key: cord-018111-5qx8tolv authors: lanski, steven l.; naga, osama title: emergency care date: 2015-03-28 journal: pediatric board study guide doi: 10.1007/978-3-319-10115-6_5 sha: doc_id: 18111 cord_uid: 5qx8tolv children less than 6 years have the greatest risk for accidental ingestion and poisoning. • children less than 6 years have the greatest risk. • jimson weed and deadly night shade produce anticholinergic toxins, e.g., atropine, scopolamine, and hyoscyamine • common garden vegetables in the solanum genus, including tomatoes, potatoes, and eggplants. • amygdalin is contained in seeds and produces hydrogen cyanide which is a potent toxin • inhibition of cellular respiration and can be lethal • ingestion of mushrooms also may have fatal consequences in species that harbor amatoxins (amanita) and related compounds products contain an aspirin • baby aspirin • regular aspirin at home includes: anti-diarrheal medications, topical agents, e.g., keratolytics and sport creams • refer to emergency departments for ingestions > 150 mg/kg • ingestion of > 200 mg/kg is generally considered toxic, > 300 mg/kg is more significant toxicity, > 500 mg/kg is potentially fatal • acute salicylism; nausea, vomiting, diaphoresis, and tinnitus • tachypnea, hyperpnea, tachycardia, and altered mental status can be seen in moderate toxicity • hyperthermia and coma are seen in severe acetylsalicylic acid toxicity • classic blood gas of salicylic acid toxicity is respiratory alkalosis, metabolic acidosis, and high anion gap • check serum level every 2 h until it is consistently down trending • initial treatment is gastric decontamination with activated charcoal, volume resuscitation, and prompt initiation of sodium bicarbonate therapy in the symptomatic patients • goal of therapy includes a urine ph of 7.5-8.0, a serum ph of 7.5-7.55, and decreasing salicylate levels • an r wave in lead avr of > 3 mm is independent predictor of toxicity • electrocardiography (ecg) parameter is superior to measured serum of tcas • stabilization of patient is the most important initial step specially protecting the airway, and ventilation support as needed, activated charcoal in appropriate patients • obtain ecg as soon as possible • ecg indication for sodium bicarbonate therapy include: qrs duration > 100 ms, ventricular dysrhythmias and hypotension • strong acid and alkalis < 2 or > 12 ph can produce severe injury even in small-volume ingestion • patient can have significant esophageal injury without visible oral burns. • wash all exposed skin with soap and water and immediately remove all exposed clothing • laceration is a traumatic disruption to the dermis layer of the skin • the most common anatomic locations for lacerations are the face (~ 60 %) and upper extremities (~ 25 %) • an evaluation for life-threatening injuries is the first priority • ongoing bleeding that may cause hypovolemic shock • applying direct pressure usually is successful • sphygmomanometer may be used for up to 2 h on an extremity • ring tourniquet on a digit for up to 30 min to help control ongoing blood loss • lacerations of the neck should be evaluated for deeper structural injuries • if developmentally appropriate, two-point discrimination at the finger pads provides the best assessment of digital nerve function • it is critical to identify foreign material within the laceration anesthetics and anxiolysis • the use of the topical anesthetic let (4 % lidocaine, 1:2000 epinephrine, and 0.5 %tetracaine) has been shown to be effective and to reduce length of stay • let usually is effective 20-30 min after application to a laceration site on the face but often needs twice that amount of time to be effective elsewhere • blanching of the site after application most often indicates achievement of effective anesthesia • a local anesthetic also may be used to prepare for placement of sutures • dermabond: it is critical that the laceration be dry and well approximated to avoid application below the epidermal surface, which may cause the wound to gape open or lead to a "dermabond oma" • evenly spaced suture placement: the general rule is sutures should be spaced the same distance as they are placed from the wound edge. for irregular wound shapes, approximate the midpoint of the wound first and then work laterally • lip laceration require special care if the injury crosses the vermilion border • it is essential to approximate the vermilion border with a suture. failure to do so may result in a poor cosmetic outcome • an infraorbital or mental nerve block along the lower gum line may be considered to reduce tissue distortion for lip lacerations, including those through the vermilion border • it may be painful and produce anxiety for the child and parent • a digital nerve block should be applied to provide adequate analgesia for this injury • if the nail has been removed during the injury, the nail bed should be repaired with absorbable sutures by using a reverse cutting needle which they designed to protect • there is no benefit to administer antivenom to unrelated species due to risk of anaphylaxis and expenses as well • surgical assessment focuses on the injury site and concern for the development of compartment syndrome • fasciotomy is indicated only for those patients with objective evidence of elevated compartment pressure • bitten extremities should be marked proximal and distal to the bite and the circumference at this location should be monitored every 15 min to monitor for progressive edema and compartment syndrome • black spider with bright-red or orange abdomen • neurotoxin acts at the presynaptic membrane of the neuromuscular junction, and decreased reuptake of acetylcholine and severe muscle cramping • pricking sensation that fades almost immediately • uncomfortable sensation in the bitten extremity and regional lymph node tenderness • a "target" or" halo" lesion may appear at the bite site • proximal muscle cramping, including pain in the back, chest, or abdomen, depending on the site of the bite • almost painless bite, and only rarely is a spider recovered • erythema, itching, and swelling begin 1 to several hours after the bite • central ischemic pallor to a blue/gray irregular macule to the development of a vesicle • the central area may necrose, forming an eschar • induration of the surrounding tissue peaks at 48-96 h • lymphadenopathy may be present • the entire lesion resolves slowly, often over weeks to months • tetanus status should be assessed and updated • signs of cellulitis treated with an antibiotic that is active against skin flora • treatment is directed at the symptoms background • the only scorpion species of medical importance in the usa is the arizona bark scorpion ( centruroides sculpturatus). • toxins in its venom interfere with activation of sodium channels and enhance firing of axons. • local pain is the most frequent symptom • usually no local reaction • in small children -uncontrolled jerking movements of the extremities -peripheral muscle fasciculation, tongue fasciculation, facial twitching, and rapid disconjugate eye movements -may misdiagnosed as experiencing seizures • severe reaction -agitation -extreme tachycardia -salivation -respiratory distress • maintenance of a patent airway and mechanical ventilation in severe cases • victims may be managed solely with supportive care: -analgesia and sedation -airway support and ventilation -supplemental oxygen administration • antivenin therapy also may obviate or reduce the need for airway and ventilatory support • status epilepticus (se) is defined as a seizure that lasts more than 30 min • treatment of se should be based on an institutional protocol, such as the following: • initial management -attend to the abcs before starting any pharmacologic intervention -place patients in the lateral decubitus position to avoid aspiration of emesis and to prevent epiglottis closure over the glottis -make further adjustments of the head and neck if necessary to improve airway patency -immobilize the cervical spine if trauma is suspected -administer 100 % oxygen by facemask -assist ventilation and use artificial airways (e.g., endotracheal intubation) as needed -suction secretions and decompress the stomach with a nasogastric tube -carefully monitor vital signs, including blood pressure -carefully monitor the patient's temperature, as hyperthermia may worsen brain damage -in the first 5 min of seizure activity, before starting any medications, try to establish iv access and to obtain samples for laboratory tests and for seizure medications -infuse isotonic iv fluids plus glucose at a rate of 20 ml/ kg/h (e.g., 200 ml d5ns over 1 h for a 10-kg child) -in children younger than 6 fig. 3 , p. s888) • bradycardia-most common pre-arrest rhythm in children with hypotension, hypoxemia and acidosis (fig. 3 ) -sinus bradycardia • maybe non-pathologic in case of well conditioned individuals like athletes • causes include: hypothermia, hypoglycemia, hypoxia, hypothyroidism, electrolyte imbalance, toxic ingestion, head injury with raised icp • treatment-identify cause and treating that condition • hr < 60 bpm in a child who is a well-ventilated patient, but showing poor perfusion, chest compression should be initiated • if hr remains below 60 despite adequate ventilation and oxygenation, then epinephrine or atropine (0.02 mg/kg-0.1 mg min and 0.5 mg max) should be given • symptomatic bradycardia unchanged by above may require pacing • av mode blocks -first degree-prolonged pr interval • generally asymptomatic -second degree-2 types • type 1-wenckebach ▪ progressive pr prolongation until no qrs propagated • type 2-regular inhibition of impulse ▪ usually every other p results in qrs -third degree-complete dissociation between p and qrs -reversible causes of cardiac arrest (fig. 4) • fig. 4 pediatric advance life support bradycardia algorithm. rosc return of spontaneous circulation, iv intravenous, io intraosseous, cpr cardiopulmonary resuscitation. (kleinman me et al. american heart association guideline for cardiopulmonary resuscitation and emergency cardiovascular care, part 14. circulation 2010, 122, suppl 3, pp. s876-s908, fig. 1 , p. s885) toxic plant ingestions. wilderness medicine nelson text book of pediatrics rattlesnake bites in southern california and rationale for recommended treatment clinical presentation and treatment of black widow spider envenomation: a review of 163 cases clinical presentation and outcome of brown recluse spiderbite envenomation by the scorpion centruroides sculpturatus epilepsy foundation of america's working group on status epilepticus. treatment of convulsive status epilepticus. recommendations of the epilepsy foundation of america's working group on status epilepticus total burn care golden hour: handbook of pediatric advanced life support pediatric advanced life support key: cord-032073-8eguv697 authors: el fakiri, k.; nassih, houda; ait sab, i.; draiss, g.; bouskraoui, m. title: epidemiology and clinical features of coronavirus disease 2019 in moroccan children date: 2020-07-12 journal: indian pediatr doi: 10.1007/s13312-020-1958-8 sha: doc_id: 32073 cord_uid: 8eguv697 objectives: this study aims to analyze the epidemiological and clinical features of coronavirus disease 19 (covid-19) in a moroccan pediatric population. methods: a retrospective study of a cohort of 74 children with rt-pcr confirmed covid-19. we collected information on clinical and laboratory features of all children (age <18 years) admitted between 2 march, 2020 and 1 april, 2020. results: the mean (sd) age of the 74 children (40 girls) was 7 (1.5) years. the mean (sd) time from illness onset to diagnosis was 2 (1) days. 54 children were asymptomatic, while eight had fever, and five cases had cough. recovery was after a mean (sd) of 12 (1) days. conclusions: covid-19 was mostly mild in the pediatric population in morocco. mergence of coronavirus disease 2019 (covid-19) has attracted global attention, and the who has declared the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection as a pandemic. as of may 25, 2020, a total of 7756 cases, which 9% of them are children, occurred in morocco [1] . worldwide, it has been reported that the disease is mostly asymptomatic, or mild-moderate in nature in children [2] [3] [4] . to date, not much information is available about covid-19 in moroccan pediatric population. our study aims to detail clinical features and outcome in moroccan children infected with sars-cov-2 virus. we retrospectively reviewed records of 74 children confirmed with sars-cov-2, who were managed in mohammad vi university hospital of marrakesh from march 2, 2020, to april 1, 2020. the ethics committee of our hospital approved this study. covid-19 pediatric cases were defined as follows: possible case: when a history of contact with a confirmed case of sars-cov-2, and/or an acute respiratory infection of unknown etiology are present; and confirmation of infection was obtained from all patients at admission by detection of sars-cov-2 nucleic acid on nasopharyngeal swab specimens using rt-pcr. all confirmed covid-19 cases <18 years were included except from newborns. parents or guardians of all participants provided informed consent enrolled in this study. we collected data regarding epidemiological, demographical, clinical symptoms, laboratory measurements, imaging findings, management, and outcome. laboratory workup carried out in all patients at diagnosis included complete blood count, crp, procalcitonin, urea, creatinine, ast, alt, ptt, aptt, d-dimer, ferritin, ldh, cpk, fibrinogen, and serum electrolytes. computed tomography (ct) scan was done in those with severe manifestations. patients were classified as follows: asymptomatic infection (children without manifestations of clinical symptoms of covid-19 testing positive to sars-cov-2); acute upper respiratory tract infection (children with fever, cough, pharyngeal pain, nasal congestion, fatigue, headache, myalgia or discomfort, and without signs of pneumonia by chest imaging or sepsis); mild pneumonia (when children have a fever, respiratory symptoms such as cough, and chest imaging indicating pneumonia, but not reaching the criteria of severe pneumonia); severe pneumonia (when any of the following criteria are present: (i) increased respiratory rate: ≥60 breaths/min (<2 years), ≥40 breaths/min (between 2 and 5 years), ≥30 breaths/min (≥5 years); (ii) oxygen saturation <94%; (iii) hypoxia; (iv) disturbance of consciousness; and, (v) food refusal or feeding difficulty, with signs of dehydration); treatment was prescribed according to the moroccan ministry of health recommendations [5] . rt-pcr tests were done on the ninth, 14th, 21st, and 28th days from diagnosis. recovery was declared when there was clinical improvement, child was afebrile for more than three days, and at least one negative rt-pcr result was obtained. all statistical data were processed using the excel professional 2016 software. out of 74 children with confirmed covid-19 included in our study, 34 (46%) were boys. the median age was 7 years (range, 2 month -17 year). medical history was marked by two cases of mild intermittent asthma, one case of type 1 diabetes, one case of epilepsy, and one case of down syndrome with intraventricular shunt. all the cases exhibited familial aggregation and had a history of close contact with their adult relatives who were diagnosed with covid-19, except for one child who contacted the disease from a housemaid, and a second one who contacted from a neighbor. all our patients had satisfactory nutritional state, as well as normal growth parameters. fifty-four (73%) children were asymptomatic. the remaining twenty patients had mild symptoms (fig. 1) , mainly symptoms of flu, with a mean (sd) time from illness onset to diagnoses of 2 (0.5) days. most frequent signs were fever (10.8%), cough (6.7%), rhinorrhea (6.7%), and diarrhea (5.4%). hematological abnor-malities were marked by lymphocytosis in 8% of cases, while the rest were characterized by high creatinine phosphokinase (cpk), lactate dehydrogenase (ldh), and mild hepatic transaminitis (<1.5 times normal) ( table i) . management consisted of supportive care: hydration, antipyretics and nutritional support. the 15year-old girl was started on chloroquine 5 mg/kg/12h for five days (after documenting a normal electrocardiogram) with azithromycin (10 mg/kg the first day; then 5 mg/kg/ day for five days) along with vitamin c (1g twice a day for ten days) and zinc (90 mg twice a day for ten days). by the third day, evolution was marked by severe side effects (diplopia, nausea, epigastric pain), when we switched to hydroxychloroquine (5 mg/kg/12h to complete a total of ten days). subsequently, improvement was noted and no new side effects were seen. breastfeeding was maintained in a two-months-old infant while respecting airborne and contact protection measures. no case was hospitalized in the intensive care unit or needed respiratory assistance. no patient died. resolution of symptoms occurred by the seventh day in most (80%) cases. the average (sd) hospital stay was of 13 (3) days (range, 10-21 days). negative rt-pcr results were obtained after a mean (sd) time of 14 (2) days (50% by ninth day, 75% by the 14th day, 94% by the 21st day), while four cases remained positive until the 28th day. in morocco, till date, approximately 600 children have been affected with covid-19. marrakesh is at the heart of the epidemic, with 19% of nationwide cases. all the pediatric cases are admitted to our center. retrospective study of these cases found that our series agrees with those previously published, suggesting that most pediatric covid-19 cases are females [6] . children of all ages were susceptible to covid-19 similar to other studies [7, 8] . the most affected proportion of children were aged between 10 and 14 years, with a mean age similar to a korean report [9] , while a spanish series found that most affected children were younger [6] . a chinese series reported that over 90% of children were either asymptomatic or with mild-moderate manifestations [4] . the majority of our cases were asymptomatic because these infections were recognized mostly through contact tracing. median time from illness onset to diagnosis was similar to the chinese series [4] . all the symptomatic cases were upper respiratory infections, while other series found more severe cases [9] [10] [11] . lymphopenia has been reported in covid-19 previously also [9] , and was seen in 3% of our children. the moroccan ministry of health approved in early april, 2020, a nationwide protocol using chloroquine or hydroxychloroquine associated with azithromycin in all covid-19 severe pediatric cases [5] . we used this protocol in only one case with an immunocompromized condition (type 1 diabetes). finally, we were well aware of the impact of the psychological state on the well-being of our children, so as recommended by massimo, et al., [12] , we organized various activities such as anniversary parties, as well as providing hospitalized children with toys and books to alleviate loneliness. in conclusion, covid-19 in moroccan children seems to be mild, with non-specific clinical and biological findings, and with a rare need of specific treatment. other studies are necessary to verify these findings from this preliminary report. the official coronavirus portal in morocco • our study describes the north african experience with covid-19 in children characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention coronavirus disease 2019 (covid-19) in children -what we know so far and what we do not epidemiology of covid-19 among children in china moroccan ministry of health recommendations for the therapeutic management of confirmed covid-19 cases screening and severity of coronavirus disease 2019 (covid-19) in children in madrid clinical and ct features in pediatric patients with covid 19 infection: different points from adults epidemiology and clinical features of coronavirus disease 2019 in children detection of covid-19 in children in early clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern china analysis of ct features of 15 children with 2019 novel coronavirus infection fostering resilience in children: the essential role of healthcare professionals and families key: cord-029518-a3507av0 authors: graf, william d.; epstein, leon g.; pearl, phillip l. title: reply date: 2020-07-22 journal: pediatr neurol doi: 10.1016/j.pediatrneurol.2020.07.001 sha: doc_id: 29518 cord_uid: a3507av0 nan we thank drs. trabacca and russo for their reflection and comments about childhood disability and the ethics of care during the exceptional circumstances of a viral pandemic. (1) we recognize the many social, educational, environmental, and health care disruptions that covid-19 has imposed on the routines of all children. such disruptions are often disproportionately stressful to the families of children with neurodevelopmental and neuromuscular disabilities, whose "nonessential" community-based support services are restricted because of the imperatives of physical distancing. drs. trabacca and russo reflect on the concepts of disability and the need for continuous disability-related care and rehabilitation as well as the relative urgency of providing such care depending on need, acuity, and other factors unique to each child and family.(2) such concepts are consistent with normative ethical theories. we agree about the importance of striking a balance between the provision of care and the need to protect vulnerable individuals to minimize morbidity and mortality resulting from covid-19. we are witnessing many changes in social norms and care standards during the first six months of the covid-19 pandemic-some obligatory and some recommended but left to the discretion of individuals. the general precautions that apply to all families (i.e. physical distancing, restricted socialization, "shelter in place", and "distance learning" school routines for children) seem to be intuitively practiced at heightened levels to better protect children with chronic conditions and disabilities-especially those who are immunosuppressed or have compromised respiratory function. these instinctive precautions appear to be similar to those taken for the elderly, who are clearly at higher risk from sars-cov-2 infections. limited data from the earliest phase of the pandemic suggested that children are less affected by sars-cov-2 infections-even those children with underlying chronic medical and neurological conditions. newer data show that children and adolescents with intellectual and developmental disabilities (idd) have higher casefatality rates (1.6%) compared to those without idd (<0.01%). (3) these trends are similar to the experience of 2009 influenza a (h1n1) viral pandemic, when children with disabilities had higher morbidity and mortality risks. in one cohort of pediatric deaths associated with h1n1, two-thirds (67%) had one or more high-risk medical conditions, and within this group 92% had high-risk medical conditions with neurodevelopmental disabilities.(4) even during typical influenza seasons, a substantial number of influenza-associated deaths occur in children, of whom one-third (33%) have chronic neurologic or neuromuscular conditions such cerebral palsy, epilepsy, and developmental encephalopathies. (5) we are also witnessing the racial, ethnic, and socioeconomic disparities in covid-19 morbidity and mortality, which should lead to a new calling to advance social justice and improve public health services. for example, people with idd with chronic health conditions are more likely to experience poverty with advancing age necessitating group living and disproportionate risks from infectious diseases. because of the heightened risks for many people with disabilities, emerging from this current pandemic will require a cautious balance between the safe resumption of educational routines, supportive therapies, and rehabilitation (i.e. easing of physical distancing) and the ongoing need of enhanced protections (e.g. mask-wearing) until covid-19-related herd immunity can be achieved. practical bioethics during the exceptional circumstances of a pandemic the ethic of care, disability and rehabilitation during the covid-19 pandemic intellectual and developmental disability and covid-19 case-fatality trends: trinetx analysis. disabil health j. 2020:100942. 4. surveillance for pediatric deaths associated with united states influenzaassociated deaths among children in the united states key: cord-010018-gl8uuqej authors: del borrello, giovanni; stocchero, matteo; giordano, giuseppe; pirillo, paola; zanconato, stefania; da dalt, liviana; carraro, silvia; esposito, susanna; baraldi, eugenio title: new insights into pediatric community‐acquired pneumonia gained from untargeted metabolomics: a preliminary study date: 2019-12-10 journal: pediatr pulmonol doi: 10.1002/ppul.24602 sha: doc_id: 10018 cord_uid: gl8uuqej background: available diagnostics often fail to distinguish viral from bacterial causes of pediatric community‐acquired pneumonia (pcap). metabolomics, which aims at characterizing diseases based on their metabolic signatures, has been applied to expand pathophysiological understanding of many diseases. in this exploratory study, we used the untargeted metabolomic analysis to shed new light on the etiology of pcap. methods: liquid chromatography coupled with mass spectrometry was used to quantify the metabolite content of urine samples collected from children hospitalized for cap of pneumococcal or viral etiology, ascertained using a conservative algorithm combining microbiological and biochemical data. results: fifty‐nine children with cap were enrolled over 16 months. pneumococcal and viral cases were distinguished by means of a multivariate model based on 93 metabolites, 20 of which were identified and considered as putative biomarkers. among these, six metabolites belonged to the adrenal steroid synthesis and degradation pathway. conclusions: this preliminary study suggests that viral and pneumococcal pneumonia differently affect the systemic metabolome, with a stronger disruption of the adrenal steroid pathway in pneumococcal pneumonia. this finding may lead to the discovery of novel diagnostic biomarkers and bring us closer to personalized therapy for pcap. community-acquired pneumonia (cap) is the single most common cause of death among children worldwide, and a leading cause of hospitalization. 1, 2 although the body of knowledge of the epidemiology, etiology, microbiology, and pathophysiology of cap has expanded over the last few decades, basic patient management questions remain largely unanswered. in fact, when confronted with a feverish child with respiratory symptoms, the single most important management question is whether or not to start antibiotics, which translates into how confident is the treating physician that the child in question does not have a bacterial lower respiratory tract infection. 3, 4 although epidemiological research has repeatedly pointed out that the large majority of lower respiratory infection in pediatric patients are caused by viruses, 2 physicians often lack the tools to reliably discriminate between bacterial and viral etiology [5] [6] [7] and a large percentage of children presenting with respiratory symptoms and fever are ultimately administered antibiotics. 8 the absence of certainty regarding cap etiology thus prompts an overtreatment with the consequence of increasing the emergence of bacterial resistance. metabolomics is the newest branch of the systems biology approach to biomedical research. [9] [10] [11] it aims to provide an unabridged description, both qualitative and quantitative, of all the metabolites (ie, molecules with a molecular weight of less than 1200 da) found in human biofluids and tissues at a given time. in other words, it aims to define particular metabolic signatures, or fingerprints, characterizing a disease state. powerful analytical tools are used to amass large amounts of data, which are analyzed and applied to previously-unsolvable, complex questions of biology. in particular, metabolomics can provide a more comprehensive overview of a diseaseʼs pathophysiology, identify new biomarkers for use in diagnostics, and point to potential therapeutic targets to consider in the search for new drugs. in the present exploratory investigation, a hypothesis-free approach based on untargeted metabolomics was applied to pediatric cap (pcap) in an effort to improve the diagnosis and clinical management of this common childhood infection. more specifically, our study aimed to elucidate whether a specific metabolic signature differentiates pneumococcal from viral pcap. 40 the study was approved by each centerʼs institutional ethics committee. written informed consent, signed by both parents, was required for a child to be included in the study; for children aged 8 years or older, the childʼs written informed assent was also required. cases eligible for this study were hospitalized children less than 14 years of age with a diagnosis of moderate to severe pneumonia. this diagnosis of cap was based on clinical presentation (presence of fever, symptoms suggestive of an acute respiratory illness defined as new cough or sputum production, chest pain, dyspnea, tachypnea), abnormal lung examination and chest x-ray results. 12, 13 chest x-rays were evaluated by a blinded radiologist to the study participants. the decision to admit a child to the hospital for cap was made by the attending physician in the emergency department. to increase the specificity of our findings and reduce the role of confounding variables, three exclusion criteria were strictly applied, concerning: infants (ie, children under 1 year of age), to avoid any diagnostic overlap between pneumonia and bronchiolitis; children with a previous diagnosis of chronic disease (hiv, asthma, immunodeficiency, chd), to reduce the pathophysiological heterogeneity between cap cases; and children given any oral or injected antibiotic therapy in the 48 hours preceding enrollment, to avoid cases of partially treated pneumonia, as the related pathophysiological profile differs from that of a lung infection devoid of any treatment. the pharmacological treatment of the recruited subjects was monitored during hospitalization to evaluate potential confounding effects on our findings. a three-step algorithm combining microbiological information obtained from the pcr assays and pct levels was used to ascertain pneumonia etiology for subsequent metabolomic analysis. 14 three variables were considered sequentially: presence or absence of respiratory viruses revealed by the multiplex pcr assay; presence or absence of s. pneumoniae on the pcr assay; and pct cutoffs of 0.25 and 2.00 ng/ml. using this algorithm, a viral etiology was assumed in the presence of respiratory viruses, the absence of s. pneumoniae, and pct < 0.25 ng/ml; a pneumococcal etiology was assumed in the absence of respiratory viruses, the presence of s. pneumoniae, and pct ≥ 2.00 ng/ml. cases not falling into either category were labeled as "undetermined" and not included in the subsequent analysis. this strategy was applied to obtain "pure" groups for metabolomic investigation, by limiting the number of false-positive cases (ie, s. cases with inconsistent results between pct measurement and pcr analysis) and were excluded from any further subclass analysis. table 1 contains the clinical and demographic characteristics of the 27 patients searching the available online metabolite databases generated a putative identification for 20 of these variables ( table 2) . pneumoniae pleural infection, 23 probably as a consequence of the aggressive metabolic activity and amino acid biosynthesis induced by s. pneumoniae replication. cyclic guanosine monophosphate (cgmp), the next significant molecule emerging from our analysis, mediates many of the proinflammatory and anti-inflammatory functions of nitric oxide (no). 36 tolllike receptor ligands induce the expression of cgmp by increasing the activity of no synthetase; in fact, endotoxin infusions in healthy volunteers have been shown to raise both exhaled no and cgmp plasma concentrations. 37 bacteria may also increase the synthesis of cgmp by producing no directly. 38 our study corroborates these previous reports and provides evidence for the plausibility of using this metabolite as a diagnostic marker of bacterial infection. another two molecules of interest to this discussion are 3-methylglutaryl-carnitine (an acyl-carnitine), and 3′-n-acetyl-neuraminyl-n-acetyllactosamine (a sialyl oligosaccharide). carnitine metabolism is tied to mitochondrial homeostasis and has long been studied in the context of severe infections. septic patients show many abnormalities in lipid metabolism, including a depletion of the cellular levels of l-carnitine, a reduction in its plasma levels, and an increase in its urinary excretion. 39 three recent metabolomic studies also found an increase in the urinary concentration of acyl-carnitines in patients with bacterial pneumonia. 20, 25, 40 indeed, the pneumococcal cytotoxin pneumolysin causes mitochondrial damage, which may account for the observed disarray in lipid metabolism. 41, 42 sialyl oligosaccharides are broken down and digested by lysosomes, and a relative increase in sialyl oligosaccharides in the course of bacterial infections may represent a transient lysosomal dysfunction. indeed, the role of lysosomes in human health and disease is just starting to be unveiled, but evidence is already accumulating of lysosomes serving as regulators of macrophage function, 43 and as key effectors of s. pneumoniae intracellular killing. 44 a recent meta-analysis of transcriptomic studies also showed that messenger rna pathway associated with lysosomal function were among the most profoundly disrupted in the course of human sepsis. 45 in short, our study points to organelle dysfunction as a crucial discriminator between bacterial and viral infection. viral pneumonia is associated with an increase in urine concentrations of glycyl-l-hydroxy-proline (gly-pro), an end product of collagen metabolism and the substrate of the enzyme prolidase, which promotes the surface expression of the interferon-i receptor and is a target of viral antagonism. 46, 47 the higher urinary levels of gly-pro found in our study may, therefore, reflect an impaired prolidase activity, which could be expected in the course of viral infection. although state-of-the-art, high-throughput analytical methods and chemometric data processing methods were used in our study, it has some weaknesses. the most important concern the fact that we did not collect samples in therapy-naive patients, and this constitutes a veritable source of bias. this issue could have been avoided by collecting urine samples from all therapy-naive children presenting to the emergency department with respiratory symptoms and a fever, and then analyzing only those obtained from children actually enrolled in the study. this will be worth bearing in mind for future metabolomic studies conducted in acute care settings. another weakness of our study concerns the small number of patients in our two groups, which may limit the validity of our findings. on the other hand, our adoption of stringent enrollment criteria and a conservative diagnostic algorithm ensured that the two groups were etiologically pure, thus enhancing the specificity of our findings. a further potential limitation of this exploratory study lies in the lack of any external validation set against which to test our models, which could only be validated internally by means of a cross-validation and stability selection to ensure the reliability of the findings emerging from the data collected. though ours is only a preliminary study, the present findings seem to be a promising starting point for the conduction of larger, validated studies. in global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis community-acquired pneumonia requiring hospitalization among u.s. children a systematic review on the diagnosis of pediatric bacterial pneumonia: when gold is bronze antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? does this child have pneumonia?: the rational clinical examination systematic review specimen collection for the diagnosis of pediatric pneumonia laboratory methods for 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expression supporting information additional supporting information may be found online in the supporting information section. how to cite this article new insights into pediatric communityacquired pneumonia gained from untargeted metabolomics: a preliminary study the authors declare that there are no conflict of interests. http://orcid.org/0000-0002-1829-3652 key: cord-023728-fgcldn4e authors: bower, john; mcbride, john t. title: croup in children (acute laryngotracheobronchitis) date: 2014-10-31 journal: mandell, douglas, and bennett's principles and practice of infectious diseases doi: 10.1016/b978-1-4557-4801-3.00061-8 sha: doc_id: 23728 cord_uid: fgcldn4e nan the term croup now generally refers to an acute respiratory tract illness characterized by a distinctive barking cough, hoarseness, and inspiratory stridor in a young child, usually between 6 months and 3 years old. this syndrome results from inflammation of varying levels of the upper respiratory tract, which sometimes spreads to the lower respiratory tract, producing concomitant lower respiratory tract findings. croup is primarily laryngotracheitis and encompasses a spectrum of infections from laryngitis to laryngotracheobronchitis and sometimes laryngotracheobronchopneumonitis. most common among the clinical argot of croup are recurrent, allergic, and spasmodic croup. most children develop croup only once or twice despite multiple infections with the viruses that are prime etiologic agents. some children have recurrent episodes of croup, however, which is often referred to as "spasmodic croup. " spasmodic croup and "allergic croup" also have been applied to cases that tend to be sudden in onset, often at night, with minimal coryza and fever, and that occur among children with a family history of croup or atopy. 4 spasmodic croup generally cannot be differentiated from a single episode of the usual type of croup, however, in its clinical manifestations or in its etiology, which is usually viral. croup is a common illness among outpatients, but few cases require hospitalization. [4] [5] [6] [7] croup occurs in 2% to 6% of young children each year. about 10% to 16% of all children experience at least one attack of croup, and 5% have recurrent croup, consisting of three or more episodes. the peak occurrence is in the second year of life, with most cases occurring between 3 months and 3 years of age. in a seattle prepaid group practice, the annual incidence of croup was 7 per 1000 for all children younger than 6 years, and the peak incidence in the second year of life was 14.9 per 1000 children. 7 among children younger than 2 years of age presenting to emergency departments in alberta, canada, for the period 1999 to 2005, the rates of croup ranged from 30.9 to 49.6 per 1000 emergency department visits. 8 hospital admissions have significantly declined in recent years in correlation with the use of effective outpatient therapy for croup. from 1979 to 1997, croup cases associated with parainfluenza viruses, estimated from the national hospital discharge survey, showed that the number of admissions among children younger than 5 years decreased by approximately one third. 5 outbreaks of measles in the united states and elsewhere serve as a reminder that rubeola in the prevaccine era often resulted in severe and complicated croup. during the 1989 to 1991 upsurge of measles cases in the united states, laryngotracheobronchitis complicated approximately 20% of the cases of measles among hospitalized patients in los angeles and houston. 18, 19 children with croup as a complication of measles tended to be younger, they had a more severe course, and 17% to 22% required intubation. in some children, the outcome was fatal. the epidemiologic patterns of croup reflect mainly the seasonal predilection of the major agents (see fig. 61-1) . parainfluenza virus type 1 predominantly occurs every other year in the fall, resulting in the major outbreaks of croup recognized biennially in odd-numbered years since 1993. 5, 11 other parainfluenza viruses have less distinctive seasonal patterns. parainfluenza type 2 virus also contributes to the cases occurring in the fall and winter, but irregularly and at lower levels. 20 parainfluenza type 3 virus appears yearly, and although it may be present throughout much of the year, parainfluenza type 3 virus predominantly occurs in the spring to fall and is the major cause of the swell of croup cases observed each spring. influenza a and b viruses and rsv also contribute to the cases in the winter and spring. rhinoviruses, enteroviruses, bocavirus, and coronaviruses are present through most of the year. in some areas, enteroviruses have an increased prevalence during the summer and fall and bocavirus is prevalent during the fall to spring (see fig. 61 -1). the shrill sonorous inspiration so characteristic of this complaint, marks very unequivocally its seat.… from some cause there is an unusual approximation of the sides of the glottis … the influence being very analogous to that produced by too strong compression of the reed against the mouthpiece of the clarinet by the lips of one who has made no great proficiency in that instrument, when a harsh, squeaking sound is produced abundantly discordant and grating to the ear. hugh ley, 1836 21 the virus initially infects the upper respiratory tract and usually produces congestion of the nasal passages and nasopharynx. subsequently, especially during primary infection, the larynx, the trachea, and sometimes the bronchi become involved. the classic signs of croup-stridor, hoarseness, and cough-arise mostly from the inflammation of the larynx and trachea. the resulting obstruction is greatest at the subglottic level because this is the least distensible part of the airway because it is encircled by the cricoid cartilage, with the narrow anterior ring and the larger posterior quadrangular lamina forming a "signet ring. " the impeded flow of air through this narrowed area produces the classic high-pitched vibratory sounds, or stridor. this is most apparent on inspiration because high linear velocity in the already narrowed airway creates a negative intraluminal pressure, narrowing the extrathoracic airway further, much as sucking on a partially occluded paper straw causes it to collapse inwardly. airway collapse is enhanced in young children because of the increased compliance of their airway walls. 22 even minimal inflammation of the membranes lining the narrow passages of the larynx and glottis in a young child results in an appreciable degree of obstruction because resistance to airflow is inversely related to the fourth power of the radius of the airway. the mucous membrane is also looser and more vascular, and the cricoid cartilage is less rigid. nasal obstruction and crying can aggravate the dynamic narrowing of the child's airway further. with the subglottic obstruction, the child's tidal volume initially declines. this is compensated by an increase in the respiratory rate to maintain adequate alveolar ventilation ( fig. 61-2 ). if the degree of obstruction worsens, the work of breathing may increase such that the child tires and can no longer maintain an adequate respiratory effort. the tidal volume may decrease further, and, as the respiratory rate declines, hypercarbia and secondary hypoxemia ensue. in addition to airway narrowing related to mucosal swelling and dynamic collapse, it is possible that upper airway inflammation leads rates decreased by 33% from 1.8 to 1.2. in ontario, the estimated annual rates of hospitalization from 1988 to 2002 also showed a decline among children younger than 5 years, and the rates were lower among children 1 to 4 years old than among infants. 9 the decline did not begin until after the winter of 1993 to 1994, however, when the annual rate per 1000 children younger than 5 years was 2.67. in 2001 to 2002, the rate had declined by 86% to 0.37. among children evaluated for croup in an emergency department, one or more viral agents were identified in 80% of specimens by reversetranscriptase polymerase chain reaction (rt-pcr) assay; the parainfluenza viruses were detected most frequently. 10 no matter what means of detection were used, studies over decades have consistently shown that the parainfluenza viruses, especially type 1, are the most frequent cause of croup. [4] [5] [6] [7] [10] [11] [12] only the parainfluenza viruses are associated with the major peaks of occurrence of croup cases (fig. 61-1 ). parainfluenza type 1 has been identified in approximately one fourth to one third of cases. parainfluenza type 3 generally is the second most commonly associated virus, accounting for 6% to 10% of cases. a small proportion of all influenza illnesses among children is associated with croup, but among croup cases, influenza accounts for 1% to 10% of cases depending on the year and circulating strain. similarly, although respiratory syncytial virus (rsv) infections are particularly prevalent among this age group, relatively few (about 5% of rsv infections) manifest as croup. more recent studies using rt-pcr methods have suggested an etiologic role for viruses other than the parainfluenza viruses. rhinoviruses, enteroviruses, adenoviruses, and bocavirus have been detected in 9% to 13% of specimens from children with croup. 10,12, 13 croup has also been observed in a small percentage of children younger than 5 years of age infected with metapneumovirus. 14 the human coronaviruses (hcov) have been identified in up to 7% of young children with acute respiratory tract infections, with the nl63 strain most often associated with croup. 15 in seoul, south korea, hcov nl63 was the second most commonly isolated virus from children presenting with croup. 16 the significance of these associations, however, is unclear because respiratory viruses often appear as coinfections and studies have been limited by small sample sizes. larger studies are needed to confirm these findings. 17 the diagnosis of croup can almost always be made on the basis of the characteristic epidemiologic features, the clinical manifestations, and the history, especially in children 6 months through 3 years of age. diagnostic procedures that upset the child may worsen the respiratory distress and should be avoided. 7 laboratory analysis generally should be limited to tests necessary for management of a more severely ill child, such as tests used to assess dehydration and oxygenation. white blood cell counts and differentials are rarely helpful or distinctive in diagnosing croup. identification of the specific viral agent also is usually unnecessary, and obtaining respiratory tract swabs and secretions is likely to augment the child's respiratory distress. viral identification may be warranted when specific antiviral therapy is being considered, such as for severely ill or high-risk children with influenza. in most instances, a rapid antigen assay, such as immunofluorescent and enzyme immunoassays, is used. 24 rapid multiplex pcr assays for respiratory viruses provide an increasingly available alternative with improved sensitivity and relatively short turnaround times. radiographic evaluation is usually unnecessary for the diagnosis of croup and, as noted earlier, should be undertaken with caution and careful monitoring of the child. among atypical cases, however, the radiologic picture may be helpful in the differential diagnosis. the characteristic manifestation of viral croup noted on an anteroposterior neck film is a 5-to 10-mm narrowed shadow of the trachea in the subglottic area. this is often described as the "hourglass" or "steeple" sign ( fig. 61-3) . the lateral view of the neck may show an increased width of the airspace in the hypopharyngeal area. dilation of the pharyngeal airway often is seen and is indicative of the child's increased respiratory effort. the diagnostic value of these radiographic findings is nevertheless questionable. they are not consistently observed in all cases of viral croup, and some studies have shown them to be of low specificity and sensitivity for confirming or ruling out viral croup. for children presenting with atypical features or history, a broad range of diagnoses should be considered. 25 a case should be considered to active constriction of the muscles of the upper trachea and larynx that might contribute to airway narrowing in some children with croup, particularly those with spasmodic croup. this might explain the association between recurrent croup and asthma or airway hyperreactivity. the disease generally comes on in the evening after the little patient has been exposed to the weather during the day and often after a slight catarrh of some days' standing. at first his voice is observed to be hoarse and pulling … he awakens with a most unusual cough, rough, and stridulous. and now his breathing is laborious, each inspiration being accompanied by a harsh, shrill noise. john cheyne, 1814 2 although abrupt onset of stridor at night may be the initial indication of illness, most children have a prodrome of mild upper respiratory tract signs of rhinorrhea, cough, and sometimes fever 12 to 48 hours before the onset of the distinctive "rough and stridulous" cough of croup. the deepening cough and hoarseness herald the onset of the respiratory stridor. the cough is not productive but has the striking deep brassy tone of a "seal's bark. "* the respiratory stridor may be accompanied by retractions of the chest wall, which are usually most marked in the supraclavicular and suprasternal areas. some children may progress to have inspiratory and expiratory stridor. the respiratory rate may be slightly elevated, but rates greater than 50 per minute are unusual in children with croup, in contrast to the marked tachypnea that is often evident with bronchiolitis. the onset of stridor commonly occurs at night; in milder cases it may improve in the morning, only to worsen again at night. children whose croup is characterized by abrupt nighttime onset with little prodrome of a respiratory tract infection, followed by daytime improvement, are often designated as having "spasmodic croup. " these children tend to have repeated episodes over several days or separated by months. generally, an episode of recurrent croup cannot be differentiated from the usual case of viral croup clinically or by viral etiology. 12 a viral etiology was identified by rt-pcr in 68% of the children, and the proportion with an identified viral infection was not significantly different between children with single and recurrent episodes of croup. a few children with recurrent croup have an underlying condition such as subglottic stenosis or gastroesophageal reflux. for most children, the course of croup is less than 3 to 4 days. although the cough may persist longer, the characteristic barking quality resolves within 2 days in most children. 23 *the characteristic cough and stridor have also been described by ley in 1836 21 as "the crowing of a cock, the yelping of a fox, the barking of a dog, the braying of an ass, or a ringing sound, as if the voice came from a brazen tube. " occasionally, recurrent episodes of stridor may be related to gastrointestinal reflux. 33 appropriate therapy for croup is determined by the severity of the child's illness. accurate assessment of the child's clinical status is essential. the natural fluctuations in the course of croup often confound this evaluation, however, as well as complicate assessment of the success of therapy. most children with mild croup may be cared for at home. keeping a child with croup comfortable and avoiding disturbing procedures are particularly important, because anxiety and crying may enhance the respiratory distress. the child should be given adequate liquids and antipyretics if necessary. despite a plethora of home therapies for croup, none has proved consistently effective. taking a child with croup outside to breathe cold air or into a shower to breathe warm mist are commonly recommended. vaporizers and other means of producing mist in the home have long been advised. in the past century, steaming tea kettles were an integral and often primary mode of therapy. nevertheless, the beneficial effects of mist have not been proved. 7, [34] [35] [36] [37] multiple scoring systems have been used to assess the severity of croup. the scoring system most frequently used is the westley clinical score. 38 the major findings on physical examination used for this score are the degree of stridor, chest wall retractions, air entry, level of consciousness or fatigue, and presence of cyanosis. guidelines for the management of croup generally have classified croup as mild, moderate, and severe, with patients with mild cases having corresponding westley scores of 0 to 2, those with moderately severe cases having scores of 3 to 7, those with severe cases having scores of 8 to 11, and patients at risk for imminent respiratory failure having scores of 12 to 17 (table 61-1) . 4, 7 the therapy recommended varies according to the assessed level of severity, but the mainstay of therapy beyond supportive care is dexamethasone. one dose of dexamethasone orally or, if necessary, intramuscularly, administered to outpatients and in emergency departments has been shown to be effective in reducing the need for hospitalization. 7, 39, 40, 41 repeated doses are seldom necessary. nebulized epinephrine, racemic epinephrine, or l-epinephrine may be added to the dexamethasone for children with severe croup. 38, 42 because improvement after nebulized epinephrine is transient, treatment may be repeated. a child treated with one of these aerosols should be observed for at least 2 hours (see table 61 -1) prior to discharge. administration of a mixture of helium and oxygen has long been used to improve gas exchange in various obstructive disorders of the upper and lower respiratory tract. little evidence exists, however, that administering heliox to children with croup is beneficial. [43] [44] [45] atypical if the child does not have the most characteristic features of croup, especially the seal's bark cough and hoarseness. the physician's most important clinical responsibility in evaluating a child with inspiratory upper airway obstruction is differentiating children with the common and usually benign viral croup from the few children who have life-threatening obstruction from bacterial epiglottitis or tracheitis. the history of a rapidly progressive course, high fever, a toxic appearance, and drooling are most characteristic of these bacterial processes, and the brassy cough of viral croup is characteristically absent. children with these symptoms demand careful evaluation and management. acute bacterial epiglottitis is usually due to infection with h. influenzae type b and has become rare since the widespread use of vaccination. 25, 26 the differentiating features of epiglottitis include the strikingly rapid onset and progression of the illness, high fever, and toxic appearance. the child is often sitting, leaning forward, and anxious and may have a muffled voice, marked dysphagia, and drooling. the history of an upper respiratory tract infection with rhinorrhea and laryngitis usually is not present. epiglottitis is almost always an indication for prompt antibiotic therapy and securing the airway by intubation in a controlled environment. bacterial tracheitis has an acute onset and presentation similar to that of epiglottitis. 7,26-29 its rapid and dramatic onset is characterized by high fever, stridor, and dyspnea with copious amounts of purulent sputum. the child may progress rapidly to complete airway obstruction. the course is unresponsive to therapy with nebulized epinephrine, and suspected cases should be managed as a medical emergency. bacterial cellulitis and abscesses of the deep neck spaces, including peritonsillar and retropharyngeal abscesses, may also manifest with similar findings of high fever, dysphagia, and drooling. 30, 31 the characteristic upper respiratory tract signs, hoarseness and barking cough, are usually not present. c. diphtheriae, although a major cause of stridor in the past, is now rarely seen in the united states and other developed countries but should still be considered in countries with low rates of immunization. 32 all of these diagnoses represent pediatric emergencies, and, as with epiglottitis, usually justify careful intubation. noninfectious causes of obstruction that mimic croup include aspiration of a foreign body, which is common in the same age group as that of viral croup; trauma to the upper airway, such as from toxic ingestions; and angioneurotic edema. 25 anatomic abnormalities, such as vocal cord paralysis and anomalies that impinge on the laryngotracheal area, may cause stridor, especially when a respiratory tract infection augments the obstruction to airflow. these include tracheal stenosis, laryngeal webs, and papillomas. in most cases, the history and lack of acute signs of respiratory tract infection allow differentiation. in the older child, pulmonary function testing may be helpful. croup remains a common illness among young children. with the currently available modalities for management, most children may be cared for at home, and the illness usually resolves within 3 to 4 days. 23 most have mild symptoms, and only about 5% of children discharged from the emergency department after corticosteroid therapy need to return because of worsening of symptoms. 46 if the child's symptoms are minimal at discharge, return within 24 hours is unlikely. in canada, of all children with croup, about 4% have been estimated to require hospitalization and intubation was required for only 1 of the 170 hospitalized children or 1 in 4500 of all children with croup. 7, 23 croup presentations to emergency departments in alberta, canada: a large population-based study parainfluenza virus infection of young children: estimates of the populationbased burden of hospitalization human rhinovirus species associated with hospitalizations for acute respiratory illness in young us children human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls burden of human metapneumovirus infection in young children role of human coronavirus nl63 in hospitalized children with croup proving etiologic relationships to disease: the particular problem of human coronaviruses glucocorticoids for croup nebulized epinephrine for croup in children evidence-based child health heliox for croup in children an inquiry into the nature, causes and cure of the croup cambridge history and geography of human disease project clinical practice: croup human parainfluenza virus-associated hospitalizations among children less than five years of age in the united states incidence and etiology of pneumonia, croup, and bronchiolitis in preschool children belonging to a prepaid medical care group over a fouryear period guideline for the diagnosis and management of croup croup presentations to emergency departments in alberta, canada: a large population-based study croup hospitalizations in ontario: a 14-year time-series analysis respiratory viruses in laryngeal croup of young children parainfluenza virus infection of young children: estimates of the populationbased burden of hospitalization the viral aetiology of croup and recurrent croup human rhinovirus species associated with hospitalizations for acute respiratory illness in young us children human coronavirus in young children hospitalized for acute respiratory illness and asymptomatic controls burden of human metapneumovirus infection in young children role of human coronavirus nl63 in hospitalized children with croup proving etiologic relationships to disease: the particular problem of human coronaviruses severe laryngotracheobronchitis as a complication of measles during an urban epidemic severe laryngotracheobronchitis complicating measles respiratory syncytial virus and parainfluenza virus an essay on the laryngismus stridulus or croup-like inspiration of infants stridor in childhood croup: duration of symptoms and impact on family functioning diagnostic assays for respiratory syncytial virus disease pediatric respiratory infections bacterial tracheitis: report of eight new cases and review changing epidemiology of life-threatening upper airway infections: the reemergence of bacterial tracheitis bacterial tracheitis clinical features and treatment of retropharyngeal abscess in children the contemporary approach to diagnosis and management of peritonsillar abscess resurgence of diphtheria recurrent croup presentation, diagnosis, and management a randomized controlled trial of mist in the acute treatment of moderate croup controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial humidified air inhalation for treating croup lack of efficacy of humidification in the treatment of croup: why do physicians persist in using an unproven modality? can nebulized racemic epinephrine by ippb for the treatment of croup: a double-blind study a randomized trial of a single dose of oral dexamethasone for mild croup glucocorticoids for croup nebulized epinephrine for croup in children evidence-based child health use of heliox in children use of helium-oxygen mixtures in the treatment of croup: a systematic review heliox for croup in children the management of croup key: cord-104078-o89bzjfi authors: muerbe, d.; kriegel, m.; lange, j.; schumann, l.; hartmann, a.; fleischer, m. title: aerosol emission of child voices during speaking, singing and shouting date: 2020-09-18 journal: nan doi: 10.1101/2020.09.17.20196733 sha: doc_id: 104078 cord_uid: o89bzjfi since the outbreak of the covid-19 pandemic, singing activities for children and young people have been strictly regulated with far-reaching consequences for music education in schools and ensemble and choir singing in some places. this is also due to the fact, that there has been no reliable data available on aerosol emissions from children's speaking, singing, and shouting. by utilizing a laser particle counter in cleanroom conditions we show, that children emit fewer aerosols during singing than what has been known so far for adults. in our data, the emission rates ranged from 16 p/s to 267 p/s for speaking, 141 p/s to 1240 p/s for singing, and 683 p/s to 4332 p/s for shouting. the data advocate an adaptation of existing risk management strategies and rules of conduct for groups of singing children, like gatherings in an educational context, e.g. singing lessons or choir rehearsals. aerosols are liquid or solid particles, which are transported in the air and not influenced by gravitation usually determined by a size less than 5 µm, that escape from the respiratory system during breathing, speaking and singing. besides droplets, they are widely accepted carriers for the transmission of sars-cov-2 viruses (morawska & cao, 2020) . due to the principles of voice production and the described accumulation of sars-cov-2-infections during choir rehearsals (hamner et al., 2020) , it is assumed that singing is connected with increased aerosol emission rates. recently, increased aerosol emissions during singing in comparison to speaking have been experimentally confirmed for adult singers (alsved et al., 2020 . further, an increased aerosol emission rate is found for raising vocal loudness (asadi et al., 2019) . this results in limitations and specific risk management strategies especially for choir singing during the covid-19-pandemic. however, data about aerosol emission during singing for children are still missing. but especially for children and young people the restrictions on ensemble and choir singing have far-reaching consequences in addition to severe cultural and financial losses. singing together is an obligatory part of school education and an important factor for the socio-emotional development of children and young people. this applies not only to music lessons in school, but also to the extracurricular sector with music schools and children and youth choirs. by now, the hygiene and performance concepts rely on aerosol emission rates during singing as collected from adults. for the first time, this pilot study presents data of aerosol formation when children sing. within the measuring range between 0.3 µm and 25 µm, about 99 % of all measured particles were smaller than 5 µm and more than 70 % smaller than 1 µm. with regard to the common understanding to denominate particles with a size smaller than 5 µm as aerosols the following results are cumulatively given for particles of size 0.3 µm -5 µm. the emission rates pm for speaking were clearly lower than for singing ( figure 1 ). whereas the median values for speaking were between 16 p/s (particles/second) and 267 p/s, this measure was between 141 p/s and 1240 p/s for singing. for shouting, pm was still higher with values from 683 p/s up to 4332 p/s. all subjects showed a clear individual increase in pm for all three 1 preprint . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint conditions. linear mixed modeling showed, that these increases in condition were significant (likelihood-ratio test; p<.00001). on average, the ratio of pm between singing and speaking was 5.87 ± 1.28 (standard error). for shouting and speaking, this ratio was 36.22 ± 1.28 (standard error). both findings were significant (p<.001). further, pm was positively correlated with the maximum sound pressure level lafmax. an increase in one unit in lafmax resulted in an increase in 0.05 units of log10 (pm). this finding was significant (p<.001). for the sustained phonation task, the median values for soft phonation (piano) were between 58 p/s and 683 p/s, this measure was between 58 p/s and 1907 p/s for loud phonation (forte). in contrast to the first task, not all subjects showed a clear increase in pm from piano to forte. this finding was mirrored by the results of the linear mixed modeling approach. the increase of pm from piano to forte was 1.91 ± 1.47 whereas condition was not significant (p=.133). nevertheless, a positive correlation to lafmax was found ( figure 2 ) which indicates that the emission rate increases with raising vocal loudness. similar to the first task, an increase in one unit in lafmax results in an increase in 0.05 units of log10 (pm) which was also significant (p<.001). the present study confirms higher emission rates of aerosols for singing in comparison to speaking also for children. as for measurements of adult professional singers, a strong intersubject variability of aerosol emission was found for singing children, too. finally, a positive correlation of particle emission with vocal loudness was confirmed, in particular reflected by the shouting condition. comparing these values with previously published data for adult professional singers (mürbe et al., 2020, http://doi.org/10.5281/zenodo.4011701) similar values for speaking, but lower values for singing were observed ( figure 3 ). for singing, the ratio in medians between adults and children was about 3.1. shouting values for children (not available for adults) were higher than singing values for adults. regarding sustained phonation with loud voice, the ratio in medians between adults and children for the forte condition was about 6.8. it must be noted that there were slight deviations between adults and children in the execution of this task, such as children were allowed to shortly breathe within the recording sequence. determined values for children are also lower than recently published data found in professional and non-professional adult singers (alsved, 2020) . there might be different reasons for the lower emission rates for child voices during singing. before mutation, there are considerable differences in the vibration characteristics of the vocal folds in comparison to adults. typical features of a child's vocal register in singing include differences in contact time and contact area of the vocal folds during each vibration cycle. there are also differences in the subglottic pressure between adults in general and children (mcallister & sundberg, 1998 , howard, 2010 . further, there are smaller anatomical proportions of the child's airways and vocal folds are shorter before mutation. on the other hand, the fundamental frequency of the voice and accordingly the contact frequency of the vocal folds might be higher, especially in comparison with male adult voices. indeed, a major reason for the lower emission rates might be the lower volume of the children's voices during singing. this was especially evident in the task with intended loud singing, even if all children of this study had a longstanding choir experience. on the contrary, in the shouting condition, which is not related to limitations in the child's singing technique, some children reached higher emission rates than adults during loud singing. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint et al., 2013) and 24 l/min for blowing (amis et al., 1999) , the measurement setup must be both, highly sensitive to detect all particles and suitable to cover the whole volume flow range. thus, different considerations were included in designing the setup for this study. first of all, a filter fan unit with a volume flow of 400 m³/h has been selected, whereas the flow of exhaled air is small compared to this and can be neglected. to avoid any disturbances regarding stagnated airflow at the measuring probe, this probe was positioned centrally in a glass pipe in which, caused by suction of the filter fan unit, the mean flow was only about 1.63 m/s. the resulting initial particle velocity during phonatory exercises was assumed to be 4.07 m/s in maximum and was added to the mean flow (see mürbe et al., 2020 for details). further, by placing a turbulence generating baffle between mouth opening and probe, there was a homogenous particle density distribution in the cross sectional area of the glass pipe. this in turn required the choice of an adequate distance between mouth opening and lpc, which was chosen to about 0.81 m and resulted in a traveling time of the particles of about 0.14 s in maximum. these experimental conditions, including a relative humidity of about 40%, result in approximately evaporated aerosols in their equilibrium state (wei et al., 2015) , which can be surveyed by the lpc with high accuracy and independently of the fluid flow at the mouth. thus, the measured emission rates can serve as a realistic estimate for a possible carriage for viruses that propagate in the environment. moreover, they allow a reliable comparison between the different vocalisation tasks. however, the emission rates reported in this study should not be interpreted as emitted droplets and aerosols directly at one's opened mouth. further issues with relevance for sars-cov-2-transmission during singing like the trajectory of larger droplets after emission from the mouth need to be studied with different methods like particle image velocimetry or phase doppler anemometry. for the assessment of the risk of sars-cov-2-transmission during singing, both, droplets and aerosols are considered as virus carriers. while virus transmission via droplets can be mainly handled by distance and hygiene rules, the risk management of transmission through virus carrying aerosols has to be addressed with further strategies (hartmann et al., 2020 , buonanno et al., 2020 . additional activities for safer ensemble and choir singing in closed rooms include limiting the number of singers and the rehearsal or performance time. this reduction of aerosol input leads to a lower cumulative aerosol concentration. on the other hand, room size and air condition systems will affect the number of potentially infectious aerosols in the room, too. especially modern mechanical ventilation systems might significantly lower the risk of aerogenic virus transmission. apart from the number of sources and the duration of singing, the individual emission rate of the singers determines the aerosol input in closed rooms. based on the current prevalence of the disease, an advanced risk management for singing together should combine the above-mentioned tools. the lower aerosol emissions for children's voices during singing might contribute to more sophisticated risk management strategies for singing in music lessons in school. these findings should be especially used to specify rehearsal and performance schedules for children's and adolescent's choirs because of the significance of education and socio-emotional development for children and young people. four girls and four boys, all 13 years old (except one girl aged 15 years), participated in the study. all of them were members of a semiprofessional children's choir (staats-und domchor berlin, mädchenchor der singakademie berlin) and had perennial choir experience between five and nine years. all children were prior to puberty vocal changes. the study was conducted according to the ethical principles based on the wma declaration of helsinki and was approved by the ethic committee of the charité-universitätsmedizin berlin, germany. informed written consent was obtained from all subjects and their parents. the investigations were carried out in a cleanroom at the hermann rietschel-institute, technische universität berlin. in this highly pure environment, the subjects wore cleanroom clothing and a headgear to further reduce the clothing's particle emission. to perform the 3 preprint . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint experiments, subjects sat in front of the test equipment, consisting of a glass pipe with a diameter of 295 mm, through which a constant airflow of approximately 400 m 3 /h was generated by suction of a filter fan unit (ziehl-abegg, künzelsau, deutschland). the sampling probe (ø37 mm) of a laser particle counter (lpc) (lighthouse solair 3100 e, lighthouse worldwide solutions, fremont, ca) was placed centrally in the pipe. the particle counter was counting with a sampling flow rate of 28.3 l/min with a measuring time increment of 10 seconds. the detected particles were assigned to six size classes between > 0.3 µm -25 µm. the emission rate p m was computed based on scaling of the particles measured at the lpc to the volume flow of the whole glass pipe. apart from the particle measurement, the sound pressure level lafmax was measured via a calibrated sound level meter (center 322_ datalogger sound level meter, center technologies, houston, tx). for detailed information about the cleanroom conditions, the particle measurement set-up and the audio equipment see . in the first task, the emission rates for three different vocal test conditions were compared: (a) speaking, (b) singing, and (c) shouting. condition (a) was reading a standardized text ("der nordwind und die sonne" by äsop), (b) singing the swedish folk song "vem kan segla" in key g-major. for condition (c), children were asked to cheer enthusiastically about a soccer game goal. the time window for a measured sequence was 30 seconds for test conditions (a) and (b) and 10 seconds for test condition (c). each test condition was repeated five times. in the second task, sustained phonation about 10 seconds was performed to investigate the impact of vocal loudness on the emission rate. subjects were asked to sustain the syllable /la/ , pitch g4 (392 hz), at the two loudness conditions soft voice (piano) and loud voice (forte). to facilitate the 10 seconds measurement time, the children were allowed to take a short breath within the recording and to repeat the syllable. statistical analysis, individually handled for the two tasks, was carried out by using linear mixed model analysis in the statistical software r including the package lmertest (kuznetsova et al., 2017) . log-valued pm data were incorporated as the response variable and condition as fixed effect. further, intercepts for subject and by-subject random slopes for the effect of condition were regarded as random effects. p-values were obtained using satterthwaite's degree of freedom method. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint airborne transmission of sars-cov-2: the world should face the reality high sars-cov-2 attack rate following exposure at a choir practice -skagit county exhaled respiratory particles during singing and talking aerosol emission is increased in professional singing aerosol emission and superemission during human speech increase with voice loudness data on subglottal pressure and spl at varied vocal loudness and pitch in 8-to 11-year-old children electrolaryngographically revealed aspects of the voice source in singing characterizing exhaled airflow from breathing and talking the measurement of airflow using singing helmet that allows free movement of the jaw fluid dynamics of human phonation and speech oral airway flow dynamics in healthy humans enhanced spread of expiratory droplets by turbulence in a cough jet risk assessment of rehearsal rooms for choir singing regarding aerosols loaded with virus estimation of airborne viral emission: quanta emission rate of sars-cov-2 for infection risk assessment lmertest package: tests in linear mixed effects models we thank the girls and boys and the accompanying staff of the staats-und domchor berlin and the mädchenchor der singakademie berlin for their personal support, and t. nawka for general discussion. the authors declare no competing interest. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprintthe copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint figure 1 . boxplots of the emission rates (pm in p/s, left y-axis) for the test conditions speaking, singing and shouting for subjects s1-s4 (girls) and s5-s8 (boys). the maximum sound pressure levels (lafmax in db spl) are also shown (right y-axis) with different colored full circles for the test conditions. 6 preprint . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprintthe copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint figure 2 . emission rate pm plotted over maximum sound pressure level lafmax for sustained syllable /la/. all five repetitions for the two loudness conditions are represented by colored points as denoted in the legend. the black solid line represents the linear regression (see inset for details), the gray colored area represents the 95% confidence region, whereas the black dashed lines restrict the 95% prediction band. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprintthe copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprintthe copyright holder for this this version posted september 18, 2020. . https://doi.org/10.1101/2020.09.17.20196733 doi: medrxiv preprint key: cord-010175-p2py9wau authors: winter, harland; chang, tien-lan title: gastrointestinal and nutritional problems in children with immunodeficiency and aids date: 1996-04-01 journal: pediatr clin north am doi: 10.1016/s0031-3955(05)70421-1 sha: doc_id: 10175 cord_uid: p2py9wau nan harland winter, md, and tien-lan chang, md children acquire human immunodeficiency virus (hiv) either perinatally from an infected mother (vertical transmission) or from infected blood or blood products. the number of children infected following a blood transfusion has dropped markedly following the institution of rigorous screening protocols for blood donors in the mid-1980s. by the early 1990s, more than 95% of newly diagnosed hiv-infected children acquired the disease via vertical infection.= the world health organization estimates that more than 10 million people throughout the world are infected with hiv (table 1) . three million of these individuals are women, most of whom are fewer than 40 years of age, whereas 500,000 of them are children. 37 thus, heterosexual transmission of hiv is the most common means of acquiring the infection when viewed from a worldwide perspective. hiv, a single-stranded rna lentivirus, infects cells that express a receptor capable of binding to the envelope glycoprotein (gp), gp 120. t lymphocytes and monocytes or macrophages that are cd4-positive are the primary targets of the virus, but reports suggesting that other cells in the gastrointestinal tract can be infected have led investigators to data from world health organization: the hiv-aids pandemic: 1993 overview. geneva: who/ gpngnp193. 1, 1993. speculate that gastrointestinal symptoms may be related to epithelial cell infection with hiv-1. fox and colleagues9 reported that hiv-1 infection of the gastrointestinal tract was limited to the lymphoid elements of the lamina propria; other investigators believe that, because intestinal epithelial cell line cultures became infected in the laboratory,1y epithelial cells were infected in vivo in hiv-infected adults.'o, the characteristics of the mucosal immune system most likely have a significant role in the pathobiology of hiv-1 disease in children; however, mucosal immune function has not been studied specifically in hiv-infected children and, thus, pediatricians are left to speculate that observations made in the adult hiv-infected population are relevant to children. table 2 summarizes gastrointestinal mucosal immunologic changes that occur in hivinfected individuals. vertical transmission occurs in approximately 30% of hiv-infected pregnant women who do not take antiretroviral therapy during pregnancy. the observations that transmission is increased in women who were symptomatic or who had more advanced aids27 and that zidovudine therapy given during pregnancy reduces perinatal transmission3 suggest that viral burden is an important factor in vertical transmission; however, the effects of maternal nutritional status, micronutrient deficiency, or acute infection on viral replication are difficult to evaluate. in addition, most hiv-infected women in africa, asia, and south america breast-feed their infants. this additional means by which infants can possibly become infected complicates assessment of factors contributing to transmission. in africa, the percentage of postnatal transmission is approximately 50y0.~~ nevertheless, the morbidity and mortality caused by formula feeding in countries where potable water is a premium and safe infant formula is not readily available seem to be greater than the risk of acquiring hiv-1 from breast milk. the current recommendation is for the hiv-exposed infant to have formula feeding if and only if safe the deterioration of the immune system and mucosal immune systems results in cellular and humoral immunoregulatory deficiencies. in the gastrointestinal tract, hiv-infected lymphocytes could migrate from the lymphoid aggregates through the mesenteric nodes, the thoracic duct, and into the circulation. following selection by receptors on high endothelial venules, these infected cells then migrate home to the lamina propria, whereby in situ hybridization isolated hiv-infected cells can be identified (fig. 1 ). most evidence 'supports the hypothesis that deterioration of mucosal immune function results in bacterial overgrowth; increased production of bacterial products, such as endotoxin; activation of mucosal lymphocytes with increased cytokine production; and probable interaction between immunoregulatory elements and epithelial cell function (fig. 2) . although the reasons for early development of lactose intolerance and malabsorption are not known, substances involved in immune regulation also may interact with intestinal epithe-lial cells, resulting in dysfunction. hiv also may have a role in the genesis of intestinal dysfunction, but data are not available. clearly, enteric infections begin to occur at the time when immune function is deteriorating (fig. 3) . the contribution of chronic intestinal infection to immune dysfunction, malabsorption, and malnutrition suggests that all of these factors are interrelated (fig. 4) . one of the more important determinants of survival for the hivinfected child is the health status of the mother. in studies from africa, if an hiv-infected mother is symptomatic or dies, her hiv-infected infant is at increased risk for chronic diarrhea partially because of the resulting reliance on formula.31 chronic diarrhea in the hiv-infected child is an important prognostic variable for predicting malnutrition and death. because of the availability of safe formula in north america and europe, the relationship between maternal health and infant survival is not as obvious. nevertheless, a chronically ill mother has an obvious negative impact on infant growth and development, particularly if no additional support is available, such as respite and day care programs designed to enrich infants' psychosocial development and nutritional status. in hiv-infected children, nausea and vomiting can be caused by infectious diseases, such as helicobacter pylori or cytomegalovirus, medications, or central nervous system disorders. in a child with nausea, anorexia may be the presenting manifestation because she or he is not able to verbalize the sensation. in these individuals, refusal to chew or eat may be caused by gingival disease or painful lesions of candida in the mouth. in many children, an identifiable agent or pathogen may not be found despite a thorough search. some of the therapeutic agents that have been implicated as causes of nausea and vomiting are as follows: altered mental status or developmental delay should alert the clinician to the possibility of central nervous system disease, such as encephalopathy caused by hiv, or pathogens, such as toxoplasmosis. lymphoproliferative disorders in the central nervous system are rare in the pediatric population; however, lymphoma of the gastrointestinal tract can cause splenomegaly resulting in compression of the stomach and early satiety. evaluation of hiv-infected children with anorexia, nausea, or vomiting should begin with a careful history, social history, physical examination, and neurologic evaluation. an upper gastrointestinal radiograph is not reliable enough to establish or rule out mucosal disease. for this reason, endoscopic evaluation is frequently necessary in children with persistent symptoms and normal hepatobiliary and pancreatic tests. mucosal biopsies may identify an enteric pathogen or inflammation that can be treated with a specific agent. if no cause can be found, symptoms can be managed with phenothiazine derivatives, such as triethylperazine maleate (torecan), prochlorperazine (compazine), or promethazine (phenergan). other agents for which anecdotal treatment experience exists in children include: benzquinamide (emete-con); trimethobenzamide hydrochloride (tigan); hydroxyzine (vistaril or atarax); metoclopramide (reglan); cisapride (propulsid); and scopolamine (transdermscop); dronabinal (marinol). if treatment fails to relieve the symptoms, re-evaluation should be considered. difficulty in swallowing (dysphagia) or pain with swallowing (odynophagia) in children can be caused by oral lesions that can be identified by careful inspection of the mouth. stomatitis caused by 2',3'-dideoxycytidine 5'-triphosphate (ddc), herpes simplex or candida is treatable if the diagnosis is established. when oral lesions are present, coexistent esophagitis should be suspected. in contrast, if the mouth is free of lesions, esophagitis cannot be ruled out. candida and cytomegalovirus are the most common infectious agents causing esophagitis. dysphagia and odynophagia in hiv-infected children are more commonly associated with candida than with cytomegalovirus. children who are taking h, antagonists seem to be at increased risk for developing candida esophagitis. medications, such as zidovudine, have been reported to cause esophageal ulceration if, when swallowed, they do not reach the stomach.6 treatment for specific causes of oral or esophageal lesions is summarized in table 3 . although enteric pathogens are frequently identified as the cause the incidence of of diarrhea and weight loss in hiv-infected enteric infection in hiv-infected children seems to be lower,4o and the relationship between diarrhea, enteric pathogens, and growth retardation is not as clearly understood. in figure 4 , the interrelationship between malabsorption, malnutrition, immune deficiency, and enteric infection is depicted. enteric infection results in intestinal injury and malabsorption, which, if not compensated by additional nutrient support, results in nutritional deficiency. the development of malnutrition causes immune deficiency, which is characterized by a defect in t-cell function that is similar to the defect caused by hiv disease. defective t-cell function results in increased susceptibility to enteric infection, and the circle is completed. hiv can interact at any of the stages of this cycle. in theory, intestinal absorption can be altered by modifying enterocyte function through immune modulators. by increasing apoptosis, hiv could cause premature senescence of enterocytes and decrease brushborder expression of disaccharidases and peptidases. some of these same agents, such as the cytokine, tumor necrosis factor-a), are upregulated by hiv infection, affect intermediate metabolism, and cause malnutrition by increasing nutrient requirements. the effects of hiv on the immune system are well known and result in immunocompromise and increased susceptibility to opportunistic infection. similar immunoregulatory abnormalities probably occur in the mucosal immune system, resulting in enteric infection. thus, hiv interacts at many levels to potentiate the development of malabsorption, malnutrition, immune deficiency, and enteric infection. giardia zarnbzia causes watery diarrhea, abdominal distention, and crampy abdominal pain.4, 22, 31 metronidazole or furazolidone is effective therapy and eradicates the organism in more than 70% of infected individuals. giardia zambzia does not occur more frequently in hivinfected children than in the general population, but retreatment may be necessary in the immunocompromised host. crypfosporidium parvum causes an acute, self-limited diarrheal illness in the immunocompetent host, but in the immunodeficient child with hiv disease, the infection causes a secretory diarrhea that is chronic and debilitating. the organism usually can be identified in the stool by immunofluorescent techniques or by kinyoun carbolfuchsin stain.7 in hiv-infected children in the united states, the incidence of cryptosporidiosis is lower than that reported in africa and south america.2, 4, 33 crypfosporidium can infect the small intestine, colon, gallbladder, biliary tract, and pancreatic duct. no therapy is consistently effective in eradicating the organism, but octreotide is reported to decrease stool reports of the beneficial effects of hyperimmune bovine colostrum suggest that this form of passive immunotherapy may be effective in hiv-infected individual^.^^ other enteric parasitic infections, including isospora bezzi and microsporidium, are rarely identified in hiv-infected children; however, blastocysfis hominis, a protozoan whose role as an enteric pathogen is still debated, may be more prevalent in hiv-infected children with diarrhea than in hiv-negative ~h i l d r e n .~ bacteria are an important cause of diarrhea throughout the world and for this reason contribute to the list of identifiable pathogens found in hiv-infected children. in africa, pathogenic strains of escherickia coli were identified in over three fourths of hiv-infected children. 22 the risk for other bacterial enteric infections is not known for hiv-infected children, but the incidence of salmonella, skigella, campylobacter, yersinia, and clostridium difficile do not seem to be increased in hiv-infected children. the incidence of helicobacter pylori may be decreased in hivinfected chi1dren.l the most serious enteric bacterial infection is mycobacterium avium-intrace2lulare, which causes a multisystemic infection involving the lungs, liver, mesenteric lymph nodes, gastrointestinal tract, and bone marrow in the most severely immunocompromised hosts with cd4 counts less than 50 cells/mm3. acidfast bacilli can be identified in the jejunal mucosa or grown from stool or blood. the most common gastrointestinal symptoms of m avium-intracellulare are abdominal pain and diarrhea, and neither responds dramatically to therapeutic intervention. combinations of medications chosen from clarithromycin, ethambutol, ciprofloxacin, amikacin, rifampin, clofazamine, and azithromycin have been tried.14 rotavirus is the viral agent that most frequently causes chronic diarrhea. in the immunocompromised child, rotaviral diarrhea can be severe, persistent, and difficult to distinguish from other agents causing secretory diarrhea. diagnosis is established by identification of rotavirus in the stool using an enzyme-linked immunoassay. enterally administered serum immunoglobulin is effective therapy,i5 but little published data exist on the treatment for rotavirus in hiv-infected children. other viral pathogens, such as adenoviruses, can cause diarrhea but also are associated with systemic infection and fulminant hepatitis. cytomegalovirus usually causes an asymptomatic enteric infection, but some individuals develop focal ulcerations in the colon or jejunum and present with bloody diarrhea and abdominal pain. gastrointestinal bleeding is unusual in hiv-infected children, but, when present, it may be caused by focal ulcerations in the colon, stomach, small intestine, or esophagus from cytomegalovirus-induced disease. merely culturing cytomegalovirus from the intestinal mucosa does not establish a link between diarrhea and the infection. histologic evidence of mucosal injury is necessary. ganciclovir and foscarnet are used to treat cytomegalovirus-induced intestinal disease in children with active symptoms. bone marrow suppression is the main serious side effect. many children with hiv disease develop lactose intolerance earlier than predicted by genetic predisp~sition.'~ nevertheless, these lactoseintolerant children do not seem to have an increased probability for growth retardation or diarrheal disease. the impact of lactose malabsorption on the nutritional health of hiv-infected children is unclear; however, children who have decreased absorption of the carbohydrate d-xylose have an increased incidence of harboring an enteric pathogen. 17 to evaluate hiv-infected children with chronic, nonbloody diarrhea, stool analysis for bacterial, viral, and parasitic infection should be performed. blood and polymorphonuclear leukocytes in the stool are indicative of colitis and should prompt evaluation of the colonic mucosa. if no enteric pathogen is identified, functional tests, such as lactose breath hydrogen and d-xylose absorption, may be useful in guiding nutritional therapy. the most beneficial diagnostic test is an upper endoscopy with biopsy. in addition to routine histology, mucosal biopsies of any focal lesions should be tested for bacterial, fungal, and viral culture and analyzed via electron microscopy. because mycobacterium and cytomegalovirus may not be detectable during endoscopic evaluation, surveillance biopsies of the jejunum should be evaluated by electron microscopy and culture. despite these diagnostic studies, enteric pathogens frequently are not identified in many hiv-infected children with diarrhea. hiv-infected children with abdominal pain should be evaluated for enteric infection, especially if they have diarrhea. fever and abdominal pain are symptoms that can indicate the presence of mycobacterium. association of these symptoms with the ingestion of milk should alert the clinician to the possibility of lactose intolerance, but for many children with lactase deficiency, the relationship is not evident. in addition, pancreatitis in the hiv-infected child is a serious and debilitating illness. not only do these children experience crampy abdominal pain, but the association with meals results in decreased caloric intake and increases the potential for malnutrition. lipase seems to be an early and sensitive marker for pancreatitis in the pediatric population.18 medications such as ddi and ddc are associated with pancreatitis, which may develop following many manths of therapy.39 other medications including pentamidine, trimethoprim-sulfamethoxazole, and dapsone have been implicated as causes of pancreatitis in children. the development of pancreatitis is an ominous event, and in one published study, the mean survival of children with pancreatitis was 8 months following the diagnosis.ls because of the guarded outcome, decisions to perform additional diagnostic tests should be made after much discussion with the health care team. if a dilated pancreatic duct is identified by ultrasonography, the indication for endoscopic retrograde cholangiopancreatography should be based on quality-of-life issues. although strictures of the pancreatic duct could contribute to the symptoms, if therapeutic intervention is not feasible, invasive diagnostic studies should not be performed. although the majority of hiv-infected children have hepatomegaly, few experience severe hepatocellular dysfunction; fibrosis; or cirrhosis that results in coagulopathy, ascites, varices, or hepatic failure. many of the medications used to treat complications of hiv disease cause hepatocellular injury or cholestasis; however, infectious agents, such as hepatitis b, that cause hepatocellular injury by immune mechanisms have milder clinical courses in immunodeficient hosts.z4 preservation of immune function in hiv-infected children could account for the apparent increase in chronic active hepatitis in the pediatric population compared with the incidence in although abnormalities in liver function tests are not diagnostic, they are beneficial as screening procedures. elevated transaminases are caused by infectious agents, medications, or nutritional deficiency and malnutrition. when the transaminases exceed four times normal, viral disease or a drug-induced hepatitis should be suspected. m avium in tracellulare, hepatic pneumocysfis carinii, fungal-induced hepatitis, cytomegalovirus, or extrahepatic biliary tract obstruction cause elevation of alkaline phosphatase. liver biopsy is necessary to identify hepatic pathogens and should be considered in a child presenting with either fever and elevated liver function tests or a focal hepatic lesion. therapeutic intervention is available for some of the viral agents that cause hepatitis, but most infectious disorders in immunodeficient hosts do not respond favorably to treatment. wasting of body mass is one of the more serious manifestations of hiv disease. in adults, the decline in lean body mass correlates with decreased quality of life and eventual death.s, l3 in children with aids, growth failure and failure to thrive have been recognized symptoms from the beginning of the epidemic.28 infants born to hiv-infected mothers seem to weigh less by 3 months of life and to be shorter by 6 months of life when compared with hiv-exposed, but noninfected infants. in long-term survivors more than 8 years of age, lean body mass wasting and short stature are common clinical features. the etiology of these derangements in growth is multifactorial, possibly including deranged metabolism, malabsorption, or decreased nutrient intake. the mechanism for the catabolic process is not known, but futile cycling of energy substrates, protein wasting, or hypermetabolism mediated by cytokines such as tnf, interleukin (1l)-1, il-6, and the interferons may contribute to the problem. the initial assessment of hiv-infected children with failure to thrive is directed at determination of caloric intake, nutrient losses, and metabolic requirements. if caloric intake is diminished, the reason for anorexia should be determined. nausea, abdominal pain, oral lesions, depression, despair, or lack of access to food need to be evaluated by the health care team. nutrient losses caused by diarrhea and malabsorption may contribute to increased nutrient requirements. enhanced metabolic requirements from febrile illnesses, recurrent infection, or from hiv replication may result in weight loss. anti-retroviral therapy can result in weight gain shortly after starting therapy. 23 counseling and oral supplements are the first steps in nutritional treatment for children with weight loss or decreased lean body mass. providing increased calories and protein may reverse the loss, but most children require additional measures of support. although nasogastric tube feeding is simple and effective for short-term management, the adverse effect on quality of life and the increased possibility of sinus disease are limiting factors. in children requiring nutritional supplementation lasting greater than 2 weeks, endoscopic placement of a gastrostomy tube button increases compliance and tolerance. as many as 150% recommended daily allowance for calories may be required to achieve weight gain in hiv-infected children. newly developed one-step gastrostomy buttons permit endoscopic insertion of devices that do not limit activity and provide access for nutritional support. despite providing sufficient nutrition to gain weight, enteral supplementation16 and gastrostomy tube feedings" do not increase lean body mass in hiv-infected children. similarly, appetite stimulants, such as megestrol acetate, a progesterone derivative, and dronabinol, a tetrahydrocannabinol derivative, do not increase lean body mass in adults infected with hiv. promising data in adults suggest that mammalian cell-derived recombinant human growth hormone therapy results in weight gain and anabolism as measured by stool nitrogen, urine nitrogen, and potassium excretion.20 if valid in the pediatric population, growth hormone could prove to be an effective treatment for failure to thrive by increasing lean body mass. anecdotal experience implicates specific vitamin deficiencies as contributing to the nutritional problems of hiv-infected children. in regions in which vitamin deficiency is endemic, it is not surprising to see the problem amplified in hiv-infected children. decreased vitamin a causes diminished t-cell response to mitogens and antigens, atrophy of lymphoid tissue,3â° and is associated with increased maternal-child transmission.z9 supplementation of vitamin a seems to increase cd4 + cells, boost antibody response, and decrease morbidity and mortality from other infectious diseases.8 the effect of vitamin a supplementation on the health of hiv-infected children in the united states is not known. other vitamins, including vitamins d, e, 8, (thiamine), b2 (riboflavin), niacin, b6, bi2, folic acid, c, and carnitine, have been evaluated in various populations of hiv-infected individuals, and although abnormalities can be demonstrated for some vitamins, deficiencies related to the generalized state of malnutrition and not specifically to hiv-induced disease are difficult to prove beyond a reasonable doubt. similarly, deficiencies of iron, zinc, and selenium have been described in hiv-infected individuals. although these minerals have an important role in immunoregulathe redundancy of the immune system to provide protection against infection suggests that by the time the system begins to fail, no single cause can be found to correct the problem. for this reason, supplementation with a single therapeutic nutrient intervention can improve laboratory phenomena, but rarely impacts on a patient's quality of life or immunoregulatory defects. patients with primary immunodeficiency disorders frequently experience gastrointestinal problems in association with other clinical manifestations of systemic disease. the respiratory and gastrointestinal tracts are exposed to the environment and, in response, have developed complex systems to protect their mucosal surfaces from pathogens. antibody production, cell-mediated immune function, complement, and phagocytic function act together to prevent infection and uncontrolled inflammation. in the gastrointestinal tract, enteric pathogens and chronic inflammatory bowel disease are the two major clinical aspects of primary immune deficiency. surprisingly, individuals with identical deficiencies may not experience similar gastrointestinal symptoms. for example, children with immunoglobulin a deficiency may be asymptomatic or may have chronic diarrhea associated with chronic intestinal inflammation disease. in general, children with t-cell defects seem to have a higher incidence of chronic gastrointestinal problems compared with children with antibody defiqiency syndromes, complement defects, or disorders of phagocytic function. table 4 lists the common primary immunodeficiencies together with the gastrointestinal manifestations commonly associated with each disorder. immunodeficient children pose a challenge to clinicians because of the interrelationship between infectious disease, metabolism, gastrointestinal tract function, psychosocial problems, and immune function. the interplay between these factors is not always clear, and frequently the best course of therapy is obscured because of an inability to determine which factors have the greatest impact on child health. to optimize therapeutic intervention, a multidisciplinary health care team must be involved with the management of children and their families. heiicobacter pylari in children with acquired immunodeficiency syndrome disseminated histoplasmosis as the acquired immunodeficiency syndrome-defining illness in an infant intestinal parasites and hiv infection in tanzanian children with chronic diarrhea centers for disease control: zidovudine for the prevention of hiv transmission from mother to infant significance of altered nutritional status in acquired immune deficiency syndrome (aids) esophageal ulceration induced by zidovudine aids, zinc deficiency and thymic hormone failure et a1 vitamin a supplementation and child mortality: a meta-analysis detection of hiv-1 rna in the lamina propria of patients with aids and gastrointestinal disease human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal tissue effect of enteral tube feeding on growth of children with symptomatic human immunodeficiency virus infection italian multicentre study: epidemiology and clinical features of pediatric hjv infection: results from an italian multicentric study on 544 children bosy composition studies in patients with the acquired immunodeficiency syndrome recommendations on prophylaxis and therapy for disseminated mycobacterium avium complex disease in patients infected with the human immunodeficiency virus benefit of oral immune globulin therapy in patients with immunodeficiency and chronic diarrhea growth and body composition in children infected with the human immunodeficiency virus-1 malnutrition and carbohydrate malabsorption in children with vertically transmitted human immunodeficiency virus 1 infection et a1 pancreatitis in pediatric human immunodeficiency virus infection hiv replication and persistence in human gastrointestinal cells cultured in vitro anabolic effects of recombinant human growth hormone in patients with wasting associated with human immunodeficiency virus infection human immunodeficiency virus detection in bowel epithelium from patients with gastrointestinal symptoms diarrhea among african children born to human immunodeficiency virus-infected mothers: clinical, microbiologic and epidemiologic features effect of continuous intravenous infusion of zidovudine (azt) in chldren with symptomatic hiv infection hepatic involvement in patients with human immunodeficiency virus infection: discrepancies between aids patients and those with earlier stages of infection pediatric acquired immunodeficiency syndrome: special considerations for developing nations efficacy of octreotide in the management of chronic diarrhea in aids perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in zaire survival in children with perinatally acquired human immunodeficiency virus type 1 infection chlehanaw j d maternal vitamin a deficiency and mother-tochild transmission of hiv-1 altered t cell subset proportions in vitamin a deficient children a prospective study of diarrhea and hiv-1 infection among 429 zairian infants chronic active hepatitis in a child with human immunodeficiency virus infection survival experience of 789 children with acquired immunodeficiency syndrome gastrointestinal symptoms in patients infected with human immunodeficiency virus: relevance of infective agents isolated from gastrointestinal tract et a1 cessation of cryptosporidium-associated diarrhea in an acquired immunodeficiency syndrome patient after treatment with hyperimmune bovine colostrum postnatal transmission of human immunodeficiency virus type 1 from mother to infant. a prospective cohort study in kigali, rwanda statement on breast feeding and hiv. who/ unicef consultative meeting of world health organization: the hiv/aids pandemic: 1993 overview. geneva: who/ gpa/cnp/93 long-term toxicity/activity profile of 2',3'-dideoxyinosine in aids or aids-related complex gastrointestinal dysfunction and disaccharide intolerance in children infected with human immunodeficiency virus key: cord-022569-ddaqfsmp authors: pappas, diane e.; hendley, j. owen title: the common cold date: 2013-02-10 journal: principles and practice of pediatric infectious diseases doi: 10.1016/b978-1-4377-2702-9.00026-x sha: doc_id: 22569 cord_uid: ddaqfsmp nan all references are available online at www.expertconsult.com transferred to the hands of uninfected individuals during brief contact; infection then results when the uninfected person transfers the virus from the hands on to his or her nasal or conjunctival mucosa. sneezing and coughing are ineffective modes of rhinovirus transmission, 11 although there is some evidence that virus could also be transmitted by aerosols generated by coughing, talking, and breathing. 12 inoculation of the oral mucosa with rhinovirus 13 or rsv 14 does not result in infection. symptoms of the common cold do not appear to result from destruction of nasal mucosa, because nasal biopsy specimens from young adults with both natural and experimentally induced colds show intact nasal epithelium during symptomatic illness. 15, 16 study by in situ hybridization of nasal biopsy specimens obtained during rhinovirus infection indicates that replication occurs in only a small number of epithelial cells. 17, 18 furthermore, in vitro studies have shown that rhinovirus and coronavirus produce no detectable cytopathic effect when replicating in a cultured monolayer of nasal epithelial cells, whereas influenza virus a and adenovirus produce obvious damage. 19 the symptoms of the common cold appear to result from release of cytokines and other mediators from infected nasal epithelial cells as well as from an influx of polymorphonuclear cells (pmns). nasal washings of volunteers experimentally infected with rhinovirus showed a 100-fold increase in pmn concentration 1 to 2 days after inoculation. 20 this influx of pmns coincides with onset of symptoms and correlates with the presence of a colored nasal discharge. 21 a yellow or white nasal discharge may result from the higher number of pmns, whereas the enzymatic activity of pmns (due to myeloperoxidase and other enzymes) may cause a green nasal discharge. a potent chemoattractant for pmns is produced by cells in culture infected with rhinovirus. 22 this chemoattractant has been identified as interleukin-8 (il-8). 23 elevated causes bronchiolitis in children 2 years or younger, influenza viruses cause febrile respiratory illness with severe lower respiratory tract involvement, adenoviruses cause pharyngoconjunctival fever, parainfluenza viruses cause croup in young children, hbov is associated with wheezing, and enteroviruses cause a variety of illnesses, including aseptic meningitis and herpangina. in temperate climates in the northern hemisphere, the predictable yearly epidemic of colds begins in september and continues un abated until spring. this sustained epidemic curve is a result of successive waves of different respiratory viruses moving through the community (figure 26 -1). the epidemic begins with a sharp rise in the frequency of rhinovirus infections in september (after children return to school), which is followed by pivs in october and november. rsv and hcovs circulate during the winter months, whereas infection due to influenza virus peaks in the late winter. the epidemic finally ends with a small resurgence of rhinovirus infections in the spring. adenovirus infection occurs at a constant rate throughout the cold season. 5 the frequency of colds varies with age. a 10-year study of families with children who did not attend a childcare facility showed that the peak incidence of colds occurs in preschool children 1 to 5 years old, with a frequency of 7.4 to 8.3 colds per year. infants younger than 1 year averaged 6.7 colds per year, and teenagers averaged about 4.5 colds per year. mothers and fathers experienced about 4 colds per year. 6 with the greater exposure of children to other preschool children in childcare facilities, the frequency of colds in children younger than 6 years has increased. thus, the typical preschool child experiences at least one uri per month throughout the cold season. viral transmission occurs primarily in the home setting, although the exact mechanism of spread has not been clearly established. colds can be spread by: (1) small-particle (<5 µm in diameter) aerosol, which infects when inhaled; or (2) largeparticle (>10 µm in diameter) droplets, which infect by landing on nasal or conjunctival mucosa; or (3) direct transfer via handto-hand contact. 7 small-particle aerosol is an effective method of transfer for influenza virus 8 and coronavirus 9 but not for rsv. 10 rhinoviruses are most likely spread by large-particle droplets or direct transfer. rhinoviruses can survive as long as 2 hours on human hands and up to several days on other surfaces. studies in young adults have shown that infected individuals commonly have rhinovirus on their hands, which can be efficiently levels of il-8 and other cytokines (il-1β, il-6) also have been demonstrated in the nasal secretions of infected individuals. 24, 25 furthermore, elevated levels of albumin and kinins (predominantly bradykinin) in nasal secretions have been shown to coincide with the onset of symptoms in experimental rhinovirus infection. 20 the elevated concentration of albumin and kinins likely results from exudation of plasma proteins due to greater vascular permeability in the nasal submucosa. the method by which viral infection initiates this vascular leak has not yet been determined. the release of kinins resulting from plasma exudation may augment the symptoms of the cold; bradykinin alone can cause rhinitis and sore throat when sprayed into the noses of uninfected individuals. 26 the paranasal sinuses usually are involved during an uncomplicated cold. in one study, computed tomographic (ct) scans obtained during the acute phase of illness revealed abnormalities of one or more sinuses in 27 (87%) of 31 young adults. 27 without antibiotic therapy, there was complete resolution or marked improvement of the sinus abnormalities in 11 (79%) of the 14 subjects in whom second ct scans were obtained 2 weeks later. in another study, mri revealed that 60% of children with upper respiratory tract infections had major abnormalities in their paranasal sinuses; these tended to resolve without antibiotic therapy. 28 it is not known whether these sinus abnormalities result from viral infection of the sinus mucosa or from impaired sinus drainage secondary to viral rhinitis. nose-blowing can generate enough pressure to force fluid from the nasopharynx into the paranasal sinuses, suggesting that nose-blowing may force mucus containing viruses, bacteria, and inflammatory mediators into the paranasal sinuses during a cold. 29 the middle ear can also be involved during uncomplicated colds. studies in school-aged children have shown that two-thirds will develop abnormal middle-ear pressures within 2 weeks after onset of a cold. 30 otitis media was not diagnosed during the study, as ears were not examined and none of the children sought medical care. it is not known whether the abnormal middle-ear pressures result from viral infection of the mucosa of the middle ear and eustachian tube or from viral nasopharyngitis with secondary eustachian tube dysfunction. symptoms of the common cold do not vary by specific causative virus. in older children and adults, rhinorrhea, nasal obstruction, and sore or scratchy throat are typical. the rhinorrhea is initially clear but may become colored as the illness proceeds. cough or sneeze may be present. fever (>38°c) is uncommon in adults. other symptoms are malaise, sinus fullness, and hoarseness. objective findings are minimal except for mild erythema of the nasal mucosa or pharynx. symptoms resolve in 5 to 7 days. compared with adults, infants and preschool children with colds are more likely to have fever (>38°c) and moderate enlargement of the anterior cervical lymph nodes (table 26 -2). 1 rhinorrhea may not be noticed until the nasal discharge becomes colored. nasal congestion can disrupt sleep and can lead to fatigue and irritability. the illness often persists in infants and preschool children for 10 to 14 days. 31 the differential diagnosis of a cold includes allergic rhinitis, vasomotor rhinitis, intranasal foreign body, and sinusitis. a diagnosis of allergic rhinitis is suggested by a seasonal pattern of clear rhinorrhea, absence of associated fever, and family history of allergy. possible associated conditions are asthma and eczema. physical findings consistent with allergic rhinitis include allergic "shiners" and "nasal salute." the detection of numerous eosinophils upon microscopic examination of the nasal mucus using hansel stain confirms the diagnosis of allergic rhinitis. a diagnosis of vasomotor rhinitis is suggested by a chronic course without fever or sore throat. the diagnosis of bacterial sinusitis is suggested by persistent rhinorrhea or cough or both for greater than 10 days. 32 the diagnosis of a cold is based on history and physical examination; generally, laboratory tests are not useful. the rapid test for detecting rsv, influenza, parainfluenza, and adenovirus antigens in nasal secretions can be used to confirm the diagnosis. rsv, rhinovirus, influenza viruses, parainfluenza viruses, and adenoviruses also can be isolated in cell culture. hcov cannot be detected reliably in cell culture, so serologic titer rise can be used for diagnosis, if necessary. polymerase chain reaction assays for diagnosis of all the respiratory viruses are available in research laboratories and increasingly in clinical laboratories; there is lack of standardization and validation for many tests offered. other methods of detection can be used but are rarely needed. at present, no antiviral agents are available that are effective for treatment of the common cold. although an array of medications may be used to relieve symptoms, there is little scientific evidence to support the use of symptomatic treatments in children. because the common cold is a self-limited illness with symptomatology that is largely subjective, a substantial placebo effect can suggest that various treatments have some efficacy. inadequate blinding of placebo recipients in a study can make an ineffective treatment appear effective. in adults with colds, first-generation antihistamines (i.e., chlorpheniramine) have been shown to provide modest symptomatic relief, with decreases in nasal discharge, sneezing, nose-blowing, and duration of symptoms. 33 this effect is presumably due to the anticholinergic effects of these medications. a randomized, double-blind, placebo-controlled study in preschool children with uris showed that treatment with an antihistaminedecongestant combination (brompheniramine maleate and phenylpropanolamine hydrochloride) produced no improvement in cough, rhinorrhea, or nasal congestion, although a larger proportion of the treated children (47% versus 26%) were asleep 2 hours after treatment. 34 numerous decongestants, antitussives, and expectorants are available over the counter, but there is no evidence to support their use in children. a study of phenylephrine, a topical decongestant, in children 6 to 18 months old showed no decrease in nasal obstruction with its use during a uri. 35 in a study comparing placebo, dextromethorphan, and codeine for cough suppression in children 18 months to 12 years old, cough decreased in all patients within 3 days, but there was no difference in cough reduction among the three treatment groups. 36 guaifenesin, an expectorant, has not been shown to change the volume or quality of sputum or the frequency of cough in young adults with colds. 37 echinacea preparations, commonly believed to be effective in the treatment of the common cold, have been shown to have no effect on the prevention or treatment of rhinovirus infection 38 as has intranasal zinc gluconate for treatment of colds 39 or prevention of experimental rhinovirus colds. 40 in january, 2008, the u.s. food and drug administration issued an advisory strongly recommending that over-the-counter cold and cough medications not be given to infants because of the risk of life-threatening side effects. antibiotics have no role in the treatment of uncomplicated uris in children. antibiotic therapy does not hasten resolution of the viral infection or reduce the likelihood of occurrence of secondary bacterial infection. 41 antibiotics are only indicated in cases of secondary bacterial infection, such as sinusitis and acute otitis media. thus, supportive measures remain the mainstay of treatment of the common cold in children. bulb suction with saline drops (about 1 teaspoon salt in 2 cups of water) may help relieve nasal congestion and remove secretions. a recent study suggests that honey given at bedtime may help reduce cough in children with upper respiratory tract infections, although honey is not recommended for children under the age of 12 months because of the risk of exposure to c. botulinum spores. 42 the common cold usually resolves in about 10 to 14 days in infants and children. new-onset fever and earache during this period may herald the development of bacterial otitis media, which occurs in about 5% of colds in preschool children. persistence of nasal symptoms for longer than 10 days has been thought to signify the development of a secondary bacterial sinusitis. however, a recent study found that 20 children hospitalized for preseptal or orbital cellulitis, indicative of bacterial sinusitis, had symptoms of acute respiratory tract infection for 7 days or less prior to hospitalization, suggesting that the complications of rhinosinusitis can occur during the first few days of a cold. 43 bacterial pneumonia is an uncommon secondary infection. for children with underlying reactive airways disease, wheezing is common during the course of a viral uri; at least 50% of asthma exacerbations in children are associated with viral infection. children who experience more than one lower respiratory tract infection (such as croup or bronchiolitis) during their first year of life have an increased risk of asthma thereafter. 44 other complications are epistaxis, eustachian tube dysfunction, conjunctivitis, and pharyngitis. the symptoms of the common cold appear to result from effects of inflammatory mediators released in response to the viral infection of the respiratory tract. as the determinants of this process are further elucidated, treatments may be developed that can interrupt or ameliorate release of inflammatory mediators and thus prevent or reduce the symptoms of the common cold. vaccines are unlikely to be useful for prevention, given the large number of serotypes of some cold viruses as well as the lack of lasting immunity to others. the use of alcohol-based hand gels has been suggested as a means of reducing secondary transmission of respiratory illnesses in the home, 45 but this was not shown to be effective in one field trial. 46 also, virucidal tissues have been shown to be effective in preventing viral passage and transmission, and may reduce secondary transmission by about 30%. 47, 48 until new methods are developed, prevention of the common cold is limited to avoiding self-inoculation (transfer of virus from contaminated fingers to nasal or conjunctival mucosa) by removing virus through handwashing or by killing virus with application of a virucide to the hands. epidemiology, pathogenesis, and treatment of the common cold human bocavirus infections in hospitalized children and adults viral etiology of common cold in children newly identified respiratory viruses in children with asthma exacerbation not requiring admission to hospital the common cold illness in the home mechanisms of transmission of rhinovirus infections an outbreak of influenza aboard a commercial airliner mechanism of transmission of coronavirus 229e in human volunteers modes of transmission of respiratory syncytial virus hand-to-hand transmission of rhinovirus colds exhalation of respiratory viruses by breathing, coughing, talking transmission of rhinovirus colds by self-inoculation infectivity of respiratory syncytial virus by various routes of inoculation light and scanning electron microscopy of nasal biopsy material from patients with naturally acquired common colds histopathologic examination and enumeration of polymorphonuclear leukocytes in the nasal mucosa during experimental rhinovirus colds detection of rhinovirus infection of the nasal mucosa by oligonucleotide in situ hybridization localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization respiratory virus infection of monolayer cultures of human nasal epithelial cells kinins are generated during experimental rhinovirus colds study of bacteria in the nasal cavity and nasopharynx during naturally acquired common colds rhinovirus infection of human embryonic lung fibroblasts induces the production of a chemoattractant for polymorphonuclear leukocytes elaboration of interleukin 8 (il-8) from fibroblast (mrc-5) cells and human nasal epithelium in response to rhinovirus (rv) challenge (abstract b43) respiratory syncytial virus-induced cytokine production by a human bronchial epithelial cell line nasal cytokine production in viral acute upper respiratory infection of childhood nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat computed tomographic study of the common cold paranasal sinus findings in children during respiratory infections evaluated with magnetic resonance imaging nose blowing propels nasal fluid into the paranasal sinuses viral respiratory infection in schoolchildren: effects on middle ear pressure clinical course of acute infection of the upper respiratory tract in children: a cohort study sinusitis in children effectiveness of antihistamines in the symptomatic management of the common cold is an antihistaminedecongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? effect of topical adrenergic decongestants on middle ear pressure in infants with common colds efficacy of cough suppressants in children antitussive effect of guaifenesin in young adults with natural colds: objective and subjective assessment an evaluation of echinacea angustifolia in experimental rhinovirus infections treatment of naturally acquired common colds with zinc: a structured review ineffectiveness of intranasal zinc gluconate for prevention of experimental rhinovirus colds upper respiratory tract infection effect of honey, dextromethorphan, and no treatment on nocturnal cough and sleep quality for coughing children and their parents timing of rhinosinusitis complications in children early respiratory infections, asthma, and allergy: 10-year follow-up of the oslo birth cohort illness transmission in the home: a possible role for alcohol-based hand gels a randomized, controlled trial of a multifaceted intervention including alcohol-based hand sanitizer and hand-hygiene education to reduce illness transmission in the home two randomized, controlled trials of virucidal nasal tissues in the prevention of natural upper respiratory infections efficacy of virucidal nasal tissues in interrupting familial transmission of respiratory agents key: cord-013473-8q0a33dr authors: hetherington, erin; mcdonald, sheila; racine, nicole; tough, suzanne title: longitudinal predictors of self-regulation at school entry: findings from the all our families cohort date: 2020-10-16 journal: children (basel) doi: 10.3390/children7100186 sha: doc_id: 13473 cord_uid: 8q0a33dr self-regulation is the ability to manage emotions, modulate behaviors, and focus attention. this critical skill begins to develop in infancy, improves substantially in early childhood and continues through adolescence, and has been linked to long-term health and well-being. the objectives of this study were to determine risk factors and moderators associated with the three elements of self-regulation (i.e., inattention, emotional control, or behavioral control) as well as overall self-regulation, among children at age 5. participants were mother–child dyads from the all our families study (n = 1644). self-regulation was assessed at age 5. risk factors included income, maternal mental health, child sex, and screen time, and potential moderation by parenting and childcare. adjusted odds ratios of children being at risk for poor self were estimated using multivariable logistic regression. twenty-one percent of children had poor self-regulation skills. risk factors for poor self-regulation included lower income, maternal mental health difficulties, and male sex. childcare and poor parenting did not moderate these associations and hostile and ineffective parenting was independently associated with poor self-regulation. excess screen time (>1 h per day) was associated with poor self-regulation. self-regulation involves a complex and overlapping set of skills and risk factors that operate differently on different elements. parenting and participation in childcare do not appear to moderate the associations between lower income, maternal mental health, male sex, and screen time with child self-regulation. the first five years of life have been identified as critical for healthy development, as they set the stage health and well-being across the life course [1] . a key developmental skill acquired in these early years is the capacity for self-regulation, which is defined as the ability to monitor and control emotions, attention, and interactions with others and the environment [2, 3] . these foundational skills, which develop from infancy and mature through adolescence, are critical to the development of positive relationships with family members, teachers, and peers [2, 4] . longitudinal studies of self-regulation show that preschoolers who could wait for two marshmallows instead of eating one immediately had higher educational attainment, lower use of addictive substances, and lower rates of obesity later in life [5] . other studies have found that poor self-regulation in the early years can increase the risk there are several identified risk factors for self-regulation in the literature. for example, lower income remains a consistent predictor of self-regulation skills. some studies suggest that economically disadvantaged children may have access to fewer resources and opportunities to engage in enrichment activities (e.g., dance classes or sports) that promote self-regulation skills [8, 11, 12] . additional research suggests that living in stressful or chaotic environments could impact self-regulation [13] . maternal depression has also been associated with the development of sub-optimal emotion regulation skills in children [14, 15] . mothers with mental health challenges may be less responsive to their children, and may not model appropriate positive social and emotional behaviors [16] . one large population based study in canada found that children of mothers with depression were less able to focus attention [17] . there is little information regarding the impact of maternal anxiety on overall self-regulation, or if the negative association between maternal mental health and self-regulation can be moderated by external factors. gender has also been identified as playing a role in the development of self-regulation. many studies note that self-regulation skills seem to develop later in boys with marked differences emerging in early childhood and persisting through middle childhood, but evidence on moderators is mixed [3, 8, 18] . finally, there is emerging evidence that screen time may impact self-regulation. two large scale studies found that increased television viewing was related to lower self-regulation skills [9, 10] . both of these studies measured screen time simultaneously with self-regulation and used short scales (five or six items) to measure self-regulation. longitudinal studies with robust measures of self-regulation are needed to better understand this association. this study focuses on two potential moderators of the association between risk factors listed above and child self-regulation: group-based childcare and parenting ( figure 1 ). previous studies suggest that childcare is associated with better behavioral outcomes, such as decreased physical aggression, lower hyperactivity, and higher prosocial behavior [17, 19] evidence from australia suggests that participation in childcare improved emotional regulation in children [20] . therefore, while evidence suggests that childcare may be beneficial for distinct elements, there is little evidence looking at the role of childcare at the larger construct of self-regulation. figure 1 . risk factors and potential moderators of self-regulation. risk factors (maternal mental health, lower income, child sex, and screen time) were measured at age 3 (or at birth in the case of child sex). group childcare (at age 3) is hypothesized to moderate the association between maternal mental health or lower income and self-regulation. parenting behaviors (at age 3) are hypothesized to moderate the association between child sex or screen time and self-regulation. previous research has examined the role of childcare as a moderator between low income and academic achievement, suggesting a potential effect on attention and cognitive skills [11, 21] however, it is not known if this moderation extends to other elements of self-regulation. the hypothesis is that childcare provides opportunities for children to interact in a structured environment with skilled providers, which facilitates development of emotional regulation and behavioral control. also, there is evidence that childcare can moderate the negative association between maternal mental health and behavioral control, however, the potential moderating role of childcare for overall self-regulation has yet to be examined [17] . parenting is thought to influence self-regulation through a modeling, interaction, and the emotional environment in the home [22] . parenting behaviors such as high levels of negative reinforcement and low levels of positive interaction are consistently associated with lower emotion regulation and greater behavioral challenges both in cross-sectional and longitudinal studies of children [23] [24] [25] . thus, it is possible that parenting practices may play a role in attenuating or exacerbating the association between male sex or screen time and children's self-regulation. in terms of parenting moderating the association between child sex and self-regulation, data from the longitudinal study of australian children found that harsh parenting did not moderate this association at ages 2 and 3 years [25] . similar results were found from the national longitudinal survey of youth among older children aged 8 and 9 years [23] . however, other studies have shown that boys' emotion regulation and behavior are more susceptible to parenting behavior than girls [26, 27] . previous research has focused on how different parenting practices are associated with increased or decreased screen time in young children [28] . however, there is little information on whether parenting may moderate the association between screen time and self-regulation. for example, the potential negative influence of screen time on children's self-regulatory abilities may be negated by supportive, positive, and engaging parenting. overall the literature points to some clear risk factors for elements of poor self-regulation, including lower income, maternal mental health, child sex, and screen time. however, how these risk factors might be moderated by childcare and parenting is less clear. the purpose of this study is to identify whether modifiable factors (such as childcare and parenting behavior) moderate known risk factors including lower income, maternal mental health and child sex on child self-regulation. specifically, we hypothesized the negative associations between child self-regulation and both lower income and maternal mental health would be moderated by participation in childcare outside the home. we also hypothesized that the associations between child self-regulation and both child sex and screen time would be moderated by parenting behavior. because overall self-regulation is group childcare (at age 3) is hypothesized to moderate the association between maternal mental health or lower income and self-regulation. parenting behaviors (at age 3) are hypothesized to moderate the association between child sex or screen time and self-regulation. previous research has examined the role of childcare as a moderator between low income and academic achievement, suggesting a potential effect on attention and cognitive skills [11, 21] . however, it is not known if this moderation extends to other elements of self-regulation. the hypothesis is that childcare provides opportunities for children to interact in a structured environment with skilled providers, which facilitates development of emotional regulation and behavioral control. also, there is evidence that childcare can moderate the negative association between maternal mental health and behavioral control, however, the potential moderating role of childcare for overall self-regulation has yet to be examined [17] . parenting is thought to influence self-regulation through a modeling, interaction, and the emotional environment in the home [22] . parenting behaviors such as high levels of negative reinforcement and low levels of positive interaction are consistently associated with lower emotion regulation and greater behavioral challenges both in cross-sectional and longitudinal studies of children [23] [24] [25] . thus, it is possible that parenting practices may play a role in attenuating or exacerbating the association between male sex or screen time and children's self-regulation. in terms of parenting moderating the association between child sex and self-regulation, data from the longitudinal study of australian children found that harsh parenting did not moderate this association at ages 2 and 3 years [25] . similar results were found from the national longitudinal survey of youth among older children aged 8 and 9 years [23] . however, other studies have shown that boys' emotion regulation and behavior are more susceptible to parenting behavior than girls [26, 27] . previous research has focused on how different parenting practices are associated with increased or decreased screen time in young children [28] . however, there is little information on whether parenting may moderate the association between screen time and self-regulation. for example, the potential negative influence of screen time on children's self-regulatory abilities may be negated by supportive, positive, and engaging parenting. overall the literature points to some clear risk factors for elements of poor self-regulation, including lower income, maternal mental health, child sex, and screen time. however, how these risk factors might be moderated by childcare and parenting is less clear. the purpose of this study is to identify whether modifiable factors (such as childcare and parenting behavior) moderate known risk factors including lower income, maternal mental health and child sex on child self-regulation. specifically, we hypothesized the negative associations between child self-regulation and both lower income and maternal mental health would be moderated by participation in childcare outside the home. we also hypothesized that the associations between child self-regulation and both child sex and screen time would be moderated by parenting behavior. because overall self-regulation is comprised of emotional, behavioral and attention elements, a secondary purpose was to understand the above associations on any or all elements of self-regulation. this study is a secondary data analysis using data from mothers and children participating in the all our families longitudinal pregnancy cohort (formerly all our babies) [29] . briefly, women who were less than 25 weeks gestation, at least 18 years of age, accessing prenatal care in calgary, and able to complete a questionnaire in english were recruited between may 2008 and may 2011. questionnaires were given out twice during pregnancy, at 4 months postpartum, and at 1, 2, 3, and 5 years. response rates varied between 69% and 99% depending on data wave and eligibility to participate in that time period [29] . the current study focuses on self-regulation in children at age 5. because we were interested in predictors of self-regulation among typically developing children, those with a diagnosed developmental delay (autism, cerebral palsy, etc.) were excluded (n = 26). for the current analysis, we included women who responded to both the three-year and five-year questionnaire (completed in 2015 and 2017; n = 1688), which is a composite response rate of 60% of 2819 eligible participants. we excluded 18 participants with incomplete information on the outcome variable, resulting in a final sample of 1644. see supplementary material figure s1 for study flow chart. this study received ethical approval from the university of calgary conjoint health research ethics board. all subjects gave their informed consent for inclusion before they participated in the study. our study received ethical approval from the conjoint health research ethics board of the university of calgary reb13-0868. the outcome measure was self-regulation skills at age 5, which was measured by parent report on the behavior assessment system for children (basc-2). the basc-2 is a comprehensive behavioral assessment including 134 questions which are summarized into 23 scales. parents rate frequency of behaviors and raw scores are converted to t-scores with mean = 50, standard deviation (sd) = 10. scores between 60 and 69 are considered "at risk" and scores of 70 are "clinically significant". consistent with the theoretical literature, we operationalized poor self-regulation as children who scored "at risk" or above on one or more of the inattention, emotional control, or executive function scales. the inattention scale covered concepts about listening and focusing attention. the emotional control scale included concepts such as losing one's temper and quick mood changes. the executive function scale included a high number of behavior control items such as hitting other children or waiting one's turn. the basc-2 is appropriate for use in the general population, has strong psychometric properties, and the scales correspond to the theoretical literature on how to measure self-regulation [4, 8] . risk factors included income, maternal mental health, child sex, screen time, childcare, and parenting, and were measured at age 3. income was self-reported household income. maternal depression was measured using the 20-item center for epidemiology studies-depression (ces-d) scale. a score of 16 or more is considered clinically relevant and cronbach's alpha in this sample was 0.89 [30] . maternal anxiety was measured using the 20 item speilberger state anxiety scale (ssai). a score of 40 or more considered clinically significant, and cronbach's alpha is this sample was 0.93 [31] . child sex was reported by mothers at birth. screen time was measured by maternal report of how much time they estimated their child spent watching television, movies, or playing videogames per day. responses ranged from less than 1 h to over 5 h and were dichotomized according to national guidelines for this age group (1 h or less compared to more than 1 h per day) [32] . children were considered to be in childcare if they spent more than 10 h a week outside the home in a group-based childcare [21] . parenting was measured using the national longitudinal study of children and youth (nlscy) parenting scales which measure positive parenting (praise and support) and hostile/ineffective parenting (anger and repeated commands). scales showed adequate internal consistency with cronbach's alphas for each scale of 0.75. because parenting scales have no validated cut-offs, we used a 1 standard deviation cut-off to indicate low levels of positive parenting and high levels of hostile/ineffective parenting. control variables included child age in months and maternal age in years. descriptive statistics were provided for all variables. among the 1644 included participants, there was less than 1% missing data on any given variable, thus we conducted a complete case analysis. to understand the components of self-regulation, the number of children scoring at risk on one or more of the inattention, emotional control, or executive function scales was calculated. the children scoring at risk on one, two, or more of each of the scales was depicted graphically. to assess effect modification, interaction terms were created for the following variables: income and childcare, maternal depression and childcare, maternal anxiety and childcare, parenting and child sex, and parenting and screen time. we developed five models to estimate odds ratios (or) and 95% confidence intervals (ci) between risk factors and self-regulation. model 1 estimated odds of poor self-regulation based on scoring "at risk" on one or more of the scales. model 2 estimated odds of poor self-regulation based on scoring "at risk" on all of the scales. models 3, 4, and 5 estimated odds of poor inattention, emotional control, or behavioral control, respectively. non-significant interaction terms (<0.05) were dropped. all models were adjusted for all other variables in the model as well as maternal age in years and child age in months. a sensitivity analysis was conducted to ensure dichotomization did not result in loss of information by running all predictors with continuous values. a robustness analysis was conducted using 20 h of childcare per week. all analyses were completed using stata v.16. descriptive statistics for participants are presented in table 1 . characteristics of poor self-regulation by constituent elements are shown in figure 2 . of the 1644 children, 354 (21.5%) were at risk on any element of poor self-regulation, and only 64 were at risk for all elements (3.9%). thirteen percent of children were at risk for poor emotional self-control (n = 221), 11.0% were at risk of poor behavior control (n = 181), and 10.9% were at risk of inattention (n = 179). among those at risk on at least one scale (n = 354) approximately 54% of children were only at risk on one scale (n = 191), 28% were at risk on two scales (n = 99), and 18% on all three scales (n = 64). the overlap between children with "at risk" levels of inattention, poor emotional control, or poor behavior control can be seen in figure 2 . adjusted odds ratios for any element, all elements, and each element of poor self-regulation can be seen in table 2 . none of the potential moderators were statistically significant, and therefore are not included in the results. increasing income was associated with decreased odds of poor self-regulation in models 1, 3, and 5. maternal mental health at 3 years (depression or anxiety) had consistently elevated point estimates across all models. for models 1, 3, and 5, maternal anxiety at 3 years was associated with increased odds for elements of self-regulation (any, inattention, and behavior control), whereas maternal depression at age 3 was associated with increased odds for being at risk on all elements or on emotional self-control only (models 2 and 4). group childcare did not moderate either of these predictors in any of the models, but was independently associated with increased odds poor self-regulation in model 3 (inattention). male children had increased odds of poor self-regulation across all models, except emotional self-control (model 4). elevated screen time was associated with increased odds of poor self-regulation in model 1 (any element) and model 3 (inattention). neither hostile/ineffective parenting or positive parenting moderated either of these associations. however, high levels of hostile/ineffective parenting were associated with increased odds of poor self-regulation across all models. table s1 with consistent results. in these models, one additional hour of screen time per day is associated with a 1.23 increased odds of any element of poor self-regulation (model 1; 95% ci 1.03, 1.47), and a 1.42 increased odds of inattention (model 3; 95% ci 1.13, 1.79). the robustness analysis increasing the hours in childcare from 10 to 20 per week did not result in any meaningful changes. adjusted odds ratios for any element, all elements, and each element of poor self-regulation can be seen in table 2 . none of the potential moderators were statistically significant, and therefore are not included in the results. increasing income was associated with decreased odds of poor selfregulation in models 1, 3, and 5. maternal mental health at 3 years (depression or anxiety) had consistently elevated point estimates across all models. for models 1, 3, and 5, maternal anxiety at 3 years was associated with increased odds for elements of self-regulation (any, inattention, and aor: adjusted odds ratio-adjusted for all variables in the table and maternal age, maternal education, and child age. ci: confidence interval. original models included the following interaction terms: income*hildcare, maternal anxiety*childcare, maternal depression*childcare, male child*hostile parenting, male child*positive parenting, screen time*hostile parenting, screen time*positive parenting. all interaction terms were dropped because they were not statistically significant (0.05) all statistically significant predictors (at 0.05) are bolded, the * refers to the mathematical symbol for multiplication. our findings revealed that there is considerable overlap between different elements of self-regulation, as measured in the current study, including attention, emotional control, and behavioral control. this is consistent with the theoretical literature [2, 4] and emphasizes that children may have challenges in one or multiple areas, possibly indicating increasing levels of severity of self-regulation challenges. contrary to expectations, neither childcare nor poor parenting moderated the associations between predictors at age 3 (income, maternal mental health, male sex, or screen time) and self-regulation at age 5. maternal mental health (maternal anxiety or depression), male sex, and high levels of ineffective/hostile parenting were consistently associated with elements of poor self-regulation across all models. higher income was generally associated with lower odds of poor self-regulation, whereas participation in childcare and screen time associations varied. consistent with previous studies, our results showed that higher income was associated with decreased odds of poor-self regulation [8, 12, 18] . however, contrary to expectations, participation in childcare did not moderate this association. we posit two possible reasons for this lack of moderation. first, our study measured time in group child care as opposed to quality of child care and quality has been shown to be a better predictor of child outcomes [20] . second, while only 35% of children were in childcare for more than 10 h per week at age 3, by age 5, almost all children were either in group childcare, preschool or kindergarten at least 10 h a week. this may have meant that a possible effect of childcare at age 3 was masked by increasing participation in childcare at the time of the outcome at age 5. our study is consistent with previous studies showing an association between maternal depression and lower emotion regulation in children [14, 15] . our study adds to our understanding of maternal mental health's role by demonstrating a consistent association between maternal anxiety and other elements of self-regulation, including inattention and behavior control. because mental health symptoms often co-occur, it is important to recognize that overall maternal mental health (characterized by either depressive or anxiety symptoms) may be an important predictor of child self-regulation. however different symptoms may operate differently on different aspects of self-regulation with depressive symptoms impacting emotion regulation (model 4) and anxiety symptoms impacting inattention and behavior control (models 3 and 5). there was an unexpected increased odds of inattention at age 5 with participation in childcare at age 3 (model 3) and non-statistically significant elevated odds of childcare influencing behavior control and any or all elements of self-regulation (models 1, 2, and 5). previous work suggests that childcare instability is associate with more hyperactivity and inattention [17] . as noted above, we were not able to account for quality or consistency of childcare which may partially explain this unexpected result. our study adds to the growing literature regarding concerns of excess screen time and child development [33, 34] . our results show a modest, but statistically significant relationship between screen time and problems with any element self-regulation (model 1; adjusted odd ratios (aor): 1.34, 95% ci 1.03, 1.73). this result was consistent whether screen time was categorized according to guidelines (1 h per day), but also showed a dose-response relationship with increasing odds for every additional hour of screen time. our study adds to our understanding of this relationship by showing that the association between screen time and self-regulation is predominantly driven by the association with inattention, as opposed to other elements of self-regulation (aor for inattention: 1.69, 95% ci 1.20, 2.38). although our study did not measure the content of screen time viewing, previous research suggests that entertainment related television content is associated with attentional problems, but not educational content, and that children in this age group are much more likely to watch non-educational content [35] . screen time among children exceeded guidelines before the global covid-19 pandemic, and is expected to increase with physical distancing measures, online learning, and parents working from home [36, 37] . child health advocates caution about increased sedentary behavior and physical health impacts during the pandemic, but more research is needed into possible developmental challenges associated with excess screen time [38] . we found no evidence for moderation of either child sex or screen time by parenting. however, our results are consistent with other cross-sectional studies linking hostile/ineffective parenting as an independent predictor of poor self-regulation [39, 40] . specifically, hostile/ineffective parenting was associated with an adjusted odds ratio of 3.32 (95% ci 2.44, 4.53) of overall poor self-regulation. there was no independent effect of positive parenting on overall poor self-regulation. while the relationship between parenting and child behavior is likely in part bidirectional [41] , our longitudinal results suggest that hostile parenting behaviors as early as age 3 may have harmful effects on the development of self-regulatory skills at age 5. while our study did not control for prior self-regulation, a study by colman et al. noted that parenting practices were still associated with later self-regulation even when controlling for earlier self-regulating skills [23] . our study's strengths include a complex measure of self-regulation as captured by three scales on the basc-2, which reflect the key components of self-regulation including emotional regulation, behavior control, and attention. while direct observation of self-regulation skills by an independent observer would be a gold-standard for measurement, the size of our sample makes direct observation unfeasible. our study had a large sample size and longitudinal design which allowed us to examine risk factors which were measured at a timepoint prior to the outcome. our study also has several limitations. first, we had a high number of non-responders, which resulted in a collective response rate over two waves of data collection at 5 years of 60%. responders were more socioeconomically advantaged (higher income and education) and older than non-responders [29] . this limits the generalizability of our results, and our findings may not be applicable to more disadvantaged groups. as we expect self-regulation challenges to be higher in more disadvantaged groups, this may mean our prevalence of self-regulation skills is underestimated and our associations with predictors to be biased towards the null. however, research from other longitudinal child behavior studies suggests that adjusted analysis minimizes the magnitude of this type of bias [42] . second, measures of maternal mental, parenting, and child behavior were all reported by mothers which could result in reporting bias [43] . however, previous research attempting to quantify reporting bias through multiple observers have found that associations remain after accounting for shared variance [44] . the goal of our study was to assess known risk factors and potential moderators, and we did not attempt to assess potential mediations. future studies could identify potential pathways and mediation mechanism. as our study is a secondary data analysis, we were not able to assess all possible factors. previous research suggests sleep is an important predictor of self-regulation, and future studies should include a measure of sleep [45] . while our findings indicate that multiple factors contribute to the development of self-regulation in early childhood, the most consistent predictors of self-regulation challenges at age 5 were lower income, male sex, and inconsistent/hostile parenting at age 3. we did not find evidence for effect modification in our models. parenting programs based on improving parenting practices that focus on positive relational interactions have been shown to improve child behavior, and can be effective at early ages [46] . with increasing levels of screen time among young children, our findings regarding screen time's negative association with attentional elements of self-regulation warrants additional research. this point is of particular concern among rising screen time due to the covid-19 pandemic. our findings suggest that risk factors for poor self-regulation in children are evident much earlier than school entry and provide an opportunity for early identification of children at risk. the following are available online at http://www.mdpi.com/2227-9067/7/10/186/s1, figure s1 : flow chart for participant enrollment and response rate, table s1 : adjusted odd ratios for poor self-regulation using continuous predictors. the intersection of health and education to address school readiness of all children school readiness and self-regulation: a developmental psychobiological approach self-regulation and academic achievement in the transition to school. in child development at the intersection of emotion and cognition commentary on the review of measures of early childhood social and emotional development: conceptualization, critique, and recommendations willpower'over the life span: decomposing self-regulation the role of emotion regulation in children's early academic success childhood self-control predicts smoking throughout life: evidence from 21,000 cohort study participants investigating correlates of self-regulation in early childhood with a representative sample of english-speaking american families children's media use and self-regulation behavior: longitudinal associations in a nationwide japanese study. matern international journal of obesityself-regulation and household routines at age three and obesity at age eleven: longitudinal analysis of the uk millennium cohort study does higher quality early child care promote low-income children's math and reading achievement in middle childhood? child dev self-regulation and the income-achievement gap intergenerational transmission of self-regulation: a multidisciplinary review and integrative conceptual framework maternal depression and anxiety across the postpartum year and infant social engagement, fear regulation, and stress reactivity early-occurring maternal depression and maternal negativity in predicting young children's emotion regulation and socioemotional difficulties maternal depression and parenting behavior: a meta-analytic review associations among child care, family, and behavior outcomes in a nation-wide sample of preschool-aged children early schooling: the handicap of being poor and male early child care effects on later behavioral outcomes using a canadian nation-wide sample quality of childcare influences children's attentiveness and emotional regulation at school entry modeling the impacts of child care quality on children's preschool cognitive development the role of the family context in the development of emotion regulation early predictors of self-regulation in middle childhood parenting and self-regulation in preschoolers: a meta-analysis. infant child dev the development of prosocial behaviour in early childhood: contributions of early parenting and self-regulation harsh parenting in relation to child emotion regulation and aggression parenting and the development of conduct disorder and hyperactive symptoms in childhood: a prospective longitudinal study from 2 months to 8 years predicting child physical activity and screen time: parental support for physical activity and general parenting styles cohort profile: the all our babies pregnancy cohort (aob) the ces-d scale: a self-report depression scale for research in the general population test manual for the state-trait anxiety inventory american association of pediatrics. media and young minds screen time use in children under 3 years old: a systematic review of correlates increased screen time: implications for early childhood development and behavior associations between content types of early media exposure and subsequent attentional problems prevalence of preschoolers meeting vs exceeding screen time guidelines screen time for children and adolescents during the covid-19 pandemic applying harm reduction principles to address screen time in young children amidst the covid-19 pandemic child routines and self-regulation serially mediate parenting practices and externalizing problems in preschool children marital hostility, hostile parenting, and child aggression: associations from toddlerhood to school age the effect of toddler emotion regulation on maternal emotion socialization: moderation by toddler gender selective drop-out in longitudinal studies and non-biased prediction of behaviour disorders convergent validity of and bias in maternal reports of child emotion concentrations and sources of cadmium, copper, lead and zinc in house dust in christchurch a developmental cascade model of behavioral sleep problems and emotional and attentional self-regulation across early childhood. behav behavioural and cognitive-behavioural group-based parenting programmes for early-onset conduct problems in children aged 3 to 12 years we wish to thank the contribution, time and effort provided by all the participants in the all our babies/all our families study. we also acknowledge the contribution of the staff, students and trainees of the all our babies/all our families team. the authors declare no conflict of interest. key: cord-252970-hnd0653u authors: de nobrega, manoel; opice, renata; lauletta, mariana machado; ayello de nobrega, christiane title: how face masks can affect school performance date: 2020-09-01 journal: int j pediatr otorhinolaryngol doi: 10.1016/j.ijporl.2020.110328 sha: doc_id: 252970 cord_uid: hnd0653u nan speech is the verbal production of language, while language is the basis of communication. language includes receptive language (understanding) and expressive language (the ability to convey information, feelings, thoughts and ideas). the language is commonly thought of in its spoken form, but it can also include a visual form, such as the brazilian sign language (libras) 1 . for verbal communication to be effective, auditory information must be understood by the listener. however, everyday communication often occurs in contexts of acoustic challenges that degrade acoustic information. external sources of acoustic challenge include background noise, competitor speech and even accent speakers 2 . listening to distorted speech is a challenging task that requires the listener to use additional cognitive resources for a successful understanding. the cognitive processes involved in hearing acoustically distorted speech are likely to include verbal work memory and attention-based performance monitoring. therefore, the acoustic challenge is not only an auditory problem, but significantly affects a variety of cognitive operations needed for linguistic and non-linguistic tasks 3 . school-aged children communicate, socialize, and learn in environments with background noise and reverberation 4 . classrooms are often noisy which can hinder the child's ability to listen and learn. excessive background noise and classroom reverberation may affect the educational performance of children with normal hearing that present other learning difficulties 5 . in addition, approximately 11 to 15% of children between 6 and 16 years of age in the united states have auditory loss ≥16 db hl in one or both ears and children with minimal/slight hearing loss represent more than 33% of this population 6 . children with minimal or mild hearing loss may have difficulties in the perception of speech in adverse hearing conditions, as well as delays in speech, language, and socio-emotional development. the academic performance of many of these children is also poorer than for children with hearing at normal levels 6 . the centers for disease control and prevention (cdc) recommends wearing face masks in public environments, when in close contact with people who do not live in your home, especially when other measures of social distance are difficult to maintain 7 . the masks have two serious problems for children: 1) the typical masks (cloth or medical) present a visual barrier to those who rely on non-verbal communication signals on the face (e.g. mouth, lips, teeth, tongue and cheeks); the child is unable to obtain visual cues, hiding the speaker's face and not allowing the lip reading and 2) the voice of the teacher is attenuated and distorted. both linguistic and non-verbal information are important for understanding social communication and interaction. in a timely publication about medical masks, goldin, weinstein, shiman 8 , 2020, reported acoustic degradations where medical masks act as lowpass filters and high frequencies (between 2000-7000 hz) are attenuated by about 3-4 decibel (db) for simple surgical masks and up to 9-12 db for n95 masks. the study by atcherson et al 9 , 2020, presents the maximum reduction of sound pressure level (spl) reduction (in db) of the different mask types as well as each type of mask in conjunction with a standard facial shield when compared to the condition without a mask (table 1) . with small exceptions, the preliminary data of atcherson et al 9 , 2020, closely reflects the results of goldin, weinstein, shiman 8 , 2020, and the presence of the face shield has had a more dramatic effect. on average, the presence of the face shield produced a total reduction by up to 29 db. it also surprises that each of the three transparent masks has mitigated the talk more than the nontransparent masks, and produced an resonant peak between 5000 and 7000 hz. although transparent masks have reduced the level of sound pressure and possibly degraded even more speech than non-transparent facial masks, they play an important role in preserving non-verbal communication slopes on face 9 . the transparent masks used with or without the facial shields help maintain access to the mouth, which can help some listeners with lip reading and other non-verbal clues such as emotion. however, it is also possible that the degradation of speech acoustics will overcome supplementation to speech understanding provided by any transparent windows 9 . the degradation of speech quality, combined with the noise / reverberation of the room and the absence of visual cues, makes speech almost unintelligible for many individuals, especially for children who are in the process of acquiring and developing speech, language, in the process of literacy and acquisition of new knowledge. parents and teachers need to be aware of these changes so that they try to avoid more implications in the academic life of children, already greatly impaired by the removal of the school. to do this, we drew up a list of guidance to help parents and teachers in this pandemic of covid-19: • awareness the parents about how facial masks, associated or not to the face shield, can harm the intensity and quality of speech and how much this can impact on the school performance of their children. • be aware of your children's daily school performance. • report what was given in class to certify the correct school understanding. • talk to children about the day at school and about the difficulties they may have • observe behavior changes that may indicate school difficulties. • speak slowly and articulate. • use features and visual support and images in the activities. • reduce environmental noise and keep the child's attention before speaking. • consider using a portable microphone. • the teacher should ask the child to repeat the instructions received, making sure that the child has really understood. • repeat the instructions or rephrase your speech if the child is not understanding what is being requested. • do not speak loudly, do not overemphasize, or exaggerate your words. • do not talk to the child while walking; always make eye contact. • avoid using flashy masks as they can compete for the child's attention, dispersing the listener's focus. • speak slowly and articulate. • use features and visual support and images in the activities. • reduce environmental noise and keep the child's attention before speaking. • consider using a portable microphone. • the teacher should ask the child to repeat the instructions received, making sure that the child has really understood. • repeat the instructions or rephrase your speech if the child is not understanding what is being requested. • do not speak loudly, do not overemphasize, or exaggerate your words. • do not talk to the child while walking; always make eye contact. • avoid using flashy masks as they can compete for the child's attention, identifying and managing common childhood language and speech impairments listening effort and accented speech listening effort: how the cognitive consequences of acoustic challenge are reflected in brain and behavior acoustical barriers to learning: children at risk in every classroom background noise levels and reverberation times in unoccupied classrooms: predictions and measurements effect of minimal/mild hearing loss on children's speech understanding in a simulated classroom advice on the use of masks in the context of covid-19. interim guidance. geneva: world health organization how do medical masks degrade speech perception? hearing review more speech degradations and considerations in the search for transparent face coverings during the covid-19 pandemic. online feature all authors actively participated in the writing of this text, having an equal share of contributions. key: cord-254235-mok10c5i authors: cooper, dan m.; guay-woodford, lisa; blazar, bruce r.; bowman, scott; byington, carrie l.; dome, jeffrey; forthal, donald; konstan, michael w.; kuppermann, nathan; liem, robert i.; ochoa, eduardo r.; pollock, brad h.; price, olga acosta; ramsey, bonnie w.; ross, lainie friedman; sokol, ronald j.; wright, rosalind j. title: re-opening schools safely: the case for collaboration, constructive disruption of pre-covid expectations, and creative solutions date: 2020-05-21 journal: j pediatr doi: 10.1016/j.jpeds.2020.05.022 sha: doc_id: 254235 cord_uid: mok10c5i nan in the us, 40% of families have school-aged children and in more than 90% of these households, at least one parent is employed outside the home. schools play an important role in these working families. 1 yet schools have been closed for approximately 2 months in an effort to curb the covid-19 pandemic and closing has had a profound influence on family health and wellbeing. when and how should they reopen? we approach these questions with limited data and past epidemics provide little guidance for covid-19. 2 but, we know this: schools will reopen. their closure is too burdensome on parents, communities, and the economy. simply put, we cannot fully re-open society without re-opening schools. this requires that children will be part of the first wave to re-emerge from shelter-in-place policies. with fast-approaching preparations required for a new school year, a collaborative team of clinicians, scientists, and educators developed this commentary to begin to highlight issues that must be considered to ensure a safe and strategically planned re-opening of schools. the american academy of pediatrics also has recently posted considerations important to the re-opening of schools. 3 in the u.s., in an urgent attempt to curb spread of sars-cov-2 and save lives, the nationwide closure of k-12 schools occured rapidly. planning for schools re-opening must be more deliberate, delineating precisely how, when, under what conditions, and base the reopening on available data. school re-opening can mitigate risks to children, families, and school personnel only if it is sensitive to community needs. models such as the cdc's whole school, whole community, whole child 4 and the school health index 5 can provide a helpful framework. systematic review of the early chinese experience reveals that patients younger than 19 years accounted for only 2.2% of 44,672 confirmed cases. although severe covid-19 is uncommon in children 6 , a picture of critically ill children in the u.s. is emerging, with up to 22% having no underlying medical condition and the medical conditions of others seemingly varying by communities served. [7] [8] [9] furthermore, without more community-based data, we don't know whether most children actually evade infection, or if infected, largely are asymptomatic. this uncertainty is dangerous. in children, who frequently require hands-on care, asymptomatic infection may pose a greater risk to susceptible individuals than might exposure to an asymptomatic adult. in addition, current data indicate that children and adults have different infection outcomes. possible mechanisms include changes in innate and adaptive immune responses with maturation, pediatric vaccinations or common infections that stimulate protective innate responses in children or conversely, previous infections with common uri coronaviruses that stimulate deleterious acquired responses in adults, and differences in virus binding and infectivity of host epithelial cells. though sars-cov-2 community surveillance testing has yet to be standardized, large scale viral nucleic acid and serological testing in children is needed to guide safe school reopening. this testing approach will require activation of non-traditional testing sites, such as homes, schools and "child-friendly" self-collection methods. testing capability is only the first step. the second is understanding the test results in the appropriate context. as large-scale testing is implemented, care must be taken to ensure that these test results are interpreted and communicated appropriately so as to inform, empower, and protect families, school personnel, and communities. the safe re-opening of schools also demands sensitivity to community inequities. all schools present unique challenges for mitigation strategies commonly implemented in the rest of society, eg, physical distancing, face coverings, and good hygiene practice. in addition, many school systems face additional challenges related to food security, safe transportation, healthcare safety nets, and emergency preparedness policies, which also often are within their purview. these interventions will be more difficult for resource-constrained title 1 schools, which often are situated in low-income and minority neighborhoods. how do we recover from the psychological, medical, and economic damage resulting from school closures? schools are a bedrock of the american social network, providing not only education, but also nutritional support, healthcare and social services. the response to pandemicrelated challenges will require augmenting existing school-based programs. the pandemic has impacted students' access to and relationships with healthcare providers, with many children needing more behavioral and medical care services. as schools re-open, school-based health centers should be expanded. these centers improve student health and educational outcomes and reduce healthcare disparities among vulnerable student populations, while providing demonstrable cost savings. 10 in addition, federally assisted school-based meal programs annually benefit nearly 30 million children. 11 student eligibility for these programs, meal distribution practices, and food safety standards must be reviewed and adjusted to meet the unprecedented circumstances. consideration must be given to the availability of these programs to student caregivers and parents, more of whom are unemployed with each passing week. finally, schools and communities must support teachers and staff returning to school. concerns and stress among schoolstaff may exacerbate already high rates of teacher turnover that disproportionately affect students attending under-resourced schools. greater school instability could undermine safe school re-opening. children with chronic conditions will be especially vulnerable during this return to school. although covid-19 symptoms are mild in most otherwise healthy children, we cannot assume that the estimated 10-15% of children with chronic diseases will be similarly resilient. children with underlying neurologic conditions and medical complexity have been among those severely affected in the u.s. [7] [8] [9] early data from italy 12 suggest that most patients with cystic fibrosis in community settings generally may be avoiding covid-19 infection through physical distancing. whether this effect can be achieved in schools remains unknown. some data suggest that children with cancer have not had severe morbidity with covid-19, 13 however this experience is not universal, 9 and the full effect of immunocompromising therapies on covid-19 risk and severity has yet to be determined. in addition, concern about covid-19 transmission could present a disproportionate barrier to school re-entry for children with cystic fibrosis or asthma who frequently have chronic, often productive cough. acute chest syndrome in children with sickle cell disease may be difficult to distinguish from covid-19 related lung disease 14 . under current conditions of increased sensitivity to possible covid-19 symptomatology, children with these chronic health disorders risk being socially shunned and unnecessarily removed from school. more research is needed to understand the risks that all children, including those with chronic conditions, may encounter in school settings in the covid-19 era. even as we curtail physical contact, we must not reflexively abandon after-school activities and physical education. this would exacerbate the more slow-moving pandemic of childhood physical inactivity and obesity, while also denying the physical and mental health enriching benefits of extracurricular activities. early-life physical activity is beneficial for child health and health across the lifespan, and physical fitness in children is associated with improved school learning. conversely, the lack of participation of adolescents in pe classes is associated with social isolation and loneliness. of note, obesity is a serious complicating comorbidity of the covid-19 pandemic in adults 15 . data preceding the pandemic indicate that obese children admitted to pediatric intensive care units required more invasive therapeutic interventions than non-obese children. 16 preparations for school reopening should include novel approaches to pe, structured recesses, and access to safe after-school activities. finally, we must recognize that re-opening schools raises a number of ethical issues, including safety, privacy, autonomy, vulnerability, proportionality, and health disparities, that impact children and their families, as well as teachers, staff, and administrators. parents and caregivers, as well as viral surveillance and contact tracing teams likely will require more frequent monitoring of the school environment. these activities will influence costs, the educational dynamic in the classroom, risks related to privacy, and the autonomy of older children and adolescents. if wearable devices or smartphones are deployed to collect health information, who will be required to seek and provide consent and at what age will children be asked to assent? what will happen if a child or caregiver refuses to comply with surveillance programs? how do long-standing issues with immigration status and health disparities influence the effective implementation of school reopening plans? in the u.s., states made rapid decisions to shutter k-12 schools in response to the pandemic. public safety dictated this haste, but safe school re-opening must be more deliberate and carefully planned. re-opening inherently carries risk and solutions that will be disruptive may need to be considered (e.g. staggered start times). it is clear that healthy school re-opening strategies will require creativity and considerable monetary investment to obtain unique pediatric data on symptoms and the dynamics of virus shedding, the ability to test for the presence of serum antibody and to understand its meaning,as well as the capability to perform contact tracing in real time related to inevitable exposures. new educational strategies must be developed, and the generally inadequate allocation of school nurses will need to be reconsidered. school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review whole child model: a new approach for improving educational attainment and healthy development for students shi | school health index | healthy schools | cdc clinical characteristics and diagnostic challenges of pediatric covid-19: a systematic review and meta-analysis severe covid-19 in children and young adults in the washington, dc metropolitan region clinical characteristics and outcomes of hospitalized and critically ill children and adolescents with coronavirus disease (covid-19) at a tertiary care medical center characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units. jama pediatr school-based health centers in an era of health care reform: building on history impact of covid-19 on people with cystic fibrosis flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment covid 19 infection in patients with sickle cell disease covid 19 and obesity. clin obes outcomes and resource use among overweight and obese children with sepsis in the pediatric intensive care unit the community at large will need to view schools as "healthy places" for children and society. this could be accomplished by building public health-focused collaboratives capable of continuous learning and rapid cycles of implementation, as covid-19 information evolves at breakneck speed. otherwise, we risk further compounding the incalculable damage already incurred by covid-19 among children across our country and the world. key: cord-033828-a54virh0 authors: wallace, rebecca; goodyear-grant, elizabeth title: news coverage of child care during covid-19: where are women and gender? date: 2020-08-13 journal: nan doi: 10.1017/s1743923x20000598 sha: doc_id: 33828 cord_uid: a54virh0 research has long observed the absence of gender in child care policy, media, and elections. however, the covid-19 pandemic has invoked critical questions about child care and its importance to states’ economic recoveries around the world. in this research note, we analyze news coverage of child care in major canadian daily newspapers to explore whether and how news narratives regarding child care are shifting in light of the covid-19 pandemic. in particular, are we seeing a focus on women and gender in child care coverage amid the compounding pressures that women face in the current social and economic climate? the results of our analysis suggest that the pandemic has not shifted the conversation on child care and that current coverage principally reflects long-standing trends in child care framing. we find that gender remains systematically written out of coverage of child care, occluded by a larger focus on health-, economic-, and accessibility-related concerns about child care services. 1. we analyze coverage of care arrangements for preschool-aged children. of course, child care or care for children encompasses more than this and includes school-aged children, especially during covid-19, when children were not in school in most jurisdictions and were doing or attempting remote schooling in many cases. our analyses only relate to coverage of child care for preschoolaged children. albanese et al. 2010; collier 2012; jenson 2009 jenson , 2012 naumann 2012; wallace and goodyear-grant 2020) despite the issue's centrality to women's success and gender equality. public debate about child care tends to focus on families and early childhood development, informed by a pro-employment social investment perspective on social policy (e.g., collier 2012; jenson 2012; naumann 2012) . even civil society groups working in the area have moved away from gender or feminist framing (collier 2012) , decentering womendistinct from parents generallyas important clients of the child care system. the covid-19 pandemic, however, has created conditions favorable to taking women and gender more seriously in the child care discussion. globally, schools and child care facilities have been closed or their operations have been significantly reduced for months, starting in mid-march 2020 in canada. unsurprisingly, data suggest that women are handling a disproportionate share of the additional work of child care and homeschooling, 2 widening existing gender gaps in the workplace and the home. at the same time, more men than ever have experienced the difficulties of managing work and child care, whether working inside or outside the home, perhaps sensitizing them to the daily gendered dimensions of working parenthood. labor force data also reveal that covid-19-related job losses have been borne disproportionately by women, and economists insist that "there will be no recovery without a she-covery; no she-covery without child care." 3 there has been a genuine acknowledgment of the pandemic's disproportionate effects on women, so the question we tackle in this article is whether women and gender have been central to news coverage of child care, which is an essential service for women's resumption of their regular work activities. in this research note, we examine print news coverage in canada from march 1 to may 31, 2020, to address the question. overall, we find similar patterns to pre-covid-19 studies, with very little focus on women or gender (e.g., albanese et al. 2010; wallace and goodyear-grant 2020) . despite widespread knowledge of the pandemic's gendered effects, news coverage of child care in canada during the first three months of covid-19 restrictions has been largely ungendered, with health, economic issues, and accessibility dominating coverage, similar to before the pandemic. to analyze news coverage of child care during the pandemic, we drew a sample of english-language news articles from the canadian major dailies database from march 1 to may 31, 2020. 4 articles included in the sample contained a relevant child care keyword in the article headline ("child care," "childcare," "daycare*," "day care*," "pre-school*," "preschool*," or "nursery school*") combined with "covid," "coronavirus," or "pandemic" anywhere in the text. our goal was to examine news coverage that focused substantively on the issue of child care, offering an opportunity to closely examine the core themes that have emerged on this critical public policy issue during the pandemic. moreover, the time frame under study captures the beginning of closures of child care facilities, schools, and nonessential services across the provinces of canada, as well as the initial stages of reopening in the regions. this allows us to examine the trajectory of discussions about child care over several weeks of the pandemic and to track how different dimensions of the issue shifted or changed in salience over time and in response to coinciding events, outbreaks, or policy changes. after removing duplicate articles, the search yielded a total of 247 news articles from 18 newspapers in canada. using computer-assisted content analysis techniques (see the appendix in the supplementary material for descriptions), we identified four key dimensions of child care in the news sample: 2. economic concerns: coverage of child care as it relates to the function of the canadian economy. 3. accessibility concerns: coverage related to maintaining child care spaces in light of the pandemic, particularly with the (temporary or permanent) closure of licensed facilities. 4. gendered concerns: coverage related to gendered aspects of child care, including the disproportionate burden of care that women have incurred throughout the pandemic. next, we describe news coverage of child care over the period, specifically analyzing the frequency of the four dimensions of care in the sample, including any shifts in framing associated with the journalist's sex or the date of coverage. table 1 displays the frequency of frame mentions in the coverage. perhaps not surprisingly, we find that the most prominent dimension of coverage that emerges during the pandemic is health-related concerns. descriptions of health risksand steps that facilities are taking to mitigate themwere raised at least once in 96% of the articles included in the study, suggesting it is a critical component of current debates about the closure and reopening of child care facilities in canada. evident in figure 1 , the health dimension was prominent in the early weeks of march amid the closure of care facilities to limit the spread of the virus. the narrative evolved over the ensuing weeks to explore the challenges of operating child care facilities for children of frontline workers and rose again in the final weeks of april and may amid discussions about safety measures in day care facilities to prevent the spread of covid-19 upon reopening. economic concerns represent the next most prominent theme in coverage of child care during the pandemic. the importance of child care to canada's economic recovery was raised in 72% of articles in the sample, particularly from the final weeks of april onward (figure 1 , p < .001), as several provinces announced their plans for "reopening" the economy. these articles generally discussed the economic fallout from the pandemic and the measures governments have taken to support families and child care businesses to ensure that they are able to reopen in the ensuing phases of the recovery. closely linked with the economic dimension are concerns about the accessibility of child care. this dimension refers to the availability of child care, including whether the number of spaces will decline as a result of new distancing and cleaning protocols, as well as how many child care centres will close as a result of economic hardship brought by extended closure or higher operation costs upon reopening. issues pertaining to the costs and availability of child careespecially amid the closure of many licensed facilities across canadawere discussed consistently throughout the pandemic thus far, mentioned at least once in 58% of the articles in the sample. consistent with previous research in the field, the gender dimension of child care was the least prominent frame in the sample, referenced in only 20% of articles. this means that four out of every five articles on child care did not even mentionlet alone carefully analyzewomen in the context of the implications of child care policy. the gender frame most commonly emerges in coverage focused on economic recovery, where often little more than a single mention of women emerges in the context of discussing the caretaking challenges that parents are experiencing during the pandemic. for example, three articles quoted conservative party leadership candidate erin o'toole, stating, "far more women than men have lost their jobs, a reflection of how hard the hospitality, service and retail sectors have been hit . . . with schools and daycares closed, many workers with kidsparticularly womenwonder how they will be able to get back to work" (platt 2020) . this notion that women are "especially" or "particularly" hard hit by the current crisis as mentioned in 14% of the articles in the sample, which did not further explore women's experiences with balancing care and work responsibilities or how gendered care imbalances affect women's economic success, personal well-being, or, indeed, the covid-19 economic recovery itself. only 6% of the articles in the sample substantively discussed genderedrelated issues regarding care work, referring to women or gender more than twice in an article. these articles highlighted the challenges that many women have faced in balancing their time between paid work and caregiving work, as well as the implications this could have on women's productivity and career advancement in the future. as one article described, "time away from work might mean not getting promotions or building up work hours associated with career advancement. as well, staying home means not paying into a pension plan or employment insurance, including maternity and paternity leave" (taylor 2020 ). the coverage of child care during the pandemic also remains silent on a multitude of gender-based inequalitiessocial and economicthat mothers face in taking on a larger proportion of child care work. for example, only 2% of articles in the sample acknowledged issues related to equal pay and the wage gap. many women also face additional demands in terms of caring for seniors, which were mentioned in 1% of the articles. further still, discussions of single mothers remain absent from the conversation on child care, similarly featured in 1% of the articles in the sample. domestic violence, which has been on the rise since the beginning of quarantine in canada (illesinghe 2020) and is integrally linked to familial care, is mentioned in fewer than 4% of articles. in effect, it seems the gendered issues related to child care during the pandemic have most frequently been conceptualized in relation to canada's economic recovery, with little substantive focus on the diverse experiences, challenges, and barriers that mothers continue to face. as figure 1 reflects, while the other child care frames show shifts in frequencies over the timeline, gender framing did not see any marked variation throughout the time period under study. gender and women, it seems, were background, low-salience features of public discourse on child care during the early stages of the pandemic shutdown and early phases of "reopening." moreover, consistent with our previous research on the framing of child benefits (wallace and goodyear-grant 2020), we also find that women journalists are more inclined than their male colleagues to speak about gender in coverage of child care ( p < .001). although there is relative parity in stories written by male and female journalists, 5 women journalists account for 80% of the gendered mentions in the sample, while male journalists account for a mere 20%. while this may be unintentionaland perhaps even a product of editorial teams' decisions to have women journalists write about women's issuesit suggests that we need to further explore the ways that women's representation may matter when it comes to ensuring that gendered perspectives are on the table in child care policy debates during covid-19 recovery efforts. around the world, child care policy and practice have critical gender-related dimensions. accessible, affordable child care is a necessary ingredient for women's equality, especially in the context of economic and social recovery from covid-19. our analyses suggest that the media information environment has not engaged sufficiently with these realities and may be contributing to the neglect of women and gender in this policy area, the normalization of gender-related care imbalances, and the removal of these challenges from the public eye and public accountability. to view supplementary material for this article, please visit https://doi.org/ 10.1017/s1743923x20000598 rebecca wallace is a sshrc postdoctoral fellow at the university of toronto: r.wallace@queensu.ca; elizabeth goodyear-grant is associate professor of political studies at queen's university and director of the canadian opinion research archive: egg@queensu.ca 5. women journalists wrote 90 articles in the sample (53% of stories included in the journalist gender analyses), while male journalists wrote 80 (47%). hiding the elephant: child care coverage in four daily newspapers feminist and gender-neutral frames in contemporary child-care and anti-violence policy debates in canada pandemic exposes existing link between isolation and domestic violence writing gender out: the continuing effects of the social investment perspective childcare politics in the 'new' welfare state: class, religion, and gender in the shaping of political agendas o'toole promises increased childcare support pandemic spurs child-care questions writing gender out or working it back in? media coverage of child benefits in canada key: cord-018604-ua5h47jg authors: dersch-mills, deonne title: assessment considerations in pediatric patients date: 2018-12-28 journal: patient assessment in clinical pharmacy doi: 10.1007/978-3-030-11775-7_28 sha: doc_id: 18604 cord_uid: ua5h47jg pharmacy assessment of pediatric patients is similar in many ways to that of adults; however there are many specific nuances that need to be considered in addition to the typical aspects included in an adult assessment. there is a lack of pediatric-specific medication research and a much higher rate of “off label” medication use, so children are at higher risk of medication errors and related harm. pharmacokinetic differences and other age-related differences result in highly variable responses to medications throughout childhood. pharmacists need to be aware of this variability and use every patient encounter as an opportunity for assessment of many aspects of medication including dose, formulation, administration, and indication. infants and children also have physiological differences that need to be considered especially when assessing efficacy, toxicity, and the patient’s overall response to medications through physical exam or use of laboratory values. lastly, a lack of appropriate medication formulations for children creates a requirement for pharmacists to specifically assess the formulations, measurement, and administration of pediatric medications. this chapter provides an approach to pediatric assessment, highlights common sources of error, and provides strategies for managing pediatric medications. pediatric pharmacy technically includes the care of any patient under the age of 18 years, although practically patients over the age of 15 can usually be cared for following similar dosing/monitoring as in adults. in canada in 2017, children under 12 years comprised ~15% of the canadian population (statistics canada, population by sex and age group 2017), and accounted for 6.4% of hospital discharges (~3% not including births in hospital) [1] . approximately 50% of canadian children receive one or more medications each year; this is up to 79% in infants <1 year old [2, 3] . while medication use is not uncommon, polypharmacy is much less common than in adult patients. around 20% of us children received at least one medication in the previous week, but less than 6% had used two or more medications in the previous week [4, 5] . the most common medications filled for children in community pharmacies in 2012 included antibiotics (amoxicillin, azithromycin, and cefprozil most commonly), asthma medications (salbutamol, fluticasone, montelukast), and medications for attention deficit hyperactivity disorder (adhd) (methylphenidate primarily) [2] . before moving forward, it is important for pharmacists to understand age-related terminology for children. gestational age (ga) is the duration of time a newborn has been in utero (full term is considered ~40 weeks) while post-natal age (pna), also known as chronological age (ca), is the duration of time since birth (e.g., 2 weeks old). corrected gestational age (cga) or post-menstrual age (pma) are terms used most commonly in infants born prematurely, and refer to their gestational age plus post-natal age. for instance, a baby born at 30 weeks ga, with a pna/ca of 10 days would have a cga/pma of 31 weeks and 3 days (commonly abbreviated as 31 + 3 weeks). a neonate (or newborn) is an infant <28 days pna/ca, or for premature infants, less than 44 weeks cga/pma. the term "infant" typically refers to a range of pna/ca from 28 days to 1 year. the term "toddler" typically refers to age 1-3 years, and "school-age" refers to age from 4 to 9 years. "adolescent" typically refers to age 10-19 years, though the true onset of adolescence is determined by the onset of puberty. these distinctions are important due to developmental changes that occur in pharmacokinetics (see more below). there is a distinct lack of research on medication use in children, which adds its own challenges to the practice of pharmacy in children. up to 90% of medication use in hospitalized children and 30% of medication use in ambulatory children are considered "off-label," that is, not included in the product labeling/monograph and thus not supported by the manufacturer [2] . only 25% of medications on the market are approved for children, and this number is even less for infants [6] . this results in a lack of detailed pharmacokinetic, dosing, adverse effect, and efficacy data for appropriate medication management in children. as well, due to the lack of studied indications in children, there is little impetus for manufacturers to make formulations appropriate for children and so formulation issues related to availability, palatability, excipients, or measurability are commonplace. due to the abovementioned factors, children are at higher risk of medication errors and have a higher risk of harm from medication errors, so the pharmacist plays an important role in caring for infants and children who use medications [7] . approximately 8% of pediatric emergency department visits are medication-related, of which 2/3 are deemed preventable (examples include adverse drug reactions, sub-therapeutic doses, or non-adherence due to a variety of factors) [8] . there are an estimated 0.85 adverse drug reactions per 100 inpatient admissions in pediatrics, of which 21% would be considered preventable [9] . statistics like this highlight the importance of a complete pharmacist assessment for children using medications. in many ways, assessment of a pediatric patient is not different than assessment of an adult patient. pharmacists should gather information on medical history, medication history, medical conditions, and any other relevant information, and then ensure that all medications are indicated, dosed appropriately, effective, safe, and adhered to. however, each of these steps contains nuances for infants and children. there may be additional steps within each component of the assessment, and there is a significantly smaller evidence base to support decisions and judgment calls made within each step of the assessment. one of the major nuances between pediatric and adult assessments is the need to consider pharmacokinetic ontogeny, or pharmacokinetic differences based on the age of the child. while it is not surprising that there are pharmacokinetic differences between children and adults, there are also important differences between premature newborns, term newborns, infants, toddlers, schoolage children, and adolescents. table 28 .1 provides a summary of major pharmacokinetic considerations in infants and children. this variability in pharmacokinetics makes dosing medications in children especially challenging as there is no "standard" dose of a medication. medication doses may vary based on cga, pna, as well as body weight or surface area. most notable is the need to use neonatal (not pediatric) dosing in newborns as the first few months of life are characterized by rapidly changing organ function (renal and hepatic most importantly) as well as changes in drugs' volume of distribution. typically, newborns are characterized by reduced renal and hepatic clearance at birth (especially with premature birth), which develops rapidly in the first month of life and reaches adult values at 6 months to 1 year of age. childhood is typically characterized by excellent renal and hepatic clearance, even exceeding that of adults in some cases. normal clearance values approach that of adults around adolescence. this is an oversimplification, given that different aspects of renal and hepatic clearance develop at different rates. full reviews of pharmacokinetic differences in children can be found in kearns et al. [10] and bartelink et al. [11] . by selecting age-appropriate doses, the pharmacokinetic differences that occur throughout childhood are taken into account. all pharmacists should ensure that medication doses in children are age and/or weight appropriate by consulting neonatal and/or pediatric dosing references with each and every prescription. in pediatric practice, the gathering of patient history is often not done with the patient themselves. until children are mature enough to provide this information themselves (note that this age varies depending on the child), parents and other caregivers are relied upon to provide an accurate history of the patient's illness(s) and medication(s). this provides an extra challenge to history gathering as the most appropriate person may not be available to provide this history, depending on the circumstances of the child's illness. changing custody or living arrangements may impact a caregiver's ability to provide a history, or one parent may be "in charge" of the medical care of the child and another caregiver might happen to be the one present at the time of pharmacists' information gathering. additionally, information related to symptoms of illness will not be provided first-hand, but rely on observations made by the caregiver. this introduces a source of potential inaccuracy or missing information that is not as commonly encountered when patients provide their own history. while medical histories of children tend to be shorter than that of adults, this is not always the case and many pediatric patients may have long medical histories before they reach school age. gathering this information is not different than gathering it for adult patients using a combination of patient (caregiver) history corroborated by medical records. an important difference to note is that in infants (especially those in the first 3 months of life), maternal pregnancy and delivery history is relevant and should be gathered wherever possible as well. maternal conditions during pregnancy and the circumstances of delivery may be very relevant to an infant's medical care. for instance, a mother using methadone for a substance abuse condition may result in her infant developing signs and symptoms of withdrawal several days after discharge home. likewise, whether or not a mother received intrapartum prophylactic antibiotics is directly related to the infant's risk of group b streptococcus infection in the newborn period. very few medications are contraindicated in breastfeeding, but knowing if an infant is receiving even small amounts of medications via breastmilk may be relevant if concerns arise regarding a potential drug interactions or adverse effect. as with medical history, medication histories are often shorter in duration and length in children as compared to adults. again, there are exceptions to this in children with complex medical needs. all relevant details collected for adult medical histories should be collected for pediatric patients, with some additional factors to consider. many pediatric medications do not come from the manufacturer in appropriate formulations for administration to children, and thus asking about the formulation is an important step in pediatric medication history. extemporaneously compounded liquids are especially risky for creating confusion, as often caregivers know the volume they provide to the child but not the concentrations. if there are multiple concentrations available due to variability in the "recipe" followed by the pharmacy during compounding, this can lead to dose errors and subsequent sequelae (see box 28.1 for an example). if there are any questions regarding the strength of a formulation or volume given, call the pharmacy that provided the previous fill and clarify what was provided. medications in tablet form (except many sustained or controlled release formulations) may be crushed or dissolved for ease of administration and the appropriateness of this practice should be assessed by the pharmacist depending on the size of the tablet, ease of splitting, and the possibility of alternate dosing intervals (e.g., a daily dose of asa 20 mg can be delivered as a half tablet [40 mg] every other day instead of a quarter tablet [20 mg] every day). some medications may be given in a "dissolve-adose" manner, whereby a tablet is crushed and suspended in a small amount of liquid, then the dose is measured from the resulting suspension. certainly, accurate dosing in this situation relies on appropriate suspension of the tablet, and this should be considered when doing an assessment of the patient's dose/response. there is no commercially available clonidine oral liquid on the market, so it is commonly compounded by pharmacies for use in infants and children who cannot swallow tablets or who require very small doses. a 10-kg child named colin is discharged from a hospital with a prescription for clonidine 50 micrograms po q6h. his parents fill the prescription at the outpatient even with commercially available appropriate formulations, administration of pediatric medications can be especially challenging. literature shows that measurement errors are common in caregivers of children and so observing the caregivers measure (and administer if appropriate) the medications may provide insight into dosing appropriateness [12] . considerations regarding the measurement device should also be made. household teaspoons are not appropriate for measuring medications, and even some medication syringes do not have appropriate markings for accurate measurement of small doses. ensuring an appropriate measuring device is an important part of a pharmacist's assessment of dosing accuracy ( fig. 28.1) . likewise, how a caregiver gives the medication to the child may be relevant. medications mixed in a small amount of food/milk immediately prior to administration is appropriate, but if it is mixed in a large amount that the child does not consume all of, the dose taken will not be correct. medications given on an "empty stomach" or to be avoided with dairy products are not likely to be given according to these restrictions in new-born infants who typically feed every 3-4 hours. in these cases, the medication may be given with feeds (formula or breastmilk) for ease of administration, but a slightly higher dose may need to be used empirically, or the dose may be titrated up based on monitoring parameters (e.g., levothyroxine based on tsh). if this occurs, the administration conditions should be kept consistent for the individual patient, even if "manufacturer recommendations" suggest otherwise. parents and caregivers may ask if it is appropriate to mix all of a child's medications together in one syringe/cup prior to administration. this practice should ideally be discouraged as it may contribute to inaccurate measurement, potential incompatibilities, and will present challenges with re-dosing or estimating the portion of dosages consumed if only part of the "mixture" is taken/ spit-up. other things to consider in the medication history of infants and children include medication storage, timing, and palatability. depending on the frequency of administration of a medication and the child's schedule (school, activities), mediation may not always be stored in an ideal manner. medications may have to go to the soccer field or to the day home, for instance, and storage conditions may be affected during transitions. the timing of medications may be impacted by adults' schedules or bedtimes. for instance, if a medication is meant to be given every 6 hours around the clock, it may have to be given four pharmacy within the hospital on their way home. the outpatient pharmacy provides them with 500 ml of 10 micrograms/ml compounded clonidine suspension with instructions to take 5 ml four times a day. colin's parents go to their neighborhood pharmacy for the next refill. that pharmacy only has a recipe for clonidine 100 micrograms/ml oral liquid and so fills the prescription with that suspension (with instructions to give 0.5 ml four times a day). at home colin's parents are used to giving 5 ml four times daily and so continue to do so. in a couple of days, colin is acting lethargic and weak. his parents take him to the nearest emergency department and while they are reviewing the medications with the team, the pharmacist there discovers the error -a 10 times overdose of clonidine. times daily (qid) instead to accommodate bedtimes. lastly, an assessment of the palatability of the medication formulation and the caregiver's report of how often the child takes/receives their full dose should be completed. these types of issues will be further explored in the section on adherence assessment. like in the adult setting, "is this therapy indicated?" is an important question to be assessed by the pharmacist. due to the relative lack of studies in pediatric patients, often medications that do not have an official indication in pediatrics are used (pediatric use is not included in the product monograph). because of the lack of appropriate information in the product labeling, alternative data sources need to be accessed to assess the use of the medication in an infant or child. pediatric medication information sources should be available and reviewed to aid in this part of the assessment, but primary literature may also have to be consulted more often than in adults. assessing whether or not an agent is "firstline" or "ideal" for a child includes special considerations that may not be as necessary in adult patients. an agent may be selected not because it has the best data to support it, but because it is the only agent with pediatric dosing information, or because it is the only one with a formulation appropriate for the age group (or it has the best tasting formulation). a medication may be selected because it has a less frequent administration schedule, accommodating a child's school or activity schedule, or to limit the number of dosage times due to unpleasantness of administration (e.g., bad taste or painful injection). in this sense, assessment of whether or not a medication is the most appropriate choice for the patient is increasingly challenging. because of differences in pathophysiology or pharmacodynamics in pediatric patients as compared to adults, an "appropriate" or "ideal" medication choice in adults may be quite different in pediatrics. likely pathogens in bacterial infec-tions differ between age groups, the causes of thrombosis or hypertension are very different in children as compared to adults, and systemic steroids can have very different safety profiles depending on the age of the child. for this reason, complete assessment of whether or not a medication is "indicated" for a child requires much more in depth look into references than for a typical adult patient. pediatric or neonatal guidelines, reviews, studies, and other literature need to be consulted for this component of the assessment. one cannot rely on what is appropriate in adult patients to be appropriate in newborns, infants, or children. as alluded to above, comprehensive dose assessment in pediatric patients requires several more steps than in adult patients. first, the pharmacist needs to determine how the medication dose is characterized: by gestational age (in newborns), post-natal age, by body weight, by body surface area, or some combination of the above. once that is determined, the pharmacist must gather the needed information to categorize the patient into the appropriate dosing range using a pediatric dosing reference. a common error is to use pediatric doses for neonates; therefore, the age of infants needs to be confirmed. in addition to selection of the appropriate dosing category, the pharmacist must also ensure that the appropriate dose for the indication in question is considered. doses for medications can vary significantly for different indications. for example, the asa dose for antiplatelet effects is 1-5 mg/kg/day, where anti-inflammatory doses range from 60 to 100 mg/kg/day. the next step is another common source of error: calculations. doses should never be estimated and calculations should never be done in the pharmacist's head. a calculator is an essential tool for pediatric pharmacists. pediatric doses are typically listed in mg/kg/day divided qxh, or can be listed as mg/kg/dose given qxh. this is a common source of error and must be carefully checked by the pharmacist. while it is common to see pediatric doses that are higher than adult doses on a mg/kg basis because of the pharmacokinetic differences noted above, it is important to note that adult maximum daily doses (total mg) should typically still be observed in pediatric patients. box 28.2 provides an example. many medications that children use are on a short-term basis only (e.g., antibiotics); however, with medications that are used on an ongoing basis, pharmacists need to ensure that doses are checked with each fill. children, and especially infants, grow quickly and medications dosed on a mg/kg basis may need adjustment for growth. each fill is an opportunity for the pharmacist to assess the need to continue a medication, its apparent effectiveness and the presence of any adverse effects as part of the decision as to whether or not to increase the dose (or discontinue it altogether, if appropriate). lastly, the pharmacist needs to identify an appropriate formulation; the one that allows the dose to be measured accurately, is (reasonably) palatable, and has suitable stability. as mentioned above, this may be a significant challenge on its own. as an additional challenge, newborns <44 weeks cga should ideally not use medica-tions containing preservatives (e.g., benzyl alcohol, propylene glycol) and children should ideally not use medications containing alcohol. this is due to adverse effects reported with these additives (gasping syndrome, metabolic acidosis, hypoglycemia) [13, 14] . however, if an alternative, preservative-free and/or alcohol-free product is not available, the benefit of the medication should outweigh the risks from a small dose of alcohol or preservative. in pediatrics, often patients are non-verbal or are not at a developmental stage where they can describe their symptoms and so a caregiver's external assessment of the patients' symptoms must be relied upon. there is a greater focus on observation of signs and symptoms when determining a patients need or response to medications. while these observations have some degree of objectivity, many assessments done in this way may include some subjectivity. for this reason, other objective measures may be relied upon more frequently in younger children than in older children or adults. for instance, the objective presence of a fever and results of key lab values (e.g. normalization of white blood cell count) can supplement a parent's subjective report of a child feeling better and acting more "like himself" in an assessment of an infection's response to antibiotics. pain scoring tools that include a measurement of heart rate, blood pressure, as well as an observation of the infants' behavior can add an objective component to a parent's assessment of their child's pain. there are a variety of pediatricspecific assessment tools for a variety of medical conditions and pharmacists should seek those out when needed. table 28 .2 includes some examples of condition-specific assessment tools for infants and children. it should be noted that dismissing a parent's assessment of their child due to its subjectivity is not advised. caregivers know typical behavior in their children and slight changes in behavior (e.g., poor feeding, decreased energy, altered sleep) can be important signs of rex is a 12-year-old boy being treated for a pneumonia using amoxicillin. he weighs 40 kg. his prescription states: 90 1350 7 mg kg day m g po tid days / / = × while 90 mg/kg is much higher than most adults would receive, this is an appropriate dose for pneumonia in children. however, the adult maximum daily dose of amoxicillin for pneumonia is 3000 mg, so rex's dose should be adjusted to 1000 mg po tid even though this will only be 67 mg/kg/day. illness or adverse medication effects in children. having said that, if subjective observations contradict objective measures, one should proceed with caution. when assessing a child's illness, there are some red flags that should illicit immediate referral to medical care. table 28 .3 depicts a list of the red flag symptoms that prompts referral in pediatric patients. physical assessment in pediatrics can be limited by both the pharmacists' knowledge of the nuances of pediatric physical exam and by the patient's tolerability of the exam itself. it is beyond the scope of this chapter to describe the differences in physical exam between children and adults, but vital sign assessment can be a simple addition to a pharmacists' assessment in many cases, and the major differences between children and adults are summarized in table 28 .4. as in adults, lab values are an important part of assessing both the efficacy and toxicities of medications in children. table 28 .5 outlines some of the most commonly used laboratory values and how they differ between children and adults. monitoring renal function is especially important for pharmacists, both for assessing the need for dose adjustment in renal dysfunction, but also for monitoring for nephrotoxicity of medications. because normal ranges of serum creatinine in children are relatively wide, serum creatinine values can double, reflecting potential acute kidney injury, but remain in the "normal" range. it is important therefore for pharmacists to follow trends in serum creatinine rather than just absolute values. in cases where the pharmacist needs to estimate renal function, the formula used in children differs from that used in adults. the most accurate and commonly used formula is called the "bedside schwartz" formula. equation 28.1 outlines this important formula. estimation of gfr in infants and especially in newborns is challenging as renal function continues to develop rapidly after birth, with most infants reaching full renal function around 6 months of age. again, following trends in serum creatinine (expecting a downward trend in the first 1-2 weeks of life) is the most effective method of assessing renal function. other factors such as urine output and hydration should also be considered in the overall assessment of renal function. renal dysfunction in children is fortunately uncommon, and all children with renal dysfunction should be followed by a pediatric nephrology team. "bedside schwarz" formula for estimating glomerular filtration rate (gfr) in children >1 year of age [30] : rash with fever fever in infant <3 months old very fast or very slow heart rate (see table 28 .4 for age-based normals) elevated respiratory rate at rest (see table 28 .4 for age-based normals) central nervous system change in/loss of consciousness lack of response to pain decreased tone/floppiness seizure-like activity cardiovascular very fast or very slow heart rate (see table 28 . very fast respiratory rate (see table 28 .4 for age-based normal values) labored or noisy breathing irregular or absent respiration dermatological skin color changes -dusky/blue very dry lips or mouth genitourinary severely reduced/lack of urine output newborn 100-205 90-160 "exercise" in infants is best represented by feeding, thus poor feeding/sweating while feeding may be a sign of cardiac compromise. congenital heart defects are a common cause of cardiac compromise in infants -echocardiography is required to assess heart structure. it is important to assess a child's heart rate at rest and not when they are crying/upset because infectious diseases are commonplace in children, interpretation of bacterial cultures is worth mentioning. sputum cultures are challenging as contamination with saliva is common. it is therefore necessary to note the presence of endothelial cells and/or nasopharyngeal flora in these cultures as they may indicate a lack of appropriate specimen. urinary samples, likewise, can be difficult to obtain appropriately without catheterization and thus have a higher likelihood of contamination by skin flora. lastly, there is a higher rate of falseplatelets same as adults newborns may have slightly lower platelets counts, with a lower limit of 150 × 10 9 /l electrolytes same as adults newborns may have slightly lower sodium (some sodium wasting due to renal immaturity) and higher k (normal state of potassium retention) values than infants and children serum phosphate also tends to be higher in infants and children due to high needs during bone growth and high energy needs creatinine newborns 27-88 μmol/l infants 18-35 μmol/l children 27-62 μmol/l adolescents 44-88 μmol/l note that creatinine in the first few days of life often reflects maternal renal function, and a downward trend is expected in the first 2 weeks of life negative blood cultures. blood cultures in children are typically limited to two bottles (adults typically use four bottles), and use smaller volumes of blood, resulting in a higher risk of false-negative results. the reduced number of bottles also makes distinguishing between pathogenic growth and contamination more difficult. in adults, growth of skin flora in one out of four blood culture bottles is typically associated with contamination; however in children growth of the same pathogen in one out of two bottles is less convincing as contamination. for these reasons, it is not uncommon to empirically treat a child for an infection despite negative cultures, purely based on signs and symptoms of infection. this represents a particular challenge for pharmacists attempting to tailor antibiotic therapy to infectious pathogens. antibiotic therapy may have to be assessed based on "typical" pathogens rather than actual. when considering "typical" pathogens, these vary by age and so pharmacists need to consider this when assessing the appropriateness of antibiotic therapy. another major factor in the "likely" bacteria pathogens is immunization status, and pharmacists should be familiar with vaccination history in patients presenting with infectious diseases. for instance, unimmunized children are at much higher risk of infection with hemophilus influenza type b (hib), which can be a significant pathogen in both meningitis and pneumonia. table 28 .6 outlines common pathogens in common infections throughout infancy and childhood, assuming vaccination in accordance with local immunization programs. an assessment of adherence in children should include not only overt nonadherence (e.g., the child dislikes the taste and spits it out, or the parent forgets to give it on the weekends) but also "covert" nonadherence (e.g., parents make measurement errors, or product is used beyond its stability date). asking to see the caregiver show the dose given as measured, and an examination of the medication bottles can assist with this. questions regarding the appropriate storage of medication are also important (e.g., using coolers for refrigerated medications on long trips). the variability of dosages required for children often make the use of solid dosage forms impractical. if the tablet is appropriate to split, and if a child's dose can be rounded to accommodate a half (or even quarter) tablet, this may be the most practical approach. however, in younger children and for smaller doses, the use of oral liquids may be the only solution. oral liquids should be mea-sured in appropriately sized devices. often, especially in infants, doses may be so small that accurate measurement becomes challenging. doses less than 1 ml are ideally measured in 1 ml (or even 0.5 ml) oral syringes in order to maximize accuracy. typically, manufacturer guidance dictates that doses <10% of the syringe size cannot be accurately measured (e.g., no less than 0.1 ml in a 1 ml syringe or 0.05 ml in a 0.5 ml syringe). occasionally, unique solutions to measurability issues need to be explored. very small doses of some injectable products (e.g., enoxaparin doses <10 mg) may be most easily measured using an insulin syringe (e.g., 1 unit = 0.01 ml = 1 mg enoxaparin). very small doses of oral medications only available in capsules may require (very careful) preparation of powder papers which involves weighing of powders from capsules and packaging in specially folded papers. whatever the situation, pharmacists must ensure that parents and caregivers using medications in children have an accurate method of measurement available as well as a practical approach to giving the medication. if a medication must be delivered to the child as an unpalatable oral liquid there are some approaches to helping mask the taste of the medication. in infants, most medications can be mixed with a small amount of formula or breastmilk to improve palatability. it is important to instruct parents or caregivers not to mix medications in a full volume of feed (i.e., a full bottle) as the complete dose may not be delivered if the full amount of feed is not taken. older children may find eating frozen treats prior to taking the medication may numb the tongue enough and reduce the bad taste. similarly, allowing the child to choose a food or drink to wash the medication taste away may be helpful. concentrated, sugary beverages or foods (honey, chocolate syrup) or other strongly flavored foods (cheeses) may help mask or remove the taste from the child's mouth. administering oral medications to children can be a significant challenge in itself. after measurement with an appropriate device, oral liquids can be given to infants mixed with a small amount of milk/formula through a bottle nipple, or for older children they can be mixed in a small amount of palatable food or liquid before administration. alternatively, oral liquids can simply be expelled into the cheek (where there are no tastebuds) followed with a drink of palatable liquid. iron liquid can stain teeth, and so rinsing the mouth is important (can also use a straw if the mediation has been diluted in a liquid). note that these precau-tions are unnecessary in infants without teeth, and most important in those with their permanent teeth. the ability to swallow oral solid dosage forms makes oral medication administration easier, and this can usually occur around age 5 or 6 years. if children struggle with pill swallowing, they can practice with candies with increasing sizes (e.g., start with sprinkles, slowly increasing the size of the candies up to the target tablet size. usually small jelly beans are sufficiently sized for most medications). children can place the medication/candy on the back of their tongue, tilt their head back, and have a large drink of liquid to facilitate this. in rare cases, infants and small children can swallow small oral dosage forms with appropriate instruction from qualified professionals. an example is levothyroxine, where crushed tablets and suspensions may not provide the necessary accuracy and part-tablets are the preferred dosage form. medications to be administered via feeding tubes (e.g., nasogastric tubes, gastrojejunal tubes) can be administered without palatability concerns; however the intestinal location of the medication administration should be considered in the context of the intestinal administration site (e.g., ensure the medication can be absorbed if administered into the jejunum), and the tubes should be flushed with water afterward to ensure complete delivery of the dose. as a final comment on adherence assessment, it is important to consider adolescents specifically. increasing independence with medication use and administration is often given to adolescents as they move toward adulthood, which requires a change in the pharmacist's approach. where previously assessment was conducted primarily with the caregivers on behalf of the child, the pharmacist should begin to include the adolescents in these conversations in an attempt to build their health literacy and knowledge of their conditions/medications. also of note, adolescents often become more self-conscious of their medical conditions and associated medication use, and strategies to increase the discreteness of ensure caregivers have a practical approach to measurement and administration of the required doses assess for palatability issues observe measurement and/or administration of medications by caregivers help transition adolescents to adulthood and independent medication use their medication use may be appreciated and improve adherence. for example, selection of a dry powder inhaler instead of a metered-dose inhaler with spacer device, or choosing a once or twice-a-day administered agent instead of one that has to be used at school. considerations such as these should come into a pharmacist's assessment as their pediatric patients move toward adulthood. assessing medication use in children has many similarities to that in adults, and should be approached in a similarly systematic way, bearing slight nuances in mind. table 28 .7 summarizes the approach to pediatric assessment, highlights common sources of errors, and provides some tips for minimizing these errors. • assessment of dose requires additional steps in children as compared to adults -categorization by age/weight, calculation of appropriate dose, and determination of accurate measurement processes are a few major steps that need to be included. • infants and children have variable pharmacokinetic and pharmacodynamic parameters, and thus dosages vary widely. the use of pediatric/neonatal references is essential for appropriate dosing and indication assessment by pharmacists. • finding appropriate formulations for children is a challenge for pharmacists. careful assessment of doses/concentrations, measurability, and method of administration need to be included in the overall medication assessment for infants and children. • interpretation of diagnostic tests and vital signs varies in children and a basic understanding of these differences is important for pharmacists assessing children medication therapy. canadian institute for health information the institute the expert panel on therapeutic products for infants, children, and youth, council of canadian academies prescription medicine use by one million canadian children prescription drug dispensing profiles for one million children: a population-based analysis medication use among children <12 years of age in the united states: results from the slone survey koda-kimble and young's applied therapeutics medication errors in children: a descriptive summary of medication error reports submitted to the united states pharmacopeia medicationrelated emergency department visits in pediatrics: a prospective observational study frequency and preventability of adverse drug reactions in paediatric patients developmental pharmacology -drug disposition, action, and therapy in infants and children guidelines on paediatric dosing on the basis of developmental physiology and pharmacokinetic considerations liquid medication errors and dosing tools: a randomized controlled experiment toxic additives in medication for preterm infants safety of "inert" additives or excipients in paediatric medicines the premature infant pain profile: evaluation 13 years after development the flacc: a behavioral scale for scoring postoperative pain in young children the faces pain scale -revised: toward a common metric in pediatric pain measurement state behavioral scale (sbs) a sedation assessment instrument for infants and young children supported on mechanical ventilation assessing distress in pediatric intensive care environments: the comfort scale the childhood asthma control test: retrospective determination and clinical validation of a cut point to identify children with very poorly controlled asthma pram score as predictor of pediatric asthma hospitalization red flags in common pediatric symptoms toronto: sickkids; c2014. pediatric physical assessment uncomplicated pneumonia in healthy canadian children and youth: practice points for management normal ranges of heart rate and respiratory rate in children from birth to 18 years: a systematic review of observational studies fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. [internet] national institute of health physiologic anemia of the newborn infant renal potassium handling in healthy and sick newborn ontogeny of renal sodium transport measurement and estimation of gfr in children and adolescents otitis media urinary tract infections in children the author wishes to express gratitude to jenny wichart and kristen blundell for their thoughtful reviews and comments. key: cord-002304-u30y2xdt authors: valentini, diletta; bianchi, simona; di camillo, chiara; vittucci, anna chiara; gonfiantini, michaela veronika; de vito, rita; villani, alberto title: fatal varicella pneumonia in an unvaccinated child with down syndrome: a case report date: 2016-11-17 journal: ital j pediatr doi: 10.1186/s13052-016-0312-1 sha: doc_id: 2304 cord_uid: u30y2xdt background: varicella is an acute infectious disease common during childhood. it has mostly an uncomplicated course in early childhood. neverthless, it may result in severe complications, especially in particular age groups and clinical conditions. down syndrome represents a risk factor for developing complications, because of the frequent comorbidities and their immunodeficiency. case presentation: a 2-year-old white caucasian female affected by down syndrome was referred to our hospital for cardiac arrest in course of varicella disease. after cardiopulmonary resuscitation and stabilization, her clinical conditions didn’t improve and she developed a massive pulmonary hemorrage, which led her to exitus. conclusions: mortality due to varicella infection is rare, but it is more common in subjects with immune deficit or chronic pathologies, and in particular age-groups. the importance of the vaccine for preventable infectious diseases is stressed in this paper, in which we present a case of death in an unvaccinated cardiopathic child with down syndrome affected by varicella. varicella is an acute, exanthematous, highly infectious disease, that most commonly occurs in childhood. varicella normally has a benign course, but can occasionally develop into a more serious illness, especially in adults, immunodeficient children, pregnant women, newborn babies [1] . a lethal outcome is very rare, with a mortality rate fluctuating between 0.29 and 0.46 deaths per 1 million. the introduction of the vaccine in 1995 has substantially decreased varicella incidence, hospitalizations, and deaths [2] . the most common complications of varicella are bacterial skin infection, sepsis, pneumonia, and central nervous system events such as cerebellar ataxia and encephalitis [3, 4] . a 2-years-old white caucasian female affected by down syndrome (ds) and surgically corrected at 3 months of age for a subaortic intraventricular defect (ivd), with a history of 2 episodes of pneumonia, was admitted in the emergency room of our hospital due to a cardiac arrest during her varicella illness. she had never been vaccinated up to the moment, that's why she contracted the disease from her sister. the night before her admission to the hospital, she began to manifest episodes of hypotonia associated to periods of crying. at 4 o'clock she began to show signs of a generalized hypotonia and she was taken to our hospital by her parents, where she arrived in cardiac arrest. after cardio-pulmonary resuscitation (cpr-pals) her spontaneous breathing was restored. the clinical course was characterized by complete areflexia, with bilateral mydriasis. breathing pattern was characterized by ards that required high frequency mechanical ventilation and nitric oxide with transient improvement. we proceeded to perform a chest x-ray (cxr), which revealed multiple foci of parenchymal spread to both lungs and pleural effusion obliterating share of the breast-phrenic cost (fig. 1 ). an abdominal ultrasound showed the presence of abdominal effusion in all quadrants and laboratory tests revealed the presence of igm antibodies against varicella, positive pcr for varicella antigen, absence of bacterial infections (coltures of blood and urine), prolonged pt and ptt, and altered d-dimer. tests for immunological functions were performed ( table 1) . the next day, the respiratory condition didn't improve and a new cxr showed an impairment of the spread, and a massive pulmonary hemorrhage. in the absence of recovery of the main indicators of organ perfusion, she was declared dead. at macroscopic examination the lungs were heavy, firm and plum-colored, with diffuse areas of hemorrhage and necrosis. histologically there are interstitial pneumonitis, diffuse necrosis and hemorrhage in the pulmonary parenchyma ( fig. 2 ). the estimated global burden of disease-specific mortality caused by varicella is considerably lower than that due to other major infectious diseases such as measles, pertussis, rotavirus, or invasive pneumococcal disease. based on conservative estimates, the global annual varicella disease burden reports 4.2 million severe complications leading to hospitalization and 4200 deaths [5] . the prevalence of immunocompromising conditions including hiv infection and the kind of treatment available, are factors which influence the course of the disease. in healthy children, varicella is usually selflimiting and benign [6] . groups at higher risk for severe complications are: neonates, infants, pregnant women, adults, and immunocompromised patients. the type of varicella complications depends on the patient's age. a study of gowin et al. demonstrates that the average age of varicella-complications in hospitalized children is 3.12 years [7, 8] . the youngest children had pneumonia, and the oldest meningitis/meningoencephalitis [9, 10] . older children considered to be more susceptible to antibody-mediated inflammatory reactions, whereas younger, less immunocompetent patients are more frequently affected by bacterial suprainfections of the skin or of the respiratory tract [11, 12] . respiratory tract infections were present in younger children, and usually developed at the beginning of the varicella infection [7] . the high frequency of respiratory tract complications reflects the biology of the virus. the virus enters the host through the respiratory tract and then spreads in the bloodstream. a cytopathic effect of hematological complications are observed in 1-2% of children with varicella. patients usually remain asymptomatic. like many other thrombocytopenias and anemias during viral infections, those in patients with varicella are transient and require no treatment. laboratory tests are not performed routinely in patients with varicella [13] . our case suffered from acute respiratory distress syndrome (ards) caused by varicella, and associated to hematological disorders that provoked the development of pulmonary hemorrhage, which caused death. children who are diagnosed with down syndrome and who have comorbidities such as immunodeficiency or cardiopathy have high rates of viral and bacterial infections such as influenza and pneumococcal infections [14] . the most common symptoms reported in children with ds are infections of the respiratory tract suggesting a b-cell defect [15] . diseases related to t-cell deficiency, such as infection with intra-cellular microorganism, fungi and opportunistic pathogens are rare [16] . varicella is one of the most infective disease that affects the pediatric population. guidelines stress the importance of an anti-varicella vaccination for all children older than 12 months as well as children with ds [17] . the only contraindication of the vaccine is severe immunodeficiency of the t cells [6] . despite the fact that most children hospitalized with varicella complications were immunologically healthy, risks are superior in subjects with chronic conditions [6, 18] . children with ds have a higher risk of being hospitalized for viral respiractory tract infections, even in the absence of coexisting risk factors [19] , and the mortality rate in severe ill ds children admitted for medical reasons is high and is predominantly associated with respiratory conditions [20] . as the burden of preventable infections in children diagnosed with chronic diseases is high in terms fig. 2 histological image that showed interstitial pneumonitis and diffuse necrosis and hemorrhage in the pulmonary parenchyma of incidence and severity, it is essential to protect these children with timely administration of vaccinations according to the current recommendations. even among populations at risk, varicella vaccine is the less used. although italian down children have the best vaccination coverage among all patients with chronic disease [21] , it is clear that it is desirable to improve vaccination coverage among risk groups and also among the healthy population. implemented interventions, with special reminders to parents and general practitioners, are necessary to promote timely vaccination in ds children who are susceptible to preventable infections and prone to severe complications. this case underlines how varicella may lead to severe, potentially life-threatening complications in unvaccinated children and adolescents, and may demonstrate too the benefits of varicella vaccination. funding diletta valentini, who wrote the first draft of the manuscript, wasn't given by anyone any grant or other form of payment to produce the manuscript. the dataset supporting the conclusions of this article is available in the bambino gesù children hospital repository. decline in mortality due to varicella after implementation of varicella vaccination in the united states varicella and its complications as cause of hospitalization acute cerebellitis in varicella: a ten years case series and systematic review of the literature analysis of data from multiple sources and assessment of universal vaccination impact in three pilot regions world health organisation. varicella and herpes zoster vaccines: who position paper epidemiology of hospital admissions for paediatric varicella infections: a one-year prospective survey in the pre-vaccine era the burden of varicella complications before the introduction of routine varicella vaccination in germany don't forget how severe varicella can be-complications of varicella in children in a defined polish population neurological complications of varicella in childhood: case series and a systematic review of the literature how frequent is varicella associated pneumonia in children? reduction in pediatric hospitalizations for varicella-related invasive group a streptococcal infections in the varicella vaccine era haematological complications in otherwise healthy children hospitalized for varicella committee on infectious diseases. policy statement: recommendation for the prevention of pneumococcal infections, including the use of pneumococcal conjugate vaccine (prevenar), pneumococcal polysaccharide vaccine, and antibiotic prophylaxis reduced numbers of switched memory b cells with high terminal differentiation potential in down syndrome down syndrome b-lymphocyte subpopulations, intrinsic defect or decresead t-lymphocyte help guide to contraindications to vaccination editorial commentary: zoster vaccine in immunocompromised patients: time to reconsider current recommendations down syndrome and hospitalizations due to respiratory syncytial virus: a population-based study children with down syndrome: clinical course and mortality-associated factors in a french medical paediatric intensive care unit immunization coverage and timeliness of vaccination in italian children with chronic diseases authors' contributions dv wrote the manuscript. sb collected the clinical and laboratory data, and wrote the manuscript. cdc collected the bibliography. av reviewed the immunization schedule for down syndrome, in order to write the discussion. mvg reviewed the clinical complications of varicella, in order to write the discussion. rdv performed the pathological analysis. av reviewed the manuscript. all authors read and approved the final manuscript. the authors declare that they have no competing interests. written informed consent was obtained from the patient's parents/legal guardians for publication of this case report and any accompanying images. a copy of the written consent is available for the review by the editor-in-chief of this journal.ethics approval and consent to participate not applicable. key: cord-009606-xz23twqx authors: vorobieva s. jensen, v.; furberg, a-s; slotved, h-c; bazhukova, t.; haldorsen, b.; caugant, d. a.; sundsfjord, a.; valentiner-branth, p.; simonsen, g. s. title: epidemiological and molecular characterization of streptococcus pneumoniae carriage strains in pre-school children in arkhangelsk, northern european russia, prior to the introduction of conjugate pneumococcal vaccines date: 2020-04-15 journal: bmc infect dis doi: 10.1186/s12879-020-04998-5 sha: doc_id: 9606 cord_uid: xz23twqx background: the 13-valent pneumococcal conjugate vaccine (pcv-13) was introduced in the national immunization programme (nip) schedule in russia in march 2014. previously, the 7-valent pneumococcal conjugate vaccine (pcv-7) was marketed in russia in 2009 but has never been offered for mass vaccination. a carriage study was performed among children in arkhangelsk in 2006. the objective was to determine the prevalence of carriage, serotype distribution, antimicrobial susceptibility and the molecular structure of streptococcus pneumoniae strains before marketing and introduction of pcv-13. methods: a cross-sectional study was conducted on a cluster-randomized sample of children and a self-administrated questionnaire for parents/guardians. nasopharyngeal samples were collected from 438 children younger than 7 years attending nurseries and kindergartens in the arkhangelsk region, russia. detailed demographic data, as well as information about the child’s health, traveling, exposure to antimicrobials within the last 3 months and anthropometric measurements were collected for all study subjects. variables extracted from the questionnaire were analysed using statistic regression models to estimate the risk of carriage. all pneumococcal isolates were examined with susceptibility testing, serotyping and multilocus sequence typing. results: the overall prevalence of asymptomatic carriage was high and peaking at 36 months with a rate of 57%. pcv-13 covered 67.3% of the detected strains. high rates of non-susceptibility to penicillin, macrolides and multidrug resistance were associated with specific vaccine serotypes, pandemic clones, and local sequence types. nine percent of isolates represented three globally disseminated disease-associated pandemic clones; penicillinand macrolide-resistant clones norway(nt)-42 and poland(6b)-20, as well as penicillinand macrolide-susceptible clone netherlands(3)-31. a high level of antimicrobial consumption was noted by the study. according to the parent’s reports, 89.5% of the children used at least one antimicrobial regime since birth. none of the hypothesised predictors of s. pneumoniae carriage were statistically significant in univariable and multivariable logistic models. conclusions: the study identified a high coverage of the pcv-13-vaccine, but serotype replacement and expansion of globally disseminated disease-associated clones with non-vaccine serotypes may be expected. further surveillance of antimicrobial resistance and serotype distribution is therefore required. streptococcus pneumoniae is a bacterial pathogen causing disease among all age groups. despite the introduction of effective vaccines, invasive pneumococcal disease (ipd) is associated with high mortality and morbidity [1] [2] [3] . as was anticipated, the introduction of the pneumococcal conjugate vaccines (pcvs) in the national immunization programmes has substantially reduced pneumococcal-related deaths worldwide [4] . immunization by conjugate pneumococcal vaccines has now been implemented in 145 countries [5] . still, according to the most recent report based on data from the world health organisation (who) and the maternal and children epidemiology estimation collaboration, in 2015, pneumococci were estimated to have caused 318,000 (uncertainty range 207,000-395,000) deaths for both hiv-infected and hiv uninfected infants and young children in the age 1-59 months globally [4] . the epidemiology of pneumococcal disease prior to the introduction of pneumococcal vaccines was dominated by the spread of global disease-causing epidemic clones, both multidrug-resistant (mdr) and antimicrobial susceptible clones [6] . the success of epidemic clones, though not well understood, has been linked to certain capsular types [7, 8] , carriage of a pilus islet [9] and various virulence factors [10] . mass vaccination has reduced the occurrence of mdr pneumococcal molecular epidemiology network (pmen) clones with serotypes covered by the vaccine. reports from countries dating to the post-pcv era show a rapid reduction of pcv-serotype-related pmen-isolates. however, some sequence types (st) st320, st433, st191 and other highly successful clones with non-vaccine related serotypes rapidly replace the disease-associated endemic clones shortly after the introduction of pcv-vaccines [11] . capsule serotype replacement in clones targeted by pcvs has also been demonstrated [12] , such as a switch from 19f to 19a in the disease-associated high-level penicillin-resistant endemic clone taiwan 19f -14 [13] . russia is a large country with an estimated infant and child population aged up to 4 years of 9.0 million in 2019 [14] . the immunization programme for infants and children in the russian federation presently includes ten less expensive vaccines, while, for example, the haemophilus influenzae type b conjugate vaccine has not been available for mass vaccination [15] . the pcv-7 was marketed in russia in 2009 but has never been offered for mass vaccination. the extended pneumococcal conjugate vaccine with 13 serotypes was licenced in russia in 2011 (pcv-13, prevenar 13, wyeth pharmaceuticals inc., marketed by pfizer inc.), and included in the russian national immunization programme (nip) schedule in march 2014 [5, 15] . immunizations are administered in a 2 + 1-dose schedule, with two primary immunizations given at 2 and 4.5 months and a booster at 15 months of age [15] . no additional catch-up immunization has been offered for the rest of the child population [15] . national immunization coverage data are only partially available, but a sharp increase of pcvcoverage was reported by the who/ united nations international children's emergency fund reporting system in the 3 years after the introduction [16] . in 2017, the rates of pcv-13 coverage were 88 and 70% for the 2nd and the 3rd doses, respectively, while the rates for the 1st dose remain unknown since 2014 [16] . neither national nor regional surveillance of incidence for ipd cases exists in russia [17, 18] . the overall incidence of pneumococcal meningitis in russia was estimated at 0.2 per 100,000 cases for all age groups, and 18% of all cases were presented by children under 5 years. the low rates of pneumococcal meningitis have been associated with suboptimal diagnostics and antimicrobial treatment preceding laboratory examinations [17, 18] . the present study was conducted in the arkhangelsk region in the northwest part of russia where no data about the pre-pcv carriage are available. in order to determine pneumococcal carriage at baseline [19] and evaluate possible effects of the introduction of pcv-13 in the russian immunization schedule, the authors performed a cross-sectional study of asymptomatic nasopharyngeal s. pneumoniae carriage in healthy pre-school children attending daycare centres (dccs) 8 years before the introduction of pcv-13. all pneumococcal isolates were analysed with regard to serotypes, phenotypic antimicrobial resistance patterns and population structure based on multilocus sequence typing (mlst). children and parents/guardians from ten dccs were invited to participate in the study. all the dccs were public childcare institutions that belonged to small towns and suburbs of the arkhangelsk region and located within a range of 13 to 44 km from the city of arkhangelsk. each dcc consisted of a nursery and a kindergarten and was attended by 21 to 200 children. besides, 32 randomly chosen healthy children living in the centrum of arkhangelsk were sampled. children and parents/ guardians were invited to participate by the announcement in the local newspaper. all children were sampled during the last week of november 2006 by one otolaryngologist. none of the children experienced symptoms of a common cold like cough, runny or stuffy nose at the date of examination. the body temperature was normal for all children on the day of sampling. the questionnaires were filled out by parents or guardians for all participants in the study. each questionnaire included questions concerning the child's health, length of breastfeeding, travelling abroad or outside of the arkhangelsk region within the last 6 months, smoking habits of family members, as well as the household size and the number of siblings and family members. information on the use of antimicrobials agents during the last 3 months prior to sampling was also collected for all children. anthropometric measurements were taken for all participants on the day of sampling. all parents/guardians were informed about the study by informational letters and a majority of the parents/ guardians participated in informational meetings. the written informed consents were filled out by parents or guardians for all participants of the study. ethical approval was obtained from the ethics research committee of north norway, the reference number of the approval 5.2006.2086 from the 23rd of june 2006 and the ethics research committee of the northern state medical university of arkhangelsk, the reference number for the approval 06/06 from the 6th of june 2006. permission to conduct the study was also obtained from the health and educational services of the arkhangelsk region. the european intervention study (euris) manual was used for isolation of bacterial strains [20, 21] . nasopharyngeal samples were transferred to the laboratory using transport media swabs (copan 114c, copan diagnostics, inc., corona, usa), and inoculated within 3 to 6 h after the arrival. samples were cultured on 5% defibrinated sheep blood agar (oxoid ltd., uk) supplemented with gentamicin (5 mg/l) and incubated at 35-37°c under anaerobic conditions for 18 to 24 h. samples were also cultured on sheep blood agar (oxoid ltd., uk) with optochin disks (ab biodisk, sola, sweden) (5 μg) and incubated in 5% co 2 at 35-37°c for 18-24 h. strains were identified as s. pneumoniae by colony morphology, negative catalase reaction, optochin susceptibility, agglutination in the pneumo-kit slidex test (biomèrieux, missouri, usa), and by the bile solubility test [22] . isolates were serotyped by the quellung reaction using serotype-specific antisera (ssi diagnostica, denmark). strains were tested for antimicrobial susceptibility by disk diffusion on iso-sensitest agar (isa) (oxoid ltd., basingstoke, uk) supplemented with nicotinamide adenine dinucleotide (mast diagnostics merseyside, uk) and 5% defibrinated sheep blood. antimicrobial paper disks (oxoid ltd., uk) containing 1 μg oxacillin (oxa), 15 μg erythromycin (ery), 30 μg tetracycline (tet), 25 μg trimethoprim-sulfamethoxazole (sxt) or 10 μg norfloxacin (nor) were used. oxa-resistant isolates (inhibition zone < 18 mm) were further examined by penicillin g (pen), cefuroxime (cxm), cefotaxime (ctx) and meropenem (mem) etests according to the manufacturer's instructions (ab biodisk). unless otherwise stated, the breakpoints defined by the norwegian working group for antibiotics (nwga) were used. nor-resistant isolates were examined by etest for their susceptibility to ciprofloxacin (cip), nor, moxifloxacin (mxf) and levofloxacin (lvx), using breakpoints from the swedish reference group for antibiotics (srga) [23] [24] [25] . multidrug-resistance (mdr) was defined as resistance to three or more antimicrobial classes [26] . the double-disk diffusion (ddd) test with ery and clindamycin (cli) (oxoid ltd., uk) was used for characterization of inducible macrolides, lincosamides, streptogramines (imls) resistance as described [27] . blunting of the cli inhibition zone indicated imls b -resistance, resistance to both ery and cli indicated constitutive resistance (cmls b ), whereas susceptibility to cli and resistance to ery indicated m-type resistance. detection of the macrolide resistance determinants ermb and mefa was performed by pcrs as previously described [28] . all strains were examined by mlst as described by enright et al. [29] and assigned to sts based on a combination of alleles at seven housekeeping loci. the seven housekeeping genes used for mlst were aroe, gdh, gki, recp, spi, xpt, and ddl. alleles were identified and isolates were assigned into sts using the pubmlst database (https://pubmlst.org/spneumoniae/). the phyloviz® programme was used for assigning the isolates into clonal complexes (ccs), defined as clusters sharing six out of seven common alleles. rstudio© version 1.1.423 {https://www.rstudio.com/} and r version 3.5.1 for windows were used for calculation of odds ratios (or), confidence intervals (95% ci), and p-values using two-tailed fisher's exact test. carriage rates were calculated as incidence rate ratios (irrs) with 95% ci. p-values < 0.05 were considered significant. we used fisher's exact test and univariable and multivariable logistic regression models to examine potential risk factors for pneumococcal carriage including sex, age, early life variables (weight and length at birth, breastfeeding length, living in arkhangelsk since birth), family and socioeconomic status (parents' education, having siblings < 5 years at the moment of examination, number of rooms at home), medication and disease (having had rhinitis, otitis or pneumonia since birth, average number of respiratory tract infections per year since birth, regular medication, any disease within a month prior to the examination, receiving antimicrobials within 3 months prior to the examination), and lifestyle factors (body height, body weight, body mass index (bmi), passive smoking). out of 766 children attending the ten selected dccs, 438 (57.2%) agreed to participate in the study and nasopharyngeal swabs were collected from all these children. the demographic data for all 438 children are given in table 1 . the percentage of parents or guardians who agreed to the participation of their children varied from 33.6 to 88.5% between institutions and the number of isolates ranged from 2 to 51 between institutions. samples were gathered from non-vaccinated healthy children aged 6 to 83 months (mean age 49.3 months), and 51.1% of the children were boys. bmi was in the range between 13 and 16 kg/m 2 for 56% of the children and greater than 16 for 43% of the children on the day of examination. only 1% of the children had a bmi of less than 13 on the day of sampling. the overall prevalence of antimicrobial consumption was high. according to the parent's reports, 89.5% of the children used at least one antimicrobial regime since birth. additionally, 38.7% (65/168) of the children with recognized carriage have been treated with antimicrobials within the last 3 months before sampling. pneumococci were isolated from 168 children (mean age 45.8 months), giving an overall carriage rate of 38.4% (ci 33.8-42.9%). the highest rate of carriage was found among the children aged from 19 to 36 months and it was lowest at the age less than 18 months ( table 1 ). the carriage rate peaked at the age of 36 months (57.0%). the carriage rate of s. pneumoniae for males and females were compared with univariable and multivariable regression models to estimate the risk of carriage (odds ratios) and did not display any statistically significant differences. sex did not influence the carriage rate of s. pneumoniae significantly ( table 1) . none of the hypothesised predictors of s. pneumoniae carriage, including sex, breastfeeding, number of rooms at home, respiratory tract infections and illness, were statistically significant in univariable and multivariable logistic regression models (table s1 ). receiving antimicrobial therapy 3 months before to sampling was not significantly associated with carriage of penicillin non-susceptible s. pneumoniae (or 0.71 with 95% ci 0.29-1.76). twenty-four different serotypes were detected in the pneumococcal collection, and 14 isolates were nontypeable (nt) ( table 2) . serotypes 19f (n = 28; 16.7%), 23f (n = 21; 12.5%), 6a (n = 18; 10.7%) and 6b (n = 16; 9.5%) were most prevalent (tables 2 and 3 ). the most diverse serotype composition was observed in children in the age groups 24 to 35 months and 36 to 47 months with a total number of 16 different serotypes in each group. the diversity of serotypes in other age groups varied from eight (age group 16 to 23 months) to 13 (age group 48 to 59 months). most isolates (5/6, 83.3%) with serotype 14 were found in samples taken from children aged less than 48 months of age. pcv-13, including serotypes 1, 3, 4, 5, 6a/b, 7f, 9 v, 14, 18c, 19a/f, and 23f, would cover 67.3% (113/168) of the isolates in the study (table 2 ). in contrast, pcv-10 provided coverage for only 50.0% (84/168) of the isolates in our collection. the coverage rate for the 23valent pneumococcal polysaccharide vaccine (ppv) was 66.7% (112/168). the rates of non-susceptibility were as follows: sxt (n = 121; 72%), tet (n = 52; 31%), oxa (n = 29; 17%), and ery (n = 18; 11%). characterization of penicillin nonsusceptible pneumococci (pnsp) and macrolide nonsusceptible pneumococci (mnsp) is given below. only a single strain was resistant to fluoroquinolones (< 1%). mdr was detected in 19 strains (11%). only 26% (43/168) of nasopharyngeal carriage strains were susceptible to all examined antimicrobials (oxa, ery, sxt and tet). the isolates displayed 60 different sts (table 3) . fortythree sts comprising 138 isolates and representing 89.9% of the entire population were assigned into 24 clonal complexes. clonal complex (cc) 15 represented by 4 different sts (st25, st423, st2995, and st2997) was found to be the most prevalent complex (8.9%, n = 15). ten percent of all sts were represented by single isolates. thirty-five of the 60 sts were identified for the first time in arkhangelsk. the majority of the pneumococcal isolates in each st was related to a single serotype. two sts, st2859 and (table 3) . three additional strains expressed serotype 6b and were associated with poland 6b -20. the mlst-based phylogeny for all 20 penicillin non-susceptible isolates is given in fig. 1 . the expected rate of pcv-13 coverage for mnsp isolates was 30% (3/10). ten pneumococcal isolates displayed non-susceptibility to pen, but were susceptible to macrolides. seven of these strains expressed serotype 23f and belonged to st1500 and were also resistant to stx. the three remaining isolates were non-serotypeable (st2996; st3186 and st3208) ( table 3 ). the analysis of all macrolide non-susceptible isolates by ddd method revealed the following phenotypes: imls b (n = 7), cmls b (n = 4), and m-type resistance (n = 5). the results were confirmed by ermb and mefa-pcrs. macrolide non-susceptibility was associated with two globally disseminated clones. six of the macrolideresistant isolates belonged to cc315 (st315 and st3200), expressed the ermb-gene and were associated with the international poland 6b -20 clone. six of the isolates belonged to st344-norway nt -42 and possessed both mefa (n = 4) and ermb (n = 2) determinants. the other 4 macrolide-resistant isolates were represented by unrelated st25, st386, st2991, and st3201 and were connected to ermb (n = 3) and mefa (n = 1) genes. this is one of the largest carriage surveys prior to the introduction of pneumococcal vaccines in russia, where serotyping, antimicrobial susceptibility testing and mlst were performed on whole strain collection [30] . moreover, the present study provides information regarding the population structure of s. pneumoniae carriage isolates in pre-school children of the arkhangelsk region between separately located dccs. the serotype distribution was diverse in the area, but globally reported epidemiological features, such as age-dependence, carriage rates a 38.4% overall frequency of pneumococcal carriage rate was found in non-vaccinated pre-school children. the carriage rate among children aged 36 months was as high as 57.0%. previous carriage studies in dccs in russia have described even higher overall frequencies of asymptomatic s. pneumoniae colonization [30] [31] [32] [33] [34] . overall, we found no significant difference in the carriage rates among children with birth weights < 2500 g, birth heights < 48 cm, none or < 3 months of breastfeeding, as well as living with siblings < 5 years. our study found an average rate of pneumococcal carriage similar to what has previously been described for populations in upper-middle-income countries at a baseline period [35] . the prevalence of carriage is independent of geographical region but strongly associated with accumulated risk factors, such as young age, high-density living conditions, and poor health conditions [36] [37] [38] . the rates of asymptomatic carriage varied markedly between different age groups in our study, and also the diversity of serotypes displayed age variation. these findings have previously been observed by others [39] [40] [41] . young children aged 19-36 months expressed the highest rates of asymptomatic colonization and the widest range of serotypes. isolates with serotype 14 (paediatric serotype) were linked to children younger than 47 months in our study. the age-dependence analysis showed a low frequency of pneumococcal colonization up to 19 months and a peak incidence at the age of 36 months with a stable decline from the age of 46 months. this tendency has previously been discovered for children living in developed and upper-middle-income countries [35] , but not for children living in low-income countries [42] . the seven most common serotypes (14, 6b, 23f, 19f, 6a, 9 v, 18c) from our study were previously described in the group of the ten most common serotypes of ipd cases globally [43] , and they are a part of pcv-13. three other pcv-13associated serotypes 1, 5 and 7f are not frequently detected among pneumococcal carriage isolates in russia [30] [31] [32] nor in other geographical areas [40, 41] but were generally related to cases of ipd in infants and young children [44] [45] [46] . none of the isolates from our study collection expressed serotype 19a reported as the eighth most prevalent globally [43] and the most common serotype in childhood ipd following pcv-7 introduction [40, 47] . still, 3.6% of the carriage isolates belonged to the pen and macrolide-susceptible taiwan 19f -14 cluster previously associated with serotype 19f to 19a replacement [13] . serotype 19a is strongly associated with pen-resistant cases of ipd and was commonly described shortly after the introduction of pcv-7 in vaccination schedules [48, 49] , leading to the inclusion of serotype 19a in the 13-valent vaccine. a high incidence of ipd due to serotype 19a has been associated with a limited number of clonal complexes (cc199, cc320, and cc276). contrary to that, a study from russia carried out by mayanskiy et al. [50] demonstrated that local serotype distribution in our study, two isolates (1.8%) belonged to serotype 15a, which is not included in pcv-13. this serotype was previously associated with mdr and was isolated from most ipd cases in the post-pcv era in several post-industrial countries [51] [52] [53] . our two serotype 15a isolates were pen and macrolide susceptible and were st2186, which was not previously associated with globally disseminated clones. a single carriage isolate from our collection displayed serotype 35b, which is a non-vaccine serotype associated with high capacity for biofilm production [7] . the isolate was susceptible to pen and macrolides, but showed resistance to tet and was associated with st3185/none-cc in contrast to previous reports [54, 55] . the expansion of serotype 35b associated with both ipd and non-ipd cases in paediatric populations has been reported in several countries after the introduction of pcv-13 [52, 54] . since the pneumococcal disease is preceded by asymptomatic colonization, the distribution of antimicrobial resistance patterns in nasopharyngeal s. pneumoniae carriage strains may predict rates of resistance in invasive isolates [56, 57] . rates of nonsusceptibility among invasive and carriage isolates changed dramatically after the introduction of pcvs in industrialized countries [51] [52] [53] 58] . furthermore, non-susceptibility to pen in invasive pneumococcal isolates after the introduction of pcvs was strongly associated with an increased mortality rate in infants and children, as well as in the elderly [2] . the study found significantly higher rates of pen and macrolide non-susceptibility than previously reported from russia before the vaccine implementation [31, 34] . high rates of mdr carriage was discovered during the survey. similar to the intermediate rate of carriage, an intermediate rate of pnsp was found. treatment with antimicrobials 3 months before sampling was not a significant risk factor for carriage of pnsp in this cohort. a high concordance between nonsusceptibility to pen and macrolides and genotypes was also noted. remarkably, a recently published study from russia demonstrated a significant rise in resistance to oxacillin, erythromycin and clindamycin in disease-associated nasopharyngeal isolates in response to pcv-13 implementation. the growing resistance was explained by the expansion of mdr endemic clone st143 with serotype 14 [59] . contrary to the reported low rates of sxt consumption in the area [60] the study found a much higher rate of resistance to sxt than previously reported [31, 33, 34] and a high rate of non-susceptibility to tet. the 2006 all-russia survey cited non-susceptibility rates of 43 and 53% to tet for the european and asian parts of the country, respectively [34] . rates of resistance are strongly associated with rates of antimicrobial consumption in local settings. according to the report from the european surveillance of antimicrobial consumption (esac) network [61] , the rates of outpatient antimicrobial consumption in russia in 2006 were the lowest among all 33 participating countries. however, the low rates of antibiotic consumption at outpatient level do not agree with the present study. on the contrary it was found that children were intensively treated with antimicrobials prior to sampling. the low level of consumption published by esac should be regarded with caution due to possible bias in the reported sales and self-medication data [62] . we observed a high prevalence of various locally disseminated sts in the area. although the arkhangelsk region has rather low rates of migration and tourism and does not border any other countries, we found a close clonal relationship with the major globally disseminated pandemic clones, thus indicating possible import. our study found st1500 with serotype 23f to be associated with pen non-susceptibility. a study carried out in siberia found a high rate of st1500 carriage isolates which were susceptible to pen thus contrasting to the arkhangelsk isolates [32] . differences in the susceptibility profiles among strains within the country may suggest the acquisition of resistance in response to local antimicrobial prescribing practices. besides, 1.2% of macrolideresistant isolates were associated with st2991 and st3201. to the authors' knowledge, these sts have never been associated with macrolide resistance before, which is also may be linked to a local treatment choice. we found that pcv-13 could be effective against 67% of the pneumococcal population and thus reduce the majority of penicillin, macrolide, and multidrug-resistant strains as previously shown in other countries [63] [64] [65] [66] . however, 1.2% of macrolide-resistant isolates were associated with non-vaccine serotypes 35f and 23a (35f-st2991 and 23a-st3201-cc346), that may replace the pcv-13-vaccine associated serotypes. st2991 is a singleton not previously related to any clonal complexes, whereas st3201 is part of the st346-cluster, which has previously been linked to pen resistance and several ipd-associated serotypes [67] . a high proportion of both penicillin and macrolide non-susceptible isolates in our study was found to be related to nt isolates. the recently published meta-analysis of estimated invasive disease potential for individual pneumococcal serotypes showed a low disease potential for non-serotypeable pneumococci [44] . however, all non-serotypeable isolates in our study were closely related and belonged to the st344-cluster, the globally disseminated pmen clone norway nt -42, vaccination against which is so far unavailable. the high effectiveness of pcvs against ipd in infants and young children has been proven in countries with well-established national surveillance. according to several reports [63] [64] [65] [66] a sharp decrease of both carriage and ipd cases with vaccine-associated serotypes has occurred shortly after the introduction of pcvs with a subsequent decline in morbidity and mortality rates associated with these serotypes. it is too early to estimate the vaccine impact in russia based on serotype distribution only. reliable national and regional surveillance of invasive and non-invasive cases is needed to determine the effectiveness of the pcvs introduction and suggest strategies concerning vaccination schedules, the choice of pcv and vaccination coverage targets. the present study has documented several important aspects of the local pneumococcal epidemiology specific for the north of european russia. the s. pneumoniae population was found to be highly diverse and had common features such as age-dependency, dominant serotypes and the presence of major epidemic clones. high rates of resistance were linked to high rates of antimicrobial consumption in the area. clonal expansion of several globally distributed pandemic clones was identified in a remote part of north european russia with low rates of migration and tourism. the effectiveness of pcv-13 introduction cannot easily be predicted. according to international experience, clonal expansion due to replacement by the globally disseminated diseaseassociated pandemic clones with non-pcv-13-serotypes can be expected. the authors propose setting up a highquality population-based national/regional surveillance system for asymptomatic colonization and serotypespecific ipd rates for monitoring effects of the vaccination programme. supplementary information accompanies this paper at https://doi.org/10. 1186/s12879-020-04998-5. additional file 1: table s1 . odds ratio of global etiology of bacterial meningitis: a systematic review and meta-analysis risk factors for death from invasive pneumococcal disease, europe streptococcus pneumoniae: epidemiology and risk factors, evolution of antimicrobial resistance, and impact of vaccines burden of streptococcus pneumoniae and haemophilus influenzae type b disease in children in the era of conjugate 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antimicrobial consumption (esac): outpatient antibiotic use in europe the inventory of antibiotics in russian home medicine cabinets effect of introduction of the pneumococcal conjugate vaccine on drug-resistant streptococcus pneumoniae nationwide surveillance of streptococcus pneumoniae in greece: patterns of resistance and serotype epidemiology impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality impact of a pneumococcal conjugate vaccination program on carriage among children in norway emergence of penicillinnonsusceptible streptococcus pneumoniae clones expressing serotypes not present in the antipneumococcal conjugate vaccine publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors thank all study participants for their involvement. we would like to thank the administration of the northern state medical university in arkhangelsk, russia for support during sample collection. we would also like to thank the administration of the regional clinical hospital in arkhangelsk for providing facilities of the microbiological laboratory for primary sample isolation. the authors acknowledge nadezda semenova, oksana lebedeva and bettina aasnaes for contribution to collection of samples. the authors also gratefully acknowledge bettina aanaes for excellent laboratory support. the authors also thank highly skilled laboratory staff of the norwegian institute of public health, oslo for assisting with serotyping and sequencing of pneumococcal isolates. authors' contributions gss, as and vvsj conceived the study. vvsj, asf, tb, as and gss designed the study. vvsj, asf, bch, as and gss contributed to the protocol writing. vvsj and tb recruited the study subjects. vvsj, gss, bch and tb contributed to collection of clinical samples. vvsj and bch carried out laboratory analysis. vvsj, asf, hcs, pvb, hcs and dac carried out data analysis. all authors wrote the manuscript and approved its publication. vvsj was granted by the quota scheme of the norwegian state education loan fund. hcs is involved with projects supported by pfizer. all other authors were funded by their individual departments. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. the data and materials are available on request from the corresponding author (veronika vorobieva solholm jensen, dept. of virus and microbiological special diagnostics, statens serum institute; artillerivej 5, dk-2300 copenhagen s, denmark. email:veronika.v.vorobieva@gmail.com), but restrictions apply under licence for the current study. the data may be publicity available upon reasonable request and with permission of the northern state medical university, arkhangelsk, russia. the permission to carry out the study was sought from the authorities of the arkhangelsk region. all parents/ guardians were informed about the study by informational letters and a majority of the parents/guardians participated in informational meetings. the written informed consents were signed by parents or guardians for all participants of the study. there was a questionnaire that parents or guardians filled out for all participants of the study. consent for publication does not apply. hans-christian slotved is involved with projects supported by pfizer. all other authors had declare that they have no competing interests. key: cord-030018-sabmw7wf authors: el-shabrawi, mortada; hassanin, fetouh title: infant and child health and healthcare before and after covid-19 pandemic: will it be the same ever? date: 2020-08-04 journal: egypt pediatric association gaz doi: 10.1186/s43054-020-00039-7 sha: doc_id: 30018 cord_uid: sabmw7wf background: the novel corona virus disease 2019 (covid-19) current pandemic is an unpreceded global health crisis. not only infection of infants, children, and adolescents is a concern for their families and pediatricians, but there are also other serious challenges that should be properly identified and managed as well. main body: we have to identify and assess the different factors that have either direct or indirect effects on child health and healthcare due to covid-19 pandemic and focus on the serious effects. it is easily realized that there are many challenging problems associated with covid-19 with short-term effects that already appeared and need urgent solutions and long-term effects that are not yet well apparent and have to be searched for and properly addressed. conclusions: covid-19 crisis has lots of impacts on child health and child healthcare, not only from the medical aspect but also from the social, psychological, economic, and educational facets. all these adverse implications have to be identified and dealt with on individual bases approach in the short and long term. since reporting of the first index cases of infection with the novel severe acute respiratory syndrome corona virus 2 (sars-cov-2) in wuhan (hubei, china) on 12 december 2019, the whole world has changed very rapidly and dramatically. on 30 january 2020, the world health organization (who) has declared the novel corona virus disease 2019 (covid-19) as a global health emergency, and shortly thereafter on 11 march 2020, it was declared as a pandemic [1] . covid-19 pandemic proved rapidly to be a major international medical problem that has many sequences on infants, children, and adolescents. worldwide, concerted efforts must be exerted in order to identify the huge problems and impacts the pandemic has created that affect child health and child healthcare, and plan prompt solutions for them. all the news, reports, and experiences from the four corners of the world are indicating that infant and child health and healthcare systems before the covid-19 pandemic have been changed to variable degrees and will probably never be the same after the pandemic in many aspects for extended periods of mankind life. covid-19 is uncommon to cause marked clinical symptoms in healthy children as compared with adults. however, asymptomatic children are able to transmit the virus to their adult contacts, and very young infants and children (as well as those with underlying comorbidities) are at increased risk to manifest severe illness [2] . covid-19 is a droplet infection that spreads rapidly to the unprotected contacts from an infected person. the infectious virus can persist on contaminated surfaces for variable times. the risk of transmission via touching contaminated paper is low, while respiratory and fecal specimens can maintain infectivity for quite a long time at room temperature. sars-cov-2 could exist in the air in poorly ventilated buses for at least 30 min. absorbent materials like cotton are safer than non-absorptive materials for protection from viral infection [3] . as children are less likely to present with serious symptoms, they may have nasal congestion, sore throat, muscular and bony aches, abdominal pain, vomiting, or diarrhea [4] . in children, common circulating corona viruses can cause common cold symptoms such as fever, rhinitis, otitis, pharyngitis, laryngitis, headache, bronchitis, bronchiolitis, wheezing, pneumonia and, in up to 57% of cases, gastrointestinal symptoms (which are more common in children than adults) [5] . some recent studies have shown that there is limited spread among children and from children to adults [6] [7] [8] . the most common manifestations in infected adults include fever, tiredness, and a dry cough [2] . in the majority of infected adults, the symptoms are mild, and more than 85% completely recover. however, the remainder may become seriously ill and some may die. more severe symptoms include difficulty in breathing, pneumonia, acute respiratory distress syndrome, and septic shock leading to multiple organ failure such as heart, liver, and kidney failure [2] . until now, there is limited evidence that maternal vertical transmission can occur, and newborn infection if occurs is due to perinatal transmission rather than prenatal [9] . it was also found that there is no transmission of the virus through breast milk; therefore, cessation of breast feeding from covid-19-infected mothers is not recommended, and infected mothers are strictly advised to follow preventive precautions such as handwashing, cleaning the breast before feeding, and using masks during breast feeding [10] . laboratory findings from children are rather similar to those in adults and include a white blood cell count that is typically normal or reduced with decreased neutrophil count and/or lymphocyte counts. thrombocytopenia may occur. c-reactive protein (crp) and procalcitonin levels are often normal. in severe cases, elevated liver enzymes, lactate dehydrogenase levels, as well as an abnormal coagulation and elevated serum ferritin and d-dimers have been reported [5] . radiologic findings in children are similar to those of adults. chest radiography mostly shows bilateral patchy airspace consolidations mainly at the periphery of the lungs, peri-bronchial thickening, and ground-glass opacities. chest computed tomography (ct) scans mostly show airspace consolidations and ground-glass opacities [5] . until now, there is no definitive evidence-based drug therapy for covid-19 neither in adults nor in the pediatric populations. current management for covid-19 is largely symptomatic and supportive care. supportive measures include sufficient fluid and caloric intake, antipyretics, oxygenation, anticoagulants, and prophylactic antimicrobial therapy to prevent superadded bacterial or fungal infections. the aim is to stabilize the clinical condition and prevent further deterioration as organ failure and secondary infections. it is better for children with mild symptoms to stay at home under medical supervision. if the child condition is deteriorating, then the child should be hospitalized as advised by the treating pediatrician [11] . confirmation of the information credibility is essential for healthcare professionals and the public in general. during crisis, rumors and false stories, misleading information, and unreliable data are sadly shared via social media leading to a state of instability and uncertainty among the community members and causing mistrust in the healthcare providers [12] . pediatricians and all other healthcare team must be cautious about starting therapies based on news or social media reports and should rely on trusted sources of evidence-based information from reliable credited sources of updated information and share those with the families in their care [13] . it is equally important that families be aware that many of what is called sham remedies have been promoted to the public. many sham treatments have been widely disseminated on social media. these include, for example, drinking warm water, gargling with saline or garlic, drinking lemon juice with honey or black seeds, use of specific homeopathic or alternative medicines, and drinking specific alcoholic drinks. none of these remedies have been proven effective in prevention or treatment, and some have been shown to be harmful, and therefore, should not be recommended [14] . healthcare facilities all over the world became suddenly overwhelmed by unexpectedly treating thousands of covid-19 patients at the same time. this has created marked congestion and an unpreceded chaos in the healthcare facilities especially in the populated regions. this has its adverse impacts and many people and particularly infants and children were and still (until the time of writing this manuscript) unable to get the proper medical care they actually need. suggested short-term measures have been proposed to the countries all over the world by the who in response to covid-19 pandemic. a comprehensive guidance to countries on the types of actions and adjustments needed to support the response [15] . there is an urging challenge of how to provide the required healthcare needed by infants and children in due time and place avoiding the possibility to catch sars-cov-2 infection if they go to seek medical advice at hospitals or healthcare facilities. the mandatory precautions including the fundamental physical distancing and infection control requirements will affect the traditional routine medical care beside that many parents are afraid to leave homes or do not want to take their child to a medical care facility with a possibility to be infected from other sick children. therefore, care givers are encouraged to share their worries and information with their pediatricians via phone calls, e-mails, or other social media applications [16] . telemedicine has been dramatically exploited in the past few months as a useful tool for long-distance clinical care more than 10-folds what has happened to it during the past decade. telemedicine can be used for education, counselling parents, and health management, and its role is professionally enlarging in many regions such as the usa and europe, but awaiting further regulatory approvals in other regions such as in egypt [17] . telemedicine may be of limited practical application in some low-income countries where resources are limited due to technical, economic, cultural, or geographical factors, but yet it needs to be tried as an alternative to face-to-face communication to get the required medical advice especially in the straight forward medical problems and concerns. with appropriate attention and caution for some issues such as patient safety, confidentiality, and suspected missed clinical information, telemedicine can be an effective way to help patients during the present covid-19 pandemic [16, 18] . it is estimated that millions of infants and children worldwide have just missed and will continue to miss their required essential vaccinations with a fear that some vaccine preventable diseases (vpd) may come back as measles and poliomyelitis. the who has stressed the importance of maintaining the essential health services during covid-19 pandemic and identified immunization as a core health service that must be offered to the target chirdren [18] . special planning and extra ordinary efforts are required to be applied quickly for vulnerable pediatric populations at increased risk of morbidity and mortality as refugees and children under custody. however, it was advised that mass vaccination campaigns should be temporarily halted or postponed to follow recommendations on maintaining proper physical distancing and infection control precautions required to combat covid-19 transmission during such campaigns [19] . covid-19 crisis has forced governments to close nurseries and schools as well as sports' clubs and gardens. it is not allowed to travel to areas where recreations can be practiced. children are not allowed to meet their friends and other relatives. they are locked down at their houses having the same repeated daily routine. similar to adults, children are likely to suffer anxiety, fear, and other psychological manifestations. children may experience negative feelings and thoughts such as fear of being hospitalized, taking injections up to a fear of their family member loss, or even their own death. this may present as behavioral disturbances, loss of appetite, sleep problems, nightmares, and many other stress-related disorders. the adolescents are also affected but to a lesser extent than children as adolescents seem to express an excellent ability to manage situations of insecurity and have a better adaptation with the changing circumstances [20] . in the wake of the global lockdown, schools are closed. children are not only obliged to stay at home for longer hours and become more vulnerable to domestic violence and other sorts of child abuse, but also there is an anticipated decrease in reporting of child maltreatment cases which includes sexual, physical, and emotional abuse. adding other adverse factors as parental unemployment and economic burdens will be negatively reflected on providing a safe healthy environment for the children to stay in. it is clear now that the measures which have been taken to control the spread of covid-19 are causing what may be called a "secondary pandemic" of child neglect and abuse [21] . the living conditions in refugee camps, crowded reception centers, or detention facilities are unfortunately a very suitable environment for covid-19 spread. there is lack of proper healthcare services and sanitary precautions beside the suboptimal physical and medical status of the children at such places. displaced children are among those with the most limited access to prevention services, testing, treatment, and other essential support. in addition, the pandemic and containment measures are likely to have negative consequences for their safety and education, which were pre-carious even before the outbreak of the disease [22] . many families are struggling with their daily lives. parents and care givers being out of work or even have already lost their jobs during the pandemic do not have enough financial resources to cope with the many changes occurring. on the other hand, the basic needs of infants, children, and adolescents must be fulfilled. with the world economy sagging into recession, it is feared that this hardship will remain and probably increase over the coming months, if not years [23] . being more vulnerable to catch infections, children suffering of chronic diseases are at high risk to get covid-19 infection. those children are suffering of marked decrease of their protective mechanisms and inner barriers to combat infections. not only that, but also if they developed covid-19 infection, there will be a potential increased risk of deterioration of their clinical status. prevention is the principal key factor for those children. they should not catch covid-19 at the first place. they must strictly stay at home avoiding any possibility to catch infection. if covid-19 infection is suspected, they must seek medical advice promptly. infants < 1 year of age and children with certain serious underlying conditions appear to be at greater risk for severe disease. the most commonly reported underlying conditions in covid-19 pediatric patients were chronic pulmonary disease, cardiovascular disease, immunosuppression (e.g., related to cancer, chemotherapy, radiation therapy, hematopoietic cell or solid organ transplant, and high doses of glucocorticoids) [24] . the overwhelming current covd-19 ongoing disaster should not make us forget other serious medical and surgical diseases and emergencies that children may suffer. pediatricians and pediatric hospitals must be prepared to provide rapid, efficient, and safe medical management accordingly. in its recent position statement, the international pediatric association (ipa) has strongly recommended that the primary care and hospital resources for children must be maintained during the current covid-19 pandemic, in order to ensure addressing the child and adolescent health priorities and providing required health management services for children with more severe covid-19 manifestations [25] . the mandatory lockdown and inevitable social distancing measures due to the covid-19 pandemic has forced the governments in many countries to close nurseries, child care centers, schools, training centers, and higher education facilities as universities and institutions. these closures have affected millions of students worldwide not only retarding their educational aspects, but also adversely affecting their emotional status and well-being. whenever the schools are reopened, the protection of children and educational facilities is particularly important. precautions are necessary to prevent the potential spread of covid-19 in school settings; however, care must also be taken to avoid stigmatizing students and staff who may have been exposed to the virus [26] . staying at home for long time and closure of sports clubs and lack of physical activities may eventually result in marked weight increase in children and adolescents and development of obesity problem with all its negative consequences. pediatricians have to alert parents and care givers for this increasing heath problem during lockdowns. on the other hand, in many developing countries, the opposite may occur; the economic adverse effect of covid-19 may result in marked decrease in the families' abilities to ensure enough food supplies for their children resulting in their suffering of undernourishment. nutritious food intake has to be offered to every individual. proper nutrition and hydration are vital for health these days. intake of more water and avoiding sugars are essential. children and adolescents should eat a variety of fresh and unprocessed foods every day to get enough vitamins and minerals [27] . what is expected after covid-19 pandemic is over? the covid-19 pandemic caused an unpreceded disturbance in the global health systems. humanity is hopeful that it may come to an end sooner rather than later especially if an effective antiviral treatment(s) and/or vaccine(s) are developed rapidly. until that moment, prevention of infection and symptomatic and supportive treatment are the best to do. therefore, revising infant and child health and healthcare plans, and prioritizing the healthcare projects are essential and mandatory issues as the world will never be the same again. both globalization and urbanization that have been two of the world's most powerful drivers in the past few decades are anticipated to be reversed by covid-19 leading to increasing the distances among people and between countries due to border closures and restricted international travel [28] . so far, the covid-19 crisis has had a great impact on child health and healthcare all over the world, not only from the medical aspect, but also from the social, psychologic, economic, and educational aspects. all these implications have to be identified and dealt with properly to avoid their short-and long-term consequences on an individual bases approach. world health organization (who). (2020) statement on the second meeting of the international health regulations (2005) emergency committee regarding the outbreak of novel coronavirus (2019-ncov) china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china stability and infectivity of coronaviruses in inanimate environments epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china coronavirus infections in children including covid-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children children and covid-19. (2020) national institute for public health and the environment, ministry of health, welfare and sport spread of sars-cov-2 in the icelandic population 2020) maternal and perinatal outcomes with covid-19: a systematic review of 108 pregnancies q&a on covid-19, pregnancy, childbirth and breastfeeding infection prevention and control during health care when novel coronavirus (ncov) infection is suspected covid-19: how to be careful with trust and expertise on social media us centers for disease control and prevention (cdc). (2020) covid-19 databases and journals coronavirus disease (covid-19) advice for the public: myth busters 2020) health systems governance and financing & covid-19 available at global telemedicine implementation and integration within health systems to fight the covid-19 pandemic: a call to action in-person health care as option b virtually perfect? telemedicine for covid-19 guiding principles for immunization activities during the covid-19 pandemic the psycho-social effects of covid-19 on italian adolescents' attitudes and behaviors is a secondary pandemic on its way? institute of health visiting united nations high commissioner for refugees (2020) joint statement as covid-19 pandemic continues, forcibly displaced children need more support than ever us centers for disease control and prevention (cdc). (2020) coronavirus disease cdc covid-19 response team (2020) coronavirus disease 2019 in children -united states promoting and supporting children's health and healthcare during covid-19 -international paediatric association position statement world health organization (who). (2020) schools & covid-19 -control & prevention guide available at the world economic forum covid action platform. the post-covid-19 world could be less global and less urban springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors stated no acknowledgement. both authors contributed equally in all steps of preparation of this work. the author(s) read and approved the final manuscript. the authors declared that they receive no funding whatsoever for this work. ethics approval and consent to participate not applicable the authors are giving their consent for publication. the authors declared that they have no conflicts of interest.author details 1 faculty of medicine, cairo university, cairo, egypt. 2 misr international university, cairo, egypt.received: 8 june 2020 accepted: 20 july 2020 key: cord-029852-yighpvle authors: chandrasekar, shyam; john, joseph; islam, kamirul title: renal complications in children with hematotoxic snakebite: more information needed date: 2020-07-29 journal: indian pediatr doi: 10.1007/s13312-020-1904-9 sha: doc_id: 29852 cord_uid: yighpvle nan we read with interest the recent article on renal complications in children with hematotoxic snakebite by islam, et al. [1] . we herein wish to raise some pertinent issues to assist in better understanding of this article. (i) though the aim of the study was to ascertain clinical and laboratory indicators predicting acute kidney injury (aki) "early" in children with snakebite envenomation; these predictors have neither been mentioned in the results nor in tables, unlike an earlier study [2] , where various clinical and laboratory parameters were reported as predictors. (ii) there is no mention of baseline hemoglobin, maximum fall in hemoglobin, serum lactate dehydrogenase, evidence of myoglobinuria, hemodynamic status, cardiac dysrhythmias, cardiac dysfunction, evidence of adrenal hemorrhage, blood pressure, creatinine etc. which would have helped interpret the results better. these would have looked at creating a list of predictors of renal complications too [2] . similarly, aki could have been due to numerous other confounders like shock, dehydration, nephrotoxic antibiotics adminis-tration etc., which have not been detailed. similarly, whether drug dose adjustments were made in those with aki has also not been mentioned. (iii) aki was appropriately defined based on the kidney disease: improving global outcomes (kdigo) criteria [3] . however, these patients were then followed up for 6 months [1] , the reason for which is not clear, because for labelling chronic kidney disease, a 3-month follow-up would have been enough. (iv) though one of the criteria for dialysis mentioned in renal complications in children with hematotoxic snakebite: more information needed this study was hyperkalemia, but the reason why medical management was not considered as an option is not apparent. similarly, other reasons for dialysis like uremia, refractory metabolic acidosis too may have been indications for dialysis in these patients, which probably have not been included. (v) it was mentioned in the methodology that "peritoneal dialysis was done in the institution and hemodialysis in a referral hospital". whether these children were excluded or followed up is not clear. details of how these children were followed up are missing. how many of these children who underwent dialysis developed 'permanent renal damage' at the 6-month follow up too has not been mentioned by authors, which could have been new information for the readers. (vi) similarly, it is not clear as to whether the authors had taken the aki stage at presentation or the maximum aki stage as per the kdigo guidelines during the hospital stay. (vii) what were the indications and timing for the renal biopsy? was doing a renal biopsy in the setting of an aki reasonably justified and ethically correct? snake-bites being medicolegal cases, it looks improbable that a renal biopsy was possible in 100% of the children who died but in only 81.4% of those who survived. (viii) it is mentioned that 59 out of 364 children (16.2%) had "permanent renal damage" [1] . this is inappropriate as the denominator should exclude the deaths as permanent renal damage can be assessed only in those who survived the episode. so, we feel that the 16 children who succumbed should have been excluded, thus increasing the percentage of children with permanent renal damage to 16.9%. (ix) we presume that the median number of vials of antisnake venom (asv) used in both groups have been mentioned in (xi) the authors have mentioned mean "bite to asv administration time" as 36.4 (5.9) minutes which seems practically difficult as their study population included patients from faraway places like the neighboring states of bihar and jharkhand. besides, the whole blood clotting time itself takes 20 minutes to process after which the asv must have been administered as per standard practice, which further delays the time to asv administration. hence, the mentioned time does not appear to be possible in these settings, as also seen in a previous study from the same region where this interval was 270 minutes [4] . (i) different clinical and laboratory parameters were already described in table i and ii of the article, and some of the determinants are similar to previous reports [2] . reasons for discrepancy with published literature were mentioned in the discussion section of the article. (ii) detailed baseline data were collected, but all of it could not be presented due to limitation on the size of the manuscript. serum ldh and adrenal hemorrhage were not assessed in our study. we appreciate your concern about cardiac dysfunction, hemodynamic status etc, but different parameters (requirement of ventilation, serum potassium level, requirement of inotropes) mentioned in table i act as surrogate markers of them. we used logistic regression and adjusted odds ratio to remove confounders. nephrotoxic drugs are avoided in viper-bite patients according to unit protocol in our set-up. (iii) in a previous research project in the same setting, the investigators noted some long-term toxicity of snakebite, as also previously reported [2] . hence we decided on a follow-up period of 6 months. (iv) in the paper, we had mentioned the unit protocol for dialysis. opinion of a nephrologist was sought before starting dialysis in all patients. (v) all study patients were followed up at our nephrology specialty clinic after discharge from hospital. (vi) if at any point of time during the hospital stay, the children developed aki, we included them in the aki group. the initial version of the manuscript had information on aki grades, but it was later edited out on the suggestion of reviewers. (vii) we did not perform renal biopsy in aki settings. we considered renal biopsy in the children who developed permanent renal damage, as per opinion of nephrologist. before doing renal biopsy, we took informed written consent from parents. snake bite, being a medicolegal case, autopsy is done in every death. samples from viscera are also routinely collected by forensic expert. we could convince parents of all such children for consent for renal histopathology examination. (viii) we used the study population as denominator because we want to identify renal complication in children with hematotoxic bites, not in the surviving children. (ix) as the data are skewed, we had summarized it as median and interquartile range [1] . the mean (sd) number of vials required were 12.3 (9.1) and 21.5 (18.9) in aki and no aki groups, respectively. (x) it is the regression model used in the study. (xi) the mentioned time is only for those who did not develop aki; it was higher for those who developed volume 57 __ july 15, 2020 correspondence aki (74.5 minutes) [1] . if we consider all children, mean time between bite and asv administration was 51.2 minutes. moreover, many of the children received the first dose of asv at the place of initial medical care, before referral to our center. the study referred to by the readers was conducted in 2012-2016 and included both children and adults [3] . due to the sustained awareness campaigns and easy availability of asv, bite to needle time is gradually decreasing. transport vehicles are also easily available for children under different government schemes. moreover, our study included children with viper-bite only, which is symptomatic at early stage leading to early seeking of healthcare. predictors of renal complications in children with hematotoxic snakebite clinical and laboratory parameters associated with acute kidney injury in patients with snakebite envenomation: a prospective observational study from myanmar summary of kdigo 2012 ckd guideline: behind the scenes, need for guidance, and a framework for moving forward a hospital based epidemiological study of snakebite in paschim medinipur district predictors of renal complications in children with hematotoxic snakebite clinical and laboratory para-meters associated with acute kidney injury in patients with snakebite envenomation: a prospective observational study from myanmar long-term health complications following snake envenoming a hospital based epidemiological study of snakebite in paschim medinipur district we read, with interest the evidence-based medicine viewpoint [1] on our recent publication [2] . the author of the viewpoint has made some notable points about the methodology, most of which were already acknowledged in our paper. the viewpoint includes some interesting observations that appear to be based on selective use of the data and has some key errors, which we wish to highlight.(i) "although a research question was not articulated…" the study hypothesis is clearly stated in the last sentence of the introduction.(ii) "the investigators chose a cluster rct design… it is difficult to judge which of the two designs is superior to compare community effects through individual empowerment of some members…" a cluster randomized design is the appropriate approach when the intervention is delivered at the level of the local population (tola). individual randomization is not possible when the intervention is delivered to a group (the self-help group). (iii) "the investigators used a computer program for randomizing pairs of tolas, although since only two tolas were randomized at a time, simple coin tossing is sufficient. paired randomization obviated the scope for allocation concealment…" there was complete allocation concealment as the tolas were assigned a code number and randomization took place in nottingham with the local trial team informed only after randomization had taken place. having the local team toss a coin would of course prevent allocation concealment.(iv) "it is also unclear what proportion of the children whose baseline data were collected, underwent data collection at the end of the study." this is stated in table 2 of the paper e.g. of 1377 children with baseline data for whz, 559 were followed up longitudinally with further data at 18 months [2] .(v) "first, it assumes that under natural circumstances, children's nutritional status declines over time. however, the authors showed no data supporting this presumption." nutritional indices deteriorated amongst children in both arms of the trial and this is a large sample. in these rural communities in bihar, we have shown that nutritional status does decline over time.(vi) "…analysis of the reasons for taking loans in the intervention arm shows that a very small proportion was used for food and supplies (in terms of percentage as well as absolute amount)." on referring to figure 3 of the paper [2] , we see that two of the top three reasons for taking loans were medical expenses and working capital for agriculture. both of key: cord-011333-yyhwtnza authors: faienza, maria felicia; chiarito, mariangela; molina-molina, emilio; shanmugam, harshitha; lammert, frank; krawczyk, marcin; d’amato, gabriele; portincasa, piero title: childhood obesity, cardiovascular and liver health: a growing epidemic with age date: 2020-02-04 journal: world j pediatr doi: 10.1007/s12519-020-00341-9 sha: doc_id: 11333 cord_uid: yyhwtnza background: the frequency of childhood obesity has increased over the last 3 decades, and the trend constitutes a worrisome epidemic worldwide. with the raising obesity risk, key aspects to consider are accurate body mass index classification, as well as metabolic and cardiovascular, and hepatic consequences. data sources: the authors performed a systematic literature search in pubmed and embase, using selected key words (obesity, childhood, cardiovascular, liver health). in particular, they focused their search on papers evaluating the impact of obesity on cardiovascular and liver health. results: we evaluated the current literature dealing with the impact of excessive body fat accumulation in childhood and across adulthood, as a predisposing factor to cardiovascular and hepatic alterations. we also evaluated the impact of physical and dietary behaviors starting from childhood on cardio-metabolic consequences. conclusions: the epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease. appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cardiovascular diseases, and diabetes risk during adulthood. obesity in children and adolescents has emerged as one of the most serious health problems, condition which threatens future health and longevity. over the past 30 years, childhood obesity rate has doubled and, in some cases, even tripled in developed countries [1] . according to the global health observatory data 2017 by world health organization (who), there are over 340 million obese children and adolescents aged [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] . the aim of this thematic review is to provide current data about the impact of excessive body fat accumulation in infancy across adulthood, as a sound predisposing factor of cardiovascular and hepatic consequences. we also discuss the impact of physical and dietary behaviors starting from childhood on obesity-related comorbidities. the rate of increase in obesity is faster in children than in adults [2] . countries with a rapid development, as china, are displaying a remarkable increase in childhood obesity, with the number of overweight and obese chinese children aged 7-18 years increasing by 28 times from 1985 to 2000 [3] . in the united states, the prevalence of obesity in the pediatric population reaches 18.5%, affecting almost 14 million of children and adolescents [4] . in italy, about 21% of children are overweight and 10% are obese, with obesity trends expected to increase further [5] . a similar trend emerged in a previous ultrasonographic study in children and adolescents in southern italy [6] . obese children have a fivefold increased risk to stay obese during adulthood, as compared to normal-weight children [7, 8] . infancy and childhood are critical moments in which key metabolic changes occur with health effects later in life. both the children born large for gestational age or small for gestational age have the risk to develop obesity and metabolic consequences (fig. 1) . genetic factors play only a minor role whilst social, economic, and environmental factors drive the increase of the obesity prevalence. the role of epigenetic factors at an early age is also important in determining adulthood metabolic abnormalities [9] [10] [11] [12] [13] . table 1 depicts the potential weight-related comorbidities in obese children. obese children are more susceptible to cardiovascular diseases (cvd) [14] [15] [16] [17] , metabolic alterations [18, 19] , orthopedic complications, and psychosocial disorders, such as low self-esteem, anxiety, social isolation, and poor academic performance [20] . in addition, obese children may show abnormalities in the liver, reproductive system, brain, as well as increased blood pressure, impaired gluco-lipid metabolism, and sleep apnea. thus, the priority is to design preventive measures to halt the number of obese children becoming unhealthy during adulthood [21] . obesity results from excessive fat accumulation in the body, usually assessed by body mass index (bmi), i.e., body weight (kg) divided by the square of height (m 2 ). according to the international classification by the who, adults are considered overweight when bmi ≥ 25 kg/m 2 and obese if bmi ≥ 30 kg/m 2 . incorrect evaluation of bmi as indicator of body adiposity can occur when muscle in children up to 2 years, the diagnosis of overweight and obesity relies on the weight/length ratio using the who 2006 reference curves. for children over 2 years, the diagnosis is based on the use of bmi using the who 2006 reference curves up to 5 years, and the who 2007 reference curves thereafter. the diagnosis of overweight is made for bmi values ≥ 85th percentile and < 95th percentile, while obesity is defined by bmi values ≥ 95th percentile [22, 23] . the 99th percentile is the cut-off used to define severe obesity since this value corresponds to a higher prevalence of cardio-metabolic risk factors and persistence of obesity later in life, as compared with lower percentiles [14] . however, the who terminology used to define severe obesity differs from younger (up to 5 years of age) compared to older children and adolescents. indeed, the 99th percentile identifies obesity in the former group, and severe obesity in the latter. the different cut-off used to define these conditions is justified by the differences in growth process at different ages [24, 25] . the recommendation to use the who reference curves relies on their higher sensibility in identifying overweight and obese children. indeed, the italian bmi thresholds [26] underestimated the prevalence, likely due to the curves based on dates collected in a time when the increase in obesity had already occurred [27] . body composition can change among different ethnicities. for example, within the same bmi, non-hispanic black children and adolescents show lower percentages of fat mass than non-hispanic white or mexican americans. this condition explains why they are less prone to become obese [28] . singapore chinese adolescents, on the other hand, tend to have higher fat mass than dutch caucasian adolescents [29] , and they are more predisposed to develop obesity-related consequences; hence, the cut-off to define overweight and obesity in asian children and adolescents is lower [30] . notably, in a recent meta-analysis, the number of genomic loci associated with height and bmi was disproportionately increased compared to previously published genome-wideassociated studies [31] . the authors suggest that the discovery of new loci will increase prediction accuracy and provide further data to explain complex trait biology. cvds are the most frequent cause of morbidity and mortality globally. atherosclerosis is one of the main contributing factors for cvd. this process begins already during childhood mostly under the influence of environmental factors. some studies suggest that maternal weight gain in early pregnancy may be a critical period for an adverse childhood cardiovascular risk profile [32] . other studies found an association between bmi in childhood and increased risk of adulthood cvd and mortality. twig et al. examined bmi in a cohort of 2,300,000 israeli aged 16 and 19 years, in the search for a correlation between death and cvd later in life. in the 40-year follow-up, a correlation existed between increased risk of cardiovascular events and all-cause mortality in adults whose bmi increased during adolescence [33] . baker et al. found similar results in a cohort of 276,853 danish children. in particular, the increase of 1 unit in bmi z score in 13-year-old children almost doubled the risk of adulthood cvd [34] . bjorge et al. found a correlation of obesity with premature death, even if the critical age range associated with such increased risk remained uncertain [35] . concerning the critical bmi threshold, aune et al. conducted a meta-analysis of the available studies investigating the correlations of bmi with all-cause mortality. the nadir existed at bmi 23-24 kg/m 2 among non-smokers, 22-23 kg/m 2 among healthy non-smokers, and 20-22 kg/m 2 when the analysis was limited to studies with longer durations of follow-up [36] . due to the strong correlation between childhood obesity and the cvd risk during adulthood, several studies aimed to identify early markers of cvd. mcgill et al. demonstrated the presence of early atherosclerotic lesions [37] , which appear first in the distal aorta and then in the carotid arteries. carotid intima-media thickness (cimt) is considered a valid marker of pre-clinical atherosclerosis, and several studies support its role as independent predictor of cvd even in asymptomatic subjects [38] . in addition, cimt may be a good marker of cardiovascular alterations in children, although studies show some discrepancies [39] . freedman et al. analyzed a cohort of 513 subjects and detected a positive correlation between bmi measured throughout life and cimt at age of 35 years. these associations, however, were restricted to adults who continued to be obese. in particular, they found the bmi-cvd correlation to be weak before the age of 11 years, but it progressively increased with age, reaching the strongest correlation among adolescents aged 15-18 years [40] . juonala et al. found no significant association between bmi measured at 3, 6, 9 or 15 years and cimt 21 years later, even though a positive correlation existed with bmi at ages 12 and 18 [41] . in a longer followup, wright et al. did not find any significant correlations between childhood bmi and cimt at the age of 50 [42] . the raising prevalence of obesity, metabolic syndrome together with insulin resistance [43] , worldwide is associated with liver abnormalities encompassing the clinical spectrum of nonalcoholic fatty liver disease (nafld). nafld occurs in the absence of other triggering factors such as hepatitis c, alcohol consumption, parenteral nutrition, or steatogenic drugs. whereas nonalcoholic fatty liver (nafl)-a relatively benign condition [44] -implies more than 5% of fatty hepatocytes without hepatocellular injury, the term nonalcoholic steatohepatitis (nash) is associated with fatty liver and hepatocellular injury revealed by the histological findings of hepatocyte ballooning, with or without fibrosis [45] . a third category is nash cirrhosis, showing current or previous evidence of histologic nash or nafl. ethnicity, age, metabolic syndrome, insulin resistance [46, 47] , dyslipidemia [48] , high intake of dietary fructose [49] [50] [51] , all influence the development of nafld [52] , with males showing higher risk than females [53] . in children, nafld is now the most common cause of liver disease [54] [55] [56] , and this trend is somewhat worrisome because even in children nash may evolve to fibrosis, cirrhosis (as early as 8 years) [57, 58] , and even liver failure [59] [60] [61] . this correlation nafld/nash, however, seems weaker in children than adults, suggesting a milder phenotype of nafld [62] . since adults with nafld have high risk to die from cardiovascular disease, clinicians and the public should be aware that children with nafld must receive a full evaluation to detect or prevent important comorbidities listed in table 1 , and including type 2 diabetes mellitus, and cardiovascular disease. based on elevated serum aminotransferases, imaging or liver biopsy, the prevalence of nafld in children and adolescents and in obese children ranges between 6 and 38%, depending on the context, the population studied, and the ethnicity ( table 2) . as reported in adults, also children with nafld remain mostly asymptomatic [8] or describe mild symptoms such as pain in the right upper quadrant or nonspecific symptoms, including fatigue and abdominal discomfort [63, 64] , or symptoms due to obesity-associated comorbidities (i.e., gallstones, gastroesophageal reflux disease, etc.) [65] . thus, physical examination should look for comorbidities, splenomegaly, and end-stage liver disease (cirrhosis). serum abnormalities include elevated liver transaminases, alkaline phosphatase, and gamma-glutamyl transpeptidase [8, 56, 58, 66, 67] which tend to improve upon adoption of healthy lifestyles (see below) [66, 68] . notably, even in children with nash the levels of aminotransferases may remain normal [69] , and this possibility is intrinsic to the limited sensitivity and specificity of serum aminotransferase levels for clinically significant nafld. due to the high and further raising prevalence of obesity and metabolic syndrome in children, recent guidelines recommend the screening of obese children as the primary screening for nafld. steps vary according to the existence of concomitant comorbidities and levels of serum transaminases (i.e., normal, moderate, and > 2 upper normal limit persistent elevation) [15] . at least in children, imaging techniques for the screening diagnosis of nafld are not routinely recommended [15, 70] , due to poor sensitivity and specificity (ultrasonography) [71, 72] , poor correlation with steatohepatitis, fibrosis (magnetic resonance) [73] [74] [75] , or detection of only advanced fibrosis, costs, lack of definitive cut-off values and need validation (magnetic resonance elastography) [76] . the role of liver biopsy (which ultimately confirms the diagnosis of nafld and determines the severity of the fatty liver disease with the presence and extent of inflammation and fibrosis [15, 56] ) needs to be discussed on a case-by-case basis. cases should include forms of more progressive nafld, possibility of table 2 studies relating diagnosis of nonalcoholic fatty liver disease with prevalence of nonalcoholic fatty liver disease in children/adolescents nhanes national health and nutrition examination surveys, nash nonalcoholic steatohepatitis, nafld nonalcoholic fatty liver disease a limited sensitivity and specificity for clinically significant nafld [71, 72] other liver diseases, and morbidly obese scheduled for bariatric surgery. in spite of the emerging epidemics of pediatric nafld worldwide, there is no established treatment so far, even when considering metformin (for improving insulin sensitivity), vitamin e (for reducing inflammatory changes in the liver), cysteamine bitartrate (as antioxidant agent), and ursodeoxycholic acid (for reducing the bile acid hepatotoxic effect) [15] . as a matter of fact, aggressive treatment of comorbidities and lifestyle intervention (diet, exercise, weight management, counseling) remain the mainstay of treatment even in pediatric nafld [77, 78] . physical inactivity affects a vast majority of children and adolescents who become prone to high obesity rates and related diseases, including cvd and nafld. promotion of programs involving physical activity has, therefore, become a relevant topic in health policy. messing et al. conclude that "multi-component interventions in childcare facilities and schools stand out prominently" [79] . molina-molina et al. have recently discussed several mechanisms for which physical inactivity might affect cvd [80] . between ages 5-6 and 8-9, there are similar increases in physical inactivity for both boys and girls, as reflected in a british cohort of 57 primary schools [81] . already during adolescence, physical activity starts to decrease, contrarily to body weight [82] . a series of factors such as dietary intake and sedentary behaviors contribute to childhood obesity [83] . the phenotype of obesity could differ depending on the children's age, gender, and family characteristics. studies on television viewing and total recreational screen time in youth might be associated with adverse cvd risk factors, such as adiposity, increased triglycerides, and metabolic syndrome [84] . other authors have linked sedentary time with diabetes and high blood pressure in obese and overweight adolescents [85, 86] . several hours of television viewing by adolescents doubles the odds for metabolic syndrome later in adulthood, as observed in a study by wennberg et al. [87] . not only sedentary behaviors, but above 10 hours of night time sleep in primary school children from germany was also associated with obesity [88] . poor dietary habits in children also increase the risk of obesity. among children, parents and caretakers have the greatest influence on their eating habits [89] . according to a study by lipowska et al., children's eating patterns are influenced by the parent-child interaction, shaping the nutritional status, which ultimately contributes to their health [90] . nutritional status of children can also have direct effect on growth, development, and nutrition related-health problems [91] . the portion size of food consumed each day depends on age, sex, stage of growth, body weight and size, and level of physical activity [92] . children who consume large portion sizes, hyper-caloric and high-energy-dense foods gain excess weight and body fat, while cvd risk increases [93] . reduced consumption of fats, carbohydrates, and added sugars and more intakes of vegetables and fruits could decrease obesity in children and risk to cvd [94] . both an optimal nutrition and regular physical activity increase the chances of healthy maturation during childhood [95] . according to elmaogullari et al., age and bmi are the most important factors to be considered in childhood obesity [96] . overall, changing dietary patterns seems the best treatment against obesity, cvd, diabetes, and nafld. the epidemic of obesity and obesity-related comorbidities worldwide raises concerns about the impact of early abnormalities during childhood and adolescence. exact evaluation of body composition parameters is required at an early age, to classify correctly the metabolic abnormalities, and to decrease the chances of further dysmetabolic changes at a later age. two key abnormalities in this context include cardiovascular diseases, and nonalcoholic fatty liver disease, a wide spectrum of conditions ranging from simple liver steatosis, steatohepatitis, and (metabolic) cirrhosis. notably, nonalcoholic fatty liver is associated with increased risk of mortality in the adults. this means that appropriate metabolic screenings and associated comorbidities should start as early as possible in obese children and adolescents. nevertheless, improving dietary intake and increasing physical activity performance are to date the best therapeutic tools in children to weaken the onset of obesity, cvd, and diabetes risk during adulthood. or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. no financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article. global prevalence and trends of overweight and obesity among preschool children global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the 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youth: approaches to the prevention and management of childhood obesity: a scientific statement from the video game playing is independently associated with blood pressure and lipids in overweight and obese adolescents screen viewing and diabetes risk factors in overweight and obese adolescents hammarstrom a. television viewing and low leisure-time physical activity in adolescence independently predict the metabolic syndrome in mid-adulthood crosssectional associations of objectively assessed sleep duration with physical activity, bmi and television viewing in german primary school children dietary behaviors and caregiver perceptions of overweight and obesity among chinese preschool children gender and body-fat status as predictors of parental feeding styles and children's nutritional knowledge, eating habits and behaviours prevalence of obesity in the united states development of food intake patterns for the mypyramid food guidance system reduction of risk for cardiovascular disease in children and adolescents dietary and policy priorities for cardiovascular disease, diabetes, and obesity: a comprehensive review physical activity and obesity in children risk factors that affect metabolic health status in obese children key: cord-017245-kxqh32ip authors: sharma, avinash; singh, surjit title: kawasaki disease date: 2016-06-02 journal: pediatric rheumatology doi: 10.1007/978-981-10-1750-6_35 sha: doc_id: 17245 cord_uid: kxqh32ip to learn about the epidemiology, aetiopathogenesis, clinical features and differential diagnosis of kawasaki disease (kd) 1. to learn about the epidemiology, aetiopathogenesis, clinical features and differential diagnosis of kawasaki disease (kd) 2. to learn about the acute and long-term management of kd a 2-year-old boy presented with high-grade fever for 8 days. the baby had been irritable and fretful and was refusing feeds. the mother consulted a paediatrician who prescribed amoxicillin. the fever, however, persisted and the baby developed swelling over the dorsum of hands and feet. the mother also noticed a rash over the trunk along with red lips and red tongue. both eyes were con-gested and there was a swelling on the left side of the neck. as the fever was continuing, she sought consultation from another paediatrician who opined that the baby needed hospitalization for further workup. he ordered an infection workup, obtained blood and urine cultures and started intravenous ceftriaxone. the baby continued to run fever. investigations showed a neutrophilic leucocytosis, raised c-reactive protein levels and an elevated erythrocyte sedimentation rate. blood and urine cultures were sterile. at this time a clinical review suggested a possibility of this being kawasaki disease. 2d echocardiography did not reveal any coronary artery abnormality. the parents were counselled and a decision was taken to administer intravenous immunoglobulin (ivig) 2 g/kg along with aspirin 30 mg/kg/day. the baby showed prompt clinical improvement. the irritability disappeared within a few hours and the fever was passive by the next day. the mother noticed that the skin over fi ngers and toes had started to peel. a repeat haemogram at this time showed thrombocytosis. the dose of aspirin was reduced to 3 mg/kg/day and the baby was discharged with a follow-up appointment after 2 weeks. kawasaki disease (kd) is an acute, self-limiting, childhood medium-vessel vasculitis. initially described in 1967 by dr. tomisaku kawasaki in japanese children as an acute mucocutaneous lymph node syndrome [ 1 -3 ] , kd may lead to coronary artery abnormalities (caas) in up to 25 % of patients if left untreated. it is for this reason that kd is considered a medical emergency. kd is the most common cause of an acquired heart disease in children in developed countries. it is now often considered to be the most common vasculitic disorder in children. the three highest incidence fi gures of kd in the world come from the far east, viz., japan, korea and taiwan. in these countries, not only is the incidence very high, it is continuing to show a rise on a year-toyear basis [ 4 -10 ] . nationwide surveys conducted in japan since 1970 show that there have been three epidemics of kd in japan and also that the incidence of kd has increased by more than two times in the last two decades [ 6 -9 ] . japan reports the highest incidence of kd in the world -the present fi gure being 265/100,000 children below the age of 5 years. korea has the second highest incidence at 134.4/100,000 children below fi ve. in taiwan the current incidence is 82.8 per 100,000 [ 3 ] . based on statistical projections, it is estimated that by 2030, there will be 1 in 700 people living in taiwan with a history of kd. the corresponding fi gure for the usa is 1 in 1600 [ 4 -6 ] . the incidence of kd, however, has remained static in europe as well as north america. in india, anecdotal reports suggest that the recognition of kd has increased signifi cantly over the last two decades, but confi rmatory epidemiologic data on incidence are not available. a hospitalbased study from chandigarh showed that the incidence was 4.54/100,000 children below 15 years, but this fi gure is, in all likelihood, a gross underestimate [ 11 ] . there is no doubt, however, that over the years awareness of kd amongst paediatricians in india has increased signifi cantly. in the years to come, kd may soon replace rheumatic fever to become the leading cause of acquired heart disease in children in india, just as in japan, europe and north america. kd affects the young with 85 % of cases being below 5 years. although it is uncommon in children below 3 months, kd has been reported in neonates as well. in india, however, the median age of occurrence of kd is higher than in japan probably because kd in infancy and young children is being missed in our country. boys seem to be affected more commonly than girls. the male/female ratio at chandigarh has been 1.8:1 [ 2 , 3 , 11 -13 ] . fascinating data on seasonal variations in the incidence of kd have emerged, and these have linked the incidence fi gures of kd in some countries (especially japan and the usa) to tropospheric wind patterns emerging from central asia. such associations have, however, not been proven in other countries, as, for instance, canada [ 14 ] . the causation of kd still remains an enigma. there have been various hypotheses and postulates regarding its aetiology [ 15 , 16 ] . infectious : there are multiple factors which suggest that kd could be an infectious illness. occurrence of the disease in childhood and its virtual absence in adulthood suggest that it may be an infectious disease, and exposure in childhood confers protective immunity, thereby protecting the individuals in adulthood. rarity of its occurrence in early infancy suggests that maternal antibodies may have a protective effect. in addition, clustering of cases in some seasons, few reports suggesting occurrence in families or communities and the clinical presentation with fever, rash and lymphadenopathy, also suggests that it might be an infectious illness. however, till date, no infectious agent has been incriminated with certainty. although several micro-organisms (e.g. streptococcus , staphylococcus , epstein -barr virus , parvovirus , coronavirus ) have been linked with kd, infection alone cannot explain the pathogenesis of the disease. superantigen mediated : the presence of excess of t-lymphocytes with vβ 2 in the coronaries, intestinal mucosa and blood in children with kd suggests that the disease might be superantigen mediated. also, some of the clinical features of kd mimic those of toxic shock syndrome which is a superantigen-mediated disorder. environmental : researchers have also suggested that there might be an environmental trigger which causes this illness. seasonal and geographical clustering can be explained on this basis. genetic : recent evidence based on genomewide association studies suggests that a genetic basis of kd seems entirely plausible. evidence for this hypothesis comes from several epidemiologic data which show that children of certain genetic background seem to have a much higher predisposition to kd. for instance, the incidence of kd amongst children of japanese ancestry in hawaii is much higher than that in other races residing there. in fact, the incidence of kd in children of japanese ancestry there is almost similar to the incidence in japanese children residing in japan. however, till date, no single gene has been implicated, and there is no suggestion of it being an inherited disorder. onouchi et al. have shown the association between kd and itpkc functional polymorphisms [ 15 , 16 ] . it appears that kd is triggered in genetically predisposed children on exposure to some infectious or environmental agent. kd is a systemic medium-vessel vasculitic disorder with a striking predilection for the coronary arteries. this preferential involvement of the coronary arteries is unique to this condition. the infl ammation involves primarily the intima and media leading to damage of the internal and external elastic lamina. the affected vessel may subsequently become ectatic or may show aneurysmal dilatation. healing of these vessels may, in due course, result in stenosis and coronary thrombosis. large coronary aneurysms, and especially giant aneurysms, may never regain normal anatomy [ 2 , 3 ] . the clinical correlates of these changes should be borne in mind. on echocardiography, a coronary artery that gets dilated in the acute phase may regain its normal diameter during convalescence. however, intravascular ultrasound studies have shown that the vessel wall may never regain its recoil and elasticity even when echocardiography suggests a normal anatomy. coronary artery involvement can also be studied by doing computerized tomography (ct) angiographic studies ( fig. 35.1 ) . coronary vessels affected in kd have a predisposition to develop calcifi cation during the healing phase. this calcifi cation may render the affected vessels unsuitable for procedures such as angioplasty and stent placement later in life. kd can also affect other arteries like the femoral and axillary. these would, however, get involved only if there has been coronary artery 1. fever : this is often high grade, may exceed 40 °c and lasts for more than 5 days. the fever typically does not respond to antimicrobials and is associated with irritability which may at times be extreme. fever >5 days plus at least four of the following: • bilateral conjunctival injection • changes in oropharyngeal mucous membranes • changes in peripheral extremities • polymorphous rash • cervical lymphadenopathy illness not explained by any other disease condition hands followed by desquamation which starts from the periungual regions of hands and feet is a characteristic sign. these changes are seen in about 90 % of children with kd. later in the course of disease, beau's lines may develop over the nails which are transverse ridges more easily felt than seen over the nails. 5. rash : an erythematous, morbilliform, nonpruritic rash can occur which begins from the trunk and involves the perineal area. the rash is transient and fades by itself. the rash of kd can be polymorphous but is never vesicular. reported to be present in more than 90 % of affected children from developed countries, it may be diffi cult to perceive in children with dark skin. 6. lymphadenopathy : unilateral, tender, cervical lymphadenopathy occurs in about 60 % of children with kd. a diagnosis of kd can be made if a child with fever for more than 5 days fulfi ls four of the aforementioned fi ve criteria. if a child has fever for less than 5 days or has less than four criteria, the presence of coronary artery abnormalities (caas) detected on 2d echocardiography would also suggest a diagnosis of kd [ 17 ] . the diagnosis of kd can be very challenging and it may test the clinical acumen of even the most astute physician. it must be clearly understood that as there is no gold standard for diagnosis of kd, one does not know the sensitivity and specifi city of the diagnostic criteria for this condition [ 18 ] . from clinical experience, it is clear that if one applies the criteria very strictly, the specifi city would be high, but this would be at the cost of sensitivity. there is no doubt whatsoever that many children with kd may not fulfi l these criteria. further, as the clinical spectrum of kd evolves over a few days, the clinical fi ndings which may have been present during the fi rst few days of the illness may no longer be evident subsequent in the course [ 19 ] . in addition to these characteristic features, some additional fi ndings suggest the possibility of kd. perianal desquamation which appears earlier than the periungual desquamation is also characteristic, and its presence should be looked for in every child having fever for more than 5 days. a transient arthritis may be seen in a quarter of the patients and may, at times, be the presenting feature of kd. reactivation of the bcg scar can be noted in some infants with kd but this is extremely uncommon in our experience. hydrops of the gallbladder may be seen during the acute phase of kd. asymptomatic anterior uveitis is not uncommon during the fi rst few days of the illness. the clinical course in kd is divided into three phases [ 2 , 13 ] : acute febrile phase : this lasts from the onset of illness to 10-14 days and is characterized by high-grade fever, irritability, rash, strawberry tongue, red cracked lips and limb changes. signs of myocarditis may appear in this phase, which include tachycardia, s3 gallop and congestive cardiac failure. subacute phase : this lasts up to 4-6 weeks and ends with return of the acute phase reactants to normal. the caas fi rst appear in this phase. convalescent phase : this lasts for months to years during which healing of the vessels occurs with remodelling and scarring. beau's lines occur during this phase. if a child does not fulfi l the criteria and has less than four features, a diagnosis of incomplete kd is proffered. incomplete kd is commonly seen in infants, and ironically this is the group of patients who are at highest risk for the development of caa. the american heart association has suggested an algorithm for identifi cation of children who do not fulfi l the criteria for kd and are suspected to have kd and so have a risk of developing caa [ 17 ] . when a child with kd presents with features that are not usually seen in this condition, a diagnosis of atypical kd is proffered. clinical features which are unusual in kd include, but are not restricted to, nephritis, seizures, acute hepatitis, neurological obtundation or hypertension [ 13 , 17 ] . because of it being an acute febrile illness, the differential diagnosis of kd includes the common infectious illnesses of childhood: scarlet fever measles hhv-6 and hhv-7 toxic shock syndrome stevens-johnson syndrome drug hypersensitivity serum sickness systemic-onset juvenile idiopathic arthritis it cannot be overemphasized that there is no pathognomonic laboratory test for kd. however, there are several investigations which may support a clinical diagnosis of kd. a normocytic, normochromic anaemia with polymorphonuclear leucocytosis is usually seen. thrombocytosis is characteristically seen after day 10 of fever, but thrombocytopenia can also occur, especially when there is an accompanying macrophageactivation syndrome. acute phase reactants like the c-reactive protein (crp) and the erythrocyte sedimentation rate are elevated during the acute phase. sterile pyuria may be found which is of urethral origin; therefore, one may not obtain this fi nding if urine is obtained by suprapubic bladder aspiration. pyuria in a sick and febrile child is liable to be misdiagnosed as a urinary tract infection [ 2 , 3 ] . ultrasonography may reveal hydrops of the gallbladder. the gallbladder may sometimes enlarge to the extent that it becomes palpable on physical examination. cerebrospinal fl uid examination is not indicated in kd. if, however, it has been carried out, one may see fi ndings consistent with aseptic meningitis. lipid abnormalities are not unusual in children with kd. serum triglycerides and low-density lipoproteins are increased and high-density lipoproteins are reduced. these abnormalities begin in acute phase and may take several months to normalize. 2d echocardiography remains the imaging modality of choice for evaluation of coronary artery abnormalities in children with kd. caas include ectasia and/or aneurysms in proximal parts of left main coronary artery, left anterior descending artery, left circumfl ex artery and/or right coronary artery. this examination needs to be carried out by a pediatric cardiologist or a physician who has the requisite training and experience in evaluation of coronary arteries. coronary arteries are said to be dilated if the size is more than 1.5 times that of the adjacent segment. coronaries with diameter of more than 3 mm in a child less than 5 years of age and more than 4 mm in older children are said to be dilated. it is preferable to use z-scores for evaluation of coronaries in children. the use of these z-scores makes the follow-up and comparison easier and more reliable. children with kd can also have several other fi ndings on echocardiography. these include a decrease in ejection fraction (suggestive of myocarditis), mild valvular regurgitation, increased brightness of the coronary vessels and pericardial effusion. all of these are indicative of an ongoing infl ammatory process. it is important to diagnose and treat kd expeditiously as delays in therapy can result in serious morbidity and occasional mortality. the mortality rate of acute kd at chandigarh is approximately 0.8 %. caas can develop in a quarter of untreated patients with kd. every child suspected to have kd should be admitted and evaluated so that close clinical observation can be carried out. it cannot be overemphasized that clinical fi ndings in kd may change from day to day, and it is of the utmost importance that these be observed and recorded methodically. treatment of kd consists of intravenous immunoglobulin (ivig) and aspirin started within the fi rst 10-12 days of illness [ 2 , 3 , 20 -23 ] . ivig is given as a single intravenous infusion of 2 g/ kg. it is generally administered over 8-12 h, but the infusion must be started slowly so as to avoid occurrence of hypersensitivity reactions. ivig has been found to be very effective if given within the fi rst 10 days of onset of illness. in case, however, the child presents late and the acute phase reactants are still elevated or if there are caas on echocardiography, ivig should still be administered. the response to ivig is often dramatic, and the irritability, so characteristic of kd, often disappears within a few hours of initiation of the infusion. fever defervescence usually occurs within 12-18 h. administration of ivig can, on occasions, be associated with signifi cant adverse effects like headache and vomiting. these are thought to be secondary to a mild aseptic meningitis which is known to be associated with administration of ivig. these can usually be managed quite easily with symptomatic treatment. ensuring adequate hydration and a slow rate of infusion of ivig is said to decrease the occurrence of these adverse effects [ 22 -25 ] . aspirin in anti-infl ammatory doses (30-50 mg/kg/day) is started along with ivig and is continued till the child becomes afebrile. thereafter, aspirin is continued in antiplatelet doses (3-5 mg/kg/day) till a follow-up echocardiography is done and found to be normal at 6-8 weeks of illness. if caas are found in follow-up echocardiography, then aspirin needs to be continued for prolonged periods. additional anticoagulation (with warfarin or low molecular weight heparin) may be required in children with large aneurysms. while therapy with ivig and aspirin has dramatically reduced the occurrence of caas in kd, a small proportion of patients (approximately 3-5 %) still go on to develop caas despite seemingly appropriate therapy having been administered. approximately 10-20 % of patients with kd either do not respond or have a recrudescence of fever that recurs within 36 h of completion of ivig infusion. such patients are said to have refractory kd. several japanese investigators [ 22 -24 ] have put forth risk scoring systems for predicting refractory kd. ogata et al. [ 22 , 23 ] showed that children who were predicted to be ivig resistant on the basis of one such scoring system showed earlier defervescence of fever when treated pre-emptively with a combination of ivig and iv methylprednisolone as compared to the group given ivig alone. the occurrence of caas was also less in the former group. miura et al. [ 24 ] showed that iv methylprednisolone, when used along with ivig in children with refractory kd, does lead to faster defervescence. the effect, however, is not long-lasting. further, the incidence of development of caas is not signifi cantly different in two groups, and the occurrence of adverse effects was signifi cantly higher in the group treated with iv methylprednisolone plus ivig. it must be noted that these scoring systems do not seem to yield reliable results in populations other than japanese and therefore may have limited utility in day-to-day clinical practice in other countries. there is no consensus on the best modality for treatment of refractory kd. therapeutic options include a repeat dose of ivig, intravenous pulse methylprednisolone or anti-tnfα agents (e.g. infl iximab). cyclosporin and plasmapheresis have also been used in such circumstances [ 2 , 3 ] . children with kd who have no caa or have only transient coronary artery ectasia require lowdose aspirin (3-5 mg/kg/day) for initial 6-8 weeks. children with a single small coronary artery aneurysm should be given aspirin at least until the disappearance of aneurysm. however, in a child with giant coronary artery aneurysm, or one with multiple coronary aneurysms, long-term antiplatelet therapy along with antithrombotic therapy in the form of oral warfarin or low molecular heparin is mandated. male sex age less than 6 months thrombocytopenia at presentation neutropaenia, hyponatraemia and hypoalbuminaemia prolonged fever or recrudescence of fever failure to respond to ivig a landmark study by kato et al. [ 25 ] showed that up to 50 % of small-to medium-sized aneurysms resolve on follow-up. giant aneurysms (>8 mm size), however, do not resolve and are associated with signifi cant long-term morbidity. even when the coronary aneurysm appears to have resolved anatomically, functional vessel wall abnormalities are known to persist and may result in myocardial ischaemia/infarction later in life. kd can be associated with signifi cant long-term sequelae. this has been conclusively borne out through recently published long-term follow-up studies carried out at san diego, usa [ 26 ] . it is obvious that kd is no longer considered to be merely a one-time disease of childhood. considering the fact that the incidence of this disease is showing a steady increase in several countries, it is likely to emerge as the commonest cause for acquired heart disease in children the world over. many of these children would grow up to be adults with coronary sequelae. kd, therefore, needs to be considered as a disease of public health importance, and health planners need to be made aware of these facts. acute febrile mucocutaneous syndrome with lymphoid involvement with specifi c desquamation of the fi ngers and toes in children text book of pediatric rheumatology nelson textbook of pediatrics epidemiology of kawasaki disease in asia, europe, and the united states epidemiologic features of kawasaki disease in acute stages in taiwan, 1997-2010: effect of different case defi nitions in claims data analysis epidemiologic features of kawasaki disease in japan: results of the 2009-2010 nationwide survey changes in epidemic patterns of kawasaki disease in japan results of 12 nationwide epidemiological incidence surveys of kawasaki disease in japan epidemiologic pictures of kawasaki disease in japan: from the nationwide incidence survey in 1991 and 1992 monitoring the occurrence of kawasaki syndrome in the united states is kawasaki disease incidence rising in chandigarh a comparison of the clinical profi le of kawasaki disease in children from northern india above and below 5 years of age kawasaki disease -an indian perspective tropospheric winds from northeastern china carry the etiologic agent of kawasaki disease from its source to japan a replication study for association of itpkc and casp3 two-locus analysis in ivig unresponsiveness and coronary artery lesion in kawasaki disease a genome-wide association study identifi es three new risk loci for kawasaki disease diagnosis, treatment, and longterm management of kawasaki disease: a statement for health professionals from the committee on rheumatic fever, endocarditis and kawasaki disease, council on cardiovascular disease in the young kawasaki disease: issues in diagnosis and treatment -a developing country perspective delayed diagnosis of kawasaki syndrome: an analysis of the problem prediction of intravenous immunoglobulin unresponsiveness in patients with kawasaki disease prediction of resistance to intravenous immunoglobulin treatment in patients with kawasaki disease corticosteroid pulse combination therapy for refractory kawasaki disease: a randomized trial the strategy of immune globulin resistant kawasaki disease: a comparative study of additional immune globulin and steroid pulse therapy adverse effects of methylprednisolone pulse therapy in refractory kawasaki disease long-term consequences of kawasaki disease. a 10-to 21-year follow-up study of 594 patients acute myocardial ischemia in adults secondary to missed kawasaki disease in childhood 1. kd is the most common cause of acquired heart disease in children in developed countries. 2. the incidence of kd varies across the world; the highest has been reported from japan. 3. there is no gold standard for diagnosis of kd, it is to be considered in a child with prolonged pyrexia, irritability and sequential appearance of clinical signs of kd. 4. the management is with ivig and aspirin. the latter is used initially in antiinfl ammatory doses initially and then reduced to antiplatelet dose. the duration of treatment depends on the coronary artery involvement. 5. there are no clear guidelines for resistant kd, most centres would use a second dose of ivig, and other choices are steroids and infl iximab. key: cord-011503-bz6iwfan authors: mcgovern, ruth; gilvarry, eilish; addison, michelle; alderson, hayley; geijer-simpson, emma; lingam, raghu; smart, debbie; kaner, eileen title: the association between adverse child health, psychological, educational and social outcomes, and nondependent parental substance: a rapid evidence assessment date: 2018-05-08 journal: trauma violence abuse doi: 10.1177/1524838018772850 sha: doc_id: 11503 cord_uid: bz6iwfan background: between 5% and 30% of children in high-income countries live with a substance misusing parent, the majority of which is below dependent levels. however, little is understood about the impact of nondependent parental substance misuse upon children. methods: we searched the international literature using rigorous systematic methods to identify studies examining parental substance misuse and adverse outcomes in children. the inclusion criteria were cross-sectional, longitudinal, case-control, and cohort studies; of children aged 0–18 years whose parents are high-risk substance misusers; reporting on their health, psychological, substance use, educational, and social outcomes. results: we identified 36 papers (from 33 unique studies), most of which were assessed as being of medium to high methodological quality (n= 28). parental nondependent substance misuse was found to be associated with adversity in children, with strong evidence of an association with externalizing difficulties (n = 7 papers, all finding an association) and substance use (n = 23 papers, all finding an association) in adolescents and some evidence of adverse health outcomes in early childhood (n = 6/8 papers finding an association). there is less evidence of an association between parental substance misuse and adverse educational and social outcomes. the body of evidence was largest for parental alcohol misuse, with research examining the impact of parental illicit drug use being limited. conclusion: methodological limitations restrict our ability to make causal inference. nonetheless, the prevalence of adverse outcomes in children whose parents are nondependent substance misusers highlights the need for practitioners to intervene with this population before a parent has developed substance dependency. , affecting the quality of the relationship between the parent and the child (cleaver et al., 2011) , lower levels of parent-child supervision (kandel, 1990) , harsh parenting (kelley, lawreence, milletich, hollis, & henson, 2015) , higher prevalence of domestic violence and other traumatic events (sprang, staton-tindall, & clark, 2008) , and family deprivation (holland et al., 2014) . many factors have been highlighted as possible mechanisms that impact upon the child, these include direct exposure to alcohol and/or drug use and to other users (advisory council on the misuse of drugs, 2003) , ineffective parenting practices and a reduction in parenting capacity brought about by the intoxicating effect of the substance and/or withdrawal from it (kandel, 1990; miller, smyth, & mudar, 1999) , and a lack of parental emotional availability and warmth (suchman, rounsaville, decoste, & luthar, 2007) as well as greater likelihood of experiencing trauma such as abuse or neglect as a child (dube et al., 2001) . due to the potential negative impact on the child, parental substance dependence is often identified as a risk factor in child welfare and child protection assessments. in england, 18% of all children in need assessments identify parental drug misuse and 19% identify parental alcohol misuse (department for education, 2016) . in the united states, parental substance misuse has been associated with up to two thirds of all child maltreatment cases (traube, 2012) . it has been estimated that 162,000 children (1%) in england may live with a dependent opiate-using parent (department for work and pensions, 2017) and between 189,119 (1%) and 207,617 (2%) children who live with an alcohol-dependent parent (pryce et al., 2017) . a far larger number of children are likely to live with substance-misusing parents whose use does not meet the diagnostic criteria for dependence. research estimates that between 5% and 30% of children in european countries live with at least one parent who misuses substances (european monitoring centre for drugs and drug addiction [emcdda] , 2010), 10.5% of children in the united states, and 13% of children in australia (dawe et al., 2007) . in the united kingdom, 30% of children aged under 16 years live with at least one parent who misuses alcohol and 8% with a parent who misuses illicit drugs (manning, best, faulkner, & titherington, 2009) . moreover, 14% of uk infants (aged under 1 year) are exposed to parental problem, drinking, or illicit drug misuse (manning, 2011) , while u.s. research estimates 13% of mothers are misusing alcohol 1 year after delivery (liu, mumford, & petras, 2015) . despite the high prevalence of parental substance misuse that is below the diagnostic criteria for dependence, little is understood about the impact of such patterns of parental substance misuse upon children. as the number of children living with a substance-misusing parent is higher than those living with a substance-dependent parent, the greatest burden of harm on a population level is likely to be experienced by these children. the furthering of knowledge in this area is fundamental to enable effective and early responses to address the needs of the families affected. this rapid evidence assessment reviews published evidence reporting on adverse health, psychological, substance use, educational, and social outcomes of children of nondependent substance-misusing parents. we limit our review to high-risk patterns of parental substance misuse. the international literature was searched in november 2016 using electronic databases medline (ovid), psychoinfo (ovid), cinahl (ebsco), scopus, applied social science index and abstract (proquest), international bibliography of social science (proquest), proquest criminal justice (proquest), proquest social science journals (proquest), proquest sociology (proquest), social service abstracts (pro-quest), and sociological abstracts (proquest). due to population flux and changes in economic conditions, we restricted our search for evidence to publications from 1998 onward. a search strategy using mesh terms, thesaurus headings, boolean, and proximity operators was adapted for each database and implemented. two researchers independently screened all titles and abstracts using specified inclusion and exclusion criteria, retrieving full articles for all potentially eligible studies and evaluating in full text. discrepancies at each stage were resolved by discussion or by consulting a third researcher if consensus could not be reached. studies adopting a cross-sectional, longitudinal, case-control, and cohort design were included if the sample consisted of children aged 0-18 years whose parents were high-risk substance misusers. to be included, studies must report on parental substance misuse that meets one of the following criteria: a pattern of alcohol consumption that leads to the presence of physical or psychological problems (typically over 35 units per week for women and over 50 units per week for men); frequent illicit drug misuse (more than once per month as defined by the crime survey for england and wales); and alcohol or illicit drug abuse defined as a maladaptive pattern of drinking/drug use, leading to clinically significant impairment or distress, as manifested by at least one related problem in a 12-month period (failure to fulfill major role obligations, use in situations in which it is physically hazardous, alcohol or drug-related legal problems, having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol or drugs; american psychiatric association, 2013). further, studies were required to include comparison samples of children whose parents were not substance misusers. the condition of interest was adversity experienced by the child defined as any negative health, psychological, child substance use, educational, and social effect. a health harm includes direct impact (e.g., brought about by accidental ingestion by the child or exposure to the substance or contaminated environments) or indirect impacts (e.g., child physical injury, health service usage, fatality); psychological harm such as internalizing (e.g., emotional or behavioral problems that are focused inward such as depression, anxiety, dissociative disorder, and eating disorder) and externalizing problems (e.g., behaviors that are directed toward the external environment including physical aggression, disobeying rules, and antisocial and offending behaviors); substance use by the child includes early onset of alcohol and/or drug use, frequent use, and experience of alcohol and/or drug problems; educational impact includes school attainment, punctuality, truancy, or suspension; and social impact includes parent-child relationship quality, family functioning and home environment, parent supervision, and experience of abuse. papers were excluded if 50% of the parent sample were dependent upon substances other than tobacco (defined as those with a diagnosis of dependence, in receipt of agonist prescribing or attendance at treatment services); insufficient detail is reported for the review team to confidently assess the criteria for high-risk substance misuse levels; were reporting on a qualitative study or were not published in english. the methodological quality of each study included was assessed according to the criteria presented in the quality assessment tool for systematic reviews of observational studies (wong, cheung, & hart, 2008) . this scale is based on a cumulative score across 5 items: external validity, reporting (2 items), bias, and confounding factors. studies achieving 67% or more in scoring were regarded as high quality, 34-66% medium, and less than 34% low quality. we have standardized the language used within the review when referring to all studies meeting the criteria for high-risk parental substance misuse. we use the term parental substance misuse when referring to studies that report on parents who misuse alcohol and/or drugs. when the source study examines only alcohol or drug misuse, we use the term parental alcohol misuse or parental drug misuse, respectively. within the tables and figures, however, we will include further clarification relating to the specific levels reported upon within the source studies. we identified 36 papers (reporting on 33 unique studies) that reported upon adverse outcomes of children of nondependent parental substance misusers. the majority (n ¼ 17) of the studies were conducted in the united states, 5 in the united kingdom and 12 in other european countries and two other countries worldwide (australia and korea). the sample sizes of the included studies ranged from 30 to 740,618 (mean sample 23,896). we assessed 13 studies as being of high methodological quality, 15 of medium quality, and 8 of low quality. we have divided the adverse child outcomes into physical health, psychological well-being, child substance use, educational, and social. figure 1 provides further details of the flow of the studies identified for the review, and the summary of findings for the included studies is presented in table 1 . table 2 highlights the implications for practitioners working with children at different developmental stages. six unique studies showed a significant positive association between parental substance misuse and negative child health outcomes. baker et al. (2015) and tyrrell, orton, tata, and kendrick (2012) conducted high-quality large uk population-based matched nested case-control studies investigating the association between maternal alcohol misuse and other risk factors for accidental child injury aged 0-5 years. children whose mother's medical record showed a history of alcohol misuse were found to have a 2-fold higher odds of long bone fracture (odds ratio [ medium more frequently and for longer than children whose mothers did not misuse substances. inpatient care episodes per 1,000 children were almost double in the group of children with substance misusing mothers to that of the comparison group (2,117 vs. and 1,184) with a mean duration of 3.3 days and 2.4 days, respectively (raitasalo, holmila, autti-ramo, notkola, & tapanainen, 2015) . this association was most pronounced in mothers who misused both alcohol and drugs. remaining studies were of low quality; therefore, caution should be applied when considering results. these studies reported that poor diet (jeffreys, hirte, rogers, & wilson, 2009 ), low weight (below the 10th percentile; joya et al., 2009) , and increased rates of dental problems (cornelius et al., 2004 , jeffreys et al., 2009 ) in children were associated with substance misuse by parents, while studies have found no correlation between parental alcohol misuse and sleep in children (tarokh & carskadon, 2010; tarokh et al., 2012) . there is strong evidence of significant positive association between parental alcohol misuse and externalizing problems, with all seven papers (reporting on six unique studies) of medium to high quality found a significant and positive relationship (kendler et al., 2013; lee & cranford, 2008; malone, iacono, & mcgue, 2002; malone, mcgue, & iacono, 2010; torvik, rognmo, ask, roysamb, & tambs, 2011) . parental alcohol misuse has been found to be associated with conduct problems (kendler et al., 2013; malone et al., 2002 , malone et al., 2010 , most defiant disorders (malone et al., 2002; malone et al., 2010) , delinquency (kendler et al., 2013) , and violence (rossow, pape, & wichstrom, 1999) . there were mixed findings relating to attention and hyperactivity difficulties in the children of alcohol misusers, with two studies finding a significant association (kendler et al., 2013; torvik et al., 2011) , while two papers from one linked study found no association (malone et al., 2002; malone et al., 2010) . only one study examined the impact of parental misuse of substances other than alcohol (torvik et al., 2011) , finding an association of modest effect size upon child attention and conduct problems. studies mostly reported association between both mothers' and fathers' substance misuse and child externalizing difficulties. one paper reported that the relationship was greater when maternal alcohol misuse was present (torvik et al., 2011) . a further study found gender-modeling associations between the parent and child; maternal alcohol misuse was found to be significantly correlated with rule-breaking and aggressive behavior in girls but not in boys, while paternal alcohol misuse was found to be significantly associated with aggressive behavior in boys but not girls (finan, schulz, gordon, & ohannessian, 2015) . there was limited evidence of a significant association between maternal or paternal alcohol misuse and internalizing disorders in children. in a medium quality study using child report measures of parental drinking, both paternal and maternal alcohol misuse were related to depression and anxiety for girls but not for boys (ohannessian, 2012) . in a small, medium-quality cohort study of korean school children aged 12-16 years, parental alcohol misuse was found to be early childhood (0-7 years) greater likelihood of being involved in an accident, self-poisoning incident, and sustaining an injury (baker et al, 2015; tyrrell et al, 2012) . requirement for medical attention and admittance to hospital (raitasalo et al, 2015) . more likely to require inpatient care for a longer period (raitasalo et al, 2015) . inadequate diet and underweight. children maybe left in places of unknown safety (freishleret al, 2014). early adolescence (10-13 years) poor dental hygiene resulting in higher likelihood dental problems, however may not access dental care (corneliuset al, 2004) . low shyness, hyperactivity, attention difficulties, and conduct problems (kendler et al, 2013) . early onset alcohol use, cigarette use, and illicit drug use (cranford et al, 2010; jeffreys et al, 2009; kendler et al, 2013; kerr et al, 2012) . externalizing and internalizing difficulties may begin to emerge (lee and cranford, 2008; malone et al, 2002; rossow et al, 1999; torvik et al, 2011) . middle adolescence (14-16 years) externalising difficulties including conduct problems, delinquent behaviour, rule breaking, aggressive behaviour, attention difficulties (finan et al, 2013; lee and cranford, 2008; malone et al, 2002; rossow et al, 1999; torvik et al, 2011) . internalising difficulties including depression and anxiety lee and cranford, 2008; ohannessian, 2012) . regular substance misuse include frequent intoxication, illicit drug use and the development of substance misuse problems ( positively and significantly associated with internalizing disorders (lee & cranford, 2008) . associations in a high-quality study however did not reach significance (malone et al., 2002; malone et al., 2010) . there is a large volume of evidence that parental substance misuse influenced their child's own substance use, with all 23 included papers (reporting on 20 unique studies) finding a significant association. this evidence is mostly of medium to high quality with only two studies being of low quality (jeffreys et al., 2009; yule, wilens, martelon, msimon, & biederman, 2013) . parental alcohol and/or drug misuse was significantly associated with early onset adolescent drinking (kerr, capaldi, pears, & owen, 2012; vermeulen-smit et al., 2012) , alcohol consumption (cranford, zucker, jester, puttler, & fitzgerald, 2010; haugland, holmen, ravndal, & bratberg, 2013; jennison, 2014; keeley, mongwa, & corcoran, 2015; shorey et al., 2013; vermeulen-smit et al., 2012) , alcohol intoxication (haugland, holmen, krokstad, sund, & bratberg, 2015; haugland et al., 2013; haugland, strandheim, & bratberg, 2012; keeley et al., 2015; rossow et al., 1999) , and the development of alcohol problems (kendler et al., 2013; lieb et al., 2002) as well as adolescent illicit drug use (delaney-black et al., 2011; haugland et al., 2012; hofler et al., 1999; hopfer, stallings, hewitt, & crowley, 2003; jeffreys et al., 2009; keeley et al., 2015; malone et al., 2002; malone et al., 2010; shorey et al., 2013) . having two parents who misuse substances was highlighted as being particularly predictive of adolescent substance use (keeley et al., 2015; swaim, beauvais, walker, & silk-walker, 2011) , with regular alcohol use being almost 4 times as likely (or ¼ 3.83, ci [1.65, 8 .89], p < .01) and past year illicit drug use almost 6 times as likely (or ¼ 5.90, ci [2.54, 13 .7], p < .001) as adolescents with two nonsubstance misusing parents (keeley et al., 2015) . there were mixed findings as to whether the mothers' or fathers' substance misuse had the strongest association with child alcohol and/or drug use. six studies found that both maternal and paternal substance misuse correlated with adolescents' alcohol (finan et al., 2015; haugland et al., 2013; keeley et al., 2015; van der zwaluw et al., 2008) and drug use (finan et al., 2015; keeley et al., 2015) to a similar size of effect. studies found that only fathers' and not mothers' substance misuse was positively associated with adolescent drinking (cranford et al., 2010; ohannessian, 2012) and the range of substances used in adolescent children (shorey et al., 2013) . further studies, however, reported only maternal alcohol misuse (kerr et al., 2012) and maternal drug misuse (yule et al., 2013) to be significantly associated with development of alcohol or drug misuse in children. when also considering child gender, both boys and girls have been found to be significantly more likely to engage with substance using behaviors if their parents misused alcohol, with boys in particular being found to experience a negative effect (haugland et al., 2012) . three papers of mixed quality reported on parental alcohol misuse and its association with negative child education outcomes. using a large cohort of over 740,000 swedish individuals, berg, back, vinnerljung, and hjern (2016) conducted a high-quality study finding that alcohol-related hospital admissions in parents were significantly associated with lower school performance in adolescents aged 15-16 years (berg, back, vinnerljung, & hjern, 2016) . school behavioral problems were associated with paternal alcohol misuse in early childhood, with a 3-fold risk of truancy, absenteeism, suspensions, and conduct problems in a medium quality study (jennison, 2014) . family dysfunction, conflict, and ineffectual parenting were found to be strongly correlated to adverse school outcomes for children in families with an alcohol misusing father. the low levels of attachment and bonding to biological fathers found to be associated with an increase in school-related behavioral problems of the children were notable. a small low-quality study in australia also found children of substance misusers were more often absent or late for school (jeffreys et al., 2009) . the literature on the social outcomes of children whose parents misuse substances was mixed. four studies of medium quality considered the association between alcohol misusing parents and the parent-child relationship. while one study showed no significant impact upon the support provided to the child from the parent (van der zwaluw et al., 2008) , a further study reported that children of alcohol misusing parents were significantly less likely to feel emotionally close to their father, either due to the impact of alcohol misuse upon the father's behavior, conflict within the home, abdication of family responsibilities, or estrangement (jennison, 2014) . parental bonding and the parent-child relationship were negatively related to both mothers' and fathers' alcohol misuse in other research (shorey et al., 2013) . there is conflicting evidence that parental monitoring is negatively associated with parental alcohol misuse. one study reported a significant association between parental alcohol misuse and lower levels of parental monitoring (shorey et al., 2013) , while a further study reported that parental alcohol misuse was unrelated to a number of measures of neglectful parenting practices (freisthler, johnson-motoyama, & kepple, 2014) . a significant association with a particularly large effect was shown in a high-quality study of the number of children of substance misusing mothers who were placed in care (raitasalo et al., 2015) . children of alcohol misusing mothers were 5 times more likely to be placed in care by their seventh birthday than those raised by nonalcohol misusing parents. those born to drug misusing mothers were over 7 times more likely to be in care by the age of 7, while children whose mothers misused both alcohol and drugs faced a 9-fold increased risk. these relationships persisted after controlling for the child's gender and mothers' socioeconomic status. once in care, children of substance misusing mothers were discharged 183% faster than those children whose mothers did not misuse substances (hussey & guo, 2005) . this somewhat counterintuitive finding is most likely to relate to an accelerated decision to place the children in permanent care however rather than reunification of the family. further, the low quality of this study means that findings should be interpreted with caution. a cohort study of children taken into care also reported on the range of abuse children may experience while living within substance misusing homes (jeffreys et al., 2009) . due to the small sample size in this study, no statistical testing could be conducted. as such, the existence of a correlation between parental substance use and abuse is unknown. it is clear from this evidence that nondependent parental substance misuse is associated with adversity in children. this evidence is more pronounced when both parents misuse alcohol and/or drugs or when one or more parents misuse a combination of alcohol and drugs. in early childhood (0-7 years), the evidence from high-quality studies suggests an increased likelihood of experiencing an injury or health concern, resulting in the need for medical care. the methodological quality of studies examining an association with diet, child weight, and dental health is however of low quality and should be interpreted with caution. maternal alcohol misuse in particular is highlighted as a key predictor for poorer child health. this may in part relate to the greater role mothers tend to play in the child's early years. however, there was a paucity of research considering substances other than alcohol and relating to fathers' substance misuse that may result in a misleading focus on mothers. the literature suggests that parental alcohol misuse increased the likelihood of externalizing problems in children, with a significant association being reported in all studies being of medium or high quality. there was less evidence for an association between parental substance misuse and internalizing difficulties such as depression and anxiety. those showing an association were of medium quality and involved children exposed to parental intoxication or where family and/or parental factors are present, while a high-quality study did not find a significant correlation. there was a large and methodologically robust evidence base consisting of 23 papers, all finding a significant and positive relationship between parental alcohol and/or drug misuse and the child's own use. the evidence appeared particularly strong in families where both parents misused substances or when the child was directly exposed to the substance misuse. social learning theory explains that we learn behavior from observing, imitating, and modeling those around us (bandura, 1997) . it is possible that when children observe their parents consuming alcohol and/or drugs, it encourages the development of normative views about substance use. further, the availability of alcohol or other substances within the home may increase the likelihood of adolescent use (peeters, koning, monshouwer, vollebergh, & wiers, 2016) . there is emerging evidence that parental alcohol misuse is predictive of educational challenges including truancy, school-related behavioral problems, and lower educational attainment, although the methodological quality of these studies varied. the involvement of child welfare services as well as out-ofhome placements for children was also higher in children whose parents misuse substances. the evidence for an association with other social and relational difficulties is however mixed. there was some suggestion that parental alcohol use was associated with lower levels of parent-child bonding, communication, and overall relationship quality. however, evidence of neglectful parenting or inadequate parental supervision was limited and at times contradictory and as such caution should be exercised when drawing conclusions regarding an association between parental substance misuse and the quality of parental supervision. methodological issues further limit the evidence. social workers often interact with families experiencing a wide range of difficulties. while social workers within children's welfare services consider it legitimate within their role to ask parents about their drug and alcohol use, they experience difficulty in identifying parents who are substance misusers (galvani, hutchinson, & dance, 2013; loughran, honhman, & finnegan, 2010) . typically, they rely upon observations of the parent's physical presentation and behavior, which is unlikely to detect levels of misuse below the diagnostic criteria for dependence (galvani et al., 2013) . furthermore, those parents who are identified as being substance misusers often do not receive an intervention, with parents expressing reluctance to engage with specialist drug and alcohol treatment providers as they did not perceive themselves as having a substance misuse problem (forrester & harwin, 2006) . this suggests that early, opportunistic intervention delivered by a nontreatment specialist may be more appropriate. there is a large amount of high-quality evidence that has accumulated to support the effectiveness of alcohol screening and brief interventions with adults who have an alcohol use disorder with nondependent populations in primary care setting (kaner et al., 2007; o'donnell et al., 2013) . however, there are no studies examining the effectiveness of screening and brief interventions with substance misusing parents including those whose children are involved with child welfare services. this represents a missed opportunity to intervene with this population before a parent has developed substance dependency. such intervention has the potential to prevent the development of more problematic patterns of use and prevent harm to children. social workers should engage in conversations with parents, which promote the parent's ability to link their substance misuse with adverse experiences and risk of negative outcomes for their child. such an interaction may replicate the "teachable moment" found to be conducive of behavior change following the delivery of brief interventions within other settings (babor & grant, 1992) and improving outcomes for children. the evidence examined within this review provides support for an association between parental substance misuse and a number of adverse child outcomes at different stages of development. there are however some notable gaps. in early childhood (0-7 years), the literature focuses upon the relationship between mothers' substance misuse and child physical health, with a paucity of research examining behavioral problems, parent-child bonding, or preparation for school as well as the impact of fathers' substance misuse. in early adolescence (10-13 years), there is a lack of research into child education outcomes, and in each stage of adolescence (10-18 years), there is a lack of research into parental substance misuse and child health. there is limited research that considers parental illicit drug misuse throughout the child's development, with the majority of research examining the difficulties in children of alcohol misusing parents. due to the inclusion of cross-sectional studies, causal relationships cannot be determined. such naive comparisons of exposed and unexposed groups cannot adequately account for the many potential confounders nor precisely account for the measurement of effect (fewell, davey smith, & sterne, 2007) . for example, genetic predisposition (agrawal & lynskey, 2008) and the interaction between genes and the environment (cleveland & wiebe, 2003) may result in intergeneration transmission of substance misuse. alcohol permissive parenting (ennett et al., 2016; hung, chang, luh, wu, & yen, 2015) , adolescent monitoring (kerr, stattin, & burk, 2010 ), lower parent-child relationship quality (donaldson, handren, & crano, 2016; el-sheikh & buckhalt, 2003; shorey et al., 2013) , and greater family conflict (el-sheikh & flanagan, 2001; kelly et al., 2011) have been associated with increased child substance misuse. furthermore, the direction of a reported relationship cannot be determined. for example, while children's conduct difficulties could be a result of parental alcohol misuse, a parent whose child has conduct difficulties may struggle to cope with their child's behavior and their alcohol consumption may increase in response. while longitudinal studies can highlight the temporal associations between variables and may offer greater insight into causation, such inferences are reliant upon the timing of the behavior in relation to the outcome. for example, studies examining the impact of parental substance misuse upon internalizing difficulties in children may assess children prior to the emergence of any symptoms or early childhood exposure to parental substance misuse may be undetected due to behavior change that predates study inclusion (katikireddi, green, taylor, smith, & munafo, 2017) . further research into the impact of parental substance misuse upon the child is needed to address the gaps in the evidence. specifically, research examining the various impacts of both alcohol and illicit drug misuse throughout the stages of the child's development. future research should include both fathers and mothers and be sufficiently powered to enable analysis of the impact of mothers' versus fathers' use upon male and female children and utilize longitudinal design, with regular follow-up throughout the child's development. this would offer opportunity for causal inferences and also enable age-related and temporal associations to emerge. there is also a need for more high-quality research examining the health, educational, and social impact of parental substance misuse. the significant variation in how substance misuse patterns are described within research has presented a great challenge to this review and ultimately in the further of knowledge in this area. there is a need for consistency in the use of terminology describing levels of parental substance misuse in future research. in considering the evidence for the impact of nondependent parental substance misuse on children, focus invariably is on risks. there is also a need to consider the protective factors that may be present, which may enhance child resilience to harm. this review has highlighted evidence that an association between parental substance misuse is greater when both parents are substance misusers. put another way, the presence of one nonsubstance misusing parent offers some protection. using the language of protection, rather than risk, affords an opportunity to view such protective factors as a possible intervention mechanism to enhance resilience. given the evidence identified that factors such as maternal closeness, attachment, and parent-child relationship quality are moderators of adversity (shorey et al., 2013) , future research should include a range of mediators and, importantly, moderators of harm, which may inform intervention development. the findings of this review suggest that the vulnerability to adverse outcomes is not restricted to children living with substance-dependent parents. rather, children may be affected by a wider continuum of harmful parental substance misuse; children who are likely to be less visible to practitioners. while practitioners may find it challenging to identify parents whose use is not within the dependent range (galvani et al., 2013) , intervening early in parental risk factors including alcohol and drug misuse to safeguard children has been highlighted in guidance for health, social care, and third sector partners (department of health, 2013; hm government, 2015; munro, 2011) . as the number of children living with a nondependent substance misusing parent is likely to be greater than those living with a substance-dependent parent, intervening with nondependent parents is likely to bring about most benefit to children on a population level. working to promote resilience and to enhance the child's protective factors is also important. parents who do not misuse substances are a resource to this end. moreover, intervening before a parent has developed a dependency has the potential to prevent the development of more problematic patterns of use and prevent harm to children. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: the authors received funding from public health england to undertake this rapid evidence assessment. https://orcid.org/0000-0002-4119-4353 ruth mcgovern is a senior research associate and nihr post doctoral fellow at the institute of health & society, newcastle university. she is also a qualified and registered social worker. her research is concerned with drug and alcohol misuse, with a particular focus upon parental misuse and the impact upon the family. eilish gilvarry is deputy medical director for appraisal and revalidation at northumberland, tyne & wear nhs foundation trust, consultant psychiatrist in addictions at newcastle addictions service and honorary professor of addiction psychiatry at newcastle university. her research concerns all aspects of drug and alcohol misuse, with a particular focus on pharmacological and psychological interventions. michelle addison is a research associate at the institute of health & society, newcastle university. she is a social scientist and her research is concerned with the relational properties of health and social inequalities impacting on socially marginalised people. hayley alderson is a research associate at the institute of health & society, newcastle university. her research is concerned with developing and evaluating interventions to reduce drug and alcohol use. emma geijer-simpson is a phd student at the institute of health & society, newcastle university. her doctoral research is concerned with developing family-involved interventions to prevent risky alcohol use and co-existing mental health difficulties in young people. raghu lingam is a professor of paediatric population health at the university of new south wales and a community paediatrician within the sydney children's hospital network. his is a clinical academic research interests are in child health services research, mental health and risk taking behaviours and in child development and disability. debbie smart is a research assistant at the institute of health & society, newcastle university. her research interests are concerned with children and families with a particular focus upon young carers and parental risk factors. eileen kaner is a professor in public health at the institute of health & society, newcastle university. she is a behavioural scientist and her research programme aims to improve health by promoting the use of evidence-based interventions to reduce lifestyle risk. a key strand of work is the development, evaluation and implementation of screening and brief alcohol interventions in a wide range of health and social care settings. hidden harm: responding to the needs of children of problem drug users are there genetics influences on addiction: evidence from the family, 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adjustment in s sample of substance-abusing mothers and their school-aged and adolescent children the effects of parental diagnosis and changing family norms on alcohol use and related problems among urban american indian adolescents sleep electroencephalogram in children with a parental history of alcohol abuse/dependence adolescence and parental history of alcoholism: insights from the sleep eeg parental alcohol use and adolescent school adjustment in the general population: results from the hunt study the missing link to child safety, permanency, and well-being: addressing substance misuse in child welfare children at risk of medicinal and non-medicinal poisoning: a populationbased case-control study in general practice parental problem drinking, parenting, and adolescent alcohol use understanding and modifying the impact of parents' substance misuse on the child the influence of paternal and maternal drinking patterns within two-partner families on the initiation and development of adolescent drinking development of a quality assessment tool for systematic reviews of observational studies (qatso) or hiv prevalence in men having sex with men and associated risk behaviours does exposure to parental substance use disorders increase substance use disorder risk in offspring? a 5-year follow-up study key: cord-034066-fsp7e5x5 authors: di figlia-peck, stephanie; feinstein, ronald; fisher, martin title: treatment of children and adolescents who are overweight or obese date: 2020-10-21 journal: curr probl pediatr adolesc health care doi: 10.1016/j.cppeds.2020.100871 sha: doc_id: 34066 cord_uid: fsp7e5x5 nan m anaging the millions of children and adolescents who are either overweight or obese has become a major challenge for the healthcare community. in 1997, an expert committee was convened by the maternal and child health bureau of the health resources and services administration (hrsa), department of health and human services, (dhhs) to develop guidelines for healthcare providers. 1 in 2005, the american medical association, in cooperation with hrsa and the center for disease control and prevention, created an expert committee to update those initial guidelines. 2 and in 2008, the agency for healthcare research and quality of the hhs came out with an evidence-based/technology assessment entitled "the effectiveness of weight management programs in children and adolescents." 3 in addition to these government-sponsored guidelines, recommendations for management of overweight and obesity in this population have been issued by multiple other organizations. the one directive they all have in common is that a multicomponent program that focuses on physical activity, diet, and behavioral change should be the first line of treatment offered. this article highlights the evidence-based data, presents the various ways in which this multicomponent approach can be implemented, and includes the roles of school programs and bariatric surgery as weight management options. family-based group sessions coordinated by a registered dietitian (rd/rdn) are a crucial part of multicomponent interventions. the academy of nutrition and dietetics, which issued its pediatric weight management evidence-based guidelines in 2015, has reported positive weight status outcomes, both shorter-term (6 months) and longer-term (12 months), when group pediatric weight management sessions and family participation are coordinated. 4, 5 individual family and mixed-format (which includes some time with individual families and some group time) approaches have been found to be superior to group-only approaches as per the latest us preventative services task force (uspstf) recommendations. 6 however, including in addition to these governmentsponsored guidelines, recommendations for management of overweight and obesity in this population have been issued by multiple other organizations. the one directive they all have in common is that a multicomponent program that focuses on physical activity, diet, and behavioral change should be the first line of treatment offered. the academy of nutrition and dietetics, which issued its pediatric weight management evidence-based guidelines in 2015, has reported positive weight status outcomes, both shorter-term (6 months) and longer-term (12 months), when group pediatric weight management sessions and family participation are coordinated. 4, 5 some group sessions may offer the opportunity for social support and improve cost effectiveness. 7 the dose of treatment has a strong impact on success. multicomponent behavioral interventions of moderate (26à75 h of treatment contact per year) to high intensity (> 75 h) for obese children and adolescents, ages six and older, have been shown to yield short term improvements in up to 12 months. obtaining a qualitative assessment of a patient's diet with a particular focus on dietary patterns thought to be linked to excess energy intake and adiposity is recommended, as intervening with these patterns can significantly reduce intake and potentially improve nutritional status. 8 tailoring interventions by considering patient and family motivation, as well as readiness for change, is optimal. the family-based approach can be modified based on the age of the patient and the degree of parental involvement. it should be noted that family involvement has been shown to be less effective when the patients are older teens. 9 behavioral treatments at the heart of behavioral treatment for obesity is determining what behaviors are modifiable and what therapies to use to help patients achieve the needed modifications. motivational interviewing (mi), which is a patient-centered counseling style, has been shown to be effective in primary care settings. 10 a dietitian should be included, as the rdn's knowledge and skill base are critical in the ongoing process of addressing the diverse needs of clients and families. 4, 10 cognitive behavioral management and gradual stepwise change have been explored in depth for childhood and adolescent obesity treatment. individuals get acclimated to recommended changes over time by making adjustments in their dietary patterns and food environment and by learning to set limits on eating unhealthy food. short-term goals are established in order to lead to long-term habits that change the way individuals and their families think about food. cognitive behavioral therapy (cbt) focuses on breaking the negative cycle that is a part of weight-related difficulties in obesity, the "maladaptive daily patterns, cognition that is distorted, and problematic behaviors" cited by wilfley et al. 11 it allows for a restructuring of daily patterns. bloom et al. explores utilizing a form of cbt known as cbt-af to address appetite awareness and cues for eating. 12 caat is an adapted version used with children and adolescents to sensitize them to recognize and respond to internal appetite cues such as hunger and satiety in order to improve their self-regulation of energy intake. results of one study showed a significant reduction in body mass index (bmi) for children in a caat group compared to those in a control group. however, this impact was only studied short term. the researchers concluded that caat holds promise as a treatment modality since overweight and obese children are often less effective in regulating food intake compared to normal weight children. 13, 14 in the transtheoretical model of change, in which change occurs in stages, the readiness of parents for personal change, as well as their readiness to help their children make changes, becomes a pivotal factor for success in a weight management program. 15 tailored messages to parents may help modulate their "decisional balance," (the value of making behavioral changes versus the value of not making any changes) and contribute to the likelihood of treatment success for their children. yet influencing parents so as to influence their children in terms of weight management behaviors can be a challenge. weight loss is a complex behavior which encompasses two separate "domains" of changeà eating habits and physical activity. although these are often considered together, each carries unique challenges with respect to perceived confidence and readiness for change. 16, 17 in a cross-sectional study with a convenience sample of parents (or guardians) of children attending a tertiary care pediatric obesity clinic, parents completed surveys initially and again on follow up visits to assess their readiness for change. 16 those in the action/ cognitive behavioral management and gradual stepwise change have been explored in depth for childhood and adolescent obesity treatment. individuals get acclimated to recommended changes over time by making adjustments in their dietary patterns and food environment and by learning to set limits on eating unhealthy food. maintenance state of change were more likely to be actively making changes to multiple eating behav-iorsài.e. availability of sugar-sweetened beverages (ssbs) and salty snacks, and in physical activity patternsài.e. reaching recommended levels of increased activity and limiting screen time. their children were more likely to be more physically active and to consume less fast food and more fruits and vegetables than the children of parents in the other stages of change. 16 parents who believed their own weight was a health problem were less ready to make changes to their children's diet. 18 these authors suggest that maintaining both parent and patient motivation should be a focal point of treatment and that this may entail a variety of approaches, such as using texting or other electronic devices to assess the stage of change for readiness and decisional support. 18 use of mobile health technology as an adjunct to behavioral based weight management strategies is becoming more common. chen and researchers reported on a convenience sample of self-identified chinese-american adolescents with bmi 85th percentile who participated in a culturally focused intervention called smart start. 19 it provided general health education, wearable fitness trackers, online educational modules, and tailored biweekly text messages. a benefit in outcome occurred in both the control and intervention groups. however, over a six month period, the intervention group, as compared to the control group, had "statistically greater changes" in bmi that were associated with less fast food intake, a lower intake of ssbs, and an increase in physical activity levels and decreased sedentary behavior. 19 overall, mobile health use has shown mixed benefits for weight management in adolescents and young adults. 20 other mobile health initiatives have resulted in weight loss in the experimental groups that was not sustained 21, 22 or have displayed no further benefits above that of the standard care group. 23 researchers have thus noted limited evidence of efficacy of mobile health interventions as a stand-alone treatment modality. 24 the impact of combining the mobile health approach with components of behavior based interventions has been examined by cueto et al. 25 they evaluated the original kurbo app (circa 2014) before it became kurbo ww. 26 designed to promote behavior change and encourage healthy lifestyle choices, it used the evidence-based traffic light diet approach 27 and kurbo health coaching through the incorporation of behavior substitutions and habit formation. 28 although kurbo includes components of behaviorbased interventions proven successful in pediatric and adolescent weight management, it has come under fire for promoting behaviors that can be perceived as overly restrictive and potentially promoting eating disorder behaviors. 29 questions have been raised based on degree of weight loss in young subscribers and whether adequate monitors are in place to determine that degree. prior studies have warned about the potential for "growth velocity to be negatively impacted when caloric intake is restricted," and thus growth velocity must be followed carefully during and after weight loss in older children and younger adolescents, and medical supervision may be warranted. 30, 31 other combined interventions utilizing mobile health apps have yielded partial success. one 12month technology-based program for adolescents with type 2 diabetes "was not sufficient to produce weight loss with the combination of web intervention and group sessions and telephone follow up, but improvements in sedentary behavior and use of behavior change strategies expected to lead to behavior change was evidenced." 32 telemedicine, in theory, should be able to compensate for some of the barriers that prevent access to and utilization of family based comprehensive behavioral interventions for child and adolescent obesity. 33 these barriers include time, transportation, access, cost, scheduling challenges, stigmatization, language barriers and more. [34] [35] [36] [37] rural populations have been studied for feasibility and satisfaction with telemedicine treatment approaches, and results have been comparable to standard treatment outcomes. 38 urban populations can face similar barriers to attendance of programs held in hospitals or university medical use of mobile health technology as an adjunct to behavioral based weight management strategies is becoming more common. settingsà delays in acquiring care, fear of being judged based on native language or residency, and possible stigmatization. 39 consequently, there have been studies here too (even prior to the covid-19 pandemic) regarding the incorporation of telemedicine as a supplemental arm of treatment modalities involving group sessions and mixed formats with medical staff including physicians, nurse practitioners (nps), nurses, psychologists, family counselors, dietitians, physical therapists, exercise specialists, and social workers. 38, 39 with the dramatic increase in the use of telemedicine brought about by the covid 19 pandemic, this modality of treatment will certainly be utilized and studied considerably more in the upcoming months and years. mobile apps have proved an engaging way to involve children in health behavior changes, 40 allowing for delivery of health information in a portable, "entertaining" way. [41] [42] [43] these apps are capable of promoting some of the expert recommendations for healthy eating and physical activity, including setting goals/limits and reducing intake of ssbs, but they often do not go deeper into behavior change. one app, hyperant tm , utilized a set of "hyper activity cards tm " to give children ideas for health-promoting behaviors including physical activity, healthy eating, and sleep. 44 however, it only provides user messages without offering the opportunity for interaction. in a meta-analysis of mobile health technologies for selfmonitoring, darling et al. concluded that self-monitoring techniques using mobile health technologies have a small but significant effect on weight status in children and adolescents. 45 population health initiatives a more "macro approach" for educating and guiding children, adolescents, their families and guardians is called for to achieve greater success in maintaining better health and weight management. several such programs are described below. the choosemyplate teaching initiative from the u.s. department of agriculture (usda) came out of the need for a vehicle to effectively and "with maximum visibility" communicate the 2010 dietary guidelines for americans (dgas) in order to foster a healthier lifestyle. 46 using print and online resources to engage the public, it was translated into several languages, incorporated into health curriculum resources created for nutrition education for children and adults, and promoted to nutrition communicators, educators and the food industry, calling upon them to "get the message out." [47] [48] [49] its message: "americans can achieve a healthier weight by eating more of some foods," was thought to be one that consumers could embrace. when one's plate has a larger proportion of lower calorie vegetables, they, in essence sense, "crowd out' the more calorically dense other foods on the plate like refined grains and high fat proteins. thus, adding foods, rather than taking away foods, can result in a calorie deficit. designed to "impact behavior during meal planning" and "perception during meal consumption," this initiative aimed to be seen by individuals and groups as a positive way of collectively altering energy balance. choosemyplate calls for a shift in consumption patterns. it emphasizes less processed foods and more of whole grains, lower fat and non-fat dairy items over full-fat varieties, water in place of ssbs, and protein alternatives, including leaner meats. along with less saturated fat and added sugars, lower sodium options are promoted. central to this multimodal plan is the plate icon ( fig. 1 ) that replaces the food guide pyramid as both visual cue and accepted standard. 48, 49 the most current recommendations, as per myplate, my wins (see below), directs people to "find your healthy eating style and maintain it for a lifetime" by making half of the meal plate fruits and vegetables (varying the veggies and focusing on whole fruits), making a quarter of the plate grains (half of them whole grains), and making the remaining quarter of the plate proteins (varying the protein routine). individuals are advised to move to low-fat or fat-free milk or choosemyplate calls for a shift in consumption patterns. it emphasizes less processed foods and more of whole grains, lower fat and non-fat dairy items over full-fat varieties, water in place of ssbs, and protein alternatives, including leaner meats. along with less saturated fat and added sugars, lower sodium options are promoted. yogurt for dairy intake, which is depicted alongside on the right of the icon's plate. the "right mix" is based on variety, amount, and nutrition content. the original myplate teaching campaign was revamped to reflect changes in the updated dgas (2015à2020). myplate, my wins, launched in 2015, strongly focuses on food patterns. it added the concept of "a healthy eating style" which can be achieved with "small changes" to promote the goal of getting individuals to realize that "what you eat and drink over time matters and can help you be healthier now, and in the future," messaging that reflected the evolving emphasis of the dgas. the public was encouraged to be more engaged and active in their health, and was invited to virtually share personal experiences with my plate, my wins on social media using #myplatemywins. the present day choosemy-plate.gov website includes printable materials, images, and graphics available as downloadable pdfs, jpgs, and other files-all in the public domain so that no permission is required to print, reproduce, or use them. resources have grown to include a host of topics, from meal planning and food safety to physical activity and seasonal resources. information continues to be available in diverse formats like toolkits, quizzes, infographics, and videos. researchers out of the behavioral health and nutrition department at the university of delaware used myplate to test whether peer education improved selfefficacy, perceptions and attitudes toward healthy eating, and physical activity. 50, 51 they concluded that peer education could promote improved knowledge and attitudes about myplate among college students and increase their self-efficacy, helping them make healthier decisions with regard to food and food intake. the pilot first year experience course curriculum developed at the university became mandatory coursework for all incoming freshmen. 41 a florida study of elementary school children whose families qualified for federal assistance via the supplemental nutrition assistance program (snap), utilized the six-lesson youth understanding myplate (yum) curriculum to teach the students through grade specific activities. the children reported an increase in intake of fruits and vegetables, grains, low-fat/fat-free dairy, healthy snacks, eating breakfast, and physical activity, compared to baseline. 52 5-2-1-0 let's go! is another nationally recognized program that aims to create environments supporting healthy choices, healthy habits, and healthy living within a multi-setting model. [53] [54] [55] [56] developed in maine in 2006 by a group of professionals on a mission to tackle childhood obesity by using evidence-based tools and strategies, it has expanded and gained momentum through its strong, far-reaching program and campaign designed to reach out to families where they live, learn, work, and play. its premise is that if children and families are exposed to the same health message in multiple places across their community, and if those places have policies and environments that support healthy choices, then children and families will be more likely to adopt those behaviors and maintain them in their daily lives. the foundation for change as modeled in the 5-2-1-0 healthy habits message is based on the following daily measures: 5 or more fruits and vegetables, 2 h or less of recreational screen time (tv/ computers to be kept out of the bedroom and no screen time under the age of 2), 1 h or more of physical activity, and 0 the foundation for change as modeled in the 5-2-1-0 healthy habits message is based on the following daily measures: 5 or more fruits and vegetables, 2 h or less of recreational screen time (tv/computers to be kept out of the bedroom and no screen time under the age of 2), 1 h or more of physical activity, and 0 sugary drinks and more water intake (fig. 2) . sugary drinks and more water intake (fig. 2) . though this message has been found to increase awareness and healthy behaviors, it remains to be seen if that will translate to concrete behavioral changes. many pediatric and primary care offices across the country have started to implement 5-2-1-0 let's go! into their practices to potentially impact the health of their patients, as have hospital-based specialty programs. the power kids weight management program of cohen children's medical center at northwell health is the authors' multidisciplinary program for overweight and obese children and adolescents, 8 to 18 years of age. in advance of meeting with program staff or at the initial assessment by the program's registered dietitian nutritionist (rdn), prior to any interventions, the patient or the parent/guardian is asked to fill out a healthy habits questionnaire adapted from and directly correlated to the 5-2-1-0 let's go! program (fig. 3) . one version is for children up to 9 years of age, another for 10 to 18-year-olds, and both are available in spanish as well as english. the power kids questionnaire uses a modified food-frequency survey style to ask questions regarding food and beverages and includes other questions that address time allocation for activity and sedentary pursuits as well as family meal patterns and access to tv. what emerges are overall patterns, habits, and choices, ending with a glimpse as to what the child or adolescent is willing to change. answers to the questions help guide the direction of behavioral, nutritional, and exercise interventions. focusing on domains where program participants exhibit deficiencies, while reinforcing already established positive health-related behaviors, helps to pave the path to successful weight management. the goal is to use the 5-2-1-0 message to encourage the children and adolescents in the program to develop healthy habits that can positively impact what would otherwise be their trajectory for further excess weight gain and the associated comorbidities of obesity. let's move is the comprehensive initiative launched in 2010 by former first lady michelle obama the same day that president barak obama signed the memorandum creating the task force on childhood obesity. in partnership with the alliance for a healthier generation, it is dedicated to solving the problem of obesity "within a generation" so that "children born today will grow up healthier and be able to pursue their dreams." 57 the focus is on creating a healthy start for children, empowering parents and caregivers, providing healthy food in schools, improving access to healthy affordable foods, and increasing physical activity. one of its many ambitious goals is the commitment to giving children a voice and a presence. families are encouraged to recognize that children can create healthy lunches from their own kitchens and express their unique preferences as to what "healthy eating" translates into for them. the healthy lunchtime challenge has drawn representatives from every state and territory in the united states, and the accumulation let's move is the comprehensive initiative launched in 2010 by former first lady michelle obama the same day that president barak obama signed the memorandum creating the task force on childhood obesity. of recipes from the annual challenges is accessible online as "historical material." 57 the let's move! outside program, developed to bridge the growing disconnect between young people and the great outdoors, and to emphasize the need for active play, has been adopted by the ymca of the usa, through its youth development division, using programs and services shown to be instrumental in their diabetes prevention program (dpp) trials. 58 eligible children and adolescents, ages 5à17, representing a wide variety of socioeconomic backgrounds, were recruited for a randomized computer-assisted intervention that included their families, to assess whether eliminating financial barriers to ymca membership could encourage increased physical activity in the environment of a supportive family. 59 extensive resources were available to those who utilized the services. all participants and their parents and guardians were scheduled to attend 4 nutrition classes administered by a registered dietitian (rd) and to return for evaluation at 2, 4, 6, 9, and 12 months. children were randomized to nutrition class only (n = 39) or nutrition class and free family ymca membership (n = 44). nutrition classes did not differentiate between those in the control and treatment groups. of the 36 evaluable participants randomized to treatment, only 27 ever visited the ymca, with a median of 5 visits reported. overall attendance at scheduled study-related visits was poor. only 2 participants in each group attended all 6 scheduled visits. for nutrition classes, at least 1 class was attended by 67% of the treatment group, but only 30% of controls. attendance in the nutrition classes led to improvements in nutritional intake for both groups. four participants in the control group and 1 in the treatment group achieved the target reduction of 2 bmi percentile points. there was a positive, but very small, relationship for ymca attendees between the number of visits and the loss of either bmi or weight, which was not statistically significant. curr probl pediatr adolesc health care, & &&&& another major initiative promoting physical activity and healthy eating among children-(in this case, as young as kindergarten and through 12th grade) that has been studied and evaluated is the nfl play 60 fit-nessgram partnership project, led by teachers in school settings across 32 national football league franchise markets. (its two most popular programs are fuel up to play 60, in collaboration with the united states dairy association (usda), and the nfl play 60 challenge created in conjunction with american heart association (aha). the latter has its own app which originally allowed users to choose an avatar with which to complete a course through a virtual outdoor park while listening to health promoting messages like "make sure you drink enough water today"it no longer includes an "in the game" motion sensor but still gauges and delivers health concepts.) the longitudinal impact of nfl play 60 programming was measured using data based on students from 497 schools who completed fitnessgram assessments annually, starting in 2011 through 2015. for schools that participated in the program, annual improvements in aerobic capacity were significantly greater for both girls and boys, compared with non-programming schools. both girls and boys in participating schools showed annual improvement in bmi healthy fitness zone achievement. students in schools that implemented the program for the entire 4 years tended to have better improvements in aerobic capacity than those in schools enrolled for only 2 or 3 years. 60 it is fair to say that each of the national initiatives described in this section had some impact on nutrition and physical activity for many children and adolescents but that the impact was modest for most and minimal for many. going forward, it can prove useful to combine the messages of these multiple programs into one unified message that can be promoted throughout the country in a way that will strengthen their message and thereby yield a stronger effect on the nutritional and physical activity patterns for the youth of the nation. advances in technology have brought about the proliferation of electronic devices now available to children and adolescents who are spending long durations of time in sedentary activities involving handheld devices and video consuls. current guidelines call for limiting sedentary screen time to 2 h or less. 61 among the many concerns being addressed is that increased time on electronics/screen time becomes a potential source of additional energy intake. in a clever harnessing of this dynamic, health professionals are exploring the use of electronics and gaming for getting children to be more physically active. games like wii/wiiu, xbox connect, nintendo, and variations of them have offered small promise. active video games can acutely increase light to moderate physical activity. however, they are unlikely to impact increased habitual activity or significantly decrease sedentary behaviors. 62 rose et al. in their systematic review of digital interventions for improving diet and physical activity behaviors in adolescents, struggled with the heterogenicity of studies not being conducive to a meta-analysis and urged setting up future research initiatives in digital health as a cost-effective medium for health promotion. 63 a great deal of thought and programing is being directed to creating challenges and monitoring progress with physical activity. and sometimes the unexpected turns up with great outcomes. for a time in 2016, the pok emon go app set off a frenzy of interest in walking, sometimes long distances, to find and catch pok emon avatars. 64 an estimated 9à21 million people used the app and increased their daily step count, with some reaching as many as 15,000 steps a day. 65 step challenges have worked well in the adult population with competitions awarding badges, status recognition, and prizes for accumulating steps. in the early 2000s portable watches that were affordable and fashionable were introduced for use in tracking steps. prior to this, they had only been available at research grade. studies exploring step tracking have shown promising results in that a positive feedback loop is established, whereby accumulating steps reinforces continuation of the activity. efforts at encouraging step initiatives in children and adolescents hone in on impacting their motivation, which is often lacking. 66 research on how to encourage more physical activity among studies exploring step tracking have shown promising results in that a positive feedback loop is established, whereby accumulating steps reinforces continuation of the activity. children and adolescents yields findings on how to most effectively use pedometers in combination with other treatment modalities. organizations including the american medical association (ama) and the united states preventive services task force (uspstf), along with healthcare organizations and professionals abroad, have recommended counseling to promote increased physical activity. 67 pedometers, which are inexpensive and wearable devices, can provide children with objective ways to self-monitor their physical activity. several studies of weight management interventions have shown that children can successfully increase their step count from baseline as part of an intervention. 68 yet these studies fail to consistently demonstrate a significant change in bmi percentile from controlled conditions. 68,69 staiano et al. were able to demonstate weight loss in groups of children issued pedometers as part of a 10week, family-based weight management intervention which included physical activity, nutrition, and behavior modification (as well as money compensation). 68 those in the group issued pedometers and a step count goal increased their daily step count, as well as reduced their bmi and bmi z score significantly more than those issued a pedometer without a step goal count. both groups saw a reduction in bmi and an increase in step count from baseline. these same children issued pedometers (with or without a step count goal) had increased subjective health and increased health-related quality of life. ostendorf et al. examined what leads some people to be consistent exercisers and demonstrated that weight loss maintainers weren't using continuous calorie restriction to maintain their weight. 70 instead, the weight loss maintainers had a much higher energy burn from exercise despite eating approximately the same number of calories per day as the control participants with overweight/obesity. it takes a significant time commitment to achieve the level of activity observed in these weight-loss maintainers. in a commentary on the role of exercise, martin and church challenge researchers to identify the physiological, psychological, and environmental factors that help people maintain weight loss through large amounts of exercise so that strategies can be implemented for future weight loss maintenance success. the benefits of exercise cannot be argued. regular exercise can lower stress, moderate anxiety, and improve overall quality of life; however, there is great variation in these outcomes. 71 targeting the agent of change knowing that parents can be effective in modulating childhood obesity by serving as role models for children's eating and physical activity behavior, and knowing the positive impact parental involvement in childhood obesity efforts carries, golan and crowl compared targeting parents exclusively for treatment with a child-only intervention. 72 group sessions were utilized in this family-based health center intervention treatment, with parents attending 14 onehour support and educational sessions that started as weekly, became biweekly, and then took place once every six weeks with clinical dietitians delivering the topics. two similar groups were established, with 15 families participating in each, discussing such topics as limited responsibilities, nutrition education, eating and activity behavior modification, decreasing stimulus exposure, parental modeling, problem-solving, cognitive restructuring, and coping with resistance. parents were encouraged to practice an authoritative parenting style as opposed to an authoritarian style. 71 in authoritative parenting, "parents are both firm and supportive and then assume a leadership role in the environmental change with appropriate granting of child autonomy," whereas in the authoritarian style, child feeding practices are controlled by the adults 73à77 children in the child-only group were prescribed a 1500 calorie per day diet and participated in 30 one-hour group sessions led by a clinical dietitian. two similar groups were held with 15 children allocated to each. the first 7 sessions were conducted weekly and the remainder were held biweekly for the period of one year. at the end of the intervention, 35% of children in the parents-only group reached a non-obese status, compared to 14% in the child-only group. at the one-year follow-up, or one year after program termination, the weight loss in the children of the parent-only group was statistically significant compared with that of the child-only group. at the two-year follow-up, there was a mean reduction in overweight of 15% in children of the parent-only group and an increase of 2.9% in children of the child-only group. at the seven-year follow-up, both treatment conditions demonstrated substantial weight loss. however, the mean reduction of overweight status was 29% in children of the parent-only group and 20.2% in those of the child-only group; 60% of children of the parent-only group, compared with only 31% of children of the child-only group, were in a non-obese status. seven years after program termination, two (6.6%) of the girls from the child-only group reported eating disorder symptoms (both bingeing and purging); none of the children in the parent-only group reported any eating disorder symptoms. family-based programs require the family to be involved. with more families having both parents in the workforce, present-day parents are less available to their children, which makes it difficult for children and adolescents waiting for them to provide a source of physical activity, to engage them in physical activity, or to accompany them to physical activity. parents are less able to enroll in family-based weight management programs if their work schedules conflict with their ability to use free time to participate. 78 interventions targeting overweight and obese children and adolescents that require a large time commitment, a commitment from family members, travel to the intervention location, and potential cost may be poorly received and underutilized. solutions to some of these challenges could be reached with innovative restructuring, telehealth, or a mixed model that may evolve over time. accordingly, researchers collaborated to examine whether utilizing a school nurse delivered intervention for overweight and obese adolescents would be feasible and acceptable, and whether it would serve to improve common obesogenic behaviors (selected for intervention) while positively impacting bmi. 78 clearly there are potentially modifiable behaviors that are associated with improving overweight and obesity. these include decreasing fast food intake, the amount of screen time, on and off dieting, depressive symptoms, low self-esteem, and weight teasing, on the one hand, as well as increasing fruit and vegetable intake through home availability and having more family meals, plus participating in moderate to vigorous physical activity. 79 they are the behaviors most targeted in nutrition interventions using medical nutritional therapy (mnt) by an rd as part of a comprehensive weight management program. increased frequency of rd visits has been associated with improved bmi outcomes in obese youth participating in these programs: "the probability of success exceeded 78% with one rd visit per month versus 43% with minimal rd exposure." 80 both the choose myplate and the 5-2-1-0 education initiatives target these potentially modifiable behaviors. in conjunction with each other, they can have a synergistic effect. healthcare professionals can use these tools together to impact behavior change sessions and establish simple lifestyle goals. many adolescents engage in extreme weight control behaviors and that number has greatly increased over time, as innumerable studies have shown. one population-based survey of adolescents attending middle and high schools in 1998à99 and again in 2008à09 by project eating and activity among teens and young adults assessed personal, psychological, behavioral, and socio-environmental factors believed to play a role in obesity. it showed that informing adolescents and young adults that increased dieting is associated with the persistence of obesity may help motivate adolescents to use more healthful means of weight management. 81, 82 this study reemphasizes the crucial importance of promoting healthy eating, improving the quality of the home food environment, and increasing physical activity as a means of preventing unhealthy weight loss behaviors. the weight management and healthy living 2015 survey from the hartman group 83 found that consumers are more interested in lasting changes and lifelong healthy eating than in crash dieting. it demonstrated that a campaign like myplate, with its message that individuals can achieve a healthier weight by eating more of some foods and less of others, can have utility in helping consumers make lifestyle changes that prove formidable. studies on energy density by b. j. rolls suggest that decreasing energy density reduces energy intake, independent of the macro nutrient mix, because of effects on satiety. 84 the indication is that diets of low energy density, which are typically rich in vegetables, fruits, legumes, and minimally processed grain products, allow individuals to consume "satisfying portions of food," while simultaneously reducing their energy intake. 84 this concept has been used in her best-selling book series volumetrics and made into a diet plan. 85 another approach which has been used in many interventions is the "traffic light" or "stoplight diet," which groups foods based on their nutrient quality and calorie density such that "red foods" should be consumed rarely, "yellow foods" infrequently, and "green foods" most often. 27 it is predicated on the idea that children can learn to substitute lower energy-dense healthy foods for less healthy higher energy-dense foods and that parents can facilitate this transition via increasing access to healthy foods and decreasing access to less healthy foods by altering food purchasing and food storage habits for the family at large. 86 the vast number of children and adolescents in the united states attend public schools. health and wellness policies and programs have traditionally been an important part of the daily curriculum of the majority of these schools. during the 20th century, mandatory physical education classes and nutrition programs, including the national school lunch program (nslp) and the school breakfast program (sbp), were implemented to address problems including "food insecurity." the current obesity epidemic among children and adolescents in the united states has stimulated the further involvement of local, state, and federal agencies in an attempt to use public schools as a venue to combat this problem. in 2004, the u.s. federal government mandated that all school districts participating in the federal meal program create a school wellness program by establishing a committee that includes individuals impacted by this problem. legislation also required the development of nutrition standards for meals and snacks served in schools, as well as the setting up of goals for physical education. the healthy hunger-free act, passed in 2010, required school districts to measure policy implementation and make these results publicly available. what follows here is a look at the impact of some of these and other programs implemented by the schools. approximately 12.2 million public school students from low-income homes are provided a nutritious breakfast as part of the federal school breakfast program (sbp), which was established in 1966 and permanently authorized in 1975. studies have shown that this may be associated with improved academic performance and a reduction in the number of students affected by food insecurity. 87, 88 the number of students participating in the sbp is less than half of those participating in the national school lunch program (nslp). to increase participation in the sbp, the federal government allows school districts to serve breakfast in the classroom (bic). 89 in new york city, more than 70% of public-school students qualify for free or reduced-price meals. researchers reported in 2013 on the impact of bic on the percentage of children going without morning food, the number of locations where food was consumed, and the estimated calories each child consumed. comparisons were made between schools that offered bic and those that did not. results showed that students in bic schools were significantly more likely to eat more than once in the morning and, on average, ate an estimated 95 additional calories each morning. 89 a similar study in the philadelphia public school system, completed and another approach which has been used in many interventions is the "traffic light" or "stoplight diet," which groups foods based on their nutrient quality and calorie density such that "red foods" should be consumed rarely, "yellow foods" infrequently, and "green foods" most often. 27 approximately 12.2 million public school students from lowincome homes are provided a nutritious breakfast as part of the federal school breakfast program (sbp), which was established in 1966 and permanently authorized in 1975. studies have shown that this may be associated with improved academic performance and a reduction in the number of students affected by food insecurity. 87, 88 published in 2018, found that bic did not affect the combined incidence of overweight and obesity among public school students. 90 however, an increasing incidence and prevalence of obesity among the students was noted. in 2003, arkansas became one of the first states to pass legislation to specifically address the epidemic of obesity. it required annual body mass index (bmi) screenings for all public school students, elimination of elementary school students' access to vending machines, and creation of physical education and nutrition standards via district physical activity and nutrition committees along with input from a child health advisory committee. 91, 92 a study published in 2018 assessing the effectiveness of this policy concluded that it was very unlikely that the arkansas act was having an impact on preventing adolescent overweight and obesity. 93 california began bmi screening during the early part of the first decade of the 21st century. the state collected bmi data annually on fifth, seventh, and ninth grade students. parental notification of the results was optional. in 2001, bmi results were sent to 35% of parents or guardians, which rose to 52% in 2008. notification in fifth and/or seventh grade on subsequent bmi z scores, when compared to no notification, showed no significant difference in reducing the prevalence of obesity among this population of students. 94 one state that offered a program that achieved better success is massachusetts. in a pair-matched, cluster-randomized, and controlled school-based trial using a convenience sample of six public high schools, eligible 9th to 11th graders were recruited to participate in "lookin good feelin good," a school nurse-delivered counseling intervention with one-on-one sessions conducted over two months during the school day, during non-academic classes held in the privacy of the school nurse's office. 95 the 5-3-2-1-0 approach was used "to support making five behavioral changes" by utilizing cognitive behavioral techniques to facilitate changes in selfmanagement behaviors through health knowledge and the development of positive outcome expectations, self-control, and behavioral capacity skills and self-efficacy." targeted adolescents completed behavioral and physiological assessments at baseline, and at 2-month and 6-month follow-ups. at two months, compared to control participants, this intervention was able to impact both increased intake of breakfast, and decreased total sugar and added sugar intake. while these particular positive results were not maintained at further follow-up, other positive outcomes were noted at 6 months when the adolescents in the intervention were more likely to drink soda less than or equal to one time a day and eat at fast food restaurants less than or equal to one time per week compared to controls. total calorie intake and calories from fat did not change significantly between groups. screen time and time spent in moderate to vigorous physical activity were not statistically affected. although there was no statistically significant difference in bmi, students in the counseling intervention schools experienced favorable improvements in their bmi compared to students in the control schools. 95 there are clear factors standing in the way of more successful outcomes. an online survey of u.s. public school administrators completed in 2016 indicates that rarely are evidence-based obesity prevention programs being implemented. 92 many programs focus on students' weights rather than on healthy lifestyles. barriers to implementation include lack of funding, time, and training. the johns hopkins evidence-based practice center completed a study of 124 school-based interventions in 2013 and reported on two kinds of programs that demonstrated high evidence of effectiveness in preventing overweight and obesity in the schoolaged population. these are (1) school-based programs that combined physical activity and diet with a home-based component and (2) school-based physical activity and diet interventions that were combined with a home and community component. 96 medication is only recommended after an unsuccessful attempt at weight loss that includes the adoption of a healthy and age-appropriate diet and an increase in daily physical activity. presently, five medications are approved for adults in the united states for long-term management of obesity. 97, 98 weight loss associated with these ranges from approximately 3%à9%. side effects and adverse reactions are common with each. for adolescents greater or equal to twelve years of age, the only prescription medication approved by the united states food and drug administration (usfda) is orlistat. no medication is approved for use in children less than twelve years of age. [99] [100] [101] orlistat is a lipase inhibitor that blocks the absorption of fat. it is recommended to be taken with each meal. although it has been demonstrated to have a good safety profile, side effects can include cramping, excessive gas, oily spotting, fecal urgency, and abdominal pain. since these side effects occur not infrequently, it can be difficult to maintain compliance with this medication. studies have shown modest weight loss efficacy when orlistat is used along with a comprehensive weight loss program. in the largest study (n = 539) of orlistat use in combination with diet, exercise, and behavioral modification, a bmi reduction of approximately 2.4%, as compared to a placebo group, was seen over a treatment period of one year. 102 the only cardiometabolic benefit seen was a small reduction in diastolic blood pressure. at the present time there are no studies reporting long-term outcomes after cessation of orlistat use. phentermine, a norepinephrine reuptake inhibitor, has been approved by the usfda for short-term use for ages seventeen or older. no randomized clinical trials of phentermine have been conducted in individuals younger than seventeen years. common side effects observed in adults using this medication include rapid heart rate, high blood pressure, anxiety, insomnia, and headache. metformin, a biguanide used predominately for glycemic control in individuals with type 2 diabetes mellitus, has been studied for use in treatment of pediatric obesity along with lifestyle interventions. 103 it does not have usfda approval for this use in children and adolescents at the present time. one systematic review of the benefits and risks of using metformin in treating obesity in this population demonstrated a statistically significant, but very modest, reduction in bmi when combined with lifestyle interventions over the short term. no serious adverse events were reported to occur among individuals in the review. the authors concluded that metformin has not been shown to be clinically superior to other options for treating childhood obesity in the short term. bariatric surgery has become an optional treatment for adolescents who are severely obese. in 2004, an expert panel of pediatric surgeons and pediatricians made recommendations regarding selection criteria for bariatric surgery in individuals less than eighteen years of age. 104 selection criteria included: (1) failed >6 months of organized attempts at weight management, (2) has attained or nearly attained physiologic maturity, (3) >50 bmi, or >40 bmi with an associated severe co-morbidity (i.e. sleep apnea, diabetes, hypertension), (4) demonstrates commitment to comprehensive medical and psychological evaluations both before and after surgery, (5) agrees to avoid pregnancy for at least a year, (6) is capable of and willing to adhere to nutritional guidelines postoperatively, (7) provides informed consent, (8) demonstrates decisional capacity, (9) has a supportive family environment, and (10) surgery would be done in centers that have experience with bariatric surgery and a team of specialists trained to provide long-term follow-up care of the metabolic and psychosocial requirements of the patient and family. as an ancillary study of its observational study of adults undergoing bariatric surgery, the national institute of diabetes and digestive and kidney diseases (nddk) created teen-longitudinal assessment of bariatric surgery (teen-labs). funding was provided to five centers in the united states to enroll at least 200 adolescent bariatric surgical patients to serve as a prospective observational cohort study aimed at assessing the clinical, epidemiological, and behavioral parameters in a select population of adolescents undergoing bariatric surgery. 105 the majority of surgical procedures completed in the study were either gastric bypass (roux-en y), which creates a small gastric pouch that is connected directly to the jejunum, bypassing the upper portion of the small intestine, or the sleeve gastrectomy, which creates a narrow stomach pouch and removes the rest of the stomach. for adolescents greater or equal to twelve years of age, the only prescription medication approved by the united states food and drug administration (usfda) is orlistat. no medication is approved for use in children less than twelve years of age. [99] [100] [101] research published in 2018 has shown an increasing use of vertical sleeve gastrectomy compared to other surgical procedures. 106 multiple publications from the teen-labs study have documented that severely obese adolescents undergoing bariatric surgery, when compared to matched adolescents undergoing medical treatment alone, had better weight loss, improvement in cardiovascular risk markers and better glycemic control. the teen-labs researchers also reported identified risks including specific micronutrient deficiencies and the need for an acceptable rate (13%) of additional abdominal procedures. [107] [108] [109] [110] [111] overall similar findings were obtained by olbers in a prospective nationwide study of 81 swedish adolescents who were severely obese and underwent roux-en y gastric bypass. 112 a single study completed by alqalhtani in saudi arabia reviewed the effects of laparoscopic sleeve gastrectomy in 114 children younger than 14 years of age (mean § sd, 11.2 § 2.5 years). it was concluded that the procedure resulted in significant weight loss, improved growth, and a resolution of comorbidities, without mortality or significant morbidity. teen-labs researchers recently compared 5-year outcomes of gastric bypass in adolescents with those of adults. they reported that adolescents and adults who underwent gastric bypass surgery had similar significant weight loss 5 years after surgery, but adolescents had a higher rate of remission of hypertension and diabetes following gastric bypass than adults. they also found that abdominal operations and short-term nutritional deficiencies were more common among adolescents than adults following surgery. 113 data from another teen-lab study demonstrated that joint pain, physical function, and health-related quality of life improved after bariatric surgery. 114 in 2018, the american society for metabolic and bariatric surgery's (asmba) pediatric committee updated their recommendations for metabolic and bariatric surgery in children and adolescents following a comprehensive literature search. they proposed that metabolic and bariatric surgery is indicated for the following adolescents: (1) bmi >35 or 120% of the 95th percentile with clinically significant comorbidities (whichever is lower), and (2) bmi >40 or 140% of the 95th percentile (whichever is lower). in addition, the patient and family should demonstrate the ability and motivation to adhere to recommended pre-and postoperative treatment. the asmba's recommendations regarding contraindications for surgery included: (1) a medical correctable cause of obesity, (2) an ongoing substance abuse problem (within the preceding year), (3) inability to adhere to postoperative dietary and medication regimens as a result of a medical, psychiatric, psychosocial, or cognitive condition, and (4) current or planned pregnancy within 12à18 months of the procedure. at the same time, their guidelines stated that treatment should not be denied to those adolescents with cognitive disabilities, a history of mental illness, a history of eating disorders that are treated, immature bone growth or low tanner stage. their overall conclusion was that surgery was safe and effective in adolescents, and that early intervention can reduce the risk of persistent obesity as well as end organ damage from longstanding comorbidities. 115 multiple publications from the teen-labs study have documented that severely obese adolescents undergoing bariatric surgery, when compared to matched adolescents undergoing medical treatment alone, had better weight loss, improvement in cardiovascular risk markers and better glycemic control. in 2018, the american society for metabolic and bariatric surgery's (asmba) pediatric committee updated their recommendations for metabolic and bariatric surgery in children and adolescents following a comprehensive literature search. they proposed that metabolic and bariatric surgery is indicated for the following adolescents: (1) bmi >35 or 120% of the 95th percentile with clinically significant comorbidities (whichever is lower), and (2) bmi >40 or 140% of the 95th percentile (whichever is lower). the american academy of pediatrics, as well, has issued guidelines in a policy statement entitled "pediatric metabolic and bariatric surgery: evidence, barriers and best practices," published in 2019. 116 they recommended considering the following factors in deciding on surgery: (1) shared decision-making including patient, parents, medical and surgical providers, (2) bmi and comorbidity, (3) physiological, psychological, and developmental maturity, (4) ability to understand risks and benefits and be able to adhere to lifestyle modifications, (5) decision-making capacity, (6) robust family and social supports before and after the procedure. concluding that there was no evidence to support the application of age-based eligibility, the aap set forth the following indications for adolescent metabolic and bariatric surgery: (1) class 2 obesity: bmi i 35 or 120% of the 95th percentile for age and sex, whichever is lower, and with an associated clinically significant disease, including obstructive sleep apnea (ahi >5), t2dm, increased intracranial hypertension, nash, blount disease, scfe, gerd, and hypertension, and (2) class 3 obesity: bmi 40, or 140% of the 95th percentile for age and sex, whichever is lower without any associated comorbid conditions. multicomponent programs that focus on diet, behavior-change, and physical acitivity are recommended as the first line of treatment for children and adolescents who are overweight or obese. treatment should be guided by the patient's developmental, cognitive, and pubertal stage of development. the range of clinicians and environments providing these services is extensive with most services being provided through multidisciplinary tertiary care clinics and providers. these interventions have been proven to be beneficial in achieving small short-term reductions in bmi. presently, there is both a lack of long-term benefit and evidence that these interventions will reduce the incidence of obesity or the associated cardio-metabolic complications for children and adolescents (and adults) in the future. an almost universal consensus recommends a significant increase in research on all interventions including minority and special-needs populations with coordinated long-term follow-up. school-based programs, pharmacotherapy, and bariatric surgery are additional approaches that are increasingly being utilized for weight loss management; of these, 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overconsumption of fat increasing healthy eating vs. reducing high energy-dense foods to treat pediatric obesity nutrition and cognitive achievement: an evaluation of the school breakfast program the school breakfast program strengthens household food security among low-income households with elementary school children evaluation of the new york city breakfast in the classroom program effect of a breakfast in the classroom initiative on obesity in urban schoolaged children: a cluster randomized clinical trial implementing school-based policies to prevent obesity: cluster randomized trial obesity preventions interventions in us public school: are schools using programs that promote weight stigma leveraging the public school system to combat adolescent obesity: the limits of arkansas's statewide policy initiative school-based body mass index screening and patient notification: a statewide natural experiment a school nurse-delivered intervention for overweight and obese adolescents childhood obesity prevention programs: comparative effectiveness review and meta-analysis association of pharmacological treatment for obesity with weight loss and adverse side effects: a systematic review and meta-analysis clinical considerations regarding the use of obesity pharmacotherapy in adolescents with obesity effectiveness of weight management interventions in children: a targeted systematic review for the uspstf severe obesity in children and adolescents: identification, associated health risks, and treatment approaches: a scientific statement from the american heart association treatment of adolescent obesity in 2020 effect of orlistat on weight and body composition in obese adolescents systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger bariatric surgery for severely overweight adolescents: concerns and recommendations teen-longitudinal assessment of bariatric surgery: methodological features of the first prospective multicenter study of adolescent bariatric surgery national trends in the use of metabolic and bariatric surgery among pediatric patients with severe obesity changes in functional mobility and musculoskeletal pain after bariatric surgery in teens with severe obesity: teen-longitudinal assessment of bariatric surgery (teen-labs) study perioperative outcomes of adolescents undergoing bariatric surgery: the teenlongitudinal assessment of bariatric surgery (teen-labs) study weight loss and health status 3 years after bariatric surgery in adolescents comparison of surgical and medical therapy for type 2 diabetes in severely obese adolescents cardiovascular risk factors after adolescent bariatric surgery laparoscopic roux-en y gastric bypass in adolescents with severe obesity (amos): a prospective, 5-year swedish nationwide study five-year outcomes of gastric bypass in adolescents as compared with adults musculoskeletal pain, physical function, and quality of life after bariatric surgery asmbs pediatric metabolic and bariatric surgery guidelines pediatric metabolic and bariatric surgery: evidence, barriers, and best practices key: cord-005750-54hul2lw authors: antonelli, massimo; azoulay, elie; bonten, marc; chastre, jean; citerio, giuseppe; conti, giorgio; de backer, daniel; lemaire, françois; gerlach, herwig; groeneveld, johan; hedenstierna, goran; macrae, duncan; mancebo, jordi; maggiore, salvatore m.; mebazaa, alexandre; metnitz, philipp; pugin, jerôme; wernerman, jan; zhang, haibo title: year in review in intensive care medicine, 2008: iii. paediatrics, ethics, outcome research and critical care organization, sedation, pharmacology and miscellanea date: 2009-02-10 journal: intensive care med doi: 10.1007/s00134-009-1433-4 sha: doc_id: 5750 cord_uid: 54hul2lw nan increasingly in paediatric intensive care, as in the adult sphere, the intensivist's focus is increasingly guided towards not only reducing mortality but also to ensuring that survival is morbidity-free. baghurst et al. [1] reported on the applicability of sequential control charts for monitoring of the quality of paediatric intensive care using risk-adjusted probabilities of death estimated by the paediatric index of mortality version 2 (pim2). a total of 10,710 patient records submitted to the australia and new zealand paediatric intensive care registry from 8 picu's were used in the report. during the 2-year monitoring period the investigators demonstrated that their methodology was able to detect one 'alarm' for poor picu performance and one 'alarm' for better than expected picu performance. in their paper, the authors present a detailed description of sequential analysis methodologies and describe their potential prospective use as tools for monitoring the performance of intensive care units. they caution that 'alarms' for poor or excessively good performance are arbitrarily set and are not necessarily indicative of 'real' problems. alarms should, however, act as triggers for investigation to ascertain whether the data is sound and if so whether true clinical over or underperformance exists. numa et al. [2] undertook a study to determine whether outcomes were influenced by time of admission to an australian tertiary paediatric intensive care unit without 24 h per day in-house intensivist cover. evening, night and weekend cover by staff intensivists was provided mainly by telephone with discretionary return to hospital to support resident paediatric staff. the authors found that a lack of in-house intensivist was not associated with any increase in riskadjusted mortality or increased length of stay. they attribute these findings to a combination of relatively experienced junior staff and the effectiveness of telephone backup and discretionary attendance from intensivists after hours. two studies in 2008 looked at the quality of survival of children after undergoing intensive care. in a case-control study, elison et al. [3] reported on a detailed neuropsychological follow-up of 16 children, with mean age 9.44 ± 2.85 years, tested a mean of 4.8 ± 1.4 months following hospital discharge. they detected the presence of impaired memory and attention in children following acute illness and links between memory anomalies and emotional/behavioural problems. these findings, if replicated in a larger study, are very important to children and their parents and teachers. knoester et al. [4] also reported on early neurocognitive sequelae of intensive care but in addition reported information on physical outcomes. they determined that 69% of children had detectable physical sequelae 3 months after picu discharge. whilst 30% of sequelae were attributed to previously unknown illness, 39% were acquired of which 8% were related to complications of picu procedures. finally, in the area of patient safety and quality, burmester et al. [5] reported on the apparent benefit of the introduction of a structured prescription education programme and standardised prescription template in a paediatric cardiac icu. the total number of prescription errors fell from a baseline of 16.8% of prescriptions to 4.8% after the implementation of the measures and this was associated with a small but statistically significant reduction in the incidence of adverse drug events. weight-based variations in drug dosing are often quoted as a factor in the known high incidence of drug errors in paediatric practice. disappointingly, tenfold miscalculations which are particularly common and dangerous in children if the decimal point is misplaced during calculations showed no improvement with the studied interventions. this report highlights the need for regular ongoing education in critical care units which typically have high prescription volumes and often see high turnover of staff, particularly 'junior' prescribers such as resident medical staff. the high mortality of septic shock in children was confirmed in a paper from wolfler et al. [6] who reported a prospective observational study across 15 italian paediatric intensive care units conducted over a period of 1 year. during the study 2,741 children were admitted to the participating picu's. the incidence of severe sepsis was 1.6% and that of septic shock 2.1%, with associated mortalities of 17.7 and 50.8%, respectively. in march 2008 the journal published a landmark paper from de oliveira et al. [7] . they studied children with septic shock who were resuscitated according to accm/pals guidelines [8] with or without scvo2 goal-directed therapy. in this randomised controlled trial, there was a significant difference in mortality rate with use of accm/ pals haemodynamic support guidelines for septic shock between patients with or without scvo 2 guided therapy. patients who received therapies directed to the goal of scvo 2 [ 70% were given more fluid, red blood cells and inotropic support after the initial resuscitation, with a resulting 3.3-fold reduction in mortality. this study supports the incorporation goal-directed therapy using the endpoint of a scvo 2 c 70% within accm/pals guidelines the use of which provided a significant beneficial impact on the outcome of children and adolescents with septic shock in this study. recently the use of vasopressin and vasopressin analogues, potent vasoconstrictors, has been reported in the management of vasodilatory shock in children. jerath reported a retrospective study of the use of vasopressin in a series of 157 children in a multidisciplinary picu. haemodynamics appear to have been favourably influenced, but the authors noted adverse effects on renal function and lower platelet counts associated with vasopressin use. yildizdas et al. [9] performed a randomised non-blinded comparison of the use of the vasopressin analogue terlipressin in a group of 58 children with refractory septic shock. although terlipressin had no beneficial effect on mortality rate in this study, its use was associated with increased mean arterial pressure, improved oxygenation, decreased length of stay in the picu and had a beneficial effect on survival time among nonsurvivors. despite these interesting early reports, the place of vasopressin and its analogues in the management of shock states in children is not yet established. until blinded, randomized, and placebo-controlled studies are conducted in children with septic shock and in other shock states which compare the use of vasopressin-like drugs to standard treatments such as noradrenaline, their use should be considered only a rescue therapy of last resort. with increased experience, improved surgical techniques, and advances in postoperative care and immunosuppressive therapy, paediatric intestinal transplantation is already into the medical mainstream. in this article, hauser and coll [10] reviewed the literature on intensive care of paediatric intestinal transplantation as well as their own experience. this article covers the following areas: the indications for intestinal transplantation, the management of critically ill children awaiting intestinal transplantation, the operative procedure, the postoperative management. this last area deals with the intestinal graft, the liver graft, the cardiovascular, respiratory and renal support, the electrolyte and haematologic management, the pain and infection control, the rejection and other alterations in graft function, the nutritional support, the problems of high stomal output, the immunosuppressive treatment, the outcomes and the upcoming challenges. the authors concluded that transplant teams accept patients with higher morbidity and higher risks for complications and indicate that many of these patients would benefit from earlier referral for transplant evaluation before severe complications develop. sedation and analgesic practices vary widely in both adult and paediatric intensive care. however, relatively little high quality evidence supports current paediatric practice. lamas et al. [11] investigated the utility of the bispectral index (bis), auditory-evoked responses (aep) and ramsay and comfort clinical scales in the assessment of sedation in critically ill children. simultaneous recordings were obtained. in children in whom neuromuscular blockade was not being used, correlation between the four methods was moderate or good. however, only bis and aep were found to be potentially reliable in those children who were both sedated and subject to neuromuscular blockade. the authors concluded that their results support the finding that the clinical scales do not evaluate the level of sedation accurately in critically ill children with neuromuscular relaxation, leading to a higher risk of over or undersedation. they suggest that in these children, bis and the aep index methods may provide a better assessment of the level of sedation. however, they caution that lack of correlation between these two methods in children with neuromuscular relaxation and the absence of a reference method to evaluate sedation in the relaxed patient means that their results must be interpreted carefully. further studies are needed. recently, akcan-arikan et al. [12] have described a modified version of the rifle criteria for paediatric patients (prifle). their proposed prifle criteria are based on a decrease in estimated creatinine clearance (eccl),and urine output is based on body weight. plötz et al. [13] independently evaluated the prifle criteria in a cohort of 103 children in a european picu. sixty children (58%) developed acute kidney injury (aki) according to prifle criteria of whom six required renal replacement therapy. the authors conclude that prifle criteria may guide the early identification of patients at risk of aki and therefore guide early initiation of therapy, with potential to avoid progress from 'risk' to injury'. hoover and colleagues reported a series of 26 children on ecmo for respiratory failure who received cvvh for [24 h and compared these to ecmo/non-cvvh casematched control children. significant findings included a faster time to desired caloric intake and reduced furosemide use in cvvh treated children. although no obvious survival benefit related to use of cvvh was demonstrated, the association of cvvh on ecmo with improved fluid balance and nutritional management was compelling. performing optimal cardiovascular monitoring in critically ill children is a considerable challenge. the journal published four papers in 2008 which address various aspects of this challenging field. durand et al. [14] investigated whether the measurement of respiratory variations in aortic blood flow velocity (d v peak ao), systolic arterial (d sap) pressure and pulse pressure (d pp) could accurately predict fluid responsiveness in ventilated children. standardised volume challenges were given to 26 children with preserved ventricular function. aortic blood flow was analysed by transthoracic pulsed doppler. whilst a positive correlation was found between d v peak ao and volume expansion-induced gain in stroke volume, measurements of d sap pressure and d pp were of little value in predicting responses to fluid augmentation in ventilated children. in a preliminary study, knirsch et al. [15] compared the measurement of cardiac output using the ultrasound cardiac output monitor (uscom) with pulmonary artery catheterderived thermodilution cardiac output in a group of 24 children undergoing cardiac catheterization. the main finding was that cardiac output measured with uscom did not reliably represent absolute values measured by pulmonary artery catheter thermodilution, with a mean percentage error higher than 30%. the limitations of transthoracic pulsed doppler cardiac output measurement in comparison to cardiac output measurement by the thermodilution technique has been recognized [16] . a number of user-dependent technical factors have been shown to influence ultrasound-derived measurements in other studies in a variety of situations. in addition, possible inaccuracy in algorithm-derived aortic valve diameter used in calculation for cardiac output from flow can introduce systematic error. many of these limitations are negated if serial measurements are used to derive trends in aortic flow rather algorithm-derived 'absolute' cardiac outputs. frey et al. [17] brought clarity to the interpretation of aspects of the photoplethysmographic wave which is displayed by most pulse oximeters. they demonstrate that it may be used to derive additional haemodynamic information in some selected situations when, for instance, arterial blood pressure monitoring is not available. the advantages of this method are its widespread use, non-invasiveness and continuity. the authors suggest that haemodynamic deterioration, whether suddenly occurring or slowly evolving over time, may be detected by this method. there is only minimal reference to photoplethysmography monitoring in the paediatric literature. three studies published in 2008 relate to aspects of the care of children undergoing cardiac surgery using cardiopulmonary bypass. tissières et al. [18] described the use of the biomarker n-terminal brain natriuretic peptide (n-probnp) and troponin i in 20 children following valvular surgery. their results demonstrated that n-probnp was superior to troponin i in reflecting clinical and echocardiographic postoperative recovery. furthermore the authors suggest that preoperative n-probnp reflected postoperative myocardial functional capacity, thus potentially helping in the early identification of patients who are at risk of chronic cardiac dysfunction. another biomarker, plasma angiopoetin-2 (angpt-2), a vascular growth factor, was found by giuliano et al. [19] to independently predict cardiac icu length of stay in a series of 48 children palliative or corrective cardiac surgery. the angiopoietins are a family of vascular growth factors that are necessary for both developmental and pathological angiogenesis. angpt-2 promotes increased vascular permeability and inflammation and has been shown to be increased in adults with congestive heart failure and the acute coronary syndrome. the authors conclude that angpt-2 appears to be an important biomarker of adverse outcome following cpb. further studies pertaining to the role of angpt-2 in the pathophysiology of capillary leak syndrome following cpb are warranted. at a more practical level, the study reported by ross-russell et al. [20] is a large prospective report of the measurement of phrenic nerve latency in 310 children before and after cardiac surgery. phrenic nerve injury being a relatively common and clinically important complication of cardiothoracic surgery). the authors ascertained an incidence of phrenic nerve injury associated with surgery of 20%. injury was associated with an increased duration of postoperative ventilation (20 vs. 96 h, p \ 0.001). of particular interest in this report is medium term follow-up which shows that one-third children recovered function within 1 months and a further one-third within 3 months. two papers recently published in the journal shed further light on the mechanisms of paediatric respiratory disease. a paper by plunkett et al. [21] addressed the question of whether the d allele of the i/d polymorphism of the angiotensin converting enzyme (ace) gene is associated with increased susceptibility to acute hypoxaemic respiratory failure (ahrf) in critically ill children. previous reports have linked the d allele of the ace gene to susceptibity for ards in critically ill adults and bronchopulmonary dysplasia in pre-term infants. in a single centre prospective study, ahrf developed in 13.9% of 216 critically ill children. there was no significant difference in the frequency of the d allele between patient groups with and without ahrf. the authors suggest that this may suggest differences in the pathogenesis of paediatric ahrf and adult ards. phospholipases a2 is an enzyme widely distributed in the body and was the focus of a report from de luca et al. [22] . the enzyme is primarily involved in the turnover of membrane phospholipids and lipid digestion. in addition phospholipase a2 is involved in inflammation pathways through the formation of eicosanoids and other inflammatory mediators. in the lungs the secretory form of the enzyme (spla2) is produced mainly by alveolar macrophages and secreted into the alveoli. spla2 has been shown to be involved in lung inflammation and surfactant degradation and it may play a role for spla2 in the development of acute respiratory distress syndrome (ards). de luca et al. provide evidence that spla2 is present in high concentrations in bronchoalveolar lavage fluid obtained from neonates with pneumonia and hyaline membrane disease. in this study, spla2 levels correlated negatively with dynamic compliance and positively with indices of poorer oxygenation. it appears therefore that the enzyme plays a role in the pathogenesis of respiratory failure in neonates. respiratory disease caused by the respiratory syncytial virus (rsv) accounts for almost 10% of admissions to picu's [23] . rsv disease is characterised by inflammation of the small airways with raised airways resistance, air-trapping and pulmonary consolidation, disproportionately effects young infants due primarily to their poor respiratory muscle reserve. icm recently published three papers describing different ventilatory strategies for infants with rsv disease. javouhey et al. [24] used noninvasive ventilation as their primary form of respiratory support in 27 infants. they applied continuous positive airway pressure (cpap) at 5-10 cm h 2 o with additional bi-level positive pressure ventilation of 12-20 cm h 2 o as required. compared to an immediately prior historical cohort of infants with the disease, the intubation rate was significantly lower (52 vs. 89% p \ 0.01). berner and colleagues [25] adopted a different strategy, successfully using high frequency oscillatory ventilation whilst allowing spontaneous breathing in a group of 9 infants with rsv. these two strategies are essentially delivering physiologically similar therapy, maintaining spontaneous ventilation and relying on cpap to maintain lung volume and reduce the work of breathing. the suggestion that cpap is clinically effective in rsv bronchiolitis possibly through reduced work of breathing in babies with rsv bronchiolitis was first made by beasley addressed similar issues in two related papers investigating the mechanics of breathing in children with severe croup and the effect of nebulization of epinephrine on measures of airway obstruction [30] . respiratory mechanics were studies in 20 infants with severe croup. patients were found to maintain minute ventilation by means of large increases in mean intrathoracic pressure required to overcome inspiratory flow limitation. nebulised epinephrine was found to result in short-lived improvement in some but not all patients with croup. both inspiratory and expiratory airway resistance fell in patients responding to nebulised epinephrine. oesophageal pressures in both studies were measured via a feeding tube and were found to be satisfactory for quantification of the acute response to nebulised epinephrine whereas flow measurements were unhelpful. finally two clinical reports address areas of the management of acute respiratory failure in children where significant differences from adult practice are evident. pathan et al. [31] reported a series of 124 children categorised as receiving 'paediatric extra-corporeal life support' in a single institution from the inception of their ecls programme in july 1992 until december 2005. clinical selection criteria operated during the study were those of severe respiratory failure failing to respond to conventional management and in whom recovery was believed to be reasonably possible. survival to hospital discharge was 62 with 59% surviving to 1 year. severity of pulmonary dysfunction pre-ecmo and the presence of shock predicted higher risk of mortality. kneyber et al. [32] raise the important question of whether we know the true incidence of the acute respiratory distress syndrome in children, or whether it is under-recognised. they retrospectively reviewed 533 mechanically ventilated children admitted to two regional dutch paediatric icu's. chest radiographs were screened for the presence of bilateral infiltrates, pao2/fio2 ratios calculated and left ventricular dysfunction ruled out by echocardiography. forty-one (7.7%) of children met criteria for ards giving a population-based incidence of ards of 2.2 per 100,000 per year. the incidence of paediatric ards is low compared to adults, but the authors suggest that many cases of ards are categorised by their underlying diseases such as viral infections, leading to significant underreporting of ards. this may be particularly important when planning randomised -controlled trials, as significant underestimation of the effected population could lead to erroneous trial designs or abandonment of trials at the planning stage due to perceived difficulty in recruiting subjects in a timely and cost-effective manner. bachmann et al. [33] investigated the level of adoption of paediatric ventilation technologies from the participants at two international conferences. the authors used the approach of rogers' which addresses both differences among individuals and characteristics of the innovation [34] . the authors concluded that whilst evidence of outcomes is the most relevant factor for assessment of potentially beneficial technologies, other factors that encourage adoption of mediocre technologies, or that retard adoption of potentially beneficial technologies, must be understood and acknowledged. in a concise review, truog [35] reminds us the specificities and issues in paediatric clinical research. universal requirements for ethical research are on one hand the respect of subject's autonomy and on the other the protection against harm (the risk-benefit ratio). respect of autonomy for a child under 18 implies that investigators, whenever possible, seek his-her assent, besides the parental authorization. protection is achieved via a drastic limitation of the risks children can be exposed during a trial: in the us, the threshold is a ''minimal risk'' for healthy children and a ''minor increase over minimal risk'' for diseased ones. then, dr truog proposes a threestep approach of evaluation of paediatric research protocols. the basic concept here is the so-called ''component analysis'': the research protocol has to be broken in several components, those part of standard care and those which are necessary for research, in addition to care. each of these components are separately analysed in terms of risk/benefit balance. however, appreciation of ''minimal risk'' is always debatable, and it is the essential role of the research ethics committee (recs, or irbs in the us) to define it on a case to case basis. minneci et al. [36] review a few recent randomized clinical trials performed on severely ill patients (the arma trial comparing a low and a lage vt in ards, the trial assessing the effect of growth hormone in icu patients and the tricc trial, on the level of blood transfusion, also in icu patients) and emphasise the crucial importance of the control group. they convincingly show that most of the controversies which followed the publication of some of them stemmed from the inappropriate design of control groups. a well designed control group has two main functions: the first one is to protect the patients enrolled in the trial, and the second is to guarantee the external validity of the conclusions of the research. if the new therapy is to replace the existing standard, it has to have been tested against this standard. authors' recommendations are that a control group should not be historical, needs to represent current care and should be enrolled along with the new treatment group. of course, in all large trials involving severely ill patients, a dsmb will monitor safety by comparing the intervention group to this control group. special difficulties are commonplace in critical care research: patients populations are frequently heterogeneous, syndromes are dealt with, instead of diseases (septic shock, ards.), many treatments are delivered with titration: vt, peep, catecholamines, blood transfusion, making the design of a control group extraordinary arduous (one size does no fit all.). zamperetti and latronico [37] give a rather grim view of the regulatory aspects of clinical research in italy. basically, directive 2001/20/ec has been literally translated and transposed in the italian legislation, thus creating a ''legal representative'', which has not been defined, at the difference of nearly all eu member states. in consequence, decisions for any specific protocols depend on local rec, with no coordination or common guidelines. similarly, a waived or deferred consent in emergency research may or may not be possible, depending of the local rec, which may base its decision on directive 2001, which prohibits it, or the oviedo convention, which makes it possible. a clear description of the convention of human rights and biomedicine (oviedo) of the council of europe is provided by elmar doppelfeld [38] . the mechanisms by which states and governments, members or not of the eu, sign and ratify the conventions and protocols produced by the council of europe are described, as well as the links between the european commission and the council (not obvious to all.). concerning research on severely ill patients (a vulnerable population), special provisions are written in the additional protocol. conditions for waiving consent (emergency) and for designation of surrogate decisionmakers in case of incapacity are specified. research on incompetent persons when no direct benefit is provided is possible, under some specific provisions. charles sprung et al. [39] published in icm their seventh paper derived from the huge ethicus database. this study has demonstrated a large gradient from northern to southern regions in europe as to the end of life decisions in icus. it was certainly tempting to see whether physician's values could explain these discrepancies. clearly, the lesser degree of end of life decisions in the south corresponds to more paternalistic views, as expressed by a more frequently cited ''unresponsiveness to therapy'', a lesser degree of documentation of their decisions and also a lesser consideration for patients' ''best interest''. however, all investigators, irrespectively of their location, gave a low priority to patient or family request. the authors conclude that ''.there is room (in europe) for greater engagement with patients and their families to promote patient autonomy in the end of life decision-making process''! end of life decisions are influenced by the religious affiliation of physicians, despite the delimitation of religion from ''acculturation'' is not always clear-cut. this was another important demonstration by the ethicus study [40] . bulöw et al. [41] review the world's major religions' points of view on end of life decisions in the icu. the jewish perspective gives a fascinating insight into a new israeli law which deals with the prohibition by halacha of withdrawing mechanical ventilation. surprisingly enough, the islamic perspective is not far from the catholic tradition (the moral of intention, for instance), but the authors take the precaution to indicate that in different countries, ''recognized religious scholars'' may have the last word. ''death rattle'' is a common occurrence after ''terminal'' extubation, at the end of life. it may destabilize families and jeopardize an otherwise well conducted withdrawal of life support in the icu. erwin kompanje et al. [42] provide an excellent overview of the phenomenon and give guidelines on how to prevent and to treat it. this is probably one of the most useful recommendations in a crucial subject, though usually ignored. the icm series on national legislations on end of life in icus, which started in 2006, continued in 2008 with austria [43] , along with the guidelines produced by the austrian association of intensive care medicine [44] and spain [45] . cabre et al. [45] have described the legal framework for end of life decision in spain. as in other european countries, the spanish society is currently concerned by controversies as to limitation of care in emergency departments or icus, a debate obscured by the absence of a clear delimitation between euthanasia and the withdrawal of life support. it is good news to learn that the court of justice of madrid finally cleared the physicians involved in the ''leganés case'' [46] from any wrongdoing. a very interesting initiative, which should be replicated elsewhere, is the choice of end of life decisions as an indicator of good quality of care by the spanish society of critical care, the semicyuc. servillo and striano [47] tell us how in italy, as in spain, end-of-life care gives fierce debates, further enhanced by the strong influence of the catholic church in such matters. dr riccio, an anaesthetist involved in the welby case has also been relaxed by justice. the debate is now focused on the introduction in the italian law of ''advanced directives''. as in other countries where laws are mute on end of life decisions, the role of professional societies (the siaarti in italy) is crucial in guiding physicians and in protecting them occasionally. sexual dysfunction seems to be highly prevalent not only in the community, but also after critical illness. although patients report sexual function to be important, symptoms of sexual dysfunction after major illness are seldom evaluated by medical practitioners. ulvik et al. [48] thus studied sexual dysfunction in trauma patients 3-8 years after discharge from the icu, using a questionnaire. the cohort comprised of 325 consecutive trauma patients over 18 years of age admitted to their icu in the period 1998-2003, of which 210 were eligible. the response rate was with 74% highly satisfactory. patients were asked to describe their sexual life both, prior to the icu admission and presently. half of the patients reported sexual function to be unchanged, 41% impaired, and 9% even to be better than before the trauma. erectile dysfunction was found to contribute in 27% of men younger than 40 years and 51% of men 40 years or older. age, being single, injury severity score, and depression were associated with a poor sexual function. the authors concluded that due to the high incidence and also the possible impact on individual quality of life, sexual function should be regularly evaluated at least in trauma patients. the saps 3 risk-adjustment system, developed from a world-wide multicenter study, has been published in 2005. as for all severity of illness systems, external validation studies are needed to proof the prognostic performance in settings different than the one the score has been developed from. ledoux et al. [49] undertook a prospective study in their institution to evaluate the performance of saps 3 and to compare it to two other systems, namely apache ii and saps ii. they included 802 consecutively to the icu admitted patients over an 8month period. with respect to discrimination, apache ii performed worse than saps ii and saps 3 models. calibration was unsatisfactory again for apache ii and for the general saps 3 model, whereas it was satisfactory for saps ii and the saps 3 model with the central european equation. the authors concluded, that the saps 3 admission score and its model for central and western europe was more discriminative and better calibrated than apache ii, but it was not significantly better than the saps ii. since this study presents as a single centre study with a low patient number, the results have to be viewed with caution. multicenter studies with higher patient numbers are required to determine the prognostic ability of a risk-adjustment system. intra-abdominal hypertension (iah) has only in the past decade received attention as a potential source of problems for critically ill patients. several recent studies have highlighted the possible impact of increased intra-abdominal pressure on renal function. dalfino et al. [50] studied the relationship between iah and acute renal failure (arf) in critically ill patients. they included all patients who were consecutively admitted during a 6-month period. iah was defined as a iap [ = 12 mmhg in at least two consecutive measurements performed at 24-h intervals. arf was defined according to the failure class of the rifle criteria. almost a third of their patients developed iah. arf developed in 19% of their patients, with a significant difference between the two groups: 43.2% in the iah versus 8.1% in the non-iah group (p \ 0.05). shock and low abdominal perfusion pressure were predictive factors for the development of arf. a cut-off point of 12 mmhg had the best predictive power for the development of arf. although raw hospital mortality was significantly higher in patients with iah, risk-adjusted mortality rate was not different between the two groups. the authors concluded, that iah is clearly an independent and strong predictor for the development of arf. however, the contribution of impaired systemic hemodynamics should also be taken into account. the impact on mortality of early coagulation disorders after severe burn injury was addressed by lavrentieva et al. [51] . in this single centre prospective study conducted on 45 patients with severe thermal burn injury the 28-day mortality rate was 33%. the presence of overt dic was related to mortality (or = 0.1). antithrombin, protein s, plasminogen activator inhibitor 1, and sofa score on day 3, protein c on day 5, and thrombin/antithrombin complexes on day 7 revealed a good prognostic value for icu mortality. the authors concluded that the severe thermal injury is associated with the early activation of coagulation cascade, presence of dic, organ failure, and increased mortality. bedside adherence to clinical practice guidelines may influence the outcome. the dissemination of medical knowledge is essential and practice surveys are important to assess practices of health-care professionals and develop strategies for more effective actions. the tecla study [52] with a multicenter, 1-day crosssectional design assessed adherence to clinical recommendations for three interventions routinely used in critical care medicine. a total of 419 patients hospitalized in the 44 participating icus in 4 countries were enrolled. red blood cell transfusion (n = 29) was performed appropriately in 22 patients (76%), while among the 390 patients who received no transfusion 4 (1%) had a valid indication. setting of tidal volume in acute respiratory distress syndrome, assessed in 45 patients, was deemed appropriate in 37 cases (82%). prescription of stress ulcer prophylaxis (n = 128) was appropriate in only 24 patients (19%), while among the 268 patients who were not treated 28 (10%) had an indication. the survey concluded that the implementation of recommendations varies across different domains of care, being suboptimal in some contexts. wheeler et al. [53] carried out an audit to quantify the variability in the concentration of drug infusions prepared in an adult intensive care unit. they also established whether there was a relationship between the quality of syringe labelling and drug preparation. they collected 149 discarded syringes containing midazolam, insulin, norepinephrine, dopamine, potassium or magnesium. residual solutions were sampled, concentrations were measured, and syringe labels were awarded a score for labelling quality based on an 11-point scale. the majority of the infusions differed from the expected concentration by more than 10%. magnesium infusions were least likely to be properly labelled. there was a positive correlation between quality of syringe labelling and drug preparation. after the introduction of a new electrolyte prescription chart, magnesium and potassium preparation significantly improved but there was still substantial variability. the authors conclude by a plea for the use of pre-prepared syringes or standardized drug preparation and labelling systems. scientific societies have published position papers recommending certain critical care pharmacy activities. in a brief report leblanc et al. [54] described the activities of international pharmacists who had a significant portion of their duties dedicated to critical care to increase the awareness of pharmacist roles to the critical care team. the authors analyzed data obtained in a website based survey. the majority of respondents (74.4% of a total of 168 pharmacists) attended medical rounds and 54.8% were involved in research. the majority of pharmacists (72.6%) were involved in drug monitoring (mainly aminoglycosides and vancomycin). a few prepared intravenous medications or total parenteral nutrition, 13 and 8.4%, respectively. authors conclude that critical care pharmacists participate in a wide range of activities and they expect that the involvement of the pharmacist in critical care teams will increase. in a prospective multicentre study, takala et al. [55] tested the feasibility of three software-driven critical care protocols. they applied software-driven protocols for cardiovascular management, sedation, and weaning during the first 7 icu-days in 174 cardiac surgery and 41 septic patients. protocol use was discontinued in 12% of patients by the treating clinician and in 6% for technical/ administrative reasons. this study advocates that multiple software-driven treatment protocols can be simultaneously applied with high acceptance and rapid achievement of primary treatment goals (initial hemodynamic stability, sedation targets, weaning time). in a prospective observational study, perren et al. [56] assessed whether cross-checking of the physician icu transfer report by icu nurses may reduce transfer report errors. about 123 patients were randomly selected at discharge from the icu and physician icu transfer reports were cross-checked by nurses using defined review criteria. about 76 (62%) transfer reports were affected by at least one error which was classified as simple (81%), serious (14%) or critical (5%). thirty-five (28%) transfer reports were considered potentially harmful. among 305 intercepted errors, 247 were prescription errors (26% of all prescriptions), 45 involved proposed procedures, and 13 were deficient in updating diagnoses. only the number of medications included in the transfer report was associated with the occurrence of at least one critical/serious error. calzavacca et al. [57] identified risk factors for mortality in 228 patients receiving one or more medical emergency team reviews during daytime hours over a 1-year-period. delayed medical emergency team activation and not-for resuscitation orders were the only factors that showed an independent association with mortality. ospina et al. [58] in a comprehensive literature review analysed which monitoring techniques have been shown to improve outcomes in icu patients, concluding that there is no broad evidence that any form of monitoring improves outcomes in the icu. through an highly sensitive search in the cochrane central register of controlled trials (central) and medline, for prospective, randomized controlled trials (rcts) conducted in adult patients in the icu and the operating room (major surgical procedures), the authors focused on the impact of monitoring on outcome. of 4,175 potential articles, 67 evaluated the impact of monitoring. forty studies were related to hemodynamic monitoring, 17 to respiratory monitoring, and 10 to neurological monitoring. positive non-mortality outcomes were observed in 17 of 40 hemodynamic studies, 11 of 17 respiratory, and in all 10 neurological studies. mortality was evaluated in 31 hemodynamic studies, but a beneficial impact was demonstrated in only 10. for respiratory monitoring, seven studies evaluated mortality, but only three of them showed an improved outcome. in a qualitative study, mc adam et al. [59] described the contributions to care that 25 family members perform while their loved one is at high risk of dying in the icu. interviews with relatives were recorded and three independent raters coded transcripts. work roles that family members take on while their loved one is in the icu consisted of active presence, patient protector, facilitator, historian, coach, and voluntary caregiver. these multiple roles performed by relatives are often not valued or go unrecognized by icu health care providers. giannini et al. [60] investigated visiting policies in 257 italian icus. median daily visiting time was 60 min and 55% of icus had one daily visiting slot. there were restrictions on number (92% of units) and type (17%) of visitors and on child visits (69%). policies were not modified for child patients in 9% of icus, nor for a dying patient in 21%. no waiting room was provided by 25% of icus. gowning procedures were required for visitors in 95% of units. in 66% of icus informative material on the unit was provided to the family on patient admission. regional area and volume of admissions significantly influenced visiting hours. one-third of icus were being rethinking their policies. verdon et al. [61] evaluated the level of burnout in 97 members of the nursing team. 28% showed a high level of burnout. among concerns reported by the nurses, only the lack of patients' co-operation, the organization of the service and the rapid patient turnover were independently associated with a high level of burnout. weinert and sprenkle [62] assessed the impact of sedative exposure on icu recall and symptoms of posttraumatic stress disorder in patients receiving mechanical ventilation. they interviewed 149 patients who required [36 h of mechanical ventilation 2 months after icu discharge. eighty patients were also interviewed at 6 months. icu recall was greater for events occurring at the end of critical illness; however, 18% of subjects had amnesia for the entire icu course. posttraumatic stress disorder prevalence was 17% at 2 months and 15% at 6 months. recall of a delirious memory during critical illness was associated with more severe posttraumatic stress symptoms. neither icu recall nor posttraumatic stress symptoms were associated with the intensity of sedative administration during mechanical ventilation. posttraumatic stress symptoms were lowest in patients either the most awake during mechanical ventilation or the least awake. in a prospective, randomised, single-blinded, controlled study, röhm et al. [63] compared sevoflurane and propofol in terms of recovery times from sedation. a total of 70 patients after elective coronary artery bypass graft surgery received either sevoflurane (n = 35) or propofol (n = 35) for short-term postoperative sedation in the icu. mean extubation times from termination of sedation (the primary outcome) were significantly shorter with sevoflurane than with propofol (22 vs. 151 min). the length of icu stay was comparable in both groups, but hospital length of stay was significantly shorter in the sevoflurane group. costs for sedation per patient were similar in both groups. suchyta et al. [64] compared mortality and discharge disposition in critically ill patients with and without drug or alcohol dependence and patients with and without psychiatric disorders. they found that patients with drug or alcohol dependence were at higher risk for icu admission compared to the general population. however, the prevalence of psychiatric disorders was significantly lower than in the general population. drug or alcohol dependence predicted shorter hospital length of stay. in a retrospective review of patient records over 2 years in 20 french city hospitals lapostolle et al. [65] evaluated 838 patients with an elevated serum digitalis concentration (digoxin [ 1.95 ng/ml or digitoxin [ 23 ng/ml), following chronic or acute exposure. of these, 67 (8%) had received antidotal therapy with fab fragments. five independent factors were associated with the use of antidotal therapy: acute overdose (or 15.74), fab fragment availability in the hospital (11.06), serum potassium (1.81), and heart rate (0.96). mortality was significantly lower in fab-treated (6%, 4/ 67) than untreated patients (15%, 117/770). the authors concluded that antidotal therapy is underused in patients with an elevated digitalis concentration and the use of identical criteria for antidotal treatment after acute and chronic poisoning should help optimize outcomes. vandijck et al. [67] compared characteristics and outcomes in icu-patients with haematological malignancies and severe sepsis/septic shock who had or had not received recent intravenous chemotherapy. among the 186 patients, there were 77 patients with severe sepsis and 109 with septic shock; 91 (49%) had received recent intravenous chemotherapy. in-hospital, and 6-month mortality rates were 45.1 versus 58.9%, and 50.5 versus 63.2% in patients with and without recent chemotherapy, respectively. by multivariate analysis, previous chemotherapy was protective. after adjustment with a propensity score for recent chemotherapy, chemotherapy was not associated with outcome. in a review article [66] on organ dysfunction in hemophagocytic lymphohistiocytosis créput et al. provides an overall overview on this entity and aims at helping clinicians to maintain a high level of suspicion regarding the diagnosis. the parts covered in this review are: the clinical and laboratory features, the cytology and histology aspects, the etiologies, the pathophysiology, the prognosis and mortality, and the therapeutic approach. the authors concluded that the management of the hemophagocytic lymphohistiocytosis requires a multidisciplinary team, and the high mortality in patients with no etiological diagnosis requires aggressive investigation and treatment. payen et al. [68] assessed blood leucocytes gene profiling in the course of the septic shock recovery period and tested the relation between encoding gene expression and protein level in 17 septic shock patients. gene expression levels were studied on a dedicated microarray of 340 genes involved in inflammatory processes. the time-related gene expression study showed significant changes in ten genes. among them, s100a8 and s100a12 had a reduced expression over time compared with d0, whereas cd74's expression increased. by rt-qpcr, the s100a8 plasma levels decrease in parallel with the gene expression decrease. the cd74 gene expression evolution significantly correlated with hla-dr monocyte expression. in a fascinating mini-series foresti et al. [69] and bauer et al. [70] reviewed the role and pathophysiological mechanisms of the heme oxygenase-carbon monoxide system (ho-co) and the challenging potential use of co as therapeutic agent. in the past decade, the use of co gas in pre-clinical experimental models of disease has produced some remarkable data indicating that its therapeutic delivery to mammals could alleviate inflammatory processes and cardiovascular disorders. however, the inherent toxic nature of co cannot be ignored, knowing that inhalation of uncontrolled amounts of this gas can ultimately lead to serious systemic complications and neuronal derangements. from a clinical perspective, a key question is whether a safe and therapeutically effective threshold of co can be reached locally in organs and tissues without delivering potentially toxic amounts through the lung. the advent of co-releasing molecules (co-rms), a group of compounds capable of carrying and liberating controlled quantities of co in cellular systems, could be a plausible alternative in the attempt to overcome the limitations of co gas. although in its infancy and far from being used for clinical applications, the co-rms technology is supported by very encouraging biological results. the application of risk-adjusted control charts using the paediatric index of mortality 2 for monitoring paediatric intensive care performance in australia and new zealand after-hours admissions are not associated with increased risk-adjusted mortality in pediatric intensive care neuropsychological function in children following admission to paediatric intensive care: a pilot investigation surviving pediatric intensive care: physical outcome after 3 months interventions to reduce medication prescribing errors in a paediatric cardiac intensive care unit incidence of and mortality due to sepsis, severe sepsis and septic shock in italian pediatric intensive care units: a prospective national survey accm/pals haemodynamic support guidelines for paediatric septic shock: an outcomes comparison with and without monitoring central venous oxygen saturation clinical practice parameters for hemodynamic support of pediatric and neonatal patients in septic shock terlipressin as a rescue therapy for catecholamine-resistant septic shock in children pediatric intestinal and multivisceral transplantation: a new challenge for the pediatric intensivist assessing sedation in critically ill children by bispectral index, auditory-evoked potentials and clinical scales modified rifle criteria in critically ill children with acute kidney injury pediatric acute kidney injury in the icu: an independent evaluation of prifle criteria respiratory variations in aortic blood flow predict fluid responsiveness in ventilated children cardiac output measurement in children: comparison of the ultrasound cardiac output monitor with thermodilution cardiac output measurement a comparison of thermodilution and pulsed doppler cardiac output measurement in critically ill children clinical applications of photoplethysmography in paediatric intensive care value of brain natriuretic peptide in the perioperative follow-up of children with valvular disease the effect of epinephrine by nebulization on measures of airway obstruction in patients with acute severe croup predictors of outcome for children requiring respiratory extra-corporeal life support: implications for inclusion and exclusion criteria acute respiratory distress syndrome: is it underrecognized in the pediatric intensive care unit? factors effecting adoption of new neonatal and pediatric respiratory technologies diffusion of innovations ethical assessment of pediatric research protocols the importance of usual care control groups for safety monitoring and validity during critical care research clinical research in critically ill patients: the situation in italy council of europe in the field of bioethics: the convention on human rights and biomedicine and other legal instruments reasons, considerations, difficulties and documentation of end-of-life decisions in european intensive care units: the ethicus study the importance of religious affiliation and culture on end-of-life decisions in european intensive care units the world's major religions' points of view on end-of-life decisions in the intensive care unit anticipation of distress after discontinuation of mechanical ventilation in the icu at the end of life endof-life decisions in austria's intensive care units recommendations on therapy limitation and therapy discontinuation in intensive care units: consensus paper of the austrian associations of intensive care medicine end-of-life care in spain: legal framework opiates at the end of life in an emergency department in spain: euthanasia or good clinical practice? end-oflife: still an italian dilemma sexual function in icu survivors more than 3 years after major trauma saps 3 admission score: an external validation in a general intensive care population intraabdominal hypertension and acute renal failure in critically ill patients early coagulation disorders after severe burn injury: impact on mortality bedside adherence to clinical practice guidelines in the intensive care unit: the tecla study variability in the concentrations of intravenous drug infusions prepared in a critical care unit international critical care hospital pharmacist activities development and simultaneous application of multiple care protocols in critical care: a multicenter feasibility study from the icu to the ward: cross-checking of the physician's transfer report by intensive care nurses a prospective study of factors influencing the outcome of patients after a medical emergency team review what type of monitoring has been shown to improve outcomes in acutely ill patients? unrecognized contributions of families in the intensive care unit visiting policies in italian intensive care units: a nationwide survey burnout in a surgical icu team post-icu consequences of patient wakefulness and sedative exposure during mechanical ventilation short-term sevoflurane sedation using the anaesthetic conserving device after cardiothoracic surgery substance dependence and psychiatric disorders are related to outcomes in a mixed icu population assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure understanding organ dysfunction in hemophagocytic lymphohistiocytosis impact of recent intravenous chemotherapy on outcome in severe sepsis and septic shock patients with hematological malignancies gene profiling in human blood leucocytes during recovery from septic shock the heme oxygenase-carbon monoxide system: regulation and role in stress response and organ failure use of carbon monoxide as a therapeutic agent: promises and challenges key: cord-255351-vp19ydce authors: lanata, claudio f.; fischer-walker, christa l.; olascoaga, ana c.; torres, carla x.; aryee, martin j.; black, robert e. title: global causes of diarrheal disease mortality in children <5 years of age: a systematic review date: 2013-09-04 journal: plos one doi: 10.1371/journal.pone.0072788 sha: doc_id: 255351 cord_uid: vp19ydce estimation of pathogen-specific causes of child diarrhea deaths is needed to guide vaccine development and other prevention strategies. we did a systematic review of articles published between 1990 and 2011 reporting at least one of 13 pathogens in children <5 years of age hospitalized with diarrhea. we included 2011 rotavirus data from the rotavirus surveillance network coordinated by who. we excluded studies conducted during diarrhea outbreaks that did not discriminate between inpatient and outpatient cases, reporting nosocomial infections, those conducted in special populations, not done with adequate methods, and rotavirus studies in countries where the rotavirus vaccine was used. age-adjusted median proportions for each pathogen were calculated and applied to 712 000 deaths due to diarrhea in children under 5 years for 2011, assuming that those observed among children hospitalized for diarrhea represent those causing child diarrhea deaths. 163 articles and who studies done in 31 countries were selected representing 286 inpatient studies. studies seeking only one pathogen found higher proportions for some pathogens than studies seeking multiple pathogens (e.g. 39% rotavirus in 180 single-pathogen studies vs. 20% in 24 studies with 5–13 pathogens, p<0·0001). the percentage of episodes for which no pathogen could be identified was estimated to be 34%; the total of all age-adjusted percentages for pathogens and no-pathogen cases was 138%. adjusting all proportions, including unknowns, to add to 100%, we estimated that rotavirus caused 197 000 [uncertainty range (ur) 110 000–295 000], enteropathogenic e. coli 79 000 (ur 31 000–146 000), calicivirus 71 000 (ur 39 000–113 000), and enterotoxigenic e. coli 42 000 (ur 20 000–76 000) deaths. rotavirus, calicivirus, enteropathogenic and enterotoxigenic e. coli cause more than half of all diarrheal deaths in children <5 years in the world. despite global success in the reduction of all cause and diarrheaspecific mortality in the past 30 years, diarrhea remains the second leading cause of death due to infections among children under five years of age worldwide [1, 2] . it is estimated that diarrhea accounted for 9?9% of the 6?9 million deaths among children under 5 in 2011 [2, 3] . several organisms have been implicated as important causes of these deaths [4, 5] , yet there has not been a review using standardized methods to determine the importance of all of the common pathogens. the child health epidemiology reference group (cherg) has estimated the causes of child deaths from major causes since 2001. we have undertaken this review to develop estimates of pathogen-specific diarrhea mortality among children under 5 years of age. we present the results of a systematic literature review of studies of diarrhea etiology in hospitalized children and use these results to estimate the global burden of diarrhea mortality by pathogen for children under 5 years of age for 2011. we searched medline, lilacs, and medscape for studies published between 1990 and 2011. we used the terms ''diarrhea'' (or ''diarrhoea''), ''gastroenteritis'', ''rotavirus'', ''e.coli'' (or ''escherichia coli''), ''salmonella'' (not ''typhi''), ''shigella'', ''campylobacter'', ''giardia lamblia'', ''vibrio'', ''cryptosporidium'', ''entamoeba'', ''norovirus'', ''calicivirus'', ''norwalk agent'', using ''and children'' as a search restriction. an example of one of the search instructions in medline-pubmed is: ''diarrhea'' [mesh] january 1, 1990 -december 31, 2011 . we also included data from the who rotavirus surveillance network for 2011 provided to us by who only from countries that had not introduced rotavirus vaccine as of december 2011 and had data covering the 12-month period. these studies used a standard protocol across the network [6] . we included studies that sought at least one of the above listed pathogens and conducted 12 or more months of surveillance among children less than 5 years of age hospitalized with diarrhea. studies must have included all diarrhea patients at the selected study site or a systematic sampling of cases for the duration of the study. we did not require a minimal number of children evaluated to be included. laboratory tests were performed on rectal swabs or stools samples. we excluded studies conducted during reported diarrhea outbreaks, those that did not discriminate between inpatient and outpatient cases, those that included patients with nosocomial infections, and those conduced in special populations, such as hiv-positive patients. we also excluded studies that did not describe adequate surveillance methods or standard laboratory methods, according to the following criteria: a) salmonella and shigella isolation in salmonella/shigella agar, xylose-lysine-deoxycholate agar, hektoen enteric agar, and selenite enrichment for salmonella [7] ; b) campylobacter isolation by use of transport media with antibiotics (skirrow's supplement or similar) and inoculation into 5% sheep blood with antibiotics (butzlers supplement or similar), cultivated at 42uc in micro-aerobic atmosphere [7] ; c) vibrio cholerae isolation by alkaline peptone water enrichment and subculture at 8 hrs into thiosulfate-citratebile salts -sucrose agar (tcbs) [7] ; d) e. coli isolation from macconkey agar and identification of etec by dna probes or polymerase chain reaction (pcr) for heat-labile (lt) or heatstable (st) toxins, cell cultures (y1, cho cells), ileal loop or mouse models [7] ; e) epec isolation by the use of hep 2 cell cultures or the presence of the plasmid for adherence (bfp) and the intimin gene (eae) identify in dna probes or by pcr [7] ; f) rotavirus, calicivirus (or norovirus), astrovirus and enteric adenovirus identification with the use of enzyme-linked immunoassays (elisa), electronic microscopy, or pcr [7] ; g) giardia lamblia identification by direct microscopic examination, or zinc-sulfate concentration from direct stools or by elisa [7] ; h) cryptosporidium spp. identification by elisa, or the modified ziehl-neelsen stain for microscopy [7] ; i) entamoeba histolytica identification by direct microscopic examination [7] . we did not include studies in areas or countries where the rotavirus vaccine was used but included data from the placebo arm of rotavirus vaccine trials. articles published in languages other than english, spanish, portuguese, italian, german and french were not included. the following enteropathogens were considered: rotavirus, enteropathogenic escherichia coli (epec), enterotoxigenic escherichia coli (etec), salmonella spp. (excluding salmonella typhi), shigella spp., campylobacter spp., vibrio cholerae o1 and o139, giardia lamblia, cryptosporidium spp., entamoeba hystolitica, human caliciviruses (genogroup i and ii norovirus and sapovirus) or astrovirus, coronavirus, and enteric adenovirus. we extracted data for all children less than five years of age for each pathogen. data from more than one hospital in a country were treated as separate studies if the presentation of data permitted. papers that published different etiological data from the same study site were grouped into one study. if co-infections were reported, they were not treated separately so each pathogen was counted as present if isolated alone or in combination. three reviewers (co, cxt, and cfl) did the primary extraction and all selected papers were reviewed by cfl and cfw independently. disagreements were resolved by cfl and/or reb. we calculated overall median proportions of positive diarrheal stool samples for each pathogen for children 0-59 months of age using the overall proportion for all children included in the study; 39 studies enrolled children from a narrower age range so we calculated for these studies an age-adjusted proportion for the 0-59 months of age group by calculating a conversion factor for age group x as the median of 0-59 prevalence over age group x prevalence (median (prev 0-59 /prev x )) using studies that reported both 0-59 and the age group x for a given pathogen. to use this method we required at least 3 studies, where each study reported both 0-59 months and age group x. in situations where less than 3 studies were available we employed an alternative method where the conversion factor for age group x was taken as the ratio of the median prev 0-59 to median prev x (median (prev 0-59 )/median (prev x )). for this approach we required that 3 or more studies contribute to each of the two medians, but dropped the method 1 requirement that individual studies report both age groups. if neither of these sets of conditions were met, we borrowed the conversion factor for the age group x from a similar age group within the same pathogen (for instance, used the conversion factor calculated for studies including infants 0-11 months of age for studies that included infants 0-5 months of age) or from a similar pathogen (conversion factor for age group x for a study on epec borrowed from studies on etec). the 0-59 months prevalence proportion for each pathogen was estimated using the median individual study 0-59 months pathogen prevalence. we stratified studies by the number of pathogens sought and calculated the unadjusted and age-adjusted medians, as described above, separately for single pathogen studies and for studies that sought 5 to 13 pathogens. for estimating the proportion of diarrheal stools due to unknown pathogens, we included 12 studies that sought 8 or more pathogens. for the numbers of diarrheal deaths attributable to each pathogen, we assume that the distribution of pathogens observed among children hospitalized for diarrhea represents the pathogen prevalence among child diarrhea deaths. we applied the ageadjusted median proportion for each pathogen and for unknowns to the overall number of diarrhea deaths of 712 000 estimated for the world in 2011 [3] , adjusting all proportions equally to be constrained to add to 100%. we explored alternative estimates using all studies selected or only those that sought 5 to 13 pathogens, constraining or not all proportions to add to 100%. the uncertainty around each estimate was calculated using bootstrap confidence intervals [8] . 'pseudo-data sets' were created by sampling studies with replacement from the real dataset. each of the 1000 pseudo-datasets was used in the estimation procedure described above to generate a corresponding 1 000 prevalence proportions. the 2?5 th and 97?5 th percentile of these proportions gave the 95% confidence interval (ci). to estimate the uncertainty of the number of deaths for each pathogen, we paired each of the 1 000 pseudo-datasets with random draws from the under 5 total mortality envelope, the proportion of total deaths attributable to diarrhea [2, 3] , and the proportion of diarrhea deaths due to unknown pathogens. the under 5 year global total mortality envelope estimate and standard deviation were calculated by sampling and combining 100 000 random draws from each of the 194 countries in the world [2, 9] . for each country, a normal mean and standard deviation was estimated from the point estimate and associated confidence interval. from 22 643 citations identified in the electronic search, 1 003 articles were selected for further evaluation (fig. 1) ; 840 articles were excluded because they had one or more of the exclusion criteria (about 35% because they were not longitudinal studies or inappropriate laboratory methods were used, 31% because no data was given for children ,5 years of age, 23% for studies that lasted less than 12 months of duration, and the rest because data were reported after rotavirus vaccine introduction, duplicate publications or reporting results on a pathogen not included in our list). a total 163 articles and 31 who rotavirus surveillance network sites were selected representing 286 inpatient studies with data for at least one pathogen [list of the 163 references can be found at www.cherg.org]. the geographical localization of the study sites is shown in figure 2 . the median and age-adjusted median proportions (with 95% ci) of isolation of each enteropathogen in hospitalized diarrhea cases are shown in table 1 . rotavirus, epec, calicivirus, and etec were the most frequently identified organisms. the sum of these age-adjusted median proportions, including unknowns was 138%, indicating a problem with many articles reporting mixed infections as separate causes. different isolation rates were observed in studies in which only one, versus at least 5 enteropathogens were sought (table 2) . rotavirus was more frequently isolated in 180 single-pathogen inpatient studies in comparison with 24 multiple-pathogen studies (39% vs. 20%, respectively, p,0?0001). the same trend was observed between single-and multiple-pathogen studies for most pathogens, but mainly for giardia lamblia (16% vs. 3%, p,0?001), shigella (24% vs. 7%, p,0?001) and v. cholerae (10% vs. 0.2%, p,0?001). very few studies sought a substantial number of pathogens. from the 286 inpatient studies, only 12 (4%) sought 8 or more pathogens (1 study with 13, 2 studies with 10, 5 studies with 9, and 4 studies with 8 pathogens). in these studies, 33?7% of cases had no pathogen identified. adjusting all proportions, including unknowns, to add to 100%, we estimated that rotavirus caused 197 000 (uncertainty range ur 110 000-295 000), enteropathogenic e. coli 79 000 (ur 31 000-146 000), calicivirus 71 000 (ur 39 000-113 000), and enterotoxigenic e. coli 42 000 (ur 20 000-76 000) deaths. these four pathogens were associated with 55% of all diarrhea deaths (table 3) . these estimates varied substantially depending on the methods used. if the proportions were not made to add to 100%, rotavirus would be said to cause 272 000 deaths or if only studies that sought .4 pathogens were selected and the proportions were adjusted to 100% rotavirus would be said to cause 126 000 deaths (table 4 ). when classifying studies by who region, most studies were done in the western pacific region (78 studies) and less in the eastern mediterranean region (19 studies) ( table 5 ). rotavirus was more frequently isolated in the western pacific region (33%) and less in the american region (23%). other comparisons were limited by few or no studies in some regions (table 5 ). in this review, we showed that more than half of the severe diarrhea episodes, most likely to result in death among children under the age of 5 years in 2011, could be attributed to rotavirus, epec, calicivirus, and etec. our estimates have been adjusted for age in studies that did not cover all children ,5 years old, and campylobacter spp to add to 100%, including a fraction of episodes with unknown etiology. such adjustments have not been done in previously published estimates for single diarrhea etiologies [4, 5, [10] [11] [12] . we identified a potential selection bias among studies that focus on a single pathogen. for example, the median proportion of diarrheal episodes with rotavirus identified varied from 39% in single-pathogen studies to 20% in studies that sought more than 4 pathogens. it is possible that studies looking for a particular pathogen are more likely to be conducted in a study site with a high prevalence of that pathogen and/or a low prevalence of other pathogens. an urban hospital that treats children of higher socioeconomic status and living in more hygienic conditions than children in rural areas may find a higher proportion of cases with rotavirus. a study of cholera done in a hospital in an endemic area may not be representative of national or regional populations. because of the low number of studies that sought multiple pathogens, we have not restricted our analysis to only those studies, in an attempt to include as much global data as possible, but it should be recognized that the inclusion of single-etiology studies may result in a biased higher estimate for some pathogens. by including 13 pathogens in this review we are able to address the problem of mixed infections, an important factor ignored in previously published single-pathogen estimates of deaths. no methodology has been developed to identify the true cause of an episode when more than one pathogen is identified in the stool. our adjustment of all percentages to fit 100% is done to correct for this problem, assuming that each pathogen is equally likely to cause the illness. this is probably not correct because some organisms are carried in the feces for a relatively long time after infection-causing illness, like norovirus [13] , or may not cause illness, especially in older children who have acquired immunity that protects against disease, but not carriage of the organism, like some protozoa [14] . this method of including all equally in the constraint to 100% of diarrhea deaths may result in an underestimate of the importance of some pathogens, such as rotavirus in young children, and overestimate the importance of others, such as giardia. we do not have data on the presence of these pathogens in the stools of asymptomatic children in the studies selected in this review so we cannot determine the attributable fraction related to each pathogen as done in other studies [15] . however, controlling for pathogens found in non-ill children does not necessarily eliminate the problem because some pathogens with long excretion periods after illness, like norovirus, may be wrongly classified as not causing diarrhea. carefully conducted longitudinal studies are needed to separate long-term excretors after illness from asymptomatic infections, to reveal the true pathogenic role of these different organisms in developing countries. we estimated that the number of diarrhea episodes for which no pathogen can be identified is 34%, which is based on studies that sought at least 8 pathogens, not necessarily all 13 and thus may be an overestimate. these ''unknowns'' could be due either to the same pathogens not detected because insensitive methods were used to identify them (either the method itself or to using a rectal swab instead of a stool sample) [16] , to the use of antibiotics prior to obtaining the stool sample, to other yet undiscovered infections, or to non-infectious causes of diarrhea. the proportion of samples with unknown causes was based on a selected group of 12 studies that searched for 8 or more pathogens. these studies do not represent the world as the rest of the studies did. the recently conducted studies called the global enterics multicenter study (gems) in 7 countries in africa and asia were designed to fill this gap [15, 17, 18] . however, they studied cases with moderate and severe diarrhea seen in health services (hospitals, emergency rooms and community clinics), not separating those being hospitalized from milder outpatient cases, therefore, those studies would not meet our inclusion criteria. given that we cannot distinguish among the reasons no pathogen was found during the episode, our estimates may represent an under-estimate, at least for some causes. we could not include some pathogens known to cause diarrhea in our review, such as organisms that cause food-borne outbreaks (i.e. clostridium perfringens [19] , or staphylococcus aureus producing enterotoxins [20] ), because there are very little data on their importance in developing countries. a recent review of rotavirus studies estimated that rotavirus caused 453 000 deaths in children ,5 in 2008 [4] . if we would apply the median proportion of 38% rotavirus isolation found in the 242 inpatient studies that sought it in our review, without any adjustment, to the 1 236 million u5 diarrheal deaths in 2008, we would estimate 472 000 rotavirus deaths in 2008. in 2011 it is estimated that diarrhea deaths have been reduced to 712 000 [3] . our estimate of 197 000 deaths due to rotavirus, using our improved methods, still represents an important global public health problem, with 23 children dying due to this condition every hour. this estimate does not account for any recent reduction in rotavirus-specific proportionate mortality due to the introduction of rotavirus vaccine, as seen in some latin america countries [21] , but these countries account for a very small fraction of global diarrhea mortality. wide scale use of the rotavirus vaccine in high mortality countries will allow a more precise estimate of the true proportion of diarrhea deaths caused by rotavirus. our estimate of 28 000 deaths for shigella is much lower than a previous estimate of 667 695 deaths due to shigellosis in children under 5 years in the world in 1995 published by kotloff et al [5] . this initial estimate was not based on a systematic review of the literature; rather, it used a single study in latin america to estimate the proportion of shigella cases that were hospitalized and a bangladeshi study to estimate the case-fatality rate of children hospitalized with shigellosis to estimate the global burden due to this organism. using the same methodology of kotloff et al but with an updated review of the literature and current case fatality rates observed in bangladesh, bardhan p et al [22] estimated that only 14 000 children younger than 5 years of age died due to shigellosis in asia in 2005. our estimates are compatible with this asian estimate. the total number of deaths due to calicivirus of 71 000 deaths has indicated to be the third most common cause of death due to diarrhea in children under 5 years of age. few studies differentiated between gi and gii norovirus and other types of human caliciviruses, but in those few that did, most of calicivirus isolated in children with severe diarrhea have been due to norovirus gii [23, 24] . patel et al [25] estimated 218 000 deaths due to norovirus among children under 5, but this was calculated using very different methods and assumptions: they used an attributable fraction due to norovirus when data on asymptomatic children was available, and applied their mean isolation rate of 12.1% from inpatient studies (not much different from our median isolation rate of 13.8%) to 1.8 million deaths due to diarrhea in the world; they did not adjust for mixed infections or unknowns. the 79 000 deaths estimated to be caused by epec represent different sub-types of this type of pathogenic e. coli, a group that requires further epidemiological studies in different parts of the world to further characterize them since some sub-types are isolated with the same frequency in diarrhea and control children [26] , new ''typical'' and ''atypical'' epec strains have been identified [27] , and in some regions have been identified to cause more persistent than acute diarrhea [28] . these estimates have several limitations. the studies included in this review were conducted in selected sites and in some cases in populations with increased risk of diarrheal diseases. thus, they may not be representative of the countries where they were conducted, nor of the world. for several regions, such as russia and the former soviet states or sub-saharan africa we have limited or no data ( fig. 2 , table 4 ). the gap of information from africa, for pathogens other than rotavirus, is most acute because of the number of diarrhea deaths in this region is very high [1] [2] [3] . no study has been conducted to identify pathogens in children who died due to diarrheal diseases, so we assume that children in need of hospitalization are the best proxy of diarrhea deaths in low to middle income countries, but this may not be true for some pathogens. another limitation is the combination of laboratory methods with different sensitivities to identify a pathogen: from the culture-based identification of salmonella or shigella to the highly sensitive real-time pcr method for norovirus. this may have affected the relative importance of one vs another pathogen in our estimates. we excluded studies on nosocomial infections, on displaced populations and on diarrhea outbreaks, which may have caused us to under-represent deaths due to some pathogens like v. cholerae. we included in our estimates a total of 13 pathogens (4 viruses, 6 bacteria and 3 parasites) that have been incriminated as causes of severe diarrheal diseases. some viruses, like adenovirus, and parasites, like g. lamblia, have not been completely documented as a cause of severe diarrhea in developing countries [14, 29, 30] . the subject of causality of diarrheal diseases is still not completely understood in settings where children are heavily exposed to many pathogens early in life. young infants may be protected by breast milk and trans-placental maternal immunity and very low doses of ingested pathogens early in life may result in subclinical infections and development of immunity. this immunity may not preclude, however, the excretion of these pathogens in the child's feces. practically all studies done in children who were studied when they were healthy as well as when they developed an acute diarrheal episode have found the same pathogens, although usually with lower frequency, in healthy states. thus, the assumption that any pathogen identified in a child with diarrhea is the cause of the episode is naive and additional methods are needed to determine the pathogenicity of microbes. with a better understanding of the pathogenicity of key organisms our estimates could be further adjusted. also, some studies suggest that children ill with a pathogen, as with epec, may excrete higher amounts in the stool, as compared with asymptomatic infections [31] , so future studies may consider quantifying the amount of each pathogen in the stool to help identifying those ill with it. finally, the review period covering studies published between 1990 and 2011 (studies were conducted with a median mid-study period of 2005, only 24 (8%) studies were done prior to 1990). we have not identified a significant change of the proportions assigned to each pathogen over time, so this does not seem to affect our estimates, as shown in fig. 3 for rotavirus. the global burden of disease study recently published cause of death estimates for 187 countries in 2010 [32] . for children ,5 years of age, gbd estimated a total of 666 000 deaths due to diarrheal diseases in 2010 while cherg estimated 712 000 deaths for 2011. gbd also estimated deaths due to 9 etiologies and produced estimates for 0-6, 7-27, and 28-364 days and 1-4 years of age. cherg estimates for 2011 in children ,5 years of age are slightly higher than gbd estimates for rotavirus (198 000 vs 173 000 rotavirus deaths, respectively), similar for epec and etec deaths (79 000 vs 73 000, and 43 000 vs 39 000, respectively), and lower for cholera, salmonella, shigella, campylobacter, entamoeba histolytica, and cryptosporidium spp. (table 6 ). gbd did not estimate deaths due to norovirus, which was the third leading cause of death in our review. gbd used rates reported in diarrhea studies published between 1975 and 2010 done in outpatients, casecontrol, and community-based studies as a reference category to adjust the proportions seen in inpatient studies. cherg only used data from inpatient studies published between 1990 and 2011. both gbd and cherg used modeling to obtain the total number of diarrheal deaths for children ,5, but unlike gbd, cherg has not used models for etiology-specific causes of deaths for each age group and for each country to produce its global estimate. age specific data and modeling may produce spurious results, more so if there are no data. for example, very few studies have been done describing causes of diarrhea in neonates in developing countries, but gbd has estimated deaths caused by each of the 9 pathogens in neonates 0-6 and 7-27 days of age (table 6 ). gbd only produced estimates for 9 etiologies of diarrhea and by subtracting the total of these estimates from the total of diarrheal deaths; they estimated the proportion of other causes of diarrheal deaths. cherg estimated the proportion due to unknowns from studies that searched for 9-13 pathogens, which we feel realistically addresses the fact that a causative agent is not identified in every illness. this also explains why we estimated a higher number of deaths in this category (176 000) than gbd for ''other causes'' which should include unknowns (109 000). gbd and cherg recognized the problem of mixed infections, but the methods used to adjust for it was different: gbd only used proportions for each etiology from inpatient studies that searched for 2-8 etiologies and used that information to produce weights to adjust their estimates in the models. we choose to constrain all proportions, including unknowns, to 100% to correct for mixed infections, which we feel it is more appropriate until better data and analytical tools are available. we have done an extensive search of the literature to include the 286 inpatient studies used in our estimates. gbd has not published the studies included, their search strategy, or modeling methods. until these are published we will not be able to completely compare these estimates. this is the first systematic review attempting to estimate the cause of deaths for these 13 enteric pathogens. rotavirus, calicivirus, enteropathogenic and enterotoxigenic e. coli cause more than half of all diarrheal deaths in children ,5 in the world. we have identified a potential selection bias in studies searching for only one enteropathogen, and the problem when mixed infections (more than one enteropathogen is identified in a stool sample taken from a child with severe diarrhea) are not taken into consideration when estimating causes of diarrheal deaths, factors that has affected previous published estimates. future studies should be done in hospital services dealing with all types of severe diarrhea, searching for all known enteropathogens, removing the effect of asymptomatic excretes, and establishing a mechanism to attribute to one enteropathogen the cause of a diarrheal episode in cases of mixed infections. checklist s1 prisma checklist (doc) estimating diarrhea mortality among young children in low and middle income countries global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since global burden of childhood pneumonia and diarrhea estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis global burden of shigella infections: implications for vaccine development and implementation of control strategies rotavirus surveillance worldwide -2009 clinical microbiology procedures handbook, 3 rd edition an introduction to the bootstrap global illness and deaths caused by rotavirus disease in children rotavirus and severe childhood diarrhea global mortality associated with rotavirus disease among children in 2004 environmental transmission of norovirus gastroenteritis lack of an adverse effect of giardia intestinalis infection on the health of peruvian children the global enteric multicenter study (gems) of diarrheal disease in infants and young children in developing countries: epidemiologic and clinical methods of the case/control study comparison of direct electron microscopy, immune electron microscopy, and rotavirus enzyme-linked immunosorbent assay for detection of gastroenteritis viruses in children diagnostic microbiologic methods in the gems-1 case/control study burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, gems): a prospective, case-control study novel insights into the epidemiology of clostridium perfringens type a food poisoning staphylococcal enterotoxins reduction in morbidity and mortality from childhood diarrhoeal disease after species a rotavirus vaccine introduction in latin america -a review decrease in shigellosisrelated deaths without shigella spp.-specific interventions diagnosis of viral gastroenteritis by simultaneous detection of adenovirus group f, astrovirus, rotavirus group a, norovirus genogroups i and ii, and sapovirus in two internally controlled multiplex real-time pcr assays norovirus highly prevalent cause of endemic acute diarrhea in children in the peruvian amazon systematic literature review of role of noroviruses in sporadic gastroenteritis age-related susceptibility to infection with diarrheagenic escherichia coli among infants from periurban characterisation of atypical enteropathogenic e. coli strains of clinical origin pathogens associated with persistent diarrhoea in children in low and middle income countries: systematic review illness and reservoirs associated with giardia lamblia infection in rural egypt: the case against treatment in developing world environments of high endemicity a systematic review and meta-analysis of the association between giardia lamblia and endemic pediatric diarrhea in developing countries quantitative real-time polymerase chain reaction for enteropathogenic escherichia coli: a tool for investigation of asymptomatic versus symptomatic infections global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study cynthia boschi-pinto of who and theresa diaz of unicef provided coordination of the involvement in cherg of their respective institutions. carolyn weidemann served as coordinator of the grant in support of cherg from the bill and melinda gates foundation. cherg provided advice on methods and interpretation of results. we thank walter mendoza for his initial literature review, cynthia boschi-pinto and laura lamberti for their support in searching for articles, and edda franco for editorial assistance. we thank the countries who provided data through the who-coordinated global rotavirus surveillance network of participating ministries of health, sentinel hospital sites, and the rotavirus laboratory network. we also thank john sanders and theresa j. ochoa for providing useful comments on early drafts of the manuscript. preliminary results of this study has been presented at cherg and food borne epidemiology reference key: cord-253251-i79h14f7 authors: kandala, ngianga-bakwin; magadi, monica akinyi; madise, nyovani janet title: an investigation of district spatial variations of childhood diarrhoea and fever morbidity in malawi date: 2005-09-01 journal: soc sci med doi: 10.1016/j.socscimed.2005.07.028 sha: doc_id: 253251 cord_uid: i79h14f7 although diarrhoea and malaria are among the leading causes of child mortality and morbidity in sub-saharan africa, few detailed studies have examined the patterns and determinants of these ailments in the most affected communities. in this paper, we investigate the spatial distribution of observed diarrhoea and fever prevalence in malawi using individual data for 10,185 children from the 2000 malawi demographic and health survey. we highlight inequalities in child health by mapping the residual district spatial effects using a geo-additive probit model that simultaneously controls for spatial dependence in the data and potential nonlinear effects of covariates. the residual spatial effects were modelled via a bayesian approach. for both ailments, we were able to identify a distinct district pattern of childhood morbidity. in particular, the results suggest that children living in the capital city are less affected by fever, although this is not true for diarrhoea, where some urban agglomerations are associated with a higher childhood morbidity risk. the spatial patterns emphasize the role of remoteness as well as climatic, environmental, and geographic factors on morbidity. the fixed effects show that for diarrhoea, the risk of child morbidity appears to be lower among infants who are exclusively breastfed than among those who are mixed-fed. however, exclusive breastfeeding was not found to have a protective effect on fever. an important socio-economic factor for both diarrhoea and fever morbidity was parental education, especially maternal educational attainment. diarrhoea and fever were both observed to show an interesting association with child's age. we were able to discern the continuous worsening of the child morbidity up to 8–12 months of age. this deterioration set in right after birth and continues, more or less linearly until 8–12 months, before beginning to decline thereafter. independent of other factors, a separate spatial process produces district inequalities in child's health. the success of any policy or health care intervention depends on a broader and accurate understanding of the socio-economic, environmental and cultural factors that determine the occurrence of disease and death. until recently, available information on childhood morbidity was derived from clinics and hospital records. however, information obtained from hospitals represents only a small proportion of all cases, since many other cases do not seek medical attention (black, 1984) . thus, the hospital records may not be appropriate for estimating the prevalence of diarrhoea for program developments (woldermicael, 2001) . policy-makers and researchers often want to know the distribution of a disease prevalence by geographical region, or association with environmental factors (diggle, moyeed, & thomson, 2002; thomson, connor, milligan, & flasse, 1996) . in this regard, mapping risk variations in child morbidity is an invaluable tool. further, the mapping of variation in risk of childhood morbidity can help improve the targeting of scarce resources for public health interventions. therefore, geographic information system (gis) is a powerful tool for public health practitioners that can easily allow them to assess patterns, trends and relationships between health events and environmental, socio-economic and other geographic factors (see for instance the case of disease surveillance, preparedness and response coordination to combat health threats such as west nile virus, anthrax, severe acute respiratory syndrome (sars) and bioterrorism (gardner & harrington, 2003) ). gis further helps us to understand childhood disease prevalence at the community level (see for instance garg, omwomo, witte, lee, & deming, 2001; mbonye, 2003 mbonye, , 2004 ) and helps to identify underserved populations, and can help public health agencies to efficiently allocate scarce program resources to appropriate locations. for example, the communicable disease control division of the boston public health commission (bphc) uses gis to help identify at-risk populations and determine where to focus efforts to vaccinate residents against influenza. this paper is based on a study of the spatial distribution of childhood diarrhoea and fever in malawi. the study applied bayesian statistical and geo-statistical techniques to the 2000 demographic and health survey (dhs) data of malawi with location (district) attributes and other information to answer specific questions about geographic inequalities in childhood disease prevalence. the dhs in malawi conducted in 2000 is a valuable resource for population-based morbidity data, although we recognize its limitation, like other dhss elsewhere, in that it relates only to reported child morbidity during the last 2 weeks before the survey. thus, our results might be influenced by the effects of seasonality in diseases prevalence. to gain an understanding of the geographic variation or patterns based on the observed morbidity prevalence, a bayesian hierarchical model was fitted, with the inclusion of spatial (district) and nonlinear metrical (mother's and child's age) covariates. of particular interest in this study, was whether a significant geographic variation in childhood diarrhoea and fever existed; and if so, what potential risk factors could explain such variation? background: characteristics of the study area malawi is an african country in the south-east region of the continent with a population of about 10 million and a population growth rate of about 2.5 percent/year (national statistical office [malawi] and orc macro, 2001; who, 1998) . with a gross national product (gnp) of us$ 170/person/year, malawi is among the 20 least economically developed countries in the world (national statistical office [malawi] and orc macro, 2001; who, 1998) . agriculture accounts for over a third of the gnp, about 90 percent of export earnings and approximately three-quarters of total employment (unicef and government of malawi, 1993) . despite economic difficulties malawi has invested a lot in health. according to unicef statistics there is a reasonably good network of health facilities in malawi (the median distance from home to the nearest facility is 5 km). for 90 percent of births, mothers have received at least one antenatal care from a trained health worker, and 86 percent of children aged 12-23 months possess a health card indicating a high under-five clinic attendance and about 90 percent of children are reported to have been vaccinated against the most common illnesses. however, improvements in health indicators have been smaller than expected. currently, the maternal mortality rate is estimated at 1120-1180/100,000 live births. life expectancy at birth is only 44 years, largely because of high mortality amongst the children. for every 1000 live births, about 135 die before the age of 1 year and 200 before the age of 5 years (national statistical office [malawi] and orc macro (2001) . findings of the 2000 mdhs point to important changes in malawi's health and demographic profile. mortality of children under age 5 has declined since the early 1990s. during the period 1988-1992, the under-five mortality rate was 234 deaths/1000 live births, compared with 189/1000 between 1996 -2000 and orc macro (2001) . although this represents important progress, the rate of the downward trend is modest and childhood mortality remains at a very high level. a comparison of the 1992 and 2000 malawi dhs shows that the prevalence of diarrhea decreased slightly from 20% to 17% between the two periods. however, the percentage of ill children who received treatment reduced. all these point to the fact that malawian children are growing up in an environment of high morbidity, low utilization of health care, and consequently high mortality risks. the census results also indicate that there is geographic variation in the rates of infant and under-five mortality with highest mortality rates in the southern regions followed by the central regions and the least in the northern regions. household socio-economic status is associated with child survival because it determines the amount of resources (such as food, good sanitation and health care) that are available to infants (millard, 1994) . measures of socio-economic status that are thought to be associated with infant heath include: maternal and paternal education; household wealth; household size; parental occupation; and rural or urban residence. kandala and madise (2004) , who used the 1992 dhs data from malawi and zambia, in their study of childhood morbidity, found that the level of maternal education was highly significant in the two countries. they also found that childhood morbidity was lower among educated women, and that although this effect attenuated with the inclusion of other socio-economic factors in the models, maternal education remained significant. lower morbidity was also reported in households with large number of adult members (kandala, 2002; kandala & madise, 2004) . the impact of the household's size should, however, not be over-interpreted, since to some extent it directly mirrors infant mortality. for instance, a household with high mortality risk will remain small. in contrast, a household's size might also reflect its wealth, as a rich household will attract occupants. again, in a large household, a child might benefit from the help of several adults. large households may benefit from scale economies in time for childcare as well as in expenditures. alternatively, they may have become better at raising children through accumulated experience (christianensen & alderman, 2001) . child-level demographic factors such as birth order, the length of preceding birth interval, and the survival status of the preceding child have been shown to be strongly associated with infant mortality and health in africa as well as asia (cleland & sathar, 1984; kandala, 2002; kandala & madise, 2004; koenig, phillips, campbell, & d'souza, 1990; madise & diamond, 1995; whitworth & stephenson, 2002) . first and higher order births, those born after birth intervals of less than 2 years, and those whose previous sibling have died appear to have high risks of morbidity and of dying in infancy. some researchers have documented evidence of a u-shape pattern in the association between maternal age and infant mortality and morbidity, with teenage and older mothers having elevated risk of child loss (bicego & ahmad, 1996; geronimus & korenman, 1993; kandala, 2002; kandala & madise, 2004; manda, 1998) . sex differentials in infant health and mortality have been observed universally. in the majority of the world regions, girls have lower mortality, at least for the first few months of life (curtis & steele, 1996; kandala, 2002; sastry, 1997) . exceptions have been noted in some asian countries. in india, girls are more than 30 percent likely to die before their fifth birthday than boys and this is thought to be the result of son preference, which is manifest in lower spending on health for girls and higher prevalence of immunization among boys (claeson, bos, mawji, & pathmanthan, 2000; timaeus, harris, & fairbarn, 1998) . historically, variations in incidence and prevalence of diarrhoea and fever have been related to family socioeconomic factors and neglected temporal and geographical gradients and other variations in risk, in order to generate hypotheses towards the causation of disease. in this paper, we take advantage of advances in giss and how the technology provides opportunities to study associations between environmental exposure and the spatial distribution of diseases. jacquez (2000) discusses how gis can be used to monitor disease outcomes, identify health risks, and design and implement intervention plans. the epidemiological approach has not yielded all the answers, but it holds great merit and much potential to further contribute to the knowledge of disease etiology. this study enhances our understanding of diarrhoea and fever prevalence in a dimension that could not have been possible prior to the availability of gis. the results will help us making further decisions in planning for diarrhoea and fever research. individual data record was constructed for 10,185 children for diarrhoea and 10,180 children for fever. each record consisted of morbidity information and a list of covariates as shown in appendix a. geo-additive logistic models were used (on the probability of a child having diarrhoea and fever during the reference period) to determine the socio-economic and demographic variables that are associated with the ailments while simultaneously controlling for spatial dependence in the data and possible nonlinear effects of covariates. the dhs data have been collected hierarchically at the family and community levels which are inter-related. standard analysis of the fixed effects covariates for child morbidity neglects this correlation structure and dependence in the data. this neglect leads to underestimation of standard errors of the fixed effects that inflates the apparent significance of the estimates (bolstad & manda, 2001) . our analysis includes this correlation structure and account for the dependence of community in the model. the model also permitted borrowing strength from neighbouring areas to obtain estimates for areas that may, on their own, have inadequate sample sizes. this gives more reliable estimates of the fixed effect standard error. the response variable in this application is defined as y i ¼ 1 if child i had diarrhoea or fever during the reference period t, and y i ¼ 0 otherwise. the commonly adopted model for the analysis of this data is the probit or logistic model, and the standard measure of effects is the odds ratio (or) (mbonye, 2003 (mbonye, , 2004 woldermicael, 2001; yoannes, streat-eld, & bost, 1992) . because of the geographical nature of our data and the presence of nonlinear effects for some covariates, the assumption of a strictly linear predictor may not be appropriate, however. we use semi-parametric models to flexibly model the effects of selected socio-economic factors, continuous (metrical) and spatial covariates. our analysis is based on a flexible geo-additive model using the district as the geographic unit of analysis, which allows separating smooth structured spatial effects from random effect and estimate the effect of continuous covariates nonlinearly without assuming a linear functional form. a probit model with dynamic and spatial effects pr was used instead; where h is a known response function with a probit link function, and f 1 . . . ; f p are nonlinear smooth effects of the nonlinear covariates and f spat is the effect of district s i 2 f1; . . . ; sg where child i lives. in a further step, we split up the spatial effect f spat into a spatially correlated (structured) and an uncorrelated (unstructured) effect: the rationale is that a spatial effect is usually a surrogate of many unobserved influences, some of them may obey a strong spatial structure and others may be present only locally. models with a predictor that contains a spatial effect are also called geo-additive models (see kammann & wand, 2003) . more detailed description of these models is available elsewhere (for example, kandala, lang, klasen, & fahrmeir, 2001; kandala & madise, 2004) . this model is an extension of the probit or logistic model with a strictly linear predictor z i ¼ a þ w 0 i g, the two main differences are the use of a flexible predictor to model the effects of covariates that clearly have nonlinear effects on diarrhoea and fever and the use flexible methods to introduce the spatial dimension on determinants of diarrhoea or fever and allocate these spatial effects to structured and unstructured (random) components. this is done jointly in one estimation procedure that simultaneously identifies socio-economic determinants, and the spatial effects that are not explained by these socio-economic determinants. in this way, we are able to identify district patterns of prevalence of diarrhoea and fever that are either related to socio-economic variables that are not in the model and that have a clear spatial pattern, or point to spatial (possibly epidemiological or environmental) processes that account for these spatial patterns. identifying spatial patterns of disease prevalence beyond the known family socio-economic determinants should also assist in poverty mapping and associated district targeting of resources (elbers et al., 2001) . the standard measure of effect is still the or for logistic model and mean for probit model (but because of the use of a fully bayesian approach that relies on prior assumption to make posterior inference, instead of 'or' or mean, we have 'posterior or' or posterior mean), and tests for significance, linear trends and interactions are not carried out as usual using likelihood ratio tests but the deviance information criteria (dic) (spiegelhalter, best, carlin, & van der line, 2002) is used instead for model fit and comparison. to account for possible departures from the assumed distribution, 95% confidence intervals (cis) for the posterior ors and probability maps (the equivalent of cis for the spatial effects) are calculated using robust standard errors estimated via markov chain monte carlo simulation techniques. the estimated coefficients follow the same interpretation as those of ordinary logistic regression: y 1 ¼ 0, y 2 ¼ 1, and exp (b i ) is the or that y ¼ 1 when x i increases by 1. note that the probit model corresponds to a logistic model with the cumulative distribution function replaced by the standard normal distribution. the coefficient of covariates (say, child's place of delivery: hospital, antenatal visit, marital status, etc.) represent the difference in posterior log odds between the various categories and they are not easy to interpret apart from the sign. taking the exponential of the coefficients gives the posterior or and exponentiating the 95% confidence limits gives the confidence interval for the or. although the estimation process is complex, 1 the estimated posterior coefficients (posterior mean) should be interpreted as those of ordinary probit models. 1 we estimated models where either a structured or an unstructured effect was included as well as a model where both effects were included. based on these results, markov random field (mrf) priors were assumed for the structured effect (fstr(s)) and penalized spline (p-spline) prior for the nonlinear effects of metrical covariates f 1 ; . . . ; f p . the analysis was carried out using bayesx-version 0.9 (brezger, kneib, & lang, 2003) , a software for bayesian inference based on markov chain monte carlo simulation techniques. we investigated the sensibility to the choice of different priors for the nonlinear and spatial and we noticed that results for this application are not sensitive to the choice of different priors. visual inspection of the maps of the observed diarrhoea and fever prevalence by regions and districts (figs. 1 and 2) suggest that regional classification conceal district variations. table 1 shows that overall, the highest prevalence of both diarrhoea and fever were observed in the central region, followed by the southern region. although the northern region reported the lowest overall prevalence of both fever and diarrhoea, it had the district with the highest fever incidence of 63 percent (nkhata bay), further confirming that regional classifications do mask important district variations. the geographical variation was apparent for the district maps for the two morbidity conditions, but from the region maps it was not apparent. the hypothesis that regional classifications conceal district variations was investigated for both levels separately using geo-additive probit models. prevalence of disease for each household were related to the distance of the household from the nearest next district and region. the region variables were categorized into dummies. there was a clear spatial pattern as observed in the distribution of diarrhoea and fever prevalence at the district level (table 1) . for example, the aggregate regional levels of diarrhoea (table 1 or left panel of fig. 1 ) in the central and northern regions of malawi mask large district variability. the geographical information given in table 1 (or right panel of fig. 1) is highly aggregated and conceals local and district specific effects. on the other hand, diarrhoea prevalence by districts in table 1 (or fig. 2 ) strongly depended on the sample size and may be rather unstable. smoothing techniques were used to stabilize the observed prevalence in the sample as shown in figs. 1 and 2 . the bivariate distributions of fixed effects included in the analysis by the outcome variables are given in appendix a, also showing significance based on chisquare (w 2 ) tests. in the bivariate analysis based on the w 2 tests, factors that where significantly associated with diarrhoea are type of breastfeeding, child's age, parental education (both mother's and father's education), number of under-five children in the household, household size, place of residence (rural-urban), antenatal visit during pregnancy, child's place of delivery and the ethnicity. for fever, these factors are type of breastfeeding, child's size at birth, child's age, parental education (both mother's and father's education), number of under-five children in the household, household size, place of residence, antenatal visit during pregnancy, child's place of delivery and ethnicity. the results for diarrhoea presented in figs. 1 and 3 suggest considerable spatial auto-correlation in the underlying posterior means. the left panel of fig. 3 reveals high-risk clusters mainly in the central districts of malawi. the result of the nonlinear effect of child's age (figs. 2 and 4) suggests that there is continuous worsening of the diarrhoea morbidity up to about 12 months of age. shown are the estimated posterior means together with the 95% cis. for comparison a regression line obtained by assuming a linear fit is added to the plot. this deterioration set in right after birth and continues, more or less linearly, until 12 months and decreases thereafter. we find the influence of the mother's age (fig. 5 ) on diarrhoea to be nonlinear. there is a general tendency for diarrhoea morbidity to decline with increasing maternal age, but the patterns for older age are inconclusive. in particular, the interpretation of results at the end of the observation (wide confidence interval) is less reliable due to few observations. with regard to the fixed parameters, table 2 shows that the prevalence of diarrhoea in malawi is lower among infants who are exclusively breastfed (but higher for those who are mixed fed), whose mothers are well educated, with a father having up to primary education (posterior mean either strictly negative or positive indicating, respectively, low risk and higher risk of diarrhoea). in general, lower parental education is associated with higher risk of diarrhoea. we did not find a statistically significant association between the risk of diarrhoea and child's sex, preceding birth interval, multiple birth (twin or singleton birth), the antenatal visits during pregnancy, birth order of the child, father's education, vaccination status, child's place of delivery (whether hospital or home), mother's marital status, child's place of residence, household size, the economic status of the household and child's size at birth. the right panel of fig. 6 reveals a strong north-south gradient in the district spatial effects in malawi with a fairly sharp dividing line that runs through the centre (the capital city lilongwe) of the country. over and above the impact of the fixed effects, there appear to be negative influences on fever in the north and centralwest that are spread and affect most of the districts there. the right panel of fig. 6 reveals also lower risk of fever in the capital lilogwe in spite of being surrounded by some of the high-risk districts. the result of the nonlinear effect of child's age (fig. 7 ) suggests that there is continuous worsening of the child morbidity rate up to about 8 months of age. fig. 8 shows the influence of the mother's age on fever to be nonlinear, but with a general tendency to decline with age. the results for the youngest and oldest maternal ages are less reliable as shown by the wide cis. the fixed parameters show that the prevalence of fever (table 3) is higher among infants of small size at birth and low parental education (incomplete primary education). children living in urban areas are associated with lower risk of fever. the variables child's sex, family size, mother's marital status, the number of antenatal visits during pregnancy, the type of feeding, preceding birth interval, multiple birth (twin or singleton birth), birth order of the child, vaccination status, child's place of delivery (whether hospital or home), the economic status of the household and child's size at birth were not statistically significant. this study has shown significant district-specific geographical variation in childhood diarrhoea and fever in malawi. the posterior mean estimates of the residual smooth spatial district effects (shades of white coloured ¼ low risk morbidity, shades of black coloured ¼ high risk morbidity, and shades of grey coloured ¼ not significant risk) are shown in the left panel of maps of figs. 3 and 6. in addition, posterior probability maps (right panel of figs. 3 and 6) indicate significance of the spatial effects (negative/positive effect on diarrhoea, grey coloured ¼ non-significant). note that the residual spatial effects are centered about zero, i.e. the average over all districts is zero, while the overall level is estimated through the intercept term in eq. (1). over and above the impact of the fixed effects, there appear to be widespread negative influences on child morbidity in the central districts. the central districts are at a lower altitude than other parts of the country. it is likely that climatic factors and associated diseases are responsible for this pronounced district pattern. food insecurity associated with drought and flooding in the shire valley, which is a result of hazardous effect of climatic variation are among possible explanations for these negative effects. furthermore, the central districts are among the high-density population areas and this environment tends to increase the child's exposure to disease. for fever, it appears that children living in northern and central-west districts are at lower risk compared with children living in the central-east and south. in general, children living in provincial capitals are at significantly lower risk compared with children in the rural areas. the negative spatial effects on child morbidity in southern districts correspond to districts that are among densely populated areas in the province; therefore, their share of disease spread may be one of the major factors of this negative impact on child morbidity. from the analysis, it also appears that living in the capital cities such as lilongwe is associated with significantly lower prevalence of fever, despite being surrounded by areas with negative district effects. living in the capital is likely to provide access to health care that is superior in ways that have not been captured adequately in the fixed effects. the same is, however, not true for diarrhoea, where some urban agglomerations, such as lilongwe, are associated with higher risk of diarrhoea. possibly because of the high density of population associated with the phenomenon of slums in urban areas. in malawi, childhood diarrhoea and fever are associated with child's age and mother's age at birth of the child. figs. 4 and 7 show the effect of child's age on diarrhoea and fever in malawi and figs. 5 and 8 show the effect of mother's age on the two ailments. shown are the posterior means together with 95% cis. for comparison a regression line obtained by a linear fit is added to the plot. while the effect of the variable ''mother's age'' is almost linear for both ailments, its effects on the variable ''child's age'' are clearly nonlinear. the linear model assumes a negative relationship between mother's age at child's birth and risk of diarrhoea or fever, and between child's age and risk of diarrhoea and fever. as we show in figs this glosses over important nonlinearity in the effects. the data suggest deterioration in child diarrhoea that sets in right after birth and continues, more or less linearly, until 12 months of age. this immediate deterioration in child morbidity was not expected, as the literature commonly associates such deterioration with weaning at around 4-6 months. in a kenyan study, children aged 1-2 years were the most vulnerable (magadi, 1997) . one reason for this unexpected finding could be that, according to the dhs surveys, most parents gave their children liquids other than breast milk shortly after birth, a factor which might contribute to infections. this is due to the influence of poor-quality nutrition that is replacing breast milk as well as the onset of infectious diseases. these diseases are often related to unclean water and food which is replacing the breast milk, and the child no longer benefits from the mother's antibodies that are transmitted through the breast milk (stephenson, 1999) . initially, the worsening health status shows up as acute under-nutrition. but then childhood morbidity develops and worsens until about age 1. at that time, the body has developed its immune system to fight the impact of infectious diseases more effectively (moradi & klasen, 2000; who, 1995) . the influence of mother's age on child diarrhoea and fever show a general tendency for child morbidity to decline with increasing maternal age. part of the explanation for the observed association of morbidity risk and younger mother's age may be attributed to the tendency for young mothers to be socially and economically disadvantaged (world bank, 2000) , and the fact that younger mothers do not often use health services as much as older mothers (magadi, madise, & rodrigues, 2000) . these results are indicative of general trends and may be of use to planners for targeting policy. tables 2 and 3) after we controlled for the spatial dependence in the data, the fixed effects show the importance of parental education, breastfeeding, ethnicity, size of child, and rural-urban residence on child morbidity. the findings are generally as expected and consistent with the literature. children of highly educated mothers or living in urban areas are at lower risk of fever than other children (cleland & sathar, 1984; curtis & steele, 1996; hobcraft, mcdonald, & rutsein, 1985; kandala, 2002; madise, banda, & benaya, 2003) . the higher rural fever risk is possibly due to the fact that rural areas in sub-saharan african are under-developed and have less public service per capita compared with urban areas (brockerhoff, 1993; kuate defo, 1996) . as a result, living in rural areas provides no access to beds with mosquito nets or better health care and increases the risk of malaria and fever. after we controlled for child, household, and districts characteristics the residential location (rural versus urban) does not affect child diarrhoea. the urban-rural effect may be captured by the district effects. furthermore, the lack of corresponding urban advantage with respect to diarrhoea may be partly attributed to growing urban poverty in many parts of sub-saharan africa, which has been associated with poor sanitation in the densely populated slum settlements leading to increased incidence of diarrhoea among children of the urban poor (magadi, 2003) . we have established in this analysis that diarrhoea and fever especially during the early months of life is sensitive to low levels of parental education. similarly, in a study of the variation in african mortality, blacker (1991) , cites the much lower levels of female education in each country. studies using wfs and dhs data have shown that about half of the education-mortality association is accounted for by the economic condition of the household (bicego & boerma, 1993; cleland & van ginneken, 1988) . we find that, maternal education rather than paternal education matters a lot in reducing diarrhoea risk, whereas both low maternal and paternal education influence fever risk. there are also some ethnic differences in terms of diarrhoea and fever risk where, for example children from the sena ethnic group are more likely to have both diarrhoea and fever compared to other children. this suggests the need for in-depth studies in these communities to understand cultural child rearing practices that may put children at an increased risk of diarrhoea and fever. it should be noted that in the dhs data set, questions regarding fever control apply also to malaria control although there is a net clinical difference between the two diseases. malaria-relevant indicators include the reported treatment and care (whether antimalarials were given and facilities attended) to under-5s who had fever in the 2 weeks preceding the interview. the interpretation of fever in this report should take into account the fact that the dhs surveys are (for logistical reasons) mostly conducted in the dry, least malarious season (africa malaria report, who, 2003) . in addition, the observed prevalence of diarrhoea can be considered as incidence rate of diarrhea. because of the short followup period of 2 weeks before the interview, we have ignored the role of competing risk, although diarrhoea may be present in different forms: persistent diarrhoea (more than 14 days), acute watery diarrhoea, or dysentery (blood in stool). other diseases that can occur concurrently with diarrhoea include measles and malaria. malnutrition also often accompanies diarrhoea. it is important to point out that some of the factors observed to be significantly associated with prevalence of both fever and diarrhoea in the bivariate analysis, such as antenatal care and delivery care, turned out not to be significant in the multivariate analysis that simultaneously controlled for spatial effects as well as the effects of other covariates. it is possible that health care utilization is a reflection of accessibility of health care services and has been captured by the spatial effects in the multivariate analysis. also vaccination status turns out to be statistically insignificant, although other studies in rural sub-saharan africa have reported immunization status of a child as an important factor associated with diarrhoea (see for instance mbonye, 2003 mbonye, , 2004 . it should be noted that in the dhs, the reliability of parental recall of vaccination status for vaccines given to infants has not been studied and it is therefore unknown and may affect these results. possible reasons for the lack of association between childhood disease and the economic status may be because, many of the household wealth indices use assets that are more likely to be found in urban areas than in rural areas. thus, most of the rural households will be in the lowest wealth category even if they have other indicators of wealth (e.g. livestock or farm machinery). the consequence of this misclassification would be to lower the risk of childhood diseases of rural households. another limitation with household wealth indices derived from dhs is that they are based on current status data so that they might not capture the true level of household wealth during the infancy of children born several years before the survey. however, since these analyses are restricted to births within 5 years of the survey, this bias will not be substantial. to explain further these inequalities in childhood diseases prevalence at district level in malawi, further research is needed to scrutinize the spatial pattern of occurrence of water-borne illnesses to specific locations. this will enable us to draw a picture of where and whether events are concentrated, which will help in turn to guide local public health response or investigation to help identify at-risk populations and determine where to focus efforts to vaccinate residents against malaria. moreover, the measure of disease prevalence used here, recall of whether a child had been ill with diarrhoea or fever in the past 2 weeks is less perfect as it is quite subjective, based on a short-term recall. future work needs to address the question of disease environment more closely. in conclusion, the study findings carry some important general pointers to policy directions. for instance, the age effect suggests the need to pay attention to child feeding practices, particularly during the first 6 months after birth. second, the nonlinear influence of mother's age indicates that childcare promotion messages should be targeted particularly to younger parents. of high significance are the district influences on child morbidity. in particular, they suggest that in malawi, some urban agglomerations are associated with higher risk of diarrhoea. also, more emphasis must be placed upon the role of remoteness as well as climatic and geographic factors on childhood morbidity. it would be of value to investigate district-level factors not included in our models, such as environmental, socio-economic, cultural and human behavioural factors involved in the etiology of the disease. the north-central divide in malawi highlights the importance of such considerations. demographic and health surveys, comparative studies no maternal education and child survival: a comparative study of survey data from 17 countries diarrhoeal diseases and child morbidity and 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burden of infection on growth failure the ecology of malaria as seen from earth observation satellites can use of health care ex-plain sex differentials in child mortality in the developing world? situation analysis of poverty in malawi birth spacing, sibling rivalry and child mortality in india diarrhoeal morbidity among young children in eritrea: environmental and socioeconomic determinants poverty analysis of the malawian integrated household survey, 1997-98 malaria: the current situation who global database on child growth and malnutrition africa malaria report. who child morbidity patterns in ethiopia key: cord-103829-mavc34a0 authors: alam, t.; ahmed, d.; ahmed, t.; chisti, m.; rahman, m.; chauhan, a.; deb, s.; dhingra, p.; dhingra, u.; dutta, a.; keshari, a.; pandey, a.; sazawal, s.; belanger, s.; kariuki, k.; karuiki, s.; pavlinac, p.; singa, b.; walson, j. l.; bar zeev, n.; cornick, j.; dube, q.; freyne, b.; maiden, v.; ndamala, c.; ndeketa, l.; wachepa, r.; badji, h.; booth, j.; coulibaly, f.; diallo, f.; haidara, f.; kotloff, k.; malle, d.; mehta, a.; sow, s.; tapia, m.; tennant, s.; anjum, r.; hotwani, a.; hussain, a.; hussain, p.; kabir, f.; qamar, f. n.; shakoor, s.; yousafzai, t.; duggan, c.; kibwana, u.; kisenge, title: extended effect of short-course azithromycin for the treatment of diarrhoea in children on antimicrobial resistance in nasopharyngeal and intestinal bacteria: study protocol for the antimicrobial resistance sub-study of the multicountry antibiotics for children with diarrhea (abcd) trial. date: 2020-07-19 journal: nan doi: 10.1101/2020.07.17.20156224 sha: doc_id: 103829 cord_uid: mavc34a0 antimicrobial resistance (amr) is a major public health challenge worldwide, threatening the important gains that have been made in reducing mortality due to infectious diseases. despite current world health organization guidelines restricting antibiotics to a small subset of children with dysentery or suspected cholera, many children with diarrhea continue to be treated with antibiotics. we aim to determine the impact of a 3-day course of azithromycin on the risk of amr at 90 and 180 days after treatment, among a subset of children and their household contacts enrolled into a multi-country, randomized, double-blind, placebo-controlled clinical trial of azithromycin children under 2 years with diarrhea in low income settings, methods and analysis the antibiotics for children with diarrhea (abcd) trial is testing the efficacy of a 3-day course of azithromycin, compared to placebo, in reducing mortality and linear growth faltering in the subsequent 6 months among 11,500 children aged 2-23 months of age across multiple sites in bangladesh, india, kenya malawi, mali, pakistan and tanzania with diarrhea and one or more of the following; dehydration, severe stunting, or moderate wasting (https://clinicaltrials.gov/ct2/show/nct03130114). a sub-set of enrolled children are randomly selected to participate in a sub-study of amr. a fecal sample (stool or rectal swab) will be collected at baseline from all enrolled children. a fecal sample and a nasopharyngeal (np) swab will be collected at day 90 and 180 after enrolment from participating children and a close household child contact. escherichia coli and streptococcus pneumoniae will be isolated and minimum inhibitory concentration for azithromycin and other commonly used antibiotics will be determined and compared between trial arms. ethics and dissemination this study was reviewed by an independent ethical review committee. dissemination of results is planned to local and international policy makers and the public. for diarrhoea have provided such long-term follow-up and close contact data, both of which are key to understanding the potential risk of short-term antibiotic use in the context of diarrhoea.  this study will also provide data on antibiotic resistance from multiple countries in sub-saharan africa and asia where availability of such data is limited.  escherichia coli and streptococcus pneumoniae will be used as indicator organisms to monitor the impact of empiric antibiotic azithromycin administration on the development of resistance in bacteria colonising the gut and nasopharynx respectively -both are suitable for this purpose as they have pathogenic potential and are also commensal organisms which may act as reservoirs of transmissible genetic resistance elements.  with only two follow-up visits at 90 and 180 days, lack of culturing of other bacterial pathogens, and minimal collection of information on other antibiotic use during follow-up, this study will not evaluate impact of azithromycin beyond 180 days, the impact on other pathogenic bacteria, nor the added impact of the use of other antibiotics on resistance profiles . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint diarrheal disease kills over 500,000 children under 5 years annually, with the majority of these deaths occurring in sub-saharan africa and south east asia. 1 diarrhea, and the enteric infections that cause diarrhea, also contribute to linear growth faltering among survivors. [2] [3] [4] the current world health organization (who) recommended management guidelines for acute diarrhoea (rehydration, supplemental zinc, feeding advice and appropriate follow-up) 5 have contributed to significant reductions in diarrhoea-associated mortality 6 . these guidelines do not suggest a role for antibiotics except in case of bloody diarrhoea (as a proxy for shigella or other invasive bacterial infections) or suspected cholera. however, approximately 40-80% of all children with self-limiting diarrhea currently receive antibiotics, despite who guidelines recommending antibiotics only to a small subset with dysentery or cholera. 7, 8 antibiotics are widely accessible in most communities in low resource settings through pharmacies and informal vendors. in clinics and hospitals, scarce diagnostic resources and consequent therapy based on clinical syndromes that are nonspecific for serious bacterial infections (i.e. therefore likely to capture viral, parasitic, and self-limiting illnesses) also drive antibiotic consumption, which is a key factor in the promotion of anti-microbial resistance (amr). 9 importantly, antibiotics are increasingly used in animal husbandry 10, 11 contributing further to the spread of resistance. overuse of antibiotics is associated with increased rates of antibiotic-resistant bacteria, unnecessary costs, and significant incidence of adverse events. the growing burden of antibiotic resistance threatens the substantial progress that has been made. moreover, the spread of enterobacteriaceae that produce extended-spectrum β-lactamases (esbls) and other multidrugresistant (mdr) organisms in both community-based and hospital-based populations threatens the efficacy of many first line antibiotics that are used to treat diseases other than diarrhea, such as bacteremia, meningitis, and pneumonia. 12, 13 the antibiotics for children with diarrhea (abcd) trial is a double-blind, individually randomized placebo-controlled trial testing whether empiric azithromycin, administered to children at high-risk of death, reduces risk of death and linear growth faltering in the months following the diarrheal episode. this trial is based on evidence that enteric bacteria, after rotavirus, are the important causes of diarrhea-attributable deaths [14] [15] [16] [17] and that many of these bacteria are associated with linear growth faltering. 2, 18 data from trials for acute respiratory illness provided clear evidence for when antibiotics were of benefit in the management of high risk children. these data and the resultant guidelines led to decreases in indiscriminate antibiotic use and reductions in resistance among isolated pathogens 19, 20 . recent cluster trial evidence suggests a mortality benefit associated with single-dose azithromycin in high-mortality regions of sub-saharan africa . 21, 22 any clinical benefit of azithromycin needs to be weighed against the potential increase in antibiotic resistance associated with an antimicrobial intervention. we seek to determine whether children treated with azithromycin for diarrhea have a higher prevalence of antibiotic resistance in gut (escherichia coli [e.coli]) and . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint nasopharyngeal (streptococcus pneumoniae [s. pneumoniae]) bacteria compared to children who will receive placebo 90 and 180 days following study drug administration. we will also evaluate resistance in the household contacts of enrolled index children at the same timepoints. the primary objectives of this nested sub-study of the abcd trial are: 1. to determine whether the prevalence of azithromycin resistance in strains of e. coli isolated from stools, and s. pneumoniae, isolated from nasopharyngeal swabs, is no different between children treated with 3-days of azithromycin or placebo in a randomly selected sub-sample of children enrolled in the abcd trial, at 90 and 180 days after treatment. resistance to other antibiotic classes will be described. to determine whether the prevalence of azithromycin resistance in strains of e. coli and s. pneumoniae isolated from the siblings or close household contacts (children under five years of age living in the same household under the care of the same primary caregiver) of the sub-sample of participating children in the objective above, is no different between contacts of children treated with 3-days of azithromycin or placebo, at 90 and 180 days after treatment. resistance to other antibiotic classes will be described. a random subset of 15% (n=1750) of children enrolled in the abcd trial 23 (n=11500) will be assigned to participate in this nested sub-study ( fig 1) . random assignment into the amr sub-study will be determined by the world health organization (who) central coordinating office as part of the intervention randomization code, stratified by site and intervention arm. children enrolled in the amr sub-study will have a stool sample (or rectal swab) collected and processed at baseline, and a fecal sample and a np swab collected and processed for culture and resistance testing at day 90 and at day 180 after enrolment. in addition, a stool sample (or rectal swab) and a np swab will also be collected from a sibling or other close household contact (child contact) of the enrolled child (index-child) at day 90 and day 180. the study will be conducted in health facilities in south asia (bangladesh, india and pakistan) and sub-saharan africa (kenya, malawi, mali and tanzania). within each country, 2-10 individual health facilities will be the sites of patient enrolment. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint abcd parent study: the main abcd trial protocol (not including the amr sub study) is fully presented elsewhere 23 . in brief, children aged 2-23 months presenting to health facilities with diarrhea will be screened for enrolment. we enrolled young children at high risk of mortality in the 180 days following an acute diarrhea episode i.e. children with severe stunting, moderate malnutrition and/or dehydration. children presenting with a history of bloody stool (as per caregiver report or health care at abcd study enrolment, 1750 randomly selected index children were recruited into the amr sub-study. these participants were selected on the basis of systematic random sampling, so that every third child in the random abcd sample was selected, during the first year of recruitment into the abcd trial (2018). samples (stool) were collected from the participating children at baseline (day 0), and from participating children and their siblings or close household contacts at day 90 and day 180. np swabs were collected from participating children and their contacts at day 90 and day 180. eligible contacts were children aged less than 60 months, who slept in the same household as the enrolled child for 5 of the last 7-nights, and who shared the same primary caregiver as the index child. if there are multiple contacts in the household who meet the eligibility criteria, then the preference for inclusion as a contact was given to the child closest in age and living in the same dwelling as the index child. contacts were followed longitudinally through day 90 and day 180 to determine within-individual changes in resistance. stool samples will be collected from all participants enrolled in the amr study at enrolment (index children only), day 90 and day 180 (index children and child contacts). if whole stool collection was unsuccessful, flocked rectal swabs (2) were collected. the stool sample or rectal swab is immediately placed in cary-blair transport media and transported to microbiology facilities (at temperatures between 2-8°c) within 24 hours of collection. np swabs were collected from all participants enrolled in the amr sub-study and from their contacts at day 90 and day 180 (but not at enrolment to reduce discomfort from the swabbing process at study entry). these are immediately be . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint transferred into a 2ml vial containing skimmed milk tryptone glucose glycerol (stgg) 24 . vials will either processed or frozen at -80˚c within 4 hours of collection. faecal samples stored in cary blair will be brought to room temperature and directly inoculated onto chromagar e.coli media (becton dickenson, usa). these will be checked for growth of e. coli after 24 hours of incubation at 35˚c ±2˚c. suspected e. coli colonies, will be identified based on colony morphology and blue colouration, a single colony will be gram stained. if the colony stains as a gram-negative rod, a further suspected e. coli colony of the same morphology and colour will be transferred to macconkey plates to obtain a pure culture. if, after 24 hours of incubation at 35˚c ±2˚c, non-lactose fermenting growth is shown, (usually pink or red growth), then the colonies will be sub-cultured onto a tsa (tryptic soy agar) plate. a spot indole test will be carried out to confirm presence of e. coli in the culture. confirmed colonies of pure e. coli will be transferred from tsa plates into three 2 ml tubes containing tryptic soya broth with 15% glycerol or microbank storage beads. the vials will then be stored at -80˚c, for future use and isolate recovery for minimum inhibitory concentration (mic) analysis. two hundred microliters of the inoculated stgg will be transferred into todd hewitt enrichment broth (5ml) containing 0.5 % yeast extract, supplemented with 1ml rabbit or sheep serum. this will be used to inoculate sheep blood agar plates supplemented with 0.5% gentamycin (sbg). after incubation for 18-24 hours at 35˚c ±2˚c in a co2-incubator, the sba will be examined for typical pneumococcal colonies; draughtsman shaped colonies surrounded by a zone of alpha-hemolysis. growth may also occur in the form of large mucoid pneumococcal colonies for specific serotypes. suspected pneumococcal colonies will be streaked onto sbg in confluent lines. after streaking, an optochin disc (5 μg optochin) will be placed in the streaked area and incubated in a co2-incubator or candle-jar at 35˚c ±2˚c for 18-24 hours. susceptibility to optochin (zone diameter >14 mm), would be confirmed as s. pneumoniae. isolates identified as optochin resistant with zone diameter less than <14 mm, will be confirmed via bile solubility test. pure cultures will be mic tested either immediately or stored in tryptic soya broth with 15% glycerol at -80˚c, for future mic analysis. antimicrobial susceptibility testing (ast) for e. coli will be performed on the beckman coulter microscan, autoscan-4. this test is a minimized version of the broth dilution susceptibility test. antimicrobial agents will be diluted in the required buffer to concentrations bridging the range of . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. rehydration and inoculation will be performed using the renok system with inoculators-d. a final volume of 115 µl ± 10 µl will be used for a concentration between 3-7x10 5 cfu/ml. panels will be incubated for 16-20 hours to a maximum of 20 hours at 35˚c ±2˚c in an atmospheric non-co2 incubator. growth in the antimicrobial wells will be checked for turbidity. if turbidity is found in the negative control well or its absence is observed in the positive control well then experiment will be repeated. panels will be processed and read in the microscan auto scan4 instrument as per manufacturer instructions for all the listed antimicrobials (appendix). microscan instruments across all sites will be set to follow the clsi 2020 guideline. because the microscan gram negative panel does not include azithromycin, e-test strips will be used to obtain azithromycin mics in e.coli. the e-test gradient strip will be used to directly quantify antimicrobial susceptibility in terms of discrete mic values. isolates recovered from frozen stocks will be suspended in 0.85% saline for a final turbidity equivalent to a 0.5 mcfarland turbidity standard. muller hinton agar will be smeared with the inoculum and the e-test strip placed on it for incubation in 35±2 o c in a non-co2 incubator for 16-20 hours. the mic value will be read from the scale in terms of μg/ml where the pointed end of the ellipse intersects the strip. pneumococcal isolates from the glycerol stock will be plated onto a tsa plate supplemented with 5% sheep blood. plates will be incubated for 16-20 hours at 35˚c ±2 ˚c at 5-10% co2. morphologically similar well isolated colonies will be emulsified in 3 ml of microscan inoculum water to create an inoculum equivalent to that of a 0.5 mcfarland turbidity standard. 100 µl of the standardized suspension will be added to 25mlof mueller hinton broth with 3% lysed horse blood broth. rehydration and inoculation will be performed using a renok system inoculator-d. after inoculation the plates will be incubated for 20-24 hours at 35˚c ±2˚c in a non-co 2 incubator. after incubation, the plates will be checked for growth in the g wells. if turbidity is found in the negative or its absence is observed in the positive control well then experiment will be repeated. visual readings . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. patients and public were not involved in the design on the antimicrobial substudy. clinical minimum inhibitory concentration (mic) cut-offs corresponding to non-susceptibility from the 2020 clinical and laboratory standards institute (clsi) will be used for defining azithromycin (and other antibiotic) resistance in isolates of e.coli and s. pneumoniae. (for azithromycin and e.coli, we will use the clsi 2020 mic break points for enterobacteriales, as defined for s.enterica ser typhimurium, as clsi 2020 does not publish an e.coli specific mic break point). mics exceeding the established cut-points corresponding to resistance and intermediate will be considered as "resistant" to maximize likelihood of detected potential signals of declining susceptibility. in the primary analysis, the denominator of these prevalence estimates will be all children enrolled in the amr sub-study whose stool was submitted for amr testing (irrespective of whether the bacteria were isolated). for the secondary analysis, we will limit comparisons to only those children in whom the bacterium was isolated. objective 1: to compare prevalence of azithromycin resistant e.coli and azithromycin resistant s. pneumoniae respectively in stool and np swabs submitted for antimicrobial resistance testing at d90 and d180 among a random subsample of enrolled participants, by trial allocation arm. we then will test whether the upper limit of a one-sided 95% ci of the difference in prevalence of resistance at day 90 and day 180 in children assigned to the azithromycin and placebo group exceeds the non-inferiority margin of 10%. this margin has been chosen based on clinical acceptability among infectious disease experts. in primary analyses, the prevalence denominator will be all children enrolled in the amr substudy, across all sites, whose stool for e.coli or np swab for s. pneumoniae was submitted for antimicrobial sensitivity testing (irrespective of whether the bacteria were isolated). the noninferiority hypothesis will be tested first using the continuity corrected χ2 test as suggested by is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint the amr study, who provided a sample, but whose sample could not be subject to an antibiotic sensitivity test because of external circumstances (covid-19 related lockdowns of the lab), will be excluded from the denominator. if for any reason, sites are unable to complete testing of all their samples, random distribution of selection of specimens for testing will be difficult to confirm, though examination for systematic bias (e.g. by date range) will be undertaken. if bias is suggested in sites that have not completed testing, these sites will be excluded from hypothesis testing. but other remaining sites will be included in non-inferiority test as outlined above. in a secondary analysis, we will also explore the effect of azithromycin among the subgroup of children enrolled from african sites and asian sites. we will also examine the effect of azithromycin on isolates wherein the prevalence denominator will be defined as those children in whom the respective bacteria were isolated and tested (i.e. azithromycin resistance in e. coli as a proportion of e. coli isolates, and likewise for s. pneumoniae). sites that have not completed testing as outlined above, will be dealt with as outlined above. for both the primary and secondary analyses, estimates of amr prevalence will be adjusted for site and other covariates that are imbalanced between the two intervention groups of the amr sub study. we will also explore the change in resistance over time within individual participating children. this will be estimated using a binomial mixed effects model, as mics will be reported categorically as resistant/sensitive. we will additionally report resistance patterns to other commonly used first and second-line antibiotics between the randomization arms in separate analyses. we will conduct the similar primary, secondary and exploratory analyses described for objective 1 in the population of sibling or close household contacts (objective 2) with the same noninferiority margin of 10%. we will only formally test for non-inferiority in the primary analyses of the prevalence sample size estimation for amr sub-study . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07. 17.20156224 doi: medrxiv preprint the primary analysis of prevalence of azithromycin resistant e. coli in stool and s. pneumoniae in np swabs will be done in all participants whose samples were submitted for antimicrobial resistance testing at day 90 and day 180. however, due potential differences in resistance by region (africa and asia) we powered the study adequately assess non-inferiority by region. therefore, the minimum number of participants required per treatment group in each region was calculated assuming an alpha of 0.05, 90% power, a noninferiority margin of 10%, and a 25% prevalence of azithromycin resistance. this was based on baseline azithromycin resistance estimates in e.coli cultured from young children in tanzania (16%) prior to mass drug administration of azithromycin 26 , in bangladesh azithromycin resistance in e.coli in cases with diarrhea was estimated to be 27% 27 . we also assumed 10% will be lost to follow-up and 10% will refuse to have the sample taken, leading to a required sample size for each region of 775 randomly selected children per region, of which 645 are assumed to provide samples for analysis. for the three sites in asia, this translated to approximately 250 children randomly selected for the amr substudy per site. we decided to include the same number of children into the amr sub study from each of the 4 african sites. the sample size for the primary objective (difference in amr between the azithromycin and placebo arm across all sites) and non-inferiority testing would therefore comprise the 1750 children recruited to the amr study from each region,750 from the asian sites and 1000 from the african sites. therefore, in the primary analyses among all children, we expect a total of 1456 stools and np swabs samples at each time point and we will >99% power to assess a non-inferiority margin of 10%. in addition, we will also assess azithromycin resistance prevalence among siblings or close household contacts of abcd participants at day 90. of the 1750 abcd child participants randomly selected for the amr sub-study, we assumed that 70% will have a potentially eligible sibling or close household contact and assumed 20% of these will refuse the sample collection. as a result, we assume 980 siblings or household contacts under 5 years. this will allow 99% power to assess a non-inferiority margin of 10% in the prevalence of resistant e. coli in stool and s. pneumoniae in np swabs, among the participant siblings/contacts. in a secondary analysis, with 420 siblings or close household contacts providing samples at the asian sites we will have >80% power to assess a difference of more than 10% between the treatment arms (non-inferiority margin). we will have ~90% power for the same analysis with 560 siblings or close household contacts providing samples for the african sites. this study will provide valuable data informing policy makers on the cost, in terms of antibiotic resistance, of expanding azithromycin use for diarrhoea. this study will provide comparative data from . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint a broad range of geographic and epidemiologic settings in south asia and sub-saharan africa and will provide data describing temporal changes in resistance patterns over time. additionally, as azithromycin is being considered for mass drug administration in high mortality settings, this study will also provide important individual-level data on the short and long-term consequences of azithromycin use in young children. the abcd team would like to thank the children and families that have participated in the trial to date. all the staff in all the participating sites are acknowledged for their dedication. the data management team at rti international are acknowledged for supporting the data management function. the abcd trial is funded through a grant from the bill and melinda gates foundation (grant no: the funders had no role in the study design. all authors contributed to the drafting of the manuscript. all authors reviewed the manuscript for intellectual content and approved the final version of the report. no authors report conflicts of interest. the trial has been approved by the who ethics review committee and by the ethics committees of all participating sites in the seven countries -bangladesh (ethical review committee of icddr,b), india written informed consent (parents/caregivers) is obtained by study staff before any trial procedures are carried out and participants' confidentiality is maintained throughout the trial in line with the standard ich-gcp principles. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint figure 1 : antimicrobial resistance study nested within the abcd trial . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted july 19, 2020. . https://doi.org/10.1101/2020.07.17.20156224 doi: medrxiv preprint global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the mal-ed cohort study global disability-adjusted life-year estimates of longterm health burden and undernutrition attributable to diarrhoeal diseases in children younger than 5 years the incidence, aetiology, and adverse clinical consequences of less severe diarrhoeal episodes among infants and children residing in low-income and middle-income countries: a 12-month case-control study as a follow-on to the global enteric multicenter study (gems) ending of preventable deaths from pneumonia and diarrhoea: an achievable goal use of antibiotics in children younger than two years in eight countries: a prospective cohort study world health organization. the treatment of diarrhoea. a manual for physicians and other senior health workers antimicrobial resistance predicts death in tanzanian children with bloodstream infections: a prospective cohort study understanding the mechanisms and drivers of antimicrobial resistance a survey of antimicrobial usage in animals in south africa with specific reference to food animals multi-drug resistant non-typhoidal salmonella associated with invasive disease in western kenya the phylogeography and incidence of multi-drug resistant typhoid fever in sub-saharan africa burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the global enteric multicenter study, gems): a prospective, case-control study use of quantitative molecular diagnostic methods to identify causes of diarrhoea in children: a reanalysis of the gems case-control study use of quantitative molecular diagnostic methods to assess the aetiology, burden, and clinical characteristics of diarrhoea in children in low-resource settings: a reanalysis of the mal-ed cohort study etiology of severe acute watery diarrhea in children in the global rotavirus surveillance network using quantitative polymerase chain reaction effects of shigella-, campylobacter-and etec-associated diarrhea on childhood growth antibiotic strategies for developing countries: experience with acute respiratory tract infections in pakistan standard management of acute respiratory infections in a children's hospital in pakistan: impact on antibiotic use and case fatality azithromycin to reduce childhood mortality in sub-saharan africa 23. team as. a double-blind placebo-controlled trial of azithromycin to reduce mortality and improve growth in high-risk young children with non-bloody diarrhoea in low resource settings: the antibiotics for children with diarrhoea (abcd) trial protocol standard method for detecting upper respiratory carriage of streptococcus pneumoniae: updated recommendations from the world health organization pneumococcal carriage working group significance testing to establish equivalence between treatments, with special reference to data in the form of 2x2 tables increased carriage of macrolide-resistant fecal e. coli following mass distribution of azithromycin for trachoma control resistance pattern and molecular characterization of enterotoxigenic escherichia coli (etec) strains isolated in bangladesh key: cord-019089-oots4fe4 authors: laya, bernard f. title: infections date: 2013-08-31 journal: radiology illustrated: pediatric radiology doi: 10.1007/978-3-642-35573-8_13 sha: doc_id: 19089 cord_uid: oots4fe4 lower respiratory tract infection is a very common illness in children and is a significant cause of morbidity and mortality. clinical signs and symptoms are nonspecific especially in infants and younger children and some even present with nonrespiratory complaints. infectious agents causing pneumonia is not limited to viruses and bacteria, but it could also be due to mycoplasma, mycobacteria, fungi, protozoa, and parasites. coinfection with two or more microbial agents can also occur. the etiologic agent of lower respiratory infection in a child is often difficult to obtain, but the patient’s age can help narrow the possible cause. microbiological tests are important but could be difficult to obtain especially in younger children. various medical imaging modalities not only play an important role as an aid in diagnosis but can also help during and after therapy. imaging can also help evaluate complications to pneumonia and exclude other causes of respiratory distress including underlying developmental anomalies, foreign body, gastroesophageal reflux disease, and aspiration. in this chapter, the imaging modalities utilized in the detection of pulmonary infections will be discussed. the spectrum of typical imaging findings for various etiologic agents in both immunocompetent and immunocompromised children will be presented. lower respiratory tract infection is the most common cause of illness in children and is a signifi cant cause of morbidity and mortality. there are also associated complications, which should be recognized in order to make correct decisions regarding interventions or management. clinical signs and symptoms are nonspecifi c, especially in infants and younger children. some children with pneumonia even present with nonrespiratory symptoms including fever, malaise, decreased appetite, irritability, weakness, chest pain, and abdominal symptoms. physical examination is also less reliable in children than adults (donnelly 2001 ) . microbiological tests are important but could be diffi cult to obtain especially in younger children. various medical imaging modalities not only play an important role as an aid in diagnosis but can also help during and after therapy. diagnosis of pneumonia calls for a combination of clinical awareness, appropriate microbiological tests, and radiological studies. the cause of pneumonia in a child is often diffi cult to identify, but the patient's age can help narrow the possible etiologies. viral pneumonia is rare in the neonatal period because of conferred maternal antibody protection. group b streptococcus and gram-negative enteric bacteria are the most common pathogen in neonates (birth to 20 days), obtained through vertical transmission from the mother during birth. from age 3 weeks to 3 months, streptococcus pneumoniae is the most common pathogen. viruses are the most frequent cause of community-acquired pneumonia in infants older than 4 months and in preschool-aged children, with respiratory syncytial virus (rsv) being the most common. for school-aged children (6-16 years old), the incidence of bacterial infections from streptococcus increases, although viral disease remains the most common cause (condon 1991 ; ostapchuk et al. 2004 ) . bacterial pneumonia can occur at any time in preschool and school-aged children and adolescents. mycoplasma pneumoniae causes 30 % of lower respiratory tract infections in school-aged children (condon 1991 ; donnelly 2001 ) . infectious agents causing pneumonia are not limited to viruses and bacteria, but it could also be due to mycobacteria , fungi, protozoa, and parasites. co-infection with two or more microbial agents can also occur. evaluation of suspected pulmonary infection is a very common indication for an imaging study in children. the role of imaging including chest radiographs, ultrasound, computed tomography (ct), and even magnetic resonance imaging (mri) is to detect the presence or exclusion of pneumonia, determine its location, characterize and describe the extent of pneumonia, exclude other causes of respiratory symptoms, and show complications. it is also an important tool for image-guided interventions. the cornerstone of imaging in children suspected of having pulmonary infection is the chest radiograph. the radiographic appearance refl ects the pathologic process occurring in the respiratory system (bramson et al. 2005 ) . frontal and lateral views are obtained when possible because hyperinfl ation and lymphadenopathy are more accurately evaluated on a lateral radiograph especially in younger children. lateral decubitus views may be useful in distinguishing free fl owing pleural fl uid versus loculated fl uid collections. chest radiographs have inherent limitations, but despite of this, there is moderate evidence to suggest that chest radiographs are suffi ciently sensitive and highly specifi c for the diagnosis of community-acquired pneumonia (westra and choy 2009 ). 13.5.20 tuberculosis: progression of lymph node disease .................................................................. 460 13.5 the use of ultrasound as an imaging tool for pulmonary infections has been increasing especially for assessment of complications. its utility is even more important because there is no associated radiation, no sedation, no specifi c preparation, and the ultrasound machine can be transported to the patient's bedside. it can be used for planning thoracentesis, thoracotomy, and image-guided drainage procedures. lower-frequency (3.5-7 mhz) sector transducers are initially used for overview through inter-and subcostal scanning, but higher-frequency (10-12.5 mhz) linear transducers are helpful for more detail in the near fi eld. the development of helical and multidetector ct has revolutionized imaging evaluation of pulmonary infections. the use of intravenous contrast medium also helps optimize the assessment of pleura, mediastinum, and pulmonary parenchyma in cases of complicated pneumonia. high-resolution ct (hrct) shows greater accuracy in characterizing diseases into interstitial, airway, and airspace processes and gives a more accurate depiction of the extent of the disease. ct has an important role when a complication is suspected, to exclude an underlying abnormality in recurrent and persistent infections, for image-guided interventions, and for the evaluation of immunocompromised children (westra and choy 2009 ) . radiation-associated risks are important to consider, and thus, a clear indication for the procedure has to be present. low radiation dose technique with 80-120 kvp, age and thoracic thickness-adjusted low milliampere-seconds, along with radiation dose modulation should be utilized. evaluation of lung parenchyma with conventional mr imaging has limitations because of the inherent low proton density and weak mr signal as related to the low physical density of the lung. however, lung parenchymal, pleural, and lymph node infl ammatory abnormalities can be visualized and characterized by mri in children with pulmonary infections. peripheral airways disease or bronchiolitis are common terms ascribed to lower respiratory infection secondary to viruses. it commonly occurs in children less than 2 years of age, typically presenting with cough, coryza, and wheezing. rsv is the most common cause, but other viral causes include rhinovirus, parainfl uenza virus, human metapneumovirus, adenovirus, infl uenza virus, coronavirus, and human bocavirus (eslamy and newman 2011 ) . following inhalation of infected aerosols, the virus migrates to small airways and alveoli resulting to bronchoconstriction and increased mucous secretion (aherne et al. 1970 ; swischuk and hayden 1986 ) . typical chest radiographic appearances are peribronchial thickening/opacities, hyperaeration, and subsegmental atelectasis ( fig. 13.1 ). the peribronchial infl ammation and edema manifests as increased peribronchial cuffi ng or thickening of the bronchial walls, which is usually asymmetric and radiates from the hila into the lung. narrowed distal airway lumen due to bronchiolar wall edema and mucus results in hyperinfl ation with areas of segmental and subsegmental atelectasis (condon 1991 ; donnelly 2001 ) . patchy areas of airspace consolidation have also been described in viral pneumonia. ct is rarely required in the investigation of viral lower respiratory infection, but the most common ct feature is peribronchial thickening and ground-glass attenuation without consolidation (tanaka et al. 1996 ) . varicella zoster virus infection is a highly contagious but a relatively benign, self-limited disease in childhood. varicella pneumonia is regarded as a serious manifestation in adults, but immunocompromised children are also at risk. clinically, cough, fever, dyspnea, chest pain, and vesicular rash are generally accompanied by mild constitutional symptoms (kim et al. 1999 ) . radiographs of the chest initially reveal nodular infi ltrates that may progress to large segmental areas of patchy consolidation, predominantly in the bases and perihilar regions. total clearing is virtually guaranteed, although punctate calcifi cations maybe evident within 2 years after acute illness ( fig. 13 .2 ). airspace disease associated with chicken pox in children occurs most often in the immunocompromised host (blickman 1998 ) . certain groups of viruses have been recently reported to cause severe respiratory infection leading to respiratory failure and even death. the severe acute respiratory syndrome (sars) caused by coronavirus a (sars-cov) created a scare in 2003 with over 8,000 cases reported from 29 different countries. sars presents with a prodrome of fl u-like illness, followed by cough, dyspnea, and possibly acute respiratory distress. the initial radiographic manifestation is the presence of focal or diffuse interstitial opacities but rapidly progresses to bilateral areas of consolidation (thibodeau and viera 2004 ) (fig. 13 .3 ). another pandemic virus is the infl uenza virus a h5n1 (avian infl uenza virus), originating from asia and spreading over many parts of the world from 2003 to 2007. more recently, infl uenza virus of swine origin, designated as infl uenza a h1n1, was fi rst reported in mexico in 2009 and has rapidly spread globally. symptoms range from asymptomatic infection to mild upper respiratory illness, viral syndrome, diarrhea, severe pneumonia, acute respiratory distress syndrome (ards), and progression to multiorgan failure. initial chest radiographs in children with a mild and self-limited clinical course are often normal, but they may demonstrate prominent peribronchial markings with hyperinfl ation and multifocal areas of consolidation (lee et al. 2010 ) (fig. 13.4 ) . the most common complication of viral pneumonia is a secondary bacterial infection. viral infection can compromise the respiratory mucosa and render the host pulmonary respiratory system susceptible to develop superimposed bacterial pneumonia (donnelly 1999 ) . postinfectious bronchiolitis obliterans (constrictive bronchiolitis or obliterative bronchiolitis) is a clinical syndrome of chronic airfl ow obstruction associated with infl ammatory changes in the small airways as response to epithelial injury associated with infections. it is particularly associated with adenovirus , rsv, varicella , and severe mycoplasma infection. the chest x-ray fi ndings are often nonspecifi c and can appear normal, but the most common abnormality is hyperaeration (yalcin et al. 2003 ). on hrct, there is a mosaic perfusion pattern ( fig. 13 .5 ). perfusion is diminished in areas of parenchymal attenuation due to vasoconstriction secondary to hypoxia. inspiratory and expiratory phases of ventilation are important in hrct to better assess air trapping in this condition (hansell et al. 1997 ) . peribronchial thickening, atelectasis, bronchiectasis, and sometimes lung volume reduction can also be seen. swyer-james is a subtype of postinfectious bronchiolitis obliterans, which is typically unilateral. it can affect one lung segment, a lobe, or the entire lung. the characteristic chest radiographic and ct fi ndings are hyperlucency due to the pulmonary hypoperfusion, reduction of vascular and hilar markings, and volume reduction of the affected lung or lobe (daltro et al. 2011 ) (fig. 13 .6 ). bacterial pneumonia occurs with the inhalation of the infectious agent into the airspaces. it is most commonly caused by s. pneumoniae , haemophilus infl uenza type b, and staphylococcus aureus . staphylococcus commonly occurs in early infancy, haemophilus most often between 6 and 12 months, and s. pneumoniae more commonly between 1 and 3 years of age. gram-negative aerobic bacteria such as pseudomonas aeruginosa and s. aureus are a major problem in patients with cystic fi brosis. patients present with cough, chest pain, and high fever. following inhalation of the infectious agent into the airspaces, acinar exudate and edema ensues, manifesting as localized airspace consolidation with air bronchogram on chest radiographs. the typical distribution is lobar or segmental, depending on the stage of progression at the time the x-ray was obtained ( fig. 13 .7a ) (condon 1991 ; donnelly 1999 ) . round pneumonia is a spherical pneumonia, usually caused by s. pneumoniae (rose and ward 1973 ) (fig. 13.7b ). it is common in children less than 8 years old, maybe due to poor development of collateral pathways of ventilation (pores of kohn and channels of lambert). when round pneumonia is seen in children over 8 years old, other etiologies should be considered. the ct manifestations of bacterial infection are areas of consolidation with or without air bronchogram, typically with a segmental or lobar distribution and involving the lung periphery (tanaka et al. 1996 ) . parapneumonic effusions occur most commonly in bacterial pneumonia. it represents a spectrum of infl ammatory fl uid collections that ranges from transudative effusion to empyema. parapneumonic effusions complicate pneumonia in 36-56 % of cases in pediatric patients (kurt et al. 2006 ) , and empyema complicates an estimated 0.6 % of all childhood pneumonias (jaffe and balfour-lynn 2005 ) . pleural fl uid can usually be detected on a frontal chest radiograph, but layering of fl uid on the lateral decubitus view distinguishes a free fl owing fl uid from a loculated fl uid. ct scan gives a better characterization of parapneumonic effusions compared to radiographs. ct fi ndings include enhancement and thickening of the parietal and visceral pleura, thickening of the extrapleural subcostal tissues, and increased attenuation of the extrapleural subcostal fat (muller 1993 ) (fig. 13.8 ). these ct characteristics do not accurately predict empyema and should not be used to distinguish between empyema and transudative effusions. in ultrasound, pleural fl uid can be characterized as simple effusion, complicated effusion, or fi brothorax (pleural thickening or fi brosis) ( fig. 13.9 ) . a simple effusion appears as a clear anechoic or cloudy hypoechoic fl uid with or without swirling particles. a complicated effusion appears as a septated or multiloculated, hypoechoic fl uid with fi brinous septations, with no clear demarcation between the lung and pleural components, while a fi brothorax appears as a thickened, echogenic rind of pleural plaque (kim et al. 2000 ) . suppurative lung parenchyma complications represent a spectrum of abnormalities including cavitary necrosis, lung abscess, pneumatocele, bronchopleural fi stula, and pulmonary gangrene. necrotizing pneumonia or cavitary necrosis is a complication of severe lobar pneumonia, characterized by massive necrosis and liquefaction of lung tissues resulting to multiple cavities rather than a solitary one. it is most commonly caused by s. pneumoniae although aspergillus and legionella have also been implicated in the pediatric population (hodina et al. 2002 ) . evidence of cavitary necrosis complicating pneumonia is often seen on ct before or in the absence of fi ndings in chest radiography. ct fi ndings include lung consolidation with decreased parenchymal enhancement, loss of lung-pleura margin, and multiple thin-walled cavities lacking an enhancing border. the adjacent visceral pleura is particularly fragile and tends to rupture, causing bronchopleural fi stula (hoffer et al. 1999 ) (fig. 13 .10 ). cavitary necrosis indicates an intense and prolonged illness, but it usually resolves without surgical intervention (donnelly and klosterman 1997 ) . lung abscesses are thick-walled cavities containing purulent material resulting from pulmonary infection. an airfl uid level with reactive rim is a typical imaging appearance, as compared to necrotizing pneumonia where cavities occasionally have air-fl uid level but without rim of enhancement (donnelly and klosterman 1997 ) (fig. 13.11 ). differentiating the two is important because abscess not responding to therapy may require drainage, whereas necrotizing pneumonia does not require invasive treatment, and intervention may even be harmful resulting in complications such as bronchopleural fi stula (hoffer et al. 1999 ) . pneumatoceles are thinwalled cysts without septations that develop within the lung parenchyma after an acute pneumonia (fig. 13.12 ) . it may represent a later or less severe stage of resolving or healing necrosis and is most often associated with s. aureus (daltro et al. 2011 ) . bronchiectasis is the most common long-term sequelae of lung parenchymal damage from pneumonia. it is best demonstrated on high-resolution chest ct scan, and the main diagnostic features are as follows: internal diameter of the bronchus is wider than its adjacent pulmonary artery, failure of the bronchus to taper peripherally, and visualization of bronchi in the outer 1-2 cm of the lung zones (eslamy and newman 2011 ) (fig. 13.13 ). pertussis is a highly contagious respiratory bacterial infection caused by bordetella pertussis . it infects mainly infants and young children causing symptoms that include mild fever, runny nose, and cough, which develops into a paroxysmal cough followed by whooping (whooping cough). pneumonia is a common complication, and untreated patients may be contagious for 3 weeks or more following onset of the cough. the spread of pertussis can be prevented by immunization. histopathologic examination reveals an infection dominated by necrotizing bronchiolitis, intra-alveolar hemorrhage, fi brinous edema, and angiolymphatic leukocytosis (paddock et al. 2008 ) . conventional radiographs reveal streaky perihilar infi ltrates with most often unilateral hilar adenopathy, a pattern sometimes called the shaggy heart appearance (blickman 1998 ) (fig. 13.14 ) . m. pneumoniae is a common ubiquitous organism and treatable cause of community-acquired pneumonia, occurring primarily in children and young adults. it accounts for up to 30 % of all pneumonia in the general population, but the highest incidence is seen in children between 3 and 14 years of age. of those infected, 50 % get tracheobronchitis, 30 % pneumonia, 10 % pharyngitis, and 10 % otitis media. clinically, symptoms are less severe but more common than in true bacterial pneumonia (blickman 1998 ) . the radiographic fi ndings are nonspecifi c, have a broad spectrum of appearances, and may present with a pattern intermediate between the classic viral and bacterial pneumonia patterns (hsieh et al. 2007 ). some authors reported that a reticulonodular pattern or nodular opacities are typical radiographic pattern (john et al. 2001 ) , while others stress the occurrence of confl uent and patchy consolidation (reittner et al. 2000 ) (fig. 13.15 ). hrct fi ndings are thickened bronchovascular bundles, ground-glass attenuation and consolidation, centrilobular nodules, and lobular distribution (tanaka et al. 1996 ; reittner et al. 2000 ) . chlamydia trachomatis is an obligate intracellular parasite. genital chlamydial infection is recognized as the world's most common sexually transmitted disease, and the high prevalence in women of childbearing age results in exposure of neonates during childbirth. chlamydia pneumonia is a neonatal infection acquired after passage of the fetus through the cervix and vagina. the infant typically presents at 3-6 weeks of age with respiratory symptoms and occasional pulmonary hemorrhage. c. trachomatis should be suspected in infants who are afebrile or nontoxic and have a dry cough. these patients often have a peripheral eosinophilic pleocytosis, sometimes with concomitant conjunctivitis (ostapchuk et al. 2004 ). most chest radiographs show bilateral hyperaeration and diffuse infi ltrates with a variety of radiographic patterns including interstitial, reticular nodular, atelectasis, coalescence, and bronchopneumonia (radkowski et al. 1981 ) (fig. 13.16 ). tuberculosis (tb) is caused by infection with the mycobacterium tuberculosis complex. once inhaled, the infected aerosolized droplet in the alveoli cascades a series of infl ammatory reaction, and the bacilli also spread to nearby mediastinal lymph nodes. the alveolar site of infection (ghon focus), the infected lymph nodes, and the associated lymphangitis form the "primary (ranke's) complex." in most immunocompetent children, the infection goes into latency and the bacilli become dormant. these children usually have a reactive tuberculin skin test (tst) and/or a positive interforon-gamma release assay (igra) test, but without clinical evidence of tb and generally no abnormalities on chest radiograph apart from the primary complex residual. primary tuberculosis disease occurs if the host is unable to contain the infection, and disease progression occurs in the lungs, the lymph nodes, and adjacent structures in the thorax or could disseminate in any part of the body. lymphadenopathy (present in 92 %) with or without a visible ghon focus is the radiographic hallmark of tb infection and usually involves the hilar and paratracheal regions. the ghon focus may be too small to be radiographically visible but can also undergo caseation and calcify ( fig. 13.17 ). disease progression may occur at the site of ghon focus, within the regional lymph nodes, or following disease spread (fig. 13.18 ). parenchymal involvement in primary pulmonary tb most commonly appears as homogeneous consolidation, although it can appear patchy, linear, nodular, and mass-like. caseation necrosis, liquefaction, or calcifi cations can be seen within the consolidation and can progress into extensive lung damage (marais et al. 2004 ) (fig. 13.19 ). enlarged and edematous hilar, paratracheal, and subcarinal lymph nodes may cause compression of the adjacent bronchus and can lead to hyperinfl ation or atelectasis of the affected lung segment. contrast-enhanced ct shows a characteristic appearance consisting of central areas of low attenuation with peripheral rim enhancement and obliteration of perinodal fat (kim et al. 1997 ) (fig. 13.20 ) . pulmonary dissemination, usually seen in very young and immunocompromised patients, leads to the formation of pulmonary nodular interstitial granulomas, usually 1-2 mm in size, throughout the lungs. chest radiographs demonstrate the usual miliary nodular pattern but ct is more sensitive for the detection of miliary tb (kim et al. 1997 ) (fig. 13.21 ) . adult-type disease presentation is common after primary infection in children over 10 years of age or via endogenous reactivation (postprimary tb) or reinfection. chest radiograph shows ill-defi ned, fi bronodular parenchymal disease and cavitation mainly involving the apical segments of the upper lobes (perez-velez and marais 2012 ) (fig. 13.22 ). aspergillus fumigatus is a ubiquitous saprophytic mold found in many environmental sites, and infection is usually via inhalation of spores, although other routes of entry also occur. infection can manifest as colonization of airway cavities and necrotic tissue, allergic disease, and invasive disease, which is usually acute and rapidly progressive severe disease (foster and alton 2003 ) . airway colonization occurs in patients with underlying airway disease such as asthma and bronchiectasis. intertwined fungal hyphae, called as mycetoma or aspergilloma, form in the pulmonary cavity or ectatic bronchi. important underlying causes are pulmonary tb with cavitation and cystic fi brosis with bronchiectasis. rounded soft tissue mass within a cavity forming an "air-crescent" sign is a typical appearance ( fig. 13.23 ). allergic bronchopulmonary aspergillosis is characterized by mucoid impaction of the proximal bronchi presenting as fi ngerlike shadows involving the upper lobes on the chest radiograph. ct demonstrates the mucoid impaction of the central airways and the bronchiectasis of the segmental or subsegmental airways (foster and alton 2003 ) . invasive disease is an aggressive, rapidly disseminating and destructive disease and occurs when host defenses are impaired. it is characterized by the occlusion of large-or medium-sized arteries by plugs of hyphae causing pulmonary hemorrhage, arterial thrombosis, and infarction. radiographic fi ndings are nonspecifi c, with multiple nodules or areas of consolidation (fig. 13.24 ) . the typical ct fi nding is the halo sign due to ground-glass attenuation representing hemorrhage surrounding the pulmonary nodule or mass (foster and alton 2003 ; eslamy and newman 2011 ) . histoplasmosis, caused by the fungus histoplasma capsulatum , is usually an asymptomatic and self-limited disease that rarely requires therapy in children other than the very young or immunocompromised. it is found in the soil of endemic areas including central united states, central america, and northern south america but has also been reported in some parts of asia (houston 1994 ) . after inhalation, the spores germinate within the alveoli inciting an intense tissue reaction characterized by granulomas, which may calcify. it spreads to the lymphatics and into the hilar or mediastinal lymph nodes, and systemic dissemination may occur in patients with impaired t-cell immunity (mcadams et al. 1995 ) . histoplasmosis falls in one of three categories: acute, chronic pulmonary, and disseminated disease. acute pulmonary histoplasmosis is a self-limited illness. chronic pulmonary histoplasmosis occurs in patients with chronic lung disease and presents similar to tuberculosis with predilection for apical and posterior segments of the lung. disseminated histoplasmosis in children is characteristically a fulminant illness, which may or may not have pulmonary involvement. radiologic manifestations parallel the clinical syndromes. acute disease usually manifests as focal parenchymal consolidation with or without ipsilateral hilar adenopathy (fig. 13.25 ) . with healing, a nodule representing a histoplasmoma may result. chronic histoplasmosis radiographically manifests as an upper lobe fi brocavitary disease indistinguishable from postprimary tuberculosis. chest radiographs of patients with disseminated disease may show miliary or diffuse reticulonodular pattern that could progress to diffuse airspace opacifi cation (mcadams et al. 1995 ) . echinococcosis, also known as hydatid disease or hydatidosis, is a parasitic infection in humans caused by dog tapeworm, echinococcus granulosus , in its larval stage. it is endemic in many sheep and cattle-raising countries throughout the world. humans are intermediate hosts and become infected through ingestion of contaminated water or vegetables. when eggs of adult tapeworm are ingested, embryos are freed and migrate through the host's gastrointestinal mucosa and enter the portal vein and lymphatic system to various parts of the body where the embryo develops into a cyst. the wall of the cysts contains three layers: the outermost, pericyst; the middle laminated membrane layer, ectocyst; and innermost germinal layer, endocyst (czermak et al. 2001 ) . the lungs are the most common sites of infection in children but majority remain asymptomatic until the cyst enlarges to cause symptoms due to mass effect or due to cyst rupture (santivanez and garcia 2010 ) . diagnosis is obtained by imaging evaluation, supported by serology. a high proportion of lung lesions are discovered incidentally on a routine x-ray, and the most prominent radiological fi nding is a dense, round, well-demarcated opacity that can resemble a neoplasm (fig. 13.26a ) . when the growth of the cyst produces erosion in the bronchioles, air between the endocyst and pericyst can produce a "crescent or inverse crescent sign." if air continues to enter the cyst cavity, endocyst membrane can be seen fl oating in the most dependent part of the pericyst cavity producing the "waterlily sign" (fig. 13.26b ) . ct recognizes the appearance of the cystic lesion including smaller cysts, assesses signs of cyst rupture, evaluates the surrounding structures, and helps exclude alternative differential diagnoses (santivanez and garcia 2010 ) . ascariasis and hookworms remain the most common intestinal nematodes in the world (sarinas and chitkara 1997 ) . in the western hemisphere, parasitic pneumonia secondary to toxoplasma gondii is associated with compromised hosts, particularly acquired immunodefi ciency syndrome (aids) patients. strongyloides stercoralis infestation is seen in patients receiving glucocorticoids or chemotherapy and in patients with aids or other causes of t-cell dysfunction (berk and verghese 1998 ) . ascaris infestation generally occurs through hand-to-mouth ingestion of food contaminated with parasite eggs, while hookworms are transmitted through larval penetration of the skin. symptomatic pulmonary disease may present with fever, cough, chest pain, hemoptysis, dyspnea, and wheezing. these pulmonary symptoms could be due to loffl er's syndrome, effects of larval tissue migration, airway reactivity or bronchospasm, superimposed bacterial infection, and chronic eosinophilic pneumonia (sarinas and chitkara 1997 ) . ascaris and hookworm infections present with peripheral eosinophilia during larval migration phase. chest radiographs could be normal or demonstrate nonspecifi c patchy pulmonary infi ltrates (fig. 13.27 ) . ct scan could depict abnormalities better and could show ground-glass pulmonary lesions with ill-defi ned margins as well as nodules (sakai et al. 2006 ). causes of immunodefi ciency can be divided into congenital (primary) and acquired (secondary). the range of respiratory complications encountered is broad and is infl uenced by both the type and degree of immunodefi ciency. chest radiographs are insensitive and may show only subtle change. hrct detects abnormalities not visible on the plain fi lm such as bronchial wall thickening, bronchial dilatation, and air trapping. various noninfectious pulmonary processes including alveolar hemorrhage, pulmonary edema, graft versus host disease, and drug reaction are also seen in the immunocompromised hosts, which can mimic pulmonary infection on imaging. the primary or congenital immunodefi ciency disorders are inherited group of disorders resulting from innate defects of the immune system. clinical manifestations are diverse and nonspecifi c, which include recurrent infections, infection with opportunistic organisms, failure to thrive, skin rashes, recurrent skin sepsis, and unusual wound healing (jeanes and owens 2002 ) . primary immunodefi ciency can be broadly divided into t-cell (cellular) immune defi ciency versus b cell (humoral defi ciency). humoral immunodefi ciencies are the most commonly encountered type characterized by defective antibody production with increased susceptibility to pyogenic infections but able to recover from viral infections (fig. 13.28 ). examples are x-linked agammaglobulinemia, iga defi ciency, and common variable immunodefi ciency. cellular immunodefi ciencies have increased susceptibility to disseminated viral and opportunistic infections. cellular immune disorders include digeorge syndrome and severe combined immunodefi ciency (collingsworth 2005 ) . acquired immunodefi ciencies in childhood can be caused by chemotherapy, radiation therapy, immunosuppressive therapy aimed at treating childhood malignancies, transplant rejection, rheumatologic disorders, or infl ammatory or infectious diseases. it can also be due to human immunodeficiency virus (hiv) infection, malnutrition, or any state of chronic debilitation. bone marrow transplant requires complete eradication of the immune system. early infectious complications are frequently caused by bacteria and fungi, most commonly gramnegative bacteria ( pseudomonas and klebsiella ) and aspergillus (fig. 13.29 ). widespread use of long-term indwelling catheters has led to an increased incidence of both staphylococcal and streptococcal pneumonia. chest radiographs may show classic focal or lobar consolidation although atypical appearance can also be seen. children are also at increased risk of viral infections, most importantly rsv, herpes simplex , adenovirus , and varicella . immunosuppressive therapy following solid organ transplantation predisposes a patient to recurrent pulmonary infections. in these patients, viral infections can be life-threatening, but pneumocystis and fungal infections ( aspergillus and candida ) can also be seen (collingsworth 2005 ) . children represent 2 % of the reported cases of human immunodefi ciency virus (hiv) infection. most children are infected after vertical transmission from their mother, and majority develop acquired immunodefi ciency syndrome (aids) early in life. there is increased susceptibility to bacterial, viral, fungal, protozoal, and opportunistic infections. lobar or segmental consolidations are the most common patterns (marks et al. 1996 ) . mycobacterial infection can be seen in aids patients, and the radiographic appearance mimics that seen in immunocompetent children with primary tuberculosis. mycobacterium avium-intracellulare is also encountered later in the course of disease and imaging fi ndings cannot be distinguished with other forms of mycobacterial infections (collingsworth 2005 ) . pneumocystis jiroveci is the most common opportunistic pulmonary infection in children with aids, occurring in up to 50 %, and is the leading pulmonary cause of death (jeanes and owens 2002 ) . radiographic appearances are variable and include hyperinfl ation with diffuse bilateral interstitial or nodular infi ltrates from the perihilar region to the periphery, which often progresses to widespread alveolar opacities with air bronchogram (fig. 13.30 ) . cavitary nodules and cysts can be seen, with pneumothorax and/or pneumomediastinum as common complications. hrct fi ndings include patchy or diffuse ground-glass opacity, consolidation, cyst or cavities, centrilobular opacities, nodules, peribronchial cuffi ng, and interlobular septal thickening (jeanes and owens 2002 ; collingsworth 2005 ) . pathological changes in virus infection of the lower respiratory tract in children parasitic pneumonia infl ammatory lung disease interpretation of chest radiographs in infants with cough and fever thoracic disorders in the immunocompromised pneumonia in children echinococcus granulosus revisited: radiologic patterns seen in pediatric and adult patients pulmonary infections maximizing the usefulness of imaging in children with community-acquired pneumonia practical issues concerning imaging of pulmonary infection in children pneumonia in children: decreased parenchymal contrast enhancement-ct sign of intense illness and impending cavitary necrosis pneumonia in normal and immunocompromised children: an overview and update chronic lung infection in children obliterative bronchiolitis: individual ct signs of small airways disease and functional correlation imaging of cavitary necrosis in complicated pneumonia lung abscess versus necrotizing pneumonia: implications for interventional therapy histoplasmosis and pulmonary involvement in the tropics mycoplasma pneumonia: clinical and radiographic features management of empyema in children chest imaging in the immunocompromised child spectrum of clinical and radiographic fi ndings in pediatric mycoplasma pneumonia pulmonary tuberculosis in children: evaluation with ct high resolution ct fi ndings of varicella zoster pneumonia ultrasound in the diagnosis of pediatric chest diseases therapy of parapneumonic effusions in children: video-assisted thoracoscopic surgery versus conventional thoracostomy drainage swine-origin infl uenza a (h1n1) viral infection in children: initial chest radiographic fi ndings the natural history of childhood intrathoracic tuberculosis: a critical review of prechemotherapy literature thoracic diseases in children with aids thoracic mycoses from endemic fungi: radiologic-pathologic correlation imaging of the pleura community acquired pneumonia in infants and children pathology and pathogenesis of fatal bordetella pertussis infection in infants tuberculosis in children chlamydia trachomatis in infants: radiography in 125 cases mycoplasma pneumoniae pneumonia: radiographic and hrct features in 28 patients spherical pneumonias in children simulating pulmonary and mediastinal masses pulmonary lesions associated with visceral larva migrans due to ascaris suum and toxocara canis : imaging of six cases pulmonary cystic echinococcosis ascariasis and hookworm viral versus bacterial infections in children: is roentgenographic differentiation possible? high resolution fi ndings in community acquired pneumonia atypical pathogens and challenges in community acquired pneumonia what imaging should we perform for the diagnosis and management of pulmonary infections? postinfectious bronchiolitis obliterans in children: clinical and radiological profi le and prognostic factors key: cord-018846-gmujrso2 authors: castagnini, luis a.; goyal, meha; ongkasuwan, julina title: tonsillitis and peritonsillar abscess date: 2015-07-14 journal: infectious diseases in pediatric otolaryngology doi: 10.1007/978-3-319-21744-4_10 sha: doc_id: 18846 cord_uid: gmujrso2 tonsillitis is one of the most common childhood infections. occasionally, it can lead to one of the most common deep space head and neck infections, peritonsillar abscess. the epidemiology, microbiology and treatment of tonsillitis and peritonsillar abscess are similar and crucial for the primary care physician, infectious disease specialist, otolaryngologist, and emergency medicine physician to understand. the routine use of tonsillectomy as a treatment option for recurrent tonsillitis and peritonsillar abscess has decreased over the last decade and clearer indications for surgery have emerged. this chapter provides an overview of the most recent literature regarding the epidemiology, microbiology, diagnosis, complications and management of tonsillitis and peritonsillar abscess. it also discusses the indications for tonsillectomy along with its complications. the tonsils are lymphoepithelial organs that function as secondary lymphoid organs. they contain specialized epithelial m cells that capture and transport antigens entering through the mouth and nose to extrafollicular regions or lymphoid follicles. the lymphoid follicles then release antibody-expressing memory b cells or plasma cells that migrate to the tonsils and produce antibodies. these antibodies are subsequently released into the tonsillar crypt lumen. all fi ve isotypes of immunoglobulins are produced in the tonsil. the most important of these isotypes is iga which functions as an important component of the mucosal immune system of the upper airway [ 3 ] . the tonsils are at their largest size during the most active immunologic activity, which is estimated to be between the ages of 3 and 10 years. after this period they display spontaneous age-depended involution [ 3 ] . chronic or recurrent tonsillitis alters the tonsillar immune system by causing shedding of the m cells and the tonsillar immunologic response to antigens weakens. the clinical signifi cance of this dysfunction is controversial. there are no data demonstrating signifi cant change in the systemic immune system after tonsillectomy [ 3 ] . tonsillitis is infl ammation of the tonsils, specifi cally the palatine tonsils. acute pharyngitis is one of the most common illnesses seen in the primary care setting accounting for up to 1.2 % of all emergency department visits and up to 6 % of offi ce visits for children and adolescents [ 4 , 5 ] . most cases in children are observed during winter and early spring when respiratory viruses are more common. during the summer months enteroviruses are responsible for the majority of cases [ 6 ] . tonsillitis caused by group a β-hemolytic streptococcus (gabhs) most commonly occurs in children 5-15 years old, affecting less than 15 % of children younger than 3 years old, 24 % of children less than 5 years old, and 37 % of school-aged children [ 7 ] . the fi nancial burden of gabhs tonsillitis is estimated to be between $224 and $539 million per year with more than half being associated to non-medical costs [ 8 ] . neisseria gonorrhoeae is an important pathogen in sexually active individuals or in victims of sexual abuse [ 6 ] . repeated episodes of all-cause tonsillitis is reported in 0.9 % of children less than 1 year old and 5.3 % of children between the ages of 1 and 4 years old [ 9 ] . tonsillitis may be caused by a viral or bacterial infection of the tonsils, most commonly the palatine tonsils. viral etiologies are the most common cause of tonsillitis in the pediatric population. common viral pathogens include enteroviruses, particularly coxsackie virus, respiratory viruses (e.g. adenovirus, rhinovirus, infl uenza virus, coronavirus, parainfl uenza virus and respiratory syncytial virus), and viruses of the herpesviridae family like epstein-barr virus (ebv), cytomegalovirus (cmv) and herpes simplex virus (hsv) [ 7 ] . the most common bacterial pathogen implicated in acute tonsillitis is gabhs, accounting for up to 30 % of all episodes of acute pharyngotonsillitis in children. less frequent bacterial causes include staphylococcus aureus , streptococcus pneumoniae , group c streptococcus, mycoplasma pneumoniae , chlamydophila pneumoniae , corynebacterium diphtheriae , arcanobacterium haemolyticum , neisseria gonorrhea , francisella tularensis , yersinia enterocolitica , and mixed anaerobic fl ora from the oral cavity [ 7 ] . fusobacterium necrophorum , a gram-negative aerobic bacilli, and the most common cause of lemierre's syndrome, has been cultured from adolescents and young adults with uncomplicated tonsillitis [ 10 ] . patients with tonsillitis present with a variety of symptoms that include sore throat, fever, chills, odynophagia, cervical adenopathy, trismus, halitosis, erythematous and exudative tonsils and tonsillar pillars ( fig. 10.2 ) . the presence of conjunctivitis, coryza, cough, stomatitis, diarrhea and hoarseness strongly suggest a viral etiology. children younger than 3 years of age may have an atypical presentation of gabhs infection called streptococcosis, which is characterized by fever, mucopurulent or serous rhinitis, and adenopathy, followed by irritability, loss of appetite and lethargy. exudative tonsillitis is rare in this age group. on physical exam, it is often diffi cult to distinguish between viral and bacterial tonsillitis, but some clinical fi ndings may provide important clues of the etiologic agent. for example, hsv typically presents with stomatitis, ebv may include lymphadenitis and coxsackie virus infections may present with throat ulcers (herpangina) or as part of hand-foot-mouth disease. complications of tonsillitis can be suppurative or non-suppurative in nature. suppurative complications include peritonsillar abscess, parapharyngeal or retropharyngeal space abscess, and suppurative cervical lymphadenitis. acute airway compromise, rheumatic fever, glomerulonephritis, and scarlet fever are non-suppurative complications of tonsillitis caused by gabhs. streptococcal toxic shock syndrome, an uncommon but rapidly progressive disease, can complicate cases of pharyngitis caused by a toxic-producing strain of gabhs [ 11 ] . tonsillitis is primarily a clinical diagnosis. supportive tests include throat cultures, gabhs rapid antigen test, and anti-streptolysin-o (aso), anti-deoxyribonuclease b (anti-dnase b), antihyaluronidase and anti-streptokinase antibody titers [ 12 ] . other tests may be helpful based on clinical suspicion, for example, ebv specifi c serology or monospot (heterophile antibody) test, ebv polymerase chain reaction (pcr) or hsv pcr as needed. the monospot test is particularly insensitive in young children, with only 25-50 % of children under the age of 12 years infected with ebv having a positive monospot test [ 13 ] . specifi c ebv serology to detect antibodies against viral capsid antigens (vca) that includes vca-igg and vca-igm in conjunction with antibodies against epstein-barr nuclear antigen or ebna are the preferred diagnostic method in this age group. a real-time ebv pcr assay is helpful in patients with immunocompromising conditions and to confi rm the diagnosis in patients with negative serology but strong clinical suspicion of infection [ 14 ] . the most important step in diagnosis is distinguishing between viral and gabhs tonsillitis as anti-bacterial agents are not effective in the treatment viral tonsillitis. furthermore, with a few rare exceptions (e.g. arcanobacterium haemolyticum , neisseria gonorrhoeae and fusobacterium spp.) anti-microbial treatment is not benefi cial for bacterial causes of tonsillitis except gabhs given that there is not a signifi cant reduction in the rate of complications or in duration of clinical symptoms [ 7 ] . seventy percent of patients presenting with sore throat are treated with antibiotics while only 20-30 % have documented gabhs tonsillitis. antibiotic treatment may be associated with adverse drug events that range from mild diarrhea to severe allergic reactions. thus, the utility of these drugs must be determined in order to avoid potential selection of resistant organisms, exposure to adverse events associated with anti-microbial use, and extra cost. treatment of gabhs is instrumental in preventing the potentially long-term and life-threatening complications associated with this pathogen, specifi cally and most importantly, arf. treatment also aids in the control of acute signs and symptoms, prevention of suppurative complications, and decreased transmission of gabhs to close contacts [ 7 ] . throat pain and fever self-resolve by 1 week and 3-5 days, respectively, after onset if left untreated; if treated, both symptoms resolve within 3 days [ 15 ] . the organisms are eradicated from the pharynx after 10 days of treatment. arf can be prevented even if therapy is initiated after 9 days of onset [ 11 ] . of note, treatment does not prevent the development of psgn [ 7 ] . the infectious disease society of america (idsa) recommends testing for gabhs unless a patient presents with symptoms strongly suggestive of a viral etiology; examples of such symptoms include cough, coryza, rhinorrhea, stomatitis or hoarseness. testing for gabhs is also not indicated in children less than 3 years old. children in this age group do not present with classic symptoms of gabhs tonsillitis and the incidence of arf is rare, affecting approximately 0.2 % of children [ 7 , 9 ] . testing for gabhs in these children should only be pursued in the presence of other risk factors such as school-aged sibling with documented infection by gabhs, close household contact with diagnosis of symptomatic disease, or with personal or family history of a gabhs complication (arf) [ 7 ] . one of the most commonly used in-offi ce diagnostic tests for gabhs is the rapid antigen detection test (radt). this test is done via throat swab of the surface of either tonsil or tonsillar fossa and posterior pharyngeal wall. swabs of other areas of the oropharynx or oral cavity may lead to false negatives. an enzyme immunoassay test with turn-around times as little as 5 min is then done. it is 95 % specifi c and 70-90 % sensitive based on the type or manufacturer of radt used. in the case of a positive radt, children should be treated with antibiotics. in the case of a negative radt, the idsa recommends a throat culture be done during the same offi ce visit. due to the variability in sensitivity of rdta based on manufacturer, the high rate of gabhs in children and implications of complications, a throat culture is recommended in order to capture any false negatives. the rapid turnaround time for radt makes it useful for rapid identifi cation and treatment of gabhs. rapid treatment decreases the risk of spread of gabhs among close contacts, the amount of time missed from school or work for caregivers, and the duration and severity of acute signs and symptoms of gabhs tonsillitis [ 7 ] . throat cultures are recommended in children in the case of negative radt prior to the administration of antibiotics in order to avoid false negative results. a single throat swab has a 90-95 % sensitivity rate when done correctly. a throat swab similar to the radt test is done and is then either processed in an in-offi ce laboratory or sent to a microbiology laboratory. if the cultures are grown in-offi ce, specifi c instructions must be followed. the swab is processed on a sheep's blood agar plate and incubated at 35-37 °c for 18-24 h. while treatment decisions can be made based on growth patterns at 24 h, a plate with no growth should be re-examined at 48 h to ensure a correct diagnosis. two major disadvantages of using throat cultures for diagnostic purposes are the training and cost associated with accurate testing as well as delayed diagnosis due to processing time. however, even a delayed diagnosis can be benefi cial. studies show that treatment of gabhs tonsillitis can be delayed up to 9 days from the onset of symptoms and still effectively prevent complications such as arf [ 7 , 16 , 17 ] . therefore, regardless of the delay in treatment, throat cultures should be done in children with negative radt [ 7 ] . other testing options include anti-streptococcal antibody titers; however, these titers are not helpful in the diagnosis of acute gabhs tonsillitis. rather, they are indicative of previous infection. antibody titers become positive 3-8 weeks after an acute infection and may persist for up to a year after the resolution of the infection. thus, they may be useful in determining the etiology of complications [ 7 , 17 , 18 ] . children with recurrent tonsillitis are sometimes chronic carriers of gabhs with superimposed viral infections. up to 20 % of asymptomatic school aged children can be carriers of gabhs in the winter and spring months [ 7 , 19 ] . the idsa does not recommend identifi cation or treatment of these chronic carriers for several reasons. distinguishing chronic carriers from recurrent acutely infected children is not possible with the current diagnostic modalities, chronic carriers of gabhs are unlikely to spread bacteria to close contacts and they are at minimal to no risk of developing complications of gabhs [ 7 ] . moreover, eradication of gabhs from colonized tonsils and adenoids is much more diffi cult than treatment of acute gabhs tonsillitis. however, certain specifi c circumstances do call for treatment of chronic carriers of gabhs [ 7 ] . these indications, along with treatment options, are discussed below in the section entitled "treatment of tonsillitis." routine post-treatment radt or throat cultures to confi rm eradication of gabhs are not recommended. post-treatment testing can be pursued in the case of a patient at high risk for developing arf (personal or family history of arf) or recurrent classic symptoms of gabhs tonsillitis shortly after the completion of treatment. testing or treatment of asymptomatic household contacts is not recommended as it has not been shown to decrease the incidence of subsequent gabhs tonsillitis [ 7 ] . treatment of viral tonsillitis primarily consists of supportive measures including bed rest, hydration, analgesics, and oral hygiene. most cases of viral tonsillitis self-resolve in 3-4 days. recommended analgesics include acetaminophen and non-steroidal anti-infl ammatory drugs (nsaids). aspirin should be avoided due to the risk of reye's syndrome, a rare severe illness characterized by rapidly progressive encephalopathy with liver dysfunction and a mortality rate of up to 40 % in children and adolescents suffering from a viral infection, especially varicella-zoster or infl uenza, in association with the use of salicylates [ 20 ] . other nsaids such as ibuprofen or diclofenac can be used. nsaids and acetaminophen not only provide pain control but also act to reduce fever. corticosteroids have proven benefi cial in the reduction of the duration and severity of other signs and symptoms, but they do not affect pain levels. thus, they are not recommended for symptomatic control in acute tonsillitis [ 7 , 21 ] . acute bacterial tonsillitis is treated with anti-microbial therapy in addition to the supportive measures listed above. penicillins target the most commonly implicated pathogen, gabhs. they are narrow spectrum drugs with the greatest safety profi le and provide the highest effi cacy at a lower cost than other alternatives. furthermore, there have been no documented cases of penicillin resistant gabhs. a ten-day course of oral penicillin or amoxicillin or a one-time dose of intramuscular benzathine penicillin g is the treatment of choice. an amoxicillin suspension is preferred for younger children due to once a day dosing and better taste that facilitates improved compliance. while a clinical response should be achieved within 24-48 h of beginning antibiotic therapy, a 10 day course of antibiotics has been shown to achieve the maximum rates of pharyngeal eradication of bacteria [ 7 ] . patients with previous non-anaphylactic allergic reactions to penicillin can be treated with fi rst generation cephalosporins for 10 days. narrow spectrum fi rst generation cephalosporins such as cefadroxil and cephalexin are preferred over broad spectrum cephalosporins such as cefaclor, cefuroxime, cefi xime, cefdinir, and cefpodoxime. approximately 10 % of patients allergic to penicillins will also be allergic to cephalosporins. these patients can be treated with a 10 day course of clindamycin, clarithromycin or a 5 day course of azithromycin. erythromycin should be reserved for treatment resistant infections due to its high rate of gastrointestinal side effects. rate of gabhs antibiotic resistance in the united states are approximately 1 % to clindamycin and 5-8 % to macrolides [ 7 , 22 ] . ampicillin and oral penicillin-based antibiotics can cause a generalized papular rash in the setting of infectious mononucleosis. thus, if infectious mononucleosis is suspected, treatment with antibiotics is not recommended. the idsa discourages the use of several antibiotics for the treatment of gabhs tonsillitis. given the high prevalence of resistant strains of gabhs, tetracyclines are not recommended and trimethoprim-sulfamethoxazole does not effectively eradicate gabhs in acute tonsillitis. newer fl uoroquinolones such as levofl oxacin and moxifl oxacin have proven active against gabhs in vitro but no in vivo effi cacy has been documented. fluoroquinolones are also expensive, broad-spectrum antibiotics with emerging resistance to streptococcus pneumoniae worldwide and are not recommended in children 18 years of age or younger due to their potential for joint and cartilage toxicity [ 7 , 23 , 24 ] . recurrent tonsillitis can be treated with penicillin, cephalosporins, macrolides, or clindamycin. if tonsillitis recurs shortly after the completion of a course of antibiotics, intramuscular penicillin should be considered. alternatively, a 3-6 week course of a penicillin coupled with a beta lactamase inhibitor such as amoxicillin plus clavulanate has been shown to be effective in treatment of recurrent tonsillitis [ 7 ] . as discussed previously, routine treatment of chronic carriers of gabhs is not recommended. however, there are a few specifi c indications for treatment. according to the idsa and the american academy of pediatrics, chronic carriers should be treated in the following circumstances: (1) during a local outbreak of arf, psgn, or invasive gabhs infection, (2) outbreaks of gabhs pharyngitis in a closed community, (3) personal or family history of arf, (4) excessive family or caregiver anxiety about a gabhs infection, or (5) if tonsillectomy is being considered only on the basis of chronic carriage of gabhs. patients meeting any of the above criteria should be treated with oral clindamycin, oral penicillin plus rifampin, oral amoxicillin plus clavulanate, or intramuscular penicillin plus oral rifampin [ 7 , 11 ] . tonsillectomy should be considered for patients suffering from chronic or recurrent tonsillitis whose frequency of infection does not decrease despite appropriate antibiotic treatment and with no other explanation for tonsillitis. specifi c indications for tonsillectomy are further discussed in the section entitled "tonsillectomy. " peritonsillar abscess is one of the most common deep space head and neck infections in children. this collection of pus is thought to be formed most commonly as a result of spread of infection from the tonsils or the minor salivary glands of weber, found on the superior tonsillar pole. the abscess forms deep to the tonsillar capsule between the tonsil, the superior constrictor muscle, and the palatopharyngeus muscle. the most common location is superior and medial to the tonsil; however it can occur lateral to the tonsil or even inferior [ 3 ] . peritonsillar abscess comprises 30 % of all soft tissue head and neck infections. in patients younger than 20 years old, the incidence of peritonsillar abscess is 0.82-0.94 cases per 10,000 patients. it is most commonly diagnosed in adolescents and young adults, but can occur in any age group with an average age at diagnosis of 13.6 years old [ 25 ] . peritonsillar abscesses are generally polymicrobial, representing the normal fl ora of the oral cavity and tonsillar area. aerobes such as gabhs, streptococcus viridans , staphylococcus aureus and haemophilus infl uenza , and anaerobes such as bacteroides spp., fusobacterium necrophorum and peptostreptococcus spp. that make up normal oral fl ora are frequently reported [ 26 ] . the most commonly isolated pathogen is gabhs. findings at presentation commonly include fever, odynophagia, trismus, erythema, bulging of the soft palate with deviation of the uvula, unilateral otalgia, drooling, and "hot potato" voice ( fig. 10.3 ). trismus is a key fi nding in patients with peritonsillar abscess and is likely related to peritonsillar infl ammation of the pterygoid muscles. inability to swallow or signifi cant odynophagia usually results in dehydration in younger patients. the diagnosis of peritonsillar abscess is typically a clinical one; however, computed tomography (ct) can be utilized in atypical presentation such as when trismus limits the utility of a physical exam, or in uncooperative young children (fig. 10.4 ) . while the use of intra-oral ultrasound for diagnosis of peritonsillar abscess has been suggested, it is not yet widely used [ 27 ] . an elevated white blood cell count and c-reactive protein are commonly found. throat culture and testing for infectious mononucleosis may be helpful to evaluate for other disease processes. complications of a peritonsillar abscess include airway distress, parapharyngeal or retropharyngeal abscess, aspiration pneumonia, and erosion into the carotid sheath. lemierre's syndrome, a severe disease characterized by thrombophlebitis of the internal jugular vein with metastatic septic emboli as a result of an acute oropharyngeal infection, is another potential complication [ 28 ] . defi nitive treatment consists of incision and drainage or needle aspiration of abscess contents, antibiotics, and elective tonsillectomy after resolution of infection. in rare cases, quinsy tonsillectomy at the time of infection can be considered. indications for quinsy tonsillectomy are discussed below in the section entitled "quinsy tonsillectomy." drainage of the abscess leads to immediate improvement in pain and hastens recovery. drainage can be done with local anesthesia in the cooperative awake patient or in the operating room. children are more likely to undergo drainage in the operating room. when performing awake, transoral drainage, a pre-procedure dose of an opioid can be helpful with patient tolerance and the degree of trismus. needle aspiration or incision and drainage appear to have equal effi cacy [ 29 ] . purulent material should be sent for aerobic and anaerobic culture. complications of drainage include bleeding, airway obstruction, and possible puncture of the carotid artery. ten to twenty percent of children undergoing incision and drainage or needle aspiration of a recurrent peritonsillar abscess will require a subsequent tonsillectomy for persistent symptoms or residual abscess contents [ 3 , 30 , 31 ] . peritonsillar abscesses recur 9-22 % of the time depending on the defi nition of recurrence which varies by practitioner and system [ 29 , 32 ] . the use of tonsillectomy as a treatment for peritonsillar abscess remains controversial. it is favored by some practitioners in the setting of recurrent peritonsillar abscesses. a tonsillectomy at the time of infection (quinsy tonsillectomy) can be considered in rare cases (see section entitled "quinsy tonsillectomy"). an interval tonsillectomy 4-6 weeks after the resolution of infection may be performed in patients with recurrent tonsillitis. antimicrobials are used as adjunctive therapy for peritonsillar abscess. combination therapy with penicillin and metronidazole is 98-99 % effective [ 32 ] . first generation cephalosporins can be used in patients with a non-anaphylactic penicillin allergy. patients with previous anaphylactic reactions to penicillin can be treated with clindamycin, clarithromycin or azithromycin. supportive therapy with hydration, pain control, and corticosteroids should also be administered [ 29 , 30 , 32 , 33 ] . tonsillectomy is one of the most common ambulatory surgeries performed in the pediatric population. recent studies show that 530,000 tonsillectomies are performed per year in children less than 15 years old in the united states [ 3 ] . a bimodal distribution of tonsillectomies is observed with the two most frequent age groups being 5-8 years old and 17-21 years old [ 31 ] . a tonsillectomy entails the removal of the palatine tonsils with their capsule from the tonsillar fossa. the indications for tonsillectomy include recurrent infection and sleep disordered breathing (sdb) . the american academy of otolaryngology-head and neck surgery (aao-hns) recommends that children that suffered from greater than seven infections in the last year or greater than fi ve infections per year in the last 2 years or greater than three infections per year in the last 3 years and fulfi lled one or more of the following criteria should undergo a tonsillectomy with or without an adenoidectomy: temperature greater than 38.3 °c, cervical adenopathy, tonsillar exudate, or positive test for gabhs. children that do not meet these criteria but have multiple antibiotic allergies or intolerances or suffer from periodic fevers, aphthous stomatitis, pharyngitis and adenitis (pfapa syndrome) or with a history of peritonsillar abscesses may also be considered candidates for tonsillectomy. a signifi cant amount of missed school or work for patients and/or caregivers due to sdb or recurrent infections should also be considered when creating a treatment plan [ 3 ] . the aao-hns emphasizes that children that do not meet this criteria may not signifi cantly benefi t from undergoing a tonsillectomy. guidelines suggest close observation and recording of frequency of episodes and symptoms instead of invasive intervention. the use of tonsillectomy as treatment of pfapa is still controversial. the aao-hns recommends consideration of tonsillectomy in these cases depending on the frequency of symptomatic illness, severity of infection and the patient's response to medical management, commonly steroid therapy [ 3 ] . two randomized control trials showed statistically signifi cant benefi t of tonsillectomy to treat pfapa [ 34 , 35 ] . tonsillectomy is recommended in the case of sdb if caused by hypertrophic tonsils and there is signifi cant possibility of improvement of other co-morbidities caused by sdb. examples of such comorbidities include growth retardation, poor school performance, and behavioral problems. the decision to undergo surgery must be made in close communication with the child's caregiver(s) [ 3 ] . complications of a tonsillectomy include throat pain, post-operative nausea and vomiting, dehydration due to delayed oral intake, post-obstructive pulmonary edema, velopharyngeal insuffi ciency and nasopharyngeal stenosis in the case of concurrent adenoidectomy, hemorrhage and death. the most common morbidity of tonsillectomy is throat pain. treatment includes over the counter analgesics and hydration. commonly used analgesics include acetaminophen and acetaminophen plus hydrocodone. the use of non-steroidal anti-infl ammatory drugs (nsaids) is generally not recommended due to a potential risk of post-operative bleeding. however, several studies show that nsaids do not signifi cantly increase the number of post-tonsillectomy bleeds requiring surgical or non-surgical intervention and that they decrease the incidence of post-operative vomiting [ 36 ] . other studies show that while aspirin is associated with increased risk of post-tonsillectomy bleeding, non-aspirin nsaids do not signifi cantly increase this risk with one exception [ 37 ] . intravenous ketorolac has been associated with post-tonsillectomy hemorrhage rates as high as 17 % [ 3 , 38 ] . studies show that post-tonsillectomy pain in children is undertreated by caregivers, primarily due to caregiver attempt at balancing pain control with overtreatment [ 39 ] . the aao-hns guidelines state that no specifi c medication or dosing interval (as needed versus scheduled) has been proven superior. it is most important that caregivers assess and re-assess a child's pain level even when the child does not spontaneously complain of pain [ 3 ] . post-tonsillectomy hemorrhage is a much less common but the most concerning complication of tonsillectomy. it is the most common complication brought to the attention of medical personnel. post-tonsillectomy hemorrhage is stratifi ed based on time after surgery in order to help delineate the cause of bleeding. primary hemorrhage is bleeding occurring within the fi rst 24 h after tonsillectomy and occurs in 0.2-2.2 % of patients. the most common cause is surgical technique or reopening of blood vessels. secondary hemorrhage is bleeding that occurs more than 24 h after surgery, most commonly on post-operative days 5-10. secondary hemorrhage is most commonly due to sloughing of the eschar as the tonsillar bed heals and occurs in 0.1-3 % of patients [ 40 ] . the incidence of post-tonsillectomy hemorrhage has been noted to range signifi cantly due to the defi nition of clinically signifi cant bleeding and the consideration of primary or secondary hemorrhage only. the use of specifi c surgical techniques to reduce the incidence of post-tonsillectomy hemorrhage is still under investigation [ 40 ] . bleeding following a tonsillectomy requires clinical evaluation and profuse bleeding may be treated with cauterization, inpatient observation, transfusion, or surgery. the rate of mortality associated with tonsillectomy has been cited as less than 1 in 20,000 [ 41 ] . the most common causes of tonsillectomy-associated death include bleeding and opioid related respiratory depression [ 31 ] . a quinsy tonsillectomy is done at the time of tonsillar infection. while tonsillectomy is generally recommended after the resolution of infection, it can be considered at the time of infection in a select few cases. indications include peritonsillar abscess in younger children; recurrent or unresponsive cases of peritonsillar abscess or in the setting of previous history of deep neck abscess, and peritonsillar abscess presenting with severe airway compromise [ 42 ] . due to the infl ammation in an infected fi eld, the risk of intraoperative, and potentially post-operative, bleeding is increased. thus, candidates for quinsy tonsillectomy must be carefully and selectively chosen. tonsillitis and peritonsillar abscess are frequently seen in the pediatric population. antimicrobial management should be directed by radt or positive throat cultures. in the case of peritonsillar abscess, acute drainage of the pus is the defi nitive treatment in addition to the use of adjunctive antimicrobial therapy. quinsy tonsillectomy can lead to bleeding complications and is typically reserved for rare cases. oral cavity and oropharynx gray's anatomy for students clinical practice guideline: tonsillectomy in children national hospital ambulatory medical care survey: 2011 emergency department summary tables antibiotic prescribing by primary care physicians for children with upper respiratory tract infections principles and practice of pediatric infectious diseases clinical practice guideline for the diagnosis and management of group a streptococcal pharyngitis: 2012 update by the infectious diseases society of america burden and economic cost of group a streptococcal pharyngitis incidence and impact of selected infectious diseases in childhood detection of fusobacterium necrophorum subsp. funduliforme in tonsillitis in young adults by real-time pcr laboratory tests in the diagnosis and follow-up of pediatric rheumatic diseases: an update infectious mononucleosis clinical evaluation of a quantitative real time polymerase chain reaction assay for diagnosis of primary epstein-barr virus infection in children antibiotics for sore throat the role of the streptococcus in the pathogenesis of rheumatic fever prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientifi c statement from the american heart association rheumatic fever, endocarditis, and kawasaki disease committee of the council on cardiovascular disease in the young, the interdisciplinary council on functional genomics and translational biology, and the interdisciplinary council on quality of care and outcomes research: endorsed by the the human immune response to streptococcal extracellular antigens: clinical, diagnostic, and potential pathogenetic implications group a streptococci among school-aged children: clinical characteristics and the carrier state nonsteroidal anti-infl ammatory drugs exposure and the central nervous system oral dexamethasone for the treatment of pain in children with acute pharyngitis: a randomized, double-blind, placebo-controlled trial community-based surveillance in the united states of macrolide-resistant pediatric pharyngeal group a streptococci during 3 respiratory disease seasons the use of systemic and topical fl uoroquinolones the use of fl uoroquinolones in children pediatric deep space neck infections in microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses peritonsillar abscess in children: a 10-year review of diagnosis and management lemierre syndrome: two cases and a review an evidence-based review of the treatment of peritonsillar abscess medical and surgical treatment of peritonsillar, retropharyngeal, and parapharyngeal abscesses mosher award thesis. peritonsillar abscess: incidence, current management practices, and a proposal for treatment guidelines an evidence-based review of peritonsillar abscess pediatric peritonsillar abscess: an overview effectiveness of adenotonsillectomy in pfapa syndrome: a randomized study a randomized, controlled trial of tonsillectomy in periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome nonsteroidal anti-infl ammatory drugs and perioperative bleeding in paediatric tonsillectomy postoperative hemorrhage with nonsteroidal anti-infl ammatory drug use after tonsillectomy: a meta-analysis intraoperative ketorolac and posttonsillectomy bleeding tonsillectomy for recurrent sore throats in children: indications, outcomes, and effi cacy hemorrhage following tonsillectomy and adenoidectomy in 15,218 patients revisit rates and diagnoses following pediatric tonsillectomy in a large multistate population immediate tonsillectomy: indications for use as fi rst-line surgical management of peritonsillar abscess (quinsy) and parapharyngeal abscess key: cord-257299-z9u12yqb authors: mansi, n.; de maio, v.; della volpe, a.; ripa, g.; malafronte, l.; de filippis, c. title: ear, nose and throat manifestation of viral systemic infections in pediatric patients date: 2009-12-31 journal: international journal of pediatric otorhinolaryngology doi: 10.1016/s0165-5876(09)70006-0 sha: doc_id: 257299 cord_uid: z9u12yqb abstract objective/methods an exhaustive review of literature was performed to investigate available data and evidences regarding pediatric otolaryngologic manifestations of viral systemic infections. results/conclusions modern otolaryngologists should be familiar with viral systemic infections since many have head and neck manifestations. cooperation between otolaryngologist, paediatrician and virologist can be considered and excellent tool in diagnosis and treatment of these diseases in particular when complications occur. there are multiple systematic viral infections that can manifest themselves in orl related organs. their actions can work directly or indirectly causing an alteration in the human immune system and a consequent secondary bacterial invasion. notable advances in the diagnosis and treatment of viral infections have been mitigated by the appearance of new pathological processes, for example aids, which often has its initial manifestations in orl regions. table 1 is a list of illnesses affecting different anatomical sites and the viral etiologies that commonly strike each particular location. considering the vast nature of the subject, we subdivided our treatment into three parts corresponding to the same groups of interrelated viral illnesses: -viruses that can cause deafness. -viruses that can cause inflammation in the upper respiratory tract. -viruses particularly relevant to ent (infectious mononucleosis, papillomatosis, herpes infections). ascertaining specific viral causes of most infections is neither necessary nor cost-effective, and should be reserved only for specific cases. clinical and epidemiological acumen remain the basis for a presumptive diagnosis. when a specific diagnosis is necessary, diagnostic procedures based on biochemical and molecular biological processes provide sensitive, specific and rapid results [1] . in most viral infections, immunity to re-infection generally lasts a short period of time due to the host's limited immunological response or, rather for an antigenic change in the virus. viral pathologies that can cause deafness can be congenital, appear in either the pre-natal or postnatal period and can also be acquired upon contact with the pathogen [2] [3] [4] (table 2 ). in particular, the hearing damage caused by congenital infections can be part of a severe syndrome (such as "congenital rubella syndrome") but more frequently it is the first and only manifestation of intrauterine infection. common childhood viral infections, such as measles and mumps are probably an unrecognized cause of acute or progressive damage to hearing [5] . in prenatal deafness, a pathogen introduced during pregnancy can provoke an arrest or alteration of the normal development of the ear, even causing lesions on the already-formed hearing mechanism [6] . the most serious lesions manifest themselves in the first three months of pregnancy, especially between the seventh and tenth week, when the cochlea is developing; this would be considered a case of embriopathy. fetopathy refers instead to lesions that form between the fourth month of pregnancy and birth. since the hearing organ has already formed in these cases, patients do not generally suffer serious alterations although the inner ear is certainly sensitive. the viruses that most frequently cause prenatal deafness are rubella and citomegalovirus (cmv). rubella is caused by an rna virus of the togaviradae family of the rubivirus genus. congenital rubella is typically passed on to the fetus from a primary infection in the mother. the virus invades the upper airways of the mother causing viremia and spreading into different sites including the placenta. it has been hypothesized that in the first gestational phases, the rubella virus provokes a chronic intrauterine infection. fetal infection in the first trimester, particularly in the first 8-10 weeks, has an extremely high risk of malformations such as hypoacusia, cardiac and ocular defects (gregg triad); however, if the rubellum infection is contracted in the second or third trimester, it results in hypoacusia and pigmented retinas. thus, the more precocious the maternal rubellum, the greater the risk of fetal infections and the more serious the fetal malformations (100% in the first month, 80% in the first trimester, 70% in the second trimester and 30% in the third). this reduction is likely due to either a maturation of the placenta after the first trimester which limits the transfer of the virus, or the greater resistance of the differentiated cells [5] . the deriving hypoacusia is generally sensorineural and bilateral and at birth can already be progressive or it can manifest itself later. the hearing damage seems to be caused by a "teratogenic" effect of interference with the normal development of the organ at the cochlear level [6, 7] . unlike other congenital infections, rubella is easily prevented. between 12 and 15 months of age, a livevirus rubellum vaccine is administered along with a measles and mumps vaccination, giving the patient immunity to rubellum for about 15 years (mmr); a booster vaccination is administered before elementary or middle school. women of child-bearing age who are not immune to rubella must undergo vaccination and not get pregnant in the following three months. vaccination immediately after giving birth is advisable for mothers at risk of being infected. citomegalovirus (cmv) is a dna virus that belongs to the herpesviridae family. it can go into latency and then reactivate and has been isolated in various sites including saliva, urine, breast milk, sperm, brain fluid, and amniotic fluid. congential cmv infection is thought to be derived from transplacental infection from a primary or recurring maternal infection occurring in the first half of pregnancy. prenatal cmv infection is contracted by contact with infected cervical secretions, breast milk, or blood derivatives. it is believed that maternal antibodies have a protective function and that most of these newborns are either born asymptomatic or are not infected by the virus in the case of contact. many women who are infected by cmv during pregnancy are asymptomatic, but occasionally develop an illness similar to mononucleosis. it is still unclear if more serious lesions are a consequence of a precocious maternal infection or of a later one during the course of gestation. nearly 10% of children with congenital cmv infection are symptomatic at birth. manifestations include delayed intrauterine growth, premature birth, microcephalus, jaundice, petechia, hepatosplenomegalia, periventricular calcification, corioretinitis e pneumonia. the virus causes deafness by infecting the inner ear and altering the organ of corti. moreover, it can cause malformations of the labyrinth of ethmoid and at the same time also lesions on the auditory tract due to secondary toxicity. the hypoacusia that establishes itself is sensorineural, almost always bilateral, and profound, generally regarding acute tones. symptomatic newborns have a mortality rate of up to 30% and 70-90% of those who survive have neurological deficits such as hearing loss, mental retardations and visual disturbances [8] [9] [10] . a vaccine for cmv is still under research. exposure to the disease in non-immunized pregnant women must be controlled, despite the fact that cmv is ubiquitous everywhere. since it is frequent in children who attend preschools, pregnant women must observe all the common norms of good hygiene after contact with or being exposed to the urine or expectorate of such children [11, 12] . in post-natal deafness, numerous infective illnesses can be responsible for serious damage to the viii nerve and the cochlear apparatus. a large part of hearing defects arising in childhood can be traced back to the intrauterine period. the most frequent forms are: viral meningoencephalitis (arbovirus, herpesvirus, mixovirus, poxvirus, etc.), mumps, chickenpox and measles. meningoencephalitis can be primitive or constitute the secondary complication of a viral infection. the forms of primitive meningoencephalitis can be both epidemic (arbovirus, poliovirus, echovirus, coxsackievirus illnesses), and sporadic (herpes simplex, varicella zoster, parotite) [13] . secondary encephalitis, such as complications of a viral infection, probably have an immunological, pathgenic mechanism. secondary encephalitis to rubella, mumps, measles, smallpox, cow's pox and other less defined illnesses are all examples. currently, deafness caused by meningoencephalitis is not infrequent among the post-natal causes of deafness; in some cases it can be caused by a virus that, before birth, reach the cochlea via the external hearing conduct by way of the vascular system, causing a relatively symmetrical bilateral sensorineural hypoacusia which is either mild-serious or profound. in other cases, deafness is due to a meningoencephalital localization of liquor infection in the first four weeks of life as a complication of neaonatal sepsis (25%). deafness caused by meningoencephalitis occurs more often in males and is found in 2/10,000 neonates born at full term and in 2/1,000 low-weight neonates. no vaccines exist for the described viral forms. mumps (parotitis) is instead caused by a paramixovirus, spread through drops of infected saliva or through direct contact with material contaminated by infected saliva. the virus probably penetrates the body through the mouth. it can be found in saliva 1-6 days before the appearance of the swelling of the salivary glands and lasts throughout the duration of the illness (usually 5-9 days). an infection usually results in permanent immunity, even when there is unilateral swelling of the salivary glands. although the illness can occur at any age, most cases occur in children between 5 and 10 years of age; it does not usually occur in children under 2 years old. breast-fed children less than one year old are usually immune. the incubation period is 14-24 days. deafness can be a complication in 5/10,000 cases of mumps. in 80% of cases, deafness is sudden and unilateral in the context of an acute infection in association with aseptic meningitis and often accompanied by tinnitus, ataxia, and vomiting. hearing loss is profound and permanent for high frequencies and can go unrecognized. damage is confined to the cochlear duct and consists in the degeneration of the vascular strip of the corti organ, the degeneration of the upper membrane, usually more serious on the basal curve of the cochlea. active immunization is obtained through a single-dose, live-virus inoculation between 12 and 15 months of age with a mmr vaccine. a booster dose is administered before starting elementary or middle school. measles, caused by a paramixovirus, is extremely contagious and is spread primarily through either the nasal and oral excretions of an individual in the prodrome or precocious eruptive stage of the disease or through the nuclei of drops dispersed in the air. the contagious stage of the illness extends from 2 to 4 days before the appearance of the eruptions until 2-5 days after their appearance. the virus disappears from the nose and pharynx secretions as soon as the eruption on the skin has cleared up. the incubation period is 7-14 days. measles virus causes permenant, bilateral deafness in 1/1000 cases. deafness appears suddenly at the same time as the cutaneous rash. the viral infection of the inner ear spreads through the vascular strip and destroys the structures of the cochlea as well as most of the nervous and ganglionic and fibers [14] . measles infection can be avoided by administering a reduced, live-virus vaccine to children between the ages of 12 and 15 months (mmr). the vaccine confers long-term immunity and provokes an antibody response similar to that of natural measles. in some cases, the vaccine can provoke a light or asymptomatic infection that is not contagious. sensitive subjects at risk of contracting measles can be protected if the live-vaccine is administered within 2 days of exposure. in other cases, such as pregnant women, or children under one year of age, an immunoglobuline specific measles vaccine (mig) or a 0,25 ml/kg im dose of serum immunoglobulin may be administered. chickenpox is caused by the varicella-zoster virus (herpesvirus) and represents its acute, invasive phase, while the reactivation from its latent phase causes the herpes zoster illness. it is believed that chickenpox, which is extremely contagious, is transmitted through drops of saliva which are infected and even more infective during the brief prodromic period and the first phase of eruption. incubation period is 14-16 days and transmission is considered possible 10-21 days after exposure. the deafness it causes can lead to the destruction of the nervous and sensorial cells of the neuroepithelia through a process of neurolabyrinthitis which can result in severe bilateral, sensorineural hypoacusia [15] . chickenpox can be prevented by inoculating with a reduced, live-virus vaccine in all healthy children between 12 and 18 months of age, after which children who lack immunity to chickenpox may be vaccinated at any time. subjects over 13 years old who have not been immunized must receive two doses of the vaccine, with a period of 4-8 weeks between doses. the severity of the disease can be lessened by administering an immunoglobuline anti-zoster (zig) or anti-varicella-zoster (vzig) within 96 hours after exposure. its use, however, is restricted to subjects at risk, like those affected by leukemia, immunodeficiency syndromes or other serious pathologies, and pregnant women. neonates with mothers who were infected by chickenpox five days before giving birth or two days after are also candidates for such treatment [16, 17] . viral respiratory infection is almost always a benign pathology. its beginning is connected with the socialization of the child, and as such is most frequent during preschool. it noticeably interferes with the child's wellbeing and provokes significant medical-social costs.unfavorable environmental factors (atmospheric pollution, passive smoking, etc.), precocious socialization, and predisposing immunological factors with immunological immaturity could all be predisposing factors. viral respiratory infections are characterized by a series of acute episodes that can involve the entire respiratory system or a single sector (pharyngotonsillitis, otitis, rhinosinusitis, laryngitis, bronchitis, pneumonia) [18] [19] [20] [21] . the damage that a viral infection can inflict on the mucous membranes of the upper respiratory tract are influenced by the reduction of the mucous flux and phagocytes as well as the increase in the bacteria's adhesiveness to mucus cells [22, 23] . an upper-resipiratory viral infection is characterized by multiple processes. first, the virus replicates itself in the epithelium, spreading fragments of the disintegrated cells into respiratory secretions and demonstrating the presence of the virus, viral peptides, or viral nucleic acids [24, 25] . the host then responds to the infection by producing a range of cellular products. some, such as alpha-interferon, are specifically anti-viral. others, such as interleukin, are aspecific. specific antibodies are produced in sequence, for example igm followed by igg and iga; the comparison of a high level of igm without an increase in igg is an index of recent infection (the comparison of blood examinations confirms the diagnosis but is only clinically useful for epidemiologic purposes. acute rhino, pharengeal and tonsillar inflammation, caused by viral infections [26] are some of the most common deseases found in pediatric populations. less frequently, the pharangeal-tonsillar forms are accompanied by an involvement of the oral and or respiratory tract mucosa [27] [28] [29] . such infections, in anglo-saxon countries, the term, upper respiratory tract infection (urti) or "common cold" is used to describe an inflammation of the upper airways [30] . the episodes, which often reoccur, effect mostly preschool-age children and have socioeconomic repercussions, which are not related to the gravity of the pathology, but mostly to the increase in the requests for visits to the doctor, the costs incurred for treatment and the days of school and work lost by the children and the parents who must look after them. the etiology of the acute forms in the respiratory airways is, initially, of a viral nature in most patients, with later, secondary bacterial infections on the mucous lesions caused by the viral agents [31] . the transmission of the pathogens responsible for the urti frequently occurs in public locations by direct or indirect contact with the nasal secretions or plugge drops from infected subjects. seasonability, which could increase or reduce sensitivity to such infections, constitutional factors, and an incomplete maturation of the immune system of the child are hypothesized to be pathogenic mechanisms. multiple viruses are responsible for these infections as described in table 1 . the course of acute, unspecific viruses is quite variable but almost always concludes with a recovery within 2-5 days as long as other complications do not develop. the most common complications are infections such as otitis media (mostly in younger children), rhinosinusitis, satellite lymphoadenitis, spreading of the infection into the lower respiratory tract and obstructed respiration, and bronchial spasms in subjects with bronchial hyperactivity. occasionally respiratory viruses are responsible for clinical pictures described as the common cold [32] , caused by picornavirus (rhinovirus, echovirus and coxackievirus), and influenza syndrome [8, [33] [34] [35] , caused by influenza viruses that initially strike the epithelium of the respiratory mucous membranes which other viral strains attach themselves to, aggravating and complicating the original clinical portrait [36, 37] . both herpangina and laryngotracheitis have a unique clinical picture. herpangina is an extremely contagious illness caused by a coxackievirus characterized by a presence of a vesicular exanthema at the velopharyngeal mucous level and acute or croup laryngotracheitis [38] [39] [40] [41] when viral infections are associated. the infections are caused by diverse viruses but more frequently by type 1 and type 2 parainfluenza viruses [42] [43] [44] , which cause an inflammation of the tracheal and subglottic muscous membrane with a charateristic symptomology (inspiratory stridor and barking cough) occasionally relapsing with serious, obstructing respiratory complications [45] [46] [47] . the varicella-zoster virus (vzv) belongs to the herpesvirus group. it is a dna virus that gives rise to chickenpox as a primary infection and to herpes zoster (hz) as a localized relapse due to modifications of the pathogenic power of the virus and/or alterations of cellular immunity [38, 48, 49] . hz is an acute cutaneous-nervous illness that is locally circumscribed and provoked by a resurgence of the vzv acquired during infancy and latent in one or more of the more sensitive ganglia of the dorsal roots of the spinal marrow and/or cranial nerves for a prolonged period of time (often decades); during the latency period the virus does not replicate itself or give any sign or symptom of its presence [50] [51] [52] . in particular, at the auricular level, the illness takes on the name herpes zoster oticus but it is also described in the auricular zone as herpes zoster auris or ramsay hunt illness, in honor of the author who, in 1907, described its characteristics and its correlation with the geniculate ganglion [53, 54] . the illness is caused by a reactivation of the vzv in the geniculate ganglion of the facial nerve; through the sensitive nervous fiber, the virus reaches the skin and causes a characteristic centrifugal root vesicular eruption. we can clinically define four stages according to the involvement of the vii n.c. the diffusion of the virus from cell to cell must be impeded with the use of antiviral drugs (5 mg/kg acyclovir administered intravenously per day in three daily doses for 7-10 days followed by an oral administration for another 7 days); results of treatment with more recent antiviral drugs (such as famciclovir and valaciclovir) are promising, while a significant inflammatory reaction reactive in the nerve must be treated with cortisonebased anti-inflammatory medication (1 mg/kg/daily for ten days) and sometimes with surgical decompression [13] . analgesics and local antiseptics should be added to treament with cortisones and antiviral medication. laryngeal papillomatosis (lp) [55, 56] is caused by subtypes of the human papilloma virus (hpv) which is a member of the papova family of viruses [57] . seventy subtypes have been described, but only hpv 11, hpv 6, and more rarely hpv 16 are specifically associated with laryngeal papillomas [58] [59] [60] . typical of such a pathology is the multifocal nature of the lesion (>85% of cases), localized on the vocal cords in 60% of cases but also involving the upper-glottic plain (35%), the oropharynx, the bronchial tree and, rarely, the cervical esophagus. in the united states, the annual incidence rate of laryngeal papillomatosis is 4.3/100,000 in children and 1.8/100,000 in adults, with a prevelance of 5.7/100,000 [61, 62] . this data is substantially analogous to that revealed in a 1991 danish study [63] which registered an annual incidence in children of 3.6/100,000. histologically, papilloma cosists of a cartilaginous fiber scaffolding with the presence of connective vascular tissue its surface surrounded by squamous epithelium. keratinizing aspects are not observed on its surface. the course of this pathology is characterized by frequent relapses and aggravations that require frequent and repeated laryngoscopy and bronchoscopy to ablate the rapidly forming pappillose formations and to avoid obstruction of the airways [64] . even if the illness is usually resolved by a spontaneous recovery, some cases can move toward an unfavorable prognosis at any time for no recognizable reason and involve the trachea, the bronchi and the lungs [65] . it is believed that hpv 11 has a greater propensity for a distal, pulmonary diffusion and that, moreover, therapeutic action, such as tracheotomy or repeated endolaryngeal ablation can favor the distal insemination of papillomas. the tracheal, bronchial, and pulmonary involvement occurs, according to various authors, in 2-4% of cases. malignant degeneration of the laryngeal papillomatosis, is a rare, but serious event and leads to an unfavorable prognosis. most described cases involve adults who have other risk factors, such as the use of tobacco, long-term illnesses, and previous exposure to radiation due to radiation therapy for papillomatosis. there is a greater probability of malignant transformation with hpv 16 but also hpv 6 and 11 are capable of oncologically transforming the nature of a cell culture [66] . in surgical treatment of laryngeal papillomatisis, many techniques are used: asportation with tweezers via indirect laryngoscopy, electro-cauterization, cryosurgery, direct asportation in larynfissure, endoscopic asportation with microlaryngoscopy in suspension. currently, most surgeons prefer endoscopic laser surgery for its high precision and the haemostatic control which the technique permits [10] . more recent techniques include argon laser photo sensitization and hematoporphyrin derivatives, known as photodynamic therapy [67, 68] , and the technique with scaples and rf ("coblation") which seems to avoid the modest heat damage and the edema which results from the use of the laser [69, 70] ; the same advantage is shared by ablation with microdebrider which is also more rapid than excision by laser. that is why it is coming ever closer to replacing the co 2 laser as the ablative method of choice for use on children [71] . despite the radical nature of the treatment, relapse is the norm. this makes reiterated procedures necessary with the possibility, occasionally, of having to resort to a tracheotomy. such a procedure should be avoided for as long as is possible because of the recognized possibility of colonization on the part of the papillomas in the region of the tracheostomy and tracheobronchial tree. the risk of the tracheobronchial tree being colonized is also believed to be a consequence of the repeated intubations. the need to lengthen the amount of time between surgical asporation of the papillomas and the possibility of complete medical resolution have spurred many researchers to find adjuvant or resolving treatments. recent studies have supplied a way to identify adjuvant therapies to control papillomatosis and its relapses such as interferon-alpha [56] , acyclovir [72] , indolo-3-carbinolo [73] , retinic acid [74] , metotressato, cidofovir [75] [76] [77] [78] . even if the above therapies have sometimes significantly reduced relapses of papillomas, we believe the most effective to be intralesional injection of cidofovir associated with surgical treatment [76] . however, none of them are able to eradicate the hpv genome from the mucous cells of the respiratory tract [79] . the most promising therapies for pl are based on both therapeutic and prophylactic hpv vaccines that are currently in experiemental phases [56, 80, 81] . the epstein-barr virus (ebv) or human herpesvirus 4 is a ubiquitous gammaherpesvirus that infects more than 95% of the world's population. the most common manifestation of the primary infection of this organism is infective mononucleosis (im), a sometimes acute, but often asymptomatic clinical syndrome which more often strikes children, adolescents, and young adults [82] . it is a self-limiting lymphoproliferative illness connected to a first contact with the epstein-barr virus. the virus generally comes into contact with the mucous membranes of the oropharanx where it causes a localized primary infection from which it can circulate through the bloodstream.the period of incubation is not known, and to be the source of infection, is often misunderstood, even if it is known that it is mainly spread orally. in particular, the cells which host cells are mainly the b-lymphocytes and the cells of the human nasalpharanx are where the virus replicates itself. the b-lymphocytes transformed by ebv are the target of a multiform immune response. the immune response (production of antibodies) documents a primary ebv infection. the cellular immune response, consisting in part of the induction of an activated, postive t-lymphocyte cd8, is mostly responsible for atypical lymphocytes which is the consequence of a primary ebv infection. the virus can be found in the oropharangeal secretions of 15-25% of healthy adults who test positive for ebv. the reactivation of ebv is generally asymptomatic, the opposite of that of the herpes simplex and varicella-zoster virus. ebv is relatively labile. it has not been isolated from environmental sources and it is not very contagious. in the majority of cases, it is believed that the incubation period is 30-50 days. the virus can be spread by the transfusion of blood derivatives but is more frequently passed on by oropharangeal contact (kissing) between a non-infected subject and a healthy carrier that asymptomatically secretes the virus from the oropharynx. during early childhood, infection occurs more frequently in lower socioeconomic classes and in conditions of overcrowding [83] . ebv has also been associated with african burkitt lymphoma and some b-cell neoplasias in immunodepressed patients (especially transplant recipients, hiv or ataxia-teleangectasia patients) and to nasalpharangeal carcinoma [29, 84, 85] . these associations are based on seriologic evidence of an increased ebv activity and on proof of nuclear antigens (epstein-barr nuclear antigens, ebna) and of ebv dna found in tumor biopsies. it has been postulated that ebv places a role in some b-cell lymphomas, polyclonally stimulating and transforming the b-lymphocytes, making them more susceptible to a successive chromosome transfer to an evolution toward an oligoclonal or monoclonal lymphoproliferation. the classic symptomology of mi includes fatigue, fever, inflammation, lyphoproliferation, however, patients can also present all or only some of these symptoms. ebv infection in children is usually asymptomatic or with a light symptomology. usually patients present with an illness that has lasted several days to a week, followed by fever, inflammation, and adenopathy. fatigue is usually highest in the first 2-3 weeks. fever reaches its peak in the afternoon or early evening with a temperature of around 39.5â°c, but can even reach 40.5â°.when fatigue and fever are the dominant signs (the so-called typhoid form), the beginning and the resolution can take longer. inflammation can be serious, painful and sedating and can resemble streptococcica inflammation. lymphoadenopathy can involve almost any group of lymphnodes but is usually asymmetrical; anterior and posterior cervical adenopathy is often relevant. the enlargement of only one lymphnode or a group of lymphnodes can be the only manifestation; in these cases, studies of the heterophiles can forgo lymph nodal biopsy or help the interpretation of alarming histopathological aspects. splenomegaly, present in around 50% of cases, is at its maximum during the second and third weeks, manifesting itself through pain the upper left quadrant. slight hepatomegaly can also be present as well as a pain on the hepatic percussion. less frequent signs are malcularpapular eruptions, jaundice, periorbital edema, and palatal exanthema [40] . infective mononucleosis is usually self-limiting. the duration of the illness is variable, usually about 2 weeks, but generally 20% of patients can go back to school or work after a week, and 50% after two weeks. patients can usually begin their normal activites again after this period but sometimes the complete resolution of asthenia requires several weeks. only in 1-2% of patients does asthenia last months. the decline happens in less than 1% of all cases and is generally caused by complications of the primary ebv infection (encephalitis, rupture of the spleen, airway obstruction). generally, the diagnosis is clinical but it must always be confirmed by laboratory testing, and, in particular, identification of ebv. it should be mentioned that the tendency of a late positive score and the elevated possibility of false negatives. treatment of mi is generally supportive and consists of antipyretic and/or analgesic drugs. the use of antibiotics is controversial while therapy is underway with cortisones, which is considered by some to be routine, but considered by other aa to be exclusively reserved for the most serious cases or complications. mi is generally considered to be a benign and self-limiting illness. however, in some, rare cases, complications can arise putting the life of the young patient at risk. serious hepatic complications are those which progress toward cirrhotic forms, reye's syndrome or in extreme cases, toward duncan's syndrome, a syndrome characterized by massive hepatitis linked to the x chromosome and caused by a defect in the immune response to ebv. respiratory complications are, in general, obstructive and linked to adenotonsillar hypertrophy or to serious interstitial pneumonia. hematologic complications are particularly alarming and can lead to the bursting of the spleen as well as neurological complcations where encephalitis is the leading cause of death. in this regard, particular attention should be paid to guillain-barrã©'s syndrome which is an inflammatory, demyelinating form that can complicate infective mononucleosis and cause a progressive paralysis of the respiratory muscles or rather a more or less diffused involvement of the cranial nerves. none declared. evaluation of recurrent respiratory tract infection in children genetic evaluation guidelines for the etiologic diagnosis of congenital hearing loss temporal relationship between human parechovirus 1 infection and otitis media in young children immune-mediated inner ear desease and parvovirus b19 the patology of ribella deafness concurrent influenza a and group a beta-hemolytic streptococcal pharyngotonsillitis role of cytomegalovirus in sensorineural hearing loss of children: a case-control study tehran, iran laserchirurgia in otorinolaringoiatria syntomatic congenital cytomegalovirus infection: neonatal morbilitã  and mortalitã  the 4 ,4 -difluoro analog of 5 -noraristeromycin: a new structural prototype for possible antiviral drug development toward orthopoxvirus and cytomegalovirus sensorineural hearing loss in postmeningitic children studying the etiology of deafness in the "deaf" schools of alexandria varicella-zoster virus infections. 1: chickenpox and shingles. treatment and prevention utility of dna microarrays for detection of viruses in acute respiratory tract infections in children premorbid factors and outcome associated with respiratory virus infections in a pediatric intensive care unit. premorbid factors and outcome associated with respiratory virus infections in a pediatric intensive care unit inner ear and facial nerve complications of acute otitis media with focus on bacteriology and virology malattie delle tonsille palatine e loro trattamento upper respiratory virus detection without parent-reported illness in children is virus-specific le basi patogenetiche delle infezioni respiratorie ricorrenti. il bambino con infezioni ricorrenti inflammatory diseases of the upper and lower airways. epidemiology and pathophysiology 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disorders of the pediatric airway: epiglottis,croup and tracheitis use of throat swab or saliva specimens for detection of respiratory viruses in children viral etiology and epidemiology of acute lower respiratory tract infections in children varicellazoster virus reactivation is an important cause of acute peripheral facial paralysis in children varicella-zoster virus load and cochleovestibular symptoms in ramsay hunt syndrome secondary intermedius neuralgia-like pain in a young child ramsay-hunt syndrome with vesicular stomatitis in a 4-year-old infant. oral surg oral med oral pathol oral radiol endod infective causes of facial nerve paralysis on herpetic inflammations of the geniculate ganglion: a new syndrome and its complications task force on recurrent respiratory papillomas. a preliminary report recurrent respiratory papillomatosis: a review recurrent respiratory papillomatosis quaderni monografici di aggiornamento aoico prevalence of human papillomavirus in the oral cavity/oropharynx in a large population of children and adolescents hspe7 treatment of pediatric recurrent respiratory papillomatosis (rrp): interim results utilizing a laryngeal staging and severity scale (lsss). sentac (society for ear, nose, and throat advances in children) meeting recurrent respiratory papillomatosis laryngeal papillomas: the epidemiology in a danish subpopulation 1965-1984 recurrent respiratory papillomatosis: juvenile versus adult forms clinical and radiological features in three cases of pulmonary involvement from recurrent respiratory papillomatosis malignant transformation of recurrent respiratory papillomatosis associated with integrated human papillomavirus type 11 dna and mutation of p53 variable light-dose effect on photodynamic therapy for laryngeal papillomas treatment of recurrent respiratory papillomatosis with argon plasma coagulation radiofrequency coblation for the treatment of laryngotracheal papillomas soft-tissue complications of laser surgery for recurrent respiratory papillomatosis american society of pediatric otolaryngology members' experience with recurrent respiratory papillomatosis and the use of adjuvant therapy acyclovir in the treatment of recurrent respiratory papillomatosis. a pilot study treatment of recurrent respiratory papillomatosis with indole-3-carbinol regression of aggressive laryngeal papillomatosis with 13-cis-retinoic acid (accutane) the histopathologic effects of cidofovir on cartilage intralesional cidofovir and surgical excision for laryngeal papillomatosis treatment of severe laryngeal papillomatosis with intralesional injections of cidofovir systemic cidofovir in papillomatosis adjuvant drug strategies in the treatment of recurrent respiratory papillomatosis can mumps vaccine induce remission in recurrent respiratory papilloma? world health organization initiative for vaccine research: state of the art of new vaccines -research & development. world health organization clinical manifestations and quantitative analysis of virus load in taiwanese children with epstein-barr virus-associated infectious mononucleosis the merck manual of diagnosis and therapy nasopharyngeal carcinoma in tunisian children: retrospective epidemiological, clinical and biological study about 48 cases unilateral tonsillar lymphoepithelioma with ipsilateral parapharyngeal space involvement: a case report key: cord-000996-ef5d81cg authors: han, seung beom; bae, e young; lee, jae wook; lee, dong-gun; chung, nack-gyun; jeong, dae-chul; cho, bin; kang, jin han; kim, hack-ki title: clinical characteristics and antimicrobial susceptibilities of viridans streptococcal bacteremia during febrile neutropenia in patients with hematologic malignancies: a comparison between adults and children date: 2013-06-17 journal: bmc infect dis doi: 10.1186/1471-2334-13-273 sha: doc_id: 996 cord_uid: ef5d81cg background: this study was performed to compare the clinical characteristics and antibiotic susceptibilities of viridans streptococcal bacteremia (vsb) between febrile neutropenic adults and children with hematologic malignancies. methods: the consecutive medical records of neutropenic patients with hematologic malignancies who were admitted to the catholic blood and marrow transplantation center between april 2009 and july 2012, and who were subsequently diagnosed with vsb were reviewed retrospectively. a comparison was made between the clinical and laboratory characteristics of adults and pediatric patients and also between patients with cefepime susceptible or not susceptible vsb. results: a total of 202 episodes (141 in adults, 61 in children) of vsb were identified. among them, 26 (12.9%) cases had severe complications including four (2.0%) cases of death attributable to vsb. for antibacterial prophylaxis, most adults received ciprofloxacin (97.1%), but children more frequently received trimethoprim/sulfamethoxazole (86.9%). oral mucositis (p = 0.005) and abdominal pain (p = 0.001) were found more frequently in adults, and cough was found more frequently in children (p = 0.004). the occurrence rates of severe complications and death attributable to vsb were not significantly different between adults and children. susceptibility rate to cefepime was significantly higher in adults than children (85.7% vs. 66.1%, p = 0.002). however, in multivariate analysis, cefepime susceptibility had no impact on clinical outcome. conclusions: there was no significant difference in clinical outcome between adults and children with vsb despite a difference in cefepime susceptibility. hence, different antibiotic treatment strategies may not be necessary. bacteremia is identified in 10-27% of febrile neutropenic patients with hematologic malignancies [1] [2] [3] , and 18-29% of the bacteremia is caused by viridans streptococci [1, 4, 5] . although gram negative bacteria were the most common isolates to cause bacteremia in febrile neutropenic patients in the past [6] , viridans streptococci are currently one of the most common isolates in both adults and children [1, 4, 5, 7] . viridans streptococcal bacteremia (vsb) has been reported to cause severe complications such as shock and acute respiratory distress syndrome (ards) in 18-39% of infected neutropenic patients and death in up to 20% [8] [9] [10] . a higher occurrence rate of these severe complications was reported in children compared to adults [11] . although the infectious diseases society of america (idsa) and korean guidelines state that β-lactam antibiotics are adequate for viridans streptococcal infections [2, 12] , it is uncertain whether the same practice guidelines can be applied to treat infections in adults and children because of the different complication frequencies [11] and the potentially different antibiotic susceptibilities to viridans streptococci in febrile neutropenic adults and children with vsb. we performed this retrospective study to compare clinical characteristics including the occurrence of severe complications and antibiotic susceptibilities of viridans streptococci between febrile neutropenic adults and children with hematologic malignancies, and to propose appropriate antibacterial treatment strategies for adults and children. the consecutive medical records of patients diagnosed with vsb during febrile neutropenia were reviewed retrospectively. the patients were admitted to the catholic blood and marrow transplantation (bmt) center between april 2009 and july 2012, and received conventional chemotherapy or hematopoietic cell transplantation (hct) for their hematologic malignancies. the catholic bmt center is affiliated with seoul st. mary's hospital in seoul, republic of korea and is a university-affiliated tertiary center with about 1,300 beds. there are separate hematology wards for adults and children, and the adult hematology ward consists of separate wards for intensive conventional chemotherapy and hct patients. the institutional review board (irb) of seoul st. mary's hospital approved this research protocol with a waiver of informed consent (kc12risi0607, approved on september 24, 2012). patients who were younger than 20 years were categorized as children, and the rest as adults according to the irb guideline, and clinical and laboratory characteristics and antibiotic susceptibilities were compared between the adults and children. the same clinical and laboratory characteristics were also compared between patients with vsb susceptible to cefepime, one of the empirical antibiotics used for febrile neutropenic patients, and those with vsb not susceptible to cefepime. data gathered on patients' demographics and clinical characteristics consisted of gender, underlying disease with remission status, type of therapy preceding febrile neutropenia, number of days from the beginning of respective therapies to the diagnosis of vsb, use of antibacterial prophylaxis, and occurrence of oral mucositis, respiratory symptoms, gastrointestinal symptoms, severe complications and polymicrobial infection by other bacteria or fungi. laboratory characteristics consisted of white blood cell (wbc) count and absolute neutrophil count (anc) upon the diagnosis of vsb, the number of neutropenic days before the diagnosis of vsb, total number of neutropenic days during the febrile neutropenic episode, and the peak c-reactive protein (crp) level within a week after the diagnosis of vsb. ceftazidime or cefepime with aminoglycoside, and piperacillin/tazobactam with aminoglycoside were administered as initial empirical antibacterial therapy for febrile neutropenia in adults and children, respectively. after three to five days of initial antibacterial therapy, an adjustment, if needed, was made according to the korean guideline for febrile neutropenia [12] . glycopeptides were given based on the indications recommended by the korean guideline [12] . blood for culture was sampled using sterile technique with one set from a peripheral vein and another set from a central catheter. in adults, 10-15 ml of blood was inoculated into each aerobic and anaerobic culture bottle (bd bactec™ plus aerobic/f, lytic/10 anaerobic/f culture vials, becton dickinson, sparks, md, usa), and in children, 1-3 ml of blood was inoculated into a culture bottle (bd bactec™ peds plus culture vial, becton dickinson, sparks, md, usa). the bottles were immediately transported to the clinical microbiology laboratory. automated culture systems were used to detect bacterial growth (bactec™ fx, becton dickinson, sparks, md, usa) and to identify the exact bacterial type (vitek®2, biomériux, hazelwood, mo, usa). antibiotic susceptibility tests were performed on a muller-hinton agar plate with 5% sheep blood, according to the clinical and laboratory standards institute (clsi) recommendations [13] . the susceptibilities were determined by using an e-test for penicillin and cefotaxime, and using a disk diffusion method for cefepime, erythromycin, clindamycin, vancomycin, and linezolid. a result of 's' was considered susceptible, and results of 'i' and 'r' were considered not susceptible. susceptibility rates to each antibiotic drug were calculated and compared between adults and children. because antibiotic susceptibilities and clinical characteristics were not significantly different among viridans streptococcal species [5, 9] , we did not identify the different species of viridans streptococci. vsb was defined as growth of viridans streptococci from at least one peripheral or central blood sample. neutropenia was defined as having an anc lower than 500/μl or an anc lower than 1,000/μl that was predicted to be lower than 500/μl within two to three days, and fever was defined as a body temperature higher than 38.0°c with a tympanic thermometer or 37.5°c with an axillary thermometer [12] . severe complications included shock, any kind of mechanical ventilator care, ards, and death. shock was defined as hypotension (mean arterial pressure less than 60 mmhg in adults, and systolic blood pressure less than the 5 th percentile to age in children) requiring an intravenous fluid bolus or inotropic agents to maintain normal blood pressure [8, 14, 15] , and ards was defined as pao 2 /fio 2 < 200 in arterial blood gas analysis of a patient with hypoxia of spo 2 < 90% and bilateral pulmonary infiltrates on the chest x-ray [16] . the severe complications were considered to be attributable to vsb if there was no clinical improvement after the diagnosis of vsb with severe complications, no other infectious isolates were detected, no deterioration in underlying malignancy was observed, and no other clinical diagnoses were made. death attributable to vsb was defined as death accompanied by severe complications attributable to vsb within 14 days after the diagnosis of vsb, and overall death included death from all causes within a month after the diagnosis of vsb [17] . statistical analysis was performed with spss statistics 17.0 (spss inc., chicago, il, usa), and statistical significance was defined as a two-sided p < 0.05. in comparisons between adults and children and patients with vsb susceptible and not susceptible to cefepime, a student's t-test was used for numerical variables, and a χ 2 test was used for categorical variables. multivariate analysis using multiple logistic regression tests was performed for statistically significant factors derived from univariate analysis to determine factors related to the susceptibility of viridans streptococci to cefepime. the peak crp level within a week after the diagnosis of vsb, predicting the development of severe complications attributable to vsb, was determined by a receiver operating characteristic (roc) curve. during the study period, there were 2,677 admissions in 1,248 adults and 4,219 admissions in 511 children for conventional chemotherapy, hct, or febrile neutropenia following chemotherapy. in adults, 745 episodes of bacteremia in 487 patients and 141 episodes of vsb in 134 patients were identified, and the incidence of bacteremia and vsb were 9.17 and 1.74 episodes per 1,000 person-days, respectively. in children, 301 episodes of bacteremia in 162 patients and 61 episodes of vsb in 54 patients were identified, and the incidence of bacteremia and vsb were 6.64 and 1.35 episodes per 1,000 person-days, respectively. among the total 202 episodes of vsb in adults and children, 42 (20.8%) cases with severe complications including 14 (6.9%) deaths were identified, and 26 (12.9%) of them, including four (2.0%) deaths were attributable to vsb. the other cases leading to mortality were due to uncontrolled underlying hematologic malignancies. multiple episodes of vsb were diagnosed in 11 patients. eight patients (five adults and three children) each experienced two episodes, and three patients (one adult and two children) each experienced three episodes of vsb. each episode was diagnosed during separate admissions. none of the patients experienced multiple episodes of severe complications. among the total 202 cases of vsb, 108 (53.5%) cases were male, and 147 (72.8%) cases suffered from acute myeloid leukemia (aml). vsb occurred a median of 12 days (inter quartile range, iqr: 10-14) after the preceding therapy. conventional chemotherapy and hct accounted for 95.0% and 5.0% of the preceding therapy, respectively. diarrhea (60/202, 29.7%) was the most common symptom accompanying fever, and was followed by oral mucositis (41/202, 20.3%) and abdominal pain (38/202, 18.8%). more children were male compared to the adult group (p = 0.010, table 1 ). aml accounted for about 70% of the underlying diseases in both adults and children, and the distribution of underlying diseases was not significantly different between the two groups ( table 1) . all children with vsb had been treated with conventional chemotherapy, whilst 92.9% of adults had been treated with conventional chemotherapy, and 7.1% with hct. the type of preceding therapy was not significantly different between the two groups ( table 1 ). the median number of days from the beginning of the preceding therapy to the diagnosis of vsb was 12 days (iqr: 10-13) in adults and 13 days (iqr: [12] [13] [14] in children, and this difference was statistically significant (p < 0.001, table 1 ). this difference in antibacterial prophylaxis occurred because fluoroquinolones are not recommended to children aged less than 18 years in korea due to the risk of skeletal abnormalities. the seven patients in the pediatric group who received ciprofloxacin prophylaxis were older than 18 years. among the symptoms accompanying vsb, oral mucositis (p = 0.005) and abdominal pain (p = 0.001) were more common in adults, and cough was more common in children (p = 0.004, table 1 ). the occurrence rates of severe complications attributable to vsb, overall mortality, and mortality attributable to vsb were not significantly different between adults and children (table 1) . crp levels were measured a median of three times (iqr: 3-3) within the first week after the diagnosis of vsb, and the peak crp levels within a week were detected a median of four days (iqr: 3-5) after the diagnosis of vsb. the frequency of measuring crp levels and the time of the peak crp levels were not significantly different between adults and children. there was no significant difference in laboratory results between adults and children ( table 1) . antibiotic susceptibility was assessed in 201/202 (99.5%) of bacterial isolates, that is, all the isolates except for one from an adult patient ( ). the susceptibility rates to cefotaxime, cefepime, and erythromycin were significantly higher in adults than in children (table 2) . comparison between patients with severe complications attributable to viridans streptococcal bacteremia and those without severe complications the median of peak crp levels within a week after the diagnosis of vsb was 27.2 mg/dl (iqr: 21.4-33.7) in patients with severe complications attributable to vsb and 17.8 mg/dl (iqr: 11.8-25.5) in those without severe complications. these were significantly different (p < 0.001). peak crp levels were detected a median of four days (iqr: 3-5) after the diagnosis of vsb in the two groups without a significant difference. the cut-off value of the peak crp level predicting the development of severe complications attributable to vsb was determined using an roc curve as 21.0 mg/dl (area under the curve = 0.772) with sensitivity, specificity, positive predictive value, and negative predictive value of 77%, 62%, 23%, and 95%, respectively. there were no other significant differences in clinical and laboratory characteristics between the two groups. the antibiotic susceptibility rate of each antibiotic drug was not significantly different between the two patient groups (table 3) . comparison between patients with viridans streptococcal bacteremia susceptible to cefepime and not susceptible to cefepime susceptibility tests to cefepime were conducted in 199 isolates, and 159 (79.9%) isolates were susceptible to cefepime (table 4 ). in univariate analysis, patients with vsb susceptible to cefepime were older (p = 0.005), more likely to be in complete remission status (p = 0.037), more likely to have received ciprofloxacin prophylaxis (p < 0.001), and had a longer duration of neutropenia before the diagnosis of vsb (p = 0.021) than patients with vsb not susceptible to cefepime (table 4) . however, there was no significant factor related to cefepime susceptibility in multivariate analysis (table 5) . medical records on the complete course of chemotherapy and antibacterial therapy for febrile neutropenia with antibiotics which have anti-pseudomonal effect since the diagnosis of hematologic malignancies were reviewed in 166 cases (124 adults, 42 children). of the remaining cases, medical records of 16 patients who had been referred from other hospitals were not completely reviewed, and 17 patients who had been newly diagnosed with hematologic malignancies were excluded because they had no previous history of antibacterial therapy for febrile neutropenia. the interval from the diagnosis of hematologic malignancy to the diagnosis of vsb was a median of three months (iqr: 2-7). among the 166 patients, 137 patients with vsb susceptible to cefepime and 29 patients with vsb not susceptible to cefepime received a median of one course (iqr: 1-2) and a median of two courses (iqr: 1-2) of antibacterial therapy for febrile neutropenia, respectively. the number of preceding antibacterial therapies for febrile neutropenia was not significantly different between patients with vsb susceptible and not susceptible to cefepime (table 4 ). we investigated the clinical and laboratory characteristics of vsb in febrile neutropenic patients with hematologic malignancies and the antibiotic susceptibilities of the viridans streptococci. the data were compared between adults and children and also in patients with vsb susceptible and not susceptible to cefepime. vsb occurred most commonly in aml patients (72.7%), 12 days (iqr: [10] [11] [12] [13] [14] after the beginning of consolidation chemotherapy (57.9%), and six days (iqr: 4-8) after the onset of neutropenia. this pattern of vsb occurrence was consistent with previous reports [18] . while oral mucositis, a risk factor for vsb, occurred in roughly 60% of patients with vsb in previous reports [9, 19] , it occurred at a lower rate of 20.3% in this study. on the other hand, gastrointestinal symptoms were common in all patient groups, and cough was common in children. considering that viridans streptococci are normal flora of the gastrointestinal and upper respiratory tracts as well as oral mucosa [20, 21] , and that mucosal damage can occur at these sites following chemotherapy or hct, this was a predictable result. since young children often cannot adequately complain of their oral and abdominal pain, and their parents or medical personnel might easily recognize objective symptoms, such as diarrhea and cough, the reported incidence of oral mucositis and abdominal pain might be lower in children than in adults. other clinical and laboratory characteristics were not significantly different between adults and children, and the aforementioned symptoms occurred in less than one-third of patients. therefore, we concluded that there were no distinctive characteristics to distinguish between vsb in adults and children. the 12.9% occurrence rate of severe complications attributable to vsb was lower than that of previous reports, which showed an occurrence rate of 18-39%, and the 2.0% mortality attributable to vsb in this study was also lower than that of previous reports, which showed mortality up to 20% [8] [9] [10] . although martino et al. [11] reported a higher occurrence rate of severe complications and death due to vsb in children than in adults, the occurrence rate of severe complications and death attributable to vsb and overall mortality were not significantly different between adults and children in the present study. previous researchers did not find significant factors related to a worse prognosis in children, and there have been few studies comparing the clinical characteristics and prognoses between adults and children. comparisons between adults and pediatric patients with severe complications attributable to vsb showed that children more commonly complained of cough and had a longer duration between the beginning of the preceding therapy and the diagnosis of vsb, similar to the comparison between all adults and children with vsb. when comparing patients with severe complications attributable to vsb and those without severe complications in this study, there was no significant difference except for the peak crp level within a week after the diagnosis of vsb. this had a low positive predictive value of 23% for the occurrence of severe complications. thus, we were also unable to identify a definite factor that could help anticipate severe complications in vsb. antibiotic susceptibility rates to cefotaxime, cefepime, and erythromycin were lower in children than in adults. although we performed both univariate and multivariate analyses to determine risk factors for decreased susceptibility to cefepime, no significant factors were found. recurrent antibiotic use may be related to the increase in antibiotic resistance [22, 23] ; however, there was no difference between patients with vsb susceptible and not susceptible to cefepime in the number of antibacterial therapies for febrile neutropenia after previous conventional chemotherapy or hct. the fact that the first-line antibiotic agent for patients with hematologic malignancies was cefepime or ceftazidime in most adults and piperacillin/tazobactam for almost all children in our hospital also supports the finding that previous antibiotic use is not related to decreased susceptibility to cefepime. we also analyzed the effect of prophylactic antibiotics on susceptibility to cefepime since ciprofloxacin, principally given to adults, has a limited effect on gram positive bacteria [24, 25] , while tmp/smx, principally given to children, has a satisfactory effect [25, 26] . the effect of prophylactic antibiotics on decreased susceptibility to cefepime may be small since antibacterial prophylaxis has been reported to be unrelated to increased antibiotic resistance in a meta-analysis [27] , and since patients in the present study received ciprofloxacin or tmp/smx rather than β-lactam antibiotics and antibacterial prophylaxis with these antibiotics is not known to trigger antibiotic resistance in viridans streptococci [22, 28, 29] . nevertheless, prophylactic antibiotic effects on decreased susceptibility to cefepime should not be ignored. viridans streptococci can acquire β-lactam resistance through transfer of the mutated penicillin binding protein gene from streptococcus pneumoniae [30, 31] , and it has been reported that the resistance of s. pneumoniae to β-lactam antibiotics after tmp/smx prophylaxis in human immunodeficiency virus-infected patients can increase by a factor of 1.71 [32] . however, resistance to penicillin of s. pneumoniae was 0.3% in nonmeningeal isolates and 83.3% in meningeal isolates, and ceftriaxone resistance was 1.9% in nonmeningeal isolates and 0% in meningeal isolates from 2008 to 2009 in the republic of korea [33] . the exact effect of prophylactic antibiotics on the development of antibiotic resistance remains controversial [2] , and the type of antibiotics, duration of prophylaxis, bacterial species, and host factors may influence the development of antibiotic resistance [22, 34] . in this study, there were no definite differences in clinical and laboratory characteristics, mortality, or occurrence of severe complications between febrile neutropenic adults and children with vsb, despite a significant difference in antibiotic susceptibility to cefepime between the two groups. antibiotic susceptibilities were not significantly related to the development of severe complications. thus, our study results show that different antibiotic treatment strategies for adults and children with vsb are not necessary. the lower susceptibility rate of 66.1% to cefepime in children may indicate the need for initial glycopeptide therapy in febrile neutropenic children. however, bacteremia is diagnosed in 10-25% of febrile neutropenic children [1] [2] [3] , and 20-30% of the bacteremia is caused by viridans streptococci [1, 4, 5] . in addition, since severe complications occurred in 6.6% of the patients with vsb according to our results, we estimate that the incidence of severe complications of vsb in febrile neutropenic children is 0.5%. therefore, considering that antibiotic susceptibility is not significantly related to the prognosis of vsb in febrile neutropenia [5, 9] , universal initial glycopeptide therapy targeting only 0.5% of febrile neutropenic children with hematologic malignancies should not be considered. instead, we should consider glycopeptide therapy if antibiotic susceptibility tests revealed that the isolated viridans streptococci were not susceptible to antibiotics being administered to the patient and susceptible to glycopeptides. this study has several limitations including its retrospective nature. we tried to eliminate selection bias by including all consecutive hematologic malignancy patients with vsb who were treated in the same hospital environment. also, there were some limitations in our tests for antibiotic susceptibility. the results of the e-test and disk diffusion method for antibiotic susceptibility in this study may be different from results of broth microdilution methods. additionally the clinical laboratory of our hospital did not perform piperacillin/ tazobactam susceptibility test for viridans streptococci; thus, we assumed that cefepime susceptibility was similar to piperacillin/tazobactam susceptibility. this assumption may not be applicable to clinical settings. lastly, past histories of antibacterial therapy for febrile neutropenia were reviewed to evaluate its effect on the differences in antibiotic susceptibility; however, information from 35 patients was missing. although we assumed that previous antibacterial therapies should not influence β-lactam susceptibilities, the relationship should be further investigated. in this study, no definite differences in clinical and laboratory characteristics or prognosis were found between febrile neutropenic adults and children with vsb. while susceptibility to cefepime was lower in children, there were no differences in clinical characteristics or prognosis between patients with vsb susceptible and not susceptible to cefepime. therefore, this study showed that different antibiotic treatment strategies for adults and children with vsb are not necessary, and also confirmed that current idsa and korean guidelines for febrile neutropenic patients may be applied to both febrile neutropenic children and adults with vsb. further studies on the cause and clinical significance of the difference in antibiotic susceptibility rates between adults and children are needed. a prospective study on the epidemiology of febrile episodes during chemotherapy-induced neutropenia in children with cancer or after hemopoietic stem cell transplantation clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america etiology and clinical course of febrile neutropenia in children with cancer clinical investigation of bacteremia in children with hemato-oncologic diseases serious complications of bacteremia caused by viridans streptococci in neutropenic patients with cancer changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria epidemiology and clinical features of bloodstream infections in hematology wards: one year experience at the catholic blood and marrow transplantation center predictors of viridans streptococcal shock syndrome in bacteremic children with cancer and stem-cell transplant recipients viridans streptococci bacteremia in children with malignancy: relevance of species identification and penicillin susceptibility viridans streptococcal bacteraemia due to penicillin-resistant and penicillin-sensitive streptococci: analysis of risk factors and outcome in 60 patients from a single cancer centre before and after penicillin is used for prophylaxis viridans streptococcal bacteremia and viridans streptococcal shock syndrome in neutropenic patients: comparison between children and adults receiving chemotherapy or undergoing bone marrow transplantation evidencebased guidelines for empirical therapy of neutropenic fever in korea performance standards for antimicrobial susceptibility testing; twentieth informational supplement. clsi document m100-s20 approach to the patient with shock. in harrison' s principles of internal medicine nelson textbook of pediatrics acute lung injury and the acute respiratory distress syndrome: a clinical review bacterial and fungal bloodstream isolates from 796 hematopoietic stem cell transplant recipients between infections with viridans group streptococci in children with cancer. pediatr blood cancer the impact of mucositis on alpha-hemolytic streptococcal infection in patients undergoing autologous bone marrow transplantation for hematologic malignancies infections caused by viridans streptococci in patients with neutropenia viridans group streptococcal infections among children with cancer and the importance of emerging antibiotic resistance reduced susceptibility to penicillin of viridans group streptococci in the oral cavity of patients with haematological disease increased carriage of resistant non-pneumococcal alpha-hemolytic streptococci after antibiotic therapy in mandell, douglas, and bennett's principles and practice of infectious diseases efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials infections during induction therapy for children with acute lymphoblastic leukemia. the role of sulfamethoxazole-trimethoprim (smx-tmp) prophylaxis. pediatr blood cancer meta-analysis: antibiotic prophylaxis reduces mortality in neutropenic patients antimicrobial susceptibility of viridans group streptococci isolated from patients with acute leukemia receiving ofloxacin for antibacterial prophylaxis emergence of quinolone resistance among viridans group streptococci isolated from the oropharynx of neutropenic peripheral blood stem cell transplant patients receiving quinolone antimicrobial prophylaxis penicillin-resistant viridans streptococci have obtained altered penicillinbinding protein genes from penicillin-resistant strains of streptococcus pneumoniae erythromycin and penicillin resistance mechanisms among viridans group streptococci isolated from blood cultures of adult patients with underlying diseases trimethoprimsulfamethoxazole prophylaxis and antibiotic nonsusceptibility in invasive pneumococcal disease ansorp study group: changing trends in antimicrobial resistance and serotype of streptococcus pneumoniae isolates in asian countries: an asian network for surveillance of resistant pathogens (ansorp) study fluoroquinolone consumption and resistance in haematology-oncology patients: ecological analysis in two university hospitals 1999-2002 submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution there is no competing interest for any authors.authors' contributions sbh, dgl, bc, and jhk designed this study. sbh, eyb and jwl collected data, and ngc and dcj analysed the data. sbh, jwl and dgl wrote the manuscript, and bc, jhk and hkk critically reviewed the manuscript. all authors read and approved the final draft. key: cord-013401-yh8cu1hx authors: hitachi, mami; wanjihia, violet; nyandieka, lilian; francesca, chepkirui; wekesa, norah; changoma, juma; muniu, erastus; ndemwa, phillip; honda, sumihisa; hirayama, kenji; karama, mohammed; kaneko, satoshi title: improvement of dietary diversity and attitude toward recommended feeding through novel community based nutritional education program in coastal kenya—an intervention study date: 2020-10-05 journal: int j environ res public health doi: 10.3390/ijerph17197269 sha: doc_id: 13401 cord_uid: yh8cu1hx community-based nutritional intervention to improve the practice of dietary diversity and child nutrition by community health workers (chws) involving nyumba kumi as small neighborhood units (snus) in communities has not yet been explored. this study was conducted in two villages in rural kenya between 2018 and 2019. in total, 662 participants (control vs. intervention: n = 339 vs. n = 323) were recruited. the intervention group received education on maternal and child nutrition and follow-up consultations. the custom-tailored educational guidelines were made based on infant and young child feeding and the mother and child health booklet. the educational effects on household caregivers’ feeding practice attitude and child nutritional status were analyzed using multiple linear regression. after the intervention, a total of 368 household caregivers (187 vs. 181) and 180 children (113 vs. 67) were analyzed separately. between the groups, no significant difference was found in their background characteristics. this study successfully improved the dietary diversity score (β = 0.54; p < 0.01) and attitude score (β = 0.29; p < 0.01). the results revealed that the interventions using chws and snus were useful to improve dietary diversity and caregivers’ attitudes toward recommended feeding. this research has the potential to be successfully applied in other regions where child undernutrition remains. abstract: community-based nutritional intervention to improve the practice of dietary diversity and child nutrition by community health workers (chws) involving nyumba kumi as small neighborhood units (snus) in communities has not yet been explored. this study was conducted in two villages in rural kenya between 2018 and 2019. in total, 662 participants (control vs. intervention: n = 339 vs. n = 323) were recruited. the intervention group received education on maternal and child nutrition and follow-up consultations. the custom-tailored educational guidelines were made based on infant and young child feeding and the mother and child health booklet. the educational effects on household caregivers' feeding practice attitude and child nutritional status were analyzed using multiple linear regression. after the intervention, a total of 368 household caregivers (187 vs. 181) and 180 children (113 vs. 67) were analyzed separately. between the groups, no significant difference was found in their background characteristics. this study successfully improved the dietary diversity score (β = 0.54; p < 0.01) and attitude score (β = 0.29; p < 0.01). the results revealed that the interventions using chws and snus were useful to improve dietary diversity and caregivers' attitudes toward recommended feeding. this research has the potential to be successfully applied in other regions where child undernutrition remains. keywords: education; intervention; child nutrition; dietary diversity; attitude; community health workers; small neighborhood units; nyumba kumi undernutrition associates with nearly half of the deaths among children under the age of five, which means approximately three million young lives are unnecessarily lost in the world [1] . furthermore, it increases the morbidity risks from several diseases among young children in the short term; in the long-term, it causes stunting and impaired cognitive development, which results in poor school performance and social development [2] . although several efforts and measures have been taken to improve the nutritional status among children worldwide, it is still estimated that twenty-one percent of children still have a stunting condition or chronic undernutrition, especially in south asia and sub-saharan africa [2] [3] [4] . rich dietary diversity is an essential component to reduce undernutrition among children; however, less than 30% of children in sub-saharan africa are fed a "minimally acceptable" diet based on the global guidelines [5] [6] [7] [8] . kenya is one of 34 countries experiencing the highest burden of child undernutrition [9] . approximately one in four children (26.2%) is estimated to be stunted in kenya [10] . tanaka et al. reported that the traditional diet pattern had low dietary diversity in their research in kenya, and children fed by the traditional diets had a higher risk of stunting compared with those who were fed by non-traditional diet patterns [11] . since dietary diversity for children depends on caregivers' knowledge, attitude, and practice [12] , it is essential to provide caregivers enough information about the appropriate feeding of children, including dietary diversities by health staff members during antenatal and postnatal care. however, those opportunities to receive such information are limited due to inadequate access to health facilities [13] . under such limited situations to access health facilities, it is proven that community-based educational programs using community health workers (chws) improve the nutritional status of children in low-income and middle-income countries [9] . however, the effect on dietary diversity by a community-based approach with chws has not been well investigated. although intervention with chws can have the potentiality to improve diet diversity, it would be challenging because of the chws' low motivation, community supports for the chws, and cooperation with existing community organizations [14] . additionally, there is another community-based structure, "nyumba kumi," small neighborhood units (snus), in kenya, which means ten households in the swahili language. it is a mechanism introduced to achieve political stability and shared values in 2013 in kenya by the presidential order. it is the smallest social unit located at the lowest governmental community policing structure [15, 16] . the combined activities of chws and nyumba kumi might have synergistic effects regarding health education in the community; however, there has been no study on this matter to date. this study aimed to prove the hypothesis that community-based nutritional educational programs cooperating with chws and nyumba kumi might effectively change the attitudes of caregivers toward feeding practices and dietary diversity for their children. this study was conducted in the kwale district of kenya, where a health and demographic surveillance system (hdss) is being supervised under nagasaki university and kenya medical research institute (figure 1 ). the hdss monitors the population dynamics every three months, and the system covers nearly 43,000 individuals in an area of 390 square km that includes ten villages [17] . of the ten villages, two villages, dumbule and miatsani, were selected and assigned to a control and an intervention group. these two villages were chosen because of the similar backgrounds in terms of (i) climate settings, (ii) ethnicity (durumas) and culture, and (iii) healthcare services (health facility and staff). furthermore, we considered the geographical distance (30 km) to avoid intervention information "cross-over" from the intervention group to the control group. for the participant selection, 662 potential participants (control: n = 339; and intervention: n = 323) were recruited from the hdss records. the study period was between february 2018 and june 2019 ( figure 2 ). information "cross-over" from the intervention group to the control group. for the participant selection, 662 potential participants (control: n = 339; and intervention: n = 323) were recruited from the hdss records. the study period was between february 2018 and june 2019 ( figure 2 ). based on the pre-intervention survey, we found 649 pairs (control: n = 329; and intervention: n = 320) of caregivers and children who were potentially eligible for the educational intervention trial. the subjects were children aged 6-59 months and their caregivers ( figure 2 ). the trial had two groups: (i) control: caregivers did not receive any education on maternal and child nutrition, and (ii) intervention: caregivers received the education between june and august 2018, and a follow-up consultation was done between september 2018 and february 2019. the educators were locally recruited qualified nutritionists, and they were trained to follow the custom-tailored educational guidelines based on the who recommended indicators of infant and young child feeding and instructions written in the mother and child health booklet [18] . the custom-tailored guidelines contained general information on maternal and child nutrition and health, considering local situations and traditional practices: (i) maternal nutrition during pregnancy and lactation, (ii) early initiation of breastfeeding, (iii) exclusive breastfeeding and duration of breastfeeding and expressing breast milk, (iv) age-appropriate complementary feeding, (v) diverse diet and food groups, (vi) proper hygiene and sanitation practices, (vii) nutrient components of foods and supplements under the maternal and child health program, and (viii) malaria and soil-transmitted helminth and family planning. the education intervention was given in the local language using teaching aids like charts, pamphlets, and models to promote participants' uptake of the materials. during the follow-up consultation, either a chw or a member of the snu visited the households in the intervention group, and they observed the households according to the list to confirm the practice they learned during the educational session. if their practices were improper, suggestions were provided as part of the educational program to follow the educational guidelines by discussing challenges and problems. our data collectors, a chw, or a member of the snu who was given training in advance, administrated a structured questionnaire survey at each caregiver's household once in the pre-and post-intervention in february 2018 and june 2019, respectively. the training sessions were given and qualified by the trained nutritionists to keep the quality of the surveys. the questionnaire was designed to investigate household status (socioeconomic and demographic variables), household caregiver situation (attitudes toward recommended feeding and diet practice), and child status (age, sex, weight, and height). for the socioeconomic status (ses), the possession or use of the following contents were asked as a binomial variable (0/1): bedrooms (<2 or 2≤); cooking fuel (firewood or other); home electrical appliances (either phone, refrigerator, or t.v. set); mobile phone; bicycle; cart; car; and house (owner-occupied or not). the ses was divided into lower and higher statuses using a median threshold of ses. besides, the household population, questions about religion (islam or others), and delivery place (home or facility) were added to the demographic variables. the household population was categorized into two groups (<5 or 5≤) based on the average household population in kwale county [19] . as asked in the household caregiver situation section in the questionnaire, caregiver attitude was assessed based on nine items corresponding to the tailored educational guidelines, and each item was scored one if the caregiver agreed (table s1 , supplementary materials). this attitude score ranged from zero to nine. the diet quality and food consumption in the previous 24 h were also asked of each caregiver. after the interview, food items were classified into 15 categories based on the fao guidelines [20] : starchy staples (grains, white tubers, and roots); vitamin a-rich vegetables (vitamin a-rich vegetables and tubers); dark green leafy vegetables; other vegetables; vitamin a-rich fruits; other fruits; legumes and nuts; dairy products (milk, yogurt, and cheese); eggs; fresh meats; organ meats; fish and seafood; oil; sweets; and spices. based on the classification, each category was binomially classified (0/1) and the sum was calculated (a.k.a. dietary diversity score (dds)). the dds ranged between zero and 15, with the higher score indicating higher diversity. moreover, the body weights of children were measured using a digital scale (seca gmbh & co.kg, hamburg, germany), and heights were scaled using a unicef length measure (available online: https://www.unicef.org/supply/documents/height-length-measuring-boards). both anthropometric scales were taken twice, and averages were recorded to minimize measurement errors in the field. z-scores for height-for-age (haz), weight-for-age (waz), and weight-for-height (whz) were calculated based on the mean according to the child growth standards published by the who in 2006 to evaluate child nutritional status [21] . responses from household caregivers who remained in the post-intervention survey were analyzed to understand caregivers' attitudes toward recommended feeding and the practice of dietary diversity. effects on child nutrition were evaluated for children who attended both pre-and post-surveys. the chi-square test was performed for categorical variables to test background differences between treatment groups: household population, ses, place of delivery, and child sex, statistically. mann-whitney u test was used for the continuous variable of child age. to assess the variable changes per treatment group at the pre-and post-intervention periods, the mean differences of household caregiver situation (dds and attitude score) and child nutritional status (haz, waz, and whz) were tested using the wilcoxon signed-rank test for matched pairs. in contrast, multiple linear regression (mlr) was performed to understand the linear relationship between the treatment groups and dependent variables. the differences (post-and pre-intervention) for household caregiver situation and child nutritional status were set as outcomes or dependent variables, and the independent variable was the treatment group. the effect of the intervention was evaluated with and without adjustments for background covariates showing p-values less than 0.2 in baseline characteristics, along with pre-intervention scores of the outcome. all statistical analyses were performed using stata 14 (statacorp llc, college station, tx, usa). adjusted coefficients with the p-value were reported. p-values less than or equal to 0.05 were considered statistically significant. qgis (3.14, 64 bit) (open source geospatial foundation, available online: qgis.osgeo.org) was used to create the study site map, and world countries were drawn using natural earth (1:50 m cultural vectors) (available online: www.naturalearthdata.com). community boundaries were based on the gadm database (available online: gadm.org). this study was approved by the kemri scientific ethics review unit (seru) (kemri seru no. 3570) and the institutional review board of the institute of tropical medicine, nagasaki university (irb # 171207184-2). the study was conducted in two villages in kwale county, kenya (figure 1 ). according to the hdss registration, the villages had 662 eligible households for nutritional education (figure 2 ). after the trial process, a total of 368 household caregivers (control vs. intervention: 187 vs. 181) and 180 children (113 vs. 67) met the eligibility criteria for the analysis (table 1) . between the groups, differences in household population (p = 0.09), ses (p = 0.43), religion (p = 0.40), and place of delivery (p = 0.66) were not significant. additionally, there was no significant difference in child characteristics in age (p = 0.18) and sex (p = 0.72). the total drop-out cases included participants who were absent at the post-intervention survey and had missing and contradictive data. significant differences in household characteristics listed in table 1 and child sex were not observed between participants who dropped out and completed both pre-and post-intervention surveys. table 2 shows within-group improvements in household caregiver situations for both control and intervention groups. from pre-to post-intervention, the means of dds increased similarly in both groups, 1.97 ± 0.45 in the control and 1.94 ± 0.53 in the intervention group (p < 0.01). likewise, the means of the attitude score by group were significantly improved (control improved: 0.46 ± 0.15; p < 0.01; intervention improved: 0.49 ± 0.41; p < 0.01). concerning child nutritional statuses, the means of haz, waz, and whz for each group had no evident changes between pre-and post-intervention ( table 2 ). the differences between pre-and post-intervention in attitude towards recommended feeding within the group are shown in table s2 (supplementary materials). in table 3 , the difference in household dds (β = 0.54; p < 0.01) and attitude score (β = 0.29; p < 0.01) between the groups demonstrated significant educational effects on the intervention group in the adjusted analysis, although no differences were shown in unadjusted modeling. no educational effects between the treatment groups were identified in child nutritional status. regarding the factors associated with the difference, pre-intervention scores of each outcome negatively related to each corresponding difference (p < 0.01). besides, significant decreases in dds were observed in the household with the population equal to or more than five members (β = −0.46; p < 0.01) and child age (β = −0.02; p < 0.01). table 3 . the effects a of educational intervention and participants demographic variables for household diet practice and child growth between pre-and post-intervention. the results indicate a significant positive impact of nutritional education with the help of chws and snus (i.e., nyumba kumi) on household caregivers' attitudes toward recommended feeding and practices of dietary diversity (table 3) . these improvements can be explained by shi and zhang's review on educational intervention for feeding practice, which identified four critical elements for successful interventions [22] . indeed, our tailored education with snus met the first essential element of cultural sensitivity, accessibility, and integration with local resources. the second key element, effective interpersonal communication, was satisfied with our educational strategy of home visit follow-ups. thirdly, snus matched the required key element of community member involvement. lastly, enrollments of chws in education met the fourth essential element, which recommended the use of existing healthcare services. furthermore, the success of this study could be better explained by the use of snus. it is well known that getting advice from someone known and who is knowledgeable about appropriate feeding practices is more likely to lead to the desired behavior changes of household caregivers [13, 23] . in this study, household caregivers had the opportunity to listen to knowledgeable advice from close known community members in the snu. recently, the kenya government adapted the snu framework or "nyumba kumi" for covid-19 control, which requires flexible and quick responses in local settings. this government action took advantage of the usefulness of using snus across the country [24] . while within-group improvements in dds and attitude scores were observed for both the control and intervention groups (table 2) , the reason could not be explained in our study. these improvements might be due to the effects of the difference in the agricultural seasonality according to the schedule for pre-and post-intervention data collection considering the reports from other studies [25] [26] [27] . however, it is difficult to conclude that the improvements were due to the seasonality because households in the areas grow several crops for cashing regardless of the season in the study areas. although neither the control nor intervention groups immediately improved child nutritional status, studies have demonstrated that educational interventions require a longer duration to observe a significant impact on child nutrition [28, 29] . therefore, successfully improved attitudes and practices of household caregivers should lead to enhancements in child nutrition status in the long term. regrettably, this study was unable to observe such long-term effects on child nutrition because of the limit of the study period, although we observed the improvement of dds and attitude scores. we need to extend the study period to have positive associations between dietary diversity and haz shown in the previous study [30] . moreover, households with more than five members had a smaller difference in dietary diversity though it was not detected in the attitude score. it may be challenging to increase dietary diversity with the limited household budget for larger families regardless of how much nutritional information they receive; therefore, educational intervention combined with other supports is required to promote behavior changes. the results revealed that the interventions using chws and nyumba kumi (snus) were useful to improve dietary diversity and caregivers' attitudes toward recommended feeding; however, we could not identify the effect on child nutritional status in the short observation period of the study. similar small neighborhood frameworks with chws can be expected to bring positive effects in other regions where similar problems of child nutrition remain. supplementary materials: the following are available online at http://www.mdpi.com/1660-4601/17/19/7269/s1, table s1 : nine question items used to assess caregivers' attitudes, table s2 : differences between pre-and post-intervention in attitude towards recommended feeding within the group, respectively. the faces of malnutrition global nutrition targets 2025: policy brief series world bank joint child malnutrition estimates regional classifications maternal participation in a nutrition education program in uganda is associated with improved infant and young child feeding practices and feeding knowledge: a post-program comparison study low dietary diversity is a predictor of child stunting in rural bangladesh consumption of animal source foods and dietary diversity reduce stunting in children in cambodia food variety-a good indicator of nutritional adequacy of the diet? a case study from an urban area in mali, west africa evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost? lancet ministry of health/kenya; national aids control council/kenya; kenya medical research institute; national council for population and development/kenya. kenya demographic and health survey relationship between dietary patterns and stunting in preschool children: a cohort analysis from kwale food and nutrition: growing well in a changing world perceptions of caregivers about health and nutritional problems and feeding practices of infants: a qualitative study on exclusive breast-feeding in kwale community health workers in low-and middle-income countries: what do we know about scaling up and sustainability? conflict resolution and crime surveillance in kenya: local peace committees and nyumba kumi nyumba kumi strategy of community policing and its impact on curbing crime; empirical assessment from kenya health and demographic surveillance system in the western and coastal areas of kenya: an infrastructure for epidemiologic studies in africa world health organization. indicators for assessing infant and young child feeding practices, part i: definition guidelines for measuring household and individual dietary diversity; food and agricultural organization of the united nations world health organization. who child growth standards: length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: methods and development recent evidence of the effectiveness of educational interventions for improving complementary feeding practices in developing countries correlates of exclusive breastfeeding practices in rural and urban niger: a community-based cross-sectional study ministry of health kenya. kenya report 167 new cases of covid-19 nairobi variations between post-and pre-harvest seasons in stunting, wasting, and infant and young child feeding (iycf) practices among children 6-23 months of age in lowland and midland agro-ecological zones of rural ethiopia seasonality affects dietary diversity of school-age children in northern ghana attitudes and practices on child feeding and care: preliminary insights from the project on linkages between child nutrition and agricultural growth. food security international development policy syntheses an integrated microcredit, entrepreneurial training, and nutrition education intervention is associated with better growth among preschool-aged children in rural ghana effectiveness of an educational intervention delivered through the health services to improve nutrition in young children: a cluster-randomised controlled trial differential effects of dietary diversity and maternal characteristics on linear growth of children aged 6-59 months in sub-saharan africa: a multi-country analysis. public heal the authors thank all our participants, field workers, and the program for nurturing global leaders in tropical and emerging communicable diseases, graduate school of biomedical sciences, nagasaki university. further, we wish to gratefully appreciate tomonori hoshi and todd saunders for great supports to edit this article and abdulatif mohamed for assistance with data collection. the authors declare no conflict of interest. key: cord-006236-2gpwf4z2 authors: nan title: abstracts from the first international conference on heart failure in children and young adults date: 2004 journal: pediatr cardiol doi: 10.1007/s00246-004-2553-9 sha: doc_id: 6236 cord_uid: 2gpwf4z2 nan safety of endomyocardial biopsy in children <2 years of age with dilated cardiomyopathy or myocarditis. debra a. dodd, md and thomas p. doyle, md., vanderbilt children's hospital, nashville, tn. concerns have been raised by others regarding the safety of biopsy in infants and young children with dilated cardiomyopathy (dcm) or myocarditis, with risk of perforation being reported as high as 33% in this group. at the same time, the utilization of heart transplantation for dcm, the availability of immunosuppression and prolonged extracorporeal membrane oxygenation (ecmo) for the management of myocarditis, and the lack of reliable noninvasive methods to separate these two diagnoses, make biopsy more imperative. since 1997 we have planned to biopsy all infants outside the immediate newborn period ( >30 days) presenting with ventricular dilatation and low ejection fraction. charts were reviewed retrospectively. 13 infants underwent cardiac biopsy from the femoral approach while sedated at a median age of 6 months (range 7 weeks-1.7 years), and median weight of 6.7 kg (range 3.8-13.5 kg). biopsies were done at a median 7 days (range 0-105 days) after the diagnosis. this included 4 patients with delayed referral from elsewhere. 7/13 were on inotropic support at the time of the biopsy. 1/13 underwent a nondiagnostic skeletal muscle biopsy prior to endomyocardial biopsy. two other infants met the above criteria for biopsy but were felt to be too unstable, with both being placed on ecmo within 24 hours of presentation. four infants presented in the first month of life at a median age of 12 days (range 9-15 days) and a median weight of 3.3 kg (range 2.4-4.2 kg) and did not undergo biopsy. in the 13 patients who underwent biopsy, the only complication was an episode of svt converted with adenosine. there were no cardiac perforations. a median of 4 pieces (range 2-6) was obtained from the right ventricle in each patient. lymphocytic infiltrate was seen in two patients, mitoabstracts-heart failure in children and adults chondrial abnormalities diagnostic of barth's syndrome in one patient, vacuole laden macrophages diagnostic of a storage disease in one patient, no abnormalities on routine stains but significant myofilament loss on electron microscopy in two patients, and nonspecific findings of hypertrophy and/or fibrosis in the remaining patients. our results suggest that endomyocardial biopsy can be done safely in most infants with dcm or myocarditis, and we feel it does contribute to optimal management of these patients. purpose: endomyocardial biopsy (emb) is routinely carried out in adults prior to cardiac transplantation but remains controversial in children. this study aims to determine the incidence of myocarditis in paediatric patients transplanted following a clinical diagnosis of dilated cardiomyopathy (dcm). methods: archived slides were examined from the explanted hearts of all paediatric patients transplanted for a diagnosis of dcm at the freeman hospital since the transplant programme began, between 1987 and 2002. control slides were examined from the explanted hearts of patients transplanted for a diagnosis of congenital heart disease. slides were examined by two specialist histopathologists using a light microscope, in a blinded manner, and scored according to the dallas criteria. results: 44 hearts were examined (38 with dcm and 6 controls). the control patients showed no evidence of myocarditis. on examination active myocarditis was found in two patients (5%). some evidence of inflammation was found in a further 21 patients (56%). we divided these into ''borderline'' myocarditis (24%) and minimal inflammation (32%). this might suggest previous myocarditis. the results of this study indicate a high prevalence of inflammation in the explanted hearts of children who have undergone transplantation for a diagnosis of dcm. only 5% had acute myocarditis. there is a need for an improved classification of the common intermediate changes that may help elucidate the cause of heart failure in this group. this has important implications on many aspects of management of sick children with heart failure with presumed dcm. when discussing the issue of biopsy for these seriously ill children the meaning of the intermediate forms of inflammation needs to be better understood. purpose: to investigate whether n terminal pro-brain natriuretic peptide (ntpro-bnp) is elevated in children with dilated cardiomyopathy (dcm), and therefore to assess whether ntpro-bnp is applicable as a marker of heart failure in children as it is in adults. methods: eight children under 16 years with cardiac failure (fs results: plasma ntpro-bnp levels were significantly elevated in children with dcm (mean 6025 pg/ml, range: 1386 pg/ml to 20570 pg/ml) compared to control children (mean 54 pg/ml, range: 11 pg/ml to 118 pg/ml), p = 0.016. the number of patients recruited was not sufficient to determine any correlation of ntpro-bnp with disease severity. conclusion: the findings of this study suggest that plasma levels of ntpro-bnp are elevated in children with dcm and its use as a marker of heart failure in adults may also be applicable to children. this was previously unreported in the paediatric population. the wide separation of ntpro-bnp levels between the normal children and those with clinical heart failure, with no healthy control child having an ntpro-bnp level >120 pg/ml and no heart failure patient having an ntpro-bnp level <1300 pg/ml, suggests that this may be a useful clinical tool in the diagnosis of less severe forms of heart failure and a means of monitoring progress in children. abbreviations: dilated cardiomyopathy (dcm), n terminal pro-brain natriuretic peptide (ntpro-bnp), fractional shortening (fs) key words: heart failure, pediatrics, dilated cardiomyopathy, and brain natriuretic peptide background: nesiritide (r-bnp) has been shown to rapidly improve hemodynamics and induce diuresis in adults with moderate to severe congestive heart failure (chf). however, description of its use in pediatric patients is scarce. purpose: review and analysis of our experience with r-bnp in pediatric patients with chf. methods: review of 4 instances of use in 3 patients based on their response in urine output (uop), weight change, dyspnea (nyha classification), and renal indices (bun/cr). results: the etiologies of heart failure were varied: (a) systolic dysfunction in a 19 year-old male with dilated cardiomyopathy secondary to duchenne muscular dystrophy, (b) ''failed fontan'' in a 16 year-old female with complex congenital heart disease, and (c) severe diastolic dysfunction in a 7 year-old male heart transplant recipient (2 administrations). each received r-bnp (1 mcg/kg bolus followed by 0.01 mcg/kg/min infusion) for 36 hours while continuing intravenous bolus diuretics. patient c 1 also received continuous infusions of torsemide, milrinone, and ''renal-dose'' dopamine prior to and during r-bnp. three administrations were in the icu with frequent, non-invasive vital sign monitoring, with the other (c 1 ) receiving continuous central venous and intra-arterial pressure monitoring. in 3 cases (a, c 1, and c 2 ), improved uop, bun/cr, weight loss, and decreased dyspnea were seen. in 2 cases (a and c 1 ) the changes were sustained. subject a had no change until 12 hours after discontinuation of r-bnp at which point uop increased from 0.23 to >2.3cc/kr/hr and was sustained over the ensuing 72 hours. his nyha class decreased from iii to ii. subject c's uop increased from 1.8 to >3.3 cc/kg/hr within 2 hours of initiating r-bnp. improvement in bun/cr and nyha scale (iii to ii) was sustained for 7 days after discontinuation of r-bnp despite weaning of additional therapies. chf symptoms relapsed and 18 days later, he received a second infusion (for 117 hours). all 4 parameters improved in the initial 36 hours followed by a blunted response with a decline in uop, increased dyspnea, weight gain, and worsened bun/cr despite addition of dopamine. subject b (nyha ii) had no response to any of the parameters. subject a developed asymptomatic hypotension that resolved within 2 hours of holding r-bnp. otherwise, vital signs were stable in all subjects and improved, in general, in those who responded favorably to r-bnp. no arrhythmia or increased ectopy was seen in any of the subjects. baseline hyponatremia in subjects a and c 2 worsened from 128 to 125 and 125 to 119 meq/l, respectively, but later recovered. patients a and b survived to discharge and patient c survived to re-transplant. conclusions: nesiritide can be used safely in pediatric subjects with moderately severe decompensated heart failure. the clinical response varies from rapid and sustained to delayed and blunted. the lack of response in the subject with fontan physiology may be secondary to a different mechanism of chf. key words: nesiritide, b-type natriuretic peptide, pediatric congestive heart failure outcome of fulminant viral myocarditis in the pediatric population. n amabile, a fraisse, p chetaille, f aubert, j camboulives, jf pellissier, p djiane., hopital de la timone, marseille, france. background: in the adult population, fulminant myocarditis is characterized by critical illness at presentation but excellent long-term survival. we sought to highlight clinical features and outcome in the pediatric population. methods: we report the evolution of 11 children admitted for fulminant myocarditis to our institution since 1998. inclusion criteria were the presence of an acute and severe heart failure associated with a history consistent with the presence of a viral illness within the 2 weeks before admission, without personal or familial antecedent of cardiomyopathy. results: the median age at presentation was 1 year (0-9 years). initial left ventricular ejection fraction by echocardiography ranged from 10 to 40% (mean: 22%). endomyocardial biopsy was performed in 3 patients and revealed histological signs of active myocarditis. a viral agent was identified in 5 cases on serological studies: human parvovirus b19 (n = 2), epstein barr virus (n = 1), varicella zoster virus (n = 1) and coxsackie (n = 1). all children were admitted in intensive care unit. nine patients required intravenous inotropic support and 8 children were intubated. all patients received corticosteroid therapy. in 5 cases, intravenous immunoglobulin infusions (2 g/kg) were associated. five subjects experienced cardio-pulmonary arrest during their hospital course with one death. four children had sustained ventricular arrhythmia. median hospitalization time in intensive care unit was 11 days (ranging from 1 to 34 days). subsequent evolution was favourable in the 10 surviving patients. after 2.5 years (0.9 to 6.4) of median follow-up time, no child has any residual cardiovascular symptom or requires any cardiac medication. no neurologic impairment was observed. left ventricular ejection fraction by echocardiography is normal in all cases (mean: 61%). conclusions: this study illustrates initial gravity of fulminant myocarditis in pediatric patients and subsequent favourable evolution. aggressive hemodynamic support is warranted for patients with this condition. background: mechanical circulatory support in the postoperative period after pediatric cardiac surgery may be associated with a higher hospital mortality, especially in centers with a low rate of usage. we retrospectively studied all the postoperative patients who required mechanical support in emergency in our institution. since january 2002, 6 children underwent mechanical circulatory support at a median age of 36 (2 to 180) months, after a median intensive care unit course of 36 (2 to 180) hours. the surgical procedure was congenital heart disease repair in 5 cases and a cardiac transplantation in one child. five patients were supported with a centrifugal pump whereas a roller pump was used in one case. five patients required support though a veno-arterial cannulation for poor cardiac output with a cardiac arrest in 3 cases. one patient had a veno-venous cannulation for an acute respiratory distress syndrome on the 8 th postoperative day after repair of a tetralogy of fallot. after a median duration of 6 (5 to 12) days, 5 patients were successfully weaned from support. one patient could not be weaned and died from multiple organ failure. three patients had renal failure, treated successfully with hemofiltration (n = 2) or peritoneal dialysis (n = 1). no patient had neurological complications. all the 5 survivors were discharged from the hospital. conclusion: emergency post-cardiotomy mechanical support can offer a favorable outcome to selected patients even in centers with a low rate of usage of this procedure. despite prolonged periods of support, our patients did not experienced irreversible neurological events, hemorrhages or infections. there were five children (4 patients with chd and 1 patient with ards) who were unable to wean off of ino and mv (avg. 5 days). after initiation of oral sildenafil, all children were weaned off ino (avg. 3 days) and all were successfully weaned from mv (avg. 10 days). two children with severe bpd, requiring chronic ventilation (data not included in table 1) were placed on sildenafil. both children were on high mv settings since birth and had failed all other medical management for their phtn. within four months after initiation of sildenafil, one child was discharged to home on low mv settings and the other child had complete reversal of his phtn by echo. no adverse effects of sildenafil, including systemic hypotension, adverse drug interaction, dysrhythmias, anaphylaxis, or headaches occurred in any patients. treatment range was 1 day to several months (some children remain on sildenafil). conclusions: sildenafil appeared to be safe and efficacious at the doses used in this pediatric population. after the initiation of sildenafil, 5 of 5 patients were weaned from ino and 17 of 18 patients were weaned off mv regardless of the etiology of the phtn. prospective trials evaluating the use of sildenafil in pediatric phtn are needed looking at dosing, safety, efficacy, and decreased need for ino. key words: sildenafil, pulmonary hypertension, children. the natriuretic peptide type b (bnp) which is produced in the ventricles of the heart, has been shown to be increased in plasma (p) during different types of hemodynamic overload of the heart. the clinical use of this peptide as a marker of cardiac strain and ventricular dysfunction, however, has not yet been fully established in children with congenital heart defects. aim: to study p-bnp levels in children with congenital heart disease with pressure or volume overload of different morphological ventricles. methods: consecutive blood samples for analysis of p-bnp and p-anp were taken during regular pre-operative investigations (surgery/catheter) in children with congenital heart defects. the hemodynamic load of the heart was evaluated by echo-doppler investigation (echo) and/or during catheterisation. hemodynamic overload of the heart was classified as: pressure overload of the left (pres lv) (aortic stenosis, coarctation of the aorta) or right (pres rv) (pulmonary stenosis) ventricle, volume overload of the left (vol lv) (ventricular septal defect, patent ductus arteriosus) or right (vol rv) (atrial septal defect) ventricle, sufficient to indicate surgery/catheter intervention according to local practice. patient with depressed ventricular function was excluded. twenty-three children without heart disease aged two weeks to 8.3 years served as a control group for the natriuretic peptide measurements. the reference intervals for bnp were 0 -18.4 ng/l and for anp 0 -43 ng/l. results: blood samples were obtained from 61 patients (38 boys, 23 girls), mean age 4,1 years (3 months-16.2 years). the p-bnp was significantly higher in the vol lv group, median 55.4 ng/l (10.7-352) (n = 16), as compared with the vol rv group 15.6 (0-105.1) (n = 19), pres rv group 18.0 (5.0-29.1) (n = 11), pres lv group 6.8 (0.7-170) (n = 15) and control group 4.7 (0-17.7), respectively (p<0.0001; kruskal wallis). the p-bnp levels were significantly higher compared with the control group for all the groups except for the pres lv group (p<0.001). p-bnp correlated with the left ventricle inner diameter in diastole (p = 0.005) and the ratio of the left atrium/aortic root dimension (p = 0.02) (spearman rank correlation). the fractional shortening of the left ventricle (fs) was within the normal range in all the groups mean 39% (26-55). no significant correlation was observed between p-bnp and the fs (p = 0.09). conclusion: the p-bnp levels increase in children with congenital heart defects during increased hemodynamic load of the heart even in the absence of systolic dysfunction. this increase is particularly pronounced in defects resulting in volume overload and dilation of the left ventricle. key words: bnp, congenital heart defect, volume overload purpose: mechanical support may be required in pediatric patients undergoing open-heart surgery. the target of this short-term support is to maintain adequate end-organ perfusion and to allow the heart to recover. we report our experience with iabp to support pediatric cardiac patients. methods: from 4/1994 to 3/2003, 19 children required iabp support in our institution. eight were infants less than 6 months of age, and the rest were over 12 months. infants' mean age at operation was 10.5 â± 8.6 (95% ci: 5.9-8.6) weeks, and median body weight (bw) was 4.2 (range: 3.5-8) kg. children's mean age at operation was 6.4 â± 4.6 (95% ci: 4.0-8.8) years, and median bw was 18 (range: 12-51) kg. the duration of iabp support was 100.8 â± 82.8h in infants, and 112.6 â± 94.1h in children. iabp was established: i. due to failure to wean of cardiopulmonary bypass-cpb (n = 7, 3 infants, 4 children); ii. prophylactically, before weaning of cpb (n = 4, all infants); iii. postoperatively in the icu, due to hemodynamic deterioration (n = 8, 1 infant, 7 children). iabp was inserted through the ascending aorta in infants, and through the femoral artery in children. results: there were four early deaths (mortality 21%). six infants (75%) and nine children (82%) weaned of iabp successfully. two patients required re-exploration for bleeding unrelated to iabp, and for drainage of recurrent loculated pneumothoraces. two infants developed thrombocytopenia. there were two late deaths, one due to mesenteric ischaemia and the other due to svc thrombosis. at a mean follow-up of 46 (range: 7-103) months all 13 long-term survivors (68.4%) showed normal ventricular function. conclusion: iabp is an effective modality of cardiac support in pediatric patients undergoing cardiac surgery. it can be safely used in children as well as in infants. in the latter, iabp insertion through the ascending aorta eliminates possible complications. introduction: anomalous origin of the left coronary artery from the pulmonary artery (alcapa) is a rare congenital lesion that results in myocardial ischemia. patients with alcapa usually present in infancy but may not be compromised until the second or third decade. impaired cardiac function combined with progressive mitral regurgitation leads to severe congestive cardiac failure or cardiogenic shock. early surgical repair to establish a two coronary system is indicated either by direct coronary reimplantation or intrapulmonary baffling together with mitral valve repair if necessary. long-term results are excellent. methods: between august 1997 to september 2003, ten patients with alcapa underwent surgical repair. age was between 2 months and 16 year. m/f was 4/6. eight patients were under 5 months; one10 years and another 16 years. five infants presented with cardiogenic shock on inotropic support and intubated prior to the surgery. all the patients were associated with moderate to severe mitral regurgitation. the entire group exhibited reduced left ventricular function with minimal ejection fraction of 12% (12%-28%). four patients underwent direct coronary artery reimplantation. five patients were corrected by intrapulmonary baffling whilst the 16-year-old boy associated with pda and coarctation required a short gortex conduit. results: one infant who presented with cardiogenic shock and gross metabolic acidosis died from multiorgan failure. all survivors showed significant improvement of left ventricular function. one patient who had intrapulmonary baffling repair initially subsequently found baffle leak and pulmonary stenosis due to large baffle underwent reoperation for baffle repair and pulmonary artery augmentation. follow up of all the survivors showed satisfactory left ventricular function (ef 40%-68%) and grade 1-2/4 mitral valve regurgitation. discussion: alcapa often presents with cardiogenic shock during infancy. surgical repair to establish two coronary systems is the goal of treatment. the results of operation with direct coronary reimplantation or intrapulmonary baffling are excellent. recover of left ventricular function and satisfactory mitral valve function is usual in long-term. intrapulmonary artery baffling may result in supravalvar pulmonary stenosis and baffle leak, which needs close follow up and may require further operation. the left ventricle (lv) has a greater ability to tolerate hemodynamic load than the right ventricle (rv). regulation of this differential response is not known. methods: hypertrophied myocardium was obtained at surgery from 9 acyanotic pediatric pts, 4 lv hypertrophy (lvh) and 5 rv hypertrophy (rvh), age range 0.15-6.7 yrs. diagnoses included subaortic stenosis, subpulmonary stenosis, and hypertrophic cardiomyopathy. gene expression (ge) with affymetrix dna microarray gene chips was performed. after log transformation, differences in mean ge between lvh and rvh groups with p value <0.01 was considered significant. genes with â�¡ 2-fold difference between the 2 groups were characterized and correlated with severity of obstruction. immunohistochemical staining was performed to detect myocyte apoptosis with tunel assay, and fibrosis with trichrome stain in myocardium from 10pts with lvh and/or rvh. results: there were 253 genes with significant differences in expression between lvh and rvh myocardial samples. 124 genes associated with myocardial hypertrophy, cytoskeleton, apoptosis, and ion channels were up regulated in lvh. rvh group had 129 genes relatively over expressed: extracellular matrix components, phospholipase a2 and c, and mitochondrial transporter proteins. fetal gene activation was present in both lvh and rvh, with relative over expression of canf and dystrophin in the lv compared to rv (p values <.01). severity of obstructive gradients in both groups correlated positively with actin and myosin ge, and negatively with apoptosis related genes (r = 0.8-0.9). anp ge correlated with lv obstruction only. fibrosis and myocyte apoptosis was present in both lvh and rvh specimens, but was greater in pts with hcm than those with isolated outflow tract lesions. conclusion: myocardium from hypertrophied lv and rv has different genomic profiles. upregulation of genes in the lvh group that activate adaptive pathways may contribute to the functional advantage observed in the lv vs. the rv with hemodynamic load, especially in pts with congenital heart disease. further analysis of these candidate genes and downstream signaling effects are warranted. key words: gene expression, ventricular hypertrophy, and congenital heart disease background: extracorporeal membrane oxygenation (ecmo) can be used to support children with severe graft failure after heart transplant (tx). severe graft failure may result from poor myocardial preservation, high pulmonary vascular resistance (pvri) or acute hemodynamic rejection. the use of ecmo as therapy for acute hemodynamic rejection has not been well described. methods: medical records of all patients (pts) requiring ecmo post-tx were reviewed. results: from 1984 to 2003, 9/215 (4%) pts required ecmo post-tx; age range 2.5 wks to 8 yrs. pre-tx diagnoses included: cardiomyopathy (5pts), congenital heart disease (3pts) and lv tumor (1pt). initiation of ecmo occurred 0-75 days post-tx. ecmo was necessary to wean from cardiopulmonary bypass in 5 pts; 2 with high pvri, 2 with poor myocardial preservation, and 1 with severe branch pulmonary stenosis. ecmo was initiated in 2 pts<4 days post-tx for an anaphylactic reaction (1pt) and aspiration pneumonia with high pvri (1pt). two pts with acute hemodynamic rejection required ecmo at 1 month (mo) and 2.5 mos post-tx. median ecmo duration was 5 days (range 0-8). one pt with high pvri died on ecmo day 1 from hemorrhage. eight pts were successfully decannulated and 7 survived to hospital discharge, with a mean follow-up of 4.6â±5.4 yrs (range 0.1-15). one pt with poor myocardial preservation was supported for 8 days as a bridge to retransplant, and 2 pts died from sepsis at 10 mo. and 15 yrs post-tx. ecmo morbidities included: stroke (4 pts, with complete resolution of deficits in 2), pulmonary hemorrhage (3pts), and cardiac tamponade (2pts). in the 2 pts with graft failure from acute rejection, ecmo duration was 5 and 6 days; both regained normal heart function and were successfully decannulated without complications. conclusions: ecmo is an effective therapy in the child with severe graft failure post-tx, with 7/9 pts (78%) surviving to discharge. the indications for ecmo post-tx include treatment of immediate graft failure as well as rescue therapy in the patient with severe acute hemodynamic rejection. key words: ecmo, heart transplant, graft failure, acute hemodynamic rejection background: ventricular assist device (vad) support is well established in treating adults with end-stage heart disease. there are limited data on using vad support in children with acquired or congenital heart disease (chd), or adults with chd. this study describes a single center's experience using vads in this patient (pt) population. methods: retrospective review of pts with chd or cardiomyopathy (cm) who required vad support. results: seven pts were identified. there were 5 pediatric pts, with a mean age of 15.3 years (9-19)) and mean weight of 74.6 kg (24-112); and 2 adult pts (37 and 38 years) with a mean weight of 64.8kg. diagnoses in pediatric pts were dilated cm in four, and corrected transposition of the great arteries (ctga) in one pt. one adult pt had ebstein's anomaly of the tricuspid valve and the other had single ventricle and failed fontan. pts were supported for a median duration of 57 days (range 11 to 164). devices used were vented-electric heartmate (n = 2), thoratec (n = 3) and novacor (n = 2). routine cannulation was performed for lvad (n = 4) or rvad (1 pt with ebstein's). the pt with ctga required modified orientation of the device (''back-to-front''). the failed fontan pt had systemic venous and main pulmonary arterial cannulation. outcomes: four pts survived to hospital discharge (1 bridged to recovery, 3 bridged to transplant), and 3 died on vad. two deaths were due to neurological complications and one due to fungal sepsis. there was one late death seven months post-transplant due to rejection. at a median follow up of 39 months after vad explantation, the 3 survivors are in nyha class i (n = 2) and ii (n = 1). conclusions: vads may be used to provide support for pediatric pts with chd or cm, or adults with chd. pathophysiology, anatomy, and size constraints in younger pts impact device implantation, orientation, and management. shortterm survival (4/7, 57%) is similar to that of adult pts with acquired heart disease. key words: mechanical circulatory support, pediatric, vad, congenital heart disease, and cardiomyopathy background: measurement of whole blood b-type natriuretic peptide (bnp) levels has been shown to detect heart failure in adults presenting with dyspnea in the acute setting. because heart failure has varied etiologies and can be difficult to differentiate, and bnp levels are age-dependent, the utility of this test was assessed in children. methods: bnp levels obtained over an 11-month period were reviewed. indications were known active heart disease compared to unknown etiology of dyspnea or hemodynamic abnormality. the triage ã� bnp bedside elisa test was used. results: of 62 subjects tested (range 0.3-37yrs of age), 7 were above 21yrs and all 7 had childhood forms of heart disease. controls (n = 16, median age 10yrs) were later proven to not have active heart disease and bnp was ordered to query presence of cardiac disease/dysfunction. heart disease group (hd, n = 46, median age 12yrs) include 8 with restrictive and 23 (5 also with single ventricle physiology) with dilated cardiomyopathy (dcar), 9 with shunt or outflow obstruction, and 6 have a fontan. all had normal systolic function except for the dcar group. 4/16 controls and 18/46 hd were inpatients; 2 and 34 required inotropes/decongestion medications, respectively. excluding the fontan group, the median bnp level was 13 for controls and 265pgm/ml for hd. using a bnp cutoff of 40, the sensitivity for active hd in this population was 85% and specificity 81%. the positive predictive value was 92% and negative predictive value 68%. 6 subjects with a fontan (median age 9yrs) were separately assessed because they had normal ventricular function and bnp is thought to derive mainly from the ventricles. their bnp's ranged from 5-54, mean 22, even though 3 were hospitalized and on decongestive drugs for ''failed fontan heart failure''. a total of 39 subjects had concurrent hemodynamic studies. using an rvedp <6 and pulmonary artery wedge pressure<11mmhg as normal filling pressures, the group with normal rvedp and wedge (n = 16, mean bnp 30pgm/ml) had a specificity of 71% and npv 77% (vs. one high pressure group) and 91% npv (vs. two high pressures group). the group with high rvedp and wedge (n = 21, mean bnp 626pgm/ml) sensitivity was 95% and ppv 83%. the group with high rvedp or wedge had a sensitivity of 89% and ppv 86%. analyzed by severity of presentation, low severity having<2 of the following criteria hospitalized, on medication, or dyspnea with routine activity, controls with low severity had a mean bnp 16 vs. hd low severity 62 (ns); high severity control 38 vs. hd high severity 810pgm/ml (p<.01). the p value between hd high severity vs. hd low severity group was <.01. conclusion: elevated bnp is associated with severity, filling pressures, and active heart disease in the pediatric population. the sensitivity of the test appears to be stronger than the specificity. however, heart failure specific to the cavopulmonary connection does not appear to be associated with an elevated bnp. key words: bnp, heart failure, pediatrics vasodilatory shock after cardiopulmonary bypass in children: use of low-dose vasopressin. lechner e, mair r, tulzer g, fraser cd*, chang ac*, children's heart center linz *texas children's hospital. systemic vasodilation and severe hypotension can occur due to septic shock or from systemic inflammatory response after cardiopulmonary bypass. successful vasopressin -therapy of vasodilatory shock secondary to sepsis or systemic inflammatory response syndrome after cardiopulmonary bypass in adults has been reported previously. data on the use of vasopressin in children with vasodilatory shock, however, is very limited and indications as well as dosing have not been established. we want to report two cases, which demonstrate the successful and save use of vasopressin in the treatment of vasodilatory shock following cardiac surgery in children. the first case is a 13 year-old male who developed vasopressor-resistant hypotension after cardiac surgery for endocarditis. as norepinephrine resulted in aggravation of the preexisting ventricular arrhythmia, vasopressin was used to maintain blood pressure. the vasopressin continuous infusion was started at 0.00002 uaekg )1 aemin )1 and titrated up to 0.0003 uaekg )1 aemin )1 . this low dose led to resolution of hypotension without causing side effects. the second case report is about a newborn that developed severe vasopressor-resistant vasodilatory shock following an arterial switch operation. vasopressin was started at an infusion rate of 0.0001 uaekg )1 aemin )1 and 15 minutes later increased to 0.0002 uaekg )1 aemin )1 . this dose led to resolution of the hypotension and increased urine output within 30 minutes. there were no side effects observed. in selected patients with vasodilatory shock after cardiac surgery, low-dose vasopressin seems to be a very potent agent compared to traditional vasopressors. (even when traditional vasopressors fail) since indications, dosing and duration of intravenous vasopressin therapy have not been established, its cautious use in children is recommended. often, due to the severity of illness and rapid deterioration, there is no opportunity to prepare or educate the child prior to implantation of the device. we wish to report our experience of helping pediatric patients adjust to the postoperative psychological and psychosocial impact of the device. methods: recognizing the importance of human growth and development, a multidisciplinary team worked with patients and families to increase familiarity with the device, encourage mastery, coping and expression of feelings. age and developmental level of the patients were considered and individual teaching plans were implemented. four categories of education emerged: breaking the news, living with the lvad, normalizing the experience, and preparing for transplant. beginning when the child emerged from anesthesia, the child life specialist and bedside nurse began explaining why the device was placed and its importance in their treatment. the child life specialist, with parental involvement, used ageappropriate materials to give the child an understanding of how the machine worked. pictures and mirrors were used to demonstrate how the device looked on their body. as patients recovered, the multidisciplinary team assisted patients and families manage life with the lvad. this included using distraction and guided imagery during daily dressing changes, pt/ ot therapies, ambulation, and transfer to the portable device to allow patients fewer restrictions and more mobility. normalizing the experience of living with an lvad is critical. a daily schedule was created including tutoring, participation in music and art therapy as well as cardiac rehabilitation in the exercise lab. visits to the ward and playroom with nursing staff were coordinated to foster peer relationships and to aid in social adjustment. results: since 1998 eight children have undergone lvad placement (3 heartmate/ 5 thoratec). median age at implantation was 12 years (range 6 to 21 years). three were female and five were male. dilated cardiomyopathy existed in seven patients and ventricular tachycardia induced heart failure in one. one patient was bridged to recovery, five patients were successfully bridged to heart transplantation, one patient expired, and one is awaiting transplant. average duration of support on lvad was 13 weeks (range of 10 days to 9 months). complications included bacteremia, endocarditis, cutaneous vad site infections, postoperative bleeding, and stroke. transition to the ward with the lvad was possible for five patients. school instruction was arranged for six patients and five attended school. all received child life services, art and music therapy, physical and occupational therapy. six patients participated in cardiac rehabilitation, four in the cardiac rehabilitation center. no intentional manipulation or disruption of lvad function occurred. working collaboratively with patients and families, the multidisciplinary team successfully helped patients cope and emotionally prepare for transplantation. conclusions: despite a lack of opportunity for preoperative teaching and preparation prior to placement of the lvad, pediatric patients can be successfully supported and can adjust with age appropriate and developmental educational strategies provided by a multidisciplinary care team. . adult pts requiring ventricular assist device (vad) support prior to ctx are at increased risk for high pra compared with pts not on support. purpose: we report one pediatric ctx centers experience with high pra in pts on vads. methods: we reviewed the histories of all pts who received pulsatile vad support between 1998 and 2003. results: we identified 8 pts, age 6 to 21 yrs (median 12 yrs); 3 pts were supported with heartmate and 5 pts with thoratec vads. prior to vad, pra was negative to weakly positive for class i and class ii antigens in all pts. serial pras were obtained every 2-3 wks. all pts had multiple transfusions of red cells and other products during and after vad placement, averaging 35 exposures per pt (range 20 to 58). four pts had infections requiring treatment while on vad support: candidemia (1), candidal endocarditis (1), pseudomonas bacteremia (1), paronychia (1) and cutaneous vad site infection (2). two pts (both with thoratec vads) developed high pras: 1 spontaneously resolved in 3 wks; the other remained elevated to 98% class i and 1% class ii antigens, and received a favorable prospective cross match at ctx. this pt had intensive immunotherapy at induction and post-ctx with plasmapheresis, ivig, atg, steroids, tacrolimus, sirolimus and mycophenolate. despite these measures, the pt had 4x rej >3a early post-ctx, treated with steroids and daclizumab; rej is now controlled and heart function is good. the average rej frequency for vad patients without high pra was 0.6 rej/pt/yr. of the 8 pts, 5 received ctx and are alive, 1 pt awaits ctx, 1 pt died while waiting, and 1 pt recovered and vad was explanted. conclusions: pra elevation, in pediatric pts on vad support, occurs infrequently despite common post-vad complications including multiple transfusions and infections. prospective crossmatching may not protect against severe rej in pts with high pra. further study is necessary to determine specific immunologic contributions of underlying risk factors. key words: ventricular assist devices, heart transplantation, pediatrics, and panel reactive antibody. pulsatile ventricular assist devices (pvads) are commonly used in adults with end stage heart failure. experience with pvad support in children is limited. purpose: we report one pediatric cardiac transplant (ctx) center's experience with pvad support. methods: we reviewed the charts of all patients (pts) on pvad support between 1998 and 2003. results: we identified 8 pts, age 6 to 21 years (median 12 yr, avg 13.9 yr) who received pvad therapy. weight ranged from 22 to 76 kg, 3 pts were<30 kg. bsa ranged from 0.85 to 2.16 m2, median 1.8 m2. diagnosis in 7 pts was dilated cardiomyopathy; 1 pt had heart failure associated with ventricular tachycardia. vad inflow cannulation was via the left ventricular apex in 7 pts, and via the left atrial appendage in 1 pt. post-vad implant bleeding occurred in all pts, with an average of 35 donor exposures (range, 20-58 units, all blood products including platelets, plasma, and cryoprecipitate) per pt. two pts required reoperation for bleeding. two pts developed early right ventricular failure on vad, but neither required bi-vad support. four pts had infections requiring treatment while on vad support: candidemia (1), candidal endocarditis (1), pseudomonas bacteremia (1), paronychia (1) and cutaneous vad site infection (2). thromboembolic stroke occurred in 1 pt. two pts developed elevated panel reactive antibody levels. no pt suffered vad malfunction. average time on vad was 12 wks (range 10 days to 8.8 months, median 62 days). of the 8 pts, 5 received ctx and are alive, 1 pt is awaiting ctx, 1 pt died (of stroke) while waiting, and 1 pt recovered and vad was explanted. kaplan-meier survival estimate was 88% at 2 years post-vad insertion (95% confidence interval 65% to 100% survival at 2 years). conclusions: pvad support can be used in pediatric pts as a bridge to transplant or to recovery. complications of pvad therapy are similar to those seen in adult pts. survival for pediatric pts on pvad is similar to, if not better than, that reported in adults. key words: ventricular assist devices, pediatrics, heart failure, and heart transplantation. background: an abnormal origin of the left main coronary artery from the pulmonary trunk (alcapa) causes chronic global left ventricular (lv) ischemia and secondary lv dysfunction. after coronary reimplantation, good recovery of lv function is generally described. however, few data are available on residual regional myocardial dysfunction. strain () (%) and strain rate (sr) (1/sec) imaging, derived by ultrasound allows quantification of regional myocardial function. methods: 13 patients after alcapa repair were included. ventricular function was assessed by both standard echocardiographic indices and sr/ imaging. aim: to evaluate right ventricular (rv) and lv longitudinal and radial function in 13 alcapa patients late after repair (>1 year) and to compare these data with 33 age comparable healthy children. results: lv and rv dimensions as well as lv fractional shortening were within normal range. mitral ring displacement was reduced for both lateral and septal motion (p <0.001). tricuspid ring displacement was normal. radial function in alcapa patients was normal as assessed by ultrasonic /sr imaging (patients: = 49 â± 12; sr = 3.4 â± 1.6 vs. normals: = 55 â± 12; sr = 3.4 â± 1.6, p = ns). regional longitudinal function, assessed by /sr imaging, was significantly reduced in alcapa patients (p<0.05). this reduction was homogeneous for each wall studied. rv regional deformation assessed in the rv free wall was normal. conclusions: late after coronary reimplantation, lv longitudinal function remains significantly reduced in alcapa patients while regional radial function completely normalizes. prolonged chronic global ischemia may have produced local subendocardial fibrosis selectively impairing long axis function. long-term consequences of reduced long-axis function must be followed. this study examines the use of ultrasound-based strain and strain rate imaging for detecting early regional changes in myocardial function in patients with duchenne muscular dystrophy (dmd). we examined 22 dmd patients aged 7.4 â± 2.6 years (range 3 to 11 years). data were compared with measurements in 29 age-matched normal controls (mean age 7.3â±2.8 years, range 3-11 years). both standard gray-scale echocardiographic measurements as well as doppler myocardial imaging data were obtained. doppler myocardial velocities, peak systolic strain rate and strain were estimated both in the radial (inferolateral wall) and longitudinal directions from the lv lateral wall, interventricular septum and rv lateral wall. standard scale-scale ultrasound indices of left ventricular function (e.g. fractional shortening; diastolic function parameters, etc.) were not different in the patient group compared to normal controls. myocardial tissue velocities were only significantly reduced in the lv lateral wall. a highly significant decrease in radial peak strain rate and strain was found in the inferolateral wall (sr 3.0â±0.4 )s vs. 4.3â±1.2 -s , p <0.001 strain 39â±12 vs. 62â±13, p <0.001). longitudinal strain rate was also reduced in the lv lateral wall ()1.8â±1.0 )s vs. -2.3â±0.9 )s , p <0.05) but not in the interventricular septum. longitudinal strain was significantly reduced in the lv lateral wall ()16â±8 vs. -28â±10, p <0.001) as well as in the interventricular septum (-22â±7 vs. -27â±7, p <0.001). the doppler myocardial imaging parameters measured in the rv lateral wall were normal. we conclude that by using strain rate and strain imaging in young duchenne patients a decrease in deformation parameters can be observed especially in the lv inferolateral wall. this suggests early cardiac involvement in the disorder. this has possible implications for the medical treatment of this patient group. moreover the technique has the potential to be used in clinical practice for detecting early myocardial dysfunction. purpose: levosimendan (ls) is a novel cardiovascular drug for the treatment of heart failure. ls improves myocardial contractility without causing an increase in myocardial oxygen demand. ls sensitizes troponin c to calcium, thus improving contractility. this sensitization is lost during diastole, allowing normal or improved diastolic function. ls also leads to vasodilatation through the opening of atp-sensitive potassium channels. the maximum recommended dose for intravenous administration is a bolus dose of 12-24 lg/kg followed by an infusion of 0.2 lg/kg/min for 24 hours in adults. the intravenous formulation of ls is indicated for short-term treatment of acutely decompensated severe chronic heart failure in adults. the purpose of this study is to evaluate our initial experience of ls in pediatric cardiac patients. methods: patient data and dosing by september 30 th 2003, ls has been given to 54 patients in our hospital, 1-4 times per patient, total amount of 81 times. data of 33 patients is presently included in this study. 24/33 patients received ls after cardiac operation or during weaning from perfusion. 7/33 patients had dilated cardiomyopathy and have received several doses of ls. one patient with earlier operated fontan received ls for acute heart failure. one patient with previously transplanted liver received ls for pulmonary hypertension. the mean age of the post operatively treated group was 0.27 years (range 0.01-6.1) and the mean age of the cardiomyopathy group was 9.5 years (range 0.01-17.9). the post op group received mean of 1.3 infusion (range 1-3) and the cardiomyopathy group mean of 2.3 infusions (range 1-4). all patients had other vasoactive drugs parallel with ls. loading dose of 12 lg/kg was given in 42/47 treatments. infusion of 0.1-0.2 lg/kg/ min was given following the loading dose. results: a loading dose of 12 lg/kg followed by an infusion of 0.1 to 0.2 lg/kg/min for 24 h was well tolerated. most patients had no clinically important effect on blood pressure or heart rate. however, 2/33 patients had mild hypotension, 1/ 33 mild headache and 1/33 sinus tachycardia. all these patients were from the cardiomyopathy group. 4/33 patients died with no connection to levosimendan treatment. 3 of these patients were from the postoperative group and one with late heart failure after fontan operation. ls was used for weaning from cardiopulmonary perfusion in 5 patients, with a failure to wean with normally used inotropes. 3/5 patients were weaned successfully after initiation of ls treatment, 2/5 patients were converted to left ventricular assisting device (lvad). both of these patients were weaned from lvad with ls. conclusion: early experience of ls in children after cardiac surgery or dilated cardiomyopathy indicates that ls is well tolerated. however, prospective pediatric studies are needed to evaluate possible advantages of ls compared with currently used vasoactive drugs. key words: levosimendan, heart failure, cardiomyopathy methods: 20 children were studied, age range from 2 to 192 months (median 32.5 months). the ted transducer emitting a 4-mhz continuous wave doppler signal was introduced orally and advanced until the characteristic descending aorta waveform was obtained on the monitor (edm ii, deltex ltd, chichester, uk). seven consecutive values of minute distance (md) were calculated and the mean taken. simultaneously the heart rate, mean blood pressure, central venous pressure and lab variables such as base deficit (arterial blood gas analysis) and blood lactate were measured and the mean for 7 consecutive values was taken for each parameter. following a fluid challenge, seven repeat pairs of measurement were made. results: scatter plot of the mean percentage difference of md against the other variables showed that there was minimal degree of linearity between the heart rate, mean blood pressure, lactate level and base deficit for the difference pre and post fluid infusion. however central venous pressure percentage difference showed more marked negative linearity. linear regression univariate analysis showed that there was no correlation between md and heart rate, mean blood pressure, lactate level and base deficit. in the case of central venous pressure percentage changes there was a definite correlation but with borderline significance (p = 0.09). our ted data showed consistent values with excellent reproducibility, confirming the accuracy of the technique. conclusions: clinical and laboratory assessment of hemodynamic status is not always reliable in critically ill children. it is therefore important to have an accurate estimate of cardiac output using a noninvasive technique such as ted, which avoids the risks associated with pulmonary artery catheterization. introduction: levosimendan is a new inodilator, whose mechanism of action includes calcium sensitization of contractile proteins and the opening of atp-dependent potassium channels. unlike inotropic drugs (b adrenergic agents and phosphodiesterase inhibitors) these drugs improve cardiac performance without intracellular calcium and camp elevation. patients and methods: we show our first two patient experience using levosimendan in our cicu. data was obtained from the patient's medical charts. intravenous loading dose was 6 mcg/ kg, followed with a continuous infusion of 0.1 -0.6 mcg/ kg/ min during a 24-hour period. clinical response was estimated through the patient's clinical condition and continuous monitoring, including heart rate and rhythm, cvp, invasive ap, urine output, arterial lactic acid and acid-base status, together with mechanical ventilation (mv) requirements and daily blood creatinine. informed consent was obtained from both parents. case 1: twelve-month-old girl, with diagnosis of dilated myocardiopathy, waiting for cardiac transplantation. referred to our unit from another institution, she was admitted in severe cardiac failure in spite of a dopamine infusion of 8 mcg/ kg/ min. milrinone was added without any significant clinical improvement. ten days after she progressed to cardiogenic shock and multiple organ dysfunction. mv together with peritoneal dialysis (pd) and an epinephrine infusion (0.1 mcg/ kg/ min) were started. twelve hours later she was still hemodynamically unstable and levosimendan was introduced in the aforementioned doses. forty-eight hours later the girl had improved significantly, being hemodynamically compensated, requiring less mv pressures and with a normal diuretic response, without any pd requirements. levosimendan was re-infused 7 days later, allowing the patient to get her heart transplant 15 days after the infusion. case 2: five-year-old girl with l-tgv, multiple vsd (perimembranous and apical) and pulmonary atresia. she had undergone two previous b-t shunts (right and left, at age 5 days and 2 years). she also had light systemic a-v valve insufficiency. a rastelli surgical procedure was performed. pos-op she developed a severe low cardiac output syndrome progressing to a multiple organ dysfunction requiring mv, epinephrine and milrinone infusions. seven days later she was extubated but had to be reintubated 24 hours later. cardiac catheterization was performed which showed no significant residual defects but little muscular vsd (qp/ qs 1.4 / 1). end diastolic pressure was high in both ventricles (22 mm hg). levosimendan was started using usual doses. forty-eight hours later she was successfully weaned from the ventilator, and discharged home a week later. follow up shows nyha class i -ii. conclusion: our short experience with the use of levosimendan shows a satisfactory clinical response, successfully bridging a patient to undergo cardiac transplantation in one patient, and helping in weaning a patient from mv and consequently discharging her home. more studies are needed in order to confirm levosimendanâ´s usefulness in congestive heart failure in children. cardiac transplantation is the end result of treatment of heart failure in many affected children. despite good early survival following heart transplantation in children, death or re-transplantation may occur from a variety of reasons including graft failure (gf) due to acute and chronic rejection. late gf in the pediatric heart transplant recipients is of great concern due to the reasonable expectation of greater longevity for these patients. the time related incidence of gf defined as death or retransplantation due to primary graft dysfunction, acute rejection, or chronic rejection has not been examined in pediatric patients. we hypothesized that the probability of gf would increase over time due to chronic rejection with graft atherosclerosis. methods: data from the 20 centers participating of the pediatric heart transplant study was analyzed to determine the incidence of gf over time and risk factors for gf. all patients ranging in age from 0 to 18years who underwent transplantation from jan. 1,1993 1, through dec. 31, 2001 were included in the analysis. actuarial and parametric methods were used to determine time-related incidence of gf. recipient and donor variables were included in both a univariate and multivariable risk factor analysis. results: 1205 patients underwent transplantation with 162 patients dying and 33 requiring re-transplantation for gf. freedom from gf was 90% at one year, 79% at 5 years, and 70% at 8 years. parametric survival analysis demonstrated an early phase and an accelerating late phase of risk for gf. the late phase was most apparent in recipients greater than 10yrs of age at transplant with 55% freedom from gf at 8 years post transplant compared to 75% for recipients less than 10yrs of age at transplant. this late phase of accelerating risk was not seen in infants transplanted at less than 6 mos. risk factors for early graft failure included younger patient age at transplant, failure to use induction therapy, and longer ischemic. late phase risk factors were older patient age at transplant, black recipient race, and previous cardiac surgery. black recipients were nearly twice as likely to die of graft failure by 5 years post transplant compared to white and hispanic recipients. conclusions: almost one third of pediatric heart transplant recipients will experience gf within 8 yrs of transplant. the presence of a late phase of accelerating gf is an important limitation on survival following heart transplantation in children. the absence of a late phase for gf in infants may reflect the development of graft tolerance in this group. late gf is more likely in older patients and black recipients. high-risk groups warrant enhanced rejection surveillance and immunosuppression to prevent gf due to acute and chronic rejection. background: information on myocardial remodeling in pediatric heart disease is sparse. our aim was to study whether expression of the cardiac sarcoplasmic reticulum ca2+-atpase (serca) and phospholamban (plb) is different in volume overloaded compared to not overloaded atrial myocardium and wether this is different in younger vs. older patients. methods: rt-pcr was used to measure mrna expression of serca and plb in atrial myocardium from 18 pediatric patients with volume overloaded right atrium and 12 patients with not overloaded atria. results: amount of transcripts was expressed as mrna molecules per 10000 28s rrna molecules. in the entire group serca mrna was lower in the volume overloaded (vo, 22â±11) compared to the not overloaded (no) atrial myocardium (38â±23, p = 0.01). there was no more difference if only the patients older than 24 (n = 10) months of age were compared (vo group 25â±15 vs. 30â±12 in the no group, p = 0.5), in the younger patients (n = 8) there was still a significant difference (vo group 20â±6 vs. 43â±28, p = 0.03). the plb mrna did not differ between vo (74â±51) and no group (120â±118, p = 0.17), again, there was a tendency to lower mrna expression in the vo group (56â±24) vs. the no group (156â±155, p = 0.09) if only patients under 24 months of age were investigated. comparing the overall group regardless of hemodynamic overload in regard to age no statistical significant difference was found between patients older than 24 months of age vs. patients younger than 24 months of age, neither for serca (p = 0.5) nor for plb (p = 0.5). conclusions: in this study we could show a significant difference of serca mrna expression in volume overloaded atrial myocardium only in patients younger than 24 months of age, also for plb there was a tendency to diminished mrna expression only in the younger patient group. this is in contrast to former reports comparing pressure overloaded ventricular myocardium in sheep (aoyagi t et al., ped res, 2001, 50: 246-253) , which showed reduced serca mrna only in adult sheep. these results are of importance as we know of age dependent differences in expression of serca in different species and in the neonate, however this study is the first investigating the combined influence of age and hemodynamic overload on pediatric atrial myocardium. as molecular changes in animal and even in adult human cardiac disease can not be adopted to the situation in infants and young children this paper adds further insights in in pediatric cardiac disease. purpose: myocardial ischemia-reperfusion (ir) stimulates the activity of cysteine proteases called calpains. calpain activity is associated with interruption of calcium-regulated contraction, degradation of contractile proteins, and enhanced cell death. immature myocardium has been shown to have elevated levels of calpain suggesting an enhanced role in neonatal ir. we hypothesized that calpain inhibition could reduce myocardial injury during ir. methods: a model of deep hypothermic circulatory arrest with cpb (dhca-cpb) was utilized. eight neonatal piglets (controls) were cooled to 18â°c on cpb, underwent 2 hours of dhca, re-warmed, and recovered for 2 hours. hemodynamics were monitored and myocardial tissue analyzed for activation of nf-kb and pro-death pathways. an additional 6 animals received 1mg/kg of the peptide calpain inhibitor (z-leu-leutyr-fmk) 1 hour before cpb and dhca. results: oxygen delivery was significantly depressed in controls at end-recovery (260 +/) 5 ml/min), but was maintained in treated animals (955 +/) 17ml/min, p <.05). calpain activity was decreased in treated animals compared with controls (102+/)22 vs. 185+/) 27 fluorescent units, p <.05) calpain inhibitor animals had higher ikb protein levels (0.61+/) .2 vs. 0.18 +/) .16 ikb/gapdh protein ratio, p <.01), and decreased nf-kb activity (80+/)22 vs. 137+/)27 densitometry units, p <.05) at end-recovery compared to controls. treated animals also demonstrated less bid cleavage and decreased caspase activity compared with controls: 37+/)10 vs. 59+/)3.5 expressed as % 15kd of total bid protein, p <.05; and 0.47+/).33 vs. 0.8+/).48 devdase activity, p <.05, respectively. conclusions: calpain inhibition resulted in maintenance of ikb and decreased nf-kb activity, which would be expected to correlate with decreased acute injury, and improved function as evident by improved oxygen delivery. decreased bid cleavage and decreased caspase activity were evident with calpain inhibition, which along with decreased nf-kb activity would likely correlate with a decrease in apoptosis and hence, decreased permanent myocardial injury. calpain inhibition decreases both acute and permanent myocardial ischemia-reperfusion injury through at least two separate pathways. background: magnetic resonance imaging (mri) facilitates a true simpson's rule approach to determination of ventricular volume indices, an approach that does not depend on geometric assumptions often invalid in the presence of cardiomyopathy. however, evaluation of cardiovascular function with mri has previously required prolonged imaging times. prolonged studies are particularly difficult for pediatric patients. purpose: to determine the feasibility of performing rapid assessment of ventricular function by mri in a pediatric population with known or suspected dilated cardiomyopathy. methods: twenty-five unsedated pediatric patients (ages 8-18 yr, m = 15â±3.8) underwent ventricular functional evaluation with a balanced fast field echo mri technique. parallel data acquisition with sensitivity encoding (sense) technique was employed with sense of 2. sequence parameters were te/tr = 1.6 ms/ 3.3 ms, flip angle 55â°, 12 slices. studies were performed on a phillips 1.5 tesla scanner. a real-time interactive method was employed to achieve true short axis positioning of the contiguous slices. vectorcardiographic electrocardiographic synchronization of the measurement sequences was utilized. free breathing (free) mri ventricular functional assessment was compared to mri assessment during very short (less than 5 second) sequential breath holds (bh). a computer assisted simpson's rule technique was employed to calculate left ventricular end systolic (lvesv) and end diastolic (lvedv) volumes, ejection fractions (lvef), and mass (lvmass) from the mri data. two-dimensional echocardiographic (echo) measurements of these parameters were performed for correlation using a biplane method. results: actual mri cardiac volume data acquisition time was less than 60 seconds in each case. denfield, m.d 1, 2, 3 ., 1 department of pediatrics (cardiology), 2 texas children's hospital and 3 texas heart institute, houston, tx. background: advanced heart failure in children is associated with high morbidity and mortality and is often refractory to standard medical therapy. acute exacerbations of chronic decompensated heart failure can be successfully ameliorated by the use of parenteral inotropic therapy (pit); however, its use in children in the outpatient setting has not been described. the purpose of this study was to review our institutional experience with the use of outpatient pit for advanced heart failure in children as bridge to transplant. methods: we performed a retrospective review of our medical records for all patients treated with pit as outpatients. results: seven patients received outpatient pit from 2/99 to 10/03 (male = 5, female = 2, mean age = 14.5 years â±3.7). etiology of heart failure included idiopathic dilated cardiomyopathy (n = 1), congenital heart disease (n = 4) and ischemic cardiomyopathy (n = 2). all patients were listed for cardiac transplantation. inotropic medications used included dopamine alone (n = 1), milrinone alone (n = 4) and dopamine and milrinone in combination (n = 2). mean dose of dopamine was 2.8 mcg/kg/min â±0.3. mean dose of milrinone was 0.25 mcg/kg/min â±0.06. therapy was initiated as inpatients. doses were not adjusted during outpatient therapy. median duration of therapy was 10 weeks (range 4 to 84 weeks). the mean number of emergency department visits per patient was greater before starting pit than after starting pit for the same duration of time (2.3 â±1.8 vs 1.1 â±2.2, p = 0.03). the mean number of hospital admissions per patient was greater prior to therapy than after starting therapy (2.1 â±1.3 vs. 1.2 â±1.8, p = 0.04). the mean ef% in patients with systolic dysfunction improved while on therapy (26 â±9% before vs. 37 â±13% after, p = 0.03). there was 1 death and 5 complications in 2 patients. the 1 mortality occurred suddenly at home. complications included catheter occlusion (n = 2), extravasation of catheter (n = 2) and line infection (n = 1). six patients underwent transplantation. conclusions: these data show that continuous parenteral inotropic therapy can reduce the frequency of emergency department visits and hospital admissions and improves ventricular systolic function in children with advanced heart failure. the mortality rate did not exceed the reported frequency of death in patients awaiting cardiac transplantation. key words: heart failure, outpatient, and inotropic therapy congestive heart failure is still a major health problem in pediatric patients. it is a complex syndrome with various neuro-hormonal and neuro-humeral activation. some investigators found that cytokines as tumor necrosis factor alpha and interleukin-6 are elevated in adult cases of congestive heart failure due to ischemic and cardiomyopathic heart failure; others mentioned that they are elevated in heart failure whatever the etiology of heart failure. we aimed to determine the serum level of one of these as il-6 in cardiomyopathic heart failure and rheumatic heart disease with heart failure and to detect the correlation between its serum level with functional stage of heart failure, cause of heart failure and left ventricular systemic dysfunction. we conducted a study involving 35 of heart failure (24 cardiomyopathic and 11 rheumatic heart disease) matched with 39 healthy control group in the same age range. cases and controls were subjected to history taking particularly for duration of illness, anthropometric measures, clinical assessment especially for stage of heart failure, echocardiography and measurement of serum level of il-6 using elisa test. we found that serum level was significantly higher in cases (95.08 â± 52.65 sd ng/dl) than in control group (7.12â± 5 sd ng/dl), significantly higher in rheumatic (119.8 â± 48.6 sd ng/dl) versus cardiomyopathic (83.7 â± 51.3 sd ng/dl) heart failure, no significant correlation with left ventricular systolic dysfunction, age, sex or esr. there was significant correlation between functional class of heart failure and the serum level of il6. serum level of il6 was significantly higher in cases of heart failure with shorter duration (<6 months, mean serum il6 was 107.9 ng/dl)) than those with longer duration (>6 months mean serum il6 level was 44 ng/dl). we concluded that il-6 is significantly elevated in heart failure and the plasma concentration of il-6 may be a clinically useful prognostic marker for longterm survival. methods: 20 cases of tof (age 3.35â±0.43) who underwent corrective procedure were selected. patients were divided into two groups according to the inotropic agents administrated, dopamine or milrinone. cardiac index (ci), the mixed venous oxygen saturation (svo2), systemic and pulmonary vascular resistance index (svri, pvri) were estimated by the thermodilution method at 3, 9, 24, 48 hours after operation. the data of 3h post-operation was considered as the baseline. results: 9 hours after surgery, cardiac index (ci) decreased 12.4% and 7.0% in dopamine group and milrinone group respectively, compared with the baseline value (p <0.01, p <0.05). 24 hours after surgery, ci of both groups had no difference compared to the baseline values (p >0.05). milrinone group had higher ci(p <0.05) and lower svri, pvri (p <0.01,p <0.05) than dopamine group (tab. 1). conclusion: tendency of lco will happen with different extent in the early post-operative period of tof. using milrinone, a phosphodiesterase-iii (pde-iii) inhibitor will benefit to prevent and treat the postoperative lco. amineva kh, gudkova a, shlyakhto e. and sejersen t,, karolinska institutet, stockholm, sweden during the past years mutation of several structural and sarcomeric proteins have been identified as causes of cardiomyopathies. among these, desmin are associated with dilated and restricted cardiomyopathies. desmin is implicated in the sarcomeric organisation, and, being associated with z-bands and intercalated disks, presents a key structure of the cytoskeleton in muscle cells. recently, we reported a desmin mutation, transmitted over several generations. this l345p missense mutation has a dominant-negative effect on filament formation, causing myopathy and cardiomyopathy. a transgenic mouse strain (dm), carrying the desmin l345p mutation, was developed in order to evaluate the effect of this mutation on cardiac and skeletal muscle pathology and function. transgenic animals with normal desmin gene were used as a control (ds mice). expression of transgenic desmin was confirmed by immunohistochemistry and western blot analysis using ha-tag antibody. here, we present data on morphological and functional analyses of heart muscle in dm and ds animals. results: in 28 week old dm mice an increase of stromal cell number, due to lymphocyte and fibroblast-like cell infiltration, was observed. cardiomyocytes, embedded in collagen fibers, and focal amorphic protein depositions in arterial adventitia and perivascular spaces were often found. in 69 week old dm mice these depositions were more prominent, being present in vascular walls, perivascular space and between muscle fibers. the latter were accompanied by granuloma formations, and caused a disruption of tissue architecture. histiocyte-like and macrophage-like cells were observed in perivascular and intermyocyte spaces. enlarged cardiomyocyte nuclei contained 1-3 nucleoli. in some myocytes perinuclear vacuolisation were observed. degree of cardiomyocyte disarray varied from mild to moderate, being more prominent in areas of fiber disruption and protein depositions. in these areas cardiomyocyte nuclei were enormously big, containing 4-5 nuclei. most of these changes were not found in ds mice, except slight variation of nuclear size and microfoci of protein depositions. conclusions: the l345p desmin mutation causes focal protein deposition in vascular walls, perivascular areas and intermyocyte spaces, accompanied by an increase in stromal cell numbers and formation of granulomas. these changes may be responsible for the development of desmin-related cardiomyopathy. remarkable progress has been made over the last 10 years on ventricular assist devices (vad) for adults with failing ventricle. but only small series describe vad as a system to keep children with otherwise intractable heart failure alive until myocardial recovery or transplantation. the berlin heart: consists of extracorporeal pneumatically driven blood pumps made out of polyurethane (10, 25, 30, 50, 60, 80 ml stroke volume), within a multi-layer flexible polyurethane membrane separating this pump-chamber into a blood and an air chamber. three-leaflet polyurethane valves in the small and mechanical valves in the larger pumps prevent blood reflux. four silicon cannulae connect the blood pumps with the right atrium and pulmonary artery, and the left atrium or apex and ascending aorta. a dacron cover in the middle part of the cannulae allows a rapid ingrowth of patient's tissue as a biologic barrier against ascending infections. the pumps are driven by a pulsatile electro pneumatic system, all bloodcontacting surfaces are heparin-coated. the drive units (ikus 2000 and heimes hd7) are both with complete back-up. patients: in 57 children, age 2 days -17 years (median 7y), artificial replacement of heart function with vad (berlin heart) had been applied for long-term support (1 -409, mean 27 days) to offer life-saving support in our hospital between 1990 and july 2003. twenty-five had lvad support and 32 were on bvad. they all were in cardiogenic shock with multiorgan failure, 8 with fulminant myocarditis, 28 cardiomyopathy without surgery before, 11 chronic stage of congenital heart disease and in 10 weaning from bypass had failed after surgery. six children were weaned from the system, 24 reached heart transplantation, 26 died on vad and one is still on the system. the overall survival of the myocarditis group is 62% and survival of the children with cardiomyopathy is 75%. causes of death were loss of peripheral circulatory resistance, multiorgan failure and shock (18), hemorrhagic and thromboembolic complications (7) and one brain death. the problems were thrombosis, bleeding and rethoracotomy. there were no severe problems with infection of the system or pump dysfunction. one child has mild cerebral residuals after cerebral infarction; the other survivors are without sequel. conclusion: prolonged circulatory support with vad is an effective method for bridging until cardiac recovery even in newborns and small children. it offers time to restore organ function. extubation, mobilisation and enteral nutrition is mostly successful and if no spontaneous improvement occurs, vad increases the chance for transplantation. compared to ecmo, ventricular assist devices can be used in with low device related morbidity and satisfying results in the myocarditis and the cardiomyopathy group. background: mechanical support with a pulsatile pneumatic ventricular assist device is a complex rescue procedure performed in children with untreatable cardiogenic shock. its impact on early and long-term survival after subsequent heart transplantation remains to be determined. methods: we reviewed retrospectively the course of 95 children (median age 8 years, range 8 days -17 years, body weight 24 kg, range 3 -110 kg) with heart transplantation. the elective-htx group (a) consists of 33 children who were treated as outpatients before transplantation. the emergency-htx group (b) comprises 44 children who were critically ill and in hospital before transplantation but without a ventricular assist device, whereas the vad-htx group (c) consists of 18 children resuscitated and supported with a pulsatile pneumatic ventricular assist device for a median time of 20 days. results: overall actuarial survival after cardiac transplantation was 86 % at 1 month, 82% at 1 year, and 78 % at 5 years without significant differences between the three subgroups. group a had the best long-term survival rate with 88 / 88 / 80%, b had a survival rate of 88 / 82 / 79 % and c 72 / 72 / 72 %. there were no differences in neurological outcome, acute cardiac rejections or transplant failure. the survival rate was significantly better in the children with cardiomyopathy compared to those with congenital heart defects (p = 0.014). conclusions: bridging to heart transplantation by pulsatile pneumatic assist device is a safe procedure in pediatric patients. after heart transplantation overall survival of these children is similar to that of patients who were bridged with inotropes, or were electively awaiting heart transplantation. background: in its most severe forms, cellular rejection in the heart transplant patient may present with severe cardiac failure, cardiac arrest or multiple organ failure. we present a case of acute rejection causing such problems in a 13-year-old female, managed with veno-arterial (va) ecmo. case report and methods: a 13-year-old female patient presented to our regional cardiothoracic center with complaints of increasing shortness of breath and lower abdominal pain. she had undergone cardiac transplantation 14 months previously for acute myocarditis, and was receiving tacrolimus/azathioprine immunosuppression. echocardiogram showed a significant pericardial effusion. she underwent general anesthesia for drainage of effusion and endomyocardial biopsy. during this she developed complete heart block requiring multiple cardiopulmonary resuscitation episodes and temporary pacing. she was then transferred, ventilated, to the pediatric intensive care unit (picu). she subsequently developed a low cardiac output state that required escalating inotropic therapy, accompanied by acute renal failure and hepatic dysfunction. she was given pulsed methylprednisolone therapy, as the biopsy showed acute rejection. in order to achieve hemodynamic stability and prevent progression of her multiple organ failure she was placed onto va+v ecmo, via surgically placed 23f right internal jugular vein cannula, 19f right common carotid artery cannula and 21f right femoral vein cannula. she was heparinized to an activated clotting time of 160-180 seconds. pump flow was 4.5 l/min (100ml/kg/min). a minntech hemofilter allowed hemodialysis. we used a medos 7000 oxygenator. inotropic support was subsequently rapidly weaned. there were no ecmo-related complications. total duration of ecmo was 159 hours. this allowed anti-thymocyte globulin (atg) immunosuppression. ecmo was weaned with a modest dose of inotropic support. the patient was transferred to the ward after 22 picu days (total duration of mechanical ventilation 17 days). her cardiac function remains borderline (echocardiogram shows 20% fractional left ventricular shortening). conclusion: ecmo has been used in other centers under similar circumstances but this is to our knowledge the first description of such a case in the literature. our patient progressed rapidly from non-specific symptoms to multiple organ failure as a result of acute rejection and cardiac arrest. although her condition was potentially reversible by prompt aggressive immunosuppressive therapy, this takes some days to take effect. the pace of her deterioration suggested to us that mechanical circulatory support would be required as a bridge to recovery. it is our opinion that the use of ecmo arrested the progression of her multiple organ failure pending cardiac recovery. al throckmorton 1 , a untaroiu 1 , pe allaire 1 , hg wood 1 , db olsen 2 , 1 university of virginia, charlottesville, va, usa 2 utah artificial heart institute, salt lake city, ut, usa. purpose: extracorporeal membrane oxygenation (ecmo), balloon pumps, and pediatric cardiopulmonary bypass (cpb) devices, which are intended for short-term use (less than 2 weeks at most), represent the only pediatric mechanical circulatory support options for infants, children, and young adults awaiting heart transplantation. the majority of these pediatric patients suffer from cardiomyopathy and congenital heart defects, often complicated by congenital heart disease. since donor organ waiting periods may be as long as 5 months in some cases, these patients could benefit tremendously from the availability of a mechanical circulatory support device for longer-term, bridge-to-transplant (btt) situations. in order to provide a viable, longer-term btt option for these patients, we have designed an implantable axial flow pediatric vad (pvad) with an impeller that is fully suspended by magnetic bearings. this pvad is a geometrically smaller scaled version of our adult axial flow pump and has a design point of 1.5 lpm to deliver 72 mmhg at 8000 rpm. this pump's design has been refined and optimized with consideration for rapid prototype manufacturing and magnetic suspension / motor component placement. methods: conventional axial pump design equations with non-dimensional scaling provided initial pump dimensions. a computational model of the pvad was created and analyzed under steady state flow conditions for rotational speeds of 7000 to 9000 rpm using these dimensions. state-of-the-art computational fluid dynamics (cfd) software enabled several stages of optimization to ensure performance and minimization of irregular flow patterns. results: cfd analysis of the optimized axial flow pvad, which measures approximately 65 mm in length by 35 mm in diameter, predicts the pump will produce 1.5 lpm at 72 mmhg for a rotational speed of approximately 8000 rpm. fluid forces exerted on the rotor under steady state conditions were also estimated to be approximately 1 newton, and the fluid efficiency was calculated to range from 20% to 30%, which are typical values for blood pumps. scalar stress estimations throughout the fluid field were performed with levels remaining below 500 pa with short residence times. conclusions: this optimized design illustrated excellent performance and will be the basis for prototype manufacturing and extensive experimental validation. prototype manufacturing will also facilitate initial, acute animal implant experiments. akintuerk h, valeske k, schranz d, children's heart center, university of giessen/germany elevated pulmonary vascular resistance (pvr) secondary to left heart failure and pulmonary venous hypertension may cause donor right heart failure after orthotopic heart transplantation. we report of 3 children with elevated pvr, who were placed on ecmo immediately after htx as a prophylactic treatment against right heart failure. patients: age at htx: 9, 20, 34 months. diagnoses: aortic stenosis with endocardial fibroelastosis (2), dilated cardiomyopathy (1). preop. pvr index: 11.2, 12.8, 11.7 wuxm2, pvr/svr-ratio 0.73, 0.73, 0.43. inhalative prostacyclin reduced pvr only in 1 of 3 children. results: ecmo-duration: 46, 62, 72 hrs. weaning with inhalative-no, iv-prostacyclin and inotropic support. pap/sapratio after ecmo-expl.: 0.4, 0.4, 0.3. pvr index 6 months after htx: 3.5, 3.9, 2.3 wuxm2. uneventful follow up over 7, 15, 18 months. discussion: ecmo allows the right ventricle to recover from ischemic disorder following htx and to adapt to elevated pulmonary pressures. in young children a marked reduction of elevated pvr due to left heart failure could be expected after htx. failing response to inhalative prostacyclin in the preoperative testing does not exclude this change in pvr. the level at which pvr becomes an absolute contraindication against htx in children remains unknown. conclusion: with prophylactic use of ecmo htx is feasible in children with highly elevated pvr. children's heart center, university giessen/germany comparative evaluation of clinical experience with ecmo (centrifugal pump, biomedicus) and the medosã�-vad (displacement pump, pulsatile flow). 5 months); postcardiotomy 9, primary organ failure after htx 5, prophylactic ecmo after htx in children with elevated pvr 3, rescue-ecmo in cardiac shock 1. vad: n = 11 results: ecmo: duration 2-21d (median 5.5 days); complications: bleeding 16, sepsis 1, thromboembolic 2, myocardial infarction 1 background: isolated ventricular noncompaction (ivnc) to measure noncompacted:compacted segment ratio, left ventricle (lv) size, ejection fraction (ef), and tei index, both at presentation and at most recent visit. medical records, electrocardiograms, holter recordings and heart rate variability (hrv) data were also reviewed. results: twenty-words: isolated ventricular noncompaction, cardiomyopathy, heart failure urine output increased from 3 cc/kg/hr to 9 cc/kg/hr with discontinuation of the intravenous furosemide infusion. serum sodium increased to 132, bun decreased to 30, and serum creatinine decreased to 0.6. the minimum dose of nesiritide was utilized through the entire course with no titration being necessary. serum monitoring of bnp demonstrated elevated bnp levels prior to starting the infusion. the levels increased appropriately with infusion and decreased to below baseline following infusion discontinuation. it was also noted that hypertensive blood pressure control improved with weaning from vasoactive drips being accomplished while on nesiritide infusion. conclusions: nesiritide was safely administered to a sick pediatric orthotopic heart transplant patient. the favorable effects noted were compensation of heart failure, improvement of renal function, and correction of hyponatremia. no hypotension or arrhythmias were noted. nesiritide was administered concomitantly with intravenous vasoactive medications without difficulty and allowed for the wean and discontinuation of these medications that have inherent side effects relating to blood pressure and arrhythmogenicity. nesiritide may become another option for the safe and efficacious treatment of decompensated heart failure or post-operative complications in the pediatric population. key words: nesiritide, heart failure, pediatric he developed hemodynamic compromise on post-operative day 16 and had evidence of humoral rejection on endomyocardial biopsy. he was treated with a steroid pulse (1000 mg x 1 and 500 x 2) and plasmapheresis therapy for a total of 5 consecutive days followed by high dose ivig. he was also maintained on an immunosuppression regimen of neoral (5.5 mg/kg/day divided every 12 hours), prednisone (0.3 mg/kg/day), and cyclophosphamide (1mg/kg/ day) key: cord-001199-9khx93c0 authors: liu, fengchen; enanoria, wayne t. a.; ray, kathryn j.; coffee, megan p.; gordon, aubree; aragón, tomás j.; yu, guowei; cowling, benjamin j.; porco, travis c. title: effect of the one-child policy on influenza transmission in china: a stochastic transmission model date: 2014-02-06 journal: plos one doi: 10.1371/journal.pone.0084961 sha: doc_id: 1199 cord_uid: 9khx93c0 background: china's one-child-per-couple policy, introduced in 1979, led to profound demographic changes for nearly a quarter of the world's population. several decades later, the consequences include decreased fertility rates, population aging, decreased household sizes, changes in family structure, and imbalanced sex ratios. the epidemiology of communicable diseases may have been affected by these changes since the transmission dynamics of infectious diseases depend on demographic characteristics of the population. of particular interest is influenza because china and southeast asia lie at the center of a global transmission network of influenza. moreover, changes in household structure may affect influenza transmission. is it possible that the pronounced demographic changes that have occurred in china have affected influenza transmission? methods and findings: to address this question, we developed a continuous-time, stochastic, individual-based simulation model for influenza transmission. with this model, we simulated 30 years of influenza transmission and compared influenza transmission rates in populations with and without the one-child policy control. we found that the average annual attack rate is reduced by 6.08% (sd 2.21%) in the presence of the one-child policy compared to a population in which no demographic changes occurred. there was no discernible difference in the secondary attack rate, −0.15% (sd 1.85%), between the populations with and without a one-child policy. we also forecasted influenza transmission over a ten-year time period in a population with a two-child policy under a hypothesis that a two-child-per-couple policy will be carried out in 2015, and found a negligible difference in the average annual attack rate compared to the population with the one-child policy. conclusions: this study found that the average annual attack rate is slightly lowered in a population with a one-child policy, which may have resulted from a decrease in household size and the proportion of children in the population. the one-child-per-couple policy in china was introduced in 1979 in an effort to raise living standards by slowing population growth. subsequently, the policy reduced fertility rates [1, 2] and household sizes, with only one dependent child found in most households. the total birth rate dropped from 2.90, before the policy was introduced, to 1.94 among women over 35 years of age, and to 1.73 among women under 35 years old in 2001. women's preferences for smaller families have changed (35% prefer one child and 57% prefer two children according to a study in 2001) [3] . the total fertility rate decreased from 2.9 in 1979 to 1.7 in 2004, with a rate of 1.3 in urban areas and less than 2.0 in rural areas. this trend has created a distinct demographic pattern for nearly a quarter of the world's population, resulting in chinese urban families with predominantly one child and rural families with predominantly two children [4] . the spread of infectious diseases may depend on demographic characteristics, environmental changes, consumption behaviors (eating, drinking, culinary culture, etc.), other behaviors (sexual contacts, drug use, hospital procedures, etc.), and host conditions (malnutrition, diabetes, immune status, etc.) [5] . while the one child policy has had economic, demographic, and sociological ramifications far beyond the scope of infectious disease transmission, it is important to understand the consequences for influenza dynamics, in part because china and southeast asia lie at the center of a global transmission network of influenza [6] . demographic changes may affect influenza transmission dynamics because children have an increased susceptibility due to lower immunity. moreover, increased viral shedding and longer infectious periods in children lead to more influenza among susceptible populations [7] . demographic characteristics have been incorporated into many modeling studies [8, 9, 10] to help understand the effects on transmission of influenza or the socioeconomic impact of mitigation strategies [11, 12] . household composition is an important determinant of the transmission of respiratory pathogens including influenza [13, 14, 15, 16, 17, 18, 19] and remains an important feature of recent transmission models [20, 21, 22, 23, 24, 25] . this paper presents a study focusing on the indirect effects of demographic changes on influenza transmission. we developed a continuous-time, event-driven, individual-based stochastic simulation model for influenza transmission in a dynamic population. we used this model to simulate transmission while assuming different demographic control policies: the one-child policy, the absence of any control policy, and a strict one-child policy. the strict onechild policy was introduced to compare influenza transmission rates with a hypothetical one-child policy to rates with an actual one-child policy, since two or more children are often allowed in rural areas and for ethnic minorities [4] ; the existing census data do not reflect the effects of truly restricting families to one child. the model was used to simulate 30 years of influenza transmission in a dynamic population as follows: (1) we initialized the population using 1975 demographic data (four years before a one-child policy was fully launched in china); (2) we calibrated the population projections by fitting the simulated population with the one-child policy to the census and compared the simulated population without the one-child policy with projections from previous literature [26, 27] in which population growth was predicted under different demographic control policies; (3) we calibrated the influenza-specific parameters by fitting the annual attack rate and secondary attack rate from the reported literature [7, 28, 29, 30, 31, 32, 33] ; and (4) we compared the simulated annual attack rate and secondary attack rate in simulated populations with and without the one-child policy. in the plenary sessions of the 2011 chinese people's political consultative conference and the national people's congress, a two-child policy was proposed to start as early as 2015 [34] . experts suggested that the one-child policy may threaten china's economic growth due to the increase in the number of older people, a decrease in the number of younger workers, as well as a sex-ratio imbalance [34] . because a two-child policy was proposed to start as early as 2015 [34] , we also forecasted influenza transmission over a ten-year period (2015 to 2024) in a population with a two-child policy. our model has three main features: (1) influenza transmission, (2) population demographics, and (3) dynamic network structure. we used a susceptible-exposed-infectious-recovered (seir) model which included waning immunity and seasonality of influenza transmission. we used census data [35, 36, 37, 38, 39] (table 1) from china, to construct a population with demographic changes under a one-child policy. a simple dynamic network structure was used to group people with household links, school links and social links, allowing influenza to be transmitted along these links in the network while changing the state of each individual (s, e, i and r). the model structure is described in the section titled model structure (and in the text s1 and figure s1 ). influenza transmission parameters were calibrated using approximate bayesian computation (abc) [40, 41] as described in the calibration section (we chose parameters' ranges based on both the english and chinese literature [42] ). the computation section briefly discusses the implementation and computations based on calibrated parameters (table 2) ; a more detailed description can be found in the text s1. natural history of influenza. individuals infected with the influenza virus first pass through a latent period when they are asymptomatic and not infectious. we assumed that viral shedding does not take place during the latent period, and that the mean duration of the latent period is 1 to 2 days [43, 44, 45] . for influenza, the infectious period is assumed to begin about one day before the symptomatic period [44] . in general, individuals infected with influenza may be asymptomatic, and yet still shed the virus. the proportion of transmission by asymptomatic individuals is assumed to be one-third to one-half that of influenza-infected symptomatic individuals [46, 47, 48, 49] . the mean period during which a person may be asymptomatic but infectious is assumed to be 1 day [50] . individuals are assumed to become symptomatic and infectious with an average duration of 1.5 to 3.8 days [43, 44, 45, 51, 52] . mathematically, we represent the course of influenza according to the diagram shown in figure 1 (and figure s2 ). in this model, we classified influenza as being mild or not being mild; individuals in each severity type progress to different stages. mild cases and non-mild cases are classified as infected prior to all symptoms and infectiousness (e 0 1 and e 1 ), infectious but asymptomatic (i 0 1 and i 1 ), or recovered with strain specific immunity (r). the non-mild cases may be symptomatic and infectious as well (i 2 ), which occurs after asymptomatic infectiousness (i 1 ). table 2 lists the durations between stages. a recovered individual loses immunity with rate m, reverting to the uninfected susceptible (s) stage. we assume that individuals have age-specific death rate d, and a birth rate b; these dynamic population demographic features which are represented by the death and birth of each individual, will be described in the demographic description section given below. for a specific individual, we assume that the duration time between two stages is randomly chosen from an exponential distribution with a given rate. immune escape and seasonality. to model antigenic drift, our model is designed such that every individual has a maximum immunity level immediately following recovery from infection by a particular strain of influenza, but this immunity gradually wanes to zero over 3 to 8 years [28, 50] . following reinfection, the immunity level is restored to the maximum value and declines at the same rate thereafter. the underlying causes of influenza seasonality remain unclear [53, 54, 55] , despite many studies postulating possible causes. suggested causes have included changes in human mixing patterns or fluctuations in human immunity and environmental humidity [56] . the transmission of seasonal influenza tends to increase substantially from november to february in the northern hemisphere and from may to august in the southern hemisphere [57] . to incorporate seasonality of influenza transmission into our model, we modeled the transmission probability per contact as a sinusoidal function of time [57] according to p trans (t)~p base ze cos(2p(1z t{h d )), so that the transmission probability, p trans , varies during the course of the epidemic. here, p base is the baseline transmission probability, t is time, and e (where we assume 2p base ,e,p base ) characterizes the degree of seasonality (e = 0 corresponds to no seasonal variation at all). we let d denote the total duration of an epidemic season (for instance, 365 days in this model) and h (an offset from time 0) is the peak time of an epidemic season. our model adopted h as november 15, corresponding to northern china where influenza peaks in the winter [58] . in this model, the probability of infection for each individual depends on the immunity level, seasonality, and the contact rates (please see the text s1 for more details). china's demographic data. the demographic data were taken from the population statistics yearbooks for china, and from five censuses carried out in 1952, 1964, 1982, 1990 and 2000 [35,36,37,38,39] . some demographic data sources were extracted from previous articles [26, 27, 39, 59, 60] in which the population growth under different population control policies were predicted. key demographic parameters used in our simulation included age, household size, age-specific death rates, and age-specific fertility rates, as shown in table 1 . initially, we stochastically sampled age and household size from distributions fitted to the demographic data [26, 39, 60] . we used dynamic age-specific fertility rates and death rates from year 1975 to 2009 to simulate the population growth under conditions of the one-child policy; calibration details of the age-specific fertility rates can be found in text. population projections without the control of a one-child policy were implemented by assuming a static age-specific fertility rate (from 1975) and fixing the birth rate to the same value that it was in 1975 (which, of course, corresponds to an unrealistic population trajectory). we also analyzed the assumption of a very strict onechild policy that allows one female to have only one child in her life-this is stricter than the one-child policy as actually implemented. finally, we conducted a simple projection of the population with a proposed two-child policy (from 2015 to 2024), which allows one female to have two children. it was implemented by increasing the fertility rate for nulliparous females. to calibrate the population, we fit the age-specific population number of each year and the average household size of each year to the census data, then compared the population projections of our model with the census data and projections described in other studies [26, 39, 60] . dynamic network structure. we simulated the transmission of influenza using a simple dynamic network structure shown in figure 2 . specifically, we assumed that each individual is located in a household and links to other household members, and we assumed that each individual has several links to other individuals outside of his/her household. these links outside the household represent contacts in the community and an individual has a lower relative contact rate with outside links than with household links. for school-aged individuals, we assume that they are in primary and middle schools, and have school links to all of their schoolmates. the contact network of this model consists of each individual's household contacts, school contacts and casual contacts, and its dynamic is reflected by updating each individual's household, school and casual contacts which will be discussed in turn. household contacts. each individual in the model has household links that are initialized by grouping individuals into households based on the household size distribution data of china in 1975, and linking all household members of each household. during simulation, each individual's household links are updated dynamically (1) when the individual leaves his/her household between his/her age 14 and 18 years as a household with onemember, (2) when the single individual over 18 years of age has found (with a partnership searching rate per year) another single over 18 years of age to live with as a two-member household, (3) at the time the individual dies (with a dynamic age-dependent . individual b has two household members (c and d), two visible casual contacts (a and e), and three visible schoolmates (f, i and j), other social contacts and schoolmates of b are not shown in this small part of contact network. if b was an index case, the household contacts would be at highest risk of being infected due to the higher contact rates among household members than the casual and school contacts (for the contact rates of different link types, please see table 2 ). doi:10.1371/journal.pone.0084961.g002 effect of one-child policy on flu transmission plos one | www.plosone.org mortality rate), or (4) at the time the individual or one of the other family members gives birth to a baby (with a dynamic agedependent fertility rate). the dynamic age-dependent mortality rate and the dynamic age-dependent fertility rate are from the population data of china from 1975 to 2009. during the simulation, an individual's mortality rate and fertility rate depend on the current simulated year and the individual's current age. the partnership searching rate per year is calibrated to fit to the observed household size from 1975 to 2009. the dynamic agedependent fertility rates under the other three scenarios are assumed to be zero if the individual already has more than one child for the strict-one-child-policy, the same as the fertility rates in 1975 for the absence of one-child policy, and doubled from 2015 to 2024 for the two-child-policy. school contacts. each individual whose age is between the primary-school-age of 6 and 12 years or between the middleschool-age of 13 and 18 years has school links that are initialized using the primary and middle schools' statistical data of gansu province in china in 1975, and are updated annually by reassigning all individuals with school ages into primary or middle schools according to year-dependent average school size from 1976 to 2009, or are updated at the time the individual dies with the dynamic age-dependent mortality rate. casual contacts. each individual may have several random contacts per day with a daily contact rate contact casual = 16. once an individual becomes infectious, all of his/her casual contacts during the infectious period are randomly chosen from the population and their contacting times are predicted and scheduled using an exponential distribution with the casual contact rate per day, contact casual . transmission via the network. once an individual becomes infectious, an infectious period will be generated using an exponential distribution with recovery rate. during the individual's infectious period, the contact times between he/she and each of his/her household members are stochastically scheduled using an exponential distribution with the contact rate per household member per day, contact house = 10; transmission between the infectious individual and the susceptible household contacts will take place at the scheduled contact times. similarly, the casual contacts of the infectious individual during the infectious period are randomly chosen from the entire population, and the contact times between the infectious individual and his/ her casual contacts are scheduled using an exponential distribution with a casual contact rate per day, contact casual = 16. transmission between the infectious individuals and the susceptible casual contacts will be active at the scheduled times. in addition, the contacts between the infectious individual and his/her schoolmates during his/her infectious period are randomly picked from the individual's school links and are scheduled by an exponential distribution with school contact rate per day, contact school = 10. the transmission between the infectious individual and the susceptible school contacts will be active at the scheduled times. once a scheduled transmissible contact takes place between the infectious individual and one of his/her susceptible household members, schoolmates, or casual contacts, a successful transmission will be completed with a transmission opportunity which is a product of the seasonal transmission probability per contact, p trans , and the chance of immune escape, 1 -m i (t), where m i (t) (defined in the text s1) is a dynamic immunity level of a susceptible individual i at time t. the dynamic immunity level of an individual depends on his/her infection history, the immunity waning rate per year and the current time. the model is initialized with 10,000 individuals whose ages are generated from the age distribution of china in 1975. the household links for each individual are initialized with household size distribution of china in 1975, and the school links for each school age individual are initialized with the average school size of gansu province in china in 1975. casual contacts of each individual are randomly selected from the population with a casual contact rate per day contact casual = 16. five exogenous infectious cases with the same influenza strain are introduced into the population on november 15th in 1975 to start influenza transmissions via the contact networks of all individuals. at the beginning of the simulation, we assume that all individuals are completely susceptible. once an individual recovered from an infection, he/she will have a 100% immunity level which wanes with 10% immunity loss rate per year (m = 0.1). the demographydependent dynamic network of the population is reflected by updating household links and school links of each individual as stated above, which also depends on the scenario of population control policy for the current simulation. as a base scenario, we assume that the one-child policy is active, thus the mortality rates for ages 0 to 120 years and the fertility rates for ages 16 existing census data reflect those demographic changes caused by the one-child policy as actually implemented. in order to assess what would have occurred in the absence of such a policy or other demographic changes, we assumed a static fertility rate of that in 1975 for females. however, a strict one-child policy includes the assumption that there is no chance for a female who already has a child to give birth to a second child, an assumption that does not hold in practice. to calibrate the demographic component of our model, we first fitted the population projection with the available demographic data, as well as with other population projections [26, 27] in which they predicted population with a one-child policy and other control measures (see figure s3 (a)). then, we fitted the population age distribution of each year to demographic data in the years from 1975 to 2004, (see figure s3 (b)). finally, we required that the average household size (see figure s3 (c)) corresponded to the census data in 1964, 1982, 1990 and 2000, which reported average household sizes of 4.43, 4.42, 3.96 and 3.44 in these years, respectively [35] . we calibrated the model using eight influenza transmission parameters: (1) mean duration of the latent period, (2) mean duration of the asymptomatic infectious period, (3) mean duration of the symptomatic infectious period, (4) probability that a case will be mild, (5) immunity waning rate, (6) the degree of immunity following infection, (7) transmission probability per contact, and (8) contact rate between two household members ( table 2) . parameters (1), (2), (3) and (4) are age-dependent parameters with 5 age categories: 0 to 4, 5 to 9, 10 to 25, 26 to 49, and 50+ years. to calibrate these parameters, we chose parameter sets randomly from a uniform distribution with given upper and lower bounds (assuming independence among parameters). the annual attack rate (averaged over 30 years) and the simulated household secondary attack rate (averaged over 30 years, and the rate of each year was averaged over all households with index cases) were computed from each set of parameters. simulations yielding average annual attack rate (ar) within the range (0.1, 0.2) [28, 29, 30, 31] , and secondary attack rate (sar) inside the range (0.09,0.32) [7, 32, 33, 61, 62, 63] , were considered plausible; calibration was done by approximate bayesian computation [40, 41] . for details of the ar and sar we cited, please see tables s1 and s2. for each household with an index case, we calculated the secondary attack rate based on the proportion of household contacts who were infected by the index case in the household during the infectious period of the index case [62, 64] . the sar was averaged by using the secondary attack rates of all households with index cases. this calculation of the sar includes partially immune household contacts [7, 32, 33, 61, 62, 63] . simulations were run for 4000 sets of parameters, resulting in 646 parameter sets that fit the acceptable ar and sar ranges stated above. parameter sets having higher or lower values of ar or sar were excluded. finally, we used the 646 fitted (non-excluded) parameter sets and used them in the model to predict and study influenza transmission in the population under three scenarios: the one-child policy, the absence of a one-child policy, and the strict one-child policy. the individual-based model was implemented and programmed in c++ [65] and r [66] following our previously published agent-based transmission models [67, 68] . c++ was used for the main simulation program and r for the analysis of data generated by the main simulation program. to add scalability for simulations of large population sizes, we used an agent-based platform abm++ [69] which supports parallel and cluster computing. simulations were performed on the rti midas cluster, a cluster with 36 compute nodes with a total of 400 compute cores and 786 gb of distributed memory, running linux distribution of centos v5.5. the running time for a single run of the model varied with input parameters in tables 1 and 2 . given a fitted set of parameters with the one-child policy and an initial population size of 10000, it took about 500 to 800 seconds for a single run on one compute core with a speed of 2.30 ghz in the cluster. we simulated 30 years of influenza transmission in a representative population of initial size 10000 under three different scenarios: a population with a one-child policy (), a population without a one-child policy (), and a population with a strict onechild policy (), (following ''one-child policy'' represents ). under each of the scenarios, we used 646 fitted sets of parameters (described in the calibration section) to simulate influenza transmission. each scenario was simulated 100 times and the annual and secondary attack rates were averaged among 100 simulated ars and sars. we then computed the partial rank correlation coefficients (prcc) [67, 70] for each input parameter and the annual attack rate under the three different policy scenarios using the 646 sets. when the prcc is close to zero, the value of the parameter has little relation to the simulation output (see the text s1). the prcc values of key parameters are listed in table 3 . finally, we calculated the annual and secondary attack rates experienced by the population under the three policy scenarios. to explore the influenza transmission factors that are likely affected by the one-child policy, we estimated the average differences in the annual attack rate (dar) and the secondary attack rates (dsar) in the populations without and with the onechild policy control. we found that the population without the . ar and sar differences between populations without the one-child policy and with the one-child policy. (a) average difference in annual attack rate (dar: 6.08% (sd 2.21%)) between populations without the one-child policy and with the one-child policy, based on 646 calibrated parameter sets which yielded the annual attack rates between 10% and 20%, and secondary attack rates between 9% and 32%. for each parameter set, we simulated the influenza trajectories under two demographic control policies, and then computed the difference in average annual attack rates over 30 years between two policies. (b) difference in secondary attack rates (dsar: 20.15% (sd 1.85%)) between populations without one-child policy and with the child-policy, based on 646 calibrated parameter sets which yielded the annual attack rates between 10% and 20%, and the secondary attack rates between 9% and 32%. for each parameter set, we simulated the influenza trajectories under two demographic control policies, and then computed the difference in average secondary attack rates over 30 years between two policies. doi:10.1371/journal.pone.0084961.g003 one-child policy had an average annual attack rate that was slightly higher than the population with the one-child policy. the distribution of the difference of annual attack rates with a mean of 6.08% per year (with standard deviation (sd) 2.21%) using 646 fitted sets of parameters, in figure 3(a) , shows that all the values reflecting the dars between population without one-child policy and population with one-child policy are positive for all sets of parameters. here, each value of dar is the difference of the average annual attack rates over 30 years between two different policies. this supports the notion that the one-child policy gradually reduced the annual attack rate. the decrease in annual attack rates may be caused by the smaller household sizes and the decreased proportion of children in the population resulting from the one-child policy. the distribution of dsar, in figure 3 (b), shows that the expectation of the dsar is 20.15% per household per year (sd 1.85%) and there is no significant difference of secondary attack rates with the one-child policy introduced. however, the one-child policy had little to no discernible effect on the secondary attack rates. a larger population size gave similar results as stated above. we performed the same comparisons of the dar and dsar, comparing populations with the existing one-child policy with a hypothetical two-child policy. we assumed the two-child policy from 2015 to 2024; the simulations for a 10-year transmission period ( figure 4 ) did not show significant differences of dar and dsar (0.22% per year (sd 0.46%) and 20.02% per household per year (sd 0.81%), respectively). in addition, we conducted sensitivity analyses by increasing the contact rate per day within household and the immunity loss rate per year and varying their values from 12 to 20 for the contact rate and from 20% to 100% for the immunity loss rate in order to compare the difference in ar and the difference in sar between populations without and with the one-child policy ( figures 5 (a) and (b)). changes in household structure and the proportion of children in the population as a result of the one-child policy could have more effects on the ar, and the difference in ar could be as high as 60% under a scenario of very high immunity loss rate per year ( figures 5(a) ). however, the results showed that the difference in sar was not very sensitive to the contact rate in the household and the immunity loss rate (figures 5(b) ). the one-child policy has been applied in china for over 30 years, causing great changes in the demographic composition of the chinese population. to address the impact of demographic changes caused by the one-child policy (or similar changes which may have arisen for other reasons) on influenza transmission, we developed a continuous-time individual-based, stochastic, simulation model for influenza transmission in dynamic populations with the support of available demographic data. after calibrating the simulated population with available demographic data and published attack rates, we simulated 30 years of influenza transmission under three assumptions: a population with a onechild policy, a population without a one-child policy, and a population with a strict one-child policy. this study provides some evidence that demographic changes caused by demographic policy may slightly affect influenza transmission in populations. simulated results from this model show that populations without childbearing policies have slightly higher annual attack rates than populations with a one-child policy. we did not find significant differences in the secondary attack rates between populations with a one-child policy and populations without it. we predicted influenza transmission over 10 years (2015 to 2024) in a population with a hypothetical two-child policy, and found negligible differences of the average annual attack rates and secondary attack rates compared to the population with a onechild policy. one limitation of our findings is that it is impossible to know what would have happened in the absence of the one-child policy. because our goal was to highlight the role of household size and other related demographic changes, we simply assumed an extrapolation from 1970s trends. in reality, demographic changes may have occurred for other reasons in the absence of a one-child policy. moreover, this model did not distinguish contacts other than household and school (for example workplace [71, 72, 73] , or community [74] ). containment measures, such as different vaccine strategies [75, 76] and travel restrictions [77, 78] , were not considered in this model, allowing for a focus on the relationship between child policies and influenza transmission. we did not distinguish antigenic diversity [79] ; because aging populations have more cross-immunity for similar strains [8] . this limitation may underestimate an aging effect on influenza transmission. all parameters used in this model were defined from existing published literature. we did not assess the differences between pandemic years versus inter-pandemic years because of the assumption that there are no changes in influenza natural history parameters during the course of over 30 years. we did not use this model to answer an important question that whether or not the demographic changes affect pathogen emergence in china because of lacking sufficient data, and this question is beyond the scope of this paper. this study found that the average annual attack rate is slightly lower in a population with a one-child policy, which may result from a decreased household size (from 4.2 in 1979 to 3.5 in 2004 in the model) and the decreased proportion of children (who are more vulnerable to infection than adults) in the population because of the dramatically reduced fertility rates from 2.9 in 1979 to 1.3 in 2004. however there is no discernible difference in the sar. a possible reason for the absence of a discernible difference is that the decrease of average household size (from 4.2 to 3.5) might not be large and fast enough to obviously reflect the change in the secondary attack rate. we compared the results of this study with other recent studies [61, 80, 81, 82, 83] about the relation between household size and sar, household size and the overall attack rate. the lower annual attack rate with smaller household size is consistent with the results from fraser et al. [61] and kwok et al. [83] , but carcione et al. [81] found that individual risk was not associated with the household size. the absence of a discernible difference in the sar observed in this study is similar to the findings in [80] in which the sar remained stable as household size increased, while the sar increased with larger household size . ar and sar differences between one-child policy and two-child policy (10 years: 2015 to 2024). (a) dar (0.22% (sd 0.46%)) between one-child and two-child policies based on 646 calibrated parameter sets which yielded the annual attack rates between 10% and 20% and the secondary attack rates between 9% and 32%. for each parameter set, we simulated the influenza trajectories under two demographic control policies, and then computed the difference in average annual attack rates over 10 years (2015 to 2024) between two policies. (b) dsar (20.02% (sd 0.81%)) between one-child and two-child policies based on 646 calibrated parameter sets which yielded the annual attack rates between 10% and 20% and the secondary attack rates between 9% and 32%. for each parameter set, we simulated the influenza trajectories under two demographic control policies, and then computed the difference in average secondary attack rates over 10 years (2015 to 2024) between two policies. doi:10.1371/journal.pone.0084961.g004 in other studies [61, 82, 83] . the above comparisons included some studies in which the sar was measured empirically, though the relation between the simulated sar and household size may be controlled by the model structure. in this model, the sar was estimated by the proportion of household contacts of an index case who subsequently became infected [62, 64] , so that the simulated sar stands in relation to the simulated epidemic, which is in the same way the real-world empirical sar and its relation to the true unobserved epidemic. author contributions figure 5 . ar and sar differences under assumptions of different contact and immunity loss rates. (a) varying the value of contact rate per day between any two members in a household (from 12 to 20) and the value of immunity loss rate per year (from 20% to 100%) yielded that under the scenario of 12 of household contact rate and 100% of immunity loss per year, the ar in the population without the one-child policy could be 60% higher than the ar in the population with the one-child policy. (b) by varying the values of contact rate per day between any two members in a household (from 12 to 20) and the immunity loss rate per year (from 20% to 100%), the sar in the population without one-child policy could be 3% higher than the sar in the population without the one-child policy, when the contact rate per day in household is 12 and the immunity loss rate per year is 80%. doi:10.1371/journal.pone.0084961.g005 has china outgrown the one-child policy? demography. of population projections and projectiles family size, fertility preferences, and sex ratio in china in the era of the one child family policy: results from national family planning and reproductive health survey the effect of china's one-child family policy after 25 years environmental and social influences on emerging infectious diseases: past, present and future global migration dynamics underlie evolution and persistence of human influenza a (h3n2) risk factors of influenza transmission in households the shifting 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spread of 2009 h1n1 pandemic controlling pandemic flu: the value of international air travel restrictions predicting the epidemic sizes of influenza a/h1n1, a/h3n2, and b: a statistical method avian influenza h5n1 transmission in households secondary attack rate of pandemic influenza a(h1n1) 2009 in western australian households influenza transmission in a community during a seasonal influenza a(h3n2) outbreak (2010-2011) in mongolia: a community-based prospective cohort study modelling the proportion of influenza infections within households during pandemic and non-pandemic years serial intervals and the temporal distribution of secondary infections within households of 2009 pandemic influenza a (h1n1): implications for influenza control recommendations the transmissibility and control of pandemic influenza a (h1n1) virus key: cord-010837-8x3bch0r authors: curran, janet a.; breneol, sydney; vine, jocelyn title: improving transitions in care for children with complex and medically fragile needs: a mixed methods study date: 2020-05-14 journal: bmc pediatr doi: 10.1186/s12887-020-02117-6 sha: doc_id: 10837 cord_uid: 8x3bch0r background: children with medical complexity are a small yet resource intensive population in the canadian health care system. the process for discharging these children from hospital to home is not yet optimal. the overall goal of this project was to develop recommendations to be included in a provincial strategy to support transitions in care for children with complex and medically fragile needs. methods: a wide assortment of stakeholders participated in this mixed method, multiphase project. during phase 1, data was gathered from a range of sources to document families’ experiences transitioning from an inpatient hospital stay back to their home communities. in phase 2, pediatricians, nurses, and health administrators participated in key stakeholder interviews to identify barriers and facilitators to a successful transition in care for children and families with complex care needs. a multi-sector consensus meeting was held during phase 3 to discuss study findings and refine key recommendations for inclusion in a provincial strategy. results: six case studies were developed involving children and families discharged home with a variety of complex care needs. children ranged in age from 15 days to 9 years old. nine telephone interviews were conducted in phase 2 with pediatricians, nurses, and administrators from across the province. a variety of inter-institutional communication challenges were described as a major barrier to the transition process. a consistent message across all interviews was the need for improved coordination to facilitate transitions in care. the consensus meeting to review study findings included physicians, nurses, paramedics, senior administrators, and policy analysts from different health and government sectors and resulted in six recommendations for inclusion in a provincial strategy. conclusions: this project identified policy and practice gaps that currently exist related to transitions in care for children with complex and medically fragile needs and their families. our collaborative patient-centred approach to understanding how children and families currently navigate transitions in care provided a foundation for developing recommendations for a provincial wide strategy. children with complex and medically fragile needs are a small yet resource intensive population within the canadian pediatric health care system [1, 2] . while these children represent less than 1% of the pediatric population, it is estimated they account for one third of pediatric health care spending [2] . yet, discussion about the needs of children with medical complexity are often overshadowed in national health reform discussions by care of chronically ill adults [3] . further, estimating the burden of illness on families, communities, and the health care system can be challenging due to the wide variation of health and social needs within this heterogeneous population. brenner et al. [4] conceptualized "children's complex care needs [as] the multidimensional health and social care needs in the presence of a recognized medical condition or where there is no unifying diagnosis" [4] (p.1647). due to the complex nature of their care needs, these children often experience frequent hospitalizations [1, 2, 5] , accounting for approximately 10% of pediatric admissions and 25% of hospital days [6] . in comparison to children without complex chronic conditions, children with medical complexity experience almost 9 times more inpatient visits and 17 times greater inpatient costs [7] . despite this high inpatient use, it is widely recognized that much of the care these children require could be provided in their home and home communities [8] [9] [10] . with as many as 89% of children with complex chronic conditions being discharged from hospitalized settings [11] , a well-coordinated and comprehensive transition from hospital to home is essential for improved patient and family outcomes and efficient use of health care resources. however, successful transitions in care for this population are characterized by a number of challenges. as many as 13 physicians from 6 distinct medical specialities and numerous other care team members across the health, educational, and community settings may be involved in the care of these children and families. this sizable care team extending across multiple services and sectors creates the potential for gaps in care coordination and communication [2] . in addition to these factors, their care needs may include dependence on medical technology at discharge (i.e. ventilator, feeding tubes, etc.), requiring adequate support in their home community which can place this vulnerable population at an even greater risk for adverse outcomes or hospital re-admissions, particularly in geographically dispersed communities [2, 8, 12, 13] . there has been increasing discussion in the literature over the past 10 years surrounding pediatric complex care, including new models of service delivery to support children with complex care needs and their families in the community [14, 15] . the american academy of pediatrics has advocated for the medical home model, grounded in family-centered primary care services, as a comprehensive, community based model of service for all children with complex care needs and their families [16] . however, current health care structures in north american are not designed to effectively support these principles of care [17] . with the multiple stakeholders involved in the care for this population, providing integrated and coordinated care for children with medical complexity in canada can prove to be challenging. a recent scoping review of the literature revealed a paucity of programs, interventions, or frameworks designed to support the transition from hospital to home for children with complex needs and their families [18] . further, findings revealed a lack of patient and family-oriented outcome measures, indicating the need for researchers and policy makers to involve families in the research process and tailor forthcoming programs and policies to the individualized needs of this population [18] . the need for clear guidelines and processes for the provision of high-quality care for children with complex and medically fragile care needs during care transitions is critical. while there are isolated tools and agreements in principle to collaboratively develop short-and longterm care plans for these children and their family, there are currently no generalizable transition processes that systemically guide transitions for this vulnerable population in nova scotia, canada. this project aimed to develop recommendations to improve the transition from hospital to home for children with complex and medically fragile needs in nova scotia. to achieve this aim, the following research objectives were addressed: (1) describe the experience of patients with complex care needs and their families during the transition from a tertiary care facility to their home community; (2) identify perceived barriers and enablers related to the existing transition process, and (3) identify key components for inclusion in a strategy to enhance the transitioning of children and families with complex and medically fragile needs to their home community. using an integrated mixed methods approach [19] , this project brought together a team of researchers, clinicians, parents/caregivers, and senior-level administrators across the province of nova scotia. data was collected from multiple sources across three phases to achieve a greater breadth and depth of understanding into the existing transition process (fig. 1) [19] . this study took place at a pediatric tertiary care facility located in nova scotia, canada, responsible for the care of children, youth, and women across the canadian maritime provinces. the canadian maritimes is composed of three provinces, with a combined population of almost 500,000 children and youth [20] . this health centre has approximately 230 baby and children beds, with estimated 15,000 acute inpatient admissions, 34,000 emergency department visits, and 210,00 outpatient visits annually [21, 22] . ethical approval was obtained from the iwk research ethics board (project #1017345). data collection occurred between 2015 and 2017. to address our first objective, a case study design was employed to develop 6 cases representing the experiences of a range of children with complex and medically fragile needs transitioning from hospital to home. we employed maximum variation sampling to ensure a representation of different age groups, levels of complexity, family structures, geography and socioeconomic status levels when possible [19] . eligibility for this study included parents or guardians of children aged 0-18 years old with one or more chronic conditions that were expected to require specialized care greater than 1 year. this eligibility criteria was created to align with current literature describing children with complex care needs [1, 4, 23] and based on expert opinion from our multidisciplinary research and clinical team. terminally ill patients were excluded from this study. clinical leads from each unit in the tertiary care facility invited potential participants according to the eligibility criteria by providing a letter of information describing the study and contact information for the research assistant. the research assistant reviewed the letter of informed consent with potential participants and they were given the opportunity to ask questions before participation. each case was informed by multiple sources of data: family, tertiary care provider, and community health care provider interviews and a structured chart audit. families were asked to identify one primary caregiver to complete the interviews and all data collection measures. all providers involved in the care of these children were invited to participate in our study. data collection occurred at four points in time: (1) two weeks prior to discharge (t1); (2) one day prior to scheduled discharge (t2); (3) one week following discharge (t3); and four weeks following discharge (t4). families were asked to complete the sf-36 tool at t1 and t4 to estimate disease burden [24] . the state trait anxiety inventory (stai) was used to assess parental anxiety and measured at t2 and t3 [25] and the brief cope was used to assess parents coping strategies at t2 and t4 [26] . our approach to data collection attempted to balance understanding a range of patient, family and health system factors relevant to the transition from hospital to home while being mindful of not contributing to caregiver burden during the transition home. the measures were chosen to capture the experiences and potential changes in stress and coping at different time points during the transition from hospital to home. the child's primary caregiver also participated in individual interviews at three time points: t1, t2, and t3. a semi-structured interview tool, developed by the research team, was used to explore caregiver's knowledge, attitudes, and beliefs about the discharge process at each time point. tertiary care and community health care providers who were directly involved in providing care to the patient and family were also interviewed on a single occasion after the child's discharge from hospital. a semi-structured interview guide was also used to explore provider's knowledge, attitudes, and beliefs about the discharge process. all interviews were audio-recorded and transcribed verbatim. interview transcripts were sorted by case and managed in nvivo 11 qualitative data analysis software [27] . transcripts were coded by two independent reviewers. a content analysis approach was used to identify important barriers and enablers of the discharge process in each case [28] . reviewers met to compare findings and coding discrepancies were resolved through discussion and consensus. to address our second objective, semi-structured telephone interviews were conducted with key stakeholders across the province to identify barriers and facilitators related to the transition from hospital to home for children with complex and medically fragile needs. an initial list of potential community stakeholder participants was identified through consultation with members of the executive leadership team of the tertiary care centre. subsequently, we used a snowball strategy inviting study participants to identify additional potential provincial stakeholders. a letter of invitation was sent to potential participants via email. data was collected through individual telephone interviews and verbal consent was obtained from all participants. a semi-structured interview guide, based on the tdf [29, 30] , was used to explore participant's experiences, attitudes and beliefs about supporting children and families through transitions in care. this interview guide was initially drafted by the principle investigator (jc) and further refined by our team of researchers and clinicians. the interviewer (sb) used prompts when appropriate to encourage participants to elaborate on their experiences and opinions. interviews were recorded and transcribed verbatim by an experienced transcriptionist. one reviewer (sb) performed deductive content analysis to sort barriers and facilitators arising from each transcript according to the 14 domains of the tdf [29, 30] . coding began immediately after the first interview and a second reviewer (jc) validated the coding in 40% of the transcripts by independently coding the first and every other transcript. participant recruitment was deemed complete and data saturation was achieved when no new barriers and facilitators were identified in the transcripts [31] . subsequently, one reviewer (sb) conducted a thematic analysis to identify important themes related to the barriers and enablers [32] . frequent checks and collaboration with research team members occurred to discuss themes as they emerged. to address our final research objective, we hosted a half-day multi-disciplinary stakeholder meeting to review findings and identify and refine key recommendations for inclusion in a policy statement. our guiding framework for the meeting was underpinned by an adapted consensus-oriented decision-making process; steps included: (1) framing the topic (through our data); (2) open discussion (of data and analysis); (3) identifying underlying concerns; (4) collaborative strategy building; (5) choosing a direction; (6) synthesizing a final strategy/proposal; and (7) identification of next steps and roles [33] . six cases representing the transition experience for a range of children with complex and medically fragile needs were created. these cases included children with an age range of 15 days to 9 years and were followed by as many as seven different speciality services. case characteristics are summarized in table 1 . table 2 provides an overview of the brief cope inventory scores for all cases. a summary of the thematic cross case analysis can be found in table 3 . the following section provides a brief overview of the key features of developed case studies. geographical distances from the tertiary care centre have been categorized dichotomously to: (1) less than an hour drive and (2) more than an hour drive. a total of 34 health care providers were interviewed across the cases and represented a range of professions which included pediatricians, physiotherapists, social workers, pharmacists, neonatologists, transition coordinators, nurse practitioners, occupational therapists, family care coordinators, dieticians, oncologists, and plastic surgeons. this case examined the hospital to home transition of a 2month-old infant with a congenital atrial septal defect and hip dysplasia who was discharged home post-operatively for ongoing monitoring and rehabilitation. the family lived more than an hour drive from the tertiary care centre and had experienced multiple admissions. key features of this case included: (1) family concerns regarding trust with certain members of the health care team and their level of knowledge regarding their child's condition and (2) extensive collaboration between different care teams which was facilitated by a nurse practitioner. summary measures of physical (pcs) and mental (mcs) health and anxiety are unremarkable (table 1) . when compared with other cases in this study, this family leveraged more dysfunctional versus problem focused strategies across the transition from hospital to home (table 2) . this case involved a 15-day-old infant born at 35 weeks gestation with fragility and a genetic anomaly. the family lived within 1 h drive from the pediatric tertiary care centre which meant that certain elements of care could remain the responsibility of the tertiary care centre's perinatal team. key features of this case included: (1) a strong sense of support surrounding the caregivers and child from family members and the tertiary and primary care team, which helped ease and support the transition home; and (2) concerns expressed by a member of the tertiary care team regarding inadequate resources in the local community to address nutritional needs of the infant, which led the perinatal team to closely follow feeding and weight gain while at home. changes were noted in pcs scores from t1 to t4 (28.9 vs 53.7) ( table 1 ). the family also leveraged a high degree of problem focused strategies during the transition home with a noted increase of positive framing techniques between t2 and t4 ( table 2) . this case examined the experience of a 10-year-old child with complicated osteomyelitis requiring multiple debridement surgeries prior to discharge to their home community located less than an hour drive from the tertiary care centre. key features of this case included: (1) a strong sense of trust in the tertiary care team prior to discharge; (2) a decreased level of confidence in the care team post-discharge due to contradictory information received by various providers; (3) communication gaps reported by the family between the home care nurse and the health centre regarding treatment needs; (4) a high level of satisfaction with home nursing services and educational information received regarding their child's treatment; and (5) an active involvement and cooperation of the child's school facilitating the accommodation of their medical needs. estimates of family anxiety and burden were stable (table 1) . brief cope scores remained relatively consistent between t2 and t4 with a reliance on problem and emotional-focused coping strategies (table 2) . this case explored the hospital to home transition of a 5 month-old infant born at 28-weeks gestation with bronchopulmonary dysplasia, gastroesophageal reflux disease and required nasojejunal (nj) feeding. the more than one-hour drive from the home community to the tertiary care centre presented a challenge, as the there was another other child in home. key features of this case included: (1) a high level of trust with the care team at the tertiary care centre; (2) difficulty with feeling involved in all care decisions due to the division of time between the health centre and home; (3) concerns from both the care team and the family about the lack of resources to manage the infant's nj tube at home; (4) cost associated with formula and prescription; (5) the process of accessing respite care; and (6) limited information provided in discharge summary to adequately inform the primary care physician of the infant's condition, requiring the caregivers to provide more detailed information about the care plan to their provider. stai and sf-36 scores were unremarkable (table 1) . when compared with other cases, this family reported limited use of coping strategies at both points in time with problemfocused strategies being most prevalent (table 2) . this case examined the hospital to home transition of a 1-year-old infant with gastric atresia with additional complex care needs who had been hospitalized since birth. the family's home community was located more than 1 h drive from the pediatric health centre. key features of this case included: (1) a high level of trust in the tertiary care team; (2) other parents on the inpatient unit act as key supports to the family; (3) satisfaction with the care from the local community pediatrician, but dissatisfaction with care received from the community hospital following misplacement of the child's feeding tube; (4) an advanced practice nurse guiding the discharge process and using a locally developed tool to guide discharge planning that was distributed to the family and home community to promote continuity of care; (5) a high level of engagement from the family helping to facilitate a smooth transition as reported by the health care team; and (6) a lack of pediatric expertise in community physiotherapy. compared with other cases this family reported the highest pcs across t1 and t4 and reported higher anxiety scores across t2 and t3. (table 1 ) this family also reported the highest rate of dysfunctional strategies at t4 when compared with other cases (table 2) . further, there was a reported decrease in the use of instrumental support once home in the community (table 2) . this case examined the transition of a 9-year-old child diagnosed with leukemia and ulcerative wounds who was discharged to a home community over an hour away following a four-month inpatient stay. key features of this case included: (1) a high level of trust with the tertiary care centre and the development of strong relationships with the nurses and other families on the unit; (2) concerns about inconsistencies regarding access to supports and resources for parents during inpatient stay; (3) high level of satisfaction with home care services, but a desire for more continuity in nursing care; (4) a 'family care coordinator' acted as key contact at the pediatric health centre and kept the family informed regarding the care plan; and (5) the family feeling prepared to care for their child's medical needs at home but not prepared for the socio-emotional challenges and stress of caring for their child within the home. this case reported the highest anxiety at t2 and t3 with an increase in mcs from t2 to t4 (27.9 to 45.9) ( table 1 ). the reported brief cope scores suggest a preference for problem and emotional focused strategies following their discharge home (table 2) . telephone interviews were conducted with nine health care providers from five health regions in nova scotia who support children with medical complexity and their families. interview participants included four pediatric registered nurses, four community health care physicians, and one administrator. data saturation was determined after the 9th interview as no new themes emerged [31] . data was organized using the tdf domains and highlighted potential barriers and enablers to the hospital to home transition for children with medical complexity (see table 4 ) [29] . the majority of participants were not aware of formal guidelines or policies to help support or inform the transition from hospital to home for children with medical complexity and their families. guidelines that were discussed included the medical home model from the american academy of pediatrics [16] , toronto sick kids complex care program [34] , and condition-specific health centre policies. a number of health care providers indicated a lack of awareness of the range of resources accessible in the community and the tertiary care facility for both families and health care providers to support this transition in care. further, given that some smaller communities may go many years in-between assuming care for a child with complex care needs, a lack of experience of how the transition process should occur was reported. participants also mentioned specific psychomotor skills that may be required by the community health care providers to care for the complex medical needs of these children. participants spoke of several systems and resources that could be used to support smoother, more effective, and efficient transitions from hospital to home for children with medical complexity and their families. this included: (1) prompt and consistent communication to the appropriate health care providers/services; (2) care coordinators located in the community and the tertiary care centre to oversee the coordination of care and support families; (3) teleconferences between all members of the care team; (4) written care plans provided to both families and providers in advance of discharge from the tertiary care facility; (5) access to additional speciality health care services within the community; and (6) online repository or system to store and organize existing beliefs about capabilities health care provider confidence "but the overwhelming theme there is that we have a system that isn't tuned to the needs of children and care for children outside of the specialized centre. so you know… and people will say to you very directly, "i don't have pediatric experience, and i'm not comfortable." parental confidence "i've seen it with our newborns that come back that have been born premature and have been in nicu, and now they're doing well, they're there just to grow. you know, they don't need the monitoring, they don't need that intensive level of care. and we find parents have a very difficult time understanding that the baby is now theirs to take care of. you know, they're not ready that now they're on the normal care track that they would have been on had baby been born at term." beliefs about consequences family burdens "because you're worried enough about your child, you don't need to worry that, you know, is the community ready, are the staff prepared? that, you know, should we land in the emergency room in 2 days' time, are they going to know who my child is? are they going to know what he or she needs? are the staff at the nearest pediatric unit prepared to take care of them or know what to do if something should arise?" hospital readmissions "i think the consequences is sometimes it leads to increased admissions into the acute care unit." breaks in the continuum of care "because sometimes they might end up presenting back to our emergency department, for example, before they've seen any of us….they might end up coming in on a friday night and seeing one of my other pediatric colleagues that didn't get any of the documentation i received. preventable adverse outcomes "well, i think we may miss some opportunities to avoid or to monitor for complications. and so in that way, you know, even if nothing happens, we haven't been there being as diligent perhaps as we could be for quality assurance and ensuring that the best health care is being provided." health care providers highlighted the need for both expertise and confidence in caring for the complex pediatric population to ensure optimal care is provided. given the rurality of many of these communities, community health care providers may have limited encounters with pediatric patients resulting in a decreased confidence in caring for their unique needs. practitioners also spoke of the varying parental confidence levels during the shift in care responsibility. parents must be adequately prepared to transition from a secure hospital environment to their homes where health care providers will not be directly overseeing their child at all times. study participants discussed various consequences that may arise without proper structures and processes in place to support the hospital to home transition for children with medical complexity and their families. these included: (1) family burdens (i.e. travelling unnecessarily to and from the tertiary care centre); (2) hospital readmission; (3) interruptions in continuum of care (i.e. providers not having access to the appropriate information); (4) preventable adverse events; and (5) poor reintegration into community (i.e. returning back to school). all study participants believed the transition from hospital to home for this vulnerable population was of great importance. when asked to rate the importance of improving this transition in care on a scale from 1 to 10, with 1 being not important, and 10 being very important, participants reported an average of 9.3/10 (range 8-10). participants highlighted the importance of improving this transition in care to ensure the delivery of patient-centred care. a common theme across all interviews was the perceived gap in efficient communication between the tertiary care centre and the receiving community providers. several community practitioners noted that being consulted early on was a key facilitator to the transition process. health care providers also discussed the inability to access certain discharge summaries and patient charts and reported not receiving care plan information in a timely manner. the variability in resources located in the home communities was discussed as both a barrier and enabler to the transition process. some communities reported having resources such as advance practice nurses, travel funds, and home care services that help support these children and families in the home. however, lack of speciality resources was highlighted as a barrier to providing adequate care for children with complex needs in some rural communities. participants also discussed various resources located at the pediatric health centre that were helpful in supporting smooth transitions in care. these included care coordinators, perinatal follow-up teams, social workers, clinical nurse specialists, specialty physicians and nurse practitioner. participants in the community frequently mentioned the importance of a having access to a key worker or coordinator assigned to each child and family. two members of the research team (jc, sb) facilitated a consensus meeting with 18 key stakeholders from across nova scotia. consensus meeting participants included community and tertiary care health care providers, paramedics, senior administrators and policy analysts from the health and education sectors who were not involved in phase 2 data collection. the consensus meeting lasted 2 hours. key findings from phase 1 and 2 were presented along with 6 proposed recommendations for inclusion in a provincial policy statement. recommendations were developed using a behaviour change lens to act as a starting point in addressing the challenges arising from phase 1 and 2 findings. key priorities in the development of the recommendations included building on existing programs and infrastructures and working with a range of stakeholder groups to co-develop new resources. we also recognized the need to make these resources accessible to end-users across the province, regardless of geographical location. each recommendation was discussed and revisions were made through a process of consensus as described previously in the methods section. two points of discussions resulted in modifications to the recommendations. first, consensus meeting participants agreed there was a need for a shared conceptual definition for children with complex and medically fragile needs to orient the present discussion, as well as future clinical and research initiatives examining this population. a number of published definitional frameworks were discussed and participants chose cohen et al.'s definitional framework as the most suitable given the recent work using this framework in a canadian context [1, 2] . second, one of the recommendations included the need for a care coordinator within each provincial health zone to act as a liaison and resource for families and health care providers. following a lengthy discussion, consensus meeting participants recommended that the coordinator role should be specified as an advanced practice nurse. see table 5 for a complete list of final recommendations. this project aimed to develop recommendations to improve the hospital to home transition for children with complex and medically fragile needs and their families in one canadian province. this multi-phased research initiative incorporated the perspectives and experiences from families, administrators, and health care professionals to co-develop 6 key recommendations for policy and practice change. in addition to these recommendations, examination of study findings revealed a variety of gaps and areas for future research to optimally support these families during transitions from hospital to home. understanding the experiences and perspectives of families of children with medical complexity is essential for designing policies and systems to improve transitions in care for this vulnerable populations [35] . cases included in this study represented a range of experiences and complexity. across all cases, there were a number of similarities between family experiences transitioning from hospital to home. prior to discharge, families reported feeling prepared to manage their child's medical care, and eager to return home once their child was medically stable. nurses were identified as a key member of a child's care team within the inpatient setting. they acted as both an educational resource, care coordinator, and emotional support, facilitating a sense of empowerment and security within families. this finding is consistent with the literature describing the role of nurses in supporting seamless discharge from hospital to home [36, 37] . similar to other studies, parents in this case sample also identified other parents as an important source of support [38] . divergence appeared across cases in regard to the availability of resources and support after returning home from hospital. while a number of parents reported having access to appropriate resources in their community, some families reported feeling inadequately supported to assume the various medical, social, and emotional care needs of their child in addition to their daily responsibilities (e.g. work, family, personal needs). parent readiness for caregiving at discharge can shape the families ongoing experience [8] . ideally, the shift in responsibility for care from hospital to home should be negotiated with parents prior to discharge [39] . the health care system is beginning to address the shift in care of these children from hospitalized to community-based settings, but work still remains to be completed to optimally support these children and families to flourish in the home [15] . there have been a number of emerging models of care to support advanced health care in the community. these proposed models range greatly in regards to their characteristics, including being both hospital-and primary caremanaged, further highlighting the lack of agreement surrounding the optimal model of care for these children [14, 16] . it is additionally important to recognize that caring for the health of the family as a whole is critical, as the child's health is often linked with that of their caregiver [40, 41] . in designing an optimal health care system for individuals with complex care needs, the commonwealth fund released 10 recommendations for policymakers [27] . of these table 5 recommendations for inclusion in provincial policy statement adopt the definitional framework for children with medical complexity (cohen et al., 2011) to identify children with intensive care needs in the province of nova scotia that are not easily met under existing policies and services. work with existing provincial programs and services (i.e. continuing care) to develop policies and tools that are unique to a pediatric population. develop a role for a pediatric advanced practice nurse in each health zone in nova scotia to act as a liaison/resource between the tertiary care facility and children discharged with medical complexities, their families and their health care providers to coordinate care and lead capacity building and education initiatives with local health care providers, children, and families. develop a comprehensive discharge plan for every child with complex care needs. the plan must be co-developed and approved by a discharge planner/advanced practice nurse, parent or caregiver-home, or community discharge coordinator prior to discharge from the pediatric tertiary care facility and will consider the medical, psychosocial and developmental requirements for patients to successfully transition back to their home community. develop a complex care information repository (ccir) for health care providers, administrators, patients and families to store and organize key resources (contact information for key personnel, clinical practice guidelines, community/hospital resources, etc). develop an educational outreach strategy to address the knowledge, skills and competency needs of health care providers across nova scotia who care for children with medical complexity. recommendations, one clearly outlines the need for greater support for caregivers, suggesting that "support might include respite care to provide relief for caregivers and assistance to help them look after their own health" ( [27] , p.4). the crucial need to enact this recommendation is further confirmed by families of children with complex care needs reporting higher levels of depression [42, 43] , stress [44] , poorer general health [43] and feelings of isolation [45] . one scoping review conducted by edelstein, schippke, sheffe, and kingsnorth (2016) identified a range of interventions aimed to mitigate the stress experienced by caregivers of children with medical complexity living in the community [46] . these programs included care coordinator models, respite care, telemedicine, financial benefits and peer support programs [46] . with the promising results emerging from this review, future high-quality research evaluating the effectiveness of these interventions on caregivers is warranted to improve the support provided to families of children with complex care needs [46] . attending to the complex multidimensional health and social care needs of this population of children requires a multidisciplinary approach [4] . timely and effective communication between all members of the care team was identified as an essential component to a successful transition home. health care providers often reported turning to specific nurses when unsure about details of a certain care plan, with most all providers expressing the desire for a key coordinator assigned to each child with complex care needs and their family to facilitate effective communication. the role of this care coordinator, or otherwise referred to as a 'key worker', in the care transition process has been gaining increasing attention over the past number of years [18, 41, 47, 48] . most recently, the canadian association of pediatric health centres has recommended the development of a key worker role to facilitate transition planning and management for all children with medical complexity and their families [48] . further, the need of a care coordinator role is also mentioned in the commonwealth fund's 10 recommendations for optimal health care for individuals with complex care needs to reduce the risk of fragmented health care delivery and facilitate timely communication amongst the care team [41] . to support this transition, key workers act as a single point of entry, enable team collaboration and streamline essential communication amongst families and health care providers [47, 48] . this key worker is a proposed strategy to mitigate the care coordination and communication challenges associated with what is often a large health team across multiple services and sectors managing the care of these children and their families. key workers not only streamline team communication, but also play a pivotal role in empowering and engaging families in the child's care [49] . as the development of this role continues, it is critical that patient-oriented research is conducted to evaluate its effectiveness, make appropriate changes to the roles based on specific contexts and to ensure optimal care delivery for this vulnerable population. an economic evaluation would also be important to estimate the relative costs and consequences of implementing this new role. health care providers reported a paucity of knowledge of specific formal guidelines or policies to guide transitions from hospital to home for children with complex care needs. however, informal processes within each discipline were followed and many teams had developed their own discharge planning tools to ensure all appropriate actions and processes were taken to ensure smooth transitions in care. while there are a number of recommendations and guidelines aimed at the supporting the care management of this population [8, 48, 50, 51] , there remains a limited number of empirically evaluated programs and interventions informing the transition from hospital to home [18] . although the transition process should be customized to the individualized needs of children and families, overarching guidelines and structures should to be in place to ensure timely transition planning and continuity in care. however, to ensure the development of relevant, comprehensive, and sustainable policy recommendations, engaging a variety of key stakeholder is crucial [52] . leveraging research techniques to bring family experiences and perspectives to the forefront of decision making is essential to ensuring family-oriented practice and policy changes are pursued. further, adopting an integrated knowledge translation approach by partnering with knowledge users throughout the research process can help ensure the knowledge being co-created will be relevant to their needs, and therefore more likely to be adopted into practice and policy [53, 54] . the recommendations stemming from this study were developed by integrating the experiential knowledge from families with the perspectives of stakeholders across the tertiary care, community care, and government sectors. results from this research serves as a critical foundation for future intervention and program design to support the entire care team, including health care providers, administrators, and families, during the often complex, dynamic, and unique transition from the hospitalized setting back into a child's home and home community. there are several limitations to note in this study. although a range of children, families, and health care providers participated in this study and we leveraged a range of data collection sources and strategies, these findings may not be generalizable to the transition experiences of all children and families with complex care needs. we developed a total of 6 cases to explore a range of experiences transitioning from hospital to home, however we recognize that this is a heterogeneous population of children and our cases may not represent the experiences of all children and families with complex care needs. further, a comprehensive understanding of the impact of the hospital to home transitions may not have been fully captured within the 1 month follow-up time in the case studies [13] . only individuals able to speak english were eligible to participate. children and families speaking other languages may have different experiences transitioning from hospital to home that were not captured by this study. children with medical complexity represent a small but resource intensive portion of the pediatric population in the canadian health care system. transitions from tertiary care to home can pose many challenges for children, families and health care providers in the recipient communities. our project identified policy and practice gaps that currently exist in one canadian province related to transitions from a tertiary care facility to home communities for children with medically fragile needs and families. our collaborative patient-centred approach to understanding how children, families, and health care providers currently navigate transitions in care provided a foundation for developing recommendations for a provincial wide strategy. children with medical complexity: an emerging population for clinical and research initiatives patterns and costs of health care use of children with medical complexity building systems that work for children with complex health care needs: editor's note children's complex care needs: a systematic concept analysis of multidisciplinary language children with medical complexity in canada children with complex chronic conditions in inpatient hospital settings in the united states variation in child health care utilization by medical complexity disabilities the cocw. home care of children and youth with complex health care needs and technology dependencies caring for children with specialized health care needs in the community: the challenges for primary care strategies to reduce hospitalizations of children with medical complexity through complex care: expert perspectives pediatric readmission prevalence and variability across hospitals medical complexity and pediatric emergency department and inpatient utilization the impacts of distance to hospital on families with a child with a chronic condition models of care delivery for children with medical complexity status complexicus? the emergence of pediatric complex care the landscape of medical care for children with medical complexity. overl park: child hosp assoc strategies to support transitions from hospital to home for children with medical complexity: a scoping review designing and conducting mixed methods research census families with children by age of children and children by age groups iwk health centre -about us report of the auditor general to the nova scotia house of assesmble. halifax: nova scotia auditor general pediatric deaths attributable to complex chronic conditions: a population-based study of washington state sf-36v2 health survey manual for the stait-trait anxiety inventory you want to measure coping but your protocol's too long: consider the brief cope how to plan and perform a qualitative study using content analysis validation of the theoretical domains framework for use in behaviour change and implementation research the behaviour change wheel (behavior change wheel) -a guide to designing interventions are we there yet? data saturation in qualitative research using thematic analysis in psychology the basics of consensus decision making complex care program. sick kids families of children with medical complexity: a view from the front lines complex care packages: supporting seamless discharge for child and family advanced practice profiles and work activities of nurse navigators: an earlystage evaluation a qualitative study of parent to parent support for parents of children with special needs negotiating lay and professional roles in the care of children with complex health care needs experts' perspectives toward a population health approach for children with medical complexity designing a high-performing health care system for patients with complex needs: ten recommendations for policymakers. the commonwealth fund; health and social care a longitudinal study of families with technologydependent children changes over time in the health of caregivers of children with health problems: growth-curve findings from a 10-year canadian population-based study enabling young 'ventilator-dependent' people to express their views and experiences of their care in hospital getting out of the house: the challenges mothers face when their children have long-term care needs children with medical complexity: a scoping review of interventions to support caregiver stress. child care health dev the role of care coordinator for children with complex care needs: a systematic review canadian association of pediatric health centres. children and youth with medical complexity (cymc) caphc community of practice (cop). national guidelines collaborative care coordination: a priority for health reform families' priorities regarding hospital-to-home transitions for children with medical complexity importance and feasibility of transitional care for children with medical complexity: results of a multistakeholder delphi process strategy for patient-oriented research. ottawa: canadian institutes of health resarch guide to knowledge translation planning at cihr: integrated and end-of-grant approaches -cihr. canada: government of canada sharing and expanding academic and practitioner knowledge in health care a refined taxonomy of behaviour change techniques to help people change their physical activity and healthy eating behaviours: the calo-re taxonomy publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all the children, families, and health care providers that committed their time to participate of this project. we also wish to acknowledge margaret champion and julia belliveau for their contributions with data collection. authors' contributions jc and jv conceived of the study, obtained funding to support the project. jc supervised the data analysis. sb participated in data collection, data analysis, and drafted the initial manuscript. both jc and jv made significant revisions to the manuscript. all authors read and approved the final manuscript. this research was funded through a translating research into care (tric) grant from the iwk health centre. funding to publish our study in an open access journal was provided through an open publication bursary from the maritime strategy for patient oriented research (spor) support unit. the datasets generated and/or analyzed during the current study are not publicly available due issues with privacy and confidentiality but are available from the corresponding author on reasonable request. ethical approval for this research was obtained at the iwk health centre by the iwk research ethics board (project #: 1017345). written informed consent was obtained from parents or guardians for participation. consent from each individual participant was obtained following procedures approved by the iwk health centre's research ethics board. written consent appendix table 6 theoretical domains framework definitions knowledge "an awareness of the existence of something" (p.88) skills "an ability or proficiency acquire through practice" (p.88) "the ability to retain information, focus selectively on aspects of the environment and choose between two or more alternatives" (p.88)behavioural regulation "anything aimed at managing or changing objectively observed or measured actions" (p.88) "a coherent set of behaviours and displayed personal qualities of an individual in a social or work setting" (p.89)beliefs about capabilities "acceptance of the truth, reality, or validity about an ability, talent, or facility that a person can put to constructive use" (p.89)optimism "the confidence that things will happen for the best or that desired goals will be attained" (p.89)beliefs about consequences "acceptance of the truth, reality, or validity about outcomes of a behaviour or a resolve to act in a certain way" (p.89)intentions "a conscious decision to perform a behaviour or a resolve to act in a certain way" (p.89) goals "mental representations of outcomes or end states that an individual wants to achieve" (p.89)reinforcement "increasing the probability of a response by arranging a dependent relationship, or contingency, between the response and a given stimulus" (p.89)emotion "a complex reaction pattern, involving experiential, behavioural, and physiological elements, by which the individual attempts to deal with a personally significant matter or event" (p.89) "any circumstance of a person's situation or environment that discourages or encourages the development of skills and abilities, independent, social competence, and adaptive behaviour" (p.90)social influences "those interpersonal processes that can cause individual to change their thoughts, feelings, or behaviours" (p.90) [29, 55] was obtained from a parent or guardian on behalf of all participants under the age of 16. the authors declare that they have no competing interest.received: 27 august 2019 accepted: 4 may 2020 key: cord-029723-g6pvyzrc authors: brenner, maria; alexander, denise; quirke, mary brigid; eustace-cook, jessica; leroy, piet; berry, jay; healy, martina; doyle, carmel; masterson, kate title: a systematic concept analysis of ‘technology dependent’: challenging the terminology date: 2020-07-24 journal: eur j pediatr doi: 10.1007/s00431-020-03737-x sha: doc_id: 29723 cord_uid: g6pvyzrc there are an increasing number of children who are dependent on medical technology to sustain their lives. although significant research on this issue is taking place, the terminology used is variable and the concept of technology dependence is ill-defined. a systematic concept analysis was conducted examining the attributes, antecedents, and consequences of the concept of technology dependent, as portrayed in the literature. we found that this concept refers to a wide range of clinical technology to support biological functioning across a dependency continuum, for a range of clinical conditions. it is commonly initiated within a complex biopsychosocial context and has wide ranging sequelae for the child and family, and health and social care delivery. conclusion: the term technology dependent is increasingly redundant. it objectifies a heterogenous group of children who are assisted by a myriad of technology and who adapt to, and function with, this assistance in numerous ways. there are an increasing number of children who require medical technology to sustain their life [1] [2] [3] [4] and, in response, an expanding array of medical technology available. this paper analyses the concept of 'technology dependent', the term commonly used to refer to these children. the current prevalence and rate of increase in the number of children who are technology dependent is difficult to determine as they depend on a number of interrelated factors including: the prevalence of particular conditions; medical and surgical interventions chosen; and finance and policies for care delivery across and within countries [5] [6] [7] . the term technology dependent stems primarily from the phrase 'technology dependence' which was coined 30 years ago by the office of technology assessment (us) [8] , describing 'a medical device to compensate for the loss of a vital body function and substantial ongoing nursing care to avert death or further disability'. to the best of our knowledge, this is the first systematic concept analysis to examine the contemporary relevance and utility of this terminology as it is currently portrayed in the literature. this is important for two key reasons: the array of medical technology now available means that the broad term of 'technology dependent' has the potential to conjure up a multitude of clinical scenarios; and the objectifying nomenclature does not reflect a child-centric approach. this paper is part of a larger body of research, the techchild project, funded by the european research council. the purpose of this research is to explore influences on the initiation of technology dependence required to sustain a child's life and to identify more appropriate child-centred terminology in an evidenced-based manner. an evolutionary concept analysis was employed as it seeks to examine the cluster of key characteristics that through common use, collectively form the real definition of a concept [9] . according to rodgers [9] , it is necessary to understand the antecedents (phenomena usually found prior to concept occurrence), the attributes of the concept, and the consequences that follow as a result. without a clear conceptual foundation, there is an ambiguity which in turn can compromise the quality of research or theory construction as the area develops [10] . rodgers' evolutionary method [9] was used to systematically analyse the concept of technology dependence in the scientific literature. this method is particularly well suited to this issue given the changing and dynamic nature of advances in medical technology. alternative approaches to concept analysis are founded in a realist paradigm, in which a reductionist approach focuses on defining a concept as a static entity. rodgers' relativist stance, in comparison, seeks to identify how a concept is portrayed in the literature using an inductive approach, while acknowledging that any understanding of a concept is evolutionary as it is influenced by dynamic contextual factors, which may be disciplinary, cultural, or theoretical [9] . rodgers' approach to concept analysis includes a set of core activities, which can be carried out simultaneously and not necessarily in a linear manner (table 1) . analysis seeks to identify what is common, the purpose of which is to identify data that is relevant to the attributes of the concept and its contextual features. thematic analysis identifies major themes presented in the literature. a three-strand approach was used to create a systematic search. an initial scoping search was run in pubmed and cinahl to identify appropriate control language using mesh and cinahl headings. control language is the language of the topic established at the start of a systematic search, against which other terms which emerge are mapped against. this includes developing a list of synonyms and consideration of reference and non-reference words for the search. a secondary scoping search was then conducted identifying appropriate keywords related to the following: technology dependence, technology dependent, complex care needs, complex medical care needs, complex healthcare needs, children with special healthcare needs, medically fragile, and medically complex children. the final search was run in pubmed, cinahl, and psycinfo using a combination of the keywords and control language. the search was limited to english-language literature published over the last 30 years up to the 31st of december 2019. the reference lists of the resulting articles were reviewed to identify any other pertinent table 1 rodgers' approach to concept analysis activities 1. identify the concept of interest and associated expressions (including surrogate terms) 2. identify and select an appropriate realm for data collection 3. collect relevant data 4. analyse the data articles. an additional hand search was conducted and a grey literature search was completed using opengrey, the systems for information on grey literature in europe (sigle), world health organization (who), national technical information service usa (ntis), and the national academies press. (fig. 1 ) duplicate articles were removed from the search and the remaining abstracts and full texts were reviewed to ensure they included reference to technology dependence. those that did not meet these criteria were not included in the concept analysis. the majority of the 164 articles identified were from north america and europe and the majority of papers are from the last 10 years, reflecting the growing population of children requiring technology to sustain their lives. each of the articles was analysed for data relevant to the (1) attributes, (2) antecedents, and (3) consequences of a child's dependence on medical technology to sustain life using a coding framework based on rodgers' evolutionary method ( table 2 ). to guide the data analysis process, a set of specific questions were formulated for each category of data set out by rodgers (table 3 ) [9] . it was important to develop a framework specific to the topic of this concept analysis to ensure a clear focus on the specific areas of interest in the review of the literature. the framework was reviewed by mbr and da, who then organised recurring themes into each category (attributes, antecedents, and consequences) (fig. 2) . in this way, the structure of the findings below is based on these three categories set out by rodgers [9] . key attributes of technology dependence required to sustain a child's life synthesis of themes from the literature identified key attributes of technology dependence in children to sustain their lives as heterogenous with a dependency continuum. clinical technological dependence in children spanned a wide range of support for multiple human systems. they included oxygen support, invasive and non-invasive mechanical ventilation, pacemaker, implantable cardioverter defibrillators (icd), ventricular drains, intravenous drugs, intravenous nutrition, gastrostomy or jejunostomy, ileostomy, colostomy, urethral catheterisation, and dialysis [7, [11] [12] [13] [14] [15] [16] [17] . we found that the majority of papers referred to children who were technology dependent as children who predominantly required respiratory or cardiac support in addition to requiring additional technological supports to support their wider clinical care needs including nutrition and gastrointestinal function. the length of time a child may be dependent on clinical technology to sustain their life can vary, depending on the range and severity of their illness. children may be dependent on a single device or multiple devices for a defined period, or they may be dependent on clinical technology for a longer period of time, depending on the complexity of their clinical presentation [12, 18] . some children have the potential of being increasingly technology dependent as their illness progresses, depending on their comorbidities [19] [20] [21] [22] [23] [24] [25] the conceptual analysis identified four domains regarding antecedents of technology dependence: clinical characteristics of the child, physician perspectives, the developing autonomy of the child, and parental engagement. specific foreground clinical characteristics which may lead to the initiation of technology dependence are identified in the literature. this includes genetic disorders, congenital disorders, issues related to prematurity or perinatal trauma, acquired external causes such as neoplasia, near drowning or trauma, following prolonged resuscitation, perisurgical anoxia, accidental suffocation, renal failure, and degenerative neurological conditions [11, 13, 24, [38] [39] [40] . the impact of different physician perspectives on care delivery is evident in the literature [38] . some suggestions for varieties in perspectives include prognostic uncertainty and varying perspectives on the meaning of death of a child in their care [41, 42] . the estimation of prognosis is a significant factor when technology dependence is initiated [43] [44] [45] [46] . where there is prognostic uncertainty, this may be compounded by consideration of the potential opportunities that may emerge with future medical technological advances [17] . on the other hand, physicians who are over pessimistic in their prognostication may not offer hope for survival [47] . it has been suggested that varying perspectives on the initiation of technology dependence may be related to physicians' views of death; for example, one study review showed that 68% of physicians regarded their patients' deaths as a personal failure [48] . care delivery to children is unique in that those receiving care are developmentally dynamic and the autonomy of those which factors (antecedents) are proposed to precede technology dependence? 3. what are the consequences of a child's dependence on medical technology? receiving care must be considered [49] [50] [51] [52] [53] [54] [55] [56] [57] . a predominant paternalistic stance is evident in that much of the literature in this area focuses on the perspectives of the clinical team or the parents and there is evidence that children are often excluded from the decision-making process [58, 59] . this may be explained by a priori beliefs of the value of a child's opinion or on limited belief of the importance of the chronological age or developing abilities of children as they age [60, 61] . literature that espouses increased autonomy of the child in decisionmaking argues that it can increase the child's trust and enhance the child-physician relationship [54, 55, 57, [62] [63] [64] [65] [66] . the concept analysis found multiple concurrent issues that affect parents when technology dependence is initiated for their child. parents may be influenced by previous experiences, for example if they have another child with a similar condition, how they experienced the care of that child and whether that child is still alive or has died [39] . they may also be so consumed by their immediate concerns for the child's survival that they may not fully understand the options available for their child's care [39, 67, 68] . the literature is replete with stressors of the parents at such critical junctures in care delivery including a feeling of lack of control over the ongoing instability of the child, insomnia, poor diet, and exhaustion [69] . a number of potential organisational challenges were also identified, including the potential for miscommunication of information to parents when more than one clinical team is involved [70, 71] ; influences of organisational culture on the degree of choice parents can exercise and the power dynamic between the parent/child and physician in decision making [72] ; and coercion or pressure put on parents to make quick decisions when decisions are time-sensitive, which can limit the level of communication and engagement to support parents [39] . supportive measures identified for parents during this time include having a dedicated coordinator to manage the various care communications; this could facilitate more thorough communication of decisions around care delivery and lead to more informed conversations engendering greater trust with families [17, 73] . finally, the consequences of the concept were identified. these are the factors (consequences) that provide biopsychosocial context beyond the initiation of technology dependence to sustain a child's life and the phenomena that occur consequently. the conceptual analysis identified four domains of consequence of the initiation of technology dependence: clinical care of the child; psychosocial sequelae for the child; family adaptation; and ongoing impact for health and social care. a literature review identified multiple issues specific to the clinical care of a child who is dependent on technology to sustain their life. they can have frequent clinic visits, are frequently hospitalised, and have a high risk of critical illness [5] [6] [7] [74] [75] [76] . these children also have more visits to the emergency department than a well child [14, 75, [77] [78] [79] . this rate of attendance is often higher than the rates of attendance of elderly patients over 85 years of age [75] . higher rates of visits are associated with greater distance from the hospital and being a younger child and having a large number of medications [24, [80] [81] [82] . children who are technology dependent may have longer stays in picu, they are more likely to be readmitted to a picu during a hospital stay, new morbidities often emerge following admission and readmission to picu, and they are more likely to die after a prolonged stay in picu than a child with an acute illness [5, 6, [83] [84] [85] . other clinical issues can include device-related complications; for example, for a child who has an icd, this may include lead dysfunction, risk of infection, and/or battery depletion [86] . there was limited attention paid in the literature to the psychological sequelae for a child who is technology dependent. protective factors against negative psychological sequelae for children assisted by technology include higher cognitive functioning of the child and greater social functioning of the [87, 88] . some-illness specific issues were found. for example, where low health-related quality of life (hrqol) was found for children who were technology dependent, the lowest scores were found for children who were technology dependent and also had a neurological impairment [88] . in addition, children who had icds were found to have a high potential for anxiety, depression, and post-traumatic stress disorder [16, 89, 90] and overall children with pacemakers were found to have lower hrqol scores than other children with chronic cardiac disease who were not dependent on a rhythm device [91] . it was also found that females and non-caucasian children living with an icd had higher prevalence of anxiety and depressive disorders than other children living with the same device [89, 92] . the adaptation of a child's family to their technology dependence is well documented for children living assisted with respiratory support, though much less so for other technology. the stress of moving out of picu and the realignment of care expectations has been identified as a period of significant stress for parents [71] . general concerns when planning to move to home includes parents' stress about becoming a clinician in the home and stress about the potential for equipment malfunction [24, 68, 71, [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] . specific challenges identified include grieving for a well child [71] ; learning to master care delivery in a variety of settings [108] ; guilt over having less time with the other children at home or relying on them for assistance in care giving [109] ; causing pain to their child when carrying out clinical procedures [109] [110] [111] [112] ; concern over sleep disturbance [108, 113] ; and difficulty accessing and delivering a large number of medications [24] . a number of papers highlight how parents obtain a sense of control as they adapt their role as primary care givers of a child who is technology dependent. this includes focusing on becoming an expert carer, focusing on the child's achievements, and the importance of their spirituality or religion to help them cope [102, 114] . resilience training has been found to have a positive effect on parents' ability to cope [115] . however, while parents often become very good clinical problem solvers [112] , they have identified specific areas for greater support when planning for discharge. this includes support for ongoing self-directed learning once they are at home, greater support to deal with the myriad of financial concerns, and greater flexibility in the level and amount of care delivery made available to them [71, 101, [105] [106] [107] 116] . the impact on siblings adapting to living with a child who is technology dependent is increasingly being documented in the literature. this includes a focus on the positive aspects of adaption such as the development of a strong attachment and having protective tendencies towards their sibling [117] . negative aspects have also been identified, including a risk of isolation, missing out on social and family events, and risk of psychological distress as the family adapts to a new way of being [117] [118] [119] . earlier papers on this topic urged caution over placing extraordinary burdens on parents and families by the introduction of life-sustaining technology in the home [120] . more recently, there is a very clear impetus internationally to encourage care of the child as close to home as possible and preferably in the home [121, 122] . the variety of challenges for health and social care delivery, related to the increasing number of children who require technology to sustain their lives, are well documented in the literature. this includes challenges in the development of integrated care for this cohort of children and co-creation of integrated care with children and their families [106, 107, 113, 123] . care delivery across acute and community care services can be complicated by inconsistent standards for discharge to home [107, [124] [125] [126] [127] . specific areas that could enhance care delivery include enhanced access to specialist care, including same-day appointments to appropriately trained physicians in the community [80, 128, 129] ; increased use of telehealth, electronic records, and patient summaries [130, 131] ; specialist home care visits in the initial week following discharge to home [81] ; and increased access to respite care in and out of the home [103, 113, [130] [131] [132] [133] [134] [135] [136] . access to, and governance of, appropriately trained nurses is identified as an ongoing challenge as this population of children grows [5, 35] . specifically, there is an increasing call for advanced practice nurses across various healthcare sectors to care for children who are technology dependent [88, 103, [135] [136] [137] and the need for an increased number of school nurses to support access to education for these children [138] [139] [140] [141] . children dependent on technology are living longer and this impacts on their transition to adult services and onward care in adult healthcare; there is a need for enhanced models of transition to adult services with established and standardised protocols [106, 125] . this concept analysis shows that the term technology dependent continues to be widely used as an umbrella term for a large group of children, without much evidence of any critical consideration of its use. the most commonly referenced definition is now 33 years old [8] . we found that literature on technology dependence to sustain a child's life refers to a wide range of clinical technology to support biological functioning across a dependency continuum, for a range of clinical conditions. this assistance is initiated within a complex biopsychosocial context and has wide ranging sequelae for the child and family and health and social care delivery. this highlighted the heterogenous nature of technology dependence, the fact that children could be assisted by one or more devices and the fact that the length of time for this assistance can vary. we also found that the language around technology dependence in the literature to date is very problem focused. the majority of work focuses on the negative sequelae of using technology to assist a child. this includes challenges with decision-making, organisational culture, frequency of hospitalisation, psychological challenges and concerns around family adaptation, and ongoing access to health and social care [6, 59, 90, 96, 113] . twenty years ago, nelson [142] , in a chapter titled 'the ventilator/baby as cyborg: a case study in technology and medical ethics', suggested that technology dependence would eventually be viewed as routine care. the question of how we understand this coexistence of human beings with the opportunities posed by advancing technological augmentations is a significant issue [143] [144] [145] . an important step is critically reviewing the use of the term technology dependent. there is a need for more contemporary language that is more solution focused and child-centric. our findings point to the redundancy of the term technology dependent, a mechanical term that continues to be used to group together a growing population of children who are assisted by technology in a myriad of ways, who adapt to, and function with, this assistance very differently. this is essential for research that is required to illuminate coping strategies and adaptation of children and their families to assistance from technology. the use of such a mechanical phrase can also detract from seeking to understand more about the phenomena happening when the use of technology is initiated, the absence of which can lead to the potential for more anecdote and personal opinion to influence actions, than empirical evidence. this is the focus of techchild, a programme of research funded by the european research council which asks just because we can, should we? an anthropological perspective on the initiation of technology dependence to sustain a child's life. the overarching aim of this project is to specifically explore influences on the initiation of technological assistance and to develop a theory to explain the initiation of this technology in the context of contrasting health, legal, and socio-political systems. within this 5-year programme, the terminology in use will be examined further and the current paper provides a foundation to this work. no specific international guidelines emerged from our search of the literature on the use of the term technology dependent. this is likely to be due to the fact that clinical guidelines predominantly focus on specific clinical presentations instead of using more broad terminology. we found that the term technology dependent encompasses a broad span of clinical areas and specialties, though the majority of papers referred to children who require predominantly respiratory or cardiac support. it is possible that some specific characteristics of other groups of children assisted by technology were not identified in this concept analysis, though the final definition may still be pertinent to the wider group of children who are assisted by technology. in an era where interventionist medicine is increasingly available for ever more medically fragile children, this concept analysis is timely. we found that the term technology dependent refers to a wide range of clinical technology to support biological functioning across a dependency continuum, for a range of clinical conditions. they are initiated within a complex biopsychosocial context and have wide ranging sequelae for the child and family and health and social care delivery. the concept analysis highlighted that this term is predominantly portrayed in the literature as a very problem-focused issue. we suggest that the term is increasingly redundant and objectifies a heterogenous group of children who are assisted by a myriad of technology and who adapt to, and function with, this assistance in numerous ways. authors' contribution mb, da and mq made a substantial contribution to conception and design of the concept analysis and mb, da and mq screened the data gathered. mb, da, mq, jec, pl and jb were involved in the acquisition of the data. all authors were involved in the interpretation of data, in drafting the article and revising it critically for important intellectual content. all authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. funding information the project is funded by the european research council 803051. conflict of interest the authors declare that they 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10.3389/fpsyg.2020.01477 sha: doc_id: 30800 cord_uid: fgvc3qw8 in order to explore the relationship between parent–child attachment, negative emotion, emotional coping style, and self-injury behavior, 662 junior high school students in four junior middle schools in china’s yunnan province were investigated using a parent–child attachment questionnaire, adolescent negative emotion questionnaire, emotional coping style scale, and adolescent self-injury behavior scale. as a result, two mediate models were created to explain how parent–child attachment affects self-injury behavior. negative emotion and emotional coping style play serial mediating roles in mother–child and father–child attachment models, respectively. the results show that negative emotion mediates between self-injury behavior and both father–child and mother–child attachment, while emotional coping style only functions between father–child attachment and self-injury behavior. by means of bootstrap analysis, negative emotion and emotional coping style have serial mediating roles concerning the impact of parent–child attachment on self-injury behavior. by comparison, the father–child and mother–child attachment have different mediating models: the former relies on emotional coping style, while the latter is associated with emotional experiences. this implies that parent–child attachment has different mechanisms in triggering self-injury behavior, which is in line with the hypothesis of attachment specificity. non-suicidal self-injury (hereafter referred to as nssi or self-injury) is the direct, deliberate destruction of one's own body tissue in the absence of suicidal intent, which is intended by the individual, rather than accidental (klonsky and olino, 2008; nock and favazza, 2009) . the incidence of self-injury among the general population is 1 ≤ 4% (sleuwaegen et al., 2017) ; however, adolescents with a history of self-injury are up by 30-40% (yulong et al., 2016; cerutti et al., 2018) . domestic studies show that the proportion of self-injury behavior among teenagers is over 20% (feng, 2008; ying et al., 2013; yinqgian et al., 2015) . thus, there is clearly a high occurrence of self-injury behavior, especially among adolescents. self-injury behavior is a negative way for individuals to deal with current problems (sornberger et al., 2013) , and causes great harm to adolescents' mental health (guvendeger et al., 2017; baetens et al., 2019) . at the same time, selfinjury behavior is also a risk factor leading to suicide. in the absence of intervention, it may lead to a high possibility of suicide among people (guan et al., 2012; ge et al., 2014) . the biosocial model also holds that an ineffective family environment is an important cause of self-injury behavior, and parents' neglect of children's emotion and abuse can most directly cause self-injury behavior (thomassin et al., 2016) . the parent-child relationship is unavoidably related to the formation and sustainable development of self-injury behavior in junior high school students. in the face of increasingly severe self-injury behavior, previous research has mainly investigated the effects of adverse family environments on adolescents' self-injury behavior, such as early traumatic experiences, emotional susceptibility, personality characteristics, stressful life events, family conflicts, etc. (fuxia et al., 2018; buser et al., 2019) . a strong parent-child attachment with an emotional link in their relationship may to some extent prevent junior high school students from self-injury behavior. however, the mechanism of how parent-child attachment affects adolescents' self-injury behavior still remains unclear. therefore, this paper mainly discusses the impact of parent-child attachment on one's self-injury behavior as well as the mechanism behind it, in an attempt to offer targeted suggestions for the prevention and intervention of self-injury behavior in junior high school students. parent-child attachment is a relatively stable relationship model formed in the communication between children and their parents, which can significantly influence children's social communication and mental health during their growth (yulong, 2015) . a study demonstrates that there are various and unique associations between family based risk factors and self-injury behavior, as well as addictive features (martin et al., 2016) . it is worth noting that the experience of adverse family life is correlated with self-injury behavior. in addition, another study shows that high-quality family relationships, such as parent-child trust and parent-child communication, were linked to fewer discipline violations, less antisocial behavior (burk and laursen, 2010) , and lower levels of anxiety, depression (nadorff et al., 2014) , and loneliness, which may further contribute to middle school students' higher emotional levels (al-yagon, 2012), their seeking help, and more positive ways to adapt to society, thus reducing the probability of selfinjury. on the contrary, the higher the degree of parentchild alienation, the higher the risk of self-injury (weihua, 2016) . in the period of adolescence, junior high school students are going through drastic changes both psychologically and physiologically, being faced with a series of adaptation problems, including physiological maturity, cognitive development, and social role transformation (guoliang and yu, 2018) . thus, when they fail to cope with family relationships, they may alleviate their pain by means of self-injury behavior (victor et al., 2012) . fuxia et al., 2018 has pointed out that parent-child attachment is an important factor in adolescents' self-injury behavior (fuxia et al., 2018) . in addition, recent studies have demonstrated that poor-quality parent-child attachment can increase the incidence of self-injury behavior (honglei et al., 2018) . interpersonal or systematic models have also pointed out that self-injury is the result of family dysfunction, and that the family environment of certain individuals will unconsciously support or strengthen their self-injury behavior (crouch and wright, 2004) . moreover, studies find that fathers and mothers play different roles in parent-child communication; the father spends relatively less time interacting with their children, and tends to engage in more physical and outdoor activities, while mothers invest time and are involved in more caring and household interactions (oliveri et al., 2018) . consequently, it is possible that father-child and motherchild relationships represent different variables that affect the self-injury behavior of junior high school students. previous research says that children have fewer problematic behaviors with a healthy father-child relationship (hardcastle et al., 2018) . meanwhile, the attachment specific hypothesis further indicates that when children undergo attachment experience with different caregivers, the multiple layers of attachment formed boast a non-differentiated degree of influence on children's social and psychological development (zborowski and mcnamara, 1998) ; i.e., the influence of father-child and mother-child attachment on children's development is not superimposed or comprehensive, but independent from one another. do father-child and mother-child attachments have the same impact on self-injury behavior? we will explore their respective mechanisms. at present, the mechanism of how parent-child attachment influences self-injury behavior stills remains unclear and requires further exploration. two main theories used to explain selfinjury behavior are the interpersonal or systematic models, as well as the emotion regulation model (yulong et al., 2016) . interpersonal or systematic models emphasize the impact of the family environment on self-injury behavior, demonstrating the influence of the family system on adolescent problematic behavior, especially from the perspective of parent-child relationships (crouch and wright, 2004) . by contrast, the emotion regulation model shows that individual self-injury behavior is a behavioral strategy to deal with negative emotions or reduce pain from the angle of emotional management (messer and fremouw, 2008) . however, these two models do not explore the negative emotions caused by parentchild relationship in the family system, so they fail to fully reveal the effects of parent-child attachment on negative emotions, emotional coping style, and self-injury behavior. in other words, the question is, as negative emotions are generated by poor parent-child relationship, why are children unable to manage their emotions effectively, and why is parent-child attachment not protective to self-injury behavior? a possible explanation is that, due to negative emotions, individuals choose self-injury behavior as a coping method, which is influenced by the parent-child relationship. a poor attachment relationship may strengthen the connection between negative emotions and self-injury behavior; good attachment weakens it. adolescents, lacking in emotional regulation and control, can possibly resort to self-punishment when facing environment changes and negative emotions. this kind of emotional coping style gives junior high school students the tendency to adopt self-injury behavior instead of other approaches when faced with poor family relationships (glassman et al., 2007) . therefore, in order to examine how and when father-child and mother-child attachment were linked to adolescents' self-injury behavior, negative emotion and emotional coping style are listed as possible mediating factors. negative emotion is a general term for subjective stress and unpleasant experiences (watson et al., 1988) , which reflects individual differences in emotional stability (watson, 2000) . previous studies have found that high-quality parent-child attachments can reduce the influence of negative emotions on individuals, and vice versa (yinqgian et al., 2015) . yan et al. (2018) have also discovered that good parent-child relationships can meet individual's emotional needs, while low-quality relationships may contribute to negative emotions as the result of parent-child alienation (yan et al., 2018) . furthermore, some studies have suggested that mother-child attachment can be directly employed to predict negative emotions, while some other studies have showed that the father-child attachment has no such obvious effect, which means the impact of the former outweighs that of the latter (yinqgian et al., 2015) . thus, all these studies have demonstrated that unhealthy father-child and mother-child attachment can directly trigger junior high school students' negative emotions, and that the influencing mechanisms are actually different. on the other hand, negative emotions may bring about self-injury behavior. a study has found that individuals with high negative emotions can probably relieve their emotional burdens through self-injury behavior, and may weaken the psycho-social function of junior high school students, leading to a series of problems inducing depression and anxiety (yulong et al., 2019) . the experiential avoidance model and emotional management model on selfinjury behavior also proposes that individuals will eliminate their unhealthy emotions through self-injury behavior when lacking an effective emotional management ability or to avoid unpleasant emotions (paivio and mcculloch, 2004; chapman et al., 2006) ; i.e., individuals manage their negative emotions by means of self-injury behavior (quanquan et al., 2017) . further, more studies have also confirmed that there is a significant positive correlation between negative emotion and self-injury behavior (yulong et al., 2019) . generally speaking, negative emotion, as a mediate variable, has a wide range of impacts on individual's cognition, motivation, and social behavior. therefore, based on the model above, it is assumed that negative emotion is to some extent related to the self-injury behavior of junior high school students. thus, we expected negative emotion may play a mediating role between father-child and mother-child attachment and selfinjury behavior. coping style refers to the strategies adopted by individuals to relieve stress under pressure (runxin and jianmei, 2016) , i.e., problem and emotional coping styles (folkman and lazarus, 1980) . some researchers have pointed out that people are more likely to adopt emotional coping methods such as enduring, escaping, venting, fantasy, and denial, when people believe there is no way out (folkman and lazarus, 1980) . probing into literature, guerreiro et al. have found that self-injury behavior is linked to emotional-directed coping strategies (guerreiro et al., 2013) . people with self-injury behaviors tend to take emotional responses, and individuals constantly resorting to emotional responses are more likely to injure themselves when dealing with adverse emotions (cramer et al., 2017) .with an observation of 965 adolescents, castro and kirchner (2017) have made it clear that adolescents with multiple self-injury behaviors would employ more coping strategies like venting, which has therefore proven a risk factor for self-injury. the evidence above shows that emotional coping style is closely associated with self-injury behavior. in a family, an adverse parent-child relationship is the direct cause of emotional coping styles (qiangqin, 2010) . as junior high school students lack social experience, when they suffer an adverse parent-child relationship, they most probably have a sense of inability, not knowing how to change their situation and being apt to resort to emotional coping methods. attachment theory has also proposed that the secure attachment formed earlier between children and their caregivers can affect the coping styles of junior middle school students (davila and levy, 2006) . meanwhile, qiangqin, 2010 has also found that father-child attachment and motherchild attachment could both significantly negatively predict emotional coping style (qiangqin, 2010) . considering this, we expected emotional coping style may play a mediating role between father-child and mother-child attachment and selfinjury behavior. moreover, there is also a close positive correlation between negative emotion and emotional coping style. domestic researchers have discovered that emotional problems are positively related to their coping styles; foreign studies suggest that negative emotion can lead to individuals reacting with such coping styles as avoiding, denying, and enduring, where emotional coping style is considered as a "response to emotion" (folkman and lazarus, 1980) . to sum up, it is believed that negative emotion may affect emotional coping style; therefore, it is essential to examine the serial mediating roles of these two factors in the correlations between father or mother-child attachment and self-injury behavior. the present study's main objective is to analyze the different roles of father-child and mother-child attachment in the development of self-injury behavior of adolescents. thus, we aim to observe the associations between parentchild attachment, negative emotion, emotional coping style, and self-injury behavior. lastly, we will analyze the pathways through which father-child and mother-child attachment is linked to self-injury behavior. therefore, this research has been guided by four objectives. first, we expected parentchild attachment to be associated with self-injury behavior, and there to be a difference between the effects of fatherchild attachment and mother-child attachment on self-injury behavior. second, we anticipated that negative emotion may play a mediating role between father-child and mother-child attachment and self-injury behavior. third, we expected emotional coping style may play a mediating role between fatherchild and mother-child attachment and self-injury behavior. finally, we expected there to be a serial mediating role played by negative emotion and emotional coping style in the correlations between father or mother-child attachment and self-injury behavior. participants for this study were recruited from the junior high schools in china's yunnan province. six hundred and seventy students were approached to take part in this study. the final sample consisted of 309 (46.7%) boys and 353 (53.3%) girls. in reference to the participants' schooling, 198 were in the first year of junior high school, 204 in the second year, and 260 in the third. the age range was between 13 and 18 (m = 15.04, sd = 1.92). the data were collected by means of cluster random sampling in the four junior high schools. ethical approval for this project was given by the executive council of yunnan normal university. the adolescents signed their informed consent. data collection occurred in a classroom context, in the presence of the supervising researcher who, in a succinct manner, administered the standard instructions, including the general objectives of the study as well as guaranteeing free will, privacy, anonymity, and confidentiality of all the information provided. parent-child attachment questionnaire (inventory of parent and peer attachment, ippa) the parent-child attachment questionnaire, compiled by armsden and greenberg (1987) , was translated by wendao et al. (2008) for use in china. this questionnaire in its revised form is composed of 75 questions that are distributed in three subquestionnaires, from which we adopt two sub-questionnaires in this study: the father-child attachment questionnaire-"i think my father is a competent father"; the mother-child attachment questionnaire-"my mother respects my feelings". each fatherchild and mother-child attachment questionnaire included 25 items, which were divided into three dimensions: trust, communication, and alienation. for each item, there are five answer options given for the father and the mother separately, in which the responses are presented on a likert style scale that varies between 1 (totally disagree) and 5 (totally agree). in this study, the cronbach's alpha coefficients of each dimension on the father scale were 0.89, 0.87, and 0.74, respectively, and those on the mother scale were 0.88, 0.87, and 0.72 separately. the negative emotion questionnaire translated into chinese by wenfeng and jianxin (2004) from the original version by bradburne and tyrrell (1969) was used with the objective of evaluating the negative emotional experience from the last 6 months. we used the sub-questionnaire of the negative affect scale. it includes six items-"i feel like i'm upset for some reason." for each item, there are four answer options, presented on a likert style scale, which varies between 1 (never) and 4 (always). the higher the score, the more intense the negative emotion. the psychometric studies performed in the present sample revealed a cronbach's alpha coefficient of 0.79. the coping style scale by shulin et al. (2000) was used to evaluate adolescents' emotional response to problems or troubles. this questionnaire in its revised form consists of 36 questions that are distributed in two sub-questionnaires. we used the subquestionnaire of the emotional coping style scale (17 items), which presents itself in four dimensions: endurance (4 item)-"i buried the unpleasant things in my heart, " escape (4 item)-"refuse to believe that bad things have happened, " venting emotion (4item)-"you will be very upset and vent to your family and friends when you can't solve the problem, " and fantasy denial (5item)-"love to do something unrealistic to eliminate trouble." for each item, there are four answer options, presented on a likert style scale, which vary between 1 (not adopt) and 4 (always adopt). the psychometric studies performed in the present sample revealed a cronbach's alpha coefficient of 0.81. the adolescent self-injury behavior scale, translated into chinese by fang et al. (2015) from the original version of the ottawa self-injury scale, was used with the objective of evaluating the adolescents' self-injury behavior from the past year. it includes 10 items-"deliberately burying your head in the water." the frequency of self-injury behavior in each way was set to 0 times, 1 time, 2-4 times, or 5 times or more, and the total score of the items was calculated as a continuous variable. the psychometric studies performed in the present sample revealed a cronbach's alpha coefficient of 0.95. the present study is of a cross-sectional nature given that the set of measurements were all carried out at the same moment in time. data treatment was carried out using the statistical program spss-statistical package for social sciences, version 22.0 for windows, and the mediate model was tested with amos 21.0. in order to test the mediating effect, the percentile bootstrap method for deviation correction was used, which is recommended by jie and minqiang (2012) . in order to control the common method deviation, we told all participants that the questionnaires were filled out anonymously, and all the data were strictly confidential and only used for scientific research. the harman single factor method was adopted to test common method deviation, and thus the exploratory factor analysis for all variables referred to in the research was carried out. the results show that the eigenvalues of 12 factors are greater than 1, and the variation explained by the first factor is 15.76%, less than 40%, which means that there is no common method deviation in this study (hao and lirong, 2004) . a total of 662 participants were recruited for the study, with the response rate being 98.8%. among the respondents, 64.3% of males and 65.1% of females never committed self-injury behavior; 58.5 and 70.9% of those who never self-injured were from rural and urban areas respectively; 79.4, 71.4, and 78.6% of the never-selfinjured students were in their first, second, and third year, respectively ( table 1) . the results of the inter-scale correlations and the respective averages and standard deviations, reported in table 2 , allow us to state that there are correlations between the variables being studied. the correlation analysis showed that there was positive correlation between mother-child and father-child attachment, but negative correlation with negative emotion, emotional coping style, and self-injury behavior. meanwhile, negative emotion, emotional coping style, and self-injury behavior were positively correlated with each other. the mediating effects of the quality of negative emotion and the emotional coping style variable were calculated using the structural equations model, through the realization of the steps of the percentile bootstrap method. the analysis of the mediating roles of the negative emotion and emotional coping style were carried out, taking into account all of the following dimensions: the negative emotion, the emotional coping style (endurance, escape, venting emotion, fantasy, and denial) as serial mediators of both the parent-child attachment (trust, communication, and alienation), and self-injury behavior. in regard to the model test that verified the parent-child attachment and self-injury behavior, the model test verified that initially. the results are listed as below. the father-child attachment model fits well (χ 2 /df = 4.21, rmsea = 0.06, nfi = 0.98, ifi = 0.97, cfi = 0.99, srmr = 0.04), and the attachment can significantly negatively affect self-injury behavior (β = −0.40, p < 0.001). the mother-child attachment model is also well fitted (χ 2 /df = 4.09, rmsea = 0.07, nfi = 0.99, ifi = 0.98, cfi = 0.97, srmr = 0.04), and this attachment can significantly negatively affect self-injury behavior (β = −0.30, p < 0.001). in summary, the father-child attachment and mother-child attachment can both significantly negatively affect self-injury behavior. the fitting degrees of the structural model and the data of fatherchild attachment were tested, and the results show that the fitting indexes of the model are sound: χ 2 /df = 2.07, rmsea = 0.04, nfi = 0.95, ifi = 0.97, cfi = 0.96, srmr = 0.03, as displayed in figure 1 . the normalized load of all the observed variables on corresponding latent variables is between 0.51 and 0.73, and the composite reliability values are all larger than the standard value of 0.6, indicating that the measurement model has reached the ideal standard, and the observed variables can well reflect the corresponding latent variables. thus, the structural model can be further tested. with negative emotion and emotion coping style taken into consideration, the significant paths are as follows: father-child attachment has a direct negative effect on negative emotion (β = −0.37, p < 0.001) and selfinjury behavior (β = −0.20, p < 0.001); negative emotion positively affects emotional coping style (β = 0.45, p < 0.001) and self-injury behavior (β = 0.21, p < 0.001); and emotional coping style positively affects self-injury behavior (β = 0.28, p < 0.01). furthermore, the percentile bootstrap method of deviation correction was employed to test mediating effects (jie and minqiang, 2012) . 5000 bootstrap samples were extracted from the original data (n ≤ 662) by repeated random sampling, and the bootstrap 95% confidence interval of the mediating effect was calculated. the results, as are demonstrated in table 3 , show that the bootstrap 95% confidence interval of the mediating paths above do not include 0, which means that father-child attachment can affect self-injury behavior through the mediating role of negative emotion and emotional coping style, and that negative emotion and emotional coping style play a serial mediating role between father-child attachment and self-injury behavior. the fitting degrees of the structural model and data of motherchild attachment were tested, and the results indicate that the fitting indexes are sound: χ 2 /df = 3.08, rmsea = 0.06, nfi = 0.91, ifi = 0.94, cfi = 0.95, srmr = 0.04, as represented in figure 2 . the observed variables can well reflect the corresponding latent variables (the calculation method is the same as above); therefore, the structural model can be further tested. with negative emotion and emotion coping style *p < 0.05, **p < 0.01, ***p < 0.001, the same as below. figure 1 | father-child attachment mediate model. father-child attachment→negative emotion→self-injury behavior −0.19*** −0.13 −0.06 father-child attachment→emotional coping style→self-injury behavior −0.08** −0.11 −0.10 father-child attachment→negative emotion→emotional coping style→self-injury behavior −0.09*** −0.08 −0.04 the lower limit and upper limit of boot ci respectively refer to the lower and upper limits of the 95% confidence interval of the indirect effect estimated with percentile bootstrap method to correct deviation; all values retain two decimal places, the same as below. *p < 0.05, **p < 0.01, ***p < 0.001. taken into account, the significant paths are as follows: motherchild attachment can directly negatively affect negative emotion (β = −0.38, p < 0.001) and self-injury behavior (β = −0.15, p < 0.001); negative emotion can positively affect emotional coping style (β = 0.51, p < 0.001) and self-injury behavior (β = 0.12, p < 0.001); and emotional coping style can positively affect self-injury behavior (β = 0.22, p < 0.01). in addition, the percentile bootstrap method of deviation correction is adopted to test mediating effects. the results, as are listed in table 4 , demonstrate that the 95% confidence interval of the mediating paths above do not include 0, indicating that the mediating effect is significant. in other words, motherchild attachment could affect self-injury behavior through the mediating effect of negative emotion, with negative emotion and mother-child attachment→negative emotion→self-injury behavior −0.10*** −0.13 −0.06 mother-child attachment→negative emotion→emotional coping style→self-injury behavior −0.09*** −0.21 −0.05 *p < 0.05, **p < 0.01, ***p < 0.001. emotional coping style playing serial mediating role between mother-child attachment and self-injury behavior. the direct effect of parent-child attachment on self-injury behavior this study finds that father-child and mother-child attachment of junior high school students can both directly negatively influence self-injury behavior, which conforms to the basic view of interpersonal or systematic models (crouch and wright, 2004) . this also supports the conclusion of previous studies; i.e., adverse parent-child attachment will lead to the students' selfinjury behavior (martin et al., 2016; gromatsky et al., 2017) . family relationships are critical to adolescents, and they tend to adopt self-injury instead of other means to ease the tension and stress once the relationships fall ill. some studies have discovered that a high-quality parent-child relationship is a protective factor. when there is a poor quality parent-child relationship, children are more likely to resort to self-injury (glenn and klonsky, 2010) , which means that a healthy parent-child relationship is an essential factor to prevent junior high school students from self-injury behavior. in addition, the higher the score of parentchild attachment, the lower the score of individual self-injury behavior, i.e., the better the quality of attachment, the more trust and cooperation between parents and children, and the lower the possibility of individual self-injury behavior. this research finds that negative emotion can mediate between father-child and mother-child attachment and self-injury behavior, i.e., parent-child attachment can not only directly, but also indirectly, effect self-injury behavior through negative emotion. it also testifies the main principles of theexperience avoidance model and emotion management model (paivio and mcculloch, 2004; chapman et al., 2006) . it demonstrates that parent-child relationships can induce negative emotion, which will further trigger the occurrence of self-injury, both being consistent with the previous studies (klonsky et al., 2003; feng, 2008) . when the individuals lack the ability to manage their negative emotion effectively, they try to relieve the emotion through self-injury. thus, it is certain that negative emotion increases the risk of self-injury behavior. additionally, father-child attachment can be negatively associated with emotional coping style, and the latter further effects self-injury behavior, which is in line with the results of previous studies (qiangqin, 2010; castro and kirchner, 2017) . owing to the lack of experience to cope with social problems, junior high school students do not know how to deal with challenging problems and tend to adopt emotional coping styles after suffering from father-child conflict. however, the emotional coping style puts more emphasis on emotion itself, which is not conducive to solving the problems, but reinforces the negative emotion and even leads to self-injury. studies have shown that the students being accustomed to the emotional coping style are slow at communication, with a significantly higher level of anxiety and depression compared with the general population, and previous studies have also proven that the continuous negative emotional coping style can result in self-injury (konick and gutierrez, 2005) . it shows that a poor quality father-child relationship will increase the chance of emotional coping style by junior high school students, thus increasing their self-injury behavior. in terms of mother-child attachment, however, a poor relationship cannot directly affect emotional coping style, which is inconsistent with former studies (qiangqin, 2010) . this is because mothers, as the main supporter of the children's lives, have established a close relationship with their children from an early age. such a bond tends to be more emotionally connected. therefore, the unhealthy mother-child attachment does not easily lead to an emotional response. at the same time, negative emotion and emotional coping style play serial mediating roles between father-child and mother-child attachment and self-injury behavior. it is believed that junior high school students can have negative emotions due to poor quality parent-child attachment (yulong et al., 2016) , under the influence of which individuals resort to a series of solutions to adapt to their negative emotions. with a sense of inability in emotional processing, they naturally surrender to the emotional coping style, which further contributes to self-injury behavior (folkman and lazarus, 1980; castro and kirchner, 2017) . as children grow up, fathers will use games and set challenges to encourage children to face dangers, overcome difficulties, and promote children's social adaptability (paquette, 2004) , which may serve as an effective indicator of adolescents' psychological elasticity (xiaoyan et al., 2011) ; mothers, however, tend to be more emotionally connected with their children. recent research has also suggested that father-child attachment and mother-child attachment have different roles in the parent-child relationship. father-child attachment has a more significant role in promoting children to cope with challenges and emotions, while mother-child attachment is mainly reflected in emotional experience. therefore, the intermediate model in this study is in line with the attachment specific hypothesis. the mother-child attachment model tends to affect emotional experience, while the father-child attachment model would affect behavioral coping style. this shows that a child's emotional connection with his mother is the basis and starting point for exploring the outside world and will affect his whole life. this is because in the early attachment relationship, infants and children internalize the interaction experience with their attachment objects into their internal working mode. when they contact others later, the internal working model will guide his behavior performance, which also supports the attachment theory. fathers are often a role model who encourages their children to face and solve problems, which is line with previous explanations (gottman, 1998) . the reason for this difference may come from traditional family rearing pattern of "strict father and gentle mother," and adolescents generally hold the stereotype that mothers are more sensitive, gentle, and modest, while fathers are decisive, independent, and vigorous, so the latter is usually imitated by children (chuanhua et al., 2003) . this study proves that father-child attachment is highly predictive of individuals' stress response, which means that father-child attachment, via words and deeds, may change the way junior high school students cope with their emotions. maybe fathers with bad behaviors such as alcoholism, smoking, etc., are more likely to pass their emotional coping styles to their children; however, mother-child attachment does not have this effect, i.e., mothers emotional coping style has less of an effect on children. in other words, mother-child attachment more depends on emotional communication and expression, so an unhealthy mother-child relationship brings more negative emotional feelings. in a word, the quality of mother-child attachment and fatherchild attachment embodies the trust and cooperation between parents and children, but they have different connotations (yan, 2016) . for example, parent-child attachment mainly promotes the emotional communication between parents and children through caring and nurturing behaviors, while parent-child attachment mainly reflects the quality of parent-child attachment by setting an example and giving confidence. the connotation of this attachment is also reflected in the process of emotional adaptation and emotional management. mothers show more emotional warmth and understanding, but fathers demonstrate more problem-solving, so mother-child attachment establishes relationship quality through positive emotions, while fatherchild attachment reflects relationship quality through problemsolving and positive response. parent-child attachment plays an important positive role in the healthy development of individuals; however, unhealthy attachment can destroy the ability for emotional adaptation and regulation. it not only directly affects the self-injury behavior of individuals, but also influences the self-injury behavior through negative emotions and negative emotional coping styles. this study provides a new angle for the intervention and education of self-injury behavior, i.e., from the perspective of attachment theory, paying attention to the impacts of fatherchild attachment and mother-child attachment work models on individual self-injury behavior. attachment mode not only has gender differences, but also differences between safe attachment and non-safe attachment. future research should further explore the relationship between non-safe attachment individuals and the relationship among negative emotion, emotional coping style, and self-injury behavior. in addition, there are some shortcomings in the study as well. first, as a cross-sectional study, the relationship between different attachment types and junior high school students' self-injury behavior could not be examined in more detail. future research may use tracking design to deepen this issue. second, this study has only examined the impact of parent-child and mother-child attachment on self-injury behavior, without referring to peer attachment. in fact, junior high school students' attachment targets are not limited to parents; peer attachment is also of huge importance. studies have suggested that the role of peer attachment has even surpassed that of parent-child attachment in their development (bogaerts et al., 2006) , but there are other different perspectives, so future research may further explore the impact of peer attachment on junior high school students' self-injury behavior. third, the measurement of each variable is entirely based on the self-report of junior high school students; the method of measuring self-injury behavior specifically is relatively single, and there may be social approval effects. thus, future research may consider combining multiple methods to obtain more comprehensive data. fourth, the measured groups are all students, and the sample size is relatively small. in later research, more group samples could be considered for investigation. first, mother-child and father-child attachment directly negatively influences self-injury behavior of junior high school students. second, father-child attachment affects self-injury behavior through separate mediation of negative emotion, through separate mediating effects of emotional coping style, and r through serial mediating effects of negative emotion and emotional coping style. third, mother-child attachment affects self-injury behavior through separate mediation of negative emotion, and through serial mediating effects of negative emotion and emotional coping style. the datasets generated for this study are available on request to the corresponding author. ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. written informed consent was obtained from the individual(s), and minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article. yt conceived the study, participated in its design, carried out the study, performed the statistical analysis, and drafted the manuscript. md and x-yb supervised the study, participated in the design of the study, helped to draft the manuscript, and revised the manuscript critically. all authors read and approved the final manuscript. this study was supported by the natural science foundation's "cognitive control of ethnic bilinguals" fund of yunnan normal university (31660282) and project from yunnan province ministry of education fund (2020j0680). adolescents with learning disabilities: socioemotional and behavioral functioning and attachment relationships with fathers, mothers, and teachers the inventory of parent and peer attachment: individual differences and their relationship to psychological wellbeing in adolescence non-suicidal self-injury in adolescence: longitudinal associations with psychological distress and rumination recalled parental bonding and personality disorders in a sample of exhibitionists: a comparative study the propagation of "coronaviruses" in tissue-culture mother and adolescent reports of associations between child behavior problems and mother-child relationship qualities: 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of parent-child attachment on children's development the relationship between parent-child attachment and negative emotion of college students: the multiple intermediary effects of interpersonal adaptation and mobile phone dependence video time, mental sub-health and self-injury behavior of middle school students the relationship between parent-child attachment, peer attachment and adolescents' negative emotion: a mediating model with regulation the effect of invalid family environment on self-injury behavior of different family types of adolescents the self-punishment function of teenagers' self-harm behavior: does it stem from guilt or shame? the relationship between parental conflict and adolescent self-injury: a regulated intermediary model attachment hypothesis of rem sleep toward an integration of psychoanalysis, neuroscience, and evolutionary psychology and the implications for psychopathology research key: cord-010411-zgdvo29n authors: biglan, anthony; elfner, karen; garbacz, s. andrew; komro, kelli; prinz, ronald j.; weist, mark d.; wilson, dawn k.; zarling, amie title: a strategic plan for strengthening america’s families: a brief from the coalition of behavioral science organizations date: 2020-04-28 journal: clin child fam psychol rev doi: 10.1007/s10567-020-00318-0 sha: doc_id: 10411 cord_uid: zgdvo29n despite significant progress in research on the treatment and prevention of psychological, behavioral, and health problems, the translation of this knowledge into population-wide benefit remains limited. this paper reviews the state of america’s children and families, highlighting the influence of stressful contextual and social conditions on child and family well-being and the concentration of disadvantage in numerous neighborhoods and communities throughout the nation. it then briefly reviews the progress that has been made in pinpointing policies that can reduce stressful contextual conditions such as poverty, discrimination, and the marketing of unhealthful foods and substances. it also describes numerous family and school interventions that have proven benefit in preventing psychological and behavioral problems as diverse as tobacco, alcohol, and other drug use; depression; antisocial behavior; academic failure; obesity prevention; and early childbearing. we argue that progress in translating existing knowledge into widespread benefit will require a nationwide effort to intervene comprehensively in neighborhoods and communities of concentrated disadvantage. we present a strategic plan for how such an effort could be organized. the first step in this organizing would be the creation of a broad and diverse coalition of organizations concerned with advancing public health and well-being. such a coalition could increase public support both for the policies needed to focus on these disadvantaged areas and the research needed to incrementally improve our ability to help these areas. this paper presents a strategic plan for reducing the prevalence of concentrated disadvantage in the usa. concentrated disadvantage consists of a tangle (sampson 2009 ) of inter-related environmental and behavioral problems such as poverty, discrimination, unemployment, substance use, single parenting, and academic failure that result in intergenerational poverty and the development of multiple psychological, behavioral, and health problems often resulting in premature death (national academy of sciences 2019b). over the past fifty years, the prevalence of such disadvantage has increased dramatically in the usa (kristof and wudunn 2020; putnam 2016) . reversing this trend and thereby reducing the prevalence of these problems will require an unprecedented organization of our national resources over an indefinite period of time. we hope that this paper will contribute to such a nationwide effort. the paper begins with a brief summary of what we know about the contextual conditions that undermine family wellbeing and the resulting patterns of family life that contribute to life-long intergenerational psychological, behavioral, and health problems. it then summarizes the extensive evidence regarding programs and policies that have proven benefit in preventing or ameliorating one or more aspects of disadvantage, as well as the research that is needed to translate existing knowledge into widespread success in reducing concentrated disadvantage and its sequelae. we then present a strategy for building a nationwide effort to strengthen family well-being with special attention to neighborhoods and communities of concentrated disadvantage. the well-being of america's families can be gauged by the quality of the contextual conditions that affect families and by the quality of family life itself. even a brief summary of the evidence indicates that many families live in stressful social contexts and have high levels of family dysfunction. among the harmful contextual conditions that have been verified by previous large-scale studies are family poverty, homelessness, contacts with the criminal justice system, discrimination, and the marketing of health-compromising behaviors in youth (e.g., unhealthful food and substances). according to the u.s. census bureau (fontenot et al. 2018) , 7,793,000 american families were living in poverty in 2017. according to the organization for economic co-operation and development (oecd family database 2018), as of 2015, the usa had the third-highest rate of poverty among 35 developed countries (16.8%). the federally defined poverty level for a family of four is $25,100 (families usa 2018). as of 2018, 17% of children lived in homes with income below the poverty level, and 38.8% were in homes below 200% of the poverty level (child trends databank 2019). a major reason for these rates of poverty is the high rate of single parenting. more than 58% of poor children live in single-mother families, and 8.3% live in single-father families. a meta-analysis by stringhini et al. (2017) of 48 studies involving 1.7 million people showed that socioeconomic status was associated with higher rates of mortality even when the researchers controlled for 25 well-established risk factors for disease. children raised in poverty had significantly greater risk of most psychological, behavioral, and health problems (jarjoura et al. 2002; matthews and gallo 2011; pampel et al. 2010 ) and shorter life expectancy (galobardes et al. 2004 (galobardes et al. , 2008 miller et al. 2011) . distinct from the effects of poverty, economic inequality is a risk factor for multiple psychological, behavioral, and health problems. pickett and wilkinson, as well as other investigators (pickett and pearl 2001; pickett and wilkinson 2010; kaplan 2019) , have shown that premature death, obesity, infant mortality, depression, social anxiety, property crimes, and homicide are greater in economically unequal countries. many of these disparities in health are found among all but the very highest-earning segments of a population. the deleterious effects of inequality appear to be due to the fact that people living in economically unequal communities are more likely to have stressful interactions with people who are above or below them in the economic hierarchy (pickett and wilkinson 2015; wilkinson and pickett 2009) . according to a national system for estimating homelessness, there were about 58,000 homeless families with children on any given night in 2017 (national alliance to end homelessness 2020). homeless children have more developmental delays, poorer academic development, and more physical illnesses and conditions, such as stunted growth, anemia, asthma, lead poisoning, and infectious diseases (hart-shegos 1999) . the criminal justice system can have a devastating impact on families. the usa has the highest rate of incarceration in the world (wagner and walsh 2016) , and there is a much higher rate of incarceration of black people, a result of disparities at every point in the criminal justice process, from arrest through sentencing (alexander 2012) . a survey of american adults indicated that 63% of black people indicated that a member of their family had been incarcerated; the rate was 42% for whites and 48% for hispanics (enns et al. 2019) . families with a parent in prison are likely to experience poverty, homelessness, and residential instability (peterson et al. 2019) . parental imprisonment often contributes to children's behavior problems, depression, poor academic performance, and antisocial behavior (parke and clarke-stewart 2001; peterson et al. 2019) . children may also experience trauma through involvement with the criminal justice system at other points (e.g., if they witness the arrest of a parent or before or during visits with a parent in prison or jail; eddy and poehlmann 2019). discrimination is widespread in the usa (national public radio, robert wood johnson foundation, & harvard t.h. chan school of public health 2018) . in addition to welldocumented effects on the health of individuals (pascoe and smart richman 2009) , discrimination affects family wellbeing due to discriminatory hiring and pay and residential segregation. however, the most damaging aspect of discrimination may simply be the frequent exposure to experiences that are threatening or aversive and that contribute to inflammatory disease (american psychological association 2016). the marketing of tobacco, alcohol, and unhealthful food and beverages harms families. although the makers of these products often argue that their marketing is not to blame for underage use of tobacco and alcohol or childhood obesity, empirical research shows that marketers target children, their messages reach children, and these messages influence youths' purchases and consumption (biglan 2004a; nestle 2002; pechmann et al. 2012) . moreover, the ready availability of illicit drugs in neighborhoods of concentrated disadvantage contributes to drug use disorders among both parents and children (ford et al. 2017; storr et al. 2004 ). each of the just-described conditions contributes to the development of psychological, behavioral, and health problems that undermine children's life chances and contribute to premature death. however, the risk of such outcomes is increased when multiple disadvantaging conditions are present. evidence for this comes from studies showing that the greater number of adverse experiences that children have, the more likely that their behavioral and physical health will be affected (anda et al. 2009 (anda et al. , 1999 felitti et al. 1998) . this underscores the necessity of targeting neighborhoods and communities of concentrated disadvantage if the nation is going to significantly reduce the number of children who are destined for multiple problems, impeded potential and premature death. a recent monograph by acevedo-garcia et al. documents the extent to which american communities have neighborhoods with extensive disadvantage (acevedo-garcia et al. 2020 ). the just-described contextual conditions contribute to the undermining of effective parenting. stressors such as poverty, economic inequality, and discrimination undermine parents' time, ability, and motivation to provide warm, responsive support of their children's development. poverty, discrimination, unemployment, and homelessness also make depression more likely. maternal depression is a risk factor for socio-emotional and cognitive delays in children (bernard-bonnin, society, health, & committee 2004) . there is also evidence that neighborhoods that are low in socioeconomic status have higher rates of some types of substance use (karriker-jaffe 2013). and, according to the substance abuse and mental health services administration (samhsa), about 12.5% of children (8.7 million) live in homes where at least one parent has a substance use disorder (lipari and van horn 2017) . parental substance use is associated with a higher likelihood of child abuse (institute of medicine & national research council 2014) and later substance use by the child (anda et al. 2002) . finally, as the proportion of marriageable men declines due to unemployment and poverty, family stability is undermined, and the rate of single parenting increases. sawhill (2013) reported that, across ethnic groups, the rate of single parenting has increased in recent years among those without a college education. schools in high poverty neighborhoods and rural communities, generally have fewer resources than schools in more affluent areas, even though it is in high poverty areas that more resources are needed (duncombe 2017) . high poverty schools need more special education, more incentives for skilled teachers, and more effective supports for social and emotional learning. the absence of these resources is one of the reasons that students perform less well in high poverty communities (garcía and weiss 2017) . evidence across a wide variety of sub-areas of behavioral science converge in a consilience about how stressful social conditions result in a "fast life" strategy where threatening environments make such a strategy more likely to result in successful reproduction (wilson 2019) , but frequently culminate in premature death. figure 1 depicts the impact of a stressful social context on parents and schools and the subsequent impact of all of these conditions on child and adolescent development. the conditions increase the likelihood that parents will have multiple problems and that, as a result, families will have frequent coercive interactions (dishion and snyder 2016) . it is well established that coercive interactions in families contribute to children's failure to develop self-regulation and to the development of aggressive and uncooperative behavior that puts them on a trajectory to fail in school and be rejected by peers dishion and snyder 2016; patterson et al. 1989 ). this rejection, in turn, leads to their joining with similarly rejected peers to form deviant peer groups. these groups become a training ground for the constellation of psychological and behavioral problems that include delinquency, substance use, risky sexual behavior, depression, and school dropout (debaryshe et al. 1993; patterson et al. 1992 patterson et al. , 1989 . this analysis is supported by research from a diversity of sub-disciplines (biglan et al. in press) . these include a wealth of evidence showing that multiple, interconnected problem behaviors result from a common set of adverse environmental conditions (biglan et al. 2004) . it is also supported by evolutionary analyses of the expression of fast life strategies that appear to have survival value in a dangerous environment (ellis and bjorklund 2012; wilson 2019) . it is shown by the evidence of epigenetic changes that make these strategies more likely (bergen et al. 2012 ). the analysis is also consistent with social psychological research contrasting the development of materialistic vs. prosocial values and the impact of threat on materialism and the association of materialism with diminished wellbeing (kasser 2016) . finally, there is clinical psychological research showing the benefits to human well-being of psychological flexibility, which is a pragmatic way of living that involves living intentionally according to one's values, a life strategy that benefits the individual and those around that individual (hayes 2019) . in addition to family influences, the quality of schools affects this developmental trajectory. as noted above, schools in high poverty neighborhoods and communities have higher rates of punitive practices and fewer resources for preventing the development of problem behavior (american psychological association, n.d.). there is one other point to be made about this developmental trajectory because it is so important for redirecting the expenditure of resources in our healthcare system. the u.s. per capita cost of healthcare is at least twice that of most other developed nations even though we lag behind these nations in health and longevity (biglan 2019) . a major yet frequently overlooked reason for these disparities is that ill health and premature death are made more likely by stressful social interactions in childhood (miller et al. 2011) . redirecting some of our healthcare expenditures to the prevention of stressful social relations in childhood is likely to make a bigger contribution to american's health than any advance in the treatment of chronic disease (biglan 2020a) . when coupled with evidence from prevention research, these findings suggest a unifying framework about the kind of environments that are needed to nurture successful development (biglan 2015a; biglan et al. 2012) . figure 2 depicts the way in which nurturing conditions contribute to the development of prosocial behavior. by prosocial behavior, we refer to constellation of behaviors that contribute to not only the individual well-being, but the well-being of those around the person. these include caring, compassion, and an orientation toward helping others (kasser 2011) . they also include the development of a wide range of academic and social skills, as well as skill in art, music, and science. the evidence indicates that the development of prosocial behavior is promoted by environments that (a) minimize socially toxic coercive interactions, (b) richly reinforce all types of prosocial behavior, (c) limit both opportunities for problem behavior (such as unsupervised involvement with highrisk peers) and influences toward problem behavior such as the marketing of tobacco and alcohol, and (d) promote psychological flexibility, which is a values focused, mindful, and pragmatic way of living. thus, in the next section, we summarize the research suggesting that this problematic fast life trajectory can be prevented through the promotion of these nurturing conditions. the figure also indicates that we need to be concerned not only with the proximal family and school influences on development but on the neighborhood and community conditions that affect families and schools and often directly affect the child. as just suggested, focusing only on the proximal family and school influences on development is insufficient. we need to be concerned with multiple systems that can improve family well-being. in this section, we review evidence on interventions designed to affect the contextual conditions that we described above. in addressing family poverty, we rely on a recent nam report, a roadmap for reducing child poverty (nasem 2019a), which thoroughly reviewed the evidence on the impact of poverty on children and the policies that have been shown to reduce it. the report identified ten policies or programs shown to reduce family poverty. contextual factors that have been instrumental in understanding family wellbeing involve many systems. we focus on policies below that could have a fundamental impact on these contextual factors. four policies both increase income and promote employment. the report deemed promotion of employment to be as valuable as increasing income because employment raises the probability that a family will continue to prosper over time. this view is consistent with our priorities in using a multi-level and systemic approach to improving family well-being. this policy supplements low paid workers' income by providing a tax credit on income they have earned. for example, people receive a refund of money previously withheld from their taxes. the credit is refundable in the sense that a worker may receive more money for their work than they would have had to pay in taxes. research on the eitc shows it reduces poverty, increases workforce participation (nichols and rothstein 2016), and increases the long-term health of family members. markowitz et al. (2017) found an association of higher tax credits with higher birth weights and longer gestation periods. unfortunately, 22 states do not offer a state eitc and an additional six states have a nonrefundable eitc (tax policy center, nd.). a nonrefundable eitc can only offset state income taxes, so the benefit is limited for low-income families with little taxable income. also, many families who are eligible for federal and state eitcs do not apply for them, thus indicating a need to increase education and access to these opportunities. these subsidies impact family income, and at the same time, they increase workforce participation because they enable family members to work who might otherwise be providing childcare. the nam report estimated that the average annual cost for childcare for a young child (age 2 through 5) is $8,600. the current federal minimum wage is $7.25 an hour, although 30 states and the district of columbia have higher minimum wages. the nam report concluded that raising the wage could reduce the availability of jobs in some places if employers reduce their workforce in response, but also cited evidence that a higher minimum wage helps lift families out of poverty. an analysis by the robert wood johnson foundation (2018) concluded that minimum wage increases are associated with improved health. specifically, adult women who became pregnant and experienced an increase in the minimum wage had a reduced likelihood of smoking and fewer low birth weight babies. increases in state-level minimum wages are associated with decreased infant mortality, suicide rates, and heart disease death rates (kaufman et al. 2020; komro et al. 2016; van dyke, komro, shah et al. 2018) . at least two workforce development programs have been shown to increase employment and earnings for poor unemployed or underemployed workers. workadvance (schaberg 2017) was reviewed in the nam report. this program works with potential employers to identify the skills they need and then trains workers on those skills. four workforce development organizations ran randomized trials evaluating the program, and though not all replicated effects, the program was shown to increase employment, earnings, and job satisfaction. in addition, the arnold foundation, which funds and monitors results of randomized controlled trials evaluating government-funded interventions, reported that a randomized trial of quest, a job training program for low-income individuals, showed that it increased recipients' annual income 20% more than the control group over a nine-year follow-up period (straight talk on evidence 2019). like workadvance, quest works with employers to identify skill sets that companies need and provides training in those skills. based on this evidence, it appears that workforce-training programs focused on training for job skills that are in demand should be one component of improving family income. additional randomized controlled trials of such programs should take place and should include ongoing monitoring of their impact. the national academy of medicine report also examined the impact of a set of policies that would directly increase family income. one is housing vouchers. the federal government provides vouchers to families with very low incomes to subsidize rent, thus reducing expenditures and often enabling moves to better neighborhoods. a randomized trial of the impact of housing vouchers showed that they contributed to lower levels of obesity and depression (ludwig et al. 2011 ) and increased later earnings of those who moved to more affluent neighborhoods before the age of 13 (chetty et al. 2016 ). the nam report (nasem 2019b) indicated that increasing housing vouchers could result in moving 3% of children who currently live in poverty out of poverty. the national academy committee on poverty reduction also concluded that an increase in the number of families receiving assistance would contribute to reducing the proportion of children living in poverty by 2.3%. the committee also estimated that this supplement to the income of poor families could reduce the number of children living in poverty by 5.3%. note that while the nam report focused primarily on how these policies would increase family income and labor force participation, most have also improved health and wellbeing. for example, the report notes that the eitc improves children's educational and health outcomes. there is evidence that when people work together, each contributing to the group's success, prejudice diminishes. the most extensive research on this strategy involves cooperative learning procedures in schools, wherein small groups of students learn to work toward a common goal. this strategy has been shown to reduce prejudice and bullying (van ryzin and roseth 2018a). paluck and green (2009) note that very little of this research has been done in real-world settings. given the extent of discrimination in the usa, its impact on public health, and the size of the workforce, it is imperative that foundations and the nih fund research to identify more effective ways to reduce prejudice in schools, work settings, and neighborhoods and communities. jurisdictions across the usa are beginning to recognize and address the harms that criminal justice involvement can cause in families. for example, some efforts are underway to reduce sentence length, eliminate incarceration, and use alternative sentences (e.g., enhanced community supervision) for certain nonviolent crimes. yet the country can do much more. the usa has not only a far higher rate of incarceration than other developed countries, it also has a much higher recidivism rate (fazel and wolf 2015) . comprehensive reform of the criminal justice system will require that its leaders make their primary goal a reduction in the incidence of crime. the pursuit of this goal will require a bigger investment in prevention, which, in turn, will require the system to become more involved in and supportive of the other sectors of society, including schools, family services, and healthcare. it will also require the adoption of evidence-based practices that can reduce recidivism. among the reforms that are likely to remedy this problem are the following. punitive practices in schools, such as zero-tolerance policies, often escalate suspensions and expulsions. this results in children's separation from school, extra-curricular activities, and peers and increases the likelihood of further offending as well as dropping out of school (american psychological association-zero tolerance task force 2008 ; insley 2001; martinez 2009; mitchell 2014) . moreover, school and justice policies that bring together at-risk youth amplify the development of antisocial behavior (dishion et al. 2006 ). these practices need to be replaced with evidence-based therapeutic interventions (lipsey 1992; lipsey et al. 2010) . involvement of parents in the criminal justice system can be traumatizing to their children at the same time that it reduces family income and the availability of a parent (peterson et al. 2019) . promising evidence points to enhanced family relationships through interventions such as parenting skills training, well-managed visitations, and improved communications (dallaire et al. 2015) . however, the evidence is not sufficient to justify widespread implementation. further research on how to reduce the harm to families affected by incarceration should be a high priority. in addition, immigration policy is currently doing substantial harm to children and families. the current highly punitive policies need to be examined in terms of the harm that they do. policy reform must start with the goal of enhancing rather than undermining family well-being-a reform which is unlikely under the current administration. as noted above, the marketing of tobacco, alcohol, and unhealthful food harms children's health and undermines parents' efforts to protect it. some progress is being made in regulating cigarette marketing because the evidence is so clear that such marketing contributes to underage smoking (biglan 2004b ) and, ultimately, to the deaths of about a third of smokers (centers for disease control and prevention 1996) . similarly, the marketing of alcohol has been shown to increase underage drinking (sargent and babor 2020) . food marketing needs similar research. to the extent that research helps to determine whether marketing is a causal influence on alcohol or unhealthful food consumption, governments should regulate such marketing in the same way it regulates tobacco marketing. it is also clear that taxing tobacco and alcohol significantly reduces the proportion of young people who smoke or drink (komro et al. 2013) . and the evidence is beginning to emerge that taxation on sugar-sweetened beverages, can reduce the consumption of these products (redondo et al. 2018) . the harm that consumption of tobacco, alcohol, and unhealthful food does to children is substantial. this problem could be reduced if federal and state governments implement inflation-adjustable taxes on alcohol and unhealthful food and that those taxes are commensurate with taxes on tobacco products. in this section, we present a brief overview of the family and school interventions that have been shown to prevent problem development in youth. the evidence documents numerous family and school interventions that make these environments more nurturing. while it is true that addressing the above-described contextual conditions is likely to improve family well-being significantly, it is unlikely that reducing problems like poverty and discrimination will ensure that every family and school adopt the most effective ways of nurturing children's development . interventions are needed at both levels. research over the past thirty years has identified a broad array of family interventions that are available across the developmental spectrum. these interventions can reduce coercive interactions, promote parental skills in reinforcing prosocial behavior, set limits on risky behavior, and promote resilience in the face of challenges that stressful environments can pose. the strategies focus on two main areas: (1) family promotion of children's social, emotional, and behavioral well-being and (2) family promotion of children's healthy lifestyle behaviors to lower risk of obesity and other chronic disease conditions. this section briefly summarizes progress in each area and discusses what strategies can help achieve broad positive parenting and family support in society. over five decades, clinical and prevention professionals have developed a broad array of parenting and family support programs to foster social, emotional, and behavioral well-being of children. hundreds of studies document the benefits of such programs for families and children from infancy through adolescence. parenting and family support programming, if broadly implemented, has the potential to impact child mental health, child abuse, academic failure, bullying, antisocial or violent behavior, substance misuse, obesity, sexually transmitted disease in adolescence, teen parenthood. these programs increase positive and nurturing parent-child interactions, kindness, cooperation in peer interactions, and safe family environments many of these programs have common elements (prinz 2012) , including the following: • adopting a positive frame: no matter the circumstances, effective programs convey an optimistic and positive approach to each family. • action focus: parents actually do things instead of simply talking with a staff member. • problem-solving orientation: emphasis on solving current problems, not on casting blame. • specific, concrete, and practical parenting strategies: programs offer menus of strategies to address parenting challenges. • collaborative goal setting: parents and staff members collaborate to set programmatic goals for each family. • consultative rather than prescriptive attitude: programs favor providing useful consultation to parents without giving them orders. such programs reflect a well-honed set of parenting practices that are adaptable to children's ages and that offer parents many ways to foster nurturance, such as. • giving rules and instructions to children before situations begin. • paying frequent attention to positive behaviors. • providing supportive prompts, coaching, and correction. • setting clear limits and boundaries. • ignoring harmless but annoying behaviors so children don't get an "audience" for these. • recognizing and encouraging behaviors that are the opposite of any identified problem behaviors. • rearranging situations so that positive behaviors result in enjoyable activities. • expressing affection and caring frequently. • developing effective ways of solving daily and recurring problems. • envisioning the future and setting specific and attainable goals. families can positively influence youth health behaviors by providing a warm and supportive setting for learning, growth, and development (kitzman-ulrich et al. 2010; wilson et al. 2017) . it is increasingly apparent that positive parent-child communication is fundamental in promoting healthy behaviors in children. specifically, a supportive family climate has a positive association with adolescent health behaviors and healthy weight status (berge et al. 2013; halliday et al. 2013; st. george et al. 2013; wilson and sweeney 2018) . research shows that higher levels of family functioning (defined as communication, joint problem solving, closeness, and appropriate behavioral control) are related to healthier body mass index, nutrition, and physical activity among adolescents. haines and colleagues (haines et al. 2016) found similar results. they discovered relationships between higher family functioning, lower obesity risk, and less sedentary behavior. other evidence indicates that improving family climate through positive interventions reduces deleterious effects of unsupportive parenting on youth weight-related outcomes, with benefits that can be detected nearly 15 years later (brody et al. 2016; wilson et al. 2017) . family programs that improve children's self-regulation also promote healthy lifestyles from early childhood through adolescence. for example, self-monitoring, which involves prompting families to keep a record of a specified behavior (e.g., in an electronic or written diary), is one of the most effective strategies for eliciting changes in diet and physical activity (michie et al. 2009 ). another common strategy is prompting specific goal setting. this includes details such as the frequency, intensity, or duration of behavior, as well as specifying when, where, and how the child plans to achieve the goal (gollwitzer 1999) . action planning, including encouraging families to identify potential barriers to performing a behavior and planning supportive ways to overcome them, is another often-used technique for promoting healthy lifestyle changes (ayotte et al. 2010; bandura 2004) . these behavior-change strategies have been increasing in family contexts to promote health-related behaviors among lowincome and ethnic minority populations. another approach for promoting healthy behaviors among youth focuses on supporting their autonomy, rather than telling them what they should do. motivational interviewing (mi) is designed to increase motivation for behavior change by listening to the child about their concerns and joining them around their personal desires to change their health or weight (miller and rose 2009) . rather than providing advice or urging specific actions, clinicians and parents use this strategy to elicit the motivation to change from individuals themselves using strategies through reflective listening and shared decision-making. the counselor or parent can then provide the child (or adolescent) with specific behavioral skills, including identifying goals, creating an action plan, anticipating potential barriers, and monitoring children's health behaviors (resnicow and mcmaster 2012) . ample evidence shows mi is an effective strategy when coupled with behavioral skills training for reducing weight problems and obesity (for a review, see armstrong et al. 2011) and for helping parents facilitate weight loss in their overweight children (resnicow et al. 2015; spear et al. 2007 ). in the mi framework, shared decision-making and autonomy support are critical skills for parents as youth transition from childhood to adolescence (ryan et al. 2006) . shared decision-making involves parents and children making decisions together in a way that facilitates sharing in ownership over plans. this encourages motivation for and enjoyment of healthy behaviors (ryan et al. 2006) . studies have demonstrated positive associations between parental autonomy support and adolescent intrinsic motivation on improving healthy lifestyle-related behaviors and adhering to weight-loss treatment (mâsse et al. 2014) . parents can also use this strategy to model problem solving and troubleshooting of barriers. research has shown that these behavioral and motivational approaches are effective for improving health behaviors from early childhood through adolescence (kahan et al. 2018; st. george et al. 2013; wilson and sweeney 2018; wilson et al. 2017) . however, in the case of these health behavior interventions, a gap between research and practice exists that limits the implementation of evidence-based interventions outside of research programs. this gap exists because we have not yet developed effective strategies for getting nonresearch settings to adopt these strategies. given the deleterious effects of parental substance use on children, interventions to address parental substance use are needed. the evidence for the value for children of treating parental substance use is currently limited. calhoun et al. (2015) reviewed four randomized trials of the impact of treating parental substance use on children. each of these studies provided some evidence that parental treatment could benefit children, either by reducing the likelihood of the children's substance use or by improving children's psychological or behavioral functioning. research on evidence-based methods for reducing family violence indicates promising effects of behavioral interventions. although much more research is required for strong recommendations about how to prevent child maltreatment, studies have shown positive effects of parenting programs that reduce risk factors such as parental depression and stress, parents' inappropriate attitudes toward child-rearing, abusive parenting behaviors, insufficient parenting skills, and minimal knowledge about child development (chen and chan 2016) . recent research on domestic violence interventions also indicates promising new efforts using cognitive-behavioral interventions. an intervention based on acceptance and commitment therapy is now being used in the state of iowa for all individuals convicted of domestic violence. the intervention joins an abusing partner around their own prosocial goals and helps them learn to step back from anger-inducing thoughts, and feelings in a self-compassionate way. in this context, they become better able to control anger and develop more nurturing ways of interacting with their family members. research on the program shows preliminary evidence that it is effective in reducing repeat domestic assault, in both community corrections and incarcerated populations (berta and zarling 2019; zarling et al. 2017) . evidence-based family interventions are essential but not sufficient for a successful impact on the well-being of children and their families. broad population reach is critical as well. reaching one family at a time (e.g., home visitation programs) has utility but does not preclude the use of collective and cost-efficient strategies to provide parenting and family support for large numbers of families. critical to population reach are multiple access points for programming, an array of delivery modalities including media, the involvement of personnel from several service sectors, de-stigmatized programming capitalizing on a range of intervention intensities, and recognition of how to take into account major social determinants of health (kaplan 2019; prinz 2019). substantial progress has also been made on school interventions that promote prosocial behavior and prevent the development of multiple problems. these programs have in common a focus on helping schools to replace punitive discipline practices with practices that promote prosocial behavior. here we briefly describe four programs that have proven benefit. pbis is a schoolwide system for promoting prosocial behavior. a team of staff members establishes and monitors pbis implementation. they establish a small number of clear rules for appropriate behavior. common rules are be responsible, be respectful, and be safe. students are then taught examples of behavior consistent with these rules in all of the venues of the school (classrooms, hallways, playground, buses). a system for increasing praise and rewards for appropriate behavior is put in place throughout the school. the pbis system monitors disruptive or inappropriate behavior throughout the school and uses the data to pinpoint settings or individuals with high rates of inappropriate behavior. this enables the pbis team to put in place more intensive interventions for particular students or settings in the school. bradshaw et al. (2012) reported a group randomized trial of the impact of positive behavior intervention and support and 37 elementary schools. they found significant reductions in behavior and concentration problems and improved social-emotional functioning, and prosocial behavior. children in pbis schools were 33% less likely to be referred to the office for inappropriate behavior. pbs is now in more than 25,000 schools throughout the nation. this is a program that teaches students to engage in positive actions throughout the school. washburn et al. (washburn et al. 2011 ) reported on three randomized trials evaluating positive action in elementary schools. in all three studies, students who were randomized to the positive action intervention showed smaller declines in positive actions than those in controls. the program appears to have arrested the typical decline in positive actions that is seen as students enter early adolescence. the randomized trial conducted in 14 chicago elementary schools showed that the students receiving positive action had significantly more positive affect and life satisfaction, and significantly lower levels of depression and anxiety (lewis 2013a (lewis , 2013b . cooperative learning was originally developed as a method of increasing student learning, especially among students who were performing poorly. this strategy involves having small teams of students work together in ways that require each student to make a contribution to the group's product. numerous studies have shown the benefit of cooperative learning in increasing academic success (roseth et al. 2008) . it has also shown a clear benefit in reducing intergroup prejudice (pettigrew and tropp 2008) . recently, a randomized trial of cooperative learning in middle schools has shown that the program significantly reduced bullying and victimization and that students in the cooperative learning condition reported less stress, fewer emotional problems, and less use of alcohol and tobacco (van ryzin and roseth 2018b). like cooperative learning, the good behavior game involves small teams of students working together cooperatively. teams that meet the criteria for appropriate behavior receive rewards such as extra time for recess. extensive research over a period of 40 years has shown that the good behavior game significantly reduces disruptive behavior (embry 2002) . a randomized trial of the benefit of the good behavior game among students in early elementary school in baltimore showed that students who played the game were significantly less likely to smoke or be arrested by middle school and that by young adulthood they were significantly more likely to graduate high school and attend college and significantly less likely to have problems with substance abuse, antisocial behavior, or suicidality (kellam et al. 2014 ). the paxis institute developed a version of the good behavior game that combines it with a set of simple behavior influence techniques called kernels. that version of the game has generally replicated the benefits of the program that were shown in previous studies (johannsson, biglan, & embry, under revision) . at this writing, more than 40,000 teachers have been trained in the implementation of this version of the game. there is also evidence of the benefit of increasing collaboration between families and schools. jeynes (2012) conducted a meta-analysis of the impact of a variety of parental involvement programs on academic success and found they increased the performance of students of all ages. similarly, sheridan, smith, moorman kim, beretvas, and park (2019) conducted a meta-analysis of 117 studies on the impact of various types of family-school collaboration on students' social-emotional functioning and found significantly better social-behavioral competence and mental health among students of all ages; effects were strongest for african american children. the components of collaboration that made a difference included two-way communication between parents and teachers and trust between parents and teachers. also important was school provision of enrichment activities for the home, parents volunteering in the classroom, and specific help to parents on how to model and reinforce desirable behavior. despite the benefits of family-school collaboration, the collaborative practices sheridan et al. (2019) identified remain largely aspirational in typical school environments (garbacz et al. 2017) . perpetuating the gap between research and practice is a lack of trust families and educators have for each other. mistrust has intensified over time through certain practices, such as the disproportionate use of discipline (townsend 2000) . to promote family well-being, evidence-based family-school systems and practices (sheridan et al. 2019) should be aligned and integrated within existing school programs and initiatives (garbacz 2020) . such alignment and integration will provide the necessary context, through two-way communication, culturally sensitive practices, and family-centered services for parents and educators to build the skills and relationships necessary to strengthen families and support children. to advance this line of work, research is needed that examines the impact of strategies for promoting collaboration on (a) the level of parent-teacher collaboration; (b) the impact on teachers' attitudes and beliefs about parents and collaboration with them, and teacher burnout/morale; and (c) factors that explain the impact of a strategy on an outcome. in addition, an examination of the implementation process should consider alignment and integration in school and community systems; parent, youth, and teacher characteristics and experiences; the school infrastructure; and the external environment (feldstein and glasgow 2008). this brief review of family and school interventions documents the availability of numerous programs that can contribute to the well-being of families and the prosocial development of children. at the same time, additional research is needed if we are going to translate this body of knowledge into a widespread benefit. continued investment in strengthening these interventions is likely to improve their effectiveness. although there is evidence of the benefit of family and school interventions for poor and minority populations, further research on reaching and affecting this population is needed (van ryzin et al. 2015) . moreover, research on combining interventions at multiple levels and on how to get these interventions widely and effectively implemented will enhance our ability to make them available to neighborhoods and communities of concentrated disadvantage. the evidence presented thus far establishes three things. first, a large proportion of children and families are living in circumstances that undermine their well-being. indeed, over the past fifty years, conditions for families have deteriorated in the u.s. (kristof and wudunn 2020; putnam 2016) , and we have fallen behind other economically developed nations (unicef 2007) . second, those at greatest risk for future psychological, behavioral, and health problems are living in neighborhoods or communities of concentrated disadvantage. our impact on child and family well-being will be limited if we do not focus policies to alleviate structural barriers to well-being and how to further provide resources and assist these neighborhoods and communities. third, there is ample evidence that changes in public policy and the wider implementation of family, school, and community interventions can prevent or ameliorate many of the factors that undermine development. in principle, we have the knowledge needed to significantly improve wellbeing in american communities. we are, however, a long way from effectively addressing family well-being. despite the availability of policies and programs that could increase the number of families that are thriving, there appears to be no systematic plan for steadily improving well-being. the national academy's 2019 report fostering healthy mental, emotional, and behavioral development in children and youth (nasem 2019b) called for a decade-long effort focused on promoting healthy development. the report further called attention to the fact that seven other academy reports had advocated for greater attention to the problems of poverty and concentrated disadvantage because these conditions constitute the greatest obstacle to successful development. in keeping with this focus, the remainder of this paper presents a strategic plan for how we might create an unprecedented effort to reduce concentrated disadvantage and thereby increase the proportion of families that support the successful development of children and adolescents. there are various sectors and policymaking bodies that are trying to address the challenges to family well-being. however, there is not a comprehensive and sufficiently cogent plan to fully impact family well-being in the u.s. for this reason, this strategic plan is addressed primarily to the key policymaking bodies, leaders in business, ngos, and foundations, child and family advocates, other key opinion leaders, and consumer groups. the proposed goals for this effort would be as follows. 1. increase the proportion of american families that meet an empirically defensible public health standard of wellbeing. 2. identify, monitor, and reduce the number of neighborhoods and communities of concentrated disadvantage. 3. promote the adoption and implementation of policies and programs that advantage families. 4. increase the amount of research relevant to reducing family disadvantage. this would include research on a. establishing a national standard for family wellbeing in the form of an index of family well-being. b. experimentally evaluating comprehensive strategies for reducing disadvantage in neighborhoods of concentrated disadvantage. there are two facets of our plan for furthering these goals. the first concerns organizing an unprecedented coalition of all sectors of society to make increasing the well-being of american families a national priority along the lines of what the nasem report on the promotion of mental, emotional, and behavioral health called for. the second is the creation of research agenda that would advance family well-being, especially in neighborhoods and communities of concentrated disadvantage. every sector of society has a role to play in reversing the deterioration of family well-being that has occurred over the past 50 years (putnam 2016) . in each sector we need to identify practices that undermine family well-being and those that enhance well-being. the foundational value for this effort is a commitment to ensuring the well-being of every person. it is only when a growing number of people do so that we will have the support for the norms and public policies that select beneficial practices and diminish harmful ones (biglan 2020a) . we envision a process in which each sector is prompted to examine whether its practices are contributing to the reduction of concentrated disadvantage. in particular, it would look for ways in which the sector undermines well-being and the degree to which it makes use of evidence-based policies and programs that enhance well-being. higher education is critical to a nationwide effort to reduce concentrated disadvantage. over the past forty years, a consilience has emerged in the human sciences regarding the conditions that people need to thrive and those that contribute to the development of psychological and behavioral problems and premature death (biglan 2015 (biglan , 2020a biglan and embry 2013; biglan et al. 2012; biglan et al. 2019; catalano et al. 2002; dishion and snyder 2014; hawkins et al. 2014; institute of medicine 2009; kasse 2011 kasse , 2016 miller et al. 2011; nasem 2019a nasem , 2019b national research council & institute of medicine 2009; wilson et al. 2014) . the 2009 report of the national academy of medicine summarized the evidence this way: "the scientific foundation has been created for the nation to begin to create a society in which young people arrive at adulthood with the skills, interests, assets, and health habits needed to live healthy, happy, and productive lives in caring relationships with others." the research and training functions of our universities need to further develop strategies for translating what we know into effective interventions for disadvantaged families. according to the society for prevention research, there are only seven ph.d. programs in prevention science in the usa; there are seven masters level programs (society for prevention research 2018). increasing their numbers is a first step in advancing effective prevention. many other areas of the human sciences have a role to play in strengthening supports for family well-being. every university should be encouraged to examine how well it is preparing the scientists and practitioners that are needed to address the needs of families. higher education can also affect the trajectory of children living in disadvantaged communities. they can work with those communities to increase the number of children who attend college. they can reduce the costs of higher education for disadvantaged children. our healthcare system needs to shift from a primary emphasis on treating diseases once they develop to preventing them in the first place. here is just one example. there is an epidemic of childhood obesity in the usa and with it, a growing tendency for children to develop what used to be called adult-onset diabetes (u.s. department of health and human services 2018). a common practice among pediatricians is to screen children for obesity and counsel them and their parents (perrin et al. 2007 ). however, there is no evidence that intervention with an already obese child affects their trajectory (homer 2009 ). on the other hand, there is extensive evidence about the impact of food industry marketing on obesity and of the benefit of increased taxation on unhealthful food (biglan 2020b) . restricting marketing and increasing the price of these foods are the practices that are needed. the same is true for the prevention of smoking and alcohol use (biglan 2020c; pechmann et al. 2012) . strengthening the ability of the public health segment of the healthcare system to practice population health promotion will have a significant impact in reducing the incidence of a wide variety of disease that we currently wait to treat. the role of the public health sector in addressing the coronavirus epidemic may increase support for public health. in any case, this is the sector of the healthcare system that can lead the reforms that are needed. recent developments in business include a movement to evaluate business practices in terms of their contribution not just to investors, but to employees, customers, suppliers, and the society as whole. the business roundtable recently embraced these values and the b corp and conscious capitalism (business roundtable, n.d.; b corporation, n.d.; mackey and sisodia 2014) movements have been promoting them for some time. concrete steps that businesses can take include: (a) identifying and eliminating practices that harm, such as the marketing of harmful products (biglan 2020b; 2020c; 2020d; 2020e; 2020f; 2020g) ; (b) assessing the well-being of employees, customers, and the communities that they operate in; and (c) adopting practices that steadily increase family income and supports for child-rearing such as high quality day care and paid parental leave. a company that truly embraces the goal of ensuring that its employees are thriving, would strive to ensure that their wages are above the poverty level. the allies in reform of business norms and practices are the leaders of the conscious capitalism and b corp movements. as discussed above, the criminal justice system can reduce harm to families by reducing the use of imprisonment and investing more heavily in rehabilitation and the prevention of juvenile crime. there are numerous organizations working to reform this system (kerman, n.d.) . they are natural allies in any effort to reduce family disadvantage. we reviewed the array of family interventions that are available to help families reduce conflict and promote prosocial skills. every community has such services. they are increasingly guided by empirical evidence about effective practice. we need to encourage the transition from reactive intervention to instances of child abuse and neglect to a system of family check-ups and provision of support that prevents problems from developing. we also described some of the school-based programs that are available to schools. here too the challenge is to increase the proportion of schools that have the resources to make use of these programs. both the reform and the effectiveness of each of these sectors will be enhanced if organizations working in any given sector form a coalition with other sectors (biglan 2020a) there are three reasons. first, the explicit embrace of the goal of enhancing population well-being by any give sector will build support for this goal in other sectors. for example, when people in criminal justice speak of reducing the incidence of juvenile crime and increasing the prevalence of prosocial youth it encourages those in other sectors to think in terms of the well-being of the entire population they serve rather than only those who seek or are remanded to intervention. second, progress in any sector makes the job easier for any other sector. for example, to the extent that criminal justice and family services improve their support of families, schools will have fewer students who lack self-regulation, engage in disruptive behavior, and fail academically. conversely, to the extent that schools are nurturing prosocial behavior, they will prevent crime. the third reason a coalition is needed is so that, speaking with one voice, the organizations in each of these sectors can look beyond a narrow focus on the problems each addresses and work to address contextual conditions that contribute to most psychological and behavioral problems as well as poor health. our systems for dealing with human problems have naturally evolved out of the need to address an emergent problem-a crime, an injury, and illness. as such they are reactive. however, the evidence presented above documents the impact of poverty, discrimination, homelessness, and concentrated disadvantage have on the entire range of problems. each sector has a stake in reducing these problems. speaking with one voice about the need to address these problems would contribute to greater support for the policies needed to address them. coalition building will need to proceed at the local, state, and national levels. increasingly community interventions are making use of the collective impact model to bring the sectors of the community together around a shared agenda (kania and karmer 2011) . at the same time, success at the local level will be enhanced to the extent that sector leaders at the state and national level are working together to achieve state and federal support for such efforts. in describing each sector, we mentioned groups within that sector that are working on reform. at the same time, there are numerous foundations and advocacy organizations that are working on the issues we address in this paper. two behavioral science organizations that are specifically working to advance effective action are the coalition of behavioral science organizations (cbso) which supported the writing of this paper and the national prevention science coalition, which is a member of the cbso and which has more than sixty national organizations affiliated with it. a formal coalition among all of these organizations is an important next step for advancing the goals we have proposed. the process of creating such a coalition would begin by inviting an initial group of organizations to formally create the coalition. the major impetus for changes in public policy and practice are the reports of the national academy of science, engineering, and medicine, surgeon generals' reports, monographs of the national institutes of health, and reports of the centers for disease control and prevention. with the publication of the recent nasem reports on poverty reduction and the promotion of mental, emotional, and behavioral health, the coalition of behavioral science organizations and the national prevention science coalition are working to publicize and build on the recommendations of these reports. behavioral scientists are beginning to do more to educate the public about how we can evolve a society that enhances everyone's well-being. npsc is regularly doing congressional briefings and publishing oped pieces in major national outlets. however, it is no longer possible to rely solely on mainstream media. since the advent of social media, it has become possible for numerous actors to reach a large audience with views, misinformation, and hateful rhetoric that would never have been widely disseminated previously (marantz 2019) . this fact has only recently come to the attention of people working mainstream media (haidt and rose-stockwell 2019) . it is imperative that those of us who are trying to influence movement in the direction of supporting everyone's well-being, make more and better use of social media to promote understanding of what is needed to improve human well-being. we believe that the two most important priorities for research are the development of a national system for monitoring both family well-being and neighborhood and community disadvantage and the development and testing of comprehensive interventions to reduce disadvantage and enhance family well-being. if the nation is going to be guided to steadily increase family well-being and reduce community disadvantage, then it needs valid and widely accepted indices of each type of well-being. ultimately, these indices should be reported annually by the federal government in the same way the indices of community economic well-being are monitored and reported. with respect to child and family well-being, the urban institute recently reported well-being and basic needs survey that is an example of the type of survey system that is needed. at the same time, systems are being created to track conditions in neighborhoods and communities. acevedo-garcia et al. (2020) have a system that reports on the conditions in communities that are likely to enhance or hinder family well-being. ultimately every community should be able to track well-being in their neighborhoods. the covid-19 pandemic has exposed virtually the entire nation to the practice of tracking well-being down to the level of the community. because of the danger of a high rate of covid-19 infections, people watch with great interest whether case rates were increasing or decreasing. states track what was working in other states and adopt practices that seem to be working. these same procedures are relevant to achieving changes in other aspects of well-being. granted the outcomes that would be focused on with a system that was monitoring family and community well-being will not attract as much attention as one that is tracking deaths due to a virus. however, that is in part because the public has not been educated about the fact that family and community well-being are critical for the prevention of premature death and virtually all of the psychological and behavioral problems that costs our nation so much. community-level monitoring of child and family wellbeing and the contextual conditions that affect families will provide the criteria by which a community can assess its progress and can maintain or modify its practices in light of the data. this process can shape the practices of each sector. for example, reductions in juvenile crime should result from adoption of evidence-based school, family, and juvenile justice practices. although it will not be possible to precisely attribute reductions in juvenile crime to one of these systems, each system can monitor how many youth and families it is reaching with evidence-based practices and can assess the impact of their services. evidence of the value of both economic development efforts and programs targeting families and schools suggests it is time to test comprehensive interventions that simultaneously address all risk factors for problems for which we have some effective solutions. interventions that only address family and school environments will leave many families in poverty. interventions that target only economic well-being will not ameliorate patterns of conflict in families, nor school cultures that undermine development and well-being . a variety of intervention strategies and evaluation methods have been used, but most have no connection to other work on this problem. there is research on workforce development, economic development, and family and school interventions that could contribute to reducing intergenerational poverty. there are community interventions focused on preventing adolescent problem behavior (hawkins et al. 2014) , efforts to strengthen supports for child and adolescent development, and collective impact approaches to bringing all sectors of communities together to address challenges. however, a truly comprehensive framework for addressing the tangle of problems will likely require all of these strategies. the principles of community organizing (hawkins et al. 2009; minkler 2012) and collective impact (cabaj and weaver 2016) are foundational for a comprehensive intervention. each of the sectors of the community needs to engage in a participatory process in which the community identifies the actions they want to take to improve wellbeing. as we indicated above, the efforts of each sector to enhance well-being will benefit from success of other sectors. to the extent that each sector supports other sectors efforts, synergistic benefits are likely. a second line of research that is essential for any comprehensive intervention consists of efforts to enhance economic well-being in the neighborhood and communities. the brookings institution (shambaugh and nunn 2018) reviewed research on place-based strategies to improve economic well-being in communities or neighborhoods of concentrated disadvantage. these included job training, tax benefits for investment in neighborhoods, subsidized employment, involving research universities in economic development, and extending the reach of existing health and nutrition programs. because of the limited number of experimental evaluations of these strategies, evidence for the benefit of programs such as enterprise and opportunity zones is, at best, weak. a third component of such interventions would be the implementation of family and school interventions that have proven benefit in enhancing family and school supports for successful development. table 1 indicates activities that promote prosociality at every stage of development, from preconception through young adulthood. to our knowledge, no community has systematically implemented a comprehensive lifespan intervention and carefully assessed its impact. the closest we have found is the harlem children's zone, whose results are encouraging (whitehurst and croft 2010) . there are also likely to be synergistic effects of efforts at different phases of development. perhaps a child did not develop cognitive problems because her parents did everything they could to ensure her well-being in utero. as a result, a kindergarten class may have one less disruptive and uncooperative child. one more child will be able to read at grade level by third grade. if that child encounters adversity later in childhood (e.g., if a parent dies), she will benefit from good programs such as the one sandler and colleagues (sandler et al. 1992) developed to aid in coping with a death in the family. most evaluations of family and school programs with demonstrated benefits have been in contexts without other programs in place. and although the benefits of many interventions are significant, the size of their impact is generally small (jones et al. 2019) , and there is no evidence that their effectiveness has been increasing over time . one reason may be that these interventions are implemented in isolation both from many of the contextual conditions that affect behavior and from ameliorative interventions at other stages of development. it is likely that ensuring supports for families and schools at every stage of development can produce a larger impact on population well-being than any of these interventions in isolation. in addition to the many programs and policies with the potential to enhance well-being in communities, it may be beneficial to promote compassion and kindness. people who have faced numerous adverse experiences are likely to be hyper-vigilant and to read others as threatening; this is an adaptive orientation in such an environment . a community-wide effort to promote patient, caring, and kind interactions may contribute to reducing aversive interactions that not only maintain suspicion and distrust but lead to high levels of stress-related physiological processes that contribute to premature death (miller et al. 2011) . for example, imagine a family moving into a community that has increasingly organized around nurturing values, and that has explicit goals and procedures for promoting prosocial behavior. imagine this family has a long history of stressful contact with schools, the criminal justice system, healthcare providers, and perhaps neighbors. such a history is common in communities of concentrated disadvantage. the family's first experience in the community is likely to be enrolling their children in school, which may make them feel nervous and defensive. but suppose the school has a program to invite new families to discover how it supports children's prosocial behavior. suppose that staff convey that they like and admire the children. the family relaxes a bit, which is likely to promote positive interactions at home. now imagine that in every encounter in the community over the next few weeks, they meet people who show an interest in them and are welcoming and helpful. each positive encounter can contribute to family members becoming more comfortable while also conveying prosocial norms and reinforcing behavior. the complexities involved in evaluating comprehensive community interventions have hampered progress in helping neighborhoods of concentrated disadvantage. here we discuss what could strengthen this work. randomized trials are expensive and difficult to conduct in whole communities, especially if the intervention to be tested is multi-faceted. and, given the complexity of the multiple problems that need to be addressed, interventions need to be multi-faceted. randomized trials are useful for evaluating impact across cases, and they have demonstrated the value of numerous family and school interventions. however, they are not the best way to tease out functional relationships between environments and behavior. the family and school interventions that have been validated by randomized trials grew out of single-case experimental designs that revealed functional relationships between parents' and children's behavior (kazdin 1978) . similarly, before we can test complex, multi-faceted interventions through randomized trials in multiple communities, we need to show they are working reliably in individual communities. moreover, randomized trials require the assumption that all communities are alike in their needs and with regard to what will work. this makes it difficult to tailor an intervention to the needs of the community and still maintain consistency of the intervention across communities. greater use of interrupted time series designs would enhance research on communities (biglan et al. 2000a, b) . these designs involve obtaining repeated measures of an individual behavior or group action and assessing the impact of a well-defined intervention or independent variable on that time series. such multiple baseline designs could help to evaluate the impact of comprehensive interventions on the wide range of aspects of child and family well-being, including economic well-being, quality of family interactions, and psychological and behavioral functioning of children and parents. by monitoring well-being in three communities or neighborhoods and implementing a comprehensive intervention in one of the communities, while continuing monitoring, but not intervening in the other two communities, we can assess whether the intervention affects measures of well-being. if an effect is detected in the first community over, for example, two years, it can be implemented in a second community. if its effects are replicated in the second community, it can be implemented in a third. such a design provides a valid experimental test of the impact of the intervention (biglan et al. 2000a, b) . these methods are also useful for discovering the impact of individual interventions. for example, a community might implement the pax good behavior game (jiang et al. 2016) in a series of three elementary schools and track its impact on disruptive behavior and students' behavioral functioning. the community might initially evaluate introduction of an evidence-based family intervention in a multiple baseline across four families. it could similarly stage and evaluate a $3,000 per child allowance in terms of its impact on family relations. these assessments of individual programs would immediately show evidence of their efficacy, which could promote wider adoption. if they did not show benefits, the community could abandon the interventions or modify them until they worked. the beauty of these designs is that providing immediate experimental assessment of the impact of an intervention can enable its improvement. rather than requiring that each community get the same thing, these designs enable continuous quality improvement, so that successive communities receive an intervention modified by the improvements made in earlier implementations. although we believe that interrupted time series designs are the most efficient and effective strategy for developing effective interventions in neighborhoods of concentrated disadvantage, we also believe that it is impossible to say precisely what experimental strategies will be most productive. it would be a mistake to dictate that all interventions or all experimental procedures should have the same features. one experimental method that should also be tried is the most design (guastaferro and collins 2019). these factorial designs are valuable for efficiently identifying which components of an intervention and which combination of components are most effective. for example, an important question in neighborhood interventions is the relative and combined impact of economic development interventions and interventions focused on changing behavior in families and schools. a factorial design would efficiently address this question. it would involve randomly assigning neighborhoods to one of four conditions: (a) a combination of economic development and school and family interventions; (b) economic development interventions alone; (c) school and family strategies alone; or (d) no intervention. this design would allow assessment of the impact of each component, as well as the impact of the comprehensive intervention. we hope that this paper has made the case for a new initiative to address the problem of concentrated disadvantage in america. the extent of the problem is clear. its impact on the health and well-being of people living in these places is well-established. its harm to the rest of the nation is measured in the costs of poor health, drug use disorders, overdose deaths, and lost productivity. the policies and programs that can ameliorate these conditions are clear. this conclusion is being written on the day in which the u.s. became the country with the greatest number of covid-19 cases. the nation and the world are getting a lesson in how to think about public health. the entire world has been mobilized to do everything it can to prevent people from becoming infected. in the process millions of people have learned to think about the entire population. the incidence and prevalence of problems in entire populations has become as important as the individual case. this gives us an opportunity to bring attention to many other problems in society that would be best dealt with through public health strategies. every significant psychological, behavioral, and health problem can be thought of in terms of its incidence and prevalence. moreover, these problems are intertwined. this means that where we have high levels of one problem we are likely to high levels of others. and, specifically, these problems are concentrated in neighborhoods and communities that are high in poverty, substance use disorders, and social conflict. thus, efforts to greatly reduce the number of families that are affected by disadvantage will have limited success if we do not focus on reducing the prevalence of highly disadvantaged places. making a difference in these places will require policies and programs that reduce harmful contextual conditions such as poverty, homelessness, and discrimination, as well as programs that directly assist families and schools in adopting the most nurturing practices. the evidence that we can affect these problems is substantial. however, the challenge is to develop and evaluate comprehensive efforts to address multiple risk factors at every stage of development. putting in place such efforts will require a coalition of all sectors of society. if we can learn to speak with one voice about the harm that is being done by allowing children to be raised in concentrated disadvantage and the fact that we have policies and programs that could greatly reduce disadvantage, we may be able to achieve unprecedented improvements in the well-being of children and families in the usa. conflict of interest the authors declare that they have no conflict of interest. ethical approval this article does not contain any data from any studies with human participants that were performed by any of 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'the people who have historically endured the biggest risks for poor mental health and the worst access to and experiences of support are among those now most exposed to the worst of the immediate shock of covid-19. ' from the lancet: child & adolescent health: 1 using social media might make up for some from the centre for mental health [https://www. centreformentalhealth.org.uk/] briefing published in june 2020: 'the covid-19 crisis has had a profound effect on the nation's mental health. while most of us will emerge without lasting negative effects, some communities and individuals are at far greater risk of worsening mental health. 'this includes people living with mental health problems, whose access to services has been interrupted; people who live with both mental health problems and long-term physical conditions that put them at greater risk of the virus; older adults who are both susceptible to the virus themselves and much the first reports on the impact of covid-19 on children and adults at risk have been published. mark foster of the child protection company picks out extracts from seven reports to provide a wider perspective on how it might affect you now and in the worst-case scenario in any upcoming lockdowns. of the negative effects of social distancing. the question is how much and what kinds of digital communication help to lessen the effects of physical distancing, as dr orben, one of the report authors says: 'some studies have shown that active socialmedia use, such as messaging or posting directly on another person's profile, increases wellbeing and helps maintain personal relationships. 'however, it has been suggested that passive uses of social media, such as scrolling through newsfeeds, negatively influence wellbeing. ' currently 69% of younger adolescents in the uk, aged 12-15, have a social media profile. from the charity young minds: young minds carried out a survey between 9 april and 10 may during lockdown, involving 1,854 parents or carers. although the parents and carers who responded to the survey were more likely than the general population to have a child with existing mental health needs, nevertheless 745 respondents said that their children had received some form of mental health support (including from the nhs, charities, schools or helplines) in the previous three months. sixty-seven percent of respondents were concerned about the long-term impact of the coronavirus, the restrictions on movement and on their child's mental health. respondents reported a range of ways in which the crisis had impacted the children and young people in their care, including: increased anxiety and depression increased sense of loss and fear (eg about going out for exercise, or uncertainty about what would happen next) increased mood swings or children becoming more emotional lack of structure and routine having a negative impact children and young people finding it difficult to sleep or having nightmares children either becoming more attached to their parents, or becoming more introverted/isolated within the house. the fall-out from the crisis on school exam results has created a crisis of confidence for many young people, uncertain of their future. its impact is far-reaching and has compounded existing inequalities made worse by covid-19. in the foreword, eif chief executive dr jo casebourne says: 'our research paints an ominous picture of a wave gathering pace beneath the surface. as lockdown conditions are eased, services face a double hit, not only from more families needing more support to deal with a wider range of problems, but also from the knock-on consequences of fewer people having received the support that would usually have been available at key moments in their lives. ' the eif report is based on 32 semistructured qualitative interviews with heads of early help services, lead practitioners, and head teachers, conducted by eif together with the charity action for children between march and may 2020. they were particularly concerned about the significantly reduced contact that universal services would have with children and families, and the impact that this may have on referrals into early help services. most interviewees recognised a particularly significant challenge in identifying children who may become vulnerable as a result of covid-19, or during the lockdown, but who were not currently known to any service. these 'out of sight' children were seen as potentially the most vulnerable. at the time of writing, only 14% of vulnerable children were attending school and only 11% attending early-years settings. ' we are less concerned about children in the children's social care system, and more concerned about the children who aren't -who aren't in touch with any services. ' 'i've got children on a child protection plan who are now at home and not coming into school … that's really depressing and that's what's keeping me awake at night. ' primary head, london professionals suspected that there would be many families who had not previously been identified as vulnerable and who would not have accessed support during this time, either because they had not tried to, or because support had not been available. professionals were also concerned about their ability to support vulnerable children and families and to identify escalating risk without home visits and without regular face-to-face contact with universal services. innovative processes to mitigate these risks and provide safety nets had been put in place, but there was a recognition that some children and families who became vulnerable or became more vulnerable during the lockdown period would inevitably be missed. schools were particularly concerned about their lack of face-to-face contact with children they knew to be facing challenges at home. the research also identified a clear sense of apprehension among professionals about the longer-term impact of the pandemic and particularly the lockdown period on vulnerable children and families. from the children's society the good childhood report 2020: 4 the good childhood report 2020 is the society's ninth annual report on the wellbeing of children in the uk. findings from a survey, conducted between april and june 2020, of more than 2,000 young people aged 10-17 across the uk, and their parent or carer include: and not all will have been able to seek, adversely affected by the pandemic attentional difficulties over a one-month period as lockdown has progressed: parents/carers of primary school age children taking part in the survey reported an increase in their child's emotional, behavioural, and restless/attentional difficulties. and parents/carers of children with special educational needs (sen) and those with a pre-existing mental health difficulty reported a reduction in their child's emotional difficulties and no change in behavioural or restless/attentional difficulties. parents/carers of secondary school age children reported a reduction in their child's emotional difficulties, but an increase in restless/attentional behaviours. adolescents taking part in the survey reported no change in their own emotional or behavioural, and restless/attentional difficulties. this report used data from 2,890 parents/ carers who took part in both the baseline questionnaire and the first follow up questionnaire. so, what does that all mean to you? quite simply it means that you need to be especially observant, when in contact with children, young people and adults at risk as lockdown eases, your practice opens up again and your contact increases. as a number of the reports indicate, some of the children will have been adversely affected by the pandemic and not all will have been able to seek, or get help. you, quite literally, could be the first person with safeguarding training that they've seen in months. so, make sure you know what to do. re-read your safeguarding policies and procedures, refresh your training and check that the contact details you have for the local agencies are current as some may have changed to cater for staff working from home. above all, remember there's no such thing as a wrong referral when it comes to safeguarding. prepare yourself well and have the confidence to report any concerns. if you' d like any help with setting up your training, give the child protection company a call on 01327 552030 or email help@ childprotectioncompany.com today. their friendly customer support team is always happy to help. the effects of social deprivation on adolescent development and mental health young people's health and wellbeing: a response to covid-19 understanding the impact, preparing for recovery the children's society. the good childhood report 2020 action for child mental health key: cord-017252-88b3preq authors: morgan, carrie i.; shah, samir s. title: pneumonia date: 2014-02-20 journal: pediatric critical care medicine doi: 10.1007/978-1-4471-6356-5_6 sha: doc_id: 17252 cord_uid: 88b3preq respiratory diagnoses continue to make up a large number of admissions to the pediatric intensive care unit (picu), most notably lower respiratory infections including pneumonia. this chapter will focus on pediatric community-acquired pneumonia (cap), immunocompromised pneumonia, and aspiration pneumonia. the pathogenesis for developing pneumonia varies; it can occur by direct inhalation of infectious particles in the air or aspiration, direct extension from the upper airways, and hematogenous spread. there are multiple levels of defense against pathogen invasion including anatomic barriers, as well as innate and adaptive immunity, which may be compromised in picu patients. the etiologies of pediatric pneumonia vary depending on age, host condition, and environmental factors like time of year and location. viruses remain the most common form of lower respiratory tract infection in children, especially in neonates. community-acquired bacterial pneumonia continues to be most prevalent in younger children as well, most often affecting children less than 5 years of age who are otherwise healthy. despite immunizations and public health initiatives, the most common bacterial causes of cap have remained largely unchanged over the last several decades and include: streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae (including non-typable strains) and moraxella catarrhalis. pulmonary infection in an immunocompromised host provides a much broader differential and must be aggressively treated without delay. this chapter will also address various imaging modalities and typical findings with pediatric pneumonia. methods for pathogen identification are broad and range from non-specific markers of illness to invasive techniques for culture. the mainstay of therapy continues to be antibiotics tailored to the patient and presumed etiology; more novel therapies may include corticosteroids or macrolide antibiotics for immune modulation. in those patients with pneumonia with effusion or empyema, drainage therapies with thoracostomy tubes or a vats procedure may be indicated. respiratory diagnoses continue to make up a large number of admissions to the pediatric intensive care unit (picu) [ 1 ] . lower respiratory tract infections are considered to be any infection beneath the anatomic level of the vocal cords, including bronchitis, bronchiolitis, tracheitis, and pneumonia [ 2 ] . pneumonia remains an important cause of pediatric morbidity and mortality. there are nearly two million pneumoniarelated deaths worldwide each year among children 5 years of age and younger [ 3 , 4 ] . in the u.s., pneumonia causes over three million outpatient visits and more than 150,000 hospitalizations each year [ 5 , 6 ] . in the developed world, early recognition and availability of antimicrobial therapies and respiratory support have lessened the mortality of pneumonia, but its morbidities remain. while widespread use of the heptavalent pneumococcal conjugate vaccine in 2000 was associated with fewer pneumonia-associated complications in infants <1 year of age, complications remained unchanged or increased in school-age children and adolescents [ 5 ] . thus, despite our best efforts at prevention through vaccination, morbidities continue to plague our patients and pneumonia remains a common cause of pediatric hospital admission. this chapter will focus on pediatric community-acquired pneumonia (cap), immunocompromised pneumonia, and aspiration pneumonia. hospital acquired pneumonia is an important type of lower respiratory infection found in the picu, but it is discussed extensively in the chapter on hospital-acquired infections elsewhere in this textbook. the defi nition of pneumonia is generally accepted to be a lower respiratory illness with fever, respiratory symptoms including tachypnea, and often, radiologic evidence of parenchymal infi ltrates [ 7 ] . the world health organization (who) has defi ned pneumonia solely based on clinical fi ndings due to the lack of radiologic studies in many parts of the world [ 8 ] . determining the type of pneumonia can help guide clinical management. previously healthy children presenting with the signs and symptoms of a lower respiratory tract infection are generally considered to have cap. aspiration involves inhaling foreign material beyond the vocal cords, often causing aspiration pneumonitis (chemical pneumonitis) or pneumonia (an infectious process secondary to the aspiration) [ 9 , 10 ] . commonly aspirated materials in children include oropharyngeal secretions, gastric contents, water, hydrocarbon, lipid, and foreign bodies [ 11 ] . guidelines for admission to the icu are available for both young children and adults, and are summarized in table 6 .1 [ 12 , 13 ] . pneumonia can occur by direct inhalation of infectious particles in the air or aspiration, direct extension from the upper airways, and hematogenous spread. anatomic and cellular protection serves as the fi rst line of defense against potential pathogens. airway mucus traps inhaled toxins and microbes and helps to transport them up and out of the respiratory tract via ciliary beating and cough, a mechanism referred to clinically as mucociliary clearance [ 14 ] . when the microbe burden or virulence of the organism surpasses the abilities of these simple mechanical protections, the innate immune response is activated. the innate immunity is responsible for immediate recognition and control of microbial invasion. in mammals, conserved receptors enable rapid recognition of pathogens to begin elimination of the infection as well as initiate the adaptive immune response. activating the innate immune receptors in the airway epithelium leads to mobilization and activation of dendritic cells, t cells, and b cells that amplify antigen recognition, antibody production, and further cellular recruitment and infl ammation [ 15 ] . the specifi cs of these interactions and signaling cascades are beyond the scope of this chapter, but are further discussed in other chapters within this text. the lower respiratory tract remains generally clear of pathogens [ 2 ] . the mechanisms by which microbes are able adapted from refs. [ 12 , 13 ] to overwhelm defensive measures and result in pneumonia vary and depend on host conditions. the most common mechanism of pathogen entry is via inhalation of infectious particles, particularly in the case of specifi c organisms that spread via respiratory droplets such as mycobacterium tuberculosis. many viruses that cause lower respiratory tract infections are also spread utilizing aerosolized modes of transmission, including respiratory syncytial virus (rsv), infl uenza, and rhinoviruses. due to their smaller size compared with bacteria, viruses consolidate more effi ciently on smaller particles [ 16 , 17 ] . hematogenous spread results in pneumonia when bacteria in the bloodstream directly deposit in lung tissue. pulmonary aspiration can occur as a result of swallowing dysfunction, gastroesophageal refl ux, anatomic anomalies such as tracheoesophageal fi stulas, or an inability to protect the airway from oropharyngeal secretions. in the picu, many patients have neurologic diseases that coexist with one, if not several, of these aforementioned mechanisms. furthermore, impaired consciousness, as may occur with head injury, intoxication, sedation, and tracheal intubation, can also impair the ability to protect the airway, diminish the cough refl ex, and exploit the patency of the anatomical connection between the larynx and trachea [ 9 , 10 , 18 ] . direct aspiration of a large inoculum of infectious organisms can result when there is impairment of the host's anatomic defense, usually the gag and cough refl ex. this most commonly occurs in children with profound neurologic impairment or during tracheal intubation [ 19 , 20 ] . viruses still remain the most common cause of lower respiratory tract infection, especially in infants [ 21 ] . the occurrence of primary viral infections and co-infections with bacterial pneumonia are receiving more attention in recent years due to advances in detection methods to improve the reliability and sensitivity in diagnosis [ 22 ] . viruses have been found in approximately 50 % of sampled patients with a range of 43-67 %, although this prevalence is diffi cult to compare across studies that utilize different identifi cation techniques [ 22 -28 ] . the most commonly noted infectious viruses were rhinovirus, human bocavirus, human metapneumovirus (hmpv), and respiratory syncytial virus (rsv). human metapneumovirus causes signifi cant respiratory infection, accounting for 5-8 % of viral pneumonia cases [ 29 , 30 ] . human bocavirus, fi rst described in 2005, is detected in up to 10 % of children with respiratory infections [ 31 ] . however, co-infection with another virus occurs in more than half of human bocavirus infected children, making its role as a predominant respiratory pathogen unclear. one possible explanation for the high prevalence of viral coinfection with human bocavirus is that this virus is shed in respiratory tract secretions for a longer period of time than other viruses [ 32 -34 ] . other important respiratory tract pathogens include adenovirus, parainfl uenza viruses, and infl uenza a or b, all of which vary in prevalence based on season and epidemic periods. the most common complication of viral pneumonia is a secondary bacterial infection. bacterial co-infection occurs in about 15-33 % of pediatric patients hospitalized with a lower respiratory tract infection [ 23 ] . the most often occurring combination was rhinovirus and streptococcus pneumoniae , though it remains diffi cult to interpret the causal role of rhinovirus in lower respiratory tract infections [ 23 , 25 ] . rsv remains an important cause of bronchiolitis in infants and can often progress to pneumonia. a recent study noted that 40 % of children admitted to the picu with rsv bronchiolitis had bacterial co-infection [ 35 ] . community-acquired bacterial pneumonia continues to be most prevalent in younger children as well, most often affecting children less than 5 years of age who are otherwise healthy. despite immunizations and public health initiatives, the most common bacterial causes of cap have remained largely unchanged over the last several decades and include: streptococcus pneumoniae , staphylococcus aureus , haemophilus infl uenzae (including non-typable strains) and moraxella catarrhalis [ 7 , 8 , 21 , 23 ] . in developing countries, other bacterial and viral etiologies must be considered, including mycobacterium tuberculosis, h. infl uenzae type b (in unvaccinated areas of the world), and the measles virus [ 8 ] . in infants under 3-4 weeks of life, the most common etiologic agents include group b streptococcus, listeria monocytogenes, and gram-negative enteric bacteria. mycoplasma pneumoniae and chlamydophila pneumoniae (formerly chlamydia pneumoniae ), once considered to occur primarily among adolescents and young adults, are increasing being recognized as a cause of cap in younger children, including those less than 5 years of age [ 21 ] . there are many causes of immunodefi ciency in pediatrics including congenital, acquired (hiv/aids), or iatrogenic (during chemotherapy or after solid organ or stem cell transplant). these states can result in defi ciencies in humoral immunity, cellular immunity, and neutrophil availability or function, making the host susceptible to not only typical pneumonia etiologies, but many opportunistic agents. thus, the approach to an immunocompromised patient must be altered to consider the type and severity of immunodeficiency, as well as the temporal pattern after chemotherapy or transplant. other considerations that are important in immunocompromised patients include neutropenia, where a low white blood cell count can hinder the patient's ability to exhibit cxr fi ndings and the lack of infl ammation can alter the clinical presentation, and environmental factors and exposures that can cause geographic and temporal clustering of pathogens [ 11 ] . the causes of pneumonia following solid organ and stem cell transplant may follow a predictable temporal relationship. in the early post-transplant period (<1 month), infections from nosocomial or iatrogenic sources are most common. in the middle post-transplant period (1-6 months), donor-associated and opportunistic infections, including reactivation of latent infections, predominate; specifi c causes include cytomegalovirus (cmv), epstein-barr virus (ebv) or human herpes virus 6 (hhv6). late post-transplant period (>6 months) etiologies include community-acquired infections as well as infections associated with profound immunosuppression [ 36 , 37 ] . in an effort to diminish the risk associated with post-transplant immunosuppression, immunosuppressive agents (e.g., calcineurin inhibitors, high-dose corticosteroids) are used sparingly when possible and most protocols include anti-viral (especially cmv), anti-fungal, and pneumocystis jiroveci (pcp) prophylaxis [ 36 ] . still, many common infections continue to pose a great risk. for example, viral infections (e.g., rsv, infl uenza, adenovirus) cause greater virulence following solid organ or stem cell transplantation immediately after transplant when cellular immunity is profoundly low. later in the course of transplantation, fungi such as aspergillus spp. and candida spp. become more prevalent causes of pneumonia with long-term steroid therapy [ 11 , 37 ] . thus, when a pulmonary process is suspected, aggressive treatment with broad-spectrum antibiotics, antifungals, and antivirals must be employed. immunocompromised patients with pulmonary infi ltrates may rapidly progress to respiratory failure and, thus, often require icu care. infection must be aggressively treated without delay, but other conditions must also be sought including pulmonary hemorrhage, malignancy, idiopathic pneumonitis, or cardiac disease [ 11 , 38 ] . the clinical presentation of aspiration pneumonitis or pneumonia can vary and like other pneumonia etiologies, aspiration can result in acute lung injury (ali) or acute respiratory distress syndrome (ards) manifested by severe pulmonary infl ammation and alveolar-capillary permeability injury. it is estimated that approximately one-third of patients with aspiration pneumonitis develop ali/ards [ 39 ] . etiologies of aspiration pneumonia depend if the aspiration is community acquired or hospital acquired. bacteriologic studies in aspiration patients have shown that community acquired aspiration pneumonias are generally the same bacterium as cap, including h. infl uenzae , s. pneumoniae , s. aureus , and enterobacteriaceae species. in those patients who aspirated in a hospital setting, the most common organisms cultured were gram-negative enteric bacteria including pseudomonas aeruginosa . these recent studies failed to grow any anaerobic organisms, refuting the prior studies that endorsed anaerobes as common etiologies [ 10 ] . the role for imaging in pediatric pneumonia is to detect the presence of pneumonia, determine the location and extent, and identify complications such as effusion or empyema. modalities include chest radiographs (cxr), ultrasound (us), and computed tomography (ct) [ 11 ] . the presence of an infi ltrate on cxr, combined with clinical and other laboratory fi ndings can aid in the diagnosis of pneumonia. however, these modalities are not suffi ciently sensitive or specifi c to reliably differentiate between viral, bacterial, and atypical bacterial causes [ 40 ] . the main use for us is to identify and characterize a parapneumonic effusion or empyema and provide image guidance for chest tube placement. this modality is limited by availability of equipment and operators. chest ct is helpful to further evaluate diffi cult cases, particularly immunocompromised children with ill-defi ned infi ltrates on cxr, complex empyema or effusion, or recurrent or chronic pneumonia [ 11 ] . imaging fi ndings in pneumonia can be non-specifi c, but when combined with other factors such as patient age, immune status, and historical information, they may help to narrow the differential diagnosis. in viral pneumonia, the most common fi ndings are bilateral symmetrical parahilar and bronchial opacities with or without atelectasis and air trapping; pleural effusions are rare ( fig. 6.1 ). this is in contrast to bronchopneumonia, a form of bacterial pneumonia that begins as peribronchiolar infl ammation and spreads to the lung parenchyma. bacterial pneumonia is characterized by consolidation and fi lling of the alveolar air spaces with exudate, infl ammation, and fi brin. bronchopneumonia is typical of many bacteria including s. pneumoniae , h. infl uenzae , s. aureus , and gram-negative enteric bacteria. the cxr often reveals fl uffy lobar consolidation or diffuse bilateral opacities extending peripherally, with or without associated pleural effusion. in aspiration pneumonia, the cxr may reveal ground-glass or consolidative opacities predominantly involving the middle and lower (dependent) lobes [ 41 ] . finally, atypical pneumonia etiologies include mycoplasma pneumoniae , chlamydophila pneumoniae and, less commonly, legionella species. the cxr fi ndings for these atypical causes are varied. diffuse interstitial infi ltrates are characteristic though other fi ndings include lobar consolidation, small bilateral pleural effusions, perihilar and peribronchial opacities that resemble butterfl y wings, or a bi-lobar reticular pattern ( fig. 6. 2 ) [ 42 , 43 ] . the etiology of pneumonia in the immunocompromised patient can be diffi cult to determine though further imaging can help elucidate the cause. respiratory failure in an immunocompromised child frequently necessitates a chest ct to better visualize the pattern and extent of disease, aid in diagnosis of the etiology, determine the need for more invasive procedures, and to increase the sensitivity of assessing treatment response [ 11 ] . fungal infections are more diffi cult to diagnose; classic fi ndings include pulmonary nodules on chest ct (fig. 6.3 ). the "gold standard" diagnosis of pneumonia is microbiological identifi cation of a pathogen from the lower respiratory tract [ 2 ] . obtaining a lrt specimen can be diffi cult, especially in children, as it may require an invasive procedure and can be contaminated with oropharyngeal bacteria. most children younger than 8 years of age cannot produce a suffi cient sputum sample, defi ned as <10 squamous or epithelial cells and >25 polymorphonuclear white blood cells per low power fi eld. therefore, most samples are obtained through either an endotracheal tube via aspiration or bronchoalveolar lavage [ 44 ] . other laboratory tests helpful in identifying the causative agent in cap can include blood cultures, viral polymerase chain reaction (pcr) tests, and bacterial serologies. commonly used diagnostic methods available for an individual microorganism may be found in table 6 .2 [ 8 ] . the clinician may also be limited by the capabilities of the laboratory in their institution for performing these tests. because of the diffi culties in determining the etiology of pneumonia, non-microbiologic approaches have been sought to differentiate serious bacterial infections from nonbacterial pneumonia [ 21 ] . many studies have evaluated markers including serum c-reactive protein (crp), blood white cell count (wbc), serum procalcitonin (pct), and erythrocyte sedimentation rate (esr), attempting to fi nd a test, or combination of tests, that would differentiate viral pneumonia from serious bacterial pneumonia necessitating antibiotic therapy [ 8 , 45 -49 ] . all of the aforementioned tests have limited utility in reliably differentiating viral from bacterial pneumonia, but when one or more of the markers are signifi cantly elevated, a bacterial etiology is more likely. thus, taken together with the clinical examination and radiologic fi ndings, these tests can aid the clinician in deciding which patients require antibiotic therapy. pct levels appear to be more sensitive than wbc, esr, and crp in identifying children with bacterial pneumonia and have been used to identify children who may benefi t from a longer duration of antibiotic therapy [ 50 ] . when non-invasive identifi cation techniques are inadequate, or when identifying the cause is especially important, such as when treating an immunocompromised host, invasive diagnostic procedures may be necessary. fiberoptic bronchoscopy with bronchoalveolar lavage (bal) is the preferred diagnostic procedure in an immunocompromised host with an unknown pathogen [ 51 ] . the sensitivity for diagnosis varies and depends on the host, pathogen, and the post-collection microbiologic detection methods employed. while many atypical organisms may be diffi cult to culture, p. jiroveci and mycobacterium infections are more easily detected in bal because of high organism burden in the lungs. the diagnosis of aspiration pneumonia is mainly clinical, often based on historical or witnessed events or conditions, and thus can be diffi cult to ascertain. if a bal is performed in suspected aspiration, the presence of lipid-laden macrophages can help diagnose the aspiration of lipophilic foods such as formula [ 52 ] . a lipid-laden macrophage index can be obtained using the oil red o stain and when high, can be very sensitive and specifi c for aspiration [ 53 ] . other invasive procedures include transbronchial biopsy if diffuse infi ltrates are present but the bal is negative, or ct-guided needle biopsy of a focal lesion. the improved diagnosis with these invasive procedures must be balanced against the risks to critically ill patients [ 54 ] . important noninfectious etiologies to rule out with these invasive procedures include lung rejection (if transplanted), post-engraftment syndrome, idiopathic pneumonitis, graft versus host disease, and bronchiolitis obliterans. children with severe pneumonia requiring admission to the picu are likely to receive intravenous antimicrobial therapy even if only until the possibility of bacterial infection can be excluded. in critically ill children with respiratory failure from pneumonia, prompt initiation of broad-spectrum antimicrobials is crucial. one study in pediatric patients with cap showed that longer delays in receipt of antibiotics were independently associated with adverse outcomes [ 55 ] . however, antibiotic resistance is increasing and the principles of appropriate antibiotic utilization must be adhered to: use of drug with narrowest spectrum, aiming for high tissue penetration, short half-life, and abiding to a short, intense duration of therapy [ 7 ] . the duration of therapy is typically 7-14 days, with 10 days being the best studied. a 7-day course may be reasonable in non-severe cases of pneumonia [ 12 ] . the choice of antimicrobial agent is based on many things including the patient's age, the type of pneumonia, and clinical and epidemiologic factors. recent guidelines published by the pediatric infectious diseases society and the infectious diseases society of america offer guidance for empiric antibiotic selection in children hospitalized with cap (table 6. 3 ) [ 12 ] . pneumonia causes a profound infl ammatory response in the lungs and it has long been postulated that regulating this infl ammation with steroid therapy may help to modulate local tissue damage and accelerate recovery for the patient. in addition, steroids are frequently utilized in other pulmonary infl ammatory conditions such as reactive airway a b the fi nding of at least a quadrupling of serum antibody levels between the acute phase and convalescence the fi nding of igm antibody in serum late in the acute phase or early in convalescence is helpful, as is a positive pcr assay of secretions from a throat or a nasopharyngeal swab rapid igm assays can provide results within 10 min. in younger children, an elevated igm titer is often diagnostic; in older children, the fi nding of at least a quadrupling of serum antibody levels between the acute phase and convalescence is diagnostic. cold agglutinin titers lack sensitivity and specifi city and thus are no longer recommended separate serum specimen because some agents (e.g., piperacillintazobactam) may cross-react with the assay. if invasive aspergillosis is suspected in high-risk patients, serial sampling is recommended. the false positive rate is higher in children than adults [ 91 , 92 ] adapted from mcintosh [ 6 ] . with permission from massachusetts medical society disease (rad) and acute respiratory distress syndrome (ards) [ 56 ] . the infl ammatory responses in pneumonia and ards are similar with increases in pro-infl ammatory cytokines concurrent with illness severity; severe pneumonia can often progress to acute lung injury (ali) or ards [ 57 -59 ] . while preclinical data support the use of steroids, current studies have not demonstrated a reduction in mortality among corticosteroid recipients compared with non-recipients. several trials, however, have shown some secondary benefi ts of steroids, including reduced length of hospital stay and reduced infl ammatory markers [ 60 , 61 ] . in contrast, a multi-center, retrospective cohort study using administrative data found that among patients not receiving concomitant beta-agonist therapy (used as a proxy for wheezing), corticosteroid recipients had a longer los and higher readmission rate compared with non-recipients [ 62 ] . at present, the lack of high quality data supporting the effi cacy of corticosteroids prevents the recommendation for the use of steroids in most patients with severe pneumonia. however, corticosteroids may provide benefi t to certain subgroups of patients such as those with acute onset of wheezing and those who meet the criteria for ali/ards [ 59 ] . macrolide antibiotics have important anti-microbial as well as anti-infl ammatory properties, though the relative importance of these two mechanisms in children with pneumonia is unknown. in adult studies, macrolides have recently been touted for their immunomodulatory effects and clinical benefi t in multiple chronic pulmonary conditions such as asthma, chronic obstructive pulmonary disease (copd), and cystic fi brosis (cf). the specifi c immunomodulatory effects are vast and include inhibition of intracellular signaling to suppress the production of transcription factors such as nf-îºb and decrease production of infl ammatory cytokines that recruit neutrophils [ 63 , 64 ] . several recent studies in adult patients with severe cap and sepsis have shown a benefi t in survival in patients treated with macrolide antibiotics in addition to the recommended antibiotics based on pathogen [ 63 , 65 -68 ] . the role of macrolides in children with pneumonia is unclear. in pediatrics, several small retrospective studies have shown that among children with atypical cap, those treated with macrolides were less likely to have persistence of signs and symptoms after 3 days of therapy [ 69 , 70 ] . among children with m. pneumoniae infection, lu et al. found a shorter duration of fever among macrolide recipients compared with non-recipients [ 71 ] . finally, a large multi-center study of 690 patients with m. pneumoniae infection defi ned by discharge diagnosis codes, the median length of hospital stay was 3 days (interquartile range, 2-6 days); macrolide recipients had a 32 % shorter length of stay compared with non-recipients [ 72 ] . pneumonia-associated complications such as empyema affect 7.5-15 % of children hospitalized with pneumonia [ 5 , 73 -76 ] . the progression from simple parapneumonic effusion to empyema occurs in stages that represent a continuous spectrum (table 6 .4 ) [ 77 ] . in the fi rst stage, there is a rapid infl ux of exudative fl uid into the pleural space as a result of increased pulmonary interstitial fl uid traversing the pleura and an increase in vascular permeability due to pro-infl ammatory cytokines. the pleural fl uid is marked by the absence of bacteria, fl uid ph >7.20, normal glucose, and ldh <3 times the upper limit of normal. at this stage, drainage is not generally required for resolution but if the effusion becomes large and piperacillin-tazobactam if concern for gram negative enteric bacteria iv cefotaxime if >20 days of age adapted from refs. [ 8 , 12 ] impairs respiratory mechanics, drainage might become necessary. the fl uid in the pleural space can fl ow freely and often layers along the lateral chest wall in decubitus fi lms or along the posterior chest wall in supine fi lms [ 37 , 78 ] ( fig. 6.4a , b) . if left untreated, exudative effusions can progress to fi bropurulent effusions characterized by the new presence of bacteria or positive microbial cultures. cellular lysis and phagocytosis in the fl uid can result in ph < 7.20, higher ldh, and low glucose. loculations begin to develop, causing these effusions to now be referred to as "complicated." a chest radiograph may be diffi cult to interpret with respect to evidence of complicated effusions. thoracic us is more accurate than chest radiographs in distinguishing simple from complicated pleural effusions. complicated effusions are associated with fl oating debris and echogenic material or septations. ultrasound is also useful in guiding pleural aspiration and drainage. chest computed tomography (ct) may be indicated to better defi ne pulmonary and pleural anatomy. thickening of the parietal pleura on a contrasted ct scan is suggestive of empyema, even if the effusions are small in size ( fig. 6.4c ) . finally, stage three is the organizing phase where fi broblasts grow into the pleural space and eventually results in a pleural peel, restricting chest mechanics. this stage often necessitates surgical decortication, especially if there is restrictive impairment [ 78 ] . the typical organisms responsible for the development of an empyema include s. pneumoniae and s. aureus . pleural fl uid cultures identify an organism in only 20-30 % of children with empyema. blood cultures are positive in 13-30 % of children with empyema [ 79 -82 ] . s. aureus is most often identifi ed in pleural fl uid culture. however, molecular identifi cation techniques reveal that most culture-negative cases are attributable to s. pneumoniae [ 83 , 84 ] . regardless of the type of effusion present, antibiotic coverage based on treatment guidelines for pneumonia are essential. a recent study on the impact of early antibiotic therapy on the laboratory analysis of pleural fl uid found that pre-treatment signifi cantly hindered a bacterial diagnosis but did not alter the biochemical parameters of the fl uid [ 85 ] . however, delaying antibiotic treatment for a thoracentesis would not be recommended in a critically ill child with respiratory failure secondary to pneumonia. the treatment of complicated effusions and empyema remains controversial but recent studies have better defi ned protocols. a complete list of the available treatments for effusions and empyema is found in table 6 .5 . small, uncomplicated pleural effusions do not routinely require drainage. moderate or large pleural effusions as well as those with evidence of septations or loculations usually require drainage. the medical options include appropriate antimicrobials and chest tube insertion with or without fi brinolytic therapy. surgical options include video-assisted thoracoscopic surgery (vats) or open thoracotomy and decortication. recent guidelines concluded that chest tube drainage with the addition of fi brinolytic agents and vats are equivalent methods of treatment and emphasize the importance of local expertise in determining the optimal approach for individual patients [ 12 , 86 ] . vats has gained popularity over conservative medical therapy as a way to directly visualize the pleural space, mechanically disrupt the adhesions, and strategically place the chest tube for optimal drainage [ 73 , 87 ] . the higher cost and risk of anesthesia with vats must be balanced against the more frequent requirement for additional drainage procedures for those undergoing primary chest tube placement. thoracotomy and decortication are rarely needed. the argument of medical management versus surgical management remains controversial. to date, at least two prospective trials in pediatrics have been completed directly comparing these methods. both trials failed to show any outcome superiority with surgical management [ 80 , 88 ] . certainly children who have a very high white blood cell count in their pleural fl uid (> 15,000), poor output drainage by chest tube, low pleural ph, the presence of bacteria in the pleural fl uid and/or bloodstream, or failure of medical therapy alone may benefi t from early vats [ 86 ] . patients who underwent vats required fewer adapted from refs. [ 12 , 78 , 93 ] additional drainage procedures, but had no difference in hospital length of stay [ 74 ] . however, one study of adults with empyema found that patients treated with a combination of tpa and recombinant human dnase required fewer surgical interventions and had a shorter length of hospital stay [ 89 ] . cost-effectiveness, balance of risks, and availability of resources also plays a role in considerations for surgical management. a comparison of multiple strategies for pediatric empyema noted that the most cost effective method was insertion of a chest tube with fi brinolytic therapy [ 90 ] . abscesses develop in localized areas of parenchymal infection that becomes necrotic and cavitates ( fig. 6.5a , b ) . primary lung abscesses can develop either in previously healthy children or in children with underlying lung disease such as congenital cystic lesions, cystic fi brosis, or immunodefi ciency. mechanisms for abscess development can include direct aspiration of infectious material, embolic phenomena, hematogenous spread from septicemia, or local extension from abdominal or oropharyngeal processes. the most common organisms include gram-positive bacteria such as streptococci, staphylococcus aureus or anaerobes. most abscesses resolve with intravenous antibiotics alone, but aspiration or drainage with a pigtail catheter may be necessary [ 37 ] . vaccines against specifi c bacteria that predominantly cause pneumonia in children, specifi cally pneumococcal conjugate vaccine (pcv-7) and h. infl uenzae vaccine (hib) have drastically lowered the prevalence of infections causes by these strains. since the introduction of pcv-7, several studies have documented its effi cacy, and the decrease in cases of h. infl uenzae are equally striking [ 7 , 21 ] . however, while pcv-7 has decreased the prevalence of invasive pneumococcal disease, the incidence of empyema is rising, the reason for which is unclear [ 76 ] . the licensure of pneumococcal conjugate vaccines that include even more serotypes (e.g., 13-valent) may further change the epidemiology of childhood pneumonia. other vaccines, such as for measles (mmr) and infl uenza, can also aid to reduce these viral infections that so commonly lead to secondary bacterial pneumonia. while vaccines appear to be our greatest effort toward preventing pneumonia in children, more work needs to be done to increase their microbial coverage and availability throughout the world. operative technique in which a small camera and instruments are inserted into the pleural space through 2-3 small (1-2 cm) incisions of the skin and muscle on the lateral chest wall to mechanically remove purulent material and pleural adhesions. a thoracostomy tube is placed through one of the existing incisions following completion of the procedure open thoracotomy operative technique where instruments are inserted into the pleural space through a single 5-8 cm incision of the skin and muscle on the posterolateral chest wall to mechanically remove purulent material and pleural adhesions. a thoracostomy tube is placed through a second smaller 1-2 cm incision following completion of the procedure general anesthesia reprinted from swami and shah [ 43 ] . with permission from mcgraw-hill three decades of pediatric intensive care: who was admitted, what happened in intensive care, and what happened afterward defi ning pneumonia in critically ill infants and children world health organization (who) childhood pneumonia mortality-a permanent global emergency national hospitalization trends for pediatric pneumonia and associated complications ambulatory visit rates and antibiotic prescribing for children with pneumonia pneumonia and other respiratory infections community-acquired pneumonia in children pulmonary complications of pediatric neurological diseases aspiration pneumonitis and aspiration pneumonia pneumonia in normal and immunocompromised children: an overview and update the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults airway mucus function and dysfunction beyond infl ammation: airway epithelial cells are at the interface of innate and adaptive immunity the role of particle size in aerosolised pathogen transmission: a review distribution of airborne infl uenza virus and respiratory syncytial virus in an urgent care medical clinic aspiration lung disease the impact of tracheal intubation on host defenses and risks for nosocomial pneumonia feeding the disabled child community-acquired pneumonia: a review and recent advances viruses in community-acquired pneumonia in children aged less than 3 years old: high rate of viral coinfection viruses and bacteria in sputum samples of children with community-acquired pneumonia viral pneumonia induced sputum in the diagnosis of childhood community-acquired pneumonia etiology of community-acquired pneumonia in 254 hospitalized children etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections etiology of community-acquired pneumonia in hospitalized children based on who clinical guidelines the changing face of pediatric respiratory tract infections: how human metapneumovirus and human bocavirus fi t into the overall etiology of respiratory tract infections in young children population-based incidence of human metapneumovirus infection among hospitalized children human bocavirus human bocavirus in children with acute lymphoblastic leukemia frequent and prolonged shedding of bocavirus in young children attending daycare human bocavirus: passenger or pathogen in acute respiratory tract infections? high incidence of pulmonary bacterial coinfection in children with severe respiratory syncytial virus (rsv) bronchiolitis infection in solid-organ transplant recipients respiratory infections: pneumonia, lung abscess, and empyema approach to the immunocompromised host with infection in the intensive care unit aspiration-induced lung injury community-acquired pneumonia in children: what's old? what's new? lipoid pneumonia: spectrum of clinical and radiologic manifestations pulmonary infections pediatric practice: infectious diseases murray and nadel's textbook of respiratory medicine value of the c-reactive protein test in the differentiation of bacterial and viral pneumonia serum procalcitonin, c-reactive protein and interleukin-6 for distinguishing bacterial and viral pneumonia in children differentiation of bacterial and viral communityacquired pneumonia in children white blood cells, c-reactive protein and erythrocyte sedimentation rate in pneumococcal pneumonia in children non-specifi c host response markers in the differentiation between pneumococcal and viral pneumonia: what is the most accurate combination? procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia role of fl exible bronchoscopy in immunocompromised patients with lung infi ltrates chronic pulmonary aspiration in children lipid-laden macrophages in induced sputum are a marker of oropharyngeal refl ux and possible gastric aspiration open lung biopsy in pediatric bone marrow transplant patients timing of correct parenteral antibiotic initiation and outcomes from severe bacterial community-acquired pneumonia in children activation and regulation of systemic infl ammation in ards: rationale for prolonged glucocorticoid therapy understanding the infl ammatory cytokine response in pneumonia and sepsis: results of the genetic and infl ammatory markers of sepsis (genims) study infl ammatory markers at hospital discharge predict subsequent mortality after pneumonia and sepsis steroids in severe pneumonia: a literature review dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study adjunct corticosteroids in children hospitalized with community-acquired pneumonia immunomodulatory agents in the treatment of community-acquired pneumonia: a systematic review mechanisms of action and clinical application of macrolides as immunomodulatory medications combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia combination antibiotic therapy with macrolides improves survival in intubated patients with communityacquired pneumonia role of mycoplasma pneumoniae and chlamydia pneumoniae in children with community-acquired lower respiratory tract infections characteristics of streptococcus pneumoniae and atypical bacterial infections in children 2-5 years of age with community-acquired pneumonia macrolide use shortens fever duration in mycoplasma pneumoniae infection in children: a 2-year experience macrolide therapy and outcomes in a multicenter cohort of children hospitalized with mycoplasma pneumoniae pneumonia primary operative versus nonoperative therapy for pediatric empyema: a meta-analysis comparative effectiveness of pleural drainage procedures for the treatment of complicated pneumonia in childhood primary early thoracoscopy and reduction in length of hospital stay and additional procedures among children with complicated pneumonia: results of a multicenter retrospective cohort study empyema hospitalizations increased in us children despite pneumococcal conjugate vaccine parapneumonic effusions and empyema parapneumonic pleural effusion and empyema blood cultures in the emergency department evaluation of childhood pneumonia thoracoscopic decortication vs tube thoracostomy with fi brinolysis for empyema in children: a prospective, randomized trial impact of the pneumococcal conjugate vaccine on pneumococcal parapneumonic empyema an epidemiological investigation of a sustained high rate of pediatric parapneumonic empyema: risk factors and microbiological associations the changing face of pleural empyemas in children: epidemiology and management molecular analysis improves pathogen identification and epidemiologic study of pediatric parapneumonic empyema impact of antibiotic therapy on laboratory analysis of parapneumonic pleural fl uid in children management of parapneumonic empyema pediatric respiratory diseases: 2011 update for the rogers' textbook of pediatric intensive care comparison of urokinase and video-assisted thoracoscopic surgery for treatment of childhood empyema intrapleural use of tissue plasminogen activator and dnase in pleural infection cost-effectiveness of competing strategies for the treatment of pediatric empyema diagnostic aspects of invasive aspergillus infections in allogeneic bmt recipients diagnostic potential of nested pcr, galactomannan eia, and beta-d-glucan for invasive aspergillosis in pediatric patients medical and surgical treatment of parapneumonic effusions : an evidence-based guideline key: cord-023942-vrs3je1x authors: powers, karen s. title: acute pulmonary infections date: 2011-12-16 journal: pediatric critical care study guide doi: 10.1007/978-0-85729-923-9_25 sha: doc_id: 23942 cord_uid: vrs3je1x acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insufficiency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least 24 h in pediatric intensive care units are diagnosed with bronchiolitis and 16% have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately 7 days. acute lower respiratory infection is a common cause of morbidity in infants and children, and at times, requires intensive care and mechanical ventilation. viral bronchiolitis and bacterial pneumonia account for the majority of lower respiratory tract infections that lead to respiratory insuffi ciency and pediatric intensive care admission. twenty-seven percent of children who require mechanical ventilation for at least 24 h in pediatric intensive care units are diagnosed with bronchiolitis and 16% have the diagnosis of pneumonia. the median length of time intubated for an acute pulmonary infection leading to respiratory failure is approximately 7 days. viral bronchiolitis remains the leading cause for hospital admission in infancy and the most frequent cause of acute respiratory failure in children admitted to pediatric intensive care units in north america. pneumonia in children younger than 5 years of age has an annual incidence karen s. powers of 34-40 cases per 1,000. community acquired pneumonia can also lead to severe respiratory compromise especially in children with pre-existing disease. a detailed understanding of the diverse etiologies and distinct clinical courses of acute pulmonary infections is essential for the pediatric critical care practioner. this chapter will focus on bronchiolitis and pneumonia as the two leading causes of pulmonary infections leading to picu admission. approximately one third of children develop bronchiolitis during the fi rst 2 years of life. of these, only 1 in 10 (3% of all infants in the united states) will require hospitalization. although hospitalization rates have increased over the last three decades, mortality remains low. overall mortality rate is 1-2%, but as high as 5% in high risk infants. most deaths occur in infants younger than 6 months of age with co-morbidities such as prematurity, congenital heart disease, congenital or acquired lung disease or immunodefi ciency. respiratory syncytial virus (rsv) was fi rst isolated in 1957 and still represents the major cause of bronchiolitis. other causative viruses include parainfl uenza, adenovirus, enterovirus, infl uenza and most recently human metapneumovirus and human bocavirus (hbov). in the northern hemisphere, rsv outbreaks occur from october to june. human metapneumovirus (hmpv) recently has been identifi ed as the causative agent in 3-19% of bronchiolitis cases, possibly surpassing parainfl uenza as the second most common etiology. its prevalence is slightly higher in the late winter and spring. parainfl uenza infections peak at 10 months of age, representing approximately 7-10% of cases of bronchiolitis. parainfl uenza (piv-3) is endemic throughout the year, but especially common in the late spring. males are 1.5-2 times more likely to require hospitalization for bronchiolitis and are likely to have more severe disease. an x-linked genetic trait that results in a reduced tolerance to hypoxia has been postulated and would be consistent with the observation of increased mortality in newborn males with infant respiratory distress syndrome. virtually all children by the age of two will have been infected with rsv, all children by the age of fi ve will have been infected with hmpv, and all children by the age of nine will have been infected with hbov. the remainder of the discussion on bronchiolitis will be divided into rsv and non-rsv bronchiolitis. although etiologic agents may differ, clinical courses are often similar. respiratory syncytial virus (rsv) accounts for 50-80% of bronchiolitis, infecting one-half of all infants within the fi rst year of life and hospitalizing approximately 120,000 infants yearly (about 3% of affected infants). approximately 10% of these infants require mechanical ventilation. co-infection with either hmpv or rhinovirus occurs in 10-30% of young children. two types of rsv exist -types a and b. type a is more common and is believed to cause more severe disease, although data is not conclusive. both types may exist simultaneously in the community. infants less than 1 year will typically shed the virus for about 9 days. children with immunodefi ciencies may shed the virus for months. the immune response varies with age and contributes to both termination of the disease and its pathologic features. the virus is transmitted from respiratory secretions by close contact with infected persons or by contact with contaminated objects or surfaces. there is a 45% rsv transmission rate within families and about one-half of hospital workers will acquire rsv. therefore, hand washing and the wearing of gowns and gloves is of primary importance to attenuate transmission. mortality from rsv bronchiolitis continues to decline with better intensive care and the use of preventive therapies. male infants are more likely to require hospitalization and usually manifest more severe disease. about ½ of all infants will be infected with rsv bronchiolitis in their 1st year of life; 3% will be hospitalized; 10% of hospitalized infants will require mechanical ventilation. antibody-mediated immunity rsv introduced onto the nasal or conjunctival mucosal surface causes profuse rhinorrhea within a few days. during the fi rst 2 months of life, passively acquired maternal antibodies are protective. however, as maternal antibody titers gradually decrease, infants become susceptible to severe disease. cell-bound iga may develop to help clear the virus. circulating igg directed against the glycoprotein (g) and fusion (f) proteins (operative in syncytia formation) on the viral surface will develop several days later. infants less than 3 months of age appear to induce a weaker antibody response likely due to the presence of maternal antibodies. virus-specifi c ige in the respiratory tract is associated with disease severity. often, complete and effective immune responses are not induced, thus re-infections are possible even during the same season. epithelial cells and alveolar macrophages are key activators of cellular immunity. although these cells enhance viral clearing, they also contribute to airway infl ammation through the release of cytokines and chemokines. these include interleukin (il)-1, tumor necrosis factor-alpha, il-6, il-8, macrophage-infl ammatory protein (mip)-1-alpha and rantes (regulated upon activation, normal t cell expressed and secreted). release of these cytokines and chemokines are believed to be partially responsible for airway infl ammation and hyperreactivity. the effects of these mediators persist beyond the acute infection and contribute to prolonged pulmonary dysfunction. children who require mechanical ventilation have lower peripheral t cell counts compared to hospitalized infants not requiring mechanical ventilation. these infants demonstrate low t cell proliferative responses and interferon (ifn-g ) production. il-12 is required for the initiation of cellular immunity. the length of time requiring mechanical ventilation has been found to be inversely related to il-12 production. the role of th1/th2-like cytokine profi les, expressed as ifn-g /il-4 ratios, is controversial. in some studies, these ratios decreased after polyclonal stimulation in hospitalized infants with rsv. however, more recent studies have shown normal ratios following polyclonal stimulation. neutrophils are the predominant cell found in the airways of infants with rsv bronchiolitis. elevated levels of il-8 are found in high concentrations in the nasal secretions of infected children and act as a neutrophil chemoattractant. further evidence of cellular induced injury is seen in post-mortem examination where peribronchial lymphocyte infi ltration with bronchial epithelial necrosis is typically present. infants typically present with tachypnea, rhinorrhea, cough, low-grade fever, irritability, poor feeding and vomiting. respiratory rates greater than 60 breaths per minute are often associated with room air saturations of less than 96%. infants may also have tachycardia, mild conjunctivitis, otitis media, or pharyngitis. low-grade fever usually persists for 1-3 days. in addition, infants may develop a metabolic acidosis from poor caloric and fl uid intake. apnea often is the fi rst presenting symptom of rsv bronchiolitis in small infants. the etiology of apnea remains unknown; however, is likely related to the immaturity of the respiratory control center in the brainstem. the incidence of apnea in infants with bronchiolitis is approximately 16-20%. the heterogeneous nature of rsv induced lung disease can cause atelectasis in some areas and overdistension in others. chest roentgenograms often show hyperinfl ation with fl attening of the diaphragms and patchy or peribronchial infi ltrates. atelectasis, especially of the right upper lobe, is often seen. infants may have high lung volumes with the functional residual capacity often being twice normal. the decrease in dynamic compliance and increase up regulation of the infl ammatory cascade with release of chemokines and cytokines are contributory to the airway infl ammation and hyperreactivity. c hapter 25 • ac ute pu lmonary i n fections in airway resistance leads to marked increase in work of breathing, often worse during expiration from lower airway obstruction. alterations in gas exchange and hypoxemia are secondary to a ventilation-perfusion mismatch. the anatomical differences between young infants and older children contribute to the severity of the disease in the young. due to the highly compliant cartilaginous chest wall and poor thoracic musculature, the infant's chest wall has diffi culty countering the lung's inherent tendency towards collapse. this leads to a greater propensity of small infants towards atelectasis compared with older children. the absence of effective collateral ventilation in infants also contributes to the development of atelectasis and impaired gas exchange. cellular debris in small airways and peribronchial edema increase airways resistance leading to wheezing as the predominant symptom in some infants. despite the potential for severe impairment in lung function, most hospitalized infants improve within 3-5 days. typically, by 2 weeks, they have normal respiratory rates, oxygenation, and ventilation. chest radiographs usually normalize by day 9. however, about 20% of infants will have a protracted course, with some mild respiratory symptoms persisting for months. viral respiratory infections have been linked to the development of asthma later in childhood. the tucson children's respiratory study group prospectively followed for 13 years, 880 infants who had bronchiolitis and found an increased risk for subsequent wheezing episodes. some infants are at an increased risk for severe rsv disease such as those with chronic lung disease due to prematurity (bronchopulmonary dysplasia), cystic fi brosis, congenital heart disease, and immunodefi ciencies. in children with cystic fi brosis, rsv accounted for 18% of symptomatic infections, 33% of hospitalizations for infants less than 1 year, and 43% of infants requiring mechanical ventilation. in a study of hospitalized infants with congenital heart disease infected with rsv, 33% required intensive care, 19% received mechanical ventilation, and 3.4% died. children having undergone hematopoietic stem cell transplants who develop rsv infections have an extremely high mortality of 60-80% despite mechanical ventilation and antiviral therapy. environmental factors such as crowding, passive exposure to tobacco smoke, and lack of breast-feeding are associated with the development of severe disease. compared to national averages, native american and alaskan children younger than 1 year of age have higher rates of infections. there are three subtypes of human parainfl uenza viruses. hpiv-3 is most frequently isolated from children with bronchiolitis, while piv-1 and piv-2 most commonly cause croup. similar to rsv, both cell-mediated hyper-responsiveness to viral antigen and virus-specifi c ige responses are observed in children with parainfl uenza bronchiolitis. upper airway edema with concomitant obstructive symptoms may be present. children that are infected with parainfl uenza have a signifi cant likelihood of developing asthma later in life. the human metapneumoviruses (hmpv) are a group of rna viruses of the paramyxoviridae family identifi ed in humans in 2001. hmpv appears to be the second most common cause of bronchiolitis in children throughout the world. the majority of children are born with maternal hmpv specifi c igg which wanes to around 25% by 6-12 months of age. by age fi ve, essentially 100% of children have been exposed to hmpv and will have neutralizing antibody to hmpv. there are two subgroups, a and b, with group a having more severe clinical symptoms. clinical presentation of children with this virus is similar to rsv. the pulmonary infl ammation generally peaks on day 5 which includes interstitial edema and infl ammatory cell infi ltrates of the bronchioles and alveoli. these infl ammatory changes can persist for up to 21 days. about half of infected children are 0-12 months of age, and infection is primarily in the winter months. human bocavirus (hbov) was recently discovered in 2003. with amino acid sequencing, this new member of the parvoviridae family was found to be closely related to the bovine parvovirus and the canine minute virus, hence the name bocavirus (bo for bovine and ca for canine). detection of the hbov from the respiratory tract in symptomatic children and its absence of detection in non-symptomatic controls strongly suggest the virus to have a role in respiratory infections in children. co-infection is commonly described in up to 60% of samples. it remains unclear if hbov is a primary pathogen or acts to exacerbate other viral illnesses. the pathogenesis of hbov has not been well described, but with the high occurrence of wheezing and lower respiratory tract symptoms in children infected with the virus, it is speculated that this virus may be a signifi cant contributor to asthma exacerbations. the majority of infected children have rhinorrhea, cough, and wheezing, however, diarrhea has been reported in up to 25% of these children. in children with high viral loads, hbov has been detected in the serum suggesting the potential for disease beyond the respiratory tract. both infl uenza a, including novel infl uenza strains such as h1n1, and infl uenza b can cause a clinical picture consistent with bronchiolitis in the small infant. these viruses may cause severe multisystem disease and are discussed in greater detail in the viral pneumonia section. rapid diagnostic assays are available for early detection of many viruses. the older assays are antigen-based and include indirect immunofl uorescence/direct immunofl uorescence (ifa/ dfa), enzyme immunoassay (eia), optical immunoassay (oia), and neuraminidase activity assays. although still widely used because they are inexpensive and technically simple, they have a low specifi city and sensitivity. molecular assays are becoming the new "gold standard" for respiratory virus detection -replacing tissue culture that may take days. the published sensitivities and specifi cities approach 100% when compared to tissue culture or antigen assay. these assays generally use polymerase chain reaction (pcr) amplifi cation. signifi cant advancements in these assays are being made to simplify the performance of the assay and decrease the required time. the most important cause of false negative test results remains poor specimen handling or inadequate sample collection. other than aiding with cohorting of hospitalized patients, serologic detection of respiratory viruses is rarely clinically useful. regardless of the viral etiology of bronchiolitis, supportive care remains the mainstay of treatment. supplemental humidifi ed oxygen is frequently needed. due to many infants being obligate nasal breathers, frequent nasal suctioning may be benefi cial to maintain an unobstructed upper airway. the affected infant or child is often unable to take adequate fl uids complicated by increased insensible losses from the respiratory tract; hence, intravenous fl uids may be required. infants and children with severe respiratory distress should be kept npo in the event respiratory failure ensues and endotracheal intubation is required. antibiotics are not routinely indicated in previously healthy children infected with rsv. progressive disease, leukocytosis, persistent fever, consolidation on radiograph or systemic toxicity should prompt an evaluation of bacterial co-infection and the use of empiric antibiotics. high risk patients often require close monitoring and care in an intensive care unit. these include infants less than 6 weeks of age or infants with a history of prematurity, congenital heart disease, bronchopulmonary dysplasia, immunodefi ciency or neurologic disease. infants with rsv bronchiolitis typically have a combination of hyperinfl ation, pulmonary infi ltrates, supportive therapy is the mainstay of treatment for bronchiolitis. ribavirin, bronchodilators, and corticosteroids have not shown to be of benefi t. secondary bacterial infections are rare. and atelectasis. therefore, no one mode of ventilation can be recommended for all infants. non-invasive positive pressure (niipp) modes (cpap or bipap) may be attempted in infants where their primary respiratory embarrassment is secondary to atelectasis. however, this may not be suitable if the disease process appears severe or protracted as prolonged use of nipp may make feeding diffi cult, cause breakdown of facial tissue, or be diffi cult to maintain without signifi cant sedation that further compromises ventilation. if an infant requires endotracheal intubation, the mode of mechanical ventilation should be tailored to the predominant lung pathology present (i.e. atelectasis versus hyperinfl ation). children with signifi cant air trapping may need mechanical ventilation similar to a child with asthma, providing low respiratory rates and longer inspiration and exhalation times. the more typical infant will lose functional residual capacity (frc) because of atelectasis and alveolar infi ltrates. therefore, despite having some air trapping, these infants often need peep to be adjusted to recruit alveoli and return frc to normal. in the setting of elevated pulmonary vascular resistance (pvr) which may occur in infants with congenital heart disease or bronchopulmonary dysplasia, lowering pvr by traditional methods such as maintaining oxygenation, deep sedation, muscle relaxation and even nitric oxide may be indicated. ribavirin is the only fda-approved antiviral drug for rsv. ribavirin inhibits viral replication and is active against rsv, infl uenza a and b, adenoviruses, and hepatitis viruses. for lower respiratory tract diseases, ribavirin is typically administered via aerosolization. in 1996, a meta-analysis of studies involving ribavirin was discouraging and was consistent with the common clinical experience that ribavirin did not improve clinical outcomes. therapy targeted at attenuating the virus-induced infl ammatory cascade has also been disappointing. corticosteroid administration was not associated with reduction in clinical scores, the need for hospitalization, or the length of hospitalization. routine use of any corticosteroid given via any route (intravenous, enteral or aerosolized) is not indicated, except in patients with pre-existing chronic lung disease. bronchodilators have not shown a clear benefi t in patients with acute rsv bronchiolitis. in 12 randomized control trials, involving 843 infants, evaluating the effect of salbutamol or albuterol on bronchiolitis, 9 (75%) showed no effect. the remaining three studies demonstrated only a small transient improvement in the acute clinical score. although the routine use of bronchodilator therapy cannot be recommended, it has become acceptable practice to attempt to see if individual infants are beta agonist responsive or not. if no clinical response is seen after a trial of a beta agonist, its use should be discontinued. in the 1990s, fi ve randomized trials involving 225 infants, evaluating the effect of nebulized adrenaline (epinephrine) on bronchiolitis showed clinical improvement, with reductions in oxygen requirement, respiratory rate, wheezing, and decrease in pulmonary vascular resistance. two of these studies showed lower hospital admission rates and earlier discharge. a 2004 cochrane systematic review suggested a potential benefi t with epinephrine administration. however, subsequent studies have not supported its routine use. as with albuterol, a clinical trial in selected infants seems reasonable. nebulized hypertonic saline has been used for treating hospitalized, as well as ambulatory, children with viral bronchiolitis with variable success. a recent cochrane meta-analysis of nebulized hypertonic saline has shown an improvement in clinical scores and decrease in hospital duration. several studies have evaluated the benefi t of surfactant and nitric oxide for severe respiratory distress. the results have been inconclusive and do not currently support their routine use. heliox, a mixture of oxygen (20-30%) and helium (70-80%) with lower viscosity than air has been used successfully in cases of airway obstruction, croup, airway surgery, and asthma to reduce respiratory effort during the period of airway compromise. several studies have shown improved respiratory distress scores in patients on heliox with continuous positive airway pressure obviating the need for intubation and mechanical ventilation. palivizumab is a neutralizing humanized mouse monoclonal antibody directed against the rsv-f glycoprotein. it was licensed by the food and drug administration (fda) in 1998 for premature infants and infants with bronchopulmonary dysplasia. the randomized, double blind, placebo controlled impact-rsv trial involving 1,502 high risk infants found a signifi cant reduction of 55% in hospitalizations. with the exception of very rare anaphylaxis, no signifi cant adverse effects have been observed. palivizumab has been approved for use in infants with congenital heart disease. the cardiac synagis study group included 1,287 children with congenital heart disease in a randomized, double blind, placebo controlled trial; it found a 45% relative reduction in rsv associated hospitalizations with no deaths attributable to the palivizumab. since cardiopulmonary bypass can decrease serum drug concentrations by about 58%, it is recommended that an additional dose be given following surgery, if continued protection is desired. palivizumab should be administered intramuscularly as 15 mg/kg every 30 days for a total of fi ve doses during rsv season, which is generally from november through march, to high risk infants. infants or children that develop an rsv infection should continue to receive prophylaxis following recovery because the naturally acquired antibodies are not fully protective. motavizumab, a new, enhanced potency, humanized rsv monoclonal antibody has demonstrated 50-100 times greater neutralizing activity against rsv. in completion of a phase iii trial, motavizumab was found equal to palivizumab for the prevention of rsv hospitalization and superior to palivizumab for reduction of rsv-specifi c outpatient medically attended lower respiratory tract infections (malris). pneumonia describes any infl ammatory condition of the lung in which the alveoli are compromised by aspirated foreign matter, infl ammatory fl uid, or cellular debris. infection is the primary cause of parenchymal injury to the lung. pathogens include viruses, bacteria and fungi. signs and symptoms of pneumonia are non-specifi c and may be occult in the young infant. children often have fever, chills, headache, malaise, restlessness, and irritability. gastrointestinal complaints such as abdominal pain, distention, or emesis may also be present in young children. the symptoms are often preceded by minor upper respiratory tract infections characterized by low-grade fever and rhinorrhea. with more signifi cant involvement of the lower respiratory tract, tachypnea, dyspnea, cough, nasal fl aring, grunting, or retractions may be seen. the older child may demonstrate productive sputum and complain of pleuritic chest pain. on auscultation of the chest, rales and/or decreased breath sounds might be heard over areas of consolidation or pleural effusions. however, due the short path for transmission of breath sounds and the small chest size in infants, breath sounds may not be decreased, even in the presence of effusions. children with pleural irritation might prefer to lie on the affected side with legs fl exed and may complain of radiating pain to the neck and shoulder or into the abdomen. community acquired pneumonia (cap) is a common, and at times, a serious infection in children. the incidence of cap is 35-40 cases per 1,000 children less than 5 years of age and 11-16 cases per 1,000 children 5-14 years of age. the exact prevalence of the etiologic agents causing pediatric pneumonia is diffi cult to ascertain. it is often diffi cult to differentiate viral from bacterial pneumonia based solely on clinical examination. specifi c pathogens causing cap can be determined in only approximately one-third of children using commonly available cultures, antigen detection, or serologic techniques. blood cultures yield pathogens in only about 10-15% of infants and children with bacterial cap and many children do not undergo viral testing as it is often unnecessary. with these inherent limitations, it is generally thought that viruses account for approximately 80% of cap in children under the age of 2 years and approximately 50% of cap in preschool children ages 2-5 years. palivizumab should be used as preventive therapy in infants with chronic lung disease and congenital heart disease. cardiopulmonary bypass signifi cantly lowers the serum level of palivizumab, so it should be redosed following surgery if continued protection desired. viral causes decline in the school age and adolescent child and bacterial causes such as streptococcus pneumoniae and mycoplasma become important pathogens ( fig. 25-1 ) . overall, bacteria account for 20-30% of community-acquired pneumonias. the likelihood of infection with different bacteria varies by age. in the newborn period, organisms from the maternal genital tract are likely causes and include group b streptococcus , escherichia coli , enteric gram-negative bacilli, listeria , and chlamydia . in older infants, streptococcus pneumoniae becomes a signifi cant cause and remains so until 6 years of age. group a streptococcus and staphylococcus aureus are uncommon causes. moraxella catarralis is a common cause of upper respiratory tract disease, but rarely causes pneumonia. about 20% of infants with pertussis will have bacterial co-infection. in children older than 6 years of age, streptococcus pneumoniae remains the most common cause. hemophilus infl uenzae type b (hib), and most recently streptococcus pneumoniae , have decreased signifi cantly as causes of cap due to the widespread use of effective vaccines. in the older child and young adolescent, the atypical pneumonias, mycoplasma and chlamydia , become more prevalent and viral causes less common. rare bacterial pneumonias can occur with animal contact and include: francisella tularensis (rabbits); chlamydia psittaci (parrots and birds); coxiella burnetii (sheep); and salmonella choleraesuis (pigs). children with congenital anatomical defects, immunodefi ciencies, and genetic disorders are at increased risk for bacterial, viral and fungal pneumonia. the airways are normally sterile below the sublaryngeal area to the lung parenchyma. there are several protective mechanisms that include anatomic and mechanical factors, local immune defenses, and the systemic immune response. microbes are fi ltered by nasal hairs or are expelled from the airways by the epiglottic refl ex, cough refl ex, and mucociliary apparatus. immunoglobulin a (iga) is the predominant immunoglobulin present in the upper respiratory tract. iga is able to bind two antigens simultaneously, forming large antigen-antibody complexes. in this manner, the microbes are neutralized and removed by ciliary clearance, thus preventing microbial binding to the epithelium. in the lower tract, immunoglobulin g (igg) provides humoral protection by opsonizing microbes for phagocytosis by neutrophils and macrophages, activating the complement cascade, and by neutralizing bacterial it is diffi cult to determine the etiologic agent causing pneumonia, but when microbial agents are identifi ed, bacteria are isolated in 20-30%. etiology of community acquired pneumonia based on age endotoxin. alveolar macrophages produce superoxide anions, hydrogen peroxide, and hydroxyl radicals that serve an important role in the host defense; however, uncontrolled production can lead to lung injury. in addition to oxygen radicals, a number of cytokines are produced by the alveolar macrophages. these include il-1, il-6, tnf, transforming growth factor-β (tgf-b ), chemotactic factors, platelet derived growth factor, and m-csf. these cytokines play a central role in phagocytic recruitment and activation. infection occurs when one or more of the defense mechanisms is altered or if the inoculum is too large. pathogens typically gain entry through inhalation of aerosolized material or through aspiration of resistant organisms inhabiting the upper airways. less frequently, pneumonia can occur via hematogenous spread. in children with bacterial pneumonia, a signifi cant portion will have a concurrent or preceding viral infection. viral infection may predispose to bacterial superinfection by reducing clearance mechanisms and by weakening the host immune response. pathogens entering the lower airways evoke an exudative consolidation of pulmonary tissues. initially, there is hyperemia of lung parenchyma due to vascular engorgement and capillary leak causing exudation and intra-alveolar fl uid accumulation. fibrin is then deposited and the airways are infi ltrated with neutrophils. consolidation causes a decrease in lung compliance and vital capacity and a total reduction in the surface area available for gas exchange. a physiologic shunt (v/q mismatch) occurs as there is increased blood fl ow through poorly ventilated segments of lung, resulting in hypoxia. compensatory hypoxic vasoconstriction may occur in an attempt to reduce v/q mismatch and hypoxia, especially in localized areas of consolidation. with treatment, resolution of consolidation will occur in 8-10 days. the exudate undergoes enzymatic digestion and is either reabsorbed or removed by coughing. if the bacterial infection extends into the pleural cavity, an empyema may result. streptococcus pneumoniae is a gram-positive diplococcus that is frequently found in the upper respiratory tract. there are over 80 capsular serotypes with 80% of infections caused by 14 serotypes. it is the most common bacterial cause for pneumonia occurring at a peak age of 13-18 months. typically, it causes a lobar or segmental consolidation, but it may manifest as patchy infi ltrates in infants. pleural effusions occur in up to 20% of children that require hospitalization (fig. 25-2 ) . pneumatocoele formation is rare. hemolytic uremic syndrome is associated with neuraminidase-producing strains. treatment is typically with a penicillin or cephalosporin. emerging resistance may require initial therapy with vancomycin. in hospitalized patients, parenteral therapy is generally needed for 48-72 h after fever resolves, followed by completion of 7-10 days of enteral therapy. pneumococcal conjugate vaccines (pcv) have been developed that confer immunity against 7 and 13 serotypes. the 7-valent pcv (prevnar) was licensed for use in the united states in 2000. a 13-valent pcv has been recently introduced and will replace the 7-valent pcv. the pcvs have been highly effective at reducing hospitalizations among children younger than 2 years for pneumococcal pneumonia. pcv is now recommended universally for children younger than 24 months of age and older children at high risk due to underlying diseases. high risk children include those with sickle cell disease and other types of functional asplenia, human immunodefi ciency syndrome, primary immunodefi ciency, children receiving immunosuppressive therapy, and children with chronic pulmonary or cardiac disease. a 23-valent pcv is available for pneumonia occurs when one or more of the host defense mechanisms are altered. viruses enhance the host susceptibility to bacterial pathogens by affecting clearing mechanisms and by weakening the host immune response. streptococcus pneumoniae is the most common bacterial cause for pneumonia. c hapter 25 • ac ute pu lmonary i n fections high risk children who need expanded serotype coverage. children with sickle cell disease or functional asplenia should continue to receive antibiotic prophylaxis regardless of whether or not they have received pneumococcal vaccines. approximately 50-75% of infants born to chlamydia trachomatis -infected mothers will become infected at one or more anatomical site, including conjunctiva, nasopharynx, rectum, and vagina. about 30% of infants with nasopharyngeal infections will develop pneumonia. the infants usually present at about 4-12 weeks of age with cough and congestion, but an absence of fever. the cough often interferes with the ability to feed. infants generally have tachypnea and rales on examination and chest x-ray frequently shows hyperinfl ation. a peripheral eosinophilia may be present. c . trachomatis is susceptible to macrolides, tetracyclines, quinolones, and sulfonamides. erythromycin for 2-3 weeks is the treatment of choice for neonatal pneumonia. mycoplasma pneumoniae and chlamydia pneumoniae play a greater role in causing respiratory tract disease in children then previously thought. an indolent course that develops over 5-7 days manifested by low-grade fever, scratchy sore throat, aches, and headaches characterizes both pathogens. after a few days, rales may be heard, particularly in the bases where the infi ltrates tend to occur. these organisms have been associated with the initiation, promotion, and exacerbation of asthma in children. in addition, a pertussis-like illness with acute bronchitis has been described. a recent study has shown that nearly half of the cases of community-acquired pneumonia in children aged 2-14 years were associated with m . pneumoniae or c . pneumoniae . classic atypical pneumonias caused by these organisms are usually mild and self-limited. however, a number of studies have suggested that severe pulmonary infection may occur in otherwise healthy children. pleural effusions, pneumatocoeles, lung abscesses, pneumothoraces, bronchiectasis, chronic interstitial fi brosis, and acute respiratory distress syndrome although rare complications, have all been reported. serological testing is the most common means of diagnosis, but this is often retrospective. cultures obtained from swabbing the nasopharynx may take several days to grow. pcr techniques are currently being refi ned and standardized. treatment with antibiotics reduces the rate of recurrent wheezing episodes, decreases morbidity, and shortens the duration of symptoms. the organisms are susceptible to tetracyclines, macrolides, and quinolones. the optimal doses and duration of treatment is unclear; however, some data suggest that prolonged treatment for greater than 2 weeks may be more desirable to decrease symptoms and eradicate the organism from the nasopharynx. chlamydia pneumoniae have an increased prevalence in older children. chest radiograph of 3 year old female with streptococcus pneumoniae pneumonia. note the combination of consolidation and effusion affecting the right lung. (image provided courtesy of fa maffei) staphylococcus aureus is a gram-positive organism that can be found on the skin, nasal mucosa, and other mucus membranes. about 20-30% of children are carriers. it is generally spread by direct contact or by respiratory particles. s . aureus is an unusual cause of lower airway disease in otherwise healthy children. it is more typically isolated from infants and young children with debilitating conditions. primary s . aureus pneumonia presents in the winter or early spring with a short febrile prodrome and a rapid onset of pulmonary symptoms. blood cultures are positive in 20-30% of patients. secondary staphylococcal pneumonia will have a more prolonged prodrome with no seasonal predilection, but is often seen after infl uenza infections. as this secondary pneumonia is usually a result of hematogenous spread, blood cultures are positive in about 90% of patients. unilateral lobar disease is more typical with primary disease, while diffuse bilateral infi ltrates are more frequent with secondary pneumonia. effusions can be diagnosed in about 15% of children at presentation, but ultimately will develop in about 75% of cases. pneumatocoeles occur in up to 45-65% of children. treatment is with nafcillin or oxacillin, but more organisms are becoming resistant and require therapy for serious or invasive disease with vancomycin, linezolid, daptomycin, or quinupristin-dalfopristin. methicillin resistant staphylococcus aureus (mrsa) was once considered to be restricted to hospitals and long-term care facilities. however, community acquired mrsa (ca-mrsa) is now a signifi cant cause of a variety of infections (including pneumonia) in children without prior health care facility exposure. the majority of community acquired mrsa infections involve minor skin and soft tissue infections, but invasive and sometimes fatal infections can occur in otherwise healthy individuals. ca-mrsa and healthcare-associated mrsa (ha-mrsa) can be distinguished by several important features. patients with ca-mrsa by defi nition have not had recent hospitalization (acute or chronic care), prolonged antibiotic use or chronic underlying disease. toxin production also distinguishes ca-mrsa from ha-mrsa. panton valentine leukocidin (pvl) is a toxin which is present in most ca-mrsa isolates, but rarely in ha-mrsa isolates. pvl toxin lyses white blood cells leading to leukopenia and a decreased ability to kill s . aureus . its production has been implicated as a contributor to the development of ca-mrsa necrotizing pneumonia. ca-mrsa isolates, unlike ha-mrsa, lack multi-drug resistance. ca-mrsa is generally more susceptible to clindamycin, trimethoprim-sulfamethoxazole and doxycycline than ha-mrsa, probably because ha-mrsa has developed resistance to survive in the healthcare setting. group a betahemolytic streptococcus (gabhs) is a gram-positive organism responsible for about 15% of pharyngitis and tonsillitis in children. it is rare as a primary cause of pneumonia. when it does occur, the children generally have high fever and appear toxic. the pneumonia is typically lobar. associated empyemas are common and pneumatocoeles may develop. there are several virulent toxin-producing gabhs m-serotypes that are associated with toxic shock syndrome. pre-existing varicella disease with disruption of skin and soft tissue as the port of entry is reported approximately 40-50% of the time. an associated pneumonia occurs in 10-20% of children with toxic shock syndrome. gabhs are highly susceptible to penicillins and cephalosporins. in cases of toxic shock, clindamycin is often added to inhibit the production of streptococcal pyrogenic exotoxins a (spe-a) and b (spe-b). about 30-40% of infants with perinatally acquired group b streptococcus (gbs) infections will have pneumonia. the infant usually has systemic disease and blood cultures are frequently positive. late-onset gbs is predominantly caused by the type iii serotype. in these infants, the infection is usually manifest as bacteremia without a focus or with meningitis. pneumonia is rare in late-onset disease. gbs is uniformly sensitive to penicillin. while staphylococcus aureus pneumonia is uncommon, effusions ultimately develop in about 75% of cases and pneumatocoeles occur in 45-60%. pertussis, or "whooping cough" is a highly contagious respiratory tract infection caused by the gram-negative pleomorphic bacillus bordetella pertussis and less commonly bordetella parapertussis . with the development and widespread use of a vaccine in the 1940s, a significant and sustained decrease in incidence has occurred. however, despite immunization rates greater than 80%, cyclical recurrences of the disease have occurred every 3-4 years since the 1980s. this is likely secondary to the waning of immunity in adolescents and young adults. under-immunized or unimmunized infants are the most vulnerable. nearly all deaths reported from pertussis occur in infants younger than 3 months of age. pertussis is often divided into catarrahal (fever, rhinnorhea and initiation of cough), paroxysmal (severe coughing episodes, lymphocytosis, potential for complications) and convalescent stages (slow waning of cough over weeks to months). complications include secondary bacterial or viral pneumonia, apnea, malnutrition, pulmonary hypertension and neurologic involvement including seizures and encephalopathy. infants less than 6 months of age are at highest risk for complications and mortality. characteristic paroxysms of cough with an end inspiratory whoop occur in children. infants may present with a nonspecifi c cough with associated apnea and cyanosis, without a whoop. adolescents may be asymptomatic or have only a mild prolonged cough. an increased white blood count up to 100,000 with a lymphocytosis is characteristic early in the course of the disease. the preferred test for laboratory confi rmation is the detection of b. pertussis dna by pcr assay. bacteriologic culture provides a defi nitive diagnosis. if administered during the early stages of the disease (fi rst 7-10 days of illness), erythromycin for 14 days may decrease symptoms and reduce the risk of spread. a 5 day course of azithromycin or a 7-10 day course of clarithromycin has been found to be as effective with less gastrointestinal symptoms. corticosteroids, bronchodilators, or intravenous immunoglobulins have not demonstrated effi cacy. supportive care with supplemental oxygen, mechanical ventilation, intravenous fl uids, maintenance of adequate caloric intake, and treatment of secondary bacterial infections are the mainstay of therapy. the use of extracorporeal membrane oxygenation in infants with hypoxemia, pulmonary hypertension and right heart failure refractory to conventional mechanical ventilation has resulted in poorer outcomes than expected. vaccination in infancy with booster doses in adolescence is preventative. about 80-85% of pneumonias in children are caused by viruses. there is considerable evidence that viral infections often precede bacterial pneumonias and cause weakening of the host defenses. viral pneumonias with rsv and parainfl uenza are discussed in more detail in the bronchiolitis section. infl uenza is the main viral cause of pneumonia in school-aged children requiring hospitalization. there are three serotypes, a, b, and c which are further divided into subtypes based on the hemagglutinin and neuraminidase genes. hemagglutinin 1, 2, and 3 and neuraminidase 1 and 2 typically infect humans. the gene segments for the surface glycoproteins are unstable, so mutations, called antigenic shift, occur regularly. epidemics occur annually during the winter months with a short, 1-3 day incubation period. the virus causes destruction of the ciliated respiratory epithelium within 1 day of symptoms. airway edema and infi ltration with infl ammatory cells into the airway mucosa and epithelium follows. slow repair occurs over 2-4 weeks. a severe fulminating pneumonia may result in hemorrhagic exudates that contain many polymorphonuclear and mononuclear cells. destruction of the respiratory epithelium often leads to secondary bacterial infections. during the 2003-2004 infl uenza season, 143 infl uenza-related deaths occurred in children; of these, 41% were less than 2 years of age. forty-fi ve percent of the older children (2-17 years of age) did not have an underlying medical condition. rare complications of although death from infl uenza pneumonia is uncommon, a signifi cant number of the children that died were previously healthy. infl uenza include acute myositis, rhabdomyolysis, myocarditis, pericarditis, reye syndrome, encephalitis, transverse myelitis, and guillain-barré syndrome. children may present with an abrupt clinical course manifested by high fever, myalgias, headaches, scratchy sore throats, and dry cough. peripheral white blood counts are usually less than 5,000. pulmonary infi ltrates often involve multiple lobes. bacterial co-infection, especially with mrsa, increases morbidity and mortality signifi cantly. rimantidine and amantadine can shorten the course for infl uenza type a disease by limiting viral replication, but only if given within the fi rst 48 h of the disease. prophylactic dosing is 70-90% effective and does not interfere with antibody production from the vaccine. both drugs have central nervous system and gastrointestinal side effects, including an increase in the incidence of seizures. oseltamivir and zanamivir have recently been approved for the treatment of infl uenza infections in children. they inhibit neuraminidase, an enzyme produced by infl uenza a and b. the course of disease in healthy adults can be reduced by 1-2 days, if started within 48 h of the onset of symptoms. zanamivir is a dry powder aerosol that must be delivered by a special breath-activated device. bronchospasm in patients with asthma has been reported. aspirin or aspirin-containing products should be avoided due to the risk of reye syndrome. immunoprophylaxis is the most effective strategy for the prevention of infl uenza infection. inactivated vaccines have effi cacy rates from 70% to 90%. currently, the inactivated vaccine is recommended for all children older than 6 months of age with high risk conditions including chronic pulmonary or cardiac disease, immunosuppressive disorders, sickle cell disease and other hemoglobinopathies, diseases requiring long-term aspirin therapy, chronic metabolic and renal diseases; healthy children aged 6-23 months; and household contacts over the age of 6 months of high risk persons. a live, attenuated infl uenza vaccine was licensed in 2003. it is administered by the intranasal route and is approved for healthy children aged 5-17 years. avian infl uenza viruses do not normally infect species other than birds and pigs. however, in 1997, the fi rst human death from avian infl uenza occurred in hong kong in a 3 year old with reye syndrome. subsequently, an epidemic occurred among humans in hong kong with close contact to live, infected poultry. the subtype h5n1 appears to be the most ominous due to its ability to rapidly mutate and infect new species. the overall mortality rate is greater than 70%. the avian viruses are not believed to be transmissible from person-to-person, but some recent cases are being investigated for this possibility. children uniformly present with fever and cough. symptoms range from typical infl uenza-like symptoms to conjunctivitis to respiratory disease and failure. signifi cant laboratory data include leukopenia and thrombocytopenia. all children who developed pneumonia and progressed to ards died. diagnosis remains diffi cult, as no tests are widely available. of the antiviral drugs available for infl uenza a, the most recent h5n1 strains in southeast asia are resistant to rimantadine and amantadine. therefore, treatment is mainly supportive. a prototype h5n1 vaccine was made available to manufacturers in april 2004, but production is diffi cult because the standard means of producing infl uenza vaccines from specially grown chicken eggs is not feasible. h5n1 kills the embryo before enough viruses can be harvested for vaccine production. in april, 2009, the centers for disease control confi rmed the emergence of a novel infl uenza a (h1n1) virus with genes from swine viruses of the eurasian lineage and genes from avian infl uenza viruses. by june, 2009, the fi rst infl uenza pandemic since 1968 was declared, affecting over 191 countries and territories. in comparison to illnesses with seasonal infl uenza, the majority of cases occurred in individuals younger than 65 years of age, with nearly half of the cases occurring in children under 18 years of age . the clinical symptoms can be typical for infl uenza; fever, sore throat, cough, and muscle aches with the addition of vomiting and diarrhea in children. a wide range of complications although antiviral medications may attenuate the course of infl uenza when given early, immunoprophylaxis with vaccines is the most effective strategy for the control of infl uenza infections. avian infl uenza has occurred in epidemics among persons with close contact to live, infected poultry. all children with pneumonia that progressed to ards succumbed to the disease. have been reported that include mild-to-moderate (otitis media, sinusitis, myositis, and febrile seizures) to more severe complications such as myocarditis, rhabdomyolysis or encephalitis. severe complications may frequently involve invasive bacterial co-infection (i.e. mrsa) and/or exacerbation of underlying medical conditions in particular asthma. children who present initially with uncomplicated infl uenza may have rapidly progressive hypoxemic respiratory failure and multiorgan system dysfunction that is refractory to all therapies ( fig. 25-3 ) . of reported h1n1 deaths, approximately 20% were in children. the majority of these children had comorbid asthma, neuro-developmental conditions, or obesity. an american academy of pediatrics work group identifi ed children at greatest risk for life-threatening h1n1 infl uenza disease (table 25-1 ) . the centers for disease control has recommended prompt empiric antiviral therapy for infants, children, and adolescents of any age presenting with suspected or confi rmed h1n1 infl uenza and any of the following conditions: illness requiring hospitalization ■ progressive, severe, or complicated illness, regardless of previous health ■ presence of signifi cant risk factors (see table ■ 25-1 ) the h1n1 strain has been found to be resistant to amantadine and rimantadine, but is usually sensitive to neuraminidase inhibitors, specifi cally oseltamivir or zanamir. in 2009, oseltamivir was emergently approved for treatment in children less than 12 months of age. resistance to oseltamivir has been reported and is thought due to the h275y mutation. interestingly, the mutation confers resistance to oseltamivir, but not to zanamivir. peramivir, a neuraminidase inhibitor, an unapproved (investigational) antiviral available in an intravenous formulation received an emergency use authorization permit from the fda for use in children with confi rmed severe refractory h1n1 infl uenza. its use should be restricted to children that are not responding to either oral or inhaled antiviral drugs or if the parenteral route is the only dependable method of drug delivery. a vaccine was manufactured and licensed using the same standards as seasonal infl uenza by late 2009. a single dose was found to provide adequate protection in children older than 10 years of age, younger children requiring two doses separated by at least 21 days. adenoviruses have been implicated in 4-10% of pneumonias in children. adenoviruses are classifi ed into 49 serotypes with types 3, 7, 7a, 11, and 21 being the most common etiologic agents of lower respiratory disease and causing a severe necrotizing pneumonitis. these serotypes are associated with serious pulmonary sequelae, such as bronchiectasis, bronchiolitis obliterans, unilateral hyperlucent lung, and persistently abnormal pulmonary function tests. adenovirus infections peak between 6 months and 5 years of age. mortality from severe respiratory infections can be high, because the disease often involves multiple organ systems. survivors may have permanent lung injury often in the form of bronchiolitis obliterans. in the immunocompromised host, mortality rates are as high as 50-80%. cidofovir has in vitro activity against adenovirus, but proof of effi cacy is limited. therapy is supportive. severe acute respiratory syndrome is a newly described pulmonary infection caused by a novel sars-associated coronavirus. sars-cov is highly contagious and was coined "the fi rst plague of the twenty-fi rst century". the disease rapidly spreads among household contacts and healthcare personnel. children less than 18 years of age account for only approximately 5% of those affected, with a mean age of 12 years. no deaths were reported among children in the 2003 outbreak. children and adults present with fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leukopenia, lymphopenia, thrombocytopenia, mildly elevated activated partial thromboplastin times, and elevated levels of lactate dehydrogenase. radiographs of the chest show non-specifi c infi ltrates. apart from diarrhea, patients have minimal extrapulmonary symptoms. early diagnosis by reverse transcription-polymerase chain reaction (rt-pcr) can be made with 80% sensitivity on nasopharyngeal aspirates within the fi rst 3 days of the illness. the clinical course follows a triphasic pattern. there is an incubation period of 2-10 days with a prodrome of high fever, chills, malaise, headache, and myalgias. diarrhea occurs in up to 20% of adults. after 2-7 days, the disease progresses to involve the lower airways with a dry non-productive cough and dyspnea. in 10-20% of cases, acute respiratory distress syndrome (ards) follows and often patients require mechanical ventilation. deaths occur from respiratory failure. young children run a milder and shorter biphasic clinical course. cough is found in approximately half the children, and crackles are rarely heard despite radiographic evidence of infi ltrates. a regimen of antibiotics, ribavirin, and corticosteroids was proposed based on initial anecdotal success. however, ribavirin has demonstrated minimal activity against sars-cov isolates in vitro . non-randomized studies of corticosteroids have reported favorable outcomes. a pediatric series of 44 children with confi rmed sars treated with ribavirin and corticosteroids showed no adverse effects and all survived. mortality from adenovirus infections remains high because of multiple organ system involvement. sars rarely affects children, and when it does, morbidity is less, with no reported mortalities. 1. neurological disorders, such as epilepsy, cerebral palsy, developmental delay and neuromuscular disorders 2. chronic respiratory diseases associated with impaired pulmonary function and/or diffi culty handling lung secretions, moderate and especially severe persistent asthma, technology-dependent children (e.g., those requiring oxygen, tracheostomy, or a ventilator) 3. primary immunodefi ciencies or conditions that require medications or treatments that result in secondary immunodefi ciencies 5. congenital heart disease 6. metabolic (e.g., mitochondrial) or endocrine disorders, especially if cardiopulmonary function is impaired adapted from http://www.aap.org/new/swinefl u.htm hantavirus cardiopulmonary syndrome is a viral zoonotic disease that affects healthy children and adolescents who are exposed to aerosols of rodent excreta. the deer mouse is the main rodent reservoir. most cases occur in the southwestern united states, but cases have been confi rmed in 30 states. hcps presents with a prodrome of fever, chills, myalgia, headache, and gastrointestinal symptoms. respiratory compromise requiring supplemental oxygen generally occurs within 72 h. the disease can progress to respiratory distress and ards. the majority of deaths result from hypoxemia and cardiac dysfunction with marked hypotension and ventricular arrhythmias. in adults, the case fatality rate is approximately 38%. a recent case series of 13 children aged 10-16 years, revealed that 92% of infected children developed hcps, 33% died, and 67% were critically ill and required mechanical ventilation. treatment is supportive as ribavirin has not been proven to reduce mortality. extracorporeal membrane oxygenation was used on two patients, one of which survived. laboratory evaluation reveals thrombocytopenia, leukocytosis, and circulating immunoblasts. an elevated prothrombin time of ³ 14 s is predictive of severe disease. no deaths were reported in children younger than 14 years of age. diagnosis can be made by detection of hantavirus-specifi c immunoglobulin m, hantavirus-specifi c rna by polymerase chain reaction, or hantavirus antigen by immunohistochemistry. respiratory infections in children with primary or acquired immunodefi ciencies requiring intensive care are not uncommon. these infants and children are susceptible to many organisms that are rarely pathogenic in a normal host. primary immunodefciencies include abnormalities or defi ciencies in immunoglobulins and antibodies, t and b cells, phagocytes, natural killer cells, and complement. acquired immunodefi ciencies include asplenia, human immunodefi ciency virus (hiv), corticosteroid therapy, and immunosuppresion used for marrow or solid organ transplants. immunocompromised children can present with attenuated signs and symptoms of respiratory infections. in addition to physical examination and chest roentgenograms, these children often require chest computed tomography to better delineate the extent of disease. bronchoalveolar lavage, needle aspiration, or lung biopsies might be required to make a defi nitive diagnosis. pulmonary specimens should be tested for common bacteria as well as for pneumocystis carinii, acid-fast bacilli, nocardia, legionella, crytococcus, aspergillus, candida, histoplasma, coccidioides, and blastomyces. viruses such as cytomegalovirus, varicella, herpes virus, and measles should be considered. pneumocystis carinii (now known pneumocystis jiroveci ) is an opportunistic pulmonary pathogen in infants and children with human immunodefi ciency virus (hiv) and other primary immunodefi ciencies, malnutrition, hematological malignancies, solid organ and bone marrow transplant recipients, and patients on high dose corticosteroid therapy for infl ammatory and collagen-vascular diseases. it is a unicellular organism that exists as a cyst (the diagnostic form). the organism attaches to the type i alveolar cells resulting in an alveolitis characterized by ventilation-perfusion mismatch and decreased pulmonary compliance. if untreated, pcp carries a mortality rate of 25-50%, and nearly 100% in the hiv-seropositive child. fortunately, the incidence has markedly decreased with the administration of chemoprophylactic agents to high risk patients. children typically present with fever, tachypnea, non-productive cough, and hypoxia with an absence of rales on auscultation of the chest. initially, they may have an elevated ph and low carbon dioxide levels. lactate dehydrogenase levels are generally elevated. bilateral diffuse alveolar infi ltrates are seen with initial hilar involvement subsequently spreading to the periphery (fig. 25-4 ) . diagnosis is made by demonstrating the organism with the methenamine silver nitrate stain on pulmonary tissue, respiratory secretions, or lung fl uid. bronchoalveolar lavage is the most widely used technique to obtain lung fl uid for diagnosis. treatment consists of supportive therapy hantavirus is rare in infants and school-aged children. no deaths have been reported in children less than 14 years of age. with supplemental oxygen; ultimately continuous positive airway pressure or mechanical ventilation may be necessary if respiratory failure occurs. trimethoprim-sulfamethoxazole (tmp-smx) is the recommended initial treatment. in patients that cannot tolerate tmp-smx, then pentamidine isoethionate should be used. corticosteroids in anti-infl ammatory doses as an adjunct to antimicrobial therapy have improved clinical outcomes. concurrent pulmonary infections were found in 35% of patients, most frequently bacterial or cytomegalovirus pneumonia. determination of the etiologic agent in pneumonia is diffi cult. fortunately, in most community-acquired pneumonias, identifi cation of the specifi c causative organism is not critical. however, in children with a complicated course that fails to respond to standard therapies, defi nitive diagnosis of the etiologic agent is essential. complete blood counts, infl ammatory markers, and chest radiographs do not differentiate the causative agents for pneumonia. blood cultures are rarely positive outside of the neonatal period. rapid antigen tests are available for rsv, parainfl uenza, infl uenza, and adenovirus. nasopharyngeal swabs for viral cultures generally take 7-8 days to become positive, and in one study, 86% of the patients had been discharged prior to the positive results. older children and adolescents might be able to produce sputum for gram stain and culture. an adequate specimen should contain more the 25 leukocytes and fewer than 25 squamous epithelial cells per low-power fi eld. in the intubated patient, sputum can be more easily acquired. however, interpretation of the results of gram stains and cultures is at times diffi cult in differentiating colonizing from pathologic organisms. colonization of the endotracheal tube may occur as early as 12 h, but most frequently between 60 and 96 h. the oropharynx becomes colonized within 36 h, the stomach at 36-60 h, and the lower respiratory tract between 60 and 84 h. in addition, a comparison of infectious agents isolated by both tracheal aspirates and bronchoalveolar lavage found only 36% concordance. bronchoalveolar lavage (bal) can be safely used to obtain secretions from the lower airways for gram stain and culture. it is especially useful in the diagnosis of pneumonia in the immunocompromised child. however, bal performed directly through the bronchoscope carries a risk of contamination. the smallest bronchoscope that can accommodate a protected specimen brush is 4.8 mm and requires a 6.5 mm endotracheal tube for passage. the smallest fl exible fi beroptic bronchoscope with a suction channel has an external chest radiograph of severe pneumocystis carinii pneumonia in a 13 month old male with combined immunodefi ciency. note the diffuse alveolar involvement and air bronchograms. (image provided courtesy of fa maffei) diameter of 2.8 mm and is too small to admit a double-sheathed brush. non-bronchoscopic double-lumen plugged catheters can be inserted blindly through the endotracheal tube to obtain a non-contaminated specimen. the sensitivity and specifi city of these samples are similar to those obtained by a bronchoscopic guided protected specimen. transthoracic needle aspirations are performed in some centers with good results. one study reported a diagnostic success rate in 59% of patients. the incidence of pneumothorax was approximately 20%, but none required subsequent placement of a pleural drainage catheter. a lung biopsy is rarely needed to make a defi nitive diagnosis. supportive treatment with oxygen and intravenous fl uids are often standard therapies. as both pneumonia and mechanical ventilation can cause an elevation in anti-diuretic hormone levels, careful fl uid monitoring is essential to avoid overhydration, excessive lung water and hyponatremia. initial antibiotic choices should be empiric and based upon the likely organisms for each age group, because of the diffi culty in identifying the causative agent. the child's respiratory status including respiratory rate, work of breathing, pulse oximetry, and central nervous system response should be closely monitored. non-invasive bi-level positive airway pressure (bipap) has been effective for use in children with mild to moderate respiratory insuffi ciency, defi ned as an a-a gradient >100 and <250 or pao 2 /fio 2 ratio <200 but >100 mm hg. serial evaluation of mask-face contact areas is essential to avoid skin breakdown. children with moderate or severe respiratory insuffi ciency often require intubation and mechanical ventilation. children with respiratory failure secondary to pneumonia often require increased positive end expiratory pressure (peep), increased inspiratory time, and aggressive pulmonary toilet to recruit alveoli. for patients requiring high levels of peep, adequate sedation is often required to prevent patient/ventilator asynchrony and barotrauma. spontaneous respirations should be encouraged while on mechanical ventilation. rarely, the use of neuromuscular blockade is required to allow mechanical ventilation. prone positioning may improve ventilation/perfusion (v/q) mismatching in dependent lung regions. lung protective strategies allowing permissive hypercapnea with small lung volumes to ventilate and appropriate peep to maintain alveolar recruitment is recommended for children with pneumonia. high frequency oscillatory ventilation can also be utilized to maintain mean airway pressure and alveolar recruitment. airway pressure release ventilation (aprv) provides recruitment of alveoli while allowing spontaneous respirations. in children with severe respiratory distress syndrome, treatment with bovine surfactant may improve oxygenation. extracorporeal life support continues to have a role in children with reversible severe acute hypoxemic respiratory failure refractory to mechanical ventilation. pneumonias can often be complicated by the development of pleural effusions and empyemas. these occur when the fl uid production by the interstitial lung tissue exceeds the maximum pleural lymphatic fl ow. parapneumonic effusions often occur from pneumonia as white blood cells and other debris of infection block the lymphatics resulting in elevation of protein in the pleural space, increase in colloid osmotic pressure, and consequent failure of fl uid reabsorption. on physical exam, the child will have decreased breath sounds over the effusion. in older children, auscultatory percussion changes might be appreciated. plain chest radiographs can reveal most clinically signifi cant effusions. ultrasound and chest computed tomograms are useful in determining the volume and quality of the fl uid and the presence of loculations. simple parapneumonic effusions or transudates can also be differentiated from exudates by using the criteria of light et al. (table 25 -2 ). a pleural fl uid ph less than 7.2 indicates a complicated effusion that is likely exudative and requires drainage whereas a pleural fl uid ph more than 7.3 suggests that the effusion may be managed with systemic antibiotics alone. complicated parapneumonic effusions or empyemas occur when the fl uid becomes purulent. during this stage, the effusions undergo a fi brinopurulent stage with many polymorphonuclear leukocytes, bacteria, and cellular debris entering the fl uid. fibrin is deposited over the pleural surfaces and loculations begin to form. the ph and glucose levels fall as the ldh levels rise. if untreated, they often progress to a third organizing stage in which the exudate non-invasive bipap ventilation can be effective for children with moderate respiratory insuffi ciency. develops into an inelastic, fi brotic peel that restricts the lung. simple parapneumonic effusions usually resolve with thoracentesis or tube thoracostomy and antibiotic treatment of the pneumonia. more complicated parapneumonic effusions have been successfully treated with thoracotomy tubes and fi brinolytics. however, although risks for bleeding are reportedly low, this therapy requires close monitoring of chest tube drainage and instillation of expensive medications with intermittent clamping of the chest tube. no single recommendation for the choice of fi brinolytic agent or dosage has been established. also, if tried late in the organizing phase, this is often unsuccessful due to loculations and the high viscosity of the purulent fl uid. surgical debridement either by open procedure or by video-assisted thorascopic surgery (vats) is often needed for organizing, complicated parapneumonic effusions. multiple studies have reported that early vats or thoracotomy for empyema leads to a shorter hospital stay. the treatment modality is best determined by the temporal stage and nature of the effusion. acute pulmonary infections are common diagnoses that require admission to the pediatric intensive care units. understanding the pathophysiology of lower respiratory infections enables the intensivist to tailor therapy to the individual child and pathogen. early establishment of a specifi c etiology and the selection of the correct treatment plan directly impacts clinical outcome. video-assisted thorascopic surgery (vats) for the treatment of empyemas has been associated with shorter hospital stay. which of the following therapies have been proven to be a consistent benefi t for rsv bronchiolitis? a. aminophylline b. bronchodilators c. corticosteroids d. ribavirin e. supportive care 2. palivizumab is indicated for which of the following children? a. a 5 month old, former 27 week premature infant who just underwent surgical repair of a large ventricular septal defect who received palivizumab 2 weeks ago b. a 9 month old, former 28 week premature infant with mild bronchopulmonary dysplasia who received palivizumab 2 weeks ago c. a 1 month old, former 36 week premature infant with peripheral pulmonic stenosis who has never received palivizumab d. a 2 month old full term infant with a urea cycle defect who has never received palivizumab e. an 8 month old, former 25 week premature infant with bronchopulmonary dysplasia who received his fi fth dose of palivizumab a month ago pleural fl uid may be classifi ed as exudative, if one or more of the following criteria are met: ■ pleural fl uid protein divided by serum protein >0.5 (sensitivity 98%, specifi city 83%) ■ pleural fl uid lactate dehydrogenase (ldh) divided by serum ldh > 0.6 (sensitivity 86%, specifi city 84%) ■ pleural fl uid ldh is more than two-thirds of the upper limit of normal for serum ldh (sensitivity 82%, specifi city 89%) adapted from light (2002) human bocavirus and acute wheezing in children american academy of pediatrics subcommittee on diagnosis and management of bronchiolitis. diagnosis and management of bronchiolitis the yield of fl exible fi beroptic bronchoscopy in pediatric intensive care patients immunological mechanisms of severe respiratory syncytial virus bronchiolitis human metapneumovirus infection in young children hospitalized with acute respiratory tract disease: virologic and clinical features a multicenter, randomized, controlled trial of dexamethasone for bronchiolitis natural infection of infants with respiratory syncytial virus subgroups a and b: a study of frequency, disease severity, and viral load the use of albuterol in hospitalized infants with bronchiolitis advances in the treatment and prevention of severe viral bronchiolitis the presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically signifi cant congenital heart disease systemic corticosteroids in infant bronchiolitis: a meta-analysis drainage, fi brinolytics, or surgery: a comparison of treatment options in pediatric empyema does vats provide optimal treatment of empyema in children? a systematic review intravenous ribavirin treatment for severe adenovirus disease in immunocompromised children clinical picture, diagnosis, treatment, and outcome of severe acute respiratory syndrome (sars) in children noninvasive therapy with helium-oxygen for severe bronchiolitis pleural effusion pleural effusions: the diagnostic separation of transudates and exudates nebulized 3% hypertonic saline solution treatment in hospitalized infants with viral bronchiolitis development of wheezing disorders and asthma in preschool children heliox therapy in infants with acute bronchiolitis nasal continuous positive airway pressure with heliox versus air oxygen in infants with acute bronchiolitis: a crossover study diagnosis and management of pneumonia in children community-acquired pneumonia in children selected populations at increased risk from respiratory syncytial virus infection human metapneumovirus and human bocavirus in children mixed respiratory virus infections mycoplasma pneumoniae and chlamydia pneumoniae cause lower respiratory tract disease in paediatric patients children's hospital respiratory syncytial virus database: risk factors, treatment and hospital course in 3308 infants and young children infection with sin nombre hantavirus: clinical presentation and outcome in children and adolescents ribavirin for respiratory syncytial virus lower respiratory tract infection: a systematic overview risk of bacterial infection in previously healthy respiratory syncytial virus-infected young children admitted to the intensive care unit infl uenza in pediatric intensive cure unit do bronchodilators have an effect on bronchiolitis? comparison of conventional viral cultures with direct fl uorescent antibody stains for diagnosis of community-acquired respiratory virus infections in hospitalized children respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years h1n1 infl uenza the impact-rsv study group. palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants high incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (rsv) bronchiolitis bench-to-bedside review: ventilator strategies to reduce lung injury -lessons from pediatric and neonatal intensive care etiological diagnosis of childhood pneumonia by use of transthoracic needle aspiration and modern microbiological methods a multicenter, randomized, double-blind, controlled trial of nebulized epinephrine in infants with acute bronchiolitis respiratory syncytial virus and other respiratory viruses effect of exogenous surfactant (calfactant) in pediatric acute lung injury. a randomized controlled trial current concepts on pulmonary host defense mechanisms in children nebulized hypertonic saline solution for acute bronchiolitis in infants bronchiolitis: recent evidence on diagnosis and management key: cord-032985-s6izbwqb authors: bellon-harn, monica l.; morris, lekeitha r.; manchaiah, vinaya; harn, william e. title: use of videos and digital media in parent-implemented interventions for parents of children with primary speech sound and/or language disorders: a scoping review date: 2020-10-01 journal: j child fam stud doi: 10.1007/s10826-020-01842-x sha: doc_id: 32985 cord_uid: s6izbwqb no review to date has focused on evaluating the use of videos and digital media in parent-implemented interventions for parents of children with primary language or speech sound disorder (ld/ssd). research objectives guiding this scoping review included an evaluation of (a) use of videos and/or other digital media in parent-implemented interventions; (b) use of videos and/or other digital media in asynchronous content; (c) the role of the parent as learner; and (d) the program impact on parents and children. this review followed a five-stage framework: (a) identify research questions; (b) identify relevant studies; (c) select studies; (d) chart the data; and (e) collate, summarize and report the results. ten studies were included. no program included parents of children with speech disorders. one fully asynchronous program was identified, though many programs included videos concurrent with direct instruction. no study described the parent as learner and only four studies examined parent satisfaction and perceptions. these four studies directly measured specific parent behavior and results indicated that the programs had a positive impact on parents’ interactions. nine of the ten studies included child outcomes. this low volume of studies suggests limited work in this area. the review describes research gaps and future directions. parent-implemented interventions for children with ld/ssd infrequently use asynchronous instructional content. evaluations of programs using self-managed or asynchronous instructional content is lacking. language disorders (ld) in children refer to significant impairment in the acquisition and use of language across modalities due to deficits in comprehension and/or production across any of the five language domains (i.e., phonology, morphology, syntax, semantics, pragmatics) (owens 2014) . speech sound disorders (ssd) in children refer to any difficulty with perception, motor production, and/or phonological representation of speech sounds that impact speech intelligibility (bernthal et al. 2017) . although prevalence data is problematic due to sampling issues and methods used to identify ld and ssd, prevalence data for children with ld range from 2.81 to 16% in children 7 years and younger (law et al. 2000) . estimates of ssd range from 2 to 25% of children ages 5 to 7 and 3.6% beyond 8 years of age (law et al. 2000; wren et al. 2016) . in a study of 24-month-old children, zubrick et al. (2007) found a prevalence estimate of 13.4% for late language emergence (lle), a condition considered to be the first diagnostic symptom of children with language impairments. further, preschool children with ld often present with ssd concurrently, which complicates the prevalence numbers and compounds the communication difficulties (haskill and tyler 2007; shriberg et al. 1986; shriberg et al. 1999) . primary ld and/or ssd (ld/ssd) in preschool years have a significant long-term impact on later communication further in life and academic success (felsenfeld et al. 1992; mccormack et al. 2011; norbury and bishop 2003) . future difficulties in language and literacy may be mitigated or prevented through the use of parentimplemented interventions with their young children (deveney et al. 2017; roberts et al. 2019) . inclusion of parents in the intervention process supports positive outcomes for their children (kaiser and hampton 2017; zevenbergen and whitehurst 2003) . through a variety of validated methods (e.g., didactic instruction, instructional/evaluative video, group discussions) parents can be trained to facilitate their child's speech and language development (roberts and kaiser 2011; sugden et al. 2016) . protocols vary in terms of approaches and strategies; however, the effectiveness of parent-implemented interventions is related to the active role of the parent as learner and facilitator (hart and risley 1995) . research suggests that parents vary in their facilitative language techniques and responsiveness according to several factors including children's language abilities and parents' educational level and socioeconomic status (christian et al. 1998; heath 1982; kuo et al. 2004; lyytinen et al. 1998) . that said, nearly all parents support their children's language skills (girolametto et al. 1996; tamis-lemonda et al. 2001) . parent-implemented interventions described as triadic interventions may facilitate parent's use of supports. in this type of intervention clinicians can teach parents to implement strategies that improve their child's speech and language (brown and woods 2015) . elements of the triadic interactions include creating a supportive context to promote parent-child engagement and teaching a range of strategies to strengthen the parent-child interactions (mccollum and yates 1994) . a triadic intervention facilitates provision of care that respects and reacts to needs, values, and preferences of families follows a familycentered approach (manolson 1992) . shared knowledge and responsibility within the therapeutic relationship promote family-centeredness and encourages greater involvement and accountability. success of parent-implemented interventions may partially be linked to parents' empowerment to take an active role in their child's development (epstein and street 2011) . effective parent-implemented interventions are not accessible to all families in the united states who need them. there are not sufficient trained personnel to serve the growing number of children eligible for early intervention services due to state fiscal issues (cason et al. 2012) . in particular, rural locations may experience a shortage of trained personnel (cason 2009 ). the negative impact is compounded since families residing in rural communities also lack access to healthcare including health promotion and prevention services. additionally, these families have lower socioeconomic status and complete less education (i.e., no high school diploma or a high school diploma/ equivalency). the recent pandemic further underscores the need for accessible programs. one way to increase access is to utilize programs that include videos and digital media in asynchronous content (i.e., content is provided for the parents to complete independently), which is cost effective and may result in positive outcomes (andersson 2018) . such programs do not rely on direct, in-person service delivery. use of videos and digital media may be included in fully asynchronous programs or a combination of asynchronous content with direct instruction. emerging data on parent-implemented interventions using asynchronous instructional content indicate promise. for example, a fully asynchronous, internet-based intervention in stuttering may be beneficial for instructing parents about identification of stuttering, knowledge about conducting practice sessions, and how to present intervention strategies as a part of the lidcombe program (van eerdenbrugh et al. 2018) . in the domain of telehealth, parent-implemented interventions may include synchronous content in which the content is presented in real-time albeit geographically distant as well as asynchronous content in which content is provided for the parents to complete independently (e.g., online module) (snodgrass et al. 2017) . for example, telehealth training of the early start denver model (i.e., a behavioral approach for children with autism) with both synchronous and asynchronous content (e.g., email, instructional modules) facilitated higher parent fidelity gains and program satisfaction than an in-person, treatment-as-usual group (vismara et al. 2018) . utilization of asynchronous instructional content within parent-implemented intervention protocols introduces new considerations for program development and evaluation. elements contributing to the effectiveness of fully self-managed internet-based programs include (1) the use of evidence-based content; (2) an interactive, self-management approach; (3) guided support; and (4) secured and user-friendly platform (ritterband et al. 2009; beukes et al. 2016 ). elements contributing to successful telehealth include (1) performing synchronous or asynchronous services with modifications; (2) ensuring that an appropriate facilitator is available; and (3) assuming responsibility for ensuring the client's safety during telehealth (richmond et al. 2017) . over time, innovations and research related to asynchronous instructional content will continue to enhance and shape our program development and evaluation (andersson 2018) . as noted, the effectiveness of parent-implemented interventions is related to the role of the parent as learner and facilitator. in programs that include asynchronous instructional content or are fully self-managed, the role of the parent as learner and the impact of the training on parent outcomes is a unique consideration. the adult learning theory of knowles et al. (2005) describes components of adult learning which may be critical in a self-managed and asynchronous digital learning environment. these include (1) adults need to know why they need to learn something; (2) adults maintain responsibility for their decisions and lives, (3) adults enter the educational activity with varied experiences; (4) adults want to learn things that they need to know in real-life situations; and (5) adults are more responsive to internal motivators than external motivators. in application, the impact of instructional content may be most effective when self-reflection and self-directed learning activities as well as videos of real-world examples are utilized (cook and dupras 2004; cummins and hulme 1997; leong et al. 2003) . further, content may be beneficial when it is immediately relevant (i.e., learning occurs in the same context in which it is applied). in light of the potential impact of videos and digital media in asynchronous parent-implemented interventions, we examined the evidence of parent-implemented interventions that include asynchronous instructional content or self-managed programs in the form of videos or digital media for parents of children with primary ld/ssd. research objectives guiding this scoping review included understanding (a) use of videos and/or other digital media in parent-implemented interventions; (b) use of videos and/or other digital media in asynchronous content; (c) the role of the parent as learner; and (d) the program impact on parents and children. a scoping review methodology is reported to be an effective approach to examine areas with emerging evidence (arksey and o'malley 2005) . this review followed a fivestage framework: (a) identify research questions; (b) identify relevant studies; (c) select studies; (d) chart the data; and (e) collate, summarize and report the results. a broad research question was identified to explore an overarching topic (i.e., how do parent-implemented interventions for children with ld/ssd utilize videos and/or digital media in asynchronous instructional content within telehealth programs or self-managed programs?). this question was combined with two specific 'scope of inquiry' question as suggested by levac et al. (2010) (i.e., what is the role of the parent as learner? and what is the program impact on parent and child outcomes?). these questions clearly define the population and concept of interest. the inclusion and exclusion criteria were developed with reference to the pico template (i.e., participants, intervention, controls, outcome measures) criteria as detailed in table 1 . study design was also included. the search string included: speech sound disorders or language disorder or phonological disorder or apraxia and child and parents and parent-implemented intervention or education or program or parent-mediated intervention or parents role or family centered care and video or e-health or digital or internet or mobile applications or online or self-guided or telemedicine or telehealth or teleeducation or telepractice. seventy-seven records were screened against the inclusion/exclusion criteria. after duplicates were removed, 65 records were screened. the first author screened the titles and 33 records were excluded. the first and second authors then independently screened the abstracts of the remaining 32 records and 22 records were excluded. a total of 10 articles were included in this review (see fig. 1 ). a pico template and specific information related to the research questions were used to chart the data. pico is widely used to frame clinically relevant questions (orlikoff et al. 2015) . the recorded information was study and location, participants, intervention type, fidelity and duration, controls, outcome measures, and study designs. three authors independently described the pico criteria. responses were compared and discussed in an iterative process. these studies included parent-child dyads ranging in age from 11 months to 10 years (see table 2 ). while all children were identified with language difficulties, delays, or disorders, no common inclusion criteria were noted. further, no children were identified with ssd. of the studies, five did not provide detailed parent demographic characteristics (allen and marshall 2011; falkus et al. 2016; konza et al. 2010; olson et al. 2016; wake et al. 2011) . five studies provided some limited demographic detail about the participating parents and children. two included parents who had a high-school degree or higher, were considered middle class, and were in their mid-30s (girolemetto et al. 1996; roberts and kaiser 2012) . baxendale and hesketh (2003) indicated that a majority of parents had a minimum of 16 years of education and only two had education beyond 18 years. children in van balkom et al. (2010) were part of a two-parent family with the mother as the main caretaker. all families had a middle-class socioeconomic status. pratt et al. (2015) included both demographic details of the parents (i.e., all mothers, monolingual speakers of spanish, high-school graduates, upper middle class) as well as home literacy behaviors (i.e., parent reading practices with their children). one study included a large sample of parent-child dyads (i.e., 285) from diverse girolametto et al. (1996) was conducted in canada. baxendale and hesketh (2003), marshall (2011), and falkus et al. (2016) were conducted in the united kingdom. van balkom et al. (2010) was conducted in the netherlands. wake et al. (2011) and konza et al. (2010) were conducted in australia. roberts and kaiser (2012) and olson et al. (2016) were conducted in the united states. pratt et al. (2015) was conducted in mexico. intervention type, duration, and fidelity table 2 identifies the intervention type used in each study and the duration of the intervention. nine studies included investigations of validated parent-implemented interventions (i.e., hanen program, enhanced milieu teaching, parent-child interaction therapy, parent video home training, and ¡leamos juntos!). one study piloted a fully self-managed digital program (i.e., utalk) to examine the impact of text messaging (olson et al. 2016) . varying levels of intervention intensity ranging from 4 weeks to 3 months were reported. roberts and kaiser (2012) did not report total treatment time, but the parents were provided 28 sessions. two of the ten studies reported on the steps they implemented to achieve high treatment fidelity. other investigators described the parent training and instructions provided but did not report measures of treatment fidelity. van balkom et al. (2010) noted the difficulty in controlling for the recommendations and tips provided to parents during home visits, and olson et al. (2016) stated that they did not assess whether parents participated in the suggested activities they provided via text messages in their study. three studies compared the intervention group to a delayed treatment group (allen and marshall 2011; girolametto et al. 1996; pratt et al. 2015) . see table 2 . three studies compared the intervention group to another intervention. baxendale and hesketh (2003) included a control group of children participating in one-to-one conventional therapy without hanen training. van balkom et al. (2010) included a control group characterized as an individualized direct child language intervention in which parent involvement was not included. wake et al. (2011) included one control group of parents not receiving a parent based program. roberts and kaiser (2012) included one control group of typically developing children and one control group of children with language impairment who were not receiving treatment. three studies did not include control groups (falkus et al. 2016; konza et al. 2010; olson et al. 2016) . table 2 presents outcome measures used in each study. the majority of studies utilized parent outcome measures consisting of metrics derived from analyzing videotaped parent-child interactions and ad hoc questionnaires and scales. two studies did not include parent outcome measures (van balkom et al. 2010; pratt et al. 2015) . nine of the studies examined program effects on child outcome measures and used metrics derived from analyzing videotaped parent-child interactions and from administering established psychometric instruments. there were no specific outcome measures common to all studies. of the studies that included metrics during parent-child interaction, four examined the relationship between parent and child productions (allen and marshall 2011; baxendale and hesketh 2003; falkus et al. 2016; konza et al. 2010) . the majority of studies focused on short-term outcomes. only wake et al. (2011) and baxendale and hesketh (2003) collected data from observation points at least 12 months apart. three studies did not include control groups (see table 2 ). four studies used a pre-post-test design with random assignment to a treatment or non-treatment control group (allen and marshall 2011; girolametto et al. 1996; pratt et al. 2015; roberts and kaiser 2012) . one study used a cluster randomized trial (wake et al. 2011 ). baxendale and hesketh (2003) used a pre-post-test with allocation by location (i.e., based on transportation and/or location to clinic) to a parent-implemented intervention or a direct child intervention. van balkom et al. (2010) used a pre-post-test design with random assignment to a parent-implemented intervention that emphasized video training or a direct child intervention or individual therapy. information related to the research questions (e.g., role of videos and digital media; role of parent as learner within the intervention; impact on parent and child) were collated and summarized. three authors independently described the study characteristics and summarized studies according to the research questions. responses were compared and discussed in an iterative process. the first two research questions were concerned with the role of videos and digital media and how it was used. in particular, we were interested in how videos and digital media were used in asynchronous instructional content or self-managed programs (see table 3 ). one study piloted a fully self-managed digital program (i.e., utalk) to examine the impact of text messaging (olson et al. 2016) . the other nine studies using validated programs targeted parent interactional strategies and included videos. van balkom et al. (2010) used videos as a core component of parent video home training. videos included positive conversations between the parent and child that were shown and discussed with certified trainers. allen and marshall (2011) and falkus et al. (2016) also used videos as a core component of parent-child interaction therapy to allow parents to observe and formally analyze how they interact with their child using a self-rating scale. girolametto et al. (1996) , baxendale and hesketh (2003) (pratt et al. 2015) . overall, the interventions used videos concurrent with varying levels of direct support, not specifically as asynchronous instructional content. it is not noted if the videos were left with the family to review and discuss independently of the trainers. the second research question was concerned with how the role of the parent as learner was detailed in the design of the programs or in the outcomes (see table 3 ). although all interventions were based on training parents, no study explicitly described or studied the role of the parent as the learner. that said, adult learning principles are components of the hanen program and central to the hanen program. table 4 presents the summary of outcomes of the eight studies that included parent outcomes. three studies without control groups reported change in parent behavior. table 3 role of videos and digital media and parent as learner study role of parent as learner girolametto et al. (1996) video were used for feedback and coaching purposes concurrent with direct instruction. adapted from hanen so adult learning principles are built-in to the intervention although not mentioned in the article. roberts and kaiser (2012) videos were used for training purposes concurrent with direct instruction during the initial four workshops of the program. no role of parent as learner reported. allen and marshall (2011) videos were used for training and evaluation purposes concurrent with direct training and evaluation. no role of parent as learner reported. pratt et al. (2015) videos were used for training purposes concurrent with direct demonstrations. no role of parent as learner reported. videos were used for training and evaluation purposes concurrent with direct training and evaluation. no role of parent as learner reported. olson et al. (2016) text messages used for educational purposes and described language stimulation activities, providing information on local, low-cost community organizations specializing in early child development, and distributing survey questions. no role of parent as learner reported. (1996) mothers' language was slower, less complex, and more focused in the treatment group than in the control group. children in the treatment group used more target words in naturalistic probes, more words in free-play interaction, and were reported to have larger vocabularies overall as measured by parent report than in the control group. children in the treatment group used more multi-word combinations and early morphemes than children in the control group. none reported. hesketh ( none reported. allen and marshall (2011) parents reduced their amount talk to balance the communication exchange with their child. children in the treatment group produced more verbal responses and had greater mlu than children in the control group. no effect on non-verbal responses was noted. children in the treatment group increased the number of verbal responses, albeit not significantly. group differences in the proportion of utterances between parents and children was not noted. roberts and kaiser (2012) parents in the treatment group had significantly higher rates of strategy use than parents in the control groups. group differences were reported in scores on the pls-4. group differences in the total number of words between the treatment and control groups were reported. pratt et al. (2015) none reported. statistically and practically significant gains on print and word awareness letter-name knowledge, but not for letter-sound knowledge subtests of the pals (spanish). none reported. falkus et al. (2016) significant changes on parent report of strategy use were noted. significant changes on mlu were noted. significant changes of the ratio parent-child speech were reported. olson et al. (2016) parents reported increased awareness of languagepromoting activities, local child development resources, and increased engagement in language-promoting activities none reported. none reported. faulkus et al. (2016) reported that significant change occurred in the parent rating scale, which is a scale used by parents to rate their performance. the significant changes in the ratio of parent and child utterances indicated that parents reduced the time they spoke and children increased the time they spoke. in konza et al. (2010) seven parents reported understanding the program and their children's communication on a 6-item evaluation questionnaire and focus group transcripts. parents in olson et al. (2016) reported via a survey an increased awareness of language-promoting activities and local child development resources as well as an increased engagement in language-promoting activities and selfreported knowledge (i.e., i know about activities that help my child learn to talk; i know places in the community where i can go to help my child learn to talk). all of the parents reported that they enjoyed the program and would recommend to other families, 96% considered it valuable to their family, and 89% reported that the program helped their child. two of the four studies comparing a parent-implemented intervention to a non-treatment control group indicated group differences on parent outcomes. girolametto et al. (1996) reported significant group differences on mothers' number of words per minute, target words, and focused stimulation strategies in that mothers in the treatment group used fewer words, more target words and more focused stimulation than the control group. roberts and kaiser (2012) reported that parents in the treatment group had significantly higher rates of enhanced milieu teaching strategies than parents in the control groups. allen and marshall (2011) reported a treatment effect on the proportion of child to parent utterances; however, no group differences were reported. two of the three studies comparing a parentimplemented intervention with a treatment control group reported positive parent outcomes. in wake et al. (2011) , a majority of parents in the treatment group reported positive program benefits and changes in parent-child communication immediately after the final session. specifically, 86 of the 100 parents in wake et al. (2011) that were asked to give feedback believed the program had led to positive changes in how they communicated with their children. seventy-two of the parents reported positive changes in their children's communication, 62 reported changes in their children's behavior, and 47 parents who had other children reported benefits in how they communicated with them. although baxendale and hesketh (2003) did not report group differences on frequency of parent use of modeling techniques or ratio of parent utterances to child utterances, for both groups the ratio of parent-child utterances equalized, and parents used more expansions and imitations. nine studies reported child outcomes (see table 4 ). two of the studies without control groups reported change in child behavior. faulkus et al. (2016) reported that significant change occurred in child mean length of utterance. konza et al. (2010) reported that five of the seven children increased their interactions so that they matched or almost matched the number of communications with their mothers. olson et al. (2016) did not have a control group and child outcomes were not reported. of the studies comparing a parent-implemented intervention to a control group, four reported group differences on child outcomes. girolametto et al. (1996) reported that children in the treatment group used more target words in naturalistic probes, more words in free-play interaction, and were reported to have larger vocabularies overall than in the control group as measured by parent report. children in the treatment group used more multi-word combinations and early morphemes than children in the control group. pratt et al. (2015) reported that children's print knowledge skills (e.g., understanding letters and sounds) changed significantly over the duration of the study in both the treatment and control group. group differences were indicated for print and word awareness and letter-name knowledge, but not for letter-sound knowledge. in roberts and kaiser (2012) group differences were reported in scores on the pls-4 and the total number of words. although allen and marshall (2011) reported a treatment effect on number of verbal initiations and child mean length of utterance, no group difference were reported. no differences were noted on the number of verbal responses or non-verbal responses. of the three studies comparing a parent-implemented intervention with a treatment control group, van balkom et al. (2010) found significant group differences on mlu, grammar, conversational coherence, and the reynell language development scales at post-treatment and follow-up. wake et al. (2011) and baxendale and hesketh (2003) did not report group differences on any child outcome measure. access to parent-implemented interventions can be increased through interventions that do not require direct, in-person service delivery. this scoping review drew together 10 studies related to the use of videos or digital media within parent-implemented programs for parents of children with ld/ssd. this low volume of studies suggests there is limited work in this area as compared to other areas of communication disorders (i.e., stuttering, hearing loss, autism). with regard to the first question, only one program utilized self-managed instructional content (olson et al. 2016) , and no program utilized asynchronous instructional content within telehealth programs. overall, the programs in this review included instructional and evaluative videos concurrent with varying degrees of direct instruction and support. it is noteworthy that no study in this review included parents of children with ssd. with regard to the second and third questions, no study explicitly described the parent as learner, though adult learning principles are built into the hanen program. eight studies examined parent outcomes; however, only four studies included measures of parent perception and satisfaction. results of these studies suggested parents felt a sense of empowerment following training, which is an important adult learning principle. for example, in falkus et al. (2016) parents were empowered by being asked to select the strategy they would like to address, to comment on their use of the interaction strategies, and to comment on the impact they felt it has had on their child's communication. participants in olson et al. (2016) reported an enhanced sense of competence and self-worth, which has been linked to empowerment (friedman et al. 2012; prelock and hutchins 2008) . four studies directly measured specific parent behavior and results indicated that the programs had a positive impact on parents' interactions. results indicated that when no control group was used or when compared to no treatment, parent-implemented interventions had greater gains on both parent and child outcomes. however, two programs that compared a parentimplemented intervention to direct child intervention did not report group differences (i.e., wake et al. 2011; baxendale and hesketh 2003) . wake et al. (2011) note the children in this study were between 2 and 3 years of age and suggest that perhaps prevention activities should happen at an earlier age. vanbalkom et al. (2010) compared parent video home training, which included videos as a dominant training component, to direct child intervention with parents of children between 2 and 3 years of age. greater gains on child outcome measures were reported for the group enrolled in the parent video home training intervention. the reviewed articles suggest infrequent use of videos and/ or other digital media in asynchronous instructional content or self-managed programs within parent-implemented interventions for children with ld/ssd. if a program design includes self-managed or asynchronous instructional content, analysis of the program's use of evidence-based content, a self-managed approach, guided support, and a secure, user-friendly platform is critical (ritterband et al. 2009 ). olson et al. (2016) was a pilot study designed to evaluate utalk, a text-based program. information related to the validity of utalk, guided supports, or security or usability of the platform was not included. further, outcome measures were non-validated surveys that appeared to be limited in their sensitivity to measure parental behavior. overall, evaluations of programs using self-managed or asynchronous instructional content is lacking. videos were used to deliver information for education purposes (olson et al. 2016 ), provide direct instruction on strategies (e.g., pratt et al. 2015) , and provide evaluative feedback (e.g., van balkom et al. 2010) . roberts and kaiser (2012) noted that, "teaching specific strategies using individualized video examples provided the initial foundation by teaching parents why and how to use each strategy" (p. 14). eighty-eighty percent of the parents in wake et al. (2011) reported that watching their own video clips was useful and 87% shared that getting feedback on their interactions with their child during the session was helpful. konza et al. (2010) reported that all of the parents felt that watching the videos of themselves and receiving feedback from a professional was very helpful. the use of online video recordings for various purposes may hold significant promise and is well suited for digital parent-implemented interventions. more research examining the impact of videos across various treatment protocols is needed. knowles et al. (2005) described multiple adult learning principles, each of which could be included in measures of parents' perceptions of a parent-implemented intervention. as noted, parent perception and satisfaction outcome measures in this review were in part linked to a sense of empowerment and the principle that adults are more responsive to internal motivators than external motivators. however, the role of adult as learner within such programs is understudied. other questions should explain how well the intervention describes for parents of young children the relevance of the intervention, allows parents to maintain responsibility for their learning, includes activities with varied and meaningful experiences, and motivates parents to continue with the program. these constructs are linked to adult learning principles that contribute to successful intervention completion. further, formative and summative evaluation of parents' perceptions should be included as outcome measures to ensure the information is accessible and beneficial from the families' perspective. finally, most of the studies in this review did not include long-term outcome measures though several of the authors called for longer-term follow-up data. it is critical to understand the immediate impact of the program as well as whether or not families continue to apply the strategies and expand their knowledge. the studies in this review did not include diverse populations. although the studies were conducted in various geographical locations, there is very little diversity in terms of race/ethnicity, education level, or socioeconomic status. the studies that reported parental demographics described parents as educated and from middle-upper socioeconomic status. as noted, parents vary in their facilitative language techniques based on several factors including educational level and socioeconomic status (e.g., heath 1982) . further, families residing in rural locations may have less access to resources. since digital programs may be a solution to meet the needs of families residing in rural locations (cason 2009; cason et al. 2012 ) programs need to be evaluated with regard to family and community resources. for example, researchers would need to ensure that internet availability would not create a barrier to access these programs and create ways to eliminate this barrier. as noted, elements contributing to the effectiveness of selfmanaged digital programs include the use of evidence-based content (richmond et al. 2017; ritterband et al. 2009 ). in other words, digital programs should utilize validated interventions while varying the delivery modality. for example, snodgrass et al. (2017) described reframing direct child interventions into parent coaching interventions through telehealth. as such, evaluation of digital programs based on validated interventions should strive to understand how the digital modality impacts parent learning and child outcomes. for example, van eerdenbrugh et al. (2018) employed the internet to deliver the lidcombe program and assessed the parents' knowledge about the disorder and how to conduct interactions and sessions. as programs move further into the digital realm, it is critical that the role of the parent as learner and facilitator is fully explicated. surveys that examine perceived motivation or competence may be beneficial in understanding the digital service delivery (e.g., intrinsic motivation inventory, deci and ryan 1982; perceived competence scale, williams and deci 1996) . overall, long-term outcomes of parent-implemented interventions are needed. interventions with asynchronous instructional content or self-managed content may have unique challenges obtaining short-and long-term follow-up measures. attrition can be a challenge for digital programs since the direct contact between clinician and parent may not be established or may be intermittent. in order to facilitate retention, parents should be able to contact the clinician via computer-mediated contact (e.g., chat function; secured email) to get clarification about the content and request additional content (buekes et al. 2016) . parents should be prompted to request more information and push notifications and reminder email could prompt participants to complete specific activities (e.g., request for complete a questionnaire, complete an activity). for parents who may have limited internet access, text messaging could be an avenue to use for these same reminders and requests for information. such strategies may facilitate completion through post-program and follow-up data collection and provide needed information regarding long-term impacts of parent-implemented intervention. however, research regarding these strategies as design features for retention through short-and long-term data collection are needed. video may be a necessary component of a digital parentimplemented intervention (cummins and hulme 1997) . in a digital realm multiple instructional purposes could be addressed and examined (i.e., deliver information related to the disorder, provide direction instruction on strategies, provide evaluative feedback). for example, video reflective activities could allow the parent to not only learn a new concept, but to reflect on what the information really means and how they may use the strategy with their child. additionally, active engagement can be done through interactive videos embedded within the program. skills adults learn must be immediately relevant and applicable with positive effects (knowles 1984) . helping parents connect information in the parent-implemented intervention with direct relevance to their child's life can be done through video examples and testimonials. access to digital programs may increase sample diversity; however, online recruitment presents its own challenges. researchers developing and evaluating digital parent-implemented interventions will need to consider how to ensure a representative sample in recruitment phases. for example, researchers may recruit on facebook groups dedicated to parenting children with disabilities or use specific twitter hashtags to identify specific parent groups (thornton et al. 2016) . finally, instructional protocols of digital programs will have unique variables (e.g., technological competencies of the user, nature of online instruction) beyond the intervention itself. as parent-implemented interventions increase the degree to which the instruction is digital, the interface between the parent and the program will need to be examined (richmond et al. 2017; ritterband et al. 2009 ). questions considering the parent's perception of the provision of an intuitive and interactive system, messages from the clinician or platform administrator, and/or online help should be asked. scoping studies intend to chart relevant literature in a particular area of interest and identify gaps in current research. one limitation is that quality assessments are not conducted. although we searched electronic databases and journals for peer-reviewed studies, it is likely that other relevant publications were not included. also, we did not include literature written in languages other than english or gray literature. such studies in other languages may be a significant source for information. the purpose of this scoping review was to understand (a) use of videos and/or other digital media in parentimplemented interventions; (b) use of videos and/or other digital media in asynchronous content; (c) the role of the parent as learner; and (d) the program impact on parents and children. the limited studies that use videos and/or other digital media in asynchronous instructional content or selfmanaged programs suggest that more program development and evaluation are needed to provide accessible parentimplemented interventions. conflict of interest the authors declare that they have no conflict of interest. ethical approval this research did not involve human participants and/or animals. the study used published research as a part of this scoping review. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. parent-child interaction therapy (pcit) in school-aged children with specific language impairment internet interventions: past, present and future scoping studies: towards a methodological framework comparison of the effectiveness of the hanen parent programme and traditional clinic therapy articulation and phonological disorders development and technical functionality of an internet-based intervention for tinnitus in the uk effects of a triadic parentimplemented home-based communication intervention for toddlers a pilot telerehabilitation program: delivering early intervention services to rural families overview of states' use of telehealth for the delivery of early intervention (idea part c) services predicting kindergarten academic skills: 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intervention for preschoolers late language emergence at 24 months: an epidemiological study of prevalence, predictors, and covariates key: cord-031409-7cs1z6x6 authors: baraitser, lisa title: the maternal death drive: greta thunberg and the question of the future date: 2020-09-04 journal: psychoanal cult soc doi: 10.1057/s41282-020-00197-y sha: doc_id: 31409 cord_uid: 7cs1z6x6 the centenary of freud’s beyond the pleasure principle (freud, 1920a/1955) falls in 2020, a year dominated globally by the covid-19 pandemic. one of the effects of the pandemic has been to reveal the increasingly fragile interconnectedness of human and non-human life, as well as the ongoing effects of social inequalities, particularly racism, on the valuing of life and its flourishing. drawing on earlier work, this paper develops the notion of a ‘maternal death drive’ that supplements freud’s death drive by accounting for repetition that retains a relation to the developmental time of ‘life’ but remains ‘otherwise’ to a life drive. the temporal form of this ‘life in death’ is that of ‘dynamic chronicity’, analogous to late modern narratives that describe the present as ‘thin’ and the time of human futurity as running out. i argue that the urgency to act on the present in the name of the future is simultaneously ‘suspended’ by the repetitions of late capitalism, leading to a temporal hiatus that must be embraced rather than simply lamented. the maternal (death drive) alerts us to a new figure of a child whose task is to carry expectations and anxieties about the future and bind them into a reproductive present. rather than seeing the child as a figure of normativity, i turn to greta thunberg to signal a way to go on in suspended ‘grey’ time. and why should i be studying for a future that soon will be no more, when no one is doing anything whatsoever to save that future? (greta thunberg) this paper is late. not just a little late but seriously forestalled. there is some pressure -an urgency produced by the centenary of freud's beyond the pleasure principle falling in 2020 -and the desire and pleasure in partaking in a collaborative, timely celebration of the work. there are the ordinary repetitions that are holding this up: a chronic relation to my own thoughts, veering towards and away from the satisfactions and disturbances of ideas connecting or linking; the chronic overwhelm produced by the difficulty of saying 'no' and resisting the temptations of an overloaded life; and the realities of overload brought on not by a chronic relation to limits but by their obliteration by the institutions and systems that govern our lives. then, of course, as 2020 has deepened, there have been the temporalities of illness, care and grief; of the suspension of time under conditions of lockdown; the stop-start of uncertainty and helplessness. for some, it has been a time of permanent and dangerous work; of intolerable waiting for others; and of the fault-lines of inequality and racial injustice urgently rupturing the otherwise monotonous rhythm of a global pandemic. in 2020, everything and nothing went on hold. during this time, i continued to work with patients, albeit 'remotely', in the strange temporality of a five times per week psychoanalysis. even with so much time, the wait between sessions can be felt to be intolerable. to be in an analysis is to be held in suspension from one session to the next. one of my patients describes the wait as an agonizing 'blank time', like the crackling of an oldfashioned tv. it is not dead time as such but the incessant noise of nothing happening. to be in the session, however, produces a different kind of disturbance: an utterly absorbing kind of time that they liken to the colour blue. we move between the absorbing blue time of the sessions to the blank, crackling, maddening time between them. there is a 'session-time' analyst, who is blue, and a 'between-session-time' analyst, who maddens with a blank, crackling absence. time is both interminable -a wait between the sessions that feels like it goes on forever -and chronic: the repetition of blue, blank, blue, blank, blue, blank… beyond the pleasure principle is freud's meditation on the temporalities of repetition and return as species-time articulates with the time of the subject. in many ways, the death drive is a temporal concept, holding together the paradoxical time in which repetition contains within it a backwards pull towards the no-time of the living organism, even as the shape of this relation describes 'a life'. 100 years later, time in the early decades of the 21st century ó 2020 springer nature limited. 1088-0763 psychoanalysis, culture & society appears oddly analogous: it seems to loop or repeat but is undercut by a pull towards no-time, since the human and planetary future is not just foreshortened but now 'foreclosed' by the immanent twin disasters of capitalist and (neo)colonial expansion (baraitser, 2017a, p. 8) . franco 'bifo' berardi has long argued that our collective human future has come and gone and that the future has outlived its usefulness as a concept (berardi, 2011) . time after the present will come, but it will not bring the promises of bettering the conditions of the now for most, this having been a central aspect of european and north american future narratives in the post-war period (toffler, 1970; lee, 2004; luhmann, 1976) . in fact, as naomi klein (2007) argues, the very folding of disaster into capitalist discourses, governmental policies and institutional practices does not stave off disaster but profits further from it, pushing the relations between the human and non-human world to the brink of sustainability. what this implies is that disaster is not a future horizon we must urgently draw back from but a condition we have already incorporated, profited from and continue to sustain in the present. in these conditions of 'crisis capitalism', whole populations are kept in a 'chronic state of near-collapse' (invisible committee, 2009, p. 31) , 1 a kind of temporal hiatus in which one goes on but without a future. amy elias (2016) has noted the intensive discussions about the 'presentism' of post-wwii globalized societies that have revolved around the idea of the loss of history (p. 35). in these narratives, a sense of a saturated, elongated, thin present is a product of a traumatized western collective consciousness confronting the unprecedented 'event' of wwii. however, these narratives, she argues, have given way in the 21st century, as humankind 'has created its own version of durational time inside (rather than outside) the box of historicity' (p. 36). this durational time is not bergson's duration that teams with experience (bergson, 1889 (bergson, /1994 (bergson, , 1896 (bergson, /2004 but the empty, timeless time of a 'marketplace duration' (elias, 2016, p. 35) , closer to the maddening crackling of nothing happening that my patient describes. in addition, as time is increasingly synchronized in the post-war period in terms of economic, cultural, technological, ecological and planetary registers, the 'present' itself becomes the management of a tension between time that is felt to be synced or simultaneous and time that is multiple or heterogeneous to simultaneity (burges and elias, 2016, p. 3) . we could think of this tension as produced by the dominating effects of european models of time (mills, 2014 (mills, , 2020 . european time is constantly imposed by the west on 'the rest' through the temporal structures of empire and enacted through colonization, exploitation, extraction and enslavement. european time comes to mediate representations of the world through the imposition of a particular account of the world-historical present on other temporal organizations -cosmic time, geological time, earth time, soil time, indigenous time, women's time, queer time, to name a few (chakrabarty, 2009; freeman, 2010; kristeva, 1981 kristeva, /1986 nanni, 2012; puig de la bellacasa, 2017) . another way to put this is that, although freud proposes that repetition leads to the ultimate suspension of time -the return to non-being -the state of nonbeing produced by temporal suspension in the early 21st century is radically unequally distributed. writing under conditions of lockdown during the covid-19 pandemic, achille mbembe (2020) states: for we have never learned to live with all living species, have never really worried about the damage we as humans wreak on the lungs of the earth and on its body. thus, we have never learned how to die. with the advent of the new world and, several centuries later, the appearance of the 'industrialized races,' we essentially chose to delegate our death to others, to make a great sacrificial repast of existence itself via a kind of ontological vicariate. non-being, or death, is a luxury that hasn't yet been learnt by the 'human', non-being having been delegated to slaves -those humans who are denied status as humans against which the category of 'human' is both founded and flounders -as well as to non-human others. unless we recognize the 'universal right to breath' (emphasis added) for all organic matter, mbembe argues, we will continue to fail to die for ourselves, the death drive being projected, that is, into the body of that which is deemed non-human. if we go on collectively refusing to die for ourselves, we could say that the temporality of the current human predicament is closer to what martin o'brien calls 'zombie time' (o'brien, 2020) . as an artist and writer living with cystic fibrosis, which gives rise to symptoms very similar to covid-19 (coughing, shortness of breath, exhaustion), o'brien has now outlived his own life expectancy. he writes: zombie time insists on a different temporal proximity to death. like the hollywood zombie which holds within it a paradox, in that it is both dead and alive, those of us living in zombie time experience death as embodied in life […] .we had come to terms with the fact that we are about to die, and then we didn't. freud's movement towards death is circular: a repetitive arc that leads us back to the inorganic, so that in some sense it too describes zombie time, the fact we have always already surpassed our death date, whereby a life is an act of return. each organism follows its own path, he tells us, to death, and that deviation is a life. a path, however, is not quite what o'brien is suggesting. here the presence of death is sutured to every aspect of life, closer perhaps to melanie klein's insistence on the death drive as a permanent unconscious phantasy that must be managed as a life-long psychic struggle (klein, 1946 (klein, / 1975 . two questions arise from this. firstly, does recognizing 'death as embodied in life' lead us to begin to die for ourselves? in this 'hour of autophagy', as mbembe (2020) puts it, we will no longer be able to delegate death to an other. we do, indeed, have to die not just in our own fashion but on our own behalf. in one reading of freud's death drive, it is associated with the freedom to do one's own thing, follow one's own path and stands as a marker of an independent life in many ways free from others -even if, as lacan would have it, not free from the big other. 2 but, as so many feminist, queer, disability, and black studies scholars have attested, living an independent life is a fantasy; it is always premised on dependency or interdependency, which so often requires the temporary or permanent tethering of the life of an other, or, more profoundly, the harnessing of 'life' itself. 3 judith butler (2020) writes in the force of non-violence that we are all born into a condition of 'radical dependency' (p. 41), that no-one stands on their own, that we are all at some level propped up by others. freud's suggestion of 'eternal return' requires practices of maintenance that have largely been accorded to women, people of colour, animals, and other non-human others. these practices of maintenance entail the temporalities of often mind-numbing repetition: reproductive and other forms of labour that support, sustain, and maintain all living systems. in order to 'deviate', someone or something else needs to preserve, maintain, protect, sustain, and repeat. those 'others' stay on the side of life, not as progression or even deviation towards death but as a permanent sustaining of life-processes. death in life requires a simultaneous articulation, in other words, of life in death, in which the temporalities of progression, regression, and repetition can be understood as supported and supplemented by another temporal element within the death drive that operates through 'dynamic chronicity': an element that animates 'life' in such a way as to allow the subject to die in its own fashion. i call this life in death the 'maternal death drive' (baraitser, 2017a) to distinguish it from the pleasure principle or the 'life' drive. secondly, if the time of the 'now', as i've elaborated above, takes the form of dynamic chronicity, a suspended yet chronically animated time that pushes out temporal multiplicity, what work needs to be done in order that this form of time retains some connection to a futurity for all? do the repetitions of 'blue blank' in their own circular fashion retain within them a relation to futurity, even if they don't exactly lead us somewhere else? i would hope, after all, that my patient may eventually, with time, come to experience the 'blue-session' analyst and the 'blank-absent' analyst as one and the same analyst, even as the agonies of having and losing may continue to be difficult. from a kleinian perspective, the time that this requires is the time in which what is hated and what is loved come to have a relation to one another, which klein calls 'depression' (klein 1946 (klein /1975 and which may entail 'depressing time'. we could say that it is the time in which we come to be concerned about the damage done to what is loved, the time whereby what is loved and what is hated can come to matter to one another, making the time of working through that of 'mattering' itself. furthermore, mbembe (2020) writes: community -or rather the in-common -is not based solely on the possibility of saying goodbye, that is, of having a unique encounter with others and honoring this meeting time and again. the in-common is based also on the possibility of sharing unconditionally, each time drawing from it something absolutely intrinsic, a thing uncountable, incalculable, priceless. (emphases in original) this would suggest that, supplementary to the time of blue-blank (saying goodbye again and again), there is another time: that of the 'in-common'. this is a time of permanent mattering, which also takes time to recognize. it is, if you like, the time in which depressive guilt survives and hence the time it takes for a future to be recognized within the present, rather than being the outward edge, the longed-for time that is yet to come. in what follows, and taking my cue from beyond the pleasure principle itself, i attempt to rework freud's death drive by drawing attention to a particular form of developmental time that lies inside the time of repetition, which i link to 'life in death'. in chapter ii of freud's essay, in the midst of his struggle with the meaning of repetition, pleasure and unpleasure, he turns to a child. the function of the child at this point in the text is to provide the case of 'normalcy' -the play of children -in order to help him understand the 'dark and dismal topic of traumatic neurosis' (freud, 1920b (freud, /2003 . the child will be 'light' (read white) and playful but turns out to be deeply troubled. instead of dragging the cotton reel along the floor as the adults intended, so it could turn and check its existence at any point, the child, standing outside the cot, throws the reel into the cot, accompanied by an o-o-o-o sound, so it cannot be seen, and then pulls it out with a 'da!' that freud describes as 'joyful' (p. 52). the pleasure of refinding, however, is postponed -in the time between 'gone' and 'found', the child plays at waiting, as it attempts to remaster the experience, freud tells us, of its 'gone' mother. this is of course also an attempt to deal with its own goneness from the imagined place of the mother; the child is standing outside the cot, after all. the passivity of being left is repeated but transformed through an act of 'revenge', a repetitive act of aggression in which, through psychic substitution, something essentially unpleasurable is turned into something 'to be remembered and to be processed in the psyche' (p. 52). the child does this by identifying with the mother, waiting in her place. my aim is to repeat freud's impulse, re-inserting a mother and child into the scene of the death drive 'proper' as a way to signal how to die on our own behalf and therefore how to go on in the suspended hiatus we appear to be living through. the maternal, as i will elaborate, appears as a non-normative developmental temporality within the death drive. in my account, the child reappears, however, in the figure of the child-activist greta thunberg. she is the child who has been invested in symbolically to carry hope for the future, a hope that she is decidedly pushing back towards those of the generation who came before her, calling on them to take action now, before it is too late. although thunberg names her vision of the world in terms of 'black and white' thinking, i draw on laura salisbury's notion of 'grey time' (salisbury, in press) in order to understand what to do with the time that remains in which action can still take place. it is always an uncomfortable thing to do, to insert a mother and child into a scene where they are ostensibly not wanted. it carries the sour smells of heteronormativity and essentialism that still cling to discussions of the maternal and relegate mother-child configurations as the counterpoint to those who are 'not fighting for the children', as lee edelman (2004) suggested in his famous polemic no future. for edelman, the death drive is a queer refusal of futurity that allows negativity to operate as a 'pulsive force' that would otherwise trap queer as a determinate stable position (p. 3). the child and mother come to represent the ultimate trap, that of development itself -the unfolding of the normative temporalities of birth, growth, development, maturation, reproduction, wealth generation and death. in some ways, this is what makes the insertion of mother-child back into discourses about the death drive rather 'queer'. in doing so, i deliberately refuse the association between motherhood and normativity and suggest that motherhood is the name for any temporal relation of 'unfurling' whereby the unfurling of one life occurs in relation to the unfurling of another, albeit out of sync. in fact, as i will elaborate below, for a life to unfurl there needs to be the presence of another life that is prepared to wait whilst life and death can come to have a relation to one another. this suspended time of waiting for life to unfurl is a non-teleological, crystalline form of developmental time based on the principle of life in death (baraitser, 2017a, p. 92) . whilst motherhood is always in danger of being squeezed out of this kind of queer theory, it is also in danger of being squeezed out of feminist theories that purport to make space for the maternal. julia kristeva's essay 'women's time' (1981/1986 ), for instance, conceptualized female subjectivity as occupying two forms of time: cyclical time (repetition) and monumental time (eternity without cleavage or escape). these two 'feminine' forms of time, she argued, work to conceal the inherent logic of teleological, historical, 'masculine' time, which is linear, progressive, unfolding and yet constantly rupturing, an 'anguished' time (p. 192) . masculine time rests on its own stumbling block, which is death. cyclical time and 'monumental' or eternal time, kristeva argued, are both accessed through the feminine, so that the feminine signifies a less 'anguished' time because it is uncoupled from the death of the subject and more concerned with suturing the subject to extrasubjective time. although this has been rightly critiqued for essentializing 'the feminine' through the normative positioning of the female subject on the side of the biological, as well as mobilizing a nonpolitical appeal to 'nature', i have argued elsewhere that, in attempting to separate the feminine from cyclical and monumental time, feminist theory designates the maternal as the keeper of species-time, in which the mother becomes a biologistic and romanticized subject attached to the rhythms of nature (baraitser, 2009, p. 5) . toril moi (1986) writes of kristeva's essay that the question for kristeva was not so much how to valorize the feminine but how to reconcile maternal time with linear (political and historical) time (p. 187). without a theory of the desire to have children (a desire that can permeate any gender configuration and that i name as maternal regardless of the gendered body that desires it), we leave the door open to the consequence of a failure to theorize and the maternal falls out of signification, time and history. moreover, motherhood is not just the desire for children but a particular form of repetitive labour relegated largely to women and particularly, in the global north, to women of colour and women from the south. although the concept of 'social reproduction' has been expanded to incorporate a much broader array of activities than caring for children, maternal labour remains distinct from other forms of domestic labour. joy james (2016) argues that the ongoing trauma and theft involved in slavery, for instance, produces not only western democracy but a repudiated 'twin' within western theory that she names 'the black matrix' (p. 256). where mothers in captivity and slavery have always provided the reproductive and productive labour that underpin wealth and culture, they are systematically erased -not just in culture but in what she calls 'womb theory' (theory, for instance, that accommodates feminism, intersectionality and antiracism, whilst still denying the maternal captive). despite this, she claims, the black matrix can act as a 'fulcrum' that leverages power against captivity (p. 257). i would argue that this power comes, in part, from the impossibility of the maternal captive remaining indifferent to her labour. subsistence farming, cooking, cleaning, household maintenance, support work and the production of status are forms of repetition from which it remains possible to emotionally disattach. but the 'labour' of maternity is 'affective, invested, intersubjective' (sandford, 2011, p. 6 ) and retains an ethical dimension that is distinct. here the maternal emerges as a figuration of the subject that is deeply attached to its labouring, whose labouring is a matter of attachment to that labour, as well as providing the general conditions for attachment (the infant's psychic struggle to become connected to the world) to take place. we could say, then, that the time of repetition under the condition that is maternity becomes the time of mattering, as opposed to the 'meaningless' time of reproduction: the time, that is, in which repetition may come to matter. this time can be felt as obdurate, distinctively uncertain in its outcome, both intensive and 'empty', and bound to the pace of the unfurling other. what is at play is a kind of crystalline developmental time within the time of history. it takes the form of repetition, but this repetition holds open the possibility of something coming to matter, rather than the death drive understood only as a return to non-being. a maternal death drive? what might this conjunction mean? freud always maintained that the two elements of psychic life that couldn't be worked through were the repudiation of femininity in both men and women, by which he meant the repudiation of passivity; and the death drive, the repetitive return again and again to our psychic dissolution or unbinding. in 'analysis terminable and interminable', written in the last years of his life, freud (1937 freud ( / 1964 ) named these the 'bedrocks' of psychic life, evoking an immoveable geological time. the permanent fixtures of psychic life that an analysis cannot shift are the hatred of passivity and the simultaneous impulse to return to an ultimate passive state, suturing the feminine to death in psychoanalysis. earlier, in beyond the pleasure principle, freud had offered an hypothesis in which, despite his conception of drives as exerting the pressure that presses for change, they are constrained by a conservatism, meaning they do not operate according to one singular temporality. this double temporality within the death drive is drawn out by adrian johnston (2005) , who has noted freud's (1905 freud's ( / 1955 ) developmental account of the drive in three essays on the theory of sexuality and later in 'instincts and their vicissitudes ' (1915/1957) , where the drive is articulated as maturing over time. johnston (2005) maintains that freud's drive is simultaneously timeless and temporal, both interminable (it repeats) and containing an internal tendency to deviate, to change its object and its aim (it develops or alters) (p. 228). after all, something happens, according to freud, that shifts the human organism from one that dies easily to one that diverges ever more widely from the original course of life (that is, death) and therefore makes ever more complicated detours before reaching death. for johnston, alteration can be understood as an intra-temporal resistance to the time of iteration, a negation of time transpiring within time. this means that the death drive therefore includes rather than negates developmental time. this is not a developmental tendency separated off and located within the selfpreservative drives or a 'life' drive but a death drive that contains within it its own resistance to negation. i would want to reclaim this doubled death drive as 'maternal', the drive that includes within it the capacity for development, for what johnston calls 'alteration', which always mediates the axis of repetition or 'iteration' (p. 344). the maternal death drive would describe the unfolding of another life in relation to one's own path towards death and marks the point that alteration and iteration cross one another. if we move from freud to klein, we see how this double temporality plays out between the maternal and child subject. i have described elsewhere how, in love, guilt and reparation, klein (1937 klein ( /1998 tells us that anxiety about maternal care and dependency on the maternal body in very early life -the relationship, that is, with a feeding-object of some kind that could be loosely termed 'breast' -is a result of both the frustrations of that breast (its capacities to feed but also to withhold or disappear at whim) and what the infant does with the hatred and aggressive feelings stirred up by those experiences of frustration that rebound on it in the form of terrifying persecutory fantasies of being attacked by the breast itself (pp. 306-43; see also baraitser, 2017b, p. 4 ). klein's conceptual infant swings in and out of psychic states that are full of envious rage and makes phantasized aggressive raids on the maternal body in an attempt to manage the treacherous initial experiences of psychical and physical survival. klein (1937 klein ( /1998 moves us closer to a more thing-like internal world permeated less with representations and more with dynamic aggressive phantasies of biting, hacking at and tearing the mother and her breasts into bits, and attempts to destroy her body and everything it might be phantasized to contain (p. 308). in klein's thinking, libido gives way to aggression, so that the defences themselves are violent in their redoubling on the infant in the form of persecutory anxiety. one's own greed and aggressiveness themselves become threatening, along with the maternal object that evokes them, and have to be split off from conscious thought. coupled with this are feelings of temporary relief from these painful states of mind (p. 307) and these 'good' experiences form the basis for what we could think of as love. it is only as the infant moves towards a tolerance of knowing that good and bad 'things' and experiences are bound up in the same person (that is, both (m)other and self) that guilt arises as an awareness that we have tried to destroy what we also love. whilst this can overwhelm the infant with depressive anxiety that also needs to be warded off, there is a chance that this guilt can be borne and a temporary state of ambivalence can be achieved that includes the desire to make good the damage done. 'unfurling', then, arises out of the capacity to tolerate the proximity of love and hate towards the mother, but the mother also needs to tolerate the time this takes -to be prepared to go back 'again and again' to the site of mattering without becoming too overwhelmed or rejecting. it is here that futurity emerges, not as that which is carried forward by the child but as this element within the death drive that i am naming as maternal, which is a capacity to tolerate repetition within the present. to return to a lacanian formulation, chenyang wang (2019) , in his work on differentiating real, imaginary and symbolic time in lacan, shows how lacan's death drive is not so much the reinsertion of the bodily or biological into the human subject but the traumatic intrusion of the symbolic into the organism at the expense of the imaginary, which evokes the real body. wang describes how what he calls the 'real future' (p. 69) does not involve the human subject. where the ego may continue to imagine a future of fulfilled wishes, hopes and expectations, in which the present is characterized as a mode of 'waiting' until the future unfolds, the death drive in fact interrupts the fantasy of the future as something unreachable or unattainable and instead returns the future to the subject as something that has already structured it. for wang, real time opens the subject to the real present that is neither instantaneous or immediate but the freedom of returning to the same place in one's own way. he sees this as the offer of the possibility of freedom that transcends the isolated, egoic individual, otherwise trapped in its established temporal order (p. 79). we could say, then, that the death drive includes rather than negates developmental time and holds out the possibility of a time that breaks free of the ego's imaginary sense of past, present and future. developmental time, from this perspective, is precisely a suspension of the flow of time, a capacity to wait for the other to unfold. maternity, in its failure to be indifferent to the specificity of its labour, implies a return, again and again, to a scene that matters, a kind of repetition that is not quite captured by the death drive as excessive access to jouissance, nor to the death drive as a deviation towards a unique form of death, but that might after all have something to do with generativity, indeed with freedom, not of the self, but of the other. the return to a scene that matters is not a kind of flowing time (anyone who has spent time with small children will know this) nor the stultifying time of indifferent labour, but living in a suspended or crystalline time, which is the time it takes for mattering to take place. finally, we can link the maternal death drive to elizabeth freeman's (2019) concept of 'chronothanatopolitics' (p. 57) that extends mattering beyond the mother-child relation to the politics of mattering in the contemporary moment. in her discussion of 'playing dead' in 19th century african-american literature, freeman notes that many african-american stories involve 'fictive rebirths'(p. 55). these are stagings of death and rebirth, not just once but multiple times, so that in these stories slaves and their descendants are constantly moving towards and away from death. feigning death, she argues, does not solve the problem of having not been 'born' as human -a position well established within afropessimist thought -but allows an engagement through repetitive staged dying with what jared sexton (2011) has called 'the social life of social death' (quoted in freeman, 2019, p. 55). freeman therefore builds on freud's death drive to develop a concept of 'chronothanatopolitics' in which life is not simply the opposite of death but the opposite of the 'presence' of death (p. 57), a temporary 'disappearing' of death within life, the counterpart to the maternal death drive as life in death. staging one's death again and again, she states, is a way of managing the life/death binary, rather than simply a commitment to life or an acceptance of unchanging black deathliness. where freud's death drive does refuse any simple opposition between life and death, freeman notes, it nevertheless proposes a universal and purely psychic drive. she calls instead for recognition of a socio-political death drive enacted by white supremacy: chronothanatopolitics is the 'production of deathliness and nonbeing by historical forces external to the subjectivity it creates for nonblack people, and forecloses for people of african descent' (p. 55). in the 21st century, we see 'playing dead' resurfacing in the 'die-ins' revived by the protest movement black lives matter. time becomes central, creating what freeman terms 'temporal conjoinments' with death (p. 85) through counting 'i can't breathe' 11 times, as eric garner did. we have seen this repeated in 2020, when protesters hold a silence or take the knee for 8 minutes and 46 seconds, the time that george floyd had his neck knelt on by the police officer who killed him on 25 may. 'mattering', in the sense of black life coming to matter, freeman notes, captures the double meaning of coming to importance and becoming-inert substance or matter, giving the phrase an ambivalent valence. mattering refuses the afropessimist insight that black life is structurally foreclosed and instead implies a more open stance towards non-being. by miming death rather than life, black lives matter activists 'commit to an (a)social life within death even as they fight for an end to the annihilation of blackness' (p. 86). here, life in death is the 'social' work of activism that counts the time that is left within black life even as it is extinguished, just as it is the social work of mothering that waits for life to unfurl towards its death without knowing when or how this will take place. miming death, again and again, is analogous to returning to the scene of mattering again and again, the hiatus within the path towards death that i have described as the maternal death drive. however, freeman's work provides the corrective to an easy universalizing of the drive, pointing us towards the way that black lives matter politicizes repetition in the name of life in death. recently i've seen many rumours circulating about me and enormous amounts of hate. (greta thunberg) in the child to come: life after the human catastrophe, rebekah sheldon (2016) charts a recent shift in the use of the child to suture the image of the future. the child, metonymic with the fragility of the planetary system and therefore in need of protection, has become 'the child as resource' (p. 16). as resource, the child is used to carry both expectations and anxieties about the future. unlike earlier iterations, the child as resource is premised on a future that cannot be taken for granted. much of the affect around ecological disasteranxiety, fear, terror, hopelessness, despair, guilt, determination, protectivenesscomes not so much from an awareness of the current effects of global climate change as they play out in the present but from the projected harm to the future that it portends. and the future, sheldon reminds us, is the provenance of the child. sheldon describes the history of this relationship between child and future as emanating from the 19th century at the same point as modern theories of 'life' begin to proliferate in darwin and of course in freud. 'the link forged between the child and the species', she writes, 'helped to shape eugenic historiography, focalized reproduction as a matter of concern for racial nationalism, and made the child a mode of time-keeping' (p. 3). in the face of anxious concerns about the deep biological past of the human species, the child held open a future through a coordination of the trio 'life, reproduction and species' with that of 'race, history and nation'. freud's child, for instance, caught both in the relentless unfolding of developmental time and the timelessness of unconscious life, is also the site of the regulation of 'life' itself. whilst these two axes of temporality (development and timelessness), as we saw above, cross one another, the figure of the child is nevertheless a 'retronaut, a bit of the future lodged in the present ' (p. 4) . yet, at the same time, sheldon's child is already melancholic. it knows its childness can't be preserved; it will be lost; just as the future is felt also to be something constantly slipping away. as a melancholic figure, sheldon suggests that the child as resource has a very specific task right now: to cover over the complex systems at work in biological materiality. as non-human animacy becomes more visible in conditions of planetary crisis, with it comes the terrifying potential (at least for the human world) of nature to slip its bonds. the child stands in for life itself at a time of vibrant and virulent reassertion of materialisms in all their forms. the child's new task, according to sheldon, becomes one of binding nonhuman vibrancy back into the human, into something safer, and into the frame of human reproduction. this perhaps helps us modulate how we might respond to the figure of greta thunberg, the climate activist who describes herself as both 'autistic' and living with asperger's, and to her work as a 'cry for help' (thunberg, 2019, p. 3) . during 2018, when she was 15 years old, thunberg started to skip school to sit outside the swedish parliament with a sign reading 'skolstrejk fö r klimatet' [school strike for climate]. 4 as a result of the school climate change movement that grew around thunberg's 'fridays for future' actions during 2019, there has been an intensive, rapid sanctification of the plain-speaking, white, plaitedhaired child now simply known as 'greta'. although she herself acknowledges that she is not unique and is part of a network of youth movements in the global south who bear the brunt in the present for the effects of climate disaster largely produced by the global north, she has nevertheless become an enormously influential figure through whom climate discussions now pass. some describe her influence as simply the 'greta effect' (watts, 2019) . there is a specific and careful simplicity to the way thunberg talks. in a speech entitled 'almost everything is black and white', she states, 'i have asperger's syndrome, and to me, almost everything is black or white' (thunberg, 2019, p. 7) . utilizing what others may see as a disability, a difficulty in seeing shades of grey, she speaks against the need for more complexity, more reflection, more science; in short, a more 'grown up' approach to climate chaos: 'we already have all the facts and solutions. all we have to do is to wake up and change […] everything needs to change. and it has to start today' (p. 11). it is this rhetorical insistence that there is no more time and that the future of her generation has been stolen by the inaction of the generation that has come before that positions her as not so much future-orientated but backed up against a closing future, looking back towards those who came before her as they continue to gaze ahead towards what they imagine is her future. as she states, 'we children are doing this to wake the adults up. we children are doing this for you to put your differences aside and start acting as you would in a crisis. we children are doing this because we want our hopes and dreams back' (p. 68). in many ways, we could see thunberg as performing a call, in the name of a human reproductive future, for the binding of nonhuman vibrancy back into the human, into something safe and stable, the child's new task that sheldon describes. we could also make a critical reading of the ways thunberg -as a contemporary incarnation of maisie in henry james ' (1897/1969 ) what maisie knew, where the child-protagonist is sacrificed to save a negligent and damaged society -re-mobilizes a discourse that re-stabilizes the differences between the generations in the name of the reproduction of the white heteronormative social bond. however, i want to read thunberg's 'black and white' thinking as metonymic with my patient's blank and blue: the oscillation between the absorbing blue of the analytic session and the suspended time of nothing happening between the sessions; the time of no-analyst and the agonies of waiting. thunberg (2019) states: 'there are no grey areas when it comes to survival. either we go on as a civilization or we don't. we have to change' (p. 8). in many ways, she refuses 'development' in the sense of klein's depressive position functioning, where blue and blank come to be understood as having a relation to one another, and insists instead on their separation, on what klein would call 'paranoid-schizoid' thinking, in which blue and blank are radically split apart, as a viable place to speak from. indeed, she goes on insisting she is a child and that development is precisely what has got us into so much trouble. she warns us that, from the perspective of blank time (the time of nothing happening), blue time is absorbing for sure, but it is short, cannot last, and time itself needs to urgently come to matter if we are to find a way out of the current predicament. if we want to repair a relationship with monumental time, there is only action or no action, blue or blank, as we have now run out of time. despite the obvious occlusion of the many brown and black children who have protested, spoken out, organized school strikes and presented to the un over the years and gained no coverage, what is striking is that the white child claims that it is her unusual perspective, in which black and white remain separate, that is our only way out. in describing what she calls 'grey time', laura salisbury (in press) reminds us that grey is not, strictly speaking, a colour at all; rather, it is a shade. as such, it is achromatic, composed of black and white in various shades of intensity, rather than hues. moving from colour to time, salisbury claims that grey time can be thought of as similarly a time that contains intensities of affect, naming grey time as 'anachromistic', a form of intensive temporality that belongs to and traverses the perceiving subject and the aesthetic object. to speak of grey time as anachromistic is to evoke an aesthetic experience that is against colour or hue, but, with its echo of anachronism, also produces a slub in the fabric of time as it is usually thought. the double gesture of the term anachromism is the attempt to speak to time's intensity rather than, as is more usual, concentrating on its flow or movement, while trying to capture an atmosphere where there is a weaving or binding in of blank, uncertain, colourless 'colour', and affect into what is felt of time. (emphasis in original) grey time, then, is an intensity of time that moves us beyond the impasse of action and no action, or blue and blank, by acting as a slub or thickening in the oscillation between the two. this thickening, if we follow salisbury, both reveals time's stuck oscillation between black and white at the same point as it acts to bind greyness into what is felt of time. grey inhabits black and white without resolving the oscillation, both intensifying the sense of time's stuckness but also drawing attention to the affect of greyness, of uncertainty. whilst the time for grey thinking, as thunberg states, may have passed, perhaps salisbury's attention to grey time is important. as the existential dangers facing humanity deepen -by mbembe's description, the destruction of the biosphere, the criminalization of resistance and the rise of determinisms, whether genetic, neuronal, biological or environmental -so perhaps greta thunberg's urgency cannot be heard until we bind the blank, uncertain, colourless affect of the grey 'now' into what is felt of time. mbembe (2020) writes of the covid-19 virus: of all these dangers, the greatest is that all forms of life will be rendered impossible. […] at this juncture, this sudden arrest arrives, an interruption not of history but of something that still eludes our grasp. since it was imposed upon us, this cessation derives not from our will. in many respects, it is simultaneously unforeseen and unpredictable. yet what we need is a voluntary cessation, a conscious and fully consensual interruption. without which there will be no tomorrow. without which nothing will exist but an endless series of unforeseen events. (emphasis in original) this is, indeed, grey time -a voluntary cessation, a conscious and fully consensual interruption to business as usual as a response to the profound ó 2020 springer nature limited. 1088-0763 psychoanalysis, culture & society uncertainty that is the reality of the interdependencies of all forms of life. although i know that there is no way for 'couch time' to have an effect without a 'session-time' analyst and a 'between-session-time' analyst eventually coming together in the time that is an analysis, it may be that we have simply run out of time. then a new psychoanalytic temporality may be needed, one that understands the simultaneous need for and suspension of development in the name of really knowing about the death drive; one in which action would no longer be simply understood as acting out but in which the mutative interpretation, the one that brings about change, can be grey, ill-timed, coming too soon and too late, before it is too late. maternal encounters: the ethics of interruption ó 2020 springer nature limited. 1088-0763 psychoanalysis postmaternal, postwork and the maternal death drive. special issue: the postmaternal after the future 1889/1994) time and free will: an essay on the immediate data of consciousness 1896/2004) matter and memory the 1911 schoolchildren strikes when the kids are united introduction: time studies today the force of non-violence the climate of history: four theses no future: queer theory and the death drive past/future time binds: queer temporalities, queer histories. durham and london beside you in time: sense methods and queer sociabilities in the american nineteenth century /1955) three essays on the theory of sexuality /1957) instincts and their vicissitudes /1955) beyond the pleasure principle beyond the pleasure principle /1964) analysis terminable and interminable a queer place and time lose your mother: a journey along the atlantic slave route semiotext(e). invisible committee, the (2014) to our friends the (2017) now. new york: semiotext(e) 1897/1969) what maisie knew the womb of western theory: trauma, time theft and the captive maternal time driven: metapsychology and the splitting of the drive /1975) notes on some schizoid mechanisms /1998) love, guilt and reparation the shock doctrine: the rise of disaster capitalism /1986) women's time chronophobia: on time in the art of the 1960s the future cannot begin: temporal structures in modern society the universal right to breathe. translated by c. shread. critical inquiry white time: the chronic injustice of ideal theory the chronopolitics of racial time introduction to women's time the colonisation of time: ritual, routine and resistance in the british empire you are my death: the shattered temporalities of zombie time matters of care: speculative ethics in more than human worlds grey time: anachromism and waiting for beckett what is maternal labour? the social life of social death: on afro-pessimism and black optimism the child to come: life after the human catastrophe no one is to small to make a difference. london: penguin, random house future shock subjectivity in-between times: exploring the notion of time in lacan's work the greta thunberg effect: at last, mps focus on climate change. the guardian publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. ó 2020 springer nature limited. 1088-0763 psychoanalysis the research in this paper was funded by a wellcome trust collaborative award, 'waiting times', grant number [205400/a/16/z] (see waitingtimes.exeter.ac.uk). data sharing is not applicable as no datasets were generated and/or analysed for this study. (2007) and hedva (2016) . 4. in doing so, she was perhaps unwittingly building on a long history of school strikes, certainly dating back at least 100 years in the uk, in which schoolchildren mobilised against caning in 1889 and later came out on strike as part of a number of localised general strikes in 1911. see bloom (2010 bloom ( , 2011 . key: cord-032017-h0cj4izx authors: roach, e. steve title: child neglect by any other name date: 2020-09-17 journal: pediatr neurol doi: 10.1016/j.pediatrneurol.2020.09.006 sha: doc_id: 32017 cord_uid: h0cj4izx nan if 50 million people say a foolish thing, it is still a foolish thing. anatole france barely three weeks old, the baby lay fighting for life due to intracranial hemorrhages resulting not from physical trauma, but from medical neglect. child neglect includes knowingly failing to protect a child from preventable harm. his parents had refused the administration of vitamin k after birth. why? because they didn't believe in doing things that are not "normal and natural." sadly, failure to administer vitamin k to newborns, typically a single injection or a series of oral doses, has become commonplace in the united states, allowing a resurgence of the deadly hemorrhagic disease of the newborn that had become almost non-existent in westernized countries. 1 schulte and colleagues noted that 28% of the babies born in private birthing centers in their area and 3.4% of the babies born at their own academic medical center failed to receive vitamin k after birth, with sometimes tragic results. 2 at first "normal and natural" sounds like a sweetly quaint and wholesome approach, until one considers the brutal reality of what it could mean to a child's chances of survival if fully implemented. in 1800, when things were certainly very "natural," only 57% of children survived to age five. a century later, that number had improved slightly to about 65%. in recent years, over 95% of children survive to age five years. 3 much of this stunning improvement in child mortality resulted from prevention and treatment of infections through improved sanitation, the development of antibiotics, and vaccines targeting once deadly and crippling diseases. no rational person would wish to experience those terrible losses again. indeed, rather than letting nature take its cruel path no matter how devastating the consequences, we should be trying to improve on the natural course in order to optimize each child's chances to survive and thrive. refusal of vitamin k administration shares with vaccine denial an unwillingness to accept the sound scientific evidence supporting the practice. lulled into complacency by the lower frequency of deadly contagious diseases in recent decades and gullibly accepting the internet-amplified comments of prominent but misinformed celebrity "spokespeople," too many parents discount the compelling proof of the safety and effectiveness of vaccines. some parents may be merely afraid and unaware of the facts, and they need only appropriate information and respectful guidance. these parents are merely advocating for their child's well-being. others seem to be so firmly entrenched in their beliefs that no amount of proof will change their mind. like their sister skeptics, the "climate deniers," the vaccine deniers defiantly dismiss any contrary information, and the introduction of additional scientific evidence only seems to strengthen their confidence in the correctness of their own unsubstantiated beliefs. we physicians must bear some of the blame here, as do many of our elected officials. by feebly accepting vaccine denial as even approaching a rational option, we become enablers of inappropriate choices by individuals who are ill-equipped to weigh the evidence or choose to ignore it. not all physicians have been so complacent, of course. the american academy of pediatrics has consistently and strongly recommended immunizations, although they could have been more direct in discussing the ethical failure that parental denial of immunizations represents. some individual physicians have taken a strong stand on the need for immunization despite the online bullying by militant vaccine deniers that often ensues. but on the whole, our collective response has been anemic. admittedly, physicians are placed in a very difficult situation when dealing with vaccine deniers. beneficence on behalf of the child, whose welfare is their primary concern, compels physicians to advocate strongly on behalf of the benefit that vaccines convey to that child. they may have a secondary obligation to educate the child's parents about the value of immunizations, but the child's wellbeing is paramount. as surrogate decision makers for their child, parents also have an ethical duty of beneficence that obliges them to embrace scientifically established procedures that will increase the child's likelihood of health and well-being. in parallel, the physician also has an obligation to avoid the spread of preventable infections in other children in their practice. and while discharging the unimmunized child from the physician's practice may initially seem like a plausible solution, abandoning the child because of their parents' failure to act in their child's best interests may not be the best approach. physicians need to avoid "science speak." we sometimes obscure the facts with thickheaded comments such as "there is no epidemiological evidence for a causal association" when we should say simply and directly that an assertion is "blatantly false." even the somewhat euphemistic term "vaccine hesitancy" lends a noblesounding aura to a very irrational and potentially deadly thought process. trying to "engage" families in order to educate and convince them of the wisdom of immunization is fine for the parents who want information and are willing to accept guidance, but this approach is clearly wasted on the entrenched vaccine deniers. perhaps our message needs to also directly articulate the concept of vaccine denial as a form of child neglect. the vaccine deniers may continue to ignore the scientific evidence, but at least there would be no room for doubt about what we physicians recommend. there is nothing good about the current novel coronavirus pandemic that is sweeping the globe, but if hundreds of thousands of coronavirus-related deaths serve to make some of the skeptics finally grasp the deadly seriousness of infections in a world without vaccines, it will have at least achieved something. a few of us can remember the similar terror surrounding the epidemics of poliomyelitis before the advent of vaccines, and none of us want to see children die from bacterial meningitis again. one hopes that the vaccine deniers will opt to accept a coronavirus vaccine when it becomes available, although recent outbreaks of preventable illnesses such as mumps and measles among immunized individuals seem to have opened few closed minds. the administration of vitamin k is about as close as one ever gets to risk free. similarly, the safety and efficacy of vaccines have been thoroughly established. vaccines do not cause autism, a bogus but persistent notion that arose from a long-since retracted 1998 publication containing fabricated data. 4, 5 about four children per 100,000 children have a febrile seizure after receiving an immunization, 6 arguably fewer children than would experience a febrile seizure during the very illnesses prevented by the vaccines. a few children have medical reasons to avoid specific vaccines, but immunizations are overwhelmingly safe. 7 the bottom-line question is "does the potential benefit of an immunization exceed the likelihood of an adverse effect?" if the answer to this question is unequivocally yes, which it almost always is for immunizations, then refusal to allow vaccination after being fully informed of the facts amounts to child neglect. 8 parents are afforded broad freedom to raise their children in keeping with their own culture and values. provided that the child is not harmed, this approach is appropriate. but injuring a child, purposely denying adequate nutrition, and failing to protect a child from preventable risk, even in the name of discipline and decorum, is taboo in most civilized cultures. ultimately a child's right to exist, free of avoidable injury or illness, should supersede a parent's right to do whatever they wish when rearing their children. parents are not always allowed to deny well-validated medical treatments for their children. a parent who attempts to deny a child chemotherapy for acute lymphocytic leukemia, for example, is typically met with a court order terminating their custody of the child until after she undergoes the needed chemotherapy. chemotherapy drugs have many serious side effects, so one can easily understand how a parent might want to avoid the whole situation. 9,10 but in the end, the child's right to live, or in this example, to maximize his odds of surviving, trumps the parents' desire to avoid chemotherapy. so why are parents allowed to forbid the administration of life-saving vaccines or vitamin k but not allowed to deny cancer chemotherapy? leukemia represents a clear and present danger to the child, while vaccines reduce the risk of disease that might or might not occur. no doubt the looming certainty of death from untreated leukemia makes it easier for the authorities to summon the courage to act, but is there an acceptable threshold for allowing a preventable risk? how much avoidable risk to a child is too much to ignore? if the imminent danger argument were reasonable, then how does one explain required car seats for children? most car trips do not result in accidents, after all, but some of them end just as tragically for the unrestrained child as would untreated leukemia. the car seat requirement is designed to maximize the odds of a child's survival in the event of an accident, and it has nothing to do with whether the danger is imminent. why are vaccines not viewed in a similar fashion? of course, few things are simple. the likelihood of some preventable infections is considerably higher than others. measles and mumps outbreaks are increasingly common, for example, while polio is nonexistent in much of the world. some of the benefit of immunizations is societal rather than individual, and vaccine denial would result in far more disease were it not for the herd immunity resulting from the responsible immunization of most children. is it fair for an individual's rejection of established scientific evidence to place their child and other people at risk in the name of personal freedom or preference? is it fair to ask others to accept the human suffering and financial burden resulting from infections that could easily have been prevented? parents also have an ethical responsibility to not promulgate preventable disease in other individuals. the argument that it is acceptable to decline vaccines because they have risks is utter nonsense, because the likelihood of preventing a disease with a vaccine is higher than the risk of a complication. 8 the family's cultural background, intentions, and level of sophistication may sometimes be relevant when defining child abuse and neglect, but never to the point of justifying a child's injury or exposure to preventable risk. while visiting the middle east, i once encountered a bedouin child with failure to thrive and hypotonia. she had numerous oval pigmented lesions on her abdomen resembling burn scars. in western countries, the sight of intentional burn marks on a malnourished child would send most of us scurrying to notify the authorities. but cautery is a commonly employed folk remedy in her culture. 11 her burns had resulted from application of a hot spoon from the campfire to her abdomen, the site thought to be responsible for her poor weight gain. was this child abuse? the family's intent was to help the child, not to hurt her, cautery was an accepted traditional ritual in their culture, and their ability to learn about better options may have been limited. yet she suffered avoidable burns and her failure to thrive was not quickly assessed by physicians, so she was harmed, despite the family's benign intentions. one might argue that vaccine denial represents a similar situation. the vaccine deniers do not intend to harm their children, of course, and in some circles, withholding vaccines is so prevalent and so entrenched that it resembles a primitive cultural belief system. but most western families who fail to immunize their children know about vaccines and have ready access to physicians and nurses who could clearly explain their risks and benefits. yet some of them opt to deny the solid science that would give their child the best odds of staying healthy. i will at least give the bedouins some benefit of the doubt. it is time to stop the political correctness and "science speak." parents should have the right to raise their children in accordance with their own preference, culture and religious beliefs, provided that their approach does not substantially increase the child's odds of an avoidable illness or injury. but given the extremely low risk of immunization and vitamin k administration, the bar for "substantial" risk should be extremely low. vaccine denial may not cross a threshold that triggers harsh measures by the authorities, but there should be no acceptable preventable risk. no matter how wellintentioned the decision may be, the willful, informed avoidance of scientifically proven measures that would improve a child's odds of optimal health and survival amounts to child neglect. physicians must rise with one voice and say "enough!" by even considering the premise that vaccine denial can be a reasonable choice by a rational individual, we become enablers of child neglect. intracranial hemorrhage in early infancy--renewed importance of vitamin k deficiency rise in late onset vitamin k deficiency bleeding in young infants because of omission or refusal of prophylaxis at birth ileal-lymphoid-nodular hyperplasia, nonspecific colitis, and pervasive developmental disorder in children ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children febrile seizure risk after vaccination in children one to five months of age responding to parental refusals of immunization of children professional responsibility and early childhood vaccination neurological complications of the treatment of pediatric neoplastic disorders a review of chronic leukoencephalopathy among survivors of childhood cancer ancient mideast cauterization practices and developmentally delayed children: a call for advocacy key: cord-016596-hxr0n1jd authors: kivekäs, ilkka; rautiainen, markus title: epiglottitis, acute laryngitis, and croup date: 2018-05-04 journal: infections of the ears, nose, throat, and sinuses doi: 10.1007/978-3-319-74835-1_20 sha: doc_id: 16596 cord_uid: hxr0n1jd epiglottitis, acute laryngitis, and croup (acute laryngotracheobronchitis) are infections of the upper airway, affecting the epiglottis, larynx, and larynx and trachea, respectively. epiglottitis is a bacterial infection, while viruses cause nearly all cases of acute laryngitis and croup. acute laryngitis in adults is usually self-limited. epiglottitis, which used to be prevalent in children under age 5, is now seen more often in adults than in children. this decline in childhood epiglottitis is due to the haemophilus influenzae type b (hib) vaccine. streptococci, including streptococcus pneumoniae, are now important causes of epiglottitis. croup is a viral infection, usually due to parainfluenza virus, that primarily affects children ages 6 months to 3 years old. epiglottitis and croup can cause life-threatening loss of the airway, and misdiagnosis or mismanagement can result in fatalities. this chapter reviews the clinical features and treatment of these three upper respiratory tract infections. epiglottitis, acute laryngitis, and croup are infections of the upper airway, affecting the epiglottis, larynx, and larynx and trachea, respectively. croup may also involve the bronchi. epiglottitis is a bacterial infection, while acute laryngitis and croup are primarily viral infections. epiglottitis was known to the ancient world. the infection was probably described by hippocrates 2400 years ago when he wrote: "there is fever, chill, pain in the head, the underpart of the jaw is swollen: the patient swallows with difficulties his saliva. the patient cannot spit, he cannot tolerate to lie down, and if he stays in this position he chokes" [1] . in 1791, the first clear description of acute epiglottitis was published, and the term "epiglottitis" was coined in 1830 [2] . invention of the laryngoscope in the 1850s allowed direct visualization of the swollen epiglottis, and soon thereafter the mirror examination of the hypopharynx and larynx became widely practiced. in the early twentieth century, the term "acute epiglottitis" became part of standard medical terminology and the role of bacteria in the pathogenesis of the disease became clear. the prognosis of the disease improved in some cases with tracheotomy, tracheostomy, or intubation. george washington, the first president of the united states, died in 1799 of an acute infection that was probably epiglottitis [3] . a tracheotomy (a new procedure then) was proposed by one of his physicians but not performed. the major advance in treatment of epiglottitis occurred following the introduction of antibiotics in the mid-twentieth century. the introduction of the haemophilus influenzae type b (hib) vaccine in 1985 dramatically decreased the incidence of epiglottitis, especially in the pediatric population. the vaccine was improved (conjugated vaccine) in 1987 and 1990 so that efficacy extended to children younger than 18 months. croup, an old term meaning "to cry hoarsely," was originally applied to cases with croup-like symptoms (inspiratory stridor, hoarseness, and a barking cough) due to diphtheria. however, diphtheritic "croup" was subsequently distinguished from viral croup by the twentieth century. croup now refers to acute viral laryngotracheobronchitis or laryngotracheitis. epiglottitis, also called supraglottitis, is an acute infection of epiglottis and surrounding supraglottic tissues that can rapidly lead to life-threatening airway obstruction. supraglottitis is a more accurate term because in many cases, several supraglottic structures are involved (e.g., aryepiglottic folds, arytenoids). prior to the introduction of the hib vaccine 30 years ago, h. influenzae type b caused most cases of epiglottitis and the disease primarily affected children younger than 5 years old. now, invasive h. influenzae type b infections are very rare in children and the incidence of epiglottitis is higher in adults than in children. before the hib vaccine, the incidence of epiglottitis in children under age 5 years was as high as 15 cases per 100,000 population. the peak incidence occurred in children under age 3. since the introduction of the hib vaccine in 1985, the incidence in children has decreased to 0.5-0.7 cases per 100,000. in finland, 50-60 cases per year of epiglottitis were seen throughout the country in 1985-1986, and this decreased to only two cases in 1992, reflecting the widespread use of the hib vaccine [4] . in sweden, the incidence of epiglottitis in children under age 5 decreased from 21 to 0.9 cases per 100, 000 following hib vaccination [5] . the median age of children affected by epiglottitis has also increased in the hib vaccine era. at one center, the median age of children with epiglottitis before 1989 was 36 months and 81 months (nearly 7 years) after 1990 [6] . the incidence of epiglottitis in adults has remained stable or has increased since the introduction of the hib vaccine [7, 8] . in finland, the annual incidence of epiglottitis in adults increased from 1.88 (1990-1999) to 4.7 (2000-2009) per 100,000 [8] . in denmark, the annual incidence in adults has been stable at 1.9 cases per 100,000 [9] . most cases of epiglottitis now occur in adults. a study from australia found that 84% of patients hospitalized for epiglottitis in the vaccine era have been adults [10] . the average age of adults with epiglottitis is mid-40s, but the range in one series was wide (age 18-92 years) [8] . epiglottitis usually occurs in previously healthy children or adults. there is no clear seasonal variation. slightly more males than females are affects, with a ratio of 1.4:1-1.7:1 in most series [8] . the epiglottis is a leaf shaped elastic cartilage with overlying loose connective tissue and a thin mucosa. the laryngeal airway in children is narrow. a comparatively minor swelling of the mucosa may cause significant airway narrowing. acute epiglottitis usually starts with swelling of the lingual surface of the epiglottis, and then spreads to the laryngeal surface and the aryepiglottic folds. bacterial invasion of the mucosa leads to fulminant infection. especially in children, the epiglottis is the primary focus of infection and other parts of larynx may not be swollen. an epiglottic abscess can develop in either adults or children. as noted above, h. influenzae type b caused most cases of epiglottitis in the pre-vaccine era. this was determined from blood cultures (positive in many children with h. influenzae epiglottitis), and some throat cultures. the true etiology of epiglottitis is now difficult to determine in most cases, because adults comprise the majority of cases and only 10% are bacteremic [8] . throat cultures are contaminated by oral flora so may not demonstrate the true pathogen. in a series of 34 adults, only one had a positive blood culture (h. influenzae), while eight with throat cultures grew oral flora organisms in seven and h. influenzae in one [11] . streptococci such as streptococcus pneumoniae and group a streptococcus are the predominant causes of epiglottitis in most series in the vaccine era [8, 9, 12] . staphylococcus aureus causes some cases, and cases due to methicillinresistant s. aureus (mrsa) have been described [13] . a large series of epiglottitis in adults reported positive blood cultures in 16 (10% of those in whom blood cultures were obtained) [8] . of these 16 cases, cultures grew streptococci (including s. pneumoniae, group a streptococcus, streptococcus milleri) in 11 (69%), s. aureus in two (13%), and gramnegative bacilli in two (13%) including a case due to pseudomonas [8] . only one patient in that study had a culture positive for h. influenzae, and that grew on a throat culture. the microbiology of epiglottitis in children is similar to that in adults. the hib vaccine effectiveness is approximately 98%, so cases of epiglottitis due to h. influenzae type b are rare but do still occur. in one series of 19 children admitted in the vaccine era, h. influenzae type b was the etiology of six cases; streptococci accounted for another six cases (s. pneumoniae, group a streptococcus, other beta-hemolytic streptococci) [14] . in immunocompromised patients, pseudomonas and candida have caused some cases of epiglottitis [15] [16] [17] . children with epiglottitis typically present with a high fever, inspiratory stridor, restlessness, and drooling. breathing difficulties may cause a toxic and anxious appearance. the child usually presents sitting forward in a "tripod" or "sniffing" position and does not want to lie down. the child's head is hyperextended to maintain a patent airway. the child has pain with swallowing and may have a sore throat. the voice is often muffled, described as a "hot potato voice." symptoms arise very quickly, in most cases within 12-24 h including symptoms of any antecedent upper respiratory tract infection. unlike croup, cough is uncommon. children with epiglottitis are often systemically unwell and the situation is considered an otolaryngologic emergency. the differential diagnosis in children may include croup (acute laryngotracheobronchitis), discussed later. however, children with croup have a barking cough and are less likely to have drooling or to insist on sitting forward in the "sniffing" position. children with croup usually appear less toxic than children with epiglottitis. symptoms of acute epiglottitis usually develop more slowly in adults than in children. the most common symptom, seen in nearly all the cases, is sore throat. in a study from finland of 308 adults admitted with epiglottitis 1989-2009, the mean duration of symptoms prior to presentation was 3.7 days, and 94% of patients complained of sore throat [8] . other symptoms included odynophagia or dysphagia (80%), fever (60%), dyspnea (38%), hoarseness (30%), muffled voice (12%), drooling (11%), cough (8%), and stridor (7%) [8] . patients with epiglottitis find breathing in the supine position difficult or impossible and prefer to sit, leaning forward with a hyperextended neck. the patient may cough although infrequently, to clear secretions in the hypopharynx. an epiglottic abscess may be present and this is a risk factor for requiring airway intervention [7] . the differential diagnosis of epiglottitis in adults includes other causes of acute sore throat and severe odynophagia. in epiglottitis, however, the sore throat is more severe than expected based on the findings of the oropharynx examination. the extent of physical examination performed prior to securing the airway should be individualized, depending on the severity of the child's illness and the likelihood that their illness is epiglottitis. rare cases of cardiopulmonary arrest have occurred with attempts at visualization of the epiglottis. similarly, asking the child to lie supine may be dangerous and respiratory arrest has been reported in this position. when acute epiglottitis is suspected, arrangements to secure the airway should be made immediately. the help of a pediatric otolaryngologist or anesthesiologist is often necessary. supplemental humidified oxygen should be given. in children who are not in any respiratory distress, clinical examination may be cautiously performed as long as airway rescue is readily available. the classic red epiglottis may be visualized by gently depressing the anterior tongue with a tongue depressor. similarly, plain neck x-rays can be obtained in the non-acute setting as the patient can remain in the seated position. the lateral view will indicate thickening of the epiglottis, similarly the anterior view will evaluate for subglottic finding which may be associated with other diagnoses in the differential such as croup. all children suspected of having epiglottitis who are undergoing x-ray evaluation should be closely monitored and observed during the entire period while these films are obtained. in more severe cases, the child should be transported to the operating room where the airway can be secured, by controlled intubation or tracheotomy, and diagnostic endoscopy can be performed. diagnostic tests such as blood cultures and routine laboratory tests (e.g., complete blood count with differential) should be performed only after the airway is secured. throat or epiglottic cultures should be obtained only after the airway is secured. if a deep neck infection or epiglottic abscess is suspected, computed tomography (ct) with contrast can be considered after the airway is secured. if acute epiglottitis is suspected, patients should be kept in the sitting position and not asked to lie down. in severe cases with impending airway obstruction, the airway should be secured prior to any attempt at examination. in most cases of adult epiglottitis, there is less risk to performing a direct examination than in children. however, a specialist such as an anesthesiologist or otolaryngologist should be on hand, as the patient can deteriorate rapidly. indirect laryngoscopy with mirror examination can usually be performed in adults to diagnose epiglottitis, although nasolaryngeal endoscopy with a flexible fiberoptic may be safer and more easily done. the diagnosis of epiglottitis is made by noting a swollen and red epiglottis, although in adults the primary site of swelling may be in other supraglottic structures. one study found swelling of the epiglottis in 73% of adults with epiglottitis but swelling of the epiglottis alone occurred in only 17% [8] . after confirming the diagnosis, the airway should be secured if necessary. an intervention (intubation or tracheotomy) may not be necessary in adults with epiglottitis. in a study of 61 patients in the vaccine era (60 adults, 1 child), only 21% required airway intervention (11 intubations, 2 tracheotomies) [12] . in a study of 308 adults with epiglottitis, 15% required airway intervention (two-thirds intubation, one-third tracheotomy) [8] . factors associated with the need for airway intervention include a rapid onset of symptoms, stridor, drooling, and tachypnea [8, 12] . diagnostic tests should be done once the airway is secured, or once it has been determined that the airway is sufficiently patent so as to not require immediate intervention. if there is a suspicion of deep neck infection or an epiglottic abscess, a ct with contrast should be considered once the airway is secure. empiric antibiotic treatment of acute epiglottitis in children or adults should cover h. influenzae, s. pneumoniae (including penicillin-resistant strains), group a streptococcus, and s. aureus (including mrsa). intravenous vancomycin plus ceftriaxone will cover these organisms. even in regions where mrsa is rare, the addition of vancomycin to ceftriaxone is usually recommended because some s. pneumoniae isolates are not susceptible to ceftriaxone, and vancomycin will provide additional staphylococcal coverage. in immunocompromised patients, an antibiotic regimen that will also treat pseudomonas should be considered (e.g., intravenous vancomycin plus either meropenem or imipenem). antibiotics can be tailored once results of blood and throat cultures are known. managing the airway is the utmost importance in epiglottitis. even in patients who appear stable, clinical deterioration can occur at any point. acute loss of the airway is the primary cause of death in epiglottitis. securing the airway by intubation usually can be performed safely, but requires experienced and expert anesthesiologists or otolaryngologists. preparations for obtaining a surgical airway, such as tracheotomy, should always coincide with any attempt at intubation, as acute airway obstruction can occur with a failed intubation attempt as discussed later. awake fiberoptic intubation can be attempted in the cooperative patient as an initial attempt to secure the airway. direct and videoassisted laryngoscopy may be attempted, but the necessary sedation requires rapid access to airway and associated swelling and secretions can limit visualization. if an emergency surgical airway is required, the type depends on the age of the patient. needle cricothyrotomy can be performed on patients of any age, but this is the preferred surgical technique in children under age 12. needle cricothyrotomy is easier to perform and less likely to damage the larynx in young children than surgical cricothyrotomy. needle cricothyrotomy provides stabilization of the patient allowing a formal surgical airway such as a cricothyrotomy or tracheotomy to be performed in a controlled manner. should immediate airway access be required, then emergent cricothyrotomy such be undertaken, with potential conversion to a standard tracheotomy if warranted. in adults with epiglottitis, the airway can be maintained without intubation in most patients (80 to 85%) [8, 12] . severe airway distress is possible in adults but less common than in children, since adults have larger airways. humidified oxygen and close monitoring (usually in an intensive care unit) may be sufficient for airway management in many adults. intravenous corticosteroids are often used in an effort to reduce supraglottic inflammation, although randomized controlled trials have not been performed to assess benefit. for adults with moderate to severe respiratory distress, more active intervention is necessary. tracheotomy is not the first choice but should be chosen if expertise in difficult intubations is limited. endotracheal intubation should be attempted only by an experienced anesthesiologist (or otolaryngologist) and always with readiness for immediate cricothyroidotomy. a failed endotracheal intubation attempt can result in immediate and total airway distress. there is no time to waste in providing an artificial airway in these cases. in cases with severe airway distress, awake tracheotomy with local anesthesia is the most secure and safe way to provide an airway. the transtracheal intubation should be also left to the most experienced airway specialists. in 10-20% of adults with epiglottitis, there is a concomitant abscess in the epiglottis. the abscess is associated with more severe symptoms and airway distress [7] . in these cases, surgical drainage of the abscess in indicated after the airway is secured. a tracheostomy is often indicated and opening of the abscess is carried out under direct laryngoscopy. acute laryngitis is a common inflammatory disorder of the larynx. typical symptoms include hoarseness, loss of voice, sore throat, and other nonspecific symptoms of upper respiratory tract infection. fever and tender cervical lymphadenopathy may be present. nearly all cases are due to upper respiratory viruses and are self-limited. patients with laryngitis caused by infection may also have fever and swollen lymph nodes. the symptoms last less than 2 weeks. acute laryngitis is the most common disease of the larynx. the true prevalence in the adult population is difficult to determine, because most patients do not seek medical attention. a study conducted by the royal college of general practitioners in the united kingdom estimated an incidence of nearly seven cases per 100,000 population per week [18] . inflammation of the larynx may involve any area of the larynx, including the supraglottic, glottic, and subglottic areas [19] . edema of the vocal cords leads to dysphonia. an upper respiratory tract infection is the most common cause of acute laryngitis and nearly all cases are viral. the viruses involved are presumed to be those that cause other common upper respiratory infections, such as rhinovirus, influenza, parainfluenza, and adenovirus [19] . rare cases of acute laryngitis are due to bacteria, or are initially viral but develop bacterial superinfection. bacterial causes include the usual respiratory bacterial pathogens (group a streptococcus, s. pneumoniae, h. influenzae, m. catarrhalis) [19] . a rare case of mrsa membranous laryngitis has been reported in a child with concurrent influenza [20] . evidence of a bacterial infection elsewhere (e.g., pneumonia, streptococcal pharyngitis) supports a bacterial etiology. noninfectious causes of laryngitis include gastroesophageal reflux, fungal infections of the larynx due to inhaled corticosteroids, and irritation from inhalers used for asthma. in most cases, symptoms develop subacutely rather than acutely, and are not accompanied by other symptoms of upper respiratory infection. in many cases of laryngitis due to noninfectious etiologies, the symptoms are chronic by the time the patient presents to the otolaryngologist. in patients whose duration of symptoms is greater than three weeks, direct visualization of the larynx should be undertaken with the consideration of a possible malignant etiology. this is especially true in patients with a significant smoking history. because most acute laryngitis cases are due to viruses, treatment is conservative and includes voice rest. a brief course of inhaled or oral corticosteroids can help reduce vocal cord inflammation, but this treatment should only be used in patients who have an urgent need to use their voice. one study found that inhaled versus oral corticosteroids reduced laryngeal hyperemia and edema to a similar degree [21] . antibiotics should not be used unless there is evidence of bacterial superinfection. a cochrane review of the literature found no benefit to the use of antibiotics for acute laryngitis [22] . croup is a clinical diagnosis referring to symptoms of acute viral laryngotracheobronchitis or laryngotracheitis, the latter description preferred by some authors [23] . the clinical presentation is due to acute laryngeal and subglottic swelling and is characterized by the abrupt onset of a barky cough, typically accompanied by hoarseness, inspiratory stridor, and respiratory distress [24] . the term "spasmodic croup" is sometimes used to refer to afebrile episodes of croup that may be recurrent [25] . croup is one of the most common causes of respiratory distress in young children, affecting approximately 5% of children during the second year of life [23] . children between the ages of 6 months and 3 years old are most often affected, although some cases occur in children as young as 3 months and rare cases occur in adolescents [24] . boys are affected approximately 1.4 times more often than girls [24] . croup occurs most often in autumn (september to december) in temperate climates [24] , but cases may occur at any point throughout the year. parainfluenza virus type 1 is the most common cause of croup and this virus produces epidemics of respiratory illness, including croup, in the fall every other year [25] [26] [27] . in north america, oddnumbered years have an increased incidence of croup compared with even-numbered years, as a consequence [24] . in a study of 144 children presenting to an emergency department in helsinki with respiratory stridor, parainfluenza viruses accounted for over 40% of cases with parainfluenza virus type 1 the most common virus identified [28] . other major causes of croup include parainfluenza virus types 2 and 3, while less common etiologies include influenza a and b and respiratory syncytial virus [25] . human metapneumovirus, adenovirus, and coronavirus cause some cases. croup is a viral infection that leads to edema of the larynx and trachea; the bronchi may also be involved. this is most critically manifested by edema within the cricoid ring, which has a fixed circumference as well as being the narrowest region of the pediatric airway. significant narrowing in this region can lead to life-threatening airway compromise. the narrowed subglottic region leads to the typical barky cough. the subglottic region of a young child is narrower and more pliable than in older individuals, and the narrowing that occurs with inspiration may be exaggerated in a young child with croup [25] . croup usually begins with nonspecific upper respiratory tract symptoms (coryza, nasal congestion), but then 12-48 h later there is the abrupt onset of a barky cough. the onset of this cough is usually late at night. stridor, hoarseness, and fever are other features of the infection. fever may be high (39.4-40 °c, or 103-104 °f), especially in cases due to influenza or parainfluenza virus [25] . respiratory distress occurs in varying degrees, depending on the severity of the airway obstruction. in mild cases of croup, stridor is absent at rest but may be present when the child is upset or crying. cases classified as moderate to severe croup are associated with stridor at rest and an increasing degree of chest wall retractions (although retractions may decrease in severe croup with impending airway failure). in severe croup, the child is agitated or lethargic. lateral and anteroposterior (ap) plain film x-rays can be obtained in stable patients, while maintaining close observation. the ap film can demonstrate subglottic airway narrowing, the classic "steeple sign" supporting the diagnosis of laryngotracheobronchitis. similarly, the lateral film can assist in evaluating for finding associated with alternative diagnoses, such as supraglottis. most cases of croup are mild, and treatment consists of symptomatic treatment plus a single dose of corticosteroid (0.15-0.6 mg/kg, maximum 10 mg) [24] . a single dose of oral dexamethasone was shown to be beneficial in mild croup in a randomized controlled trial [29] . humidified air has a long history of use in treating croup, but there is evidence that it is not effective and should not be used [24] . children with moderate to severe croup require evaluation in an emergency department. care must be taken to keep the child calm (e.g., the child can sit on the parent's lap), as agitation can worsen symptoms. treatment of moderate croup is with a single dose of dexamethasone and oxygen as needed [24] . very brief courses of corticosteroids are well tolerated and safe in children [30] . treatment of severe croup includes blow-by oxygen (optional unless cyanosis is present), corticosteroids, and nebulized epinephrine. the ben-efit of nebulized epinephrine in respiratory distress is rapid but short term. onset of the effect starts within 10 min and lasts from 1 to 2 h [4] . retreatment with nebulized epinephrine may be required. children with severe croup may require admission to a pediatric intensive care unit, and intubation is required in some children (<3%). the diagnosis of bacterial tracheitis should be considered in children with a high fever and a toxic appearance; this diagnosis requires treatment with antibiotics. epiglottitis, acute laryngitis, and croup (acute laryngotracheobronchitis) are infections of the upper airway, affecting the epiglottis, larynx, and larynx and trachea, respectively. epiglottitis is a bacterial infection, while viruses cause nearly all cases of acute laryngitis and croup. acute laryngitis in adults is usually self-limited. epiglottitis, which used to be prevalent in children under age 5, is now seen more often in adults than in children. this decline in childhood epiglottitis is due to the haemophilus influenzae type b (hib) vaccine. streptococci, including streptococcus pneumoniae, are now important causes of epiglottitis. croup is a viral infection, usually due to parainfluenza virus, that primarily affects children ages 6 months to 3 years old. epiglottitis and croup can cause sudden and life-threatening loss of the airway, and misdiagnosis or mismanagement can result in fatalities. with appropriate management, however, death from these infections is very rare. oeuvres completes d'hippocrate avec le texte grec en regard collationne sur les manuscrits et toutes les editions acute epiglottitis: historical highlights and perspectives for future research death of a president disappearance of epiglottitis during large-scale vaccination with haemophilus influenzae type b conjugate vaccine among children in finland epiglottitis in sweden before and after introduction of vaccination against haemophilus influenzae type b effects of haemophilus influenza type b immunization the rising incidence of adult acute epiglottitis and epiglottic abscess acute supraglottitis in adults in finland: review and analysis of 308 cases acute epiglottitis: epidemiology, clinical presentation, management and outcome epiglottitis in sydney before and after the introduction of vaccination against haemophilus influenzae type b disease long-term outcome of critically ill adult patients with acute epiglottitis supraglottitis in the era following widespread immunization against haemophilus influenzae type b: evolving principles in diagnosis and management complicated adult epiglottitis due to methicillin-resistant staphylococcus aureus epiglottitis in the hemophilus influenzae type b vaccine era: changing trends pseudomonas aeruginosa supraglottitis in a six-month-old child with severe combined immunodeficiency syndrome candida epiglottitis in immunocompromised patients membranous laryngitis in a child use of inhaled versus oral steroids for acute dysphonia antibiotics for acute laryngitis in adults clinical practice: croup american academy of pediatrics textbook of pediatric care croup hospitalizations in ontario: a 14-year time-series analysis pediatric hospitalizations for croup (laryngotracheobronchitis): biennial increases associated with human parainfluenza virus 1 epidemics respiratory viruses in laryngeal croup of young children a randomized trial of a single dose of oral dexamethasone for mild croup the cochrane library and safety of systemic corticosteroids for acute respiratory conditions in children: an overview of reviews. evid based child health key: cord-003822-gbwsplgq authors: elmore, dominique; yaslam, balfaqih; putty, krista; magrane, thomas; abadir, anthony; bhatt, saloni; frazier, marie; flesher, susan title: is fever a red flag for bacterial pneumonia in children with viral bronchiolitis? date: 2019-08-06 journal: glob pediatr health doi: 10.1177/2333794x19868660 sha: doc_id: 3822 cord_uid: gbwsplgq we hypothesized that fever in children with viral bronchiolitis indicates the need for consideration of superimposed bacterial pneumonia. we conducted a retrospective study of 349 children aged 2 years and younger with diagnoses of respiratory syncytial virus (rsv) and viral upper respiratory infection. data were analyzed using pearson χ(2) test. one hundred seventy-eight children had rsv with no other identified virus. the majority of children (56%) who had only rsv were afebrile. febrile children with rsv were over twice as likely to be diagnosed with bacterial pneumonia as those who were afebrile (60% vs 27%, p < .001). in the 171 children who had bronchiolitis caused by a virus other than rsv, 51% were afebrile. these children were 8 times more likely to be diagnosed with pneumonia than those who were afebrile (65% vs 8%, p < .001). evaluation of febrile children with viral bronchiolitis may allow early diagnosis and treatment of secondary bacterial pneumonia. several previous studies have revealed potential morbidity from bacterial pneumonia in patients with respiratory syncytial virus (rsv). rsv infection may increase the risk for pneumococcal pneumonia. 1 rsv increases the virulence of streptococcal pneumonia by binding to penicillin-binding protein 1a. coinfection with rsv and streptococcus pneumoniae is associated with severe and often fatal pneumonia. 2 physicians must be mindful of the potential for secondary bacterial pneumonia in viral bronchiolitis so that it can be promptly treated. as pediatricians, we follow the guidelines published by the american academy of pediatrics. the 2014 guidelines dealing with evaluation and management of viral bronchiolitis promote supportive care, and note that routine radiographic or laboratory studies are not necessary. 3 while these guidelines are paramount to treating viral illness, it is imperative that the physician recognizes at what point further investigation is warranted. missing a secondary pneumonia could result in delay in antibiotic treatment, transfer to the pediatric intensive care unit (picu), or intubation. following a respiratory season at our institution, we noted that children with viral illness who also had a fever tended to have a worse clinical course versus afebrile patients. we hypothesized that fever may be a marker for secondary bacterial pneumonia in patients with viral bronchiolitis. fever is defined as temperature ≥100.4°f. if a patient developed a fever and the workup showed pneumonia, then antibiotics could be started quickly rather than waiting until after worsening of the patient's clinical condition. our hypothesis is based on the following anecdotal evidence from our practice: 1. children with bronchiolitis with fevers often seem to worsen and require subsequent transfer to picu. 2. children with just rsv bronchiolitis who are doing well are usually afebrile. 3. children with rsv, fevers, and increasing respiratory distress who are given antibiotics for a secondary bacterial infection seem to have quick resolution of fever with rapid improvement in condition. our objective is to investigate whether children with viral bronchiolitis with fever are more likely to have a diagnosis of secondary bacterial pneumonia than their counterparts without fever. the study included patients ages 2 years and younger who were admitted from july 1, 2015, to june 30, 2017. international classification of diseases (icd) ninth revision codes 466.11 (acute bronchiolitis due to rsv), 466.19 (acute bronchiolitis due to other infectious organisms), and icd 10th revision codes j21.0 (acute bronchiolitis due to rsv), j21.1 (acute bronchiolitis due to human metapneumovirus), j21.8 (acute bronchiolitis due to other specified organisms), and j21.9 (acute bronchiolitis, unspecified) were used to identify patients with acute bronchiolitis who were admitted to the inpatient service and the picu. the data were extracted from the appalachian clinical and translational science institute-clinical data warehouse. diagnoses included rsv, viral upper respiratory infection, pneumonia, respiratory distress, or respiratory failure. for diagnoses of pneumonia, radiographic reports were reviewed and words such as "infiltrate," "consolidation," and "pneumonia" were included in the study. the diagnosis of bacterial pneumonia requiring antibiotics is a physician judgment based on the following criteria: leukocytosis with left shift, elevated total neutrophil count, elevated c-reactive protein (crp), elevated procalcitonin, chest radiograph, and clinical appearance. in a study using procalcitonin levels to guide clinical management, lower procalcitonin levels had fewer clinical features of infection. procalcitonin can provide valuable information to guide clinical decisions. 4 viral infections were diagnosed by hospital viral respiratory panel polymerase chain reaction (table 1 ). fever was defined as a temperature of ≥100.4°f. in addition to bivariate analysis, considering fever and pneumonia, additional trivariate and bivariate analyses were performed regarding temperature ranges and pneumonia. pearson χ 2 test was used to analyze results. this research was submitted to our university institutional review board and was approved. the irbnet id is 1083099-2. of the 349 children included in the study, 178 were rsv positive. the majority of children (56% or 100 children) with diagnoses of rsv were afebrile. febrile children who were rsv positive were more than twice as likely to be diagnosed with bacterial pneumonia as those who were afebrile (47/78 or 60% vs 27/100 or 27%, p < .001). in the 171 children who had rsv-negative bronchiolitis (diagnosis of viral infection other than rsv), 88/171 (or 51%) were afebrile. febrile children with rsv-negative bronchiolitis were 8 times more likely to be diagnosed with pneumonia as afebrile children (54/83 or 65% vs 7/88 or 8%, p < .001). additional bivariate and trivariate analyses of both rsv-positive and rsv-negative bronchiolitis did not show any significant difference between the occurrence of pneumonia in children with fevers in the 100.4°f to 100.9°f range versus fevers in the >102°f range. the study demonstrates that fever can be used as a marker indicating a need to investigate for secondary bacterial pneumonia in children with rsv and other viral illnesses. children with viral illnesses who had a fever were more likely to have diagnoses of pneumonia, whether they had rsv-positive or rsv-negative illness. the literature supports the need to be wary of the possibility of bacterial pneumonia in children with bronchiolitis. rsv infection decreases bacterial clearance, potentially predisposing to secondary bacterial pneumonia despite increased lung cellular inflammation, and suggests that functional changes occur in the recruited neutrophils that may contribute to the decreased bacterial clearance. 5 bacterial infection, based on a significant rise of antibody titer and/or on detection of pneumococcal antigen in serum or urine, was observed in 39% of the children with rsv infection. we conclude that a bacterial pathogen should be actively sought when managing patients with lower respiratory tract syndromes, especially in those who have evidence of rsv infection. 6 the interaction between viruses and bacteria is probably much more common and clinically significant than previously understood. respiratory viruses frequently initiate the cascade of events that ultimately leads to bacterial infection. early recognition and treatment of these patients will lessen morbidity and mortality. 6 based on the findings at our institution, we believe that fever is a marker indicating a need to investigate for bacterial pneumonia. there are several limitations to our study. since sputum cultures are not collected unless a patient is intubated, a definitive bacterial cause cannot be confirmed in most cases. as previously discussed in methods, the diagnosis of bacterial pneumonia is a physician judgment. part of the reason our study is important is that literature does not elucidate any way to definitively determine the presence of bacterial pneumonia in a non-intubated child. several studies have tried to address this issue. crp is elevated when bacterial pneumonia is present, but it has less than desirable specificity for distinguishing viral from bacterial pneumonia. 7, 8 procalcitonin is a better indicator than crp. a procalcitonin less <0.1 has been found to rule out bacterial infection; however, higher values show overlap in procalcitonin levels found in viral and bacterial sources. 9 therefore, we are left with clinical judgement based on looking at multiple factors. since laboratory testing and imaging are discouraged in the initial management of bronchiolitis, perhaps fever can indicate such testing is justified to assist physicians in clinical decision making. a subsequent study will further examine the prevalence of fever during rsv bronchiolitis. literature shows that some viruses such as adenovirus and enterovirus definitely cause fever. 10 our anecdotal experience is that children with rsv alone usually do not have fevers unless they have a secondary bacterial infection. for the sake of clarity in our future study, we will exclude viral causes other than rsv. while our current study shows the majority of children with bronchiolitis do not have fevers, we did not investigate other causes of fever such as pyelonephritis and otitis media. the future study will look for these additional possible bacterial causes of fever and may show an even lower percentage of children with just rsv bronchiolitis who have a fever. febrile children with viral bronchiolitis were 2 to 8 times more likely to be diagnosed with a secondary bacterial pneumonia compared with their afebrile counterparts. delay in care of respiratory illnesses can significantly increase morbidity and mortality. further research is warranted to investigate the need for more aggressive evaluation of febrile children with viral bronchiolitis. we are aware of the limitations and plan to further investigate our findings. we feel this study is relevant because the data discussed could result in a change in practice for viral bronchiolitis in our young patient population. dr drafted the initial manuscript, coordinated, supervised, and participated in data collection, and approved the final manuscript as submitted; by, kp, sb, tm and aa designed the data collection instruments, coordinated, supervised, and participated in data collection and approved the final manuscript as submitted; sf and mf conceptualized and designed the study, coordinated, supervised and participated in data collection, reviewed and revised the manuscript and approved the final manuscript as submitted. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. susan flesher https://orcid.org/0000-0002-3208-7097 association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of us hospitalization data respiratory syncytial virus increases the virulence of streptococcus pneumoniae by binding to penicillin binding protein 1a. a new paradigm in respiratory infection clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis procalcitoninguided use of antibiotics for lower respiratory tract infection decreased bacterial clearance from the lungs of mice following primary respiratory syncytial virus infection respiratory viruses and children perch study group. association of c-reactive protein among children aged <5 years in the perch study the utility of c-reactive protein in differentiating bacterial from nonbacterial pneumonia in children procalcitonin accurately identifies hospitalized children with low risk of bacterial community-acquired pneumonia the repertoire of adenovirus in human disease: the innocuous to the deadly key: cord-026977-prrjscnd authors: forsner, m.; elvhage, g.; ewalds-kvist, b. m.; lützén, k. title: moral challenges when suspecting abuse and neglect in school children: a mixed method study date: 2020-06-16 journal: child adolesc social work j doi: 10.1007/s10560-020-00680-6 sha: doc_id: 26977 cord_uid: prrjscnd the world health organization (who), concludes that child maltreatment is a global concern calling for a multi sectoral interdisciplinary approach. school professionals, such as social workers, teachers, and health care professionals are in positions to discover and report maltreatment enabling social workers to intervene. however, a variety of reports reveal an evident gap between incidences and frequency of number of cases reported. a review of relevant research indicates that the problem of “not reporting” suggests that moral conflicts are activated in the process of decision-making. the aim was to gain a deeper understanding of school professionals’ experiences of reporting suspected neglect and abuse to the social welfare board. in a mixed method approach 32 school professionals, such as teachers, social workers, nurses and psychologists participated in interviews and responded to questionnaires. findings from the qualitative content analysis were compared to the quantitative analysis in a meta-analysis. moral conflicts occur when faced with making decisions about how to best deal with a child’s situation. thoughts about the child’s best interest and relationship with his/her parents as well as the informants´ own safety, were central. the comparative metaanalysis of both data sets revealed these conflicts commence with a moral sensitivity of possible negative consequences for the child. moral sensitivity can be viewed as a “good” personal attribute, it paradoxically might lead to moral stress despite an open ethical climate. based on the results of this study, further research on the interpersonal aspects of dealing with moral conflicts involved in reporting suspected child abuse is indicated. protection services to intervene in cases of maltreatment a "multi sectoral approach" is required. there are many official sectors of professionals who are by law entrusted to observe and report any suspected childhood abuse and neglect. school is the primary sector where professionals have daily contact with pupils, enabling early detection. however, a discrepancy between the number of children exposed to neglect and abuse and the number of officially reported cases has been detected. the question why professionals who are by law delegated to report suspected child abuse and neglect fail to do this needs to be explored. if the professionals in a school system have an accumulated knowledge to be able to identify child maltreatment and competence there must be a dimension that has yet to be explored. in this study, a focus is placed on the ethical nature of reporting suspected child abuse. from a relational ethical perspective, moral conflicts occur in situations in which one person has the authority to make decisions for another; for example, persons who are by legislation judged not to be competent or have the capacity to understand the nature and consequences of decisions that are made on their behalf. although a country may have routines that clearly regulates the responsibility and directions in responding to suspected child maltreatment, it appears that the "human" factor has not adequately been attended to in relevant research of child maltreatment. a personal awareness of how decisions and consequences of actions taken can be conceptualized as moral sensitivity; that one's decision may lead to actions that may have negative outcomes for another person (lützén, 2006) . in this current study we explore school professionals' experiences and deliberations in situation when they suspected child abuse and neglect from an ethical perspective. a mixed method approach included combining qualitative and quantitative data-collection methods, which will be further developed in following sections. the united nations convention on the rights of the child (un, 1989) was developed in recognition of the claim that "the child, for the full and harmonious development of his or her personality, should grow up in a family environment, in an atmosphere of happiness, love and understanding". however, this is not always the case. according to who (2016) a quarter of all adults have been physically abused as children. moreover, worldwide inequality in children's circumstances results in child maltreatment (gilbert et al., 2012) including all forms of physical and emotional ill-treatment (who, 2016) . even national inequality plays a vital role for the risk of maltreatment (bywaters, 2015) . lundén (2011) identifies four areas of maltreatment, namely, "emotional unavailability in the parent-child relation, emotional neglect, physical neglect, and abuse" (pp. 33-34) . according to the annual report for 2016 from united nations children's fund (unicef) child protection systems existed in 139 countries according (unicef, 2017) and national mandatory legislature for reporting child maltreatment exists in many countries. this was also the case in the usa (steen & duran, 2014) , australia, and canada (mathews & kenny, 2008) as well as most european countries according to the european union agency for fundamental rights (fra, 2016) . wiklund (2006) observed that neglect and physical abuse was less frequently reported in sweden in comparison anglo-saxon countries. the swedish national board of health (snbh) estimated reports about maltreatment in 154/1000 children up to 17 years old during 2018. of these 73% were 6-17 years old and approximately 75% were mandatory reports. the reports often concerned the same child (mean 1.9 reports per child) (snbh, 2019). however, according to cocozza, gustafsson, and sydsjo (2007) notifications in sweden represent the tip of the iceberg, which is also recognized in other studies conducted in sweden (svensson, andershed, & janson, 2015; talsma et al., 2015) as well as in other countries (feng, huang, & wang, 2010; goebbels, nicholson, walsh, & de vries, 2008; toros & tiirik, 2016) . these documented facts indicate that children's well-being may also be seriously affected leading to lifelong consequences. research and international publications clearly address the health, social and, judicial aspects of child abuse and the need for early detection and interventions. what seems to be lacking is a discourse, grounded in empirical research, on the ethical aspects of reporting suspected child abuses. in many related studies, other concepts analogous to an ethical framework were used. meyers and cornille (2002) for example, found that "emotional distress" and "compassion fatigue" were commonly experienced by professionals engaged in child protection. similarly conrad and kellar-guenther (2006) , found that approximately half of child-protection staff suffered from compassion fatigue. megan-jane johnstone, a scholar well-known for her work on bio-ethics, pointed out two decades ago, that the ethical aspect of child abuse has to date not received appropriate attention. according to johnstone, "child abuse constitutes a significant moral problem and as such, demands a substantial moral response" (1999, p. 192) . in a publication (20 years later), johnstone maintained that despite legislation, reporting suspected child abuse to a relevant authority is inconsistent in many countries (johnstone, 2019, pp. 352-355) . she states that "reliable data is needed" in order to produce reliable interventions (p. 354), in agreement with johnstone's standpoint that obstructions to mandatory reporting of child abuse has not given attention to the ethical aspects, supports the need for a research design that focuses on how school professionals describe their personal involvement-feelings and actions taken-in cases of suspected maltreatment-and how they have dealt with their duty to report. the purpose of this present study was to investigate school professionals' experiences of dealing with suspected child abuse and neglect-and how they think, reason and act. consequently, the following overarching research questions guided the study design: 1. what concrete incidents of reporting suspected child abuse stand out as particularly difficult for school professionals? 2. what are school professionals' thoughts and reasoning when they decide to report or not to report suspected child abuse? 3. how can their concerns and actions taken be described as morally challenging? the concept of moral sensitivity, comprising, feeling, benevolence and genuineness, as described by one of the co-authors of this study, provided a theoretical framework for the study (lützén et al., 1995) . briefly, the concept of moral sensitivity can historically be traced to the idea of "moral sense" introduced by the philosophers hutcheson and shaftesbury in the eighteenth century. moral sense was viewed as an intuitive faculty that was aroused by a person-s perception of a situation as opposed to rationalist theory of ethics, that objectivity, rational and principled thinking were the only valid ways of knowing what actions to take. hume (1990) , in contrast, upheld the idea that feelings are required in being able to distinguish between "virtuous" and "vicious" actions. in other words, subjectivity, and a feeling for humanity was the main components of moral sense as opposed to rational and principlebased judgment. more current, the interpersonal approach to understanding morality, as a subjective awareness of a person's vulnerability can be linked to a phenomenological approach to ethics. for example, tymeiniecka (1986), introduced the moral sense in her work on morality from the standpoint of benevolence, intersubjectivity and context. these dimensions were also identified using the grounded theory research method in a psychiatric health care context in which patients had limited freedom in their own care (lützén, nordin & brolin, 1994) . timans, wouters and heilbron (2019) recommend the use of a mixed-method research approach in social science. in agreement with these authors, the intention of this study design was to contribute to an understanding of the moral dimension of how a selected group of participants think and act when they suspected child abuse and neglect. the mixed method design also gave a dynamic option to expand the scope and thereby improved the analytic power of the study (levitt et al., 2018; timans et al., 2019) . the design consisted of three components: (1) purposeful selections of participants. (2) qualitative and quantitative data are collected simultaneously and analyzed, while the former data's focus is on individual experience and the latter on group's focus on means of responses relative to report child abuse and neglect. (3) comparative analysis of both research approaches intended to validate the result of the study. narrative interviews can capture emotional elements of significance, whereas, quantitative data, such as the scales that were used in this study could be compared with the qualitative analysis and lead to a meta-analysis. thus, the mixed method design required researchers who could contribute to the analysis of data with their knowledge namely ethics, nursing, social work and psychology. the swedish social services act (sfs, 2001:453) legislates that municipalities are responsible for ensuring a good and secure childhood and obliged to intervene in cases of child abuse and neglect. the municipalities through social workers, have the responsibility to intervene in cases of child abuse and neglect. mandatory reporting to social welfare board about children at risk concerns everyone working with children, including preschool, primary and secondary school. according to the swedish education act (sfs, 2010:800) school attendance is mandatory for children from age 6 to 16 years. child corporal punishment is prohibited by swedish parental code (sfs, 1949:381) . in january 2020 the united nations convention on the rights of the child was incorporated as swedish law (2018, p. 1197). the study was performed within the primary school system in sweden. all schools in sweden follow government legislation as to infrastructure, level of competence of professional staff and curriculum. the swedish education act (sfs, 2010:800) advocates a holistic view on educational goals as well as promotes social development and health for all pupils. consequently, all schools are obliged to provide access to inter-professional schoolhealth teams consisting of the school principal, nurse and doctor as well as social workers employed as counsellors. also psychologists, and teachers with pedagogical competence in guiding children with learning difficulties are a part of the school-health team. the purposeful sampling was aimed at including participants with various occupations as well as a broad variation of schools within a geographic area. six primary schools in the middle of sweden, in rural area (n = 1), small town (n = 2) and big city (n = 3) were included, representing both public and private regime. the principal from each of the six included schools approved and distributed information about this study to all personnel. thirty-two persons: 27 women and five men volunteered, one of them did not answer the questionnaire (table 1 ). the school health team (n = 18) was represented by principals, nurses, counsellors and psychologists. the teaching staff (n = 16) was represented by teachers and auxiliary staff. face-to-face interviews were performed by combining two interview techniques, the narrative interview (riessman, 2008) and the "think-aloud" method (drennan, 2003) . the purpose of the narrative interviews was to gain knowledge of the participants' experience of concrete situations when they suspected abuse and neglect of a pupil. the "think aloud" interview technique was chosen to generate new perspectives, while responding to the three questionnaires. the interviews were conducted by the first and second author. an interview guide was used to promote stability in data collected (graneheim & lundman, 2004) . first, some background questions were asked about their professional role and experiences, followed by an open request: "please tell about a situation in which you considered to report child abuse or neglect to social services". the understanding of the decision-making process was deepened using follow-up questions such as "what happened then?" "how did you react on that?" to clarify details in the narratives. during the course of the data collection, follow up questions were supported by insights from earlier interviews. when the narrative part was exhausted the questionnaires described below were introduced with the request: "please think aloud when you respond to the questions in the questionnaires". the interviews lasted approximately 1 h and were recorded and thereafter transcribed verbatim. in order to place a focus on the moral dimension of reporting child abuse and neglect, questionnaires about moral sensitivity, moral stress and ethical climate, were chosen. all three instruments have been extensively used in international studies separately or together: the moral sensitivity questionnaire (msq) moral sensitivity in this study is conceptualized as a genuine concern for the welfare of others who are in vulnerable situations along with an awareness of the consequences of one's actions (lützén, 1993) . moral sensitivity is stimulated by observations and thoughts that are of moral relevance. consequently, moral sensitivity produces feelings that have an evaluative function as to the consequence of one's actions. the original moral sensitivity questionnaire consisted of 30 items was developed by lützén (1993) and later modified by reducing the number of items to nine (lutzen, dahlqvist, eriksson, & norberg, 2006) . work related moral stress questionnaire (wrms), was developed by lützén et al., and is based on the supposition that a conflict between two or more alternative actions to take, causes moral stress. for instance, in situations where one person has a commitment to do what is best for the well-being of another, can lead to moral stress. an example is when a person perceives that the morally "right" thing to do is circumscribed by practical realities (lutzen, blom, ewalds-kvist, & winch, 2010) . the questionnaire contained nine statements regarding stress the participants may have experienced when concerned about the welfare of a pupil. the ethical climate survey (ecs) was originally developed by olson (1998) to measure how nurses perceive the ethical climate of their workplace and translated into swedish by lutzen et al. (2010) . the questionnaire consists of 26 items. for our study, the questionnaires were all adapted to the school environment, i.e. mostly by changing the word "patient" to "school pupil", leading to msq-s, wrms-s, ecs-s. when responding to the questionnaires the participants were asked to think out loud, as shown in one response to a question in the moral stress questionnaire: my ability to perceive pupils' needs …"yes, that can be the case, so i'll put a 5 there". in addition, the participants completed requests for information about their occupation, age and education. the think-aloud interviews provided information about how the questions were interpreted. the transcriptions were analyzed using the respond problem matrix considering five types of problems that respondents often experience when answering questions in a survey: lexical, temporal, logical, omission/exclusion, and/or computational problem (conrad & blair, 1996) . none of these problems were identified. on the contrary the participants expressed the questions as relevant and easy to understand. the transcribed narrative parts of the interviews were subjected to qualitative content analysis inspired by graneheim and lundman (2004) , to show the logic in how content is abstracted, interpreted, and connected to the aim. at first, the transcriptions were read as a whole and then divided into meaning units i.e. parts in the text relating to the same central meaning. these meaning units were condensed i.e. shortened while still maintaining the core meaning. these units were coded and analyzed according to similarities and differences resulting into categories. the analysis was performed by first author in collaboration with second author. the first author was experienced in this specific method of qualitative content analysis (forsner, nilsson, finnstrom, & morelius, 2016) . to strengthen trustworthiness, the analysis was discussed between authors. furthermore, to provide transparency in the analytical process and credibility of the results, quotations from the transcribed text are provided. the transcribed interview citations were translated into english, which means that we did not correct any grammatical errors. the results were computed with ibm, spss software, versions 24. the participants' responses to the questionnaires were subjected to descriptive statistics, principal component analysis with several high communalities (above .80) and all loading markers were set to be above .40. the occurrence of several high loading markers above .80 compensate for a smaller sample size. in agreement, a thumb rule of a ratio of 10 cases to 1 independent variable was employed in our research (maccallum, widaman, zhang, & hong, 1999) . to assure the strength of the components, each component was reliability-tested by cronbach alpha (nunnally, 1994) . for linear regression analysis this ratio is also appropriate (tabachnik & fidell, 1989, p. 129 ; table 2 , f2 = .61). by the latter method we answered the questions which predictors are valid for the moral dimensions. spearman correlations and one-sample t-test were likewise applied when considered correct. the methods were chosen to explore relationships among variables in one sample, while keeping the confidentiality principle intact for the participants. to fulfill the mixed-method design, both data sets was subjected to comparative meta-analysis. the narrative analysis was interpreted in light of the statistic findings in a comparative analysis. the emotional elements of significance were captured in narrative data whereas, quantitative data, such as the scales could be compared with the qualitative analysis and lead to a meta-analysis. the benefits of the study were considered to outweigh any possible risk for the participants. in line with the declaration of helsinki, participants were assured of their rights of voluntary participation and confidentiality. participants were assured that they could talk about their experiences without revealing identity of the persons mentioned, and that all data was going to be handle with caution to protect from identification. the participants were offered counselling if reflections on situations caused bad memories. the study was approved by the regional ethical board in uppsala, sweden (2014/439). the participants described situations in which they had considered whether to report or not when they encountered pupils who they suspected were exposed to abuse and/or neglect. most of them recalled more than one example of abuse and neglect, which resulted in a total of 63 cases. the participants went through three phases when facing child maltreatment: (a) awareness (b) deliberation and (c) aftermath. their experiences during the phases are described in seven categories (a) feeling concerned and worrying about the child, (b) to report or not; the best for the child; maintaining the relationship with the child as well as with the parents; (c) negative consequences from actions; and longstanding concerns. awareness appeared as feeling concerned and worrying about the child. signs of neglect, psychological or physical, or of physical or sexual abuse raised concerns. neglect was detected when the participants observed parental shortcomings such as lack of bonding, inability to provide adequate clothing, nutrition and security as one of the participants told: "and he had to cook his own food". alcohol and other drugs came up as problems among the older children. also unauthorized school absences were recurring problems and made the participants feel concerned about the child as exemplified in this quote. "we had no idea about their home situation, but it was through the younger girl, aged 11 years, that /…/ she cried and cried and just wanted to go home and the older girl, aged 15 years, also stayed at home. but she showed no other signs". these signs made the participants aware of possible abuse and/or neglect. awareness also was demonstrated in experiences when worrying about the child's wellbeing. sensing that something wasn't all right with the child was 'exemplified in this quote: "so everything he said was worrying me". these kinds of episodes made the participants aware of possible maltreatment. when deliberating whether to report or not and what was the best for the child appeared to conflict with the conviction of the importance of maintaining the relationship with the child as well as with the parents. difficulties in determining what was best for the child were reported: "but this is really hard, how to think what is best for the child". sometimes, worries about the child were vague and reporting seemed too intrusive: "we were not sure if it was a child who was a mythomaniac or if it was true". some said that a negative experience from a previous situation had given them doubts that reporting would be beneficial to the child. also, the participants felt that helping the child themselves rather than reporting was the best thing to do as one of the participants recalled: "his mother was not to count on /…/ she wants him all well but she doesn't have the ability/…/ but there we have always tried to compensate". in this as well as other cases, the participants said that they were against reporting and didn't trust that the child would benefit from notifying the social service. also, participants expressed a feeling that reporting could further aggravate the situation for the child as reflected in the following comments: "then unfortunately it's like this, we report and report. no, there's no intervention. everything has to be voluntary and then we see the children feeling bad and maltreated but no change in spite of the report from us. i can give several examples. and you lose, you lose motivation maybe; yes, you know, you think twice before you report". however, others had no hesitations, but to act and report promptly as told by one of the participants "but if someone is maltreated and is abused for different reasons then you have to intervene no matter what". the latter was often the case when abuse was evident. the participant wanted to maintain a relationship with the child and/or the child's family and feared that notification might disrupt the relationship. the relationships with parents were emphasized as important in terms of being able to help the child. the interviews uncovered the risk of damaging parents' trust when reporting maltreatment. the participants gave examples when parents had expressed disappointment and/or anger when they had reported child abuse and neglect to authorities. sometimes the relationship with the parents even became hostile as told by one teacher: "that mom, she still hates me more than anything". by contrast, some participants described the opposite, talking about a deepened relationship with the family as well as the child. also deliberating as to whether to report or not report, the participants told about sharing their doubts and seeking support from colleagues, school health team and the principal. sometimes these discussions had led to reports and other times to a decision to not report to the social services. both situations were experienced as strenuous. in the interviews the aftermath of negative consequences from actions and longstanding concerns appeared to strongly influence the participants' experience. reporting to authorities could mean the loss of the child's trust. others told about being confronted by children who were disappointed and angry when contacted by the social services. still others told about children being forbidden to have any further contact. not attending the lessons with the teacher responsible for notification or as told by this school nurse: "the girl was forbidden to come to me and then when her sibling started at school the sibling was also not allowed to visit me". threats and aggressive confrontations from the parents were frequently narrated, exemplified by this participant who received a threatening telephone call from a dad: "do you know what kind of weapons i've got here?" even examples of threats to the participants' children were reported. also being questioned by their colleagues was described "i got a lot of crap" and that colleagues expressed conflicting opinions without being familiar with the facts. frustration about dysfunctional collaboration with the social services were frequently expressed as exemplified in this quote: "i was called to the social welfare office /…/ and this, it was about that the dad could argue and blast me down /…/ and the principal gave me support but i got no support from the social workers". the fact that the participants' experiences led to longstanding concerns were obvious. some of stories originated far back, one as far as twenty years ago. "but for sure it's still with me /…/ i think a lot about how it is for the boy /…/ if he has any contact with his dad, whether it ended, whether it, like, got better". examples of this came up both when their concerns for a child had led to a report to the social services and in cases without notification or when the participant did not know whether someone else had reported the case. these longstanding concerns seemed to affect the participants both emotionally and morally. the number of questions in each employed instrument pertaining to work-related moral stress, the ethical climate and moral sensitivity, are described in table 1 . also, the questionnaire's internal reliability is denoted in forms of cronbach's alpha in table 1 . the work-related moral stress was explained by means of a significant linear regression model (f[2.29] = 8.906, p = .001). it showed that 38% of the total variance in the work-related moral stress variable was explained by the ethical climate and professionals' moral sensitivity. when analyzing an individual explanatory factor's significance, it was found that the ethical climate was not a significant explanatory variable to work-related moral stress. in contrast, moral sensitivity contributed to the model uniquely and significantly by explaining 38% of the variance in workrelated moral stress according to the squared part correlation ( table 2) . the participants' responses about the school's ethical climate were reduced to four reliability-tested clusters to find out whether different clusters of the three questionnaires complemented each other. the participants' opinions along with descriptive data as well as correlations between the clusters within the school's ethical climate as well as with school professionals' experience of work-related moral stress are depicted (table 3) . the participants' work-related moral stress was reduced by pca and yielded two components. the components' correlations with moral sensitivity in the school environment are depicted in table 4 . the participants' moral sensitivity is depicted in table 5 . also correlations with work-related moral stress in school are denoted (table 5) . to furthermore understand the moral challenges when suspecting child abuse and neglect, the narrative data was interpreted in light of the statistic findings. thus, expressions such as "felt concern for the child" and "to do what is best" builds on a cognitive awareness and moral motivation to do what one feels is right. the participants in our study said that their hesitation to report was in concern of the negative consequences a report may have for the child. the participants assessed their ability to perceive the needs, and to identify pupils who are in distress, as satisfactory. their awareness of the conflict between the obligation to act and the moral awareness of the possibility of doing harm, appears to be the main conflict in this study. the interpretation of the participants' experiences can be viewed as a decision-making process, not necessarily linear, that is initiated by feelings of concern for the welfare of the child (see fig. 1 ). these feelings initiated a cognitive awareness of the consequences of decisions that will have an immediate or future impact on the child. the participants, in this study, expressed a sense of personal vulnerability; being exposed to threats and being questioned by colleagues and social service as to their observations of suspected child abuse. in some cases, the participants' concern for the welfare of the child and lack of parental care seemed to lead to a change in their professional role, substituting their professional role for a proxy parental role. the aim of this study was to gain a deeper understanding of school professionals experience when they suspect child abuse and neglect and how they think, reason and act. the findings of this study cast light on the moral complexity involved in the course of decision-making process whether to report-or not to report-child abuse and neglect to social services. an awareness of the child's dependency on each decision that is made, places a pressure on the professional to make the right decision. the situations that were described by the participants clearly substantiates johnstone's claim that child abuse is a significant moral issue. the words used by the participants in their narratives highlight the feeling dimension of moral sensitivity that helps a person in "knowing" what is at stake in the decision-making process (lützén, 1993) . the participants were worried that reporting to social services would damage their relationship with the child, by betraying the child's confidence and thus affecting the possibility to help the child. similar findings came up in focus groups with swedish school nurses (kraft & eriksson, 2015) . the school professional's awareness of a child's vulnerability and of how their decision, to report or not report, can impact on the relationship to his or her parents can be interpreted as the cognitive dimension of moral sensitivity (lutzen et al., 2010) . lundén (2011) found that the relationship to parents as well as support from social services influence the tendency to report suspected abuse. it is possible that this was also the case in the current study. collaboration with social services, as well as support from colleagues, were perceived as important for the motivation to report suspected child abuse. also, contrary negative experiences from collaboration with social services made school professionals disinclined to report long afterwards. the findings of feng, chen, fetzer, feng, and lin (2012) also indicate that once teachers know about child abuse, their intention to report is most influenced by factors in their employing school. social workers need to be aware of the importance of trusting collaboration with school professionals to facilitate their intention to report, without hesitation, every noticed sign of maltreatment and abuse. the participants' responses to the questionnaires show that work-related moral stress was explained by moral sensitivity and not by the ethical climate as the result of earlier research (lutzen et al., 2010) . the participant's satisfaction with ethical climate may have contributed to the fact that thoughts of leaving their employment were not prominent. available support and resources for ethical concerns influence the ability to endure higher levels of moral stress and still be satisfied with the job situation (ulrich et al., 2007) . moreover, high "compassion satisfaction", i.e., a good feeling related to the ability to help others, correlated with fewer burnout symptoms (conrad & kellar-guenther, 2006) . it is possible that this was also the case in the current study because the participants described engagement in teaching as well as in the pupils' well-being. kraft and eriksson (2015) found that school nurses' primary intention was to support maltreated children. this intention was also revealed in the narratives in the current study and may to some extent conflict with the intent to report. alvarez, kenny, donohue, and carpin (2004) argue that failure to report child maltreatment leaves hundreds of thousands of children and their families without the needed interventions and, furthermore, increases the risk of further maltreatment. furthermore, they say that the reason why professionals ignore the legal mandate to report abuse is their inability to recognize the signs, along with misunderstanding of the law and worries of negative consequences. yet, the findings of the current study, however, suggest that the interviewed school professionals were competent to identify signs of maltreatment in their pupils and that they understood the request of the law. apprehension of negative consequences to themselves, seemed to prohibit reporting, but most prominent barrier to reporting was fear of negative consequences for the child. from a quantitative standpoint the sample size, although normally distributed, is a limitation for generalization or external validity, however fulfilling the rule of thumb of 10 cases for each independent variable. as regards generalization or external validity to other groups, we suggest that future researchers seek a larger group, when realistic. presently, our methods were tailored for one undivided group to avoid compromising confidentiality by putting the participants at risk of identification. namely, maccallum et al. (1999) suggest that the minimum sample size depends upon the nature of the data itself, most remarkably on its 'strength'. strong data is data in which item communalities are consistently high, that components exhibit high loadings on a substantial number of items (at least three or four) and the number of factors is small. these criteria were satisfied. from a qualitative research standpoint the sample size and purposeful sampling is satisfactory (sandelowski, 1995; levitt et al., 2018) . however, one limitation might be that persons who volunteer to be interviewed might have had more negative experiences than those not participating, thus, biasing the findings. however, since the study aimed to specifically shed light on the participants' situations and particularly the ethical dimensions experience, the purposeful sampling was appropriate. the mixed-method design strengthened both data sampling as well as analyses (timans et al., 2019; levitt et al., 2018) . the study did shed light on the phenomenon from a variety of perspectives by inviting both teachers and school-team members including principals, nurses, counsellors and psychologists to participate in. another limitation with the study is that it is not possible to guarantee the principle of anonymity. thus, we have adopted the principle of confidentiality by not revealing details that make it possible to identify neither the participants nor the persons mentioned in the interviews. furthermore, face to face interviews might make the participants reluctant to share experiences casting an unkind light on their role in the situation. however we interpreted the fact that the participants disclosed situations when they didn't decide to report as an indication that the participants were honest when narrating about their experiences. in order for social workers to be able to utilize intervention methods, early detection of suspected child abuse and neglect to child protection services is essential. the purpose of this study was to investigate school professionals' experiences with perspectives from teachers, nurses and psychologists as well as social workers. we think that the findings also appear to be of importance for social workers responsible to investigate the situation and intervene in the child's best interest. foremost, they need insight into the situation for teachers and others who have daily contact with children and adolescents and have the professional knowledge to able detect early signs of abuse and/or neglect. moreover, a closer collaboration with school professionals may help to increase social workers' understanding of moral challenges when deliberating what is best for the child may result in the low frequency of reporting. since there is a proven gap between current maltreatment and reported cases social workers are not informed and are then unable to help, leaving the abused and neglected child without early appropriate interventions. our study revealed a chain of moral conflicts beginning with the school professionals' moral awareness of the negative consequences of reporting suspected child abuse and neglect would bring about. problematic interactions with social services, colleagues and parents seemed to serve as obstacles rather than as openings for collaboration. although moral sensitivity can be viewed as a good characteristic, it paradoxically leads to moral stress if the prime and dominant problem is not re-solved. an unexpected finding was that some of the participants, in their struggle to decide what to do, seemed to have a closer relationship with the child, hence on the brink of leaving their professional role. whether our interpretation of this finding is correct or not should be an imperative focus for further research. notwithstanding that this is a small study, further research on the relational and interactive aspects of dealing with moral aspects involved in reporting suspected child abuse is required. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. why are professionals failing to initiate mandated reports of child maltreatment, and are there any empirically based training programs to assist professionals in the 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(reports about child maltreatment. national survey entryway into the child protection system: the impacts of child maltreatment reporting policies and reporting system structures föräldrabalken (swedish parental code) kap 6, 1 § socialtjänstlagen (swedish social act) skollag (swedish educational act) lag om förenta nationernas konvention om barnets rättigheter (law conserning convention on the rights of the child) a survey of swedish teachers' concerns for preschool children at risk of maltreatment using multivariate statistics facing suspected child abuse-what keeps swedish general practitioners from reporting to child protective services? scandinavian journal of primary health care mixed methods research: what it is and what it could be preschool teachers' perceptions about and experience with child abuse and neglect analecta husserliana yearbook of phenomenological research ethical climate, ethics stress, and the job satisfaction of nurses and social workers in the united states convention on the rights of the child. retrieved december 9 united nations children´s fund child maltreatment signs of child maltreatment. the extentand nature of referrals to swedish child welfare agencies acknowledgements open access funding provided by umea university. we would like to thank the participants of the study who generously shared their time and experiences. we express our gratitude to karin lundén for sharing her expertise about child maltreatment. grants from the afa insurance supported this research project. key: cord-000028-uj7lyawj authors: longtin, jean; bastien, martine; gilca, rodica; leblanc, eric; de serres, gaston; bergeron, michel g.; boivin, guy title: human bocavirus infections in hospitalized children and adults date: 2008-02-17 journal: emerg infect dis doi: 10.3201/eid1402.070851 sha: doc_id: 28 cord_uid: uj7lyawj studies have reported human bocavirus (hbov) in children with respiratory tract infections (rtis), but only occasionally in adults. we searched for hbov dna in nasopharyngeal aspirates (npas) from adults with exacerbations of chronic bronchitis or pneumonia, from children hospitalized for acute rtis, and from asymptomatic children during the winter of 2002–2003 in canada. hbov was detected in npas of 1 (0.8%) of 126 symptomatic adults, 31 (13.8%) of 225 symptomatic children, and 43 (43%) of 100 asymptomatic children undergoing elective surgery. another virus was detected in 22 (71%) of the 31 hbov-positive npas from symptomatic children. two clades of hbov were identified. the pathogenic role of hbov in rtis is uncertain because it was frequently detected in symptomatic and asymptomatic children and was commonly found with other viruses in symptomatic children. h uman bocavirus (hbov) is a newly described human virus closely related to bovine parvovirus and canine minute virus. it is currently classifi ed in the genus bocavirus within the family parvoviridae. this virus was fi rst identifi ed in respiratory tract specimens from swedish children with lower respiratory tract infections (rtis) (1) . nucleic acid amplifi cation has detected hbov in respiratory samples of children with acute respiratory disease, with incidence rates ranging from 3% to 19% . however, the pathogenic role of hbov is uncertain because other viruses have been frequently detected in hbov-positive children with lower rtis (range 37%-90%) (2, 3, 7, (9) (10) (11) (20) (21) (22) . the objective of this study was to describe the incidence and clinical manifestations of hbov infections in children and adults with respiratory tract symptoms, including a control group of children without symptoms. respiratory samples from adults were obtained from a previous study conducted from december 2002 to april 2003 at 3 university-affi liated hospitals in the province of quebec, canada (24) . two groups of patients were enrolled: those >40 years of age with chronic obstructive pulmonary disease (copd) who came to emergency departments with exacerbation of their illness (including patients with pneumonia), and those >18 years of age without copd who were admitted to the hospital with a diagnosis of community-acquired pneumonia. patients were excluded from the study if they came to the hospital >7 days after onset of symptoms. respiratory samples from children were obtained from a case-control study, the results of which have been published (25) . participants included children <3 years of age who were hospitalized from december 2002 to april 2003, at laval university hospital center in quebec city, quebec, canada. case-patients were children admitted for an acute rti (mostly bronchiolitis, pneumonitis, and laryngotracheobronchitis) who had a nasopharyngeal aspirate (npa) collected as part of investigation of their illness. a specifi c questionnaire was completed at admission by a research nurse in the presence of the parents. at the end of hospitalization, charts of the children were reviewed to collect clinical and laboratory data. eligible controls were children hospitalized during the same period for any elective surgery (ear, nose, and throat surgeries in 71% of the cases). these children had no concomitant respiratory symptoms or fever at admission. the study nurse obtained a signed consent from parents and an npa was obtained during surgery. the original studies were reviewed and approved by the ethics committees of all participating healthcare centers. all pediatric (from case-patients and controls) and adult (case-patients only) npa specimens were previously analyzed by using a multiplex real-time pcr assay for infl uenza a and b viruses, human respiratory syncytial virus (hrsv), and human metapneumovirus (hmpv) (24, 25) . for symptomatic children, viral cultures and antigen detection assays were performed upon request by the treating physician. remaining specimens were frozen at -80°c until subsequent hbov pcr studies. nucleic acids were extracted from 200 μl of npa by using the qiaamp viral rna mini kit (qiagen, inc., mississauga, ontario, canada). a duplex hbov pcr (taqman assay) was used to amplify conserved regions of np-1 and ns-1 genes as described (14) , except that the ns-1 forward primer was replaced with primer 5′-tag ttg ttt ggt ggg arg a-3′. probes were labeled with 6-carboxyfl uorescein (fam) or tetrachloro-6-carboxyfl uorescein (tet) at the 5′ end and with a quencher at the 3′ end. amplicons were 81 bp (np-1) and 74 bp (ns-1), respectively. duplex amplifi cation was conducted by using 1 μmol/l ns-1 forward primer and 0.4 μmol/l ns-1 reverse primer and the 2 np-1 primers. taqman probes were used at concentrations of 0.1 mmol/l for the np-1 gene and 0.2 mmol/l for the ns-1 gene (14) . the amplifi cation master mixture consisted of 2.5 mmol/l mgcl 2 , 3.33 mg/ml bovine serum albumin, 0.2 mmol/l of each of the 4 deoxynucleotide triphosphates (amersham biosciences, uppsala, sweden), 10 mmol/l tris-hcl, 50 mmol/l kcl, 0.625 u promega taq dna polymerase (fisher scientifi c, markham, ontario, canada) combined with taqstart antibody (bd biosciences clontech, palo alto, ca, usa), and 3 μl dna in a fi nal volume of 25 μl. pcr amplifi cation (180 s at 94°c and 45 cycles for 10 s at 95°c, 30 s at 58°c, and 30 s at 72°c) was performed in a smart cycler thermal cycler (cepheid, sunnyvale, ca, usa). a pcr extension step of 5 min at 72°c was performed at the end of the cycling protocol. an hbov infection was defi ned by a positive pcr result for np-1 and ns-1. the duplex assay had a sensitivity of 10 genome copies for np-1 and ns-1 gene targets on the basis of quantifi cation analysis of positive control plasmids. half of the hbov-positive samples were randomly selected for phylogenetic analysis, which consisted of amplifying and sequencing a 842-bp region of the vp1/vp2 genes as described (6) . the vp1/vp2 nucleotide sequences from this study, as well as prototype sequence type (st)1 and st2 (1), were entered into a multiple alignment generated by clustalw software version 1.83 (www.molecularevolution.org/software/clustalw) and corrected through fi nal visual inspection with the seqlab application (wisconsin package version 10.3; accelrys, san diego, ca, usa). phylogenetic analyses were conducted with the mega version 3.1 software (26) by using the distance method and the neighbor-joining algorithm with kimura-2 parameters. topologic accuracy of the tree was evaluated by using 1,000 bootstrap replicates. proportions of clinical characteristics in different groups of patients were compared by using the χ 2 test or the fisher exact test. the wilcoxon nonparametric test was used to compare age distribution and length of stay. analyses were performed by using sas software version 9.1 (sas institute, inc., cary, nc, usa). hbov dna was detected in npa samples from 1 (0.8%) of 126 symptomatic adults (71 years of age) and from 31 (13.8%) of 225 symptomatic children (mean age 17 months, median age 15 months). however, hbov was detected more frequently (43%, p<0.001) in the 100 asymptomatic control children (mean age 22 months, median age 23 months). another virus was detected in 22 (71%) of 31 hbov-positive npas from symptomatic children. the virus most commonly co-isolated with hbov was hrsv (16/31, 52%), followed by infl uenza a/b (3 cases), hmpv (3 cases), adenovirus (1 case), and parainfl uenza virus (1 case). two children were infected with 2 other viruses in addition to hbov. the median age of symptomatic children with hbov infection (15 months) was signifi cantly greater than that of symptomatic children without hbov infection (8 months; p<0.0001). the hospital length of stay was similar for children positive for hbov dna (mean 5.1 days, median 4 days) and those negative for hbov dna (mean 6.6 days, median 3 days) (p = 0.9). clinical characteristics of hbov-positive children are summarized in the table. there were signifi cantly fewer bronchiolitis episodes in children infected only with hbov than in children infected only with hrsv (p<0.0001). none of the children with single hbov infections and only 2 (6%) of all 31 hbov-infected children were admitted to the intensive care unit. in the control group of asymptomatic children who underwent elective surgery, ear, nose, and throat surgery was more frequently performed in children with hbov infections (36/43, 84%) than in children without hbov infections (35/57, 61%) (p = 0.014). ear, nose, and throat elective surgeries consisted mainly of myringotomies, adenoidectomies, and tonsillectomies. the 1 adult with an hbov infection was a 71-year-old man (a smoker) who came to the hospital for a copd exacerbation and was treated with systemic corticosteroids and antimicrobial drugs. no other microbiologic agents (bacteria or viruses) could be identifi ed in his sputum or npa. he was hospitalized for 11 days. sequence analysis of the hbov vp1/vp2 genes performed on ≈50% of hbov-positive specimens showed 2 distinct clades of viruses (figure) . these genotypes clustered with the original strains described by allander et al. (st1, genbank accession no. dq000495, and st2, gen-bank accession no. dq000496) (1). there was no temporal link between the clades because both were equally distributed throughout the study period. no obvious relationship was found between clades and the presence or absence of symptoms. results from our study indicate that hbov was rarely detected in adults with respiratory symptoms but was frequently detected in symptomatic and asymptomatic children during the 2002-2003 winter season. hbov was detected in npa samples from 1 (0.8%) of 126 symptomatic adults, 31 (13.8%) of 225 symptomatic children, and 43 (43%) of 100 asymptomatic children. another virus was detected in 22 (71%) of 31 hbov-positive samples from symptomatic children. overall, these data do not support a pathogenic role for hbov in acute rtis in children. the full spectrum of clinical diseases associated with hbov infections and the epidemiology of this new parvovirus are not fully understood. this is particularly true for adult patients in whom few studies have been performed. allander et al. (1) found no hbov dna in 112 culturenegative npa samples from adults with respiratory symptoms. bastien et al. (5) reported an overall rate of infection of 1.5% in respiratory samples negative for other viruses, with no differences between age groups. maggi et al. (16) reported only 1 hbov-positive sample from an adult with lymphoma in 62 bronchoalveolar lavages (bals). these investigators also tested 22 nasal swabs from adults with persistent asthma symptoms and found no samples positive for hbov. fry et al. (10) identifi ed hbov dna in 1% of adults >20 years of age hospitalized with pneumonia in thailand. kupfer et al. (27) described a case of hbov infection associated with severe atypical pneumonia in a patient with non-hodgkin lymphoma who was also infected with cytomegalovirus in a bal sample. we found 1 case of hbov infection in an adult, which represented 0.8% of the tested population. the hbov-positive adult did not show immunosuppression but was treated with corticosteroids for a copd exacerbation. overall, our results are consistent with those of previously described studies and support the fact that hbov infection is rare in adults but may occur more frequently in those with other illnesses or immunosuppression. studies have reported hbov dna in 3%-19% of children with rtis. rates of detection tend to be higher in children <1 year of age (4, 10) . the incidence of hbov infections also tends to be higher in samples from the lower respiratory tract, such as npa or bal (4.4%-19%) (2, 7, 9, 11, 13, 19, 21, 22) , than in nasal swabs (1%-6%) (10, 15, 16, 18) . the percentage of co-pathogens in our hbov-positive children (71%) was comparable with those reported in the literature, with rates of co-infections ranging from 35% to 90% (2, 3, 7, (9) (10) (11) (20) (21) (22) . moreover, coinfecting viruses detected in conjunction with hbov in our population were similar to those described in other studies, i.e., hrsv, infl uenza a virus, and adenovirus (11, 23) . the high frequency of hbov detection (43%) in our asymptomatic children contrasts with the results of the few other studies that included a control group of asymptomatic children. fry et al. (10) detected hbov dna in only 1% of nasal swabs from asymptomatic patients. maggi et al. (16) did not detect hbov dna in nasal swabs from 51 asymptomatic children (including 30 healthy infants with a mean age of 6 months and 21 preadolescent healthy children with a mean age of 12.8 years). however, these studies analyzed nasal swabs instead of npa or bal samples for hbov detection, which may result in lower rates of viral detection, as shown in symptomatic persons. allander et al. (2) did not detect hbov in any of 64 asymptomatic children (median age 4.1 years, range 5 months to 14 years) but used nasal swabs in asymptomatic patients and npa samples in symptomatic patients. furthermore, their control group was also older than our population (mean 18.6 months, median 18 months). kesebir dna in nasal washes from 96 asymptomatic children <2 years of age seen at a clinic compared with 22 (5.2%) of 425 various samples from symptomatic children sent to a hospital clinical laboratory. none of the previous studies used a control group consisting of children matched for age and week of admission and analyzed the same type of respiratory samples for cases and controls. our positive results for hbov were confi rmed by using 2 sets of pcr primers targeting different genes (np1 and ns1) in a duplex pcr assay and by subsequent testing with a third set of primers (vp1/vp2) for sequencing. also, sample preparation and pcr amplifi cation were performed in separate laboratory areas following the stringent quality control program of our institution. thus, it is unlikely that our positive results were due to pcr cross-contamination. our method was also very sensitive (detection limit = 10 genome copies), which probably enabled an increased in-fection rate compared with previous reports. we cannot exclude the possibility that prior rtis (in the few weeks preceding sampling) occurred in our asymptomatic children hospitalized for an elective surgery or that hbov could establish a prolonged infection in children compared with other respiratory viruses. however, the 3× higher detection rate in controls than in symptomatic children make these explanations unlikely. we did not quantify hbov dna load in samples from our study, which could have been different between asymptomatic and symptomatic children. nevertheless, we detected hrsv, hmpv, and infl uenza virus rna in <1% of the same npa samples from those asymptomatic children compared with a rate of 43% for hbov dna (25) . at the very least, our results should raise concerns about the pathogenic role of hbov in children. we detected 2 hbov genotypes circulating at the same time in both symptomatic and asymptomatic children during the winter of 2002-2003 in quebec. this result is consistent with fi ndings of other groups from north america and europe during 2002-2004 and highlights the fact that hbov lineages do not appear to be geographically clustered (1, 6, 9, 12) . the seasonality of hbov infection is still a matter of debate, but it seems to involve primarily the colder months of the year (9, 20, 21) . however, most studies, including ours, were performed during the typical respiratory virus season, which may have introduced a bias. additional studies are needed to address the prevalence of hbov outside the respiratory virus season and its role in nonrespiratory syndromes. moreover, the possibility that this virus might be transmitted and isolated in the respiratory tract, but could cause viremia and other clinical syndromes such as gastroenteritis, should be investigated. vicente et al. analyzed 527 stool samples from children with gastroenteritis and no respiratory symptoms and found a positivity rate of 9.1% for hbov (with a co-infection rate of 58%) (22) . in conclusion, our study shows that hbov was frequently detected in both symptomatic and asymptomatic children during the winter of 2002-2003 in quebec city. conversely, this virus was rarely found in the adult population during the same period. further studies are needed to establish whether this recently described parvovirus is pathogenic by using well-matched control groups and sequential samples to detect viral persistence. 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adults with communityacquired pneumonia and exacerbation of chronic obstructive pulmonary disease human metapneumovirus infections in hospitalized children mega3: integrated software for molecular evolutionary genetics analysis and sequence alignment severe pneumonia and human bocavirus in adult we thank johanne frenette and chantal rhéaume for technical contributions.dr longtin is a resident in infectious diseases and medical microbiology at laval university in quebec city, quebec, canada. his research interests include the epidemiology of emerging viruses and pharmacokinetic studies of antiretroviral agents. key: cord-018408-ttae193b authors: haddad, imad y.; cornfield, david n. title: pneumonia and empyema date: 2008-11-15 journal: the respiratory tract in pediatric critical illness and injury doi: 10.1007/978-1-84800-925-7_17 sha: doc_id: 18408 cord_uid: ttae193b nan pneumonia is defi ned as infection and infl ammation of the lower respiratory tract in association with parenchymal radiographic opacity. this defi nition excludes bronchiolitis, tracheitis, neonatal pneumonia, and noninfectious causes of pneumonia and pneumonitis, and these are not discussed in this chapter. in the pediatric intensive care unit (picu), several pneumonia types may be encountered. first, a previously healthy child may be admitted to the picu because of severe community-acquired pneumonia (cap). the pneumonia is usually caused by organisms that are prevalent in the out-of-hospital environment. second, patients with genetic or acquired immune defi ciency commonly develop severe pneumonia with opportunistic infections that usually do not infect healthy children. these immunocompromised patients commonly have been given chemo-radiotherapy for cancer or are receiving immune-suppressive agents to prevent rejection episodes following solid organ and hematopoietic stem cell transplantation. third, both previously healthy and immunocompromised patients may acquire nosocomial pneumonia during their hospital stay. mechanically ventilated patients are at especially high risk to develop nosocomial ventilator-associated pneumonia (vap). finally, aspiration pneumonia caused by chronic inoculation of the lower respiratory tract with large amounts of less virulent bacteria in a susceptible host prone to aspiration is also observed in the picu. this classifi cation of pneumonia types in the picu is important because it has major implications on the causative microbial agent and, thus, the choice of initial empiric treatment that may be life saving. this chapter reviews respiratory host defenses that maintain sterility of the lower respiratory tract. in addition, the pathogenesis, classifi cation, and treatment options for pneumonia and empyema in the picu patient are briefl y discussed. potent expiratory maneuver is of fundamental importance in preventing material from being aspirated into the lungs. the conducting airways also contain several antimicrobial substances, including immunoglobulins (igg and secretory iga), and complement that bind and enhance the elimination of microbial agents. in addition, airway epithelial and alveolar type (at) ii cells secrete several antimicrobial peptides. one of the best characterized families of antimicrobial peptides are the defensins, which are cysteine-rich peptides possessing broad antimicrobial activity [4] . an important recent discovery is the expanding role of respiratory airway epithelium in innate immune defenses by mechanisms that mimic those noted in phagocytic cells. respiratory epithelial cells, including atii cells, express tlr and are capable of expressing a variety of cytokines that amplify infl ammation. the importance of innate immunity in epithelial cells was confi rmed in mice with specifi c inhibition of nuclear factor (nf) κb activation that was restricted to distal airway epithelial cells. mice lacking the ability to activate nfκb in epithelial cells exhibited impaired infl ammatory response to inhaled lps [5] . these data provide evidence that distal airway epithelial cells and the signals they transduce play a key physiologic role in lung infl ammation in vivo. alveolar type ii cells also secrete surfactant proteins (sp)-a and d. both sp-a and sp-d are collagen-like lectins (collectins) that agglutinate and/or opsonize pathogens and enhance their phagocytosis by innate immune cells such as alveolar macrophages and neutrophils [6] . surfactant proteins a and d may have additional immunoregulatory functions [7] and also may exhibit direct bactericidal effects by inducing damage to the bacterial cell membrane [8] . the functions of sp-a and sp-d in host defense are listed in table 17 .1. in the distal airspaces, alveolar macrophages are the fi rst phagocytic cell type encountered by pathogens entering the lung. macrophages have the capacity to induce the generation of large amounts of cytokines, chemokines, matrix metalloproteinases (mmp), nitric oxide, and potent oxidants that participate in antimicrobial defenses. in contrast, interstitial macrophages are located in the lung connective tissue and serve as both phagocytic cells and antigen-processing cells. tumor necrosis factor (tnf)-α, a macrophage-derived multifunctional cytokine, is expressed early in both patients with and animal models of pneumonia [9] . microbes also induce macrophages to generate potent chemokines that attract circulating neutrophils and monocytes into the lungs. cytokines/ chemokines amplify infl ammatory responses and orchestrate the polarization and transition of innate to adaptive immunity that function to eliminate invading microorganisms [10] . figure 17 .2 summarizes the cellular and secretory peptides that are components of host defense against microbes in the lower respiratory tract. disorders associated with impaired mechanical, innate, and adaptive host responses that may lead to the development of pneumonia in a susceptible host are listed in table 17 .2. the upper respiratory tract is normally colonized with nonpathogenic bacterial fl ora, but physical and immunologic host defenses generally ensure that bacteria that gain access to the lower respiratory tract are cleared. pneumonia occurs because of an impairment of host defenses (as discussed earlier), invasion by a virulent organism, or invasion by an overwhelming inoculum of less virulent organisms. there are fi ve main modes of pathogen entry into the lower respiratory tract. inhalation of infectious particles is probably the most important pathogenic mechanism in the development of cap, with particular importance in pneumonia of those caused by legionella species and mycobacterium tuberculosis. contact with contaminated fomites also may be important in the acquisition of viral agents, especially respiratory syncytial virus. the viral agents that cause pneumonia proliferate and spread by contiguity to involve lower and more distal portions of the respiratory tract. inhalation is also a common cause of pneumonia caused by contaminated ventilator tubes. endosome tlr5 tlr7/ trl8 tlr9 tlr10 tlr11 tlr12 tlr13 cd14 figure 17.1. toll-like receptors (tlr) and their ligands. lps, lipopolysaccharide; hsps, heat shock proteins. in addition to inhalation, pneumonia arises following the aspiration of microorganisms from the oral cavity or nasopharynx. invasive disease most commonly occurs upon acquisition of a new serotype of the organism with which the patient has not had previous experience. most episodes of vap are thought to develop from the aspiration of oropharyngeal secretions containing potentially pathogenic organisms. aspiration of gastric secretions may also contribute, although likely to a lesser degree. tracheal intubation interrupts the body's anatomic and physiologic defenses against aspiration, making mechanical ventilation a major risk factor for vap. the term aspiration pneumonia should be reserved for pneumonia or pneumonitis resulting from the aspiration of large amounts of gastric or oropharyngeal contents that may contain a large inoculum of relatively nonvirulent bacteria. the pathogens that commonly produce cap or vap, such as streptococcus pneumoniae, gram-negative bacilli, and staphylococcus aureus, are relatively virulent bacteria so that only a small inoculum is required and the aspiration is usually subtle. in immunocompromised individuals, an additional mode of pneumonia acquisition is bacteremia and sepsis. hematogenous deposition of bacteria is responsible for some cases of pneumonia caused by staph. aureus, pseudomonas aeruginosa, and escherichia coli. reactivation of pathogens can take place in the setting of defi cits of cell-mediated immunity. pathogens such as pneumocystis carinii/jiroveci, m. tuberculosis, and cytomegalovirus (cmv) may remain latent for many years after exposure, with fl ares of active disease in the face of immune compromise. reactivation tuberculosis occasionally occurs in immunocompetent hosts. direct inoculation rarely occurs as a result of surgery or bronchoscopy but may play a role in the development of pneumonia in patients supported with mechanical ventilation. the direct extension of infection to the lung from contiguous areas such as the pleural or subdiaphragmatic spaces is rare. community-acquired pneumonia community-acquired pneumonia refers to pneumonia in a previously healthy person who acquired the infection outside a hospital. it is one of the most common serious infections in children, with an incidence of 34 to 40 cases per 1,000 children in the industrialized world [11] . a subset of these patients will require picu admission. admission to the intensive care unit should be considered for patients with persistent hypoxemia despite oxygen therapy, recurrent apnea, signs of respiratory fatigue with or without mental status changes, or evidence of compensated or decompensated shock. infants less than 6 months of age and children with comorbid conditions such as bronchopulmonary dysplasia, cystic fi brosis, neuromuscular disorders, congenital heart disease, and immunodefi ciency disorders have limited respiratory reserves and, therefore, are at increased risk for respiratory failure during a pneumonia episode. for the adult population, the american and british thoracic societies have developed guidelines for hospital and icu admissions for patients with severe cap [12] . according to the american thoracic society guidelines, admission to the icu is needed for patients with severe cap, defi ned as the presence of either one of two major criteria, or the presence of two of three minor criteria. the major criteria include need for mechanical ventilation and septic shock; the minor criteria include systolic blood pressure ≤90 mm hg, multilobar disease, and a pao 2 /fio 2 ratio <250. in addition, a pneumonia severity index (psi) score identifi es adults at increased risk of medical complications and death [13] . however, similar guidelines or scores to grade the severity of pneumonia in children have not been developed. children admitted to the picu because of cap are more commonly infected with bacterial than viral pathogens. streptococcus pneumoniae is the most commonly identifi ed bacterial cause of cap in infants and children older than 1 month. pneumonias caused by group a streptococcus and staph. aureus are less frequent. haemophilus infl uenzae pneumonia has become uncommon following the widespread use of haemophilus infl uenza type b immunization. viruses are identifi ed most often in children <5 years of age. respiratory syncytial virus is the most common viral etiology during infancy, with adenovirus, infl uenza virus, parainfl uenza virus, and the recently described human metapneumonovirus (14) also not infrequently detected. mycoplasma pneumoniae and chlamydia pneumoniae are more common in older children and adolescents [11] . in may 1993 an outbreak of an acute febrile illness associated with respiratory failure, shock, and high mortality was identifi ed by investigators from the centers for disease control and prevention (cdc) as being caused by a hantavirus. in the united states, 95% of the cases occurred west of the mississippi after environmental exposure to infected deer mouse saliva, urine, or feces. in addition, a novel coronavirus was identifi ed as the causative agent of severe acute respiratory syndrome (sars), a new respiratory illness that affects adults and children, although the severity of the disease is less in children than in adults [15] . another cause of severe pneumonia that should be considered is tuberculosis. a history of contact with a person with pulmonary tuberculosis is usually elicited. finally, uncommon causes of cap in otherwise healthy children are fungal infections including coccidiodes immitis, histoplasma capsulatum, and blastomyces dermatitidis. these organisms should be included in the differential diagnosis as a cause of pneumonia only if there is a history of residence or travel to an area of endemic infection. occasionally, infection with strep. pneumoniae [16] and mycoplasma pneumoniae [17] can cause necrotic pneumonia secondary to an invasive organism or exaggerated host immune response. compared to patients with pneumonia and parapneumonic effusions, children who developed necrotizing pneumonia exhibited a more protracted hospital course associated with higher rates of complications, including bronchopleural fi stulas and need for thoracotomy for fi stula repair or lobectomy. none of the necrotizing pneumonia patients were immune defi cient [18] . the diagnosis of cap is usually made based on the presence of respiratory symptoms (cough, retractions) in a febrile and tachypneic child. the presence of infi ltrates on chest radiographs confi rms the diagnosis of pneumonia. infi ltrates are generally either interstitial or alveolar. although alveolar infi ltrates are more commonly observed during bacterial pneumonia [19] , in most studies, the pattern of infi ltrates has not been shown to correctly differentiate viral from bacterial pneumonia [20] . chest radiographs will also detect the presence of pleural effusions, pneumatoceles which are observed during staphylococcal pneumonia, or presence of air-fl uid levels indicative of abscess formation. after initial stabilization, diagnostic testing should be performed rapidly, avoiding delays in the administration of initial empiric therapy. in addition to a chest radiograph, an admitted patient should have a complete blood count and differential and routine blood chemistry testing (including glucose, serum sodium, liver and renal function tests, and electrolytes). all admitted patients should have oxygen saturation assessed by pulse oximetry and supplemental oxygen administered as needed. arterial blood gas should be measured in any patient with severe illness to assess both the level oxygenation and the degree of carbon dioxide retention. for critically ill patients with pneumonia, an aggressive approach to determine the causative microbial agent is warranted. microbiologic confi rmation is ultimately obtained for approximately 30%-50% of children with cap [21]. if a pleural effusion is present, aspiration of pleural fl uid for gram stain and culture prior to starting antibiotics is valuable. blood culture may reveal organisms in up to 30% of patients with bacterial pneumonia [22] . sputum collection is usually not practical for infants and children, and bacterial organisms recovered from the nasopharynx do not accurately predict the etiology of pneumonia. however, recovery of viruses and other atypical pathogens from the nasopharynx is more predictive. bacterial organisms recovered from tracheal secretions obtained through an endotracheal tube may or may not refl ect the causative agent(s) responsible for lower respiratory tract infection. specimens are considered appropriate for examination if they contain ≤10 epithelial cells and ≥25 polymorphonuclear leukocytes under low power [23] . the primary purpose of tracheal aspirate samples is to visualize a bacterial morphology of an organism that was not anticipated so that appropriate drugs can be added to the initial antibiotic regimen (e.g., staph. aureus or an enteric gram-negative antibiotic). bronchoalveolar lavage (bal) has been shown to be a rapid, relatively safe, and relatively noninvasive diagnostic procedure to obtain lower respiratory tract samples for microbial identifi cation and analysis. other techniques that can be used to identify pathogens include antigen detection of bacteria and viruses using immunofl uorescence, polymerase chain reaction, and serology such as cold agglutination test for m. pneumonia. the specifi city of the cold agglutination test for m. pneumonia is almost absolute, although the sensitivity is only about 50%. detection of mycoplasma igm by enzyme-linked immunoabsorbant assay (elisa) is a sensitive technique and should be considered for children [24] . immunocompromised patients are those whose immune mechanisms are defi cient because of congenital immune defi ciency syndromes, acquired immunologic disorders, or exposure to cytotoxic chemotherapy and steroids. in addition, recipients of solid organ and hematopoietic stem cell transplantation (hsct) are frequently given life-long treatment with immunosuppressive agents designed to prevent graft rejection or graft-versus-host disease. patients who develop severe neutropenia (i.e., an absolute neutrophil count ≤500 cells/ml) or lymphopenia for prolonged periods of time are at greatest risk to develop a variety of infectious complications, including life-threatening pneumonia. the lung is the predominant site of opportunistic infection in the immunocompromised patient [25] . immunosuppressed patients are predisposed to develop infections by ubiquitous microorganisms that do not normally cause disease in healthy people. they are also more susceptible to the usual causes of pneumonia, which can affect anyone. the sequence in which different organisms appear in the immunosuppressed and post-transplant recipients is fairly characteristic. nosocomial bacterial infections remain the most common cause of pneumonia during the early posttransplant, neutropenic phase. staphylococcus aureus and gramnegative pathogens predominate. in addition, fungal infections with candida and aspergillus species are not uncommonly seen during a severe neutropenic phase. the second period, from 1 to 6 months after solid organ transplant, is the time when opportunistic infections more commonly associated with transplantation, including nocardia, p. carinii/jiroveci, and cmv are observed [26] . during the third period, after 6 months, patients are categorized into different risk groups depending on the level of function of their allograft and the degree of immunosuppression they have received. those who are on minimal immunosuppression therapy are subject mainly to the same pathogens as the rest of the community. those with allograft dysfunction and ongoing heavy immunosuppressive therapy remain subject to all of the opportunistic infections seen during the second period. lung transplant recipients who develop bronchiolitis obliterans and hsct recipients who develop graft-versus-host disease remain especially at risk for infections [26] . pulmonary infi ltrates in the immunocompromised host may be caused by a variety of organisms, and may have noninfectious causes. because progression to respiratory failure may be rapid, an aggressive approach to diagnosis and treatment is necessary to limit morbidity and mortality. initial broad-spectrum therapy is important, with alterations of the empiric regimen once the clinical situation has stabilized and more diagnostic information has been obtained. in the immunocompromised host, bal procedure should be performed promptly to rule out infectious etiologies. lists suggested bal fl uids analysis studies and cultures. bronchoalveolar lavage is very helpful in the diagnosis of p. carinii/jiroveci, cmv, tuberculosis, and some fungal infections. however, the ability of bal fl uids analysis and culture to detect invasive aspergillosis, one of the most lethal infectious complication after transplantation, is limited [27] . the diagnostic yield for aspergillus species infection has been enhanced by the recently developed elisa that detects galactomannan, a fungal cell wall component released during invasive disease [28] . histopathologic analysis and culture of open lung biopsy specimens may provide accurate determination for the cause of pulmonary infi ltrates in pediatric patients [29] . however, open lung biopsy is associated with a signifi cant surgical risk in critically ill patients. open lung biopsy is most effective and least risky when performed early in the course of patients who develop nodular infi ltrates that require rapid differentiation between fungal infections and more benign lesions [30] . chemoprophylaxis against opportunistic infections is an important component of management of the post-transplant immunosuppressed patients. before the widespread introduction of chemoprophylaxis, p. carinii pneumonia (pcp) was observed to be a common opportunistic infection among transplant recipients. with the administration of low-dose trimethoprim-sulfamethoxazole or an alternative prophylactic agent such as pentamidine, pcp can be effectively prevented [31] . prophylaxis is also recommended for cmv in high-risk cmv seronegative recipients. such prophylaxis includes intravenous ganciclovir for 14 days, followed by oral ganciclovir capsules for three months [32] . aspiration pneumonia refers to the pulmonary consequences resulting from the abnormal entry of fl uid, formula, or endogenous secretions into the lower airways. there is usually compromise in host defenses that protect the lower airways, including glottic closure, cough refl ex, and other clearing mechanisms. histories of seizure, anesthesia, or other episode of reduced level of consciousness, neurologic disease, dysphagia, or gastroesophageal refl ux are all risk factors for aspiration. the risk of aspiration is especially high after removal of an endotracheal tube because of the residual effects of sedative drugs, the presence of a nasogastric tube, and swallowing dysfunction related to alterations of upper-airway sensitivity, glottic injury, and laryngeal muscular dysfunction [33] . aspiration pneumonia may be classifi ed into three clinical syndromes: chemical pneumonitis, bacterial infection, and airway obstruction. in animal models, development of chemical pneumonitis requires a 1 to 4 ml/kg inoculum of fl uid with a ph of 2.5 to initiate an infl ammatory reaction that may lead to pulmonary fi brosis [34] . bacteria, present in the aspirated oropharyngeal and gastric secretions, may also lead to pneumonia. aspiration pneumonia may involve particulate matter or foreign body, which, in addition to causing airway obstruction or refl ux airway closure, may synergistically contribute to acid-induced lung injury [34] . true aspiration pneumonia, by convention, usually refers to an infection caused by less virulent bacteria, primarily anaerobes, which are common constituents of the normal fl ora in a susceptible host prone to aspiration. pneumonia is commonly caused by oropharyngeal fl ora, including anaerobic gram-negative bacilli (bacteroides fragilis, fusobacterium nucleatum, peptostreptococcus, and prevotella) and anaerobic gram-positive bacilli (clostridium, eubacterium, actinomyces, lactobacillus, and propionibacterium). aspiration usually occurs when the patient is supine during or immediately after feeding. in the supine position the right upper lobe is the most dependent part of the lung and is most frequently affected. commonly, impaired airway protective responses are observed. the presence of tracheoesophageal malformations should be investigated if recurrent aspiration is noted in an otherwise healthy infant. the clinical presentation and course of chemical pneumonitis after inhalation of gastric contents ranges from mild and selflimited to severe and life threatening, depending on the nature of the aspirate and the underlying condition of the host. in the absence of witnessed inhalation of vomit, diagnosis is diffi cult and requires a high index of suspicion in a patient who has risk factors for aspiration. in the absence of an obvious predisposition, the abrupt onset of a self-limited illness characterized by dyspnea, cyanosis, and low-grade fever associated with diffuse rales, hypoxemia, and alveolar infi ltrates in dependent lobes should suggest aspiration [35] . if bal is performed, assessment of lipid-laden macrophage index using oil-red-o stain is helpful in confi rming the diagnosis [36] . the presence of foul-smelling putrid discharge in sputum or pleural fl uid is regarded as diagnostic of anaerobic infection. patients often have prolonged fever and productive cough, frequently showing blood in the sputum, which indicates necrosis (tissue death) in the lung. if aspiration is persistent, fi brosis and bronchiectasis may result. a number of interventions (e.g., positioning, dietary changes, drugs, oral hygiene, tube feeding) have been proposed to prevent aspiration patients with an observed aspiration should have immediate tracheal suction or bronchoscopy to clear fl uids and particulate matter that may cause obstruction. the use of corticosteroids in the treatment of chemical pneumonitis is controversial [37] , and antibiotics should not be used early in the course unless a superimposed bacterial infection is suspected. the national nosocomial infection surveillance (nnis) program sponsored by the cdc defi nes vap as pneumonia in patients who have been on mechanical ventilation for >48 hr and have developed new and persistent radiographic evidence of focal infi ltrates. in addition, patients had to have two of the following: temperature >38′c, leukocytosis (white blood cell >12,000/mm 3 ), and purulent sputum (>25 white blood cells/high-powered fi eld on tracheal aspirate gram stain). after blood stream infections, vap is the second most common cause of nosocomial infections in picus. the mean vap rate in children ranges from 6 to 12/1,000 ventilator days, accounting for 20%-50% of hospital-acquired infections [38, 39] . infections acquired in the picu are associated with a signifi cantly increased risk of death [40] . nosocomial pneumonia and vap are typically categorized as either early onset (occurring in the fi rst 3-4 days of mechanical ventilation) or late onset. this distinction is important microbiologically. early-onset nosocomial pneumonia and vap are commonly caused by antibiotic-sensitive, community-acquired organisms (e.g., strep. pneumoniae, and staph. aureus). late-onset nosocomial pneumonia and vap are commonly caused by anti-biotic-resistant nosocomial organisms (e.g., p. aeruginosa, methicillin-resistant staph. aureus, acinetobacter species, and enterobacter species). during the winter respiratory viral season, all patients in a medical care environment are at risk for disease due to respiratory syncytial virus, parainfl uenza, and infl uenza viruses. legionnaire's disease is a multisystem illness with pneumonia caused by legionella species usually present in contaminated water. legionnaire's disease is less common in children than adults. compared with postmortem lung biopsies and culture results, the use of clinical criteria to diagnose vap (lung infi ltrates, leukocytosis, purulent secretions, fever) had a sensitivity of 69% and a specifi city of 75% [41] . clearly, a number of noninfectious causes of fever and pulmonary infi ltrates can also occur in these patients, making the above clinical criteria nonspecifi c for the diagnosis of vap. lung infi ltrates may be caused by pulmonary hemorrhage, chemical aspiration, or atelectasis. fever may be caused by a drug reaction, extrapulmonary infection, or blood transfusion. autopsy results in a series of patients with acute lung injury demonstrated that clinical criteria alone led to an incorrect diagnosis of vap in 29% of clinically suspected cases [42] . these limitations have encouraged the use of invasive approaches to sample and culture material from the lower respiratory tract for accurate diagnosis of vap. ventilator-associated pneumonia is most accurately diagnosed by quantitative culture and microscopic examination of lower respiratory tract secretions, which are best obtained by bronchoscopy and bal [43] . cultures of tracheal aspirates are not very useful in establishing the cause of vap [44] . although such cultures are highly sensitive, their specifi city is low even when they are cultured quantitatively [45] . combining clinical and bacteriologic evaluation is probably the best way to achieve the objectives of correctly diagnosing vap and appropriately using antimicrobial agents. the main aims of this diagnostic approach are to rapidly identify patients with true lung bacterial infection, to select appropriate initial antimicrobial therapy, to adjust therapy based on antibiotic sensitivities, and to withhold antibiotics from patients without vap. guidelines for the prevention of vap in children are lacking, but data extrapolated from adult studies support routine elevation of head of bed 30°, appropriate use of sedatives and muscle relaxants, and adequate oral and circuit hygiene [46] . empyema is the presence of purulent material containing polymorphonuclear leukocytes and fi brin in the pleural cavity. empyema is usually a complication of inadequately treated bacterial cap, although it may occur after trauma, thoracic surgery, or intrathoracic esophageal perforation. although parapneumonic pleural effusions are noted in up to 34&-40% of children with pneumonia, empyema is rare, present in 1%-2% of cases [47] . the formation of an empyema can be divided into three stages: exudative, fi brinopurulent, and organizing. during the exudative stage, pus accumu-lates. this is followed by fi brin deposition and loculation of pleural fl uid known as the fi brinopurulent stage. the organizing stage is characterized by fi broblast proliferation; at this time there is the potential for lung entrapment by scarring [48] . typically, the pleural fl uid in empyema is exudative, caused by protein leakage from the capillaries because of increased permeability and increased hydrostatic pressure during the infl ammatory process. although the distinction between transudates and exudates is sometimes diffi cult to make, several features favor an exudative process. if at least one of the following three criteria is present, the fl uid is virtually always an exudate: (1) pleural fl uid protein >2.9 g/dl or protein/serum protein ratio greater than 0.5; (2) pleural fl uid lactate dehydrogenase (ldh)/serum ldh ratio greater than 0.6; and/or (3) pleural fl uid ldh greater than two thirds the serum ldh [49, 50] . the most common organisms that cause empyema in children are strep. pneumoniae, staph. aureus, and group a streptococci. haemophilus infl uenzae is rarely encountered since the advent of the h. infl uenzae b vaccine. mycoplasma pneumoniae and viruses can rarely result in exudative pleural effusions. in a series of 72 pediatric patients with empyema, 24% were secondary to anaerobic infection [51] . these data highlight the importance of anaerobic bacteria in selected cases of empyema in children and adolescents. in addition, tuberculosis should always be considered in the differential diagnosis, and a purifi ed protein derivative test should be performed. the differential diagnosis of patients with pleural effusions is shown in table 17 .4. the presence of fever associated with clinical signs of bacterial pneumonia is a clue to an underlying pneumonia as the cause of the effusion. a lateral decubitus radiograph, ultrasonography, or computed tomography may differentiate whether the fl uid is loculated. a sample of the fl uid should be obtained by thoracentesis in order to determine if the effusion is a transudate versus exudate. pleural cultures are positive in approximately one half of pediatric patients with empyema. blood culture and urine latex agglutination may help to identify a bacterial pathogen. a pneumatocele or pneumothorax seen on chest fi lm suggests staph. aureus as the cause of the empyema. until a specifi c organism is identifi ed, empiric antibiotic therapy should be instituted. this might include a third-generation cephalosporin and antistaphylococcal β-lactamase-resistant penicillin. antibiotics can be adjusted once an organism is identifi ed. antibiotic therapy should be intravenous until the patient becomes afebrile and then should be continued orally for an additional 2-3 weeks. there is major debate as to the proper adjuvant treatment of children with empyema. prospective, randomized and controlled studies of children with empyema are lacking. with the exception of starting appropriate or empiric antibiotics, there is no consensus on when and in whom to place a chest tube, instill fi brinolytic agents, or take to the operating room [52] . in 1992, light suggested that chest tubes should be inserted if the pleural fl uid is gross pus, if the gram stain of the pleural fl uid is positive, if the pleural fl uid glucose level is below 40 mg/dl, or if the pleural fl uid ph level is less than 7.00 [53] . if drainage with a chest tube is unsatisfactory, either urokinase or tissue plasminogen activator (tpa) should be injected intrapleurally [54, 55] . if drainage is still unsatisfactory, a decortication should be considered [56] . a stage-related approach to the management of empyema is perhaps most effi cacious and cost-effective [57] . in the exudative stage, conservative treatment using tube drainage may suffi ce. fibrinolytic treatment may be useful during the fi brinopurulent stage. in contrast, aggressive treatment using surgical decortication may be necessary during the organizing stage. with the advent of video-assisted thoracoscopy (vats), these traditional approaches to management of empyema in children are being challenged. video-assisted techniques offer distinct advantages in the accurate staging of the disease process, effectiveness of management of organizing pleural disease, and post-operative patient comfort [58] . in a retrospective study, the performance of early vats (<48 hr after admission) in children with empyema was associated with signifi cantly decreased length of hospital stay compared with performance of late vats (>48 hr after admission) [59] . children treated for empyema generally recover and have no residual sequelae. radiographs at the time of discharge usually show pleural thickening that later resolves. follow-up pulmonary function tests and physical examination are also usually normal or consistent with mild restrictive disease [60] . most epidemiologic investigations have clearly demonstrated that the indiscriminate administration of antibiotic agents to patients in the picu has contributed to the emergence of multiresistant pathogens with potentially increased morbidity and mortality. the prevalence of penicillin-resistant strains of strep. pneumoniae, methicillin-resistant staph. aureus, vancomycin-resistant enterococcus, and gram-negative bacteria producing extended-spectrum β-lactamase is increasing. despite these concerns, it is clear that patient survival may improve if pneumonia is correctly and rapidly treated. in adults, inappropriate initial antibiotic therapy is strongly associated with fatality [61] . therefore, it may be concluded that empiric antibiotics for the treatment of severe pneumonia are indicated. the choice of antibiotics is based on several factors, including the age of the patient, the type of pneumonia, and the local resistant patterns of predominant bacterial pathogens. suggested choices for initial empiric antibiotic coverage for pneumonia in the picu are listed in table 17 .5. aspiration pneumonia occurring in the community can be treated with ampicillin-sulbactam. empiric treatment for pneumonia in immunocompromised hosts requires broad-spectrum gram-positive and gram-negative coverage. immunocompromised patients are especially susceptible to a variety of life-threatening opportunistic viral and fungal pneumonias that require prompt diagnosis and aggressive treatment. for example, trimethoprim-sulfamethoxazole or pentamidine should be given for p. carinii/jiroveci, amphotericin b or caspofungin for candida and aspergillus species, acyclovir for herpes, amantadine for infl uenza, ganciclovir or foscarnet for cmv, and ribavirin for severe respiratory syncytial virus. empiric regimens may need to be modifi ed once results of cultures and antibiotic susceptibility testing are available. the infl ammatory response to infection is necessary for host defense but can contribute to the systemic toxicity and lung injury that may result from pneumonia. in some settings, adjunctive treatment of lower respiratory infections with antiinfl ammatory agents can reduce morbidity. corticosteroids have a well-documented role in the management of p. carinii/jiroveci pneumonia. in a multicenter trial, infusion of hydrocortisone signifi cantly decreased length of hospital stay and prevented mortality in adult patients with cap [62] . corticosteroids also may be effective under some circumstances in the treatment of infl ammatory sequelae of respiratory tract infection, such as tuberculous pleurisy and bronchiolitis obliterans organizing pneumonia (boop). strategies targeting specifi c cytokines have not been effective to date but remain active areas of investigation. enhanced understanding of the interactions of pathogen components with tlrs may be helpful one day in controlling and containing infectious diseases. immunization has reduced the incidence of several serious childhood diseases. immunization against infl uenza and increasingly resistant pneumococci can play a critical role in the prevention of pneumonia, particularly in immunocompromised patients. pleiotropic function of toll-like receptors myeloid differentiation factor 88 is essential for pulmonary host defense against pseudomonas aeruginosa but not staphylococcus aureus toll-like receptors: linking innate and adaptive immunity epithelial antibiotics induced at sites of infl ammation respiratory epithelial cells regulate lung infl ammation in response to inhaled endotoxin host defense functions of pulmonary surfactant human surfactant protein a suppresses t cell-dependent infl ammation and attenuates the manifestations of idiopathic pneumonia syndrome in mice interactions of pulmonary collectins with bordetella bronchiseptica and bordetella pertussis lipopolysaccharide elucidate the structural basis of their antimicrobial 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study swallowing dysfunction in patients receiving prolonged mechanical ventilation pathogenesis of gastric particulate lung injury: a comparison and interaction with acidic pneumonitis aspiration pneumonia the lipid-laden alveolar macrophage as a marker of aspiration in parenchymal lung disease effects of corticosteroids in the treatment of patients with gastric aspiration guidelines for preventing health-care-associated pneumonia, 2003: recommendations of cdc and the healthcare infection control practices advisory committee nosocomial infections in pediatric intensive care units in the united states. national nosocomial infections surveillance system prevalence of nosocomial infections in pediatric intensive care unit patients at us children's hospitals fourth decennial international conference on nosocomial and healthcare-associated infections clinical diagnosis of ventilator associated pneumonia revisited: comparative validation using immediate post-mortem lung biopsies diagnosis of nosocomial bacterial pneumonia in acute, diffuse lung injury management of bacterial pneumonia in ventilated patients. protected bronchoalveolar lavage as a diagnostic tool diagnosis and differential diagnosis of ventilatorassociated pneumonia diagnostic effi ciency of endotracheal aspirates with quantitative bacterial cultures in intubated patients with suspected pneumonia. comparison with the protected specimen brush the prevention of ventilator-associated pneumonia pleural empyema pathophysiology of pleural space infections pleural effusions: the diagnostic separation of transudates and exudates diagnostic value of tests that discriminate between exudative and transudative pleural effusions microbiology of empyema in children and adolescents thoracic empyema in children: early surgical intervention hastens recovery pleural diseases medical management of parapneumonic pleural disease tissue plasminogen activator as an adjuvant therapy for pleural empyema in pediatric patients management of postpneumonic empyemas in children rational treatment of empyema in children favorable outcome of parapneumonic empyema in children managed by primary video-assisted thoracoscopic debridement the changing face of pleural empyemas in children: epidemiology and management empyema in children: clinical course and long-term follow-up clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study key: cord-018545-fk17n2bx authors: dorofaeff, tavey; mohseni-bod, hadi; cox, peter n. title: infections in the picu date: 2012 journal: textbook of clinical pediatrics doi: 10.1007/978-3-642-02202-9_268 sha: doc_id: 18545 cord_uid: fk17n2bx nan effective control of infections starts at the community level, outside the hospital. there are a number of important initiatives that, although simple and not necessarily intensive care related, have the greatest impact on the outcomes of infections. these include provision of adequate and age appropriate foods, breast feeding, drinkable water, provision of mosquito nets and shelter, avoidance of overcrowding, sanitization, and prevention of disease by vaccination. these are basic needs and requirements of mankind as a basis of good health. they are attainable in the largest cities or the most remote areas. infections are one of the commonest causes of mortality in the pediatric intensive care unit (picu), with a mortality of up to 50%, depending on the origin of the infection. infections in the intensive care unit can be divided into those that occur outside the hospital (community acquired) and those that occur within the walls of the hospital and beyond 48 h of admission (nosocomial). preventive measures give the most benefit, both outside and inside the hospital. good hand washing, good respiratory care practice, and judicious use of antibiotics are examples of effective interventions that reduce the rate of nosocomial infections. sepsis comprises up to 25% of admissions to a typical pediatric intensive care unit. shock and management of septic shock are discussed elsewhere in this text. however basic principles of management are the same and are not, and should not be, limited to the intensive care unit. treatment should commence as soon as the recognition of any septic process is underway be it in the field, the clinics, emergency departments, or on the wards. in the community, on the hospital wards, and in the picu, timely identification of illness and access to skilled healthcare personnel are crucial steps limiting the development of organ dysfunction and failure. early identification means early resuscitation and early treatment. this may be hours or in some cases days prior to the admission to the picu. this early recognition and intervention gives the patient the greatest chance of surviving a significant infection. crucial to the management of any serious infection in the intensive care unit and elsewhere is the early use of appropriate antibiotics. early identification of most bacteria is almost universally by the way of a gram stain. this can be performed in any microbiology lab, in the field, or a clinic that is suitably equipped. though references such as the ''red book'' (american academy of pediatrics) give invaluable information on the appropriate antimicrobial therapy for a given microbe or infectious syndrome, there is no substitute for a well informed, up-to-date infectious diseases physician or microbiologist. they are able to provide information on local isolates, patterns of sensitivity, and best management practices for a large variety of infections. the majority of the bacteria listed below will be referenced elsewhere; they are highlighted to reflect their frequency of identification in the picu. additionally, the immunocompromised host will be at risk from a number of opportunistic infections that will be discussed later in this chapter. these bacteria have a tendency for multiple antibiotic resistances. there are a number of other medically significant bacteria that only periodically present in the pediatric intensive care unit. these bacteria are prevalent in some regions and not elsewhere. they will not be discussed further in this chapter. fungi (of importance in the picu) classification • yeasts (e.g., candida or cryptococcus sp.) • molds -filamentous fungi (e.g., aspergillus sp. and trichophyton sp.) • dimorphic fungi -yeasts in tissue but grow in vitro as molds (e.g., histoplasmosis) candida. c. albicans has the highest incidence in the critical care environment followed by c. parapsilosis, c. tropicalis, c. glabrata, and c. krusei. localized and systemic infections in neonates and immunocompromised children. any organ can be involved: mucous membranes, larynx, esophagus, brain, eyes, lungs, heart, kidneys, liver, and spleen. aspergillus. a. fumigatus is the most common species in invasive aspergillosis, followed by a. flavus, and a. nigra. localized and systemic infection in immunocompromised children (particularly post stem cell transplant and in children with aml); in the skin, subcutaneous tissues, nasopharynx, lungs, brain, and virtually any other organ. endemic mycosis (histoplasmosis, blastomycosis). pneumonitis, hepatosplenomegaly, fever in children with t-cell dysfunction and in those with hiv infection. coccidioides immitis. pneumonia, meningitis in children with t-cell dysfunction and in those with hiv infection. cryptococcus neoformans. pneumonia, meningitis in children with t-cell dysfunction and in those with hiv infection. human herpes viruses 1. herpes simplex virus (hsv, types 1 and 2) (a) systemic infection in the neonate with shock and coagulopathy and severe liver failure (b) encephalitis, hepatitis (c) local (mouth, esophagus, larynx, lungs, heart, liver, kidneys, cns) or systemic disease in organ and stem cell transplant and immunocompromised patients 2. cytomegalovirus (cmv) (a) congenital infection in the neonate with systemic involvement (b) localized (liver, lungs, heart, kidneys, gi, cns, eyes) or systemic infection in solid organ and stem cell transplant as well as immunocompromised patients 3. epstein-barr virus (ebv) (a) infectious mononucleosis (b) burkitt's lymphoma, x-linked lymphoproliferative disorder (xl-lpd), post transplant lymphoproliferative disorder (ptld) (c) localized (liver, heart, lungs, kidneys, gi, cns) it is likely that viral infections have been underestimated both in their frequency and the degree of morbidity they cause. indisputably, in the modern day, hiv (human immunodeficiency virus) is one of the most significant viral pathogens worldwide, particularly in africa and developing nations that do not have the available resources to prevent spread among the community and more importantly maternal infection of the newborn. this leads to a range of morbidities as discussed in the immunocompromised section of this chapter. viral infections are mostly diagnosed clinically on the basis of history and physical examination as well as the regional prevalence of viral diseases. there are a number of ways to test for the presence of a particular virus from either patient blood or other body fluids. these are: tissue culture, serology and seroconversion, immunoflouresence, and pcr (polymerase chain reaction). only two of these are of any use to the intensivist: pcr and immunoflouresence. the turnaround time for viral culture and serum serology is inefficient in the critical care context. respiratory viruses (respiratory syncytial virus, influenzae, adenovirus, parainfluenzae, and human metapneumovirus) are the main contributors to viral disease in the picu, as they are in the general pediatric population. in the picu the majority of patients that develop significant degrees of illness are those who have significant comorbidities. conditions such as ex-prematurity, chronic lung disease, neuromuscular diseases, and congenital heart disease are probably the most common of these. herpes virus family, particularly herpes simplex virus (hsv), is the next important contributor to the burden of viral disease. all members of this family (hsv, ebv, cmv, and vzv) can cause serious infections in the neonate and in immunocompromised children. all services that treat the acutely unwell child (and adult) are at risk of being overwhelmed in an epidemic. national and regional planning needs to be undertaken prior to the advent of any serious infection where ever possible. (examples are sars -severe acute respiratory syndrome, or h1n1 ''swine flu.'') this is encapsulated in the worldwide pandemic planning taking lessons from the sars epidemic and the last major (in terms of mortality) influenza epidemic, the ''spanish flu'' that was prevalent from 1918 to 1920. at a hospital or an organizational level the concept of ''surge strategy'' is used. this is an organization based contingency plan to deal with large numbers of patients admitted simultaneously (i.e., mass trauma casualties or epidemics). in the case of influenza (or sars) this is relevant to the intensive care in that there is a finite capacity of any unit to provide mechanical ventilation. in addition to this, the institution is responsible for the protection of health care workers who are at high risk to contract an infectious illness and become a patient themselves. this would further increase the burden of illness and has the potential to limit available human resources. the prevalence of hiv in the general population and, in particular, in children in many developing countries poses significant stress on limited resources. hopefully, with more effective preventive programs to control vertical transmission of the infection and with availability of affordable anti-hiv medications, the quality of care for hiv-infected children will improve and the need for intensive care will diminish. regional or local experience is crucial in the management of many infections. dengue fever and viral hemorrhagic fevers, which are of more global importance, will be reviewed in more detail. dengue infections, caused by the four antigenically distinct dengue virus serotypes (den1, den2, den3, den4) of the family flaviviridae, are the most important arbovirus diseases. dengue is the most widely distributed mosquito-borne viral infection of humans, affecting an estimated 100 million people worldwide annually. dengue hemorrhagic fever usually occurs in children, with peaks in incidence at 7 months of age (with dengue-immune mothers), and at 3-5 years of age (during a second infection with a new serotype). it is spread throughout the tropical and subtropical zones between 30 n and 40 s where environmental conditions are optimal for viral transmission by aedes mosquitoes, principally aedes aegypti. the disease is endemic in se asia, the pacific, west africa, the caribbean, and the americas. global warming, by increasing the range of aedes mosquito, has the potential to lead to more widespread disease. who has classified the severity of dengue infection on the basis of a combination of clinical and laboratory findings (presence of hypotension and shock, tourniquet test, lowest platelet count, plasma leakage represented by high hematocrit level) in to: • dengue fever • dengue hemorrhagic fever • dengue shock syndrome (dss) viral hemorrhagic fever is a loosely defined category that includes infections from a host of viruses leading to similar clinical syndromes and sharing a similar severity of illness. otherwise, these viruses are different from each other with regard to their reservoir hosts, geographic distribution, and taxonomy. risk factors for exposure also vary among these infections and hence the control methods are geared to specific infections and their causative agents and intermediate hosts. in endemic areas diagnosis is by and large clinical and is confirmed by serological tests and viral pcr or culture. there are vaccines developed for some of these viruses. as a group, the treatment for these infections in the picu is mainly supportive and includes measures to: • optimize hemodynamic state and treat shock • monitor and control brain edema and intracranial hypertension • support ventilation and gas exchange with noninvasive or invasive ventilation • treat coagulopathic state if symptomatic • provide renal replacement therapy if needed; monitor and optimize glucose and electrolyte levels exhaustive discussion of this topic is beyond the current chapter, so the most important ones are briefly mentioned here. yellow fever is endemic in tropical africa between 15 n to 10 s and in parts of central and south america between 10 n and 40 s. in the life-cycle of this virus, in different parts of the world, mosquitoes (a. aegypti, haemagogus, and sabethes), monkeys, and people are involved; however, epidemic mosquito-borne human-to-human transmission can occur. after an incubation period of 3-10 days, fever, headache, malaise, nausea and vomiting, and musculoskeletal pain occur suddenly. initially, the clinical signs may include conjunctivitis, flushing of the skin, and relative bradycardia. in about 10% of cases the illness deteriorates with development of shock, systemic toxicity, gi bleeding, renal dysfunction, liver failure and jaundice, encephalopathy, and systemic bleeding. this latter picture is associated with a high mortality rate (30-50%). differential diagnosis includes other viral hemorrhagic fevers, viral hepatitis, leptospirosis, malaria, typhus, typhoid fever, brucellosis, rickettsial disease, and some intoxications. therapy is supportive and these patients may need intensive care admission for hepatic, renal and circulatory failure. who has recommended routine childhood vaccination in endemic areas (for children >4 months of age). vector control is important in highly populated areas to reduce the risk of epidemic transmission. lassa fever causes as many as 300,000 cases and 5,000 deaths each year in west africa and is a leading cause of maternal and fetal deaths. the virus is carried by mastomys huberti and mastomys erythroleucus, the rodent reservoirs whose infectious excretions are the source of human infections in west africa. in adults and children, early illness includes fever, malaise, headache, and musculoskeletal pain. these nonspecific symptoms progress over 4-5 days to include pharyngitis, cough, chest pain, diarrhea, and vomiting. in endemic areas, a purulent pharyngitis, with conjunctivitis, head and neck edema, and mucosal bleeding are highly specific signs of lassa fever. in severe cases, the illness may be complicated by hypovolemic shock, encephalopathy, respiratory distress caused by laryngeal edema, pleural effusions, or pneumonitis. liver failure, systemic and gi/gu bleeding, and myocarditis can occur. mortality is between 15% and 30%. there are anecdotal reports of the use of intravenous ribavirin in critically ill children with lassa fever but treatment is mainly supportive. lassa fever has been transmitted from person to person during hospitalization. universal exposure precautions should be observed as well as contact and droplet precautions. cchf is caused by a nairovirus (family bunyaviridae), and is transmitted by hyalomma ticks and by contact with infectious body fluids. the geographical distribution of the hyalomma ticks covers africa, the middle east and mediterranean areas, eastern russia, and west asia. the incubation period is from 2 to 9 days. illness onset is abrupt and nonspecific, with fever, chills, rigors, intense headache, and generalized muscle pain. onset of bleeding in the skin, mucous membranes, and the gi tract usually occurs after 3-6 days of illness. hepatitis, liver failure, circulatory failure, shock, and ards can ensue with mortality in up to 30% of cases. treatment is mainly supportive. the virus is sensitive in vitro to ribavirin, and this agent has been used in management of cchf with variable success (who). the value of immune plasma from recovered patients for therapeutic purposes has not been demonstrated, although it has been employed on several occasions (who). patients with suspected or confirmed cchf should be cared for by staff using added droplet and contact precautions. hfrs is caused by old world hantaviruses (family bunyaviridae). the reservoirs are small rodents, and humans are infected percutaneously or by direct exposure. clinical illness has an abrupt onset with fever, severe musculoskeletal pain, renal failure, systemic and gi bleeding, circulatory failure, and shock. this form of the disease is more common in asia and eastern europe. in hantavirus pulmonary syndrome (hps) (mainly seen in the americas), within 12-24 h of onset of symptoms, most patients develop some degree of hemodynamic instability and pulmonary edema accompanied by hypoxemia to full blown ards. petechiae of the head and neck are common but overt hemorrhagic symptoms are not. treatment is supportive and in those who survive, recovery is usually rapid. when given early in the course of illness, intravenous ribavirin has improved survival rate in hfrs but not in hps. steroids reduce the severity of the symptoms but do not increase the survival rate. malaria is singled out here because it is the most significant parasitic disease in humans with an estimated 500 million infections annually that result in 1-3 million deaths. the majority of these deaths are in children younger than 5 years of age and most are in africa. in developed countries malaria is the most common cause of febrile illness with no localizing signs in travelers returning from developing countries. the most important aspects of severe malaria are reviewed, which, for the most part, is caused by plasmodium falciparum. indicators of severe and complicated falciparum malaria and prognostic signs (world health organization 2000) cerebral malaria unrousable coma (gcs < 11/15), with peripheral p. falciparum parasitemia after exclusion of other causes of encephalopathy severe anemia hgb < 5 g/dl in the presence of parasitemia >10,000 per ml impaired consciousness of any degree, prostration, jaundice, intractable vomiting, parasitemia >2% in nonimmune individuals. levels of parasitemia should be interpreted in the light of immunity. patients with complicated malaria should be managed as severe malaria, i.e., with parenteral antimalarials even though they do not necessarily meet the criteria of severe disease. for details of management, review > chap. 101, ''malaria''. the world health organization defines cerebral malaria as unrousable coma in the presence of p. falciparum parasitemia when other causes of encephalopathy have been excluded. the precise etiology of cerebral malaria is not certain. most likely it is caused by sequestration of infected erythrocytes. this condition has a high mortality that likely results from brain micro vascular ischemia, infarction, and secondary cerebral edema. cerebral malaria is a medical emergency that requires: 1. supportive care: (a) continuous monitoring of vital signs. for a detailed discussion on sepsis, and the diagnosis and management of shock, please review the appropriate chapters (> chap. 61, ''bacterial sepsis and shock''). toxic shock and necrotizing fasciitis are two particular sepsis syndromes that require a special reference. toxic shock syndrome (tss) is caused by two bacteria: staphylococcus and streptococcus. s. aureus is a gram-positive coccus that is grouped in clusters. it is responsible for a number of infections ranging from skin sepsis, pneumonia, and joint infections to endocarditis. phage transformed staphylococcus produces a toxin that initiates a syndrome known as toxic shock syndrome (tss). this came to light in the 1980s with the ''menstrual shock'' syndrome. a non menstrual form was also identified. this was associated with staphylococcus sepsis at surgical sites, skin or joint infections, and with staphylococcal pneumonia. this syndrome is said to be ''superantigen'' mediated. the toxin proteins produced by the staphylococcus are able to ''cross-link'' the t-cell receptor without being processed by an antigen presenting cell (apc). this leads to an uncontrolled cascade of cytokines and immune system up regulation. at the level of the capillary this leads to inflammation and increasing permeability with secondary organ dysfunction (renal impairment, cardiac, pulmonary, and liver dysfunction). clinically this is manifested by skin erythema, tachycardia, hypotension, hypoxia and other critical organ dysfunction. initially this is subtle but rapidly develops into multi organ dysfunction. see the table below for the criterion upon which a diagnosis of staphylococcal toxic shock is made. treatment consists of recognition of the process, draining any collections of pus, and debridement, if that is appropriate. at the same time initiation of large volume fluid resuscitation, inotropic support and support of failing lungs with oxygen and ventilation if needed. antistaphylococcal antibiotics should be administered (this includes an antibiotic to cover for methicillin resistant staphylococcus). clindamycin being an anti-ribosomal antibiotic (50s bacterial ribosome) has a theoretical advantage in reducing the amount of toxin produced prior to antibiotic induced death of the bacterium. intravenous immunoglobulin (ivig) is a treatment for severe toxic shock that is progressing to multi-systems dysfunction. it has a proven efficacy in toxic shock in reducing the mortality of severe disease. this is thought to be via two general mechanisms. the first is by binding directly to the toxin. the second is by its immuno-mediatory properties. major criteria (all required) 1. fever !38.8 c 2. hypotension (orthostatic or shock) 3. rash (erythematous early and desquamative later) minor criteria (any three required) 1. gastrointestinal: vomiting or diarrhea 2. muscular: severe myalgia or cpk !2x upper limit of normal 3. mucous membranes: vaginal, oropharyngeal, or conjunctival hyperemia 4. renal: urea or creatinine !2x upper limit of normal, or urinalysis with >5 wbc per high-power field 5. hepatic: total bilirubin, ast or alt !2x upper limit of normal 6. blood: platelet count <100,000/ml 7. cns: disorientation or change in level of consciousness without focality, noted when fever and hypotension are absent streptococcal toxic shock is a syndrome that is analogous to staphyloccal toxic shock syndrome in that it is a superantigen mediated toxin related dysfunction of the immune system. group a beta-hemolytic streptococcus is most commonly associated with streptococcal toxic shock syndrome. clinical presentation is very similar to staphylococcal toxic shock. see table below. treatment consists of appropriate antibiotics. clindamycin is used for antimicrobial and antitoxin producing properties as previously mentioned. ivig here too has a role in reducing the mortality of severe disease. intensive care therapy consists of fluid resuscitation (large volume) and support of organ dysfunction (inotropes, ventilation, renal replacement therapy). hypotension or shock, plus any two of the following: 1. scarlet fever rash 2. abnormal liver function tests 3. renal insufficiency 4. disseminated intravascular coagulopathy (dic) 5. acute respiratory distress syndrome (ards) 6. soft tissue necrosis definite: preceding requirements + isolation of group a streptococcus from a normally sterile body site probable: preceding requirements + isolation of group a streptococcus from a non sterile body site necrotizing soft tissue infections are aggressive soft tissue infections that cause extensive necrosis, and include necrotizing cellulitis, fasciitis, and myonecrosis. the following clinical findings may be present: • erythema or discolored skin also the following systemic signs may be present: • local pain and tenderness out of proportion to physical findings • pain or tenderness that extends past the margin of apparent affected skin area necrotizing fasciitis is a surgical emergency. it is caused by a number of organisms: group a beta-hemolytic streptococci and other streptococci, staphylococcus, clostridium, pseudomonas, klebsiella, serratia, neisseria, escherichia, morganella, proteus, shigella, vibrio, salmonella, pasturella, enterobacter, corynebacterium, cryptococcus, fusobacterium, peptococcus, eikenella, bacteroides. the most common causative agent is group a streptococcus. pathologically it is characterized by micro angiopathic thrombosis and necrosis along superficial and deep fascial planes. the illness is associated with a breach of the integument. this can be by superficial infection, surgery or trauma. non steroidal antiinflammatory drugs are implicated in the pathogenesis. in children there is an association with varicella (chickenpox) infection. clinically the lesions appear either pale or have violaceous discoloration, often edematous, and there may be crepitus from gas forming bacteria. pain and tenderness in excess of that expected is a feature. the concern for the intensivist is the physiological decompensation that can lead to rapid cardiovascular collapse. broad-spectrum (and appropriate) antibiotics are indicated, and mechanical ventilation and cardiovascular support may be needed. urgent and wide surgical debridment of the affected areas is indicated. in cases of streptococcal necrotizing fasciitis there may be additional benefit from human immunoglobulin (ivig) therapy. though this has not been subjected to clinical trials, given the high mortality rate of necrotizing fasciitis and the biologically plausible consideration that ivig could neutralize the effects of streptococcal superantigens, its use can be justified. other treatments that have been used are: • vacuum-assisted wound closure (particularly in patients who have had large wound debridement) • hyperbaric oxygen (anecdotal evidence) the child, especially the infant, presenting with upper airway obstruction (uao) demands immediate attention. acute inflammation of the upper airway is of greater importance in small children because of the smaller diameter of the airway, hence the greater degree of obstruction from a similar amount of inflammation (resistance changes inversely to the fourth power of the radius of the airway). the following signs and symptoms are particularly worrisome: • inspiratory and expiratory stridor • active expiration (use of the rectus abdominis muscle when exhaling) • apnea or irregular breathing • increasing tachycardia (if no intervention is done tachycardia may be followed by decreasing heart rate which is usually a pre-arrest sign) • hypoxemia (late sign) • change in neurological status (becoming increasingly inconsolable and restless, or a child who ''stops fighting'' and becomes fatigued and hypotonic) there are many scoring systems for severity of the uao in children. the following is one suggested by downes et al. in 1980 . of note there is no mention of the neurological status in this scoring system. level of alertness and consolability of a small child are very important indicators of the severity of the uao. immediate management of acute severe stridor outside the picu, independent of underlying cause: • keep the child and the parent as calm as possible. do not separate the child from parent. • give the parent an oxygen mask to hold near the child's face. • call for help urgently from someone with expertise in airway management (usually an anesthesiologist). • give nebulized epinephrine (im epinephrine if airway obstruction is due to anaphylactic reaction). (skip nebulized epinephrine if you suspect epiglottitis.) • do not send the child to the radiology department for a lateral x-ray of the neck. • do not administer any sedative medications to the patient. • do not do attempt to draw blood for investigations. • place ecg monitoring leads and pulse oximetry probe without disturbing the child. • do not attempt to place an iv line (obviously you would place an iv/io access if the child has already had a respiratory or cardiac arrest). • the airway expert will decide to take the child to the or for intubation, or transfer to the picu. in children, there are many causes of acute uao, including infections (viral, bacterial) such as infectious mononucleosis, croup, epiglottitis, tracheitis, peritonsillar abscess, retropharyngeal abscess, diphtheria. noninfectious causes include foreign body, severe allergic reactions, acute angioneurotic edema, airway burn, trauma, and post-extubation in the picu. there are many causes of chronic/recurrent uao. in the history there may be chronic/recurrent symptoms. these patients may become symptomatic acutely (often with a viral respiratory infection) mimicking acquired acute upper airway obstruction. examples are: choanal atresia, laryngotracheomalacia, vascular ring, laryngeal web, subglottic stenosis, subglottic haemangioma, vocal cord palsy, recurrent angioneurotic edema. in this section the infectious causes of uao are addressed to. the more common infectious etiologies that may present with severe uao in children are: • croup or viral laryngotracheobronchitis • bacterial tracheitis • epiglottitis viral croup is the most common form of uao in children 6 months to 6 years of age (mostly 6 months to 2 years) and is more common in the autumn and early winter. the site of obstruction is the subglottic area. obstruction is caused by inflammation and edema. the most common viral etiology is parainfluenza, but influenza, enterovirus (coxsakie and echovirus), rsv, adenovirus, paramixovirus, rhinovirus, and hsv can cause a similar clinical picture. human metapneumovirus has been implicated in a few reports. in immunocompromised children, candida sp. can cause a similar presentation. there is a prodrome of mild fever and uri symptoms for 1-2 days before the onset of stridor. the stridor is characteristically harsh, dry, high pitched, and inspiratory. a ''barking'' or ''seal-like'' cough is prominent and usually worse at night. these children do have a voice, though hoarse, and they do not have trismus, dyphagia, or significant drooling. children with stridor at rest should be admitted for observation, while those with severe uao should be admitted to a picu. up to 15% of children with croup require hospitalization. usually no investigations are needed. administration of steroids (oral route is as good as intramuscular) in the emergency room has decreased the rate of hospitalization. hospitalized children with croup should receive a short course of oral or intravenous steroids (an example of a regimen is: dexamethasone 0.6 mg/kg iv/ po as an initial dose followed by 0.15 mg/kg q 6 h iv/po). inhaled nebulized epinephrine 1:1,000 solution (0.5 ml/kg, up to 5 mg) reduces the severity of obstruction and stridor. this can be repeated as required. the child must be observed for at least 2 h after a dose of nebulized epinephrine as the effects are transient. the decision on when to intubate a child with croup is a clinical one. if, despite maximum medical treatment there is not a clinical improvement or perhaps deterioration, a decision to intubate should be made or at least considered. a gentle and smooth intubation, using a tube one size smaller than usual for the age of the child, should be performed by a skilled and experienced practitioner. these children are at risk of accidental extubation and need proper securing of the ett, skilled nursing care, and adequate sedation only once the airway has been secured. most clinicians extubate the child 2-6 days later, when an audible air leak has developed around the ett and fever has settled. epiglottitis, or acute bacterial supraglottitis, is a bacterial infection of the laryngeal inlet, and is usually caused by h. influenzae type b (hib). with ''classical'' hib epiglottitis, the peak age of involvement is 2-3 years of age. since the introduction of the hib vaccine, the incidence of this disease has fallen dramatically, but the vaccine does not offer 100% protection. also, other organisms like s. aureus, s. pneumoniae, group a + b streptococcus, and n. meningitidis have been implicated as causative agents. the incidence of these latter organisms is higher in adolescents and older children. noninfectious causes of epiglottitis have been described in the following conditions: kawasaki's disease, stevens-johnson syndrome, airway burn, caustic ingestion, post-radiotherapy, angioneurotic edema, trauma (including trauma from intubation), leukemia, and lymphohistiocytosis. granulomatous states can cause a more chronic picture (sarcoidosis, tb, or wegener's granulomatosis). as fewer and fewer physicians have seen even one case of epiglottitis, it is important to have a high index of suspicion in any febrile child with uao. the following signs are highly suspicious of epiglottitis: • usually there are no prodromal signs and symptoms. • a few hours of high fever and tachypnea. • pain with swallowing, hence drooling is common. • reluctance to speak. • the child looks ill, with circumoral pallor, and a ''toxic'' appearance. • there is minimal or no coughing. • stridor is low-pitched and muffled, more like a snore. • child prefers to sit forward in the tripod position with mouth open and is reluctant to move his head or neck. if you have suspicion (on clinical grounds) that a child may have epiglottitis: • do not make the child lie down. • do not separate the child from parent. • do not examine the throat. • do not place an iv cannula. • do not order a lateral x-ray of the neck. • do not order any blood work. • do not transport a child with epiglottitis between hospitals unintubated. • the child should be accompanied by an expert in difficult airway management to the operating room for examination under anesthesia and securing airway if needed. the technique for induction of anesthesia is beyond the scope of this chapter. generally the inhalational method is performed in the sitting position (position of comfort for the child), and once the child loses consciousness intravenous access is secured and the rest of the monitoring is applied. laryngoscopy and intubation is only attempted after adequate depth of anesthesia has been obtained. blood cultures and a swab from the inflamed epiglottis should be sent and a 3 rd generation cephalosporin should be given once an iv is in place. when back in picu, accidental extubation can have disastrous consequences. skilled taping of the ett, nursing care, and adequate anaelgesia/sedation cannot be over emphasized. usually after 12-48 h of intravenous antibiotics the patient can be safely extubated, once the fever has subsided and presence of a leak is documented and the child is able to swallow (the child is not drooling). some practitioners prefer to reevaluate by direct laryngoscopy with the patient deeply sedated or anesthetized. if the causative organism is proved to be hib, in families with siblings under 4 years of age or families with an immunocompromised child, prophylaxis with rifampicin should be provided. bacterial tracheitis is characterized by profuse purulent secretions or sometimes by pseudomembrane formation in the tracheal lumen. the median age of the patient is 5 years. s. aureus is the most common etiology, though other gram-positive and less commonly gram-negative microorganisms might be causative. in immunocompromised children candida and aspergillus can cause tracheitis. these children usually have a high fever, they look toxic, and the stridor characteristically is high pitched and composed of both inspiratory and expiratory components. cough is usually prominent and they may have dysphonia or aphonia. drooling can be seen with bacterial tracheitis. these patients are at risk of airway obstruction. they require appropriate antimicrobial therapy, observation, and intubation by experts if warranted. community-acquired pneumonia (as opposed to nosocomial or hospital acquired pneumonia) is a common pediatric diagnosis that leads to admission to hospital for intravenous antibiotics and supportive respiratory therapy. pneumonia means inflammation of the lung parenchyma caused by infection and the diagnosis is made clinically in a febrile child with respiratory signs and symptoms who has evidence of consolidation on cxr. blood cultures frequently fail to reveal the infecting organism in pneumonia. tracheal aspirate, or more reliably, bronchoalveolar lavage (bal) and on occasions lung biopsy are required. children with immunodeficiency or malignancy undergoing therapy are a common example of where bal and/or lung biopsy may be necessary. • mycobacterium tuberculosis s. pneumoniae and s. aureus are the most important bacterial pathogens in children with pneumonia who need intensive care admission. as a general rule, truly focal disease, confined to a single lobe, is more likely to be due to bacteria. an ill child with unilateral pleural effusion most likely has s. pneumoniae or s. aureus pneumonia. viral • rsv • influenza a, b, c • parainfluenza routes to acquire infection: • inhalation of infected particles (most common) • aspiration • hematogenous invasion of the lower respiratory tract with viruses and bacteria leads to inflammatory changes characterized by migration of neutrophils into the alveoli. together with alveolar macrophages they provoke the production of inflammatory exudates and cellular debris that lead to consolidation of the lung parenchyma. the surrounding areas can be affected by atelectasis. • spo 2 <90% in high concentrations of inspired oxygen (>60% fio 2 ) • excessive work of breathing which may lead to exhaustion • shock and hemodynamic instability • change in neurological status (agitation or alteration of the level of consciousness) reasons of failure to respond to treatment on the pediatric ward or as outpatient: • development of an empyema or less commonly a lung abscess • underlying lung disease such as: bronchopulmonary dysplasia (bpd, in ex-premies), cystic fibrosis, inhaled foreign body, tracheobronchomalacia or post tracheal surgery, or infected congenital lung cyst • diagnosed or undiagnosed immunodeficiency states (primary, hiv, leukemia) • children with neuromuscular diseases, weakness, or spasticity such as muscular dystrophies, myasthenia, spinal muscular atrophy, or cerebral palsy • inappropriate antibiotics, inappropriately low dose or resistant bacteria • non bacterial pneumonia (viral pneumonia or alternative pathogen such as tuberculosis) once the culture results (bal, blood culture, sputum culture) and sensitivities are known the therapy should be tailored to the antibiotic sensitivities of the causative organism(s). • empyema. more commonly seen with s. pneumoniae and s. aureus pneumonia. generally a chest drain is needed. the use of fibrinolytics and surgery are areas for debate and local advice from thoracic or general surgeons and physicians from the respiratory and infectious diseases services should be sought. bronchiolitis is a seasonal viral infection of the lower respiratory tract that mainly affects infants. the usual cause is respiratory syncytial virus (rsv), although influenza, parainfluenza, adenovirus, and human metapneumovirus can cause a similar syndrome. in young infants, chlamydia and b. pertussis can cause respiratory illness with a more prolonged course that initially may resemble bronchiolitis. 20-25% of infants with bronchiolitis may have a secondary bacterial infection. infants with bronchiolitis have fever, cough, difficulty in feeding, and, on occasion, audible wheezing. on examination bronchiolitis is a syndrome characterized by respiratory distress, hyperinflation of the chest, and wheezes with fine inspiratory crackles heard on auscultation. apnea may occur even before onset of clinically significant respiratory distress, especially in ex-premature infections in the picu and very young infants. though not common, neonates may present with hypothermia and a sepsis like syndrome. the following groups are at increased risk of severe infection: • ex-premature infants and neonates • infants with congenital heart disease • infants with immune deficiency • infants with neuromuscular disease the virus causes direct damage to the respiratory epithelium with resultant inflammation, increased secretions, small airway obstruction. areas of hyperinflation and atelectasis exist simultaneously throughout the lung. this leads to ventilation and perfusion (v/q) mismatch and hypoxia. hyperinflation flattens the diaphragm and makes breathing less efficient. should they require respiratory support, many of these infants can be managed with noninvasive continuous positive airway pressure (cpap) at 4-8 cm h 2 o. this reduces the work of breathing and improves oxygenation. suction to maintain patency of airways is of crucial importance. if the saturations remain low and/or the infant continues to have frequent apneas despite providing noninvasive ventilatory support intubation of the trachea is indicated. • intubation is usually required for several days. • inadequate humidification and inadequate tracheal suctioning cause endotracheal tube blockage or lung atelectasis followed by increasing pressure and fio 2 requirements. • as a general rule, the best ventilatory mode is one that assists spontaneous respiratory efforts; keep the child's own respiratory and coughing efforts by providing enough comfort (sedation) and pressure support. • peep or cpap (initially at 4-6 cm h 2 o) may reduce the work of breathing. • apply enough peak inspiratory pressure (pip) to achieve visible chest excursions and if higher pressures (>30 cm h 2 o) are needed, let the paco 2 gradually rise to 75-80 mmhg with arterial ph > 7.2 (permissive hypercapnia). particular issues in infants with congenital heart disease and bronchiolitis: • infants with left to right shunts have more frequent viral and bacterial respiratory infections, and have higher morbidity and more prolonged course with bronchiolitis. • infants with palliated single ventricle physiology and those with limited cardiac output (for example severe valvar aortic stenosis) have high morbidity and mortality with bronchiolitis. • bronchiolitis and other viral respiratory infections in infants with congenital heart disease lead to operative delays and increasing complications post cardiac bypass surgery (e.g., pulmonary hypertension). in any infant with rsv bronchiolitis and congenital heart disease awaiting surgery, it is suggested to wait for 2-3 weeks before proceeding with bypass and surgery. the american academy of pediatrics has specific recommendations on prophylactic monthly injection of rsv monoclonal antibody in ''at risk'' infants during the cold season. however, the use of this approach has only been shown to aid a small number of patients. this section reviews: • myocarditis • infective endocarditis • infectious pericarditis • wound infection after cardiac surgery myocarditis is an inflammatory disease of the heart muscle characterized in its active phase by cellular infiltrates and myocardial necrosis. however myocarditis can have cellular infiltrates with little or no myonecrosis. most cases of myocarditis are thought to have a viral etiology; however, viruses are infrequently isolated. the most common viral causes include the enterovirus family particularly coxsackievirus b and adenovirus. other viral causes are influenza, cmv, hsv, parvovirus, rubella, varicella, mumps, hiv, and ebv. myocarditis has a number of other non viral etiologies, some infective and some not. they include bacteria, rickettsia, fungi, protozoa, pharmaceuticals, toxins, and connective tissue/autoimmune disorders. typically viral myocarditis begins as a systemic viral illness with flu-like symptoms. as the virus infects the myocytes the immune system is up regulated and cd4 t-helper cells and cd8 cytotoxic t cells are stimulated along with proinflammatory cytokines. persistence of the viral rna and production of no by the myocytes have been linked to myocardial tissue damage. myocarditis can present in a number of ways: • out of hospital cardiac arrest/sudden death • cardiogenic shock (may mimic sepsis) • congestive heart failure (increasing dyspnea, lethargy) • dysrhythymias -bradycardia, tachycardia whilst sepsis and hypovolemic shock are more common than cardiogenic shock from myocarditis, it should always be in the differential. sometimes acute ''decompensation'' of these children is heralded by abdominal distension and vomiting. teenagers may complain of a feeling of ''impending doom'' or severe chest discomfort. clinically, signs of tachycardia/tachypnea, gallop rhythm, hyperdynamic precordium, and displaced apex are often present. hepatomegaly and in older children elevated jugular venous pressure (jvp) are usually present. crackles on auscultation are often present in the chests of older children. chest x-ray (cxr) may show an enlarged heart, pulmonary venous congestion, alveolar edema, kerley b lines, and in some cases pleural effusions. in acute myocarditis the heart may often look normal in size on the cxr. a 12-lead ecg is useful to assess underlying rhythm, assess for ischemia and for the subtle ecg changes that are sometimes evident with myocarditis; st-t changes, reduced qrs voltage, widened qrs. echocardiography is absolutely necessary to assess structure and function of the heart and to assess for a pericardial effusion. involvement of appropriate specialists is important -cardiologists, intensivists, and cardiothoracic surgeons work cooperatively to manage and stabilize these patients. treatment of myocarditis is largely supportive. immunomodulation using steroids, intravenous immunoglobulin, and immunosuppressive agents is controversial. identifying any modifiable contributors, i.e., toxins and drugs, is of crucial importance. supportive therapy for heart failure associated with myocarditis ranges from diuretics and afterload reduction, addition of inotropic support to placing the patient on mechanical circulatory support. dopamine and dobutamine increase contractility but also heart rate and myocardial oxygen consumption. milrinone is an intravenous phosphodiesterase inhibitor that improves contractility and at the same time, reduces the afterload. enoximone is an oral phosphodiesterase inhibitor that is available in europe, but not in north america. levosimendan is a calcium sensitizer and improves contractility. it has limited availability world wide. positive intrathoracic pressure, given noninvasively via a face mask (cpap), reduces lv afterload and may improve cardiac output in the setting of lv dysfunction. failed medical therapy or deteriorating function will usually indicate the need for extracorporeal support and ultimately heart transplantation. mechanical support (ecls, ''berlin'' heart) is frequently used as a ''bridge'' to recovery or transplant. for a complete review of endocarditis review the cardiology chapter in this book. the major reasons a child with endocarditis may need admission to picu are: infections in the picu 1. congestive heart failure due to worsening valvar regurgitation 2. congestive heart failure with abrupt onset due to valve apparatus rupture/perforation, or dehiscence of a prosthetic valve 3. systemic to pulmonary artery shunt obstruction 4. arrhythmia 5. renal failure 6. embolic events to (a) brain (b) heart (c) lungs (d) bowel (e) extremities for a complete review of pericarditis and tamponade, please review the cardiology chapter in this book. acute inflammation of the pericardium in a previously healthy child has usually been assumed to be viral. in most cases a causative agent is not detected (hence the term ''idiopathic'' pericarditis). an upper respiratory infection usually precedes the onset of symptoms by 10-14 days. the reported viral pathogens include coxsackievirus, adenovirus, rsv, varicella, hepatitis b, hiv, and post influenza vaccine. primary infectious pericarditis that may need picu care is usually purulent bacterial pericarditis. these patients are generally toxic looking. the infection in the pericardium rarely occurs in the absence of infection elsewhere (hematogenous spread). in comparison with the viral (idiopathic) pericarditis, the incidence of tamponade and hemodynamic instability is much higher with purulent pericarditis. s. aureus is the most common cause of purulent pericarditis. other bacteria include h. influenzae, n. meningitides, and s. pneumoniae. in developing countries, tubeculous pericarditis is a common cause of chronic constrictive pericarditis. therapy depends on the hemodynamic status of the patient. a toxic-looking child with physiological signs and symptoms of tamponade should be transferred urgently to the catheterization laboratory or to the intensive care unit for percutaneous drainage of the pericardial collection. sometimes the pus in pericardium is so thick or organized (esp. with h. influenzae) that percutaneous drainage may not be sufficient and the child will need open surgical drainage. with tamponade physiology, administration of fluid boluses can temporarily increase the intracardiac ''filling'' and stabilize the patient until the definitive treatment (percutaneous or surgical drainage) is performed. broad-spectrum intravenous antibiotics with good antistaphylocccal coverage should be commenced promptly if purulent pericarditis is suspected. surgical wound infections after cardiac surgery can be categorized as superficial (cellulitis) or deep (mediastinitis). the patient usually presents a few days after the procedure, but may occur up to 2 months after the initial operation. the important signs are erythema and induration at the surgical incision. the child may be irritable and have a mild fever. there may be a leukocytosis with ''left shift'' and elevated inflammatory markers such as c-reactive protein (crp) or erythrocyte sedimentation rate (esr). in addition to the wound erythema with or without purulent discharge there may be signs of sternal instability with ''crepitus'' on direct pressure over the sternum. diagnosis nevertheless is a clinical one and relies on a high index of suspicion. the risk factors are: neonates, long cardiopulmonary bypass time, delayed sternal closure, and reexploration of the chest for postoperative bleeding. the most common organisms associated with sternal wound infections are s. aureus, s. epidermidis, enterococcus species, and candida species. antibiotic treatment should begin as soon as a sternal wound infection is suspected and a wound swab has been sent. blood cultures should be sent from both peripheral and central venous sites whenever possible. the initial antibiotic regimen should consist of broad-spectrum gram-positive (anti-staphylococcal) coverage, with the addition of gram-negative coverage if the patient is septic or mediastinitis is suspected. if there is not a rapid improvement or the patient deteriorates the sternal wound may need to be surgically explored and debrided. antibiotics should be given for 10 days to 2 weeks for cellulitis and for 4-6 weeks for deep wound infections. meningitis is an inflammation of the leptomeninges of the brain. for a review of ''aseptic'' meningitis which also includes viral causes of meningitis, please look at the neurology and infectious disease chapters in this textbook. suffice to mention that patients with ''aseptic'' meningitis are usually not as sick as those with purulent meningitis, and the csf abnormalities are not as prominent. patients with bacterial meningitis have a number of reasons for requiring intensive care. the most common clinical scenarios are coma and seizures. the local inflammatory response to bacteria multiplying in the csf involves polymorphonuclear leukocytes, the endothelium, complement, and cytokines. this results in an alteration in the cerebral blood flow and venous drainage, vascular inflammation, and obstruction to csf flow and reabsorption. the infection within the meninges may extend to the surrounding brain parenchyma. the commonest bacteria are s. pneumoniae, n. meningitidis, and h. infuenzae. in the neonatal period, the likely causative organisms are different: group b streptococcus, l. monocytogenes, and gram-negative bacilli are the commonest. this profile will be modified depending on the local vaccination policy, socioeconomic status of the children in the area, and local/regional epidemics of disease. none the less the intensive care management is similar: 1. broad-spectrum cns penetrating antibiotics with narrowing of spectrum of antibiotic cover once results of cultures of the blood and csf are known. antibiotics with high csf/brain tissue penetrance must always be used. in areas with high incidence of s pneumonia penicillin resistance (including the united states), empiric therapy for community-onset bacterial meningitis is both vancomycin and a 3rd generation cephalosporin. acute complications of bacterial meningitis are: • hyponatremia (serum sodium <135 micromole/l): this is usually due to the syndrome of inappropriate secretion of antidiuretic hormone (siadh). there is hyponatremia and low serum osmolarity without signs of hypovolemia. hyponatremia can cause convulsions. cerebral salt wasting is a much rarer condition that gives hyponatremia with signs of volume contraction. siadh is treated by free water restriction and cerebral salt wasting is treated with sodium (either iv or po) supplementation. in a hyponatremic child with convulsions give 3% nacl 3-5 ml/kg intravenously. it is important to note that the change of serum sodium (and hence serum osmolarity) is of more importance in some cases than the absolute serum sodium. a sudden drop in serum sodium (greater than 0.5-1.0 micromole/h) should be treated with hypertonic saline. • seizures: convulsions that occur early in the course of purulent meningitis are usually generalized and have less prognostic significance than those occurring later. etiology of convulsions in meningitis can be any of the following: brain edema, diffuse ischemia, hyponatremia, subdural collection, sinus venous thrombosis, or focal infarction. • subdural effusion: this complication is seen more commonly in neonates and infants. a good practice is to measure the head circumference daily in any infant with meningitis. the diagnosis is made or confirmed by neuroimaging. if the effusion is large, or if it is associated with focal signs, convulsions, or signs of increased intracranial pressure, a neurosurgical consultation is necessary. • obstructive hydrocephalus: obstructive hydrocephalus occurs when the pus (often with high protein content) in the ventricles blocks the outflow of csf. this situation occurs more frequently in small infants and neonates. similar to meningitis, seizures, focal or generalized signs, and coma, are common presentations. the list of differential diagnosis is long and includes: aseptic meningitis, post infectious encephalitis and noninfectious encephalopathies (metabolic, vascular, demyelinating disease, tumor). the most frequent causes of acute encephalitis include: enteroviruses, hsv, vzv, ebv, adenovirus, influenza virus, and m. pneumoniae. mumps, measles, and rubella infections are rarely seen in developed countries. in many parts of the world arboviruses are major causes of endemic encephalitides. tuberculosis is always high on the list of differential diagnosis in developing countries. diagnosis: csf can be completely normal, but usually contains >10 leukocytes/mm 3 (mainly lymphocytes), mildly increased protein level and mildly reduced to normal glucose level. in children with hsv encephalitis, the csf may contain red blood cells. csf in addition to cell count, chemistry and culture should be sent for pcr for viral agents. csf pcr can be helpful in a number of the infectious encephalopathies. for example: m. pneumoniae, mycobacterium, cmv, ebv, vzv; where the organism may not be cultured from the csf. brain imaging (ct or mri) can be helpful in the diagnosis. in hsv encephalitis there may be focal edema and enhancement seen in the temporal area. this is relatively specific for hsv infection of the brain. the electroencephalogram may show focal periodic epileptiform activity in frontal and temporal parts of the brain. this is common in hsv disease. diffuse slow waves generalized over the cerebral cortex may also be seen. this may either represent encephalitis or be secondary to sedatives and anticonvulsants used in the picu. the primary use of eeg is in the management of seizures. finally, when the etiologic diagnosis is not clear, or the patient is deteriorating despite treatment, brain biopsy may be performed. treatment is largely supportive. as for meningitis this consists of appropriate antimicrobial (antiviral) therapy. there should be no delay in starting acyclovir if hsv is suspected or considered. the dose is 30 mg/kg/day for 10 days. when m. pneumoniae is suspected antibiotics with good penetration into the brain (ciprofloxacin, or azithromycin) should be used. additional management includes airway protection for coma and seizures. medical and surgical therapies for management of intracranial hypertension, as discussed above should be adhered to. adem is an acute or sub acute inflammatory demyelinating disease of the cns (brain and spinal cord). in contrast to multiple sclerosis it is a monophasic illness. adem is considered a parainfectious disease and the precipitants include infection with upper respiratory tract viruses, influenza, group a streptococcus, ebv, vzv, measles, mumps, rubella, and mycoplasma. clinical presentation may involve fevers, seizures and a constellation of neurological phenomena. commonly these are coma, focal neurological deficits or alterations in personality and behavior. often a recent ''viral infection'' is present in the history. the lumbar puncture is done to exclude infections. csf may have normal white cell count or mild pleocytosis (mainly lymphocytes), and mild to significant protein elevation. the cultures and pcr should be negative. neuroimaging is the main diagnostic tool for adem mri is the modality of choice, as the ct is normal in 40% of cases. the typical mri findings are multiple disseminated asymmetrical hyperintense lesions on t2wi and flair in the white matter and basal ganglia. the cerebrum is more involved than the cerebellum. treatment: (1) continue antibiotics and antivirals until final csf cultures and pcr results are confirmed to be negative. (2) once infection is ruled out methylprednisolone ''pulse'' dose at 30 mg/kg/day (maximum 1 g) for 3 days followed by oral prednisolone 2 mg/kg/day for 2 weeks. this is followed by a 4 weeks weaning regimen. (3) plasma exchange or ivig for relapsed or refractory adem. gbs is an immune-mediated polyneuropathy that is usually preceded by a viral or bacterial infection of the respiratory or gi tract 1-3 weeks prior to presentation. gbs is the most common cause of acute paralysis in developed countries and is characterized by progressive, ascending, symmetric motor weakness and loss of reflexes. the sensory symptoms (extremity pain, paresthesia) and autonomic irregularities (tachycardia, bradycardia, hypertension, hypotension, arrhythmia) can be prominent. there are usually no sensory deficits in physical examination. infections known to precede the onset of paralysis are: cmv, ebv, vzv, campylobacter jejuni, mycobacterium tuberculosis, hiv, and m. pneumoniae. the pathogenesis involves an immune response against the infectious agent and has components that cross-react with those of the peripheral nervous system. diagnosis is clinical but is aided by csf and electrophysiology testing. the csf shows a high protein content and low/normal white cell count. this may be missed if the lumbar puncture is done early in the first week of the illness. electrophysiology will show decreased conduction velocity in the peripheral nerves. treatment: ivig at 2 g/kg/day for 2-5 days or plasma exchange. (two courses for mild gbs and four to five courses for severe illness.) corticosteroids have not demonstrated effectiveness in gbs and are not recommended. indications for picu admission: • for respiratory support • for plasma exchange • autonomic instability (hypo-or hypertension, arrhythmia) botulism is a toxin mediated disease caused by c. botulinum. symptoms start a few hours and up to 6 days after exposure to the toxin. the cranial nerves are involved initially with difficulty swallowing, abnormal speech (abnormal cry in infants) and eye movements (ptosis). other symptoms may include nausea, vomiting, constipation, and abdominal distension. as the illness progresses it causes paralysis of the extremities and respiratory muscles to various degrees. in infants the disease can be mild with hypotonia and constipation as the main findings. also in infants there is sometimes a history of ingestion of honey before the onset of symptoms (honey may contain the spores of c. botulinum). diagnosis is made from a combination of clinical findings and electromyography. stool for botulinum toxin or serum serology is confirmatory but takes time. treatment is with antitoxin to remove circulating toxin but this will not affect the toxin already present at the neuromuscular junction. specific botulinum immunoglobulin is not readily available world wide. the cost is prohibitive for a lot of countries and the cost-benefit analysis is only favorable for those patients requiring mechanical ventilation. penicillin and metronidazole are given to eradicate the source of toxin production. aminoglycosides and steroids should not be given as they may worsen the neurosmuscular transmission defect and increase muscular weakness. if the source of the c. botulinum is a wound (i.e., wound botulism) then it will need surgical debridement. indications for admission to picu: • respiratory support • autonomic instability children are increasingly surviving diseases that until recently were considered untreatable. there are more potent, intense chemotherapy regimens being used and increasingly there are more patients who undergo solid organ and stem cell transplants. these treatments and interventions particularly with immunosuppressants, though frequently successful, leave patients at considerable risk for severe infections. neutropenia is defined as the absolute neutrophil count (anc) [anc = pmn + band count] <1,000/mm 3 , and is generally associated with cancer and its treatment. the risk of infection is particularly high with: • rapid drop in anc • anc < 100/mm 3 (profound neutropenia) • prolonged neutropenia fever in neutropenic patients is defined as an oral/ tympanic membrane temperature >38 c in two repeated measurements over a 4 h period or one measurement above 38.5 c. the portals of entry of infectious agents are usually: the oral mucosa, the gut, the upper/lower respiratory tract, and central vascular lines. the most common organisms are gram-positive cocci (s. aureus, s. epidermidis, and strep. viridans), gram-negative bacilli (e. coli, k. pneumoniae, p. aeroginosa), and fungi (candida, aspergillus). recently the spectrum of pathogens has begun to change, with the emergence of more gram-negative and fungal infections. this is likely due to an increase in resistant pathogens in the face of the use of very broadspectrum antibiotics, intensity of therapy (high-dose chemotherapy and stem cell transplant) and prolonged neutropenia. the single most important risk factor for fungal infection is the duration of neutropenia. it is standard of practice to start antibiotics for a child with anc < 500 who is febrile. initial empiric therapy for febrile neutropenia consists of a b-lactam antibiotic and an aminoglycoside, plus a glycopeptide if a coagulase negative staph or enterococcus is suspected or isolated, if the child is in shock, has an endoprosthesis or a vascular tunnel infection. if patient has a history of arabinoside-c administration and has severe mucositis strep viridans infection is highly suspected and vancomycin should be added. if perianal infections in the picu tenderness is present add anaerobic coverage (metronidazole or clindamycin). after 4-5 days of fever and neutropenia adding an antifungal is the usual practice of most oncologists. infants with a severe combined or t-cell immune deficiency usually present early in the first few months. defects in cell-mediated immunity can result from congenital disorders such as digeorge syndrome, severe combined immunodeficiency disease (scid) and wiskott-aldrich syndrome. they can be secondary to lymphomas, immunosuppressive medications or chronic illness. acute viral infections such as measles and pertussis are also known to decrease a patient's cellmediated immunity. typical infections are pneumocystis jiroveci pneumonia (formerly carinii), cmv pneumonitis, rsv pneumonitis, disseminated enteroviral infection, and invasive fungal infection. patients are highly susceptible to infections with intracellular organisms such as salmonella, listeria, mycobacteria, herpes family viruses (cmv, ebv, and hsv), as well as fungi and protozoa. in older children and those with secondary immunodeficiencies, these infections tend to be reactivated disease. children with chronic mucocutaneous candidiasis and chronic granulomatous disease typically present early in life with recurrent candida and staphylococcal infections. neonates with adhesion molecule deficiency usually present with delayed separation of the umbilical cord stump, increased polymorphonuclear count, and increased incidence of bacterial infections. children with primary humoral immune deficiency usually present between 6 months and 5 years of age. the onset is consistent with the time when the level of placentally transferred maternal antibodies (igg) has declined. these defects as well as complement deficiency and asplenia are more commonly associated with infections by encapsulated microorganism such as h. influenza, n. meningitides, and s. pneumoniae. although patients with these conditions are mainly susceptible to bacterial infections involving the upper and lower respiratory tract, they can have protracted diarrhea with giardia or echovirus. defects in the late complement component (the ''attack'' component, c5-9) are prone to recurrent neisseria infections. children with early complement defects usually have autoimmune and rheumatologic manifestations. fulminant meningococcemia is also associated with properdin deficiency (alternative complement pathway). hsct is now an established treatment for a host of immunologic, metabolic, hematological, and neoplastic disorders. the ''stem cells'' may be obtained from the patient (autologous). alternatively from an hlacompatible related or unrelated donor (allogeneic). there is little risk of acute or chronic graft versus host disease (gvhd) with autologous hsct. currently there are three sources for stem cells: bone marrow, peripheral blood, and umbilical cord blood. generally with the umbilical cord stem cell transplant the speed of engraftment is lower, but so is the risk of gvhd. with peripheral blood stem cell transplant engraftment occurs faster but the risk of gvhd is also higher. with bone marrow stem cell transplant the speed of engraftment and the risk of gvhd is somewhere between the other two sources. with unrelated umbilical cord blood and t-cell depleted bone marrow or blood stem cell transplant, the risk of graft failure is higher. there is a higher risk of infection with occurrence of gvhd, and with graft failure. the conditioning regimens used to prepare the patients generally consists of high-dose chemotherapy with or without regional or total body irradiation. post transplant, there is a period of pancytopenia and though the neutrophil count usually normalizes after 3-4 weeks it is not unusual for these patients to need red cell or platelet transfusions for much longer. the risk of infection is influenced by rapidity of myeloid recovery and the rate of lymphoid reconstitution. the speed of restoration of adequate immune function is highly variable. the stem cell source, hla compatibility, purging or t-cell depletion of the graft prior to transplant, and severity of gvhd are important factors. in the early post-transplant period (first 100 days), transplant centers employ prophylactic measures to reduce the risk of infection. these measures vary between different centers, and include: • prophylactic antibiotics (for pcp, candida, hsv, cmv) • administration of ivig • environmental precautions (isolation and barrier nursing) in the early post-transplant period, patients are most susceptible to infections caused by both gram-negative and gram-positive organisms and by fungi. there is a higher risk of cmv pneumonitis in patients with gvhd (largely due to the need for immunosuppressive treatments). cmv negative recipients who receive transplant from a cmv positive donor are at highest risk for cmv pneumonitis. children who have undergone hsct and are admitted to picu have a particularly poor prognosis. pneumonia, mechanical ventilation, and the need for renal replacement therapy are especially poor prognostic factors. those with septic shock and line sepsis have the best prognosis. in addition to bacteria, the most commonly isolated organisms are cmv, rsv, adenovirus, candida, aspergillus, and pcp. in a recent report from great ormond street hospital in london, uk, only 56% of these patients survived to discharge. similar to children who have received hsct, children receiving solid organ transplants are prone to infections before and after the transplant. the main differences are: 1. patients after solid organ transplants are usually less immunosuppressed than hsct patients and are not at risk of immune reconstitution syndrome and its associated inflammatory and infectious complications. however they are at risk of surgery-related complications and postsurgical infection issues (wound infection, bacteremia, atelectasis/pneumonia, urinary tract infection). 2. infection of the transplanted organ due to latent or colonizing organisms present in either the donor or recipient can lead to invasive widespread disease in the immune suppressed post-transplant recipient. an example of this is the child with cystic fibrosis colonized with pseudomonas species; those colonized with b. cepacia are particularly at risk of developing resistant infection post lung or combined heart/lung transplants. 3. children receiving solid organ transplants are at risk of reactivation of latent infections, such as cmv. but, unlike hsct patients who most commonly present with cmv pneumonitis in recipients of solid organ transplants the cmv disease depends on the sites where the virus is latent and on the organ that has been transplanted. lung, heart/lung, and liver transplant patients are most vulnerable to systemic disease. cmv infection can precipitate rejection and increase vulnerability to other infections such as fungal infections. 4. ebv-associated post transplant lymphoproliferative disorder (ptld) is a potentially fatal complication of solid organ transplant. the risk of ptld is higher in children who were ebv seronegative prior to the sot. ebvrelated infection in sot patients may present in several different ways: asymptomatic or nonspecific viral syndrome, mononucleosis syndrome, and ptld. the latter can have a spectrum from fever, lymphadenopathy and diarrhea to full blown lymphoma. tissue biopsy is necessary to establish the diagnosis of ptld. the mainstay of therapy consists of decreasing immunosuppression. chemotherapy and biological treatments (such as anti-cd20 monoclonal antibodies) have been used. the most common reason children with hiv/aids are admitted to the picu is respiratory distress. septic shock and cns involvement (encephalopathy, encephalitis, and meningitis) are other common conditions leading to admission. in addition to the bacteria, viruses and mycoplasma that cause infections of the lower respiratory system in the non-hiv patient, there are a number of other opportunistic infections and inflammatory conditions to consider in the hiv-infected patient. these are commonly: • pneumocystis jiroveci • cmv pneumonitis • tuberculosis • fungal infections • lymphoid interstitial pneumonitis (lip) • immune reconstitution inflammatory syndrome (iris) most infants with respiratory failure will not have a previous diagnosis of hiv infection when they present. in non-endemic areas, especially during the colder season, such infants would be diagnosed and treated initially as cases of bronchiolitis. the possibility of an underlying immune deficiency and or aids should be considered in any infant who responds poorly to treatment or who has risk factors. these include failure to thrive, history of recurrent chest infections, hepatosplenomegaly, adenopathty, severe persistent oral thrush, or abnormal neurological signs. in sub saharan africa, tb and other bacterial pneumonias were common in both hiv-infected and uninfected children who presented with respiratory failure. however pneumocystis and cmv pneumonitis occurred almost exclusively in infants who were hiv-infected. the majority of cases of p. jiroveci pneumonia present in the first 6 months of life. usually these children are quite hypoxemic. high fever is uncommon compared with bacterial pneumonia. there is a diffuse, bilateral air space or interstitial involvement on the chest x-ray. occasionally there is a ''ground glass'' appearance. in an hiv positive patient with bilateral diffuse parenchymal or interstitial infiltrates on cxr, the development of pneumothorax is suggestive of p. jiroveci infection. diagnosis is by bronchoalveolar lavage (bal). even if a child develops pneumocystis while on prophylactic therapy, high-dose intravenous trimethoprim/sulfamethoxazole should be started. prophylaxis may have failed because of poor compliance. if one suspects drug resistance then other agents should be used (pentamidine, dapsone). methylprednisolone at 2-4 mg/kg/day divided in four doses should be administered in moderate to severe cases (practically all children with pneumocystis who are admitted to picu) for 5 days and then tapered. untreated, it is universally fatal. with proper therapy the mortality is less than 10%. the risk factors for mortality are the severity of respiratory failure and the severity of immunosuppression. lip in children with aids is associated with increased risk of lower respiratory tract infections including bronchiectatsis. this condition can produce severe ventilation/perfusion mismatch and hypoxemia but may also be asymptomatic. the cxr shows diffuse infiltrates and hilar lymphadenopathy persisting for >2 months despite antibiotic therapy. usually cxr changes are worse than clinical symptoms. lip can be related to ebv infection or to an exaggerated immunological response to inhaled or circulating antigens or both. steroids have been used in the treatment of symptomatic lip. coexistence of hiv and tb accelerates the course of both of these infections. the risk of miliary and extra pulmonary tb is higher in children with aids and the course is more likely to be severe and rapid. a child with hiv infection is five to ten times more at risk of active tb. in countries with high prevalence of tuberculosis, the who suggests bcg vaccination of all neonates at birth but not in any child/infant with clinical aids. for treatment of tb, please refer to the chapter in this book. mac can produce a systemic illness in children infected with hiv that is characterized by fever, chronic diarrhea, abdominal pain, malabsorption, lymphadenopathy, and obstructive jaundice. mac usually would not present with significant lung disease in these children. iris occurring weeks after the initiation of specific anti-hiv treatment may on occasion be severe enough to cause respiratory failure warranting admission to the icu, though it can also indicate latent or incipient mycobacterial disease. this (iris) is a diagnosis of exclusion and requires a bal and possibly a transbronchial biopsy. management is usually with corticosteroids. other than sepsis and respiratory failure, the other conditions that may bring the child with aids to the intensive care unit are (to name the more common ones): • cns infections (bacterial, mycobacterium, fungi, cryptococcus, viruses, and rarely cns toxoplasmosis), acute hiv encephalopathy • hiv-related cardiomyopathy • severe diarrhea and shock due to cryptosporidium or other microorganisms • liver failure due to infections or drugs • complications of antiviral medications such as acute pancreatitis, acute liver failure, stevens-johnson syndrome an important aspect of care for these children in the picu for the staff is risk of exposure to body fluids and of needle stick injury. universal exposure precautions should be strictly adhered to. it is imperative that all staff be aware of the guidelines and procedures after exposure to biological fluids in their institutions and seek advice from the occupational health department immediately if exposed. as increasing numbers of immunocompromised children with fungal and viral infections are admitted to the pediatric intensive care units, common antifungal and antiviral medications that are used against these infections are briefly reviewed. for a complete review of these topics, the reader is referred to chapters on individual fungal and viral infections in this book. increasingly systemic fungal infections have become more significant in morbidity and mortality of immunocompromised patients in intensive care units. factors that have been associated with this increase are: • use of more potent and broad-spectrum antibacterial agents • prolonged and severe neutropenia • prolonged and severe immune dysfunction (primary or secondary) • having central venous lines and invasive devices • total parenteral nutrition (tpn) the most common fungal pathogens causing systemic illness in critically ill children are candida and aspergillus species. in recent years there has been an increasing importance of uncommon fungal pathogens such as non-albicans candida species, fusarium species, trichosporon species, and dematiaceous fungi. in an immunocompromised patient with a positive fungal culture from a central venous line, current guidelines strongly advocate removal of the line. traditionally with invasive candidiasis, amphotericin b (amb) has been the first-line drug to use. however, intravenous flucanozole and itraconazole could be considered. in non-neutropenic patients positive for c. albicans (but not other candida species) fluconazole is as effective as amb. in empirical treatment of prolonged febrile neutropenic patients (>4-5 days) amb should be started. clinical trials have shown that liposomal preparations of amphotericin b (l-amb) have similar, but not better, efficacy compared with conventional amb preparations. some authors recommend a liposomal preparation of amphotericin as a preferred first-line treatment. unfortunately, high cost can be prohibitive in many parts of the world. in general, the l-amb agents cause less fever, rigors, nausea, and vomiting. they are also less nephrotoxic. voriconazole, a second generation triazole, can be used for empirical treatment of febrile neutropenic patients in place of l-amb. in patients with invasive aspergillosis it has been shown that initial therapy with voriconazole leads to a better response and improved survival with fewer side effects. echinocandins such as caspofungin have been used in combination with amb or voriconazole in more resistant cases of invasive aspergillosis with persisting fevers. micafungin and anidulafungin are two other agents in this family. antifiungals (old and new) have a large potential for side effects and drug-drug interactions. clinicians need to be aware of the specific profiles of the drugs they use from this antimicrobial family. below are the common agents likely to be used in the intensive care unit. hiv drugs have not been discussed. please refer to the chapter on hiv for more detailed discussion of these agents. there are two main groups of antiviral agents: various types of nosocomial infections in pediatric intensive care units, blood stream infections had the highest incidence, followed by lower respiratory infections and urinary tract infections. a basic mandate of medicine is ''primum non nocere'' -first do no harm. while it is inevitable that some patients may acquire nosocomial infections, these infections cause significant morbitiy and mortality. the overall mortality attributable to the various nosocomial infections within the picu has been estimated to be between 10% and 15% and infections acquired in the picu are associated with an increased risk of death, with a relative risk of 3.4. it is widely appreciated that these infections can be minimized by a number of simple interventions, most important of which is hand washing; ''clean hands save lives.'' in a review of the related literature between 1990 and 2002, it was shown that between 11% and 48% of nosocomial infections could have been prevented. blood stream infections are common. not surprisingly they are most common in those patients who are the most debilitated, receiving mechanical ventilation and have central venous lines in situ for longest time, urinary catheters and other artificial surfaces. the spectrum of infections also has a predictable frequency. gram +ve infections are the most common bacteremias (whether or not associated with a central line) followed by gram àve and then fungi. typically fungi are found in those patients on tpn or long term, broad-spectrum antibiotics and immuosuppressed. central venous lines (cvl) are used to provide secure intravenous access for administration of medications such as vasopressors and inotropes, to monitor pressures, blood oxygen saturations, and for intravenous nutrition. in a survey of picu's in the united states the rate of cvl infection was 7.6 per 1,000 catheter-days. in neonates the corresponding figure was 11.3 per 1,000 catheter-days. in europe the cvl infections occurred at a rate of 10.9 infections per 1,000 catheter-days. measures taken at time of insertion of the cvl significantly reduce the incidence of infection. strict aseptic technique (gowns/gloves/mask and wide sterile field), use of chlorhexidine (as opposed to povodine/iodine), and minimal trauma (use of ultrasound and experienced operators) are all very important factors at the time of insertion. chlorhexidine disks topically placed upon the skin at the insertion site and antibiotic impregnated lines are used by some units but not proven to be of value. cuffed and tunneled lines such as hickman lines, port-a-cath lines and picc (peripherally inserted central catheter) have a significantly lower rate of infections than standard central lines that are inserted in the intensive care. where long term therapy >1 week is required consideration should be undertaken to the insertion of one of these types of lines. site of insertion is important. the femoral vein is easy to cannulate with fewest insertion complications. however, it is more likely to become infected and thrombosed. it is good as a temporary line but early consideration should be given to removing and/or repositioning access. to prevent central line infection minimization of the ''opening'' of the line on a daily basis is important. asepsis on line ports prior to use (with alcohol or chlorhexidene) is critically important. ultimately to reduce infection rates lines should be kept for the briefest time possible. difficulty of insertion and type of ongoing therapy come into this cost-benefit analysis. when there is a suspicion that a central venous line has become infected then blood cultures should be drawn from the line and from a peripheral puncture. broad-spectrum antibiotics that cover the bacteria above (vancomycin and gentamicin for example) should be commenced. the line should be removed if at all possible. an attempt to sterilize the line may be made in the circumstances where the line is ''precious'' and not easily replaced. this can involve alternate infusion of antibiotics through all lumens and the use of antibiotic ''locks.'' this is defined as a respiratory infection that occurs 48 h post admission for mechanical ventilation. the respiratory infection is defined by: fever/hypothermia, crackles on physical exam, new respiratory infiltrates on cxr, deteriorating ventilatory status (tachypnea), cough, deteriorating gas exchange, elevated or depressed white cell counts. this may or may not be in the presence of bacterial isolates from a sterile respiratory sample (i.e., bal). there are age specific criteria for the diagnosis of vap. the cdc has produced a document that lists the specific criteria. this can be found at: http://www.cdc.gov/ncidod/hip/nnis/members/pneumonia/final/pneumocriteriav1.pdf. the incidence of vap in the picu is 6-11.6 per 1,000 ventilator-days. the diagnosis of vap is challenging and controversial. there are a number of simple interventions to reduce the incidence of vap. they are: 1. elevate head of the bed to 30 2. ventilator tubing: (a) dependant positioning of ventilator tubing to avoid aspiration (b) removal of excess condensate (c) limit frequency of tubing change unless required 3. suctioning: (a) limiting amount of saline lavage when suctioning (b) sterile technique (gloves and sterile catheter) + (gowns/masks and eye wear for protection of staff) 4. mouth care: frequent mouth cares with chlorhexidene-based wash 5. feeding: (a) early institution of feeding (b) avoidance of gastric over distension (c) limiting use of antacid therapy to high risk patients (i.e., burns, head injury) 6. avoid/limit antibiotic therapy to minimize chance of colonization with antibiotic resistant flora urinary tract infection is directly proportional to the length of time that a foley catheter is in place. frequently, patients are on antibiotics that will suppress urinary infections. however, virtually all intensive care patients with urinary catheters will acquire urinary sepsis if their stay is prolonged. more than 90% of hospital acquired uti's occur in catheterized children. the best intervention (as with central lines) is early removal of the catheter. when strict measurement of urinary output is not needed and the likelihood of urinary retention (due to illness or drugs) is not an issue then catheters should be removed. intermittent catheterization can be considered as an intervention to avoid a permanent foley catheter where retention is an issue in a longer term patient. if an icu patient develops fever or unexplained sepsis then it is mandatory that a urine specimen be sent for microscopy and culture. this is especially important in the patient with a catheter. if urinary sepsis is proven then consideration for catheter removal should be given. broad-spectrum antibiotics that cover the spectrum of bacteria listed above should be commenced. antibiotics should be specifically weighted to cover the gramnegative bacteria as these are most common. surgical site infections are a less frequent infection but none the less important source of infectious morbidity. if a wound is ''dirty'' or contaminated such as a traumatic soiled wound or contaminated peritoneum from perforated appendicitis then broad-spectrum antibiotics should be commenced in high dose. at the same time, appropriate surgical management should be undertaken to deal with the contaminated wound. the surgical team will usually offer guidance on this issue. if a wound is ''clean,'' for example a surgical incision, the surgical team will generally have a preference for antibiotic prophylaxis. commonly a second generation cephalosporin will be used. this should be given at time of the operation and for a defined and limited time thereafter. prolonged prophylaxis has been shown not to prevent inevitable wound infections and promotes emergence of multiple antibiotic resistances. for wounds that become infected in the intensive care unit, swabs should be taken of any discharge. surgical review should be initiated and the wound dressed (with frequent changes). appropriate antibiotics should commence. opening of the wound and drainage/debridement of infected tissue is the responsibility of the managing surgical team. all intensive care units should have the ability to isolate for airborne and body fluid infectious organisms. simple hand washing is very important (before and after examining patients or attending the bed side). where this is not infections in the picu practical an alcohol-based hand gel can be used. from simple hand washing a graduated appropriate degree of isolation and infection control processes should be undertaken, i.e., gowns, gloves, respiratory protection -masks with increasing filtering ability to full respirators. negative pressure rooms (with antechambers) are usually reserved for respiratory isolation for the protection of staff and other patients. positive pressure rooms are for protective isolation of the patient who is immunocompromised. negative pressure isolation and strict barrier isolation is reserved for highly infectious pathogens. sars and ebola virus are examples where this may be necessary. all intensive care staff should strictly adhere to hand washing practices (with a chlorhexidine based product). unfortunately this is not the case and medical staff are often the worst offenders in this regard. active and repeated awareness campaigns should be carried out to reinforce this basic but very important healthcare related activity. severe infectious processes are common reasons for admission to the pediatric intensive care unit. children in the picu are at risk for developing severe infections. increasingly children with a dysfunctional immune system survive their primary illnesses and are admitted to the picu with severe infections. secondary immune deficiency is common in the course of prolonged critical illness. rapid sampling of body fluids and commencement of broad-spectrum antibiotic cover is of the utmost importance. it is shown that even 5 min of delay in starting appropriate antibiotics has been associated with increased mortality. if there are reasons to believe there is an anatomical source of infection (collection of pus, infected central venous line, infected prosthesis etc.) often the antibiotics would not achieve their effects until the source of infection is dealt with effectively (surgical evacuation/ removal, drainage). optimizing the hemodynamic status of the patient (oxygen delivery, addressing preload, after load, and contractility) should start from the moment one considers the diagnosis of sepsis or severe life threatening infection. diagnostic and therapeutic interventions all go hand in hand and start in parallel from the initial encounter with the patient. it is vital that every unit has an updated knowledge of the prevalence and sensitivity of the micro organisms prevalent in their community and in the hospital. colleagues in clinical microbiology or infectious disease departments are invaluable members of any picu team in dealing with these issues. prophylactic measures such as effective hand washing, observing strict sterility while placing central venous lines, measures to reduce incidence of the vap, discontinuing the invasive lines and catheters when not indicated anymore, and adherence to universal exposure precautions should be implemented and monitored and audited regularly. they save more lives and money than much more expensive interventions. effective antibiotic stewardship, tailoring the antibiotic coverage when sensitivities of the causative organisms are known, and discontinuing broad-spectrum antibiotics as soon as clinically prudent will decrease the burden of antimicrobial resistance in the intensive care unit. supportive care of children with cancer: current therapy and guidelines from the children's oncology group incidence of pediatric and neonatal intensive care unit-acquired infections. national nosocomial infections surveillance system; pediatric prevention network viral sepsis in the pediatric intensive care unit bts guidelines for management of pleural infection in children infection control and the prevention of nosocomial infections in the intensive care unit ventilator-associated pneumonia in the pediatric intensive care unit: characterizing the problem and implementing a sustainable solution necrotizing fasciitis in children: diagnostic and therapeutic aspects clinical practice parameters for hemodynamic support of pediatric and neonatal septic shock: 2007 update from the american college of critical care medicine goal-directed management of pediatric shock in the emergency department cdc guidelines on the diagnosis of ventilator associated pneumonia toxic shock syndrome in children epidemiology, pathogenesis, and management manson's tropical disease british thoracic society guidelines for the management of pleural infection prognostic factors in pediatric cancer patients admitted to the pediatric intensive care unit epidemiology and outcome of necrotizing fasciitis in children: an active surveillance study of the canadian paediatric surveillance program acute bronchiolitis and croup ventilator-associated pneumonia in neonatal and pediatric intensive care unit patients risk factors for healthcare-associated infection in a pediatric intensive care unit a national point-prevalence survey of pediatric intensive care unit-acquired infections in the united states; pediatric prevention network concept of operations for triage of mechanical ventilation in an epidemic outcome of children requiring admission to an intensive care unit after bone marrow transplantation infections of the airway the global neonatal and pediatric sepsis initiative infections in the intensive care unit urgences et soins intinsifs paediatriques severe malaria: lessons learned from the management of critical illness in children sepsis and septic shock: a global overview pediatric critical care surge capacity critical care outcomes in the hematologic transplant recipient clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the infectious diseases society of america management of severe dengue in children infectious diseases in the pediatric intensive care unit rogers' textbook of pediatric intensive care red book: 2009 report of the committee on infectious diseases nosocomial infections in pediatric patients: a european, multicenter prospective study; european study group hand washing in the intensive care unit: a big measure with modest effects evidence behind the who guidelines: hospital care for children: what treatments are effective for the management of shock in severe dengue? epiglottitis and croup a prospective study of ventilator-associated pneumonia in children predictors of mortality in patients undergoing autologous hematopoietic cell transplantation admitted to the intensive care unit london world health organisation (2005) pocket book of hospital care for children: guidelines for the management of common illness with limited resources. who, geneva zar hj, apolles p, argent a et al (2001) the etiology and outcome of pneumonia in human immunodeficiency virus-infected children admitted to intensive care in a developing country infections in the picu key: cord-255915-7hkn37p2 authors: garstang, j.; debelle, g.; anand, i.; armstrong, j.; botcher, e.; chaplin, h.; hallett, n.; morgans, c.; price, m.; tan, e. e. h.; tudor, e.; taylor, j. title: effect of covid-19 lockdown on child protection medical assessments: a retrospective observational study in birmingham, uk. date: 2020-08-14 journal: nan doi: 10.1101/2020.08.09.20170977 sha: doc_id: 255915 cord_uid: 7hkn37p2 objectives to determine any change in referral patterns and outcomes in children (0-18) referred for child protection medical examination (cpme) during the covid-19 pandemic compared to previous years. design retrospective observational study, analysing routinely collected clinical data from cpme reports in a rapid response to the pandemic lockdown. setting birmingham community healthcare nhs trust, which provides all routine cpme for birmingham, england, population 1.1 million including 288,000 children. participants children aged under 18 years attending cpme during an 18 week period from late february to late june during the years 2018, 2019, and 2020. main outcome measures numbers of referrals, source of disclosure and outcomes from cpme results there were 78 cpme referrals in 2018, 75 in 2019 and 47 in 2020, this was a 39.7% (95%ci 12.4-59.0) reduction in referrals from 2018 to 2020, and a 37.3% (95%ci 8.6-57.4) reduction from 2019 to 2020. there were fewer cpme referrals initiated by school staff in 2020, 12(26%) compared to 36 (47%) and 38 (52%) in 2018 and 2019 respectively. in all years 75.9% of children were known to social care prior to cpme, and 94% of cpme concluded that there were significant safeguarding concerns. conclusions school closure due to covid-19 may have harmed children as child abuse has remained hidden. there needs to be either mandatory attendance at schools in future or viable alternatives found. there may be a significant increase in safeguarding referrals when schools fully re-open as children disclose the abuse they have experienced at home. nearly 400,000 children in england each year are defined as 'children in need'; these are children who require additional services, including safeguarding, to maintain a satisfactory level of health or development(1). since the lockdown began, there are burgeoning concerns that child protection referrals have decreased, with professionals reporting limited opportunities to make accurate assessments of children's needs(2). statutory guidance sets out the specific roles and responsibilities of agencies for undertaking child protection enquiries when a child or young person is referred for suspected maltreatment(3), including formal child protection medical examinations (cpme). the purpose of cpme is to provide a holistic assessment of the child's health, document any injuries and determine possible causes including the reasonable likelihood of injuries being inflicted or noninflicted. a report is provided to inform any child protection investigations. cpmes are performed or supervised by an experienced consultant paediatrician (4) , adhering to rigorous standards in respect of consent; conduct of the examination; documentation of history; findings and formulation; photodocumentation; and report writing (5) , with reports subject to regular peer review (6) . birmingham is the second largest city in the uk, with a diverse population and is the largest local authority in europe. it is also a relatively young city, with 23% of its population being children under the age of 16 years (7) . the proportion of children subject to a child protection plan is higher than for the uk as a whole (8) and thirty-five percent of children live in poverty (8) . in birmingham cpmes are generally undertaken within a community setting during working hours, often for children who have disclosed maltreatment to school or nursery staff, who then refer them to birmingham children's trust (social care). children with suspected sexual abuse are assessed separately, within specialised, regional child sexual assault referral centres. hospital-based paediatricians perform cpmes for those children with more significant injuries requiring treatment and for out-of-hours referrals. during the covid-19 lockdown the community based cpme service provided extended hours (6 april to 23 may 2020) that covered evenings and weekends to minimise hospital attendance so an increase in referrals for cpme was expected. schools are at the frontline of child safeguarding; educational staff are often the first to report potential child abuse. this raises concerns that vulnerable children are now invisible to professionals and potentially 'at risk' in homes where families face even greater hardships (8) . such 'collateral damage' (9) has been borne out by evidence that only 10% of children on a child protection plan or 'inneed' were attending schools that were remaining open specifically for their benefit and even where schools are open for selected year groups, attendance remains very low (10) . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint although there has been much professional concern about the potential risk children have faced at home there have been limited data, with one report of an increase in abusive head trauma noted in london (11) and a short report from the north-east of england noting a dramatic decrease in cpme referrals (12) . this current study was designed as a rapid response to fill gaps in knowledge about child protection referrals during the covid-19 pandemic. the aim was to determine differences in the number and outcomes of child protection referrals for cpme in birmingham during the covid-19 pandemic lockdown (march to june 2020) compared with the same periods in 2018 and 2019. our research questions were: what is the difference in child protection referrals during the covid-19 pandemic compared to previous years? are there differences in demographic details, referral source and outcomes for children presenting for child protection medical examination during the covid-19 pandemic compared to previous years? retrospective observational study of referrals for cpme. it adhered to strobe guidance (13) . all children aged 0-18 attending for cpme at birmingham community healthcare trust (bcht), england. bcht provides specialist cpme for the population of birmingham, total population 1.1 million of which 288,000 are children aged <18 (7) . data were collected for all cpme for 18-week periods in 2018, 2019 and 2020, from the last week in february, when schools returned following the half-term holiday, to the end of june. we obtained a list of all children referred for cpme from the booking service and accessed the electronic patient records (epr) for these children, obtaining copies of reports from cpme. we read the reports, and completed an anonymised data extraction form for each cpme (on-line supplementary file 1). the data collection form was in three parts: i) child demographic data, including age, gender, school age group (pre-school, primary, secondary, post-16), in a special school or not, ii) referral details including whether an index case or referred as a sibling group, source of initial disclosure, who the allegation was against, whether the child had previous referral to social care and if so, the current social care status, and whether the child had ever been on a child protection plan, and iii) outcomes of the cpme including whether there were physical findings to . cc-by-nd 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint support non-accidental injury (nai) or neglect, and, if so, what were the physical findings; likelihood of nai; whether nais were present on more than one body part; were their injuries consistent with previous nai; whether the report indicated significant safeguarding concerns; if the concerns were related to factors other than nai; and, if so, what? outcomes were taken either directly from the conclusion of the cpme report, or if the conclusion was unclear, were determined based on the description of injuries and events within the report. if the cpme was not available, we used the epr for demographics, referral source and safeguarding history, omitting data on outcomes of cpme. prior to commencing data extraction, all the clinicians reviewed 10 anonymised cpme reports which were then reviewed and discussed by the whole group. this enabled any differences in interpretation of cpme to be resolved and ensured quality and consistency of data extraction. clinicians worked in pairs, consisting of a specialist consultant in child protection (either named or designated doctors for safeguarding) and a specialist trainee in paediatrics, all of whom have a minimum of four years postgraduate medical training in child health. each case had data extracted independently by the consultant and trainee, to ensure consistency. in the event of disagreement the case was reviewed by another consultant. as this was an observational study, no sample size calculation was undertaken. the time period included the last week in february which was before there was significant concern in schools about covid-19. data collection continued for the month of june to enable any change in referral cpme patterns with the partial reopening of some primary schools. anonymised data were entered into spss. cases were analysed by the year of referral. if children had more than one cpme during the study period, each cpme was considered as a separate case. referral rates between years for the whole 18-week period were compared using incidence rate ratios (irr). irrs for two weekly time-periods comparing 2018/19 with 2020 were also calculated and plotted on a graph with 95% confidence intervals. to compare differences in variables between the years, kruskal-wallis tests were run for continuous variables (age, number of types of injuries) and chi-square tests were run for categorical variables. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint this study involved clinicians analysing routinely collected patient data, from patients within their own clinical service, it therefore does not require hra ethical approval. the study was approved by the research and innovation department in birmingham community healthcare trust. as a rapid observational study using retrospective records we were unable to include children who had been through a cpme or their parents in the study. however we have a children and young people's advisory group whom we intend to involve in the dissemination and guidelines for practitioners. there were 200 cpmes during the study period; 193 had cpme reports available with complete information from 191. there were fewer cpme referrals in 2020 compared to previous years, as shown in figure 1 is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint the two weekly data shows that there was a significant drop in referrals for a 6-week period from weeks 3/4 to weeks 7/8, see figure 2. there was some evidence of an increase in referrals during weeks 9/10 in 2020 after which referral rates were broadly similar, with all confidence intervals crossing 1, apart from weeks 15/16 when there were no referrals in 2020. a summary of referrals, demographics, social care history and outcomes of cpme is shown in table 1. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint school there were significantly fewer referrals made by school or early years staff in 2020 compared to other years, with only two school referrals received after lockdown. there was no increase in referrals or disclosures from other sources. in each year, several referrals were initiated when children disclosed abuse to grandparents and non-resident parents or by relatives who witnessed abuse. there were significantly fewer girls referred in 2020. in total across all years, 67% of children were index cases who disclosed potential abuse, or had concerning injuries noted by others leading to referral; the remaining 33% were siblings of these index cases. across all years 75.9% of children were known to social care at any time prior to cpme, 53% were open cases in receipt of support from social care immediately prior to cpme and 39% were currently or had previously been subject to a child protection plan (where maltreatment has been substantiated). the findings in 51% of all cpme were that there was evidence of non-accidental injury (nai) or neglect, with 55% of these children having injuries, typically bruising, on more than one area of their body implying more significant nai. in 90% of all cpme it was concluded that there were significant safeguarding concerns: even if there was not evidence to substantiate nai, there were significantly fewer children in this category in 2018, but the reasons for this are unclear. there was no other . cc-by-nd 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. this study found a significant drop of 39% (95%ci 14-57%) in cpme referrals during 2020 compared to previous years. this drop coincides with the near total absence of referrals made by schools after school closure in march, with no recovery in school referrals after schools partially re-opened in june. referrals from other sources did not increase in 2020, showing that other agencies did not fully compensate for school closure. the children referred for cpme in 2020 had similar social care histories to other years with the majority being previously known to social care and approximately half being open cases at the time of referral. in all years, the vast majority of cpme reports concluded that there were significant safeguarding concerns relating to physical abuse, domestic violence, emotional abuse or neglect. our trust is the largest provider of community paediatric services in england, managing all requests for outpatient cpme for birmingham residents. the extended hours offered during lockdown meant that we could include children with minor injuries needing cpme who ordinarily would be managed by acute hospital trusts, so our findings may actually be an under-estimation of the decreased referral rate. our findings should be generalisable outside of birmingham, as this is a large multicultural city with above average levels of social deprivation and is the largest local authority in europe. although the drop in cpme referrals has been noted elsewhere in the uk (12), the longer duration of our study enabled us to examine any effects of the partial re-opening of schools. our detailed analysis of referral details and outcomes identified the change in referral patterns this year, which is a novel finding. as our cpme service covers a fixed population, we can be certain that changes in referral patterns are genuine, unlike tertiary paediatric centres whose referrals are determined by clinical need not home address (11) . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint our findings further evidence the hidden harm to children from covid-19. the significant decrease in cpme referrals is likely largely a result of school closure and the partial re-opening of schools has not altered this trend. attending school provides children and young people with access to a trusted adult and a safe space outside of the family home. removing this provision increases the potential risk of abuse going unseen. many schools have made strenuous efforts to maintain contact through remote methods, but these are not always private and it is not known who else may be in the room. although uk government guidance was for vulnerable children, identified as those with an allocated social worker, to continue attending school, less than 10% did so (10) . nearly half of those referred for cpme were not in this category so had no protection. disclosures to school staff by older children also protects younger siblings from abuse. missed sentinel nai such as bruising, may lead to children subsequently presenting with serious injuries (14) (15) . these sentinel nai are typical of community cpme referrals and the drop in referral rate therefore represents a much greater risk of harm. while uk government policy is for mandatory school attendance from september, it is vital that this is encouraged and enforced by schools given that currently less than 40% of eligible primary school pupils are attending (10) . low attendance rates may enable abusing parents to keep their children at home with few questions asked: there must be robust face to face welfare checks for those who do not attend. once back at school, many children may disclose abuse that occurred during closure, and children's services may struggle to meet demand. as months will have passed since the abuse, there may be little physical evidence to support allegations, in turn reducing the weight of corroborative evidence to support child protection measures and risking children feeling they are not believed. child abuse carries long-term risks for cumulative physical and mental health problems (16, 17) , and without intervention a cycle of intergenerational poor parenting and abuse may result (18) . there were 30 fewer cpme referrals than expected during 2020: given that birmingham accounts for 2% of children referred for social care assessment nationally (1) we estimate that there are approximately 1500 (95%ci 538-2192) potentially abused or neglected children in england who remain hidden from services. this number may be considerably greater with the suspected rise in rates of child abuse during lockdown. we face an epidemic of unreported, unrecognised child abuse with long-term implications for society as a whole. getting all children back into school will reduce the risk, but may not undo the harm that has already occurred. should there be a further lockdown, safeguards must be put in place to prevent vulnerable children coming to harm. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . https://doi.org/10.1101/2020.08.09.20170977 doi: medrxiv preprint we need to continue to evaluate cpme referral patterns and outcomes as children return to school, to help understand the hidden harms from covid-19. there should be robust analyses of inpatient nai cases to determine any increase in severe injuries. research should include hearing children's lived experiences so that appropriate safeguards can be put in place should schools have to close in future. longer-term research is needed to ascertain and treat the mental health and behavioural outcomes that may result from abuse during school closures. as 'child safeguarding is everyone's business' (19) learning how to protect children during an event such as covid-19 should be a multiagency process, and perhaps the national safeguarding children's panel should take this forward. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted august 14, 2020. . the impact of the covid-19 pandemic on services from pregnancy through age 5 years for families who are high risk or have complex social needs. nihr policy research unit children and families; 2020. 3. legislation.gov.uk. children act 1989 c safeguarding children and young people: roles and competencies for healthcare staff. intercollegiate document royal college of paediatrics and child health child protection peer review for doctors who safeguard children. royal college of paediatrics and child health population and census [internet] wider collateral damage to children in the uk because of the social distancing measures designed to reduce the impact of covid-19 in adults. bmjpo attendance in education and early years settings during the coronavirus outbreak rise in the incidence of abusive head trauma during the covid-19 pandemic who has been missed? dramatic decrease in numbers of children seen for child protection assessments during the pandemic. archives of disease in childhood observational studies: getting clear about transparency pathways to harm, pathways to prevention: a triennial analysis of serious case reviews complexity and challenge: a triennial analysis of serious case reviews the association between exposure to childhood maltreatment and the subsequent development of functional somatic and visceral pain syndromes the burden of mental ill health associated with childhood maltreatment in the uk, using the health improvement network database: a population-based retrospective cohort study. the lancet psychiatry intergenerational transmission of child abuse and neglect: real or detection bias? science working together to safeguard children a guide to inter-agency working to safeguard and promote the welfare of children key: cord-015893-e0fofgxq authors: ryhal, bruce title: viral disease, air pollutants, nanoparticles, and asthma date: 2011-05-03 journal: bronchial asthma doi: 10.1007/978-1-4419-6836-4_11 sha: doc_id: 15893 cord_uid: e0fofgxq health care providers who treat patients with respiratory disease are often asked by their patients, “what caused my asthma? and what causes my asthma suddenly to become worse?” these questions have always been difficult to answer, and moving directly to a discussion of the management of asthma is a much easier road to take. in recent years, though, enough information has accumulated about the causes of asthma that one can weave a story containing useful advice that may help patients participate in the management of their disease. and there are also recent studies that can provide answers to the questions posed by physicians who have watched in puzzlement as their previously well-controlled asthma patients have spiraled rapidly out of control. this story has been growing increasingly complex, with an ever-expanding cast of players that sometimes creates a tangled web of interactions. viral respiratory tract infections are the most common triggers of significant asthma • exacerbations. "upper respiratory tract infections" (uris) do not just involve the upper respiratory • tract. human rhinovirus (hrv), which causes the common cold, is the virus most likely to • trigger an asthma exacerbation. in contrast to the usual spring and summer temperate zone pollen season, viral infec-• tions begin to peak in the fall. the number, species, and typical course of viral respiratory tract infections that trigger • asthma vary with a person's age. both acute sinusitis and asthma exacerbations are associated with viral respiratory tract • infection and therefore antibiotics are rarely needed in uncomplicated cases. sulfur dioxide, nitrogen dioxide, ozone, and particulate matter in air pollution may • exacerbate asthma, and patients should be cautioned to stay indoors when levels of these irritants are high. indoor air pollution, especially from tobacco smoke, can be reduced with benefit to the • asthma patient. introduction health care providers who treat patients with respiratory disease are often asked by their patients, "what caused my asthma? and what causes my asthma suddenly to become worse?" these questions have always been difficult to answer, and moving directly to a discussion of the management of asthma is a much easier road to take. in recent years, though, enough information has accumulated about the causes of asthma that one can weave a story containing useful advice that may help patients participate in the management of their disease. and there are also recent studies that can provide answers to the questions posed by physicians who have watched in puzzlement as their previously well-controlled asthma patients have spiraled rapidly out of control. this story has been growing increasingly complex, with an ever-expanding cast of players that sometimes creates a tangled web of interactions. this chapter will look at how viral infections, air pollution, and possibly nanoparticles may act as causal agents of asthma. the concept of causal agent, though, has a variety of different interpretations. in general, agents may act on the respiratory tract to initiate asthma or to exacerbate it. initiation (or inception or development) of asthma refers to the start of asthma in a patient who was previously entirely free of this problem. an exacerbation (or trigger or precipitating event) means the significant and often sudden worsening of an established chronic asthmatic condition. avoidance of a proven initiating factor, if possible, could permit the primary prevention of asthma. in contrast, avoidance of triggering events will not halt the disease but only decrease the number of exacerbations in someone who already has chronic illness. in studying and treating asthma, identification of a specific trigger is usually much easier than trying to prove an initiating cause. viruses that affect asthma are acting on a complex and varied phenotype, and therefore the outcome of each infection can be quite varied. a simple linear cause-and-effect relationship between a viral infection and an asthmatic episode usually does not exist. koch's modified postulates for infection-caused disease are: the microorganism must be present in every case of the disease. • the microorganism must be isolated from a diseased organism and grown in pure • culture. the cultured microorganism should cause disease when introduced into a healthy • organism. the microorganism must be recovered from an inoculated, diseased experimental host. • this linear way of looking at viral-induced disease is not comprehensive enough to allow sufficient insight into the relationship between viral illness and asthma. no one viral infection consistently causes asthma in all or even most individuals. systems biology, though, can provide a conceptual framework for better understanding of the virus-asthma interaction. systems biology looks at the web of factors in the initial state of the individual patient and then examines how one or more external or internal influences perturb this state (1). in fig. 1 , the path taken by system a illustrates how one factor, for example a simple rhinovirus infection, may have very little long-term effect on mucosal inflammation in an individual with no atopic stressors and no genetic propensity toward asthma. this individual will return quickly to equilibrium and a low inflammatory state. the path of system b illustrates how multiple stressors, including genetic factors and atopic immune development, may interact with a viral infection to cause a long lasting or perhaps permanent change in the level of mucosal inflammation. some details of risk factors will be outlined and discussed in this chapter, but systems biology or systems medicine cannot yet specify each feature of the set of interactions in a way that leads to firm predictions about asthma. out of the complexity of the systems approach, though, some simple and compact principles do emerge, so that every precondition does not have to be known to predict the outcome of intervention or treatment. some general factors that appear to be important in the asthmatic response to viral infection include: though two-dimensional paper does not allow multidimensional maps, we can walk down a branching path in a narrative fashion to show the interaction of factors important in viral-caused asthma. in most of the twentieth century, the office or hospital diagnosis of viral respiratory infection was most often a good guess, a probability statement. common and more affordable viral molecular diagnostics, especially reverse transcriptase pcr (rt-pcr), and viral culture can now improve the accuracy of the guess when precision is needed. viruses may be detected in symptomatic or in asymptomatic patients. two thirds or more of acute respiratory tract infections (rtis) occurring in the community can be identified as viral. traditionally, these have been divided into upper and lower rti, but the difference between upper and lower infection seems to be more indistinct than previously believed. human rhinovirus (hrv), for example, replicates initially in the upper respiratory tract yet may cause extensive lower respiratory tract illness. the frequently used term viral upper rti (urti) is somewhat of a misnomer. the most commonly occurring respiratory virus is hrv, which accounts for nearly half of cases of viral respiratory illness, followed by influenza virus and coronavirus, with lesser contributions from parainfluenza virus, respiratory syncytial virus (rsv), adenovirus, metapneumovirus, and other miscellaneous viral species (2) (see table 1 ). the three main types of viruses that are known to affect asthma are hrv, rsv, and influenza. the peak periods of viral infection tend to vary from year to year, but generally in north america rhinovirus peaks in the fall and early spring, influenza in the early winter, and rsv in midwinter (fig. 2) . many communities can monitor the progress of these annual epidemics with viral culture and molecular diagnostics, thereby giving physicians a higher probability of knowing in advance what virus a patient may have. a molecular diagnostic panel is commercially available for identifying acute viral respiratory infection, though the cost-effectiveness of this type of testing for routine clinical use is yet to be determined. more details of the immunobiology of the major asthmogenic viral infection, hrv, have been revealed in the past several years (3) . the intercellular adhesion molecule icam-1 found on nasal epithelial cells is the attachment point for the majority of serotypes of hrv(4). hrv is divided into clades or strains hrv-a, hrv-b, and hrv-c. hrv-c has proven extremely difficult to culture. there are over 100 different serotypes (5). viral species influence asthma in the various age groups in different ways. age is a marker for the development and maturation of the immune system, which diversifies greatly over time. as the human body ages, the immune system molds itself to the environment to become a mirror image of specific, usually protein, molecules in the external local surroundings. age also has an important effect on the physics of scaling in the respiratory system. airway resistance is inversely proportional to the fourth power of diameter, which enlarges with age until young adulthood and then slowly declines. small increases in airway diameter therefore lead to huge reductions in airway resistance and give more "breathing room." about 80% of significant, prolonged wheezing episodes in children are triggered by respiratory viruses and hrv is most often involved (3). the common rhinovirus cold accounts in large part for the fall seasonal peak of asthma in school-age children. epidemiologic evidence combined with viral molecular diagnosis has suggested that this peak is a consequence of children returning to the classroom with the subsequent spread of respiratory viruses, mainly rhinoviruses (6) . viral exacerbations of asthma tend to be prolonged and severe. triggers such as a gust of pollen-laden breeze may be ameliorated by moving the young patient indoors, and exercise triggers can be removed by stopping the exercise, but a viral trigger is usually steady and persistent and replicates within the body. a study of children aged 6-8 years with asthma concluded that an asthma exacerbation was of a greater severity if a viral infection was present as opposed to a nonviral illness (7) . airway hyperreactivity and a corresponding cough and wheeze may be noted for well over 4 weeks after a rhinovirus infection in the asthmatic child. atopy confers additional risk on asthmatic children who become ill with respiratory virus infection (10) . school-aged children with atopic asthma, as opposed to those with nonatopic asthma, have been noted in a number of studies to experience more frequent symptomatic colds, more episodes of viral-triggered asthma, and more prolonged airway hyperreactivity after the colds (7) (8) (9) . the tendency to have higher numbers of symptomatic rtis and a longer duration of illness was also noted for allergic children in general, with and without asthma (9) . parents of children with atopy and asthma tend to be frustrated by the prolonged recovery time compared with their nonatopic siblings, and school absences are more problematic. inhaled corticosteroids and leukotriene receptor antagonists (ltras) are well known to control the number of wheezing exacerbations in school-age children with chronic persistent asthma, an effect that appears to encompass those episodes caused by viral illness. a survey of school children in ontario found that children presenting in september to the emergency department for asthma exacerbations, presumably mostly viral triggered, were less likely to have used preventive anti-inflammatory medications than their counterparts who did not have such severe exacerbations (12) . a retrospective study suggested that inhaled fluticasone and salmeterol administered prior to and during the fall could reduce the morbidity of the fall viral season in patients with asthma (13) . a trial of a montelukast added to usual asthma therapy was able to attenuate the fall asthma peak in one study (14) though this effect did not reach statistical significance in a later trial (15) . inhaled corticosteroids might be expected to prevent viral-induced wheezing in children with minimal chronic disease as well. a preventive effect, though, has not been consistently shown in clinical trials. a study conducted in school-aged children without persistent disease but with a history of viral-triggered wheezing demon strated that inhaled beclomethasone diproponate was not superior to placebo in reducing future episodes. the inhaled steroid failed to reduce days with symptoms, or the frequency, severity, or duration of episodes of upper or lower respiratory illness (11) . preventive medication should therefore be targeted especially to those patients with persistent chronic asthma. for acute treatment of a viral-provoked asthma exacerbation, oral systemic corticosteroids continue to be the most effective choice (16) and are part of the current therapy protocols (17). use of high-dose acute corticosteroid inhalers continues to be studied with varying success. whether vaccination can prevent asthma exacerbations is unclear. the expert panel report concluded that influenza vaccine does not reduce the frequency or severity of asthma exacerbations during the influenza season (17). many patients in the community with asthma experience severe complications from an influenza infection, so all reasonable means of prevention should still be taken, including vaccination. the influenza virus appears to be a less potent trigger of asthma than hrv, and influenza peaks are not as well correlated with childhood asthma peaks as in the case of hrv. an oral influenza antiviral (oseltamivir) improved pulmonary function and reduced exacerbation frequency in one randomized, placebo-controlled trial in school-age asthmatic children who had influenza (18) . unfortunately, increasing resistance of the influenza virus to antiviral agents limits their use as a long-term strategy to reduce illness in asthmatic children. the concept of using antivirals to reduce asthma morbidity in children seems theoretically promising. the preschool years can lay the groundwork for the later asthma issues of the type that have been discussed. diagnosing viral-triggered asthma in infants and preschool children, though, must be done with caution. asthma is defined as a chronic disease, and several, or even many, self-limited acute wheezing illnesses do not necessarily add up to a chronic illness. often children in this age group will experience wheezing in association with a variety of viral infections. parents are naturally anxious about treatment and prognosis in these children. preschool children who experience rsv-and hrv-induced wheezing are more likely to develop asthma in later years. the childhood origins of asthma study (coast) showed that viral wheezing illnesses in infancy and early childhood caused by hrv were the most significant predictors of the subsequent development of asthma at age 6 (19) . a bidirectional causation has been proposed with rsv: severe rsv was associated with a short-term increase in bronchial hyperresponsiveness, and, in turn, the presence of asthma was associated with long-term increased susceptibility for severe rsv disease (20) . whether early childhood viral infection initiates a series of events that lead to asthma has been an area of much interest and study. one analysis showed that infants reaching 4 months of age at the winter virus peak had a 29% increased risk of developing later asthma compared with those reaching age 1 year at the winter peak (21) . if viruses do initiate asthma in some patients, then prevention of rsv or hrv or a similar illness in a critical time period might prevent or reduce the frequency of asthma in later years. nonatopic infants who had received palivizumab (a humanized mab against rsv) for prevention of rsv infection showed an 80% reduction in risk of recurrent wheezing from ages 2 to 5 (22) , though no effect was noted in atopic children. the hypothesis that early viral infections lead to asthma is made less convincing by epidemiologic studies showing that frequent exposure to viral rtis throughout early childhood may actually decrease the risk of later asthma. studies in the united states and in the united kingdom have shown that day care attendance and other factors that increase the frequency of viral rtis reduce the risk of later (after 5-6 years) frequent wheezing (23, 24) . one interesting medical editorial on this topic was subtitled with tongue-in-cheek, "please sneeze on my child" (25) . that strategy may not be practical, but clinicians should be able to reassure worried parents that day care exposure does not seem to result in a long-term risk of asthma. while the factors that contribute to the development of asthma are still unclear, there is little doubt that viral infections act as potent triggers of asthma in preschool children. as noted, hrv is the most potent of triggers, though all hrvs do not seem to be alike. pathogenicity of hrv appears to vary among groups a, b, and c. hrv-c was found in a study of hospitalized preschool children to be associated with asthma more often than hrv-a (26), and hrv-c was noted to be the most frequent type found in patients presenting to the emergency department (27) . in contrast, experimental infection with a type of hrv-a resulted in no worse illness in allergic than in nonallergic subjects (28) . knowledge of a circulating virulent hrv strain in the community could put clinicians on the alert for more serious symptoms in their asthmatic patients with colds. there are several competing classification systems for the wheezing preschool child that aim to help with prognosis and treatment ( table 2) . as a conceptual model, one can create two opposing poles. at one pole is the small child who experiences rare mild wheezing with acute viral illness, has no wheezing or cough between episodes, and has no atopy or parental asthma. these children appear to benefit very little or not at all from acute or chronic corticosteroid therapy for viral-triggered wheezing illness (29) . at the other pole are children who wheeze daily or weekly, have an atopic history, have a parental history of asthma, and may be on chronic controller therapy. a viral infection in these children appears to be a trigger that requires a step up in asthma therapy, perhaps to a burst of oral corticosteroids. between these poles of severity are many children whose therapy must be individualized. the criteria from the national asthma education and prevention program help select preschool children who may benefit from acute and/ or chronic corticosteroids. these guidelines use the asthma predictive index (30) to specify which wheezy small children have or likely will have chronic asthma and could benefit from various forms of inhaled and oral corticosteroid therapy. owing to concerns about oral corticosteroids, other forms of treatment for viral wheezing have been examined in preschool children. a study in 1-to 6-year-old children showed a benefit of episodic high-dose inhaled steroids with viral rti and wheezing (31) , though some adverse effects on growth were noted. the effectiveness of a ltra, montelukast, was examined in a study of 2-5 year olds with a history of intermittent asthma. this study showed a reduction of typically viral-induced asthma exacerbations in children given the ltra as a daily controller (32) . both inhaled corticosteroids and ltras are options to control chronic asthmatic wheezing in this age group (17). prolonged or chronic cough after viral rti may be a problem. preschool children, whether asthmatic or not, spend a considerable percentage of the year with viral rti symptoms that are distressing to patient and parent. the years from teen through young adulthood tend to be the healthiest years of an individual's life. an expanded antiviral immunologic repertoire helps in reducing the number of annual viral rtis. while childhood is the time of most frequent viral rtis, young adults who are exposed to their own small children may have a secondary peak near their 30s. acute sinusitis is a common problem in this age group. sinusitis has been known to precede a worsening of asthma, and episodes of acute sinusitis have often been the occasion for a course of antibiotics. the entity of viral rhinosinusitis, though, is far more common than previously believed. a viral rti can produce a week or more of purulent discharge and radiographic abnormalities of the sinus cavities on ct scans (33) . most acute sinusitis is not predominantly initiated by bacteria nor, at least in the first week or so, antibiotic-responsive (34, 35) . the mechanism by which acute viral sinusitis becomes linked with worsening asthma is generally through the association of both diseases with viral infection (fig. 3) . the adult group of patients with asthma diverges into several different phenotypes, likely representing various diseases. asthma is often said to be a syndrome rather than one disease. different phenotypes may have varying responses to viral infection. a cluster analysis divided asthma patients into five different groups. one group, "benign asthma" seemed to have well-controlled symptoms regardless of triggers, viral or otherwise. another group that was female preponderant, "obese nonesosinophilic," had minimal atopy or eosinophilic inflammation yet a high level of symptoms in response to typical triggers (36) . chronic adult diseases of previously unknown cause have occasionally been found, in whole or in part, to have an infectious etiology. these include peptic ulcer disease (helicobacter pylori), polyarteritis nodosa (hepatitis b and c), reactive arthritis (shigella and chlamydia), and lyme arthritis (borrelia burgdorferi). a survey of asthma patients, of mean age 38, suggested that 45% of initial attacks started after an illness suggestive of a respiratory infection (37) . this subset tended to be nonatopic and may represent a distinct phenotype. viral and nonviral initiating infectious agents have been proposed for adult "infectious asthma," including mycoplasma, chlamydia, adenovirus, and adult rsv, but reasonable proof of an infectious mechanism is still pending. regardless of initiating cause, asthma is exacerbated in adults, as in children, by viral respiratory infections. respiratory virus is found at least 50% of the time in adults with asthma exacerbations, but not as frequently as in childhood acute significant wheezing episodes (3). older and elderly adults experience some degree of immune senescence but also have expanded specific antiviral immunity. the types of viral illness that exacerbate asthma are slightly different than in younger years. the peak of ed visits and asthma admissions for adults over 50 tends not to be in the fall but rather from december to january, suggesting a broader range of viral triggers than in the fall rhinovirus peak (38) . the contribution of influenza to excess morbidity in older adults is well known, but less generally appreciated is the contribution of rhinovirus to serious illness. concomitant heart disease, chronic obstruction pulmonary disease, and hypertension can make viralexacerbated asthma a more complicated and serious illness in older adults. a rhinovirus outbreak in a nursing home for elderly patients resulted in two thirds of the affected patients having lower respiratory tract symptoms, nearly one-third requiring corticosteroid or bronchodilator therapy, and three individuals having serious morbidity including one death (39) . a peak of rhinovirus rti may be seen in grandparents who care for small children. consistently effective treatments for viral-caused respiratory disease have been frustratingly slow to arrive in the modern pharmacopoeia. despite these obstacles, however, a proactive approach, including vaccination and respiratory hygiene, can improve the care of the patient at risk for viral illness and bronchospasm and avert complications. since the time of albert einstein, scientists have known to be wary of "spooky action at distance." particles that affect the respiratory tract must first be dispersed into the air and enter and contact the respiratory tissue to have an effect. these particles vary in size from molecules in the angstrom range (1 × 10 −10 m), to so-called nanoparticles (1-100 × 10 −9 m), to large pollen grains (50 × 10 −6 m), on up to the largest dust particles that can remain suspended in air (about 100 × 10 −6 m). air particles are divided into several common ranges for study purposes: • pm10 -particulates of an aerodynamic diameter of less than 10 mm or 10,000 nm • fine particles of diameters below 2.5 mm or 2,500 nm • ultrafine particles or nanoparticles of diameters below 0.1 mm or 100 nm study of the real-world, clinical effects of the individual components of air pollution is challenging since most or all components tend to be released into the air at about the same time. unwanted and/or unhealthy gases and particles make up the components of air pollution. outdoor air quality issues vary to great extent by specific location and depend on weather and climate, the level of vehicle traffic, and the type of fuel used for energy and manufacture. in the united states, the office of air quality planning and standards (oaqps) has established the national ambient air quality standard (naaqs) for each of the several pollutants. carbon monoxide, lead, nitrogen dioxide (no 2 ), ozone, sulfur dioxide (so 2 ), and particulate matter in the air have maximum exposure standards (fig. 4) . studies of the effect of air pollution on health attempt to use statistical analysis to separate the individual contribution of each component of pollution. additionally, provocation/exposure testing can be performed in the laboratory. many of the same questions that can be asked about viral disease can be asked about air pollution -does it initiate asthma and does it trigger asthma? clearly not everyone breathing air pollution gets asthma or wheezing, but exposure does seem to increase the risk. a population study in the netherlands found that children with higher exposure to traffic-related pollutants (no 2 , particulate matter) were more likely to develop asthma (40) . data from the taiwan children health study showed an increased prevalence of bronchitic symptoms among children with long-term exposure to outdoor air pollutants (41) . in addition to irritant properties, air pollution may contain immunologically active particles. nanoparticles, including particles of diesel exhaust, which are suspended in air are especially interesting to immunologists studying the development of asthma. they have been proposed to act as adjuvants and immunomodulators (42) . most diesel particulates have sizes of less than 1 mm and represent a mixture of fine particles and nanoparticles. acute wheezing may be triggered by exposure to high levels of pollutant gases including nitrogen dioxide, sulfur dioxide, and carbon monoxide. burning of fossil fuels is the main source of these pollutants in most locations. nitrogen dioxide and sulfur dioxide gases diffuse rapidly and impact upon the wet respiratory tract to produce highly irritating acids. sulfur dioxide can cause respiratory constriction in asthmatic patients at concentrations of 0.1 ppm when exercising (44) . healthy adults begin experiencing increased airway resistance at 5 ppm, and even nonasthmatic adults will develop bronchospasm at 20 ppm, though these levels would be highly unusual in outdoor air pollution. nitrogen oxides, and especially no 2 , are also irritating to the upper and lower respiratory tracts at low levels, and patients with asthma are more susceptible to these adverse effects. higher concentrations of outdoor no 2 were associated with more asthma symptoms in a study of inner city children (45) . though the mechanism of action is uncertain, exposure to carbon monoxide in city air was found in one european study to worsen lung function in adult patients with asthma (43) . ozone, while of critical importance to global health in the upper atmosphere, is an especially noxious chemical when generated at or near ground level. ozone (o 3 ) is not produced directly by traffic or by hydrocarbon burning. instead, the combination of no 2 and hydrocarbons with air and sunlight form the secondary pollutant ozone. high average ozone and airborne particulate matter were associated with more frequent asthma symptoms and ed visits and hospital stays in a study of asthma sufferers in the san joaquin valley in california (46) . ozone from air pollution has been shown to exacerbate asthma in children and adults, though this effect may be greater in children (47) . a study of over 90,000 emergency department visits in atlanta for pediatric asthma showed a relationship to ozone and primary pollutant concentrations from traffic sources. these pollutants increased ed visits even at relatively low concentrations (48) . the study of particulate matter in the air is quite complex, since the exact composition varies geographically. in general, high levels of particulate matter have long been associated in epidemiological studies with increased levels of respiratory disease. ongoing research is examining the importance of particle size, fine versus more coarse, in asthma and chronic respiratory illness. one study in turkey showed an 18% rise in asthma admissions when air contained high levels of coarse particles (49) . in contrast, a us study did not find increased hospitalizations for respiratory disease during those periods with high coarse particle levels (50) . the evidence for a negative effect on health from suspended fine particles is stronger (51) . genetic and phenotype differences may be important in the sensitivity of the asthma patient to air pollution. the risk of childhood asthma in mexico city was modulated in some children by genes controlling the response to oxidative stress, such as might occur while breathing ozone (52) . advice on how to avoid high concentrations of air pollutants is important for asthma patients. air pollution, like pollens and viruses, follows a seasonal pattern, and knowledge of the local pattern can help the primary physician with diagnosis and treatment. in the united states, a daily air quality index (aqi) is computed and distributed for most large population areas. the aqi, which is determined on the basis of the highest pollutant of the day, may be considered safe for patients with chronic respiratory disease if less than 50 (green zone). on days with poor air quality, asthma sufferers should come inside where pollutant levels are typically much lower. indoor ozone levels vary from 10 to 80% of outdoor concentrations, depending on the size of outdoor air flows into a building (53) . although asthma patients should continue their controller therapy during periods of high air pollution, pretreatment with controller medications may not always be successful. budesonide treatment in one study was not successful in preventing ozone-triggered functional airways impairment in test subjects with mild persistent asthma (54). while outdoor air pollution rightly receives a great deal of media and government attention, indoor air pollution can make living inside hazardous as well. fortunately, indoor air problems are usually amenable to personal control and behavioral advice. air quality issues may occur in both home and work environments. the field of occupational medicine examines workplace concerns and is reviewed in another chapter. home air quality is typically not regulated, though pollution may result from several indoor sources. hydrocarbon fuels are, of course, burned inside as well as outdoors. indoor gas cooking and heating stoves may produce no 2 , high levels of which have been associated with increased asthma symptoms in children (55) . good ventilation is essential if natural gas is to be burned indoors. indoor nitrogen oxides are also produced by wood-burning stoves, especially if not well vented. the most serious and prevalent type of home air pollution is secondhand or environmental tobacco smoke (ets). the risk from this indoor pollutant begins in utero. maternal smoking during pregnancy is associated with increased infant wheezing (56) . this risk of respiratory morbidity continues to increase with postnatal parental smoking (57) . laws regulating indoor tobacco smoking in one european country were followed by improved quality-of-life scores in a group of asthmatic indoor workers (58) and also by a reduction in the overall rate of hospitalizations for childhood asthma (59) . as noted previously, indoor ozone is usually much less than outdoor levels. in recent years, though, indoor ozone generators have been marketed to the public for odor control and purported heath benefits. a us epa review has warned the public about the potential hazards of adding an additional amount of a measured air pollutant to the indoor air. this chapter has examined some of the most significant initiating and exacerbating causes of asthma. viral respiratory infections, and to a lesser extent air pollution, are common triggers of exacerbations and may interact with individuals to affect the development of some forms of asthma. these causal factors do not exist in isolation but rather interact with the personal attributes of each patient, including his or her genetic and environmental background. the role of viruses and pollutants in asthma is important knowledge that has consequences for prevention, treatment, and avoidance of illness. helpful education may be given to patients and appropriate treatments selected, and health care providers can avoid the considerable human effort and resources wasted on interventions that are useless or harmful. viral and pollutant triggers demonstrate that the highly complex inflammatory asthmatic response is called forth on many more occasions than simply by the contact of pollen grains and other allergens with the respiratory tract. since so much of immune inflammation seems to have arisen from the need to combat infection, the interaction between asthmatic inflammation and viral infection is a natural topic for further investigation. some of the most significant advances in medical care have come through the treatment and prevention of viral illnesses, and furthering the understanding of respiratory viruses is a worthy priority for the future study of asthma prevention and treatment. in addition to natural harmful infectious particles, humans in recent decades have added many substances of their own creation, including the molecules and particles that constitute indoor and outdoor air pollution. control of this problem is very important for overall respiratory health. important action and advice is available for each asthma patient. by understanding and anticipating respiratory viral infections and air pollution as important causes of asthma, the health care provider can provide superior care for those who suffer from this chronic disease. thanks to albin leong md and denise ryhal bsn for helpful comments and for reviewing portions of this manuscript. the clinical applications of a systems approach a case-control study of acute respiratory tract infection in general practice patients in the netherlands the role of rhinovirus in asthma exacerbations expresssion of intercellular adhesion molecule-1 (icam-1) in nasal epithelial cells of atopic subjects: a mechanism for increased rhinovirus infection? common cold, uncommon variation understanding the september asthma epidemic weekly monitoring of children with asthma for infections and illness during common cold seasons duration of postviral airway hyperresponsiveness in children with asthma: effect of atopy allergic children have more numerous and severe respiratory infections than non-allergic children role of viral respiratory infections in asthma and asthma exacerbations effect of inhaled corticosteroids on episodes of wheezing associated with viral infection in school age children: randomised double blind placebo controlled trial the september epidemic of asthma exacerbations in children: a search for etiology dispensing of fluticasone propionate/salmeterol combination in the summer and asthma-related outcomes in the fall attenuation of the september epidemic of asthma exacerbations in children: a randomized, controlled trial of montelukast added to usual therapy the back to school asthma study: the effect of montelukast on asthma burden when initiated prophylactically at the start of the school year national asthma education and prevention programs expert panel report 3: guidelines for the diagnosis and management of asthma oral oseltamivir improves pulmonary function and reduces exacerbation frequency for influenza-infected children with asthma wheezing rhinovirus illnesses in early life predict asthma development in high-risk children the causal direction in the association between respiratory syncytial virus hospitalization and asthma evidence of a causal role of winter virus infection during infancy in early childhood asthma the effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic children siblings, day-care attendance, and the risk of asthma and wheezing during childhood day-care attendance, position in sibship, and early childhood wheezing: a population-based birth cohort study day care, siblings, and asthma-please, sneeze on my child a novel group of rhinoviruses is associated with asthma hospitalizations association between human rhinovirus and severity of acute asthma in children effects of allergic inflammation of the nasal mucosa on the severity of rhinovirus 16 cold oral prednisolone for preschool children with acute virus-induced wheezing the asthma predictive index: a very useful tool for predicting asthma in young children preemptive use of high-dose fluticasone for virus induced wheezing in young children montelukast reduces asthma exacerbations in 2-to 5-year-old children with intermittent asthma computed tomographic study of the common cold effect of amoxicillin-clavulanate in clinically diagnosed acute rhinosinusitis antibiotics for acute maxillary sinusitis cluster analysis and clinical asthma phenotypes infectious asthma: a reemerging clinical entity? epidemiology of asthma exacerbations a rhinovirus outbreak among residents of a long-term care facility traffic-related air pollution and the development of asthma and allergies during the first 8 years of life air pollution and prevalence of bronchitic symptoms among children in taiwan the immune effects of naturally occurring and synthetic nanoparticles carbon monoxide pollution is associated with decreased lung function in asthmatic adults medical management guidelines for sulfur dioxide (so 2 ): agency for toxic substances and disease registry acute respiratory health effects of air pollution on children with asthma in us inner cities outdoor air pollution and uncontrolled asthma in the relationship between visits to emergency departments for asthma and ozone exposure in greater short-term associations between ambient air pollutants and pediatric emergency department visits particulate matter (pm(2.5), pm(10-2.5), and pm(10))and children's hospital admissions for asthma and respiratory diseases: a bidirectional casecrossover study coarse particulate matter air pollution and hospital admissions for cardiovascular and respiratory diseases among medicare patients epidemiological evidence of effects of coarse airborne particles on health nicotinamide adenine dinucleotide (phosphate) reduced:quinone oxidoreductase and glutathione s-transferase m1 polymorphisms and childhood asthma indoor ozone: north carolina public health epidemiology budesonide reduces neutrophilic but not functional airway response to ozone in mild asthmatics health effects of indoor nitrogen dioxide and passive smoking on urban asthmatic children international study of wheezing in infants:risk factors in affluent and non-affluent countries during the first year of life interactive effect of family history and environmental factors on respiratory tract-related morbidity in infancy respiratory symptoms, pulmonary function, and markers of inflammation among bar workers before and after a legislative ban on smoking in public places smoke-free legislation and hospitalizations for childhood asthma asthma and wheezing in the first 6 years of life definition, assessment, and treatment of wheezing disorders in preschool children: an evidence-based approach key: cord-254852-qr5gdmbc authors: grief, samuel n.; loza, julie k. title: guidelines for the evaluation and treatment of pneumonia date: 2018-08-14 journal: prim care doi: 10.1016/j.pop.2018.04.001 sha: doc_id: 254852 cord_uid: qr5gdmbc pneumonia is a common cause of respiratory infection, accounting for more than 800,000 hospitalizations in the united states annually. presenting symptoms of pneumonia are typically cough, pleuritic chest pain, fever, fatigue, and loss of appetite. children and the elderly have different presenting features of pneumonia, which include headache, nausea, abdominal pain, and absence of one or more of the prototypical symptoms. knowledge of local bacterial pathogens and their antibiotic susceptibility and resistance profiles is the key for effective pharmacologic selection and treatment of pneumonia. pneumonia is a leading cause of hospitalization among both adults and children in the united states, accounting for more than 800,000 hospitalizations and more than 400,000 emergency department visits in 2014. 1, 2 it is among the most expensive conditions treated in us hospitals with national aggregate costs of $9.5 billion in 2013. 3 a causal pathogen is often not identified. a 2015 prospective, multi-center study by the centers for disease control and prevention identified a responsible pathogen in only 38% of cases of community-acquired pneumonia (cap) in adults requiring hospitalization. 4 cap is an infection of the lung parenchyma that is acquired outside of hospitals or extended-care facilities. 5 viral pathogens were identified in 27% of cases and bacterial pathogens in 14% of cases. 5 in adults of all ages, human rhinovirus and influenza were the most frequently identified viruses. 5 streptococcus pneumoniae is the most common causal bacterium. staphylococcus aureus and enterobacteriaceae were significantly more common among patients requiring intensive care unit (icu) level care. 4 other bacteria identified in cap include mycoplasma pneumoniae, chlamydophila pneumoniae, and haemophilus influenzae. 5 less common bacterial causes include mycobacterium tuberculosis, legionella sp, and pseudomonas aeruginosa. these and other bacteria may be considered more likely in patients with certain risk factors ( table 1) . 6 diagnosis a diagnosis of pneumonia should be considered in patients presenting with acute onset fever or chills and cough. the cough may be described as productive. additional symptoms frequently seen include fatigue, anorexia, and pleuritic chest pain. important components of a history include recent travel, history of underlying lung disease, and smoking history. 4,6 a study by diehr and colleagues 7 found that history of alcoholism or bloody sputum have relative risk of 1, so the presence of these findings is not predictive of pneumonia. physical examination findings frequently appreciated in patients with pneumonia include decreased breath sounds, rales, tactile fremitus, and crackles. 4, 8 tachypnea and hypotension are more worrisome symptoms that may also be seen and require urgent evaluation. 4 it is imperative to maintain a high level of suspicion in immunocompromised or elderly and nursing home patients, because they frequently display fewer overt symptoms of pneumonia when compared with the general population. 8, 9 no individual component of the history or physical examination is useful in diagnosing pneumonia, but the presence of multiple findings is required ( table 2 ). in adults presenting with acute cough, the baseline probability of pneumonia is only 5%. absence of any vital sign abnormality (blood pressure, heart rate, respiratory rate) reduces the predicted probability of pneumonia to 1%. 8 a chest radiograph should be ordered for any patient with abnormal vital signs defined as temperature higher than 100 f, heart rate higher than 100 bpm, or respiratory rate higher than 20 bpm. imaging should also be obtained for physical examination abnormalities of crackles or decreased breath sounds in a patient without asthma. 10 infectious disease society of america 2016 guidelines recommend imaging with a demonstrable infiltrate to confirm the diagnosis of pneumonia and to exclude other causes of cough and fever such as acute bronchitis. 11 although x-ray imaging is a mainstay of diagnosis of pneumonia, the british thoracic society recommends the entire clinical picture should be considered when making a decision to treat. 12 a systematic review found that among patients who are sick enough to be admitted with a clinical diagnosis of cap but have a normal initial chest radiograph, approximately 1 in 10 will develop radiographic evidence of pneumonia within 72 hours. 8 in such cases, it is appropriate to treat the patient empirically for pneumonia and repeat imaging in 24 to 48 hours. 11 community resources and access to imaging may also affect decision to treat without imaging. routine blood and sputum culture testing is costly and often low-yield. 13 however, more extensive diagnostic testing should be considered in patients who are at risk for infection with unusual pathogens, who are not responding to treatment, or when additional testing is likely to change antibiotic management (table 3) . 11, 12 it is reasonable to consider respiratory viral polymerase chain reaction (pcr) to determine viral causes of symptoms, so that inappropriate antibiotic use can be limited. additional testing for m. tuberculosis should be considered in a patient presenting with persistent cough, particularly in the setting of weight loss, malaise, night sweats, or hemoptysis. additional risk factors for tuberculosis (tb) include immigration from an endemic country, residing in a homeless shelter, intravenous drug use, or human immunodeficiency virus (hiv) infection. persons who work with people at high risk for tb infection are also considered high risk. 12, 14 treatment most cases of pneumonia can be managed in the outpatient setting. several severity assessment tools have been developed to help determine appropriate treatment settings. the pneumonia severity index (psi) considers 20 variables to stratify patients into 1 of 5 risk categories (i-v) based on risk of death within 30 days. 15 given the number of parameters required, it is not frequently used in general practice. the curb65 assessment tool was introduced in 2003 by the british thoracic society. 16 similar to the psi, it calculates risk of 30-day mortality, but instead only uses 5 variables (confusion, urea, respiratory rate, blood pressure, and age >65), with one point awarded for each if present, allowing for greater ease of use. 15, 16 the crb65 can be calculated without blood urea and thus is useful in the outpatient setting. a recent systematic review and meta-analysis found no significant difference in test performance when comparing the 3 severity tools. 15 it was noted that the psi negative likelihood ratio suggests it may be superior in identifying low-risk patients, and the curb65 and crb65 may be superior in identifying high-risk patients. 15 a curb65 or crb65 score of 0 or 1 demonstrates low risk of mortality and suggests a patient can be managed in the outpatient setting. a score of 3 or higher should warrant hospital admission. it is always appropriate to consider a patient's social circumstances and treatment wishes when making treatment decisions 12,16 ( fig. 1 ; curb65 score 12 ). when available, treatment of cap should be guided by local resistance patterns. in previously healthy patients who are appropriate for outpatient treatment, recommended first-line treatment is with a macrolide antibiotic such as azithromycin targeting the most common causal pathogen s. pneumoniae. doxycycline is an alternative option. patients with comorbidities such as diabetes; chronic heart, lung, renal, or liver disease; alcoholism; asplenia; impaired immune system; or recent antibiotic use within the last 3 months have an increased risk for drug-resistant s pneumoniae. as such, a respiratory fluoroquinolone or b-lactam plus a macrolide is recommended ( table 4 ). 11 a 2014 cochrane review found no significant differences in efficacy between antibiotic regimens, although there were differences in adverse effects when comparing antibiotics within a single class. 17 patients appropriate for inpatient non-icu treatment should also be treated with a respiratory fluoroquinolone or macrolide with b-lactam. patients should be treated for a minimum of 5 days and should be clinically stable with resolving symptoms before treatment is discontinued. 11, 18 patients with high severity of infection or with extrapulmonary manifestations may benefit from longer duration of therapy, such as 7 to 10 days or until improving. 11, 12 in recent years, there has been emerging data supporting the use of adjunctive corticosteroids in the inpatient treatment of cap. as this is an area of research, multiple recent systematic reviews and meta-analyses have been published, some with conflicting findings. a 2011 cochrane review that included relevant cap studies through the year 2010 showed that corticosteroid use accelerates time to symptom resolution and clinical stability, with infrequent adverse effects. 19 similarly, a 2015 systematic review by siemieniuk and colleagues 20 included studies from 2011 through mid-2015. their analysis of 13 randomized controlled trials found significantly decreased mortality in severe pneumonia, decreased need for mechanical ventilation, decreased occurrence of acute respiratory distress syndrome, decreased time to clinical stability, and shorter duration of hospitalization. 20 hyperglycemia requiring treatment occurred more frequently in patients treated with corticosteroids. 20, 21 the most recent idsa and bts guidelines do not make recommendations regarding the routine use of adjunctive corticosteroid for cap. 11, 12 given the variations in dose and route of administration, an optimal agent and dose is unknown. further research is needed to determine steroid dosing and duration, as well as what patient populations are most likely to benefit from its use. 20, 21 there are a large number of studies assessing the role of the infection biomarker procalcitonin in diagnosis and monitoring of patients with bacterial infections. 22 a cochrane 2017 meta-analysis in the primary care setting concluded that the use of procalcitonin to guide initiation and duration of antibiotic treatment results in lower risks of mortality, lower antibiotic consumption, and lower risk for antibiotic-related side effects. 23 procalcitonin values too low or too high usually exclude bacterial infection, but not always. 24 per practitioner discretion and, depending on patient complexity and other comorbidities, a follow-up appointment after successful management in the primary care setting may be arranged. at this appointment, repeat x-ray imaging to confirm resolution of pneumonia is not indicated if the patient seems clinically well. in patients with persistence of symptoms or who have a high risk of lung cancer (age > 50, >30 pack year smoking history), repeat x-ray imaging or low-dose computerized tomography (ct) scan to screen for lung cancer can be considered. 12 in the united states, the pneumococcal conjugate vaccine (pcv13 or prevnar-13) is recommended for all babies and children younger than 2 years, all adults aged 65 years or older, as well as children and adults aged 2 years through 64 years who are at increased risk for pneumococcal disease due to certain medical conditions. 24 the pneumococcal conjugate vaccine has been shown to have an observed 46% reduction in vaccine-type pneumococcal cap, persisting for at least 4 years after receiving the vaccine. 25, 26 the pneumococcal polysaccharide vaccine (ppsv23 or pneumovax 23) is recommended for all adults aged 65 years or older, all cigarette smokers aged 19 to 64 years, as well as children and adults aged 2 to 64 years with certain medical conditions. 27 a 2013 cochrane review found that the polysaccharide vaccine is effective in preventing invasive pneumococcal disease in healthy adults. vaccine efficacy was, however, poorer in adults with chronic illnesses. 28 pneumonia is considered "nonresolving" if there is an inadequate clinical response despite antibiotic treatment. 11 the incidence of treatment failure is 6% to 15% and is associated with a 5-fold increase in mortality. 29 idsa broadly classifies nonresponse into 2 different groups: (1) progressive pneumonia characterized by clinical deterioration and (2) persistent pneumonia with absence or delay of clinical stability. 11 progressive pneumonia with deterioration is characterized by respiratory failure and/ or septic shock and typically occurs within 72 hours. persistent pneumonia with absent or delayed response is typically considered after a time period of 72 hours, because this is often regarded as the median time required for clinical stability. 11, 29 concern for nonresponse in a patient with pneumonia should initiate a systematic evaluation of possible causes. host factors that may explain poor response should be considered, including high initial severity score, risk factors for infection with unusual organisms, underlying comorbidities, or risk factors for multi-drug-resistant pathogens ( table 5) . 24 in areas with high prevalence of hiv or tb, testing is recommended. 30 results of initial microbiological tests such as blood or sputum cultures should be reviewed, including any sensitivity data. repeat blood cultures should be obtained in the setting of clinical deterioration. additional laboratory testing for s. pneumonia and legionella pneumophila via urine antigen testing may be performed, because they may remain positive for days after initiating antibiotic treatment. additional imaging such as chest ct may be beneficial for assessing interval progression or improvement or identifying pleural effusions, lung abscesses, or pulmonary embolism. if pleural effusions are identified in a patient with treatment failure, thoracentesis should be performed to evaluate for empyema. in select patients, bronchoscopy with protected bronchial sampling or bronchoalveolar lavage (bal) may be beneficial to provide diagnostic information for infectious causes and noninfectious mimics, such as pulmonary eosinophilia, drug-induced pneumonitis, sarcoidosis, or pulmonary fibrosis. 11, 29 primary or metastatic neoplastic lesions obstructing the bronchus may cause accumulation of secretions distal to the obstruction, predisposing to infection. both hodgkin and non-hodgkin lymphoma can present with lung involvement, with typical radiographic findings of hilar or mediastinal adenopathy, but may also have a presenting pattern that suggests infection. 31 elderly patients with pneumonia may not exhibit typical symptoms or physical examination findings seen in younger adults, such as pleuritic chest pain, cough, fever, and leukocytosis. 32 signs and symptoms more frequently seen in older adults include falls, decreased appetite, or functional impairment. 32 a change in mental status should prompt evaluation for an infectious cause. 9, 11 as with any adult, risk factors for atypical or drug-resistant pathogens should guide treatment. elderly patients with history of stroke or known dysphagia are at an increased risk for aspiration pneumonia. residents of nursing homes or long-term care facilities are at an increased risk for methicillinresistant staphylococcus aureus (mrsa) or multidrug-resistant (mdr) pathogens. 32 evaluation of a returned traveler should include the following: appropriate history covering the travel itinerary (location and activities), onset of illness related to travel, vaccines or prophylaxis received, diet, sexual history, and exposure to animals. 30, 33 respiratory tract infections are among the most common health care complaints affecting returned travelers and are diagnosed in up to 24% of returned patients with fever. 30, 34 although upper respiratory tract infections are more common, the severity and possible mortality associated with lower respiratory tract infections such as pneumonia make it a must-not-miss diagnosis in the returned traveler. as in the united states, s pneumoniae, h. influenzae, and s. aureus are the dominant pneumonia isolates in developing countries. it must be considered that bacterial resistance patterns from different countries may differ in these otherwise commonplace bacteria. 34 respiratory symptoms occur in up to half of patients with malaria, and the presentation may seem similar to that of pneumonia. thus, in a patient returning from a malariaendemic area, blood smear testing for malaria should be performed. 35 increased time spent at hotels or on cruise ships in a patient presenting with symptoms of pneumonia should increase suspicion for legionella. 30 travelers returning from east and southeast asia, as well as australia, with a severe pneumonia may have been exposed to burkholderia pseudomallei-the causative agent of melioidosis, which can cause severe necrotizing pneumonia and has 14% to 40% mortality despite appropriate antibiotic therapy. 30 severe pneumonia may also be because of viruses such as influenza, middle eastern respiratory syndrome, or hantavirus. a returned traveler with pneumonia with eosinophilia should raise suspicion for helminth infection. 30, 34 histoplasma capsulatum is a dimorphic fungus that is relatively common in north, central, and south america and given its growth in bird and bat droppings is associated with activities such as cave exploration. coccidioides immitis is endemic in the southwest united states and northern mexico, as well as smaller areas in central america. it is spread through inhalation of spores found in the soil. fungal infection with h. capsulatum and c immitis are often asymptomatic but may also present as a flulike illness with fever, malaise, and dry cough 1 to 3 weeks after exposure. 34, 36 ventilator-associated pneumonia ventilator-associated pneumonia (vap) is a type of pneumonia that occurs in patients who have been intubated or mechanically ventilated by means of a tracheostomy for at least 48 hours. 37, 38 mechanical ventilation modifies the oropharyngeal and tracheal environment, allowing oral and gastric secretions to enter the lower airways. 37 it is this change in lower respiratory tract bacterial flora that precipitates the beginning of pneumonia. vap is common. approximately 30% of patients who receive mechanical ventilation will develop vap. 39 vap should be suspected when signs of pulmonary infection (fever, purulent secretions, leukocytosis) and radiologic evidence (air bronchograms, infiltrates) are present; bacteriologic confirmation usually follows. 40 sensitivity and specificity of the diagnostic criteria discussed earlier are 69% and 75%, respectively. 40 other useful diagnostic criteria have been developed, incorporating additional symptoms and similar signs and laboratory/radiologic criteria. 41 once vap is clinically suspected, early empirical treatment is favored. delaying treatment and/or not appropriately covering for the likely microbial culprit are both associated with higher morbidity and mortality. [42] [43] [44] [45] microbiology microbial organisms associated with vap have been identified ( table 6 ). early versus late-onset vap organisms have also been documented. 46, 47 acinetobacter, citrobacter, pseudomonas, and klebsiella are the most predominant late-onset organisms, warranting more aggressive antibacterial intervention. 47 bacterial confirmation usually requires secretion sampling, either via bronchoscopic or via nonbronchoscopic methods. obtaining pleural fluid, when present, under ultrasound guidance, is recommended. 37 endotracheal aspirates are easily retrieved but have a high false-positive rate in icu patients due to airway colonization. 37 bronchoscopic retrieval of distal airway specimens via bal or protected-specimen brush techniques is the best, but requires a trained bronchoscopist. 37 selection of antibiotics is typically done empirically and based on whether the patient has any risk factors for mdr pathogens ( table 7 ) and whether onset of vap is early (defined as within first 4 days of being in the icu) or late (5 days or later). 37, 38, 48 evaluation and treatment of pneumonia empirical treatment should also be determined as a result of knowledge of local distribution of pathogens and their antimicrobial susceptibility patterns. 49 early-onset vap without mdr risk factors typically should be prescribed one of the following antibiotic options 37 : for late-onset and/or mdr factor patients, appropriate antibiotic options would include one or more of the following 37 : antipseudomonal cephalosporins (eg, cefepime, ceftazidime) antipseudomonal carbapenems (imipenem or meropenem) beta-lactam/beta-lactamase inhibitors (piperacillin-tazobactam) with an antipseudomonal fluoroquinolone (ciprofloxacin) or aminoglycoside plus linezolid or vancomycin (if mrsa risk factors are present) telavancin is indicated for vap for susceptible isolates of s. aureus when other therapies are not suitable. dose and frequency of administration of the antibiotic choices discussed earlier are documented extensively elsewhere. 38 atypical antibiotic choices, such as colistin, polymyxin b, telavancin, inter alia, are rarely indicated but can be used when antimicrobial resistance warrants these agents. 48 typically, consultation with an infectious disease physician or clinical pharmacist with expertise and familiarity when using these drugs is a sine qua non. 48 pediatric pneumonia epidemiology pneumonia is a very common affliction of childhood. pneumonia accounts for 13% of infectious illnesses in infants and toddlers younger than 2 years. 50 worldwide, approximately 150 million new cases of pneumonia occur annually among children younger than 5 years. 50 pneumonia is the leading cause of death in children younger than 5 years in developing countries, accounting for 16% of all deaths of children younger than 5 years and killing 920,136 children in 2015. 51, 52 most childhood pneumonia (cp) can be treated in the outpatient setting. the rate of hospitalization for cp through age 18 years varies per year, but in 2006 it was 201.1 per 100 000. 53 infants younger than 1 year had the highest rate of hospitalization (912.9 per 100 000), whereas children aged 13 to 18 years had the lowest rate (62.8 per 100 000). 53 signs and symptoms of cp are often nonspecific and depend on several factors including age, microbial organism, and underlying health of the patient. clinical acumen is key to successfully diagnosing cp. the universal symptom of cp is cough. other symptoms may include chest pain, headache, arthralgia, nausea, and abdominal pain. 54 most common signs to look for include fever, tachypnea, labored breathing, rhonchi, crackles, and wheezing. 54 other physical signs to identify include grunting, nasal flaring, and chest retractions because these increase the likelihood of cp. 55 diagnostic testing is usually performed, when available, and would include assessment of oxygen saturation by pulse oximetry, chest radiograph, complete blood cell count, respiratory microbial panel by pcr, ultrasound of the chest (when medically indicated), and cultures. disagreement about whether blood cultures are warranted exists in the literature. as per a recent study, blood cultures have not been shown to assist with clinical management in children hospitalized with pneumonia. 56 the infectious diseases society of america, however, recommends blood cultures for all hospitalized children with pneumonia. 57 etiologic microbial organisms differ, depending on age of the child. in infants, toddlers, and preschoolers, viruses predominate ( table 8) . less common bacterial organisms may infect newborns (see table 8 ). in older children, bacteria are the more common culprit ( table 9 ). atypical organisms may be involved when children are immunocompromised or have other underlying comorbidities (see table 9 ). in order to provide optimal care to a child with pneumonia, it is important to determine the severity of the pneumonia and the child's clinical status. most children will not require inpatient admission; criteria exist to help stratify severity of pneumonia and necessity of hospitalization (box 1 and 2) . choosing an antibiotic for cp is initially always an empirical process and based on local and regional microbial susceptibility and resistance patterns, along with the child's age, immunization status, and any underlying, preexisting health conditions. 50, 54, 58, 59 most children can be treated with oral antibiotics in the outpatient setting. first-line and preferred agent is still amoxicillin. 50, 54, 57, 59 alternative agents are cephalosporins and macrolide antibiotics; however, increasing resistance to penicillin derivatives and macrolides should be noted 60 ( children and infants for whom there is concern about careful observation at home or who are unable to comply with therapy or unable to be followed-up children and infants who have respiratory distress and hypoxemia (oxygen saturation <92%) (see table 2 ) children and infants with comorbidities (eg, asthma, cystic fibrosis, congenital heart disease, diabetes mellitus, neuromuscular disease) poor feeding and/or signs of dehydration have been linked to development of childhood tendonitis/tendinopathy, yet recent literature indicates these disabling side effects are rare. 61,62 inpatient treatment guidelines have also been established ( table 11) . isolation of the particular microbial organism is ideal, but not required, in order to determine duration of therapy. uncomplicated pneumonia treatment in the outpatient setting usually should last 5 to 10 days. 54 inpatient admission for pneumonia warrants longer duration of antibiotic therapy, typically 7 to 10 days of combined parenteral and oral therapy or at least 1 week after becoming afebrile. 58 complicated cases of pneumonia will require a minimum of 2 weeks of therapy once lack of fever is confirmed and may be extended for up to 4 weeks. 58 the switch from parenteral to oral therapy may occur after 24 to 48 hours of documented lack of fever but is not always practical in complicated and/ or icu-admitted patients. 63 pneumonia is a common, well-recognized respiratory infection seen in primary care settings. triage of the usual presenting symptoms will generally set into motion a typical course of action, including physical examination and possibly imaging to confirm clinical suspicion. further testing depends on treatment venue (outpatient vs inpatient) and other specific criteria (see table 3 ). empirical antibiotic therapy is the cornerstone of treatment, and knowledge of local and regional microbial susceptibility and resistance will bolster the success rate of outpatient management of pneumonia, regardless of demographic and/or accompanying morbidities. special circumstances and scenarios that may occur, including nonresolving pneumonias, pediatric or geriatric populations, travel-related infections, among others, will necessitate a more careful attention to history, physical examination, and antibiotic selection. trends in hospital inpatient stays in the united states national hospital ambulatory medical care survey: 2014 emergency department summary tables national inpatient hospital costs: the most expensive conditions by payer community-acquired pneumonia requiring hospitalization among u.s. adults the washington manual of outpatient internal medicine. philadelphia: lippincott williams & wilkins community-acquired pneumonia in adults: diagnosis and management prediction of pneumonia in outpatients with acute cough: a statistical approach the rational clinical examination: evidence-based clinical diagnosis common questions about pneumonia in nursing home residents predicting pneumonia in adults with respiratory illness infectious diseases society of america/ american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults bts guidelines for the management 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acute pneumonia: a "bad omen pneumococcal vaccination j what you should know j cdc polysaccharide conjugate vaccine against pneumococcal pneumonia in adults updated recommendations for prevention of invasive pneumococcal disease among adults using the 23-valent pneumococcal polysaccharide vaccine (ppsv23) vaccines for preventing pneumococcal infection in adults what is the best approach to the nonresponding patient with community-acquired pneumonia? pulmonary infections in the returned traveler non-infectious mimics of community-acquired pneumonia the management of community-acquired pneumonia in the elderly cdc yellow book 2018: health information for international travel travel-related respiratory infections general approach to the returned traveler histoplasmosis and other endemic fungal infections ventilator-associated pneumonia overview of nosocomial pneumonias treatment of hospital-acquired and ventilator-associated pneumonia in adults incidence of and risk factors for 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children 60 days through 17years of age factors associated with antimicrobial resistance and mortality in pneumococcal bacteremia parenteral-oral switch in the management of pediatric pneumonia key: cord-023817-39r3a4fd authors: singh, namita; burpee, tyler title: rotavirus and noroand caliciviruses date: 2012 journal: textbook of clinical pediatrics doi: 10.1007/978-3-642-02202-9_120 sha: doc_id: 23817 cord_uid: 39r3a4fd nan rotavirus is the most common cause of severe diarrhea in infants and children of developed and developing countries worldwide. globally, rotavirus gastroenteritis causes the death of more than half a million children younger than 5 years of age. this illness creates a disease burden to virtually all societies around the world. rotaviruses are included in genus rotavirus, part of the reoviridae family. negative contrast electron microscopy reveals the viral particles take on a wheel-like appearance in feces, leading to the prefix ''rota.' ' rotavirus particles are large in size (1,000 å ), nonenveloped, and have three concentric layers of proteins surrounding a viral genome. the genome is comprised of 11 segments of double-stranded rna, a characteristic that allows reassortment during natural infection to yield new strains. these segments encode six structural viral proteins (vps) that form virus particles and six nonstructural proteins (nsps). the nsps are synthesized in infected cells and interact with host proteins to influence pathogenesis and the immune response to infection. the rotavirus outer capsid shell is made of the protein vp7. spike-like projections protrude through the capsid shell and are formed by the glycoprotein vp4. the threelayered capsid renders it stable and resistant to the acidic ph in the stomach and to the digestive enzymes in the small intestine. this eases the fecal-oral transmission and delivery of the virus into the small intestine, where rotavirus causes pathological changes in structure and function. rotaviruses can be classified into groups a-e, according to antigenic groups on the major capsid antigen, vp6. only groups a, b, and c have been shown to infect humans, with group a causing the preponderance of human rotaviral gastrointestinal disease. rotaviruses are further classified into g and p types based on the identification of antigens on the outer capsid proteins vp7 and vp4. most severe infections in young children are caused by serotypes g1-4. in general, the more densely populated countries show the most complex patterns of serotype prevalence. during the last two decades, g1 infections appear to have predominated globally. worldwide, approximately 40% of hospitalizations for diarrhea in children younger than 5 years of age are attributable to rotavirus infection. the virus is identified in the stool in 10-40% of children admitted for acute diarrhea in developing countries and 35-50% in developed countries. over 525,000 children younger than 5 years of age die annually from rotavirus, with more than 85% of these deaths occurring in african and asian nations. in the united states, prior to the vaccine's introduction, rotavirus infection accounted for 400,000 doctor visits, 200,000 emergency room visits, 50,000 hospitalizations, and 20-60 deaths per year, with costs amounting to $1 billion yearly. see > fig. 120 .1: rotavirus disease burden. virtually all children have been infected with rotavirus by the age of 5, with various degrees of severity. it is common to have progressively less severe subsequent rotavirus infections as each causes a boost in mucosal immunity. serious rotavirus infections occur most often in children 4-24 months of age. neonatal infection is often asymptomatic in healthy, full-term infants, presumably due to passive immunity from transplacental and breastmilk antibodies. adults are rarely severely affected, but roughly 20% of adult household contacts of an infected infant may develop symptomatic disease. rotavirus gastroenteritis has a seasonal variation pattern. in the united states and other countries with a temperate climate, infections predominate during the winter months, with annual epidemics occurring between december and june. regional variations also exist within particular climates or countries. for example, the united states rotavirus season starts in the southwest in the fall and ends in the northeast in the spring. in europe, the season begins in the southern region and spreads north over the fall to spring months. rotavirus infections fluctuate less in the tropics, though a recent systematic review of 26 studies from tropical areas concluded that infections were more prominent in the coolest and driest months of the year. rotavirus is primarily transmitted person-to-person via the fecal-oral route. in developing regions, it may also be spread via fecally contaminated water. infected individuals usually shed large quantities of virus, up to 10^10 particles per gram of stool. as few as ten viral particles may cause infection in rotavirus-naïve patients. viral shedding may occur up to 2 days prior to the initiation of symptoms and continues for an average of 4 days, though shedding has been reported for up to 21 days in immunocompetent patients. immunocompromised patients may excrete the virus for even longer periods. the virus may survive at least 4 h on hands, days to weeks on environmental surfaces, and up to weeks in drinking water. transmission is increased in settings such as child day-care centers and family homes, where diaper changing has been identified to be the highest-risk activity. additionally, rotavirus has been found on toys, faucets, hand-washing areas, and even food preparation areas, indicating that fomites may play a role in viral transmission. the high infectivity, presymptomatic shedding, and prolonged environmental life span are all important factors in the transmission of rotavirus. the transmission from animals to humans is rare. there is evidence, however, that animal rotaviruses can infect humans via direct transmission of the virus or by contributing one or more rna segments to reassortants with human strains. the respiratory spread of rotavirus via aerosolized particles has also been suggested. rotavirus has been detected in respiratory secretions in a small number of patients, and cases of pneumonia have been described. rotavirus rna from air samples taken from rooms of hospitalized children with rotavirus gastroenteritis indicate that airborne spread may be a route of transmission of rotavirus, especially in hospital and day-care settings. rotavirus has its most profound effects in the gastrointestinal tract, yet systemic infection has been reported. rna and proteins of rotavirus have frequently been detected in the blood of infected children, as well as the liver, heart, lung, and central nervous system. rotavirus particles are ingested orally. in the small intestine, the vp4 spikes on the capsid surface may be proteolyzed by the enzyme trypsin. this cleavage causes a conformational change in the spike structure, which then exposes other attachment sites on the surface glycoprotein. the virus is then attached to host receptors on enterocytes, and the entry process begins. the outer capsid shell is removed, and double-layered particles are inserted into the cytoplasm. these particles produce capped viral messenger rnas (mrnas) that are then displaced from the transcribing particles into the cell cytoplasm. there, they are then translated into proteins and replicated to new genomic rna. this viral replication process is unique and occurs in viroplasms, electron-dense structures near the cell nucleus, and endoplasmic reticulum. newly assembled particles with newly replicated dsrna bud into the endoplasmic reticulum from the viroplasm and are equipped with outer capsid proteins. fully developed virus particles are released from enterocytes via cell lysis or delivery of particles to the apical plasma membrane of cells. rotavirus primarily invades mature enterocyte villi, sparing the intestinal crypts. with enterocyte destruction, fluid moves into the intestinal lumen, resulting in a net loss of fluid and electrolytes in stool. malabsorption occurs secondary to the loss of absorptive enterocytes, the decreased synthesis of lactase and other digestive enzymes, and the alteration of tight junctions between enterocytes that leads to paracellular leakage. the rotavirus toxin, nsp4, is a nonstructural glycoprotein that may contribute to the pathophysiology by inducing a secretory component to the diarrhea. this viral enterotoxin is reported to increase intracellular calcium and activate cellular chloride channels, in turn increasing the secretion of chloride and consequently water into the lumen. nsp4 has also been found to activate the secretory reflexes of the enteric nervous system (ens), further contributing to diarrhea. microischemia of villi, impaired polar transport of sucrase-isomaltase to the membrane surface, neuronally mediated intestinal hypersecretion, and altered intestinal motility are other possible mechanisms of rotavirus injury. histologically, rotavirus is associated with a wide spectrum of changes, ranging from virtually normal mucosa or mild enterocyte vacuolization and loss to more significant villous blunting and crypt hyperplasia. the degree of inflammation is usually milder than that caused by other intestinal pathogens. there appears to be no direct correlation between histological findings and disease symptoms. after a 2-7 day incubation period, symptoms often start abruptly with vomiting, followed by watery diarrhea. this is a noninflammatory process, with blood and white cells typically absent from the stool. in about one-third of patients, fever of over 38.9 c is reported. other clinical features of acute rotaviral infection include anorexia and lethargy, with abdominal cramping being less common. the diarrhea can range from mild to severe, with resultant dehydration, shock, electrolyte imbalance, and even death. severe, dehydrating rotavirus infection occurs mostly in children age 3-35 months. rotavirus is generally a selflimited virus, with vomiting settling within 24-48 h and diarrhea in 2-7 days. some studies have noted respiratory symptoms and otitis media in up to half of patients with rotavirus infection. intussusception in rotavirus infection may be caused by a disturbance in the motility of the gastrointestinal tract during an acute infection, as opposed to a typical lead point. lipopolysaccharides may slow intestinal motility through the induction of various inflammatory agents, such as prostaglandins, cytokines, and nitric oxide. the center for disease control and prevention (cdc) defines a confirmed case of rotavirus gastroenteritis as diarrhea (3 or more loose stools within 24 h) or vomiting (1 or more episodes in a 24 h period) in a child with a positive stool detection of rotavirus by a standard assay, such as an enzyme immunoassay (eia). confirmation of rotavirus infection is necessary for reliable surveillance and can be clinically useful to avoid inappropriate antimicrobial use. the most widely used method to detect rotavirus antigen in stool is eia. these assays typically detect the rotavirus group antigen present on vp6. many eia kits are commercially available, providing rapid, inexpensive results with 90-100% sensitivity. strains may be further characterized by additional enzyme immunoassay or reverse transcriptase polymerase chain reaction (rt-pcr). research centers use other techniques for detection and surveillance of rotavirus, including electron microscopy, rt-pcr, nucleic acid hybridization, sequence analysis, and culture. these techniques are more labor intensive and provide little additional clinical utility. the non-bloody, watery diarrhea of rotavirus gastroenteritis is clinically indistinguishable from that caused by other enteric viruses, including norovirus and other caliciviruses, enteric adenovirus, and astrovirus. that said, rotavirus associated acute diarrhea may be more severe and more frequently associated with fever and vomiting. the presence of blood or leukocytes in the stool should suggest alternative diagnoses, including bacterial etiologies such as salmonella, shigella, yersinia, campylobacter, and escherichia coli. noninfectious etiologies, including intussusception, must also be considered in the infant with this presentation. protozoal infection, particularly entamoeba histolytica, giardia lamblia, and cryptosporidium parvum, should also be included in the differential diagnosis. as mentioned, rotavirus infection is most frequently selflimited, with cessation of vomiting within 2 days and diarrhea within 7 days. severe, dehydrating infection occurs more often in young children from age 3-35 months. malnutrition is known to increase the severity of infection, with delayed small intestinal recovery and altered inflammatory responses. acute complications include dehydration, sodium imbalance, and possible seizures. reye syndrome, encephalitis, rectal bleeding, and intussusception have all been associated with rotavirus, but evidence showing a causative effect is lacking. rotavirus gastroenteritis is generally a self-limited illness, and treatment is largely supportive. initial management should focus on the identification and correction of any underlying fluid and electrolyte imbalance. the assessment of dehydration and the use of oral rehydration therapy are critical and are reviewed elsewhere in this text (> chap. 187, ''acute gastroenteritis in infants and children''). undernourished children are particularly at risk of severe and/or persistent symptoms, and great care must be taken to encourage early resumption of normal feeding, typically including breastfeeding. there is no role for antibiotics in the treatment of rotavirus gastroenteritis. the use of antiemetics and antidiarrheals is generally avoided. please see > chap. 187, ''acute gastroenteritis in infants and children'' for further details. the oral administration of a probiotic, lactobacillus gg, is effective in both reducing viral shedding and shortening symptom duration by roughly 1 day. this improvement is most notable when the probiotic is given early in the course of the illness and seems most prominent in young children. the mechanism may be due to an enhancement of the immune response against the virus. orally administered human immune globulin, as an investigational therapy in immunocompromised patients, was found to shorten the course of diarrhea and decrease viral excretion. further investigation is required, and the cost-benefit ratio may not justify usage of this therapy on a wide-scale basis. rotavirus attack rates are similar between developed and developing regions, suggesting that improved sanitation is unlikely to play a significant part in disease prevention. the high infectivity of the virus makes control measures difficult. rotaviruses are relatively resistant to chemical disinfectants used widely in hospitals. effective agents include chlorhexidine gluconate and quaternary ammonium compounds with high alcohol content (70%). hand washing with plain soap is often ineffective against rotavirus and may even spread the virus over a larger area of the hands. the use of a waterless, alcohol-based handcleaning agent before and after patient contact is recommended. breastfeeding plays a protective role against acquiring rotavirus. this may be due to the presence of anti-rotaviral secretory iga and trypsin inhibitors in breast milk. breast-fed infants also excrete fewer viruses than formula-fed infants. based upon the significant morbidity and mortality of childhood rotaviral infection worldwide, great attention has been focused upon the development of a successful vaccine. since 1983, multiple candidate vaccines have been tried. initially, vaccines based upon the use of animal rotavirus strains that are not pathogenic in humans failed to provide sufficient clinical protection. rotashield (wyeth-lederle vaccines, philadelphia, pa), a tetravalent simian/human reassortant rotavirus vaccine, was licensed by the fda in 1998, based upon data showing an 80-100% protection against dehydrating rotavirus diarrhea. within 9 months of its release, the cdc's vaccine adverse event reporting system (vaers) reported 15 cases of intussusception in infants who had received the vaccine. subsequent case control and retrospective cohort studies verified a temporal association. the relative risk for intussusception within 2 weeks following the first vaccine dose exceeded 20 in both studies, prompting the vaccine's withdrawal from the market. two subsequent oral rotavirus vaccines are now licensed in many nations around the world, including the united states. these vaccines have led to the decline of rotaviral infection and mortality worldwide. rotarix™ (glaxosmithkline biologicals, rixensart, belgium, 2006) is based on a live attenuated human rotavirus strain, g1p. rotateq™ (merck & co., inc., whitehouse station, nj, usa, 2008) is a pentavalent human-bovine reassortant, with a low rate of replication in the human gastrointestinal tract and a low rate of fecal shedding. large phase iii clinical trials have demonstrated that both rotarix™ and rotateq™ are well tolerated. they have also been demonstrated to be immunogenic and highly efficacious, preventing 74-87% of all cases of rotavirus gastroenteritis and greater than 85% of those associated with severe diarrhea. in africa and asia, where more than 85% of rotavirus associated deaths occur, rotateq™ vaccination reduced cases of severe rotavirus diarrhea by greater than 50% during the first year of life when the disease burden and mortality is greatest. the world health organization's strategic advisory group of experts declared that rotavirus vaccines should be included in national immunization programs worldwide, particularly in nations with high diarrheal fatalities. diarrhea-associated deaths in these developing countries could be reduced by 25%. the rotateq™ vaccine is recommended to be given as a three-dose series to infants between the ages of 6-32 weeks. the rotarix™ vaccine is recommended to be administered as a two-dose series at the ages of 2-4 months. details of the vaccine schedules are provided in > table 120 .1. contraindications to the rotavirus vaccine include a previous severe life-threatening allergic reaction to any components of the vaccine and some immunocompromised states. data from the cdc's vaers has shown that the observed rate of intussusception in rotateq™-vaccinated children is not higher than the age-adjusted background rate of intussusception. similarly, studies show no increased risk of kawasaki syndrome with the administration of rotateq™ vaccine. since the introduction of these vaccines in 2006, the incidence of rotavirus diarrhea in infants has dramatically decreased. one study noted that from 1986 to 2006, nearly 20% of hospitalized gastroenteritis patients younger than 5 years of age tested positive for rotavirus in the stool. in the three seasons after vaccine introduction (2007) (2008) (2009) , the percentage dropped to 12.4%, 9.6%, and 6.4%, resulting in a decline of 66% by the study's termination. furthermore, the rotavirus season has been found to be shortened and delayed. see > fig. 120 .2: hospitalizations in children due to laboratory-confirmed rotavirus gastroenteritis. newer approaches, such as non-replicating virus-like particle (vlp) vaccines, are presently being evaluated. meanwhile, the current rotavirus vaccines remain a success in decreasing the morbidity and mortality from this global health disease. norwalk virus carries historical import as the first confirmed viral etiology for human gastroenteritis when it was identified by electron microscopy in stools from a severe outbreak of diarrhea in norwalk, ohio in 1972. subsequently, similar appearing viruses were often called ''norwalk-like viruses.'' recent reclassifications now define the family as caliciviridae, which are 20-40 nm, non-enveloped, single-stranded rna viruses. within this family are four distinct genera. the norovirus genus accounts for roughly 95% of calicivirus-associated gastroenteritis and is discussed here in greater detail. the other three genera (sapovirus, lagovirus, and vesivirus) are less clinically relevant. human norovirus strains are classified into several distinct genogroups and subgroups. genogroup ii has been identified as the most common strain infecting humans worldwide. a new pandemic strain emerges every 2 -4 years. noroviruses are the most common cause of nonbacterial gastroenteritis outbreaks worldwide. infections may occur year round, though more cases are reported during winter months. both children and adults can be affected. the center for disease control (cdc) estimates that noroviruses cause 21 million cases of gastrointestinal illness annually in the united states, accounting for half of all foodborne disease outbreaks. norovirus infection leads to an estimated 70,000 hospitalizations and 500 deaths annually in the united states. there, only rotavirus leads to more hospitalizations for gastroenteritis in children. in developing countries, norovirus is also a common etiology for diarrhea. in india and peru, 15% and 31%, respectively, of stool samples in hospitalized pediatric gastroenteritis patients tested positive for norovirus via pcr ( > table 120 .2). . not to be given after 8 months of age rotavirus and noro-and caliciviruses norovirus outbreaks frequently occur in closed environments, such as cruise ships, camps, nursing homes, or schools. typically, the outbreaks originate from direct contamination by an infected food handler. food contaminated at its source, such as oysters from contaminated water, has also been described. as the viruses are highly contagious, outbreaks can be explosive, with potentially thousands of people being infected in a short period of time. norovirus is typically transmitted via the fecal-oral route or through the ingestion of contaminated food or water. additionally, vomitus has been shown to contain infectious particles. as few as 10-100 virions are required for infection. once exposed, roughly 30% of individuals may shed the virus prior to the onset of symptoms. viral shedding then peaks 1-3 days after illness develops and may persist for up to 3 weeks. the virus is stable from freezing temperatures up to 60 c. all of these factors contribute to the ease of spread and the potential for large outbreaks. the incubation period ranges from 12 -48 h. disease onset is then quite rapid, with vomiting and non-bloody, watery diarrhea. fever occurs in roughly 40% of cases, and other constitutional symptoms such as headache, myalgias, and chills are common. in one-third of patients, the illness is often mild and short-lived, with 85% of patients experiencing less than 3 days of vomiting and diarrhea. the risk for dehydration requiring hospitalization is greatest in children less than 5 years of age and in adults 65 years and older. in the infected host, the proximal duodenum demonstrates villous broadening and blunting, crypt-cell hyperplasia, cytoplasmic vacuolization, and inflammatory cell infiltration into the lamina propria. histologically, the stomach and colon are spared. intestinal brush border enzymes are diminished during acute infection, with resultant carbohydrate malabsorption. mild steatorrhea is also noted. the prominent nausea and vomiting associated with norovirus gastroenteritis may relate to delayed gastric emptying, which has been documented in symptomatic adults. the preponderance of vomiting and the high attack rate across all age groups are characteristic features of calicivirus gastroenteritis. norovirus outbreaks can be distinguished from those caused by preformed toxins by the slightly longer incubation period (12-48 h vs. 2-6 h for toxins) and the emergence of secondary cases in household contacts. in general, calicivirus infection tends to have a milder, less dehydrating course than rotavirus. that said, the illness is not reliably clinically distinguishable from that caused by other enteric viruses, including rotavirus, enteric coronavirus, enteric adenovirus, and astrovirus. human noroviruses cannot be cultured. reverse transcriptase polymerase chain reaction (rt-pcr) can be used to detect viral rna from stool or emesis samples, in addition to environmental swabs from food or water, in special circumstances. the technique is challenging as human caliciviruses are genetically diverse. consequently, several sets of primers must be used to confirm infection. real-time quantitative rt-pcr assays have increased both the sensitivity and specificity of this diagnostic modality. rt-pcr detection is available in some public health and research laboratories but is not readily commercially available in most areas. enzyme immune assays (eias) for norovirus detection have been approved for commercial use in some countries, though the poor sensitivity of current assays (<50%) limits their use in sporadic cases. in outbreak situations, however, they can be used to rapidly identify norovirus as the causative agent. in many situations, microbiologic confirmation of a suspected norovirus outbreak is not possible. the ''kaplan criteria'' were developed in 1982 to distinguish outbreaks caused by norovirus from those caused by bacterial etiologies. the criteria (vomiting in greater than 50% of affected persons, a mean illness duration of 12-60 h, a mean incubation period of 24-48 h, and no bacterial pathogen identified in stool culture) are highly specific (99%) and moderately sensitive (68%) in this regard. as roughly 30% of norovirus-induced outbreaks will not satisfy all four criteria, it is still important to consider this virus in the appropriate clinical setting. until norovirus diagnostic tests become widely available, the application of these criteria may be the most useful diagnostic aid in identifying food-borne gastroenteritis outbreaks due to norovirus. as noted above, calicivirus gastroenteritis is, in general, fairly mild and self-limited. immunocompromised hosts, infants, and the elderly are at the highest risk for protracted illness and more severe dehydration. reports have arisen suggesting an association of norovirus with necrotizing enterocolitis in newborns, benign seizures in infants, and inflammatory bowel disease exacerbations in pediatric patient. further studies are required to investigate these possible links. there is no specific treatment available. as with other causes of viral gastroenteritis, supportive care and attention to fluid and electrolyte balance is crucial. please see > chap. 187, ''acute gastroenteritis in infants and children'' for additional details. during an outbreak, preventing secondary spread is important in halting further progression. enforcing personal hygiene, using contact precautions, decontaminating environmental surfaces, and using an rotavirus and noro-and caliciviruses alcohol-based hand sanitizer have all been found to decrease the spread of infection. people with diarrhea due to norovirus refrain should refrain from the use of recreational water venues, such as pools and lakes, for at least 2 week following the resolution of symptoms. the development of effective preventative measures is of great interest, given the significant socioeconomic burden of large, prolonged outbreaks. in contrast to rotavirus, humans do not acquire long-term immunity with norovirus infection, making vaccine development challenging. a virus-like particle vaccine is currently being evaluated. acute infectious nonbacterial gastroenteritis: intestinal histopathology. histologic and enzymatic alterations during illness produced by the norwalk agent in man detection by pcr of eight groups of enteric pathogens in 4, 627 faecal samples: re-examination of the english case-control infectious intestinal disease study (1993-1996) diagnosis of noncultivatable gastroenteritis viruses, the human caliciviruses immune response of children who develop persistent diarrhea following rotavirus infection real-time surveillance to assess risk of intussusception and other adverse events after pentavalent, bovine-derived rotavirus vaccine natural history of human rotavirus infection discovery of rotavirus: implications for child health rotavirus antigenaemia and viraemia: a common event? rotavirus: to the gut and beyond! norovirus infection as a cause of diarrhea-associated benign infantile seizures asymptomatic endemic rotavirus infections in the newborn the zoonotic potential of rotavirus reduction in acute gastroenteritis hospitalizations among us children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 us states vpd surveillance manual transmission of rotavirus and other enteric pathogens in the home. pediatric infect disease j (the healthy home summit: the significance of cleanliness and disinfection in the home and its link to infection control) detection of rotavirus rna in hospital air samples by polymerase chain reaction (pcr) * 828 update on rotavirus trends and the importance of surveillance intussusception: 354 cases in 10 years norovirus gastroenteritis rotaviruses: from pathogenesis to vaccination probiotics for children: use in diarrhea oral bacterial therapy reduces the duration of symptoms and of viral excretion in children with mild diarrhea protection against neonatal rotavirus infection by breast milk antibodies and trypsin inhibitors gastrointestinal norovirus infection associated with exacerbation of inflammatory bowel disease intussusception, infection, and immunization: summary of a workshop on rotavirus progress in understanding norovirus epidemiology seasonality of rotavirus disease in the tropics: a systematic review and meta-analysis how do the rotavirus nsp4 and bacterial enterotoxins lead differently to diarrhea? role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea abnormal gastric motor function in viral gastroenteritis human caliciviruses in symptomatic and asymptomatic infections in children in vellore, south india human caliciviruses as a cause of severe gastroenteritis in peruvian children rotavirus gastroenteritis: why to back up the development of new vaccines? pathogenesis of intestinal and systemic rotavirus infection quantitative evaluation of rotaviral antigenemia in children with acute rotaviral diarrhea natural history of human calicivirus infection: a prospective cohort study reducing absenteeism from gastrointestinal and respiratory illness in elementary school students: a randomized, controlled trial of an infection-control intervention estimating the rotavirus hospitalization disease burden and trends, using capture-recapture methods norwalk virus: how infectious is it reevaluation of epidemiological criteria for identifying outbreaks of acute gastroenteritis due to norovirus: united states outbreak of necrotizing enterocolitis caused by norovirus in a neonatal intensive care unit safety and efficacy of a pentavalent human-bovine (wc3) reassortant rotavirus vaccine evaluation of two commercial enzyme immunoassays for the detection of norovirus in faecal samples from hospitalised children with sporadic acute gastroenteritis rotavirus incidence and genotype distribution before and after national rotavirus vaccine introduction in belgium a functional nsp4 enterotoxin peptide secreted from rotavirus-infected cells protein-energy malnutrition delays small-intestinal recovery in neonatal pigs infected with rotavirus key: cord-022467-j2trahab authors: loo, may title: select populations: children date: 2009-05-15 journal: complementary and alternative medicine doi: 10.1016/b978-0-323-02028-2.50015-2 sha: doc_id: 22467 cord_uid: j2trahab nan the majority, usually seeking cam therapy as an adjunctive management for pain and other discomforts related to the oncologic illness or to medications. 207 in the general pediatric population, chiropractic is the most common form of cam treatment used by children. reports indicate that children made up 1% of chiropractic patients in 1977 and 8% in 1985. 303 a survey of the boston metropolitan area revealed that an estimated 420,000 chiropractic visits were made by children in 1998. 237 childhood disorders being treated include pain, respiratory and gastrointestinal tract problems, ear infection, enuresis, and hyperactivity. 303 homeopathy was the second most popular form of cam therapy used by children in spiegelblatt's 1994 report. 386 in 2001, however, the university of pittsburgh found that homeopathy was the most common cam therapy used by children who visited an emergency department (ed). 329 also, in a 2000 survey of homeopathic practitioners in massachusetts, children constituted one third of patient visits. 236 homeopathic remedies are highly diluted substances that induce self-healing. these remedies are readily available from a variety of sources, including some grocery stores. although homeopathy may be safe and effective in many childhood conditions, many practitioners believe that homeopathic remedies are best used as adjunctive therapy to conventional medicine in chronic conditions and in acute disorders that respond poorly to conventional therapy. 197, 198 acupuncture is the third most common therapeutic method used in children 386 but has the largest body of scientific data compared with other cam therapies. 248 a harvard survey of 47 patients with a median age of 16 years who received acupuncture treatment, which included needle insertion, moxa/heat, cupping, and magnets, reported that 67% of patients rated the therapy as pleasant and 70% thought treatment helped their symptoms. 209 electrical stimulation, laser, heat, magnet methods, and acupressure or acumassage 324 are effective alternatives to needles for treating children with needle phobia. acupuncture and traditional chinese medicine (tcm) have been used in asia and europe to treat a wide spectrum of childhood illnesses. their use in the united states has been recent but is growing rapidly in popularity. naturopathy ranks with acupuncture as the third most common complementary therapy used by children, 385 although scientific data are sparse. currently, evidence-based information is limited about safety and efficacy of herbal remedies, especially in terms of dosage and application in infants and children, who may be more susceptible to some of the adverse effects and toxicities because of differences in physiology and immature metabolic enzyme systems. 293, 412 other cam treatments used in children include touch therapy (therapeutic touch), osteopathy, oligotherapy, and hypnosis. religious practices such as prayer have also become prevalent in the pediatric population. 22 children have reported the ability to readily feel energy field from touch therapy. 118 the increasing support for therapeutic touch (tt) 223, 226 has been anecdotal with little scientific data. approximately 9% of children receiving treatment with cam therapies seek osteopaths, 386 who claim success in treating many common childhood conditions, including colic and otitis. 19 approximately 4% of pediatric cam visits are to oligotherapists, 386 who administer poorly absorbed trace elements such as copper, manganese, and zinc to improve health. relaxation training and imagery are forms of hypnosis that have also been effective in children. 309 in fact, children seem to be able to learn relaxation training better and faster than adults. 122 table 11 -1 summarizes the cam therapies most often used to treat various pediatric conditions. box 11-1 lists additional and recent surveys and reviews of cam therapies used to treat pediatric conditions. vaccination is an essential component of pediatric well-child care and has both public health and educational ramifications because up-to-date vaccination is required for vaccine safety is monitored closely. adverse events are reported to the vaccine adverse event reporting system (vaers), administered by the centers for disease control and prevention (cdc) and the u.s. food and drug administration (fda). approximately 10,000 adverse cases are reported each year. data are shared internationally by independent scientific experts on the joint committee on vaccination and immunization and committees of the medicines control agency. surveillance results in product withdrawal when there is clear evidence of a safety issue. 300 currently, several serious pediatric conditions are controversially attributed to vaccination: immune compromise, 377 neurologic sequelae, autism, and crohn's disease. the medical community has expressed concern about the effects of vaccination on an immature immune system, especially in neonates. 419 controversial debates are ongoing regarding the possible connection between vaccination and autoimmune illnesses, such as the association between measles and anti-hepatitis b virus (hbv) vaccines with multiple sclerosis. tetanus toxoid, influenza vaccines, polio vaccine, and others have been related to autoimmune phenomena ranging from autoantibody production to full-blown illness, such as rheumatoid arthritis and guillain-barré syndrome. recent evidence suggests that autism may be related to the immune system. 273 the mechanism of autoimmune reactions after immunization has not yet been elucidated. one possibility is molecular similarity between some viral antigen (or other component of the vaccine) and a self-antigen. this similarity may be the trigger to the autoimmune reaction. 16, 374 before 1991, whole-cell pertussis vaccine was used, composed of a suspension of formalin-inactivated bordetella pertussis b cells. convulsions occurred in 1 case to 1750 doses administered, and acute encephalopathy occurred rarely, at 10.5 cases per million doses administered. sudden infant death syndrome (sids) and infantile spasms have also been suggested to be associated with diphtheria-pertussis-tetanus (dpt) vaccination. 103 in the 1970s, reports linking pertussis vaccine with infant brain damage attracted media attention, 227 which in turn caused great parental and professional anxiety; the immunization rate fell from 80% to 30%. between 1976 and 1988, three major pertussis epidemics occurred in the united states, resulting in more than 300,000 hospitalizations and at least 70 deaths. 300 in countries such as sweden, japan, united kingdom, ireland, italy, and australia, antivaccine movements targeted pertussis whole-cell vaccines. 129 opponents to the pertussis vaccine have argued that the risks of vaccination outweigh the benefits. 103 the largest study to date conducted by the national institute of child health and human development at the national institutes of health (nih) revealed that sids was actually less likely to occur in recently vaccinated infants. 165 another large study showed that the permanent neurologic sequelae due to pertussis vaccine are so rare as to be unquantifiable. 280 nevertheless, concerns about brain damage led to the development of acellular pertussis vaccine (dtap) that contains purified, inactivated components of b. pertussis cells. this form is associated with a lower frequency of adverse events and is more effective in preventing pertussis disease. dtap was first licensed for the fourth and fifth doses of the pertussis series in 1991 and for the primary series in 1996. several studies conducted in europe and africa revealed that u.s.-licensed dtap vaccines have efficacy ranging from 71% to 84%. currently, only acellular pertussis vaccine is used. 103 no encephalopathy has been reported. hypotonic hyporesponsive episode (hhe) is the sudden onset of hypotonia, hyporesponsiveness, and pallor or cyanosis that occurs within 48 hours of vaccination, usually after pertussis vaccine administered to children under 2 years of age. hhe occurred in approximately 1 of every 1750 dta vaccinations. the largest published report of 40,000 cases concluded that although hhe does occur after the administration of dtap and other non-pertussis-containing vaccines, it is generally benign, self-limited, and nonrecurrent. 92 the connection of encephalopathy with pertussis vaccine was biologically more plausible than the proposed link between pertussis, measles vaccines, and autism. 300 the incidence of autism has increased from 1 in 10,000 in 1978 to 1 in 300 in 1999 in some u.s. communities. a study of 60 autistic children suggests that autism may be caused by a pertussis toxin found in the dpt vaccine. the toxin separates the g-alpha protein from retinoid receptors, which are critical for vision, sensory perception, language processing, and attention-characteristic problems of autism. those children most at risk have at least one parent with a preexisting g-alpha protein defect, presenting clinically with night blindness, pseudohypoparathyroidism, or adenoma of the thyroid or pituitary gland. natural vitamin a may reconnect the retinoid receptors. 273 in recent years, discussion has increasingly centered on the controversy concerning the possible association of the measles-mumps-rubella (mmr) vaccine with autism and crohn's disease.* the chinese were among the first populations to vaccinate, beginning with smallpox vaccine, which was injected intranasally. tcm considers most childhood illnesses to occur at superficial levels, and vaccination actually introduces pathogens, still considered energetically active, into deeper blood levels of the body. in addition, tcm also posits that the body can usually effectively handle only one process at a given time. when two separate processes occur at the same time, the human system could become overwhelmed, especially the tender system of an infant or a young child. therefore, although multiple vaccines given at the same time are less traumatic for children and save nursing time, they can easily overwhelm an immature immune system and make the child weak and deficient. 352 although the fear of epidemics motivates the chinese to vaccinate all their children, tcm practitioners in the west often advise against immunization. 320 there is discrepancy among the homeopaths regarding recommendation of conventional vaccines. a german questionnaire survey reported that homeopathic physicians generally do not refuse vaccinations but show a preference for the dpt vaccines. 239 a british survey conducted between 1987 and 1993 reported that preference for homeopathic remedies for illnesses and religion were the most common reasons parents refused immunization; 21% believed the risk of diseases to be less than the risk of vaccination and would seek homeopathic treatment if any illness developed in their children, and 17% believed that children "are protected by god and not by vaccines." 379 a u.s. cross-sectional descriptive survey of 42 homeopathic practitioners and 23 naturopathic practitioners in massachusetts revealed that the majority of the practitioners did not actively recommend immunizations. 236 many homeopaths recommend homeopathic vaccines, which are not yet supported by scientific data. 399 a random sample survey by mail of 1% of american chiropractors revealed that one third believe there is no scientific proof that immunization prevents disease, that vaccinations cause more disease than they prevent, and that contracting an infectious disease is safer than immunization. 66 a reported 81% believed that immunization should be voluntary and that spinal adjustment is a viable alternative. a crosssectional, descriptive survey of 90 chiropractics in the boston metropolitan area reported that only 30% actively recommended childhood immunization. 237 the decision of whether or not to immunize a child is difficult for both parents and practitioners. the advantages of vaccination are difficult to refute, but the temporal relationship between immunization and side effects and the controversies surrounding potential risks are disconcerting. although data are insufficient on cam approaches to vaccination today, practitioners should be aware of the slow yet steady trend toward alternatives and should properly address parental concerns and questions regarding immunization. 348 each practitioner needs to inform parents of the most up-to-date pros and cons of vaccination, be as objective as possible, put aside personal belief systems, and be supportive and understanding of whichever decision the parents make. parents need to become as informed as possible, consider all the pros and cons, weigh the risks and benefits, and realize that ultimately they must live with the outcome of their decision. the common cold is the most frequent infection in children in the united states and throughout the industrialized world. 394 a preschool-aged child has an average of 4 to 10 colds per year. the clinical symptoms vary greatly without any correlation with specific viruses. 94, 121 the majority of the symptoms are mild, consisting of rhinorrhea, sneezing, nasal congestion and obstruction, postnasal drip, and cough. there may often be additional symptoms of low-grade fever, sore throat, clear eye discharge, digestive discomfort, and general malaise. 180, 213, 276 some common viruses that cause upper repiratory tract infections (uris) include rhinovirus, coronavirus, adenovirus, respiratory syncytial virus (rsv), influenza virus, and parainfluenza virus. 101, 121, 139 transmission varies with different viruses. for example, rsv spreads primarily through contact with symptomatic children and contaminated objects, whereas influenza spreads mainly through airborne droplets. the precise route of transmission for rhinovirus remains controversial. 139 the virulence of rhinovirus is maximum in infants before 1 year of age (median age 6.5 months) 327 and in immunocompromised children. 330 wheezing is associated with rsv in children younger than 2 years of age and with rhinovirus in those over age 2. 338 simultaneous infection by more than one virus, such as rsv and adenovirus together, can also occur frequently in the pediatric population. many children may also have associated bacterial infection, such as haemophilus influenzae conjunctivitis. 327 the viruses gain entry into host cells through specific viral surface proteins, which cause tissue injury and result in clinical disease. 432 recent studies suggest that the host's response to the virus, not the virus itself, determines the pathogenesis and severity of the common cold. proinflammatory mediators, especially the cytokines, appear to be the central component of the response by infected epithelial cells. 158, 417 specific viral diagnosis is not necessary because of the benign, self-limiting nature of the disease 294 and the prevalence of different viruses overlapping from fall to spring, which makes it difficult to determine precisely which virus or viruses are causing the symptoms. 121 current medical management of uri remains symptomatic, controversial, and in most cases, ineffective. fluid, rest, humidifier, and saline nose drops constitute the mainstay of nonpharmacologic treatment. topical adrenergic agents do not have systemic side effects, but overuse can result in rebound congestion. 84, 114 antihistamine and combinations of antihistamine with decongestants are the ingredients in at least 800 over-the-counter (otc) cold remedies. the majority of studies have concluded that antihistamines are of marginal or no benefit in treating cold symptoms. 47, 110, 153, 254, 383 dextromethorphan is an antitussive that is abundant in otc formulations. although this medication is reportedly safe when taken in the recommended dosages, there have been cases of "recreational" use by teenagers, and deaths by overdose have been reported. 291 codeine is ineffective in controlling uri cough. 95 medications are often overprescribed, leading to higher health care costs 102 and dangerous side effects, such as greater antibiotic resistance. 257 more steroids are prescribed, which leads to a myriad of complications. 274 although interferon has been shown to produce good protection against infection, the high doses necessary to produce a prophylactic effect are often associated with serious undesirable side effects, including nasal stuffiness, bloody mucus, and mucosal erosions, 213 and the trauma of daily intramuscular injection makes it an unlikely remedy for children. 169 research for new medical therapies for the common cold is directed toward increasing resistance to or immunity against the viruses. histamine antagonists are not indicated in the common cold. 369 antiinflammatory mediators 417 and specific antiviral agents 361 may be promising. development of an effective vaccine against the common cold is unlikely because of the large number of viral serotypes. 213 rhinovirus, for example, has at least 100 different immunotypes. 158 although viral uri is a benign illness of short duration, it can lead to bacterial complications such as otitis media, sinusitis, lower respiratory tract infections, mastoiditis, and even meningitis. 330 scientific data on cam treatment for the common cold are surprisingly sparse. in 1971, linus pauling carried out a meta-analysis of four placebo-controlled trials and concluded that vitamin c alleviates cold symptoms, but subsequent reviews indicated that the role of vitamin c in uri is still controversial. [146] [147] [148] 199 although breast-feeding has been believed to protect against infection in infants, studies have been inconsistent in demonstrating its efficacy. in a 4-year prospective study that actively tracked breast-feeding and respiratory illnesses in 1202 healthy infants, breast-feeding was found to reduce significantly the duration of respiratory illnesses during the first 6 months of life. 75 a retrospective review from saudi arabia of randomly selected charts revealed that a direct correlation exists between duration of breast-feeding and frequency of uri in the first 2 years of life. 1 a hospital-based descriptive recall study from sri lanka examined the relationship between breastfeeding and morbidity from respiratory illnesses in infants. of the 343 infants, 285 were admitted and 58 were controls. an inverse relationship was found between the length of breast-feeding and incidence of respiratory illnesses. 319 a nutritional study of 170 healthy newborns followed for 6 months demonstrated that breast-feeding lowers frequency and duration of acute respiratory tract infection compared with formula feeding. 251 a more recent japanese study examined the incidence of pathogenic bacteria isolated from the throat of 113 healthy infants fed with different methods. 166 no pathogens were detected in breast-fed and mixed-fed infants, while h. influenzae and moraxella catarrhalis were isolated from the oropharynx of formula-fed infants. the investigators suggest that breast milk may inhibit the colonization by respiratory bacterial pathogens of the throat of infants. the mechanism was thought to be enhancement of mucosal immunity against respiratory tract infection. in addition to the presence of secretory immunoglobulin a (iga), another mechanism may be the presence of complex carbohydrates in human milk. these glycoconjugates may exert various antipathogenic effects, such as inhibiting the binding of pathogens to the receptors and reducing the production of bacterial toxins. 299 however, a u.s. study that examined nasopharyngeal swabs from 211 infants at 1 month of age and swabs from 173 of these infants at 2 months of age (keeping environmental parameters similar, e.g., number of children in household, number of siblings in day care, proportion with recent uri) revealed that the exclusively breast-fed (n = 84) and exclusively formula-fed (n = 76) infants did not differ significantly in the number of pathogens. 196 a multicenter randomized trial was conducted in 31 hospitals in the republic of belarus. 228 evaluation within the first year revealed that breastfeeding had no significant reduction in respiratory tract infection compared with the control group. a survey from singapore of breast-feeding mothers at 6 months postpartum revealed no significant differences in the rates of uri between breast-fed and non-breast-fed infants. 64 data are sparse on acupuncture, herbal, and homeopathic remedies for treatment of uri, especially in children. most data are uncontrolled, clinical reports. current information on adults supports efficacy of acupuncture for treating the common cold. 172, 311, 454, 462 acupuncture has been shown to increase the velocity of the nasal mucociliary transport in chronic rhinitis patients. 454 one possible use of acupuncture in uri is its potential effect on the immune system. 322 when chinese herbs were pasted onto acupoints for treating rhinitis and bronchitis in infant, serum immunoglobulin m (igm), igg, complement c3, and especially iga levels increased. 461 acupuncture has also been shown to increase t lymphocytes. 404 even massaging local acupoints was effective in relieving symptoms and in enhancing immune functions, with increases in immune indices that persisted for at least 6 months. 466 one report of acu massage of only one point for just 30 seconds resulted in clinical relief from nasal congestion, even though there was no change in nasal airway resistance or airflow. 403 these reports are encouraging for parents because acupressure can be easily learned by nonprofessionals, is well tolerated by children of all ages (including infants), has no side effects, and costs nothing. a clinical trial administering a nontoxic chinese herbal mixture to 305 infants demonstrated more than 95.1% effectiveness in treatment of uri. 465 in a single-blind trial using a chinese herb for acute bronchiolitis with serologic evidence of rsv, 96 hospitalized children were randomized into three treatment groups: herbs, herbs with antibiotics, and antibiotics alone. herbal treatment was found to decrease symptoms and duration of illness without adverse effects. 218 in a randomized, controlled trial using an herbal mixture, 89 children in the treatment group demonstrated 92% efficacy versus 67% of 61 children in the control group. 255 there was no description in the abstract (original article in chinese) of what constituted control (e.g., placebo herb, no treatment, conventional drugs) or what constituted efficacy (e.g., improvement in symptoms, duration, of illness). further rigorous studies are needed to demonstrate safety and efficacy of herbal treatment. a recent clinical trial that included children over age 12 years and used a fixedcombination homeopathic remedy for a mean 4.1 days of treatment reported that 81.5% reported subjective feelings of being symptom free or significantly improved without complaint of any adverse side effects. 4 a randomized, double-blind, placebocontrolled study from great britain of 170 children with a starting median age of 4.2 years in the experimental group and 3.6 years in the placebo group concluded that individually prescribed homeopathic remedies seem to be ineffective in reducing symptoms or decreasing the use of antibiotics in pediatric patients with uri. 78 otitis media (om) represents a continuum of conditions that include acute om, chronic om with persistent effusion, chronic suppurative om, recurrent om, unresponsive om, and om with complications. 28 acute otitis media (aom) is most prevalent in young children 8 to 24 months of age. approximately two thirds of all children will have had at least one episode of aom before age 3 years, and half of them will have recurrences or chronic serous om with effusion into early elementary school years. 132 by the time the child reaches adolescence, aom occurs infrequently. 443 almost one third of pediatric office visits are for treatment of aom. 109 the most common etiologic factors are allergic rhinitis 72,336 and ascending bacterial or viral agents from the nasopharynx attributable to eustachian tube dysfunction. the most common viral culprits are rsv, 10 influenza virus, 153 and adenovirus. 108 two thirds of middle ear infections are caused by bacteria. 109 the predominant organisms are pneumococci, h. influenzae, m. catarrhalis, 53, 305, 358, 388 and group b streptococcus. 325 bacterial pathogens adhere to mucous membranes, and colonization ensues. the severity of infection or the response to the invading bacteria depends on the health of the child's immune system. 53 the humoral system is especially significant in protecting the middle ear cavity from disease, and the nasopharyngeal lymphoid tissues are the first line of defense against bacterial colonization. 335, 359 the sterility of the eustachian tube and tympanic cavity depends on the mucociliary system and on secretion of antimicrobial molecules, such as lysozyme, lactoferrin, and betadefensins. 313 evidence indicates that a number of children with recurrent episodes of aom have minor immunologic defects. 359 pneumococcus is by far the most virulent of aom bacteria. it causes approximately 6 million cases of om annually in the united states. 468 uncontrolled pneumococcal otitis can lead to meningitis. 416 the incidence of aom is higher in winter and early spring. clinically, the child with aom presents with earache and fever, usually accompanied by upper respiratory symptoms such as rhinorrhea. on otoscopic examination the tympanic membrane varies from hyperemia with preservation of landmarks to a bright-red, tense, bulging, distorted appearance. in advanced stages of suppuration the tympanic membrane ruptures with a gush of purulent or blood-tinged fluid from the ear. 108 because viral or bacterial om usually cannot be distinguished by otoscopic examination, aom is usually treated empirically, using antibiotics such as amoxicillin that have a high concentration in the middle ear fluid. 214, 224 however, the widespread use of antibiotics has resulted in increasing resistance to the more common medications. 53, 358 currently, 10% of children with aom are recalcitrant to antibiotic therapy. 277 the prevalence of resistant organisms tends to increase in the winter months. 43 economically, treatment failure due to drug resistance has been responsible for further escalating the billions of dollars spent treating aom. 287 in addition, antimicrobials suppress normal flora, which is beneficial to the host because the antibiotic can interfere with and therefore prevent pathogenic infections and may enhance recovery from uris. 43 on the other hand, since the advent of antibiotics, complications such as mastoiditis and intracranial infections have significantly decreased. 297 the current focus is on prevention of aom. breast-feeding confers lifesaving protection against infectious illness, including otitis. 134, 156 pneumococcal conjugate vaccine (pcv), approved in 2000 for use in the united states, covers the seven serotypes that account for about 80% of invasive infections in children younger than age 6 years. pcv was demonstrated to have more than 90% efficacy 468 and has resulted in a modest reduction of total episodes of aom. 317 the goal of pcv is to prevent symptomatic infections in the middle ear and prevent colonization of the pneumococci that can cause subsequent middle ear infections. 41 pcv may eliminate nasopharyngeal carriage of pneumococci. 235 however, because pcv only prevents disease caused by the most common serotypes, there is concern that the nonvaccine serotypes will become more common, especially in children less than 2 years of age. 317 an effective rsv vaccine for the infant and young child could greatly decrease om disease. 10 intranasal spray of attenuated viruses is currently under investigation, in the hope that early antiviral therapy would reduce the risk of om after uri. 137, 153 chronic otitis media with effusion (ome) is one of the most common diseases in childhood. 91 ome is associated with infection, eustachian tube obstruction, allergic or immunologic disorders, and enlarged adenoids. 108 the serous fluid still contains bacteria, such as h. influenzae and pneumococci. 48 ome has been implicated to be an immune-mediated disease 91 because immune complexes have been demonstrated in the middle ear effusion, 268 and highly organized lymphatic tissue has been found in the middle ear mucosa. 422 the rationale for treating ome is prevention of recurrence of aom. currently, a once-daily antibiotic regimen is the recommended prophylaxis. the benefit is also weighed against the increasing risk of emergence of resistant bacteria. 134 when antibiotics fail to control recurrent om, a short trial of prednisone may be prescribed. surgery is recommended when medical treatment fails, 277 especially when the child has hearing loss. 305 tympanostomy tubes appear to be beneficial in ome but are of less value in chronic suppurative otitis. 134 increase in hearing loss has been reported with insertion of ventilation tubes. 144 adenoidectomy is sometimes recommended, 193 especially after tympanostomy tube failure. 134 any safe and effective cam therapy for om would be an important contribution to the pediatric population. large-scale, randomized, controlled studies for cam treatment would need medical collaboration, especially for otoscopic examination and tympanometry. 366 in addition, since aom has a high rate of spontaneous resolution, any clinical study must also prove that treatment effect is faster than natural improvement. although breast-feeding has been found to reduce uri, data concerning its association with frequency or duration of om have been conflicting. epidemiologic reports consistently provide evidence of protection of young children from chronic otitis with prolonged breast-feeding. 138 a u.s. study that followed 306 infants at well-baby visits in two suburban pediatric practices reported that the cumulative incidence of first om episodes increased from 25% to 51% between 6 and 12 months of age in infants exclusively breast-fed versus 54% to 76% in infants formula-fed from birth. 89 there was a two-fold risk of first episodes of aom or ome in formulafed babies in the first 6 months. a danish study that evaluated 500 infants using monthly questionnaires reported no statistical difference in the breast-fed versus formula-fed infants in incidence of om. 355 an earlier jewish study comparing 480 infants visiting a pediatric ed with 502 healthy infants found that breast-feeding significantly reduced infectious diseases, including om in infants under 5 months of age. 76 a study from switzerland evaluated 230 children with aom by administering individualized homeopathic medicine in the pediatric office. 119 if there was insufficient pain reduction after 6 hours, a second (different) homeopathic medicine was given. antibiotics were given if there was lack of response to the second dose. pain control was achieved in 39% of the patients after 6 hours, with another 33% after 12 hours. the resolution rate was 2.4 times faster than in placebo controls. no complications were observed in the study group. 119 in a u.s. double-blind, placebo-controlled pilot study, 75 children ages 18 months to 6 years with ome and ear pain and/or fever for more than 36 hours were randomized into individualized homeopathic medicine or placebo group. 181 no statistically significant results were noted. a british nonblinded, randomized pilot study was done with 33 children ages 18 months to 8 years who had ome and hearing loss greater than 20 db and an abnormal tympanogram. 150 the results revealed that the homeopathy group had more children with a normal tympanogram, fewer referrals to specialists, lower antibiotic consumption, and a higher proportion with a hearing loss less than 20 db at follow-up. however, the differences were not statistically significant. further research with larger groups is needed for a definitive trial. in a prospective, observational study carried out by one homeopath and four conventional ear-nose-throat (ent) physicians, a single (nonindividualized) homeopathic remedy was compared with nasal drops, antibiotics, and antipyretics. 125 children between 6 months and 11 years of age were included in the study. homeopathic treatment was given to 103 children and conventional treatment to 28 children. homeopathic remedies were found to be significantly more effective in reducing duration of pain and in preventing relapses. because om tends to affect predominantly young children, it would be more appropriate for studies to compare results in children of similar age rather than a wide range of ages, from infancy to preadolescence. a retrospective, nonrandomized study of 46 children under 5 years of age receiving 3 weeks of treatment from a single chiropractor reported a decrease in om symptoms. the limitations to this study included retrospection and a lack of comparison with the natural course of ear infections. 124 an israeli controlled clinical trial examined the efficacy and tolerance of ear drops made with naturopathic extracts in the management of aom pain. 362 ranging in age from 6 to 18 years, 103 children were randomized into the treatment group and control group using a conventional anesthetic ear drop. there was statistically significant improvement in both groups, indicating that the naturopathic ear drops were as effective as the anesthetic ear drops. the university of arizona has initiated a study of the use of echinacea, a dietary supplement, in the prevention of recurrent om. 261 acupuncture data are lacking on treatment of om in children. 411 the theoretical potential benefit of acupuncture would appear to be its effect on the immune system, as discussed in the section on uri. allergic rhinitis affects 5% to 9% of children. 113 perennial rhinitis is related to allergens that children are exposed to continuously, such as animal dander, house dust mites, mold, and feathers. seasonal rhinitis is related to seasonal pollenosis and rarely affects children under age 4 or 5 years. 100 allergic diseases are major causes of morbidity in children of all ages, 437, 447, 448 and allergic rhinitis is a significant cause of middle ear effusions. 72, 267, 336, 452 conventional therapy usually consists of avoidance of allergens, use of air-clearing devices, desensitization shots, and medication with antihistamines and at times steroids, both of which are frequently abused. 179, 200 antihistamines may be beneficial when sneezing and itching are present. 114 cam therapy is common among children with allergic diseases in sweden 155 and is becoming more popular in the united states, although scientific data specifically on children are still lacking. physicians have become more aware of the importance of nutrition 384, 424 and environmental factors in the development of allergic symptomatology in childhood. 289, 396, 446 a prospective, longitudinal study of healthy infants followed from birth to 6 years of age concluded that recurrent wheezing is less common in nonatopic children who were breast-fed as infants. 450 hypnosis has been reported anecdotally to be effective in hay fever. 439 homeopathic efficacy has received increasing attention in recent years, 342 but data consist of adult studies. an international multicenter study involving 30 investigators in four countries and 500 patients with three diagnoses, including upper and lower respiratory tract allergies, concluded that homeopathy appeared to be at least as effective as conventional medicine. 345 another multicenter study using a randomized, double-blind, placebo-controlled parallel group design also demonstrated that homeopathic preparations differ from placebo for allergic rhinitis. 408 homeopathic remedies for allergic children are unsupported by scientific studies at this time. an adult study using changes in conductance of specific acupuncture points for diagnosis and treatment demonstrated statistically significant changes that correlated with clinical improvement. 195 in a randomized study of 143 patients that included older teenagers, desensitization was compared with specific acupuncture treatment for allergic asthma, allergic rhinitis, or chronic urticaria. the study was ridden with multiple, tedious variables. the conclusion that acupuncture was significantly more effective than desensitization in improving symptoms and in reducing recurrence in all three conditions did not give a breakdown in age groups. 228 in a clinical report of 75 chronic allergic rhinitis cases that included three cases in children 6 to 10 years of age and 17 cases in 11-to 20-year-olds, two different acupuncture treatments were administered according to tcm diagnoses. there was a cumulative 40% cure rate without age differentiation. 454 asthma is the most common cause of chronic illness in childhood, with approximately 10% of children in the united states carrying the diagnosis. 259, 297, 442 a significant number of school days are lost because of asthma. a wide variation of incidence is found in different countries, with the highest rates in the united kingdom, australia, and new zealand and the lowest rates in eastern europe, china, and india. 296, 442 in recent years, prevalence of asthma is increasing worldwide, especially in children under 12 years of age. 17, 382 although asthma can have onset at any age, 80% to 90% of asthmatic children have their first symptoms before 4 to 5 years of age. 297 children up to age 4 years have distinct symptoms and require special consideration. 36 they have increased health service utilization, including a higher annual rate of hospitalization, 298 which has almost doubled in the united states from 1980 to 1992 for children 1 to 4 years of age. 17 the same trend is observed by other nations worldwide. 9,18 among american children ages 5 to 14 years, asthma death rates almost doubled from 1980 to 1995. 17 new zealand and canada have observed a similar increase in severity and mortality. 73, 387 asthma is a diffuse, reversible, obstructive lung disease with three major features: bronchial smooth-muscle spasm, edema and inflammation of the mucous membrane lining the airways, and intraluminal mucus plugs. 442 during the last two decades, chronic airway inflammation, rather than smooth muscle contraction alone, has been recognized as playing the key role in the pathogenesis of asthma in adults. 63, 131 although this association is less well established in children, recent guidelines for managing asthma in the pediatric population still have emphasized that treatment be directed toward the inflammatory aspects of the disease. 206, 402, 440 chronic inflammation is caused by the local production of inflammatory mediators and an increase in recruitment of inflammatory cells, predominantly eosinophils and mast cells. studies in young adults suggest that the chronic inflammation may be responsible for longterm pulmonary changes, including bronchial hyperresponsiveness, airway remodeling, and irreversible airflow obstruction. because of difficulties in conducting studies in infants and young children, pediatric information is incomplete. 230 limited studies have detected increases in inflammatory cells and thickening of the lung basement membrane in infants and young children and have found that asthmatic children have significantly lower lung function at 6 years of age compared with nonwheezers when both groups of children began with the same baseline at age 6 months. these data support the possible presence of an asthmalike inflammation at a very early age that is associated with nonreversible impairment of lung function. 263 the excessive inflammatory changes indicate that asthma is caused by a poorly regulated "immunologic runaway response" that, instead of protecting the host, destroys normal structure. increased concentrations of proinflammatory mediators, such as histamine and leukotrienes, are found in the airways as well as the blood and urine of asthmatic patients 131 during an acute attack and after allergen and exercise challenge. 34 strong evidence correlates asthma with rsv infection; children who enter day nursery before age 12 months and who are exposed to viruses early in life have built up immunity, with decreased development of allergies. 88 in most children, whose asthma is triggered mainly by respiratory infections at a younger age, asthma symptoms appear to remit by the adolescent years. 263 in older children and teenagers, emotions play a significant role both as the cause of symptoms and as the result of interplay of a chronic illness affecting the child's self-image and family dynamics. 297 the latest asthma management guidelines classify pediatric asthma into four groups of severity: mild intermittent, mild persistent, moderate persistent, and severe. 206 mild intermittent asthma can be typified by exercise-induced asthma, a common pediatric condition. status asthmaticus, defined as progressive respiratory failure that does not respond to conventional management, is becoming more prevalent in american children. 442 conventional treatments for pediatric asthma vary from allergen avoidance to state-of-the-art biochemical therapy. avoiding allergens has been a successful management of asthma since the sixteenth century. asthma is a much more complex problem today because of the increasing number of pollutants and chemicals in the environment that are potential allergens for children. 157 parental education, especially in regard to smoking, can reduce hospital admissions. 449 because infections that trigger asthma attacks are mostly viral, 31 antibiotics are not routinely indicated. medication consists primarily of bronchodilators and inhaled steroids, which are now justified as first-line therapy, 191 both as long-term management 402 and for acute attacks. 231 because growth suppression due to inhaled corticosteroids has been well documented, 61 it is important to distinguish infants with early-onset asthma from those with transient wheezing. 469 recently, the fda has also approved leukotriene receptor antagonists for use in asthmatic children under 4 years of age. 380 these agents counteract the hyperimmune response, resulting in diminished airway inflammation and decreased eosinophilia in the airway mucosa and peripheral blood. 34 parents turn to cam for their asthmatic children because of drug side effects or fear of taking long-term medication, especially steroids. 11,62 a recent survey from texas of 48 multicultural parents of children with asthma reported the usage of a variety of cam therapies, including homeopathy, herbal therapy, vitamins, and massages. hispanic parents were more likely to use herbal and massage therapies, whereas african-american parents often turned to prayers. 269 the relatively abundant studies on cam therapy in asthma are on adults and often have flaws in methodology. significant improvement 15,308,310 and even complete cure 83 have been demonstrated with hypnosis, although most studies had weak designs. hypnosis was recommended for children because they were found to be more hypnotizable, 68 but it is unclear whether the efficacy of hypnosis in asthmatic children is a reflection of children's greater suggestibility or a result of a more reversible disease process. 439 in a recent preschool program, 25 children ages 2 to 5 years received treatment with seven hypnotherapy sessions. the number of physician visits was reduced, and parental confidence in self-management skills increased. 217 tcm has been used to treat asthma for centuries. asthma epitomizes the chinese medicine concept of "winter disease, summer cure," which means the best treatment for asthma should be given during the summer, when the child is symptom free. in china, many asthmatic children who were treated with herbal patches applied to acupoints during the summer had minimal or no symptoms during asthmatic seasons. 37, 58, 320 although several recent adult studies used herbs for asthma, 107 only two involved children. a controlled study comparing herbal treatment of 30 children with penicillin and aminophylline treatment of another 30 children revealed no significant difference in the response from the two groups. 242 a multicenter doubleblind, placebo-controlled clinical herbal study from taiwan evaluated 303 asthmatic children using tcm diagnoses. 170 the children were randomized into three different herbal and placebo groups. although both groups showed improvement, the herbal groups showed greater improvement in symptomatology and in biochemical changes, such as increase in total t cells and decrease in histamine. an animal experiment using a 13-herb concoction revealed 99.1% efficacy in easing bronchial spasm. 170 another animal study with an herbal preparation demonstrated strong smooth muscle relaxation through inhibition of histamine and acetylcholine. 242 from the pediatric standpoint, it would be worthwhile to follow the development of external tcm approaches and noninvasive acupuncture. one clinical obser-vation of pasting chinese herbs to acupuncture points in 72 infants with acute bronchitis showed high cure and improvement rate, especially in infants. 461 humoral immune substances, especially iga, were found to be increased after treatment. another clinical observation reported 78% efficacy in 46 children treated with external application of plasters made of herbal mixtures with antitussive and antiasthmatic properties and 88% efficacy in 17 children treated with antiasthmatic herbal patches. success was also reported with a different herbal patch for acute attacks. the patches were well received by the children. 401 improvement from acupuncture treatment has been reported in asthmatic adults. 392, 406, 428, 463 despite methodologic weaknesses, it still seems that acupuncture may help asthma, especially drug-induced or allergic asthma. 439 in some european countries, almost a fourth of general practitioners believe in the efficacy of acupuncture in the treatment of asthma. 216 its role in the united states is still controversial; some physicians accept acupuncture's effectiveness, 426 whereas others criticize data based on poorly conducted studies. 5 the few current studies and clinical reports on acupuncture treatment of children with asthma are generally favorable. 168, 457 a german practitioner reported good results treating asthmatic children using a simple acupuncture regimen in uncontrolled clinical experience. 145 one study demonstrated that although acupuncture did not affect the basal bronchomotor tone, when administered 20 minutes before exercise, acupuncture was shown to be effective in attenuating exercise-induced asthma, 128 which is common in children. one possible mechanism of acupuncture is in reducing the reflex component of bronchoconstriction, but not in influencing direct smooth muscle constriction caused by histamine. 460 for children who are fearful of or who cannot tolerate needles, safe and painless treatments such as cupping and auricular press pellets, 457 laser acupuncture, 288, 292 and massage of acupuncture points 168 have also been found to be effective. the most interesting future role for acupuncture in asthma lies in its potential both in stimulating an immune response and, more importantly, in regulating or modulating a hyperimmune response. at this time, ample biochemical data in the literature support the theory that acupuncture activates both the humoral and the cellular immune systems to protect the host.* studies have also demonstrated that acupuncture can modulate the synthesis and release of proinflammatory mediators. 192, 256, 458 current hypotheses suggest that this is most likely mediated through a common pathway connecting the immune system and the opioids, 30,321,363 which has been well known to be associated with analgesic effects of acupuncture. homeopathic remedies have been reported to be remarkably effective in asthma in adults, 120, 345, 427 and homeopathic doses of allergens have been shown to alleviate allergic symptoms and desensitize patients to allergens. 433 however, there is paucity of scientific data on homeopathy in both children and adults, as well as a lack of consensus among homeopaths as to the appropriate treatment, administration regimen, or potency for asthma. 439 homeopathic practitioners believe that in chronic conditions such as asthma, homeopathic remedies can stimulate the child's innate healing ability, thereby leading to improvement. 197, 198 two recent large reviews on the role of homeopathy in clinical medicine concluded that, except for the occasionally demonstrated benefit, little scientific evidence exists to support the use of homeopathy in most clinical settings. 159, 439 the availability of homeopathic, nutritional, and herbal remedies without a prescription is appealing to the asthmatic adolescent's desire for independence. 12 in a number of european countries, chiropractic is often used for treatment of asthma. 186 one of the many difficulties in evaluating chiropractic efficacy lies in the varying abilities of the manual therapy practitioners. natural human differences exist in manual applications and techniques. the practitioners have various training backgrounds, including physiotherapy, respiratory therapy, chiropractic, and osteopathy. a danish questionnaire survey of 115 families with children up to age 7 years reported that 92% of parents who sought chiropractic help considered the treatment beneficial for their children. 77, 423 an australian survey reported that the most common cam visits were to chiropractors. 87 a u.s. prospective, observer-blinded, clinical pilot evaluated 36 children from 6 to 17 years of age with mild to moderate persistent asthma for chiropractic treatment in addition to optimal medical management. 42 children were randomized into treatment and sham spinal manipulative therapy (smt) for 3 months. the children with combined smt and medical treatment rated their quality of life substantially higher and their asthma severity substantially lower, and their improvements were maintained at 1-year follow-up. however, there were no significant changes in lung function or hyperresponsiveness. further research is needed to determine which components of the chiropractic encounter are responsible for the improvements. a controlled, patient-blinded trial of chiropractic manipulation for 91 children with mild or moderate asthma randomized the children into an active or a simulated chiropractic manipulation for 4 months. 20 each subject was treated by 1 of 11 participating chiropractors, selected by the family according to location. no significant benefit was observed in the treatment group. a few studies in adults generated statistically insignificant data. 176 one study found subjective but not objective improvements in individuals with asthma who received treatment in a chiropractic clinic. 186 a 2001 systematic review revealed that the majority of the studies on smt had poor methodology; the two good studies did not demonstrate significant differences between chiropractic smt and sham maneuver. 167 the reviewers concluded that the evidence is still insufficient at this time to support the use of manual therapies for patients with asthma. a german pilot study of 15 children ages 5 to 11 years with bronchial asthma combined relaxation using various techniques, including progressive muscle relaxation, autogenic training, fantasy travels, mantras, and periodic music, and demonstrated significant improvement in a number of pulmonary function parameters. 142 however, it is difficult to interpret the results because of the variety of techniques used. 143 a u.s. review of anecdotal reports indicated that massage therapy can improve asthmatic symptoms. [110] [111] [112] diarrhea acute diarrhea is a common occurrence in the pediatric population and a significant cause of pediatric morbidity and mortality in both developed and underdeveloped countries. 79, 302, 354 each year an estimated 54,000 to 55,000 u.s. children are hospitalized for diarrhea, 136 and more than 4 million infants and young children worldwide die of acute infectious diarrhea. 354 infants under 3 months of age have the highest risk for hospitalization and mortality. 304 children under age 3 years have an average of approximately 2.5 episodes of gastroenteritis per year in the united states. 143, 302 internationally, the average is approximately 3.3 episodes annually. 354 both diagnosis and treatment continue to be problematic in the pediatric population. 260 the infectious pathogens that cause acute diarrheal episodes in children include viruses, bacteria, and parasites. 229 transmission is most likely through the fecal-oral route, from ingesting contaminated food or water, 434 or in infants and toddlers, by mouthing contaminated toys. the nature of food-borne diseases is changing as more mass-produced, minimally processed, and widely distributed foods result in nationwide and international outbreaks of diarrheal disease instead of just a few individuals who shared a meal. 143 a majority of the cases are caused by viral infections. rotavirus is the most prevalent, 264 and human astrovirus (hastv) is a significant cause of diarrheal outbreaks. 434 frequently, children are co-infected by several viruses. viral diarrhea tends to involve the small bowel, producing large, watery, but relatively infrequent stools. 82 these illnesses usually have short, self-limiting courses, 6 typically lasting 3 to 7 days. 264 however, the diarrheal bouts can be devastating to children with compromised immune systems or structural abnormalities of the gastrointestinal tract. 143 the most common bacterial agents are enteropathogenic escherichia coli, shigella/salmonella, and campylobacter. 82, 264 these are much more virulent pathogens that usually cause mucocal injury in the small and large intestines, producing frequent, often bloody stools containing leukocytes. 82 e. coli has become an important public health problem in recent years, causing more than 20,000 cases of infection and up to 250 deaths per year in the united states. 220, 381 transmission of infection is most often linked to consumption of contaminated meat, water, unpasteurized milk, leafy lettuce, alfalfa sprouts, and goat's milk, 220, 413 and exposure to contaminated water in recreational swimming sites. 413 the most common parasitic infection is giardia lamblia, which often causes secretory diarrhea without blood 264 and frequently leads to chronic diarrhea. 161 diagnosis and treatment are still inconsistent. because most acute diarrheal conditions are self-limited, physicians often do not obtain stool cultures or examination for ova and parasites because the results are not available sometimes for several days. stool culture can identify different types of bacteria, but detection of specific enteropathogenic strains of e. coli requires specific serotyping that is not performed in routine stool cultures. 220 it is expensive, time-consuming, and often not sufficiently specific or sensitive and therefore is not recommended for routine diagnosis. 151 the primary treatment focus is on correction of dehydration, 275 which is the most important cause of morbidity and mortality in acute diarrhea. 243 oral rehydration treatment (ort) with solutions containing appropriate concentrations of electrolytes and carbohydrates is recommended by the world health organization (who) and has significantly reduced mortality. 82, 140, 367 after rehydration, early refeeding with a lactose-free 82 or normal, age-appropriate diet 229 is important for reducing diarrheal duration, severity, and nutritional impact. supplementation with specific dietary ingredients that are lost in diarrhea, such as vitamin a, zinc, and folate, is also recommended. 140 because most of the acute infectious diarrheal conditions are viral, patients do not require antimicrobial therapy. 326, 333 the rotavirus vaccine was put on the market in the united states in october 1998. this vaccine, as the natural infection, decreases the risk of acute rotavirus diarrhea by 50% and the risk of severe diarrhea with dehydration by more than 70%. 367 improving hygiene such as handwashing is also important, especially in day care. breast-feeding is one of the most important preventive measures. 351 continuation of breast-feeding has been found to control acute diarrheal episodes 140 and lower the frequency and duration of acute diarrhea, especially in infants under 6 months of age. 251 a large-scale randomized trial was conducted in 31 hospitals in the republic of belarus. evaluation within the first year revealed that breast-feeding significantly reduced the risk of gastrointestinal tract infection compared with the control group. 228 however, a survey from singapore of breast-feeding mothers at 6 months postpartum revealed no significant differences in the rates of diarrheal diseases between breast-fed and non-breast-fed infants. 64 treatment with antimicrobial therapy must be instituted carefully and only with specific identification of pathogen and drug sensitivity. with the increasing frequency of antibiotic resistance, common antibiotics may be ineffective in patients with acute diarrhea. 143, 351, 367 treatment of salmonellosis with antibiotics can prolong the carrier state and lead to a higher clinical relapse rate. 143 injudicious antimicrobial therapy may also lead to susceptibility to other infections, enhance colonization of resistant organisms, 29, 143 and disrupt the normal intestinal flora, the body's natural defense against infection. 270 homeopathy has the most convincing evidence of efficacy in treating diarrhea in children. a randomized, double-blind clinical trial comparing homeopathic medicine with placebo in the treatment of acute childhood diarrhea was conducted in nicaragua in 1991. eighty-one children 6 months to 5 years of age were given treatment with individualized homeopathic medicine. standard ort was also given. there was a statistically significant decrease in the duration of diarrhea in the treatment group. 182 although criticisms of the study include homeopathic theory being inconsistent with scientific belief 378 and possible toxicity of the dilute homeopathic remedies, 210 the report was also praised for being an impressive, 54 well-designed 44 study that paves the way for future research into the efficacy of homeopathy and other cam therapies. 115 using the predefined measures based on the 1991 study, the same group of researchers more recently carried out a similar study and replicated the same findings of decrease in the duration of diar-rhea and number of stools in 126 children in nepal, ranging in age from 6 months to 5 years. 183 a few studies have demonstrated effectiveness of acupuncture in pediatric diarrhea. the treatment protocols in point selections generally depend on tcm diagnoses, with the majority of points chosen on the two major digestive channels. 109, 190, 245, 398, 455 acupuncture has also been shown to induce favorable anatomic and biochemical changes in improving intestinal peristaltic function and in enhancing both humoral and cellular immunity. 244 a randomized study comparing shallow acupuncture treatment (needles inserted superficially and withdrawn swiftly) with drugs in 761 children ages 1 to 35 months reported significantly higher therapeutic effect in the acupuncture group. 244 the diagnosis and subsequent choice of points were based on tcm principles, not on stool culture results. unlike the homeopathy study, this investigation grouped together patients with acute and chronic diarrhea. in a clinical trial using one chinese herbal formula for treatment of acute diarrhea, there was significant reduction of symptoms and duration of diarrhea. 38 a clinical report of 20 years' application of a seven-herb concoction in 419 children demonstrated 96.4% improvement and 90% cure rate. 241 this nonrandomized, nonblinded report used tcm diagnoses that encompassed a variety of diarrheal conditions, including acute, chronic, infectious, and noninfectious diarrhea. the mechanisms were hypothesized as eliminating pathogenicity, improving immunity, accelerating intestinal digestion, and inhibiting intestinal peristalsis. in a clinical report comparing chinese herbs to western medicine in 158 children with diarrhea due to rotavirus, the herbs were reported to be superior and had a viral inhibitory rate of 71.43%, but no mention was made of the efficacy of conventional medicine. 435 chronic nonspecific diarrhea of childhood differs from acute diarrhea in that it is not associated with significant morbidity. once potentially serious causes are excluded, appropriate diet can be instituted to minimize complications, and reasonable time is then allowed for spontaneous resolution. 414 in a nonrandomized clinical trial involving 30 children ages 3 months to 8 years with chronic diarrhea of 2 to 4 months' duration that was unresponsive to western medicine and tcm, individualized acupuncture treatment eliminated symptoms and normalized stools. 109 infantile colic is estimated to affect 20% to 30% of all infants under 4 months of age and remains a medical enigma of nature versus nurture. colic may represent a heterogeneous expression of developmental variance, unmet biologic needs, psychologic or emotional distress from poor parent-infant interaction, intrinsic temperamental predisposition, colonic hypermotility, 278 or milk allergy.* although colic is selflimiting by 3 to 4 months of age, treatment is mandated because the psychologic consequences may result in a disturbed mother-infant relationship. 174, 355 evidence suggests that uncontrollable crying is the precipitating factor in many cases of infant abuse. 178, 441 because the precise etiology is not understood, the therapeutic goal of western medicine is not aimed at "curing" colic but at containment of the crying. 328 removing cow's milk protein from the mother's diet, changing formula, and prescribing antispasmodic medications are the mainstays of conventional treatment and may be helpful. 69 treatment is often directed toward behavioral changes in mothers. parents may be referred for therapy to learn parenting and coping skills. cam treatments yield inconsistent results. herbs have not yet been proven to be efficacious, 265 although a survey of 51 hispanic mothers in an urban neighborhood in texas revealed that herbal teas were commonly used for colic. 346 evidence is controversial for chiropractic treatment of colic. a multicenter prospective, uncontrolled study of 316 colicky infants involving 73 chiropractors in 50 clinics in the united kingdom for 3 months demonstrated efficacy with chiropractic smt in controlling colic, as reported by mothers in 94% of cases. 215 a retrospective questionnaire study in 1985 revealed satisfactory results of chiropractic treatment in 90% of infants. 301 a randomized, blinded, placebo-controlled clinical trial of 100 infants with typical colic reported that chiropractic manipulation was no more effective than placebo. 307 however, a randomized, controlled, 2-week trial comparing smt with the drug dimethicone demonstrated significantly better results in the chiropractic treatment group. 444 craniosacral therapists empirically claim success in treatment of colic. 19 massage therapists have also found empirically that touch therapy can decrease severity of colic. 111 in a finnish clinical trial, 58 infants less than 7 weeks of age perceived as colicky by their parents were randomized into an infant massage group (n = 28) and a crib vibrator group (n = 30). 173 over 4 weeks there was no difference in the reduction of colicky crying between infants receiving massage and those with a crib vibrator, leading the investigators to conclude that the decrease of crying reflects more the natural course of early infant crying and colic than a specific effect of intervention. therefore infant massage is not recommended as treatment for colic. enuresis is defined as inappropriate or involuntary voiding during the night at an age when urinary control should be achieved. 7 enuresis is a complex disorder with poorly understood pathogenicity and pathophysiology. it affects children worldwide, 297 with about 5 to 7 million children affected in the united states 281 and as many as 30% of school-age children in italy. 48 the condition is classified as primary nocturnal enuresis (pne) when the child has never been dry at night or secondary nocturnal enuresis (sne) when wetting follows a dry period, usually after an identifiable stress. 203, 297 by age 8 years, 87% to 90% of children should have nighttime dryness. 65 in 85% of pne patients, bedwetting is monosymptomatic, with a spontaneous remission rate of 15% per year of age. both the etiology and the pathophysiology of enuresis are still not well understood. multiple factors may interplay: genetic and psychologic predispositions, delayed maturation of the central nervous system, sleep disorders, urinary reservoir abnormalities, detrusor-sphincter incoordination, and urine production disorders. 48 although enuresis is benign, treatment is warranted because of adverse personal, family, and psychosocial effects. 281, 282 nocturnal enuresis delays early autonomy and socialization because of a decrease in self-esteem and self-confidence and a fear of detection by peers. the child may be at increased risk for emotional or even physical abuse from family members. 368, 438 the conventional treatment modalities are still controversial. because the vast majority of pne cases resolve spontaneously with time, treatment should carry minimal or no risk. the moisture alarm is both safe and inexpensive and should be the treatment of choice in most cases 65, 286, 357 but is often the one least prescribed. 15, 258 the medications imipramine and ddavp were frequently chosen as first-line treatment choices. adjunctive therapy may include bladder-stretching exercises, which have a success rate of 30%, and behavioral conditioning. 357 numerous cam therapies are available for childhood enuresis; the most common are hypnosis, acupuncture, and biofeedback. less common cam therapies are chiropractic and nutrition management. hypnotherapy has been recognized by conventional practitioners as a potentially effective therapy. 262, 286 uncontrolled studies have reported high rates of success. 24, 67, 74, 308, 310 in one comparative study of imipramine and direct hypnotic suggestion with imagery for functional nocturnal enuresis in 5-to 16-year-old patients, 76% of the imipramine group and 72% of the hypnosis group had positive response. 21 after termination of treatment, the hypnosis group continued practicing self-hypnosis. at 9-month follow-up, 64% of the hypnosis group maintained dryness compared with only 24% of the imipramine group. hypnosis and self-hypnosis were found to be less effective in younger children (ages 5 to 7 years) compared with imipramine treatment. hypnotherapy has the added advantage that nonphysician health care professionals, such as nurse practitioners, can easily learn the technique to help children. 163 a recent review of controlled studies reported promising findings for hypnosis in children with enuresis, but none of the interventions can currently qualify as efficacious. a major limitation is the lack of treatment specification via a manual of its equivalent. 283 the requirement that the child practice the self-hypnosis technique several times a day limits compliance with the program. 286 acupuncture has been used as an effective treatment for enuresis since at least the 1950s. 459 current worldwide literature in general demonstrates its viability as either a primary or an adjunctive therapy for the enuretic child.* a turkish clinical study on 162 subjects treated with electroacupuncture therapy reported a success rate of 98.2%. 418 acupuncture has been found to be successful both in decreasing the occurrence of enuresis during treatment and in exerting a long-term effect after treatment. 35, 48, 370 parents also report a decrease in sleep arousal threshold. 35 although the precise mechanism of acupuncture is still unknown, a multidisciplinary approach that included acupuncture demonstrated on electroencephalography (eeg) that treatment normalized activities of the cerebral cortex. 415 data from china usually consist of clinical reports of large sample populations. results in one study of 500 patients treated with acupuncture on only two body points demonstrated cure in 476 patients (98%), improvement in 14, and no response in 10 patients. 459 number of treatments ranged from one to three in 453 patients and four to six in 23. another study of 302 enuretic children ages 3 to 15 years (10 over 15 years; oldest 23 years) used tcm diagnosis of organ imbalance and different combinations of acupuncture points, with 10 treatments constituting one course. 453 the results showed that 221 patients were cured, 71 showed marked improvement, and 10 were "effectively" treated. treatment using scalp acupuncture has also been reported to be successful. in one clinical study, 59 children ages 4 to 17 years were treated for 10 to 15 sessions, and some needed a second course. 61 cure was obtained in 9 children, marked improvement in 27, improvement in 19, and no response in 4 children. in all these clinical reports, subjects of a wide range of ages were included in the same study; the discussions were short and generalized, giving very few or no details about the children (e.g., types of enuresis, duration of enuresis, number of wet nights, types of improvement); the methods of treatment were laden with numerous variables (e.g., number of points, treatment courses). a clinical study from italy of 20 children with bladder instability due to uninhibited contractions of the detrusor muscle reported that acupuncture treatment was successful in gradual elimination of enuresis in 11 and improvement of symptoms in 7 children. the mechanism was not clarified. 284 a russian clinical trial of using acupuncture specifically for enuresis due to neurogenic bladder dysfunction demonstrated that acupuncture was beneficial in 17 of 25 children. 194 in a clinical report of 54 enuretic children, short-term success in reducing wet nights was 55% with acupuncture versus 79% with ddavp, whereas long-term success rates were 40% and 50%, respectively. 48 a zagreb report of a clinical trial of acupuncture treatment on 37 children with mean age of 8 years who failed psychotherapy demonstrated a statistically significant decrease in enuresis even at 6 months after treatment. 350 a self-controlled regulating device operating on the principles of acupuncture was found to be effective in the treatment of nocturnal enuresis attributable to neurogenic bladder dysfunction. 233 a controlled clinical study of 40 children between 5 and 14 years of age randomly selected into four groups of 10: treatment with ddavp alone, acupuncture alone, combined ddavp with acupuncture, and placebo. efficacy of treatment, expressed as a percentage of dry nights, was high in both ddavp and acupuncture groups, but the combined-treatment group had the best results. 52 a scandinavian clinical trial used traditional chinese acupuncture for treatment of primary persistent pne in 50 children ranging in age from 9 to 18 years. the response rate was monitored at 2-week, 4-week, and 3-month intervals. 370 within 6 months, 43 (86%) of children were completely dry and 2 (10%) were dry on at least 80% of nights, leading the clinicians to conclude that acupuncture is effective, with stable results. another scandinavian study investigated the efficacy of electroacupuncture in treating 25 children ranging in age from 7 to 16 years. 35 twenty treatments were administered over 8 weeks. the number of dry nights consistently increased when the children were reevaluated at 3 weeks, 3 months, and 6 months after treatment. five children had more than 90% reduction of wet nights at 6 months, and 65% had more dry nights at the 6-month follow-up. a recent teaching round at the china academy of traditional chinese medicine in beijing discussed successful acupuncture treatment of a complicated case of enuresis in a 16-year-old student who had previously failed both western and chinese medicines for his physical and emotional sequelae. 171 using tcm diagnosis of organ imbalances, the treatment combined body acupuncture, scalp acupuncture, and auricular acupressure seed. the patient began improving after three treatments in the first week. he received 3 more weeks of treatment, with no recurrence of enuresis at 6month follow-up. children are often unwilling to undergo needle acupuncture because of fear of pain, 61 prompting researchers to use noninvasive forms of acupuncture. simple acumassage has been previously reported to be beneficial to the enuretic child. 21 an austrian prospective, randomized trial evaluated efficacy of laser acupuncture versus desmopressin in 40 children over age 5 years with pne. 337 at 6-month follow-up, the desmopressin-treated group had 75% success rate with complete resolution of symptoms, an additional 10% had a more than 50% reduction in wet nights, and 20% did not respond. the laser acupuncture group had 65%, 10%, and 15% rates, respectively. the results were not statistically significant. therefore laser acupuncture should be considered as an alternative, noninvasive, painless, cost-effective, and short-term therapy in children with normal bladder function and high nighttime urine production. worldwide reports have demonstrated efficacy in treating enuresis with biofeedback, 164, 250, 318, 332 which aims at learning or relearning of influence of involuntary functions. 266 a clinical study from italy treated 16 boys and 27 girls ages 4 to 14 years with detrusor-sphincter dyssynergy. biofeedback was successful in all the children, with sne resolving significantly sooner than pne and girls responding better than boys. two-year follow-up still revealed an 87.18% success rate, with 80% at 4 years. 332 in a french study, 120 children with three predominant urinary disorders that included nocturnal enuresis were treated with biofeedback. detrusor-sphincter discoordination was diagnosed in 33 children. pelvic floor biofeedback produced excellent results in these children. 323 belgian investigators reported a clinical biofeedback study of 24 children with median age of 10.4 years who did not respond to anticholinergics. 164 seventeen subjects had complete resolution of enuresis, six had a decrease in symptoms, and one child did not respond. at 6-month follow-up, two children in the cured group had recurrence of enuresis. another study from belgium also reported success in using biofeedback in 26 children with pseudo-detrusor-sphincter dyssynergy; 17 were completely cured, and 5 improved considerably. 266 a spanish study used biofeedback to treat unstable detrusor in 65 enuretic children; complete disappearance of symptoms was seen in 70.5%, with improvement in 78.2%. 318 in a u.s. report of 8 boys and 33 girls ages 5 to 11 years who underwent an average of 6 hours of biofeedback for nocturnal and diurnal enuresis, improvement was noted in 90% of nocturnal enuresis and 89% of diurnal enuresis. 272 another u.s. clinical study used biofeedback for 21 children with dysfunctional voiding; 17 (81%) had an excellent response, 3 (14%) had a fair response, and 1 (5%) was too inconsistent to rate. 70 the average number of sessions to achieve a consistent urodynamic response was 3.7 (range 2 to 14). average follow-up was 34 months (range 14 to 51 months). the investigators recommended biofeedback as an effective method that requires only a short period for treating dysfunctional voiding. 70 all these worldwide studies were clinical reports, not randomized, controlled, blinded studies. the efficacy of chiropractic manipulation in enuresis has been inconsistent. one clinical report identified an 8-year-old boy with functional enuresis who had successful treatment with manipulation. 37 in an uncontrolled study of 175 children ages 4 to 15 years, with responses monitored by parents, chiropractic manipulation resulted in only 15.5% success. 234 however, a randomized, controlled clinical trial of 57 children demonstrated that 25% of the treatment group had 50% or more reduction in enuretic symptoms, although the pretreatment to posttreatment change in wet night frequency was not statistically significant, and there was no long-term follow-up. 341 a comprehensive review of the literature revealed that smt was no more effective than the natural regression of enuresis with age. 225 food allergy as a cause of enuresis has been in the literature for several decades. 106 a recent study of children with severe migraine or attention deficit disorder (add) included 21 children with enuresis. oligoantigenic diets were successful in curing 12 children and improving enuresis in 4 other children. relapse of wetting occurred when foods were reintroduced; the substances implicated most often were chocolate, citrus, fruits, and milk from cows. 281 although no studies are available on naturopathic approaches, which focus on natural remedies (e.g., corn silk and tea, tea and honey), physicians should not dismiss parental opinion that these remedies may be safe and effective. the future of treatment for enuresis should combine various methods to increase the probability of treatment success and minimize risk to the child. 281 atopic dermatitis affects almost 10% of all children 56 and 20% of children ages 3 to 11 years. 201, 202 it accounts for more than 30% of outpatient pediatric visits. 95 most children with atopic dermatitis typically come to medical attention with cradle cap and facial and extremity rashes by age 2 to 3 months. 95 despite considerable research, the etiology of allergic disease remains poorly understood. 16 allergic dermatitis can be thought of as an inherited skin "sensitivity" that reacts to various external allergens and changes in psychologic states. 357 food causes atopic dermatitis in 50% of infants, 20% to 30% of young children, and 10% to 15% of children after puberty. 395 topical steroids remain the main therapeutic method. dermatologists tend to prescribe antibiotics and use potent topical steroids, 343 which are more readily absorbed in children and can result in hypothalamic-pituitary-adrenal axis suppression. 179 new immune modulators have shown promise in severe atopic dermatitis. 149, 212 cam therapies are increasingly used for dermatitis, 127 although most of the information is in clinical reports, and research data are limited. a database review of 272 randomized clinical trials of atopic eczema covering at least 47 different interventions revealed that evidence is still insufficient to make recommendations on maternal allergen avoidance for disease prevention, herbs, dietary restrictions, homeopathy, massage therapy, hypnotherapy, or various topical cam therapies. 162 a multicenter randomized clinical trial conducted in 31 hospitals in the republic of belarus reported that breast-feeding significantly reduced the risk of atopic eczema compared with the control group in the first year of life. 228 psoriasis was found to worsen with cam treatments such as herbs, dietary manipulation, and vitamins. 116 dietary management with evening primrose oil, rich in gamma-linolenic acid, has been found to be inconsistently effective in small studies. fish oil supplements (enriched in n-3 polyunsaturated fatty acids) have also been used. 357 various herbs offer relief for eczema. 127 a placebo-controlled, double-blind trial used a chinese herbal prescription specifically formulated for widespread nonexudative atopic eczema. thirty-seven children were randomly assigned to 8-week active treatment and placebo, with an intervening 4-week "washout" period. the response to active treatment was significantly superior to placebo, without evidence of hematologic, renal, or hepatic toxicity. 373 the same investigators monitored the children over the following 12 months. eighteen children had at least a 90% reduction in eczema, and five showed lesser degrees of improvement. 374 two randomized, double-blind placebo-controlled trials from singapore revealed that a concoction of 10 chinese herbs was efficacious in the treatment of atopic dermatitis in both children and adults, and that the mechanism may be through the beneficial immunosuppressive effects. toxicity is a concern, however, because exact dosing of the active derivatives is difficult to achieve. 339 acupuncture treatment of acne has been reported to be successful 247 in as many as 91.3% of adolescents given treatment. 456 other tcm techniques have also been reported to be helpful. 57 a clinical trial treated 20 children with severe, resistant atopic dermatitis with hypnosis. 393 nineteen showed immediate improvement, 10 maintained improvement in itching, and 9 maintained improvement in sleep disturbance 18 months after treatment. homeopathy is frequently used to treat dermatitis. in one homeopathic clinic in israel, more than 80% of the patients expressed satisfaction with treatment. however, the authors of the survey believed that homeopathic medicine complements conventional medicine and is not an alternative. 316 chiropractic treatment has also been sought by children for allergic problems. 303 a small british study tested the hypothesis that massage with essential oils (aromatherapy) used as a complementary therapy in conjunction with normal medical treatment would help to alleviate the symptoms of childhood atopic eczema. 9 eight children were randomized into the treatment group, who were massaged with oil, and the control group, massaged without essential oil. no significant difference was found between the two groups. there was a later deterioration of eczema in the oil massage group, suggesting allergic contact dermatitis provoked by the essential oils themselves. attention deficit-hyperactivity disorder (adhd) is the most common neurodevelopmental disorder of childhood, with a prevalence rate between 2% and 11%, 373 averaging about 5%. 14, 371, 405 the road constellation of hyperactive, inattentive, and impulsive symptoms combined with the multiple comorbid conditions makes the definition and adhd controversial and the diagnosis flawed. 405 adhd is a chronic, heterogeneous condition with academic, social, and emotional ramifications for the school-age child. 371 the disabling symptoms persist into adolescence in approximately 85% of children and into adulthood in approximately 50%. 14, 32 there is a developmental pattern in the primary symptoms of the disorder; hyperactivity diminishes while attentional deficits persist or increase with age. 371 the precise etiology of adhd is still unknown, and assessment and management remain diverse. medication continues to be the mainstay of treatment, with methylphenidate (ritalin) the treatment of choice. 141 the tricyclic antidepressants were added as an alternative medication in the 1970s, 32 with clonidine, buspirone (buspar), and other antidepressants and neuroleptics added to the list in the 1980s. 55, 60 although it is generally agreed that drugs are beneficial on a short-term basis, there is a paucity of data on the long-term efficacy and safety of medications, especially in children younger than 3 years of age. these drugs have not been shown to produce long-term gains academically or socially. 90 besides pharmacotherapy, a multimodal approach using a combination of drugs and other methods, such as cognitive-behavioral therapy (cbt), psychotherapy, social skills training, and school interventions, is frequently prescribed for adhd. cbt represents the most widely used alternative to pharmacotherapy, although previous studies have shown disappointing results. 2, 3, 45, 177 in 1992 the national institutes of mental health (nimh) began a 14-month, multisite clinical trial, the multimodal treatment study of adhd (mta). 160, 189 the results indicated that high-quality medication management (with careful titration and follow-up) and a combination of medication and intensive behavioral therapy were substantially superior to behavioral therapy and community medication management. there is slight advantage of combination of medication and behavioral therapy over medication alone. psychotherapy can be an effective adjunct to medication 364,365 but usually requires a long-term commitment to several years of treatment. concerns about side effects of medication, 232,391 treatment acceptability, 27,334 and compliance are additional factors that complicate management of the adhd child. clearly, there is room to explore safe, acceptable, and relatively easy alternatives. interest is increasing in more natural, holistic integrative approaches to adhd. studies using cam therapy for treating adhd encompass more than the usual research difficulties because of the complexity and heterogeneity of the disorder, as well as subjective evaluation by parents and teachers of a wide range of 18 characteristics that may qualify for several different diagnoses. a majority of the cam therapies to date continue to have mostly anecdotal and empiric evidence. the few welldesigned studies include biofeedback, herbal medicines, dietary modifications or supplements, and acupuncture. 46 studies have demonstrated that there is a significant difference in baseline eeg measurements in children with attention deficit disorder (add) compared with normal-achieving preadolescent males. these differences occur mainly in the parietal region for on-task conditions 187 and in the cortex and corticothalamic excitatory and inhibitory interactions. 252, 255 biofeedback or neurofeedback is a technique for modifying neurophysiology for learning. 252 in 1991 a critical review of 36 studies in which biofeedback was used as a treatment for hyperactivity indicated that biofeedback alone had not been effectively evaluated, and methodologic problems limit generalizations that it may be applicable to the entire hyperactive population. 238 a 2001 review continues to indicate that although anecdotal and case reports cite promising evidence, methodologic problems coupled with a paucity of research preclude any definitive conclusions as to the efficacy of enhanced alpha and hemisphere-specific eeg biofeedback training. 340 some recent studies using more sophisticated technology claim that neurofeedback can improve attention, behavior, and intellectual function in the child with add, 49, 246, 253 with measurable eeg improvement in the frontal/central cortex. 295 its stabilizing effect has also been found to last as long as 10 years after treatment. 407 hypnotherapy and biofeedback do not appear to alter the core symptoms of adhd but may be helpful in controlling secondary symptoms. these methods allow children to become active agents of their own coping strategies. 26 a mailed questionnaire survey of 381 children with adhd with a 76% response rate reported that 69% were using stimulant medication and that 64% of the respondents used or were using a nonprescription therapy. diet therapies constitute the most common cam therapy (60%). 397 one review of cam therapy lends support to individualized dietary management and specific trace element supplementation in some children with adhd. 26 nutritional management of add includes elimination diet, megavitamins, 26,372 supplements, and trace element replacement. simple sugar restriction seems ineffective. 14 the well-known feingold diet eliminates natural salicylates, food colors, and artificial flavors. studies have demonstrated mixed results. 211 megavitamins were demonstrated to be ineffective in the management of add in a two-stage study with clinical trial and double-blind crossover. potential hepatotoxicity is a major concern with use of megavitamins. 152 in a recent longitudinal, nonrandomized clinical trial, 17 adhd children were given a glyconutritional product containing saccharides known to be important in healthy functioning and a phytonutritional product containing flash-dried fruits and vegetables. 93 five children were not receiving methylphenidate (ritalin), six children were taking prescribed doses of methylphenidate, and the remaining six children had their medications reduced by half after 2 weeks. the glyconutritional supplement was administered for the entire 6 weeks, and the phytonutritional supplement was added after 3 weeks. the teachers and parents rated behavioral items for adhd, oppositional defiant disorder, and conduct disorder. the conclusion was that the glyconutritional supplement decreased the number and severity of adhd, associated odd and cd symptoms, and side effects of medications during the first 2 weeks of the study; there was little further reduction with the addition of the phytonutritional supplement. the three groups did not differ statistically in degree or reduction of symptoms. 93 this 6-week study had too many variables and too few subjects without control for a definitive conclusion, although the concept of simple nutritional supplement is important to explore. there is increasing interest in abnormality of fatty acid metabolism as the etiology of at least some features of adhd. 344 these abnormalities can range from genetic abnormalities in the enzymes involved in phospholipid metabolism to symptoms that were reportedly improved after dietary supplementation with long-chain fatty acids. 436 in a randomized, double-blind, placebo-controlled trial of docosahexaenoic acid (dha) supplementation, 63 children ages 6 to 12 years receiving stimulant medication were randomly assigned to receive dha supplementation or placebo for 4 months. there was no significant improvement in the treatment group. 429 oligotherapy focuses on deficiency of trace elements in children with add. 221, 389 in a polish controlled clinical trial, magnesium deficiency was found in blood and in hair of hyperactive children. 390 fifty 7-to 12-year-old add children were given a magnesium supplement of 200 mg/day for 6 months while the control group of 25 children continued on their medical regimen. increase in magnesium contents in hair correlated with a significant decrease of hyperactivity in the treatment group, whereas hyperactivity actually intensified in the control group. the same investigators also found deficiencies of copper, zinc, calcium, and iron, with magnesium being the most common deficiency, in 116 children with adhd. 389 a thorough literature review of alternative treatments for adhd identified 24 cam therapies and reported that chinese herbal treatment has promising pilot data. 14 a clinical trial using chinese herbs in the treatment of 66 children with a diagnosis of hyperkinesia based on the american psychiatric association's diagnostic and statistical manual of mental disorders, ed 3 revised (dsm-iiir) criteria demonstrated 84.8% effectiveness in ameliorating hyperactivity and improved attention and school performance. 401 the herbal remedy was prepared according to the tcm diagnosis of common energetic (qi) imbalance found in these children. clinical observations were substantiated by laboratory findings of significant increase in urinary content of norepinephrine, dopamine, dihydroxyphenylacetic acid, cyclic adenosine monophosphate, and creatinine. 401 in a randomized study, chinese herbal treatment was found to be comparable to methylphenidate but had fewer side effects. 464 research is currently being conducted to investigate the efficacy of herbal and homeopathic remedies because current evidence is inconsistent or lacking. 26 in a prospective, randomized, double-blind pilot study funded by nih that integrated dsm-iv diagnostic criteria, conventional theories of frontal lobe dysfunction, and neurotransmitter abnormalities with traditional chinese theories of energetic imbalances, laser acupuncture was used in the treatment of adhd in 7-to 9-year-old children. 249 preliminary data on the six children in the treatment group showed promise in reducing signs and symptoms of adhd. using conners scale as a weekly follow-up measure, improvement in classroom behavior was reflected by substantial drops in the teachers' scores before and after treatment in five of six children. the parents' scores dropped in three children but did not change in the other three children (figures 11-1 and 11 -2). one child was promoted to the gifted program, and another demonstrated marked improvement in learning disabilities. there are no data at this time on homeopathic or chiropractic treatment of adhd, although many practitioners claim anecdotal success with the use of homeopathic desipramine (norpramin) and manipulation. pediatric use of cam therapies continues to increase. 385 it is therefore advisable for physicians who treat children to take a thorough history of cam use, especially in those with chronic disorders, to become knowledgeable about the various alternative therapies that can complement conventional care. this allows practitioners to consider possible adverse effects or interactions of cam with conventional therapy, to open lines of communication with cam providers, and even to consider integrating effective cam therapy into their medical regimen. although cam therapy is in general considered safe, there have been a few reports of significant side effects. 219, 271 continuous research is needed to investigate the safety and efficacy of cam therapies for children; to address explicitly the tremendous heterogeneity between and among the practices, beliefs, and providers of professional and lay services; and to study how cam may enhance the quality of mainstream health services. 208 although children are entitled to new therapies, pediatric research in cam is further complicated by children's vulnerability to violation of their personal rights and to risk exposure. 420 in children of the same age, varying cognitive capacity can be required for informed consent. 315, 353 differences in physiologic maturation can change the kinetics, end-organ responses, and toxicity of therapy, so data from adult studies cannot be extrapolated for children. 240 even in conventional medicine, children are often rendered "therapeutic orphans" 376 because of history of abuses in pediatric research, a heightened sensitivity to risks in children-especially since the thalidomide 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cases of bronchial asthma preliminary study of traditional chinese medicine treatment of minimal brain dysfunction: analysis of 100 cases clinical and experimental study on yifei jianshen mixture in preventing and treating infantile repetitive respiratory infection clinical investigation on massage for prevention and treatment of recurrent respiratory tract infection in children pneumococcal conjugate vaccine for young children prevention of asthma morbidity: recent advances key: cord-023712-nptuuixw authors: bower, john; mcbride, john t. title: bronchiolitis date: 2014-10-31 journal: mandell, douglas, and bennett's principles and practice of infectious diseases doi: 10.1016/b978-1-4557-4801-3.00068-0 sha: doc_id: 23712 cord_uid: nptuuixw nan with bronchiolitis we have to contend with illness that's now and disease that comes then; for many such infants a mold has been cast, perhaps by their unborn and unknown past, which destines that they shall in time wheeze again. for them this disease is the far, boding knell of vulnerable lungs to a microbe's dark spell. -caroline breese hall (1939-2013, the original author of much of this chapter and to whose memory it is dedicated) bronchiolitis is the most common acute viral lower respiratory tract illness occurring during the first 2 years of life. much interest and effort have been aimed at determining the pathogenesis and management of this illness among hospitalized and outpatient children. despite this, concerns and controversies continue. bronchiolitis has acquired during its long lineage a notable number of sobriquets, including "acute catarrhal bronchitis, " "interstitial bronchopneumonia, " "spastic bronchopneumonia, " "capillary or obstructive bronchitis, " and, more commonly, "wheezy bronchitis" and "asthmatic bronchiolitis. " the diversity of these terms is indicative of the past and ongoing confusion and difficulty in clinical differentiation of bronchiolitis from asthma and infectious asthma. these entities usually refer to repeated episodes of wheezing that may be triggered by infectious agents and tend to occur in children beyond infancy. the definition of bronchiolitis varies but usually applies to children younger than 2 years of age with a first episode of wheezing commonly associated with fever, cough, rhinorrhea, and tachypnea. 1,2 consensus does exist, however, that bronchiolitis continues to impose a major and increasing health care burden. bronchiolitis has been estimated to be the leading cause of all hospitalizations among infants in the united states. 3, 4, 5 etiology bronchiolitis was not recognized as a distinct entity until the 1940s and was initially thought to be caused by bacteria. 6, 7 viruses are now known to be the prime cause of the syndrome and the associated characteristic pathology of the lower respiratory tract. respiratory syncytial virus (rsv) is the major pathogen identified. the roles played by other viral agents are controversial and depend partly on the population being studied and the laboratory methods used for detection. correlation with disease is particularly problematic because viruses that commonly infect this young age group can cause high rates of asymptomatic infection or prolonged shedding, including adenoviruses and human bocavirus (hbov). in addition, some agents, such as rhinoviruses, may trigger asthmatic airway inflammation and bronchospasm without causing the small airway pathology characteristic of infection of the lower respiratory tract with bronchiolitis. rsv has been identified as the principal agent in two thirds of the cases of bronchiolitis, and in hospitalized patients the proportion is likely higher. 1, 8, 9 other viruses that commonly have been identified as single or coinfecting agents among children with bronchiolitis include human metapneumovirus (hmpv), the parainfluenza viruses, influenza viruses, rhinoviruses, human coronaviruses (hcov), and hbov (table 68-1) . among the parainfluenza viruses, parainfluenza virus types 1 and 3 are more commonly associated with bronchiolitis in hospitalized children than type 2. 10 illnesses with hmpv and rsv are generally indistinguishable, although lower respiratory tract illness with hmpv is usually less severe. [11] [12] [13] both rsv and hmpv occur from fall to spring, but activity of hmpv in the community is generally less intense. [11] [12] [13] hospitalized children with hmpv infection tend to be slightly older than children with rsv, and almost all children are infected with hmpv by 5 to 10 years of age. 12 influenza a and b viruses frequently cause lower respiratory tract disease among children younger than 2 years of age, but the proportion manifesting as bronchiolitis is less than that observed with rsv. [13] [14] [15] with the use of sensitive molecular techniques, additional viruses have been identified in young children with bronchiolitis including hcovs (see chapter 157) and hbov (see chapter 149). hcovs are composed of four different strains, including the novel strains hcov-nl63 and hcov-hku1, and have been identified in 7% of young children hospitalized with respiratory illness. 16 however, an equal percentage of asymptomatic children younger than 5 years of age have been observed to shed hcov. 16 the parvovirus hbov is increasingly being detected by reverse-transcriptase polymerase chain reaction (rt-pcr) in respiratory and fecal specimens from adults and children • diagnosis is clinically based on presence of rsv in the community, initial episode of wheezing, and evidence of upper respiratory infection. • other causes of wheezing in early childhood should be excluded, such as congenital heart disease with failure, foreign body aspiration, dysphagia, and asthma. • apnea may occur early in the course of viral bronchiolitis, usually in infants younger than 44 weeks' postconceptional age. • therapy is supportive and includes hydration, oxygen, and respiratory support as needed. • corticosteroids and bronchodilators are not generally beneficial. • hypertonic saline aerosols delivered three times daily may hasten recovery but have not been widely adopted. • respiratory support by high-flow nasal cannula may prevent or delay intubation in patients with apnea or respiratory failure. 26 despite the steady rates of hospitalization for bronchiolitis, the mortality rates associated with bronchiolitis have declined in the united states to fewer than 400 deaths per year. 3, 27 most deaths (79%) occur in infants younger than 1 year, primarily during the first several months of life. children with chronic conditions, especially conditions affecting cardiopulmonary function, are most likely to develop severe or fatal bronchiolitis. children with prematurity and the associated chronic lung disease have a fivefold increased risk of developing disease requiring hospitalization than children with no comorbid conditions. 3, 28, 29 multiple demographic, environmental, and biologic factors have been associated with increased rates of hospitalization among otherwise normal children. bronchiolitis is more common in boys, especially among children with more severe illness, with a male-to-female ratio of about 1.5 : 1. 30 other factors that have been associated with a greater likelihood of severe illness include young maternal age, lower cord blood antibody titers to rsv, lower socioeconomic status, tobacco smoke exposure, living in crowded surroundings, having older siblings, daycare attendance, lack of breast-feeding, a predisposition to atopy or hyperreactivity of the airway, and illness caused by rsv. 11, [31] [32] [33] infants with specific genotypes predicted to modify innate mucosal immunity are at greater risk of severe rsv infections. 34 a similar mechanism might explain the fact that certain ethnic groups of infants have higher rates of hospitalization for bronchiolitis. native american and native alaskan children have hospitalization rates two to three times higher than those of the general population of u.s. children of the same age. 35 nevertheless, the major independent risk factor for bronchiolitis requiring hospitalization is young age, within the first 6 months of life. 11, 33 pathophysiology in 1940, engle and newns 6 carefully described the pathology of a severe and often fatal lower respiratory tract disease they observed in young infants. they called this "proliferate mural bronchiolitis. " their findings of the generalized involvement of the respiratory epithelium of the small airways have been confirmed as being characteristic of infection-induced bronchiolitis among young children. the virus initially replicates in the epithelium of the upper respiratory tract, with subsequent spread within a few days to the lower tract airways ( fig. 68-1 ). early inflammation of the bronchial and bronchiolar epithelium occurs along with peribronchiolar infiltration, mostly with mononuclear cells, and edema of the submucosa and adventitia. the respiratory epithelium becomes necrotic and is sloughed into the lumina of the airways. subsequently, the epithelium proliferates and shows cuboidal cells without cilia ( fig. 68-2) . with a spectrum of upper and lower respiratory illnesses, including bronchiolitis. hbov has been reported as a sole pathogen in 1% to 6% of young children with bronchiolitis and as a coinfection in 6% to 20% of bronchiolitis cases. however, hbov is shed for prolonged periods and may be detected long after the clinical manifestations associated with acute infection have resolved. 8, 17, 18, 19, 20 viruses that are primarily agents of upper respiratory tract infections are also commonly identified in specimens obtained from children with bronchiolitis. notable among these are the picornaviruses (rhinoviruses and enteroviruses) and adenoviruses. the direct role of these viruses in causing bronchiolitis is uncertain because their high prevalence in this age group makes them common agents of dual infection. 8, 9 rhinoviruses, with more than 100 serotypes, are identified in 3% to 30% of children with bronchiolitis, and more than half the time they are present as coinfecting agents, most commonly with rsv. 8, 21 interpreting the role of rhinoviruses in children with bronchiolitis is complicated by the association of rhinovirus with episodes of wheezing from reactive airway or asthma exacerbations. 21 one group that appears to be at particular risk for severe lower respiratory tract infection due to human rhinoviruses are very-low-birth-weight infants. 22 enteroviruses have been identified in up to 7% of children hospitalized with bronchiolitis and are usually present as coinfecting viruses. 9 it remains uncertain whether dual viral infections increase the risk of developing more severe illness with bronchiolitis. 8, 9 studies examining whether hmpv coinfection is associated with more severe rsv lower respiratory tract disease suggest an increase in disease severity among hospitalized children, but this has not been consistently demonstrated. 9,23-25 bronchiolitis shows a yearly seasonal pattern that varies according to geography and climate. in temperate climates, the peak occurrence of cases is during the winter to early spring and usually correlates with the prevalence of rsv in the community. outbreaks of bronchiolitis are less distinctive in warmer and tropical climates where rsv occurs over longer periods. bronchiolitis cases in these areas may be seen throughout the year, and the prevalence of cases depends on the seasonal patterns of the known and yet unknown agents associated with bronchiolitis (see table 68 -1). bronchiolitis is most common during the first year of life, with the peak attack rate occurring between 1 and 10 months of age and among hospitalized cases between 2 and 5 months of age. each year, 1% to 3% of infants younger than 12 months of age are hospitalized with bronchiolitis; 80% are younger than 6 months of age. for the period 1997 to 2006, age-specific rates of hospitalization for bronchiolitis remained steady with an overall rate of 26 per 1000 children younger than 1 year of age and 48.9 per 1000 for infants younger than 3 months of age. 4,5 for children older than 1 year of age the rate was 1.8 per 1000. 4 overall, rsv disease accounts for up to 24% of hospitalizations among lethargy and poor feeding. retractions of the chest wall, flaring of the nasal alae, and grunting are evidence of increased work of breathing. the hallmark of bronchiolitis is the rapid variability of the child's respiratory signs. auscultatory findings may vary from only wheezing or crackles, to both, or to neither. decreasing lung sounds on auscultation associated with increasing dyspnea and diminished movement of air may indicate progressive obstruction and impending respiratory failure. dehydration commonly accompanies bronchiolitis, resulting from paroxysms of coughing, which may trigger vomiting, and from poor oral intake related to the child's respiratory distress and lethargy. tachypnea increases the fluid requirement further. of children hospitalized with bronchiolitis in the united kingdom, 82% on admission had feeding difficulties that lasted an average of 27 hours. 36 supplemental oxygen was administered at the time of admission to 22% of the children whose mean pulse oxygen saturation was 94%. within 6 hours of admission, 70% were given supplemental oxygen, although the mean pulse oxygen saturation level decreased an average of 2%. no correlation was observed between the pulse oxygen saturation level obtained at 6 hours and the administration of supplemental oxygen or the length of hospital stay. infants whose feeding difficulties resolved and who continued to be hospitalized for supplemental oxygen administration only had no evidence of clinical deterioration. considering that bronchiolitis is one of the most frequent causes of pediatric ambulatory visits and hospitalization, children at low risk for developing complicated illness have been evaluated to determine which children may be safely discharged home. among children younger than 2 years of age presenting with bronchiolitis at 30 u.s. emergency departments during 2004 to 2006, 57% were discharged to home. 37 characteristics of the children whose home discharge was safe included age 2 months or older, a history of eczema, respiratory rates inflammatory changes of variable severity are observed in most small bronchi and bronchioles. because resistance to airflow is related inversely to the cube of the radius of the airway, the inflammation and edema make the lumina of small airways in infants particularly vulnerable to obstruction (see fig. 68-1) . plugs of necrotic material and fibrin may completely or partially obstruct the small airways. smooth muscle constriction does not seem to be a major factor in the obstruction. in areas peripheral to sites of partial obstruction, air becomes trapped by a process similar to a "ball-valve" mechanism. negative intrapleural pressure exerted during inspiration allows air to flow beyond the point of partial obstruction. on expiration, however, the size of the lumen decreases, resulting in obstruction and gas trapping. in areas peripheral to obstruction, trapped air is eventually absorbed, which results in multiple areas of atelectasis. this absorptive atelectasis is accelerated when a child breathes high concentrations of oxygen, which is absorbed into the blood much faster than nitrogen. the degree of atelectasis or hyperinflation that develops is greater in infants than it would be in older children or adults because collateral channels that maintain alveolar expansion in the presence of airway obstruction are not well developed early in life. the physiologic correlates of airway obstruction are dyspnea, tachypnea, a diminished tidal volume, and a diminished ratio of ventilation to perfusion resulting first in arterial hypoxemia. when an infant is no longer able to compensate for the disordered gas exchange by increasing ventilation, hypercarbia may ensue. the pathologic process may progress to involve the alveolar walls and spaces, producing an interstitial pneumonitis. recovery tends to be slow, requiring several weeks. bronchiolitis commonly has a prodrome of several days that is marked by upper respiratory tract signs, especially coryza, cough, and fever, which is usually mild. lower respiratory tract involvement may be signaled by the development of a prominent cough, followed by an increased respiratory rate, and nonspecific systemic symptoms such as a b management of bronchiolitis. 2 complete blood cell count values vary in children with bronchiolitis and have not been shown to be helpful in determining the diagnosis or therapy of bronchiolitis. 2 additional diagnostic procedures should be reserved for children whose history, findings, or clinical course are not as expected. although rapid diagnostic testing is generally unnecessary, it may be useful at times for implementing appropriate infection control, monitoring seasonal patterns of respiratory pathogens, restricting antimicrobial use, or providing confirmation of the diagnosis in children with unusual clinical presentations or severe disease. timely diagnosis of specific viral respiratory pathogens may occasionally be necessary to guide specific antiviral therapy in children with high-risk conditions or severe illness with influenza or rsv. rapid diagnostic approaches to identifying the common viral agents of bronchiolitis include tissue culture, antigen detection, and pcr. nasopharyngeal washes provide the most appropriate specimen. when available, tissue culture by shell vial technique can provide positive culture results within several days. rapid antigen detection includes direct and indirect immunofluorescent assays, optical immunoassays, and enzyme immunoassays. these rapid viral antigen techniques are most commonly used because of their ease, cost, and availability of results within hours. 52 rapid real-time pcr testing is becoming increasingly available for the simultaneous diagnosis of multiple respiratory viruses and is capable of high sensitivity and specificity, as well as short turnaround times. 53 the positive predictive value of all these viral assays significantly diminishes when the prevalence of the agent, such as rsv or influenza, is low in the community. serologic tests to determine the etiologic agent are rarely helpful in clinical management and may be difficult to interpret because a young infant would have maternally acquired antibody to many of the viral agents of bronchiolitis. the differentiation of wheezing caused by rsv infection from wheezing caused by many other mechanisms in infants is challenging because rsv occurs in epidemics. during the height of the epidemic, it is tempting to assume that rsv is the culprit in any wheezing infant. the differential diagnosis of wheezing in an infant is broad and requires a careful history and examination. 54 congestive heart failure is most important to consider because infants with left-to-right shunt are likely to become symptomatic and present with tachypnea and wheezing at around 8 to 10 weeks of age. gastric reflux and aspiration may produce a picture that is indistinguishable clinically from acute bronchiolitis. an asthma exacerbation precipitated by a viral infection is possible, particularly in infants with a strong family history of asthma. other considerations include foreign body aspiration, vascular ring, cystic fibrosis, and immunodeficiency. supportive care is the mainstay of therapy for outpatient and inpatient children. guidelines for care have been published and updated. 2 at home, care is aimed primarily at comfort, maintaining adequate hydration, and treating fever if necessary. 2,55 young children, especially infants, are particularly compromised by a respiratory rate of 60 or greater per minute and by the increased nasal congestion and mucus production in the lower respiratory tract. these may result in diminished fluid intake, inability to sleep, increased work of breathing, and the risk of requiring assisted ventilation. clearance of secretions by administering chest percussion or deep pharyngeal and tracheal suctioning has been ineffective in the management of bronchiolitis and is not advised. 2 among more severely ill children with hypoxemia, supplemental oxygen administration may be of prime importance. the spo 2 level at which supplemental oxygen should be administered is not well defined, however, and is controversial. although spo 2 levels of 90% to 95% on room air have been commonly used, the american academy of pediatrics has advised for previously healthy infants that supplemental oxygen should be initiated when persistent measurements of spo 2 levels less than 90% are obtained. 2 in fact, the use of pulse oximetry in previously healthy children without signs of respiratory distress has not been associated with a better clinical outcome but has led to increased use of medical services and cost and is not routinely recommended. 2 other factors than just the spo 2 level should be considered in the that were below normal for age, oxygen saturation levels 94% or greater, no or mild chest wall retractions, fewer treatments with bronchodilators during the first hour, and adequate oral intake. the acute course of bronchiolitis typically lasts 3 to 7 days. a minority of children with rsv lower respiratory infection presents with critical hypoxemia, apnea, or respiratory failure and immediately requires intensive care. most children admitted to the hospital are less severely affected, and relatively few of them deteriorate dramatically after admission. in one study, less than 2% of previously healthy children admitted to the regular floor for rsv infection subsequently required intensive care. 38 most infants improve within 3 to 4 days, with a gradual recovery period of 1 to 2 weeks, but cough may persist longer. the median duration of illness in one study of ambulatory children with bronchiolitis was 12 days. after 3 weeks, 18% remained symptomatic, and after 4 weeks, 9% were still ill. 39 gender, weight, or respiratory rate was not predictive of longer illness. complications associated with bronchiolitis occur most frequently in infants within the first several months of life, in premature infants, and in children with chronic cardiac, pulmonary, and immunodeficiency diseases. 3, [27] [28] [29] the most serious complication is progression to respiratory failure. although the risk of respiratory failure is relatively low for most children with rsv bronchiolitis, a small number of severely affected infants will require assisted ventilation in most intensive care units each year. intubation and ventilation are usually indicated by recurrent severe apnea or hypercapnic/hypoxemic respiratory failure. apnea, one of the most frequent acute complications, occurs in 3% to 21% of infants. [40] [41] [42] apnea typically is the presenting manifestation, occurring after several days of respiratory symptoms that may be so mild as to go unnoticed. infants who present with apnea are at risk of developing severe lower respiratory disease even as the apnea typically resolves within a day or two. apnea is most likely to occur in premature infants and in infants within the first 2 months of life (e.g., infants who are younger than 44 weeks' postconceptional age). the apnea does not seem to be obstructive, generally has a good prognosis, and is not associated with an increased risk of sudden infant death syndrome subsequently. aspiration has been shown to be a frequent complication in infants hospitalized with rsv bronchiolitis. 43, 44 it is possible that infants with preexisting dysphagia are at increased risk of severe bronchiolitis with rsv infection, so this may represent association rather than causation. secondary bacterial infections complicating bronchiolitis are uncommon, and concurrent bacterial infections occur in 0% to 7% of bronchiolitis cases. 28, [45] [46] [47] [48] concurrent bacterial infections most frequently are urinary tract infections, unrelated to the bronchiolitis. bacterial coinfections have been less common in children with bronchiolitis than in control children without bronchiolitis. the most frequent clinical association observed in infants hospitalized with bronchiolitis is subsequent episodes of recurrent wheezing, estimated to occur in 30% to 50% of infants hospitalized with bronchiolitis. the pathogenesis of this link is unclear (see chapter 160). controversy continues over the extent to which this association is explained by a genetic predisposition to both severe rsv disease and subsequent wheezing or by an effect of rsv infection itself. 49 nevertheless, the prognosis for most children with recurrent episodes of wheezing during early childhood is good. among most children, the episodes diminish or disappear before reaching the teenage years. 50,51 the diagnosis of bronchiolitis may be made for most children on the basis of the characteristic clinical and epidemiologic findings. these include the acute onset of the typical constellation of respiratory tract findings of cough, wheezing, and increasing respiratory effort after an upper respiratory tract prodrome, particularly during the winter respiratory season, in a child younger than 2 years of age. 2 laboratory and radiologic studies are unnecessary for diagnosis; they do not change the outcome for most children and are not routinely recommended. the assessment of the severity of the bronchiolitis should also be based on the child's history and physical examination according to the american academy of pediatrics' guidelines on the diagnosis and times a day) has been shown to result in more rapid clinical improvement and shortened length of stay in infants with rsv bronchiolitis without evidence of side effects. 62 nevertheless, this therapy has not been universally adopted because several studies have been unable to show benefit and because of the theoretical but unsubstantiated concern that the hypertonic saline aerosol might induce bronchospasm in infants with asthma. ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide), a synthetic nucleoside, is available for aerosol treatment for rsv bronchiolitis among hospitalized infants. the drug is not recommended routinely, however, and should be considered only for infants with severe disease at high risk of severe illness (see chapters 44 and 160). 2 several approaches are used to provide direct respiratory support for the small number of young infants or those with underlying abnormalities who develop life-threatening apnea or respiratory failure during an episode of bronchiolitis. noninvasive approaches that have been used to avoid intubation include continuous positive airway pressure, heliox, and high-flow nasal cannula therapy (hfnc). [63] [64] [65] the first two have not been consistently shown to be adequately beneficial to justify the challenge of administration. hfnc, however, may be effective in preventing or delaying the need for intubation. 66, 67 prevention prevention of the clinical entity of bronchiolitis is a goal unlikely to be reached in the near future because of its multiple etiologies and varying pathogenesis. for prevention of bronchiolitis associated with primary rsv infection, prophylactic administration of humanized monoclonal antibodies directed against the rsv f protein has been effective in reducing the rate of rsv hospitalization among high-risk infants who are premature and have comorbid conditions affecting cardiopulmonary function (see chapter 160). 29, 68 the mainstay of preventing bronchiolitis remains the interruption of the spread of the infectious agent to infants and to the young age group of children who develop bronchiolitis. preventing contact of the child with individuals who have signs of illness may be helpful, but many individuals may have infection that is asymptomatic or mild enough that it is unrecognized. multiple infection-control procedures are recommended for rsv and other agents of bronchiolitis, but among these the most effective, whether in the hospital or home, are good hand hygiene and education of personnel and families (see chapter 160). decision to administer supplemental oxygen. additional risk factors to consider include underlying chronic conditions, poor feeding, clinical respiratory distress, fever, and acidosis, which may shift the oxyhemoglobin association curve such that appreciably lower levels of pao 2 may occur at spo 2 levels greater than 90%. therapeutic agents most frequently used for rsv bronchiolitis include bronchodilators, corticosteroids, and antibiotics. of infants hospitalized with rsv infection in north america, europe, and australia, 75% to 80% were treated with bronchodilating agents, 10% to 40% were treated with corticosteroids, and 15% to 40% were treated with intravenous antibiotics. 56 multiple studies have shown these therapies as inconsistently effective, and none is routinely recommended. 2 a cochrane review of the use of bronchodilators for bronchiolitis concluded that the limited transient improvement using various clinical scoring systems observed was associated with questionable clinical benefit. 57 a subsequent review of the evidence by the american academy of pediatrics reached a similar conclusion and recommendation against the routine use of bronchodilators for infants with initial episodes of wheezing. 2 the addition of anticholinergic medications to the therapeutic regimen has not been shown to improve the course of viral bronchiolitis. these recommendations may not apply to children who have had recurrent wheezing before the episode of viral bronchiolitis. multiple trials have examined the use of nebulized, oral, and parenteral corticosteroid medications among children with bronchiolitis. most of these trials have not included specific viral identification and are heterogeneous in design and in the populations included. reviews that analyzed the randomized and controlled trials concluded that the evidence was insufficient to recommend routine use of these medications for bronchiolitis. [58] [59] [60] a subsequent large, placebo-controlled trial of oral dexamethasone therapy was conducted in 20 emergency departments over three rsv seasons among 608 children 2 to 12 months old with their first episode of wheezing. administration of a single oral dose of 1 mg/kg of dexamethasone had no effect on the subsequent rate of hospitalization or the clinical assessment score, even among children with a family history of asthma. 61 review of this and the previous studies resulted in the current recommendation that corticosteroid medications should not be used routinely in the management of bronchiolitis. 2 nebulized hypertonic saline (most commonly 3 ml of 3% saline combined with a bronchodilator delivered by jet nebulization three the complete reference list is available online at expert consult. acute bronchiolitis diagnosis and management of bronchiolitis recent trends in severe respiratory syncytial virus (rsv) among us infants respiratory syncytial virus−associated 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prevention of serious rsv disease in high risk infants key: cord-016130-5q9ufu28 authors: linday, linda a. title: nutritional supplements and upper respiratory tract illnesses in young children in the united states date: 2010-12-17 journal: preventive nutrition doi: 10.1007/978-1-59259-880-9_21 sha: doc_id: 16130 cord_uid: 5q9ufu28 key points: in the united states, children have lower blood levels than adults of eicosapentaenoic acid (epa), an important ω-3 fatty acid that helps decrease inflammation; vitamin a, the “anti-infective” vitamin; and selenium (se), a trace metal that is an intrinsic part of glutathione peroxidase, an important free-radical scavenging enzyme. epa, vitamin a, and se are important in controlling inflammation and can be supplied by oral nutritional supplements. cod liver oil contains epa (and other important ω-3 fatty acids), and vitamin a as well as vitamin d. fish oil contains ω-3 fatty acids (including epa) but no vitamins. our clinical research demonstrates that daily supplementation with a flavored cod liver oil (which meets european purity standards) and a children’s multivitamin-mineral with trace metals, including se, can decrease morbidity from upper respiratory tract illnesses, otitis media, and sinusitis in young children living in the united states. these supplements can be used by practitioners on an individual basis, when clinically indicated; the supplements can be purchased in the united states without a prescription. socioeconomically disadvantaged children are at risk for micronutrient deficiencies. however, their families may not be able to afford to purchase these supplements, which are not available through medicaid, the special supplemental nutrition program for women, infants and children, or the food stamp program. if our results are confirmed in larger studies, a system change will be needed to provide these supplements to nutritionally vulnerable, socioeconomically disadvantaged children living in the united states. key element in the pathophysiology of these disorders. this chapter discusses the role of essential fatty acids, vitamins, and trace metals in the pathophysiology of inflammation; reviews our clinical research on the use of a lemon-flavored cod liver oil (which meets european purity standards) and a children's chewable multivitamin-mineral with se for the prevention and adjunctive treatment of these disorders; reviews the history of cod liver oil, including its importance in the discovery of vitamin d and the anti-infective properties of vitamin a; and discusses the current clinical use of these supplements. if additional research confirms the utility of these supplements in improving the health of young children, the problem of access to these supplements by socioeconomically disadvantaged children in the united states will need to be addressed. children under age 5 yr had an average of 20.7 million ambulatory care visits per year for upper respiratory conditions in the united states from 1993 to 1995, with another 14.5 million visits per year for om during the same time period (1) . in addition to their cost, unnecessary health care visits for the treatment of colds generate a significant number of inappropriate antibiotic prescriptions (2, 3) , although the situation is now improving (4, 5) . bacterial antibiotic resistance is considered to be a major public health problem in the united states, and an interagency federal action plan has identified the decrease of unnecessary antibiotic prescriptions as critical to combating antimicrobial resistance (6) . in 1996, gates (7) estimated that the total annual cost of treating om with effusion in the united states was $5 billion, including both direct and indirect costs. this estimate included the cost of surgical placement of tympanostomy tubes (ventilation tubes placed in the tympanic membrane of the ear), a procedure that is commonly performed for the treatment of this disorder (8) . frequent om with effusion in early childhood may be associated with later speech and language problems, although causative relationships have not been definitively established (9, 10) . sinusitis also is a common and costly condition (11) ; in 1996, overall health care expenditures for sinusitis in the united states were estimated to be $5.8 billion, of which $1.8 billion was for children age 12 yr or younger. the primary treatment of sinusitis in children is medical management. adenoidectomy may be helpful (12) , although endoscopic sinus surgery is reserved for chronic, refractory cases (13, 14) . chronic sinusitis has a major negative impact on the quality of life of children whose disease is sufficiently severe to require endoscopic sinus surgery (15). viral illnesses usually are brief and self-limited conditions. however, viral infections produce inflammation, enhance nasopharyngeal bacterial colonization and adherence, alter the host's immune defenses, and are associated with bacterial complications, including acute om (16) , sinusitis, and pneumonia (17, 18) . acute om occurs in about 20% of children with viral upper respiratory infections (17) . although viral vaccines are in development, the use of vaccines to prevent upper respiratory tract infections is hampered by the large number of different viruses causing these infections (17) . the us advisory committee on immunization practices voted to recommend influenza vaccination for children ages 6 to 23 mo for the coming influenza season of 2004 to 2005; the impact of this recommendation remains to be seen (19) . despite the fact that streptococcus pneumoniae is the most common cause of bacterial acute om, the heptavalent pneumococcal polysaccharide conjugate vaccine only produced a 6% reduction in the overall number of episodes of acute om from any cause (20) . of inflammatory eicosanoids (29) . the level of ω-3 fatty acids and other pufas is largely determined by diet, unlike proteins, whose structure is genetically determined (26, 30) . changes in dietary habits in the united states in the last 20 to 30 yr have markedly increased the amount of ω-6 efa consumed (as in vegetable oils), whereas the amount of consumed ω-3 efa (as in cod liver oil and fish oil) has decreased (26, 31, 32) . the optimal ratio of ω-6/ω-3 efa in the diet is 3 to 4:1; in the united states, it is currently 10 to 20:1. this abnormal ratio has been linked with numerous disease states, especially those associated with inflammation. ω-3 fatty acid levels can be increased by eating more fatty fish and by consuming nutritional supplements such as cod liver oil, algalderived long-chain fatty acids, or fish oils (26, 31, 32) . free radical-induced lipid peroxidation may play a role in the acute (33) (34) (35) and chronic inflammation (36) of a guinea pig model of acute, unilateral om caused by infection with s. pneumoniae. inflammatory mediators have been demonstrated in both experimental and human middle ear effusions; these mediators include leukotrienes and prostaglandins, which are metabolites of aa and are derived from phospholipids in cell membranes. treatment with specific inhibitors of these mediators has prevented the development of om in some animal models of om (37) . free radicals are significant components of the inflammatory response, which is part of the pathophysiology of pneumococcal infections (38) and the influenza a virus (39) ; the latter are important causes of om. reactive oxygen species (ros) (40) have also been implicated in sinusitis. the association between respiratory virus infections and acute om in children is well-established (41, 42) . oral supplementation with efas (43) and zinc (44) has been shown to decrease the incidence of respiratory infections in children. trace elements (including zinc and se) have been shown to have important effects on the regulation of immune responses (45) . supplementation with ω-3 fatty acids has been reported to be beneficial in preventing infection in surgical patients (46) . the importance of ω-3 fatty acids and trace metals (including zinc and se) is already recognized in the relatively new field of "immunonutrition" (47) (48) (49) . the clinical efficacy of antioxidants in the treatment of om has been reported by two groups of russian investigators (50, 51) . of interest is the work of ginsburg (52) , who proposed that the main cause of tissue damage in infectious and inflammatory conditions is synergistic interactions among ros, microbial hemolysins, enzymes, and cytokines. antibiotics may have anti-inflammatory actions in additional to their antibacterial effects (53, 54) . macrolide antibiotics, effective in the treatment of adults with chronic rhinosinusitis (55) , have anti-inflammatory properties that contribute to this effect. however, the overuse of antibiotics is associated with the development of bacterial antibiotic resistance. in finland, the prevalence of macrolide-resistant group a streptococci diminished after the heavy use of macrolide antibiotics decreased (56) . in this age of antibiotic resistance, it is preferable to use antibiotics for their antibacterial effects rather than as anti-inflammatory agents. in our first study (57) , we obtained blood samples from 44 children undergoing clinically indicated ambulatory surgery at the new york eye & ear infirmary (nyee). there were 39 subjects in the tympanostomy tube group (tt); these children were undergoing placement of tympanostomy tubes for frequent ear infections and/or persistent middle ear effusion, with or without concomitant adenoidectomy and/or tonsillectomy. their mean (± standard deviation [sd]) age was 3.8 ± 1.8 yr; 72% were male; approximately half were hispanic and half were white; approximately half were private patients; and almost half were taking vitamin supplements. the comparison group (comp) was composed of children undergoing eye-muscle surgery as well as those undergoing ear, nose, and throat procedures such as bronchoscopy or laryngoscopy that did not involve the ears, adenoids, or tonsils. these subjects were slightly older, with a mean age of 5.7 ± 1.8 yr, and there was a lower percentage (20%) of private patients. no demographical information was available for the six adults in the adult control group (ac), supplied by ann moser of the peroxisomal disease section of the kennedy krieger institute genetics laboratory (baltimore, maryland). data regarding red blood cell (rbc) fatty acids, trace metals, and vitamin a were available for subsets of these subjects. the rbc fatty acid data are summarized in table 1 . the mean values for epa were lower in both groups of nyee children than in the acs supplied by kennedy krieger. the mean rbc epa values were: (a) tt = 0.31% ± 0.02% (standard error [se]), (n = 16); (b) comp = 0.31% ± 0.04% (se), (n = 5); and (c) ac = 0.48% ± 0.4% (se), (n = 6). these differences were statistically significant when analyzed by both parametric (anova, p < 0.002; f[2,24] = 8.336) and nonparametric (kruskal-wallis anova by ranks, p = 0.007; h[2, n = 27] = 9.924) tests. no other significant differences in rbc fatty acids were noted among the three groups, although additional differences might become apparent with larger sample sizes. in 1986, japanese investigators reported lower plasma levels of ω-3 fatty acids in young normal and atopic children than in adults (58) . they ascribed these findings to dietary changes in japan in the 30 yr prior to the study. data for plasma se, zinc, and copper for the children in the tt group are summarized in table 2 ; data from the published literature for children (59) and adults (25) for these parameters is also included, as are international system units. there was no statistically significant difference between the mean plasma se for study subjects (tt = 110 ng/ml ± 16.3 sd; n = 39) and the published values for children. both groups of children had lower se levels than published values for adults (p < 0.005, anova; f = 20.442; f[0.005] 3140 = 4.47) (60). statistical analyses were performed only for se because only the variances for se were homogeneous (bartlett's test for homogeneity of variances (60). the mean plasma vitamin a (retinol) level for the tt group was 39.1 μg/dl ± 10.8 (sd); (range: 23.6-72.1 μg/dl; n = 39). (multiply conventional units by 0.0349 to convert to international units [61] ). ballew (62) defined an inadequate vitamin a level as less than 20 μg/dl and a suboptimal vitamin a level as less than 30 μg/dl. the upper limit of the pediatric reference range for vitamin a is 80 μg/dl (61) . therefore, overall, the values for our subjects were within the reference range. russell (63) stated that a vitamin a level of 40 μg/dl predicted normal dark adaptation 95% of the time; 69% (27/39) of our subjects had vitamin a levels less than or equal to 40 μg/dl, although parents denied symptoms of night blindness for all children. our finding is consistent with ballew's (62) report that the 75th percentile for serum retinol levels in children ages 4 to 8 yr was 39.0 μg/dl. in addition, 15% (6/39) of our sample had suboptimal levels (<30 μg/dl), although none were inadequate (62) . in this suboptimal group, five of six children were not taking vitamin supplements, five of six children were hispanic, five of six children were general service patients, and four of six children were female (all of whom were hispanic). the overrepresentation of hispanic children in the subgroup of children with suboptimal vitamin a levels was also consistent with previous reports (62) . on a group basis, there was no statistically significant difference in the mean vitamin a levels between the subgroup of children whose families reported that they were taking vitamin supplements (39.7 μg/dl ± 11.6 sd; n = 17) and the subgroup of children whose families reported that they were not taking vitamin supplements (38.7 μg/dl ± 10.4 sd; n = 22). our subjects took a variety of prescription and over-the-counter vitamin preparations; no children were receiving or had taken cod liver oil; only one child in the fatty acid subgroup had a history of fish oil ingestion. of the eight different children's vitamin preparations examined, all contained vitamin a palmitate, vitamin a acetate, and/or β-carotene. the blood-level data (57) revealed that (a) study children had lower levels of rbc epa than adult controls; (b) 69% of study children had plasma vitamin a (retinol) levels in the lower reference range, with 15% in the suboptimal range; and (c) study subjects, like other children, had lower levels of plasma se than adults. therefore, for our clinical studies, we chose cod liver oil as a source of both vitamin a and epa and used it in conjunction with a marketed children's chewable multivitamin/mineral preparation containing se. we specifically chose cod liver oil as a source of vitamin a on the basis of our blood-level data, which revealed no significant difference in the vitamin a levels between the subgroups of children who were taking vitamin supplements and those who were not. although we could have used fish oil as the source of epa, fish oil does not contain vitamin a or d. the detailed contents of these supplements are shown in table 3 . the vitamin a content of cod liver oil used in our initial pilot study on om was 2000 to 2500 iu/teaspoon (5 ml); in the subsequent two studies, the vitamin a content was decreased to 1000 to 1250 iu/5 ml. to explore the clinical utility of these supplements, we then performed an open-label secondary prevention study, in which each child served as his or her own control (64) . we studied one om season, from september 1, 2000 to march 31, 2001 (57) . all children were patients of the soho pediatrics group, a private group practice in lower manhattan, new york. children were required to have had at least one episode of om from september 1 to november 30, 2000 (the early portion of om season under consideration). children with a known allergy to fish were excluded. eight children were enrolled, ranging in age from 0.8 to 4.4 yr; seven were caucasian, half were female, and all families were english-speaking. after enrollment, subjects received 1 teaspoon of lemon-flavored norwegian cod liver oil and one-half of a tablet of carlson's scooter rabbit chewable multivitamin-mineral (mvm) tablet per day (see table 3 ). mothers were instructed to crush the mvm tablet, measure the cod liver oil, and mix both in a small amount of food (such as applesauce, yogurt, or rice cereal) to administer the supplements to their children. parents were informed verbally and in writing that supplements were to be given only in the amounts required by the study and that study supplements were to be kept out of reach of children. of the eight children who entered the study, one could not tolerate the taste of cod liver oil. the remaining seven children received antibiotics for om for 12.3 ± 13.4 (p < 0.05; mean ± sd) fewer days during supplementation than before supplementation during the om season under study (see fig. 1 ). five of seven subjects had no additional episodes of om during supplementation, although it had no apparent effect on established serous middle ear effusions in two children. however, because our study lacked a randomized, parallel control group, we could not exclude the possibility that the decreased antibiotic usage we found might have occurred without the use of study supplements. based on our prior research (discussed in ref. 57 ) and the historical studies on cod liver oil and upper respiratory illnesses (65), we hypothesized that use of the study supplements by young children would decrease their doctor visits for upper respiratory illnesses during the late fall, winter, and early spring. we studied the effect of daily use of these supplements on the number of pediatric visits by young, inner-city, latino children from late autumn 2002 to early spring 2003 (83). we did not have a matched placebo for liquid cod liver oil. although adults and older children can swallow capsules, infants and toddlers cannot. furthermore, if capsules were cut open to administer the contents, the distinctive odor and taste of cod liver oil would immediately become apparent (57) . the absence of a matching placebo for liquid cod liver oil precluded our performing a classical double-blind, placebo-controlled study. lack of a placebo coupled with the fact that cod liver oil can be purchased without a prescription by interested parties (57, 66) led us to choose a study design in which we randomized pediatric sites, rather than individual patients. this type of design has been used in the worldwide studies of vitamin a supplementation, which are discussed in subheading section 5.3, that have included randomization by ward, household, village, or district (67) . it was also used in a food-consumption study to avoid changes in food habits resulting from knowledge of the other treatment (68) . randomized site design is commonly used in behavioral and educational studies where no placebo is possible (69) (70) (71) (72) ; a recent study of herd immunity and the pediatric heptavalent pneumococcal vaccine also used a randomized site design (73) . to minimize the influence of the study on the behavior of the participating families (69), we used a "no-contact" control group (74, 75) , which has also been used in behavioral and educational studies. the study was performed at pediatrics 2000, a multisite, private, pediatric group practice in new york city. two of the offices with similar demographics (low-income latino families), located 1.1 miles apart in upper manhattan, were randomized to a supplementation site and a medical records control site. study participants were children ages 6 mo to 5 yr of either gender and any race, religion, or nationality who were patients enrolled at the two offices where the study was being performed. study participants were required to be in new york city from enrollment through april 2003 (with the exception of brief vacations), and to have some type of medical insurance. patients who routinely received additional health care at other practices or medical centers were excluded; children with known fish allergy, a chronic, life-threatening condition (such as hiv/aids or cancer), feeding disorders, and epilepsy were also excluded. study materials were available in both english and spanish. per practice routine, two professional coders reviewed all charts from both sites, coded the visits, and entered the data into a computer with ndc medisoft™ network professional 7.02 software (76) . participants in the medical records control group were enrolled from october 21 to november 10, 2002; those in the supplementation group were enrolled from november 11 to december 12, 2002. we were unable to randomize enrollment at the two sites because the lemon-flavored cod liver oil used in the study (which was manufactured in norway) had been reformulated with less vitamin a (77) and was delayed in the us customs office. the study follow-up/supplementation period ended on may 1, 2003. a total of 94 children (47 at each site) were enrolled in the study. the mean age of the supplementation group was 2.03 yr (±1.04 sd), and the mean age of the control group was 2.08 yr (±1.10 sd). there were no statistically significant differences in the demographical characteristics of the study participants in the two groups: most were latino children from low-income families (as indicated by health insurance), and their mothers were predominantly unmarried immigrants from the dominican republic whose first language was spanish. children of at least 1 yr of age received 1 teaspoon of carlson's lemon-flavored cod liver oil per day and one-half tablet of carlson's scooter rabbit chewable mvm, the same doses used in our previous research administered in the same manner (57) . however, the vitamin a content of the cod liver oil was approximately half that used in our first pilot study of om (see table 3 ). thus, the full dose of supplements provided a total of 3750 iu of vitamin a and 700 iu of vitamin d per day. however, in the current study, the starting dose of supplements was halved for children ages 6 mo to 1 yr .visits were classified as upper respiratory visits, other illness visits, or visits not analyzed on the basis of the icd-9 visit code (78) . the primary outcome measure was upper respiratory visits during the follow-up/supplementation period; other illness visits during the same time period were considered as secondary outcome measures. as shown in figs. 2 and 3 and table 4 , the supplementation group had a statistically significant decrease in the mean number of upper respiratory visits over the course of the follow-up/supplementation period (p = 0.042; r = 0.893; r 2 = 0.797; y = 0.602 −0.002x), whereas the medical records control group had no change in this parameter (p = 0.999; r = 0.0006; r 2 = 0.0000; y = 0.259 + 1.43 × 10 -6 x). there was no statistically significant change in the mean number of other illness visits for either study group during the same time period. although there was a significant difference in the pattern of decreasing upper respiratory visits over time in the supplementation group, there was no difference in the total number of visits made by the two groups. data were analyzed on an intention-to-treat basis. as reported by their parents, 70% of our subjects completed a 5-to 6-mo course of lemon-flavored cod liver oil. by comparison, only 47% of families reported compliance with antibiotic prophylaxis for om in a study of latino children who attended an otolaryngology clinic (79) . our favorable compliance rates may partly result from the fact that young children in the dominican republic are often given cod liver oil or similar supplements, although families rarely continue this practice after moving to the united states. inflammation and edema of the sinonasal mucosa are important in the pathophysiology of sinusitis. based on our previous research and the similarities between om and sinusitis (80), we hypothesized that these nutritional supplements would also be effective adjunctive therapy for the treatment of children with chronic and/or recurrent sinusitis. therefore, we performed a 4-mo, open-label, dose-titration study in which each patient served as his or her own control (64, 81) . study participants were private pediatric otolaryngology outpatients of jay n. dolitsky, md, who resided in the new york metropolitan area and had a clinical diagnosis of chronic and/or recurrent sinusitis as well as symptoms of at least 3 mo of duration that were refractory to treatment with antibiotics. subjects were between ages 2 and 18 yr, of either gender and any race, religion, or nationality. children with known allergy to fish; chronic, life-threatening condition (such as hiv/aids or cancer); feeding disorder; seizure disorder; known cystic fibrosis; aspirin-intolerant asthma; and family plans to move outside the metropolitan area during the course of the study were excluded. subjects were enrolled from late january to early march 2003 and received supplements for 4 mo from the time of enrollment. primary endpoints were the number of doctor visits for acute respiratory illnesses and the child's sinus symptoms, which were quantified using a pediatric sinusitis symptom questionnaire (82) . the starting dose of supplements in the current study was the same as in our previous research (57): 1 teaspoon (5 ml) of carlson's lemon-flavored cod liver oil and one-half of a tablet of carlson's scooter rabbit chewable multivitamin-mineral per day (providing a total of 3750 iu of vitamin a and 700 iu of vitamin d per day). the vitamin a content of the cod liver oil was lower than in our first pilot study of om (57) but was the same as that used in our study of latino children (83; see table 3 ). supplement doses could be doubled to an intermediate dose (providing 7500 iu of vitamin a and 1400 iu of vitamin d per day) within 2 to 3 wk . if higher doses were needed, cod liver oil was discontinued and fish oil was administered instead (fish oil does not contain vitamin a or d). the maximum dose of fish oil was 3 g/d, and the maximum dose of multivitamin-minerals was four half-tablets per day (providing 10,000 iu of vitamin a and 800 iu of vitamin d per day). the titrated doses of vitamins a and d were higher than those used in our previous study (57) but were well-below the lowest daily toxic doses of these vitamins (61) (19,860 iu/d for vitamin a and 2800 iu/d for vitamin d). the us food and drug administration (fda) considers fish oil at dosages up to 3 g per day as safe for adults and children (84) . our four subjects were caucasian males, ranging in age from 4.2 to 9.8 yr, with chronic/recurrent sinusitis for at least 3 yr prior to entry in the study. three subjects had a positive response; one subject dropped out for administrative reasons. the responders had decreased sinus symptoms, fewer episodes of acute sinusitis, and fewer doctor visits for acute illnesses at 4, 6, and 8 wk after beginning study supplements. their parents reported that they had begun to recover from upper respiratory illnesses without complications, which was unusual for these children, as was improvement in springtime; their improvement had previously been limited to the summer months or periods of home-schooling. our findings are consistent with prior work by other clinical investigators. in a study of upper respiratory tract infections in young children, wald and colleagues (85) noted that an inflamed respiratory mucosa may not completely recover between episodes of infection. parsons (86) hypothesized that inflammation and edema of the sinonasal mucosa was the primary event in sinusitis, with bacterial infection as a secondary phenomenon. chronic/recurrent sinusitis is a debilitating disorder that may require treatment with intravenous antibiotics and/or endoscopic surgery. use of these supplements as adjunctive therapy for children with chronic/recurrent sinusitis is an inexpensive, noninvasive intervention that clinicians can use for selected patients, pending the outcomes of definitive, large, well-controlled studies. in the 1930s, during the pre-antibiotic era, lipoid aspiration pneumonia was reported with cod liver oil, mineral oil, and egg yolk, which were used at that time to treat sick and debilitated infants (87) . in 1950, caffey (88) reported vitamin a toxicity in children who were mistakenly treated with high-dose, long-term vitamin a administered in highly concentrated fish liver oil preparations that were available at that time. however, none of caffey's patients had received cod liver oil, and the highly concentrated fish liver oil preparations they received are no longer available in the united states. in our clinical studies, parents were instructed to crush the half-tablet of mvm, measure the cod liver oil, and mix both with a small amount of food (such as applesauce, yogurt, or rice cereal) before administering the supplements to their child. additionally, parents were informed both verbally and in writing that supplements were to be given only in the amounts required by the study and that study supplements were to be kept out of reach of children. the principal investigator spoke spanish, and all parental study materials were available in both spanish and english. to date, we have not encountered problems with aspiration or overdose in our studies. there is a clear association between viral respiratory infections and acute exacerbations of asthma in both children and adults (17) . there is also a link between sinusitis and asthma (89, 90) , with rhinovirus infections linked to both sinusitis and exacerbations of asthma (90) . additionally, latino children have a high incidence of asthma (91) . in view of the results of our studies (57, 81, 83) , we believe that these supplements could be clinically useful for young children (particularly latino children) with asthma, and we are currently beginning to organize research in this area. similarly to other countries worldwide (92) , socioeconomically disadvantaged children in the united states are at risk for micronutrient deficiencies (57, 62, 93) . although the supplements used in our research can be purchased in the united states without a prescription, their cost may pose an excessive financial burden to lowincome families. cod liver oil does not have a national drug code number, it is not available through medicaid in new york, and the children's vitamins we have located that are available through this system do not contain se or other trace metals. additionally, cod liver oil is not available through the united states department of agriculture (usda) special supplemental nutrition program for women, infants and children (wic); our request for such availability can be found online at http://www.fns.usda.gov/wic/anprmcomments/ ihp-06.pdf. furthermore, purchase of vitamins with us food stamps is not permitted (see http://www.fns.usda.gov/fsp/faqs.htm#9). if our results are confirmed in larger studies, a system change will be required to provide these supplements to nutritionally vulnerable, socioeconomically disadvantaged children living in the united states. egyptian and greek physicians may have understood the value of liver (high in vitamin a) for the treatment of night blindness, an early ocular manifestation of vitamin a deficiency (94, 95) . the use of fish oils in medicine was mentioned by hippocrates, and pliny discussed the use of dophin liver oil for the treatment of chronic skin eruptions (96) . however, these classical physicians did not appear to know about the use cod liver oil. the coastal fishermen of northern europe apparently used cod liver oil for many years for the treatment of aches and pains (96, 97) . however, the first recorded use of cod liver oil by physicians was from the manchester infirmary in england during the 1780s (96, 97) , where it was found to be very effective for "old pains" and "rheumatism," which were probably cases of osteomalacia (a bone disease of adults) (96) . the pattern of discovery was that the use of cod liver oil by fishing folk and peasants was accidentally observed by a physician, who then tried it and made it known to the medical profession (96) . guy (96) states that there was no further mention of cod liver oil in the english medical literature until its revival in 1841 by bennett, who had observed its use in germany. bennett reported that in holland, cod liver oil had obtained a wide reputation as a cure for rickets (a bone disease of children) "long before its remedial properties were acknowledged by physicians" (see ref. 97, p. 67) . in the 1820s, schenk and schuette published independent reports in the german literature regarding the value of cod liver oil for curing rickets (97) , and schuette reported that he used cod liver oil successfully for 25 yr. cod liver oil for the treatment of rickets was introduced in france by trousseau in the 1830s (97) . the demand for cod liver oil was so great that all types of substitutes were used, and reports of failure, contamination, and substitutes for cod liver oil began to appear in the literature before the middle of the 19th century. vitamin a was discovered as the result of a long, incremental process with contributions by numerous investigators (95, 98) . at the end of the 19th century and the beginning of the 20th century, nutritional theories were tested under well-controlled laboratory conditions through the administration of experimental diets to animals, and specific factors necessary for their growth and survival began to be identified. during this time, frederick hopkins, at cambridge university, proposed that there were "accessory factors" in foods that were necessary for life but that had not been previously identified; casimir funk named these factors "vital amines" or "vitamines" (65) . in 1913, in the same issue of the journal of biological chemistry, two groups independently reported the existence of a fat-soluble factor that was essential for the growth of rats (65, (99) (100) (101) . mccollum and davis of the university of wisconsin (99) demonstrated that after a certain age, the growth of rats was dependent on an ether extract from eggs or butter. using a different experimental diet, osborne and mendel (100) , of yale university, found that there was an "essential accessory factor" in butter needed for the normal growth of rats. this fat-soluble growth factor, originally termed "fat-soluble a," soon became known as "vitamine a" (65). the discovery of vitamin d was closely tied to work on the prevention and treatment of rickets. during the industrial revolution, rickets spread rapidly throughout europe, particularly among the urban poor, who lived in the sunless alleys of factory towns and urban slums (97) . in 1918, mellanby (102) , an english physician and professor of pharmacology, reported the first animal model of rickets, which he developed in puppies. in a simple, two-page report to the physiological society, he noted that the daily administration of foods such as butter, cod liver oil, or 500 cc of milk (among others) was effective in preventing rickets in his model, whereas casein and linseed oil were among the substances that were ineffective. mellanby felt that rickets was a deficiency disease and stated that "the anti-rachitic accessory factor has characters related to the growth accessory factor [vitamin a], although it is not identical with the latter …" (ref. 102, p. xi) . however, mellanby was not able to distinguish these two factors; this was accomplished by mccollum and his new collaborators at johns hopkins university. in the 1920s, mccollum and his colleagues developed a rat model of rickets that could also be cured with cod liver oil. they were then faced with the same question that perplexed mellanby: was the anti-rachitic factor vitamin a, or was it another substance with a similar distribution as fat-soluble vitamin a (103)? it was known that the vitamin a-deficient animals in these studies often developed ocular abnormalities, including dryness of the eyes, corneal ulceration, and blindness, similar to xeropthalmia in humans (65) . additionally, hopkins demonstrated that oxidation destroyed fat-soluble a (103) . using these facts, in 1922, mccollum and his colleagues (104) reported that when cod liver oil was oxidized for 12 or 20 h, it could no longer cure xerophthalmia, although it could prevent rickets. therefore, they concluded that the anti-xerophthalmic and the anti-rachitic properties were a result of two distinct substances, and that the antirachitic factor, which specifically regulated bone metabolism, was the more heat-stable factor. because this was the fourth vitamin to be discovered, mccollum's group named it vitamin d in 1925 (97) . the fact that both exposure to sunlight and cod liver oil could prevent or cure rickets was perplexing and controversial (105) . careful experiments by chick and coworkers (103) , working in vienna from 1919 to 1922, confirmed the value of both cod liver oil and sunlight in the prevention and treatment of rickets in young infants. in 1919, huldschinsky (97), a pediatrician in berlin, used light from a mercuryvapor quartz lamp (which includes ultraviolet [uv] wavelengths) to cure four cases of advanced rickets in children with up to 2 mo of treatment. when huldschinsky exposed one arm of a rachitic child to the uv irradiation, he found that the rickets in the child's other arm was cured to the same degree as in the exposed arm. therefore, he concluded that phototherapy was not a local effect and speculated that as a result of exposure to uv light, something was formed in the skin that was then carried to other sites, where it had its anti-rachitic effect (105) . in 1925, hess and weinstock (97) reached similar conclusions based on experimental work in animals. these theories were confirmed in 1936, when windaus, working in germany, demonstrated that skin contains the natural prehormone of vitamin d, which is converted to vitamin d 3 when the skin is exposed to uv irradiation (including light from a mercury-vapor lamp) (97). historical investigators were well-aware of an association between rickets and respiratory diseases. in their 1917 paper on rickets, hess and unger stated that "rickets is a predisposing cause of these respiratory diseases (pulmonary tuberculosis, pneumonia, and whooping cough)" (ref. 106, p. 1583 ). in her 1927 paper on community control of rickets, eliot stated that "susceptibility to upper respiratory infections, such as colds, bronchitis and pneumonia, is greatly increased in infancy and early childhood by rickets" (ref. 107, p. 114 ). based on prior animal studies and clinical work by german investigators, ellison discounted the contribution of vitamin d in the efficacy of cod liver oil for measles. nonetheless, he acknowledged that "it is possible that some adjuvant effect was obtained from the co-operation of the two factors [vitamins a and d]" (ref. 108, p. 710 ). in a 1936 study of vitamins a and d (individually or combined) for children hospitalized with measles, mackay noted "there is much to indicate that resistance to infections is reduced in children suffering form an overt deficiency of either of these vitamins [vitamin a or d]" (ref. 109, p. 127 ). semba noted that cod liver oil, a rich source of vitamins a and d, was used as a treatment for tuberculosis for more than 100 yr (110) . in the 1840s, charlotte brontë, the author of jane eyre, suffered from tuberculosis, and her treatment included cod liver oil (111) . a 1917 textbook on tuberculosis, although recognizing that there was no specific treatment for tuberculosis at that time, stated that "one of the oldest and best established remedies for the treatment of tuberculosis is cod liver oil" (ref. 112, p. 467); however, the mechanism of action of cod liver oil was unknown. the situation had changed little by 1946, when goldberg's textbook stated that cod liver oil "has been used empirically for many centuries in the treatment of pulmonary tuberculosis without any definite knowledge of its action" (ref. 113 , p. c-81). however, the use of cod liver oil for tuberculosis faded as specific treatments were developed, and "cod liver oil" is not listed in the index of a modern textbook on tuberculosis (114). mellanby (see section 4.3.) had a large colony of dogs that were maintained on experimental diets. in 1926, mellanby reported, "at one period in the course of my experimental investigations on dogs, the work was greatly hampered by the development of an inflammatory condition of the lungs" (ref. 115, p. 518), which was bronchopneumonia. on postmortem examination, the pneumonia was largely restricted to the vitamin adeficient dogs, and he speculated that this might be relevant to respiratory illness in children (65, 115) . in 1928, green and mellanby reported that a deficiency of vitamin a, but not vitamin d, caused increased infections in a rat model, leading them to call vitamin a an "anti-infective" agent; they speculated that this was related to the epithelial changes caused by vitamin a deficiency (116) . in 1932, ellison (65, 108) reported the results of a study of concentrated cod liver oil for children who were hospitalized with measles. ellison was aware of mellanby's work on the anti-infective properties of vitamin a and also knew that vitamin a deficiency damaged epithelial cells in the respiratory tract (117, 118) . ellison specifically chose to study measles because it was "a disease which attacks epithelial defences and whose incidence is greatest in those members of the community who are most likely to be suffering from various grades of vitamin deficiency…the children of the poorest classes" (ref. 108, p. 709). he studied 600 children under age 5 yr who were admitted to the grove hospital (london) with measles. the cases were randomized by ward to treatment with a highly concentrated cod liver oil preparation or a control treatment of standard treatment (no placebo was used). treatment with cod liver oil reduced measles mortality by approximately one-half, from 8.7% in the control group to 3.7% in the treated group (65, 108) . based on animal studies and german clinical work, ellison attributed the efficacy of cod liver oil to vitamin a, although he did concede that some adjuvant effect could have been obtained from the cooperation of the two factors (108) . a subsequent study published in 1936 (65, 109) reported that neither vitamins a and d together nor vitamin d alone had an effect on reducing the mortality rate from measles. however, the control mortality rate in this later study decreased to 2.6%, making it difficult to demonstrate an improvement. by 1940, numerous studies had been conducted to evaluate the ability of vitamin a (usually given as cod liver oil) to decrease the incidence of respiratory infections. the results were mixed, with about half showing a positive impact and the rest demonstrating no effect (65) . however, cod liver oil did have a significant impact on decreasing industrial absenteeism (65) . in a 1935 study of cod liver oil for the prevention of the common cold in school children, the investigator was not able maintain a control group given no supplements because enthusiastic families purchased cod liver oil for their children outside of the study (65, 66) ; this finding is relevant to our current work. with the introduction of sulfa antibiotics and penicillin in the 1930s to 1940s (65), as well as the improvements in diet in industrialized countries in the late 1930s, interest in anti-infective therapy shifted to antibiotics and away from vitamin a (98). in the mid-1920s, uv radiation of food and a variety of other substances was demonstrated to produce anti-rachitic properties (105) . steenbock patented the addition of provitamin d to foods followed by uv irradiation to produce anti-rachitic activity. in the 1930s, the addition of provitamin d 2 to milk followed by uv irradiation was widely practiced in the united states and europe. rickets was eradicated as a significant public health problem in the countries that used this vitamin d fortification process (105) . in the late 1940s, otto isler and his collaborators in basel reported the synthesis of all-trans-vitamin a from the inexpensive precursor β-ionone (95) . in the same time period, arens and van dorp (94) reported the synthesis of retinoic acid. within a few years, the price of vitamin a fell 10-fold, and it became economically feasible to add vitamin a more generally to foods. during the latter part of the 19th century, cod liver oil was rarely used in america, although the reason for this lack of use is not clear (96, 97) . however, there was a resurgence in interest, and in 1917, hess and unger wrote, "for many years cod liver oil has been regarded as the sovereign remedy for rickets" (ref. 106, p. 1583) . they successfully prevented rickets with cod liver oil in susceptible african-american babies in a lowincome neighborhood in new york city (106, 119) . hess urged officials to dispense cod liver oil at the baby health stations at cost, but they declined because it would be too expensive, and they thought that additional milk would be preferable to cod liver oil (106) . cod liver oil and sunlight were highly valued for the prevention of rickets, and nurses taught mothers of infants how to use these remedies for their infants (107) . from the 1920s to the 1940s, many children in the united states were given cod liver oil each day (26, 65) with orange juice (which was know to prevent scurvy). however, older preparations of cod liver oil had an unpleasant taste, the quality of different preparations was erratic (119) , and medical professionals became concerned about lipoid aspiration pneumonia (87) and vitamin a toxicity (88) . by the 1950s, cod liver oil had been largely replaced by synthetic vitamins in the united states; however, the latter do not contain ω-3 fatty acids, which have anti-inflammatory properties (26) and important effects on immune function (47, 120) . in norway, the norwegian nutrition council continues to recommend supplementation with cod liver oil beginning at age 4 wk, because it provides ω-3 fatty acids in addition to vitamin d (121). before columbus made his first voyage to america, basque fisherman were secretly fishing the massive stocks of cod and other groundfish off the new england coast (122, 123) . their salt cod was a staple in mediterranean markets, and cod was a staple of the european diet for more than 400 yr (122) . although fishermen exploited cod for centuries, the technological innovations of the 20th century led to the collapse of cod stocks in north america. motorized boats dragged the ocean floor with massive trawl nets, destroying both cod fish and their habitat. factory ships with refrigeration have almost erased the limit to the amount of cod that can be caught and sold internationally without spoiling (123) ; increasingly powerful and accurate sonar produces detailed readouts of nooks where schools of fish may lurk; and shipping fleets can position themselves precisely through use of the satellites of the global positioning system (124) . despite growing regulations on allowable catches and fishing equipment, cod stocks have continued to decrease across the north atlantic. in 1992, the canadian government declared a temporary moratorium on cod fishing; the moratorium was extended in 1994. in 2003, with cod stocks showing no sign of recovery, the canadian government banned all cod fishing off its eastern provinces and identified some cod populations as endangered. the us government also imposed restrictions on cod fishing (123) . however, it is unclear whether north atlantic cod stocks will recover. the level of polychlorinated biphenyls (pcbs) and dioxins in fish and fish oils has become a concern as oceans have become progressively contaminated with industrial waste. this issue was addressed in the united kingdom and europe by purity standards (125) , which were revised and made more strict in 2002 (126) . in the same year, the uk food standards agency reported that exposure to dioxins had decreased by 75% over the previous 20 yr and that the levels of dioxins and pcbs found in most of the samples in their most recent fish oil survey were lower than in previous surveys that were performed in 1994 and 1996 (126) . mercury contamination of fish is also a concern, and the fda advises that young children and women of childbearing age should avoid tilefish, swordfish, shark, and king mackerel because of their elevated levels of mercury (127) . however, an analysis of us fish oil supplements revealed no detectable mercury, with a limit of detection of 0.1 μg of mercury per gram (128). after a 40-yr hiatus, interest in the anti-infective properties of vitamin a was rekindled in the 1980s by the observation of increased mortality in indonesian children who had vitamin a deficiency and xerophthalmia (65, 129) . the first symptom of eye disease from vitamin a deficiency is night blindness; at this stage, bitot's spots (superficial, foamy gray, triangular spots) may be present on the conjunctiva (129, 130) . this is followed in later stages by xerophthalmia (dryness of the conjunctiva), keratomalacia (corneal ulceration), and blindness (77) . since the 1980s, numerous studies have been performed regarding the effect of vitamin a supplementation on the health of children in developing countries. for a complete review of this subject, the reader is referred to chapter 23, as well as reviews (110, 131, 132) , and meta-analyses (67, 133, 134) . for the purpose of this chapter, the findings are summarized to provide a basis of comparison to the status of vitamin a in the developed world as well as to provide a perspective on the results of our research. vitamin a supplementation of children in developing countries decreased overall childhood mortality by about 30% (67, 132) . community-based studies of vitamin a supplementation have indicated that it may decrease the severity, but not the incidence, of diarrhea (131) . in children hospitalized with measles in the developing world, vitamin a supplementation decreased mortality by an average of 60% (67, 132, 135) ; the decrease in mortality from measles-related pneumonia was particularly noteable (67) . the modern studies are consistent with the results of ellison's historical study of cod liver oil for children who are hospitalized with measles (see section 4.6.). the role of vitamin a supplementation in measles is also consistent with the fact that infectious diseases that induce the acute-phase response transiently depress serum retinol concentrations, that vitamin a deficiency impedes the normal regeneration of mucosal barriers damaged by infection, and that it also diminishes the immune function of white blood cells (136, 137) . however, several placebo-controlled trials have demonstrated that high-dose vitamin a supplementation is not effective in decreasing the severity of pneumonia in hospitalized children in developing countries and that large doses of vitamin a may be harmful when given to well-nourished children in these areas (132, 134) . additionally, vitamin a supplementation is not effective for children who are hospitalized with pneumonia caused by respiratory syncytial virus, which is a paramyxovirus similar to measles and an important cause of infantile bronchiolitis and pneumonia (138, 139) . in a multicenter study performed in the united states, patients who received vitamin a actually had longer hospital stays than those who received placebo (138) . infection with hiv has become increasingly prevalent in many developing countries. vitamin a supplementation of children younger than age 5 yr who are hiv-positive decreases aids-related deaths as well as total mortality and morbidity from diarrhea (140) . small, frequent doses of vitamin a may be more protective than large, periodic doses. additionally, adequate dietary vitamin a intake is associated with a significant decrease in mortality (141) , diarrheal and respiratory infections (142) , and stunting (143) . new strategies in vitamin a supplementation in developing countries include targeting at-risk populations, improving dietary sources of vitamin a, using horticultural approaches, fortifying food, and addressing multinutrient deficiencies (140). modern studies of vitamin d indicate that calcitriol (1,25 dihydroxyvitamin d), the active form of vitamin d, has important nonclassical effects beyond the regulation of calcium metabolism. these include the modulation of hormone and cytokine production and secretion as well as the regulation of proliferation and differentiation (144) . calcitriol, a potent inhibitor of human t-lymphocyte proliferation (145, 146) , and vitamin d analogs have been shown to be effective in the prevention and treatment of some models of autoimmune disease in rodents-particularly autoimmune diabetes in mice (144, 147, 148) . in 1997, muhe and colleagues (110, 149) reported the importance of nutritional rickets in the development of pneumonia in developing countries. this is consistent with the work of historical authors discussed earlier, who were also aware of this association. vitamin a deficiency that is severe enough to cause blindness is uncommon in the developed world (62) . however, some segments of the us population, particularly socioeconomically disadvantaged children (93) as well as african-and mexican-american children (62), may have suboptimal levels of vitamin a. in 1932, ellison recognized that children from lowincome households were the most likely to have vitamin deficiencies (see section 4.6.) (108) . consistent with these reports, in our original study, five of six children with suboptimal levels of vitamin a were hispanic general-service patients (57) . additionally, young children in the united states-particularly those in the toddler and preschool age groups-may not have adequate dietary intakes of vitamin a (150) . in developed countries, high intakes of vitamin a (but not β-carotene) by pregnant women have been associated with teratogenesis (151), leading to recommendations that prenatal vitamins should contain no more than 8000 iu of preformed vitamin a (152) . additionally, high intakes of vitamin a by postmenopausal women in the united states (153) and 49-to 51-yr-old men in sweden (154) have been associated with a higher risk of hip fractures. as a result, vitamin a supplementation and fortification of food with vitamin a in western countries has been questioned (77) . as discussed under section 3.3., the amount of vitamin a in norwegian cod liver oil has been reduced. nonetheless, the norwegian nutrition council continues to recommend supplementation with cod liver oil beginning at age 4 wk, because it provides ω-3 fatty acids in addition to vitamin d (121). numerous investigators have stated that vitamin a deficiency rarely exists alone and that it is usually accompanied by variety of other nutritional deficiencies (92, 131, 132, 134, (155) (156) (157) (158) . in a 1986 review, mejía (92) noted that vitamin a deficiency primarily affects the world's most underprivileged populations, which, because of their limited socioeconomic condition, also lack a variety of other essential nutrients. he emphasized the importance of the interaction between nutrients and reviewed the established relationships of vitamin a status to protein, dietary fat, vitamin e, zinc, and iron (92) . mejía also mentioned the more controversial links of vitamin a to iodine metabolism; vitamins c, k, and d; calcium, and copper. realizing that the relationships might be direct or indirect, he emphasized the importance of considering these interactions when "treating or preventing vitamin a deficiency both at the clinical and at the population levels" (ref. 92, p. 95) . olson (155) reported that deficiencies of various other nutrients, including protein, α-tocopherol (vitamin e), iron, and zinc, adversely affects the transportation, storage, and utilization of vitamin a. he also noted that the absorption of vitamin a and carotenoids is markedly reduced when diets contain very little fat (<5 g/d). more recently, villamor and fawzi (132) stated that supplementation with vitamins and minerals in addition to vitamin a is likely to "reduce the burden of adverse health outcomes," because of the physiological interactions between nutrients and overlapping micronutrient deficiencies, including iron and zinc. semba (98) noted that antenatal supplementation with multivitamins reduced fetal deaths and low birthweight in pregnant women who were infected with hiv, but vitamin a alone had no significant effect. semba (110) also discussed the role that other deficiencies of vitamin d (149) and zinc (159) may have in susceptibility to respiratory infections. we agree with semba, who stated that "further studies are needed to address the use of vitamin a in multi-micronutrient supplements, as there is increasing evidence that other coexisting micronutrient deficiencies may limit the efficacy of vitamin a" (ref. 131, p. 105). our work is consistent with the historical uses of cod liver oil, vitamin a as the "antiinfective" vitamin, the link between rickets and respiratory tract infections, the modern understanding of immunomodulatory effects of vitamin d, the importance of ω-3 fatty acids and trace metals in decreasing inflammation, the clinical observation that inflamed respiratory mucosa may not completely recover between episodes of infection, and the current concept of the importance of multiple micronutrient deficiencies. we have demonstrated that use of flavored cod liver oil (which meets european purity standards) and a chewable children's multivitamin-mineral with trace metals, including se, can decrease morbidity from upper respiratory tract illnesses, om, and sinusitis in young children living in the united states. these supplements were particularly wellaccepted by latino families from the caribbean, where use of cod liver oil is a cultural tradition. currently, there is adequate information for practitioners to recommend the use of these supplements, when indicated, to their individual patients; information for practitioners and families is available online at http://www.drlinday.com. the supplements can be purchased in the united states without a prescription. further research is needed to evaluate the effect of the supplements on antibiotic prescription for these illnesses and to explore their role as adjunctive therapy in asthma. additionally, our findings need to be confirmed in larger studies to facilitate large-scale, policy decision making. use of these supplements has the potential to improve children's health and decrease the cost of their health care. however, cod liver oil does not have a national drug code number and is not available through medicaid in new york, and the children's vitamins we have located that are available through this system do not contain se or other trace metals. also, cod liver oil is not available through the usda wic program; our request for such availability can be found online at http://www.fns.usda.gov/wic/anprmcomments/ ihp-06.pdf. furthermore, purchase of vitamins with us food stamps is not permitted (see http://www.fns.usda.gov/fsp/faqs.htm#9). socioeconomically disadvantaged children living in the united states are at risk for micronutrient deficiencies. although the supplements used in our research can be purchased in the united states without a prescription, their cost may pose an excessive financial burden to low-income families. if our results are confirmed in larger studies, a system change will be needed to provide these supplements to nutritionally vulnerable, socioeconomically disadvantaged children living in the united states. this work was supported in part by the department of otolaryngology of the new york eye and ear infirmary (new york, ny). j. r. carlson laboratories, (arlington ambulatory health care visits by children: principal diagnosis and place of visit antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis misconceptions about colds and predictors of health service utilization trends in antimicrobial prescribing rates for children and adolescents reduction in antibiotic use among us children interagency task force on antimicrobial resistance: a public health action plan to combat antimicrobial resistance. part 1: domestic issues cost-effectiveness considerations in otitis media treatment the role of adjuvant adenoidectomy and tonsillectomy in the outcome of the 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among sudanese children dietary vitamin a intake in relation to child growth vitamin d analogues in insulin-dependent diabetes mellitus and other autoimmune diseases: a therapeutic perspective comparison of the effects of 1,25-dihydroxyvitamin d3 on t lymphocyte subpopulations the immunobiology of vitamin d 1,25-dihydroxyvitamin d3 prevents insulitis in nod mice prevention of autoimmune diabetes in nod mice by 1,25 dihydroxyvitamin d3 case-control study of the role of nutritional rickets in the risk of developing pneumonia in ethiopian children subclinical vitamin a deficiency: a potentially unrecognized problem in the united states teratogenicity of high vitamin a intake continuing caution is needed vitamin a intake and hip fractures among postmenopausal women serum retinol levels and the risk of fracture recommended dietary intakes (rdi) of vitamin a in humans nutrition and development: other micronutrients' effect on growth and cognition iron and zinc supplementation improves indicators of vitamin a status of mexican preschoolers impact of zinc supplementation on morbidity from diarrhea and respiratory infections among rural guatemalan children heights, il) donated the nutritional supplements used in this research but had no other role in the design or conduct of the study. information for practitioners and families regarding this research is available at http://www.drlinday.com. key: cord-014813-qej5a8ks authors: rose, m. a. title: feuchter husten und protrahierte bakterielle bronchitis bei kindern und jugendlichen date: 2018-06-08 journal: pneumologe (berl) doi: 10.1007/s10405-018-0191-9 sha: doc_id: 14813 cord_uid: qej5a8ks persistent cough is one of the most common reasons patients present to outpatient practices. especially in children, chronic cough (>4 weeks) is a significant burden on the child and family. while in the past, the lower airways were considered sterile, the concept of a physiologic microbiome of the lower respiratory tract has increasingly emerged. of the differential diagnoses of chronic cough, protracted bacterial bronchitis (pbb) is more common in otherwise (pulmonary) healthy children under 6 years of age. tracheomalacia may primarily exist or be the result of mechanically straining coughing, whereas apart from a reduced alveolar phagocytosis, there is usually no systemic or local immune weakness. instead, an activated innate immunity with increased gene expression of the interleukin-1β signaling pathway can be immunologically detected. here too, it is difficult to differentiate between cause and effect of chronic inflammatory events. today, pbb and non-cf bronchiectasis, i.e., bronchiectasis not caused by cystic fibrosis (cf), are two sides of a disease spectrum of suppurative lung diseases, thus, making consequent therapy and long-term pediatric pneumological support of children with chronic productive cough necessary. röntgendiagnostik kam es im ersten viertel des 20. jh. zu einem quantensprung der pneumologischen diagnostik [10] . in der neuzeit beschrieb der französische arzt rené laënnec erstmals im frühen 19. jh. die csld; erst 100 jahre später sind erste chirurgische interventionen und bildgebungen dokumentiert. so beschrieb roles in den 1930er-jahren die schlechte prognose der unbehandelten csld und stellte die lobektomie als methode der wahl vor [3] . erst mit der verfügbarkeit von antibiotika in den 1950er-jahren, schutzimpfprogrammen, verbesserter ernährung und gesundheitsversorgung konnten die csdl auch bei kindern soweit zurückgedrängt werden, dass sie mittlerweile nur noch in ressourcenschwachen ländern und bevölkerungsschichten mit erschwertem zugang zu medizinischer versorgung häufiger vorkommen [9] . die derzeitige definition der protrahierten bakteriellen bronchitis (pbb) gem. european respiratory society fordert feuchten husten von mindestens 4 wochen dauer, eine mit mindestens 10 4 cfu/ml ("colony-forming units", kolonienbildende einheiten) in der bronchoalveolären lavage (bal) oder im sputum nachgewiesene monoinfektion der unteren atemwege und eine besserung des hustens nach einem 2-wöchigen empirischen antibiotikazyklus (meist amoxicillin-clavulansäure, amoxi-clav) entsprechend einer mikro-biologisch gesicherten pbb ("mikrobio-pbb"). hiervon wird die klinisch diagnostizierte pbb ("klinische pbb") unterschieden, die ebenfalls mindesten 4 wochen feuchten husten sowie genesung nach einem 2-wöchigen empirischen antibiotikazyklus (meist amoxi-clav) vorsieht, allerdings auf den erregernachweis verzichtet, dafür aber den ausschluss anderer ursachen feuchten respektive produktiven hustens fordert. eine verlängerte pbb ist definiert als mikrobiologisch gesicherte oder klinische pbb, die sich erst nach 4 wochen antibiotika bessert. unter rezidivierender pbb werden>3 episoden mikrobiologisch gesicherter oder klinischer pbb/jahr verstanden [8] . oft besteht parallel eine chronische rhinosinusitis mit postnasalem abtropfen ("post nasal drip" das profil der bal zeigt typischerweise eine neutrophile atemwegsentzündung (neutrophile granulozyten: 25-44 %) bei erhöhter gesamtzellzahl (188-426 × 10 6 zellen/dl). erhöhtes interleukin(il)-8, aktive matrixmetalloproteinase-9 und il-1β korrelieren mit dem grad der neutrophilie. andere proinflammatorische mediatoren sind α-defensine, il-1-signalweg-zytokine, cxcr2-genund cxcr2-proteinexpression. es waren il-1β und verwandte mediatoren mit bal-neutrophilie, hustensymptomen und rezidivneigung assoziiert. bekanntlich kommt es bei starken entzündungsreaktion, die am häufigsten im rahmen von infektionen auftreten, zum neutrophileneinstrom und apoptose, gefolgt von mikrobiellem abräumen und oftmals nachfolgender nekrose des gewebes, wobei der eigentliche eiter v. a. feuchter husten · kinder · eitrige lungenerkrankungen · bronchiektasie · chronische tracheobronchitis abstract persistent cough is one of the most common reasons patients present to outpatient practices. especially in children, chronic cough (>4 weeks) is a significant burden on the child and family. while in the past, the lower airways were considered sterile, the concept of a physiologic microbiome of the lower respiratory tract has increasingly emerged. of the differential diagnoses of chronic cough, protracted bacterial bronchitis (pbb) is more common in otherwise (pulmonary) healthy children under 6 years of age. tracheomalacia may primarily exist or be the result of mechanically straining coughing, whereas apart from a reduced alveolar phagocytosis, there is usually no systemic or local immune weakness. instead, an activated innate immunity with increased gene expression of the interleukin-1β signaling pathway can be immunologically detected. here too, it is difficult to differentiate between cause and effect of chronic inflammatory events. today, pbb and non-cf bronchiectasis, i.e., bronchiectasis not caused by cystic fibrosis (cf), are two sides of a disease spectrum of suppurative lung diseases, thus, making consequent therapy and long-term pediatric pneumological support of children with chronic productive cough necessary. wet cough · children · suppurative lung disease · bronchiektasis · chronic tracheobronchitis aus abgestorbenen leukozyten besteht [10] . in . tab in anbetracht zunehmender antibiotikaresistenzen auch unter antibiotic-stewardship-gesichtspunkten zu berücksichtigen. da in der vergangenheit bei kindern mit chronischem husten nur punktuell eine erregersuche betrieben wurde, sind chronisch eitrige lungenerkrankungen vermutlich untererfasst worden. in einer großen türkischen arbeit wurden 563 kinder mit chronischem husten unter-sucht; . abb. 2 enthält exemplarisch den vorgehensalgorithmus und die ergebnisse [5] . persistent bacterial bronchitis: time to venture beyond the umbrella perspective protracted bacterial bronchitis: the last decade and the road ahead protracted bacterial bronchitis: reinventing an old disease reversible bronchial dilatation in children: comparison of serial high-resolution computer tomography scans of the lungs evaluation of 563 children with chronic cough accompanied by a new clinical algorithm paediatric chronic suppurative lungdisease: clinicalcharacteristicsandoutcomes defining lower airway bacterial infection in children with chronic endobronchial disorders ers statement on protracted bacterial bronchitis in children theepidemiologyof chronic suppurative lung disease and bronchiectasis in children and adolescents chronic suppurative lung disease in children: definition and spectrum of disease riskfactorsforbronchiectasis in children with cystic fibrosis recurrent, protracted and persistent lower respiratory tract infection: a neglected clinical entity offen bleibt die kritische frage, inwieweit die pbb ein vorläufer von bronchiektasie ist. sowohl bei cf als auch bei immundefekten ist ein im hrct abbildbares, potentiell reversibles stadium mit erweiterungkleinereratemwege geläufig [4, 11] . auch ist von der bronchiektasie bekannt, dass deren voranschreiten gestoppt werden kann, wenn der zugrunde liegende pathomechanismus erfolgreich unterbunden wird. somit ist bei patienten mit pbb zu erwarten, dass ein teil in eine bronchiektasie übergehen wird, auch wenn aktuell hierfür noch keine gesicherten befunde vorliegen, eine erfolgreiche therapie dies jedoch verhindern kann. alternativ sind fälle plausibel, wo eine gut auf 2 wochen therapie ansprechende pbb-episode ohne nachfolgendes rezidiv eine transiente abwehrschwäche ausdrückt, z. b. nach einer virusinfektion. zukünftig werden möglicherweise genetische oder epigenetische signalwege und biomarker erkannt, die einen benignen, gut behandelbaren verlauf von einem zugrunde liegenden mukosalen immundefekt a priori abgrenzen lassen. in jedem fall sollte bei rezidivierenden pbb-episoden unabhängig vom lebensalter eine differenzierte abklärung mit erregernachweis erfolgen [1] . key: cord-022292-msz4au4b authors: gershan, william m. title: cough date: 2009-05-15 journal: practical strategies in pediatric diagnosis and therapy doi: 10.1016/b978-0-7216-9131-2.50006-3 sha: doc_id: 22292 cord_uid: msz4au4b nan the previous response or lack of response to some therapies for recurrent and chronic cough can provide important information (see table 2 -3). furthermore, some coughs may be caused or worsened by medications (table 2-4) . a history of accompanying signs or symptoms, whether localized to the respiratory tract (wheeze, stridor) or elsewhere (failure to thrive, frequent malodorous stools) can give important clues (table 2-5; see tables 2-2 and 2-3) . it is essential to remember that the daily language of the physician is full of jargon that may be adopted by parents but with a different meaning from that understood by physicians. if a parent says that a child "wheezes" or "croups" or is "short of breath," it is important to find out what the parent means by that term. because many disorders of childhood have genetic or nongenetic familial components, the family history can provide helpful information: are there older siblings with cystic fibrosis (cf) or asthma? is there a coughing sibling whose kindergarten class has been closed because of pertussis? similarly, the key to today's problems may be found in the past: was the child premature and, if so, did he or she spend a month on the ventilator, and does he or she now have chronic lung disease (bronchopulmonary dysplasia)? did the toddler choke on a carrot or other food 3 months ago? did the child receive a bone marrow transplant a year ago? is the child immunized? did the infant have a tracheoesophageal fistula repaired in the neonatal period? *infections include upper (pharyngitis, sinusitis, tracheitis, rhinitis, otitis) and lower (pneumonia, abscess, empyema) respiratory tract disease. † anatomic abnormality includes tracheobronchomalacia, tracheoesophageal fistula, vascular ring, abnormal position, or take-off of large bronchi. 1 common; 2 less common; 3 much less common. cf, cystic fibrosis; ger, gastroesophageal reflux. initial inspection often reveals the seriousness of an illness: is the child struggling to breathe (dyspnea)? does the child have an anxious look? can the child be calmed or engaged in play? is the child's skin blue (representing cyanosis) or ashen? does the child appear wasted, with poor growth that may indicate a chronic illness? the respiratory rate is often elevated with parenchymal lung disease or extrathoracic obstruction. respiratory rates vary with the age of the child (fig. 2-3) and with pulmonary infection, airway obstruction, activity, wakefulness and sleep, fever, metabolic acidosis, and anxiety. odors may also give helpful clues. does the examining room or the clothing smell of stale cigarette smoke? is there a foul odor from a diaper with a fatty stool, which may suggest pancreatic insufficiency and cf? is the child's breath malodorous, as can be noticed in sinusitis, nasal foreign body, lung abscess, or bronchiectasis? it has been said that the examination of the lungs begins at the fingertips. cyanotic nail beds suggest hypoxemia, poor peripheral circulation, or both. the examiner looks for the presence of digital clubbing ( fig. 2-4) , which makes asthma or acute pneumonia extremely unlikely. the absence of digital clubbing but a history of severe chronic cough in an older child makes cf unlikely. the shape of the chest gives information. is the anteroposterior (ap) diameter increased, which indicates hyperinflation of the lungs from obstruction of small airways (asthma, bronchiolitis, cf)? is this diameter small, as can be seen with some restrictive lung diseases with small lung volumes (muscular dystrophy, spinal muscular atrophy)? the normal infant has a "round" chest configuration, with the ap diameter of the chest about 84% of the transverse (lateral) diameter. with growth, the chest becomes more flattened in the ap dimension, and the ap-to-transverse ratio is closer to 70% to 75%. although obstetric calipers can be used to give an objective assessment of the ap diameter of the chest, most clinicians rely on their subjective assessment of whether the diameter is increased: does the patient look "barrel-chested"? intercostal, subcostal, suprasternal, and supraclavicular retractions (inspiratory sinking in of the soft tissues) indicate increased effort of breathing and reflect both the contraction of the accessory muscles of respiration and the resulting difference between intrapleural and extrathoracic pressure. retractions occur most commonly with obstructed airways (upper or lower), but they may occur with any condition leading to the use of the accessory muscles. any retractions other than the mild normal depressions seen between an infant's lower ribs indicate a greater-than-normal work of breathing. less easy to notice than intercostal retractions is their bulging out with expiration in a child with expiratory obstruction (asthma). contraction of the abdominal muscles with expiration is easier to notice and is another indication that a child is working harder than normal to push air out through obstructed airways. inspection of the spine may reveal kyphosis or scoliosis. there is a risk of restrictive lung disease or static pneumonia if the curvature is severe. palpating the trachea, particularly in infants, may reveal a shift to one side, which suggests loss of volume of the lung on that side or extrapulmonary gas (pneumothorax) on the other side. placing one hand on each side of the chest while the patient breathes may enable the examiner to detect asymmetry of chest wall movement, either in timing or in degree of expansion. the former indicates a partial bronchial obstruction, and the latter suggests a smaller lung volume, voluntary guarding, or diminished muscle function on one side. palpating the abdomen gently during expiration may allow the examiner to feel the contraction of the abdominal muscles in cases of expiratory obstruction. palpation for tactile fremitus, the transmitted vibrations of the spoken word ("ninety-nine" is the word often used to accentuate these vibrations), helps determine areas of increased parenchymal density and hence increased fremitus (as in pneumonic consolidation) or decreased fremitus (as in pneumothorax or pleural effusion). the percussion note determined by the examiner's tapping of one middle finger on the middle finger of the other hand, which is firmly placed over the patient's thorax, may be dull over an area of consolidation or effusion and hyperresonant with air trapping. percussion can also be used to determine diaphragmatic excursion. the lowest level of resonance at inspiration and expiration determines diaphragmatic motion. because lung sounds tend to be higher-pitched than heart sounds, the diaphragm of the stethoscope is better suited to pulmonary auscultation than is the bell, whose target is primarily the lower-pitched heart sounds (table 2-6). the adult-sized stethoscope generally is far superior to the smaller pediatric or neonatal diaphragms, even for listening to small chests, because its acoustics are better. the two-headed stethoscope enables the user to hear homologous segments of both lungs simultaneously in order to identify instances in which there is a delay in air entry or exit. the traditional single-headed stethoscope is adequate in most children with cough. the ability to recognize normal breath sounds comes with practice ( fig. 2-6 ). adventitious sounds come in a few varieties, namely, stridor, crackles, rhonchi, and wheezes. other sounds should be described in clear, everyday language. stridor is a continuous musical sound usually heard on inspiration and is caused by narrowing in the extrathoracic airway, as with croup or laryngomalacia. crackles are discontinuous, representing the popping open of air-fluid menisci as the airways dilate with inspiration. fluid in very common and suggests the diagnosis; ++, common; +, uncommon; -, almost never and makes examiner question the diagnosis. respiratory disorders larger airways causes crackles early in inspiration (congestive heart failure); crackles that tend to be a bit lower in pitch ("coarse" crackles) than the early, higher-pitched ("fine") crackles are associated with fluid in small airways (pneumonia). although crackles usually signal the presence of excess airway fluid (pneumonia, pulmonary edema), they may also be produced by the popping open of noninfected fibrotic or atelectatic airways. fine crackles are not audible at the mouth, whereas coarse crackles may be. crackles is the preferred term, rather than the previously popular "rales." rhonchi, or "large airway sounds," are continuous gurgling or bubbling sounds typically heard during both inhalation and exhalation. these sounds are caused by movement of fluid and secretions in larger airways (asthma, viral uri). rhonchi, unlike other sounds, may clear with coughing. wheezes are continuous musical sounds (lasting longer than 200 milliseconds), caused by vibration of narrowed airway walls, as with asthma, and perhaps vibration of material within airway lumens. these sounds are much more commonly heard during expiration than inspiration. the chest radiograph is often the most useful diagnostic test in the evaluation of the child with cough. table 2 -7 highlights some of the radiographic features of the most common causes of cough in pediatric patients. radiographic findings are often similar for a number of disorders, and thus these studies may not indicate a definitive diagnosis. chest films are normal in children with psychogenic (habit) cough and in children with sinusitis or gastroesophageal reflux (ger) as the primary cause of cough. a normal chest radiograph indicates the unlikelihood of pneumonia caused by respiratory syncytial virus (rsv), influenza, parainfluenza, adenovirus, chlamydia species, or bacteria. although children with cough resulting from cf, mycoplasma species, tuberculosis, aspiration, a bronchial foreign body, or an anatomic abnormality usually have abnormal chest radiographs, a normal radiograph does not exclude these diagnoses. hyperinflation of the lungs is commonly seen on chest films of infants with rsv bronchiolitis or chlamydia pneumonia, and a lobar or round (coin lesion) infiltrate is the radiographic hallmark of bacterial pneumonia. the diagnosis of sinusitis cannot be sustained with normal sinuses on radiograph or computed tomography (ct) scan. the white blood cell (wbc) count may help exclude or include certain entities for a differential diagnosis, but, with the possible exception of pertussis, can seldom establish a diagnosis with certainty. a wbc count of 35,000 with 85% lymphocytes strongly suggests pertussis, but not every child with pertussis presents such a clear hematologic picture. the presence of a high number or large proportions of immature forms of wbcs suggests an acute process, such as a bacterial infection. immunoglobulins provide supportive evidence for a few diagnoses, such as chlamydial infection, which rarely occurs without elevated serum concentrations of immunoglobulins g and m. specific bacteriologic or virologic diagnoses can be made in a number of disorders causing cough, including rsv, influenza, parainfluenza, adenovirus, and chlamydia pneumonia. in most cases, these diagnoses are based on culturing the organism from nasopharyngeal washings. in some cases, the viruses can be rapidly identified with immunofluorescence or amplification of viral genome through polymerase chain reaction (pcr). in bacterial pneumonia, the offending organism can be cultured from the blood in a small proportion (10%) of patients. a positive culture provides definitive diagnosis, but a negative culture specimen is not helpful. throat cultures are seldom helpful (except in cf) in identifying lower respiratory tract organisms. sputum cultures and gram stains may help guide initial empirical therapy in older patients with pneumonia or purulent bronchitis, but their ability to identify specific causative organisms with certainty (again with the exception of cf) has not been shown clearly. infants and young children usually do not expectorate but, rather, swallow their sputum. specimens obtained via bronchoscopy may be contaminated by mouth flora, but heavy growth of a single organism in the presence of polymorphonuclear neutrophils certainly supports the organism's role in disease. if pleural fluid or fluid obtained directly from the lung via needle aspiration is cultured, the same rules apply: positive cultures are definitive, but negative cultures are not. bacterial antigen detection in serum or urine by various techniques (latex agglutination) can help identify pneumococcus and haemophilus influenzae type b. a number of specific tests can help to establish diagnoses in a child with cough (see table 2 -7). these include a positive response to bronchodilators in a child with asthma; visualizing the red, swollen epiglottis in epiglottitis (to be done only under very controlled conditions, as described later); the bronchoscopic visualization of the peanut, plastic toy, or other offender in foreign body aspiration; a positive purified protein derivative in tuberculosis; and several studies of the esophagus in ger. several imaging techniques, such as ct or magnetic resonance imaging (mri), can help to delineate various intrathoracic anatomic abnormalities. finally, multiple tests can be employed to confirm the diagnosis of cf (table 2-8). infections are the most common cause of acute cough in all age groups and are responsible for some chronic coughs. the age of the patient has a large impact on the type of infection. viral upper respiratory infections (common cold); croup (laryngotracheobronchitis); viral bronchiolitis, particularly with rsv; and viral pneumonia are the most frequently encountered respiratory tract infections and hence the most common causes of cough in infancy. viral illness may predispose to bacterial superinfection (croup and staphylococcus aureus tracheitis or influenza and h. influenzae pneumonia). cold symptoms and signs usually include stuffy nose, with nasal discharge (rhinorrhea); sore throat and sneezing frequently occur. there may be fever, constitutional signs (irritability, myalgias, headache), or both. cough is common and may persist for 5 to 7 days. the mechanism by which upper respiratory infections cause cough in children is undetermined. in adults, it is generally thought that "postnasal drip"-that is, nasal or sinus secretions draining into the posterior nasopharynx-causes cough and, in fact, may be one of the most frequent causes of cough. indeed, sinus ct in older patients , or the phalangeal depth ratio, is normally less than 1 but increases to more than 1 with finger clubbing. the dpd/ipd ratio can be measured with calipers or, more accurately, with finger casts. the hyponychial angle is measured from lateral projections of the finger contour on a magnifying screen and is normally less than 180 degrees but greater than 195 degrees with finger clubbing. schamroth's sign is useful for bedside assessment. the dorsal surfaces of the terminal phalanges of similar fingers are placed together. with clubbing, the normal diamond-shaped aperture or "window" at the bases of the nail beds disappears, and a prominent distal angle forms between the end of the nails. in normal subjects, this angle is minimal or nonexistent. ( whispering pectoriloquy produces clearer sounding whispered words (e.g., "ninety-nine"). pmi, point of maximal impulse. with colds often reveals involvement of the sinus mucosa. whether this is true in children remains undetermined. other authorities believe that cough in a child with a cold indicates involvement (inflammation or bronchospasm) of the lower respiratory tract. the physician's bias on this matter will probably influence how to treat the child with cough accompanying a cold. in adults, the cough of the common cold may respond to a combination antihistaminedecongestant preparation, presumably from the decreased postnasal drip. it is uncertain whether such treatment is effective or indicated in children, particularly young infants, in whom toxicity of the drugs may be a greater concern than in adults. common viral pathogens include rhinovirus, rsv, and parainfluenza virus. the differential diagnosis includes allergic rhinitis, which often demonstrates clear nasal secretions with eosinophils and pale nasal mucosa, in contrast to mucopurulent nasal secretions with neutrophils and erythematous mucosa. infectious croup (see chapter 5) is most common in the first 2 years of life. its most dramatic components are the barking ("croupy") cough and inspiratory stridor, which appear a few days after the onset of a cold. in most cases, the patient has a low-grade fever, and the disease resolves within a day or two. in severe cases, the child can be extremely ill and is at risk for complete laryngeal obstruction. there may be marked intercostal and suprasternal retractions and cyanosis. stridor at rest signifies significant obstruction. diminishing stridor in a child who is becoming more comfortable is a good sign, but diminishing stridor in and of itself is not necessarily good: if the child becomes fatigued because of the tremendous work of breathing through an obstructed airway and can no longer breathe effectively, smaller-than-needed tidal volumes make less noise. low yield on culture in paroxysmal stage. pleural effusion relatively common. 6 blood culture positive in 10%; needle aspiration of pleural fluid or lung fluid may yield organism; bacterial antigen in urine. in older infants and children, common pathogens include pneumococci and group a streptococci; staphylococcus aureus is rare and may be associated with pneumatoceles or empyema. 7 localized hyperinflation is common; localized atelectasis in common; inspiratory-expiratory films may show ball-valve obstruction. 8 esophageal biopsy specimen shows esophagitis. 9 multilobular or multisegmental, dependent lobes. 10 (?) lipid-laden macrophages from bronchoscopy or gastric washings; barium swallow or radionuclide study showing aspiration. right-sided arch, mass effect on airways, mass identified; magnetic resonance imaging (mri). bronchoscopy; computed tomography; mri. +++, almost always-if not present, must question diagnosis; ++, common; +, less common; -, seldom-if present, must question diagnosis. +bld cult, blood culture may be positive; bronch, bronchoscopy can reveal the foreign body; diff, diffuse or scattered; ↑ eos, increased eosinophil count; esoph ph, prolonged esophageal ph probe monitoring; ge, gastroesophageal; hyper, hyperinflated; ig, immunoglobulin; infil, infiltrates; ↑ ly, increased lymphocyte count; +np cult, nasopharyngeal culture positive for specific organism; paraflu, parainfluenza virus; pcr, polymerase chain reaction; ↑ pmn, increased polymorphonuclear neutrophil count; ppd, purified protein derivative (tb); rad, reactive airways disease; rsv, respiratory syncytial virus; tb, tuberculosis; ↑ wbc, increased white blood cell count. it is important to distinguish croup from epiglottitis in the child with harsh, barking cough and inspiratory stridor because the natural histories of the two diseases are quite different (see table 2 -7). epiglottitis occurs more commonly in toddlers than in infants (see chapter 5). treatment of mild croup is usually not needed. for decades, pediatricians have recommended putting a child with croup in a steamy bathroom or driving to the office or emergency room with the car windows rolled down. (it is likely that these remedies are effective because of the heat exchange properties of the upper airway; air that is cooler or more humid than the airway mucosa will serve to cool the mucosa, thus causing local vasoconstriction and probably decreasing local edema.) in a child who has stridor at rest, hospitalization is indicated. symptomatic, often dramatic relief through decreased laryngeal edema can usually be achieved with aerosolized racemic epinephrine (2.25% solution, 0.25 to 0.5 ml/dose). it is essential to remember that the effects of the epinephrine are transient, lasting only a few hours, although the course of the illness is often longer. the result is that when the racemic epinephrine's effect has worn off, the child's cough and stridor will probably be as bad or even worse than before the aerosol was administered. this is not a "rebound" effect: the symptoms are not worse because of the treatment but, rather, because of the natural progression of the viral illness. repeating the aerosol will probably again have a beneficial effect and reduce the likelihood of requiring a tracheotomy or endotracheal intubation. a child who responds favorably to such an aerosol needs to be observed for several hours because further treatment may be needed. a single dose of dexamethasone (0.6 mg/kg orally, intramuscularly, or intravenously) reduces the severity and hastens recovery. aerosolized steroids (budesonide) may also be effective in patients with mild to moderately severe croup. bronchiolitis is a common and potentially serious lower respiratory tract disorder in infants (see chapters 3 and 5). it is caused usually by rsv but on occasion by parainfluenza, influenza, or adenovirus. it occurs in the winter months, often in epidemics. rsv bronchiolitis is seen uncommonly in children older than 4 years. typically, "coldlike" symptoms of rhinorrhea precede the harsh cough, increased respiratory rate, and retractions. respiratory distress and cyanosis can be severe. the child's temperature is seldom elevated above 38°c. the chest is hyperinflated, widespread crackles are audible on inspiration, and wheezing marks expiration. the most striking laboratory abnormalities are in the chest radiograph, which invariably reveals hyperinflation, as depicted by a depressed diaphragm, with an enlarged retrosternal air space in as many as 60% of patients, peribronchial thickening in approximately 50%, and consolidation and/or atelectasis in 10% to 25%. the diagnosis is confirmed with demonstration of rsv by immunofluorescent stain or pcr of nasopharyngeal washings. in most cases, no treatment is needed because the disease does not interfere with the infant's eating or breathing. apnea is a common complication of rsv bronchiolitis in young infants and may necessitate close monitoring. in severe cases, often those in which there is underlying chronic heart, lung, or immunodeficiency disease, rsv can be life-threatening. in these cases, hospital care with supplemental oxygen and intravenous fluids is indicated. the effect of aerosolized bronchodilators is not clear but is probably beneficial in some infants. the aerosolized antiviral agent ribavirin may be beneficial for the sickest infants. it is expensive and difficult to administer; it needs to be given 12 to 18 hours per day (some studies advocate 2 hours three times a day) and may block ventilator tubing and valves. ribavirin may improve oxygenation but should not be used in lieu of mechanical ventilation in patients with hypoxia and hypercarbia (respiratory failure). viral pneumonia can be similar to rsv bronchiolitis in its manifestation, with cough and tachypnea, after a few days of apparent upper respiratory infection. there can be variable degrees of fever and of overall illness. infants and children with viral pneumonia may appear relatively well or, particularly with adenovirus, may have a rapidly progressive course, which ends in death within a few days after the onset of illness. frequent symptoms include poor feeding, cough, cyanosis, fever (some patients may be afebrile), apnea, and irt, immunoreactive trypsinogen. respiratory disorders rhinorrhea. frequent signs include tachypnea, retractions, crackles, and cough. cyanosis is less common. the most common agents causing viral pneumonia in infancy and childhood are rsv, influenza, and parainfluenza. adenovirus is less common, but it is important because it can be severe and leave residua, including bronchiectasis and bronchiolitis obliterans. adenovirus pneumonia is often accompanied by conjunctivitis and pharyngitis, in addition to leukocytosis and an elevated erythrocyte sedimentation rate (esr); the esr and leukocyte count are usually not elevated in other types of viral pneumonia. additional viral agents include enteroviruses and rhinovirus. radiographs most often reveal diffuse, bilateral peribronchial infiltrates, with a predilection for the perihilar regions, but occasionally lobar infiltrates are present. pleural effusions are not common. on occasion, if an infant is extremely ill, bronchoscopy with bronchoalveolar lavage may be indicated to isolate the virus responsible for the pneumonia. treatment is largely supportive, with oxygen and intravenous fluids. mechanical ventilation may be necessary in a small minority of infants. in young infants, the afebrile pneumonia syndrome may be caused by chlamydia, ureaplasma, or mycoplasma species; cytomegalovirus; or pneumocystis carinii. in this syndrome, cough and tachypnea are common. severe pneumonia may develop in neonates as a result of herpes simplex. pertussis is an extremely important cause of lower respiratory tract infection in infants and children. the causative organism, bordetella pertussis, has a tropism for tracheal and bronchial ciliated epithelial cells; thus, the disease is primarily bronchitis, but spread of the organism to alveoli, or secondary invasion by other bacteria, can cause pneumonia. the disease can occur at any age, from early infancy onward, although its manifestations in young infants and in those who have been partially immunized may be atypical. most commonly, pertussis has three stages: • catarrhal, in which symptoms are indistinguishable from the common cold • paroxysmal, dominated by repeated forceful, paroxysmal coughing spells; many spells may be punctuated by an inspiratory "whoop," post-tussive emesis, or both • convalescent, in which the intensity and frequency of coughing spells gradually diminish each stage typically lasts 1 to 2 weeks, except the paroxysmal stage, which lasts many weeks. the chinese term for pertussis translates to "100 days of cough." most children are entirely well between coughing spells, when physical findings are remarkably benign. infants younger than 3 months of age may have the most severe illness, and in this age group, the rate of mortality from pertussis is as high as 40%. diagnosis can be difficult because the definitive result-namely, culturing the organism from nasopharyngeal secretions-requires special culture medium (bordet-gengou, which must be prepared fresh for each collection). culture specimens are much less likely to be positive during the paroxysmal stage than during the catarrhal stage, when the diagnosis is not being considered. fluorescent antibody stains (for the antigen) of secretions are also helpful if they are positive, but, similarly, they are more likely to be positive before the paroxysmal stage. serum antibodies against b. pertussis may occasionally be helpful, although they are often difficult to interpret in immunized individuals. perhaps the laboratory test that is most helpful is the wbc count, which is typically elevated; values are as high as 20,000 to 50,000, with lymphocytes predominating. pcr is also useful. chest radiographic findings are nonspecific. infants with severe disease may require hospitalization. treatment is largely supportive, with oxygen, fluids, and small frequent feedings for patients who do not tolerate their normal feedings. treatment with erythromycin estolate (50 mg/kg/day for 14 days, every 6 hours, orally) decreases infectivity and may ameliorate the course of the disease if given during the catarrhal stage. studies suggest that azithromycin or clarithromycin may also be effective. in some patients, aerosolized bronchodilators (albuterol) or systemic steroids may help, although such treatment is controversial. cough suppressants are not helpful, but good hydration, oxygenation, and nutrition, in addition to not disturbing the infant, are important. complications include those related to severe coughing (table 2-9) and those specific to pertussis, such as seizures and encephalopathy. pertussis is prevented by three primary immunizations (at 2, 4, and 6 months of age) and regular booster immunizations at 15 to 18 months and 4 to 6 years of age. pertussis infection produces lifelong immunity. chlamydia trachomatis can cause pneumonia in young infants, particularly those aged 3 to 12 weeks. cough, nasal congestion, lowgrade or no fever, and tachypnea are common. conjunctivitis is an important clue to chlamydial disease but is present in only 50% of infants with chlamydial pneumonia at the time of presentation. affected infants may have a paroxysmal cough similar to that of pertussis, but post-tussive emesis is less common. crackles are commonly heard on auscultation, but wheezing is much less common than the overinflated appearance of the lungs on radiographs would suggest. the organism may be recovered from the nasopharynx by culture or antigen testing. the complete blood cell count may reveal eosinophilia. chlamydial infection responds to oral erythromycin therapy (40 to 50 mg/kg/day, every 6 hours for 10 to 14 days). ureaplasma urealyticum pneumonia is difficult to diagnose but causes cough in some infants. there are no particularly outstanding features to distinguish this relatively uncommon infection from viral pneumonias. bacterial pneumonia is relatively less common in infants than is viral pneumonia but can cause severe illness, with cough, respiratory distress, and fever. chest films are strikingly abnormal; the wbc count is elevated. treatment is with broad-spectrum intravenous antibiotics effective against pneumococci, group a (possibly b) streptococci, and, if illness is severe, s. aureus. cefotaxime with or without nafcillin may be effective. in early childhood, as children attend day care and nursery schools, they are constantly exposed to respiratory viruses to which they have little or no immunity (e.g., rhinoviruses, adenoviruses, parainfluenza, and coxsackievirus). such children may have as many as 6 to 8 or even more colds in a year. the remarks concerning colds and cough in infants (see previous discussion) apply to this older age group. the differential diagnosis of rhinorrhea is noted in table 2 -10. the sinuses may become the site for viral and subsequent secondary bacterial infection spreading from the nasopharynx (fig. 2-7) . the signs and symptoms are usually localized, including nasal congestion, a feeling of "fullness" or pain in the face ( fig. 2-8) , headache, sinus tenderness, day or night cough, and fever. maxillary toothache, purulent nasal discharge for more than 10 days, a positive transillumination (opacification), and a poor response to oral antihistamines or nasal decongestants are important clues. sinus radiographs or (more accurate) ct scan may facilitate the diagnosis of sinusitis by demonstrating opacification of the sinus with mucosal thickening. sinusitis is thought to be a cause of cough in adults and can probably be listed, with lower certainty, as a cause of cough in children. sinusitis is frequently seen in other conditions known to cause cough, especially cf, asthma, and ciliary dyskinesia. it may be difficult to ascertain whether the cough is a direct result of the sinus infection or the underlying problem (purulent bronchitis in the child with cf or ciliary dyskinesia, exacerbation of asthma). in the first two situations, it may not matter because treatment is the same. in the case of the child with asthma, it is important to treat the asthma with bronchodilating and antiinflammatory agents, as well as to treat the infected sinuses with antibiotics. the treatment of sinusitis involves the use of oral antibiotics active against the common pathogens (streptococcus pneumoniae, nontypable h. influenzae, moraxella catarrhalis, and, in rare cases, anaerobic bacteria or streptococcus pyogenes). treatment regimens include the use of amoxicillin, amoxicillin-clavulanate, cefuroxime, cefpodoxime, or cefdinir. amoxicillin is considered the initial agent of choice. oral (pseudoephedrine, phenylephrine) or topical (phenylephrine, oxymetazoline) decongestants may be of benefit by increasing the patency of the sinus ostia, which permits drainage of the infected and obstructed sinuses. oral antihistamines may benefit patients with an allergic history. treatment with antimicrobial agents should continue for at least 7 days after the patient has responded. this may require 14 to 21 days of therapy. many patients with presumed sinusitis recover without antibiotic therapy. complications of acute sinusitis include orbital cellulitis, abscesses (orbital, cerebral), cranial (frontal) osteomyelitis (pott puffy tumor), empyema (subdural, epidural), and thrombosis (sagittal or cavernous sinus). see previous text and chapter 5. viral pneumonia. the features discussed for viral pneumonia in infants are relevant for viral pneumonia in older children. the differentiation of viral or atypical pneumonia from classical bacterial pneumonia is noted in table 2 -11. bacterial pneumonia. bacterial pneumonia is more common in toddlers and older children than in infants. the most common pathogen is s. pneumoniae; other bacterial causes vary with age ( table 2-12) . cough may not be as prominent a presenting symptom or sign as tachypnea and grunting, sometimes (especially in infants) with vomiting (see table 2 -11). raised respiratory rates (≥50 in infants 2 to 12 months old, ≥40 in children 1 to 5 years old) plus retractions and grunting with or without hypoxia (oxygen saturation <90%) have a high specificity and sensitivity for pneumonia. chest pain, abdominal pain, headache, or any combination of these symptoms may occur. upper lobe pneumonia may produce meningeal signs, and lower lobe involvement may cause abdominal pain and an ileus. examination of the chest shows tachypnea but may be otherwise surprisingly normal. in older children, there may be localized dullness to percussion, with crackles or amphoric (bronchial) breath sounds over a consolidated lobe. the chest film may be normal in the first hours of the illness, inasmuch as the radiographic findings often lag behind the clinical manifestations. nonetheless, both posteroanterior and lateral views are the main diagnostic tools; lobar consolidation is usual, with or without pleural effusion. in infants, the pattern may be more diffuse and extensive. some clinical and radiographic features may be suggestive of the bacterial cause of pneumonia. children (especially infants) with staphylococcal pneumonia are more likely to have a rapid overwhelming course. staphylococcal pneumonia may be accompanied by more extensive radiographic abnormalities, including multilobar consolidation, pneumatocele formation, and extensive pleural (empyema) fluid. the presence of a pleural effusion is not helpful in indicating the specific bacterial diagnosis because other bacterial pneumonias may be accompanied by pleural effusion. pleural effusions may represent a reactive parapneumonic effusion or an empyema. pleural fluid may be characterized as transudate, exudate, or complicated empyema, the latter necessitating closed chest drainage with a chest tube (table 2-13). if the effusion is of sufficient size, as demonstrated by a lateral decubitus film or ultrasonography, a thoracentesis is indicated to differentiate the nature of the effusion and to identify possible pathogens. differentiating among the causes of bacterial pneumonia can be done with certainty only with positive cultures from blood, pleural fluid, fluid obtained by direct lung tap, or, in rare cases, sputum. current or previous antibiotic treatment diminishes the yield of such cultures. the presence of bacterial antigens in the urine for s. pneumoniae or h. influenzae provides strong evidence of the causative agent. bronchoscopy with or without lavage may yield helpful specimens from the progressively ill child or the child who has not responded promptly to empirical antibiotics. treatment is with antibiotics. cefotaxime or ceftriaxone is the drug of choice for the previously healthy child who requires hospitalization with lobar pneumonia. for the critically ill child, vancomycin may be considered for possible resistant s. pneumoniae. many children with pneumonia do well with oral antibiotics (amoxicillin, amoxicillin-clavulanate, oral cephalosporins) and respond within hours to the first dose. a smaller number may require hospitalization and intravenous antibiotics along with supportive measures (e.g., oxygen and intravenous fluids). repeated or follow-up chest films may remain abnormal for 4 to 6 weeks after pneumonia and are not indicated for a single episode of uncomplicated pneumonia (i.e., no effusion, no abscess, and good response to treatment). children with suspected pneumococcal pneumonia must be monitored carefully because of the possibility of resistance to penicillin and cephalosporin. mycoplasma pneumoniae is a common cause of pneumonia among school-aged children. the disease often occurs in community outbreaks in the fall months. the illness typically begins with table 2 -11); atypical in terms of extrapulmonary manifestations, low-grade fever, patchy diffuse infiltrates, poor response to penicillin-type antibiotics, and negative sputum gram stain. sars, severe acute respiratory syndrome. extrapulmonary symptoms (i.e., sore throat, myalgias, headache, fever), which then progress to include worsening cough, paroxysmal at times. patients do not often appear acutely ill, but cough may persist for weeks. there may be no specific abnormalities on the chest examination, although a few crackles may be heard, and about one third of younger patients wheeze. the radiographic findings in mycoplasmal pneumonia can mimic almost any intrathoracic disease; scattered infiltrates with nonspecific "dirty" lung fields, predominantly perihilar or lower lobes, are common, and lobar infiltrates and pleural effusion are occasionally seen. laboratory data (complete blood cell count, esr, sputum culture) may not be helpful. a rise in antimycoplasmal immunoglobulin g over 1 to 2 weeks may be demonstrated but is seldom helpful in guiding therapy. a positive immunoglobulin m response may be useful, although it can persist in serum for several months and, consequently, may not indicate current infection. pcr may be helpful. the cold agglutinin test yields positive results in about 70% of patients with mycoplasmal pneumonia, but they are also positive in other conditions, including adenovirus infection. the more severe the illness is, the greater is the frequency of positive cold agglutinins. the diagnosis is often made from the history of an older child who has a lingering coughing illness in the setting of a community outbreak, unresponsive to most (non-erythromycin) antibiotic regimens. treatment is with erythromycin (azithromycin or clarithromycin are alternatives in children younger than 8 years, whereas tetracycline or doxycycline can be administered to older children), which usually shortens the course of the illness. extrapulmonary complications of mycoplasmal infection include aseptic meningitis, transverse myelitis, peripheral neuropathy, erythema multiforme, myocarditis, pericarditis, hemolytic anemia, and bullous otitis media (myringitis). in patients with sickle cell anemia, severe respiratory failure and acute chest syndrome may develop. infection with chlamydia pneumoniae mimics respiratory disease resulting from m. pneumoniae, inasmuch as it occurs in epidemics, is seen in older children, and produces an atypical pneumonia syndrome and pharyngitis. the incidence of tuberculosis is increasing as a result of acquired immunodeficiency syndrome, homelessness, urban poverty, and immigration from endemic countries. tuberculosis must be considered in the child with chest disease that is not easily explained by other diagnoses, especially if the child has been exposed to an adult with active tuberculosis. nonetheless, tuberculosis is an infrequent cause of cough in children, even in those with active disease. the diagnosis is made primarily by skin testing (purified protein derivative [ppd]); a history of contact with a person who has tuberculosis; and recovery of the organism from sputum, bronchoalveolar lavage, pleural fluid or biopsy, or morning gastric aspirates (table 2-14). the yield from these procedures is relatively low, even from children with active pulmonary tuberculosis. the patterns of disease in normal hosts include primary pulmonary tuberculosis, with subsequent inactivation usually noted in young children and reactivation pulmonary disease among adolescents. primary pulmonary disease is often noted as a lower or middle lobe infiltrate during the period of t lymphocyte reaction to the initial infection. before resolution, the mycobacterium tuberculosis infection may disseminate to the better oxygenated upper lobes and extrathoracic sites, such as bone, or the central nervous system. if the immune response contains the initial infection, the radiographic findings may be indistinguishable from those of any other pneumonic process. with altered immune function, however, there may be progressive local disease, dissemination to miliary pulmonary disease, or early reactivation (months to 5 years) at distal sites, which produces tuberculous meningitis or osteomyelitis. reactivation of upper lobe pulmonary disease may produce cavities that are similar to the disease among adults. cavitary and endobronchial lymph node involvement are highly infectious, in contrast to the much less contagious nature of the hypersensitivity reaction noted in primary pulmonary disease. treatment of active disease, especially in regions of multidrugresistant tuberculosis, consists of three or four drug regimens, including isoniazid, rifampin, pyrazinamide with or without streptomycin, and ethambutol. risk of infection based on history and ppd induration size are presented in table 2 -14. inhaling food, mouth or gastric secretions, or foreign bodies into the tracheobronchial tree causes acute, recurrent, or chronic cough. interference with normal swallowing disrupts the coordination of swallowing and breathing that prevents aspiration. structural causes of disordered swallowing include esophageal atresia (in neonates), strictures, webs, or congenital stenoses. mediastinal lesions (tumors, lymph nodes), including vascular rings, may compromise the esophageal lumen and esophageal peristalsis, increasing the likelihood of aspiration. functional disorders include central nervous system dysfunction (e.g., coma, myopathy, neuropathy) or immaturity, dysautonomia, achalasia, and diffuse esophageal spasm. prior neck surgery, including tracheostomy, may alter normal swallowing. tracheoesophageal fistula and laryngeal clefts are congenital malformations with direct physical connections between the tracheobronchial tree and the upper gastrointestinal tract; oral contents enter the lungs directly. making the diagnosis of aspiration as the cause of cough may be difficult. barium contrast studies during swallowing may help characterize these disorders if barium enters the trachea. because most patients aspirate sporadically, a normal barium swallow does not rule out aspiration. radionuclide studies can be helpful if ingested radiolabeled milk or formula is demonstrated over the lung fields at several-hour intervals after the meal. bronchoscopy and bronchoalveolar lavage that recover large numbers of lipid-laden macrophages suggest that milk aspiration has taken place; however, the finding is neither sensitive nor specific for aspiration. treatment depends largely on the cause of aspiration. because many patients who aspirate do so because of lack of neurologic control of swallowing and breathing, it is often difficult to prevent. even gastrostomy feedings cannot prevent aspiration of oral secretions. in extreme cases, tracheostomy with ligation of the proximal trachea has been employed. this prevents aspiration but also prevents phonation, and it must be considered only in unusual situations. aspiration pneumonia is often treated with intravenous penicillin or, preferably, clindamycin to cover mouth flora of predominant anaerobes. additional coverage against gram-negative organisms (an aminoglycoside or cefepime) may be indicated if the aspiration is nosocomial. any child with cough of abrupt onset should be suspected of having inhaled a foreign body into the airway. toddlers, who by nature put all types of things into their mouths and who have incompletely matured swallowing and airway protective mechanisms, are at high risk. infants with toddlers or young children in the household who may "feed" the baby are also at risk. in older children, it is usually possible to obtain an accurate history of the aspiration event. these events are described as choking, gagging, and coughing while something (e.g., peanuts, popcorn, small toys, sunflower seeds) is in the mouth. the child may come to the physician with cough and wheeze immediately after the event, with a clear history and a straightforward diagnosis. in many children with a tracheobronchial foreign body, however, the initial episode is not recognized; these children may not come to medical attention for days, weeks, or even months (fig. 2-9 ). the initial episode may be followed by a relatively symptomless period lasting days or even weeks, until infection develops behind an obstructed segmental or lobar bronchus. at this point, cough, perhaps with hemoptysis, with or without wheeze, recurs. on physical examination early after an aspiration episode, there is cough, wheeze, or both, often with asymmetry of auscultatory findings. there may be locally diminished breath sounds. later, localized wheeze or crackles may be detected. in some cases, the two-headed stethoscope may enable the examiner to recognize that a lobe or lung has delayed air entry or exit in comparison with the other side. the triad of wheezing, coughing, and decreased breath sounds is present in fewer than 50% of patients. the presence of laryngotracheal foreign bodies often manifests with stridor, retractions, aphonia, cough, and normal radiographs. chest radiographs may be normal in 15% of patients with intrathoracic foreign bodies but should be obtained in both inspiration and expiration, because in some cases the only abnormality is unilateral or unilobar air trapping, which is occasionally more clearly identified with a view in expiration. in this view, an overdistended lung that had appeared normal on the inspiratory view does not empty, but the normal, unobstructed lung empties normally. this phenomenon causes a shift of the mediastinum toward the emptying lung (away from the side with the obstructing foreign body). in other patients, localized infiltrate or atelectasis may be present behind the obstructing object. in a few patients, it may be possible to identify the foreign body itself; nonetheless, most inhaled food particles are not radiopaque and cannot be seen on radiographs. aspiration is usually unilateral (80%); 50% to 60% of the objects are in the right lung (the lobe depends on body position-supine versus standing-but is often the right middle lobe). the definitive diagnostic and therapeutic maneuver is bronchoscopy; either the flexible or rigid open-tube bronchoscope enables direct visualization of the object; the rigid instrument also enables its removal. ger is a common cause of cough in all age groups (see chapter 16). the typical patient is an infant in the first 6 months of life who spits up small amounts of milk frequently after feedings. this "regurgitant reflux" most commonly resolves by 1 year of age. however, many toddlers and children continue to have reflux, although it may be "silent" or nonregurgitant (without spitting up). in most people with ger, it is merely a nuisance or not noticed. in some there are sequelae, and this condition is designated gastroesophageal reflux disease (gerd). one manifestation is cough; the mechanisms for the cough are not fully understood. aspiration of refluxed material is one mechanism for cough but is probably not very common in neurologically intact children. a major mechanism for gerd with cough is mediated by vagal esophagobronchial reflexes (bronchoconstriction), stimulated by acid in the esophagus. whether acid in the esophagus is sufficient stimulus to cause bronchoconstriction by itself or whether it merely heightens bronchial reactivity to other stimuli is not yet clear (see chapter 3). many children with reactive airways disease have cough or wheeze that is difficult to control until their concurrent ger is also treated. many episodes of cough caused by gerd occur in children with asthma that is difficult to control. the diagnosis of gerd must also be considered in the child with chronic or recurrent cough with no other obvious explanation. the child who coughs after meals or at night, when the supine position may provoke ger, should be evaluated for ger. if ger is confirmed, the next step is a therapeutic trial of antireflux therapy (see chapter 16). if the results of the therapeutic trial are negative or equivocal, it may make sense to establish a causal relationship between the ger and the cough, by using the modified bernstein test. during this test, hydrochloric acid and saline are alternately infused into the esophagus through a nasoesophageal tube while the child is observed for cough or wheeze or while the older child undergoes serial pulmonary function tests. if the symptoms occur or if pulmonary function deteriorates during acid but not saline infusion, it is likely that esophageal acidification through ger is the cause of the child's cough or wheeze. treatment in a child whose cough is related to ger may be accomplished by treating the reflux (see chapter 16) or by a combination of antireflux and antiasthma treatment (see chapter 3). theophylline may worsen ger by lowering the tone of the lower esophageal sphincter, and some drugs that increase lower esophageal sphincter tone may cause bronchoconstriction. on occasion, the cough may be abolished by stopping all antiasthma medications. in such cases, the cough was a manifestation of reactive airways with esophageal acidification as the trigger for bronchospasm; the esophageal acidification was caused by the bronchodilator effects on the lower esophageal sphincter. inhaled bronchodilators are less likely than oral or intravenous drugs to cause ger. cough is frequently the sole or most prominent manifestation of asthma; wheezing may be entirely absent. in fact, reactive airway disease or asthma (see chapter 3) is almost certainly the most common cause of recurrent and chronic cough in childhood. some of the features that characterize the cough of a child with asthma are listed in table 2 -15. treatment for asthma manifesting as cough is the same as the treatment for asthma (see chapter 3). cf is a common cause of recurrent or chronic cough in infancy and childhood. cf occurs in 1 in 2500 live births among white persons, is far less common among african americans (1 in 17,000), and is rare among native americans and asians. early diagnosis improves the poor prognosis for untreated cf; if untreated, many patients die in infancy or early childhood. with current state-of-the-art care, median length of survival is to age 31. cf is a genetic disorder, inherited as an autosomal recessive trait. the cf gene is on the long arm of chromosome 7; more than 1000 mutations have been identified at the cf locus. of these mutations, one (δf508, indicating a deletion, δ, of a single phenylalanine, f, at position 508 of the protein product) is the most common, responsible for 70% to 75% of all cf chromosomes. the currently recognized mutations account for approximately 90% of cases. the mutation affects the gene's protein product, termed cystic fibrosis transmembrane regulator, which acts as a chloride channel and affects other aspects of membrane transport of ions and water. not all the consequences of the defective gene and protein have been determined. most explain the long-observed clinical manifestations of the disease, including thick, viscid mucus in the tracheobronchial tree, leading to purulent bronchiolitis and bronchitis with subsequent bronchiectasis, pulmonary fibrosis, and respiratory failure; pancreatic duct obstruction, leading to pancreatic insufficiency with steatorrhea and failure to thrive; and abnormally high sweat chloride and sodium concentrations. the airway disease in cf is characterized by infection, inflammation, and endobronchial obstruction. the infection begins with s. aureus, h. influenzae, escherichia coli, klebsiella species, or combinations of these organisms but eventually is dominated by nonmucoid or mucoid pseudomonas aeruginosa. other organisms, such as burkholderia cepacia, xanthomonas maltophilia, alcaligenes xylosoxidans, aspergillus fumigatus, or nontuberculous mycobacteria may also appear; their significance remains undetermined. in some patients, b. cepacia has been associated with rapid deterioration and death, and in others, aspergillus species has caused allergic bronchopulmonary aspergillosis. the airway inflammation in all patients with cf appears to be the result of toxic substances, including elastase, released by neutrophils as they respond to the endobronchial infection and by similar enzymes released by the invading organisms. cf may manifest at birth with meconium ileus (10% to 15% of patients) or later, with steatorrhea and failure to thrive despite a voracious appetite, in an apparent effort to make up for the calories that are lost in the stool (see chapter 15). the most common presenting symptom is cough, which may appear within the first weeks of life or may be delayed for decades. the cough can be dry, productive, or paroxysmal. cough may respond to antibiotics or perhaps steroids, but it is less likely to improve with bronchodilators (see tables 2-3 and 2-5). although cf is a genetic disease, there is often no family history. furthermore, in atypical cases, patients may not have pancreatic insufficiency (usually present in 85% to 90%) and thus may not demonstrate steatorrhea and failure to thrive. in addition, malabsorption may not be evident in the neonatal period. there is no such thing as a child who looks "too good" to have cf; common abnormalities found on physical examination are noted in table 2 -16. one of the most important physical findings is digital clubbing. in most patients with cf, clubbing develops within the first few years of life. although the list of conditions associated with digital clubbing (table 2-17) is long, they are less common than cf, or the incidence of digital clubbing with these conditions is low. there is some relationship between the degree of pulmonary disease severity and the degree of digital clubbing. a child who has had years of severe respiratory symptoms without digital clubbing is not likely to have cf. the diagnosis is confirmed by a positive sweat test or confirming the presence of two cf mutations on chromosome 7. the sweat test, if not performed correctly in a laboratory with extensive experience with the technique (as, for example, in an accredited cf center), yields many false-positive and false-negative results. the proper technique is to use the gibson-cooke method, with quantitative analysis of the concentration of sodium, chloride, or both, in the sweat produced after pilocarpine iontophoretic stimulation. chloride (and sodium) concentrations higher than 60 meq/l are considered positive indications, and those lower than 40 meq/l are negative (normal). healthy adults have slightly higher sweat chloride concentrations than do children, but the same guidelines hold for positive tests in adults. the non-cf conditions yielding elevated sweat chloride concentrations are listed in table 2 -18. false-negative results of sweat tests can be seen in cf children presenting with edema or hypoproteinemia and in samples from children with an inadequate sweat rate. sweat testing can be performed at any age; newborns within the first few weeks of life may not produce a large enough volume of sweat to analyze (75 mg minimum), but in those who do (the majority), the results are accurate. indications for sweat testing are noted in table 2-19. in patients for whom sweat testing is difficult (e.g., because of distance from an experienced laboratory, small infants who have not produced enough sweat, patients with extreme dermatitis, or patients with intermediate-range sweat chloride concentrations), dna testing can be useful. demonstration of two known cf mutations confirms the diagnosis. finding one or no known mutation makes the diagnosis less likely but is not exclusive, inasmuch as there are patients with not-yet-characterized mutations. furthermore, commercial laboratories do not identify all of the 1000-plus mutations. recovery of mucoid p. aeruginosa from respiratory tract secretions is strongly suggestive of cf. similarly, pansinusitis is nearly universal among cf patients but is quite uncommon in other children. some states are using a neonatal screen for cf. the cf screen is for immunoreactive trypsinogen (irt) levels, which are elevated in most infants with cf for the first several weeks of life. (some states do genetic testing on dna.) because of the very high sensitivity of this test (almost no one with cf has normal irt levels) and because early institution of treatment is beneficial, this test may come into wider use. its main drawback is that it has relatively poor specificity; as many as 90% of the positive results on the initial screen are false-positive results. if an infant's irt screen is positive, the test should be repeated; at 2 to 3 weeks of age, which is when the test is repeated, the false-positive rate has fallen dramatically but is still quite high (25%). definitive testing needs to be carried out on infants with two elevated irt levels. in the unusual older child whose appendix is removed and examined carefully by a knowledgeable pathologist, the diagnosis may be suggested by the typical histologic appearance of the appendix (the mucus-secreting glands are overdistended with eosinophilic material). laboratory data that may support the diagnosis of cf include absence of stool trypsin or chymotrypsin. this suggests pancreatic insufficiency, which occurs most commonly in cf but can be seen in other diseases. the test is not perfect even for confirming pancreatic insufficiency, because intestinal flora may produce or destroy trypsin. pulmonary function test findings with an obstructive pattern, incompletely responsive to bronchodilators, are consistent with cf but, of course, can be seen in other conditions. conversely, some patients with cf also have asthma and may show a marked response to a bronchodilator. complications of cf that should suggest the diagnosis are noted in table 2 -20. the treatment of patients with cf requires a comprehensive approach, best performed in, or in conjunction with, an approved cf center. several studies have shown survival to be significantly better in center-based care than in non-center-based care. the treatment of the pulmonary aspects of cf involves approaching the obstruction, infection, and inflammation that cause the cough. cough should be monitored closely, and any increase in frequency or in the intensity should be taken as an indication that there is worsening endobronchial infection, inflammation, or both. because active infection and inflammation lead to irreversible lung damage, such changes need to be taken seriously and treated aggressively. this is just as true for the appearance of a mild morning cough in the child who was previously cough free as it is for severe coughing spells that keep a child awake through the night. obstruction is treated with physical means (chest physical therapy, with percussion, vibration, and postural drainage) to dislodge the mucus into the large central airways, where cough can then effectively clear it. studies have shown this rather crude and timeconsuming procedure to be effective in helping to maintain lung function acutely and over a period of years. variations on the physical maneuvers to help with mucus clearance include forced expiratory technique, positive airway pressure face masks, and masks with expiratory flutter valves. the frequency with which any of these physical means of expelling mucus should be used varies but should be increased with signs of active infection and obstruction. other approaches to relieving obstruction in the bronchial tree include the use of inhaled bronchodilators (despite a paucity of studies showing their long-term efficacy) and mucolytic agents. n-acetylcysteine (mucomyst) has been available for years, but it may cause tracheobronchial irritation, with bronchorrhea, bronchospasm, or both, in an unacceptably high proportion of patients. an inhaled drug, dornase alfa, or recombinant human dnase (pulmozyme), is clearly effective in the test tube for liquefying the thick mucus associated with cf. this occurs because 40% of the mucus viscosity in cf is attributed to dna released from dying polymorphonuclear cells. another drug that appears promising is amiloride. long available as a diuretic, amiloride can bring about a partial correction of the membrane transport defects in cf. amiloride aerosols seem to decrease sputum viscosity and increase cough clearance. in a small 6-month study, aerosolized amiloride appeared to slow the decline in lung function. the approach to endobronchial infection in children with cf includes prevention and treatment. prevention involves immunizing patients with cf against preventable respiratory pathogens, particularly influenza, measles, and pertussis. prevention also means avoiding unnecessary exposure to respiratory viruses (e.g., at day care centers). it should not mean avoiding school or other social functions and settings, because this approach is invariably futile and can cause severe emotional damage. however, spread of bacteria, especially resistant organisms such as b. cepacia, between patients is a concern. treatment of infection usually proceeds in a stepwise manner. if colonies of h. influenzae or s. aureus are present, appropriate antibiotics should be initiated. if no recent throat or sputum specimens for culture are available, and if the patient is young with very mild lung disease, empirical therapy can also be directed at those organisms. in the older or sicker patient who has any sign of chronic pulmonary involvement, such as pulmonary overinflation, infiltrates on a chest film, digital clubbing, or severe coughing spells, it makes sense to include antibiotics effective against p. aeruginosa (fig. 2-10 ; table 2 -21) . treatment of the inflammation associated with cf is evolving. some patients benefit from short-term oral prednisone. a 4-year study of alternate-day prednisone showed improved pulmonary function but unacceptable side effects (e.g., glucose intolerance, growth failure) in those taking 2 mg/kg/day and similar side effects (although less severe) in those taking 1 mg/kg/day. the beneficial role of oral nonsteroidal antiinflammatory agents has been demonstrated; the role of inhaled topical steroids and α1-antitrypsin is being investigated. table 2 -22 lists the main anatomic abnormalities (most of them congenital) that cause cough. vascular rings and slings are often associated with inspiratory stridor because the abnormal vessels compress central airways, most commonly the trachea (see chapter 5). the patient may also have difficulty swallowing if the esophagus is compressed. the diagnosis may be suspected from plain films of the chest, especially those showing tracheal deviation and a right-sided aortic arch. further support for the diagnosis can be found at bronchoscopy (which shows extrinsic compression of the trachea or a mainstem bronchus), barium swallow study (which shows esophageal compression), or both. the definitive diagnosis is made with magnetic resonance imaging, angiography, or magnetic resonance angiography. treatment is surgical. pulmonary sequestration is relatively unusual, occurring in 1 in 60,000 children. it occurs most commonly in the left lower lobe and can manifest in several ways (fig. 2-11 ; see table 2 -22) . the chest radiograph usually shows a density in the left lower lobe; this density often appears to contain cysts. the feature distinguishing a sequestered lobe from a complicated pneumonia is that the blood supply arises from the aorta and not the pulmonary circulation. doppler ultrasonography and angiography provide the definitive diagnosis. the treatment is surgical removal. cystic adenomatoid malformation is a rare condition. it manifests in infancy with respiratory distress in nearly 50% of cases; the other half may manifest as cough with recurrent infection later in childhood or even adulthood. the chest film reveals multiple cysts, separated by dense areas. chest ct scans can help make the diagnosis with near certainty. surgical removal is the treatment. congenital lobar emphysema occurs in one of 50,000 live births. it can manifest dramatically with respiratory distress in the neonatal period or later (fig. 2-12) , with cough or wheeze, or as an incidental finding on a chest radiograph. radiography shows localized overinflation, often dramatic, with compression of adjacent lung tissue and occasionally atelectasis of the contralateral lung because of mediastinal shift away from the involved side. the appearance on chest ct scan is typical, with widely spaced blood vessels (as opposed to congenital cysts, for example, which have no blood vessels within the overinflated area). bronchoscopy can document patent bronchi and should probably be performed in older children, in whom congenital lobar emphysema can be confused with acquired overinflation of a lobe as the result of bronchial obstruction, as with a foreign body. if the disease is symptomatic, treatment is surgical. tracheoesophageal fistula is common, with an incidence of about one in 5000 live births. of these fistulas, the large majority (85%) are associated with esophageal atresia; only 3% are the isolated, h-type fistula (a patent esophagus with fistulous tract connecting the esophagus and trachea). a neonate with esophageal atresia experiences respiratory distress, excessive drooling, and choking and gagging with feeding. the h-type fistula causes more subtle signs and may be undiagnosed for months or even years. the child may have only the diagnosis is not challenging in the infant with esophageal atresia; a nasogastric tube cannot be passed, and swallowed barium outlines the trachea. in the older child with h-type fistula, a barium esophagogram may or may not reveal the fistula. bronchoscopy and esophagoscopy should permit direct visualization of the fistula; however, the opening may be hidden in mucosal folds. treatment is surgical. many children born with tracheoesophageal fistula have recurrent cough and lower respiratory tract infection for many years, even after successful surgical correction. the cough is characteristically the harsh cough of tracheomalacia, which is present at the site of the fistula. the infections result from several causes, including ger, with or without aspiration, and altered mucociliary transport. treatment involves regular chest physical therapy and early and aggressive use of antibiotics whenever there is evidence of increased pulmonary symptoms. hemangiomas may be present within the airway and can cause cough, rarely with hemoptysis; stridor (if the hemangioma is high in the airway) and respiratory distress (if the hemangioma is large) may also occur. in rare cases, with very large airway hemangiomas, there may even be dysphagia from extrinsic compression. about 50% of children with airway hemangiomas have cutaneous hemangiomas as well. the diagnosis is made with bronchoscopy. as with cutaneous hemangiomas, these lesions may resolve spontaneously over the first year or so. however, if they cause symptoms, it may not be advisable or possible to wait for them to resolve. many airway hemangiomas regress with steroid treatment, although others have been shown to respond to interferon-α. laser ablation may be indicated in some refractory cases. in the case of a large subglottic hemangioma, a tracheostomy is frequently performed and maintained until the mass regresses. enlarged mediastinal lymph nodes, such as those resulting from tuberculosis, leukemia, other hematologic malignancies, or other infections, are occasionally a cause of cough in children (tables 2-22 and 2-23). these nodes are usually seen on plain films of the chest. the x-ray study or bronchoscopy may show extrinsic compression of the trachea. treatment is directed at the underlying cause. occasionally bronchial stenosis, either congenital or acquired, may cause cough. the diagnosis is made with bronchoscopy, after suspicion has been raised by the child's having recurrent infiltrates in the same lobe, especially with localized wheeze. treatment may be difficult. in some cases, endoscopic balloon dilatation or airway stent placement is successful; in others, surgical resection of stenotic areas may be necessary. bronchogenic cysts are uncommon, but they can cause cough, wheeze, stridor, or any combination of these. they may also cause recurrent or persistent pneumonia if they block a bronchus sufficiently to interfere with normal drainage of the segment or lobe. radiography may show localized overinflation if the cyst causes a ball-valve-type obstruction. the cyst itself may or may not be seen on plain films. bronchoscopy reveals extrinsic compression of the airway. ct studies often definitively show the lesion. surgical removal is indicated. on occasion, a school-aged child may develop a cough that lasts for weeks, often after a fairly typical cold. this cough occurs only during wakefulness, never during sleep. in many cases, the cough is harsh and foghorn-like. it often disrupts the classroom, and the child is asked to leave. the child is otherwise well and may seem rather unbothered by the spectacle created. there has been no response to medications. it seems that this type of cough, often termed "psychogenic," or "psychogenic cough tic," but perhaps more accurately and humanely thought of as habit cough, has given the child valuable attention. this attention then serves as the sustaining force, and the cough persists beyond the original airway inflammation. in the small minority of cases, there may be deep-seated emotional problems, of which the cough is the physical expression. during the history or physical examination, the child appears completely well and may cough when attention is drawn to the child or when the word "cough" is uttered. the physical examination findings are otherwise completely normal, as are laboratory values. because this may occur in any child, evidence of mild reactive airways disease (history or pulmonary function testing) does not rule out the diagnosis. once a physician has seen a child with this problem, it is usually possible to make the diagnosis with certainty on entering the examining room or, indeed, from the hallway outside the room. treatment can prove more difficult. there are several treatment schools, summarized in tables 2-24 and 2-25. one approach is "the bed sheet," in which the child is told that he or she coughs because of weak chest muscles. a bed sheet is wrapped tightly and uncomfortably around the chest "to serve as added support for the muscles … [and] with this support, the muscles would then be able to suppress [the] cough." the child is to go to school wearing the bulky bed sheet under his or her clothes and may not remove the sheet until he or she is certain that the cough will not return. the authors who describe this method call it a "reinforcement suggestion technique." some view this approach as demeaning to the child. whatever its mechanism of action, this method was reported to have been successful in 31 of 33 patients. postnasal drip is thought to be a major cause of cough in adults. the mechanism by which this occurs is unclear, and most pulmonologists believe that this must remain a diagnosis of exclusion for explaining cough in children. bronchiectasis is defined as an abnormal dilation of the subsegmental bronchi and is usually associated with chronic cough and purulent sputum production. it occasionally occurs after severe pneumonias (bacterial or viral); it eventually develops in nearly all patients with cf. diagnosis may, on occasion, be made with plain chest radiographs, but high-resolution ct scanning is the diagnostic procedure of choice, replacing bronchography. treatment of bronchiectasis consists of chest physiotherapy and postural drainage, occasionally bronchodilators and mucolytic agents, and antibiotic therapy during exacerbations. surgical resection may be indicated in cases that are progressive and localized when medical therapy has failed. the prognosis of bronchiectasis depends on the underlying cause. bronchiectasis associated with cf is fatal, although many cases of bronchiectasis remain stable or may even regress with therapy. conditions in which the cilia do not function properly (dysmotile cilia or ciliary dyskinesia) lead to cough, usually because infection (and bronchiectasis) occurs in the absence of normal mucociliary transport. treatment is similar to that for cf, with regular chest physical therapy and frequent and aggressive use of antibiotics at the first sign of airways infection, most commonly increased cough. there are several varieties of interstitial lung disease: desquamative, lymphoid, and "usual" (see chapter 3). all are very uncommon in childhood, and little is known about their causes, courses, or treatment. one type of pediatric interstitial lung disease, the lymphoid type, is becoming much more common, inasmuch as it is seen in human immunodeficiency virus (hiv) infection. interstitial lung disease manifests with cough, dyspnea, and crackles on examination. because the diagnosis is based on histologic findings, lung biopsy is required. the only exception to this may be in the child with documented acquired immunodeficiency syndrome who has new pulmonary infiltrates and symptoms, in whom bronchoscopy and bronchoalveolar lavage are initially used to diagnose infection (p. carinii, cytomegalovirus). interstitial lung disease in a patient with a chronic seborrhea-like dermatitis should suggest the diagnosis of histiocytosis x. heart failure can cause cough but seldom as its sole clinical manifestation. pulmonary hemosiderosis is a rare, and often fatal, condition of bleeding into the lung that can manifest with cough. if sputum is produced, it is often frothy and blood-tinged. there may be frank hemoptysis. however, the cough may be nonproductive, or the sputum may be swallowed. some cases are associated with milk perform all possible tests can tell patient and family: "we've reinforces the idea of a physical cause ruled out all physical problems." in one study, resolution followed bronchoscopy ("aversive stimulus"?) apply an aversive stimulus has worked in some patients by definition, this treatment is unpleasant (e.g., an electric shock to forearm) try the "bed sheet" (see text) seems to work in most patients demeans the patient try placebo drugs probably works in some patients is a dishonest technique provide psychotherapy may work in some patients is unnecessary in most patients; labels the patient as having a psychological problem gently explain that there is no physical works in some patients is resented by some families focused on cause and this is a habit that the body an organic cause or treatment has sustained prevent mouth breathing by holding a has worked in some patients not known button between the patient's lips apply speech therapy techniques (see works in many patients: can be presented is resented by some families focused on table 2-25) as specific therapy; nonthreatening organic cause or treatment treatment is often unsatisfactory; the mortality rate is as high as 50%. milk products should be eliminated from the patient's diet, and underlying collagen vascular disease should be treated. some affected children seem to respond to corticosteroids or cytotoxic drugs (e.g., azathioprine, cyclophosphamide, and chlorambucil), but the episodic nature of the disease, with some clear cases of spontaneous resolution, makes it difficult to evaluate therapies. see chapter 3. tumors, which fortunately are rare in childhood, can cause cough, usually because of bronchial blockage, either extrinsic or endobronchial (see table 2 -23). the diagnosis is usually made from bronchoscopy, chest ct, or both. treatment depends on the cell type, but it usually involves at least some surgical removal. chemotherapy or radiation may be used in some cases. isolated tracheomalacia or bronchomalacia is uncommon but can cause cough in some children. the cough of tracheomalacia is typically harsh and brassy. treatment is difficult but, fortunately, is seldom needed. some children, usually preschoolers, may episodically awaken at night with stridor and a harsh, barking cough indistinguishable from that of viral croup. this entity is termed spasmodic croup and is of unclear origin. viral and allergic causes have been postulated. ger may be the cause in some patients. treatment with cool mist or racemic epinephrine is effective in most patients. if ger is the underlying cause, antireflux treatment is beneficial. obliterative bronchiolitis is very rare except in lung transplant recipients. in other instances, it may arise after adenovirus, measles, or influenza pneumonia; after exposure to certain toxins; or in other rare circumstances. children may exhibit cough, respiratory distress, and exercise intolerance. the diagnosis is suggested by the pulmonary function or radiographic evidence of small airways obstruction; however, these findings are not always present. not all chest films show overinflated lungs, and not all pulmonary function tests show decreased small airways function. the definitive diagnosis is histologic via open or transbronchial biopsy. no specific treatment is available. most children with obliterative bronchiolitis recover, but many progress to chronic disability or death. the child who coughs out blood or bloody mucus presents special diagnostic and therapeutic challenges. although hemoptysis is relatively uncommon in children, particularly among those without cf, many conditions can cause it (table 2-27) . it is important (and not always easy) to distinguish cases in which blood has originated in the tracheobronchial tree (true hemoptysis), the nose (epistaxis), and the gastrointestinal tract (hematemesis). table 2 -28 gives some guidelines to help localize sites of origin of blood that has been reported or suspected as hemoptysis. none of these is foolproof, partly because blood that has originated in one of these sites might well end in another before being expelled from the body; for instance, blood from the nose can be swallowed and vomited or aspirated and coughed out. infection is among the most common causes of hemoptysis. lung abscess and tuberculosis need to be considered. bronchiectasis can readily cause erosion into bronchial vessels, often made tortuous by years of local inflammation, and produce hemoptysis. other infectious settings are less common and include necrotizing pneumonias and fungal and parasitic lung invasion. foreign bodies in the airway can cause hemoptysis by direct irritation, by erosion of airway mucosa, or by secondary infection. pulmonary embolus is uncommon in children and adolescents, but it needs to be considered in the differential diagnosis of an adolescent with hemoptysis of unclear origin. clues to the diagnosis of pulmonary embolus include a positive family history, severe dyspnea, chest pain, hypoxia, a normal chest film, an accentuated second heart sound, an abnormal compression ultrasonographic study of the leg veins, a positive homans sign, a positive helical ct scan, and a high-probability lung ventilation-perfusion scan. the diagnosis of several causes of hemoptysis is straightforward. for example, hemoptysis that occurs immediately after a surgical or invasive diagnostic procedure in the chest should suggest an iatrogenic problem. the chest film can help suggest lung abscess, pulmonary bronchoscopy can sometimes localize a bleeding site, identify a cause (e.g., a foreign body or endobronchial tumor), or recover an offending bacterial, fungal, or parasitic pathogen. in many instances, bronchoscopy does not help except by excluding some possibilities, because either no blood or blood throughout the tracheobronchial tree is found. bronchial artery angiography may help to identify the involved vessel or vessels. treatment of hemoptysis depends on the underlying cause. it can be a terrifying symptom to children and their parents, and a calm, reassuring approach is essential. because hemoptysis is seldom fatal in children, reassurance is usually warranted. furthermore, hemoptysis most often resolves, and treatment of the bleeding itself is not often needed. what is required is treatment of the underlying cause of the hemoptysis, such as therapy for infection, removal of a foreign body, or control of collagen-vascular disease. when death occurs from hemoptysis, it is more likely to be from suffocation than from exsanguination. in cases of massive bleeding, the rigid open-tube bronchoscope may help suction large amounts of blood while ventilating and keeping unaffected portions of lung clear of blood. interventional radiologists treat as well as localize a bleeding site by injecting the offending vessel with occlusive substances, such as gelfoam or silicone coils. in extremely rare instances, emergency lobectomy may be indicated. cough itself seldom necessitates specific treatment. nonetheless, cough is not always completely benign (see table 2 -9). most complications are uncommon, and most accompany only very severe cough, but some are serious enough to justify treatment of the cough itself. cough suppressants include codeine and hydrocodone (two narcotics) and dextromethorphan (a nonnarcotic d-isomer of the codeine analogue of levorphanol). such agents should be used only for severe cough that may produce significant complications (see table 2 -9). for most diseases, suppressing the cough offers no advantage. disadvantages include narcotic addiction and loss of the protective cough reflex with subsequent mucus retention and possible superinfection. demulcent preparations (sugar-containing, bland soothing agents) temporarily suppress the cough response from pharyngeal sources, and decongestant-antihistamine combinations may reduce postnasal drip and thus cough in adults. evaluation of chronic or recurrent cough the cough and the bedsheet managing cough as a defense mechanism and as a symptom. a consensus panel report of the american college of chest physicians bacterial tracheitis: report of eight new cases and review computed tomographic study of the common cold epidemiology, pathogenesis, and treatment of the common cold does this patient have sinusitis? diagnosing acute sinusitis by history and physical examination report of the committee on infectious diseases chlamydial respiratory infections infant pneumonitis associated with cytomegalovirus, chlamydia, pneumocystis, and ureaplasma: follow-up value of radiological follow-up of childhood pneumonia etiology and treatment of pneumonia report of a workshop on respiratory viral infections: epidemiology, diagnosis, treatment, and prevention pulmonary manifestations of acquired immunodeficiency syndrome standardized diagnosis of pneumonia in developing countries the causes of hospital-treated acute lower respiratory tract infection in children hypoxaemia in young kenyan children with acute lower respiratory infection the evaluation of the child with recurrent chest infections bronchoscopic removal of aspirated foreign bodies in children tracheobronchial foreign bodies subglottic foreign bodies in pediatric patients tracheobronchial foreign bodies cystic fibrosis the cystic fibrosis genotype-phenotype consortium. correlation between genotype and phenotype in patients with cystic fibrosis prospects for gene therapy in cystic fibrosis prediction of mortality in patients with cystic fibrosis wheezing in infants with cystic fibrosis: clinical course, pulmonary function, and survival analysis physiotherapy in cystic fibrosis efficacy and safety of short-term administration of aerosolised recombinant human dnase i in adults with stable stage cystic fibrosis the diagnosis of cystic fibrosis: a consensus statement emerging therapies for cystic fibrosis pseudomonas cepacia: pulmonary infection in patients with cystic fibrosis effect of long-term treatment with inhaled budesonide on adult height in children with asthma a clinical index to define risk of asthma in young children with recurrent wheezing airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age low-dose inhaled corticosteroids and the prevention of death from asthma third international pediatric consensus statement on the management of childhood asthma. international pediatric asthma consensus group venous thromboembolic complications in children clinical assessment and management of massive hemoptysis massive haemoptysis: medical management will usually arrest the bleeding pathogenesis and management of hemoptysis in children cough is important because it is a symptom and sign of underlying disease that frequently merits treatment. in the acute setting, severe disease, including massive hemoptysis or profound dyspnea or hypoxemia, warrants immediate attention, rapid diagnosis, and rapid management. certain chronic conditions, including those that suggest cf and those in which symptoms have persisted and interfere with a child's daily activities and quality of life, warrant further evaluation and treatment. finally, a child whose cough fails to respond to what should have been reasonable treatment should be referred to a pulmonary specialist (table 2-29) . key: cord-029480-3md13om6 authors: meix-cereceda, pablo title: educational values in human rights treaties: un, european, and african international law date: 2020-07-21 journal: hum rights rev doi: 10.1007/s12142-020-00599-6 sha: doc_id: 29480 cord_uid: 3md13om6 while human rights treaties provide a formidable set of principles on education and values, domestic courts often tend to adjudicate claims in terms of local arguments for or against each particular educational practice. this article explores how international human rights law could inspire the interpretation of domestic law and educational practice, without neglecting specific cultural aspects. firstly, the article reviews the sociological debate on values in education and shows its importance for the legal discussion. secondly, some critical contestations of international cultural human rights are outlined, as well as certain arguments to justify the importance of this model. the study of international law follows: the un, the european court of human rights, and three relevant african charters, as well as every reference to education made by the african commission on human and peoples’ rights and by the african court is examined. lastly, a comparative section reveals a certain cultural commonality inspired by the un treaties, but also reflects some cultural and institutional differences between the european and the african regional systems. educational action in schools. botha (2019, 185) has advocated the importance of international law as a reference and inspiration for interpreting domestic law and practice on educational matters involving human rights. with regard to national legal systems, du plessis (2019, 49 and 2020) has pointed out the exemplarity of the preamble of the south african national education policy act 27 of 1996 when it proclaims that "the education system must be transformed into one which serves the needs and interests and upholds the fundamental rights of all the people of south africa." nevertheless, the concrete result in each learner's education will vary according to a complex interaction of all the aforementioned factors. using a sculptural metaphor, constitutions and international human rights treaties would provide a sediment of values to the educational clay. however, this clay will be modeled, to a greater or a lesser extent, by the hands of all the aforementioned actors. the starting point of this piece is that education always implies the transmission of certain values which, nevertheless, are sometimes in a tension with each other or even contradict each other. therefore, the absorption of values in each learner's case is not easily controlled by one single force but is the result of many influences. the child's own freedom will in all probability play a major role in how these values intertwine and weigh on their moral decisions. the notion of human rights culture has been contested as reflecting a eurocentric philosophy of the individual. indeed, as stoppioni (2020, 2) has recently reminded, "the fundamental problem of the european conception of human rights would be to focus exclusively on the individual and to forget the group". a harsher critique considers that "'human rights' are, as such, a false ideological universality, which masks and legitimizes a concrete politics of western imperialism, military interventions and neocolonialism" (žižek 2005) . these arguments criticize what bonfiglio (2018) has called "human rights colonialism," which the same author has sought to overcome by proposing an intercultural theory of human rights. from an african perspective, justice mokgoro (1998, 8) , of the constitutional court of south africa, has claimed the proximity between human rights and the traditional values of ubuntu, while acknowledging that the communal dimension of ubuntu could enrich the interpretation of western law. in this regard, she mentions in particular the following ideas: -the original conception of law perceived not as a tool for personal defense, but as an opportunity given to all to survive under the protection of the order of the communal entity -communalism which emphasizes group solidarity and interests generally, and all rules which sustain it, as opposed to individual interests, with its likely utility in building a sense of national unity among south africans -the conciliatory character of the adjudication process which aims to restore peace and harmony between members rather than the adversarial approach which emphasizes retribution and seems repressive. the lawsuit is viewed as a quarrel between community members and not as a conflict. the importance of group solidarity requires restoration of peace between them -the importance of public ritual and ceremony in the communication of information within the group -the idea that law, experienced by an individual within the group, is bound to individual duty as opposed to individual rights or entitlement. closely related is the notion of sacrifice for group interests and group solidarity so central to ubuntu(ism) -the importance of sacrifice for every advantage or benefit, which has significant implicants for reciprocity and caring within the communal entity even if they were not written apropos of education, these reflections seem especially relevant to the debate on educational values, in particular with respect to which values the school system ought to promote and the related problem of conflict and restorative justice in schools. the abovementioned critical views, however, cannot undermine the importance of international protection. as will be discussed especially in "african union: commonality and specificities", regional international bodies have both the necessary independence from states and the ability to deliver a relevant view in terms of idiosyncratic proximity. in addition, the lack of adequate solutions in certain domestic cases would prove the necessity of international protection for at least certain categories of subjects. this seems of particular relevance in the case of children, arguably the most vulnerable subjects of human rights. some examples from southern african domestic courts may be helpful to illustrate the latter claim. in some cases, national courts have selected international rulings that may be isolated in a court's body of case law or not applied as a meaningful precedent by the international court itself. for instance, in the arundel school case 2 the constitutional court of zimbabwe ruled against the application of certain pupils who had been obliged to attend school prayer by the new headmistress. the pupils' parents, who were jehova's witnesses, had expressly declared their faith upon the application for admission of their children, and the children had been attending the school before the arrival of the new headmistress. despite the fact that the application had been filed by the parents, the constitutional court expressly declared the right to expel the pupils, which the school had not yet carried out. even more surprising, however, was the fact that the constitutional court based on the european court's reasoning in the case of valsamis of 1996, which has been changed in more recent rulings on similar claims, such as the cases of folgerø (2007), zengin (2007), or yalçın (2014) (see below, "european court of human rights" for details). in other cases, national courts simply refrain from using international law as a source of inspiration, even when it could reinforce the authority of their own rulings. in this regard, the generally protective constitutional court of south africa rarely integrates arguments from international law when ruling on matters concerning children and education. in the case of the juma musjid primary school, 3 the principle of the child's best interest was only discussed in terms of national constitutional law in spite of the importance that international law has in this field (see below "full development of the human personality and best interest of the child"). in this case, an eviction order was sought by the owner of the land where a school was based. the constitutional court mentioned certain international treaties and soft law on the right to education, 4 and even a us supreme court ruling, 5 but no international decisions by african or un bodies were considered. the constitutional court held that the kwazulu-natal high court had failed to take account of the interests of the learners and, instead, had simply "privileged the right to property over the learners' right to a basic education" (para 71). nevertheless, the court considered that the children had been successfully accommodated by other schools and therefore ruled for the owners and granted the order of eviction. another important case from south africa concerned the pregnancy policies adopted by several schools. in the welkom and harmony high schools case, 6 the constitutional court declared these policies unconstitutional for being contrary to a number of rights including non-discrimination, the right to education, and the respect of the child's best interest. 7 as will be discussed below, the african commission on human and peoples' rights has often sought to convince states and schools of the need to ensure school attendance of girls in general, and very especially in the case of pregnancy. nevertheless, and despite a specific allegation by one of the parties, the constitutional court did not mention any rule of international law in its judgment. other situations and cultural practices may deeply affect the full development of children and their right to education, as demonstrated by the achpr's appeals against genital mutilation, child labor, child marriage, and other forms of denial of the right to schooling, as will be discussed in the following sections of this article. while it is difficult to conceive international remedies as a valid instance for reviewing every domestic ruling, they are certainly useful for both denouncing and inspiring educational and legal practice. state authorities-but also individualsshould take notice of the problems detected by international bodies and, with the help of available or new domestic remedies, gradually work toward the improvement of such problems in daily practice. in this regard, the article seeks to provide a comprehensive view of the educational values advanced in three international human rights jurisdictions: the un, the european court of human rights, and the african instruments. part of the elements protected by these jurisdictions is shared by the other systems, but each of them has developed certain specificities. concerning the latter, an effort has been made to examine every allusion to education made by the african court on human and peoples' rights (hereinafter african court) and the african commission on human and peoples' rights (hereinafter achpr). lastly, some comparative considerations on the three systems will be outlined. the universal declaration of human rights (hereinafter udhr) 8 includes a remarkable set of educational values. they have been further developed by some of the major human rights treaties sponsored by the un. four kinds of values seem relevant in this regard. the "full development of the human personality" principle is expressly mentioned in art 26 para 2 of the udhr and has been adopted as the main goal of education by many treaties and even constitutions. in order to grasp the meaning of this principle, it may be worth exploring some interesting variations across different international treaties and declarations. in 1959, 11 years after the udhr, the declaration of the rights of the child 9 would state that education "will promote (the child's) general culture, and enable him, on a basis of equal opportunity, to develop his abilities, his individual judgement" (principle 7). this declaration acknowledged the relationship between a person's awareness of the world that surrounds them ("general culture") and the development of their personality both in terms of their talents ("abilities") and their moral sense ("individual judgment"). thirty years later, the convention on the rights of the child (crc) would rephrase and widen these ideas stating the following: (…) the education of the child shall be directed to: (a) the development of the child's personality, talents and mental and physical abilities to their fullest potential (…). 10 the main purpose thus became the development of talents and abilities, both mental and physical, as part of the more complex concept of the "child's personality." the 1959 declaration, on the other hand, included what is nowadays considered the main goal that should guide not only education but generally any measure concerning children. indeed, after the abovementioned statement, principle 7 went on as follows: the best interests of the child shall be the guiding principle of those responsible for his education and guidance; that responsibility lies in the first place with his parents. full development of the personality and a child's best interest thus appear clearly connected if we consider the udhr and the declaration of the rights of the child jointly. this connection may be useful in order to construe the principle of best interest in some difficult cases. indeed, when the 1959 declaration referred to the best interests 8 adopted 10 december 1948 unga res 217 a(iii) (udhr). 9 declaration of the rights of the child (proclaimed by the general assembly, resolution 1386 (xiv), a/res/ 14/1386, 20 november 1959) (drc). 10 convention on the rights of the child (adopted on 20 november 1989, entered into force 2 september 1990) 1577 unts 3 (crc) art 29 para 1. of the child as "the guiding principle of those responsible for his education", it also specified that this responsibility lies "in the first place with his parents". this phrase certainly means that parents are, prima facie, considered the fittest to decide what that interest may be. nevertheless, there may be some cases where parents may not be able or willing to distinguish between their own interest or belief, on one hand, and the child's best interest on the other: child labor, 11 underage marriage, 12 female genital mutilation (girls' circumcision), 13 or recruitment into militias 14 are only some of the most dramatic examples. in these cases, it may be difficult to justify an intervention of public authorities based solely on the principle of "the child's best interest," as parents might claim that international law enables them "in the first place" to determine that interest in each case. nevertheless, a joint interpretation of this principle and the full development of the child's personality may prove useful in this regard. an individual's personality may keep developing through all stages of life, which means that full development is almost an ideal, or, from a legal perspective, a principle permanently subject to the possibility of progression. this seems even clearer in the case of a child. therefore, if a decision from the parents may pose a clear threat to the child's future development, intervention from public authorities would then be justified insofar as necessary (and not any further) to safeguard the child's future possibilities of personal development. another interesting variation can be found in the international covenant on economic social and cultural rights 15 : (…) education shall be directed to the full development of the human personality and the sense of its dignity (…) human dignity has been considered as a single human right 16 and as a theoretical foundation of the entire legal system (solozábal echavarría 1994 , 2489 and garcía guerrero 2014 and even of the state (häberle 2004, 319) . from a practical perspective, however, if a person's human rights are violated or even threatened, that person may in all probability not lead a decent life. this paragraph from the icescr hence reminds that the right to education is almost literally a "key right," which raises in children and adults awareness of their own dignity, and eventually allows them to fight for their rights by any means acceptable in their society. from an economic 11 the african commission for human and peoples' rights (achpr) sent on 23 march 2018 a letter of urgent appeal to the authorities of uganda "concerning alleged child labour in extractive industries, particularly gold mining." 12 association pour le progrès et la défense des droits des femmes maliennes (apdf) and the institute for human rights and development in africa (ihrda) v republic of mali african court of human and peoples' rights 11 may 2018, especially paras 71-78. in addition, the achpr's 40th activity report (of 2016) acknowledged that "in january 2016, child marriage was declared illegal in zimbabwe by the constitutional court" (para 27.a.ix). 13 the achpr's 34th activity report (2013) found positive developments for human rights in this regard in senegal and the achpr's 36th activity report (of 2014) in four states of the sudan. 14 the achpr's 34th activity report (2013), para 21, denounced the situation in the republic of congo. 15 perspective, education would allow individuals from poorer origins to improve their situation-which is often described with the "social lift" metaphor. 17 these ideas can be summarized in the words of the committee on economic, social and cultural rights (cescr), which conceives education as "an empowerment right". 18 one last important aspect that un-promoted treaties often link to full individual development is the "strengthening of respect for human rights and fundamental freedoms". this phrase is used to describe one of the two basic aims of education according to art 26 para 2 of the udhr (the other one being the full development of the human personality). the phrase between quotes has thus come to represent, in international legal terms, the effort of the society to create a conscience in the child. in this regard, an early but powerful wording can be found in the 1924 geneva declaration of the rights of the child: the child must be brought up in the consciousness that its talents must be devoted to the service of fellow men. it is however the convention on the rights of the child that enshrines the richest catalog of educational and developmental aims. from the perspective of this paper, there are at least two interesting references in its text. firstly, the convention's preamble reminds that the "child should be fully prepared to live an individual life in society". secondly, and elaborating on this idea, art 29 para 1 even claims that "the education of the child shall be directed to: (…) (d) the preparation of the child for responsible life in a free society (…)". two different aspects should be underlined here. on the one hand, this sentence reminds that the child is to be educated in order to become a healthy adult, which prevents exploitation and generally any abusive treatment, considering that a child is not yet an adult. but, on the other hand, the fact that the child will eventually develop into an adult also stresses the need to gradually promote a certain responsibility and maturity. therefore, education should prepare a child to live autonomously in a free society. preparing a child for freedom also means preparing it for responsibility, for making its own rules and taking its own decisions as a useful member of the society, to quote principle 7 of the 1959 un declaration of the rights of the child. this link between individual development and respect for human rights paves the way for the second of the aims mentioned in the general international law. the second aim of education would be clearly political. with different variations, most of the texts include understanding, tolerance, and peace among their political aims for education. a good example can be found in art 26 para 2 of the udhr, according to which, education "shall promote understanding, tolerance and friendship among all nations, racial or religious groups, and shall further the activities of the united nations for the maintenance of peace". the promotion and maintenance of peace has been the most important principle of international law at least since the establishment of the united nations in 1945 (white 1997, 3) . it was enshrined in the charter of the united nations 19 as the maintenance of "international peace and security". the reference to "understanding, tolerance and friendship among all nations, racial or religious groups" would enable the primary goal of maintaining peace. nevertheless, it can be seen as a more ambitious purpose, too. in this respect, it seems that the udhr expects, or even promotes, the emergence of a global society, which in turn would be expected to achieve much more than preventing its peoples from going to war against each other. over 40 years later, the convention on the rights of the child would repeat and widen the ideals of the universal declaration in this respect. the reference to nations and racial and religious groups was then completed with the more flexible "friendship among all peoples, ethnic, national and religious groups and persons of indigenous origin." moreover, the equality of sexes also joined the previous understanding, peace and tolerance. it is probably needless to remind that between the 1948 udhr and the 1989 crc, the international convention on the elimination of all forms of racial discrimination 20 and the convention on the elimination of all forms of discrimination against women 21 had been adopted, putting these problems on the international agenda. international law thus acknowledges the importance that children are made aware of the society's complexity as part of their growth and education process, and of the need to respect and equally treat every individual regardless of their social circumstances. indeed, the relationship between human rights and education can be conceived in dialectic terms. in this regard, promoting human rights in education by celebrating difference 22 could in turn make education a force for social cohesion and understanding. the school system could enhance the child's awareness of different cultural approaches to sensitive or controversial matters, bearing in mind the age and maturity of the learners. for instance, discussion could be encouraged on the role of religion in society, the importance of art, the relationship between freedom of speech and political correctness, environmental conscience, sex or drugs, to name but a few of these controversial matters. a number of authors have underlined these ideas by naming human rights education a human right itself (alfredsson 2001, 273; benedek 2007, 1) . despite the claim for universality of human rights and the importance of promoting mutual understanding, the social circumstances surrounding a child are also important for education, as the third aim from the un treaties conveys. 19 charter of the united nations (adopted 26 june 1945, entered into force 24 october 1945) (un charter) art 1 para 1. 20 international convention on the elimination of all forms of racial discrimination (adopted 7 march 1966, entered into force 4 january 1969) 660 unts 1. 21 convention on the elimination of all forms of discrimination against women (adopted 18 december 1979, entered into force 3 september 1981) 1249 unts 1. 22 mittler (2000, 10) has developed a model of inclusive education. in his words, "inclusion implies a radical reform of the school in terms of curriculum, assessment, pedagogy and grouping of pupils. it is based on a value system that welcomes and celebrates diversity arising from gender, nationality, race, language of origin, social background, level of educational achievement or disability" (emphasis added.) the third kind of values that are found in most declarations and treaties have to do with what sociologists would call the "meso" or middle level of societies. international law thus reveals an awareness of the importance that intermediate bodies (groups) have in a person's life. the family-despite its diminishing size in many societies-is considered the main channel for the flow of values from the groups that make a society to the child. language, cultural values, and moral and religious references, as well as many other traditions, are gradually absorbed by the child in an environment of such high affectivity as the family. all of these ideas could be summarized as the protection of cultural pluralism in education. indeed, even a treaty as sparing in educational matters as the international covenant on civil and political rights includes a reference to religious and moral education, if only to proclaim the right of parents to ensure that such education is delivered "in conformity with their own convictions". 23 nevertheless, it is very difficult to construe this principle as a right to ensure that any education involving moral or even religious contents can only be attempted in conformity with the convictions of families. the reasons would be twofold. on the one hand, the scope of contents potentially affected by moral or religious views is so wide that it would be practically impossible to carry out an institutionalized education. thus, equal access to formal education 24 and other principles that are part of the right to education would be made void. on the other hand, the aforementioned principles of the full development of the human personality and the best interest of the child justify that certain contents of public interest be addressed in a non-indoctrinatory manner, even against parental wishes. sex education has frequently been a controversial matter, 25 but teaching in certain languages in some parts of the world can be just as disputed. 26 however, it is the crc that best captures the essence behind the need to ensure pluralism in education. in its preamble, the states parties acknowledge "taking due account of the importance of the traditions and cultural values of each people for the protection and harmonious development of the child". also, when discussing placement of the child outside its original family, art 20 para 3 mandates that "(…) due regard shall be paid to the desirability of continuity in a child's upbringing and to the child's ethnic, religious, cultural and linguistic background." moreover, art 29 para 3.c places the following values among the aims of education: the development of respect for the child's parents, his or her own cultural identity, language and values, for the national values of the country in which the child is living, the country from which he or she may originate, and for civilizations different from his or her own (emphasis added). however, the importance of all these cultural values does not prevent art 14 para 1 from proclaiming "(…) the right of the child to freedom of thought, conscience and religion". we may inquire about the purpose of stressing cultural specificity in international human rights treaties. this does not seem an appropriate occasion for developing all the complexity of the tension between the universality of human rights and their implementation in different cultural environments. but it may be useful to point out a few considerations on the matter, in particular concerning the topic of this article. cultural traditions may have a great value in collective terms, for example as a way of preserving different valid approaches to the world and to mankind. according to the african court, culture should be construed in its widest sense encompassing the total way of life of a particular group, including the group's languages, symbols such as dressing codes and the manner the group constructs shelters; engages in certain economic activities, produces items for survival; rituals such as the group's particular way of dealing with problems and practicing spiritual ceremonies; identification and veneration of its own heroes or models and shared values of its members which reflect its distinctive character and personality. 27 however, this does not appear as the main argument to ponder here. when discussing child education and values, other considerations seem to take precedence. the rights of parents to instill certain values and, generally, the protection of specific groups and their traditions find a strong justification in the need of a certain psychological stability of the child, a feeling of safety which is crucial for a healthy development of the young who will, over time, become adults. childhood, once again, is not only protected on account of its intrinsic value-which it clearly has, as the right to the child's freedom of conscience underlines-but also because it is the seed of tomorrow's adults that will shape society. a fourth kind of values, still not very common in international law on education, refers to a growing concern in other domains of international law. art 29 para 1 of crc shows this concern in the following terms: [states parties agree that the education of the child shall be directed to (…)] e. the development of respect for the natural environment. given the overwhelming scientific analyses that place human activity at the origin of global warming, and of air, water, and land pollution among many other environmental hazards, the fact that this fundamental value is mentioned as a goal of education in only one of the major conventions on human rights can only be received with surprise. nevertheless, it is a perfectly valid obligation under international law, enshrined in a treaty that is binding for 196 states parties, three more than the member states of the united nations. the usa seems to be the only state not to have ratified or adhered to this convention (of which, however, it is a signatory). the european court of human rights (hereinafter ecthr) has produced approximately 40 judgments and decisions on educational matters. concerning values in education, the court's rulings stem from the second sentence of article 2 of the first additional protocol 28 to the convention. 29 this sentence reads as follows: in the exercise of any functions which it assumes in relation to education and to teaching, the state shall respect the right of parents to ensure such education and teaching in conformity with their own religious and philosophical convictions. in spite of this rather open wording, the ecthr has nevertheless managed to develop a rich case law. it is not possible to examine all of these rulings in detail or to discuss some of the ecthr's excesses. i will therefore limit the analysis to a broad summary of three principles before focusing on how they apply to human rights education, given its relevance for the discussion. firstly, the ecthr has displayed a rather extensive conception of the states' "margin of appreciation". this is especially true in matters of religious symbols, either personal (swiss teachers, 30 turkish students, 31 or french learners 32 ) or institutional. among the latter, the italian "crucifix case" 33 is widely known, but earlier rulings dealt with religious freedom and national celebrations in greek schools. 34 secondly, the ecthr has frequently applied the "best interest of the child" doctrine whenever this interest could be endangered by parental religious or philosophical 28 convictions: the abovementioned cases of kjeldsen 35 and jiménez alonso, 36 or the decision in the konrad v germany case, 37 are some of the most prominent examples on sex education (the first two) and compulsory schooling (the third one). the best interest of the child principle, however, has occasionally been subordinated to a state's margin of appreciation whenever there has been a conflict between the two. for instance, a conflict between the best interest of the child and the french principle of secularism, or the italian defense of the crucifix, or the greek celebration of the national day. most of the cases mentioned in the previous paragraph exemplify this statement. a third group of cases has developed from 2007. these rulings deal with indoctrination in the classroom. they address the instilment of certain religious values through specific ritual practices in compulsory classes for underage learners 38 or a disproportionate attention to certain religious doctrines and a practical neglect of others. 39 the ecthr has upheld the applicants in all such cases. human rights education (hre) was mentioned above as one of the key instruments for education to perform as an empowerment right (see above "promoting understanding, tolerance, and peace"). it can be provided as an autonomous subject or transversally through different subjects, or even as non-formal education. 40 in some cases, however, a vivid controversy has been prompted by the introduction of a specific subject in the school system. this was the case of spain after 2006, when the new subject on "education for citizenship and human rights" was denounced and legally challenged by the political opposition and the catholic church. the subject was deemed constitutional in a number of rulings by both the supreme court 41 and the constitutional court, 42 but the central claim of the opponents to the bill deserves some consideration nevertheless. according to this claim, the curriculum of the subject would have been indoctrinating because it reflected an intent of the state to instill certain moral values. in the opinion of the applicants, such an objective would be the prevalent responsibility of the families and therefore the state should refrain from interfering with it. while the highest domestic courts held that certain values could be legitimately taught by the school system, the case never reached the ecthr and hence the question may remain whether the spanish subject would have been sanctioned by the european court or, on the contrary, whether it would have been declared indoctrinating. however, the ecthr has delivered a number of rulings on the legitimacy of teaching values within the education system. in this respect, the abovementioned cases from norway and turkey are useful precedents. 43 as explained, parts of the curricula in these cases were considered indoctrinating on account of the prevalence granted to certain religious beliefs and rites. interestingly, however, the ecthr made it clear that the teaching of values in school entails a valuable opportunity for young people to appreciate and respect difference and even to experience the commonality of many moral principles that underlie various systems of beliefs. 44 concerning the spanish case, and given that no specific aspects of the curriculum had been challenged before the national courts, it seems arguable that the ecthr would have upheld the decision to introduce the education for citizenship and human rights subject. the misgivings of the applicants concerning the spanish subject stem perhaps from the understanding that state values essentially equal a particular government's values. nonetheless, this is precisely the boundary between acceptable hre and unlawful and indoctrinating ideological reeducation. openness and debate should be part of hre, and teachers should refrain from conveying their own views where the discussion goes beyond the common principles underlying society. this can certainly be a thin line and may not necessarily avoid the risk of complaints by specific parents, but a teacher or educator who adopts a meticulous and open approach would in all probability be in accordance with the view of the ecthr. human rights treaties fostered by the organization of african unity (oau) and its successor the african union (au) include certain interesting obligations from the perspective of values in education. in addition, the african commission on human and peoples' rights (hereinafter the achpr) has provided, and continues to do so, valuable resolutions and other soft law instruments as well as case-based decisions through its communications procedure. the achpr's activity reports are also an invaluable source of information to keep track of both "positive developments" and "areas of concern" for human rights in the continent. 43 see n. 38 and n. 39. 44 case of folgerø, cit. (see n. 38), para 88: "the intention was that the school should not be an arena for preaching or missionary activities but a meeting place for different religious and philosophical convictions where pupils could gain knowledge about their respective thoughts and traditions (…). in the view of the court, these intentions were clearly consonant with the principles of pluralism and objectivity embodied in article 2 of protocol no. 1". and para 89: "(…) from the drafting history it emerges that the idea was that the aim of avoiding sectarianism and fostering intercultural dialogue and understanding could be better achieved with an arrangement, such as here, bringing pupils together within the framework of one joint subject (...) moreover (…) the second sentence of article 2 of protocol no. 1 does not embody any right for parents that their child be kept ignorant about religion and philosophy in their education." a similar reasoning in paras 58 & 59 of the zengin case (see n. 39). the key document of african instruments on human rights is the african charter on human and peoples' rights (hereinafter, african charter). provisions on education, however, appear scarce in the african charter, and there is only one specific reference on art 17 para 1: "every individual shall have the right to education". apparently, and when compared to un provisions on education's goals and values, there is no reference to such values in the basic african instrument. nevertheless, it should be noted that article 17 also refers to free participation in the community's cultural life as a right of every individual (para 2) and to the duty of the state to promote and protect "morals and traditional values recognized by the community" (para 3). this systematic proximity induces the consideration that education, participation in the community's cultural life, and the protection of moral and traditional (non-colonial) values are deeply connected in the african charter's spirit. this interpretation will be further discussed in "african morals, traditional values and cultures, and other specific political principles" below. in contrast to the african charter on human and peoples' rights, the african charter on the rights and welfare of the child 45 displays a rich wording when dealing with educational values. this treaty has been so far ratified by 49 states and signed by another five. only one state (morocco) has done neither. 46 in addition, some provisions of the african charter on democracy, elections, and governance will be discussed. 47 up to the present, 34 states have become parties to it and fifteen others have become signatories. six states, however, have accomplished neither yet (botswana, egypt, eritrea, libya, morocco, and tanzania). 48 let us now focus on the values that should guide education according to these three charters. although this fundamental aim does not differ in substance from the one set in the udhr and the core international human rights instruments, african instruments have included certain elaborations that deserve specific consideration. art 11 para 2 of the african child charter includes a phrase that is almost identical to another in the convention on the rights of the child, which seems a reasonable outcome given the proximity of their respective adoptions (1989 for the crc and 1990 for the acc). the first of the goals mentioned reads as follows: the promotion and development of the child's personality, talents and mental and physical abilities to their fullest potential. 45 african charter on the rights and welfare of the child (adopted 11 july 1990, entered into force 29 november 1999) (african child charter or acc). 46 however, and beyond this initial commonality with un-fostered treaties, the african conception seems particularly concerned about the importance of education-and leisure (udombana 2006 49 )-for individual self-development in general and for promoting awareness of the own rights in particular. not by chance, in 2013, the achpr identified among its "areas of concern" the fact that "many children are not in school despite the provision of free and compulsory education in some state parties, due to socio-cultural and political considerations, among others 50 ; moreover, the achpr has included as a "positive development," among other measures taken to protect the rights of children, "the introduction of school feeding programs in south africa to encourage parents to send their children to school". 51 as well as the fact that certain states "(…) have put in place educational systems that are specifically tailored to suit the mobile lifestyles of their indigenous populations/ communities (namibia) (…)". 52 despite these achievements, certain "socio-cultural" patterns seem to hinder some specific groups, in particular women and girls. many examples can be found in the achpr's activity reports. among these, in 2012, the special rapporteur on the rights of women in africa informed the commission that "the situation of women in the rural areas remains dire, and in the area of education, the problem of girls' access to education despite the progress made by some countries" (sic). 53 more recently, the achpr intensified its appeal in order to denounce the "continuing discriminations and practices against women and girls, including the exclusion of pregnant girls from the education system and refusing them to take public examinations, which violates their right to education and serves to perpetuate other discriminations against them". 54 in this regard, the achpr has also addressed letters of urgent appeal to certain governments that seemed to embrace these convictions, as revealed by "the statement made by the tanzanian authorities on 22 june 2017 to the effect that pregnant girls and teen mothers would no longer be allowed to attend school and continue their education". 55 fully aware of these hindrances, one of the most recent legal instruments in african human rights, the african charter on democracy, elections, and governance, directed its state parties "to provide free and compulsory basic education to all, especially girls, rural inhabitants, minorities, people with disabilities and other marginalized social groups", 56 as well as to ensure "the literacy of citizens above compulsory school age, particularly women, rural inhabitants, minorities, people with disabilities, and other marginalized social groups". 57 49 art 12 of the acc refers to the right "to engage in play and recreational activities appropriate to the age of the child." see also n.j. udombana (2006, 190) . 50 achpr, 34th activity report (2013), para 21.vii. emphasis added. 51 achpr, 36th activity report (2014), p. 11, para v. emphasis added. 52 achpr, 30th activity report (2011), para 251. 53 achpr, combined 32nd and 33rd activity reports (2012), para 251. 54 achpr, 38th activity report (2015), para 41.b.vi. emphasis added. 55 achpr, 43rd activity report (2017). 56 acdeg art 43 para 1. 57 acdeg art 43 para 2. thus, an instrument apparently intended for political rights mandates the establishment of a free and compulsory education system and grants special attention to disadvantaged groups. nevertheless, it must not surprise that a charter on democracy, elections, and governance refers to education in such detail. to quote john dewey's classic book democracy and education, "the realization of a form of social life in which interests are mutually interpenetrating, and where progress, or readjustment, is an important consideration, makes a democratic community more interested than other communities have cause to be in deliberate and systematic education" (dewey 1916, 100-101). more recently, and from the perspective another regional system for the protection of human rights, the inter-american court of human rights considered education as the "epitome of indivisibility and interdependence of all human rights". 58 despite the political importance of education, however, complaints brought before the achpr through the communications procedure have often addressed insufficiency of funding or facilities, as well as a lack of dedicated teaching staff. 59 so far, it may be concluded that african instruments on human rights consider the very accessibility to school education as a key element for the first value that should guide education: the full development of the child's personality. therefore, great interest is placed in countering social and cultural convictions that limit such accessibility. despite its clear connection with the previous aim, the importance that different african instruments attach to this matter recommends devoting a specific subsection to its discussion. after the development of the child's personality, the african child charter considers that education should be directed to: fostering respect for human rights and fundamental freedoms with particular reference to those set out in the provisions of various african instruments on human and peoples' rights and international human rights declarations and conventions 60 the concept of education as an "empowerment right," already mentioned above, has been received in the african instruments on human rights. indeed, this idea was already present in the african charter despite the scarcity of its provisions on education. 61 as such empowerment right, education helps the child-and future adult-to take informed decisions (thus increasing individual freedom) and live in better conditions (improving a certain equality and fostering solidarity). one specific example of better 58 gonzales lluy and others v ecuador inter-american court of human rights series c no 298 (1 september 2015) para 234. see also hevia rivas (2008, 143 and 2010, 29) . 59 socio economic rights and accountability project v. nig., comm. 300/2005, 25th achpr aar annex (may-nov 2008) . the complaint was declared inadmissible due to lack of proof concerning the exhaustion of domestic remedies. 60 acc, art 11 para 2.b. 61 african charter, art 25: "state parties (…) shall have the duty to promote and ensure through teaching, education and publication, the respect of the rights and freedoms contained in the present charter (…)." living conditions would be "understanding of primary health care" (art 11 para 2.e), which is of great importance given the threat of epidemics and viral infections in the continent (yellow fever, malaria, ebola, hiv, or the covid-19 pandemic). the wording of the acc, however, does not aim so much at raising awareness of the own human rights as it does at fostering respect for human rights. both aims (raising awareness and fostering respect) are not completely diverse, but the second might seem more ambitious. moreover, from a political perspective, democracy is enhanced if citizens are more and better educated, and in particular with regard to human rights. education on human rights and democracy (more commonly "human rights education") thus appears as a highly valuable resource. to be sure, the achpr has long been aware of its importance, as it showed with its resolution on human and peoples' rights education 62 of 1993 and other statements. 63 the member states of the african union have, for their part, displayed a clear interest in promoting this kind of education, as the african charter on democracy, elections, and governance demonstrates. according to this instrument, state parties undertake to implement programs and carry out activities designed to promote democratic principles and practices as well as consolidate a culture of democracy and peace. to this end, state parties shall: (…) 4. integrate civic education in their educational curricula and develop appropriate programs and activities. 64 the importance of this obligation is further underlined by another provision. indeed, civic education shall be "systematic and comprehensive" and, more importantly, it shall aim "to encourage full participation of social groups with special needs in democracy and development processes". 65 these provisions of the acdeg allow for three considerations. firstly, education is considered essential for the political participation of social groups (in this case, specifically those with special needs). once again, the idea of education as empowerment, now applied to groups with special needs. thus, the educational aim of fostering respect for human rights appears linked with the value of solidarity within society. secondly, the reference to "(social) groups" reminds of the abovementioned "intermediate bodies." among these, political parties are of particular importance in a parliamentary democracy. political parties, however, would be hardly democratic if their militants were unable to grasp the significance-and debate on the substance-of complex decisions advanced by their leaders. in a presidential democracy, the political 62 resolution on human and peoples' rights education, adopted by the achpr at its 14th session, december 1993. the text is available at https://www.ohchr.org/en/issues/education/training/compilation/pages/5 resolutiononhumanrightseducation (1993) .aspx. 63 in its 35th activity report, of 2013, the achpr highlighted "lesotho's (…) new curriculum for schools which includes components of human rights issues affecting children." 64 acdeg, art 12. emphasis added. 65 acdeg, art 31 para 2. party does not necessarily enjoy the same significance, but the education of those called to vote (especially a pluralistic and non-indoctrinating human rights education) remains of paramount importance. according to experts, "political representation means choosing, electing representatives, selecting the political class" (bonfiglio 2013, 90; similarly, randall 2007, 85-86) , which confirms the importance of education as a crucial element for democracy. however, historically, in african politics, this has not excluded the possibility that the power of granting educational opportunities (e.g., through scholarships) was used, conversely, as an "enormously effective instrument of oneparty consolidation" (coleman and rosberg 1964, 666) or, more brutally, that teachers and health workers "were forced to attend political education meetings" under mugabe's rule in zimbabwe (laakso 2007, 243) . this confirms how strongly education can affect the political system. thirdly, the african conception of civic education appears in close connection with that of "development." if the notion of development may come as a novelty when discussing educational values, other principles deeply connected with it have been present in african human rights instruments since its early days. the ideas of independence, decolonization, and the highly interesting principle of african solidarity have more recently led to an emphasis on economic and social development. this, however, should not be deemed incompatible with the preservation of traditional values, territorial integrity, and african unity, as will be discussed below ("african morals, traditional values and cultures, and other specific political principles"). despite the strong connection of this principle with the full development of the personality, the authors of the african child charter have chosen to present it as a different goal. this principle is closely linked with the "universal" political aims of the core international human rights instruments as well. 66 nevertheless, the preparation for responsible life in freedom does not only apply to children, but also to adults, and, importantly, even to those incarcerated. 67 let us turn to the wording of the acc. its art 11 para 2 provides the following: the education of the child shall be directed to: (…) (d) the preparation of the child for responsible life in a free society, in the spirit of understanding, tolerance, dialogue, mutual respect and friendship among all peoples, ethnic, tribal and religious groups. while the general drafting and many of the elements appear very close, or even identical, to the relevant paragraph of the crc's, 68 some differences should be underlined. the african wording thus features some new elements but, strangely enough, others have been erased. among the latter, "in the spirit of" the crc appeared 66 see above "promoting understanding, tolerance and peace." 67 achpr, 31st activity report (of 2011), para 30. 68 crc, art 29 para 1.d. see above "full development of the human personality and best interest of the child". the references to "peace," "equality of sexes," "friendship among all (…) national groups," and "persons of indigenous origin". the removal of the reference to national groups may be explained by the introduction, instead, of two new and more elaborate paragraphs on the matter (namely, e and f). however, the reasons behind the other three suppressions appear obscure, and the result, difficult to approve. the additions, nevertheless, enrich the text of the provision with some aspects of african legal and political thinking. perhaps the most evident would be the reference to "tribal" groups as a basic organizational form of many african societies, a notion criticized for the "lack of conceptual groundwork and empirical testing" on whether and how ethnicity affects voting preferences (elischer 2013, 25) . moreover, the ideas of "dialog" and "mutual respect" are also an important part of african culture, as the traditional notion of ubuntu expresses well (venter 2004, 149 and le roux 2000, 43) . as vervliet (2009, 64) has written, "in (…) ubuntu, the human person does not stand on his own, but becomes more human in relation with other people". lastly, the reference to the "peoples" is not an innovation of the african instrument, but it certainly acquires a new significance given the importance of this notion in the continent's legal tradition of human rights. it should be noted that the african charter, the achpr, and the african court on human and peoples' rights all bear the reference to the peoples in their very names, thus showing their importance as a subject of rights. human and peoples' rights thus appear closely connected in the african conception. unfortunately, the study of collective rights would require an in-depth approach that clearly exceeds the scope of this article. the un convention on the rights of the child referred to the development of respect for the child's "own cultural identity, language and values, for the national values of the country in which the child is living, the country from which he or she may originate, and for civilizations different from his or her own". receptive to the influence of its immediate un precedent, the african child charter picked up the baton and included four different provisions that expand these ideas. the relevant parts of art 11 para 2 mandate the following: the education of the child shall be directed to: (…) (c) the preservation and strengthening of positive african morals, traditional values and cultures; (…) (e) the preservation of national independence and territorial integrity; (f) the promotion and achievement of african unity and solidarity; article 12, in turn, further elaborates on the right to culture: state parties shall respect and promote the right of the child to fully participate in cultural and artistic life and shall encourage the provision of appropriate and equal opportunities for cultural, artistic, recreational and leisure activity. firstly, from the perspective of moral education, the acc is unorthodox but honest when it accepts that not all african morals, traditional values, and cultures are necessarily "positive" and hence deserve to be promoted. among the positive aspects, the abovementioned notion of ubuntu requires a socially valuable orientation of individual rights. in their definition of the african child, nthontho and ogina (2020) highlight the collective effort behind the education of the young. they illustrate this cultural pattern with the traditional saying that "it takes a village to raise a child". this communalist approach to human rights and education is genuinely african and is not to be found-at least not with the same intensity-in other conceptions. 69 another example of traditional values inspiring human rights can be found in the south african constitutional court's ruling on the khosa case. 70 according to kamga (2018, 641) , when the constitutional court held that "everyone's right to access social security encompasses permanent residents in the country" (including children), it was inspired by the values of ubuntu. on the other hand, a more negative aspect would be the use of corporal punishment. while it was banned by the south african schools act in 1996, this ban was subsequently challenged by 196 independent christian schools. the constitutional court, however, upheld the act in a memorable ruling by justice albi sachs. 71 by limiting its advocacy to the positive inheritance, the acc separates itself from the wording of the older african charter, which did not include any differentiation but rather mandated the protection of any "morals and traditional values recognized by the community." still, despite the more advanced contents of the acc in this regard, basing on the african charter may include some advantages, too. an important one concerns the possibility of using the rather open communications procedure of article 55, thus attracting the attention of the achpr and, perhaps, driving it to use its "good offices" in search of a friendly settlement, or a recommendation, or even to submit the case to the african court. 72 in this regard, certain complaints have been addressed to the achpr despite the strict wording of its article 25 ("every individual shall have the right to education"). among these, for example, a case of 2003 concerning cameroon reflected an attempt by the complainants to demonstrate a linguistic, cultural, and educational undermining of the anglophone parts of the country by the government, thus trying to push the achpr to ponder on the argument of respect for cultural specificity and the protection of linguistic minorities. the achpr, nevertheless, rejected the complaint on article 17 due to lack of sufficient proof 73 (but accepted several others, including certain forms of discrimination such as that of the english language in business transactions 74 ). the notion of culture, in the second place, is not only destined to the stationary status of preservation. the use of the term strengthening in art 11 para 2.c and especially that of participation (linked in article 12 with artistic and with recreational and leisure activities) bring the educational treatment of culture closer to its dynamic essence. education should help the children to understand and preserve their cultural heritage but also to enjoy and develop it. the african charter confirms this interpretation when it includes the right to "freely" "take part in the cultural life of his community" next to the very recognition of the right to education. 75 thirdly, the references to "national independence," "territorial integrity," "african unity," and "african solidarity" are of a more political nature and reflect the historical circumstances to which the rise of the human rights movement in africa was bound. indeed, all of these ideas seem in line with the basic orientations of the organization of african unity since its inception. it should be interesting to remind that in 1963, the african heads of states and governments declared themselves "determined to safeguard and consolidate the hard-won independence as well as the sovereignty and territorial integrity of our states, and to fight against neo-colonialism in all its forms". 76 a purpose later reinforced in the preamble of the very african charter on human and people's rights, where the member states of the oau again showed themselves conscious of their duty to achieve the total liberation of africa, the peoples of which are still struggling for their dignity and genuine independence, and undertaking to eliminate colonialism, neo-colonialism, apartheid, zionism and to dismantle aggressive foreign military bases and all forms of discrimination, particularly those based on race, ethnic group, color, sex, language, religion or political opinions. summarizing, the protection of african cultural values in human rights' instruments reveals the struggle of the continent to become politically independent and economically developed while (dynamically) preserving the best of its traditional identity. one last aim of education according to the african child charter concerns the development of respect for the environment and natural resources. 77 once again, the acc takes up the baton of the un convention on the rights of the child, until then the only un instrument on human rights to have mentioned environmental awareness as an educational value. given the rich resources of the african continent, also from an economic perspective, the african instrument expands the scope in order to instill respect for natural resources as well. indeed, natural resources have historically been over-exploited, either by colonial powers 78 or under self-rule. the latter, nevertheless, were often responsible for some of the first conservation efforts as well (van eeden 2014, 640). 75 african charter art 17 para 2. 76 organization of african unity charter, 25 may 1963, (oau charter) preamble. 77 acc art 11 para 2.g. 78 c.w. de kiewiet (1941, 188) , in his history of south africa, wrote that "in all the great colonial regions of the world the history of the ruthless exploitation of natural resources is a full one." this provision, therefore, points to the aim of delivering the continent from economic exploitation. in doing so, it is perfectly coherent with the african charter's proud declarations that "all peoples shall freely dispose of their wealth and natural resources. this right shall be exercised in the exclusive interest of the people. in no case shall a people be deprived of it." 79 some of the most infamous cases of recent history are closely linked with this defense of the environment against large transnational companies backed by some governments. the most notorious is probably the niger delta dispute, 80 but the aforementioned achpr/kenya case concerning the rights of the ogiek community of the mau forest is a more recent example. both un and regional systems reflect certain humanistic values that, despite different wordings and circumstances, may be considered essentially common to all three conceptions. perhaps the best example is the principle of the full development of the personality (often linked with the child's best interest doctrine), but clearly not the only one. the promotion of understanding, tolerance, and of specific cultural values is also present in every human rights system. on the darker side, the risk of cultural indoctrination has made its appearance in both the european and the african contexts. despite these common aspects, regional systems also reveal specific conceptions that are due to each continent's own history and current challenges. in the african system, the different charters reflect a rather open understanding of cultural values and traditions by granting every individual the right to "freely participate" in cultural life. the historical struggle for political independence, economic development, and environmental protection has also left its mark on educational values. concerning the enforcement of the charters, however, the communications procedure before the achpr may only lead to the adoption of decisions that are technically not binding for the states parties involved. this lack of binding force when discussing individual communications may explain why certain statements throughout the achpr's periodical activity reports have adopted a strongly critical style, for example with regard to access to education for pregnant girls. a more frequent intervention of the african court might be desirable, but both the institutional framework and the system's budget entail limitations. the ecthr, on the other hand, may seem less demanding than the achpr in its requirements to states parties. examples of this are the frequent recourse to the margin of appreciation doctrine and the ecthr's acquiescence to france's broad interpretation of secularism or italy's defense of the crucifix as a symbol of universal values. however, this acquiescence in matters that are highly controversial within certain societies could paradoxically reflect a stronger institutional system and hence a smaller need to react to all challenges. this institutional strength (at least when compared to other human rights systems) arises from the solid position of the ecthr as the only international protector of the echr and from the mandatory nature of its rulings for the 79 african charter art 21 para 1. 80 soc. and econ. rights action ctr. v. nig, comm. 155/96, 15th achpr aar annex v (2000 -2001 . states parties involved. nevertheless, and most importantly, the ecthr receives and adjudicates a far larger number of cases than any other human rights system. this grants the european court the opportunity to rule on each case considering the social, political, and legal specificity of the state concerned, rather than motivated by the need to develop a notion that is valid for the whole continent. it therefore seems to have more occasions to develop a nuanced body of principles. such a system, however, requires greater funding by states parties. the importance of international human rights law: contestations and reasons" and stoppioni protocol to the african charter on human and peoples' rights on the establishment of an african court on human and peoples' rights comm. 266/2003, 26th achpr aar annex the right to human rights education human rights education intercultural constitutionalism: from human rights colonialism to a new 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nations and the maintenance of international peace and security acknowledgments the author wishes to kindly thank prof johan beckmann, prof everard weber and dr. andré du plessis, from the university of pretoria's department of education management & policy studies. this research was made possible by the university of pretoria's visiting professors program. conflict of interest the author declares that he has no conflict of interest.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-259694-8uv291b5 authors: sloan, carlie j.; mailick, marsha r.; hong, jinkuk; ha, jung-hwa; greenberg, jan s.; almeida, david m. title: longitudinal changes in well-being of parents of individuals with developmental or mental health problems date: 2020-08-21 journal: soc sci med doi: 10.1016/j.socscimed.2020.113309 sha: doc_id: 259694 cord_uid: 8uv291b5 a large body of work demonstrates the impact of caregiving burden on the well-being of parents of individuals with developmental conditions or mental health problems. however, a relative dearth of research examines this impact longitudinally into parents' older age. objective. the current study examines (1) longitudinal changes in the effect of having a child with a developmental or mental health problem on parental negative affect, psychological well-being, and somatic symptoms, (2) age and gender moderations on these effects, and (3) the unique impact of factors related to the child's condition. method. this study employs hierarchical linear regression models to examine longitudinal survey data from midlife adults (n = 1,101) from two waves of the national study of midlife in the united states (midus). results. models revealed some evidence for age attenuation of the impact of caregiving stress. parents of children with developmental problems still had higher negative affect, poorer psychological well-being, and more somatic symptoms on average than parents in a comparison sample, whereas parents of children with mental health problems only showed evidence of higher negative affect compared to this sample. within-group analyses also revealed differences between each parenting group into later adulthood. conclusions. parents of individuals with developmental or mental health problems may be at risk for poorer well-being late in life. yet, age and gender differences as well as diagnostic group differences nuance these findings. parenting a child with a developmental or mental health problem can be a significant source of stress. the effects of caring for a child with one of these diagnoses on parental wellbeing have been documented across both parental age groups and domains of well-being. compared to parents of children without such conditions, parents of children with developmental or mental health problems experience poorer psychological health, increased daily and global negative affect, and increased daily and global physical symptoms (ha et al., 2008a; seltzer et al., 2009) . additionally, parents of children with developmental and mental health problems experience greater caregiving burden, such as more restrictions on their time (smith and grzywacz, 2014 ) and more negative parenting experiences (song et al., 2016) compared to parents of children without such conditions. for instance, parents of children with developmental conditions or mental health problems have reported a greater burden associated with caregiving (greenberg et al., 1997) , attributing more stress to their child with special needs than to other siblings (baxter et al., 2000) . furthermore, this type of caregiving has been associated with physiological dysregulation (barker et al., 2012; seltzer et al., 2009) , accelerated cognitive aging (song et al., 2016) , and being more vulnerable during periods of economic downturn (song et al., 2018) . in general, providing care for a child with these conditions can contribute to a feeling of chronic stress for parents (baxter et al., 2000; masefield et al., 2020) , which presents a particularly troubling problem, as children with such conditions are likely to reside in the home longer than their typically-developing peers (seltzer et al., 2001) . this study presents a longitudinal extension of a previous cross-section study of examining the potential age-attenuation of the stress of caring for a child with disabilities on the well-being of parental caregivers (ha et al. 2008) . ha and colleagues (2008) found that midlife j o u r n a l p r e -p r o o f longitudinal changes in well-being of parents 2 parents of children with developmental or mental health problems had significantly higher negative affect and more somatic symptoms than a comparison sample of parents. furthermore, those with children with developmental conditions also had poorer psychological well-being than the comparison sample. additionally, among those with children with developmental or mental health problems, older parental age of onset of the child's condition was protective of parental well-being, and longer duration of the child's condition also predicted better health outcomes, suggesting that parents may adapt to the stress of their caregiving role over time. although these findings provide initial evidence of potential adaptation among parents, they are limited by cross-sectional designs. longitudinally, parents of individuals with developmental conditions have shown declines in some aspects of physical and psychological well-being into old age, with parents whose child still resided at home during adulthood at greatest risk (namkung et al., 2018) . therefore, there is still much to be learned about how the impact of caregiving stress changes over time, especially for parents of children with mental health problems, who may be less likely than individuals with developmental conditions to continue residing at home into adulthood. additionally, longitudinal data provides the opportunity to examine within-person change, which more accurately assesses whether parents truly adapt to this role over time. normative samples of adults generally evidence increases in well-being across adulthood. for example, older adults show reduced negative affect, greater well-being, and fewer negative emotional experiences compared to younger adults (carstensen and charles, 1998) . this trend has multiple explanations. for one, older adults, having lived longer, have access to a wider range of experiences and behavioral skills. therefore, older adults have more practice with j o u r n a l p r e -p r o o f longitudinal changes in well-being of parents 3 interpreting social situations and regulating their emotions, as well as more varied exposure to such experiences (hess et al., 2005) . this improvement in emotion regulation helps explain general improvement in affective well-being (charles, 2010) . furthermore, socioemotional selectivity theory (carstensen et al., 2003) posits that because of a perceived decrease in the time remaining in life, older adults increasingly prioritize emotion-related goals, such as family and interpersonal relationships. not only do emotions themselves become more salient through the lifespan (carstensen et al., 2003) , but older adults also cognitively attend more to positive and less to negative emotional material, and negative experiences are more easily forgotten for older adults (charles, 2010) . the strengths and vulnerability integration model (i.e., charles, 2010) is based in socioemotional selectivity theory, but additionally posits that along with age-related strengths such as emotion regulation and salience of positive events, aging can also be accompanied by certain vulnerabilities that make dealing with emotional experiences more difficult. one such vulnerability occurs in the presence of chronic stress. when chronic stressors persist over long periods, negative experiences become unavoidable: despite advanced emotion regulation skills, adults may not have the option of reappraising or directing attention away from the source(s) of certain stressors. for example, empirical studies have found that compared to younger adults, older adults are less reactive to daily stress that was avoided, but equally reactive to stress when it does occur (charles et al., 2009) . in other words, unavoidable stressors present a meaningful threat to well-being, even for older adults. over time, persistent exposure to unavoidable stressors may reduce the actual capacity for emotion regulation (charles, 2010) . that is, chronic stress may work to cancel out the normative age-related benefits of emotion regulation. j o u r n a l p r e -p r o o f longitudinal changes in well-being of parents 4 as a chronic stressor, caring for a child with developmental or mental health problems may alter trajectories of age-related patterns in well-being for this subset of parents. for example, the finding that older parental age at onset of the child's disorder is associated with better health (ha et al., 2008) , suggests that older parents have built up emotional resources throughout the lifespan that can help alleviate the stress associated with caregiving. however, little is known about how patterns of chronic stress may change as children themselves grow older and become less likely to live at home. in general, interactions between parents and their adult children get more positive with time, and parent-child dyads tend to engage in behaviors that maximize positive feelings in the tie and minimize dissent as children age (birditt et al., 2009 ). however, this may be less true of parent-child dyads characterized by stressful relationships, such as when the adult child has a disability or other chronic condition. for instance, parents report more negative than positive interactions with children experiencing various physical and emotional problems (birditt et al., 2016) , which have been shown to negatively impact physiological stress responses (birditt et al., 2016; seltzer et al., 2009 ). utilizing longitudinal data will allow us to evaluate whether these negative patterns persist or attenuate over time for parents whose adult child has developmental or mental health conditions. the stress associated with parenting a child with developmental or mental health problems affects parents differentially depending on both personal characteristics of the parent and those associated with the diagnosis itself. for instance, previous work has suggested that mothers are particularly vulnerable to the impacts of parenting a child with such problems, in terms of both subjective well-being and physical health (see pinquart and sörensen 2006 for meta-analysis) . for instance, mothers' economic situations may be more heavily impacted by j o u r n a l p r e -p r o o f longitudinal changes in well-being of parents 5 caregiving burden than that of fathers, resulting in lower earnings and less time spent working (parish et al., 2004; seltzer et al., 2001) . additionally, they may be at risk for more physical symptoms associated with caregiving burden than fathers (namkung et al., 2018) , as well as poorer mental health outcomes (homan et al., 2020; penning and wu, 2016; smith and grzywacz, 2014) , and cognitive functioning (song et al., 2016) . however, other work has suggested that gender does not moderate the effects of parental caregiving stress (ha et al., 2008) , and that mothers potentially benefit more from the positive aspects of caregiving compared to fathers (homan et al., 2020) . therefore, further investigation into gender differences in caregiving stress is needed. additionally, parents of children with developmental conditions display different patterns of well-being than parents of children with mental health problems (greenberg et al., 1997; ha et al., 2008a; seltzer et al., 2001) . for example, parents of individuals with mental health problems may face more unpredictability in daily experiences with their child, whereas parents of individuals with developmental conditions tend to adapt family routines more sustainably, especially given the typically younger age of onset of these conditions (seltzer et al., 2001) . furthermore, parents of children with mental health problems may be at greater risk for financial problems such as unexpected costs and barriers to services (song et al., 2018) . therefore, one must consider each group individually, asking whether parents of children with developmental and mental health problems adapt such that they reach more normative levels of well-being in older adulthood, or if this type of parenting presents as a chronic stressor with lasting impact over the lifespan. the current study used data from a representative sample of midlife-to-older adults who have at least one child with a developmental condition or mental health problem and from a comparison group of parents to better understand how health and well-being change throughout the lifespan. some models implemented in the current study were previously tested by ha and colleagues (2008) using cross-sectional data that were collected between 2004 and 2006. the current study extended these analyses by incorporating a second wave of data from the same respondents, collected approximately 10 years after the previous wave. based on the crosssectional findings from this sample (i.e., ha et al., 2008) and theoretical propositions, our hypotheses are: 1. having a child with a developmental or mental health problem will predict higher negative affect, lower psychological well-being, and a greater number of somatic symptoms, at both a baseline time point and a 10-year follow-up, compared to parents of children without these problems. having a child with a developmental condition or mental health problem will be associated with net increases in negative affect, decreases in psychological well-being, and increases in somatic symptoms from the first time point to the second. a. parental age will moderate these effects such that older parents of children with developmental or mental health problems will not show elevated negative affect. b. parental gender will moderate these effects such that mothers will experience greater detrimental effects on well-being compared to fathers. 3. within groups, longer duration of the child's condition and older parental age will be related to better parental well-being for parents of children with developmental or mental health problems. at the first time point, 430 respondents were identified as having a child with any developmental, mental health, or other diagnosis; 55 of these had only children with other conditions such as injuries, health problems like diabetes and heart conditions, or vision / hearing impairments, that were not included in this study. of the remaining respondents, 305 had completed the data necessary for inclusion. inclusion was contingent upon having participated in both a structured phone interview and a battery of questionnaires, which included the questions used in the following analyses. the comparison sample was drawn from respondents who reported having at least one child, but who did not have any children with a developmental or mental health diagnosis, or other chronic condition. additionally, this group must not have provided care for more than one month to a family member or friend who, "because of a longterm, physical or mental condition, illness, or disability was not able to take care of him-or herself." these criteria left a sample of 2,024 participants in the comparison sample. of 2,329 eligible participants (305 parents of individuals with disabilities or mental health problems and 2,024 comparison respondents), 1,656 participated in midus iii. of these, 11.7% (n = 194) were excluded from the present analyses because they completed the telephone interview but did not return the self-administered questionnaire mailer, which contained the outcome variables of interest for this study. additionally, some parents in the comparison sample no longer met the inclusion criteria at midus iii. a group of 108 parents had a child diagnosed with a developmental condition or mental health problem between midus ii and iii. furthermore, 285 parents had reported caregiving responsibilities between midus ii and iii that would preclude them from being in the comparison sample; 32 of these were those who also had a child with a new diagnosis; thus, 361 respondents were dropped to retain a true comparison sample. therefore, the total sample consisted of 108 parents of children with developmental conditions, 86 parents of children with mental health problems, and 907 comparison parents (n = 1,101). attrition due to death accounted for 31.7% of all attrition (30 respondents from the samples of parents of children with developmental or mental health problems and 245 from the comparison group). compared to the longitudinal sample, those who completed midus ii but did not complete midus iii (including the deceased) had a lower income and education level, were less likely to be employed, and were less likely to be married. considering those who survived until midus iii (i.e., those who could have participated but did not), those who remained in the longitudinal sample were older by 4.10 years. respondents with children with developmental or mental health problems were no more likely to drop out than those in the comparison sample. attrition was higher for parents of children with developmental conditions (38.6%) versus those with children with mental health problems (33.3%). table 1 gives the j o u r n a l p r e -p r o o f breakdown of conditions and age of onset for the conditions included in the analytic sample, which is comparable in proportions to the sample analyzed in ha and colleagues' (2008) analysis of the sample. [ table 1 here] negative affect. the scale for negative affect (mroczek & kolarz, 1998 ; α time 1 = .83, α time 2 = .85) consisted of six items that assessed how often in the past 30 days the respondent felt: so sad nothing could cheer you up, nervous, restless or fidgety, hopeless, that everything was an effort, and worthless. responses were on a likert-type scale from 1 (all of the time) to 5 (none of the time) and were reverse coded so that higher responses indicated more negative affect. the total negative affect score was the sum of these six items. this sum was calculated when at least half (3 or more) of the items had been completed and when this was true, individual mean imputation was used. psychological well-being. the measure for psychological well-being was the sum of six domains of well-being: autonomy, environmental mastery, purpose in life, positive relations with others, personal growth, and self-acceptance (ryff, 1989) . each domain is assessed on seven items, for a total of 42 items (α = .89 at times 1 and 2). responses were on a likert-type scale from 1 (strongly disagree) to 7 (strongly agree). items were coded so that higher scores indicate greater psychological well-being. as with the measure of negative affect, mean imputation was used for those who had scores on more than half (four or more) of the items for each domain, and sums were calculated. somatic symptoms. the measure of somatic symptoms (α time 1 = .70, α time 2 = .73) was a count of up to seven physical symptoms: headaches, backaches, sweating a lot, aches / joint j o u r n a l p r e -p r o o f stiffness, trouble falling or staying asleep, leaking urine, or aches / pain in extremities. these particular symptoms were chosen in order to maintain consistency from ha and colleagues (2008) analyses of this sample. respondents reported how often they had experienced these symptoms in the last 30 days, from 1 (not at all) to 6 (almost every day). the cutoff score was 4 (several times a month) or greater for a symptom to be counted. parenting type. parenting type was coded as a categorical variable, based on whether the respondent was a parent of a child with a developmental condition (coded 1), mental health problem (coded 2), or a child without these diagnoses (coded 0). some respondents (n = 13) qualified for both parenting type categories, as they had either one child who would fit into both the developmental and mental health problem categories, or one child in each category. these respondents were categorized into either the developmental or mental health groups based on criteria determined by ha and colleagues (2008) in their previous examination of this sample. these were (1) which condition was more chronic, and (2) which had the longer duration. therefore, if the child had both a chronic developmental condition and a chronic mental illness, the decision was that they should be placed in the developmental condition group as these problems begin earlier in life than mental health diagnoses. this resulted in four respondents being placed in the developmental conditions group, and nine in the mental health problems group. responses from time 2 were used to measure all sociodemographic variables, to capture respondents' current situation. age and sex were included as predictors in this study. age was measured in years, based on the respondent's birthdate. sex was assessed with one item during the telephone interview, with response options, "male," "female," and "don't know." sex was measured at time point 1. the following were also j o u r n a l p r e -p r o o f included as control variables: race (1=non-hispanic white, 0 = others), education (in years), income, employment status (1 = working for pay, 0 = not working for pay), marital status (1 = married, 0 = unmarried), number of children, and number of co-resident children. to address between-group differences in the outcome variables of interest (hypothesis 1), analyses of variance (anovas) were used with parenting group (developmental condition, mental health problem, or comparison group) as the grouping factor. post-hoc tests for individual group differences used dunnett's t3 t-tests, which account for unequal variances across groups. power analyses based on the smallest sample size (n = 86 for the mental health parent group) suggested that these anovas had sufficient power to detect small-to-medium effect sizes (cohen's f of .19 or greater). to measure change from time 1 to time 2 (hypothesis 2), we used hierarchical linear regressions with time one levels as predictors of time two outcomes to examine the effects of parental group, age, and sex on change in the outcome variables, as well as their interaction effects, while controlling for potentially confounding variables. due to different patterns of missingness across the outcome variables of interest, we conducted a sensitivity analysis running the models with only those with complete data for all outcome variables (n = 1,073). the pattern of results remained the same for this sample, therefore we decided to use the models with the most possible data. power analyses suggested that the full models were well-powered to detect even small effect sizes (based on a cohen's f 2 of .02; cohen, 1988) . specifically, the model for negative affect had a power of .83, the model for psychological well-being had a power of .84, and the model for somatic symptom had a power of .83 to detect a small effect size. finally, we used multiple linear regressions to examine within-group effects of conditionrelated variables on the well-being of parents of individuals with developmental and mental health problems separately at time two (hypothesis 3). due to the smaller sample sizes, these models were sufficiently powered to detect medium effect sizes (cohen's f 2 of .15 or greater) but not smaller. the models for the developmental conditions parent group had sufficient power (above 80%) to detect effect sizes of cohen's f 2 of .12 or greater, while the models for the mental health parent group had sufficient power to detect effect sizes of cohen's f 2 of .16 or greater. for within-group comparisons of these outcomes at time one, see ha et al., 2008 . table 2 .008). dunnett's t3 tests were used to probe these interactions, to account for unequal variances between the three groups. specifically, parents of children with mental health problems were older than those in the comparison group (p < .001) and developmental disabilities parent group (p = .001). they were also less likely to be employed than those in both the comparison (p < .001) and developmental disabilities parent group (p < .001), and less likely to be married than those in the comparison group (p = .001). those with children with developmental conditions had more children than the comparison group (p = .001) and more children who resided at home percentage of female respondents (i.e., mothers) was lower in the comparison group than in both samples of parents whose children had disabilities (p = .001 compared to parents of individuals with developmental disabilities, p < .001 compared to parents of individuals with mental health problems). among the groups of parents with children with developmental or mental health problems, there were group differences in condition-related variables. specifically, the duration of the condition was longer among those with children with developmental disabilities compared to parents of children with mental health problems (t (179) = 3.72, p < .001). additionally, their children were older (t (165) = -3.74, p < .001), and less likely to be female than those in the mental health group (t (192) = -2.76, p = .006). table 2 presents group by timepoint anovas as well as the results of post-hoc dunnett's t3 tests probing specific between-group differences, which test hypothesis 1. there was an omnibus effect of time on increased somatic symptoms across the three groups (f (1, 2183) = 7.07 p = .01), as well as a downward trend in negative affect over time (f (1, 2164) = 3.44, p = .06). of interest, there were also omnibus effects of parenting group on negative affect (f (2, 2164) = 40.71, p < .001), psychological well-being (f (2, 2196) = 10.39, p < .001), and somatic symptoms (f (2, 2183) = 21.02 p < .001) across timepoints. specifically, at time 1, our results repeated the previous crosssectional analyses conducted by ha and colleagues (2008) , with parents of individuals with developmental conditions having higher negative affect (p < .001), poorer psychological wellbeing (p = .017), and more somatic symptoms (p < .001) compared to a comparison sample of parents. additionally, parents of individuals with mental health problems had higher negative affect (p = .015) and more somatic symptoms (p = .004) than comparison parents at time 1, which was also consistent with the previous analysis of a similar sample (ha et al., 2008) . this is in line with hypothesis 1. there was not evidence for group by time interaction effects for any of the three outcomes, indicating that group differences present at time 1 largely persisted at time 2, but failing to support the specific trajectories predicted in hypothesis 2. at time 2, parents with children with developmental conditions had higher negative affect (p < .001), lower psychological well-being (p = .037), and more somatic symptoms than those in the comparison group (p = .001), supporting hypothesis 1. in contrast, parents of children with mental health problems had higher negative affect that the comparison group (p = .013), but did not differ in terms of psychological well-being (p = .269) or somatic symptoms (p = .120), partially supporting hypothesis 1. parents of children with developmental conditions and mental health problems did not differ from each other on any of the measured outcomes. mean levels of each outcome variable at each timepoint are displayed in figure 1 . [ table 2 here] [ figure 1 here] table 3 displays results of hierarchical regressions assessing longitudinal change in parental well-being, which tested hypothesis 2a and 2b. model 1 includes only parenting group and demographic variables, model 2 includes moderating effects of age by parenting group, and model 3 includes moderating effects of sex by parenting group. all models control for time 1 outcomes. in model 1, there was a significant main effect of having a child with either a developmental condition (β = 0.65, t (979) = 2.36, p = .019) or mental health problem (β = 0.70, t (979) = 2.36, p = .019) in predicting elevated negative affect. these results partially support hypothesis 2. older age was associated with declining psychological well-being (β = -0.22, t (1002) j o u r n a l p r e -p r o o f = -2.41, p = .016), but not the other two outcomes. additionally, being female was predictive of increases in psychological well-being (β = 3.51, t (1002) = 2.31, p = .021). [ table 3 here] age and sex moderations were partially supported for parents' negative affect. a significant age by condition interaction was found for the effect of parenting a child with a developmental condition on negative affect (β = -0.05, t (977) = -1.98, p = .048). a simple slopes test was used to probe this interaction, which revealed that the effect of parenting a child with developmental conditions on negative affect was only observed for younger parents (-1 sd; β = 1.09, t (977) = 3.09, p = .002) but not older parents (+1 sd; β = 0.03, t (977) = 0.06, p = .952). the region of significance test showed that the slope was significant and positive for those under 63.12 years old. this effect was not significant for parents of individuals with mental health problems. in other words, these results provide some support for age attenuation of the effect of caring for a child with a developmental disability on negative affect. this interaction is consistent with hypothesis 2a, and is reflected in figure 2 . age did not moderate the effect of parenting a child with a developmental disability or mental health problem on parents' psychological well-being or somatic symptoms. additionally, a gender by condition interaction was found at the trend level such that the effect of caring for a child with a mental health problem had a greater impact on the negative affect for fathers than for mothers (β = -1.16, p = .054). a simple slopes test confirmed that the effect of having a child with a mental health condition was associated with increased negative affect for fathers (β = 1.43, t (977) = 2.96, p = .003) but not for mothers (β = 0.27, t (977) = 0.74, p = .459). this is depicted in figure 3 three condition-related factors that may be related to well-being were examined: duration of the child's condition, having multiple children with disabilities or mental health problems, and whether or not the target child co-resided with the parent at time 2. a summary of results appears in table 4 . [ table 4 here] among parents of individuals with developmental conditions, mothers had a higher number of somatic symptoms than fathers (β = 0.84, t = 2.10, p = .038). additionally, a trendlevel effect emerged suggesting that having a child who remained in the parental household was associated with poorer psychological well-being for parents of individuals with developmental conditions (β = -15.34, t = -1.81, p = .074). among those with children with mental health problems, longer duration of the child's condition was associated with elevated negative affect (β = 0.14, t = 2.42, p = .018), whereas parent's current age was associated with lower levels of negative affect (β = -0.17, t = -3.22, p = .002). these results provide mixed support for hypothesis 3. the results of this longitudinal study paint a bittersweet picture for the change in the well-being of parents of individuals with developmental and mental health problems, similar to evidence suggested by previous longitudinal work (e.g., baxter, cummins, & yiolitis, 2000; namkung et al., 2018) . parents in both of these groups showed normative decreases in negative affect over time that were in line with those experienced by the sample as a whole (see table 2 for time effects). this was especially true for older parents. however, the experience of normative age-related changes in well-being also suggests that group differences present at earlier timepoints persisted into later life. for instance, average levels of negative affect were higher among both parents of children with developmental problems and mental health conditions compared to parents of non-disabled children, even into late life, which provided support for hypothesis 1. interaction probes revealed that the significance was driven by the younger age group, who showed a blunted decrease in negative affect over time compared to older parents (see figure 2 ), which supports hypothesis 2a. although not statistically significant, younger parents (< 65 years old) were more likely to still reside with their child with a developmental condition (23%) compared to older parents (12%) at the second wave of data collection. therefore, these parents may experience a more active caregiving role compared to older parents. parents of children with developmental conditions also retained poorer psychological well-being and physical symptoms compared to parents of children without these conditions. in contrast, parents of children with mental health problems no longer differed from the sample of comparison parents in terms of psychological well-being or somatic symptoms by the second time point (see table 2 ). contrary to previous findings (e.g., herring et al., 2006; homan et al., 2020; parish et al., 2004; smith and grzywacz, 2014) and hypothesis 2b, a sex interaction j o u r n a l p r e -p r o o f showed that the negative affect of fathers was more vulnerable to impacts of caregiving stress than that of mothers (see figure 3 ). it is possible that fathers have fewer sources of social support compared to mothers, and therefore have fewer buffers against the stress of these unique caregiving situations. examining the reasons why change in well-being may differ for aging fathers and mothers will be an important area of future study. within-group analyses of parents of children with developmental and mental health problems revealed potential differences in how time impacts the effect of caregiving burden (see table 4 ). specifically, having a child with a developmental disability was particularly harmful for mothers' negative affect, and may impact negative affect levels more if the child still resides at home. these findings are consistent with gender differences discussed in other literature (namkung et al., 2018; penning and wu, 2016; pinquart and sörensen, 2006) , as well as the idea that parents whose child resides at home into adulthood may be particularly vulnerable to the effects of caregiving burden (namkung et al., 2018) . furthermore, for parents of individuals with mental health problems, a longer duration of the condition was associated with higher levels of parental negative affect. on the other hand, older current age was associated with lower levels of negative affect. this is consistent with the position of the strengths and vulnerability integration model (charles, 2010) , which emphasizes the potential for chronic stress to work against normative age-related improvements in well-being. however, also in line with socioemotional selectivity theory, older parents may be in a better position to combat this impact by utilizing more advanced emotion regulation strategies and other interpersonal resources. the intricacies of combining age-related increases in well-being with the chronicity of caregiving stress make results difficult to interpret, and may help to explain the relatively lower j o u r n a l p r e -p r o o f reliability of these findings. therefore, replication of these results with larger and more diverse samples will be critical in informing any future prevention or intervention efforts. regardless, it is noteworthy that condition-related factors are predictive of parental well-being longitudinally, when few parents were still co-residing with the target child (only 19% of target children coresided at time 2, compared with 38% at time 1). perhaps the largest strength of this study is its longitudinal design, which allowed us to examine change in well-being over a span of approximately 10 years. additionally, given the age of the sample, we were able to examine change in many factors that vary throughout the lifespan but are often captured only at one time point, such as the co-resident status of the child and the impact of the condition's duration on parental well-being, in addition to capturing multiple instances and measures of well-being itself. this revealed important nuances compared to previous cross-sectional work with this and similar samples. finally, the results are strengthened by the fact that the study utilized a nationally representative sample of parents whose participation was not motivated by or dependent on their child's condition, which is uncommon in other work related to non-normative parenting. despite the methodological strengths of this study, the results must be interpreted in light of its limitations. by combining parents into the broad categories of having children with developmental conditions, mental health problems, or neither of these problems, we lose some within-group variation that comes with the qualities of the diagnosis. for instance, masefield and colleagues (2020) notes that caring for children with multiple disabilities may pose the greatest risk to caregiver health, while individual disabilities may be differentially associated with specific health outcomes. certainly, differences in diagnostic categories affects the impact of caregiving stress, as well as how stress manifests in the daily lives of parents (i.e., consistent low-level stress versus more acute stress), as well as the long-term nature of the disability. although these nuances were beyond the scope of the current study, future work with larger samples and more power to detect such effects should consider within-group change among parents of children with more specific diagnoses. due to the long nature of the study, unmeasured factors likely play a role in influencing the physical and psychological health of these participants, which should be probed in future studies. finally, as with any study covering such a lengthy period, we were faced with non-random attrition and mortality issues that limited power to detect more specific effects. in general, the evidence for lifespan gains in well-being presented in this study provides support for socioemotional selectivity theory (carstensen et al., 2003) as a useful tool for modeling age-related change in populations as well as at the person level. additionally, this study provides opportunities to further examine the strengths and vulnerabilities hypothesis by suggesting that some age-related gains in psychological well-being are observed even in the face of chronic stressors such as caregiving stress, while others, such as changes in affect, may be undermined by this type of stress. furthermore, given the important group differences between types of caregivers (e.g., those for children with developmental conditions versus those with mental health problems), this study contributes to a body of research suggesting that specific elements of the caregiving experience may contribute to unique strengths and vulnerabilities in the face of chronic stress (e.g., ha et al., 2008; song et al., 2018) . additionally, the current study aligns with previous work that has identified vulnerabilities within groups of parents caring for children with developmental or mental health j o u r n a l p r e -p r o o f problems that may be uniquely exacerbated in times of acute stress, such as the current global covid-19 pandemic. for instance, parents of children with developmental and mental health problems can be more heavily impacted by downturns in the economy (song et al., 2018) , as well as being at risk for psychological, physiological, and cognitive dysregulations (ha et al., 2008; seltzer et al., 2009; song et al., 2016) . presumably, these adverse effects may be intensified during periods such as this one, when finances are more uncertain, time spent at home has increased, and access to resources may be very limited. therefore, prevention efforts aimed at improving the quality of life of families during periods of acute stress such as the current pandemic should pay special attention to the vulnerabilities of these groups of parents, including the vulnerabilities identified in the current study. overall, this study supports that parenting a child with developmental or mental health problems is a challenge that impacts the well-being of parents, even into their child's adult years and when fewer children reside in the home. however, these difficulties are nuanced by other within-person factors, such as age and sex, as well as factors related to the duration and time of a condition's diagnosis. future research should include contextual factors, such as social support, employment stress, and other relevant factors may influence how parents with high caregiving stress can cope. it is critical to identify malleable factors such as these, that could serve as intervention targets within this population. additionally, research particularly with older samples could consider the potential benefits and rewards of unique caregiving situations. for instance, older parents who are more attuned to positive emotionality and social experiences may also be more likely to experience positivity in their interactions with their adult children with disabilities or mental health conditions. overall, future work should attempt to probe how parents in these f-values reported here are within-timepoint; one-way anovas were conducted for all other variables; dunnett's t3 tests were used to probe specific effects and account for unequal variance between groups; two-tailed significance tests were used with an alpha level of .05; total degrees of freedom for f-tests ranged from 1,016 -1,098; a indicates a significant mean difference between the comparison and developmental groups b indicates a significant difference between the comparison and mental health groups c indicates a significant difference between the developmental and mental health groups d indicates a difference between time 1 and time 2 scores across groups note. r = respondent; all coefficients reported are unstandardized; + = p < .10; * = p < .05; ** = p < .01; *** = p < .001 j o u r n a l p r e -p r o o f table 2 . specific results of a group × time anova for each outcome are displayed in table 2 . j o u r n a l p r e -p r o o f older parents experienced declines in negative affect over time, while younger parents did not experience this benefit. slopes that contributed to a significant interaction effect are denoted with an asterisk (*). simple slopes test revealed that there was a positive association between parenting a child with a developmental condition and negative affect for parents 63.12 years and younger. j o u r n a l p r e -p r o o f fig. 3 . negative affect by parenting type and gender. fathers of individuals with mental health problems experienced increases in negative affect, while mothers did not. slopes that contributed to a significant interaction effect are denoted with an asterisk (*). simple slopes test revealed that the association between parenting a child with a mental health problem and negative affect was significant and positive for fathers but not mothers. j o u r n a l p r e -p r o o f daily stress and cortisol patterns in parents of adult children with a serious mental illness parental stress attributed to family members with and without disability: a longitudinal study daily interactions in the parent-adult child tie: links between children's problems and parents' diurnal cortisol rhythms if you can't say something nice, don't say anything at all": coping with interpersonal tensions in the parent-child relationship during adulthood emotion in the second half of life socioemotional selectivity theory and the regulation of emotion in the second half of life strength and vulnerability integration: a model of emotional well-being across adulthood now you see it, now you don't: age differences in affective reactivity to social tensions the differential effects of social support on the psychological well-being of aging mothers of adults with mental illness or mental retardation age and gender differences in the well-being of midlife and aging parents with children with mental health or developmental problems: report of a national study behaviour and emotional problems in toddlers with pervasive developmental disorders and developmental delay: associations with parental mental health and family functioning age and experience influences on the complexity of social inferences generativity and well-being of midlife and aging parents with children with developmental or mental health problems the caregiver health effects of caring for young children with developmental disabilities: a meta-analysis. matern lifelong parenting of adults with developmental disabilities: growth trends over 20 years in midlife and later life economic implications if caregiving at midlife: comparing parents with and without children who have developmental disabilities caregiver stress and mental health: impact of caregiving relationship and gender gender differences in caregiver stressors, social resources, and health: an updated meta-analysis psychosocial and biological markers of daily lives of midlife parents of children with disabilities life course impacts of parenting a child with a disability health and well-being in midlife parents of children with special health needs the impact of the great recession on midlife and older parents of individuals with a mental health problem or a developmental disability cognitive aging in parents of children with disabilities key: cord-029481-8pq1oaa4 authors: whitcomb, caroline green title: review of doug selwyn (2019). all children are our children: new york: peter lang. 202 pp. isbn 9781433161643 (paperback) date: 2020-07-21 journal: postdigit sci educ doi: 10.1007/s42438-020-00172-x sha: doc_id: 29481 cord_uid: 8pq1oaa4 nan [o]ngoing health crisis and the role that education plays within the larger picture of inequality, of the complex interplay of systems based on class, privilege, racism, sexism and on maintaining a status quo that serves those in power. (selwyn 2019: 17) in addition, selwyn provides clear steps towards bringing safety, well-being, and health to our children. amidst today's cries for change and the pandemicforced rethinking of education, selwyn's articulation of the intentional weaving of societal evils for the ill of our children and his vision for a more just and equitable future make this work a necessary read. for selwyn, an understanding of us population health is necessary for understanding the failed educational system. selwyn (2019: 17) quotes jean anyon: '[t]rying to fix an urban school without fixing the neighborhood in which it is embedded is like trying to clean the air on one side of a screen door.' his research unveils facts and statistics which counter the american perception that the united states of america is a benevolent, generous, christian nation. the oecd ranks the usa 29th out of 35 countries in infant mortality, and yet the nation spends twice as much on per-person healthcare than the average of the other oecd countries. after rolling out pages of statistical truths, selwyn (2019: 24) states, '[i]n the oecd the u.s. ranks 35 th out of 37 th in terms of poverty and inequality.' while the rest of the world may have a far clearer picture of the usa, nothing will change until americans move beyond blind patriotism and see ourselves as we truly are. in a 2020 article, selwyn continues this work, explaining us health and inequality in terms of the pandemic. people living in poverty are more likely living in environmentally unsafe environments and are more likely to develop asthma and other respiratory diseases, heart problems, high blood pressure, and diabetes. they are most vulnerable to the virus because they are more likely to have these pre-existing conditions, more likely to have to keep working to feed their families, and less able to isolate at home. they may well be the people we are standing next to, or who are serving us. (selwyn 2020) selwyn maintains the pandemic has highlighted the nation's health crisis, and trump's attempt to eliminate the affordable care act in the midst of a national catastrophe must be recognized by americans as an epitome of historic cruelty. much of selwyn's book is given to identify the issues which prevent students from receiving a liberatory, democratic education. the chapters focus on inequality, chronic stress, environmental factors, corporate capitalism, the purpose of education, high stakes standardized testing, and how we deny our children (selwyn 2019 ). selwyn's comprehensive explanation demonstrates how these are wreathed together, ultimately resulting in the continued oppression of the american subaltern. selwyn's weaving of practical solutions and examples of reform within his critical research sets this work apart. selwyn describes finland's educational transformation from a mediocre system in the 1960s to one of the world's best today. currently, finland's child poverty level is under 5 %, while the us is over 20 %. 'every school has equally educated teachers and equivalent facilities, with equivalent resources, equivalent class sizes, and equal expectations for the education that each student will receive' (selwyn 2019: 29) . this is a sharp contrast to the us historic and present-day educational system which supports ongoing societal stratification. finland's educational philosophy, based on the work of american theorist john dewey, states: 'all pupils can learn if they are given proper opportunities and support, that understanding of and learning through human diversity is an important educational goal, and that schools should function as small-scale democracies' (selwyn 2019: 29) . through finland, selwyn demonstrates there are alternatives if the usa is willing to change. resisting an ivory tower critique, selwyn's goal is not to catapult readers into a state of depression but to provide doable solutions that will hopefully ignite greater winds of change. selwyn's chapter on chronic stress is eye-opening, and when one considers the additional stress resulting from the pandemic and rise in racism, these truths become alarming. selwyn's examination of the stresses experienced by the oppressed includes perceived discrimination, socioeconomic status and environment, efforts to adapt to the dominant culture, and daily and long-term poverty (selwyn 2019: 49) . in his discussion of the stress caused by high stakes standardized tests, selwyn quotes a test booklet instruction manual. a student who becomes ill and vomits on his or her test booklet or answer document and is able to continue the test should be given a new test booklet or answer document so that he or she can continue. later, the student's responses and demographic information must be transcribed into the new test booklet...do not return the soiled test materials to pearson. (selwyn 2019: 56) selwyn's response is perfect: 'what kind of people set up a system that assumes it likely that at least some students are going to be so upset by what they are required to do that they vomit? and i confess it was tempting to send dozens of bags of vomit-covered test booklets to the testing office.' (selwyn 2019: 56) while the thought of shipping vomit-covered test booklets to pearson probably brings a smile to the face of most educators, this example represents the heart of selwyn's message. 'we present ourselves to ourselves and to the world as a society that values life, that values children, that values family. our actions at the state and legislative levels do not come close to matching our words.' (selwyn 2019: 6) in chapter eight, selwyn continues this vein of thinking by discussing the ways we deny our children language, culture, point of view, the reality of maturation and development, play, the fact that people learn differently, and hope. when everything is determined by others, from what is studied, to how it is studied, to when it is studied and the pace of that study, and then how it is assessed, students learn that their voices, views, and values do not matter. and when they are denied their language, their culture, their history, their interests, and their voices, it becomes clear that the only meaning they can make it is that they don't matter. (selwyn 2019: 130) what can be done? the usa is in a state of disarray, and we are desperate for a new vision, a vision we can all be proud of. to this, selwyn asks and answers, 'what can schools do?' (selwyn 2019: 132) . he offers specific advice to teachers and advice to society at large. many of his suggestions are based upon personal experience, the changes he made in his classroom, and teaching which proved transformative. selwyn focuses on relationships. 'everyone i spoke with and everything i read places relationships as the most significant of the factors that make it possible for students to be healthy, happy, and academically successful' (selwyn 2019: 134) . he posits relationships must extend outside of the teacher/student relationship and involve families and the community. advisory systems are critical in middle school and high school as students move from one teacher to many. relationships are key, not only in the educational setting but at large. empathy grows as we become intimate with those labeled different from ourselves. in regard to society, selwyn suggests building free healthcare clinics adjacent to schools, connecting schools with the farming community, backpack programs, extending recess, and p.e. and all while providing opportunities to grow and learn. 'schools are places in which students can further their understanding of how and why systems intersect and why those systems have an impact on their lives' (selwyn 2019: 160) . in the final chapter, selwyn reminds readers that neutrality is a political act. interestingly, he highlights the black lives matter movement in seattle's schools in 2016. while selwyn primarily focuses on the roles we must play at the school and community level, he also offers some insight into what must also take place at state and national levels. today, as we stumble towards the coming elections amidst heightened racism, horrific killings, protests, and the continual rise of covid-19 cases, selwyn's calls for solidarity, active citizenship, and critical thinking are all the more necessary. while writing this review, i had the opportunity to seek selwyn's current perspective on the state of the nation. for selwyn, the united states of america is in a different place than it was just 3 or 4 years ago. today, city officials, school boards, administrators, and educators have the historic opportunity to question who we are, what it means to educate, how we define curriculum, and how we create a more just educational system for our children. for once, the status quo will not work, the pandemic has forced educational change. the question now becomes what will teachers do and what will we do with this opportunity? with a clarion call, selwyn's book concludes: 'we have a choice to make, about whether to allow ... greed and ... lust for power and profit to continue to destroy our health and our democracy, or whether we will stand and say no to them and yes to our health and well-being, and to our children' (selwyn 2019: 194) . i have only one critique of this work, the cover. in creole (2013), stephen cosgrove, an american children's book author, writes, '[n]ever judge someone by the way he looks or a book by the way it's covered; for inside those ... pages, there's a lot to be discovered' (cosgrove 2013: 34) . do not judge a book by its cover, sage advice. i have to admit i judged the humdrum cover and in so doing nearly missed out on a book every american educator should read. through selwyn's all children are our children (2019), we have been given a fresh glimpse into the hidden aspects of our societal ills and an opportunity to evoke true change. read the book, heed the wisdom, implement the solutions, and do not let the cover stop you. all children are our children covid 19 reveals underlying truths about our society. greenfield recorder key: cord-263688-xz2hnym0 authors: varghese, litty; zachariah, philip; vargas, celibell; larussa, philip; demmer, ryan t; furuya, yoko e; whittier, susan; reed, carrie; stockwell, melissa s; saiman, lisa title: epidemiology and clinical features of human coronaviruses in the pediatric population date: 2017-05-08 journal: journal of the pediatric infectious diseases society doi: 10.1093/jpids/pix027 sha: doc_id: 263688 cord_uid: xz2hnym0 background: the epidemiology and clinical features of human coronaviruses (hcovs) in children are not fully characterized. methods: a retrospective study of children with hcov detected by reverse-transcriptase polymerase chain reaction (rt-pcr) was performed for a community cohort and a children’s hospital in the same community from january 2013 to december 2014. the rt-pcr assay detected hcov 229e, hku1, nl63, and oc43 in nasal swabs from symptomatic children ≤18 years. factors associated with increased severity of illness in hospitalized children were assessed by multivariable logistic regression. results: human coronavirus was detected in 261 children, 49 and 212 from the community and hospital, respectively. the distribution of hcov types and seasonal trends were similar in the community and hospital. community cases were older than hospitalized cases (median age, 4.4 versus 1.7 years, respectively; p < .01), and a minority of community cases (26.5%) sought medical attention. among the hospitalized children with hcov detected, 39 (18.4%) received respiratory support and 24 (11.3%) were admitted to the pediatric intensive care unit (picu). age <2 years (odds ratio [or] = 5.0; 95% confidence interval [ci], 1.9–13.1) and cardiovascular (or = 3.9; 95% ci, 1.6–9.5), genetic/congenital (or = 2.8; 95% ci, 1.1–7.0), and respiratory chronic complex conditions ([cccs] or = 4.5; 95% ci, 1.7–12.0) were associated with receiving respiratory support. genetic/congenital (or = 2.8; 95% ci, 1.1–7.4) cccs were associated with picu admission. severity of illness was similar among hospitalized children with different hcov types. conclusions: children in the community with hcov detected generally had mild illness as demonstrated by few medically attended cases. in hospitalized children, young age and cccs, but not hcov type, were associated with increased severity of illness. until recently, epidemiologic studies for hcov were limited, in part because of a lack of commercially available diagnostic assays. however, us food and drug adminstration (fda)-approved assays that use reverse-transcriptase polymerase chain reaction (rt-pcr) technology now enable rapid, sensitive, and specific detection of the hcov types 229e, oc43, nl63, and hku1, from respiratory tract specimens and therefore allow more comprehensive studies of the epidemiology and clinical features of persons who have hcov detected [11] . the current study presents a unique opportunity to expand our understanding of hcov in ill children from the community and children admitted to a hospital in the same community, who were tested using the same rt-pcr assay. the objectives of this study were to (1) characterize the epidemiology of hcov detected in children from a community-based cohort and in hospitalized children, (2) assess the clinical features of illnesses with different hcov types detected, and (3) evaluate potential risk factors associated with increased severity of illness, defined as the use of respiratory support and/or hospitalization in the pediatric intensive care unit (picu). from january 2013 to december 2014, a retrospective study was performed to identify children ≤18 years of age with hcov detected in respiratory tract in nasal or nasopharyngeal swab specimens collected using flocked nylon swabs. if a child had more than 1 positive test for hcov, subsequent episodes were included if a different hcov type was detected. there was no minimum time frame between subsequent episodes, but we used chart reviews to confirm these were distinct episodes. the columbia university medical center (cumc) institutional review board approved this study; the community cohort provided written informed consent to be in the study, verbal consent for swabs, and children were granted a waiver of verbal assent; a waiver of informed consent was granted for hospitalized children. children from the community cohort were participants in the mobile surveillance for ari/ili in the community (mosaic) study (centers for disease control and prevention, grant number: 1uo1ip000618), based in the washington heights and inwood areas of northern manhattan, who tested positive for hcov during the surveillance period [12] . the mosaic study performs prospective community-based surveillance for acute respiratory illness (ari) using text messaging. households in the mosaic study were selected using a random sample of participants who were previously enrolled in a large, community-based survey (https://www.dbmi.columbia. edu/impact/wicer/, last accessed: april 14, 2017). households receive twice-weekly text messages inquiring if any members have ari symptoms, and ill individuals are swabbed in their homes by research staff if they had 2 of the following: fever/ feverishness, cough, pharyngitis, rhinorrhea/nasal congestion, and body aches. children less than 1 year of age meet criteria for swabbing if they have rhinorrhea/congestion only. swabs were not collected if subjects refused collection or if they were no longer symptomatic at the time of collection. children in the hospital group were admitted to the newyork-presbyterian morgan stanley children's hospital (msch) and cumc and were tested for respiratory pathogens according to the medical judgment of their treating providers. respiratory pathogen testing for inpatients at msch is recommended only in the presence of active respiratory symptoms. hospitalized children had their first positive hcov test either the day before admission (eg, in the emergency department [ed]) or within the first 2 calendar days of admission, to exclude subjects with healthcare-associated infection. nasal swabs from the community and nasopharyngeal swabs from hospitalized subjects were analyzed by multiplex rt-pcr using the same fda-approved filmarray respiratory panel 1.7 (biofire diagnostics, inc., salt lake city, ut) that identifies 20 respiratory pathogens including the following: adenovirus and coronavirus (strains hku1, nl63, 229e, oc43); human metapneumovirus and rhinovirus/enterovirus; influenza (strains a, a/h1, a/h3, a/h1-2009, b); parainfluenza virus (strains 1, 2, 3, 4); respiratory syncytial virus (rsv); as well as the bacterial respiratory pathogens mycoplasma, pertussis, and chlamydophilia. the community samples were tested in a research laboratory, and the hospital samples were tested in the clinical microbiology laboratory at cumc. to assess the clinical features associated with acute respiratory infections in the community cohort, research staff asked participants about the presence of fever (defined as ≥37.8°c), their maximum temperature, feeling feverish, cough, sore throat, runny nose/nasal congestion, body aches, chills, headache, and wheezing. medically attended events were defined as reported visits to the primary care provider or urgent care, admissions to the ed, and/or hospitalizations. coinfection was defined as the presence of 2 or more viruses in the same pcr test. to assess the severity of illness in hospitalized children with hcov detected, their electronic medical records were reviewed to determine the type of respiratory support they received, including oxygen delivered by high-flow nasal cannula or nasal cannula, continuous positive airway pressure, bilevel positive airway pressure, intubation, and mechanical ventilation and/or picu admission for management of respiratory illness. to evaluate potential risk factors associated with increased severity of illness in the hospitalized children with hcov, demographic (eg, age, sex) and clinical characteristics (ie, chronic complex conditions [cccs]), hcov types and viral coinfection associated with respiratory support (defined above), and/ or picu admissions were collected from the electronic medical record. chronic complex conditions included prematurity (<37 weeks gestation in children <2 years of age), cardiovascular, gastrointestinal, genetic/congenital, hematologic/immunologic, malignancy, metabolic, neuromuscular, renal, and respiratory conditions [13, 14] . time trends for each hcov type were generated for the community and hospital groups. differences in the proportions of hcov types detected in the community versus the hospital group were compared using χ 2 tests. demographic and clinical characteristics of children in both groups with different hcov types were compared using analysis of variance for continuous variables and χ 2 test for frequencies. among hospitalized children, bivariate analyses assessed the associations of demographic characteristics, clinical factors, hcov types, and presence of viral codetections, with increased severity of illness, ie, receiving respiratory support and/or admission to the picu. to determine the possible impact of viral codetections, severity of illness was compared between hospitalized children with and without viral codetections. because only 9 children in the community cohort had codetections, an analysis comparing those with and without codetections was not performed. so that the analysis of severity of illness would not reflect the impact of other clinical factors, children admitted to the picu and/or to the floor who required respiratory support for postoperative care or to manage cccs and were subsequently found to have a positive test for hcov were excluded (n = 16). multivariable logistic regression analyses were conducted to examine the associations between any predictor variables with a p value of <.1 in the bivariate analyses and each of 2 severity of illness outcomes, ie, receiving respiratory support and admission to the picu. analysis was repeated to adjust for duplicate patients by including a clustering variable for each unique patient to calculate robust standard errors. risk factors with a p value <.05 in the multivariable analyses were considered significant. analyses were conducted using sas 9.3 (sas institute, cary, nc) and r 3.3.2 (r foundation for statistical computing, vienna, austria). among 455 positive rt-pcr tests in pediatric participants in the community cohort, 49 (10.8%) were positive for hcov. of 2582 positive rt-pcr tests performed among hospitalized children, 212 (8.2%) were positive for hcov. thus, this study included 261 children ≤18 years of age. households (n = 321) in the community cohort had an average of 4.8 members, and of the 1550 participants, 669 were children ≤18 years of age. the baseline distribution of age groups was 0-1 year (37, 5.5%), >1 year-5 years (138, 20.6%), >5 years-10 years (187, 28.0%), and >10 years-18 years (307, 45.9%). participants were primarily latino and publically insured. the refusal rate to obtain swabs over the study period was <1%. the majority of specimens (82.3%) were collected within 3 days of symptom onset. the characteristics of the 49 children in the community cohort (median age 4.4 years, mean 6.9 years) with hcov detected are shown in (table 1 . the most common hcov types detected were nl63 (30.6%) and oc43 (42.9%). the proportion of all hcov types detected, except 229e, was highest among 1-5 year olds ( figure 1a ). five (10.2%) children also had other respiratory viruses detected, and 4 children (8.2%) had more than chronic complex conditions other than asthma included diabetes (n = 1), neurologic conditions (n = 4) and prematurity (n = 1). one hcov type detected (table 1) . most (73.5%) community cases did not report cccs other than asthma (20.4%). the characteristics of the 212 hospitalized children (median age 1.7 years, mean 3.2 years) are shown in (table 2) . hospitalized children with hcov were significantly younger than the children in the community cohort (3.2 vs 6.9 years, p < .01). the most common hcov types were oc43 (40.1%) and nl63 (36.3%). the proportion of all hcov types in the hospital group was highest in children 1-5 years of age ( figure 1b) [5] ) including 4 children with 2 hcov types detected. over half (61.3%) of the hospitalized children had 1 or more cccs, most commonly respiratory (20.3%) and cardiovascular (16.5%) conditions. significantly more hospitalized children had cccs than those in the community cohort (61.3% vs 26.5%, respectively; p < .001). mostly similar time trends for hcov were noted among the community cohort and hospitalized children (figure 2 ). human coronavirus was detected predominantly from the late fall to spring, with different types predominating in different years, eg, hku1 predominated in winter 2013-2014 and oc43 predominated in winter 2014. these trends appeared similar in the community and hospital groups ( figure 3a and b) . in the community cohort, the most commonly reported symptoms associated with hcov were runny nose/nasal congestion (87.8%), cough (85.7%), and sore throat (30.6%). fever (14.3%), feeling feverish (22.4%), and headache (6.1%) were relatively uncommon, and no participants reported wheezing. the median duration of reported illness was 7 days (interquartile range = 4-14 days). symptoms associated with the 4 hcov types were similar across all types, with the exception of cough (p = .02), which was most likely to be reported by those with oc43 (95.2%) followed by hku1 (90%), nl63 (86.7%), and 229e (42.9%). thirteen (26.5%) children in the community cohort sought medical attention for their illness; all had visits to their primary care provider, and none were admitted to the ed or were hospitalized. the frequency of medically attended events among the hcov types was similar (28.5%, 30.0%, 40.0%, and 28.5% with 229e [2 of 7], hku1 [3 of 10], nl63 [6 of 15] , and oc43 [6 of 21], respectively). in 12 (24.5%) cases, children and/or their household members missed a total of 23 days of school and/or work due to the child's illness. among hospitalized children, the most common symptoms reported were cough (66.9%), nasal congestion (55.2%), fever (54.2%), runny nose (38.2%), and wheezing (19.3%). symptoms associated with the 4 types were similar, with the exception of nasal congestion (p = .02), which was most commonly noted in those with oc43 (65.9%) followed by hku1 (61.8%), 229e (45.0%), and nl63 (42.8%). croup was diagnosed in 11 cases, 7 (63.6%) of them appearing in those with nl63 and 4 (36.4%) in those with oc43. overall, 45 (21.2%) hospitalized children had increased severity of illness; 39 (18.4%) received respiratory support and 24 (11.3%) were admitted to the picu. among children without viral coinfections, 32 (20.3%) had increased severity of illness; 29 (18.4%) received respiratory support and 15 (9.5%) were admitted to the picu (table 3 ). the proportion of children receiving respiratory support and/or admitted to the picu was similar among the hcov types (p = .9). the median hospital length of stay was 11 days (mean, 17.1 days) for those admitted to the picu and 3 days (mean, 4.8 days) for those not admitted to the picu. a similar proportion of those with (n = 58) and without (n = 154) viral codetections received respiratory support ( (table 4 ). in bivariate analyses, children <2 years of age and those with any ccc or specifically with cardiovascular, genetic/ congenital, neuromuscular, or respiratory cccs were more likely to receive respiratory support (table 4 ). those with cardiovascular or genetic/congenital cccs were more likely to be admitted to the picu. in the multivariable analyses, children <2 years of age and those with cardiovascular, genetic/ congenital, or respiratory cccs were more likely to receive respiratory support, and those with genetic/congenital cccs were more likely to be admitted to the picu (table 5) . clustered regression by patient to account for duplicates in the sample produced similar results. we had 2 complementary datasets to provide new characterization of hcov epidemiology as well as severity of illness among both community-dwelling and hospitalized children with respiratory infections that tested positive for hcov. we found that hospitalized children with hcov were younger than those in the community cohort and more likely to have cccs. seasonal trends as well as the distribution of 4 hcov types were similar in the community and hospitalized group; oc43 was most common followed by nl63 in both settings. this is similar to findings from other studies conducted in children in the community or the hospital [15] [16] [17] . as others have previously reported, we noted that different types predominated in different winters [18, 19] . in both the community and hospitalized groups, we found that hcov types generally were associated with similar clinical features. there were relatively few medically attended events in the community group, and no participants were admitted to the ed or hospitalized. among hospitalized children, no type was significantly associated with an increased likelihood of receiving respiratory support and/or picu admission. however, in the hospitalized group, we did find that demographic and clinical factors were associated with increased severity of illness including age <2 years and cardiovascular, genetic/congenital, and respiratory conditions. others have also observed a substantial burden of disease associated with hcov nl63 or oc43 in children <5 years of age with severe disease occurring more often in the presence of underlying medical conditions [16] . our results supported an association between hcov nl63 and croup, which has been noted in multiple studies [20, 21] . our findings suggest that hcov hku1 could be a pathogen; this type was detected in 10 (20.4%) children in the community group and 34 (16.0%) in the hospitalized group including 24 without codetections. there were no discernible differences in the host factors, clinical symptoms, severity of illness, or frequency of coinfections associated with hku1 compared with the other 3 types. our study had limitations. the findings from the community cohort may not be generalizable because this population was largely latino/hispanic and under active surveillance for respiratory illnesses. findings from our hospital sample are likely to reflect referral center bias because cumc is a tertiary pediatric care center, and, as such, there is an overrepresentation of children with cccs. collection of nasal swabs for the community surveillance component of the study versus nasopharyngeal swabs in the hospital could have impacted viral detection. we did not capture healthcare-acquired infections, and we could have missed additional hcov detections [22] . we collected symptoms differently in the 2 groups; symptoms in the community cohort were reported by the participants, whereas symptoms in hospitalized children were extracted from the medical records. subjective symptoms may have been underreported for younger children in the community cohort leading to bias. due to the small sample, our analysis did not assess the impact of specific types of viral codetections or bacterial coinfections with mycoplasma, bordetella, or chlamydophila pneumoniae. although testing was done only for symptomatic individuals in this study, respiratory infections could have been incidental to the reason a child was hospitalized. we most likely did not accurately determine the percentage of children with asymptomatic shedding of hcov compared with those for whom hcov was the primary cause of their symptoms. there could also have been other confounding conditions, eg, presence of bacterial superinfection, which contributed to the clinical picture that were not assessed. we lacked healthy controls with which to compare our cohorts. finally, our analysis was limited by relatively few cases with increased severity of illness. in conclusion, children from the community with hcov detections were mostly 5 years of age and younger with nonmedically attended illness. among hospitalized children with hcov detected, a significant number received respiratory support and/ or were admitted to the picu, and this was the same for children without coinfection. children less than 2 years of age and those with cccs were at risk of increased severity of illness. clinical manifestations and severity of illness were similar among the 4 hcov types studied. in this study, we demonstrated that coronaviruses were detected in a significant proportion of children in both community and hospital settings and could be a contributor to clinically significant respiratory illnesses. future multicenter studies with representative study samples conducted over a longer time period should be done to provide additional insights into the epidemiology and clinical features of hcov. author contributions. investigators from the centers for disease control and prevention (cdc) took part in designing and conducting the study, analyses and interpretation of the data, and review and approval of the manuscript. coronaviruses: important emerging human pathogens clinical impact of human coronaviruses 229e and oc43 infection in diverse adult populations identification of a new human coronavirus characterization and complete genome sequence of a novel coronavirus, coronavirus hku1, from patients with pneumonia the association of viral and bacterial respiratory infections with exacerbations of wheezing in young asthmatic children a prospective, community-based study on virologic assessment among elderly people with and without symptoms of acute respiratory infection clinical impact of human coronaviruses 229e and oc43 infection in diverse adult populations coronavirus 229e-related pneumonia in immunocompromised patients coronative antibody tires in sera of healthy adults and experimentally infected volunteers human coronavirus nl63 infection and other coronavirus infections in children hospitalized with acute respiratory disease in hong kong, china multiplex pcr and emerging technologies for the detection of respiratory pathogens mosaic: mobile surveillance for acute respiratory infections and influenza-like illness in the community children with complex chronic conditions in inpatient hospital settings in the united states pediatric deaths attributable to complex chronic conditions: a population-based study of washington state the dominance of human coronavirus oc43 and nl63 infections in infants characterization of human coronavirus oc43 and human coronavirus nl63 infections among hospitalized children <5 years of age the pediatric burden of human coronaviruses evaluated for twenty years epidemiology and clinical presentations of the four human coronaviruses 229e, hku1, nl63, and oc43 detected over 3 years using a novel multiplex real-time pcr method human (non-severe acute respiratory syndrome) coronavirus infections in hospitalised children in france croup is associated with the novel coronavirus nl63 role of human coronavirus nl63 in hospitalized children with croup coronavirus-related nosocomial viral respiratory infections in a neonatal and paediatric intensive care unit: a prospective study key: cord-024673-cl8gydrj authors: rosen, lawrence d.; felice, kate tumelty; walsh, taylor title: whole health learning: the revolutionary child of integrative health and education date: 2020-05-12 journal: explore (ny) doi: 10.1016/j.explore.2020.05.003 sha: doc_id: 24673 cord_uid: cl8gydrj nan adverse childhood experiences (aces), potentially traumatic events disproportionately affecting our most vulnerable children, greatly increase risk for poor physical and emotional health outcomes in adults. toxic stress, triggered by aces-related trauma, significantly affects nervous, endocrine, and immune system functioning, even altering dna and ultimately brain structure via epigenetic mechanisms. clinical phenomena resulting include distractibility, impulsivity, emotional dysregulation and a multitude of learning difficulties. children thus impacted are at higher risk for physical and emotional health challenges throughout their lifetimes and more likely to engage in health-risk behaviors. (11) compounding the above challenges, aces via toxic stress pathways also lead to widening health disparities. (12) aces are common, with nearly 2/3 of adults reporting at least one type of ace in childhood and approximately 1/4 reporting experiencing at least three types, (13) and they are costly: the estimated price to families, communities, and society exceeds hundreds of billions of dollars annually. (14) impact on education the impact of aces in schools has a reciprocal effect compounding the challenges faced by a child who has experienced trauma. exposure to early trauma affects brain development and reaction to stimuli, specifically in the limbic system and cortex. (15) this presents challenges to learning, most prominently in the child's executive function, language development, communication, and emotional regulation. a reciprocal effect occurs as the child has challenges not only in learning, but also in reactivity to stimuli in the classroom, such as rejection, failure, negative reinforcement, and punishment. a limbic system shaped by trauma makes the brain state one of constant -fight or flight‖, rather than the relaxed alertness necessary for learning. when the learning process is challenging, it is exacerbated by emotional reactivity, a struggle to regulate, and a perception of threat whether one exists or not. thus, the impact on aces in the classroom can make obstacles to educational success seem insurmountable. responsive pedagogy and educator awareness of mental, emotional, and behavioral health have proven effective in mitigating aces in educational settings. the same limbic brain that perceives threat and activates fear also thrives in an environment rich with positive relationships, reinforcement, and support. (15) although aces can hinder the academic performance and success of a child, their impact can be mitigated and academic growth can be facilitated with a supportive and safe learning environment, strong relationships in the classroom, and a concerted effort to keep the child in school. reducing academic and attendance challenges contributes to greater academic success, attenuates the impact of adverse experiences into adulthood, and improves health outcomes across the lifespan.(16) educational policy has become increasingly reflective of the need to consider the overall wellbeing of the child -physically, socially, and emotionally -with a focus upon systems and programs that support that holistic scope. an emphasis on social emotional learning (sel) in schools has become an educational priority, as a way to reduce barriers to educational success and to build awareness and understanding of the role of emotional and community wellness in longterm learning and health outcomes. sel, as defined by the collaborative for academic, social, and emotional learning (casel), is -the process through which children and adults understand and manage emotions, set and achieve positive goals, feel and show empathy for others, establish and maintain positive relationships, and make responsible decisions.‖(17) the five key components of sel are self-awareness, self-management, social awareness, relationship skills, and responsible decision-making. while educators inherently recognize the value of educating the whole student by attending to their mental, emotional, and behavioral needs, it has only become a curriculum requirement in recent years, and in certain states. additionally, many schools have independently implemented facets of sel-enabling pedagogy in place, drawing from various health promoting domains such as mindfulness programs, nature education, nutrition learning including teaching kitchens, schools gardens, and cognitive-based physical education. while these initiatives have shown promise, they are staggered and siloed, implemented and evaluated inconsistently across schools, districts, and states. the centers for disease control and prevention support school wellness policies in theory but only cite nutrition and physical activity as critical components. (18) the whole school, whole community, whole child (wscc) model recognizes the need for improved collaboration between health and education systems to best serve students. (19) while the wscc paradigm broadens the scope of health promotion to include psychosocial concerns and encourages family and community involvement, it leaves out other promising pieces of a comprehensive integrated program, like mindfulness and the other domains cited previously. though aces and sel have risen to the forefront of educational policy awareness, actually building comprehensive programs can be quite challenging, particularly when educators may be fully aware of the need but lack the time and support to implement and study interventions. the complex interplay between health and educational challenges demands creative new collaborations between both spheres. the siloed solutions of yesterday no longer adequately serve, and the choreographed coordination of health promotion components is needed. access to an integrated, comprehensive, and customizable sel-based wellness studies program, designed to mitigate aces and improve long term health via self-care competency, would greatly benefit students, educators, families, and communities. furthermore, it would complement and amplify existing successful school and community initiatives, creating an accessible, proactive, and holistic wellness creation model for children and families. we call this approach -whole health learning‖ (whl). at its core, whl represents the application of core pediatric integrative health principles (20) to the educational environment, including these four key values: • preventive: focus on health promotion and creation, favoring proactive strategies to reactive solutions. • context-centered: children are nurtured within the context of healthy families, communities, and schools. • relationship-based: only through open communication and building trust are we best able to work together to ensure each child's optimal wellbeing. • participatory: creating health should be a collaborative process, actively encouraging participation and putting children in control of their own health. delivered via an integrated framework of whole health domains, whl best addresses the complex needs of today's students, serving as a bridge to sustainable, life-long emotional and physical wellbeing. when students graduate high school with a competency in wellness studies, they will have established a foundation for life-long behavioral habits that optimize health outcomes. these habits are what we term -lifestyle prescriptions‖ -nutrition, exercise, sleep, mindfulness, nature -the bedrock of integrative health practice. the whl pilot -named the -wellness studies program‖ -engaged middle school students (grades 6-8) and included mindfulness, nutrition, cognitive fitness, and nature education components. it was informed by nj sel standards,(22) as well as best practices of partner organizations assisting in program delivery. created by and supplemented with feedback from both educators and students, the program was implemented as a series of workshops introducing specific wellness concepts, each building successively upon the other through reinforcement and experiential learning. the pilot program ran until june, 2019 and was funded for re-implementation for the 2019-2020 school year. the wellness studies program is among the earliest known efforts to integrate a set of distinct wellness programs into a unified learning experience designed to meet academic and sel goals. program metrics have been collected and are currently in analysis. the goal is to refine the program and expand to a number of other schools in different geographic regions throughout the u.s. over the next several years. perhaps one day, wellness studies programs will be fully embedded within all u.s. schools as part of a national public wellness initiative. there may be no better method to effectively and equitably improve the health of our nation while simultaneously reducing health care costs. over the past twenty years, integrative health experts have recognized the emerging cascade of socially-determined illnesses and their long-term effects, issuing repeated warnings about the need for urgent action to prevent further erosion of the physical and mental health and wellbeing of our nation's children. despite significant investments by healthcare entities and philanthropic organizations, children's health has continued to deteriorate. the circular impact of poor health on education, and of learning challenges on short-and long-term health, is magnified by the increasing toll of aces and resulting toxic stress on our most vulnerable youth. yet there is hope; evidence suggests that proactive, participatory, community-based interventions are effective strategies to mitigate health risks. recently, several national entities have recognized the value of infusing more holistic health learning in schools, perhaps the most accessible and costeffective environments in which to teach lifelong habits leading to positive health behaviors and, ultimately, health outcomes. (25) the report highlights three key promotion and prevention strategies, one being programs delivered in school settings. notable is a priority -to teach children in preschool and grades k-12 social and emotional skills, including mindful awareness practices.‖ this expressed support of whole health learning programs within schools as effective means to ameliorate the impact of aces on education and health is welcome. however, educators alone cannot be asked to solve the immense challenges inherent in creating and sustaining an optimally effective and cost-effective health promotion system. the institute of medicine, in a 1997 report titled -schools & health: our nation's investment,‖(26) cautioned, -the schools of yesteryear were not expected to solve the health and social problems of the day by themselves; the medical, public health, social work, legislative, and philanthropic sectors all pitched in. given the scope and complexity of the health problems of today's children and young people, it is again likely that schools will not be able to provide solutions without the cooperation and support of families, community institutions, the healthcare enterprise, and the political system.‖ this remains the case, nearly a quarter of a century later. the iom report noted that -a strong interconnected infrastructure will be essential if cshp [coordinated school health programs] are to become established and flourish.‖(26) what was an empirical study of chronic diseases in the united states: a visual analytics approach age, period, and cohort trends in mood disorder indicators and suicide-related outcomes in a nationally representative dataset prevalence and treatment of depression, anxiety, and conduct problems in us children epidemiology and impact of health care provider-diagnosed anxiety and depression among us children environmental injustice: children's health disparities and the role of the environment. explore (ny) the growing pediatric health gap: environmental injustice threatens our future. explore (ny) kids count data book: state trends in child well-being understanding snap, the supplemental nutrition assistance program effects of poverty centers for disease control and prevention. preventing adverse childhood experiences (aces): leveraging the best available evidence committee on psychosocial aspects of child and family health; committee on early childhood, adoption, and dependent care; section on developmental and behavioral pediatrics. the lifelong effects of early childhood adversity and toxic stress prevalence of adverse childhood experiences from the 2011-2014 behavioral risk factor surveillance system in 23 states preventing adverse childhood experiences the body keeps the score: brain, mind, and body in the healing of trauma education and learning in the context of childhood abuse, neglect and related stressor: the nexus of health and education whole community pediatric integrative medicine: vision for the future. children (basel) emotional well-being: emerging insights and questions for future research the goldie hawn foundation fostering healthy mental, emotional, and behavioral development in children and youth: a national agenda evolution of school health programs key: cord-259823-ia1g5dt4 authors: gowin, ewelina; bartkowska-śniatkowska, alicja; jończyk-potoczna, katarzyna; wysocka-leszczyńska, joanna; bobkowski, waldemar; fichna, piotr; sobkowiak, paulina; mazur-melewska, katarzyna; bręborowicz, anna; wysocki, jacek; januszkiewicz-lewandowska, danuta title: assessment of the usefulness of multiplex real-time pcr tests in the diagnostic and therapeutic process of pneumonia in hospitalized children: a single-center experience date: 2017-01-15 journal: biomed res int doi: 10.1155/2017/8037963 sha: doc_id: 259823 cord_uid: ia1g5dt4 the aim of the study was assessment of the usefulness of multiplex real-time pcr tests in the diagnostic and therapeutic process in children hospitalized due to pneumonia and burdened with comorbidities. methods. the study group included 97 children hospitalized due to pneumonia at the karol jonscher teaching hospital in poznań, in whom multiplex real-time pcr tests (ftd respiratory pathogens 33; fast-track diagnostics) were used. results. positive test results of the test were achieved in 74 patients (76.3%). the average age in the group was 56 months. viruses were detected in 61 samples (82% of all positive results); bacterial factors were found in 29 samples (39% of all positive results). the presence of comorbidities was established in 90 children (92.78%). on the basis of the obtained results, 5 groups of patients were established: viral etiology of infection, 34 patients; bacterial etiology, 7 patients; mixed etiology, 23 patients; pneumocystis, 9 patients; and no etiology diagnosed, 24 patients. conclusions. our analysis demonstrated that the participation of viruses in causing severe lung infections is significant in children with comorbidities. multiplex real-time pcr tests proved to be more useful in establishing the etiology of pneumonia in hospitalized children than the traditional microbiological examinations. acute respiratory tract infections are the most common infectious diseases among children. the incidence of community-acquired pneumonia in europe is 33/100,000 in the age group < 5 years [1] . its clinical manifestation includes symptoms ranging from mild rhinitis to severe pneumonia leading to respiratory failure. the risk group of severe disease course includes children < 5 years of age, especially boys, individuals in immunosuppression, and patients suffering from chronic diseases [2] . establishing the etiological factor is a difficult task. there are no clinical, radiological, or biochemical markers that would enable the differentiation between bacterial and viral infections [3] . this frequently results in the overuse of antibiotics in the therapy of acute respiratory infections. british, american, and polish guidelines state that, in children hospitalized due to pneumonia, microbiological examinations should include blood cultures, the detection of the presence of viruses with the use of pcr (polymerase chain reaction) or immunofluorescence in material collected from the nasopharynx (smear or upper respiratory aspirate), the assessment of antibodies against mycoplasma and chlamydophila in classes igm and igg, and the comparison of antibody levels in the acute phase of the disease and during convalescence [4] [5] [6] . in children it is difficult to collect reliable material for microbiological analysis in a low or noninvasive manner and retain its representativeness of the lower respiratory tract flora. nasal smear cultures are not useful in establishing the etiology of pneumonia. the pathogens grown in a such manner include both physiological flora as well as flora that could potentially cause pneumonia. on the other hand, microbiological cultures need to be secured before antibiotic therapy is commenced, which is impossible in many cases. the solution to this problem is the detection of microbial genetic material in, for example, the material acquired from nasal smear cultures. it is, however, important to remember that pcr results may be positive in the case of persistent infections; in some pathogens prolonged shedding is observed even up to 7 months since the beginning of an infection [7] . another problem is that traditional bacterial cultures are insufficient to establish the etiology, mainly due to the significant participation of viruses in the etiopathogenesis of these infections. this especially concerns children in their first year of life, in whom viral infections may be responsible for even 67% of pneumonia cases [8] . the currently used molecular examinations enable quick identification of numerous pathogens. detecting the influenza virus with pcr is a widely accepted and utilized method of confirming infection [9] . this is also true for the respiratory syncytial virus (rsv). the main drawback of tests detecting just a single pathogen is the necessity of requesting every examination separately, collecting samples for analysis multiple times, and making decisions concerning the selection of pathogens for analysis. test panels used for establishing the presence of the most important bacterial and viral pathogens enable simultaneous detection of the most significant etiological factors. a separate problem is that, apart from the accepted viral etiology, pneumonia may also be caused by new viruses, such as the human metapneumovirus (hmpv), human coronavirus, or bocavirus [10] . molecular techniques are more sensitive and capable of diagnosing more viruses [11] . prompt and accurate diagnosis is important for infection control and surveillance, patient cohorting, treatment choices, and avoiding antibiotics. previous experience with the use of the multiplex realtime pcr tests in the population of children is limited [11] [12] [13] [14] . aim of the study is the assessment of the usefulness of multiplex real-time pcr tests in the diagnostic and therapeutic process in children hospitalized due to pneumonia and burdened with comorbidities. the study group was composed of children hospitalized due to pneumonia in the period between 01.2014 and 02.2015 at the karol jonscher teaching hospital in poznan, in whom multiplex real-time pcr tests (ftd respiratory pathogens 33; fast-track diagnostics) were used in the diagnostic process. ftd respiratory pathogens 33 is an in vitro test with eight multiplex real-time pcr reactions for the qualitative detection of the following viruses, bacteria, and fungi causing respiratory infections: influenza a, b, and c; parainfluenza viruses 1 the analysis included the following factors: age, sex, comorbidities, immunosuppression, low body mass, airways obstruction, and respiratory failure requiring admission to icu (intensive care unit). respiratory samples (throat or nasal swabs) were collected from all patients. the next step was extraction of pathogens' genetic material either dna or rna, followed by amplification of specific regions by real-time polymerase chain reaction. the presence of specific pathogen sequence in the reaction is reported as a cycle threshold value. apart from the multiplex real-time pcr method, also traditional microbiological culture tests were performed in the studied children: blood cultures, nasopharynx smear cultures, and respiratory aspirate cultures. positive microbiological cultures were defined a ≥105 cfu/ml. all the described tests were done as diagnostic tests during hospitalization. informed consent was obtained from parents/legal guardians on admission to hospital. analysis. data were presented as percentages or medians and range means and standard deviations. interval data were analyzed by mann-whitney test since data did not follow normal distribution (kolmogorov-smirnov test). nominal data were analyzed by chi-square test of independence or in case of zero observed frequencies an exact fisher-freeman-halton test was used. data were analyzed with the use of statistical packages statistica 10 (statsoft, inc.) and statxact 8.0 (cytel); all tests were considered significant at < 0.05. the study group included 97 patients, 52 boys and 45 girls; the average age in the group was 56 months. the presence of comorbidities was established in 90 children (92.78%), including respiratory system diseases in 25 cases, cardiac diseases in 21 cases, neurologic diseases in 13 cases, and neoplastic diseases in 9 cases. immunosuppression was identified in 11 patients (11.34%). the details are provided in table 1 . positive test results were achieved in 74 patients (76.3%). the presence of a viral factor was established in 61 samples (82% of all positive results); bacterial factors were found in 29 samples (39% of all positive results). the presence of the genetic material of a single pathogen was found in 34 children (45% of all positive results). the details of the analysis are presented in table 2 . on the basis of the obtained results, 5 groups of patients were established: when comparing these groups, no differences were found in terms of age, day of material collection in relation to hospitalization time, or the necessity of icu stay. radiological image analysis was not sufficient to unambiguously diagnose the etiology of pneumonia or respiratory infection. the presence of airflow obstruction was significantly higher in patients with a viral etiology ( = 0.0011). on admission 54% of children with negative real-time pcr results had elevated procalcitonin levels. this proportion is significantly higher when compared to patient with established etiology ( = 0.0186). such difference was not observed while comparing proportion of patients with markedly elevated crp levels (>50 mg/dl). the prevalence of increased procalcitonin levels (>2 ng/ml) was higher in patients without established etiology. the difference is of statistical significance. such differences were not observed when comparing number of patients with increased crp levels. airflow obstruction was found in 44 patients (45%); 75% of them had viral etiology of pneumonia. the difference was of statistical significance ( = 0.0011). the most frequently identified pathogen was rsv in 23 children (23.7%), and rhinovirus (rh) was found in 19 patients (19.6%), adenovirus (adv) in 11 (11.3%), cytomegalovirus (cmv) in 10 (10.3%), and pneumocystis jiroveci (pnp) in 9 (9.3%). purely bacterial etiology was established in 8 patients (8.2%). the details are presented in figure 1 . relations were found between age and the presence of individual microorganisms: infections of rsv etiology were more frequent in younger children (median age 10.5 months versus 42 months; = 0.0133); airflow obstruction symptoms were also more frequent in this group ( = 0.0008). in children under the age of one, the dominant pathogen was rsv, which was found in 32% of patients in this age group. 56% of all positive results for rsv occurred in children in their first year of life. blood cultures were performed in 75 children, in 62 cases they were sterile (82,67%), bacterial flora growth occurred in 13 cases, and in 3 (4%) cases it was pathological (s. aureus, serratia sp., and e. coli). respiratory aspirate cultures were performed in 64 children, they were sterile in 15, physiological respiratory tract flora growth was achieved in 28 cases, and in 23 it was pathological; in 8 of these cases the results were confirmed with multiplex real-time pcr tests. nasal smear cultures were performed in 58 children, they were sterile in 15, and the presence of pathological flora was found in 17 cases (29.31%); in 5 of these cases the results were confirmed with multiplex real-time pcr tests. detailed results of microbiological analyses of patients with at least one positive microbiology results are presented in table 3 . in the group of children with negative results of multiplex pcr tests, blood cultures were positive in 3 cases (e. coli, serratia, and s. aureus), tracheal aspirate cultures were positive in 7 (in 4 of them pathological flora was grown), and nasal smear cultures indicated the presence of pathogenic flora in 5 cases (see details in table 3 ). test results enabled the implementation of targeted therapy in 13 patients; details are presented in table 4 . the acquired results confirm the usefulness of multiplex real-time pcr tests in establishing the etiology of severe pneumonia in hospitalized children. probable etiology of pneumonia was diagnosed in 76% of children with the use of this method. after the exclusion of children with neoplastic diseases from the group, this percentage increased to 79.54%. similar percentages of positive results are often encountered in the literature [8, 12, 14] . bierbaum et al. achieved positive results of multiplex real-time pcr tests detecting only viral factors in 76% of cases in a group of children below the age of six with symptoms of respiratory tract infection and the dominant pathogen was rsv [12] . in a study conducted by mengelle et al. on a group of 914 children with symptoms of respiratory infection, 90% of the collected samples were positive, with rh, rsv, and if (influenza virus) as the most frequent pathogens [15] . in our analysis, we found a more significant participation of rsv; however, only patients with pneumonia underwent the analysis. the general lower participation of the viral factor in comparison to the [16] . in an italian study within a group aged 5-14 years, etiology was established in 77% of cases with the use of molecular analysis. the presence of viruses was revealed in 65% of samples and bacteria in 40% of samples, while mixed etiology was present in 28% of children [17] . mengelle et al. demonstrated that infections caused by more than one virus are common and occurred in 30% of the children included in his study. the sensitivity of virus detection of the multiplex realtime pcr method is high and reaches almost 90% [11] . when genetic material of several pathogens is revealed with the use of the pcr method, it may result from a simultaneous infection caused by two pathogens or from an infection in a patient who is already a carrier of another pathogen. it may also result from establishing the presence of viral genetic material after a previous infection, through the so-called virus shedding. it is estimated that the etiology of pneumonia is mixed in about 30% of children [18] . some works point out that there is a relation between the type of viral factor and the risk of coinfection. martic et al. found coinfections with different pathogens in 50% of infections caused by adenovirus [19] . the high percentage of coinfections in our study may be explained by the specificity of the study group. the majority of the children were burdened with the presence of chronic diseases, and some of these patients were in immunosuppression. the presence of bacterial coinfection is frequent in viral etiology of pneumonia; however, bacteria are not always responsible for active infections. in children with pneumonia, establishing the presence of viruses in the upper respiratory tract is considered as a probable etiological factor. positive results may also be achieved in individuals in temporary asymptomatic carrier state during convalescence after a previous infection [13] . it is, therefore, necessary to remain very cautious when interpreting examination results. the clinical significance of human rv rna detection in respiratory samples remains unclear [20] . the pcr method does not enable unambiguous differentiation between infection and carriage, even with the use of the quantitative method. it needs to be stated, however, that comparative studies of carriage significantly more often indicated the presence of s. pneumoniae in children with pneumonia compared to the healthy population [21] . the available literature contains reports stating that higher numbers of viruses were usually associated with milder disease course [20] . the exception was the coinfections with rsv and hmpv [22] . infections of this type are characterized by intensified obstruction symptoms [22] . in our group, the children with infections caused by mixed pathogens did not differ from the children with infections caused by single pathogens, in terms of both the severity of disease course and intensity of inflammatory reaction. the high percentage of positive results of examinations detecting viral genetic material points to the significance of viruses in the occurrence of pneumonia in children. the literature indicates that viruses may be responsible for the majority of pneumonia cases in children [8, 16] . in our group, in the case of hospitalized children, some patients received outpatient antibiotic therapy, which was then continued during inpatient care in all cases. therefore, all samples were collected during antibiotic therapy, on the fifth day on average. hence, it is not possible to completely exclude the presence of bacterial factors, which were not identified in the upper respiratory tract later on due to the ongoing antibiotic therapy. this may explain the relatively low percentage of bacterial genetic material detected in the group we analyzed. the current guidelines recommend the use of antibiotic therapy in children hospitalized due to pneumonia, but the lack of clinical improvement despite the application of broadspectrum antibiotic therapy may suggest a viral cause of infection [4] [5] [6] . the studied group was unique due to the high participation of patients with comorbidities, some of them in immunosuppression. such patients are at a higher risk of severe course of infection and prolonged hospitalization. the diagnosis of a viral etiology of infection enables moderate use of antibiotics and allows for more emphasis on symptomatic treatment, which is the most beneficial for such patients. because viruses are easily transmitted from patient to patient, advanced infection control methods are critical in controlling the spread of viruses [20] . rsv turned out to be the most frequently detected pathogen, especially in the group of children under the age of one. moreover, it was frequently the only identified pathogen. in children from risk groups, rsv causes infections with severe course, and it is characterized by high infectiousness. diagnosing rsv as the etiological factor enables the isolation of or cohorting the patients in order to reduce the spread of the infection and the implementation of the recommended management for severe obstruction [4, 5] . research is currently being conducted on the implementation of antiviral drugs which are more effective than the previously used ribavirine [23] [24] [25] . in the case of viral infections such as influenza, the establishment of the etiological factor enables the implementation of specific treatment. in the studied group, a single case of influenza was found, but the year in which the study was conducted was not an epidemic year. molecular tests for detecting the influenza virus only are widely applied. they are very useful during epidemic seasons, but it is important to remember that the disease may occur also outside such periods. in certain situations, it may be difficult to select a diagnostic test only on the basis of symptoms. moreover, in the case of influenza, the time of treatment implementation is crucial. therefore, including influenza in the standard diagnostic set prevents the omission of this important infection factor. the conducted analysis showed limited usefulness of traditional microbiological examinations in the diagnostic process of pneumonia. taking blood cultures is also considered standard in severe pneumonia, but its usefulness is not significant. in a group of patients with radiologic confirmed pneumonia, esposito revealed the presence of s. pneumoniae in 14.3% of cases; 91.8% of the diagnoses were based on positive results of real-time pcr tests conducted on material collected from the respiratory tract, while positive results of blood cultures were present only in 8.14% of cases [22] . nasopharyngeal swabs cultures often show flora growths that may constitute colonization. in our analysis, traditional microbiological examinations revealed the presence of potentially pathogenic bacteria in material collected from 31 children; in 11 of these cases there was agreement with the results of multiplex real-time pcr tests. in 8 patients it was not possible to assess the agreement of research methods due to the fact that in the ftd respiratory pathogens 33 test microorganisms such as pseudomonas aeruginosa, escherichia coli, or serratia sp. are not detected. the majority of previous works assessed the results of multiplex real-time pcr tests conducted in admission rooms on all patients reporting with respiratory symptoms [15] [16] [17] . because of the costs associated with these tests, it is difficult to use them in such a manner in daily practice. the mentioned analyses seem to be more epidemiological in nature. in our work we made an attempt to assess the usefulness of tests which were conducted during hospitalization in children with severe pneumonia not responding to standard therapy. in this group of patients, the benefits of the applied treatment were satisfactory in relation to the diagnostic cost incurred. the confirmation of viral etiology was very important, especially in the group of children at a risk of severe course of infection. in such a unique group of patients, constituted by children burdened with comorbidities, under immunosuppression, and after marrow stem cell transplants, the implementation of targeted treatment should be taken into consideration with the use of modern antiviral drugs, as well as such steps as isolation and the reduction of immunosuppression. in the guidelines of the neutropenia management it is strongly advised to isolate patients with documented respiratory viruses until symptoms resolve [20] . there are some limitations to our study. we have collected a heterogenic group of patients (different indication for testing, different comorbidities, and chronic diseases). the number of patients and the number of specimens were too small to perform elaborate statistical analysis. sample collection for microbiological cultures was incomplete. the exact timing of sample collection relative to antibiotic administration was not accurately documented. similar problems were described in other clinical studies in this subject topic. our analysis demonstrated that coinfection with viruses is common in severe lung infections in children with comorbidities. multiplex real-time pcr tests proved to be more useful in establishing the etiology of pneumonia in hospitalized children than the traditional microbiological examinations widely used in the applicable diagnostic process to date. informed consent was obtained from parents/legal guardians on admission to hospital. this article does not contain any studies with human participants performed by any of the authors. this study is done based on analysis of patients' medical records; all tests were done as diagnostic tests during hospitalization. estimates of world-wide distribution of child deaths from acute respiratory infections acute respiratory infections in children procalcitonin, creactive protein and leukocyte count in children with lower respiratory tract infection british thoracic society guidelines for the management of community acquired pneumonia in children: update the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america rekomendacje postępowania w pozaszpitalnych zakażeniach układu oddechowego viral pneumonia impact 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community-acquired pneumonia in hospitalized children based on who clinical guidelines etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections epidemiology and virology of acute respiratory infections during the first year of life: a birth cohort study in vietnam multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children viral infections in immunocompromised patients frequent detection of viral coinfection in children hospitalized with acute respiratory tract infection using a real-time polymerase chain reaction antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? new options in the treatment of respiratory syncytial virus disease successful treatment of parainfluenza virus respiratory tract infection with das181 in 4 immunocompromised children chemotherapy of respiratory syncytial virus infections: the final breakthrough all authors declare that they have no conflict of interests. key: cord-034973-1yucjgp5 authors: burgason, kyle a. title: using loseke to examine the influence of laws, myths, and claims making on sex offenders’ socially constructed realities date: 2020-11-09 journal: sn soc sci doi: 10.1007/s43545-020-00005-5 sha: doc_id: 34973 cord_uid: 1yucjgp5 the realities surrounding sex offenders in the united states can often times be inundated with preconceived and even false certainties. a consequence of such misleading beliefs for sex offenders can be the creation of urban legends and myths that motivated individuals can use to back an agenda and that can bring unintended collateral damage creating false realities for offenders, their families, law enforcement, and the community. this study utilizes loseke’s lens to examine the socially constructed realities in which sex offenders in the united states are forced to live. the history of the treatment of sex offenders is detailed from colonial america through child sexual abuse panic of the 1980s and into the current cyber age. we review laws passed in the 1990s, through the first part of the new millennium, which fueled individuals’ fear of sex offenders. additionally, we explore how claims-makers use myths and socially constructed realities to create social problems for sex offenders, generate public fear and resentment, and pressure policy makers and legislatures to pass laws that promise false hope and false security to communities. finally, myths associated with cyber sexual offenders are explored. solutions to combat myths are offered to legitimize the true reality surrounding sex offenders. the laws concerning sex offenders seek to achieve protection for citizens of a community, incapacitation of offenders, and possible rehabilitation and a return to society of a productive citizen. the realities surrounding sex offenders can often times be false (griffin and miller 2008; social and harris 2016) , perpetrated by countless to have a socially constructed reality, one must start with identifying a social problem, and having the problem gain enough support and backing to be deemed legitimate. whether the social problem is real or not is often of little consequence, it simply must be believed. shotter (1993) notes in our arguments about the nature of things we must realize, our statements, whether true or false, are not always about real things, sometimes what they refer to is imaginary. as such, one first must understand what a social problem is, and how individuals go about constructing them. spector and kitsuse (1977) define social problems as the activities of individuals or groups making assertions of grievances and claims with respect to some conditions (75). they agree with loseke (2003) in that the conditions that lead to the creation of a social problem must meet a certain criterion. the term social problem as defined by loseke (2003, p. 6 ) is used to indicate that something is wrong; it refers to conditions evaluated as wrong because they create harm. the second part of the definition is, the condition must be widespread, which means it must hurt more than a few people. the third part of the definition is, the social problem must be able to be changed by humans. the final part of the loseke definition is, the social problem and conditions should be changed (loseke 2003) . the two basic conditions that make up a social problem are objective and subjective. objective conditions are conditions that we can see; they are about measurable and widespread conditions in the environment and they are about the living, breathing people who are hurt by these conditions, or who create these conditions (loseke 2003) . the objective condition is seen as having an intrinsically or malignant nature standing in contrast to a normal society, this makeup of the social problem is usually accompanied by an identification of the conditions that cause the problem and by proposals as to how the problem might be handled (blumer 1971) . the subjective conditions are those that cannot be observed. peoples' ideas about risks matter more than the actual risk measured by objective indicators (loseke 2003) , as noted by zatz (1987) chicano youth gangs and crime the creation of a moral panic (kraska 2004) . in actuality, most social problems exist in terms of how they are defined and conceived in a society instead of being an objective condition with a specific objective make up. a social problem does not exist for a society unless it is recognized by the society to exist. in not being aware of a social problem, a society does not perceive it, address it, discuss it, or do anything about it; the problem is just not there (bulmer 1971) . the societal definition gives the social problem its nature, lays out how it is going to be approached, and shapes what is done to correct it (bulmer 1971) . therefore, whatever people perceive to be a social problem, can in fact become one if they can convince enough individuals in society the problems exist. this can be accomplished by constructing realities where the conditions meet or appear to meet the four-part definition for a social problem. these realities are the result of an intricate process of learning and constructing meanings and definitions of situations through language, symbols, and interactions with other people (kraska 2004) . the social problems and realities are not constructed on their own, they need people to create them, accept them, and allow them to gain power and legitimacy. these people are often referred to as the actors (kraska 2004; loseke 2003) in the social problem construction game. social constructionism focuses on the process by which a social problem is constructed (kraska 2004; spector and kitsuse 1977) . the focus by the criminal justice system on sex offenders did not happen overnight. criminal justice is a social construction that shifts with intellectual perspective, political influence, social sentiment, cultural values, and the interests of powerful groups in society (kraska 2004) . some authors describe social constructionism as a dramaturgy, where the actors work hard to construct and maintain an effective impression of themselves through the orchestration of appearances (kraska 2004) . as with any social problem, there are certain actors, known as claims-makers, pushing for the problem and another group of actors, known as the audience, for which the claims are targeted. before establishing who can be a claims-makers and an audience member for the sex offender constructed realities, one must clearly understand what a claim is and who claims-makers and audiences are, and what they do. a claim is any verbal, visual, or behavioral statement that seeks to persuade audience members to define a condition as a social problem, or a demand one party makes on another (loseke 2003; spector and kitsuse 1977) . notice no mention of a factual or true statement is contained within the definition. this is what makes the process of constructing social problems and realities different from other problems, objective and empirical evidence need not exist as myths alone can serve as the basis for claims, and is often the case when it comes to sex offenders. we learn about myths from our parents, people in church, socializing with friends, and from teachers. myths are conceptual schemes that help us interpret reality and organize our thoughts and beliefs about reality. they organize how we see reality; they allow us to adhere to our particular belief system even when contradicted by reality. thus, myths tell us where society's problems reside, where we should look for solutions, and what solutions are acceptable (kappeler 2004 power of myths comes not from their ability to reflect reality accurately but from the power and legitimacy they gain over time, and eventually become truths for many people. myths can be restricted to specific criminal justice events, always presented as occurring regularly or with increasing frequency (kappeler 2004 ) just as the sex offender scare was through the 1980s and into the 1990s by means of claims making. claims making is the process of trying to convince the public a particular issue or situation which should be defined as a social problem (macionis 2005; spector and kitsuse 1977) . the process begins with the belief that people create meaning because meaning is not inherent in objects; individuals who create this meaning are the claims-makers, or put another way, the people who pitch the claims or myths to the audience (loseke 2003) . the other groups of actors in a social construction drama are the audience members. a social constructionism audience is those people who evaluate the believability and importance of what claims-makers say (loseke 2003; spector and kitsuse 1977) . they are critical because a social problem is created only when audience members evaluate claims as being believable and important. how and where the claims and myths are pitched to the audience are important in addressing whether or not the conditions are significant enough to be considered worth the audiences' time. it is important to remember there are multiple claimsmakers pitching multiple claims to audiences at the same time. it is up to the claimsmakers to use the correct pitching techniques and myths to make their particular problem seem like the one warranting the most time and resources. audiences have a limited caring capacity and only have time to address the most important claims (loseke 2003) . a social problem must gain social endorsement if it is to gain respectability in public discussion. if the social problem does not obtain audience support, it is doomed. just because a social condition is recognized as crucial by some people in a society does not mean the problem will break through into the area of public consideration. if the social problem fails to obtain legitimacy, it struggles and deteriorates outside of the arena of public action (blumer 1971) . loseke (2003) suggests using particular motivational frames to make one's claim more enticing. for those fearing sex offenders, a motivational frame could be for the parents and children of the community to appeal to emotion with stories of sexually abused children; however, there is also a chance to appeal to cultural themes. two possible themes used to construct a motivational frame in the case of parents of children and victims would be through family, and fair play. fair play, because members of the victims' groups would claim it is unfair their children, as well as themselves, must live in fear because a sexual predator lives in the neighborhood, and is not banned from commuting to libraries, schools, playgrounds, and other places where innocent children convene. the theme of family, because strong families are one of the backbones of our nation, and if a member suffers from a sexual assault, be it an elderly person or a young child, that family's world comes crashing down around them. they lose faith in moral goodness, local law enforcement, and possibly their faith in a higher power. their motivational frame might be effective if it includes the fact that having someone being violated by a sexual offender affects the entire family negatively. whether one is a claims-maker for or against sex offenders' rights, it comes down to which side makes the more compelling argument to the policymakers. one need only look to the victims of sex offenders and their families to see the sn soc sci (2021) claims-makers in this drama, and two of the most popular audiences would have to be communities where sex offenders live and lawmakers. innocent children as victims in their home communities are one of the main groups examined when talking about sex offenders. the possible claims-makers in this drama would be parents of children who had been victims of sexual assault by registered sex offenders, or couples with young children that have a registered offender living in their neighborhood. the claims these groups could use would be the emotion-filled story of their own child's, or another child's, experience with a sex offender. such as the story of 10-year-old jetseta gage, a mentally challenged girl who was kidnapped, raped, and murdered at the hands of convicted sex offender roger bentley, only to be stuffed into the cabinet below a sink in his trailer (amw 2006) . as kraska (2004) notes one of the largest, most powerful, and widely accepted claims-makers for criminal justice issues such as sex offenders is the media. the media plays and has played a powerful role in educating the public and influencing public policy in everyday ventures as well as with criminal justice issues. they have a vested interest in the promotion of criminal justice myths because their public is fascinated with sensationalized crime, and crime has become a media product which sells better than any other media commodity (kappeler 2004) . zatz (1987) notes at the most visible level, social problems and the responses to them are created in part by the media. the media confirm, distort, and structure the conflict between the claims-makers and the deviant group (kraska 2004) , in this case sex offenders. the media are important because they offer claims-makers the largest possible audiences, and because they can reach many different people, as our world gets larger and more mobile we must rely on the media to tell us about it. it is logical to argue claims presented through the media will influence more audience members' understanding of social problems (loseke 2003) . loseke (2003) notes television becomes particularly important when claims are presented as factual news or based on facts, because these programs encourage viewers to evaluate claims as truthful. on any given day, there are numerous events that are potentially important, but only some become the topic of news shows, producers and editors decide what is and what is not news. they decide how to package the stories in ways that will captivate audience members. on a day-to-day basis, there are predictable biases in how those stories are presented (loseke 2003) . the history of the influence of media on sexual abuse started in the late 1970s with women recalling repressed memories of being raped when they were children (jones 1999) . media attention surged through the 1980s particularly after allegations of sexual abuse at mcmartin preschool in california in 1984, the day school scandal in fells acres, massachusetts in 1984, and the case of new jersey nursery school worker kelly michaels who was absurdly accused of 280 counts of sexual assault in 1987 (rabinowitz 2003) . during these years, the media's focus was on the hidden problem of child sexual abuse, the pain the survivors of such abuse endured, and the need to raise the country's attention to the prevalence of the problem (beckett 1996) . later in the eighties it was found the aforementioned cases were all hoaxes that were conjured up in the minds of the young children and drawn out by the corrupt tactics used by investigators. the media's focus on sexual abuse ranging from awareness of the problem to false allegations of abuse influenced therapy practice and research sn soc sci (2021) 1:6 6 page 6 of 21 on the topic (jones 1999 ). jones states research and publications about the problem of sexual abuse went from none in the early 1980s to 14 articles by 1989. publications about sexual abuse leapt to almost 1500 articles from 1995 to 1998 mirroring the emphasis placed on sexual abuse by the media during those years. in terms of therapy, the media's attention on false memories, which were blamed on therapists, had an impact on therapist treatment. the once accepted belief of repressed memories became controversial, causing therapists to become wary of the subject for fear of lawsuits (jones 1999) . the other audience in which sex offender claims-makers would most likely be pitching to would be lawmakers. the parents of victims and young children as claims-makers would use the aforementioned emotion-filled stories of heartbreak and evil and sensationalized media reports to convince lawmakers the rules regarding sex offenders should be strengthened. along with legislatures, these emotionfilled stories would likely attract more followers to the movement for the claimsmakers, the more americans who support a social problem; the more policymakers must be attentive (loseke 2003) . it is strength in numbers form of claims making. another vital strategy is making the claim at the right time, if one can produce a large number of people during election time all fighting for the same conditions to be recognized, the claims-makers might come to a certain understanding with a particular candidate. such promises might be, "if this issue is brought before the legislature and gets the laws changed, i can promise you all of these votes" (loseke 2003, p. 60) . you have the offenders arguing the requirements of the laws such as notification and proximity laws are too harsh, and need to be lessened, and in dealing with the same social problem you have the groups of parents, victims, and other supporters trying to persuade the laws are too lax, and need to be strengthened. the actors try to show sex offenders are inherently evil and pose a significant threat to the children of the community. make the audience members see that the presence of offenders in the community means increased worry to parents, and that having these people live in communities with regular people and children causes an increased threat to the safety and innocence of the children. the aforementioned strategies are the grounds that claims-makers use to pitch the claim. punishments for most crimes throughout the early years of america had religious overtones, and sexual offenses were no exception. sex crimes were considered sins, and public shaming, flogging, and other degradation ceremonies were common (friedman 1993; roth 2005; shelden 2008) . each region of the country had different degrees of punishment; in the chesapeake, hard flogging was common, as was being pulled behind a boat until nearly drowning (roth 2005). in the late eighteenth century and early nineteenth century, the criminal justice system paid less attention to sex crimes as catching and punishing offenders required very precise social conditions, both cultural and structural. cultural because enough people within the community had to find the act offensive, and structural as laws against sex crimes were difficult to enforce except in small communities (freidman 1993) . in larger sn soc sci (2021) 1:6 page 7 of 21 6 environments such as new york and philadelphia, it would be next to impossible to be aware of all sexual crimes taking place, especially those perpetrated in poor working-class communities. between 1750 and 1796 in the superior court of massachusetts, just 4.3% of the indictments were for moral and sexual crimes (freidman 1993) . following the progressive era and beginning in 1937 in michigan, were the sexual psychopath laws. by the mid-1970s, more than half of the states had mentally disordered sex offender laws (masters et al. 2011) . these laws allowed the state to confine sex offenders with a mental disease for indefinite periods in a psychiatric hospital instead of corrections facilities. such laws were abandoned when determinate sentencing came to be popular; however, many called for a return to indeterminate sentencing for violent sex offenders. many violent sex offenders with fixed sentences were released back into society to reoffend. current sex offender statutes in most states allow the incarceration period to be extended beyond the original courtmandated because of fear that sex offenders, once released, will reoffend (masters et al. 2011). as such, offenders are confined for what they are believed likely to do in the future, not for the crime they committed. even during the early years of the unites stated, loseke's propositions were applicable to sex crimes. there was a wrong, as sexual crimes were viewed as a sin. it was widespread, as each region of the country had its own sanctions. finally, we can infer that communities tried to change the problem via the punishments described in an attempt to repent or get right with god for the sins committed. having violent sex offenders released after serving a determinate sentence led the state of washington to create the sexually violent predator law (svp). under the svp act, recidivists may be declared sexually violent predators, confined to a mental health system, and required to stay until considered cured (masters et al. 2011) . masters et al. states even though preventive detention laws are popular with the general public, their future is uncertain. under existing law, sexual predators can be freed only after they have been effectively "cured." however, most psychiatrists consider sexual predation to be an anti-social behavior rather than a mental illness and argue it cannot be cured. the washington state psychiatric association called for the repeal of the state's sexual predator law going on record to assert sexual predation is not a mental illness, but falls under criminal conduct (masters et al. 2011 ). these doctors declared sexually violent predator laws give offenders what is equivalent to a sentence of life imprisonment. this could lead to slippery-slope mentality in that if recidivism is going to be the basis for determining mental illness and confining offenders in mental institutions, people could call for indeterminate sentences for other repeat felony offenders as well. loseke's (2003) tenants are prime display over the course of the next few cases discussed. the wrong is the sexual assault and/or death of jacob wetterling, megan kanka, adam walsh, and pam lyncher. loseke's second proposition is also present as the conditions were most assuredly widespread as these attacks were celebrated cases that made national and international headlines as many others go unreported to national media. in addition, these cases were spread across the entire country. tenant three is supported in that all of these cases lead to the laws and legislation sought by individual wanting justice for the victims and to prevent such atrocities sn soc sci (2021) 1:6 6 page 8 of 21 from happening again. loseke's fourth proposition is a natural progression from her third as it would be rare event to find someone in favor of allowing sexual assaults on innocent victims. as such, this social problem (violent sexual assaults) should be changed to protect potential victims of sexual predators. the reader should keep these tenants in mind as they read through the following cases and visualize the techniques and methods detailed in the previous section that are utilized by claimsmakers to achieve their desired result. then, one must ask if those ends (socially constructed realities in which many offenders are forced to live) justify the means (the myths perpetuated by some claims-makers). prior to 1994, few states required convicted sex offenders to register their addresses with local law enforcement. major federal statutes dealing with crimes by sexual offenders were named after victims in the cases. the high-profile cases began with the story of young jacob wetterling, leading to one of the most important pieces of legislation written to date on laws governing convicted sex offenders, the jacob wetterling act. the jacob wetterling crimes against children and sexually violent offender act was enacted on september 13, 1994 (reno 1998 national center missing kids) . this requires state implementation of a sex offender registration program for persons convicted of a criminal offense against a minor, or a sexually violent offense (42 u.s.c. 14071; sex offender sentencing; reno 1998). the act requires offenders to be registered for at least ten years as well as update address information when they move and verify the registered address periodically (reno 1998). the registration alone was not enough, as was revealed just a month and half before the jacob wetterling act was enacted by the murder of 7-year-old megan kanka by a released sex offender. the public backlash called for programs to provide the public with information regarding released sex offenders. megan kanka was a 7-year-old girl from hamilton township, new jersey whose family unknowingly lived across the street from jessie timmendequas, a twice-convicted sex offender. on july 29, 1994, timmendequas used the promise of seeing his new puppy to lure young megan into his home where he proceeded to rape, strangle, and eventually murdered megan (masters et al. 2011; national center missing kids; walker 2006) . in 1996, president clinton signed a federal law that mandated states develop a registry of known sex offenders (national center missing kids). the law requires law enforcement personnel to make information on registered sex offenders available to the public (reno 1998; masters et al. 2011; national center missing kids; sex offender sentencing; walker 2006) . while the jacob wetterling act and megan's laws were linked directly with keeping children safe from sexual predators, the case of pam lychner shows adults also can be the victims of sex offenders. pam lychner was a 36-year-old real-estate agent from spring valley village, texas who was assaulted by william david kelley, while selling her home in 1990 (sex offender sentencing). following the attack lychner founded "justice for all," a victims' rights advocacy group that lobbies for tougher sentences for violent criminals (sex offender sentencing). lychner is also credited with helping to formulate the language for the bill that created a national database that helps track offenders and bears her name. the pam lychner sex offender tracking and identification act of 1996 requires perpetrators of particularly serious offenses and recidivists be subject to lifetime registration (reno 1998). despite the implementation and improvements made in the above-mentioned acts, and because mobility has increased significantly in our society (friedman 1993) , many sex offenders continued to offend. the national center for missing and exploited children reports that numerous offenders failed to comply with registration duties and remain undetected due to the inconsistencies among state laws. lawmakers recognized this problem along with the burden faced by law enforcement to keep track of the increasing number of offenders and took action. their solution was based on another high-profile case, adam walsh. adam walsh was a 6-year-old boy from hollywood, florida who was kidnapped from a store and murdered (child search 2003) . consequently, the adam walsh child protection and safety act mandates specific registration requirements for sex offenders in all states (pub. l. 109-248 2006; national center missing kids). additionally, the adam walsh act contained details concerning internet sexual abuse, which was quickly becoming widespread in the latter part of the 1990s and into the early part of the new century. it imposed criminal penalties for participation in a child exploitation enterprise, increased penalties for registered sex offenders who committed a felony sex offense against a minor, and prohibited the embedding of deceptive words or images in a website to deceive individuals into viewing obscene material. when the adam walsh act passed, online sexual predators were by no means new, but had become the new norm in soliciting young victims. loseke's (2003) arguments are even more salient in the cyber age as computers help to expand the social problem as outline in tenant two. with the advent of the internet and smart-phones, the problem of sexual assault and exploitation is even more widespread and ubiquitous. while computers and the internet open a world of possibilities for children, they can be exposed to dangers. computer telecommunications have become one of the most prevalent techniques used by pedophiles to share illegal photographic images of minors and to lure children into illicit sexual relationships and attempt to sexually exploit children through such online services. as the reader will see going forward, with the greater reach of the internet, loseke's third proposition is satisfied as claims-makers and legislatures alike moved feverishly to create and implement more laws and legislation in hopes of changing the national issue. similar to before, nearly all would agree that this particular problem should be changed as the use of the internet for sexual exploitation often inclines to put one of the most vulnerable segments of our population as the main targets for predators, children. some of the techniques used by these individuals to gain trust include attention, affection, kindness, and even sending gifts. these offenders listen to and empathize with children, and use ample time, money, and energy in selecting a victim with the ultimate goal of lowering the child's inhibitions and slowly introducing sexual content into their communications (fbi). young people are often the victims of a variety of internet crimes, including solicitations to engage in sexual acts for commercial gain through production and distribution of child pornography or for personal sn soc sci (2021) five percent received sexual solicitations that made them upset or afraid; of these victims, 37% were between the ages 10 and 13. another 3% were asked to allow contact or a meeting offline. the anonymity that the internet affords offenders makes it difficult to get accurate information about them; the true identity, age, and gender of the perpetrators may be different from what they state. victims believed nearly all the perpetrators were strangers. two-thirds of all solicitations came from self-described males. approximately two-thirds of solicitations occurred in chat rooms; 24% were instant messages. one-quarter of respondents received unwanted sexual material, more boys 57% compared to girls 42% (connelly 2001; finkelhor et al. 2000) . nearly half of the victims did not tell anyone about the solicitation; of those who did, about a quarter informed a parent. as access to internet technologies expands via increased use of wireless and handheld technologies, monitoring internet communications has become increasingly challenging. with the emergence of the internet and other communications innovations creating more opportunity for criminals to solicit victims (roth 2005), lawmakers and law enforcement were pressured to pass legislation and enforce new laws to help ensure the safety of children online. the child pornography prevention act of 1996 and the federal bureau of investigation's innocent images national initiative were the results of citizens' requests. the investigation of a missing juvenile from prince george's county, maryland in 1993 by the fbi lead to the discovery of two suspects who had sexually exploited numerous juveniles over the past 25 years and the creation of the innocent images national initiative (iini). further investigation into these activities determined adults were routinely utilizing computers to send sexually explicit images to minors and, in some instances, to lure minors into engaging in illicit sexual activity. in 1995, based on information developed during this investigation, the iini addressed the illegal activities conducted by users of commercial and private online services and the internet. the child pornography prevention act of 1996 followed the cases of megan kanka and jacob wetterling and expanded the federal prohibition on child pornography to include not only pornographic images made using actual children, but also any visual depiction, which is or appears to be of a minor engaging in sexually explicit conduct. as well as any image that is advertised, promoted, presented, described, or distributed in such a manner that conveys the impression or depicts a minor engaging in sexually explicit conduct (u.s. code. vol. 18 2256 1996), making online pornographic images and words of children or to children a strict liability crime. this means all intent has been removed from the criminal act, one either possessed child pornography or did not, as it takes one's intentions completely out of the circumstances and the accused's mental state is irrelevant to guilt or innocence and the chief evidentiary proof rests in the act alone (nemeth 2004) . myths that create the realities as loseke's (2003) propositions have been met, the wrong identified (sexual assault), having widespread effect (numerous victims), changes can be made by people and should be made (laws enacted by claims-makers such as the media, coupled with the resulting legislation). boundless myths often associated with such offenders, have also been generated, leaving many sex offenders as well as citizens living in socially constructed realities. the current study selected seven myths commonly associated with sex offenders. these myths were , as well from an informal write-in poll asking undergraduate students taking an introduction to criminal justice class at a midsized southern university, to provide two statements they believed true of the master statuses of sex offenders. the myths examined in the current study is by no means an exhaustive list as there exists a wealth of myths surrounding sex offenders and the literature on the topic is overwhelming, as no one article can do full justice to all research on sex offenders. what we have attempted to do is use loseke's (2003) formulations to demonstrate how each of these myths could be easily create and perpetuate a socially constructed reality in the hands of a motivated claims-maker. one of the most popular myths is sex offenders have high recidivism rates social and harris 2016) , which is not supported by empirical research (harris and hanson 2004; helmus et al. 2012; langan and levin 2002; langan et al. 2003; nieto and jung 2006; prentky et al. 1997; sample and bray 2003, 2006; tewksbury et al. 2012) . some studies of treated sex offenders show great variability in recidivism with rates ranging from 0 to 50% for any offense. offenders who participated in cognitive-behavioral treatments, which include monitoring in the community by probation or parole personnel suggest increased positive outcomes with recidivism rates ranging from 0 to 18% (jones 1999) . in a meta-analysis of recidivism studies, hanson and bussiere (1998) similarly found that recidivism rates for sex offenders varied considerably, with an average across all studies was 13.4%. a 2003 study by the u.s. department of justice found that within three years of prison release, 5.3% of sex offenders were arrested for another sex crime. according to the study, sex offenders were less likely than non-sex offenders to be rearrested for any offense: 43% of sex offenders verses 68% of non-sex offenders (beck and brien 2004) . beck and brien (2004) note another study conducted in canada found of 4,724 sex offenders, nearly 75% had not been charged with another sexual offense after 15 years. according to the available research, the average recidivism rate for sex offenders is low when compared to rates for other crimes. a plausible explanation for such variation might be dependent on the offender and offense characteristics, such as whether or not the perpetrator is a chronic sex offender or someone who was caught on their first offense. another prevalent myth concerning sex offenders is that strangers are more likely to sexually abuse children than family members (abc news 2006; craun sn soc sci (2021) levenson and d'amora 2007; meloy et al. 2008; snyder 2000; vanzile-tamsen et al. 2005) . the reality is of the 500,000 children who are molested each year (macionis 2005, p. 173) , only 10% of the offenders were strangers, 90% are family, friends, and people known to the child (masters et al. 2011) . most of the legislation aimed at controlling sex offenders is focused on the perpetrators being strangers. children are actually at greater risk of sexual abuse from family members. this myth feeds the fear of parents and communities about strangers within their neighborhoods and their childrens' lives. many schools are teaching young children the difference between a "good touch" and a "bad touch" and emphasizing the need to tell an adult if a person acts toward them in a manner they feel is wrong (macionis 2005). on the surface, this seems like a fine idea, but if as the research suggests, the offender is someone the child knows, possibly even a family member or parent, it seems doubtful a child will inform on a family member or parent to another adult. a third myth surrounding sex offenders is sex offender registries reduce sexual assaults (agan 2011; drake and aos 2009; letourneau et al. 2010; meloy et al. 2007; prescott and rockoff 2011; sandler et al. 2008; schram and milloy 1995; tewksbury and jennings 2010; vasquez et al. 2008; veysey and zgoba 2010; zevitz and farkas 2000; zgoba et al. 2008 ) and proximity laws reduce sexual assaults (barnes et al. 2008; davey 2006; loney 2008; meloy et al. 2008; nieto and jung 2006; tregilgas 2010; zandbergen et al. 2010) . in reality, there is little evidence these registries and proximity laws provide effective protection from or act as a deterrent to repeat sex offenders. a sex offender study dealing with 10 states found the passage of sex offender registration and notification laws demonstrated no systematic influence on the number of rapes committed in the states. most of the states in the sample showed no significant differences in the average number of rapes committed before and after the sex offender laws (vasquez et al. 2008) . the majority of proximity laws require offenders not live within a thousand or several thousand feet of a place where children congregate. this can cause serious problems in some suburban neighborhoods where most of the community has several schools and parks. with offenders being forced from urban areas, they are settling in masses in the suburbs of larger cities where many families live. polk county iowa chief deputy of police bill vaughn stated since october 10 of 2005, a month after the 2000-foot law was put into action, the number of sexual offenders living in rural polk county jumped from 76 to 114 as offenders have had to relocate (dobbs 2005) . offenders are being forced into these clumps similar to "hoovervilles" pushing them away from their work, families, and homes. some registered offenders are not abiding by the proximity laws. a study by tewksbury and mustaine (2006) found nearly 22% of a 96-person sex offender sample in seminole county, florida was found living within 1000 feet of a playground or park, 14.6% near an elementary school or day care center. the authors added together the child congregation locations to gauge how many of these locations sex offenders lived near. data indicated that 31.3% live near at least one-child congregation location, 14.6 near two locations, and 3.1% near three locations. they also found out that 12 out of 21 sexual offenders of minors were actually breaking florida law by living sn soc sci (2021) near places children congregate. a similar study by walker et al. (2001) found 48% of registered sex offenders with child victims lived within 1000 feet of day cares, parks, and schools. it is not just real-world sex offenders that deal with socially constructed realities as the new millennium brought a hyper focus on the internet and social media, the world of online sexual offenders is not without its own myths that have been constructed through claims-makers such as the media and community fear. a number of the following myths examined in the current study were identified by college students and centered on predators on the internet. one such myth is about internet sex offenders using deception and trickery to lure small children on the internet into violent sexual meetings. in reality, the majority of internet-originated sex crimes involve adult men who use the internet to meet and seduce underage adolescents into sexual encounters. the offenders use internet communications such as instant messages, e-mail, and chartrooms to meet and develop intimate relationships with victims. in most cases, victims are aware they are conversing online with adults (wolak et al. 2008) . wolak et al. (2008) note media stories and much of the internet crime prevention information available and suggest it is naïve and inexperienced young children who are vulnerable to online child molesters and it is this that makes them vulnerable. the research indicates, however, by the preteen years, child internet users comprehend the social complexities that exist online at similar levels compared to adults (wolak et al. 2008; yan 2006) . as children grow older and become more experienced online, they participate with more advanced and interactive internet users, which puts them at greater risk than younger, less experienced children who use the internet in simpler, less interactive ways (wolak et al. 2008) . another myth surrounding online sexual victimization identified by students is social networking sites have increased the risk of sexual victimization by online predators. in reality, a study conducted between june and october 2007, consisting of over 400 interviews with police about online sex crimes showed no cases of sex offenders stalking and abducting minors based on information posted on social networking sites (wolak et al. 2008) . the study suggested online predators do not stalk their victims, but actively seek out those victims susceptible to seduction. the study also showed children with profiles on social networking sites, even those trying to meet new people, were no more likely than other children to have uncomfortable or inappropriate contacts with online users. an additional myth identified by students associated with online sex offenders is online predators are violent pedophiles. the reality is online predators primarily target adolescents as opposed to young children (wolak et al. 2004 ). most online predators do not fit the clinical definition of a pedophile, which is, an individual who is involved in sexually arousing fantasies, urges, or behaviors involving sexual activity with a prepubescent child (apa 2000) . young children were found to be less accessible online compared to teenagers, as young children are more supervised and less likely to respond to the advances of predators because children are less interested in relationships and romance (wolak et al. 2008) . teenagers with certain characteristics identified as more vulnerable such as those with poor relationships with their parents, who experience loneliness and depression, and who are gay or questioning boys (wolak et al. 2004) . violence is a rare occurrence in online sex sn soc sci (2021) crimes. evidence from wolak et al. (2008) study suggests online predators are not among the sex offenders who abduct or assault victims. most online child predators are patient enough to develop relationships with victims and shrewd enough to move those relationships offline (wolak et al. 2008) . it would seem offenders are aware of how to speak to teens to gain and keep their trust through the face-to-face meeting if one was to occur. the final myth examined here is violent sex crimes against children have increased because of the internet. the reality is several sex crimes and abuse indicators have shown declines during the same period in which the use of the internet has been expanding (freeman-longo 2000) . from 1990 to 2005, the number of sexual assault cases validated by authorities declined 51 percent (finkelhor and jones 2006) . for example, the rate of sexual assaults reported by teenagers to the national crime victimization survey declined by 52% between 1993 and 2005. additionally, a statewide survey of students in minnesota also showed declines in sexual abuse during this period (wolak et al. 2008) . having examined the many myths that have been used to construct the realities of sex offenders, both in real life and online, it is not difficult for one to infer these realities carry with them consequences for the offenders and communities alike. the construction of social realities based on myths hides contradictions in logic, reality, and carries consequences. myths may seem harmless, but when associated with the criminal justice system they can have dire consequences for individuals and society (kraska 2004 ). one of the major effects of these realities is the laws that establish where sex offenders can live. using information gathered from census tracts for several counties in florida, mustaine et al. (2005) investigated to see if registered sex offenders are more likely to be found in areas with greater social disorganization due to choice or because of stigmatization. the study found negative location characteristics were higher in the census tracts of sex offenders as compared to the rest of the county and the nation. these tracts had higher levels of unemployment, more families living below the poverty line, and the educational level tended to be lower, fewer homes were lived in by owners, housing values were lower, and household income was lower in these census tracts. the study also found that tracts with higher concentrations of sex offenders are more disorganized and less desirable than tracts with lower concentrations of offenders, as these high concentration tracts also had locational, household, and housing characteristics which signified they were more disorganized and disadvantaged places to live (mustaine et al. 2005 ). the conclusion reached by this study was communities with characteristics of social disorganization are likely to be the homes of registered sex offenders as offenders live in these areas because they are relegated to such a location. a similar study conducted by mustaine et al. (2006) investigated if registered sex offenders currently reside in different locations than they did when arrested, and if offenders did change locations, are their current residences located in more or less socially disorganized locations than their residences at the time of arrest. the study found residential location typically changes after being arrested for a sex offense, and of those who changed locations, half moved to less disorganized areas, and half moved to more socially disorganized areas. those offenders that lived in less socially disorganized areas originally were more likely to move downward after registration, while sn soc sci (2021) those who already lived in highly socially disorganized areas were more likely to stay the same or have minimal movement . these studies suggest convicted sex offenders are living in the more socially disorganized areas where quality work and community support tend to be the lowest. the research implies it is not the choice of offenders to live in these areas, but rather many are forced to comply with residency restrictions. another problem myth-based realty can bring on sex offenders is aggravation and isolation within a community. this can lead to increased rates of negative consequences for offenders including amplified stress, shame, harassment, job loss, loss of friends, and community harassment or vigilantism (ackerman and sacks 2012; lasher and mcgrath 2012) . notably, all of these consequences can be counterproductive insofar as they can lead to reoffending (freeman and sandler 2010; hanson et al. 2009 ). some libertarians believe the residency and notification laws are unfair and are an additional punishment beyond the offender serving his or her time. many offenders are released back into hostile, rejecting communities that have been influenced by media and have few support systems; here the offenders are expected to lead a functional crime-free life while facing difficulty finding housing and employment, threats or harassment, vigilantism, and ostracism from the community (walker 2006) . these constructed realities can take a toll on offenders' families economically, socially, psychologically, and even physically (levenson and tewksbury 2009) as well as bring about increased community fear. an evaluation in wisconsin of community notification laws where people were informed via public meetings resulted in citizens leaving feeling more worried about being victimized than they did when they were unaware of the offender being in neighborhood. research has also shown the collateral effect of such realities including a decline in home values for homes close to registered sex offenders (linden and rockoff 2008; pope 2008) . they have led to extensive financial and resource allocation costs for law enforcement to implement and impose community notification programs (zgoba et al. 2008) . likewise, probation and parole agencies have had to invest significantly more time to aiding offenders in finding housing and jobs (zevitz and farkas 2000) . a group often overlooked are the families of offenders. these realities can take a significant toll on them economically, socially, psychologically, and even physically (levenson and tewksbury 2009) . a final issue worth noting with these realities may well encompass sex offenders who are not violent predators, pedophiles, or rapists, yet still are required to register. this includes individuals who "moon" people, people arrested for urinating in public, and gay and bisexual men convicted of cruising parking lots for sexual partners in public places (jones 1999) . being aware of the socially constructed realities that sex offenders are living, and examining the history of the laws that the myths and realities help to create, might provide people with a more accurate perspective of the daily obstacles faced by convicted sex offenders. the current study demonstrated the usefulness of using loseke's (2003) tenants to examine and understand how a motivated group of individuals (claims-makers) can take a true social problem (sexual assaults) and use fear and false narratives to sn soc sci (2021) establish and perpetuate myths associated with sex offenders, which in turn can lead to the needless fear and suffering of both offenders and citizens. a possible solution to the problems currently affecting these offenders could be a different type of monitoring. as described above, certain members of society only become more fearful or more likely to be vengeful when they are aware of the sex offenders in their neighborhoods. only notifying law enforcement of the offender's presence in the neighborhood could possibly reduce both fear and chances of vigilantism. the members of the community would not have to know the identity of the offenders and could continue living their lives without concern. the actions and location of the offenders would be the responsibility of law enforcement and the use of full gps tracking for all offenders could be employed. the gps tracking ankle bracelet, which allows law enforcement to track the offender continuously throughout the day, is the most expensive of all tracking bracelets costing around $7.25 per offender per day (roos 2005) . although more expensive, this method of tracking would allow officers to know the exact location of offenders throughout the day including when approaching or loitering in a restricted area. however, recent studies have shown no discernible difference in recidivism between gps-tracked offenders and those that were not tracked via gps (levenson and d'amora 2007; tennessee board of probation and parole 2007; turner et al. 2007) . some conceivable solutions to the online sex offender problems lie not with posting personal information, as millions of children use facebook, instagram, and snap chat safely. rather the preventative focus needs to be on controlling and monitoring interactions as online-initiated sexual assaults come about through direct communication between predators and victims (wolak et al. 2008 ). this could include talking to children about what types of behavior or signals predators will be looking for, as well as what topics to avoid speaking about online such as loneliness, dislike of one's parents, and sex. additionally, better investigation and monitoring techniques on the part of computer forensic investigators could serve to quell this problem. as burgason and walker (2013) outline as forensic investigators may be able to build a case based on a few encase searches and a dump of images, videos, and communication, other cases are more complicated and require a more in-depth investigation (5). as such, the study details the benefits of utilizing optimal foraging theory as a blueprint to track how offenders use the internet for illicit purposes as "being able to follow an offender from one website to another can aid in establishing timelines of events and in developing profiles, motives, and establishing behavior of the offender. this can aid greatly in complex investigations and prosecutions" (burgason and walker 2013) . laws regarding sex offenders have enticed myths, and these myths have driven the creation of constructed realities that are teeming with problem for offenders, their families, and citizens alike. the claims-makers throughout the past two decades have been successful in getting support from proper audiences, from the media circus surrounding child sex offenses in the 1980s and early 90s, to the passing of the internet pornography and stalking laws. many social problems tend to lose their appeal after a certain number of years. sexual assaults are in the minority in that they show no signs of stopping or even slowing down since obsession started in the mid-1990s. in fact, as recently as the summer of 2020 as the sn soc sci (2021) covid 19 pandemic was in full swing across the nation, a moral panic concerning sex offenders gripped the upper west side of manhattan. to quell the spread of the pandemic, new york city officials started filling boutique hotels with homeless individuals including more than a dozen sex offenders. this did not sit well with some of the "well to do" members of the community and their elected representative who quickly began perpetuating a number of the myths outlined above. one particular city official addressed mounting concerns to her constituents stating, "all level 3 sex offenders have been moved out" and that she was "demanding that all remaining offenders be moved out as well." it was not until days after the offenders had been removed that the official softened her stance contending "i initially took an extreme position and stated that 'no registered sex offenders should be allowed on the upper west side'-but that's not realistic. there are around 1,600 registered offenders across manhattan, and neighborhoods cannot wall themselves off" (mckay 2020). as this incident shows, even today, loseke's (2003) tenants hold true as the homeless sex offenders were viewed as the social problem that was widespread across the upper west side of manhattan. a number of citizens and official thought the problem should be changed and could be changed by taking action. the claims-makers organized, utilized myths to elicit fear from the community, and were able to have the offenders removed from the area. sexualized crime, particularly crimes involving a protected class of citizens such as children, will always garner attention from powerful audiences such as politicians and lawmakers. furthermore, as long as the media, police, and other claims-makers are willing to use myths to construct realities against sex offenders, they have little chance of convincing enough people they are not as dangerous as perceived. this study identified many of the myths that accompany online sexual predators as well and demonstrated the vitality of loeske's (2003) from early colonial american clear through to the present-day nyc. from the internet being full of violent pedophiles, to social networking sites being a hot spot for predators to solicit victims, empirical evidence has busted these myths. solutions have been offered to help to rectify the problem of sex offenders causing fear and stress within society, as well as suggestions in educating individuals, especially children, of the dangers involved in becoming interactive with strangers online. to change policy, one needs to identify a social problem and gather enough support to bring the said social problem to a public arena. the issue many sex offenders face is finding support for their side of this social problem. while this study alone may not be able to change the minds of enough people, it could serve as a starting point toward a reform of the laws working against sex offenders and many communities. it might also help to quell some of the myths that serve as the building blocks to the socially constructed realities which many sex offenders and their families suffer through on a daily basis. it the authors hope that the current study can be utilized to properly inform the public as to the true nature of sex offenders' lives, as we now have the aid of empirical evidence in support of our argument, while cynics can only cling to their myths. myths about sex offenders can general strain theory be used to explain recidivism among registered sex offenders sex offender registries: fear without function? analyzing the impact of a statewide residence restriction law on south carolina sex offenders trends in the us correctional populations: recent findings from the bureau of justice statistics culture and the politics of signification: the case of child sexual abuse social problems as a collective behavior optimal foraging theory's application to internet sex offender search behavior: a theoretical model for computer forensic investigations the adam walsh story internet crimes against children. office for victims of crime misperceptions of sex offender perpetration: considering the impact of sex offender registration iowa's residency rules drive sex offenders underground blog/sex-crime s/child -sex-myths division of criminal justice services (2014) myths and facts county molester ban carries costs. the des moines register drake e, aos s (2009) does sex offender registration and notification reduce crime? a systematic review of the research literature the impact of megan's law on sex offender recidivism: the minnesota experience does residential proximity matter? a geographic analysis of sex offense recidivism a parent's guide to internet safety why have child maltreatment and child victimization declined? highlights of the youth internet safety survey myths and facts about sex offenders the adam walsh act: a false sense of security or an effective public policy initiative? child abduction, amber alert, and crime control theater predicting relapse: a meta-analysis of sexual offender recidivism studies public safety and emergency preparedness canada a meta-analysis of the effectiveness of treatment for sexual offenders: risk, need, and responsivity absolute recidivism rates predicted by static-99r and static-2002r sex offender risk assessment tools vary across samples: a metaanalysis the media and megan's law: is community notification the answer in: kraska pb (ed) theorizing criminal justice: eight essential orientations theorizing criminal justice: eight essential orientations recidivism of sex offenders released from prison in 1994 the impact of community notification on sex offender reintegration: a quantitative review of the research literature effects of south carolina's sex offender registration and notification policy on deterrence of adult sex crimes social policies designed to prevent sexual violence. the emperor's new clothes? collateral damage: family members of registered sex offenders public perceptions about sex offenders and community protection policies there goes the neighborhood? estimates of the impact of crime risk on property values from megan's laws nowhere to go, miami sex offenders live under bridge behind the homeless, sex-offenders debacle dividing new york city's once serene upper west side sex offender laws in america: can panic-driven legislation ever create safe societies? making sense out of nonsense: the deconstruction of state-level sex offender residence restrictions social disorganization and residential locations of registered sex offenders: is this a collateral consequence residential location and mobility of registered sex offenders sex offenders: history the impact of residency restrictions on sex offenders and correctional management practices: a literature review (crb # 06-008) fear of crime and housing prices: household reactions to sex offender registries recidivism rates among child molesters and rapists: a methodological analysis do sex offender registration and notification laws affect criminal behavior? megan's law: final guidelines for the jacob wetterling crimes against children and sexually violent offender registration act, as amended. department of justice crime and punishment: a history of the criminal justice system are sex offenders different? an examination of rearrest patterns does a watched pot boil? a time-series analysis of new york state's sex offender registration and notification law community notification: a study of offender characteristics and recidivism. urban policy research, washington state institute for public policy office of justice programs, united states department of justice controlling the dangerous classes: a history of criminal justice in america, 2nd edn. pearson allyn and bacon sexual assault of young children as reported to law enforcement: victim, incident, and offender characteristics evaluating public perceptions of the risk presented by registered sex offenders: evidence of crime control theater? menlo park tennessee board of probation and parole (2007) monitoring tennessee's sex offenders using global positioning systems: a project evaluation where to find sex offenders: an examination of residential locations and neighborhood conditions assessing the impact of sex offender registration and community notification on sex-offending trajectories a longitudinal examination of sex offender recidivism prior to and following the implementation of sorn sex offender treatment in the united states: the current climate and an unexpected opportunity for change implementation and early outcomes for the san diego high risk sex offender (hrso) gps pilot program. university of california, irvine, center for evidence-based corrections the impact of sexual assault history and relationship context on appraisal and responses to acquaintance sexual assault risk the influence of sex offender registration and notification laws in the united states: a time-series analysis sex offenses and offenders reconsidered: an investigation of characteristics and correlates over time the geographic link between sex offenders and potential victims: a routine activities approach internet-initiated sex crimes against minors: implications for prevention based on findings from a national study online predators and their victims: myths, realities and implications for prevention and treatment what influences children's and adolescents' understanding of the complexity of the internet? ed) theorizing criminal justice: eight essential orientations residential proximity to schools and daycares: an empirical analysis of sex offense recidivism the impact of sex-offender community notification on probation/parole in wisconsin megan's law: assessing the practical and monetary efficacy key: cord-254556-1zthrgy1 authors: taylor, sylvia; lopez, pio; weckx, lily; borja-tabora, charissa; ulloa-gutierrez, rolando; lazcano-ponce, eduardo; kerdpanich, angkool; angel rodriguez weber, miguel; mascareñas de los santos, abiel; tinoco, juan-carlos; safadi, marco aurelio p.; lim, fong seng; hernandez-de mezerville, marcela; faingezicht, idis; cruz-valdez, aurelio; feng, yang; li, ping; durviaux, serge; haars, gerco; roy-ghanta, sumita; vaughn, david w.; nolan, terry title: respiratory viruses and influenza-like illness: epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample date: 2016-09-22 journal: j infect doi: 10.1016/j.jinf.2016.09.003 sha: doc_id: 254556 cord_uid: 1zthrgy1 background: better population data on respiratory viruses in children in tropical and southern hemisphere countries is needed. methods: the epidemiology of respiratory viruses among healthy children (6 months to <10 years) with influenza-like illness (ili) was determined in a population sample derived from an influenza vaccine trial (nct01051661) in 17 centers in eight countries (australia, south east asia and latin america). active surveillance for ili was conducted for approximately 1 year (between february 2010 and august 2011), with pcr analysis of nasal and throat swabs. results: 6266 children were included, of whom 2421 experienced 3717 ili episodes. rhinovirus/enterovirus had the highest prevalence (41.5%), followed by influenza (15.8%), adenovirus (9.8%), parainfluenza and respiratory syncytial virus (rsv) (both 9.7%), coronavirus (5.6%), human metapneumovirus (5.5%) and human bocavirus (hbov) (2.0%). corresponding incidence per 100 person-years was 29.78, 11.34, 7.03, 6.96, 6.94, 4.00, 3.98 and 1.41. except for influenza, respiratory virus prevalence declined with age. the incidence of medically-attended ili associated with viral infection ranged from 1.03 (hbov) to 23.69 (rhinovirus/enterovirus). the percentage of children missing school or daycare ranged from 21.4% (hbov) to 52.1% (influenza). conclusions: active surveillance of healthy children provided evidence of respiratory illness burden associated with several viruses, with a substantial burden in older children. respiratory viruses and influenza-like illness: epidemiology and outcomes in children aged 6 months to 10 years in a multi-country population sample introduction acute respiratory tract infections (artis) comprise the most common illnesses worldwide, and children often experience several episodes a year. 1 in children, clinical presentation can range from mild, uncomplicated upper respiratory tract illness to severe lower respiratory tract infection (lrti) including pneumonia, bronchiolitis, croup and exacerbations of asthma or wheezing. 2 the world health organization estimated that 1.9 million children died from arti in 2000, 70% in africa and south east asia. 3 in 2011, pneumonia alone led to 1.3 million deaths worldwide in children less than 5 years of age. 4 most artis are caused by viruses, but until the advent of multiplex polymerase chain reaction (pcr) techniques, it was often not possible to identify accurately specific viral infections in clinical cases. 5, 6 the pathogens considered responsible for most arti are respiratory syncytial virus (rsv), influenza a and b, parainfluenza viruses types 1, 2 and 3, and adenovirus. 2 several new pathogens associated with arti have been identified more recently, including human metapneumovirus (hmpv), rhinovirus, coronavirus, human bocavirus (hbov) and parainfluenza 4. 2, 7 vaccine efficacy trials provide intensive, active followup of a well-defined population and can be used to evaluate viral epidemiology. as part of a trial of pandemic influenza vaccines, which included 1 year of prospective, active, community-based surveillance for influenza-like illness (ili) in 17 centers in eight countries, 8 we evaluated the prevalence and incidence of respiratory viruses in children 6 months to less than 10 years of age at first vaccination. samples were obtained from an efficacy trial of two pandemic influenza h1n1 vaccines (nct01051661 sponsored by gsk vaccines). 8 an analysis estimating the prevalence of rsv in ili has been previously reported. 9 here, we report data on all respiratory viruses evaluated, a secondary analysis objective. healthy children 6 months to <10 years of age were enrolled in a randomized, observer-blind, parallel group, multi-country trial of as03-adjuvanted versus nonadjuvanted monovalent pandemic h1n1 vaccines. 8 the trial was conducted in 17 centers in australia, brazil, colombia, costa rica, mexico, the philippines, singapore, and thailand between 15 february 2010 and 19 august 2011; enrollment took up to 6 months and timing varied by country. the trial was approved by an institutional review board for each center and written informed consent was obtained from parents/guardians. parents were instructed to contact the study center within 24 h if the child became ill. active surveillance via scripted telephone contact was conducted from 2 weeks after first vaccination, and contact made every 1e2 weeks to day 385 for each child, regardless of time of enrollment. ili was defined as temperature !38.0 c by any route and at least one of: new/ worsening cough, sore throat, stuffy nose, or runny nose. study staff visited the child's home to collect one anterior nasal swab and one throat swab, ideally within 24 h of ili onset, and at most within 7 days. collection could also take place at a study center or hospital if necessary. swabs were transported in a single tube of m4rt transport medium, stored at à70 c and maintained on dry ice during transport. a 7-day symptom-free period was required between new ili episodes. sample testing was performed by standard multiplex pcr techniques. 8, 10 analysis of viral epidemiology the viruses evaluated were influenza (subtypes a-h1, a-h3 and b), parainfluenza (subtypes 1, 2, 3 and 4), rsv (subtypes a and b), hmpv, rhinovirus/enterovirus (the assay did not distinguish between them), adenovirus, coronavirus (subtypes 229e, oc43, nl63 and hku1) and hbov. first analyzed separately, influenza, parainfluenza and coronavirus subtypes were grouped in a post-hoc analysis. the main outcome variable was pcr-confirmed infection with the stated viruses in nasal/throat swabs in children with ili. this included infection with the virus under consideration alone (single infection) or with the virus under consideration plus one or more of the other viruses (co-infection). single and co-infections were also recorded separately. clinical characteristics of ili episodes were reported by the parents of the children, and any hospitalization or medical attendance (by a doctor or other healthcare professional, not including sample collection by study staff) were recorded. pneumonia was defined as acute illness (one or more of fever !38 c, new or worsening cough, dyspnea, consistent auscultation findings [rales or diminished breath sounds], pain in the chest or abdomen when breathing, or purulent or blood-stained sputum production) and radiologic findings consistent with pneumonia. the total cohort included all children enrolled in the randomized trial. the total cohort with ili episodes tested by multiplex pcr included all children enrolled who experienced an ili and had an adequate nasal/throat sample tested by multiplex pcr. the analysis of prevalence of respiratory viruses in ili and clinical characteristics associated with ili was performed in the total cohort with ili episodes tested by multiplex pcr. the analysis of overall incidence of ili, medically-attended ili and hospitalized ili in which respiratory viruses were detected was performed in the total cohort. the prevalence of respiratory viruses among ili episodes was calculated as: where x is the number of ili episodes with nasal/throat samples positive for the virus and n is the total number of ili episodes with samples collected within 7 days and tested. as there was at least 7 days between two ili episodes, it was assumed that each episode was independent. exact 95% confidence intervals (ci) were computed. 11 prevalence was stratified according to country, age at the time of the ili episode (6e11, 12e23, 24e35, 36e59, 60þ months) and whether the child was medically attended or hospitalized. the incidence per 100 person-years (py) of virusassociated ili in the study population was calculated as: where n is the total number of children enrolled in the trial, ε i is the total number of virus-positive ili episodes for subject i, and d i is the follow-up period for subject i. incidence rates were stratified according to country and age group at the time of the ili episode. exact 95% poisson cis were calculated. 12 observations with incomplete data for the outcome variable and ili episodes for which no nasal/ throat sample was taken were removed from the analysis. missing data were accounted for by calculating the missing proportion for each country and age group, then multiplying the py by (1 minus missing proportion). the trial included 6266 children (total cohort). after excluding children with no ili or inadequate samples, 2421 children experienced 3717 ili episodes (total cohort with ili episodes tested by multiplex pcr). participant flow is shown in supplement fig. 1 . demographics were similar in both cohorts, except that children in the total cohort were older (median 55 versus 42 months) (supplement table 1 ). a respiratory virus was detected in 2958 of 3717 ili episodes (79.6%). rhinovirus/enterovirus had the highest overall prevalence (41.5%), followed by influenza (15.8%), adenovirus (9.8%), parainfluenza and rsv (both 9.7%), coronavirus (5.6%), hmpv (5.5%) and hbov (2.0%) ( table 3 ]). co-infection was detected more often with adenovirus and hbov (fig. 1 ). single infections with parainfluenza, hmpv and coronavirus were identified at approximately the same frequency as co-infections ( fig. 1 ). however, parainfluenza 4 and coronavirus 229e were identified more often as co-infections, whilst coronavirus nl63 was identified more often as a single infection (supplement table 3 ). in all countries, rhinovirus/enterovirus was the most prevalent (36.9e59.2%), whilst hbov was least prevalent (0.8e4.7%) ( table 1) . influenza prevalence ranged from 6.1% to 18.5%; parainfluenza prevalence was approximately 10% except in brazil (5.8%) and singapore (6.1%) ( table 1) . (table 1) . influenza was most prevalent (21.3%) in the oldest children (60þ months), followed by 36e59 months (15.6%) and the other age groups (9.8e12.3%) ( table 2 ). all other viruses were least prevalent in the oldest group (table 2) . there was a less obvious pattern in the other age groups, but, in general, prevalence declined with age except for influenza ( table 2) . the incidence of detected respiratory viruses associated with ili reflected their prevalence. the overall incidence per 100 py (total cohort, all children randomized) was 29.78 for rhinovirus/enterovirus, 11.34 for influenza, 7.03 for adenovirus, 6.96 for parainfluenza, 6.94 for rsv, 4.00 for coronavirus, 3.98 for hmpv and 1.41 for hbov (table 3) . australia had the highest incidence of hmpv (5.08) and the second highest of rsv (7.03), but low incidence of the other viruses relative to other countries ( table 3 ). the philippines, singapore and thailand also had low incidences of most viruses in ili relative to the latin american countries ( table 3) . detection of the respiratory viruses at different times during the year was highly variable across countries (fig. 2aeh) . the overall incidence of medically-attended ili associated with viral infection per 100 py (total cohort, all children randomized) ranged from 1.03 for hbov to 23.69 for rhinovirus/enterovirus (table 3) . corresponding values for incidence of hospitalized ili associated with viral infection were 0 for hbov and 0.81 for rhinovirus/enterovirus (table 3) . clinical characteristics of ili episodes associated with a single respiratory virus (i.e. no co-infection) are shown in table 4 . median duration of ili episodes ranged from 8.9 to 13.4 days. few children were hospitalized but most were medically attended outside study procedures. the percentage of children missing school or daycare was highest with influenza-associated ili (52.1%), followed by hmpv (41.5%), adenovirus (39.0%), rhinovirus/enterovirus (37.6%), coronavirus (31.1%), rsv (30.2%), parainfluenza (28.1%) and hbov (21.4%) ( table 4 ). sore throat was experienced by 25e52% of children, cough by 62e97%, stuffy nose by 40e62%, and runny nose by 66e84% (table 4 ). fever was part of the ili definition and therefore experienced by all children. cough was reported in almost all children with influenza, parainfluenza, rsv, hmpv and coronavirus infections, but only in 60e70% of children with rhinovirus/ enterovirus, adenovirus and hbov infections. there were no medically important differences in clinical characteristics between children with a single viral infection compared with children with multiple infections (supplement table 4 ). a total of 58 pneumonia cases were identified among the 6266 children enrolled in the overall clinical trial, corresponding to a detection rate of 0.9%. of the 58 cases, 32 met the definition of ili and were therefore eligible for sample collection as per the clinical trial protocol. a sample was collected within 7 days of onset of ili symptoms for 20 of these 32 cases: one case in thailand, three in the philippines, five in brazil, five in mexico and six in colombia (table 5) . no virus was detected in three cases, a single infection was detected in 10 cases (four rhinovirus/enterovirus, two parainfluenza, one influenza, two rsv and one hmpv), and co-infection was detected in seven cases (table 5) . nine children were hospitalized. rhinovirus/enterovirus had the highest prevalence and incidence in ili of all respiratory viruses tested in all countries, followed by influenza, adenovirus, parainfluenza and rsv, coronavirus, hmpv and hbov. the burden of ili associated with respiratory viruses was considerable, with a high proportion of children being seen by a medical professional and many missing school or daycare. our analysis benefited from being part of a clinical trial, as previously described. 9 most importantly, we conducted 1 year of prospective, active community surveillance of healthy children in tropical and southern hemisphere countries where prospective data are lacking. most studies of viral epidemiology use hospital-based surveillance because community-based surveillance is difficult and expensive. however, hospital-based surveillance tends to capture only the most severe illness and many cases are missed in developing countries because of limited hospital access. our analysis avoided these limitations and allowed us to capture the burden of virus-associated ili in communities. understanding community epidemiology is essential to implement effective control measures. other advantages of being part of a clinical trial included a wellcharacterized population, wide age range up to 10 years, samples taken from a high proportion of children, consistent methodology between countries, and use of sensitive and validated pcr assays. the trial was conducted in eight countries encompassing australia, south east asia and latin america. the exact timing of enrollment varied somewhat between countries, but was planned so that data collection was performed during the peak 2010e2011 influenza season for each individual country. as stated in the methods, all children were followed for 385 days, with the complete period of surveillance for the study occurring between 15 february 2010 and 19 august 2011. this allowed us to compare the distribution of viruses across the different countries. there was considerable variation in the incidence and prevalence of the viruses by country, although rhinovirus/enterovirus had by far the highest incidence and prevalence in all countries. hbov had consistently the lowest incidence and prevalence. several other studies have evaluated the prevalence of viruses in children with respiratory illness. the relative prevalence of the different circulating viruses varied by study. however, the main circulating viruses were similar between studies and with our study, and included picornaviruses (including rhinovirus), adenovirus, rsv, bocavirus, pivs, hmpv, influenza and coronavirus. 13e17 rhinoviruses are classified in the picornavirus family, of the enterovirus genus. 7 a high prevalence of this family has been reported in other studies in different settings. 13,14,18e20 as in our study, an australian study with active community-based surveillance of healthy preschool-age children with arti found that picornaviruses (including rhinoviruses) were the most frequently detected (41.3%). 13 however, other viruses were detected less frequently than in our study: rsv (6.6%), parainfluenza (4.1%), influenza a and hmpv (both 3.7%), adenovirus (3.1%) and coronavirus nl63 (1.5%). 13 in another prospective australian study in children aged 6 months to 3 years reporting ili, rhinovirus was again the most commonly detected. 15 however, in contrast to our results, adenovirus was detected at the same frequency as rhinovirus, followed by parainfluenza 3, polyomavirus, hmpv and hbov. 15 influenza (a/h1n1) and rsv were relatively uncommon; approximately 40% of children were fully or partially vaccinated against influenza. rhinovirus is not always the most commonly detected virus in children with respiratory disease. in children under 5 years of age hospitalized for lrti in thailand, the most commonly detected viruses were rsv (19.5%), rhinovirus (18.7%), hbov (12.8%) and influenza (8.2%). 16 a study of children aged <3 years hospitalized for lrti in brazil found that rsv was most prevalent (53.5% of episodes), followed by hmpv (32.3%), rhinovirus (20.8%), influenza (12.7%), hbov (10.4%), parainfluenza and adenovirus (both 6.5%) and coronavirus (1.2%). 17 in our analysis, influenza prevalence increased with age. the other viruses showed the opposite trend, with the lowest prevalence observed in the oldest children (60þ months). there was a less obvious pattern in younger ages, but, in general, prevalence of all viruses except influenza declined with age. despite this, the burden of illness remained considerable in older children. there was a clear seasonal pattern for influenza, rsv and hmpv in most countries, and to a lesser extent for rhinovirus/ enterovirus. a previous study found that, although there was no clear seasonal peak for rhinovirus/enterovirus, onset seemed to correspond with the start of the school year in the usa. 18 a limited one year analysis of human rhinoviruses and enteroviruses in ili in latin america showed a year-round temporal distribution throughout central and south america. 21 however, human rhinovirus c species displayed opposite seasonal trends on either side of the equator, accounting for a higher percentage of ili cases north of the equator between september and january, while south of the equator detection increased between april and july. 21 as part of the study, all children received a monovalent influenza a/h1n1 pandemic vaccine; one or two doses of an as03-adjuvanted vaccine were administered or two doses of an unadjuvanted vaccine. trivalent seasonal influenza vaccination rate in the present study was approximately 18%. influenza a subtype h1 was not isolated in any children; influenza a subtype h3 was isolated in 9.0% of children; and influenza b was isolated in 5.7% of children. no difference between the study vaccine groups was observed. cases associated with influenza were least likely to be co-infected with other respiratory viruses. rhinovirus/ enterovirus was also more common as a single infection. adenovirus and hbov were found more often as a coinfection. bacterial co-infection was not measured as part of this study. in the us-based influenza incidence surveillance project, which evaluated the most commonly detected viruses in outpatients with arti or ili, threequarters of all co-infections involved adenovirus and rhinovirus/enterovirus. 18 a uk-based analysis found negative associations between influenza a and hmpv, and between influenza a and rhinovirus. 22 positive associations were found between parainfluenza and rhinovirus, rsv and rhinovirus, adenovirus and rhinovirus, and parainfluenza and rsv. 22 no correlation was found between co-infection and clinical severity in a study in brazil evaluating children under 5 years who sought medical care for respiratory tract infections. 23 more research is needed to understand the interaction of respiratory viruses, and the host response to infection. there were no clear differences between viruses in the severity of illness. most ili episodes were medically attended. ili associated with influenza resulted in the highest proportion of children missing school or daycare (52%), although 20e40% of children infected with the other viruses also missed school or daycare. there was no difference between viruses in the proportion of children hospitalized. clinical features were variable depending upon the viral infection associated with the ili episode. study limitations have been described previously. 9 only healthy children participated in the trial, limiting generalizability. in addition, our study did not include any children aged <6 months and only a limited number of children aged 6e11 months, so our findings are mainly relevant to older children. fever was part of the ili definition, and therefore we would have missed cases in children with no fever. to put this into perspective, in the influenza incidence surveillance project, 34% and 43% of cases among children aged 1e4 years and 5e17 years, respectively, met the arti definition which did not require fever, but did not meet the ili definition which did require fever. 18 however, our definition of ili was somewhat broader (except in children under 2 years of age) and us data may not be generalizable to the tropical and southern hemisphere countries in our study. the inclusion of only healthy children in the study and the exclusion of cases with no fever would have underestimated the burden. we also could not discriminate between rhinovirus and enterovirus by pcr, therefore the exact prevalence and incidence of each one could not be determined. finally, our study included only a small number of pneumonia cases (n z 20), limiting the conclusions that can be drawn regarding the distribution of viral infection in these cases. the overall pneumonia detection rate in the clinical trial (0.9%) is higher than, but in line with, what has been reported in the us for hospitalized cases. 24 however, our sample collection rate among pneumonia cases was only 62.5% compared with 80.0% for ili overall. in conclusion, our active surveillance of healthy children as part of a vaccine efficacy trial provided evidence of the burden of respiratory illness associated with a range of viruses. a substantial burden of illness occurs in older children. data on the epidemiology of respiratory viruses determined from active surveillance of healthy children are generally lacking, and are particularly sparse in the developing countries included in our study. a considerable amount of the burden would not be identified through hospital-based surveillance. these novel data fill an important gap in our knowledge of the epidemiology of viruses contributing to the substantial burden of respiratory disease in children, and may be useful in informing priorities for implementation of existing vaccine programs and development of new vaccines. this work was supported by glaxosmithkline biologicals s.a. who was the sponsor of the study and was involved in all stages of study conduct, including analysis of the data, and in addition paid the costs related to the development of the publication of this manuscript. epidemiology of viral respiratory infections viral infections of the lower respiratory tract: old viruses, new viruses, and the role of diagnosis estimates of world-wide distribution of child deaths from acute respiratory infections global burden of childhood pneumonia and diarrhoea comparison of multiplex pcr assays and conventional techniques for the diagnostic of respiratory 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preschool-aged children using parentcollected specimens clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in hiv-infected and hiv-uninfected south african children epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness incidence and etiology of acute lower respiratory tract infections in hospitalized children younger than 5 years in rural thailand severe lower respiratory tract infection in infants and toddlers from a non-affluent population: viral etiology and co-detection as risk factors viruses associated with acute respiratory infections and influenza-like illness among outpatients from the influenza incidence surveillance project picornavirus, the most common respiratory virus causing infection among patients of all ages hospitalized with acute respiratory illness respiratory viruses within homeless shelters in marseille, france human rhinoviruses and enteroviruses in influenza-like illness in latin america respiratory viral infections during the 2009e2010 winter season in central england, uk: incidence and patterns of multiple virus co-infections concurrent detection of other respiratory viruses in children shedding viable human respiratory syncytial virus community-acquired pneumonia requiring hospitalization among us children all authors participated in the design, or implementation, or analysis and interpretation of the study results; as well as in the development of this manuscript. all authors had full access to the data and gave final approval before submission.terry nolan, charissa borja-tabora, pio lopez, lily weckx, rolando ulloa-gutierrez, eduardo lazcano-ponce, angkool kerdpanich, miguel angel rodriguez weber, abiel mascareñas de los santos, marco aurelio p safadi, aurelio cruz-valdez and juan-carlos tinoco were coordinating investigators, and together with sumita roy-ghanta, david w vaughn and ping li were responsible for the conduct of the flu q-pan h1n1-035 pri (nct01051661) trial. fong seng lim, marcela hernandez-de mezerville and idis faingezicht also contributed to study material and data collection.sylvia taylor led the epidemiology team in collaboration with gerco haars.yang feng was responsible for the statistical input; statistical expertise was also provided by gerco haars, sumita roy-ghanta, ping li and terry nolan. serge durviaux led the laboratory analysis.terry nolan, charissa borja-tabora, yang feng, david w vaughn and sylvia taylor were members of the core writing team. terry nolan and sylvia taylor contributed equally to this manuscript and the corresponding author was responsible for the submission of the publication. the the authors moreover thank magali ribot (gsk vaccines) for multiplex pcr testing, jean-yves pirçon (gsk vaccines) for critical review of the statistical analysis and mich ele seil (keyrus biopharma on behalf of gsk vaccines) for writing the study report.mary greenacre (independent medical writer) was paid by gsk vaccines to prepare the manuscript draft and sophie vanwetswinkel (xpe pharma and science on behalf of gsk vaccines) provided editorial assistance and manuscript coordination. lily weckx declares research grants from gsk to federal university of são paulo for conduct of three clinical trials and received payment from gsk, novartis, pfizer, and sanofi for board membership or lectures.rolando ulloa-gutierrez discloses having received honoraria from gsk for the original influenza a h1n1 clinical trial discussed here, as well as from gsk, sanofi pasteur, pfizer/ wyeth and merck as a speaker in the past.marco aurelio p safadi has received grants to support research projects and consultancy fees from novartis, gsk, pfizer and sanofi pasteur.fong seng lim discloses having received travel grants from gsk as well as a grant from gsk to his institution to perform clinical trials.marcela hernandez-de mezerville declares having received honoraria from gsk for the original influenza a/ h1n1 clinical trial discussed here, as well as travel support from gsk, sanofi pasteur and pfizer outside the submitted work in the past.idis faingezicht received payment from gsk as principal investigator in a previous vaccine clinical trial and as co-investigator in the influenza a/h1n1 clinical trial.pio lopez, eduardo lazcano-ponce, angkool kerdpanich, miguel angel rodriguez weber, abiel mascareñas de los santos, juan-carlos tinoco, and aurelio cruz-valdez report having nothing to disclose. supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jinf.2016.09.003. key: cord-002227-x1ddi8wg authors: li, wanli; an, xinjiang; fu, mingyu; li, chunli title: emergency treatment and nursing of children with severe pneumonia complicated by heart failure and respiratory failure: 10 case reports date: 2016-07-29 journal: exp ther med doi: 10.3892/etm.2016.3558 sha: doc_id: 2227 cord_uid: x1ddi8wg pneumonia refers to lung inflammation caused by different pathogens or other factors, and is a common pediatric disease occurring in infants and young children. it is closely related to the anatomical and physiological characteristics of infants and young children and is more frequent during winter and spring, or sudden changes in temperature. pneumonia is a serious disease that poses a threat to children's health and its morbidity and mortality rank first, accounting for 24.5–65.2% of pediatric inpatients. due to juvenile age, severe illness and rapid changes, children often suffer acute heart failure, respiratory failure and even toxic encephalopathy at the same time. the concurrence in different stages of the process of emergency treatment tends to relapse, which directly places the lives of these children at risk. severe pneumonia constitutes one of the main causes of infant mortality. in the process of nursing children with severe pneumonia, intensive care was provided, including condition assessment and diagnosis, close observation of disease, keeping the airway unblocked, rational oxygen therapy, prevention and treatment of respiratory and circulatory failure, support of vital organs, complications, and health education. the inflammatory response was proactively controlled, to prevent suffocation and reduce mortality. in summary, positive and effective nursing can promote the rehabilitation of children patients, which can be reinforced with adequate communication with the parents and/or caretakers. severe pneumonia is a common life-threatening disease, particularly for children, and is more common in infants and young children (1, 2) . the estimated worldwide incidence of severe pneumonia in children less than 5 years of age is 50-80 per 1,000 person-years and the mortality is 1.0-5.5 per 1,000 person-years (3) (4) (5) . it often occurs in the winter and spring, with acute onset, complex clinical manifestations and fast-changing condition, which usually involves the circulation, nervous and digestive systems (1) (2) (3) . as a result, severe pneumonia produces corresponding clinical symptoms, such as respiratory failure, heart failure, toxic encephalopathy and intestinal paralysis, which endanger the lives of children in the short term, and is the first cause of death of pediatric inpatients (6, 7) . it is listed as the one of the four diseases requiring prevention and treatment in children by the ministry of health (8, 9) . pneumonia may occur at any point of the year, but is more common in the months of winter and spring or during the time of climate variability. the disease may be the primary illness, or secondary one after an acute infectious disease, such as bronchitis and measles, upper respiratory tract infections and whooping cough, and has a high morbidity and mortality rate in china (10) . as reported by several studies, the number of annual pneumonia patients in china is ≤21 million individuals, and among the children with pneumonia, 7-13% cases are of severe pneumonia, which ranks fifth amongst various diseases leading to death (11) (12) (13) (14) (15) (16) . the aim of this study was to conduct a retrospective analysis of the clinical data of 10 cases of children presenting with severe pneumonia at the xuzhou children's hospital between january 2009 and june 2012, retrieve and review the literature, and summarize emergency treatment and nursing experience. general information. ten cases of children diagnosed with severe pneumonia according to the guidelines of the world health organization were included in the present study (16) . in this group, there were 6 males and 4 females, aged 1 month to 6 years. the children patients were hospitalized due to fever, cough, asthma, dry and wet rales could be heard in lung auscultation, and a chest x-ray showed thickened lung markings with visible punctate and flake-like shadows. the children patients refused any intake of dairy products or food. there was one case of concurrent toxic encephalopathy, 1 case of gastrointestinal bleeding, and 1 case of toxic intestinal paralysis. the physical examination showed a body temperature of 38.5-40˚c, pulse rate of 120-190 beats/min, breathing of 30-60 beats/min, and dry and wet rales could be heard in lung. the x-ray examination showed thickened lung markings, and flake-like shadows, and abdominal palpation showed enlarged liver and spleen. respiratory or circulatory functions were at different levels of exhaustion. treatment. after admission, comprehensive emergency treatment measures were taken, such as improving the ventilation function, oxygen uptake, maintaining airway patency, administration of cardiac and diuretic drugs, reduction of intracranial pressure, and conducting anti-infection and symptomatic support measures. nine cases were successfully treated, 1 case succumbed to respiratory failure, and the success rate was 90%. condition assessment and diagnosis. a detailed inquiry of the medical history was carried out to determine whether the children patients had a history of recurrent respiratory tract infection, and whether they had measles, whooping cough and other respiratory diseases prior to onset, as well as whether the children patients had a full-term birth or asphyxia, and if the growth and development of children patients after birth was normal (16) (17) (18) . conditions such as fever, cough, extent of choked asthma, the presence or absence of breathing, faster heart rate, pulmonary rales, orthopnea, nose flap, three depression signs and cyanosis, as well as clinical manifestations of infected circulatory, digestive, and nervous system were assessed. evaluation of blood routine examination, chest x-ray, and etiology test results were conducted. psychological and social conditions of children and parents were also assessed (19) . common condition assessment and diagnostic criteria included: i) air exchange impairment, related to lung inflammation; ii) invalid airway clearance, related to excessive and sticky respiratory secretions, frail children patients, and inability to expectorate; iii) hyperthermia, related to lung infection; and iv) malnutrition, related to inadequate intake, increased consumption. close observation of the condition. attention was paid to changes in total peripheral resistance blood pressure (bp), the presence of double suction, such as nodding-like breathing, apnea and other conditions indicating respiratory failure. the presence of exacerbation of dyspnea, dysphoria, quickening heart rate, and an enlarged liver in a short period of time suggested heart failure (20) (21) (22) . children patients with severe wheezing often suffered respiratory acidosis due to retention of carbon dioxide. drowsiness, convulsions or coma in sick children suggested an occurrence of toxic encephalopathy. medicines such as antibiotics, antiasthmatic drugs, cardiac drugs and other medications were administered to patients at the appropriate dosage, the appropriate time and in an accurate manner. side effects of various drugs were observed, and if children patients showed signs of dysphoria, quickening heart rate, worsening asthma, or enlarged liver in a short period of time, indicating heart failure, then the infusion rate was reduced. in our study, close observation of consciousness, pupil changes and muscle tension was carried out, and if manifestations of intracranial pressure such as drowsiness, convulsions, irregular breathing and increased muscle tension appeared, immediate rescue steps were taken. abdominal distension and decreased or disappearing bowel sounds were observed, in order to detect toxic intestinal paralysis in time (23) . emergency treatment and therapy for respiratory failure. type i respiratory failure refers to the lone presence of hypoxemia and absence of hypercapnia, featuring ventilation dysfunctions, blood change of pao 2 ≤60 mmhg, and paco 2 which can be maintained at normal level or reduced (24) . type i respiratory failure also refers to the coexistence of hypoxemia and hypercapnia, impairment of ventilatory function and gas exchange functions, severe lung lesion, obstruction of trachea and bronchia caused by sticky secretions, blood change of pao 2 <60 mmhg, and paco 2 >50 mmhg. main clinical manifestations of children patients with type i pneumonia with respiratory failure include, poor mental state or dysphoria, polypnea, cyanosis of lips, dyspnea, nasal flaring and three depression signs. these symptoms are difficult to distinguish from type ii respiratory failure, and can be observed only by blood gas analysis, which shows a marked difference between type i and ii. type ii respiratory failure shows symptoms of type i respiratory failure and in addition more often than not, it also has symptoms such as shallow breathing, irregular rhythm, slow breathing, drowsiness or coma and even jaw breathing in some patients (25, 26) . in our study, changes in condition and changes in blood were closely observed, and where required, a tracheal intubation ventilator was employed to improve the cure rate. oxygen uptake. nasal catheter is easily blocked by secretions, leading to failure of effective uptake oxygen, and is therefore difficult to utilize. we employed the conventional oxygen mask inhalation method, which is comfortable and without stimulation, and was easily accepted by children (27, 28) . after using oxygen, once hypoxia was improved, timely adjustment of the oxygen flow or deactivation of oxygen was needed, because inadequate oxygen concentration such as excessive or overtime concentration may lead to changes such as lung tissue edema atelectasis and proliferation of alveolar capillary. the humidification bottle contained 50% alcohol, aiming to reduce the alveolar surface tension and help improve ventilation. maintenance of airway patency and administration of various aerosol inhalation therapies. i) this group of children patients took appropriate clinostatism according to the state of disease. under normal conditions, the children were placed in a horizontal position, with neck raised high, in order that airways would be unblocked. for children patients with severe heart failure and wheezing, semi-recumbent position was taken to reduce the burden on the heart and lungs (29, 30) . for children patients with increased respiratory secretions, the lateral position was useful to expectorate and prevent aspiration. ii) patients received daily routine aerosol inhalation, turning drugs into aerialfog-like fine particles, inhaled to the bronchioles or alveoli, which diluted secretions and had an anti-inflammatory and anti-allergic function and reduced local inflammatory exudates, in addition to reducing airway resistance and improving ventilation. aerosol inhalation time was 10-15 min and afterwards sputum suction was carried out immediately in order to clear respiratory secretions. commonly used drugs included: 20,000 units of gentamicin, 2-3 mg of α-chymotrypsin, 1-2 mg of dexamethasone, and 20 ml of saline. the dual role of the aforementioned ultrasonic aerosol inhalation was useful to reinforce treatment of children with severe pneumonia. according to the disease, aerosol inhalation was conducted every 4 or 6 h, with sputum suction ensuing, which produced a good suction effect for children patients with many sticky respiratory secretions. it should be noted that if patients had excessive sputum, the sputum suction was also carried out once prior to using ultrasound aerosol inhalation therapy, followed by thorough sputum suction. in the whole process of aerosol inhalation, providing oxygen inhalation or enhancing oxygen concentration effectively prevented the occurrence of hypoxemia (31) . iii) hypocalcemia may produce laryngospasm and tongue tenesmus, which causes obstruction and sudden suffocation. first, the child patient's tongue tip was pulled outside the mouth, and then artificial respiration was conducted, with most patients being able to relieve themselves spontaneously. pressurized oxygen was given, endotracheal intubation was carried out if necessary and calcium was replenished immediately. iv) when nasal obstruction caused breathing difficulties, 1% ephedrine drops were used after clearing away nasal secretions with a cotton swab, to maintain the airway patency. v) the diet of children with severe pneumonia was affected due to high fever, vomiting, diarrhea and other factors. when children patients were unable to eat, it was appropriate to supplement water, electrolytes, vitamins, and give them high-calorie, high protein, digestible food, that was eaten in small amounts but frequently, to prevent satiety from interfering with respiratory function. vi) previous findings showed that, ambroxol and low-dose heparin coupled with aerosol inhalation significantly shortened the time of the disappearance of all the clinical signs and improved overall efficiency of the clinical treatment (32, 33) . there was no bleeding and other adverse reactions involved in the clinical treatment process, which had advantages such as easy administration, safe use, inexpensiveness, a significant effect, and less adverse effects in the treatment of children with severe pneumonia, and was thus worthy of wider application. since the application of mechanical ventilation is prone to cause ventilator-related complications, to improve the successful rescue rate of children with severe pneumonia and shorten the course of treatment, the use of ncpap may be considered a priority. for severe pneumonia, ncpap can support cardiopulmonary function, and its early application can improve timely oxygenation, stabilize disease, prevent disease progression, reduce ventilator application and average hospitalization time in pediatric intensive care unit as well as avoid the adverse effects caused by intubation (34) . however, two points are important when applying it to infants: i) grasp indications and standard of respiratory failure that the children comply with; ii) over ncpap application process, nasal and oral secretions should be immediately removed, raising the neck high, to strengthen expectoration in order to maintain airway patency. operating parameters of using the ncpap oxygen therapy machine in our department: i) oxygen concentration inhaled (fio2) 40 or 90%; ii) the oxygen flow 4-12 l/min; and iii) the beginning pressure was maintained at 3-4 cm h 2 o. after observing 2-4 h, the adjustment of pressure was determined by clinical symptoms, signs and blood gas analysis. ncpap is an effective treatment for severe pneumonia with respiratory and heart failure, and can quickly correct hypoxemia, reduce endotracheal intubation and mechanical ventilation demand (35) . it has a positive effect and can reduce the stimulation of children, thus decreasing any occurrence of ventilator pneumonia. in addition, parents readily accepted this treatment (36) . short-term intubation ventilator was utilized when there was: i) respiratory arrest or respiratory and cardiac arrest; ii) sputum congestion, dyspnea, serious cyanosis; and iii) blood paco 2 >60 mmhg, in order to accelerate the discharge of paco 2 and reduce respiratory acidosis. emergency treatment and treatment of heart failure. when children patients coughed, their body temperature increased to ≤40˚c and was accompanied by dyspnea, dysphoria, pale face, cyanosis, drowsiness, fixed moist rales in lung, respiratory rate of ≥60 beats/min, heart rate of ≥160-180 beats/min in quiet state, low and blunt heart sound, gallop rate, and a progressively enlarged liver, 3 cm beyond the ribs or an increase of ≥1.5 cm in a short period of time. the above, as well as cold extremities and weak pulse, constituted clinical manifestations of a heart failure. in this situation, oxygen inhalation and tranquilizers were given immediately, 0.5 µg/(kg x min) and milrinone, a second generation of phosphodiesterase ⅲ (pde-ⅲ) inhibitor, which acts on the β receptor accessory pathway, was administered to maintain heart function. by selectively inhibiting pde-ⅲ in myocardial cells, increasing intracellular cyclic adenosine monophosphate levels, promoting calcium influx, enhancing calcium concentration in myocardial cytolymph, milrinone strengthens myocardial contractility, increases cardiac output, and exerts direct relaxation on vascular smooth muscle, dilates blood vessels and reduces cardiac preload and afterload. milrinone demonstrates a better clinical efficacy in the treatment of children with pneumonia complicated by heart failure than catecholamines (37) . emergency treatment and treatment of toxic encephalopathy and intestinal paralysis. when children show signs of exhaustion, dysphoria, coma, increased muscle tension, irregular breathing, and increased cerebrospinal fluid pressure, toxic encephalopathy should be considered. timely administration of sedatives, oxygen and mannitol are important in order to ease cerebral edema. decrease in intracranial pressure. in the present study, any changes including children' pupillary light reflex, headache, vomiting, consciousness, breathing, pulse, temperature, and fluctuation in bp were closely observed. the head was raised 15-30˚ to facilitate the intracranial venous return, leading to a corresponding reduction in intracranial pressure. precaution was taken when using dehydrating agent as well as to prevent it from leaking from blood vessels, and to prevent tissue necrosis. when administering furosemide, its effect and adverse drug reactions were observed. if intracranial pressure increased, lumbar puncture was avoided as much as possible, but if it had to be carried out then rescue preparation was performed. cerebrospinal fluid flow is not be in excess to avoid the formation of hernia. control of fever and convulsions. an increase in body temperature leads to an increased oxygen consumption in brain tissue, and aggravating cerebral hypoxia, which causes cerebral edema and nerve cell damage (38) . immediate measures must be taken to control hyperpyrexia by combining the use of artificial hibernation to decrease the temperature, lower metabolism and protect the central nervous system. the drug of choice is the application of cold compressors of chlorpromazine to the head, wearing ice caps and decreasing the temperature with drugs, thereby reducing hyperpyrexia-induced damage to brain tissue. for children patients in the study, when intracranial pressure increased, the motor cortex wass stimulated, causing convulsions and exacerbating cerebral hypoxia and brain edema, thereby aggravating intracranial pressure. the ward was kept quiet and visitors were avoided. treatment and care were performed simultaneously, as much as possible, and operating and any negative stimuli were reduced to prevent convulsions. seizures required the focus of intensive nursing, a dental pad was placed between the upper and lower teeth to prevent tongue bite, and extra gear was added to prevent any fall damage during sleep. drugs, such as phenobarbital and diazepam were administered to control fear. restless children were guarded by specially-assigned persons to prevent scratches and fall damage. heads of children in a coma were leaned to one side, to facilitate the discharge of secretions. should be given. for any child having a seizure, it was considered improper for the fright-checking agent to forcibly press the child's body, in order not to cause fractures. treatment of abdominal distention. abdominal distention often occurs in children with pneumonia, leading to children feeling uncomfortable and unrest, which hinders normal breathing. a hot water bag was placed on the abdomen, to facilitate venting. anal venting was also used and children became quiet after venting. if abdominal distention did not improve, it suggested the presence of toxic intestinal paralysis, and a poor prognosis. anti-infective therapy. after a clear diagnosis of severe pneumonia, collecting blood for bacterial culture and sensitivity test was performed prior to the use of antibiotics when conditions permitted. a separate venous access for antibiotics was established as much as possible, to rationalize the use of antimicrobial drugs and avoid side effects. in principle, the application of antimicrobial drugs was carried out on the basis of evidence-based medicine, but a majority of them are classified as empirical treatment. as the therapeutic window of children with severe pneumonia was very small, the initial drugs for treatment covered an antibacterial spectrum as broad as possible, as well as all the pathogens. there were sufficient data displaying that the inappropriate choice of anti-infective drugs for initial therapy and untimely appropriate treatment (effective therapy of antigens) had adverse consequences on the prognosis. the main indicators of efficacy were a decrease in body temperature, improvement in poisoning symptoms and ability to drink water or conduct breast-feeding or food intake. in general, 3-5 days after the body temperature became stable, the drug dosage was reduced and gradually discontinued. intravenous injection of immune globulin is considered a safe and effective method for the treatment of children with severe pneumonia. it can rapidly improve immunoglobulin g (igg) levels in the patient's blood; enhance the body's resistance to infection and immune function. by passively accepting lgg, the body acquires resistance to a variety of microbial infections. high-dose intravenous igg infusion can increase the igg concentration 3-to 6-fold in circulating blood compared to a normal person. therefore it has the ability to prevent infections. using igg infusion concurrently with antibiotics can be used to treat bacterial infections and has a broad anti-bacterial and viral spectrum, as well as a dual function of anti-bacterial antigens and viral antigens. in summary, positive and effective nursing can promote the rehabilitation of children patients, reduce the incidence of complications and children's mortality, thus play an important role in the rehabilitation of children with severe pneumonia. psychological counseling may also be strengthened. children feel a sense of inadaptation with regard to unfamiliar environment by instinct. they cried and even refused infusion in the face of examination and treatment by strangers. therefore, nurses must be careful and gentle to children patients. for older children, they were able to explain to them the importance of the infusion and blood tests for the treatment of the disease, and increase their sense of trust in the medical staff. health education is also essential, nurses should communicate more with parents and acquaint them with relevant knowledge and inform them regarding the prevention and treatment of diseases, such as that children usually need to do exercise, enhance nutrition, bask more in sunshine and engage in outdoor activities, ensure 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somu; srinath, m. v. title: does a crying child enhance the risk for covid-19 transmission? date: 2020-04-26 journal: indian pediatr doi: 10.1007/s13312-020-1870-2 sha: doc_id: 264242 cord_uid: zfv30l3o nan sars and mers epidemic. asian pac j allergy immunol. 2020;38:1-9. 11. ruf br, knuf m. the burden of seasonal and pandemic influenza in infants and children. does a crying child enhance the risk for covid-19 transmission? [6] . extrapolating the same logic even a crying and screaming child should produce aerosol super-emission. although an operational definition for agp is in place, the relation to crying and its possible effects of increased aerosol generation has so far not been stressed. in a pandemic situation, we need to ponder on some points: even infants and toddlers who come for routine vaccinations or non-respiratory complaints can be asymptomatic carriers or in pre-symptomatic period of transmission; implementing source control measures like face mask and social distancing in this age group practically difficult; crying, a common occurrence in this age group, also increases the risk of aerosol generation and transmission; and, proximity of these kids to caregivers and their attenders along with sustained crying either due to anxiety or fear might further increase the risk and load of aerosol. in view of the yet unknown increased risks posed by expected or unexpected crying of asymptomatic children in the transmission of covid-19, it may be prudent to make every effort to avoid examining a crying child without adequate precautions. the pandemic of coronavirus disease (covid-19) has led all of us to recalibrate both our personal and professional life [1] . in our routine pediatric outpatient practice for non-covid cases i.e. well baby visits and kids presenting with afebrile, non-respiratory symptoms, a surgical face mask with proper hand hygiene and gloves has been recommended for health care professionals [2] . however, for those handling aerosol-generating procedures (agp), respirators and additional personal protection equipment (ppe) are recommended [3] . aerosol is defined as suspension of fine solid particles or liquid droplets in air or another gas. aerosols of varying severity are generated on sneezing, coughing, talking and also during normal breathing [4] . agps are believed to produce aerosols and droplets as source of respiratory pathogens that exposes the health care workers to pathogens causing acute respiratory infections including severe acute respiratory syndrome coronavirus 2 (sars-cov-2) [5] . agps are generated on performing certain medical procedures like intubation, manual ventilation, non-invasive ventilation, tracheostomy insertion etc. on infected cases. however, it is not clear if the risk is due to direct airborne transmission or secondary exposure to respiratory droplets. it is established that even loud speaking results in increased aerosol generation i.e. aerosol super-emission symptoms be treated, irrespective of their comorbidity? why do pediatricians appear to be unwilling to consider employing the covid-19 treatments that are available, e.g., hydroxychloroquine and azithromycin [4] ? these drugs (which are already widely used in pediatrics in other indications) certainly have side effects that are of concern, but their use in a hospital environment shall allow these side effects to be monitored and ensure greater safety for the patient [5] . in the absence of specific antiviral treatments, pediatricians need more virological, epidemiological, and clinical data to better treat and manage covid-19 infections. it should be kept in mind that children, even when asymptomatic, may be a potential cause of spread and transmission of the disease in their communities [6] . in light of this, barrier precaution needs to be rigorously applied within families in order to protect the elderly. acute respiratory syndrome coronavirus 2 (sars-cov-2) infection is uncommon in children [1] , with greater morbidity and mortality in adults and elderly. a number of hypotheses may explain the low susceptibility of children to covid-19 virus [2] viz, (i) immaturity and limited function of angiotensin-converting enzyme 2 (ace2) receptors in children, as undifferentiated cells that express low levels of ace2 are not readily infected by sars-cov; (ii) the immature innate immune system in young children results in less inflammation and consequently fewer symptoms; and, (iii) possible crossreactivity of antibodies against other viruses (influenza, adenovirus, respiratory syncytial virus etc.) with the sars-cov-2, which could provide partial protection. as covid-19 infection is not universally mild in children [3] , it is important that they are protected as a vulnerable population, as still there is limited data on the risk factors for severe infection in children. the long-term effects on the lungs of covid-19 in children are not known, even for those with moderate symptoms. in patients hospitalized in french pediatric units in recent weeks, the chest computed tomography (ct) scans have often been pathological, even in children with limited respiratory sign with associated decline in lung function (unpublished data). in light of this, should not all children with moderate to severe respiratory coronavirus disease (covid-19) in children -what we know so far and what we do not. indian pediatr infection control in stand-alone out patients and small nursing homes in the setting of covid government of india. novel coronavirus disease 2019 (covid-19): guidelines on rational use of personal protective equipment rapid expert consultation on the possibility of bioaerosol spread of sars-cov-2 for the covid-19 pandemic aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: a systematic review aerosol emission and superemission during human speech increase with voice loudness epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china key: cord-255972-u7v0es5w authors: hashikawa, andrew; sells, jill; dejonge, peter; alkon, abbey; martin, emily t.; shope, timothy r. title: child care in the time of covid-19: a period of challenge and opportunity. date: 2020-07-17 journal: j pediatr doi: 10.1016/j.jpeds.2020.07.042 sha: doc_id: 255972 cord_uid: u7v0es5w nan such as head start and military-sponsored programs, receive federal funding, but these represent only a small fraction of ece arrangements. 1 the high operating costs of ece are passed onto families in the form of tuition and can represent a substantial proportion of a family's income; in some states, the price approaches or exceeds in-state college tuition. 6 high-quality ece has become cost-prohibitive to most poor and minority families. 4, 6 the federal government has provided some funding to states that is intended to subsidize ece costs for low-income families (eg, child care and development fund, temporary assistance for needy families, and the social services block grant), but these funds cover only 30% of total child care expenditures nationally. 1 similarly, federal tax credits, which only apply to middle-class families, average <10% of the cost of full-time child care. 1 furthermore, over 50% of the us population lives in child care 'deserts,' or census tract areas that either completely lack ece services or only have one-third of the licensed child care capacity needed by families. 5 ece deserts are more frequently found in rural, low-income areas, and also are associated with a high proportion of minority residents. 5 even in locations with sufficient ece capacity, many parents report having significant difficulty finding back-up child care when their child is sick and cannot attend their regular ece program. 7 parents often rely on non-parental relatives such as the child's grandparents for emergency child care; now, the pandemic has limited this back-up option because of the concern for the spread of covid-19 to more vulnerable, high-risk family members. 8 the pandemic has impacted the availability of ece, both in the early months of the pandemic and likely into the future as well. in most states, social-distancing policies shuttered nonessential businesses temporarily, but there was a variety of responses related to ece programs. some states closed all organized ece programs, others allowed exemptions for programs that cared for children of essential workers, and some did not close any programs. ece program closings varied so markedly from state to state that dashboards were created to track different state closings. 9 during covid-19, as businesses closed and parents were furloughed or worked from home, demand for ece from these parents decreased, reducing attendance and decreasing revenue to ece programs, resulting in further closures of programs for financial reasons. an estimated 60% of ece programs 8 closure of ece programs caused problems for essential workers (e.g., health care workers, first responders, transit workers, grocers). a nationally representative survey of parents found that over one-third of respondents found it "very difficult" to find child care, nearly double that from the same period 6 months prior, and particularly remarkable considering simultaneously decreased demand because of historically high unemployment. 8 only 22% of essential workers were able to continue their previous ece arrangements during the pandemic and parents were nearly twice as likely to report difficulties finding quality ece programs within their budget. 8 many low-income essential workers were without paid leave, did not have an available family caregiver, or also were less likely than high-income parents to be able to work remotely. 8 however, even among parents who could work from home, a national survey reported that 43% still required child care. 8 the financial unsustainability of ece programs typically, the majority of revenue for ece programs is derived from tuition fees, and 80% of child care program expenses are related to payroll; most experts view this as unsustainable. 6 indeed, previous regional disasters and societal upheaval consistently have demonstrated the fragility of the ece infrastructure. 11, 12 for example, most ece programs are a low-margin business and have limited access to recovery funds. therefore, if they are closed for relatively brief periods in excess of several weeks, they cannot meet payroll or pay rent, often resulting in permanent closure. 12 subsequently, the lack of available ece programs for families after disasters significantly affects recovery efforts by keeping families from working and businesses from rebounding economically. 11, 13 although ece is considered a critical service by the federal emergency management agency for regional recovery, ece programs are underprepared for emergencies and are usually overlooked during disaster recovery planning. 11, the covid-19 pandemic has placed substantial financial strains on the industry, with smaller ece programs vulnerable to permanent financial collapse, and very little direct federal or state public financial support. one national survey conducted by the national association for the education of young children in march, 2020 found that many ece owners questioned the future viability of the ece industry. 15 the survey revealed that 50% of ece programs were losing income because families were unable to pay, with another 25% losing additional income because states reimbursed providers based on attendance rather than enrollment for low-income families receiving child care subsidies, and thus these payments decreased as well when children stayed home. 15 this is dire news for a workforce that is overwhelmingly female, minority (40%), significantly underpaid (double the proportion of workers living below the poverty line compared with other industries), and lacking health insurance despite having many underlying chronic health conditions. 6, 16 ccr&r agencies have reported that the attrition of the child care workforce is among the top concerns for ece programs during the pandemic. 10 the federal government has met some of the immediate ece needs during the pandemic but fallen short in other areas. realizing the ece system's importance to the economic infrastructure, congress included specific provisions for the ece sector when passing the two trillion dollar coronavirus aid, relief, and economic security (cares) act. the cares act included $3.5 billion in discretionary funding to states to help support ece through payment assistance to programs experiencing decreased enrollment, emergency child care for essential workers, financial assistance to parents working in critical sectors, and funding for purchasing supplies to stay open or reopen. 17 currently, most ece providers, with little cash reserves and high overhead costs, are unsure if they can remain in business without further financial support from the state or federal government. 15 other additional legislation to financially support the ece industry is currently pending in congress. 18 the ece system also was not included when the department of homeland security identified sixteen groups of critical infrastructure sectors during the covid-19 pandemic. 19 the designation as critical essential infrastructure workforce is a way to assist states and local governments in prioritizing accommodations for employees critical to operations so they can continue to work during the pandemic. 19 the lack of standardized regulation, preparation, and health support for ece there are no comprehensive federal regulations for the safe and healthy operation of ece programs, other than federally funded head start and military programs. instead, regulations are developed at the state level, resulting in a high degree of national variability in the health and safety requirements for licensed programs. even within states, ece practices and policies vary between programs, and a significant proportion of ece in the us is unlicensed and unregulated. 4 across states and local jurisdictions, ece agencies and programs have variable access to support from health professionals such as child care health consultants to discern needs, inform the development of standards for daily operation, disseminate these standards, and support implementation. these standards include adequately detailed and updated emergency, disaster, and pandemic plans, which most licensed ece businesses lack despite being required for licensing in many states. 10, 20, 21 there has not been a nationally coordinated effort to develop, disseminate, and implement effective, adequately detailed guidance for the ece system during the covid-19 pandemic. initial centers for disease control and prevention (cdc) recommendations offered guidance for programs that remained open to care for children of essential workers. 22 this guidance was replaced by advice for programs "that remain open" and was complemented by a protocol offered to commercial businesses regarding social distancing, cleaning, and screening as they re-open. 23, 24 these guidelines remain largely insufficient for the day-to-day operational needs of most ece programs. national standards for ece-including those related to emergencies and infection control-exist for health and safety in child care, which are published in caring for our children (cfoc) by the american academy of pediatrics, the american public health association, and the national resource center for health and safety in child care and early education. 25 however, there is no mechanism to rapidly modify, update and disseminate these standards to meet the needs of the covid-19 pandemic. existing cfoc standards do not address the new concerns expressed by ece workers during the pandemic, which include: determining the risks for ece workers, establishing whether physical distancing in young children is feasible and effective, providing more details about cleaning and disinfecting, defining new group size requirements, defining the proper use of sars-cov-2 screening tests, handling readmission of children with symptoms or positive covid-19 tests, and establishing guidelines for temperature checks (type of thermometer, fever threshold for exclusion, when to take temperatures after the initial screening). 26 without federal or other national guidance, each state government and local health department is left to develop their own ece health policies. sars-cov-2 is not yet well understood, with a distinct lack of pediatric sars-cov-2 epidemiologic studies in group settings to guide policy and practice. 27 in part, this is because a large proportion of infected children have asymptomatic or mild covid-19 clinical courses. although uncommon, childhood cases of covid-19 can also be severe. the multisystem inflammatory syndrome in children (mis-c) associated with sars-cov-2 infection, which shares some characteristics with kawasaki disease, has prompted a recent cdc alert. [28] [29] [30] [31] however, because most children with sars-cov-2 infection have mild to no symptoms, childhood cases often are detected only through contact tracing related to an adult clinical case. [30] [31] [32] as a result of under-detection in children, the extent to which children may fuel community spread of sars-cov-2, as with other respiratory illnesses , is currently unknown. [32] [33] [34] the recommendations to close ece programs and schools, however, were derived from epidemiologic transmission studies of influenza, which has disproportionately higher transmission rates and clinical disease in young children. 33, 37 at present, sars-cov-2, compared with influenza, appears to infect fewer and cause milder clinical disease in young children, and have higher transmissibility among adults. [30] [31] [32] 38 sars-cov-2 surveillance data in group settings are not yet available, but neither are published reports of widespread child-tochild transmission of covid-19 in ece or school settings, suggesting transmission in these settings is either uncommon or unrecognized due to mild or asymptomatic infection. [32] [33] [34] however, media reports of covid-19 outbreaks in schools in israel and child care centers in texas require further research to determine the extent of child-to-child transmission from infected adults to children. 35, 36 modeling for sars-cov-2, and other coronavirus epidemics of sars and mers demonstrates that the effect of child care and school closures on reducing transmission and mortality in society, in general, is minimal. 37 although cdc-informed policies and regulations have been put forth regarding business, industry, and school re-openings, these protocols largely provide insufficient detail for ece programs. 38 the main challenge is that the proposed reopening procedures hinge on key nonpharmaceutical interventions to combat sars-cov-2 transmission-physical distancing, respiratory etiquette, handwashing, and masking. although effective in the general population, these practices are difficult to implement and maintain in groups of very young children. daily health checks: cdc guidance recommends daily screening of children for fever and illness symptoms on arrival, 24 yet this may be challenging for large ece programs to implement because measuring temperatures in young children is more challenging and time-consuming when compared with older children, staggering of morning arrivals are cumbersome for parents headed to work, and) the less risky outdoor screenings would be problematic during inclement weather. personal protective equipment: the cdc recommends that child care workers wear cloth masks and have suggested gowns for extensive contact. child care workers have questions about the frequency of gown changes because infants and toddlers frequently drool, cry, or spit-up when being held. similarly, young children do not effectively wear masks for prolonged periods and children under the age of two years should not wear masks because of concerns for suffocation. 24 respiratory etiquette and hand hygiene: although it is clear that respiratory etiquette and hand hygiene must be practiced by staff, 24 studies combining respiratory etiquette and hand hygiene for caregivers and children, and environmental cleaning, sanitizing, and disinfecting surfaces in ece programs show only a modest benefit in the reduction of respiratory virus transmission. [39] [40] [41] [42] the modest effect is likely because these interventions do not reduce droplet spread, the primary transmission mode of most respiratory viruses, including sars-cov-2. cleaning, sanitizing, and disinfecting: the cdc recommends cleaning and disinfecting frequently touched surfaces. 18 however, the high frequency with which young children touch objects and each other makes this challenging. time and resources are limited in ece programs and the ability to do this effectively and repeatedly for all potentially touched surfaces often is not practical. group size and ratios: the cdc recommends to "maintain an adequate ratio of staff to children to ensure safety," group cohorting, and avoiding mixing of different ages, but does not give any guidance on group size. 23, 24 a review of all 50 states' individual re-opening guidelines posted online (june 30, 2020) showed that 36% of states (n=18) recommended a group limit of 8-10 children; 20% of states (n=10) a limit between 11-20 children; 8% of states (n=4) a limit of 21-25 children; and 36% of states (n=18) have no suggested group size limits. 9 challenges to downsizing classroom groups include decreasing available child care access for working parents, not enrolling enough children to keep the ece program financially viable, having enough staff to maintain adequate child-to-staff ratios, and having enough available rooms or physical space to keep smaller groups apart. exclusion and return-to-care: the cdc recommends that programs "require sick children and staff to stay home," 24 yet research indicates that children often experience minor or no symptoms when infected with sars-cov-2. on average, children in ece programs experience ~6 upper respiratory infections per year, with younger children and children in their first year of group child care experiencing substantially more. 43 excluding all children with runny nose or congestion, symptoms listed by the cdc as potential covid-19-related symptoms, 44 guidance for school re-entry," which is focused predominately on the kindergarten through 12th-grade population and makes recommendations tailored to school settings. 38 ece programs would benefit from a similar document, with guidelines and operating considerations tailored to their needs. an expedited process to develop such guidance from experts in covid-19, pediatrics, public health, and child care health is needed and should build from existing cfoc and cdc guidance. even though there remain gaps in covid-19 specific information that need further research, there is an important role for pediatric health experts to provide some structured guidance based on both expert group consensus and best available evidence to assist ece directors in operating their programs and in providing consistent messaging to parents. this guidance should address, as a starting point, the following significant challenges identified to date: daily health checks: guidelines should consider strategies that would facilitate the daily health check in ece programs (e.g., use of non-contact infrared skin thermometers 46 or screening for symptoms prior to arrival by using numerous available covid-19 apps). respiratory etiquette and hand hygiene: young children cannot be relied upon to practice respiratory etiquette and good hygiene practices consistently. instead, efforts should focus on effective strategies that improve hand hygiene among ece providers and children. 48, 49 cleaning, sanitizing, and disinfecting: although sars-cov-2 transmission is primarily via the respiratory route, some transmission may occur from touching surfaces and fomites contaminated with viable virus. ece programs would greatly benefit from having more detailed guidance for efficient cleaning, sanitizing and disinfection and alternative strategies (e.g., rotating availability of toys) that address their unique population and environment. group size and age group ratios: smaller group size is an important strategy to reduce viral transmission compared with larger group sizes, especially because physical distancing is not a viable strategy among young children. although research studies on optimal group size for reduction of sars-cov-2 transmission are still necessary, a national recommendation for group size, balanced by the constraints of the ece environment, is necessary. exclusion and return-to-care: although medical evidence regarding the epidemiology of sars-cov2 transmission among children is lacking, there is a role for pediatric health experts to provide structured, consensus guidance based on the best available evidence. having national exclusion and return-to-care recommendations can guide ece administrators and directors in operating their programs, provide a better framework for local public health departments to manage outbreaks, and to provide consistent messaging to parents. conduct research to answer critical questions about sars-cov-2 in young children. the development of best practice guidelines for ece programs is linked to a better understanding of sars-cov-2 epidemiology in young children. we need more high-quality surveillance and transmission studies of children in ece and school settings. in addition, we need further studies delineating pediatric attack rates and the likelihood of symptoms after infection. these studies are critical to determine when children, who are infected or exposed, can return to care, and these recommendations may differ from those for adults. 50 the role of antibody testing needs to be explored further to determine which antibodies confer immunity and decreased transmissibility, and for how long. these data will have implications on procedures and practices such as the daily health check, use of ppe, infection control and prevention practices, group size and exclusion, and return-tocare guidelines, all of which may need to be updated as covid-19 research evolves. 3. increase health support for child care programs. many states have cchcs working in their public health departments who provide regular assessments and consultation to help ece administrators, directors, and providers improve the quality of health and safety in their programs. 51, 52 cchcs have ongoing relationships with local ece programs, public health departments, resource and referral agencies, and primary care pediatric practices. they should be engaged as key partners with pediatric and public health professionals to inform, disseminate, and support the implementation of new guidance for operation during covid-19. funding for cchcs is inconsistent across states and should be supported by local and state health departments or federal programs for improving the health of ece programs. pediatric health providers and the national early childhood training and technical assistance systems, including the national center on early childhood health and wellness (and its successor national center on health, behavioral health, and safety), should support families and ece providers by translating evidence into common messages and best practices. the designation, although it does not guarantee additional federal funding, would at least bring the necessary awareness to local and state governments of the need to prioritize accommodations for the ece workforce in addition to other critical infrastructure workers. designating the ece system as critical infrastructure may also promote greater collaboration between ece stakeholders and local government policymakers to facilitate increased disaster preparedness planning to ensure ece programs are ready to meet the challenges of future emergencies beyond this pandemic. for economic development: child care in state economies 2019 update say hello to that new spin studio and goodbye to your child care. the new york who's minding the kids? child care arrangements tragedy of child care in america center for american progress: child care deserts child care aware: the us and the high price of child care: an examination of a broken system emergency department and urgent care for children excluded from child care bipartisan policy center nationwide survey: child care in the time of coronavirus child care aware: state by state resources -statewide child care status save the children: child care -an essential service for disaster recovery national association for the education of young children: child care in crisis understanding the effects of the coronavirus pandemic the health and working conditions of women employed in child care administration for children and families: summary of child care provisions of coronavirus aid, relief, and economic security act or child care is essential act, bill profile. 2020. 19. cybersecurity and infrastructure security agency: identifying critical intrastructure during covid-19 disaster preparedness among michigan's licensed child care programs pandemic influenza preparedness among child care center directors in schools.html?cdc_aa_refval=https%3a%2f%2fwww.cdc.gov%2fcoronavirus%2f201 9-ncov%2fspecific-groups%2fguidance-for-schools.html 23. cdc activities and initiatives supporting the covid-19 response and the president's plan for opening america up again. 2020. 24. centers for disease control and prevention: guidance for child care programs that remain open covid-19 in children: the link in the transmission chain. the lancet infectious diseases childhood multisystem inflammatory syndrome -a new challenge in the pandemic multisystem inflammatory syndrome in u.s. children and adolescents acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic. circulation. 2020. 31. centers for disease control and prevention health alert network: multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease 2019 (covid-19) (han00432) to what extent do children transmit sars-cov-2 virus? journal of paediatrics and child health no evidence of secondary transmission of covid-19 from children attending school in ireland, 2020. euro surveillance : bulletin europã©en sur les maladies transmissibles npr: after reopening schools, israel orders them to shut if covid-19 cases are discovered more than 300 children in texas day cares have caught covid-19, and the numbers are rising school closure during the coronavirus disease 2019 (covid-19) pandemic: an effective intervention at the global level? jama pediatr covid-19 planning considerations: guidance for school re-entry effect of infection control measures on the frequency of upper respiratory infection in child care: a randomized, controlled trial appropriate time-interval application of alcohol hand gel on reducing influenzalike illness among preschool children: a randomized, controlled trial an open randomized controlled trial of infection prevention in child day-care centers transmission and control of infections in out-of-home child care infectious diseases in early education and child care programs covid-19) information for pediatric healthcare providers covid-19 in children, pregnancy and neonates: a review of epidemiologic and clinical features clinical accuracy of a non-contact infrared skin thermometer in paediatric practice. child: care, health and development moving personal protective equipment into the community: face shields and containment of covid-19 hand hygiene compliance and environmental determinants in child day care centers: an observational study criteria for return to work for healthcare personnel with suspected or confirmed covid-19 (interim guidance) improvement of child care programs' policies, practices, and children's access to health care linked to child care health consultation child care health consultation improves health and safety policies and practices there is an urgent need to address the lack of cohesive national guidance for ece programs through a collaboration of pediatric, public health, and child care experts. informed by the best science about sars-cov-2 in children, stakeholders must work together to develop, disseminate, and implement guidance that thoughtfully considers young children's physical, developmental, and social-emotional needs along with the realities of operating ece programs.guidance must build from existing health guidance and leverage systems of consultation and technical assistance to support dissemination and implementation. further federal funding is needed for covid-19 that meets the significant knowledge gaps in the pediatric population so that policymakers, public health experts, and health providers can provide science-informed recommendations to ensure the health and safety of children in ece programs. key: cord-263556-y8vx4ie2 authors: koistinen, annamari; lukkarinen, minna; turunen, riitta; vuorinen, tytti; vahlberg, tero; camargo, carlos a.; gern, james; ruuskanen, olli; jartti, tuomas title: prednisolone for the first rhinovirus‐induced wheezing and 4‐year asthma risk: a randomized trial date: 2017-08-06 journal: pediatr allergy immunol doi: 10.1111/pai.12749 sha: doc_id: 263556 cord_uid: y8vx4ie2 background: previous findings show that corticosteroid treatment during the first acute wheezing episode may reduce recurrent wheezing in children with high rhinovirus genome load at 12‐month follow‐up. longer‐term effects have not been investigated prospectively. methods: after pcr confirmation of rhinovirus from nasopharyngeal aspirate, 79 children with the first acute wheezing episode were randomized to receive orally prednisolone or placebo for 3 days. the initiation of asthma control medication before the age of 5 years was confirmed from medical record and/or from parental interview. the outcome was the time to initiation of regular asthma control medication. interaction analysis examined rhinovirus genome load. results: fifty‐nine (75%) children completed the follow‐up. asthma control medication was initiated in 40 (68%) children at the median age of 20 months. overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo (p=.99). rhinovirus load modified the effect of prednisolone regarding the time to initiation of asthma control medication (p‐value for interaction=.04). in children with high rhinovirus load (>7000 copies/ml; n=23), the risk for initiation of medication was lower in the prednisolone group compared to the placebo group (p=.05). in the placebo group, asthma medication was initiated to all children with high rhinovirus load (n=9) during the 14 months after the first wheezing episode. conclusions: overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo. however, prednisolone may be beneficial in first‐time wheezing children whose episode was severe and associated with high rhinovirus load. (clinicaltrials.gov, nct00731575). systemic corticosteroid treatment has not been found effective for acute treatment or secondary prevention of asthma in young wheezing children overall. [1] [2] [3] [4] the limitation of prior studies has been the lack of subgroup analyses that might identify responsive children. 5 rhinovirus-induced wheezing is strongly associated with recurrent wheezing and asthma up to age 13 years. 6, 7 we have previously shown in two randomized controlled trials (rcts) in first-time wheezing children (using both post hoc 8 and prospective designs 9 ) that a 3-day course of oral corticosteroid (ocs) may reduce the risk of recurrent wheezing, especially in children with high rhinovirus genome load. previously, using a design of rct, the effect of ocs treatment on the wheezing recurrence in rhinovirus-affected first-time wheezing children has only been investigated up to 12 months. 9 in the current analysis, our aim was to investigate the need for initiation of regular asthma control medication in the 4-year follow-up. based on our previous findings, 8, 9 we hypothesized that in children with high rhinovirus genome load, the effect of ocs is likely to last beyond 12 months by reducing the need for initiation of long-term asthma control medication. vinku2, a randomized, placebo-controlled trial ("vinku" means wheeze in finnish) prospectively investigated the long-term effectiveness of short course of oral prednisolone (prednisolon ® , leiras takeda, helsinki, finland; during the first rhinovirus-induced wheezing episode, first dose 2 mg/kg, then 2 mg/kg/d in 2 doses for 3 days, maximum 60 mg/d, given as minced 5 mg tablets) until the age of five. 9 inclusion criteria were age 3-23 months, delivery at ≥36 gestational weeks, first acute wheezing episode (parental report and confirmed from medical records), and nasopharyngeal aspirate positive for rhinovirus by pcr. exclusion criteria were a chronic non-atopic illness, previous systemic or inhaled corticosteroid treatment (ics), or a need for intensive care unit treatment. 9 the study was approved by the ethics committee of the turku university hospital and was commenced only after obtaining written informed consent from the guardians. at study entry, patients were examined by study physician and blood samples and nasopharyngeal aspirate were taken. children were reexamined by study physician 2 weeks, 2 months, 12 months, and 4 years after the first wheezing episode. parents were interviewed by study physician using standardized questionnaire at study entry and 12-month and 4-year follow-ups. the electronic patient charts were reviewed regarding asthma medications, therapy adherence, and asthma symptoms for the full follow-up period. the randomization protocol was described earlier. 9 the trial was double-blinded until the 12-month follow-up (clinicaltrials.gov, nct00731575). the primary outcome was the time to initiation of asthma control medication until the age of 5 years. the initiation of the medication was based on the 2007 national asthma education and prevention program (naepp) guidelines for the diagnosis of asthma in children aged <5 years. 10 the need for asthma control medication was defined as ≥4 wheezing episodes (≥1 diagnosed by a physician) within a year that lasted >1 day and affected sleep, in addition to one major risk factor (physician diagnosed atopic eczema, aeroallergen sensitization, or parental history of asthma) or two minor risk factors (wheezing apart from colds, blood eosinophil count (b-eos) ≥0.40×10 9 /l or food sensitization) and/or prolonged symptoms lasting >4 weeks and requiring symptomatic treatment >2 days per week, and/or two exacerbations requiring systemic corticosteroids within 6 months. 10 in some children, asthma control medication was started after the third acute wheezing episode according to the finnish guidelines. 11 the interaction analysis included the effect of rhinovirus genome load (ie, copy number) on the effectiveness of prednisolone vs placebo on the main outcome. an in-house pcr test was used for detecting rhinovirus species a, b, and c, enteroviruses, and respiratory syncytial virus (rsv) a and b from nasopharyngeal aspirate. 12 12 both an in-house and a commercial pcr tests were used, because according to our experience, the sensitivity of the tests, especially concerning on detection of rhinovirus, differs. rhinovirus or rsv detected by either in-house or multiplex pcr was defined as positive. human bocavirus was analyzed using pcr and serology. 13 b-eos and total and allergen-specific serum immunoglobulin e (ige) levels were analyzed using the routine diagnostic procedures of the the original power analysis was performed for 12-month, not 4-year, follow-up. 9 baseline differences in patient characteristics between treatment groups were analyzed using t test (age), mann-whitney u test (b-eos, total ige, 25(oh)d, rhinovirus genome load, duration of breast feeding, and delay in starting the study drug), chi-square test (sex, any sensitization, eczema, parental allergic rhinitis, paternal smoking, pet ownership, and coinfection), or fisher exact test (counts <5; admission to the ward, atopic eczema, parental asthma, maternal smoking, and virus etiology). the cox model was used for risk of the primary outcome. it included the main effects of dichotomized rhinovirus genome load and intervention group and the interaction effect of rhinovirus genome load by intervention group. the cox model included no covariates, as no significant differences in patient characteristics were found. survival times were censored at the age of 5 years if the event did not occur earlier. the cutoff level for rhinovirus genome load was identified by testing different copy number levels. the threshold was selected by considering significant p-value for rhinovirus load vs group interaction effect similar to our previous report. 9 ibm spss version 22 (spss inc, chicago, ill, usa) was used for statistics. a total of 79 children were randomized to receive prednisolone or placebo during their first acute wheezing episode. during the follow-up period, 10 children were excluded from the analysis due to insufficient follow-up time (dropouts), nine due to insufficient data about rhinovirus genome load, and one due to initiation of ics for another reason (figure 1 ). finally, 59 (75%) children were analyzed (inpatient:outpatient, 80%:20%). the excluded patients did not differ from the included patients according to age, sex, atopic characteristics, viral etiology, or any other asthma-related factors listed in table 1 (table s1). at study entry, the mean age of the 59 patients was 13 months (standard deviation [sd] 6 months), 18 (31%) were sensitized, and 23 (39%) had eczema (table 1) . twenty children (34%) had at least two viruses detected in their airways. rhinovirus genome load varied across patients, with a median of 4300 copies/ml (interquartile range [iqr] 79-16 000); 23 (39%) of the patients had a rhinovirus genome load level >7000 copies/ml ( table 2 ). median delay in starting the study drug was 45 hours (iqr: 41-71). the treatment groups did not differ in any patient characteristics shown in table 1 and table s2 . in the prednisolone group 22 (76%) children and in the placebo group 22 (73%) of the children received at least one ocs course during the follow-up. different cutoff levels for rhinovirus genome load was tested, and three different levels were noticed statistically significant ( table 2) . as the differences in final results did not differ significantly depending on the cutoff (data not shown), the same level with the earlier report was used. 9 10 in five children, asthma control medication was started after the third acute wheezing episode. 11 overall, prednisolone did not affect the time to initiation of asthma control medication when compared to placebo (p=.99; figure 2) . however, the level of rhinovirus genome load at study entry modified the effect of prednisolone in terms of the time to initiation of asthma control medication (rhinovirus load x study drug interaction, p=.04, figure 3 ). in children with a rhinovirus genome load of >7000 copies/ ml, the risk for initiation of asthma control medication was lower in the prednisolone group (n=14) compared to the placebo group (n=9; hazard ratio [hr] 0.38; 95% confidence interval [ci] 0.14-1.01, p=.05, figure 3 ). the asthma control medication was exclusively started to all placebo-treated children with high rhinovirus load within the subsequent 14 months after the first wheezing episode (figure 3 ). median age of the children at the time of the initiation of asthma medication was 16 months (iqr: 9-22 months). in children with a rhinovirus genome load of ≤7000 copies/ml, no differences were found between the prednisolone (n=15) and placebo groups (n=21; hr: 1.4, 95% ci: 0.58-3.2, p=.46, figure 3 ). no clinically significant adverse events were reported during the acute phase. this is the first randomized placebo-controlled trial to investigate the effect of ocs treatment until preschool age in carefully characterized young children suffering from their first acute rhinovirus-induced wheezing episode. we had three main findings: first, ocs was not found to be effective overall when regarding the time to initiation of asthma control medication. second, in the placebo group, asthma risk was high: regular asthma control medication was initiated to all children with high rhinovirus genome load during the subsequent 14 months after the first acute rhinovirus-induced wheezing episode. third, short course of prednisolone decreased the risk of asthma control medication in children with the first severe wheezing episode caused by high rhinovirus genome load. all of these findings are in line with previous data on the increased asthma risk associated with early rhinovirus-induced wheezing. [6] [7] [8] probable explanation for the association between rhinovirus infection and risk of asthma may be that pre-existing airway inflammation in asthma-prone children predisposes to rhinovirus infection. 15 moreover, high rhinovirus genome load has been associated with more severe airway inflammation. [16] [17] [18] [19] in asthma-prone patients, interferon responses can be deficient, thus increasing virus replication and promoting type 2 t-cell responses in respiratory epithelial cells. 20, 21 moreover, rhinovirus infection may further intensify the inflammation by increasing the expression of eotaxin and interleukins 4 and 13, as well as by stimulating the immigration of eosinophils, macrophages, and neutrophils. 22 our placebo group finding of an exceptionally high risk for initiating regular asthma control medication in children with high rhinovirus genome load is consistent with these earlier findings. nevertheless, we were surprised by the speed of asthma progression in these children. clinically, ocs treatment is recommended for asthma exacerbations in children, but effectiveness of ocs for the secondary prevention of asthma has not been confirmed in overall analysis of rcts our study population, especially those with high rhinovirus load, most likely represent the cluster a. most 9,16-19 but not all 25, 26 previous studies have shown the higher rhinovirus genome load to be associated with more severe and/or longer duration of acute lower respiratory illness. there are no previous data concerning the long-term outcomes beyond 12 months. 9 we used f i g u r e 2 the time to initiation of asthma control medication in children randomized to receive prednisolone or placebo for the first rhinovirus-induced wheezing episode. no difference was found in overall analysis f i g u r e 3 the time to initiation of asthma control medication in children randomized to receive prednisolone or placebo for the first rhinovirus-induced wheezing episode. data are represented according to the rhinovirus genome load. children with a rhinovirus genome load of >7000 copies/ml had longer time to initiation of asthma control medication in prednisolone group when compared with the placebo group. in the placebo group, asthma medication was initiated to all children with high rhinovirus genome load (n=9) during the 14 mo after the first wheezing episode more sensitive pcr (real-time pcr) compared to our previous study (conventional pcr and liquid hybridization), 8 which also allows quantification of rhinovirus genome load. here, we also used highly concentrated samples, while previous studies that did not find a relationship between viral shedding and outcomes 25, 26 used nasal wash samples to estimate genome load. these differences in methodology may explain apparent discrepancies between our results and those earlier studies. the strengths of the study include careful characterization of the patients and rct design although blinding was opened (as planned) for the 12-month report. 9 however, our study has some limitations. the sample size was small but large enough to generate statistically significant results consistent with our previous studies. 8, 9 most patients were hospitalized which raises questions about the generalizability of our results to outpatients or mild wheezing illness. 27 rhinovirus diagnostics caused a delay in administration of the study drug which could have contributed to the lack of effectiveness of prednisolone in overall rhinovirus analysis (in addition to more sensitive pcr). in our earlier post hoc analysis with no delay in initiation of study drug and no quantitative rhinovirus detection, prednisolone was found effective in all children with rhinovirus and/or eczema. 8, 28 the inflammatory profiling of t helper 1 and t helper 2 mediators in different subgroups would increase the interest of our findings but we did not do the profiling. moreover, there were many cutoff levels of rhinovirus genome load with significant p-value. in this study, we made a decision to be in line with the earlier follow-up. 9 in summary, early systemic short-course prednisolone treatment may be beneficial in reducing the risk for asthma control medication during the first 5 years in first-time wheezing preschool children whose episode was severe and associated with high rhinovirus genome load. the results call attention to different phenotypes of bronchiolitis and early wheezing, 5 which are likely to respond differently to different therapies. the natural course of asthma inception may be modifiable when high-risk children are identified early, even at the time of the first wheezing episode, and targeted with an effective intervention strategy. systemic glucocorticoids in childhood expiratory wheezing: relation between age and viral etiology with efficacy efficacy of a short course of parentinitiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial oral prednisolone for preschool children with acute virus-induced wheezing corticosteroids in respiratory diseases in children a clustering approach to identify severe bronchiolitis profiles in children recurrent wheezing 36 months after bronchiolitis is associated with rhinovirus infections and blood eosinophilia early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence prednisolone reduces recurrent wheezing after first rhinovirus wheeze: a 7-year follow-up short-and long-term efficacy of prednisolone for first acute rhinovirus-induced wheezing episode expert panel report 3: guidelines for the diagnosis and management of asthma -full report working group set up by the finnish medical society duodecim and the finnish cardiac society, helsinki. current care guidelines: asthma; 2012. www.kaypahoito.fi the first wheezing episode: respiratory virus etiology, atopic characteristics, and illness severity clinical assessment and improved diagnosis of bocavirus-induced wheezing in children bronchiolitis: age and previous wheezing episodes are linked to viral etiology and atopic characteristics basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection rhinovirus load and disease severity in children with lower respiratory tract infections impact of rhinovirus nasopharyngeal viral load and viremia on severity of respiratory infections in children impact of human rhinovirus types and viral load on the severity of illness in hospitalized children with lower respiratory tract infections clinical, virological and epidemiological characteristics of rhinovirus infections in early childhood: a comparison between non-hospitalised and hospitalised children deficient antiviral immune responses in childhood: distinct roles of atopy and asthma th2 cytokines impair innate immune responses to rhinovirus in respiratory epithelial cells understanding the association of human rhinovirus with asthma glucocorticoid actions on airway epithelial responses in immunity: functional outcomes and molecular targets comparison of viral load in individuals with and without asthma during infections with rhinovirus a mechanistic role for type iii ifn-λ1 in asthma exacerbations mediated by human rhinoviruses rhinovirus-induced bronchiolitis: lack of association between virus genomic load and short-term outcomes association between respiratory infections in early life and later asthma is independent of virus type sensitization at the first wheezing episode increases risk for longterm asthma therapy we thank biomedical laboratory scientist heidi jokinen from additional supporting information may be found online in the supporting information tab for this article. key: cord-253502-v2hh3w3r authors: leung, c.w.; chiu, w.k. title: clinical picture, diagnosis, treatment and outcome of severe acute respiratory syndrome (sars) in children date: 2004-11-05 journal: paediatr respir rev doi: 10.1016/j.prrv.2004.07.010 sha: doc_id: 253502 cord_uid: v2hh3w3r children are susceptible to infection by sars-associated coronavirus (sars-cov) but the clinical picture of sars is milder than in adults. teenagers resemble adults in presentation and disease progression and may develop severe illness requiring intensive care and assisted ventilation. fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leucopaenia, lymphopaenia, thrombocytopaenia, mildly prolonged activated partial thromboplastin times and elevated lactate dehydrogenase levels are common presenting features. radiographic findings are non-specific but high-resolution computed tomography of the thorax in clinically suspected cases may be an early diagnostic aid when initial chest radiographs appear normal. the improved reverse transcription-polymerase chain reaction (rt-pcr) assays are critical in the early diagnosis of sars, with sensitivity approaching 80% in the first 3 days of illness when performed on nasopharyngeal aspirates, the preferred specimens. absence of seroconversion to sars-cov beyond 28 days from disease onset generally excludes the diagnosis. the best treatment strategy for sars among children remains to be determined. no case fatality has been reported in children and the shortto medium-term outcome appears to be good. the importance of continued monitoring for any long-term complications due to the disease or its empiric treatment, cannot be overemphasised. severe acute respiratory syndrome (sars), a newly described infectious disease caused by the novel sarsassociated coronavirus (sars-cov), has become a major threat to public health globally. 1-4 sars is highly contagious and has been aptly coined 'the first plague of the twenty-first century'. the disease is characterised by transmission in healthcare and household settings and through intriguing superspreading events which were pivotal in its global spread. [5] [6] [7] [8] [9] [10] [11] superspreading events including a major hospital outbreak, in-flight transmission on board commercial paediatric respiratory reviews (2004) summary children are susceptible to infection by sars-associated coronavirus (sars-cov) but the clinical picture of sars is milder than in adults. teenagers resemble adults in presentation and disease progression and may develop severe illness requiring intensive care and assisted ventilation. fever, malaise, cough, coryza, chills or rigor, sputum production, headache, myalgia, leucopaenia, lymphopaenia, thrombocytopaenia, mildly prolonged activated partial thromboplastin times and elevated lactate dehydrogenase levels are common presenting features. radiographic findings are non-specific but highresolution computed tomography of the thorax in clinically suspected cases may be an early diagnostic aid when initial chest radiographs appear normal. the improved reverse transcription-polymerase chain reaction (rt-pcr) assays are critical in the early diagnosis of sars, with sensitivity approaching 80% in the first 3 days of illness when performed on nasopharyngeal aspirates, the preferred specimens. absence of seroconversion to sars-cov beyond 28 days from disease onset generally excludes the diagnosis. the best treatment strategy for sars among children remains to be determined. no case fatality has been reported in children and the short-to medium-term outcome appears to be good. the importance of continued monitoring for any long-term complications due to the disease or its empiric treatment, cannot be overemphasised. ß 2004 elsevier ltd. all rights reserved. abbreviations: sars, severe acute respiratory syndrome; sars-cov, sars-associated coronavirus; rsv, respiratory syncytial virus; ards, acute respiratory distress syndrome; cxr, chest radiograph; hrct, high-resolution computed tomography; boop, bronchiolitis obliterans-organising pneumonia; npa, nasopharyngeal aspirate; rt-pcr, reverse transcription-polymerase chain reaction; ifa, immunofluorescence assay; elisa, enzyme-linked immunosorbant assay. *correspondence to: c.w. leung; e-mail: leungcw@ha.org.hk. airliners, transmission in a hotel and a large-scale community outbreak in a densely populated residential complex, primarily resulting from environmental contamination by a 'superspreader' with diarrhoea, were well described. 5, 6, [12] [13] [14] [15] the disease first started as a mysterious outbreak of atypical pneumonia in the guangdong province of southern china in november 2002. by july 31, 2003, up to 29 countries and regions of the world had been affected by sars. a worldwide total of 8098 cases of probable sars, 1707 (21%) of these being healthcare workers and 774 deaths (9.6%) were recorded. 16 in hong kong, the toll was 1755 affected individuals, including 386 (22%) healthcare workers and 299 deaths (17%). 16 the subsequent reemergence of the first six sporadic cases of sars, two of which were probably laboratory-acquired, did not result in local transmission in singapore, taiwan and china. [17] [18] [19] [20] children appeared to be less affected by the disease, with smaller case numbers and less severe illness reported. [21] [22] [23] [24] all age groups are susceptible to sars-cov, which is new to humans. however, rapid isolation of diseased adults, whose infectivity is lower in the first few days of illness, has contributed to reduced frequency of household exposure for children. the exact number of children affected by sars worldwide is unknown as the age breakdown of reported cases was not available or incomplete for some of the affected countries (who sars surveillance team, personal communication). it is estimated that children <18 years of age only accounted for about 5% of the total affected. there was no reported mortality in children (who sars surveillance team, personal communication). a total of 121 children aged <18 years were registered in the e-sars database of the hospital authority of hong kong, accounting for 7% of all patients notified. the crude age-specific attack rate for children in hong kong was 8.9 per 100 000 persons <18 years of age. serologic confirmation of sars was documented in 89 children (6.6 per 100 000 persons <18 years of age). sixty-four children with clinical disease and seroconversion to sars-cov were managed in the authors' hospitals. the experience with this cohort of laboratory-confirmed patients forms the basis of the clinical information presented in this review. 22, 23 most children reported worldwide were previously healthy and there was no sex predominance. thirty-five (55%) of the 64 children managed by the authors were girls. the male to female ratio was 1:1.2. their mean and median ages were 11.7 and 12 years, respectively. the youngest patient was a 56-day-old premature infant, which is the youngest case reported to date. 25 comorbidity was only present in 5 children (8%) but none of them were immunocompromised. an epidemiologic link was available in the vast majority of children with sars, which appeared to be the most important clue leading to diagnosis in an epidemic situation. worldwide, children were usually secondary household contacts of affected adults, some of whom were healthcare workers or international travellers returning from areas with local transmission of sars. transmission among children or from children to adult contacts was uncommon. about 60% of serologically confirmed children in hong kong were victims of a point source community outbreak due to environmental contamination. 14 the actual proportion of children being secondary household contacts in the particular outbreak could not be determined given the short incubation period between exposure, either to a common environmental source or an index household member, and presentation. there is no published report on the differences in susceptibility and communicability between children and adults. any apparent difference might be related to different risks of exposure for the two age groups. sars is largely an atypical pneumonia with minimal or no extrapulmonary manifestation, apart from diarrhoea. 26 cellular tropism of the sars-cov has been demonstrated primarily in pneumocytes and surface enterocytes of the small bowel. 27 the clinical presentation of sars is nonspecific, with features overlapping those of atypical pneumonia caused by other respiratory pathogens such as influenza virus (including highly pathogenic avian influenza viruses), parainfluenza virus, adenovirus, respiratory syncytial virus (rsv), mycoplasma pneumoniae, chlamydia pneumoniae, chlamydia psittaci and legionella pneumophila. the clinical course of sars in adult patients is well described and appears to follow a triphasic pattern. 6, [28] [29] [30] [31] [32] following an incubation period of 2-10 days (mean 6.4 days, 95% ci 5.2 to 7.7), adults present with a prodrome characterised by high fever (temperature >38 8c), chills or rigor, malaise, headache, dizziness and myalgia. upper respiratory symptoms such as coryza and sore throat are mild and uncommon. diarrhoea is a presenting feature in 6-20% of adult patients. 6, 26, 30 after 2-7 days the disease progresses to involve the lower respiratory tract and a dry, non-productive cough or dyspnoea becomes prominent. in 10-20% of cases, progression to acute respiratory distress syndrome (ards) necessitating intubation and assisted ventilation is observed. mortality results primarily from respiratory failure and a significant proportion of patients recover from pulmonary destruction over an extended period. sars appears to run a less aggressive clinical course in children compared with adults. the severity of illness varies and the extent of asymptomatic infection is unknown, although it is believed to be uncommon. children are usually hospitalised 3-4 days after the onset of symptoms. in one paediatric case series, the mean duration of fever before admission was 3.7 ae 0.6 days (median 3, range 0-12). 23 the most common presenting clinical features in children include fever, malaise, cough, coryza, chills or rigor, sputum production, headache and myalgia (table 1) . 22, 23 lethargy, poor feeding or anorexia, nausea, vomiting, diarrhoea, abdominal pain, sore throat, dyspnoea and dizziness are less commonly encountered. less than 20% of children may pass loose to watery stools, but profuse diarrhoea is rare throughout the course of illness. blood and mucus in the stool, features suggestive of inflammatory enterocolitis, have not been reported. cough, predominantly unproductive in nature, is only found in just over half of the children at presentation. definite physical signs of consolidation are hardly evident and crepitations (crackles) on chest auscultation are unusual despite prominent radiographic evidence of pulmonary infiltrates, even in patients who develop respiratory distress, hence the description of 'atypical' pneumonia. lymphadenopathy, hepatosplenomegaly or clinical bleeding is absent. skin rash is an exceedingly rare manifestation. 22 hypoxaemia is seldom noted at presentation and generally develops towards the end of the first week or the beginning of the second week of illness in severe cases. 33 the youngest patient, however, presented with a cyanotic attack, dyspnoea, cough and hypothermia with subsequent development of fever. 25 teenagers (aged >12 years) may resemble adults in presentation and disease progression. they tend to have more constitutional upsets and systemic symptoms of malaise, chills or rigor, headache, myalgia and dizziness are significantly more common ( table 2) . they appear sicker, have a greater need for oxygen therapy and other respiratory support and may require intensive care. 33 children 12 years of age generally have milder symptoms and coryza is significantly more common ( table 2) . they appear to run a milder and shorter clinical course. the clinical picture is sometimes indistinguishable from other viral infections of the upper respiratory tract, thus posing a diagnostic challenge. the clinical course of sars in the majority of children follows a biphasic pattern. the phase of viral replication, which lasts for a few days, is characterised by an abrupt onset of fever and constitutional symptoms in association with an increase in body viral load. 34 the phase of immunopathologic damage is marked by the progression of pneumonia and hypoxaemia, when the body viral load declines and an exaggerated host immune response supervenes. 35 the prodromal and pneumonic phases of the disease, however, may be less distinct in comparison with adult patients. progression to ards, or the third phase as in adults, is only seen in a very small number of children, predominantly adolescents. the natural history of untreated sars in both adults and children remains unclear. as most patients worldwide had received some form of empiric treatment in the form of antiviral agents with or without corticosteroids, the probability of spontaneous recovery could not be ascertained. nevertheless, three children with mild disease had recovered on supportive therapy alone in the authors' cohort. 22, 23 anecdotal reports of extrapulmonary manifestations of sars, in the form of central nervous system dysfunction and probable viral hepatitis, have been described in adults. [36] [37] [38] atypical presentation of sars, in the form of non-specific febrile illness or febrile non-pneumonic respiratory illness, have been observed in both children and adults. 23, 39, 40 such cases are likely to evade clinical detection in the absence of a definite contact history with patients with suspected or confirmed sars. the full spectrum of clinical as well as subclinical illnesses caused by infection with sars-cov will unfold with further epidemiological studies and case reports. as sars is basically a pneumonic infection, chest radiograph (cxr) is therefore an essential diagnostic tool. the principal radiographic abnormality of sars in children is illdefined airspace shadowing, which presents as ground-glass opacities and/or unifocal, lobar or multifocal areas of consolidation. [21] [22] [23] [24] 41, 42 unilateral focal opacity was reported as the most common finding in one paediatric case series and was evident in 86% of children at presentation (fig. 1 ). 22 in adults, regions of airspace disease predominate in the lower lobes but are also noted elsewhere. 6 there appears to be no predominant distribution pattern of consolidation in children. [21] [22] [23] cxr opacities are most often peripheral or mixed central and peripheral in location. the lung opacities show a tendency to progress, with increase in size or involvement of multiple areas either unilaterally or bilaterally in moderate to severe cases. rapid progression to unilateral multifocal or bilateral involvement, with reduction in lung volumes in the second week of illness, is typical in children who develop severe hypoxaemia (fig. 2) . 23 in the advanced stage of the disease, which only occurs in a very small number of children, widespread ground-glass opacities and diffuse patchy consolidations are seen, likely representing progression to ards. pneumonic changes may not be apparent at presentation as mildly symptomatic individuals may be identified early in the prodromal period through contact tracing of patients diagnosed with sars. repeat cxr examination, as guided by failure of resolution of symptoms or change in clinical condition, will clarify the picture by revealing new pulmonary infiltrates as the disease progresses. frequent monitoring of cxr changes has the additional benefit of detecting early radiographic deterioration in many patients, heralding clinical deterioration. radiographic resolution, on the other hand, generally lags behind clinical improvement. complete resolution of the airspace opacities can take more than a month in the most severely affected children. 23 no preliminary evidence of pulmonary fibrosis, bronchial wall thickening, bronchiectasis or lung volume loss was observed on follow-up in one paediatric case series. 23 viral pneumonias tend to show reticulo-nodularity as well as a symmetrical perihilar peribronchial pattern of infiltration which is sometimes marked by hilar adenopathy. 43 in contrast to pneumonias caused by other respiratory pathogens, the cxr of children with sars shows no evidence of interstitial disease, hilar adenopathy, mediastinal widening, significant pleural effusion, cavitation, abscess formation, pneumatocele, pneumothorax or pneumomediastinum. [21] [22] [23] [24] 41, 42 nevertheless, the radiographic features of sars in children are non-specific. radiological differentiation of sars from other commonly encountered childhood respiratory illnesses causing airspace disease can be difficult. 41 high-resolution computed tomography (hrct) of the chest has been used as an early diagnostic tool in clinically suspected children with initial negative or equivocal chest radiographs. [21] [22] [23] [24] 41 hrct findings may include groundglass opacification, unifocal or multifocal consolidation in subpleural, peripheral or central regions and interlobular septal and intralobular interstitial thickening (fig. 3) . the characteristic peripheral alveolar opacities are reminiscent of bronchiolitis obliterans-organising pneumonia (boop). 6, 21, 44 in general, hrct is sensitive in detecting more extensive airspace consolidation and ground-glass attenuation than cxr. the investigation is particularly useful when lung parenchymal abnormalities are minimal early in the course of illness, or being obscured by the diaphragm and the cardiac silhouette. the utility of chest hrct lies in the early confirmation of airspace disease in radiographically inapparent cases with a strong contact history and clinical features highly suspicious of sars, thus allowing prompt isolation and monitoring for clinical and radiological deterioration. the haematological and biochemical abnormalities of sars in children are neither diagnostic nor specific. like adults, the most consistent haematological finding is lymphopaenia, which is present in about 70% of children at presentation and about 90% during the course of illness. 22, 23 depletion of lymphocytes may be secondary to the direct cytopathic effect of the virus, cytokine-mediated apoptosis, lymphocyte margination due to increased cortisol secretion from activation of the hypothalamic-pituitary-adrenal axis or the administration of high-dose glucocorticoids, which have a profound lympholytic effect, especially on t lymphocytes. [45] [46] [47] other haematological abnormalities such as leucopaenia, thrombocytopaenia and mildly prolonged activated partial thromboplastin times are observed in about 30% of children. anaemia is rarely found at presentation and is only detected in <5% of children. 22, 23 unlike adults, a significant drop in the haemoglobin level during the course of illness that necessitates discontinuation of empiric antiviral therapy, namely ribavirin, has not been observed. [22] [23] [24] reactive thrombocytosis on recovery from sars is significantly more common in children 12 years of age. 23 this phenomenon is sometimes observed in children recovering from systemic viral infections and is probably not related to the use of corticosteroids. despite an abnormal clotting profile with elevated d-dimer levels and the detection of lupus anticoagulants in a small number of children, bleeding events or thrombotic complications have not been reported. 22, 48 the most common biochemical abnormality in children with sars is an elevated lactate dehydrogenase level, which is present in about 50% at presentation and about 70% during the course of illness. elevated alanine aminotransferase levels are seen in <20% of children at presentation and <50% during the course of illness. elevation of creatine kinase levels vary from 10% to 40% between case series. 22, 23 teenage patients tend to have more derangement of laboratory parameters and they may take longer to resolve. 22 similar to human infection with avian influenza a h5n1 virus, cytokine dysregulation is believed to be pivotal in the immunopathogenesis of sars among adults and children. serial monitoring of the plasma inflammatory cytokine profile using flow cytometry in a cohort of eight paediatric patients suggests that the caspase-1-dependent pathway in infected macrophages is selectively activated, as reflected by substantial elevation of circulating interleukin-1b levels. 49 conversely, interleukin-6 and tumour necrosis factor-a levels, which are markedly increased in human infection with avian influenza a h5n1 virus, are not overtly elevated throughout the course of illness. 50, 51 the predominant activation of the th1 immune response facilitates viral clearance and may explain the rapid recovery of children. as sars is a newly emerging infectious disease with unknown aetiology initially, the initial case definitions of suspected and probable sars promulgated by the world health organization were meant for surveillance and were necessarily broadly inclusive and non-specific. patients were categorised based on clinical, radiologic and epidemiologic features and after exclusion of alternative diagnoses. the original who surveillance case definitions for sars required that lower respiratory symptoms of cough, short-ness of breath or difficulty breathing were present. applying this would have missed many children who do not present with the above symptoms. the lack of sensitivity and specificity of the initial who case definitions have generated uncertainty in individual case management at the point of care. 24, 52 with more understanding of the disease and identification of a novel coronavirus as the causative agent, the case definitions of sars were revised on may 1, 2003. 53 as the clinical and radiologic features were non-specific, much emphasis was placed on the identification of an epidemiologic link to suggest the diagnosis. the vast majority of patients in the last epidemic had a clear history of exposure, either to patients suspected of or diagnosed with sars, or to a setting where recent local transmission was occurring. when the epidemic was over, an epidemiologic clue became more difficult to ascertain in sporadic cases that re-emerged. the latest who case definitions in the post-outbreak period now incorporate both clinical and laboratory elements, with further emphasis on clearly defined microbiologic criteria besides exclusion of alternative diagnoses (table 3) . 54 nevertheless, careful epidemiologic history taking remains essential in the diagnostic work-up and early implementation of appropriate infection control measures in suspected patients. important questions to ask in the 'peace time' include: (1) history of recent travel to pre-viously sars-affected areas or areas with an increased likelihood of animal to human transmission of sars-cov infection; (2) close contact with a suspected sars patient; (3) history of recent hospitalisation or contact with a healthcare facility; (4) individuals who are either healthcare workers or laboratory workers with potential exposure to sars patients or live sars-cov; and (5) link to a cluster of cases of unexplained respiratory illness in the community. microbiological investigations are the cornerstones for the confirmation of sars. the diagnostic work-up should include tests for pathogens which cause communityacquired pneumonia in children. 23 a blood culture is also needed. for children with productive cough who are old enough to produce a reliable specimen, sputum for bacterial culture should be performed. nasopharyngeal aspirate (npa) should be saved for rapid antigen detection of influenza a and b, rsv, adenovirus and parainfluenza types 1, 2 and 3, using direct immunofluorescence assays. urine samples may be tested for legionella pneumophila and streptococcus pneumoniae antigens. npa specimens should also be inoculated into different cell lines for isolation of respiratory viruses. serologic studies should include mycoplasma pneumoniae igm and paired acute and convalescent sera for igg against mycoplasma pneumoniae, chlamydia pneumoniae, chlamydia psittaci, legionella pneumophila, influenza a and b, rsv, adenovirus and parainfluenza types 1, 2 and 3. specific tests for the detection of sars-cov include: (1) molecular or nucleic acid amplification test using reverse transcription-polymer-ase chain reaction (rt-pcr); (2) antibody tests; and (3) cell culture. 55 in view of the high transmissibility of sars in hospitals, laboratory confirmation of the diagnosis early in the course of illness is vital to allow for the best utilisation of the limited isolation and cohorting facilities in most hospitals. rapid diagnosis with rt-pcr tests targeting specific segments of the sars-cov genome, primarily the polymerase gene, were used extensively during the last epidemic. [1] [2] [3] [56] [57] [58] [59] the method can be applied to nasopharyngeal aspirates, nose and throat swabs, saliva, sputum, endotracheal aspirates, bronchoalveolar lavage, stool, urine, plasma and serum. nasopharyngeal aspirates, combined nose and throat swabs and stool are the most commonly used. experience in hong kong and toronto suggests that the first generation conventional rt-pcr assays in use at the time of the initial outbreak lacked sufficient sensitivity to clinically rule out sars. 1, 60 despite initial optimism, the test has a sensitivity of 30% in npa, 28% in combined nose and throat swabs and 20% in stool in the first 5 days of illness. 61 it only reaches a maximum sensitivity of 60% when performed on upper respiratory specimens collected between days 9 to 11 from onset of fever (government virus unit, public health laboratory centre, hong kong special administrative region. data on file), where day 10 coincides with the maximum viral load in npa specimens as clinical picture, diagnosis, treatment and outcome of sars in children 281 a person with a history of: fever (!38 8c) and one or more symptoms of lower respiratory tract illness (cough, difficulty breathing, shortness of breath) and radiographic evidence of lung infiltrates consistent with pneumonia or rds or autopsy findings consistent with the pathology of pneumonia or rds without an identifiable cause and no alternative diagnosis can fully explain the illness laboratory definition of sars a person with symptoms and signs that are clinically suggestive of sars and with positive laboratory findings for sars-cov based on one or more of the following diagnostic criteria: (a) pcr positive for sars-cov using a validated method from: at least two different clinical specimens (e.g. nasopharyngeal and stool) or the same clinical specimen collected on two or more occasions during the course of the illness (e.g. sequential nasopharyngeal aspirates) or two different assays or repeat pcr using a new rna extract from the original clinical sample on each occasion of testing (b) seroconversion by elisa or ifa negative antibody test on acute serum followed by positive antibody test on convalescent phase serum tested in parallel or four-fold or greater rise in antibody titre between acute and convalescent phase sera tested in parallel (c) virus isolation isolation in cell culture of sars-cov from any specimen and pcr confirmation using a validated method measured in adult patients. 35 the low viral load in the upper respiratory tract in the initial few days of illness poses a diagnostic challenge. the lower respiratory tract as the primary target of sars-cov infection is the probable explanation. sputum specimens appear to have a higher diagnostic yield but productive cough is uncommon in sars patients in the early phase of illness and sputum is difficult to obtain in children. the overall diagnostic yield in the second week of illness increases to >80% when stool specimens are also examined, with stool yielding better results than respiratory specimens. 61 improving rna extraction from the specimen can markedly improve the sensitivity of conventional rt-pcr assays. when a modified rna extraction protocol is combined with an optimised real-time rt-pcr assay, a sensitivity of 80% and specificity of 100% can now be achieved in the first 3 days of illness, using npa as the preferred specimen. 57 a recently described real-time nested pcr assay performed on throat swabs is capable of detecting <10 copies of viral genome per reaction and achieves a much shorter turn-around time than conventional nested rt-pcr. 62 the technique of real-time rt-pcr has also been applied to plasma and serum samples. it has been shown that 50% of plasma and 78% of serum samples are positive for sars-cov rna during the first week of illness in adult sars patients. 63 a detection rate of 87.5-100% obtained in the plasma of eight paediatric patients within the first week of illness similarly suggests that plasma sars-cov rna quantification is a very sensitive and potentially useful early diagnostic tool. 34 the potential advantages of realtime rt-pcr include an increase in sensitivity, reduction in analytical time, reduction of risk of carry over contamination and availability of quantitative result for disease monitoring and prognostic purposes. 63 interestingly, despite a milder clinical course in paediatric patients, no significant differences in plasma viral loads are observed in plasma samples taken from paediatric and adult sars patients within the first week of admission and at day 7 after fever onset. 34 obtaining an npa specimen has been regarded by some as a hazardous procedure posing significant risk to the operator, although it is the best specimen for the rapid diagnosis of sars and the exclusion of other pathogens in the early phase of illness. to obviate the need for the protection of healthcare workers, an ingenious method for self-obtaining nasopharyngeal specimens through conjunctiva-upper respiratory tract irrigation (curti) has been described as an alternative. 64 the lack of serologic evidence of prior sars-cov infection in humans suggests that the virus has only recently entered the human population, presumably from an animal reservoir in southern china. 65, 66 specific igm and igg antibodies appear in response to sars-cov infection, with their levels changing during the course of the infection. serum antibody testing by immunofluorescence assay (ifa) or enzymelinked immunosorbant assay (elisa) have been developed to diagnose sars. 1, 3, 35, 67 the ifa test detects igm and igg antibodies and yields positive results in 16% and 55% of cases, respectively, after 10 days of illness. both are detectable in 91% of ifa tests by 25 days. 68 an indirect immunofluorescence test for igg antibody provides a sensitivity and specificity of 100%. 67 the elisa test detects a mixture of serum igm and igg antibodies, 80% and 85% respectively being positive by the second week. detection rate for both is 100% by week 3. the decay curves suggest that igm seropositivity is lost by about 12 weeks, while igg titres peak at 4 weeks and remain elevated until 12 weeks. 69 the antibody response is usually negative until 10 days from onset of symptoms. by day 28, seroconversion is demonstrated in 93% of sars patients despite corticosteroid therapy. 35 seroconversion from negative to positive or a !four-fold rise in igg antibody titres indicates recent infection. no detection of antibody in serum obtained >28 days from onset of illness indicates an absence of sars-cov infection and is the only laboratory method for excluding the diagnosis. 70, 71 serologic testing appears to be the best method for confirming sars, with positive rates ranging from 93% to 99%. 35, 52, 61 igm or other antibody assays have not been successful in closing the diagnostic window within the first week of illness. 65 even if some patients seroconvert early, the utility of serology is confined to retrospective diagnosis given the generally long lag time to seroconversion. igg usually remains detectable after resolution of the illness but the duration of persisting protective neutralising antibodies and their boosting response remain unknown. sars-cov can be isolated from respiratory secretions, blood or stool by inoculating cell cultures and growing the virus. vero e6 cells and fetal rhesus monkey kidney cells are suitable to support the viral growth, with the cytopathic effect demonstrable by 2-6 and 2-4 days respectively after inoculation. [1] [2] [3] the cultured virus must be identified as sars-cov with further tests, primarily rt-pcr assays. 61 the major limitation of viral culture in sars is its very low sensitivity. in one paediatric series, the virus was only successfully isolated from npa cultures in 16% of children. 23 negative cell culture results, like negative rt-pcr results, do not exclude sars infection. cell culture is also a very demanding test and primary virus isolation takes too long to be meaningful for early diagnosis. furthermore, amplification of the viable virus is associated with a potential biohazard, necessitating biosafety level three containment. culture-based diagnostic techniques are unlikely to be widely available but with the exception of animal inoculation, it is the only way to show the existence of viable sars-cov. 4, 72 the usual 'gold standard' of microbiological diagnosis, namely the isolation of the pathogen, has limited application in sars. during the global outbreak of sars, it was understandable that treatment was empiric, given the explosive epidemic of a life-threatening infection in multiple countries before the viral agent was even identified. time for planning, let alone conducting, a well-designed prospective clinical trial to assess the efficacy of any treatment regimen was simply not there. a proposed regimen consisting of antibiotics, ribavirin and corticosteroids was based on initial anecdotal successes in 2 outbreak studies in adult patients. 6, 28 subsequently, a standard treatment protocol was developed by a group of physicians in hong kong, which included (1) antibiotics for treatment of community-acquired pneumonia caused by usual and by atypical pathogens, (2) ribavirin as a broad-spectrum antiviral agent targeting the presumed viral etiology of sars, and (3) immunomodulating agents in the form of glucocorticoids. 73 a similar regimen in children consisting of antibiotics and ribavirin, with or without corticosteroids, was used. 21, 74, 75 in adult patients, the high incidence of deranged liver function, leucopaenia, severe lymphopaenia, thrombocytopaenia and progression to ards suggests severe systemic inflammatory damage induced by sars-cov. 1 the pathogenesis of the infection is postulated as an over-exuberant immunopathological reaction or a ''cytokine storm'' resulting from unrestricted viral replication during the early stages of the disease. findings consistent with cytokine dysregulation are the radiological changes of multifocal, flitting, boop-like features with progression to ards, the histological changes of macrophage infiltration and diffuse alveolar damage and the dramatic clinical and radiologic improvement with high-dose corticosteroid therapy. 1, 76 the viral load in sars followed an inverted v pattern, with progressive fall in viral shedding after day 10-15, correlating with seroconversion. 35 the logical approach to preventing severe disease is to restrict viral replication and to modulate inappropriate immunological responses. in principle, antiviral agent should be prescribed first during the phase of active viral replication, followed by an immunomodulator if the former fails and the patient is affected by immune hyperactivation. the use of ribavirin in adults and children has been reported by groups of investigators worldwide. 1, 6, [21] [22] [23] [24] [28] [29] [30] 35, [77] [78] [79] [80] [81] [82] ribavirin was empirically chosen in sars because of its broad-spectrum of activities against dna and rna viruses. ribavirin was also known to be effective in the treatment of fulminant murine hepatitis, which is caused by an animal coronavirus. in the murine hepatitis model, ribavirin exerted an immunomodulatory effect by decreasing the release of proinflammatory cytokines from the macrophages and switching the immune response from a th 2 to a th 1 response. 83, 84 however, it was later learnt that ribavirin demonstrated no or minimal activity against sars-cov isolates in vitro. 85, 86 in vitro testing indicated that ribavirin failed to inhibit replication or cell to cell spread at low drug concentrations. 87 although inhibitory activity was demonstrated at high drug concentrations, the resultant cytotoxic effects were undesirable. 88 it appeared that due to the low activity of ribavirin in vitro, inhibitory concentrations might not be achieved clinically without causing significant toxicity. investigators in canada have generally used ribavirin at a higher dosage similar to that recommended for treatment of several viral haemorrhagic fever syndromes and have observed severe adverse events in adult patients. booth et al. reported that 40% of patients had elevated hepatic transaminase levels, 14% had sinus bradycardia, 76% had haemolysis with haemoglobin levels declining by at least 2g/ dl in 49% and that 18% had to discontinue treatment. 30 knowles et al. reported that 61%, 58% and 46% of 110 patients had haemolytic anemia, hypocalcemia and hypomagnesaemia, respectively. 89 children appear to tolerate ribavirin much better than their adult counterparts. [21] [22] [23] [24] solid clinical data to demonstrate the efficacy of ribavirin is lacking. the limited data suggest that, at least in adults, dosages of about 2g/d might be effective while not causing severe adverse reactions. such doses should be considered for further studies. doses lower than 1g/d appear ineffective. 85 the only randomised controlled trial involving the use of ribavirin in the treatment of sars was conducted in china by zhao et al. the open-label study failed to demonstrate any efficacy and led the investigators to conclude that ribavirin, given at 400-600 mg/d, was less effective than early and aggressive use of corticosteroids combined with non-invasive ventilatory support. 77 non-randomised studies of corticosteroids have been reported in both adults and children with seemingly favourable outcomes in terms of clinical and radiologic improvements, suggesting that the combined use of ribavirin and corticosteroids might be effective. 1, 6, [21] [22] [23] 28, 33, 35, 73, 82, 90, 91 other reports on the combined regimen were inconclusive or failed to demonstrate obvious benefit. 30, 78, 79 in the paediatric series reported by leung et al., 95% and 84% of the 44 children with laboratory-confirmed sars were treated with ribavirin and corticosteroids respectively, without significant adverse events and all patients recovered. 23 in the series reported by chiu et al., 95% and 62% of the 21 children received ribavirin and corticosteroids, respectively and achieved similar outcomes. 22 all were subsequently confirmed by seroconversion to sars-cov after the report was published. bitnun et al. reported the use of ribavirin without corticosteroids in 10 children with probable sars but virologic confirmation was lacking. 24 in contrast, zeng et al. treated 33 children with chinese traditional medicine and antibiotics with good results. only 10 of the children had an epidemiologic link to sars, however, and virologic data were not available. 92 the use of corticosteroids in viral infections is controversial and is potentially hazardous. as an immunosuppressive agent, corticosteroids might promote viral replication, enhance infectivity and possibly cause a rebound of infection. it is known that in acute viral respiratory infections, early-response cytokines such as tumour necrosis factor, interleukin-1 and interleukin-6 mediate lung injury. the rationale for using corticosteroids is to suppress the ''cytokine storm'' which is thought to be the main factor accounting for the progression of disease. but using corticosteroids with possibly ineffective antiviral therapy in patients with viral pneumonitis can be hazardous. 93 despite the initial success of corticosteroids in the treatment of sars, the report of an adult patient whose clinical course was complicated by fatal aspergillosis was disturbing and had even led others to recommend close laboratory monitoring for aspergillosis in sars patients receiving corticosteroids. 94, 95 in retrospect, we do not think that ribavirin alone has any significant effect in halting disease progression and corticosteroids are probably unnecessary for children who do not develop moderate to severe hypoxaemia. in our experience, as with others, corticosteroids may be life saving in patients who are threatened by impending acute respiratory failure. we cannot categorically recommend this treatment strategy in view of the small number of children treated and the lack of objective evidence from a controlled trial. the place of corticosteroids in the rescue therapy of patients who have clearly experienced failure of supportive care remains to be determined. no evidence-based therapeutic approach for sars exists although more than 30 papers have been published internationally that mention antiviral treatment. various other antiviral and immunomodulating agents have been used in adult patients with preliminary success. these include the use of lopinavir / ritonavir in combination with ribavirin and corticosteroids, interferon a plus corticosteroids and convalescent plasma from patients. [96] [97] [98] [99] their true role in the treatment of children is unknown. knowledge generated by detailed bioinformatic analysis of the sars-cov genome can be harnessed to identify possible targets for antiviral therapy, such as enzymatic proteins of the viral replicase-transcriptase complex. this approach has been reviewed by davidson and siddell who concluded that the most economical and effective way to contain the virus would be the therapeutic use of antiviral agents to block viral entry to target cells or to inhibit intracellular viral replication. 100 in vitro studies have highlighted the antiviral potential of several compounds, including recombinant human interferon b-1a, interferon b-1b, glycyrrhizin, human monoclonal antibody against the spike protein of sars-cov and small interfering rna. [101] [102] [103] [104] [105] with more understanding of the pathogenesis as well as the clinical course of the disease, treatment will evolve. the best treatment for sars in adults and children remains unknown. time is now on our side to plan for clinical trials should the disease re-emerge. with increased vigilance, rapid detection and effective infection control measures, outbreaks of sars seem less likely. it might never be possible, therefore, to recruit a sufficient number of patients to complete the trials and give us an early answer. in adults, the risk factors for severe illness are advanced age, high initial absolute neutrophil counts, low platelet counts, high initial or peak lactate dehydrogenase levels and positive rt-pcr results for npa specimens. 6, [106] [107] [108] [109] only one paediatric series has identified risk factors for severe illness in terms of requirements for oxygen and intensive care. these include a sore throat, a high neutrophil count at presentation, and peak neutrophilia. the finding of sore throat as an independent risk factor is intriguing but may be incidental, given the small number of patients. no association between the presence of sore throat and the detection of sars-cov by rt-pcr or culture in npa specimens, which might correlate with higher viral load, could be demonstrated. 23 the short-term outcome of sars among children is good in comparison to adults. no case fatality has been reported. the need for intensive care and mechanical ventilation was up to 23.2% and 13.8% respectively in adults. 6 chiu et al. reported that 9.5% of children required oxygen supplementation and none required assisted ventilation. 22 leung et al. reported an oxygen requirement in 20.5% and assisted ventilatory support in 6.8% of children. 23 the figures for oxygen requirement and assisted ventilation in the two paediatric series combined are 17% and 5%, respectively. diffuse thinning and shedding of hair was observed in 41.5% of children in one series, generally at 2-3 months after disease onset. the condition was self-limiting and spontaneous recovery occurred within 1-3 months. this is consistent with acute telogen effluvium secondary to febrile systemic illness, critical care or severe psychologic stress in life-threatening situations. 23 li et al. examined the radiologic and pulmonary function outcomes of 47 children, 6 months after diagnosis and detected mild radiologic abnormalities with hrct and in pulmonary function testing in 34% and 10.5% respectively. 110 however, all children were asymptomatic and had normal clinical examination, premorbid hrct and pulmonary function test results were not available for comparison. in contrast, some adult patients have devel-oped pulmonary fibrosis despite recovery from the primary illness. 111 the psychological impact of separation, isolation in an intimidating hospital environment, bereavement and family disintegration following the death of close adult family members in children who recovered from sars are immense. however, children appear to be more resilient than adults in psychological adjustment to sars and serious psychological sequelae were not evident 3 months after discharge. 23 continued monitoring for delayed onset of psychological problems in children is essential. children who have recovered from the acute illness should be monitored for the possibility of continued viral shedding and the development of pulmonary sequelae and postviral complications (e.g. chronic fatigue), as well as for any long-term complications of high-dose corticosteroid therapy. children are susceptible to infection by sars-cov. despite the milder clinical picture, the good short-to medium-term outcome and the availability of reliable early diagnostic techniques, treatment remains controversial. the long-term outcome of sars in children remains unknown. there are still enormous gaps in our knowledge about sars. much work needs to be done, urgently. sars is largely an atypical pneumonia with minimal or no extrapulmonary manifestation apart from diarrhoea. the clinical picture of sars is milder in children but teenagers may develop severe illness resembling adults. the clinical, radiologic and laboratory features of sars are non-specific. an epidemiologic link is the most important clue to diagnosis in an outbreak situation. refined rt-pcr assays can achieve a sensitivity of 80% in the early diagnosis of sars in the first 3 days of illness. npa specimens are the preferred specimens for rt-pcr assays in the first week of illness. both npa and stool specimens should be tested in the second week. a negative rt-pcr result cannot exclude the diagnosis. absence of seroconversion beyond 28 days from disease onset generally excludes the diagnosis. apart from supportive treatment, including oxygen therapy and assisted ventilation, other treatment modalities remain unproven. molecular biology of sars-cov and mechanisms of its genome expression. pathogenesis of sars-cov infection. natural history and full spectrum of sars-cov infection. improved early diagnostic techniques. 'gold standard' of diagnosis. novel therapy and vaccine. longitudinal follow-up for long-term outcome and persistence of protective immunity to reinfection. coronavirus as a possible cause of severe acute respiratory syndrome identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel coronavirus associated with severe acute respiratory syndrome koch's postulates fulfilled for sars virus update: outbreak of severe acute respiratory syndrome -worldwide a major outbreak of severe acute respiratory syndrome in hong kong sars transmission among hospital workers in hong kong sars infection among health care workers in beijing, china cluster of severe acute respiratory syndrome cases among protected health-care workers -toronto, canada probable secondary infections in households of sars patients in hong kong secondary household transmission of sars in-flight transmission of severe acute respiratory syndrome (sars): a case report transmission of the severe acute respiratory syndrome on aircraft outbreak of severe acute respiratory syndrome (sars) at amoy gardens, kowloon bay, hong kong: main findings of the investigation world health organization. summary of probable sars cases with onset of illness from 1 severe acute respiratory syndrome (sars) in singapore -update 2 -sars case in singapore linked to accidental laboratory contamination severe acute respiratory syndrome (sars) in taiwan, china update 4 -review of probable and laboratory-confirmed sars cases in southern china new case of laboratory-confirmed sars in guangdong, china -update 5 clinical presentations and outcome of severe acute respiratory syndrome in children severe acute respiratory syndrome in children: experience in a regional hospital in hong kong severe acute respiratory syndrome among children children hospitalized with severe acute respiratory syndrome-related illness in toronto a young infant with severe acute respiratory syndrome enteric involvement of severe acute respiratory syndrome-associated coronavirus infection tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases a cluster of cases of severe acute respiratory syndrome in hong kong identification of severe acute respiratory syndrome in canada clinical features and short-term outcomes of 144 patients with sars in the greater toronto area world health organization. preliminary clinical description of severe acute respiratory syndrome severe acute respiratory syndrome adolescent twin sisters with severe acute respiratory syndrome (sars) serial analysis of the plasma concentration of sars coronavirus rna in pediatric patients with severe acute respiratory syndrome clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study possible central nervous system infection by sars coronavirus detection of sars coronavirus rna in the cerebrospinal fluid of a patient with severe acute respiratory syndrome sars-associated viral hepatitis caused by a novel coronavirus: report of three cases relative rates of non-pneumonic sars coronavirus infection and sars coronavirus pneumonia severe acute respiratory syndrome without respiratory symptoms or abnormal chest radiograph findings severe acute respiratory syndrome (sars): chest radiographic features in children severe acute respiratory syndrome (sars) in a paediatric cluster in singapore roentgenographic features of common pediatric viral respiratory tract infections thin-section ct of severe acute respiratory syndrome: evaluation of 73 patients exposed to or with the disease haematological manifestations in patients with severe acute respiratory syndrome: retrospective analysis lymphopenia in sars (letter) apoptosis may explain lymphopenia of sars (letter) severe acute respiratory syndrome and lupus anticoagulants in children inflammatory cytokine profile in children with severe acute respiratory syndrome pathology of fatal human infection associated with avian influenza a h5n1 virus induction of proinflammatory cytokines in human macrophages by influenza a (h5n1) viruses: a mechanism for the unusual severity of human disease evaluation of who criteria for identifying patients with severe acute respiratory syndrome out of hospital: prospective observational study world health organization. case definitions for surveillance of severe acute respiratory syndrome (sars) world health organization. alert, verification and public health management of sars in the post-outbreak period severe acute respiratory syndrome (sars): laboratory diagnostic tests rapid diagnosis of a coronavirus associated with severe acute respiratory syndrome (sars) early diagnosis of sars coronavirus infection detection of sars coronavirus in patients with severe acute respiratory syndrome by conventional and real-time quantitative reverse transcription-pcr assays evaluation of reverse transcription-pcr assays for rapid diagnosis of severe acute respiratory syndrome associated with a novel coronavirus interpretation of diagnostic laboratory tests for severe acute respiratory syndrome: the toronto experience detection of sars coronavirus in patients with suspected sars sensitive and quantitative detection of severe acute respiratory syndrome coronavirus infection by real-time nested polymerase chain reaction quantitative analysis and prognostic implication of sars coronavirus rna in the plasma and serum of patients with severe acute respiratory syndrome conjunctival-upper respiratory tract irrigation for early diagnosis of severe acute respiratory syndrome crouching tiger, hidden dragon: the laboratory diagnosis of severe acute respiratory syndrome isolation and characterization of viruses related to the sars coronavirus from animals in southern china immunofluorescence assay for serologic diagnosis of sars the application of indirect immunofluorescence assay in the diagnosis of severe acute respiratory syndrome profile of specific antibodies to the sarsassociated coronavirus combining clinical and epidemiologic features for early recognition of sars public health guidance for community-level preparedness and response to severe acute respiratory syndrome (sars) version 2. supplement f: laboratory guidance. appendix f7 -fact sheet for clinicians: interpreting sars-cov test results from cdc and other public health laboratories newly discovered coronavirus as the primary cause of severe acute respiratory syndrome development of a standard treatment protocol for severe acute respiratory syndrome sars reference pmh/pwh interim guideline on the management of children with sars lung pathology of fatal severe acute respiratory syndrome description and clinical treatment of an early outbreak of severe acute respiratory syndrome in guangzhou, pr china severe acute respiratory syndrome (sars) in singapore: clinical features of index patient and initial contacts clinical description of a completed outbreak of sars in vietnam icu management of severe acute respiratory syndrome identification and containment of an outbreak of sars in a community hospital clinical course and management of sars in health care workers in toronto: a case series inhibition of murine hepatitis virus infections by the immunomodulator 2,3,5,6,7,8-hexahydro-2-phenyl-8,8-dimethoxy-imidazo[1,2a]pyridine (pr-879-317a) ribavirin inhibits viral-induced macrophage production of tnf, il-1, the procoagulant fgl 2 prothrombinase and preserves th 1 cytokine production but inhibits th 2 cytokine response antiviral treatment of sars: can we draw any conclusions? ribavirin in the treatment of severe acute respiratory syndrome (sars) severe acute respiratory syndrome (sars) and coronavirus testing -united states inhibition of sars coronavirus infection in vitro with clinically approved antiviral drugs common adverse events associated with the use of ribavirin for severe acute respiratory syndrome high-dose pulse versus nonpulse corticosteroid regimens in severe acute respiratory syndrome treatment of severe acute respiratory syndrome in health-care workers clinical characteristics and prognosis of 33 children with severe acute respiratory syndrome in guangzhou area sung jj (authors' reply). the use of corticosteroids in sars fatal aspergillosis in a patient with sars who was treated with corticosteroids real time assay of aspergillus should be used in sars patients receiving corticosteroids treatment of severe acute respiratory syndrome with lopinavir/ritonavir: a multicentre retrospective matched cohort study role of lopinavir/ritonavir in the treatment of sars: initial virological and clinical findings interferon alfacon-1 plus corticosteroids in severe acute respiratory syndrome: a preliminary study treatment of severe acute respiratory syndrome with convalescent plasma potential for antiviral treatment of severe acute respiratory syndrome interferon-b 1a and sars coronavirus replication treatment of sars with human interferons glycyrrhizin, an active component of liquorice roots, and replication of sars-associated coronavirus potent neutralization of severe acute respiratory syndrome (sars) coronavirus by a human mab to s1 protein that blocks receptor association inhibiting sars coronavirus by small interfering rna severe acute respiratory syndrome: clinical outcome and prognostic correlates outcomes and prognostic factors in 267 patients with severe acute respiratory syndrome in hong kong coronavirus-positive nasopharyngeal aspirate as predictor for severe acute respiratory syndrome mortality prognostic factors for severe acute respiratory syndrome: a clinical analysis of 165 cases radiological and pulmonary function outcome of children with sars thin-section ct in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience key: cord-104491-uu2rbtem authors: andiman, warren a. title: where have all the “aids babies” gone? a historical memoir of the pediatric aids epidemic in new haven and its eventual eradication date: 2020-09-30 journal: yale j biol med doi: nan sha: doc_id: 104491 cord_uid: uu2rbtem s.l. was one of our first hiv-positive babies. he was born at yale-new haven hospital (ynhh) in 1982. his mother was a sex worker who also injected drugs. he died at 3½ years following multiple episodes of opportunistic infection and metastatic lymphoma. in the years between 1986 and 1990, 163 hiv-positive mothers gave birth at ynhh. the mother-to-child transmission (mtct) rate was 20 percent. women represented 8 percent of all hiv cases in the us compared with 29 percent in new haven. we had a six times greater proportion of children living with hiv. the mean number of hiv-exposed babies rose annually from 26 (1985-87) to 37 (1988-90). our first team of caregivers comprised a nurse practitioner, a social worker, and me. we were, in time, joined by a growing number of colleagues. enlightened and generous hospital administrators provided us with outpatient space and the promise of continued funding to support additional staff and in 1987, an independent pediatric aids care program. we implemented the proven mtct prevention guidelines articulated in the pediatric aids clinical trials group (pactg) protocol 076 and by 1995, the mtct rate at ynhh fell to 9 percent. since 1996, the mtct rate at ynhh has been zero percent. combination antiretroviral therapy, cart, made its debut in the mid-1990s; five classes of drugs with multiple agents in each were licensed between 2003 and 2013. we designed individual treatment plans for each child and gradually entered an era when our clinic was populated with healthier long-term survivors. our program flourished, based on a multidisciplinary approach which honored interprofessional collaboration. on the morning of january 15, 1985, a jolting banner headline appeared on the front page of the journal-courier (new haven, conn., 1973 -1987 : "candida lawler dies; autopsy due." 2 the newspaper's publishers understood that their readers were already familiar with ms. lawler's story; articles revealing her identity had been published in the new haven register as early as february 1984 [1] . her story received national attention when the cbs television news magazine, 60 minutes, revealed grave concerns about ms. lawler, a 29-year-old woman living with hiv, and whether she and others who were similarly afflicted, should be quarantined. city officials believed that their isolation would stanch the spread of the deadly infection during high risk sexual liaisons with sex workers and sharing syringes during illicit drug use. shawn, ms. lawler's son, 2 was one of our first three "aids 1 babies" and the earliest to whom that label could be applied with certainty. he was born in september 1982, and spent the first 2 months of his life withdrawing from heroin and methadone-drugs that had traversed the placenta. ms. lawler had what are now known as significant risk factors for people living with hiv/aids, including drug use and engagement in sex work. rehabilitation efforts had failed. at the time of her premature death from aids-related pneumonia, the journal-courier mourned the "once vivacious and beautiful woman with long black coal hair…who now appeared aged and emaciated." she might well have been designated new haven's "patient zero," the first publicly-named and shamed aids patient in the elm city. however, a search of the medical records at yale-new haven hospital (ynhh) would have revealed names of at least a dozen additional patients living with hiv. lawler was one among many women living with hiv, but mother-to-child transmission was not yet widely recognized as a possible outcome of maternal infection. at age 2½ months, shawn 2 recovered uneventfully from a bout of bronchiolitis, but was re-admitted 5 months later, lethargic, malnourished, and covered with a disfiguring purplish rash. he had hepatosplenomegaly and marked lymphadenopathy. his discharge diagnoses included disseminated meningococcemia and failureto-thrive. months later, he developed intractable oral thrush and candida diaper dermatitis. he had suffered hair loss, seborrhea, and eczema. he was thinner. these striking clinical signs, particularly his multiple infections and skin diseases, ultimately suggested an immunologic deficit. a comprehensive diagnostic work-up was undertaken. abnormal numbers of "atypical lymphocytes" were found in his blood and he failed to respond to skin test antigens. lymphocyte subset enumeration revealed far too few cd4+t cells, an aberration shared with his mother. we had recently learned that these abnormalities were characteristic of a new disease, referred to by some as "grid," or "gay-related immunodeficiency disorder," "the gay plague." in the early 1980s, the disease spread among men who had sex with men and intravenous drug users, including women. we wondered whether shawn, a toddler, was similarly affected. did ms. lawler pass hiv to her baby during pregnancy, at the time of birth, or perhaps, post-partum through breastfeeding. ms. lawler's blood was send to max essex's lab in boston. he had developed a test for human t-cell leukemia virus iii, htlviii, the name of the virus thought to be the cause of the world's newest immunodeficiency disease. ms. lawler carried antibodies to htlviii. (hiv was the name later assigned by an international congress.) shawn's blood carried the same antibodies. initially, we were unable to determine whether his antibodies were acquired from his mother in utero or were raised actively in response to his own infection. shawn followed an insidious downhill course, common in the early years of the epidemic. there were no antiretrovirals and few drugs to treat some of his multiple infections. at 9 months of age, shawn was admitted to the hospital in respiratory distress. his chest x-ray revealed many large nodules and impressive mediastinal lymphadenopathy. cultures for the usual suspects were negative, but a lung biopsy showed evidence of lymphoid interstitial pneumonitis (lip), an entity only rarely reported in adults and almost never in children. lip was, for the first 10 years of the epidemic, the most common aids-related illness in the pediatric population, an ominous predictor of advanced hiv disease. nevertheless, it responded temporarily to steroids and during his second year of life, shawn gained some weight, was less breathless and more playful. shawn presented with weakness of his left hand and face at age 21 months. a ct scan of his head revealed a mass lesion deep in the midbrain. normal bone marrow was replaced by a b cell lymphoma. several courses of chemo-and radiotherapy stabilized his condition for almost a year, during which time he lived in a crib in an isolation room with other infants infected with hiv. the final event was an unrelenting metastatic infection with mycobacterium avium intracellulare (mac), resulting in grotesque enlargement of his regional lymph nodes, liver, and spleen. standard anti-infective agents and two experimental drugs donated by the cdc, ansamycin and clofazimine (neither of which is currently used), did nothing to change the course of the infection. shawn died at 3½ years of age. hiv-infected 3 babies began to appear regularly in the emergency room and various clinics. the obstetricians were caring for ever-increasing numbers of women testing positive for hiv. in new haven, the mean number of hiv-exposed babies rose annually from 26 to 37 (1988-90) . in fact, 20 percent of all babies born to mothers testing positive for hiv were also testing positive and in immediate need of complex and prolonged interdisciplinary care. we had moved into crisis mode. simultaneous with our need to devise an effective intervention, i had my first triennial leave, a mini-sabbatical during which i could devote myself exclusively to learning more about hiv and aids. previously, i had been involved in research studying the ways in which the epstein-barr virus displayed its pathology in both healthy and immunodeficient children. but now we were witness to the debut of a novel disease caused by a puzzling new virus, one that snared mothers and infants, in addition to men. new diseases weren't being seen that often-a rule that seems to have been broken with some frequency of late (viz. zika, west nile, mers, sars, covid-19). i reasoned that this was my chance to enter a challenging clinical arena on the ground floor, to make this growing plague the center of my academic focus moving forward. descriptions of pediatric aids came to us from the earliest epicenters as graphic retrospective reports. four of the "hot spots" were cities with large indigent populations, people who used drugs, men who had sex with men, and some of their female sex partners: new york city, newark, san francisco, and miami. the majority of babies were infected intrapartum with infectious blood and genital secretions, less so in utero. at the start of my explorations, i sought allies who could show me the ropes, introduce me to a few patients, and teach me some of the relevant clinical science. none of my usual teachers in the pediatrics department could help because they knew no more than i did, having read a few articles and listened to ominous stories on the news. so i made inquiries of colleagues in the department of internal medicine who had been caring for most of the patients. they all came up with the same name, leetha fraulino, aprn. i was surprised to learn that fraulino was a nurse practitioner who had come to ynhh from her previous position as a clinician with the greater new haven visiting nurses association. among her clients in the community were a handful of adult aids patients, some of whom had already spent some time in the hospital and some who were safely managed at home. she recognized the need for a place where the growing number of patients living with hiv could be followed in specialized settings, where they could receive both medical and much-needed psychosocial support. she imagined a place where preventive and supportive care, that included access to good nutrition and decent housing, would forestall the need for visits to the emergency department that frequently ended in moves to the icu. hospital administrators, alarmed by the increasing numbers of uninsured, critically ill patients and the uncompensated costs incurred in their care, agreed to give fraulino access to a few examining rooms in one of the ambulatory clinics for one afternoon a week. she was acquainted with many of her former clients and agreed to have me join her on her daily rounds. we reviewed x-rays, checked the results of laboratory tests, and shared insights we had gathered from the patients with the residents and nurses, including details of each one's social situation, and relationships with significant others and family. having anticipated a surge of hiv-positive babies, fraulino welcomed the chance to have a pediatrician as her ally. we were among the first troops on the front lines, joined in battle against a powerful new foe. i was hooked and my professional life was forever changed. the histories shared by most hiv-positive mothers and their female kinfolk indicated that their babies had been born into "at risk families." about half the mothers had used intravenous drugs which they often shared. some were sex workers and still others reported that they did not consume illicit drugs but had had sexual relationships with men who had. babies born addicted to drugs were immediately transferred to hospital units that were specially equipped to care for these irritable, tremulous, jittery newborns who sometimes spent weeks or months in isolettes at a distance from bright lights and disturbing sounds. they were swaddled and received round-theclock feedings on demand. among a series of impediments, we faced one insurmountable problem: we were not able to discharge hiv-exposed babies to the care of mothers still battling addiction; and experienced foster parents refused to take "aids babies" into their homes for fear of infection. there was only one alternative-the nurses, doctors, and social workers became their de facto guardians. the babies stayed in the hospital for months, sometimes for more than a year. in the early 1980s, we cared for an average of 26 hiv-exposed infants, born each year to hiv-positive mothers. we were obliged to track down a group of persons connected to each index mother, e.g. current and former sex partners, people who injected drugs, and older children. we invited them to meet with us to learn of their infection status. these meetings were long and excruciating. most of the contacts never imagined they might be carrying hiv, complicated by the fact that they might have already spread the virus to unknowing partners. they all needed to be directed to healthcare centers-destinations other than emergency rooms or the community, clinic, or hospital. physician specialists volunteered to help us in the clinics. they knew that aids was a growing epidemic, that they would soon be called upon. they wanted to be well-prepared, knowing they would become the teachers, transmitting their knowledge to the junior troops who were gathering close behind. well-concealed beneath the armor of denial and girded by their selfless efforts, there was sometimes a gnawing worry about the possibility of getting infected with hiv by accidental needlestick, a saliva or vomit-laden splash, perhaps by a urine, fecal, or blood-soaked bed, or maybe a bite or scratch by an agitated patient. (other than by sex or needle-sharing, the risk posed by other behaviors or body fluids was still unknown.) ynhh, the academic epicenter of medical care in southern connecticut, was committed to serving the entire population of new haven and the surrounding towns. its promise of excellent care for all who presented themselves was being challenged by the financial burdens incurred in caring for those who required costly emergency and prolonged intensive care. our team was called upon to educate an already receptive hospital administration. we were invited to present the facts of the epidemic, in all its alarming detail, to the hospital board of trustees. we reminded them that the uncontrolled demand for expensive care could be mitigated by creating a program devoted to longitudinal outpatient care for both adults and children, similar to those for patients with other chronic diseases. the caregivers would forge trusting relationships with their patients in a way that would ensure adherence to care and stimulate the creation of individualized care plans. we would introduce new treatments as soon as they became available. the social workers would focus their efforts on the financial, nutritional, and housing needs of the patients. timely arrangements could be made for in-home nursing care. we would strengthen the education of parents, spouses, friends, and neighbors. our first formidable ally was dr. john fenn, a surgeon and the hospital's chief of staff. he had heard of our work and already learned a bit about the clinical aspects of aids. he knew that the hospital was carrying a heavy burden and that babies and toddlers were beginning to fill isolettes in the nurseries and cribs on the wards. dr. fenn invited himself to make rounds with us a few times a week. he was deeply affected by what he saw and heard. after scrubbing, gowning, and masking, he would sometimes sit on the bed listening to patients' stories. he thanked fraulino and me and commended us for keeping abreast of every patient's status and carried these stories and descriptions of our daily routines to the hospital president, the chairmen of internal medicine, pediatrics, obstetrics and gynecology, and the vice president for nursing. in the wake of these meetings, fraulino and i "walk-in" clinics. those with substance abuse disorders were transferred to drug rehabilitation programs. women were given appointments with gynecologists who would provide access to birth control, cancer screenings, and treatment for sexually transmitted infections. we helped the homeless mothers, rejected by their families, to find housing and food stamps. by the mid-1980s, we had access to reliable antibody assays and both antigen and nucleic acid-based tests that allowed us to measure accurately the present status and arc of the epidemic in children and women of childbearing age. we compared the demographic features of hiv infection in new haven with the state of connecticut and the entire country. we learned that new haven was different! cumulative data through december 1986, revealed that women represented 8 percent of aids cases in the us compared with 29 percent in new haven. similarly, children represented 1 percent of all national cases compared with 6 percent of our local cases. new haven had more than double the proportion of infected drug users compared with the rest of the country. in 1989, the connecticut department of public health reported that one in every 33 african american women giving birth in new haven was hiv-positive, a proportion twice that of all women giving birth in the state, regardless of ethnicity. national statistics revealed that connecticut ranked fourth per capita in the incidence of aids in women and first per capita in the nation in the incidence of aids in children. intravenous drug use by the mother or her partner was the risk behavior that precipitated infection in 87 percent of the babies. in the us, the majority of patients were white (60% white, 38% black and hispanic) whereas in new haven, hiv infection was far more common in people of color (61% black, 14% hispanic, 25% white and other). we lived and worked in a small american city (population estimated 125,000) with a disproportionate onslaught of aids. we were crippled by a dearth of antiretrovirals and effective anti-infectives for many of the opportunistic infections. we needed more clinicians and financial aid to support our efforts. slowly, providers with a multiplicity of skills emerged from their quotidian workplaces and asked fraulino and myself if they could help. june holmes, msw, was one of the first to volunteer. she already knew some of the patients through her work in other parts of the hospital. like fraulino and me, she believed she would be most effective if she could serve our patients even before they were hospitalized and, again, at time of discharge. continuity of care was paramount, starting with the trust built during the first encounter, whether in interviewed on multiple occasions for articles in the new haven register, the new haven advocate, channel 8, the local tv station, and a few radio shows. i remember a few occasions when we chided reporters for having portrayed our patients in a light that may have stoked fear and derision among news consumers. it took some time to sensitize the media and other people of influence. in time, the hospital's board of trustees gave the go-ahead for the "official" creation of the "aids care program." soon the city of new haven and local charitable organizations joined us in common cause. fraulino, now the aids program coordinator and clinical supervisor and b. joyce simpson, rn, mph, once described in great detail the institutional response to the aids epidemic, using ynhh as the paradigm. they reminded us that public teaching institutions are responsible for making subspecialty expertise and stateof-the-art technology accessible to the public and local community needs and providing treatment with new antiretrovirals and anti-infectives. fraulino continued to see all the adults and children with aids-related diagnoses and introduced me to them as the medical director. she assessed their needs and assisted patients and their families to gain access to necessary support services. she participated in discharge planning in conjunction with the nursing and medical staff and developed a long-term plan for each patient. she organized the outpatient clinics and acted as the primary liaison between the inpatient and outpatient settings. in response to a growing patient population, the hospital mounted a second phase of planning. over the course of a year, we were introduced to additional subspecialists, with either adult or pediatric credentials. simpson became our pediatric research nurse and pediatric aids program coordinator. she collected, organized, and analyzed data that fulfilled the specific aims of our various grants. we also welcomed an educator with a graduate degree in public health who oversaw hiv testing and counseling services and two hiv counselors with backgrounds in nursing. the social workers guided families through the onerous process of applying for entitlements, including supplemental security income (ssi) and medicaid. finally, we developed cordial relationships with allies from pediatric and adult psychiatry, neurology, surgery, the chaplain's office, the child life program (evaluates developmental milestones and provides play therapy), nutritional services, respiratory therapy, and pharmacy. the team recognized the importance of establishing collaborative relationships with community-based agencies and organizations. we were living in the midst of a public health crisis and we saw ourselves as the catalysts for change. either individually or in pairs we educated leaders in the visiting nurses association, the methadone maintenance programs, the department of children and met with the same leaders to provide first-hand accounts in all their startling details. we made clear our need for funding and asked for official promises by the hospital and medical school to establish an aids care program, in perpetuity, dedicated to the ongoing outpatient and inpatient care of hiv-infected patients of all ages. we believed that health professionals on the front lines could be effective only with generous private and public support and the backing of two superlative academic institutions-ynhh and yale medical school. at the insistence of two successive chairs of pediatrics, doctors howard pearson and joseph warshaw, the hospital agreed to support half my salary. the pediatrics department would contribute much of the remainder to support my teaching efforts and a small percentage of my ongoing research projects. in a letter written in january 1988, dr. fenn agreed to relieve me of some of my responsibilities in the adult aids effort, by funding two new half-time physician slots. both these physicians would serve the rapidly expanding adult population and i would be allowed to spend more time with the children who were hiv-positive and their families. the hospital also assigned us pediatric clinic space for one, and then two afternoons a week. full time rn and social service positions were added to the mix. dr. fenn penned an official note to dr. warshaw that fully acknowledged the work that fraulino and i had already done. he wrote the following: "the goal in the recent expansion of the program was to allow warren andiman and leetha fraulino some relief from their extraordinary burden and to make sure that the hospital was supplying resources commensurate with the magnitude of the epidemic facing us. i am comfortable that we are doing our part and that we have now provided dr. andiman with the help he most certainly needed and the opportunity to engage in other academic activities." ynhh serves the entire city of new haven, and with the university they are the city's largest employers. as such, the hospital and medical school are obliged to foster cordial relations with the city's leaders and provide them a voice in its stated missions. to keep these leaders apprised of the magnitude and severity of the "aids problem," g. harold welch, the president of the hospital, invited me to meet three city aldermen. after the dinner meeting, he wrote: "the three aldermen who attended are all members of the ynhh board of trustees." the meeting was designed to foster "helpful communication between the city's leaders, their constituents and the hospital. the hope was that the city would take appropriate action in the future." it did, in fact, "take a village" to support our program and keep its accomplishments in the public eye. the media started to take increasing interest in our work and in the changing state of the epidemic. fraulino and i were its attention on the rapid identification and treatment of aids-defining conditions, primarily opportunistic infections, but also certain malignancies, e.g. lymphoma and sarcoma, central nervous system afflictions, including aids encephalopathy, and chronic skin conditions. in the late 1980s, treatments were limited, and cures were unattainable. the relentless pace of disability and disease continued. fifty percent of our hiv-infected children died before the age of 5 years. most of our hiv-positive children had challenging home lives, including difficulties accessing food, transportation, and decent living conditions. their lives were chaotic, lonely, and stressful. some had already lost family members to aids and others faced the possibility of a parent's incarceration or hospitalization. following years of reluctance on the part of "professional" foster parents to bring babies living with hiv into their homes, we joined with the connecticut state department of social services and rolled-out intensive educational programs that featured infection control guidelines. the state increased payments to cover the costs of fostering a fragile, chronically ill child. these inducements encouraged some foster families to care for "aids babies." for the most part, these placements proved to have positive outcomes. there were impressive gains in growth and development and increased adherence to clinic visits and prescription refills. the number of hospital "boarder babies" slowly decreased and by 1989, fell to zero. sometimes the child remained in foster care temporarily, until the mother was released from prison or committed to a drug treatment program. adequate housing was required for family reunification. remarkably, some foster families adopted the children they had nurtured so successfully. the minority of hiv-infected children who reached school age, were consigned to a space in the basement of a municipal building and were "taught" by someone with little or no requisite educational background or training. no classroom in new haven's public schools found space for a child living with hiv. the task of righting this discriminatory practice fell to the pediatric aids care program. our nurses, social workers, and i became community educators whose principal goal was to share the evidence that hiv is not spread by casual contact and that minor incidents of bleeding, spitting, urinating, and even biting, could be managed by the simple application of standard precautions: gloves, soap and water, and the prudent use of diluted household bleach, as needed. at some point, as the abysmally inadequate education of our patients was deemed untenable, i was asked to serve as families (dcf; formerly dcys, department of child and youth services), community aids support groups, like aids project new haven, churches sympathetic to our philosophy of care, connecticut hospice, and other long-term aids residency facilities. the collaborations resulted in improved care and a modest reduction in costs that would otherwise have been borne by the hospital. the pediatric aids epidemic in new haven grew at an alarming rate. along with the hiv-positive babies, who constituted 20 percent of our patient population, we decided early on to continue to follow, temporarily, the 80 percent of babies who had been exposed to the virus but were uninfected (some 130 infants by 1990). we had to guarantee their safe release either to their biological mothers or to foster parents, often close relatives. we found placements for those "new" mothers who required drug treatment and safe housing. the early development of the now independent pediatric program mirrored in many ways the genesis of the adult program. therefore, we were not surprised when a willing group of talented, motivated, and energetic health professionals with diverse skills asked if they could help. we found assignments along the entire spectrum of their training-attendings, residents, post-docs, rns, aprns, social workers, nursing, and medical students. at the beginning, few of these assignments were designated as "official" and none was accompanied by bonuses or special treatment. these were professionals who incorporated their work with hiv-positive children into elective slots or a variety of required outpatient rotations. by 1990, the hospital recognized the need to split the aids care program in two: an adult medicine arm and a pediatric arm. it was obvious that the number of patients needing urgent care was growing too rapidly to remain under the aegis of one medical director who had other clinical, research, and teaching obligations. also, my training as a general pediatrician with expertise in infectious diseases was no longer a good match for the enormous challenge posed by a population of seriously ill adults with life-threatening diseases and chronic conditions. the hospital set out to hire two experienced, academically-trained internists who had already served on the front lines of a city-wide aids epidemic similar to ours. the two saviors, gerald friedland and peter selwyn, by now leaders in the field, and both from montefiore hospital in the bronx, ny, joined the effort in 1990 to lead the adult program. in the absence of an effective antiretroviral agent, the pediatric aids care program initially focused much of 1991. the regimen was comprised of antepartum zdv, given orally 5 times daily, starting at 14 to 34 weeks post-conception and continuing through the remainder of the pregnancy. zdv was also administered to the mother intravenously during labor and delivery. the newborn received oral zdv syrup, beginning at 12 hours postpartum and continuing every 6 hours for the first 6 weeks of life. periodic hiv cultures were done to distinguish between infants infected in utero and those infected intrapartum or postpartum. based on data derived from the 364 mother-infant pairs who completed the study, zdv treatment was associated with a 68 percent reduction in mtct (8% in the treatment group vs 26% in the placebo group). the drug regimen was well-tolerated. when the study results were published, the cdc recommended that the protocol be applied universally to all hiv-positive pregnant mothers. as per the cdc recommendations, we implemented the 076 protocol and by 1995, the mtct rate at ynhh dropped to 9 percent, half the rate we witnessed previously. simpson, our pediatric research nurse made herself available, even at night, to attend the delivery of every hiv-positive mother. she guided the nurses and mothers through the steps of the pactg 076 protocol. she met with each mother and learned about her social support system and living situation. she discovered whether there was money to buy formula, diapers, and clothing. the mother received her first 2-week appointment to the pediatric hiv clinic and a prescription for her child's zdv syrup. before hospital discharge, the nursing staff judged whether the mother could provide a safe home for her baby. the side effects associated with zdv were easily managed, but the inevitable appearance of resistance convinced us that additional antiretrovirals were needed to use in combination with zdv. combination treatment met its earlier success with regimens for tuberculosis and subsequently, for other complex infections and cancer chemotherapy, diseases in which drug resistance had been a significant obstacle to cure. we participated in large multicenter clinical trials assessing the utility of combining non-nucleoside reverse transcription inhibitors (nnrtis), e.g. nevirapine, with a growing number of newer nucleoside reverse transcriptase inhibitors (nrtis) e.g. lamivudine. in time, the protease inhibitors, entry/ fusion inhibitors, and integrase inhibitors were licensed sequentially in the decade between 2003 and 2013. drug side-effects and resistance demanded that we follow the children closely and prepare to intervene with either temporary or permanent alterations in individual drug regimens. in good time, we witnessed varying declines in an expert witness in a complaint brought by the american civil liberties union against the city of new haven. based on the preponderance of the scientific evidence and the recognition that the children were being discriminated against on the basis of physical disability, a clear violation of the american disabilities act, the presiding judge found in favor of the right of hiv-positive schoolchildren to an education equal to their same age peers. as a result, our children gained admission to the city's classrooms with the promise that only the child's teacher, the school nurse, and the principal would be informed of the student's hiv status, an important concession that became operative in instances of accident or emergency. the most basic principle of public health, prevention, had not been fulfilled. we were treating disease but not preventing it. the fda approved the use of zidovudine (zdv, azt) to treat advanced hiv disease in adults. but we learned that zdv, the first in a new class of drugs, reverse transcription inhibitors, provided only short-term survival advantage and its benefits lasted only a few months. despite these disappointments, we convinced some of our pediatric pharmacists to create a syrupy concoction of zdv powder that could be fed by mouth to infants and toddlers. (once a drug is licensed, it can be used off-label if prescribers believe that the benefits outweigh the risks.) we knew of only two adverse reactions, mild anemia and liver dysfunction and monitored both by doing periodic blood tests that led to a change in dose or discontinuation of the drug, if necessary. as in adults, zdv treatment resulted in only temporary clinical improvement-weight gain, greater alertness and activity level, and fewer life-threatening infections. within a few years, the fda approved the use of zdv for children. we were buying time in the hope that more effective antiretroviral agents would arrive. clinical relief is not prevention. fifteen to 20 percent of hiv-positive mothers were still transmitting hiv to their offspring and with some exceptions, the infected babies died before the age of 5 years. nevertheless, we witnessed a veritable miracle in 1994, when the results of the nih-funded study, pactg protocol 076 was published. until that time, strategies for reducing the risk of vertical transmission of hiv were limited to the avoidance of pregnancy altogether or refraining from breastfeeding, which was the most common cause of postnatally-acquired hiv. the double-blind placebo-controlled study, pactg 076, investigating the effects of antiretroviral therapy during pregnancy, was initiated in the parties expressing vehement objections argued that administering hiv tests by way of blood draw to newborns, absent informed consent and expressly against the will of the parents involved, constitutes an illegal search, forbidden under the fourth amendment to the us constitution. the cha filed a motion for a temporary restraining order enjoining the execution and enforcement of the law a mere "scant hours" before the law was scheduled to go into effect. because the judge presiding over the us district court concluded that the plaintiff had not proved the likelihood of success in demonstrating that the statute at issue was unconstitutional, the motion for a temporary restraining order was denied and the law went into effect. despite the law, by 1999 there was only limited evidence that providing antiretroviral therapy to the newborn would lessen the severity of infection, even if there was no prior treatment of the mother during the latter part of pregnancy, labor, and delivery. we now know that early postnatal treatment does lower the viral load in the infant and limits damage to the immature immune system. we also know that the discovery and treatment of hiv infection in a previously untested mother may be lifesaving and nearly always prevents vertical infection in all subsequent births, if the mother continues her treatment. connecticut public act no. 99-2 was the powerful tool we were waiting for. we went into the community and educated physicians who cared for pregnant women. we urged them to become familiar with the new statute and to call us with questions. our nurses constructed detailed protocols for the labor and delivery floors. the mothers were given postpartum appointments to the high risk obstetrics clinic and their infants made visits to the pediatric hiv clinic at 2 weeks of age, while still receiving oral zdv. we had foreknowledge of the impressive preliminary results of the pactg 076 prevention study and had been following its guidelines, even before the study was published. this head start and our intensive educational efforts in the hospital and community resulted in a steady decline in the number of newborns testing hiv-positive. the last infant that tested hiv-positive was born at ynhh in 1996. for each of the past 24 years, we have screened and treated about twenty hiv-positive pregnant women, a significant decrease from earlier decades. none of the babies born to hiv-positive mothers between 1996 and late 2019 were infected. 4 nevertheless, we still care for a few hiv-positive children who have come to us from other parts of the world, mainly africa, and for a handful of adolescent men who have had sex with older hiv-positive men. viral loads and rises in cd4+ t-cell numbers to more normal levels. many of the children felt better and returned to their regular activities, including school attendance. as with adults, combination therapy with an ever-increasing number of agents, altered forever the natural history of pediatric hiv infection, changing it from a rapidly fatal to a chronic, manageable disease, including for some who had survived beyond early childhood. despite these gains, our pre-eminent wish remained unshaken, i.e. to eradicate mtct of hiv, a goal that would prevent the life-long morbidities and suffering that accompany pediatric hiv infection and its attendant limitations and stigma. the pactg 076 protocol, when practiced consistently, proved to be a lifesaver. for all mothers at risk who sought prenatal care and were not already being treated with antiretrovirals, hiv testing was offered. if the test results were positive, simple drug regimens were prescribed along with intensive counseling and admonitions to adhere closely to the instructions for drug compliance. hiv care and obstetric care were linked. when close to term, the mothers were given explicit instructions to appear early in labor, so that zdv could be administered intravenously before their baby's birth. but routine hiv screening was not yet part of obstetric care and it soon became obvious that we were missing some women at risk: those who failed to receive prenatal care and those who did receive care but whose hiv infection status was unknown or not recorded. we posed an audacious question: shouldn't hiv testing be a mandatory part of obstetric care? in the early years, hiv testing was permitted only after a counseling session and signed consent. times change. connecticut public act no. 99-2 became law on october 1, 1999 after much contentious opposition mounted by the connecticut civil liberties union foundation, the connecticut hospital association (cha), and by editorials and harsh opinion pieces in local newspapers. the first part of the law read as follows: [2] ." (2.9%) had been mildly symptomatic or asymptomatic; c). 512 (70%) were seroreverters, i.e. they permanently lost all passively-acquired maternal antibody and were uninfected; d). 12% were deceased and 9.3% were lost to follow-up. once we had optimal practices in place for preventing mtct of hiv and managing the care of children who survived without the burden of lifelong infection, we formally joined the pactg. the pactg (now impaact) is a consortium of academic pediatric institutions charged with testing the efficacy of new antiretrovirals and anti-infectives. we also tested live virus vaccines for their safety in hiv-positive children whose immune function had been restored by antiretrovirals. lastly, we participated in a detailed collaborative natural history study of hiv-infected and hiv-uninfected peers who were exposed to hiv perinatally, i.e. affected but not infected. ultimately, between the years 1994 and 2007, we enrolled scores of children in one or more clinical trials each. the results of these studies meant healthier and more productive lives for thousands of infected and affected hiv-affected children worldwide. among hiv-positive children born prior to 1996, about half, our longer-term survivors, were healthy enough to attend school free of the bane of aids-related conditions. many children were lucky to have found loving foster families who later adopted the children they had raised. the number of "active" patients in in our care fell by 50 percent in the decade ending in 2005. the 51 survivors met with our caregivers every 3 to 4 months. eighty percent ranged in age from 8 to 18 years; 16 percent were older than 18, and 4 percent were younger than 8 years. fifteen children died in the years between 1990 and 1995, half in the hospital and half at home or in hospice. there were only three deaths between 1996 and 2005. among our long-term survivors (lts), adverse medical and social issues are common. their outcomes have ranged from excellent to poor. over 50 percent have maintained undetectable viral loads and cd4+ t-cell counts in the normal range. the number of emergency visits and hospitalizations has fallen precipitously. however, non-adherence to medical regimens, unprotected sexual intercourse, stigmatization, unchecked family discord, depression, and school drop-outs have stymied the realization of the fully successful social and physical outcomes we had hoped for. many families failed to disclose the hiv diagnosis to their children for fear of precipitating untoward psychological repercussions, including long-term stigma. some hiv-positive young after a half dozen years of familiarizing myself with the protean manifestations of pediatric aids, i began participating in research studies that would answer pressing clinical questions. i re-examined the statistics extracted from older studies conducted without benefit of appropriate study design and methodologies. intending to correct these deficiencies, i set myself the task of embarking upon a prospective, longitudinal cohort study to determine the true risk of mtct of hiv, the relationship between the degree of immunodeficiency and the incidence of aids-defining illnesses and survival, and the connection between specific gestational variables and transmission risk. between 1987 and 2007, i was awarded an uninterrupted series of grants and contracts, the first few of which were designed to answer definitively the questions i had enunciated. the earliest of my grants coincided with the inauguration of two private foundations created to support basic and clinical research on hiv and aids: amfar (the american foundation for aids research) and egpaf (the elisabeth glaser pediatric aids foundation). we joined an international alliance of american and european academic centers and our collective data ultimately became the basis for what we now know about the epidemiology, pathogenesis, and natural history of pediatric aids. among the most important of our local and international collaborative findings were the following: i). among babies born to hiv-positive mothers and followed since birth at ynhh between the years 1986 and 2007, the overall risk of transmission of hiv was 9 percent (range 0-20%); ii). the risk of mtct was 20 percent for mothers who received no antiretrovirals during labor and delivery versus 4 percent for mothers who received antenatal and intrapartum antiretrovirals and whose newborns received zdv for the first 6 weeks of life (as per pactg protocol 076); iii). among ynhh mothers who received antiretroviral therapy during pregnancy, the risk of mtct was 6 percent for those whose cd4+t-cell counts were <200 cells/ul versus 0 percent for those mothers with median cd4+ t-cell counts >500/ ul; iv). a meta-analysis of more than a dozen prospective cohort studies (including ours) by the international perinatal hiv group demonstrated that elective c-section before onset of labor and before rupture of membranes, resulted in a decline in the risk of vertical transmission from 19 percent to 10 percent. when c-section was combined with antiretroviral therapy during the third trimester, the risk of mtct of hiv fell further, to 2 percent; v). among 733 hiv-exposed children enrolled in our prospective study (including those enrolled in collaborative studies during which they had received varying lengths and combinations of antiretrovirals), we recorded the range of clinical outcomes in 2007: a). 43 (5.8% had been severely or moderately symptomatic; b). 21 women and men became parents unintentionally, but all their offspring are uninfected (all the pregnant young women complied with their prenatal clinic appointments and took their medications). a minority of our lts have completed high school, college, or job-training and a few have been successfully employed. a handful have been incarcerated on drug charges or acts of violence. one patient, lost to follow-up, died by gunshot. those of us working in resource-rich countries encountered the "coming of age" of the first and largest cohort of hiv-positive children-those born between the early 1980s and the late 1990s. we confronted their need for a major health care transition. data collected by the cdc in 2007, revealed that approximately 24,000 american youth, ages 13-24 years, were living with hiv/aids. this was a 25 percent increase from 2004, attributed to high-risk adolescent sexual behavior and increasing survival of children infected perinatally. developmentally appropriate youth ought to receive care in adult healthcare practices sometime in their early 20s. but there are numerous everyday tasks that represent major hurdles for many teens, in particular adherence to their medical regimens. ultimately, with diligent guidance, most of them progress to a point where they can be safely transitioned. during the years 2006-07, under the guidance of sostena romano aprn, mba, our longest-serving nurse practitioner, and anne murphy, msw, we transitioned 30 patients, ages 15 to 26 years of age, to adult practices: 13 to yale's adult nathan smith clinic, nine to other hospital-based clinics in connecticut, and eight to private practices close to the patients' homes. we have continued this practice as our patients enter late adolescence and young adulthood. the eradication of mtct of hiv in new haven was made possible by the confluence of six nourishing streams: 1). the creation of effective antiretrovirals, anti-infectives, and sensitive diagnostic tests; 2). the flood of grants and contracts from federal, state, local, and private funding agencies; 3). wise and generous support from yale-new haven hospital and the department of pediatrics; 4). the passage in 1999 of connecticut public act no. 99-2; 5). the creation of an effective multidisciplinary approach to care which honors respectful interprofessional collaboration; 6). the spontaneous and enthusiastic union in common cause of doctors, nurses, social workers, students, administrators, and volunteers to serve patients in need, their families and friends, in new haven county and beyond. rethinking complicity in the surveillance of sex workers: policing and prostitution in america's model city special session reduction of maternal-infant transmission of hiv-1 with zidovudine treatment european collaborative study: children born to women with hiv-1 infection: natural history, and rate of transmission a prospective cohort study of children born to hiv-infected mothers. trend in the risk of vertical transmission, mortality, and aids-indicator diseases public act no. 99-2 duration of ruptured membranes and vertical transmission of hiv-1: a meta-analysis from 15 prospective cohort studies update on successes and challenges regarding mother-to-child transmission of hiv-1 transition from pediatric to adult healthcare services for young adults with chronic illnesses: special case of human immunodeficiency virus infection 1 this term was widely used in medical circles and the media in the 1980s to refer to hiv-exposed infants who faced lengthy hospitalizations to ease them through withdrawal from opioids and/or cocaine as they awaited foster home assignments. the term has disappeared now that the rates of vertical transmission of hiv have fallen to negligible numbers. 2 names of patients have been changed to protect their identity. 3 all babies born to hiv-infected mothers are "hiv-positive" until 7 to 15 months of age because they all acquire hiv antibodies transplacentally. but only a fraction are "hiv-infected." eighty percent are "exposed" to hiv and are temporarily hiv-positive, but remain "uninfected." 4 unfortunately, in late 2019, an hiv-positive baby was born at ynhh after a gap of 23 years. the teenage mother received prenatal care at a clinic unaffiliated with ynhh. she was non-compliant with the antiretroviral regimen that was prescribed for her. she was surprised to learn that her newborn baby was infected. the baby received antiretrovirals soon after birth, the mother's regimen was re-started, and the baby's biological father appeared for testing and treatment. all three have been adherent to their various regimens and, as of last report, all are doing well. since the start of 2020 we have followed nine hiv-exposed babies, but no mother-to-child transmissions of hiv have occurred. key: cord-016542-gia859eu authors: argent, a. c.; kissoon, n. “tex” title: the needs of children in natural or manmade disasters date: 2009-11-19 journal: intensive and critical care medicine doi: 10.1007/978-88-470-1436-7_32 sha: doc_id: 16542 cord_uid: gia859eu disasters have been described as “events of sufficient scale, asset depletion, or numbers of victims to overwhelm medical resources” [1] or as “a serious disruption of the functioning of a community or a society causing widespread human, material, economic or environmental losses that exceed the ability of the affected community or society to cope using its own resources” [2]. importantly, that definition goes on to state: “a disaster is a function of the risk process. it results from the combination of hazards, conditions of vulnerability and insufficient capacity or measures to reduce the potential negative consequences of risk.” disasters have been described as "events of sufficient scale, asset depletion, or numbers of victims to overwhelm medical resources" [1] or as "a serious disruption of the functioning of a community or a society causing widespread human, material, economic or environmental losses that exceed the ability of the affected community or society to cope using its own resources" [2] . importantly, that definition goes on to state: "a disaster is a function of the risk process. it results from the combination of hazards, conditions of vulnerability and insufficient capacity or measures to reduce the potential negative consequences of risk." disasters may occur in many forms (table 32 .1); in different settings and levels of complexity; with variable amounts of warning and very different consequences for people. the number of natural disasters have increased in the last century and doubled within the last 30 years, with many more people affected. during the same period the proportion of disasters that are manmade has increased from 16.5% in the 1970s to 42% in the 1990s (not including "complex emergencies") [3] . as the density of population across the world increases (related both to population growth and increasing urbanization) it is likely that the frequency and impact of disasters will continue to increase. climate change (with associated extreme weather conditions; change in regional weather and associated change in distribution of pathogens and vectors) is likely to exacerbate this trend. increasingly, plans are being put in place to cope with disasters [2] . sadly, many of the most devastating disasters in recent times have taken place in poorer countries not only are children caught up in general disasters, but they are sometimes specifically involved in tragedies that affected institutions where large numbers of children were grouped together in schools (as happened in china in 2008). some mass casualty events have even been specifically targeted at children. as reviewed by rassin et al. [6] there have been a number of attacks that have specifically targeted schools and nursery schools across the world, resulting in significant mortality and morbidity among children at those institutions. although many disaster plans make provision for the care of vulnerable sectors of the population, relatively few plans are specifically geared for the needs of children and particularly for children across the full range of developmental stages. unless those needs are specifically addressed in the planning for and organization of disaster relief, it is inevitable that children will suffer unnecessary harm. some of the reasons for the vulnerability of children in disasters are outlined in table 32 .2. children are vulnerable at virtually all phases of disasters, and it is important to highlight both their specific needs and the skills and resources that are required to fulfill those needs at various stages [7] . in the acute phase of physical disasters such as tsunamis and earthquakes, children have been particularly vulnerable to death and injury. with limited strength and capacity to flee and/or find shelter from danger, mortality has been particularly high in young children in these events [8] . in a survey of mortality in the aceh province of indonesia following the 2005 tsunami, the age-specific mortality in the age-group of children 0-9 years was 19.8%, which was higher than all other age groups other than >70-year-olds. [8] . in eastern coastal areas of sri lanka, the mortality among children (during the same tsunami) aged less than 5 years was 31.8%, vs. 23.7% for children aged 5-9 years and 7.4% for adults aged 20-29 years (p<0.001) [9] . at a red cross field hospital in kashmir in 2005, 145 (45.9%) of patients attending for emergency care were under the age of 14 [10] . in the 1985 gas explosion disaster in bhopal children were particularly affected by gas inhalation, aggravated by the tendency of many toxic gases to gravitate to ground level. children were also less able to use clothes or other methods to limit their inhalation of toxic gases [11] . the pattern of injury suffered by children in physical disasters has also differed from those of adults. commenting on their experience in pakistan, laverick et al. [12] noted that children often presented with scalp injuries and le fort facial fractures as if they had been looking up when the masonry began to fall on them, instead of protecting themselves by lying face down (as the adults did). the care of children in acute disasters may be considerably complicated when parents have been killed or injured, or when children have been separated from their parents. apart from the psychological trauma of separation, consent for procedures and ongoing care is also problematic [13] . even after the acute phase of a disaster children remain more at risk for injury in the "damaged environment." following hurricane katrina one team commented on the higher rates of injury for children saying: "the most common injuries in children were lacerations and punctures caused by debris. several children were bitten by animals, many of which were stray pets with unknown rabies status. many of the wounds were infected, likely because clean water and antibacterial ointment were unavailable. cellulitis resulting from insect bites was also particularly common in children." [14] . children may be particularly susceptible to injury from disasters involving chemical or radioactive contamination (table 32. 2). while rapid decontamination is ideal, decontamination of small children may pose challenges both to healthcare workers and to the children [15] and there are no existing tested and proven guidelines [16] . children are also at higher risk of hypothermia (table 32. 2) and small children will require considerable assistance in the process of decontamination. as children may be accompanied by their parents, pediatric facilities should ideally have the resources to decontaminate accompanying parents [15] . guidelines for chemical and radioactive material decontamination are available in many centers [17, 18] ; although some protocols have been suggested [16] , there is a need for altered protocols that reflect pediatric needs [19] . unfortunately, few centers are adequately equipped to decontaminate large groups of children in terms of facilities; appropriate washing environments to ensure adequate privacy, temperature control for small children, and adequate numbers of trained and equipped staff to decontaminate large numbers of small children [17] . this is particularly true in the developing world where industrial chemical accidents are probably more likely. in general, children and especially infants are more susceptible to infection than adults. thus children may be afflicted as part of a widespread infective process (possible influenza epidemic) but they may also develop infections in the environment that develops subsequent to a disaster. ligon [20] and watson have recently reviewed the infectious diseases that may be problematic following disasters. often the environment following a disaster may be highly contaminated (toxins, sewerage, dead bodies, etc.) with limited access to clean water and frequent overcrowding of survivors. in that context infections spread via hands are particularly frequent unless particular attention is paid to hand washing. many survivors may have wounds, which again have risk of being contaminated, either during the incident or soon thereafter. meticulous cleaning of wounds and debridement of devitalized and infected tissue is particularly important. this may be difficult to achieve with limited pediatric services. respiratory infections may be more frequent in conditions following disasters. children may be particularly vulnerable to viral infections, and also to infections such as tuberculosis when crowding exists. every effort must be made to ensure that patients with known tuberculosis receive ongoing therapy, and if possible are kept away from children. gastrointestinal infections (including hepatitis) are a particular problem in the context of limited water and sewerage disposal facilities. children are particularly vulnerable to gastro-enteritis and attention must be paid to prevention and arranging oral rehydration facilities to resuscitate and treat children. outbreaks of infections such as cholera [21] , rotavirus [22, 23] , tetanus [24, 25] , malaria [26] [27] [28] , typhoid [29] , shigellosis, novovirus, leptospirosis, and others have all been documented following natural disasters [20] . other pathogens that have been involved in outbreaks of disease include viruses including dengue [27] , and malaria [26] [27] [28] . rabies may be a problem in some parts of the world. it is important to note that when people are grouped together into a high population density, a much higher level of immunization is required to prevent the development of epidemics [30] . following the 2007 tsunami, spread of measles was documented in a population that had had 1 dose of vaccine following the tsunami [31] . clearly early involvement of public health experts in the management of disaster aftermath is vitally important. a manual has been produced by the who to provide guidance for health care workers who may be called on to provide care for children in humanitarian disasters. one of the issues that is often seen as a priority following disasters is the disposal of dead bodies. in fact these are not a major infection hazard, and it is likely that it would be better to try and allow families every opportunity to mourn and bury their dead, rather than to use mass graves [20] . urgent and rapid epidemiological assessments by teams with pediatric expertise may be useful in disease prevention and treatment following disasters. there is limited data available on the effect of respiratory viral pandemics on children [32] . however, experience from the sars outbreak in toronto in 2004 highlighted the need for extensive planning for infection control measures before the outbreak of an epidemic and management of epidemics involving children using a family-based approach [33] . children are particularly vulnerable to adverse effects of isolation, and this may be a significant problem in management of other outbreaks [33] . in the case of sars there seemed to be limited spread of the infection from children to adults [34] but that may not be so in other pandemics. schools and institutions for children may be also an important source of cross-infection in communities exposed to pandemic infections. following disasters there may be an increased exposure to many toxins. carbon monoxide poisoning has occurred on many occasions because of the means used to provide power and warmth [35] . following hurricane katrina in the usa >200,000 people were rendered homeless and many were given temporary accommodation in mobile homes. many of those homes were found to be contaminated with formaldehyde, and the management of related symptoms was complicated by the fact that the healthcare structure surrounding those in displaced housing was inadequate [36] . in many settings the post-disaster environment may have many dangers such as unstable masonry, exposed power and gas lines, contaminated soils and environments, etc. children with their capacity for exploration and limited knowledge of potential dangers may be at substantial risk, particularly if adult supervision is compromised (as will usually be the case post disaster). there is relatively little data available that compares the rates of mortality following conflicts with baseline data. guha-sapir and gijsbert reviewed data from 37 available datasets, and showed that there were considerable differences in mortality rates for children following conflicts [37] . in most cases the rates or death increased sharply, although there were other situations in which mortality rates dropped, largely related to populations who were displaced as a result of the conflicts. in mass displacements (usually as a consequence of war or civil strife) children under 5 have often had the highest mortality. in these situations "complex emergencies" defined as "relatively acute situations affecting large civilian populations, usually involving a combination of war or civil strife, food shortages and population displacement, resulting in significant excess mortality" [38] may occur. essentially these disasters combine many of the individual components of issues described above. during the 1980s the mortality of children aged 1-14 in areas such as northern ethiopia (in 1985) and southern sudan (1988) were extremely high [38] . in the 1990s crude death rates in refugees in some parts of africa were 5-25 times higher than the crude death rates of the nondisplaced (with rates of up to 80 times described [39] , and the rates were highest in children under 5 years of age [40] ) leading toole et al. to state that "children under the age of 5 regularly bear the brunt of the death toll associated with complex emergencies" [41] . likewise in 1996, 54% of all the deaths among refugees from rwanda and burundi who fled to eastern zaire were under the age of 5 [42] . a recent publication [43, 44] has reviewed much of the data. one of the problems quoted is that much data is in "gray data" which is not readily available to the greater audience. children are also affected by the patterns of adult mortality. in many settings such as the indonesia tsunami three women died for each man [45] , and as most child care is provided by women, their children would have been adversely affected. fortunately much has been learned about the management of complex disasters [46] , and there is hope that future events will provide better care for children. the issues of relief work in complex disasters are extremely complex and challenging to all concerned. there is a large body of evidence documenting the psychological problems of children who have been exposed to disaster situations [47] [48] [49] which has been recently reviewed [50] [51] [52] [53] . specific and focused care is required from the time of the disaster onwards to ameliorate the long-term psychological problems for children affected by disasters [54] . particular attention needs to be focused on the family [55] . penrose et al. have recently highlighted the importance of involving children in the process of planning for disaster, as well in the recovery phases following events. children can offer useful knowledge and information, and it is deeply in their interests to feel part of the processes that surround actual and potential disasters. "the children consulted have clear ideas about the information, knowledge, and skills that they and their communities need to be better prepared for future disasters; all we have to do is listen." [56] . the same authors have raised many issues surrounding children's rights in disasters and ways in which they can be addressed [56] . it is also important to bear in mind that dealing with child victims of disasters or mass casualty events can be extremely demanding and emotionally devastating for healthcare and rescue workers [57, 58] . specific steps must be taken to provide support to these people both during and after the events. in any disaster, there may be direct (e.g., injury related to the earthquake), or indirect consequences (e.g., subsequent epidemics) which may be physical or psychosocial in nature [30] (or both). not only are children more likely to suffer injury in physical disasters, the facil-ities available for their care are likely to be more limited than would be the case for adults. the special needs of injured children include: a range of equipment sizes; personnel with special expertise in dealing with children; increased nursing requirements post intervention, etc. particular insight into the needs of children and the availability of specific pediatric resources will be required by any team coordinating both planning for and response to any disaster in which significant numbers of children are involved [1, 14, 59, 60] . even within well-resourced areas children's services in general have extremely limited capacity to deal with a surge and there are limited alternatives [61] . recent reviews considered options for surge management for adult patients, but did not include children [62] [63] [64] . although up to 45% of the population in developing countries may be pediatric, there are usually far fewer pediatric services than there are adult services. in the usa about 37% of hospitals have both emergency departments and separate hospital wards with specific facilities for children, while 10% do not admit children [65, 66] . only 5.5% had all the equipment recommended for emergency care for children, while about 50% had 85% of the equipment suggested in the 2001 guidelines [67] . thus capacity to accommodate a large surge of pediatric patients may be limited, even in countries as well-resourced as the usa. kanter and moran [68] have reviewed the adequacy of pediatric beds in new york city for mass casualty purposes. the current bed numbers could accommodate approximately 250 children per 1 million population assuming no surge in current demand and that all beds were available. even if there were reductions in the intensity of care to allow 20% more admissions, it would not be possible to accommodate more than 300 children per million population and more than 63 children per million in picu even if the standards of care were altered to allow quadruple the usual throughput. disaster situations involving 500 children per million and with 30% requiring intensive care would almost always exceed picu capacity. to further compound the situation 55% of all picu capacity was located in four hospitals. the who has recently launched a campaign aimed at ensuring that health facilities remain safe during and after disasters "health facilities are only truly safe from disasters when they are accessible and functioning, at maximum capacity, immediately after a hazard strikes." (http://www.who.int/hac/techguidance/safehospitals/en/ index.html ) (safe hospitals document) and this is of particular relevance to pediatric facilities. there is frequently a "surge" in demand for injury care shortly after the onset of the disaster. at a teaching hospital in sri lanka for instance there was a 50% increase in admissions on the day of the 2005 tsunami (with 89% injuries). the rate of admissions for injury remained high for the next week [69] . however, the ongoing need for additional care may be high, particularly in the setting of burns (or other injuries requiring multiple surgical procedures or investigations) or children requiring intensive care. thus the surge may be sustained, and is always superimposed on existing service requirements. fortunately, there are few reports of disasters overwhelming the capacity of children's hospitals. however during the hurricane katrina disaster in new orleans, it was necessary to move significant numbers of critically ill children and neonates away from affected areas to other hospitals. patients requiring transportation included those affected directly by the hurricane, but also those who were in neonatal and pediatric wards and critical care areas at the time of the event [70] . this may be much more challenging or even impossible in other contexts. it may be necessary to provide accommodation for parents and caretakers at the health facility where the children are being cared for. this may be particularly important when the surrounding environment is significantly affected by the disaster [71] . following the early phase of a disaster shortage of healthcare facilities for children (if facilities have been damaged during the acute incident) may remain a significant problem for a long period unless there is focused rehabilitation of pediatric services. even provision of accommodation and health care for relatively well (but displaced) children may be a problem [59] . the equipment required for the care of children (and particularly small children and infants) is different from that required for adults. in a study of preparedness of pediatric disaster assistance teams, mace and bern reviewed the availability of pediatric resources. pediatric equipment was missing as follows: airway, 16%; intravenous lines, 37%; cervical collars, 38%; medicines, 38%; broselow tape, 46%; backboards, 62%. pediatric patients were included in disaster drills 63% of the time [72] . a review of emergency departments in the usa again showed significant deficiencies in availability of pediatric equipment [65] . recommendations to ensure the availability of pediatric equipment include appropriate stocking of pediatric emergency departments [67] , some stockpiling in pediatric practice offices [1] , or the collection of pediatric equipment in international relief equipment collections. the majority of injuries requiring early treatment will be orthopedic and hence there is a major need for orthopedic devices which may be short supply, particularly in the countries affected [73] . this was also expressed by laverick et al. with regard to their experience following the pakistani earthquake [12] . experience has shown that there may be many spinal cord injuries [74, 75] after earthquakes. children have different food and pharmaceutical requirements than adults. for small infants, breast feeding remains the most important source of nutrition and should be a. c. argent, n."tex" kissoon 404 encouraged if at all possible. a study from pondicherry following the 2005 tsunami showed that breastfed infants who were given formula feeds had a threefold higher incidence of diarrhea [76] . noji et al. [77] have commented on the challenges of providing appropriate medication, immunization resources, and nutritional support for children following disasters. extensive recommendations relating to these problems are available from the who [2] . pediatric expertise is required at many stages of the management of a disaster involving significant numbers of children [60, 78] . this ranges from triage systems at the point of first contact with the injured children, through emergency and intensive care services, to ongoing medical and rehabilitative care. expertise is also required at different levels in the organization of relief efforts from management of the casualties, management of evacuation and transportation, allocation of resources, and management of overall relief organization. the number of people within rescue and health care services who are trained and experienced in the care of children may be extremely limited. mace and bern [72] reviewed the capacity of disaster medical assistance teams in the usa to respond to pediatric emergencies and found major deficiencies in the training curriculum with pediatric topics such as trauma, disaster triage, burns, pain management, and mental health missing in 33, 36, 42, 42 , and 45% of the time, respectively. data from emergency units in israel showed that the staff were significantly less well prepared to cope with pediatric mass casualties than with adults [6] . there is a need to involve pediatric trained personnel in the disaster management process [14] at all levels. however, those personnel are unlikely to be of significant assistance unless they have gone through some training [79] as the skills required in an acute disaster are very different to normal pediatric practice. management of large groups of patients requires multiple levels and command structures. at the point of first patient contact, and subsequently in the hospital services, there is a need for triage systems. triage systems used for adults may overestimate the severity of injury of children [60] , and not be a problem when small numbers of children are involved. however, when large numbers of children are affected it is important that pediatric triage systems be used. a number of systems have been devised including the pediatric triage tape, simple triage and rapid treatment (start), jumpstart, and careflight systems. jumpstart was the only system available to 32% of disaster medical assistance teams in the usa [72] . however, when application of the systems was assessed in a south african emergency department the careflight system had the highest specificity and sensitivity with similar performance from the pediatric triage tape. the jumpstart and start systems did not function well [80] . weiner et al. [14] , within the context of disaster relief for hurricane katrina, have clearly described the role that pediatric subspecialty teams within the national disaster management system can play. the teams that were deployed had been trained specifically prior to that event, and had prepared for the possibility of a hurricane affecting new orleans. a recent survey of emergency medical systems in the usa showed that although 72.9% of agencies had mass casualty plans in place, only 13.3% reported having specific pediatric mass casualty plans [81] . planning for the needs of children is complicated by a number of factors. children are not a homogeneous group of people. children of different ages and developmental stages have very different needs (infant foods vs. adult nutrition), capacity to respond to situations (adolescents vs. infants), vulnerability to infection (infants vs. adolescents), needs for parental care, etc. there are also children with specific needs, and in the richer parts of the world there is an ever-growing population of children who are dependant on technology such as home ventilators. some disasters are completely unexpected, and detailed planning to deal with such events is impossible. however, many disasters are predictable and with increasing access to geological, meteorological, and other data across the world, many regions will have increased capacity to consider and plan for disasters. while it may be impossible to make adequate plans for events such as the kashmir earthquake in 2005 in which some 86,000 people were killed and 80,000 injured [82, 83] , there are many other disasters for which appropriate planning can and should be made. in many cases children are included under the category of "vulnerable people," and specific plans are not made to deal with the needs of children. improving pediatric emergency care needs should be at the forefront of every disaster planner's agenda [19] . appropriate disaster planning should include: measures to reduce the injury during possible disasters, organization of emergency and pre-hospital services to deal with emergencies, plans for utilization of health services and utilities such as hospitals and intensive care units, and contingency plans to provide accommodation and resources to support both the rescue efforts and the ongoing needs of displaced people in the 2008 sichuan earthquake, which is reported to have killed some 90,000 people, the chinese government has reported that 5,335 children died when school buildings collapsed on them (http://www.timesonline.co.uk/tol/news/world/asia/arti-cle6239476.ece accessed 2nd june 2009). appropriate building standards for institu-a. c. argent, n."tex" kissoon 406 tions in areas at risk for seismic events could reduce death toll, even though it could be argued that the devastation was related to the force of that particular earthquake. in 2007 rassin et al. [6] found that in israel, despite well-developed plans for mass casualty events, there were "no epidemiologic data concerning children affected by mces in israel and no unique recommendations to enable the ministry of health to prepare for coping with such pediatric casualties." shirm et al. [81] have completed a recent survey of emergency departments across the usa showing that about 50% have not met with schools or child care agencies to discuss the care of children in the event of a mass casualty. the role of adults who are in charge of children such as teachers, nurses, and caregivers should be defined. particular responsibilities of organizations that care for large groups of children whose needs will differ depending on the age group and the particular characteristics of the children at that institution -e.g., special schools and hospitals -should beaddressed. in addition, plans should be developed to deal with children whose caregivers are missing. a crucial part of pediatric planning for disasters is comprehensive involvement of the communities that may be affected [84] . disaster planning can take place at many different levels within the community, both national and international. to some extent the level of planning is also affected by the relative size of the likely disaster. planning of disaster management processes and structures should incorporate schools and educational facilities. incorporation of pediatric health services in planning may include the utilization of both public and private resources and the designation of some adult hospitals as alternative centers for pediatric care. planning is constrained by the resources available, and if health care resources are already inadequate or are functioning at the limits of capacity, then it may not be possible to plan for large disasters in any meaningful way. it is in this scenario that the international community may have a role in developing resources with which to assist in the amelioration of disasters across the world. with regard to organization of responses to emergencies, a common theme is that there needs to be centralized control centers that monitor and keep processes in action. a deep concern is that the people and systems that are put in this position are fully competent to deal with children's issues. these concerns arise from the recognition of the following: 1. it is often relatively easy to get resources (often the wrong ones) in the short term, but much more difficult over a longer period of time. 2. the need to get the correct resources, and not what the people in other countries want to give. 3. the need to work out how to deal with "excess resources" and make sure that these are not actually sources of development of ongoing crime and corruption. olness et al. [85] have described their experience of establishing and running training courses for health professionals in management of children's needs in disasters and emergencies. the training course is based on the extensive experience of faculty who have worked in emergencies across the world on many occasions. some of the topics to be covered in the course include: definition and overview of disasters; the international humanitarian disaster response system; rapid epidemiological assessment; triage; malnutrition; renal emergencies for children in disasters; water, shelter, and sanitation; logistics and resource management; personal preparedness; infectious diseases and immunization; and the psychosocial issues for children who suffer disasters. however there is considerable evidence of major deficiencies in the training programs for staff who may be required to care for pediatric mass casualties [72] . the aap (all the websites related to disasters) the who (website-based materials), and other organizations have put significant emphasis on involvement of families in preparation for disasters [1] . a number of authors have considered the principles of resource allocation in the context of mass disasters [86] [87] [88] . one of the underlying problems from a critical care perspective is that many intensive care systems are currently operating at 98% of capacity [88] . there is also data suggesting that the capacity to upscale intensive care facilities for adults (even with a gradual onset disaster) would be maximum at 30%. it is likely that the potential to increase pediatric intensive care beds to cope with mass casualties may be substantially less that that. essentially it is likely that in most countries of the world there would be limited capacity within the health systems to deal with a significant surge in demand for acute services for children. in most developing countries there is simply no capacity at present to deal with the current demand, and in both situations we will have to work out how to provide the best possible care to the affected children. while some general principles appear to be recognized for the triage of adult patients [86, [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] , there is very little published material on the allocation of scarce resources for children in the context of mass casualties or disasters [80, 98] . the tenets of the accountability for reasonableness [99] [100] [101] [102] may be useful in working through this process. as it is simply not tenable for clinicians involved in disaster care to make these decisions on their own, there is an urgent need for communities across the world to consider and discuss the possible approaches to allocation of scarce clinical resources in disasters in their region. this may be relatively straightforward within countries, but becomes extremely problematic in the context of disasters in countries where foreign healthcare workers are brought in as part of the response to the emergency. the long-term consequences of disasters may affect every level of society; however, there is a specific need to address the health care needs of people who have either been displaced or severely affected by the disaster. in many cases healthcare services will be curtailed in the disaster and these need to be rebuilt and redeveloped in a configuration that is appropriate to the new context. in addition, development of those services must take into the account the health consequences of the disaster which may operate over a range of time scales. particular attention may need to be paid to the ongoing development of mental health services. in the bhopal gas tragedy in 1985, it was estimated that the death toll 1 week after the event was approximately 2,500, by the end of 1989 the mortality was estimated to be 3,598, and by the end of 1994 the numbers were approximately 6,000. by 2001 it was estimated that disaster-related deaths may have been between 15,000 and 20,000 [11] . thus the systems required for health effects may need long-term commitment. in summary, planning must address the unique needs of children (immediate and long-term) the context of the likely disaster, and the resources available. planning should involve clinicians, health planners, the public, and children. protocols and processes should be devised a priori and should be transparent, taking into consideration the ethical principles of fairness and equitable care. pediatric disaster preparedness: best planning for the worstcase scenario risk reduction and emergency preparedness: who sixyear strategy for the health sector and community capacity development. world health organization mass casualty management systems. strategies and guidelines for building health sector capacity. world health organization global assessment of national health sector preparedness and response. world health organization critical concepts for children in disasters identified by handson professionals: summary of issues demanding solutions before the next one emergency department staff preparedness for mass casualty events involving children abc of conflict and disaster. the special needs of children and women tsunami mortality in aceh province who died as a result of the tsunami? risk factors of mortality among internally displaced persons in sri lanka: a retrospective cohort analysis characterisation of patients treated at the red cross field hospital in kashmir during the first three weeks of operation the union carbide disaster in bhopal: a review of health effects asian earthquake: report from the first volunteer british hospital team in pakistan overcoming legal obstacles involving the voluntary care of children who are separated from their legal guardians during a disaster fema's organized response with a pediatric subspecialty team: the national disaster medical system response: a pediatric perspective a mass casualty incident involving children and chemical decontamination disaster preparedness: hospital decontamination and the pediatric patient-guidelines for hospitals and emergency planners decontamination of multiple casualties who are chemically contaminated: a challenge for acute hospitals health care facility-based decontamination of victims exposed to chemical, biological, and radiological materials principles of disaster planning for the pediatric population infectious diseases that pose specific challenges after natural disasters: a review cholera in disasters: do vaccines prompt new hopes? the post-tsunami outbreak of diarrhoeal diseases in car nicobar island, india, was caused by human group a rotavirus g2 strains outbreak of rotaviral diarrhoea in a relief camp for tsunami victims at car nicobar island, india a tsunami related tetanus epidemic in aceh, indonesia outbreak of tetanus cases following the tsunami in aceh province selective ambulatory management of plasmodium falciparum malaria in paediatric refugees malaria and dengue infection after tsunami in southern thailand deficiencies in disaster funding: malaria epidemics are predicted in tsunami regions from el nino conditions disasters in health. typhoid epidemic in jamaica public health in crisis affected populations. a practical guide for decision makers. humanitarian practice network at the overseas development institute measles transmission following the tsunami in a population with a high one-dose vaccination coverage pandemic influenza planning for children and youth: who's looking out for our kids? pediatric epidemic crisis: lessons for policy and practice development severe acute respiratory syndrome in children carbon monoxide poisonings after two major hurricanes-alabama and texas building integrated mental health and medical programs for vulnerable populations post-disaster: connecting children and families to a medical home conflict-related mortality: an analysis of 37 datasets prevention of excess mortality in refugee and displaced populations in developing countries the public health aspects of complex emergencies and refugee situations refugees and displaced persons. war, hunger, and public health mass population displacement. a global public health challenge health situation of refugees in eastern zaire child health in complex emergencies caring for children amidst chaos: guidelines to maintain health among the most vulnerable: women and children in global disasters lessons learned from complex emergencies over past decade psychological symptoms of turkish children and adolescents after the 1999 earthquake: exposure, gender, location, and time duration the psychosocial consequences for children of mass violence, terrorism and disasters caring for children and adolescents in the aftermath of natural disasters american academy of pediatrics committee on psychosocial aspects of child and family health, task force on terrorism. psychosocial implications of disaster or terrorism on children: a guide for the pediatrician psychological impact of disasters on children: review of assessment and interventions post-disaster victimization: how survivors of disasters can continue to suffer after the event is over research with children exposed to disasters recommendations to reduce psychological harm from traumatic events among children and adolescents family context and young children's responses to earthquake children's rights in emergencies and disasters reactions and needs of tristate-area pediatricians after the events of september 11th: implications for children's mental health services a critical concern: pediatrician self-care after disasters caring for evacuated children housed in the astrodome: creation and implementation of a mobile pediatric emergency response team: regionalized caring for displaced children after a disaster delphi study into planning for care of children in major incidents creating a regional pediatric medical disaster preparedness network: imperative and issues definitive care for the critically ill during a disaster: medical resources for surge capacity: from a task force for mass critical care summit meeting definitive care for the critically ill during a disaster: a framework for optimizing critical care surge capacity: from a task force for mass critical care summit meeting augmentation of hospital critical care capacity after bioterrorist attacks or epidemics: recommendations of the working group on emergency mass critical care availability of pediatric services and equipment in emergency departments: united states, 2002-03 factors associated with ability to treat pediatric emergencies in us hospitals committee on pediatric emergency medicine and american college of emergency physicians, and pediatric committee (2001) care of children in the emergency department: guidelines for preparedness pediatric hospital and intensive care unit capacity in regional disasters: expanding capacity by altering standards of care the impact of the tsunami on hospitalizations at the tertiary care hospital in the southern province of sri lanka getting kids from the big easy hospitals to our place (not easy): preparing, improvising, and caring for children during mass transport after a disaster american academy of pediatrics committee on medical liability, task force on terrorism (2006) the pediatrician and disaster preparedness needs assessment: are disaster medical assistance teams up for the challenge of a pediatric disaster? treating natural disaster victims is dealing with shortages: an orthopaedics perspective epidemiology of spinal cord injuries in the 2005 pakistan earthquake spinal cord injury management and rehabilitation: highlights and shortcomings from the 2005 earthquake in pakistan feeding of infants and young children in tsunami affected villages in pondicherry the historical development of public health responses to disaster planning for major incidents involving children by implementing a delphi study training needs of pediatricians facing the environmental health and bioterrorism consequences of september 11th comparison of paediatric major incident primary triage tools prehospital preparedness for pediatric masscasualty events profile of injuries arising from the 2005 kashmir earthquake: the first 72 h earthquake injuries and the use of ketamine for surgical procedures: the kashmir experience children and megadisasters: lessons learned in the new millennium training of health care professionals on the special needs of children in the management of disasters: experience in asia, africa, and latin america ethical triage and scarce resource allocation during public health emergencies: tenets and procedures clinical review: allocating ventilators during large-scale disasters-problems, planning, and process clinical review: mass casualty triage-pandemic influenza and critical care disaster triage systems for large-scale catastrophic events earthquakes and trauma: review of triage and injury-specific, immediate care mass-casualty triage: time for an evidencebased approach evolving need for alternative triage management in public health emergencies: a hurricane katrina case study ethical issues in resource triage triage in mass casualty incidents: challenges and controversies creating order from chaos: part i: triage, initial care, and tactical considerations in mass casualty and disaster response simple triage scoring system predicting death and the need for critical care resources for use during epidemics disaster preparedness, triage, and surge capacity for hospital definitive care areas: optimizing outcomes when demands exceed resources a procedure based alternative to the injury severity score for major incident triage of children: results of a delphi consensus process priority setting in a hospital critical care unit: qualitative case study bedside rationing by health practitioners: a case study in a ugandan hospital combining evidence and values in priority setting: testing the balance sheet method in a low-income country fairness and accountability for reasonableness. do the views of priority setting decision makers differ across health systems and levels of decision-making? federal emergency management agency website for children the youngest victims: disaster preparedness to meet children's needs tex" kissoon key: cord-267139-r8rg0iqq authors: scaggs huang, felicia a.; schlaudecker, elizabeth title: fever in the returning traveler date: 2018-03-31 journal: infectious disease clinics of north america doi: 10.1016/j.idc.2017.10.009 sha: doc_id: 267139 cord_uid: r8rg0iqq millions of children travel annually, whether they are refugees, international adoptees, visitors, or vacationers. although most young travelers do well, many develop a febrile illness during or shortly after their trips. approaching a fever in the returning traveler requires an appropriate index of suspicion to diagnose and treat in a timely manner. as many as 34% of patients with recent travel history are diagnosed with routine infections, but serious infections such as malaria, enteric fever, and dengue fever should be on the differential diagnosis due the high morbidity and mortality in children. millions of children travel annually, whether they are refugees, international adoptees, visitors, or vacationers. [1] [2] [3] [4] in 2015, the international tourism organization reported 1.2 billion overseas trips. 5, 6 although most young travelers do well, many develop febrile illnesses during or shortly after their journeys. 7 in a study of european children, 53% of all pediatric patients with travel-related infections were visiting friends and relatives (vfrs), 43.4% were tourists, and 2.4% were immigrants. 8 most illnesses are selflimited childhood infections that do not require subspecialist consultation. however, 28% of 24,920 ill american travelers sought care at travel clinics after returning home. 9 additionally, young children with fevers can present a diagnostic dilemma because they may not report symptoms and can be at risk for severe disease, such as malaria. as awareness of tropical illnesses rise in parents, such as the increase in multidrug-resistant bacteria worldwide or the emergence of epidemics with zika virus in south america, families may be more anxious about serious infections as an etiologic factor of fevers. approaching fevers in the returning traveler requires an appropriate index of suspicion to diagnose and treat the child in a timely manner. this article offers a framework on how to address these issues by discussing diseases based on geography, incubation period, and affected organ systems, as well as risk factors, diagnostic techniques, and resources. a thorough history is an important initial step when evaluating a pediatric traveler with a fever ( table 1) . discussing a detailed travel itinerary develops a timeline of exposures that can be unique to an urban or rural setting ( table 2) . many children receive vaccinations and/or antimicrobial prophylaxis, but reported adherence does not preclude an illness with a particular pathogen. up to 75% of travelers do not adhere to the recommended malaria prophylaxis. 10 many travel vaccines, including typhoid vaccine, provide only partial protection despite proper administration of these immunizations. 11 a medically complex individual may have sought care outside of the united states due to necessity or medical tourism, which can increase the risk of infection through body fluid exposures. multidrug-resistant pathogens can also be associated with health care exposure. up to half of hospitalized children in zimbabwe are colonized with extended spectrum beta lactamase producing enterobacteriaceae on admission to the hospital, 12 a problem that is increasingly seen worldwide. underlying medical conditions, such as asplenia or immunosuppression from chemotherapy, may predispose children to overwhelming infections and sepsis. refugee children from countries such as syria are susceptible to vaccine-preventable diseases such as polio due to infrastructure breakdown. 13 fever is a common and anxiety-provoking sign for parents that can be exacerbated by overseas travel. up to 34% of patients with recent travel history are diagnosed with routine infections. 3 of the 82,825 cases of infection in travelers from 1996 to 2011 reported to geosentinel, a worldwide data collection network on travel-related diseases, 4% of cases were considered to be life-threatening. 14 a study in swiss children showed that 0.45% of emergency room visits were due to travel-related morbidities with fever and gastrointestinal symptoms being the most common complaints in 63% and 50% of patients, respectively. 8 the temporality of travel to the onset of fever can offer important clues to the etiologic factors of fevers ( table 3) . because the causes and clinical outcomes associated with fevers in pediatric travelers vary from self-limited to deadly, a systems-based approach can lead to prompt diagnosis and treatment that evaluates for the most likely and serious diseases early in the illness course. according to geosentinel, 91% of patients with an acute, life-threatening illness will present with fever. 14 there are a broad range of potential tropical infections, including malaria, dengue fever, and enteric fever. the incidence of emerging infections such as zika virus and chikungunya are not yet known. in both adults and children, pneumonia, sepsis, meningococcemia, and urinary tract infections that were acquired at home or overseas should be on the differential diagnosis. the initial workup of a febrile child without a clear source will be based on the history, physical examination, and risk factors but commonly includes a complete blood count, liver function tests, creatinine, urinalysis, and blood cultures. 1, 3 malaria smears are also frequently helpful. other tests to consider include serologies for dengue fever scaggs huang & schlaudecker or other potential etiologic agents, polymerase chain reaction for zika virus or other pathogens, chest radiographs, and cultures of the urine and stool. patients with altered mental status may require head imaging and lumbar puncture. the most common and concerning causes of fever in a returning pediatric traveler are highlighted next. [50] [51] [52] fever in the returning traveler plasmodium falciparum malaria is one of the most common tropical infections. approximately 15% to 20% of all imported malaria cases are diagnosed in the pediatric population in industrialized countries each year. 3 malaria is transmitted via the nocturnal-feeding anopheles genus of mosquito. children who are vfrs are more likely to become infected with malaria than traditional tourists. 3 nonimmune children are also susceptible to severe malaria from other malaria strains such as plasmodium vivax 15 and many young patients can present with atypical symptoms such as abdominal pain and vomiting. 16 older children may present with paroxysmal fever, fatigue, myalgias, headache, abdominal pain, back pain, hepatosplenomegaly, and hemolytic anemia. additionally, severe malaria is more common in children after the first month of travel due to the incubation period of p falciparum (7-90 days), especially in those who visited sub-saharan africa. 17, 18 overall, sub-saharan africa is one of the most common geographic regions for acquisition, comprising 71.5% of cases according to a geosentinel study of travelers migrating or returning to canada from 2004 to 2014. 19 malaria should remain on the differential diagnosis for up to a year in an acutely ill, febrile child after travel to an endemic area where p vivax and p ovale strains are present. 17 interestingly, 20% of malaria cases can be acquired during trips as short as 2 weeks with less utilization of pretravel services being a contributing factor. 19 a minimum of 3 thick and thin blood smears must be performed before malaria can be excluded, preferably collected during febrile episodes. the specificity of blood smears is high but the sensitivity can be low depending on the experience of the individual interpreting the slides. 17 rapid diagnostic tests that detect specific proteins or lactate dehydrogenase are alternatives for diagnosis at medical centers with limited experience in microbiologic evaluation for malaria. 20 the result should be confirmed, however, through the state public health department. in general, a febrile child without a localizing source or splenomegaly, thrombocytopenia, or indirect hyperbilirubinemia, in addition to exposure to an endemic area, should be presumptively approached as having malaria until an alternative diagnosis can be made. 21 treatment of malaria is well-established by the centers for disease control and prevention (cdc) guidelines. children with acidosis, hypoglycemia, hyperparasitemia, end-organ dysfunction, and severe anemia meet the criteria for severe malaria and require prompt administration of parenteral medication. there is a growing body of evidence that artesunate may reduce mortality compared with quinidine and is becoming more common as first-line therapy in pediatric patients. 22, 23 artesunate must be obtained through the cdc malaria hotline (1-770-488-7788) because it is not routinely available in the united states. 24 quinidine may be initiated until the medication arrives. completion of therapy with an oral regimen for uncomplicated chloroquine-resistant p falciparum, such as atovaquone-proguanil, can be offered when the child is able to tolerate the medications and the parasite burden has decreased to less than 1%. severe disease is less common in p vivax and p ovale and infection can be treated with chloroquine or hydroxychloroquine in most areas outside of indonesia and papua new guinea. enteric fever accounts for 18% of the 3655 cases with life-threatening tropical diseases reported to geosentinel. most recorded cases were from the indian subcontinent and in vfrs. 1 infection with salmonella typhi and salmonella paratyphi are clinically indistinguishable with fever, abdominal pain, nausea, vomiting, myalgias, and arthralgias. diarrhea is greater than 2.5 times more common in infants than older children or adults, 25 although constipation can also be seen. patients can exhibit a fever in the returning traveler typhoid mask with dull features and confusion, as well as a stepladder fever progression with rising temperatures over time in untreated individuals. relative bradycardia and rose spots are also classic signs. 25 complications such as gastrointestinal bleeding are more common in young children who have been ill for 2 weeks or more. 1 transmission is fecal-oral, and humans, especially adults, may be chronic carriers. diagnosis of enteric fever is confirmed through cultures. the most sensitive sterile site is bone marrow (80%-95%). blood culture has the highest yield during the first week of illness (70%), and stool cultures are more sensitive as the duration of illness increases. 26 stool studies should be performed on all fellow travelers, and they must be monitored for signs of illness. other abnormal laboratory findings include transaminitis and a normal or decreased white blood cell count. the antimicrobial of choice for treatment varies based on the area in which the infection was acquired because multidrug resistance is increasing. empiric treatment with ceftriaxone or fluoroquinolones is typically recommended. strains in latin america and the caribbean can be susceptible to ampicillin and trimethoprimsulfamethoxazole. south and southeast asian serovars more frequently require azithromycin or cefixime. 27, 28 children with multidrug-resistant strains have more complications such as myocarditis and shock than children infected with susceptible strains but case fatality is similar (1.0% vs 1.3%, respectively). 29 relapse of infection can occur despite appropriate therapy, with the highest mortality in young children (6%). 29 dengue remains an important cause of fever in travelers returning from all tropical regions except africa. 30 the prevalence is rising, even in the united states, with 50 to 100 million global cases reported yearly and 22,000 deaths, primarily in children. 31 risk factors are dissimilar from those for malaria because transmission occurs in urban areas during the daytime due to the vector aedes aegypti, whereas malaria transmission is more common in rural areas from dusk to dawn with the anopheles species mosquito. 32 some patients may be asymptomatic, whereas others have hemorrhagic fever and shock. the illness presents as 3 distinct phases: (1) febrile phase over 3 to 7 days characterized by myalgias, headache, retroorbital pain, and rash; (2) critical phase of 24 to 48 days with plasma leakage; and (3) convalescent phase. 32 a rising hemoglobin and gallbladder wall thickening due to increased vascular permeability suggests the development of severe dengue in children. repeat infections with a different strain may lead to more severe disease. 31 serologies are most commonly used for diagnosis, although some rapid diagnostic tests are available. in cases in which infection is unclear, it may be helpful to repeat serologies 2 weeks after initial testing to monitor for an increase in titers. other common laboratory findings include leukopenia and thrombocytopenia. 33 treatment consists of hydration and avoidance of salicylate-containing products to decrease the risk for bleeding. 32 children who develop severe dengue with hemorrhage and shock may require blood products. no antivirals or vaccines are currently available. in recent years, arboviral illnesses transmitted via infected aedes aegypti mosquitos have caused epidemics of zika virus and chikungunya in south america. a european study of travelers returning from brazil in 2013 to 2016 reported that of the 29% of patients with travel-related complaints, 6% had dengue fever, 3% had chikungunya, and 3% had zika virus infection. 34 the prevalence of yellow fever, which is seen throughout low-resource settings and shares the same vector, has remained stable. 35 these infections are difficult to distinguish clinically with fever, retroorbital pain, conjunctivitis, and myalgias. knowledge on perinatal infection with zika and the neurodevelopmental sequelae of affected infants is rapidly evolving. 36 a canadian study found that 5% of travelers developed neurologic complications such as guillain-barre syndrome with zika, suggesting there is much to learn with this disease in nonperinatally acquired infections. 37 at this time, treatment is primarily supportive. additional tropical diseases associated with fevers are outlined in table 4 . vomiting and diarrhea are common complaints in returning travelers. up to 40% of children less than 2 years of age may develop diarrhea, with 15% requiring medical services. 38 fevers, nausea, and vomiting can be seen with norovirus that occurs worldwide and is frequently associated with contaminated food and water on cruise ships. 39 rotavirus, however, is one of the most frequent causes of diarrheal illnesses worldwide and is a common cause of infant mortality in low-resource settings. 5 the hepatitides present with a broad range of disease from mild abdominal pain and vomiting to fulminant liver failure, although serious complications are uncommon in pediatric travelers. 40 community-acquired clostridium difficile is uncommon in children but infection should be considered if the patient received recent antimicrobials. 41 geosentinel data reported that 2% of patients diagnosed with clostridium difficile after travel were 10 to 19 years of age. 42 there are many other causes of both febrile and nonfebrile gastrointestinal illness in children ( table 5) . in the pediatric population, common respiratory infections may be seen on return from international trips including pharyngitis, sinusitis, otitis, and pneumonia from pathogens commonly seen in the united states, such as streptococcus pneumoniae and rhinovirus. 4, 43 local epidemiology of infections can be helpful in diagnosis and management and is available through the cdc. in some tropical regions, influenza may occur throughout the year and should hence remain on the differential for patients who warrant treatment with oseltamivir. 44 mycobacterium tuberculosis is an important etiologic factor of lower respiratory tract disease worldwide and should be considered in children with risk factors or who do not recover with antimicrobials for bacterial pneumonia. 26 of note, children younger than 3 years of age are more likely to present with miliary tuberculosis or neurologic involvement than adult patients. there are also many other less common causes of febrile respiratory tract infections ( table 6) . children who present with dysuria, hematuria, and fevers may require urinalysis and culture to evaluate for urinary tract infection and/or pyelonephritis. gross hematuria with the passage of clots in an afebrile child with exposure to freshwater in africa, the middle east, china, and southeast asia should be tested for the helminth parasite from the genus schistosoma via serologies or microscopic identification of eggs in stool. 45 praziquantel is the treatment of choice and may improve anemia and nutrition in some children. 46 patients who may have early disease or a high parasite burden may require a repeat treatment. 45 children who are at risk for sexual abuse and adolescents should undergo testing for sexually transmitted infections such as chlamydia trachomatis and neisseria gonorrheae. rashes are a source of concern for parents without the context of travel and may be even more worrisome after going abroad. the differential diagnosis includes typical childhood illnesses, such as roseola or staphylococcal cellulitis, in addition to tropical infections. a study of canadian travelers from 2009 to 2012 found that cutaneous larva migrans (13%) and skin and soft tissue infections (12.2%) were some of the most common infectious dermatologic complaints among tourists. 47 in countries where vaccination rates are low, varicella zoster virus or rubella may cause disease, especially in young children who have not completed their immunization series. measles remains an important risk, with tourists comprising 44% of the 94 cases reported to geosentinel from 2000 to 2014, and 13% of patients being younger than 18 years of age, although this may represent underreporting due to the surveillance system's primarily adult focus. 48 petechiae on the extremities in an illappearing child may indicate a serious systemic process such as meningococcal or rickettsial infection. there are many other infections with primarily dermatologic manifestations that may not cause fevers ( table 7) . 49 as the numbers of children who travel abroad continues to increase, clinicians need to remain up-to-date on potential etiologic factors for febrile illnesses on families' return home. after ruling out life-threatening disorders that can be acquired locally or internationally, physicians are able to develop a focused diagnosis and management plan best suited to the patient's clinical picture. there is a growing body of resources to assist clinicians, such as the cdc (www.cdc.gov/travel/) and geosentinel (www.istm.org/geosentinel) for data on epidemiology, geography, and other risk factors. in the future, physicians will need to be prepared to deal with the global epidemic of antimicrobial drug resistance, evolving epidemics and pandemics caused by emerging pathogens, reemerging infections due to vaccine hesitancy or international conflicts, and medical tourism in both healthy and medically complex children. fever after international travel etiology and outcome of fever after a stay in the tropics imported malaria in children: a review of clinical studies evaluation of the sick child following travel to the tropics estimate of worldwide rotavirusassociated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis international tourist arrivals up 4% reach a record 1.2 billion in 2015 spectrum of disease and relation to place of exposure among 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malaria? south east asian quinine artesunate malaria trial (seaquamat) group. artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial artesunate versus quinine in the treatment of severe falciparum malaria in african children (aquamat): an open-label, randomised trial artesunate is available to treat severe malaria in the united states an appraisal of the clinical features of pediatric enteric fever: systematic review and meta-analysis of the age-stratified disease occurrence evaluation and management of illness in a child after international travel enteric (typhoid) fever in travelers azithromycin versus ceftriaxone for the treatment of uncomplicated typhoid fever in children systematic review of the global epidemiology, clinical and laboratory profile of enteric fever seasonality, annual trends, and characteristics of dengue among ill returned travelers dengue in travelers arboviral and other illnesses in travellers returning from brazil yellow fever vaccines and international travelers clinical impact of non-congenital zika virus infection in infants and children surveillance report of zika virus among canadian travellers returning from the americas incidence and clinical features of traveler's diarrhea in infants and children traveler's diarrhea: updates for pediatricians epidemiology of travel-associated and autochthonous hepatitis a in austrian children analysis of clostridium difficile associated diarrhea in pediatric patients with antibiotic-associated diarrhea clostridium difficile infection in returning travellers bordetella pertussis infections in travelers: data from the geosentinel global network update: influenza activity-united states and worldwide schistosomiasis in travellers and migrants single dose metrifonate or praziquantel treatment in kenyan children. ii. effects on growth in relation to schistosoma haematobium and hookworm egg counts dermatoses among returned canadian travellers and immigrants: surveillance report based on cantravnet data measles in the 21st century, a continuing preventable risk to travelers: data from the geosentinel global network dermatologic conditions of the ill returned traveler: an analysis from the geosentinel surveillance network b-virus and free-ranging macaques fever on return from abroad. in: acute medicine -a practical guide to the management of medical emergencies approach to fever in the returning traveler the yellow book: health information for international travel key: cord-004458-t2iynltq authors: corten, lieselotte; morrow, brenda m. title: use of airway clearance therapy in children hospitalised with acute lower respiratory tract infections in a south african paediatric hospital date: 2020-02-19 journal: s afr j physiother doi: 10.4102/sajp.v76i1.1367 sha: doc_id: 4458 cord_uid: t2iynltq background: little is known about the prescription, frequency and nature of airway clearance therapy (act) in children hospitalised with lower respiratory tract infections (lrtis). objectives: to describe the characteristics and outcomes of children hospitalised with lrtis at a tertiary paediatric hospital in south africa and to investigate the role and impact of act in these children. method: a retrospective folder review of children hospitalised with lrti between january and june 2015 was conducted, extracting data on demographic characteristics, health condition, act interventions and patient outcomes. results: a total of 1208 individual cases (median [iqr] age 7.6 (2.8–19.0) months), in 1440 hospitalisations, were included. the majority of children were hospitalised primarily for the management of bronchiolitis. comorbidities were present in 52.6% of patients during at least one of their hospitalisations. airway clearance therapy was administered in 5.9% (n = 85) of admissions, most commonly conventional (manual) act. transient oxyhaemoglobin desaturation was reported in six children, and one child developed lobar collapse an hour post-treatment. no other adverse events were reported. the median (iqr) duration of hospitalisation was 2.3 (1.5–5.0) days, and the overall mortality rate was 0.7%. children hospitalised for presumed nosocomial infections and pneumonia had the longest length of stay, were more likely to receive act and had the highest mortality rate. conclusion: airway clearance therapy was infrequently used in this population and was more commonly applied in those with nosocomial lrti and pneumonia. clinical implications: although act was generally well tolerated, safety has not been ascertained, and oxygen saturation should be carefully monitored during therapy. lower respiratory tract infections (lrtis), particularly pneumonia, are among the leading causes of mortality in children under 5 years of age worldwide (liu et al. 2015:430-440) . respiratory disease may cause increased volume and viscosity of pulmonary secretions, ciliary dyskinaesia and ineffective cough, which may impair pulmonary secretion clearance with subsequent sequelae related to airway obstruction (fink 2007 (fink :1210 (fink -1221 . physiotherapists can facilitate airway clearance using techniques that mobilise pulmonary secretions, known as airway clearance therapy (act) (morrow 2019:1-12) . these techniques can be passive techniques, performed manually by the therapist (e.g. positioning, percussions and vibrations), or active techniques requiring cooperation (e.g. the active cycle of breathing technique, autogenic drainage and positive expiratory pressure techniques) (morrow 2019:1-12) . although act may be used in the clinical management of children with lrtis, there is a lack of evidence regarding the safety and effectiveness of act in this population. in children hospitalised with pneumonia, contradicting results have been found regarding the effectiveness of act in this population (abdelbasset & elnegamy 2015:219-226; corten et al. 2018 corten, jelsma & morrow 2015:256; lukrafka, fuchs & fischer 2012:967-971; moura da silva et al. 2015 paludo et al. 2008:791-794) . in children hospitalised with bronchiolitis, however, it is agreed that act should not be routinely applied (caffrey osvald & clarke 2015:1-3; figuls et al. 2016:cd004873) . a recently published state-of-the-art review concluded that act should not be performed http://www.sajp.co.za open access routinely in children with lrti but rather treatment should be prescribed on an individualised basis following clinical assessment (morrow 2019:1-12) . there is little recent evidence available on current physiotherapy practices relating to the prescription, frequency and nature of act in children hospitalised with lrtis, or investigating the adherence to guidelines. furthermore, published data regarding adverse events associated with act in this context are also lacking. this study aimed to describe the characteristics, health condition, course and outcome of children hospitalised with lrtis at a tertiary paediatric hospital, with specific reference to the role and impact of act in these children. this was a retrospective folder review of routinely collected clinical data of children hospitalised at red cross war memorial children's hospital (rcwmch), cape town, south africa, from january 2015 to june 2015, with a clinical diagnosis of any lrti. children from birth to 18 years, admitted to any ward in rcwmch, with any community-or hospital-acquired lrti were eligible for inclusion. folders were identified using primary diagnostic codes (icd 10 codes) for a range of respiratory conditions or clinical signs of respiratory disease, and physiotherapy department records were used to identify patients who were referred for and/or received act during the study period. a standard pre-structured data extraction form, validated for content by two experts, was used to record data on demographic information, comorbid conditions, acts administered and any associated complications, and patient outcomes. no identifying information, except for folder number, was recorded during data extraction. for cases with multiple admissions during the study period, demographic data were collected for the first admission only to avoid pseudo-replication. institutional ethical approval (hrec 717/2015) was obtained from the human research ethics committee (university of cape town) for the study. the need for written informed consent was waived owing to the retrospective study design. in total, 1756 cases were initially identified, of which 399 folders were duplicates and 1357 folders were screened for eligibility ( figure 1 ). fifty-four folders were excluded as the child did not have an lrti, and 93 folders were missing. therefore, a total of 1208 patient folders were included in the descriptive folder review. of these, 1038 patients (85.9%) were hospitalised once between january and june 2015. the remaining 172 (14.2%) were hospitalised multiple times during the study period. the demographic characteristics of the included children can be found in table 1 . of the 35 hiv-infected children, 29 (82.9%) had received antiretroviral therapy prior to or at the time of admission. no information was available regarding antiretroviral therapy for the other six patients. most hospitalisations were primarily for the management of bronchiolitis (46.0%), followed by pneumonia (36.5%), unspecified acute lrti (10.0%) and other conditions (0.2%). no primary diagnosis of lrti was documented in 106 (7.4%) cases; however, the discharge diagnosis included lrti. after extensively reviewing the clinical course, these children were presumed to have developed nosocomial lrti during their hospital stay. positive sputum or blood cultures were available in 245 admissions (17.0%). table 2 presents the prevalence of associated organisms, for each diagnostic category, as identified on sputum or blood culture. one child in the category 'other' tested positive for respiratory syncytial virus (rsv) and cytomegalovirus. the majority of children presented with tachypnoea and tachycardia on admission. signs of respiratory distress were evident in 1361 hospitalisations (94.5%), with tachypnoea being the most common (81.6% of hospitalisations), followed by recessions (69.2%). other signs of distress were alar flaring (23.5%), tracheal tug (8.5%), head bobbing (4.8%), cyanosis (0.4%) and feeding problems (0.4%). the median (iqr) temperature and peripheral oxygen saturation in room air at admission were 37.0°c (36.7°c -38.0°c) and 96.0% (94.0% -98.0%), respectively. children received non-invasive and/or invasive mechanical ventilation during 258 hospitalisations (17.9%) (one-hundred and fifty children were diagnosed with pneumonia, 51 were diagnosed with bronchiolitis, 40 were diagnosed with presumed nosocomial lrti and 17 were diagnosed with unspecified lrti). continuous positive airway pressure was the most common form of ventilation (n = 234, 90.7%), followed by invasive intermittent positive pressure ventilation (n = 62, 24.0%), pressure control ventilation (n = 12, 4.7%), highfrequency oscillatory ventilation (n = 11, 4.3%), bilevel positive airway pressure (n = 11, 4.3%) and synchronised intermittent mechanical ventilation (n = 3, 1.2%). the median (iqr) duration of ventilator support was 3.0 (2.0-5.0) days. twenty-five children (2.1%) had a known history of tuberculosis (tb). the episode of tb occurred at a median (iqr) of 8.2 (6.3-45.7) months prior to the first day of admission. most children (82.1%) had not been hospitalised for a prior respiratory disease before their first admission during the study period. for those who were hospitalised previously, the most recent hospitalisations occurred at a median (iqr) of 8.9 (4.8-14.6) months prior to the index admission. of the total sample, 52.6% had one or more clinically significant comorbidity(ies) during at least one of the hospitalisations in the study period. respiratory comorbidities were most common (17.6%), followed by cardiac (16.4%) and metabolic/nutritional comorbidities (13.9%). the common chronic and acute comorbidities (present in 10 or more children) are presented in table 3 . a significant association was seen between the primary diagnostic category and the presence of at least one chronic comorbidity (yates x 2 = 170.5, p < 0.001) or acute comorbidity (yates x 2 = 55.7, p < 0.001), with the highest proportion of comorbidities seen in children admitted with pneumonia. in total, 108 cases were referred to the physiotherapy department (7.5%). airway clearance therapy was given in 85 of these cases (5.9%) (forty-seven cases were diagnosed with presumed nosocomial lrti, 22 were diagnosed with pneumonia, 14 were diagnosed with bronchiolitis and two were diagnosed with lrti), with the majority of act interventions (75.9%) started during the first week of hospitalisation. approximately, half the patients received bidaily treatment (49.4%), one received more than bidaily act (1.2%) and the remainder (47.1%) received daily act. airway clearance therapies were performed for a median (iqr) of 3.0 (1.0-6.0) days per admission. table 4 presents an overview of the act modalities performed. transient desaturation occurred in six cases (7.2%) (three desaturated to levels between 85% and 89%, and three desaturated to below 85%), during or immediately after act: during positioning in left side lying (n = 2), suctioning (n = 1), suctioning and vibrations (n = 1), percussions and vibrations (n = 1) and breathing exercises in the sitting position (n = 1). one child presented with right upper lobe collapse more than an hour after act. no other adverse events associated with act were reported. a significant association was found between the primary diagnostic category and whether or not act was given (yates χ² = 312.5, p < 0.001). airway clearance therapies were most often given for children hospitalised with presumed nosocomial infections and pneumonia, and least often in children admitted with bronchiolitis. furthermore, children with bacterial organisms were more likely to receive act (yates χ² = 158.3, p < 0.001). the most predictive factors for receiving act were chronic respiratory comorbidities, neuromuscular disorders, history of previous hospitalisation for a respiratory condition and receiving mechanical ventilation during admission (50.0% of the ventilated patients received act). this final logistic regression model provided the best prediction with a -2 log likelihood ratio of 514.1 (p < 0.001). the median (iqr) length of hospitalisation was 2. forward stepwise multiple regression analysis was performed to identify factors that influenced the duration of hospitalisation. the final model accounted for 47.1% of the variance. mechanical ventilation was the factor that influenced the length of hospital stay the most, explaining 19.4% of variance. it is also seen that children who received act stayed in hospital for longer (explaining 6.5% of the variance). furthermore, chronic comorbidities were more predictive of a longer hospital stay than acute comorbidities (table 5 ). in total, 10 children (0.7%) died while hospitalised during the study period (table 6) . a significant association between mortality rate and diagnostic category was found (yates χ 2 = 45.5, p < 0.001). mortality was higher for children who developed presumed nosocomial infections, followed by pneumonia, compared to other diagnostic categories. there was a significant association between delivery of act and mortality (yates χ² = 41.96; p < 0.001). the majority of children admitted with lrtis were younger than 1 year of age, male, hiv uninfected, and born at term, similar to other published studies (forster et al. 2004:709-716; hasan et al. 2014:e45-e52; hatipoglu et al. 2011:508-516; wolf et al. 2006 :320-324). the disproportionate gender representation may relate to differences in sex hormones, influencing immune response through lymphocyte and macrophage function (muenchhoff & goulder 2014:s120-126) . furthermore, male infants have narrower peripheral airways compared to female infants, possibly contributing to increased lrti severity (tepper et al. 1986:513-519) . in our study, the primary diagnosis of bronchiolitis and pneumonia was made in 46.0% and 36.5% of cases, respectively. this is similar to previous studies that reported between 55% and 60% of in-patients as having bronchiolitis and 35% -45% diagnosed with pneumonia (forster et al. 2004:709-716; hatipoglu et al. 2011:508-516) . more viral than bacterial organisms were isolated. this confirms the results of a previous south african study, where human rhinovirus, rsv and adenovirus were most often identified in children with lrti (white et al. 2016:443-445) . hasan et al. (2014:e45-e52) reported that rsv was the most common viral agent, followed by rhinovirus. this is the same as our results, albeit in different proportions (19.5% and 18.7%, respectively, in hasan et al.'s report compared to 44.1% and 38.0% here). a study conducted on turkish children with viral lrti also reported rsv as the main pathogen (55.6%) in children younger than 1 year of age, followed by parainfluenza, which was the most common viral isolate in older children (hatipoglu et al. 2011:508-516) . we found mycobacterium tuberculosis to be the most common bacterial organism (4.9%), followed by klebsiella pneumoniae (4.5%). another south african study reported acinetobacter baumannii as the most common bacterial organism, followed by klebsiella pneumoniae (20.6%) (ghani et al. 2012:e275-e281) . although our rate for klebsiella pneumoniae identification was similar to that reported by hasan et al. (2014:e45-e52 ) (4.1%), it was only the seventh most common bacterial agent in the latter study. our study is limited by the low rate of available sputum/blood cultures, with no standardisation of sampling, potentially overestimating the proportions of some organisms whilst missing others. ventilator support was given during 17.9% of the hospitalisations. this proportion is higher than a previous report, where the proportion of children receiving mechanical ventilation was only 1.0% (wolf et al. 2006:320-324) . however, the study did not specify whether non-invasive ventilation was included, in addition to invasive mechanical ventilation (wolf et al. 2006:320-324) . one or more comorbidities were present in just over half the cases, with respiratory problems the most common, followed by cardiovascular disorders. in a study by wang, law and stephens (1995:212-219) on canadian children hospitalised with rsv lrti, the proportion of comorbidities (22.6%) was lower than here (52.6%). this might relate to different methodologies and comorbidity selection (wang et al. 1995:212-219) . furthermore, we included any lrti, not merely rsv lrti. of the 5.9% of hospitalisations that received act, the majority of treatments were commenced in the first week of hospitalisation. however, seven children only received act more than 2 weeks after admission. vibrations and modified postural drainage (excluding the head-down position) were performed most often, with 49.4% of the children receiving bidaily treatment. airway clearance therapy is not recommended as routine management for children with bronchiolitis, by the american association for paediatrics, based on the results found in a systematic review by figuls et al. (american academy of pediatrics 2014 figuls et al. 2016:cd004873) . although the national institute for health and care excellence agrees with this recommendation for most children, they do specify that act can be given to children with bronchiolitis with relevant comorbidities, if requiring act for facilitation of mucus clearance (caffrey osvald & clarke 2015:1-3). in our study, act was given less frequently to children with bronchiolitis or unspecified lrti, which conforms to the guidelines for the management of children with bronchiolitis. in children with pneumonia, little evidence is available regarding the use of act as part of disease management. two systematic reviews have been published, including up to three randomised controlled trials on this topic, without clear recommendations for or against the use of act in these children (chaves et al. 2013:cd010277; corten et al. 2015:256) . however, small benefits have been reported in other studies (abdelbasset & elnegamy 2015:219-226; santos et al. 2009:23) , indicating the need for further research in this field. the children who were most likely to receive act were those with bacterial nosocomial infections or pneumonia and those with chronic comorbidities. therefore, it is recommended that further research be conducted on the use and safety of act in children presenting with these conditions. adverse events of act are rarely mentioned and described in the literature, which was also the case in our study. six children did, however, desaturate during act. one child presented with a lobar collapse more than one hour after act, and given the time delay, it is unlikely that this adverse event was directly related to act. owing to the observation of desaturation during act, monitoring of peripheral oxygen saturation is recommended during the performance of act. a study on the use of act in children with bronchiolitis mentioned that no adverse events occurred; however, it is unclear as to which adverse events were under consideration (postiaux et al. 2011:989-994) . as the rate of adverse events was low in our study and very little literature is available on this topic, act appears to be safe for use in children with lrti, but this requires confirmation in prospective clinical studies. chronic comorbidities were the most likely predictors for receiving act during hospitalisation. children with presumed nosocomial infections were more likely to receive act, followed by children hospitalised for pneumonia. these data, however, may have been biased because the majority of children classified as presumed nosocomial infections were included based on physiotherapy referral and not through diagnostic code search identification. in children hospitalised for pneumonia, multiple comorbidities were identified, for which act might be indicated. children with positive bacterial culture were treated more often by the physiotherapists than children with viral isolates. no previous studies have investigated the association between act and isolated organisms; therefore, confirmation of the results in a larger prospective study is recommended. children were hospitalised for a median of 2.3 days; however, children with presumed nosocomial infections were hospitalised for a significantly longer duration (14.3 days). in addition to clinical outcomes, cost prevention and high demands for hospital beds in lower-resourced countries could be contributing factors for short duration of hospital stay (argent et al. 2014:7-14) . however, three randomised controlled trials on children hospitalised with pneumonia reported a median duration of hospital stay of six to eight days (corten et al 2018 lukrafka et al. 2012:967-971; paludo et al. 2008:791-794) , which is similar to the duration of hospitalisation for pneumonia in our study. the length of hospital stay was associated with whether or not children received ventilator support; had chronic heart conditions; received act, desaturation on admission; and had cerebral palsy, genetic disorder or acute comorbidities. in a study conducted by rodriguez et al. (2014:269-276) , predictors for disease severity in children with rsv lrti, partially based on length of hospital stay, were aged younger than 6 months, born prematurely, with a pre-existing lung disease or congenital cardiac disease. our finding that receiving act was associated with increased duration of hospital stay may reflect the increased likelihood of receiving act in those who developed nosocomial infections (green et al. 2015:305-312) . however, the rct by lukrafka et al. also reported a median 2 days longer hospital stay in children who received act, compared to controls, which was not statistically significant, possibly owing to insufficient sample size (lukrafka et al. 2012:967-971) . other studies have not reported significant differences for length of stay when receiving act in children hospitalised with pneumonia (corten et al. 2018 paludo et al. 2008:791-794) . prospective studies are recommended to confirm these results and to determine causality. pneumonia is still the most common cause for mortality in children younger than 5 years of age worldwide (liu et al. 2015:430-440) . in our study, the overall mortality rate for children with an lrti was low; however, a greater proportion of children with presumed nosocomial infection (5.7%) died. the mortality rate for children with a clinical diagnosis of pneumonia was 0.6%. these mortality rates, although slightly higher, are comparable to the rates found in children younger than 5 years hospitalised with acute lrti in rural thailand, with 0.3% overall mortality rate (hasan et al. 2014:e45-e52) . all children included in our study, who died during the study period, presented with multiple comorbidities and seven of the 10 children were older than 4 years of age. the cause of death could therefore be multifactorial and not solely attributed to lrti. airway clearance therapy was associated with an increased mortality rate, which has not been previously reported. however, causality cannot be determined on the basis of this study design. considering most children admitted with pneumonia had comorbidities, this may explain the higher mortality observed in this group. this study revealed that a relatively small proportion of children with lrti received act. airway clearance therapy was mostly applied in children with presumed nosocomial infections, followed by pneumonia. given the paucity of high-level evidence, act is therefore used in clinical practice based on physicians' and physiotherapists' expert opinion. it is therefore recommended that more research regarding act in children with nosocomial infections and pneumonia be conducted. this is particularly important considering that the duration of hospitalisation was longer and the mortality rate was higher in children with nosocomial infections and pneumonia, compared to those admitted with other lrtis, especially bronchiolitis. this study also found that act, as performed at this research site, appears relatively safe to perform in children with lrti. however, the study was not designed or powered to determine safety, and further prospective, controlled clinical trials are recommended to confirm this finding. it is recommended that peripheral oxygen saturation be continuously monitored during act, in order to promptly identify desaturation and implement appropriate management. as more than half the children included in this study presented with comorbidities, research is warranted to investigate the use of act in children hospitalised with lrti and comorbidities, both chronic and acute. effect of chest physical therapy on pediatrics hospitalized with pneumonia clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis pediatric intensive care in south africa: an account of making optimum use of limited resources at the red cross war memorial children's hospital nice clinical guideline: bronchiolitis in children chest physiotherapy for pneumonia in children (review) assisted autogenic drainage in infants and young children hospitalized with uncomplicated pneumonia, a pilot study chest physiotherapy in children with acute bacterial pneumonia chest physiotherapy for acute bronchiolitis in paediatric patients between 0 and 24 months old forced expiratory technique, directed cough, and autogenic drainage prospective population-based study of viral lower respiratory tract infections in children under 3 years of age (the pri.de study) an investigation into the prevalence and outcome of patients admitted to a pediatric intensive care unit with viral respiratory tract infections in cape town quantifying the burden of hospital-acquired bloodstream infection in children in england by estimating excess length of hospital stay and mortality using a multistate analysis of linked, routinely collected data incidence and etiology of acute lower respiratory tract infections in hospitalized children younger than 5 years in rural thailand viral etiology in hospitalized children with acute lower respiratory tract infection global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis chest physiotherapy in paediatric patients hospitalised with community-acquired pneumonia: a randomised clinical trial airway clearance therapy in acute paediatric respiratory illness: a state-of-the-art review chest physiotherapy for pneumonia in children: a systematic review sex differences in pediatric infectious diseases chest physical therapy for children hospitalised with acute pneumonia: a randomised controlled trial evaluation of an alternative chest physiotherapy method in infants with respiratory syncytial virus bronchiolitis predictors of severity and mortality in children hospitalized with respiratory syncytial virus infection in a tropical region respiratory physiotherapy in children with community-acquired pneumonia physiologic growth and development of the lung during the first year of life pediatric investigators collaborative network on infections in canada (picnic) prospective study of risk factors and outcomes in patients hospitalized with respiratory syncytial viral lower respiratory tract infection acute viral bronchiolitis in south africa: viral aetiology and clinical epidemiology comparison of human metapneumovirus, respiratory syncytial virus and influenza a virus lower respiratory tract infections in hospitalized young children the authors would like to thank ms ebrahim for her assistance in collecting the data for this study. they would also like to thank the medical records office of red cross war memorial children's hospital for their assistance in retrieving folders for the study. dr corten received the margaret roper scholarship from the division of physiotherapy for her phd study at the university of cape town. the department of paediatrics and child health research award (university of cape town) provided funds for this study. data sharing is not possible as no ethical approval was obtained to share sensitive data from a vulnerable patient population. the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. the authors have declared that no competing interest exists. l.c. collected and analysed the data and wrote the initial drafts of the paper under the supervision of b.m. both authors contributed to protocol development and results interpretation. b.m. also contributed to the write-up and approved the final version of the manuscript. key: cord-022156-mm8en4os authors: isaiah, amal; pereira, kevin d.; correa, armando g. title: tracheal infections date: 2015-07-14 journal: infectious diseases in pediatric otolaryngology doi: 10.1007/978-3-319-21744-4_12 sha: doc_id: 22156 cord_uid: mm8en4os infectious processes of the trachea represent a distinct clinical entity with an evolving landscape owing to advances in airway management and vaccination practices. untreated inflammatory processes of the trachea may present in the form of acute airway obstruction, potentially resulting in significant morbidity and even mortality. therefore it is important to recognize the cardinal features of some of the common tracheal infectious processes to differentiate them from non-infectious pathology, as the latter is associated with a more indolent course. as with most other infectious processes of the airway, pathogens causing tracheal infection can be bacterial, viral or fungal in nature. viral etiology represents the most common cause of laryngotracheal infection in a child. bacterial infections of the trachea are responsible for more significant morbidity, including prolonged hospitalization, need for endotracheal intubation and even an occasional tracheostomy. the current chapter describes the clinical features and microbiology of tracheal infections at large, explores the utility of diagnostic tests, and provides an algorithm for management. a plethora of epidemics , changes in immunization practices and endotracheal intubation have resulted in a better understanding of the pathogenesis of tracheal infections. historic descriptions fi rst appeared for croup; with the name derived from anglo-saxon root kropan referring to a child with a barking cough. this was fi rst described in print as early as 1854 [ 1 ] . much deliberation ensued concerning the treatment of this condition, with o'dwyer being the fi rst physician credited with treatment of acute croup either by insertion of a modifi ed endotracheal tube [ 2 ] or a tracheostomy [ 3 ] in separate instances. the fi rst reported case of tracheitis was published in 1823 by pierre blaud [ 4 ] . an increase in incidence was observed during each infl uenza a virus pandemic-h1n1 during the great spanish fl u (1918), asian fl u caused by h2n2 (1957), hong kong fl u resulting from h3n2 (1968), and more recently the pandemic h1n1 of 2009. autopsies performed during the 2009 pandemic showed tracheal denudation, maceration, de-epithelialization and other pathologic changes consistent with tracheitis [ 5 ] . bacterial tracheal infections still maintain a low level of presence in infants and children presenting with symptoms of airway obstruction, requiring icu admission and potentially endotracheal intubation. different diagnostic terms have been used for conditions that affect the larynx and trachea. although it is useful to distinguish between supraglottic and subglottic laryngitis, this distinction is often diffi cult when the child is fi rst seen. laryngotracheitis or croup syndrome is a useful preliminary descriptive diagnosis until more defi nitive information is available [ 6 ] . " croup syndrome " also has been used to emphasize the variety of possible causes and location of laryngotracheal disease. in this chapter, "croup" is used to refer to subglottic laryngitis or laryngotracheitis, presumably viral. " epiglottitis " is an imprecise term often used in place of the better " supraglottitis " as the epiglottis may be minimally involved in some cases in which most of the swelling is in the aryepiglottic folds. preferred terms for tracheal infections are (with the usual terms in parentheses): croup, supraglottitis (epiglottitis), and suppurative tracheitis, laryngotracheitis, laryngotracheobronchitis, or laryngotracheobronchopneumonitis (bacterial tracheitis), depending on the extent of the bacterial superinfection [ 6 ] . tracheal infections have a signifi cantly lower incidence compared to infections of the upper respiratory tract, with 1-5 % of all children requiring outpatient evaluation for viral croup within the fi rst 3 years of life. croup also requires hospital admission in about 1.3-5.6 % of all children evaluated for the same in emergency settings [ 7 , 8 ] . viral croup has the highest incidence in the second year of life and is virtually non-existent in the fi rst 3 months. the incidence is slightly higher in male children (odds ratio = 1.43), and is highest in late fall and early winter [ 7 ] . a time-series analysis performed from a large number of children admitted with a principal diagnosis of croup in ontario suggested a strong component of seasonality, with a biennial mid-autumn peak and annual summer trough [ 9 ] . of interest, the overall number of hospitalizations has continued to decrease in the last 20 years, given the improvement in diagnosis and treatment. marx et al. [ 10 ] from the centers for disease control (cdc) studied the overall burden of croup and showed that the mean annual number of croup hospitalizations is about 41,000 (range, 27,000-62,000/year) in the u.s. ninety-one percent of hospitalizations occur among children <5 years of age. the authors also reported that minor peaks in croup hospitalizations occurred each year in february, and major peaks occurred in october of odd-numbered years, which coincides with peak parainfl uenza type 1 activity . supraglottitis , in contrast, has no seasonal peak. this disease, almost always caused by haemophilus infl uenzae type b and accompanied by bacteremia, has been virtually eradicated by widespread immunization during infancy. while the peak age frequency for croup is 1-3 years, supraglottitis occurs in older children, with a peak between 3 and 6 years. suppurative tracheobronchitis also tends to be a disease of preschool and school-age children [ 6 ] . the reported incidence for bacterial tracheitis in the literature is about 0.1/100,000 [ 11 ] . this estimate was based on the combined experience of four pediatric intensive care units. the incidence of tracheal infections caused by other pathogens such as fungal or mycobacterial origin is exceedingly low. over the last two decades, the availability of nebulized epinephrine as well as injectable corticosteroids have changed the landscape of serious, life-threatening tracheal infections, with the re-emergence of bacterial tracheitis. currently, bacterial tracheitis has three times the risk of respiratory failure associated with it than epiglottitis and viral croup combined [ 4 ] . acute laryngotracheitis, considered to be the most common cause for croup, is almost exclusively caused by viral organisms. both bacteria and viruses may be responsible for infections with collateral components, such as laryngotracheobronchitis, and the more general laryngotracheobronchopneumonitis. in 1958, the fi rst evidence for association between croup and two newly isolated myxoviruses, parainfl uenza virus types 1 and 2, resulted in separation of two categories of cases-mild, requiring only outpatient follow up, and severe, requiring hospitalization [ 12 ] . parainfl uenza is a rna paramyxovirus that actively replicates in respiratory epithelial cells and is comprised of four major serotypes. parainfl uenza type 3, more commonly associated with bronchiolitis or bronchopneumonia, can also produce severe croup in an endemic pattern, while type 4 is rarely seen. parainfl uenza 1 and 2, account for >65 % of all causes of croup. a large series studied 6165 instances of lower respiratory tract infections (lris) wherein approximately 75 % of all isolates were identifi ed as parainfl uenza viruses. of these, parainfl uenza type 1 accounted for about 60 %. conversely, the propensity of the various organisms to produce symptoms of croup reached 60 % for both parainfl uenza 1 and 2. for parainfl uenza type 3, the number dropped to about 30 %, whereas all the other microorganisms accounted for about 5-15 %. thus, parainfl uenza viruses were the most common cause for all age groups; whereas respiratory syncytial virus (rsv) caused croup in infants and the infl uenza viruses and m. pneumoniae were signifi cant causes of croup only in children older than 5 years of age. summertime croup may be due to enteroviruses, adenovirus, or parainfl uenza type 3. among other important viral pathogens causing tracheal infections, rsv was studied in isolates from sentinel practices in england and wales from 1975 to 1990, during which an increase in mortality, by as much as 60-80 %, was observed in comparison with parainfl uenza and infl uenza viruses [ 13 ] . prematurity is associated with an increased risk for mortality, with factors such as a decrease in gestational age, increased perinatal oxygen requirements and discharge within 3 months of the rsv season increasing the likelihood for hospitalization [ 14 ] . among the rare viral causes, measles, by virtue of immunosuppression, leads to a bacterial superinfection that results in a condition termed measles-associated bacterial tracheitis (mabt) , which carries an increased risk for need of artifi cial airway and intensive care admission [ 15 ] . bacterial tracheitis is much less common when compared to that of viral origin. previous reports have shown that the most consistent organism is s . aureus , followed by s . pneumoniae and m. catarrhalis [ 4 ] . due to the universal immunization against h. infl uenzae type b , the incidence has dropped signifi cantly. similarly, immunization against c . diphtheriae has restricted the incidence of diphtheritic tracheitis to unimmunized children only. reports of this are largely limited in modern literature, compared to the beginning of the century when tracheostomy was a routine practice to circumvent acute airway obstruction due to formation of pseudomembranes [ 16 ] . fayon et al. [ 17 ] studied independent risk factors for development of bacterial tracheitis in a large series of children admitted to the picu (n = 955), and found that the incidence of bacterial nosocomial tracheitis in that population was about 1.8 %. the pathogens isolated in this series were in agreement with other studies of bacterial tracheitis, comprising staphylococcus aureus and gram-negative bacteria, and sometimes, mixed fl ora. in this population, tracheitis was attributed to young age, with smallsized airways in which thick secretions and mucosal infl ammation being blamed for impairment of air fl ow and increased stasis. head trauma, neuromuscular blockade and mechanical ventilation were independent variables that increased the risk of infection, but the last two risk factors may be physiologically collinear, given that most patients who were administered neuromuscular blockade were intubated, and vice versa. given the evolution of design features of modern day endotracheal tubes as well as enhanced monitoring of cuff pressures, reports of laryngotracheitis induced by indwelling endotracheal tubes have largely been limited to historic data [ 18 ] . modern endotracheal tubes use materials that intrinsically inhibit or are coated with substances such as micronized silver to reduce bacterial growth by providing less scaffolding for colonization [ 19 , 20 ] . infectious agents such as mycobacterium tuberculosis and fungi have been previously reported to have caused isolated instances of tracheal infection with a picture of long-term respiratory failure requiring a tracheostomy during the course of treatment that may be prolonged [ 21 ] . chronic aspiration as well as gastroesophageal refl ux (gerd) may accelerate laryngotracheal injury facilitating the development of tracheitis in those children. despite the narrow spectrum of pathogens isolated from the plethora of tracheal infections described, these can have varied presentations, and typically differ in the outpatient vis-à-vis inpatient setting. acute viral croup manifests in the form of a viral prodrome characterized by clear rhinorrhea, lowgrade fever, sore throat (in older children) and cough [ 22 ] . this usually lasts about 12-72 h, and typically progresses to hoarseness and the pathognomonic croupy cough that has a bark-like character. rarely, febrile convulsions can occur. nighttime symptoms are usually worse which frequently prompts the parents to seek care in the emergency room. the typical course of progression goes through stridor that is inspiratory in nature but may also be associated with an expiratory component that results from unique features of the larynx in young children [ 23 ] . the infant larynx is narrowest in the subglottic segment, and infl ammation of this area results in a fi xed obstruction that leads to expiratory stridor. children presenting multiple times with acute viral croup may have a masked presentation of subglottic stenosis wherein the already narrowed subglottic larynx is further reduced in diameter due to croup-related infl ammation [ 24 ] . hoarseness results from edema of the true vocal cords, often reducing their mobility. wheezing is infrequently present. with increased severity, suprasternal and intercostal retractions may be present, and tachycardia and tachypnea are relatively common. it is important to note that reduction in the intensity of stridor in a sick-appearing child may be sign of impending respiratory failure as airfl ow may be reduced to the point where stridor may not be present. when an infectious cause is not present in croup, the clinical course is abbreviated, with the noticeable absence of the viral prodrome. this condition is frequently referred as " spasmodic croup ", although episodic croup is a more appropriate term as it is typically triggered by an allergic etiology and often recurs [ 25 ] . pediatric angioedema shares features with croup, but is often associated with facial or neck swelling that is acute in onset [ 26 ] . rarely, an undetected foreign body may masquerade as acute croup. although a viral prodrome may be absent, an unsuspecting physician may be drawn into an acute airway emergency due to commonality of symptoms [ 27 ] . the severity of viral croup may be assessed using one of the many scoring systems available. the most well-known of these, the westley croup score [ 28 ] , utilizes key clinical signs including chest retractions, stridor, cyanosis, level of consciousness and air entry to obtain a composite score that is predictive of the need for intubation. as croup is primarily a clinical diagnosis, the utility of the westley score, as with other stratifi cation systems, such as the alberta clinical practice guideline working group [ 29 ] , may be limited to use in a research scenario. for example, using the westley score , johnson et al. [ 30 ] showed that ≥ 85 % of children present with symptoms of generally mild croup, and less than 1 % were diagnosed with severe croup. peltola et al. [ 31 ] studied the clinical courses of croup caused by parainfl uenza and infl uenza viruses to highlight the differences in morbidity caused by the different viral strains in hospitalized children. in general, there were no signifi cant differences in the patterns of clinical features due to infections with the three parainfl uenza subtypes, except that parainfl uenza 3 was associated with wheezing. however, children with croup due to microbiologically-confi rmed infl uenza virus tended to be hospitalized for longer (4 days vs . 2 days for parainfl uenza). in addition, the rates of readmission were higher for infl uenza due to the relapsing course of respiratory distress during the few days following discharge. the requirements for corticosteroids as well as supplemental oxygen also tended to be higher for those caused by infl uenza virus, emphasizing its enhanced virulence. notwithstanding the generally predictable course of viral croup, it is important to differentiate it from other acute disorders of the pediatric airway. rapidity in progression to high fever, odynophagia, anxiety and relative aphonia should always alert the practitioner to supraglottitis (epiglottitis), which is a rare occurrence following introduction of universal immunization against hemophilus infl uenzae type b . posturing in the upright position and extension of the neck with drooling in an anxious-appearing child mandates the need to secure the airway in a controlled setting such as the operating room. care should be taken to not agitate the child for that may precipitate respiratory collapse. if there is history to suggest incomplete immunization, laryngeal diphtheria should be considered. this condition tends to have a slower progression, and has historically been associated with the presence of exudative membranes in the oropharynx. bacterial tracheitis typically is a secondary infection following a primary viral respiratory infection due to a cascade of events resulting from tracheal mucosal injury, impaired phagocytic function and cytopathic effects of the viral infection. this condition usually is recognized after reasonable efforts to treat viral croup have failed. children with bacterial tracheitis are acutely ill, with symptoms to suggest dehydration and organ failure in the presence of other host factors such as immunodefi ciency. often seen in an inpatient setting in children admitted to the icu with respiratory failure, bacterial tracheitis can have a variable presentation in the absence of pathognomonic clinical signs [ 32 ] . the cardinal initial signs of bacterial tracheitis include cough, stridor and a rapidly changing course of illness that progresses to respiratory failure quickly. children affected are usually older (>5 years). other symptoms on admission may include choking episodes, dyspnea, dysphagia, neck pain, dysphonia and agitation. in one study by bernstein et al. [ 33 ] , children younger than 5 years of age were twice as likely to be intubated, compared to older children. the same study compared changing fi gures for mortality-prior to the 1940s, the mortality rate for bacterial tracheitis approached 40 %, but with advances in mechanical ventilation and airway management, that fi gure has dropped to 0-20 % in more recent series. from the majority of studies, it is clear that the diagnosis of acute viral croup is chiefl y based on clinical examination and does not necessitate laboratory testing. that said, if there is suspicion for a concurrent lower respiratory tract infection, white blood cell count with differential, as well as routine postero-anterior/lateral chest and neck radiographs may be indicated. in viral croup, the white count is often at the high end of normal, and may be higher in approximately 50 % of hospitalized children [ 34 ] . administration of corticosteroids may cause leukocyte demargination, which can lead to spuriously elevated counts during the course of treatment. plain fi lm radiography often is utilized to evaluate laryngotracheal edema in croup, but has inconsistent results. the typical picture is that of narrowing of laryngeal air column in the subglottic segment, approximately for ~5-10 mm below the level of the vocal cords, resulting from mucosal edema [ 35 ] . this has been historically referred to as the steeple sign ( fig. 12.1 ), but is observed only in ~50 % of instances [ 23 ] . this, coupled with reduced sensitivity for differentiating between viral croup, epiglottitis and bacterial tracheitis undermines the usefulness of routine radiographs for diagnosis. however, some investigators such as mills et al. [ 36 ] , have reported sensitivity and specifi city of >90 % respectively. the best practice in these circumstances is to consider radiographs in those children in whom the clinical presentation is atypical and whose respiratory status is stable enough to undergo positioning prior to obtaining the fi lms [ 23 ] . alveolar gas exchange is usually not affected by viral croup, unless there is concurrent presence of laryngotracheobronchitis, asthma or pulmonary insuffi ciency [ 23 ] . thus, pulse oximetry and respiratory rate have been shown to have poor correlation with clinical status or hypoxia due to artifacts [ 37 ] . evidently, the uncompromised standard is clinical observation with pulse oximetry as a useful adjunct in instances wherein the lower airway is also affected. in cases where operative control of the airway is required, telescopic tracheobronchoscopy , aided by the ventilating bronchoscope provides the gold standard for assessment of the airway in severe croup, or when alternate pathology, such as supraglottitis, is suspected. in the ambulatory setting, children who present with recurrent croup should be examined for concurrent abnormalities. chun et al. [ 38 ] evaluated 30 children who were previously diagnosed with recurrent episodes of croup. a third of these children were found to have synchronous lesions such as subglottic stenosis, edema and cysts. in the same study, abnormal rigid endoscopic fi ndings were more likely to be seen in children under the age of 3 years, highlighting the need for a higher index of suspicion and lower threshold for performing airway endoscopy in this age group. microbiologic investigations to determine etiology are increasingly being performed due to the availability of molecular and standard virologic methods. these tests are usually not recommended for diagnosis in mild cases of croup, but may be warranted in children hospitalized and/or requiring mechanical ventilation. real-time polymerase chain reaction (rt-pcr) and viral cultures are also indicated with atypical courses of the infection, as described by reports of novel pathogenic strains for viral croup, e.g. coronavirus nl63 detected in samples isolated from europe [ 39 ] . an improved panel based on an rt-pcr assay has been developed for infl uenza a and b viruses, rsv and parainfl uenza 1, 2, 3 and 4. according to one study, the application of pcr increases the sensitivity of respiratory viral diagnosis, with results being made available within 6 h, thus increasing clinical relevance [ 40 ] . with claimed sensitivity of ~80 % and specifi city approaching 100 %, several authors have increasingly validated their cost-effectiveness [ 41 ] . as mentioned earlier, the routine use of these tests in mild croup is unsubstantiated. in children undergoing rigid endoscopy or endotracheal intubation for bacterial tracheitis and other serious airway infections, routine contact bacterial cultures and broncho-alveolar lavage with cultures may be obtained to facilitate culture-directed therapy. jones et al. [ 42 ] fi rst described laryngoscopically-directed cultures in bacterial tracheitis from copious mucopurulent material obtained from the subglottis, which grew s. aureus in most instances (fig. 12.2 ) . plain fi lm radiographs in these instances are consistent with progression of an infl ammatory response (fig. 12.3 ) . these results have been replicated from a number of other centers [ 32 , 43 , 44 ] . the treatment of tracheal infections has evolved over the course of the twentieth century, from initial descriptions of primitive endotracheal intubation to tracheostomy performed for acute airway distress secondary to laryngeal diphtheria [ 1 -3 ] . the fi rst recognized form of treatment was the use of mist (humidifi ed aerosol) produced by hot water, historically reported by keeping children close to a running tub with the door closed, leading to accumulation of mist. discovery of therapeutic benefi ts from the use of corticosteroids and racemic epinephrine have revolutionized the manner in which croup is treated, and advanced in mechanical ventilation as well as development of rigid telescopes have improved treatment of tracheal infections of bacterial origin as well. these therapeutic strategies are summarized below. croup kettles were fi rst introduced in the late nineteenth century to provide aerosolized mist to alleviate the symptoms of viral croup [ 45 ] . later, cool mist was observed to have the same degree of therapeutic benefi t as warm mist, and this avoids the risk of burns. there are at least three postulated fig. 12.2 endoscopic photographs of ( a ) early bacterial tracheitis, with increase in exudates seen in the subglottis without overt purulence, ( b ) crusting and purulence seen that progressed to ( c ) erythema, pseudomembranes and overall infl amed-appearing tracheal mucosa arrows point to anatomical changes that can be due to ongoing tracheal infl ammation mechanisms, which include (i) a soothing effect on infl amed mucosa, (ii) reduced viscosity of tracheal secretions and (iii) activation of laryngeal mechanoreceptors leading to reduction of turbulence [ 23 ] . however, humidity may also trigger bronchospasm, thus the duration of therapy should be carefully monitored. recent studies have, however, shown that the benefi ts offered by mist treatment may be overemphasized. three separate studies, that did not include untreated controls, determined that the effi cacy of aerosolized mist may not be proportional to the degree of mist saturation, for e.g. the effects of humidity at three different levels (100 %, 40 % and 33 %) remained the same [ 46 ] . in yet another study, the effect of nebulized saline was identical to mist. lastly, a recent cochrane review of data concluded that the benefi t of mist therapy remains unproven [ 47 ] . despite the various recommendations for dosages, routes and drugs for use of corticosteroids, a number of large-scale studies have exemplifi ed their therapeutic effi cacy. their mechanism of action is related to the reduction of vascular permeability, resulting in a reduction of laryngeal and tracheal mucosal infl ammation. russell et al. [ 48 ] in a cochrane collaboration reviewed 38 studies and showed that corticosteroids resulted in a rapid improvement of westley score, fewer return visits and/or readmissions, reduction of stay in the emergency room as well as the overall need for concurrent use of epinephrine. the benefi ts are not readily apparent in children with mild croup as the symptoms begin to resolve in about the same time taken for steroids to show treatment benefi t. following adoption of corticosteroids as a standard fi rst line of therapy in acute viral croup, overall hospitalization and the burden of the disease on healthcare systems worldwide began to fall. this was acknowledged following the guidelines formulated by the canadian pediatric society that encouraged the use of intravenous dexamethasone as initial treatment of croup [ 9 ] . among steroids, dexamethasone is used in a dose of 0.6 mg · kg −1 body weight given either orally or by the intramuscular route. as dexamethasone is a potent steroid with a prolonged half-life, repeat doses are often unnecessary. other investigators have shown that orally administered dexamethasone is as effi cacious as parenteral formulations. the choice of route should hence be determined based on cost and availability. yet another study failed to show differences in therapeutic benefi t between three different doses (0.15, 0.3 and 0.6 mg · kg −1 ) of dexamethasone, so a single dose (0.6 mg · kg −1 ; maximum of 8 mg) may be suffi cient in the outpatient setting [ 49 ] . a double-blind, randomized control trial compared three different treatment strategies that included placebo, nebulized budesonide and oral dexamethasone [ 50 ] . in this study, the overall rates of hospitalization were much less in the group treated with dexamethasone (23 %), compared with budesonide (38 %) and far less compared with placebo (77 %). other studies have also advocated for the use of aerosolized budesonide given the rapidity of its action and effectiveness comparable to that of nebulized epinephrine [ 51 , 52 ] . the primary benefi t offered by the use of aerosolized/nebulized epinephrine is the reduced need for intubation. early studies showed immediate clinical benefi t with use of 2.25 % racemic epinephrine, and the more recent studies demonstrated the same amount of benefi t for l-epinephrine at a ratio of 1:1000 used with 5 ml saline [ 53 ] . initial studies represented a major paradigm shift in management of children with severe croup, obviating the need for endotracheal intubation or tracheostomy [ 54 ] . the therapeutic effects of epinephrine are mediated via α-adrenergic receptors that results in constriction of capillary arterioles and reduced infl ammation. unfortunately, although the effects are almost immediate, they only last approximately 2 h, and hence the child should be watched for a reasonable period of time prior to discharge. this therapy may be suitable even in the outpatient setting if the observation period is adequate, although lack of improvement at about an hour following treatment may convert an outpatient encounter to hospitalization [ 55 ] . when conditions such as tetralogy of fallot, tachycardia or ventricular outlet obstruction co-exist, epinephrine should be used cautiously [ 23 ] . with the peak effect occurring between 30 and 60 min, the child should be carefully monitored for the rebound effect-which usually occurs 3 h after treatment. the recommended dose is thus 2.25 % (0.25 ml in 3.75 ml of saline) for children <6 months of age and 0.5 ml for infants and children >6 months. substituting isotonic with hypertonic saline (3 %) may enhance the effect by absorbing water from the submucosa. when respiratory failure is impending (cyanosis, severe retractions with lack of airfl ow, and persistent desaturations), endotracheal intubation is indicated until laryngeal edema resolves. this is usually transient and rarely evolves into a need for long-term mechanical ventilation, in children treated with steroids during the course of intubation, the time to extubation is shortened and the need for reintubation also is reduced [ 56 ] . use of the physiologic leak test, by either vocalization around the cuff, or sustained difference in inspiratory and expiratory tidal volumes serves as a guide for extubation in these children. since its description in 1979, use of helium as a carrier for oxygen (heliox) has benefi cial effects in reducing eddy currents that interact with each other and thereby reduce turbulent fl ow. heliox is routinely used in children with post-extubation stridor to reduce the risk of re-intubation. as an appreciable number of children with severe croup progress to respiratory failure needing an artifi cial airway, using heliox can reduce the work of breathing by easing the delivery of oxygen to the lower airway past the site of obstruction. assessments with croup scores and blood gas analyses reaffi rm the benefi cial role of heliox as a useful adjunct to potentially circumvent the need for endotracheal intubation [ 57 ] . a randomized trial showed benefi t comparable to racemic epinephrine in moderate to severe croup [ 58 ] . as the etiology of croup is not bacterial, there is no role for routine use of antibiotics. in the past, inappropriately prescribed antibiotics have been reported to cause superinfections, prolongation of hospital stay as well as general increase in costs [ 29 ] . however, when the diagnosis of bacterial tracheitis is strongly suspected, the management changes wherein culture-directed antibiotic therapy is the gold standard of treatment. empiric therapy with coverage that includes s. aureus , s. pyogenes , s. pneumoniae and h. infl uenzae is indicated. in an era when both hospital-acquired and communityacquired methicillin-resistant s. aureus (mrsa) are prevalent, the combination of vancomycin and a third generation cephalosporin (such as cefotaxime or ceftriaxone) is a reasonable choice until identifi cation and susceptibility of the causative organism is established. in an intubated patient, tracheal aspirates should be obtained. a very useful adjunct to anti-microbial therapy is the use of frequent pulmonary toilet and debridement of tracheal pseudomembranes under bronchoscopic guidance [ 59 ] . in the presence of other co-morbidities such as immunosuppression, mortality increases. reported complications of bacterial tracheitis include pneumomediastinum, sepsis and multi-organ failure, bronchospasm and impaired gas-exchange due to the burden of pseudomembranes with toxic shock syndrome [ 60 ] . severe croup caused by infl uenza viruses as a part of epidemics may require treatment with neuraminidase inhibitors [ 61 ] . with the increasing number of options to treat croup, an algorithm is useful to stratify the burden of the disease and dictate an appropriate protocol. this is shown in fig. 12 despite the relative commonality of laryngotracheal infections, there are no clearly defi ned guidelines by national organizations for their treatment. the clinical picture can be often frightening to the parents who bring the child to the emergency room. fortunately, the vast majority of children show signs of rapid improvement after initiation of treatment using steroids and racemic epinephrine. only a very small proportion of children require hospitalization and an even smaller proportion require intubation and mechanical ventilation. complications are rare exceedingly rare. in contrast, bacterial tracheitis may have varied presentations and often requires endotracheal intubation and debridement in the operating room. mortality is higher but early institution of culture-directed therapy is known to reduce the severity of disease and the incidence of complications. it is important for the astute clinician to recognize the symptoms of croup and maintain a high index of suspicion for conditions that masquerade as croup, such as a foreign body, supraglottitis (epiglottitis), subglottic stenosis and other anatomic abnormalities. remarks on croup and its treatment fifty cases of croup in private practice treated by intubation of the larynx, with a description of the method and of the dangers incident thereto changing epidemiology of life-threatening upper airway infections: the reemergence of bacterial tracheitis pulmonary pathologic fi ndings of fatal 2009 pandemic infl uenza a/h1n1 viral infections moffet's pediatric infectious diseases: a problem-oriented approach croup: an 11-year study in a pediatric practice lower respiratory tract illness in the fi rst two years of life: epidemiologic patterns and costs in a suburban pediatric practice croup hospitalizations in ontario: a 14-year timeseries analysis pediatric hospitalizations for croup (laryngotracheobronchitis): biennial increases associated with human parainfl uenza virus 1 epidemics bacterial tracheitis: a multicentre perspective association of type 2 hemadsorption (parainfl uenza 1) virus and asian infl uenza a virus with infections croup impact of infl uenza and respiratory syncytial virus on mortality in england and wales from rehospitalization for respiratory syncytial virus among premature infants measles-associated bacterial tracheitis bacterial tracheitis caused by corynebacterium diphtheriae nosocomial pneumonia and tracheitis in a pediatric intensive care unit: a prospective study new therapy for postintubation laryngeal edema and tracheitis in children reduced burden of bacterial airway colonization with a novel silver-coated endotracheal tube in a randomized multiple-center feasibility study biofi lm formation in endotracheal tubes. association between pneumonia and the persistence of pathogens tracheitis in pediatric patients viral croup viral croup subglottic stenosis in infants and children corticosteroid treatment of laryngotracheitis v spasmodic croup in children pediatric angioedema: ten years' experience subglottic foreign bodies in pediatric patients nebulized racemic epinephrine by ippb for the treatment of croup: a doubleblind study antibiotic prescribing for canadian preschool children: evidence of overprescribing for viral respiratory infections clinical courses of croup caused by infl uenza and parainfl uenza viruses bacterial tracheitis: a varied entity is bacterial tracheitis changing? a 14-month experience in a pediatric intensive care unit pillsbury 3rd hc. severe hospitalized croup: treatment trends and prognosis viral croup: current diagnosis and treatment the usefulness of lateral neck roentgenograms in laryngotracheobronchitis experience of pulse oximetry in children with croup utility of bronchoscopy for recurrent croup croup is associated with the novel coronavirus nl63 rapid and sensitive method using multiplex real-time pcr for diagnosis of infections by infl uenza a and infl uenza b viruses, respiratory syncytial virus, and parainfl uenza viruses 1, 2, 3, and 4 a sensitive, specifi c, and costeffective multiplex reverse transcriptase-pcr assay for the detection of seven common respiratory viruses in respiratory samples bacterial tracheitis reexamined: is there a less severe manifestation? otolaryngol head neck surg bacterial tracheitis management of the sick infant controlled delivery of high vs low humidity vs mist therapy for croup in emergency departments: a randomized controlled trial humidifi ed air inhalation for treating croup glucocorticoids for croup outpatient treatment of moderate croup with dexamethasone: intramuscular versus oral dosing a comparison of nebulized budesonide, intramuscular dexamethasone, and placebo for moderately severe croup nebulized budesonide is as effective as nebulized adrenaline in moderately severe croup nebulized budesonide for children with mild-tomoderate croup state of the evidence for standard-of-care treatments for croup: are we where we need to be? ten-year experience with ippb in the treatment of acute laryngotracheobronchitis racemic epinephrine in the treatment of laryngotracheitis: can we identify children for outpatient therapy? placebo-controlled trial of prednisolone in children intubated for croup effi cacy of helium-oxygen mixtures in the management of severe viral and post-intubation croup a randomized comparison of helium-oxygen mixture (heliox) and racemic epinephrine for the treatment of moderate to severe croup bacterial tracheitis-an old disease rediscovered bacterial tracheitis in children prevention and control of infl uenza. recommendations of the advisory committee on immunization practices (acip) clinical practice. croup key: cord-265850-v83dwt6k authors: thomas, michael s. c.; rogers, cathy title: education, the science of learning, and the covid-19 crisis date: 2020-05-25 journal: prospects (paris) doi: 10.1007/s11125-020-09468-z sha: doc_id: 265850 cord_uid: v83dwt6k in the covid-19 crisis, the science of learning has two different responsibilities: first, to offer guidance about how best to deal with the impact of the current situation, including lockdown and home-schooling; and second, to consider bigger questions about what this large-scale educational experiment might mean for the future. the first part of this viewpoint summarises advice for parents on mental health, and on becoming stand-in-teachers. the second part, taking the longer view, considers the potential negative impact of the covid-19 crisis in increasing inequality in education; but also the potential positive impact of driving innovations in technology use for educating children. alongside the many new challenges posed by the covid-19 crisis is a somewhat familiar one: how to translate scientific evidence into public policy. politicians (in the uk at least) recite the mantra "we are led by the science", but in reality politicians, not scientists, lead. science focuses on mechanisms, the how and the why, while politicians have the daunting job of turning that into the "so what do we do?". on a smaller scale, the science of learning faces the same challenge. how can a scientific understanding of teaching and learning inform the much broader canvas of education policy and educational practices? more specifically, how can the slow, cumulative knowledge built up through research translate to meet classroom teachers' immediate needs? in the current crisis, with schools closed, children at home, and parents expected to take on teaching duties, psychology and the science of learning have two different responsibilities. the first is to offer guidance about how best to deal with the current situation. the second is to consider bigger questions about what this large-scale educational experiment might mean for the future. the association for psychological sciences (apa 2020) has summarised advice on the social impact of lockdown for both children and adults, as well as considering the implications of the increased anxiety produced by the pandemic. some of the main points concerning mental health include: • loneliness can make you ill by increasing stress, which can severely impact physical and mental health. while epidemiological models are good at measuring tangibles such as infection and mortality rates, they are less able to measure social costs such as loneliness. the consequences are no less real for those suffering. • parents' own mental health is important for children's development since caregivers are children's primary emotion regulators in times of stress. parents need to look after their own mental health, for the sake of their children as well as themselves. • symptoms of anxiety and depression correlate with level of media exposure. since this pandemic saturates us with information 24 hours a day, it is recommended that adults choose only one or two times a day to watch or read news updates. parents also need to be aware of the information passed on to children, both factual and emotional, because children will learn from whatever information is around them. • changing behaviour is hard, particularly when the consequences seem quite abstract (e.g., don't scratch your nose because that'll protect your grandpa). gaining knowledge about how things work can help. for younger children, rule-based information such as "wash your hands" is much less effective without explaining why and how it works (reducing illness transmission, staying healthy). similarly, for those who have become stand-in-teachers overnight, the science of learning can provide some general pointers: • remember that learning can be slow and difficult; maintaining motivation and minimising frustration is key. • make learning meaningful to the child: what do they want to learn about? for younger children, follow their lead. for older children, who are following stricter learning roadmaps, try to relate topics in subjects they don't like to topics in subjects they do, e.g., relate testing for chlorine gas in chemistry to a history lesson on the use of chlorine as a weapon in the first world war. • promote autonomy by giving children choice and flexibility. try encouraging them to create their own timetables, including breaks and snack times. • give frequent, positive verbal feedback; it acts as a powerful reward which can promote better learning. • most important of all, physical exercise, a good diet, and sufficient sleep are the cornerstones of any effective learning. we all hope that covid-19's negative impact on education will be short-lived. but the reality is that many countries in the world are now participants in the biggest unplanned experiment that education has ever seen. what are some of the possible outcomes? on the downside, the requirement for children to continue their studies at home may exacerbate differences in educational progress caused by inequalities. children from homes with fewer resources and less opportunity for parental support risk falling behind, widening pre-existing gaps. worse still, some children may feel unsafe in their homes. children of well-off parents often live in bigger houses, have their own bedrooms, support from two parents rather than one, and better access to technology, books, and other learning resources, not to mention basics such as food. at least in school, pupils share the same spaces, lessons, teachers, and resources, which levels opportunities to some extent. moreover, studying at home will affect some age groups more than others. teenagers, whose emotional development propels them to move away from parents and carers and towards friends and peers, are likely to be more adversely affected. on the potential upside, the new forced reliance on technology in education may accelerate some changes that had already begun. might the pandemic cause educators to think harder about the current models of educational provision, learning faster about which uses of technology are successful and which are not? granted, the initial versions of education at home often look quite like the traditional teacher-led classroom, with teachers setting work to be completed at home, supplemented by some websites or online tutoring for narrow skills such as spelling or arithmetic. but perhaps there are also initial glimpses of what a technology-led revolution in education might look like: teachers serving as curators for virtual learning environments, which children can explore together with classmates to solve problems. in these environments, children can self-regulate their learning, switching to video tutorials or guidance from teachers when they need to learn new skills to proceed. think minecraft, roblox, and youtube. of course, this kind of revolution is some way off. perhaps more importantly, returning to our opening theme of the role of policymakers, policy is not the only driver of these innovations. instead, progress is driven by the cultural and commercial technology ecosystem. this crisis has made it apparent that school-provided it systems for computerbased learning are becoming redundant. they are too expensive, too cumbersome, and too quickly out of date. perhaps we need instead to move to personal devices integrated into schools. just as we turn on airplane mode when we get on a plane, perhaps we will turn on education mode when we enter school. this suggests the policy solutions needed to reshape education through technology are not prescriptive, but regulatory. policy needs to incentivise commercial developers to move into education. the role of policymakers, by contrast, should be to understand and mitigate the possible risks of technology use in children, as documented by research. as a starting point, these risks include screen time addiction and intolerance of boredom, displacement of other activities (e.g., homework, play), social media bullying, unreliable information, sleep disruption, violent or otherwise age-inappropriate content, and data protection issues. the wholehearted engagement of teenagers with computer games demonstrates that such games can, in principle, be powerful tools for affecting behaviour. deliberate attempts to create games that deliver learning-to gamify education-have so far been relatively poor because their focus has been on content and not game mechanics. such mechanics, triggering engagement and curiosity in children, are understood much better by wellresourced commercial game developers. this is where government incentivisation may be effective, to encourage commercial developers to produce engaging and powerful educational games and learning environments. one can hope that, despite the many dark sides of the current pandemic, there might also be a sliver of silver lining for education. human behavior in the time of covid-19: learning from psychological science educational neuroscience: development across the lifespan publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations his work focuses on translational research and the dialogue between educators, psychologists, and neuroscientists. he has just edited a new book on this topic united kingdom) is completing her doctoral studies in educational neuroscience, investigating the relationship between the development of cognitive control skills and creativity in children. previously, she spent twenty years working as a producer, presenter, and creative director in the tv industry key: cord-268426-sz9ftmxr authors: maalla m’jid, najat title: hidden scars: the impact of violence and the covid-19 pandemic on children’s mental health date: 2020-09-10 journal: child adolesc psychiatry ment health doi: 10.1186/s13034-020-00340-8 sha: doc_id: 268426 cord_uid: sz9ftmxr more than 1 billion children are exposed to violence every year. the devastating immediate and long-term impact of violence on the mental health of children is well established. despite commitments made by the international community to end violence against children and support their mental health, there has been a serious lack of investment and capacity to provide quality, rights-based, culturally appropriate mental health care globally. the arrival of the covid-19 pandemic has magnified these challenges. this article outlines how the risk of children experiencing violence has increased and how the pandemic has weakened the capacity of child protection and mental health services to respond. the article argues for child protection, mental health and other core services to be prioritized during and after the pandemic. a failure to do so will undermine the international community’s ability to achieve the sustainable development goals by 2030 and to fulfil its obligations under the un convention on the rights of the child. adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article' s creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article' s creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. the creative commons public domain dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. we are in quarantine, and we can't go out. the situation is very bad. people are experiencing anguish and desperation at home. (natalia, age 16, peru). [1] the un convention on the rights of the child guarantees the right of every child to freedom from violence and to the highest attainable standard of mental health. similarly, the 2030 agenda for sustainable development pledges to end all forms of violence and to promote mental health and well-being. yet more than 1 billion children-half of all children in the world-are exposed to violence every year [2] . they face violence in many forms and in many places, whether they are online or offline. a child can be the target of violence, can witness it directly, or be otherwise exposed to it. the devastating immediate and long-term impact of violence on the mental health of children is well established. these consequences include depression, post-traumatic stress disorder, borderline personality disorder, anxiety, substance use disorders, sleep and child and adolescent psychiatry and mental health eating disorders, and suicide. exposure to childhood violence can increase a wide range of adult psychopathologies, including disorders that affect mood, anxiety levels and behaviour [3] . despite commitments made by the international community, there has been a serious lack of investment and capacity to provide quality, rights-based, culturally appropriate mental health care globally, even though mental health is consistently identified by children themselves as a major concern [4] . far too few children with mental health problems receive the right support at the right time. the arrival of the covid-19 pandemic has magnified these challenges. while the data we have so far are only indicative, the mitigation measures taken in response to covid-19 have heightened the risk of children experiencing or being exposed to violence at home due to school closures, confinement measures, and added family stress related to job loss, isolation, and anxieties over health and finances [5] . the world health organization has also reported that children with disabilities, children in crowded settings and those who live and work on the streets are particularly vulnerable to violence and abuse [6] . the widespread use of online platforms to mitigate the impact of school closures on children's education has exacerbated the problem of violence against children online, with children spending a greater proportion of unsupervised time on the internet. in addition to the impact of the violence experienced by children during the pandemic, the stress and uncertainty associated with the outbreak potentially has significant negative effects on children's mental wellbeing. in consultations undertaken directly with children, they have expressed that they feel more unsafe, insecure, scared, lonely and isolated [1] . child abuse is less likely to be detected during the covid-19 crisis, as child protection agencies have had to reduce monitoring to avoid spreading the virus, and teachers are less able to detect signs of ill treatment with schools closed. the disruption of protective services can have a particularly high toll on children who are already in a vulnerable situation, such as those living in humanitarian settings. moreover, the increase in people in need of mental health or psychosocial support during the pandemic has been compounded by the interruption to health services in many countries. care systems have been affected by mental health staff being infected with the virus and the closing of face-to-face services. in many countries, community services have been unable to meet [6] . the result has been that many children with existing mental health conditions have not been able to receive the necessary care and support. the pandemic will also have a negative impact in the longer term. the economic crisis will roll back development gains in tackling poverty and will increase children's vulnerability to violence. the world bank has estimated that up to 100 million more people may be forced into extreme poverty [7] . the international labour organization and unicef report that a one percentage point rise in poverty leads to at least a 0.7 per cent increase in child labour in certain countries, which will reverse the progress on decreasing child labour for the first time in twenty years [8] . poverty is also a driver of child trafficking, sexual exploitation and recruitment of children into criminal gangs, as well as into armed groups and forces. equally, poverty increases the risk of child marriage: the united nations population fund projects that an additional 13 million child marriages may take place over the next 10 years [9] . the united nations issued a joint agenda for action on child protection and covid-19 to highlight the steps states need to take to ensure that children's protection from violence is prioritized in the response to the pandemic [10] . it was guided by the call of the un secretary-general to ensure that what began as a health crisis does not evolve into a broader child-rights crisis. action on mental health is a crucial component of this agenda for action. it called for practical support to be provided to parents and caregivers, including how to talk about the pandemic with children, how to manage their own mental health and the mental health of their children, and tools to help support their children's learning. it further urged states to ensure the continuity of childcentred services as a core element of the response to covid-19, including mental health and child protection services. there have been important steps taken by states to achieve this: such initiatives should be evaluated and those found to be effective should be emulated and scaled up. as the international community looks ahead to building back better after the covid-19 pandemic, there is an opportunity for governments worldwide to reassess priorities. mental health and child protection services must be recognized as life-saving and essential services-along with other health services, social protection and education-as part of an intersectoral and child rights-based response. advancing human development and reducing inequalities, especially for children, calls for a major investment. this includes actions targeting the drivers of violence against children. it should also encompass the modernization and scaling up of mental health services as an [11] . in a forthcoming report on the harmful impact of violence on the mental health of children, i will highlight a range of cost-effective, evidence-based interventions that can be promoted to achieve this. it is essential that children be part of the solution in the immediate and recovery phase of this pandemic. even during this challenging time, children's resilience, activism, and sense of solidarity are remarkable. with the use of digital technology, children around the world are providing peer-to-peer support to help ease the stress they experience, taking their activism online to share safety information among their peers and volunteering to provide support to other children in need. the financial impact of the pandemic will undoubtedly affect the resources at states' disposal to mitigate its effects. however, even where resources are constrained, there is always a choice. the cost to children and to society of not strengthening mental health and child protection systems in the recovery phase is simply too high to ignore. we are at a crucial turning point in the lives of the generation of children who will be most affected by covid-19. we must do all that we can to ensure they do not become the main victims of the pandemic, but instead build a better world where their rights are promoted and protected, and where no child is left behind. if we fail to do so, the promises made to children through the convention on the rights of the child and the 2030 agenda will not be kept. children's voices in times of covid-19: continued child activism in the face of personal challenges global prevalence of past-year violence against children: a systematic review and minimum estimates the enduring impact of violence against children amsterdam: child helpline international policy brief: covid-19 and the need for action on mental health substantial investment needed to avert mental health crisis. who projected poverty impacts of covid-19 international labour organization and united nations children's fund. covid-19 and child labour: a time of crisis, a time to act. ilo and unicef impact of the covid-19 pandemic on family planning and ending gender-based violence, female genital mutilation and child marriage united nations inter-agency working group on violence against children. agenda for action. 2020 annual report to the un human rights council publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. the author read and approved the final manuscript. not applicable. not applicable. not applicable. not applicable. the author has no competing interests.received: 31 august 2020 accepted: 4 september 2020 key: cord-014608-g3p19coe authors: nan title: pneumococcal colonization and carriage date: 2014-12-01 journal: pneumonia (nathan) doi: 10.1007/bf03399438 sha: doc_id: 14608 cord_uid: g3p19coe nan homologous recombination is one of the main evolutionary forces affecting streptococcus pneumoniae. the highly recombinogenic nature of this species allows introduction of genetic material with selective advantages in carriage, the state that is a prerequisite for the development of pneumococcal invasive diseases. to study the impact of recombination on the evolution of a carriage pneumococcal population, whole genome sequencing was used to characterize 3,085 pneumococcal carriage isolates from a 2.4 km 2 thai refugee camp collected over a 3-year period. this high sampling density allowed us to characterized genetic exchanges in the pneumococcal population at a high resolution. recombination 'hotspots' showed remarkable consistency between lineages, some of which were associated with drug resistance. temporal trends in recombination at these sites reflected changes in antibiotic consumption, suggesting recombination facilitates adaptation to changing selection pressures. the highest frequencies of receipt and donation of dna fragments exchanged through homologous recombination were observed in non-encapsulated lineages, implying a potential role in diversification and adaptation of the overall population played by these non-vaccine target lineages. these findings expand our understanding of pneumococcal population in carriage and help inform the design of future intervention strategies. d. bogaert 1 1 the netherlands individuals differ markedly in their susceptibility to and clinical presentation of respiratory infections, despite that most young children and many adults are colonized with potential bacterial pathogens like streptococcus pneumoniae. the reasons for these individual differences are not yet fully understood, but clearly multifactorial. besides pathogen-related (virulence)-factors, host-related factors like immune-status and genetic background and environmental factors, a possible fourth factor might be of relevance, i.e. the commensal community of bacteria 'hosting' these potential pathogens. the collective genomes of these commensal inhabitants are referred to as the human microbiome. this microbiome contains highly complexity communities of bacteria, which differ between individuals and even more between niches. the human microbiome in general has shown crucial for an appropriate development of our immune system and our mucosal barriers, and for prevention of pathogen adherence and expansion. we studied the development and composition of microbiota of the upper respiratory tract in different age-groups and in relation to environmental and disease characteristics. we observed highly complex and nichespecific communities of bacteria. even within the upper respiratory tract, the microbiota composition differs depending on the exact anatomical location. furthermore, the composition of respiratory microbiota varies with host and environmental factors like age, season, infant feeding, and viral presence. moreover, our data suggest a correlation between the presence and abundance of specific bacteria and stability of microbiota, as well as susceptibility to respiratory infections. finally, clear evidence has been found for patterns of bacterial interactions within the respiratory microbiota, with a central role played by streptococci. no conflict of interest pneumonia 2014 volume 3 isppd-9 / pneumonia 2014 mar 9-13;3: oral poster abstracts although cohort studies have indicated associations between streptococcus pneumoniae and other microbes in the nasopharynx, they do not allow statements on causality. here a unique experimental human pneumococcal carriage model is used to study whether the nasopharyngeal microbiome is perturbed by pneumococcal exposure and whether a specific composition determines subsequent establishment of pneumococcal carriage. healthy adult volunteers were assessed for pneumococcal carriage by culture of nasal wash samples (nws). those without naturally acquired pneumococcal carriage received an experimental intranasal pneumococcal challenge with serotype 6b or 23f. the composition of the nasopharyngeal microbiome was longitudinally studied by 16s rdna pyrosequencing on nws collected before and 2, 7 and 14 days after challenge. among the 40 selected volunteers 10 were natural carriers and 30 were experimentally challenged. microbiome composition data were attained for 117 nws. by principal component analysis of the individual nasopharyngeal communities before challenge we identified 5 distinct microbiome profiles. natural pneumococcal carriage was particularly common in one of these profiles (p = 0.005). a more diverse microbiome (p = 0.034) and low presence of corynebacterium spp. (p = 0.046) prior to challenge were associated with establishment of pneumococcal carriage. whereas the nasopharyngeal microbiome was not perturbed after exposure to serotype 6b, its diversity increased upon exposure to serotype 23f (p = 0.004). five nasopharyngeal microbiome profiles were identified with different natural pneumococcal carriage rates. a more diverse microbiome and low presence of corynebacterium spp. prior to challenge were associated with establishment of pneumococcal carriage. perturbation of the nasopharyngeal microbiome upon pneumococcal exposure seems to be strain dependent. r. das 1 , m. larose 1 , r. bucala 2 , j.n. weiser 1 1 internal medicine, university of pennsylvania school of medicine, philadelphia, usa; 2 internal medicine, yale school of medicine, new haven, usa human genetic polymorphisms associated with reduced expression of macrophage migration inhibitory factor (mif) have been linked to the risk of community-acquired pneumonia (cap). since streptococcus pneumoniae is a leading cause of cap and nasal carriage is a precursor to invasive disease, we explored the role of mif in pneumococcal colonization using a mouse model. pneumococcal colonization led to local and systemic mif production. mice deficient in mif (mif -/-) were prone to higher density and more prolonged colonization compared to wild-type. the delayed clearance in mif -/mice correlated with reduced recruitment of nasopharyngeal macrophages. the upregulation and positive feedback provided by monocyte chemotactic protein-1 (mcp-1 or ccl2) was impaired in the mif -/mice. in vitro, pneumococcal infection of macrophages induced transcription and release of mif, processes dependent on bacterial expression of the pore-forming toxin, pneumolysin, and induction of map kinase phosphorylation. a point mutation in pneumolysin, which eliminates pore-formation, was sufficient to abrogate macrophage production of mif. correspondingly, nasal colonization with pneumolysin-deficient bacteria led to decreased local mif upregulation and reduced macrophage recruitment. prior work has demonstrated that pneumolysin-deficient bacteria show delayed clearance of colonization; this effect was eliminated in mif -/animals. downstream of primary clearance, mif -/animals also demonstrated reduced anti-pneumococcal antibody production and reduced ability to clear secondary colonization. finally, delivery of mif to the nasopharynx restored macrophage recruitment and pneumococcal clearance. our work suggests that mif is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in the genetic susceptibility to cap. no conflict of interest pneumonia 2014 volume 3 background and aims: data on the nasopharyngeal carriage prevalence of streptococcus pneumoniae across age groups are important to help predict the impact of introducing pneumococcal conjugate vaccines (pcvs) into routine vaccination programmes, given their important indirect effect. yet most carriage studies are conducted in children <5 y only. we investigated whether carriage rates in young children could be used to infer those in older age groups. methods: we conducted a systematic review of studies providing carriage estimates across age groups in healthy populations not previously exposed to pcv, using medline and embase. we used bayesian linear meta-regression background: the impact of 7-valent pneumococcal conjugate vaccine (pcv) in developed countries was enhanced by indirect protection of unvaccinated individuals, mediated by reduced nasopharyngeal carriage of vaccineserotype pneumococci. the potential indirect protection of 10-valent pcv (pcv10) in a developing country setting is unknown. we sought to estimate the effectiveness of programmatic introduction of pcv10 in kenya against carriage of vaccine-serotype pneumococci and non-typeable haemophilus influenzae (nthi). methods: pcv10 was introduced into the infant vaccination program in kenya in january 2011, accompanied by a catch-up campaign in kilifi county for children <5 years. we conducted annual cross-sectional studies of carriage among an age-stratified, random population sample in the 2 years before and 2 years after pcv10 introduction. approximately 500 individuals were enrolled each year. carriage prevalence ratios in the 2 years following pcv10 introduction compared to baseline were determined by log-binomial regression. results: among children aged <5 years the prevalence of vaccine-serotype, non-vaccine-serotype and nthi carriage was 0.34, 0.41 and 0.54, respectively, at baseline and 0.13, 0.57 and 0.40, respectively, after pcv10 introduction. adjusted prevalence ratios were 0.36 (95%cis: 0.26-0.51), 1.37 (1.13-1.64 ) and 0.62 (0.52-0.75), respectively. among individuals ≥5 years, the adjusted prevalence ratios for vaccine-serotype pneumococci and nthi were 0.34 (95%cis: 0.18-0.62) and 0.71 (0.56-0.89), respectively. conclusion: following programmatic use of pcv10 in kilifi, carriage of vaccine-serotypes was reduced by 64% in children <5 years and 66% in older individuals. these findings suggest that pcv10 introduction in africa will have a substantial indirect effect on invasive pneumococcal disease. transwell experiments in preliminary experiments. conclusion: results suggest s. salivarius-mediated inhibition of pneumococcal adherence is not megaplasmiddependant, and requires s. salivarius contact with host cells. as such, inhibition of pneumococcal adherence is likely to be mediated by competition for binding, rather than by megaplasmid-encoded bacteriocins. this work may facilitate the development of novel strategies for the prevention of pneumococcal colonisation and disease. isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 m. daana 1 , g. rahav 2 , h. jaber 2 , a. hamdan 3 , a. thalji 4 , f. jaar 5 , a. goral 2 , e. glazer 2 , w. awida 2 , m. raz 6 , g. regev-yochay 2 1 primary care, maccabi healthcare services, jerusalem, israel; 2 infectious disease unit, sheba medical center, ramat gan, israel; 3 primary care, private clinic, nabulus, palestine (via israel); 4 primary care, private clinic, ramalla, palestine (via israel); 5 primary care, private clinic, bethlehem, palestine (via israel); 6 jerusalem-hashfela dis., maccabi healthcare services, modiin, israel background: type1 pilus proteins are potential targets of future protein-based vaccines. yet, piliated strains were reported to decrease soon after pcv implementation. here we report a differential effect of pcv7 on carriage of non-piliated strains in a population-based study comparing a vaccinated vs. nonvaccinated population before and after pcv7 implementation. methods: consecutive annual cross-sectional surveys of sp carriage among children <3.5y were performed from 2009 (pre-pcv) to 2011 (post-pcv). palestinian children from a) ramalla, nabulus and bethlehem living under palestinian-authority's (pa) health policy, where pcv7 was not yet implemented and b) east-jerusalem (ej) where pcv7 was implemented (7/2009). clinical data were collected and sp/serotype/antibiotic susceptibilities were identified. presence of type1 pilus was determined by rrgc pcr. results: a total of 983 and 1772 children from ej and pa were screened. sp carriage was ~30% and was not affected by vaccination policy (after adjusting for age/region/year/recent antibiotic treatment). carriage of vt7 strains decreased significantly following pcv implementation (52% to 22%, p < 0.001). the decrease was mainly of nonpiliated vt strains, while piliated-vt strains did not decrease. piliated strains consisted 50% of all vt in 2009 vs. 80% in 2011, (p < 0.001). in addition, piliated non-vt13 strains emerged, from 1% (2009) to 25% (2011). the emerging nonvt13 piliated serotypes were 35b, 11a and 19b. pcv implementation was associated with increased carriage of piliated strains (adjusted odds ratio (aor): 2.6, 95%ci: 1.2-6.4). conclusion: the differential effect of pcv7 on non-piliated strains suggests that type1 pilus confers an intrinsic advantage for colonization and that pilus proteins are attractive vaccine targets. background and aims: in april 2010 the 7-valent pneumococcal conjugate vaccine (pcv7) was replaced by the 13-valent pcv. we investigated pneumococcal carriage in children eligible for pcv7 or pcv13 and their household contacts. methods: eligible families in hertfordshire and gloucester were identified and a nasopharyngeal swab obtained from consenting household members between july 2012 and march 2013. samples were cultured for streptococcus pneumoniae and serotyped by standard methods. for each serotype the ratio of its prevalence in invasive pneumococcal disease (ipd) to its carriage prevalence (case:carrier ratio, ccr) was calculated. results were compared with previous carriage studies in 2001/2 and 2008/9, before and after pcv7 introduction. results: 217 households were included. among <5 year-olds 47.7% (95% confidence interval 41.8-53.5) were carrying a pneumococcus compared with 51.0% in 2008/9 and 48.4% in 2001/2. the odds of carrying a pcv7 serotype was significantly reduced in 2008/9 and 2012/3 relative to 2001/2, while the odds of carrying any of the extra six pcv13 serotypes increased after pcv7 introduction but declined significantly after pcv13 introduction. the ccrs for the frequently-carried serotypes were relatively low, with the highest ccr observed for serotypes 7f, 19a, 3, 8, and 33f . across the three carriage studies, ccr estimates were stable for nearly all serotypes. conclusion: carriage of pcv13-only serotypes has rapidly reduced post-pcv13 introduction in both vaccinated and unvaccinated individuals with a continued decline in transmission of pcv7 serotypes. carriage rates in children remain unchanged, but the low ccrs of replacing serotypes should further reduce overall ipd across all age groups. background: meningitis continues to be associated with high mortality. in papua new guinea (png), streptococcus pneumoniae is now the most important cause of meningitis. where introduced, pneumococcal conjugate vaccines have helped to reduce disease burden but due to limited serotype coverage these vaccines do not protect against all pneumococcal lineages and may contribute to serotype replacement. serotype-independent protein-based vaccines incorporating several pneumococcal proteins present in all pneumococcal strains may be more favourable. methods: focusing on serotypes 2, 5 and 7 (common causes of meningitis in png), we characterised 40 invasive pneumococcal isolates from meningitis cases and 22 carriage isolates from png to identify dominating clonal complexes. results: multi-locus sequence typing (mlst) from 3 main serotype clusters revealed sequence types (sts) common in eastern europe, suggesting importation of these lineages. png pspa types correlated with the serotypes. serotype 2, 5 and 7b/c were associated with the pspa haplotypes 7, 1 and 11, respectively. no sequence variation within the pspa sequences of a clonal complex was observed. broad cross-reactivity was observed when 9 pneumococcal isolates from png with different pspa types were tested for binding with monoclonal antibodies specific for semiconserved pspa sequences. 9/9 and 7/9 strains were recognized by pspa and stkp-specific monoclonal antibodies, respectively. conclusion: we have identified dominating clonal complexes with limited genetic diversity within the pneumococcal population of colonisation and disease isolates in the eastern highlands of png. more studies incorporating mlst and pspa typing are needed to shed light on the country-wide diversity of pneumococci in png. background and aims: while there are several studies addressing pneumococcal colonization of the upper respiratory tract in young children, less is known about carriage in the elderly. this work aimed to evaluate the patterns of streptococcus pneumoniae carriage in adults over 60 years of age in portugal. methods: between april 2010 and december 2012, nasopharyngeal and oropharyngeal swabs were obtained from adults over 60 years of age, living in an urban area (n = 1,945) or in a rural area (n = 1,416). pneumococci were isolated by routine procedures, serotyped, genotyped (mlst), and antibiotyped. associations between carriage, socio-demographic and clinical data were analyzed by multiple logistic regression. results: carriage was higher in the rural area than in the urban area (3.4% vs 1.4%, respectively, p < 0.001). overall, the carriage rate was 2.3%. multiple logistic regression identified as risk factors for pneumococcal carriage, living in the rural area (or=2.0, 95%ci:1.2-3.5), being at a nursing home (or=2.0, 95%ci:1.1-3.6) and smoking (or=4.4, 95%ci:1.9-9.2). in total, 77 pneumococci were isolated, representing 26 serotypes and 40 sequence types (sts). the most prevalent serotypes were 19a (13.0%), 6c (9.1%), 22f (9.1%), 23a (9.1%), and 35f (7.8%). most isolates (93.5%) had previously described sts. non-susceptibility to penicillin was found in 11.7% of the isolates and resistance to macrolides in 19.5%; 15.6% of all isolates were multidrug resistant. conclusion: pneumococcal carriage in the elderly is low and there is a high serotype and genotype diversity. living in the rural area, being at a nursing home and smoking were risk factors for pneumococcal colonization. background: in developing countries like india, hiv infected children access antiretrovirals late, when their cd4 count drops <350. hiv viral load, not cd4 count may be more accurate in predicting risk of np colonization and ipd in these children. objective: to determine the association between hiv viral load and pneumococcal colonization. methods: np swabs were taken at 8 week intervals 4 times across 6 months from hiv infected children in a pneumonia prevention study. information on age, art status, cd4 count, viral load, and weight for age z-score was collected in pneumococcal vaccine naïve hiv infected children. results: out of 47 children, 16 had no pneumococcal colonization over six months (group-1), 31 (66%) had at least one episode of colonization (group-2). 9/47 (19%) of children were in art, 5 in group-1 and 4 in group-2. the mean age of children in both groups was 5. mean cd4 count was comparable 684 vs 703 in group-1 and group-2 (p = 0.89). mean waz-score was -2.9 vs. -3.09 (p = 0.71). children in group-2 had a mean viral load of 153,515 almost twice that of group-1, 80,050. two children had viral loads of 1 x10 6 in group-2 whereas the highest viral load in group-1 was 4x10 5 . conclusion: hiv infected children not qualifying for art but with high viral loads have increased risk of colonization with pneumococcus. access to pneumococcal vaccines for this high risk group in developing countries is important. background: hiv infected adults and children are at disproportionately high risk of invasive disease from streptococcus pneumoniae. pneumococcal conjugate vaccines (pcvs) are effective in hiv infected individuals but are not yet available in government programs. objective: to determine baseline carriage of streptococcus pneumoniae in vaccine naïve mother child pairs affected by hiv, and dynamics of transmission over the course of six months. methods: we are conducting an interventional study on the effect of the pneumococcal conjugate vaccine, pcv-13, and the hib conjugate vaccine on nasopharyngeal carriage, of these vaccine preventable pathogens, in families affected by hiv, in west bengal. four nasopharyngeal samples were collected from pneumococcal vaccine naïve, hiv infected children ages 2-15 years, and their mothers, at two month intervals over the course of six months. calcium alginate swabs were collected and placed in stgg media and processed in the microbiology laboratory using standardized protocols. isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 results: 404 nasopharyngeal swabs have been collected from hiv infected children and 375 swabs from their mothers. in children 100/404 (24.7%) swabs grew pneumococcus and 19/375 (5%) swabs in adults were positive for pneumococcus. fifty children have completed six months of follow-up. in this group, 35/50 (70%) children had at least one out of four swabs grow pneumococcus over the course of six months. initial results show that in 31/50 children (62%), pneumococcal carriage disappeared within 2 months. in 4/50 (8%), carriage persisted for > 2 months, and in one case for > 4 months. background: pneumococcal colonization in nasopharynx (np) is known to precede pneumonia, and np density is suggested to correlate with disease severity. we studied the correlation between pneumococcal dna density in np, and anti-cps immunoglobulins (ig) levels to homologous serotypes, in adult community-acquired pneumonia (cap). serotypes were grouped according to case fatality rates (cfr; weinberger, 2004) . methods: in a prospective study of 235 adult cap patients, admission sera were collected, and culture on blood, sputum, np-aspirate (npa) and np-swab were performed. quantitative pcr on npa for pneumococcal dna (spn9802) densities (log-10 dna copies/ml) were performed. anti-cps ig-titres to homologous serotypes were measured by optical density and compared (%od) with pooled sera from post-vaccinated adults. the vaccination frequency was very low. results: of 68 cap patients with np pneumococcal dna, 47 patients with culture-positive pneumococcal aetiology had admission ig-titres determined. no overall correlation between colonization rates and ig-titres was noted (table). in cases with medium/low cfr serotypes, colonization densities were significantly higher in those with high, than low, ig-titres. no difference in duration from onset of illness to admission was noted between serotype categories. conclusion: in pneumococcal cap, high colonization densities and high admission ig-titres correlated well for serotypes associated with medium/low cfr. thus, a significant bacterial load in np may be necessary for pneumonia development, in patients colonized with these serotypes. mean log-10 copies/ml (standard deviation) p value background: optochin (op) and bile solubility tests (bst) have good specificity when applied to isolates from clinical specimens which have a high pretest probability of identification of pneumococci. the same tests may have different analytical specificity for nasopharyngeal isolates as the upper respiratory tract is a reservoir for both pneumococci and non-pneumococcal streptococci. non-pneumococcal confounding of op and bst is known. objectives: we applied lyta pcr and sequencing to nasophayngeal isolates of 'pneumococci' as reference methods for identification from nasophayngeal swab cultures. methods: nasopharyngeal swabs were collected from well children 3 months to 5y of age from karachi, pakistan as part of a pneumococcal carriage study to evaluate pcv-10 impact. swabs were collected in stgg media and subcultured on sheep blood agar (sba). isolates with suggestive colony morphology (draughtsman or mucoid, alpha hemolytic) were selected for op and bst. 40 pneumococcal isolates were selected for study on the basis of difficulty in identification (small op zones or discrepancy in op and bst). pneumococcal autolysin gene lyta was detected isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 by pcr, followed by sequencing (macrogen inc.) as reference identification methods. blast analysis by appending sequences to ncbi database using clustalw2 is ongoing. results: of 40 isolates selected, 12 isolates had discrepant op and bst results (op resistant but bile-soluble). lyta was detected in 29 of 40 isolates (72.5%). results from sequencing of the pcr product are under evaluation by blast analysis. conclusion: results obtained indicate that suggestive colony morphology, op and bst used together may still confound pneumococcal identification from nasopharyngeal samples. background: due to the significantly increased risk of invasive disease, hiv infected adults and children are an important group to access pneumococcal conjugate vaccines. nasopharyngeal colonization precedes invasive disease; determining the pneumococcal serotypes colonizing the nasopharynx of hiv infected individuals is important in the design of new pneumococcal vaccines. objective: to determine pneumococcal serotypes from nasopharyngeal samples in vaccine naïve hiv infected mothers and children. we are conducting an interventional study looking at the effect of the pneumococcal conjugate vaccine, pcv-13, on nasopharyngeal carriage in families affected by hiv in west bengal. here we report baseline serotypes from 43 isolates taken from vaccine naive mothers and children infected with hiv. samples were collected using calcium alginate swabs and stored in stgg media. these were processed using standard microbiologic methods and pneumococcal isolates were then serotyped at a reference laboratory. results: serotype results for 43 isolates from 35 children and 8 mothers are available. 4 out of 8 strains in mothers are vaccine represented strains-3, 19a, 4. three strains in mothers are not vaccine represented-13, 6c, 34. in children 12 out of 35 serotypes are vaccine represented--14, 19a, 19f, 3, 6a, 6b, 9v. the most common serotype was 19a (5/43) and 13 (6/43). 16/43 (37%) of isolates are represented in pcv-13. serotypes that are not vaccine represented include10a, 11, 11a, 12, 15a, 15c, 18a, 20, 24f, 29, 31, 36, 38 (one each) , 34 (2 isolates), 6c (3 isolates), and 13 (6 isolates). background and aims: insight into bacterial colonization patterns of potential pathogens and commensals in the nasopharynx might elucidate healthy and/or susceptible conditions for development of respiratory disease. we therefore studied the dynamics of microbiota profiles over time in young children. methods: we characterized the consecutive nasopharyngeal microbiota profiles of 60 healthy children at the ages of 6 weeks, and 6, 12 and 24 months by 16s gs-flx-titanium-pyrosequencing, and analyzed the consecutive profiles by spectral co-regularized clustering and biomarker detection algorithms. results: overall, we identified 6 distinct microbiota profiles represented by the dominant genera moraxella, haemophilus, streptococcus, or staphylococcus, a combination of dolosigranulum and corynebacterium, plus cluster-specific low abundant biomarker bacteria. we observed specific patterns of change over time, with more stable patterns marked by early presence and high abundance of the moraxella and corynebacterium/ dolosigranulum clusters, and less stable profiles marked by high abundance of the haemophilus or streptococcusdominated clusters. the streptococcus-dominated profile was additionally shaped by high abundance of prevotella, gemella, bacteroidetes (unclassified), acinetobacter and porphyromonas, and observed in on average 15% of the samples, decreasing from 20% in 6-week-olds to 7% in 24-months-olds. together with the haemophilus-dominated profile, the streptococcus-dominated profile was associated with increased frequency of parent-reported respiratory infections. the current study enabled us to gain insight in the dynamic nature of nasoparyngeal microbiota in infants. our results suggest that the composition of early-life microbiota is associated with long-term stability and may predict susceptibility to disease. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: the fiji pneumococcal project (fipp) evaluated a reduced dose pcv7 primary series in infancy, followed by the 23vpps at 12 months of age. children receiving 0 or 1 pcv7 dose were given a catch-up dose at 2 years of age. immune hyporesponsiveness was observed in children aged 18 months who were given 23vpps, compared with those who were not. here we assess the long-term impact of 23vpps vaccination on carriage rates and densities of pneumococci and other common bacterial species. we also compared differences in carriage of pneumococcal serotypes, and examined differences between the two main ethnic populations. methods: nasopharyngeal swabs (n = 194) were collected from a subset of healthy fipp participants now 5-7 years old. pneumococci were identified by standard culture-based methods and serotyped by latex agglutination/ quellung. carriage rates and densities of pneumococci, haemophilus influenzae, staphylococcus aureus and moraxella catarrhalis were determined by quantitative pcr. results: preliminary analysis found there were no differences in pneumococcal carriage rates (40 vs. 52%) or vaccine-type carriage (20 vs. 17%) for 23vpps recipients compared with non-recipients. similar results were found for pneumococcal densities. analysis of the impact of 23vpps vaccination on carriage of other species is ongoing. indigenous fijian children had significantly higher carriage rates of pneumococci (57 vs. 14%), h. influenzae (63 vs. 24%) and m. catarrhalis (86 vs. 41%), and lower carriage of s. aureus (23 vs. 41%) compared to indo-fijian children. conclusion: initial analysis shows 23vpps receipt at 12 months has no long-term impact on pneumococcal carriage rate or density. background: in july 2011 the expanded program of immunization (epi) program of the gambia replaced pvc7 with pcv13. we used this opportunity to determine the impact of replacing pcv7 with pcv13 on the prevalence of pneumococcal nasopharyngeal carriage. methods: healthy gambian infants who had received 3 doses of a pcv were recruited. nasopharyngeal swabs were collected from infants and their mothers during cross-sectional surveys undertaken in april-june 2011 (pcv7 group) and in april-june 2012 (pcv13 group). pneumococci were isolated following standardized methods and serotyped by latex agglutination. results: 339 and 350 mother/infants pairs were recruited in the pcv7 and pcv13 vaccinated groups respectively. the overall pneumococcal carriage rate in infants was similar in the two groups (85.8% and 84.3%, p = 0.902). carriage of pneumococci of pcv7 and pcv13 vaccine types (vt) was lower in the pcv13 than in the pcv7 vaccine recipients [4.9% versus 9.4% (p = 0.025) for pcv7-vt and 18.0% versus 33.3.0% (p < 0.001) for pcv13-vt, respectively]. the prevalence of carriage of the six additional serotypes included in the pcv13 and not in the pcv7 vaccine was 13.4% in the pcv13 and 23.9% in the pcv7 recipients respectively (p = 0.001). however, there was a significant increase in non-typable pneumococci among pcv13 compared to pcv7 vaccinated children (0.6% versus 6.6%, p = 0.005). prevalence of carriage in mothers was similar in both surveys for all study endpoints. conclusion: replacing pcv7 by pcv13 decreased the prevalence of pneumococcal carriage of vaccine type pneumococci in vaccinated gambian infants one year after introduction of pcv13 but not in their mothers background: 7-valent pneumococcal vaccine (pcv7) was implemented for infants in the dutch national immunization program (nip) in 2006, and replaced by pcv10 in 2011. eradication of vaccine serotype from carriage and emergence of non-vaccine serotypes was observed, with particularly high peaks in serotype 19a carriage 4.5 years after pcv7-implementation (spijkerman,2012) . this suggests a vaccine-induced disbalance among serotypes circulating in children. methods: we performed a cross-sectional study 6.5 years after pcv-implementation (2012/13), studying pneumococcal carriage in 330 pcv10-vaccinated 11-month-old children and 330 pcv7-vaccinated 24-month-old children. present results were compared with carriage data in identical age groups from before, and from 3 and 4.5 years after pcv7-implementation (n ≈ 330/group). bootstrap calculations were performed to investigate changes in diversity of serotypes carried (hanage,2010) . results: in 2012/13, carriage of vaccine-type pneumococci had almost completely disappeared, but overall pneumococcal carriage was similar to the pre-vaccination carriage rates. after 6.5 years, distribution of nonvaccine serotypes was more similar to pre-pcv7 data, indicating a more evenly distributed ranking, and no serotype was exceeding a carriage rate of 10%. between 2010 and 2012/13, the high carriage rates of serotype 19a had declined from 12% to 9% in 11-month-old children and from 14% to 8% in 24-month-old children. conclusion: our data suggest a new balance in non-vaccine serotype carriage emerging in vaccinated children 6.5 years after the first pcv implementation in the dutch nip. carriage of serotype 19a declined more prominently in pcv7 vaccinated children and not in pcv10 vaccinated children, and is more likely to a newly achieved balance rather than cross-protection by pcv10. center for american indian health, johns hopkins bloomberg school for public health, baltimore md, usa; 2 emory university, rollins school of public health, atlanta ga, usa background: pneumococcal conjugate vaccines (pcvs) reduce vaccine serotype pneumococcal nasopharyngeal (np) colonization prevalence and density in vaccinated children. establishing the relationship between the child's colonization density and the colonization status of close contacts may partly explain the mechanism of pcv indirect effects. methods: american indian households participated in a continuous, cross-sectional np colonization study (january 2010-april 2012). an np specimen was collected from each participant and pneumococcus isolated by culture. a subset of np specimens from households comprised of a child <8 years of age, mother and father were selected for subsequent testing by lyta quantitative pcr. pneumcococcal colonization of >105 colony forming units (cfu)/ml was categorized as dense. multilevel logistic regression analysis measured odds of parental colonization by child's density accounting for intra-household correlation. results: 223 families were identified for this analysis (n = 669 participants); 28% of participants (n = 189) were positive for pneumococcus. children were more frequently colonized than their parents (53% vs. 16%; p<0.01) and more densely colonized than their parents (10 5.4 vs. 10 4.6 cfu/ml; p < 0.01). adjusting for the study site where subjects were sampled and differences between american indian tribes, parents living with a densely colonized child had a greater odds of being colonized (odds ratio (or): 2.6, p < 0.01); mothers were not more likely to be colonized than fathers (or: 1.09, p=0.3). conclusion: dense pneumococccal colonization of children is associated with a greater likelihood of parental colonization. reducing strain-specific colonization density among children through pcv could reduce colonization and risk of disease in family members and other close contacts. background and aims: nasopharyngeal (np) carriage of streptococcus pneumonia is an important risk factor for invasive pneumococcal disease. this study characterizes np carriage rates and loads of s. pneumoniae in the first 12 weeks of life in a rural cohort in the gambia. methods: 480 np swabs were collected from 120 infants at monthly intervals from within minutes of birth to 3 months. quantitative pcr targeting the autolysin gene (lyta) was performed on the dna extracts from the swabs. results: preliminary results from 76 newborns showed a significant increase in pneumococcal carriage (p < 0.01) with 32 % at birth, 59% at one month, 68% at two months and 85% at three months. the mean pneumococcal load also increased significantly from 1.09x10 1 cells/ml at birth, increasing to 1.56x10 3 cells/ml, 1.72x10 3 cells/ ml and 1.80x10 4 cells/ml at one, two and three months respectively, (x 2 (3) = 84.103, p < 0.01). logistic regression analysis revealed that birth weight >3.1kg (odds ratio (or) 1.72, 95%ci 1.04-2.84, p = 0.03), health centre rather than hospital births (or 0.38, 95%ci 0.18-0.78, p < 0.01), and having 1-3 older siblings (or 2.1, 95%ci 1.07-4.16, p = 0.03) all significantly increased pneumococcal carriage. however gender had no significant effect (or 1.21, 95%ci 0.75-1.94, p=0.44). after adjusting for birth weight, place of birth and number of siblings, only place of birth and having 1-3 siblings remain significant, (or 0.38, 95%ci 0.18-0.80, p = 0.01) and (or 2.13, 95%ci 1.00-4.56, p = 0.05) respectively. conclusion: both pneumococcal carriage and load increase significantly within weeks of birth which could implicate susceptibility to neonatal infections. this data is important for future studies looking at natural pneumococcal protection dynamics in neonates and young infants. bacterial pneumonia due to streptococcus pneumoniae remains the leading cause of hospital admission in hiv infected individuals. pneumococcal conjugate vaccine (pcv) are effective in hiv infected individuals for the prevention of invasive disease from this pathogens; however, it is not yet available through government programs in india. studies looking at the impact of these vaccines on nasopharyngeal colonization in families affected by hiv can potentially inform health policy in india. we describe the design for our ongoing study looking at the impact of pneumococcal conjugate vaccine in families affected by hiv being carried out in west bengal. organizing a community based clinical study depends much on cultural expectations and socio-political scenario of the sites involved. we describe our experience with different tools used in the consent and follow up process in our study u. devi 1 , v. malik 1 , j. mahanta 1 1 bacteriology, regional medical research centre north east region(icmr), dibrugarh, india background & aims: sequence types prevailing in northeast india are not known. we present sequence types currently completed. methods: dna was extracted using phenol-chloroform method. primer pairs used for amplifying the seven housekeeping genes namely aroe, gdh, gki, recp, spi, xpt and ddl were obtained from those listed in mlst website (http://spn.mlst.net/). amplicons were sequenced on both sides (commercially) and sequences were edited using genious pro v 5.4.6. the core sequences were uploaded to pneumococcus database for allele and st identification. results: table below isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: although indirect effects of pneumococcal conjugate vaccination (pcv) have been welldocumented in adults, there are few data regarding the herd effects in young infants. this age group are too young to be vaccinated with pcv but are at high risk for severe bacterial infections. fiji introduced pcv10 in 2012. the impact of 10valent pneumococcal conjugate vaccine (pcv10) introduction on nasopharyngeal carriage is being monitored as part of the new vaccine evaluation project. the indirect effects of pcv10 introduction will be measured in young infants (5-8 wk) through annual carriage surveys (pre-and post-pcv10 introduction). methods: nasopharyngeal swabs were collected from 500 healthy infants aged 5-8 wk before, and one year after, pcv10 introduction. swabs were stored in stgg and frozen at -80°c until analysis. streptococcus pneumoniae, staphylococcus aureus, and haemophilus influenzae were detected using quantitative pcr, and pneumococcal molecular serotyping performed by microarray. results: preliminary analysis of the pre-pcv10 swabs found carriage rates of 30% for s. pneumoniae, 23% for s. aureus, and 27% for h. influenzae. serotyping by microarray found that 40% of pneumococci identified were pcv10 serotypes. we are currently examining swabs taken one year post-pcv10 introduction to investigate potential herd immune effects on nasopharyngeal carriage in this age group. conclusion: our studies in fiji provide a unique opportunity for investigating pcv impact in young, unvaccinated infants. data will help to evaluate potential herd effects on carriage of pneumococcal serotypes and other pathogens in young infants in a low-income country setting. background and aims: detection of multiple serotypes of streptococcus pneumoniae is necessary to understand the effects of pneumococcal conjugate vaccination in carriage studies. this study aimed to compare serotyping by latex agglutination and microarray within the context of a 7-valent pneumococcal conjugate vaccine (pcv-7) trial. methods: nasopharyngeal swabs (nps) were collected from 22 newborns at regular intervals up to 12 months of age. all children received at least three doses of pcv-7. s. pneumoniae was identified by conventional microbiology techniques. s. pneumoniae isolates were serotyped using the latex agglutination and microarray sweep method. results: microarray detected 2, 3 and 4 serotypes in 28%, 11% and 3% of 157 nps respectively, compared to 7%, 1% and 0% by latex agglutination (p < 0.001). although a common serogroup was detected in 94% of nps by both methods, latex agglutination was more likely to miss co-carried low abundance serotypes. for instance, in one nps both methods detected serotype 6a/b, however, latex agglutination did not detect serotypes 37, 16f and an nt which had relative abundance of 8%, 6% and 3% by microarray respectively. in four other nps collected from the same subject at consecutive timepoints, serotype 16f was present but appeared to be cleared from carriage by latex agglutination. the predominant serotypes detected by latex agglutination were 19a(10%) and 13(9%) while by microarray they were 13(8%) and 19a(7%). conclusion: we report improved detection of multiple serotypes using microarray method over latex agglutination. highly sensitive molecular techniques should be employed in post-vaccine implementation carriage studies. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: monitoring the dynamics of pneumococcal carriage makes it possible to evaluate the epidemiological characteristics of streptococcus pneumoniae disease and the theoretical coverage offered by pneumococcal vaccines. it has been demonstrated that the nasopharyngeal (np) sampling of respiratory secretions is superior to oropharyngeal (op) sampling for identifying pneumococci carried by younger children, but adult data are conflicting and there are no studies of adolescents. methods: in order to compare the efficiency of op and np sampling in identifying and quantifying s. pneumoniae carriage in healthy adolescents, two swab samples were obtained from 530 adolescents aged 15-19 years, the first taken from the posterior pharyngeal wall through the mouth (op) and the second through the nose (np). bacterial genomic dna was tested for the autolysin-a (lyta) and wzg (cpsa) genes of s. pneumoniae in order to evaluate pneumococcal carrier status. positive cases were serotyped. results: s. pneumoniae was identified in 35.8% of the op swabs and 3.5% of the np swabs (p < 0.0001). the serotypes included in the 13-valent pneumococcal conjugate vaccine (pcv13) were found in all but two op samples (98.9%) and only 64.7% of the np samples (p <0.0001). the most frequently identified pcv13 serotype in both groups was 19f, followed by serotypes 5 and 9v. conclusion: op sampling appeared significantly more effective than np sampling in identifying and characterising pneumococcal carrier status in adolescents. this suggests that op sampling should be used when evaluating the dynamics of pneumococcal carriage among adolescents and the theoretical coverage offered by pcv13. background: hiv-infected children are at high risk for pneumococcal disease. antimicrobial-resistant streptococcus pneumoniae can lead to poor clinical outcomes and increased cost of medical care. we examined antimicrobial susceptibility among nasopharyngeal pneumococcal isolates obtained from hiv-infected children in mozambique before the introduction of the 10-valent pneumococcal conjugate vaccine (pcv10) in april 2013. methods: between october 2012 and march 2013, we enrolled hiv-infected children age <5 years presenting for routine care at seven hiv clinics in 3 sites, including maputo (urban-south), nampula (urban-north), and manhi?a (rural-south). a single nasopharyngeal swab was obtained and cultured following broth enrichment. susceptibility to commonly-used antibiotics was evaluated for pneumococcal isolates using broth dilution susceptibility tests according to definitions from the 2013 clinical laboratory standard institute guidelines. serotyping was performed using quellung reaction. results: a total of 343 isolates were obtained from 336 hiv-infected children. overall, 304 (88.6%) isolates were resistant to co-trimoxazole, 56 (16.3%) to erythromycin, 23 (6.7%) to chloramphenicol, and 1 (0.3%) to amoxicillin. none were resistant to ceftriaxone or penicillin. three isolates had intermediate resistance to penicillin (mic=4); all 3 were pcv10 serotypes. the proportion of resistant isolates that were serotypes covered by pcv10 for cotrimoxazole, erythromycin, chloramphenicol and amoxicillin was 51.6%, 97.6%, 72.7% and 100% respectively. conclusion: given the low prevalence of β-lactam resistance, those agents continue to be useful first-line antibiotics for treating pneumococcal disease in hiv-infected children in mozambique. pcv10 introduction will likely lead to an important decline in the circulation of resistant pneumococci in this population. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: we have previously reported that experimental human carriage was an immunizing and protective event. now, in volunteers inoculated with pneumococcus, we characterize the kinetics of circulating antigen-specific plasma and memory b cell populations in blood and further characterize their phenotype in blood and in the lung (bronchoalveolar lavage (bal)). method: healthy volunteers were inoculated with a 6b pneumococcal strain. blood samples were collected at days 0, 7, 14 and 35 post inoculation for elispot analyses. flow cytometric analysis were performed using b cells purified with anti-cd19 microbeads. cells were labeled for surface phenotype and cellular antigen-specificity determined using biotinylated capsular polysaccharide (ps) 6b labeled with anti-biotin-fitc. results: we evaluated igg and iga secreting plasma and memory b cells to ps6b, whole cell pneumococcus, pspa, pspc and flu in 96 samples collected from 25 volunteers (15 carriers and 10 non-carriers). preliminary analysis revealed a transient increase in the numbers of circulating plasma cells peaking at day 7 for ps6b and at day 14 for pspa. carriage increased b1a but not b1b cells in blood at day 21. we are now analyzing the impact of carriage upon b cell populations in the lung. conclusion: while b1a cells produce serum antibody, b1b cells are involved in long-term protection against bacterial pathogens such as pneumococcus. our results suggest that although pneumococcal nasal exposure is immunizing and elicits antibodies, this response may be restricted to the b1a and not the b1b subset. acknowledgements: the bmgf gce and mrc-fapesp background and aims: respiratory viral infections may affect bacterial colonisation of the human nasopharynx and efficiency of transmission. the particular interaction between influenza and streptococcus pneumoniae (sp) has received particular attention. we investigated whether trivalent live attenuated influenza vaccine (laiv) influences nasal carriage and density of sp in healthy children. methods: 151 children were recruited into a randomised controlled stepped-wedge study to start laiv (2 doses, one month apart) either at an initial study visit or one month later, with nasopharyngeal swabs taken 7 and 28 days after each dose, allowing comparisons both between vaccinated and unvaccinated children and pre-and postvaccine. swabs, stored in stgg, were analysed using real-time pcr (rt-pcr) for lyta. results: at 7 days post-vaccination s.pneumoniae was detected (ct<35) in 69.2% children and 66.2% of controls (p = 0.706) with similar density in the two groups at both day 7 and 28 (p =0.50 and 0.46, respectively). likewise, when values pre-and both 7 and 28 days post-first vaccine dose were compared in all children studied, no differences in colonisation rates were shown. conclusion: laiv did not cause detectable changes in rates or density of nasal carriage with pneumococcus, measured by pcr, in this population, among whom colonisation rates were high. it seems possible that while infection with wild type influenza and other respiratory viral infections may affect bacterial colonisation, the largely sub-clinical infection caused by attenuated vaccine viruses do not. isppd-9 / pneumonia 2014 mar 9-13;3:1-286 b. morales-aza 1 , p. sikora-liszka 1 , l. januario 2 , f. rodrigues 2 , a. finn 1 1 cellular and molecular medicine, university of bristol, bristol, united kingdom; 2 infectious diseases unit & emergency service, hospital pediatrico de coimbra, coimbra, portugal background and aims: studies comparing rates and/or densities of streptococcus pneumoniae (sp) colonisation in children with respiratory infections and in health are conflicting. we tested the hypothesis that they are unchanged in acute otitis media with spontaneous otorrhoea (aomso) . methods: in february-march 2011 we swabbed 516 children attending nurseries(an) and 104 with aomso. nasopharyngeal swabs were stored at -80°c in stgg broth and 50µl cultured using standard techniques. sp, haemophilus influenzae (hi) and moraxella catarrhalis (mc) were identified and densities assessed by scoring numbers of colonies (0-5 where 5 is >100). results: 80% of the children with aomso attended nurseries. by univariate analysis, rates of colonisation and mean densities did not differ apart from mc density. by multivariate analysis (adjusting for age), colonisation rates and densities for both hi and mc were lower in aomso. the mean total number of bacterial species identified was similar in the two groups (1.7vs1.8; p =0.674). conclusion: children with aomso did not have higher rates or densities of sp but significantly lower densities of both hi and mc were seen. this relative imbalance between species in otitis may point to the ecological conditions predisposing to disease. pneumococcal conjugate vaccines (pcv) were implemented from 2006 in the uk. colonisation precedes disease therefore carriage can be an early indicator of epidemiological changes. circulating pneumococci were highly characterised to assess vaccine impact and generate data informative to future vaccine policy and formulation. nasopharyngeal swabs were collected from children of four years of age and under each winter from 2006/7 to 2010/11. pneumococci were isolated using conventional microbiology. next generation sequencing was utilised to comprehensively type isolates and determine sequence variation in numerous genes important to pneumococcal typing and virulence using a single method. carriage remained stable. conversely pcv7 and pcv13-unique vaccine serotypes (vt) significantly decreased with concomitant increases in non-vaccine serotypes (nvt). significant decreases for vt 6a, 6b, 19f and 23f and increases for nvt 21, 23b, 33f and 35f were detected. significant changes were observed for associated genotypes. novel non-synonymous sequence variation was observed to be common in capsular defining genes within serotypes, particularly for serogroups 19 and 6. newly described serotypes 6d and 6g sequences were detected. ten novel pneumolysin protein alleles were observed. pneumolysin sequences associated with non-pneumococcal streptococci were detected in pneumococci and vice-versa. serotype replacement resulted in increased nvt colonisation, which could progress to disease cases. future control of pneumococcal disease through vaccination will require response to replacement, targeting prevalent replacing serotypes or broader acting pneumococcal vaccines. however strategies should account for potential target diversity and consequent specificity. whole genomes offer an invaluable resource for documenting sequence variability of genes throughout the genome. background and aims: the 13-valent pneumococcal conjugate vaccine (pcv13) replaced the 7-valent pneumococcal conjugate vaccine (pcv7) in the alaska childhood immunization schedule in 2010. we assessed the indirect effect of pcv13 on pneumococcal colonization and disease in alaskan adults. methods: to determine pneumococcal colonization, we recruited a convenience sample of residents of all ages from 8 rural villages and children aged <5 years at 2 urban pediatric clinics annually during 2008-2012; we determined their pcv13 vaccination status and obtained nasopharyngeal swab specimens. pneumococci were identified/serotyped by standard laboratory methods. we identified invasive pneumococcal disease (ipd) cases, defined as streptococcus pneumoniae cultured from a sterile site, through conducting statewide surveillance. results: during 2008-2012, we recruited 4,310 children aged <5 years (89% with >1 dose pcv13 in 2011-2012) and 8,336 adults aged >18 years. overall pneumococcal carriage among rural and urban children <5 years and adults >18 years remained stable (mean/year: 66%, 35%, and 14%, respectively). from 2008 through 2012, pcv13 serotype carriage declined among children <5 years (13%-4%, p-value for trend <0.01) and adults >18 years (4%-1%, p <0.01). during 2011-2012, 6/943 (<1%) adults >50 years were colonized by pcv13 serotypes. pcv13-ipd rates among alaskan adults >18 years declined from 8.2/100,000 persons in 2008 to 5.2/100,000 in 2012 (p-value <0.01). conclusion: pediatric pcv13 vaccination provided indirect protection against vaccine-type colonization and ipd to unvaccinated adults. potential benefits to adults aged >50 years from routine pcv13 vaccination appears to be small because pcv13 serotype carriage is low and pcv13-ipd rates are declining due to indirect protection. exposure to streptococcus pneumoniae in the nasopharynx is thought to eventually lead to protective immunity. the role of anti-protein serum antibodies in mediating this immunity is unclear but vaccines incorporating pneumococcal proteins are being developed. we investigated the immunogenicity of individual proteins following pneumococcal colonisation in kenyan and burmese infants to establish whether antigen immunodominance is similar in diverse communities. nasopharyngeal swabs to detect pneumococcal colonisation and serum samples at various time points were obtained in two separate studies from burmese refugee and kenyan infants. sera was analysed for igg to 27 pneumococcal proteins using multiplex electrochemiluminescence and titres compared between the cohorts. prevalence of nasopharyngeal colonisation was compared at 18 and 36 weeks. statistical analysis was performed on log-transformed data using r. significance was defined of p-value less than 0.05. cross sectional prevalence of carriage at 18 weeks was 83% and 81% and at 36 weeks was 81% and 86% in the kenyan and burmese cohorts, respectively. when comparing igg to individual proteins, the top 8 immuno-dominant proteins were identical between the two cohorts. burmese infants had significantly higher birth igg titres than the kenyan cohort to 22/27 antigens. however the ratio of 9m:birth igg titres were significantly higher for the kenyan cohort whose titres at 9 months were higher to all antigens (15/27 significantly). despite differences in the kinetics of igg production after birth, similar antigens were immunodominant in these two diverse populations. this data suggests that vaccines based on protein antigens are likely to have universal value. the immune response to colonisation is important in the pathogenesis of streptococcus pneumoniae but the role of anti-protein antibodies is unclear. to assess this we studied the relationship between anti-protein serum igg, salivary iga (sal-iga) and pneumococcal colonisation among american indian children and adults. adults and children (mean age 4y3m) had nasopharyngeal swabs taken monthly for 6 months to detect colonisation and saliva and serum collected at months 0 and 6. individuals who became colonized at any time were age matched to those never colonized. igg and sal-iga titres to 27 pneumococcal proteins were measured using multiplexed electrochemiluminescence. overall for the entire cohort, adults had higher igg and sal-iga than children for 24/27 proteins. at entry to the study, only igg to pneumolysin correlated with protection against pneumococcal acquisition, and this only in adults. in adults who became colonised an increase in sal-iga to 15/27 proteins with no significant changes in igg was seen. in contrast children acquiring pneumococcus had higher igg titres to 15/27 proteins at month 6 compared with month 0, but no changes in sal-iga. there were no changes in antibody titres during the study in uncolonised adults or children. pneumococcal colonisation stimulated different patterns of immune responses in adults and children. previous antigen experience and the maturity of the immune system appears critical in determining the serological outcome of pneumococcal acquisition in the nasopharynx. of the proteins studied, only anti-pneumolysin serum responses correlated with protection against pneumococcal acquisition, and this was only observed in adults. introduction: streptococcus pneumoniae (sp) vaccination induces general and local immune response. according to our preliminary results, in vaccinated children, reduction in penicillin resistance in nasopharyngeal isolates have been found. as the further step of the study, for confirmation of phenotype difference, the serotype distribution has been investigated. aim: the study was conducted to assess the serotype distribution in nasopharyngeal carriage in pediatric population vaccinated with a conjugate 13-valent vaccine (pcv13) as compared to non-vaccinated children. methods: all sp isolates obtained during the randomized, prospective study has been performed to assess the serotype distribution of sp strains isolated from carriage among 750 children aged 17 months-60 months of age. the study group consisted of 359 fully, age appropriately immunized children by using pcv13 within the official vaccination program in the city of kielce (schedule -at 3, 5, 14 months of life) and 391 children not vaccinated against pneumococci living in the same region (the city of ostrowiec). nasopharyngeal swabs were obtained by trained medical personnel, cultured in certified laboratory, sp isolates have been tested by using the quellung method in reference laboratory according to standard previously described procedure. results: the prevalence of pneumococcal carriage was similar in vaccinated and non-vaccinated children (28,4% vs 27,6% respectively). the serotype analysis in vaccinated carriers showed only 5% serotypes covered by the pcv13 in comparison to 57% in non-vaccinated population (p < 0.0001). conclusion: vaccination with pcv13 has significant impact on the reduction of vaccine covered serotypes in sp carriers and correlates with penicillin resistance of these isolates. introduction: pneumococci commonly colonize the nasopharynx of children. iceland introduced pneumococcal conjugate vaccine (pcv-10) in the childhood vaccination program in 2011. the aim was to investigate changes in serotype prevalence and antimicrobial susceptibility before vaccinated children attend the day care centres. material and methods: nasopharyngeal samples were collected annually from healthy children age 2-6 years, attending fifteen day care centres in the greater reykjavík area during 2009-2013. the children´s parents answered a questionnaire about antibiotic use during the 6 months before the sampling. results: the number of children sampled annually varied between 420 and 516. the mean carriage rate of pneumococci was between 56% and 72%, decreasing significantly with age (for 2013, each additional year of age: odds ratio (or)=0.81, p = 0.016). the proportion of children carrying penicillin non-susceptible pneumococci (pnsp) was 5-8%, also decreasing with age (for 2013, each additional year of age: or=0.61, p = 0.026). the pnsp was highest among children receiving antibiotics up to 30 days prior to sampling (for 2013: or=2.6, p = 0.026). the serotype proportions varied considerably from year to year for most of the serotypes. the most common types were 6b (13%) we investigated the impact of vaccination on nasopharyngeal (np) carriage and lower airway infection (lai) in these children, many of whom receive long-term azithromycin therapy. methods: children were enrolled, and np swabs and bronchoalveolar lavage (bal) fluid were collected under anaesthetic, stored at -80 o c and processed, as previously described. lai was defined as >10 4 cfu/ml bal fluid. data were recorded on vaccines administered since birth. azithromycin resistance was defined as mic>0.5 mg/l. results: from 2007 to 2013, 155 indigenous children aged 5.2 to 154.6 (median 27.1) months with hrct-confirmed bronchiectasis were enrolled; 89 (57%) were male. there were no significant differences in np carriage or lai between vaccine groups (table). isppd-9 / pneumonia 2014 mar 9-13;3:1-286 †azir, azithromycin-resistant spn strain(s) as % children (80% of resistant strains had mic≥16mg/l); *vaccine serotypes in bold, azir serotypes in italics. there are currently insufficient data to draw conclusions regarding vaccine impact. temporal trends and the emergence of multi-resistant non-vaccine serotypes (e.g. 15a) also need to be considered. pcv studies are ongoing. pneumococcal carriage prevalence at baseline did not differ by individuals receiving art during follow-up or not (21.0% vs. 20.6%, p = 0.99). individuals who received art had higher pneumococcal carriage than individuals who did not receive art (25.5% vs. 19.6%, p = 0.03), particularly for serotypes not included in pcv13 (15.9% vs. 9.5% p = 0.004). following adjustment, increased odds of carriage were still observed for individuals on art, but results were non-significant (all serotypes: or1.36, 95%ci 0.85-2.17, p = 0.20; non-pcv13 serotypes: or1.90, 95%ci 0.98-3.68, p = 0.06). conclusion: pneumococcal carriage in hiv-positive adults in malawi remained high despite start of art, with a tendency to increased carriage of non-pcv13 serotypes. hiv-positive adults on art remain an important reservoir for pneumococcal diversity. we investigated whether this decrease was reflected in pneumococcal carriage dynamics, by studying seasonal and long-term patterns in pneumococcal carriage in karonga, northern malawi, over a three-year period. methods: mother/infant pairs were recruited in a longitudinal study investigating the effect of maternal hiv-status on infant pneumococcal acquisition. nasopharyngeal swabs were collected monthly for one year from infants, mothers and siblings <5 years of age. samples were collected between january 2009 and november 2011, before introduction of pneumococcal conjugate vaccine. we used generalized additive mixed models to examine seasonal and long-term trends in pneumococcal carriage incidence, adjusted for age and maternal hiv-status. results: in total, 185 mother/infant pairs and 140 siblings were included in the study. pneumococcal incidence was seasonal, with the highest incidence in the cold season (p < 0.001). a decreasing trend in pneumococcal incidence was observed in all age groups over the three-year study period (p < 0.001). for serotype 19a an upward trend was observed for infants (p <0.001) and siblings (p = 0.01). in infants, pneumococcal incidence decreased from 49.3% (95%ci 42.4-56.2%) in the cold season in 2009 to 38.4% (95%ci 32.6-44.5%) and 22.1% (95%ci 14.2-31.8%) in the same months in 2010 and 2011. conclusion: before introduction of pneumococcal vaccination in malawi, pneumococcal carriage incidence dramatically decreased during the study period. seasonal and long-term trends need to be taken into account when evaluating vaccine effectiveness, in particular when a before-after design is used. background: monitoring nasopharyngeal carriage complements invasive pneumococcal disease surveillance and provides information on circulating serotypes. we report the impact of 13-valent pneumococcal conjugate vaccine (13vpcv) on nasopharyngeal carriage in western australian aboriginal people after 13vpcv replaced 7vpcv in the national immunization program in july 2011. methods: nasopharyngeal swabs (nps) were collected opportunistically from aboriginal children and adults living in urban, rural and remote areas of western australia three years before and two years after 13vpcv was given to aboriginal children in a 2-4-6-month schedule. specimens were cultured using selective media and pneumococci serotyped using the quellung reaction. results: among 823 nps cultured post-introduction of 13vpcv, the pneumococcal carriage rate in children <5yrs was 65% and 31% in people ≥5yrs compared with 72% and 35%, respectively, in 1500 ns collected pre-introduction of 13vpcv. the most common serotypes following introduction of 13vpcv were 16f (9%), 19f (9%), 11a (7.5%) 6c (7.5%), and 19a (7%) in children <5yrs and 19f (9%), 10a (6%), 15b (6%), 6a (5%) and 6c (5%) in older people. carriage of the six additional 13vpcv serotypes declined from 18.3% to 15.0% in children <5yrs. conclusion: overall pneumococcal carriage rates in west australian aboriginal people remain high with limited decline post-13vpcv introduction. three of the most commonly carried serotypes in children <5yrs are not covered by pcv13 while serotype 19f (included in pcvs since 2001) continues to be commonly carried. ongoing surveillance is needed to follow the longer term impact of 13vpcv, identify emerging serotypes and inform future vaccine development. n. iwanaga 1 , s. nakamura 1 , k. oshima 1 , t. kajihara 1 , t. takazono 1 , y. imamura 1 , k. yanagihara 2 , k. izumikawa 1 , t. sunazuka 3 , s. omura 3 , s. kohno 1 1 department of molecular microbiology and immunology, nagasaki university graduate school of biomedical sciences, nagasaki, japan; 2 department of laboratory medicine, nagasaki university hospital, nagasaki, japan; 3 kitasato institute for life sciences, kitasato university, tokyo, japan background and aims: streptococcus pneumoniae (the pneumococcus) colonizes the mucosal surfaces of the human upper respiratory tract (urt), and occasionally leads to invasive disease. regulation of nasopharyngeal colonization could be a candidate for preventing pneumococcal infections. we investigated whether macrolides, which have variant immunomodulatory effects, could promote the clearance of pneumococcal colonization via immunomodulation. methods: peritoneal macrophages extracted from mice were pretreated with clarithromycin (cam) and azithromycin (azm). the levels of cytokines in the supernatant were determined by elisa and cytokine array, and intracellular chemokine analysis was performed by flow cytometry. the cell signaling pathway was also analyzed by westernblotting and gene silencing assay. the macrolides-mediated pneumococcal clearance was examined by using intranasal bacterial challenge in mice. em900 (a novel 12-membered non-antibiotic macrolides but has an immunomodulatory effect) was orally administered throughout this experiment. urt lavages were analyzed for the kinetics of colonization, the cellular response and inflammatory cytokines. results: the production and mrna expression of ccl2 of peritoneal macrophages were significantly induced by cam and azm treatment in a dose-dependent manner. intracellular ccl2 was also detected by flow cytometry. westernblotting showed phosphorylation of nf-kb 15 minutes after macrolides-treatment. the density of pneumococcus in urt was significantly decreased in em900 treated mice compared to untreated mice at 14 days after pneumococcal inoculation. coincidentally, the recruitment of macrophages and ccl2 mrna expression in nasal cavity were significantly increased by administration of em900. conclusion: immunomodulatory action of macrolides promotes the clearance of pneumococcal nasopharyngeal colonization by inducing the accumulation of macrophages to urt. background and aims: nasopharyngeal colonisation is the initial step in pathogenesis of pneumococcal diseases, including otitis media. pneumococcal vaccines are less effective against otitis media than they are against systemic pneumococcal infections. previous studies have suggested that streptococcus salivarius, a commercial probiotic originally isolated from the throat, could be a potential pharyngeal probiotic. we investigated the effects of s. salivarius on pneumococcal colonisation and otitis media by using in vitro and in vivo models of infection. methods: high (5 to 10 times more than pneumococci), medium (approximately equal) or low (5 to 10 times less) numbers of s. salivarius were added before, with, or after pneumococci (pre-, co-, and post-administration respectively) to human epithelial ccl-23 cells in vitro. the percent colonisation of pneumococci was determined after 3 h incubation. in experiments using infant mice, repeated pernasal administration of s. salivarius (~10 7 colony forming units (cfu)/dose) was used as an intervention in a model of pneumococcal colonisation and otitis media. bthere was a time-dependent (pre-administration more effective than co-and post-administration) and dosedependent (high numbers more effective than medium or low numbers) inhibition of pneumococcal adherence to ccl-23 cells by s. salivarius. however, s. salivarius colonised the nasopharynx of mice poorly, and did not alter pneumococcal colonisation levels or the development of otitis media in vivo. conclusion: our data indicated that s. salivarius can inhibit pneumococcal colonisation in vitro, but not in infant mice. further well-designed human trials are warranted to evaluate s. salivarius as a potential probiotic to reduce otitis media. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background: using nasopharyngeal carriage as a marker of vaccine impact, pneumococcal colonisation and its relation to invasive disease and demographic attributes were examined in children, their parents, and older adults in the uk following the introduction of pcv7 and prior to pcv13. methods: nasopharyngeal swabs were collected, between november 2010 and september 2011, from children 25-55 months of age who had previously received three doses of pcv7, their parents, and adults aged 65 years and over. pneumococcal serotyping was performed according to who guidelines with non-typeable isolates further analysed by comparative genomic hybridisation (cgh) microarray. surveillance of invasive pneumococcal disease (ipd) in england and wales was conducted throughout the corresponding time period. results: pneumococcus was isolated from 47% of children, 9% of parents and 2.2% of older adults. for the corresponding groups the proportion of serotypes covered by pcv7 were 1.5%, 0% and 15.4%, with a further 20%, 44.4% and 7.7% coverage added by those in pcv13. in each group the proportion of ipd due to the serotypes covered by pcv7 were 1.0%, 7.4% and 5.1% with a further 65.3%, 42.1% and 61.4% attributed to those in pcv13. a significant correlation between contact with children and pneumococcal carriage in older adults was noted. conclusion: in this population the rate of carriage is highest in children and those exposed to them. direct vaccine impact is exemplified by the low carriage and ipd rates of pcv7 serotypes in vaccinated children, whilst the indirect effects of herd protection are implied by similar observations in unvaccinated parents and older adults. background and aims: kenya introduced 10-valent pneumococcal conjugate vaccine (pcv10) for infants at 6, 10, and 14 weeks in february 2011 without catch-up vaccination for older children. we evaluated pcv10 impact on pneumococcal carriage among children living in a crowded, informal settlement. methods: we conducted cross-sectional carriage surveys during october to december in 2009, before vaccine introduction, and 2012, after vaccine introduction, among randomly-selected children <5 years old in kibera, an urban slum in nairobi. vaccination histories were verified. nasopharyngeal swabs were placed in stgg media, and specimens were cultured for streptococcus pneumoniae isolation after broth enrichment. pneumococcal isolates were serotyped by multiplex-pcr and quellung reaction. results: among 545 children in 2009 and 309 in 2012, median ages were 2.3 and 1.0 years, respectively. the proportion of children <5 years colonized with pneumococci was similar in 2009 and 2012 (90% and 92%, respectively). among all children, pcv10 serotypes were found in 38% in 2009 compared to 17% in 2012 (percent change, -54%; p < 0.001). serotypes with the greatest reductions were 19f (percent change, -67%) and 9v (percent change, -65%). pcv10 serotypes decreased by 57% in infants <12 months (p < 0.001) and 59% in children 1-4 years (p < 0.001). in a subset of unvaccinated children 1-4 years old (n = 85), pcv10 serotypes decreased by 61% (p < 0.001). conclusion: less than 2 years after pcv10 introduction, declines in pcv10-type colonization were substantial even in children not eligible for vaccination. our data suggest that herd effects are seen early in a program without catchup vaccination. introduction: the nasopharynx of children is the main habitat of pneumococci. the difference in pneumococcal carriage between healthy children and children with upper respiratory tract infections (urti) is usually speculative. the aim of the study was to compare serotypes and antibiotic susceptibilities of pneumococci in healthy carriage and children with urti. material and methods: a comparison was made between isolates collected during studies of pneumococcal carriage of children attending day care centres in 2009-2012 (dcc group), and nasopharyngeal clinical samples from children with upper respiratory tract infections (cs group) submitted to the microbiology laboratory at landspitalinn during the same period. comparisons were made between children of the same age. results: there were 1281 isolates from children in the dcc group and 770 in the cs group. the most common serotypes were 23f, 6a, 19f, 6b and 19f, 6a, 23f, 6b in the dcc and cs group respectively. the difference was significant for 19f (p < 0.0001), 23f (p = 0.02) and non-typable (p < 0.0001) isolates. penicillin non-susceptible pneumococci were more common in the cs group (265 isolates, 34%) compared to the dcc group (171 isolates, 14%), the difference being significant in the age groups 1.5-1.9 years (p = 0.03), 2-2.9 years (p = 0.001) and 4-4.9 years of age (p = 0.02). multi-resistant streptococcus pneumoniae was also more often found in the cs group (33% vs. 14%). conclusion: there was a significant difference in carriage of the main serotypes between the two study groups and a significantly higher resistance rate in the cs group. isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: the carriage of streptococcus pneumoniae in the nasopahrynx of children has been shown to precede disease and serves as a source of transmission in a community. we carried out the present study to determine the culture positivity and antibiotic susceptibility pattern of s. pneumoniae from nasopharynx of children. methods: as a part of community based acute respiratory infection (ari) surveillance in villages of ballabhgarh block of haryana, north india. naso-oropharyngeal swabs were collected from 1378 children suffering from ari (alri-542, auri-836) and 253 controls in the age group 0-10 years from aug 2012 to aug 2013. a total of 202 urine samples (alri-177 and 25 controls) were also collected from these children to screen for pneumococcal antigen by binaxnow. ethical approval was obtained from the institutional review committee. results: a total of 68 children out of 1378 (5%) having ari, were culture positive for s.pneumoniae in nasopharyngeal swabs. age wise distribution of s.pneumoniae culture positivity was 0-2 years -alri-28/316; auri-13/214, 2-5 years -alri-5/159, auri-3/32 and 5-10 years -alri-3/67, auri-7/302. among controls, 9 were also positive in 0-2 yrs. all isolates were sensitive to penicillin & resistant to co-trimoxazole. erythromycin resistance was seen in 18%. of the 202 urine samples positivity for pneumococcal antigen was alri-88/177 and control-12/25 with age wise distribution as 2-5yrs-alri-46/88, control-10/16. the study showed that pneumococcal positivity among children was high in our community especially in the age groups of 0-2 years. all strains remain penicillin sensitive and cotrimoxazole resistant. background and aims: nasopharyngeal (np) carriage of pneumococcus predisposes young children to invasive pneumococcal disease. this study characterizes the impact of the seven-valent pneumococcal conjugate vaccine (pcv7) on pneumococcal carriage and the microbiome in the first year of life. methods: np swabs were collected from 102 subjects from birth to twelve months at regular intervals. g1 (n = 39) and g2 (n = 30) subjects were from pcv7 naive communities and g3 (n = 39) subjects were from widely vaccinated communities. g1 subjects received pcv7 after 8 months while g2 and g3 subjects were vaccinated at 2, 3 and 4 months. microbiology techniques were used to culture and serotype pneumococci. microbiome analysis was conducted by bar-coded 16s-rrna gene pyrosequencing. results: overall pneumococcal carriage was 79% (95%ci:75 -82%), 75% (95%ci:71-79%) and 82% (95%ci:79-85%) for g1, g2 and g3 participants respectively. the prevalence of pcv7 serotypes was 29% (95%ci:24-34%) among the g1 subjects, significantly higher than among subjects from g2 14% (95%ci:11-18%) and g3 5% (95%ci:3-7%) p < 0.001. the most common pcv7 serotypes were 19f (4%), 14 (4%) and 23f (3%) while the predominant non-vaccine serotypes were 19a (13%), 13 (4%), 35b (4%) and 15b (3%) among all the children. in the first eight months of life, there were 6-fold more significant changes at the genus level (including lactococcus and staphylococcus) among g1 compared to g3 subjects. conclusion: early exposure to pcv7 does not reduce pneumococcal carriage but alters the carriage of vaccine serotypes and impacts the development of the microbiome which has important implications for the long-term effectiveness of pcv. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 j.y.r. lai 1 , r. marsh 1 , h. smith-vaughan 1 background and aims: bacterial viability can be affected by storage and transport conditions prior to processing. in remote settings, temporary storage conditions before transport to a laboratory may be necessary. this study aims to determine optimal storage conditions for maintaining pneumococcus and nontypable haemophilus influenzae (nthi) viability prior to processing or long-term storage at -80°c. methods: the study was conducted in two phases: i) a controlled in vitro experiment using four pneumococcal serotypes and one nthi to determine bacterial survival at varying concentrations in different storage conditions (liquid nitrogen (ln2) vapour shipper, dry ice, domestic freezer, domestic fridge, ice bricks, crushed ice) prior to -80°c storage; ii) investigating the impact of the different storage conditions on the viability of pneumococcus and nthi using nasopharyngeal (np) swabs. results: the in vitro experiments showed no significant difference between survival of different pneumococcal serotypes subject to different storage conditions up to 24 hours after inoculation. placement of isolates directly into a ln2 vapour shipper led to approximately 30% loss of nthi viability; findings suggest that freezing at -20°c may be necessary before ln2 shipper storage. conclusion: transport conditions for np specimens need to account for the storage and transport needs of individual bacteria of interest, and will depend on time required for temporary storage. for studies requiring a ln2 vapour shipper, specimens may need prior freezing at -20°c to maximise viability of nthi. methods: children were eligible if they were resident in a participating remote indigenous community between september 2008 and december 2012 and were 0 to <6 years of age. this analysis compares np carriage in pcv7and phid-cv10-vaccinated children (>=2 doses) < 36 months of age. results: carriage of either pneumococcus (spn) or non-typeable h. influenzae (nthi) was ~90%; around 35% pneumococci were penicillin non-susceptible and 16% azithromycin resistant. conclusion: pneumococcal and nthi carriage is almost universal in young indigenous children, regardless of vaccine type. replacement non-susceptible non-pcv types now dominate. post-booster analyses are warranted. broader vaccine protection from an early age is urgently needed. phid-cv10 serotypes 15% 11% conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background: otitis media (om) in high risk children is caused by co-infection with pneumococcus (spn) and nontypeable haemophilus influenzae (nthi). prevenar7 (pcv7) has not had a significant impact on tympanic membrane perforation (tmp) rates of 20% by 6 months in aboriginal children in the northern territory. an early, mixed vaccine schedule which maximises potential activity against diverse pathogens may be beneficial. methods: a randomised controlled trial (rct) of i) 10-valent pneumococcal h. influenzae protein d conjugate vaccine synflorix (phid-cv10) versus ii) 13-valent pneumococcal conjugate vaccine (pcv13) (at 2,4,6 months) versus iii) an early combination schedule of phid-cv10 at 1,2 and 4 months with additional pcv13 at 6 months. allocation is concealed and primary outcome (immunogenicity at 7 months of age) is assessed blind. estimated sample size is 339. nasopharyngeal (np) carriage and om are secondary outcomes. results: eighty seven infants have been randomised, 3 have withdrawn. overall prevalence of om, tmp and np carriage at 1, 2, 4, 6 and 7 mo is shown in table 1 . conclusion: high risk populations may benefit from variation of standard vaccine schedules but implementation challenges necessitate high quality evidence to support such variations. this trial provides first rct data on om, immune response and carriage in phid-cv10 and pcv13 vaccinees, and will evaluate a novel early combined option for high risk children. background and aims: the impact of conjugate pneumococcal vaccines alters the dynamics of streptococcus pneumoniae serotypes carriage necessitating surveillance of disease. prospective surveillance of pneumococcal carriage was conducted from april 2009 in a university-tertiary care hospital in hong kong sar. all paediatric patients hospitalized with with respiratory illness and/or fever with a nasopharygeal aspiration performed were included. methods: nasopharyngeal aspirates (npa) collected in to a modified transport medium were analyzed using routine microbiological procedures. micro-broth based methodology (clsi) was used to obtain the mic of the isolates while sequential-multiplex pcr (cdc/atlanta) were used for serotyping. results: data was analyzed for 6-monthly intervals; april-september and october-march. of the 10,909 npa samples, 1359 (12.5%) yielded s. pneumoniae. over the 7 time periods, a significant reduction in the pneumococcal isolation rates (p < 0.007, chi square for trend) was identified. of the 1291 isolates available for further analysis, the commonest serotypes were 19f (14%), 6b and 6c (9.8% each).percentage of serotypes/ groups included in the pcv 7 ranged from 50.2% in april-sept 2009 to 24.2% in oct-2011-march 2012, whilst those included in the pcv13 ranged from 66.5% to 40.4% for the same time periods (p < 0.005, chi square for trend). the overall cefotaxime non-susceptibility rate at meningitis and non-meningitis breakpoints (clsi) were 29.4% and 12.9% respectively. isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 conclusion: pneumococcal carriage rates among hospitalized children showed a significant reduction with the introduction of pneumococcal vaccination in hong kong. however, continuous monitoring is needed to identify long term trends that may come with serotype replacement. background: streptococcus pneumoniae, haemophilus influenzae and staphylococcus aureus are potentially pathogenic bacteria which colonize the nasopharynx (np), with hiv-infected children at greater risk for invasive disease. pneumococcal conjugate vaccine (pcv) reduces np-colonization by the vaccine-serotypes, but may affect the equilibrium of np-colonization by other bacteria in healthy children. we compare the bacterial np-colonization between hiv-infected (n = 321) and hiv-uninfected (n = 243) children vaccinated with 7-valent pcv at 6, 10 and 14 weeks of age. methods: children in soweto, south africa, had np-swabs for bacterial culture taken prior to the three pcv-doses (visits 1-3) and at 19.5, 39, 47 and 67 weeks of age (visits 4-7). swabs were cultured for bacteria by standard methods and pneumococcal serotyping done by the quellung method. results: prevalence of vaccine-serotype colonization was similar between hiv-infected and hiv-uninfected children, except visit-6 (p = 0.019); figure. overall pneumococcal (visits 1-4) and non-vaccine serotype (visits 1-5) colonization were lower in hiv-infected children. hiv-infected children had lower prevalence of s. aureus colonization at visit-1 (p < 0001), but higher prevalence from visit-4 onward (p < 0.05); whereas h. influenzae colonization was greater among hiv-uninfected from visit-2 (p < 0.05). conclusion: although hiv-infected children had a similar prevalence of vaccine-serotype colonization compared to hiv-uninfected children, they had a lower prevalence of non-vaccine serotype and h. influenzae colonization, but higher prevalence of s. aureus colonization. background and aims: up to one million children die every year due to pneumococcal disease. streptococcus pneumoniae infections increased in both incidence and severity in persons with congenital or acquired immunodeficiency. there is lack of information on the impact of pneumococcal vaccine on children older than those covered by the expanded program of immunization (epi) vaccine schedule and in those infected with hiv, as successful immunity is dependent on mounting a sufficient immune response to the vaccine. this study aimed to (1) determine the number and proportion of children carrying new (not present at baseline) vaccine serotypes of s. pneumoniae isolated from nasopharyngeal swabs at 6±2 months post vaccination in recipients of prevenar13® compared with those given hib vaccine. (2) to determine the serum antibody response (>4-fold and geometric mean concentration) to pneumococcal vaccine serotypes at 3±1 months after vaccination. method: this was a double blinded crossover randomised controlled trial of the efficacy of prevenar13® in preventing acquisition of nasopharyngeal carriage of s. pneumoniae among hiv infected children aged 1-14 years. eligible participants were randomised into prevenar13® or hib vaccines each given at baseline and 3±1 months later. nasopharyngeal and serum samples were collected at baseline and 3±1 months later. results: we have enrolled 73 under five children, the overall pneumococcal isolation rate at baseline was 71% (n = 73) and 73% (n = 68) after two doses. serotyping is still done but results will be available at the conference. conclusion: pneumococcal colonisation is common in children with hiv/aids, vaccination may reduce it but replacement colonisation may occur. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background and aims: acute otitis media (aom) is one of the most common infections in children. there are several bacterial species among principal aom-associated pathogens but the leading role is usually attributed to streptococcus pneumoniae. this study was performed to clarify etiology of bacterial aom and compare it with nasopharyngeal colonization. methods: we examined middle ear fluid (mef) obtained from 310 patients with aom who were ≤60 month old (age median, 28 months) at five pediatric hospitals in moscow (russia). in parallel, in 305 patients nasopharyngeal swab was collected. serotyping was performed by specific antisera from statens serum institute (ssi) (denmark). results: culture-positive aom was observed in 39% (121/310) of patients. s. pneumoniae was isolated in 55%, staphylococcus pyogenes in 22%, staphylococcus aureus in 14%, haemophilus influenzae in 12%, and moraxella catarrhalis in 8% of culture-positive patients. among 67 s. pneumoniae mef isolates, 15 different serotypes were identified but 6 leading serotypes contributed to >75% of the distribution (19f, n = 17; 3, n = 12; 6b, n = 9; 14, n = 5; 19a, n = 5; 23f, n = 4). mef and nasopharyngeal serotypes were the same in >90% (32/35) of cases. in a patient with aom, isolation of s. pneumoniae or s. pyogenes from the nasopharynx increased the probability of aom of that particular etiology to 60% or 75%, respectively. s. pneumoniae isolates displayed reduced susceptibility or resistance to penicillin (29%), macrolides (26%), co-trimoxazole (50%). the leading bacterial pathogen in children with aom was s. pneumoniae. available pneumococcal polysaccharide conjugate vaccines (pcv) cover from >90% (pcv-13) to 61% (pcv-7 and pcv-10) of the aomassociated serotypes. background and aims: pneumococcal infections remain a major medical problem associated with high morbidity and mortality. moreover, the resistance of streptococcus pneumoniae to conventional antibiotics is constantly growing. implementation of pneumococcal conjugate vaccines (pcvs) has dramatically reduced the incidence of the vaccine type-associated pneumococcal diseases in many countries. however, information on seroepidemiology of s. pneumoniae in russia is limited. methods: we performed serotyping and antibiotic susceptibility testing on 867 noninvasive pneumococcal isolates prospectively collected in 2009-2013 from children (median age 3.5 years) who sought medical care at five pediatric hospitals in moscow. the isolates were recovered from nasopharynx (71.2%), middle ear fluid (14.3%), and lower respiratory tract specimens (13.6%). results: in total, 45 different serotypes were identified. the leading serotypes included serotypes 19f (21.6%), 6b (12.8%), 23f (10.1%), 14 (9.1%), 6a (8.3%), and 3 (7.6%). the frequency of the pcv-7, -10, and -13 serotypes was 58.2%, 59.8%, 78%, respectively. the rate of the multidrug resistant pneumococci (mdr, i.e. resistant to >=3 antimicrobials) was 21.5%. the majority of the mdr isolates had serotype 6b, 14, 19a, and 19f . penicillin nonsusceptibility displayed 27.5% of the isolates. the resistance rate to erythromycin was 26.1%. among the examined erythromycin-resistant strains, 54% had erm(b) gene and 13% had mef gene as a single resistance determinant, whereas both determinants were found in 31% of these strains. conclusions: our data predict a good coverage of the circulating s. pneumoniae by the pcvs and could be useful for evaluating serotype distribution in support of pcv introduction in russia. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 background: invasive pneumococcal diseases (ipd) are responsible for almost 1 million deaths per year among children under five years of age. streptococcus pneumoniae, one of the main causative agents, has over 90 serotypes yet the current conjugate vaccine only includes 13 serotypes (pcv13). pneumococcal proteins are conserved across all serotypes and therefore hold potential as vaccine candidates. aims: this study aimed to investigate the transfer of antibodies against major pneumococcal antigens from pregnant mothers to their infants, and to correlate antibody concentrations with nasopharyngeal carriage (npc). methods: we analysed plasma from mother's (up to 3 months post-birth) and infants (cord blood only) to determine antibody concentrations and avidity to recombinant pneumolysin (rply), pneumococcal surface protein a (pspa) and choline-binding protein a (cbpa) using an in-house igg elisa. results: antibody transfer was antigen-dependent with significantly higher levels of antibodies against pspa and cbpa in mothers compared to cord blood but similar levels for rply. pspa and cbpa were better transferred than rply from mother to child (p = 0.0001 and p = 0.0024 respectively). antibodies to pspa and cbpa but not rply were retained up to 3 months in mothers with no significant difference in the avidity index at any time-point. conclusion: our pilot data shows that transfer of antibodies against major pneumococcal proteins from mother to child is antigen-dependent. further work will explore the relationship with npc. this information together with current studies on infant antibody development will help to elucidate levels of antibodies required for protection against npc and invasive disease. background and aims: nowadays, pneumococcus is the major cause for meningitis, with a mortality rate of 15%-40%. meningitis survivors may suffer from severe sequelae such as learning impairment, deafness, mental retardation, hydrocephalus and more. meningitis is characterized by an acute inflammation. we hypothesize that functional alterations in the brain may result from immune independent pathways since treatment with dexamethasone, in addition to the antibiotic treatment, did not improve therapy outcome. previous studies in our laboratory identified a group of cell-wall adhesins and their target molecules in lung derived epithelial cells. currently we study the possible involvement of those adhesin in streptococcus pneumoniae interaction with brain derived neural cells. methods: the ability of the recombinant adhesin to interfere in s. pneumoniae adhesion to human u251 glioblastoma multiforme and nsc-34, a hybrid of mouse neuroblastoma and embryonic mouse motor neurons, cells was studied. using confocal microscopy, the existence of the previously identified receptors in those cells was analyzed. results: under conditions in which the bacteria do not affect survival, wu2 strain adhered to u251 and nsc-34 cells. rgts, rptsa, rfba and rnox were found to inhibit bacteria adhesion to the cells. previously identified putative target molecules such as bmper, mmrn1, eps 1, pcdh19 and intβ4 were found to be expressed in both cell lines. conclusion: s. pneumoniae gts, ptsa, fba and nox protein were found to mediate bacterial adhesion to neural cells. moreover, previously identified target molecules to bacterial adhesins were found to reside in the neural cells. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 preliminary results of risk factors for pneumococcal carriage in young infants and children in fiji prior to pcv10 are shown. methods: 499 healthy 5-8 week old infants and 500 healthy 12-23 month old children participated in a crosssectional survey documenting risk factors for pneumococcal nasopharyngeal carriage. nasopharyngeal swabs were collected using standard methods. pneumococci in young infant swabs were identified by lyta quantitative pcr (qpcr). dominant α-haemolytic morphology, and an example of each morphological variant in children's swabs, were identified as pneumococci using standard methods. risk factors were assessed by multivariate logistic regression. results: for young infants, univariate analysis showed rural residence and living with other young children to be significant risk factors for carriage. after controlling for confounding, only rural residence was associated with carriage (odds ratio (or) 4.02, 95% ci 1.85 -8.73, p < 0.001). for children, univariate analysis showed coryza, cough, living with > 2 children, birth by vaginal delivery, and being indigenous fijian to be risk factors for carriage. after controlling for confounding, carriage was associated with being indigenous fijian (or 2.51, 95% ci 1.70 -3.71, p < 0.001), and birth by vaginal delivery (or 2.17, 95% ci 1.14 -4.16, p < 0.024). conclusion: preliminary findings suggest carriage risk factors may differ by age. however, results are preliminary and final analyses will be presented at the meeting. pneumococcal nasopharyngeal colonization is a pre-requisite for pneumococcal disease (pd); hiv-infection increases the risk of pd. we investigated pneumococcal colonization and serotypes acquisition in perinatally hiv-exposed children. 333 hiv-infected and 491 hiv-exposed-uninfected (heu) children who were randomized to isoniazid or placebo (p1041, tb-prophylaxis study), had 6 schedule visits between 6-42 months of age at which nasopharyngeal swabs were collected for pneumococcus serotyping. no pneumococcal vaccine was given. at study entry, 81% of the hiv-infected children were asymptomatic, 4% moderately symptomatic and 1% severely symptomatic for aids. hiv-infected children were less likely to be colonized with 13-valent pneumococcal conjugate vaccine (pcv13) serotypes than heu at 6 months of age (31.5% vs. 43.3%; p = 0.03), however, no differences in colonization were observed at the other visits. over the 36 months study period pneumococcal colonization increased in both hiv-infected and heu children from 45.1% to 76.9% (p-value for trend < 0.001) and from 57.1% to 60.2%, respectively (p-value = 0.014). the rate of overall new serotype acquisition was lower among hiv-infected than heu children (47% vs. 52%; p = 0.008), while pcv13-serotypes acquisition was similar in both groups (33-36%) and non-pcv13 serotypes were acquired less frequently by hiv-infected (11.0%) compared to heu (14%; p=0.009). acquisition of non-typeable pneumococcus was more common in hiv-infected (4%) than in heu (2%; p = 0.033). pcv13-serotypes new acquisition was common in our population and similar rates were observed in hiv-infected and heu children. despite a greater susceptibility to pd in hiv-infected children, overall and non-pcv13 acquisition rates were lower in hiv-infected compared to hiv-uninfected children. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 the 7-valent pneumoccocal conjugate vaccine (cv7) was introduced into the south african immunization program in 2009 as a three-dose schedule at 6 weeks, 14 weeks and booster at 9 months age. we studied the rate of new serotypes acquisitions in children receiving this schedule and compared it to a historical cohort of pcv-unvaccinated children. children aged 5-8 weeks were enrolled from december/09 to april/10, while the historical cohort was enrolled in 2007. participants had nasopharyngeal swabs done on seven occasions between one-month following the second pcv7 dose up until two years, with the same schedule undertaken among the historical cohort. swabs were cultured for pneumococcus. a total of 1551 nasopharyngeal swabs from 236 pcv7-vaccinated children were collected during the study, from which 1059 (68.3%) were positive for pneumococcus. the prevalence of pneumococcal colonization peaked at 41 weeks of age (n = 175/228, 76.8%) and ranged between 63-69% thereafter. overall colonization by pcv7-serotypes was 21.7%. during the first two years of life pcv7-vaccinated children acquired pneumococci less frequently than unvaccinated children (46.2% vs. 55.9%, p < 0.001), especially pcv7-serotypes (11.3% vs. 25.0%, p < 0.001). non-vaccine serotypes were acquired more often by pcv7-vaccinated compared to -unvaccinated children (32.4% vs. 27.4%, p = 0.018). acquisition of non-typeable pneumococci was similar between pcv7-vaccinated and -unvaccinated children (2.6% vs. 3.5%, p = 0.24, respectively). this study demonstrates that the 2+1 schedule implemented in south africa has resulted in a reduced risk of vaccine-serotype acquisition among pcv7-vaccinated children. as such, there is expected to be reduced transmission and consequently indirect protection against pneumococcal disease among unvaccinated individuals in south africa. s.a. nzenze 1 , a. von gottberg 2 , t. shiri 1 , l. de gouveia 2 , a. violari 3 , m.c. nunes 1 , s.a. madhi 2 1 background and aims: central australian aboriginal communities have amongst the highest reported rates of respiratory infections worldwide. there are however no community level data on the prevalence of respiratory symptoms and respiratory pathogens that may be associated with those symptoms. our aim was to address this knowledge gap. methods: we convenience sampled every individual who presented for any reason to a remote community clinic over a three week period in a non-epidemic respiratory season. demographic and clinical data were obtained. anterior nasal swabs were collected and tested for adenovirus, respiratory syncytial virus (rsv), influenza virus, parainfluenza viruses (pivs) types 1,2 3, human metapneumovirus (hmpv), rhinoviruses (rvs), coronaviruses (hcov) (oc43, 229e,nl63 + hku1), bocavirus, ki and wu polymaviruses (ki and wupyv), streptococcus pneumoniae, haemophilus influenzae, moraxella catarrhalis, staphylococcus aureus (including methicillin-resistant staphylococcus aureus (mrsa)), and bordatella pertussis using real-time pcr methods. results: 140 participants were enrolled, contributing 153 study visits and 150 nasal specimens; 21% were aged < 5 years. a respiratory symptom was present in 74 (48.4%) of all episodes. at least one virus was present in 50% of episodes with a specimen, at least one bacterium in 80% of episodes and viral-bacterial coinfection was present in 28.7%. respiratory symptoms were 2.4 times (95%ci 1.4 -4.3) more likely in episodes of viral-bacterial coinfection than those without. conclusions: the prevalence of both symptoms and pathogens are high this population. interventions to reduce the burden of respiratory disease in this population will require community wide approaches to reduce infection and carriage in both children and adults. background and aims: aboriginal children in remote regions of central australia have the highest yet reported rates of hospitalised, world health organisation (who) defined, radiologically-confirmed pneumonia. we aimed to describe the respiratory viruses and bacteria detected in deep nasal swabs associated with hospitalised pneumonia in these children. methods: datasets from two studies of hospitalised pneumonia in central australian aboriginal children aged less than 5 years were combined. chest xrays were assessed for consolidation according to the who protocol and by a paediatric pulmonologist (pp). deep nasal swabs collected on admission were analysed by pcr for 6 bacteria (streptococcus pneumoniae, haemophilus influenzae, staphylococcus aureus, moraxella catarrhalis, chlamydia pneumoniae and mycoplasma pneumoniae) and 17 viruses (human rhinoviruses, adenovirus, human metapneumovirus, respiratory syncytial viruses a and b, influenza viruses a and b, parainfluenza types 1, 2 and 3, bocavirus, wu and ki polyomaviruses and human coronaviruses huk1, oc43, nl63 and 229e). results: complete clinical, radiological and laboratory data were available on 103 children. fifty percent (n = 51) had pp-confirmed lobar consolidation and 28% (n = 29) had consolidation as per the who protocol. at least one bacterium was identified in 92.2% of all children, at least one virus in 42.7% and both viruses and bacteria were detected in 39.8%. there were no statistically confirmed differences between lobar and non-lobar pneumonia with respect to any organism. conclusion: there appears to be no clear relationship between nasal detection of respiratory viruses and bacteria and the presence of radiologically-confirmed lobar consolidation in aboriginal children hospitalised with pneumonia. introduction: upper respiratory tract mucosal surfaces are primary sites of pneumococcal infections. pneumococcal vaccines may induce production of salivary iga and igg. mucosal antibody responses to pneumococcal vaccines were investigated in a pneumococcal conjugate vaccine (pcv7) trial in papua new guinea. methods: children were randomized to receive pcv7 in a 0-1-2 (neonatal) or 1-2-3-month (infant) schedule or no pcv7. all children received pneumococcal polysaccharide vaccine (ppv) at age 9 months. saliva was collected at ages 1, 2, 3, 4, 9, 10 and 18 months. salivary iga and igg concentrations to all pcv7 serotypes and ppv serotypes 1, 3, 5, 7f, 19a were measured in 420 samples (60 children) using a multiplex fluorescent bead-based assay. results: pcv7 had little impact on salivary iga before 9 months but geometric mean titres (gmts) for salivary igg to serotypes 4, 18c and 19f were higher at ages 2-4 months in pcv7 recipients than in controls. at ages 9 and 10 months, gmts for pcv7-serotype-specific iga were 100-1778 and 891-6607 ng/ml, respectively; in pcv7-primed children and 78-1479 and 74-3020 ng/ml in unprimed children. equivalent ranges for salivary igg were 38-723 and 478-12928 ng/ml in pcv-primed children and 27-214 and 40-300 ng/ml in unprimed children. average mean fold increases (mfis) in pcv7-serotype-specific iga 1 month post-ppv were 7.6, 5.5 and 2.6 in neonatal, infant and control groups, respectively and 20.4, 12.0 and 1.3 in neonatal, infant and control groups for pcv7-serotype-specific igg. conclusion: pcv7 generally primes mucosal immune responses for boosting by ppv at 9 months. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 streptococcus pneumoniae causes serious illnesses such as pneumonia, meningitis, and acute otitis media. a main antigenic determinant of s. pneumoniae is polysaccharide (ps), which shows a poor immunogenicity as a t cell independent antigen. in this study, we applied cationic liposome for s.pneumoniae ps and examined immune responses such as mucosal iga, systemic igg and t-cell response. mucosal immunity is one of the important issues because the pathogen enters the host through the respiratory mucosa. a vaccine inducing the production of protective secretory iga, as well as systemic igg, would be desirable. the cationic liposomal ps showed higher respiratory mucosal iga compared to pneumococcal conjugate vaccine. and cationic liposome brought the t-cell dependent immunity against pneumococcal polysaccharide showing considerable high t-cells proliferation compared to ps only and high interleukin-4 (th2 marker) production. and the cationic liposome showed a depot effect at the injection site, which could induce a prolonged presentation of the incorporated antigen. all of the results were induced with a formulation composed of ps and liposome without any additional carrier proteins. these results suggest that cationic liposomal ps could be useful for immune responses against a polysaccharidebased s. pneumoniae vaccine. s.s. park 1 , s. pyo 1 , d. rhee 1 1 caseinolytic protease l (clpl) is a member of hsp 100 family, found mostly in gram-positive bacteria. here we report the characterization of recombinant clpl protein, a major heat shock protein (hsp) in streptococcus pneumoniae (pneumococcus) in vitro. previously, we characterized clpl with 6-his tag at the n-terminal on chaperone and atpase activities. however, n-terminal his-tag affected clpl functions. therefore, clpl was rechracterized without his-tag. clpl has adp and atp hydrolase activity by using either mg 2+ or mn 2+ , but mn 2+ stimulates atp hydrolase activity than mg 2+ . mn 2+ increases atp hydrolase activity as well as refolding and heat aggregation prevention activities. however, clpl does not seem to require auxiliary factors (dnakje system) for chaperone activity. clpl forms hexamer in the presence of adp, atp, and atp-γ-s. mutagenesis studies on the two walker a motifs (k127a, t128a and k458a, t459a), displayed that two nucleotide binding domains are involved in chaperone and atp hydrolase activities and hexamerizaion. taken together, pneumococcal clpl is a mn-dependent auxiliary-factor independent chaperone. s. pelton 1 , k. shea 2 , k. hsu 3 , a. loughlin 3 1 pediatrics and epidemiology, boston universithy schools of medicine and public health, boston, usa; 2 epidemiology, boston universithy school of public health, boston, usa; 3 pediatrics, boston universithy school of medicine, boston, usa background: changes in prevalence of nasopharyngeal (np) carriage of nonvaccine pneumococcal serotypes (nvst) may herald increases in ipd caused by these serotypes and potential erosion of vaccine effectiveness. objective: to evaluate changes in pneumococcal serotypes (all, nvst, pcv7, and pcv13 unique) in the np following substitution of pcv13 for pcv7 in children <2 years with catch-up through 5 years. methods: demographic information and np cultures were obtained from 5,307 children <5 years seen in primary care between 7. 1.2010 and 6.30.2013 . all isolates of streptococcus pneumoniae (sp) were serotyped by quellung reaction with type-specific antisera. results: the overall prevalence of sp carriage was 22.8%, and was lowest during summer months. no significant changes in the carriage prevalence of all sp, nvst, or pcv7 serotypes were observed. carriage of pcv13 unique serotypes declined over time (figure 1 ). streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. the pneumococcal nasopharyngeal carriage preceded and is a source of the spread of disease to others pneumococcal. indonesia is the country with the highest incidence of pneumonia in southeast asia, and lombok island in western part of indonesia has a highest pneumonia incidence. methods and results: pneumococcal nasopharyngeal isolate has been done in 1200 healthy children aged 2 months to 5 years of 5 health centre in central lombok, lombok island. on those isolates, optochin test, pcr assay, and sensitivity to antibiotics were performed. the prevalence of s. pneumoniae carrier rate was 46.17%, with distribution in less than 2 years of age and above were 26.8% and 48.8%, respectively. most commonly serotypes were 6a/b, 19f, 23f, 15b/c, and 19a. all serotypes were susceptible to majority of antibiotics, except to cotrimoxazole (36 %). overall of isolates belonged to strains covered by 50,1 % for pcv10 and 55,3 % for pcv13. we found 74.7% of the subjects exposed to passive smoking and 74.7% have pneumococcal positive isolate conclusion: the prevalence of nasopharyngeal carriage of s. pneumoniae is very high and most commonly serotypes found are quite similar to those reported ten years ago in the same area. approximately a half of carriages were covered by either pcv10 or pcv13. the serotypes distribution should be conducted to other areas to achieve the overall figure of pneumococcal pharyngeal isolate coverage by pcv background: invasive disease due to streptococcus pneumoniae is one of the leading cause of death in children under 5 years of age. nasopharyngeal colonization precedes the invasive disease in some children. factors influencing nasopharyngeal colonization by s. pneumoniae would probably help in prevention of serious illness such as pneumonia, meningitis and septicaemia. aims: to study the demographic profile of children with nasopharyngeal colonisation of s. pneumoniae. methods: a total of 500 children between 6 months to 5 years were included in the study. a detailed questionnaire was filled for each child to delineate the vaccination status, underlying risk factors and socioeconomic status. nasopharyngeal swabs were obtained from children following strict protocols and were plated immediately in the appropriate culture plates. results: out of the 500 children, 45 had grown s. pneumoniae in the nasopharyngeal swab culture. majority was males, less than 2 years of age and belonged to families with a lower income. other risk factors that were identified were average ventilation in the house hold and over crowding in a few of them. majority had received hib vaccine. smoking, duration of breast feeding, attending day care and predisposing respiratory infection or use of antibiotics did not influence nasopharyngeal colonization. conclusion: nasopharyngeal carriage of s. pneumoniae is common in male children less than 2 years of age belonging to families with a lower income. background and aims: acute respiratory tract infection (ari) is a leading cause of morbidity and mortality in young children. streptococcus pneumoniae is the most common bacterial pathogen of pneumonia in children. we used ari surveillance platform to identify common bacterial pathogens associated with acute respiratory symptoms in children below 10 years. methods: a dynamic cohort of children (population at inception 2754) in four villages of ballabgarh was kept under weekly surveillance from aug'12 to aug'13. all children were screened weekly for presence of any respiratory symptom (cough, sore throat, ear ache/discharge, nasal discharge/congestion, shortness of breath/respiratory difficulty). these ari cases were further assessed by nurses and classified into acute upper respiratory tract infection (auri) and acute lower respiratory tract infection (alri) as per who guidelines. age-matched healthy controls from same village were also selected. naso-pharyngeal swabs were taken from all-alri, controls and 5% of auri. primary cultures were done on blood agar and chocolate agar at aiims. results: in 2666 child years of surveillance in last one year -408 alri, 793 auri and 243 control naso-pharyngeal samples were taken. s. pneumoniae was found positive in 61 samples (alri-32;7.8%, auri-20;2.5%, control-9;3.7%), haemophilus influenzae positive in 21 samples (alri-13;3.2%, auri-7;0.9%, control -1;0.4%) and staphylococcus aureus positive in 6 samples (alri-5;1.2%, auri-1;0.1%, control -nil). the incidence of s. pneumoniae, h. influenzae and s. aureus in children with alri was 12.0 (95%ci:8.3-16.7), 4.9 (95%ci:2.7-8.1) and 1.9 (95%ci:0.7-4.2) per 1000 child years respectively in the population. conclusion: s. pneumoniae was found to be the most common bacterial respiratory pathogen followed by h. influenzae and s. aureus in children with alri in this community. conclusion: pneumococcal nasopharyngeal colonization has changed profoundly since the introduction of conjugate vaccines and overall colonization by pneumococcus has declined in recent years. by 2012, non-vaccine serotypes have nearly completely replaced vaccine serotypes. the impact on clinical disease remains to be seen. results: 827 pneumococcal isolates were collected over these 3 periods; an overall pneumococcal carriage rate of 63%. prevalence rates varied from 51% in 2004 (188/370 samples) to 66% in 2008 (145/220 samples) and 68% in isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 2012 (494/723 samples) . also the prevalence of individual serotypes/groups covered by pcv13 varied considerably on the 3 time points with a natural increase in prevalence of serotype 1 (0 to 13%), 4 (0 to 2%) and 14 (6 to 12%) and a natural decrease of serotype 18c (1 to 0.3%). serotypes/groups 6 and 23f remained stable (approx. 30%) whereas non-vaccine serotypes 16, 34 and 38 emerged. the theoretical pcv13 coverage varied in time between 66% and 87%. conclusions: overall pneumococcal carriage rates, serotypes distribution and theoretical vaccine coverage were highly variable between 2004 and 2012. we conclude that surveillance of pneumococcal carriage at a single timepoint can under-or overestimate the long-term impact of pcv-13 in high-risk populations. background and aims: portugal is one of the few countries where pcvs are widely used despite not being part of the national immunization program (nip) nor being reimbursed. we evaluated the evolution of serotypes carried by young children over a 17-year period, spanning the pre-vaccine era up to the early-pcv13 era. methods: nasopharyngeal swabs were obtained from children (0-6 years) attending day-care in lisbon/oeiras area in yearly cross-sectional studies conducted between 1996-2012. pneumococci were isolated and serotyped. pcv use was extracted from the child's immunization bulletin. results: 8,313 swabs were obtained (average 593/year). carriage remained stable (average 61.5%). use of pcv7 gradually increased to >70% between 2007-2010. pcv10 use was low (≤5%). pcv13 use was 63% by 2012 (among those born after 2009). major shifts have occurred in circulating serotypes (figure) . pcv7 types have declined substantially but are still in circulation. in 2012, the 6-extra pcv13 types and non-pcv13 types (including 6c) accounted for ~10% and ~75% of all isolates, respectively. in 2012, the 6-extra pcv13 types were significantly less frequent among pcv13 vaccinated than among pcv13 non-vaccinated carriers (2.9% vs 19.6%, p<0.001). isppd-9 / pneumonia 2014 mar 9-13; 3:1-286 conclusion: significant changes in carried serotypes have been occurring although not as dramatic as those reported in countries that introduced pcvs in the nip. whether these changes will be sustained is uncertain. health authorities should consider universal introduction of pcvs in portugal. objective: to provide epidemiological data on streptococcus pneumoniae carriage in high risk population, this study focuses on the serotype distribution and antibiotics susceptibility of s. pneumoniae carriage in hiv-infected children in jakarta, indonesia. materials and findings: nasopharyngeal swabs were collected from 90 hiv sero-positive children age 4 to 144 months. s. pneumoniae was identified by conventional and molecular methods. serotyping, antibiotics susceptibility test, and sequence type were performed by sequential multiplex pcr, the disk diffusion method and mlst respectively. we identified s. pneumoniae in 42 children (46.7%). serotype 19f was identified most commonly (n = 8, 19.0 %) followed by 9a and 6a/b (n = 4, 8.5%), 23f (3 isolates), 9v, 35b, 11a (two isolates each) and serotypes 18, 12f, 15b/c, 3 and 35f (single isolates each). antibiotic susceptibility was observed for chloramphenicol (85.4%), erythromycin (73.2%), clindamycin (78.0%)) and sulphamethoxazole-trimethoprim (39.0%). furthermore, multidrugs resistant isolates of serotype 19f belonging to the st320 clone (3 isolates) and the st263 clone (2 isolates) were identified. conclusion: our study gives insight into prevalence and serotype distribution of s. pneumoniae strains among young hiv patients in indonesla. these findings may help to decide upon potential preventive strategies targeting invasive pneumococcal disease in indonesia. background: invasive disease due to streptococcus pneumonia is one of the commonest causes of death in children. some pneumococcal serotypes that colonizes nasopharynx of healthy children can lead to invasive disease. it is important to identify the serotypes colonizing the nasopharynx to enable prevention by way of vaccination. aims: to determine the serotype profile of s. pneumonia isolated from healthy children. methods: a total of 500 children between 6 months to 5 years were included. a detailed questionnaire was filled to delineate the vaccination status, underlying risk factors and socioeconomic status. nasopharyngeal swabs were taken as per protocol and plated immediately.. serotyping was done using statens kit. results: 45/500 grew s. pneumoniae. 6b was the commonest serotype identified (16/45), most of them were infants with overcrowding and improper ventilation.6 children who had 23f serotype were > 2 years of age and overcrowding was again found to be a significant risk factor. 19f was seen in 5 children and there was no significant risk factor associated. serotypes 14, 4,18c, 19v and nontypeable were seen in 3, 3, 1, 1, and 10 children respectively. factors like duration of breast feeding, smoking and previous respiratory infection did not have any influence on the carriage rate. conclusion: nasopharyngeal carriage was found to be common in healthy children without any significant risk factors. serotype 6b was the commonest serotype isolated. background and aims: we recently published a set of updated world health organization (who) standard methods for detecting pneumococcal carriage, including sample collection, transport and storage, pneumococcal identification and serotyping. methods: we identified key changes in the 2013 revised recommendations compared with the 2003 guidelines. results: a single nasopharyngeal swab in stgg medium remains the sample of choice. important changes are: new recommendations or major changes specimen type document swab quality collect nasopharyngeal and oropharyngeal swabs from adults. calcium alginate, rayon, dacron or nylon swabs are acceptable for culture-based studies. swabs of inert material (e.g. nylon or dacron) should be used for molecular methods. flocked swabs have many desirable characteristics. swab collection, transport and storage 1 ml stgg medium. freeze at -80°c as soon as possible, no 'safe limit' for 4°c storage, store at -20°c for days (not weeks). culture 10 µl of specimen, record if larger volume. coba and cna plates acceptable alternatives to gentamicin-blood agar. recording semi-quantitative growth is optional at least one α-haemolytic colony (representing the dominant morphology). if other colonies are tested, results should be analysed separately. real-time lyta is the current best molecular identification approach. optochin non-susceptible isolates should be tested for bile solubility. 'wet' or 'dry' quellung method is gold-standard. latex agglutination acceptable, other methods may be suitable. important areas for future research will be described. there are important differences between the 2003 and 2013 guidelines. adherence to standard methods will reduce variability when conducting pneumococcal carriage studies. background and aims: the impact of viral upper respiratory tract infection (urti) on pneumococcal load in the human nasopharynx is uncertain. we hypothesised that acquisition of a viral urti would be associated with an increase in nasopharyngeal pneumococcal concentration in children <5 years, followed by a subsequent decrease. methods: all members of 47 households from kilifi district, coastal kenya, had nasopharyngeal swabs (nps) collected twice weekly during jan-june 2010 and tested by a respiratory multiplex pcr. swabs from children <5 years old collected two weeks before, during and four weeks after a first episode of respiratory syncytial virus (rsv) or rhinovirus with urti symptoms were also tested by quantitative real-time pcr for lyta and alu targets as a measure of pneumococcal load per μg of human dna present in the swab transport medium. results: fifty-three viral episodes were available for study. pneumococcal carriage was universal among study participants and co-infecting viruses were present in 35% of swabs. the geometric mean increase in pneumococcal concentration with acquisition of viral infection was 4-fold, p<0.001, and remained so when the analysis was restricted to swabs without co-infecting viruses. pneumococcal concentration fell 0.6-fold after viral urti but without statistical significance, p=0.144. conclusion: the modest increase in pneumococcal concentration may be an important contributing factor to the development of bacterial pneumonia or invasive pneumococcal disease among children with preceding viral respiratory tract infections at a population level. the impact on population level transmission of pneumococcal carriage during viral urti is potentially even greater. with the worldwide introduction of pneumococcal conjugate vaccine (pcv), it is imperative that carriage serotypes in children are determined in areas of vaccine introduction. pcv10 was introduced in pakistan in april 2013. methods: from two districts of sindh (karachi and matiari) 698 nasopharyngeal swabs were collected from children aged 3 months to 5 years in january 2013 (before pcv-10 introduction). swabs were subcultured on sheep blood agar and isolates with suggestive colony morphology were tested for optochin sensitivity. we found that 561 (80.4%) of the specimens yielded pneumococci. a sampling of 100 isolates, representing 100 different swabs, were shipped to the centers for disease control and prevention(cdc), atlanta ga, for serotyping using sequential real time triplexed-pcr reactions according to published cdc protocols. results: fifty-three of 100 isolates have been serotyped. of these 34 %(n=18) were 6a/b/c/d, 20.8% (n=11) were 23f, 15.%1(n=8) were 19a, 7.5%(n=4) were 19f, 7.5%(n=4) were 18c/f/b/a, 7.5%(n=4) were 9v/a, 5.7%(n=3) were 14 and 1.9%(n=1) were determined to be serotype 4. serotype determination of remaining 47 isolates is ongoing. resolution of common serogroups into individual serotypes will be carried out by quellung at cdc. conclusion: this is the first report of nasopharyngeal pneumococcal serotypes from pakistan. nasopharyngeal carriage rate among children in lower sindh is high. data obtained so far reveals high prevalence of vaccine serotypes (all either pcv10 or pcv10-related). complete serotyping of all 561 pneumococcal isolates is critical to confirm these early observations. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 k.m. shea 1 , a. rabbani 1 , s.i. pelton 2 1 epidemiology, boston university school of public health, boston, usa; 2 pediatrics, boston university school of medicine, boston, usa background: children with certain chronic diseases are at increased risk for ipd, but it is not known whether this is because they are more likely to be colonized with streptococcus pneumoniae, or because they are more likely to develop disease once colonization has occurred. methods: we compared the rate of s. pneumoniae colonization in children <5 years with underlying comorbidities to the rate in children without comorbidities. demographic information and nasopharyngeal specimens were collected from 2,441 children <5 years seen in primary care at a large urban u.s. hospital after introduction of pcv13, from july 2010-july 2013. standard microbiologic methods were used to characterize pneumococcal serotypes, and patient records were used to ascertain comorbidities. results: one third (n=937) of our study population had ≥1 comorbidity. among 2,211 recorded comorbidities, wheezing was the most common (61.6%), followed by sickle cell haemoglobinopathies (12.3%), prematurity (12.2%), and chronic heart disease (7.0%). children with a diagnosis of wheeze or asthma in their clinical record had a higher rate of colonization than children without a wheeze or asthma diagnosis (26% vs. 21%, p=0.054). although not statistically significant, children with other chronic lung (22% vs. 18%) and kidney diseases (30% vs. 22%) also had higher rates of s. pneumoniae colonization. conclusion: children with medical record evidence of wheeze appear to have increased rates of s. pneumoniae colonization. future analyses will provide insight into whether this association persists after controlling for covariates such as age and vaccination. funding: aspire award in pediatric vaccine research from pfizer, inc. background: nasopharyngeal carriage is a precursor for pneumococcal disease and can be useful for evaluating pneumococcal conjugate vaccine (pcv) impact. we studied pre-pcv pneumococcal carriage among hiv-infected and -uninfected children in mozambique. methods: between october 2012 and march 2013, we enrolled hiv-infected children age <5 years presenting for routine care at seven hiv clinics in 3 sites, including maputo (urban-south), nampula (urban-north), and manhiça (rural-south). we also enrolled a random sample of hiv-uninfected children <5 years old from a demographic surveillance site in manhiça. a single nasopharyngeal swab was obtained and cultured following broth enrichment. pneumococcal isolates were serotyped by quellung reaction. (13%), 23f (13%), 6a (9%), 6b (6%), 19a (5%), 13 (5%) and 14 (5%) were most common; serotype could not be determined for 36 (6%). the proportion of isolates included in the 10-and 13-valent vaccines (pcv10 and pcv13) was 47% and 64%, respectively, with no significant differences by hiv status. conclusion: pneumococcal carriage was common, with little variation by geographic region or hiv status. serotype coverage of pcv10, which was introduced in mozambique in april 2013, was lower than that of pcv13. ongoing carriage studies will show whether pcv10 will have similar benefits for hiv-infected and -uninfected children. background and aims: determining nasopharyngeal carriage of pneumococcal serotypes is a valuable epidemiological surveillance tool. however, current serotyping methodologies are limited in their ability to detect multiple serotype carriage, thus underestimating the complexity of carriage by missing rare or low abundant serotypes. the health protection agency conducted a longitudinal nasopharyngeal carriage study (a) of 489 individuals in england over 10 months pre-pcv7 in 2001/2 and a cross-sectional study (b) of 400 individuals post-pcv7in 2009. conventional culture and serotyping identified 932 and 125 swabs containing pneumococci respectively. the swabs were stored at -70 o c in skimmed milk, tryptone, glucose, glycerol broth (stgg). the present study used a dna microarray to re-examine a sample of swabs previously yielding a single serotype to assess the prevalence of co-colonisation with multiple serotypes. methods: 410/932 pneumococcal-positive swabs from study a and 115/125 from study b were re-examined using a molecular serotyping dna microarray (hinds et al). results: 17% samples contained multiple serotypes: 14% contained two, 2% three and 0.4% four serotypes respectively. a further 13% samples contained "serotype variants" where cps loci did not match known serotypes; possibly indicating non-typable pneumococci, novel serotypes or closely related streptococcus spp. conclusion: the dna microarray detected 17% co-colonisation in a subset of swabs from previous carriage studies, despite long-term storage at -70 o c for several years. conventional methods had only detected 0.16% co-colonisation. emergence of non-vaccine serotypes post-conjugate vaccine introduction may partly result from unmasking rather than serotype replacement. co-colonisation will have a significant impact on future modeling studies. background: the cholesterol-dependent pore-forming toxin pneumolysin is a key virulence factor of streptococcus pneumoniae. it has been shown to be the cause of apoptosis and complement activation, as well as cause damage to tissues in the lung and brain. detection of pneumolysin by tlr4 has been described; however reports are conflicting, depending on the model and bacterial strain used. there are very few reports about the role of tlr4 in the detection of pneumolysin in human primary immune cells. methods: human monocyte-derived dendritic cells (dcs) were treated with sirna to tlr4 and infected with unencapsulated serotype 4 pneumococci (t4r), the pneumolysin mutant (t4rδply) or treated with highly purified recombinant pneumolysin. the secretion of the pro-inflammatory cytokine il-12p70 was measured in the cell culture supernatant of infected dcs. results: the pneumolysin mutant t4rδply induces il-12p70 secretion levels in dcs which are up to 2000 times higher than the levels induced by t4r. the il-12p70 secretion in response to both strains is dependent on the uptake of the bacteria by dcs and does not require tlr4. recombinant pneumolysin, in contrast, induces tlr4dependent secretion of il-12p70. conclusion: we do not currently understand the complex signaling effects of pneumolysin on dcs. our results indicate that the stimulation with purified toxin has different effects on dcs than in the context of infection with whole bacteria. we hypothesize that pneumolysin has an inhibitory function in the context of bacterial infections and we are setting out on investigating this effect with our future studies. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 introduction: because children are the main transmitters of pneumococci, carriage studies focussing on the young provide good information on the circulating serotypes. in 2011, the 13-valent pneumococcal conjugate vaccine (pcv13) replaced the 7-valent vaccine (pcv7), which was used since 2006 for childhood immunisation in norway. we assessed vaccine-induced changes in carriage among children younger than 6 years by comparing the pcv13 sample with a pre-vaccine and pcv7 sample. methods: a cross-sectional sample with questionnaire data and nasopharyngeal swabs was obtained in autumn 2013 from children attending day-care centres in and near oslo, the norwegian capital. all isolates were serotyped and antimicrobial-susceptibility was tested. results were compared to samples obtained in autumn 2006 (611 swabs, 539 isolates) and autumn 2008 (602 swabs, 563 isolates). results: we obtained 367 swabs with 244 isolates (carriage-prevalence 62% [95%ci 54-70]) but continue sampling until ≥800 swabs are obtained. carriage was highest among the youngest (<24 months; 80% [95%ci 67-89]). in the pre-vaccine and pcv7 samples, the overall prevalence was 78% [95%ci 73-82] and 80% . the prevalence of pcv13-serotypes decreased from 540/1000 to 316/1000 to 93/1000 children, respectively. the decrease was observed in all age-groups. while after pcv7 introduction the prevalence of non-vaccine serotypes increased from 336/1000 to 606/1000, after switching to pcv13, the prevalence remained constant (569/1000). non-pcv serotypes 21, 35f, 11a and 23a have become the dominant serotypes. conclusion: preliminary results indicate decreased carriage of vaccine serotypes after switching from pcv7 to pcv13, with no increase in carriage of non-vaccine serotypes. background: three leading pathogens responsible for bacteremic pneumonia in hiv infected children are streptococcus pneumoniae, staphylococcus aureus, and haemophilus influenzae. bacterial interference, or competition amongst organisms in the nasopharyngeal space, is well documented. studies investigating dynamics of these associations in hiv infected mother and children are not well reported. aim: to investigate bacterial associations of s. pneumoniae, s. aureus, and h. influenzae in the nasopharynx of mother and children with hiv infection methods: four nasopharyngeal samples were collected from pneumococcal vaccine naïve, hiv infected children ages 2-15 years, and their mothers, at two month intervals over the course of six months. calcium alginate swabs were collected and placed in stgg media and processed in the microbiology laboratory using standardized protocols. we have collected about 404 from children and 375 from mother, till now. overall dual carriage with pneumococcus and s. aureus was found to be 13/404 in children and 3/375 in mothers (all hiv infected). similarly, dual carriage with pneumococcus and h.influenzae was found to be 25/404 in children and 2/375 in mothers. a positive association was seen between pneumococcus and h. influenzae [odds ratio (for mother): 13.84; 95% ci : 1.06-126.82; odds ratio (for children): 5.62; 95% ci : 2.74-11.66]. any association between pneumococcus and s. aureus was not found in hiv infected mother or children [odds ratio (for mother) : 1.29; 95% ci: 0.23-4.78; odds ratio (for children) : 0.67; 95% ci: 0.32-1.33]. no conflict of interest isppd-9 / pneumonia 2014 mar 9-13;3:1-286 the perch study group 1 1 international vaccine access center, johns hopkins bloomberg school of public health, baltimore, usa background: low specificity of definitions for pneumococcal pneumonia (pp) limits evaluation of pneumococcal conjugate vaccine (pcv) impact. we investigated the usefulness of absent streptococcus pneumoniae carriage in assessing pp. methods: perch studies severe/very severe hospitalized pneumonia among children aged 28d-59m. the presence of nasopharyngeal (np) carriage by pcr (lyta) or culture was calculated among cases using microbiologicallyconfirmed pneumococcal pneumonia (mcpp), who-defined alveolar consolidation (cxr-ac), and cxr-ac or other infiltrate plus elevated c-reactive protein (crp) as outcome measures. odds ratios, adjusted for site and age, were calculated. *south africa only npv of pneumococcal carriage for mcpp was relatively high (table) . npv for the cxr-ac outcomes were lower. stratifying by prior antibiotic use and pcv status had little impact on findings. npv decreases as prevalence of pp increases and specificity decreases (figure). figure: negative predictive value of carriage as a function of specificity and prevalence of pneumococcal pneumonia among childhood cases of severe/very servere hospitalized isppd-9 / pneumonia 2014 mar 9-13;3: conclusion: absence of pneumococcal carriage might increase specificity of pp definitions which might be applicable in pcv impact evaluations. however, the lower npvs for cxr-ac and for cxr-ac/other infiltrate plus elevated crp need further clarification. pediatrics, queen silvia's children's hospital sahlgrenska university, gothenburg, sweden; 2 pediatrics, sahlgrenska university hospital, gothenburg, sweden background and aims: the serotype distribution of pneumococci has changed after large-scale use of pneumococcal conjugate vaccines (pcv). data indicate that serotypes also changed over time before availability of pcv. the aim of this study was to compare serotypes of pneumococci obtained from normally sterile body fluids in 2 swedish studies with strains isolated during the 1970s + 1980s and during 1998 -2001, i.e. long before any pcv was available. methods: 215 strains were serotyped in the old and 836 strains in the new study. serotyping was performed with the capsular swelling test. results: the 7 most common serotypes in the first study were in descending order 3, 4, 14, 7f, 23f, 6a and 6b and in the new study 1, 7f, 9v, 14, 4, 12f and 6b. significant increases were seen in serotypes 1 (2 -14 %), 9v (2 -9 %) and 12 f (<1 -6 %). serotype 3 decreased significantly (12 -4 %). serotype 19a, which has increased significantly in the us after widespread use of pcv7 and in 2 countries before pcv7 was introduced, (israel, korea), remained unchanged in the present comparison (3.7 and 3.1 %). conclusions: major changes in the serotype distribution occurred in sweden (as in many other countries) before any pcv was available. changes in serotype distribution may therefore in some cases be due to natural changes and not only to replacement of vaccine types with nonvaccine types. studies have demonstrated that carriage is a necessary precondition for invasive pneumococcal disease (ipd). we assessed pneumococcal np colonization prevalence in india and in neighboring countries to assess if there were systematic differences. methods: we reviewed published and unpublished studies reporting on pneumococcal colonization prevalence among healthy children <15 years of age in india and neighboring countries from 1993 to 2013. study characteristics, colonization prevalence, and antibiotic resistance were systematically abstracted. we compared agespecific colonization prevalence in india to other countries. results: we identified 15 pneumococcal np colonization studies from india and 21 from surrounding countries. in all studies, colonization prevalence increased immediately following birth and peaked between 5-9 months of age; peak prevalence for studies in india (range: 46-77%) was similar to other countries (42-85%). colonization prevalence did not decline markedly (>30%) in any studies during age 1-10 years, except one india study with a rapid decrease after age 7 months. pneumococcal np colonization prevalence after age 1 year in india (range 20-57%) overlapped with prevalence in other countries (28-83%). data were insufficient to determine whether antimicrobial resistance or antibiotic use explained variation in colonization between studies. conclusions: pediatric pneumococcal np colonization prevalence in india is similar to surrounding countries. risk factor prevalence for np colonization was not reported and may explain colonization variation between studies. pneumococcal colonization prevalence varies between studies but does not systematically vary between countries in south and southeast asia. isppd-9 / pneumonia 2014 mar 9-13;3:1-286 pediatric immunology and infectious diseases, wilhelmina children's hospital university medical center utrecht, utrecht, netherlands; 2 centre for immunology of infectious diseases and vaccines, national institute for public health and the environment (rivm), bilthoven, netherlands; 3 diagnostic microbiology, regional laboratory of public health, haarlem, netherlands background and aims: the gold standard for streptococcus pneumoniae carriage detection is the conventional culture of a nasopharyngeal swab. saliva however, has a history of being one of the most sensitive methods in surveillances on pneumococcal colonisation (heffron, 1939) . here, we compared the sensitivity of nasopharyngeal swabs and saliva samples from pcv7-vaccinated 24-month-old children tested for s. pneumoniae and nasopharyngeal serotype carriage using conventional and molecular diagnostic methods. methods: nasopharyngeal and saliva samples were simultaneously collected from 289 asymptomatic 24-month-old children, cultured and pneumococcal strains were serotyped by quellung method. dna extracted from harvests of all bacterial growth on pneumococcus-selective medium was tested for s. pneumoniae and serotypes present using quantitative-pcr (qpcr) targeting species-specific genes lyta (carvalho, 2007) and piaa and sequences specific for subset of serotypes (azzari, 2010). results: altogether 240 (85%) of 289 24-month-old children were identified as carriers by any method. molecular detection of s. pneumoniae in culture-enriched nasopharyngeal samples had highest sensitivity (73%) followed by qpcr of cultured saliva (60%) and conventional culture of nasopharyngeal swabs (57%). isolation of live pneumococci from saliva generally failed due to abundant polymicrobial growth. for the subset of serotypes targeted by qpcr (1, background and aims: saliva has a history as being one of the most sensitive methods for streptococcus pneumoniae carriage detection (heffron, 1939) . here, we applied molecular diagnostic methods to study pneumococcal carriage in saliva from schoolchildren. methods: saliva was collected from 50 students (aged 5 to 10 years) of a rural school near utrecht, transported to the lab on wet ice, cultured and the remaining volume stored frozen. cultures were inspected for s. pneumoniae colonies and then all bacterial growth was harvested. dna extracted from raw and culture-enriched samples was tested for the presence of s. pneumoniae specific genes lyta and piaa using quantitative-pcr (qpcr) and considered positive when both genes had c t values below 40. sample serotype composition was determined in dna extracted from culture-enriched saliva samples using qpcr (azzari, 2010) and by analysing sequences generated by conventional pcr (carvalho, 2010; carvalho 2013) . results: two children (4%) were culture-positive for s. pneumoniae. thirty-two (64%) children were qpcr-positive for s. pneumoniae in raw saliva and 44 (88%) in culture-enriched samples. using molecular methods to determine sample serotype composition, we detected 83 pneumococcal strains of 22 serotypes in 40 of 50 samples from carriers, with 26 carriers (59% of 44) positive for 2 to 6 serotypes. conclusion: conventional culture detection of s. pneumoniae in saliva is extremely difficult due to saliva's polymicrobial nature. these limitations were addressed by combining culture-enrichment and sensitive molecular methods, resulting in more than ten-fold higher rates of pneumococcal carriage and high rates of co-colonisation detected in schoolchildren. pneumococcal colonization and carriage comparison of the 2003 and 2013 world health organization (who) guidelines for detecting upper respiratory carriage of streptococcus pneumoniae department of infectious disease surveillance and control, national institute for health and welfare portugal; 10 epidemiology and demography, kemri-wellcome trust research programme, kilifi, kenya; 11 vaccine programme unit, national institute for health and welfare key: cord-265506-fxus6n65 authors: westrupp, elizabeth m.; karantzas, gery; macdonald, jacqui a.; olive, lisa; youssef, george; greenwood, christopher j.; sciberras, emma; fuller-tyszkiewicz, matthew; evans, subhadra; mikocka-walus, antonina; ling, mathew; cummins, robert; hutchinson, delyse; melvin, glenn; fernando, julian w.; teague, samantha; wood, amanda g.; toumbourou, john w.; berkowitz, tomer; linardon, jake; enticott, peter g.; stokes, mark a.; mcgillivray, jane; olsson, craig a. title: study protocol for the covid-19 pandemic adjustment survey (cpas): a longitudinal study of australian parents of a child 0–18 years date: 2020-08-31 journal: front psychiatry doi: 10.3389/fpsyt.2020.555750 sha: doc_id: 265506 cord_uid: fxus6n65 background: the covid-19 pandemic presents significant risks to the mental health and wellbeing of australian families. employment and economic uncertainty, chronic stress, anxiety, and social isolation are likely to have negative impacts on parent mental health, couple and family relationships, as well as child health and development. objective: this study aims to: (1) provide timely information on the mental health impacts of the emerging covid-19 crisis in a close to representative sample of australian parents and children (0–18 years), (2) identify adults and families most at risk of poor mental health outcomes, and (3) identify factors to target through clinical and public health intervention to reduce risk. specifically, this study will investigate the extent to which the covid-19 pandemic is associated with increased risk for parents’ mental health, lower well-being, loneliness, and alcohol use; parent-parent and parent-child relationships (both verbal and physical); and child and adolescent mental health problems. methods: the study aims to recruit a close to representative sample of at least 2,000 adults aged 18 years and over living in australia who are parents of a child 0–4 years (early childhood, n = 400), 5–12 years (primary school n = 800), and 13–18 years (secondary school, n = 800). the design will be a longitudinal cohort study using an online recruitment methodology. participants will be invited to complete an online baseline self-report survey (20 min) followed by a series of shorter online surveys (10 min) scheduled every 2 weeks for the duration of the covid-19 pandemic (i.e., estimated to be 14 surveys over 6 months). results: the study will employ post stratification weights to address differences between the final sample and the national population in geographic communities across australia. associations will be analyzed using multilevel modeling with time-variant and time-invariant predictors of change in trajectory over the testing period. conclusions: this study will provide timely information on the mental health impacts of the covid-19 crisis on parents and children in australia; identify communities, parents, families, and children most at risk of poor outcomes; and identify potential factors to address in clinical and public health interventions to reduce risk. the world health organization declared covid-19 a pandemic on the 11 th of march 2020. consistent with government responses around the world, the australian federal and state governments introduced an increasingly strict regime of social distancing/ isolation measures to slow the rate of infection (1) . these measures may present significant risks to the population, over and above the health threat associated with covid-19 (2, 3) . findings from a cross-sectional study of 2,077 participants recruited in 22 countries in late march and early april 2020 indicated that adult mental health symptoms at that time were elevated compared to historical norms, with participants' concern about the covid-19 pandemic and loss of employment associated with higher levels of mental health problems (4) . it is as yet unknown what the full impact of the pandemic will be on australian families. the covid-19 pandemic represents an unprecedented confluence of risk in australia and globally in this century, including: (1) a high level of uncertainty in regard to the parameters, time frames, and outcomes of the pandemic; (2) high rates of unemployment or underemployment, and housing and economic uncertainty; (3) threat to, or reduction of protective factors, such as social and community connection, physical activity, access to greenspace, and other co-curricular activities; and restricted access to clinical, community, family, and other supports and services; (4) increased pressure on parents to supervise and/or home-school children while juggling working from home; and (5) risk associated with being 'locked in' with family members in close quarters. it is unknown what effect the combination of these risks may have on the population of parents. however, each of these factors have an evidence-base demonstrating potential risks to adult and child mental health and wellbeing (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) . there is evidence showing increased risks of mental health problems, drug and alcohol use, and family violence during and after crisis events and disasters (5) (6) (7) 17) . job loss, employment uncertainty, and difficulties in juggling work and family roles are associated with increases in parent mental health problems, couple conflict, and child mental health problems (8) (9) (10) (11) (12) (13) (14) (15) (16) . finally, there is evidence that quarantine is associated with a range of negative psychological outcomes including post-traumatic stress symptoms, confusion, and anger (3) . it is important to understand the experiences and consequences of the covid-19 pandemic for all australian families in order to plan for appropriate intervention and support, both during and after the pandemic period. however, the pandemic is likely to have a disproportionate effect on vulnerable parents and families. there is an urgent need to understand the impact for families with pre-existing risk factors to ensure that any public health interventions are appropriately tailored to these subgroups (2) . mental health problems are highly prevalent, affecting approximately one in five adults in australia (18) . it will be important to understand how adults with a pre-existing mental health problem or other personal vulnerabilities, such as difficulties in managing relationships and emotions (i.e., attachment insecurity and difficulties regulating emotions), respond to the covid-19 pandemic. in addition, approximately one in seven children and adolescents experience a mental health or neurodevelopmental disorder, such as attention-deficit/hyperactivity disorder or autism spectrum disorder, equating to about 560,000 young people in australia (19) . in australia and other nations, child mental health problems are clustered in places of disadvantage (20) . to88 date, there is limited evidence as to how place-based epidemic management affects disadvantaged communities. this study represents an important opportunity to understand how australian communities and families affected by such conditions adjust to a global pandemic. further, adults with chronic physical health conditions (such as diabetes, cardiovascular disease, and autoimmune conditions) are also at increased risk of negative outcomes via the potential for (1) more serious illness outcomes (21), (2) exacerbation of their health condition(s) caused by psychosocial stress and depression (22) (23) (24) ; and increased risk of infection in context of immune system impairment (25) or immunosuppressive treatments (26) . this study will investigate the impact of covid-19 on the health and wellbeing of parents, children, and families. specifically, the study will examine: this is a longitudinal cohort study of australian parents of a child aged 0-18 years. the study comprises two sets of online surveys scheduled on a regular basis for the duration of the covid-19 pandemic. the surveys include: 1. a repeated baseline survey (20 min) scheduled at baseline and at 3-month intervals and 2. a brief longitudinal survey (10 min) scheduled every 2 weeks. the time frame of the study will extend across the duration of the social distancing measures implemented by the australian federal and state governments to manage the covid-19 pandemic in australia. the federal government released a statement estimating that the likely time frame will be a period of six months from march 2020 to september 2020 (27) . the regularity and time-frame of the longitudinal surveys will be reviewed every 2-3 months to ensure that benefits of regular follow-up are weighed against potential for participant burden and fatigue. participants will be eligible to participate if they are an australian resident, 18 years or over, and are a parent of a child aged 0-18 years. survey information and advertisements will be written in english, so it is expected that people with adequate english fluency will complete the survey. parents will be recruited via paid and unpaid social media advertisements. a range of methods will be used to target specific groups to increase the representativeness of the sample (e.g., targeting via postcodes and demographic factors). the style and wording of advertisements is important in determining recruitment success. consistent with prior research, this study will employ advertisements that: (1) refer to research; include the deakin university affiliation, refer to the incentive (as detailed below), and are written in engaging yet plain language (28) . participants will primarily be recruited via the social media platform, facebook, given demonstrated success in recruiting hard-to-reach populations on this platform (29, 30) . a project 'business' facebook page will be established to maintain contact with participants, affiliate organizations, and the wider public. the page will be monitored regularly by project staff and any content/comments deemed inappropriate or offensive will be promptly removed. both paid and unpaid recruitment strategies on facebook will be used in the current study. unpaid strategies will include making contact with established interest groups, parenting groups, and organizations on facebook via the project facebook page and/or deakin university email (i.e., where email addresses are provided), and requesting that these sites endorse our project by posting the project advertisement so that it is visible to their group members. paid strategies will involve using facebook's systems to target recruitment to specific subpopulations via demographic variables (e.g., parents of children 0-18 years; fathers, remote/regional postcodes, and parents speaking a language other than english), posting paid advertisements on all available platforms, including facebook and instagram. we will also use other social media platforms (e.g., reddit, twitter, instagram, and whatsapp) following the same protocols to post both paid and unpaid advertisements as per our current use of facebook. the study aims to recruit a minimum of 2,000 parents of a child 0-4 years (early childhood, n = 400), 5-12 years (primary, n = 800), or 13-18 years (secondary, n = 800). the advertisements used for recruitment will contain a web hyperlink which will direct participants to an initial qualtrics survey website. the landing page for the survey will contain a brief description of the purpose of the research. on the next page, participants will be asked two eligibility questions, checking that they are a parent of a child 0-18 years and that they currently live in australia. if participants are not eligible to participate, they will be directed out of the survey with an explanation of the eligibility criteria. eligible participants will then be presented with a plain language statement and online consent form available for download as a pdf document. on this page, participants will be asked to check a box that confirms that they have read the plain language statement, which they understand its contents, and consent to participate in the study. participants will then be asked to provide contact information with details of their first name, phone number, and email address. a brief explanation will be provided that this information will assist the research team in contacting the participants for the follow-up survey, sending reminders, and contacting winners of the monthly prize draw. on completion of the baseline survey, participants will be automatically allocated a unique id number, which will be embedded in their subsequent surveys to identify them and link their data. an invitation (and web link) will be included at the end of the qualtrics baseline survey inviting the potential participant to 'friend' the cpas page on facebook. this is intended as a strategy to maximize participant retention rates and promote participant connectedness to the study. facebook allows a stable means of communication where participants can be contacted for future time points of the study regardless of changes in contact details. this request would be a means of keeping the study in the minds of participants as study updates and news would appear on the participant's own facebook 'news feed.' only one email request would be sent with no follow-ups, even if the request is declined or ignored. no changes would be made to the previously approved facebook privacy settings. participants will be re-contacted every 2 weeks after completion of the baseline survey via an automated email invitation. participants will be recruited on a rolling basis to maximize reach and sample size. regardless of whether a participant responds in a given week, participants will remain on the active list and will continue to receive survey invites and reminders. all emails to participants will contain an opt-out link with two options: to opt-out from the survey or to opt-out of the study entirely. participants who open the baseline survey, consent to participate, and who have provided their contact details but did not complete the full version of the online baseline survey will be sent an email reminder about completing the survey 24 hours later. participants will be sent an email reminder 24 hours after each fortnightly longitudinal survey is sent. if participants have not completed a survey or made contact with the study team over a period of three consecutive surveys, the team will use a range of methods to attempt to re-engage participants in the study. this may include sending an additional follow-up email, sending an sms reminder and/or calling the participant on their mobile phone number, or contacting the participant via facebook (refer to section facebook tracing, below). we will limit all contacts to a maximum of 1 direct contact (i.e., involving communication from the participant) within a week, via email, sms, or voicemail message. in order to understand reasons for participant drop out, we will ask participants two brief questions when making contact via phone, a question asking about the participants' reasons for not completing follow-up surveys ("day to day life is very busy"; "want to complete but forget or never get around to it"; "change in your circumstances-decrease in job hours/loss job; increase in job hours, gained employment, started studying, stopped studying, change in caregiving responsibilities"; "lost interest in the survey"; "other") and a question assessing participants' level of functioning ("compared to when you first completed the survey in aprilthis was around the beginning to middle of the most restrictive period in australiawould you say you are going about the same, better, or worse right now? "). for participants whom we are not able to contact (no email response or a return to sender email; and no evidence that we reached the correct participant's phone-i.e., no identifying voicemail message or the number was disconnected), we propose attempting contact via facebook. facebook searches will be conducted to generate evidence from which to identify participants. only publicly available information will be viewed based on information publicly visible on users' profiles, "liked pages," "groups," or "check-ins" to verify the location of the participant, compared to their last known residential address. if the study team has strong evidence to link a facebook user with the identity of a previous participant, participants will be contacted through facebook messenger. research has shown benefits associated with the use of incentives in social media recruitment via facebook (28, 31) . participants will be entered into a prize draw for 1 of 10 au $50 online gift vouchers if they have completed at least one survey for every month of the survey. we have estimated vouchers based on a study of six months' duration (6 prize draws, 10 vouchers offered at each draw, a total of 60 vouchers). consent will be obtained at baseline. participants will also complete separate (optional) consent to be contacted for future research participation. participants will be informed that they are under no obligation to participate and advised that they are free to withdraw at any time without consequences. study data will be managed using qualtrics, hosted at deakin university (32) . data will be downloaded from the qualtrics server on a weekly basis and stored on servers maintained by deakin university. table 1 provides an outline of study measures. where possible, measures will be harmonized with the longitudinal study of australian children (lsac), a population representative sample of australian families. lsac includes two cohorts of children and families recruited in 2005 and followed biennially on an ongoing basis (altogether, n = 10,000 at baseline) (52). first name, email address, mobile number, and postcode. about adult: age, gender, country of birth, aboriginal and torres strait islander status, language other than english spoken at home, education, relationship status, whether living with partner, and number of children in the household. demographics prior to covid-19: employment, study, household income, source of income, and shortage of money. items about housing: type of dwelling, owned or rented, number of bedroom, number of people living in house, satisfaction with quality of housing, and access to private outdoor space at current home. about partner: gender; partner's relationship to child, employment, and education. about child: age, gender, and education setting. items adapted from the coronavirus health impact survey (crisis) v0.1 (33) . household: covid-19 diagnosis, test result, or symptoms. about adult: participant or family members affected by covid-19 (fallen ill, hospitalized, self-quarantine, and passed away), financial problems or housing and food insecurity related to covid-19, working from home, frequency and type of contact with work colleagues, impact on family life, food/ medical shortages, use of media, feelings and attitudes about covid-19, impact of covid-19 on family life (short-answer question, "how has covid-19 affected your family life?"), coping strategies (short-answer question, "what strategies are helping you to stay calm in the current situation?"), frequency of use of news sources (newspapers, television, social media, radio, rated on 6-point scale from 'not at all' to 'multiple times per day'), appraisals of covid-19 as a serious health risk, and whether likely to catch covid-19 (both rated on a 7-point scale from 'strongly disagree' to 'strongly agree'). about child: presence of a daily routine at home, time outside home (going to stores, parks, etc.), child's relationship quality with their friends (rated on 5-point scale from 'a lot worse' to 'a lot better'). whether school classes are running on campus, school attendance on campus or online. for children homeschooling: whether child home with parent while they work, child's internet/computer access at home, whether they have assignments to complete from home, amount of school work completed each day, and parents rating of how well they are managing child's home learning (4-point scale from 'very poorly' to 'very well'). personal wellbeing index (34) (seven items). seven domains: standard of living, personal health, achieving in life, personal relationships, personal safety, community-connectedness, and future security. example item: "how satisfied are you with … your standard of living?" rated on a 11-point scale from 'no satisfaction at all' to 'completely satisfied'. introvert/extrovert (one item, designed for the current study) "do you consider yourself an introvert?" rated on a 7-point scale from 'introvert' to 'extrovert.' depression and anxiety scale (dass) 21-item version (35) . three subscales: depression, stress, and anxiety (seven items each). example item: "i found it hard to wind down." rated on a 4point scale from 'did not apply to me at all' to 'applied to me very much, or most of the time.' mental or physical health diagnosis (baseline and one fortnightly survey only) one item (baseline): "have you ever had a professional diagnose or treat you for a mental or physical health condition? what was the condition?" one item (presented at one fortnightly survey): have you ever been treated or diagnosed for any of the following chronic physical conditions by a health professional? ulcerative colitis, crohn's disease, endometriosis, cardiovascular disease (e.g., coronary heart disease, stroke, and heart failure); hypertension (clinically high blood pressure), type 1 diabetes, type 2 diabetes, and other. physical activity (one item) from the longitudinal study of australian children (lsac). item: "about how many days each week do you do at least 30 min of moderate or vigorous physical activity (like walking briskly, riding a bike, gardening, tennis, swimming, running, etc)?" rated from 1 to 7 days. sleep (one item) from lsac. item: "during the past month, how would you rate your sleep quality overall?" rated on a 4point scale from 'very good' to 'very bad.' alcohol consumption (one item) from lsac. item: "how often do you have a drink containing alcohol?" rated on a 7-point scale from 'never' to 'every day. ' cigarette smoking (one item) from lsac. item: "how often do you smoke cigarettes?" rated on a 3-point scale from 'do not smoke at all' to 'at least once a day.' experiences in close relationships scale-relationship structures (ecr-rs) (38) (nine items). two subscales: attachment anxiety baselinefortnightly type online intervention likelihood of using self-guided or therapist assisted online mental health intervention (two items) baselinefortnightly the longitudinal study of australian children (lsac) is a population-representative government-funded study comprising of two cohorts of children and their families recruited in 2005 and followed biennially (together, n = 10,000). and attachment avoidance. example item: "it helps to turn to people in times of need." rated on a 7-point scale from 'strongly disagree' to 'strongly agree.' brief resilience scale (brs) (39) (six items). example item: "i tend to bounce back quickly after hard times." rated on a 5-point scale from 'strongly disagree' to 'strongly agree.' ucla loneliness scale (40) social support (one item) from lsac. item: "overall how do you feel about the amount of support or help you get from family or friends living elsewhere?" rated on a 4-point scale from 'i get enough help' to 'i don't get any help at all' and 'i don't need any help.' social provisions scale (45) (one item selected). item: "when i am feeling stressed about a new or unknown situation, i can rely on my partner to comfort me." rated on a 7-point scale from 'strongly disagree' to 'strongly agree.' secure base characteristics scale (46) (one item selected). item: "my partner encourages me to draw on my skills and abilities to deal with challenges". rated on a 7-point scale from 'strongly disagree' to 'strongly agree.' postcodes used to derive neighborhood disadvantage according to the socio-economic indexes for areas (seifa) advantage and disadvantage (47) . interpersonal mindfulness in parenting (iem-p) (48) (three items). example item: "when i'm upset with my child, i notice how i am feeling before i take action." rated on a 5-point scale from 'almost never' to 'almost always.' emotion-focused parenting (three items). example item: "when my child experiences strong emotions (sad, angry, scared), i connect with them and provide comfort and support." rated on a 5-point scale from 'almost never' to 'almost always.' parenting irritability (five items) from lsac. example item: "in the past 6 months, how often would you say … i have raised my voice with or shouted at this child." rated on a 10-point scale from 'not at all' to 'all the time.' global child health from lsac. item: "in general, is your child's current health…" rated on a 5-point scale from 'excellent' to 'poor.' professional diagnosis or treatment (one item). item: "has your child ever been diagnosed or treated for any of the following by a health professional?" response options (rated yes/no): adhd; autism, asperger's, other autism spectrum; oppositional defiant or conduct disorder; speech or language disorder; head injury, epilepsy, seizure (s), febrile convulsions; disability; and other (free text). the short mood and feelings questionnaire (smfq) (50) (13 items). one scale: depression. example item: "your child felt miserable or unhappy." rated on a 3-point scale from 'not true' to 'true.' modified brief spence children's anxiety scale (51) (four selected items). one scale: anxiety. example item: "my child worries about things." rated on a 4-point scale from 'never' to 'always'. swanson, nolan, and pelham -iv questionnaire (snap-iv) (53) parent rating scale, opposition/defiance subscale (four selected items). example item: "often actively defies or refuses adult requests or rules" rated on a 4-point scale from 'not at all' to 'very much.' loneliness (one item) adapted from the coronavirus health impact survey (crisis) (33) . item: "during the past 2 weeks, how lonely has your child been?" irritability (one item) adapted from the coronavirus health impact survey (crisis) (33) item: "during the past 2 weeks, how irritable or easily angered has your child been?" child mood (eight items) (fortnightly survey only). item: "please indicate below how your child is feeling: happy, sad, content, bored, excited, anxious, alert, tired." rated on a 11-point scale from 'not at all' to 'very much.' physical activity (one item) adapted from lsac. item: "about how many days each week does your child do at least 30 min of moderate or vigorous physical activity (like walking briskly, riding a bike, swimming, running, etc)?" rated from 1 to 7 days. sleep pattern (one item) from lsac. item: "how much is your child's sleeping pattern or habits a problem for you?" rated on a 4-point scale from 'not a problem at all' to 'a large problem.' sleep regularity (one item) from lsac. item: "does the study child go to bed at regular times?" rated on a 5-point scale from 'never' to 'always.' screen time (two items) adapted from lsac. "about how many hours on a typical weekday does your child watch tv or videos at home not for educational purposes? (e.g., youtube, instagram, tiktok, streaming services such as netflix)." rated on a sliding scale from 1 to 24 hours. online intervention (three items). items: "the covid-19 pandemic and the associated measures to increase social distancing have caused many people to feel stressed and worried. how likely would you be to use an online or smartphone intervention for the following reasons: mental health support for yourself, mental health support for your child, and parenting support." rated on a 5-point scale from 'not at all' to 'extremely likely.' mental health intervention (two items). items: "should you experience a mental health difficulty in the future, how likely are you to use a … self-guided internet-or smartphone-app based treatment program? therapist-assisted internet-or smartphoneapp based treatment program?" rated on a 5-point scale from 'extremely likely' to 'extremely unlikely.' data will be prepared in stata version 16 (54) . missing data will be addressed using either full information maximum likelihood estimation or multiple imputation by chained equations, depending on the analysis. both methods rely on the untestable assumption that missingness is ignorable. sensitivity analyses (e.g., in the form of selection models or pattern mixture models) will be conducted to evaluate impact of violation of this assumption on modeled results (55). analyses will be conducted in stata version 16, or where relevant, in mplus version 8 (56) . the planned approach for testing aims 1-3 is outlined below. where relevant, all associations will be investigated in unadjusted analyses, and then in adjusted analyses, the latter controlling for the baseline effects of factors known to be associated with adult socio-emotional adjustment (gender, age, health, family demographic factors). decisions about the inclusion of specific covariates in each model will be made using directed acyclic graphs (dags) (57) . associations will be analyzed using multilevel modeling in either a latent variable or mixed effects framework to: (i) account for the clustered nature of time points within individuals while (ii) also modeling between-individual differences in rate of change over time. in these models, we will regress an outcome (e.g., mental health) on to 'time,' any moderator variables of interest, and background covariates. we anticipate 'time' being treated as a continuous predictor in all models (with the baseline timepoint coded as 0 and then numbered consecutively), but we will also consider treating 'time' as a categorical variable with discrete categories of time demarcated by important events that may occur during the pandemic window. the influence of potential moderators on the relationship between these associations will be investigated by including interaction terms (e.g., moderator x time). we will use post-stratification weights, generated through a raking approach (58) to compensate for differences between the final sample and the national population across geographic community clusters, parent age, gender, educational attainment, and country of birth (australia/new zealand versus other). we will ensure that strata sample sizes are large enough to not unduly influence the overall results. power is demonstrated for our key analyses involving within person relationships during the longitudinal study. given the clustered nature of the study of time points nested within participants, the effective sample size (ess) for the study is given by ess = nm/(1+(m-1)r) (59) , where n = number of participants aiming to be recruited, m = number of data points per cluster, and r = the within cluster correlation. based on a 6-month window of data collection and fortnightly assessments (estimated 14 assessments), the smallest sample of 400 participants (parents of a child 0-4 years) has an ess = 746 assuming a conservative within cluster correlation of r = .5. using monte carlo simulation (10,000 draws) in mplus 8, an ess = 746 would provide 98.2% power to detect a true effect of interest (e.g., time related change in parent mental health problems) of even small magnitude (b = .14, representing just 2% extra variance accounted for in the outcome above a base level of~10% by other variables in the model; at a = .05, twotailed). thus, the study is well powered for even small true effects of interest. note that even if participants only complete two of the assessments (ess = 533), this would still provide 92.7% power to detect the above-mentioned effect for our smallest age stratified group (parents of a child 0-4 years). additionally, for any between person relationships (e.g., differences between families), even the minimum sample size of 400 would provide 84.8% power to detect effects of the above-mentioned size. thus, the study is well powered. qualitative data will be analyzed using thematic analyses to determine the common themes that arise from the participant answers to the two short-answer questions posed regarding parent's coping strategies and impact of covid-19 on family life (60), thematic analysis is a method of analyzing qualitative data that is focused on identifying, examining, and recording major patterns or themes in the data. the current study has been approved by the deakin university human ethics advisory group (project number: heag-h 52_2020). we use brief screening measures to assess adult and child functioning. these measures are routinely used in populationlevel, large scale, longitudinal surveys, but are not designed to collect clinical information, thus the scales cannot be used to diagnose physical or mental health conditions. participants will be provided with a plain language statement that outlines the key constructs assessed in the study, reminds participants they can withdraw at any time, and provides information on where participants can seek help if any of the questions do cause them discomfort or distress. it will be possible for participants to skip any of the questions/items in the survey, and to facilitate this, none of the special case assessment items on the online survey form will be coded as a 'forced' answer. in the event that a participant expresses significant risk to themselves or others (e.g., suicidal ideation) in free-text comments, such as in the qualitative data, the lead investigator (ew), a registered clinical psychologist, will contact the participant to offer information on support services and referral options. results will be disseminated in peer reviewed journals, via the media, online, and at academic conferences. a plain language summary of results from the study will be made available to participants upon request. participants are advised of the process to request a plain language summary of the results in the plain language statement. participants are invited to provide optional consent to be contacted for future research, such as further follow-up beyond 6 months. this process would involve a new ethics application. participants will also be invited to consent to their de-identified information being stored on public repositories for the purposes of data sharing. if consent is provided, participant data will be stored securely. all information about the study (including publication preprints, data access, and analytic code) will be available at https://osf.io/78g5t/. at the conclusion of the study, recruitment materials, the project landing page, and online survey materials will be deactivated or removed. all data will remain securely stored on deakin university servers. information collected in this research project involves children who are under 18 years old, thus data will be kept until the youngest child turns 33 years of age. the study was launched on the 8 th of april, 2020. as at the 26 th of april, 2,375 eligible participants had completed the baseline survey. the covid-19 pandemic presents significant risks to the mental health and wellbeing of australian families. this project seeks to investigate the manifold impacts of the pandemic, including the impacts for families in regards to job loss, employment conditions, home-schooling, and unprecedented lifestyle changes associated with social distancing measures. chronic stress and social isolation have potential risks for adult mental health, couple and family relationships, and children's health and development (8) (9) (10) (11) (12) (13) . the novel contribution of the current study will be the repeated measures design, which will facilitate the tracking of changes in mental health over time in relation to the developing situation around the world. this project is designed to provide timely information to government and communities on the mental health effects of the emerging covid-19 crisis on australian parents and children. this information can then be used to inform the development of assessment and screening tools to identify those parents, families, and children who may be most at risk. furthermore, the findings of this research can guide health practitioners and policy makers regarding the factors that should be the focus of clinical and public health interventions to reduce risks of adult mental health, family breakdown, and child maladjustment when faced with such health crises in the future. finally, the findings from this study can be used to develop practical information and advice for families in how to deal with such crises and create positive family environments to buffer against mental health problems, family dysfunction, and child maladjustment. the studies involving human participants were reviewed and approved by deakin university human ethics advisory group (project number: heag-h 52_2020). the patients/participants provided their written informed consent to participate in this study. department of health, coronavirus (covid-19) health alert. in: department of health ag multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science the psychological impact of quarantine and how to reduce it: rapid review of the evidence psychological and epidemiological predictors of covid-19 concern and health-related behaviors psychiatric epidemiology and disaster exposure in australia the hidden disaster: domestic violence in the aftermath of natural disaster interpersonal violence and mental health outcomes following disaster the effects of chronic stress on the human brain: from neurotoxicity, to vulnerability, to opportunity stress, burnout and depression: a systematic review on dna methylation mechanisms social isolation in mental health: a conceptual and methodological review an overview of systematic reviews on the public health consequences of social isolation and loneliness chronic stress, cognitive functioning and mental health mental health affects future employment as job loss affects mental health: findings from a longitudinal population study maternal work-family conflict and psychological distress: reciprocal relationships over 8 years crossover of parents' work-family conflict to family functioning and child mental health parents' transitions into and out of work-family conflict and children's mental health: longitudinal influence via family functioning postdisaster course of alcohol use disorders in systematically studied survivors of 10 disasters national survey of mental health and wellbeing 2007: summary of results report on the second australian child and adolescent survey of mental health and wellbeing. department of health community factors influencing child and adolescent depression: a systematic review and meta-analysis world health organisation. coronavirus disease 2019 (covid-19) situation report -51. world health organization (2020) stress" and coronary heart disease: psychosocial risk factors the world trade center attack: increased frequency of defibrillator shocks for ventricular arrhythmias in patients living remotely from new york city lessons learned about stress and the heart after major earthquakes frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study media statement 22 mar 2020 prime minister. update on coronavirus measures recruiting for health, medical or psychosocial research using facebook: systematic review the optimising health literacy (ophelia) process: study protocol for using health literacy profiling and community engagement to create and implement health reform using internet to recruit immigrants with language and culture barriers for tobacco and alcohol use screening: a study among brazilians the use of social media in recruitment for medical research studies: a scoping review a metadatadriven methodology and workflow process for providing translational research informatics support the coronavirus health impact survey (crisis) v0 developing a national index of subjective wellbeing: the australian unity wellbeing index the structure of negative emotional states: comparison of the depression anxiety stress scales (dass) with the beck depression and anxiety inventories development and validation of a brief version of the difficulties in emotion regulation scale: the ders-16 development and validation of an internationally reliable short-form of the positive and negative affect schedule (panas) the experiences in close relationships-relationship structures questionnaire: a method for assessing attachment orientations across relationships the brief resilience scale: assessing the ability to bounce back the revised ucla loneliness scale: concurrent and discriminant validity evidence self-expressiveness within the family context: psychometric support for a new measure the list of threatening experiences: the reliability and validity of a brief life events questionnaire growing up in australia: the longitudinal study of australian children the measurement of perceived relationship quality components: a confirmatory factor analytic approach the provisions of social relationships and adaptation to stress relationship influences on exploration in adulthood: the characteristics and function of a secure base technical paper socio-economic indexes for areas (seifa) assessment of mindful parenting among parents of early adolescents: development and validation of the interpersonal mindfulness in parenting scale parenting measures in the longitudinal study of australian children: construct validity and measurement quality the short mood and feelings questionnaire (smfq): a unidimensional item response theory and categorical data factor analysis of self-report ratings from a community sample of 7-through 11-year-old children identifying children with anxiety disorders using brief versions of the spence children's anxiety scale for children, parents, and teachers studies aiof. melbourne: australian institute of family studies parent and teacher snap-iv ratings of attention deficit hyperactivity disorder symptoms: psychometric properties and normative ratings from a school district sample statacorp. stata statistical software. release the prevention and treatment of missing data in clinical trials mplus user"s guide. mutheń & mutheń reducing bias through directed acyclic graphs calibrating survey data using iterative proportional fitting (raking) sample size calculations for clustered and longitudinal outcomes in clinical research using thematic analysis in psychology conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited all authors contributed to the conceptualization of the study, drafting of the study protocol, and selection of survey items/ measures. ew drafted the manuscript, and together with tb, developed all study materials, including the online qualtrics survey and the study adverts. the current study was funded through the centre for social and early emotional development, a strategic research centre at deakin university. we would like to thank all participating parents and their families for their involvement in the study. key: cord-265530-hn7fi5cv authors: jansen, danielle; kosola, silja; arevalo, lourdes cantarero; gaspar de matos, margarida; boode, karin; saxena, sonia; dratva, julia title: child and adolescent health needs attention now, and in the aftermath of the covid-19 pandemic date: 2020-08-01 journal: int j public health doi: 10.1007/s00038-020-01446-8 sha: doc_id: 265530 cord_uid: hn7fi5cv nan there is mounting concern that large-scale covid-19 containment and physical distancing policies are likely to impact adversely on the lives of millions of children, adolescents and their families (mckee and mccartney 2020) . there is also a justified fear that in particular children and adolescents in vulnerable life situations, such as children receiving statutory care, with special needs or at risk of abuse and violence, will be victims of this unprecedented and unexpected global crisis (jansen et al. 2017, 29) . these groups were already less likely to seek and receive care prior to covid-19 and are at risk of educational underachievement (jansen et al. 2017) . the extent to which children and adolescents are affected will depend on the variation in nature and strictness of the policy response globally and also across europe. a comparison of the seven countries in which the eupha child and adolescent public health section (caph) directorate lives and works (denmark, finland, the netherlands, portugal, spain, switzerland, and the uk) yielded both identical policy responses, such as physical distancing and closing of schools, and differences, such as restrictions on gathering ranging from no gathering allowed (spain) to more liberal policies allowing for up to 10 people to meet throughout the peak pandemic (denmark and finland). all day care facilities and schools were closed with the exception of finland and opening of school policies varied considerably. none of the countries restricted access to acute care; however, all, except for denmark, restricted elective and planned care to some extent. preventive care was partly restricted in the netherlands, portugal, switzerland and the uk, but in most countries, it was explicitly advised to continue with vaccination programs for children age 0-24 months. in addition to policy, the communication of containment policies messages is of relevance. in five of the countries, prevention policies and public health messaging was provided in foreign languages for minority groups including sign language, but in the uk and portugal health communications and policies information were not translated nor was sign language provided (uk). variation herein reflects the variation in health outcomes. further, differences in pre-corona economy are certain to cause variation in managing the health and economic crises. already now child poverty rates differ considerably across europe, alone across the seven countries child poverty rate ranges from 3.7 (denmark) to 19.6 (spain) (oecd 2020). innovative interventions and adaptations of existing interventions were implemented to mitigate adverse consequences of the pandemic. national interventions focussed on acceptance of public health measures, implementation of the covid-19 policies, and on influencing mechanisms as well as direct mitigation of the negative economic consequences of the covid-19 measures and policies taken. some initiatives aimed directly at children and adolescents, such as the provision of child and adolescent friendly information about covid-19 or help parents to cope and speak with children about covid (switzerland). many countries delivered education via television to improve access to schooling (the netherlands, portugal, switzerland) or provided school meals as take away food (finland). similarly, there were interventions aimed to improve access to care, via providing online consultations (the netherlands, spain and denmark) and helplines for children and adolescents with mental health problems (denmark, portugal). there is an urgent need to formulate immediate policy for both acute and long-term care with a focus on children and adolescents to ensure that the collateral damage of covid-19 is as limited and short-term as possible. we differentiate child and adolescent public health into eight core public health priorities, all most probably affected by the pandemic (children's commisioner 2018): (1) injuries, (2) mental health (3) maltreatment, (4) risky behaviors, (5) nutrition in early life and prevention of childhood and adolescent obesity, (6) vaccination uptake, (7) access to health care, and (8) inequity in child development and learning. for some health priorities, first evidence is already available. a study from new zealand reported a reduction of 48% in injury-related admissions in children aged 0-14 years (christey et al. 2020) , while the usa observed an increase in daily number of calls to poison centers for exposures to cleaners and disinfectants, also in children (chang 2020) . in north-italy a 77-88% decrease in emergency department visits compared to 2018 and 2019 was observed (lazzerini et al. 2020) , probably related to a reduction of accidents, ''stay at home'' policy and fear of contracting covid-19. symptoms in children with preexisting mental illnesses are shown to worsen (jiao et al. 2020, 12, 13) , while others develop them (lee 2020, 11) . regarding child and adolescent nutrition, a longitudinal study among children and adolescents in italy showed that eating changed in an unfavorable direction 3 weeks into their confinement during the national lockdown (pietrobelli et al. 2020, 22) . the eupha child and adolescent public health section (caph) directorate launched a call to all members of the eupha section to report on their ongoing studies to provide an overview on the research and their contribution to tackle the covid-19 impact on child and adolescent health. non-members, worldwide, are invited to participate (surveylink: https://ww3.unipark.de/uc/caph). solid data and research in child and adolescent health is ever so important, as is identifying the most vulnerable and providing targeted support. the caph directorate encourages public health researchers to investigate both beneficial and adverse effects of the covid-19 pandemic and make use of the variety in covid-19 policies and interventions for further understanding of measures and health consequences in the context of children and adolescents. cleaning and disinfectant chemical exposures and temporal associations with covid-19-national poison data system uk children's commissioner vulnerability report variation in volumes and characteristics of trauma patients admitted to a level one trauma centre during national level 4 lockdown for covid-19 in new zealand public health practice and policy to improve child and adolescent health in europe behavioral and emotional disorders in children during the covid-19 epidemic delayed access or provision of care in italy resulting from fear of covid-19 mental health effects of school closures during covid-19 mitigating the wider health effects of covid-19 pandemic response oecd (2020) child poverty index, latest available data 2015-2019. oecd.org. accessed effects of covid-19 lockdown on lifestyle behaviors in children with obesity living in verona, italy: a longitudinal study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest the authors declare that they have no conflict of interest.ethical approval the authors followed the ethical standards in their research for this editorial. no data in humans were collected for this manuscript. key: cord-262892-n38r8n70 authors: sheikh, jamila; wynn, bridget a.; chakraborty, rana title: nutritional care of the child with human immunodeficiency virus infection in the united states: a historical and contemporary perspective date: 2015-05-08 journal: health of hiv infected people doi: 10.1016/b978-0-12-800769-3.00009-3 sha: doc_id: 262892 cord_uid: n38r8n70 in well-resourced settings, early infant diagnosis and administration of life-saving antiretrovirals (arvs) have significantly improved clinical outcomes in pediatric human immunodeficiency virus (hiv) infection. the dramatic increase in survival rates is associated with enhancements in overall quality of life, which reflect a multidisciplinary, holistic approach to care. current optimism starkly contrasts with the outlook and prognosis two decades ago, when failure to thrive and wasting syndrome from uncontrolled pediatric hiv infection resulted from poor oral intake, malabsorption, chronic diarrhea, and a persistently catabolic state. the tenets of care developed from that era still hold true in that all infants, children, and adolescents with hiv require comprehensive nutritional services in addition to effective combination antiretroviral therapy (cart). this chapter will review the principles of nutrition in the preand post-cart eras and discuss the etiologic factors associated with malnutrition, with an emphasis on interventions that have favorably impacted the growth and body composition of infants, children and adolescents with hiv. the global pandemic of human immunodeficiency virus (hiv) infection has had grave consequences in the lives of affected infants, children, and adolescents, with more than 33% of infant and child mortality attributed to hiv infection in endemic locations [1] . in settings where voluntary and public resources are insufficient to provide long-term care, millions of children initially cared for by relatives have now been orphaned. however, many guardians themselves get sick or become overwhelmed by the number of dependents for whom they have to provide care. the growing number of street children and child-headed households are often the outcomes of a chain of events that begin with the hiv infection of a mother, her partner, or both. in the united states, perinatal transmission has decreased to such a significant extent that current estimates indicate less than 200 infants born with hiv annually [2, 3] . with the implementation of recommendations for universal prenatal hiv counseling and testing, antiretroviral (arv) prophylaxis, scheduled cesarean section delivery, and avoidance of breastfeeding, the rate of transmission events has decreased to less than 1% in the united states and europe [4] [5] [6] [7] [8] . however, there remains an unacceptable annual rate of newly diagnosed hiv-1 infections among infants in the united states, with the persistence of marked racial and economic disparities [9] . most pediatric hiv infections (>90%) are caused by vertical transmission, with events more common to areas where antenatal hiv seroprevalence is high [10] ; 21 countries in sub-saharan africa and in south, east, and southeast asia account for more than 90% of the pregnant women needing arvs to prevent vertical transmission. however, global rates of new hiv infections and prevalence among young people have fallen in many countries, likely due to reductions in vertical transmission rates and improvement in access to effective cart, which has decreased secondary transmission events. a clinical overview perinatal infection occurs at a time of relative immunologic immaturity. the inability to control viremia exposes the thymus and other lymphoid tissue to hiv-1-mediated destruction at a time of active thymopoiesis and lymphopoiesis [11] . given that the virus is transmitted from the mother and that the degree of human leukocyte antigen class i sharing between mother and infant is high, the virus could evade the protective immune response of the newborn, which results in accelerated disease progression [12] . in contrast to adults, hiv-1-related symptoms, cd4+ t cell depletion, or both develop in most untreated vertically infected children within the first few years of life [13] . in addition, plasma hiv-1 ribonucleic acid (rna) levels remained elevated over the first 2 years among infants [14] and do not decrease to less than 10 5 copies/ml through at least the third year of life [15] . the prolonged elevation of plasma hiv-1 rna levels may be related to the kinetics of viral replication, the size of the pool of host cells that are permissive to viral replication, and immature virus-specific immune responses. ii . nutrition and lifestyle the infection in perinatally infected infants and children progresses more rapidly than in adults. although 4% of the world's population with hiv-1 infection comprises children, 20% of all aids deaths were previously in this group. early studies before the era of cart indicated that a subset of children (~25%) progressed very rapidly to aids within 1 year. the median time to aids for the remaining 75% was 7 years [13] . in adults, opportunistic infections (ois) are often secondary to the reactivation of pathogens acquired before hiv infection. in contrast, in infants and children with vertical infection, ois often reflect primary acquisition of host pathogens during ongoing hiv replication and advancing immunosuppression. for example, young children with active tuberculosis more often present with miliary disease. without effective cart, the most common ois in children include serious bacterial infections such as pneumonia and bacteremia. common copathogens and ois that are difficult to eradicate without successful immune reconstitution include chronic mucosal or disseminated infections with herpesviruses, namely, cytomegalovirus (cmv), herpes simplex virus (hsv), human herpes virus 8 (hhv8) and varicella zoster virus (vzv). primary disseminated and reactivated tuberculosis is a major cause of morbidity and mortality among children with hiv in communities where infection with the pathogen is endemic. disseminated disease with mycobacterium avium complex may occur in children with hiv and advanced immunologic deterioration. pneumocystis jiroveci (formerly carinii) pneumonia (pcp) is a common and serious oi associated with a high mortality rate. pneumonia most often manifests between 3 and 6 months of age in infants with vertically acquired hiv infection. candidiasis (topical, oral, esophageal, and tracheobronchial) is the most common fungal infection in these children. causes of acute and chronic central nervous system (cns) infections include those caused by cryptococcus neoformans, and toxoplasma gondii. less commonly observed ois include cryptosporidiosis and systemic fungal infections. clinical presentations include hepatosplenomegaly, failure to thrive, oral candidiasis, recurrent diarrhea, parotitis, cardiomyopathy, hepatitis, nephropathy, developmental delay, encephalopathy, lymphoid interstitial pneumonitis, recurrent bacterial infections, and specific malignancies. malignancies include non-hodgkin b-cell burkitt-type lymphomas, leiomyosarcomas, and kaposi sarcoma, which are commonly described in children with hiv who are of sub-saharan african ethnicity. in the united states, in clinical practice, the number of ois seen in children with hiv has decreased, reflecting the widespread use and administration of effective cart regimens. however, ois continue to be the presenting symptom of hiv infection in infants due to lack of antenatal testing in mothers or in adolescents and young adults who are increasingly infected through horizontal transmission. the intestine is a primary target organ for hiv. hiv infection causes a depletion of cd4+ t lymphocytes in gut-associated lymphoid tissue, including selective loss of a subset of t helper cells called th17 lymphocytes, which are important in gut mucosal containment of extracellular pathogens such as salmonella typhimurium. th17 cells are lost early in retroviral infection and are not replenished over time. this depletion impairs long-term gastrointestinal (gi) mucosal integrity and permeability, causing increased bacterial translocation and immune activation. the intestinal mucosa is also the main reservoir of hiv in the body despite effective virologic suppression with cart. among untreated children with hiv, as many as 80% will have one or more intestinal disorders at a given time, with iron malabsorption present nearly 50% of the time [16] . hiv enteropathy is secondary to direct hiv-mediated injury and indirect immune-mediated injury to the gi tract mucosa in the absence of specific opportunistic enteropathogens, perhaps reflecting selective loss of th17 lymphocytes. hiv enteropathy can occur in children and adolescents at all stages of hiv infection. clinical manifestations include chronic diarrhea, increased intestinal permeability, malabsorption, and malnutrition. histologic changes include lymphocytic infiltration of the gi tract mucosa, villous atrophy and blunting, and crypt hyperplasia [17, 18] . a direct cytopathic effect of hiv on the intestinal mucosa is supported by the observation that clinical signs and symptoms improve after initiation of effective cart in association with virologic suppression and immune reconstitution of cd4+ t cells [19] . acute, recurrent, and chronic diarrhea associated with malabsorption and growth impairment frequently occur in children with untreated hiv infection and advancing immunosuppression. commonly identified infective enteropathogens include bacteria (salmonella, shigella sp.), viruses (including rotavirus, adenovirus, cmv), parasites (entamoeba, giardia, cryptosporidia, microsporidia, isospora), and opportunistic fungi [20] . in children with hiv, frequent and persistent watery diarrhea is the most common presentation of cryptosporidial, microsporidial, and isosporidial infections, associated with abdominal cramps, fever, vomiting, anorexia, weight loss, and poor weight gain [7] . untreated chronic severe diarrhea may cause malnutrition, failure to thrive, severe dehydration, or a combination of all these problems. gi tract disease caused by cmv may include esophagitis, gastritis, pyloric obstruction, hepatitis, pancreatitis, colitis, ascending cholangitis and cholecystitis. signs and symptoms may include nausea, vomiting, dysphagia, epigastric pain, icterus, and watery diarrhea. stools may be bloody. sigmoidoscopy in cmv colitis provides nonspecific results, showing diffuse erythema, submucosal hemorrhage, and diffuse mucosal ulcerations. specific causes of diarrhea in representative adult subjects with aids are presented in table 9 .1 [21] . data reflect prospective follow-up of 1,933 participants in the swiss hiv cohort study; 560 diarrheal episodes were evaluated by standardized stool examination, with intestinal infections diagnosed in less than 50% of chronic diarrheal episodes [22] . the site and severity of infection vary according to the infecting organism. oral mucosal ulcerations secondary to infectious agents such as candida albicans, cmv, or hsv cause inflammation and pain during swallowing or after eating, which may lead to reduced oral intake. opportunistic enteropathogens such as cryptosporidium, cmv, and microsporidia [23] may affect the hepatobiliary system and pancreas in addition to the gi tract, resulting in vomiting, abdominal pain, and malabsorption. in resource-limited settings, disease with mycobacterium tuberculosis is the most common cause of death in subjects with hiv. hiv and tuberculosis (tb) accelerate disease progression and mortality and are associated with marked clinical wasting; the extent of wasting is related to the severity of tb [24] . the largest proportion of newly diagnosed children with hiv in many us centers are foreign born and at higher risk of prior and potentially ongoing exposure to tb. tb is almost always transmitted to children by an adult, most commonly a household contact, and the infection in children is primary infection rather than reactivated disease as in adults. there should be an increased index of suspicion of tb infection and disease in children with hiv, particularly in the context of clinical wasting and a low threshold for empiric antituberculosis therapy, even when diagnostic investigations fail to identify a tb-causing organism. the combination of underlying hiv infection, nutritional status (particularly protein-energy malnutrition), and host immunity are inextricably interdependent. in the united states, prior to the widespread administration of effective cart, the predominant effect of advancing immunosuppression on nutritional status in children with hiv was wasting and negative energy balance, which predicted both morbidity and mortality [25] . in the pre-cart era, ois were major precipitants of weight loss, necessitating prevention or prompt diagnosis and treatment to prevent wasting and to promote weight recovery [26] . growth in children with hiv was persistently below normal standards, with reduced height and weight velocities, compared with hiv-exposed but uninfected children. in 1994, the centers for disease control and prevention (cdc) defined wasting in children younger than age 13 years as (1) persistent weight loss of more than 10% of baseline; (2) downward crossing of at least two percentile lines on the weight-for-age chart in a child aged 1 year or older; or (3) less than the 5th percentile on the weight-for-height chart on two consecutive measurements at least 30 days apart, plus chronic diarrhea or documented fever for at least 30 days, whether intermittent or constant [27] . in addition to ois, other etiologies that contribute to abnormal growth in untreated hiv infection in children include a synergistic combination of inadequate dietary intake, gi malabsorption, increased energy utilization, and socioeconomic adversity. the prevalence of malnutrition in children with hiv varied among centers in the united states with up to 30-50% of children followed up in pediatric hiv programs having demonstrable evidence of protein-energy malnutrition, which, in turn, exacerbated the immunosuppressive effects of hiv [28] . common patterns of wasting included an early decline in weight and height in the first 3 months of life or early linear stunting with a normal weight-to-height ratio. progressive wasting with low weights and heights were also well recognized and more commonly associated with infectious enteropathogens. sequential follow-up demonstrated that growth in children with untreated hiv infection remained below growth in age-matched and gender-matched uninfected controls. malabsorption also results in macronutrient and micronutrient deficiencies. micronutrient deficiencies are widespread and compound the effects of hiv infection in children. deficiency can manifest in conditions such as fatigue, reduced learning ability due to anemia (iron deficiency), and impaired immunity [29] . such deficiencies reflect inadequate nutrient intake and the consequences of excessive losses due to ois, diarrhea, and malabsorption, as previously described. other micronutrients that can also be malabsorbed resulting in deficiency include vitamin b12, folic acid, thiamine, zinc, selenium, calcium, and magnesium, and fat-soluble vitamins a and d [21] . the evidence base for the specific effect of micronutrient supplementation in children with hiv is limited, but a recent cochrane review of 11 studies with 2,412 participants made the following key recommendations for practice. benefits of periodic vitamin a supplementation in children over 6 months of age with hiv infection in resource-limited settings were supported by data from three african trials and were consistent with evidence of benefits of supplementation in uninfected children. zinc supplements reduced diarrheal morbidity and had no adverse effects on disease ii. nutrition and lifestyle progression in a single safety trial in south african children. children with hiv should therefore receive zinc supplements in the management of diarrhea and severe acute malnutrition in the same way as uninfected children with the same conditions. the review emphasized that micronutrient deficiencies and immune dysfunction in children with hiv would only be restored with effective suppression of hiv replication [30] . cart consists of drugs that target the life cycle of hiv at specific enzymes or receptors to inhibit replication thereby preserving or restoring immune function. specific goals of administration of cart include maximally reduction of the plasma viral load below the limit of detection (<50 copies/ml), prevention of a selection of drug-resistant strains and maintenance of good immunologic status (repopulation with cd4 + -naã¯ve t cells), and prevention of clinical disease progression and ois. clinical trials of cart in infants and children with hiv have demonstrated dramatic reductions in morbidity and mortality (>80-90%) in the united states since widespread implementation from 1996 onward, so the vast majority of infants and children with hiv-1 can now be expected to survive to adulthood [31, 32] . five classes of arv drugs are commonly available for hiv therapy. two classes target the enzyme reverse transcriptase-non-nucleoside reverse transcriptase inhibitors (nrtis) and the non-nrtis. a third class-protease inhibitors (pis)-target viral protease, whereas integrase inhibitors target that corresponding enzyme. in addition, ccr5 inhibitors target the viral co-receptor ccr5 on permissive target cells. hiv-1 mutability is largely the result of errors introduced into the viral genome during replication. the hiv genome is approximately 10,000 nucleotides long, and each new virion has an average of one mutation. this results in a large pool of quasi-species of viral variants that are incapable of productive infection but some of which may provide an adaptive benefit, for example, the development of art resistance, to the virion. drug-resistance of the virus can develop during cart administration because of poor adherence, a regimen that is not potent, or a combination ii. nutrition and lifestyle of these factors resulting in incomplete virologic suppression. in addition, primary drug resistance may occur in arv-naive infants and children who can become infected with the resistant virus. aggressive, multidrug cart as early in infection as possible, with daily adherence for an indefinite period, is advocated to fully suppress viral replication and to preclude the selection or emergence of resistant viral variants. resistance testing has enhanced the ability to choose effective initial regimens as well as second-or third-line regimens. therapeutic strategies continue to focus on timely initiation of arv regimens that are capable of maximally suppressing viral replication in order to prevent disease progression, preserve or restore quantitative and qualitative immunologic function, and reduce the development of drug resistance [33] . difficulties with long-term adherence to cart-particularly in infants and children because of variable drug administration, absorption, and metabolism; pretreatment with maternal cart and vertical transmission of drug-resistant virus; acceptability and palatability of medications; and refrigeration of syrup formulations in warm climates-are all well documented. long-term follow-up of infected infants and children involves longitudinal determinations of prognostic markers, including number and percentage of cd4 t cells, and viral load [34] . such parameters provide a useful framework for the time to initiate and change therapy but involve frequent venipuncture in minors. long-term toxicities include lipodystrophy syndrome [35] and lipid abnormalities, cardiomyopathy, mitochondrial toxicity and lactic acidosis, renal tubular acidosis [36] , hypersensitivity reactions, and cns toxicity. fortunately, the availability of new drugs and drug formulations has led to the use of more potent regimens with reduced short-term toxicity, lower pill burden, and less frequent medication administration, all factors that are associated with better adherence and outcomes. enteral [37, 38] or parenteral supplementation and appetite stimulants [39] can improve the nutritional status and weight in children with untreated hiv infection but have little effect on the growth velocity of height. however, effective virologic suppression with cart was shown to improve mean weight, weight for height, and muscle mass in 67 children with hiv, in whom pi-based therapy was initiated and maintained for a median of 5 months. these effects were independent of virologic suppression and improved cd4 t-lymphocyte counts [40] . these findings were also noted in the pediatric aids clinical trial group 219 study, which ii. nutrition and lifestyle found that pi therapy improved both weight and height z-score annually, after adjusting for cd4 cell count, age, gender, and race [41] . in the era of cart, following the introduction of pi-containing regimens, hiv-associated mortality decreased by greater than 80-90%, with significant declines in opportunistic and related infections [31, 32] . these encouraging outcomes have been tempered by the side effects associated with arvs. altered body composition, lipid abnormalities, and abnormal regulation of glucose metabolism are consequences that result in an increased risk of cardiovascular disease, reflecting complications of inflammation with uncontrolled hiv infection and the specific arv drugs as outlined. in children, adolescents, and adults, a clear syndrome of abnormal fat redistribution or lipodystrophy and metabolic changes associated with administration of cart is well described. patterns of lipodystrophy vary from peripheral fat wasting, or lipoatrophy, in the face, extremities, and buttocks to central fat accumulation, or lipohypertrophy, in the abdomen, dorsocervical spine regions (buffalo hump), and breasts. both conditions may occur alone or in combination [42, 43] and can be difficult to assess in a growing child or adolescent, since changes in body fat occur normally during childhood and puberty [44] . lipodystrophy in children with hiv is clinically evaluated by examination or self-report and has been documented to be as high as 32% [45] . dual-energy x-ray absorptiometry (dexa) quantifies total, trunk, and limb fat. observational studies in children with lipodystrophy show decreased total and extremity fat and a greater trunk-to-extremity fat ratio in children with hiv compared with uninfected children [46, 47] these changes are drug specific and associated with duration of therapy, with prolonged treatment and older age more likely to result in lipodystrophy. treatment with nrtis, including stavudine (d4t), zidovudine (azt), and didanosine (ddi), is associated with a lower percentage of extremity fat and higher percentage of trunk fat and trunk-to-extremity fat ratio even after adjustment for wasting and stunting [21, 43] . these changes in body fat distribution often cannot be reversed even after switching to less lipodystrophic arv regimens. in cohorts of children receiving a pi regimen, higher rates of dyslipidemia have been documented, with higher fasting lipids, cholesterol, and triglycerides. lipodystrophy in patients results in much higher waist-tohip ratios and elevated fasting insulin levels and blood pressure, which ii. nutrition and lifestyle are all significant risk factors for cardiovascular disease [21] . for children without lipodystrophy, up to one fifth show symptoms of dyslipidemia. in summary, when selecting arv regimens, care must be taken to consider the above life-long side effects and their consequences. at a time when newer less lipodystrophic first-line regimens, including tenofovir, abacavir, ritonavir-boosted pis (atazanavir and darunavir), and the integrase inhibitors, most with the added advantage of once daily administration, are available in the united states, regimens that include zidovudine, didanosine, and stavudine should be prescribed less often to children with hiv to reduce these potential long-term toxicities. metabolic syndrome reflects a series of clinical conditions, including elevated triglyceride, low levels of high-density lipoprotein (hdl) cholesterol, hyperglycemia and insulin resistance, increased body fat distribution around the waist, and high blood pressure, all of which collectively increase the risk of cardiovascular disease. in individuals with hiv, the prevalence of metabolic syndrome is higher than in the general population and estimated to be 7-45% [21, 48] . although uncontrolled hiv in the absence of cart can cause low hdl cholesterol and high triglycerides, as discussed previously, arvs also induce body fat redistribution in conjunction with metabolic changes. earlier pis, including treatment doses of ritonavir (without boosting other pis), nelfinavir, and ritonavir-boosted lopinavir (kaletra) were documented to increase lipid plasma concentrations, including serum triglycerides, cholesterol, low-density lipoprotein (ldl) cholesterol, and apolipoprotein e and to lower hdl. virologic control with the newer pis, integrase inhibitors, tenofovir, and abacavir may be associated with increases in serum hdl, in the absence of these metabolic complications. when compared with population norms, children with hiv were noted to have lower-than-expected bone mineral density (bmd) for their age and gender that may have been associated with delays in growth, sexual maturity, duration of hiv infection, ethnicity, and disease severity [49] . a more recent large study of 236 american children and adolescents with hiv, aged 7-24 years, showed that males with hiv had significantly lower bmd at tanner stage 5 compared with uninfected males [50] . reduced bmd secondary to cart administration was first described in 2001 from dexa scans in vertically infected children, with the severity of osteopenia directly related to lipodystrophy [51] . however, a longitudinal study from 2013 in 66 dutch children showed an association between longer cart duration and increases in spinal bmd z-scores [52] . lopinavir-ritonavir ii. nutrition and lifestyle [50] , full-dose ritonavir [53] , and tenofovir [54] are associated with lower bmd in children. the principles of maintaining good bone health in youth with perinatal hiv infection is the same as those recommended for all youth in general. adolescents should therefore receive at least 1,300 mg calcium per day and at least 600 iu vitamin d per day through their diet, by supplementation, or both [55] . immune reconstitution inflammatory syndrome (iris) is a diseasespecific inflammatory response that can occur after treatment with arvs is initiated, reinitiated, or changed, resulting in effective virologic suppression and immune reconstitution of naã¯ve and memory cd4+ t cells. iris has been noted to occur in children who begin art while they have severe malnutrition, are severely immunosuppressed [56] , or both. risk factors therefore include a low cd4 nadir and high viral load levels prior to the initiation of cart. these children and adolescents often have numerous documented ois before, during, and after cart initiation [56] . further research is needed to reduce complications and to optimize clinical management when they do occur. the interaction between hiv infection and nutrition is of great importance, and these two factors are interdependent, since strategies to improve nutritional status both quantitatively and qualitatively have been demonstrated to have a beneficial effect on clinical outcome and the immunologic course of the hiv infection. through the course of their disease, infants and children with hiv have numerous nutritional needs, which reflects, as previously described, impaired absorption, decreased oral intake, and increased nutrient requirements. specific adverse outcomes secondary to specific nutritional deficiencies include the inability to achieve normal weight for height; malnutrition and wasting; growth failure and stunting; and neurocognitive, neurodevelopmental, and oral motor delay often from hiv encephalopathy. early nutrition intervention is, therefore, essential and must be addressed simultaneously with the administration of cart, antimicrobial prophylaxis, and neurodevelopmental interventions. collectively, a ii. nutrition and lifestyle multidisciplinary approach is most effective in improving health outcomes and overall quality of life. in the pre-cart era, the nutritional causes of malnutrition reflected (1) decreased oral intake caused by anorexia and by oral and esophageal lesions often from opportunistic pathogens, (2) gastroesophageal reflux and aspiration, (3) regression or nonattainment of key developmental milestones associated with oromotor dysfunction and impaired mastication, (4) malabsorption, (5) increased energy requirements and metabolism from ois with associated negative energy balance, (6) vomiting and diarrhea from gastrointestinal (opportunistic) enteropathogens, and (7) indirect immune-mediated enteropathy. at a time when effective cart was unavailable and faced with a debilitating catabolic disease and rapid disease progression in infants and children with hiv, nutritional interventions that were developed in the early 1990s by pediatric providers targeted four key areas: 1. prompt management of diarrhea. in addition to isolation of opportunistic enteropathogens and prescribing appropriate antimicrobials for infectious etiologies, management of diarrhea mandates assessment of hydration status and rehydration by the oral or intravenous route. modification of diet in the setting of underlying food intolerance such as lactose or fat malabsorption, including pancreatic enzyme supplementation; and vitamin and mineral supplementation. other recommendations included introduction of a mechanical soft diet and nutritional supplementation. 4. management of nausea and vomiting. in addition to appropriate antiemetic agents, treatment also included recommendation of small frequent meals, liquid intakes between meals, and nutritional supplementation. 5. management of anorexia included small nutrient dense foods, nutritional supplementation, and appetite stimulants such as megestrol acetate. these early nutrition needs related to the unique physiologic demands for growth and development, so even today, interventions should be individualized according to the child's specific needs and relate to disease stage, gastrointestinal function, and growth [57] . as a corollary, the energy and protein requirements for infants and children with hiv have not yet been established because individual needs vary, depending on age, growth, and the clinical and immunologic status that may increase energy and protein needs. infants and children with hiv who have slow weight gain are often prescribed high-protein, high-calorie diets. if nutritional needs are not met through a typical high-calorie, high-protein diet, then additional support may include oral nutritional supplements and overnight feeding through nasogastric or gastrostomy-tube feedings. a commercial formula with intact protein may be appropriate for children without underlying gastrointestinal pathology. infants and children with hiv who have gastrointestinal malabsorption should receive a semi-elemental formula to maximize absorption. elemental formulas are typically prescribed when semi-elemental formulas are not tolerated. infants and children with hiv who are unable to consume adequate calories orally often benefit from supplemental tube feeding. enteral tube feeding supplementation improves weight gain in children with hiv who have growth failure [37, 38] . nasogastric tube feedings should be initially attempted and include night-time feedings, which allow the child to eat normally throughout the day. complications relating to nasogastric tube feedings include sinusitis and the technical inability of the caregiver to place the tube or administer the feedings [21] . if delivery of feedings through a nasogastric tube improves growth, then placement of a more permanent device such as a gastrostomy tube should be considered. enteral supplementation with gastrostomy feeding has improved nutrition in a number of chronic childhood illnesses by providing adequate energy intake to promote weight gain when oral intake is poor. miller et al. [37] first investigated the effects of gastrostomy tube feeding on weight gain, height, body composition, immune parameters, morbidity, and mortality in 1995 on 26 children with hiv. weight z-scores before therapy were -1.6 and had decreased to -2.2 on initiation of nasogastric feedings. gastrostomy tube feedings significantly improved weight z-scores to get back to baseline approximately 5 months after initiation of feeding. significant predictors of response to gastrostomy tube feedings included higher cd4 counts at initiation and lower weight-for-height z-scores at baseline. these findings suggested that early intervention during acute weight loss offers the best chances of improving weight in children with hiv. children with the greatest improvement in weight after gastrostomy tube placement spent less time in hospital and had a greater likelihood of survival compared with children who did not gain weight [37] . this small but important study demonstrated that early nutritional intervention improved quality of life and reduced morbidity in children with hiv at a time when effective cart was unavailable. in the cart era, compliance with medical therapy is often improved with more reliable delivery of arvs through the gastrostomy tube and is associated with improved cd4 t-lymphocyte counts, virologic suppression, and improved longitudinal growth. guarino et al. tested the hypothesis that nutritional support improves intestinal and immune functions in 62 italian children with hiv; 16 received enteral nutrition through continuous feeding, and 46 received total parenteral nutrition. the authors documented a significant increase in cd4 cell count, xylose levels, and body weight in those receiving enteral nutrition, suggesting that nutritional intervention may restore intestinal absorption and increase cd4 cell numbers if initiated early in the course of pediatric hiv infection [58] . enteral feeding is preferred over parenteral nutrition to preserve the gut structure. parenteral nutrition should be used only in those children unable to tolerate or gain weight on enteral supplementation, those who have recurrent or chronic biliary tract or pancreatic disease, and those who have intractable diarrhea with weight loss [21] . megestrol acetate is an oral synthetic progesterone used since the early 1990s as an appetite stimulant. weight gain tends to be associated with increase in body fat rather than muscle. clarick et al. investigated the effects of megestrol acetate treatment on weight gain and linear growth in 19 children with hiv who had growth failure. the average duration of the study was 7 months. the study concluded that megestrol acetate was associated with weight gain but not linear growth during the treatment period. after the megestrol acetate treatment was discontinued, poor weight gain and weight loss were again noted [39] . given the dramatic reductions in morbidity and mortality and the improved longitudinal growth in children with hiv in the united states since the widespread implementation of effective cart, megestrol acetate and other therapeutic agents (including growth hormone and the anabolic steroid oxandrolone) are prescribed very rarely, if at all, to subjects with hiv. in the 1980s and early 1990s, the devastating effects of hiv infection on the health of infants, children, and adolescents became apparent and required a rapid and effective response globally. over time, in the united states, with the introduction of arvs, the clinical manifestations associated with hiv infection as well as its treatment were seen to increase, driven by the short-and long-term toxicities of these new formulations in combination. in children with hiv, these manifestations reflected metabolic changes; wasting and stunting from gastrointestinal dysfunction were most often described in the 1980s, but new clinical concerns in the early 2000s were related to altered body composition, lipid abnormalities, and abnormal regulation of glucose metabolism. these complications were often attributed to the first-generation nrtis and pis. the longterm cardiovascular risks of these arvs on subjects with hiv are still unknown. after 2007, newer pis and integrase inhibitors became more widely available and appear to have fewer metabolic adverse effects, although ongoing surveillance of these arvs and tenofovir will be important to evaluate incidences of renal tubular dysfunction and bmd. in the course of the changes in art over the previous two decades, optimal nutritional support has continued to be a cornerstone of pediatric and adolescent hiv care, applying the same principles developed from the early 1990s to effectively support infants, children, and adolescents with hiv. these principles include ongoing comprehensive nutritional assessments and follow-up. when cart providing effective viral suppression was unavailable, enteral and parenteral support was associated with improved weight and body composition and overall survival and is still a key part of care for children and adolescents who present with advanced hiv disease. in addition, periodic vitamin a supplementation in children with hiv who are older than 6 months of age is supported by clinical trials in africa. children with hiv should also receive zinc supplements in the management of diarrhea and severe acute malnutrition in the same way as uninfected children with the same conditions. investigators should continue to study the effects of oral hypoglycemic agents, lipidlowering medications, and lifestyle changes on cardiovascular risk factors in patients with lipodystrophy and hyperlipidemia at this time when obesity has become endemic in many communities in the united states. this unfortunate development on long-term health also has implications for children and adolescents with hiv across the united states. nevertheless, the overall outlook for children with hiv has improved significantly since the 1990s, as reflected in the reduced rates of morbidity and mortality and improved quality of life. perhaps a measure of the latter is the overall medication burden. figure 9. 1 is a child's medications, as shown by oleske et al. [57] . figure 9 .2 shows the pill burden for a number of adolescent patients in the united states in 2014. the last paragraph of dr. oleske's article still relevant for 2014. to quote directly, "compassionate, comprehensive, and coordinated clinical care services are required for all hiv-infected infants and children through adolescence. we must not underestimate their needs. as we improve their longevity with advances in primary hiv therapies, we must not let quality of life suffer due to a lack of nutritional intervention." global, regional, and national causes of child mortality in 2008: a systematic analysis achievements in public health reduction in perinatal transmission of hiv infection-united states recent trends in the incidence and morbidity that are associated with perinatal human immunodeficiency virus infection in the united states combination antiretroviral strategies for the treatment of pregnant hiv-1-infected women and prevention of perinatal hiv-1 transmission european collaborative study mother-to-child transmission of hiv infection in the era of highly active antiretroviral therapy 2 the high number of medications for an adolescent with hiv in 1 the slew of daily medications for a 13-year-old long-term surviving patient with perinatally acquired hiv in 1996 included: zidovudine (azt), didanosine (ddi), trimethoprim/sulfamethoxazole (tmp/smx), fluconzol, megase, prednisone, acyclovir, dapsone, biaxin, zalcitabine (ddc), albuterol, isonicotinylhydrazine (inh), rifampin, ranitidine (zantac) two-dose intrapartum/newborn nevirapine and standard antiretroviral therapy to reduce perinatal hiv transmission: a randomized trial low rates of mother-to-child transmission of hiv following effective pregnancy interventions in the united kingdom and ireland earlier initiation of art and further decline in mother-to-child hiv transmission rates racial/ethnic disparities among children with diagnoses of perinatal hiv infection -34 states towards universal access: scaling-up priority hiv/ aids interventions in the health sector hiv-1 infection in children: a clinical and immunologic overview evolution and transmission of stable ctl escape mutations in hiv infection the european collaborative study association of human immunodeficiency virus (hiv) load early in life with disease progression among hiv-infected infants the relationship between serum human immunodeficiency virus type 1 (hiv-1) rna level, cd4 lymphocyte percent, and long-term mortality risk in hiv-1-infected children management of gastrointestinal disorders in children with hiv infection hiv enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in hiv/microsporidia-infected jejunal mucosa enteropathies in the developing world: neglected effects on global health ritonavir combination therapy restores intestinal function in children with advanced hiv disease aetiology and management of malnutrition in hiv-positive children nutritional aspects of hiv-infected children receiving highly active antiretroviral therapy enteric infections and diarrhea in human immunodeficiency virus-infected persons microsporidia infection in patients with human immunodeficiency virus and unexplained cholangitis nutritional status in malawian patients with pulmonary tuberculosis and response to chemotherapy prospective analysis of patterns of weight change in stage iv human immunodeficiency virus infection nutrition in paediatric hiv infection magnitude of body-cell-mass depletion and the timing of death from wasting in aids centers for disease control and prevention 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age unicef tracking progress on child and maternal nutrition: a survival and development priority micronutrient supplementation for children with hiv infection incidence of opportunistic and other infections in hiv-infected children in the haart era declines in mortality rates and changes in causes of death in hiv-1-infected children during the haart era hiv-1 drug resistance in hiv-1-infected children in the united kingdom from national study of hiv in pregnancy and childhood collaborative hiv paediatric study increased lipodystrophy is associated with increased exposure to highly active antiretroviral therapy in hiv-infected children persistent non-gastrointestinal metabolic acidosis in pediatric hiv-1 infection gastrostomy tube supplementation for hiv-infected children effect of enteral tube feeding on growth of children with symptomatic human immunodefi-� ciency virus infection megestrol acetate treatment of growth failure in children infected with human immunodeficiency virus the effect of protease inhibitors on growth and body composition in hiv-infected children impact of protease inhibitor-containing combination antiretroviral therapies on height and weight growth in hiv-1-infected children prevalence, evolution and risk factors for fat atrophy and fat deposition in a cohort of hiv-infected men and women pediatric hiv/aids cohort study. body fat distribution in perinatally hiv infected and hiv-exposed but uninfected children in the era of highly active antiretroviral therapy: outcomes from the pediatric hiv/aids cohort study regional body fat distribution in relation to pubertal stage: a dual-energy x-ray absorptiometry study of new zealand girls and young women european paediatric lipodystrophy group antiretroviral therapy, fat redistribution and hyperlipidaemia in hiv-infected children in europe morphologic and metabolic abnormalities in vertically hiv-infected children and youth longitudinal changes in regional fat content in hiv-infected children and adolescents the metabolic syndrome in hiv predictors of bone mineral density in human immunodeficiency virus-1 infected children total body and spinal bone mineral density across tanner stage in perinatally hiv-infected and uninfected children and youth in pactg 1045 bone mineral loss through increased bone turnover in hiv-infected children treated with highly active antiretroviral therapy bone mineral density increases in hiv-infected children treated with longterm combination antiretroviral therapy antiviral therapy and bone mineral measurements in hiv-infected youths comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in hiv-infected adults: 48-week results from the assert study vitamin d status in children and young adults with perinatally acquired hiv infection severe malnutrition and metabolic complications of hivinfected children in the antiretroviral era: clinical care and management in resourcelimited settings historical perspectives on the evolution in understanding the importance of nutritional care in pediatric hiv infection effects of nutritional rehabilitation on intestinal function and on cd4 cell number in children with hiv key: cord-273620-gn8g6suq authors: szczawinska‐poplonyk, aleksandra; jonczyk‐potoczna, katarzyna; breborowicz, anna; bartkowska‐sniatkowska, alicja; figlerowicz, magdalena title: fatal respiratory distress syndrome due to coronavirus infection in a child with severe combined immunodeficiency date: 2012-11-30 journal: influenza other respir viruses doi: 10.1111/irv.12059 sha: doc_id: 273620 cord_uid: gn8g6suq please cite this paper as: szczawinska‐poplonyk et al. (2012) fatal respiratory distress syndrome due to coronavirus infection in a child with severe combined immunodeficiency. influenza and other respiratory viruses doi: 10.1111/irv.12059. coronaviruses have been demonstrated to contribute substantially to respiratory tract infections among the child population. though infected children commonly present mild upper airway symptoms, in high‐risk patients with underlying conditions, particularly in immunocompromised children these pathogens may lead to severe lung infection and extrapulmonary disorders. in this paper, we provide the first report of the case of a 15‐month‐old child with severe combined immunodeficiency and coronavirus hku1‐related pneumonia with fatal respiratory distress syndrome. severe combined immunodeficiency (scid) is a genetically and clinically heterogeneous group of the most severe primary immunodeficiencies, characterized by the absence of functional t lymphocytes resulting in profound impairment of the cellular and humoral adaptive immunity. depending on the genetic defect, b lymphocytes and natural killer (nk) cells may be present or absent and this feature constitutes the basis for the classical division into t-b + scid and t-b)scid, with further subdivisions into nk+ and nk) disorders. 1 respiratory tract infection is a common manifestation in children in question and may be present within the neonatal period or in early infancy. opportunistic pathogens may lead to rapidly progressive, fatal interstitial pneumonitis accompanied by hyperinflation resulting from small airway obstruction or to persistent bronchiolitic presentation. apart from pyogenic bacteria, such as pseudomonas aeruginosa, stenotrophomonas spp, burkholderia spp, as well as mycobacteria and fungi, in particular pneumocystis jiroveci, respiratory viruses like respiratory syncytial virus (rsv), adenovirus, parainfluenza virus, human metapneumovirus (hmpv) and other viruses -cytomegalovirus (cmv), varicella-zoster virus (vzv), and epstein-barr virus (ebv) are associated with severe pneumonia in scid children. 2 human coronaviruses (hcov) hcov-229e and hcov-oc43 and related new strains hcov-nl63 and hcov-hku1, identified after the epidemic outbreak of severe acquired respiratory syndrome (sars) coronavirus, are likely to be common respiratory viruses in otherwise healthy children and were not implicated in severe lung infections in immunocompromised patients thus far. 3 in this report we present the case of a child with delayed-onset scid and fatal respiratory coronavirus infection. a 15-month-old girl was referred to the university hospital due to persistent fever and interstitial pneumonitis for the purposes of diagnosis and treatment. she was the first child of young, non-consanguineous parents, born from the first pregnancy which was terminated in the 39th week of gestation using cesarian section surgery because of condylomata acuminata due to human papilloma *the institution to which the work should be attributed. virus (hpv) infection in the mother. in early infancy, mild eczema on the child's face, in the perioral and periorbital areas was observed. by the end of the first year of life the child had thrived and had not suffered from any severe infections. she received live bcg vaccine, tetanus and diphtheria toxoids, inactivated pertussis, inactivated poliomyelitis, recombinant hepatitis b and conjugated pneumococcal as well as haemophilus influenzae b vaccines without adverse reactions after the immunizations. on admission the child demonstrated paroxysmal nonproductive cough and clinical signs of respiratory insufficiency along with injected oral pharyngeal mucosa and dry erythematous lips. fine papular skin eruption affecting the face was observed. neither peripheral lymph nodes nor internal organs of the abdominal cavity were palpable. during hospitalization, lymphopenia, anemia, and thrombocytosis (the peak platelet count was 778 · 10 9 ⁄ l) as well as increased levels of inflammatory markers and coagulopathy were found in laboratory tests. dilation of the right coronary artery was revealed in echocardiography, giving rise to the suspicion of kawasaki disease and the instituting of treatment with aspirin and immunoglobulins. despite intensive pharmacotherapy with antibiotics, trimethoprime ⁄ sulfamethoxazole, acyclovir and antifungal agents, rapid deterioration of the child's clinical state and the exacerbation of respiratory insufficiency accompanied by progression in radiological features of the respiratory distress syndrome (rds) occured. on a chest x-ray, massive alveolar and interstitial infiltrations with bilaterally decreased aeration of the lung fields and blurred borders of the diaphragm and the heart shape (as shown on figure 1 ) were discernible. differential diagnostics that included examinations of the tracheal aspirate samples aimed at infectious agents were carried out. infections with viruses -rsv a and b, parainfluenza viruses 1,2, and 3, influenza a including h1n1 subtype and b, adenoviruses, cmv, ebv, mpv, rhinovirus, human immunodeficiency virus (hiv), with bacteria, such as streptococcus pneumoniae, haemophilus influenzae, legionella, bordetella pertussis, mycoplasma pneumoniae, chlamydophila pneumoniae, as well as with fungi -candida spp. and p. jiroveci were excluded based on negative pcr examinations, whereas the human coronavirus hku1 -rna proved positive. peripheral blood lymphocyte flow cytometric immunophenotyping revealed a total lack of expression of antigens characteristic for cd4 and cd8 t-cell subsets as well as nk cells along with the presence of functionally immature transitional and naïve b cells. this scid phenotype was subsequently confirmed by bone marrow flow cytometric evaluation. however, the presence of few nk cells was revealed, indicating for t-b + nk + scid. intensive therapy and mechanical ventilation conducted in the department of pediatric anesthesiology and intensive care did not contribute to either clinical or radiological improvement and the child died because of multiorgan failure. analysis of the available data concerning the effects of non-sars human coronaviruses (hcov) in children suggests that their clinical relevance in children is substantial, particularly in the hospital settings, even though the incidence of hcov airway infections are generally less frequent than with other viruses which have an established role in respiratory disease, such as rsv and influenza. 4 however, detailed epidemiological data on the prevalence of hcov infections in children are discordant, ranging from 2ae5% of nl63 strain in young children with bronchiolitis reported by ebihara et al. 5 to 18% in the study by vabret et al. 6 in different age groups of the child population. moreover, seroconversion with regard to hcov-229e and above-mentioned hcov-nl63 in young children was much higher and was estimated to 42ae9-50% and 75%, respectively. 7 the characteristics of clinical manifestation of coronavirus respiratory tract infection are predominantly reliant on case reports, and in otherwise, healthy children are comparable with bronchitis, bronchiolitis, and pneumonia due to other viral infections. the epidemiological study by kuypers et al. 8 indicated that a considerable proportion of coronavirusinfected children had underlying chronic central nervous system, cardiovascular, pulmonary, allergic, and renal or hepatic conditions and diseases. these authors also paid attention to immunocompromised pediatric patients with acute lymphocytic leukemia and organ transplant recipients as a high-risk group for the development of severe lung disfigure 1 . the chest x-ray of a 15-month-old child with severe combined immunodeficiency and respiratory distress syndrome due to coronavirus hku1 infection. note the massive alveolar and interstitial infiltrations, with bilaterally decreased aeration of the lung fields and blurred borders of the diaphragm and the heart shape. ease. however, it is worth noting that coronavirus respiratory infections have not been described in children with genetically determined immunodeficiencies thus far and this is the first report of a documented hcov-hku1-related pneumonia with the rds in a child with scid. it is also interesting to note that the preliminary clinical diagnosis in this patient was kawasaki disease, what is consistent with the hypothesis by esper et al. 9 regarding the association between kawasaki disease with hcov infection, supported by identification of the 'new heaven' coronavirus (hcov-nh) in 72ae7% of respiratory specimen from affected children. the identification of hcov-hku1 provides a novel insight into the epidemiology and clinical implications of coronavirus infections in severely immunocompromised children and indicates for consideration of this pathogen-related etiology of respiratory infection in scid. further, epidemiological studies are necessary to define the impact of hcov on lung disease in children with immunodeficiencies. the expanding clinical and immunological spectrum of severe combined immunodeficiency pneumonia in normal and immunocompromised children: an overview and update the widening scope of coronaviruses effects of coronavirus infections in children detection of human coronavirus nl63 in young children with bronchiolitis human coronavirus nl63 seroepidemiology of group 1 human coronaviruses in children clinical disease in children associated with newly described coronavirus subtypes association between a novel human coronavirus and kawasaki disease the assistance of dr husam samara from the department of immunology for the flow cytometric immunophenotyping of peripheral blood and bone marrow leukocytes is acknowledged. the authors have no competing interests. key: cord-268190-r428y2j9 authors: vivanti, alexandre j.; deruelle, philippe; picone, olivier; guillaume, sophie; roze, jean-christophe; mulin, blandine; kochert, fabienne; de beco, isabelle; mahu, sophie; gantois, adrien; barasinski, chloé; petitprez, karine; pauchet-traversat, anne-françoise; droy, alcyone; benachi, alexandra title: post-natal follow-up for women and neonates during the covid-19 pandemic: french national authority for health recommendations date: 2020-05-11 journal: j gynecol obstet hum reprod doi: 10.1016/j.jogoh.2020.101805 sha: doc_id: 268190 cord_uid: r428y2j9 introduction: in the context of the stage 3 sars-cov-2 epidemic situation, it is necessary to put forward a method of rapid response for an has position statement in order to answer to the requests from the french ministry of solidarity and health, healthcare professionals and/or health system users’ associations, concerning post-natal follow-up for women and neonates during the covid-19 pandemic. methods: a simplified 7-step process that favours has collaboration with experts (healthcare professionals, health system users’ associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. a short and specific dissemination format, which can be quickly updated in view of the changes in available data has been chosen. in the context of the stage 3 sars-cov-2 epidemic situation, it is necessary to put forward a method of rapid response for a has position statement in order to answer to the requests from the french ministry of solidarity and health, healthcare professionals and/or health system users' associations. a simplified 7-step process that favours has collaboration with experts (healthcare professionals, health system users' associations, scientific societies etc.), the restrictive selection of available evidence and the use of digital means of communication. a short and specific dissemination format, which can be quickly updated in view of changes in available data has been chosen. step 1) selection of requests and identification of issues requiring a rapid response by the president of the has college. step 2) data selection and analysis by the has teams in close collaboration with experts named by the national professional councils (conseils nationaux professionnels -cnp) and french scientific societies. data selection has been restricted to the best levels of evidence and in descending order: step 3) drafting of provisional rapid responses by a select working group: has team, previously appointed experts and patient associations step 4) review and consultation / information of stakeholders. this step includes a panel of designated healthcare professionals as well as representatives of the french institutions (french general health directorate, high council for public health). these reviews are carried out electronically and allow a response within a short time frame. step 5) finalization of the rapid responses by the previously appointed working group. step 6) validation and dissemination of the rapid responses by the has. the texts are then published in a short format on the website of the has, scientific societies and associations involved. a warning is included in the text: "these recommendations, drawn up on the basis of the knowledge available at the date of their publication, are subject to change and are likely to be updated in light of new available data". the experts' ties of interest are analysed by the has ethics officer and the legal department, on the basis of the information available in the "dpi-health and transparency-health" databases, and are provided to the members of the has college for their information step 7) regular update of the rapid responses taking into account the developments in the scientific literature and the recommendations from scientific societies. before any early discharge from the maternity ward, the newborn is examined by a paediatrician according to the situations mentioned above: before 48 hours, at 48 hours of life and after 96 hours. -it is advisable that a post-natal care consultant accompanies women, particularly those in precarious situations or those in vulnerable psychological or social situations, in order to: -carry out screening, prevent complications and identify them early in order to refer the patient to another professional if necessary -identify a need for follow-up or additional assistance or referral via the appropriate channels. -newborns of a covid+ mother should be considered carriers of the virus. the american academy of pediatrics (aap) and society of obstetricians and gynecologists (sogc) recommend that newborns of a covid+ mother be considered suspect for covid-19. the authors suggest that the value of a screening test is to organize postpartum j o u r n a l p r e -p r o o f care and to provide close monitoring of the newborn 7, 8 . in the french context, the has considers it more prudent to consider any newborn of a covid+ mother as a carrier of the virus. testing the newborn is therefore not justified. the precautions to be taken are to stay confined at home with the child, to avoid too close contact with family members (especially siblings and people at risk), to wear a surgical mask and to have strict hand hygiene. temperature and appearance of symptoms of respiratory infection should be monitored in both mother and child. current data, feedback from professionals in the field on the impact of carrying out screening tests on maternity practices, the conditions of return home and findings on child health do not make it possible to systematically recommend a screening test for children. if the mother's covid status is known, that of the newborn must in fact be considered to be identical. in case of the slightest symptom, both mother and child should be tested. the conditions and organization of the return home follow the has recommendations while adapting to the context of the epidemic 6 . j o u r n a l p r e -p r o o f -a first routine visit is carried out by a midwife ideally within 24 hours after leaving the maternity unit. the mother leaves the maternity unit with this appointment. -a second visit can be scheduled if decided by the midwife, by remote consultation or faceto-face depending on the situation. if necessary, she will contact the obstetrician and/or the paediatrician and/or the general practitioner. -other visits can be planned according to the medical aspects to be monitored, the mother's vulnerabilities or social or psychological context, and/or if the mother or the couple feel they need them; they can be carried out by remote consultation. for at-risk women, if hospitalization at home is indicated, it should be preferred depending on the resources available locally 11 . the first health certificate "to be drawn up within the first eight days of life" is systematically issued by a doctor (paediatrician or general practitioner). it can be filled in when leaving the maternity unit. given the shorter length of stay in the maternity unit, it is recommended that a newborn child be examined in person between the 6 th and 10 th day after the birth, preferably by a paediatrician or a general practitioner. the newborn's visit planned during the second week (close medical supervision of the infant) is left, during an outbreak of covid-19, to the decision of the paediatrician or general practitioner who examined the child between the 6 th and 10 th day postpartum. -bleeding, infectious, thromboembolic, urinary, digestive, scarring and pain risk concern about their maternal capacity 11 ; situation of domestic violence in the context of lockdown 12 . psychological support may be necessary. -breastfeeding difficulties, adapted response to newborn crying. -risk of child abuse, especially shaken baby syndrome: the quality of support from family and friends is essential, as is recourse to psychological support 13 . -in a context of lockdown and family isolation, it is essential to reinforce postnatal monitoring by remote consultation, particularly for monitoring breastfeeding 14 -communication and town/hospital organization is essential for the appropriate care of the mother and child. -early examination of the newborn by the paediatrician in the maternity ward before discharge in the same way as for discharge at 48 hours has to be considered, as well as early and rapid follow-up by the midwife at home. monitoring by bilirubinometer should take place after 24h according to the local organization. the results of neonatal screening tests should be routinely recorded in the child's health record. -systematic neonatal screening for metabolic diseases: in view of the lockdown measures taken by the post office, which have an impact on the delivery of "blotting paper" tests to neonatal screening reference centres, discharge from the maternity ward after 48h will ensure that neonatal screening can be carried out in good conditions. the implementation of these rapid responses implies essential support for the care offer, which is currently below standard in the context of the covid the general practitioner and all home-visiting healthcare professionals must be informed of the mother's infection. newborns without comorbidities can stay with their covid-19+ mother and be breastfed (unless the mother asks to be separated from her child). group (gpip) do not currently recommend separation of mother and child and do not contraindicate breastfeeding 10 . a mother with covid-19 and her child are monitored by their general practitioner and, if necessary, the paediatrician for the newborn. at the same time, the midwife can ensure postnatal supervision of the mother and the child in liaison with the referring obstetrical team. any woman or child with signs of severe covid-19 or aggravating comorbidities should be taken to a health care facility. -active monitoring of her temperature and onset of symptoms of respiratory infection (fever, cough, breathing difficulty, sensation of suffocation etc.). -strict lockdown with the child. -too close contact with family members should be avoided. -a mask (surgical mask) should be worn. -strict hand hygiene: hands should be washed before taking care of the child. j o u r n a l p r e -p r o o f -the general practitioner or the nurse should contact the mother every 24h to follow-up on the infection (tracing the results to be recovered and calls made), giving priority to remote consultation or remote care when possible. -postnatal monitoring of mother and child by the midwife in liaison with the referring obstetrical team. -exit from isolation after recovery as in the general population. 15 -consultation with a doctor three weeks after discharge. -active monitoring of temperature and the onset of symptoms of respiratory infection (fever, cough, breathing difficulties, etc.), diarrhoea. -strict lockdown with the mother. -it is not recommended for newborns to wear masks -first consultation within 24 hours of arrival at home with the midwife, then a consultation between the 6 th and 10 th day postpartum, preferably at the paediatrician's or general practitioner's practice, in accordance with the safety protocol in place (for example at the end of a consultation with a paediatrician at a special clinic for newborns or small infants). although compulsory, in the event of a covid-19 epidemic, examination of the newborn planned during the second week (close medical supervision of the infant) is decided by the paediatrician or general practitioner who examined the child between the 6 th and 10 th postpartum. -any symptoms in the newborn should be reported to the health care professional who looks after the child and should give rise to a consultation, and determine the frequency of follow-up. -in case of emergency: go to the paediatric emergency department of the reference hospital having first called the emergency services. -no data are available on the impact of early maternal infection during pregnancy on child development: close monitoring of the child at each visit 16, 17 . j o u r n a l p r e -p r o o f as with any person confirmed to be covid-19+, self-isolation at home for 14 days after the onset of the first symptoms is recommended and special precautions should be taken. the precautions applicable to women with covid-19 are the same as for the general population (barrier measures, social distancing, lockdown) to reduce the risk of transmission. specific recommendations also apply. monitoring instructions and hygiene precautions to be observed must be given and explained to the woman or couple before leaving the maternity unit. mother and child organisation at home after leaving the maternity unit -at home, the mother is advised to isolate with the child, if possible, in a separate room, avoiding contact with the other occupants, and to air the room regularly. a hotel room is available if the mother prefers (covisan system in paris, or equivalent elsewhere). -the cot should be placed about six feet from the mother's bed or chair. -all occupants should wash their hands frequently after using the bathroom and toilet, which must be cleaned regularly with bleach or disinfectant. -surfaces touched regularly (door handles, mobile phones, etc.) are cleaned daily and disinfected). -it is not advisable to receive visits unless they are essential, such as visits from a midwife, nurse, childcare worker or home help. studies show that the viral genome is not found in the breast milk of covid-19j o u r n a l p r e -p r o o f during examination or care of the newborn, during the first month of life, it is recommended to wear a mask and to wash hands beforehand (using soap or had sanitizer) the newborn must be seen again for the first month visit in person. mandatory vaccinations must be administered at two months of life (possible from 6 weeks). have a physical examination of the newborn between the 6 th and 10 th day after birth carried out by a paediatrician or a general practitioner within the framework of an organized care system. : propose follow-up by remote consultation or face-to-face based on the assessment of the clinical situation, but also on the woman's social and psychological context. ensure the physical and mental well-being of the mother, maintain psychological support for women, including remotely, and accompany the mother or couple in their parenting practices the jaundice risk assessment must be integrated into the reasoning leading up to the decision for discharge from the maternity unit. for each child, compilation of a jaundice profile based on the normogram 23 , combined with the recognition of risk factors for severe hyperbilirubinemia, ensures that the child is discharged in optimal safety conditions and thus reduces the risk of readmission to hospital for hyperbilirubinemia. jaundice follow-up procedures should: be effective within 24 hours of early discharge from the maternity unit. enable quantification of jaundice. enable physical evaluation of the child (weighing) and breastfeeding (observation of a feed). identify a possible return route (if necessary) to a care facility. parents must be informed of the warning signs and of who to contact in the event of an emergency prior to discharge 24 . it is recommended that jaundice data be recorded in the child's health record, or that this information (risk factors, profile outcome, diagnosis and test results) be mentioned on the immediate post-partum liaison sheet for the professional(s) providing follow-up 6 . in practice, if the midwife does not have a bilirubinometer, she should be able to arrange for a bilirubin test at the maternity ward. as part of early discharge during the covid-19 pandemic, it is important to monitor clinical signs and arrange for bilirubin monitoring at a private practice or at the hospital if necessary. in the event of jaundice, phototherapy must be organized via secure channels in the maternity unit where the woman gave birth. the authors declare no competing interests j o u r n a l p r e -p r o o f avis du 31 mars 2020 relatif à la prévention et à la prise en charge des patients à risque de formes graves de covid-19 ainsi qu'à la priorisation des tests diagnostiques clinical characteristics of pregnant women with covid-19 in wuhan clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records. the lancet cov-2 from an infected mother to her newborn clinical features and obstetric and neonatal outcomes of pregnant patients with covid-19 in wuhan, china: a retrospective, single-centre, descriptive study sortie de maternité après accouchement : conditions et organisation du retour à domicile des mères et de leurs nouveau-nés american academy of pediatrics. management of infants born to mothers with covid-19 covid 19 pendant la grossesse pregnancy outcomes, newborn complications and maternal-fetal transmission of sars-cov-2 in women with covid-19: a systematic review propositions de la société française de néonatalogie et de la société française de pédiatrie concernant les nouveau-nés dans le contexte d'épidémie à covid-19 situations pathologiques pouvant relever de l'hospitalisation à domicile au cours de l'ante et du post-partum repérage des femmes victimes de violences au sein du couple saint-denis syndrome du bébé secoué ou traumatisme crânien non accidentel par secouement le guide de l'allaitement maternel sortie de maternité après accouchement : conditions et organisation du retour à domicile des mères et de leurs nouveau-nés american college of obstetricians and gynecologists. covid-19 obstetric preparedness manual maternal and perinatal outcomes with covid-19: a systematic review of 108 pregnancies coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know experience of clinical management for pregnant women and newborns with novel coronavirus pneumonia in tongji hospital, china centers for disease control and prevention. pregnancy and breastfeeding. information about coronavirus disease ad interim indications of the italian society of neonatology endorsed by the union of european neonatal & perinatal societies. maternal & child nutrition world health organization réginal office for europe. covid-19 and breastfeeding management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation we would like to extend our thanks to mrs madeleine akrich, france artzner, anne evrard from the collectif interassociatif autour de la naissance (ciane) who read the recommendations. key: cord-258049-l55mx4lp authors: mansbach, jonathan m.; clark, sunday; piedra, pedro a.; macias, charles g.; schroeder, alan r.; pate, brian m.; sullivan, ashley f.; espinola, janice a.; camargo, carlos a. title: hospital course and discharge criteria for children hospitalized with bronchiolitis date: 2015-01-28 journal: j hosp med doi: 10.1002/jhm.2318 sha: doc_id: 258049 cord_uid: l55mx4lp background: for children hospitalized with bronchiolitis, there is uncertainty about the expected inpatient clinical course and when children are safe for discharge. objectives: examine the time to clinical improvement, risk of clinical worsening after improvement, and develop discharge criteria. design: prospective multiyear cohort study. setting: sixteen us hospitals. participants: consecutive hospitalized children age <2 years with bronchiolitis. measurement: we defined clinical improvement using: (1) retraction severity, (2) respiratory rate, (3) room air oxygen saturation, and (4) hydration status. after meeting improvement criteria, children were considered clinically worse based on the inverse of ≥1 of these criteria or need for intensive care. results: among 1916 children, the median number of days from onset of difficulty breathing until clinical improvement was 4 (interquartile range, 3–7.5 days). of the total, 1702 (88%) met clinical improvement criteria, with 4% worsening (3% required intensive care). children who worsened were age <2 months (adjusted odds ratio [aor]: 3.51; 95% confidence interval [ci]: 2.07‐5.94), gestational age <37 weeks (aor: 1.94; 95% ci: 1.13‐3.32), and presented with severe retractions (aor: 5.55; 95% ci: 2.12‐14.50), inadequate oral intake (aor: 2.54; 95% ci: 1.39‐4.62), or apnea (aor: 2.87; 95% ci: 1.45‐5.68). readmissions were similar for children who did and did not worsen. conclusions: although children hospitalized with bronchiolitis had wide‐ranging recovery times, only 4% worsened after initial improvement. children who worsened were more likely to be younger, premature infants presenting in more severe distress. for children hospitalized with bronchiolitis, these data may help establish more evidence‐based discharge criteria, reduce practice variability, and safely shorten hospital length‐of‐stay. journal of hospital medicine 2015;10:205–211. © 2015 society of hospital medicine although bronchiolitis is the leading cause of hospitalization for us infants, 1 there is a lack of basic prospective data about the expected inpatient clinical course and ongoing uncertainty about when a hospitalized child is ready for discharge to home. 2 this lack of data about children's readiness for discharge may result in variable hospital length-of-stay (los). [3] [4] [5] one specific source of variability in discharge readiness and los variability may be the lack of consensus about safe threshold oxygen saturation values for discharge in children hospitalized with bronchiolitis. 6, 7 in 2006, the scottish intercollegiate guidelines net-work recommended a discharge room air oxygen (rao2) saturation threshold of 95%. 8 the same year, the american academy of pediatrics (aap) bronchiolitis clinical practice guideline stated that oxygen is not needed for children with rao2 saturations 90% who are feeding well and have minimal respiratory distress. 9 there is a need for prospective studies to help clinicians make evidenced-based discharge decisions for this common condition. we performed a prospective, multicenter, multiyear study [10] [11] [12] to examine the typical inpatient clinical course of and to develop hospital discharge guidelines for children age <2 years hospitalized with bronchiolitis. we hypothesized that children would not worsen clinically and would be safe to discharge home once their respiratory status improved and they were able to remain hydrated. we conducted a prospective, multicenter cohort study for 3 consecutive years during the 2007 to 2010 winter seasons, as part of the multicenter airway research collaboration (marc), a program of the emergency medicine network (www.emnet-usa.org). the number of participating sites varied over the 3 years: 13 in year 1, 16 in year 2, and 14 in year 3. each month from november 1 until march 31, site investigators across 12 us states used a standardized protocol to enroll a target number of consecutive patients from the inpatient wards and the intensive care unit (icu). we aimed to enroll 20% of our total sample from the icu. to over sample children in the icu, the ward and icu enrollments were separate. once the site reached their target enrollment for that month, the investigators would stop enrollment until the beginning of the following month. all patients were treated at the discretion of the treating physician. inclusion criteria were an attending physician's diagnosis of bronchiolitis, age <2 years, and the ability of the parent/guardian to give informed consent. the exclusion criteria were previous enrollment and transfer to a participating hospital >48 hours after the original admission time. therefore, children with comorbid conditions were included in this study. all consent and data forms were translated into spanish. the institutional review board at each of the 16 participating hospitals approved the study. of the 2207 enrolled children, we excluded 109 (5%) children with a hospital los <1 day due to inadequate time to capture the required data for the present analysis. among the 2098 remaining children, 1916 (91%) had daily inpatient data on all factors used to define clinical improvement and clinical worsening. thus, the analytic cohort was comprised of 1916 children hospitalized for bronchiolitis. investigators conducted detailed structured interviews. chart reviews were conducted to obtain preadmission and daily hospital clinical data including respiratory rates, daily respiratory rate trends, degree of retractions, oxygen saturation, daily oxygen saturation trends, medical management, and disposition. these data were manually reviewed, and site investigators were queried about missing data and discrepancies. a follow-up telephone interview was conducted with families 1 week after discharge to examine relapse events at both 24 hours and 7 days. we used the question: "how long ago did the following symptoms [eg, difficulty breathing] begin [for the] current illness?" to estimate the onset of the current illness. pulse was categorized as low, normal, or high based on age-related heart rate values. 13 presence of apnea was recorded daily by site investigators. 14 nasopharyngeal aspirate collection and virology testing as described previously, site teams used a standardized protocol to collect nasopharyngeal aspirates, 11 which were tested for respiratory syncytial virus (rsv) types a and b; rhinovirus (rv); parainfluenza virus types 1, 2, and 3; influenza virus types a and b; 2009 novel h1n1; human metapneumovirus; coronaviruses nl-63, hku1, oc43, and 229e; enterovirus, and adenovirus using polymerase chain reaction. 11, [15] [16] [17] defining clinical improvement and worsening clinical improvement criteria were based on the 2006 aap guidelines. 9 for respiratory rate and oxygen saturation, clinicians estimated average daily respiratory rate and oxygen saturation based on the recorded readings from the previous 24 hours. this estimation reflects the process clinicians use when rounding on their hospitalized patients, and thus may be more similar to standard clinical practice than a calculated mean. the respiratory rate criteria are adjusted for age. 18, 19 for daily estimated average oxygen saturation we used the aap criteria of rao2 saturation of 90%. considering that oxygen saturation is the main determinant of los, 20 healthy infants age <6 months may have transient oxygen saturations of around 80%, 21 and that errors in estimation may occur, we included a lowest rao2 of 88% in our improvement criteria. by combining the dichotomized estimated oxygen saturation (90% or not) with the lower limit of 88%, there was little room for erroneous conclusions. a child was considered clinically improved on the earliest date he/she met all of the following criteria: (1) none or mild retractions and improved or stable retractions compared with the previous inpatient day; (2) daily estimated average respiratory rate (rr) <60 breaths per minute for age <6 months, <55 breaths/minute for age 6 to 11 months, and <45 breaths/minute for age 12 months with a decreasing or stable trend over the course of the current day; (3) daily estimated average rao2 saturation 90%, lowest rao2 saturation 88% 21 ; and (4) not receiving intravenous (iv) fluids or for children receiving iv fluids a clinician report of the child maintaining oral hydration. children who reached the clinical improvement criteria were considered clinically worse if they required intensive care or had the inverse of 1 of the improvement criteria: moderate/severe retractions that were worse compared with the previous inpatient day, daily average rr 60 with an increasing trend over the current day, need for oxygen, or need for iv fluids. all analyses were performed using stata 12.0 (stata-corp, college station, tx). data are presented as proportions with 95% confidence intervals (95% cis), means with standard deviations, and medians with interquartile ranges (iqr). to examine potential factors associated with clinical worsening after reaching clinical improvement, we used v 2 , fisher exact, student t test, and kruskall-wallis tests, as appropriate. adjusted analyses used generalized linear mixed models with a logit link to identify independent risk factors for worsening after reaching clinical improvement. fixed effects for patient-level factors and a random site effect were used. factors were tested for inclusion in the multivariable model if they were found to be associated with worsening in unadjusted analyses (p < 0.20) or were considered clinically important. results are reported as odds ratios with 95% cis. we performed several sensitivity analyses to evaluate these improvement criteria: (1) we excluded the lowest rao2 saturation requirement of 88%, (2) we examined a 94% daily estimated average rao2 saturation threshold, 22 (3) we examined a 95% daily estimated average rao2 saturation threshold, 8 and (4) we examined children age <12 months with no history of wheeze. there were 1916 children hospitalized with bronchiolitis with data on all factors used to define clinical improvement and clinical worsening. the median number of days from the beginning of difficulty breathing until admission was 2 days (iqr, 1-5.5 days; range, 1-8 days) and from the beginning of difficulty breathing until clinical improvement was 4 days (iqr, 3-7.5 days; range, 1-33 days) ( figure 1 ). the variance for days to admission was significantly less than the variance for days to clinical improvement (p < 0.001). in this observational study, clinicians discharged 214 (11%) of the 1916 children before meeting the definition of clinical improvement. thus, 1702 (89%; 95% ci: 87%-90%) children reached the clinical improvement criteria, had a los >1 day, and had data on all factors ( figure 2 ). of the 1702 children who met the clinical improvement criteria, there were 76 children (4%; 95% ci: 3%-5%) who worsened ( figure 2 ). the worsening occurred within a median of 1 day (iqr, 1-3 days) of clinical improvement. forty-six (3%) of the children required transfer to the icu (1 required intubation, 1 required continuous positive airway pressure, and 4 had apnea), 23 (1%) required oxygen, and 17 (1%) required iv fluids. eight percent of children met multiple criteria for worsening. a comparison between children who did and did not worsen is shown in table 1 . in general, children who worsened after improvement were younger and born earlier. these children also presented in more severe respiratory distress, had moderate or severe retractions, oxygen saturation <85% at hospitalization, inadequate oral intake, and apnea documented during the hospitalization. neither viral etiology nor site of care influenced whether the children worsened after improving. however, stratified analysis of children based on initial location of admission (ie, icu or ward) showed that among the children admitted to the icu from the emergency department (ed), 89% met the improvement criteria and 19% clinically worsened. in contrast, among children admitted to the ward from the ed, 89% met the improvement criteria, and only 2% clinically worsened. stratified multivariable models based on the initial location of admission from the ed (ie, icu or ward) were not possible due to small sample sizes after stratification. none of these children had relapse events requiring rehospitalization within either 24 hours or 7 days of discharge. on multivariable analysis (table 2) , independent risk factors for worsening after reaching the clinical improvement criteria were young age, preterm birth, and presenting to care with more severe bronchiolitis represented by severe retractions, inadequate oral intake, or apnea. to further evaluate the improvement criteria in the current analysis, multiple sensitivity analyses were conducted. the frequency of clinical worsening after reaching the improvement criteria was stable when we examined different ra02 criteria in sensitivity analyses: (1) excluding ra02 as a criterion for improvement: 90% met improvement criteria and 4% experienced clinical worsening, (2) changing the average ra02 threshold for clinical improvement to 94%: 62% met improvement criteria and 6% experienced clinical worsening, and (3) changing the average ra02 threshold for clinical improvement to 95%: 47% met improvement criteria and 5% experienced clinical worsening. furthermore, stratifying by age <2 months and restricting to more stringent definitions of bronchiolitis (ie, age <1 year or age <1 year 1 no history of wheezing) also did not materially change the results (see supporting figure 1 in the online version of this article). we compared the 214 children who were discharged prior to reaching clinical improvement with the 1702 children who reached the clinical improvement criteria. the 214 children were less likely to be age <2 months (22% vs 30%; p 5 0.02). these 2 groups (214 vs 1702) were similar with respect to in this large, multicenter, multiyear study of children hospitalized with bronchiolitis, we found that children present to a hospital in a relatively narrow time frame, but their time to recovery in the hospital is highly variable. nonetheless, 96% of children continued to improve once they had: (1) improving or stable retractions rated as none/mild, (2) a decreasing or stable rr by age, (3) estimated average rao2 saturation 90% and lowest rao2 saturation of 88%, and (4) were hydrated. the 4% of children who worsened after clinically improving were more likely to be age <2 months, born <37 weeks, and present with more severe distress (ie, severe retractions, inadequate oral intake, or apnea). based on the low risk of worsening after clinical improvement, especially among children admitted to the regular ward (2%), we believe these 4 clinical criteria could be used as discharge criteria for this common pediatric illness with a predominantly monophasic clinical course. variability in hospital los for children with bronchiolitis exists in the united states 3 and internationally. 4,5 cheung and colleagues analyzed administrative data from over 75,000 children admitted for bronchiolitis in england between april 2007 and march 2010 and found sixfold variation in los between sites. they concluded that this los variability was due in part to providers' clinical decision making. 5 srivastava and colleagues 23 addressed variable clinician decision making in bronchiolitis and 10 other common pediatric conditions by embedding discharge criteria developed by expert consensus into admission order sets. they found that for children with bronchiolitis, the embedded discharge criteria reduced the median los from 1.91 to 1.87 days. in contrast to the single-center data presented by white and colleagues, 24 the prospective, multicenter marc-30 data provide a clear understanding of the normal clinical course for children hospitalized with bronchiolitis, determine if children clinically worsen after clinical improvement, and provide data about discharge criteria for children hospitalized with bronchiolitis. although there is a lack of rigorous published data, the lower tract symptoms of bronchiolitis (eg, cough, retractions) are said to peak on days 5 to 7 of illness and then gradually resolve. 25 in the present study, we found that the time from the onset of difficulty breathing until hospital admission is less variable than the time from the onset of difficulty breathing until either clinical improvement or discharge. although 75% of children have clinically improved within 7.5 days of difficulty breathing based on the iqr results, the remaining 25% may have a more prolonged recovery in the hospital of up to 3 weeks. interestingly, prolonged recovery times from bronchiolitis have also been noted in children presenting to the ed 26 and in an outpatient population. 27 it is unclear why 20% to 25% of children at different levels of severity of illness have prolonged recovery from bronchiolitis, but this group of children requires further investigation. given the variability of recovery times, clinicians may have difficulty knowing when a child is ready for hospital discharge. one of the main stumbling blocks for discharge readiness in children with bronchiolitis is the interpretation of the oxygen saturation value. 6, 8, 9, 20, 28 however, it should be considered that interpreting the oxygen saturation in a child who is clinically improving in the hospital setting is different than interpreting the oxygen saturation of a child in the ed or the clinic whose clinical course is less certain. 22 in the hospital setting, using the oxygen saturation value in in the aap guideline, 9 4% of children clinically worsened after they met the improvement criteria, a clinical pattern observed previously with supplemental oxygen. 28 this unpredictability may explain some of the variation in providers' clinical decision making. 5 the children who worsened, and therefore deserve more cautious discharge planning, were young (<2 months), premature (<37 weeks gestational age), and presented in more severe distress. those children admitted to the icu from the ed worsened more commonly than children admitted to the ward (19% vs 2%). interestingly, the viral etiology of the child's bronchiolitis did not influence whether a child worsened after reaching the improvement criteria. therefore, although children with rv bronchiolitis have a shorter hospital los than children with rsv bronchiolitis, 11 the pattern of recovery did not differ by viral etiology. in addition to unsafe discharges, clinicians may be concerned about the possibility of readmissions. although somewhat controversial, hospital readmission is being used as a quality of care metric. [29] [30] [31] one response to minimize readmissions would be for clinicians to observe children for longer than clinically indicated. 32 however, shorter los is not necessarily associated with increased readmission rates. 33 given that the geometric mean of hospital charges per child with bronchiolitis increased from $6380 in 2000 to $8530 in 2009, 34 the potential for safely reducing hospital los by using the discharge criteria proposed in the current study instead of other criteria 8 may net substantial cost savings. furthermore, reducing los would decrease the time children expose others to these respiratory viruses and possibly reduce medical errors. 35 our study has some potential limitations. because the study participants were all hospitalized, these data do not inform admission or discharge decisions from either the ed or the clinic; but other data address those clinical scenarios. 22 also, the 16 sites that participated in this study were large, urban teaching hospitals. consequently, these results are not necessarily generalizable to smaller community hospitals. although numerous data points were required to enter the analytic cohort, only 9% of the sample was excluded for missing data. there were 214 children who did not meet our improvement criteria by the time of discharge. although the inability to include these children in the analysis may be seen as a limitation, this practice variability underscores the need for more data about discharging hospitalized children with bronchiolitis. last, site teams reviewed medical records daily. more frequent recording of the clinical course would have yielded more granular data, but the current methodology replicates how data are generally presented during patient care rounds, when decisions about suitability for discharge are often considered. we documented in this large multicenter study that most children hospitalized with bronchiolitis had a wide range of time to recovery, but the vast majority continued to improve once they reached the identified clinical criteria that predict a safe discharge to home. the children who worsened after clinical improvement were more likely to be younger, premature infants presenting in more severe distress. although additional prospective validation of these hospital discharge criteria is warranted, these data may help clinicians make more evidence-based discharge decisions for a common pediatric illness with high practice variation, both in the united states 3 and in other countries. 4, 5 infectious disease hospitalizations among infants in the united states a hospital is no place to be sick variation in inpatient diagnostic testing and management of bronchiolitis watson ph international variation in the management of infants hospitalized with respiratory syncytial virus. international rsv study group population variation in admission rates and duration of inpatient stay for bronchiolitis in england impact of pulse oximetry and oxygen therapy on length of stay in bronchiolitis hospitalizations pulse oximetry in pediatric practice in: nhs quality improvement scotland. edinburgh, scotland: scottish intercollegiate guidelines network diagnosis and management of bronchiolitis prospective multicenter study of children with bronchiolitis requiring mechanical ventilation prospective multicenter study of viral etiology and hospital length of stay in children with severe bronchiolitis apnea in children hospitalized with bronchiolitis evaluation of the cardiovascular system: history and physical evaluation apnea in children hospitalized with bronchiolitis respiratory viral infections in patients with chronic, obstructive pulmonary disease evaluation of real-time pcr for diagnosis of bordetella pertussis infection evaluation of three real-time pcr assays for detection of mycoplasma pneumoniae in an outbreak investigation normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies development of heart and respiratory rate percentile curves for hospitalized children effect of oxygen supplementation on length of stay for infants hospitalized with acute viral bronchiolitis. pediatrics longitudinal assessment of hemoglobin oxygen saturation in healthy infants during the first 6 months of age. collaborative home infant monitoring evaluation (chime) study group prospective multicenter study of bronchiolitis: predicting safe discharges from the emergency department delays in discharge in a tertiary care pediatric hospital using quality improvement to optimise paediatric discharge efficiency bronchiolitis in infants and children: treatment; outcome; and prevention wolters kluwer health duration of illness in infants with bronchiolitis evaluated in the emergency department duration of illness in ambulatory children diagnosed with bronchiolitis a clinical pathway for bronchiolitis is effective in reducing readmission rates measuring hospital quality using pediatric readmission and revisit rates pediatric readmission prevalence and variability across hospitals preventability of early readmissions at a children's hospital. pediatrics hospital readmission: quality indicator or statistical inevitability? children's hospitals with shorter lengths of stay do not have higher readmission rates trends in bronchiolitis hospitalizations in the united states preventable adverse events in infants hospitalized with bronchiolitis key: cord-254277-hr5g1tkq authors: rozdilsky, janlyn r. title: enhancing sibling presence in pediatric icu date: 2005-12-12 journal: crit care nurs clin north am doi: 10.1016/j.ccell.2005.07.001 sha: doc_id: 254277 cord_uid: hr5g1tkq critical illness of a child affects all members of the family, including well brothers and sisters. stress in their lives results from changes in parental behaviors, caregiving arrangements, and family relationships. these changes, along with limited understanding and information about the crisis, create feelings of confusion, loneliness, jealousy, and sadness, as well as physical symptoms and behavior changes. educating pediatric icu nurses about the needs and reactions of well siblings enables them to optimize support to siblings and educate parents. a sibling policy guarantees that choice and support are offered in a consistent and thorough manner to each critically ill child’s family; this helps to ensure that the family unit has the abilities to nurture the ill child and other well children. four-year-old jamie stands transfixed and rigid at the foot of his infant sister's crib. she has required intubation and ventilation for an acute viral respiratory illness. jamie's eyes are wide. his mother strokes his hair, rumpled from a night of sleeping in the family waiting room. you ask if he has any questions. he shakes his head '' no'' but wants to leave immediately. before you can reassure him, he is at the door. his mother escorts him back to the waiting area. he does not return for the remainder of your shift. samantha, 16 years old, rushes frantically over to her sister's bedside. her 14-year-old sister, sibyl, remains unresponsive, still under the effects of anesthesia from surgery to repair internal and orthopedic injuries sustained in a car crash last night. sibyl's face is puffy and pale, with a few superficial abrasions and bruises. samantha grabs her mother and cries, ''her face, her face-just look at her face. you said she was going to be okay.'' you explain the temporary nature of her sister's appearance, and samantha becomes more upset. sibyl begins to move and her monitor alarms. samantha becomes even more distressed and is requested to return to the family waiting area. sam has cerebral palsy and yesterday had spinal surgery to correct severe scoliosis of the spine. sam is intubated and asleep with the help of analgesics and sedatives. his 10-year-old brother, jason, saunters into the room. he looks at his sleeping brother, then asks if sam has had any seizures since his operation. the nurse answers that he has not had any. jason then wants to know why his brother is not awake, and if sam will be able to have dinner tonight. hospitalization of a child dramatically affects the entire family, including well siblings. a critically ill child demands highly technical and patient-focused nursing; how we respond to their well siblings influences the view, the response, and the coping of well brothers and sisters. although family-centered care is integral to the pediatric settings, the focus often is on the critically ill child and parents. the needs of parents are widely identified [1] [2] [3] [4] [5] [6] [7] [8] ; however, little has been written regarding the brothers and sisters of the critically ill child. nurses may overlook siblings and assume parents and other family members are supporting them; however, distraught parents may not have the insight to identify the needs of their well children [9] , not know how to explain the situation [10] , or even realize that well siblings benefit from being with their ill sister or brother. siblings frequently remain invisible, are relegated to the waiting room, are rushed in and out, or are sent home with relatives. although most pediatric icus (picus) permit sibling visits [9, 11] , few have developed sibling policies or educational resources. this results in little staff or parental education regarding well sibling needs and little support for the sibling when present. integrating knowledge of child development and well sibling stressors, along with understanding of illness and family adaptation, creates a sibling policy that enables picu nurses to use their expertise and situation to provide holistic care to critically ill children and their family support systems. family-centered care seeks to understand experiences from the perspective of the child and their family [12] . while families work toward maintaining integrity by supporting each other, each member's actions and reactions have a dynamic influence on roles and relationships within the family [1] . because parental reactions strongly determine the family's abilities to cope and rebuild after critical illness of a child [1] , assessing the impact of parental reactions, along with changes in routine and relationships within the family, is important in facilitating well sibling care. admissions to picu cause a great deal of parental guilt associated with not recognizing symptoms, not seeking care quickly enough, or not preventing the occurrence. parents are on a '' roller coaster'' of emotion during this time [1] , and often must adjust to an outcome involving some form of loss [1, 5] . not surprisingly, the critically ill child becomes the focus of the parents' lives [1, 2, 5, 13] . everything else is put aside to protect, to comfort, and to make decisions related to the critically ill child [1 -3,6,14] how this obvious stress, grief, preoccupation, and fatigue specifically influence parenting and interactions with well children has been explored only partially. changes in parent behavior are a significant source of stress [15 -17] . well siblings perceiving parenting changes of less supervision, less emotional availability, and greater anger showed higher stress compared with those not reporting these changes [10, 15] . greater parental behavior changes were reported by well siblings than by the parents themselves [18] ; this indicated that parents are unaware of their own responses when immersed within the crisis of a critically ill child. because understanding of illness results from a interplay of educational, social, and cultural influences, parents with limited formal education or who are socially disadvantaged may have less understanding of the complexities of the situation, fewer problemsolving strategies, and fewer resources to cope with their ill child's situation. therefore, they are less able to support well siblings [8, 15] . lower socioeconomic status of the mother correlates with increased well sibling anxiety [15, 19] , possibly related to less maternal attention toward well siblings and less ability to assist them through the event [15] . how specific cultural understanding of illness influences parental reactions has not been explored [8] . however, if language barriers, religious beliefs, and ethnic health care practices limit understanding or acceptance of the science and technology inherent in the intensive care setting, ensuing parental stress and conflict is perceived by well siblings and adds to their stress. the extra demands of a critically ill child necessitate reframing and reassigning parenting and other family roles and duties [7] , especially if the picu is located some distance from the family home or hospitalization is of long duration. although substitute parenting is undertaken in an effort to normalize the lives of well siblings [7] , these arrangements can produce feelings of vulnerability, uncertainty, and emotional abandonment [15] . research is unclear on what care arrangements minimize sibling stress. knafl [20] found that siblings cared for outside their home or by rotating caregivers had increased stress as compared with well siblings who were cared for in their homes by a consistent caregiver. simon [16] found that siblings who were cared for outside their home by neighbors had less stress than did siblings who were at home with relatives; differences were attributed to the relatives being more upset. sibling stress also was greater if parents expected well siblings to adjust easily to these changes [20] . clearly, changes from the usual living situation or routine [15 -17] coupled with parental absence can create stress for the siblings. siblings play an important role in each other's emotional and psychologic development-and aside from parents-form the most long and enduring relationship within a child's life [21] . sibling bonds before hospitalization influence well sibling reactions. siblings describing themselves as ''best friends'' show increased stress levels as compared with those who rated their relationship as less close [16] . pediatric intensive care hospitalization creates changes within sibling bonds. carnevale [1] described the parental attachment to the injured child as immediately increasing, and bonds between the other well children strengthened to support each other through the initial crisis and parent's divided attention. at the same time, sibling bonds with the injured child weakened slightly, related to absence from the family unit and fear of losing the ill sibling. siblings bonds often must be reworked following the critical illness, and may change permanently to protect or distance the ill or injured child. given changes in family social structure that produce more one-parent, two working-parent, and blended families, the impact of siblings on one an-other may be even greater [17, 22] . older siblings provide substitute parenting during hospitalization [2] . how this change in relationship alters future sibling relationships requires further study. because there are no studies that explore responses of well siblings to the critical illness of their sister or brother, responses of children with siblings in other acute care settings, and children's general concepts of illness provide the framework for nursing and parental interventions. knowledge of growth and development is crucial in understanding well siblings' reactions and planning interventions [9,23 -25] . piaget [26] described understanding as constructed through increasingly sophisticated processes involving biologic maturation, assimilation of experiences, and social interactions. children's understanding of illness follows a similar maturational pattern of prelogical, concrete logical, and formal logical sequencing [27] . in the prelogical stage, the young child is unable to see self as separate from others, and so react similarly to those around them. thus, sensing their parents' emotional distress and physical reactions, the child reacts in like manner. because object permanence has not developed, separation from parents and siblings produces distress; what is out of sight ceases to exist in the world of the toddler. this egocentric perspective places themselves central to world happenings with illness resulting from something immediate in their lives. for the toddler, cause and effect are unclear, and creates ''magical thinking'' where thoughts influence happenings (eg, not sharing a toy with a sibling can be seen as causing their sibling's illness). likewise, not thinking about an event can prevent its happening. jamie, the 4-year-old who was described earlier, wants to leave his infant sister's bedside and refuses subsequent visits as a way of coping with a situation that he does not understand. unfortunately, hospitalization also may be seen as punishment, especially if parents have used this threat as disciplinary measure [23] . during the stage of concrete logical explanation, the preschooler to early school-aged child begins to distinguish self from surroundings and realize cause and effect. illness, although not always visible, is something internal with an external cause, such as germs. wellness is dependent upon conformity to rules, so children may become extremely diligent at routines, such as hand washing. children understand more than they can articulate, so they need to be provided with information rather than having to ask questions. although multiple points of view are understood, experience is lacking to determine the validity of each perspective; this results in misconceptions about illness if varying explanations are used. the formal logical explanation of illness in the older child and adolescent, as in the adult, is grounded in the understanding of physiologic processes. formal education, and social and cultural factors strongly influence the development of this abstract form of reasoning [23, 28] ; however, experientially acquired knowledge creates a novice-toexpert progression in conceptualizing illness, and increases perception and problem solving related to illness experiences [27] . therefore, well siblings with previous illness experiences often have a greater understanding of their ill sibling's situation [27] , especially if many of the circumstances are similar [28] . in the third vignette at the beginning this article, justin, at 10 years of age, demonstrates a mixture of concrete and formal logic. he asks about sam's seizures, something familiar, but he does not understand the other unfamiliar aspects of sam's intensive care. because most well siblings have no previous experience with the picu environment, information provided by nursing staff and parents influences their interpretation and coping with critical illness. children are acutely aware of changes in their environment. when well-meaning adults try to shield them from unpleasant situations by providing little or no information, their stress is accentuated [5,15, 29 -31] . because children's imaginations are their strength and weakness, gaps in information are filled with vivid and imaginative pictures that often are more distressing than reality [5, 21, 29] . the situation-imagined or real-can produce emotional, psychologic, and physical disruptions [24] if coping resources are exceeded. feelings of isolation and loneliness can be severe [32, 33] , fueled by diminished attention from parents, substitute caretaker arrangements, and lack of information about what is happening. physical or emotional separation from parents also can be interpreted as withdrawal of love, abandonment, punishment, or rejection. diminished attention from parents can lead to jealousy. this can be expressed in statements such as, ''my parents pay less attention to me because they love me less'' [1] . feelings of resentment may surface in the form of angry outburst, acting out, and attention-seeking behaviors. guilt surrounding these new feelings and behaviors only adds to the well siblings' stress and may precipitate regression or reversion to previous coping behaviors. young siblings may require their favorite blanket or toy, seek more attention, or become withdrawn and cling to parents. older children may disconnect from friends, depend excessively on parents, and need detailed instructions on previously mastered tasks. other manifestations of stress in well siblings may include physical symptoms, such as inability to sleep, bad dreams, refusing to eat, overeating, or bedwetting [24, 34] . whether siblings are provided with information is not the question, but when and how this information is shared can add to sibling stress or enable growth within the crisis situation [24] . family members, including siblings, are not mere visitors but are an essential component of the ill child's life [1] . sibling presence helps to facilitate family adaptation to hospitalization [15] , can help to retain the feeling of ''family'' [7, 33] , and helps children integrate a stressful situation into their lives [9, 16] . presence at the bedside helps siblings cope with the intense emotions, stress, and change that are brought about by this event [1, 10, 11, 16, 21, 31, 34, 35] . siblings have an opportunity to see, feel, and touch their sibling, so they can reassure themselves that they really exist [15] ; this helps them to dispel fantasies in young children, such as jamie [5, 33] . being with their ill sibling may assist older well siblings in understanding the changes in their lives, why parents need to be with the ill child, and why parents are acting differently. understanding can bring increased feelings of control that potentate adaptation and growth in the situation. shared experiences, even if stressful and unpleasant, can unite a family and produce growth and adaptation within the family [36] . support and interventions that are aimed at maintaining a functioning family unit will assist with the hospitalized child's recovery and integration back into their family [1] . nurses caring for critically ill children are situated ideally to lessen the detrimental effects of intensive care hospitalization on well siblings through direct interventions that are aimed at preparing siblings for the picu environment, and through indirect interventions that are aimed at parental education and support. development of a sibling policy is instru-mental in optimizing the well sibling's presence in the picu; however, barriers to implementation need to be identified and eliminated for successful integration of siblings. sibling presence: a good idea but not on my shift despite evidence that supports the importance of including children in any family member's hospitalization, there has been resistance to children's presence in icus expressed as concerns of increased nursing time, increased risk of infections, effects on the patient, and psychologic trauma to the child. whatever the underlying reason, children virtually have been unseen in many intensive care settings. when children's hospitals were established, restricting visitors was a way of protecting them from the undesirable influence of their impoverished environments. with advances in medicine and professionally trained nurses, hospitals became militarily regimented institutions with ''doctor knows best'' paternalism. families were relegated to short sunday visits, least they upset their children and hospital routine [23] . even now, despite more family-centered initiatives, nursing and medical staff still question the effect of children's presence on workflow [9, 10, 33] and nursing time [29] , and worry about supervision [33, 37] . although there has been little investigation of staff concerns, several studies indicate increased staff acceptance following the experience of facilitated sibling visits; this suggests that reluctance is of habit, rather than necessity [37 -39] . transmission of infection from well siblings to brothers and sisters within the picu has not been investigated; previous studies within neonatal intensive care settings have not validated these concerns [39 -42] . because most problematic organisms are hospital-acquired or of endogenous origin, the risk of infection from the well sibling should be no greater than from any other visitor, as long as infectioncontrol measures (eg, hand washing) are adhered to (sharon cronk, rn, bsn, infection control practitioner, personal communication, 2004). there is no documentation of the reverse situation of well siblings contacting infection from the ill sibling or hospital setting. although adherence to isolation precautions decreases the risk of infection, the development of antibiotic-resistant strains of bacteria and pandemics of little understood illnesses (eg, severe acute respiratory syndrome) raise the question of risk to well siblings. mcivor [43] acknowledged increased risk to infants younger than 9 months of age because of immature humoral immunity. personal colleagues suggest that siblings who are younger than 2 years of age have little concrete understanding of the situation and immature immune responses, and should be restricted from bedside visitation. although actual infection risks to well siblings needs further investigation, parents need to be informed of the infection risks to well children that are inherent in any hospital setting, not only the picu. studies done in adult intensive care concluded that family presence does not produce any greater physiologic stress, as reflected in vital signs, than other care interventions [44] . it is essential that picu nurses assess the effects of any interactionsparental, sibling or health care staff-on their patient and implement alternatives if detrimental changes result. for the awake and aware child, sibling visitations help to maintain a feeling of normalcy and routine and foster a sense of caring and family integrity. there is only one mention of a poorly supervised toddler pulling out a medication line. the resulting consequence was a stricter limitation on visiting by young siblings, rather than an increase in preparation and supervision of the sibling [35] . the main reason cited by parents for limiting children's visits is the desire to protect the well siblings from the sights and sounds of the picu [9 -11,31] . parents often feel unprepared or incapable of supporting the well sibling because of their own distress or believe that the child is too young to understand or cope [31] . however, this lack of information and the lack of bedside presence leaves well siblings formulating their own interpretations; they often imagine that the situation is worse than reality [21, 29] . simply permitting well siblings to visit without preparation and support may have unintended consequences. well siblings who visited daily demonstrated greater stress than those who visited every other day or weekly; this suggests that intense contact may be more anxiety producing than reducing [16] . there are few anecdotal reports of children experi-encing nightmares after a nonfacilitated visit to an adult icu [25] ; however, children who were prepared for what they saw before visiting a critically ill parent were not frightened but did desire more information [34] . nicholson and colleagues [35] reported fewer negative behaviors in children who visited an adult icu following a facilitated visitation program; this suggests the importance of nursebased interventions. the desire to protect is echoed by nursing staff that limit or deny sibling presence [9 -11,31] . nurses need to examine honestly whether this is used as a way to protect siblings or a way to shield themselves from the demands and emotions that are generated by children visiting because sibling presence humanizes the critically ill patient [9] . however difficult, providing emotional care for the siblings can provide rewards that are not gleaned from other aspects of intensive care nursing, and provide a way of knowing the ill child though his or her siblings [45] . this points to the importance of providing parents and nurses with education that alleviates their concerns and policies that provide strategies to support siblings at the bedside. a sibling policy indicates to families that they are valued and that thought is given to all members of the family. a sibling policy enables the nurse to make sound clinical decisions based on knowledge of growth and development; family systems theory; and current literature applied in a skilled, caring, consistent, and individualized manner-not just bending the rules whenever it seems to be justified [10] . structured visitation programs have been introduced and advocated by adult and neonatal intensive care areas as a way of increasing staff comfort levels in dealing with children and diminishing resistance to child visitation [11,25,35,37 -39] . these programs include a screening for infection, facilitated visits, and a debriefing session after the visit. although evaluation of these programs is limited, no reports of such programs within picu were found. this may be due to the picu nurses' comfort in working with children and broad acceptance of family-centered care within these units. help from the clinical nurse specialists, child life workers, and social workers may be valuable. because not all picus have these supports and many situations occur during off hours, education of the bedside nurse is essential for ensuring sibling support is available night and day. sibling policy should be reviewed with all parents, even those not asking about well sibling presence, because it introduces the possibility of sibling presence. it also provides time for parents to share concerns about sibling coping and care arrangements, and offers the nurse insight into family dynamics, adaptation, and understanding of the situation. it also may identify financial, travel, and accommodation concerns that require interventions through other resources and agencies. preparation for the well sibling should begin with a discussion with the parents because they know their children the best. although parental perspectives need to be respected, parents often express reservations about how to explain the situation to their children. the nurse can support the parents to do this or provide the previsit preparation for the sibling. whoever is speaking with the child needs to be honest, even if this is painful. children, who believe that they are lied to-even as a protective strategymay develop distrust of the people they love and depend upon the most [24] . it is not necessary to tell everything, but rather to share the seriousness of the illness and understandings of what may happen, including the changes that may result in the well sibling's life. reassure the sibling that they did nothing to cause the illness, and provide accurate information about the risk of themselves or others becoming ill with the same thing and measures that are taken to minimize the risk [5, 24] . helping parents to prepare for their well child's reactions and questions enables confidence in their parental role. providing verbal or written information about common reactions of siblings provides examples of how to explain illness and deal with reactions in a developmentally appropriate manner (table 1) . alerting parents to extreme reactions, such as per-vasive feelings of guilt, persistent regressive behavior, use of alcohol or drugs, or threats of self-harm, needs to be included so parents recognize maladaptive behaviors and seek early professional interventions. it is essential that verbal explanations reinforce any written material to ensure comprehension where literacy and language difficulties exist. previsit discussion should include a health screening that focuses on current health, immunization status, and contact with infectious disease. a structured approach using a checklist as a guide ensures that no important information is missed (box 1). a brief visual check of the sibling can validate there are no ''cold'' symptoms, rashes, or other obvious exclusionary conditions. rather than repeating the health screen with each sibling visit, educate parents to monitor the entire family's health, including adult visitors, and inform the staff of any changes before entering the picu. if the sibling does not meet the health screening criteria, it is essential that he or she receives an explanation of why he or she cannot visit. siblings need to be assured that they have done nothing wrong, can visit in the future, and strategies should be undertaken to maintain sibling contact (eg, sending pictures, stories, or videos to be shared). offering alternative strategies and a tentative time as to when visiting may be feasible should be provided. visiting with precautions may be warranted if opportunity for sibling presence is limited, as in endof-life situations. parents often may feel hesitant about their abilities to represent the situation accurately and appreciate the nurse's assistance. preparation of the sibling should focus on what they will see, hear, and smell during the visit, including a brief general description as to their brother or sister's level of consciousness, obvious injuries, and invasive tubes and lines. mentioning that their brother or sister is unclothed may help to alleviate discomfort for older schoolaged children or adolescents who are struggling with body image and modesty. time should be given time for the well sibling to process this information, appropriate to their devel-opmental level and urgency of the situation. for young children like jamie, presenting information as close to the time of the visit as possible increases understanding and retention. older children, like samantha, may benefit from time to think about, ask questions, and psychologically prepare for the visit, which may lessen the emotional outbursts at the bedside. provision of a handout tailored especially to the older sibling may help them to feel more included in the information process. sibling decisions not to visit need to be respected but explored for misunderstandings that are leading to fears. the choice of visiting later should be left open to accommodate changing needs and desires (box 2). whenever possible, arrange the first visit when the nurse can give the sibling some attention, guidance, and be available for questions. with 4-year-old jamie, for example, pointing out familiar and normal behaviors (eg, opening eyes) and familiar objects (eg, a mobile for his infant sister) can help him to feel more secure in a strange environment. simple explanations of ecg leads as ''special stickers'' and intravenous lines as a way of getting water when someone cannot drink can reduce fear of equipment. blood transfusions can be referred to as ''special red medicine'' for preschoolers who often equate blood with experiences of trauma. although the most alarming sights (eg, wounds, external fixation dechildren may not want to visit their brother or sister. they should not be forced to visit. ask them again in a few days because they may change their minds. here are some other ways that they can keep in contact with their sick brother or sister: vices, drains) should be covered for young siblings who may not understand their necessity, the fascination of the school-aged sibling with technology may trigger questions about where tubes disappear to, what is under the covers, or the purpose of various equipment. although answering questions does take up nursing time, how questions are answered is important. words used with youngsters, such as jamie, need to be chosen carefully because they can be interpreted in their literal sense. avoid words with mixed meanings or synonyms, such as ''dye'' and ''die.'' death and anesthetized states should not be described as ''going to sleep'' because the young child then may fear going to sleep. keep initial visits brief, usually 5 to 10 minutes. younger children have limited attention spans. as with 4-year-old jamie, their concepts of permanence may have them wanting only a quick look to assure themselves that their sibling still exists and then wanting to leave. older children and teenagers have concerns about how others see them, and may struggle to maintain composure. for them, an initial short visit provides a graceful way out of a difficult situation. older children also want to appear grown up and knowledgeable so they may not ask any questions and say that they understand when they do not. encouraging questions can provide the nurse with insight into what meaning the situation has for them and their family. the nurse also needs to anticipate overreaction by adolescents that may be out of proportion and border on hysterics. with samantha, the nurse's calm demeanor and explanations of why her sister looks the way that she does and how this is expected to improve may dispel fears. helping her focus on what she can do for her sister (eg, holding a hand or putting on lotion) may provide a channel for her emotions and a moment for her to regain composure. it is important to address siblings directly-rather than through a parent-to help decrease their feelings of invisibility. during times of stress, sibling's normal feelings of jealousy, rivalry, and hostility may become more pronounced. an adolescent's angry, ''you know he isn't the saint everyone is making him out to be'' [1] illustrates the need for discussion of overwhelming and conflicting emotions. acknowledgments of ''you must have many feelings and questions about your brother/sister'' can diffuse the situation, minimize parental reprimands, and focus attention away from the remark while still acknowledging sibling needs. encourage parents to respond to the feelings behind the outbursts rather than what was said. help parents reassure siblings that it is common to have a mixture of feelings during times of stress. although structured preparation is ideal, it should not limit the frequency and timing of sibling visits. a few minutes of briefing at the doorway or at the bedside to discuss the predominant sights, sounds, and smells may help the well sibling prepare if formalized preparation is not feasible, such as in a life-threatening situation. children, like adults, may remember how they were treated more than what they actually were told or saw during stressful times. the nurse must also be able to accept silencesituations where words cannot express the emotional burden that is weighing on all members of the family. obviously, admission to a picu signifies a lifethreatening illness. well siblings often ask the nurse, sometimes unexpectedly, if their brother or sister will die. although the nurse needs to be respectful of the parent's decisions regarding how poor prognosis is explained, it is essential that the sibling receive honest answers. the nurse can assist the parents to share with them what is known and not known about the situation. when death is imminent, the nurse can share with parents what is known about children's understanding of death at different developmental levels. remind parents that school-aged and older siblings probably already know the gravity of the situation having gleaned their own interpretations from overheard conversations, parents' demeanor, previous experiences, and their own observations. just as parents need time to say goodbye, so too do siblings. if possible, specific time for brothers and sisters with their parents should be provided, keeping in mind that older siblings may need privacy to express emotions. give siblings the same opportunities that are offered to parents-the chance to hold infant siblings, or share a last snuggle in bed with an older sibling. children should never be forced into behaviors. giving a goodbye kiss may be awkward for the adolescent sibling, so suggesting giving a hand a squeeze or whispering a private message into the dying child's ear may be more accepted by this age group. siblings may remember little else but being included in this life event. understanding of children's concepts of health, illness and death, developmental expressions, and coping strategies may better prepare the nurse for the emotional expressions of grief by the well siblings. without this, strong emotional reactions of the sibling may be a source of extreme stress for the nurse who already is struggling with not being able to sustain the child's life. being able to provide effective support by being attentive, calm, and honest during the ill child's death may assist the family bereavement process [46] as well as bring a sense of closure for the nurse. the hospital can be a frightening place for children. efforts aimed at creating a child-friendly atmosphere need not be elaborate or costly. if the child is in a private room, inclusion of siblings' names on a family name board gives siblings feeling of inclusion and importance while assisting busy, often changing nurses in caring for the family. the physical atmosphere of the family area should be inviting to siblings. inclusion of child-sized tables and chairs, movies, books, toys, and drawing materials at different developmental levels can make siblings feel welcome and help pass the time. families should be encouraged to stay at child-friendly facilities with resources especially for siblings (eg, playrooms, outside play equipment, and communal family areas). this encourages interaction with siblings from other families, and provides much needed opportunities for play and interaction. if isolation precautions are needed, the use of child-sized pajama gowns as isolation gowns can make the sibling feel more comfortable and provide better protection than a gapping adult gown. if time permits, the sibling can be given isolation masks to decorate. the use of various nose and whisker combinations can lighten the atmosphere; having the parents and health care team wear these creations give the sibling a sense of accomplishment and pride. although nurses provide many types of support to the ill child they cannot overlook the needs of well siblings. nurses cannot and should not serve as surrogate parents; however, the support and education that they offer can diminish well sibling feelings of loneliness and isolation. direct interventions that are aimed at helping the sibling prepare for sights and sounds of the setting help them to maintain a sense of control and help them feel included and useful. providing parents with research-based insights into the impact of hospitalization on the well siblings helps them to understand the effects of hospitalization, maintain a parenting role, and anticipate stress produced by altered routines. a sibling policy ensures that parents are aware of the possibility of sibling presence, helps them approach discussions with well siblings in a developmentally based way, and provides them with proactive strategies to assist well siblings to cope. for nurses, an understanding of well sibling stressors enhances preparation and guidance given to siblings, and diminishes nurse anxiety associated with sibling presence. a sibling policy provides nurses with a framework upon which to base assessments and ensures that interventions to support siblings are provided at the bedside; these enhance family-centered care. although the picu setting is only a portion of a child's hospitalization, much of the family's adaptation to the illness and the future begins here. although more research is required to strengthen the evidence to support the effectiveness of such interventions and demonstrate which interventions are most effective, helping to strengthen and maintain the ties that bind children to parents and siblings to each other can only enhance the family's abilities to care for each of its members. striving to recapture our previous life: the experience of families with critically ill children. the official journal of the canadian association of parental stress in critical care identified need of parents in a pediatric critical care unit families in pediatric critical care: the best option psychosocial aspects of pediatric critical care needs of parents of critically ill children parental experiences and meaning construction during a pediatric health crisis a critique of studies exploring the experiences and needs of parents of children admitted to pediatric intensive care units the needs of children visiting on adult intensive care units: a review of the literature and recommendations for practice children visiting family and friends on adult intensive care units: the nurse's perspective preparing children for visiting parents in the adult icu evaluation and development of potentially better practices for improvement of family centered care the needs of parents with a child in a pediatric intensive care unit parents of children in the pediatric intensive care unit: what are their needs siblings of hospitalized children: assessment and intervention perceived stress of nonhospitalized children during the hospitalization of a sibling early predictors of poor coping outcomes in children following intensive care hospitalization and stressful medical encounters perceived changes in siblings of hospitalized children: a comparison of sibling and parent reports effect of visitation upon siblings of hospitalized children parent's views of the responses of siblings to pediatric hospitalization needs of children during critical illness of a parent or sibling sibling relationships: more important now than ever evaluating children's literature as a source of patient education helping children through an adult's serious illness: roles of the pediatric nurse children visiting in the adult icu: a facilitated approach psychology of the child. new york7 basic books children's illness concepts: old and new paradigms concepts of illness causality in a pediatric sample: relation to illness duration, frequency of hospitalization and degree of life threat promoting a family-centered visitation makes a difference information needs of siblings of critically ill children impact of adult critical care hospitalization: perceptions of patients, spouses, children, and nurses perceptions of isolation: the impact of critically ill siblings on well children sibling visitation: research implications for pediatric and neonatal patients experience in children of critical ill parents: a time of emotional disruption and need for support effects of child visitation in adult critical care units: a pilot study sibling bereavement and grief responses attitudes about sibling visitation in the neonatal intensive care unit a research-based sibling visitation program for the neonatal icu implementing potentially better practices for improving family centered care in the neonatal intensive care unit: successes and challenges a comparison of infection rates in a newborn intensive care unit before and after adoption of open visitation bacterial colonization in neonates with sibling visitation sibling visitation: effects on newborn infection rates should children be restricted from visiting a relative in intensive care? cardiovascular responses to family visits in coronary care unit patients caring for patient's families. in: clinical wisdom and interventions in critical care: thinking in action approach. philadelphia7 w. b. saunders; 1999 parental coping and bereavement outcome after the death of a child in the pediatric intensive care unit key: cord-257751-n7w1psr4 authors: halperin, daniel t. title: coping with covid-19: learning from past pandemics to avoid pitfalls and panic date: 2020-06-30 journal: glob health sci pract doi: 10.9745/ghsp-d-20-00189 sha: doc_id: 257751 cord_uid: n7w1psr4 it is imperative to concur on the main transmission routes of covid-19 to explain risk and determine the most effective means to reduce illness and mortality. we must avoid generating irrational fear and maintain a broader perspective in the pandemic response, including assessing the possibility for substantial unintended consequences. as we wrestle with how best to mitigate covid-19, it is imperative to concur on the likely main drivers of transmission (notably, infection clusters resulting from prolonged indoor respiratory exposure) in order to clearly explain risk and to determine the most effective, realistic behavioral and other means to reduce illness and mortality. n at the same time, we must avoid generating irrational fear and maintain a broader perspective, including assessing the possibility for substantial unintended consequences from the response to the pandemic. i n june 1981, when the first cases were reported of what became known as aids, i was living in the san francisco bay area. as the waves of death mounted, i volunteered at a hospice in oakland, california, and later conducted epidemiological research at the university of california. there are major differences between hiv and severe acute respiratory syndrome coronavirus 2 (sars-cov-2) and their resulting pandemics (aids and coronavirus disease ([covid -19] ). however, i'm having déjà vu: from the devastating number of deaths and the pervasive atmosphere of confusion, fear, and often panic. tragically, political leaders from ronald reagan to nelson mandela were slow to respond to the aids epidemic. all sides engaged in acrimonious ideological warfare that often ignored the epidemiological evidence. in hindsight, health authorities also made some decisions-especially under the pressure of needing to act immediately-that led to suboptimal and ultimately costly outcomes. 1, 2 policies often became hardwired over time and difficult to walk back, even after new evidence appeared. well-meaning but overly simplistic messages such as, "always use a condom with anyone or die" inadvertently created other problems. 1, 3, 4 earlier openness to innovative approaches, such as male circumcision and addressing sexual networks, could have saved many lives, particularly in sub-saharan africa. 1, 2, 5 in subsequent years, as greater funding for research and treatment eventually poured in, a kind of "aids exceptionalism" also became imbedded. 6 during the first years of the aids response, much was unknown regarding the causes and main modes of transmission. yet, even after hiv was identified in 1983 and the basic science became clearer, a great deal of uncertainty, persecution of marginalized groups, and terror persisted. rumors proliferated that anything from mosquitoes to using contaminated condoms to sharing toothbrushes were spreading the virus. in the 1990s, after earvin "magic" johnson tested positive for hiv, counseling centers became overrun by the "worried well." 1, 3 heterosexual college students flooded centers to get tested, petrified from having engaged in deep kissing or intimate touching "without protection," thereby diverting attention from those who were actually at significant risk of infection. with covid-19, much remains unclear, but some basic facts are known and more emerge daily. yet, a palpable climate of confusion and anxiety pervades. (one mindboggling indication is that the johns hopkins university coronavirus resource center website is recording some 4 billion hits a day! 7 ) although under such circumstances fear-even when it becomes irrational-is understandable and can help motivate behavior change, 1, 8 panic often leads to poor decision making and other unintended consequences. 9,10 moreover, there are troubling signs that we have failed to learn other important lessons from the previous pandemic, including the danger of polarized infighting. for example, politicians and the media as well as some medical experts are presenting us with a false dichotomy: having to choose between recklessly abandoning mitigation efforts to reopen the economy versus rigidly continuing present lockdown measures. the u.s. territory of puerto rico where i reside implemented a nearly complete shutdown in mid-march after the first death here (of an italian cruise ship passenger). since then, many people, convinced the virus is "everywhere" and infection is nearly unavoidable, won't leave their homes even to pick up groceries. when delivery services became overwhelmed, elderly and sick persons sometimes have not been able to obtain essential supplies. most of those who do drive or go outdoors use masks (needlessly) even when far away from other people. wearing masks in the hot, humid climate can be uncomfortable and has created issues, including elderly persons fainting while waiting in the sun for a long time to enter stores (which often only allow a handful of customers to enter at once). until recently, joggers and others were stopped and occasionally fined by police for venturing outside or for violating the 7 pm curfew, which remains in effect after nearly 3 months. (even in most of the world's hardest-hit countries, such as spain and italy, people are now allowed outdoors to exercise.) numerous restaurants, especially asian-owned ones, have closed after losing takeout customers. some stores require customers to wear gloves, despite evidence suggesting limited utility or that their use may actually increase risk of infection. 11 in puerto rico, as in other parts of the world, many people (even many youth) with asthma are terrified of experiencing severe outcomes if they become infected with the virus, prompting shortages of inhalers and other critical supplies. the u.s. centers for disease and prevention (cdc) website lists people with asthma near the top of those at risk of severe covid-19 outcomes, even though only 1 clinical study has investigated whether a relationship exists and has found no link. 12 although other emerging data strongly appear to confirm the lack of an association, 13 it is unclear whether the cdc will correct its public information. what is clear, based on evidence from several countries (and despite media attention to statistically anomalous cases of healthy and younger victims), is that severe outcomes and deaths from covid-19 are overwhelmingly associated with preexisting (and especially multiple) serious illnesses such as diabetes and heart disease, [14] [15] [16] more so in men and particularly when exacerbated by obesity and smoking. 17, 18 indeed, it may be that advanced age alone, in the absence of such predisposing conditions, is less of an independent risk factor than has been assumed. firstly, the elderly are more likely to have chronic illnesses, which confounds the association between outcomes and age. moreover, the fact that between 96% (in the united states 16 ) and more than 99% (in italy 14 ) of covid-19-related deaths, at any age, have occurred in persons with preexisting conditions could suggest that even very old but otherwise healthy people may not be at greatly elevated risk of dying from the disease. further research and analysis, including assessing whether the important angiotensin-converting enzyme 2 protein (ace-2) is more prevalent in the elderly 19 could help explain the often higher infection (not only higher mortality) rates in older populations. 20 in any case, such data underscore the ongoing need in general to prioritize preventing chronic diseases, which kill more than 40 million people annually (over 80% in lower-and middleincome countries), 21 and to address underlying conditions such as obesity and smoking. 22, 23 regarding covid-19 prevention, it is imperative for experts to agree on what are the likely main transmission routes and to carefully determine which are, accordingly, the most effective (and realistically achievable) behavioral and other ways to reduce morbidity and mortality. it is probable that, as with other respiratory illnesses such as influenza, most covid-19 infections occur from close exposure to coughing, sneezing, shouting, singing, or other direct and relatively prolonged contact with someone who is symptomatic or presymptomatic. (there is evidence that some asymptomatic carriers are contagious, but from existing studies they appear not to represent a very substantial proportion of total covid-19 transmission.) in february, a team of world health organization (who) researchers led by david heymann investigated the outbreak in wuhan, china, and concluded that the large majority of transmission events occurred within indoor clusters 24 between family members (accounting for 75%-85% of estimated infections) and coworkers, with no identified cases of child-to-adult transmission identified. 15 in addition, some data suggest that severity of outcomes is associated with initial exposure it may be that advanced age alone, in the absence of preexisting conditions, is less of an independent risk factor than has been assumed. it is probable that most infections occur from close exposure to coughing, sneezing, shouting, singing, or other direct and prolonged contact with an infected person. coping with covid-19: learning from past pandemics to avoid pitfalls www.ghspjournal.org viral-load levels. [24] [25] [26] moreover, it increasingly appears that infection risk from contaminated surfaces has been at least somewhat overstated, as the cdc recently acknowledged. 27 indeed, it is conceivable that future science historians may conclude that many current covid-19 prevention strategies had little if any impact, particularly because they targeted drivers of spread accounting for no more than a small proportion of total infections. as some experts eventually did with hiv, 1,4 they could also help the public distinguish between those behaviors and situations posing the highest risk for covid-19 infection, those of likely lower risk (such as the virus lingering on hard surfaces for extended periods), and those of highly unlikely or no risk (such as being outdoors with no one else around). although the cdc has posted some basic guidance on its website (in the frequently asked questions section) regarding how covid-19 is mainly transmitted, the public would benefit from a more clearly communicated 28 and much more robust public information campaign (e.g., including the virtual equivalent of placing a leaflet under every u.s. resident's door). this would help reduce time and attention spent addressing lowrisk concerns, such as when healthy people avoid leaving home for necessary activities even if carefully taking precautions. there is a crucial distinction between risk of indoor transmission-where physical distancing (whether mandated or voluntary) and perhaps other measures 28, 29 are critical-versus risk of outdoor transmission, which is far lower (possibly by an order of magnitude) for various reasons, including dissipation of droplets in the air 28, 30 and the deactivating effects of ultraviolet radiation and heat. [31] [32] [33] a contact tracing study from china found that 80% of infections involved household members and 34% involved mass transit (multiple potential transmission routes were considered), whereas only a single infection event of the 7,324 cases investigated was linked to casual outdoor transmission. 28, 30, 34 although politicians and the media have been obsessed with the danger of frolicking on beaches (or of participating in protest gatherings), a vastly greater risk is the common (public health) admonition for sick persons to remain home as long as possible before seeking hospital care, without providing access to alternative, clinically-provisioned quarantine residences, as several asian countries and iceland have successfully instituted. [35] [36] [37] delays in seeking care not only diminish survival chances but also expose household members to significant infection risk. 14, 35, 36, 38 is 6 feet distancing strictly necessary? one example of inconsistent public health messaging is that european and asian authorities and the who recommended physical distancing based on data that droplets containing the virus had been identified almost a meter away from coughing individuals. in the united states, for some reason 1 meter was initially translated into 5 feet and subsequently became "over 6 feet." although perhaps arguably not the highest priority, it would be useful for the cdc and other experts to determine whether such abundance-of-caution guidance is worth maintaining or perhaps is not scientifically warranted, and may inadvertently feed excessive concern. (in fact, the entire concept of physical or "social" distancing is not specifically relevant to transmission risk, primarily related to respiratory droplets: the pertinent issue is not the distance per se between people's bodies but rather between their faces, particularly if unmasked. for example, if 2 people are positioned back-to-back, then obviously the distance can safely be much less.) this issue of distancing is particularly relevant as weather improves and outdoor exercise becomes more common, as many health departments 28,30,39 encourage people to do (even though a hypothetical model based on untested assumptions sparked alarm by suggesting that joggers or cyclists could spread the virus over greater distances 40 ). and critically, as the economy begins to reopen, it would be especially challenging for some businesses (and eventually schools) to adhere strictly to a 6-foot rule. this could be particularly excessive for outdoor activities, including construction, farming, recreation, and outdoor dining. it is certainly more practical to maintain a distance of about 3 feet than 6 feet in many situations, such as grocery shopping (where interactions are typically brief) or while strolling with a companion. indeed, it is likely that more "surgical"-more carefully targeted and realistic, evidence-based approaches 4,41-43 -could be similarly efficacious as more extreme isolation strategies that have been there is a crucial distinction between risk of indoor transmission, where physical distancing is critical, versus the risk of outdoor transmission, which is far lower. future historians may conclude that many current prevention strategies had little impact because they targeted unlikely drivers of infection. the pertinent factor is not the physical distance between people's bodies, but rather the distance between their faces. coping with covid-19: learning from past pandemics to avoid pitfalls www.ghspjournal.org global health: science and practice 2020 | volume 8 | number 2 widely implemented. for example, singapore had initially achieved a notably effective response without shutting schools. 44 (however, subsequently there was a surge in cases due to an outbreak in crowded migrant-worker dormitories.) taiwan, which never closed its schools, has continued to report very few cases. similar to the first severe acute respiratory syndrome (sars) epidemic in 2002-2004, 45, 46 the vast majority of children infected with sars-cov-2 escape severe outcomes. there has been much media attention to multisystem inflammatory syndrome in children (mis-c), which has features similar to kawasaki disease. however, of the more than 7 million covid-19 infections reported worldwide to date, only a few hundred cases of mis-c have been identified so far. 47, 48 (although the usual kawasaki disease is more common in east asia, in the united states about 5,000 cases occur annually. 48 ) of more than 400,000 covid-19 deaths reported worldwide, some 20 children are known to have died, about half of them in the united states and the rest in europe. by comparison, more than 200 children died last year from the flu in the united states alone, along with some 10,000 others from various childhood diseases. 49 further contextualizing the mis-c and other childhood deaths from covid-19, in the united states, per-capita mortality in persons aged 85 years and older is 2,000 times higher than in children aged 15 years and younger. 50 (an intriguing question posed by some researchers is whether mis-c is definitely or always caused by covid-19, considering that in some cases up to one-third of afflicted children have tested negative for covid-19, both on polymerase chain reaction and antibody tests. 51 ) although the emerging mis-c must be closely monitored, as with kawasaki disease most cases appear to recover fairly rapidly, especially if detected and treated early. [46] [47] [48] because young people typically come in contact with many other children and adults, they are often efficient spreaders of respiratory pathogens. however, growing evidence suggests that, as with the earlier sars, 45, 46 children are less likely to become infected with sars-cov-2. [52] [53] [54] [55] [56] [57] [58] according to the cdc, only about 1.5% of u.s. cases of covid-19 have been reported in persons aged 18 years or younger. 59 researchers theorize that previous exposure to other coronaviruses (e.g., those producing many of the common colds frequently acquired by children) may confer some partial resistance to sars-cov-2. 47, 52, 54 interestingly, when blood samples collected before fall 2019 (i.e., before people began getting infected) were analyzed, about half the people studied appeared to already have some protective t-cell immunity to the new virus, resulting from past exposure to other coronaviruses. 60 importantly, young people also produce smaller amount of the aforementioned ace-2 protein, a critical nasal cell entry point for both sars viruses. 19, 47, 52 moreover, the evidence suggests that even when children do become infected, they are probably considerably less contagious than adults. 46,53-58,62 a recent german study found viral loads in infected children at levels comparable to adults. however, the number of children studied was very small and other methodological concerns have been raised. more importantly, although for some pathogens (such as hiv) viral load is highly associated with infectivity, the implications of viral load for covid-19 clinical progression and contagiousness remain unclear. 53, 54, 61 because the many asymptomatic youth infected with covid-19 are not coughing or sneezing, they emit far fewer infectious droplets. and remarkably, contact tracing studies conducted in china, iceland, netherlands, and united kingdom have failed to identify a single case of child-toadult infection of thousands of transmission events analyzed. 15,36,52-57 a review of household transmission studies from several asian countries concluded that less than 10% of household clusters involved a child index case, 62 and a analysis of different covid-19 interventions in the united states found no evidence for the impact of school closures. 63 it should be noted that some of these data probably underestimate children's actual contagiousness, as they were collected after lockdowns and other mitigation measures had been implemented. however, the striking findings from the contact tracing studies in particular, as well as the evidently significant biological differences between covid-19 and other respiratory pathogens, suggest that children are not major sources of infection, especially as compared to the common cold strains of coronaviruses, for example. even without the substantial amount of data that emerged subsequently (which presumably would have reduced the predicted impact of school closures), in march 2020, modelers from the imperial college of london estimated that closing schools might prevent only 2%-4% of premature deaths in the united kingdom (i.e., predominantly of older adults with predisposing conditions such as chronic diseases, obesity, and smoking, who could become directly or indirectly infected from schoolchildren.) 64 in contrast, the modelers estimated that 17%-21% of total deaths can be prevented from self-quarantining at home. in denmark, norway, and new zealand, where schools reopened in april 2020, the numbers of new covid-19 cases have continued to fall, similar to trends in finland, france, germany, netherlands, and vietnam, where schools all reopened in mid-may or earlier (though cases have increased in madagascar, but perhaps not mainly due to reopening schools). it will, of course, be vitally important to implement adequate testing and safety measures for teachers and other school employees 68, 69 and to closely monitor the data as schools also begin reopening in australia, israel, japan, and elsewhere (even as some u.s. school districts and colleges have announced that fall 2020 instruction will be conducted strictly online). (in switzerland, health authorities also announced permission for grandparents to hug their young grandchildren. 70 ) certainly, as decisions are made regarding the reopening of schools, it must be taken into account that school closures have been depriving over a billion students worldwide of essential classroom learning, vital social connections, and physical activity. in addition, socioeconomic disparities are increasingly exacerbated, as some families have the technological, parental academic assistance, and other resources to enhance online learning, while less privileged children fall further behind. 54, 55, 58, 71 other huge consequences of school closures include documented surges in child abuse; hunger from missed subsidized meals; and greater anxiety, depression and isolation, which often are most acutely experienced by students with autism, down syndrome, attentiondeficit/hyperactivity disorder and other special needs challenges. [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] one alternative to lockdown: moving toward herd immunity? although many experts continue to believe that stayin-place measures are needed to flatten the curve, others have proposed a phase 2 alternative-instead of attempting to prevent any new infections-of essentially allowing younger and healthier people to gradually return to work and school, based on a herd-immunity strategy. 43, 44, 81, 82 although many of them could eventually become infected, most individuals would be expected to experience relatively mild to moderate symptoms and, ideally after self-quarantining, would effectively be "naturally vaccinated" (i.e., they would presumably no longer be contagious, for perhaps a year or more). such an approach assumes, of course, that reinfection is uncommon, which-although most experts believe is quite probably the case-remains unconfirmed. 83, 84 note that if previous infection does not confer immunity, it may prove very difficult to develop a vaccine that does so. this sort of herd-immunity approach could be strongly enhanced by large-scale antibody testing to identify previous infection, as china, germany, spain, united kingdom, and some u.s. locales have begun to implement. 85, 86 crucially, we must determine how best to isolate or otherwise protect the most vulnerable populations from infection-certainly no easy task. if it were to be the case, as previously discussed, that elderly but otherwise healthy people are not actually at considerably greater risk of severe illness or death, then clearly this would make the challenge somewhat less daunting. however, the evidence is not yet sufficient to base policy on this still-hypothetical possibility. although obviously far from ideal, something akin to such an alternative approach may emerge (including perhaps in some lower-income regions) as one of the least terrible, more realistic longer-term alternatives, until a vaccine is available. interest in such strategies is intensified by the potential for a resurgence of infections once containment measures are eased, including a possible second wave in late 2020 and early 2021. outcomes will need to be rigorously assessed in places like sweden, where despite most businesses and schools having stayed open, covid-19 deaths have been declining, though not as sharply as in most other european countries. 87 ongoing attention has focused on sweden's percapita death rate being much higher than in other scandinavian countries. however, a crucial difference is that in sweden most reported cases (not only deaths) have occurred heavily among the elderly, 20 particularly those residing in long-term care homes-similarly to the situation in belgium, france, italy, netherlands, spain, and the united kingdom. 50, 87, 88 those countries (and, for example, the new york/new jersey area) all have higher reported death rates than sweden, despite tightly locking down since at least late march 2020. that sweden's covid-19 mortality is lower than in those european countries becomes even more evident if comparing via excess mortality (current deaths compared to typical levels in preceding 50, 87, 88 whereas in denmark and norway, similar to the situation in germany, japan, and south korea, a much larger proportion of infections has for some reason occurred in relatively younger people, 20 consequently resulting in considerably lower covid-19 death rates. apparently also very salient, if rarely mentioned, is that recent immigrants in sweden have suffered disproportionally far greater infection and mortality rates, reportedly due in part to insufficiently targeted prevention campaigns. 90, 91 by one estimate, perhaps 40% of all covid-19 deaths in the capital city, stockholm, have been solely among somali refugees (who comprise a minority of foreign-born immigrants in the city, after iraqis, syrians, and afghans, in that order). 90 non-european residents also comprise-differently than the case elsewhere in scandinavia-the majority of the country's nursing home employees. 90 although certainly understandable, the possible fear by the swedish government of a xenophobic or islamophobic backlash may, however, have resulted in grave public health consequences, reminiscent of prevention campaigns during the earlier aids years that shifted attention, also understandably but similarly deleteriously, away from those at highest risk to avoid homophobia and discrimination against marginalized groups. 1, 3 it also appears noteworthy that in the 5 u.s. states that never imposed stricter isolation measures, 92 observable increases in new cases have not occurred, as compared to demographically and otherwise similar neighboring rural states that implemented tight lockdowns. 93 this observation is consistent with the fact that modeling predictions in late april 2020 of a sharp uptick of death across the united states, 94 as many (largely rural) states began reopening, turned out to be considerably overdrawn. 93, 95 a key implication of the experience from the 5 non-lockdown u.s. states and sweden is not that death rates in those places have been lower than elsewhere, but if outcomes generally have not been worse, this suggests that similar results may be achieved at a less drastic economic and societal cost. (in the case of sweden, a fairer comparison would be to more epidemiologically similar european countries, rather than utilizing the "ecological fallacy" of comparing its experience only to the other scandinavian nations.) in any case, the urge to apply an either/or, one-size-fitsall approach, which also hampered the response to aids and some other past health crises, 1, 2, 4, 5 should be questioned, including in lower-and middle-income world regions. 93,96-100 it is crucial that an evidence-based and transparent debate underpin decisions, 41 obviously taking into consideration the unprecedented consequences of financial collapse and lost income resulting from a prolonged economic shutdown, 9, 44, 82, [99] [100] [101] [102] [103] [104] [105] as most painfully experienced among socioeconomically disadvantaged populations. 106 such disruptions are being felt most dangerously in the lowest-income regions of sub-saharan africa and south asia, where the prospect looms for unintended consequences of harrowing proportions. 73, [96] [97] [98] [99] [100] [101] [102] 105, 107 these include potentially vast increases in deaths from malaria, tuberculosis, measles, polio, diarrheal and other diseases, and malnutrition, as vaccination, maternal and child health, family planning, and other basic services are suspended due to lockdowns or are deprioritized while health efforts increasingly focus on covid-19. 71, [96] [97] [98] [99] [108] [109] [110] [111] [112] [113] considering that young children are likely to be particularly impacted, this would represent an even greater magnitude of devastation if measured in terms of years-of-life-lost, and not only via crude mortality numbers. the catastrophic number of deaths directly resulting from covid-19-which eventually may eclipse the estimated 1 million from the "hong kong" flu in 1968-1969, 114 (when the world's population was less than half of today's)-along with the many who could suffer long-term sequelae, 115, 116 must be considered alongside the increased mortality and compromised outcomes for it is noteworthy that in the 5 u.s. states that never imposed stricter isolation measures, observable increases in new cases have not occurred. the urge to apply an either/or, onesize-fits-all approach should be resisted. coping with covid-19: learning from past pandemics to avoid pitfalls www.ghspjournal.org global health: science and practice 2020 | volume 8 | number 2 the numerous persons suffering from non-covid-19-related cardiac arrest, stroke, appendicitis, and other urgent conditions who have been denied medical attention or have delayed treatment for fear of seeking hospital care. 38, [117] [118] [119] moreover, job losses and mass school closures from the lockdowns are intensifying socioeconomic disparities, including potentially dooming hundreds of millions of children to long-term educational, psychosocial, and vocational disadvantages. 54, 55, 58, 64, 71, 75, 78, 99 policy makers, such as the who, foreign donors, and local governments, appear to be making enormously consequential decisions without fully taking into account some key demographic as well as potentially significant climate [31] [32] [33] 120 and childhood vaccinerelated 121,123 differences between lower-income regions (characterized typically by more rural populations and an age pyramid dominated by young people) and europe and north america (more urban, older, and often more obese populations, thus probably much more vulnerable to covid-19 mortality). [96] [97] [98] [99] 124, 125 furthermore, it is critical to consider the consequences of remaining inside (often cramped) living quarters for extended durations, including reported increases in domestic violence [126] [127] [128] and child abuse, [72] [73] [74] 127 as well as other physical and mental health issues related to chronic diseases 30 ; obesity 79 ; social isolation 10 ; anxiety, depression, and suicide 10, 30, 39, [75] [76] [77] [78] ; obsessivecompulsive disorder 129 ; poisoning from overuse of toxic cleaning products 10 ; and autism, attentiondeficit/hyperactivity disorder, and other developmental challenges. 80 as has occasionally occurred with other health crises such as hiv/aids, 1,6 we must not lose sight of the bigger picture. it is sadly possible, especially in the lowest-income regions, that the remedy could be worse-perhaps tragically even far worse-than the disease itself. how the west sparked the aids epidemic and how the world can finally overcome it the invisible cure: why we are losing the fight against aids in africa last night in paradise: sex and morals at the century's end quarantine fatigue is real. the atlantic public health. reassessing hiv prevention putting a plague in perspective death counts become the rhythm of the pandemic in the absence of national mourning a meta-analysis of fear appeals: implications for effective public health campaigns it's dangerous to be ruled by fear five ways to conquer your covid-19 fears coronavirus: can latex gloves protect you from catching deadly virus? the independent clinical characteristics of 140 patients infected with sars-cov-2 in wuhan asthma is absent among top covid-19 risk factors, early data shows 99% of those who died from virus had other illness, italy says report of the who-china joint mission on coronavirus disease 2019 (covid-19) hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-covid-net, 14 states coronavirus: obesity doubles risk of needing hospital treatment, study suggests. the independent smoking is associated with covid-19 progression: a meta-analysis number of coronavirus cases by age group (for various countries) chronic illnesses: un stands up to stop 41 million avoidable deaths per year. un news annual medical spending attributable to obesity: payer-and service-specific estimates puerto rico's man-made disasters will kill more people than natural catastrophes. miami herald reducing risks from coronavirus transmission in the home-the role of viral load how long you are exposed to coronavirus can determine if you get sick, experts say. miami herald why are some people so much more infectious than others? new york times virus 'does not spread easily' from contaminated surfaces or animals, revised cdc website state erin bromage: covid-19 musings blog review of "covid-19 outbreak associated with air conditioning in restaurant stop shaming people for going outside. the risks are generally low, and the benefits are endless. business insider uv light influences covid-19 activity through big data: trade-offs between northern subtropical, tropical, and southern subtropical countries will coronavirus pandemic diminish by summer? massachusetts institute of technology effects of temperature and humidity on the daily new cases and new deaths of covid-19 in 166 countries indoor transmission of sars-cov-2 the successful asian coronavirus-fighting strategy america refuses to embrace how iceland beat the coronavirus multi-risk sir model with optimally targeted lockdown the characteristics of household transmission of covid-19 don't cancel the outdoors; we need it to stay sane towards aerodynamically equivalent covid-19 1.5 m social distancing for walking and running the pandemic is too important to be left to the scientists lockdown can't last forever: here's how to lift it is our fight against coronavirus worse than the disease? new york times facing covid-19 reality: a national lockdown is no cure severe acute respiratory syndrome in children these theories may help explain why. national geographic an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study what's the strange ailment affecting children with covid-19? wired the major causes of death in children and adolescents in the united states 43% of covid-19 deaths are in nursing homes and assisted living facilities housing 0.6% of u.s. forbes los niños tienen menos receptores en la nariz para que el coronavirus penetre en el organismo. el país the way to save our kids is to reopen our schools and camps. daily beast the missing link? children and transmission of sar-cov-2, don't forget the bubbles the case for reopening schools the case for reopening schools this fall should schools reopen? kids' role in pandemic still a mystery spread of sars-cov-2 in the icelandic population crossref 58. when easing lockdowns, governments should open schools first coronavirus disease 2019 in children -united states coronavirus in children: risk factors, contagiousness, viral loadwhat we know so far as schools consider reopening. reuters children are unlikely to have been the primary source of household sars-cov-2 infections strong social distancing measures in the united states reduced the covid-19 growth rate the lancet child adolescent health. pandemic school closures: risks and opportunities back to school? tracking covid cases as schools reopen. center for global development blog post is it safe to reopen schools? these countries say yes reopening schools in denmark did not worsen outbreak, data shows. reuters the complex question of reopening schools swiss hugging experiment key to answers on covid-19 risk in kids. sydney morning herald today's children are the pandemic generation. washington post as hospitals see more severe child abuse injuries during coronavirus, "the worst is yet to come there is violence in the house': children living under lockdown risk abuse the world over suffering in silence: how covid-19 school closures inhibit the reporting of child maltreatment it's not children's education we should worry about, it's their mental health. forbes a third of americans now show signs of clinical anxiety or depression, census bureau finds amid coronavirus pandemic the coronavirus pandemic is pushing america into a mental health crisis how the stress and isolation of coronavirus could create "a perfect storm" for child abuse and neglect -and what you can do to help. market watch covid-19 related school closings and risk of weight gain among children life with an autistic child can be difficult. during a pandemic it can be grueling. stat news a fiasco in the making? as the coronavirus pandemic takes hold, we are making decisions without reliable data. statnews a plan to get america back to work reinfection could not occur in sars-cov-2 infected rhesus macaques can you get covid-19 twice? germany could issue thousands of people coronavirus 'immunity certificates' so they can leave the lockdown early. business insider blood tests show 14% of people are now immune to covid-19 in one town in germany sweden's coronavirus strategy is not what it seems. washington post tracking covid-19 excess deaths across countries; official covid-19 death tolls still under-count the true number of fatalities sweden cared more about islamophobia than saving elderly in nursing homes from coronavirus. frontpage mag the hidden flaw in sweden's anti-lockdown strategy. the government expects citizens to freely follow its advice-but not all ethnic groups have equal access to expertise. foreign policy five republican governors: our states stayed open in the covid-19 pandemic. here's why our approach worked the covid-19 lockdown "natural experiment" that has already been conducted models project sharp rise in deaths as states reopen do lockdowns save many lives? in most places, the data say no for covid-19, will the hic blueprint work in lmics? glob health sci pract limiting the spread of covid-19 in africa: one size mitigation strategies do not fit all countries. lancet glob health when lockdown becomes a death sentence: the coronavirus response in the developing world. the politic covid-19 in nepal: where are we after 9 weeks of lockdown? new spotlight nepal india's coronavirus lockdown leaves vast numbers stranded and hungry billions are out of work and millions of kids could die from coronavirus's economic fallout coronavirus: worst economic crisis since 1930s depression, imf says. bbc news lifting lockdowns: the when, why and how. economist covid-19 is undoing years of progress in curbing global poverty hispanics are almost twice as likely as whites to have lost their jobs amid pandemic kenya is turning a public health crisis into a lawand-order one polio, measles, other diseases set to surge as covid-19 forces suspension of vaccination campaigns who estimates malaria deaths could double because of interruptions caused by covid-19. healio infectious disease news early estimates of the indirect effects of the covid-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study effects of the covid-19 pandemic on routine pediatric vaccine ordering and administration-united states family planning efforts upended by the coronavirus. foreign policy forgotten pandemic offers contrast to today's coronavirus lockdowns scientist who fought ebola and hiv reflects on facing death from covid-19 weird as hell': the covid-19 patients who have symptoms for months. guardian people are dying at home': virus fears deter seriously ill from hospitals. guardian fear of covid-19 leads other patients to decline critical treatment. ny times with' 'of' or 'because of'. malcolmkendrick. org blog common sense reasons why the africa continent is escaping the worst of the pandemic. africa expat wives club blog correlation between universal bcg vaccination policy and reduced morbidity and mortality for covid-19: an epidemiological study an old tb vaccine finds new life in coronavirus trials. the scientist could 'innate immunology' save us from the coronavirus? ny times a tool to estimate the net health impact of covid-19 policies. center for global development blog dfid policy brief: rapid review of physical distancing in africa. department for international development 6 months of coronavirus lockdown could mean 31 million more cases of domestic violence, un says. cbs news domestic violence calls mount as restrictions linger: 'no one can leave'. new york times domestic violence and coronavirus: hell behind closed doors. the nation the hellish side of handwashing: how coronavirus is affecting people with ocd. the guardian the following individuals generously contributed to competing interests: none declared. key: cord-264612-paewji35 authors: øverlien, carolina title: the covid‐19 pandemic and its impact on children in domestic violence refuges date: 2020-08-18 journal: child abuse rev doi: 10.1002/car.2650 sha: doc_id: 264612 cord_uid: paewji35 the covid‐19 pandemic has resulted in negative consequences for children exposed to violence and abuse. domestic violence refuge staff were greatly concerned about children both living outside and inside refuges. domestic violence refuges have played a pivotal role during the covid‐19 pandemic and should receive wider acknowledgement and greater support for their work. i n response to the rapid worldwide spread of the coronavirus, a national lockdown was announced in norway on 12 march 2020. all daycare centres and schools were closed immediately, as were many small businesses, including restaurants and shops. moreover, all gatherings, such as sporting events and concerts, were banned. these and numerous other restrictions in norway during the spring of 2020 represented the most extreme measures enforced by the norwegian government since the second world war. many of the restrictions have significantly impacted the lives of children and adolescents, especially the closing of daycare centres, schools and arenas in which many children spend their leisure time, such as football fields, swimming pools and art centres. children and adolescents were not allowed to play with more than a few children at the same timeand preferably the same children each timekeeping at least one-metre distance between them. services vital for children and adolescents' physical and mental health, such as school health services and community health clinics for children and adolescents, were also closed or had reduced hours. in addition, child protection services in norway reported reduced capacity due to employees' self-isolation efforts, and that they were receiving fewer reports of abuse and neglect of children (muladal, 2020) . although the strict guidelines and rules have most certainly had an impact on all children and adolescents, children living in households with domestic violence may be at particular risk as a result of the pandemic. in the past few months, mainstream media, non-governmental organisations (ngos), international organisations and researchers have all called attention to the issue of child abuse and neglect as a particularly problematic consequence of social distancing and other virus control measures. end violence against children (2020) emphasises the vulnerabilities of children during times of crisis, such as the covid-19 pandemic. a national helpline for children in norway has reported a sharp increase in the number of calls from worried children since the lockdown, many concerning conflicts and tension at home (jørnholt and mjaaland, 2020) . the world health organization (2020a) has reported an increase in violence and abuse against women and girls, and that security, health and financial concerns may increase tension in the home. a recently published overview of studies on the impact of pandemics on violence against women and children (peterman et al., 2020) argues that 'the regional or global nature and associated fear and uncertainty of pandemics provide an enabling environment that may exacerbate or spark diverse forms of violence against women and children' (p. 3). peterman et al. (2020) document nine direct and indirect causes of the link between pandemics and violence against women and children, among which are: economic instability; an inability for women (and children) to escape the abuser; and quarantine and social isolation. families with low socioeconomic status and/or living in overcrowded areas are particularly vulnerable (marques et al., 2020) . other voicessuch as green (2020), bradbury-jones and isham (2020) and usher et al. (2020) have also raised serious concerns about the impact of the covid-19 pandemic on children and adolescents. green (2020) argues that, if attention is not shifted to the wellbeing of children exposed to violence and abuse, we risk an 'irreversible scarring of a generation,' as we might have a 'second pandemic' in the form of increased child abuse and neglect (p. 1). bradbury-jones and isham (2020) draw attention to the paradox that governments around the world have asked their citizens to stay home, but little attention has been paid to the consequences of this request for women and children living with domestic violence and abuse. along these lines, usher et al. (2020) call for governments and policy makers to take responsibility for raising awareness around the risk for increased domestic violence and abuse, and to spread information to the public about services and the need to report any abuse-related concerns to the authorities. these editorials, published in international peer-reviewed journals, emphasise the need for more research and knowledge building on all issues related to the pandemic and domestic violence. however, to date, there is very little empirical data on the impact of the pandemic on the issue of domestic violence and abuse, also from the perspective of service providers. in this short report, i provide insight into the situation of domestic violence refuges in norway during the spring of 2020 and their concern for their youngest clients. domestic violence refuges have existed in norway since 1979. refuges were originally meant for women and children; however, in 2010, men were also 'children living in households with domestic violence may be at particular risk as a result of the pandemic' 'there is very little empirical data on the impact of the pandemic on the issue of domestic violence and abuse' allowed to seek support and shelter in refuges (for a discussion on the inclusion of males in refuges, see côté et al. (2018) ). for the past 40 years, these refuges have been a haven in which victims of domestic violence and abuse can be safe from their abusive partners and parents; in addition, the refuges have also had the important role of putting domestic violence on the political agenda (øverlien, 2011) . since the implementation of the shelter act in 2010, it is obligatory for all municipalities in norway to provide refuge services to their inhabitants. with this new law, the local authorities became responsible for the total cost of refuge services in the country, and legal requirements regarding the content and quality of the services were imposed (bakketeig et al., 2014) . in this act, children's rights are specified in accordance with the united nations convention on the rights of the child. this means that children and adolescents living in refuges with a parent have the right to have their needs for care, safety and schooling met, and be included in any issues that concern them and their everyday life at the refuge. many of the 46 domestic violence refuges in norway have at least as many children as adults under their roofs. in 2018, 1842 adults stayed one or more nights at a refuge in norway, and during the same year, 1452 children and adolescents under the age of 18 stayed with one of their parents at a refuge (the norwegian directorate for children, youth and family affairs, 2020). the length of stay varies greatly. although the refuges are meant to be used for acute situations and short-term protection of victims of violence and abuse, children often stay for long periods of time, together with a parentespecially in larger cities where there is a shortage of available and affordable housing. as both political driving forces and safe havens for victims of domestic violence, the refuges play a key role in norwegian society. as such, when reports began arriving from different parts of the world concerning a possible increase of domestic violence and abuse during the covid-19 pandemic (see, for example, godin, 2020) , my colleagues and i constructed a web-based survey to distribute to all refuges in norway (n ¼ 46). the survey was anonymous, the respondents were not asked any personal information about themselves, the refuge, or the clients. hence, formal ethical approval from an ethical board was not required. the survey was distributed on 8 april 2020 with the aim of obtaining an overview of the impact of the covid-19 crisis and the virus control measures implemented on 13 march 2020 on victims of domestic violence and abuse. the survey contained 15 items with fixed answers, follow-up questions and an opportunity for the refuges to provide supplementary qualitative descriptions and examples. one reminder was sent on 20 april 2020 and the survey was closed on 23 april 2020. in total, 46 refuges took the survey, giving a response rate of 100 per cent. we asked the leaders of the refuges to respond. if they were unable, they could pass the survey on to an employee with extensive knowledge of the situation at the refuge. as the survey was taken between 8 and 23 april 2020, it covers the four to six weeks following the implementation of the government's strict, wide-ranging virus control measures. the questions focused on four main topics: 1) changes in the '[the survery] covers the four to six weeks following the implementation of the government's strict, wide-ranging virus control measures' and children in domestic violence refuges services due to the pandemic; 2) the refuges' cooperation with other services; 3) what the refuge staff saw as most worrying in the current situation and what they saw as vital in order to support victims; and 4) changes in the requests and motivations for contacting the refuges. some of the questions related specifically to children. the results of these questions, using descriptive statistics analysed in spss, are presented below. for additional insight into the concerns of refuge staff, everything from the comment field concerning children was also analysed. as 56 per cent of the respondents reported that there had been a reduction in the number of requests from clients, many expressed concern that it is 'too quiet out there,' and that victims of domestic violence and abuse are not receiving the help and protection they need during the pandemic. one key survey question concerned specific groups that the refuge staff were particularly worried about: 'during the coronavirus crisis, are there any groups of victims of violence and abuse that you are particularly worried are not getting the protection they need?' the group the refuge staff reported being most concerned about was children, with a total of 83 per cent reporting this concern. as most children and adolescents were present in the home during the pandemic, and as many parents were working from home, parents and children were spending the majority of the day in the same physical space. survey comments indicate that the refuge staff were concerned about children outside of the refuge living in households with domestic violence and children living in the refuges but not receiving the support that they need due to the pandemic. regarding children living in households outside of the refuge and experiencing domestic violence, the refuge staff expressed great concern for children and adolescents living with abusive parents who may be experiencing increased stress during the pandemic. almost half of the respondents (43%) reported that their clients believed the presence of children in the home during the day increased the risk of violence and abuse. in addition, 57 per cent answered that their clients reported that the virus control measures, and the coronavirus crisis itself, were increasing stress for the abusers. as one respondent commented: ' we believe that children who lived with violence before the pandemic are now even more exposed … and that the exposed parent is now even less able to protect the child.' and according to another: 'with families living with prolonged stress, perhaps a worse economy and declining hopes for the future, it is easy to imagine that those who already struggle, now struggle even more. our greatest fear is that we will see more suicides or familicide. if the hole gets too black and the road too long …' 'many expressed concern that it is 'too quiet out there'' in addition, the refuge staff were concerned that children exposed to violence who were living outside of the refuge would no longer receive the help that they need from professionals; and, moreover, that the violence they experience would remain undisclosed, as contact between adults outside of the family and the abused child is dramatically reduced. as one respondent reported: ' we are concerned about the children who now have no support from the social services, at the same time as they are struggling because of isolation [not seeing their] friends and a closed-down societyschools, daycare, after-school activities, etc.' another expressed concern that: 'vulnerable groups, previously followed up with by different parts of the social and health sector, now have less contact and follow-up, hence, fewer are "keeping track." this also includes the children.' closed schools and daycare centres are of particular concern for the refuge staff as, for many children living with domestic violence and abuse, school represents normality and a zone free from the abusive parent. school staff can also be important in terms of supporting children living in difficult situations. in norway, it is mandatory that school staff report concerns about abuse to the child protection services; as such, they also represent an important safety net for children and adolescents exposed to violence. many refuges in norway cooperate with ngos, such as save the children and the red cross, whose volunteers arrange activities for the children and help them with homework. other refuges have rooms where the children can play with visiting friends. some also cooperate with daycare centres and schools that send teachers to instruct those children living for longer periods at the centres and who are unable, for security reasons, to leave the refuge. however, social and pedagogical contacts such as these have been discontinued during the pandemic. one respondent explained that: 'all activities for children arranged by volunteers, such as playgroups and help with homework, have ended … we no longer permit visitors from outside of the refuge.' another described it as follows: 'all activities involving physical contact have stopped. all children are usually offered some kind of pedagogical activity at the centre, by schools or daycare centres, but that is now cancelled.' according to a third respondent: 'it has been really demanding with all the children who have not gone to school, but stayed at the refuge 24/7 with no alternative activities. digital schooling and support from parents in crisis. we need more resources for those kids.' 'closed schools and daycare centres are of particular concern for the refuge staff' 'social and pedagogical contacts … have been discontinued during the pandemic' refuge staff also described how everyday life at the refuges has changed for the children since the start of the pandemic. in addition to the discontinuation of visits from friends, professionals and volunteers, the play areas, group meals and visits to other families' rooms have also been restricted. as one respondent wrote: ' we ask everyone to spread out in the house, as much as possible, the children only play within their family, they can't sit with other children and eat, watching tv etc. all common meals at the centre have stopped … they can't visit each other's rooms. we have to watch that they don't get physically too close.' while raising serious concerns, in particular about children and adolescents, the respondents' comments also underlined that refuges are accustomed to crisis situations, and that their staff members are flexible and creative and used to solving problems quickly. as one respondent stated: ' we are educated, we keep calm, and we are highly trained to deal with challenging situations. our staff has stepped up in every possible way.' another emphasised that '[o] ur strength is that we are good at readjusting and making the best of what we've got. we quickly got new routines in place. ' the pandemic has undoubtedly placed great demands on the refuges. as many as 90 per cent reported that they have had to adjust their organisation to accommodate the government's new requirements while simultaneously fulfilling their obligation to provide support and shelter for victims of domestic violence and abuse. however, the many comments about the situation faced by children, in particular, highlight that, though challenging, these adjustments include making changes with the best interest of the child in mind. national strategies to the covid-19 pandemic differ between counties, and the re-opening of societies is at different stages (world health organization, 2020b). in the neighbouring country sweden, restrictions have not been as rigorously enforced as in norway. at the time of writing, restrictions that have been lifted in norway still remain in place in ireland and the uk. since the distribution of the survey reported on in this short report, daycare centres and schools in norway have slowly begun to reopen. some after-school activities have also started up once more, and children and adolescents are again allowed to play football (albeit in smaller groups) on oslo's public football fields. some of the strictest virus control measures are being lifted, and the domestic violence refuges are reporting an increase in contact with clients, including children. however, the lives of children and adolescents remain very much affected by the pandemic, and there is reason to believe that the last few months have seen an increase in violence against children. it is now of greatest importance that all social and health services, as well as daycare centres and schools, are vigilant 'there is reason to believe that the last few months have seen an increase in violence against children' concerning the negative consequences of the pandemic, now that children are returning after many weeks of self-isolation. norway has an extensive social and health sector focusing on children, and the issue of domestic violence and abuse has been high on the political agenda for several years. however, we know that violence towards and abuse of children too often remain undisclosed, and that many children do not get the support that they need and to which they have a right. institutions and services for children and adolescentsparticularly those who provide safety and support to children living with domestic violence and abuseare now more crucial than ever. in addition to receiving the necessary support so that they can provide the same services as before the pandemic, they need additional resourses to be proactive, and find new, creative ways to reach out to children and adolescents in vulnerable situations. this includes domestic violence refuges, which have played a pivotal role during the covid-19 pandemic and will continue to do so. they need to be acknowledged for the work that they do and provided with the resources they need to not only keep children safe, but also support their schooling, arrange activities and allow for play, while continuing to follow the required social distancing and virus control measures. krisesentertilbudet i kommunene. evaluering av kommunenes implementering av krisesenterloven the pandemic paradox: the consequences of covid-19 on domestic violence the inclusion of males in domestic violence shelters: an everlasting debate protecting children during the covid-19 outbreak: resources to reduce violence and abuse as cities around the world go on lockdown, victims of domestic violence look for a way out risk to children and young people during the covid-19 pandemic dobbelt så mange barn og unge kontakter alarmtelefonen [twice as many children and adolescents contact the helpline violence against women, children, and adolescents during the covid-19 pandemic: overview, contributing factors, and mitigating measures coronatiltakene: barnevernet får faerre bekymringsmeldinger [coronameasures: child protection services receives fewer reports the norwegian directorate for children, youth, and family affairs (bufdir). 2020. refuges in norwegian municipalities abused women with children or children of abused women? a study of conflicting perspectives at women's refuges in norway pandemics and violence against women and children. working paper 528 family violence and covid-19: increased vulnerability and reduced options for support world health organization. 2020a. covid-19 and ending violence against women and girls world health organization key: cord-023713-daz2vokz authors: devereux, graham; matsui, elizabeth c.; burney, peter g.j. title: epidemiology of asthma and allergic airway diseases date: 2013-09-06 journal: middleton's allergy doi: 10.1016/b978-0-323-08593-9.00049-8 sha: doc_id: 23713 cord_uid: daz2vokz nan epidemiology is the study of the distribution of disease in populations. it is essential for assessing the spread and burden of disease. it is the appropriate method for understanding the cause and pathogenesis of disease. research into allergy has had a long history with many changes in direction, and the language that has been developed to describe what has been found has changed over time. this can lead to confusion. in this chapter, we use the term sensitization to indicate the production of immunoglobulin e (ige) antibodies in response to allergens. we use the term allergy to refer to the presence of one or more diseases associated with ige sensitization, the most common of which are asthma, eczema, and rhinitis. the term atopy was originally introduced to account for the observation that the main allergic diseases occurred in the same families and appeared to have a common origin. however, it is often used synonymously with the term allergy. test standards. good tests should possess reliability and validity. 1 a test is reliable if it always gives the same answer when applied under similar circumstances. validity implies that the result of the test coincides well with the true condition of the person being tested. validity has two components: sensitivity, which is the ability of the test to identify an existing condition, and specificity, which is the ability to identify as normal people who are free of the condition. measuring the validity of a test for a condition that is poorly defined, such as asthma, is a problem because it presupposes a gold standard test with which the proposed test can be compared. although validity in an absolute sense may always be contested, what is as important in epidemiologic studies is standardization, meaning that the test is identical wherever and by whomever it is administered. validity is essential to the measurement of absolute prevalence, but in many epidemiologic studies, we are as interested in relative prevalence, such as relative prevalence between age groups, countries, or districts, or differences between people exposed to various environmental or genetic risks. standardization is essential for this, and considerable effort has been made to provide standardized measures, particularly for international studies. tests of sensitization. sensitization can be assessed directly by determining the presence of specific ige to allergens in serum. in many places, mites, grass, and cat allergens are among the most common allergens, and most sensitized individuals can be identified by testing for relatively few allergens. 2, 3 some test kits can identify a mixture of several allergens. in the past, they have been used to test for the occurrence of sensitization, and this may be cost-effective, but it leaves unclear which allergens are » epidemiology is the study of the distribution of disease and, by extension, its causes and consequences, mostly in general populations. » the rates of allergic sensitization and allergic diseases have been increasing, although the increase in prevalence of allergic diseases has slowed among children. » allergic disease is less common in rural parts of low-income countries, although allergic sensitization can be common in these areas. » there has been very little success in explaining the increased prevalence of allergic disease, although it has been linked to urbanization. the great changes observed in prevalence and distribution strongly suggest a major role for the environment. » factors that initiate allergy and allergic diseases should be differentiated from factors that exacerbate them after they have been established. » allergies are affected by environmental factors, including diet; exposure to a normal, diverse microflora; infections; exposure to air pollutants; and occupational exposures. » allergy is not associated with higher mortality rates or loss of lung function, but asthma is associated with both. » outcomes for asthma can be considerably improved by good management. test of whether someone had asthma. what had been provided was, in his view, no more than a description. second, he pointed out that most diseases were concepts rather than "things" and that their definitions were therefore bound to be contested. since then, there have been many attempts to define asthma (table 48-1) , although most have paid little attention to the issues raised by this led to more complicated descriptions but not to any greater clarity. some have introduced additional assumptions about mechanisms and causes. despite these strictures, asthma has been an enduring and trusted concept clinically, but a separate question remains about how the condition can be identified in epidemiologic studies. there are effectively three broad methods of identifying asthma in surveys: questionnaires asking about diagnosed asthma, questions about the symptoms of asthma, and physiologic tests of airway responsiveness. questions asking whether someone has asthma, often qualified by asking whether a doctor has ever confirmed the diagnosis, are common. they are regarded as highly specific, meaning that there are few people who answer this question in the affirmative but do not have asthma, but there are many people who may be defined as asthmatic who deny that they have the condition. the worst characteristic of these questions is the lack of standardization. the answers to the questions depend on local medical practice and the terms used by health professionals when talking to patients. variations in the use of the term asthma likely have influenced estimates of time trends and observed differences in mortality between countries. over the past 50 years, the prevalence of people with asthma has increased markedly, and there has been much debate about whether this can be explained by differences in the way the term has been used. this possibility is supported by the encouragement given to pediatricians, particularly from the 1980s onward, to diagnose all wheezy children as asthmatic because this would encourage the use of medication and was shown to enhance the quality of life of children regardless of the exact diagnosis. 15 in the 1980s, kelson and heller sent scenarios of patients who had died to a representative group of physicians signing death certificates in several european countries. 16 one scenario (box 48-1) described a person who had some symptoms of asthma but many of the features of chronic obstructive lung disease. figure 48 -1 shows the relationship between the proportion of the physicians in each country ascribing this death to asthma and the national mortality rate for asthma. 17 there is a strong suggestion that the way doctors in each country view such marginal cases may be influencing the national mortality data. whether this is still the case is uncertain. since then, there has been a major increase in international consensus documents. asking about symptoms rather than diagnosed disease avoids some of these problems, and efforts have been made to find suitable questionnaires and to standardize them across countries. the most commonly used questionnaire for children is that developed for the international study of asthma and allergies in childhood (isaac). 18 for adults, the questionnaire developed for the international union against tuberculosis and lung disease (iuatld) 19, 20 was subsequently adapted for use in the european community respiratory health survey (ecrhs) 21 and was further adapted for the world health survey. 22 responsible for symptoms. microchip technology and the development of recombinant and purified allergens have enabled testing for several allergens simultaneously and allowed more precise identification of the relevant allergens. the technology remains expensive and is not widely used in epidemiologic studies. an alternative method of identifying sensitized individuals is to undertake skin-prick tests. they do not require a laboratory and do not involve taking blood. the technique involves introducing a small amount of allergen under the outer layers of the skin using a needle or lancet and reading the size of the wheal that appears in the 15 minutes after the test is applied. 4 this is compared with the wheal produced by a control solution (usually the diluent in which the allergens have been dissolved) and with a positive (usually histamine) control that tests whether the skin is able to respond to the release of mediators that the allergen induces. skin tests have more operatordependent variation than serologic tests, because they are influenced in part by the technique of the technician, but they typically are cheap and provide an immediate answer, which can be more satisfactory for the patient or participant. the criterion for a positive test result varies according to the purpose of testing. using any test greater than the diluent control is more repeatable and less prone to observational error and reflects well the presence of allergen-specific ige. 5 however, in a clinical context, small wheals are rarely associated with allergic disease that can be ascribed to that allergen, and in a clinical context, wheals less than 3 mm in diameter usually are discounted as irrelevant. defining the prevalence of sensitization in a population depends to some extent on which allergens are tested. in western europe and the united states, there is little change in overall prevalence after five or six allergens have been included in the panel. 2, 3 although less is known about other countries, mite allergens appear to be widespread in tropical and subtropical areas. for the most part, skin tests and serologic tests for sensitization give similar results when technical failures and differences between allergens are taken into account. however, they are not equivalent. skin tests also depend on the ability of mast cells to degranulate and for the skin to respond to histamine. when skin test results are negative, clinical allergy is unlikely even in the presence of specific ige. 3 modern attempts to define asthma start with the ciba guest symposium of 1958 on the terminology, definitions, and classification of chronic pulmonary emphysema and related conditions. 6 the symposium defined asthma as "the condition of subjects with widespread narrowing of the bronchial airways, which changes its severity over time spontaneously or under treatment, and is not due to cardiovascular disease". it further identified the clinical characteristics as "abnormal breathlessness, which may be paroxysmal or persistent, wheezing, and in most cases, relief by bronchodilator drugs (including corticosteroids)." soon after the publication of this report, scadding, one of the contributors to the symposium, made two important points. 7 first, what had been described as a definition in the report was not a true definition in that it did not provide a clear year definition ciba foundation 6 1959 condition of subjects with widespread narrowing of the bronchial airways, which changes its severity over short periods spontaneously or during treatment american thoracic society 8 1962 disease characterized by increased responsiveness of the trachea and bronchi to various stimuli and manifested by widespread narrowing of the airways that changes in severity spontaneously or as a result of therapy world health organization (who) 9 1975 chronic condition characterized by recurrent bronchospasm resulting from a tendency to develop reversible narrowing of the airway lumina in response to stimuli of a level or intensity not inducing such narrowing in most individuals american thoracic society 10 1987 clinical syndrome is characterized by increased responsiveness of the tracheobronchial tree to a variety of stimuli. major symptoms are paroxysms of dyspnea, wheezing, and cough, which may vary from mild and almost undetectable to severe and unremitting (i.e., status asthmaticus). primary physiologic manifestation of this hyperresponsiveness is variable airway obstruction, occurring in the form of fluctuations in the severity of obstruction after bronchodilator or corticosteroid use, or increased obstruction caused by drugs or other stimuli, as well as evidence of mucosal edema of bronchi, infiltration of bronchial mucosa or submucosa with inflammatory cells (especially eosinophils), shedding of epithelium, and obstruction of peripheral airways with mucus. nhlbi/nih 11 1991 lung disease with the following characteristics: (1) airway obstruction that is reversible (but not completely in some patients) spontaneously or with treatment, (2) airway inflammation, and (3) increased airway responsiveness to a variety of stimuli. nhlbi/nih 12,13 1993 1995 1997 chronic inflammatory disorder of the airways in which many cells play a role, particularly mast cells, eosinophils, and t lymphocytes. in susceptible individuals, this inflammation causes recurrent episodes of wheezing, breathlessness, chest tightness, and cough in early morning. symptoms are usually associated with widespread but variable airflow limitation that is at least partly reversible spontaneously or with treatment. inflammation also causes an increase in airway responsiveness that is associated with a variety of stimuli. nih/nhlbi 14 2002 chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. the chronic inflammation causes an increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. these episodes are usually associated with widespread but variable airflow obstruction that is often reversible spontaneously or with treatment. nhlbi/nih, national heart, lung, and blood institute/national institutes of health. symptom questionnaires do not have the disadvantages of reported diagnoses, but they have problems of their own. first, used alone, symptoms are rarely diagnostic of a condition. this may not be a serious problem when there is no need for an accurate diagnosis in every case, but some symptoms are highly nonspecific. there may be considerable crossover of symptoms between different airway diseases such as asthma and bronchitis. second, the interpretation of similar symptoms may vary among different people. this may become a serious problem when making comparisons in the settings of different cultures and languages. in translating asthma questionnaires, there may be particular problems in translating terms such as wheeze when there may not be an equivalent word, and even people who speak the same language may interpret wheeze differently. given the lack of a gold standard to test these questionnaires against, their validity cannot be fully assessed, because it depends in part on whether they are seen as plausible indicators of the presence of asthma and standardization against a plausible alternative indicator. in the iuatld questionnaire, this indicator was the airway response to histamine, which usually increases tests. 24 they have some of the same limitations as reversibility testing. more promising has been the use of bronchial challenge tests, most of which use a direct bronchoconstrictor such as histamine or methacholine. lung function is assessed before and after inhaling increasing doses of the agent. the decline in lung function (usually the forced expiratory volume in 1 second [fev 1 ]) is regarded as a marker of asthma. 25, 26 this may be expressed as the dose or concentration of agent that produces a given (often 20%) fall in lung function, in which case the result usually is dichotomized as those falling by at least that amount (i.e., hyperresponsive) and those that do not (i.e., normal). alternatively, the slope of the dose-response curve has been used as a continuous measure of airway reactivity, a method that uses epidemiologic information more efficiently but may be clinically less intuitive. 27 development of these tests for use in surveys has provided a tool for assessing a physiologic measure associated with asthma. there is little difference between the use of histamine and methacholine, but methacholine is more widely used because it has fewer side effects. one disadvantage of nonspecific challenge tests is that they produce positive results for those with asthma and also with chronic obstructive pulmonary disease (copd). 28, 29 this has led to the use of alternative agents that act indirectly by releasing mediators from mast cells in the airway. challenge agents include adenosine, hypertonic solutions (e.g., saline, mannitol), exercise, and cold, dry air. these alternatives have not been used as widely as methacholine. exercise testing usually has been confined to studies of children. its effects depend on weather conditions (e.g., cold, dry conditions produce a greater stimulus than warm, moist conditions), and it requires well-motivated groups of participants. equipment to provide cold, dry air has not been widely available. use of saline and mannitol has promise, but they have not been widely used in surveys. the theoretical advantage of using these methods is that they are less likely to provoke airway constriction in those with copd. allergic rhinitis has been investigated much less frequently than asthma using epidemiologic approaches. population-based studies are made difficult by misclassification arising from reliance on questionnaires to establish the presence of allergic rhinitis. typically, the questionnaires used by epidemiologists ascertain self-reports of responders having something they call allergic rhinitis or hay fever. nonetheless, studies show that allergic rhinitis is among the most common chronic diseases. symptoms of individuals with rhinitis include sneezing, nasal irritation, rhinorrhea, and nasal blockage. 30 these symptoms can also involve the eyes, ears, and throat, including postnasal drainage. 31 allergic rhinitis is most commonly classified as seasonal, perennial, or occupational, 30 but a recent guidelines statement advocated classifying allergic rhinitis as intermittent or persistent. 32 the symptoms of allergic rhinitis are associated with exposure to allergen sources such as pollens, pets, and house-dust mites (hdms). 30 symptoms result from inflammation induced by a specific ige-mediated immune response to the allergens. 31 criteria for diagnosing chronic rhinosinusitis have been published. 33, 34 a questionnaire based on the symptomatic part of this definition has been devised and tested for epidemiologic surveys. 35 in patients with asthma. although it is not diagnostic of asthma, it is reassuring to find that answers to the questionnaires can predict the results of the alternative test 19 and that they can do this in approximately the same way in different countries and different translations. 20 for the isaac questionnaires, a video was developed that demonstrated the symptoms of asthma, and it was used to help standardize comprehension of the questionnaire in different settings. 23 although fully validated questionnaires for diagnosing asthma are not available, the current questionnaires do allow comparison of symptoms that plausibly represent conditions close to asthma in a standardized way. although cautious interpretation is always advisable, they have enabled substantial advances in our knowledge of the relative distribution of the condition. an objective test for asthma that did not depend on interpretation of questionnaires would be ideal, and several tests have been proposed. the lack of a gold standard for diagnosing asthma and the similarity of asthma to other conditions make a perfectly validated test unattainable, but tests do provide additional tools to check the findings of surveys that use questionnaires only. the physiologic tests for asthma have been based on the definition of asthma as a condition of the airways that changes its severity over time spontaneously or after treatment (box 48-2). reversibility of airway obstruction after use of a bronchodilator (i.e., reversibility testing) has been used in clinical studies to distinguish between asthma and fixed airway obstruction, and some have used it as a test in surveys to identify asthma. the difficulty lies in interpreting the results. a positive test result indicates the likely presence of asthma, but a negative test result is uninformative. because a patient with asthma who is receiving good treatment or in remission for some other reason does not respond to a bronchodilator, this approach has not found much use in surveys of the general population. spontaneous changes in airway caliber can be assessed using peak flow diaries, a clinical technique that has been commonly used in primary care in the united kingdom. although they can be difficult to use in large-scale studies, they do provide data comparable to that using more invasive bronchial challenge kingdom, and the netherlands. low prevalence rates were found in spain, iceland, and italy. the second phase of the isaac study estimated the prevalence of positive skin-prick test responses to at least one of six allergens in children between the ages of 8 and 12 years living in 18 sites, mostly in western europe. 40, 41 estimated prevalence ranged from 11.6% in tallin, estonia, and 16.5% in mumbai, india, to 39.5% in rome, italy, and 44.7% in almeira, spain. unlike in western countries, the prevalence of sensitization in africa heavily depends on the methods used to assess sensitization. in rural areas, the prevalence of positive skin-prick test results is very low, whereas the prevalence of allergen-specific ige is high. the high prevalence of allergen-specific ige in poor rural areas was first shown in zimbabwe (formerly called southern rhodesia) by merrett and associates, 42 but the dissociation in these environments between specific ige levels and skin test results also has been shown in kenya 43 and south africa. 44 where skin test results are negative, even in the presence of specific ige to aeroallergens, clinical allergy is rare. 3 asthma is a global problem. it is estimated that approximately 300 million people worldwide have asthma. 45 prevalence rates for children and adults are substantially different in countries around the world. the first phase of the isaac study provides the most extensive information on variation in childhood asthma prevalence. in 1998, the isaac steering committee reported findings for 463,801 13-to 14-year-old children (155 centers in 56 countries) and 257,800 6-to 7-yearold children (91 centers in 38 countries). 46 for the younger and older children, the prevalence of asthma symptoms was based on a positive response to this question: have you had wheezing or whistling in the chest in the past 12 months? across countries, there was an approximately twentyfold range of prevalence, with the highest rates usually found in more developed countries (figs. 48-2 and 48-3) . the countries with the highest prevalence rates (>20%) were the isle of man, the united kingdom, new zealand, ireland, australia, peru, panama, costa rica, the united states, and brazil. the ecrhs assessed geographic variation in asthma among 140,000 adults from 22 countries. a sixfold variation in the prevalence of current asthma was found among the countries. 21 a high (>7%) prevalence of asthma was found in australia, new zealand, the united states, ireland, and the united kingdom. asthma prevalence of less than 4% was found in iceland, parts of spain, germany, italy, algeria, and india. current asthma was defined in the ecrhs as "having an attack of asthma in the past 12 months or currently taking medicine for asthma." the ecrhs did not examine many sites outside the developed market economies, but the world health survey interviewed adults older than 18 years of age in six continents using questions derived from the ecrhs on wheezing and diagnosed asthma. 22 the prevalence of diagnosed asthma ranged from 1.8% in vietnam to 32.8% in australia (fig. 48-4) . a very wide variation in the prevalence of diagnosed asthma (and wheezing) was found in all countries, regardless of gross national income per capita adjusted for purchasing power parity. in countries eczema similar to allergic rhinitis, the epidemiology of eczema is less well understood than the epidemiology of asthma. eczema, also known as atopic dermatitis, is a pruritic rash characterized by chronic, recurrent papular lesions typically affecting skin at the flexor surfaces, buttocks, and back of the neck. infants frequently have involvement of the face. in its acute and subacute forms, eczema is characterized primarily by erythema and a papular eruption, but in its chronic form, it is characterized by lichenification of affected areas. allergic sensitization plays an important role in provoking eczema flares, particularly in pediatric patients. 36 some studies have relied on physician diagnosis to define eczema, but standardized questions have been developed for identifying eczema cases with or without additional information from standardized examination. 37 these questions are included in the isaac questionnaire, and they focus on the chronic and recurrent nature of the rash, its location, and the presence of pruritus. during the past 10 years, food allergy has received increased attention, and there is a growing body of literature available regarding its epidemiology. food allergy is an immune-mediated reaction to a food. it can produce a wide spectrum of clinical manifestations, including acute ige-mediated reactions, mixed ige-mediated and non-ige-mediated reactions that are often characterized by insidious gastrointestinal symptoms, and non-ige-mediated syndromes such as allergic colitis and food protein-induced enterocolitis syndrome. even among patients with acute ige-mediated types of food-allergic reactions, symptoms can vary and include one or many of the following: urticaria, angioedema, pruritus, cough, wheezing, hoarseness, vomiting, diarrhea, oral pruritus, hypotension, and rhinorrhea. because the diagnosis is based on the clinical history and diagnostic test results, with the gold standard being a double-blind, placebo-controlled food challenge, conducting large epidemiologic surveys can be difficult because of reliance on questionnairebased tools for identification of food allergy and evidence of ige sensitization. because there is no validated questionnaire for food allergy and many reported food allergies are not confirmed when a full diagnostic evaluation is completed, estimates obtained from questionnaires are likely to be inflated. 38 the prevalence of sensitization depends on the selection of allergens. for this reason, the relative prevalence of responses to a standardized panel of allergens is more informative than an absolute prevalence. the ecrhs estimated the prevalence of specific ige (≥0.35 ku/l) to mites (dermatophagoides pteronyssinus), cats, grass (timothy grass), or cladosporium among young adults between the ages of 20 and 44 years in 35 centers, mostly in western europe. 39 the prevalence of a positive response to any of the four common allergens ranged from 16.2% to 44.5% ,with a median prevalence of 33.1%. high prevalence rates were found in australia, new zealand, the united states, the united rates for different questionnaire-based indicators of asthma: physician report, current disease, and the symptom of wheezing used in the national health and nutrition survey of the united states from 1976 through 1980. 47 questions that ask about asthma or wheeze provide estimates that are almost twice those of questions asking about either alone, and this difference varies with age. for those between the ages of 3 and 17 years, with the lowest incomes (<us$3000), none of 20 sites had a prevalence of diagnosed asthma of more than 10%; among countries with intermediate incomes, 3 (19%) of 16 countries had a prevalence higher than 10%; and among counties with the highest incomes (<us$8000), 7 (26%) of 27 countries had a prevalence above 10%. the national health interview survey (nhis) and the national health and nutrition examination survey (nhanes) include random samples of the whole u.s. population. both also provide periodic prevalence estimates. standardization of the methods of prevalence surveys is essential because the wording of questions on asthma or other aspects of data collection may affect estimates based on the questionnaires. for example, table 48 -2 provides prevalence country wheeze is much more likely to be associated with a diagnosis of asthma. state-specific asthma prevalence data for adults are available from the 2010 behavioral risk factor surveillance system (brfss), a state-based, random-digit-dialed survey of noninstitutionalized u.s. adults age 18 years or older. it was conducted by the centers for disease control and prevention (cdc) and the state or territorial departments of health. information was gathered from all 50 states, puerto rico, the virgin islands, and the district of columbia. the definition for current asthma was based on providing positive answers to two questions: have you ever been told by a doctor, nurse, or other health professional that you had asthma? do you still have asthma? the overall current asthma prevalence rate was 8.6%, ranging on the mainland from 6% in tennesee to 11.1% in vermont ( fig. 48-5) . 48 asthma prevalence rates in the united states vary with demographic and social conditions. figure 48-6 gives prevalence rates from the nhis for 2008 through 2010. children have more reported asthma than adults, women have more than men, those in poverty have more asthma than those not in poverty, asian respondents reported less asthma than any other group, and all other racial groups have more asthma than white respondents. 49 estimating incidence and prevalence of allergic rhinitis is as challenging as for asthma. the diagnosis is symptom based, and there is no consensus for measurement. some attempts have been made to estimate the incidence of allergic rhinitis using cohort or longitudinal data. in a birth cohort study from germany that followed 587 children for 7 years, 50 15% of them developed seasonal allergies, defined as a combination of exposure-related symptoms and sensitization. a 23% cumulative incidence rate was determined in a 23-year longitudinal study of 738 college students. 51 the researchers also observed that regression of hay fever symptoms was inversely related to age of onset. almost 85% of those with hay fever onset before 5 years of age had improvement of their symptoms. the isaac researchers collected data on 12-month prevalence of allergic rhinoconjunctivitis for children 13 to 14 years old from 56 countries. 46 allergic rhinoconjucntivitis was defined as having a problem with sneezing or a runny or a blocked nose without a cold or flu and accompanied by itchy, watery eyes. there was a thirtyfold variation in the prevalence rate among the sites, from 1.4% to 39.7%. estimates for adults obtained in the ecrhs ranged from 9.5% in algeria to 40.9% in australia. 21 the median prevalence of nasal allergies in the ecrhs was about 21%. countries with significantly high prevalence rates were the netherlands, belgium, switzerland, france, the united kingdom, new zealand, australia, and the united states. chronic rhinosinusitis is an inflammation of the nose and paranasal sinuses lasting over 12 weeks. another multicenter european study estimated the prevalence of chronic rhinosinusitis using a questionnaire based on the european position paper on rhinosinusitis and nasal polyps (ep 3 os) on symptom criteria 35 to be about 11% among adults, ranging from 7% in helsinki, finland, to 27% in coimbra, portugal. the condition was more common in women, in younger participants, and in smokers. 52 the worldwide prevalence of eczema was best documented in isaac phase three, in which the prevalence for 6-to 7-year-old children ranged from 0.9% in india to 22.5% in ecuador. 53, 54 the worldwide prevalence of eczema in children 6 to 7 years of age has increased in most regions of the world and has remained stable only in western, northern, and eastern europe. for this younger age group, the prevalence in isaac phase three was 7.9%, an increase from the prevalence in phase one of 6.1%. the overall prevalence among 13-to 14-year-old adolescents declined to 7.3% in isaac phase three from 8.8% in phase one. the regions with the most striking increases in eczema prevalence were asia and latin america. a growing number of population-based studies have estimated food allergy prevalence and incidence. the prevalence of food allergy and the foods that are most commonly implicated in food allergy vary widely across the world. for example, a metaanalysis found that the self-reported prevalence of food allergy ranged from 3% to 35%. 55 although some of the heterogeneity observed is attributable to study methodology, other studies that have focused on specific geographic regions and populations support the notion that there is marked worldwide heterogeneity in food allergy prevalence. for example, in the united states, the estimated prevalence of food allergy is 4% to 8% among children, 56, 57 and in australia, a prevalence of more than 10% among 1-year-old children has been reported. 58 in contrast, findings from a population-based birth cohort from the united kingdom indicate that between 2.2% and 5.5% of infants have food allergy in the first year of life, 59 and in other u.k. studies, the estimated prevalence of food allergy among 6-year-old children is 1.6% to 2.5%, 60 and among adolescents, it is 2.3%. 61 an international study that used allergen-specific ige data for young adults confirmed the heterogeneity of food allergy prevalence observed in the questionnaire-based studies. 62 in this study, prevalence of sensitization to any 1 of 24 foods ranged from 7.7% in iceland to 24.6% in the united states. however, sensitization to the major foods, such as fish, egg, and milk, was uncommon (<1%). the incidence and prevalence of allergy to specific foods have been studied. a random telephone survey administered in 2002 to estimate the prevalence of seafood allergy in the united states found that 2.3% of the general population reported allergy to fish or shellfish. 63 another telephone survey was conducted in 1997 and repeated in 2002 and 2010 to estimate the prevalence and incidence of peanut and tree nut allergies. 64, 65 the prevalence rate of peanut or tree nut allergy was stable at 1.4% among adults, but it increased from 0.6% to 1.2% to 2.1% among children during this period. in contrast, data from u.k. general practices were used to estimate a prevalence rate of peanut allergy of 0.05%, and a school-based survey in singapore and the philippines estimated a prevalence rate of peanut and tree nut allergy of less than 1%. 66 in australia, the prevalence of peanut allergy may be higher than that observed in the united states or united kingdom, because the prevalence of peanut allergy among 1-year-old children was estimated to be 3%. 58 there is limited information about the epidemiology of allergic gastrointestinal diseases. however, the incidence and prevalence of eosinophilic esophagitis appear to have increased over the past decade. a range of gastrointestinal symptoms and mucosal eosinophilia characterizes eosinophilic esophagitis. approximately one half of cases demonstrate ige sensitivity to foods. 67 what was once thought to be a rare disease was found people born later in the century having a higher prevalence of disease throughout their lives. in cross-sectional surveys, this pattern of disease is indistinguishable from a decline in disease with age. in the ecrhs, there was almost no net change in the prevalence of sensitization over the 8 years between the surveys within any birth cohort, but succeeding birth cohorts had increasingly high prevalence rates. a subsequent analysis of some british data showed that this phenomenon was apparent in successive birth cohorts since at least the 1930s. 72 to evaluate changes in prevalence, repeated surveys are required for the same populations and using the same instruments for assessment. in the 1950s and 1960s, smith in birmingham, england, first observed that the prevalence of asthma was rising among schoolchildren undergoing school medical examinations. 73 since then, many studies have assessed changes in prevalence. these studies are summarized in figure 48 -7, which by one study based in switzerland to have increased in incidence from 1.2 to 7.4 per 100,000 adults from 1989 to 2009. 68, 69 in another study in hamilton county, ohio, the incidence in children younger than 19 years old has increased from 0.009 to 0.013% per year, and the prevalence has increased from 0.01% to 0.04% from 2000 to 2003. 67 a few studies have made serial assessments of the levels of ige specific to common allergens in the same populations over many years. these studies have shown a fairly consistent increase in the prevalence of sensitization over time. analysis of the data from the tucson 70 and the first and second ecrhs surveys 71 found that the apparent decline in the prevalence of sensitization with age was more easily explained as a birth cohort effect. the apparent effect of age results from 1956 1958 1960 1962 1964 1966 1968 1970 1972 1974 1976 1978 1980 1982 1986 1988 1990 1992 1994 1996 1998 2000 1984 2002 0.1 1 10 100 year of survey germany in two surveys made very close together in time and seem unlikely to represent a long-term trend. 80 the isaac reassessed prevalence of asthma and other allergic diseases by questionnaire for 6-to 7-year-old children in 66 centers in 37 countries and for 13-to 14-year-old children in 106 centers in 56 countries. 45 the results for asthma prevalence are given in figure 48 -9. among the younger children, rates were more commonly rising than declining, whereas among the older children, the rising and declining rates were more evenly balanced. among the older children in centers with a high prevalence, the rates were more likely to be declining. in the united states, the nhis, a population-based interview survey of u.s. households, is a key source of information on trends in the prevalence of asthma. 81 before 1997, prevalence estimates were based on a positive response to one question: during the past 12 months, did you have asthma? in 1997, the nchs redesigned the nhis questionnaire. consequently, answers to the nhis questionnaire after 1996 cannot be compared with those in previous surveys because the new questions assess asthma morbidity differently. 82 lifetime incidence is measured by this question: have you ever been told by a doctor or other health professional that you had asthma? the prevalence of asthma attacks is obtained by a positive response to another question: during the past 12 months, have you had an episode of asthma or asthma attack? the asthma attack prevalence in 2009 was 4.2% for all age groups. in 2001, nchs added a question (do you still have asthma?) after the lifetime incidence question to provide estimates of current asthma prevalence (table 48 -3). the 2009 estimates indicate that 8.2% of u.s. residents currently have asthma that has been diagnosed by a doctor or other health professional. 49 table 48 -3 provides the estimates for asthma prevalence before and after the revisions of the nhis questionnaire. 83 figures 48-10 and 48-11 show data from the nhis with different estimates of prevalence of asthma over time for children and adults and by race or ethnic group. for children and adults, the 12-month and lifetime prevalence rates increased over time. current and attack prevalence rates have not shown a marked trend since the use of these outcomes began. prevalence rates also vary among racial and ethnic groups; this variation likely reflects differences in genetic, environmental, social, shows the changes in prevalence over time plotted on a logarithmic scale. most of the studies surveyed children, although a few looked at military conscripts in countries with compulsory military service. the very large variations in the absolute prevalence estimates reflect differences in the definitions used and the populations examined. from the late 1950s to the mid-1990s, the values rose uniformly at a rate that represented a doubling of prevalence approximately every 14 years, and this occurred regardless of the definition used and the starting prevalence. only in the mid-1990s did reports begin to suggest that this increase had slowed down. a much smaller number of studies have assessed changes in the prevalence of airway responsiveness ( fig. 48-8 ). during the 1980s, a small number of studies showed increases in prevalence over time. [74] [75] [76] [77] the study of dubois, which showed a yearly increase in prevalence among belgian conscripts over 14 years, is particularly persuasive given the difficulties of standardizing the tests. since the 1980s, most studies have shown a flattening of or a decline in prevalence, [76] [77] [78] although increases were seen in a study from ghana, 79 and a large increase was observed in year prevalence (%) asthma period prevalence current asthma prevalence asthma attack prevalence and cultural influences among population groups. 84 between 1980 and 1996, the prevalence of asthma had increased from 3.1% to 5.4% among whites and from 3.3% to 6.5% among blacks, representing cumulative increases of approximately 4% per annum. 85 between 2001 and 2009, rates of current asthma had increased from 7.2 % to 7.8% among whites, a cumulative increase of approximately 0.8% per annum, and from 8.4% to 11.9% among blacks, a further increase of approximately 4% per annum (see fig. 48 -11). 86 many of the studies that reported changes in the prevalence of asthma and wheeze also found increased reporting of other allergic diseases, most notably allergic rhinitis and eczema in children. as for asthma, almost all studies reporting before the mid-1990s found increases in other atopic conditions with time. since then, results have been more mixed, and the isaac has provided a more representative spread of data than is possible from individual studies. (fig. 48-12 ) 53 for the 6-to 7-yearold children, most sites showed an increase in prevalence of allergic rhinoconjunctivitis and eczema in the 5 years after the baseline surveys of isaac phase one. for the 13-to 14-year-old children, the changes were more evenly distributed between increases and decreases, and the size of the annual percentage change (positive and negative) appeared to be proportional to the initial value. a follow-up of the ecrhs sample approximately 9 years later estimated an incidence rate of rhinitis of 7.5 cases per thousand people per year. males had a greater risk in childhood and a lower risk in adulthood of incident rhinitis compared with females. atopic subjects had the highest incidence of rhinitis, at more than 22 cases per thousand people per year. 87 were compared for fathers (5.4%) and sons (15.4%) and for mothers (5.8%) and daughters (20%). later findings from a u.k. study suggested that the prevalence of hay fever had been stable in the latter half of the 2000s. 95 the worldwide prevalence of eczema among 6-to 7-year-old children has increased in most regions of the world and has remained stable only in western, northern, and eastern europe. for this younger age group, the prevalence found in the isaac phase three was 7.9%, an increase from the prevalence in phase one of 6.1%. the overall prevalence among 13-to 14-year-old children declined to 7.3% in the isaac phase three from 8.8% in the isaac phase one. the regions with the most striking increases in eczema prevalence were asia and latin america. two cross-sectional chinese studies from chongqing showed a statistically significant increase in food allergy prevalence, from 3.5% in 1999 to 7.7% in 2009, among young children between the ages of 0 and 24 months. 96 these studies also showed that sensitization to food allergens assessed by positive skin-prick test results had almost doubled, rising from 9.9% to 18% during the same 10-year period. other than these studies, there is little evidence on time trends using food challenge tests in general populations, although there is more circumstantial evidence for an increase over time. the prevalence of allergic rhinitis has increased over time in the united states. the 2004 nhis estimated a seasonal allergic rhinitis prevalence of 9%, 88, 89 an increase of 66% from the prevalence estimate of 5.4% based on the 1970 nhis. 90 the 2004 nhis estimated that about 25.3 million americans, 6.7 million of them younger than age 18 years, have allergic rhinitis. 88, 89 the survey also showed geographic variation in the prevalence of seasonal allergic rhinitis, with the highest estimated prevalence for the western united states (10.8%), followed by the northeast (9.5%), south (8.0%), and midwest (7.2%). studies in other countries have also documented an increase in the prevalence of allergic rhinitis over time. von mutius and colleagues 91 observed a significant increase in hay fever prevalence among schoolchildren from leipzig, germany. the hay fever prevalence rate in the 1991-1992 survey was 2.3%; in the 1995-1996 survey, the prevalence had increased to 5.1%. an italian retrospective study compared data on allergic rhinitis prevalence among italian recruits observed in 1983 and from 1993 to 1995. 92 the investigators found a significant increase in allergic rhinitis prevalence, from 1.5% in 1983 to 2.2% in the 1993-1995 period. results from surveys conducted in 1989 and 1997 of an adult danish population showed a significant increase of 61% in the prevalence of allergic rhinitis after adjustment by age and gender. 93 a scottish study observed a threefold increase in the age-adjusted prevalence rate of hay fever between 1972 and 76 and 1996 in middle-age adults. 94 the hay fever prevalence rates change per year (%) mean prevalence (%) eczema d some genotypes were specifically associated with childhoodonset asthma. 113 gender data from epidemiologic studies consistently reveal male gender to be a risk factor for asthma among young children, whereas studies of adolescents and adults show females to be at greater risk. a review of prospective studies showed that male children were at greater risk for incident asthma or wheeze, and studies of adolescents or adults showed females to be at greater risk. 114, 115 one hypothesis explaining the excess of asthma seen in boys during childhood is the different airway geometry in boys and girls. boys have smaller airways for a given lung size than girls. lower flow rates were found for boys 4 to 6 years of age, 116 and they have higher airway resistance compared with girls of the same age. 117 this difference in airway anatomy predisposes boys to more wheezing, and they have a higher incidence of lower respiratory tract infections. 118 , 119 martinez and coworkers 120 suggested that reduced lung function was a key determinant of wheezing in boys and girls. in the tucson study, lung function was measured within weeks of birth in 124 healthy infants. the subsequent incidence of wheezing illness over the first 6 years of life was increased in boys with high respiratory resistance and in girls with low functional residual capacity. one hypothesis for females being at higher risk of developing asthma or wheeze during adolescence or adulthood is the smaller relative airway caliber in women compared with men after puberty. 121 epidemiologic studies consistently show an association between atopy and asthma, although the strength of the association varies with the index used and the study population. part of the problem lies in the ambivalent nature of the term asthma.the symptoms of asthma in older adults also can indicate copd, and the differential diagnosis may be difficult even in a clinic. a distinction used to be made between asthma and other wheezy syndromes in children. however, the management is very similar, the distinction has fallen largely into disuse, and use of the term nonatopic asthma has become common for children, whereas it was prviously reserved for a condition associated with eosinophilic inflammation but negative skin test results that predominantly presented in middle age, often among women, and had a relatively poor prognosis. the idea that atopic and airway components of asthma are distinct 101, 109 has been confirmed by genetic studies thatidentified gene polymorphisms associated with asthma but not obviously related to the regulation of ige or associated immunologic responses. isaac found little variation in the prevalence of nonatopic asthma that could be explained by the local gross income, but prevalence of asthma associated with sensitization became less common in low-income settings. 41, 122 the distinction is important, because atopic asthma in children apears to have a less benign course than nonatopic disease. 123 burrows and colleagues 124 assessed this association in a random sample selected from tucson, arizona, using skin tests with local antigens as an index of atopic status. in children 3 to 14 years old, atopy was strongly associated with attacks of wheezing and dyspnea, regardless of whether asthma had been diagnosed. later analyses of the tucson population indicated that the total serum ige level was more strongly associated with the prevalence of asthma, 125 an association that was also found in an nhanes analysis (discussed later). another study using self-reported during the 14-year period from 1990 to 2004, hospital admissions for food allergy showed continuing increases of 5 to 26 cases per million people overall and 16 to 107 cases per million children, particularly in the 14-year-old age group. hospital admissions attributed to "dermatitis due to food" increased in england and wales from 5 cases per million people in 1990 to 26 cases per million people in 2004, an increase of almost 13% per annum. 97, 98 apart from true changes in the epidemiology of food allergy, alternative explanations for this dramatic increase in health care use for presumed food allergy include changes in the coding behavior of doctors, changes in the awareness and behavior of patients, and changes in the health care system. in the united states, the nhis recorded much smaller increases in parent-reported food allergy, 99 although such reports are usually regarded as unreliable. increasing reports of more specific complaints of peanut allergy have been made for children in the united states 56 and the united kingdom. 100 a genetic component of asthma has long been recognized, based initially on the observation that asthma tends to cluster in families. familial aggregation, twin, genetic linkage, and association studies subsequently provided evidence to support this hypothesis. detailed descriptions of the molecular genetics of asthma and atopic disease are provided in chapter 22. family aggregation studies compare disease occurrences between family members. disease aggregation between siblings and between parents and children supports a hereditary component, whereas increased aggregation between spouses suggests that environment is more important. however, aggregation among related individuals may represent shared genes or a common household environment. evidence of a hereditary component of asthma has been demonstrated in numerous family-based studies. [101] [102] [103] [104] population-based studies also have shown an increased prevalence of asthma among first-degree relatives of index cases. [105] [106] [107] [108] [109] twin studies compared disease frequency in monozygotic (mz) twins, who share 100% of their genes, with dizygotic (dz) twins, who share on average 50% of their genes. this is another method to determine the relative contribution of genetic and environmental factors. a greater occurrence of disease in mz than in dz twins is evidence for a genetic component to the disease because both types of twins are assumed to share environmental factors similarly. significantly higher concordance rates for mz twins have been observed in some small studies. 110 larger studies of twin registries also suggest a significant genetic contribution to asthma. in 6996 twin pairs from the swedish twin registry, edfors-lubs found the prevalence of asthma to be 3.8%. 111 the higher concordance of asthma in mz (19.8%) over dz (4.8%) pairs suggests that genetic factors contribute to asthma. similarly, duffy and associates observed a 30% concordance in mz twins and 12% in dz twins in a total of 2902 australian pairs. 112 whole-genome association studies have identified specific loci associated with clinical asthma. the genes associated with total ige levels were not strongly associated with asthma, and many related methodologic issues complicate the study of diet and disease. 134 obtaining unbiased exposure estimates is difficult because of recall problems, difficulties in measuring intake, and limited range of variation in the western diet. 135 diet is fundamental to existence and is closely associated with many lifestyle, social, cultural, and environmental factors that may influence the development of disease. although many studies adjust for potential confounders, it has been argued that this is insufficient and that many or all of the reported associations between diet and disease are likely to be confounded by social and behavioral factors acting across the life course. 136, 137 several reviews on the topic of diet and asthma and allergic disease are available. [138] [139] [140] [141] [142] [143] [144] observational and randomized studies have directly correlated dietary sodium levels with increased bronchial responsiveness to histamine challenge. [145] [146] [147] one study showed this response occurred in males but not in females. 146 ecologic data from england and wales support these experimental findings; the purchases of table salt correlated with the regions of increased asthma mortality for men and children. 131 other population-based studies, however, have not shown a relationship between urinary sodium levels and methacholine airway responsiveness, [148] [149] [150] although two did show an association with higher levels of potassium excretion. 148, 150 britton and associates 151 found that increased magnesium intake was associated with a reduced risk of bronchial hyperresponsiveness and wheeze. because of the relationships among sodium, potassium, and magnesium, these investigators suggest the possibility that low levels of dietary magnesium may confound the association of sodium and potassium with bronchial hyperresponsiveness or asthma. 151 a systematic review of the clinical trials of dietary sodium reduction in persons with asthma concluded that dietary sodium reduction does not significantly improve asthma control. 152 dietary sodium reduction was associated with some improvement in lung function in people with exercise-induced asthma, but because extremely large reductions in sodium intake were required, the clinical utility, as distinct from the potential public health relevance of this finding, is likely to be small. a systematic review of the studies correlating asthma and allergic disease in children with dietary intake or status of vitamin a, vitamin c, vitamin e, selenium, zinc, copper, iron, fruits, vegetables, and components of the mediterranean diet identified 62 eligible reports. 138 there were no randomized, controlled trials, and all studies were judged to be at moderate to substantial risk of bias. meta-analyses demonstrated that serum vitamin a was lower in children with asthma compared with controls (odds ratio [or] = 0.25; 95% confidence interval [ci], 0.10 to 0.40). the meta-analyses also showed that high maternal dietary vitamin e intake during pregnancy was protective against development of childhood wheezing (or = 0.68; 95% ci, 0.52 to 0.88) and that maternal adherence to a mediterranean diet during pregnancy was protective against persistent wheeze (or = 0.22; 95% ci, 0.08 to 0.58) and atopy (or = 0.55; 95% ci, 0.31 to 0.97) in children. seventeen of 22 fruit and vegetable studies reported beneficial associations with asthma and allergic outcomes. although weak, the available epidemiologic evidence supports dietary intake of vitamin a, vitamin d, vitamin e, zinc, fruits, vegetables, and a mediterranean diet for the prevention of asthma. 138 the fatty acid composition of the diet, particularly the relative amounts of n-3 (ω-3) and n-6 (ω-6) polyunsaturated fatty diagnosis of hay fever in a population sample from western pennsylvania showed atopy to be more common in asthmatic than nonasthmatic children. 126 two other studies demonstrated parental atopy and asthma as risk factors for asthma in their children. 127, 128 the results also demonstrated a complex interaction between these factors and the gender of the child. a study of 525 new zealand children assessed the relationship of total serum ige levels at the age 11 years and asthma, and investigators found that the prevalence of diagnosed asthma was strongly related to the serum ige level (p trend < .0001). 129, 130 asthma was not reported for children with ige levels of less than 32 iu/ ml, whereas 36% of children with ige levels of 1000 iu/ml or higher had asthma. asthma and atopy are closely linked, and the causal nature of the factors seems to be complex and require more investigation. nonetheless, atopy in parents and children does increase the risk of asthma and can be used as an empiric predictor. 131 diet diet, including breastfeeding, food intolerance and sensitivity, and intake levels of specific micronutrients, has been investigated as a potential risk factor for asthma for over 2 decades. in 1987, burney 132 was among the first to propose diet as a potential explanation for the rising frequency of asthma, suggesting the possibility that increasing salt intake might have a role. the rationale for investigating diet as a possible risk factor for asthma and allergic disease is that diet has changed in recent decades and biologically plausible mechanisms exist. many dietary constituents have been investigated for potential involvement in the pathogenesis of asthma and allergic disease, including antioxidants (e.g., vitamin e, vitamin c, carotenoids, flavonoids), polyunsaturated fatty acids, vitamin d, folate, 122, 133 foods (e.g., fruits, vegetables), metals or trace minerals (e.g., sodium, magnesium, selenium, zinc, copper), and components of the mediterranean diet ( increased ige levels, eosinophilia, methacholine responsiveness, asthma-related hospitalization, exacerbations, use of antiinflammatory medication, and use of oral corticosteroids and with reduced asthma control scores. 169 analogous findings have been reported for adults with asthma. 170 similarly, for children with atopic dermatitis, lower serum 25-oh-d concentrations have been associated with increased severity of atopic dermatitis. 171 longitudinal cohort studies quantifying vitamin d status before the development of disease are not subject to many of the limitations of cross-sectional studies, such as reverse causation, whereby the vitamin d status of an individual is influenced by the presence of disease (e.g., children with asthma may spend more time indoors). a systematic review and metaanalysis of the longitudinal studies relating maternal vitamin d status during pregnancy to childhood outcomes concluded that high maternal dietary vitamin d intake is associated with a reduced risk of children wheezing up to the age of 5 years (or = 0.56; 95% ci, 0.42 to 0.73). 138 however, maternal dietary vitamin d intake during pregnancy is not indicative of total body vitamin d status, because 90% of vitamin d is derived from cutaneous exposure to ultraviolet light. in contrast to maternal dietary vitamin d intake, high (>75 nmol/l) maternal serum 25-oh-d levels in late pregnancy have been associated with an increased likelihood of childhood eczema at age 9 months and asthma at age 9 years. 172 during infancy, increased vitamin d intake has been associated with an increased risk of atopic dermatitis at age 6 years and an increased likelihood of allergic rhinitis and atopic sensitization at the age of 31 years. 173, 174 in later childhood, an increased serum 25-oh-d concentration at 4 years of age has been associated with a reduced likelihood of asthma at 8 years of age, 175 and an increased serum 25-oh-d concentration at 6 years of age has been associated with a reduced likelihood of asthma, rhinoconjunctivitis, and atopic sensitization at 14 years of age. 176 the epidemiologic data support the hypotheses that vitamin d may have beneficial and adverse influences on the development of asthma and allergic disease. ongoing clinical trials are clarifying the potential clinical role of vitamin d in modifying the risk of developing asthma and as an adjunct to asthma and atopic dermatitis therapy. although breastfeeding of infants is recommended because of well-documented benefits for mother and child, the effects of breastfeeding on the subsequent development of atopic dermatitis, wheezing disease, and asthma are not clear. 177, 178 conceptually, the advantageous consequences of breastfeeding for the infant include acquisition of maternal antibodies and immune-competent cells such as macrophages and leukocytes and protection against early occurrence of lower respiratory tract infections. however, breastfeeding may also be a route of exposure to a variety of immunologically active substances from the mother, such as tobacco smoke, cow's milk, eggs, wheat, maternal ige, and sensitized lymphocytes. 135 many studies have investigated the association between breastfeeding, asthma, wheezing illness, and atopic disease, and they have been subject to several systematic reviews, most of which highlight the limitations and difficulties in conducting and interpreting such studies (e.g., confounding, recruitment bias, reporting bias, reverse causation, variation in breastfeeding patterns, inability to randomize and blind). the systematic reviews have themselves been reviewed in consensus documents, which conclude that the exclusive breastfeeding for 3 to 4 months of acids (pufas) found in fish and vegetable oils, respectively, 153 affects cell functioning. fatty acids appear to have specific roles in inflammatory and immune responses, and changes in fatty acid consumption are a postulated cause of the rising incidence of asthma and other allergic diseases. 154, 155 conflicting observational data relating n-3 and n-6 pufa intake or status during pregnancy, childhood, and adulthood to asthma and allergic disease have been surpassed by intervention trials. a 2008 systematic review with meta-analysis evaluated the interventional studies of n-3 and n-6 pufa supplementation in the context of primary prevention of asthma and allergic disease. 143 ten reports from six double-blind, randomized, controlled trials were identified. four studies compared n-3 pufa supplements with placebo, and two studies compared n-6 pufa supplements with placebo. the meta-analyses failed to identify any consistent or clear benefits associated with n-3 pufa supplementation during pregnancy or infancy for atopic dermatitis two subsequent trials reported the consequences of n-3 pufa supplementation during pregnancy. in the first, highdose n-3 pufa supplementation of 117 pregnant women from 25 weeks' gestation and during breastfeeding reduced the incidence of food allergy and ige-associated atopic dermatitis in children in the first year of life compared with placebo (2% versus 15% [p < .05] and 8% versus 24% [p < .05], respectively). 156 in the second, larger study of 368 pregnant women, high-dose n-3 pufa supplementation from 21 weeks' gestation until delivery did not reduce the incidence of ige-associated disease or atopic dermatitis during the first year of life compared with placebo (rr = 0.70 [95% ci, 0.45 to 1.09] and rr = 0.64 [95% ci, 0.40 to 1.02], respectively). 157 there is insufficient evidence to recommend pufa supplementation in any period of life as a means of reducing the burden of asthma and allergic disease. the role of vitamin d in the cause asthma and allergic disease remains unclear. the increase in asthma and allergic disease in developed countries has been attributed to early-life vitamin d supplementation as rickets prophylaxis, 158 and widespread vitamin d deficiency is thought to be a consequence of more time being spent indoors and the active promotion of sun avoidance. 159 cross-sectional, observational studies have reported vitamin d status to be no different 160 or increased in adults 161 with asthma but decreased in children with asthma. 162, 163 blood levels of 25-hydroxyvitamin d (25-oh-d) concentrations were found to be lower in adults with atopic dermatitis and allergic rhinitis. 164, 165 in two studies using nhanes data, blood levels of 25-oh-d have been no different in adults with evidence of atopic sensitization; however, atopic sensitization was associated with reduced blood 25-oh-d levels in children and adolescents in one study 166 but not in adolescents in the other. 167 the effect of blood 25-oh-d levels on current wheeze depended on age and atopic status in another study using nhanes data, with nonatopic individuals and adults 50 years of age or older having a greater risk of wheeze if they had lower 25-oh-d levels. 168 in children with asthma, lower blood levels of 25-oh-d have been associated with increased asthma severity, including have reported associations between the prevalence of asthma and obesity, it is not possible to exclude reverse causation, whereby asthma may contribute to obesity through inactivity and use of oral corticosteroids. the most relevant data come from prospective cohort studies that have assessed risk for incident asthma in relation to initial weight or bmi. beuther and sutherland systematically reviewed prospective studies evaluating the association between bmi and incident asthma among adults. 190 meta-analysis of the data from 333,102 subjects participating in the seven identified studies demonstrated that being overweight or obese (bmi ≥ 25) was associated with an increase in the rate of 1-year incident asthma (or = 1.51; 95% ci, 1.27 to 1.80), with evidence of a dose effect for being overweight (or = 1.38; 95% ci, 1.17 to 1.62) or obese (or = 1.92; 95% ci, 1.43 to 2.59). there was no difference between sexes. a systematic review of similar literature for children and adolescents concluded that obesity precedes and is associated with the persistence and intensity of asthma symptoms. 191 in observational designs, a potential methodologic concern is that nonspecific respiratory symptoms resulting from cardiorespiratory loading and deconditioning may be misclassified as asthma. careful studies of children and adults suggest that asthma is not inappropriately overdiagnosed in the obese. 192, 193 observational studies have also reported adverse associations for bmi, obesity and overweight, and atopic dermatitis and atopic sensitization in children and adults. [194] [195] [196] [197] a retrospective case-control study of children with a mean age of 7.0 years confirmed an association between obesity and atopic dermatitis and reported that early-life and prolonged obesity was associated with atopic dermatitis. atopic dermatitis was more prevalent among children who were obese before 2 years of age (or = 15.1; 95% ci, 1.51 to 151) and between 2 and 5 years of age (or = 2.58; 95% ci, 1.24 to 5.41). obesity after the age of 5 years was not associated with atopic dermatitis. children who were obese for 2.5 to 5.0 years (or = 2.64; 95% ci, 1.13 to 6.18) and for more than 5 years (or = 3.40; 95% ci, 1.34 to 8.63) were more likely to be diagnosed with atopic dermatitis. 197 infants at high risk for atopic disease reduces the likelihood of atopic dermatitis and that breastfeeding beyond 3 to 4 months appears to confer no additional benefit. 179, 180 the available evidence also suggests that the breastfeeding of infants at low risk for atopic disease does not reduce the incidence of atopic dermatitis. the evidence for a protective effect of breastfeeding against respiratory disease is controversial. although breastfeeding appears to reduce the incidence of virus-associated wheezing episodes in young children (<4 years), the evidence of an effect on breastfeeding on the development of asthma is inconsistent. systematic reviews suggest that exclusive breastfeeding for 3 to 4 months is associated with a reduced risk of asthma in children 2 to 5 years old, but this beneficial effect is limited to infants at high risk for atopic disease. some systematic reviews have revisited the literature relating breastfeeding to childhood atopic dermatitis, asthma, and wheezing. a systematic review examining the association between exclusive breastfeeding for 3months or longer and the development of childhood atopic dermatitis identified 21 reports from 27 study populations and concluded that there was no strong evidence that exclusive breastfeeding confers a beneficial effect on the development of childhood atopic dermatitis (summary or = 0.89; 95% ci, 0.76 to 1.04), even in children at high familial risk (or = 0.78; 95% ci, 0.58 to 1.05). 181 another systematic review clarified the association between breastfeeding and childhood asthma and wheezing after 5 years of age. 182 it examined 31 publications and concluded that breastfeeding for 3months or longer did not confer any beneficial effect on the incidence of asthma and wheezing illness after the age of 5 years. the summary odds ratio for any breastfeeding and wheezing was 0.97 (95% ci, 0.90 to 1.04), and for exclusive breastfeeding and wheezing, it was 0.96 (95% ci, 0.86 to 1.06). the prevalence of obesity increased dramatically in many countries, particularly western and other developed countries in the latter decades of the twentieth century. in the united states, for example, the prevalence of overweight and obesity among adults rose sharply across the 1990s, such that most adults are now overweight. 183 the prevalence of childhood overweight is also rising rapidly. 183 the rise in obesity parallels the rise of asthma, and a hypothesis has been advanced that obesity could be a risk factor for asthma. 184 several mechanisms have been postulated for the association, including the mechanical effects of obesity, a higher frequency of gastric esophageal reflux, upregulation of immunologic and inflammatory correlates of obesity, and a shared genetic basis for both conditions. 185, 186 the association of obesity with asthma has been investigated in children and adults. camargo and colleagues offered one of the first reports in their 1999 paper based on the nurses' health study ii. 187 the body mass index (bmi) in 1991 was positively and strongly associated with asthma risk over the next few years (fig. 48-13) . 188 similar studies have addressed obesity and asthma in children. in a cross-sectional study using nhanes iii data, von mutius and colleagues 188 found a positive association between bmi and asthma risk (or = 1.77; 95% ci, 1.44 to 2.19) by comparing the highest and lowest quartiles of bmi. in the tucson study, girls becoming overweight or obese between the ages of 6 and 11 years had a sevenfold increased risk for asthma. 189 although many cross-sectional observational studies ≥30.0 at 7 years. because most children are not hospitalized for lower respiratory tract disease, these results apply only to the more severe infections. a population-based study of children in east boston, massachusetts, however, found that a history of bronchiolitis or croup was a predictor of increased airway responsiveness. 209 in another boston area study, children from a birth cohort with lower respiratory tract infection (i.e., croup, bronchitis, bronchiolitis, or pneumonia) in the first year of life were twice as likely to report two or more episodes of wheeze than children with no lower respiratory tract infection. 210 the tucson children's respiratory study provides relevant data on follow-up from birth to age 13 years. 158, 211 results from this longitudinal study show that rsv infection was associated with an increased risk of infrequent and frequent wheeze by age 6 years. 211 the relative risk for wheeze after 3 years of age for children with rsv infection compared with children with no rsv infection decreased over time. the relative risk decreased with age from 3.2 and 4.3 at age 6 years to no risk at age 13 years for infrequent wheeze and frequent wheeze, respectively. 198 support for the idea that severe rsv-associated respiratory disease probably does not contribute to the development of asthma has been provided by a large (8280 pairs) danish twin registry study that applied genetic variance and direction of causation models to data on rsv-associated hospitalization and the development of asthma. 212 a model in which asthma caused rsv-related hospitalization fit the data significantly better than a model in which rsv-related hospitalization caused asthma, suggesting that rsv infection does not cause asthma but reflects an underlying predisposition to asthma. the role of viruses in the natural history of asthma has been highlighted by several longitudinal cohort studies. the wisconsin childhood origins of asthma (coast) study prospectively evaluated the timing, frequency, severity, and cause of symptomatic viral infection in the first 3 years of life in relation to later wheezing illness in a cohort of 289 neonates at high familial risk for asthma. 213 by using molecular technologies to identify viral infections in nasal lavage samples collected routinely and when symptomatic, this study highlighted the prognostic importance of hrv. having one or more hrvassociated wheezing episodes during the first 3 years of life was more strongly associated with wheezing in the third year (or = 10.0; 95% ci, 4.7 to 23.0) than having one or more rsv-associated wheezing episodes during the first 3 years of life (or = 3.0; 95% ci, 1.6 to 5.8). first-year wheezing associated with hrv was the strongest predictor for third-year wheeze (or = 6.6). 213 the pattern of viral respiratory tract infection in the first 3 years was different for children with or without asthma at the age of 6 years (fig. 48-14) . 214 asthma at 6 years of age was strongly associated with hrv-associated wheeze in the first 3 years of life (or = 9.8; 95% ci, 4.3 to 22.0). the frequency of hrv-induced wheezing episodes increased in the first 3 years of life for children diagnosed with asthma by age 6, whereas for children without asthma, hrv-associated wheezing episodes declined in the first 3 years (see fig. 48-14) . almost 90% of children with hrv-associated wheezing episodes in year 3 had been diagnosed with asthma by the age of 6 years, and hrv-associated wheeze was a more robust predictor for subsequent asthma than atopic sensitization to aeroallergens. asthma at 6 years of age was also associated with rsv-associated wheezing episodes in the first 3 years (or = 2.6; 95% ci, 1.0 to 6.3). the likelihood of asthma by age 6 years being associated with rsv-induced wheeze in the first 2 years of life was increased these findings are provocative and indicate another potential risk factor for asthma and allergic disease, one that is increasingly prevalent and amenable to intervention. a better understanding of the mechanisms and potential role of intervention in the primary and secondary prevention of disease is needed. respiratory infections are common in the first years of life, and they provoke wheezing in children with or without asthma. less certain is whether viral or other respiratory infections have a direct role in the pathogenesis of asthma or they merely reveal that a child is predisposed to asthma. investigation of the association of viral infection and asthma has been limited by available technology, with culture, serology, and antigen detection having 30% to 50% detection rates. the newer molecular technologies have improved the rates of viral detection up to about 90% and have revealed the importance of previously unknown viruses, such as human rhinovirus c (hrv-c). lower respiratory tract infections in children, which are caused by hrvs, respiratory syncytial virus (rsv), parainfluenza viruses, and other pathogens, are universal in childhood. a community-based study in tecumseh, michigan, estimated that children experience, on average, 2.1 lower respiratory tract infections in the first year of life and 1.5 such infections between 1 and 2 years of age. 119 another cohort study of respiratory illnesses from birth through 18 months in albuquerque, new mexico, adapted a surveillance system similar to the one used in tecumseh and found comparable incidence rates from 1988 through 1992. 198 the incidence of severe episodes of viral respiratory infections was captured in another study using surveillance through a pediatric group practice. 118 this study showed that 25% of children were affected in the first year of life, that 12% had annual occurrences by age 5 years, and that 8% of children 6 to 8 years old experienced annual episodes of infection. follow-up studies of children with a history of hospitalization for respiratory infections suggest that these illnesses may predispose to the development of asthma. in several studies, children with past hospitalizations tended to have abnormal lung function that was indicative of airflow obstruction, including hyperinflation, increased respiratory resistance, and reduced spirometric flow rates. [199] [200] [201] [202] [203] [204] [205] [206] in children with past hospitalizations, increased airway reactivity occurred after assessment by exercise, cold air inhalation, methacholine, or histamine inhalation challenge. [201] [202] [203] infants hospitalized with rsv-associated bronchiolitis are more likely to wheeze and develop asthma later in childhood. a study of swedish children found that those who were hospitalized with rsv bronchiolitis in infancy were almost nine times more likely to have physician-diagnosed asthma at age 13 years than those without infection. 207 being hospitalized with rsv bronchiolitis in infancy was an independent risk factor for current asthma and recurring wheezing (or = 9.3; 95% ci, 3.6 to 24.5). henderson and colleagues 208 described the relationship of hospitalization for rsv bronchiolitis in infancy and asthma in a population-based birth cohort study of more than 8000 children from the united kingdom. hospitalization for rsv bronchiolitis was associated with physician-diagnosed asthma at age 7 years (or = 2.5; 95% ci, 1.4 to 4.3) only among nonatopic children. no association was observed for children with atopy type 16 (hrv-16) replicates more readily in the airway epithelial cells of people with asthma, and the airway epithelial cells are more likely to lyse and have greatly impaired interferon-λ (ifn-λ) and ifn-β responses. van der zalm and coworkers reported that increased neonatal airway resistance was related to an increased likelihood of hrv-associated wheeze in the first year of life (or = 1.77; 95% ci, 1.16 to 2.69). 218 hrv was originally classified as serotypes hrv-a and hrv-b, but in 2007, a novel hrv designated hrv-c was identified using reverse transcription-polymerase chain reaction (rt-pcr). 219 hrv-c has been implicated in the natural history of wheezing disease and asthma, and it appears to have prognostic importance. in a prospective, population-based study of 1052 children younger than 5 years of age who were hospitalized in two u.s. counties with acute respiratory illness or fever, hrv was detected in 16%, and hrv-c was isolated slightly more than 50% of them. children from whom hrv-c was isolated were significantly more likely than those with hrv-a or hrv-b to have underlying high-risk conditions such as asthma (or = 2.32; 95% ci, 1.05 to 5.23). 220 in australia, hrv serotypes were isolated from 88% of 128 children 2 to 16 years old who presented to the hospital with acute asthma. hrv-c was isolated from 59% of the children, and these children had higher asthma severity scores than those infected with hrv-a or hrv-b. 221 in a study of children hospitalized in hong kong, hrvs were isolated from 85% of 128 children admitted because of acute asthma and from 33% of 192 control, nonatopic children hospitalized with nonasthma respiratory conditions. 222 hrv-c was isolated from 70% of the children with acute asthma and 19% of the controls, and children with hrv-c were more likely to require supplemental oxygen. these studies implicate hrv-c in most episodes of acute asthma requiring hospital attention. hrv-c appears to be more virulent than other hrv serotypes, particularly in children with atopic sensitization. 223 although the major focus has been on viral respiratory tract infection, asymptomatic early-life bacterial airway colonization has also been associated with childhood wheeze and asthma. 224 in the copenhagen prospective study of asthma in childhood, 321 neonates at high familial risk for asthma had their hypopharyngeal regions sampled at 1 month of age, and the children were then followed up to 5 years of age. neonatal colonization of the hypopharyngeal region by streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis (but not staphylococcus aureus) in isolation or in combination was associated with increased likelihood of subsequent wheeze, hospitalization with wheeze, and asthma. hypopharyngeal colonization at 1 year of age was not associated with neonatal colonization or the development of wheeze or asthma. although has been postulated that early-life bacterial colonization induced neutrophilic airway inflammation with consequent wheeze and asthma, it also has been suggested that neonatal airway colonization by these bacteria reflects defective early-life innate immune responses that predispose to asthma. 225 asthma-like symptoms, especially in young children, often are treated with antibiotics, and an association has been observed between the use of these drugs and the risk of asthma. the simultaneously increased use of antibiotics in children and the increasing prevalence of asthma in developed countries has led to the hypothesis (consistent with the hygiene hypothesis) that antibiotic use may contribute to asthma by altering the normal colonization of gut flora in infants and increasing the only for children who had also had hrv-associated wheezing episodes. measurement of lung function in the coast cohort at age 8 years demonstrated that hrv-associated wheezing episodes in the first 3 years of life were associated with reduced lung function: fev 1 of 96% of predicted for those with hrvassociated wheeze versus 102% for no hrv-associated wheeze (p < .03). similar differences were found for absolute fev 1 , forced expiratory volume in 0.5 second (fev 0.5 ), and forced expiratory flow determined over the middle 50% of a patient's expired volume (fef ). 215 lung function at age 8 was not associated with the frequency of hrv-associated wheeze nor with rsv-associated wheeze. although studies such as coast demonstrate that hrv respiratory infection is prognostically more important than rsv infection for subsequent asthma, whether virus-associated wheezing episodes (particularly hrv) contribute to the pathogenesis of asthma or are merely manifestations of infection in children predisposed to asthma remains an unanswered question. there is evidence supporting the concept that children predisposed to asthma have lung function and airway epithelial abnormalities from very early in life that increase the likelihood of virus-associated wheezing episodes. [216] [217] [218] human rhinovirus cross-sectional studies. in one of the earliest reports, northway and coworkers 234 considered the first possibility-that asthma is a long-term consequence of bronchopulmonary dysplasia (bpd). bpd is a syndrome of chronic lung disease in premature infants who are mechanically ventilated for at least 1 week as a treatment for rds. the clinical diagnosis requires the symptoms of persistent respiratory distress during infancy, dependence on supplemental oxygen, and abnormal chest radiographs. northway and colleagues 235 then studied adolescents and young adults born between 1964 and 1973 who had bpd in infancy and compared their long-term pulmonary outcomes with those of two control groups. they found that most subjects with a history of bpd in infancy had pulmonary dysfunction. moreover, the increase in airway reactivity was not associated with a more frequent family history of asthma in this sample or with an increased prevalence of atopy. these findings suggest that lung injury resulting from mechanical ventilation of premature infants has a role in the pathogenesis of persistent pulmonary dysfunction that is similar to asthma. bertrand and associates 236 investigated the role of rds in prematurity in the pathogenesis of airway hyperresponsiveness (ahr) in subjects who did not have bpd as infants. the group with a history of rds had evidence of more hyperinflation and airway obstruction compared with controls. however, results from the histamine challenge to determine ahr and familial aggregation of ahr were inconclusive. the incidence of airway reactivity was elevated among cases and controls and among the mothers and siblings of cases and controls. the investigators suggest that the elevated incidence of ahr among mothers of both groups supports the hypothesis that there may be an association between the onset of premature labor and airway reactivity. because no comparison group was established for mothers of term children, however, this assertion cannot be affirmed from the study. some researchers have investigated the effect of very low birth weight (vlbw < 1501 g) and bpd on asthma development in birth cohorts. [235] [236] [237] [238] [239] [240] [241] children with vlbw were followed for 8 years as part of the newborn lung project conducted in wisconsin and iowa. 237, 238 results at age 5 years did not show a consistent association between asthma and bpd. 237 children with diagnosed bpd and children with radiographically identified bpd had about a threefold and twofold increase, respectively, in the risk of bronchodilator use up to age 2 years, adjusted for birth weight, gestational age, gender, race, and neonatal center. among children with bpd, the prevalence of ever having asthma at age 8 years did not show a difference by the period of birth. 238 however, the prevalence of wheezing in the last year at 8 years of age decreased from 50% to 16% over time. as the researchers observed, this finding could have resulted from the introduction of surfactant therapy as a bpd treatment. prematurity as a risk factor for asthma has been explored in cross-sectional studies. [242] [243] [244] [245] [246] [247] a significant association between current asthma prevalence and premature girls was observed in a study of 5000 schoolchildren. 243 significantly more premature children had a family history of asthma than did term children, and this association was stronger among children who required mechanical ventilation as premature infants. another german study of schoolchildren did not show an association between former or current asthma and low birth weight (lbw < 2500 g) among premature children. 244 however, bronchial hyperresponsiveness was significantly increased in children born at atopic, helper t cell type 2 (th2) immune responses. 226, 227 in support of this hypothesis, humans exposed to stable and farm environments, which are rich in microbes, show significantly reduced levels of asthma and atopic disease compared with those in other rural or nonrural environments. 227 other studies have shown that the different proportion of aerobic and anaerobic gut flora in children from sweden compared with estonia parallels the difference in atopy incidence between these populations. 227, 228 animal studies also support the hypothesis. mice given oral antibiotics had altered intestinal flora and impaired helper t cell type 1 (th1) immune responses. 229 epidemiologic studies of asthma and allergic disease in relation to antibiotic use are beset by biases, including reverse causality (i.e., asthma leads to more common prescription of antibiotics) 230 and confounding by indication (i.e. respiratory infections leading to antibiotic use may be implicated in the development of asthma). to illustrate this problem, in a carefully conducted tucson birth cohort study, information on illness, antibiotic use, and physician visits was ascertained on seven occasions in the first 9 months of life and correlated with the development of asthma and allergic disease up to the age of 5 years. 231 a significant association between the number of early-life courses of antibiotics and asthma was reported. the number of physician visits was associated with the number of antibiotic courses and with asthma. however, after adjustment for the number of physician visits, antibiotic use was not associated with asthma, and it was concluded that any association between early-life antibiotic use and asthma was an artifact of the number of physician visits for illness, which was strongly associated with antibiotic use and risk of asthma. two systematic reviews have provided insight into the possible causative association between early-life antibiotic use and asthma and allergic disease. a systematic review of studies that have related antibiotic exposure during pregnancy or in the first year of life with risk of childhood asthma identified relevant 22 studies. 232 antibiotic use in the first year of life was associated with an increased likelihood of childhood asthma (or = 1.52; 95% ci, 1.30 to 1.77). stratified analysis indicated that retrospective studies reported the strongest associations (or = 2.04; 95% ci, 1.83 to 2.27) compared with database and prospective studies (or = 1.25; 95% ci, 1.08 to 1.45) . studies that addressed potential biases by adjusting for respiratory infections reported the weakest associations (or = 1.16; 95% ci, 1.08 to 1.25). a second systematic review focusing on longitudinal studies identified 18 studies, and a meta-analysis indicated that antibiotic use was associated with subsequent wheeze or asthma (or = 1.27; 95% ci, 1.12 to 1.43). 233 however, after eliminating nine studies with a high risk of bias, the magnitude of the association was reduced (or = 1.12; 95% ci, 0.98 to 1.26). both systematic reviews concluded that there might be a weak link between antibiotic use and subsequent asthma and that biases had exaggerated the strength of any association that might exist. premature birth has been associated with the development of symptoms consistent with asthma and other long-term pulmonary sequelae in a number of studies. the cause of the sequelae is uncertain. the pulmonary injury may be acquired during mechanical ventilation of preterm infants with respiratory distress syndrome (rds), from the rds itself, or from some other facet of prematurity. prematurity has been examined as a risk factor for asthma in cohort studies of affected children and in plants (e.g., grain dust, flour, latex, castor bean, green coffee bean), enzymes (e.g., subtilisin from bacillus subtilis, papain, fungal amylase), wood dust or barks (e.g., western red cedar, oak, reactive dyes), drugs (e.g., penicillin, methyldopa), metals (e.g., halogenated platinum salts, cobalt), and others such as oil mists. they have been classified according to possible pathogenetic mechanisms: high-molecular-weight agents that induce specific ige antibodies; low-molecular-weight substances, such as isocyanates, for which underlying mechanisms are largely unknown; and irritant gases, fumes, and chemicals that induce occupational asthma by nonimmunologic mechanisms. 255 more extensive coverage of these agents and the topic is available elsewhere. 256, 257 other causes of occupational asthma have been identified through clinical reports, epidemiologic investigations, and population studies. jaakkola and colleagues 258 conducted a casecontrol study in finland. risk for asthma was found to be increased for several occupational groups, including some for which occupational asthma had not been previously reported, such as being a male or female waiter. le moual and coworkers 259 explored associations for occupation and occupational exposures with asthma in 14,000 participants in a french survey conducted in 1975. several jobs were associated with an increased risk of asthma of about 50%. a similar analysis was reported for the united states based on the nhanes iii. 260 several studies provide estimates of the overall importance of occupational asthma. kogevinas and colleagues 261 analyzed data from more than 15,000 young adults participating in the ecrhs. an estimated 6.9% of asthma was attributed to occupation, with asthma defined by asthma symptoms or use of medication and assessed by questionnaire. when asthma was defined by questionnaire responses and bronchial hyperresponsiveness, the attributable risk estimated for occupation increased to 9.9%. among members of a u.s. health maintenance organization, one third of persons identified as having new or recurrent asthma were classified as having a potential association with work as the basis for asthma. 262 blanc and toren 263 conducted a meta-analysis of studies on occupational asthma from 1966 to mid-1999. the median attributable risk estimate for occupational asthma was 9% for all studies identified. when the study quality was taken into account and analyses were limited to those of higher quality, the estimate was 15%. these estimates included new-onset asthma and reactivation of preexisting asthma. outdoor air pollutants can be classified by origin as natural or manmade. among the naturally occurring air pollutants are particulate matter (including bioaerosols), volatile organic compounds, and ozone. for asthma, the key manmade pollutants result from combustion of fossil fuels in cars, power plants, heating devices, and industrial point sources and from emissions of chemicals from manufacturing facilities, storage tanks, and accidental releases. in the united states, air pollutants have been categorized on the basis of their regulation under the clean air act as criteria pollutants (e.g., lead, nitrogen dioxide [no 2 ], sulfur dioxide [so 2 ], particulate matter [pm], ozone [o 3 ], carbon monoxide [co]) and as air toxics, a specified listing of 189 chemicals that includes some irritants relevant to asthma. 264 these pollutants are a concern throughout the world's polluted cities and regions. many cities and smaller towns and term with lbw compared with children born with normal birth weight, with values adjusted for height, gender, and age. a study conducted as part of the ecrhs examined birth characteristics and asthma symptoms in young adults from norway. 245 the researchers observed a significant decrease in asthma symptoms per 500-g increase in birth weight, adjusted for gestational age, length at birth, parity, maternal age, gender, adult height, hay fever, and current smoking habits. race and socioeconomic status may be determinants of prematurity and asthma. to test the hypothesis that prematurity was a risk factor for asthma independent of race or socioeconomic status, oliveti and colleagues 248 performed a case-control study using a population restricted to african-american children from impoverished inner-city census tracts in cleveland, ohio. their findings confirmed previous findings with regard to prematurity and lbw. asthmatic children had significantly lower birth weights and gestational ages than nonasthmatic children and were more likely to have required positive-pressure ventilation (ppv) after birth. the risk of asthma was increased more than three times for children receiving ppv after birth. however, the increased risk of asthma due to lbw and prematurity was not significant when maternal history of asthma, bronchiolitis, lack of prenatal care, low maternal weight gain, and ppv were considered simultaneously. 248 this suggests that lung injury and perhaps mechanical ventilation lead to an asthma-like syndrome, rather than lbw and prematurity directly. researchers have examined the lung function of preterm children over time. koumbourlis and associates 249 followed 17 preterm children with chronic lung disease, including bpd, from 8 to 15 years of age. the investigators observed improvements in the lung volumes of these patients throughout childhood and into adolescence, and these improvements were experienced by all children, regardless of the severity of the neonatal chronic lung disease. if patients had airway obstruction, it was primarily localized to the smaller airways, associated with ahr, and relatively fixed over time. two systematic reviews have investigated the association between prematurity and childhood asthma and wheezing outcomes. patelarou and colleagues identified nine studies that had reported on the association between adverse birth outcomes (e.g., premature, lbw, vlbw, fetal growth retardation) and early (0 to 2 years) childhood wheeze. 250 they concluded that adverse birth outcomes were associated with wheezing in early life. similarly, a systematic review that identified 19 studies reported that preterm (<37 weeks' gestation) was associated with an increased likelihood of childhood asthma (or = 1.074; 95% ci, 1.072 to 1.075). 251 these results suggest that premature infants with or without neonatal respiratory disease may be at higher risk for asthma or a syndrome similar to asthma than term infants. however, the mechanistic pathways involved and the potential interactions with other asthma risk factors, such as viral respiratory infections and susceptibility genes, remain uncertain. occupational asthma is defined as variable airflow limitation or bronchial hyperresponsiveness due to exposure to a specific agent or conditions in a particular occupational setting but not to stimuli encountered outside the workplace. 252 several hundred agents have been identified as causes of occupational asthma. 253, 254 they include animal allergens (e.g., urine, dander), for children from east germany, where pollution originated from burning brown coal and industrial emissions. 290 however, living in west germany was not an independent risk factor for asthma after adjustment for sensitivity to pollen, hdms, and cat allergens. another german study conducted from 1995 through 1996 obtained similar results. 289 current asthma prevalence for children from munich was 5.1%, compared with the prevalence for their counterparts from dresden of 4.0%. significant differences in physician-diagnosed asthma prevalence were observed by comparing children in munich (10.3%) and those in dresden, former east germany (5.8%). 289 a study enrolling children 8 to 12 years of age who were living in hong kong compared physician-diagnosed asthma prevalence in a high-pollution district and a low-pollution district. 291 the researchers found that asthma prevalence was almost doubled in the high-pollution area compared with the low-pollution area. some studies have investigated the possible role of specific air pollutants in the development of asthma. in a cross-sectional study that was conducted as part of the isaac phase two and enrolled the same german children from dresden, an increase in estimated traffic-related exposure to benzene was associated with an increased prevalence in physician-diagnosed asthma after adjusting for potential confounders. 292 however, this association reached statistical significance only when the home and school addresses used as the exposure indicators were combined. the prevalence of asthma was not associated with concentrations of so 2 , no 2 , and co. an increase in the exposure to air pollutants (except ozone) was associated with an increased prevalence of physician-diagnosed asthma in 5421 nonatopic children (5 to 7 years and 9 to 11 years old). this relationship was not observed in atopic children. another cross-sectional study evaluating the effects of general air pollution was conducted among 165,173 high school students in taiwan as part of the isaac. 293 the researchers investigated the role of long-term exposure (i.e., annual average concentration) to air pollution and the prevalence of asthma. long-term exposure to total suspended particles, no 2 , co, ozone, and airborne dust was associated with increased prevalence of asthma after adjusting for exercise, smoking, alcohol consumption, incense use, and environmental tobacco exposure. a similar study of 331,686 middle school students living in 24 counties and cities in taiwan found a positive association between physician-diagnosed asthma prevalence and exposure to co and nitrogen oxides (no x ) when adjusted for age, history of atopic eczema, and parental education. 294 baldi and coworkers 295 reanalyzed data from a survey of 3193 children and 20,310 adults from seven french towns between 1974 and 1976. they estimated a significant increase (or = 1.24; 95% ci, 1.08 to 1.44) in asthma prevalence per 50 µg/m 3 in the so 2 3-year-period annual mean after adjusting for age, education, and smoking status. the association remained significant when they restricted the analysis to adults reporting their first attack after moving to the study areas. they did not observe this relationship for children. these cross-sectional studies address the prevalence of asthma, which reflects the incidence and duration of the disease. if air pollution increases the duration of asthma, the prevalence would be increased, even without an effect on incidence. the clearest evidence of a causal association between outdoor air pollution and childhood asthma comes from cohort studies. villages in the developing world have the problem of smoke from biomass fuel use for indoor cooking and heating that is emitted outdoors. 265 although it is accepted that exposure to outdoor air pollution can exacerbate existing asthma, 266-269 the role of outdoor air pollution in the development of childhood asthma is less well established. however, there is increasing evidence, especially from studies with a focus on exposure related to traffic within urban areas, that implicates outdoor air pollution in the development of childhood asthma [270] [271] [272] and lung function. 273 the outbreaks of acute asthma in barcelona illustrate the consequences of exposure to an airborne contaminant and the need to investigate asthma epidemics. during the 1980s, a remarkable series of epidemics of asthma occurred in barcelona, a port city. careful analysis of one outbreak showed spatial clustering near the harbor, and an epidemiologic investigation showed a very strong association between unloading of soybeans at the harbor and occurrence of the epidemics. 274 an antigen was identified in the soybeans that proved to be responsible for the outbreaks. 275 the outbreaks were traced to releases of dust at a particular silo, and control measures were enacted. 276 subsequently, a review of the historical record showed that there had been similar outbreaks of soybean asthma in new orleans. 277 a large body of experimental and observational evidence links outdoor air pollution to exacerbation of asthma. [266] [267] [268] [269] [278] [279] [280] [281] [282] [283] compilations of the evidence can be found in the criteria documents prepared by the u.s. environmental protection agency (epa) for particulate matter and ozone. 282, 283 human experimental studies have provided some insights, showing for example, that the oxidant pollutants nitrogen dioxide and ozone may enhance the effects of allergens, possibly by increasing the permeability of airways. 284, 285 epidemiologic data, primarily coming from studies of panels of persons with asthma or of medical morbidity, have shown that the adverse effects of air pollution on asthma are relevant clinically and are significant from a public health perspective. there is uncertainty about the relative effects of specific pollutants compared with the overall toxicity of the air pollution mixture. 286 gent and colleagues investigated the effect of exposure to ozone and particulate matter of 2.5 µm in diameter (pm 2.5 ) in a u.s. cohort study of 271 asthmatic children. 287 among children using maintenance medication, the level of ozone, but not pm 2.5 , was significantly associated with worsening of respiratory symptoms and an increase in rescue medication use. significant associations were not found for children not using maintenance medication. these findings suggest that children with asthma using maintenance medication are especially vulnerable to ozone, even after adjusting for exposure to pm 2.5 and at air pollution levels below the epa air quality standards. various lines of epidemiologic evidence continue to indicate a potential role of air pollution in the cause of asthma. crosssectional studies have investigated asthma prevalence and air pollution. after the unification of east and west germany, studies were conducted to compare respiratory diseases among children who had a relatively homogenous genetic background but had experienced exposures to air pollution at very different concentrations. [288] [289] [290] [291] in a study conducted between 1989 and 1992, children 9 to 11 years old from munich (west) had a higher prevalence of physician-diagnosed asthma than those from leipzig and halle (east). 288 current asthma prevalence among children living in west germany, an area with a greater amount of heavy road traffic, was 5.9%, compared with 3.9% also raised. the disparity between cross-sectional and prospective studies suggests that although the incidence of asthma among those living close to traffic is increased, it is not evident at a population level because of the small effect size and the lack of variation in the distance between home and traffic. cohort studies published since the comeap are consistent with its findings, but they also highlight a possible early-life effect and the importance of exposure while at school. the dutch prevention and incidence of asthma and mite allergy (piama) birth cohort study related symptom data prospectively collected annually from 3863 children up to the age of 8 years to land-use regression estimates of individual no 2 , pm 2.5 , and soot exposures at their birth addresses. 271 pm 2.5 was associated with an increased annual incidence of asthma (or 1.28; 95% ci, 1.10 to 1.49), prevalence of asthma (or = 1.26; 95% ci, 1.04 to 1.51), and asthma symptoms (or = 1.15; 95% ci, 1.02 to 1.28). the associations between outcomes and no 2 and soot exposures were similar, but there was a high correlation (r > 0.9) for pm 2.5 , no 2 , and soot exposures. only 48% of the cohort were still living at the birth address at age 8 years, and the associations between pollutants and outcomes were evident only in those who had not moved house; for the children who had moved from the birth addresses, the only significant association was between pm 2.5 and the prevalence of wheezing symptoms (or = 1.15; 95% ci, 1.00 to 1.32). the southern californian health study evaluated 2497 symptom-free children recruited in kindergarten or the first grade (≤6 years old) from 13 communities, each with continuous ambient ozone, no 2 , pm 2.5 , and pm 10 measurement. 272 the incidence of asthma in the subsequent 3 years was determined by annual questionnaires and correlated with individualized estimates of traffic-related pollution at home and at school. the incidence of asthma was increased by nonfreeway traffic-related pollution at home (hazard ratio [hr] = 1.51; 95% ci, 1.25 to 1.81) and at school (hr = 1.45; 95% ci, 1.06 to 1.98) . although the balance of evidence suggests an association between outdoor air pollution and the development of asthma in some individuals who live near busy roads, there does not appear to be an association between air pollution and the development of asthma at the population level. moreover, the welldocumented increase in asthma prevalence in the latter decades of the twentieth century cannot be readily explained by changes in levels of the major combustion pollutants. the emerging association between traffic-related emissions and asthma requires further investigation. in the home and other indoor environments, children and adults inhale diverse pollutants that may be associated with the risk for asthma. 279, 301 they include combustion-source emissions from cooking stoves and ovens, space heaters fueled by gas or kerosene, wood-burning stoves or fireplaces, and tobacco smoking; volatile and semivolatile organic compounds released from household products, furnishings, and other sources; and allergens from insects, molds, mites, rodents, and pets. 279, 301 many of these pollutants can be present in higher concentrations indoors than outdoors, providing a rationale for studies that have examined indoor pollutants as factors that may cause or exacerbate asthma. for example, in a prospective cohort study of inner-city u.s. children with asthma, indoor no 2 302 and pm 303 were associated with asthma symptoms. the associations were independent of each other and of outdoor the traffic-related air pollution and childhood asthma (trapca) study is a birth cohort study of children from the netherlands, germany, and sweden that is funded by the european union. 296 preliminary results from the 1756 german children followed for their first 2 years of life showed a 23% (95% ci, 1.00 to 1.51) increase in the risk of asthmatic, spastic, or obstructive bronchitis for those living close to major roads (<50 m) compared with children farther away. a cohort study of almost 5000 children between the ages of 5 and 7 years, who lived in nine communities surveyed in the california children's health study and four other communities, was started in 2003 to evaluate characteristics that might increase children's susceptibilities to the effects of traffic-related pollution. 297 preliminary results showed that living within 75 m of a major road was associated with an increased risk of physician-diagnosed asthma (or 1.29; 95% ci, 1.01 to 1.86), prevalent asthma (or = 1.50; 95% ci, 1.16 to 1.95), and wheeze (or = 1.40; 95% ci, 1.09 to 1.78). among long-term residents (i.e., living in the same home since the child was 2 years old or younger) with no parental history of asthma, an increased risk of physician-diagnosed asthma (or = 1.85; 95% ci, 1.11 to 3.09), prevalent asthma (or = 2.46; 95% ci, 1.48 to 4.09), and wheeze (or = 2.74; 95% ci, 1.71 to 4.39) was associated with living within 75 m of a major road. increased risk was not associated with the exposure for children with a parental history of asthma and for short-term residents. the adventist health study on smog (ahsmog) is a prospective cohort study that enrolled more than 3000 nonsmoking adults (27 to 87 years old) living in california in 1977. 298 in the first 10 years of follow-up, abbey and colleagues 298 examined 79 incident asthma cases in relation to pm and found a 30% increased risk of asthma for a 1000 hr/yr exposure to concentrations of pm 10 that exceeded 100 µg/m 3 . a later report on the ahsmog participants used the 1973-1992 8-hour mean ozone concentration as the exposure and found that the risk of developing asthma doubled per 27 parts per billion increase for males but not in females after adjusting for age, education, respiratory infection before age 16 years, and smoking status. 299 a systematic review commissioned by the u.k. committee on the medical effects of air pollution (comeap) was established to investigate whether outdoor air pollution causes asthma. 300 this 2010 review identified 14 cross-sectional studies relating asthma prevalence in more than four cities to quantitative pollution measures; the number of cities ranged from 6 to 62 and covered europe, north america, and asia. a metaanalysis revealed no significant associations between no 2 , pm 10 , or so 2 and period prevalence of wheeze and lifetime prevalence of asthma. the review also identified 14 studies of 10 birth cohorts and 11 studies of cohorts recruited during child or adulthood. in these studies, exposures were individualized by modeling, usually to the individual's home address. in contrast to the cross-sectional studies, meta-analysis revealed associations between no 2 and the incidence of asthma (or = 1.07; 95% ci, 1.01 to 1.14; 11 studies) and between pm 2.5 and the incidence of asthma (or = 1.43; 95% ci, 1.01 to 2.02; 5 studies). the comeap systematic review concluded that the evidence from the cohort studies is consistent with a significant increase in the incidence of asthma associated with no 2 and pm from traffic sources. the possibilities of air pollution aggravating existing subclinical asthma and residual confounding by factors associated with asthma and residential proximity to traffic were assessed early indoor allergen exposure and physician-diagnosed asthma or wheeze and did not find an association. they concluded that their results did not support the hypothesis that allergen exposure causes asthma. prospective cohort studies have studied the relationship between exposure to mold and the risk of asthma. a study of 1916 finnish children 1 to 7 years old used parents' reports of mold and dampness as a surrogate for exposure to aeroallergens in the home. 320 after 6 years of follow-up, exposure to mold was found to be an independent risk factor for asthma among finnish children. the incidence of physician-diagnosed asthma was double for children in homes with reported mold odor compared with those that did not. jaakkola and jaakkola reviewed the literature on indoor molds and asthma, and they concluded that exposure to molds at home increases the risk of asthma among adults and that exposure to molds at work increases the risk of wheezing. 321 they observed that exposure to indoor molds increases the severity of asthma and that removing the source relieves or eliminates symptoms and signs of asthma. sensitization to mold has been linked to the presence, persistence, and severity of asthma. 322, 323 a review of housing interventions designed to improve outcomes concluded that asthma symptoms could be reduced by removing moldy items and eliminating leaks and other moisture sources in homes. 324 intervention studies with avoidance of aeroallergens and food allergens have not consistently found a reduction of asthma risk among children. the canadian childhood asthma primary prevention study included 545 high-risk children who were randomized to intervention (i.e., avoidance of hdm by use of mattress covers and acaricides, pets, and passive smoking and encouragement of breastfeeding with delayed introduction of solid foods) or to control groups before birth. 325 for 380 children at 7 years of age, the prevalence of physician-diagnosed asthma was significantly lower for the intervention group (15%) than for the control group (23%). another intervention study of a birth cohort of 110 high-risk children living on the isle of wight assessed asthma (i.e., wheeze and bronchial hyperresponsiveness) prevalence at age 8 years and found that the asthma risk was ninefold higher for the control group than the intervention group. 326 intervention included breastfeeding by a mother on a low-allergen diet or giving a hydrolyzed formula and reducing hdm exposure with an acaricide and mattress covers. however, the australian childhood asthma prevention study, which included 516 highrisk children randomized to an hdm avoidance intervention group or control group, did not find a significant reduction in the prevalence of current asthma at age 8 years for the intervention group compared with the control group. 327 a systematic review and meta-analysis of prospective birth cohort studies evaluating the effects of allergen (i.e., hdm or dietary) avoidance during pregnancy concluded that early-life allergen avoidance in isolation does not reduce the likelihood of asthma in children at age 5 years (or = 1.22; 95% ci, 0.83 to 1.78). however, multifaceted antenatal intervention that combines breastfeeding with allergen avoidance and maternal smoking cessation does reduce the likelihood of asthma in children at age 5 years (or = 0.73; 95% ci, 0.55 to 0.97). 328 exposure to tobacco smoke has serious adverse effects on the respiratory tract. perhaps because of the sensitivity of the concentrations of the pollutant. a full examination of this literature is beyond the scope of this chapter, but reviews of indoor air pollution are available. 279 whether these exposures by themselves, in the absence of underlying genetic susceptibility, can cause asthma is uncertain. 301 however, mounting evidence indicates that maternal smoking is associated with an increased risk for asthma in offspring and later exacerbations of asthma (see "involuntary or passive smoking") and that levels of allergen exposure are associated with the incidence of asthma and wheezing. however, there have been only limited investigations of indoor air pollution and the incidence of asthma linked to risk factors other than passive exposure to tobacco smoke. an institute of medicine committee reviewed the evidence on indoor air pollution and childhood asthma and derived conclusions regarding causation and exacerbation. 301 this topic also has been reviewed elsewhere. 304, 305 several investigations have addressed the prevalence of asthma and exposure to nitrogen oxides from cooking stoves. homes with natural gas-fueled or propane-fueled cooking stoves tend to have no 2 levels substantially above those of homes with electric stoves. 306 some investigations indicate a general increased risk of respiratory symptoms, including wheezing, in households with gas stoves, but the data are inconsistent and not indicative of increased asthma incidence caused by nitrogen oxides. 31, 307 the myriad exposures to volatile and semivolatile organic compounds that can occur in homes and other locales have been investigated as risk factors for childhood asthma. although many cross-sectional studies report an association between volatile organic compound exposure and asthma in children 308, 309 and adults, 310, 311 these studies cannot establish causality and are beset by the problem of reverse causality, whereby parents modify their houses (e.g., laminate flooring) as a consequence of their children developing asthma. 312 cohort studies suggest that maternal volatile organic compound exposure during pregnancy can influence the development of childhood allergic disease. 313 this is an area of ongoing research because of the potential for intervention by behavioral modification and low volatile organic compound technology. studies of indoor allergens have largely focused on the status of children with asthma in relation to levels of allergen rather than considering the levels of allergens as predictors of asthma. 314 a prospective cohort study conducted in the united kingdom found levels of hdms in the home to predict later development of asthma, and children with higher levels of hdm antigen in their homes tended to wheeze at a younger age. 315 the german multicentre allergy study followed 1314 children from birth to 13 years of age and found that sensitization to perennial allergens such as hdms, cat hair, and dog hair that developed before 3 years of age was associated with a loss of lung function at school age. 316 a u.s. study of 474 children indicated that exposure to two or more dogs or cats in the first year of life might reduce subsequent allergic sensitization risk to multiple allergens during childhood. 317 not all studies support the conclusion that allergen exposure causes asthma. a british cohort study did not find a significant association between levels of hdm exposure and sensitization or wheeze. 318 results from a german birth cohort of 939 children followed until age 7 years showed a strong association between sensitivity to hdm allergens or cat allergens and wheezing from 3 years of age. 319 however, the investigators also during pregnancy has also been associated with increased in vitro cord blood mononuclear cell proliferative and cytokine responses after stimulation with allergens. 339, 340 there is extensive literature on the relationship between passive smoking and childhood wheeze and asthma. a systematic review identified 79 relevant prospective cohort studies. 341 exposure to maternal (prenatal and postnatal), paternal, and household sources of cigarette smoke was associated with an increased likelihood of children wheezing up to the age of 18 years. the strongest associations for childhood wheeze were for postnatal exposure to maternal cigarette smoking: wheeze at 2 years or younger (or = 1.70; 95% ci, 1.24 to 2.35), 3 to 4 years (or = 1.65; 95% ci, 1.20 to 2.68), and 5 to 18 years (or = 1.18; 95% ci, 0.99 to 1.40). the associations between exposure to maternal, paternal and household cigarette smoke and childhood asthma were not as strong as for wheeze, but they were most noticeable for maternal smoking during pregnancy: childhood asthma at 2 years or younger (or = 1.85; 95% ci, 1.35 to 2.53) and 5 to 18 years (or = 1.23; 95% ci, 1.12 to 1.36). paternal smoking was associated with an increase in childhood asthma between 3 and 4 years, and household smoking was associated with an increase in childhood asthma after the age of 3 years. the children's health study based in california reported a transgenerational association, suggesting that exposure to cigarette smoke in utero may have epigenetic effects. 329 in a nested case-control study of children at 5 years of age (279 with asthma and 412 controls), the likelihood of childhood asthma was increased if the mother (or = 1.5; 95% ci, 1.0 to 2.3) or the maternal grandmother (or = 2.1; 95% ci, 1.4 to 3.2) smoked during pregnancy. 342 if the mother and grandmother smoked during pregnancy, the likelihood of childhood asthma was increased further (or = 2.6; 95% ci, 1.6 to 4.5). although allergic rhinitis is common, few epidemiologic studies have focused on this disease. the most frequently cited risk factors include increasing age, atopy, and high socioeconomic status. 343 parental history is positively associated with the development of allergic rhinitis in offspring. in the tucson birth cohort study, a maternal history of physician-diagnosed allergy was significantly associated with a diagnosis of rhinitis by age 6 years (or = 2.2; 95% ci, 1.35 to 3.54). 344 perinatal and infant risk factors have been examined. for example, younger gestational age at birth has been associated with a decreased risk of allergic rhinitis. 345, 346 some researchers have postulated that early-life exposures to microbes may modulate risk of allergic rhinitis, and this hypothesis has been supported by the observations that birth by cesarean section is a risk factor for allergic rhinitis, 347 as is reduced diversity of the intestinal microbiota in infancy. 348 other risk factors under investigation include genetics, 349 early-life exposure to infections, acetaminophen use, 350 oral contraceptive use, 351 and indoor and outdoor air pollution exposure. 352 risk factors for eczema include gender, race or ethnicity, family history, early-life antibiotic use, environmental exposures, and dietary factors, including breastfeeding, timing of the introduction of solids, and inclusion of probiotics. family history of asthmatic lung to cigarette smoke, young smokers tend to have somewhat greater lung function and less underlying airway responsiveness than nonsmokers-a phenomenon sometimes referred to as the healthy smoker effect. 329 nonetheless, substantial data show that active smoking increases nonspecific responsiveness of the airways, perhaps by inducing inflammation 329 or by narrowing baseline airway caliber in older people. 28 smokers also tend to report wheezing more frequently than nonsmokers, and wheezing tends to decline after cessation of smoking. increased airway responsiveness in active smokers also tends to abate after smoking cessation. 329, 330 a systematic review of studies exploring the temporal association between active smoking and asthma reported that most studies indicated that people who smoked were at increased risk for asthma. 331 these studies evaluated diverse sample populations and used different methods, and the review highlighted the potential for residual confounding by health behaviors (e.g., physical exercise). the review concluded that although active smoking might be a risk factor for asthma, the evidence was insufficient to conclusively state whether smoking was a causal or proxy risk factor for asthma. the nonsmoking child is exposed to second-hand smoke, a name given to the mixture of sidestream smoke released by a burning cigarette and the mainstream smoke exhaled into the air by the smoker. this mixture has also been called environmental tobacco smoke. smoking adds respirable particles and irritant gases to indoor air, and it represents one of the major sources of fine particles in the air of u.s. homes. 332 exposure of children to particles and gases in tobacco smoke has been documented by measuring personal exposures and using biomarkers that indicate the levels of tobacco smoke components absorbed into the body. 333 cotinine, a major metabolite of nicotine, has been extensively investigated in children in relation to parental smoking. compared with children living in households in which there is no smoking, children living with smokers tend to have substantially higher cotinine levels. 332, 333 in the past, exposure to second-hand smoke was widespread. almost all participants, including nonsmokers, in the 1988-1990 nhanes iii had detectable serum cotinine levels. 334 ten years later, nhanes iv showed a dramatic reduction in cotinine levels, 335 a trend that has continued. 331 exposure to second-hand smoke contributes to both the causation and the exacerbation of asthma. first, passive smoking may increase the risk of more severe lower respiratory tract infections during the early years of life. 336 second, the direct toxic effects of second-hand smoke may induce and maintain the heightened nonspecific responsiveness of airways found in asthmatic children. third, many children have secondhand smoke exposure during gestation and after birth. substantial evidence suggests that in utero exposure to tobacco smoke components affects fetal airway and immune system development. young and associates assessed nonspecific airway responsiveness using a histamine challenge for 63 normal infants at a mean age of 4.5 weeks. 337 even at this young age, parental smoking and a family history of asthma were associated with an increased level of airway responsiveness. in a similar prospective investigation, hanrahan and colleagues found that children whose mothers smoked during pregnancy had a lower level of airway function soon after birth. 338 maternal smoking later epidemiologic studies provided a deeper understanding of the physiologic consequences of having childhood asthma and indicated that the lungs of these children might already have heightened airway responsiveness at birth. birth cohort studies that include indices of ventilatory function and airway responsiveness during the first weeks of life indicate that infants at risk for asthma because of a parental history of asthma and atopy already have heightened responsiveness to a challenge. 337 the tucson study clarified the early natural history of wheezing. 120,372 martinez and colleagues described the natural history of wheezing beginning before 3 years of age and found that some children had only transient early wheezing. children who continued to wheeze up to 6 years of age were more likely to have mothers with a history of asthma and to have an elevated serum ige levels, suggesting that the early wheezing represented asthma. children whose wheezing did not persist had diminished airway function in early life but did not tend to have mothers with asthma or elevated ige levels. the pattern of persistence of wheezing during childhood and into adulthood was similar in a smaller cohort study of 100 children in england, who were followed from birth to age 22 years. 373 in this highrisk cohort, early wheezing was not likely to persist, but wheezing at 11 years of age did tend to persist. the results of these studies imply that clinicians should be cautious in labeling all early childhood illnesses with wheezing as asthma, because some children are predisposed to wheeze with respiratory infections because of reduced airway function. population-based groups of children have been followed over time in prospective cohort studies (table 48 -5) . because most of these studies have drawn participants from defined populations, there is less potential for bias by the selection process, and the children with asthma are more likely to be representative. information collected from childhood to early adulthood is available from several investigations, including two particularly large studies involving lengthy follow-up: the cohort study in australia and the 1958 birth cohort study in the united kingdom. 374, 375 findings of a number of smaller studies have been similar (see table 48 -5). one of the first studies using a birth cohort design was conducted in australia, initially by williams and mcnicol. 374, [376] [377] [378] on enrollment in 1964, the children were 7 years of age, and after 35 years of follow-up, they were 42 years old. [376] [377] [378] wheezing tended to track over time, but 43% were no longer wheezing at 28 years of age, and only 32% had wheezing at least weekly. those with more severe wheezing at age 28 years tended to have a lower level of lung function tested by spirometry and to have a higher degree of airway responsiveness to a methacholine challenge. over time, some improved, but an approximately equal proportion worsened. at age 42 years, 60% of the group with wheezy bronchitis at baseline was free of wheeze, and only 5% of this group had persistent asthma. 378 symptoms continued in 70% of the original asthma group and in 90% of the severe asthma group. almost one half of the severe asthma group continued to have persistent asthma at age 42 years. those with severe asthma had suffered a loss in lung function by 14 years of age, but this loss did not progress in adulthood. children with milder symptoms did not have a significant loss of lung function. in another large, long-term study, members of the 1958 birth cohort in the united kingdom were followed up to age 33 years. 375, 379, 380 parents were interviewed when the participants eczema has been identified as a risk factor for eczema in several studies, 353 pointing to genetic determinants of eczema. loss-offunction mutations in the filaggrin gene (flg), which encodes a protein critical to skin barrier function, have been directly linked to eczema, and approximately 42% of people heterozygous for these mutations develop eczema. 354 black and asian race or ethnicity is a risk factor, along with male gender, 353, 355 although isaac phase three found that worldwide, boys were less likely to have eczema than girls. earlylife exposure to endotoxin appears to protect against the development of eczema, as reported in several studies. 356, 357 dietary factors, including breastfeeding, infant formulas, timing of solid food introduction, and supplementation with probiotics, have been studied. neither breastfeeding nor timing of solid food introduction has been associated with protection against eczema. [358] [359] [360] [361] [362] [363] evidence suggests that hydrolyzed infant formulas and supplementation with probiotics may afford some protection against eczema, 364, 365 but study results are mixed, and infection by the probiotic organism has been reported in infants receiving probiotic supplementation. established risk factors for food allergy include male gender for children, eczema, and an atopic family history. [366] [367] [368] other possible risk factors are diet and feeding practices during early childhood. controversy exists about whether early allergen introduction or allergen avoidance may predispose to the development of food allergy. the natural history of asthma is a concern for affected children, their parents, the clinicians providing care, and researchers. parents ask whether the child will outgrow asthma, and clinicians should be able to answer this question. researchers have studied the natural history of asthma and searched for factors that determine prognosis. during adulthood, the former asthmatic child may be exposed to environmental agents, including cigarette smoke, which may adversely affect respiratory health. childhood asthma has been postulated to increase the likely adverse effects of these exposures and other long-term consequences, such as persistent physiologic impairment from airway remodeling. 369, 370 initial information on the natural history of childhood asthma largely came from cohort studies of children attending general practices or clinics. 140, 371 these studies, some dating to the 1930s, were a principal source of data on the natural history of asthma until population-based investigations were implemented beginning in the 1960s. these early studies provided evidence of waning of clinical symptoms over time in a substantial proportion of children with asthma. however, most children tended to remain symptomatic. interpretation of these data is constrained by differences between past and current therapeutic approaches, possible lack of representativeness of children receiving care at a particular clinical facility, and by diversity of the research methods. 140 these studies drew the participants from general practices and clinics, and presumably, more severe asthma was represented. nevertheless, they provide evidence that the prognosis is favorable for some children with asthma, even in an era antedating contemporary therapeutic approaches. bronchial challenge testing, and allergy testing. of the 613 participants with complete data for the follow-up period, 14.5% had persistent wheezing into adulthood, and only 27.4% never reported wheezing. the remainder had various patterns of intermittent wheezing. predictors of persistent wheezing included sensitization to hdms, female sex, and smoking at age 21 years. pulmonary function was reduced in those with persistent wheezing. evaluation of the natural history of asthma in adults is complicated by the occurrence of copd and the potential difficulty of separating copd from asthma. in adults, asthma includes disease originating in childhood and following its natural course into adulthood and asthma developing during the adult years. these natural histories have not been carefully delineated, although the lengthier studies of childhood asthma can provide information on its course into adulthood. there is less information on asthma in adulthood that is comparable to that on childhood asthma, such as the longitudinal picture of symptoms and clinical status. however, the effect of having asthma on the decline of lung function has been assessed, and there is limited information on the development of irreversible airflow obstruction in persons with asthma (table 48-6 ). the evidence on asthma and change in lung function over time is inconsistent with some studies showing were 7, 11, and 16 years of age, and the participants themselves were interviewed at age 23 and 33 years. asthma tended to remit over time; of the children with a report of asthma or wheezy bronchitis before 7 years of age, only 10% had wheezing in the last year at age 23 years, although this figure increased to 27% at age 33 years. 375 lung function was evaluated in a sample of 1060 of the participants with a history of asthma or wheezy bronchitis and 275 controls. 380 for those not reporting wheezing at age 33 years, lung function was only slightly reduced compared with controls. for those with wheezing, fev 1 was reduced by approximately 10% compared with controls. similar results were found in a 1994 follow-up study of 181 dutch individuals. 381 subjects were extensively tested as children 25 years earlier and reexamined as adults. the data revealed that 11% of persons were no longer considered asthmatic, 25% had an fev 1 greater than 90% of predicted, 21% were no longer bronchial hyperresponsive, and 40% did not report asthmatic symptoms. results of these studies support the hypothesis that early intervention in mild asthma may lead to improved outcomes. in a longitudinal, population-based, cohort study carried out in dunedin, new zealand, 382 1139 children were enrolled, and a substantial proportion was followed to age 26 years with repeated assessment by questionnaires, lung function testing, in the copd group and a 20-ml loss in the intermediate group. the balance of the evidence indicates that a diagnosis of asthma is associated with an increased rate of fev 1 decline (see table 48 -6). perhaps reflecting this excess decline, many elderly persons with asthma have fixed airflow obstruction. 389 there are few studies on the clinical course of asthma in adults (table 48-7) , and as airway obstruction becomes fixed with advancing age, separating asthma from copd becomes increasingly difficult. in the study by schachter and coworkers, 384 of the male participants age 18 years or older with asthma, 75% improved and only 1% worsened during follow-up. among female participants, 58% improved and none worsened during follow-up. bronniman and burrows 390 followed 136 asthmatics, who were drawn from the general population sample in tucson, arizona, of 2300 persons, over a 9-year period. participants were classified as in remission if they had active disease at baseline and on follow-up denied medication use, asthma attacks, and frequent attacks of shortness of breath with wheezing during the preceding year. after 9 years of follow-up, 22% were in remission, with the highest rate found among those between 10 and 19 years of age at enrollment (65%) and the lowest rate found for those between 40 and 49 years of age (6%). remission was more common in those with less frequent wheezing, less frequent asthma attacks, and less frequent attacks of shortness of breath with wheezing. remission was significantly less likely increased decline in persons with asthma compared with controls and others showing no difference between asthmatics and controls. peat and woolcock followed 92 persons with asthma, who were 22 to 69 years old on enrollment, and 186 control participants from busselton, australia. 383 the asthmatic individuals had lower lung function values at enrollment and the fev 1 declined at 15 ml/yr more in the persons with asthma compared with the controls. schachter and colleagues 384 followed the lung function of 73 persons with asthma and 278 with wheezing. over a 6-year interval, there was a similar excess loss of fev 1 in the persons with asthma. ulrik and lange 385 followed subjects over a 5-year period and found that asthmatic subjects had lower baseline lung function values and an excess annual decline in fev 1 compared with nonasthmatics; the excess annual decline was 39 ml in asthmatic men and 11 ml in asthmatic women. some individuals with asthma appear to eventually develop irreversible airflow obstruction, which has been related to duration and severity of asthma. 356, 387 a continuing effect of asthma was found when follow-up was extended to 15 years. 388 other studies have not shown increased loss of function associated with having a diagnosis of asthma. burrows and colleagues 389 examined the course of asthma over 10 years in 27 asthmatics from the general population and compared them with two other groups: 45 copd subjects and 45 subjects who did not fit clearly into either group. the asthmatic subjects had a 5 ml/yr decline in fev 1 , compared with a 70-ml decline years. this was a highly 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distinct clinical entity with lifelong significance? the state of childhood asthma in young adulthood decline in lung function in the busselton health study: the effects of asthma and cigarette smoking the characteristics of bronchial asthma among a young adult population mortality and decline in lung function in 213 adults with bronchial asthma: a ten year follow up key: cord-259501-iggw1exl authors: kim, yong yean; lew, judy f.; keith, bahareh; telisma, taina; nelson, eric j.; brantly, alexis c.; chavannes, sonese; anilis, gina; yang, yang; liu, mingjin; alam, meer taifur; rashid, mohammed h.; morris, john glenn; madsen beau de rochars, valery e. title: acute respiratory illness in rural haiti date: 2019-02-14 journal: int j infect dis doi: 10.1016/j.ijid.2019.02.003 sha: doc_id: 259501 cord_uid: iggw1exl objectives: acute respiratory infection (ari) is the most common cause of childhood morbidity and mortality in developing countries, including haiti. our objective was to detect pathogens found in children with ari in rural haiti to help develop evidence-based guidelines for treatment and prevention. methods: retrospective study of students with ari at four schools in rural haiti. viral and/or bacterial pathogens were identified by qpcr in 177 nasal swabs collected from april 2013 through november 2015. results: most common viruses detected were rhinovirus (36%), influenza a (16%) and adenovirus (7%), and bacteria were streptococcus pneumoniae (58%) and staphylococcus aureus (28%). compared to older children, children aged 3–5 years had more influenza a (28% vs. 9%, p = 0.002) and adenovirus detected (14% vs. 3%, p = 0.01). similarly, s. pneumoniae was greatest in children 3–5 years old (71% 3–5yrs; 58% 6–15 years; 25% 16–20 years; p = 0.008). children 3–10 years old presented with fever more than children 11–20 years old (22% vs 7%; p = 0.02) and were more often diagnosed with pneumonia (28% vs 4%, p < 0.001). conclusions: younger children had increased fever, pneumonia, and detection of influenza a and s. pneumoniae. these data support the need for influenza and pneumococcus vaccination in early childhood in haiti. hospital-based studies on children in haiti have shown that acute respiratory infection (ari) is the leading cause of child morbidity and mortality (perry et al., 2005; vinekar et al., 2015) . earlier studies in resource-poor settings have identified streptococcus pneumoniae, haemophilus influenzae type b and staphylococcus aureus as important bacterial causes of ari, and respiratory syncytial virus (rsv) and influenza as important viral causes (rudan et al., 2008) . many of these prior studies used technically difficult and labor intensive tests that included bacterial and viral culture (rudan et al., 2008) . the use of diagnostic nucleic acid technology has increased detection of infectious agents associated with ari. a multicountry study that included haiti showed that agents detected in hospitalized children less than 5 years of age who had pneumonia included rsv, influenza a and b, parainfluenza viruses, adenovirus and human metapneumovirus (hmpv) (bénet et al., 2017) . in that same study, analysis of bacterial agents showed high detection of streptococcus pneumoniae and mycoplasma pneumoniae leading the authors to conclude that vaccination efforts for streptococcus pneumoniae will be beneficial. whereas hospital-based studies are informative, most patients do not require hospitalization and much less is known about ari in school-aged children treated at outpatient clinics. in 2012-2013 we assessed outpatient illnesses in children who attended four schools in rural haiti (gressier/leogane) and showed that ari was the most common complaint among 1,357 clinic visits (beau de rochars et al., 2015) . the objective of this retrospective study is to analyze which infectious agents are detected in haitian children presenting with ari in the outpatient setting. knowledge gained from this study will guide clinical care and public health vaccine campaigns. enrollment criteria were all students with complaints of fever and respiratory symptoms who attended one of four schools managed by the christianville foundation network in gressier, haiti. the christianville foundation partners with university of florida (uf) to address public health challenges in the haitian community. these schools were previously described with one having pre-k through 12th grade with approximately 800 students, and three schools having pre-k through the 6th grade with 130-180 students each (beau de rochars et al., 2015) . school clinic staff included one physician and two nurses who evaluated and managed patients as per standard clinic procedures, and obtained a nasal swab from each participant as part of routine clinical care using the bd universal viral transport kit (bd company, franklin lakes, new jersey). given the lack of access to x-ray or pulse oximetry, criteria to obtain swab was based on clinical criteria of history of fever and respiratory symptoms. diagnosis of upper vs lower respiratory infection was based on physical exam. swabs were initially stored at à20 c with testing anticipated soon after collection at the uf laboratory in haiti; due to technical difficulties, de-identified coded swabs were transported in bulk on dry ice to uf and then stored at à80 c until processed. when laboratory studies were completed, clinic staff retrospectively linked a limited clinical data set with results. the study protocol was reviewed and approved by the university of florida irb. samples were thawed on ice and pulse vortexed 5 times. total nucleic acid (including dna and rna) were then isolated using the rtp pathogen kit per manufacturer's protocol (stratec biomedical, birkenfeld, germany). total dna and rna were analyzed by multiplexed rt-pcr using the ftd respiratory pathogen 21 plus kit (fast-track diagnostics, sliema, malta) on an applied biosystems 7500 rt-pcr system. targets were 18 viruses and 5 bacteria: influenza a (flua), influenza b (flub), influenza a/h1n1 (flua/h1n1), rhinovirus (rv), coronaviruses (nl63, 229e, oc43, hku1), parainfluenza (hpiv 1, 2, 3, 4), hmpv a/b (hmpv), bocavirus (bv), mycoplasma table 1 percentage of school children with nasal swabs by school location, age, sex and month/year. * estimated average enrollment during the collection time period. pneumoniae, respiratory syncytial viruses a/b (rsv), adenovirus (hadv), enterovirus (ev), parechovirus (hpev), chlamydia pneumoniae (cp), s. pneumoniae, haemophilus influenzae type b (h. influenzae b), and s. aureus. both ftd respiratory pathogen 21 plus kit controls and independent swab samples known to be positive for rsv, hadv, influenza and coronaviruses were used to validate the results. all patients were examined by the clinical staff. fever was defined as greater than 37.9 degrees celsius. pneumonia was defined as history of fever with cough or congestion and clinical examination findings of crackles, grunting, or decreased breath sounds. two-sided fisher's exact was used to compare the detection rates of agents by age groups, sex, seasonality and clinical parameters, with type i error controlled at 0.05. p-values were not adjusted for multiple comparisons. we also used the fisher's exact test for the co-detection analysis. all tests were conducted using the r software version 3.3. agents detected in 5% of patients were prioritized for analysis. age groups for analytical comparisons were 3-5 years (group a), 6-10 years (group b), 11-15 years (group c) and 16-21 years (group d), with some comparisons using consecutive age groups combined. eight children had samples obtained twice and their visits were separated by an average of 6 months (2-17 months). given the passage of at least 2 months, each patient encounter (i.e., sample) was considered a unique entity for analysis. swabs were collected from 177 children attending four different schools during school attendance from april 2013 through november 2015: school a (75%), school b (17%), school c (6%) and school d (2%). the average age was 8.7 years (range = 3-20 years); female sex = 54%. a total of 76% of samples (133/174) with date information were collected during the september to june school year of 2013-14, two samples were collected in april 2013 (1%), and the remainder 22% (39) were collected from february-june (excluding december-january) and august-november of 2015 [ table 1 ]. given that etiology of ari changes by age, we first looked at agents detected by age. younger children had flua, hadv and s. pneumoniae detected more often than older children, while s. aureus detection peaked in children with ages between the youngest and oldest age groups. analysis of viruses showed that more children in age group a had flua detected (28%) when compared to groups b (10.5%, p = 0.02), c (4%, p = 0.01), and d (11%, p = 0.10). significantly more children in age group a had hadv (14%) detected than children in groups b-d combined (3%), p = 0.01. for bacterial agents, s. pneumoniae detection was greatest in children in the age group a (71%) followed by groups b (58%) and c (59%), with the least in d (25%). significantly more group a-c children had s. pneumoniae detected (64%) than those in group d (25%), p < 0.001. although h. influenzae b detection decreased with age, this difference was not statistically significant. for s. aureus, table 2 viruses and bacteria detected in children by age. p value obtained using two-sided fisher's exact. detection was highest in the group b-c children (43%), with significantly less s. aureus detected in groups a (14%) and d (14%), both p < 0.01 [ table 2 ]. the mean number of total agents detected per child in age groups a, b and c was higher at 1.9-2.0 than in group d at 1.2. significantly more children in age groups a (62%), b (58%) and c (74%) had 2 or more agents detected than children in group d (32%), p < 0.04 for each comparison to group d. analysis of the number of viral agents detected showed no significant difference was seen between the proportion of children who had !1 viral agents detected between age groups a (77%), b (67%), c (67%) or d (68%). however, significantly more bacterial agents were detected in age groups a, b and c children than in group d. the proportion of children with !1 bacterial agent(s) detected per age group were: groups a (75%), b (82%), and c (81%) versus group d (36%), p < 0.001 for each comparison to group d. the most common viruses detected in children overall with fever and respiratory complaints (n = 177) were rv (36%), flua (16%, including 13% due to flua/h1n1) and hadv (7%). more rarely detected were rsv, bv and hpev. s. pneumoniae was the most common bacteria detected at 58%, followed by s. aureus at 28%, and h. influenzae b at 3%. [supplemental table s1 ] co-detection was common with 322 agents detected in 177 patient samples. at least one viral agent (range 1-3) was detected in 71% of children and at least one bacterial agent in 72% (range 1-3), with 18% having greater than 1 virus and 18% with greater than 1 bacterial spp. detected in the 177 patient samples. only 10 children (5.6%) had no agent detected. the average number of any agent detected (viruses + bacteria) per child was 1.8 [ table 3 ]. analysis by age groups showed no significant difference in viral detection. however, when looking at bacterial detection and co-detection of two or more agents, the oldest age group d had significantly less frequent detection (p < 0.001 for bacteria, p = 0.031 for co-detection of two or more agents). more children had flua as the sole pathogen (39%) than those who solely had hadv (0%, p = 0.017), ev (0%, p = 0.017), or s. pneumoniae (19%, p = 0.04) detected. co-viral detection was less common in children with flua (21%) than in children with hadv (83%, p < 0.001) and ev (100%, p < 0.001). co-bacterial detection was also less common in children with flua (57%) than in children with hadv (100%, p = 0.007) and ev (91%, p = 0.063) [ table 4 ]. evaluation for relationships between specific agents showed that ev was 100% correlated with concurrent rv detection (11/11, p < 0.001); both picornaviruses having possible correlates by pcr. in contrast, flua and flub was negatively correlated with rv detection (p = 0.0022 and p = 0.027, respectively). evaluation between viral and bacterial correlates showed 100% of children with hadv also had s. pneumoniae detected (12/12, p = 0.0014). detection of s. aureus was negatively associated with that of flua; despite 27.7% of all children having s. aureus detected, none of the 28 children with flua detected were co-detected with s. aureus, p < 0.001. no other agents showed significant co-detection relationship. no significant differences were found between females and males regarding total viral plus bacterial agents, total viral or bacterial agents, or specific agents detected by pcr. table 3 co-detection in children with ari by age. of 174 samples that had date of collection data, 133 (76%) were collected from children during the school year of september 2013 through june 2014 for this one season evaluation. the number of children tested were not evenly distributed with 1-6 tested in sep, oct, dec, feb, mar, jun and 13-57 tested in nov, jan, apr, may. analysis of specific agents detected monthly showed seasonality was significantly associated with influenza detection. more children had flua/h1n1 detected during the months of oct-dec 2013 (14/63, 22%) than children during the school year outside of those months (0/70, 0%, p < 0.001) [ figure 1 ]. similarly, more children had any flu (a/h1n1 + a/not h1n1 + b) detected in oct-dec 2013 (16/63, 25%) compared with those in the other 2013-14 school months combined (8/70, 11%, p = 0.044). although no other agents with at least a 5% (7 of 134) detection rate were found to table 4 co-detection of agents from 179 children with respiratory complaints in an out-patient setting. have seasonality, it was noted that all rsv detected occurred in nov 2013 and rsv detection was more common in nov 2013 (4/57, 7%) than in the other school year months combined (0/76, 0%, p = 0.032). of 158 children who had clinical data, primary diagnoses were upper respiratory tract infection (urti, excludes group a streptococcal [gas] pharyngitis) at 67%, lower respiratory tract infection (lrti) at 21% and 'other' at 12%. twenty-five (16%) children had more than 1 diagnosis. fever was detected at the time of presentation in 28 (18%) children and was significantly more common in children with lrti (24%) or with 'other' diagnoses (53%) when compared to those with urti (9%), p 0.04 for both analyses [ table 5 ]. fever and specific virus analysis showed a significantly higher percentage of children detected with flua (50%), separately flua/ h1n1 (47%), and flua or flub (48%) had fever recorded compared to those with rv (12%). for bacteria detection, neither s. pneumoniae or s. aureus were associated with fever when compared to children without s. pneumoniae or s. aureus, respectively. analysis of specific viral or bacterial agents detected showed more children with flua or flub had lrti (33%) compared to urti (15%) [ table 5 ]. none of the 6 children with primary diagnosis of tonsillitis had any viruses detected, whereas 5/8 (63%) with primary diagnoses of parasitosis or febrile syndrome had flua/h1n1 or hadv detected. [data not shown] fever and lrti separately were associated with the younger age groups. significantly more children aged 3-10 years had fever detected (22%) when compared to children aged 11-20 years (7%, p = 0.02). similarly, lrti was more common in 3-5 year old children (36%) compared to those 6-10 years (19%), 11-15 years (8%), and 16-20 years (0/21, 0%), and this was statistically significant when comparing groups a-b (28%) to c-d (4%), p < 0.001. evaluation of medications given showed only 2 of 158 (1.3%) children did not receive any medications. antibiotics were given to 44 (27.7%) children that included 31 (94%) diagnosed with lrti with the rest attributed to primary-or co-diagnoses of tonsillitis, bacterial skin, urinary tract or sinus infections. of the 31 with lrti, 30 received amoxicillin and 1 co-trimoxazole. overall, the three most common medications given were acetaminophen (74%, 117), mucolytic +/à beta agonist +/à expectorant mix (52%, 83), and vitamin c (47%, 74). for the 101 children with uncomplicated uri diagnosis (no concurrent known bacterial infections), 22% received one, 69% two, and 7% all three of these drugs. compared to children diagnosed with uncomplicated uri, children with lrtis or 'other' diagnoses did not significantly differ in percent receiving these medications. this is one of the largest retrospective studies of pediatric outpatients with ari in rural haiti. the overall findings of rv as the most common virus detected followed by influenza in haiti is comparable to that found in studies of children in other tropical, resource-poor countries (hoffman et al., 2012; schlaudecker et al., 2012; taylor et al., 2017) . however, hmpv in children with ari was detected less often (3%) in this study compared to similar studies (11-14%) (al-sonboli et al., 2006; banerjee et al., 2007; taylor et al., 2017) . these and other studies showed hmpv caused a high percentage of severe ari in those <2-5 years of age (ali et al., 2013; panda et al., 2014) , suggesting the lower detection rate seen in this study may be due to the older median age in this study, and differences between outpatient study compared to previous inpatient studies. rsv detection was significantly lower at only 2.3% of tested patients compared to previously published reports of 30-40% in other developing countries where the bulk of the children were seen in hospitals or emergency rooms (mccracken et al., 2013; dawood et al., 2015; bouzas et al., 2016) . this low level of detection may have been due to initial storage of nasal swabs at à20 c which has been found to decrease rsv detection (nunes and moura, 2006) and our patients being 3-20 years old when the highest rate of the rsv positivity are typically among children 2 years of age. low detection of rsv was also seen in a study of 4,242 pediatric patients that showed detection of rsv infection at 3.4 à7.2% in older children 3-14 years of age compared to 18.7-29.2% in 4 months to 2 years old (liu et al., 2014) . it is possible that by the time haitian children are 3 years of age, the risk for significant infection has greatly declined in comparison to those in less resource poor countries where rsv and hmpv can continue to cause significant disease in those <5 years old. future studies on rsv and hmpv that included children <3 years of age in both outand in-patient setting could help better understand their clinical impact. consistent with other studies is the finding that detection of influenza (a, including a/h1n1, and b) was significantly associated with increased clinical symptoms of fever at presentation and lrti diagnosis especially in younger children (laforce et al., 1994; cox and subbarao, 2000; descalzo et al., 2016) . introduction of flua and flub vaccine in younger and school aged children could significantly decrease its clinical impact, including decrease spread to siblings and adults at home. a study that ascertained peak influenza activity in 70 tropical or subtropical countries suggested that timing of influenza vaccine in haiti should be in april based on data from nearby countries including cuba and dominican republic (no haiti data) (hirve et al., 2016 ). yet in this evaluation of children in haiti for the school year of 2013-14, the peak detection of influenza appeared to be in oct-dec 2013. this finding suggests that immunization in haiti should begin by august/september, similar to october for mexico, guatemala and jamaica in the 70 nation study. increased testing in haiti for peak detection over several years is needed to determine best timing of influenza vaccinations. the high detection rate of s. pneumoniae (58%) and h. influenzae b (3.4%) compared to affluent countries may reflect the lack of s. pneumoniae vaccine in the immunization program in haiti and limited h. influenzae b vaccinations which only began in late 2012 (mbelle et al., 1999; abdullahi et al., 2008; agrawal and murphy, 2011; who, 2013a; adegbola et al., 2014) . agent-specific vaccination has been shown to decrease s. pneumoniae and h. influenzae b colonization and subsequent infection in children (dagan et al., 2002; agrawal and murphy, 2011; alvarez et al., 2016) . the decrease in s. pneumoniae and h. influenzae b detection with increased age is likely attributed to protective antibodies developing due to infections (mbelle et al. 1999; dagan et al., 2002; peraza et al., 2004) . despite this decrease, the high colonization rates and associated risk for infection strongly supports introduction of s. pneumoniae and continuation of h. influenzae b vaccine in those <5 years of age (who, 2013b; who, 2012) . furthermore, future determination of the s. pneumoniae serotypes found in 58% of the overall cohort could help identify the usefulness of available vaccines. although multiple studies of lrti in developing countries have implicated infection with s. pneumoniae, h. influenza type b and s. aureus as the major bacterial causes of severe pneumonia (shann, 1995) , this study detected high rates of these pathogens in nonsevere outpatients. possibly the problem of high rates of colonization could have masked some primary or secondary bacterial infections. future studies may benefit from blood cultures along with pcr to assess disease burden and from more extensive patient follow-up. in addition, community case-control studies and studies where the incidence of pneumonia is measured pre-and postvaccination may clarify disease burden and attributable fraction of colonization versus active disease from these pathogens (rudan et al., 2008; levine et al., 2012; morpeth et al., 2017) . the 20% incidence of lrti in this ari study is consistent with previous findings that 10-20% of children with ari may develop pneumonia (panda et al., 2014) . virtually all patients who had lrti diagnosed were treated with an antibiotic considered appropriate by the world health organization (who, 2014). however, >50% of patients received one or more "common cold" medications that are generally not advised by who, particularly in young children (who, 2001) . the risks/benefits of such medications are an issue in both resource rich and poor countries, but the latter have an additional fiscal burden related to treatments that may have unproven efficacy and potential toxicities. limitations of the study are related to the developing world setting. as discussed above, due to the use of nasal swabs with pcr based detection, we can comment on the pathogens detected at the time of symptoms but cannot directly point to the pathogen as the etiology. the lack of corresponding tests for the diagnosis of pneumonia such as chest x-ray, pulse oximetry, or blood culture is due to lack of resources in the rural clinic setting. another resource related issue is the skewing of the patient population to the younger age group since only one out of the four schools provides middle school or high school education. also there are gaps in data during the vacations and holidays when schools are closed such as for winter vacation in december which may present a bias in the data. lastly, since the school clinic was in location a, children who were ill in other locations enrolled on the study were less able to travel to the clinic which likely presented a bias based on resource distribution. in conclusion, school-aged children in rural haiti between 3 and 5 years old had influenza a and streptococcus pneumoniae detected and pneumonia diagnosed more often than older children. the children presenting with these agents detected in this outpatient study were less ill compared to previous inpatient studies. future research should include community-based case-control studies to assess colonization versus active infection. this study also supports ongoing advocacy for influenza and pneumococcal vaccines in young haitian children. pre-post studies (e.g. a stepped wedge design) during these vaccination campaigns would define the impact of 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(hib) vaccination position paper world health organization. revised who classification and treatment of childhood pneumonia at health facilities: evidence summaries we thank the children and their parents for their willingness to participate in this study as well as the tireless contributions of the christianville foundation to collaborate in this impactful study. respiratory swab samples known to be positive for rsv, adenovirus, influenza and coronaviruses were generously donated by dr. kenneth rand and howard rampersaud at the university of florida shands hospital. none. we have read and complied with the policy of the journal on ethical consent as stated in the guide to authors. this study was reviewed and approved by the university of florida irb. supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.ijid.2019.02.003. key: cord-265445-bazcczdj authors: arias-bravo, guisselle; valderrama, gustavo; inostroza, jaime; reyes-farías, marjorie; garcia-diaz, diego f.; zorondo-rodríguez, francisco; fuenzalida, loreto f. title: overnutrition in infants is associated with high level of leptin, viral coinfection and increased severity of respiratory infections: a cross-sectional study date: 2020-02-18 journal: front pediatr doi: 10.3389/fped.2020.00044 sha: doc_id: 265445 cord_uid: bazcczdj objective: to investigate the relationship of overnutrition (obese and overweight) with severity of illness in children hospitalized with acute lower respiratory infections (alris), frequency of viral coinfections and leptin levels. methods: we studied 124 children <2 years old that were hospitalized for alri. nutritional status was calculated by z-scores according to weight-for-age z-scores, length or height-for-age z-scores, and weight-for-height z-scores. nasopharyngeal aspirates (npas) were obtained and viral respiratory pathogens were identified using reverse transcription polymerase chain reactions (rt-pcr). respiratory syncytial virus (rsv) load was assessed using quantitative rt-pcr. npa and plasma leptin level were measured. clinical data and nutritional status were recorded, and patients were followed up until hospital discharge. viral coinfection was defined as the presence of two or more viruses detected in the same respiratory sample. severity of illness was determined by length of hospitalization and duration of oxygen therapy. results: children with overnutrition showed a greater frequency of viral coinfection than those with normal weight (71% obese vs. 37% normal weight p = 0.013; 68% overweight vs. 37% normal weight p = 0.004). a lower rsv load was found in obese (5.91 log(10) copies/ml) and overweight children (6.49 log(10) copies/ml) compared to normal weight children (8.06 log(10) copies/ml; p = 0.021 in both cases). in multivariate analysis, obese, and overweight infants <6 months old were associated with longer hospital stays (rr = 1.68; ci: 1.30–2.15 and obese: rr = 1.68; ci: 1.01–2.71, respectively) as well as a greater duration of oxygen therapy (rr = 1.80; ic: 1.41–2.29 and obese: rr = 1.91; ci: 1.15–3.15, respectively). obese children <6 months showed higher plasma leptin level than normal weight children (7.58 vs. 5.12 ng/μl; p <0.046). conclusions: in infants younger than 6 months, overnutrition condition was related to increased severity of infections and high plasma leptin level. also, children with overnutrition showed a greater frequency of viral coinfection and low rsv viral load compared to normal weights children. these findings further contribute to the already existent evidence supporting the importance of overnutrition prevention in pediatric populations. acute lower respiratory tract infections (alris) are a common illness in children <5 years old, with significant morbidity and mortality in infants and young children under the age of two (1) (2) (3) . respiratory syncytial virus (rsv) is the most important viral pathogen causing alris in young children (4) . there are many risk factors related to alris. some of these are relative to pathogens, such as viral load (5) , while others are directly associated with the host, such as prematurity, inadequate breastfeeding, and undernutrition (6) . the influenza ah1n1 2009 pandemic showed, for the first-time, that obesity is a risk factor for the severity of alris in adults (7, 8) . pediatric obesity has also been described as a risk factor for lower respiratory tract infections, as well as the severity and morbidity of these infections (9) . however, the empirical evidence needed to estimate the impact of overnutrition (including overweight and obese conditions) on the severity of viral respiratory infections in children is still lacking (10) . overnutrition causes an excessive accumulation of body fat. it is a highly prevalent condition and has been ranked as the foremost epidemic of the twenty-first century (11) . obesity results in a chronic state of inflammation with systemic implications for immunity (12) . leptin, cytokine-like hormone that is positively correlated with the body mass index, mediates upregulation of suppressor of cytokine signaling (socs) proteins (13) . socs proteins are involved in the negative regulation of janus-activated kinase-signal transducer and activator of transcription (jak-stat) signaling and the induction of type i and type ii ifns and pro-inflammatory cytokines, suggesting a potential mechanism by which respiratory viruses response in obesity may be attenuated (8, 14, 15) . in addition to immune modulation of obesity, alterations in membrane lipid composition have been observed in erythrocyte from obese children. the membrane composition has also revealed an increase in cholesterol content as has the cholesterol to phospholipid molar ratio, both of which have been positively correlated with a decrease in membrane fluidity, body-mass index, and plasma cholesterol levels (16) . cholesterol is a critical structural component of lipid rafts, key structures in binding and endocytosis of respiratory viruses (17) . in accordance with this, it could be expected that the membrane of obese children's respiratory cells may undergo some type of modification that could benefit the entry of respiratory viruses. hence, the objective of this study was to estimate the relationship of overnutrition on severity of illness in infants (aged between 0 and 5 months) and children (aged between 6 and 24 months) hospitalized with alris. moreover, frequency of viral coinfection, rsv viral load and levels of leptin according to nutritional status were evaluated. a cross-sectional study was conducted for 2 consecutive epidemic periods (from may to august) in 2016 and 2017. patients were selected based on following inclusion criteria: children <24 months old that were hospitalized for alri at two medical centers in santiago, chile: urgencia materno-infantil at clínica dávila and dr. exequiel gonzález cortés hospital. patients were classified as having bronchiolitis, bronchitis or pneumonia. diagnoses were made in patients with dyspnea, signs of lower respiratory tract infections (wheezing, retractions) and/or a positive chest x-ray (infiltrates, atelectasis and air trapping). the clinical and demographic characteristics of each patient were also recorded. the exclusion criteria were: children with nutritional risk and/or undernourished children, newborns <28 days old, patients with a diagnosis of recurrent wheezing, previous hospitalization for any cause, primary or secondary immunodeficiency, gestational age of <37 weeks, bronchopulmonary dysplasia, previous mechanical ventilation, congenital heart disease, respiratory infection during the previous 2 weeks, corticosteroid intake 72 h before sample was taken, and children with negative samples for respiratory viruses. figure s1 shows exclusion criteria. children were classified into three groups according to their nutritional status (ns) using who anthro 2011 v.3.2.2 program: normal weight, overweight, and obese. ns was determined by z-scores according to the following anthropometric indicators: weight-for-age z-scores, length or height-for-age z-scores, and weight-for-height z-scores. normal weight was defined as −0.9 to 0.9 sd, overweight as 1.0 to ≤2.0 sd and obese as >2 sd. undernourished children and those with nutritional risk were defined with a weight-forage z-score and weight-for-height z-score of <1 sd, below the mean, and were therefore excluded from the study. the weight of each patient was measured at hospital admission. disease severity was assessed by using the standard criteria of length of hospitalization and duration of treatment with supplemental oxygen (18, 19) . approximately 3 ml of nasopharyngeal aspirate (npa) were collected from each patient, usually during the admission process (<3 h) and always within the first 24 h of hospitalization. secretions from both nostrils were aspirated without flushing using a soft catheter placed in a collection trap with 3 ml of sterile saline solution and immediately transported on ice to the laboratory. aliquots of 2 ml were stored at −80 • c for viral analysis. aliquots of 1 ml were centrifuged at 1,000 g for 15 min at room temperature and the supernatants obtained were stored at −80 • c until determination of leptin level. viral rna and dna were simultaneously extracted from 150 µl of the npa samples using the viral rna isolation kit nucleospin (macherey-nagel r , düren, germany) following the manufacturer's instructions, and stored at −80 • c, until use. viral infection was detected with real-time pcr kit argene r (biomérieux, marcy-i ′ étoile, france), for rsv, human metapneumovirus (hmpv), parainfluenza virus 1-4 (hpiv), human coronavirus (hcov), adenovirus (adv), bocavirus (hbov), influenza a (flua), influenza b (flub), and rhinovirus/enterovirus (hrv/hev), following the manufacturer's instructions. viral co-infection was defined as the presence of two or more viruses detected in the same respiratory sample. forty-five patients that tested positive for rsv were selected using the argene r real-time pcr kit. a new aliquot was used with 150 µl of npa. nucleic acids were extracted using the viral rna isolation kit nucleospin (macherey-nagel r , düren, germany). the qrt-pcr was performed using the takyon tm rox probe mastermix dttp blue kit (eurogentec, usa), using primers with n1 (5 ′ -ggaacaagttgttgaggt ttatgaatatgc3 ′ ) and n2 probes (cttctgctgtcaa gtctagtacactgtagt-3 ′ ) (20) . the conditions of the pcr reaction were: preincubation at 95 • c for 3 min; 40 cycles at 95 • c for 10 s and 60 • c for 30 s. threshold cycles of positive samples for rsv were compared with the standard of curves generated by the amplification of known plasmid copy numbers of the pgem-t dna (promega) containing primer targets. in order to determine the effective amount of copies of viral dna molecules contained in each sample of the endogenous rnase p gene, the taqman r rnase p kit (applied biosystems, woolston, uk) was used. the cq values were interpolated and normalized according to the following formula: cq normalized sample = (cq viral sample) × (cq rnase p of the sample)/average value of cq of all the rnase p samples) (21) . rsv quantification was reported as log 10 copies/ml. about 2 ml of blood were collected in sodium heparin collection tubes (bd vacutainer) usually during the admission process. the sample was centrifuged at 1,000 g for 15 min at room temperature. the plasma obtained was divided into aliquots and stored at −80 • c. leptin concentration in plasma and npa was measured using the magnetic luminex r assay (r&d), according to manufacturer protocol. descriptive analyses, medians (ranges), and frequency distributions were used to summarize the demographic and baseline attributes of patients. associations among the dependent and independent variables were assessed by either the χ 2 , fisher's exact or mann-whitney tests. spearman's test was used to estimate the association between viral load and severity. multivariate poisson regression models were used to determine the factors that predict severity of infection (length of stay and duration of oxygen therapy). multicollinearity analyses among the independent variables were performed and none were observed. the cutoff point for multicollinearity was determined as variance inflation factor <5 and tolerance >0.2. we did not include birth weight in the multivariate regression model because it increases the multicollinearity in the model (variance inflation factors from 2.32 to 6.47). the relative risk (rr) for increased length of stay and oxygen therapy was calculated by taking the estimated poisson regression coefficient (β) for each variable and transforming it by eβ [exp * confidence interval] of each independent variable for the model. statistical significance was set at p < 0.05 for all analyses, along with a 95% confidence interval (ci). all analyses were performed with stata 14.1 software (statacorp, texas, usa). a total of 160 children were screened, and 124 patients were eligible for this study ( figure s1 ). the clinical and demographic characteristics of patients are presented in table 1 . obesity was found in 13.7% of the patients, 25.8% were overweight, and 60.5% presented normal weights. most of the children had both breastfeeding and complete vaccination schedules. the principal diagnosis was pneumonia (55.6%), followed by bronchiolitis and bronchitis ( table 1) . a total of 63 (50.8%) patients tested positive for a single respiratory virus, while another 61 patients (49.2%) tested positive for more than one respiratory virus. of these, 50 (82.0%) tested positive for two viruses and 11 (18.0%) for three viruses. rsv was the most frequently detected virus in 88 cases (70.9%), followed by hrv/hev in 33 (26.6%) and hbov in 27 (21.7%). most viruses were found in coinfection (figure 1 ). no differences were found between ns and type of virus detected ( figure s2) . nutritional status and coinfection (≥2 viruses) were evaluated to assess the effect of overnutrition in viral coinfection. obese and overweight infants showed a greater frequency of coinfection (obese 71% and overweight 68%) than those with normal weights (37%) (p = 0.013 and p = 0.004 respectively) (figure 2a) . no significant differences were found between overweight and obese infants (p = 0.839). the effect of obesity and overweight conditions on the rsv load was assessed in 46 infants (10 obese, 14 overweight, and 22 normal weight) with available nasopharyngeal samples. the median of rsv loads in obese infants was 5.91 log 10 copies/ml (min: 3.22 log 10 copies/ml and max: 7.86 log 10 copies/ml) and 6.49 log 10 copies/ml (min: 3.71 log 10 copies/ml and max: 8.11 log 10 copies/ml) for overweight infants, while those with normal weights had a median of 8.06 log 10 copies/ml (min: 4.15 log 10 copies/ml and max: 9.17 log 10 copies/ml). the difference between obese and overweight infants compared to those with normal weights was significant (obese p = 0.0205 and overweight p = 0.0212, respectively) ( figure 2b) . no significant differences were found between overweight and obese infants (p = 0.6395). no correlation was evidenced between rsv load and length of hospital stay (r = −0.124; p = 0.411) or days of oxygen therapy (r = −0.097; p = 0.517). tables 2, 3 present the results of the multiple poisson regression by transforming beta coefficients from the regression into relative risk calculations, which allowed us to test and evaluate the hypothesis that overnutrition is associated with the severity of viral respiratory infections, by adjusting covariates. when studying all of the patients, we found that only an overweight condition proved to be associated with a greater severity of infection both in length of stay ( also, we analyzed whether assisted ventilation is related to nutritional status and our results suggest that assisted ventilation, as a proxy of severity, was not statistically associated with overnutrition (fisher's exact, p = 0.862). no significant differences were seen between leptin level and nutritional status in both plasma and npa samples (figure 3) . on the other hand, we analyzed npa and plasma leptin level in children according to nutritional status separating by age group analyzed above (less or greater than 6 months) (figure 4) . we found a higher plasma leptin level in obese children <6 months than normal weight children <6 months (figure 4c ; 7.58 vs. 5.12 ng/µl; p < 0.046). obesity and alris constitute two important morbidity factors in the world, and its relationship began to be studied after the influenza h1n1 pandemic (7, 8) . in a multivariate analysis, we found that obese and overweight infants <6 months old were associated with disease severity as defined by longer hospitalization and oxygen therapy treatment. some previous studies have examined the impact of nutritional status on respiratory infections in children. similar to our results, rivera-claros et al. concluded that obesity is a risk factor for worse clinical course of acute lower respiratory tract infections in chilean infants with rsv infections and without chronic disease (9) . a study of 1,129 polish children found that overweight children had a higher risk for acute upper respiratory tract infections (22) . another observational study of 1,116 children hospitalized with community-acquired pneumonia in the united states, found that overweight or obese children were more likely to be admitted to the icu (23). however, it is still unclear why children with overnutrition have proven to be more prone to have severe respiratory infections. we found that in the group of children <6 months, plasma leptin level of obese patients was higher than normal weight patients. it is described that the adipose tissue acts as an endocrine organ, producing adipokines that exert immunomodulatory effects. leptin is a pro-inflammatory adipokine produced primarily in adipose tissue that increases in proportion to the body adiposity. the primary function of leptin is the control of appetite via the hypothalamus, and it has been established as a key hormone in deregulation of immune responses in obese patients (24) . teran-cabanillas et al. (13) showed that leptin induces socs3 overexpression which leads to reduced type i ifn production in obese patients. downstream in the route of type i ifns, the antiviral 2 ′ -5 ′ -oligoadenylate synthetase 1 (oas1) gene is also activated via jak-stat. we analyzed a small number of samples available for expression of oas1 gene. despite not finding significant differences, we found a tendency to decrease the expression of the oas1 gene in overweight and obese patients compared to normal weight children (data not shown). some studies have related leptin level with hepatitis virus infection. in the study by caner et al. (25) leptin levels were found unaltered in children with acute hepatitis a. however, tóth et al. (26) showed an association between the changes of serum leptin levels in children and the severity of hepatitis disease. it remains to be determined whether the infection by respiratory viruses affects leptin levels. we analyzed plasma and npa leptin level according to age (data not shown). we found that children <6 months showed higher plasma leptin level than older children, regardless of nutritional status (5.26 vs. 1.29 ng/µl; p < 0.0001). most of children <6 months (69%) were exclusive breastfeeding at the time of sampling. savino et al. (27) observed a positive association of breast milk leptin values not only with maternal body mass index but also with maternal and infant serum leptin values. on the other hand, it has been described that infants have an increased risk of obesity later in life if they have an overweight or obese mother (28) which can be reduced with the use of lowprotein feedings after 3 months (29) . chile has one of the highest prevalence rates of overweight and obesity in latin america (30) . overweight has 39% prevalence and obesity has 29%; 51% of women in reproductive age have a state of overnutrition (31). according to this, we speculate that the excess weight of mothers causes an increase of leptin in children under 6 months who receive breastfeeding, and this could have an impact on the severity of viral infections. therefore, further studies are needed to study the effect of breast milk leptin in infants. here, we have shown for the first time to our knowledge, that obesity and overweight conditions are associated with viral coinfections in children hospitalized for lrtis. although it is still unclear why this is so, there is some evidence that can start to shed light on this association. it has been reported that the erythrocyte membrane responds very early to modifications of plasma lipoproteins and suggest that in childhood obesity a modified transfer of cholesterol from plasma to erythrocyte membrane may take place (16) . several viruses use cholesterolrich microdomains (lipid rafts) to infect host cells (32) (33) (34) , as has been shown in influenza virus infections. influenza a virus rafts serve as a site for concentrating viral proteins and promoting the re-production of infectious viruses (35) . moreover, it has been reported that rsv uses lipid rafts in the plasma membrane as attachment platforms to enter normal human bronchial epithelial cells (36) . according to this, it is possible that the membrane composition of the respiratory tract cells of children with overnutrition is modified in a way that favors the entry of respiratory viruses. it has long been known that coinfections exhibit a phenomenon called viral interference, where one virus blocks the growth of another (37), thus the high frequency of simultaneous respiratory infections in obese and overweight patients is somewhat surprising and needs further study. consequently, we believe that overnutrition in children could alter the composition of cholesterol in the membrane of the respiratory epithelial tissue, facilitating the entry of viruses in different cells, which could explain the results obtained in this study. an inadequate immune response might also allow a greater entry of these pathogens. obesity provokes an imbalance in the immune system, including an aberrant type i interferon response, which are the key cytokines involved in the early immune response to viral infections (38) . the increase in coinfection related to obesity and overweight conditions may have additional health effects. it was recently reported that asthma in children between 6 and 8 years old is more frequent and severe in those that have been previously hospitalized with viral coinfection-bronchiolitis, compared to those with single infections (39) . the long-term effects of metabolic changes caused by early onset obesity must be explored in followup studies. obese and overweight patients, in addition to exhibiting high levels of viral coinfections as well as more severe infections, also presented lower viral loads than infants with standard weights. through a mathematical model, hrv, the fastestgrowing virus, reduces the replication of the remaining viruses during a coinfection, while piv, the slowest-growing virus is suppressed in the presence of other viruses (40). according to this, coinfections could limit the increase of rsv load because of competition for resources with other viruses. these results are in agreement with those previously described by garcia-mauriño (41) , where high viral load was associated with less severe rsv in children. a possible limitation of our study is that we analyzed npa samples using the rt-pcr method. it is unknown if this highly sensitive molecular technology detects only pathogens that cause lrtis or if some of the viruses detected could be commensal pathogens (42) . some of these detections might represent post infectious shedding. we addressed and controlled this problem by excluding children that had suffered from respiratory infections 2 weeks prior to the study. effective interventions are required to reduce childhood obesity. meanwhile, further research is needed to determine the role of leptin and other immunological markers in the severity of viral infection and to understand the pathophysiology of viral coinfection as it relates to nutritional status as well as to explore the epithelial-specific response to respiratory viruses in primary cells of lean and obese child. the datasets generated for this study 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we thank the children and their parents, the clinicians and staff of dr. exequiel gonzález cortés hospital and urgencia materno-infantil, clínica dávila for participating in this study. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped. 2020.00044/full#supplementary-material conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 arias-bravo, valderrama, inostroza, reyes-farías, garcia-diaz, zorondo-rodríguez and fuenzalida. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-267610-bzbr9ios authors: anastassopoulou, cleo; spanakis, nicholas; tsakris, athanasios title: sars-cov-2 transmission, the ambiguous role of children and considerations for the reopening of schools in the fall date: 2020-09-03 journal: future microbiology doi: 10.2217/fmb-2020-0195 sha: doc_id: 267610 cord_uid: bzbr9ios nan transmission of both sars coronaviruses leading to super-spreading events is plausible [17] . however, accumulating evidence shows that, in contrast to sars-cov-1, sars-cov-2 is transmitted before the onset of symptoms by symptomatic persons and even by asymptomatic individuals [18, 19] . droplets of saliva and other secretions are expelled from the respiratory tract (the mouth and nose) not only during such obviously forceful expiratory activities as sneezing and coughing, but also during breathing, particularly during intense physical exercise, talking, laughing and singing. we cannot help but wonder whether the extrovert nature of people from the south of europe, who typically speak loudly and have increased and often demonstratively affectionate social contacts not only with significant others, but also with friends and acquaintances and, notably, with extended family members, including elderly grandparents, has contributed to the devastating trajectories of the epidemic in countries like italy and spain. respiratory exhalations do not solely consist of mucosalivary droplets that follow short-range semi-ballistic emission trajectories allowing for a dichotomy between large and small droplets, as the still adopted by the who and other agencies transmission model originally proposed by william f wells for tuberculosis in the 1930s had suggested. instead, according to the new model for respiratory emissions, exhalations consist of clusters of varying in size droplets, trapped in a multiphase turbulent gas (a puff ) cloud of a locally moist and warm atmosphere that prevents evaporation, thereby considerably extending the time and distances virus particles can travel [20] . the implication of the current model is that a multiplicity of biophysical parameters determines the rates at which droplets of all sizes settle out or evaporate, depending not only on their size, but also on the degree of turbulence and speed of the gas cloud, coupled with the properties of the ambient environment (temperature, humidity and airflow), further perplexing the matter. airborne transmission of aerolized virus particles, which has just been identified as an additional, if not the dominant, spreading route of covid-19, appears to have contributed to the successful propagation of the novel coronavirus [21] . this latest finding prompted 239 scientists from 32 countries to urge the who and other bodies to address this potential in conjunction with contact transmission and mandate face covering in public to mitigate the airborne microdroplet transmission, in an open letter published on 6 july [22] . hence, the correlates of the sustained human-to-human transmission of sars-cov-2 have not been clearly defined yet. school closures that are commonly suggested for mitigating epidemics of respiratory infection were among the first social distancing measures implemented during this pandemic. decreases in covid-19 cases were indeed noted after school and daycare closures in many communities, even though modeling studies predicted that school closures alone would prevent only 2-4% of deaths, much less than other social distancing interventions, according to a review from the uk led by university college london [23] . from the early phases of the outbreak, it became apparent that adult pathogenesis varies with age and gender since older men with comorbidities (e.g., diabetes or cardiovascular disease) were at higher risk for severe illness from covid-19 [24] [25] [26] . at the other end of the spectrum, children generally experience less severe disease and have better prognosis after infection with sars-cov-2 [27] , although a multisystem inflammatory syndrome (mis-c) resembling kawasaki disease and toxic shock syndrome-like conditions has been observed in pediatric patients [28] . in addition, infants and preschool-aged children may be prone to more significant illness than older children [29, 30] . several explanations have been suggested for the typically low morbidity and mortality in children, including fewer underlying medical conditions and healthier respiratory tracts because of less exposure to cigarette smoke and air pollution and stronger innate immune responses [31] . an alternative explanation for the generally benign disease course in pediatric cases pertains to the less mature, and thus of decreased functionality (e.g., binding potential)-ace2 protein receptors for sars-cov-2 entry into cells. in agreement with this reasoning, data suggest that sars-cov-2 infections in children involve the upper rather than the lower respiratory tract, the typical site of severe covid-19 disease where ace2 receptors are more abundant [29] . the role of children in the transmission of the novel coronavirus is unclear [32] . by fitting an age-structured mathematical model to epidemic data from china, italy, japan, singapore, canada and south korea, davies et al. estimated that susceptibility to infection in individuals under 20 years of age was approximately half that of adults aged over 20 years and that interventions aimed at children might have a relatively small impact on reducing sars-cov-2 transmission, particularly in settings where the transmissibility of subclinical infections is low [33] . studies from israel and greece that examined the dynamics of covid-19 transmission within families showed significantly lower infection rates in children compared with adults residing in the same household [34, 35] . in a study of young children from northern france [36] , sars-cov-2 infection was found to be largely mild or asymptomatic and there was no evidence of onwards transmission from children in the school setting in line with previous studies from australia, ireland and france [37] [38] [39] . primary or elementary school children aged 6-11 years were less likely to transmit the virus compared with high school aged children who could transmit the virus as efficiently as adults. a large, carefully conducted study from south korea corroborated these results [40] . the reason why children younger than 10 years might transmit to others much less often than adults could be because of the air volume, and therefore of the virus-laden air, normally exhaled by children that is smaller or closer to the ground, making it less likely that adults would breathe it in. older children in middle and high school, who can be as tall as adults and yet may have some of the same unhygienic habits as young children, were found to be even more likely to infect others compared with adults by this south korean study [40] . analysis of 3303 covid-19 pediatric patient sputum samples by christian drosten's group in germany using two different pcr systems to assess viral load, determined that children under the age of 19 produce virtually the same average levels of viral rna as adults [41] . another study from chicago showed that children younger than 5 years had tenfold to 100-fold greater amount of sars-cov-2 viral rna, which correlates with infectious virus [42] , in their upper respiratory tracts compared with older children aged 5-17 years or adults aged 18-65 years [43] . sampling bias due to the increased possibility of asymptomatic infection in children that reduces the chances of being tested early in infection when virus levels in the nasopharynx are high, could explain the disparity in results from different studies. since viral rna levels in the feces remain high for more than three weeks after the onset of symptoms in contrast to viral rna in the nose and saliva that decline drastically within 1-2 weeks, analyzing stool samples for transmissible virus from mildly symptomatic and asymptomatic children could provide the experimental data to validate this argument [44] . viral replication in the gi tract and prolonged fecal shedding by infected children, particularly for infants and younger children who are not toilet-trained, may have substantial implications for community spread in day-care centers, schools and homes [29, 32] . further studies are needed to clarify the role of children in the transmission of the novel coronavirus. in this respect, a large prospective nih-funded study of 6000 people from 2000 us families in 11 cities, called human epidemiology and response to sars-cov-2, will help determine the incidence of novel coronavirus infection in children in the usa and whether rates differ between children who have asthma or other allergic conditions and children who do not [45] . the new us centers for disease control and prevention (cdc) guidelines on education and child care support the opening of schools in the fall. the main arguments in favor of the return to in-person schooling come from early reports that suggest that children are less likely to be infected than adults (at least based on nasopharyngeal viral rna detection as discussed in the previous subsection), and when they do contract covid-19, they generally have less serious illness. as of 21 july 2020, children and adolescents under 18 years old accounted for under 7% of covid-19 cases and less than 0.1% of covid-19-related deaths in the usa. schools, an important part of the infrastructure of communities, are indeed critical for the socialization and education of children, especially for students who rely on special education services (e.g., speech and occupational therapy). however, the evidence about whether returning to school results in increased transmission or outbreaks is inconclusive. transmission in schools appears to mirror rates in the community and, therefore, school reopenings seem to be safe when community sars-cov-2 transmission rates are low, as shown by international studies that have assessed how readily covid-19 spreads in schools [46] . school children are nonetheless anticipated to contribute to the community transmission of sars-cov-2 through their large numbers of daily social contacts, some of which are intergenerational, with older age groups where the risk for more severe illness is increased. hence, the reopening of schools should be considered carefully, with continuous monitoring of possible resurgence in infections through frequent testing and isolation of infected -and perhaps more importantly of infectious -students, educators and other staff, for their safety and for the safety and wellbeing of their families. the current centers for disease control and prevention guidelines do not recommend universal screenings by schools; instead, they strongly encourage parents or caregivers to monitor their children every day for 'signs of infectious illness', most likely referring to symptoms that, if present at all, are perceived differently by infected individuals, and to keep sick students at home. when schools reopen, additional strategies to limit transmission should be implemented as at other essential workplaces, including hand hygiene, physical distancing considering the recent advances in the biophysics of host-to-host respiratory disease transmission, respiratory etiquette and masks for older children. such mitigation measures would also help contain other respiratory infections in the community. alternative plans for virtual learning should be in place in the event of a school closure if community transmission levels cannot be controlled. finally, an alternative consideration that could provide both direct and indirect benefit given that children may contribute to adult infections and develop life-threatening disease themselves, is that vaccine development efforts for covid-19 should perhaps also consider the pediatric population. until we have safe and efficient prophylactic vaccines or therapeutics, or until sars-cov-2 becomes endemic, we have to continue to expect the unexpected from this novel coronavirus, the even brief encounter of which with our species, has changed the world forever. no specific funding was obtained for this study. the authors declare no competing interests. the authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. this includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. no writing assistance was utilized in the production of this manuscript. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia coronavirus disease 2019 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(covid-19) in the french alps ncirs. covid-19 in schools -the experience in nsw contact tracing during coronavirus disease outbreak, south korea an analysis of sars-cov-2 viral load by patient age. medrxiv culture-competent sars-cov-2 in nasopharynx of symptomatic neonates, children, and adolescents age-related differences in nasopharyngeal severe acute respiratory syndrome coronavirus 2 (sars-cov-2) levels in patients with mild to moderate coronavirus disease epub ahead of print) viral rna load in mildly symptomatic and asymptomatic children with covid-19 the national institute of allergy and infectious diseases (niaid) school openings across globe suggest ways to keep coronavirus at bay, despite outbreaks key: cord-263619-p17oomzn authors: moss, william j.; griffin, diane e.; feinstone, w. harry title: measles date: 2009-01-30 journal: vaccines for biodefense and emerging and neglected diseases doi: 10.1016/b978-0-12-369408-9.00030-5 sha: doc_id: 263619 cord_uid: p17oomzn abstract measles is a highly contagious disease characterized by a prodromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. measles virus is a nonsegmented, single-stranded, negative-sense rna virus and a member of the morbillivirus genus in the family of paramyxoviridae. although rna viruses have high mutation rates, measles virus is an antigenically monotypic virus and the surface proteins responsible for inducing protective immunity have retained their antigenic structure. the public health significance is that measles vaccines developed decades ago from a single measles virus strain remain protective worldwide. prior to the development and widespread use of measles vaccine, 30 million cases of measles were estimated to occur each year, resulting in more than 1 million deaths. several live, attenuated measles vaccines are available, either as single-antigen vaccines or in combination with rubella and mumps vaccines (mr and mmr vaccines). most of the currently used measles vaccines were derived from the edmonston strain of measles virus that was isolated by enders and peebles in 1954. measles vaccines are recommended for all susceptible children and adults for whom the vaccine is not contraindicated. despite progress in reducing measles mortality, measles remains a major cause of vaccine-preventable death and an important cause of morbidity and mortality in children, particularly sub-saharan africa and in asia. the ideal measles vaccine would be inexpensive, safe, heat-stable, immunogenic in neonates or very young infants, and administered as a single dose without needle or syringe. a number of vaccine candidates with some of these characteristics are undergoing preclinical studies, including dna vaccines and various viral and bacterial vectored vaccines. the high infectivity of measles virus is a characteristic suitable to a biothreat agent. however, increasingly high levels of measles vaccination coverage throughout the world as part of accelerated measles control efforts would protect many from the deliberate use of measles virus as a biothreat agent. genetic engineering of a measles virus strain that was not neutralized by antibodies induced by the current attenuated measles vaccines would likely have reduced infectivity, as suggested by the fact that wild-type measles viruses have not mutated to alter their neutralizing epitopes. measles virus meets many of the biological criteria for disease eradication. measles virus has no nonhuman reservoir, can be accurately diagnosed, and measles vaccination is a highly effective intervention. where measles virus differs from smallpox and polio viruses is that it is more highly infectious, necessitating higher levels of population immunity to interrupt transmission. it remains unclear whether the threat from bioterrorism precludes stopping measles vaccination after eradication, but provision of a second opportunity for measles vaccination likely could be stopped following eradication. measles is a highly contagious disease characterized by a prodromal illness of fever, cough, coryza, and conjunctivitis followed by the appearance of a generalized maculopapular rash. deaths from measles are due largely to an increased susceptibility to secondary bacterial and viral infections, attributed to a prolonged state of immune suppression. despite the development of an effective attenuated vaccine, measles remains a leading measles vaccines are recommended for all susceptible children and adults for whom the vaccine is not contraindicated. despite progress in reducing measles mortality, measles remains a major cause of vaccine-preventable death and an important cause of morbidity and mortality in children, particularly sub-saharan africa and in asia. the ideal measles vaccine would be inexpensive, safe, heat-stable, immunogenic in neonates or very young infants, and administered as a single dose without needle or syringe. a number of vaccine candidates with some of these characteristics are undergoing preclinical studies, including dna vaccines and various viral and bacterial vectored vaccines. the high infectivity of measles virus is a characteristic suitable to a biothreat agent. however, increasingly high levels of measles vaccination coverage throughout the world as part of accelerated measles control efforts would protect many from the deliberate use of measles virus as a biothreat agent. genetic engineering of a measles virus strain that was not neutralized by antibodies induced by the current attenuated measles vaccines would likely have reduced infectivity, as suggested by the fact that wild-type measles viruses have not mutated to alter their neutralizing epitopes. measles virus meets many of the biological criteria for disease eradication. measles virus has no nonhuman reservoir, can be accurately diagnosed, and measles vaccination is a highly effective intervention. where measles virus differs from smallpox and polio viruses is that it is more highly infectious, necessitating higher levels of population immunity to interrupt transmission. it remains unclear whether the threat from bioterrorism precludes stopping measles vaccination after eradication, but provision of a second opportunity for measles vaccination likely could be stopped following eradication. iii. viral vaccines figure 30.1 countries reporting measles cases (indigenous or imported) in [2005] [2006] since its emergence thousands of years ago. measles virus most closely resembles rinderpest virus, a pathogen of cattle, and likely evolved as a zoonotic infection in communities where cattle and humans lived in close proximity. measles virus is believed to have become established in human populations about 5000 -10,000 years ago when human populations achieved sufficient size in middle eastern river valley civilizations to maintain virus transmission. abu becr, an arab physician also known as rhazes, is generally credited with distinguishing smallpox from measles in the 9th century. he dated the first description of measles to the 6th century. however, epidemics identified as measles were not recorded until the 11th and 12th centuries, and measles was first mentioned as a childhood disease in 1224. the name " morbilli " was derived from the italian meaning " little diseases " to distinguish it from plague, " il morbo. " sanvages in 1763 defined morbilli as measles, but called it rubeola, leading to confusion with rubella. introduction of measles into previously unexposed populations has been associated with high mortality. one quarter of the population on the fiji islands died after the introduction of measles virus in 1875. millions died as a result of european exploration of the new world, largely due to the introduction of diseases such as smallpox and measles into native amerindian populations. the high mortality from these diseases facilitated european conquest of the americas ( mcneill, 1976 ) . many of the basic principles of measles epidemiology and infection were elucidated by peter panum, a danish physician who was sent to the faroe islands in 1846 during a large measles epidemic ( panum, 1938 ) . panum deduced the highly contagious nature of the disease, the 14-day incubation period, the lifelong immunity following infection, and postulated a respiratory route of transmission. measles virus first was isolated from the blood of david edmonston and others by enders and peebles (1954) . the development of vaccines against measles soon followed. measles virus is a spherical, nonsegmented, singlestranded, negative-sense rna virus and a member of the morbillivirus genus in the family of paramyxoviridae. other members of the morbillivirus genus are rinderpest virus and canine distemper virus. although rna viruses have high mutation rates, measles virus is an antigenically monotypic virus, meaning that the surface proteins responsible for inducing protective immunity have retained their antigenic structure. the public health significance is that measles vaccines developed decades ago from a single measles virus strain remain protective worldwide. measles virus is killed by ultraviolet light and heat. attenuated measles vaccine viruses retain these characteristics, necessitating a cold chain for transportation and storage. the measles virus rna genome consists of approximately 16,000 nucleotides and is enclosed in a lipidcontaining envelope derived from the host cell. the genome encodes eight proteins, two of which (v and c) are nonstructural proteins and are transcribed from the phosphoprotein (p) gene. of the six structural proteins, p, large protein (l), and nucleoprotein (n) form the nucleocapsid housing the viral rna. the hemagglutinin protein (h), fusion protein (f), and matrix protein (m), together with lipids from the host cell membrane, form the viral envelope. the h protein interacts with f to mediate fusion of the viral envelope with the host cell membrane ( malvoisin and wild, 1993 ) . the primary function of the h protein is to bind to the host cellular receptors for measles virus. the two identified receptors are cd46 and cd150 (slam). cd46 is a complement regulatory molecule expressed on all nucleated cells in humans. slam, an acronym for signaling lymphocyte activation molecule, is expressed on activated t and b lymphocytes and antigen-presenting cells. the binding sites on h for these receptors overlap and strains of measles virus differ in the efficiency with which each is used. wild-type measles virus binds to cells primarily through the cellular receptor slam whereas most vaccine strains bind to cd46; however, most measles virus strains can use both cd46 and slam as receptors during acute infection ( schneider et al., 2002 ) . additional, as yet unidentified receptors for measles virus exist on human endothelial and epithelial cells ( andres et al., 2003 ) . other measles virus proteins are involved in viral replication. the p protein regulates transcription, replication, and the efficiency with which the n assembles into nucleocapsids ( spehner et al., 1997 ) . the m protein links ribonucleoproteins with envelope proteins during virion assembly. the functions of v and c proteins have not been clearly defined, but both appear to contribute to the virulence of measles virus by regulating transcription and sensitivity to the antiviral effects of interferon (ifn) α / β ( valsamakis et al., 1998 ; patterson et al., 2000 ) . variability within the genome is sufficient to allow for molecular epidemiologic investigation. genetic characterization of wild-type measles viruses is based on sequence analysis of the genes encoding the measles virus fatal disease ( good and zak, 1956 ) . monkeys depleted of cd8 ϩ t-lymphocytes and challenged with wildtype measles virus had a more extensive rash, higher measles virus loads, and longer duration of viremia than control animals, further confirming the importance of cellular immunity in measles virus clearance ( permar et al., 2003 ) . cd4 ϩ t-lymphocytes also are activated in response to measles virus infection and secrete cytokines capable of modulating the humoral and cellular immune responses. plasma cytokine profiles show increased levels of ifn-γ during the acute phase, followed by a shift to high levels of interleukin (il)-4 and il-10 during convalescence ( moss et al., 2002 ) . the initial predominant th1 response (characterized by ifn-γ ) is presumed to be essential for viral clearance, while the later th2 response (characterized by il-4) promotes the development of measles virusspecific antibodies. the duration of protective immunity following wild-type measles virus infection is generally thought to be lifelong. the immunologic mechanisms involved in sustaining high levels of neutralizing antibody to measles virus are not completely understood, although general principles of immunologic memory probably govern this process. immunologic memory to measles virus includes both continued production of measles virus-specific igg antibodies and the circulation of measles virus-specific cd4 ϩ and cd8 ϩ t-lymphocytes ( ovsyannikova et al., 2003 ) . although immune protection is assessed by measurement of antimeasles virus antibodies, long lasting cellular immune responses almost certainly play an important role in protection from infection and disease. young infants in the first months of life are protected against measles by maternally acquired igg antibodies. an active transport mechanism in the placenta is responsible for the transfer of igg antibodies from the maternal circulation to the fetus starting at about 28 weeks gestation and continuing until birth ( crowe, 2001 ) . three factors determine the degree and duration of protection in the newborn: (1) the level of maternal antimeasles antibodies; (2) the efficiency of placental transfer; and (3) the rate of catabolism in the child. although providing passive immunity to young infants, maternally acquired antibodies can interfere with the immune responses to the attenuated measles vaccine by inhibiting replication of vaccine virus. in general, maternally acquired antibodies are no longer present in the majority of children by 9 months of age, the time of routine measles vaccination in many countries. women with vaccine-induced immunity tend to have lower antimeasles virus antibody titers than women with naturally acquired immunity, and their children may be susceptible to measles at an earlier age. n and h proteins. one of the most variable regions of the measles virus genome is the 450-nucleotide sequence at the carboxy-terminal of the n protein, with up to 12% variability between wild-type viruses. the world health organization (who) recognizes 8 clades of measles virus (designated a through h) and 23 genotypes ( world health organization, 2006 ) . new genotypes likely will be identified with enhanced surveillance and molecular characterization. as measles control efforts intensify, molecular surveillance of circulating measles virus strains can be used to document interruption of measles virus transmission and to identify the source and transmission pathways of measles virus outbreaks ( rota and bellini, 2003 ) . molecular epidemiologic tools also would be important in documenting deliberate bioterrorist introductions of wild-type or genetically modified measles virus strains. host immune responses to measles virus are essential for viral clearance, clinical recovery, and the establishment of long-term immunity. the early nonspecific (innate) immune responses that occur during the prodromal phase of the illness include activation of natural killer (nk) cells and production of ifn-α and β . these innate immune responses contribute to the control of measles virus replication before the onset of more specific adaptive immune responses. the protective efficacy of antibodies to measles virus is illustrated by the immunity conferred to infants from passively acquired maternal antibodies and the protection of exposed, susceptible individuals following administration of antimeasles virus immune globulin ( black and yannet, 1960 ) . the first measles virus-specific antibodies produced after infection are of the igm subtype, followed by a switch to predominantly igg3 and then to igg1 and igg4 isotypes ( isa et al., 2002 ) . iga antibodies to measles virus are found in mucosal secretions. the most abundant and rapidly produced antibodies are against n, and the absence of antibodies to n is the best indicator of seronegativity to measles virus. antibodies to h and f proteins contribute to virus neutralization and are sufficient to provide protection against measles virus infection. evidence for the importance of cellular immunity to measles virus is demonstrated by the ability of children with agammaglobulinemia to fully recover from measles, whereas children with severe defects in t-lymphocyte function often develop severe or epidemiology prior to the development and widespread use of measles vaccine, 30 million cases of measles were estimated to occur each year, resulting in more than 1 million deaths. despite progress in reducing measles mortality, measles remains the most frequent cause of vaccinepreventable death and an important cause of morbidity and mortality in children, particularly in sub-saharan africa and in asia ( henao-restrepo et al., 2003 ) . the disease burden due to measles decreased over the past several decades due to a number of factors. measles mortality declined in developed countries in association with economic development, improved nutritional status and supportive care, particularly antibiotic therapy for secondary bacterial pneumonia. remarkable progress in reducing measles incidence and mortality has been, and continues to be, made in resource-poor countries as a consequence of increasing measles vaccine coverage, provision of a second opportunity for measles vaccination through supplementary immunization activities, and efforts by the who, the united nations children's fund (unicef) and their partners to target 45 countries for accelerated and sustained measles mortality reduction. specifically, this targeted strategy aims to achieve ͼ 90% measles vaccination coverage in every district of the 45 countries and to ensure that all children receive a second opportunity for measles immunization ( world health organization, 2001 ) . provision of vitamin a through polio and measles vaccination campaigns has contributed further to the reduction in measles mortality ( world health organization, 2005 ) . in 2003, the world health assembly endorsed a resolution urging member countries to reduce the number of deaths attributed to measles by 50% by the end of 2005 compared with 1999 estimates. overall global measles mortality in 2005 was estimated to be 345,000 deaths (uncertainty bounds 247,000 and 458,000 deaths) ( wolfson et al., 2007 ) . this estimate represents a 60% decrease from 1999, when the global number of measles deaths was estimated to be 873,000 (uncertainty bounds 634,000 and 1,140,000 deaths). the largest decrease in measles mortality was in africa, contributing 72% of the global reduction in measles mortality. measles incidence has a typical temporal pattern characterized by annual, seasonal epidemics superimposed upon longer epidemic cycles of 2 -5 years or more. in temperate climates, annual measles outbreaks typically occur in the late winter and early spring. these annual outbreaks are likely the result of social networks facilitating transmission (e.g., congregation of children at school) and environmental factors favoring the viability and transmission of measles virus ( fine and clarkson, 1982 ) . measles cases continue to occur during the interepidemic period in densely populated communities but at low incidence. the longer cycles occurring every several years result from the accumulation of susceptible persons over successive birth cohorts and the subsequent decline in the number of susceptibles following an outbreak. in the absence of a vaccination program these longer epidemic cycles tend to occur every 2 -4 years. measles vaccination programs that achieve coverage rates in excess of 80% extend the interepidemic period to 4 -8 years by reducing the number of susceptible individuals. humans are the only reservoir for measles virus, a characteristic important for the potential eradication of measles. nonhuman primates may be infected with measles virus and develop an illness similar to measles in humans, with rash, coryza, and conjunctivitis. however, populations of wild monkeys are not of sufficient size to maintain measles virus transmission. measles virus is transmitted primarily by respiratory droplets small enough to traverse several feet but too large to remain suspended in the air for long periods of time. the symptoms induced during the prodrome, particularly sneezing and coughing, enhance transmission. measles virus also may be transmitted by the airborne route, suspended on small particles for a prolonged time. direct contact with infected secretions can transmit measles virus, but the virus does not survive long on fomites as it is quickly killed by heat and ultraviolet radiation. the average incubation period for measles, the time from infection to clinical disease, is approximately 10 days to the onset of fever and 14 days to the onset of rash (range 7 -18 days). the incubation period may be shorter in infants and following a large inoculum of virus, and longer in adults. during this seemingly quiescent period, the virus is rapidly replicating and infecting target tissues. measles virus is one of the most highly contagious infectious agents and outbreaks can occur in populations in which less than 10% of persons are susceptible. chains of transmission commonly occur among household contacts, school children, and health care workers. generally, persons with measles are infectious for several days before and after the onset of rash, when titers of measles virus in the blood and body fluids are highest. as with many other acute viral infections (sars-coronavirus being an exception), the fact that measles virus is contagious prior to the onset of recognizable disease hinders the effectiveness of quarantine measures. measles virus can be isolated in tissue culture from the urine as late as 1 week after rash onset. detection of measles virus in body epidemiology maculopapular rash appears first on the face and behind the ears, and then spreads in a centrifugal fashion to the trunk and extremities. the rash lasts for 3 -4 days and fades in the same manner as it appeared. in uncomplicated measles, clinical recovery begins soon after appearance of the rash. complications occur in up to 40% of measles cases, and the risk of complication is increased by extremes of age, malnutrition, and vitamin a deficiency ( morley, 1969 ) . complications of measles have been described in almost every organ system. the respiratory tract is a frequent site of complication, with pneumonia accounting for most measles-associated deaths ( duke and mgone, 2003 ) . pneumonia is caused by secondary viral or bacterial infections, or by measles virus itself. pathologically, measles virus infection of the lung is characterized by multinucleated giant cells, formed when measles virus proteins on the cell surface allow cells to fuse. other respiratory complications include laryngotracheobronchitis and otitis media. mouth ulcers, or stomatitis, may hinder children from eating or drinking. many children with measles develop diarrhea, which further contributes to malnutrition. keratoconjunctivitis is common after measles, particularly in children with vitamin a deficiency, and was a frequent cause of blindness. because the rash of measles is a consequence of the cellular immune response, persons with impaired cellular immunity, such as those with the acquired immunodeficiency syndrome (aids), may not develop the characteristic measles rash. these persons have a high case fatality and may develop a giant cell pneumonitis due to measles virus ( moss et al., 1999 ) . t-lymphocyte defects due to causes other than hiv-1 infection, such as cancer chemotherapy, are also associated with increased severity of measles. rare but serious complications of measles involve the central nervous system. postmeasles encephalomyelitis complicates approximately 1 in 1000 cases, mainly older children and adults. encephalomyelitis occurs within 2 weeks of the onset of rash and is characterized by fever, seizures, and a variety of neurological abnormalities. the finding of periventricular demyelination, the induction of immune responses to myelin basic protein, and the absence of measles virus in the brain suggest that postmeasles encephalomyelitis is an autoimmune disorder triggered by measles virus infection. other central nervous system complications that occur months to years after acute infection are measles inclusion body encephalitis (mibe) and subacute sclerosing panencephalitis (sspe). in contrast to postmeasles encephalomyelitis, mibe and sspe are caused by persistent measles virus infection. mibe is a rare but fatal complication that affects fluids by a variety of means, including identification of multinucleated giant cells in nasal secretions or the use of reverse transcriptase-polymerase chain reaction (rt-pcr), suggests the potential for a prolonged infectious period in persons immunocompromised by severe malnutrition or human immunodeficiency virus type 1 (hiv-1) infection ( dossetor et al., 1977 ; permar et al., 2001 ; riddell et al., 2007 ) . however, whether detection of measles virus by these methods indicates prolonged contagiousness is unclear. in densely populated urban settings with low vaccination coverage rates, measles is a disease of young children. the cumulative distribution can reach 50% by 1 year of age, with a significant proportion of children acquiring measles virus infection before 9 months, the age of routine vaccination. as measles vaccine coverage increases, or population density decreases, the age distribution shifts toward older children. in such situations, measles cases predominate in school-age children. infants and younger children, although susceptible if not protected by immunization, are not exposed to measles virus at a rate sufficient to cause a large disease burden in this age group. as vaccination coverage increases further, the age distribution of cases may be shifted into adolescence and young adulthood, as seen in measles outbreaks in the united states, brazil, and australia ( hutchins et al., 1996 ; de quadros et al., 1998 ; lambert et al., 2000 ) , necessitating targeted measles vaccination programs for these older age groups. the high infectivity of measles virus is a characteristic suitable to a biothreat agent. however, increasingly high levels of measles vaccination coverage throughout the world as part of accelerated measles control efforts would protect many from the deliberate use of measles virus as a biothreat agent. genetic engineering of a measles virus strain that was not neutralized by antibodies induced by the current attenuated measles vaccines would likely have reduced infectivity, as suggested by the fact that wild-type measles viruses have not mutated to alter their neutralizing epitopes. clinically apparent measles begins with a prodrome characterized by fever, cough, coryza, and conjunctivitis. koplik's spots, small white lesions on the buccal mucosa inside the mouth, may be visible during the prodrome and allow the astute clinician to diagnose measles prior to the onset of rash. the prodromal symptoms intensify several days before the onset of rash. the characteristic erythematous and individuals with defective cellular immunity and typically occurs months after infection. sspe is a slowly progressive disease characterized by seizures, progressive deterioration of cognitive and motor functions followed by death that occurs 5 -15 years after measles virus infection, most often in persons infected with measles virus before 2 years of age. there are conflicting and inconclusive data suggesting that measles virus infection causes or contributes to the development of chronic diseases, including multiple sclerosis, paget's disease, inflammatory bowel disease, and otosclerosis ( perry and halsey, 2004 ) . however, no causal association has been established between measles and these conditions. the characteristic clinical features of measles are of sufficient sensitivity and specificity to have high predictive value in regions where measles is endemic. however, laboratory diagnosis is necessary where measles virus transmission rates are low or in immunocompromised persons who may not have the characteristic clinical manifestations. infection with rubella, parvovirus b19, human herpes virus 6, and dengue viruses may mimic measles. detection of igm antibodies to measles virus by enzyme immunoassay (eia) is the standard method of diagnosing acute measles ( bellini and helfand, 2003 ) . alternatively, seroconversion using igg-specific eia, hemagglutinin inhibition, complement fixation, or virus neutralization assays can be used to diagnose acute measles based on testing serum or plasma obtained during the acute and convalescent phases. measles virus can be isolated in tissue culture from white blood cells, respiratory tract secretions, and urine, although the ability to isolate measles virus diminishes quickly after rash onset. amplification and detection of measles virus rna by rt-pcr from blood, urine, and nasal discharge is highly sensitive in detecting measles virus rna and allows sequencing of the measles virus genome for molecular epidemiologic studies. no specific antiviral drug is used routinely to treat measles virus infection, although the broad antiviral agent ribavirin has been used to treat immunocompromised persons or persons with sspe, alone or in combination with ifn-α or intravenous immunoglobulin ( forni et al., 1994 ; solomon et al., 2002 ) . the major components of case management include provision of vitamin a, prompt treatment of secondary bacterial infections, and nutritional support. several placebo-controlled trials have demonstrated marked reductions in morbidity and mortality in hospitalized children with measles treated with vitamin a. the who recommends administration of two daily doses of 200,000 iu of vitamin a to all children with measles 12 months of age or older. lower doses (100,000 iu) are recommended for children less than 12 months of age. overall, this regimen resulted in a 64% reduction in the risk of mortality (rr ϭ 0.36, 95% ci 0.14 -0.82) ( d'souza and d'souza, 2002 ) . pneumonia-specific mortality is reduced, and the impact is greatest in children less than 2 years of age ( d'souza and d'souza, 2002 ) . secondary bacterial infections are a major cause of morbidity and mortality following measles ( duke and mgone, 2003 ) , and effective case management involves prompt treatment with antibiotics. various strategies have been used to guide antibiotic therapy in children with measles. antibiotics are indicated for children with measles who have clinical evidence of bacterial infection, including pneumonia, otitis media, skin infection, eye infection, and severe mouth ulcers. streptococcus pneumoniae and haemophilus influenza type b are the most common causes of bacterial pneumonia following measles, and antibiotic therapy should be directed against these pathogens. whether all children with measles, or all hospitalized children with measles, should be given prophylactic antibiotics remains controversial. limited evidence suggests that antibiotics administered as prophylaxis to all children presenting with measles may reduce the incidence of pneumonia but not mortality ( duke and mgone, 2003 ) . the potential benefits of antibiotic prophylaxis need to be weighed against the risks of accelerating antibiotic resistance. vitamin a has been widely distributed through polio and measles supplemental immunization activities as well as through routine child health services. pooled analysis of community-based studies of vitamin a supplementation of apparently healthy children resulted in a 39% reduction in measles-associated mortality ( villamor and fawzi, 2000 ) . thus, vitamin a is not only effective in reducing mortality when used to treat hospitalized children with measles but community-based supplementation programs also can result in measles mortality reduction. respiratory droplets from infected persons serve as vehicles of transmission by carrying infectious virus to epithelial cells of the respiratory tract of susceptible hosts. during the 10 -14 day incubation period between infection and the onset of clinical signs and symptoms, measles virus replicates and pathogenesis children following measles virus infection. functional abnormalities of immune cells have also been detected, including decreased lymphocyte proliferative responses ( hirsch et al., 1984 ) . dendritic cells, major antigenpresenting cells, mature poorly, lose the ability to stimulate proliferative responses in lymphocytes, and undergo cell death when infected with measles virus in vitro ( servet-delprat et al., 2000 ) . the dominant th2 response in children recovering from measles can inhibit th1 responses and increase susceptibility to intracellular pathogens ( griffin et al., 1985 ; griffin and ward, 1993 ) . the production of il-12, important for the generation of th1-type immune response, decreases following binding of the cd46 receptor ( karp et al., 1996 ) and is low for several weeks in children with measles ( atabani et al., 2001 ) . this diminished ability to produce il-12 could further result in a limited th1 immune response to other pathogens. furthermore, engagement of cd46 and cd3 on monocytes induces production of high levels of il-10 and transforming growth factor (tgf)-β , an immunomodulatory and immunosuppressive cytokine profile characteristic of regulatory t cells ( kemper et al., 2003 ) . the role of these cytokines in the immune suppression following measles is supported by in vivo evidence of elevated levels of il-10 in the plasma of children after measles virus infection ( moss et al., 2002 ) . attenuation of measles virus was achieved primarily by serial passage in chick embryo cells. the first attenuated measles vaccine licensed in the united states was edmonston b. this vaccine was immunogenic and widely used between 1963 and 1975, but was frequently associated with fever and rash. the schwarz and moraten (more attenuated) strains were derived from the original edmonston strain but further attenuated through additional passage in chick embryo fibroblasts. despite differences in their passage history, these vaccine strains have identical genomic sequences ( parks et al., 2001 ) . the moraten vaccine (merck) is the only measles vaccine used in the united states, whereas the schwarz vaccine is used in many countries throughout the world. other attenuated measles vaccines have been produced from locally derived wild-type strains, particularly in russia, china, and japan. one vaccine strain, the edmonston-zagreb vaccine, was also passaged in human diploid cells after attenuation in chick embryo fibroblasts, which may account for its increased immunogenicity and reactogenicity. measles vaccines spreads within the infected host. initial viral replication occurs in epithelial cells at the portal of entry in the upper respiratory tract and the virus then spreads to local lymphatic tissue. replication in local lymph nodes is followed by viremia (the presence of virus in the blood) and the dissemination of measles virus to many organs, including lymph nodes, skin, kidney, gastrointestinal tract and liver, where the virus replicates in epithelial and endothelial cells as well as monocytes and macrophages. although measles virus infection is clinically inapparent during the incubation period, the virus is actively replicating and the host immune responses are developing. evidence of these processes can be detected. during the incubation period, the number of circulating lymphocytes is reduced (lymphopenia) . measles virus can be isolated from the nasopharynx and blood during the later part of the incubation period and during the several days prior to the onset of rash when levels of viremia are highest. the prodrome ends with the appearance of the measles rash. the rash results from measles virusspecific cellular immune responses and marks the beginning of viral clearance from blood and tissue. histologic examination of the rash reveals infected capillary endothelial cells and a mononuclear cell infiltrate ( kimura et al., 1975 ) . clearance of infectious virus from the blood and other tissues occurs within the first week after the appearance of the rash, although measles virus rna can be detected in body fluids of some children for at least several months using a rt-pcrbased assay ( permar et al., 2001 ; riddell et al., 2007 ) . the intense immune responses induced by measles virus infection are paradoxically associated with depressed responses to unrelated (nonmeasles virus) antigens, lasting for several weeks to months beyond resolution of the acute illness. this state of immune suppression enhances susceptibility to secondary bacterial and viral infections causing pneumonia and diarrhea, and is responsible for much measlesrelated morbidity and mortality ( beckford et al., 1985 ; greenberg et al., 1991 ) . delayed-type hypersensitivity (dth) responses to recall antigens, such as tuberculin, are suppressed ( tamashiro et al., 1987 ) and cellular and humoral responses to new antigens are impaired following measles virus infection ( coovadia et al., 1978 ) . reactivation of tuberculosis and remission of autoimmune diseases have been described after measles and are attributed to this state of immune suppression. abnormalities of both the innate and adaptive immune responses have been described following measles virus infection. transient lymphopenia with a reduction in cd4 ϩ and cd8 ϩ t-lymphocytes occurs in are relatively heat stable in the lyophilized (dry) form, but rapidly lose potency when exposed to heat after reconstitution. in the 1960s, a formalin-inactivated, alum-precipitated measles vaccine (fimv) was licensed and administered to children in the united states. three doses of inactivated vaccine elicited a protective antibody response but antibody titers waned within months ( carter et al., 1962 ) . up to 60% of immunized children exposed to measles developed atypical measles, characterized by high fever, pneumonitis, and a petechial rash on the extremities ( fulginiti et al., 1967 ; nader et al., 1968 ) , leading to withdrawal of the fimv in 1967. in a rhesus macaque model, atypical measles was shown to be associated with immune complex deposition in affected tissues and a systemic and pulmonary eosinophilia ( polack et al., 1999 ) . the antibody response consisted of high levels of complement fixing antibodies with low avidity for measles virus, characteristics that may have promoted exaggerated immune complex formation and disease. seroconversion rates with attenuated measles vaccines in young infants are low because of immunologic immaturity and the interference of transplacentally acquired maternal antibodies with replication of vaccine virus ( gans et al., 1998 ) . to protect young infants against measles, high-titer preparations containing 10 -100 times the standard dose of vaccine virus were evaluated in several countries. seroconversion rates in 4 -6 month old infants immunized with high-titer measles vaccine were comparable to those of 9 -15 month old children vaccinated with standard-titer measles vaccine, and the protective antibody response persisted for over 2 years. however, high-titer measles vaccine resulted in a poorly understood increase in mortality in immunized girls 1 -2 years after vaccination compared to girls immunized with standard-titer vaccine at 9 months of age ( holt et al., 1993 ; aaby et al., 1996 ) . the increased mortality was attributable to infections commonly associated with measles, such as diarrhea and pneumonia. although these studies were carried out in countries with different levels of socioeconomic development, excess mortality was observed only in countries with poor socioeconomic conditions and frequent malnutrition (senegal, haiti, and guinea bissau). the basis for the increased mortality in girls is not understood. several live, attenuated measles vaccines are available worldwide, either as single-antigen vaccines or in combination with rubella and mumps vaccines (mr and mmr vaccines). recently, a combined measlesmumps-rubella-varicella vaccine was licensed by the united states food and drug administration (proquad, merck and co., inc.). licensed combination vaccines do not reduce the immunogenicity of the measles component. most of the currently used measles vaccines were derived from the edmonston strain of measles virus that was isolated by enders and peebles in 1954. these vaccines have undergone different passage histories in cell culture, but nucleotide sequence analysis shows less than 0.6% genetic differences between the vaccine strains. vaccines in widespread use that were derived from the edmonston measles virus stain include the schwarz, edmonston-zagreb, and moraten strains. vaccines derived from other measles virus strains include cam-70, and shanghai 191. the live, attenuated measles vaccines are typically cultured in primary chick embryo or human diploid (e.g., edmonston-zagreb) cells for several days. the supernatant fluid is harvested and frozen. vaccine stocks are quality and safety tested before they are lyophilized. measles vaccines may contain sorbitol or gelatin as stabilizers and the antibiotic neomycin, but do not contain thimerosal. traces of the reverse transcriptase of an avian retrovirus can be found in vaccines cultured in chick embryo fibroblasts but there is no evidence that this is harmful to vaccine recipients. prior to use, the vaccine must be reconstituted in sterile diluent. measles vaccines lose about half of their potency after reconstitution if stored at 20 ° c for 1 h, and lose almost all potency if stored at 37 ° c for 1 h. measles vaccines are recommended for all susceptible children and adults for whom the vaccine is not contraindicated ( table 30 .1 ). adolescents and young adults may constitute a susceptible population, recommendations of the advisory committee on immunization practices for the united states • a two-dose schedule with mmr vaccine is recommended. • the first dose is recommended at 12 -15 months of age. • the second dose is recommended at 4 -6 years of age. • adults at increased risk should receive special consideration for measles vaccination, including international travelers, students attending colleges and other post-high school educational institutions, and persons who work at health care facilities. • measles vaccine is not indicated for persons with severe hypersensitivity (anaphylaxis) to neomycin or gelatin, or who are severely immunocompromised. • measles vaccine should be administered at 9 months of age. • a second opportunity for measles vaccination should be provided through mass measles vaccination campaigns. • hiv-infected children should receive measles vaccine at 6 and 9 months of age, unless severely immunocompromised, because of their increased risk of severe measles. the proportion of children who develop protective antibody titers following measles vaccination depends on the presence of inhibitory maternal antibodies and the immunologic maturity of the vaccine recipient, as well as the dose and strain of vaccine virus. frequently cited figures are that approximately 85% of children develop protective antibody titers when given measles vaccine at 9 months of age and 90 -95% respond when vaccinated at 12 months of age ( cutts et al., 1995 ) . concurrent acute infections may interfere with the immune response to measles vaccine, although this is probably uncommon ( scott et al., 1999 ) . polymorphisms in human immune response genes also influence immune responses to measles vaccine ( ovsyannikova et al., 2004 ) . the duration of immunity following measles vaccination is more variable and shorter than following wild-type measles virus infection, with an estimated 5% of children developing secondary vaccine failure at 10 -15 years after vaccination ( anders et al., 1996 ) . immunologic boosting from repeated exposure to measles virus may play a role in maintaining protective antibody levels in communities with measles virus transmission ( whittle et al., 1999 ) . the who encourages measles vaccination of all susceptible children and adults. because measles can be more severe in hiv-infected persons and the risk of serious adverse events appears to be small, the who recommends that asymptomatic hiv-infected persons, and even those who are symptomatic but not severely immunocompromised, receive measles vaccine. the american academy of pediatrics recommends that severely immunocompromised children and adults, defined by low cd4 ϩ t-lymphocyte cell counts or percentage, should not receive measles vaccine because of the potential risk of vaccine-related pneumonitis. measles vaccine is contraindicated in persons with a history of anaphylactic reaction to neomycin, gelatin, or other vaccine components. fever occurs in approximately 5 -15% of recipients 6 -12 days following measles vaccination, and a rash occurs in approximately 5% of recipients. these signs and symptoms are a consequence of the host immune response to replicating measles vaccine virus, but do not result in serious morbidity or mortality. rarely, thrombocytopenia may occur. although assumed to be rare, the risk of disease caused by attenuated measles vaccine virus in hivinfected persons is unknown. the only documented case of disease induced by vaccine virus in an hiv-infected person was in a 20-year-old man who died 15 months after receiving his second dose of measles vaccine ( angel et al., 1998 ) . he had a very low cd4 ϩ t-lymphocyte cell count but no hiv-related symptoms at the time of including university students, health care workers, and military recruits. a single dose of measles vaccine provides lifelong immunity in the majority of vaccine recipients. however, a second opportunity for measles vaccination provides protection to those with primary vaccine failure and a chance to reach unvaccinated children. the second opportunity may be delivered through routine health services at school entry or through supplementary immunization activities such as national immunization days. measles vaccines are usually injected subcutaneously but can be administered intramuscularly. each 0.5 ml dose of vaccine contains at least 1000 infective units of measles vaccine virus. the optimal age of measles vaccination is determined by consideration of the age-dependent increase in seroconversion rates following measles vaccination and the average age of infection. in regions of intense measles virus transmission, the average age of infection is low and the optimal strategy is to vaccinate against measles as young as possible. however, both maternally acquired antibodies and immunologic immaturity reduce the protective efficacy of measles vaccination in early infancy ( gans et al., 1998 ) . in many parts of the world, 9 months is considered the optimal age of measles vaccination ( halsey, 1983 ) , and is the age recommended by the expanded program on immunization (epi). most countries following the epi schedule administer measles vaccine alone, although more countries are introducing combined measles and rubella vaccines as rubella control programs expand. under some circumstances, provision of an early dose of measles vaccine at 6 months of age (e.g., in outbreaks or to hiv-infected children) is appropriate. in regions that have achieved measles control or elimination, where the risk of measles in infants is low, the age of measles vaccination is increased to ensure that a higher proportion of children develop protective immunity. for example, in the united states the first dose of measles vaccine is administered at 12 -15 months of age, as the combined mmr vaccine. measles vaccine induces both humoral and cellular immune responses. antibodies first appear between 12 and 15 days after vaccination and peak at 21 -28 days. igm antibodies appear transiently in blood, iga antibodies are predominant in mucosal secretions, and igg antibodies persist in blood for years. vaccination also induces measles virus-specific t-lymphocytes ( ovsyannikova et al., 2003 ; wong-chew et al., 2004 ) . although both humoral and cellular responses can be induced by measles vaccine, they are of lower magnitude and shorter duration compared to those following wild-type measles virus infection ( ward et al., 1995 ) . vaccination. ten months later he developed giant cell pneumonitis and measles vaccine virus was identified in his lung. fatal, disseminated infection with measles vaccine virus has been reported rarely in persons with other impairments of immune function ( monafo et al., 1994 ) , and mibe due to vaccine virus was reported in a child with an uncharacterized immune deficiency ( bitnun et al., 1999 ) . much public attention has focused on a purported association between mmr vaccine and autism following publication of a report in 1998 hypothesizing that mmr vaccine may cause a syndrome of autism and intestinal inflammation ( wakefield et al., 1998 ) . the events that followed, and the public concern over the safety of mmr vaccine, led to diminished vaccine coverage in the united kingdom and provide important lessons in the misinterpretation of epidemiologic evidence and the communication of scientific results to the public ( offit and coffin, 2003 ) . the publication that incited the concern was a case series describing 12 children with a regressive developmental disorder and chronic enterocolitis. nine of the children had autism. onset of the developmental delay was associated by the parents with mmr vaccination in eight children. this simple temporal association was misinterpreted and misrepresented as a possible causal relationship, first by the lead author of the study and then by the media and public. subsequently, several comprehensive reviews and additional epidemiological studies rejected evidence of a causal relationship between mmr vaccination and autism ( destefano and thompson, 2004 ) . one of the most conclusive studies was a large retrospective cohort study of over half a million danish children that found the relative risk of mmr vaccine for autistic disorder to be 0.92 (95% confidence interval, 0.68 -1.24) ( madsen et al., 2002 ) . aerosol administration of measles vaccine was first evaluated in the early 1960s in several countries, including the former soviet union and the united states. more recent studies in south africa ( dilraj et al., 2000 ) and mexico ( bennett et al., 2002 ) have shown that aerosol administration of measles vaccine is highly effective in boosting antibody titers, although the primary immune response to aerosol measles vaccine is lower than following subcutaneous administration ( wong-chew et al., 2004 ) . administration of measles vaccine by aerosol has the potential to greatly facilitate measles vaccination during mass campaigns, and the who plans to test and bring to licensure an aerosol measles vaccine by 2009. the ideal measles vaccine would be inexpensive, safe, heat-stable, immunogenic in neonates or very young infants, and administered as a single dose without needle or syringe. the age at vaccination should coincide with the epi schedule to maximize compliance and share resources. finally, a new vaccine should not elicit atypical measles upon exposure of immunized individuals to wild-type measles virus and should not be associated with prolonged immunosuppression, adversely affecting immune responses to subsequent infections. a number of vaccine candidates with some of these characteristics are undergoing preclinical studies ( table 30 .2 ). naked cdna vaccines are thermostable, inexpensive, and could theoretically elicit antibody responses in the presence of passively acquired maternal antibody. dna vaccines encoding either or both the measles h and f proteins are safe, immunogenic, and protective against measles challenge in na ï ve, juvenile rhesus macaques ( polack et al., 2000 ) . a different diagnosed, and measles vaccination is a highly effective intervention. although measles virus displays sufficient genetic variability to conduct molecular epidemiologic analyses, the antigenic epitopes against which protective antibodies develop have remained stable. measles virus differs from smallpox and polio viruses, however, in that it is more highly infectious, necessitating much higher levels of population immunity to interrupt transmission. potential barriers to measles eradication include: (1) lack of political will; (2) difficulties of measles control in densely populated urban environments; (3) the hiv epidemic; (4) waning immunity and the potential transmission from subclinical cases; (5) transmission among susceptible adults; (6) the risk of unsafe injections; and (7) unfounded fears of disease due to measles vaccine ( orenstein et al., 2000 ) . whether the threat from bioterrorism precludes stopping measles vaccination after eradication is a topic of debate, but, at the least, a single-dose rather than a two-dose measles vaccination strategy could be adopted ( meissner et al., 2004 ) . the elimination of endemic measles virus transmission in large geographic areas, such as the americas, suggests that global eradication is feasible with current vaccination strategies ( de quadros, 2004 ) . many believe this to be a realistic and morally imperative goal, but, as polio eradication efforts have shown, the endgame may be full of challenges. • measles is highly contagious viral infection. • great progress has been made in measles control and elimination through accelerated efforts, including increased routine vaccination coverage rates and supplementary immunization activities. • despite the reduction in measles cases and deaths, measles remains a leading cause of vaccinepreventable death worldwide. the high infectivity of measles virus is a characteristic suitable to a biothreat agent. • increasingly high levels of measles vaccination coverage throughout the world would protect many from the deliberate use of measles virus as a biothreat agent. • measles vaccine virus can be used as a vector to deliver genes derived from other pathogens. • genetic engineering of a measles virus strain that was not neutralized by antibodies induced by the current attenuated measles vaccines would likely have reduced infectivity, although this is not certain. construct, containing h, f, and n genes and an il-2 molecular adjuvant, provided protection to infant macaques in the presence of neutralizing antibody ( premenko-lanier et al., 2003 , 2004 . alternative techniques for administering measles dna, such as alphavirus ( pan et al., 2005 ) , parainfluenza virus ( skiadopoulos et al., 2001 ) , or enteric bacterial ( pasetti et al., 2003 ) vectors, also are under investigation. immune responses to intranasal administration of measles virus vaccines is enhanced by the use of adjuvants ( chabot et al., 2005 ) . novel oral immunization strategies have been developed using plant-based expression of the measles virus h protein in tobacco ( webster et al., 2005 ) . these vaccines induced humoral immune responses following both primary immunization and as a booster dose after a dna prime. in addition, attenuated recombinant measles virus vaccines have been used as vectors for the delivery of genes from other pathogens ( tangy and naim, 2005 ) . immune globulin can be given intramuscularly to susceptible persons within 6 days of exposure to prevent or lessen the severity of disease. postexposure immunoprophylaxis is indicated for those at high risk of severe disease, including susceptible household contacts between 6 months and 1 year of age, pregnant women, and immunocompromised persons. where resources are not limited, hiv-infected children, or those exposed to hiv but whose infection status is unknown, should receive postexposure immunoprophylaxis. persons who are not immunocompromised and who have received at least one dose of measles vaccine at 12 months of age or older should not receive postexposure immunoprophylaxis. if given with 72 h of exposure, measles vaccine may provide protection against disease. the possibility of measles eradication has been discussed for almost 40 years ( sencer et al., 1967 ) . serious consideration of measles eradication began in the late 1960s as smallpox eradication was nearing completion and the effective, long-term immunity induced by measles vaccine became apparent. measles virus meets many of the biologic 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maintaining immunity against measles in vaccinated children in west africa has the 2005 measles mortality reduction goal been achieved? a natural history modelling study induction of cellular and humoral immunity after aerosol or subcutaneous administration of edmonston-zagreb measles vaccine as a primary dose to 12-month-old children world health organization progress in reducing measles mortality -worldwide world health organization global distribution of measles and rubella genotypes -update world health organization united nations children's fund. measles mortality reduction and regional elimination strategic plan key: cord-265112-fjn05uag authors: koistinen, annamari; turunen, riitta; vuorinen, tytti; söderlund‐venermo, maria; camargo, carlos a.; ruuskanen, olli; jartti, tuomas title: vitamin d, virus etiology, and atopy in first‐time wheezing children in finland date: 2014-12-29 journal: pediatr allergy immunol doi: 10.1111/pai.12308 sha: doc_id: 265112 cord_uid: fjn05uag nan medical records), and written informed consent from a parent or guardian. exclusion criteria consisted of chronic non-atopic illness, previous systemic or inhaled corticosteroid treatment, or need for intensive care unit treatment. the study was commenced only after obtaining written informed consent from the parent. the study protocol was approved by the ethics committee of the turku university hospital. at study entry, the guardian was asked to fill in a standard health questionnaire (online supplementary). the child was then physically examined by a study physician, a nasopharyngeal aspirate sample was obtained for viral diagnostics using a standardized procedure, (5) and a baseline blood sample was drawn. wheezing refers to expiratory breathing difficulty with high pitch sound during expiration. eczema was defined as atopic eczema when ige sensitization was present. the need for hospitalization was decided by an on-duty physician outside of the study team. the illness severity score is a summed score for the degree of dyspnea (0 = none, 1 = mild, 2 = moderate, 3 = severe), type of breathing (0 = normal, 1 = use of stomach muscles, 2 = use of intercostal muscles, 3 = nasal flaring), severity of auscultatory findings (0 = none, 1 = expiratory, 2 = inspiratory and expiratory, 3 = audible without stethoscope) an assessment of expiratory:inspiratory time (0 = 1:2, 1 = 1:1, 2 = 2:1, 3 = 3:1). the children were discharged from the hospital when the respiratory symptom score was <3, and there was no more wheezing. parents filled a diary of respiratory symptoms (cough, breathing difficulty, noisy breathing, symptoms during sleep, use of bronchodilators) for 2 weeks after hospital discharge. see more details on online supplementary. serum 25ohd measurements were taken by liquid chromatography-tandem mass spectrometry at massachusetts general hospital (boston, usa). blood eosinophil count and serum levels of allergen-specific ige for common allergens (cut-off >0.35 ku/l, phadiatop combi â ; phadia, uppsala, sweden) were analyzed by the routine diagnostics of the central laboratory of turku university hospital. rhinovirus species a, b, and c, enteroviruses, and respiratory syncytial virus (rsv) a and b were detected within 3 days from refrigerated nasopharyngeal aspirates using 'in house' reversetranscriptase pcr at the virus diagnostic laboratory, department of virology, university of turku. in addition, a multiplex pcr test (seeplex rv12 ace detection; seegene, seoul, korea) was used for detection of rhinovirus a and b, adenovirus, coronavirus (229e, nl63, oc43 and hku1), human metapneumovirus, influenza a and b virus, parainfluenza virus types 1-3, and rsv a and b virus after long-term storage in à80°c. human bocavirus-1 was analyzed using pcr and serology, as previously described (5) . to analyze the virus load (i.e., copy number), a sterile flocked swab (catalog number 502cs01; copan, brescia, italy) was first dipped in the aspirate and then diluted with 1 ml of phosphate-buffered saline. basic statistical analyses two sample t-test, one-way anova, spearman correlation, and regression analysis were used to analyze the association between 25ohd concentration and different variables. multivariable linear regression analysis was used for age-adjusted analyses. rhinovirus load was logtransformed before analysis. parametric variables are expressed as mean and standard deviation (s.d.) and nonparametric variables as median and interquartile range (iqr). linear regression results are expressed as mean difference and 95% confidence intervals (ci). a two-sided p < 0.05 was considered statistically significant. all analyses were performed using sas enterprise guide 4.3 (sas institute, cary, nc, usa). of the 125 children eligible for the study, 12 declined participation. after exclusion of another six patients, because of the lack of vitamin d measurements, 107 children were included in the analytic cohort (fig. 1) . mean age was 12 months (s.d. 6 .0) and 72 (67%) were boys. fifty-nine (55%) children had atopy or another allergy-related characteristic (i.e., sensitization, blood eosinophil count >0.4 9 10 9 /l, or atopic eczema). at least one virus was detected in 100% of the samples, rhinovirus in 82 (77%) children, respiratory syncytial virus in 31 (29%), and bocavirus in 19 (18%) children. seventeen (16%) children had serodiagnosed acute bocavirus infection, and pcr-diagnosed bocavirus was found in 18 (17%) children. virus coinfection was detected in 41 (38%) children. mean 25ohd concentration was 86 nmol/l (s.d. 21, range 35-150). five (5%) children had serum 25ohd concentration <50 nmol/l and 34 (33%) <75 nmol/l. serum 25ohd level of 100 nmol/l or higher was detected in 28 (26%) of the children ( table 1, table s1 ). in unadjusted analysis, serum 25ohd concentration was inversely associated with age (p < 0.0001), female sex (p = 0.03), bocavirus etiology (p = 0.007), and blood eosinophil count over 0.4 9 10 9 /l (p = 0.01), but not with sensitization, atopic eczema, rhinovirus etiology, or rsv etiology (all p > 0.2). in ageadjusted analysis, 25ohd concentration was inversely associated with female sex, but not with atopic characteristics or virus etiology. atopic characteristics did not modify the association of 25ohd concentration and virus etiology. no association was found between 25ohd and hospital admission, season of recruitment, indoor pets, family history of asthma, virus coinfection, or illness severity, including illness duration before admission to hospital, heart rate, blood oxygen saturation, temperature and illness severity score at study entry, duration of hospitalization, and duration of respiratory symptoms within 2 weeks after discharge ( table 2, table s2 ). in our study, age was a major determinant of 25ohd concentration in first-time wheezing children. despite that all participating families, at the 4-year follow-up visit (n = 77), reported having given vitamin d supplement during early life, a strong inverse association was seen in our study as well as in earlier studies (6, 7) . we speculate that the supplement use becomes more irregular after early childhood. on the contrary, the incidence of atopic sensitization increased with age. one might expect an association between 25ohd and atopy (or other atopic characteristics) in these kinds of circumstances (2), but we did not find it in age-adjusted analysis. a recent casecontrol study by stenberg et al. (6) reported an association between vitamin d insufficiency and wheezing in young children, but they did not find an association between vitamin d status and atopy-related factors. a few studies of young children without wheezing, or of older children, have reported an inverse association between the 25ohd level and atopic dermatitis or severity of atopic dermatitis (2, 7, 8) . the differences between our finding and these other studies may be explained by the adequate mean 25ohd concentration in our study population (86 nmol/l). in the other studies, the mean levels of serum 25ohd were much lower than in our studyfor example, 29 nmol/l (8) and 48 nmol/l (7). besides atopy, a low 25ohd concentration has been reported to be associated with increased susceptibility to acute respiratory infection (9). we did not find a connection between 25ohd and specific respiratory virus infection, not even for sensitive markers of rhinovirus load, virus coinfection or prolonged shedding of bocavirus (based on combined pcr and serology diagnostics) in wheezing children. urashima et al. (10) studied the effect of vitamin d intake on susceptibility to influenza a infections in japanese school children and reported an inverse effect. however, they did not measure serum 25ohd levels. a population-based study of science et al. (9) reported that low serum 25ohd levels are associated with increased risk of acute respiratory infections. compared to our study, the median levels of serum 25ohd were again lower in this study (62 nmol/l), which may explain the significant associations. our study has some limitations. our sample size was rather small. moreover, as few children had 25ohd levels <50 nmol/ l, vitamin d deficiency could not be investigated. our results may not be applicable for children in other countries because finnish children are instructed to take a daily vitamin d supplement. although the intake of vitamin d supplement was not closely recorded, we did assess the best measure of vitamin d status, serum 25ohd level. in conclusion, in wheezing children receiving vitamin d supplement of 400 iu per day with mean 25ohd level of 86 nmol/l (iqr 71-101 nmol/l), the 25ohd level was not associated with rhinovirus, rsv or bocavirus infection, virus coinfection, atopy, or severity of illness. these results generate the hypothesis that serum 25ohd levels thought to be adequate for healthy children are sufficient also for high-risk children susceptible to asthma. low serum 25-hydroxyvitamin d levels are associated with increased risk of viral coinfections in wheezing children latitude, sunlight, vitamin d, and childhood food allergy/anaphylaxis institute of medicine (us) committee to review dietary reference intakes for vitamin d and calcium maternal vitamin d status affects bone growth in early childhood-a prospective cohort study short-and long-term efficacy of prednisolone for first acute rhinovirusinduced wheezing episode subnormal levels of vitamin d are associated with acute wheeze in young children low vitamin d serum level is inversely associated with eczema in children and adolescents in germany vitamin d deficiency is associated with diagnosis and severity of childhood atopic dermatitis low serum 25-hydroxyvitamin d level and risk of upper respiratory tract infection in children and adolescents randomized trial of vitamin d supplementation to prevent seasonal influenza a in schoolchildren in relation to this paper, the authors have no conflict of interest. additional supporting information may be found in the online version of this article: table s1 . additional patient characteristics by quartile of serum 25-hydroxyvitamin d concentration table s2 . additional associations between patient characteristics and serum 25ohd concentration appendix s1. parental questionnaire. appendix s2. clinical score chart at the emergency room or hospital ward. appendix s3. symptom and medication diary for 2 weeks after discharge. key: cord-268042-qhrhymle authors: skokauskas, norbert; leventhal, bennett; cardeli, emma leventhal; belfer, myron; kaasbøll, jannike; cohen, judith title: supporting children of healthcare workers during the covid-19 pandemic date: 2020-07-18 journal: eur child adolesc psychiatry doi: 10.1007/s00787-020-01604-6 sha: doc_id: 268042 cord_uid: qhrhymle nan coronavirus disease 2019 (covid-19) is a disease caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2). the who 2019 "novel coronavirus global research and innovation forum: towards a research roadmap" highlights several knowledge needs, including what are the relevant, acceptable and feasible approaches for supporting the physical health and psychosocial needs of those providing care for covid-19 patients [1] . the roadmap is broad and detailed; however, we believe more attention should be given to the psychosocial well-being of the children of healthcare workers. during the covid-19 pandemic, extraordinary measures are being taken to protect the general population and, in particular, healthcare workers. the general population control measures (i.e., the closure of businesses and educational institutions, travel restrictions, and social distancing) are stressful for families, especially children. when social distancing and quarantine constitute everyday life experiences, the effects of well-known and critical protective factors for resilience and mental health (i.e., social and community support) are substantially disrupted. social distancing strategies disrupt healthy routines needed by children and increased exposure to trauma in childhood poses risks for later development of many forms of psychopathology, including anxiety, depression, posttraumatic stress disorder (ptsd), disruptive behavior, and substance abuse [2] . when there are adverse outcomes for their children, there is an inevitable, negative impact on their parents. if their parents happen to be healthcare workers and first responders, it will surely impair their ability and willingness to work during any crisis, including the covid-19 pandemic [3] . children of healthcare workers are at greater risk for a stress response, because they have at least some, if not full, awareness of the risks that their parents are facing at work. as a result, these youth are more vulnerable to stress and trauma due to the fear that their parents may be infected and/ or even die from covid-19-or even worse, face the dire consequences if it actually happens. healthcare workers and first responders are appropriately concerned about their children. if they can have more confidence that practical support is available to support their children during these challenging times, it will inevitably improve their ability and willingness to work effectively during the covid-19 pandemic. with careful planning and design, it is possible to provide help for children of healthcare workers and first responders. using online strategies to provide interventions built on a foundation derived from the principles of evidence-based child trauma treatment, programs can reduce traumatic stress symptoms in children while building resilience and strengthening coping strategies. trauma-focused cognitive behavioral therapy is an evidence-based child and parent intervention designed to help children recover from traumatic life events. it has a strong evidence base, having been evaluated for community settings use in many countries [4] . tf-cbt components have demonstrated efficacy in improving children's disaster-related ptsd symptoms when delivered in a web-based format [5] . supports such as this are needed throughout the pandemic including the period in which lives gradually return to "normal." who (2020) 2019 novel coronavirus global research and innovation forum: towards a research roadmap childhood adversities and first onset of psychiatric disorders in a national sample of us adolescents healthcare workers' willingness to work during an influenza pandemic: a systematic review and metaanalysis a randomized effectiveness study comparing trauma-focused cognitive behavioral therapy with therapy as usual for youth web intervention for adolescents affected by disaster: population-based randomized ontrolled trial ethical approval ethical approval for this letter was not applicable. all authors declare that the submitted work has not been published before (neither in english nor in any other language) and that the work is not under consideration for publication elsewhere. key: cord-273322-zz733a0k authors: zhao, yang; sun, de lin; bouchard, heather c.; zhang, xin xin; wan, gang; hao yi, wei; he, shu xin; jiang, yu yong; pang, lin title: coronavirus disease 2019 versus influenza a in children: an observational control study in china date: 2020-08-31 journal: biomedical and environmental sciences doi: 10.3967/bes2020.080 sha: doc_id: 273322 cord_uid: zz733a0k this study aimed to understand the differences in clinical, epidemiological, and laboratory features between the new coronavirus disease 2019 (covid-2019) and influenza a in children. data of 23 hospitalized children with covid-19 (9 boys, 5.7 ± 3.8 years old) were compared with ageand sex-matched 69 hospitalized and 69 outpatient children with influenza a from a hospital in china. the participants' epidemiological history, family cluster, clinical manifestations, and blood test results were assessed. compared with either inpatients or outpatients with influenza a, children with covid-19 showed significantly more frequent family infections and higher ratio of low fever (< 37.3 °c), but shorter cough and fever duration, lower body temperature, and lower rates of cough, fever, high fever (> 39 °c), nasal congestion, rhinorrhea, sore throat, vomiting, myalgia or arthralgia, and febrile seizures. they also showed higher counts of lymphocytes, t lymphocyte cd8, and platelets and levels of cholinesterase, aspartate aminotransferase, lactate dehydrogenase, and lactic acid, but lower serum amyloid, c-reactive protein, and fibrinogen levels and erythrocyte sedimentation rate, and shorter prothrombin time. the level of alanine aminotransferase in children with covid-19 is lower than that in inpatients but higher than that in outpatients with influenza a. pediatric covid-19 is associated with more frequent family infection, milder symptoms, and milder immune responses relative to pediatric influenza a. pediatric covid-19 is usually associated with mild symptoms [2] ; however, knowledge on the differences between pediatric covid-19 and other pediatric diseases is rare. influenza a is a common and fatal respiratory viral infectious disease in children of all ages. school institutions are prone to cause large-scale infections among children. during the influenza season, > 40% of pre-school children and 30% of school-age children may be infected with influenza a [3] . although most children will recover within a week, some high-risk children may develop serious complications which can result in death. young children are especially vulnerable with about onethird of these deaths occurring in children under 5 years old who do not exhibit underlying comorbidities. death can occur within 3-7 d of symptom onset. nucleic acid detection is essential for the diagnoses of covid-19 and influenza a viruses, given that covid-19 does not have typical early detection symptoms. however, only a few hospitals and agencies are qualified to perform nucleic acid tests for covid-19. therefore, a comprehensive comparison of the clinical and non-clinical features of influenza a and covid-19 will help in the early diagnosis and treatment of these two diseases. this study compared the clinical characteristics, epidemiology, and routine laboratory test results between 23 inpatients (5.7 ± 3.8 years; 9 boys, 39% of total) with pediatric covid-19 (recruited from january 1 to march 28, 2020) and age-and sexmatched 69 inpatients and 69 outpatients with pediatric influenza a (from january 1 to december 31, 2019) who received treatment in the beijing ditan hospital in beijing, china, which has been designated as treatment facility of infectious diseases including covid-19. the study followed the helsinki declaration and was approved by the ethics committee of beijing ditan hospital affiliated to capital medical university. written informed consents of both pediatric patients (if possible) and their guardians were obtained. to avoid biases induced by illness severity (inpatients are often related to more severe symptoms than outpatients), both inpatients and outpatients with pediatric influenza a were recruited. a group of outpatients with pediatric covid-19 were not included because all children diagnosed with covid-19 should be hospitalized in china. the diagnostic criteria for children with covid-19 were based on the diagnosis and treatment protocol for novel coronavirus pneumonia (trial version 7) issued by the china national health commission & state administration of traditional chinese medicine [4] . the inclusion criteria for the (1) covid-19 group were inpatients aged < 16 years and diagnosed by sars-cov-2 nucleic acid test and for the (2) influenza a groups were inpatients and outpatients aged < 16 years old and diagnosed by influenza a antigen. children were excluded if they showed positive results in any of the following tests and diagnoses: respiratory syncytial virus, adenovirus, parainfluenza virus, rhinovirus, sputum culture, throat swab, blood culture, mycoplasma condensation test, chlamydia antibody, rotavirus, norovirus, immunodeficiency disease, and other underlying diseases. qualified professionals in beijing ditan hospital collected oropharyngeal or nasal swabs or sputum from children suspected to have covid-19 and nasal swabs or sputum from children suspected to have influenza a. sars-cov-2 nucleic acid positive detection was performed by real-time fluorescence reverse transcription polymerase chain reaction (rt-pcr kit: 2019-ncov orf 1ab/n pcr fluorescence probe method). influenza a antigen was determined with immunofluorescence by an immunology laboratory. nasal swabs or sputum respiratory pathogens (chlamydia, influenza a and b, adenovirus, respiratory syncytial virus, rhinovirus, and coxsackie virus) were detected by immunofluorescence. patients with diarrhea were tested with rt-pcr to detect rotavirus, shigella utilized agglutination assay, and mycoplasma with condensation agglutination test. bacterial infection was detected by sputum culture or with blood culture methods. the values of white blood cell classification vary with age in children. there are different characteristics of lymphocyte distribution in normal children throughout development. the proportions of lymphocytes and neutrophils are the same in children between 4 and 6 years old. lymphocyte counts are greater before age 4, but after age 6, the neutrophil count is higher. these counts are divided into three age groups: < 4 years old, 4-6 years old, and > 6 years old. matlab (v2020a; mathworks, inc., natick, ma, usa) software was utilized for statistical analyses. continuous variables were analyzed with either twosample t-tests or mann-whitney u tests, depending on whether the assumptions of normal distribution and variance homogeneity were met. categorical variables were analyzed using chi-squared tests. two-tailed p value < 0.05 was considered statistically significant. we found that patients with covid-19 was associated with a higher ratio of in-home infection than influenza a inpatients (95.6% vs. 21.7%, p < 0.001, table 1 ), consistent with previous reports [2] . we observed that most children with covid-19 were infected primarily by family members, while children with influenza a were infected by family members, classmates, and other patients in the hospital. the incidence of covid-19 infection not due to family cluster is rare because chinese children have been quarantined at home since the outbreak of covid-19. however, the potential outbreak of covid-19 in schools is high in countries considering lifting the quarantine to reopen schools. the association between covid-19 and the fatal multisystem inflammatory syndrome in children (mis-c) warned by united states centers for disease control and prevention [5] creates further concern for a serious outbreak among children. as shown in table 1 and influenza a inpatients, respectively; p = 0.006) and febrile seizures (0.0% vs . 33.3%, p = 0.001). compared with influenza a outpatients only, patients with covid-19 also showed lower rates of cough (17.4% vs. 72.5% for covid-19 and influenza a outpatients, respectively; p < 0.001) and fever (43.5% vs. 91.3%, as higher rate of low fever (i.e., < 37.3 °c: 56.5% vs. 1.4%, p < 0.001). the mortality rate of covid-19 is higher in adults (e.g., > 4% in wuhan city, hubei, china) than in children [6] . sars-cov-2 invades the human body through angiotensin-converting enzyme 2 (ace 2) which infects human respiratory epithelial cells [7] . the intracellular response induced by ace 2 in alveolar epithelial cells is lower in children than in adults [1] , which may explain the milder covid-19 symptoms experienced by children than by adults. the symptoms of fever, cough, and diarrhea were found in both patients with covid-19 and influenza a. therefore, the diagnosis of either disease should rely on other clinical indices. high fever temperature, stuffy nose, runny nose, sore throat, vomiting, and muscle pain in the limbs were less frequently detected in children with covid-19 than in those with influenza a. cases of viral meningitis, high fever convulsions, and death were not found in pediatric covid-19 but in pediatric influenza a. however, milder symptoms in pediatric covid-19 do not imply that fewer efforts are necessary for diagnosis, early monitoring, and treatment of covid-19. in the early epidemic studies in china, including this study, pediatric covid-19 cases are scarce, and children with covid-19 have been found to exhibit milder symptoms than both adults with covid-19 and children with influenza a. however, more pediatric cases worldwide have been reported since the pandemic of covid-19 started. studies in the united kingdom and italy report that children with covid-19 experience systemic rash, heart inflammation, and arterial swelling symptoms, which are similar to kawasaki disease [8] , but these have not yet been reported in children in china. it is possible that the sars-cov-2 has mutated during the pandemic and has induced new symptoms. moreover, some of the symptoms may have been overlooked at the beginning of the pandemic due to the limited cases of pediatric covid-19. new manifestations of pediatric covid-19 and the development of novel diagnoses and treatments targeting these new symptoms require continuous attention. as shown in table 2 , compared with both inpatients and outpatients with influenza a, children with covid-19 exhibited higher levels of aspartate aminotransferase [(37.5 ± 56.1) vs. these laboratory findings suggest milder immune responses and therefore fewer immune damages in pediatric covid-19 than in influenza a. this is consistent with the clinical manifestations of children with covid-19. we also found higher cholinesterase level in children with covid-19 than those with influenza a. during the immune response, an acetylcholine transmitter is released from peripheral nerve endings and activates α7nachr on the surface of the macrophage membrane. this response links the antiinflammatory effects of the nervous system to the immune system and mediates a more direct and quicker inflammation response [9] . studies on the cholinergic anti-inflammatory pathway in covid-19 may help in understanding the pathogenesis of covid-19, which could contribute to more precise interventions or prevention strategies. abnormal blood coagulation is an important comorbidity of patients with severe covid-19 [10] . autoimmune disorders are closely related to covid-19 in adults with abnormal coagulation and thrombotic event. children with covid-19 did not exhibit abnormal changes in coagulation function and even showed shorter prothrombin time and lower fibrinogen quantitative than children with influenza a. these findings suggest the differences in the pathogenesis between pediatric and adult covid-19 and between pediatric covid-19 and pediatric influenza a. this study has several limitations. first, the sample size of the pediatric covid-19 group was small due to the control of the outbreak in china and the relatively low incidence of covid-19 in children. second, the samples are only from china and do not reflect specific effects of race, culture, and socioeconomic status on global pediatric covid-19. third, the differences and associations between covid-19 and infectious diseases other than influenza a are still unknown. international collaborations are urgently needed to investigate the pathogenesis and clinical responses of pediatric covid-19 and to develop widely applicable diagnoses and intervention approaches. in conclusion, pediatric covid-19 is associated with higher incidence of family cluster, milder symptoms, and milder immune responses than note. p1, p -values of covid-19 vs. influenza a inpatients. p2, p -values of covid-19 vs. influenza a outpatients. a only two cases in this group. b only one case in this group. c no case in this group. a, b, c not enough data for statistical analyses. mean ± sd for continuous variables and number of positive cases (proportion of positive cases) for categorical variables are shown. covid-19, covid-19 group; influ-in, influenza a inpatient group; influ-out, influenza a outpatient group. alb, albumin; alt, alanine aminotransferase; aptt, activated partial thromboplastin time; ast, aspartate aminotransferase; b, b lymphocyte; ck-mb, creatine kinase isoenzyme; crp, c-reactive protein; esr, erythrocyte sedimentation rate; hbdh, hydroxybutyrate dehydrogenase; ldh, lactate dehydrogenase; nk, natural killer cell; pt, prothrombin time; saa, serum amyloid; u/l, units per liter; wbc, white blood cell. a pneumonia outbreak associated with a new coronavirus of probable bat origin coronavirus infections in children including covid-19 an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children estimates of global seasonal influenza-associated respiratory mortality: a modelling study national health commission and state administration of traditional chinese medicine. diagnosis and treatment protocol for novel coronavirus pneumonia for parents: 5. multisystem inflammatory syndrome in children (mis-c) associated with covid-19 hypokalemia and clinical implications in patients with coronavirus disease 2019 (covid-19) sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor explained: inflammatory syndrome in children possibly linked to covid-19 importation and humanto-human transmission of a novel coronavirus in vietnam abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia key: cord-023748-3kfy36hg authors: lye, patricia s.; densmore, emily m. title: fever date: 2017-05-12 journal: nelson pediatric symptom-based diagnosis doi: 10.1016/b978-0-323-39956-2.00039-x sha: doc_id: 23748 cord_uid: 3kfy36hg nan temperature is controlled by the thermoregulatory center, located in the preoptic area of the anterior hypothalamus. the thermoregulatory center receives input from peripheral receptors and the temperature of the blood bathing the hypothalamus and acts on autonomic, endocrine, and behavioral mechanisms to maintain the body temperature at a particular set point. the hypothalamic set point normally maintains body temperature around 37°c, but there can be significant variation among individuals. normal temperatures range from 36-37.8°c, depending on the time of day, with the peak in the afternoon (5-7 p.m.) and the trough in the early morning (2-6 a.m.). although the circadian rhythm is not well established in infancy, it becomes more reliable by the 2nd year of life. the febrile response not only produces an elevation in body temperature but also causes physiologic changes that enhance the individual's ability to eliminate infection. production of acute-phase reactants and alterations in metabolism and endocrine function are examples of these changes. acute-phase reactants-proteins that are produced in response to infection or injury-include ceruloplasmin, c-reactive protein, haptoglobin, amyloid a, complement, and fibrinogen. hormones and cytokines, some of which are endogenous pyrogens, regulate the production of acute-phase proteins. exogenous pyrogens, such as bacteria or endotoxins, generate the production of endogenous pyrogens, which play a vital role in prostaglandin-related set point elevation and regulation of acute-phase responses. fever results when the thermoregulatory set point is elevated above the normal set point; the hypothalamus then generates physiologic changes involving endocrine, metabolic, autonomic, and behavioral processes. diversion of blood from peripheral vessels to central vessels causes coolness of the extremities but helps increase core temperature. shivering increases metabolic activity and heat production. the affected patient may feel cold and seek a warmer environment or add clothing to feel warmer and prevent heat loss. once these processes have resulted in increasing the core temperature to match the elevated set point, the thermoregulatory center works to maintain the temperature as it does during normothermia. the thermoregulatory point returns to normal once the infection is resolved. the hypothalamus then produces physiologic changes to decrease the core temperature; these include sweating, dilation of cutaneous blood vessels, and the sensation of feeling hot, which may lead to behaviors such as removing clothing or seeking a cooler environment. fever has both positive and negative effects. high body temperatures may impair the reproduction and survival of some invading microorganisms by decreasing required nutrients, such as free iron, or by increasing immunologic responses such as phagocytosis. however, at extremely high temperatures, immunologic responses may be impaired. fever increases the basal metabolic rate by 10-12% for each degree celsius elevation of temperature. this increases oxygen consumption, carbon dioxide production, and fluid and caloric needs. fluid requirements increase 100 ml/m 2 /day for each 1°c rise in temperature above 37.8°c. heat illness must be distinguished from fever as a cause for elevated body temperature. in heat illness, there is an unregulated rise in body temperature, despite the fact that the hypothalamic set point is normal. it can result from excessive heat production or inadequate heat dissipation. temperatures may reach extreme heights and can result in multiorgan dysfunction and death. restoration of normal body temperature in heat illness is mandatory (table 39 .1). a child with fever of recent onset with no obvious historical or physical explanation for the fever is said to have fever without source (fws). bacterial pathogens account for a small but clinically significant number of cases. the risk of bacterial infection decreases with increasing age and is highest for infants less than 3 months of age, compared to infants and toddlers 3-36 months of age, and even lower for children over the age of 36 months. most of the patients in all age groups have a self-limited viral illness. the challenge is to identify which children have fever caused by bacterial pathogens, or other pathogens requiring treatment, in order to avoid the morbidity and mortality associated with delayed treatment, balanced against the risks of testing or treatment when neither is needed. bacterial infection must be considered in immunocompromised patients or those with central lines or shunts. studies in adults suggest that patients with high fever (>105 o f) and rigors have a higher risk of bacterial infection; exceptions to this include influenza and adenoviral infections. oral thermometry can be considered for cooperative patients who are older than 4-5 years of age. axillary temperatures are commonly done and tympanic membrane and temporal artery temperatures are newer modalities with some studies examining their reliability. axillary temperatures are less precise than rectal temperatures. there is a correlation between axillary and rectal temperature measurements; the axillary temperature is usually 0.5-0.85°c lower. tympanic membrane thermometers are often inaccurate in children. temporal artery temperature measurement correlates well with rectal temperature in some studies, but has been shown to be inferior when patients are febrile. it can be considered in settings when children are not likely to be febrile and are over 3 months of age. when detection of fever is critical for diagnosis and management, rectal temperatures should be used in the child 3 years of age and younger. many children will have a source for fever identified on their history and/or physical examination. if no focus of infection is found on the physical examination, the clinician must rely on history and observation to determine the appropriate next steps. the child may appear ill or well. ill-appearing children are typically lethargic or irritable. they may show signs of shock, including weak peripheral pulses, tachycardia, poor perfusion, respiratory distress, mottling, cyanosis, or decreased mental status (table 39 .2). after thorough clinical and laboratory evaluation, ill-appearing children should be admitted to the hospital, and will likely need empiric antibiotic treatment. infants and children with fever without source who do not appear ill create important decision processes in terms of evaluation and management. the physician's ability to make a hypothesis about the child's degree of illness, on the basis of observation, is critical in the evaluation. an objective scoring measure may be used in an effort to assess serious illness in young febrile children. the acute illness observation scale (aios) (table 39. 3), also known as the yale observation score, is a 6-item predictive model graded on a scale of 1-5. use of the aios in conjunction with the history and physical examination has a higher sensitivity for identifying serious illness than history and physical examination alone. the aios is most useful in patients younger than 24-36 months; it has not been shown to provide sufficient data to identify serious illness in 4-to 8-week-old infants, and has not been evaluated in infants less than 4 weeks old. most children who present with fever without source (fws) are subsequently determined to have a self-limited benign viral infection. in 1 study in 2-36 month old children who presented with fws, 76% had 1 or more known pathogenic viruses found; 57% had adenovirus, human herpesvirus 6 (hhv-6: roseola), enterovirus, or parechovirus detected. other identifiable viruses include respiratory syncytial virus, parainfluenza viruses, influenza viruses, varicella (chickenpox), human metapneumovirus and parvovirus (fifth disease/erythema infectiosum). measles, mumps, and rubella are uncommon in developed countries but have been reported in epidemics following imported cases or in underimmunized communities. although rapid testing for viral pathogens is often readily available, a detailed investigation to identify a viral pathogen is not necessary unless the confirmation of a viral infection will change the acute diagnostic plan; treatment with antivirals is an option (hsv, influenza) if the fever is prolonged and evolves into fuo or if there is end-organ involvement, as in hepatitis, myocarditis, encephalitis, or meningitis. most viral infections do not have simultaneous co-infection with a bacterial pathogen. exceptions include croup due to parainfluenza history a detailed history may reveal a potential source for infection. a complete history addresses several important issues: (1) onset and duration of fever; (2) degree of temperature; (3) by what method and in which anatomic site the temperature was taken; (4) medications given, including antipyretics, antibiotics, or home remedies; (5) environmental exposures; (6) associated symptoms; (7) ill contacts; (8) recent immunizations, and (9) recent travel. inquiry into the child's medical history may reveal important information such as recurrent febrile illnesses, primary or acquired immunodeficiency, or medications such as chemotherapy that alter host defenses. rectal temperature measurement is considered to be the gold standard for children 3 years of age or younger. the most widely accepted definition of fever is rectal temperature of 38°c (100.4°f) or higher. it is important to consider that infants, especially those younger than 2 months of age, may have a blunted febrile (or hypothermic) response to infection. hence, lack of fever should not be used as a criterion for ruling out infection in infants. although rectal temperature measurement is the gold standard, it should be avoided in neutropenic immunocompromised patients, in whom rectal manipulation may seed the blood with bacteria. two of 4 criteria, 1 of which must be abnormal temperature or abnormal leukocyte count: 1. core temperature >38.5°c (101.3°f) or <36°c (96.8°f) (rectal, bladder, oral, or central catheter) 2. tachycardia: mean heart rate >2 sd above normal for age in absence of external stimuli, chronic drugs or painful stimuli or unexplained persistent elevation over 0.5-4 hr or in children <1 yr old, persistent bradycardia over 0.5 hr (mean heart rate <10th percentile for age in absence of vagal stimuli, β-blocker drugs, or congenital heart disease) 3. respiratory rate >2 sd above normal for age or acute need for mechanical ventilation not related to neuromuscular disease or general anesthesia 4. leukocyte count elevated or depressed for age (not secondary to chemotherapy) or >10% immature neutrophils sepsis plus 1 of the following: 1. cardiovascular organ dysfunction, defined as: despite >40 ml/kg of isotonic intravenous fluid in 1 hr: • hypotension <5th percentile for age or systolic blood pressure <2 sd below normal for age or • need for vasoactive drug to maintain blood pressure or • 2 of the following: • unexplained metabolic acidosis: base deficit >5 meq/l • increased arterial lactate: >2 times upper limit of normal • oliguria: urine output <0.5 ml/kg/hr • prolonged capillary refill: >5 sec • core to peripheral temperature gap >3°c (5.4°f) 2. ards as defined by the presence of a pao 2 /fio 2 ratio ≤300 mm hg, bilateral infiltrates on chest radiograph, and no evidence of left heart failure or sepsis plus 2 or more organ dysfunctions (respiratory, renal, neurologic, hematologic, or hepatic) sepsis plus cardiovascular organ dysfunction as defined above mods presence of altered organ function such that homeostasis cannot be maintained without medical intervention virus, which may predispose to bacterial tracheitis and influenza, which may predispose to bacterial pneumonia. the sequence may be biphasic with viral symptoms followed by improvement, followed by worsening symptoms of the bacterial superinfection, or both phases may not be apparent as the child demonstrates no improvement or deterioration. respiratory syncytial virus (rsv) may predispose patients to otitis media. noninfectious conditions manifesting with fws are extremely rare. historical clues (recurrences, chronicity) or systemic signs usually indicate malignancy or rheumatic disorders. if the history and physical examination are not suggestive, these diagnoses need not be pursued. heat-related illness or drug ingestion may be considered if supported by the history. fever caused by immunizations may not be accompanied by other signs or symptoms, but the history should suggest immunization as the cause. utis are the most common serious bacterial infection in children less than 36 months of age who present with fws. utis are almost always occult in children younger than 24 months because the symptoms, except for fever, are nonspecific or nonexistent. uti occurs in 7% of febrile children younger than 2 years. the prevalence of uti varies by height of the fever, duration of the fever, age, gender, race, and circumcision status. children with fever greater than 39°c are at a higher risk of utis. boys with fever for more than 2 days and girls with fever for more than 1 day are more likely to have a uti. higher rates of utis are found in girls, especially those younger than 12 months of age. for febrile boys younger than 3 months of age, 20.1% of those who are uncircumcised have a uti; for circumcised boys the rate is 2.4%. uti rates are higher among white infants than among black infants and among children with abnormal genitourinary tract anatomy or neurogenic bladder. urine specimens should be obtained from the following children with fws: those with a history of uti, those with a history of urinary tract anomalies or vesicoureteral reflux, all infants younger than 2 months, girls younger than 12-24 months, uncircumcised boys younger than 12 months, and circumcised boys younger than 6 months. there is an age-associated risk of bacteremia with utis, particularly in infants. the incidence of bacteremia in patients younger than 2 months with uti is 10%. the incidence of bacteremia in patients younger than 2 months with uti ranges from 4-15% depending on the setting. opinions regarding when to obtain blood cultures in infants with uti differ, but a reasonable approach would be to obtain blood cultures in children younger than 2-6 months with suspected uti, and in older infants with uti if they are ill-appearing (urosepsis). occult bacteremia is defined by the presence of a positive blood culture for pathogenic bacteria in a febrile patient who does not appear extremely ill and who has no focus of infection, excluding otitis media. following the introduction of the 7-valent pneumococcal vaccine in 2007, invasive pneumococcal disease decreased dramatically. pneumococcal bacteremia decreased from 80% of the cases of bacteremia to 30%. most cases of bacteremia in children were not occult. bacteremic children were either ill or had a focus of infection, such as a uti. in 1 study, the rate of occult bacteremia after 2007 was 0.25%. after the 13-valent pneumococcal vaccine was introduced in 2010, the incidence of invasive pneumococcal disease in children less than 5 years old decreased again with 1 state-based population study showing incidence rates dropping from 46/100,000 to 23/100,000 with the age group most involved being children 2-23 months of age. escherichia coli is the most common cause of bacteremia in children aged less than 12 months, all due to utis. other less common causes of bacteremia in young as a marker for invasive disease caused by e. coli than by s. pneumoniae, thus its utility has declined with the reduction of the incidence of invasive pneumococcal disease. similarly, band counts are less commonly used, except in the 29-60 day old infant as part of identifying a low-risk cohort. a wbc count of 5,000-15,000 is generally considered normal for children over 1 month of age. a wbc count less than 15,000/mm 3 or even leukopenia may be found in children with n. meningitidis bacteremia. a minority of children with occult nontyphoidal salmonella bacteremia have been found to have a wbc count exceeding 15,000/mm 3 . c-reactive protein (crp) and procalcitonin combined with a urine dipstick (the lab score) can be used to screen for bacterial infection. this combination of tests has been validated for children 7 days to 36 months of age. pcr is useful in identifying the cause of fever for common viruses such as respiratory syncytial virus, influenza viruses, parainfluenza viruses, enteroviruses, parechovirus, adenoviruses, or herpes simplex virus. additional methods available or in development that may be helpful to identify serious bacterial infections and distinguish bacterial from viral infections utilize molecular microbiology methods. gene expression profiles of the patient's peripheral blood leukocytes demonstrate different biosignatures of rna production that may differentiate bacterial from viral infections. this method does not identify the children are n. meningitidis, nontyphoidal salmonella, staphylococcus aureus, and group a streptococcus. neisseria meningitidis bacteremia is frequently associated with serious sequelae. children with n. meningitidis bacteremia are much more likely to progress to meningitis than are those with s. pneumoniae bacteremia. nontyphoidal salmonella bacteremia is often accompanied or preceded by enteritis. in some instances, particularly in young infants, the diarrhea is mild or even absent. the prevalence of salmonella bacteremia among patients with salmonella enteritis has been reported to be between 2% and 45%; fever is not always present. salmonella infection seldom causes serious complications in patients with normal host defenses and resolves spontaneously. infants younger than 3 months, malnourished, and immunocompromised individuals are exceptions. evaluation is usually divided into 4 different age ranges: younger than 1 month, 1-3 months, 3-36 months, and older than 36 months. testing for each individual age group is based on risks for diseases and prevalence of pathogens. most acute diarrhea and fever is caused by viral pathogens in developed countries. obtaining a stool culture is indicated if bacterial enteritis is indicated by the presence of risk factors in the history, such as blood in the stool or certain exposures (petting zoos) (see chapter 11). febrile infants younger than 3 months have a higher incidence of serious bacterial infections than older infants. the relatively high incidence of bacterial disease probably results from a combination of factors unique to this age group: decreased opsonin activity; decreased macrophage function; decreased neutrophil function; poor immunoglobulin g antibody response to encapsulated bacteria; and susceptibility to bacterial pathogens such as group b streptococci (gbs), gram-negative enteric organisms, and listeria monocytogenes. the incidence of early-onset group b streptococcal infections has decreased with routine screening and the intrapartum treatment of gbs-positive pregnant women; the incidence of late-onset gbs (>1 week) has not decreased. e. coli is the most common organism causing bacterial infections in neonates and young infants. in very young infants, clinical evaluation alone is inadequate for excluding serious bacterial infections. management of febrile infants younger than 28 days includes a sepsis evaluation and hospitalization for parenteral antimicrobial therapy pending culture results. the reasoning for this conservative approach lies in the difficulty in evaluating the behavioral state of neonates, the rapid clinical deterioration of infants with bacterial infections, the immature neonatal immune system, and the possibility of life-threatening viral infections caused by herpes simplex viruses (hsv) or enteroviruses. sepsis evaluation should include culture of the csf, blood, and urine; a complete blood cell count with differential; examination of the csf for cells, protein, and glucose; and urinalysis. a chest radiograph should be considered if the patient has signs or symptoms of a respiratory infection. testing (blood and csf pcr for hsv) and treatment for possible hsv infection should be considered in ill-appearing infants, those with a seizure prior to presentation, and those with a vesicular rash consistent with hsv. a combination of clinical evaluation and laboratory studies can be used to define a specific population of infants aged 29-60 days who do not appear ill and are at low risk for bacterial infections. infants at low risk for bacterial infections are those who are previously healthy with no focus of bacterial infection on physical examination and who have negative laboratory screening results. a number of prospective studies have contributed to the development of specific low-risk screening criteria (table 39 .4). the age groups included vary by study, ranging from 0-90 days to 29-56 days. because there are differences in study criteria used to define infants at low risk for bacterial infections the most conservative values have been used in the guidelines presented in this chapter. negative laboratory screening results consist of a wbc count of 5000-15,000/mm 3 ; fewer than 1500 bands/mm 3 or a band-to-neutrophil ratio of less than 0.2; fewer than 10 wbcs/hpf and no organisms on urinalysis; and fewer than 8 wbcs/hpf and no organisms on csf gram stain. some experts also include a negative chest radiograph and, when diarrhea is present, a stool examination with fewer than 5 wbcs/hpf. most experts suggest that febrile infants 29-60 days old who meet the low-risk criteria and have access to close follow-up can be managed as outpatients. blood, urine, and csf cultures should be obtained before empirical antibiotic treatment so that viral and bacterial causes specific pathogen. rapid multiplex pcr combined with standard blood culture methods may identify a specific pathogen much sooner (~20 hours) than standard blood culture techniques. specific bacteria may be identified using 16s ribosomal rna bacterial gene detection. this method does not require bacterial growth. 16s rrna detection may be helpful when antibiotics were administered before the sample was obtained, and in patients with ventilator-associated pneumonia or bacteria that grow poorly or are present in effusions or tissues (heart valves). blood cultures are the gold standard for determination of bacteremia. although blood cultures do not provide immediate results, methods allow for continuous and more rapid detection of bacterial growth. blood cultures are easy to perform and provide essential information in the diagnosis and management of patients with possible bacteremia. preliminary blood culture results are typically available within 24 hours, with positive identification of most organisms within 48 hours. false-negative blood culture results may be due to prior treatment with antibiotics, missing an episode of bacteremia if it is intermittent, and inoculation of too little blood into the culture media. alternatively, too much blood inoculated into the blood culture bottle may yield a false-negative result because of ongoing killing of bacteria by neutrophils. three to 5 ml of blood should be added to each blood culture bottle. false-positive results may be due to inadequate skin preparation, leading to contamination with skin flora. a positive urine culture was once considered the gold standard; current recommendations include a urinalysis that has pyuria (defined as >5 wbcs/high-power field [hpf] on the microscopic examination or a positive leukocyte esterase on dipstick) and a positive urine culture for a uropathogen in an appropriately collected specimen. fifty to 100,000 colonies of a single organism is considered positive (see chapter 18). children should have a catheterized urine specimen obtained, unless they are toilet-trained and can supply a clean voided specimen. suprapubic aspiration is acceptable but requires technical expertise, and parents often perceive it as unsuitably invasive; it may be the only alternative for boys with severe phimosis. the use of plastic receptacles attached to the perineum should be discouraged because contamination from skin and fecal flora commonly occurs. lumbar puncture is indicated if the patient is younger than 28 days or if a diagnosis of sepsis, meningitis, or encephalitis is considered, regardless of the child's age. normal cerebrospinal fluid (csf) findings, including chemistry, cell count with differential, gram stain, pcr, and culture, help exclude the diagnosis of meningitis. less than 1% of children with normal preliminary csf results have a positive culture; in most of these, the pathogen is n. meningitidis. thus, even in the presence of normal preliminary csf results, close follow-up is essential. chest radiographs are usually normal in children who have fws. respiratory signs or symptoms, such as tachypnea, retractions, crackles, wheezing, rhonchi, nasal flaring, grunting, cough, or hypoxia, may predict chest radiograph findings consistent with pneumonia. in practice, pneumonia can often be diagnosed solely on the basis of the clinical findings of fever, tachypnea, and crackles; chest radiographs are not always necessary. however, chest radiographs may be useful in evaluating for the presence of pleural effusion or other complications of pneumonia. screening urinalysis (ua) for uti should be considered in children with a history of uti, children with a history of urinary tract anomalies or vesicoureteral reflux, girls younger than 12-24 months, especially when the temperature is greater than 39.0°c, uncircumcised boys younger than 12 months, and circumcised boys younger than 6 months. blood cultures are recommended for children with probable utis who are less than 6 months of age. a febrile child with moderate leukocyte esterase on urine dipstick testing or pyuria on an appropriately collected specimen should be treated presumptively for a uti. urine cultures should be obtained for any patient with a suspected uti. the choice of antibiotics should be guided by knowledge of the common pathogens that cause utis and by patterns of antibiotic sensitivity in the community. hospitalization should be considered for the child who is vomiting, is dehydrated, or appears ill; for those in whom compliance is likely to be poor; and for any patient with underlying renal or urologic anomalies. examination and culture of the csf are the only tests to exclude the diagnosis of meningitis and encephalitis. they should be considered in any child in whom the diagnosis of sepsis, meningitis or encephalitis is suspected on the basis of the history, observation, and physical examination findings. outpatient management of children with fws is acceptable for those with a low probability of meningitis, good follow-up, and reliable caregivers. blood cultures should be obtained for all children in whom sepsis or meningitis is suspected. empiric treatment with antibiotics should be considered in those suspected of sepsis or meningitis after appropriate cultures are obtained. in summary, management of children aged 3-36 months with fever is based on clinical experience and numerous study results: • child who appears ill on initial evaluation or on follow-up: admit to the hospital for parenteral antibiotics after appropriate laboratory evaluation. • well-appearing children with fws should be screened for utis, based on their number of risk factors. risk factors for girls are: age <12 months, white race, temperature greater than 39°c, and fever for 2 or more days. girls 2-24 months of age with 1 or more of these risk factors have a greater than 1% probability of having a uti, and should be screened for a uti. for boys, the risk factors are uncircumcised status, nonblack race, temperature greater than 39°c, and fever for over 24 hours. all uncircumcised boys less than 12 months old, even if they don't have other risk factors, should be screened for a uti. for boys who are circumcised, 2 or more of the other risk factors increases the risk to over 1% and they should be screened. • child with positive blood culture: reevaluation should occur in any child whose blood culture is presumptively positive. if the blood is found to contain n. meningitidis or haemophilus influenzae (which has been rare since the advent of h. influenzae b immunization), a csf sample and a repeat blood culture should be obtained, and the child should be admitted to the hospital for parenteral antibiotics, pending the results of the cultures. the child with occult pneumococcal bacteremia who appears well and is afebrile when returning for a follow-up may be managed as an outpatient with parenteral ceftriaxone followed by oral antibiotics according to the sensitivity of the organism. because of the concern of pneumococcal resistance to penicillin, a 2nd dose of intramuscular ceftriaxone may be given until sensitivity results are available. if the culture is positive for nontyphoidal salmonella organisms and the child is younger than 3 months, full sepsis evaluation and intravenous antibiotics are recommended. oral antibiotics and close follow-up are recommended for older children with salmonella bacteremia. • child with positive urine culture: if the child is afebrile and appears well, treatment with oral antibiotics is recommended, according to the sensitivity of the organism. may be distinguished. an alternative strategy is to manage such infants as outpatients, without empirical antibiotic therapy, after blood, csf, and urine cultures are obtained. although most of the original studies on outpatient management of febrile infants included infants aged 2-3 months, many experts agree that infants aged 2-3 months can be managed safely according to the guidelines for infants and children aged 3-36 months (table 39 .4). regardless of whether the clinician chooses to treat the patient with empiric antibiotics, all low-risk infants should be re-evaluated within 24 hours. those who appear ill or who have positive culture results should be admitted for parenteral antibiotics. if a child appears well and all culture results are negative, close follow-up should be continued and a 2nd return visit made in 24 hours. the risk of bacteremia for children with fws in this age group has decreased with the routine use of pneumococcal vaccines. the most common occult bacterial infection in this age group is uti. for children in this age group who appear ill, a full sepsis evaluation should be undertaken (table 39 .5). infants are at low risk if they appear well, have a normal physical examination, and have a caretaker reachable by telephone, and if laboratory tests are as follows: • cbc: <20,000 wbc/µl • urine: negative leukocyte esterase • csf: leukocyte count less than 10 × 10 6 /l infants are at low risk if they appear well and have a normal physical examination, and if laboratory tests are as follows: • cbc: <15,000 wbc/µl; band: total neutrophil ratio <0.2 • urine: <10 wbc/hpf; no bacteria on gram stain • csf: <8 wbc/µl; no bacteria on gram stain • chest radiograph: no infiltrate • stool: no rbc; few to no wbc infants are at low risk if they appear well and have a normal physical examination, and if laboratory tests are as follows: • cbc: 5,000-15,000 wbc/µl; peripheral absolute band count <1,500/µl • urine (enhanced urinalysis): 9 wbc/µl and no bacteria on gram stain • csf: 5 wbc/µl and negative gram stain; if bloody tap, then wbc:rbc ≤1 : 500 • chest radiograph: no infiltrate • stool: 5 wbc/hpf with diarrhea infants are at low risk if they appear well and have a normal physical examination, and if laboratory findings are as follows: • cbc: 5,000-15,000 wbc/µl; absolute band count ≤1,500/µl evaluation and management of ill-appearing children older than 36 months with fever without source are similar to those of younger children. for children in this age group who do not appear ill, no screening diagnostic tests are indicated. close attention should be paid to environmental exposures and ill contacts because of the high likelihood of increased contacts in this school-aged cohort. bacterial meningitis is usually a disease of infants and young children. the attack rate is highest between the ages of 3 and 8 months; 66% of cases occur in children younger than 5 years of age. bacterial meningitis is seen during all seasons; however, there may be a seasonal correlation between the presence of preceding respiratory pathogens in the upper respiratory tract and the subsequent development of bacterial meningitis. bacterial meningitis usually occurs sporadically. clusters of cases have been noted in day care centers, colleges, and other closed communities. bacterial meningitis occurs more frequently in children with traumatic fractures of the cribriform plate or paranasal sinuses or with a cochlear implant (pneumococci); in children who have undergone neurosurgical procedures such as ventricular shunts (s. aureus, s. epidermidis, corynebacterium species); in children with congenital or acquired immunodeficiencies (pneumococci, l. monocytogenes, meningococci); in children with anatomic or functional asplenia (pneumococci, meningococci); and in children with sickle hemoglobinopathies (pneumococci). there may be a genetic predisposition in some groups to the development of meningitis, inasmuch as there is an increased incidence of h. influenzae type b meningitis in navahos and eskimos. bacterial meningitis manifests in 2 patterns. in the 1st, the symptoms develop slowly over several days, the initial symptoms being those of a nonspecific illness. the signs and symptoms of meningitis develop subsequently. in the 2nd pattern, the disease develops suddenly and quickly, the 1st indications of illness being the signs and symptoms of meningitis and/or sepsis. the manifestations of meningitis depend on the child's age. in infants, the findings are usually nonspecific and may be subtle; they include vomiting, diarrhea, irritability, lethargy, poor appetite, respiratory distress, seizures, hypothermia, and jaundice. only 50% of affected infants have fever; some present only with fever. it is uncommon for affected young infants to have a stiff neck; only 30% have a bulging fontanel. older children present with more specific meningeal signs. they complain of a headache that is described as being severe, generalized, deep-seated, and constant. they complain about neck stiffness, caused by inflammation of the cervical dura and reflex spasm of the extensor muscles of the neck. there is pain and limitation of motion on flexion of the short duration and inconsistent development of increased intracranial pressure, papilledema is usually not seen at presentation. when it is present, venous sinus thrombosis, subdural effusion, or an intracranial abscess must be considered. seizures occur before hospital admission in up to 20% of affected patients. children with meningitis may also present with cutaneous findings. although commonly associated with meningococcal disease, purpura, petechiae, or a diffuse nonspecific maculopapular rash may be present in meningitis caused by any of the common bacterial pathogens (see chapter 40). septic arthritis may be seen simultaneously with bacterial meningitis. this has been assumed to be caused by simultaneous localizing infection after a primary bacteremia. reactive arthritis caused by immune complex deposition is also seen with bacterial meningitis. this arthritis affects 1 large joint and appears 5-7 days after treatment for meningitis has started. in general, arthritis occurring acutely with meningitis should be assumed to be infectious (see chapter 33). various eye disorders have also been described with acute bacterial meningitis, including transient cataracts, paralysis of the extraocular muscles, pupillary dysfunction, dendritic ulcers, endophthalmitis, cortical blindness, and conjunctivitis. recurrent episodes of bacterial meningitis rarely occur. potential etiologies include congenital csf fistulas (inner ear, dermal sinus, neuroenteric cysts, lumbosacral sinus tracts), traumatic or surgical csf fistula (skull fracture, postoperative nasal surgery, cochlear implant), immunodeficiency states and parameningeal infections (mastoiditis, sinusitis, craniofacial osteomyelitis). the definitive diagnosis of meningitis is based on examination of the cerebrospinal fluid (csf). the csf is usually obtained via a lumbar puncture (spinal tap). the lumbar puncture is performed by introducing a small-bore, short-beveled, spinal needle with a stylet into the subarachnoid space at the l3-l4 or l4-l5 level (figs. 39.2 to 39.4). a needle with a stylet is used to minimize the risk of introducing a nest of epidermal cells into the subarachnoid space that may later grow into a cord-compressing epidermoid tumor. approximately 3 ml of fluid is removed for analysis. there are a few contraindications for the performance of a lumbar puncture. the 1st is cardiorespiratory compromise. performance of the lumbar puncture requires that the child be held in flexion to open the intervertebral spaces. in seriously ill children or children with significant underlying cardiac or pulmonary disease, this positioning may be enough to cause respiratory compromise. the lumbar puncture may need to be postponed, be performed cautiously with continuous oxygen saturation monitoring, or performed with the patient in the sitting position. second, children with increased intracranial pressure from a focal central nervous system (cns) lesion, such as brain abscess or tumor, or from illnesses associated with cerebral edema have a high risk of cerebral herniation after a lumbar puncture. if signs or symptoms of increased intracranial pressure are present, the lumbar puncture should be postponed until the increased pressure is lowered with appropriate treatment. if a lumbar puncture is delayed, appropriate antibiotic therapy should be initiated without further delay. third, a lumbar puncture should not be done if the spinal needle must pass through an area of infection on its way to the subarachnoid space. to do so might introduce pathogens into the cns that could cause meningitis. epidural hematomas causing lower limb paralysis may be a complication of lumbar punctures in children with bleeding disorders. therefore, in children with hemophilia, disseminated intravascular of the neck, but lateral movement of the neck may be normal and pain-free. they also complain of nausea, vomiting, anorexia, and photophobia. on examination, they demonstrate irritability, mental confusion or altered consciousness, nuchal rigidity, and, occasionally, hyperesthesia and ataxia. the clinician demonstrates nuchal rigidity by feeling resistance and observing a painful response while flexing the patient's neck. the stiffness may not be recognized until the end of flexion. the neck usually can be rotated without symptoms. in the child who is crying and tensing the muscles, nuchal rigidity may be demonstrated if the examiner places 1 hand under the occiput of the supine patient and lifts the child. if the neck does not flex, it is stiff. alternatively, a sitting child may be observed following an object as it falls to the floor. the child who flexes the neck to look at the object does not have nuchal rigidity. in the presence of meningitis, flexion of the neck causes spontaneous flexion of the legs at the hips and knees, the brudzinski sign ( fig. 39.1) . the kernig sign is elicited when the patient lies supine and, with the knee flexed, the leg is flexed at the hip. the knee is then extended. a positive sign is present if this movement is limited by contraction of the hamstrings and causes pain. absence of nuchal rigidity is found in 1.5% of older children with meningitis; it may be absent in children who have overwhelming infections, are deeply comatose, or who have focal or global neurologic impairment. as many as 15% of children with bacterial meningitis initially present in a comatose or semicomatose state (see chapter 31). because a b specific agents) of pathogenic organisms. opening pressure measurements are obtained with the head of the bed flat and with the child relaxed and in the lateral decubitus position with the back no longer tightly flexed. the upper limit of normal value in children 1-18 years of age is less than 25 cm of water. opening pressure is less than 5 cm h 2 o in premature infants and less than 10 cm h 2 o in normal newborns. opening pressure measurements are elevated if the lumbar puncture is performed with the patient in the sitting position and if the patient is combative or performing the valsalva maneuver. obstructive hydrocephalus, hyperventilation, or removal of fluid can all lead to lowering of the measurement. children with bacterial meningitis usually have a mean opening pressure of 18 ± 7 cm h 2 o. normal csf is clear and colorless (table 39 .6). blood in the csf indicates a traumatic lumbar puncture or a cns hemorrhage. obtaining a rbc count on tubes 1 and 3 may differentiate the 2 conditions because the count is unchanged in cns hemorrhage but may decline in traumatic taps. centrifugation of the csf sample may also help differentiate between a traumatic tap and a cns hemorrhage. when blood has been present in the csf for several hours, the csf is xanthochromic after centrifugation. however, if the blood was recently mixed with csf, as in the case of a traumatic tap, the supernatant is clear. xanthochromic csf can also be caused by icterus or an elevated csf protein concentration. the normal values for wbcs in the csf are shown in table 39 .6. most children with bacterial meningitis have a wbc count of at least 1000/mm 3 in their csf, but, in general, more than 6/mm 3 in children after the neonatal period is considered abnormal. normal values for neonates are 0-18 (mean: 6) wbcs in the csf. an absolute neutrophil count exceeding 3/mm 3 (neutrophils may be as high as 35%) is also considered abnormal and evidence of a coagulopathy, or thrombocytopenia, lumbar puncture should be postponed until the bleeding disorder is corrected, and extra care should be taken to avoid a traumatic lumbar puncture. such children should be monitored after the procedure for the development of neurologic deficits. empirical therapy may be started while the coagulopathy is corrected. other, rarer complications of lumbar puncture include cortical blindness from compression of the posterior cerebral artery against the tentorium cerebelli, causing ischemic infarction of the occipital lobes. cervical spinal cord infarction, with respiratory arrest and flaccid tetraplegia, may occur if intracranial hypertension causes herniation of the cerebellar tonsils through the foramen magnum with resulting compression of the anterior spinal artery or its penetrating branches. post-lumbar puncture headache may occur in up to 10% of older children and adults; it is presumably caused by persistent csf leakage at the lumbar puncture site. the csf is examined for red blood cells (rbcs), white blood cells (wbcs) and differential, glucose, protein, and the presence (by culture, by gram stain or other stain, or by antigen or dna-pcr testing for on occasion, the spinal needle is advanced too far and passes through the subarachnoid space and penetrates the richly vascularized ventral epidural space. blood is thereby introduced into the subarachnoid space, and the csf appears bloody. this occurrence is often called a traumatic tap. it is then difficult to know whether the wbcs seen on examination of the csf are caused by csf pleocytosis or are peripheral blood wbcs contaminating the csf. to aid in this determination, the ratio of wbcs to rbcs in the csf is compared with the ratio of wbcs to rbcs in the patient's peripheral blood. a higher ratio in the csf indicates the presence of csf pleocytosis. when the csf ratio is at least 10 times higher than the blood ratio, bacterial meningitis is indicated, with a sensitivity of 88% and a specificity of 90%. conversely, the negative predictive value for the presence of bacterial meningitis of a less than 10-fold difference between the ratios is 99%. traumatic taps usually do not alter the csf glucose, gram stain, or culture findings, which are often abnormal with bacterial meningitis. when there is doubt about the validity of the cell count after a bloody tap, the lumbar puncture should be repeated after several hours by introducing the spinal needle 1 intervertebral space above the original tap site. in normal csf, the glucose concentration is two-thirds that of serum glucose concentration. the csf glucose concentration is low in most infected infants and younger children and in 45% of school-aged children with bacterial meningitis. in children older than 2 months of age, a csf/serum glucose ratio of less than 0.4 is 80% sensitive and 98% specific for the presence of bacterial meningitis. the presence of rbcs in a csf sample that is promptly analyzed does not affect the glucose concentration. the normal csf protein concentration is less than 45 mg/dl in children older than 2 months. the mean csf protein concentration is 90 (range, 20-170) in full-term infants and 115 (range, 65-150) in preterm infants. the csf protein concentration is elevated in more than 90% of younger children with bacterial meningitis but in only 60% of infected school-aged children. every 1000 rbcs in the csf (from a traumatic tap) increases the protein concentration by approximately 1 mg/dl. the presence of bacterial pathogens in the csf should be investigated. microscopic examination of a gram-stained sample of the fluid is performed first. the sensitivity of this test is directly related to the number of organisms in the csf and is inversely related to the age of the patient. the gram stain identification of certain organisms, such as h. influenzae, may be problematic. a decision whether to treat a child for bacterial meningitis should not be based on the gram stain alone; the definitive diagnosis is based on the csf culture. rapid diagnostic tests for bacterial antigens in csf, including countercurrent immunoelectrophoresis and latex particle agglutination, suffer from variations in sensitivity and specificity that limit their value in clinical practice. some patients will have been treated with antibiotics before the lumbar puncture is performed. when the csf from such a child is examined, organisms may not be seen on gram stain or recovered on culture. however, abnormalities of csf cell count (including elevated leukocytes), protein concentration, and glucose concentration usually continue to suggest the diagnosis of bacterial meningitis. in this setting, presumptive treatment for bacterial meningitis is initiated. if an organism is identified by culture or antigen detection, definitive antibiotic treatment is administered. if no organism is identified, the decision to continue treatment depends on the clinical suspicion of bacterial meningitis and the exclusion of other causes of aseptic meningitis (tables 39.7 and 39.8). newer laboratory techniques that utilize pcr to detect bacterial pathogens are being developed and may be useful in the diagnosis of bacterial meningitis in patients who have been treated with antibiotics before lumbar puncture. routine computed tomography (ct) of the head is not indicated in children with suspected meningitis. even though children with bacterial meningitis have increased intracranial pressure, most ct scans are normal. in addition, most lumbar punctures do not result in cerebral herniation in patients with meningitis. ct should be reserved for children who show clinical signs of herniation or cerebral edema and for those who may have an intracranial mass causing signs and symptoms similar to meningitis. usually, the peripheral blood wbc and platelet counts are elevated with bacterial meningitis. a low wbc count and thrombocytopenia may also be seen; these are associated with overwhelming infection and a poor outcome. the sensitivity (70%), specificity (54%), and negative predictive value (81%) of the differential wbc count are too low to render the differential wbc examination useful in making the diagnosis of bacterial meningitis. blood cultures may be useful in identifying the bacterial pathogen of meningitis. however, a negative blood culture may be found in up to 33% of children with meningococcal meningitis, 20% of children with pneumococcal cases, and 10% of patients with h. influenzae type b meningitis. these numbers increase with prior antibiotic therapy. in addition, there is a negative correlation between the length of illness before diagnosis and the rate of positive blood cultures. a bacterial meningitis score has been developed to attempt to distinguish between bacterial and aseptic (nonbacterial) meningitis in patients with csf pleocytosis. the risk of bacterial meningitis is low if none of the following criteria are present: history of a seizure with the illness, blood neutrophil count ≥10 × 10 9 cells/l, positive csf gram stain, csf protein ≥80 mg/dl, or csf neutrophil count ≥1 × 10 9 cells/l. this diagnostic tool is 99% sensitive and 62% specific for bacterial meningitis. it should only be applied to non-ill-appearing children older than 2 months without petechiae, purpura, or other concerning findings on examination who have not been pretreated with antibiotics. aseptic meningitis is an inflammatory process of the meninges, most often characterized by acute signs and symptoms of meningeal irritation; csf pleocytosis, usually with a predominance of mononuclear cells; a normal or, less frequently, elevated csf protein concentration; normal or, less often, low csf glucose concentration; and no organisms demonstrable by gram stain or bacterial cultures. there are many causes of aseptic meningitis (see table 39 .7). the most common cause is viral infection; up to 90% of cases are caused by enteroviruses and arbovirus. the definitive diagnosis is made by identifying the organism in the csf. however, this is not always possible, and other causes must be excluded by history, presence or absence of associated symptoms, and appropriate laboratory tests (tables 39.7 and 39.8). enteroviral meningitis occurs most often during the summer and early fall months. transmission is via the fecal-oral route, and young children exhibit increased transmission of the viruses and more severe disease in comparison with other age groups. initially, patients may have a respiratory tract infection, a nonspecific febrile illness, or vomiting and diarrhea. viral infection of the meninges occurs 7-10 days after initial exposure. the clinical course may be biphasic. virus from the oropharynx can be cultured only during the 1st 5-7 days of the illness but may be excreted in stool for 6-8 weeks. children with viral meningitis present with fever, nuchal rigidity, irritability, headache, and vomiting. less common symptoms are anorexia, drowsiness, photophobia, myalgia, and malaise. as in bacterial meningitis, affected young infants often lack meningeal signs. in addition, children may have an altered sensorium, but focal neurologic signs are rare. seizures are more common in infants. the number of wbcs in the csf varies from zero to several thousand (table 39 .6). up to 75% of initial (early in the illness) csf specimens contain a predominance of polymorphonuclear cells. mononuclear cells predominate by 2 days after the onset of symptoms. of children with enteroviral meningitis, 18% may have decreased csf glucose concentrations, whereas 12% may have elevated csf protein. treatment of enteroviral meningitis is supportive. admission to the hospital may be required while bacterial meningitis is being ruled out and for intravenous hydration. analgesics and antipyretics may also be indicated. the lumbar puncture performed to diagnose viral meningitis is often helpful in ameliorating the acute symptoms. the mechanism for this is not clear. the outcome is quite good for patients in whom common viral pathogens cause aseptic meningitis. sequelae in older children are rare. adverse outcomes are more common (but unusual) in children who have viral meningitis during the 1st year of life. speech and language development may be affected. treatment and outcome for the other types of aseptic meningitis depend on the underlying cause. tuberculous meningitis is an important treatable cause of aseptic meningitis. during the primary pulmonary tuberculous infection and enteroviruses and arboviruses cause most cases of infectious encephalitis in children. enterovirus encephalitis, uncommon without meningeal involvement, is suggested by epidemic occurrence and presence of typical prodrome or associated findings (table 39 .8); prompt diagnosis is by pcr for enterovirus in csf, blood, throat, or stool specimens. a csf or blood specimen is preferred because pcr may identify enterovirus in throat and especially stool for weeks after the primary infection has resolved. arbovirus encephalitis is suggested by mosquito or tick exposure and epidemic occurrence and is diagnosed by findings of arbovirus immunoglobulin m in csf or blood or by paired serologic findings for immunoglobulin g. infections with herpes simplex virus (hsv) occur throughout the year. in neonates, hsv encephalitis usually occurs between 7 and 21 days of age; may produce focal or generalized cns disease; and may occur with or without conjunctivitis, oral mucosal involvement, vesicles on skin, or disseminated disease (hepatitis, pneumonia, septic appearance). after the neonatal period, hsv encephalitis is usually isolated to the cns and classically produces necrotizing encephalitis with a focus in the temporal lobe. symptoms in persons with hsv encephalitis range broadly from those suggesting mild aseptic meningitis to the presence of status epilepticus and coma and then death. in addition to neutrophils and monocytes, csf examination may show increased numbers of erythrocytes and elevated protein. ct, mri, and an electroencephalogram (eeg) may suggest a temporal lobe focus. specific diagnosis is by pcr of csf for herpes simplex dna. csf culture is usually negative. in the appropriate clinical setting, presumptive therapy with intravenous acyclovir, 60 mg/kg/day given every 8 hours, is indicated while the results of pcr of csf for hsv are awaited. autoimmune encephalitis. anti-d-methyl-d-aspartate receptor (anti-nmdar) encephalitis is a novel and relatively common form of encephalitis. data from the california encephalitis project showed that anti-nmdar encephalitis was the most common identifiable cause of encephalitis in their cohort, which included patients from 6 months to 30 years. most of the cases occurred in children and adolescents. patients present with similar features as viral encephalitis, but seizures, language dysfunction, psychosis, autonomic dysfunction, movement disorders, and eeg abnormalities are more common in these patients. in adults, fuo is defined as an illness lasting more than 3 weeks, a fever higher than 38.3°c (101°f) on several occasions, and uncertainty subsequent lymphohematogenous spread to extrapulmonary sites, tubercle bacilli produce local microscopic granulomas in the cns and meninges. if this primary cns infection is not contained by host defense mechanisms (t lymphocytes, monocytes), or if host defense mechanisms fail at a later period, tuberculous meningitis may result. meningitis occurs weeks to months after the primary pulmonary process. the symptoms of tuberculous meningitis are insidious and subacute (weeks to months). stage 1 is a prodrome with nonspecific manifestations (apathy, poor school function, irritability, weight loss, fever, night sweats, nausea); stage 2 is heralded by the onset of neurologic signs (headache, cranial neuropathy, nuchal rigidity, signs of increased intracranial pressure); and stage 3 manifests with altered levels of consciousness (lethargy, stupor, coma). meningismus is not present in all patients. the diagnosis is supported by a history of contacts with adults with known active tuberculosis, a chronic cough, or human immunodeficiency virus (hiv) disease or by a history of immigration, poverty, or homelessness. in addition, the patient's chest radiograph is consistent with active or, more often, quiescent tuberculosis (parenchymal-hilar node calcifications, infiltrates, hilar adenopathy, and, in rare cases, endobronchial or cavitary lesions), and the patient's tuberculin skin test yields a positive result (see chapter 2). cranial ct or magnetic resonance imaging (mri) may show the most intense meningeal inflammation around the base of the brain or inflammatory mass lesions (tuberculomas). the csf results (table 39 .6) include profound hypoglycorrhachia, a high csf protein, lymphocyte-or monocytepredominant cells (usually 500 cells/mm 3 ), increased opening pressure, and, on occasion, tubercle organisms on acid-fast staining. pcr amplification of mycobacterium tuberculosis dna aids in making a more rapid diagnosis than does culture of csf, sputum, or gastric aspirates, which traditionally requires 2-6 weeks. the differential diagnosis depends on the stage of the illness. encephalitis is inflammation of the brain parenchyma, whereas meningoencephalitis is inflammation of the brain accompanied by inflammation of the meninges. meningoencephalitis is distinguished from aseptic meningitis by evidence of brain parenchymal involvement, including behavior or personality changes; altered level of consciousness (including agitation or coma); generalized seizures; focal neurologic signs, including focal seizures and focal motor defects (hemiparesis or ataxia); or movement disorders. bartonellosis in developed countries and brucellosis and typhoid in developing countries. often patients with an fuo have atypical manifestations of common childhood bacterial or viral diseases rather than unusual or uncommon disorders. the evaluation of a child with fuo centers on a detailed history and physical examination. taking the history should be repeated because parents often remember important details after the initial interview. the physical examination findings may also change during the course of the investigation revealing important clues (fig. 39 .5, table 39 .11). the history should include the time of day of the fever, who measured the temperature, and the instrument that was used to measure the temperature. increased temperatures after exercise and in the afternoon often represent normal variations. the appearance of the of diagnosis after a 1-week study in the hospital (table 39 .9). in pediatrics, the defined duration of fever is variable, from 8 days to 3 weeks (average, 2 weeks). this may be dependent on the age of the patient, with shorter periods of fever in young infants and more traditional adult standards in adolescent patients. fuo is defined as a temperature higher than 38°c (100.4°f) daily for at least 8-14 days and no diagnosis after an initial evaluation. the initial evaluation recommended varies but always includes a noncontributory history and physical examination, and nondiagnostic initial laboratory and radiologic tests. in accordance with this definition, the differential diagnosis for fuo in children is large ( child while febrile is also important. increased temperature without sweating might be seen in a child with ectodermal dysplasia or factitious fever. the pattern of fever should be noted (fig. 39.6 ). sustained fever, intermittent fever, and relapsing fever have been associated with different disease states. sustained or remittent fever remains elevated with little variation during the day and has been associated with enteric (typhoid) fever, tularemia, and rickettsial diseases such as typhus and rocky mountain spotted fever. intermittent fever normalizes at least once a day and is associated with tuberculosis, abscesses, lymphomas, juvenile idiopathic arthritis (jia), and some forms of malaria. children with relapsing fever have afebrile days between febrile episodes. relapsing fever has been associated with rat bite fever, borrelia species infection, malaria, brucellosis, subacute bacterial endocarditis, african trypanosomiasis, lymphomas, and lyme disease. saddle-back or double-hump fever lasts a few days, is followed by an afebrile day or 2, and then returns. it has been associated with some viruses and dengue fever. double quotidian fever (2 fever spikes each day) occurs in kala-azar, malaria, and gonococcal endocarditis. periodic fevers occur as acute febrile episodes separated by prolonged afebrile, healthy periods. diseases to consider include cyclic neutropenia, familial mediterranean fever, and the syndrome of periodic fever, aphthous stomatitis, pharyngitis, and adenitis (pfapa). periodic fever syndromes have different prevalence patterns in different ethnic groups and different inheritance patterns. a detailed family history is particularly important when these diagnoses are considered (see chapter 41). unfortunately, neither the fever pattern nor the duration is specific for a particular cause. fevers lasting for more than 1 year are not usually infectious; factitious fever, rheumatic or granulomatous disorders, familial diseases, or malignancies need to be considered in these patients. a history of rash is important for diagnosing lyme disease, jia, and acute rheumatic fever (see chapter 40). a history of pica is associated with visceral larva migrans and toxoplasmosis. exposure to domestic and wild animals should be identified to exclude zoonoses (see chapter 40). the food history should be detailed and should include water sources, use of game meats, cooking practices, and consumption of unpasteurized, raw milk, or soft cheese. travel history is critically important in the establishment of a differential diagnosis. areas visited, accommodations, activities, prophylactic treatments, animal and insect exposures, and water and food sources should be reviewed. coccidioidomycosis, histoplasmosis, malaria, lyme disease, and rocky mountain spotted fever have regional distributions. children who have traveled to or have emigrated from developing countries are at increased risk for endemic diseases and m. tuberculosis (table 39.12) . previous medical records should be reviewed. weight loss is important for diagnosing many chronic diseases such as lymphoma, tuberculosis, and inflammatory bowel disease. poor weight gain and growth, with or without gastrointestinal symptoms, may be the only historical clue to inflammatory bowel disease (see chapter 11). hiv risk factors in the parents and child should be reviewed. past and current medications should also be reviewed. the review of systems may reveal heat intolerance, palpitations, tremors, and declining quality of schoolwork in a child with hyperthyroidism. a history of severe head trauma may be associated with hypothalamic dysfunction and central fevers. whenever possible, the patient should be examined during a febrile episode. a high fever in the absence of an increased pulse may be present in a patient with factitious fever. to verify this diagnosis, the temperature of freshly voided urine may be recorded. tremor, tachycardia, palpitations, exophthalmos, lid lag, eyelid retraction, and smooth, flushed skin with diaphoresis are suggestive of hyperthyroidism. the ophthalmologic examination should include assessment of visual acuity, extraocular motion, visual field integrity, and gaze, as well as inspection of external structures and ophthalmoscopic examination (see chapter 32). conjunctivitis, iritis-uveitis-scleritis, or both may be seen in a variety of infectious conditions, including epstein-barr virus (ebv) infection, leptospirosis, rickettsial infection, and cat-scratch disease. conjunctivitis, uveitis, or both occur with kawasaki disease, systemic lupus erythematosus (sle), polyarteritis nodosa, and jia. sarcoidosis may be associated with conjunctival and uveal tract nodules. a thorough ophthalmoscopic evaluation (and, if needed, slitlamp examination) should be performed. sarcoidosis may be accompanied by vascular occlusions, hemorrhages, vascular sheathing, and preretinal inflammatory exudates. cytomegalovirus (cmv) produces chorioretinitis associated with white infiltrates near vessels and confluent depigmented areas. histoplasmosis causes small atrophic spots and, in rare cases, focal granulomas of the retina and choroid. toxoplasma gondii is a common cause of recurrent retinochoroiditis. retinal changes also occur with bacterial endocarditis. tuberculosis can cause formation of choroidal tubercles and also ulcerative palpebral conjunctival lesions. slit-lamp examination may also reveal iridocyclitis in jia, behçet syndrome, and inflammatory bowel disease. the frontal and maxillary sinuses should be palpated for tenderness. the nares should be inspected for inflamed mucosa and purulent discharge. tympanic membranes should be viewed and insufflated (see chapter 4). the mouth should be checked for lesions, inflammation, and tooth tenderness. behçet syndrome may manifest with oral aphthous lesions. inspection of teeth and gums may reveal a dental abscess. exudative and nonexudative pharyngitis is associated with ebv infection, tularemia, leptospirosis, and cmv. pfapa syndrome is characterized by periodic fever, aphthous stomatitis, pharyngitis, and cervical adenopathy. candida infection in the mouths of children older than 2 years may result from immunodeficiency such as hiv or from the use of inhaled steroids. the neck should be examined for adenopathy or thyroid enlargement (see chapter 36). the rest of the lymphatic system should be carefully examined. a single tender node may be seen with cat-scratch disease. generalized adenopathy can be seen in cmv infection, ebv infection, and systemic jia (see chapter 33). the musculoskeletal examination should include assessments of strength and of active and passive range of motion and evaluation for warmth, tenderness, or swelling of joints. irritability and pain on palpation over a bone or disuse pseudoparalysis may be the 1st clue to osteomyelitis. bone pain may also result from neoplastic infiltration of the bone marrow or sickle cell anemia. unexplained fever, arthralgias, and arthritis may be present with acute rheumatic fever, jia, lyme disease, kawasaki disease, sle, polyarteritis nodosa, and behçet syndrome (see chapter 33). myalgias occur commonly with viral diseases such as influenza, and may be present with rickettsial diseases, polyarteritis nodosa, takayasu arteritis, and dermatomyositis. careful auscultation of the heart and lungs is essential. a mitral or aortic regurgitant murmur may be the initial finding of endocarditis or of carditis in children with acute rheumatic fever. a pericardial friction rub may also suggest jia, sle, rheumatic fever, malignancy, or viral pericarditis. the abdomen must be carefully palpated for evidence of masses or hepatosplenomegaly (see chapters 14 and 17). abdominal tenderness may be present with abdominal abscesses, hepatosplenomegaly, and inflammatory bowel disease. a rectal examination should be performed, and stool should be tested for occult blood. sexually active girls should have a pelvic examination. pain on movement of the uterus during the pelvic examination may indicate pelvic inflammatory disease. specific serologic studies aid in the diagnosis of cmv, toxoplasmosis, brucellosis, tularemia, hepatitis a, b, and c, and leptospirosis. biopsies of lymph nodes, the skin, the liver, or bone marrow may be indicated. radiologic studies that may be of benefit if directed by the history, physical examination findings, and initial laboratory study results include sinus ct, abdominal imaging, or total body mri (to evaluate for occult osteomyelitis, malignancy, histiocytic disorders). the complete blood cell count with differential is neither specific nor diagnostic, except in rare circumstances, such as seeing lymphoblasts on the blood smear. approximately 30% of patients have abnormal white blood cell counts; 46% may have a left shift, lymphocytosis, atypical lymphocytes, or blasts. an elevated esr or crp indicates inflammation. the esr is usually (70-90% of the time) high in children with fuo caused by infectious pathogens, malignancies, and rheumatic diseases. of patients with an esr less than 10 mm/hr, 90% have a self-limited viral disease. urinalysis and urine culture identify occult infections, particularly in young girls. the urinalysis may also be abnormal in patients with endocarditis and rheumatic and other inflammatory disorders. unexpected consolidations, calcifications, interstitial changes, perihilar adenopathy, or cardiomegaly (heart failure, pericarditis) may be found on chest radiographs. chest films are abnormal in 10-15% of patients with fuo. ct of the chest may reveal abnormalities not detected by a chest x-ray. specialized radiologic studies performed without specific diagnostic clues from the history, physical examination findings, or initial laboratory evaluation results have a low yield. whole body mri is another technique that may be useful in children with fuo. it is helpful in identifying abnormal areas in bones, such as with occult osteomyelitis. a wide variety of infections have been identified in children with fuo including subacute bacterial endocarditis, urinary tract infections (uti), sinusitis, abscesses, osteomyelitis, and rheumatic fever. bacterial endocarditis. bacterial endocarditis is rare in children; incidence increases with advancing age and history of preexisting heart disease (see chapter 8). a new murmur or a change in the characteristic of an existing murmur may not be initially evident. vegetations also may not be visible initially by transthoracic echocardiography; a transesophageal approach is much more sensitive. serial blood cultures with anaerobic and aerobic media are necessary for definitive diagnosis. urinary tract infection. both upper and lower urinary tract infections may be asymptomatic, and leukocytes may not always be present in urine (see chapter 18). sterile pyuria may be present with tuberculosis, nongonococcal urethritis, viral cystitis, kawasaki disease, reactive arthritis, interstitial nephritis, and other rheumatic diseases. renal ultrasonography may show areas of decreased echogenicity, enlarged echogenic kidneys, and renal or perinephric abscesses. kidneys may be enlarged with acute pyelonephritis. a ct scan with contrast may show infected parenchyma as a nonenhancing lucency. nuclear medicine renal scans also identify active areas of infection and old scars. sinusitis. factors that decrease the size and patency of the ostium, or impair the mucociliary transport system predispose a child to sinusitis. ethmoid and maxillary sinuses are present at birth. the frontal sinuses usually appear near 5 or 6 years of age but may be asymmetric or absent. sphenoid sinuses may be seen radiographically by 9 years of age. prolonged nasal congestion, headache, purulent nasal discharge, sore throat, daytime cough, tender teeth, and halitosis may be present the skin must be inspected for evidence of rashes and other lesions (see chapter 40). jia may manifest with an evanescent, salmon-colored macular rash over the trunk and joints that may appear and disappear rapidly and be evident only during febrile periods. dermatomyositis is characterized by a heliotropic rash of the upper eyelids and an erythematous eruption (vasculitis) over the extensor surfaces (gottron sign). sle may manifest with a butterfly rash over the nose and malar regions, signs of photosensitivity in sun-exposed areas, or vasculitis. the rash of kawasaki disease is erythematous and may manifest in many forms; it is most commonly a diffuse maculopapular rash. in rocky mountain spotted fever, there are macular erythematous spots on the wrists, ankles, or forearms that may become maculopapular and expand centripetally to the proximal extremities and torso; palms and soles may be involved and petechiae may develop later in the course of the illness. endocarditis may be associated with splinter hemorrhages or janeway lesions (painless, small, erythematous or hemorrhagic lesions on the palms and soles). lyme disease usually manifests with erythema migrans. this rash begins at the site of the tick bite and is erythematous with a pale center. the rash radiates out from the bite in a circular manner and persists for weeks; satellite secondary lesions may also appear. tularemia, salmonellosis, listeriosis, and ebv infections may feature generalized maculopapular rashes. laboratory evaluation should proceed in a stepwise, focused manner with emphasis on identifying serious illnesses with defined interventions (see fig. 39 .5). initial studies should include a complete blood cell count with differential, erythrocyte sedimentation rate (esr) measurement, crp, blood cultures, urinalysis, urine culture, tuberculin skin tests with controls (anergy panel) or gamma interferon release assay, and chest radiograph. because ebv infection is common in childhood, viral-specific antibody titers may also be obtained at the initial evaluation (see chapter 36). further studies should be directed from days to months. regional lymphadenopathy with 1 or more nodes occurs proximal to the skin site 1-9 weeks after inoculation. the node or nodes become enlarged and tender and may have overlying erythema. the lymphadenopathy usually resolves after 2 months but may last up to 3 years. affected children may have adenopathy with fever, headache, malaise, anorexia, sore throat, and conjunctivitis (see chapter 36). q fever. q fever is caused by coxiella burnetii, formerly classified as a rickettsia. it manifests with headache, fever, chills, malaise, and, on occasion, respiratory symptoms. hepatic, cardiac, and cns involvement may occur. rash is usually not seen. domestic farm animals, cats, rodents, and marsupials may be infected. pasteurization destroys the organism in milk. diagnosis is made by serologic testing. rat bite fever. rat bite fever is a relapsing fever caused by streptobacillus moniliformis or spirillum minus. s. moniliformis is a pleomorphic gram-negative bacillus transmitted by rat bite or by contaminated food or water. in 1-10 days after exposure, patients may exhibit fever, chills, malaise, and muscle aches. a rash may form on the extremities; arthralgias and arthritis may occur. complications include abscesses, pneumonia, endocarditis, myocarditis, and meningitis. diagnosis is made by blood culture or culture of other infected fluid, such as abscess aspiration. tularemia. francisella tularensis is the causative agent of tularemia. the disease is spread by contact with wild animals, such as rabbits and squirrels, and by insects that bite these animals, such as mosquitoes, ticks, and deer flies, as well as by contaminated water. a maculopapular nodule forms at the portal of entry and later becomes ulcerated. the child may present with fever, chills, and headache. lymphadenopathy, pharyngitis, conjunctivitis, hepatosplenomegaly, and pneumonia may also occur. diagnosis is made by serologic study. brucellosis. brucellosis is caused by gram-negative coccobacilli: brucella abortus, b. melitensis, b. suis, or b. canis. the microorganisms are found in sheep, goats, cattle, swine, and dogs. infection may occur by airborne spread or by ingestion of meat or milk. the child may present with fever, chills, malaise, headache, arthralgias, or myalgias. pneumonia, cardiac involvement, and cns involvement occur in rare cases. diagnosis is made by special culture techniques and serologic study. leptospirosis. leptospirosis is caused by members of the spirochete genus leptospira. infection is spread by contact with the urine of wild or domestic animals. in 1-2 weeks after exposure, patients experience the abrupt onset of fever, chills, nausea, vomiting, headache, and occasionally conjunctival suffusion and rash. liver, renal, and cns involvement may also occur. diagnosis is made by special culture techniques and serologic testing. blastomyces dermatitidis is a saprophytic fungus with both yeast and mycelial forms; it is found in the soil all over the world but is common in the americas. it is endemic in the southeast and midwest regions of north america. infections with this fungus may be disseminated or pulmonary. the diagnosis is made by visualization of single-budding yeast in clinical material, culture on sabouraud agar, or serologic tests. histoplasma capsulatum is a yeast found in soil in the ohio river valley and other locations in the united states that causes pulmonary and disseminated disease. diagnosis is made by the demonstration of the microorganism in biopsy specimens or by complement-fixing antibody. in children with sinusitis. ct studies may be helpful. rhinoscopy may show purulent material at the ostium of an infected sinus. infectious complications of sinusitis include dural space empyema or brain abscesses. abscesses. hepatic, renal, perinephric, pelvic, and subphrenic abscesses may present with fuo. internal jugular thrombophlebitis may manifest with prolonged fever and severe neck pain. liver abscess may manifest with right upper quadrant tenderness and hepatomegaly. blood cultures and liver function study results are often normal. the diagnosis may be made with mri, ct with contrast, or ultrasonography. the diagnosis of perinephric abscesses is made with ct with contrast or ultrasonography. ct or ultrasound guidance may be used to direct percutaneous drainage of many abscesses. pelvic abscesses should be suspected in children with fuo who have abdominal, rectal, or pelvic tenderness. osteomyelitis. osteomyelitis usually follows bacteremia, but it sometimes follows penetrating injury. tenderness to palpation over the infected site is common. abnormalities in plain films appear late (2 weeks). mri is the imaging modality of choice. the blood or bone culture is often positive, and the esr is often elevated. suppurative myositis may mimic osteomyelitis and manifest as an fuo. rheumatic fever. acute rheumatic fever may cause fuo; the diagnosis is made by fulfillment of the jones criteria, updated in 2015 (see chapter 8). initially, a child may present with polyarthralgia and an increased esr. elbows, wrists, knees, and ankles are frequently involved. the later migratory nature of the true arthritis differentiates rheumatic fever from jia. bacterial syndromes that cause fuo in children include agents of the following: • lyme disease • cat-scratch disease • q fever • rat bite fever • tularemia • brucellosis • leptospirosis lyme disease. lyme disease is caused by the spirochete borrelia burgdorferi and is transmitted by the ixodes dammini and i. pacificus ticks. the usual manifestation of early lyme disease is with erythema migrans, an erythematous, annular, expanding rash with central clearing. the rash resolves 1-30 days (usually 2 weeks) after exposure. patients may exhibit fever, chills, fatigue, headaches, malaise, myalgias, arthralgias, and lymphadenopathy. early disseminated lyme disease follows 2-8 weeks after exposure; facial nerve palsy, peripheral neuropathy, cardiac conduction defects, myocarditis, and aseptic meningitis may occur. diagnosis is made clinically in early localized lyme disease because serology lacks sensitivity and specificity during early infection and because erythema migrans is so specific for lyme disease. diagnosis of early disseminated lyme disease requires a typical clinical illness, exposure to ticks known to carry b. burgdorferi and serologic evidence of infection with a 2-tier testing strategy. the initial test is an enzyme-linked immunosorbent assay (elisa) or immunofluorescent (ifa) test. if this result is equivocal or positive, a western immunoblot is performed. western blot should not be performed if the elisa is negative or has not been performed because it lacks specificity in this setting. cat-scratch disease. cat-scratch disease is a febrile illness associated with cats (usually kittens) and, more rarely, dogs. bartonella henselae, which may be transmitted by the cat flea and by cat saliva, is the etiologic agent. after a scratch or bite, a papule forms and may persist parasites fuo in children may be caused by parasitic infections, including (1) babesiosis, (2) toxoplasmosis, and (3) toxocariasis. babesiosis is caused by babesia microtia and is a parasite of rodents transmitted to humans by tick bite. infection may result in fever, chills, nausea, vomiting, night sweats, myalgias, and arthralgias. identification of the organism in a thick smear of red blood cells is diagnostic. t. gondii is a protozoan parasite. children become infected from eating contaminated, undercooked meat or from exposure to the feces of domestic cats. most infections acquired postnatally are asymptomatic but children may develop a mononucleosis-like illness (see chapter 36). toxocariasis (previously visceral larva migrans) results from ingestion of larvae of toxocara canis or from t. cati shed in dog and cat feces, respectively. infection results in fever, intense eosinophilia, hepatomegaly, and hypergammaglobulinemia. lung, heart, and cns involvement is rare. the eye may become infected. diagnosis is presumed with increased eosinophils and hypergammaglobulinemia, and elevated titers of isohemagglutinin to a and b blood group antigens. in a child who has traveled to or lives in a developing country, consideration must be given to the area, water sources, and activities. some causes of fuo to consider include malaria, hepatitis, typhoid fever, tuberculosis, and amebic liver abscess (table 39 .12). malaria is transmitted by the bite of an infected mosquito carrying 1 of the 5 species of the plasmodium genus that cause disease in humans. the patient experiences chills, rigors, high fever, diaphoresis, and headaches. the incubation period varies among species, from 1 week to several months. demonstration of the parasite on thick peripheral blood smear is diagnostic. risk for malaria can be checked for areas of the world on www.cdc.gov/malaria. hepatitis a may be contracted by ingestion of contaminated food or water. hepatitis b and c viruses are transmitted through blood products or sexual contact. diagnosis is by serologic testing. symptoms can include fever, malaise, jaundice, hepatomegaly, nausea, and anorexia. hepatitis b and c can become chronic (see chapter 15). enteric fever is caused by infection with 3 serovars of s. enterica, which includes s. typhi. after ingestion of contaminated water or food, incubation lasts from 1-6 weeks. persistent fever, headache, malaise, anorexia, and rose spots are clinical hallmarks of enteric fever. diagnosis is by blood culture. tuberculosis may manifest as fuo in children (see chapters 2 and 36). affected children may have pulmonary or extrapulmonary disease. the signs and symptoms of pulmonary disease may vary greatly from weight loss, tuberculin skin test conversion, and low-grade fever to mass effect from mediastinal lymphadenopathy and fulminant disseminated pulmonary involvement with miliary infiltrates or, in rare cases, cavitation. nonpulmonary tuberculosis more commonly manifests as fuo, inasmuch as positive chest radiograph findings and pulmonary signs may initiate an early work-up for tuberculosis. hematogenous spread may cause liver, heart, or renal involvement. ingested bacilli may result in gastrointestinal tuberculosis. the diagnosis requires demonstration of coccidioides immitis is found in soil in the southwestern united states. infections in humans are associated with a febrile pulmonary disease characterized by cough, rash, and chest pain. diagnosis is usually made serologically. cryptococcus neoformans is often found in pigeon droppings and can cause a variety of diseases. the diagnosis is made by culture or by identification of encapsulated yeast in collected specimens. psittacosis and lymphogranuloma venereum are chlamydial causes of fuo. chlamydia psittaci may be transmitted by infected birds and produces respiratory illness with fever. cardiac, liver, cns, and thyroid involvement are rare. diagnosis is made serologically. c. trachomatis is a sexually transmitted organism that causes urogenital infections, perihepatitis, invasive lymphadenopathy (lymphogranuloma venereum), neonatal conjunctivitis, and neonatal pneumonia. diagnosis is by cell culture and rapid antigen tests. rocky mountain spotted fever. rocky mountain spotted fever manifests with fever, headache, intense myalgias, and abdominal symptoms. a characteristic rash is usually present by the 6th day of illness. the rash covers the palms, wrists, soles, and ankles and progresses from macular to petechial. the disease can last up to 3 weeks. many end organs, including the heart, kidneys, and cns, can be involved. transmission of the causative agent, rickettsia rickettsii, occurs by tick bite. diagnosis is made by pcr testing of blood. ehrlichiosis and anaplasmosis. these infections are caused by ehrlichia chaffeensis, anaplasma phagocytophilia, and e. ewingii and are transmitted by the lone star tick. anaplasmosis is caused by anaplasma phagocytophilia and is transmitted by the black legged deer tick. these illnesses are usually seen in the southeastern and upper midwestern united states, respectively, and have manifestations similar to that of rocky mountain spotted fever. the patient presents with headache, myalgias, fever, chills, nausea, vomiting, weight loss, thrombocytopenia, and leukopenia. rash is inconsistent but may be seen after 1 week. pulmonary and renal complications can occur. mental status changes are less frequent. diagnosis is confirmed by pcr. cytomegalovirus infection. cmv may cause a mononucleosis-like syndrome in children. generalized or cervical adenopathy may be seen along with fatigue, malaise, fever, hepatosplenomegaly, and abdominal pain (see chapter 36). a morbilliform rash may also be present. retinitis, hepatitis, colitis, and pneumonia may occur in children with impaired immune systems. the virus is transmitted by contact with secretions. infection is diagnosed by culture (nasopharyngeal, blood, urine) or by the detection of specific immunoglobulin g and immunoglobulin m antibodies. infectious mononucleosis. infectious mononucleosis is typically caused by ebv and may manifest with fever, exudative pharyngitis, malaise, and fatigue (see chapter 36). the appearance of rash is sometimes preceded by amoxicillin therapy, but rash may occur without antibiotic administration. tender lymphadenopathy and hepatosplenomegaly may occur. the diagnosis may be made by nonspecific tests (heterophile antibody or monospot) in older patients, but these studies are unreliable for young children. specific antibody tests against viral capsid antigen, early antigen, and nuclear antigen are recommended in younger children. treatment is supportive. human immunodeficiency virus infection. infection with hiv or associated opportunistic infections or associated malignancies is another cause of fuo in children. neuroblastoma may manifest as abdominal, thoracic, or pelvic masses; spinal cord compression; bone pain; hypertension; hepatomegaly; diarrhea; and fever (see chapter 17). diagnosis is aided by radiologic studies and urinary catecholamine measurements and is confirmed by biopsy. both acute lymphocytic leukemia and acute nonlymphocytic leukemia may manifest with lethargy, pallor, bleeding, fever, bone pain, lymphadenopathy, and arthralgias. diagnosis is made by blood smear and bone marrow biopsy. pheochromocytomas are rare catecholamine-secreting tumors; 10% occur in children. these tumors manifest with paroxysmal or sustained hypertension, headache, excessive sweating, fever, hyperglycemia, and palpitations. the tumors are usually in the adrenal medulla, but 35% of those occurring in children are multiple or extraadrenal. diagnosis is made by measuring urinary or plasma metanephrine or catecholamine levels. localization of tumor is by ct, mri, or iodine 131-metaiodobenzylguanidine scanning. familial mediterranean fever is an autosomal recessive trait seen in sephardic jews and people of middle eastern descent. the fever may be accompanied by joint, abdominal, and chest pain. anhidrotic ectodermal dysplasia is an x-linked recessive disorder associated with decreased ability to sweat, dental abnormalities, and sparse hair. eyebrows and eyelashes may be absent. fever may result from the inability of the body to cool itself. diagnosis is made by skin biopsy that shows an absence of eccrine glands. drug fever is a diagnosis of exclusion. some drugs are more likely than others to cause drug fever (α-methyldopa, quinidine, penicillins). there is no characteristic fever pattern. there is a highly variable lag time between the initiation of the drug and the onset of fever, and there is an infrequent association with rash or eosinophilia. some drugs may cause fever by virtue of physiologic side effects. anticholinergic drugs may decrease sweating and diminish the body's ability to cool itself. chronic salicylate intoxication can cause increased heat production by uncoupling oxidative phosphorylation. kawasaki disease may manifest with a variety of signs, including rash; lymphadenopathy; conjunctival hyperemia; strawberry tongue; erythematous lips; swelling of hands and feet; arthralgia; arthritis; myocarditis; late desquamation of hands, feet, and perineal area; and sterile pyuria. fever may be high and spiking. diagnosis is by fulfillment of clinical criteria (see chapter 40). inflammatory bowel disease (ibd; ulcerative colitis, crohn disease) may manifest with fuo. ulcerative colitis may manifest with bloody diarrhea, fever, fecal urgency, and straining (see chapter 11). pyoderma gangrenosum, arthritis, and erythema nodosum can also be seen. crohn disease (regional enteritis) may manifest with abdominal pain, fever, anorexia, and growth failure. diarrhea may develop later. arthritis, erythema nodosum, and finger clubbing may also occur. diagnosis of ibd is by endoscopy and histology. acid-fast bacilli from sputum, gastric aspirate, or the affected organ. skin testing may yield negative results even with positive controls. intestinal infection with entamoeba histolytica may produce invasion of the mucosal lining and spread to other organs such as the liver. amebic liver abscess may manifest with fever, weight loss, right upper quadrant pain, and anorexia. the patient may have painful hepatomegaly without splenomegaly. the abscess may be localized with abdominal ultrasonography or ct. diagnosis is by serologic study. rheumatic diseases as a cause of fuo are the 2nd most common identified cause of fuo after infections. in a systematic review, the most common causes were jia and sle (see chapter 33). jia is a diagnosis that requires time to identify all of its manifestations and to exclude other entities. jia is defined by arthritis of unknown origin that begins in a child younger than 16 years and persists for a minimum of 6 weeks. jia is divided into 3 subtypes: systemic, polyarticular, and oligoarticular. the systemic form often manifests with prolonged high fever. affected children often have a daily fever and may have a fine macular rash, arthralgias, arthritis, hepatosplenomegaly, or pericardial involvement. polyarticular jia may manifest with arthritis, low-grade fever, morning stiffness, anorexia, and weight loss. polyarteritis is a necrotizing vasculitis that may manifest with myalgia, arthralgia, fever, vasculitic skin lesions, and abdominal pain. cardiac, cns, and renal involvement may also occur. the esr usually is markedly elevated. biopsy and the presence of antibodies to proteinase 3 and myeloperoxidase (antineutrophil cytoplasmic antibodies) are helpful. sle may manifest with fever, photosensitivity, mouth sores, weight loss, rash, myalgias, malaise, and hepatosplenomegaly. patients may also have serositis and renal involvement. laboratory tests that are helpful include lupus erythematosus cell preparation and those for antinuclear antibody, anti-smith antibody, anti-ribonuclear protein antibody, anti-ro (sjögren syndrome type a) antibody, and anti-la (sjögren syndrome type b) antibody. behçet syndrome is very rare in children but may manifest with fuo. patients may have aphthous stomatitis, arthritis, genital ulcers, uveitis, and erythema nodosum. hodgkin disease, lymphoma, neuroblastoma, and leukemia may all manifest as fuo. in young children, leukemia, neuroblastoma, and lymphoma should be suspected, whereas in adolescents, hodgkin disease and ewing sarcoma are more common as causes of fuo. hodgkin disease may manifest with firm, nontender adenopathy, fever, night sweats, and weight loss. diagnosis is made through biopsy. non-hodgkin lymphoma may manifest as painless adenopathy, cough or dyspnea from a mediastinal mass, abdominal mass, nerve compression, bone pain, fever, and weight loss. diagnosis is by biopsy. sweating, tachypnea, or tachycardia. if factitious fever is suspected, the temperature should be obtained while the patient is observed. the temperature of freshly voided urine can also be recorded. other patients may produce actual diseases that cause true fevers, such as by injecting infected pyogenic material subcutaneously or intravenously or by taking toxic levels of thyroid hormone. once the diagnosis is documented, psychiatric care is indicated. if no diagnosis is made, most patients are clinically well and asymptomatic on follow-up. some may be determined to be healthy from the start; most are in good health at follow-up, whereas few have symptoms at the end of evaluation. some may have relapses of fever for a few months. jia, inflammatory bowel disease, and pfapa syndrome may not be immediately diagnosed but usually manifest typical symptoms and signs within 2 years of the onset of the fuo. hyperthyroid states may manifest with fuo. children usually have multiple symptoms, such as irritability, tremor, eyelid lag, and exophthalmos. diagnosis is made from thyroid function studies. factitious fever may be a form of factitious disorder imposed on self (formerly munchausen syndrome) or medical child abuse (formerly munchausen syndrome by proxy) (see chapter 26). a variety of techniques have been used to falsely elevate a recorded temperature. a mercury thermometer may be rubbed between hands or placed near a light bulb. hot liquids may be placed in the mouth before an oral temperature is taken. hot rectal douches have also been reported to raise a rectally taken temperature. even with pathologic fevers, there is some circadian rhythm to the temperature curve; with factitious fever there is no rhythm. in addition, there is usually no vasoconstriction, many children with fever will have a source identified on their initial history and physical examination. red flags include patients with symptoms or signs of sepsis (tachycardia, hypotension) or meningitis or encephalitis (fever, headache, irritability, altered mental status and for the older child, meningismus). affected infants with meningitis are more likely than older children to have subtle and nonspecific symptoms. a child with fever of recent onset with no adequate historical or physical explanation for the fever is said to have fever without source (fws). because of the high volume of children with fws, it is important to have a reliable system for individual patient evaluation and management. although the majority of patients with fws have a self-limited viral illness, 5-10% have an invasive bacterial infection, with young infants at highest risk. because of the potential for morbidity and mortality from the organisms that cause invasive disease, identification of patients at high risk is essential. although there is no single, timely series of tests that correctly categorizes all patients, the combination of careful clinical evaluation and appropriate laboratory screening criteria can help identify a level of risk in children of different ages. the reduction of bacteremia due to vaccine-serotype pneumococcus has led to a careful reduction in diagnostic testing, especially in the 3-36 month old child with fws. red flags include a history of immunodeficiency or other chronic medical illness, no prior immunizations, toxic appearance, signs of shock, petechiae or purpura, poor responsiveness, and other signs of altered mental status. some children, who are initially thought to have fws, develop into patients with fuo. definitions of fuo in children vary. a practical definition balancing different recommendations is fuo is a temperature higher than 38°c (100.4°f) daily for at least 8-14 days and no diagnosis after an initial evaluation. work-up of the patient with fuo should proceed in a stepwise manner. it should be kept in mind that many patients with fuo have unusual, atypical, or complicated manifestations of common childhood illness, mainly infections. red flags include weight loss, night sweats, signs of organ system dysfunction or failure, or unstable vital signs suggestive of sepsis. only in this last category should a rapid diagnostic approach be performed and empirical antibiotic therapy initiated. temperature measurement in pediatrics: a comparison of the rectal method versus the temporal artery method randomized trial of rapid multiplex polymerase chain reaction based blood culture identification and susceptibility testing comparison of temporal artery to rectal temperature measurements in children up to 24 months effect of bundling and high environmental temperature on neonatal body temperature fever pathophysiology international pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics the effects of bundling on infant temperature the future possibilities of diagnostic testing for the evaluation of febrile infants rectal versus axillary temperatures: is there a significant difference in infants less than 1 year of age? fever and antipyretic use in children rapid diagnosis of infection in the critically ill: a multicenter study of molecular detection in bloodstream 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evaluation of young infants with fever: review of the literature impact of the 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis in us children management and outcomes of care of fever in early infancy serious bacterial infections in febrile infants in the post-pneumococcal conjugate vaccine era systematic review of the diagnostic accuracy of c-reactive protein to detect bacterial infection in nonhospitalized infants and children with fever diagnostic accuracy of the urinalysis for urinary tract infection in infants < 3 months of age prevalence of urinary tract infection in childhood-a meta-analysis invasive pneumococcal disease after implementation of 13-valent conjugate vaccine diagnostic value of clinical features at presentation to identify serious infection in children in developed countries: a systematic review decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine comparison of the test characteristics of procalcitonin to c-reactive protein and leukocytosis for the detection of serious bacterial infections in children presenting with fever without source: a systematic review and meta-analysis central nervous system infection csf opening pressure in children with optic nerve head edema reference range for cerebrospinal fluid opening pressure in children normative cerebrospinal fluid profiles in febrile infants clinical features suggestive of meningitis in children: a systematic review of prospective data diagnosis and management of meningitis predictors of bacterial meningitis in the era after haemophilus influenzae the frequency of autoimmune n-methyl-d-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the california encephalitis project lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment acute bacterial meningitis in infants and children natural history of neonatal herpes simplex virus infections in the acyclovir era safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections does this child have bacterial meningitis? a systematic review of clinical prediction rules for children with suspected bacterial meningitis cerebrospinal fluid opening pressure in children: experience in a controlled setting tuberculous meningitis meta-analysis of bacterial meningitis score validation studies central nervous system tuberculosis in children: a review of 30 cases cerebrospinal fluid protein concentration in pediatric patients report of the committee on infectious diseases incidence of rash after amoxicillin treatment in children with infectious mononucleosis fever of unknown origin in children: a systematic review do penicillins really increase the frequency of a rash when given during epstein-barr virus primary infection? prolonged fever of unknown origin prolonged fever of unknown origin in children hemophagocytic syndrome in children: an important diagnostic consideration in fever of unknown origin prolonged fever in children: review of 100 cases usefulness of scanning procedures for diagnosis of fever of unknown origin in children long-term follow-up of children with fever of unknown origin rocky mountain spotted fever in children key: cord-031482-atltc10d authors: arkow, phil title: human–animal relationships and social work: opportunities beyond the veterinary environment date: 2020-09-05 journal: child adolesc social work j doi: 10.1007/s10560-020-00697-x sha: doc_id: 31482 cord_uid: atltc10d a species-spanning approach that incorporates clients’ relationships with their companion animals into family genograms, schools of social work curricula, continuing education, interviews, assessments, and interventions offers increased career opportunities, professional and personal growth and development, and a more comprehensive resolution of clients’ issues, social justice concerns, and the prevention of family violence. this article identifies six reasons why social workers should be cognizant of human–animal relationships and introduces nine ways, with action steps, in which social workers can include these relationships into training and practice outside the more developed field of veterinary social work. these venues include: agencies working in child protection and child sexual abuse; children’s advocacy centers and courthouse facility dogs; animal shelters; domestic violence shelters; public policy advocacy; clinical practice; agencies working with older and disabled populations; veterinary sentinels for intimate partner violence; and pet support services for homeless populations. such attention to the human–animal bond can utilize social workers’ problem-solving skills to improve delivery of services, identify clients’ risk and resiliency factors, enhance social and environmental justice, expand academic inquiry, and increase attention to all of the vulnerable members of families and communities. system arousal, and improving physical fitness by providing an impetus to exercise (friedmann, 2019) . there is, conversely, substantial evidence of animal abuse as a potential precursor and indicator of interpersonal violence often linked to child maltreatment, intimate partner violence and elder abuse (arkow, 2015a) . pets occupy central roles in many interpersonal and intrafamilial relationships (turner, 2006) . they may serve as significant others, confidants, attachment figures, and sources of companionship (mcnicholas & collis, 2006) . they can be vital members of an individual's support system and facilitators to foster social capital, trust, civic participation and a sense of safety and community (wood, martin, christian, houghton, & kawachi, 2017) . the relationships between humans and animals in a household may mirror the status of the health and safety of the people in that family (hoffer, hargreaves-cormany, muirhead & meloy, 2018) . inquiring about children's and adolescents' experiences with animals can help social workers address risk and resilience factors. pets' physical condition and behaviors can provide clues to human experiences and family functioning. human-animal relationships are contextual for learning and resilience in the wake of family violence. strengthening these relationships, and helping people better understand their animals' behaviors, can promote well-being in both species and enable people to leverage inclusion and a sense of belonging in community relationships. animal rights arguments about inherent "speciesism" in humans' relationships with other animals should resonate well with social work's commitment to social justice and fighting oppression (national link coalition, 2019a) . this article explores six reasons why human-animal relationships can be significant to social workers' responsiveness to their clients and nine areas outside the veterinary social work environment where an understanding of clients' interactions with animals can be directed into enhanced professional and personal growth, innovative species-spanning solutions, and potential career opportunities. the american veterinary medical association (2018) estimated that 57% of u.s. households owned a pet, including 76.8 million dogs, 58.3 million cats, plus birds, horses and other companion animals. pets are predominantly found in households self-defined as "family" rather than "non-family" and the highest rates of dog and cat ownership continue to be among households with children. primary responsibility for pets' care continues to rest overwhelmingly with the female members of the household. pet ownership rates are higher in rural areas and lower in densely urbanized cities. there are unexplained racial and ethnic disparities in the rates of pet ownership; pets are found in 64.7% of white households, compared with latino/hispanic (61.4%), asian (46.6%), and black/african american (36.9%). some pet owners describe veterinarians as "the other family doctor" (national link coalition, 2019b) . two studies reported that 87% (risley-curtiss et al. 2006a; risley-curtiss, holley, & wolf, b) and 97% (risley-curtiss et al., 2006a, b) of multi-ethnic pet owners agreed that their pets are members of the family. in short, social workers exploring a client's home life and family dynamics may be missing a significant piece of the puzzle if they neglect to inquire about the client's animals and the attachments, relationships, and problems with them. in addition to appreciating a client's individual and familial attachments or antipathy toward pets, social workers can achieve a fuller understanding of a client's connectivity or isolation from the community by seeing human-animal relationships in a social context. social capital (as contrasted with human capital, economic capital, cultural capital, technological capital, or other community resources) is the connectivity among people which enhances cooperation for mutual benefit. the concept was popularized by putnam (2000) describing the networks and other forces that build social cohesion, personal investment, reciprocity, civic engagement, and interpersonal trust among community residents. notably absent, however, from the work of putnam and other social capital researchers was inclusion of the influence of pets in a community (arkow, 2013) . this knowledge gap was addressed by wood et al. in studies in australia (wood, giles-corti, & bulsara, 2005; wood, giles-corti, bulsara, & bosch, 2007 and the u.s. (2017) which reported companion animal ownership to be positively associated with social capital, civic engagement, perceptions of neighborhood friendliness, and a sense of community. the ability of pets to generate interpersonal communications was greater than minor conversational exchanges among dog-walkers: the visible presence of people walking dogs and the impetus dogs provide for people to be outdoors and use park areas ameliorated negative mental health conditions and gave residents a feeling of greater collective safety and sense of community. companion animal owners were found to be more likely to participate in volunteer, school and sports activities, professional associations and environmental campaigns. they were reported to be more likely to vote and to exchange favors with neighbors. arkow (2019a, 2013) proposed a converse, that the absence of companion animals in communities where rates of pet ownership are lower and incidence of animal problems is greater might contribute to less social connectivity and cohesion. levinthal (2010) used geospatial mapping techniques to correlate the distribution and prevalence of animal neglect, abuse and dog fighting in philadelphia with domestic violence and child maltreatment. she reported a highcrime neighborhood seemed to predict animal abuse, and that animal neglect correlated with demographic, cultural, and structural aspects of block groups, suggesting social disorganization may lead to animal neglect. campbell (2019) used geospatial mapping techniques to report direct correlations between animal control complaints and domestic violence incidents in neighborhoods in indianapolis. bruni (2019) suggested a way to push back on "the degradation of our country's civil culture" can be found in walking one's dog in public spaces. dog walks encourage "honest-to-goodness conversations with actual strangers" that leave their owners "feeling a little less isolated, a little less disconnected" and discourage americans retreating into "increasingly homogeneous enclaves." dog-walking encourages mutual courtesy and reciprocal generosity. "when you're about to bend down and scoop up your beloved's odoriferous bequest, there's no snobbery and no timidity, only solidarity," he wrote. there is something immensely powerful about animals that attracts and motivates humans, a force that is especially compelling with youths. whether discussing pet ownership, fascination with wild animals, or imaginary animals, children are particularly engaged, and asking about animalrelated experiences can provide important information and establish a caring persona and a trusting relationship (melson & fine, 2015; boat, 2010) . a pet is a communication waiting to happen. a recurring theme in the literature is that companion animals are what messent (1983, p. 37) first called "social lubricants," icebreakers who facilitate social support and interpersonal communications (garrity & stallones, 1998) . the nonjudgmental nature and unconditional positive regard of human-animal interactions can be a useful bridge for establishing rapport between therapists and clients (arkow, 2015b). because animals slip under the radar of human defense mechanisms, clients who are fearful, traumatized or under stress may be more willing to talk about their concerns for their animals before opening up and describing their own vulnerabilities (melson & fine, 2015) . fawcett and gullone (2001) reported that even the mere observation of animals can result in reduced physiological responses to stressors and increased positive mood. lange, cox, benert, & jenkins (2006) reported animals can introduce a calming effect, stress-reducing humor, increased feelings of safety, experienced empathy, and motivation among adolescents attending anger management sessions. chandler (2005) wrote that discussing pets can easily segue into a discussion about the client's family support system and how well he or she is utilizing personal resources. an interaction with a therapy animal can enhance social workers' listening responses, convey empathy and help the client access feelings. she observed that it is not the mere presence of an animal, but rather the orchestrated child-dog and child-therapist interactions, that can facilitate client motivation and participation, enhance the relationship with the client, stimulate client focus and attention to task, and reinforce positive client change. margaret mead's oft-quoted adage (1964) that "one of the most dangerous things that can happen to a child is to kill or torture an animal and get away with it" has been substantiated with research. a growing body of evidence suggests that bonds formed or broken with companion animals in childhood reverberate and resonate across the lifespan (jalongo, 2004) . childhood acts of committing or witnessing animal cruelty: may be sentinel warnings that a child is living in a dysfunctional environment and may be exhibiting other antisocial behaviors (gullone, 2012) ; are a prime risk factor for perpetrating animal cruelty, bullying behaviors and violence against humans; and may lead to desensitization, decreased empathy, learned maladaptive coping mechanisms, and unresolved feelings of anger, fear and resentment, particularly if the child is also experiencing co-occurring family violence (ladny & meyer, 2019) . correlations between childhood exposure to animal abuse and bullying behaviors have been reported by several authors (for example, see baldry, 2005; gullone & robertson, 2008; henry & sanders, 2007; parkes & signal, 2017; sanders & henry, 2015; vaughn et al., 2011; walters, 2019) . currie (2006) reported that children exposed to domestic violence were three times more likely to have been cruel to animals than children not exposed to intimate partner violence (ipv). there is increasing academic and programmatic recognition of animal abuse and neglect as sentinel indicators of concurrent or future family violence, particularly child maltreatment and child sexual abuse, ipv and elder abuse. social workers may find that when animals are abused people are at risk, and when people are abused animals may be at risk (arkow, 2019b) . emotional attachments to companion animals are often exploited by abusers in violence-prone households to control and coerce victims in domestic violence, sexual assault, child abuse, and elder abuse situations (ascione & arkow, 1999) and fear of leaving a pet behind is a significant barrier that keeps women and children from extricating themselves from abusive situations (roguski, 2012; ascione, 2007) . households marked by ipv have higher-than-average rates of pet ownership and are extreme high-risk environments when animal abuse is also present: nearly 80% of ipv survivors where suspects also had histories of animal abuse feared they would be killed, 76% had been strangled and 26% had been forced into non-consensual sex. multidisciplinary collaborations were seen as critical in prevention, detection and intervention to address substantial risk of harm for all children, adults and animals residing in the home (campbell, hicks, thompson, & wiehe, 2017) . grief over the loss of a pet is a broad, complex construct, which can be complicated by pet owners' perceptions that they have minimal social support sources and negative veterinary interactions (rémillard, meehan, kelton, & coe, 2017) . the loss of a pet through death or disappearance, and the decisions inherent in determining whether euthanasia of a beloved animal companion is necessary and appropriate, can generate significant emotional trauma for human members of families as well as staffs of veterinary facilities and animal shelters (see, e.g., barnard-nguyen, breit, anderson, & nielsen, 2016; carmack, 2003; dunn, mehler, & greenberg, 2005; laing & maylea, 2018; miller, prout, rourke, lefkowitz, & boyer, 2014; ross, 2005) . social workers who have had training in grief and loss theory are well positioned to be resources for individuals experiencing these emotions and can aid them in making difficult decisions and navigating the options available. because pets generally have shorter lifespans than humans, families are likely to witness significant life-cycle events such as birth, serious illness and death of their animal companions, who are often seen by children as peers and family members. the inevitable death of a pet can bring a profound sense of loss, with patterns of bereavement similar to those experienced with the death of a human family member or friend, and thus an opportunity for social work intervention. several studies have reported that by adolescence the majority of children have experienced pet loss through death or disappearance (melson & fine, 2015) . social workers can play important roles in offering grieving clients opportunities for validation of their feelings, memorialization of the animal, resolution of potential feelings of guilt, and closure. social work's interest in human-animal relationships has its origins in the practitioner-client-patient dynamics of the veterinary hospital or clinic. from modest beginnings at the veterinary hospital of the university of pennsylvania in 1978 (quackenbush, 1981; quackenbush & glickman, 1983) , the field of veterinary social work has grown dramatically in recent years. the term veterinary social work is believed to have been coined in 2002 by elizabeth strand, founding director of the veterinary social work certificate program at the university of tennessee-knoxville. today, dozens of students have been trained in the four areas of veterinary social work: the link between human and animal violence; grief and loss; animal-assisted interactions; and compassion fatigue management. this work may include: • supportive grief support and counseling with end-of-life decisions and follow-up. • advocacy and brokering of resources. • circulating reading materials and educational packets. • crisis intervention. • assessment of suicidal tendencies, mental health issues and domestic violence issues. • facilitation of a pet loss support group for hospital clientele and the community. • staff debriefing sessions. • client consultations and follow-up. • presentations to staff. • referral of mental health services for staff. • recommendations to administrators. • making improvements to client comfort on-site. (larkin, 2016) as the field of veterinary social work gains additional recognition both within and outside the world of social work, additional opportunities will continue to emerge whereby an understanding of human-animal relationships becomes a valuable asset in many aspects of social work practice. this process can begin with something as simple as routinely including pets in family genograms and adding relevant coursework in schools of social work and continuing education as well as field placement opportunities. by demonstrating additional opportunities for social workers to include human-animal relationships in interventions and assessments and to be aware of community resources that can resolve clients' animal-related concerns, social workers can be more holistic and effective in resolving clients' needs and challenges and preventing further abuse of vulnerable members of families and communities. social work's legacy of facilitating collaborative community change can open up many new career opportunities by incorporating human-animal relationships into social work practice. inquiring about the presence (or absence), stability (or turbulence), attachments, dangerousness, history, and status of animals within clients' lives can help social workers to obtain more comprehensive family assessments, validate important intra-familial relationships, build stronger support networks, support resiliency, gain earlier recognition of abusive behaviors, and address clients' animal care concerns with practical, appropriate and affordable solutions. these emerging opportunities include: despite the social reformer origins of child protective services established by humane societies and spcas in the latter third of the 19th century (hoy-gerlach, delgado, sloane, & arkow, 2019), there is a peculiar and unfortunate irony in that child and animal welfare agencies today operate wholly independently with little to no trans-species cross-fertilization of ideas, information or collaboration (arkow, 2010; walker, 1980; zilney & zilney, 2005) . this inter-agency communications gap can have tragic consequences, as with a case in brooklyn, n.y. in which a child whose family was under investigation by child protective services was killed by a dangerous dog in the home (baker & stelloh, 2011) . the author has heard anecdotally of three children under the aegis of child protection agencies in oxford, fla., and st. john, n.b., canada, who were killed by pet snakes. the potential impact of animals in the lives of children cannot be overstated and warrants expanding the ecological lens of child welfare work to include animals (risley-curtiss, 2013). companion animals are found in 67.7% of households with children under age 6 and 74.6% of households with children over age 6 (avma, 2007). melson (2001) reported that pets are more likely to be a part of children's growing up than are siblings or fathers, and that animals are pervasive in children's media, stories, imagination, and play. she reported that words for different animals-dog, cat, duck, horse, bear, bird and cow-are among the first 50 words that toddlers learn; children include dog and cat in their initial productive vocabularies more than any other words except mama and daddy. an estimated 80 to 90% of children first confront the loss of a loved one when a pet dies, disappears, or is abandoned (melson & fine, 2015) . melson (2013) reported that children, from an early age, view animals as living actors who have autonomy, intentionality and feeling. children are often animals' caregivers; since opportunities for and encouragement of nurturing others are rare in childhood, nurturing animals makes up a large proportion of childhood caregiving experiences. because caring for pets is gender-neutral, companion animals may develop innate nurturing skills in boys and feelings of mastery and self-efficacy among children who feel dependent and powerless. many children turn to their pets for reassurance and emotional support during times of stress. companion animals may assist children in feeling security and unconditional love and contribute to a child's cognitive and language development (risley-curtiss, 2013) . companion animals may be sentinels of unsafe environmental conditions, mirroring family tensions and serving as cues in assessments that explore family issues. as one of the sub-systems within a complex family system, the inclusion of questions and observations about the current and past presence of animals in a child's environment, the meaning those animals have for each family member, their care, and whether any of them have been killed or hurt can be important to effective family-centered practice (risley-curtiss, 2013) . children may feel safer talking about their pets' experiences before they disclose their own, thereby opening a friendly channel where children can provide important information (melson & fine, 2006; boat, 2010) . introducing therapy animals into the interview process can further advance this process, easing the stresses of such sessions, establishing rapport, providing the child with a sense of comfort, and creating a less threatening environment (menzies, 2003) , particularly in working with sexuallyabused children (reichert, 1998) . of particular concern is the nexus of animal sexual abuse or bestiality with child sexual abuse. edwards (2019) reported 31.6% of animal sex offenders also had histories of sexually offending children or adults and 10.8% had prior convictions for child pornography. her survey of 456 offenders arrested for bestiality between 1975 and 2015 found at least 213 children and 28 adults had been directly sexually victimized by the offenders, and that in 25 arrests (5.5%) animal pornography had been used to groom a child for sexual behavior. the canadian centre for child protection (2018) reported significant overlaps of animal and human sexual abuse in a study of 38 cases of bestiality. in 82% of cases, sexual abuse of children occurred as frequently as, if not more frequently, than coerced sexual abuse of an animal. in 68% of cases involving both child and animal sexual abuse, the offender was in a position of trust over the child, usually a close family member. child welfare workers can obtain more accurate and useful assessments of child safety and well-being by taking several steps: • in conducting child welfare checks and ongoing case management, look for: potentially abused, neglected or dangerous animals (e.g., aggressive dogs, poisonous reptiles, exotic species, dog-and cock-fighting paraphernalia); animals needing veterinary care; excess numbers of animals; and inadequate food, water or shelter. animal health issues such as fleas or other parasites could have a direct impact on the health of the humans in the home. include these findings in evaluations of the child's living environment, lifestyle and risk factors as potential threats to the child's well-being. such conditions may also be illegal under a jurisdiction's laws. • consider a turbulent history of frequent turnover of animals as potential indicators of a family's inability to make strong, lasting emotional attachments. • include the child's emotional attachment to pets as a key support which may help build resiliency and a protective factor that mitigates. treat the death or disappearance of animals as potentially as emotionally charged as the death of a human family member. • identify whether the child has been traumatized by witnessing or causing the abuse or death of animals. • consider animal maltreatment as a factor that supports a finding of child abuse or neglect. • report suspected animal maltreatment to the animal control/services, humane society/spca, or law enforcement agency in that jurisdiction. 1 the reporter need not prove that animal abuse occurred, but rather introduces the case into those agencies' investigative systems to vet the information and follow through as appropriate. confidentiality restrictions may be waived in reporting to another such law enforcement agency, or when the welfare of the client and others in the household is threatened. establishing channels of communication with animal welfare agencies in advance can simplify the cross-reporting process when a case of suspected abuse occurs. • a history of animal cruelty, and a child's emotional attachments to animals, may have evidentiary importance in court trials, dispositions and hearings involving child maltreatment, custody, visitation, removal, and protection orders. by asking three simple open-ended questions, social workers can learn much about a child's experiences with the animals and humans who share his or her environment: • are there animals at home? • how are they cared for? • are you worried about their welfare? follow-up questions about their names, breeds, play activities, deaths or disappearances, recent health problems or injuries, and secrets the child shares with them may fill in details of the family dynamics, patterns of power and control, and risk and resiliency factors in the child's life. facility animals in children's advocacy centers, casa (court appointed special advocates), guardians ad litem programs, and courtrooms provide emotional support to sexual abuse survivors as they undergo forensic examinations, re-live their experiences, and confront their abusers (labahn, 2015) . as of may, 2020, an estimated 238 dogs are working in courtrooms and children's advocacy centers in 40 states, plus others in canada, australia, chile, and europe (courthouse dogs foundation, 2020a , 2020b , 2020c . elaborate precautions prevent handlers from violating client confidentiality and keep the dog's presence from adversely eliciting sympathy from a jury. judges must balance the accommodation for a vulnerable witness with the potential for prejudice which could impact the defendant's right to a fair trial. extensive guidelines on best practices protect the interests of the animal, the victim, the defendant, and the criminal justice system (courthouse dogs foundation, 2015) . social workers in victim services can be trained to be facility animal handlers or secondary dog handlers to allow the children to spend more time with the dogs after concluding their testimony. they can facilitate interactions between the dogs and distraught family members and stressed facility staff and be resources who connect individuals and institutions with facility animals in their community. nonprofit animal welfare and governmental animal control agencies have historically operated in isolation outside the purview of human services agencies, leading to a "silo" effect in which cross-disciplinary and trans-species collaborations rarely occur (becker & french, 2004) due to increased specialization, avoidance of "mission creep" and fear of violating confidentialities. consequently, interagency cooperation and cross-training is minimal, resulting in a significant barrier to change. meanwhile, animal shelter workers experience significant stressors including animal suffering and euthanasia, responsibility for life, abusive clients, negative public perceptions, and attachments to animals under their care (schneider & roberts, 2016) without recognizing that their counterparts in human services often experience similar stressors. this lack of knowledge and coordination among community systems constricts the potential for creative and effective collaborations and can increase the risk of harm to people and animals in situations where both human and animal abuse co-occur. social workers can facilitate bridging these segregated service delivery systems through the profession's longstanding commitment to community-level action, intervention and change. social workers can work with animal shelters to organize species-spanning community coalitions, link organizational champions, and connect consumers and professionals for the well-being of underserved and at-risk individuals and family members (long & kulkarni, 2013) . social workers can help animal shelters build capacity by coordinating inter-disciplinary interaction and communication, gathering data, conducting research, and building resources. increasing cross-systems knowledge and promoting individual and institutional relationships across systems, particularly vis-à-vis cross-reporting animal, child and elder abuse, can protect vulnerable 1 unlike coordinated state-run child protection systems, animal protection is handled exclusively on the local level by a fragmented patchwork of independent government animal control/services agencies, municipal/county law enforcement, and nonprofit humane societies/spcas. a national directory of animal abuse investigation agencies in over 6,500 jurisdictions is available at https ://natio nalli nkcoa litio n.org/how-do-i-repor t-suspe cted-abuse . populations and develop stronger community services (long & kulkarni, 2013) . numerous animal shelters, often working with juvenile and adult detention centers, have implemented animal-assisted therapy interventions where individuals who have offended, or who are at risk, train dogs with behavior problems who are at risk of being euthanized. using positive reinforcement techniques, these programs teach teamwork, non-violent conflict resolution and collaboration skills to save animals' lives and modify the behaviors of abusive and traumatized individuals (arkow, 2019b). animal shelters appear poised for such systemic change. the service philosophy in the animal shelter community is evolving to recognize that treating the symptoms of animal welfare problems, such as animal homelessness, abuse and neglect, is only a stopgap solution: to be truly effective, underlying community and family dysfunction and violence must be addressed (petlynx, 2011). hoy-gerlach et al. (2019) described promising opportunities for social work field placements in community animal shelters, including: reducing staff and volunteers' compassion fatigue in an exceedingly difficult and emotionally draining work environment; placement of shelter pets as emotional support animals; strengthening community responsiveness to violence through assessing overlaps and differences between child, elder and animal abuse investigations; creating and implementing educational programming across child and animal protection systems; and increasing community awareness of the link between violence to animals and violence to humans. animal control and humane officers frequently have access to pet owners' homes in the course of their investigations, and in the process may observe conditions detrimental to the welfare of children, youth and others. in addition, cruelty investigations which result in the removal of animals from a home could be an additional stressor on the family system and could lead to increased risk for vulnerable family members. social workers can train shelter personnel on the intersectionality of animal abuse and human violence and the procedures for making referrals to social services agencies. other untapped social work opportunities in animal shelters might include: strengthening collaborations with domestic violence shelters and mobile meals programs; directing and expanding pet visitation programs for long-term care facilities and animal-assisted interventions for at-risk populations; developing pet loss grief support groups; developing safety net supportive programming for individuals who experience a medical, economic or housing crisis that temporarily makes it difficult to keep an animal; defusing contentious confrontations with shelter clients; resolving customers' complaints and needs for services; and connecting pet owners with community resources, such as low-cost pet and veterinary services, animal behavioral counselors, pet food banks, and social services agencies. social workers provide essential services to survivors of intimate partner violence and their children in numerous ways, including advocacy, practice and public policy. they serve as advocates in women's shelters, criminal courts, protective order offices, hospital ers, police victim services units, government and nonprofit agencies, military family advocacy centers, fatality review teams, and elsewhere. their work encompasses crisis intervention, investigations, counseling, case management, legal services, public policy, and referrals to and liaison with community resources. all of these aspects of social work practice can take on an additional dimension by incorporating human-animal relationships into the perspective. research findings suggest that in working with pet-owning domestic violence victims, social workers must consider the welfare of the women's pets in order to effectively help the women achieve safety for themselves and their families (strand & faver, 2005) . domestic violence shelters in the 1990s began raising awareness that significant numbers of survivors (usually, but not always, women) and their children are either turned away from safehouses that will not accept their pets or are refusing to leave abusive situations for fear of what would happen to their pets if they left. these fears range from the mundane-that no one remaining at home would provide adequate care-to the tragedies of seeing animals tortured and killed in an emotional extortion that warns partners that they themselves could be the abuser's next victims. the issue reached national awareness in 2006 when susan walsh, 50, told legislators in maine that her husband had retaliated against her and her children and prevented her from leaving a frightening relationship by killing her pets and farm animals: "it wasn't just the cats and the dogs i had, it was the sheep and the chickens -i was terrified for their welfare. i knew if i were to leave, he wouldn't hesitate to kill them. he had done it before." (belluck, 2006) . to address the problem, then-gov. john baldacci signed into law the first of what are now laws in 35 states plus puerto rico and the district of columbia specifically allowing courts to include pets and, in some cases, livestock in domestic violence protection-from-abuse orders. these allow courts to grant petitioners exclusive care, custody and control of animals, and to forbid respondents from harming, taking or disposing of animals or even coming near them (national link coalition, 2019c). abusers' obsessive jealousy and control can become a manipulative tool for power over partners and children by exploiting the vulnerability their emotional attachment to pets. 71% of battered women reported that their abusers had harmed, killed or threatened animals as coercive control (ascione, weber & wood, 1997) . 25% to 40% of abused women delay seeking safety in fear for the welfare of their animals (mcintosh, 2002) . 41% of ipv offenders had histories of animal cruelty (febres et al., 2014) , which is one of the four strongest risk factors for becoming a batterer (walton-moss, manganello, frye, & campbell, 2005) . animals are chosen as soft targets because abusers believe that they can get away with it because police generally don't care about animal abuse (roguski, 2012) . when perpetrators of ipv also have a history of animal abuse, victims experience 20 to 50 violent incidents before contacting police and the risk of lethality to first responders doubles (campbell, thompson, harris, & wiehe, 2018) . the risks encapsulated in these and similar findings are further escalated vis-à-vis the impact on children in these households: 87% of coercive ipv animal abuse incidents occurred in the presence of the woman; 75% occurred in the presence of the children (quinlisk, 1999) . 32% of domestic violence survivors in shelters reported their children had also harmed animals, repeating the intergenerational cycle of violence (ascione, 1998) . batterers have been reported to sexually abuse animals, threaten pets to get children to do something, or force the child to kill the pet (jury, thorburn, & burry, 2018) . the national link coalition (2017) modified the "power and control wheel" frequently used to graphically depict the dimensions of domestic violence to demonstrate how animal abuse is incorporated in abusers' coercive control tactics, as shown in fig. 1 . in response to these situations, domestic violence shelters are developing collaborative foster care programs with local animal welfare agencies to provide off-site "safe havens" for the animal survivors, thereby removing one barrier that prevents families from escaping abuse (ascione, 2000) . more recently, a program called saf-t-sheltering animals and families together-is helping more than 200 domestic violence shelters in the u.s. and other countries build co-sheltering facilities for pets to keep all family members together and safe (phillips, 2019) . grant funding is available to help shelters with capital costs and survivors with veterinary and boarding expenses (national link coalition, 2019d). these concerns dictate bringing social workers into the planning process for innovative and collaborative intakes, assessments, responses, and referrals that incorporate human-animal relationships. serious gaps often separate domestic violence and animal shelters: although concern for the safety of pets and livestock is a barrier to individuals leaving situations of ipv in urban and rural areas, one study reported that 76.92% of animal welfare representatives and 53.33% of human service representatives, respectively, reported no collaboration between their agencies (saskatchewan spca & stops, 2016). acts of animal cruelty in mental health assessments and rehabilitation of abusers and in the specialized domestic violence assessment of risk to children. • including relocation of pets in domestic violence agencies' safety plans (national link coalition, 2014). • obtaining information from local animal welfare and control agencies about prior investigations at the household. • inviting animal-assisted therapy teams into shelters to help comfort survivors. • counseling children regarding incidents of animal maltreatment, death or disappearance of pets that they may have witnessed or committed. • developing community education campaigns to alert the public and cross-train professionals about how animal abuse is linked with ipv. veterinarians, in particular, whose staffs and clients are predominantly female, should begin to recognize a responsibility to serve as resources for survivors of ipv (larkin, 2018; newland, boller, & boller, 2019) . the well-established role of social workers as advocates for social justice provides additional opportunities to advance legislation that recognizes human-animal relationships, the beneficial aspects of pet ownership on individual and community health and well-being, and the adverse effects of animal abuse on human welfare and safety. as an underserved population, animals are classified as property and have long been ignored by the legal system; legislators frequently trivialize campaigns to protect their interests for the simple reasons that animals don't vote and human concerns are widely viewed as being more pressing. however, recognition of the foundation that animal abuse is linked to human violence and therefore improving animal welfare improves human society is generating a new respect for animal welfare legislation. current relevant public policy issues include legislation that would: • allow courts to include pets and/or livestock in protection-from-abuse orders (currently enacted in 35 states, puerto rico and the district of columbia) (national link coalition, 2019c). • allow courts to award custody of pets in divorce and marriage dissolutions based upon the animals' best interests, similar to long-standing similar provisions affecting child custody (four states). • redefine animal abuse when committed as coercive control as also being an act of domestic or dating violence (11 states). • allow acts of violence against animals to be included in criteria for extreme risk protection orders that bar domestic violence abusers from obtaining firearms. • allow courts to appoint pro bono advocates to represent animals' interests in criminal cruelty cases, similar to established court appointed special advocates (casa) provisions for children (three states). • mandate or permit child welfare, adult protection and animal services agencies to cross-report incidents of suspected animal, elder and child abuse to each other, and veterinarians to report suspected animal, child and elder abuse to appropriate agencies, with immunity from civil and criminal liability and professional disciplinary sanctions. • increase penalties for bestiality (now often considered animal sexual abuse) based upon increased evidence of its co-occurrence with child sexual abuse and child pornography. as of august, 2020, having sex with animals is still legal in hawai'i, new mexico, west virginia, and wyoming. • increase penalties for acts of animal cruelty when committed in the presence of a child or adolescent. clinical social workers may become aware of clients' human-animal interactions through recognizing a client's attachments and issues vis-à-vis the animals in his or her environment and by introducing animals for therapeutic purposes to enhance the client-practitioner relationship. in one of the earliest writings on the nexus of social work and human-animal interactions, netting, wilson, & new (1987) outlined seven ways in which social workers can contribute to human-animal bonding: • being sensitive and supportive in counseling clients who have pet-related problems. • being aware of clients' relationships with their pets and assisting in locating support services that include pet care. • being aware of policies that affect pet ownership, such as restrictive housing conditions, and advocating for clients' pet-related interests. • assessing clients to determine their readiness to accept pet-related interventions. • being critical of how pet-related programs are developed and collaborating with animal professionals. • acknowledging potential benefits and problems which may accompany pet-related programs. • linking veterinarians into the human services referral network. more recently, silverman (2018) published a brief guide to ways in which social workers can utilize animals as a bridge between a therapist and patient in private practice. animals can expedite rapport building with patients who have issues with attachment disorders and enhance the motivation to attend the session which improves retention and treatment outcomes. animals may function as a surrogate of the therapist and allow for more ethical therapeutic touch, which could be a corrective experience for those with histories of trauma. fostering the human-animal connection may help patients identify sustainable, long-term support to manage symptoms and maintain functioning after the therapeutic relationship with a clinical social worker has ended. she identified four categories of animals utilized in a helping capacity: • service animals, which are individually trained to do specific tasks for a person with a physical or sensory disability. clinical social workers may recommend that a patient consider having a service animal and identify resources to obtain one. • emotional support animals, a newer and vaguer category, that provide emotional benefits to a person diag-nosed with a mental health disorder that impairs or limits functioning in one or more life domains. • comfort dogs, introduced in disaster responses to offer a calming presence to survivors and first responders. • animal-assisted therapy animals, professionally evaluated to be introduced in treatment plans with intentional, goal-directed activities to complement traditional interventions. social workers should note that spouses and partners may be jealous of a disabled individual's dependence upon and emotional attachment to a service animal. also, the emotional support animal system has a potential for egregious abuses by individuals getting their animals so designated solely to accompany them on airplane flights; online services will provide such documentation from mental health professionals who have never examined the client. human-animal bonds may be particularly robust with older clients and present unique challenges. for individuals who are socially isolated, pets may be a significantly vital source of companionship and emotional support. caring for a pet may be an especially strong motivator for a client to get out of bed, have a daily routine, nurture another being, or go for a walk. the animal may be a last link to a deceased spouse (arkow, 2015a). human-animal social work issues relevant to older adults include: • animal neglect: more than 92% of adult protective services respondents to a national survey reported animal neglect coexisting with a client's inability to care for himself/herself, indicating that reports of animal neglect may be an important warning sign for vulnerable adults' self-neglect (lockwood, 2002) . animals may be neglected by frail elders who lack financial resources, transportation, or physical or mental capacity to care for them adequately (peak, ascione & doney, 2012 ). • self-neglect: frail elders may neglect their own needs by spending limited financial resources on their animals' food and medications. some may refuse to go into hospitals, assisted living or long-term healthcare facilities unless provisions are made for their pets (boat & knight, 2000) . • coercive control: in more than two-thirds of domestic/ elder abuse cases, the perpetrators were family members who may neglect or abuse the elder's pet as a form of control or retaliation, out of frustration over their caretaking responsibilities, or as a way to extract financial assets from the victim (humane society of the u.s., 2005). • bereavement: isolated seniors may experience profound grief and depression upon the death of a beloved pet. some seniors are reluctant to replace departed pets in fear that the animals will outlive them (boat & knight, 2000) . many older adults, particularly the widowed and elderly, are at risk of emotional trauma and experience significant disruptions in eating, sleeping, job-related responsibilities and other daily routines and decreased socialization behaviors following the death of a pet (quackenbush, 1984) . • denied services: home health aides, social workers and other caregivers may be reluctant to enter seniors' dwellings if they fear the presence of aggressive animals or deteriorated environmental conditions linked with animal hoarding or neglect (boat & knight, 2000) . • animal hoarding: animal hoarders may come from any cohort but they are statistically over-represented by older women (patronek & nathanson, 2009 ). animal hoarders (and their children) often live in unhealthy environments surrounded by dozens and even hundreds of living and deceased animals in states of neglect, starvation and suffering. stereotypical hoarders, often labeled as "cat ladies," have been reported as living in a self-fulfilling cycle of social isolation: they gravitate towards animals because they are uncomfortable around people, and other people choose not to associate with them because of their excess number of animals. many are experiencing mental health issues and a collaborative, multi-agency response is invariably required (patronek, loar, & nathanson, 2006) . nathanson (2009) , in identifying four core barriers that limit adult protective services workers' involvement in these cases, called animal hoarding one of the most perplexing and problematic human-animal relationship and a deviant behavior associated with extremely deleterious conditions of comorbid animal and selfneglect. she identified training programs that can better prepare human services professionals to respond to these clients and engage in trans-species and interdisciplinary efforts essential for the safety, health and well-being of the hoarder, human and animal dependents, property, and community. social workers, whether in private practice, nonprofit organizations or governmental adult protective services agencies, can recognize the import of these human-animal relationships, locate support services for the animals and make appropriate referrals including temporary foster care and other pet services for owners who are in need of hospitalization, long-term care or other social services. social work input on multidisciplinary teams can help to resolve the particularly challenging psychosocial aspects of animal hoarding. and social workers should be attuned to the potential that a client's requesting a veterinarian to have all of his or her pets euthanized is a potential sentinel warning sign for suicidal behavior. social workers can help train veterinarians in recognizing this warning sign and responding with appropriate referrals. an emerging frontier is exploring veterinary medicine's response to suspected domestic violence. an incident in deland, fla. in 2018, when a woman being held captive at gunpoint by her abusive boyfriend was able to alert veterinary staff who in turn called the police (robbins, 2018) , brought to national attention what was just beginning to be discussed in professional journals: how should veterinarians and their staffs, the majority of whom now are women (kelly, 2017) , respond to suspected domestic violence in their clientele? (newland et al., 2019; larkin, 2018; allison, satterwhite, ramaswamy, hynek, & agnew-svoboda, 2017) . veterinarians in the united kingdom and new zealand have taken the most proactive responses in addressing this concern. medics against violence, a scottish collaborative of human and veterinary healthcare professionals, created a domestic abuse veterinary initiative to train veterinarians to help pet owners needing to escape domestic violence; the initiative was featured in a british veterinary association guidance for responses to suspected domestic abuse (animal welfare federation and the links group, 2016). in 2015, the scottish government put £115,000 into a national campaign to train 100,000 front-line professionals in the three fields identified as most likely to encounter domestic violence survivors: dentists, veterinarians and hairdressers (paterson, 2015) . the u.k.'s code of professional conduct for veterinary surgeons states, "given the links between animal, child and domestic abuse, a veterinary surgeon or veterinary nurse reporting suspected or actual animal abuse should consider whether a child or adult within that home might also be at risk" (royal college of veterinary surgeons, 2016). the new zealand veterinary association supported a national legislative response to family violence by describing veterinary medicine as a "three-dimensional profession" with a unique voice in issues that transcend animal life, human life and the environment. nzva called for domestic violence protection-from-abuse orders to specifically include animals, and for changing the definition of domestic violence to include "coercive control" which would cover emotional and psychological abuse to family members through threat or harm to pets or farm animals (national link coalition, 2015) . the veterinary council of new zealand (2013), whose code of professional conduct includes a recommendation that veterinarians confronted with situations of animal abuse should consider whether people within that home might also be at risk, published a guidance that included suggestions on preparing the practice and responding to domestic violence. social workers can help to introduce a response to intimate partner violence as a public health matter to a profession which has been reluctant to get involved, due to a lack of training and fears for personal safety, and help veterinary clinics develop protocols for response and dissemination of literature about community domestic violence resources to their clients. they can also coordinate programs linking students at colleges of veterinary medicine with local domestic violence shelters, such as has been done at texas a & m, mississippi state university, and the university of georgia. social workers can respond to the needs of pet owners who are homeless, whose attachments to their animal companions are often stronger compared with the general population (labrecque & walsh, 2011 ). an estimated 5% to 10% of the 3.5 million americans who experience homelessness every year have dogs and cats, with rates as high as 25% in some areas. because the vast majority of homeless shelters do not allow pets, these restrictions deter pet owners from seeking essential shelter (o'reilly-jones, 2019). many individuals who live on the street keep pets, primarily dogs, for emotional support, safety, a sense of responsibility, to combat loneliness (labrecque & walsh, 2011; williams & hogg, 2016; arnott, 2004) , and as social catalysts to attract passers-by who may offer them money (irvine, kahl, & smith, 2012; anderson, snow, & cress, 1994) . social workers can coordinate veterinary and foster care for the animals and advocate for pet-friendly co-shelters for the homeless much as has been done in domestic violence shelters (phillips, 2019) . social workers can participate in such programs as the street dog coalition, operating in 30 states, in which social work, veterinary and medical school students host clinics and provide resources to help the pets of homeless pet owners. an accurate representation of the roles of animals in families, and of social work's responsiveness to these dynamics, is compromised by several factors. despite the above-cited market research data indicating a widespread population of companion animals and their over-representation among families with children, relatively little is known about the racial, ethnic, socioeconomic, age-related, or geographic demographics of pet-owning families, as such information has never been included in the u.s. census (arkow, 2019a). meanwhile, until recently, social workers have historically ignored the central role that companion animals may play in the lives of their clients, adopting an anthropocentric view underpinned by human rights and social justice (laing & maylea, 2018) . this is reflected in reports (national link coalition, 2020) that identified only 24 schools of social work in the u.s. and seven in canada that are believed to include the topic of human-animal relationships in either undergraduate or graduate level study, or in the absence of such courses have a faculty member known to have a specialization in the human-animal bond. it is hoped that publications such as this will begin to address these shortcomings and increase awareness of human-animal relationships in the lives of social workers' clients. the inclusion of human-animal relationships should be considered more widely in training and practice as part of social work's commitment to social and environmental justice and fighting oppression and seen as an expanding opportunity for research, practice, advocacy, and advancing public policy. in the process, additional career opportunities may open up with this species-spanning approach to resolving individual, family and community challenges. such inclusion can begin with something as simple as routinely including companion animals in genograms, ecomapping, and definitions of family support systems (risley-curtiss, 2010; hodgson & darling, 2011) . as assessing clients' needs is an important step in developing the best plan to solve clients' problems, including pet protective factors in clients' ecologies should be considered a relevant environmental factor in social work practice theory (sato, 2011) . collecting information about all the pets and humans in a family communicates interest and concern for the whole family and demonstrates an integrated approach to care that can help in planning appropriate interventions and preventive care. human-animal bond awareness can be further expanded by adding relevant coursework and field placements in schools of social work and training programs in continuing education. given the established links between animal cruelty and other forms of violence within the family system (arkow, 2019b), questions about human-animal interactions and relationships and clients' committing and/or witnessing acts of animal abuse should be systemically, not just optionally, introduced in intakes and assessments. incorporating the significance of human-animal interactions can help modernize what has been an intrinsic anthropocentrism of social work's theoretical foundations. growing opportunities both within and beyond the veterinary environment will help convince educators, researchers and practitioners that this species-spanning approach is worthwhile and offers opportunities for career development, personal fulfillment and improved service delivery. veterinary social work blends the human side of veterinary medicine with the animal side of social work. as awareness of and interest in veterinary social work continues to grow, additional opportunities will emerge whereby social workers with an abiding interest in animals as well as people can help their clients, society, and the non-human members of families and communities. battered women's reports of their partners' and their children's cruelty to animals safe havens for pets: guidelines for programs sheltering pets for women who are battered emerging research on animal abuse as a risk factor for intimate partner violence child abuse, animal abuse and domestic violence: linking the circles of compassion for prevention and intervention the abuse of animals and domestic violence: a national survey of shelters for women who are battered boy, 4, is mauled to death by dog in brooklyn home animal abuse among preadolescents directly and indirectly victimized at school and at home pet loss and grief: identifying at-risk pet owners during the euthanasia process making the links: child abuse, animal cruelty, and domestic violence new maine law shields animals in domestic violence cases understanding the role of animals in the family: insights and strategies for clinicians experiences and needs of adult protective services case managers when assisting clients who have companion animals dogs will fix our broken democracy following the links: the critical role of animal control in improving detection and prevention of family violence characteristics of intimate partner violence incidents and the environments in which they occur: victim reports to responding law enforcement officers intimate partner violence and pet abuse: responding law enforcement officers' observations and victim reports from the scene bestiality" as reflected in canadian case law grieving the death of a pet animal assisted therapy in counseling facility dogs at children's advocacy centers and in legal proceedings: best practices courthouse facility dogs in the u appellate case law casa/gal programs animal cruelty by children exposed to domestic violence social work with a pet loss support group in a university veterinary hospital. social work in health care arrest and prosecution of animal sex abuse (bestiality) offenders in the united states cute and cuddly and a whole lot more? a call for empirical investigation into the therapeutic benefits of human-animal interaction for children adulthood animal abuse among men arrested for domestic violence the animal-human bond: health and wellness effects of pet contact on human well-being animal cruelty, antisocial behaviour, and aggression: more than a link the relationship between bullying and animal abuse in adolescents: the importance of witnessing animal abuse bullying and animal abuse: is there a connection? pets in the family: practical approaches violence in animal cruelty offenders rediscovering connections between animal welfare and human welfare: creating social work internships at a humane society helping vulnerable adults and their pets confrontations and donations: encounters between homeless pet owners and the public the world's children and their companion animals: developmental and educational significance of the child/ pet bond. washington: association for childhood education international pet abuse as part of intimate partner violence. wellington, nz: national collective of independent women's refuges veterinary medicine is a woman's world. veterinarian's money digest providing comfort, companionship, and relief: the use of courtroom dogs homeless women's voices on incorporating companion animals into shelter services traumatized witnesses: review of childhood exposure to animal cruelty they burn brightly, but only for a short time": the role of social workers in companion animal grief and loss is counseling going to the dogs? an exploratory study related to the inclusion of an animal in group counseling with adolescents for human needs, some veterinary clinics are turning to a professional: social workers see a place for themselves in veterinary practice when domestic violence arrives at the clinic door: how veterinary staff can respond to abused clients and patients the community context of animal and human maltreatment: is there a relationship between animal maltreatment and human maltreatment: does neighborhood context matter? (doctoral dissertation making the connection between animal cruelty and abuse and neglect of vulnerable adults cross-reporting of interpersonal violence and animal cruelty: the charlotte project animals as social supports: insights for understanding animal-assisted therapy the links between animal abuse and family violence, as reported by women entering shelters in calgary communities cultural factors in the cause and prevention of pathological homicide why the wild things are: animals in the lives of children children's ideas about the moral standing and social welfare of non-human species animals in the lives of children animals in the lives of children animal assisted therapy and young people: a review of selected literature social facilitation of contact with other people by pet dogs a therapist's guide to treating grief after the loss of a pet: a three-tier model animal hoarding: slipping into the darkness of comorbid animal and self-neglect three-dimensional" new zealand veterinarians respond to domestic violence the connection between animal cruelty and societal violence and vulnerability schools of social work with humananimal interactions in curriculum the human-animal bond: implications for practice considering the relationship between domestic violence and pet abuse and its significance in the veterinary clinical and educational contexts when fido is family: how landlordimposed pet bans restrict access to housing revisiting a link: animal abuse, bullying, and empathy in australian youth vets enlisted in bid to stop domestic abuse. the national animal hoarding: structuring interdisciplinary responses to help people, animals and communities at risk a theoretical perspective to inform assessment and treatment strategies for animal hoarders adult protective services and animal welfare: should animal abuse and neglect be assessed during adult protective services screening 2010 national urban animal report start-up manual bowling alone: the collapse and revival of american community the pet connection: its influence on our health and quality of life pets, owners, problems, and the veterinarian: applied social work in a veterinary teaching hospital. the compendium on continuing education for the small animal practitioner social work services for bereaved pet owners: a retrospective case study in a veterinary teaching hospital child abuse, domestic violence, and animal abuse: linking the circles of compassion for prevention and intervention individual counseling for sexually abused children: a role for animals and storytelling exploring the grief experience among callers to a pet loss support hotline social work practitioners and the human companion animal bond: a national study expanding the ecological lens in child welfare practice to include other animals she was family:" women of color and their animal human connections the animalhuman bond and ethnic diversity florida woman held captive by boyfriend slips note to vet staff pets as pawns: the co-existence of animal cruelty and family violence pet loss and children: establishing a healthy foundation code of professional conduct for veterinary surgeons, supporting guidance no. 14 (client confidentiality). london: royal college of veterinary surgeons nonhuman animal cruelty, bullying, and behavioral difficulties among women saskatchewan society for the prevention of cruelty to animals and saskatchewan towards offering partnership solutions (stops) to violence social workers' attachments to their pets, organizational structures, and their impact on professional assessment regarding the roles pets play in clients' lives (doctoral dissertation) shelter-specific occupational stress among employees in animal shelters the role of animals as therapeutic aids in private practice battered women's concern for their pets: a closer look the role of companion animals throughout the family life cycle effects of childhood adversity on bullying and cruelty to animals in the united states: findings from a national sample guidance for veterinarians dealing with cases of suspected or actual animal abuse and family violence the link between interpersonal violence and animal abuse a study on the relationship of child abuse and pet abuse animal cruelty and bullying: behavioral markers of delinquency risk or causal antecedents of delinquent behavior? risk factors for interpersonal violence and associated injury among urban women the health and welfare of dogs belonging to homeless people wa: petcare information & advisory service and the centre for the built environment and health (school of population health) the pet connection: pets as a conduit for social capital? more than a furry companion: the ripple effect of companion animals on neighborhood interactions and sense of community social capital and pet ownership-a tale of four cities reunification of child and animal welfare agencies: cross-reporting of abuse in wellington county key: cord-261151-27ocvgnw authors: becker, jessica e.; smith, joshua r.; hazen, eric p. title: pediatric consultation-liaison psychiatry: an update and review date: 2020-04-25 journal: psychosomatics doi: 10.1016/j.psym.2020.04.015 sha: doc_id: 261151 cord_uid: 27ocvgnw background: in recent years, there has been an increasing burden of child and adolescent mental illness recognized in the united states, and the need for pediatric mental health care is growing. pediatric consultation-liaison psychiatrists are increasingly playing a role in the management of medical and psychiatric disease for pediatric patients. the field is a fast-moving one, with understanding of new neuropsychiatric disease entities; reformulation of prior disease entities; and new, interdisciplinary treatments and models of care. methods: in this study, we aim to review recent advances in the field of pediatric consultation-liaison psychiatry, including new diagnostic entities, updated management of frequently encountered clinical presentations, and developments in systems of care. conclusion: the advances in pediatric consultation-liaison psychiatry are broad and serve to promote more streamlined, evidence-based care for the vulnerable population of psychiatrically ill pediatric medical patients. more work remains to determine the most effective interventions for the wide array of presentations seen by pediatric consultation-liaison psychiatrists. mental illness in children is a growing concern in the united states; the 2016 national survey of children's health found that approximately 17% of u.s. children under age 18 suffer from a mental health disorder. 1 when these children are medically hospitalized, pediatric consultation-liaison (c-l) psychiatry services can help to manage psychiatric care and improve medical outcomes. moreover, much like in adult c-l psychiatry, these services can assist medical teams in managing the acute onset of neuropsychiatric disease, including delirium and catatonia, as well as help to identify and treat psychiatric symptoms and sequelae of systemic illnesses and treatments. 2 with the rise of pediatric mental health needs and the increased numbers of pediatric psychiatry patients boarding on inpatient pediatric wards awaiting placement in psychiatric facilities, the demand for psychiatric consultation to pediatric patients has been growing over the last decade. 2 despite the growth in demand, as well as rapidly expanding research and changing clinical practices in the field, a comprehensive update of the field has not been completed for over twenty years. 3 as such, in this article, we review recent literature and provide an update on clinical and system-based care in pediatric c-l psychiatry, with a particular focus on the inpatient setting. subsequently, we describe the evolution of training and practice patterns for child psychiatric consultation and identify areas in need of future studies in the field. the intent of this article is to provide a useful update for pediatric and adult consultation-liaison psychiatrists alike, recognizing that many hospitals may not have dedicated pediatric consultation-liaison psychiatric staff to evaluate pediatric patients. psychiatric consultations are requested for children in the inpatient pediatric setting for a wide variety of reasons. while some reasons overlap with requests made of adult psychiatric consultants, others are unique to the pediatric population or require a specific developmental approach. in 2016, shaw and colleagues published the results of a survey of practice patterns completed by 64 independent pediatric c-l psychiatry services. 2 the survey results highlighted the most common reasons for pediatric psychiatric consultation to include suicide risk assessment, assistance in the diagnosis and management of medically unexplained symptoms, adjustment to medical illness, assessment for psychopharmacologic intervention, delirium, treatment non-adherence, and the management of children admitted to pediatric units to await psychiatric hospital placement (boarding). 2 thus, the role of the pediatric psychiatry consultant is a varied one and involves components both of primary psychiatric management and of close collaboration with the pediatric medical team. moreover, child psychiatric consultants must be knowledgeable about the diagnosis and management of psychiatric diseases that are particularly prevalent in children, such as feeding and eating disorders or attention-deficit/hyperactivity disorder (adhd). in the subsequent sections, we review updates in common reasons for inpatient child psychiatric consultations and associated management strategies. of note, while consultation for treatment non-adherence is of great importance given its associated high morbidity and mortality, 2 this topic has been addressed in detail in a recent cochrane review and will therefore not be covered in this update. 4 per the aforementioned 2016 study by shaw and colleagues, the most frequent reason for consultation to pediatric psychiatry was suicide risk assessment. 2 this information is consistent with other literature that shows an increased risk for suicide in patients with serious medical illness 5 and the presence of psychopathology in 90 percent of suicide decedents. 6 thus, c-l psychiatrists are uniquely equipped to intervene in the medical setting. the joint commission (tjc) sentinel event database reported 1,089 suicides occurring from 2010 to 2017 in patients evaluated within 72 hours of care in an inpatient or emergency department setting. the most common root cause identified was shortcomings in suicide risk assessment. in 2016, tjc recommended screening all patients for suicidal ideation with a brief, standardized, and evidence-based screening tool. 7 therefore, for the pediatrician and pediatric c-l psychiatrist, utilization of such a tool is essential. examples include the ask suicide-screening questions (asq) toolkit, 8 patient health questionnaire-9 (phq-9), 9 columbia-suicide severity rating scale (c-ssrs), 10 and suicide behavior questionnaire-revised (sbq-r), 11 all of which have evidence supporting their use in the pediatric patient population. 12 using these tools, brahmbhatt and colleagues developed streamlined clinical pathways for pediatric hospitals to implement efficient and evidence-based youth suicide assessment strategies in hospitalized patients. 13 services should be aware that these new recommendations may increase staff burden, time spent in screening, and documentation requirements. thus, institutional accommodations may be needed. the presence of medically unexplained symptoms is another common reason for pediatric psychiatric consultation, 2 and one whose management has shifted over time, reflecting a broader change in thinking about these cases. with the release of the diagnostic and statistical manual of mental disorders fifth edition (dsm-5), important revisions were made to the diagnostic criteria for somatic symptom and related disorders (ssrds), which are often a consideration in patients with medically unexplained symptoms. whereas previously the diagnosis of a somatic symptom disorder required the symptoms to be medically unexplained, this is no longer required. this change reflects current thinking about somatic symptom disorders, including the idea that these disorders can and often do exist in patients who suffer from organic medical conditions that also contribute to their symptoms, and that a diagnosis of somatic symptom disorder should not be made simply because a patient's symptoms do not have an identifiable medical cause. 14 in keeping with this newer thinking, a working group of pediatric c-l psychiatrists from across north america, sponsored by the american academy of child and adolescent psychiatry (aacap), has recently released the first evidence-informed clinical pathway to help standardize the diagnosis and management of ssrds in pediatric patients. 15 this pathway emphasizes early involvement of child psychiatry during a hospital stay when ssrd is part of the differential diagnosis; close interdisciplinary team collaboration, communication, diagnostic evaluation, treatment, and disposition planning; an interdisciplinary family meeting if the diagnosis of ssrd is made; and involvement of rehabilitation services as appropriate. 15 moreover, this workgroup has published scripts that can be used with families for clear, consistent communication about the ssrd diagnosis. 15 another consideration that may be relevant when evaluating a child with medically unexplained symptoms is medical child abuse, also known as caregiver-fabricated illness. while rare, the incidence of medical child abuse is estimated at approximately 0.5 to 2.0 per 100,000 children; and most health care practitioners will encounter the condition at some point during their practice. 16 recent consensus has shifted away from the previous terminology of munchausen syndrome by proxy or factitious disorder by proxy. medical child abuse is a more broadly encompassing term used to classify when a child receives unnecessary and potentially harmful medical care as a result of a caregiver falsifying or inducing medical or psychological symptoms in the child. 16 the shift from the munchausen syndrome or factitious disorder by proxy terminology to that of medical child abuse or caregiver-fabricated illness represents a shift in focus on the child as a victim of abuse, rather than on the caregiver's motivation, which can be widely variable. 16 just as with ssrds, recent guidance emphasizes that medical child abuse should not be a diagnosis of exclusion. 16, 17 if the primary team or consulting child and adolescent psychiatrist is concerned about medical child abuse as part of the differential diagnosis of a child's symptoms, a multidisciplinary team evaluation, including medical, psychiatric, child protection, and legal teams, should be completed. 16 a pediatric c-l psychiatrist has an important role in both recognizing and treating psychopathology in the child, including potential sequelae of trauma related to the abuse, as well as working with the broader team to reverse the trend toward medicalization and minimize unnecessary medical intervention. pediatric c-l psychiatrists may also be asked to evaluate patients with altered mental status, particularly when psychiatric symptoms predominate. while the differential diagnosis for acute changes in mental status is broad, we highlight here important recent updates for the pediatric psychiatric consultant's consideration. a wide variety of systemic disease can lead to psychosis in children and adolescents, including epilepsy, endocrinopathies, autoimmune diseases, genetic and metabolic disorders, and nutritional deficiencies, among others. 18, 19 one recent retrospective study found that 12.5% of children evaluated over a seven-year period in an urban hospital setting who met criteria for a schizophrenia spectrum disorder were ultimately found to have a medical cause or contribution to their psychotic symptoms. 19 such causes are important to identify when present, as they may impact medical management and prevent future complications. neuronal cell surface antibodies, which are associated with autoimmune encephalitis, have been found in up to nine percent of first episode psychosis patient cohorts. 20 autoimmune encephalitis (ae) is a recently-recognized disease entity, treatable by immunotherapy, which can present with behavioral changes, psychosis, changes in memory and cognition, altered levels of consciousness, seizures, and dysautonomia. 21 in ae, autoantibodies against neuronal cell-surface markers, ion channels, and receptors can lead to disruption of neuronal signaling and brain atrophy. 21 while these autoantibodies can develop spontaneously, they can be triggered in the setting of a tumor or virus as well; family history of autoimmune disease may also be associated with development of ae. 21 perhaps the most widely recognized such disorder is anti-nmda receptor (anti-nmdar) encephalitis, which primarily presents in children and young adults. 21 the behavioral changes noted in children can include insomnia, irritability, temper tantrums, agitation, and decreased verbal output; while adolescents can present with hallucinations, delusions, and catatonia. 21 while most identified patients with anti-nmdar encephalitis progress to having autonomic instability and seizures, some patients present with purely psychiatric symptoms, with one study estimating that 4% of anti-nmdar encephalitis patients presented with solely psychiatric symptoms. 22 thus, ae should be a consideration in young patients with acute onset of psychiatric symptoms, including new onset of psychosis or sudden development of severe behavioral change without clear stressor. the consulting pediatric psychiatrist should work with the primary medical team and neurologic consultants to determine diagnostic work-up, which can include serum and cerebrospinal fluid autoantibody panels, magnetic resonance imaging and other imaging modalities, and electroencephalogram. given susceptibility to neuroleptic malignant syndrome in these patients, careful consideration must be given to treatment of psychiatric symptoms; 21 sedating agents, such as benzodiazepines and valproic acid, may be most helpful. since its conceptualization two decades ago, pediatric c-l psychiatrists have been increasingly evaluating patients regarding concern for pediatric autoimmune neuropsychiatric streptococcus infection and has been considered a potential variation of syndeham chorea, while pans, a more general term, can present after any infection. 23 in addition to its rapid onset, pans is distinguished from primary ocd by other potential associated factors, including an earlier age of onset; personality changes; behavioral regression; new attentiondeficit/hyperactivity disorder (adhd) symptoms; cognitive changes; changes in oral intake and output, such as food refusal and frequent urination; sleep changes; psychosis; sensory changes; and fine motor deterioration. 23 treatment for pans and pandas can include antibiotics, antiinflammatories, immunotherapy, and plasma exchange, in conjunction with standard psychiatric treatments for ocd and tics, including psychopharmacologic agents and cognitive-behavioral therapy. 23, 24 occupational therapy can also be useful for fine motor sequelae, such as handwriting regression. 23 while bringing to light the interface between the immune system and psychiatric disease, pans/pandas have also garnered substantial debate. 23 controversy over these syndromes is related to difficulty isolating their phenotypes from those of children with primary ocd; the heterogeneity in reported clinical presentations and large number of potential triggers, which can make identification and appropriate treatment difficult; the high frequency of streptococcus infections in children and of elevated titers in asymptomatic children; and the concern that a family's report that a child suddenly became unwell may lead to overlooking of important history, precluding a true biopsychosocial approach to the child's condition. 23 impair recovery from critical illness, cause agitation, and induce perceptual disturbances. 27 though often under-recognized, pediatric delirium is a common problem, present in at least 20-25% of critically ill patients, 28 and is associated with increased cost of care, 29 length of hospitalization, 30 mortality rate, 31 and the risk of future development of post-traumatic stress disorder symptoms for both patients and their families. 32 risk for pediatric delirium is increased in mechanically ventilated or restrained patients; in infants due to central nervous system immaturity; and in children with relative delays in cognition, motor function, or language. 31, 33 in recent years, multiple screening tools have been developed for pediatric delirium. the pediatric confusion assessment method for the intensive care unit (pcam-icu) and cornell assessment for pediatric delirium (capd/capd-r) are commonly used. the capd is derived from the pediatric anesthesia emergence delirium (paed) scale, 26 has specific questions for hypoactive delirium, and can be used in children of all ages with or without developmental delay. 28 the pcam and its preschool version for children under 5 years old (pscam-icu), are derived from the adult cam rating scale which utilizes dsm criteria. both tools also require a richmond agitation sedation scale (rass) score above -4 for assessment. 26, 34 commonly used medications including opioids, antihistamines, anesthetics, diuretics, glucocorticoids, and benzodiazepines may exacerbate delirium. 26, 31 in one recent study, benzodiazepines were found to be an independent risk factor for pediatric delirium, but opioids were not. while opioid use should still be limited, this finding suggests the targeting of analgesia over sedation in delirious patients, ideally optimizing mobilization and improved pain recognition. 35 other evidence-based means of pediatric delirium prevention include reduction of pain, sleep disturbance, 36 and physical restraint use; addressing sensory and communication difficulties; ensuring early mobilization; 35, 36 and providing frequent re-orientation, including use of familiar items from home, and the consistent presence of the child's caregivers. 26 with regard to treatment, there are currently no fda-approved medications in the treatment of delirium in adult or pediatric patients. furthermore, the available evidence for the management of delirium is primarily focused on adult patients. however, the literature on treatment of pediatric delirium continues to grow; and, along with extrapolation from adult studies, specific treatment recommendations can be formed. at present, there is evidence-based support for the use of antipsychotics, alpha-2 agonists, and melatonin in adult and pediatric delirium and valproic acid in adult delirium alone. 37 clinical pathways have been developed through the physically ill child committee of the american academy of child and adolescent psychiatry in an effort to standardize management of pediatric delirium based on evidence and expert consensus. there are pathways for both prevention and management of pediatric delirium which can be helpful in guiding management of this condition. 38 antipsychotics have been the mainstay of delirium treatment, with haloperidol, risperidone, olanzapine, and quetiapine showing equivalent safety profiles and improvement in agitation, sleep-wake disturbance, and symptom severity. [39] [40] [41] they may also result in decreased utilization of deliriogenic agents. [39] [40] [41] very low dosages can be used to treat infants and toddlers, with higher doses needed in adolescents. 26, 42 however, recent studies from the adult literature have called the utility of antipsychotics in delirium into question. 43, 44 greater research into the mode of action in both adult and pediatric patients is needed. additional treatments available in pediatric delirium include melatonin and alpha-2 agonists. clonidine and dexmedetomidine have been safely used in the intensive care setting, are associated with a decreased risk of delirium by reducing use of opioids and benzodiazepines, and have been shown to decrease incidence and duration of emergence delirium in pediatric patients. 26, [45] [46] [47] when compared to clonidine, dexmedetomidine has a shorter half-life, greater opioid-sparing effect, and fewer adverse effects. 48 at present, the benefits of melatonin in delirium are unclear, though supplementation may be of clinical benefit given that its secretion from the pineal gland is decreased in critical illness. 49 regardless, given the relatively benign nature of melatonin, administration in cases of delirium with co-morbid sleep disturbance is recommended. 50 catatonia catatonia in children is often under-diagnosed and under-treated, but recognition of this dangerous and potentially lethal syndrome in the pediatric population has been growing in recent years. 51,52 some one-fifth of pediatric catatonia cases are due to underlying medical conditions, including infections, seizures, autoimmune diseases, metabolic diseases, toxidromes, and medication side effects, making it particularly relevant in the inpatient pediatric medical setting. 51 yet, the diagnosis of catatonia can be a challenging one to make in children and adolescents, resulting in treatment delay of this serious condition, given indeterminate presentations that may overlap with other presentations. for instance, some developmental disorders, including autism spectrum disorder, prader-willi syndrome, and kleine-levin syndrome, are associated with higher rates of catatonia; however, features of the underlying developmental disorder, such as stereotypic movements and decreased speech in autism spectrum disorder, may appear similar to signs of catatonia and must be carefully delineated. 52 moreover, sorg et al. recently presented the case of a patient whose history of oppositional behavior led to misattribution of inappropriate laughter, echolalia, waxing/waning mutism, refusal to follow commands, and lack of cooperation, resulting in delayed identification and treatment of his catatonia syndrome. 51 additionally, certain symptoms of catatonia, such as behavioral agitation and urinary incontinence, may be more common in children than in adults; 51 yet, these same symptoms can be associated with a variety of diagnoses in children. as in adults, a bush-francis scale can be used to assess symptoms of catatonia, though a validated scale specifically designed for children and adolescents, the pediatric catatonia symptom rating scale, was recently developed. 53 first-line treatment should be with intravascular or intramuscular lorazepam. exacerbating medications, such as dopamine d2 receptor-blocking agents like antipsychotics, should be discontinued and avoided. should the patient's symptoms not improve with escalating doses of lorazepam, there is evidence that nmethyl-d-aspartate antagonist medications, such as amantadine or memantine, can be useful to augment treatment. 51 if symptoms remain refractory or the patient develops life-threatening symptoms, such as vital sign instability or other signs of malignant catatonia, electroconvulsive therapy (ect) should be considered; however, the practitioner should be mindful that some states have age restrictions and regulations in place that may limit access to ect for pediatric patients. 51 boarding in recent years, many hospitals have been admitting children awaiting psychiatric hospitalization to inpatient pediatric floors under non-medical admissions, a practice that has been termed "boarding" and that has become a common reason for child psychiatric consultation. tjc defines "boarding" as holding a patient in a temporary location in the hospital while awaiting placement that is not yet available. 54 boarding is also the appropriate term for children admitted medically with co-occurring psychiatric and medical needs who, once medically stable, are maintained inpatient medically while awaiting placement in a psychiatric inpatient unit. 54 boarding has become more commonplace in recent years as emergency department (ed) visits for child psychiatric emergencies have been increasing -nearly doubling since 2001 55while the availability of pediatric inpatient psychiatric beds nationally has been decreasing. 55, 56 these opposing trends have led to a crisis, with pediatric patients often waiting days for treatment in an inpatient psychiatric setting. eds are generally not equipped to handle longer-stay patients and often do not have the same support services that medical pediatrics floors may have, such as child life or occupational therapy services; 56 as a result, increasing numbers of pediatric psychiatric patients are being admitted to board on inpatient pediatric floors to await psychiatric placement. one study based in a single medical center over an 18-month period found that 50% of children meeting criteria for involuntary psychiatric hold were admitted to the pediatric medical unit, where they received suboptimal care and accrued a cost of over $4000 per patient. 57 children with complex psychiatric needs, such as those with autism or developmental delays, as well as those with more acute psychiatric needs, may be particularly difficult to place into psychiatric facilities. 54, 56, 58 paradoxically, then, the children perhaps most in need of immediate psychiatric care are often the patients relegated to waiting the longest for placement. boarding pediatric patients with psychiatric emergencies on the inpatient pediatric floor poses particular challenges, as the dedicated physical and therapeutic supports of the inpatient psychiatric unit are not available. as compared to inpatient psychiatric units, pediatric medical floors may be unlocked; allow access to potential mechanisms of injury; have less optimal supervision; and have limited, if any, staff trained to manage psychiatric patients. 56 thus, in addition to providing medication recommendations, the consulting pediatric c-l psychiatrist must work with the primary team to devise a safe plan for the patient while the patient is admitted to the pediatric floor. recent consensus guidelines for pediatric psychiatric patients in the ed may serve as a reference for agitation contingency planning once patients become boarders; these guidelines suggest non-pharmacologic de-escalation techniques, such as verbal and behavioral de-escalation, as a first-line for agitation in children, followed by medication interventions ranging from diphenhydramine, lorazepam, and clonidine to atypical antipsychotic medications. 59 while pediatric boarding cannot replace the structure and services of an inpatient psychiatric unit, consulting pediatric psychiatrists can provide supports beyond medication management. in an effort to advance a patient's psychiatric care while they await appropriate level of care, the consulting pediatric psychiatry team can liaise with outpatient treaters and may be able to deliver or arrange for brief bedside therapy. gallagher and colleagues at boston children's hospital recently demonstrated that by providing brief supportive or behavioral therapy, medication recommendations, behavioral plans, and safety observations, scores on the clinical global impression scale for pediatric boarders improved significantly from admission to discharge. 54 a common reason for psychiatric consultation in the pediatric medical setting is adjustment to medical illness, particularly given the impact of a chronic medical condition on a child's development. 2, 60 as the psychological and neurobiological sequelae of chronic physical illness are increasingly recognized, the contribution from mental health providers to medically ill pediatric patients is being increasingly recognized and formalized, particularly among certain illnesses, such as pediatric cancers, epilepsy, cystic fibrosis, and sickle cell disease. [60] [61] [62] [63] for instance, the cystic fibrosis (cf) foundation and european cystic fibrosis society recently partnered to produce consensus guidelines on implementing developmentally-appropriate psychoeducation and screening for anxiety and depression in cf patients and their caregivers, as well as recommendations for specific treatments, such as cognitive behavioral therapy, ssri medications, and benzodiazepines. 64 kazak et al. composed a recent literature review demonstrating the need for routine, systematic assessments of psychosocial needs in children and caregivers with cancer, 65 while the international posterior fossa society determined in a recent consensus meeting that identification and treatment of emotional and behavioral morbidities in this population is an important avenue for upcoming work. 66 these developments suggest that routine screening for psychiatric disease in children with medical conditions is becoming more commonplace, though work remains to expand such practices more broadly to children with a variety of other chronic and non-chronic medical illnesses. the prevalence of autism spectrum disorder (asd) has been rising steadily for decades, with recent estimates indicating that 1 out of 40 children in the united states meet criteria for asd. 67 this is of particular relevance for pediatric c-l psychiatrists, as children with asd have higher rates of medical illness than the general population, including higher rates of epilepsy, gastrointestinal disorders, allergies, obesity, nutritional deficiencies, and certain kinds of immunologic disorders. 68 as a result, children with asd have higher rates of healthcare utilization than the general population, including a significantly higher frequency of both ed visits 69 and inpatient medical admissions. 70 the length of stay for medical admissions is approximately 50% greater for patients with asd compared to typically developing patients, 71 reflecting the complexity of the needs of this patient population. children with asd and their families often face considerable challenges when interfacing with the medical system, particularly during inpatient medical admissions, and are often dissatisfied with their care. 72, 73 some of these challenges are rooted in the core symptoms and impairments associated with asd. 74 impairments in communication and social interactions can make it difficult for patients to express their symptoms, needs, and concerns to medical providers, and conversely it can be difficult for providers to clearly express their intentions to the patient. sensory stimuli associated with the hospital environment that many medical providers take for granted, such as the sound of monitors or the feel of a hospital identification bracelet, have been shown to make hospitalization more stressful for patients with asd, many of whom have sensory sensitivities. 75 finally, many individuals with asd take comfort in strict adherence to routines, which are disrupted by hospitalization, and have difficulty in unfamiliar settings. pediatric c-l psychiatrists are often called upon to help patients with asd and their families navigate the difficulties associated with medical hospitalization, a role that can be expected to grow as diagnoses of asd continue to increase. the psychiatrist's role begins with a thorough, developmentally-informed assessment that gathers relevant information about the patient's level of cognitive functioning, preferred communication methods, past psychiatric history, active psychiatric symptoms, and risk of challenging behaviors such as agitation, aggression, or self-injury. 74 the history should include a review of potential triggers for agitation or distress, as well as ways that the patient typically expresses distress and effective strategies for soothing the patient. this information, along with collateral from outpatient providers, can be integrated into a patient-specific care plan designed to prevent distress and provide contingencies for managing difficult behaviors that may arise. 76 there are several elements commonly used in such plans that have been shown to be effective. generally, these may involve facilitating communication, reducing anxiety associated with unfamiliar providers and routines, and sensorybased approaches to reduce triggers and employ helpful soothing strategies. 77-79 a more detailed discussion of these strategies can be found in a 2019 review in psychosomatics by thom et al. 73 pharmacologic interventions for pediatric inpatients with asd include management of comorbid psychiatric symptoms, such as anxiety or hyperactivity, identifying medications, such as corticosteroids, that have the potential to exacerbate behavioral difficulties, and preventing and treating disruptive behaviors. 74 some patients may benefit from a temporary increase in preadmission medications targeting anxiety or agitation while they are in the hospital. coordination with outpatient providers and a thorough history that includes past adverse medication reactions as well as use of as-needed medications that have been helpful is particularly important, as children with asd and intellectual disability may exhibit sensitivity to medications, including potential for paradoxical reactions to medications, such as benzodiazepines, that are commonly used in the hospital setting. 80 with the release of the dsm-5, several conditions frequently assessed and treated by pediatric psychiatric consultants were defined and revisited. 14 one notable addition was the definition of a new diagnosis, avoidant/restrictive food intake disorder (arfid), expanding the scope of the previously defined feeding disorder of infancy and early childhood. 81 whereas anorexia nervosa is defined as a restriction of energy intake leading to low body weight associated with fear of gaining weight and impaired perception of one's body weight or shape, arfid patients also have restriction of energy intake but do not have impaired perception of their weight or shape. 82 given its recent delineation, the full burden of arfid in pediatric populations is not yet well known. 81, 83 however, studies have indicated a prevalence of approximately 3% in school-aged children, with estimates as high as 10-20% of patients within eating disorder programs. 81 various studies have suggested that compared to other eating disorder patients, arfid patients tend to be younger, to have more medical and psychiatric comorbidities, and to be more often male. 83 children with arfid may be medically hospitalized for low weight or malnutrition. in making the diagnosis, the pediatric c-l psychiatrist should be mindful that direct medical or psychiatric causes of disordered eating have been ruled out in patients with arfid. 83 as the disorder is increasingly recognized, guidelines for diagnostic and treatment approaches are being developed, including recommended work-up. 84 moreover, a thorough assessment of the patient's attitude towards weight and body image is vital to verify the arfid diagnosis and to rule out other eating disorders. 84 screening tools, such as the pica arfid and rumination disorder interview (pardi), eating disorders in youth questionnaire (edy-q), and nine-item arfid screen (nias) can also be useful in making the diagnosis and tracking symptoms over time. 84 once the diagnosis has been made, the treatment for arfid requires a multidisciplinary approach to achieve weight restoration and address disordered eating behaviors. in addition to ruling out medical causes or sequelae of the restrictive eating symptoms, pediatricians should be involved to set a reasonable target goal weight for the patient. 84 mental health providers, including psychiatrists and behaviorists, gastroenterologists, dietitians, occupational therapists, and speech and swallow specialists may all play a role in arfid treatment. 84, 85 medications that have shown some efficacy in the treatment of arfid patients include cyproheptadine, olanzapine, mirtazapine, lorazepam, and fluoxetine, though none is approved by the u.s. food and drug administration for this purpose and there have been no large, double-blind, randomized studies. 83, 84 more research is needed to determine standardized medication recommendations for arfid. in the past decade, the number of youth seeking treatment for substance use disorder (sud) has risen significantly, 86 a phenomenon mirrored in the inpatient setting. in the united states, egorova and colleagues reported that in 2012, 483,281 pediatric medical inpatient admissions were associated with a behavioral health diagnosis, with 26% of those diagnoses being sud. 87 more recently, a study by the canadian institute for health information reported that between the years 2017 and 2018, five percent of pediatric medical inpatient hospitalizations for patients age 10-24 were related to harm from substance use. 88 for the pediatrician, rapid identification is paramount, given the increased risk of lifelong dependence 89, 90 and the potential negative impact of sud on a myriad of medical conditions. [90] [91] [92] [93] [94] in this population, psychiatric consultation can be of great benefit, given the high degree of psychiatric co-morbidity 95 as the need for pediatric psychiatric consultation grows, innovations have been coming to the field to allow more streamlined training, clinical care, and care systems. here, we highlight these innovations and comment on the ongoing need for continued evolution and research in pediatric consultation-liaison psychiatry. though psychiatric consultation to medical specialties has been a practice in the united states for at least a century, 98 ever-growing demand and energy in the field has led practitioners more recently to consider how best to label their role. psychosomatic medicine was the term for the psychiatric consultation subspecialty approved by the american board of medical specialties (abms) in 2003 and was previously used by the national academy of the field, the academy of psychosomatic medicine (apm). more recently, concern grew that the term psychosomatic medicine was too narrow for the work of the subspecialty and implied that practitioners focus on somatoform disorders only, rather than the broad array of psychiatric manifestations of disease. 98 as such, after several decades of growing momentum, and with support of its members and the american psychiatric association, the apm advocated for the subspecialty to be renamed consultation-liaison psychiatry, which was approved in october 2017; this was followed a month later by apm voting to change its name to the academy of consultation-liaison psychiatry. 98 the term consultation-liaison (c-l) psychiatry reflects the broader scope of clinical practice, beyond somatoform disorders, as well as the unique role of c-l psychiatrists in connecting with other medical providers to provide holistic patient care. as need for child psychiatric c-l care grows, the formalization of training in this subspecialty is increasingly important. walker et al. have succinctly laid out the various paths to prepare trainees for work in pediatric c-l psychiatry and the strengths and weaknesses of each. 99 more recently, recognizing that most training of pediatric c-l specialists occurs in child and adolescent psychiatry fellowships and that formalized goals for this education did not exist, aacap's physically ill child committee assembled a special interest study group to develop best practices of c-l education for child and adolescent psychiatry fellows. 100 this group developed and published core competencies for pediatric c-l psychiatry training, using the subcompetency framework developed by the accreditation council for graduate medical education (acgme). 100 more work is needed to build on this framework and establish more formalized curricula for training across programs. as requests for child psychiatric consultation grow, efforts have been made by aacap's physically ill child committee and others to standardize practice patterns across settings. clinical pathways have been developed in an attempt to standardize the care of ssrds, delirium, and suicide risk screening, based on evidence, when available, and expert consensus. 13, 15, 38 this growing trend for evidence-based and best practices in child psychiatric consultation aims to improve quality of care. given the success of these pathways, and the broad range of complicated illnesses evaluated by child psychiatric consultants, there is ample opportunity in the field for creation of future pathways. in a time of ever-growing technological advancement, there has been recent growth of methods used to connect practitioners with one another and with patients. aacap's physically ill child committee maintains a useful electronic listserv that connects pediatric c-l psychiatrists from across the country, providing a mechanism of sharing and disseminating best practices and innovations, a nexus for research collaborations, and a way for individual clinicians to obtain rapid access to expert consultation for unique clinical challenges that inevitably arise in the field. technological innovation has also impacted clinical care more directly through the advent of telepsychiatry, the use of communication technology to conduct remote psychiatric evaluation and management. telepsychiatry has been most widely used in outpatient and emergency department settings, but has also been utilized to conduct inpatient psychiatric consultations when access to in-person psychiatric providers is limited. 101, 102 in the wake of the covid-19 pandemic in 2020 and associated attempts to limit traffic in hospitals for infection control purposes, many hospitals rapidly implemented pediatric telepsychiatry consultation models. as these programs roll out, there will be a need for future studies to evaluate the efficacy of telepsychiatry in the inpatient pediatric setting, as such programs may allow for expanded access to child psychiatric c-l services across the country. as the healthcare payer landscape shifts from fee-for-service models to population health and risk-sharing strategies, child psychiatric consultations will likely have an increasing role in management. recent studies have shown a high growth of medical hospitalizations and costs for children with comorbid psychiatric disease, as compared to those without; 103 as well as longer hospital lengths of stay and higher rates of hospital readmission for medical illnesses in children with psychiatric disease. [104] [105] [106] initial evidence suggests that psychiatric intervention may improve overall medical outcomes, healthcare utilization, and costs in these populations. for instance, in a recent study of pediatric admissions at a freestanding, tertiary pediatric hospital, bujoreanu et al. demonstrated that earlier involvement of child psychiatric consultation led to shorter lengths of stay and lower overall hospital charges; 107 and evidence suggests that psychiatric intervention for children with particular chronic medical conditions can lead to lower overall healthcare utilization. 108, 109 future research should build on this work to assess systematically the benefit and cost-effectiveness of pediatric psychiatric consultation for children with comorbid medical and psychiatric illness. in the wave of population health strategies, the importance of preventative psychiatric care in the outpatient medical setting has also been increasingly recognized, with benefits for long-term medical and psychiatric outcomes. such outpatient integrated care systems, which range from care coordination to colocation to collaborative care models to fully integrated medical-psychiatric practices, are increasingly being developed; and their value to expand psychiatric treatment access and improve outcomes is increasingly being recognized. 110, 111 asarnow et al. recently completed a review of randomized, controlled trials of a variety of pediatric integrated medical-behavioral care and found good benefit for mental health outcomes, particularly for collaborative care models and for treatment models; the study found weaker evidence for the use of integrated care for preventative care or for substance use. 110 this review was limited by the small number of available trials evaluating integrated care in the pediatric population. 110 thus, future work remains to systematically evaluate the benefits and costs of the multitude of integrated care models in order to determine the most useful and efficient strategies for outpatient child psychiatric consultation management. in this article, we have reviewed recent updates in disease classification and clinical management to inform the psychiatric consultant evaluating pediatric patients. we have also described recent changes to practice of the field from a systems level, including areas of ongoing research. as the need for pediatric consultation-liaison psychiatry has grown, the core principles of the field have remained stable, including formulating both medical and psychiatric illness through a developmental lens and utilizing a collaborative, team-based approach. however, as we have reviewed, there have been several recent advances that propel the field forward, including the development of new diagnostic and disease entities; updates in clinical management; and systems-level changes, such as efforts to develop more streamlined and evidence-based care, technological advances to connect patients and practitioners, and new 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cord-274123-wgigtgl9 authors: dube, felix s.; kaba, mamadou; robberts, f. j. lourens; tow, lemese ah; lubbe, sugnet; zar, heather j.; nicol, mark p. title: respiratory microbes present in the nasopharynx of children hospitalised with suspected pulmonary tuberculosis in cape town, south africa date: 2016-10-24 journal: bmc infect dis doi: 10.1186/s12879-016-1934-z sha: doc_id: 274123 cord_uid: wgigtgl9 background: lower respiratory tract infection in children is increasingly thought to be polymicrobial in origin. children with symptoms suggestive of pulmonary tuberculosis (ptb) may have tuberculosis, other respiratory tract infections or co-infection with mycobacterium tuberculosis and other pathogens. we aimed to identify the presence of potential respiratory pathogens in nasopharyngeal (np) samples from children with suspected ptb. method: np samples collected from consecutive children presenting with suspected ptb at red cross children’s hospital (cape town, south africa) were tested by multiplex real-time rt-pcr. mycobacterial liquid culture and xpert mtb/rif was performed on 2 induced sputa obtained from each participant. children were categorised as definite-tb (culture or qpcr [xpert mtb/rif] confirmed), unlikely-tb (improvement of symptoms without tb treatment on follow-up) and unconfirmed-tb (all other children). results: amongst 214 children with a median age of 36 months (interquartile range, [iqr] 19–66 months), 34 (16 %) had definite-tb, 86 (40 %) had unconfirmed-tb and 94 (44 %) were classified as unlikely-tb. moraxella catarrhalis (64 %), streptococcus pneumoniae (42 %), haemophilus influenzae spp (29 %) and staphylococcus aureus (22 %) were the most common bacteria detected in np samples. other bacteria detected included mycoplasma pneumoniae (9 %), bordetella pertussis (7 %) and chlamydophila pneumoniae (4 %). the most common viruses detected included metapneumovirus (19 %), rhinovirus (15 %), influenza virus c (9 %), adenovirus (7 %), cytomegalovirus (7 %) and coronavirus o43 (5.6 %). both bacteria and viruses were detected in 73, 55 and 56 % of the definite, unconfirmed and unlikely-tb groups, respectively. there were no significant differences in the distribution of respiratory microbes between children with and without tb. using quadratic discriminant analysis, human metapneumovirus, c. pneumoniae, coronavirus 043, influenza virus c virus, rhinovirus and cytomegalovirus best discriminated children with definite-tb from the other groups of children. conclusions: a broad range of potential respiratory pathogens was detected in children with suspected tb. there was no clear association between tb categorisation and detection of a specific pathogen. further work is needed to explore potential pathogen interactions and their role in the pathogenesis of ptb. electronic supplementary material: the online version of this article (doi:10.1186/s12879-016-1934-z) contains supplementary material, which is available to authorized users. lower respiratory tract infection (lrti) is a leading cause of mortality and morbidity in children under five years, accounting for approximately 1 million deaths in 2013 globally [1] . pulmonary tuberculosis (ptb) is an important cause of lrti and may present as acute or chronic disease [2] . tb is increasingly recognised as a primary cause or as a comorbid condition in children hospitalized with pneumonia, particularly in settings endemic for human immunodeficiency virus (hiv) and tb [3] . diagnosis of ptb in children is largely made based on clinical and radiological features, which may be nonspecific. therefore ptb cannot be easily differentiated from other causes of acute or chronic lrti [4] . recent studies have reported detection of polymicrobial infections in children with lrti [5] . further, ptb has increasingly been reported in children presenting with acute pneumonia; culture confirmed tb was reported in 8 % of south african children hospitalized with acute pneumonia with no difference by hiv status [6] . a recent meta-analysis confirmed mycobacterium tuberculosis in 7.5 % of childhood pneumonia cases in tb endemic areas [3] . there are limited published data on the role of other respiratory pathogens amongst patients suspected to have tb [7] . in africa, only one study, conducted in botswana, has addressed this question amongst adult ptb suspects. this study reported microbiologically confirmed tb in 118/229 (52 %); mycoplasma pneumoniae infection in 36/218 (17 %) and pneumocystis jirovecii infection in 4/141 (3 %) of ptb suspects [7] . co-infection with two or more pathogens was documented in 25 % of patients [7] . in our studies of south african children hospitalised with suspected ptb, 16 % of children hospitalised with suspected ptb had microbiologically-confirmed ptb, 48 % were classified as unconfirmed-ptb and 37 % were classified as unlikely-ptb (children in whom tb was excluded and who improved in the absence of tb therapy) [8] . approximately half of the children were treated for ptb, including all children with definite ptb and most with unconfirmed ptb [8] . these data raise several questions around potential co-infections including the extent to which these may contribute to disease or severity in ptb, the aetiology of lrti amongst children with symptoms suggestive ptb and the role of other potential respiratory pathogens in those without tb. we have recently shown [5] that specific pathogens (including bordetella pertussis, influenza virus, respiratory syncyntial virus [rsv], adenovirus, parainfluenzavirus, bocavirus) are detected significantly more frequently from the nasopharynx (np) of children with pneumonia than age-matched controls, and so are likely to play an important role in pneumonia aetiology. we therefore conducted a preliminary study to investigate the diversity of potential respiratory pathogens in the np of children hospitalised with suspected ptb. the population studied in this study has been previously described [8] . briefly, we enrolled children under 15 years of age suspected of ptb presenting (between july 2011 and may 2012) at red cross war memorial children's hospital (rch), a specialist referral paediatric hospital in cape town, south africa. verbal assent was obtained from children older than seven (7) years of age and informed consent was obtained from a parent or legal guardian for all children. suspected tb was defined as having history of a cough and one of the following: i) a household contact with tb within the previous three months, ii) loss of weight or failure to gain weight in the previous three months, iii) a positive tuberculin skin test (tst) to purified protein derivative (ppd; 2tu, ppd rt23, staten serum institute, denmark, copenhagen), or iv) a chest radiograph suggestive of ptb. a positive skin test was defined as 5 mm or more of transverse induration in children with hiv infection or 10 mm or more in children without hiv infection [9] . children were excluded if the child was on tb treatment or tb prophylaxis for more than 72 h, and if they could not be followed-up (not resident in cape town). all patients with laboratory confirmed tb and those diagnosed with tb based on clinical and radiological criteria were referred for tb therapy at a local clinic in accordance with south african national guidelines [10] . children were followed up at 1 and 3 months to assess response to therapy or improvement without tb treatment. all children received care in the public health system that includes free expanded programme on immunisation (epi) for diphtheria, pertussis (whooping cough), and tetanus (dpt), haemophilus influenza type b, and streptococcus pneumoniae (7-valent pneumococcal conjugate vaccine [pcv] from 2009, replaced with 13-valent pcv in 2011). two paired induced sputa and a nasopharyngeal (np) swab specimens were collected from each child and transported to the laboratory within 2 h of collection. np swabs were obtained before sputum induction using nylon flocked swabs (copan italia, brescia, italy) by trained study staff [11] . each np swab was immediately placed into 1.5 ml primestore® transport and stabilization medium (primestore® mtm, longhorn vaccines and diagnostics, san antonio, tx) and stored at −80°c within 2 h of collection until further batch processing. samples were randomly selected from a convenience subset of 214 children, over a 1-year period for testing of np specimens for other microbes. as the volume obtained on induced sputum specimens was small, the entire specimen was required for detection of m tuberculosis, for optimal management and as this study was nested within a broader study investigating better diagnostics for tb in children [11] . we did not want to compromise this primary aim and only np samples were available for study of other respiratory pathogens. induced sputum specimens were submitted to the national health laboratory services (nhls) medical microbiology laboratory at groote schuur hospital (cape town, south africa) for mycobacterial liquid culture (bactec mgit, becton dickinson microbiology systems, cockeysville, md) and nucleic acid amplification testing (xpert mtb/rif, cepheid, sunnyvale, ca). children were categorised as 'definite-tb' (i.e. culture or xpert mtb/rif positive for m. tuberculosis), 'unlikely tb' (i.e. no clinical diagnosis of tb with improvement on follow-up without tb treatment) and 'unconfirmed tb' (all others) [12] . multiplex pcr testing of nasopharyngeal samples np swabs were thawed at room temperature (22°c) and vortexed for 15 s. thereafter, 400 μl of each sample was transferred to a zr bashingbeadstm lysis tube (zymo research corp., irvine, ca) and subjected to mechanical lysis on a tissuelyzer lt (qiagen, hilden, germany) [13] . the lysed samples were then centrifuged at 10,000 × g for 1 min to pellet all cellular debris. aliquots of 250 μl of the supernatant were transferred to a 2 ml sterile tube (sarstedt, nümbrecht, germany) and 4 μl of an exogenous internal control (equine arteritis virus) was added to each sample prior to automated total nucleic acid extraction on the qiasymphony sp instrument using the qiasymphony® virus/bacteria mini kit (qiagen, hilden, germany). total nucleic acid was eluted in 60 μl elution buffer and stored at -80°c until further processing. nucleic acid amplification was performed using the ftd resp33 kit according to the manufacturer's instructions (fast-track diagnostics, luxembourg). the assay comprises eight multiplex real-time pcr reactions for the detection of nucleic acid targets (additional file 1: table s1 ). results were interpreted according to manufacturer's instructions using the ftd resp33 analyser, an in-house java based program (available at http://www.gematics. com/analyser.html). exploratory statistics were performed using stata software (stata corporation, college station, tx), whilst the openly available statistical environment r, version 3.1.1 [14] was used for more detailed analyses. pearson's chisquared test was used to compare the occurrence of each microbe between children with definite tb and unlikely tb with yates' continuity correction. permutation tests were used to determine which microbe pairs were statistically concurrent. briefly, for each pair of microbes, x and y, the observed number of concurrences (m) was counted. the null hypothesis was that there was no relationship between microbes x and y and that the co-occurrences were purely random. the null hypothesis was tested by generating random permutations of the occurrences of x and y. the number of concurrences under these random conditions was then counted, m 1 . by repeating the permutation process 10 000 times, 10 000 random concurrences were obtained as follows: m 1 , m 2 ,…, m 10000 . the shape of the null-distribution, the distribution of co-occurrence counts under purely random conditions, was estimated from the 10 000 observed values of the permutation test. the achieved significance level (asl) was computed as the number of permuted co-occurrences that were equal to or greater than the observed number of concurrence (tail probability under the null-distribution). this can be interpreted as a nonparametric p-value [15] . linear discriminant analysis (lda) and quadratic discriminant analysis (qda) [16] were used to optimally discriminate respiratory microbes occurring in relation to tb status. the lda is visually represented in a canonical variate analysis (cva) biplot and the qda in a qda biplot [16] . the visualizations provide information on how the different tb groups overlap and to what extent the detection of microbes differs between the groups. for all the tests, a p-value less than 0.05 was used as the limit of statistical significance. the human research ethics committee (hrec 045/ 2008) of the faculty of health sciences, university of cape town, south africa approved this study. hiv-infected, with similar hiv prevalence by tb category. immunization records were available for 162 out of 214 (76 %) children included in this study. among children for whom data on immunization profile was available, the vaccination status was up to date in 78 % of children, while among the remaining 22 % (36/162), at least one scheduled immunization was missing. none of the risk factors considered in table 1 was associated with the occurrence of any microbes pertussis even after adjusting for potential confounders (additional file 1: table s3 ). nucleic acid of at least one of the 33 targeted respiratory microbes was detected in 97 % of 214 np specimens. the most common bacteria detected were moraxella catarrhalis (64 %), s. pneumoniae (42 %), h. influenzae spp (29 %) and staphylococcus aureus (22 %) ( table 2 ). m. pneumoniae (9 %), b. pertussis (7 %) or c. pneumoniae (4 %) were detected less frequently. the most frequently detected viral targets were human metapneumovirus (hmpv) (19 %), rhinovirus (15 %), influenza c virus (9 %), adenovirus (7 %), cytomegalovirus (7 %) and coronavirus o43 (5.6 %) ( table 2) . seasonal patterns were observed for hmpv, rhinovirus, enterovirus and influenza viruses with peak prevalence in late winter (august) and spring (november). in addition, a seasonal pattern was detected for tuberculosis (additional file 1: figure s1 ). no distinct seasonal patterns were observed for other microbes. a single bacterial target was detected in 39/214 (18 %) of samples tested. two bacterial targets were detected in 53/214 (25 %), and three bacterial targets detected in 111/214 (52 %). a single viral target was detected in 71/214 (33 %) of samples, two viral targets in 47/214 (22 %) and three or more viral targets in 10/214 (5 %) specimens. bacteria alone were detected in 86/214 (40 %) of samples, viruses alone were detected in 11/214 (5 %) of samples and both viruses and bacteria in 117/214 (55 %) of samples. a detailed overview of all possible pairs of co-occuring respiratory microbes, irrespective of tb category (additional file 1: table s2 ). these co-occurences were further tested for significance (table 3 ). significant bacterial-bacterial associations included interactions between m. catarrhalis and each of m. pneumoniae, s. pneumoniae and h. influenza spp. viral-viral associations included: bocavirus and influenza a virus, parainfluenza 1 virus and coronavirus nl63 as well as hmpv and enterovirus. significant viral -bacterial associations were common particularly between h. influenza (type b or non-type b) and a range of viruses, including enteroviruses, hmpv, influenza c, influenza a and cytomegalovirus. when the unconfirmed tb group is excluded from the lda analysis, the lda biplot is reduced to a onedimensional plot (additional file 1: figure s2 ). in this case, the presence of rhinovirus, coronavirus 043, adenovirus, parainfluenza 1, hmpv, bocavirus, c. pneumoniae, s. pneumoniae, h. influenzae type b, m. catarrhalis, influenza virus c virus, and b. pertussis best discriminated cases with definite-tb from those with unlikely tb. quadratic discriminent analysis did not identify any significant association between definite-tb and unlikely-tb groups. however, visual inspection of the qda biplot (fig. 2) showed that hmpv, coronavirus 043, influenza c virus, rhinovirus, cytomegalovirus and c. pneumoniae formed the dominant microbial profile associated with definite-tb cases. in contrast, m. pneumoniae, h. influenzae, p. jirovecii, enterovirus, influenza b virus and rsv a/b were associated with the unlikely-tb category. this is the first comprehensive detailed study of the diversity of respiratory microbes detected in children presenting with suspected ptb in a tb endemic setting and showed that multiple potential pathogens are present in th nasopharynx of such children. the ftd33 multiplex real-time pcr detected at least one of the 33 microbial targets in 97 % of np swabs from children suspected of ptb. detection of multiple bacterial and viral targets was common. bacterial species frequently found as commensals in the nasopharynx were most commonly detected [17, 18] . they include m. catarrhalis (64 %), s. pneumoniae (42 %), h. influenzae spp (29 %), and s. aureus (22 %). in addition, potential pathogenic organisms were detected in the nasopharynx including rsv, c. pneumoniae and b. pertussis. the prevalence of b. pertussis was 6 % in our study. similar detection rates (1-9 %) were reported in other south african settings in children with lrti including at our study site, 10-20 years post transition from whole-cell vaccines to acellular vaccines (south african infants are vaccinated with dtap-ipv/hib; pentaxime®, sanofi pasteur) [19] . the prevalence of some clinically relevant viral targets (rsv, bocavirus and adenovirus) in this cohort is lower than that previously reported in children with lrti [20] [21] [22] . the observed differences may be explained by our enrolment criteria which targeted symptoms suggestive of ptb. however, viral pcr positivity of hmpv, enterovirus and influenza virus is similar to a recent case-control study that also showed their association with community acquired pneumonia [20] . as with bacteria, care needs to be taken with the interpretation of molecular detection of some viruses in np specimens, since target nucleic acid may be detected for some time after resolution of symptoms, and from otherwise healthy children [23, 24] . in this study, some microbes showed no association with any of the tb categories. these included m. catarrhalis, and s. pneumoniae. a randomised controlled trial of the efficacy of pcv9 in south african children showed decreased rates of culture-confirmed and clinically diagnosed tb in pcv9 recipients hospitalised with lrti compared with placebo recipients (relative risk reduction 43 %) [6] . this suggests that coinfection with m. tuberculosis and s. pneumoniae causes severe infection requiring hospitalization. although common in our cohort, s. pneumoniae did not cluster together with the tb or unlikely-tb groups, however we measured np colonization which is likely to be an inaccurate measure for the contribution of s. pneumoniae to lrti. we have recently shown [5] that specific pathogens (specifically b. pertussis, influenza virus, rsv, adenovirus, parainfluenzavirus, bocavirus) are detected significantly more frequently from the np of children with pneumonia than age-matched controls. in this study we detected all of these organisms, irrespective of tbclassification, suggesting that these pathogens may play a role in the exacerbation of symptoms in children with tb as well as accounting for the respiratory illness of a subset of the children without tb. whilst we detected multiple significant co-occurrences between different microbes in this study, these require more detailed assessment in a larger group of children. for example, the co-occurrence between m. catarrhalis, s. pneumoniae and h. influenzae, may reflect age-specific colonization patterns as previously reported [25, 26] . other microbial co-occurrences, such as the association between s. aureus and p. jorovecii, were unexpected. we are currently conducting a larger, longitudinal study to better understand these co-occurences [27] . we were unable to identify significant associations between individual nasopharyngeal microbes and tb classification. discriminant analysis identified that the presence of c. pneumoniae, hmpv, coronavirus o43, influenza c virus, rhinovirus and cytomegalovirus best discriminated children with definite tb. the significance of co-detection of these microbes in children with tb is unclear, and needs to be further assessed. one possibility is that the relative immune suppression or lung pathology associated with ptb may render the host susceptible to other respiratory infections, or alternatively, that intercurrent infection may be immunosuppressive, predisposing to an accelerated clinical course or likelihood of symptoms in children with ptb. active tb is associated with suppression of cellular immune responses, which are critical for the control of intracellular infections [28] such as many of those associated with definite tb in this study. however, in this study, individual microbes were each only detected in small numbers of children which limits our ability to draw firm conclusions in this regard. a recent south african study has shown an increased risk of death in adults with tb-influenza a virus coinfection (adjusted relative risk ratio [arrr] 6.1) compared to tb infection alone [29] . in contrast, de paus et al. did not find a correlation between the seroprevalence of influenza antibodies and the development of clinically active tb in an indonesian cohort [30] . they did however show an association between elevated antibody titres against influenza a and the clinical stage of tb lung disease suggesting recent re-infection with influenza precedes clinical presentation with ptb [30] . a limitation of this study is the lack of a control group of children without lower respiratory symptoms. we are therefore unable to infer whether the pathogens detected played a role in the development or exacerbation of symptoms in this cohort. further limitations include sampling of the nasopharynx rather than the lower respiratory tract, limiting the ability to infer causality for lung co-pathogens. klebsiella pneumoniae, legionella spp and salmonella targets were excluded from analysis due to problems with assay specificity for these targets. in conclusion, this study describes the detection of multiple respiratory microbes in the nasopharynx of children hospitalised with suspected ptb. whilst there was no clear separation between the pathogens present in the airways of children with and without ptb, c. pneumoniae, hmpv, coronavirus o43, influenza c virus, rhinovirus and cytomegalovirus formed the dominant microbial profile in children with ptb but this failed to reach statistical significance on testing of each individual microbe. in contrast, p. jirovecii, h. influenzae spp, rsv, m. pneumoniae, influenza b virus and enteroviruses were more consistently detected in children without tb although not statistically significant. this pilot work may signal broader differences in the microbial ecology of the upper respiratory tract of these children, which warrants further study. additional file 1: figure s1 . seasonal distribution of viruses and bacteria. figure s2 . canonical variate analysis (cva) biplot depicting the spread of respiratory pathogens in the definite tb (red line) and not tb (blue line) groups only. observations under each group are denoted by "+" signs and the median of each group by the red and blue ovals. table s1 . target pathogens in the ftd respiratory pathogens 33 multiplex realtime pcr assay. table s2 . summary of all paired pathogen co-occurrence counts *. table s3 . risk factors associated with the occurrence of each microbes. (pdf 565 kb) global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis understanding latent tuberculosis: a moving target tuberculosis as a cause or comorbidity of childhood pneumonia in tuberculosis-endemic areas: a systematic review advances in the diagnosis of pulmonary tuberculosis in hiv-infected and hiv-uninfected children aetiology of childhood pneumonia in a well vaccinated south african birth cohort: a nested case-control study of the drakenstein child health study role of streptococcus pneumoniae in hospitalization for acute community-acquired pneumonia associated with culture-confirmed mycobacterium tuberculosis in children: a pneumococcal conjugate vaccine probe study etiology of pulmonary infections in predominantly hiv-infected adults with suspected tuberculosis accuracy of the xpert mtb/rif test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in cape town, south africa: a descriptive study urine lipoarabinomannan testing for diagnosis of pulmonary tuberculosis in children: a prospective study national tuberculosis management guidelines detection of streptococcus pneumoniae from different types of nasopharyngeal swabs in children evaluation of tuberculosis diagnostics in children: 1. proposed clinical case definitions for classification of intrathoracic tuberculosis disease. consensus from an expert panel a comparison of the efficiency of five different commercial dna extraction kits for extraction of dna from faecal samples r: a language and environment for statistical computing an introduction to the bootstrap visualisation of quadratic discriminant analysis and its application in exploration of microbial interactions associations between pathogens in the upper respiratory tract of young children: interplay between viruses and bacteria clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx incidence and diagnosis of pertussis in south african children hospitalized with lower respiratory tract infection respiratory viruses associated with community-acquired pneumonia in children: matched case-control study etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections viral and atypical bacterial detection in acute respiratory infection in children under five years clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in hiv-infected and hiv-uninfected south african children identification of respiratory viruses in asymptomatic subjects: asymptomatic respiratory viral infections dynamics of nasopharyngeal colonization by potential respiratory pathogens early acquisition and high nasopharyngeal co-colonisation by streptococcus pneumoniae and three respiratory pathogens amongst gambian new-borns and infants investigating the early-life determinants of illness in africa: the drakenstein child health study immunosuppression during active tuberculosis is characterized by decreased interferon-gamma production and cd25 expression with elevated forkhead box p3, transforming growth factor-beta, and interleukin-4 mrna levels influenza virus infection is associated with increased risk of death amongst patients hospitalized with confirmed pulmonary tuberculosis in south africa the influence of influenza virus infections on the development of tuberculosis we thank the national health laboratory service diagnostic microbiology at groote schuur hospital (cape town, south africa) for the microbiological tb testing. we further wish to thank lesley workman, charmaine barthus, widaad zemanay, layla hendricks, nchimunya hapeela, whitney barnett and the rest of the study team for their help and technical assistance. we thank the western cape health department and the staff at red cross children's hospital for their support of the study. informations in our database is confidential, however, data used for the analysies is available upon request. authors' contributions mpn, mk and hjz conceptualised and supervised this study. mpn and hjz obtained funding. fsd performed the experiments and analysed data with supervision from sl, who performed the linear and quadratic discriminant analysis (lda and qda). mk, mpn, hjz, fjlr, sl and lat contributed to experimental design, data analysis and manuscript preparation. all authors reviewed, contributed to, and approved the final manuscript. the authors declare that they have no competing interests. submit your next manuscript to biomed central and we will help you at every step: key: cord-269266-ygewa5xd authors: wurzel, danielle f.; mackay, ian m.; marchant, julie m.; wang, claire y. t.; yerkovich, stephanie t.; upham, john w.; smith-vaughan, heidi c.; petsky, helen l.; chang, anne b. title: adenovirus species c is associated with chronic suppurative lung diseases in children date: 2014-04-18 journal: clinical infectious diseases doi: 10.1093/cid/ciu225 sha: doc_id: 269266 cord_uid: ygewa5xd background. the role of human adenoviruses (hadvs) in chronic respiratory disease pathogenesis is recognized. however, no studies have performed molecular sequencing of hadvs from the lower airways of children with chronic endobronchial suppuration. we thus examined the major hadv genotypes/species, and relationships to bacterial coinfection, in children with protracted bacterial bronchitis (pbb) and mild bronchiectasis (be). methods. bronchoalveolar lavage (bal) samples of 245 children with pbb or mild (cylindrical) be were included in this prospective cohort study. hadvs were genotyped (when possible) in those whose bal had hadv detected (hadv(+)). presence of bacterial infection (defined as ≥10(4) colony-forming units/ml) was compared between bal hadv(+) and hadv negative (hadv(−)) groups. immune function tests were performed including blood lymphocyte subsets in a random subgroup. results. species c hadvs were identified in 23 of 24 (96%) hadv(+) children; 13 (57%) were hadv-1 and 10 (43%) were hadv-2. an hadv(+) bal was significantly associated with bacterial coinfection with haemophilus influenzae, moraxella catarrhalis, or streptococcus pneumoniae (odds ratio [or], 3.27; 95% confidence interval, 1.38–7.75; p = .007) and negatively associated with staphylococcus aureus infection (p = .03). young age was related to increased rates of hadv(+). blood cd16 and cd56 natural killer cells were significantly more likely to be elevated in those with hadv (80%) compared with those without (56.1%) (p = .027). conclusions. hadv-c is the major hadv species detected in the lower airways of children with pbb and be. younger age appears to be an important risk factor for hadv(+) of the lower airways and influences the likelihood of bacterial coinfection. the burden ( prevalence, cost, and importance) of protracted bacterial bronchitis (pbb) and bronchiectasis (be) are increasingly appreciated [1] [2] [3] [4] . pbb is the most common cause of chronic cough in children presenting to pediatric pulmonologists in some series [1, 5] . over the last 2 decades, the diagnosis of be in children and adults has increased [6, 7] . both conditions are characterized by chronic wet cough, lower airway endobronchial suppuration with bacterial infection, intense airway neutrophilia, and upregulation of inflammatory and immune markers [5, [8] [9] [10] . it is hypothesized, but remains unproven, that pbb and be represent a clinical continuum based upon degree of severity, sharing common triggers and/or pathophysiology [11] . to date, research into the microbiology of chronic suppurative lung diseases (pbb and be) in children has largely focused on bacterial pathogens, with a paucity of research into viral contributors. viral-bacterial coinfection is associated with heightened neutrophilic inflammation of the lower airways of children [12] . human adenovirus (hadv) detection is associated with lower airway neutrophilic inflammation in children with chronic respiratory symptoms, [13] and is significantly more likely to be present in the lower airways of children with pbb, compared with controls [14] . hadvs (particularly types 1-5, 7, 14, and 21 ; members of hadv species b, c, and e) are known to be associated with future small airways dysfunction and bronchiectasis [15, 16] . however, no studies, to our knowledge, have examined the hadv genotypes in the lower airways of children with chronic endobronchial suppuration to investigate a possible role in pathogenesis. thus, we studied the bronchoalveolar lavage (bal) of 245 children with pbb and mild be. we aimed to identify (1) the prevalence of hadv; (2) the diversity of genotypes/species using sequence analysis, and (3) whether presence of hadv increased the odds of bacterial coinfection. we hypothesized that, in the lower airways of children with pbb and mild be, certain hadv genotypes/species would predominate, and that presence of hadv increases the risk of bacterial coinfection. children included in this study were a subset of a larger prospective, longitudinal cohort study on chronic cough in children [12] . ethical approval was obtained from the queensland children's health services human research ethics committee (hrec/03/qrch/17). written informed consent was obtained from the parents/guardians. children were recruited between march 2008 and september 2013, covering 6 winter seasons. of 398 children undergoing flexible bronchoscopy and bal for clinical indication, 245 were diagnosed with pbb or be, and were therefore eligible for inclusion. children were divided into 2 groups: bal positive for hadv (hadv + ) or bal negative for hadv (hadv − ). key demographics and cough characteristics were obtained via completion of a standardized clinical questionnaire. prospective follow-up of participants was undertaken with daily cough diaries and monthly contact via email or telephone. basic immune function tests were performed on peripheral blood, including full blood examination, immunoglobulins (igg, iga, igm, ige), igg subclasses, specific antibody (igg) responses to haemophilus influenzae type b and clostridium tetani, and lymphocyte subsets (including cd16 + and cd56 + natural killer [nk] cells). bronchoscopy and bal were performed as described previously [13] , in accordance with european respiratory society guidelines [17] . quantitative bacteriology and cellularity on bal specimens were undertaken as outlined in a prior study [8] . standardized semiquantitative culture of bal fluid was undertaken using routine laboratory techniques, as described previously [8] . infection with major respiratory pathogens (h. influenzae, moraxella catarrhalis, streptococcus pneumoniae, and staphylococcus aureus) was defined by bacterial load of ≥10 4 colony-forming units (cfu)/ml bal, using standard culture techniques described elsewhere [8] . real-time polymerase chain reaction (pcr) [18] [19] [20] [21] was used to detect a conventional panel of respiratory viruses in all, and an extended panel in a random subset of, children. viruses included hadvs, respiratory syncytial virus, human influenza a virus, human influenza b virus, human parainfluenza viruses 1-3 (hpiv1-3), human metapneumovirus (standard panel), human rhinoviruses, human bocavirus, human coronaviruses (nl63, oc43, 229e, hku1), wu polyomavirus, and ki polyomavirus (extended panel). hadv pcr testing was undertaken on all bal samples at a clinical laboratory (pathology queensland, royal brisbane and women's hospital, brisbane, australia), using a previously described method [22] , to identify hadv + participants. a random subset of hadv isolates, based upon sample availability, from 26 hadv + on bal children, underwent nucleotide sequencing at a research laboratory (queensland paediatric infectious diseases laboratory, brisbane, australia). hadv genotyping, based on the hexon gene hypervariable regions 1-6, was conducted as previously described [23] . in brief, 2 µl of nucleic acid extract was amplified in a nested pcr reaction. round 1 contained primers (0.38 µm; adhexf1-tictttgaca-ticgiggigtictiga and adhexr12-ctgtciacigcctg rttccaca), magnesium chloride (4.75 µm), buffer, and mytaq hs dna polymerase (bioline kit, australia) and was incubated for 1 minute at 94°c followed by 35 cycles of 94°c for 1 minute, 45°c for 1 minute, 72°c for 2 minutes, and a final incubation at 72°c for 1 minute. round 2 used 2 µl of the round 1 pcr product as template, the same conditions but different primers (adhexf2-ggyccyagyttyaarccctaytc and ad-hexr2-ggttctgtcicccagagartciagca). round 2 pcr products were checked by agarose gel electrophoresis, purified, and subjected to nucleotide sequencing (australian equine genetics research centre, uq) results were analyzed to determine the hadv genotype (geneious pro version 6.1). relationships between hadv genotypes, sequenced from 24 hadv + study children, were illustrated in a phylogenetic tree ( figure 1 ) constructed using the neighbor-joining method (with evolutionary history inferred) in mega5 [24] after sequence alignment in geneious version 6.1 [25] . additional sequences were included from genbank (labeled with genotype and accession number) to define the species according to a previously described approach [23] . be was diagnosed based on radiological criteria [26] in children with clinical symptoms consistent with be [27] . all had evidence of mild (cylindrical) be on high-resolution computed tomography (ct) scan (reconstructed from a multidetector ct scan). a diagnosis of pbb was made in children who fulfilled the following criteria: (1) history of chronic (≥4 weeks) wet cough, (2) prospective evidence (supported by cough diaries) of response to 2 weeks of amoxicillin-clavulanate antibiotics, and (3) absence of clinical pointers suggesting an alternative cause for cough [5] . descriptive statistics were used to summarize baseline patient characteristics. median and interquartile range (iqr) were reported as data were nonnormally distributed. univariate analyses were performed using pearson χ 2 (or fisher exact test) for categorical variables. mann-whitney u test was used for 2group comparisons and kruskal-wallis test for >2-group comparisons of continuous variables. binary logistic regression was used to calculate odds ratios and p values. a 2-tailed p value of <.05 was considered statistically significant. statistical analyses were performed using ibm spss version 20.0 (ibm spss, armonk, new york). a neighbor-joining method of phylogenetic analysis of human adenovirus (hadv) genotypes and their assigned species. the 24 nucleotide sequences (approximately 800 nt long) from the hexon gene of hadv-positive samples from study patients are prefixed with royal children's hospital (rch). the evolutionary distances were computed using the maximum composite likelihood method [23] and are in the units of the number of base substitutions per site. additional sequences for speciation are included from genbank (labeled with genotype and accession number in bold). the percentage of replicate trees in which the associated taxa clustered together in the bootstrap test (500 replicates) are shown next to the major branches. of the 245 children with pbb or be, 40 were hadv + and 205 hadv − . the median age of the children in the study was 30 months (iqr, 17-63 months), 23 months (iqr, 14-47 months) in those with pbb, and 57 months (iqr, 30-87 months) in those with be. the median age was similar between hadv + and hadv − groups in children with be (p = .312), table 1 . in children with pbb, those in the hadv + group were significantly younger than the hadv − group (p = .001). there were no differences in the sex of the children according to hadv status within the pbb or be groups (p = .248 and p = .703). no seasonal differences in hadv detection rates were observed (p = .506). cd 16 + and cd56 + nk cells were elevated above the normal range in 20-25 (80%) of hadv + and 64 of 114 (56.1%) of hadv − children (p = .027). when hadv was excluded, similar rates of nk cell elevation were seen in children with or without standard panel respiratory viruses detected in bal (p = .601). basic immune function tests were otherwise normal. hadv genotyping was performed on a random subset (based upon sample availability) of 26 hadv + on bal children. of 24 typeable hadv isolates, 23 (96%) were identified as hadv species c; 13 (57%) as hadv-1, and 10 (43%) as hadv-2. a single hadv + isolate was identified as genotype 4, species e, in a child with low-grade fever and mild upper respiratory tract symptoms at time of bronchoscopy (figure 1 ). the major bacterial pathogens detected in both hadv + and hadv − groups were h. influenzae, m. catarrhalis, and s. pneumoniae. hadv + status showed positive association with each major bacterial pathogen (table 2) . staphylococcus aureus was the fourth most common bacterium causing lower airway infection; however, a significant negative association with hadv + status was observed (p = .03). lower airway infection with 1 or more of the 3 major bacteria showed significant positive association with hadv detection (odds ratio [ although there were slightly more detections of hadv-1 compared to hadv-2, no further associations between individual genotypes and bacterial coinfection were observed (data not shown). the hadv + group was more likely to have lower airway infection with multiple (2 or more) major bacterial species (excluding s. aureus), compared with the hadv − group (or, 2.471 [95% ci, 1.228-4.969]; p = .011). however, on age adjustment, using multiple logistic regression, this association was no longer significant (or, 1.674; [95% ci, .807-3.475], p = .166). mycoplasma pneumoniae detection rates (using pcr) were similar between hadv − and hadv + groups (4 in hadv − and a 1 in hadv + groups; p = .580). similarly, standard panel respiratory viruses were detected at similar rates in hadv − and hadv + children. there were 3 (1.5%) and 0 detections of influenza virus (p = 1.00) and 10 (4.9%) and 2 (5%) detections of hpiv (p = 1.00) in the hadv − and hadv + groups, respectively. respiratory syncytial virus was detected in 11 (5.4%) and 0 (p = .22), and human metapneumovirus was detected in 5 (2.4%) and 0 (p = .594) children in the hadv − and hadv + groups, respectively. of 52 (41 hadv − and 11 hadv + ) participants who had extended viral panel testing of bal, approximately a quarter of hadv − children were human rhinovirus positive on bal (n = 10 [24.4%]) compared with more than half of hadv + children (n = 6 [54.5%]; p = .054). likewise, human bocavirus was detected less commonly in hadv − , compared to hadv + children (1 of 41 [2.4%] vs 3 of 11 [27.3%] ; p = .026). human coronavirus (oc43) was detected in 1 hadv − participant and no hadv + participants (p = 1.00). this is the first study to examine the hadv genotypes detectable in the lower airways of children with chronic endobronchial suppuration (pbb and bronchiectasis). we found hadv species c (genotypes 1 and 2) to be the major hadv species in the bal of these children, irrespective of season. we have also shown that lower airway bacterial infection, with h. influenzae, m. catarrhalis, and s. pneumoniae, but not s. aureus, are increased in hadv + children. younger age is an independent predictor of infection with hadv and common respiratory bacteria, and age increases the odds of viral-bacterial coinfection. our finding of elevated cd16 and cd56 nk cells in the blood of 80% of hadv + children provides indirect evidence of a systemic immune response to hadv in the airways of these children. the hadv-c species, comprising genotypes 1, 2, 5, 6, and 57, is one of the most frequent hadv species known to infect the respiratory tract of children [28] . infection can result in a range of clinical manifestations, from uncomplicated upper respiratory infection to severe pneumonia. most primary hadv-c infections occur within the first 2 years of life [29] . the highest levels of hadv dna are detected in adenotonsillar tissue of 2-year-old children undergoing routine adenoidectomy or tonsillectomy, and the amount of hadv dna decreases with increasing age [30] . hadvs demonstrate the ability to establish latent infection within lymphocytes [30] , tonsillar tissue [31] , and the lung [32] and are capable of evading host innate immune responses via multiple mechanisms [33] . several studies have demonstrated hadv's propensity to establish latent and/or persistent infection within the upper and lower respiratory tract [34, 35] . in a recent longitudinal study of children with chronic upper respiratory infections, 13 had repeated hadv detection; 8 carried an identical hadv genotype on successive occasions, suggesting chronic rather than repeated infection [34] . using repeated lower airway sampling, macek and colleagues demonstrated persistence of hadv in the lower airways of 9 of 11 children with persistent asthma [35] . in adults, matsuse and colleagues showed increased presence of latent hadv dna in the lung tissue of patients with chronic obstructive pulmonary disease (copd), compared with those without copd [32] . no studies to date, however, have genotyped hadv in lower airways of children with chronic endobronchial suppuration. a higher prevalence of hadv in the airways of patients with chronic respiratory diseases has led to speculation that "smoldering hadv at the site of lung inflammation" [30] contributes to the pathogenesis of chronic lung diseases, including asthma in children [35] and copd in adults [32, 36] . marin et al showed that hadv was detected in 78.4% of nasopharyngeal samples of asthmatic children during symptom-free periods, vs 5% of healthy controls [37] . furthermore, we have recently shown that hadv is significantly more likely to be detected in bal fluid of children with pbb (23%) compared with controls (4%) [14] . it is possible that chronic inflammatory diseases of the respiratory tract predispose to hadv persistence in the respiratory tract, or that hadvs induce an inflammatory response that may be a key factor in chronic respiratory disease pathogenesis. if the latter is correct, the association of hadv with bacterial infection of the lower airways is likely to be a relevant and significant finding. childhood lower respiratory infections are known to cause bronchiectasis. nontypeable h. influenzae (nthi) is the most common bacterium in the lower airways of children with pbb and other chronic lung diseases [5, 38, 39] . recently, de schutter and colleagues showed that nthi is also the commonest cause of (nonresponsive or recurrent) community-acquired pneumonia in children [40] . similarly, compared with controls, elevated rates of h. influenzae, m. catarrhalis, and s. pneumoniae infection are detected in the lower airways of children with pbb [14] . the propensity for codetection of hadv with bacterial pathogens (eg, nthi), has been documented in studies on human respiratory diseases [41, 42] . however, the most convincing evidence for microbial synergy arises from an animal study on otitis media. in a chinchilla model of experimental otitis media due to hadv-1 (species c) and nthi, suzuki et al demonstrated a synergistic effect of the 2 pathogens. they found that inflammation was greatest in the presence of both hadv and nthi, compared with hadv or nthi alone. furthermore, timing of inoculation was important. hadv inoculation prior to nthi inoculation resulted in the greatest tympanic membrane inflammation and mucosal dysfunction [43] . we have previously shown that neutrophilic lower airway inflammation is maximal in the presence of viral-bacterial coinfection of the airways of children [12] . it is indeed plausible that hadv-c and h. influenzae may also play a synergistic role in the initiation and/or exacerbations of chronic suppurative lung diseases in children, and further research is needed. the negative association of hadv with s. aureus in the lower airways observed in the present study may be due to the increased presence of other bacterial pathogens (eg, h. influenzae) in hadv + compared with hadv − children. negative associations between s. pneumoniae and s. aureus [44] [45] [46] [47] [48] and between h. influenzae and s. aureus [44, 45] are well described in studies of the upper respiratory tract. these interactions are believed to reflect natural competition between colonization with these organisms [48] . hence, our findings in relation to hadv in the lower airways of children with pbb and be are likely to have clinical relevance and may represent an important clue to the underlying pathogenesis of these disease processes. our hypothesis is based upon several key findings. these include (1) a predominance of hadv-c in the airways of these children, with a plausible mechanism for disease; (2) the presence of elevated nk cell levels in hadv + children (however, not in those with other standard panel respiratory viruses), indicating a systemic immune response to hadv in the lung; (3) previous research linking hadv (in the nasopharynx and/or lung) to heightened neutrophilic inflammation and lymphopenia of the lower airways (suggestive of active viral replication) [13] ; and (4) the demonstrated association between hadv + status and lower airway bacterial infection (the latter being a key feature of pbb and be). it is therefore unlikely that hadv is an innocent bystander, as early epidemiologic studies suggested. although we have described 2 novel and important findings, several limitations to our study merit discussion. first, although our cross-sectional data highlights important associations, we cannot attribute causality. repeated lower airway sampling would be needed to establish the temporal sequence of lower airway infection and determine a cause-and-effect relationship. however, subjecting children to repeated general anesthesia for lower airway sampling, solely for research, would be unethical. second, we did not include hadv serology in our blood test panel. this ideally requires repeat venipuncture, which was not feasible in our context as many children in the study reside outside the brisbane area. with regards to methods of hadv detection, although culture detects infectious virus, pcr is more sensitive and is the current clinical standard [16] . although a positive pcr for hadv does not readily distinguish infectious from noninfectious virus, the identification of hadv dna indicates that infection has occurred at some stage. further, hadv's association with a systemic immune response (ie, elevated nk cells) supports the notion that hadv may play a clinically relevant role. third, we detected few conventional respiratory panel viruses (other than hadv) and only performed extended viral panel analyses on a subset, limiting our ability to explore other possible viral-bacterial and viralviral interactions. last, the strong relationship between age and hadv status, and the increased odds of bacterial coinfection with hadv in younger children, is likely to be significant. this finding raises the question of whether younger children are predisposed to polymicrobial infection, via immature immune system processes, rather than a true viral-bacterial interaction. timing of hadv acquisition, with respect to age, may therefore be important in further evaluating the link between hadv and future development of pbb and/or be. we conclude that hadv-c genotypes 1 and 2 are the dominant hadv species infecting the lower airways of young children with chronic endobronchial suppuration. the significant association between hadv and lower airway bacterial infection suggests a possible role of hadv-c in the pathogenesis of chronic suppurative lung diseases in young children. our findings may have implications for targets in the prevention of chronic suppurative lung diseases; however, further research to definitely establish causality would be required. a cough algorithm for chronic cough in children: a multicenter, randomized controlled study the burden of disease in pediatric non-cystic fibrosis bronchiectasis non-cystic fibrosis bronchiectasis economic burden of non-cystic fibrosis bronchiectasis in the first year after diagnosis from a us health plan perspective evaluation and outcome of young children with chronic cough australian institute of health and welfare trends in bronchiectasis among medicare beneficiaries in the united states prospective assessment of protracted bacterial bronchitis: airway adenovirus and suppurative lung diseases • cid 2014:59 (1 july) • 39 inflammation and innate immune activation lower airway microbiology and cellularity in children with newly diagnosed non-cf bronchiectasis bronchiectasis: breaking the cycle of inflammation and infection 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of human bocavirus in respiratory, fecal, and blood samples by real-time pcr co-circulation of four human coronaviruses (hcovs) in queensland children with acute respiratory tract illnesses in 2004 pring-akerblom p. rapid and quantitative detection of human adenovirus dna by real-time pcr molecular typing of human adenoviruses by pcr and sequencing of a partial region of the hexon gene mega5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods bronchoarterial ratio on high-resolution ct scan of the chest in children without pulmonary pathology: need to redefine bronchial dilatation chronic suppurative lung disease and bronchiectasis in children and adults in australia and new zealand disseminated adenovirus disease in immunocompromised and immunocompetent children adenovirus infections in young children prevalence and quantitation of species c adenovirus dna in human mucosal lymphocytes detection of adenovirus nucleic acid sequences in human tonsils in the absence of infectious virus latent adenoviral infection in the pathogenesis of chronic airways obstruction immune evasion by adenoviruses persistence of adenovirus nucleic acids in nasopharyngeal secretions: a diagnostic conundrum persistent adenoviral infection and chronic airway obstruction in children immunodetection of adenoviral e1a proteins in human lung tissue persistence of viruses in upper respiratory tract of children with asthma respiratory bacterial pathogens in the nasopharynx and lower airways of australian indigenous children with bronchiectasis haemophilus influenzae and the lung (haemophilus and the lung) microbiology of bronchoalveolar lavage fluid in children with acute nonresponding or recurrent community-acquired pneumonia: identification of nontypeable haemophilus influenzae as a major pathogen the interaction between respiratory viruses and pathogenic bacteria in the upper respiratory tract of asymptomatic aboriginal and non-aboriginal children mixed microbial aetiology of community-acquired pneumonia in children synergistic effect of adenovirus type 1 and nontypeable haemophilus influenzae in a chinchilla model of experimental otitis media microbial interactions during upper respiratory tract infections long-term effect of pneumococcal conjugate vaccine on nasopharyngeal colonization by streptococcus pneumoniae-and associated interactions with staphylococcus aureus and haemophilus influenzae colonization-in hiv-infected and hiv-uninfected children association between carriage of streptococcus pneumoniae and staphylococcus aureus in children effect of conjugate pneumococcal vaccine followed by polysaccharide pneumococcal vaccine on recurrent acute otitis media: a randomised study colonisation by streptococcus pneumoniae and staphylococcus aureus in healthy children acknowledgments. we thank the families that participated in this study; sophie anderson-james, carol willis, and joanna tuppin for their assistance with patient recruitment, data entry, and study coordination; and xiaoyan lu (us centers for disease control and prevention) for guidance in hadv genotyping.disclaimer potential conflicts of interest. i. m. m. has received payment for consultancy services from firebrick pharma. j. w. u. has served on the advisory board for novartis and has previously received payments for lectures or served on speakers' bureaus for astrazeneca, gsk, novartis, and boehringer. all other authors report no potential conflicts.all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord-017291-bhe34dky authors: cohen, cheryl; reubenson, gary title: influenza date: 2017-05-05 journal: viral infections in children, volume i doi: 10.1007/978-3-319-54033-7_2 sha: doc_id: 17291 cord_uid: bhe34dky influenza is one of the commonest infections in human populations, and causing substantial morbidity and mortality globally. the influenza virus is divided into different types and subtypes, three of which are currently circulating widely in humans: influenza a(h3n2) and influenza b. the virus undergoes constant evolution, leading to annual seasonal winter epidemics in temperate countries and necessitating annual updates to the vaccine. rarely, completely new influenza viruses can emerge in human populations, giving rise to influenza pandemics. children aged <5 years (especially those <2 years) and those with underlying illness such as cardiac, respiratory and severe neurologic disease have an increased risk of severe outcomes associated with influenza. pregnant women have an increased risk of severe influenza. complications may involve the respiratory tract (e.g. otitis media or pneumonia) or, less commonly, other organ systems (e.g. encephalitis or myocarditis). specific antiviral treatment should be offered as soon as possible for hospitalized children with presumed or confirmed influenza and for influenza of any severity for children at high risk of severe complications of influenza without waiting for laboratory confirmation. antiviral treatment is usually not warranted for uncomplicated influenza as this is usually self-limiting. annual influenza vaccination should be offered to all individuals at increased risk for complications of influenza. vaccine cannot be given to children aged <6 months but maternal influenza immunization during pregnancy is recommended and can confer protection to the young infant. influenza is one of the commonest infections in human populations, infecting a significant percentage of the population each year and causing substantial morbidity and mortality globally. while seasonal influenza is an important cause of morbidity and mortality, novel influenza virus strains can emerge with the potential to cause global pandemics. children are a common source of inluenza transmission in the community and form an important risk group for severe influenza illness (particularly infants and children with underlying chronic illnesses). influenza viruses are enveloped viruses from the family orthomyxoviridae [1] . influenza has a negative sense rna genome divided into eight segments. the segmented genome allows for exchange of genes between influenza viruses of the same type through genetic reassortment. two types of influenza viruses, influenza a and b, cause epidemic disease in humans. the influenza a viruses are divided into subtypes and influenza b viruses into lineages based on their antigenic structure. the influenza a subtypes are differentiated based on characteristics of the haemagglutinin (ha) and neuraminidase (na) surface antigens. haemaglutinin is responsible for virus attachment during the early stages of infection and is the main antigen against which the host immune response is directed. neuraminidase facilitates the release of mature virus from the cell surface. currently there are two influenza a subtypes (influenza a(h3n2) and influenza a(h1n1)pdm09 and two influenza b lineages (yamagata and victoria) co-circulating globally in human populations. influenza a viruses of at least 17 ha and 9 na subtypes have been isolated from animals such as birds, pigs, horses and dogs. because many different ha and na subtypes can circulate in animals, animals such as birds and pigs may be the reservoir of emerging influenza virus subtypes which can infect humans [1] . several of these subtypes such as influenza a(h7n1) or influenza a(h5n2) can cause severe illness and even death in individuals in close contact with animals but are not able to be efficiently transmitted from person-to-person [2] . antigenic drift is the emergence of new influenza virus antigenic variants as a result of point mutations and recombination which occurs during viral replication [1] . this frequent emergence of antigenic variants contributes to seasonal influenza epidemics and leads to the requirement for annual assessment of the need to update the viruses included in the influenza vaccine. antigenic shift is a term for larger genetic changes which occur infrequently in influenza a viruses. new, or substantially different, influenza a virus subtypes which emerge in humans, have the potential to cause pandemics if they are efficiently transmitted between humans in the presence of little or no pre-existing population immunity [2] (fig. 2.1 ). epidemiology including pandemics it is estimated that 5-20% of the population become infected with influenza each year and about 20% of these develop symptomatic illness. rates of influenza infection are highest in children aged 5-15 years [3] . annually in children aged <5 years there are approximately 90 million new cases of influenza, 20 million cases of influenza-associated acute lower respiratory tract infection (alri) (13% of all cases of paediatric alri) and one million cases of influenza-associated severe alri (7% of all severe alri) globally [4] . between 28,000 and 111,500 influenza-associated deaths in children <5 years are estimated to occur each year, with 99% of these occurring in developing countries. influenza is associated with approximately 10% of respiratory hospitalizations in children <18 years worldwide ranging from 5% in children aged <6 months to 16% in children aged 5-17 years [5] . influenza-associated hospitalization rates are more than three times higher in developing than industrialised countries. the incidence and mortality associated with influenza can vary substantially from year-to-year as a result of different circulating types and subtypes with differing propensity to cause severe illness. years in which influenza a(h3n2) predominates may typically be associated with increased risk of severe disease [6] . people of all ages may develop symptomatic influenza infection but the highest rates of influenza-positive influenza-like illness (ili) are seen in children aged 2-17 years [7] . school-age children are an important source of infection in the community and influenza outbreaks can occur in schools during the influenza season [8] . during the influenza season, influenza is an important cause of school absenteeism. illness in children can cause a substantial economic burden as a result of caregiver absenteeism from work to care for ill children as well as outpatient visits in children and can lead to additional antibiotic courses being prescribed. hospitalizations and mortality during the influenza season can be substantial. in severe influenza seasons, the large number of medical care visits as a result of influenza can overwhelm health systems. the highest rates of influenza-associated hospitalizations and deaths are typically seen in individuals aged ≥65 years, <5 years and those with underlying medical conditions that confer an increased risk for severe influenza [9] . children aged <2 years and, to a lesser extent, those aged 2-5 years have increased rates of influenzaassociated hospitalization and mortality compared to older children. children with underlying illnesses, particularly cardiac, respiratory and severe neurologic disease have an increased risk of severe outcomes associated with influenza. a study from south africa, found that amongst children aged <5 years, malnutrition, prematurity and hiv infection were associated with increased odds of influenza-associated hospitalization [10] . hiv-infected children have an approximately two times elevated risk of influenza hospitalization and are more likely to die of influenza once hospitalized compared to hiv-uninfected children [11, 12] . pregnant women have an increased risk of severe influenza. some studies suggest that influenza in pregnancy may be associated with adverse outcomes in infants born to these women (such as low birth weight, pre-term birth and stillbirth), but others have disputed this [13] . in temperate climates influenza typically causes annual seasonal epidemics in the winter months, between april and september in the southern hemisphere and between october and april in the northern hemisphere [9, 14] . in more tropical climates influenza commonly circulates year-round with two or more peaks which may coincide with climatic events such as the rainy season [15] . this may present challenges for decision-making around the best time to vaccinate and which vaccine formulation (the northern or southern hemisphere) should be used (see section on vaccines) [16] . the start, peak, size and duration of the influenza season may vary substantially from year-to-year. seasonal influenza can give rise to outbreaks in closed settings such as schools, these can occur at any time of year but are more common during the influenza season [9] . influenza pandemics are caused by the emergence and spread in human populations of a new influenza a virus with either a new or substantially altered ha or na combination against which there is little or no immunity in humans, which is easily transmitted between humans and causes clinical illness in humans [1] . the emergence of a pandemic influenza strain is unpredictable and can occur through two mechanisms. firstly, a host could be simultaneously infected with two different influenza virus subtypes which could allow for exchange of genetic material or reassortment and the emergence of a new subtype. for example this could occur if a pig were infected by both a human and avian origin influenza subtype simultaneously with genetic exchange leading to the emergence of a virus adapted to spread in humans, but with ha and/or na not currently circulating in humans. the second way that novel subtypes can emerge is if avian or other animal adapted subtypes are directly transmitted to humans and then undergo adaptation to allow transmission between humans. currently some avian influenza virus subtypes such as influenza a(h5n2) can be transmitted to humans, usually following close contact with poultry, and cause severe infections. however, these viruses are not adapted for efficient transmission from person to person and therefore have not given rise to a new pandemic strain [2] . global surveillance for new influenza virus strains is essential for early identification of novel strains to allow a global public health response. the 1918 pandemic of influenza a(h1n1) is widely acknowledged as the most severe in recent times with an estimated >20 million deaths worldwide. other recent pandemics (1957, asian flu h2n2 and 1968 hong kong flu h3n2) have been associated with a lower death toll [17] . a characteristic of pandemic influenza strains is the shift in the age distribution of deaths from predominantly affecting the extremes of age (young infants and the elderly) to mortality in young adults aged 20-40 years [17] . although influenza pandemics can cause substantial mortality, the annual cumulative deaths each year, associated with seasonal mortality, far outweigh this burden. in 2009, a novel influenza a virus, influenza a(h1n1)pdm09 emerged in the human population and caused a global pandemic. this virus, was antigenically distinct from the h1n1 virus which had been circulating in human populations from 1997 to early 2009 and was thought to have entered the human population from pigs (hence the colloquial name "swine flu"). the overall mortality burden of this strain was estimated at between 123,000 and 203,000 deaths globally, similar to the annual mortality burden from seasonal influenza, although this strain did exhibit the characteristic pandemic age shift, disproportionately affecting individuals aged 20-40 years [18] . subsequently, influenza a(h1n1)pdm09 has been circulating in human populations and immunity in the population has built up. influenza a(h1n1)pdm09 has become the predominant h1n1 seasonal train, replacing those that previously circulated and behaves like any other seasonal influenza virus [9] . influenza is predominantly spread person-to-person by large droplets and through direct contact with respiratory secretions [19] . the contribution of airborne transmission is unclear. the incubation period for influenza typically ranges from 1 to 4 days (median 2 days) [20] . influenza virus is typically shed from the nasopharynx for up to 5 days after illness but viral shedding may be longer in severely ill individuals, young children and immunocompromised individuals. the reproductive number for influenza is between 1 and 2 and the serial interval usually estimated at 2-3 days. an individual's susceptibility to infection and disease will depend on host characteristics including preexisting cellular or humoral immunity to influenza [20] . young children may have no pre-existing immunity to influenza, but older children and adults have often been exposed to circulating influenza several times before and may also have pre existing immunity from vaccination. natural immunity is not fully protective, largely because of the variability of influenza ha and na. influenza virus replication predominantly occurs in the respiratory tract columnar epithelial cells, with infection leading to loss of cilia and cell death [20] . damage to the respiratory tract as well as immunologic changes can lead to increased susceptibility to bacterial superinfection. viremia with influenza is relatively uncommon although constitutional symptoms are a prominent feature of clinical disease. in most children influenza infection results in acute self-limiting upper respiratory tract (urt) symptoms, however, systemic manifestations are not uncommon [21] . factors that influence clinical presentation include: age of the child, previous influenza exposure, vaccination status, underlying disease states or co-morbidities, as well as viral factors. children are considered important influenza "vectors" and are often responsible for introducing the virus into their homes and broader social settings [22] . influenza classically presents with the sudden onset of systemic (fever, myalgia, headache, and malaise) and urt symptoms (sore throat, cough, rhinitis). since many patients do not have all these typical symptoms, accurate clinical diagnosis is challenging particularly in the younger pre-verbal child and outside of the influenza season [23] . a large study evaluating the clinical presentation of influenza in children found that almost all (95%) had fever; cough (77%) and rhinitis (78%) were also very common, but much lower proportions experienced headache (26%) or myalgia (7%) [24] . younger children have not yet been exposed to influenza very often and so have yet to acquire immunity to a substantial repertoire of circulating seasonal influenza strains. they, therefore, are more likely to develop severe or complicated disease [25] . further, they are less likely to manifest with classic symptoms, experience higher fevers (not uncommonly associated with febrile convulsions), less prominent urt involvement and more gastro-intestinal symptoms (vomiting, diarrhea, abdominal pain, loss of appetite). examination may be completely normal in some children, others may manifest with tachypnea, conjunctival injection, nasal inflammation and discharge, or cervical lymphadenopathy. oropharyngeal findings are often limited, even in those children complaining of a sore throat [24] . symptoms of uncomplicated influenza usually start improving within a few days, but symptoms lasting more than a week are not uncommon. cough, in particular, may persist for a number of weeks, but steady improvement can be expected [26] . the differential diagnosis of influenza largely depends on the presenting symptoms and clinical findings, but includes other respiratory viruses (rhinovirus, coronavirus, respiratory syncitial virus, human metapneumovirus, adenovirus, parainfluenza) and some bacterial urt infections (streptococcus pyogenes, mycoplasma). the clinical manifestations of these conditions are very similar, regardless of the implicated pathogen [27] . all influenza strains may result in severe illness and knowing which infection a particular child has, is not helpful in predicting their disease course. complications may involve the respiratory tract (e.g. otitis media, pneumonia) or, less commonly, other organ systems (e.g. encephalitis, myocarditis). otitis media may occur in as many as 50% of cases; this may be related to the influenza virus itself or secondary infection with bacteria or other viruses [24, 28] . symptoms of acute otitis media generally present a few days after onset of influenza symptoms. lower respiratory tract complications may include the following [21, 29] : • laryngo-tracheo-bronchitis ("croup") • bronchiolitis • pneumonia-especially in children <2 years of age, often mild but may be severe, rapidly-progressive and occasionally fatal, particularly if associated with secondary bacterial infection (usually streptococcus pneumoniae or staphylococcus aureus). a variety of radiographic appearances have been described • acute exacerbation of asthma-this is the most common respiratory tract complication of influenza. central nervous system involvement can include the following [30] [31] [32] : • aseptic meningitis • acute cerebellitis • transverse myelitis • guillain-barré syndrome • febrile seizure • necrotizing encephalitis • postinfectious encephalitis (also referred to as acute disseminated encephalomyelitis). neurologic complications appear to be more common in younger children and in those with underlying neurologic and neuromuscular disease. following the rapid decline in aspirin use over the last few decades, influenza-associated reye syndrome is now rare. mild transient myositis is common with influenza infection; it is more likely with influenza b and is associated with moderate elevations in creatine kinase levels [24] . acute myositis is an important, severe, but rare, complication of influenza infection [33] . it presents with extreme muscle tenderness, often involving the calf muscles, extreme elevations in creatine kinase as well as significant myoglobinuria. during influenza season, influenza should be considered in all children presenting with suggestive clinical features-this includes those already admitted to hospital, as nosocomial transmission of influenza is well described. influenza should still be considered outside of the influenza season, particularly in travelers and children residing in tropical and sub-tropical climates where year-round influenza transmission occurs. accurate clinical diagnosis of influenza is challenging, particularly in younger children. the lack of specific signs or symptoms results in patients receiving diagnoses of "influenza-like illness" or "viral upper respiratory tract illness" unless further diagnostic testing is undertaken. this degree of diagnostic uncertainty should be acknowledged, however, since most such cases are self-limiting and management is largely supportive, there is usually no need to obtain a precise microbiological diagnosis. currently available diagnostic tests for influenza include the following [23, 34] : • rapid, point-of-care, antigen detection tests a number of different tests are currently available, although they remain unavailable in many settings. they provide results within 30 min, and, when used appropriately, are helpful in confirming influenza infection. in general, they are insufficiently sensitive to reliably exclude the disease. further, their performance will depend on which antigens are expressed by currently circulating strains. when influenza activity is low, positive results are likely to be false-positives, however, their positive predictive value improves as influenza activity increases. conversely, during periods of high influenza activity, false-negatives are more likely and may warrant additional testing in some patients. since diagnostic confirmation seldom affects management of such children, the use of these tests is generally not recommended in low-resource settings and should be used judiciously in better-resourced areas. when used, it should be clear in the clinician's mind as to how the result is going to alter treatment: positive results can potentially reduce antibiotic usage and allow for early use of antivirals in those at high risk of complications or severe disease. however, it is important to recognize that the identification of influenza does not exclude the presence of bacterial co-infections. these tests are currently considered to be the most reliable for the diagnosis of influenza in children. amongst the available options, they are the most sensitive and specific. they can be performed on most respiratory samples, most commonly nasopharyngeal aspirates or swabs. they are also able to differentiate influenza a and b, as well as subtypes of influenza a. more recently, point-of-care pcr assays have becomes available in some developed world settings. they are performed on nasal swabs and can supply a reliable result in as little as 15 min. while, not currently available in most developing world settings, if more affordable they could become an important new influenza diagnostic. since the live attenuated influenza vaccine contains influenza genetic material, recent receipt of this vaccine will also result in a positive pcr test. these are also performed on nasal or nasopharyngeal swabs and allow for the direct or indirect detection of influenza antigens. influenza a and b can be differentiated, however, the sensitivity of these tests is moderate and, particularly during periods of high transmission, negative tests may need to be repeated using a more sensitive methodology (pcr or culture). • viral culture viral culture takes at least 48-72 hours and so has limited utility in the routine diagnosis of influenza. however, they are helpful as part of surveillance activities and isolates can be used to inform annual vaccine planning. a variety (hemagglutination-inhibition, enzyme-linked immunosorbent assay (elisa), and complement fixation assays) of serological assays can be performed but are of limited diagnostic value as they require acute and convalescent sampling. a fourfold increase in titre allows for a retrospective influenza diagnosis to be made. their primary role is as a research tool. antivirals are available for the specific treatment of influenza. two classes of antiinfluenza drugs are available: neuraminidase inhibitors (e.g. oseltamivir, zanamivir) and m2 inhibitors (e.g. amantadine, rimantadine). both classes are inactive against all other respiratory viruses. resistance can emerge in circulating influenza virus strains and for this reason antiviral resistance should be constantly monitored through surveillance and recent guidance consulted for the latest antiviral resistance profiles. • neuraminidase inhibitors [35] neuraminidase inhibitors prevent the release of new virions from influenza infected cells and are active against both influenza a and b. oseltamivir is the most widely available member of this drug class and can be used for children and adults. it is dosed orally and is approved for both treatment and prevention of influenza. it is available both in capsule form and as a powder for suspension, although the suspension has a relatively short shelf life and is often substantially more expensive than the capsule. as a result, the capsule is the most widely used formulation. when the oral suspension is unavailable the capsule can be opened and diluted with sweetened liquids to provide the appropriate dose. zanamivir is predominantly available as an inhaled formulation, although intravenous zanamivir is available for investigational use, particularly for severely ill patients or those with suspected or confirmed oseltamivir-resistant virus. the inhaled preparation is contra-indicated in children with a history of wheezing or other chronic respiratory condition. its use is not recommended for children younger than 5 years of age. peramivir is an intravenous neuraminidase inhibitor that is not approved for use in children and is not widely available. neuraminidase inhibitors are generally well tolerated. common side effects include nausea, vomiting and rash, as well as bronchospasm with zanamivir. neuropsychiatric symptoms have been linked to oseltamivir use, particularly in japan, however, more recent evidence suggests no such causative link [36, 37] . severe adverse reactions have been reported but are considered rare [38] . the mainstay of influenza prevention remains immunization, but in high risk situations, amongst partially or unimmunized children, chemoprophylaxis can be considered. both pre-and post-exposure chemoprophylaxis have been advocated, however, concerns regarding induction of oseltamivir-resistance have tempered enthusiasm for this approach and their prophylactic use is increasingly discouraged. antiviral treatment should be offered as soon as possible for hospitalized children with presumed or confirmed influenza and for influenza of any severity for children at high risk of severe complications of influenza (table 2 .1) [39] . timely oseltamivir treatment can reduce the duration of fever and symptoms. there are no prospective randomized controlled trials of treatment efficacy of neuraminidase inhibitors in hospitalized children and for severe outcomes but observational data suggest that treatment does reduce the risk of hospitalization and death, although there is some controversy in the literature (table 2. 2) [40] . treatment should be initiated as early as possible. the benefit of any treatment is maximal early in the course of the disease and should be started within 48-72 hours of symptom onset. influenza diagnosis may not have been confirmed within this timeframe and so treatment will often be initiated empirically prior to microbiological confirmation. some evidence suggests benefit to those with very severe illness even when treatment is initiated later than 72 hours into the disease course. therefore, in table 2 .1 children at high risk of severe influenza in whom influenza antiviral treatment is recommended by the centers for disease control and prevention (cdc) and american academy of pediatrics (aap) current guidance [9, 39] 1. children aged <2 years 2. persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), or metabolic disorders (including diabetes mellitus) or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability, moderate to severe developmental delay, muscular dystrophy, or spinal cord injury) 3. persons with immunosuppression, including that caused by medications or by hiv infection 4. persons who are receiving long-term aspirin therapy 5. american indian/alaska native persons 6. residents of chronic care facilities patients with severe or complicated disease, treatment should be initiated even if >48 hours after illness onset. children meeting the clinical criteria for treatment should be treated irrespective of whether they have been vaccinated. since influenza is generally a mild, self-limiting disease in previously well children, most such children will not require antiviral treatment even when they present soon after symptom onset. treatment of such children increases the risk of adverse events, potentially increases the risk of resistance developing and may deplete medicine supply for those in greater need. • adamantanes [9, 39] these agents target the influenza a m2 protein, which is essential for efficient viral replication. they have no activity against influenza b and are not active 10 mg (two 5-mg inhalations) twice daily 10 mg (two 5-mg inhalations) once daily against currently circulating influenza a strains. as such, there use is not currently recommended for the treatment or prevention of influenza. it has been suggested that they may have a role, in combination with oseltamivir, for the treatment of oseltamivir-resistant influenza a. vaccines and guidelines for vaccination influenza vaccination can be given to any person who wishes to reduce the risk of becoming ill during the influenza season. some countries such as the united states of america (usa) and united kingdom (uk) recommend influenza vaccination for all children, or all individuals. in addition, special effort should be made to vaccinate children at risk of severe influenza listed in table 2 .3. individuals such as healthcare personnel and childcare providers (especially those in contact with infants aged <6 months and children with underlying risk conditions) should be vaccinated to reduce the risk of transmission to high risk children. lastly, pregnant women are recommended to receive influenza vaccination, to reduce the risk of severe illness in the mother, to provide direct protection to the young infant through trans-placental transfer of maternal antibodies and to reduce the risk of transmission of influenza from the mother to the young infant [41] . iiv3 has been available for many years and includes inactivated components of two influenza a (one each of influenza a(h1n1)pdm and influenza a(h3n2)) and one influenza b strains. since the 1980s, two antigenically distinct influenza b lineages (victoria and yamagata) have been circulating globally. this is a limitation of iiv3, as protection may be reduced when the circulating influenza b strain is of the lineage which is not included in iiv3. the iiv4 includes an additional strain of the other influenza b lineage not included in tiv to make a total of four strains and thus potentially offers additional benefit of protection against both circulating influenza b lineages. inactivated influenza vaccines (iiv3 and iiv4) contain no live virus. standarddose iiv should contain 15 μg of each haemagglutinin antigen in each 0.5 ml dose. iiv3 and iiv4 are available in formulations for both intramuscular (im) and intradermal (id) use but the id formulation is only licensed for use in individuals aged 18 years and older. two formulations of iiv3 manufactured using technologies that do not include eggs have become available in recent years, but neither is licensed for individuals aged <18 years. these are cell-culture based inactivated influenza vaccine and recombinant influenza vaccine. d. hiv infection e. sickle cell anemia and other hemoglobinopathies f. diseases that necessitate long-term aspirin therapy, including juvenile idiopathic arthritis or kawasaki disease g. chronic renal dysfunction h. chronic metabolic disease, including diabetes mellitus i. any condition that can compromise respiratory function or handling of secretions or can increase the risk of aspiration, such as neurodevelopmental disorders, spinal cord injuries, seizure disorders, or neuromuscular abnormalities j. morbid obesity k. pregnancy 2. children aged 6 months-59 months as this group (particularly those aged <24 months) has an increased risk of influenza-associated hospitalization and mortality b. individuals who come into contact with children at risk of severe influenza 1. all household contacts and out-of-home care providers of the following: children with high-risk conditions; and children younger than 5 years, especially infants younger than 6 months 2. all health care personnel (hcp) 3. all child care providers and staff; and 4. all women who are pregnant, are considering pregnancy, are in the postpartum period, or are breastfeeding during the influenza season laiv is a live attenuated influenza vaccine which is administered intranasally and licensed for use in individuals aged 2-49 years of age. since 2013 the laiv has only been available in a quadrivalent formulation. adjuvanted formulations of influenza vaccine are licensed for use in individuals aged ≥65 years in the usa but not currently in children [39] . they have been shown to have a higher efficacy then iiv in a randomized controlled trial in children [42] . adjuvants have several potential advantages over more traditional vaccine formulations including increased immunogenicity, potentially reducing the amount of antigen required. they elicit a more robust immune response and could potentially reduce the number of doses needed in children. children aged 6 months through 8 years should receive two influenza doses administered ≥4 weeks apart the first time influenza vaccine is administered. for young children who require two doses of influenza vaccine, vaccination should not be delayed to ensure that both doses are given with the same product. any licensed, effective influenza vaccine product may be used for each dose. it is important to document all doses of influenza vaccine administered in the child's medical records. in temperate countries, influenza vaccine should be administered as soon as possible after the influenza vaccine becomes available. the recommended dosage of influenza vaccine for patients of different age groups is described in table 2 .5 [9] . influenza vaccine effectiveness depends on characteristics of those being vaccinated (age and health), whether there is a good match between the circulating viruses and the viruses contained in the vaccine, and on influenza types and subtypes circulating each year. in general, influenza vaccines work best among children ≥2 years and healthy adults. older people (≥65 years), children <2 years and severely immunocompromised individuals often have poorer immune responses to inactivated influenza vaccine (iiv) compared with healthy adults. however, even for these people influenza vaccine still provides some protection. other products, e.g. high-dose influenza vaccine and adjuvanted vaccines, have been shown to be more effective in certain groups [43] but these vaccines may not be available in all settings and are not licensed for use in all age groups. there have been a number of studies of iiv effectiveness in children aged 6-59 months. for seasonal iiv in young children, two doses of influenza vaccine provides better protection than one dose in the first season a child is vaccinated. estimates of iiv efficacy in young children are limited and vary by season and study design. efficacy is lower in children aged 6-23 months. data are unclear as to the effectiveness in hiv-infected children aged <5 years [44] . a randomized controlled trial of laiv3 in healthy children aged 15-71 found a vaccine effectiveness of 92% (95% ci 65-96%). several other randomized controlled trials and observational studies have demonstrated high efficacy of laiv3 against laboratoryconfirmed influenza. studies comparing efficacy of iiv and laiv have generally found that laiv has similar, or better efficacy, than iiv. since 2013, laiv4 has replaced laiv3 as the available laiv. licensure was on the basis of immunogenicity studies. in 2016, conflicting findings on the effectiveness of laiv emerged from different settings, with the usa withdrawing its recommendation for laiv use in the 2016-2017 influenza season based on concerns of reduced effectiveness, particularly against the a(h1n1)pdm component of the vaccine [9] . studies from europe in the same seasons found moderate laiv effectiveness, similar to that of iiv for the same year [45, 46] with recommendations for laiv remaining unchanged in england and europe. vaccinating individuals at risk of severe influenza may provide direct protection for these individuals. in addition, vaccinating individuals in close contact with people at risk for severe influenza may provide indirect protection through preventing transmission to high-risk individuals. vaccinating children can protect children directly and the general population indirectly. this strategy is especially important for individuals in whom influenza vaccine is not indicated, such as children aged <6 months (who may be protected through maternal immunization) [47] [48] [49] . a randomized controlled trial conducted in south africa has shown that when pregnant women receive the influenza vaccine, their risk of developing influenza is halved, as is the risk to their infants in the first 24 weeks of life [47] . the vaccine has been shown not only to be efficacious for prevention of influenza in both mothers and their infants, but also safe [47] [48] [49] . vaccination of healthcare workers may decrease the risk of spreading influenza to their patients. recent influenza vaccination does not preclude a diagnosis of influenza as the vaccine is not 100% effective. because of the large year-to-year variability in influenza vaccine effectiveness depending on the circulating influenza strains, many countries publish annual estimates of influenza vaccine effectiveness using a test-negative case-control study design. a systematic review of test-negative case-control studies found that the pooled ve was 33% (95% ci 26-39) for h3n2, 54% (46-61) for type b, 61% (57-65) for h1n1pdm09, suggesting reduced protection of available vaccines against influenza a(h3n2) in recent years [50] . [35, 39] the iiv is an inactivated vaccine, and has a well-established safety record. it is safe for use in pregnancy and in children ≥6 months of age. minor illness, with or without fever, is not a contraindication to influenza vaccine administration. clinicians should always consult the manufacturer's package insert for current contraindications and precautions for particular products. contraindications to the administration of iiv include: • a history of severe (anaphylactic) hypersensitivity to any components of the vaccine including, egg protein, or after previous dose of any influenza vaccine. anaphylaxis is rare and a careful history will distinguish between anaphylactic reactions and allergic reactions like rashes. mild egg protein allergy is not a contraindication for influenza vaccine • infants <6 months of age. precautions to iiv administration include: • persons with moderate to severe illness with or without fever should preferably be immunized after symptoms have resolved • person who developed guillian-barrè syndrome within 6 weeks of receiving an influenza vaccine. contraindications to the administration of laiv include the following: • children 2-4 years of age with a history of recurrent wheezing or a medically attended wheezing episode in the previous 12 months because of the potential for increased wheezing after immunization • children with the diagnosis of asthma • children with a history of egg allergy • children who have received other live virus vaccines within the past 4 weeks; however, other live virus vaccines can be given on the same day as laiv • children who have known or suspected immunodeficiency disease or who are receiving immunosuppressive or immunomodulatory therapies • children who are receiving aspirin or other salicylates • any female who is pregnant or considering pregnancy • children with any condition that can compromise respiratory function or handling of secretions or can increase the risk for aspiration • children taking an influenza antiviral medication (oseltamivir or zanamivir), until 48 hours after stopping the influenza antiviral therapy • children with chronic underlying medical conditions that may predispose to complications after wild-type influenza infection. as for all vaccines, influenza vaccine should be administered in a setting where there is the ability to respond to acute hypersensitivity reactions. the most common adverse events following intramuscular iiv administration are pain and tenderness at the injection site. fever can occur in 10-35% of children aged <2 years within 24 hours of vaccination, but is much less common in older children. in trials, when iiv are administered, 16-20% of those vaccinated experience local reactions in the arm, lasting for 1 or 2 days. short-term reactions (mild fever, malaise and muscle pains) have been reported in a much smaller proportion in the first few hours following vaccination. trials of the split and subunit vaccines show even fewer systemic reactions. there have been no strong temporal or causal associations of the current vaccines with more severe reactions. anaphylaxis is very rare but does occur as with all vaccines. more severe adverse events, like guillain-barré syndrome have been reported with a particular vaccine in the 1970s but they are extremely rare. with the modern influenza vaccines, the causative risk is either found to be very rare (0.8 per million doses) [51] or there is no causal link found at all [52] [53] [54] and more association is found with influenza infection than vaccination [55] . an increased risk of fever and febrile seizures was reported from australia in 2010 associated with the southern hemisphere iiv3 produced by csl biotherapeutics (now sequirus) [39] . following this, many countries do not recommend the csl iiv3 for children aged <9 years. influenza vaccination during pregnancy has been shown to protect both the mother and her baby (up to 6 months old) against influenza [47, 48, 56, 57] . influenza vaccination is safe in pregnancy and influenza vaccines have been administered to millions of pregnant women over many years and have not been shown to cause harm to pregnant women or their babies [58] . the most common adverse events associated with laiv include runny nose or nasal congestion, headache, lethargy and sore throat. laiv should not be administered to children with marked nasal congestion as this can reduce vaccine delivery. the safety of laiv is not established in people with a history of asthma, diabetes mellitus, or other high-risk medical conditions associated with an elevated risk of complications from influenza. the use of laiv in young children with chronic medical conditions is not recommended in the usa but is in some other countries. appropriate hand and respiratory hygiene (cough etiquette) has been shown to reduce influenza transmission in children in day-care or school [59] . sick children and adults should remain at home and not attend school or work until symptoms have resolved to prevent transmission of influenza to others. surveillance for emerging respiratory viruses comparative community burden and severity of seasonal and pandemic influenza: results of the flu watch cohort study global burden of respiratory infections due to seasonal influenza in young children: a systematic review and metaanalysis global role and burden of influenza in pediatric respiratory hospitalizations, 1982-2012: a systematic analysis estimating deaths due to influenza and respiratory syncytial virus incidence of medically attended influenza during pandemic and post-pandemic seasons through the influenza incidence surveillance project closure of schools during an influenza pandemic prevention and control of seasonal influenza with vaccines recommendations of the advisory committee on immunization practices-united states, 2016-17 influenza season risk factors for influenza-associated severe acute respiratory illness hospitalization in a high hiv prevalence setting-south africa severe influenzaassociated respiratory infection in high hiv prevalence setting, south africa mortality amongst patients with influenza-associated severe acute respiratory illness, south africa maternal influenza and birth outcomes: systematic review of comparative studies twenty-five years of outpatient influenza surveillance in south africa influenza seasonality in the tropics and subtropics-when to vaccinate? seasonal influenza vaccine policy, use and effectiveness in the tropics and subtropics-a systematic literature review pandemic versus epidemic influenza mortality: a pattern of changing age distribution global mortality estimates for the 2009 influenza pandemic from the glamor project: a modeling study transmission of influenza a in human beings inactivated influenza vaccines the underrecognized burden of influenza in young children clinical practice. prevention and treatment of seasonal influenza prevention of influenza in children clinical presentation of influenza in unselected children treated as outpatients clinical and epidemiologic characteristics of children hospitalized with 2009 pandemic h1n1 influenza a infection duration of cough in acute upper respiratory tract infections understanding the symptoms of the common cold and influenza a longitudinal study of respiratory viruses and bacteria in the etiology of acute otitis media with effusion respiratory viruses in laryngeal croup of young children neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factors acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year review neurological manifestations of influenza infection in children and adults: results of a national british surveillance study influenza-associated myositis in children seasonal influenza in adults and children-diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the infectious diseases society of america healthcare workers handbook on influenza. the national institute for communicable diseases (nicd) the association between oseltamivir use and adverse neuropsychiatric outcomes among tricare beneficiaries, ages 1 through 21 years diagnosed with influenza assessment of neuropsychiatric adverse events in influenza patients treated with oseltamivir: a comprehensive review neuropsychiatric adverse effects of oseltamivir in the fda adverse event reporting system committee on infectious diseases. recommendations for prevention and control of influenza in children neuraminidase inhibitors for preventing and treating influenza in healthy adults and children vaccine against influenza who position paper oil-inwater emulsion adjuvant with influenza vaccine in young children efficacy of high-dose versus standard-dose influenza vaccine in older adults efficacy and immunogenicity of influenza vaccine in hiv-infected children: a randomized, double-blind, placebo controlled trial effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds-a nationwide cohort study finland, influenza season 2015/16 effectiveness of seasonal influenza vaccine for adults and children in preventing laboratory-confirmed influenza in primary care in the united kingdom: 2015/16 end-of-season results influenza vaccination of pregnant women and protection of their infants effectiveness of maternal influenza immunization in mothers and infants maternal influenza vaccination and effect on influenza virus infection in young infants variable influenza vaccine effectiveness by subtype: a systematic review and meta-analysis of testnegative design studies the guillain-barre syndrome and the 1992-1993 and 1993-1994 influenza vaccines guillain-barre syndrome and the 1978-1979 influenza vaccine guillain-barre syndrome and influenza vaccination in the us army, 1980-1988 guillain-barre syndrome in the united states, 1979-1980 and 1980-1981. lack of an association with influenza vaccination investigation of the temporal association of guillain-barre syndrome with influenza vaccine and influenza like illness using the united kingdom general practice research database maternal influenza immunization and reduced likelihood of prematurity and small for gestational age births: a retrospective cohort study influenza vaccine given to pregnant women reduces hospitalization due to influenza in their infants safety of influenza vaccination during pregnancy effectiveness of hand hygiene interventions in reducing illness absence among children in educational settings: a systematic review and meta-analysis key: cord-268176-tb12txdf authors: garcia de avila, marla andréia; hamamoto filho, pedro tadao; jacob, francine letícia da silva; alcantara, léia regina souza; berghammer, malin; jenholt nolbris, margaretha; olaya-contreras, patricia; nilsson, stefan title: children’s anxiety and factors related to the covid-19 pandemic: an exploratory study using the children’s anxiety questionnaire and the numerical rating scale date: 2020-08-09 journal: int j environ res public health doi: 10.3390/ijerph17165757 sha: doc_id: 268176 cord_uid: tb12txdf the repercussions of the covid-19 pandemic on children’s lives deserve attention. this study aimed to assess the prevalence of anxiety among brazilian children and its associated factors during social distancing during covid-19. we used a cross-sectional design with an online survey from april to may 2020 in brazil. we included children aged 6–12 years and their guardians. the children’s anxiety questionnaire (caq; scores 4–12) and the numerical rating scale (nrs; scores 0–10) were used to measure anxiety. we enrolled 157 girls and 132 boys, with a mean age of 8.84 (±2.05) years; 88.9% of respondents were mothers. based on caq ≥ 9, the prevalence of anxiety was 19.4% (n = 56), and higher among children with parents with essential jobs and those who were social distancing without parents. in logistic regression, the following variables were associated with higher caq scores: social distancing without parents; more persons living together in home; and education level of guardians. based on nrs > 7, the prevalence of anxiety was 21.8% (n = 63); however, no associations with nrs scores were found with the investigated variables. these findings suggest the necessity of implementing public health actions targeting these parents and their children at the population level. coronaviruses are a large family of enveloped, single-stranded, zoonotic rna viruses. a novel form of the coronavirus-sars-cov-2-causes covid-19, which was first reported in china, and has caused a global pandemic [1] . the spread of covid-19 infection requires continually improving knowledge about its epidemiology [2] . in brazil, sars-cov-2 has greatly influenced children nationwide; events such as school closures have affected daily life [1] . however, groups have expressed the importance of maintaining the educational opportunities of children, despite the covid-19 int. j. environ. res. public health 2020, 17, 5757 2 of 13 pandemic [3] . it is important that children have access to peers to maintain social and cognitive development. additionally, the lack of access to such services can be particularly harmful for vulnerable children and/or families; notably, there has been an increase in physical, emotional, and sexual violence against children reported during the covid-19 pandemic [4] . the covid-19 symptoms in children are milder than in adults; children have a better prognosis, and deaths are extremely rare [5] . a systematic review reported that children with covid-19 often recovered within 1-2 weeks after disease onset. at that time, no cases of death from covid-19 had been reported in the age range of 0 to 9 years, and only one death in the age range of 10 to 19 years [2] . although most children appear to experience less severe physical illness and have much lower mortality rates than other age groups from covid-19 infection, they remain at substantial risk for negative outcomes given the widespread economic and societal disruption resulting from the pandemic [6] . the consequences of covid-19 on children are vast in terms of their health, safety, and well-being [7] . the influence of changes in the daily lives of children should not be underestimated. other family members' health and emotional states will affect children, and negative influences from the environment could greatly impact their health. the covid-19 pandemic has led to isolation and restrictions, which are significantly disrupting for children; they are not well understood, and have been shown to be both confusing and frightening [7] . studies have consistently concluded that quarantine was an important public health measure to reduce the number of people infected and the number of deaths [8] . however, the social distancing that has been imposed on children has caused massive upheaval [7] . children have received home schooling under the guidance of their parents or carers, whose attention was divided among taking care of the children, the home, and the home office. most publications about people´s anxiety levels in conjunction with covid-19 have focussed on adults; attention should also be paid to children's situations. an increase in the prevalence of depression, insomnia, post-traumatic stress disorders, and feelings of anger and frustration was observed in a population from the city of wuhan, china [9] . a population-based study in hong kong during the covid-19 pandemic showed that 14% had anxiety [10] . the majority of the respondents in a chinese study during covid-19 were women, and 28.8% reported moderate to severe anxiety [11] . children´s development has been influenced by the covid-19 pandemic; their health is influenced by their experiences, as well as that of the adults around them [12] . the world health organisation has presented recommendations for facing the psychological and mental consequences of the pandemic, which is essential for children. they must also have opportunities to express their fears and doubts in their own ways. it was therefore important to measure the experiences of children at the height of the pandemic of the century. it was necessary to listen to how children described their experiences, anxiety levels, and perspectives during the covid-19 pandemic [13] . the present study highlights children´s perspectives by using a questionnaire adapted for children. the aim of the study was to assess the prevalence of anxiety among brazilian schoolchildren and study the anxiety factors associated with social distancing during the global covid-19 pandemic. a cross-sectional study using non-probability and convenience sampling methods was conducted between 25 april and 25 may 2020 in brazil. we used an online survey to collect information (https://forms.gle/qhkt4hxqbuntz4pc6). the study sample consisted of brazilian children between 6 and 12 years of age and their guardians, all of whom were social distancing. guardians under 18 years of age were excluded from this study. the children´s anxiety questionnaire (caq, scores range from 4 to 12) and the numerical rating scale (nrs, scores range 0 to 10) were used to measure anxiety in the children. the authors of the caq, a swedish instrument, aimed to develop a questionnaire that would be easy to administer, had solid psychometric measures, and could be used to assess self-reported anxiety in young children [14, 15] . it is based on the state-trait anxiety inventory [16] . the caq contains four items with four images of facial expressions, with three response options, each representative of a different level of emotional intensity [14, 15] . the children give their responses based on the four facial expressions, one at a time, and then choose between three steps (i.e., a little (1), some (2) , and a lot (3)). the faces of happy/content and calm/relaxed are measured as 3-2-1, and the faces of tense/nervous and worried/afraid are measured as 1-2-3. the range for this instrument is 4 to 12 points, with 4 points signifying no anxiety and 12 points signifying the highest level of anxiety. recently, the caq in brazilian portuguese was validated, as demonstrated by satisfactory results among professionals and children; however, these data are unpublished. the caq has previously shown construct validity in conjunction with out-patient surgery [14, 17] . the nrs is an 11-point scale that is scored from 0 to 10. in the past few decades, the nrs has been validated for the evaluation of pain intensity in children [18] and assessing unpleasantness. however, there are no agreed upon nrs anchors for measuring unpleasantness in children [19] . in this study, anxiety was assessed using the nrs, wherein 0 was equivalent to 'calm', and 10 meant 'very anxious'. mild anxiety is expressed with scores of 1, and 2; moderate anxiety: 3, 4, 5, 6, and 7; and intense anxiety 8, 9, and 10 [20] . the nrs is easy to administer, and there is good evidence for its construct validity [19] . similar forms of self-reports have previously been validated for use in school-aged children who have undergone care in hospitals [21, 22] . an online survey using the google forms platform was distributed by three researchers through social media (twitter, facebook, instagram) and personal contacts (whatsapp) that expanded through snowballing. a brief written description of the study and its objectives was sent to guardians. we instructed the guardians and children about how to participate and guided the guardians on how to fill in their data and conduct the interview with their children. the online survey evaluated the sociodemographic profiles and current conditions regarding the social distancing and isolation of the children and their guardians. the guardians used the caq and the nrs following the survey instructions; the survey had a total of 25 questions. the quantitative variables measured for children were: gender; age; if they were on vacation; if they were home schooling; social distancing with the father, mother, both, or others; if the parents had an essential job; if they had a chronic disease or disability; how many people were in the same house; suspected or confirmed diagnosis of covid-19 in the house; for how long the children had been social distancing; and the size of their home. the quantitative variables for guardians were: relationship with the children (mother, father, and others), schooling (elementary school, high school, college, or postgraduate degree); income reduced during the pandemic (yes or no); and guardians were asked about how much they thought their children understood the pandemic (a lot, some, a little, or nothing). to test the normal distribution of the data, the shapiro-wilk test was used. comparisons between the groups were performed using the mann-whitney-u test for unpaired data that were not normally distributed. for multiple-group comparisons, the kruskal-wallis tests, followed by dunn's tests, were performed. the scores were handled as ordinal data, and thus, the spearman´s rho correlation coefficients were calculated between the caq and nrs scores. the chi-square test, as a two-tailed test (n > 30), and fisher´s exact test were employed to compare proportions in the different groups. odds ratios (or) were calculated to test the association between the outcome variables, such as the dependent variable (nrs or caq), as binary categories defined (</>): for the caq, a score higher/lower than the mean value plus a standard deviation, the cut-off value was set at the level [low < 9 or high ≥ 9]); scores of 9 and higher than 9 indicated intense anxiety. for the nrs, the cut-off value was set at the level [low ≤ 7 or high > 7]; thus, scores of 8 or higher indicated intense anxiety. a logistic regression was performed to test associations between the dependent variable (i.e., high (≥9) or low anxiety scores of the caq and (>7) nrs, respectively) and the independent variables. for all tests, the level of statistical significance was set at 5%. for the statistical analyses, we used ibm spss statistics for macbook, version 24 (ibm corp., armonk, n.y., usa). this research was approved by the research ethics committee of brazil (caae: 30547320.0.0000.0008 and opinion n • 4.128.847) and complied with resolution no. 510/2016, which establishes the guidelines and regulatory rules for research involving humans. the guardians and children agreed to participate in the research through an electronic record/register. of the 289 children and their guardians who were included in this study, 54.3% (n = 157) were girls, and 45.7% (n = 132) were boys, with a median age of 9 years (interquartile range = 4). most of them (45.7%, n = 132) were social distancing with both parents; 27% (n = 77) were with their mothers; 8% (n = 24) were with their fathers, and 19% (n = 56) were with someone else. few children had a suspected or confirmed diagnosis of covid-19 (1.7%, n = 5 and 5.9%, n = 17, respectively). over half of the children were on vacation (53%, n = 153), and 90% (n = 261) of the children were being home schooled; they did not attend physically. nearly sixty percent (58%, n = 168) of the guardians reported that their children understood the actual pandemic situation relatively well. among the guardians, 257 (88.9%) were mothers, 11 (4%) were fathers, and 20 (7%) had another type of relationship with the children. they had a mean age of 38.97 (±6.54) years. of the guardians, 46.4% (n = 134) had completed postgraduate studies, 31.1% (n = 90) had graduated from university, 16.3% (n = 47) had finished high school, and 6.2% (n = 18) had completed elementary school. on average, roughly four people (±1.38) were living at home, the house size was 212.02 m 2 (±sd 402.85), and the hours spent social distancing was 22/day (±7.71). over half (53%, n = 153) said their normal income had decreased, and 18% (n = 51) replied that the mother or father had maintained an essential job. according to the descriptive analyses, the girls scored higher on caq than the boys did (p = 0.047, median test); however, these differences were not found for the nrs (p = 0.929). children who were maintaining social distance with both their parents had lower scores on the caq than those who were isolated with a person other than their parents (p = 0.002). there were no significant differences in the scores of caq or nrs in terms of whether the child was on vacation, was being home schooled, or had an immediate connection to someone with a covid-19 diagnosis, the level of the child's comprehension, or a decrease in household income. there were no statistical differences between the prevalence of anxiety, for caq (p = 0.879), or for nrs by the age of the children (p = 0.408) ( table 1) . table 2 shows the prevalence of anxiety according to both scales by the associated variables. according to caq (caq ≥ 9), the prevalence of anxiety was 19.4% (n = 56). for girls, the prevalence was 21% (n = 33) and, for boys, 17.4% (n= 23), without statistical difference. the prevalence of anxiety according to nrs (nrs > 7) was 21.8% (n = 63), and there were no statistically significant differences in the prevalence between the girls 22.3% (n = 35) and boys 21.2% (n = 28) ( table 2 ). according to the caq scores, the prevalence of anxiety was higher among the children with parents with essential jobs, 31.4% (n = 16) vs. 16 .8% (n = 40), and when keeping social distance without parents (35.7%, n = 20). this was followed by social distancing only with the mother (20.8%, n = 16). lower scores were found among children who were staying only with their fathers or with both guardians. there were no statistically significant differences for nrs and the studied variables, but the prevalence of anxiety was highest among the children who maintained social distance with someone other than the parents (28.6%, n = 16). regarding the age of the guardians (figure 1) , there was an inverse association between the age of the caregiver and the children's scores on the caq (p = 0.002). this association did not reach statistical significance for the nrs scores (p = 0.078). furthermore, the correlation between the caq and nrs scores was weak but significant (r = 0.461; p < 0.001). the prevalence of anxiety was highest among the children who maintained social distance with someone other than the parents (28.6%, n = 16). regarding the age of the guardians (figure 1) , there was an inverse association between the age of the caregiver and the children's scores on the caq (p = 0.002). this association did not reach statistical significance for the nrs scores (p = 0.078). furthermore, the correlation between the caq and nrs scores was weak but significant (r = 0.461; p < 0.001). as shown in table 3 , children with guardians who had a higher educational level exhibited more comprehension of the pandemic than did children whose guardians received less education. among the six children with no comprehension of the situation, three were cared for by guardians with the lowest level of education. figure 2 shows the respective caq and nrs scores of the children and their perceived comprehension of the pandemic categorised as a lot, some, a little, and nothing. there was no association between the children's perceived comprehension of the situation and their scores on caq (p = 0.416) or nrs (p = 0.283). the children who understood the pandemic situation did not exhibit more anxiety than those who did not understand it at all (figure 2 ). as shown in table 3 , children with guardians who had a higher educational level exhibited more comprehension of the pandemic than did children whose guardians received less education. among the six children with no comprehension of the situation, three were cared for by guardians with the lowest level of education. we found that age distribution differed between the education level groups (p = 0.002). post hoc analysis showed that the difference was between high school and postgraduate; postgraduates were older than those who had only finished high school (p = 0.001). table 3 shows the association between caq scores and the independent variables included in the study. higher levels of anxiety (caq ≥ 9) were associated with social distancing, the number of persons at home, guardians' age, and education level of the guardians. children keeping social distance without their parents had higher levels of anxiety than children with both parents at home (p = 0.029). the greater the number of persons at home, the greater the anxiety score (p = 0.024). regarding the guardians' education level, children whose guardians had a postgraduate (p = 0.019) or university education level (p = 0.024) had lower anxiety scores on the caq than those whose guardians had only elementary school (reference category). in line with the descriptive analyses, a positive statistical significance was found for the interaction between the guardians' age and education level (p = 0.022). children whose guardians were among the youngest and with the lowest levels of education among the participants had higher caq scores than children whose guardians were older and more educated (for postgraduate b = 0.996, for university graduate b = 0.995, p < 0.05; table 4 ). we found that age distribution differed between the education level groups (p = 0.002). post hoc analysis showed that the difference was between high school and postgraduate; postgraduates were older than those who had only finished high school (p = 0.001). table 3 shows the association between caq scores and the independent variables included in the study. higher levels of anxiety (caq ≥ 9) were associated with social distancing, the number of persons at home, guardians' age, and education level of the guardians. children keeping social distance without their parents had higher levels of anxiety than children with both parents at home (p = 0.029). the greater the number of persons at home, the greater the anxiety score (p = 0.024). regarding the guardians' education level, children whose guardians had a postgraduate (p = 0.019) or university education level (p = 0.024) had lower anxiety scores on the caq than those whose guardians had only elementary school (reference category). in line with the descriptive analyses, a positive statistical significance was found for the interaction between the guardians' age and education level (p = 0.022). children whose guardians were among the youngest and with the lowest levels of education among the participants had higher caq scores than children whose guardians were older and more educated (for postgraduate b = 0.996, for university graduate b = 0.995, p < 0.05; table 4 ). table 5 shows the results of the binary logistic regression for nrs and the independent variables included in the study. no association was found between the nrs scores and the studied variables. independent of the selected cut-off value of nrs > 6, > 7, or ≥ 9, there was no association between the nrs scores and the covariates, or when using logistic regression or multinomial regression analyses. multinomial regression analysis revealed that when the dependent variable was set as a group of anxiety (mild, moderate, and intense), unlike the caq score, none of the variables was guardians for the anxiety reported with the nrs scores, except for confirmed covid-19 cases at home, which was guardians for a difference between mild and moderate anxiety (data not shown). the present study assessed children's anxiety during the covid-19 pandemic in order to assist healthcare professionals in understanding children´s reports of anxiety. comprehending children's emotions was quite challenging, because the situations they experienced may not have characteristics in common with any previous event in their lives. thus, giving them a voice was an essential strategy. in the present study, the prevalence of anxiety among children was between 19.4% (n = 56), using the caq, and 21.8% (n = 63), using the nrs. compared to previous research, this study found a high prevalence of anxiety. the worldwide prevalence of any anxiety disorder among children according to diagnostic and statistical manual (dsm) and international statistical classification of diseases and related health problems (icd) was shown to be 6.5% [23] . in brazilian preadolescents (aged 11-12 years), the prevalence of anxiety was 6.2% according to the icd-10 classification [24] . in the united states, a study that analysed data from the 2016 national survey of children's health (nsch), reported that the prevalence of anxiety was 7.1% among children aged 3-17 years (6.6% in children aged 6-11 years and 10.5% in children aged 12-17) [25] . however, the criteria for dsm and icd were not used in our study. previous research suggested an association between seropositivity for coronaviruses and a history of mood disorders [26] . it is also thought that the severity of a stress reaction is related to the degree of exposure to a disaster. for example, earthquakes that damaged houses and family members were associated with more severe fear, anxiety, depression, or physical symptoms. young schoolchildren and girls were especially vulnerable [27] . another study demonstrated that these anxiety symptoms were more often associated with girls [28] . in our study, greater levels of anxiety were also exhibited by girls than boys. our data collection was based on children's self-reports of anxiety. it is important to use validated instruments that can gauge what they are intended to measure. the caq is a newly developed instrument that needs further validation. for example, the appropriate cut-off score has not been confirmed. however, the caq has been used in a couple of studies [14, 17] . as for the children's characterisation, the mean age group was approximately 8.8 years, with a slight increase in girls. among their guardians, most had university and postgraduate levels of education. according to the instituto brasileiro de geografia e estatística (ibge), the level of education of the brazilian population over 25 years old was distributed as follows: 6.4% had no schooling, 40.2% had incomplete or complete elementary school, 31.9% had incomplete or complete high school, 4.0% were incomplete graduate, and 17.4% were complete graduate [29] . the possibility of selection bias should be considered because of the exclusion of digital illiterates who were not involved in this study. this has been reported previously [30] . however, the use of digital environments for data collection was the most suitable for the current pandemic, and internet research was safer and more convenient for participants. the present study shows that guardians´education levels affect their children's perceived comprehension of the situation but not their anxiety levels. however, the guardians´age in combination with their education level directly affect their children's anxiety level. guardians with higher education could probably offer more support to their children in several ways. they could invite their children to speak about covid-19, could listen with the aim of understanding what their children knew, and explain misunderstandings. these parents may be providing further information about the prevention of virus contagion. they could be creating a safe environment where emotions can be freely expressed so that they can pay attention to their children's anxiety levels and filling evenings/after-dinner time with pleasant activities [31] . the lowest education level in parents corresponds to the highest prevalence of obese school children (aged 8 to 9 years) [32] , and an association has been found between parental education and parent-reported child mental health (for children aged 4 to 11 years old) [33] . children have the right to understand what is happening around them as it can affect them. covid-19 is a global threat, which children can hear about even as it affects them and their loved ones. the rights of children [34] continue to matter even during covid-19, including the articles of the child convention in terms of development, democratic rights education, protection, right to one's own family, and right to support. children's perceived comprehension can be a positive aspect during the pandemic. according to unicef, children might find it difficult to understand what they are seeing online or on tv, and they are vulnerable to anxiety, stress, and sadness. the guideline 'how to talk to your child about covid-19 recommends that parents ask their children open questions and that they listen to the answers. other recommendations include that parents be honest and use age-appropriate language, watch their children's reactions, show sensitivity to their anxiety levels, and close conversations with care [35] . play is an essential part of children's physical and social development; however, during isolation and social distancing, the world is relying on technology to learn, live, and stay connected [36] . the most important thing for children is to have adults around them to meet their needs and to help them feel secure, calm, and supported in their own sense of control [37] . children feel better when they can communicate their feelings in a supportive environment. adults need to be authentic about the uncertainty and psychological challenges of the pandemic, without overwhelming children with their own fears. this honesty should encompass a coherent explanation for what the children are observing and grant permission for children to safely talk about their feelings [38] . the majority of the guardians in this study were older (mean age: 38.97 years); however, we found that the younger the guardians were, the higher the anxiety levels exhibited by the children. it may be a question of the resilience of the guardians; perhaps, it was a question of the stability of their professions and finances when exhibiting worries to the child. another factor to consider was that young guardians in this socioeconomic group had fewer children; it was possible that these children did not have other children to play together with. neither possibility was investigated in this study. these findings were in line with previous studies of how the age of parents, especially the mother, affect the mental health of children, among other health conditions and outcomes. remmerswaal and muris [39] found during the previous swine flu that children aged 7-12 years had a significant relationship between their level of fear and their parents' level of fear. in another study, children whose mothers had a high level of education, compared to children with uneducated mothers, showed a reduced risk of suffering from emotional difficulties [40] . similar results have also been reported during the covid-19 pandemic; a correlation was found between mothers' state of anxiety scores and the trait anxiety scores of their children (ages 9 to 12 years old) [41] . children who were keeping social distance with both their mother and father had lower caq scores than those who were isolated with a person other than their parents. this finding confirmed the important role of parents in children's lives, perhaps especially in this pandemic. a study conducted in china reported the presence of psychological difficulties in children during the covid-19 pandemic, with fear, clinging, inattention, and irritability as the most severe symptoms for younger children [42] . parents and other family members are encouraged to increase their communication with children to address their fears and concerns, play games, engage in physical activity, and use music therapy in the form of singing to reduce the worry, fear, and stress that children may feel [43] . another interesting result in the present study showed the opposite: parents who kept their jobs had children who experienced more anxiety. this result highlights children´s insecurity when their parents are not with them during the crisis. the serious implications of this finding and experiences from the covid-19 pandemic highlight the need for effective strategies to strengthen families and help them protect the children [44] . parents' presence is important for children, and children need to feel safe within their families. if children lack emotion-focused conversations with their parents, it can lead to anxiety about the emotional state of their parents [32] . the significance of the correlations between children´s anxiety levels and other factors was only shown in caq scores, not in the nrs scores. the caq considers different feelings/domains in measuring a child's anxiety than the nrs. the focus of the caq on anxiety-compared to the nrs, which only has one item on anxiety-may explain this difference; however, further studies are needed to investigate the causes of this difference. however, the prevalence of anxiety found in this group was similar between the caq and nrs. minimising children's anxiety may depend on addressing children's restriction from engaging in their regular activities. other aspects of the pandemic will appear with time. intensive research to find a vaccination will provide new research questions among children. the experience of benefits and risks with vaccination, and accessibility to vaccination will prompt repeating this study on children´s reported anxiety. this study had several limitations. first, the data collection occurred online; this excluded participants without the computer skills necessary to access the survey, and probably there was a selection bias arising from the social media interpersonal connections through which the survey was circulated. second, we guided participants on how to use the caq and nrs with their children, but we are unsure if they filled in the instruments according to our recommendations. third, we did not investigate how many children were in the same house; we did not exclude guardians who participated twice, since they had two children. finally, the questionnaire did not capture how well the children actually comprehended the situation, but the adults' opinion on this. there was no objective measurement of the children's understanding; the adult respondents were asked their subjective opinion of the extent to which the children understood the pandemic, taking age into consideration. therefore, caution should be taken in generalising the results to the brazilian population. the prevalence of anxiety among the children during the covid-19 pandemic in this group was 19.4% (n = 56), according to the caq, and 21.8% (n = 63), according to the nrs. these results are higher than the prevalence reported for children under normal conditions (6.5%). higher levels of anxiety were associated with social distancing without parents, a higher number of persons living at home, and a low education level reported for the parent or guardian. the highest levels of anxiety were found among children with both young and less educated guardians. these findings suggest the necessity of implementing public health actions targeting these parents and their children at the population level. severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review supporting the continuation of teaching and learning during the covid-19 pandemic annotated resources for online learning challenges and burden of the coronavirus 2019 (covid-19) pandemic for child and adolescent mental health: a narrative review to highlight clinical and research needs in the acute phase and the long return to normality systematic review of covid-19 in children shows milder cases and a better prognosis than adults children are at risk from covid-19 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among children after the wenchuan earthquake in china factors associated with people's behavior in social isolation during the covid-19 pandemic children and the covid-19 transition: psychological reflections and suggestions on adapting to the emergency relationship between 8/9-yr-old school children bmi, guardians' bmi and educational level: a cross sectional survey how to talk to your child about coronavirus disease 2019 (covid-19) the covid-19 pandemic: technology use to support the wellbeing of children talking to children about the coronavirus|breeze-children's rights in society protecting the psychological health of children through effective communication about covid-19 children's fear reactions to the 2009 swine flu pandemic: the role of threat information as provided by guardians influence maternal background has on children's mental health effect of the covid-19 pandemic on anxiety among children with cystic fibrosis and their mothers behavioral and emotional disorders in children during the covid-19 epidemic mitigate the effects of home confinement on children during the covid-19 outbreak parenting in a time of covid-19 the authors declare no conflict of interest. key: cord-285965-mar8zt2t authors: su, liang; ma, xiang; yu, huafeng; zhang, zhaohua; bian, pengfei; han, yuling; sun, jing; liu, yanqin; yang, chun; geng, jin; zhang, zhongfa; gai, zhongtao title: the different clinical characteristics of corona virus disease cases between children and their families in china – the character of children with covid-19 date: 2020-03-25 journal: emerg microbes infect doi: 10.1080/22221751.2020.1744483 sha: doc_id: 285965 cord_uid: mar8zt2t this study aims to analyze the different clinical characteristics between children and their families infected with severe acute respiratory syndrome coronavirus 2. clinical data from nine children and their 14 families were collected, including general status, clinical, laboratory test, and imaging characteristics. all the children were detected positive result after their families onset. three children had fever (22.2%) or cough (11.2%) symptoms and six (66.7%) children had no symptom. among the 14 adult patients, the major symptoms included fever (57.1%), cough (35.7%), chest tightness/pain (21.4%), fatigue (21.4%) and sore throat (7.1%). nearly 70% of the patients had normal (71.4%) or decreased (28.6%) white blood cell counts, and 50% (7/14) had lymphocytopenia. there were 10 adults (71.4%) showed abnormal imaging. the main manifestations were pulmonary consolidation (70%), nodular shadow (50%), and ground glass opacity (50%). five discharged children were admitted again because their stool showed positive result in sars-cov-2 pcr. covid-19 in children is mainly caused by family transmission, and their symptoms are mild and prognosis is better than adult. however, their pcr result in stool showed longer time than their families. because of the mild or asymptomatic clinical process, it is difficult to recognize early for pediatrician and public health staff. in late 2019, an outbreak of pneumonia with unknown etiology was found in wuhan, hubei province, china. then the pathogen was isolated soon and named the 2019 novel coronavirus (2019-ncov) on 12 january 2020 [1] and on 11 february, the international committee on taxonomy of viruses announced that its official classification is severe acute respiratory syndrome coronavirus 2 (sars-cov-2). the virus spread very fast in wuhan. even more unfortunate, as the chinese spring festival is approaching, aggregation of large numbers of people flow caused it to spread quickly across the country and even spread to more than 100 countries [2] . the current case reports are mainly concentrated in hubei province and adults, but cases of children outside hubei province are rare. meanwhile, the clinical characteristics of cases in hubei province and other provinces were significantly different. here, we report the clinical manifestations, laboratory test results, imaging characteristics, and treatment regimen of nine sars-cov-2 infected children and their families in jinan, shandong province to increase awareness of this disease, especially in children. a retrospective review was conducted of the clinical, lab tests, and radiologic findings for nine children and their families admitted to the jinan infectious diseases hospital identified to be nucleic acid-positive for sars-cov-2 from 24 january 2020 to 24 february 2020. sample collection and pathogen identification after admission to the hospital, respiratory tract samples including sputum and nasopharyngeal swabs were collected from the patients, which were tested for influenza, avian influenza, respiratory syncytial virus, adenovirus, parainfluenza virus, mycoplasma pneumoniae and chlamydia, along with routine bacterial, fungal, and pathogenic microorganism tests. real-time pcr used the sars-cov-2 (orf1ab/n) nucleic acid detection kit (bio-germ, shanghai, china) and performed refer to previous literature [3] . all the patients were recorded with basic information and epidemiological histories [4] including (1) history of travel or residence in wuhan and surrounding areas or other reported cases within 14 days of onset; (2) history of contact with new coronavirus infection (nucleic acid-positive) 14 days before onset; (3) history of contact with patients with fever or respiratory symptoms from wuhan and surrounding areas, or from communities with case reports within 14 days before onset; (4) cluster onset, along with disease condition changes. laboratory test results were compiled, including standard blood counts, blood biochemistry, c-reactive protein (crp), procalcitonin (pct), erythrocyte sedimentation rate(esr), interleukin-6 (il-6) and myocardial enzyme spectrum. additional data collected included medical imaging, treatment regimens, and prognosis (any severe complications, including death), and recover or discharge date (table 1) . this study was conducted in accordance with the declaration of helsinki. informed consent was waived because of the retrospective nature of the study and the analysis used anonymous clinical data. continuous data are expressed as medians and ranges, and categorical data are presented as counts and percentages. there were three boys, six girls and their 14 families admitted to jinan infectious disease hospital of shandong university were investigated in this study. the youngest of the nine children was a pair of elevenmonth-old twins and the oldest is nine years and 9 months old (mean age was 4.5 years, median age 3.5 years, table 1 ). there were 16 families were infected by sars-cov-2, and 14 adults were enrolled in this study (two patients hospitalized in another hospital). the 14 patients consisted of 8 males and 6 females with a mean age of 42.9 years (median age, 37 years [range, 30-72 years]). all nine pediatric patients came from eight families. as shown in table 1 , six children had no information from the epidemiological data, 7/14(50%) of the adults were infected through household contact, 5 (35.8%) was found to be infected after returning from wuhan or hubei in late january 2019 and 2 (14.2%) patients couldn't find the exact source of infection. as shown in table 2 , 8/9 (88.9%) children had normal or decreased white blood cell counts, consistent with the main characteristic of viral infection. six children (66.7%) showed increased ck-mb. alt, ast and the other index of liver and kidney were all normal. all inflammation indicators, including crp, pct, esr and il-6 were all within the normal range. two children (22.2%) showed bronchitis and one (11.1%) showed bronchial pneumonia. one (11.1%) boy (the older of the twins) showed pulmonary consolidation and ground glass opacity on the first day ( figure 1 (a)) admitted in the hospital, and disappeared after five days (figure 1(b) ). five other (55.6%) children showed no abnormal chest radiograph. all the adult patients had normal (10/14, 71.4%) or decreased (4/14, 28.6%) white blood cell counts and 10 (71.4%) have lymphopenia. there were 4 (28.6%) patients had increased crp, pct, serum amyloid a (saa), d-dimer and il-6, meanwhile, their ct-scan showed larger lung consolidation. compared to children, there were only two (14.3%) patients showed increased ck-mb. ferritin in the adult patients were higher than the children but most of them were normal (11/14, 78.6%). the imaging of adult chest was mix and the most common characters of imaging were pulmonary consolidation (50%), nodular shadow (42.9%), and ground glass opacity (ggo, 35.7%) (figure 2) . four (28.6%) adults showed normal chest imaging. at present, there are no drugs available that can target sars-cov-2. therefore, treatment was focused on symptomatic and respiratory support. all the children inhaled interferon and one of the twins was prescribed ribavirin (10-15 mg/kg.d) in addition. ten (71.4%) adults with pneumonia were treated lopinaviritonavir (200/50 mg, 2 tablets, bid), interferon and chinese medicine. the patients with higher infection index (such as crp, pct, esr, saa, il-6) were prescript antibiotics for 5-7 days in addition. all the nine children and 14 adult patients recovered in 2-3 weeks and were discharged after two negative nucleic acid tests. unfortunately, our follow up found that there were five discharged children were admitted again before we submit this article because their stool showed positive result in sars-cov-2 pcr. meanwhile, all their families were negative in all the specimen. coronaviruses are a large family of viruses that are known to cause illness ranging from the common cold to more severe diseases. aa an enveloped rna virus, cov is ubiquitous in humans, other mammals, and birds, which can cause respiratory, digestive, liver and nervous system disorders [5, 6] . to date, six covs have been known to cause human infection [7] . among them, two zoonotic viruses, sars-cov and mers-cov, were responsible for serious outbreaks: in china in 2002-2003 [8, 9] of particular concern, our observations found that all the children were diagnosed after their families, which indicated that they were infected by the household contact. however, after an epidemiological investigation, we found that six adults (42.9%) had a definite or suspicious contact history and six families (42.9%) contacted them were infected, while the other two patients (14.3%) denied any epidemiological history. among them, the father of case 9 did not contact anyone who came back from wuhan or hubei, but also denied contact with any person with respiratory symptoms. at the same time, through official investigations, they did not find that someone was diagnosed with sars-cov-2 infection on the vehicle he was travelling on, prompting the virus to spread. in addition, from the official information, more and more patients can't find the clue of infection and more and more cluster outbreak showed that no contact, no close communication and even never go out the door. so, we think that these phenomena maybe suggest that: (1) the virus spreads very strongly and the transmission of the virus may not be limited to contact, droplets and airborne transmission, and aerosol transmission may also exist, which was similar to sars [11] . (2) the virus may be carried asymptomatically after infecting the human body but can infect other people. in china, the sars outbreak of 2003 is still impressive, because the 2002-2003 sars outbreak infected 8422 individuals leading to 916 deaths in eight affected areas [12] . during the sars outbreak, there were less children patients and the symptoms are significantly milder in children than in adults [13] [14] [15] [16] . similarly, the official data to date suggest that children infected with the sars-cov-2 are relatively rare too [17] , and their overall symptoms are significantly mild. the main reasons for this phenomenon may be: (1) the range of activities for children is relatively small, they are mainly infected by their adult families. and, as an rna virus, the sars-cov-2 virus maybe also is prone to mistakes in replication, mutating, and surviving without recognition by the immune system, but can also cause a decline in virulence. so, children are infected with second or third generation or even fourth generation virus and they get milder symptoms; (2) it may be because of differences in the immune responses of children compared to adults. one hypothesis is that the innate immune response, that is the early response that is aimed broadly at groups of pathogens, tends to be more active in children. the innate immune system is the first line of defense against pathogens. cells in that system respond immediately to foreign invaders. the adaptive immune system, by contrast, learns to recognize specific pathogens, but takes longer to join the battle. if the innate immune response is stronger in children exposed to sars-cov-2, they may fight off infection more readily than adults, suffering only mild symptoms. other coronaviruses, including sars and mers, also show this pattern [18] . (3) the number or function of ace2 receptors in children is not as good as in adults. recently, one studies had investigated the role of the ace2 receptor and found that the sars-cov-2 uses the sars-coronavirus receptor ace2 and the cellular protease tmprss2 for entry into target cells [19] . as we know, the distribution of ace2 receptors in different organs and populations is different. therefore, it may be that different receptor levels or functions in children and adults lead to different severity of illness. (4) other reasons: such as children have fewer basic diseases, children smoke less, and children have strong self-healing capabilities and so on. ck-mb is an indicator of myocardial injury. in the present study, we found six children and two adults had high ck-mb, which means that sars-cov-2 can cause heart injury. it is reported that the main mechanisms of sars-cov-2-induced myocardial injury may be the direct injury of virus, the inflammatory storm and the distribution of ace2 receptor [20] . as human lifestyles change, more and more viruses are spreading across species. current research confirms that sars-cov-2 are transmitted from animals to humans. like other viruses, the relationship between sars-covs and humans has the following possibilities: (1) the virus disappears for some unknown reasons, such as sars-cov. (2) viruses coexist with humans and have seasonal onsets, such as flu influenza viruses. the first is the best outcome of the current situation, but the second possibility is very large. if, as we analyzed above, many people, especially children with mild or no clinical symptoms carry the virus but do not develop the disease, however, the virus spread very strongly, it may lead to the silent spread of the disease and leading to major losses. therefore, the chinese government will face greater risks after school starts and work resumes. and, clinicians, especially pediatricians, need to be vigilant to prevent widespread spread of the disease. children who have infected family members should be monitored or evaluated and family clustering should be reported to ensure a timely diagnosis. in addition, just before we submit, we found that five of six discharged children returned to the hospital because of positive pcr in their stool, however, their families were all negative. one girl (case 3) didn't return to the hospital but isolated in home because she had mild mental symptoms after discharge. although positive results cannot confirm there were live virus in the stool or not. however, for insurance of public health, they were admitted to the hospital again to get clinical observation. interestingly, their onset was later than their families, but the period of positive pcr was longer than adults. we should pay more attention to this phenomenon and study the possible mechanism. several important limitations of this study should be noted. first, the size was small. second, the retrospective study included only of children who were hospitalized in one hospital. but as one of the rare reports in children out hubei province, it's helpful to improve the ability to recognize patients with mild illness. further studies with large multi-center samples are needed. in conclusion, by analyzing 23 confirmed cases of covid-2019 in jinan, shandong province, this study's findings indicate that new control measures should include rapid medical assessment and removal of the case from the home, as well as increased awareness of the importance of protective measures after symptom onset. public health measures such as home isolation should be aimed at minimizing such risk factors when addressing household transmission of serious infections spread through droplet transmission. geneva: world health organization who. coronavirus disease (covid-2019) situation reports clinical characteristics of novel coronavirus cases in tertiary hospitals in hubei province national health commission of people's republic of china e24e2faf65953b4ecd0df4.pdf?ich_args2=464-11172813 036679_88eae94af1a195e2d387e01ae83b27b9_10001 002_9c896c2fdec2f9d99f38518939a83798_c8745eab2a 416ddd81cb9150f1f76daf coronavirus pathogenesis fatal swine acute diarrhoea syndrome caused by an hku2-related coronavirus of bat origin epidemiology, genetic recombination, and pathogenesis of coronaviruses infectious diseases. battling sars on the frontlines epidemiology and cause of severe acute respiratory syndrome (sars) in people's republic of china isolation of a novel coronavirus from a man with pneumonia in saudi arabia clinical features and short-term outcomes of 144 patients with sars in the greater toronto area summary of probable sars cases with onset of illness from 1 severe acute respiratory syndrome in children: experience in a regional hospital in hong kong clinical presentations and outcome of severe acute respiratory syndrome in children new and emerging infectious diseases the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china the novel coronavirus 2019 (2019-ncov) uses the sarscoronavirus receptor ace2 and the cellular protease tmprss2 for entry into target cells heart injury signs are associated with higher and earlier mortality in coronavirus disease 2019 (covid-19) we thank all patients involved in the study. dr zhang and gai had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. no potential conflict of interest was reported by the author(s). this study was funded by the jinan science and technology bureau [grant number 201907032]. the funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. xiang ma http://orcid.org/0000-0001-6139-4355 key: cord-018585-hrl5ywth authors: sens, mary ann; koponen, mark a.; meyers, sarah title: other pediatric accidental deaths date: 2014-02-10 journal: forensic pathology of infancy and childhood doi: 10.1007/978-1-61779-403-2_30 sha: doc_id: 18585 cord_uid: hrl5ywth injury, both intentional and accidental, is the most common cause of death in children throughout the world. many injury patterns that are seen in children are similar to those in adult populations; however, others differ, reflecting the age, stature, and development of children. this chapter focuses on differences in injury patterns of children across the spectrum of childhood development and growth, including injuries and fatalities that primarily occur in infancy and early childhood. risk factors for injury and death are identified within the context of childhood development. topics covered include deaths associated with motorized and nonmotorized vehicles including pedestrian, occupant, and operator fatalities; farming and ranching deaths; drowning, boating, and diving deaths; fires and burns, including electrical deaths; animal-related deaths; falls; and airway-associated deaths. there are significant disparities in childhood injury and death among racial, ethnic, geographic, and socioeconomic groups. a brief consideration of these differences is provided to assist in forensic case examination. accidental injuries cause a high proportion of deaths in children. in some age groups, injury is the leading cause of childhood death. injuries and death differ across the spectrum of childhood development and growth (agran et al. 2001 (agran et al. , 2003 . an understanding of these differences is critical to the performance of a forensic investigation and autopsy in children and adolescents; conversely, well-performed forensic investigations and autopsies will identify risk factors and opportunities to reduce childhood morbidity and mortality from injuries. pediatric vehicle-related injuries and deaths are commonly seen in forensic pathology. infants and children may be occupants in motor vehicles or may be pedestrians struck by motor vehicles. children may be operators of recreational vehicles, including bicycles, and in adolescence, drivers of motorized vehicles. worldwide, over 260,000 children die annually in road-related crashes, and children accounted for 21 % of all road fatalities (world health organization 2012b). childhood deaths from vehicle-related events are highest in africa and are consistently increased in low-and middle-income countries as compared to higher-income countries throughout the world (world health organization 2004) . each year in the united states (usa), about 1,400 children under the age of 14 years are fatally injured while passengers in motor vehicles, and another 200,000 sustain injuries, many of which significantly impair the child's quality of life (department of transportation (us), national highway traffic safety administration (nhtsa) 2009). the centers for disease control and prevention (cdc) in the usa estimates that restraint systems for children (positioning, age, and weight-appropriate car or booster seats, lap and shoulder harnesses, etc.) prevent 400-500 fatalities each year (centers for disease control and prevention 2012e). these same initiatives also reduce childhood fatalities in other regions of the world. however, restraint systems may also cause injury and death, particularly when improperly used for the age, size, and development of the child, or when a child is seated in the front seat of a vehicle. the american academy of pediatrics and the cdc have each produced guidelines and best practices for child passenger safety (centers for disease control and prevention 2012e; american academy of pediatrics committee on injury, violence and poison prevention 2011). children under the age of 13 years should always ride in the rear seats of vehicles. as a general guideline, rear-facing car seats should be used until the age of 2 years. after 2 years of age, forward-facing child seats should be used until the child is over 4 years of age or 40 lb (18 kg). belt-positioning booster seats should be used after that point until adult lap-shoulder seat belts fit appropriately at upper thighs and chest when a child is over 8 years of age and 4 0 9 00 (1.4 m) tall. disabled children have a similar incidence and distribution of injuries related to safety restraint use as compared to children without disabilities (huang et al. 2009 ). a review of forensic findings from passenger airbag injuries demonstrates that face, upper extremity, and chest injuries are more common in children than adults, and isolated head injuries are more common in infants as compared to older children (sato et al. 2002) . in the majority of airbag injuries, a child was unrestrained or improperly restrained in the front seat, and all injured infants were in the front seat in rear-facing child restraint seats ( fig. 27.1a, b) . the smaller stature of children and infants and the position of the head closer to the upward deploying airbag may account for the mechanism of these injuries. the relatively flat and horizontal character of the atlanto-occipital (ao) articulation in children also places them at greater risk of ao dislocation or separation (saveika and thorogood 2006) . other large studies have confirmed passenger airbag injuries when children under 14 years of age occupy the front passenger seat (newgard and lewis 2005) . head injuries occur in children restrained with adult seat belts (fig. 27.2a, b ). an adult-designed shoulder harness may cross the child's face and/or neck. children may slip the belt under an arm or behind the back, compromising the restraint of the upper torso making these areas susceptible to injury in a collision with rapid deceleration. in a crash, the unrestrained forward motion of the child's upper body may cause the head to collide with knees or parts of the vehicle. small children may also "submarine" completely out of an adult restraint system on impact, become airborne, collide with the interior of the vehicle and/or other occupants, or may be ejected from the vehicle (tibbs et al. 1998 ). children are more vulnerable to blunt abdominal injury from vehicular seat-belt restraints as compared to adults, particularly when child booster seats are not used or the child is inappropriately restrained by the lap-shoulder harness system designed for adults (lapner et al. 2001) . current recommendations call for use of special child restraint systems until the child is over 4 0 9 00 (1.4 m) tall, and the lap restraint can be positioned on the upper thighs (not the abdomen) and the shoulder harness crosses the chest while not crossing directly over the neck (american academy of pediatrics committee on injury, violence and poison prevention 2011). the immature pelvis of a child under the 4 0 9 00 (1.4 m) height requirement cannot be appropriately restrained with the lap-shoulder harness until the child is tall enough to position the harness in the correct areas (across the thighs and not the abdomen). abdominal-wall contusions are infrequent in both optimally and suboptimally seat belt-restrained children, but when abdominal contusions are present, they often herald intra-abdominal injury (lutz et al. 2004) . intestinal injury, perforation, and shearing of the fixed ligaments and mesenteric structures are the most common abdominal manifestations of pediatric seat belt-related injuries (davies 2004) . because the small anterior pelvis of a child is not appropriately stabilized by the lap restraint system designed for adults, deceleration allows the seat belt to override the child's pelvis, producing hyperflexion of the child over the lap belt. this forces the abdominal organs against the vertebral column and momentarily increases the intraluminal pressure of the hollow organs, resulting in sudden compression. in addition to the abdominal injuries, the deceleration-induced compression and hyperflexion of the abdomen may also cause lumbar spine and sacral injuries (hart et al. 2004; papavasiliou et al. 2007) . intestinal compromise may be immediate or may occur days to weeks after the injury (hardacre et al. 1990; lynch et al. 1996) . pedestrian deaths in children demonstrate age differences in the types and patterns of injury. in children under the age of 4 years, deaths from "backover" accidents in driveways peak in incidence, likely due to the small stature of children, their tendency to "hide" or play behind parked vehicles, and their lack of awareness of the dangers of moving vehicles. crush injuries of young children, usually occurring from low-velocity impacts resulting from vehicles backing out of home driveways, are often fatal due to blunt-force injuries of the head (including closed-head injuries), skeleton, and torso (partrick et al. 1998) . the most common vehicles involved in these accidents are sport utility vehicles (suv), trucks, and minivans, as opposed to passenger cars (sedans, compact cars, etc.), perhaps due to the increased frequency of larger vehicle ownership by families with small children and the increased "blind spot" of vehicles with higher ground clearance behind the vehicle. in contrast to most other vehicular head injuries, these "backover" injuries are generally static; that is, they do not have significant rotational and accelerationdeceleration components. pedestrian injuries of older children tend to be on roadways rather than home driveways. this reflects cognitive awareness of the age groups: younger children are more at risk of mid-road impacts, associated with impulsive behaviors, such as darting into traffic in areas other than crosswalks; older children and adolescents are more likely to be involved in pedestrian accidents at crosswalks and intersections. as compared to head injuries sustained in "backover" collisions, head injuries in pedestrian roadway accidents in older children and adolescents tend to be complicated by rotational and acceleration-deceleration components as opposed to isolated static forces. the site and character of pediatric pedestrian injuries also reflects the child's age and development (chakravarthy et al. 2007 ). the point of vehicular impact (bumper) in a small child is at the head or chest level, both sites that are above the child's center of gravity. because of this injury location, the initial impact usually results in a second impact, with the initial impact projecting the child away from the vehicle and against another fixed object, usually the ground. consequently, the child may be run over by a subsequent vehicle. in contrast, the impact point in older children is below the child's center of gravity, resulting in impact patterns similar to that of adults. in older children, the impact point is at the legs with the body projected over or onto the hood of the car. rotational motion is seen in these impacts with the legs rotating over the head on impact and with increasing speed, and the entire body may somersault over the vehicle following hood/windshield impact. the injury patterns seen in children reflect these different impact patterns, with head, neck, and chest injuries more common in pediatric pedestrian injury populations than in the adult population (chakravarthy et al. 2007 ). pedestrian accidental deaths are more common in males and in children from minority groups, particularly in lower socioeconomic areas (american academy of pediatrics committee injury, violence, and poison prevention 2009). this may relate to socioeconomic considerations including denser traffic patterns, increased vehicular speed, on-street parking, fewer guard-monitored crosswalks near schools or playgrounds, poor sidewalk maintenance, increased need for pedestrian transportation within lower socioeconomic communities, and reduced safety awareness (hotz et al. 2009 ). gender differences, as well as the potential influence on parental supervision, have been examined in the context of improving pedestrian safety (barton and schwebel 2007 ). geographic information system (gis) studies have assisted in targeting high-risk areas and led to a reduction in both injuries and fatalities (weiner and tepas 2009; statter et al. 2011 ). children may be drivers/operators of a variety of nonmotorized vehicles (wagons, bicycles, gravity go-carts) or "off-road" non licensed motorized vehicles (golf carts, all-terrain vehicles, snowmobiles, motorized go-carts). accidents from these vehicles cause a disproportionate incidence of injury in children when compared to adult populations (siman-tov et al. 2012; lord et al. 2010; hamming and henry 2009; curran and o'leary 2008; kelleher et al. 2005; decou et al. 2003; rice et al. 2000) . children operating bicycles may be injured from falls, collisions with objects, or collisions with other vehicles, including motorized vehicles. head injuries, including traumatic brain injury, are the most common cause of fatalities involving bicycles; however, blunt-traumatic injury to abdominal organs, abdominal-wall injury, and genital injuries may occur, usually from impact with handlebars or bicycle frame (de jong et al. 2011; klin et al. 2011; rowell and chin 2011; widni et al. 2011; nellensteijn et al. 2009 ). helmet use reduces the occurrence and severity of head injuries in bicycles and other motorized and nonmotorized vehicle accidents. (barnes et al. 2012; juang et al. 2010; pardi et al. 2007 ). some trauma centers report an increase in severe thoracic and abdominal injuries from bicycle accidents in children as helmet use increases, reducing the incidence of severe head injuries. (klin et al. 2009) . a 1995 review of 2,333 bicycle-related injuries in the national pediatric trauma registry (usa) further identified children with mental disorders as a high-risk group for bicycle injury and suggested targeted prevention programs (li et al. 1995) . training and licensing prior to the operation of off-road and all-terrain vehicles is not as regulated, or as common, as licensed road vehicles (upperman et al. 2003) . the vehicles are often operated off-road and on irregular terrains, which contribute to vehicle instability and subsequent vehicle rollovers (finn and macdonald 2010) . crush injuries and asphyxia may result from rollovers of heavy off-road vehicles onto individuals. blunt trauma, fractures, and amputations may occur from impacts with trees, fences, or other obstacles. "clothesline" injuries, including deep lacerations or cervical fracture, may occur to the face and neck when vehicles pass under horizontally strung fence lines. in some instances, multiple children are involved in an accident when an off-road vehicle is being driven with children riding on sleds or skateboards tied behind the vehicle (similar to waterskiing). if the vehicle makes a sudden turn, the increased rotational velocity may throw the child who is on the skateboard/sled away from the vehicle, resulting in blunt-force injuries due to the primary impact and/or a secondary impact with a subsequent structure (tree, vehicle, etc.). the majority of these accidents occur at lower velocities than traditional motor vehicle accidents, although some motorized off-road vehicles can reach speeds of 30 mph (50 km/h) or more, increasing the likelihood of fatal injuries and approaching patterns seen in traditional motor vehicle collisions. adolescent drivers of licensed motor vehicles have higher accident and death rates as compared to adults. injury patterns are similar, since adult size and stature are generally reached by the age of legal vehicular licensing. many provinces, states, and countries have limited the adolescent (14-18 years of age) motor vehicle licensing in several manners, including increasing the minimum driving age, mandating driving courses, restricting hours of driving, limiting the number of adolescents in a vehicle, or requiring a licensed adult driver in the car (russell et al. 2011 ). these and other regulations reflect efforts to reduce accidents and fatalities among adolescents until driving skills become more accomplished. some jurisdictions may also limit or have additional requirements before licensing adolescents to operate motorcycles or may restrict operators less than 18 years of age to a smallersized motorcycle. on private property and some indian reservations, state or provincial driving laws may not be applicable or enforceable, and children may drive motorized vehicles at a younger age. there are some unusual vehicle injury mechanisms that forensic pathologists need to consider in pediatric death investigations. infants are more susceptible to carbon monoxide toxicity due to the greater affinity of fetal hemoglobin. individuals with hemoglobinopathies, such as sickle-cell anemia or thalassemia, may also have increased susceptibility to carbon monoxide toxicity (blumenthal 2001) . rarely, defective motor vehicle exhaust systems may produce high levels of carbon monoxide within the interiors of moving or idling vehicles. "open-air" carbon monoxide poisoning is a well-known hazard around combustion engine exhaust, even from vehicles in outdoor spaces. asphyxia and positional asphyxia may occur with vehicle rollovers, entrapment within vehicle restraint systems, or in automatic window or door closure systems. findings at autopsy are similar to other asphyxia deaths, with petechial hemorrhages often seen in eyes and intrathoracic cavity and hemorrhage within sinuses and sphenoid processes. cyanosis, often intense, is present above the restraint area. often the lividity patterns reflect the entrapment, clothing, and/or vehicular restraints ( fig. 27 .3a-e). delayed sequelae of motor vehicle injuries may cause death days or weeks after the motor vehicle accident, following a period of apparent recovery in the intervening time. in these instances, investigative skill is required to correctly ascertain the initiating cause of injury. chest impacts may produce cardiac contusions, including injury to ventricular free walls, papillary muscles, or the ventricular septum. these injured areas may rupture acutely, causing death ( fig. 27.4) . alternatively, the contusion may result in an aneurysm, infarction, or ventricular rupture days or weeks after the initial injury. cardiac contusion results from blunt-traumatic impact to the chest with compression of the heart against the sternum and/or spine. the momentarily high intrathoracic pressure with deceleration may also contribute to this type of injury. abdominal trauma may produce ileus or injury to hollow organs, particularly the small intestine, resulting in rupture and/or peritonitis several days following the injury. vascular trauma does occur in children, but less commonly than in the adult population (eddy et al. 1990; riches et al. 2002; choit et al. 2006) . these vascular injuries usually present acutely with hemorrhage or infarction, but may be delayed in discovery or presentation. although uncommon, children may also develop pulmonary thromboemboli as a result of local trauma to the leg (fig. 27.5) or prolonged immobilization and present as sudden death days or weeks later. death from hyperthermia of infants and children left in cars is well known and increasing in incidence since the recommendation of placing infants in carriers in the back seat. usually these tragic deaths result from a caregiver forgetting that the infant is in the vehicle. the temperature in closed vehicles may rapidly rise well over the ambient temperature, and car interiors may reach 140 o f (60 o c) or more within 15 minutes (mclaren et al. 2005) . infants are most at risk for this event since older children may be able to independently leave vehicles and/or alert adults to their presence. autopsy findings are generally nonspecific in car hyperthermia deaths, although intrathoracic petechiae are often seen (fig. 27.6) . body temperature at time of discovery is important to confirm hyperthermia; however, this is often not available to the forensic investigator. interior vehicle temperature is often not recorded and, if available, may not be reliable, as opening the car door will rapidly disperse heat, resulting in an erroneously low measurement. due to the rapidity of heat exposure in a vehicle, vitreous electrolytes may not demonstrate a dehydration pattern, as is seen in slower exposure to high temperatures. if a victim survives, complications of disseminated intravascular coagulation (dic) and multisystem organ failure may be fatal hours-to-days after the hyperthermic event. there is considerable variation in the certification of the manner of death in these tragic events, with some practitioners certifying as accidents and others as homicides. collisions with trains, either as an occupant in a vehicle or as a pedestrian, have high fatality rates. in contrast with adult pedestrians who are usually intoxicated and trespassers on rail yards, railroad employees, or individuals committing suicide, child pedestrians may be playing on or crossing rail tracks, riding bicycles or walking next to a moving train, or attempting to board, exit, or ride on top of a train. traumatic amputations and head injuries are the most common features of these accidents (thompson et al. 1983; blazar et al. 1997 ). farm-and ranch-related injuries and deaths in children are slowly decreasing in many parts of the world; however, farm and ranch operations remain among the most dangerous occupations, second only to mining, in terms of injuries and deaths (solomon 2002; lachowski 2009; cdc 2012b) . unlike mining, children are often involved in farming and ranching activities, exposing them to dangers, both by working and living within farming and ranching environments (pickett et al. 2005) . most childhood injuries occur in a nonworking capacity rather than being actively engaged in agricultural work at the time of the injury (hendricks and goldcamp 2010) . estimates of the cost of injuries and deaths of children on us farms alone exceed 1.3 billion usd annually (zaloshnja et al. 2012 ). there are several dangers in the farm and ranching environment. heavy equipment is used daily, creating risks for children by operating equipment, riding with others on the equipment, or simply being in the vicinity of operation. farm machinery is consistently the most common cause of injury and death in both the north american and the uk farm-related incidents (angoules et al. 2007 ). drowning in natural lakes, irrigation 㤠fig. 27 .3 (continued) lividity patterns contrast with blanched areas of compression. note the imprint from eye glasses. (b) scleral petechiae from the same child. numerous petechial hemorrhages, some confluent, are present in the sclera, conjunctiva, and the periorbital skin. retraction of the eyelid may be necessary to fully appreciate the presence and extent of petechial hemorrhages. petechial hemorrhages are caused by rupture of small vascular channels, usually venules, and are often present in cases of asphyxia, classically above the point of compression where venous return is compromised. (c) petechiae on the visceral surface of the lungs in the same child. (d) epicardial petechiae from the same child. visceral pleural and epicardial petechiae were first described as "tardieu spots" and initially described as pathognomonic of asphyxial deaths. they are commonly seen in asphyxia, but may be present in a variety of non-asphyxial mechanisms of death. (e) congestion and hemorrhage within the inner ear of the same child. pressure changes from compression may cause sphenoid and inner ear hemorrhages similar to those seen in barotrauma or drowning deaths dams, or streams within farms is another common cause of death in farm children. asphyxial deaths can occur from hypoxic closed spaces or slipping into grain storage bins. lacerations, skeletal fractures, amputations, and blunt-traumatic injuries result from falls occurring in farming activities or entrapment in farm equipment. complex tools, firearms, and sharp implements are necessary for farming and ranching and pose a danger of injury and death in children. falls from, or kicks by, large animals and a wide variety of animal bites also occur more commonly within rural settings. off-road vehicles, such as atvs and snowmobiles, are more common in rural settings, increasing the risk of injury and death from the use of these vehicles by children (lim et al. 2004 ). there are minimal gender differences in injury and death in children under the age of 5 years in farm and ranching activities; however, over the age of 5 years, boys have a higher rate of injury than girls . boys are more involved in hazardous tasks involving heavy equipment and tractors, whereas girls more commonly are involved in animal care and agriculture. disparities exist for minority populations with higher incidence of injury and death in farms owned by hispanics, african-americans, or native americans (goldcamp et al. 2006a, b; layne et al. 2009 ). finally, the remote location and low population density of many farming communities lead to slower emergency response and increased travel time to trauma centers. all of these factors tend to increase the mortality of injuries. tractors are the leading cause of farm fatalities and injuries in all age groups, but pose several particular hazards to children (schwebel and pickett 2012) . inspection of the safety status of tractors in rural kentucky (usa) revealed significant safety issues in the majority of examined vehicles (cole et al. 2009 ). similar conditions of tractors are likely present in most rural communities and explain the high incidence of injuries and fatalities related to children operating, or present around, this type of . thymic petechiae were seen at autopsy. (b) epicardial petechiae and hemorrhages were present. petechiae were also present on the visceral pleural surface. intrathoracic petechiae are consistently seen in hyperthermic deaths and are attributed to terminal gasping in an auto-resuscitation attempt farm vehicle and the diverse forensic findings that may occur in tractor deaths. nearly half of the tractors examined in the study lacked rollover protection structures (rops). most tractors did not have seat-belt and harness systems, or these systems were difficult to use, putting all operators, particularly young operators or youngsters riding with adults, at risk. many tractors had a narrow front-wheel stance, creating stability issues and increasing the risk of rollover accidents. many tractors had loose or damaged seats. protective shields for starting were present on just over half the trailers examined, and nearly a third had the starting mechanism fully exposed. rearwheel fenders exposed operators to moving tires in nearly 40 % of the tractors. fully functional mounting and dismounting access steps and handrails were present in less than half of the operating tractors and, when present, were designed for an adult body. many tractors had no functional lights, and nearly 70 % had no rear-view mirrors. complicating these design and safety issues is the fact that all of these devices are designed for adult operators, not children. ergonomic studies have demonstrated that even optimally functioning devices may have significant limitations for young operators who have not reached adult stature (chang et al. 2010 ). operation of tractors, equipment, and vehicles is common on family farms well before the age of normal driving licensing. in the usa and canada, children from farms and ranches have an average of 6 years' experience in driving tractors and other farm equipment on family farms prior to formal licensing for motor vehicles (marlenga et al. 2001) , indicating that many farm and ranch children routinely begin driving farm equipment at the age of 10 years or younger. children on farms and ranches also have higher incidence of falls, lacerations, animal bites, and large-animal blunt-trauma injury. when these are fatal, the trauma is similar to that seen in adults. with any perforating injury, secondary microbial infection may occur. secondary infections may be more common with injuries sustained on farms and ranches, reflecting contamination with dirt, animal excrement, and other foreign substances present in these environments. farm and ranch residents may also be exposed to pesticides, herbicides, and a variety of hazardous inorganic chemicals, many of which are not common in urban settings and may cause severe injury and death (neidich 1993) . the use of alternative or supplemental heating, such as woodstoves, contributes to the higher incidence of rural fires and fire-related deaths. even exposure to hazardous crops, such as tobacco, may be a cause of morbidity in farm children (mcknight and spiller 2005) . drowning is the second leading cause of childhood death by unintentional injury in the usa, the first leading cause in australia, and the third most common cause in the world (world health organization 2012c). actual deaths may be higher, since world figures do not account for flooding, tsunamis, boating, and water-transport deaths. drowning is more common in children under the age of 5 years, a fact likely associated with minimal swimming skills, lapses in supervision, impulsive child behavior, and attraction to water. drowning is more common in males and often increased in lower socioeconomic classes and minority groups with children of african-american heritage at 1.3 times the rate of caucasian agematched children and native american/alaskan native children 1.7 times the rate of caucasian age-matched children (centers for disease control and prevention 2012c). infants and nonmobile children are at highest risk of death in home bathing situations or immersion in buckets containing water. older children more commonly drown at swimming locations such as pools and natural water sites. most of the drowning fatalities are related to the child's inability to swim; however, even children with proficient swimming skills acquired in pools or still water may drown with unexpected tidal and current flows present in some natural bodies of water. the contribution of trauma, natural disease, carbon monoxide, drugs, alcohol, hypothermia, or other risks must be investigated in drowning deaths. many drownings occur when individuals have no intention of entering the water, that is, falling off docks or boats, water-transport accidents, or breaking through ice in a snowmobile or car. according to statistics of the international life saving federation (ilsf), approximately 25 % of drownings occurs in individuals with swimming skills, or in water less than a meter deep, and 40 % within 2 m of the pool edge or shore (international life saving federation 2012). drowning is an asphyxial death resulting from immersion in a liquid, usually water, with resulting anoxic changes. "near drowning" is defined as a recovery or resuscitation following submersion/immersion. following a "near-drowning incident," individuals may recover completely or succumb at a later time from complications of anoxic injury and secondary medical complications. rarer occurrences of drowning deaths include "hyperventilation drowning," seen in swimmers, usually youths, who hyperventilate to increase underwater swimming distance. the resultant hypocarbia may decrease the physiological stimulus for air, resulting in anoxia, unconsciousness, and subsequent drowning. "secondary drowning" and "delayed drowning" are terms used when an individual, often a young child, aspirates water and appears to recover but develops a sudden deterioration of pulmonary function several hours after the event. some use the term "immersion syndrome" when an individual has a catastrophic event, usually cardiovascular, while in the water and dies from the precipitating event or loses consciousness, resulting in drowning. certification of these immersion-syndrome deaths may be problematic and is often classified as accidental drowning when the precipitating event cannot be recognized or proven. a consideration of potential components of drowning assists in the forensic interpretation of findings (burford et al. 2005) . the pathophysiology of drownings involves lung and airway effects with resulting cerebral anoxia. in most drownings, the initial insult results from water within the airways and lungs causing inadequate oxygenation. aspiration of mud, debris, sand, or vomit into the bronchial tree and alveoli may also occur and complicates the physiological response. this also increases the risk of acute respiratory distress syndrome (ards), chemical pneumonitis, and pneumonia if the individual is successfully resuscitated. freshwater inactivates pulmonary surfactant on contact, resulting in atelectasis, further complicating oxygenation and increasing the pulmonary blood shunting physiological response. osmotic forces may draw more fluid into alveoli from pulmonary intravascular spaces. the resulting anoxia and acidosis have the most immediate and consequential impact on central-nervous-system (cns) function, although other organ systems may be involved in pathophysiological changes. these changes include cardiac dysrhythmias, blood-pressure changes from catecholamine release, carbon dioxide retention, and hypothermia. metabolic acidosis is significant in "near-drowning" victims. although initial experiments suggested that fluid and electrolyte imbalance and hemoglobin/hematocrit changes from osmolality differences played a major role in drowning, these changes may not be as common or as important as first thought. deaths are reported in "secondary" or "delayed drowning" scenarios where acute lung injury and rapid pulmonary failure from inhaled water, debris, or chemicals within water produce death several hours after the event. forensic findings in all drowning deaths are nonspecific; thus, drowning is a diagnosis of exclusion. numerous tests have been proposed for establishing the diagnosis of drowning, including diatom presence and electrolytes or other substance differences in right versus left cardiac blood; however, none have proven sufficiently valid for forensic use. tenacious froth, often with slight blood tingeing, may be present in the mouth and nares and is thought to result from an admixture of water, pulmonary surfactant, mucus, and blood plasma protein (fig. 27.7) . this finding is supportive of drowning but is not present in all cases, and the absence should not be used as criteria for excluding drowning. internally, froth and water are often present in the airway; the lungs are often heavy and edematous. during the process of drowning, individuals may swallow large quantities of water, distending the stomach. this constellation of heavy, waterlogged lungs often with water in the stomach is termed "wet drowning" and is present in the vast majority of drowning deaths; however, in a minority (about 10 %) of drownings, there is no water in lungs, airways, or stomach. laryngospasm is postulated to occur in these cases closing the airway and resulting in "dry drowning." in all drowning cases, the struggle to breathe or submersion below 2 m of water may also result in pressure changes reflected in hemorrhage in the inner ear and sinuses that may occasionally be seen at autopsy (fig. 27.8) . hemolysis of red blood cells may be present if copious quantities of freshwater are present. often lividity patterns have a bright red tone when drowning has occurred in cold water (fig. 27.9 ). all of these findings however are nonspecific and may occur in other deaths. conversely, drowning may occur with none of these signs. finally, in deaths from "near drowning" or "secondary drowning," the findings at autopsy will more closely reflect the anoxic and secondary complications rather than the original drowning event. forensic investigations of all drowning deaths should rule out the presence of trauma or other incapacitating events eg. (insect/aquatic stings, traumatic falls, entanglement in docks/ropes/flora, fatigue) as a component to the drowning. the presence of natural disease, including cardiac arrhythmias, epilepsy, metabolic derangements (eg. diabetes), and other potentially incapacitating conditions, should also be investigated in drowning fatalities. carbon monoxide is present, often in fig. 27 .7 foam cone in drowning. this 6-year-old child drowned in freshwater. a tenacious froth, often blood tinged, exudes from the nares and/or mouth in many drowning deaths. it is caused by agonal breathing and the mixing of air, water, and respiratory mucous. it may extend to the trachea and more distal bronchi. although commonly seen in drowning, it is not specific; drownings may occur without this finding, and similar froth may be seen in other non-drowning deaths, such as acute drug overdoses/toxicities fig. 27 .8 hemorrhage in the mastoid sinuses in drowning. this is a common, but nonspecific, finding in drowning and is thought to be related to pressure changes lethal levels, in boats and around other internal combustion engines, and carbon monoxide quantitation should be performed in any water-or near-water-related death in which gas-powered engines were possibly present in the vicinity at the time of the incident (jumbelic 1998) . routine drug and alcohol screening should be performed to rule out incapacitating toxicities such as alcohol or opiate intoxication. depending on potential medical and other case findings, additional toxicology or clinical testing, including vitreous electrolyte, ketone, and glucose levels, may be helpful (byard and summersides 2011) . forensic investigations of drowning deaths should document water temperature to assess the potential role of hypothermia in the context of the case. if there is a possibility of diving contributing to the death, careful neck examination, including a posterior neck dissection and cervical spinal cord examination, should be performed to rule out contributions to neck and cervical injury. fires and burns are a common cause of injury and death in children throughout the world (international association for the study of insurance economics 2009). burns are usually unintentional, but may be intentionally inflicted. in house fires, children under 4 years are at the highest risk of death, followed by the elderly (centers for disease control and prevention 2010). fire deaths have striking disparities in occurrence, with victims more likely to be from a lower socioeconomic group and of native american or african descent as compared to caucasians (istre et al. 2001; flynn 2010) . the incidences of both fires and fatalities are higher in rural areas contrasted with urban populations. most fire deaths occur in the home, particularly in homes without working smoke detectors. infants and very young children are at greater risk of succumbing fig. 27.9 skin coloration in cold-water drowning. lividity patterns may have brighter red tones in cold-water drowning, hypothermia, or refrigeration. carbon monoxide can also produce a cherry red coloration and should be investigated in any drowning where the potential exists for exposure to internal combustion engine exhaust to fire-and combustion-related injury due to the presence of fetal hemoglobinrelated carbon monoxide toxicity and the inability to recognize and appropriately react to the fire. children may tend to hide within the house or seek out sentimental items, such as personal belongings or pets, delaying their escape from the burning house. young children may be the cause of the fire, resulting from inappropriate use of matches, lighters, and candles, and are thus at the fire's origin and are therefore exposed to the first effects of the fire. a brief analysis of the components of fires is helpful in understanding the forensic findings (peck 2011) . smoke is readily produced in fires, particularly home fires, and comprises the airborne solid and liquid particulates of combustion. smoke is a direct eye and pulmonary irritant and is invariably accompanied by the toxic gas carbon monoxide (co) with environmental levels of 5 % or more. the carboxyhemoglobin (cohb) saturation level in a human exposed to this level of co gas will rise to 40 % or more within 30 seconds (peck 2011) . other toxic gases such as hydrogen cyanide (from synthetic fibers or materials) or the highly irritating acrolein (from wood and natural products) may also be present (einhorn 1975) . concomitantly, environmental oxygen levels in the fire environment diminish from the consumption of oxygen by combustion. humans become significantly physically impaired with oxygen levels below 17 %, and mental judgment is compromised at 14 % (peck 2011) . house fires may smolder with oxygen levels at 12 %, and all fires have an oxygen-deficient environment. the hypoxic environment likely contributes to fatalities in fires, but this impact cannot be directly measured by current technology used at autopsy. thermal conditions of a fire are also important to some forensic findings (peck 2011) . temperatures in most house fires reach 300 f (150 c) within 5 minutes. in some structures, such as an aircraft, much higher temperatures (approximately 1,100 o c) may be present within 2 minutes. a fire often reaches a "flashover" point, where the thermal radiation causes surfaces to reach their ignition temperature. at this point, near-simultaneous ignition of materials occurs, and the fire spreads to involve the complete room or structure within seconds. temperatures may soar at this point to over 2,000 f (1,000 c) within the structure. similar rapid acceleration in combustion and temperature may occur when partial collapse of a structure or opening a door creates a rush of oxygen causing rapid fire growth. all fire deaths must be autopsied to confirm the identity of the victim, establish the cause of death, and eliminate non-fire causes of death. the autopsy should include full-body radiographic studies to detect debris, projectiles, or skeletal fractures especially if the external examination is compromised by extensive fire damage. in many children, particularly infants and small children, dental identification is precluded due to the immature developmental stage of dentition and the lack of dental records. this may require investigators to seek dna confirmation of identity when visual identification is not straightforward. although rare, temperatures and duration of house fires may reach cremation thresholds, resulting in limited remains of small individuals, including children, necessitating thorough scene examination. in these instances, assistance from a forensic anthropologist may be helpful in increasing the percentage of remains recovered. the abundant smoke of most house fires is demonstrated at autopsy by readily apparent soot present in nares (fig. 27 .10) and airways (figs. 27.11 and 27.12) . the presence of soot below the true vocal cords is indicative of breathing soot-filled air and is not a fire artifact. in conjunction with the thermal injury, carbon monoxide saturation may be within the lethal range and may play a more significant role in causing the death as compared to the thermal injuries. pulmonary edema and froth in the nares (fig. 27.10 ) and upper airway are often present. skin blistering may be present (fig. 27.13) , and geographic desquamation of the hands, also this may be from direct thermal injury or may occur postmortem as an artifact of the fire/heat referred to as degloving, may occur ( fig. 27 .14). more severe heat injury results in extensive charring and reduction in body mass, sometimes with marked reduction in the size and bulk of the extremities and head. bodies may assume the so-called pugilistic posture, a postmortem artifact of heat-related, differential muscle contraction. victims of "flashover" fires or explosions, such as from natural gas leaks or incendiary devices, often have minimally elevated or normal carbon monoxide saturation levels and an absence of soot in the airways, which may be intensely hyperemic (fig. 27.15 ). in this scenario, death is usually related to heat-induced laryngospasm or vagal-reflex cardiac arrhythmia. pulmonary contusion or hemorrhage may be present from blast injuries if an explosion has occurred; debris or bomb material may be embedded in the victims. hemorrhage in the inner ears and sphenoid processes may be apparent at autopsy in such explosions and subsequent fires. 27 .14 "degloving" in thermal injury. the epidermal layer may blister and "deglove" in fire deaths. this is usually a postmortem artifact. fingerprint impressions may be made from the "glove" to aid in identification if suitable preinjury prints are available for comparison fig. 27 .15 tracheal hyperemia in thermal injury. in flash fires or steam burns, there may be minimal soot deposition within the airway. the trachea may be intensely hyperemic from burns of superheated air. edema is often present traumatic injuries, falls, and blunt trauma from structural collapse may be present in fire fatalities. these injuries may be the primary cause of death, contribute to the cause of death by restricting egress from the fire, or occur postmortem. heat-related fractures of bones, including the skull, occur in fires and should not be mistaken for premortem injury. a common fire-related artifact is an epidural accumulation of blood and marrow; however, this is readily distinguished from a premortem epidural hematoma by the granular, foamy, or flaky texture and brownish coloration. the victim's skin may be dry with large splitting defects exposing the underlying fascia or abdominal cavities (fig. 27.16) . clothing or objects near the victim may burn or melt and be deposited on the skin. care must be taken to distinguish these postmortem artifacts from actual premortem injury. assistance from anthropologists is helpful in many fires to accurately recover and identify bone fragments which may be difficult to recognize among fire debris at the scene (figs. 27.17 and 27.18). radiological examination is extremely helpful, but suspicious findings must be confirmed by direct examination (fig. 27.19) . toxicology testing for alcohol and drugs is important in fire fatalities, since the use of these substances may contribute to the start of the fire or failure to successfully leave the burning structure. testing for carbon monoxide is needed in all fire deaths, and testing for additional toxicants (such as cyanide) may be necessary for a complete forensic investigation. select cases may benefit from co saturation levels at different anatomic sites; for example, co saturation of a fresh subdural hematoma or an area of trauma may reveal different levels compared with to cardiac blood, indicative of prefire trauma contributing to death. in cases where there are no/minimal airway-soot fig. 27 .16 skin splitting artifact in thermal injury. skin splitting in fires is a known postmortem artifact and should not be mistaken for sharp force injury. note the yellow base of the surface and lack of vital reaction. the slight reddish appearance is from drying and nonlethal-co saturation levels, death prior to fire must be seriously considered in the investigation. if an incendiary device is suspected, consultation with experts at the time of the initial investigation and autopsy will assist in the specialized collection of evidence from victims which is required for case investigation. contact with or immersion in hot liquids or gases is more common in infants and small children than adults. scalding is the most common burn injury in the pediatric age group (shah et al. 2011) ; however, most accidental scalding injury is not fatal, so this is less commonly encountered at autopsy. the skin in a scalding injury is markedly erythematous, blistered, or, with severe injury, completely denuded with intense underlying erythema. sharp borders are invariably present between injured and uninjured areas. a characteristic of scalding injury is the distinctive injured/uninjured pattern created by different modalities of injury, including pouring, splattering, or immersion. in an accidental scalding injury, irregular patterns of splattering are often present on the face, hands, or upper body often from children pulling or tipping pans of hot liquids from stoves. in immersion injury, larger, more confluent areas of burning are seen which correspond to the child being dipped or held in hot water. the buttocks, back, and feet are small-bone fragments such as this may not be recognized by responders. consultation with forensic anthropologists is extremely helpful in the recovery of human material in a fire scene the most commonly burned areas. characteristic of the immersion burn is the sparing of injury in skin folds, such as inguinal regions or behind the knees, resulting from the child withdrawing the lower extremities to avoid the immersion. large-immersion pattern scalding injury is indicative of inflicted trauma. children under 4 years of age are most at risk of immersion injury, and this form of inflicted trauma is often precipitated by adult frustration with toilet training of the young. deaths from scalding injuries result from direct thermal injury or complications of these injuries. vitreous chemistry and microbiological studies may be of value in investigating these deaths. water is the most common medium for scalding injuries, likely due to its universal availability. infants' and young children's skin is more susceptible to thermal and scalding injury (diller 2006) , and burns can occur within 3 seconds with water temperatures 140 f (60 c) or higher (feldman et al. 1978 (feldman et al. , 1998 . many residential water heaters are set to this temperature or higher, increasing the risk and ease of injury to children. fatal chemical burns are uncommon in pediatrics but may occur in young children from exposure to caustic household chemicals, such as lye (elshabrawi and a-kader 2011) . most of the fatal injuries involve ingestion, and deaths may occur following prolonged medical intervention. fig. 27.19 misleading radiologic image in a fire death. these fragments were recovered from a house fire. routine radiologic imaging showed a radio-opaque object suggestive of a projectile (a: circled). retrieval and subsequent cleaning of this object (b, c) demonstrated it was a metal button from jeans contact with hot objects is a cause of childhood burns and is often seen in child abuse (toon et al. 2011 ). in the forensic setting, these are usually a component of an inflicted-injury pattern and not the primary cause of death. in many instances, patterned impression of the causative object, such as a hot plate, cigarette, poker, or other object, is present. it is critical to document these pattern injuries with extensive photography and detailed measurements. as with other patterned injuries, body curvature and positioning may cause interrupted patterns or may assist in interpretation of body posture or defensive positioning when inflicted. deaths from fireworks are rare, but a large percentage of these fatalities are in children. deaths usually result from blunt-traumatic injury and/or flash fire resulting from fireworks (smith et al. 1996) . rarely blast and explosive injuries are a component of these deaths. in many burn injuries, death occurs after considerable time has passed from the time of the injury with numerous intervening medical and surgical procedures. the original pattern of burn injury may not be present, and there are usually a number of medical complications leading to the demise. burn victims are susceptible to a wide variety of infections, electrolyte and metabolic derangements, and medical complications including ards, dic, and multisystem organ failure. careful documentation of medical interventions and events is part of the forensic autopsy of these patients. death certification must accurately relate medical complications back to the initiating injury. most childhood electrical fatalities result from low-voltage electrocution in the home (rabban et al. 1997 ). household appliance cords or extension cords are the most common causes of electrocution in children, followed by wall outlets. younger children may contact cords orally or via a conductive foreign object such as a key or pin. less commonly, contact with poorly grounded and electrified appliances or heaters may cause electrocution. high-voltage electrocution is rare in young children but may be seen in adolescents, particularly among males. an even rarer event is death due to lightning injury in the pediatric population; however, fetal death due to maternal electrocution may be seen even when the mother survives the lightning strike. the findings of electrical injury in children are similar to those seen in adults, and the elements of forensic investigation and autopsy are identical. electrical injury is challenging since often there are no distinguishing features. a high index of suspicion, through scene investigation and consultation with electricians, is critical to identifying and appropriately categorizing these deaths. low-voltage (<1,000 v) electrocution is the most common type of electrocution in both children and adults. the classic "joule burn" or electrical mark is present in approximately half of the cases. when present, it identifies the point of electrical current entering or exiting the body. the skin may be whitish (fig. 27.20) surrounding a raised, oval, or round crater with hyperemic borders and a pale center (fig. 27.21) . the shape of the burn may relate to the conductor shape in contact with the skin. charring or edema is often present, and prolonged contact may result in deep burning of tissue. microscopically, a "streaming" appearance of cells and nuclei is often present accompanied by thermal homogenization of the dermis, deep fascia, and underlying tissue fig. 27.22 ). the epithelial basal layer of the skin is often detached. these changes are supportive, but not diagnostic of electrical injury. occasionally, trace evidence of metal deposition from wires may be present at the site of electrical contact. the point where electric current exits the body is usually more difficult to identify and may be entirely absent. when present, it may have many of the characteristics of the site of current entry. deaths from low-voltage electrocution are caused from electrical disturbances, primarily ventricular fibrillation of the cardiac conduction system or respiratory paralysis from interference with brainstem function, both autonomic disturbances that leave no physical trace to be identified at autopsy. high-voltage electrocution (over 1,000 v) is uncommon in the pediatric population and, when present, has the same characteristics of blast injuries and flash burns as with adult deaths due to high-voltage electrocution. death is usually related to blast effects, thermal injury, and secondary trauma rather than to an electrical interruption of cardiac or brainstem function. with extremely high voltage, charring and bone fusion may be present, and the muscles will appear gray-white from the effects of temperature. skin may be denuded, and the hair is often scorched or a lighter color following high-voltage electrocution. lightning strikes are uncommon events, and, because of the extremely short time interval of electrical exposure, over two-thirds of victims survive a lightning strike. in the event of a death, the majority of findings may be nonspecific. a faint, erythematous, arborizing pattern on the skin, the so-called lichtenberg figure, may be present initially, but will subsequently fade in a relatively short time frame. rupture of eardrums and opacification of corneas may occur in lightning injury. falls are a part of normal childhood, an expected result of the need for exploration, as the young push their limits in developing coordination and locomotion skills while navigating their environment. most falls are inconsequential; however, each year in the usa, 2.8 million children seek emergency department care for falls (centers for disease control and prevention 2012d). analysis of fall data in children can identify intervention strategies to reduce this common cause of injury (khambalia et al. 2006) . falls are responsible for death in over 46,000 children annually (world health organization 2012a) and may be a component of inflicted injury of children. delineation of these injuries is one of the most challenging tasks in forensic pathology. fatal injury from falls usually involves trauma to the head, although extremity fractures and internal injuries can occur and may cause death. the assessment of the degree of injury relative to the presenting story is a key component in distinguishing accidental and inflicted injury in the evaluation of a fall. in general, short-distance falls (less than 10 ft or 3 m) and falls down stairs rarely produce fatal injury to children (chadwick and salerno 1993; chadwick et al. 1991; chiaviello et al. 1994a) . the presence of an adult may complicate injury to the child as falls occurring with children being carried down stairs by an adult have a higher injury index and more frequent skull fractures than falls down stairs by children themselves (joffe and ludwig 1988) . the added mass of an adult and secondary impact(s) may be responsible for the increased severity of injury. numerous studies of falls in specific situations exist in the literature including falls from buildings (vish et al. 2005) , playgrounds (centers for disease control and prevention 2012a; petridou et al. 2002) , beds/couches (belechri et al. 2002) , high chairs (schalamon et al. 2006) , infant walkers (shields and smith 2006; chiaviello et al. 1994b ), child-restraint seats (desapriya et al. 2008) , infant slings/ carriers worn on adult bodies (frisbee and hennes 2000) , heights (thompson et al. 2011; murray et al. 2000) , and in hospital settings (jamerson et al. 2009 ). case reports of severe injury from accidental stairway and short-distance falls exist (lantz and couture 2011) , although the presence of severe head injury is more indicative of inflicted trauma. disparities exist in pediatric falls. falls with injuries are more common in children of nondominant populations and lower socioeconomic classes (faelker et al. 2000; shenassa et al. 2004 ) in most but not all countries (engstrã¶m et al. 2002) . this is correlated to older and poorer conditions of environmental factors, such as reduced repair of playground equipment, older model cribs and beds, and poor maintenance of stairwells, balconies, and windows in lower socioeconomic populations. forensic investigation and autopsy in childhood deaths from falls is challenging since inflicted versus accidental trauma is often the question. careful and extensive photography of injuries, full radiological examination, fixation of the brain, and extensive histology are considered a baseline in the performance of the autopsy. specialized dissections, such as removal of optic nerves, eyes, and posterior neck dissections including examination of cervical spinal roots (matshes et al. 2011 ) may assist in interpretation. when there is a question of inflicted skeletal trauma, removal of the affected bone and the contralateral control bone may be important for evaluation. careful review of all clinical records and police investigation is required for optimal interpretation. correlation or identifying points of discordance with the given clinical history of how the event occurred is critical for case assessment. it may be helpful to have at least one meeting with all interested professionals, including clinicians providing care, radiologists (if appropriate), police and investigating agencies, child-protective services, and legal prosecutorial representation if jurisdictionally allowed. the adage "we speak for the deceased as discoverers of truth, not makers of cases" rings true in evaluation of the difficult area of pediatric deaths due to falls. the rapid advances in imaging and pediatric head-trauma interpretation will likely assist in defining appropriate studies and interpretations as more evidencebased practices in forensic medicine evolve. most children have many positive exposures to animals -from appreciation of wild animals, visits to zoos, and caring for animals as pets, companions, or livestock. care and responsibility for animals is a major step in normal childhood development; abuse of animals is a critical warning sign of behavioral problems. with this overarching exposure to animals, childhood injuries and fatalities occur in a variety of animal-related scenarios (bury et al. 2012a, b) . the majority of these fatalities occur either with large animals or with commonly encountered animals such as dogs. injuries and deaths associated with large animals are increasingly seen both in and outside rural environments. the non rural increase is primarily due to the popularity of horseback riding among urban and suburban youth. a horse can weigh over 1,000 lb (450 kg) and reach speeds approaching 40 mph (65 km/h), both accounting for the inherent dangers of this sport. this danger is amplified for young children where the injury rate for children in horseback riding is nearly twice that of adults from both falls and kicks from horses (jagodzinski and demuri 2005) . a mexican proverb states "it is not enough for a man to learn to ride; he also must learn how to fall," alluding to the danger admixed with the joy of this sport. most injury in horseback riding occurs when the rider falls off the horse; occasionally, this is complicated by a secondary kick from the horse, being stepped on by the horse, or through entrapment in a stirrup and subsequent dragging. the use of "break-free" stirrups can decrease the risk of entrapment and dragging following a dismounting fall. in nearly a third of horse-related injuries, the child is not riding the horse, but is kicked while in the vicinity of the horse. head injuries are the most common and the most serious type of injury, accounting for most fatalities in horserelated accidents (ghosh et al. 2000) . in children, upper-extremity injury is more common than lower-extremity injury. injuries to the back, pelvis, chest, and abdomen do occur, but with much less frequency in children as compared to adult horse enthusiasts. horse-related injury is second in severity only to pedestrian versus motor vehicle injury, and horse-related injury has greater severity than injury from atvs, bicycles, and passenger-related motor vehicle crashes (bond et al. 1995) . helmet use reduces the severity of injury and the likelihood of death. nearly five million dog bites occur every year in the usa, with over 40 % occurring in children under 14 years of age (centers for disease control and prevention (cdc) 2001). children, particularly those under the age of 5 years, are more likely to have provoked dogs, often unintentionally through play, and are often incapable of escape or defending themselves from a dog attack. most dog bites are generally single bites to the extremities and are usually not fatal; however, most dog attacks and fatalities involve multiple bites to the head and neck region where extensive mutilating and defleshing injuries may occur. exsanguination and air embolism via neck veins are common causes of death in dog attacks. most dog-attack fatalities have multiple puncture wounds from the teeth and extensive defleshing from the tearing and hunting behavior of the dog(s). severity of injury and increase in fatal attacks may be increased when more than one dog is involved due to "pack" behavior (tsokos et al. 2007 ). abrasions and shallow incised wounds from paws or friction contact abrasions from surfaces may also be present. large breed dogs may cause crushing injuries to the very young, including infants and toddlers, resulting in severe skull fractures and cerebral injuries. several studies have examined the incidence and breed characteristics of fatal dog attacks, but may be confounded by the lack of accurate data into breed type actually present in a community as well as the effects of legislation restricting ownership of certain breeds (raghavan 2008; sacks et al. 2000) . bite-prevention programs show initial promise in educating young children about safe behavior with dogs (meints and de keuster 2009) . special considerations at autopsy of a fatality involving a dog bite include documentation of any canine odontological trauma for comparison (de munnynck and van de voorde 2002) . when an animal is captured, examination of material between the teeth or within the gastrointestinal tract at necropsy may confirm human tissue. consultation with veterinarians is very useful for testing of an animal for rabies, tumors, or other conditions that may have led to the attack, including examination for prior animal maltreatment, starvation, or training for fighting activity. investigation of the events leading to the attack, including a history of dog behavior, breed characteristics, and any precipitation or provocation by the victim, is helpful in reconstructing the events and interpreting injury patterns. bites and other trauma from animals may also be a cause of delayed death from microbial infections contracted from oral animal flora, human skin flora, or subsequent contamination of the original bite (dendle and looke 2008) . a wide variety of wild animals, on both land and sea, may cause injury and death in both provoked and unprovoked attacks. children are often more susceptible due to their decreased ability to flee or defend themselves, lower cognitive awareness of danger, and provoking animal attack behavior either intentionally or through play. the smaller mass and stature of young children also increases risk of fatal outcome of a wild-animal attack. many animals may attack causing injury and death including bears, feral dogs, coyotes, cougars, and wolves on land and sharks or other predatory fish in the sea. predatory land animals usually maul and bite victims, and if hunger precipitated the attack, the predators may devour most of the victim. large non predatory animals, such as cattle or moose, may cause injury and death from a stampede or trampling of victims. in water, sharks are the most common human predator. sharks may swim very near land and docks and attack surfers and swimmers. shark attacks are characterized by large bites and tearing of limbs and viscera. examination of the body for bite marks or fragments of teeth may assist in species identification. crocodiles and alligators are territorial animals and may attack individuals within their home wetlands. alligators are generally timid but may lose their fear of humans when fed or with repeated contact. in contrast, large crocodiles are more predatory by nature. both species can move very fast on both land and in water, increasing the danger of attacks to small children. these species will occasionally drag victims underwater, preserving a portion of the body for later consumption. their jaws exert the most pressure of any predator (erickson et al. 2012) , with up to 3,700 lb per square inch pressure (25.5 mpa, 255 bar, 251 atm), causing instantaneous massive trauma to victims. all these predators produce findings in child victims similar to those seen in adults, although children may be more susceptible due to their small size and inability to defend or flee from an attack. rarely, smaller sea life may sting or envenomate victims, causing injury or death, by either venom or secondary drowning. in all these animal attacks, the findings at autopsy are similar to those in adults. with the wide variety of animals and predators throughout the world, forensic pathologists should be aware of regional species that may cause injury and death. fatal envenomation may occur from several land-based (snakes, scorpions, spiders) or marine-based creatures (jellyfish, stonefish, octopus, portuguese man-o'-war, cone snails). autopsy findings vary with specific venomous species and may be subtle, requiring detailed historical investigation and/or careful cutaneous evaluation for envenomation site (williams and milroy 2012) . venomous-snake fatalities are uncommon, but young children may be particularly susceptible due to their small body mass ). insect bites and stings may also produce death from anaphylaxis, zoonotic transmission of disease, or rarely overwhelming envenomation. worldwide, the deadliest "animal" is the mosquito, causing malaria across wide areas of the tropics as fig. 27 .23 cutaneous site of a snake bite. this 3-year-old child collapsed suddenly while playing in the tall grass at a campsite. her family reported a single scream before the collapse. she was unresponsive and could not be resuscitated. later, this site of likely envenomation was found on her thigh fig. 27 .24 dissection at site of snake envenomation. hemorrhage is clearly present in the subcutaneous tissue tracts, and direct envenomation of an artery is identified a variety of animals and insects are natural scavengers in the postmortem period (byard 2011) . the disfigurement caused by postmortem predation is considerable, and care must therefore be taken to avoid confusion with premortem injury fig. 27 .26 postmortem ant bites. this 3-month-old infant was found deceased after a sleep period. scene investigators were concerned with the lesions identified on her arm, raising the possibility of child abuse. the irregular and shallow erosions are typical of postmortem ant bites. these normally have a yellow base, but drying artifact can darken the lesions, suggesting a vital reaction. it is critical to correctly assess postmortem artifact from abuse and traumatic injury in any forensic investigation fig. 27 .27 postmortem rodent activity. lesions from rodent postmortem predation have shallow and irregular contours and are often centered on natural orifices, such as eyes or sites of premortem injury. note the uniform shallow contours and yellow base of this lesion, both indicative of postmortem rodent predation. similar patterns may be seen with some aquatic predators, such as crabs in cases of drowning in crab-infested waters (figs. 27.26 and 27.27 ). there are striking regional differences in postmortem scavenging activity, and forensic pathologists should be aware of local scavenging patterns. forensic pathologists and investigators should also be aware that household pets often are involved in postmortem predation (buschmann et al. 2011 ). choking hazards are greatest in very young children due to the proclivity of infants and toddlers to place objects in their mouths, the lack of cognitive awareness of dangers in this age group, the smaller upper airway, and poorer cough reflex in very young children. in contrast with adults, where alcohol, drugs, and/or neurological impairment may be predisposing factors in airway-associated deaths, these factors are usually not a component of pediatric airway-associated fatalities. food, coins, and balloons are the most common objects causing obstruction in children (altkorn et al. 2008; rimell et al. 1995) . total obstruction of the upper airway produces rapid loss of consciousness and death. occasionally, a child is found dead without a history or suspicion of airway compromise, even in a supervised environment. physical findings in airway-associated ("choking") deaths may or may not include external petechiae or head and neck cyanosis; however, internal intrathoracic petechiae are usually present. the object is usually readily found within the larynx or trachea (figs. 27.28, 27.29, and 27.30 ), or at the carina (fig. 27.31 ). occasionally resuscitative efforts may force the object into the proximal major bronchi. objects smaller than the expected caliber of a child's airway may cause death either through laryngospasm or direct obstruction of a scarred and narrowed airway. children most at risk for airway scarring are those who had been previously intubated, particularly as a preterm neonate. game-playing asphyxial deaths occur primarily in older children and young adolescents (le and macnab 2001; andrew et al. 2009 ). widely termed the "choking fig. 27 .28 airway obstruction by a balloon. this was the autopsy finding in a 5-month-old infant who was found deceased by his caregiver. the father had lain down with the infant on a quilt and both fell asleep. on awakening, the father found the infant unresponsive a few feet off the quilt. autopsy revealed an object in the upper trachea game" within the literature and community, this activity usually involves a form of strangulation to achieve a brief period of euphoria. strangulation may be achieved by use of hands, ligature, or noose and may be self-administered or done by others. rarely, a variant of chest compression produces the asphyxial state. the resulting cerebral hypoxia is reported as a "high" with light-headedness or a few seconds of unconsciousness. with release of external neck compression, a "rush" or "tingling" is described among children experiencing this activity. this activity is commonly known among preadolescents and goes by over 75 local variations in both name and activity (centers for disease control and prevention (cdc) 2010; macnab et al. 2009 ) and is seen throughout the world (noirhomme-renard and gosset 2011). the cases presenting to a forensic service usually involve solo-game playing and are often initially thought to be suicidal hanging deaths (andrew and fallon 2007) . the physical findings at autopsy are similar to other strangulation or hanging deaths (figs. 27.32 and 27.33) , and the key to recognition is within the scene and death bean obstruction at the carina. this 8-month-old child was visiting his grandparents, crawling on the kitchen floor during a family gathering. he stopped moving and adults thought he was napping. a few minutes later, they noticed a darkening blue tone to his lips and tried to arouse him. he was unresponsive and ems was called. he presented to the medical examiner's office as a sudden death in infancy during sleep. a sack of pinto beans had spilled in the kitchen the day before; adults thought all were cleaned up. the child had found a single bean in a floor crevice investigation ( fig. 27.34 ). the activity is usually hidden from adults, but is widely acknowledged among peers, who usually regard the activity as a safe, drug-free "high," a part of thrill-seeking activity and risk-taking behavior of early adolescence. there are no indications of suicide at the scene or by history, and there is no evidence of autoerotic activity. the incident usually occurs in a private location that the child regards as safe, often within a home or school. the children are often "good kids," without behavioral, mental health, school, or drug/alcohol use problems. there are minimal gender differences in most studies, although some studies show a male predominance. in the usa, it is more common in hispanic and native american/alaskan native populations as compared to caucasian populations (toblin et al. 2008) . key to recognition at the scene is the "private yet safe" location, the simplicity of the noose, absence of suspension, and facile ability to self-extricate from the compressing object (fig. 27.34) , which usually is a simple loop against which youngsters lean. there are often wear marks on hooks or furniture from previous episodes or historical incidences of syncopal episodes, voice changes, new onset headaches, abrasions on the neck, disorientation after time alone, or accessing various electronic activities (websites, blogs, chat rooms) fig. 27 .33 layered neck dissection in ligature hanging. careful neck dissection after removal of the cns and body organs may reveal hemorrhage within strap muscles of the neck, corresponding to the site of constriction for asphyxial games. the absence of suicidal ideation, depression, or farewell messages is also important to ascertain. invariably, peers will either acknowledge similar past group or individual "game playing" or confirm that the victim sought information about game-playing asphyxia. although some describe this as a new risk, it may be a continuum of asphyxial games of past preadolescent generations, such as "breath holding" or hyperventilation to achieve momentary alterations of consciousness. the recent deadly inclusion of ligatures and nooses greatly increases the potential for death, especially when children engage in this activity alone. autoerotic or sexual asphyxia deaths in children are rare and when they occur tend to be in older adolescent males (sauvageau and racette 2006) . key findings of autoerotic deaths are generally scene-related with sexually explicate material and/or sexual devices present, privacy of the scene, evidence of masturbatory activity, sexual fetishes, bondage or masochistic activity, and often elaborate asphyxial producing and escape mechanisms (shields et al. 2005a, b) . a review of cases from australia and sweden revealed no autoerotic deaths below the age of 20 and confirmed the male predominance seen in previous studies (byard and winskog 2012) . fig. 27 .34 scene findings in game-playing asphyxia. this simple loop was present suspended from slats of an upper bunk. the child would lean against the loop as part of game playing; however, in this instance, unconsciousness prevented the simple action of lifting the head to remove neck constriction accidental deaths and injuries occur in all socioeconomic, ethnic, and racial groups. however, disparities exist in the occurrence, severity, and numbers of fatalities from pediatric injuries caused by both accidental and non accidental modalities. in the usa, african-american (brown 2010) , hispanic (mallonee 2003) , and native american children (goldcamp et al. 2006a; berger et al. 2009 ) all have higher rates and severity of injury and death over caucasian children, even when adjusted for socioeconomic class. rural and frontier children are also at higher risk of injury and death during childhood as compared to their urban and suburban counterparts (cherry et al. 2007) . forensic pathologists play an important role in correctly identifying traumatic injury and risk factors within larger communities, as well as in groups within the population they serve through a complete medical legal death investigation. accidental injury in infancy and childhood is a common, and often preventable, cause of childhood morbidity and mortality. many of the types of injury are similar to adults; however, others have differences in incidence and character of injury that are unique to the stature and development of a child. it is imperative that forensic investigations of these deaths include information salient both to the preventability of future deaths and addressing the disparities that exist within gender, socioeconomic, and other class characteristics. injury remains the most common cause of childhood death in most parts of the world. prevention strategies rely in no small part on accurate assessment of the causes of death and injury in children. forensic pathology and forensic medicine can contribute significantly in efforts to improve child safety, health, and life. asphyxial games in children and adolescents update on "the choking game prevalence and current concepts of management of farmyard injuries prevention of traumatic brain injury in youth and adolescents the roles of age, gender, inhibitory control and parental supervision in children's pedestrian safety bunk versus conventional beds: a comparative assessment of fall injury risk injury and injury prevention among indigenous children and 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and tooth-pressure experimentation socioeconomic differences in childhood injury: a population based epidemiologic study in ontario tap water scald burns in children tap water scald burns in children: 1997 a population-based study of all-terrain vehicle-related head and spinal injuries characteristics of home fire victims. quincy: national fire protection association adult-worn child carriers: a potential risk for injury horse-related injuries in pediatric patients nonfatal injuries to household youth on native american operated farms nonfatal injuries to household youth on racial minority-operated farms in the us pediatric injuries associated with the use of children's wagons in the united states delayed onset of intestinal obstruction in children after unrecognized seat belt injury pediatric sacral fractures injury surveillance for youth on farms in the changing farm injury trends by sex for youth living on us farms preventing pediatric pedestrian injuries children with special health care needs: patterns of safety restraint use, seating position, and risk of injury in motor vehicle crashes international life saving federation: drowning prevention. drowning facts and figures deaths and injuries from house fires horse-related injuries in children: a review child health corporation of america nursing falls study task force. pediatric falls: state of the science stairway injuries in children sledding injuries: a rationale for helmet usage open air carbon monoxide poisoning unsafe at any speed-kids riding all-terrain vehicles risk factors for unintentional injuries due to falls in children aged 0-6 years: a systematic review bicycle-related injuries in children: disturbing profile of a growing problem blunt pancreatic trauma in children engagement of children in agricultural work activities-scale and consequences of the phenomenon fatal acute intracranial injury, subdural hematoma, and retinal hemorrhages caused by stairway fall children in crashes: mechanisms of 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of trauma, neglect, violence and abuse extensive and mutilating craniofacial trauma involving defleshing and decapitation: unusual features of fatal dog attacks in the young all-terrain vehicle rules and regulations: impact on pediatric mortality pediatric window falls: not just a problem for children in high rises application of electronic surveillance and global information system mapping to track the epidemiology of pediatric pedestrian injury analysis of nonsexual injuries of the male genitals in children and adolescents fatal envenomations -snakes and other creatures update. world health organization, health statistics and health information systems world health organization. children and road traffic injury. world health organization/unicef. department of violence and injury prevention and disability media center fact sheets: drowning incidence and cost of injury among youth in agricultural settings key: cord-264486-o01s0upf authors: du, wenjun; yu, jinhong; wang, hui; zhang, xiaoguo; zhang, shouwei; li, qiang; zhang, zhongfa title: clinical characteristics of covid-19 in children compared with adults in shandong province, china date: 2020-04-16 journal: infection doi: 10.1007/s15010-020-01427-2 sha: doc_id: 264486 cord_uid: o01s0upf aims and background: the covid-19 outbreak spread in china and is a threat to the world. we reported on the epidemiological, clinical, laboratory, and radiological characteristics of children cases to help health workers better understand and provide timely diagnosis and treatment. methods: retrospectively, two research centers’ case series of 67 consecutive hospitalized cases including 53 adult and 14 children cases with covid-19 between 23 jan 2020 and 15 feb 2020 from jinan and rizhao were enrolled in this study. epidemiological, clinical, laboratory, and radiological characteristics of children and adults were analyzed and compared. results: most cases in children were mild (21.4%) and conventional cases (78.6%), with mild clinical signs and symptoms, and all cases were of family clusters. fever (35.7%) and dry cough (21.4%) were described as clinical manifestations in children cases. dry cough and phlegm were not the most common symptoms in children compared with adults (p = 0.03). in the early stages of the disease, lymphocyte counts did not significantly decline but neutrophils count did in children compared with adults (p = 0.02). there was a lower level of crp (p = 0.00) in children compared with adults. there were 8 (57.1%) asymptomatic cases and 6 (42.9%) symptomatic cases among the 14 children cases. the age of asymptomatic patients was younger than that of symptomatic patients (p = 0.03). even among asymptomatic patients, 5 (62.5%) cases had lung injuries including 3 (60%) cases with bilateral involvement, which was not different compared with that of symptomatic cases (p = 0.58, p = 0.74). conclusions: the clinical symptoms of children are mild, there is substantial lung injury even among children, but that there is less clinical disease, perhaps because of a less pronounced inflammatory response, and that the occurrence of this pattern appears to inversely correlate with age. since the first atypical pneumonia case was reported in wuhan, china on december 31, 2019 [1] , the pathogen was soon identified [2] and tentatively named 2019-ncov by the world health organization (who) [3] . on 11 feb 2020, the world health organization officially named it sars-cov-2 (severe acute respiratory syndrome coronavirus-2) and the sars-cov-2 infection was named as the covid-19 (coronavirus disease 2019) [4] . the infection quickly spread in china, and internationally [5, 6] and is still on-going. previous studies reported the main clinical characteristics of covid-19. fever, cough, shortness of breath, muscle ache, confusion, and headache were described as clinical manifestations. laboratory tests and chest computed tomographic (ct) scans were also evaluated and the results suggested that decreased lymphocyte counts and bilateral pneumonia were common clinical features, especially in severe cases [7, 8] . at present, there is no effective anti-virus drug and vaccine for covid-19, so early detection and isolation treatment are important to control the progression and spread of the disease. however, the current data mainly come from hubei province, especially from wuhan city. clinical features, especially in children, have not been reported outside hubei province. in this study, we analyzed and compared the epidemic characteristics and clinical features in children and adults in shandong province, china. the aims were to help health workers better understanding the clinical features of covid-19 in children and provide timely diagnosis and treatment. the present study is a retrospective descriptive clinical study. a total of 67cases including 53 adult and 14 children cases of confirmed covid-19 from the jinan infectious diseases hospital and rizhao people's hospital, which were the designated hospitals in jinan and rizhao city, between 23 jan 2020 and 15 feb 2020 were enrolled in this study. the project was approved by the ethics board of jinan infectious hospital (no. 20200203). informed consent was obtained from each patient or their guardian. all patients enrolled in this study were diagnosed according to the pneumonia diagnosis and treatment plan for the new coronavirus infection formulated by the national health commission (trial version 5) [9] . diagnostic criteria for asymptomatic cases: individuals infected by sars-cov-2 who remain asymptomatic throughout the course of the infection with or without abnormal chest ct imaging findings. diagnostic criteria for mild cases: mild clinical symptoms, no radiographic findings of pneumonia. diagnostic criteria for common cases: fever, respiratory symptoms, and radiographic manifestations of pneumonia. diagnostic criteria for severe cases: (1) respiratory distress, respiratory frequency ≥ 30 times/min; (2) hypoxemia, with resting oxygen saturation ≦ 93%; and (3) arterial partial oxygen pressure (pao 2 )/oxygen absorption concentration (fio 2 ) ≦ 300 mmhg (1 mmhg = 0.133 kpa). the diagnostic criteria for critical cases: (1) respiratory failure and mechanical ventilation is required; (2) shock; and (3) complicated with other organ failure requiring icu care. there are four types of infection: (1) imported cases defined as a history of a sojourn in hubei province within 14 days of onset of the illness. (2) family cluster defined as 3 or more than 3 people with confirmed cases in one family. (3) close contact defined as close contact with cases from hubei province. (4) unclear; the method of infection is unknown. a child is defined as less than 18 years of age. the medical records of patients were analyzed. information recorded included demographic data, exposure history, symptoms, signs, laboratory findings and chest computed tomographic (ct) scans. epidemiological, clinical, laboratory, and radiological characteristics data were obtained with data collection forms from electronic medical records. the date of disease onset was defined as the day when the symptom was noticed. throat swab specimens were collected from patients with suspected covid-19. covid-19 was confirmed by rt pcr using the same protocol. the dual-target detection kits were provided by the shanghai jienuo company. results: the cut-off value was 40, a ct value < 37 was positive, a ct value > 40 was negative, and 37-40 was a gray area (the diagnosis needs to be repeated). to characterize the effect of sars-cov-2 on the biochemical indicators and production of cytokines in the acute phase of the illness, plasma cytokines (pct, crp, and il-6) and biochemical indicators were measured using the human cytokine standard 27-plex assays panel and the bio-plex 200 system(bio-rad, hercules, ca, usa) for all patients according to the manufacturer's instructions. the normal range for each indicator is shown in table 2 . retrieved data were recorded into microsoft ® excel for mac (version 16.30) and analyzed. the statistical package for social sciences version 16.0 (spss 16.0;spss inc., chicago, il, usa) and the prism statistical software package (version 5.0; graphpad software inc. la jolla, ca, usa) were used. measurement data were described as mean ± standard deviation. background factors were compared using student's t-test (numerical data) or the χ 2 test (categorical data). differences were regarded as significant if the p value was less than 0.05 on either side. a retrospective analysis was performed on patients in jinan and rizhao, shandong province from 23 jan to15 feb 2020. there were 53 adult cases among the 67 cases, with a median age of 41.47 years (range 21-65 years), and 26 cases (49.1%) were males. most of cases were mild (8 cases, 15.1%) and conventional (44 cases, 83%), with only 1 severe case (1.9%). the most common symptoms at onset of the illness were fever (60.4%), dry cough (54.7%), phlegm (37.7%), pharyngalgia (35.8%) and fatigue (32.1%). less common symptoms were, headache (20.8%), anorexia (15.1%), myalgia (13.2%), chest distress (11.3%), nausea (5.7%), diarrhea (3.8%), dizziness (3.8%), and vomiting (1.9%) ( table 1) . there were 14 children cases among the 67 cases, with a median age of 6.2 years (range 0-16 years), and 6 cases (42.9%) were males. all the cases in children were familial clusters (p = 0.00), with 3 cases (21.4%) of the mild type and 11 cases (78.6%) of the conventional type and no severe or critical case. clinical symptoms in children were mild or even absent, only 5 (35.7%) cases showed signs of fever, 3 cases (21.4%) had dry cough, and 1 case had phlegm, other clinical signs of headache, fatigue, pharyngalgia, and myalgia were rare in children. none of the children developed anorexia, chest distress, dyspnea, nausea, vomiting, diarrhea, dizziness, or abdominal pain. however, dry cough and phlegm were not the most common symptoms in children compared with adults (p = 0.03) ( table 1) . laboratory tests of children and adults were analyzed. the results showed that the white blood cell counts of children were all normal, with decreased neutrophil counts (p = 0.00) and increased lymphocyte counts (p = 0.00) compared with adults ( table 2) . considering the physical characteristics of the children with lymphocytes making up 60% of the white blood cells before 6 years and the proportions of lymphocytes and neutrophils in white blood cells being close to that of adults after 6 years, we further analyzed the difference in blood cell counts between children over 6 years and adults. there are 5 cases over 6 years (35.7%) among 14 children cases, the neutrophil counts (1.62 ± 0.34 × 10 9 /l) were more decreased in children over 6 years than in adults (p = 0.02). however, lymphocyte counts (1.91 ± 0.93 × 10 9 /l) showed no difference (p = 0.41) between the two groups. covid-19 caused liver function damage, cardiac muscle damage, and coagulation function changes. the abnormal rate of alt, ast, ldh, ck, myo, pt, and d-dimer was 17%, 7.5%, 18.9%, 15.1%, 3.8%, 13.2%, and 35.8% in adults and 7.7%, 7.7%, 50%, 28.6%, 0%, 7.1%, and 35.7% in children, respectively ( table 2 ). the value and positive rate of ldh in children were more significantly increased than in adults (p = 0.01; p = 0.02) ( table 2 ). according to evaluation of infection indicators, the value of pct showed no difference between children and adults, however, the value and positive rate of crp were more significantly increased in adults than in children (p = 0.00, p = 0.02) ( table 2 ). of the 67 cases, 56 cases had complications of lung injuries (83.6%) including 11 children and 45 adults. a total of 6 children (64.5%) and 30 adults (66.7%) had lung injuries with bilateral involvement, with no difference between the two groups (p = 0.45). however, lung injuries in adults were more severe compared with that in children ( table 2 , fig. 1 ). there were 8 (57.1%) asymptomatic cases and 6 (42.9%) symptomatic cases among the 14 children cases, with a median age of 3.98 years, and 5 cases (62.5%) were males in the asymptomatic cases and with a median age of 9.17 years, and 1 case (16.7%) was male in the symptomatic cases. the age of asymptomatic patients was younger than that of symptomatic patients (p = 0.03) ( table 3) . the white blood cell and lymphocyte counts were more decreased in symptomatic children cases than that in asymptomatic children cases (p = 0.04, p = 0.04). although there were statistically significant differences in levels of cr and ast between asymptomatic and symptomatic children cases, these differences were within the normal range and had no practical clinical significance. even among asymptomatic patients, 5 (62.5%) cases had lung injuries including 3 (60%) cases with bilateral involvement, with no difference compared with that of symptomatic cases (p = 0.58, p = 0.74) ( table 3 ). the severe acute respiratory syndrome corona virus 2(sars-cov-2) infection outbreak has spread in china and around the world [10, 11] . who defined it as a public health emergency of international concern (pheic). coronaviridae (covs) are the largest known single stranded rna viruses [12] . they have been categorized in three groups, alpha-covs, beta-covs, and gamma-covs according to phylogenetic analyses and antigenic criteria [11] . the human severe acute respiratory syndrome (sars) virus, the middle eastern respiratory syndrome (mers) virus, and the sars-cov-2 all belong to beta-covs [13] . the bat coronavirus (bcov) and the sars-cov-2 share 96.2% sequence identity. bats were once thought to be the source of sars-cov-2. however, sufficient evidence is lacking. a total of 67 cases including 53 adult and 14 children cases, of which only 1 case was the severe type and no one was in critical condition, is far lower than reported in wuhan [14, 15] . there were no deaths reported because of few cases of the severe or critical type. the reason for this is considered as follows: (1) there is no major epidemic in the regions except hubei province for strong prevention and control and (2) the virulence and pathogenicity of the virus decrease in the 2nd and 3rd generation of transmission [16] . all cases of children belong to the mild or conventional type of covid-19, and all children are part of family clusters. previous studies found no cases in children, who were once thought to be less susceptible [17] . according to the current trend, all people including children are susceptible to sars-cov-2, and person-to-person transmission develops familial clusters [18] . the reason why all children are in family a retrospective analysis on clinical features of children of covid-19 compared with that of adults from two research centers was made. the findings showed that clinical symptoms were mild in children with fever and dry cough being the most common symptoms, and other symptoms were rare. however, dry cough and phlegm are not the most common symptoms in children compared with adults. this is because a lower inflammatory response to lung injuries causes milder clinical symptoms in children compared with adults. previous reports indicated that decreased lymphocytes counts were common clinical features, especially in severe cases [7, 8] . as a result of viral infection, white blood cell and lymphocyte counts can be reduced by consumption. however, similar results did not appear in our study, with only a total of 6 cases including 1 case of a child with decreased lymphocytes counts, and the value of lymphocytes counts showed no significant differences in children over 6 years compared with adults. on the other hand, neutrophil counts decreased in children compared with adults (p = 0.02). so, lymphocyte decline is not an important indicator for the diagnosis of childhood cases and the neutrophil count decline should be focused on. these may be due to a lower inflammatory response in children. sars-cov-2 infection may induced lung injuries, liver function damage, cardiac muscle damage, kidney damage, and coagulation function changes [7, 8] . among these laboratory tests, elevated ldh is more common in children than in adults (p = 0.02). an elevated ldh is commonly seen in cardiopulmonary disease and inflammation. the elevated ldh suggests that the sars-cov-2 infection appears to be more likely to cause cardiopulmonary injury and inflammation in children, although lung inflammation in children is less severe than in adults. of course, since the level of ldh is not high in children, it may not have practical clinical significance. both crp and il-6 are major indicators of inflammation. an elevated level of crp and il-6 was shown in adults, but not in children, which suggests that inflammation caused by viral infection, especially in the lungs, is less severe in children than in adults. in addition, lung injuries are not uncommon in children and are characterized by bilateral involvement, which is similar to that of adults. however, lung injuries in adults were more severe compared with children (fig. 1) . of the 14 children cases, 8 cases were asymptomatic cases. the age of asymptomatic patients was younger than that of symptomatic patients. the white blood cell and lymphocyte counts were more decreased in symptomatic children cases than that in asymptomatic children cases, which was due to a lower inflammatory response in asymptomatic children cases. even among asymptomatic patients, 62.5% of cases had lung injuries. therefore, lung injuries caused by sars-cov-2 is still relatively obvious. the ct findings may further provide the reason why elevated levels of crp were shown in adults, but not in children and elevated levels of ldh are common in children. the spike-protein (s) of sars-cov that mediates entrance to human respiratory epithelial cells by interacting with cell surface receptor angiotensin-converting enzyme 2 (ace2) is the most important means of pathogenesis [19, 20] . the number of ace2 receptors are significantly lower in children than in adults and more in the lungs than in other organs [20] , which may be the primary reason why children have fewer clinical symptoms and organ dysfunction than adults and lung injuries even among asymptomatic children cases. in addition, the weak immune response triggered by viral infection because of children's weakened immune function maybe responsible for this state. in summary, most cases in children were mild and conventional cases, with mild clinical signs and symptoms, our data suggest that there is substantial lung injuries even among children, but that there is less clinical disease, perhaps because of a lower pronounced inflammatory response, and that the occurrence of this pattern appears to inversely correlate with age. acknowledgement thanks to dr. edward c. mignot, shandong university, for linguistic advice. author contributions yjh takes responsibility for the integrity of the data and the accuracy of the data analysis. yjh, wh, zxg, and zsw had full access to all data in the study. dwj had the idea of and designed the study. lq contributed to the review and zzf approved the final version. the authors have no conflicts of interest to disclose. ethical approval the project was approved by the ethics board of jinan infectious hospital (no. 20200203). pneumonia of unknown cause-china, emergencies preparedness, response, disease outbreak news, world health organization (who) early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia chinese center for disease control and prevention. coronavirus disease (covid-19) situation reports chinese center for disease control and prevention. coronavirus disease (covid-19) situation reports epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study clinical features of patients infected with 2019 novel coronavirus in wuhan interpretation of "guidelines for the diagnosis and treatment of novel coronavirus (2019-ncov) infection by the national health commission (trial version 5 a novel coronavirus from patients with pneumonia in china the continuing 2019-ncov epidemic threat of novel coronaviruses to global health: the latest 2019 novel coronavirus outbreak in wuhan, china origin and evolution of pathogenic coronaviruses genomic variance of the 2019-ncov coronavirus who. novel coronavirus (2019-ncov) situation reports. situation report-23 clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china coronaviruses post-sars: update on replication and pathogenesis early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating personto-person transmission: a study of a family cluster coronavirus spike proteins in viral entry and pathogenesis comparative genetic analysis of the novel coronavirus (2019-ncov/sars-cov-2) receptor ace2 in different populations key: cord-286531-3syf6upw authors: dong, chuanmei; cao, simin; li, hui title: young children’s online learning during covid-19 pandemic: chinese parents’ beliefs and attitudes date: 2020-09-08 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105440 sha: doc_id: 286531 cord_uid: 3syf6upw online learning has been widely promoted to replace traditional face-to-face learning during the covid-19 pandemic to maintain young children’s learning and play at home. this study surveyed 3275 chinese parents’ beliefs and attitudes around young children’s online learning during the lockdown of the covid-19 pandemic. most parents (92.7%) in the study reported that their children had online learning experiences during the pandemic, and many (84.6%) spent less than a half-hour each time. the parents generally had negative beliefs about the values and benefits of online learning and preferred traditional learning in early childhood settings. they tended to resist and even reject online learning for three key reasons: the shortcomings of online learning, young children’s inadequate self-regulation, and their lack of time and professional knowledge in supporting children’s online learning. also, the hardship caused by the covid-19 pandemic has made them suffering, thus more resistant to online learning at home. the results suggested that the implementation of online learning during the pandemic has been problematic and challenging for families. the chinese parents were neither trained nor ready to embrace online learning. the paper concluded with implications for policymakers and teacher education. learning, opportunities, and learning experiences children receive at home (erdogan, johnson, dong, & qiu, 2019) . to fill this research gap, this study endeavors to understand how chinese parents perceive their young children's online learning during the covid-19 lockdown through a large-scale online survey. online learning refers to "the learning experienced through the internet" either in the synchronous or asynchronous environment where students engage with instructors and other students at their convenient time and place (singh & thurman, 2019, p. 302) . online learning has seen a fast growth during the past decade because it has greater flexibility in terms of time, place and pace of the study, easier and more effective access to a wider variety and greater quantity of information, and lower financial cost (chen, 2010; khurana, 2016) . in a globalized digital age, government agencies, educational institutions, corporations worldwide are increasingly promoting online learning, resulting in a shift from traditional face-to-face classes to distance and online learning (aldhafeeri & khan, 2016) . with the advancement of new communication technologies, online learning can provide a rich, authentic learning ecology that can facilitate collaboration and interdependence between learners (aldhafeeri & khan, 2016) . however, researchers (chen, 2010; o'doherty, dromey, lougheed, hannigan, last, & mcgrath, 2018) have expressed their concerns about the quality of online learning and highlighted the main difficulties in creating an online learning community with a high degree of social presence and engagement. in addition, some scholars are also concerned about the major problems of online learning, such as social isolation, lack of interactivity and participation, delayed or insubstantial amount of feedback (khurana, 2016) . similarly, young children's digital learning has also been debated and criticized. some scholars (jiang & monk, 2015; radesky, eisenberg, kistin, gross, block, zuckerman, & silverstein, 2016) highlighted their concerns about online risks and dangers, addiction to videos, social isolation, and physical health issues. others suggested that parents play the mediating role to prevent harm and regulate children's online activities, such as setting up technology use rules for and monitoring their children's media use (nouwen & zaman, 2018) . all these concerns, however, could not prevent online learning from rapidly expanding in the past decade and extensively reaching millions of young learners at an unprecedented speed (franklin, burdette, east, & mellard, 2015; silverman, 2020; zalaznick, 2019) . more and more online programs have been developed and delivered to support young children with disabilities and/or living in remote or disadvantaged situations to provide learning flexibility (smith, burdette, cheatham, & harvey, 2016; zalaznick, 2019) . in addition, online technologies have become the social, cultural, and personal artifacts that inhabit the contemporary child's 'multimodal lifeworld' (arnott & yelland, 2020) . it thus should be promoted to build a multimodal learning ecology for contemporary children, parents, and teachers. while online learning appears to be more prevalent in the future (franklin et al., 2015) , a lack of research has addressed online learning in the early years, specifically. this study will fill this gap by surveying chinese parents who have engaged in their young children's online learning during the covid-19 pandemic. parents' beliefs and attitudes around early digital and online learning have been found polarized in the past decade. on the one hand, parents have started to appreciate the value of digital devices and tended to feel comfortable with young children's use at home (livingstone, mascheroni, & dreier, 2015; mikelic preradovic, lesin, & sagud, 2016; sharkins, newton, albaiz, & ernest, 2016) . they also supported the appropriate use of digital devices in early years settings (isikoglu erdogan, johnson, dong, & qiu, 2019; kumpulainen & gillen, 2019) . in particular, parents even held positive attitudes towards young children's computer use and believed that children should gain valuable technical skills and should be educated on how to use computers to enhance their academic development and future opportunities, such as employment (hatzigianni & margetts, 2014 , perradvoci et al. 2016 ). in the increasingly diverse digital landscape, parents believed that a range of digital and online technologies could offer young children new knowledge and learning. and those parents with a higher education level tended to believe that digital and online learning can develop children's learning competencies, language, self-expression, and social competencies (lepicnik-vodopivec & samec, 2013) . on the other hand, parents were concerned about the dangerous content on the internet and the risks of unrestricted digital use. they were worried about the impact of digital use on children's social and health development (plowman et al., 2012; lepinic & samec, 2013; jiang & monk, 2016) . more recently, due to the rapid growth of screen technologies (e.g., ipads, smartphones), parents have expressed their uncertainty about whether mobile devices could be beneficial or harmful to their children and how to adopt these mobile screen technologies (radesky et al., 2016 , livingstone et al. 2015 , erogan et al., 2019 . the eu kids online project (livingstone, 2015) , for instance, revealed that parents with higher income and education had employed a wide range of practices and strategies to manage restrictions for digital device use and had spent efforts to promote offline activities for children while limiting digital activities at home. some parents set rules and limits on the frequency and duration of using digital devices but did not recognize the importance of their role and involvement in supporting young children's technological engagements (plowman 2012 , hatzigianni & margartts, 2014 . the studies, as mentioned above, have explored parents' perspectives and practices on children's digital use in general, leaving their beliefs and attitudes about online learning unstudied. in particular, during the covid-19 pandemic, the sudden shift to online learning has presented new opportunities and unexpected challenges to the affected young children and their parents. under such unique circumstances, there is a need to examine parental beliefs and attitudes concerning online learning and readiness and acceptance to make this drastic shift. furthermore, most of the existing studies are western-centric and may not represent views from the eastern countries, where the culture and educational philosophies might differ. indeed, parental beliefs about digital technologies and media are not formed in a vacuum; instead, they are shaped by cultural norms (mansour, 2008) . thus, it is of great theoretical importance to understand chinese parental beliefs and attitudes around young children's online learning during the lockdown as a unique study in terms of time and place. the outbreak of covid-19 in wuhan started spreading in china in december 2019, and then was declared as the public health emergency of international concern by the world health organization (who) on 30 january 2020. the national authorities worldwide have responded to this crisis by implementing travel bans, lockdowns, workplace hazard controls, and facility closures. preschools, schools, and universities have been closed either on a nationwide or local basis in 172 countries, affecting approximately 98.5 % of the world's student population (unesco, 2020) . china is no exception. as an urgent response to the covid-19 pandemic, in early february 2020, the ministry of education of china (2020a) mandated that all schools and universities stop face-to-face teaching and use internet platforms to deliver online learning. school children were required to attend online classes to continue their education. although preschools were not required to deliver online learning and had no mandatory online educational programs, ece stakeholders including educators from public sectors and private curriculum developers were proactively engaged in designing digital curriculum resources and introducing educational apps and platforms to guide parents to support their children's learning and play at home (ministry of education, 2020b). under such circumstances, many chinese parents followed the suggestions from teachers and educational authorities to provide online learning to their children during the lockdown. such influences on parents in adopting online learning are not difficult to understand in chinese sociocultural contexts. chinese early childhood education is shaped by its social culture and educational tradition. confucian culture has strongly influenced the relationships between teachers and children in chinese society (llasera, 1987) , which has laid great emphasis on adoring authority and respecting teachers (hargreaves, 2000) . tobin et al., (1989, p. 209 ) found that the role played by chinese preschools and teachers in the relationship with families is "explicitly political and ideological." preschools are viewed as social representatives, so they have the "right and responsibility" to correct the deficiencies of indulgent parents. preschool teachers, "as government employees with a governmental mandate," carry authority into their interactions with parents and see their roles as supporting and correcting parents (tobin et al., 1989) . accordingly, the controversial digital and online learning for young children has been conducted under this unique and special circumstance in china. without training and preparation for online teaching, chinese parents and teachers have been engaged in this brand new experiment of digital and online learning for young children. naturally and expectedly, these parents and teachers might have encountered many difficulties, problems, obstacles in this unexpected experiment. thus, this unique scenario has provided an ideal arena for us to understand chinese parents' beliefs and attitudes around young children's online learning at home. accordingly, this study aims to address the following research questions through an online survey: 3. what were chinese parents' attitudes towards online learning for their young children? this survey study was conducted in an inland city of henan province, which is located in the central area of china. altogether 3275 parents whose children were enrolled in local early childhood education programs voluntarily completed the online survey. the majority of them were aged between 30-39 years (68.3%), and between 20-29 years (19.8%), few were aged between 40-49 years (11.0%), very few were 50 years or above (0.9%), and none was under 20 years. their educational levels were very diversified: junior secondary school, high school, associate degree, bachelor, and postgraduate degree. and their occupation also varied greatly: government/public organizations, state-owned enterprise, private enterprise, personal owned business, freelancer, and unemployed. most of the parents have one or two children; very few of them have three or four plus. half parents (50.5%) reported their children were 3-4 years old, and some (34.5%) were 4-5 years old. the background information of the sample is presented in table 2 below. the questionnaire consists of three parts and includes 41 closed questions and two openpart iii: parents' beliefs and attitudes around online learning. this section adopted a five-point likert scale (ranging from "strongly disagree" to "strongly agree") to ask for parents' perspectives about online learning. the 27 questions could be classified into three subscales. the 27 questions could be classified into three subscales. subscale one is about the pros and cons of online learning (9 items): parents were asked to compare online learning with the traditional face to face approach. to generate an initial pool of question items for measuring parents' beliefs and attitudes, previous studies on online learning (aldhafeeri & khan, 2016 , o'doherty, dromey, lougheed, hannigan, last, & mcgrath, 2018 , singh & thurman, 2019 were identified and reviewed. in particular, the two doctoral theses on the role and the effects of online learning were used to guide the design of the questionnaire items (chen, 2010 , khurana, 2016 . in their doctoral work, they compared both traditional and online education and examined the pros (e.g. convenience) and cons of online learning (e.g. lack of social presence) for learners. the main advantages and shortcomings identified in their study were 're-examined' in this study. specifically, the questions were centered on the efficiency, content, cost, effect, learning atmosphere, outcomes of online learning for young children and families. subscale two is focused on the value of online learning for young children (10 items): parents were asked to evaluate the value of online learning based on the five learning and developmental areas ( wellbeing, language, society, science, and arts) outlined by the educational authorities (ministry of education, 2012). as indicated earlier in the literature, specific research studying online learning in the early years is limited, this study aimed to fill this research gap by studying parents' beliefs about and attitudes towards the value of online learning for young children. as a result, the frequent topics and heated debates (e.g. brady & hill, 1984; elkind, 2007; house, 2012 , plowman, mcpake, & stephen, 2012 parents were asked to evaluate the impact of online learning on parenting and family education suggested by the educational authorities (ministry of education, 2020). since this study was conducted during the pandemic, online learning was provided as an alternative approach to supporting children's learning and family education at home. the questions were also used to examine the impact of online learning on parenting and family education (see the questionnaire in an appendix). the internal consistency of part iii was measured, and the reliability for its three subscales was 0.80, 0.89, and 0.78, respectively, indicating satisfactory reliability. the survey was administrated in middle march 2020 after parents and children had been quarantined at home for two months since china imposed national lockdown in late january. all the parents and young children had gained substantial experiences with online learning. the participants were invited by their children's preschools to complete this online survey conducted on wenjuanxing (www.wjx.cn), the leading online survey platform in china that provides functions equivalent to amazon mechanical turk. the participants were clearly informed throughout the study that participation in this research was completely voluntary, and they could withdraw their participation at any time without any reason. both quantitative and qualitative approaches were adopted in analyzing the data in this study. first, the quantitative data were analyzed using ibm spss 26.0 software. first, data cleaning was conducted, and the very few missing values (<0.5%) were replaced with the mean of the concerned variable. second, descriptive statistical analysis was performed to calculate the frequency, mean, and sd of parents' characteristics and children's online learning activities during the outbreak of covid-19. finally, for analysis, the responses were given a score for each item from one to five: 1=strongly disagree; 2=disagree; 3=neutral; 4 =agree; 5=strongly agree. items that were phrased negatively were subsequently re-coded to make the scales read in the 'positive' direction, lower scores, therefore, reflecting negative or less positive beliefs. the mean scores were calculated for each scale, which provides an overall picture of the parental responses. second, the qualitative data collected from the two open-ended questions were analyzed using nvivo 12 software. the two questions are: (1) what areas would you allow your child/ren to continue to learn online after the pandemic? 2) what are your comments or opinions on young children's online learning? the research team collaboratively conducted data coding and analysis. the process of coding the data was cyclical and iterative, involving numerous conversations among the two coders to eliminate inconsistencies in interpreting the data due to who was coding. throughout the coding process, coders worked from the same codebook, as exemplified in table 1 , which allows each coder in the research team to consistently and reliably analyze the data. the qualitative data were parents' brief comments to the open-ended questions, and they were mainly 1-3 short sentences. generally, the qualitative data collected were straightforward for generating categories. the two coders also met to discuss any disagreements of coding and used strategies (e.g. redefining the codes) to reach agreement on coding. thematic analysis (braun & clarke, 2008) was employed to identify, analyze, and report patterns generated from the data. the qualitative data analysis followed their step-by-step guide in six phases. (1) familiarising ourselves with the data; (2) generating initial codes, such as opposing online learning; (3) searching for themes; (4) refining and reviewing themes; (5) defining and naming themes; and (6) writing qualitative results. for instance, parents' comments were first coded into two broad categories: supporting online learning and opposing online learning. the initial categories were then reorganized and sorted into themes around reasons for and against online learning. among all the reasons identified, the three themes emerged: shortcomings of online learning, young children's inadequate selfregulation, and parental lack of time and professional knowledge. overall, most parents (92.7%) reported that their children had online learning experiences during the pandemic, and many (84.6%) spent less than a half-hour each time. specifically, these parents indicated that their children learned online once (43.1%) or multiple times (18.4%) per day, whereas some had only once or twice or three times per week. in addition, about one-third of the children had less than 15 minutes of online activities per time, and some had an average between 15-20 minutes. the majority of the parents used free online learning resources with no or meager cost. and the children's online learning was mainly delivered and guided by preschool teachers or other staff; some were guided by online apps, webs, and others, as shown in table 3 . table 4 presents the analysis results about the young children's online learning activities during covid-19. first, many young children watched the recorded lessons online once, or multiple times per day, some children watched only once or twice or three times per week, only a small percentage of them never did so. the children's online learning content was varied, including literacy, brain exercises, and science, as well as arts. a small number of parents commented in the open question that their children were learning physical exercise and language online. second, many young children attended the live class online once, or multiple times per day, some children attended only once or twice or three times per week, about of them never did so. third, many young children used wechat once, or multiple times per day, some children used it only once or twice or three times per week, and many of them never did so. fourth, many young children used the learning apps once, or multiple times per day, some children did it only once or twice or three times per week, but half of them (50.7%) never did so. fifth, majority of the children attended online with parent presence once (38.5%) or multiple times (31.3%) per day, some children did it only once (2.8%) or twice or three times (22.0%) per week, very few of them (5.3%) never did so. sixth, many children interacted with the instructor online once or multiple times per day, some children did this only once or twice or three times per week, many of them (16.3%) never did so. last, many parents interacted with the instructor online once (20.6%), or multiple times per day, half of them interacted only once or twice or three times (48.8%) per week, whereas many of them (17.3%) never did so. the quantitative data showed that the parents had relatively less positive beliefs about the value of online learning. the subscale one measured parental beliefs about the pros and cons of online education compared to traditional learning in educational settings. the mean for this scale was 2.54, with a medium standard deviation of 0.61. only a small percentage of participants believed that online learning has better learning content (18.4%), better learning outcomes (11.0 %), and is more efficient (12.6%) than the traditional approach. about half parents neither agreed nor disagreed on the statements about the pros and cons of online learning, indicating a neutral position on the value of online education. there were very few parents (1.7%) among those who provided the comments, indicating that under the special pandemic situation, online education can be used to support children's learning. furthermore, the qualitative data indicated that the parents believed that traditional learning in educational settings was better than online learning in creating a learning atmosphere with better learning outcomes. some parents even commented that "online learning at home does not have a learning atmosphere" (parent 7), "the efficiency of online learning is not high " (parent 30), and "online learning atmosphere is not good " (parent 14). these parents also explained their negative beliefs on online learning: lacking social interactions with peers, children did not treat online learning as a formal class; therefore were unable to focus on the learning. in addition, parents found it difficult to manage children's online learning at home as they did not have teachers' authority, as shown in the following quotes from their responses to the two open questions. the quantitative analysis indicated that the parents were less positive about the benefits of online learning. the subscale two had a mean of 2.80 and a medium standard deviation of 0.66. a small percentage of parents believed that online learning could enhance young children's language development (21.2%), literacy (25.2%), social skills (24.8%), independent skills (17.8%), arts (21.1%) and physical health (10.9%). in general, more parents perceived that online learning could help children gain more science knowledge (37.6%). approximately half of the participants had a neutral attitude towards the role of online learning for supporting children's development in language, literacy, independence, social skills, science knowledge, and arts. the qualitative analysis found that some parents commented that "during the special [pandemic] situation, children can learn online" (parent 1). in contrast, others argued that "although children can learn via online approaches, the learning quality is not good" (parent 20), and "the learning effect of online learning is bad" (parent 2). some parents further explained that young children had weak self-regulation and a short attention span thus could not engage in online learning. for instance, they commented " children are too young, and their mind can't concentrate" (parent 17) and "online learning efficiency is low, and children's self-regulation is poor, " (parent 10) and "their initiative is not high, although they were learning the content as they were in school." in addition, the parents indicated their strong resistance and opposition towards online education caused by their concerns about the negative effects on children's development. as shown in the following quotes from their responses to the two open questions, the parents believed that online learning had more harm to young children than its benefits. among all the concerns, the most critical one is about the negative effect on young children's eye vision. some parents emphasized the potential harm to young children's social development and physical health, especially eye vision. there was a dilemma for parents to adopt online learning for their children, as revealed by a parent: children can learn some knowledge via online approaches, but they would develop an interest in watching smartphones and tv, which is not good for their eyes. in general, many parents stated harm and challenges caused by online learning without mentioning any benefits, as shown in the following quotes. the quantitative data from subscale three measured parents' beliefs and attitudes about the impact of online learning on parenting and family education, with a mean of 3.21 and a standard deviation of 0.57. approximately half parents believed that online learning kept their children from doing nothing at home during the outbreak of covid-19 (60.5%) and improved parent-child relationship (47.6%) and inspired their educational ideas (47.8%), and allowed them to see that children can participate in many forms of activities (45.9%). overall, the parents had slightly more positive perceptions of the impact of online learning on their family education. in contrast, the qualitative data found that some parents perceived children's online learning as inconvenient, challenging, and time-consuming. about 1.6% of the parents expressed that "[online learning] wastes too much adults' working time (parent 16) and adds burden to parents (parent 26) and affects parents' work significantly (parent 31). this is because children do not have adequate self-control abilities (parent 34), and children's online learning needs parents to stop their job to accompany them at home (parent 17) and cost time and efforts (parent 30). in addition, these parents mentioned various barriers for them to implement home online learning, including time constraints and professional knowledge in teaching children. notably, the parents who had more than one child identified more barriers to their younger children's online learning and juggled between their carer and worker responsibilities. in total, about 8.7% of the parents commented that they would not recommend online learning in the early years, and they hoped online learning to be ceased as soon as possible after the pandemic. for instance, one parent wrote "disapprove online learning after the kindergarten reopens," while another commented, "hope to start kindergarten soon to implement traditional education." among these parents, some questioned the 'appropriateness' of online learning and similarly stated, "children are too young with weak self-regulation, and online learning is not appropriate," and ' online learning is not suitable for young children" (parent 19). such finding is also supported by the quantitative findings that only a few parents (8.9%) were willing to pay for online learning after the pandemic, and more than half of parents indicated that they would not allow their children to learn online once the covid-19 lockdown is over. as the first exploration of chinese parents' beliefs and attitudes around online learning during the covid-19 pandemic, this study has found that many young children had online learning experiences that were delivered by their kindergarten teachers or online learning apps at no or low cost. their parents, however, had different views about this online learning experience. this section will discuss these findings and their implications for future studies and practical improvements. firstly, this study found that the parents held a belief that online learning is less effective than traditional learning in early childhood educational environments. they believed that online education lacked a learning atmosphere and social interactions to engage young children, resulting in poor learning outcomes. these generally negative beliefs about online learning could be related to the two major causes. the first one is that the lockdown of covid-19 has caused a sudden shift to online learning. thus, it has challenged the traditional parental understanding of childhoods and expectations about early childhood educational practices, which should include free play and outdoor activities (stephen & edwards, 2018) . as noted by arnott and yelland (2020, p.126) , "challenges remain in our understanding of childhoods in the 21 st century and in integrating new technologies into children's learning cultures." the dominant ideas and popular discussion about childhoods in a digital age are either passive/at-risk or empowered (craft, 2012; dong, 2018; mertala, 2019b; stephen & edwards, 2018) . such polarised debates have led parents and educators to believe that young children's use of digital technology is inappropriate and often caused dilemma and confusion for those seeking to incorporate digital technologies into young children's learning (dong & mertala, 2020; house, 2012; isikoglu erdogan et al., 2019) . to support educators, parents, and children to use new technologies better, researchers advocated a reconceptualization of 'childhoods' and 'play' in the digital age so digital artifacts can be embraced as unique and distinct resources to provide them with new opportunities for learning and play (arnott & yelland, 2020; edwards, 2016) . therefore, these chinese parents need to update their knowledge and develop a new understanding of 'childhoods,' 'learning,' and 'play' through parental education or family-school partnership programs. the second cause might be the major shortcomings of online learning, as noted by the critics (khurana, 2016; chen, 2020; doherty et al., 2018) : social isolation and lack of interactivity, which have repeatedly been reported by the parents during this unexpected experiment. vlachopoulos and hatzigianni (2016) have emphasized the need to address critical issues around students' online learning experiences and course outcomes. this study, however, found that all these critical issues had not been solved, even though many advancements had been made in digital and online technologies. therefore, chinese parents tended to have negative perceptions of digital and online learning. secondly, this study found that most chinese parents had a major concern about vision problems caused by online and digital learning. such concern has been shared by many parents and early childhood educators internationally (hatzigianni & kalaitzidis, 2018; mertala, 2019a; sharkins et al., 2016; wartella & jennings, 2000) . in china, the prevalence of myopia appears to have rapidly increased in recent years, and more and more young children are reported to be short-sighted (ku, steptoe, lai, hu, chu, yen, & chen, 2019) . this problem has been attributed to the increased screen-time by the public (guarino, 2018) . therefore, the ministry of education and the seven other national authorities jointly issued (ministry of education, 2018) to regulate children's technology use by limiting the screen time. therefore, this concern reported by the chinese parents in this study is sensible and should be carefully addressed by the developers and designers of digital and online learning programs. thirdly, this study found that the parents were also worried about the lacking of physical activity as well as the addiction to screens such as tv and smartphones caused by digital and online learning. this concern is also reasonable and understandable, given that all the young children were quarantined at home during the covid-19 pandemic, and digital and online learning became their only channel to interact with teachers and peers. this finding is consistent with the existing ones that have suggested that parents and educators were concerned about the negative effect of screen time on young children's health development (edwards et al., 2012; livingstone et al., 2015; radesky et al., 2016; rhodes, 2017) . the chinese parents in this study reported using different strategies to restrict digital device use and making many efforts to promote offline activities for children while limiting digital activities at home. and some chinese parents have even planned to stop children's access to online learning once the pandemic is over. all these findings jointly indicated that chinese parents tended to view digital and online learning negatively. though this study was conducted in a different context (china) at a unique time , the findings of chinese parents' negative beliefs and attitudes around online learning are consistent with some western studies conducted in eu countries (livingstone, 2015 et al.,) and australia(australian government, 2019), which found that parents have been concerned about online risks and too much online time. specifically, the recent national survey of 3520 parents of children aged 2-17 that parents believed that their children spent too much time playing games, using social media, and streaming tv shows. however, the chinese parents tended to be more worried about children's eye vision deterioration caused by watching screens, which may be due to their younger age of their children in this study. first, this study found that chinese parents tended to reject online learning because their children had no or low self-regulation. this finding provides empirical evidence to support the claim that self-regulation is a prerequisite for successful online engagement and learning (vlachopoulos & chatzigianni, 2017) . furthermore, the chinese parents highly valued the linkage of self-regulation to the confucianism heritage that children should be self-restraint and self-regulate to follow the social rules and norms. this is more than the definition of self-regulation: "self-generated thoughts, feelings, and behaviors oriented to attaining goals" (zimmerman, 2002, p. 65) . however, this finding indicates that chinese parents might expect their children to learn and show self-control and self-regulation at a young age (luo, tamis-lemonda, & song, 2013) . second, this study found that chinese parents tended to reject online learning because their children were uninterested, inactive, and unfocused during online learning. this finding suggests that the young chinese children could not be regarded as self-regulated learners, who should be "metacognitively, motivational and behaviourally actively participants in their learning" (zimmerman, 1990, p. 4) . this finding, however, contradicts with the existing ones that young children were strongly interested in media and technology (sharkins et al., 2016) and that chinese children were curious and excited about digital programs (dong, 2016; dong & mertala, 2019; jiang & monk, 2015) . this discrepancy might be caused by the difference in the quality of digital and online learning, as one parent said that "the content of online learning is not very attractive to children" (parent 3). therefore, it might be the poor quality and boring content of online learning that has caused the resistance and even rejection of chinese children and parents. the media of digital and online learning itself might not be the cause. this is why vlachopoulos and hatzigianni (2017) suggested that the design of online learning played an important role in shaping learners' perceptions of online learning. third, this study found that many parents, especially those with more than one child, tended to reject online learning because they had no time to support children's online learning at home. this finding is consistent with that study by (li, shi, wu, & li, 2020) , who found chinese parents of only-child tended to have more opportunities and educational resources than those of non-only children. the parents of only-child would invest more time and energy to help their child to excel in academic performance. besides, the chinese parents in this study generally perceived online learning as time-consuming and burdensome. similarly, smith et al. (2016) found that online learning required parents' significant time commitment. but the american parents in their study still wanted to be engaged in their children's online learning, even though they were shocked by the time required to support their child's online learning. the chinese parents in this study, however, did not realize the importance of their involvement and tended to reject to support their children's online learning. last but not least, this study found that the parents were negative about online learning because the covid-19 lockdown had made them suffering from the hardships and the unexpected demand from online learning. they felt unable to educate young children as their conventional role was not the teacher of a child, and they were not trained to do so. chinese parents and grandparents were often blamed by teachers for spoiling their children (tobin, hsueh, & karasawa, 2009) and allowing too much screen time (dong & mertala, 2019 . therefore, they tended to feel unconfident to teach their children at home and believed that their "children listen more to their teachers and have a better learning atmosphere at school" (parent 13). accordingly, they were so eager to send their children back to preschools. digital and online learning is gaining popularity due to its advantages, such as greater flexibility, wider access, and low cost (khurana, 2016; chen, 2010) . however, this study found that the implementation of online learning during the covid-19 pandemic has been problematic and challenging for chinese families. chinese parents generally had negative beliefs and attitudes about the values and benefits of online learning and preferred traditional learning in early childhood educational environments. this is because they were neither trained nor ready to embrace online learning. the hardship caused by the covid-19 pandemic has made them suffer, thus more resistant to online learning at home. and these chinese parents were more concerned about the shortcomings of online learning, their children's inadequate self-regulation, and their lack of time and professional knowledge in supporting online learning. this study, however, has certain limitations. first, a large-scale quantitative study can provide representative and diversified evidence about the target topic. still, it has no way to gain an in-depth understanding of individualized situations and problems. interview or mixed-methods studies should be conducted to thoroughly explore chinese parents' authentic views, concerns, and difficulties. second, this online study simply collected self-report data, which might have a socially desirable bias. further studies with triangulation of methods (i.e., teacher-, self-, and peer-report) are needed to cross-check the results. nevertheless, for the first time, this study has investigated chinese parents' beliefs and attitudes concerning digital and online learning during the outbreak of covid-19. the national lockdown has unavoidably affected many children's physical attendance at educational settings and made online learning an emergent alternative to maintain the continuity of learning and play at home (early childhood australia, 2020; silverman, 2020). even though online learning has been widely promoted in china to replace traditional education during the pandemic, the findings of this study indicate that the chinese parents were neither trained nor ready for doing so. this implies that the educational authorities need to do more to get chinese parents ready for online learning and to consider more about young children's age and learning interests. the findings from this study have implications for policymakers and educators globally who are promoting online learning as an alternative to young children and their families during the pandemic. the promotion and implementation of online learning to replace traditional early childhood education during emergent situations like covid-19 need to be carefully considered and well planned to support families, rather than adding extra burdens to them. this means that the promoters should consider the complexity and diversity of families (e.g. more than one child learning online and parents' working full time at home) when suggesting an online class to young children, and provide parents with flexibility and convenience. in addition, the provider of online learning should improve the design of online programs (e.g. easy login) to make parents effortless in using the program. elkind, d. 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(equity). district administration self-regulated learning and academic achievement: an overview becoming a self-regulated learner: an overview. theory into practice: becoming a self-regulated learner ☒ the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.☒the authors declare the following financial interests/personal relationships which may be considered as potential competing interests:there is no research fund fo the project and the research has followed ethical procedure throughout the study. there is no conflict of interest. key: cord-274996-fk510s1v authors: babatunde, gbotemi bukola; van rensburg, andré janse; bhana, arvin; petersen, inge title: stakeholders' perceptions of child and adolescent mental health services in a south african district: a qualitative study date: 2020-10-02 journal: int j ment health syst doi: 10.1186/s13033-020-00406-2 sha: doc_id: 274996 cord_uid: fk510s1v background: in order to develop a district child and adolescent mental health (camh) plan, it is vital to engage with a range of stakeholders involved in providing camh services, given the complexities associated with delivering such services. hence this study sought to explore multisectoral dynamics in providing camh care in one resource-constrained south african district as a case study, towards informing the development of a model for district mental health plan and generating lessons for mental health systems strengthening to support camh services using the health systems dynamics (hsd) framework. hsd provides a suitable structure for analysing interactions between different elements within the health system and other sectors. methods: purposive sampling of 60 key informants was conducted to obtain an in-depth understanding of various stakeholders' experiences and perceptions of the available camh services in the district. the participants include stakeholders from the departments of health (doh), basic education (dbe), community-based/non-governmental organizations and caregivers of children receiving camh care. the data was categorized according to the elements of the hsd framework. results: the hsd framework helped in identifying the components of the health systems that are necessary for camh service delivery. at a district level, the shortage of human resources, un-coordinated camh management system, lack of intersectoral collaboration and the low priority given to the camh system negatively impacts on the service providers' experiences of providing camh services. services users' experiences of access to available camh services was negatively impacted by financial restrictions, low mental health literacy and stigmatization. nevertheless, the study participants perceived the available camh specialists to be competent and dedicated to delivering quality services but will benefit from systems strengthening initiatives that can expand the workforce and equip non-specialists with the required skills, resources and adequate coordination. conclusions: the need to develop the capacity of all the involved stakeholders in relation to camh services was imperative in the district. the need to create a mental health outreach team and equip teachers and caregivers with skills required to promote mental wellbeing, promptly identify camh conditions, refer appropriately and adhere to a management regimen was emphasized. page 2 of 12 babatunde et al. int j ment health syst (2020) 14:73 policy documents have helped to spur this [49] [50] [51] , notably the world health organization's (who) policy framework for child and adolescent mental health policies and plans [49] . however, the paucity of specific national camh policies and national implementation guidelines, poor intersectoral collaboration and the shortage of camh resources still hinder the provision of optimal child and adolescent mental health services in many countries [25] . the burden of camh has been well-described, especially in lmics [17, 37] . barriers to camh service provision in lmics will undoubtedly be aggravated by the covid-19 pandemic, an event that will substantially test the resilience and responsiveness of district health systems. it has already been noted that the pandemic will add to the current camh burden, and a strong system of governance, service provision and financing will be vital to ensure the well-being of children and adolescents [19] . two considerations have especially been part of strategies to reform camh services, namely task-sharing and intersectoral working. while camh services have historically been framed to be the sole responsibility of specialists, some recent studies have revealed the possibility and significance of integrating camh services into primary health care (phc) through the tasksharing approach [25, 30, 35, 47] . notably, the mental health gap project (mhgap) [51] includes guidelines for the management of several camh conditions at phc level within a task-sharing approach. in terms of intersectoral working, camh has historically been under the stewardship of the health sector. an intersectoral approach that involves the collaboration of other sectors such as education, social development and juvenile justice is required to achieve an effective camh system of care [10, 11] . while these considerations have been central to south africa's health policy landscape, the country lacks a wellarticulated camh strategy which is required to achieve a functional camh collaborative system at a district level [27, 33] . in the development of such a strategy, there is a need to involve a wide variety of stakeholders across multiple sectors, including caregivers, teachers, community and spiritual leaders [26] . haine-schlagel et al. [22] , emphasized that engaging various stakeholders was critical to achieving an effective camh service delivery. these multiple stakeholders, particularly teachers and caregivers (parents, grandparents, foster parents and other family members), are perceived to be active gatekeepers to camh care, given their vital role in identifying and seeking help for children and adolescents with mental (behavioural, emotional, social and developmental) disorders. despite the inclusion of camh in core national documents like the policy guidelines on child and adolescent mental health [14] and the national mental health policy framework and strategic plan 2013-2020 [16] , within the ideals of integrated, collaborative care (including task-sharing and intersectoral working, little to no guidance exists for provincial and district governments to translate national guidelines into operational tools for district governance of camh services. considering this, the study aimed to explore multisectoral dynamics in providing camh care in one resource-constrained south african district as a case study, towards informing the development of a model for district mental health plan and generating lessons for mental health systems strengthening to support camh services. the study was guided by the health service delivery (hsd) framework which describes health service delivery as a process by which policies, services providers and infrastructures are organized to achieve the goal of the health system which is to provide easily accessible and quality healthcare services [46] . the framework consists of ten elements, they include, (1) goals and outcomes, (2) values and principles, (3) service delivery, (4) the population, (5) the context, (6) leadership and governance, (7) finances, (8) human resources, (9) infrastructure and supplies, (10) knowledge and information. the premise of the hsd framework is that the health system is an open system which is often shaped and influenced by different societal factors. it describes health service delivery as a process by which policies, services providers and infrastructures are organized to achieve the goal of the health system which is to provide easily accessible and quality healthcare services. moreover, resources such as budget allocation, human resources, infrastructure and supplies, knowledge and information are fundamental to achieving a viable healthcare system for the populace. the population (service users) are described as major players within the health system. the authors emphasized that they are not mere patients but also citizens having rights to access quality healthcare. governance, as described by the hsd framework, entails policy guidance, coordination of the different stakeholders and activities at different levels of care and effective distribution of resources to ensure equity and accountability [46] . an instrumental case study which is used to obtain an in-depth understanding of specific issues was conducted with the amajuba district municipality as the unit of analysis [42] to explore the experiences of providing and accessing camh services in the district. employing a phenomenological qualitative approach using semi-structured interviews, the design allowed for the generation of in-depth information about lived experiences from multiple stakeholder perspectives [38] . the study was conducted in the amajuba district municipality, in the north-west region of the kwazulu-natal province of south africa. the district which covers 6911 km 2 with a population estimate of about 442,266, is made up of 3 sub-districts and comprises rural and periurban communities [1, 20] . amajuba has been identified as a resource-constrained district as it has limited numbers of health professionals, including mental health specialists to provide adequate health care services for the populace [20] . the bulk of the district's camh service capacity is situated in its three provincial hospitals. the district was a site for government piloting of the national health insurance programme-a government-driven initiative aimed to unify south africa's two-tiered health system by establishing a centralised funding mechanism in order to achieve universal health coverage [15] . as part of its pilot site status, the district had limited school mental health services as part of the integrated school health programme, an extension of the revitalisation of phc, that includes teams of health care workers (hcws) visiting schools to conduct basic screening and referral services [3, 31] . research participants were purposively identified according to their positions in the departments of health, social development and education. snowball selection was applied, leading to the identification and participation of 60 key role players involved in providing mental health care to children and adolescents in the district. participants included managers and mental health professionals from the department of health, managers, educators and mental health support workers from the department of basic education, non-governmental service representatives, as well as caregivers of children and adolescents living with mental health challenges. a list of camh cases and conditions identified in the district over 12 months have been published elsewhere [6] . these conditions included autism spectrum disorder, attention-deficit/ hyperactivity disorder (adhd), different forms of intellectual disability, depression, schizophrenia, bipolar affective disorders, mood disorder, anxiety, conduct disorder, mental and behavioral disorders tied to substance abuse. a full list of participants and the characteristics of children whose caregivers were included in this study are presented in tables 1 and 2 . data gathering for this study took place from february to march 2019. semi-structured interviews were used, allowing for the use of probes and follow-up questions to steer the discussion while allowing for the generation of in-depth subjective information [4, 13] . the interview guide was informed by the findings of an initial review of literature on the barrier and facilitators of camh services in low-and -middle-income countries [5] and the hsd framework. the interview guide covered a range of questions that explored the roles played by each stakeholder in relation to camh services, their perceptions, and experiences of child and adolescent mental health; experiences of accessing and providing camh services, and suggested pathways for systems improvement. all the stakeholders included in this study were either physically visited in their offices or contacted via e-mail, text messages, and telephonically to inform them and solicit their participation in the study. the majority of the stakeholders responded positively, and interview dates and time were secured. the operational manager at the madadeni hospital psychiatric out-patient department and the clinical psychologist at the newcastle hospital assisted with identifying caregivers and introduced them to the researchers. the caregivers were then informed about the study during clinic days and twenty caregivers consented to participate in the study. interviews were conducted in english and isizulu, depending on interviewee preference. the primary researcher (gbb), a doctoral student, conducted the english interviews while the isizulu interviewers were conducted by a trained research assistant with a bachelor's degree, who is proficient with the use of both isizulu and english language. the research assistant is also a resident of the community, and this facilitated easy rapport with the stakeholders. the interviews were audio-recorded, transcribed verbatim, translated, and back-translated where required. transcribed data were analysed using gale et al. 's [18] framework method, a summary process for managing and analysing qualitative data, which produces a series of themed matrices [44] . accordingly, six steps were followed: (1) transcription, (2) familiarisation, (3) deductive organisation of codes based on the elements of the hsd framework, (4) inductive coding of sub-themes under the hsd coding framework, (5) reviewing data extract and charting (6) mapping and interpretation of data [18, 40] . using these interconnected steps enabled the researchers to sort, scrutinise, categorise and chart the themes and associated sub-themes that emerged from the data set [8, 48] . the categories were reviewed to identify existing connections and differences between the themes from the different groups of stakeholders [45] . the excel software package (2019) was used in creating framework matrices and coding the entire data set. the accuracy of transcripts was checked against original recordings, and the two researchers (gbb and av) who conducted the analysis compared results at regular time points to harmonise the content of themes derived from raw data. also, the classification was discussed iteratively between the researchers, with input from study supervisors (ab and ip). to further ensure trustworthiness, the data set was thoroughly read through to confirm that the data was meaningfully clustered under the the themes and subthemes of the findings are presented here in narrative form, according to the constructs of the health system dynamics framework, starting with service delivery. direct quotations are added to illustrate key points. themes under this component will describe the structure of the camh system in the amajuba district. this includes a general "overview of camh services", and "identification and referral". camh services in amajuba district municipality were diverse. public sector professional mental health services were provided in a largely centralised fashion by psychologists based at the district regional hospital. this hospital served as a referral point for at-risk learners identified within the school system. service providers who helped to identify and refer children and adolescents potentially requiring mental health care were situated at different levels of the community, health and education systems, and included nurses in clinics, social workers in the communities, educators, learner support agents and school health nurses in schools. beyond the public health system, there were also a variety of non-government service providers who provided mental health services such as awareness campaigns, assessment and referrals to a limited degree. this included general practitioners, religious counsellors, non-governmental/non-profit organizations (ngos/npos) and traditional healers. in terms of the content of camh services, health care involved psychotherapy and psychopharmacological support, largely provided in the hospitals. educators and caregivers mentioned additional interventions to assist children in the school environment and at home. extra classes were organized for learners identified to be dealing with psychological challenges and struggling academically. they expressed that these interventions were insufficient and were negotiating for professional psychological assistance for the learners from the department of education. further, the department of social development provided disability grants to children with intellectual disabilities and autism, illustrated by the following: "i was advised to register her for the disability grant from the government, so that helps cater for her needs. we are fine financially because she receives the grant." (caregiver 4). a service that was described as especially problematic was early identification of camh problems and appropriate referral; with most camh conditions identified and referred by the school system-but were generally quite late in the illness progression, when they were affecting children's academic performances. very few cases were identified by health workers in hospitals, phc clinics, ward-based primary health care outreach teams (wbphcots), or by the caregivers. this finding was illustrated by the following: "in most cases what i found is that children are identified by their educators. they are identified there in school and then referred to the clinic and then from the clinics to us here. and, there are few cases where children are brought to the hospital for other things and mental health issues are picked up as a secondary problem that is seen, but otherwise in most cases it's the educators unless a child has a clear mental health issue that is visible then the child is brought into the health system by the caregiver." (clinical psychologist 1). once a child has been identified as needing mental health care, further steps depend on the specific space where identification occurred, and the nature of the perceived need. the educators and learning support agents (lsa) in schools mentioned that they provided some initial assessment and interventions before referring the children for further care. however, four of the twelve schools visited within the district still did not have any skilled staff or resources to provide initial camh assessment or interventions to assist their learners, they also did not have any information on the referral pathways. integrated school health programme (ishp) teams were yet to adopt mental healthcare into their activity portfolio. "we identify learners who have special needs, behavioral problems or learners who are abused physically, emotionally and socially. firstly, we screen those learners, fill the necessary forms and then we sit down with the learners to find out what the problem is, identify how we can help and if we cannot help, we call in supervisors from the dbe district office, then they will come and assist. they either do one-on-one sessions or sometimes they will take a group for assessment. after assessing them, if they see that the learners do have problems, they refer those learners to special schools. if it's a behavioral problem, they make sure that they do follow-up interventions like counselling or social work consultation and they refer some of the learners to the psychologists." (lsa, school c). a principal mentioned the need to train educators to prevent inappropriate referral and labelling. "….to take this matter seriously we need some resources to assist the schools, then the training of teachers also is important. i don't want teachers to wrongly identify and say it behaviour problem when the learner does not want to write due the relationships you have with that learner-so training of teachers is very important-so that they can be able to identify the learner." (principal 1). a senior mental health professional highlighted that the psychologists are mostly the first point of contact for children and adolescents with camh conditions within the hospital (most of the referrals from the schools are addressed to them) and they refer them to the appropriate specialists for cases in need of more specialized interventions. according to one of the psychologists: "when they come to us, they are mostly accompanied by their caregivers, if maybe they come from school they come with their educators. so, we do the debriefing to sort of understand the child's condition and give us a picture of what is going on so that we can determine which services they need, and then if they need to be referred to other specialists, we do that. (clinical psychologist 1) . the psychologist also mentioned inappropriate referral from schools, children with learning disabilities that should be referred to educational psychologists are referred to the clinical psychologists. this is due to the shortage of educational psychologists in the district, thereby resulting in back referral. "children with learning difficulties are often referred to us but we always refer them back to the department of education because they have an educational psychologist. we understand that she is the only one for the district, and she's not coping. because of this, schools tend to push them towards the department of health, but we don't do those assessments". (clinical psychologist 1). the availability and organization of camh resources in the district are presented below, according to human resources, infrastructure, and supplies, knowledge, and information. participants described a severe shortage of human resources to deal with camh problems within the departments of health and basic education. the service providers within doh mentioned that they are overwhelmed due to limited camh human resources, increasing camh workload and inadequate camh training for non-specialists. there was a widely-held view that camh services are limited in the district, but there was also sympathy from several participants that the few service providers were doing their best, and-under the circumstancespurportedly provided highly responsive care. caregivers were appreciative of the good communication and friendly engagement of key mental health professionals. this was illustrated by the quotation below: "we got a very great help, they really helped us, especially the provincial hospital… the services were very good, and they were very helpful. the medication he receives here is helping a lot. they communicate with me properly, i was even able to ask questions and they could answer, they have been very caring towards me and the child, so i can say it was very good. " (caregiver 2). the lack of mental health human resources, and the resulting limitations in providing care, was bemoaned by one mental health participant as follows: unfortunately, we can't see them more than once a month like everyone else because of staff shortage. however, if there is an urgent need for treatment, like sometimes we do fear that these persons might do something to harm themselves then we try to squeeze them in, but we just see them once a month. we usually make appointments in the mornings for people to come and see us… however, for school going-children we do make provisions for them, we see them in the afternoons, we schedule their appointments for 2 pm, so that at least they will be able to go to school in the morning. " (psychologist 1). some medical professionals noted that camh services provided opportunities for self-development, as most of them are medically qualified professionals without formal qualifications in psychiatry or child and adolescent psychology. "i enjoy providing camh services …it's very interesting and challenging but i learn from the experience and it motivates me to develop my skills…i was working with a doctor who was about to retire so i joined her and she exposed me to one or two things before she left. i have some years of experience in it now, but i'm not a child and adolescent specialist, we don't have any in the district as well. " (medical officer 1). the psychiatrist suggested that the camh system could be strengthened through the development of outreach teams to expand the camh workforce, ensure consistent in-service training across all the departments involved in delivering camh services, particularly for phc nurses to facilitate the integration of camh services into primary health care, conduct awareness campaigns and provide psychosocial support to families to strengthen the existing camh system. schools so that they can do in-service training and awareness campaigns… visit families because they need to capacitate them and support them. also, training, i have been yearning for this, the phc staff members should undergo camh training. " (psychiatrist). findings revealed that there were very few special schools catering for children with special needs in the district, and only two of them were equipped to admit children with camh conditions. an educator from one of the two schools stated that the school was overpopulated due to the increasing prevalence of camh in the district: "at first, we had the capacity of 150, but due to the increasing number of children with mental disabilities we have about 350 leaners, our school is full. " (educator 2, special school 1). there was widespread concern about the challenge of finding suitable schools for children whose mental health needs could not be met by their current schools. some children were not enrolled into school at all, because they were rejected by the mainstream schools, with the limited special schools available in the district being overwhelmed due to the lack of space and shortage of resources. a caregiver relates this as follows: "i once struggled to find a school for him and i am still having that challenge because i am yet to find one that can accept him. " (caregiver 7). in cases where caregivers were successful in placing their children in special schools, they received additional support in the form of transport services, as described below: "he is now studying in a special school, where they have trained teachers who are knowledgeable about his condition, so i am happy he is in the right place. they taught him how to write when he got there…he's now trying to write his name. it is just okay because they also provide him with transport. " (caregiver 13). the chief director of special schools from the district department of education explained the school placement procedure. "first, we do the placement assessment, when a leaner is referred for special school placement. a committee which consist of an occupational therapist, physiotherapist, the hod and the class teacher will sit to decide. we assess the physical ability of the child and then cognitive assessment all these assessments will assist us with class placement. you know, sometimes the learner comes to us at the age of 10 and never accessed any form of education, but we can't place them in the first year of school. after series of assessments, once we realize the level of assistance needed by the learner, we then recommend placement, we will then ask the parents to sign a consent form where they would agree that the learner should be enrolled into a special school. " (chief director, special schools). a caregiver also voiced her concern about the lack of higher education or opportunities for career development for adolescents with mental disabilities. "my worry is that when they reach the age of 18 they should not just stay home, there must be something for them to do because people take advantage of children in these kinds of conditions because a lot of them tend to wonder in the street after they leave school. maybe the government could help build a school that can take those that are over the age of 18. " (caregiver 17). there seemed to be a lack of knowledge in communities on identifying mental health symptoms at an early stage. in some cases, caregivers noticed some symptoms at an earlier stage, but they couldn't specify the nature of condition and did not access care for the child until they were identified and referred from school. these caregivers also mentioned that they could not seek help for the children because they didn't have a clear understanding of the conditions, where and how to seek medical care. this is illustrated below: "i noticed before the school called me, but i couldn't take any step because i didn't know what the problem was and where to take him for treatment until he was referred by the school, they gave me a letter and i took her to the hospital. " (caregiver 14) . some caregivers reported that they noticed certain symptoms of abnormality. although they couldn't ascertain the nature of the problem, they immediately sought help for the child. two of the caregivers took their children to the clinics close to them and were referred to the hospital while others took their children directly to the hospital. however, the caregivers who took their children directly to the hospital mentioned that they were requested to obtain referral letters from the school or a clinic. the following excerpt refers: "we noticed the problem at home, but we couldn't identify it as autism, so i brought him here to the hospital but then they said i should get a letter from his school about his condition. " (caregiver 11). the results under this component reveal the characteristics of the camh service users mainly caregivers of children with camh challenges in the district. government stakeholders described particular challenges in engaging with caregivers of children and adolescents with mental health needs. many caregivers were yet to accept their children's conditions and struggled to comply with the prescribed treatment regimen, and highlighted below: "i love working with the children but some of the caregiver are in denial they don't adhere to what you tell them whether its homework, time keeping, bookkeeping. it's kind of frustrating because you know the child should be improving, but the child is not because the parent or caregivers are not adhering. " (psychologist 1). the challenging nature of child and adolescent mental health conditions led to many of the caregivers describing feelings of concern, helplessness and exhaustion, as expressed below: "i cried a lot and even now i haven't accepted it because i have two children, both have same condition. i accepted with the first one, but i couldn't accept with the second one. it was really hard, and people were talking all they want about me and making fun of me that they rejected my children from school. " (caregiver 4). the complicated nature and under-resourcing of camh conditions further have a substantially negative effect on educators, not to mention the critical weight such conditions have on children's functioning, daily interactions with their environment, emotions, behaviors and academic performance, resulting in, among others, poor academic performance, school truancy and dropout. the below quotation refers: "their conditions affect us a lot; particularly it makes me sad. it affects us to such an extent that we end up not knowing what to do because we encounter such problems each and every day and there is no way we can help the children. it also affects their academic performance many of them are not doing very well academically, and some of them exhibit some behavioral problems. sometimes we spend extra time to assist some of them, we visit their homes and even give some learners money to buy grocery. " (educator 2). participants pointed to the lack of a coordinated system of camh care as a major barrier to providing and accessing camh services in the district. this was exemplified by, particularly, poor intersectoral collaboration, and the lack of a standardised procedure and coordination for delivering camh services across the various departments in the district. there were no adequately integrated procedures for managing and reporting camh cases. one participant referred to the overall system of care for children living with camh conditions in the district as "disjointed". an example of this disjointedness was that certain services were packaged for children in different age groups across the two hospitals, which often required caretakers to find means of transporting the children between the hospitals to access different specialist services. this is illustrated in the quotation below: factors that were perceived to impede camh service provisioning from the wider contexts of the district emerged. the coalescence of the district disease burden and resource shortages resulted in very limited health awareness being conducted, which in turn resulted in poor mental health literacy. tied to this barrier, it was often mentioned that there are high levels of stigma towards mental illness among children and adolescents, illustrated by the following: "she does get discriminated which is something that pains me a lot. we are even afraid to send her to the shops and they even discriminate her because of the school she is going to. " (caregiver 14). dysfunctional family systems were raised as a major risk factor and barrier to accessing camh services for children. the participants particularly emphasized the absence of parents-leaving children to the care of grandparents and other family members or leaving adolescents to care for themselves as a major problem in the community. the following quotation illustrates this point: "…most are from broken families; they stay with elderly people and we've got children heading the family. " (principal). "some of the parents are not staying with their children, they work and stay out of town… they come on month ends-just providing money-and leave the children to guide themselves. some children are in distressful situations because they were in a way abandoned by their parents. " (sanca coordinator). the study sought to explore service providers and service users' experiences of providing and accessing camh services and their perceptions of the available camh services in the district using the health system dynamics framework. key barriers and facilitators emerged for camh in the amajuba district municipality. certain community factors such as low mental health literacy resulting in misconceptions and stigmatization, and the dysfunctional nature of the family system within the communities were highlighted as major camh risk factors within the district that impedes access to camh services. community-based stigma can prevent caregivers from seeking help for their children, heflinger and hinshaw [23] stated that stigmatization increases the burden caused by mental illness and is a major barrier to accessing and utilizing mental health services. according to brannan and heflinger [7] , caregivers of children with mental disorders often experience the pernicious impacts of stigma and therefore delay accessing mental health services for their children. the study further revealed that the shortage of resources particularly camh specialists, lack of intersectoral collaboration and poor coordination, financial restrictions, and the low priority given to camh services in the district negatively impacts on the state of camh and serves as barriers to accessing camh services in the district. nevertheless, the few available camh specialists were perceived to be competent and dedicated to delivering quality services but could benefit from systems strengthening initiatives that could expand the workforce and equip them with the required skills, resources and adequate coordination. these findings corroborate the findings of a recent study conducted in the western cape province of south africa by mokitimi et al. [32] which highlighted inadequate camh resources, lack of priority for camh services and low levels of advocacy for camh services as major weaknesses of camh services in the province. the shortage of educational psychologists which resulted in inappropriate referrals, disruption of assessment procedures for children with intellectual disabilities and increased workload for the limited available clinical psychologists was reported as a major barrier to camh services by the doh stakeholders. hence, the need to employ more educational psychologists by the department of education to address the needs of children with learning challenges was suggested. stakeholders also suggested the provision of in-service camh training for psychiatric nurses, school health nurses, social workers and phc workers which could facilitate the adoption of a task-sharing approach considering the shortage of camh specialists in the district. while schools play a vital role in the identification and referral of camh challenges [36] , the dbe stakeholders reported that they lack the required skills, time and tools to adequately screen and refer children thereby hindering many children and adolescents living with camh conditions from accessing the required camh services. the lack of appropriately defined referral pathways for children and adolescents identified as having mental health problems also emerged as a major barrier to providing adequate camh services within the school environment. as mentioned earlier, the majority of children within the school environment identified as in need of mental health services were referred directly to the hospitals which resulted in bottlenecks, with long waiting lists. therefore, the dbe stakeholders suggested that efforts to build teachers' capacity to facilitate early identification, screening and referral for children and adolescents at risk to optimize their health and development, as well as their academic potential, should be explored. this would assist the teachers to distinguish between learning problems that should be referred to educational psychologists, social problems that require social work interventions and mental health conditions that require the services of clinical/counselling psychologists. a study conducted by cappella et al. [9] , emphasized the significant roles of teachers in delivering camh services. they proposed the use of an ecological model to strengthen teachers' capacity and facilitate active collaboration with mental health specialist for the reformation of schoolbased mental health services in low resource settings. the study underlined the lack of a coordinated and integrated system of camh services particularly the lack of collaboration between the different sectors providing camh services in the district. this lack of adequate coordination and collaboration accounts for the inadequate communication between the different sectors, undefined screening/assessment procedure and referral pathways which results in delayed access to mental health care and the development of required interventions to address the various conditions affecting children. this finding is similar to the findings of previous studies conducted in ghana, uganda, zambia and south africa [27, 33, 43] which identified the consequences of a weak intersectoral collaboration for the delivery of mental health services particularly camh services in low resource settings. the study participants emphasized the impact of camh conditions on the academic performance of children and adolescents which is further compounded by the shortage of special schools, the difficulties associated with securing school placements, the inadequate attention paid to the quality of education obtained and the lack of opportunities to pursue higher or vocational education after completing basic education for children and adolescents with camh challenges. many children and adolescents living with learning disabilities are not receiving the required educational help for their special needs leaving them to helpless. this finding corroborates the findings of a study conducted in a south african peri-urban township by saloojee et al. [41] who found that many children with intellectual disabilities are not enrolled in schools. the caregivers mentioned financial constraints, lack of knowledge on how to access the available services and lack of psychosocial support which they encountered daily in their pursuit to alleviate the conditions of their children. previous studies [2, 12, 21, 28, 34, 39] have also highlighted the psychological, physical and financial burden associated with caring for people with mental health challenges and the need to develop interventions that would equip caregivers with skills to alleviate these burdens. caregivers are central to camh prevention and effective management but require consistent support to acquire the necessary coping, communication, resilience, problem-solving and stress management skills. moreover, the need for intensive camh awareness programs was suggested by the participants as well as the need to organize camh outreach teams to disseminate camh information and implement community based camh services in the district. according to the participants, these strategies will increase the knowledge of camh within the communities and could eliminate stigma and misconceptions around camh conditions. however, hinshaw [24] proposed that stigma operates on multiple levels and mere public education programs might not resolve the problem of stigmatization. therefore, the need to incorporates different change strategies targeted at the different interacting levels within the communities is required. while a purposive sampling technique was used in selecting the study participants to obtain in-depth information on the current state of camh in the district, we acknowledge the various categories of stakeholders were a product of the differential availability of the stakeholders. it is possible that we might not have adequately captured the perspective of other key informants, particularly those within other sectors outside the dbe, doh and ngos/ cbos partnering with doh and dsd. however, the study included different categories of stakeholders to obtain rich data about the experiences and perceptions of camh service delivery in the district. the findings of this study suggest the need to create a district camh intersectoral coordinating or liaison forum to facilitate joint camh service planning and implementation to develop intersectoral agreements, developing defined referral pathways between relevant sectors, mobilizing resources, optimizing available resources within each sector, clarifying roles and responsibilities of the different sectors, promoting awareness and staff training on camh. moreover, the need for continuous in-service training and capacity building through supervision and mentorship for stakeholders in each of the sectors cannot be overemphasized as in-service training, mentorship and specialists support can facilitate the acquisition and the willingness to implement new skills. additionally, the development of management guidelines specifying the management procedures (identification, assessment, referral, treatment/interventions) for each sector and at the different levels of care should be prioritized. it is important to address the educational needs of children and adolescents living with camh challenges by mobilizing resources such as providing learning equipment, building more classrooms and creating professional support teams to expand the capacity of the available special schools to accommodate children and adolescents living with severe camh conditions specifically learning difficulties in the district. increased attention should also be paid to educating and providing the necessary socioeconomic support for caregivers of children and adolescent with camh conditions. caregivers should be sensitized about the importance of actively participating and complying with the management regimen recommended for their children's conditions within the health care system and school. it is also important to invest in a rigorous approach to disseminating mental health education especially camh information within the district to eliminate discrimination and stigma. these information dissemination strategies should include the transmission of camh messages using public-social media platforms, ensure regular camh information contacts at the community levels and provide adequate support and education at the family level. in conclusion, the need to build the capacity of all the involved stakeholders in relation to camh services is imperative in the district. although teachers and caregivers are not in a position to treat camh conditions, they can be equipped to identify children and adolescents with incipient mental health problems so that they access care early on in the illness progressions. they can also be equipped with knowledge and skills to support children and adolescents with mental health problems and adhere to management regimens. teachers could be assisted to promote mental health and resilience, identify and refer camh conditions through enhancing their mental health literacy and providing them with validated and appropriate screening tools. creating mental health outreach teams could further facilitate camh awareness within the communities thereby enhancing camh literacy and access to quality camh services. this could also potentially relieve the burden of care placed on the limited specialists and ensure a functional and sustainable collaborative system of camh care in the district. amajuba district municipality spatial development framework. 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action programme: scaling up care for mental, neurological and substance use disorders publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we would like to thank all the study participants who devoted their time and insight, mr. mercury nzuza, miss. patricia ndlovu, mr. fortune ngubeni and miss. kgothalang rethabile khadikane for the support provided during the data collection phase. the views expressed do not necessarily reflect the uk government's official policies. the funder did not have any involvement in the study design, collection, analysis or interpretation of data or writing of the manuscript. gbb and ip conceptualised the study, gbb collected data, gbb and av analysed data and gbb drafted the manuscript. av, ab and ip reviewed the manuscript, provided substantive revision. all authors read and approved the final manuscript. this study is an output of the programme for improving mental health care (prime). this work was financially supported by the uk department for international development (201446). g. b. b receives the university of kwazulu-natal scholarship. the datasets used and analysed during the current study are available from the corresponding author on reasonable request. gatekeeper permission was obtained from the relevant government departments, and ethics approval was provided by the biomedical research ethics committee, faculty of health sciences, university of kwazulu-natal (reference number be098/18). following an informed consent procedure, permission to participate and audiotape the qualitative interviews was obtained from each respondent. not applicable. the authors declare that they have no competing interests. key: cord-267907-zbsbqj9o authors: brown, samantha m.; doom, jenalee r.; lechuga-peña, stephanie; watamura, sarah enos; koppels, tiffany title: stress and parenting during the global covid-19 pandemic date: 2020-08-20 journal: child abuse negl doi: 10.1016/j.chiabu.2020.104699 sha: doc_id: 267907 cord_uid: zbsbqj9o background: stress and compromised parenting often place children at risk of abuse and neglect. child maltreatment has generally been viewed as a highly individualistic problem by focusing on stressors and parenting behaviors that impact individual families. however, because of the global coronavirus disease 2019 (covid-19), families across the world are experiencing a new range of stressors that threaten their health, safety, and economic well-being. objective: this study examined the effects of the covid-19 pandemic in relation to parental perceived stress and child abuse potential. participants and setting: participants included parents (n = 183) with a child under the age of 18 years in the western united states. method: tests of group differences and hierarchical multiple regression analyses were employed to assess the relationships among demographic characteristics, covid-19 related stressors, mental health risk, protective factors, parental perceived stress, and child abuse potential. results: greater covid-19 related stressors and high anxiety and depressive symptoms are associated with higher parental perceived stress and child abuse potential. conversely, greater parental support and perceived control during the pandemic may have a protective effect against perceived stress and child abuse potential. results also indicate racial and ethnic differences in covid-19 related stressors, but not in mental health risk, protective factors, perceived stress, or child abuse potential. conclusion: findings suggest that although families experience elevated stressors from covid-19, providing parental support and increasing perceived control may be promising intervention targets. it is well-established that exposure to stressors play an important role in child maltreatment potential (rodriguez-jenkins & marcenko, 2014; whipple & webster-stratton, 1991) . exposure to stressors can lead to cognitive, emotional, and physical fatigue, which may in turn place undue strain on the parent-child relationship (deater-deckard, 2004) . indeed, as parental stress levels rise, parents may be more likely to engage in harsh parenting (beckerman et al., 2017) , thereby increasing the risk of child maltreatment (martorell & bugental, 2006; rodriguez & green, 1997) . however, certain factors, such as perceived control over stressful events or supportive family environments, may act as buffers to decrease distress and the risk of child maltreatment (frazier et al., 2011; li et al., 2011) . despite ample evidence linking individual and family level stressors with poor parenting and child maltreatment, families across the world are collectively experiencing a new range of stressors that threaten their health, safety, and economic well-being due to the global coronavirus disease 2019 (covid-19) pandemic. although is not the only global public health challenge to threaten society, it will likely have long-term negative impacts on today's children and families. the greater awareness of the impact of stress as we all experience a global pandemic offers an opportunity to better understand how stressors external to the family increase risk of maltreatment. as such, this study examined the influence of risk and protective factors on parents' perceptions of stress and risk of child abuse potential during the covid-19 pandemic. stress can accumulate as a result of a broad range of factors. in the context of child maltreatment, a large body of literature focuses on stressors at the individual and family levels (i.e., ontogenic and microsystem levels, respectively; cicchetti & lynch, 1993; cicchetti & rizley 1981 ). that is, child maltreatment may occur from stressors that result from economic hardship, low education, single parenthood, or a large number of dependent children (centers for j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 3 disease control and prevention, n.d.; sedlak et al., 2010) , among others, but that might not otherwise impact persons outside of the family. research indicates that there is not a single factor that is related solely to child maltreatment; instead, the accumulation of risk factors is a more robust indicator of adverse outcomes (patwardhan et al., 2017; sameroff, 1979) . moreover, the extent to which co-occurring stressors affect adverse outcomes, such as poor parenting behaviors, may be due, in part, to the ways through which individuals perceive these events as stressful. in other words, the degree to which situations in one's life are appraised as stressful (i.e., perceived stress) can influence adaptive versus maladaptive outcomes (cohen et al., 1983; lazarus, 1977) . consequently, parents experiencing elevated levels of cumulative stress show more rigid and abusive parenting behaviors (hutchison et al., 2016; liu & merritt, 2018; yang, 2015) . the global covid-19 pandemic is a stressor that originated outside of the family system but given the novelty and uncertainty concerning this disease, it is likely to be perceived as a significant stressor for many parents and children. in fact, emerging research has shown that parents' perceived impact of covid-19 is associated with increased parenting stress and, in turn, increased risk of harsh parenting (chung et al., 2020) . even for families who have not been directly exposed to the virus, they are likely to experience indirect effects of the covid-19 pandemic (van bavel et al., 2020) . for example, in countries outside of the united states, covid-19 has led to serious mental health burden (e.g., marazziti et al., 2020; pierce et al., 2020) , with the prevalence of anxiety, depression, and sleep problems ranging from 18% to 35%, especially among younger individuals who are preoccupied with thoughts regarding the disease (huang & zhao, 2020) . given that there are already mental health implications associated with the covid-19 health crisis, children in families with more risk factors may be more vulnerable j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 4 to child maltreatment. indeed, parents with elevated stress and co-occurring anxiety and depressive symptoms have been shown to be less responsive to their children's needs, which in turn is a strong predictor of child abuse potential (mcpherson et al., 2008) . although several public health efforts were taken to mitigate transmission of covid-19 after its emergence, these efforts have had unintended consequences that could further impact parent-perceived stress and poor parenting. specifically, actions included recommendations to increase physical distancing as well as to close schools, childcare agencies, and many customer service businesses. as a result, families are more likely to experience increased social isolation, the inability to access supportive and educational services, and economic difficulties, which may exacerbate stress in many households. in fact, social isolation increases susceptibility to stress and may have harmful effects on both mental and physical health (hawkley & cacioppo, 2010) . parents who are faced with competing demands of limiting social interactions and remaining at home with their children may be particularly vulnerable during this time; research shows that continual close contact under stress is a risk factor for aggressive behaviors and violence (brooks et al., 2020; greenaway et al., 2014; reynolds et al., 2008) . furthermore, some families are experiencing other challenges, such as working from home while also caring for and educating their children. given that school and childcare professionals are central to identifying concerns of abuse and neglect (fitzpatrick et al., 2020; u.s. dhhs, 2020) , children who may have once been identified as at risk in these settings may be more vulnerable to maltreatment as they spend most of their time at home. some families are also experiencing more financial strain as a result of the changing economy and increasing unemployment. although the stresses of poverty have long been associated with increased risk of child maltreatment, several specific economic indicators may be particularly implicated in abuse potential. for example, the rise in j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 5 unemployment and foreclosure rates are associated with an increased likelihood of investigated and substantiated maltreatment (frioux et al., 2014) . in addition to changes in the economy, other social conditions may worsen the impact of covid-19 related stressors on overall perceptions of stress and parenting, particularly among minoritized populations. the centers for disease control and prevention (2020) reported that covid-19 disease burden is disproportionately high among racial and ethnic minority groups, such that black/ african american and latinx individuals are more likely than their white counterparts to acquire the illness, be hospitalized, and die from covid-19 (centers for disease control and prevention, 2020) . systemic inequities contribute to disparities in health outcomes among minoritized populations. for example, families of racial and ethnic minorities experience racism and discrimination (e.g., brondolo et al., 2009) and may be less able to social distance due to increased segregation into residential housing, (iceland et al., 2010; popescu et al., 2018) , limited paid sick leave (bartel et al., 2019) , and inadequate access to health insurance and health care phillips et al., 2000) . these economic and social inequities may in turn place minoritized families at greater risk for increased stress and disparate outcomes during the covid-19 pandemic. however, not all parents experiencing cumulative stressors from covid-19 may be at risk of higher perceived stress or poor parenting, suggesting that protective factors may mitigate the impact of covid-19 on parental stress and child abuse potential. specifically, adaptive coping strategies and supportive family environments may serve as protective factors for families experiencing stress and may differentially influence abuse potential. for example, perceived control is a key construct in understanding stress and coping (dijkstra & homan, 2016) . indeed, the belief that one has influence over life events is related to different psychological and j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 6 behavioral outcomes. perceived control over present events is associated with decreases in overall stress, anxiety, and depression as well as better adjustment across situations (ballash et al., 2006; frazier et al., 2004; grote et al., 2007) . similarly, other coping strategies, such as acceptance, or the ability to accept negative thoughts or experiences without judging them, are strongly and negatively associated with perceived stress (donald & atkins, 2016) . in addition to adaptive coping strategies, supportive family environments may also be promotive in the context of parenting. previous research shows that mother's perceptions of family support are associated with less parenting stress; thus, parents with more support are better able to engage in positive parenting (deater-deckard, 1998; sanders et al., 2014) . consistent with the ecologicaltransactional model of child maltreatment (cicchetti & lynch, 1993; cicchetti & rizley 1981) , risk and protective factors compete at each level of the ecology, namely the macrosystem (cultural level factors), exosystem (community level factors), microsystem (family level factors), and ontogeny (individual level factors) to affect maltreatment and developmental outcomes of children. experiencing multiple risk factors across levels of the ecology may increase risk of child abuse potential in an additive manner. importantly, however, certain factors may also protect a family from the accumulation of stress, thereby acting as main effects in decreasing the risk of maltreatment. despite a robust literature on myriad risk and protective factors implicated in parentperceived stress and child maltreatment, little research has been done to examine the extent to which cumulative stressors from global pandemics shape overall perceptions of stress and impact parenting. indeed, very few articles have been published to date regarding covid-19 in relation to stress and family violence (e.g., campbell, 2020; prime et al., 2020) , particularly risk of child abuse potential. the current study offers exploratory evidence to address the following research procedure families were recruited from child-and family-serving agencies and educational settings in the rocky mountain region of the united states. agency staff shared the study with families they served. families were also contacted about the current study by phone or email if they had participated in previous studies conducted by the research team. parents, aged 18 years or older, with a child under the age of 18 years were invited to participate in the study and provided an online survey link that was administered via qualtrics. the survey was available from april 21, 2020 to may 9, 2020 and took approximately 20 minutes to complete. participants were compensated with a $10 gift card after completion of the survey. two hundred and sixteen participants began the survey; however, 33 participants were not included in final analyses for the following reasons: (1) they did not correctly complete a study validation question to ensure they were not completing questions at random (n = 21), (2) they indicated that another caregiver in the household completed the survey (n = 4); these participants were removed to eliminate interdependent data, and (3) they did not complete at least half of the survey (n = 8); participants could progress through the survey and select 'prefer not to answer' to questions they did not wish to answer in order to indicate study completeness. therefore, the final sample included 183 j o u r n a l p r e -p r o o f demographic characteristics. basic demographic characteristics included parent age, gender, race/ ethnicity, education, relationship status, receipt of financial assistance, and number of adults and children in the household. the following variables were recoded for analyses: parent gender (0 = male, 1 = female), relationship status (0 = single or partner not living in the home, 1 = married or partner living in the home), and financial assistance (0 = not receiving financial assistance, 1 = receiving any financial assistance). in addition, because few participants identified as american indian or alaska native (n = 1), asian (n = 4), or other race/ ethnicity (n = 1), racial and ethnic categories were recoded as follows: 1 = american indian or alaska native, asian, mixed race/ ethnicity, or other race/ ethnicity ("other or mixed race/ ethnicity"), 2 = black/ african american, 3 = latinx, and 4 = non-latinx white, with non-latinx white as the reference category. because no or few participants had no schooling (n = 0) or indicated the highest education completed was 1 st -8 th grade (n = 3) or trade school (n = 7), education categories were recoded as follows: 1 = less than high school, 2 = high school graduate/ ged, 3 = some college, 4 = associates degree or trade school, 5 = four-year college degree, and 6 = post graduate degree. for each demographic characteristic, participants could also select "prefer not to answer"; these responses were subsequently recoded as missing. covid-19 stressors were assessed using investigator developed questions. using a checklist, parents were asked to indicate whether they or their children experienced any stressors as a result of covid-19 stay-at-home restrictions and school and childcare closures in the following domains: 1) parent mood or stress, 2) parent physical j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 9 health, 3) parent's relationship/ interactions with partner, 4) parent's relationship/ interactions with child(ren), 5) child(ren)'s physical health, and 6) child(ren)'s academics/ learning. given prior research on cumulative risk in relation to child maltreatment (e.g., lamela & figueiredo, 2015) , which postulates that poor outcomes are due to the accumulation of individual risk factors, items were dichotomously coded to indicate whether stressors in that category occurred (0 = no, 1 = yes); these items were subsequently summed to create a total covid-19 risk score. parents were also asked whether or not they knew someone who tested positive for covid-19 (0 = no, 1 = yes) or who died from covid-19 (0 = no, 1 = yes); these responses could include a partner or spouse, child, family member, friend, or someone else they know. finally, parents were asked an open-ended qualitative question, "in general, how has your life been affected (e.g., mental, physical, financial health, relationship difficulties, etc.) by covid-19 and recommendations to isolate?" mental health risk factors. parent anxiety, depression, and sleep were assessed as possible mental health risk factors. parental anxiety was measured by a single item from the general anxiety disorder-7 scale (gad-7; spitzer et al., 2006) : "during the past two weeks, i felt nervous, anxious, or on edge" (0 = not at all, 1 = several days, 2 = more than half the days, 3 = nearly every day, 4 = prefer not to answer). the item was recoded into a dichotomous anxiety indicator where "not at all" was coded as 0 and "several days" to "nearly every day" were coded as 1. "prefer not to answer" responses were coded as missing. parental depression was measured by a single item from the center for epidemiologic studies depression scale (cesd-r; radloff, 1977) : "during the past week, i felt depressed" (1 = rarely or none of the time, 2 = some or little of the time, 3 = occasionally or a moderate amount of time, 4 = most or all of the time, 5 = prefer not to answer). the item was recoded into a j o u r n a l p r e -p r o o f dichotomous depression indicator where "rarely or none of the time" was coded as 0 and "some or little of the time" to "most or all of the time" were coded as 1. "prefer not to answer" responses were coded as missing. poor parental sleep was measured by a single item indicator from the center for epidemiologic studies depression scale (cesd-r; radloff, 1977) : "during the past week, my sleep was restless" (1 = rarely or none of the time, 2 = some or little of the time, 3 = occasionally or a moderate amount of time, 4 = most or all of the time, 5 = prefer not to answer). the item was recoded into a dichotomous depression indicator where "rarely or none of the time" was coded as 0 and "some or little of the time" to "most or all of the time" were coded as 1. "prefer not to answer" responses were coded as missing. protective factors. parental support, perceived control over the covid-19 pandemic, and acceptance were assessed as possible protective factors. parental support was measured using the parental support subscale from the parent-child relationship inventory (pcri; gerard, 1994) . the parental support subscale consists of nine items measuring the level of emotional and social support a parent receives. parents indicate the extent to which they agree or disagree with each item (1 = strongly agree, 2 = agree, 3 = disagree, 4 = strongly disagree). example items include: "when it comes to raising my child, i feel alone most of the time", "i sometimes feel overburdened by my responsibilities as a parent", and "i have someone to help me do chores around the house." three items are reverse coded, items are summed, and higher scores indicate positive parenting characteristics (i.e., higher parental support). in this sample, the pcri parental support subscale demonstrated acceptable reliability (α = .71). perceived control over the covid-19 pandemic was measured by the present control subscale of the perceived control over stressful events scale (frazier et al., 2011) . the present j o u r n a l p r e -p r o o f control subscale consists of eight items measuring the extent to which individuals believe they have control over a current event; we asked parents to respond to each item with regard to the covid-19 pandemic and how they have felt in the past two weeks (1 = strongly disagree, 2 = disagree somewhat, 3 = agree somewhat, 4 = strongly agree). example items include: "there isn't much i can do to help myself feel better about the event", "how i deal with this event now is under my control", and "when i am upset about the event, i can find a way to feel better." four items are reverse coded, items are summed, and higher scores indicate better perceived control over the stressful event. in this sample, the present control subscale demonstrated acceptable reliability (α = .79). regulation questionnaire-short form (cerq/sf; garnefski et al., 2001) . the acceptance subscale consists of two items measuring an individual's thoughts and cognitive strategies after having experienced a negative event (1 = never, 2 = sometimes, 3 = regularly, 4 = often, 5 = always). items include: "i think that i have to accept that this has happened" and "i think i have to accept the situation." items are summed and higher scores indicate better coping (i.e., higher acceptance). in this sample, the cerq/sf acceptance subscale demonstrated acceptable reliability (α = .78). primary outcomes. perceived stress and child abuse potential were assessed as the primary outcomes of the study. perceived stress was measured by the perceived stress scale (pss-10; cohen et al., 1983) . the pss-10 consists of 10 items measuring individuals' thoughts and feelings regarding potentially stressful situations that occurred in the past month (0 = never, 1 = almost never, 2 = sometimes, 3 = fairly often, 4 = very often). example items include: "in the last month, how often have you been upset because of something that happened unexpectedly?", j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 12 "in the last month, how often have you felt nervous and stressed?", and "in the last month, how often have you found that you could not cope with all the things that you had to do?" items are summed and higher scores indicate greater perceived stress. in this sample, the pss-10 demonstrated good reliability (α = .83). child abuse potential was measured using a revised version of the brief child abuse potential inventory (cap inventory; milner, 1986; ondersma et al., 2005) . the original cap inventory (milner, 1986) consists of 160 total items, which are shown to distinguish parents who may be abusive from those who may not (milner & wimberely, 1980) . the cap inventory can be divided into factor scales describing psychological difficulties and interactional problems (e.g., distress, rigidity, family conflict, loneliness). to reduce participant burden, for this study, 10 items were used from a brief version of the cap inventory (ondersma et al., 2005) , specifically from the loneliness, rigidity, and family conflict factor scales in which participants were asked whether they agree or disagree with several statements. example items include: "my family fights a lot", "children should never disobey", and "a child needs very strict rules." items are summed and higher scores indicate greater child abuse potential. in this sample, the revised cap inventory demonstrated good reliability (α = .80). descriptive statistics (means, standard deviations, and percentages) were used to describe the sample demographic characteristics and study variables. because emerging research has shown that families of diverse racial and ethnic identities may be disproportionately impacted by the covid-19 pandemic, chi-square and one-way anova analyses were conducted to examine whether there were racial and ethnic differences in covid-19 risk factors, mental health risk factors, and protective factors. next, relationships among key variables of interest were j o u r n a l p r e -p r o o f running head: stress, parenting, and covid-19 13 examined using pearson's bivariate correlations. finally, hierarchical multiple regression analyses were conducted to test correlates of: (1) parental perceived stress and (2) child abuse potential. for each of the two regression models, correlates were entered sequentially in four steps: first, demographic characteristics; second, covid-19 risk factors; third, mental health risk factors; and fourth, protective factors. this allowed for an assessment of the unique relationships between covid-19 and mental health risk factors and study outcomes as well as whether protective factors mitigated perceived stress and child abuse potential over and above these risks. prior to conducting hierarchical multiple regression analyses, we examined variables for missingness using little's test of missing completely at random (mcar; little, 1988) and found that values were not missing at random (p = .39); therefore, missing data were handled with listwise deletion. to examine responses to the single open-ended question regarding how participants' lives have been affected by covid-19 and recommendations to isolate at home, qualitative template analysis was used to explore stressors as well as potential positive experiences. common themes were then identified within these categories, which allowed for a hierarchical method of coding in which broad themes were used to encompass more specific codes and/or patterns (padgett, 2008) . the themes identified were then summed across participant responses to calculate their frequencies and percentages. two of the authors coded a subset of the questions with high rates (85%) of interrater reliability. detailed sample characteristics are provided in table 1 . participants included parents, ages 18 to 55, of a child under the age of 18 years. the majority of participants were mothers and racially/ ethnically identified as non-latinx white, followed by latinx, other or mixed race/ ethnicity, or black/ african american. participants were mostly married or had a partner living in the home and had some college or higher education. participants indicated that they received some form of financial assistance, with most participants receiving medicaid coverage, followed by food stamps, women, infants, and children (wic), free or reduced cost childcare, unemployment, cash assistance/ temporary assistance for needy families (tanf), housing assistance, alimony/ child support, or other financial assistance. regarding stressors from covid-19, participants reported experiencing approximately 3.5 stressors, on average, which most often included stressors due to changes in parent mood or general stress, followed by changes in parent's relationship/ interactions with child(ren) and with partner, parent physical health, and child(ren)'s academics/ learning and physical health. over half of the sample knew someone who tested positive for covid-19 and slightly over one-quarter of the sample knew someone who died from covid-19. most participants also indicated that they experienced high levels of anxiety symptoms, depressive symptoms, and poor sleep in the past one to two weeks. participants reported that there were on average approximately two adults and two children in their households. [insert table 1 about here] regarding racial and ethnic differences in covid-19 risk factors, mental health risk factors, and protective factors, there were no significant differences across racial and ethnic groups for knowing someone who tested positive, x 2 (3) = 4.03, p = .26; or died from covid-19, 3.60, sd = 1.41) was also significantly higher than the mean score of covid-19 related stressors for black/ african american parents (m = 2.14, sd = .90; 95% ci, .28 -2.62). results of the bivariate correlations among key study variables can be found in table 2 . the first hierarchical multiple regression model regressed parental perceived stress on demographic characteristics, covid-19 risk factors, mental health risk factors, and protective factors. results for each block are reported separately in text, while results for the hierarchal multiple regression model retained from the fourth block can be found in table 3 .05) were significantly and negatively associated with perceived stress, indicating that these factors may mitigate and protect against increased perceived stress. [insert table 3 .14, p < .001). specifically, parental support (b = -.23, p < .001) and perceived control over the covid-19 pandemic (b = -.11, p < .05) were significantly and negatively associated with abuse potential, indicating that these factors may mitigate and protect against increased risk of child abuse potential. [insert table 4 about here] participants were asked to describe how their life has been affected by covid-19 and recommendations to isolate at home. several themes were identified from the single open-ended question inquiring about their experiences. table 5 provides the frequency and percentages of themes that emerged from participant responses. participants reported that they experienced increased stressors in the areas of: (1) loss of employment or income/ inability to provide for family, (2) uncertainty about the future, (3) inability to see family or friends or socialize with others, (4) relationship difficulties, (5) general stress and feeling tired, (6) poor mental health, (7) poor physical health, (8) meltdowns and/or boredom from children, (9) difficulties managing children's academics, (10) fear of contracting the virus or hearing about people dying from the virus, (11) lack of supports, and (12) difficulties managing work from home. loss of employment or income and an inability to provide for their family was the most salient stressor. for example, one parent stated, "it's been difficult trying to pay my bills with being unemployed at the moment." another parent said, "[our] financial health has been very poor with both of us out of work and not qualified for unemployment. this leads to greater stress." some parents reported negative impacts on their own health and well-being in order to care for their children. specifically, one parent expressed that "to make sure my baby is taken care of during this time…i sometimes go without food." the inability to see family or friends or socialize with others was also a common stressor among participants. one parent stated, "i have found myself to be stressed and on edge constantly. i miss interacting with people outside my home and office." parents reported that their mental health has also been impacted by the stay-at-home restrictions. one parent reported, "depression has affected us in our household." other parents reported experiencing multiple stressors that intersect across themes. for example, a parent expressed "experiencing fear and anxiety about contracting the virus." this parent also stated, "i was laid off my job, so i feel worried financially about the future." one parent described that the inability to go outside increases stress and "more meltdowns" from their children. another parent reported: it's been mentally and physically stressful dealing with quarantine. small house. my husband has been recovering from… [an] injury and now has to be a teacher, housekeeper, and try to heal himself at the same time. it's hard for me to go to work every day as an essential worker and be exposed to potential infection. finances are a mess and we are relying on food stamps and food banks/ free dinners. despite participants reporting an increase in stressors, some parents reported no change or positive change as a result of recommendations to self-isolate and stay at home. positive or neutral themes emerged as follows: (1) (earls et al., 2008; lau et al., 2008) . disease control and prevention, 2020; hooper et al., 2020) , and several studies indicate that stress processes in families may differ both within and across racial and ethnic groups (gomel et al., 1998; goosby et al., 2012) . particularly for latinx families, familismo is commonly recognized as a core latinx value. familismo involves strong identification with and attachment to a nuclear extended family as well as an obligation to provide both material and emotional support to one's family (calzada et al., 2012) . the absence of family support due to the stay-athome restrictions and physical distancing could explain latinx parents' higher report of covid-19 related stressors compared to other racial and ethnic groups. however, the cultural context regarding physical distancing and social support were not systematically assessed in this study and should be considered in future research examining the impact of covid-19 on domains of parenting, health, and wellness. although information concerning covid-19 is continuing to evolve, results were somewhat unexpected with regard to participants' reports of knowing someone who tested positive or died from covid-19; over half of the sample reported knowing someone who tested positive for the virus, with approximately one-quarter of the sample knowing someone who died. consistent with prior research, however, it was anticipated that families would report experiencing financial strain during the pandemic and this is another major source of stress among families. indeed, lower-income individuals tend to live in urban settings, in more crowded conditions both by neighborhood and household composition, and are more likely to be employed in public-facing occupations (e.g., services and transportation), which may be a barrier to physical distancing (webb-hooper et al., 2020) . furthermore, the economic crisis in 2008 also affected the labor market and individual's health and wellness (mucci et al., 2016) , thereby highlighting the toll that health and economic crises may have on general perceptions of stress j o u r n a l p r e -p r o o f and mental health. qualitative findings provide further insight into participants' experiences about how their life has been affected by covid-19 and the stay-at-home restrictions, specifically with regard to their financial, physical, and mental health as well as their children's well-being and ability to assist with their children's academics. an accumulation of stressors due to covid-19 is a key risk factor implicated in higher parent-perceived stress whereas anxiety and depression are associated with both higher parentperceived stress and child abuse potential. these results suggest that the greater number of stressors experienced from covid-19 may act as a salient determinant of general parental stress, but negative perceptions of stress could be particularly higher among parents who also report feelings of anxiety and depression. that cumulative stressors from covid-19 did not significantly relate to increased risk of child abuse potential in this sample is favorable. although cumulative stress, in general, is strongly associated with child maltreatment, our findings indicate that stressors specific to covid-19 may not intensify maltreatment risk, though future research is needed to test the long-term implications of the covid-19 pandemic on myriad child and family outcomes. further research would also benefit from the use of standardized measures to better assess the impacts of covid-19 on risk of child maltreatment and to replicate these results. given that some parents expressed positive benefits as a result of the stay-at-home restrictions, such that recommendations to isolate at home also corresponded with more time spent with their children, it is possible that these positive changes had an impact on parenting. in contrast, certain sociodemographic and mental health risk factors were linked to risk of abuse potential. specifically, families receiving financial assistance and parents with higher symptoms of anxiety and/or depression were at increased risk. these findings corroborate extant research j o u r n a l p r e -p r o o f demonstrating robust relationships between low income, mood disorders, and maltreatment risk (drake & johnson-reid, 2014; liu & merritt, 2018; lorant et al., 2003) . in spite of the positive associations among covid-19 and mental health risk factors, parental perceived stress, and child abuse potential, protective factors also mitigated adverse outcomes. specifically, parents' present perceived control over the covid-19 situation decreased their perceptions of stress and risk of child abuse potential. a large body of research examining perceived control shows that parents with higher perceived control over life events are more likely to be able to use available resources to manage stressors (duchovic et al., 2009) . despite limited existing research of perceived control during the covid-19 pandemic, research shows that with regard to health-related outcomes, in general, levels of perceived control predict changes in health over time (infurna et al., 2011) . moreover, in the parenting context, parents with lower present control have higher levels of parenting stress (harrison & sofronoff, 2002) . because families are likely to experience a lack of support from external sources, such as from schools or childcare settings during the covid-19 pandemic, it is important that the support they receive within the home impacts their perceived stress and parenting. indeed, findings from the current study suggest that the level of emotional and social support a parent receives is significantly associated with lower perceptions of stress and risk of child abuse potential. these findings are promising because, in light of the difficulties associated with the global pandemic, families who may be coming together to provide support may also be alleviating stress and its consequences. given that the majority of participants were mothers, support for mothers, in particular, should be considered as research indicates they take on more of the household and familial duties regardless of socioeconomic status (bianchi et al., 2012) . while perceptions of control over the covid-19 situation and parental support were protective for parents in this sample, other cognitive strategies, such as their level of acceptance after having experienced a negative event was not. prior research shows that interventions that promote acceptance, such as mindfulness, may mitigate general stress (e.g., baer et al., 2012) . however, given that the majority of parents reported anxious and/or depressive symptomology and that individuals with clinical-level concerns are more likely to have lower levels of acceptance (roemer et al., 2009) , it is possible that it may be difficult to manage the uncertainty and unintended consequences associated with covid-19. longitudinal research and randomized controlled trials are needed to determine the directionality and causality of these associations. this study has several limitations. the sample was relatively small and only families involved with service agencies and educational settings in the rocky mountain region of the united states were invited to participate. the sample was also largely comprised of mothers who racially and ethnically identified as non-latinx white. although results here may be similar to those found in racially and ethnically diverse families living in different geographic regions, findings cannot be broadly generalized. in fact, minoritized families are more likely to experience greater social inequities than their white counterparts, which may in turn exacerbate risk of poor outcomes during global health crises. despite efforts to reduce participant burden by administering a brief survey, a limitation of this study was that the survey included single item indicators to assess mental health risk. in addition, a revised version of the child abuse potential inventory was used. although this may serve as a proxy for child maltreatment potential, further research should use both objective and subjective measures with known psychometric properties to reliably and validly assess mental health and maltreatment risk. also, the survey was only administered in english, limiting the j o u r n a l p r e -p r o o f opportunity to capture the experiences of non-english speaking parents. the sample also included parents with a child under the age of 18 years; thus, this study included a large age range of children, which may influence the impact of covid-19 related stressors as well as the importance that protective factors may have in determining stress and parenting outcomes. finally, this study was cross-sectional. therefore, causal inferences cannot be made. longitudinal research is needed to evaluate the effects of the covid-19 pandemic and prolonged stay-at-home restrictions among diverse families across the world. in addition, more research is needed to better understand how children's age may influence parent stressors and child abuse potential during the covid-19 pandemic. despite these limitations, these findings elucidate the important associations of covid-19 related stressors and mental health risk with parental perceived stress and child abuse potential and the role that protective factors may play in mitigating these adverse associations. as such, this study has several implications for prevention and intervention programming to reduce parental stress and child abuse potential during the covid-19 pandemic. for example, given that higher perceived control was associated with lower perceived stress, mindfulnessinformed or cognitive-behavioral strategies that are known to promote flexible responding in situations may improve outcomes for parents (brown et al., 2018; pagnini et al., 2016) . moreover, in addition to the emotional and social support a parent receives within their family, providers and educators serving families could connect families with other community resources to broaden their support networks. also, providing culturally responsive whole-family programs and services that benefit children and parents as well as their extended family may offer additional support, particularly for latinx families and families impacted by greater financial strain (prime et al., 2020) . this may include supporting transportation costs, implementing telehealth services, or ensuring a culturally safe practice environment. finally, policy solutions, including expanding community partnerships and streamlining partnerships across service sectors that aim to reduce disparities and promote more equitable outcomes for marginalized children and families are also needed (campbell, 2020) . in conclusion, this study examined the risk and protective impacts of the covid-19 pandemic in relation to parental perceived stress and child abuse potential among families in the western united states. agencies that serve families during the pandemic will benefit knowing about stressors parents experience due to covid-19 and what factors may increase or reduce stress and risk of child maltreatment. as most research has been conducted outside the context of a global health crisis with significant health, social, and financial implications, the current research provides preliminary insight into factors affecting families during the covid-19 pandemic. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f note. n = 157; b = unstandardized coefficient, (se) = standard error,  = beta (standardized coefficient), ci = 95% confidence interval; total r 2 = r square for the final retained model from block 4; reference category indicated in (). *p < .05, **p < .01, ***p < .001. note. n = 156; b = unstandardized coefficient, (se) = standard error,  = beta (standardized coefficient), ci = 95% confidence interval; total r 2 = r square for the final retained model from block 4; reference category indicated in (). *p < .05, ***p < .001. table 5 prevalence of qualitative themes from participants' experiences regarding theme n (%) loss of employment or income /inability to provide for family 52 (34.7) uncertainty about the future 9 (6.0) inability to see family or friends or socialize with others 25 (16.7) medicaid and covid-19: at the center of both health and economic crises weekly change in mindfulness and perceived stress in a mindfulness-based stress reduction program family functioning, perceived control, and anxiety: a mediation model racial and ethnic disparities in access to and use of paid family and medical leave: evidence from four nationally representative datasets the role of negative parental attributions in the associations between daily stressors, maltreatment history, and harsh and abusive discipline housework: who did, does or will do 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parenting, and covid-19 37 generalized anxiety disorder: the gad-7 department of health & human services, administration for children and families, administration on children, youth, and families using social and behavioural science to support covid-19 pandemic response covid-19 and racial/ethnic disparities the role of parental stress in physically abusive families the effect of material hardship on child protective service involvement range parent age relationships inventory -parent perceived control over stressful events -present control n = 183; percentages that do not equal 100% indicate missing data; categories of financial assistance and stressors from covid-19 poor physical health (e.g., lack of physical activity n = 150; qualitative themes from participants reporting on their experiences from covid-19 are not mutually exclusive all authors declare that there are no conflicts of interest. the authors are indebted to our community partners for their time and extremely grateful to the families who shared their experiences with us. running head: stress, parenting, and covid-19 key: cord-288930-h13cxuh3 authors: lim, faye j; wake, zoe v; levy, avram; tempone, simone; moore, hannah c; richmond, peter c; de klerk, nicholas; conway, nicholas t; keil, anthony d; effler, paul v; smith, david w; blyth, christopher c title: viral etiology and the impact of codetection in young children presenting with influenza-like illness date: 2016-07-20 journal: j pediatric infect dis soc doi: 10.1093/jpids/piw042 sha: doc_id: 288930 cord_uid: h13cxuh3 background: children with acute respiratory tract infection (arti) frequently exhibit virus-virus codetection, yet the clinical significance of arti remains contentious. using data from a prospective cohort of children with influenza-like illness, we examined the virology of arti and determined the clinical impact of virus-virus codetection. methods: children aged 6 to 59 months who presented to a tertiary pediatric hospital between influenza seasons 2008 and 2012 with fever and acute respiratory symptoms were enrolled, and nasal samples were collected. respiratory viruses were identified by culture and polymerase chain reaction. we compared demographics, presenting symptoms, and clinical outcomes of children with a single-virus infection and those in whom 2 or more viruses were detected (virus-virus codetection). we used logistic regression models and estimated marginal means to calculate the adjusted odds ratios and probabilities of symptom presentation, prescription of antibiotics, and hospitalization. results: of 2356 children, a virus was detected in 1630 (69.2%) of them; rhinovirus (40.8%), influenza (29.5%), and respiratory syncytial virus (26.4%) were detected most commonly. two or more viruses were detected in 25% of these children. after we adjusted for demographic factors, children with virus-virus codetection had greater odds of presenting with cough (adjusted odds ratio [aor], 1.9; 95% confidence interval [ci], 1.2–3.1) and rhinorrhea (aor, 1.8; 95% ci, 1.1–2.9) than those with a single-virus infection, although both symptoms were common. children with influenza and respiratory syncytial virus combined had the highest probability of hospitalization (55%; 95% ci, 35%–73%), which was significantly greater than for those with influenza infection alone (22%; 95% ci, 16%–29%). conclusions: overall, virus-virus codetection has limited impact on clinical severity among children with influenza-like illness. however, infection with specific pathogen pairs might be associated with more severe outcomes. routine diagnostics to identify specific viruses should be restricted to common pathogens. acute respiratory tract infections (artis) in children place a significant burden on families and the community. commonly recognized viral pathogens that cause arti include influenza viruses, respiratory syncytial viruses (rsvs), parainfluenza viruses, human rhinoviruses, adenoviruses, and coronaviruses [1, 2] . advances in laboratory diagnostic techniques have resulted in the discovery of new viruses, including human metapneumovirus (hmpv) and polyomaviruses [3, 4] , yet a number of these pathogens have an uncertain pathogenicity [5, 6] . codetection can be defined as the detection of 2 or more pathogens in a single sample. with the improved sensitivity, availability, and affordability of modern diagnostics, virus-virus codetections are increasingly being found. the incidence of virus-virus codetection has been reported to be between 15% and 45%, depending on age, location, and testing methods [7] [8] [9] . the clinical significance of codetection in patients with arti remains contentious; the literature has described negligible to deleterious effects [9, 10] . with this study, we describe the virology of arti in children aged 6 months to 4 years who presented to a tertiary pediatric hospital in australia with influenza-like illness during influenza season. this study also enabled us to specifically examine the impact of virus-virus codetection on clinical symptoms and outcomes. western australia (wa) spans 2.5 million km 2 and has a population of approximately 2.5 million people, 7% of whom are younger than 5 years [11] . princess margaret hospital for children (pmh) is the only tertiary pediatric hospital in the state and is located in metropolitan perth, where approximately 80% of the population resides [12] . commencing in 2008, the western australia influenza vaccine effectiveness (waive) study was an observational cohort study established to determine the effectiveness of inactivated influenza vaccine. patient recruitment was conducted at pmh (and at selected general practices in metropolitan wa in 2008-2009). because of the small numbers recruited and differences in presentations, data from children who presented to the general practices were removed from our analyses. patient recruitment coincided with the annual influenza seasons. the start and end of the influenza seasons were defined by the infectious diseases surveillance unit at pathwest laboratory medicine wa by using a combination of indicators, including the weekly proportion of positive laboratory influenza test results. as a guide, 2 consecutive weeks with more than 10% positive influenza test results often coincides with the beginning of influenza season in wa. additional details on study design are described elsewhere [13] . all children 6 to 59 months of age who presented to pmh with a history of fever (according to parental report) or with a measured temperature of greater than 37.5°c at presentation and with at least 1 acute respiratory symptom within the previous 96 hours were eligible for enrollment. all children transited through the pmh emergency department. a proportion of these children were subsequently admitted to the hospital, and the remainder of them were discharged home from the emergency department. children with a known immunodeficiency disorder, with current or recent immunosuppressive treatment, or who received immunoglobulin in the previous 3 months were excluded from the study. patient demographics, medical history, and presenting symptoms were collected through a parental questionnaire. comorbidities recorded included prematurity, asthma, and chronic cardiac, neurological, and respiratory conditions. influenza vaccination status was determined by parental report and confirmed through the australian childhood immunisation register or by contacting immunization providers. vaccination status for other vaccines was not collected. a follow-up questionnaire regarding illness outcomes, including details of hospital admission(s), use of antibiotics, and time to recovery, was given to families to complete within 7 to 10 days after enrollment. a retrospective review of medical records was undertaken when hospitalization data were recorded incorrectly or missing. no follow-up was conducted for antibiotic use if data were missing. samples were collected from the children at enrollment with midturbinate nasal swabs (copan diagnostics, inc., murrieta, california). if a nasopharyngeal aspirate had already been collected by hospital staff as part of clinical care, that sample was used in lieu of a nasal swab. viral culture (madin-darby canine kidney cells, diploid lung fibroblasts) and multiplex tandem polymerase chain reaction (pcr) were used to detect all viruses except picornaviruses and hmpv [14, 15] . picornaviruses were detected by using nested pcr [16] targeting the 5′ untranslated region of the picornavirus genome, and sequencing was used to assist with the identification of rhinoviruses and enteroviruses. hmpv was tested by using an immunofluorescent assay (simulfluor hmpv immunofluorescent assay [millipore, temecula, california]) and pcr. all patients were subjected to the same panel of tests, and testing methods were consistent throughout the study period with the exception of testing for hmpv, which was based on clinical need. although both immunofluorescence and pcr assays were used throughout the study period, pcr testing was more common in later years. for all viruses (except hmpv), positive viral detection was defined as detection by viral culture and/or pcr. positive detection of hmpv was defined as detection by immunofluorescence and/or pcr. all influenza types/subtypes (i.e., influenza a/ h1n1, a/h3n2, and b) were grouped for analysis. similarly, subgroups of parainfluenza viruses (i.e., parainfluenza types 1-4) were grouped together for analysis. infection was defined as the detection of 1 or more viruses (i.e., rhinovirus, influenza, rsv, parainfluenza, adenovirus, coronavirus, and/or hmpv). codetection was defined as detection of 2 or more viruses in a single diagnostic sample. prematurity was defined as less than 37 weeks of gestation at birth. out-of-home care was defined as attendance at a playgroup, mothers' group, day care center, kindergarten, or preschool. hospital length of stay refers to the duration from admission to discharge. symptoms investigated included cough, rhinorrhea, wheeze, dyspnea, rash, diarrhea, and vomiting, and the outcomes investigated were antibiotic prescription and hospital admission. data cleaning and analyses were performed in microsoft excel, epibasic [17] , and spss version 23 (spss, inc., chicago, illinois). categorical variables were compared by using pearson's χ 2 tests. logistic regression models were used to calculate odds ratios (ors) with 95% confidence intervals (cis) to compare those with single infection to those with virus-virus codetection. dependent variables were symptoms (e.g., presence of cough or rhinorrhea) and outcome variables (e.g., hospitalization or use of antibiotics). we calculated adjusted ors (aors) by including the following covariates in the logistic regression models: age, sex, aboriginal status, prematurity, presence of comorbidities, outof-home care, and household smoking. age was included as a categorical variable in the models (6-11 months, 12-23 months, 2 years, 3 years, and 4 years [reference group]). covariates were selected on the basis of known epidemiological or clinical risk factors for codetection. data from all patients were included in the adjusted models unless they had data on 1 or more covariates missing. to investigate the impact of specific pathogen pairs, analyses were repeated for the most common pathogen pairs. estimated marginal means of logistic regression models were used to calculate probabilities with 95% cis for antibiotic prescribing and hospitalization for those infected with common pathogen pairs. this study was approved by the pmh human research ethics committee (approval 1673/ep), the western australian aboriginal health ethics committee (approval 212 06/08), and the university of western australia research ethics committee (approval ra/4/1/6456). of the 2356 patients enrolled, the majority of them (n = 1848 [78.4%]) were enrolled when they presented to the pmh emergency department. of these patients, 6.3% (n = 117) were subsequently admitted to the hospital. the median age was 22.0 months (interquartile range, 14.0-35.0), 54.9% were male, and 5.7% were of aboriginal or torres strait islander decent. children born preterm accounted for 13.5% (n = 319) of the patients. children with comorbidities accounted for 15.1% (n = 355) of this cohort. of those who had 1 or more comorbidity, asthma (n = 218 [61.4%]) and other chronic respiratory conditions (n = 54 [15. 2%]) were the most common. of 2356 patients, questions relating to outcomes (e.g., antibiotics use) were completed for 52.8% (n = 1244). although parents were requested to complete these questions 7 to 10 days after enrollment, the mean time to completion was 19.3 days (range, 0-149 days; median, 10 days). data on antibiotic prescription after enrollment were available for 51.0% (n = 1201) of the patients, 483 (40.2%) of whom were prescribed antibiotics. combining data from the questionnaires and a review of the hospital records resulted in near-complete data on hospitalization (99.4% [n = 2341]); 610 (26.1%) were hospitalized. of those who were admitted to the hospital, the median length of stay was 2 days (interquartile range, 1-3 days). overall a greater proportion of children with multiple viruses detected were younger than 2 years than those with a single-virus infection (65.4% vs 51.2%, respectively; p < .001; table 1 ). those with codetection also had greater odds of presenting with cough and rhinorrhea than those with a single-virus infection, although both symptoms were common in both groups ( table 2 ). this effect remained after adjusting for other covariates. it should be noted that, although less common, diarrhea was observed more frequently in children with viral codetection. there were no significant differences between patients with a single-virus infection and those with virus-virus codetection in the odds of being prescribed antibiotics (aor, 1.1; 95% ci, 0.8-1.5) or being hospitalized (aor, 1.1; 95% ci, 0.8-1.4) ( table 2) . we then selected the 3 most common pathogens (rhinovirus, influenza, and rsv) and investigated associations of infection with specific pathogen pairs with antibiotic prescriptions and hospitalization. after adjusting for other covariates, patients with both influenza and rsv detected had a 52% probability (95% ci, 28%-76%) of being prescribed antibiotics, and there was a trend toward more frequent prescription than those with influenza or rsv infection alone (figure 2) . similarly, the probability of being hospitalized was highest in those with influenza and rsv detected (probability, 55%; 95% ci, 35%-73%) and was significantly greater when compared with those with influenza infection alone (probability, 22%; 95% ci, 16%-29%) ( figure 3 ) and with a trend towards increased hospitalization observed compared with rsv infection alone (probability, 43%; 95% ci, 36%-51%). this is one of the largest single-site prospective studies of children up to 4 years of age that specifically investigated the incidence of and clinical outcomes associated with virus-virus codetection. our findings indicate that although differences in demographics, risk factors, and symptoms are identifiable, in general, virus-virus codetection is unlikely to be associated with more severe clinical illness among young children with influenza-like illness. infection with specific pathogen pairs might be associated with an increased probability of hospitalization, as was observed with influenza and rsv. this finding has implications in pediatric healthcare facilities, where the isolation of all children with acute respiratory viral infection is difficult during periods of peak respiratory virus activity and cohorting of children is frequently required before the availability of diagnostic test results. we detected small differences between the symptoms presented by patients with a single-virus infection and those presented by patients with virus-virus codetection. however, these symptoms were common and therefore likely to be of little clinical relevance. in contrast, the clinical outcomes chosen (i.e., antibiotic use and hospitalization) were more indicative of disease severity, but they are subject to clinical judgement and therefore can be less sensitive measures of disease severity. accordingly, we observed no significant differences in the these results are consistent with data from previous systematic reviews, which found negligible differences between outcomes in children and adults with virus-virus codetection compared to peers with single-virus infection [18, 19] . however, the results of additional analyses of pathogen pairs suggest that some combinations of specific viral pathogens, such as influenza and rsv, are potentially more significant than others. this result corroborates data from our recently completed systematic review in which we specifically investigated clinical outcomes in children with codetection; we found no differences overall, but the results suggest that some pathogen-specific effects might be present [20] . our data suggest that future research in this area should segregate analysis according to specific pathogen pairs when the numbers allow. we chose to exclude bocavirus and enterovirus detections from the analyses because their pathogenicity in arti is still not well established. bocavirus is often implicated in both symptomatic and asymptomatic codetection and is thought to have a prolonged period of shedding [6] ; both of these features might confound any associations between codetection and clinical severity. in contrast, the results of studies on the role of enteroviruses in arti are suggestive of pathogenicity [21] ; however, the numbers in those studies were small. for these reasons, detections of both viruses were excluded from the analyses presented here. repeat analyses including these viruses did not change the overall findings (supplementary tables 1 and 2 ). an important consideration when interpreting these findings is that active (and pathogenic) infection and viral shedding cannot be distinguished. prolonged viral shedding for some respiratory viruses, particularly rhinovirus, has been well documented [22, 23] . quantitative analysis might be of assistance in distinguishing these clinical states but has not yet become commonplace in the diagnostic laboratory for respiratory viruses. one limitation of our study is that only children who presented to 1 hospital with influenza-like illness and fever were eligible for enrollment. as a consequence, it is possible that these children were at the more severe end of the disease spectrum, which might have biased our results. during the course of this study, there was a shift from using an antigen-based assay to using pcr for detecting hmpv, although both methods were used throughout the study period. we elected to include detections from both methods but acknowledge that differences in the performance of these methods would mean that potential cases of hmpv might have been missed in earlier samples. these changes, and clinical discretion in testing for hmpv, may explain the proportion of hmpv detections in this cohort, which was lower than that in other studies [24, 25] . additional limitations of this study include missing outcomes data, particularly for antibiotic prescription. in addition, data on diagnosis at discharge were not collected, which might have helped to indicate the severity of symptoms. moreover, despite enrolling nearly 2500 children, the number of patients infected with specific pathogens and pathogen pairs was relatively small. future studies using routinely collected, linked administrative data might assist in addressing both issues. nonetheless, ours was one of the largest single-site studies to specifically investigate the effects of virus-virus codetection in young children by using a wide panel of tests for respiratory pathogens. our results are similar to those reported elsewhere, which adds to the validity of the findings [26] . we conclude that the impact of virus-virus codetection on disease severity in children who present with influenza-like illness is likely to be limited to those infected with specific pathogen pairs. therefore, routine screening for virus-virus codetection in this population should be restricted to those with common respiratory pathogens, and efforts to reduce cross infection should focus on these specific pathogens. detection of respiratory viruses by molecular methods epidemiology of viral respiratory infections the role of infections and coinfections with newly identified and emerging respiratory viruses in children presence of the newly discovered human polyomaviruses ki and wu in australian patients with acute respiratory tract infection human rhinovirus c: age, season, and lower respiratory illness over the past 3 decades human bocavirus-the first 5 years single versus dual respiratory virus infections in hospitalized infants: impact on clinical course of disease and interferon-[gamma] response multipathogen infections in hospitalized children with acute respiratory infections evaluation of viral co-infections in hospitalized and non-hospitalized children with respiratory infections using microarrays multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children rates calculator, version 9.5.5. perth, western australia: health information centre, department of health article22012-13?opendocument&tabname=s ummary&prodno=3218.0&issue=2012-13&num=&view=. accessed november 13 effectiveness of trivalent flu vaccine in healthy young children duplex realtime reverse transcriptase pcr assays for rapid detection and identification of pandemic (h1n1) 2009 and seasonal influenza a/h1, a/h3, and b viruses an economical tandem multiplex real-time pcr technique for the detection of a comprehensive range of respiratory pathogens improved detection of rhinoviruses in nasal and throat swabs by seminested rt-pcr epibasic version 2.0 clinical disease severity of respiratory viral co-infection versus single viral infection: a systematic review and meta-analysis single and multiple respiratory virus infections and severity of respiratory disease: a systematic review systematic review and meta-analysis of respiratory viral coinfections in children global reemergence of enterovirus d68 as an important pathogen for acute respiratory infections duration of rhinovirus shedding in the upper respiratory tract in the first year of life persistence of rhinovirus and enterovirus rna after acute respiratory illness in children use of an innovative webbased laboratory surveillance platform to analyze mixed infections between human metapneumovirus (hmpv) and other respiratory viruses circulating in alberta (ab) human metapneumovirus in hospitalized children in epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness acknowledgments. we acknowledge peter jacoby for his assistance with the logistic regression analyses and gabriela willis for her assistance with cross-checking the data, and we thank members of the vaccine trials group, particularly christine robins, who managed the study. we also thank all the parents and children who participated in the waive study. potential conflicts of interest. all authors: no reported conflicts of interest. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. supplementary materials are available at journal of the pediatric infectious diseases society online. author contributions. c. c. b., p. c. r., p. v. e., and d. w. s. conducted the waive study; p. c. r., d. w. s., and c. c. b. conceptualized this study; a. l. and s. t. conducted the laboratory work; z. v. w. and n. t. c. conducted the preliminary data cleaning and analyses; f. j. l. conducted data cleaning and analyses with assistance from h. c. m., n. d. k., and c. c. b.; and f. j. l. and z. v. w. jointly wrote the first draft of the manuscript. all authors critically revised and approved of the final version of the manuscript. key: cord-283138-18q23z8l authors: balasubramanian, s.; rao, neha mohan; goenka, anu; roderick, marion; ramanan, athimalaipet v title: coronavirus disease 2019 (covid-19) in children what we know so far and what we do not date: 2020-04-09 journal: indian pediatr doi: 10.1007/s13312-020-1819-5 sha: doc_id: 283138 cord_uid: 18q23z8l pediatric coronavirus disease-19 (covid-19) infection is relatively mild when compared to adults, and children are reported to have a better prognosis. mortality in children appears rare. clinical features of covid-19 in children include fever and cough, but a large proportion of infected children appears to be asymptomatic and may contribute to transmission. it remains unclear why children and young adults are less severely affected than older individuals, but this might involve differences in immune system function in the elderly and/or differences in the expression/function of the cellular receptor for severe acute respiratory syndrome coronavirus 2 (sars-cov-2)angiotensin converting enzyme 2 (ace2). laboratory findings and chest imaging may not be specific in children with covid-19. diagnosis is by reverse transcriptase-polymerase chain reaction (rt-pcr) testing of upper or lower respiratory tract secretions. this review additionally considers covid-19 in immunosuppressed children, and also suggests a management algorithm for the few children who appear to present with life threatening infection, including the potential use of antiviral and immunomodulatory treatment. the most significant threat to global child health from sars-cov-2 is unlikely to be related to covid 19 in children, but rather the socio-economic consequences of a prolonged pandemic. c oronavirus disease-2019 (covid-19) is a global health crisis. the clinical characteristics, disease progression and outcome in children and young adults appear significantly milder compared to older individuals. since first being reported in wuhan, china in december 2019, covid-19 has rapidly spread to affecting over 200 countries worldwide. children account for 1-5% of diagnosed covid-19 cases [1] ; although, many infected children may be asymptomatic and therefore not diagnosed without population screening. at the time of writing, in india, the number of virologically confirmed covid-19 positive cases is 5273 (149 deaths) as per the ministry of health and family welfare (mohfw) [2] . coronaviruses are a family of enveloped, single stranded, zoonotic rna viruses which can rapidly mutate and recombine, leading to novel viruses that can spread from animals to humans [3] . the precise events that led to the emergence of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) causing covid-19 remain unknown. sars-cov-2 is transmitted through inhalation of respiratory droplets of an infected person and touching surfaces contaminated with the virus. in previous coronavirus epidemics, children globally accounted for 6.9% of sars 2002-3 infections and 2% of middle east respiratory syndrome (mers) infections. it appears that sars-cov-2 has a higher transmission capability compared with the closely related viruses causing sars 2002-3 and mers [4] . the true case fatality rate (cfr) of covid-19 infection is currently unknown due to lack of population-scale longitudinal data. thus, estimates of cfr currently vary between 0.5-5% [1, 5] . the sars-cov-2 virus utilizes angiotensin converting enzyme 2 (ace2) receptors as its cell surface receptor, similar to the sars 2002-3 virus. ace2 is expressed in highly byciliated epithelial cells in the human lungs and this receptor allows the virus to attach to the cell [6] . the ace2 receptor is also expressed in the intestines, potentially accounting for the gastrointestinal symptoms that commonly occur in the early stage of the illness. volume 57 __ may 15, 2020 balasubramanian, et al. severe covid-19 disease is characterized by three phases: the first being the viral phase; the second being the cytokine storm; and the third encompassing acute respiratory distress syndrome (ards), impaired cardiac function and death [7] . the cytokine storm appears to be driven by a dysregulated host immune response [8] and might contribute to mortality [9] . the profile of the cytokine storm associated with severe covid-19 disease is similar to that of secondary hemophagocytic lymphohistiocytosis (hlh), which is a rare complication of other viral infections (3.7-4.3%) [8] . secondary hlh is characterized by fulminant and fatal hypercytokinemia with multiorgan failure. in severe infection, lower peripheral lymphocyte counts (cd4 and cd8 t cells), higher interleukin (il) levels (il-6 and il-10), decreased interferon-gamma expression in cd4+ t cells and higher d-dimer and fibrin degradation products (fdp) levels, leading to increased thrombosis and multiorgan injury has been described. moreover, patients with severe infection may also have abnormal coagulation parameters, perhaps related to high expression of ace2 receptors in vascular endothelial cells. most infected children are likely to be secondary cases and acquire the infection after exposure to a covid-19 positive adult, although there are no longitudinal data to confirm this yet. intra-family transmission may be important [10] . an as yet unquantified proportion of children with covid-19 is asymptomatic and may contribute to transmission. it is unknown whether covid-19 is acquired by contact with infected feces [10, 11] . in a report of 10 children admitted for covid-19 with positive nasopharyngeal swabs, 8 of 10 children demonstrated persistently positive real time reverse transcriptase-polymerase chain reaction (rt-pcr) of rectal swabs after their nasopharyngeal testing had become negative [12] . it remains unclear whether the detection of virus by rt-pcr in fecal matter represents active viral replication or residual viral genomic material; however, it appears that viral shedding from the digestive tract might be greater and last longer than that from the respiratory tract [12] . multiple reports have demonstrated that children and young adults have a milder form of the disease compared to adults [13] . asymptomatic, mild and moderate infections comprise over 90% of all children who have tested positive for covid-19 with fewer severe and critical cases (5.9%) compared to adults (18.5%) [13] . the possible reasons for lower number and milder infections in children and young adults include lower exposure to virions, being isolated at home and minimal exposure to pollution and cigarette smoke contributing to healthier respiratory tracts. the elderly may be susceptible to severe covid-19 disease by their qualitatively different immune response, encompassed by the terms 'immunosenescence' and 'inflammaging' [14] . viral co-infection may be important in potentially leading to limited replication of the sars-cov-2 by direct virus-to-virus interaction and competition [15] . additionally, the distribution, maturation and functioning of viral receptors such as ace2 may be important in age-dependent susceptibility to severe covid-19 [13, 16] . due to smaller number of reported cases in children, it is at present challenging to delineate the clinical characteristics of children with severe covid-19 infection, combined with the lack of a clear biomarker to indicate severity of infection [17] . dong, et al. [13] , in the largest pediatric review of 2143 children, described that 13% of virologically confirmed children were asymptomatic. this makes epidemiological inference problematic since asymptomatic children are less likely to be tested and may still contribute to transmission. in addition, a significant proportion of children can also have coinfections with other viruses, and the detection of sars-cov-2 may therefore be clinically insignificant [11] . it has been proposed that the outcome for some children may be worse due to exposure to antenatal smoking and obesity [17] . another theory that has been postulated is the protective role of bacillus calmette-guérin (bcg) vaccine in covid-19. bcg vaccination has been associated with heterologous immunity to other pathogens, potentially by a phenomenon called 'trained immunity' involving innate cells such as macrophages, monocytes and epithelia [18] . trials are underway to understand if bcg vaccination may offer protection against covid-19. children of all ages can be infected with covid-19, with more cases reported in younger children and infants [13] . acknowledging the possible reporting biases discussed above, there is no age or sex preponderance [13] and the median age of infection is 6.7 years (rangenewborn to 15 years) [19] . the incubation period of covid-19 in children has been reported as 2 days (range-2 to 10 days) [1] . at the time of diagnosis, 13-15% of virologically positive children may be asymptomatic [13, 19] . the most common symptoms described at onset in children are fever (50%) and mild cough (38%) [10] . fever is present in about 40% of volume 57 __ may 15, 2020 balasubramanian, et al. covid-19 in children children [19] . other clinical features include sore throat, rhinorrhea, sneezing, myalgia, fatigue, diarrhea and vomiting. children may have more upper respiratory symptoms than lower respiratory symptoms [13] , and appear to recover in 1-2 weeks [20] . in the largest pediatric cohort to date, dong, et al. [13] describe suspected and confirmed cases based on symptoms, laboratory abnormalities, chest imaging, and rt-pcr/genomic analysis. the severity of covid-19 was divided into asymptomatic, mild, moderate, severe and critical. severe covid-19 accounted for 18 (2.5%) of virologically confirmed cases, and furthermore the definition of severe included children with only mild hypoxia. critical covid-19 was observed in 3 (0.4%) of virologically confirmed cases, defined by the presence of ards or organ failure. though data on chronology of complications and predictors of mortality is available in adults, there is insufficient data on predictors of mortality in children. the ministry of health and family welfare (mohfw) [2] in their updated guidelines (as of 7 april, 2020) has categorized patients into three groups -those with mild, moderate and severe illness, and have designated covid dedicated facilities for their treatment. rt-pcr testing of nose and throat swab for detection of sars-cov-2 nucleic acid has been recommended as the confirmatory test for covid-19 [21] . other alternative samples for rt-pcr include bronchoalveolar lavage or endotracheal aspirate. the government of india has now advised the use of antibody tests in patients with symptomatic influenza-like illness (ili) in 25 districts across the country, or 'covid hotspots' [22] . based on the results of the antibody test, confirmatory rt-pcr and clinical assessment, hospital treatment or home isolation measures are instituted, with contact tracing measures as per protocol. the limited data in children describes relatively lower rates of lymphopenia and elevated inflammatory markers compared to adults [1] . henry, et al. [23] summarized the findings from 12 studies on 66 children and reported normal leucocyte counts (69.2%), neutropenia (6.0%), neutrophilia (4.6%) and lymphopenia (3.0%). c-reactive protein (crp) and procalcitonin were high only in 13.6% and 10.6% of cases, respectively. slight elevation of liver transaminases is common [23] . it is recommended to monitor the lymphocyte count and crp as signs for severe infection, while using procalcitonin levels to detect potential bacterial co-infection [23] . chest x-ray findings in children appear to be nonspecific. children with mild disease should not routinely need computed tomography (ct) chest imaging in view of the high radiation exposure [24] . when ct is performed, ground glass opacities is seen in one third of patients [19] . peripheral distribution of lung lesions has been noted, with multilobar involvement [25] . consolidation with surrounding halo sign is considered typical of pediatric patients [26] . however, chest ct alone cannot accurately diagnose covid-19 due to similar radiological presentations with other infections. patients admitted with severe infection are known to have elevated plasma levels of il-2, il-7, il-10, granulocyte colony stimulating factor (gcsf), interferon-gamma-inducible protein 10 (ip10), monocyte chemoattractant protein 1(mcp1), macrophage inflam-matory protein 1-alpha (mip1a) and tumor necrosis factor (tnf) alpha [9] . in a study comprising of 150 confirmed covid-19 cases in wuhan, china, elevated ferritin (mean 1298 ng/ml vs 614 ng/ml; p<0.001) and il-6 levels (p<0.0001) were found in survivors compared to non-survivors [7] . these cytokines are produced by inflammatory macrophages which have been implicated in the cytokine storm. this is similar to previous outbreaks of mers and sars 2002-3 in terms of having high proinflammatory cytokines in patients with severe disease [27] . upon suspicion of covid-19 infection, immediate infection prevention control (ipc) measures must be instituted. standard precautions such as hand hygiene, use of personal protective equipment (ppe), safe waste management and cleaning and disinfection of equipment must be followed as per the guidelines issued by the mohfw [2] . for the few children who will require admission to a healthcare facility, the cornerstone of management is supportive therapy including adequate nutrition and calorie intake, fluid and electrolyte management and oxygen supplementation. communication with parents and alleviating anxiety is an important part of management. in adults with severe covid-19, early intubation and mechanical ventilation with lung protective strategies and prone positioning has been recommended [20] . antibiotics may be indicated if bacterial super-infection is suspected. there are no randomized clinical trial data to guide treatment of the very few children that present with lifethreatening covid-19 including severe pneumonia, volume 57 __ may in the absence of data from these trials, clinicians may be left in the difficult scenario of deciding whether to pursue treatment with antiviral drugs and immunomodulatory therapies for children with severe covid-19. a relatively new antiviral drug being tested in adults with covid-19 is remdesivir, which in combination with chloroquine has been found to inhibit sars-cov-2 growth in vitro [28] . interferon alpha-2b and oral lopinavir/ritonavir together with corticosteroids for complications and intravenous immunoglobulin for severe cases has been recommended in one report in china [29] . a hiv test should be performed before commencing antiviral treatment, in particular lopinavir/ritonavir. the mohfw has allowed off label use of hydoxychloroquine in combination with azithromycin in adults with severe disease and requiring intensive care [2] . however, these treatments are not currently recommended in children below the age of 12 years. corticosteroids are not routinely recommended and might exacerbate covid-19 associated lung injury [30] . ivermectin, the broad spectrum anti-parasitic agent, has in vitro antiviral action against sars-cov-2 [31] . owing to the cytokine storm syndrome in covid-19, there may potentially be a role of immunomodulators in treating patients with severe infections to ameliorate pulmonary inflammation and hopefully improve mortality. there is an established role of anakinra (il-1 blockade) in survival benefit of patients with hyperinflammation, without increased adverse events [8] . a multicenter randomized control trial (rct) of the il-6 receptor blocker, tocilizumab is in progress in china for adults with covid-19 pneumonia and raised il-6 levels (chictr2000029765) [32] . there may also potentially be a role of janus kinase inhibitors (jki), since these drugs block downstream inflammatory pathways and may alter cellular viral entry [33] . a suggested management algorithm based on the limited observational data from adults is depicted in figs. 1 and 2 . the common drugs used in covid-19 are detailed in table i covid-19 in children children with covid-19 are likely to need any specific therapy other than supportive treatment, and the decision to start antiviral or immunomodulatory treatment should therefore be made carefully in consultation with experts in pediatric infectious disease and immunology. given that severe covid-19 appears very rare in children, an important part of this assessment is ascertaining whether a positive rt-pcr for sars-cov-2 is a clinically important factor in explaining the child's condition, or whether more occult pathology may be responsible. for neonatal management of covid-19 infected mothers, it is recommended to have a separate room adjacent to the delivery room for neonatal resuscitation or for resuscitation staff to maintain atleast a 2 meter gap between the infected mother and newborn [34] . only essential personnel should attend the delivery with full ppe, with the mother following meticulous hand hygiene and wearing a mask. standard neonatal resuscitation measures are to be followed and positive pressure ventilation if needed should be provided by a selfinflating bag and mask rather than a t-piece resuscitator. if the baby requires intensive care, a single patient room is ideal preferably with negative pressure. the baby should be tested at 24 hours of life and repeat testing should be performed at 48 hours. antivirals/hydroxychloroquine/steroids or intravenous immunoglobulin (ivig)should not be administered to the newborn. the baby should then be tested every 48-72 hours until two consecutive negative tests. it is critical that breastfeeding shouldbe encouraged with the mother wearing a mask. the baby should be vaccinated prior to discharge from the hospital. data on children with immunocompromised conditions and covid-19 are scarce, but severe disease may be more common in adults with cancer [35] . despite concerns that immunocompromised children may have severe infection analogous to infection with adenovirus, rhinovirus, influenza, respiratory syncytial virus, and experience from previous pandemics (such as influenza h1n1),antiga,et al. [36] described that children who were immunocompromised were not at greater risk of severe covid-19, probably owing to the fact that a functional host innate immune response is the main driver for lung damage. in bergamo, among 200 transplant recipients including 10 inpatients, 100 with autoimmune liver disease and three undergoing chemotherapy for hepatoblastoma (inpatients), none had clinical pulmonary disease, despite the fact that 3 patients tested positive for sars-cov-2, suggesting that the immunocompromised may be protected by their weaker immune response. no data is available on severity of covid-19 infection in children with malnutrition, rheumatic heart disease or human immunodeficiency virus (hiv) positive children. several vaccines against sars-cov-2 are in development; however, it remains unclear when a successful vaccine might be rolled out. studies on factors responsible for immune dysregulation may provide insights into developing vaccines capable of inducing durable protective immunity and avoiding vaccinerelated adverse events. this unprecedented pandemic should prompt improved global surveillance of infectious diseases, as well as cooperation and communication so that the global society remains interconnected and limits the spread of this outbreak. lastly, we fear the greatest impact on children from covid-19 is likely to be delayed presentation of other childhood illnesses due to fear and ignorance amongst parents/families. this coupled with the impact of economic uncertainty on those in the low socioeconomic strata, is likely to have a greater adverse impact on child health in india in these uncertain times. contributors: sb, avr-initiated the preparation of the manuscript;nmr: substantial contribution to the conception and design of the work, and prepared and finalized the draft; sb, avr, ag, mr-substantial contributions to the acquisition, analysis, and interpretation of data for the work, sb, avr, ag, mr-revising it critically for important intellectual content;sb, nmr, ag, mr, avr: final approval of the version to be published, and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. funding: none; competing interests: none stated. systematic review of covid-19 in children show milder cases and a better prognosis than adults ministry of health and family welfare coronavirus infections in children including covid-19. pidj sars-cov-2/ : a storm is raging. jci estimating case fatality rates of covid-19 covid-19: knowns, unknowns, and questions. msphere why is covid-19 so mild in children? acta paediatr covid-19: consider cytokine storm syndromes and immunosuppression clinical features of patients infected with 2019 novel coronavirus in wuhan a case series of children with 2019 novel coronavirus infection: clinical and epidemiological features. cid covid-19 in children: initial characterization of the pediatric disease characteristics of pediatric sars-cov-2 infection and potential evidence for persistent fecal viral shedding epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china the impact of immunosenescence on pulmonary disease virus-virus interactions impact the population dynamics of influenza and the common cold are children less susceptible to covid-19? jmii covid-19 infection in children bcg-induced cross-protection and development of trained immunity: implication for vaccine design.front immunol sars-cov-2 infection in children. nejm sars-cov-2 infection in children: transmission dynamics and clinical charateristics revised guidelines on clinical management of covid -19 advisory to start rapid antibody based blood test for covid-19 laboratory abnormalities in children with novel coronavirus disease 2019. cclm covid-19 in children: the link in the transmission chain radiographic and clinical features of children with 2019 novel coronavirus (covid-19) pneumonia. indian pediatr clinical and ct features in pediatric patients with covid-19 infection: different points from adults mers-cov infection in humans is associated with a pro-inflammatory th1 and th17 cytokine profile remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury the fda-approved drug ivermectin inhibits the replication of sars-cov-2 invitro chinese clinical trial registry. a multicenter, randomized control trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (covid-19) baricitinib as potential treatment for 2019-ncov acute respiratory disease perinatal-neonatal management of covid-19 infection -guidelines of the federation of obstetric and gynecological societies of india (fogsi), national neonatology forum of india (nnf), and indian academy of pediatrics (iap) cancer patients in sars-cov-2 infection: a nationwide analysis in china coronaviruses and immunosuppressed patients bpaiig position statement: sars-cov-2 treatment guidance version 1.2 key: cord-269087-f9hyntvf authors: li, x.; qian, k.; xie, l.-l.; li, x.-j.; cheng, m.; jiang, l.; schuller, b. w. title: a mini review on current clinical and research findings for children suffering from covid-19 date: 2020-04-04 journal: nan doi: 10.1101/2020.03.30.20044545 sha: doc_id: 269087 cord_uid: f9hyntvf background: as the novel coronavirus triggering covid-19 has broken out in wuhan, china and spread rapidly worldwide, it threatens the lives of thousands of people and poses a global threat on the economies of the entire world. however, infection with covid-19 is currently rare in children. objective to discuss the latest findings and research focus on the basis of characteristics of children confirmed with covid-19, and provide an insight into the future treatment and research direction. methods: we searched the terms "covid-19 or coronavirus or sars-cov-2" and "pediatric or children" on pubmed, embase, cochrane library, nih, cdc, and cnki. the authors also reviewed the guidelines published on chinese cdc and chinese nhc. results: we included 25 published literature references related to the epidemiology, clinical manifestation, accessary examination, treatment, and prognosis of pediatric patients with covid-19. conclusion: the numbers of children with covid-19 pneumonia infection are small, and most of them come from family aggregation. symptoms are mainly mild or even asymptomatic, which allow children to be a risk factor for transmission. thus, strict epidemiological history screening is needed for early diagnosis and segregation. this holds especially for infants, who are more susceptible to infection than other age groups in pediatric age, but have most likely subtle and unspecific symptoms. they need to be paid more attention to. ct examination is a necessity for screening the suspected cases, because most of the pediatric patients are mild cases, and plain chest x-ray do not usually show the lesions or the detailed features. therefore, early chest ct examination combined with pathogenic detection is a recommended clinical diagnosis scheme in children. the risk factors which may suggest severe or critical progress for children are: fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bilateral or multi lobed infiltration, pleural effusion or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those who underly diseases. for those critical pediatric patients with positive sars-cov-2 diagnosis, polypnea may be the most common symptom. for treatment, the elevated pct seen in children in contrast to adults suggests that the underlying coinfection/secondary infection may be more common in pediatric patients and appropriate antibacterial treatment should be considered. once cytokine storm is found in these patients, anti-autoimmune or blood-purifying therapy should be given in time. furthermore, effective isolation measures and appropriate psychological comfort need to be provided timely. since late december 2019, the numbers of unknown registered cases of pneumonia originating from a novel coronavirus had outbroken in wuhan, hubei province, china. a fast outbreak could be observed rapidly reaching other provinces and cities of china, and subsequently, to many countries around the three big oceans. now, the epidemic of the 2019 novel type of coronavirus (sars-cov-2) has threatened the lives of thousands of people and posed a global threat on the economics of the whole world. on 11 february 2020, the world health organization (who) named the disease related to sars-cov-2 officially as the 2019 coronavirus disease (covid-19) [1] [2] [3] . coronaviruses (cov) are members of the subfamily coronavirinae in the coronaviridae family, nidovirales order. cov consists of four genera: α, β, γ, and δ coronaviruses. the alpha-and beta-coronaviruses infect only mammals, while the gamma-and delta-coronaviruses mainly infect birds. covid-19 belongs to the β genus coronaviruses [1] . sars-cov-2 is a novel human coronavirus (hcovs) besides four hcovs ((α-coronaviruses (229e and nl63), β-coronaviruses (oc43 and hku1)), middle east respiratory syndrome coronavirus (mersr-cov), as well as the severe acute respiratory syndrome-related coronavirus (sars-cov) [1] . it is an enveloped positive single-stranded rna virus with 60-140 nm in diameter. the shape of sars-cov-2 is spherical or elliptical [4, 5] . the consistency of whole genome sequence of sars-cov-2 with sars-like coronavirus in bats (bat-sl-covzc45) ranges from 86.9% [5] to 89% [6] . "the sars-cov-2 is sensitive to ultraviolet light and heat, and it can be inactivated at 56℃ for 30 minutes. lipid solvents, except chlorahexidine, such as ethyl ether, and 75 % ethanol can also effectively inactivate the virus" [2, 4] . up until 22 march 2020, there have been 333,751 cases confirmed with covid-19 and 14,524 people died of it worldwide (data from the who). however, cases of pediatric patients infected with covid-19 are currently rare -even though the situation of covid-19 has become more urgent and severe around the world. thus far, literature on children with covid-19 is comparably rare. to help better understand how it would affect children and what is the latest specific clinical and research finding on children with it, we provide a mini-review based on 25 literature references covering the fields of epidemiology, clinical manifestation, accessary examination, treatment, and prognosis of pediatric patients with covid-19. the selection process is described in detail in the next section. we have searched the query string "covid-19 or coronavirus or sars-cov-2" and "pediatric or children" (publication date was restricted in 1 year) on pubmed, embase, cochrane library, nih, cdc, and cnki by 16 march 2020. we yielded 85 articles on pubmed, 1 on embase, none on cochrane library, 8 on cnki, none on cochrane library, nih, and cdc. subsequently, we went over the abstracts of those articles to see whether they were related to the current pandemic and ruled out overlapping literature. ultimately, we ended up with 25 articles (17 in english, 8 in chinese -cf. references) including 3 reviews to read the full article. afterwards, we excluded those with relatively lower confidence level compared to literature on the same topic. in addition, we reviewed the guidelines related to covid-19 published on the chinese cdc and chinese nhc. note that at the time, literature on the topic is growing rapidly, and search results may differ quickly. in the following, we provide the summary obtained. according to these published retrospective studies and guidelines, "the main source of infection are patients infected with covid-19 with or without clinical symptoms" [4] . furthermore, during the period of incubation, those infected also have the ability to transmit the virus [6, 14] . normally, covid-19 is spread through respiratory droplets. close contact with symptomatic or asymptomatic patients with a positive covid-19 test is also a route of transmission. moreover, current research comes to the conclusion that sars-cov-2 can be transmitted via the fecal-oral pathway as well [4] . however, mother-infant vertically or breast milk transmission remains unclear. it is reported that the youngest individual with a covid-19 diagnosis is only 36 hours old. in addition, two neonates were diagnosed with covid-19. thus, vertical-transmission appears possible [11] . normally, humans are generally susceptible to sars-cov-2. current obersvation has it that, among the patients confirmed with sars-cov-2 (44,653 cases) until february 11, 2020, in china, 2.1% were between 0-19 years old, which suggested that the population of pediatric patients were rather small [9] . moreover, the epidemiological data showed that children who suffered from a sars-cov-2 infection were mainly all rights reserved. no reuse allowed without permission. the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/10.1101/2020.03.30.20044545 doi: medrxiv preprint resulting from familial aggregation [4, 9] . the epidemiological study of hcov among children based on 3,883 pharyngeal swab samples in 2015 also showed that the positive rate of hcov decreased with age, and the positive rate of hcv dna was highest in the < 1 year old group [17] . according to the data of the dong y' group, which focused on 2,143 pediatric patients with positive sars-cov-2 tests forwarded to the chinese center for disease control and prevention, young individuals of any age were susceptible to sars-cov-2. however, younger children, particularly infants, were more at risk of sars-cov-2 infection [10] , while neonates -especially preterm infants -show mostly insidious and non-specific symptoms [11] . like many other pediatric respiratory systems infectious disease, at the onset of covid-19, not specifically, children affected by sars-cov-2 mainly present asymptomatic or only mild symptoms of the respiratory or gastrointestinal systems such as fever, cough, mild diarrhea, or headache. the majority of the young patients had low to medium fever, or even none [4, 9] . dyspnea, shortness of breath, nostrils flaring, cyanosis, moist rales on auscultation, and other pneumonia symptoms may appear with the progress of covid-19 alongside toxic symptoms of systemic infection, such as lethargy, mental fatigue, reduced appetite, and others. critical patients may manifest a respiratory failure largely invariant to oxygen treatment; moreover, even septic shock, multiple organ failure, and coagulation dysfunction may occur [3, 4, 8, 18] . according to the current literature on the pediatric cases, children confirmed with covid-19 mostly had good prognosis, with considerably less severe to critical progress (5.9%) as compared to adult patients (18.5%). this suggests that, compared with adult patients, clinical manifestations of pediatric patients with positive sars-cov-2 tests may be milder [4, 10] . laboratory testing according to the diagnosis and treatment recommendations by the national center for children's health and disease, "routine blood test white blood cell count of children with sars-cov-2 is usually normal or decreased, with generally lower lymphocyte count; severe cases may exhibit progressive lymphocytopenia. creactive protein (crp) is mostly normal or increased. procalcitonin (pct) is also at normal level in most cases. elevation of liver enzymes, muscle enzymes and myoglobin, and increased level of d-dimer could be seen in severe cases" [4] . nucleic acid testing is the gold standard of laboratory diagnosis. sars-cov-2 nucleic acid can be detected by rt-pcr or by viral gene sequencing of upper airway specimens (pharyngeal/nasal swabs) and lower airway specimens (sputum, bronchoalveolar lavage fluid), urine, stool, conjunctival secretions, or blood samples. other methods include that isolation of sars-cov-2 particles from human cells by viral cultures [4] . imaging features "given chest x-ray examination in the early stage of pneumonia cases, chest images show multiple small patchy shadows and interstitial changes, remarkable in the lung periphery. in severe cases, bilateral multiple ground-glass shadows, infiltrative opacity and pulmonary consolidation may develop, accompanied by rare pleural effusion" [4] . however, because most pediatric patients with covid-19 belong to the mild category, the plain chest x-ray of them usually do not capture the lesions detailed characteristics of the lungs. in the result, diagnoses may be taken wrongly. to circumvent this, chest ct seems crucial to be taken early on [8] . in fact, chest ct scanning can well show pulmonary lesions due to the high sensitivity and tomography. in bilateral lungs, it provides segmental consolidation as well as ground glass opacity (ggo). in those young patients who are severely infected, several lobar can be affected [4] . additionally, for infants, especially preterm babies, abdominal radiography may exhibit the characteristic intestinal ileus [11] . covid-19 infection should be taken as possibility once a criterium is met within the epidemiological history and two of the clinical manifestations in [4] hold. a positive diagnosis can be stated if: "1) throat swab, sputum, stool, or blood samples tested positive for sars-cov-2 nucleic acid using rt-pcr; 2) genetic sequencing of throat swab, sputum, stool, or blood samples are being highly homologous with the known sars-cov-2; 3) sars-cov-2 granules are being isolated by viral culture from throat swab, sputum, stool, or blood specimens " [4] . for those suspected patients with negative nucleic acid detection, for identification of serum antibody holds: positive serum sars-cov-2 -specific igm, or specific igg antibody titer during recovery are at minimum four times above the level in the acute phase [2, 4] . covid-19 was categorized by clinical manifestations, lab test outcome, and chest x-ray/ct imaging into five categories: firstly, asymptomatic infection, followed by mild, and moderate, reaching to severe, and critical. the diagnostic criteria are referred to in [2, 4] . in terms of management principles, one can stress the importance of "early identification", "early isolation", "early diagnosis", and "early treatment" [4] . generally, without certain effective cure, treatments of covid-19 consist of both symptomatic and respiratory supports. for now, antiviral treatments (virazole, oseltamivir, and interferon) are the standardised drugs for covid-19 patients. application of countermeasures reported so far includes usage of antibiotics, immunoglobulin, intravenous steroid, and tcm. in mild cases, one should refrain from applying broad-spectrum antibiotics or corticosteroids" [4] . further, in severe as well as critical cases, "antibiotics, corticosteroids, bronchoalveolar lavage, mechanical ventilation, and other more invasive intervention, such as blood purification and extracorporeal membrane oxygenation (emco) should be applied cautiously, based on cost-benefit evaluation" [4] . finally, as to discharge, the young patients need to show a return to their normal temperature of the body for a minimum of three consecutive days, significant recovery of their respiratory system, and succeed in having two consecutive, but at least one full day apart negative test results for respiratory pathogenic nucleic acid. depending on the situation, home isolation is subsequently advised over two full weeks. [4, 11] . most asymptomatic or mild patients had a good prognosis. so far, there is one registered death case of a child patient. in addition, child covid-19 cases were mild, with a one to two week recovery time subsequent to onset [9] . however, severe and critical cases may be left with long-term lung damage [19] . brain damage such as chronic demyelination and seizures as comorbidity of pediatric patients with hcov have also been reported [15] . to our best knowledge on covid-19, among the patients confirmed with covid-19, the population of pediatric patients is rather small [4] . the children confirmed with covid-19 mostly have good prognosis. a single child patient passed away; for other child patients, progression of the disease was observed as mild [9, 10] . yet, in more general, infectious diseases often tend to behave less aggressively in child patients. for severe respiratory distress syndrome (sars), the total death ratio is reported within 7% to 17%. for individuals with less than 24 years of age, the death ratio is 0% compared to 50% mortality rates in adults older than 65 years [9] . looking at those cases of covid-19 judged as severe, children's rate is also considerably below adults' rate (49.0%, 1023/2087) [19] . the main explanation would be:1. one possible reason is that children have been protected well resulting in lower potential exposure with the virus due to considerably lower travelling track record and potentially relatively higher indoor time. 2. children possess more active innate immune systems, including mostly fully functional lungs owing to low exposure to smoking induced and other air pollution. 3. children do not really have complex underlying disorders. 4.the differences in distribution, maturation and function of viral receptor angiotensin converting enzyme ii (ace2) are usually named a potential cause for age-based differences in infection rate. ace2 was already considered a cell receptor for sars-cov [9] . recent reports indicate that ace2 in ciliated bronchial epithelial cells and type ii pneumocytes is also likely the binding receptor for sars-cov-2. a usual theory for children's lower sensitivity to sars-cov-2 is based on their less maturity and lower function of ace2 compared with that in adults [9] . nevertheless, the children, especially infants, who are confirmed with covid-19 could be an insidious infectious source because of their asymptomatic or mild symptomatic infection due to a weak immune system or their own physical characteristics. a largely asymptomatic infant with covid-19 with high viral load was reported in singapore, and this case highlights the difficulties in establishing the true incidence of covid-19, as asymptomatic individuals may play important roles in human-to-human transmission in the community [13] . a study focused on 24 asymptomatic infections identified that the infection period of asymptomatic patients may be as long as three weeks, and the infected patients may develop into serious diseases [14] . furthermore, the bad habits of young children such as sucking hands, putting their hands all around and unwilling to wash hands could be important risk factors in contact transmission for children. thus, it is necessary to guarantee family daily prevention to keep children from covid-19 infection and assure awareness of the importance of its early diagnosis. also, during the epidemic period, children's health clinics and vaccination clinics should be reduced reasonably, and parent-child activities, kindergartens, primary schools, and other group activities related to children should be suspended. in clinical case, screening was mostly based on the epidemiological track record. additional basis were raised body temperature and symptoms of the respiratory tract. for children, it is more important to trace close contact history, and pathogen examination needs to be timely executed along with longitudinal monitoring through viral nucleic acid detection. further isolation recommendations and ongoing nucleic acid testing are also recommended for discharged patients [14] . additionally, it appears crucial to follow up with infants'respiratory as well as gastrointestinal symptoms and vital indications steadily, which is the most susceptible population in children, at mild onset that could progress into severe at a later stage [11] . moreover, for screening the suspected cases, since "most of the pediatric patients are mild cases, plain chest x-ray often fails to show the lesions or the detailed features, leading to misdiagnosis or missed diagnosis" [4, 8, 16] . as a consequence, chest ct early on is seen mandatory. also, a number of suspected pediatric patients with a negative nucleic acid of sars-cov-2 virus were rightfuly considered potential infection cases in accordance with usual chest ct visible lesions. this further encourages early diagnosis and treatment, but also isolating of infected children in effective ways [8] . in a recent report, the authors studied the ct features of 20 children, and came to the conclusion that consolidation with surrounding halo signs are frequent in children with covid-19. interestingly, these are dissimilar from those of grown-ups. one may assume such consolidation with surrounding halo signs as a distinctive feature of young individuals affected [8] . another study reported the ct results of 3 children with positive covid-19 diagnosis which showed patchy ground-glass opacities that were similar, but more modest compared to reports in adults [18] .however, the samples of both studies are indeed small, in the future, large-scale studies focusing on the imaging features of children with covid-19 are needed. furthermore, the data from the first group also showed that the pct has significantly increased in 80% of the cases in this study with or without coinfection evidence existing, which is not common in adult patients [8] . this suggests that the underlying coinfection or secondary infection may be more common in pediatric patients. if a secondary infection/coinfection is suspected, a collection of the specimen should be executed to detect potential secondary bacterial and/or fungal infections, and routine antibacterial treatment also should be considered in this situation [2, 8] . in 2017, a large-scale retrospective research focusing on epidemiology as well as on clinical attributes of hcovs (hku1, 229e, oc43, and nl63) in the pediatric population (261 cases) showed the risks linked to aggravation of infection. the risk factors were: younger than two years of age and in addition cardiovascular, genetic or congenital and respiratory chronic complex conditions which in the context of requiring respiratory support. genetic or congenital underlying disorders were associated with picu admission [17] . for those critical pediatric patients with positive covid-19 diagnosis, the most frequently observed symptoms were polypnea, then fever, and finally coughing [19] . some severe or critical children were found to have an excessive active immune response, which may result in long-term lung injury as well as fatal health problems. coronaviruses including sars-cov-2, sars, and mers were proved to have the potential ability to lead to significant and peculiar destructive host immune response that is related to severe lung damage. researches exhibited the lung impairment is mostly observed in patients in a critical state, linked to a cytokine storm, marked by raised levels of pro-inflammatory cytokines (il-1β, il-6, il-12, tnf, ifn-γ), as well as of anti-inflammatory cytokines (il-4, il-10, il-13, tgf-β) [12, [19] [20] [21] [22] [23] [24] [25] . these findings suggest that it is necessary to detect the indicator of the inflammatory and immune status, which could help doctors to assess the clinical progress, be on alert for severe and critical cases, and provide anti-autoimmune or blood-purifying therapy in time, once cytokine storm occurs [2, 19] . early identification and diagnosis of the severe/critical pediatric patients are always the priority to result in appropriate treatment and good prognosis. in the latest version of "scheme for diagnosis and treatment of the 2019 novel coronavirus pneumonia", pediatric patients with " fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bilateral or multi lobed infiltration, pleural effusion or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those which underly diseases (congenital heart disease, bronchopulmonary dysplasia, respiratory tract deformity, abnormal hemoglobin, severe malnutrition, etc.) and/or, immune deficiency/hypofunction (long-term use of immunosuppressant drugs)", are in high risk progressing into severe to critical illness, and intravenous immunoglobulin may be considered in those children [2] . for those children isolated alone from their parents, maternal separation may cause anxiety and depression to infants or children. for this reason, their psychological caretaking for their wellbeing needs to be assured. all of the treatment plan and segregation situation have to be discussed with the responsible care-takers of the young individuals. psychologists or suited related experts are required to help cease their anxiety and panic. in conclusion, the numbers of children with covid-19 pneumonia infection are small, and most of them come from family aggregation. symptoms are mainly mild or even asymptomatic which allow children to be a risk factor for transmission. thus, strict epidemiological history screening is needed for early diagnosis and segregation. this holds especially for infants, who are more susceptible to infection than other age groups in pediatric age, but have most likely subtle and unspecific symptoms. they need to be paid more attention to. ct examination is a necessity for screening the suspected cases, because the majority of the young covid-19 infected are classified as mild infection, and plain chest x-ray mostly gives not sufficient insight into the lesions or lung details. therefore, early chest ct examination combined with pathogenic recognition is a recommended clinical diagnosis scheme in children. the risk factors which may suggest severe or critical progress for children are: fast respiratory rate and/or; lethargy and drowsiness mental state and/or; lactate progressively increasing and/or; imaging showed bi-or multi-lobed infiltration, pleural effusion, or rapidly expending of lesions in a short period of time and/or; less than 3 months old or those who underly diseases. for those critical pediatric patients with positive sars-cov-2 diagnosis, polypnea may be the most common symptom. for treatment, the elevated pct seen in children in contrast to adults suggests that the underlying coinfection/secondary infection may be more common in pediatric patients and appropriate antibacterial treatment should be considered. once cytokine storm is found in these patients, anti-autoimmune or bloodpurifying therapy should be given in time. finally, it is of crucial importance to assure early isolation combined with best possible psychological support for the young patients. origin and evolution of pathogenic coronaviruses national health commission of the people's republic of china. scheme for diagnosis and treatment of 2019 novel coronavirus pneumonia (the 7th trial edition) department of maternal and child health of the national health commission of the people's republic of china. scheme for novel coronavirus infection prevention and control for children and pregnant women diagnosis and treatment recommendations for pediatric respiratory infection caused by the 2019 novel coronavirus & china novel coronavirus investigating and research team. a novel coronavirus from patients with pneumonia in china a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-toperson transmission: a study of a family cluster epidemiological characteristics of human coronaviruses among children in wuhan clinical and ct features in pediatric patients with covid-19 infection: different points from adults are children less susceptible to covid-19? epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china. pediatrics working committee on perinatal and neonatal management for the prevention and control of the 2019 novel coronavirus infection coronavirus sars-cov-2: a brief perspective from the front line a well infant with coronavirus disease 2019 (covid-19) with high viral load clinical characteristics of 24 asymptomatic infections with covid-19 screened among close contacts in nanjing human coronavirus oc43 infection induces chronic encephalitis leading to disabilities in balb/c mice chest computed tomography in children with covid-19 respiratory infection epidemiology and clinical features of human coronaviruses in the pediatric population clinical features of pediatric patients with covid-19: a report of two family cluster cases clinical features of severe pediatric patients with coronavirus disease 2019 in wuhan: a single center's observational study characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72,314 cases from the chinese center for disease control and prevention clinical features of patients infected with 2019 novel coronavirus in wuhan reducing mortality from 2019-ncov: host-directed therapies should be an option severe acute respiratory syndrome: historical, epidemiologic, and clinical features middle east respiratory syndrome coronavirus infections and immune responses this work was partially supported by the zhejiang lab's international talent key: cord-281132-7hk6ze9k authors: falahi, s.; sayyadi, h.; abdoli, a.; kenarkoohi, a.; mohammadi, s. title: the prevalence of human bocavirus in <2-year-old children with acute bronchiolitis date: 2020-08-03 journal: new microbes new infect doi: 10.1016/j.nmni.2020.100736 sha: doc_id: 281132 cord_uid: 7hk6ze9k acute bronchiolitis is one of the most common lower respiratory tract infections in children with less than 2 years of age. nowadays, molecular methods provide an opportunity to better understand the etiology of bronchiolitis. several viral agents including respiratory syncytial virus (rsv), rhinovirus, parainfluenza and human bocavirus (hbov) are responsible for acute bronchiolitis. there are growing studies on the prevalence of hbov in patients with bronchiolitis. the present systematic review and meta-analysis were conducted to determine the pooled prevalence of hbov in the respiratory samples of children with acute bronchiolitis. a literature search was conducted in the databases of pubmed, scopus and web of science to recruit studies reporting the frequency of hbov in <2-year-old children with acute bronchiolitis from 2005 to 2019. only studies that used polymerase chain reaction (pcr)-based methods to detect the virus in nasopharyngeal samples were included. a total of 22 studies assessing 6751 cases were analyzed. according to the meta-analysis based on the random-effects model, the overall prevalence of hbov in children with <2 years old was obtained 13% (95% ci: 0.09-0.17). additionally, the rates of single (as the sole organism) and mixed (in combination with other viruses) hbov infections were 4% and 9%, respectively. this study showed a high rate of hbov detection in children with acute bronchiolitis. this should be considered as part of a diagnostic test panel for respiratory infections in children with bronchiolitis. bronchiolitis is a common respiratory tract infection in children. it is associated with inflammation, edema, increased mucus production, and the necrosis of the epithelial cells of bronchioles [1] bronchiolitis primarily presents with the symptoms of upper respiratory tract infections. these include nasal congestion, fever, and cough progressing to wheezing and tachypnea. because the lungs and immune system of young children are not fully maturated, acute bronchiolitis can be a serious clinical condition leading to the blockage of airways in these children. acute bronchiolitis is generally diagnosed based on clinical and chest x-ray (cxr) examinations; however, complete blood cell count (cbc) can also be helpful [2] . several respiratory viruses are known to cause bronchiolitis, among these, respiratory syncytial virus (rsv) is responsible for 70% of the cases. other causative agents include human rhinovirus (hrv), type a and b influenza viruses, parainfluenza, adenovirus, human coronavirus, and human bocavirus (hbov) which is a relatively new etiology of bronchiolitis. studies on the pathogenic role of hbov in humans are on the rise [3] . hbov is a non-enveloped dna virus that belongs parvoviruses from bovine and canine [4] . hbov, which has been detected in respiratory, fecal, urine, saliva, and blood specimens, shows a global distribution [5, 6] . after the identification of hbov, many studies have reported this virus as a cause of acute respiratory diseases in children. however, the frequent co-detection of hbov with other viruses in patients' samples has debated its role as a true pathogen, and some suggested the virus as a passenger agent [7, 8] . on the other hand, although hbov persistence is not fully understood, hbov dna remains in the tissues of children's respiratory tract for a long time after the primary infection, it may be one reason for identifying hbov as a co-infection in some studies [7, 9, 10] . so far, there has been one fatality reported in an immunocompetent child due to severe acute bronchiolitis caused by hbov [11] . some studies have described the hbov as the second or third most prevalent cause of bronchiolitis [3, 12] . the seasonal distribution of hbov is similar to that of rsv leading to a prominent coincidence between these two infections [13] . overall, the prevalence of hbov has been widely variable in patients with bronchiolitis in different studies [14] . here, we conducted a systematic review and meta-analysis to estimate the frequency of hbov in < 2-year-old children with acute bronchiolitis. searching and selection of related articles according to the preferred reporting items for systematic reviews and meta-analyses (prisma) recommendations [15] , we searched various databases including pubmed, scopus and web of science for related articles using the medical subject heading (mesh) terms of "bocavirus", "hbov", "prevalence", "frequency", "epidemiology", "acute bronchiolitis", "lower respiratory tract infection", and "acute respiratory tract infection" either alone or in combination with each other applying the boolean operators (and, or). all the related papers published from january 2005 to october 2019 were retrieved. after removing duplicates, the abstracts and full texts of the studies were reviewed. in addition, to make sure that the search was complete, the reference lists of eligible articles were also manually searched for related works. furthermore, the links to "similar articles" on the pubmed had been opening to find other relevant papers. all english-language research articles published on the prevalence of hbov in children with acute bronchiolitis were enrolled. other types of articles including reviews and letters to editors were excluded. in addition, studies that used nonmolecular methods for detecting the virus were excluded. studies performed on children older than 2 years were removed from the assessment. the following data was collected and recorded into a checklist: first authors' names, year of publication, the country of study conduction, the number of cases, the number of male and female subjects, sample types, patients' mean age, the number and percentage of positive samples, and finally the rates of single (only hbov) and mixed (hbov along with other pathogen) infections. to analyze and combine the results of different studies, a binomial distribution was considered for the prevalence of the virus in each study. the standard errors were calculated based on this distribution. heterogeneity was assessed using the cochran q test and i 2 index. based on the high heterogeneity rate among the studies, the random effects model was used for meta-analysis. meta-regression analysis was applied to investigate the sources of heterogeneity and the relationship between the virus prevalence and each of sample size and year of publication. sensitivity analysis was also used to investigate the impact of each study on the calculation of the final outcome. all the analyses were performed in stata 11 software, and p values less than 0.05 were considered significant in all the statistical tests. a total of 2936 articles were collected upon the initial search in the electronic databases. of these, 722 duplicate studies were removed. by subsequent screenings, 1814 additional articles were excluded according to our exclusion criteria. after that, the full texts of 400 articles were carefully assessed. of these, 378 studies met at least one exclusion criterion. finally, 22 articles were included in the meta-analysis process (fig. 1) . in this study, a total of 22 articles comprising of 6751 children with a mean age of 6.7 months (95% ci: 5.1-8.3) were included in the meta-analysis process. the details of the reviewed articles [12, 13, [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] have been shown in table 1 . the rate of heterogeneity among the studies was high (97.4%), and therefore the random effects model was used for metaanalysis. sensitivity analysis was also used to investigate the impact of each study on the calculation of the final outcome (fig. 2) . based on studies conducted from 2005 to 2019, the overall prevalence of hbov in the airway samples of <2-year-old children with bronchiolitis was estimated as 13% (95% ci: 0.09-0.17) (fig. 3) . the lowest and highest frequencies of hbov were reported by cangiano et al. (1.8%) and macao et al. (37.1%), respectively (fig. 4) [27, 30] . a meta-regression model was used to investigate the relationship between the prevalence of hbov in children and each of the year of study and sample size. fig. 4 shows the relationships between the prevalence of hbov and the year of study conduction (fig. 4a ) and sample size (fig. 4b) . although there were decreasing trends in the prevalence of hbov by elevations in the year and sample size, with respect to the obtained p values and regression coefficients (0.444 and 0.235, respectively), these associations were not statistically significant. for calculating the prevalence of single hbov infection in <2year-old children with bronchiolitis, a total of 15 articles were included in the meta-analysis process. the total number of children in these studies was 4487 with an average age of 6.7 months (95% ci: 5.1-8.3). as the rate of heterogeneity among the studies was high (83.2%), the random effects model was used for meta-analysis. as shown in fig. 5 , the prevalence of hbov as a single infection in <2-year-old children with bronchiolitis was 4.4% (95% ci: 3.0-5.7, fig. 5 ). the prevalence of hbov as a coinfection in these children, which was estimated based on studies on 6751 children with an average age of 6.7 months, was 8% (95%ci: 0.04-0.12, fig. 6 ). bronchiolitis is a major cause of hospitalization due to respiratory infections among children with the age of <6 months. several viral agents including respiratory syncytial virus, hrv, influenza, and human metapneumovirus have been associated with bronchiolitis in children. in addition to the abovementioned viruses, hbov has also been reported as a cause of bronchiolitis; however, this association is still controversial. in fact, some studies have described a considerably wide range of hbov infection in patients with bronchiolitis [36, 37] . the findings of our study estimated an overall prevalence of 13% for hbov infection in <2-year-old children with bronchiolitis. these results support previous studies in which hbov has been frequently detected in the samples of patients with bronchiolitis, sometimes even as the second or third most common viral agent [12] . the rate of hbov infection in children with bronchiolitis varies from 1.8% to 37% in different countries [27, 30] . among the studies assessed here, the lowest and highest frequencies of hbov were reported by cangiano et al. (1.8%) in italy and macao et al. in portugal (37.1%). this indicates that geographical location may be one of the factors contributing to the heterogeneity observed among the analyzed studies. in accordance, the prevalence of hbov has been variable between different countries, and even within countries [27, 30] . most of the assessed studies had been conducted in spain and italy. four studies in italy from 2005 to 2016 reported frequencies from 1.8% to 12.5% [13, 27] . our findings also suggested that the prevalence of hbov may be associated with the year of study conduction. another study conducted in 2016 reported a hbov prevalence of 1.8% in children with a mean age of 2.1 months [27] . according to previous studies, the prevalence of hbov infection is generally higher within the ages of 3 to 6 months [2] . based on the meta regression model, hbov prevalence showed a decreasing trend over time. although this observation was not statistically significant, this declining trend may be related to improved health conditions, educations, and also increasing awareness about the transmission ways of respiratory infections. although the overall prevalence of hbov infection was estimated as 12.9%, the incidence of the virus as a single agent was 4%. this supports previous reports noting that hbov is more commonly identified as a mixed infection in association with other viruses [8] . although hbov infection is diagnosed throughout the year, but it peaks during winter and spring [38] . nevertheless, the seasonal occurrence of hbov is still a subject of debate, and there are increasing evidences suggesting the higher frequencies of the viral infection in the cold months of the year, especially in january and february [36] . so, sampling time can also be a factor contributing to the heterogeneity among the studies. in fact, in studies with a longer sampling time (e.g. 1-year period), the prevalence of respiratory infections may be underestimated compared to studies performed during the months showing a peak activity of respiratory viruses. this can actually be a source of bias in these studies. therefore, this factor should be considered in meta-analysis studies to investigate the prevalence of respiratory viruses. in this study, although inclusion criteria were applied to select studies on a similar population (i.e. children younger than new microbes and new infections, volume 37 number c, september 2020 2 years) and with same detection methods (i.e. molecular assays), there was still a high heterogeneity among the studies. it seems that several factors such as seasonal distribution, age spectrum, year of study, geographical location, and sampling time may be responsible for the heterogeneity observed among the studies. from the limitations of this study was a high heterogeneity among the studies. furthermore, there were no reports in many countries limiting our results to certain geographical locations. the data obtained here shows that hbov infection is relatively frequent in children with bronchiolitis aged <2 years old. hbov may be either a cause or a risk factor for bronchiolitis in these children. therefore, this virus should be considered when determining the etiology of bronchiolitis in young children. it is also recommended to incorporate hbov testing in bronchiolitis diagnostic panels. viral infections of the lower respiratory tract: old viruses, new viruses, and the role of diagnosis epidemiology, clinical, and laboratory characteristics of bronchiolitis in hospitalized children risk factors for bronchiolitis severity: a retrospective review of patients admitted to the university hospital from central region of slovenia the prevalence of human bocavirus as a co-infection in <2-year-old children with bronchiolitis based on the random effects model. the points represent percentages, and the lengths of lines display 95% confidence intervals in each study risk of acute gastroenteritis associated with human bocavirus infection in children: a systematic review and meta-analysis human bocavirus in iranian children with acute gastroenteritis human bocavirus and acute wheezing in children human bocavirus: current knowledge and future challenges human bocavirus: passenger or pathogen in acute respiratory tract infections? human bocavirus infection and respiratory tract disease identified in a uk patient cohort comparison of tissue distribution, persistence, and molecular epidemiology of parvovirus b19 and novel human parvoviruses parv4 and human bocavirus acute human bocavirus 1 infection in child with life-threatening bilateral bronchiolitis and right-sided pneumonia: a case report viral etiology of bronchiolitis among pediatric inpatients in northern taiwan with emphasis on newly identified respiratory viruses respiratory syncytial virus, human bocavirus and rhinovirus bronchiolitis in infants high viral load of human bocavirus correlates with duration of wheezing in children with severe lower respiratory tract infection preferred reporting items for systematic reviews and meta-analyses (prisma) statement and publication bias cocirculation of genetically distinct human metapneumovirus and human bocavirus strains in young children with respiratory tract infections in italy determination of the frequency of human bocavirus and other respiratory viruses among 0-2 years age group children diagnosed as acute bronchiolitis analysis of human metapneumovirus and human bocavirus viral load infection with multiple viruses is not associated with increased disease severity in children with bronchiolitis detection of new respiratory viruses in hospitalized infants with bronchiolitis: a three-year prospective study recurrent wheezing and asthma after bocavirus bronchiolitis human bocavirus infection in hospitalized children in italy human bocavirus quantitative dna detection in french children hospitalized for acute bronchiolitis correlation between bocavirus infection and humoral response, and co-infection with other respiratory viruses in children with acute respiratory infection risk factors for severe bronchiolitis caused by respiratory virus infections among mexican children in an emergency department viral aetiology of bronchiolitis in hospitalised children in qatar bronchiolitis: analysis of 10 consecutive epidemic seasons risk factors for bronchiolitis severity: a retrospective review of patients admitted to the university hospital from central region of slovenia acute bronchiolitis: a prospective study broad respiratory virus detection in infants hospitalized for bronchiolitis by use of a multiplex rt-pcr dna microarray system etiology of bronchiolitis in a hospitalized pediatric population: prospective multicenter study sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus? clinical risk factors are more relevant than respiratory viruses in predicting bronchiolitis severity etiology of acute bronchiolitis and the relationship with meteorological conditions in hospitalized infants in china th1 and th2 cytokine levels in nasopharyngeal aspirates from children with human bocavirus bronchiolitis etiology, seasonality, and clinical features of viral respiratory tract infections in children hospitalized with acute bronchiolitis: a single-center study respiratory viruses in bronchiolitis and their link to recurrent wheezing and asthma human bocavirus as an important cause of respiratory tract infection in taiwanese children the authors declare no conflict of interest. there is no funding for this study. key: cord-274443-r6ponjr4 authors: lawson, monica; piel, megan h.; simon, michaela title: child maltreatment during the covid-19 pandemic: consequences of parental job loss on psychological and physical abuse towards children date: 2020-09-04 journal: child abuse negl doi: 10.1016/j.chiabu.2020.104709 sha: doc_id: 274443 cord_uid: r6ponjr4 background: job loss resulting from the covid-19 pandemic presents significant risk for child abuse. protective factors, such as reframing coping, may mitigate the risk of job loss on child maltreatment. objective: the current study investigated factors associated with child maltreatment during the covid-19 pandemic, including parental job loss, and whether cognitive reframing moderated associations between job loss and child maltreatment. method: a community sample of 342 parents (62% mothers) of 4to 10-year-olds (m = 7.38, sd = 2.01; 57.3% male) living in the united states completed online questionnaires regarding experiences with covid-19, the parent-child conflict tactics scale, and the family crisis oriented personal evaluation scales. results: two logistic regression analyses evaluated predictors of whether parents psychologically maltreated or physically abused their children during the pandemic controlling for maltreating history, parental depressive symptoms, financial stability, parent age, parent gender, child age, and child gender. parents who lost their jobs (or = 4.86, 95% ci [1.19, 19.91], p = .03), were more depressed (or = 1.05, 95% ci [1.02, 1.08], p < .01), and previously psychologically maltreated their children (or = 111.94, 95% ci [28.54, 439.01], p < .001) were more likely to psychologically maltreat during the pandemic. regarding physical abuse, a significant interaction between job loss and reframing coping emerged (or = 0.76, 95% ci [0.59, 0.99], p = .04). among parents who lost their jobs, the probability of physical abuse decreased as reframing coping increased. conclusions: job loss during the covid-19 pandemic is a significant risk factor for child maltreatment. reframing coping may be an important buffer of this association on physical abuse and presents implications for maltreatment prevention. with mounting unemployment rates, nationwide school district closures, and stay at home orders, the novel coronavirus (covid-19) pandemic abruptly and significantly upheaved the daily lives of young children and families across the globe. in particular, the the stress and coping model of child maltreatment indicates that the impact of life stressors on a parents' propensity for committing child abuse depends on their dispositional coping strategies (hillson & kuiper, 1994) . coping has been defined as the cognitive and behavioral strategies used to manage external or internal demands caused by stressors (lazarus & folkman, 1984) . emotion-focused coping strategies, which aim to regulate emotional responses and reactivity to stressors, may be especially beneficial when individuals encounter stressors that are out of their control to objectively change (hillson & kuiper, 1994; lazarus & folkman, 1984) . emotion-focused coping strategies may be effective in mitigating negative emotions and stress caused by job loss resulting from the covid-19 pandemic given that individual families cannot objectively change the economic consequences of the pandemic. one particular form of emotion-focused coping that may be specifically helpful in alleviating negative emotions caused by stressors and bolstering well-being during the covid-19 pandemic is positive reframing. positive reframing is a cognitive emotion-focused coping strategy where individuals emphasize their strengths and reappraise and redefine the implications of stressors as being less critical than initially conceptualized (hillson & kuiper, 1994; lazarus & folkman, 1984) . positive cognitive reframing has been observed to buffer the negative psychological consequences of job loss (garrett-peters, 2009 ) and the negative impact of economic adversity and stress on family relationships (gomel, tinsely, parke, & clark, 1998; mckelvey, fitzgerald, schiffman, & von eye, 2002) . in addition, positive cognitive reframing enhances parental mental health and parenting quality among families experiening significant stressors, such as a child being diagnosed with a chronic illness or a developmental disability (benson, 2010; martin et al., 2012) . although the evaluation of associations among job loss, cognitive reframing, and parental abusive behaviors is unique to the current investigation, maladaptive coping strategies have been observed among maltreating parents (cicchetti & lynch, 1993; cicchetti & toth, 2005) , suggesting that ineffective coping strategies may importantly contribute to the etiology of child maltreatment. within the context of the covid-19 pandemic, negative coping strategies are anticipated to exacerbate the impact of economic stressors on child abuse (usher, navjot, durkin, gyamfi, & debra, 2020) . positive coping strategies may buffer such risk (cuartas, 2020) . guided by an ecological approach and the family stress and stress and coping models of child maltreatment, the potential buffering role of parental positive cognitive reframing on the association between parental job loss and psychological maltreatment and physical abuse was evaluated among parents of 4-to 10-year-olds living in the united states. examining factors associated with child maltreatment among families with young children is critical because younger children are significantly more at-risk for child abuse (u.s. department of health and human services, 2020) and may be especially vulnerable to family stress. parental job loss during the covid-19 pandemic was anticipated to be positively associated with psychological maltreatment and physical abuse. among parents who lost their jobs because of covid-19 related economic downturns, the probability of psychologically maltreating and physically abusing their children was anticipated to decrease as positive reframing increased. this association was anticipated to emerge even when controlling for parental maltreating history, parental depression, and family financial stability. participants included a community sample of parents of 4-to 10-year-olds recruited from facebook ads and from amazon mechanical turk (mturk) to participate in an online study regarding the impact of the covid-19 pandemic on family interactions. inclusion criteria included being a parent of a child between the ages of 4-to 10-years-old, being english speaking, and living in the united states. in addition, given the larger focus of the study on family interactions, all participating parents had to be in a committed romantic relationship. facebook ads were created and purchased to recruit families. the ads were targeted to only appear in newsfeeds of parents of preschool and elementary aged children that were in a romantic relationship and living in the united states. an invitation to participate in this project was also posted to the laboratory's facebook page, which resulted in minimal snowball sampling. similarly, the survey was only made available to mturk workers that previously qualified as meeting the inclusion criteria to increase recruitment of participants that met requirements. mturk is an online platform where workers are recruited to complete a variety of tasks and has been used extensively in the behavioral sciences for administration of online studies (buhrmester, talaifar, & gosling, 2018; buhrmester, kwang, & gosling, 2011; mason & suri, 2012 for reviews) . although there are concerns regarding the representativeness of data collected through crowd sourcing methods, mturk samples have been observed as representative of the general u.s. population (buhrmester et al., 2011; mason & suri, 2012) . the advantage of providing quick data collection is especially important given the urgency of understanding behavior during the covid-19 pandemic and the restrictions on conducting face to face human subjects research imposed by social distancing guidelines and institutional review boards in the united states. data were extensively screened following recommendations for cleaning data from crowd sourcing platforms (buhrmester et al., 2011 (buhrmester et al., , 2018 . participants were dismissed from the survey if they failed: (1) captcha bot detection questions, (2) questions regarding inclusion criteria, and (3) one of the seven attention checks. ballot stuffing was prevented in that users could only access the survey once and would not be able to access the survey a second time if dismissed. participants were forwarded that they would be dismissed from the survey if they failed an attention check, a practice shown to increase data quality (mason & suri, 2012) . participants were excluded from analyses if any of the following occurred: (1) the majority of the survey was not completed, (2) the survey was completed in under 25 minutes, (3) outlandish or duplicate responses were provided to open-ended questions, or (4) response patterns such as straightlining and consistently alternating between low and high value responses were detected. after cleaning the dataset for these criteria, data from 363 parents (62% mothers; mage = 37.52, sd = 6.20) recruited from facebook (n = 47) and mturk (n = 316) were retained. the majority of parents were caucasian (80.4%), followed by african american (6.3%), hispanic (5.8%), asian american (5.0%), and multiracial/other (2.5%). the majority of parents reported on male children (56.5%). children were evenly represented across the seven age groups (mage = 7.37, sd = 2.01; 11-19% of children for each age group). the majority of families (54.4%) had an annual income of $75,000 or higher. families represented the geographical regions of the united states (18.5% northeast, 22.9% southeast, 25.6% midwest, 20.9% west, and 12.1% southwest). the survey design and administration procedures followed best-practice methods for data collection using participants recruited online (buhrmester et al., 2011 (buhrmester et al., , 2018 . after providing informed consent, participants answered questions concerning the eligibility criteria, followed by demographic questions, questions regarding their experiences with covid-19, and several additional questionnaires about family interactions. the questionnaire measuring psychological maltreatment and physical abuse was administered at the end of the assessment to not bias earlier responses by asking about violence towards children. the survey was designed to take approximately 30-45 minutes to complete. participants were compensated with a $5 payment in the form of a mturk transaction or an electronic amazon gift card for facebook users. all recruitment and study procedures were approved by the institutional review board at the university of texas at san antonio. data were collected from mid-april to mid-may, 2020, during the peak of unemployment in the united states due to the covid-19 pandemic (as of august, 2020). participants completed a questionnaire regarding background information of themselves and their partner, such as age, ethnicity, employment status, education, and household income. parents also provided information about their children's age, ethnicity, and gender. participants completed a questionnaire regarding their experiences with the covid-19 pandemic, including the economic impact of covid-19 on their family. of specific interest in the current study, participants reported whether they lost their jobs due to covid-19 related economic consequences and the number of months their family would be able to continue living at their current address and at their current standard of living if the covid-19 pandemic were to last for several months without considering government stimulation packages and eviction freezes. responses to the latter question served as the financial stability variable and were scored on the following scale: 1 (less than 1 month), 2 (1-to 2-months), 3 (3-to 6-months), 4 (7-to 12-months), 5 (more than 1 year). for the job loss variable, parents who worked prior to the pandemic and lost their jobs because of covid-19 related economic disruptions were scored as 1 (job loss) and parents who did not lose their jobs or did not work prior to and during the pandemic were scored as 0 (no job loss). the conflict tactics scale parent-child version (ctspc; straus, hamby, finkelhor, moore, & runyan, 1998) was used to determine whether parents psychologically maltreated and physically abused their children within the past year (i.e., maltreating history) and within the past week during the covid-19 pandemic. the past week time frame was selected to standardize the number of days reflected on while answering the questions. this was important given the sporadic manner in which covid-19 infiltrated and impact different states and cities during the early weeks of the pandemic. the psychological maltreatment subscale consisted of five items capturing verbal and symbolic acts intended to cause psychological pain or fear (e.g., "i swore or cursed at my child." and "i threatened to spank or hit but did not actually do it."). the physical abuse subscale included 13 items regarding acts of corporal punishment (e.g., "i hit him/her on the bottom with something like a belt, hairbrush, a stick, or some other hard object."), severe assault (e.g., "i slapped him/her on the face or head or ears."), and very severe assault (e.g., "i burned or scalded him/her on purpose."). following coding conventions, participants reported the frequency in which these actions occurred within the past year and the past week on a 7-point scale: 0 (never), 1 (once), 2 (twice), 4 (3-to 5-times), 8 (6-to 10-times), 15 (11-to 20-times), 25 (20+ times). the ctspc has adequate psychometric properties (straus et al., 1998; tonmyr, draca, crain, & macmillan, 2011) and has been used in previous research as a self-report measure of parental psychological maltreatment and physical abuse towards children (grych, wachsmuth-schlaefer, & klockow, 2002; tonmyr et al., 2011) . internal consistency was adequate in the current study (mean α = .71). following recommendations for scoring the ctspc for a general population without known histories of maltreatment (straus et al., 1998) , psychological maltreatment and physical abuse were coded dichotomously. parents were scored as '0' if they did not endorse any of the items and as '1' if they endorsed at least one item, regardless of frequency. separate dichotomous variables were created for psychological maltreatment and physical abuse within the last year and the past week. the family crisis oriented personal evaluation scales (f-copes; mccubbin, olson, & larsen, 1981) measures problem solving and coping strategies employed by families when encountering hardship and difficult situations. the f-copes contains 30 items and five subscales (i.e., reframing, passive appraisal, acquiring social support, seeking spiritual support, and mobilizing the family to acquire and accept help). the reframing subscale was used in the current study and consist of eight items assessing the degree to which families respond to problems and difficulties by redefining stressors to make them more manageable (e.g., when encountering stressors, we respond by "believing we can handle our own problems" and "defining the family problem in a more positive way so that we do not become too discouraged."). parents rated the extent to which they agreed with each item on a 4-point scale, with higher values indicating more agreement. the f-copes has demonstrated adequate psychometric properties ( mccubbin et al., 1981) and has been used as a measure of coping among families encountering significant challenges (mckelvey et al., 2002) . internal consistency for the reframing subscale was adequate in the current study (α = .81). the center for epidemiologic studies depression scale (ces-d; radloff, 1977) is a commonly used 20-item, self-report measure assessing depressive symptoms among the general population. respondents rated the frequency in which they experienced depressive symptoms within the past week on a 4-point scale: 1 (not at all or less than 1 day), 2 (1-to 2-days), 3 (3-to 4-days), 4 (5-to 7-days). the ces-d had adequate internal consistency in the present study (α = .80) and was included as a covariate in all substantive analyses given robust associations between parental depression and child maltreatment (cicchetti, 2016) . data from five parents were excluded from the following analyses because the parents did not have custody of their children. sixteen additional participants were excluded from the analyses due to missing data (n = 7) or being an outlier on at least one continuous variable (n = 9). in total, the following analyses were conducted with data from 342 parents (n = 42 recruited from facebook; n = 300 recruited from murk). parents recruited from mturk were significantly older (m = 37.71, sd = 6.12) than parents recruited from facebook (m = 35.26, sd = 4.39), t(65.68) = 3.21, p < .01, d = 0.46. significantly fewer fathers were recruited from facebook (21.4% fathers) and fewer mothers were recruited from mturk (59.7% mothers), χ (1) = 5.59, p = .02. all other demographic characteristics did not significantly differ by recruitment source. significantly more parents recruited from facebook (38.1%) and significantly fewer parents recruited from mturk (15.0%) physically abused their children within the past week, χ (1) = 13.41, p < .001. whether parents psychologically maltreated their children in the past week did not significantly differ by recruitment source, χ(1) = 1.73, p = .19. recruitment source was included as a covariate in the main analyses. parent ethnicity was not significantly associated with whether parents psychologically maltreated, χ (4) = 3.53, p = .47, or physically abused, χ (4) = 8.35, p = .08, their children within the past week and was not considered further. descriptive statistics, including means and standard deviations, and bivariate correlations among the study variables are presented in table 1 . parental job loss was positively and significantly associated with psychological maltreatment (r = .19, p < .001) and physical abuse (r = .19, p < .001) towards children in the past week. parents who lost their jobs during the pandemic additionally engaged in more historical physical abuse (r = .15, p < .01). parents who reported using more reframing coping strategies were less likely to have a history of physical abuse (r = -.11, p = .04) and to psychologically maltreat (r = -.17, p = .001) and physically abuse their children in the past week (r = -.15, p < .01). younger parents were more likely to have a history of psychologically maltreating (r = -.11, p = .04) and physically abusing their children (r = -.16, p < .01) and were more likely to engage in such behaviors during the pandemic (r = -.18, p < .01; r = -.20, p < .001, respectively). younger children were more likely to be physically abused (r = -.17, p < .01 past year, r = -.16, p < .01, past week) and psychologically maltreated during the past week (r = -.19, p = .001). parents from families with more financial stability were less likely to physically abuse their children during the pandemic (r = -.20, p < .001). parents reporting more depressive symptoms were more likely to psychologically maltreat (r = .23, p < .001 past year; r = .34, p < .001 past week) and physically abuse their children (r = .24, p < . 001 past year; r = .29, p < .001 past week). male children were more likely to be psychologically maltreated (r = .12, p = .02 past year, r = .20, p < .001 past week). all significant correlations were small to medium in size. consistent with the national unemployment rates in the united states during the time of the assessment (department of labor, 2020a, 2020b), approximately 13% of parents in the current investigation reported losing their jobs during the covid-19 pandemic. whether parents lost their jobs during the pandemic was a significant predictor of whether parents psychologically maltreated, χ(1) = 11.77, p = .001, or physically abused their children during the pandemic, χ(1) = 12.60, p < .001. significantly more parents who lost their jobs psychologically maltreated and physically abused their children during the pandemic than expected. of parents who lost their jobs (n = 43), 72.09% psychologically maltreated their child during the pandemic. whereas, for parents who did not lose their jobs (n = 299), 44.15% psychologically maltreated their children during the pandemic. regarding physical abuse, of parents who lost their jobs, 37.21% physically abused their children. a minority of parents (15.05%) who did not lose their jobs physically abused their children during the pandemic. in addition, having a history of psychologically maltreating and physically abusing children during the year before the covid-19 pandemic was a significant predictor of whether parents psychologically maltreated, χ(1) = 137.03, p < .001, and physically abused their children during the pandemic, χ(1) = 104.87, p < .001. of parents with a history of psychologically maltreating their children (n = 229), 70.00% psychologically maltreated their children during the pandemic. whereas, for parents that did not psychologically maltreat their children in the past year before the covid-19 pandemic (n = 113), the majority (97.35%) did not engage in such acts during the pandemic. similar results were found for physical abuse. of parents with a history of being physically abusive (n = 112), approximately half (48.21%) physically abused their children during the pandemic. for parents without a history of being physically abusive (n = 230), the majority (96.96%) did not physically abuse their children during the pandemic. the main analyses consisted of two binary logistic regressions to examine predictors of whether parents psychologically maltreated or physically abused their children during the covid-19 pandemic. the following covariates were included in both models based on the results from the descriptive analyses: recruitment source (0 = facebook, 1 = mturk), parent age, parent gender (0 = female, 1 = male), child age, child gender (0 = female, 1 = male), financial stability, parental depressive symptoms, prior psychological maltreatment (0 = no history, 1 = history), and prior physical abuse (0 = no history, 1 = history). parental job loss (0 = no job loss, 1 = job loss) and reframing coping were entered as separate variables along with their interaction. all continuous covariates were mean centered. results from both analyses are presented in table 2 . the model examining psychological maltreatment was a significantly better fit for the data compared to the null model, χ(12) = 218.90, p < .001. the model accounted for 63.1% (nagelkerke r square) of the variance in whether parents psychologically maltreated their children during the pandemic. the model correctly classified 82.7% of the cases, with 77.1% correct classification for parents that did not engage in psychological maltreatment and 89.0% correct classification for parents that psychologically maltreated their children in the past week during the covid-19 pandemic. parental job loss (b = 1.58, se = 0.72, p = .03), parental depressive symptomology (b = 0.05, se = 0.02, p < .01), parental psychological maltreating history (b = 4.72, se = 0.70, p < .001), and note. n = 342. psychological = psychological maltreatment, physical = physical abuse. † p < .10 * p < .05 ** p < .01 *** p < .001 children's gender (b = 0.74, se = 0.32, p = .02) were uniquely predictive of whether parents psychologically maltreated their children during the covid-19 pandemic. the odds that parents who lost their jobs during covid-19 would also psychologically maltreat their children were 4.86 times higher than those of parents who did not lose their jobs. as parental depressive symptoms increased by one unit, the odds of psychologically maltreating children during the pandemic increased by 1.05. the odds that male children would be psychologically maltreated were 2.09 times higher than those of female children. the odds that parents with a history of psychologically maltreating their children would psychologically maltreat their children during the pandemic was 111.94 times higher than those of parents that did not have a history psychologically maltreating their children prior to the pandemic. the model examining physical abuse was a significantly better fit for the data compared to the null model, χ(12) = 130.62, p < .001. the model accounted for 52.2% (nagelkerke r square) of the variance in whether parents physically abused their children during the pandemic. the model correctly classified 88.3% of the cases, with 95.7% correct classification for parents that did not physically abuse their children and 54.1% correct classification for parents that physically abused their children during the pandemic. parental depression (b = 0.04 se = 0.02, p = .04) and being physically abusive before the pandemic (b = 3.00 se = 0.50, p < .001) were significant predictors of whether parents physically abused their children during the pandemic. as depressive symptoms increased by one unit, parents were 1.04 times more likely to physically abuse their children. the odds that parents with a history of being physically abusive would physically abuse their children during the pandemic was 20.10 times higher than those of parents without a history of being physically abusive in the past year. importantly, although parental job loss and cognitive reframing coping strategies were not significant unique predictors of physical abuse (b = -0.09, se = 0.60, p = .88; b = 0.04 se = 0.05, p = .49, respectively), a significant interaction between parental job loss and cognitive reframing coping emerged, b = -0.27, se = 0.13, p = .04. see fig. 1 . for parents who lost their jobs due to covid-19 related economic downturns, the probability of physically abusing their children decreased as reframing coping strategies increased. reframing coping was not associated with physical abuse among parents who did not lose their jobs. there is immense concern that the covid-19 pandemic will have unforeseen consequences for children's safety and well-being. numerous public health organizations point to the economic downturn in the united states, and parental job loss specifically, as amplifying risk for child abuse (substance abuse & mental health services administration, 2020; the alliance for child protection in humanitarian action, 2020; who global, 2020). consistent with the study hypotheses and prior observations of increased rates of child abuse during economic crises (brooks-gunn et al., 2013; schenck-fontaine et al., 2017) , the current investigation identified parental job loss during the covid-19 pandemic as a robust predictor of psychological maltreatment and physical abuse towards children during the pandemic. however, among parents who lost their jobs, positive cognitive reframing was a significant buffer of this association on physical abuse. the findings support growing concerns that the economic conditions caused by the covid-19 pandemic will impact children's well-being and are consistent with ecological theories regarding the etiology of child maltreatment. children of parents who experienced job loss related to the covid-19 pandemic were nearly five times as likely to be psychologically maltreated during the pandemic compared with children of parents who did not lose their jobs. psychological maltreatment includes behaviors such as verbally threating to harm children, belittling, and ridiculing children. children that have been psychologically maltreated exhibit higher rates of aggression, hyperactivity, conduct problems, anxiety, and depression across the lifespan (cicchetti, 2016) , even when considering whether children were also physically or sexually abused (spinazzola et al., 2014) . thus, parental job loss during the covid-19 pandemic presents significant risk for children's concurrent development and long-term adjustment through increased psychological maltreatment. parental job loss was additionally associated with an increased probability of physical abuse during the pandemic. this association, however, depended on the manner in which parents reported habitually coping with stressful experiences. among parents who lost their jobs due to the covid-19 pandemic, the probability of physical abuse decreased as parental positive cognitive reframing increased. positive cognitive reframing was not associated with the probability of physical abuse among parents who did not lose their jobs. physical abuse, as measured in the current study, represents behaviors ranging in severity from corporal punishment (e.g., spanking, slapping, hitting with an object) to assault (e.g., kicking, hitting body parts other than the bottom) and very severe assault (e.g., hitting as hard as possible). the negative sequelae of physical abuse in multiple developmental domains has been extensively observed (cicchetti, 2016 for review) . the findings of the current study suggest that positive cognitive reframing among parents who lost their jobs due to the covid-19 pandemic protects children against physical abuse and could potentially mitigate the effects of parental job loss on children's development and maladaptation during and after the covid-19 pandemic. losing a job is a salient life-stressor (infurna & luthar, 2016) , even during times when the national economy is relatively healthy. the economic and public health uncertainty caused by the covid-19 pandemic likely exacerbates the stress and strain caused by job loss. the destructive role of stress on parenting quality is noted throughout the child maltreatment literature and etiology theories, such as the family stress model (conger & elder, 1994) . the family stress model postulates that accumulating stress caused by economic adversity, including job loss, increases risk for child maltreatment. the finding that the risk for psychological maltreatment increased among parents who lost their job during the pandemic is consistent with the family stress model. the stress and coping model of child maltreatment similarly emphasizes the risk of stress on child maltreatment, but also states that the manner in which life-stressors infiltrate parent-child relationships depends on the dispositional coping skills and strategies of the family (hillson & kuiper, 1994) . positive coping strategies are postulated to mitigate the effects of stress on parenting and child abuse. in the current study, positive cognitive reframing represented coping strategies where strength to overcome obstacles is emphasized and stressors are reappraised, redefined, and made more manageable (lazarus & folkman, 1984; mccubbin et al., 1981) . the finding that positive cognitive reframing served as a protective buffer against the effect of job loss on physical abuse during the covid-19 pandemic is consistent with our hypothesis and the stress and coping model of child maltreatment. positively reframing job loss likely reduces negative affect and associated stress, which, in turn, reduces risk for physical abuse. positive cognitive reframing protected against the effect of job loss on physical abuse, but was not significantly associated with psychological maltreatment. physically abusive parents are likely to also engage in psychological maltreatment, but not all psychologically maltreating parents are also physically abusive (cicchetti, 2016) . in the current investigation, many more parents reported psychologically maltreating than physically abusing their children. perhaps the threshold for which stress spills over to the parent-child relationship in the form of psychological maltreatment is lower compared to the threshold for committing physical abuse. coping strategies may be inactivated, and thus ineffective in altering behaviors, if the stress threshold for spill over to the parent-child relationship is low. positive cognitive reframing may be more potent in mitigating risk of ecological stressors, including job loss, on more severe forms of child maltreatment, such as physical abuse. parental depressive symptoms and maltreating history were significant predictors of psychological maltreatment and physical abuse during the pandemic. parental depression is a robust predictor of harsh parenting and has been emphasized in etiological models as a key risk factor for child maltreatment (belsky, 1993; cicchetti & lynch, 1993; cicchetti & toth, 2005) . in addition, as anticipated, parents were more likely to psychological maltreat and physically abuse their children during the pandemic if they had a history of maltreating their children. the odds of being psychologically maltreated and physically abused during the pandemic were 112 and 20 times higher, respectively, among children that were maltreated in the year prior to the pandemic. these results indicate that parental depressive symptoms and maltreating history are important risk factors for child maltreatment during the covid-19 pandemic. these results additionally strengthen the findings regarding associations among job loss, positive cognitive reframing, and maltreatment during covid-19, which emerged when statistically controlling for parental depressive symptoms and maltreating histories. the current study has several strengths, including the examination of risk and protective factors at multiple levels of ecology on child maltreatment and the timely manner of data collection, which occurred during the peak of unemployment rates in the united states resulting from the covid-19 pandemic (as of august, 2020; department of labor, 2020a , 2020b , 2020c . in addition, given that the vast majority of studies evaluating the impact of job loss on child maltreatment have been conducted with state and county aggregate data, the family-level analysis approach of the current investigation importantly contributes to the extant work. there are several limitations of the current investigation despite these strengths. participants were recruited through online social media and crowd sourcing platforms. although such methods are popular in behavioral research and the current study adhered to best-practice guidelines for conducting online studies, data collected from online convenience samples may not be representative of the general population. the sample size was also somewhat small for online studies. future research with a larger sample size will be necessary to confirm the current findings. in addition, data were cross-sectional and collected via parental report. longitudinal studies are needed to ascertain the directionality of the observed associations and the long-term implications of the covid-19 pandemic on children's health and safety. studies that incorporate a mixed-method approach and reports from multiple informants such as child protective service records and observations of family interactions will further corroborate observations from the current study. lastly, future research identifying additional factors contributing to physical abuse during the covid-19 pandemic will be necessary given the current logistic regression model correctly classified physically abusive parents 54% of the time. studies that uncover additional factors contributing to physical abuse during the pandemic will further inform interventions and policies. findings from the current investigation suggest that the economic consequences of the covid-19 pandemic on employment in the united states has impacted family relationships, in particular whether parents were likely to physically or psychologically abuse their children. although whether parents lost their jobs was an important predictor of child maltreatment during the covid-19 pandemic, so was the manner in which families coped with stressors. these findings offer important implications for practice and policy. identification of families at-risk, and particularly those experiencing job loss resulting from the pandemic, parental depressive symptoms, and with histories of child maltreatment in the past year, allows for targeted intervention and prevention strategies. although children and families are currently less connected to systems with mandated reporters due to social distancing protocols during the covid-19 pandemic, there remains an opportunity for outreach from educators, child welfare workers, and other professionals involved in supporting the well-being of children and families. even if virtual contact is the primary method for health and safety reasons during the pandemic (usher et al., 2020) , connecting and visually checking in with children and families is critical to providing support as well as intervention. the intentional outreach and connection with parents may also support their mental health and promote positive coping strategies. training for parents and professionals should focus on teaching and enhancing coping skills such as positive cognitive reframing, which can provide additional support to buffer the evolving consequences of covid-19, and in particular the ecological consequences of job loss, on families and children. emphasizing strengths and redefining the implications of stressors is consistent with a familycentered approach and empowers parents to develop positive coping strategies amidst the economic and public health uncertainties caused by the global pandemic. child maltreatment prevention programs often incorporate elements of cognitive reframing training and have supporting evidence indicating that such training reduces harsh parenting and child welfare involvement (bugental et al., 2020) . embracing the complexity of child maltreatment requires an understanding of the ecological considerations and attention to various levels of intervention. job loss is expected to impact economic stability as a factor increasing risk for child maltreatment. however, because financial stability was statistically controlled in the present analyses, our model suggests it is not the financial instability resulting from job loss that increases incidences of maltreatment, but rather the job loss itself. losing a job can result in decreased social contact and emotional support from colleagues and friends, benefits, and even potentially a sense of purpose. job loss can be damaging to individual's self-concept, which seems to be especially important in the united states as many adults associate their job or profession with their identity (garrett-peters, 2009 ). although losing a job could have positive effects, like providing opportunities to explore new interests, such positive outcomes of job loss are likely diminished by the national economic crisis caused by the covid-19 pandemic. the stress of losing a job further exacerbates stress of parenting and general health and safety concerns related to the covid-19 pandemic. given evidence that covid-19 is transmitted through interactions with others in the community, there is a complex balance among supporting the economy, keeping people employed, and maintaining public health. understanding the health pandemic as trauma and the consequences of job loss exacerbating stress and likelihood of child maltreatment requires programs and policies that address trauma and child protection. more than ever, agencies need to be trained in trauma informed practice and understanding of the cumulative impact of traumatic experiences and ecological factors impacting child maltreatment. in addition, shifting focus from addressing primarily risk factors, to identifying factors of resilience, may help to address the complexity of parental stress and child maltreatment prevention during and after the pandemic. service delivery models for child welfare agencies and professionals have and must continue to shift to support children and families during the unique circumstances of the covid-19 pandemic. many organizations have altered their traditional delivery of services to overcome obstacles related to social distancing, such as providing virtual services (usher et al., 2020) . beyond increasing access and funding for professionals and mandated reporters to continue providing services in a safe manner during the pandemic, creating community accountability for child and family well-being is critical. increasing community awareness and commitment to child protection, and developing and enhancing supports for families to utilize when encountering stressful situations, can increase positive parenting and promote child well-being, which is especially critical during the pandemic. as the covid-19 pandemic is an ongoing global crisis (as of august, 2020), our understanding of the economic and public health impact and best practices for promoting health and safety, including reducing risk for child maltreatment, during the covid-19 pandemic is developing. findings from the current investigation identify that parental job loss during the pandemic can be detrimental to children's safety by increasing risk for psychological maltreatment and physical abuse during the covid-19 pandemic, which likely have long-term implications given the negative sequelae of child maltreatment. efforts to maintain jobs and to bolster families' mental health and effective coping strategies are paramount during this time of uncertainty, especially among families known to be at-risk and with prior histories of child maltreatment. organizations must adapt service delivery models to address the unique challenges of covid-19. providing targeted strategies that are trauma-informed and address the ecological considerations of job loss through cognitive reframing may promote the resilience and support needed to effectively intervene and prevent future child maltreatment during the pandemic. monica lawson, phd, assistant professor, department of psychology, college for health community, and policy, the university of texas at san antonio; megan h. piel, phd, assistant professor, department of social work, college for health, community, and policy, the university of texas at san antonio; michaela simon, ba, graduate student, department of psychology, college for health community and policy, the university of texas at san antonio none. antenatal risk factors for child maltreatment: linkage of data from a birth cohort study to child welfare records. child abuse and neglect economic disadvantage in complex family systems: expansion of family stress model etiology of child maltreatment: a developmental-ecological analysis coping, distress, and well-being in mothers of children with autism the great recession and the risk for child maltreatment a cognitive approach to child abuse prevention amazon's mechanical turk: a new source of inexpensive, yet high-quality, data? an evaluation of amazon's mechanical turk, its rapid rise, and its effective use an increasing risk of family violence during the covid-19 pandemic: strengthening community collaborations to save lives 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children's representations of family relationships a stress and coping model of child maltreatment resilience to major life stressors is not as common as thought stress, appraisal, and coping caution! men not at work: gender-specific labor market conditions and child maltreatment family functioning and coping styles in families of children with cancer and hiv disease conducting behavioral research on amazon's mechanical turk family crisis oriented personal scales (f-copes) family stress and parent-infant interaction: the mediation role of coping see which states and cities have told residents to stay at home. the new york times are economic trends associated with childmaltreatment? preliminary results from the recent recession using state level data the relationship between unemployment and child maltreatment: a county-level perspective in california the ces-d scale: a self-report depression scale for research in the general population income inequality and child maltreatment risk during economic recession local job losses and child maltreatment: the importance of community context the great recession and risk for child abuse and neglect fourth national incidence study of child abuse and neglect (nis-4): report to congress. u.s. department of health and human services, administration for children and families unseen wounds: the contribution of psychological maltreatment to child and adolescent mental health and risk outcomes identification of child maltreatment with the parent-child conflict tactics scales: development and psychometric data for a national sample of american parents intimate partner violence and child abuse considerations during covid-19 technical note: protection of children during the coronavirus pandemic (v.2) measurement of emotional/psychological child maltreatment: a review department of health and human services family violence and covid-19: increased vulnerability and reduced options for support housing insecurity, maternal stress, and child maltreatment: an application of the family stress model addressing violence against children, women and older people during the covid-19 pandemic: key actions key: cord-292929-s8pnm9wv authors: ashikalli, louicia; carroll, will; johnson, christine title: the indirect impact of covid-19 on child health date: 2020-09-16 journal: paediatr child health (oxford) doi: 10.1016/j.paed.2020.09.004 sha: doc_id: 292929 cord_uid: s8pnm9wv since the detection of covid-19 in december 2019, the rapid spread of the disease worldwide has led to a new pandemic, with the number of infected individuals and deaths rising daily. early experience shows that it predominantly affects older age groups with children and young adults being generally more resilient to more severe disease (1–3). from a health standpoint, children and young people are less directly affected than adults and presentation of the disease has shown different characteristics. nonetheless, covid-19 has had severe repercussions on children and young people. these indirect, downstream implications should not be ignored. an understanding of the issues is essential for those who hope to advocate effectively for children to prevent irreversible damage to the adults of the future. this article reviews some of the evidence of harm to children that may accrue indirectly as a result of pandemics. it explores the physical and psychological effects, discusses the role of parenting and education, offering practical advice about how best to provide support as a health care professional. one of the 'positives' to emerge from the covid-19 pandemic in the uk has been a dramatic increase in the availability and use of remote consultations (4) . driven initially by a need to protect and safeguard patients and healthcare professionals, the early experiences have shown that many routine reviews and some acute consultations can be successfully managed remotely. telemedicine or telehealth is becoming the new norm and can be used as an alternative to face-toface consultations, eliminating the risk of infection ( figure 1 ) (5) . any technology available such as phone and texting, email, and video, has now been employed to be able to provide therapy. by being able to employ many different means of communication, it makes telemedicine available to a greater number of patients. even so, there can still be inequalities in accessing healthcare as within different communities there is a difference in availability of communications means. it has been clear from early experience in the uk that there is a great difference in the availability of high quality internet connectivity between families which has limited the use of some approved, data-secure platforms such as attend anywhere. the issue of health disparities, the gap in access and quality of care are still present. solutions for the nhs have not been cheap. however, in the longer term these may be cost effective and eliminate some expenses e.g. travel, parking for families. some aspects of routine care for children have been hampered. the significant reduction in availability of lung function testing for children with chronic respiratory diseases is a concern. in some instances, these have been partially overcome with provision of home testing with either peak flow meters or portable spirometers which allow more nuanced care and advice to be given (6) . engaging the public in planning and decision making, together with educating parents and children efficiently, has proven useful when implementing public health strategies (7). some strategies appear to have an evidence base. for instance it is suggested that social distancing might be more adhered to if public health officials portray it as an act of altruism, giving a sense of duty to protect the child's loves ones (8) . the direct approach may also be helpful and has certainly been tried. for example, the canadian prime minister specifically thanked children for their efforts which could only be accounted as an act to increase the feeling of social duty to the youth (9). the universal use of face masks and the inclusion of younger children within any guidance is still being debated. when it comes to children there are more issues to consider including the availability of masks of different sizes to fit well on the face as well as the risk of suffocation in children younger than two years (10) . additionally, when it comes to younger children, it is more challenging to persuade them not to take the mask off. innovative ideas have started to emerge, with disney designing fabric face masks with the children's favourite characters to help children in accepting to use them (11) . whilst initial data does not suggest that children with comorbidities are at particularly increased risk of severe covid-19 disease (12) (13) (14) , the challenge of maintaining a good continuity of care for existing patients and adequate diagnostic care for children presenting for the first time remains. children with chronic diseases and their carers have been particularly anxious about the impact that covid-19 could have on them. this can be partially resolved for many by maintaining communication with these families, providing reassurance, advising on hygiene measures, and educating on covid-19. where children fall outside clear guidelines, tailored and individualised plans offer reassurance for all of those involved with the provision of care. at the start of this pandemic in the uk the advice given to the families with children with many chronic diseases was to shield the whole household to prevent the risk of severe illness. in hindsight, some of the advice was unduly cautious but faced with uncertainty public health authorities, paediatricians and primary care physicians erred on the side of caution. for some families, the increased anxiety may have longer term consequences. the act of shielding can have severe impacts on a child's physical and mental health. for example, going back to school could be beneficial for children with cerebral palsy or musculoskeletal problems as school provides developmental support and gives access to therapies. as ongoing research suggests a low disease severity amongst the young and the negative effects of shielding, experts questioned whether shielding children with many comorbidities was ever justified. this led to the reformation of the strict guidelines. with social distancing rules being slowly lifted and school re-opening, the rcpch has provided new guidelines for shielding (15) . one of the medical sectors highly affected by the pandemic is the emergency department (ed) (16) . normally, in the uk the emergency services are unnecessarily overused, leading to overcrowding and stretching of resources particularly during weekends and evenings. however, regional data suggests that there was a decrease of more than 30% in the cases of children presenting to the paediatric ed by march 2020 and this decline in activity has been maintained into the summer. this has certainly helped to prevent services from being deluged and allowed time for new processes and health protection procedures to be put in place. whilst this change in behaviour could discourage unnecessary attendance to ed, it could also put at greater risk children with serious pathologies that require treatment. in the uk, safeguarding has always been an important concern (17). during a time of a global pandemic, where focus is on the direct results of the disease, vulnerable children experiencing maltreatment and neglect at home are put on the side-line. long home confinement, together with frustration, agitation, and aggression, creates opportunities to harm children. moreover, the loss of the safety net provided by schools, social care and health professionals decreases the number of abuse cases reported. without spotting narratives or signs of abuse, home becomes a very dangerous place for the vulnerable children. unfortunately, there is a trend of increasing incidences of domestic violence and calls to child support lines reported (18) . children and teenagers exposed to violence, either as witnesses or victims could experience detrimental effects on their physical and mental health. incomplete immunisation has always been a worrying issue and unfortunately, during a pandemic, this issue can be easily neglected. this could expose communities at risk of an outbreak of a vaccinepreventable disease. for this reason, the who have declared immunisation as a core health service that should be safeguarded and conducted under safe conditions. consequently, they have prepared documents that explain the reasoning behind this and respond to any questions the public or health authorities might have. (19, 20) . in recent years, weight gain during periods of school closure, especially during summer vacations, has been a worrying issue amongst the paediatric community (21) . when comparing behaviours during summer and school season, accelerated weight gain is observed during the summer holidays (21) . a school closure during a pandemic is not equivalent to summer vacations. nonetheless, there are distinct similarities such as the lack of structure during the day, the increase in screen time and a change in sleeping routines ( figure 2 ). in fact, a small longitudinal observational study conducted in verona italy during this pandemic, has shown that the unfavourable trends in lifestyle discussed above, were observed amongst obese children and adolescents (22) . the covid-19 pandemic has further risk factors that might exacerbate the epidemic of childhood obesity (23) . firstly, as out-of-school time has increased more than a regular summertime, it has increased the period that children are exposed to obesogenic behaviours. secondly, parents are stocking up shelves with highly processed and calorie dense food. this action is justified by the need to maintain food availability and minimise the number of trips outside. this, however, exposes children to higher calorie diets. thirdly, social distancing and stay-at-home policies introduce the risk of decreasing opportunities for physical activity. school physical activities were removed, playgrounds could not be kept clean, parks closed their gates, community centres offering afterschool programs shut their doors. children living in urban areas, confined within small apartments are at a greater risk of adopting a sedentary lifestyle. lastly, there has been an increasing trend on the use of video games which counts as a sedentary activity and leads to excessive screen use (24). this obesogenic behaviour needs to be taken seriously and tackled as it could have profound consequences which are not easily reversible. moreover, we should have in mind that adult obesity and its comorbidities are associated with covid-19 mortality (25) , which raises the question whether overweight or obese children will have more severe repercussions upon contracting covid-19. therefore, there is a need to maintain a structured day routine for the children which includes playtime and exercise time, a restriction on calories, a regular sleep pattern and supervision of screen time ( figure 3 ). although emphasis is given to the obesogenic effects of the pandemic, there is also the issue of malnourishment as many students rely on school meals. in fact, school meals and snacks could represent up to two thirds of the nutritional needs in children in the usa (26) . in addition to not receiving the appropriate nutrition through school, children could be exposed to cheaper, unhealthy food choices. in the uk a partial safety-net has been established and maintained over the summer period following a successful campaign by the english footballer, marcus rashford (26) . this will offer some support to children who already received free school meals. however, not all children in the uk and many others worldwide will be protected. insecurity over food availability causes longterm psychological and emotional harm to the children and parents. a collaboration amongst who, unicef and ifrc has provided comprehensive guidance to help protect schools and children, with advice in the event of school closure and for schools that remained open (28) . important points in this guidance document are the emphasis given to a holistic approach towards children by tackling the negative impacts on both learning and wellbeing and to educate towards covid-19 and its prevention. even so, these guidelines can only be considered as checklists and tips for each government to use accordingly. china provided a successful example of an emergency home schooling plan (29) , where a virtual semester was delivered in a well organised manner through the internet and tv broadcasts, yielding satisfactory results. however, digital learning is an imperfect system that brings to the surface the inequalities caused by poverty and deprivation. many children have had either limited, shared or no online access either as a result of a lack of equipment (laptops or tablets) or internet access. some parents struggled with the provision of adequate supervision. this issue was significantly more challenging for parents with additional educational needs e.g. adhd or learning difficulties, for those with many children of different ages and for those children who might have additional carer responsibilities. it was also much more difficult for parents who were being expected to work from home at the same time. the full effects of a temporary 'pause' in many children's education in the uk remain to be seen but the effects are likely to widen the gap between children from more deprived backgrounds. since the beginning of the 21 st century, there have been several major disease outbreaks including the severe acute respiratory syndrome (sars) in 2003, the h1n1 influenza pandemic in 2009 and the ebola in 2013. however, mental health research was largely overlooked. the absence of mental health services during previous pandemics increased the risk of psychological distress to those affected (30) . there are variable psychological manifestations as a result of a pandemic. early childhood trauma can affect a child in many ways (31) . it can increase the risk of developing a mental illness and it can also delay developmental progress. moreover, early childhood trauma in the form of adverse childhood experiences (aces) can have profound effects that manifest in later life such as an increase in substance abuse and problems with relationships or education as well as increase the risk of chronic diseases such as asthma, obesity and attention deficit hyperactivity disorder (32) . about 30% of isolated or quarantined children during the h1n1 pandemic in the united states of america met the criteria for post-traumatic stress disorder (ptsd) (33) . this study noted the lack of professional psychological support to these children during or after the pandemic. out of the much smaller percentage of children that did receive input from mental health services, the most common diagnoses were anxiety disorder and adjustment disorder. moreover, the same study also showed that one quarter of parents would also fulfil the criteria for ptsd which shows that parental anxiety and mental health can be reflected upon other members of the family including the children. events and conditions can have effects on our physical and mental health. these act as stressors or triggers and can predispose anyone, including children to adverse responses; either physical or psychological. the stressors that could impact a child during a pandemic are shown in figure 5 . the duration of the lockdown appears to be particularly important. researchers have shown that the longer the quarantine, the higher the chances of mental health issues emerging in adults. it is unknown whether the same applies to children (8) . some children and young people (cyp) will be more vulnerable to the adverse consequence of any stressors and these pre-pandemic predictors should also be considered. in a child, such predictors could include the age of the child and a history of mental illness. there is a complex link between mental health and social background. families with lower incomes face tough choices about how to cope with the day-to-day challenge of providing basic necessities (e.g. food, clothing and heating) and may be less able to give priority to the mental health of their children (or themselves). when considering what can influence mental health, the link between physical and mental health should also be considered. the physical health of a child can be affected either directly or indirectly by covid-19. this raises the question of how this could affect the psychological wellbeing too and if it would lead to a vicious cycle. the sudden advance in telemedicine in the uk has been one of the unexpected changes brought about by covid-19. it has been helpful in maintaining some health care for physical ailments ranging from acute illness to review of children with chronic conditions like asthma, diabetes and cystic fibrosis. it can also be used for psychological counselling for parents or children. this can help children learn how to cope with mental health problems via professional help within the security of their own house (34) . telemedicine for mental health is already established in some countries. the psychological crisis intervention, is a multidisciplinary team program developed as a collaboration amongst a few chinese hospitals that uses the internet to provide support (30) . telemedicine is most probably not sufficient in managing and providing for the mental health needs of the high numbers affected. when the already limited access to trained professionals is struck by a global pandemic, the shortage of professionals and paraprofessionals becomes noticeable and therefore the needs of the high number of patients are not met (35) . when dealing with mental health a hierarchal and stepwise approach that starts in the community is helpful ( figure 6 ). integration of behavioural health disorder screening tools within the response of public health to a pandemic is crucial to cope with demand. these should recognise the importance of identifying the specific stressors and build on the epidemiological picture of each individual to identifying those cyp at greatest risk of suffering from psychological distress (36) . following the correct identification of patients in the community, the next step involves an appropriate referral. interventions can vary according to the individual's presentation and can include psychoeducation or prevention education. any behavioural and psychological intervention should be based on the comprehensive assessment of that patient's risk factors (35) . for instance, researchers have shown that specific patient populations such as the elderly and immigrant workers may require a tailored intervention (37, 38) . this hypothesis could therefore be stretched to children and teenagers as their needs are different to adults. the rapid changes that both parents and children are forced to face and the uncertainty of an unpredictable future have been compared to the loss of normalcy and security that palliative care patients are faced with and paediatric palliative care teams may be well-placed to provide psychological support to families (39) . community organisations have a significant role to play in addressing mental health problems. they empower communities and provide tailored support. when this support comes from organisations which understand the community, the community's beliefs are embodied within the programs offered. it is therefore becoming obvious that best results will only be yielded if different bodies work together. this stresses how crucial it is to maintain good communication between community health services, primary and secondary care institutions. this is to ensure patients receive a timely diagnosis and better follow-up (35) . conversely, poor communication could delay meeting the needs of the patients. the internet is a potentially useful tool for the provision of mental health support. there are a lot of reliable resources online that anyone could use effectively without being in direct contact with professionals. large organisations such as unicef have provided online documents to help teenagers protect their mental health during the pandemic. many books about the current pandemic and its psychological impact are being released electronically for free for the public (34) . likewise, online self-help interventions such as cbt for depression can be used by anyone experiencing such symptoms. this type of intervention and signposting of lower risk cyp and families to safe, well-constructed resources is highly efficient, allowing mental health professionals to focus more intensive interventions on higher risk individuals. the online world is more easily accessible and much more appealing to older children and teenagers. as young people are becoming the experts of this virtual world, it is only logical to use social media for our benefit. successful mental health campaigns in the past used hashtags on social media like instagram and twitter to increase awareness of mental health problems (40) . with more bloggers and social media influencers talking about mental health, together with the use of hashtags, the societal benefits become apparent. a strong feeling of empowerment is built that helps combat the stigma of mental health. moreover, there is a therapeutic benefit through the provision of information on how to find professional support or self-management strategies. even though online gaming can have negative impacts on young people's physical health, during a period of home confinement, it provides a mean for friends to stay in contact. both online gaming and the yet extensive use of social media have the potential of bringing people closer together and gives a feeling of solidarity. regarding young children, using online resources on their own might not be an easy task, although they are surprisingly becoming experts of the web too. nonetheless, there are many resources designed with the purpose to explain the pandemic to children and alleviate their anxiety as well as promoting good hygiene. a good example is the collaboration of sesame street with headspace, a mindfulness and meditation company, to create youtube videos that help young children tackle stress and anxiety. parents, carers, or older siblings could all help the young ones to access these resources. the power of technology and the artificial world is becoming a turning point for societies today. interestingly, an artificial intelligence program has been created with the purpose of identifying people with suicidal ideations via scanning their posts on specific social media platforms. once identified, volunteers take appropriate steps to help these individuals. during a time of extensive home confinement, where the use of the web becomes even more prominent, such programs might again provide a service to society by identifying teenagers struggling with mental health (41) . healing through creative expression is a popular tool amongst child therapists and is has proven useful in previous pandemics too (31) . during the ebola break, a dynamic art program was established for liberian children. it focused on how therapeutic expressive arts could teach coping skills and build healthy relationships in a safe and supportive space for children to express themselves and experience healing; interventions that showed positive results early on. the advantage of art programs like this is that once they are built by mental health professionals and child health specialists, they can be delivered in the communities using paraprofessionals who receive appropriate training. this allows the projects to be implemented at a wider area while more children benefit from. parents should provide a core pillar of support for children, with school and teachers, the rest of the family and friends providing robust supporting pillars. with home confinement, these supporting pillars break down and the parent becomes the only resource for a child to seek help from. when the wellbeing of the child is at risk, it is important for parents to monitor the children's behaviours and performance. open communication is necessary to identify any issues; physical or psychological. having direct conversations about the pandemic can prove useful in mitigating their anxiety. a common notion is for parents to shield their children from bad news to protect them. it is true that most of the information about the pandemic that children are exposed to is not directed to them and it hence becomes overwhelming. however, children will still ask important questions and ask for satisfactory answers. shielding the world from them is not the right answer. parents should practice active listening and responding appropriately to any questions the child might have as well as adapting their responses to the child's reactions. narrating a story or encouraging the child to draw what is on their mind might enable the start of a discussion. attention also needs to be given to any difficulties sleeping and the presence of nightmares as it could be a sign that the child is not coping well. although strict monitoring of behaviours is required, it is a very delicate issue and it should not put the child into an uncomfortable position. with daily home confinement, it is important to respect the children's privacy and identity. whilst it may seem overwhelming to families to provide all the information required to children there are already many reliable resources available online about how best to maintain the health and wellbeing of their children through this pandemic. unicef has provided online resources for parents to use with emphasis given on how to talk to a child about the pandemic and provide comfort. similarly, the who have also provided a series of posters on parenting during the pandemic again with the purpose of promoting the wellbeing of children. parents and carers are often portrayed as superheroes. however, even these superheroes may experience anxiety and fear during a pandemic. the psychological health of parents and their children seem to be inextricably linked and ptsd is commoner in children whose parents are experiencing it too (33) . as parents with poorer mental health might not be able to respond to the needs of their children effectively, then addressing this is important. alleviating their stressors will help improve mental health. priority should be given in ensuring that the basic needs of these families are met, including food provisions, financial support, and healthcare access. once these are provided, there are higher chances that any psychological support can have a positive effect on parents. such support can have multiple different dimensions and various tools can be utilised. such tools should be easily accessible, put to practice quickly and aim to strengthen mental resiliency. for instance, behavioural practitioners are suggesting the use of acceptance and commitment therapy (42). anecdotally the consequence of a prolonged period of lockdown for some families in the uk has been a positive one. home confinement can benefit interactions and help children to engage in family activities. this may help strengthen family bonds and meet the psychological needs of a developing mind. collaborative games fight loneliness and strengthen family relations. other activities that families could do together include learning new skills like cooking or taking up new hobbies like building puzzles. researchers have also shown that during the brief school closure due to the a/h1n1 influenza pandemic in 2010, as time went by, parents became more prepared and started planning more activities. this gave more reasons to young people to stay at home and helped in encouraging social distancing; which proved harder at the start of the influenza pandemic (43). the impact of the covid-19 pandemic goes beyond the risk of a severe acute respiratory response. it has posed severe social and economic consequences worldwide. children and young people have been exposed to very severe repercussions which if not addressed, could have even worse outcomes in the future. therefore, governments, communities, non-governmental organisations and healthcare professionals need to work in collaboration to prevent causing irreversible damage to a generation. systematic review of covid-19 in children shows milder cases and a better prognosis than adults covid-19 epidemic: disease characteristics in children covid-19 in children: initial characterization of the pediatric disease european and united kingdom covid-19 pandemic experience: the same but different promoting and supporting children ' s health and healthcare during covid-19 -international paediatric association position statement managing asthma during covid-19: an example for other chronic conditions in children and adolescents including the public in pandemic planning: a deliberative approach the psychological impact of quarantine and how to reduce it: rapid review of the evidence prime minister appeals to canadian children to follow social distancing rules | cbc news to mask or not to mask children to overcome covid-19 disney creates fabric face masks for children | daily mail online challenges in chronic paediatric disease during the covid-19 pandemic: diagnosis and management of inflammatory bowel disease in children new clinical needs and strategies for care in children with neurodisability during covid-19 covid-19 is no worse in immunocompromised children, says nice covid-19-'shielding' guidance for children and young people where have all the children gone ? decreases in paediatric emergency department attendances at the start of the covid-19 pandemic of 2020 child health in 2030 in england : comparisons with other wealthy countries. r coll paediatr child heal isolated at home with their tormentor": childline experiences increase in calls since closure of schools guiding principles for immunization activities during the covid-19 pandemic frequently asked questions ( faq ) immunization in the context of covid-19 pandemic understanding differences between summer vs. school obesogenic behaviors of children: the structured days hypothesis lockdown on lifestyle behaviors in children with obesity living in covid-19-related school closings and risk of weight gain among children telehealth solution for vulnerable children with obesity during covid-19 feeding low-income children during the covid-19 pandemic covid-19: ifrc, unicef and who issue guidance to protect children and support safe school operations mitigate the effects of home confinement on children during the covid-19 outbreak recommended psychological crisis intervention response to the 2019 novel coronavirus pneumonia outbreak in china: a model of west china hospital playing to live: outcome evaluation of a community-based psychosocial expressive arts program for children during the liberian ebola epidemic adverse childhood experiences: assessing the impact on physical and psychosocial health in adulthood and the mitigating role of resilience posttraumatic stress disorder in parents and youth after health-related disasters online mental health services in china during the covid-19 outbreak. the lancet psychiatry psychological interventions for people affected by the covid-19 epidemic. the lancet psychiatry a nationwide survey of psychological distress among italian people during the covid-19 pandemic: immediate psychological responses and associated factors mental health services for older adults in china during the covid-19 outbreak the neglected health of international migrant workers in the covid-19 epidemic applying palliative care principles to communicate with children about covid-19 understanding why people use twitter to discuss mental health problems behavioral and emotional disorders in children during the covid-19 epidemic •% of total enrolled learners: 56.8% •153 country-wide closures •affected learners: 1,190 •% of total enrolled learners: 68% •150 country-wide closures •affected learners: 1,091 key: cord-008695-y7il3hyb authors: nan title: pandemic flu: clinical management of patients with an influenza-like illness during an influenza pandemic date: 2007-01-25 journal: j infect doi: 10.1016/s0163-4453(07)60001-2 sha: doc_id: 8695 cord_uid: y7il3hyb nan • this document is intended for use in the uk in the event that the world health organisation declares that an influenza pandemic has started 1 , and the department of health in england (uk-wide lead agency on pandemic influenza, including the devolved administrations) has declared uk pandemic alert level 2 (cases of pandemic influenza identified within the uk). • these guidelines are not relevant for the management of patients affected by seasonal/interpandemic influenza, lower respiratory tract infections, community-acquired pneumonia or exacerbations of chronic obstructive pulmonary disease (copd). • once an influenza pandemic is under way, users are strongly urged to ensure that they refer to the most up-todate version of these guidelines (from web-based access points). synopsis 1. clinical management of adults referred to hospitals s1.1. severity assessment in hospital • patients with uncomplicated influenza infection would be expected to make a full recovery and do not require hospital care. • in uncomplicated infection, the illness usually resolves in seven days although cough, malaise and lassitude may persist for weeks. • patients with worsening of pre-existing co-morbid medical conditions should be managed according to best practice for that condition with reference to published disease-specific guidelines, if available, for example, the national institute of clinical excellence's copd guideline. • in hospital, patients with influenza-related pneumonia and who have a curb-65 score of 3, 4 or 5 (see box a) are at high risk of death and should be managed as having severe pneumonia. • patients with bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia should be managed as having severe pneumonia regardless of curb-65 score. • patients who have a curb-65 score of 2 are at increased risk of death. they should be considered for short stay inpatient treatment or hospital supervised outpatient treatment. this decision is a matter of clinical judgment. • patients who have a curb-65 score of 0 or 1 are at low risk of death. they can be treated as having non-severe pneumonia and may be suitable for home treatment. • patients with primary viral pneumonia or a curb-65 score of 4 or 5 should be considered for hdu/icu transfer. • general indications for hdu/icu transfer include: (1) persisting hypoxia with pao 2 < 8 kpa despite maximal oxygen administration (2) progressive hypercapnia (3) severe acidosis (ph < 7.26) (4) septic shock • patients with influenza admitted to intensive care unit should be managed by specialists with appropriate training in intensive care, respiratory medicine and/or infectious diseases. pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s3 s1.4. general investigations • the following investigations are recommended in patients referred to hospital: who this applies to full blood count all patients urea and electrolytes all patients liver function tests all patients chest x-ray all patients pulse oximetry all patients. if <92% on air, then arterial blood gases. patients with cardiac and respiratory complications or co-morbid illnesses. c-reactive protein if influenza-related pneumonia is suspected • in those patients who are subsequently followed up in a hospital outpatient clinic or by a general practitioner a repeat chest x-ray should be obtained at around six weeks if respiratory symptoms or signs persist or where there is a higher risk of underlying malignancy (especially smokers and those over 50 years of age). • further investigations including a ct thoracic scan and bronchoscopy should be considered if the chest x-ray remains abnormal at follow up. s1.5. microbiological investigations s1.5.1. early in a pandemic (uk alert levels 1, 2 and 3) • virology all patients (1) nose and throat swabs in virus transport medium. (2) if presentation is more than seven days after onset of illness, an 'acute' serum (5 10 ml clotted blood) should be collected and a 'convalescent' sample (5 10 ml clotted blood) obtained after an interval of not less than seven days. • bacteriology patients with influenza-related pneumonia (1) blood culture (preferably before antibiotic treatment is commenced) (2) pneumococcal urine antigen (20 ml urine sample) (3) legionella urine antigen (20 ml urine sample) (4) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who: (i) are able to expectorate purulent samples, and (ii) have not received prior antibiotic treatment. (5) paired serological examination for influenza/other agents. acute serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both 5 10 ml clotted blood). • virology not routinely recommended • bacteriology patients with influenza-related pneumonia in accordance to the severity of illness. (a) non-severe pneumonia (curb-65 score 0, 1 or 2) no routine testing. in patients who do not respond to empirical antibiotic therapy, sputum samples should be sent for gram stain culture and antimicrobial susceptibility tests. b severe pneumonia (curb-65 score 3, 4 or 5, or bilateral cxr changes) blood culture, preferably before antibiotic treatment is commenced pneumococcal urine antigen (20 ml urine) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who are able to expectorate purulent samples, and have not received prior antibiotic treatment. paired serological examination for influenza/other agents. 'acute' serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both 5 10 ml clotted blood). tracheal or endotracheal aspirate samples, if available, should be sent for gram stain, culture and antimicrobial susceptibility testing. s1.6. general management s1. 6 • hypoxic patients should receive appropriate oxygen therapy with monitoring of oxygen saturations and inspired oxygen concentration with the aim to maintain pao 2 8 kpa and sao 2 ges; 92%. high concentrations of oxygen can safely be given in uncomplicated pneumonia. • oxygen therapy in patients with pre-existing chronic obstructive pulmonary disease complicated by ventilatory failure should be guided by repeated arterial blood gas measurements. non-invasive ventilation may be helpful. • in patients without pre-existing copd who develop respiratory failure, niv may be of value as a bridge to invasive ventilation in specific circumstances when level 3 beds are in high demand. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted at all times. • patients should be assessed for cardiac complications and also volume depletion and their need for additional intravenous fluids. • nutritional support should be given in severe or prolonged illness. • temperature, respiratory rate, pulse, blood pressure, mental status, oxygen saturation and inspired oxygen concentration should be monitored and recorded initially at least twice daily and more frequently in those with severe illness or requiring regular oxygen therapy. an early warning score system is a convenient way to perform this. • in patients who are not progressing satisfactorily a full clinical reassessment and a repeat chest radiograph are recommended. • patients should be reviewed 24 hours prior to discharge home. those with two or more of the following unstable clinical factors should consider remaining in hospital: (1) temperature >37.8ºc (2) heart rate >100/min (3) respiratory rate >24/min (4) systolic blood pressure <90 mmhg (5) oxygen saturation <90% (6) inability to maintain oral intake (7) abnormal mental status • follow up clinical review should be considered for all patients who suffered significant complications or who had significant worsening of their underlying disease, either with their general practitioner or in a hospital clinic. • at discharge or at follow up, patients should be offered access to information about their illness, take home medication and any follow up arrangements. • it is the responsibility of the hospital team to arrange the follow up plan with the patient and the general practitioner. • individuals should only be considered for treatment with antivirals (neuraminidase inhibitors) if they have all of the following: (1) an acute influenza-like illness (2) fever (>38ºc) and (3) been symptomatic for two days or less. • treatment schedule: adults oseltamivir 75 mg every 12 hours for five days. (dose to be reduced by 50% if creatinine clearance is less than 30 ml/minute, i.e. 75 mg od). • patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite lack of documented fever. • hospitalised patients who are severely ill, particularly if also immunocompromised, may benefit from antiviral treatment started more than 48 hours from disease onset, although there is no evidence to demonstrate benefit, or lack of it, in such circumstances. s1.8. antibiotic management s1.8.1. influenza • previously well adults with acute bronchitis complicating influenza, in the absence of pneumonia, do not routinely require antibiotics. • antibiotics should be considered in those previously well adults who develop worsening symptoms (recrudescent fever or increasing dyspnoea). • patients at high risk of complications or secondary infection (appendix 2) should be considered for antibiotics in the presence of lower respiratory features. • most patients can be adequately treated with oral antibiotics. • the preferred choice includes co-amoxiclav or a tetracycline. • a macrolide such as clarithromycin (or erythromycin) or a fluoroquinolone active against streptococcus pneumoniae and staphylococcus aureus is an alternative choice in certain circumstances. • most patients can be adequately treated with oral antibiotics. • oral therapy with co-amoxiclav or a tetracycline is preferred. • when oral therapy is contra-indicated, recommended parenteral choices include intravenous co-amoxiclav, or a second or third generation cephalosporin (cefuroxime or cefotaxime). • a macrolide (erythromycin or clarithromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative regimen where required eg. for those intolerant of penicillins. currently levofloxacin and moxifloxacin are the only recommended fluoroquinolones licensed in the uk. • antibiotics should be administered within four hours of admission. • patients with severe pneumonia should be treated immediately after diagnosis with parenteral antibiotics. • an intravenous combination of a broad spectrum b-lactamase stable antibiotic such as co-amoxiclav or a second (e.g. cefuroxime) or third (e.g. cefotaxime) generation cephalosporin together with a macrolide (e.g. clarithromycin or erythromycin) is preferred. • an alternative regimen includes a fluoroquinolone with enhanced activity against pneumococci together with a broad spectrum b-lactamase stable antibiotic or a macrolide. currently levofloxacin is the only fluoroquinolone with an intravenous formulation licensed in the uk. • patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and the temperature has been normal for 24 hours, providing there is no contra-indication to the oral route. • for most patients admitted to hospital with non severe and uncomplicated pneumonia, seven days of appropriate antibiotics is recommended. • for those with severe, microbiologically undefined pneumonia, ten days treatment is proposed. this should synopsis 1. clinical management of adults referred to hospitals synopsis of main recommendations pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s5 be extended to 14 to 21 days where staph aureus or gram negative enteric bacilli pneumonia is suspected or confirmed. • for those with non-severe pneumonia in hospital on combination therapy, changing to a fluoroquinolone with effective pneumococcal and staphylococcal cover is an option. • adding further antibiotics effective against mrsa is an option for those with severe pneumonia not responding to combination antibiotic therapy. • high fever (>38.5ºc) and cough or influenza-like symptoms. these children should seek advice from a community health professional. if there are no features that put them at high risk of complications they should be treated with oseltamivir, and given advice on antipyretics and fluids. children aged <1 year and those at risk of complications (appendix 2) should be seen by a gp. • high fever (>38.5ºc) and cough or influenza-like symptoms, plus at risk group. these children should be seen by a gp or in a&e. children may be considered at increased risk of complications if they have cough and fever (or influenza-like illness) and temperature >38.5ºc, plus either chronic co-morbid disease or one of following features: breathing difficulties severe earache vomiting >24 hours drowsiness these patients should be offered an antibiotic as well as oseltamivir (in those >1 year of age) and advice on antipyretics and fluids. children aged <1 year with none of the above features should be treated with antipyretics and fluids with a low threshold for antibiotics if they become more unwell. • indicators for hospital admission are: (1) signs of respiratory distress. markedly raised respiratory rate grunting intercostal recession breathlessness with chest signs (2) cyanosis (3) severe dehydration (4) altered conscious level (5) complicated or prolonged seizure (6) signs of septicaemia extreme pallor, hypotension, floppy infant • most children admitted to hospital are likely to need oxygen therapy and/or intravenous support as well as antibiotics and oseltamivir. • indications for transfer to high dependency or intensive care are: (1) failure to maintain sao 2 > 92% in fio 2 > 60% (2) the child is shocked (3) severe respiratory distress and a raised paco 2 (>6.5 kpa) (4) rising respiratory rate and pulse rate with clinical evidence of severe respiratory distress with or without a raised paco 2 (5) recurrent apnoea or slow irregular breathing (6) evidence of encephalopathy • when there are no picu beds available, children will have to be triaged on the basis of the severity of their acute and co-existing disease, and the likelihood of their achieving full recovery. • a full blood count with differential, urea, creatinine and electrolytes, liver enzymes and a blood culture should be done in all severely ill children. • a cxr should be performed in children who are hypoxic, have severe illness or who are deteriorating despite treatment. • pulse oximetry should be performed in every child being assessed for admission to hospital with pneumonia. • virology all children (1) nasopharyngeal aspirate or nose and throat swabs (2) if presentation is more than 7 days after onset of illness, an 'acute' serum (2 5 ml clotted blood) should be collected and a 'convalescent' sample (2 5 ml clotted blood) obtained after an interval of not less than 7 days. • bacteriology children with influenza-related pneumonia (1) blood culture (before antibiotic treatment is commenced) (2) sputum samples obtained from older children (3) paired serological examination for influenza/other agents. • virology not routinely recommended • bacteriology children with influenza-related pneumonia (1) blood culture (before antibiotic treatment is commenced) (2) sputum samples obtained from older children • patients whose oxygen saturation is 92% or less while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above 92%. • when children are unable to maintain oral intake, supplementary fluids should, when possible, be given by the enteral route. intravenous fluids in those with severe pneumonia should be given at 80% basal levels. • children can be safely discharged from hospital when they: (1) are clearly improving (2) are physiologically stable (3) can tolerate oral feeds (4) have a respiratory rate <40/min (<50/min in infants) (5) have an awake oxygen saturation of >92% in air. • in the setting of a pandemic, children should only be considered for treatment with antivirals if they have all of the following: (1) an acute influenza-like illness (2) fever (>38.5ºc) and (3) been symptomatic for two days or less • oseltamivir is the antiviral agent of choice. • in children who are severely ill in hospital oseltamivir may be used if the child has been symptomatic for <6 days (but there is no evidence to demonstrate benefit, or lack of it, in such circumstances). • children (a) who are at risk of complications of influenza or (b) with disease severe enough to merit hospital admission during an influenza pandemic should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae. • for children under 12 years co-amoxiclav is the drug of choice. clarithromycin or cefuroxime should be used in children allergic to penicillin. for children over 12 years doxycycline is an alternative. • oral antibiotics should be given provided oral fluids are tolerated. • children who are severely ill with pneumonia complicating influenza should have a second agent added to the regime (e.g. clarithromycin or cefuroxime) and the drugs should be given intravenously to ensure high serum and tissue antibiotic levels. to facilitate preparedness planning, this document has been written in advance of the emergence of the next influenza pandemic, at a time when the identity of the causative virus remains unknown. these guidelines are based on the best evidence available from previous pandemic and interpandemic influenza periods. the guidance may evolve as clinicopathological information on the eventual pandemic virus emerges. once an influenza pandemic is under way, users are strongly urged to refer to the most up-todate version of these guidelines (from web-based access points). seasonal influenza is a familiar infection in the uk, especially during winter. every year strains of influenza (type a or b) circulate, giving rise to clinical consultations in primary care (age-specific impact varies by season), episodes of hospital treatment (mainly in older persons and young children, but occasionally in working age adults), and deaths (mainly in the elderly). treatment in primary care and hospital may be required due to the direct effects of influenza virus infection or its possible complications, most commonly secondary bacterial pneumonia. increases in gp consultations for influenza-like illness and winter bed pressures are frequently associated with periods of known community influenza activity 6 . pandemic influenza occurs when a new influenza a virus subtype emerges which is markedly different from recently circulating subtypes and strains, and is able to: • infect humans; • spread efficiently from person to person; • cause significant clinical illness in a high proportion of those infected. because the virus is novel in humans, a high proportion of the population will have little or no immunity, producing a large pool of susceptible persons; accordingly the disease spreads widely and rapidly. influenza pandemics occur sporadically and unpredictably. in 1918, a devastating and unusual pandemic caused by influenza a/h1n1 ('spanish flu') killed between 20 and 40 million people worldwide. other pandemics that followed had a less devastating impact but were nevertheless severe. influenza a/h2n2 ('asian flu') emerged in 1957, and h3n2 ('hong kong flu') in 1968; both produced roughly 1 million excess deaths worldwide 7 . the circumstances still exist for a new influenza virus with pandemic potential to emerge and spread, and the longest interval so far recorded between pandemics is 39 years (1918 1957) . the unpredictability of the timing of the next pandemic is underlined by the occurrence of several large outbreaks of highly pathogenic avian influenza associated with epizootic transmission to humans 8 . by far the most serious has been the massive and unprecedented outbreak of highly pathogenic influenza (a/h5n1) affecting poultry in east and south east asia in late 2003, which is still continuing. this outbreak has so far been associated with a small number of human cases but a high proportion of deaths. recently, epidemiological and virological changes have been reported from northern vietnam which may indicate that the virus is beginning to adapt to humans 9 . although the emergence of an a/h5n1 strain with capacity to spread efficiently between humans is neither inevitable nor imminent, international concern has increased regarding the possibility that avian influenza a/h5n1 may evolve to produce the next pandemic. other events and developments that inform the creation of this guidance are the development and licensing of a new class of drug (neuraminidase inhibitors) active against influenza, and uk government's announcement of plans to procure 14.6 million treatment courses of oseltamivir (tamiflu ® ) 10 for use in the uk in the event of a pandemic. be involved in the management of patients with influenza. it is intended that these guidelines also be of value to health-care practitioners who do not usually manage patients with influenza but may be called upon to do so in a pandemic situation. modification of some recommendations at a local level may be necessary in specific instances. these guidelines are not relevant for the management of patients affected by seasonal influenza, sporadic acute exacerbations of chronic obstructive pulmonary disease (aecopd), lower respiratory tract infections (lrtis) or community-acquired pneumonia (cap). at the primary care level, a national operational plan including the following three broad areas is deemed important: (a) clinical management of patients with influenza (b) management of patient demand, including patients who do not have influenza (c) health service delivery plans these guidelines cover the first of these areas and will serve as the source document for the primary care operational plan. the primary care operational plan will incorporate all three areas within a single reference and is being developed by the dh in collaboration with the rcgp and the bma. even though it is impossible to predict with certainty the impact of the next pandemic, based upon the available epidemiological and modelling information, it is clear that it will generate demands for health care which may saturate or overwhelm normal nhs acute services for a period of time, perhaps several weeks or months. accordingly, it should be anticipated that the nhs (in common with all health systems around the world) will need to revert to emergency arrangements. these are laid out in further detail in operational guidance for health service planners 4 , the uk operational framework for stockpiling, distributing and using antiviral drugs in the event of pandemic influenza 5 and in the primary care operational plan. with regard to the delivery of medical care for patients with influenza this is normally achieved through: • gp treatment of community patients 'well' enough to be managed in the community • hospital care in acute medicine for persons considered too ill to be managed at home. in the event of a pandemic, the following additional care settings may have to be considered as the threshold for hospital admission rises: • treatment of patients in the community (who would normally receive care from a gp) by other health-care professionals (nurses, paramedics, pharmacists etc.) following treatment guidance laid out in this publication and using prescription-only medicines according to patient group directives (pgds). • treatment of patients in their own homes or in temporary intermediate care facilities by a gp, following treatment guidance laid out in this publication when, under normal circumstances, such patients would have been admitted for hospital care. • treatment of severely ill patients in hospital by medical and nursing teams who do not normally manage patients with influenza or community-acquired pneumonia, in areas of the hospital not normally used for providing medical care (for example, surgical teams and bed space diverted from routine elective work towards pandemic response). the recommendations offered in the current guidelines are based on a matrix of evidence centred mainly around seasonal influenza, expert opinion and group consensus. grading of these recommendations based on the strength of the evidence base was deemed inappropriate. section 2. epidemiology and health impact projections (1) the scale and severity of illness (and hence consequences) caused by pandemic influenza generally exceed those of even the most severe winter epidemics. (2) mortality in the uk is likely to exceed 50,000 deaths, possibly appreciably higher. (3) besides the elderly, excess mortality is also likely in younger adults and children. (4) modelling studies suggest that after a case occurs in hong kong, because of international travel, it will take less than one month for the virus to reach the uk. (5) once cases begin to occur in the uk it will take only two to three weeks before activity is widespread and roughly a further three weeks (six weeks after initial cases in uk) until activity peaks. (6) it is possible that there will be more than one epidemic wave (with an interval of several months) and, if a second wave occurs, it may be more severe than the first. (7) cumulative clinical and serological attack rates across all waves together may be in the order of 25% and 50% respectively. (8) increases in demand for health-care services are likely to be very substantial in both primary care and hospital settings. when an influenza pandemic occurs, a substantial proportion (possibly all) of the population is likely to be non-immune, producing a large pool of susceptible persons. in past pandemics, the scale and severity of illness (and hence consequences) have been variable but broadly of a §2. epidemiology and health impact projections introductory observations higher order than even the most severe winter epidemics. it is reasonable to expect this to be the case with the next pandemic as well. excess mortality due to influenza occurs in most winter seasons but is especially marked during epidemics. the average annual excess mortality attributable to influenza in recent years is around 12,000 deaths per annum in england and wales 11 , although there is considerable yearly variation and some years are notably much higher than the average (est. 26,000 in 1989/90 epidemic). excess mortality in england and wales associated with the three pandemics of the twentieth century has also varied widely; this was estimated at 198,000 civilians in 1918/19, and 37,500 in 1957/58. in 1968/69 and 1969/70 (both seasons considered to be associated with the influenza a/h3n2 pandemic), there were an estimated 31,000 and 47,000 deaths respectively 7 . therefore the extent of mortality associated with the next pandemic cannot be reliably predicted although it is reasonable to plan for a scenario worse than a severe winter epidemic of normal influenza. typically, there are changes in the age-distribution of cases compared with seasonal influenza. mortality, which in typical seasonal influenza is usually confined to age groups over 65 years, tends to be increased in younger age groups. the size of any increase in morbidity and mortality and the extent to which a shift in age distribution occurs depend on a variety of factors including the nature of the pandemic virus and pre-existing immunity but appears to be a consistent phenomenon 12 . therefore, clinicians can expect to see relatively larger amounts of influenza-related illness in younger adults compared with normal winter activity. at least one third of all excess deaths may be expected in persons under 65 years of age. virological and clinical surveillance of influenza have improved markedly since the last pandemic in 1968. however, the extent of international travel has also grown. modelling studies using transmission characteristics based on the 1968/69 pandemic and international air-traffic data from 2002 indicate that the approximate delay between a first case in hong kong and first introduction to uk will be less than one month 13 . in terms of the spread within the uk, it will probably take only two to three weeks from the initial introduction(s) until activity is widespread and a further three weeks (six weeks from initial uk cases) until activity peaks. the temporal and spatial spread of a pandemic strain is important, particularly in terms of the demand placed on health-care services. pandemic activity taking the form of a brief but severe peak in cases will be more difficult for all services to cope with, compared with an identical number of cases distributed over a longer time course. for example, during the a/h3n2 pandemic a long first wave occurred in the winter of 1968/9 with morbidity and mortality approximately at the same level as the previous seasonal influenza; but in the following winter of 1969/70 a short and more severe epidemic occurred with a threefold higher peak in general practice consultation rates and a four-fold higher peak in mortality attributed to influenza, bronchitis and pneumonia. the high peak in consultation rates is well illustrated in fig. 2 .1. in 1918/19, the a/h1n1 pandemic occurred in three distinct epidemic waves: early spring 1918, autumn 1918 introductory observations §2. epidemiology and health impact projections s10 provisional guidelines from bis/bts/hpa in collaboration with the department of health, version 11 (2 october 2006) and late winter 1919. the second wave was by far the largest and case-fatality rates were also higher than in the first wave. the a/h3n2 pandemic caused an epidemic wave in the winter of 1968/69 but a more severe one in 1969/70. in contrast, the second wave of the 1957/58 pandemic in the uk was very small in comparison to the first 7 . thus it should be considered a possibility that more than one wave of influenza will occur within a few months of the emergence of a pandemic virus and a subsequent wave could be worse than the first. it is impossible to predict reliably with precision the level of excess mortality that will be experienced in the next pandemic. however, table 2 .1 illustrates the broad range of excess mortality that it is reasonable to consider, based on various realistic combinations of case fatality rate and clinical attack rates derived from previous pandemics and epidemics. a case fatality rate of 0.37% corresponds to the aggregate rate observed in recent epidemic seasons (1989/90, 1991/92, 1993/94, 1995/96, 1996/97, 1997/98 and 1998/99) and the 1957 pandemic, although the overall case-fatality rate observed in the 1918 19 pandemic was in the region of 1 2%. a clinical attack rate of around 25% corresponds to the approximate clinical attack rate seen in all three previous pandemics of the twentieth century. thus, a figure of at least 50,000 excess deaths is likely. using mathematical projections, it is possible to illustrate the potential impact of the next pandemic, but these do not amount to accurate predictions. table 2 .2 summarises the number of events that might be expected by a gp with 1000 patients on his/her list and by a pct serving a population of 100,000 persons. using the same assumptions, table 2 .3 illustrates the number of events by week over an assumed 15-week (single wave) pandemic period in a typical pct population of 100,000. most major acute trusts receive patients from a catchment area spanning several pcts and the figures below require pro-rata adjustment before applying to individual hospitals. section 3. clinical features in adults (1) influenza is clinically defined as the presence of fever and new (or, in those with chronic lung disease, worsening) cough of acute onset in the context of influenza circulating in the community. this clinical definition may be modified once a pandemic occurs. (2) the spectrum of clinical disease associated with a pandemic strain cannot be forecast. (3) pneumonia, either primary viral or secondary bacterial, is the commonest complication of influenza in adults. (4) neurological complications are rare in adults. the clinical manifestations of infection by influenza viruses are diverse, ranging from asymptomatic infection to fulminant respiratory distress leading to respiratory failure and death. furthermore, the presence of an influenza-like illness (ili) comprising of a combination of fever, cough, sore throat, myalgia and headache is not specific for influenza infection. other respiratory pathogens that may present with an ili include viruses such as respiratory syncytial virus (rsv), adenovirus, rhinovirus and parainfluenza virus, as well as bacterial pathogens such as chlamydia pneumoniae, legionella sp., mycoplasma pneumoniae and streptococcus pneumoniae [14] [15] [16] . studies that have examined the value of a clinical definition of ili in the diagnosis of influenza infection have not always used the same clinical definition for an ili and have included different study populations, making comparison between studies complicated. a systematic review of the literature in this area identified the threefold combination of the presence of fever, cough and acute onset to be the most predictive clinical features. the accuracy of this clinical definition was higher in persons aged 60 years and above compared to patient groups without age restrictions [positive likelihood ratio (95% ci) 5.4 (3.8 7.7) vs 2.0 (1.8 2.1)] 17 . the probability of influenza infection also increases with increasing level of fever 18, 19 . importantly, the predictive value of clinical definitions based on an ili increases when influenza virus is known to be circulating in the community 15, 17, 20 . in cohort studies, correlation of ili with laboratory-confirmed influenza infection ranges from 25% to 45% while in clinical trials, rates of 70% have been consistently reported 15, [21] [22] [23] .. these findings relate to influenza infections during interpandemic periods. during a global influenza pandemic, when a pandemic strain is known to be circulating locally in an immunologically susceptible population, the presence of an ili would be expected to be highly predictive for influenza infection. (however, the extent to which a clinical diagnosis of ili becomes predictive during a pandemic will also be determined by the behaviour of the public. if many who would not normally present to a health professional are prompted to present, then the predictive value of a clinical diagnosis of ili will be reduced.) the following description will relate mainly to interpandemic influenza a infections. influenza b and c are not considered pandemic threats. different strains may be associated with different clinical presentations and disease severity. for instance, there is evidence to suggest that the h3n2 subtype causes more severe disease than h1n1 subtype 24 . the spectrum of clinical disease associated with a new influenza a subtype (eg. a pandemic strain) cannot be determined currently and may differ from that described for interpandemic influenza. the incubation period prior to the onset of symptoms is commonly two to four days (range 1 7 days). in adults, the illness typically presents as an abrupt onset of fever accompanied by a range of other symptoms as listed in box 3.2 [25] [26] [27] [28] [29] . fever is the paramount symptom and may reach 41ºc although more usually it ranges between 38ºc and 40ºc. the peak occurs within 24 hours of onset and lasts typically for three days (range 1 5 days) [25] [26] [27] [28] [29] . the cough is generally dry although in up to 40% of cases it may be productive. a productive cough together with chest tightness and substernal soreness is more common in patients with underlying chronic lung disease. myalgia affects mainly the back and limbs. gastrointestinal symptoms such as vomiting and diarrhoea are uncommon (<10%) in adults. abdominal pain is rare. clinical findings include a toxic appearance in the initial stages, hot and moist skin, a flushed face, injected eyes and hyperaemic mucous membranes around the nose and pharynx. tender cervical lymphadenopathy is found in a minority (~10%) of cases. wheezing or lung crackles are recognised findings (~10%) more commonly noted in patients with coexisting chronic lung disease. although the overall clinical picture of uncomplicated influenza in any specific age group is similar for different influenza a subtypes, the frequency of certain symptoms may vary. for instance, during the 'asian' pandemic of 1957 (h2n2), headache and sore throat were frequent initial symptoms 30 . in uncomplicated infection, the illness usually resolves in seven days although cough, malaise and lassitude may persist for weeks. influenza virus infection has been associated with worsening in the clinical condition of patients with a range of existing medical conditions, such as, heart failure, diabetes, coronary heart disease, asthma and chronic obstructive airways disease (copd). in addition, specific complications associated with influenza infection regardless of co-existing medical conditions are recognised (table 3 .1). based on data from interpandemic influenza, certain persons are identified as being at high risk from influenza-related complications. such patients are similar to the group currently recommended for influenza vaccination by the department of health. these include those of all ages with chronic respiratory disease including asthma, chronic heart disease, chronic renal disease, chronic liver disease, immunosuppression due to disease or treatment, or diabetes mellitus, and all those aged 65 years or older, or those in long stay residential care (see appendix 2). in the course of a pandemic, it may emerge that the patient group at high risk of complications differs from the group currently identified. in such circumstance, details of the 'high risk' patient group will be altered according to relevant clinico-epidemiological data. the incidence of pneumonia (defined as a combination of respiratory symptoms and signs supported by chest radiographic changes consistent with infection) complicating influenza infection varies widely, from 2% to 38%, and is dependent on viral and host factors [25] [26] [27] . pneumonia generally occurs more frequently and with greater severity in patients with pre-existing chronic cardiac and respiratory conditions. patients who develop pneumonia may present with symptoms and signs indistinguishable from pneumonia related to other viral and bacterial pathogens. in the context of an influenza pandemic, the presence of an ili and new or worsening dyspnoea should prompt a careful examination for the presence of complicating pneumonia. two main types of influenza-related pneumonia are recognised: primary viral pneumonia and secondary bacterial pneumonia [25] [26] [27] [28] . patients with primary viral pneumonia typically become breathless within the first 48 hours of onset of fever. an initially dry cough may become productive of blood-stained sputum. cyanosis, tachypnoea, bilateral crepitations and wheeze on chest examination and leucocytosis are usual. the commonest chest radiographic abnormality is of bilateral interstitial infiltrates predominantly in the mid-zones, although focal consolidation is also well recognised. rapid clinical deterioration with respiratory failure may ensue 31 . the mortality in hospitalised patients is high (>40%) despite maximum supportive treatment on intensive care [25] [26] [27] [28] . in the majority of fatal cases, death occurs within seven days of hospital admission. secondary bacterial pneumonia is more common (up to four times) than primary viral pneumonia. typically, symptoms and signs of pneumonia develop during the early convalescent period (four to five days from onset of initial symptoms). in others, symptoms of pneumonia blend in with the initial symptoms of influenza. chest radiography usually demonstrates a lobar pattern of consolidation. mortality rate ranges from 7% to 24% [25] [26] [27] [28] [29] 32 , although some small studies report higher mortality rates. the spectrum of pathogens implicated is similar to that observed in cap and includes streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae and groups a, c and g b-haemolytic streptococci 27, 28, [33] [34] [35] . different pathogens have predominated at different times. for instance, in the 1918 pandemic, h. influenzae, b-haemolytic streptococci and s. pneumoniae were the predominant pathogens isolated. in 1968, s. pneumoniae was the predominant pathogen (48%) followed by staph. aureus (26%) and non-typeable h. influenzae (11%) 34 . notably, staph. aureus was identified two and a half times more frequently during the 1968 pandemic compared to pneumonia occurring in the interpandemic period 34, 36 . secondary staphylococcal pneumonia is associated with a higher incidence of lung abscess formation (14% vs 2%) and carries a poorer prognosis compared to non-staphylococcal pneumonias (mortality 47% vs 16%) 25, 29, 32, 37 . during the 1957 pandemic, staph. aureus was the predominant bacterial pathogen isolated in fatal cases of influenzarelated pneumonia (up to 69% of cases in some series) 25 . bacterial and viral pneumonia can occur concurrently. in these instances, the chest radiograph may demonstrate lobar consolidation superimposed on bilateral diffuse lung infiltrates. the mortality rate in mixed viral bacterial pneumonia is high (>40%), as for primary viral pneumonia [25] [26] [27] [28] . minor abnormalities on ecg such as st segment deviation, t wave changes and rhythm disturbances have been described in uncomplicated influenza illness. they have been reported in up to 81% of patients hospitalised with influenza 25 . most do not have cardiac symptoms. myocarditis and pericarditis are occasionally encountered in severe illness 38, 39 . post mortem evidence of necrotising myocarditis has been reported in patients without clinically significant myocarditis in the antemortem period. in contrast with myalgia affecting the back and limbs which is common on initial presentation, myositis generally develops after the subsidence of the acute upper respiratory tract symptoms. the gastrocnemius and soleus muscles are typically involved with pain and tenderness to palpation. complete recovery usually occurs in three days. elevation in serum creatine phosphokinase is recognised 40, 41 . rarely, this is associated with myoglobinuria and renal failure 42, 43 . myositis is more commonly described in children than in adults. central nervous system (cns) involvement in adults is uncommon. most reports originate from japan and occur in children 44, 45 . the main clinical syndrome is an encephalitis or encephalopathy manifesting in the form of decreased consciousness and seizures about three days (range 0 7 days) following the onset of upper respiratory tract symptoms. focal neurological signs such as paresis, aphasia, choreoathetosis and cranial nerve palsies are less common. cerebrospinal fluid (csf) examination may be normal or reveal an elevation in protein or white cell count. imaging by ct or mri may be normal and if so, is indicative of a good prognosis and full recovery may be anticipated 46 . young age and abnormal ct/mri findings are associated with a poor outcome including death or recovery with severe neurological sequelae. [a fuller description is given in section 4.2. 6.] acute necrotising encephalopathy is a rare fulminant syndrome associated with multifocal brain lesions that is described mainly in japan 46 . other rare manifestations include transverse myelitis and guillain barré syndrome 47,48 . reye's syndrome, characterised by an encephalopathy, acute fatty liver, association with aspirin use and high mortality (~40%), is a special situation that is almost exclusively seen in children and adolescents 46 . nevertheless, physicians managing adults are advised to be aware of this complication. [a fuller description is given in section 4.2.6.1.] other complications rarely encountered in adults with influenza a infection include toxic shock syndrome in conjunction with secondary staph. aureus infection 49,50 and parotitis 51 . otitis media is more commonly encountered in children than adults. human infections have been caused by different avian influenza a viruses in the past, including h9n2, h7n7, h7n3 and h7n2. in recent years, outbreaks of human infections by a novel strain of avian influenza a (h5n1) have raised particular concerns globally regarding the risk of a human pandemic 52 . these concerns have been due in part to recognition that (a) avian influenza a (h5n1) can pass directly from birds to humans and (b) once in humans, avian influenza a (h5n1) causes severe disease with a high mortality. the full spectrum of human illness associated with avian influenza a (h5n1) infection is not completely known. descriptions of the clinical features of influenza a (h5n1) infection in humans are based largely on case series of hospitalised patients. subclinical infections, mild illnesses and atypical presentations of influenza a (h5n1) infections in humans have been reported, but the frequency of such infections is difficult to determine [53] [54] [55] . in hospitalised patients, an ili similar to that associated with seasonal influenza a (h1n1 or h3n2) infection is recognised. gastrointestinal symptoms are present in a relatively large proportion of both adult and paediatric cases, in contrast to the relatively low incidence of gastrointestinal symptoms in seasonal influenza. the majority of patients develop a severe primary viral pneumonia usually associated with lymphopenia, thrombocytopenia and deranged liver function tests. renal failure and multiorgan failure may develop subsequently. mortality is high. a more detailed description is given in appendix 10. should influenza a (h5n1) acquire efficient humanto-human transmission capabilities, it may result in an influenza pandemic. in such an event, the clinical features of human h5n1 disease may alter. (1) the commonest presenting features of influenza during an epidemic are fever, cough and rhinorrhoea. in infants, fever with non-specific symptoms or diarrhoea and vomiting is common; in older children pharyngitis and headache are frequent. (2) the clinical features of influenza in children during a pandemic cannot be forecast. (3) children with underlying respiratory or cardiac disease, immune compromise or who are nonambulant are more likely to be severely affected. (4) the younger the child the more likely hospital admission will be needed. the clinical features of influenza presenting in a pandemic cannot be predicted as they appear to be dependent on the strain of influenza and, in some respects, the host. a new strain of influenza a responsible for an epidemic or pandemic may result in a different spectrum of clinical features than previous strains 56, 57 . common features during previous epidemics have been described and depend on the age of the child. the studies of clinical features are hospital based and are therefore likely to reflect more severe illness. these are nevertheless informative as one of the main issues in a pandemic is which patients require hospital admission. in young children presenting to primary care in a non-pandemic influenza season there are no specific clinical features that distinguish influenza from other winter viruses 58 . neonates may present with non-specific signs of sepsis such as pallor, floppiness, (poor peripheral circulation, poor tone), lethargy, poor feeding, episodes of apnoea 59 . fever may be the only presenting feature. a north american study identified influenza as the most common reason for children aged 0 60 days being admitted to hospital during an epidemic with fever as the only clinical feature 60 . fever may be the only presenting feature in this age group too. they may also be irritable and toxic and are more likely than older children to present with gastrointestinal symptoms such as diarrhoea and vomiting. febrile convulsions, particularly repeated convulsions, are positively associated with influenza a 61 . otitis media is also a common complication in children 62 . admission rates for under two year olds are 12 times higher than for children aged 5 17 years 63 . the presentation does not differ significantly from adults. common features are sudden onset of high fever, chills (76 100%), cough, headache, sore throat, fatigue (51 75%), nasal stuffiness and conjunctivitis (26 50%) . fever tends to settle two to four days later though a dry cough and clear nasal discharge last for one to two weeks 59 . a clinical prediction model from north america for influenza in children has shown that the triad of cough, headache and pharyngitis had a sensitivity of 80% and a specificity of 78% for a positive viral culture for influenza 64 . the subjects, mean age six years, presented during an epidemic to a suburban emergency department with a febrile respiratory illness and one or more symptoms of influenza. a finnish retrospective study of children referred to hospital from 1980 to 1999 with influenza confirmed by antigen testing reported that the median age for those with influenza a was two years. the most common features were cough, fever and rhinorrhoea 62 . these were also the commonest features reported in a chinese study where the mean age of the subjects with influenza a was four years 65 . conditions these children 66 (table 4 .1) and those who are not ambulant 67 experience substantial morbidity during influenza seasons, with a disproportionate number requiring inpatient care and ventilatory support. of the 22% of (table 4 .2) as in adults, influenza can present with either primary viral pneumonia or bacterial pneumonia most commonly caused by s. pneumoniae or staph. aureus. there is much less published about pneumonia complicating influenza in children. an outbreak of severe pneumococcal pneumonia in children occurred in iowa in the winter of 1995 96. this was coincident with an epidemic of influenza (h1n1). compared with controls, patients were 12 times more likely to have rare experienced a recent influenza-like illness. they were also more likely to have family members with the illness and to have positive serology in the convalescent period. many of these patients required chest drainage 69 . another study in 2002 of 202 children with proven influenza reported that 78 who had chest radiographs had either radiographic evidence of viral pneumonia or normal radiographs. no child had lobar pneumonia reported 70 . evidence from recent outbreaks of avian influenza (h5n1) in hong kong and vietnam suggests that while some children had mild disease 71 , others appeared to have multi-organ disease including acute respiratory distress syndrome (ards) 57 . all children who developed progressive pneumonia with ards died. there were no reports of bacterial pneumonia. there is no reason to believe that, apart from ards, pneumonia complicating influenza presents differently from community-acquired pneumonia in children 72 . the general clinical indicators for severity assessment of lower respiratory tract infection are summarised in the bts guidelines 72 (appendix 8). failure to improve following 48 hours of antibiotics, or deterioration including a new, distinct spike of fever, should also be treated as severe and further complicating factors sought. the clinical course of croup caused by influenza appears to be more severe than croup caused by the more common parainfluenza virus 73 . it is more likely to be complicated by bacterial tracheitis 62 . influenza is a well recognised cause of otitis media 74 . it is the commonest bacterial superinfection of influenza and is reported in approximately 25% of patients aged <5 years 75 . influenza ranks second only to respiratory syncytial virus as a cause of bronchiolitis 76 . the clinical features are the same 77 . children with influenza may present with febrile convulsions. in a community study in the netherlands, recurrent febrile seizures were positively related to influenza a. it was recommended that children who have had a previous febrile convulsion should be immunised against influenza a 61 . these complications are described in small case series. this is defined as depressed or altered level of consciousness including lethargy and/or extreme irritability in younger children or significant change in personality or behaviour persisting beyond 24 hrs or confusion (older children). encephalopathy usually presents as seizures within several days of the onset of fever 78 . seizures at this point are usually the first symptom of involvement of the central nervous system. febrile convulsions, which are more likely to be repeated with influenza than with other causes of fever, generally occur with the onset of fever. disturbances of behaviour and neurological deficit have been reported. a rapid and severe clinical course is usual with encephalopathy and is thought to be due to brain oedema mediated by cytokines rather than by direct invasion of the brain. steroids are therefore considered. 202 children with encephalopathy were recognised in japan between 1997 and 2001. death occurred in 31%, residual neurological deficit in 26% and full recovery in 43% 79 . this is a rare childhood acute encephalopathy associated with liver dysfunction. the cause is unknown but it typically follows viral illness and there is a clear association with aspirin therapy: thus an innate susceptibility coupled with aspirin taken for relief of viral symptoms. influenza (particularly influenza b) is commonly implicated 80 . there was a dramatic fall in incidence following warnings about aspirin use in children 81 . it is possible that children on long term aspirin treatment for medical conditions may be at increased risk if they develop influenza infection. reye's syndrome is characterised by protracted vomiting and encephalopathy in afebrile patients with minimal or absent jaundice, and hepatomegaly in 50% of patients. it comprises: • acute non-inflammatory encephalopathy with an altered level of consciousness • elevation of ammonia levels 24 48 hours after the onset of mental status changes (the most frequent laboratory abnormality) • hepatic dysfunction with a liver biopsy showing fatty metamorphosis or a more than three-fold increase in alanine aminotransferase (alt), aspartate aminotransferase (ast) neurological symptoms usually occur 24 48 hours after the onset of vomiting. lethargy is usually the first neurological manifestation. diarrhoea and hyperventilation may be the first signs in children younger than two years. other investigations: head ct scanning may reveal cerebral oedema but results are usually normal. an electroencephalogram (eeg) may reveal slow wave activity in the early stages and flattened waves in advanced stages. cerebrospinal fluid may or may not have increased opening pressure with white blood cells (wbcs) fewer than 9/ml 3 (usually lymphocytes). there is no specific treatment for reye's syndrome. key aspects of management are correction of metabolic imbalance and reduction of intracranial pressure. advice should be requested from a specialist in metabolic medicine. many children have an underlying inborn error of metabolism. mortality has fallen from 50% to less than 20% as a result of earlier diagnosis and more aggressive therapy. acute necrotising encephalopathy (ane): this occurs mainly in japan where it was first described in 1995. an estimated 100 deaths per annum are related to central nervous system complications of influenza in japan 82 . this suggests either a genetic predisposition for this complication or a variation in the strains of influenza circulating in japan. ane is characterised by high fever, convulsions and coma in children aged one to five years. the onset is two to four days after the respiratory symptoms, and fewer than 10% of patients survive 83 . there are no specific markers although some patients have raised liver transaminases. in many, the csf is normal. symmetrical multi-focal brain lesions are seen and bilateral thalamic involvement is characteristic and may be demonstrated on mri 83 . this is defined as encephalopathy plus two of the following: fever of 38ºc or higher, seizures, focal neurological findings, wbc >5 cells/ml in csf, eeg findings consistent with encephalitis, abnormal neuro-imaging 84 . these must be considered when a child presents with altered level of consciousness or irritability. there is good evidence of an increased risk of meningococcal disease following influenza infection 85 . during a pandemic, the focus will be on diagnosing influenza-related illness. other neurological conditions or drug toxicity, for example, may be missed. a literature review of 316 cases of myositis 86 suggested that this was a complication mainly of schoolchildren. the calf muscles are predominantly affected. rhabdomyolysis and renal failure are rare. these are also rare complications but have been described in children with underlying medical conditions 62 . section 5. general management and investigations in primary care with widespread concern during a pandemic, a significantly increased demand for advice and consultation should be anticipated. there are likely to be significantly higher consultation rates for all types of respiratory tract infections including those which are normally managed well at home using over-the-counter remedies (e.g. febrile colds, sore throat with temperatures). consequently, demand management in both the practice and the pct will be crucial to avoid the service's capacity to triage care being overwhelmed. guidance on demand management and health service delivery is given in the primary care operational plan (see section 1.4) 87 . management decisions of patients with influenza should be based primarily on: • an assessment of illness severity • identification of whether the individual is in an 'at risk' group • current advice from doh/local public health officials based on the epidemiology of the pandemic patients who are not considered to be at high risk and who have no features suggesting severe disease or complications may not need to be seen in face to face consultations by a primary care clinician. all patients presenting in general practice with symptoms suggestive of influenza (except perhaps those in whom urgent admission is required) should be given general advice and advice on symptomatic treatment. it is important that clinicians identify and address individual concerns and expectations, provide information about the illness, and provide information about what patients can do to help themselves and when they should seek further help. some useful facts that can be provided to the patient are included in box 5.1. there is little scientific evidence for most symptomatic and self-help treatment, but experience suggests that some of the following may help, and are unlikely to cause harm: • treat fever, myalgias and headache with paracetamol or ibuprofen • rest • drink plenty of fluids • avoid smoking • consider: short course of topical decongestants, throat lozenges, saline nose drops many infants and children will have coughs and mild fevers which may be due to other infections such as respiratory syncytial virus, especially over the winter months. these children should be managed in the usual way at home by parents with antipyretics and fluids. (note: aspirin should not be used in children.) management of these children is determined by disease severity (see appendix 5). the principles of symptomatic management are similar to those for adults. box 5.1. information about influenza to provide to patients • influenza is caused by a number different types of 'influenza' viruses. • the incubation period is typically one to four days and infected adults are usually contagious from the day of illness onset to five days after. children are typically contagious for seven days, although sometimes for longer. • fever usually declines after two to three days and normally disappears by the sixth day. • cough, weakness and fatigue can persist for one to two weeks and up to six weeks. • antibiotics do not benefit most people with influenza but are sometimes needed to treat secondary infections. (important note: this information may be modified once a pandemic occurs) • fever for four to five days and not starting to get better (or getting worse) • started to feel better then developing high fever and feeling unwell again • if taking antiviral drugs (eg. oseltamivir), symptoms should start to improve within two days. lack of any improvement after two days from starting antiviral drugs is an indication to re-consult. (important note: this information may be modified once a pandemic occurs) • children under one year of age year and those at high risk of complications (see appendix 2) should be seen and assessed by a gp or at the a&e department. • children over one but under seven years of age may be seen by a nurse or a gp and those aged seven years and above may be seen by a member of the community health team (e.g. community pharmacist). • all children (and parents) should be given advice on antipyretics and fluids. • aspirin is contraindicated in children (aged under 16 years). examples of what should prompt a patient to re-consult are given in box 5.2. patients who are started on antiviral agents (see section 7 for indications for antiviral use) would be expected to begin to improve within 48 hours of starting treatment. failure to improve two days after starting an antiviral agent is an indication to re-consult. at the time of re-consultation, an alternative diagnosis should be considered as well as the occurrence of any influenzarelated complications. • any rapid deterioration following first consultation should prompt a patient to re-consult. • failure to improve two days after starting an antiviral agent is an indication to re-consult. • if the first consultation did not involve contact with a physician, re-consultation should preferably involve a physician, usually a gp. 5.5. what general investigations should be done in the community? • general investigations, including a chest x-ray, are not necessary for the majority of patients managed in the community. the aim of microbiological investigations early in a pandemic (uk alert levels 1, 2 and 3) will be to confirm that influenza a is circulating in the local community. once a pandemic is established (uk alert level 4), microbiological investigations are not recommended routinely or likely to be available readily. routine testing for bacterial pathogens is not recommended at any stage. • where possible, early in a pandemic (uk alert levels 1, 2 and 3), nose and throat swabs, or nasopharyngeal swabs (in children), in virus transport medium should be submitted to the local laboratory. • once a pandemic is established (uk alert level 4), microbiological investigations are not recommended. section 6. criteria for hospital referral 6 .1. which adults require hospital referral? adults with uncomplicated influenza infection usually do not require hospital referral. patients who might require hospital admission fall into two main groups: those with worsening of a pre-existing medical condition and those with an influenza-related complication. patients who experience a worsening or clinical deterioration of pre-existing medical problems due to influenza infection should be managed according to recommended best practice for the medical condition in question. for instance, a patient with an acute exacerbation of copd triggered by influenza infection should be managed according to current nice guidelines for copd 88 . those with a worsening of a pre-existing condition are likely to be in a group at 'high risk' of influenzarelated respiratory complications and consequently at risk §6. criteria for hospital referral part 1. clinical management in primary care pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s21 . this group should be promptly reassessed if the illness is getting worse to consider hospital referral. pneumonia is the commonest influenza-related complication requiring hospital admission. patients complaining of new or worsening dyspnoea should be carefully assessed for signs of pneumonia. if pneumonia is diagnosed, disease severity assessment is recommended and hospital referral made accordingly. there is no validated severity assessment tool developed specifically for influenza-related pneumonia. the crb-65 score (table 6 .1) is a well validated severity assessment tool developed for patients with community-acquired pneumonia (cap) 89, 90 and recommended in the british thoracic society cap guidelines 2004 for use in the community setting 72 . it is offered as an example of an assessment tool for influenza-related pneumonia. the use of any severity assessment tool does not replace clinical judgement. a patient's social circumstances should also always be taken into account. in view of the rapid and fulminant course of primary viral pneumonia, patients with pneumonia who have bilateral chest signs (crackles) should be considered for hospital referral. other influenza-related complications are uncommon. there are no specific recommendations relating to criteria for hospital admission or disease severity assessment in these cases. • patients with clinically defined uncomplicated influenza infection would be expected to make a full recovery. they require good symptomatic management, access to antiviral treatment, information about the natural history, and advice as to when to re-consult. • patients with new or worsening symptoms particularly shortness or breath or recrudescent fever not responding to treatment should be examined to assess the presence and severity of influenza-related pneumonia. • patients with worsening of pre-existing co-morbid medical conditions should be managed according to best practice for that condition with reference to published disease-specific guidelines, if available. • in patients with influenza-related pneumonia clinically, hospital referral and assessment should be considered for patients with a crb-65 score of 1 or 2 (particularly score 2) and urgent admission for those with crb-65 score of 3 or more. • patients with bilateral chest signs of pneumonia should be referred to hospital for further assessment regardless of crb-65 score. • the crb-65 score does not replace clinical judgment. • the antiviral treatment of choice is oseltamivir (tamiflu tm ). this is given as a five-day course of oral tablets; 75 mg twice daily for adults. liquid suspension is available for children from the age of one year upwards. (see table 7 .1.) from clinical trial data accrued to date and based on seasonal, interpandemic influenza, the anticipated positive effect of antivirals in a pandemic will be: (a) a reduction of illness duration by 24 hours, and therefore more rapid mobilisation of affected individuals including essential workers (b) a possible reduction in hospitalisation of infected individuals (c) a reduction of subsequent antibiotic use by infected individuals the evidence accrued to date does not suggest there will be a reduction of overall mortality, nor does it rule it out. 7.4. who should receive antiviral drugs? • ideally, antiviral treatment should be offered to every patient who is over one year of age who (a) has an acute influenza-like illness (b) has fever ( 38ºc in adults, or 38.5ºc in children) and (c) presents within 48 hours of the onset of symptoms. • exceptions: (i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite the lack of documented fever. (ii) immunosuppressed patients, including those on long-term corticosteroid therapy, may suffer more prolonged viraemia, and could possibly benefit from antiviral therapy commenced later than 48 hours after the onset of ili. (iii) patients who are severely ill, but who have not been hospitalised due to non-clinical reasons, may benefit from antiviral therapy commenced later than 48 hours after the onset of ili. there is no strong evidence to support antiviral use in these exceptional situations. the commonest adverse effect of oseltamivir is nausea in about 10% of patients. this can be managed with mild anti-emetic medication. other side-effects are listed in appendix 9. national distribution arrangements are laid out in the uk operational framework for stockpiling, distributing and using antiviral drugs in the event of pandemic influenza 5 and the primary care operational plan. the drug will be made available through these arrangements to pharmacies, pcts and/or gp surgeries. • pcts are encouraged to plan for the delivery of antivirals to the large numbers of previously healthy persons with an ili via community health professionals, including community pharmacists. • gps should focus their efforts on assessment and management of those persons at high risk of complications (see appendix 2) and patients developing complications. section 8. antibiotic use in primary care the use of antibiotics in adults with influenza not complicated by pneumonia is determined by (a) the presence of any co-morbid illnesses and (b) the timing of first consultation with respect to the onset of symptoms. features of an acute bronchitis, with cough, retrosternal discomfort, wheeze and sputum production are an integral part of the influenzal illness. in previously well individuals who do not have pneumonia or new focal chest signs, antibiotics are not indicated. if the patient is seen later in the course of the illness and the illness is worsening, for instance with recrudescent fever or increasing breathlessness, a worsening bacterial bronchitis §8. antibiotic use in primary care part 1. clinical management in primary care pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s23 or developing pneumonia is possible and the use of antibiotics should be considered. in selected patients, a delayed antibiotic prescription may be offered at first consultation. the antibiotic prescription should come with clear instructions that the antibiotics should be used if the illness is not starting to settle after two days or if there is worsening of symptoms. the potential advantage of this approach of delayed antibiotic prescription is to minimise rates of reconsultation 91 . there are no robust data regarding the effect of such an approach on the incidence of influenzarelated complications. those at high risk of influenza-related complications because of (a) chronic obstructive pulmonary disease (copd) and/or (b) other severe co-morbid diseases should be strongly considered for antibiotics at first consultation. if, having started antibiotics, patients do not begin to improve over the next 48 hours of antibiotic treatment (or if they get worse) they should be advised to re-contact their gp for assessment of pneumonia and its severity (see sections 3 and 6). antibiotics should cover the likely bacterial pathogens including s. pneumoniae, h. influenzae, m. catarrhalis and staph. aureus. the preferred first choice of antibiotic for nonpneumonic bronchial infections, including those patients with copd, should include an effective oral b-lactamase stable agent such as a tetracycline (e.g. doxycycline) or co-amoxiclav. a macrolide (e.g. erythromycin or clarithromycin) is an alternative for those intolerant of the preferred first choices, whilst remembering the possibility of antimicrobial resistance. clarithromycin has better activity against h. influenzae than azithromycin. further details regarding the principles of antibiotic use including antibiotic resistance patterns are given in section 14. • patients without severe pre-existing illnesses and who have uncomplicated influenza, or simple bronchitis, do not routinely require antibiotics. • patients without severe pre-existing illnesses who are seen later in the course of illness and who have developed significant worsening of symptoms (particularly recrudescent fever or increasing breathlessness) should be considered for antibiotics. • patients with copd and/or other severe pre-existing illnesses, and who are therefore at high risk of influenzarelated complications, should be strongly considered for antibiotics at first consultation. • most patients can be adequately treated with a week's course of oral antibiotics. • the preferred choice of antibiotic needs also to cover infection with staph. aureus for example either doxycycline or co-amoxiclav (see table 8 .2). • a macrolide (e.g. erythromycin or clarithromycin) is an alternative choice in certain circumstances. the principles of antibiotic selection for patients with influenza-related pneumonia who can be managed in the community are similar to those for the management of sporadic community-acquired pneumonia in general except that adequate cover for staph. aureus, in addition to cover for s. pneumoniae, should be included in any empirical regimen. for this reason a tetracycline, such as doxycycline or oral co-amoxiclav, is the preferred regimen (table 8 .2). a macrolide (e.g. erythromycin or clarithromycin) is an alternative for those intolerant of the preferred first choices. macrolide (erythromycin 500 mg qds po or clarithromycin 500 mg bd b po) a an alternative regimen is provided for those intolerant of or hypersensitive to the preferred regimen. b clarithromycin may be substituted for those with gastrointestinal intolerance to oral erythromycin and also has the benefit of twice daily dosage and better cover against h. influenzae. abbreviations: od, once daily; bd, twice; tds, 3 times; qds, 4 times. secondary bacterial infections particularly pneumonia and otitis media are common in children with influenza. s. pneumoniae, staph. aureus and h. influenzae are the most common pathogens encountered during influenza outbreaks. • children in any one of the following groups should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae: (1) those at risk of complications of influenza (see appendix 2). (2) those with one or more of the following adverse features: (a) breathing difficulties (b) severe earache (c) vomiting for more than 24 hours (d) drowsiness. part 2. clinical management of adults referred to hospital section 9. severity assessment of adults referred to hospital 9.1. what severity assessment strategy is recommended for patients referred to hospital with influenzarelated pneumonia? there is no validated severity assessment tool developed specifically for influenza-related pneumonia. the curb-65 severity assessment tool as described in the bts cap guidelines 2004 is recommended for the stratification of hospitalised patients with influenza-related pneumonia into disease severity groups 72 (table 9 .1). in addition, the presence of diffuse bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia is an adverse prognostic feature. such patients should be treated as for severe pneumonia. in all instances, clinical judgement is essential when assessing disease severity. • patients with bilateral lung infiltrates on chest radiography consistent with primary viral pneumonia should be managed as having severe pneumonia regardless of curb-65 score. • in hospital, patients with influenza-related pneumonia who have a curb-65 score of 3 or more are at high risk of death and should be managed as having severe pneumonia. • patients who have a curb-65 score of 2 are at increased risk of death. they should be considered for short stay inpatient treatment or hospital-supervised outpatient treatment. this decision is a matter of clinical judgement. • patients who have a curb-65 score of 0 or 1 are at low risk of death. they can be treated as having non-severe pneumonia and may be suitable for home treatment. 9.2. when should transfer to a high dependency unit (hdu) or intensive care unit (icu) be considered? the indications for transfer to hdu or icu are no different in patients with influenza infection compared to other patients. most patients who might require hdu/icu care will have influenza-related pneumonia or a severe exacerbation of underlying comorbid illness, e.g. exacerbation of copd. in a pandemic situation when hdu/icu beds may not be readily available, prioritisation of patients on an individual basis matched against available resources will be expected. • patients with primary viral pneumonia or a curb-65 score of 4 or 5 should be considered for hdu/icu transfer. • general indications for hdu/icu transfer include: (1) persisting hypoxia with pao 2 < 8 kpa despite maximal oxygen administration (2) progressive hypercapnia (3) severe acidosis (ph < 7.26) (4) septic shock • patients with influenza admitted to an intensive care unit should be managed by specialists with appropriate training in intensive care, respiratory medicine and/or infectious diseases. in acute uncomplicated influenza the chest x-ray is usually normal. when primary viral pneumonia occurs as a complication, particularly in elderly adults the chest x-ray often shows multiple infiltrates or consolidation. cavitations or pleural changes suggest bacterial superinfection. in combined viral-bacterial pneumonia, the clinical features typically appear later than primary viral pneumonia and the chest x-ray often shows cavitation or pleural effusions. secondary bacterial pneumonia usually occurs after apparent improvement from the viral infection; the chest x-ray may show consolidation. • a chest x-ray should be obtained during assessment of a suspected case of influenza seen in the hospital setting (accident and emergency department or acute admissions ward). • in those patients who are subsequently followed up in a hospital outpatient clinic or by a general practitioner a repeat chest x-ray should be obtained at around six weeks if respiratory symptoms or signs persist or where there is a higher risk of underlying malignancy (especially smokers and those over 50 years of age). • further investigations including a ct thoracic scan, and bronchoscopy should be considered if the chest x-ray remains abnormal at follow up 72 . in those patients with illness severe enough to present to secondary care the following tests may be useful: full blood count: a leucocytosis with left shift may occur in those with primary viral pneumonia, mixed viralbacterial pneumonia or secondary bacterial pneumonia. (lymphopenia has been noted in human cases of severe avian h5n1 influenza.) urea and electrolytes may reveal evidence of hypo or hypernatraemia or renal impairment. liver function tests are usually normal. creatine kinase (ck) may be elevated in those with severe myalgia. c-reactive protein (crp) is unlikely to be helpful except where superimposed bacterial infection is suspected 72 . however, the diagnostic value of crp in lower respiratory tract infections remains controversial 92 . • the following blood tests should be obtained in patients admitted to hospital: (1) full blood count; (2) urea, creatinine and electrolytes; (3) liver function tests; (4) creatine kinase (if myositis is suspected). • in patients with suspected secondary bacterial infection, the c-reactive protein (crp) level may aid diagnosis. in acute uncomplicated influenza larger airway function remains normal. however, there is often an increase in bronchial reactivity which may persist for many weeks after resolution of the infection 93 . lung function tests are unnecessary in most patients. section 11. microbiological investigations for adults in hospital 11 .1. introduction the guidelines provided below are based on the assumption that when cases are first occurring in the uk as part of a global pandemic, it will be possible to perform full microbiological investigations in all new cases of influenzalike illness and influenza-related pneumonia. as case numbers rise, possibly to pandemic levels, full or indeed any microbiological investigation will become increasingly difficult. thus, data on the relative frequency of different bacterial causes of influenza-related pneumonia and their antimicrobial susceptibilities amongst investigated cases gathered earlier in the pandemic should be available to guide and refine empirical antimicrobial therapy choices for cases occurring later in the pandemic. the most likely pathogens implicated in influenzarelated pneumonia are streptococcus pneumoniae, staphylococcus aureus, haemophilus influenzae and to a lesser extent b-haemolytic streptococci (see section 3.3). in the early phases (uk alert levels 1, 2 and 3 see appendix 1) of a pandemic, microbiological diagnostic approaches should focus on confirming influenza as the primary illness, defining bacterial causes of influenza-related pneumonia, and optimizing both specific (for individual patients) and general (for populations) antimicrobial treatment recommendations. in later pandemic phases (uk alert level 4) with the much higher caseloads anticipated, microbiological investigation should be focused on patients with severe influenza-related pneumonia unresponsive to empirical antimicrobial therapy. actual and practical local level transition to less intense microbiological investigation may occur at uk alert level 3 in some regions as the number of local cases is likely to vary between regions. §11. microbiological investigations for adults in hospital part 2. clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s27 it will be necessary to perform full microbiological investigations on all hospitalised cases, including patients with severe and non-severe influenza-related pneumonia, in order to: confirm influenza as the primary infection, optimize treatment options for the patients investigated and define the most common bacterial causes of influenzarelated pneumonia and their antimicrobial susceptibility patterns. the latter data will help to inform empirical antimicrobial therapy of subsequent cases for which microbiological investigation may not be undertaken fully, or at all. in influenza, rapid virological tests, viral culture and pcr of respiratory samples will yield positive results between one and seven days after illness onset. however, if presentation is more than seven days after the onset of influenzalike illness then such sampling and testing is unhelpful. instead, serum samples for serological testing for evidence of recent influenza infection are recommended. specific detailed microbiological guidance for taking and handling specimens from individuals at risk of avian influenza prepared by prof maria zambon of health protection agency (hpa) centre for infections is available at: www.hpa.org.uk/infections/topics_az/avianinfluenza/ guidance/microbiological_guidance.htm bacteriological investigations are only recommended in patients with influenza-related pneumonia. legionella pneumophila infection is not normally associated with influenza-related pneumonia. despite this, legionella urine antigen tests should be performed on severe cap cases in the early stages of an outbreak/incident in order to confirm legionella infection is not the reason for a local increase in pneumonia admissions. these recommendations are modified from those contained in the british thoracic society community acquired pneumonia (bts cap) guidelines 2001 [thorax 2001;56(suppl iv), see sections 5.7, 5.8 and 5.9 (pp. iv23 iv28)] and the 2004 update (see pages 4 5), both available at: www.brit-thoracic.org.uk/ iqs/bts_#guidelines_pneumonia_html. sputum investigative efforts must be focused on quality samples (i.e. those from patients who are able to expectorate purulent samples, and have not received prior antibiotic treatment) and not dissipated on large numbers of poor quality samples. it is important to acknowledge that the criteria for quality samples may only be met for a minority of admissions. laboratories should offer a reliable sputum gram stain for appropriate samples, as on occasions this can give immediate indication of likely pathogens. the most likely influenzarelated pneumonia pathogens are s. pneumoniae, staph. aureus and h. influenzae, all of which may present a characteristic appearance on gram stain of purulent sputum. laboratories performing sputum gram stains should adhere to strict and locally agreed criteria for interpretation and reporting of results. a. virology all patients: • nose and throat swabs in virus transport medium should be collected from all patients and submitted to the local laboratory. the relevant laboratory should be notified of the suspected diagnosis and there should be close liaison over sample collection, handling and transport. • rapid testing by direct immunofluorescence or rapid eia test, virus culture and/or pcr should be undertaken according to local availability and/or referred to an appropriate laboratory • during uk alert level 1, when the uk is on high alert for the first cases of pandemic influenza, suspected cases are likely to be investigated by local health protection teams from the health protection agency and its partner organisations in the devolved administrations. • during uk alert levels 1 and 2, clinicians dealing with suspected cases of pandemic influenza should ensure that the local health protection team is informed and involved from the outset. • the health protection agency and its partner organisations in the devolved administrations have established a network of more than 20 laboratories across the uk which have been proficiency tested in molecular diagnosis of influenza a/h5n1. access to this service should be via local health protection teams. • if presentation is more than seven days after onset of illness, an 'acute' serum (5 10 ml clotted blood) should be collected and a 'convalescent' sample (5 10 ml clotted blood) obtained after an interval of not less than seven days. the two sera should be examined serologically for evidence of recent influenza infection. b. bacteriology patients with influenza-related pneumonia: • the following bacteriological tests should be performed: (1) blood culture (preferably before antibiotic treatment is commenced) (2) pneumococcal urine antigen (20 ml urine sample). agents. acute serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both 5 10 ml clotted blood) and the two sera stored for subsequent testing. once a pandemic is established, virological investigations are not recommended routinely and in a pandemic situation may not be readily available. the diagnosis of influenza will be based on clinical findings. if influenza-related pneumonia is present, the degree of microbiological investigation will be directed by disease severity and the presence of co-morbidities. in influenza-related pneumonia, examination of sputum should be considered for patients who do not respond to empirical antibiotic therapy. this will be particularly relevant if staph. aureus is identified as a common influenza-related pneumonia pathogen during the early phase of the pandemic as, in contrast to s. pneumoniae and h. influenzae, antimicrobial susceptibilities of this organism are less predictable and empirical choices more speculative. a. virology not routinely recommended. b. bacteriology patients with influenza-related pneumonia: (i) non-severe pneumonia (curb-65 score 0, 1 or 2) • sputum samples should be sent for gram stain culture and antimicrobial susceptibility tests in patients who do not respond to empirical antibiotic therapy. (ii) severe pneumonia (curb-65 score 3, 4 or 5) • specific investigations should include: (1) blood culture, preferably before antibiotic treatment is commenced. (2) pneumococcal urine antigen (20 ml urine). (3) sputum gram stain, culture and antimicrobial susceptibility tests on samples obtained from patients who: (i) are able to expectorate purulent samples, and (ii) have not received prior antibiotic treatment. sputum specimens should be transported rapidly to the laboratory. (4) paired serological examination for influenza/ other agents. 'acute' serum should be collected and a 'convalescent' sample obtained after an interval not less than seven days (both 5 10 ml clotted blood) and the two sera stored for subsequent testing. (5) tracheal or endotracheal aspirate samples, if available, should be sent for gram stain, culture and antimicrobial susceptibility testing. section 12. general management of adults admitted to hospital 12 initial management will depend on the assessment of the reason for admission, the presence of complications, and the impact of the influenza on any pre-existing disease, or psychosocial factors. for instance, some elderly patients may require admission for social reasons. in broad terms, the most likely clinical reasons for admission will be (in order of frequency): • lower respiratory tract complications: non pneumonic bacterial exacerbation of chronic lung disease such as copd (possibly with a mixed viral infection) secondary bacterial pneumonia mixed bacterial and viral pneumonia primary viral pneumonia • cardiac complications: exacerbation of pre-existing cardiac disease with cardiac failure and/or arrhythmia primary myocarditis • other complications: exacerbation of other pre-existing disease, such as diabetes mellitus neurological complications rhabdomyolysis severe sinusitis the initial management is likely to most usually involve that of respiratory and cardiac complications, especially pneumonia and these are discussed below. management of other less common primary influenzal complications (such as rhabdomyolysis, encephalopathy) is not covered. all influenza patients admitted to hospital with abnormal cardiorespiratory symptoms and signs, including influenzarelated pneumonia, should have a chest radiograph and an electrocardiogram and should have oxygenation assessed by pulse oximetry, preferably whilst breathing air (see section 10). those with sao 2 < 92% should have arterial blood gas measurements, as should all patients with features of severe illness. knowledge of the inspired oxygen concentration is essential to the interpretation of blood gas measurements and should be clearly recorded with the blood gas result. continuous oxygen therapy is indicated for those patients with pao 2 < 8 kpa, hypotension with systolic bp <100 mmhg, metabolic acidosis with bicarbonate <18 mmol/l or respiratory distress with respiratory rate >30/min 94 . the aim of oxygen therapy should be to maintain pao 2 at >8 kpa or sao 2 > 92%. unless complicated by severe chronic obstructive pulmonary disease with ventilatory failure, high concentrations of oxygen of 35% or greater are indicated and can be safely used. high concentration oxygen therapy given to patients with pre-existing chronic obstructive pulmonary disease §12. general management of adults admitted to hospital part 2. clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s29 who may have co 2 retention can reduce hypoxic drive and increase ventilation-perfusion mismatching. in such patients initial treatment with low oxygen concentrations (24 28%) should be progressively increased on the basis of repeated arterial blood gas measurements, the aim being to keep sao 2 > 90% without causing a fall in arterial ph below 7.35, in line with the management strategy recommended in the nice copd guidelines 95 . non-invasive ventilation (niv) may be of value in patients with copd who are in acute hypercapnic respiratory failure 72,96 . the use of niv in patients with respiratory failure due to severe pneumonia but without co-existing copd has not been shown to influence mortality 72,96 . nevertheless, during an influenza pandemic when critical care level 3 beds 97 are in high demand, niv may be of value as a bridge to invasive ventilation in specific circumstances. in all instances, the risks of infection due to the dissemination of respiratory droplets related to the use of niv must be taken into account when deciding on management strategies. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted and observed at all times, including the use of personal protection equipment (ppe) (see uk infection control guidance for pandemic influenza) 3 . all patients should be assessed for volume depletion and may require iv fluids. the potential for influenza to cause cardiac decompensation, either through exacerbation of pre-existing cardiac disease or from a primary myocarditis, should be borne in mind, with any complicating heart failure and arrhythmias being managed in the usual way. physiotherapy may be of benefit in selected patients with excess bronchial secretions, particularly those with concurrent chronic obstructive pulmonary disease. in cases of severe illness requiring prolonged hospital admission, increased nutritional support whether enteral, parenteral or via naso-gastric feeding should be arranged. • hypoxic patients should receive appropriate oxygen therapy with monitoring of oxygen saturations and inspired oxygen concentration with the aim to maintain pao 2 > 8 kpa and sao 2 > 92%. high concentrations of oxygen can safely be given in uncomplicated pneumonia. • oxygen therapy in patients with pre-existing copd complicated by ventilatory failure should be guided by repeated arterial blood gas measurements. non-invasive ventilation may be helpful. • in patients without pre-existing copd who develop respiratory failure, niv may be of value as a bridge to invasive ventilation in specific circumstances when critical care level 3 beds are in high demand. respiratory and/or critical care units experienced in the use of niv are best placed to ensure the appropriate infection control measures are adopted at all times. • patients should be assessed for cardiac complications and also volume depletion and their need for additional intravenous fluids. • nutritional support should be given in severe or prolonged illness. 12.3. what monitoring should be conducted during a hospital stay? pulse, blood pressure, respiratory rate, temperature, oxygen saturation (with a recording of the inspired oxygen concentration at the same time) and mental status should be measured initially at least twice daily. this is most conveniently performed using an early warning score (ews) chart, which all ward staff should be familiar with. those with severe illness, requiring continuous oxygen or cardiovascular support, should be monitored more frequently. failure to improve clinically within 48 hours should result in a full clinical reassessment and failure to improve over 4 days is an indication to repeat the chest radiograph. • temperature, respiratory rate, pulse, blood pressure, mental status, oxygen saturation and inspired oxygen concentration should be monitored and recorded initially at least twice daily and more frequently in those with severe illness or requiring regular oxygen therapy. • an early warning score system is a convenient way to perform this. • in addition to a full clinical reassessment, a chest radiograph should be repeated in patients who are not progressing satisfactorily. there will be considerable pressure to discharge patients early during a pandemic. the type and availability of out-of-hospital facilities will dictate hospital discharge decisions. some guidance regarding simple parameters to review when considering hospital discharge can be obtained from a recent us prospective, multi-centre, observational cohort study of 680 patients admitted to hospital with cap 98 , and is offered as advice for all patients admitted with influenza-related respiratory complications. • patients should be reviewed before 24 hours of discharge home. those with two or more of the following unstable clinical factors should be considered for continued hospital management: (1) temperature > 37.8ºc, (2) heart rate >100/min, (3) respiratory rate >24/min, (4) systolic blood pressure <90 mmhg, (5) oxygen saturation <90%, (6) inability to maintain oral intake, it is usual practice to arrange 'routine' hospital clinic follow up and repeat the chest radiograph at around six weeks after discharge for acute respiratory illness such as pneumonia. however, there is no evidence on which to base a recommendation regarding the value of this practice in patients who have otherwise recovered satisfactorily. it is also not known whether there is any value in arranging clinical follow up in a hospital clinic rather than with the patient's general practitioner. during an influenza pandemic situation, it is likely that only patients who developed complications or who had significant worsening of their underlying disease will be offered clinical review at one or other venue. at discharge, patients should be offered access to information about their take-home medication, smoking and lifestyle advice as appropriate, potential future complications and action to take in the event of a relapse of symptoms. • follow-up clinical review should be considered for all patients who suffered significant complications or who had significant worsening of their underlying disease, either with their general practitioner or in a hospital clinic. • at discharge or at follow up, patients should be offered access to information about their illness, take-home medication and any follow-up arrangements. • it is the responsibility of the hospital team to arrange the follow-up plan with the patient and the general practitioner. section 13. use of antivirals in hospitalised adults 13 .1. what drugs should be used for antiviral treatment during a pandemic? oseltamivir (neuraminidase inhibitor) will be the mainstay for therapy in the pandemic. the m2 inhibitors, amantadine and rimantadine, are unsuitable for use for treatment due to the rapid emergence of resistance together with sideeffects. from clinical trial data accrued to date and based on seasonal, interpandemic influenza, the anticipated positive effect of antivirals in a pandemic will be: (a) a reduction of illness duration by 24 hours, and therefore more rapid mobilisation of affected individuals including essential workers; (b) a possible reduction in hospitalisation of infected individuals; (c) a reduction of subsequent antibiotic use by infected individuals. there is insufficient evidence accrued to date to determine the effect of antivirals, if any, on overall mortality. therefore the major utility of antivirals will be to maintain the essential workforce, and reduce hospitalisation and antibiotic treatment of complications. (neuraminidase inhibitors) during a pandemic? • individuals should only be considered for treatment with neuraminidase inhibitors if they have all of the following: (1) an acute influenza-like illness (2) fever (>38ºc) and (3) been symptomatic for two days or less • treatment schedule: adults: oseltamivir 75 mg every 12 hours for 5 days. dose to be reduced by 50% if creatinine clearance is less than 30 ml/minute. • exceptions: (i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, make still be eligible despite lack of documented fever. (ii) hospitalised patients who are severely ill, particularly if also immunocompromised, may benefit from antiviral treatment started more than 48 hours from disease onset. this advice reflects the lack of robust evidence to guide the use of antivirals in these exceptional circumstances and places a high value on the potential benefits of antiviral therapy. drugs available for treatment and prevention of infection by influenza are summarised in table 13 .1. there are four drugs available, the older agents amantadine and rimantadine and the neuraminidase inhibitors oseltamivir and zanamivir. older agents: the older agents, amantadine and rimantadine (rimantadine is not currently licensed in the uk), are related substances that act by blocking the ion-channel function of the influenza virus m2 protein. this protein, although a minor surface constituent of the influenza virus particles, is essential for virus replication. these agents are only active against influenza type a. amantadine is not recommended by nice for treatment and/or prophylaxis of interpandemic influenza, so in the absence of national stockpiling, supplies of amantadine can be expected to be very low. h5 viruses in south east asia are resistant to amantadine, so this agent may play no role at all depending on the nature of the pandemic strain. two neuraminidase inhibitors so far have been developed to the level of entry into the formulary: zanamivir is a modification of neu5ac2en, a dehydrated neuraminic acid derivative. oseltamivir is a similar molecule except it has a cyclohexene ring and replaces a polyglycerol moiety with lipophilic sidechains. oseltamivir can be taken by mouth, whereas zanamivir must be inhaled, using a diskhaler device. an intravenous formulation of zanamivir has been developed but its efficacy has not been established. this may be relevant for the management of ventilator cases. both drugs are active against influenza type a as well as type b viruses. older agents. both amantadine and rimantadine are effective for the treatment of type a influenza virus infection if treatment is begun within 48 hours of the onset of illness 99 . historical data show that they can shorten the illness by approximately one day but their efficacy in preventing complications, hospitalisations, or deaths has never been established. although these drugs are effective, their use in clinical influenza treatment has been limited as a result of their proclivity to induce viral resistance, and their side-effect profile. several large clinical trials have demonstrated the utility of zanamivir and oseltamivir in treatment of adults with influenza in the community ( virtually all studies on the efficacy of neuraminidase inhibitors to reduce complications have been conducted with oseltamivir, and this drug has been shown to have some effect on outcomes other than time to recovery. in a meta-analysis of adults and adolescents with a virologically proven influenza illness, oseltamivir treatment reduced overall antibiotic use for any reason by 26 105 . so far, the neuraminidase inhibitors have not been extensively investigated in patients who are at the highest risk of serious complications of influenza. such patients include the elderly and those with serious cardiopulmonary illness, such as chronic obstructive pulmonary disease. the neuraminidase inhibitors have not been associated with a reduction in mortality, but the clinical trials conducted so far have not been appropriate to measure this. it is not known for certain whether the neuraminidase inhibitors will be effective in pandemic influenza because their use has only been assessed in inter-pandemic influenza, where the virulence is moderate and there is some degree of host immunity. the antiviral activity is likely to be adequate; in vitro, all neuraminidase inhibitors have been demonstrated to have a broad spectrum of activity against multiple avian influenza viruses 106 . the older agents, rimantadine and amantadine, were studied in both the 1968 hong kong pandemic and again when h1n1 influenza appeared in a pandemic in 1977. their efficacy has been reviewed by hayden 99 . when the older agents were given for four to eight week periods as prophylaxis in a community setting, their protective efficacy against influenza illness averaged 70% compared with placebo. this compares with 80 90% efficacy observed with the same agents in studies during the interpandemic period. when amantadine or rimantadine are used to treat patients, resistant viruses emerge rapidly and approximately 30% of treated children or adults will shed resistant variants starting two to five days after the onset of treatment 104 . the resistant viruses shed from these patients retain full virulence, infectivity and transmission potential. when contacts of cases treated with amantadine or rimantadine are given post-exposure prophylaxis with these older agents, the reduction in secondary cases is minimal 107 . in contrast, the frequency of emergence of resistance during treatment with the neuraminidase inhibitors is reported to be low. however, during studies of experimentally induced influenza a/h1n1 infection in healthy adults, 4% of participants shed viruses with a histidine to tyrosine substitution at position 274 within the binding site of oseltamivir 108 . in these cases the volunteers had increased influenza viral load within the nasopharynx but there was no deterioration of symptoms. so far, there have been no proven instances of transmission of oseltamivir or zanamivir-resistant variants in field clinical trials, but the experience is relatively small currently. sequence analysis of h5n1 human isolates from north vietnam have revealed virus with a 274 y (resistant) sequence. although the isolate was not fully resistant, its ic50 for oseltamivir was shifted upwards and it is therefore less susceptible to oseltamivir than other h5n1 isolates that had been tested from the region. the patient from whom the virus was isolated was concurrently being treated with oseltamivir. both amantadine and rimantadine can cause nausea and vomiting in a small percentage of individuals receiving them (table 13 .1). unfortunately amantadine is also associated with very unpleasant central nervous system side-effects including anxiety, depression, insomnia and hallucinations. the side-effects are dose-related and do resolve with discontinuation of the drug. in the case of the neuraminidase inhibitors, both drugs appear relatively safe. zanamivir has very few side-effects, but can result in bronchospasm which might be potentially serious in patients with asthma. oseltamivir requires dose-reduction in patients with low creatinine clearance (<30 ml/min). nausea occurs in 5 15% of oseltamivir recipients but is seldom severe enough to lead to drug discontinuation (see table 13 .3). antimicrobial chemotherapy will be indicated primarily for respiratory complications due to secondary bacterial infections, principally influenza-related pneumonia. the majority of patients with exacerbations of chronic obstructive pulmonary disease (copd) and other chronic lung conditions due to secondary bacterial infections, such as bronchiectasis, will also require antimicrobial chemotherapy, as will some patients with severe sinusitis. few pneumonias and lower respiratory tract infections are defined microbiologically at initial assessment and hence most prescribing is empirical. in broad terms the antimicrobial management of these patients should follow the guidance offered in relevant national guidelines for the management of community-acquired pneumonia and copd, but modified in the light of the different range of pathogenic bacteria that may be implicated, specifically staph. aureus infection. in the minority of cases, the aetiology may be determined after hospital admission, thereby permitting modification of the initial empirical regimen. although the pathogens responsible for communityacquired pneumonia are diverse, in the case of bacterial pneumonia complicating influenza the principal pathogens which should be covered by any initial empirical antimicrobial therapy include s. pneumoniae, h. influenzae and staph. aureus. the latter is said to be more common with combined viral bacterial pneumonia, as some strains of staphylococci have synergistic effect with the virus. gram-negative enteric bacillary infection is also sometimes seen. exacerbations of copd will be largely associated with s. pneumoniae, h. influenzae, and moraxella catarrhalis. severity assessment and the association of pre-existing co-morbid disease is essential in predicting prognosis and in turn determines management, choice of antibiotic therapy and its method of administration (see section 9). during an influenza pandemic this will be principally related to concerns about the local pattern of antimicrobial resistance of staph. aureus, and assessing the possibility of methicillin-resistant s. aureus (mrsa) being present locally. clinicians should be kept closely informed of any local shift in antimicrobial resistance patterns, both at the start and during a pandemic. staphylococcus aureus is widely resistant to penicillin 109 and an increasing number are now methicillin-resistant (mrsa); when occurring in the community this generally reflects hospitalisation within the recent past or residence within a nursing home 110 . hence, b-lactamase unstable penicillins (penicillin g, aminopenicillins) and, in the case of mrsa, isoxazolyl penicillins (flucloxacillin, cloxacillin) and cephalosporins, are inappropriate for such infections. the true incidence of resistance among pathogens in the community is difficult to estimate since most laboratory samples come from selected populations. with this limitation in mind, the presence of b-lactamase production among h. influenzae varies geographically but ranges from 2% to 17% 111, 112 in various parts of the uk. m. catarrhalis has a high rate of b-lactamase production. antibiotic resistance among s. pneumoniae is of concern world wide, owing to the dominance of this organism as a cause of community-acquired pneumonia and because penicillin and macrolide resistance are frequently linked 112, 113 . however, to date it is not a common enough problem in the uk to influence initial antimicrobial management decisions. recent data provided by the hpa of antimicrobial sensitivities of respiratory pathogens isolated from blood and respiratory samples during the last three to four years (robert george, personal communication) found macrolide resistance amongst about 10 14% methicillinsensitive staphylococcus aureus (mssa) isolates and 12 19% of s. pneumoniae. macrolides, apart from clarithromycin, have poor in vivo activity against h. influenzae. by contrast, tetracycline resistance was around 5 8% for s. pneumoniae, 3% for h. influenzae and 2 8% for mssa. fluoroquinolones have activity against methicillinsensitive staphylococcus aureus (mssa), with mic 90 figures of 1.0 mg/l for ciprofloxacin, 0.5 mg/l for levofloxacin and 0.12 mg/l for moxifloxacin 114 . modern fluoroquinolones (oral moxifloxacin and oral and iv levofloxacin currently licensed in the uk) are therefore a possible choice for secondary bacterial infections following influenza where mssa is a likely pathogen. a recent pharmacokinetic and pharmacodynamic in vitro study indicated that moxifloxacin 400 mg od had advantages over ciprofloxacin 500 mg bd or levofloxacin 500 mg od in antimicrobial effects against staph. aureus 115 . the quinolones, levofloxacin or moxifloxacin, also provide cover against s. pneumoniae and h. influenzae. mrsa is an unlikely pathogen in the uk in the context of community-acquired respiratory bacterial infection following influenza, and fluoroquinolones are not sufficiently active against mrsa. there are no robust research studies available to provide evidence-based guidance on the best empirical choice of antimicrobial therapy for bacterial complications of influenza. for these reasons the recommendations for treatment have been made on the basis of assessing a matrix of laboratory, clinical, pharmacokinetic and safety data, interpreted in an informed manner and taking account of other published guidelines 116 . in those with chronic lung disease, particularly copd, bacterial exacerbation will be the commonest cause of admission. it is likely that all such patients sufficiently ill to require hospital admission with an exacerbation will require antibiotics. management of their underlying macrolide (erythromycin 500 mg qds po or clarithromycin 500 mg bd b po) or fluoroquinolone with enhanced pneumococcal activity (e.g. levofloxacin 500 mg od po or moxifloxacin 400 mg od po c ) if iv needed: co-amoxiclav 1.2 g tds iv or cefuroxime 1.5 g tds iv or cefotaxime 1 g tds iv macrolide (erythromycin 500 mg qds iv or clarithromycin 500 mg bd b iv) or levofloxacin 500 mg od iv c 3. hospital-treated, severe pneumonia co-amoxiclav 1.2 g tds iv or cefuroxime 1.5 g tds iv or cefotaxime 1 g tds iv plus macrolide (erythromycin 500 mg qds iv or clarithromycin 500 mg bd b iv) fluoroquinolone with some enhanced pneumococcal activity (e.g. levofloxacin 500 mg bd iv, po c plus, either macrolide (erythromycin 500 mg qds iv or clarithromycin 500 mg bd b iv) or b-lactamase stable antibiotic (co-amoxiclav 1.2 g tds iv or cefuroxime 1.5 g tds iv or cefotaxime 1 g tds iv) a an alternative regimen is provided for those intolerant of or hypersensitive to the preferred regimen. b clarithromycin may be substituted for those with gastrointestinal intolerance to oral erythromycin and also has the benefit of twice daily dosage and better cover against h. influenzae. c levofloxacin and moxifloxacin are the only currently uk-licensed fluoroquinolones with enhanced activity against s. pneumoniae, in addition to cover for staph. aureus. levofloxacin comes in an oral and a parenteral formulation and is licensed for severe pneumonia. moxifloxacin comes in an oral formulation only in the uk and is not licensed for severe pneumonia. in the future, other fluoroquinolones such as gemifloxacin and gatifloxacin are likely to extend this choice, when licensed in the uk. abbreviations: od, once daily; bd, twice; tds, 3 times; qds, 4 times: iv, intravenous; po, oral. switch from parenteral drug to the equivalent oral preparation should be made as soon as clinically appropriate, in the absence of microbiologically confirmed infection. in the case of the parenteral cephalosporins, the oral switch to co-amoxiclav 625 mg tds is recommended rather than to oral cephalosporins. condition, such as copd, should follow standard guidelines, including the use of corticosteroids if indicated. antibiotics should cover the likely bacterial pathogens, including s. pneumoniae, h. influenzae, m. catarrhalis and staph. aureus. oral therapy should be sufficient for those without adverse severity features and who are able to take oral medication. the preferred first choice of antibiotic for nonpneumonic bronchial infections should include an effective oral b-lactamase stable agent such as co-amoxiclav, or a tetracycline, such as doxycycline. a macrolide is an alternative for those intolerant of the preferred first choices, whilst remembering the possibility of antimicrobial resistance. clarithromycin has better activity against h. influenzae than azithromycin. a newer-generation fluroquinolone (e.g. levofloxacin or moxifloxacin) with enhanced activity against s. pneumoniae is an alternative choice if there is increased likelihood of resistance or local issues that dictate such a choice. • previously well adults with acute bronchitis complicating influenza, in the absence of pneumonia, do not routinely require antibiotics. • antibiotics should be considered in those previously well adults who develop worsening symptoms (recrudescent fever or increasing dyspnoea). • patients at high risk of complications or secondary infection (appendix 2) should be considered for antibiotics in the presence of lower respiratory features. • most patients can be adequately treated with oral antibiotics. • the preferred choice includes co-amoxiclav or a tetracycline. • a macrolide such as clarithromycin (or erythromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative choice in certain circumstances. patients will be suffering from primary viral pneumonia, or combined viral bacterial pneumonia, or secondary bacterial pneumonia. the features of each of these are covered in section 3. all patients with pneumonic involvement should receive antibiotics. the principles of antibiotic selection for nonsevere influenza-related pneumonia is similar to those for the management of sporadic community-acquired pneumonia in general 72 , except that adequate cover for staph. aureus should be included in any empirical regimen. it is also not felt necessary to routinely provide cover for atypical pathogens (mycoplasma pneumoniae, chlamydia sp., coxiella burnetti, legionella sp.) during a pandemic as the large majority of patients will be hospitalised as a direct result of influenza and its complications caused by bacterial infection. for these reasons oral co-amoxiclav or a tetracycline such as doxycycline is the preferred regimen (table 14 .1). when oral therapy is inappropriate, parenteral coamoxiclav or a second-or third-generation cephalosporin is offered as an alternative. based on in-vitro data, the activity of selected cephalosporins against mssa in the uk in descending rank order is cefuroxime (mic90 1 2 mg/l) > cefotaxime (mic90 2 mg/l) > ceftriaxone (mic90 16 mg/l) [robert george, personal communication]. only cefuroxime and cefotaxime are recommended as cephalosporins offering adequate mssa cover within an empirical regimen. a macrolide or one or the new fluoroquinolones are identified as alternatives in hospitalised patients, in specific circumstances. these include those intolerant of penicillins or where local microbiological surveillance suggests they are better choices. at the time of completing these guidelines, only levofloxacin and moxifloxacin are licensed and available in the uk for pneumonia. flucloxacillin is not recommended as part of an empirical regimen because its activity against a narrow spectrum of pathogens (predominantly staph. aureus) would require it to be used in combination with more than one other antibiotic. it is offered as the antibiotic of choice in confirmed methicillin-sensitive staph. aureus (mssa) infection. regardless of the regimen selected it is critical that the antibiotics be administered promptly (within four hours of admission), and in the case of the patient with severe pneumonia without delay, by the admitting doctor in the admissions ward or by the general practitioner if delays are expected in the hospital admission process. delays in administration of antibiotics are related adversely to mortality in some studies, particularly when managing elderly patients 117, 118 . following initial assessment and empirical therapy, progress should be monitored carefully. the route and choice of antibiotic treatment will require adjustment, either by stepping up and broadening the spectrum of microbiological activity in the light of clinical deterioration or as a result of positive microbiological information, or stepping down with improvement as discussed below. • most patients can be adequately treated with oral antibiotics. • oral therapy with co-amoxiclav or a tetracycline is preferred. • when oral therapy is contra-indicated, recommended parenteral choices include intravenous co-amoxiclav, or a second or third generation cephalosporin (cefuroxime or cefotaxime respectively). • a macrolide (erythromycin or clarithromycin) or a fluoroquinolone active against s. pneumoniae and staph. aureus is an alternative regimen for those intolerant of penicillins. currently levofloxacin and moxifloxacin are the only recommended fluoroquinolones licensed in the uk. • antibiotics should be administered within four hours of admission. mortality is greatly increased in those with severe pneumonia (section 9). the illness may progress before microbiological information is available. preferred and alternative initial treatment regimens are summarised in table 14 .1. the recommendation of broadspectrum b-lactam regimens plus a macrolide in those with severe influenza-related pneumonia is based on the following rationale: (a) while s. pneumoniae and staph. aureus remain the predominant pathogens, gram-negative enteric bacilli, although uncommon, carry a high mortality 119 . (b) the recommended empirical regimen will offer double cover for the likely pathogens implicated in influenzarelated pneumonia and there is some evidence to indicate that combination therapy is associated with better outcomes in severe pneumonia 120 . (c) although there is no evidence of an increased incidence of infection by atypical pathogens in influenzarelated pneumonia, in severe pneumonia it is felt necessary to include cover for atypical pathogens, particularly legionella sp. as it may not be possible at the outset to distinguish between patients with sporadic severe community-acquired pneumonia in whom legionella infection is important, and influenzarelated pneumonia. parenteral administration of antibiotic is recommended in those with severe community-acquired pneumonia regardless of the patient's ability or otherwise to take oral medication. this is to ensure prompt, high blood and lung concentrations of antibiotic. a fluoroquinolone is offered as an alternative, despite limited data on their use in severe pneumonia 121 . at the time of writing, levofloxacin is the only licensed and available agent in the uk for severe pneumonia. it is marketed in parenteral and oral formulations. however, until more clinical experience is available we recommend combining it with another agent active against s. pneumoniae and staph. aureus such as a broad-spectrum b-lactam or macrolide when managing severe influenzarelated pneumonia. • patients with severe pneumonia should be treated immediately after diagnosis with parenteral antibiotics. • an intravenous combination of a broad-spectrum b-lactamase stable antibiotic such as co-amoxiclav or a second-(e.g. cefuroxime) or third-(e.g. cefotaxime) generation cephalosporin together with a macrolide (clarithromycin or erythromycin) is preferred. • an alternative regimen includes a fluoroquinolone with enhanced activity against pneumococci together with a broad-spectrum b-lactamase stable antibiotic or a macrolide. currently levofloxacin is the only such fluoroquinolone licenced in the uk. • patients who have been in hospital within the last few months have a higher chance of carrying mrsa as opposed to patients who have not been hospitalised recently. therefore due consideration should be given to the possibility of mrsa if they are known or suspected to have a staphylococcal pneumonia and/or are not responding to empirical therapy. 14.7. when should the iv route be changed to oral? there can be no rigid recommendation concerning the timing of transfer to oral therapy and further studies of this area are needed 122 . any decision must be individualised on the basis of assessing all factors, including the absence of any contraindications to oral administration, the availability of any microbiological information regarding aetiology of the infection and clear evidence that the patient is responding to initial therapy. the recommended guideline is that oral therapy be considered in a patient who has shown clear evidence of improvement and whose temperature has resolved for a period of 24 hours. • patients treated initially with parenteral antibiotics should be transferred to an oral regimen as soon as clinical improvement occurs and the temperature has been normal for 24 hours, providing there is no contraindication to the oral route. 14.8. for how long should antibiotics be given? until there are more precise methods to reliably identify microbiological and clinical end-points, the duration of therapy will remain subject to clinical judgement and custom. for these reasons the duration of therapy will vary by individual patient, disease severity and speed of resolution. • for most patients admitted to hospital with nonsevere and uncomplicated pneumonia, seven days of appropriate antibiotics is recommended. • for those with severe, microbiologically undefined pneumonia, ten days treatment is proposed. this should be extended to 14 21 days where s. aureus or gramnegative enteric bacilli pneumonia is suspected or confirmed. 14.9. failure of initial empirical therapy in those patients who fail to respond to initial empirical therapy, several possibilities need to be considered, the first of which is whether the correct diagnosis has been made. radiographic review is recommended for the community-and hospital-managed patient. this may also indicate complications of pneumonia such as pleural effusion/empyema, lung abscess or worsening pneumonic shadowing, which will be more common in the presence of staphylococcal infection. the initial empirical antibiotic regimen may need to be reassessed. however, compliance with, and adequate absorption of an oral regimen should first be considered. microbiological data should be reviewed and further specimens examined, with a view to excluding staph. aureus and gram-negative bacillary infection. in the hospital-managed, non-severely ill patient, changing to a new fluoroquinolone such as levofloxacin provides a second alternative. in the severely ill patient already receiving a b-lactam/ clarithromycin regimen, it is recommended that further staphylococcal cover is added to include cover for mrsa 123 . in addition, urgent referral to a respiratory physician should be made for clinical assessment including the possible need for bronchoscopic sampling. other rapid mrsa diagnostic techniques are in the evaluation stage. • for those with non-severe pneumonia in hospital on combination therapy, changing to a fluoroquinolone with effective pneumococcal and staphylococcal cover is an option. • adding further antibiotics effective against mrsa is an option for those with severe pneumonia not responding to combination antibiotic therapy. specific pathogen-directed antibiotic therapy 14.10 . what are the optimum antibiotic choices when specific pathogens have been identified? when a pathogen has been identified, specific therapy as summarised in table 14 .2 is proposed. in transferring patients from empirical to pathogen-targeted therapy, the regimen and route of administration will be determined by the continued need for parenteral therapy and known drug intolerance. these recommendations are again based on a synthesis of information, which includes in vitro activity of the drugs, appropriate pharmacokinetics and clinical evidence of efficacy gleaned from a variety of studies. the choice of agent may be modified following the availability of sensitivity testing or following consultation with a specialist in microbiology, infectious disease or respiratory medicine. close liaison with the local microbiology service will be essential during a pandemic. currently s. pneumoniae highly resistant to penicillin (mic 4 mg/l) is uncommon in the uk. however, it is important that the situation is monitored and in future §14. use of antibiotics in hospitalised adults part 2. clinical management of adults referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s37 either ciprofloxacin 400 mg bd iv or piperacillin 4 g tds iv ± gentamicin or tobramycin (dose monitoring) higher doses of penicillins or alternative regimens may need to be considered. staphylooccus aureus is an uncommon cause of sporadic community-acquired pneumonia in the uk, but will assume much greater potential importance during a pandemic. most community isolates are methicillin-sensitive although the recent increase in mrsa in hospitalised patients may result in subsequent readmission with an mrsa infection, secondary to influenza. options for methicillin-sensitive and -resistant infections are based on parenteral administration in view of the serious nature of staphylococcal pneumonia. • if a specific pathogen has been identified, the antibiotic recommendations are summarised in children with high fever (>38.5ºc) and cough or influenzalike symptoms will be seen by a community health professional (a nurse or doctor if under seven years of age). if there are no features that put them at high risk of complications they should be treated with oseltamivir, and given advice on antipyretics and fluids. children under one year of age and those at risk of complications (appendix 2) should be seen by a gp. children may be considered at increased risk of complications if they have: cough and fever (or influenza-like illness) and temperature >38.5ºc and either (i) chronic co-morbid disease (see appendix 2) or (ii) one of the following features • breathing difficulties • severe earache • vomiting > 24 hours • drowsiness these patients should be offered an antibiotic as well as oseltamivir (in those over one year of age) and advice on antipyretics and fluids. children under one year of age with none of the above features should be treated with antipyretics and fluids with a low threshold for antibiotics if they become more unwell. the most severely ill children should be referred for assessment for admission. in a pandemic situation, paediatric high dependency and intensive care beds are likely to fill quickly and will be insufficient to meet demand. children will have to be triaged by the senior paediatrician on duty in consultation with tertiary specialists in respiratory medicine, paediatric intensive care or paediatric infectious diseases. triage will be on the basis of the severity of the child's (a) acute and (b) co-existing disease and the likelihood of the child achieving full recovery. where admission is not possible §16. general investigations for children in hospital part 3. clinical management of children referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s39 the tertiary specialists will provide advice and support on management to the general paediatrician. in the h5n1 cases reported from vietnam 125 all seven children had wbc < 4.0 (mean 2.44) and 6/7 had a lymphopenia <1.0 (mean 0.66). six of the seven children died. in contrast, only two of the seven children reported from hong kong died but they were both leukopenic and lymphopenic. the survivors had a mean wbc of 12.44 and lymphocyte count of 3.11 126 . four of five cases reported from thailand were lymphopenic 127 . in influenza a thrombocytopenia (<100) is found in 5 7% 71, 84 . thrombocytopenia was found in four out of seven cases of h5n1 infection in vietnamese children 125 . liver transaminases are raised in 27% of influenza a patients 124 and were raised in six out of six of those measured in the hong kong h5n1 outbreak 126 and five out of six in those measured in vietnam 125 . c-reactive protein (crp) is unhelpful in influenza with values <10 in 55% 84 ; <20 in 72% 62 and >80 in only 5% 62 . the cd4/cd8 ratio was inverted in the two children and three adults in whom it was measured in the vietnam outbreak (mean 0.7; range 0.59 1.08). two of these patients survived 125 . • a full blood count with differential, urea, creatinine and electrolytes and liver enzymes and a blood culture should be done in all severely ill children. one of the largest studies of the value of chest radiography was undertaken in children aged between two months and five years with community-acquired pneumonia managed as outpatients with time to recovery as the main outcome 128 . chest radiography did not affect the clinical outcome in these children with acute lower respiratory infection. this lack of effect was independent of clinicians' experience. there are no clinically identifiable subgroups of children within the who case definition of pneumonia who are likely to benefit from a chest radiograph. the authors concluded that routine use of chest radiography was not beneficial in ambulatory children aged over two months with acute lower respiratory tract infection (lrti). clinicians basing the diagnosis of lower respiratory infections in young infants on radiographic diagnosis should be aware that there is variation in intraobserver and interobserver agreement among radiologists on the radiographic features used for diagnosis. there is also variation in how specific radiological features are used in interpreting the radiograph. a recent study on standardization of cxr interpretation in paediatric pneumonia illustrates the importance of standardised training 129 . the cardinal finding of consolidation for the diagnosis of pneumonia appears to be highly reliable 130 and reasonably specific for bacterial pneumonia (74% of 27 patients with alveolar shadowing had bacterial proven pneumonia) 131 but overall chest radiography is too insensitive to be useful in differentiating between patients with bacterial pneumonia and those whose pneumonia is nonbacterial 132, 133 . in the context of an influenza pandemic, a cxr will not distinguish viral pneumonia from viral illness with bacterial superinfection, and all children with signs of pneumonia should be treated with antibiotics. • a cxr should be performed in children who are hypoxic, have severe illness or who are deteriorating despite treatment. oxygen saturation (sao 2 ) measurements provide a noninvasive estimate of arterial oxygenation. pulse oximetry will be a key tool in assessment and management and it is essential that it is used correctly and that users are aware of the possibility of artefactually low readings. the oximeter appears easy to use and requires no calibration. however, it requires a pulsatile signal from the patient. it is also highly subject to motion artefacts. to obtain a reliable reading: (1) the child should be still and quiet. (2) when using paediatric wrap around probes, the emitting and receiving diodes need to be carefully opposed. (3) a good pulse signal (plethysmograph) should be obtained. (4) once a signal is obtained, the saturation reading should be watched over at least 30 seconds and a value recorded once an adequate stable trace is obtained. • pulse oximetry should be performed in every child being assessed for admission to hospital with pneumonia. to be read in conjunction with the corresponding section for adults (section 11 in part 2). as with adults, the extent of virological and microbiological investigations undertaken in children should vary according to the stage of the pandemic and additionally according to the severity of an individual case. it should be noted however, that the clinical features of influenza in children are less characteristic than in adults (see section 4) and the need for special diagnostic tests is therefore greater 62, 134, 135 the utility of rapid influenza tests has been demonstrated in studies where rapid knowledge of a diagnosis of influenza (within ten minutes) has been shown to have an impact on clinicians' behaviour with respect to antibiotic use, performance of other tests and admission to hospital 136, 137 . it may be imagined that in a pandemic situation such a test could result in earlier use of antiviral therapy and a more rational approach to hospital admission and to prophylaxis of contacts. however, using a molecular reference standard, one test was shown to have low sensitivity (44%) but high specificity (97%) suggesting that its role might better be to 'rule in' influenza rather than 'ruling it out' 138 . similar conclusions have been made with other commercial rapid tests 139, 140 . as a reflection of this, rapid antigen tests were positive in only two of six patients with avian influenza a (h5n1) 125 . the need for bacteriological tests in cases of influenza with pneumonia is also logical and the range of pathogens similar to adults 36,69,141-145 except that legionella infection is extremely unlikely to occur in a previously healthy child and legionella-specific antigen testing is therefore unnecessary. the urinary pneumococcal antigen tests in children may lack both sensitivity and specificity and should be interpreted with care 146, 147 . sputum collection in children is also unreliable although in older children (e.g. over 12 years of age) it may be possible and should be handled as indicated for adults. a. virology all children: during an influenza pandemic children are likely to be admitted to hospital because of the severity of their disease and its complications or because of the impact of influenza on pre-existing disorders such as cardiac, respiratory or neurological disease. management of preexisting disorders is outside this guideline. • the most common reason for admission is likely to be: (1) lower respiratory tract disease with either a viral or bacterial or mixed pneumonia. • other reasons for admission include: (2) severe gastroenteritis (3) cardiac disease viral myocarditis (4) encephalitis children should be triaged to ward or hdu/picu after severity assessment (section 15). an influenza pandemic is likely to occur in the winter months when other winter viruses responsible for paediatric morbidity and hospital admission are circulating (such as rsv and adenovirus). particularly in the early stages of a pandemic (uk alert levels 1 3) it will be important to use rapid virological tests in an attempt to cohort influenzapositive and rsv-positive infants separately and to separate from other patients (see uk infection control guidance for pandemic influenza) 3 . hypoxic infants and children may not appear cyanosed. agitation may be an indication of hypoxia. patients whose oxygen saturation is less than 92% while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above 92%. nasal cannulae do not deliver a fio 2 more than around 40% even at flow rates of 2 l/min in infants and 4 l/min in older children. alternative methods of delivering higher concentrations of humidified oxygen such as a head box or a venturi face mask may be necessary. if sao 2 > 92% cannot be maintained with an fio 2 of 60% then additional support such as cpap, bipap or intubation and ventilation should be considered. • patients whose oxygen saturation is 92% or less while breathing air should be treated with oxygen given by nasal cannulae, head box, or face mask to maintain oxygen saturation above 92%. children who are unable to maintain their fluid intake due to breathlessness, fatigue or gastroenteritis need fluid therapy. where possible additional fluid should be by the enteral route, and where nasogastric tube feeds are used, the smallest tube should be passed down the smallest nostril to minimize effects on respiratory status. severely ill children may need intravenous fluids, and if the child is in oxygen therapy intravenous fluids should be given at 80% basal levels (to avoid complications of inappropriate adh secretion) and serum electrolytes should be monitored. the monitoring will depend on the child's condition. severely ill children will need continuous monitoring of heart rate, respiratory rate, oxygen saturation and neurological status. all children on oxygen therapy should have four-hourly monitoring including oxygen saturation. chest physiotherapy is not beneficial in previously healthy children with pneumonia. children with underlying conditions such as cystic fibrosis or neuromuscular weakness will benefit from intensive physiotherapy. children with influenza are generally pyrexial and may have some pain, including headache, chest pain, arthralgia, abdominal pain, and earache from associated otitis media. pleural pain may interfere with depth of breathing and may impair the ability to cough. antipyretics and analgesics can be used to keep the child comfortable and to help coughing. 18.9. when can children be safely discharged from hospital? in a pandemic situation there will be great pressure on hospital beds. all children should be assessed for discharge at least twice daily. children should not remain in hospital if they are receiving therapy that could be given in the community. in previously healthy children suitable discharge criteria would be: (1) child is clearly improving (2) child is physiologically stable (3) child can tolerate oral feeds (4) respiratory rate is <40/min (<50/min in infants) (5) awake oxygen saturation is >92% on air. most children will make an uneventful recovery and not require follow up. those with a prolonged illness may be followed up by their general practitioner. only children with severe disease and/or at high risk of sequelae need hospital follow up. children with lobar collapse should have a follow-up cxr. follow-up cxrs after acute uncomplicated pneumonia are of no value where the patient is asymptomatic 148, 149 . to be read in conjunction with the corresponding section for adults (section 13 in part 2) five antiviral agents are theoretically available for the therapy of influenza in children: the m2 ion channel inhibitors amantadine and rimantadine (both administered orally and for influenza a only), the neuraminidase inhibitors oseltamivir (administered orally) and zanamavir (administered through an inhaler), and ribavirin (aerosolised). the limitations of amantadine and rimantadine are detailed in section 13, particularly in the context of a pandemic where resistance may already be present 150 . both have been shown to be effective in the treatment of influenza a in children 151 . concerns exist about the development of resistance during therapy for both agents 151, 152 . a household study showed that treatment and prophylaxis with rimantadine resulted in rapid selection and transmission of drug resistant virus 153 . in a double-blind randomised, placebo controlled study, 217 children (1 12 years of age) received oseltamivir with a resultant reduction in the median duration of illness, incidence of otitis media as a complication of influenza (12% vs 21%) and the need for antibiotic prescriptions in those with influenza (68 of 217, 31% vs 97 of 235, 41%; p = 0.03) compared to placebo 103 . the most common sideeffect was vomiting (5.8%). a systematic review and meta-analyses published in 2003, which included studies up to december 2001, included only two studies of zanamivir and one study of oseltamivir 103 in which these drugs were administered for treatment of influenza a or b in children under 12 years of age 154 . the reduction in the median time to alleviation of symptoms for influenza-positive children when compared with placebo was 1.0 day (95% ci: 0.4 1.6) for zanamivir and 1.5 days (0.8 2.2) for oseltamivir. across all ages a 29% (10 44%) relative reduction in complications requiring antibiotics was observed for zanamivir, and for children specifically a 35% relative reduction was observed for oseltamivir. this was updated through to december 2002 in a cochrane review 155 . using its search criteria it identified two trials of oseltamivir (one in healthy children 103 and one in children with asthma which was later published 156 and only one with zanamivir. its conclusions were therefore the same with respect to median illness duration in healthy children. a significant reduction in complications (otitis media) was noted for oseltamivir while a trend to benefit was seen for zanamivir 155 . vomiting was significantly more common among oseltamivir recipients than placebo recipients (15% vs. 9%). the review noted that there may be a difference in efficacy according to serotype, with oseltamivir showing a significant reduction in time to resolution for influenza a (34%) but not b (8.5%) 155 . with respect to children with asthma there was a trend to reduction in time to freedom from illness for oseltamivir recipients but this did not reach statistical significance. oseltamivir appeared to result in a more rapid improvement in pulmonary function, and was well tolerated in children with asthma 155, 156 . the cochrane review concluded that oseltamivir was the preferred drug as it has shown a benefit with regard to secondary complications. it also concluded that there was no evidence of benefit in at-risk children (i.e. asthma). from the perspective of pandemic use however, it should be noted that there was no evidence of harm in this group. with regard to dosing of oseltamivir, pharmacokinetic studies have suggested that young children clear the drug faster than older children, adolescents and adults and therefore need higher doses 157, 158 . the major practical issue with regard to zanamivir is its mode of administration limiting its use to children over the age of five years (fda guidance: over seven years of age) 155 . the development of resistance to oseltamivir in children may be more common than appreciated and more common than seen in adults. in one study resistance mutations were documented in 18% of 50 children 158 . this has implications for widespread use in a pandemic situation. one particular issue with regard to paediatric use of oseltamivir is the apparent age limitation on its license (i.e. not for children under one year of age). this is particularly important because during epidemic years, of all children with influenza, it is children under six months of age who are most likely to be hospitalised 159 . the basis for this exclusion appears to be that rat data have shown high mortality in infant rats at seven days of age when given a dose of 1000 mg/kg together with high brain levels of oseltamivir, assumed to reflect the immature blood brain barrier at this age. this is reflected in product literature and an fda alert although there are no published data. as a result, there are few human data in this age group as it was felt that it would be difficult to monitor cns toxicity in this age group. however, because of a fear of encephalopathy due to influenza in young children, japanese paediatricians §19. use of antivirals in hospitalised children part 3. clinical management of children referred to hospital pandemic flu. clinical management of patients with an influenza-like illness during an influenza pandemic s43 have been using it in infants and data on 102 consecutive infants from japan revealed no encephalopathy or mortality in recipients 160 . a second japanese report where 47 children under one year were treated (4 mg/kg/day) showed similar efficacy for fever to a group of older children and no serious adverse effects 161 . there are no data on the effectiveness of oseltamivir if given more than two days from onset of illness. it is likely to be less effective and in particular to have little or no effect after five to six days of illness unless the child is immunosuppressed. giving oseltamivir to sick hospitalised patients is theoretically likely to decrease their infectivity and so may be useful but there are no data to support this. in a double blind placebo controlled study children hospitalized with influenza who had been ill for 48 hours or less and who had a temperature of 37.8ºc or more were randomised to receive either ribavirin or placebo. sixtytwo patients (35 in the placebo group, 27 in the ribavirin group) had a confirmed diagnosis of influenza. the time to reduction of temperature to 38.3ºc or less for the ribavirin group was 8.9 hours compared with 22.6 hours for the placebo group (p = 0.04). there were no other differences detected between groups 162 . there have been no further published studies in the 11 years since this report, thus ribavirin cannot be recommended at this time. • in the setting of a pandemic, children in the community should only be considered for treatment with antivirals if they have all of the following: (1) an acute influenza-like illness (2) fever (>38.5ºc) and (3) been symptomatic for two days or less. • oseltamivir is the antiviral agent of choice. • treatment schedule for children over one year: body weight 15 kg, i.e. <3 years: 30 mg every 12 h body weight >15 23 kg, i.e. 3 7 years:45 mg every 12 h body weight 24 kg, i.e. >7 years: 75 mg every 12 h • in children who are severely ill in hospital oseltamivir may be used if the child has been symptomatic for less than six days. • oseltamivir may be considered for the treatment of infants under one year of age, especially those with severe influenza. this would need to be done following appropriate discussion with the parents highlighting the concerns from the animal data and the relative paucity of human data in this age group. section 20. use of antibiotics in hospitalised children 20 .1. who should get antibiotics? secondary bacterial infections, particularly pneumonia and otitis media, are common in children with influenza. a case control study during an outbreak of severe pneumococcal pneumonia demonstrated that patients with severe pneumonia were 12 times more likely to have had an influenza-like illness and four times more likely to have positive influenza serology than controls 69 . infections with staph. aureus and h. influenzae are also more common during influenza outbreaks. a randomized controlled trial of antibiotics in 85 children aged four months to 11 years presenting with influenzalike symptoms during an influenza epidemic showed a decreased incidence of pneumonia in the antibiotictreated group (2.4% vs 16.3%, p = 0.031) 163 . there was no change in duration of fever or incidence of acute otitis media. interestingly only one out of seven of the cases of pneumonia in the placebo group was thought to be bacterial. the authors postulated that as bacterial proteases facilitate propogation and pathogenesis of influenza in a mouse model, decreasing bacterial numbers and hence protease levels in the lung may decrease viral pneumonia. another randomized trial of cephalosporins vs macrolides in 365 japanese children with influenza-like symptoms showed faster alleviation of fever (3.8±1.4 vs 4.3±1.4 days, p = 0.006) in the macrolide group and a decrease in number with cxr evidence of pneumonia (2 vs 13 cases, p = 0.002; 14/15 had interstitial changes) 164 . the authors postulate that anti-inflammatory effects of macrolides may be responsible. • children who (a) are at risk of complications of influenza or (b) have disease severe enough to merit hospital admission during an influenza pandemic should be treated with an antibiotic that will provide cover against s. pneumoniae, staph. aureus and h. influenzae. the antibiotics of choice must cover the likely pathogens as above. rarely a blood culture or pleural tap will provide the pathogen. the antibiotics should then be specifically tailored, e.g. iv benzylpenicillin or oral amoxicillin for s. pneumoniae and flucloxacillin or clindamycin for staph. aureus. part 3. clinical management of children referred to hospital §20. use of antibiotics in hospitalised children s44 provisional guidelines from bis/bts/hpa in collaboration with the department of health, version 11 (2 october 2006) a recent randomized controlled trial of the equivalence of oral amoxicillin vs iv benzylpenicillin in 252 children admitted to hospital with community-acquired pneumonia showed no difference in duration of illness or complications 165 . oral antibiotics should be given provided oral fluids are tolerated. 20.5. antibiotic choice for severe or complicated pneumonia? children who are severely ill with pneumonia complicating influenza should have a second agent which provides good cover for gram positive organisms added to the regime (e.g. clarithromycin or cefuroxime) and the drugs should be given intravenously to ensure high serum and tissue antibiotic levels. section 21. acknowledgements, committee members and affiliations 21 chronic obstructive pulmonary disease (copd) including chronic bronchitis and emphysema, and such conditions as bronchiectasis, cystic fibrosis, interstitial lung fibrosis, pneumoconiosis and bronchopulmonary dysplasia (bpd). asthma requiring continuous or repeated use of inhaled or systemic steroids or with previous exacerbations requiring hospital admission. children who have previously been admitted to hospital for lower respiratory tract disease. chronic heart disease congenital heart disease, hypertension with cardiac complications, chronic heart failure and individuals requiring regular medication and/or follow-up for ischaemic heart disease. chronic renal disease nephrotic syndrome, chronic renal failure, renal transplantation. chronic liver disease cirrhosis, inflammatory bowel disease diabetes and chronic metabolic disorders diabetes mellitus requiring insulin or oral hypoglycaemic drugs. immunosuppression and malignancy due to disease or treatment: asplenia or splenic dysfunction, hiv infection at all stages, malignancy. patients undergoing chemotherapy leading to immunosuppression. individuals on or likely to be on systemic steroids for more than a month at a dose equivalent to prednisolone at 20 mg or more per day (any age) or for children under 20 kg a dose of 1 mg or more per kg per day. long-stay residential care homes residents this does not include prisons, young offender institutions, university halls of residence. others doctors retain discretion in identifying additional individual patients who they recognise as at high risk of serious complications should they develop influenza; for example patients with haemoglobinopathies, neurological diseases with muscle weakness, cerebral palsy or children on long-term aspirin who are at increased risk of reye's syndrome. a the high-risk groups described in this appendix are largely based on data from interpandemic influenza. during the course of a pandemic, the definition of 'high-risk groups' may differ. if so, details of the 'high-risk' patient group will be altered according to relevant clinico-epidemiological data. users are strongly advised to refer to the latest version of these guidelines at all times. treat as severe pneumonia antibiotics not indicated <8.5 kg -7.5 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influence of bacterial superinfection on the clinical course of influenza. studies from the influenza epidemics in stockholm during pneumonia complicating asian influenza influenza a myocarditis developing in an adult liver transplant recipient despite vaccination: a case report and review of the literature rhabdomyolysis and myoglobinuric renal failure complicating influenza in a young adult acute myopathy associated with influenza a/texas/1/77 infection. isolation of virus from a muscle biopsy specimen high incidence of acute myositis with type a influenza virus infection in the elderly influenza and myoglobinuria in brothers myoglobinuria associated with influenza a infection a pregnant woman with influenza a encephalopathy in whom influenza a/hong kong virus (h3) was isolated from cerebrospinal fluid isolated lesions limited to the bilateral substantia nigra on mri associated with influenza a infection influenza virus and cns manifestations the spectrum of antecedent infections in guillain-barre syndrome: a casecontrol study myelitis associated with influenza a virus infection toxic shock syndrome complicating influenza a infection: a two-case report with one case of bacteremia and endocarditis toxic shock syndrome following influenza a infection acute parotitis associated with influenza type a: a report of twelve cases avian influenza: assessing the pandemic threat. who atypical avian influenza (h5n1) fatal avian influenza a (h5n1) in a child presenting with diarrhea followed by coma avian influenza a (h5n1) infection in humans human disease from influenza a (h5n1) avian influenza virus infection of children in vietnam and thailand prospective study of the viral aetiology and clinical course among children in the community with cough and fever nosocomial influenza in children recurrence of febrile seizures in the respiratory season is associated with influenza a influenza a and b virus infections in children influenza in children clinical predictors of influenza in children clinical features of influenza a and b in children and association with myositis the burden of influenza illness in children with asthma and other chronic medical conditions the impact of influenza a on children with disabilities the impact of influenza in children severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection impact of the rapid diagnosis of influenza on physician decision-making and patient management in the pediatric emergency department: results of a randomized, prospective, controlled trial childhood severe acute respiratory syndrome in taiwan and how to differentiate it from childhood influenza infection clinical courses of croup caused by influenza and parainfluenza viruses prevalence of various respiratory viruses in the middle ear during acute otitis media influenza virus infection in infancy and early childhood welliver sr rc. a comparison of epidemiologic and immunologic features of bronchiolitis 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hemisphere trialists) study group efficacy and safety of oseltamivir in treatment of acute influenza: a randomised controlled trial. neuraminidase inhibitor flu treatment investigator group neuraminidase inhibitors for preventing and treating influenza in healthy adults oral oseltamivir treatment of influenza in children safety and efficacy of the neuraminidase inhibitor gg167 in experimental human influenza impact of oseltamivir treatment on influenza-related lower respiratory tract complications and hospitalizations comparison of efficacies of rwj-270201, zanamivir, and oseltamivir against h5n1, h9n2, and other avian influenza viruses study of 1-adamantanamine hydrochloride used prophylactically during the hong kong influenza epidemic in the family environment selection of influenza virus mutants in experimentally infected volunteers treated with oseltamivir a comparison of antimicrobial resistance rates in grampositive pathogens isolated in the uk from mrsa bacteraemia in patients on arrival in hospital: a cohort study in oxfordshire antimicrobial resistance in haemophilus influenzae from england and scotland in 1991 trends in the antimicrobial susceptibility of bacterial respiratory tract pathogensfindings of the alexander project antibiotic resistance among clinically important gram-positive bacteria in the uk a critical review of the fluoroquinolones: focus on respiratory infections antistaphylococcal effect related to the area under the curve/mic ratio in an in vitro dynamic model: predicted breakpoints versus clinically achievable values for seven fluoroquinolones quality of care, process, and outcomes in elderly patients with pneumonia community-acquired pneumonia in patients receiving home care prognosis and outcomes of patients with community-acquired pneumonia. a meta-analysis severe pneumonia and a second antibiotic the next generation: fluoroquinolones in the management of acute lower respiratory infection in adults comparison of 7 versus 10 days of 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acquired pneumonia: a closed loop audit comparison of clinical characteristics of influenza and respiratory syncytial virus infection in hospitalised children and adolescents influenzalike illness criteria were poorly related to laboratoryconfirmed influenza in a sentinel surveillance study effect of a rapid influenza diagnosis effect of rapid diagnosis of influenza virus type a on the emergency department management of febrile infants and toddlers near patient testing for influenza in children in primary care: comparison with laboratory test comparison of binax now and directigen for rapid detection of influenza a and b new point of care test is highly specific but less sensitive for influenza virus a and b in children and adults association of invasive pneumococcal disease with season, atmospheric conditions, air pollution, and the isolation of respiratory viruses fatal influenza a virus infection in a child vaccinated against influenza toxic shock syndrome. a newly recognized complication of influenza and influenzalike illness fulminant pneumonia caused by concomitant infection with influenza b virus and staphylococcus aureus preceding respiratory infection predisposing for primary and secondary invasive haemophilus influenzae type b disease performance of the binax now streptococcus pneumoniae urinary antigen assay for diagnosis of pneumonia in children with underlying pulmonary diseases in the absence of acute pneumococcal infection evaluation of rapid assay for detection of streptococcus pneumoniae urinary antigen among infants and young children with possible invasive pneumococcal disease the utility of chest radiography in the follow-up of pneumonia references s58 provisional guidelines from bis/bts/hpa in collaboration with the department of health value of radiological follow up of childhood pneumonia re-emergence of fatal human influenza a subtype h5n1 disease recovery of drug-resistant influenza a virus during therapeutic use of rimantadine high 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aerosolized ribavirin in young children hospitalized with influenza: a double-blind, multicenter, placebo-controlled trial efficacy of antibiotics against influenza-like illness in an influenza epidemic effect of maclorides on duration and resolution of symptoms and complication of pneumonia in children with influenza a randomised controlled equilanence trial to compare oral and intravenous treatment and the direct and indirect costs of treating children with community acquired pneumonia: pivot trial human influenza a h5n1 virus related to a highly pathogenic avian influenza virus outbreak of avian influenza a (h5n1) virus infection in hong kong in 1997 avian influenza a challenge to global health care structures in addition, antivirals may be considered in the following exceptional situations:(i) patients who are unable to mount an adequate febrile response, e.g. the immunocompromised or very elderly, may still be eligible for antiviral treatment despite the lack of documented fever. (ii) severely ill and immunosuppressed patients, including those on long-term corticosteroid therapy, may benefit from antiviral therapy commenced later than 48 hours after the onset of ili. (iii) severely ill children <1 year old. (parents must be informed that oseltamivir is not licensed for children <1 year old.) the first recorded instance of human infection by avian influenza h5n1 occurred in may 1997 in hong kong. the first patient was a 3-year old child who presented initially with symptoms of fever, sore throat and abdominal pain. he later developed reye's syndrome, ards, multi-organ failure and eventually died 166 . a total of 18 persons were subsequently infected before the outbreak ended in december 1997 126, 167 . half the patients were aged 18 years and below and only two were aged over 50 years. abdominal symptoms, such as diarrhoea, vomiting and abdominal pain, were described in ten (56%) patients. eleven (61%) had a severe illness characterised by pneumonia occurring within 14 days of symptom onset, lymphopenia, deranged liver function tests and a high mortality [six (55%) of 11 patients with pneumonia]. secondary bacterial infections were not identified as the cause of the pneumonias.the most recent human outbreak of influenza a (h5n1) infection began in december 2003. the clinical features of hospitalised patients infected by the re-emergent avian influenza a (h5n1) in 2004 were similar to those described in patients in 1997 (table a10 .1). children and young adults were the main groups affected. gastrointestinal symptoms were common. the presence of lymphopenia and deranged liver function tests was again associated with a poorer prognosis 125 .since december 2003, over 150 cases had been reported to the who 168 . the mortality rate among hospitalised patients has been generally high (>40%). death has occurred an average of ten days after the onset of illness and most patients have died of progressive respiratory failure.there has been a review of avian influenza a (h5n1) infection in humans up until september 2005 55 . updated information can be found at www.who.int/csr/disease/avian_influenza/en/. key: cord-000254-bufbjdmw authors: clement, annick; nathan, nadia; epaud, ralph; fauroux, brigitte; corvol, harriet title: interstitial lung diseases in children date: 2010-08-20 journal: orphanet j rare dis doi: 10.1186/1750-1172-5-22 sha: doc_id: 254 cord_uid: bufbjdmw interstitial lung disease (ild) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. these disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. typical features of ild include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ild. consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. several classifications for ild have been proposed but none is entirely satisfactory especially in children. the present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. the following diagnostic grouping is used to discuss the various causes of pediatric ild: 1) exposure-related ild; 2) systemic disease-associated ild; 3) alveolar structure disorder-associated ild; and 4) ild specific to infancy. therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. the outcome is highly variable with a mortality rate around 15%. an overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy. interstitial lung disease (ild) in infants and children represents a heterogeneous group of respiratory disorders that are mostly chronic and associated with high morbidity and mortality (around 15%) [1, 2] . these disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. typical features of ild include the presence of diffuse infiltrates on chest radiograph, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange [3] . there have been many different approaches to the classification of ild, with major shifts based on clinical investigation, improvement in chest imaging, and collaboration with pathologists. in 1998, katzenstein and myers proposed four histopathologically distinct subgroups of idiopathic interstitial pneumonias: usual interstitial pneumonia (uip), desquamative interstitial pneumonia (dip) and a closely related pattern termed respiratory bronchiolitis-associated ild, acute interstitial pneumonia (formerly hamman-rich syndrome), and non specific interstitial pneumonia (nsip) [4] . in 2002, an international multidisciplinary consensus classification of idiopathic interstitial pneumonias was proposed by the american thoracic society (ats)/european respiratory society (ers) [5] . this classification defined a set of histologic pattern that provided the basis for clinico-radiologic-pathologic diagnosis, with the final pathologic diagnosis being made after careful correlation with clinical and radiologic features. however, as discussed in several reports, the classification schemes of adult ild are not satisfactory for the pediatric cases which seem to comprise a broader spectrum of disorders with a more variable clinical course [6] . in addition, pediatric histologic patterns often do not resemble pathologic features of lung tissues from adults and some forms are only observed in children younger than 2 years. among the proposed classifications for pediatric ild, one strategy frequently used is to separate the primary pulmonary disorders and the systemic disorders with pulmonary involvement. recently, an additional group has been introduced which is based on the concept that some pediatric ild are observed more frequently in infants, while others are more specific to older children. the last ers monography on ild provided a chapter on pediatric classification which is based on a clear distinction between children aged 0-2 years and children over 2 years-old [7] . indeed the stage of lung development and maturation should be taken into consideration when approaching a diagnosis of pediatric ild. in this view, a new term "diffuse lung disease" has recently been introduced that comprises a diverse spectrum of lung disorders with impaired gas exchange and diffuse infiltrates by imaging. these disorders, more prevalent in young children, include diffuse developmental disorders, lung growth abnormalities, neuroendocrine cell hyperplasia and pulmonary interstitial glycogenosis, surfactant dysfunction disorders, disorders related to systemic diseases, disorders of immunocompromised host, and disorders of normal host caused by various insults such as aspiration syndrome or infections [8] . some diseases are mostly observed in older children such as systemic diseases, idiopathic disorders as described in adults (dip, uip, nsip and lymphoid interstitial pneumonia (lip)), unclassifiable ild and also infectious disorders [9] . it is important to point out that the pathologic processes underlying the so-called diffuse lung diseases involve not only the alveolar structure but also the distal part of the small airways and the conducting zone, i.e. the terminal bronchioles. terminal bronchioles are lined with a simple cuboidal epithelium containing clara cells, basal cells and a limited number of ciliated cells. clara cells secrete nonsticky proteinaceous compounds to maintain the airway in the smallest bronchioles, which constitute the quiet zone between the conducting and the respiratory lung zones [10] . the terminal bronchioles are surrounded by a spiral of smooth muscle. each of the terminal bronchioles divides to form respiratory bronchioles which contain a small number of alveoli. consequently, the term of diffuse lung disease refers to disorders that can affect both the distal part of the conducting and the respiratory lung zones, and include ild as well as pathological processes leading to obstruction/ obliteration of small airways [8] . therefore, diffuse lung diseases encompass a broader group of diseases than ild which refers to disorders that affect the respiratory function of the lung and consequently the pulmonary structure responsible of the diffusion of gases between blood and air (i.e. the alveolar epithelium, the interstitium, and the pulmonary capillary endothelium). the present review focuses on ild in immunocompetent children, and excludes pulmonary consequences of previous lung injury in situations of chronic aspiration syndromes, resolving acute respiratory distress syndrome, and bronchopulmonary dysplasia. an estimated prevalence of 3.6 per million has been reported by dinwiddie and coworkers through a national survey of chronic ild in immunocompetent children in the united kingdom and ireland over a three year period (1995) (1996) (1997) (1998) [1] . this prevalence is certainly under-estimated due to the lack of standardized definitions and the absence of organized reporting systems. from the limited published data composed mainly of case reports and small series, it seems that pediatric ild occurs more frequently in the younger age and in boys [11] . in addition, nearly 10% of cases appear to be familial [12] . the understanding of the mechanisms underlying the development and progression of ild remains elusive [13, 14] . indeed, for a long time, chronic ild and pulmonary fibrosis were believed to result mainly from chronic inflammation following an initial injury to the alveolar epithelial lining [15, 16] . in cases of limited injury, it was thought that the reparative attempt could reverse the trend toward fibrosis. by contrast, in situations of continuing injury, the repair process driven by inflammatory molecules produced by the local cells will result in scarring and structural changes. therefore, by targeting the inflammatory response, the belief was that fibrosis could be prevented or controlled. this theory explains the large use of anti-inflammatory therapy with, however, limited clinical efficacy. based on clinical and experimental observations, a new paradigm has progressively emerged with the alveolar epithelium being viewed as a key actor in the development of ild [17] [18] [19] . following injury, alveolar epithelial cells (aec) may actively participate in the restoration of a normal alveolar architecture through a coordinated process of re-epithelialization, or in the development of fibrosis through a process known as epithelial-mesenchymal transition (emt) [20] . complex networks orchestrate emt leading to changes in cell architecture and behaviour, loss of epithelial characteristics and gain of mesenchymal properties. the reasons for epithelial cell loss and inappropriate re-epithelialisation are still debated, but ongoing apoptosis is believed to be a key component in the progression of the disorder [21] . prolonged denudation of the basement membrane contributes to altered interactions and cross-talk between aecs and mesenchymal cells, resulting in profound modifications of cell functions with imbalanced production of oxidants, proteases, and polypeptide mediators including cytokines and growth factors such as transforming growth factor (tgf)-β and endothelin (et)-1. a consequence is the perpetuation of a vicious cycle with tgf-β promoting epithelial cell apoptosis, which in turn increases the local production of tgf-β [22] . et-1 is also considered to be an important actor, based on the current knowledge of its numerous functions including fibroblast and smooth muscle cell mitogen, and stimulant of collagen synthesis [23, 24] . recent studies showed that et-1 is produced by aec, and could induce alveolar emt via stimulation of endogenous tgf-β production. ild may be caused by myriad etiologies with differing prognoses and natural history. indeed, multiple factors may injure the alveolar epithelium and initiate the development of ild [25] . the initiating injury can be introduced through the airways and the circulation, or can occur as a result of sensitization. consequently, the mechanisms underlying disease progression will be influenced by the causative event as well as by the host and the environment. these mechanisms are developed through interactions of multiple pathways, which include apoptotic pathways, developmental pathways, and endoplasmic reticulum (er) associated pathways ( figure 1 ). apotosis plays a central role in lung remodeling associated with ild [26] . an important molecule in the events associated with epithelial cell apoptosis is tgf-β, which is overexpressed in ild. downstream events linked to upregulation of tgf-β include modifications in the expression of various components of the cell cycle machinery, mainly the cyclin-dependent kinases (cdk) system that plays an essential role in ensuring proper cell cycle progression. recently, much work has been focused on the protein p21cip1, a member of the cdk inhibitor family. this protein promotes cell cycle arrest to apoptosis in cases of cellular dna damage. interestingly, upregulation of p21cip1 has been reported in the lung tissues of patients with pulmonary fibrosis, primarily in hyperplastic alveolar epithelial cells [27] the increased expression of p21cip1 can favour the process of epithelial cell apoptosis. apoptotic cells can also produce tgf-β. a consequence would be the perpetuation of a vicious cycle with tgf-β promoting epithelial cell apoptosis, which in turn increases the local production of tgf-β. recently, it has been suggested that genes associated with lung development and embryonic pathways could be involved in aberrant epithelium-mesenchymal crosstalk and epithelial plasticity, and could therefore participate in the development of chronic ild. selman and coworkers reported that lung fibrosis is characterized by enrichment for genes associated with cell adhesion, extracellular matrix, smooth muscle differentiations, and genes associated with lung development [28] [29] [30] [31] . during emt in the embryonic period, cells undergo a switch from a polarized epithelial phenotype to a highly motile mesenchymal phenotype [32] . molecular processes governing emt are induced by a cooperation of receptor tyrosine kinases or oncogenic ras (rtk/ras) pathway and tgf-β signaling [33] . recently, additional pathways and effectors have been reported to play a role in the induction of emt, such as wnt//β-catenin, notch and sonic hedgehog signalling [34] . recent reports strongly suggest that the er stress may represent an important mechanism of the altered repair process observed in the alveolar epithelium of fibrotic lung [35] . situations associated with abnormal regulation of the cascade of events leading to the formation of mature protein result in either misfolding or mistargeting of the protein. these events trigger induction of intracellular aggregate formation and er stress, which can lead to cell death through apoptosis and autophagic pathways [36, 37] . several stimuli including oxidant-antioxidant imbalance, viral proteins, inflammatory molecules, nutrient deprivation may induce er stress [38, 39] ( figure 2 ). among the cytoprotective mechanisms available are the er chaperones such as binding immunoglobulin protein (bip). interestingly, mutant bip mice have been reported to die within several hours of birth from respiratory failure due to impaired secretion of pulmonary surfactant by type 2 aec. in these animals, expression of surfactant protein (sp)-c was reduced and the lamellar bodies were malformed, indicating that bip figure 2 alveolar structure disorder-associated ild and er stress. the (endoplasmic reticulum) er and its protein maturation machinery allow the synthesis of mature secretory and membrane proteins with specific folded conformation. in situations of stress induced by genetic mutations or environmental factors, unfolded or misfolded proteins are retained in the er and induce a defence mechanism called the er stress response. the induction of er chaperones is critical to increase the er folding capacity allowing the production of correctly folded protein. when this defence mechanism is impaired, the misfolded proteins can either be degraded by the proteasome or form protein aggregates. protein aggregates are toxic and can cause conformational diseases. within the alveolar epithelium, misfolding of sp-c could trigger induction of intra-cellular aggregate formation and er stress, with consequently development of alveolar structure disorder-associated ild and conformational disease. plays a critical role in the biosynthesis of surfactant [40] . several recent reports suggest the possible implication of er stress in ild, with activation of stress response markers in fibrotic lung tissues. it is now well established that surfactant dysfunction plays an important role in the development and progression of ild. pulmonary surfactant is a multimolecular complex constituted of phospholipids and proteins secreted by type 2 aec into the alveolar space. it assures alveolar stability by reducing surface tension along the epithelial lining and this role involves mainly the lipids and the specific hydrophobic sp, sp-b and sp-c. other important players in surfactant metabolism include the atp-binding cassette, sub-family a, member 3 (abca3) and the thyroid transcription factor 1 (ttf-1). surfactant deficiency can be induced by a number of primitive and secondary mechanisms. among them are genetic defects with mutations in sp-b gene (sftpb) as well as genes coding for sp-c (sftpc), abca3, and ttf-1 [41] [42] [43] . more than 30 sftpb (located on chromosome 2) mutations have been identified among patients with a congenital deficiency in sp-b. for sftpc located on chromosome 8, at least 35 mutations have been described, localized primarily in the coohterminal brichos domain [44, 45] . a proposed function of the brichos domain is a chaperone-like activity, which could prevent misfolding and aggregation of the parent protein. alterations in the brichos domain could therefore lead to diseases through mechanisms related to abnormal protein processing and cell toxicity [46] . recently, several studies have also documented the role of abca3 deficiency in ild. abca3 functions in the transport of surfactant lipids into lamellar bodies and is required to maintain pulmonary surfactant phospholipid homeostasis. another contributor of ild is ttf-1 (nk2 homeobox 1) dysfunction. ttf-1 is a critical regulator of transcription for the surfactant protein sp-b and sp-c. it is encoded by a gene located on chromosome 14q13 and is composed of three exon and two introns [47] . it is expressed in the thyroid, brain and lung. stem cell dysfunction represents a new domain of investigation. alveolar epithelium regeneration and repair requires activation and proliferation of tissue-resident (progenitor) cells and their differentiation to replace the damaged cells [48] . however, unlike cancer cells, stem cells are not immortal and display decreasing telomere length with aging [49] . telomere shortening has been documented to be associated with reduced capacity for stem cell renewal, and decreased activity of telomerase, the polymerase responsible for telomere maintenance. the stem cells of the alveolar epithelium are the type 2 aec, and expression of telomerase has been documented in these cells [48] . experimental studies have also indicated that telomerase is expressed mainly during lung development with a peak expression before birth followed by a decrease to nearly undetectable levels in mature alveolar epithelium. interestingly, telomerase expression and activity could be reinduced in normal quiescent type 2 aec exposed to oxidative stress [50] . the current understanding is that a population of type 2 aec may have the capacity to survive injury through telomerase activation, and consequently may be responsible for repopulation of the damaged alveolar epithelium. on the basis of reports of pulmonary disorders in dyskeratosis congenita (a rare hereditary disease of poor telomere maintenance), recent and exciting findings have documented mutations in the telomerase gene in familial idiopathic pulmonary fibrosis [51] . in addition, it is likely that environmental factors such as inflammation, oxidative stress, or virus infection may modify telomerase activity and account for the development of organ-specific disease associated with telomerase dysfunction. in this view, new data in chronic respiratory diseases support the concept that alveolar stem cell dysfunction may play an important role in the rate of progression or severity in ild [52] . the question whether telomerase mutations or telomere dysfunction may be implicated in pediatric ild needs to be addressed in prospective studies, one possible tool being determination of telomere length in circulating leukocytes. the frequency of lung fibrotic disorders is much lower in children than in adults. some clinical situations have features certainly unique to children, but many of these diseases overlap their adult counterparts with the primary event being injury and damage of the alveolar epithelium [11, 13] . yet, the overall outcome and prognosis of the diseases in children are thought to be less severe than in adult patients. in addition, pediatric ild is more responsive to therapeutic strategies than adult ild [9] . these differences may be explained by the types of initial injury, which may not be similar due to changes in the host environment. another explanation is the modifications of the process of wound healing with age. comparison of the response to injury in foetal and adult skin shows clear differences [53] . skin wound healing in the foetus is characterized by complete regeneration of the skin and the absence of scar formation. progressively with age, the skin looses the capacity to regenerate the original tissue architecture with the result being scar formation that extends outside the wound bed. the process of healing involves the coordinated regulation of cell proliferation and migration and tissue remodeling, predominantly by polypeptide growth factors [54] . the slowing of wound healing that occurs in the aged may be related to changes in the activity of these various regulatory factors. in a study on the role of aging in the development of cardiac fibrosis in the rabbit, differences in the cascade of events leading to myocardial remodeling were observed, with mainly the presence of more myofibroblasts synthesising collagen and expressing high levels of tgf-β in older animals [55] . a study of growth factors involved in skin wound healing in young and aged mice also showed age-dependent changes. expression of all the fibroblast growth factors was diminished in aged mice, even in healthy skin. in addition, the post-wound regulation of expression of these factors and of tgf-β was less pronounced and slower than in young mice. these findings are in agreement with data observed in muscle that indicated significant alterations in the tgf-β production with age [56, 57] . other potential mechanism is linked to the observation that injury in adult tissues does in certain circumstances stimulate tissue regeneration, depending on the presence of small subsets of primitive stem cells. stem cells are the self-renewing, primitive, undifferentiated, multipotent source of multiple cell lineages [49] . while such cells are critical for development and growth through childhood, residual pools of adult stem cells are hypothesized to be the source of the frequently limited tissue regeneration and repair that occurs in adults [58] . unlike embryonic stem cells, adult stem cells are not immortal, and show decreasing telomere length with increasing age. the naturally limited replacement capacity of such endogenous stem cell pools may occur via exhaustion of the stem cell pool or arise as a consequence of inherited or acquired mutations that alter proper stem cell function [59] . the limited life span of cells may result from replicative senescence in response to various stresses including dna damage, oxidants, and telomere erosion [52] . all these forms of injury have been documented in the lung from adult patients with ild. the prevalence of children ild is higher in the younger patients: more than 30% of patients are less than 2 years at diagnosis, as recorded by the recent ers task force. 7% have parental consanguinity and nearly 10% of case siblings were affected by similar diseases. there is a male predominance with a sex ratio of 1.4. the presenting clinical manifestations are often subtle and nonspecific. the onset of symptoms is, in most cases, insidious and many children may have had symptoms for years before the diagnosis of ild is confirmed. however, the majority of patients has symptoms for less than one year at the time of initial evaluation. the clinical manifestations vary from asymptomatic presentation with radiological features suggestive of ild to more characteristic presence of respiratory symptoms and signs such as cough, tachypnea and exercise intolerance [9, 60] . these varying presentations are also reflected in the report published by fan et al. who systematically evaluated the clinical symptoms and physical findings of 99 consecutive children with ild [2] . common symptoms at presentation included cough, dyspnea, tachypnea and chest wall retraction, exercise limitation and frequent respiratory infections. cough is observed in almost 75% of the patients, is normally non-productive and does not disturb sleep. tachypnea is observed in 80% of patients and is usually the earliest and most common respiratory symptom. unexplained fever is also reported in almost one third of infants. failure to thrive (37%), tiring during feeding and weight loss are also common symptoms, mainly in young patients. although a history of wheezing may be elicited in almost 50% of the patients, wheezing is documented by physical examination in only 20% of the cases. the frequent clinical findings are inspiratory crackles (44%), tachypnea and retraction. in a child with a normal birth history, these are strongly suggestive of ild. other findings associated with an advanced stage of lung disease include finger clubbing (13%) and cyanosis during exercise or at rest (28%) [9, 61] . during physical examination it is essential to check the presence of associated non-respiratory symptoms such as joint disease, cutaneous rashes, and recurrent fever suggestive of collagen-vascular disorders. details should also be obtained on precipiting factors such as feeding history, infections, or exposure to dust and drugs. in addition, information on relatives or siblings with similar lung conditions should be gathered. plain radiographs are usually performed in a child suspected of ild at first presentation, but the information provided is often limited and the key chest imaging tool for diagnosis is the high resolution computed tomography (hrct), which can visualize the parenchymal structure to the level of the secondary pulmonary lobule. hrct technique for ild diagnosis has been extensively discussed [62] [63] [64] . to optimise spatial resolution, there is a general agreement to use thin sections, the smallest field of view and a sharp resolution algorithm. the most common hrct feature of ild is widespread ground-glass attenuation. intralobular lines, irregular interlobular septal thickening and honeycombing are less common findings. large subpleural air cysts in the upper lobes adjacent to areas of ground-glass opacities have been also reported in young children with ild. these cysts are interpreted as paraseptal or irregular emphysema. hrct is useful for ild diagnosis and selection of lung area to be biopsied. it is proposed that it also may contribute to monitor disease activity and/or severity. however, evaluation is still needed to support a role of hrct as a follow up tool in pediatric patients. pulmonary function testing (pft) techniques are well established in children and adolescents. however, children aged 2-6 years represent a real challenge in pulmonary function assessment as they cannot be sedated and find it difficult to cooperate with all respiratory manoeuvres. in 2007, an ats and ers statement on pft in preschool children summarized the current knowledge on the pft techniques suitable for young children [65, 66] . although pft does not provide specific information, it represents a useful investigation for both the diagnosis and the management of ild [11] . generally, in ild, pulmonary function abnormalities reflect a restrictive ventilatory defect with reduced lung compliance and decreased lung volumes [67] [68] [69] . vital capacity (vc) is variably diminished; the decrease in total lung capacity (tlc) in general is relatively less than in vc. functional residual capacity (frc) is also reduced but relatively less than vc and tlc, and residual volume (rv) is generally preserved; thus the ratios of frc/tlc and rv/tlc are often increased. airway involvement is observed only in a minority of patients. lung diffusing capacity of carbon monoxide (dlco) or transfer factor (tlco) is often markedly reduced and may be abnormal before any radiological findings. however, dlco corrected for lung volume may also be normal in many children. hypoxemia as defined by a reduced resting arterial oxygen saturation (sao 2 ) or a reduced resting arterial oxygen tension is often present. hypercarbia occurs only late in the disease course. during exercise the above described dysfunctions become even more pronounced. thus, gas exchange during exercise might be a more consistent and sensitive indicator of early disease [3] . bronchoalveolar lavage (bal) usefully provides specimens for cytological examination, microbial cultures, and molecular analysis. besides infections, bal can be of diagnostic value in several situations. in the context of pulmonary alveolar proteinosis, bal abnormalities are characterized by milky appearance fluid, abundant proteinaceous periodic acid schiff positive material, and presence of foamy alveolar macrophages (am) [70] . bal can also be diagnostic for pulmonary alveolar haemorrhage [11] . this diagnostic is easy when the bal fluid has a bloody or pink color, but its gross appearance may be normal. microscopic analysis may then be of value by documenting the presence of red blood cells in am or haemosiderin laden am [71] . among other situations, the diagnosis of langerhans cell histiocytosis can be performed with the use of the monoclonal antibodies revealing the presence of cd1a positive cells (in more than 5% of the bal cells) [72] . lipid disorders with lung involvement represent another indication of bal. this includes congenital lipid-storage diseases (gaucher's disease and niemann-pick disease) or chronic lipid pneumonia due to chronic aspiration [73, 74] . however, in cases of aspiration syndromes, the presence of lipid laden am is sensitive but not specific [75] . in other pathological situations, bal can usefully serve to direct further investigations. accumulation of bal t-lymphocytes with prevalence of cd4+ cells is suggestive of sarcoidosis, whilst prevalence of cd8+ cells is suggestive of hypersensitivity pneumonitis [76] . also, an increase in bal eosinophils suggests pulmonary infiltrates associated with eosinophilia syndromes [77] . depending of the underlying diseases, a number of cellular and molecular investigations can be proposed including the studies of various surfactant components, phospholipids and apoproteins [78] . with increasing recognition of the different patterns of ild and their clinical significance, histological investigation has become increasingly important. depending on disorder presentation, biopsy may concern more accessible organs than the lung such as the skin or the liver in sarcoidosis. histological evaluation of lung tissue usually represents the final step in a series of diagnostic approaches. different methods may be used to obtain lung tissue. the major difference between individual methods lies mainly in balancing invasiveness against the potential for obtaining adequate and sufficient tissue for diagnosis. the techniques of choice are open lung biopsy and video assisted thoracoscopy biopsy. in children, open lung biopsy usually provides sufficient tissue with few complications related directly to the biopsy procedure [79] . video assisted thoracoscopy biopsy is an alternative to open lung biopsy, and it has been shown that the procedure can be safely performed, even in small children [80] . the place of other methods like transbronchial lung biopsy and percutaneous needle lung biopsy in appropriate diagnosis of pediatric patients with ild has to be established [81] [82] [83] . the lung histological patterns that can be observed in ild have been reviewed by the ats/ers [5] . in children, they include mainly: dip, nsip, and lip. dip is characterized by airspaces filled with am, thickened alveolar septa, scattered mixed inflammatory cells and minimal fibrosis. many alveolar spaces are lined by hyperplastic type 2 aec. recently, association with surfactant disorders has been reported [41, [84] [85] [86] . nsip encompasses a broad spectrum of abnormalities with varying degrees of alveolar wall inflammation or fibrosis. the cellular pattern of nsip is characterized by mild to moderate interstitial chronic inflammation and type 2 aec hyperplasia in inflammation areas. it has been reported in a variety of underlying conditions including connective tissues diseases and surfactant disorders. lip features include a marked diffuse infiltrate of mature lymphocytes, plasma cells and histiocytes within the pulmonary interstitium, particularly the alveolar walls. they are often associated with either connective tissues disorders or immunodeficiency states, both congenital and acquired [9] . another pattern described mainly in adults is diffuse alveolar damage (dad), which includes diffuse homogeneous thickening of alveolar interstitial walls with myofibroblast accumulation, prominent type 2 aec hyperplasia and atypia, and hyaline membranes containing surfactant proteins and cellular debris [87] . usual interstitial pneumonia (uip) is rare in children [88] . it is characterized by severe remodeling of the alveolar structure with heterogeneous appearance consisting of contiguous areas of normal lung, dense scarring, and bronchiolar abnormal proliferation. interstitial inflammation is usually mild to moderate. histologic patterns of ild unique to infancy are described below. laboratory tests are used to exclude a number of respiratory diseases in childhood that does not typically present with ild such as chronic aspiration syndromes, resolving acute respiratory distress syndrome, tuberculosis, cystic fibrosis, bronchopulmonary dysplasia and diffuse pulmonary disease such as cystic fibrosis. laboratory tests also verify the absence of immunodeficiencies [3] . when these conditions have been eliminated, the spectrum of investigations that should be performed for the diagnostic approach will be guided by the history and clinical presentation in each individual child. these investigations are discussed below for the various disorders. in addition, an increasing number of blood and bal biomarkers for evaluation of disease severity and progression is currently investigated. the studied molecules include various cytokines and chemokines, surfactant protein d, krebs von den lungen-6 antigen (kl-6), matrix metalloproteinases mmp1 and mmp7 and defensins [89] [90] [91] [92] . a large number of pathological situations can impair gas exchange and contribute to progressive lung damage and ild. consequently, diagnosis approaches need to be organized by cause, with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. indeed, in a number of pathological situations, no final diagnosis is proposed and the conclusion reported by the physician in charge of the patient is ild of unknown cause. however, information from recent studies highlights the concept that lung insults caused by substances from the environment or in the context of systemic diseases are largely under-estimated and should be more often discussed considered in the diagnostic process. based on this consideration, the following diagnostic grouping for pediatric ild can be considered 1) exposure-related ild; 2) systemic disease-associated ild; 3) alveolar structure disorder-associated ild; and 4) ild specific to infancy. accordingly, a step-by-step etiological diagnostic approach is required and is summarized in figure 3 . once the diagnosis of ild is established on clinical, radiological, and functional findings, a careful history should be obtained for potential exposure-related diseases leading to discuss the need for specific serum antibodies against offending antigens. the following step focuses on the search for systemic disease associated ild, oriented by the presence of clinical and functional extra-pulmonary manifestations. in such situations, additional investigations should include specific serum antibodies and possibly tissue biopsies in organs other than the lung. finally, elimination of these 2 groups of causes with a lung restricted expression of the disease allows discussing the potential interest of a lung biopsy. exposure-related disease refers to diseases caused by a sufficient level of exposure (dose) to components with target organ contact, and subsequent biologic changes and clinical expression. many agents have been associated with pulmonary complications of various types including ild. the adult literature has provided extensive lists of candidate molecules [93] . in children, the potential involvement of these molecules is not similar as the environmental conditions and the use of therapeutic drugs differ. it is important to point out that exposure-related diseases are certainly under-estimated in the pediatric age. one reason is linked to the fact that the diagnosis is less often discussed than in adults as pediatricians and other child health care providers do not usually have the expertise necessary to take an environmental history. in this review, the most frequent causes of exposure-related ild are discussed. hypersensitivity pneumonitis (hp) is a cell-mediated immune reaction to inhaled antigens in susceptible persons [94, 95] . in children, hp is often associated with exposure to antigens in the home environment as well as with certain hobbies. the most frequent types of hp include bird fancier's diseases, humidifier lung diseases, and chemical lung diseases. bird fancier's diseases are induced by exposure to birds with the antigens being glycoproteins in avian droppings, and on feathers. importantly, respiratory symptoms in exposed patients who have only one pet bird at home should raise the suspicion of hp [96] . humidifier lung diseases (air conditioner lung, misting fountain lung, basement lung diseases) are caused mainly by free-living amoeba and nematodes, as well as bacteria and fungi. chemical lung diseases can be induced by various inorganic antigens such as those from vaporized paints and plastics. low-molecular-weight chemicals may react with proteins in the airways, thus forming complete antigens. once exposure history is obtained, additional information is required and includes biologic tests allowing measurements of environmental contaminants and interpretation of the results by environmental medicine experts. as hp is believed to be an adult disease, children are often diagnosed at the chronic stage of the disease resulting of a long-term exposure to low levels of inhaled antigens. children can develop subtle interstitial inflammatory reactions in the lung without noticeable symptoms for months [97] . clinical features in the classic form include non productive cough, dyspnea, malaise, asthenia and occasional cyanosis [95] . lung function abnormalities are not specific and appear similar to changes observed in other ild. hrct abnormalities vary from ground glass attenuation predominantly in the mid-upper zone to nodular opacities with signs of figure 3 search for ild etiology in children. ild is defined by the presence of diffuse infiltrates on chest radiographs or chest high resolution computed tomography, and abnormal pulmonary function tests with evidence of a restrictive ventilatory defect (in older children) and/or impaired gas exchange. the search for etiology requires a systematic step-by-step diagnostic strategy for identifying: exposure-related ild; systemic disease-associated ild; alveolar structure disorder-associated ild; and ild specific to infancy. air-trapping [62, 63, 98] . laboratory tests focus mainly on the search for serum-precipitating igg antibodies against the offending antigen [95] . however, the presence of these antibodies is considered to be of questionable clinical relevance for diagnosis, as it is observed in up to 50% of serum samples of exposed but asymptomatic individuals. bal cell profile study typically shows an increase in total cell count with a remarkable elevation in the percentage of lymphocytes often over 50% with a decreased cd4/cd8 ratio [95, 97] . however, in contrast to studies in adults, the cd4/cd8 ratio could be within the normal range for children [76] . histopathologic evaluation of lung tissue is usually not necessary for the diagnosis of hp. at the present time, there is no diagnostic test that is pathognomonic for hp, and only significant predictors of hp are identified. the most significant diagnostic tool is a detailed environmental exposure history. other diagnostic features include: positive precipitating antibodies to the offending antigen; recurrent episodes of symptoms; symptoms occurring 4-8 h after exposure; occurrence of diffuse parenchymal lung disease by lung function and hrct; bal abnormalities with lymphocytic alveolitis and increased cd8+ t cells. medication, drug, radiation and tobacco exposure drugs used in inflammatory or cancer pediatric diseases can cause ild. they include anti-inflammatory agents (e.g. aspirin, etanercept), immunosuppressive and chemotherapeutic agents (e.g. azathioprine, methotrexate, cyclophosphamide), antibiotics, cardiovascular agents, and, for teenagers, illicit drugs [99, 100] . there are no distinct clinical, radiographic or pathologic patterns, and the diagnosis is usually made when a patient is exposed to medication known to result in lung disease, with a timing of exposure appropriate for disease development and elimination of other causes of ild. treatment relies on avoidance of further exposure and corticosteroids in markedly impaired patients. exposure to therapeutic radiation in the management of pediatric cancer may also results in ild. patients presenting within 6 months of therapy generally have radiographic abnormalities with ground glass patterns in both radiation-exposed and unexposed tissue [101] . the association between tobacco use and ild is less well appreciated than the relation with chronic obstructive pulmonary disease (copd). in addition, pediatric patients do not usually have a significant smoking history to develop respiratory disorders [102] . connective tissues disorders (ctd) are a heterogeneous group of immunologically mediated inflammatory diseases. their origins are multifactorial with genetic, constitutional and environmental elements contributing to their development. ctd refers to any disease that has the connective tissues of the body as a primary target of pathology. the connectives tissues are composed of two major structural proteins, elastin and collagen, with different types of collagen proteins in each tissue [103] . many ctd feature abnormal immune system activity associated with inflammation. pulmonary manifestations of ctd may include both vascular and interstitial components. from recent reports, the incidence of ild in the context of ctd appears to be higher than previously appreciated [104, 105] . importantly, ild may precede the development of clinically obvious ctd, sometimes by months or years. table 1 provides information on suggestive clinical and serological features in selected conditions. the main disorders to be considered in childhood are rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. the other include sjögren syndrome, dermatomyositis and polymyositis, ankylosing spondylitis, and mixed connective tissue disease. rheumatoid arthritis rheumatoid arthritis (ra) is an inflammatory disorder defined by its characteristic diarthroidal joint involvement. it is the most common ctd in children, but pulmonary involvement is less frequent than in adults. genetic and environmental factors seem to be important contributors of disease progression, with influence of sex (more frequent in male), presence of two copies of the hla-drb1 "shared epitope" (hla-dr se) and anticyclic citrullinated peptide antibody (anti-ccp), and possibly tobacco exposure [106, 107] .almost 50% of patients with ra have specific serologic abnormalities several years before the onset of joint symptoms, and the findings of elevated serum levels of igm rheumatoid factor or anti-ccp is associated with a high risk for the development of ra [107] . systemic sclerosis systemic sclerosis (ssc) is characterized by a progressive dermatologic abnormality [108] . its etiology remains unknown; it is believed to be a complex disease in which interactions between environmental, auto-immune, and genetic factors result in various disease phenotypes [109] . although it is a rare disease in childhood, the diagnosis is based on skin disease. cardiopulmonary complications are common and have been associated with death in young patients. almost all patients with ssc have serum antinuclear antibodies. the other autoantibody markers are listed in table 1. recently, the presence of anti-dna topoisomerase ii autoantibody has been reported to be a key factor in the development of ild, in association with class ii mhc status (hla-dr3, hla-dpbi) [110] . systemic lupus erythematosus systemic lupus erythematosus (sle) is an auto-immune disorder characterized by the involvement and dysfunction of multiple organ systems. the mechanisms of tissue injury involve autoantibody production and immunocomplex formation leading to an inflammatory process. diverse clinical phenotypes are observed, including a variety of mucocutaneous lesions, non erosive arthropathy, renal disease (glomerulonephritis and interstitial nephritis), lung disease, pericarditis, and a spectrum of neurologic disorders. laboratory abnormalities are characterized by the presence of antibodies reactive to nuclear (ana) and cytoplasmic antigens. pulmonary vasculitis are observed in vasculitic syndromes that preferentially affect small vessels (arterioles, venules, and capillaries). they include the anti-neutrophil cytoplasmic antibody (anca)-associated vasculitis (wegener's granulomatosis, churg-strauss syndrome, and microscopic polyangitis) that share histologic similarities without immune deposits; anti-glomerular basement membrane (gbm) disease; henoch-schönlein purpura and cryoglobulinemia vasculitis. vasculitic syndromes that affect large/medium vessels (such as kawasaki's disease, polyarteritis nodosa) only occasionally affect the lung [111] . wegener's granulomatosis wegener's granulomatosis (wg) is a rare disease of uncertain cause. it seems to affect children as much as adults with an increasing reported incidence around 2.75 cases/million/year, mostly in teenagers with a reported median age of 14.2 years (4-17 years) [112, 113] . it is characterized by inflammation in a variety of tissues including blood vessels (vasculitis). wg primarily affects the upper respiratory tract, lung, and kidneys. the diagnosis is based on the combination of symptoms and a biopsy of affected tissue with necrotising granulomatous vasculitis in the absence of an infectious etiology. the diagnosis is further supported by positive blood tests for cytoplasmic-staining (c)-anca pr3 type [114] . churg-strauss syndrome churg-strauss syndrome (css) is a granulomatous small-vessel vasculitis. the cause of this allergic angiitis and granulomatosis is not known, but autoimmunity is evident with the presence of hypergammaglobulinemia, increased levels of immunoglobulin e (ige), and perinuclear-staining (p)-anca. the diagnosis relies on biopsy evidence for vasculitis and at least 4 criteria among the following: moderate to severe asthma, blood eosinophilia (at least 10%), and nonfixed pulmonary infiltrates with extravascular eosinophils on biopsy [115] . twenty-nine pediatric cases have been reported so far in the literature, with lung involvement in 72% of [116] . anti-glomerular basement membrane disease goodpasture syndrome is a rare disease that involves rapidly progressive kidney failure along with lung disease and is characterized by the deposition of anti-gbm antibodies. several cases have been reported in the pediatric literature. the autoantibodies mediate tissue injury by binding to their reactive epitopes in the basement membranes. this binding can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane. the principle component of the basement membrane is type iv collagen which can be expressed as 6 different chains, from alpha1 to alpha6. the goodpasture antigen has been localized to the carboxyl terminus of the noncollagenous domain of the alpha3 chain of type iv collagen. the anti-gbm antibody can usually be found in serum [117] . strong evidence exists that genetics play an important role. patients with goodpasture disease have an increased incidence of hla-drb1 compared to control populations [118] . granulomatous disorders are characterized by the presence of granulomas defined as a focal, compact collection of inflammatory cells in which mononuclear cells predominate. granulomas form as a result of tissue injury by a wide variety of agents including microorganisms, antigens, chemical, drugs and other irritants. in other situations including sarcoidosis, the etiologic factors remain to be determined. sarcoidosis sarcoidosis is a chronic inflammatory disease in which granulomatous lesions can develop in many organs, mainly the lung. its cause remains obscure, and most likely involves environmental and host factors [119] . the current concept is that a still unknown stimulus activates quiescent t cells and macrophages leading to recruitment and activation of mononuclear cells, with, as a consequence, granuloma formation, alveolitis, and in some cases interstitial lung fibrosis [120] . sarcoidosis is relatively uncommon among children. its diagnosis is based on a combination of suggestive clinical features, with histologically-documented noncaseating granuloma, in the absence of other known causes of granuloma formation [121] . the incidence and prevalence of sarcoidosis are reported to be influenced by age, race and geographic localization [122] . although the youngest patients reported were infants 2 and 3-months old, most of the cases in children occur in preadolescents and adolescents. from the national patient registry on patients with sarcoidosis in denmark during the period 1979-1994, 81 patients with a confirmed diagnosis were ≤16 years of age [123] . the calculated incidence was 0.29 per 100.000 person-years. in children ≤4 years of age, the incidence was 0.06; it increased gradually to 1.02 in children aged 14-15 years. marked racial differences in the incidence and prevalence of sarcoidosis have been reported by many authors [122] . various reports in the literature also indicate that race and ethnicity affect both the patterns of organ involvement and disease severity. in a follow-up study we have conducted in 21 children with pulmonary sarcoidosis, 12 children were black [124] . also the number of organs involved was higher in the black than in the caucasian children. clinical manifestations in sarcoidosis are the consequences of local tissue infiltration with sarcoid granuloma. therefore, disease expression depends on the organ or system involved and a variety of symptoms and physical findings can be observed [125] . the modes of presentation include non-specific constitutional symptoms, alone or associated with symptoms related to specific organ involvement. in the report of children with sarcoidosis in denmark, the most common non specific symptoms were asthenia, weight loss, and fever [123] . clinical findings mainly include respiratory manifestations, lymphadenopathy, skin lesions, ocular and central nervous system abnormalities. the most common radiographic findings are hilar lymph node enlargements, with or without lung changes. lung function abnormalities are frequently observed in children with restrictive pulmonary pattern and abnormal diffusing capacity [126] . other investigations such as bal documenting a lymphocytic alveolitis with increased cd4/cd8 ratio, and elevated serum angiotensin-converting enzyme may provide additional evidence of sarcoidosis [127] . other granulomatous disorders in children a number of pathological situations are associated with granulomatous disorders defined by the presence of non-caseating granuloma in biopsied tissues. infections are the main causes of other granulomatous diseases, and are in some cases related to disorders of neutrophil function such as chronic granulomatous disease (cgd) [128] . most children with cgd present with recurrent bacterial and fungal infections. the most frequently encountered pathogens are staphylococcus aureus, aspergillus, burkholderia cepacia, and enteric gram negative bacteria [129] . the most prominent pulmonary lesions include an extensive infiltration of the lung parenchyma and hilar adenopathy. in some situations, a homogeneous distribution of small granulomatous lesions can occur, with a radiological appearance of miliary tuberculosis. the other granulomatous diseases can be seen in other described diseases, such as immune disorders (including crohn's disease and histiocytosis x), hs pneumonitis, vasculitis disorders or neoplasms. lysosomal diseases gaucher's disease is an autosomal recessive disease and the most common of the lysosomal storage diseases. it is caused by a genetic deficency of the enzyme lysosomal gluco-cerebrosidase that catalyses the breakdown of glucocerebroside, a cell membrane constituent of red and white blood cells. the consequence is an accumulation of glucocerebroside in reticuloendothelial cells, leading to excessive deposition of fatty material in the spleen, liver, kidneys, lung, brain and bone marrow. pulmonary expression is mainly characterized by physiologic involvement (reduction in lung the diffusion capacity and the functional residual volume). lung imaging may show interstitial changes [130] . niemann-pick diseases are genetic diseases primarily due to deficiency of sphingomyelinase resulting in the accumulation of sphingomyelin within lysosomes in the macrophage-monocyte phagocyte system, mainly the brain, spleen, liver, lung, and bone marrow. histology demonstrates lipid laden macrophages in the marrow, as well as "sea-blue histiocytes" on pathology. the infantile form with a dominant neurologic expression is rapidly fatal. in older patients, cases of ild have been reported [131] . hermansky-pudlak syndrome is a heterogeneous group of autosomal recessive disorders associated with accumulation of a ceroid-like substance in lysosomes of a variety of tissues. it is characterized by albinism, bleeding tendency associated to poor platelet aggregation and systemic complications associated to lysosomal dysfunction. a chronic inflammatory process may explain the progressive development of ild and fibrosis [132] . familial hypercalcemia with hypocalciuria familial hypercalcemia with hypocalciuria is caused by autosomal dominant loss-of-function mutations in the gene encoding the calcium-sensing receptor (casr), a g-protein coupled membrane receptor expressed in many tissues [133] . loss-of-function mutations in casr impair the feedback inhibition of parathyroid hormone secretion in response to a rise in the blood calcium concentration. the result is hypercalcemia associated with inappropriately normal or mildly elevated levels of parathyroid hormone. in the kidneys, mutations in casr prevent the feedback inhibition of calcium reabsorption in situation of hypercalcemia, leading to relative hypocalciuria. respiratory symptoms are usually mild and associated with reduction in the lung diffusion capacity. lung histology indicates the presence of foreign body giant cells and mononuclear cells infiltrating the alveolar interstitium, without circumscribed granulomas. langerhans'-cell histiocytosis is part of the histiocytosis syndromes, which are characterized by an abnormal proliferation of langerhans' cells [134] . the langerhans cells are differentiated cells of monocyte-macrophage lineage that function as antigen-presenting cells. the origin of the expanded population of langerhans' cells is unknown; in adults, the only consistent epidemiologic association is with cigarette smoking. these cells may form tumors, which may affect various parts of the body. most cases of pediatric langerhans'-cell histiocytosis are observed in children between ages 1 and 15 years, with usually bone involvement (80%) including the skull. the tumors produce a punched-out appearance on bone x-ray, and can cause fracture without apparent traumatism. langerhans'-cell histiocytosis can also affects various organs including the lung [135] . children with pulmonary langerhans'-cell histiocytosis present in a variety of ways. they can be asymptomatic or present common symptoms such as nonproductive cough and dyspnea. hrct of the chest is a useful and sensitive tool for the diagnosis. indeed, the combination of diffuse, irregularly shaped cystic spaces with small peribronchiolar nodular opacities, predominantly in the middle and upper lobe, is highly suggestive of pulmonary langerhans'-cell histiocytosis [63] . other abnormalities include ground-glass attenuation. the presence of increased numbers of langerhans' cells in bal fluid (identified by staining with antibodies against cd1a) with a proportion greater than 5 percent is also strongly suggestive of pulmonary langerhans'-cell histiocytosis. histologically, the cellular lesions forms nodules containing a mixed population of cells with variable numbers of langerhans' cells, eosinophils, lymphocytes, plasma cells, fibroblasts, and pigmented alveolar macrophages. several forms of ild have been reported to occur with inflammatory bowel diseases (crohn's disease) and celiac disease [136] . primary biliary cirrhosis and chronic hepatitis have also been reported to be associated with parenchymal lung dysfunction [137, 138] . in addition, there are reports on ild in association with neurocutaneous disorders (tuberous sclerosis, neurofibromatosis, ataxia-telangiectasia) and amyloidosis [139] . depending on the causes, the components of the alveolar structure (the epithelium and the alveolar space, the interstitium, and the pulmonary capillary endothelium) can be involved differently and can serve as primary targets of the underlying pathological processes. based on history, clinical presentation, bal data, and, most important, on information from lung tissue studies, the disorders can be gathered in groups according to predominant structural targets (figure 4 ). the disorders affecting primarily the alveolar epithelium and the alveolar space share common histopathological description, with preserved pulmonary architecture, hyperplasia of type 2 aec, interstitial infiltrates composed of immuno/inflammatory cells and scattered myofibroblasts, and the alveolar space filled with either immuno/inflammatory cells, desquamated materials, or components derived from surfactant lipid and protein complex. in the coming years, it is likely that the list of disorders will expand rapidly with the availability of specific tissue markers. currently, the following grouping can be proposed: infections, surfactant disorders, and eosinophilic lung diseases. infections the role of infection, mainly viral, in the development and progression of ild is sustained by a number of human and experimental reports. from recent knowledge, it is strongly suggested that latent viral infections may be involved in the pathogenesis of ild, through targeting of the alveolar epithelium. the main virus implicated include adenovirus, members of human herpes virus family (epstein-barrr virus and cytomegalovirus), and respiratory syncitial virus [140] . number of other viruses can also be involved such as influenza a, hepatitis c, or even human immunodeficiency virus (hiv) in immunocompetent children [141] [142] [143] [144] . human adenovirus being predominantly respiratory pathogens, adenovirus infections can cause a variety of pulmonary symptoms and can persist for long periods of time. several studies in adult patients have indicated that the adenovirus gene product e1a could be detected figure 4 alveolar structure disorder-associated ild. depending on the causes, the alveolar structure components can be involved differently and serve as primary targets of the underlying pathological processes. based on history, clinical presentation, bal and lung tissue information, the disorders can be gathered in groups according to the predominant alveolar targets: epithelium, vascular or interstitial components. in lung tissues by in situ hybridization in up to 16% of cases of idiopathic pulmonary fibrosis. the causative role of the virus in the initiation of the disease remains uncertain, but it may be an important factor in its progression as treatment with corticosteroids may make patients more susceptible to adenovirus infection or reactivation from latency. e1a has been shown to increase the production of tgf-β and to induce lung epithelial cells to express mesenchymal markers, thereby contributing to remodeling of the alveolar structure [145] . isolation of the virus from the throat and serologic studies are diagnostic supportive, but the diagnosis is confirmed by the detection of the virus in lung tissues. epstein-barrr virus (ebv) and cytomegalovirus (cmv) are widespread pathogens that share the characteristic ability of herpesviruses to remain latent within the body over long periods. in mice, the control of herpesviruses replication have also been reported to be associated with the arrest of lung fibrosis [146] . ebv is present in all populations, infecting more than 95% of individuals within the first decades of life. infection by cmv is reported in 60% of individuals aged 6 and older and more than 90% of aged individuals have antibodies against cmv. in addition, cmv is also the virus most frequently transmitted to a developing fetus. most healthy people who are infected by ebv and cmv after birth have no symptoms, but infection is important to certain high-risk groups of infants and immunocompromised individuals. several studies in the adult literature have reported an increased incidence of ebv and cmv infection in patients with pulmonary fibrosis, associated with virus dna-positive lung tissue biopsies in several cases [147] . however, so far, no evidence of causal relationship between viruses and pulmonary fibrosis has been provided. respiratory syncytial virus (rsv) is the most common cause of viral lower respiratory tract infection. it affects people of all ages, and can cause severe disease in infants, in older immunodeficient children and the elderly. an intriguing feature of rsv infection is the susceptibility of previously infected individuals to reinfection with antigenically closely related viruses or the identical virus strain. recently, increased interest has been focused on the contribution of persistent rsv in several chronic lung diseases including chronic obstructive pulmonary disease [148] . the role of rsv in the physiopathology of theses disorders as well as and the mechanisms of its persistence remain to be elucidated [149] . interestingly, in a recent work on the histopathology of untreated human rsv infection, the presence of the virus in aec has been documented [150] . from these various data, a role of rsv in the development of ild needs to be investigated. immunostaining with rsv-specific antibodies of tissues from lung biopsy should be proposed. among the other pathogens, chlamydophila pneumoniae and mycoplasma pneumoniae are currently drawing increasing consideration. they are frequent causes of community acquired pneumonia in children. before the age of 10 years, almost 70% of children have had chlamydophila pneumoniae infection based on serological studies [151] . these pathogens are intracellular organisms that primarily infect respiratory epithelial cells and alveolar macrophages and have the propensity to persist within several cell types such as macrophages. they are well known to cause a wide variety of respiratory manifestations, with possible progression towards diffuse parenchymal diseases associated with interstitial infiltrates on chest imaging and reduction in the lung diffusion capacity [152] . regarding legionella pneumophilia infection, progression towards ild has been infrequently reported in adult patients. results from recent studies provided evidence that viruses can infect the alveolar epithelium and may be documented in lung tissues from patients using virus dna detection and immunohistochemistry. a number of specific antibodies are currently available and should prompt to investigate the presence of the above cited viruses in the lung tissues from children with ild. surfactant disorders surfactant disorders include mainly genetic surfactant protein disorders and pulmonary alveolar proteinosis the deficiency in sp-b is a rare autosomal recessive condition known to be responsible for lethal neonatal respiratory distress. rare survivals have been described in partial deficiencies [153, 154] . the sftpc mutation i73t (c.218 t > c) is the more prevalent mutation. others are described in only one family. the phenotype associated with sftpc mutations is extremely heterogeneous leading from neonatal fatal respiratory failure to children and adults chronic respiratory disease with ild [45] . recessive mutations in the abca3 gene were first attributed to fatal respiratory failure in term neonates but are increasingly being recognized as a cause of ild in older children and young adults. over 100 abca3 mutations have been identified in neonates with respiratory failure and in older children with ild [86, [155] [156] [157] [158] [159] [160] [161] . mutations in the ttf-1 gene are associated with "brainlung-thyroid syndrome" which combines congenital hypothyroidism, neurological symptoms (hypotonia, chorea), and ild of variable intensity [162] [163] [164] [165] [166] [167] [168] . so far, few mutations have been reported, mostly in exon 3 [169, 170] . pulmonary alveolar proteinosis (pap) is a rare lung disorder characterized by alveolar filling with floccular material derived from surfactant phospholipids and protein components. pap is described as primary or secondary to lung infections, hematologic malignancies, and inhalation of mineral dusts. recently, the importance of granulocyte/macrophage colony-stimulating factor (gm-csf) in the pathogenesis of pap has been documented in experimental models and in humans. gm-csf signaling is required for pulmonary alveolar macrophage catabolism of surfactant. in pap, disruption of gm-csf signaling has been shown, and is usually caused by neutralizing autoantibodies to gm-csf. therefore, the emerging concept is that pap is an autoimmune disorder resulting in macrophage and neutrophil dysfunction. in a recent report, it has been reported that gm-csf autoantibodies are normally present in healthy individuals, but at lower levels than in pap patients [171] . in addition, in vitro experiments indicated that these autoantibodies reduce gm-csp signaling similarly in healthy individuals and in pap patients. at levels above a critical threshold, gm-csf autoantibodies are associated with multiple impaired gm-csf dependent myeloid function [172] . several cases of genetic defects in the common beta chain for the gm-csf receptor have been documented [173] . eosinophilic lung diseases eosinophilic lung diseases constitute a diverse group of disorders of various origins. the diagnosis is suggested by the presence of pulmonary infiltrates on chest imaging and peripheral eosinophilia. it is confirmed by the presence of increased amounts of eosinophils in bal and/or lung tissue eosinophilia. in this section, eosinophilic vasculitis will not be discussed (see chapter 6.2.2). the search for an etiology includes a combination of clinical and laboratory investigations. eosinophilic lung diseases of known cause in children include mainly allergic bronchopulmonary aspergillosis, parasitic infections and drug reactions. eosinophilic lung diseases of unknown cause comprise loeffler syndrome (characterized by migrating pulmonary opacities), acute eosinophilic pneumonia, and chronic eosinophilic pneumonia [174, 175] . the idiopathic hyper-eosinophilic syndrome is a rare disorder observed mainly in adults; it is characterized by prolonged eosinophilia and a multiorgan system dysfunction due to eosinophil infiltration with pulmonary involvement documented in almost half of the patients [176, 177] . alveolar capillary dysplasia and pulmonary capillary hemangiomatosis the pulmonary capillaries form a dense sheet-like meshwork composed of short interconnected capillary segments. the capillary meshes are wrapped over the alveoli, with only a single sheet of capillaries between adjacent alveoli on the same alveolar duct. impaired development of this vascular network can be caused by genetic defects, prematurity or injury. aberrant angiogenesis documented in pediatric patients include mainly alveolar capillary dysplasia, and pulmonary capillary hemangiomatosis [178] . alveolar capillary dysplasia is a rare disorder, presenting with persistent pulmonary hypertension of the newborn [179] . the strongest diagnostic features are poor capillary apposition and density, allied with medial arterial hypertrophy and misalignment of pulmonary vessels [180] . pulmonary capillary hemangiomatosis is also a rare disease that is characterized by proliferation of capillary-sized vessels within the alveolar walls of the lung [181] . intimal thickening and medial hypertrophy of the small muscular pulmonary arteries are present resulting in elevated pulmonary vascular resistance. most cases appear sporadic. chest imaging shows nodular pulmonary infiltrates and septal lines. a definitive diagnosis can be made only by histologic examination. interestingly, capillary proliferation in the alveolar wall has been reported in hereditary haemorrhagic telangiectasia [182] . lymphatic disorders alveolar structure formation is characterized by refinement of the gas exchange unit and functional adaptation of endothelial cells into vessels including pulmonary lymphatics. the pulmonary lymphatic network promotes efficient gas exchange through maintaining interstitial fluid balance. lymphatic disorders can be classified as primary or secondary. congenital errors of lymphatic development can lead to primary pulmonary lymphatic disorders that include lymphangiomas and lymphangiomatosis, lymphangiectasis, and lymphatic dysplasia syndrome [183, 184] . lymphangiomas are focal proliferations of well differentiated lymphatic tissue, and lymphangiomatosis describes the presence of multiple lymphangiomas. most of these disorders are discovered in fetuses or during the early postnatal period. lymphangiectasis is characterized by pathologic dilation of lymphatics. the term "lymphatic dysplasia syndrome" includes congenital chylothorax, and the yellow nail syndrome (a triad of idiopathic pleural effusions, lymphedema, and dystrophic nails) [185] . secondary forms of lymphatic disorders result from a variety of processes such as chronic airway inflammation that impair lymph drainage and increase lymph production [186] . diffuse alveolar hemorrhage syndromes diffuse alveolar hemorrhage (dah) syndromes are caused by the disruption of alveolar-capillary basement membrane as a consequence of injury to the alveolar septal capillaries, and less commonly to the arterioles and veinules. the hallmarks are intra-alveolar accumulation of red blood cells, fibrin, and hemosiderin-laden macrophages. it is important to point out that approximately one third of patients with dah do not manifest hemoptysis, and bal can be extremely helpful if this entity is suspected by showing the presence of siderophages or red blood cells within the alveoli. dah can be observed in association with systemic findings or without evidence of associated diseases. in children, situations of dah in the context of other disorders are reported in several forms of vasculitis discussed above. other disorders that can also be accompanied by dah include pulmonary hypertension and congenital heart diseases, pulmonary veino-occlusive disease, arteriovenous malformations and hereditary haemorrhagic telangiectasia, coagulation disorders, and celiac disease [187] . in the absence of systemic findings, isolated pulmonary capillaritis should be discussed with the search for positivity of the antiglomerular basement membrane antibody with linear deposits in the lung tissue biopsy as well as suggestive serologic features such as p-anca antibodies [188] . idiopathic pulmonary hemosiderosis is a diagnosis of exclusion based on patient presentation with acute, subacute, or recurrent dah, on the results of lung biopsy showing evidence of 'bland' pulmonary hemorrhage (ie, without capillaritis or vasculitis), and after exclusion of the conditions listed above [189] . in this situation, red blood cells leak into the alveolar space without evidence of damage and/or inflammation of the alveolar capillaries. in addition, the diagnosis of idiopathic pulmonary hemosiderosis can only be considered after exclusion of diseases induced by environmental factors such as pesticide and cow's milk (heiner's syndrome) [190] . this syndrome is a hypersensitivity disease that affects primarily infants, and is caused by antibodies to cow's milk proteins. the diagnosis is supported by positive milk precipitin test and rapid improvement of symptoms and pulmonary infiltrates on chest imaging after exclusion of milk proteins. in the resolution phase of tissue injury, elimination of mesenchymal cells and recruited inflammatory cells is essential for restoration of normal cellular homeostasis. dysregulated repair process in ild is associated with accumulation and dysfunction of interstitial fibroblasts [191] . in the coming years, it is likely that progress in the understanding of the mechanisms involved in the impaired myofibroblast apoptosis as well as evasion of these cells from immune surveillance will open new areas of investigations and will provide support for the characterization of disorders that affect primarily the alveolar interstitial components in pediatric ild. indeed, recently, distinct intrinsic differences in gene expression pathways has been reported between control and lung fibrosis myofibroblasts which suggests that ild myofibroblasts are pathological cells with fundamental changes [192] . in the context of ild, pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia, and chronic pneumonitis in infancy have been reported to be exclusively observed in very young children [8] . pulmonary interstitial glycogenosis (pig) is a non lethal disease, reported in neonates with respiratory distress syndrome developed shortly after birth [193, 194] . very few cases are described so far but it seems to have a male preponderance [195] . the histological hallmark of pulmonary interstitial glycogenosis is the accumulation of monoparticulate glycogen in the interstitial cells on lung biopsy. it is thought to represent a maturation defect of interstitial cells that leads them to accumulate glycogen within their cytoplasm [8, 196] . it is discussed that pig could meet "chronic pneumonitis in infancy" as this remains a generalized term [87] . as well, pig could be considered as a premature lung disease, but more than half of published cases were in term infants [195, 197, 198] . the long term consequences in these infants need to be ascertained. neuroendocrine cell hyperplasia of infancy (nchi) is also a non lethal disease characterized by tachypnea without respiratory failure. the human airway epithelium contains highly specialized pulmonary neuroendocrine cells (pnec) system. it's function remains unknown but is hypothysed to act in modulation of fetal lung growth and in post-natal stem cell condition [199] . the pnec system permits synthesis and release of serotonin and neuropeptides such as bombesin [200] . as normal bombesin levels decrease after mid-gestation, its overexpression in nchi could be attributed to a nonregression of neuroendocrine cells [201] . clinical presentation is typically a respiratory distress in post-natal young infant (mean age 3.8 months in a large serie, but cases in older children have been reported [202] . hrct shows patchy centrally ground-glass opacifications and air trapping [203] . on lung biopsy, the histological abnormality is hyperplasia of neuroendocrine cells within bronchioles documented by bombesin immunohistochemistry. the follow-up reveals in some cases the persistence of tachypnea and oxygen requirement for several months. usually, there is a good prognosis [7, 8, 196, 202] . chronic pneumonitis in infancy was first described by katzenstein et al. [4] . the clinical and radiologic features are similar to those observed in other forms of ild. specific histologic abnormalities include diffuse thickening alveolar septa, hyperplasia of type 2 aec, and presence of primitive mesenchymal cells within the alveolar septa. in some cases, foci of pulmonary proteinosis-like material have been observed in air spaces. the prognosis has been reported to be poor with a high mortality rate. other disorders associated with pulmonary development and growth abnormalities encompass a broader spectrum of respiratory manifestations and are more adequately integrated in the classification of diffuse lung diseases [8] . management of children with ild includes administration of oxygen for chronic hypoxaemia, and maintenance of nutrition with an adequate energy intake, immunization with influenza vaccine on an annual basis is recommended along with other routine immunizations against major respiratory pathogens [11] . in addition, aggressive treatment of intercurrent infections and strict avoidance of tobacco smoke and other air pollutants are strongly recommended. a very few children do not require any treatment and recover spontaneously. in the majority of cases, treatment with immunosuppressive, anti-inflammatory, or anti-fibrotic drugs is required for weeks, months or even years [1, 9, 61] . various drugs discussed below can be used, but no guidelines for treatment of ild in children have been proposed so far. the major reason is the very limited number of pediatric patients available for a prospective clinical trial. in addition, controlled studies with a placebo arm are unacceptable because of the poor prognosis of untreated cases and the reported efficacy of anti-inflammatory therapies in a number of pediatric ild. at the present time, the main therapeutic strategy is based on the concept that suppressing inflammation may most likely prevent progression to fibrosis. among the anti-inflammatory agents used in pediatric ild, steroids are the preferred choice, administered orally and/or intravenously. this has been well illustrated by the results of the ers task force on pediatric ild [9] . oral prednisolone is most commonly administered at a dose of 1-2 mg/kg/day [1] . children with significant disease are best treated with pulsed methylprednisolone at least initially [61, 204] . this is usually given at a dose of 10-30 mg/kg/day for 3 days consecutively at monthly intervals. the minimum number of cycles recommended is 3 but treatment may need to be continued for a longer period of 6 months or more depending on response. when the disease is under control, the dosage of methylprednisolone can be reduced or the time between cycles can be spaced out. the disease may then be controlled with oral prednisolone preferably given as an alternate day regime. in few cases oral prednisolone is used from the beginning simultaneously with intravenous methylprednisolone but this is only recommended in those with very severe disease. methylprednisolone may be effective when other forms of steroids administration fail without significant side effects. an alternative to steroids is hydroxychloroquine with a recommended dose of 6-10 mg/kg/day. individual case reports have described a response to hydroxychloroquine even in the presence of steroid resistance [1, 205, 206] . some groups have proposed to base the decision as to which agent to use on the lung biopsy findings, with a preference for steroids in case of large amount of desquamation and inflammation and for hydroxychloroquine if increased amounts of collagen representing pre-fibrotic change are found. however, as documented in the ers task force on pediatric ild, the preferred choice between steroids or hydroxychoroquine in children is highly dependent on the expertise of the center in charge of the patient, and does not seem to be oriented by the histopathological pattern [9] . in case of severe disease, steroids and hydroxychloroquine may be associated. in situations of inefficiency of steroids and hydroxychloroquine, other immunosuppressive or cytotoxic agents such as azathioprine, cyclophosphamide, cyclosporine, or methotrexate may be used. these treatments have been used mainly in situation of autoimmune disorders. promising therapeutic options include macrolides. indeed, these antibiotics have been shown to display a number of anti-inflammatory and immunomodulatory actions. although the mechanisms and cellular targets specific to macrolide activity remain to be elucidated, beneficial effects in several chronic lung diseases including chronic obstructive pulmonary diseases (copd) and cystic fibrosis have been reported [207, 208] . of interest is the ability of macrolides to accumulate in host cells including epithelial cells and phagocytes. in a recent report, a favorable response to treatment with clarithromycine has been described in an adult patient with dip [209] . other new therapeutic strategies currently proposed in adult patients target fibrogenic cytokines. the th1 cytokine interferon-γ has an antifibrotic potential through suppression of th2 fibrogenic functions. antagonists to tgf-β include pirfenidone and decorin. the use of molecules directed against tnf-α such as the soluble tnf-α receptor agent etanercept is also under investigation. to date, there are no reports on the use of these novel therapies in pediatric ild. finally, in the coming years, it is likely that an expanding number of molecules aimed at favoring alveolar surface regeneration and repair through activation and proliferation of tissue-resident (progenitor) cells will come out. depending on the underlying diseases, several specific treatment strategies needs to be considered. these include whole lung lavage for pulmonary alveolar proteinosis, which has been reported to be effective by removing the material from the alveolar space [210] . gm-csf has also been shown of interest in this disease [171] . other strategies such as interferon-α for pulmonary haemangiomatosis are effective [211] . in recent years, lung transplantation has emerged as a viable option in children of all ages, even in young infants, and lung or heart-lung transplantation may be offered as an ultimate therapy for end-stage ild [11] . the outcome and survival do not seem to be different from those reported in conditions others than ild, although comparisons are difficult to establish due to the limited number of reported cases. response to treatment and outcome can be evaluated in children based on several criteria such as decrease in cough and dyspnea, increase in oxygenation at rest and sleep, and changes in pulmonary function tests [1, 11] . improvement on thoracic hrct may also be seen, but tends to occur over a much longer period of time. reports in pediatric ild have not shown a good correlation between histological findings and outcome. some children with relatively severe fibrosis on lung biopsy make good progress, whereas others with mild desquamation have a poor outcome. this is probably due to the variable severity of the disease in different parts of the lung especially in relation to the particular area biopsied, despite hrct guidance. overall a favorable response to corticosteroid therapy can be expected in 40-65% of cases, although significant sequelae such as limited exercise tolerance or the need for long-term oxygen therapy are often observed. reported mortality rates are around 15%. the outcome for infants is more variable [1, 61] . pediatric ild comprises a large spectrum of disorders, with compelling evidence that some of these disorders are observed more frequently in infants, while others are more specific to older children. ongoing basic research will provide new insights into the molecular basis of ild pathogenesis (including genetic factors causing familial disease) in children, and is expected to identify important preclinical markers of disease, pathways of disease regulation, and novel potential targets for therapeutic intervention. for the future, there is a strong need for international collaboration which will allow collecting sufficiently large cohorts of patients with specific entities in order to perform proper therapeutic trials. as a prerequisite, however, a clear and standardised classification of the histopathology of the underlying conditions is critical. such multicenter trials will help to reduce the still considerable morbidity and mortality in children with ild. abbreviations (ards): acute respiratory distress syndrome; (aec): alveolar epithelial cells ankylosing spondylitis; (ab): antibodie; (anti-ccp): anticyclic citrullinated peptide; (anti-gbm): antiglomerular basement membrane anca): anti-neutrophil cytoplasmic antibody; (ana): antinuclear antibodies u1-rnp): anti-u1-ribonucleoprotein; (sao2): arterial oxygen saturation binding immunoglobulin protein; (bal): bronchoalveolar lavage; (casr): calciumsensing receptor; (cgd): chronic granulomatous disease; (copd): chronic obstructive pulmonary disease; (css): churg-strauss syndrome; (ctd): connective tissue disorders; (cmv): cytomegalovirus; (c): cytoplasmicstaining; (dip): desquamative interstitial pneumonia; (dad): diffuse alveolar damage; (dah): diffuse alveolar hemorrhage; (dlco): diffusing capacity of the lung for carbon monoxide functional residual capacity; (sftpb): gene coding for sp-b; (sftpc): gene coding for sp-c; (gm-csf): granulocyte/ macrophage colony-stimulating factor human immunodeficiency virus; (hp): hypersensitivity pneumonitis; (ig): immunoglobulin; (ild): interstitial lung disease lymphocytic interstitial pneumonia; (mmp): metalloproteinases; (mpa): microscopic polyangiitis; (mctd): mixed connective tissue disease; (nchi): neuroendocrine cell hyperplasia of infancy; (nsip): non-specific interstitial pneumonia pulmonary function testing; (pig): pulmonary interstitial glycogenosis pulmonary neuroendocrine cells; (rv): residual volume; (rsv): respiratory syncitial virus; (ra): rheumatoid arthritis; (rnp): ribonucleoprotein; (srp): signal recognition particle systemic lupus erythematosus; (ssc): systemic sclerosis; (ttf-1): thyroid transcription factor 1; (tlc): total lung capacity; (tlco): transfer factor of the lung for carbon monoxide; (tgf): transforming growth factor; (uip): usual interstitial pneumonia idiopathic interstitial pneumonitis in children: a national survey in the united kingdom and ireland factors influencing survival in children with chronic interstitial lung disease diffuse parenchymal lung disease. cape town: karger idiopathic pulmonary fibrosis: clinical relevance of pathologic classification european respiratory society international multidisciplinary consensus. classification of the idiopathic interstitial pneumonias pediatric interstitial lung disease: children are not small adults paediatric interstitial lung disease diffuse lung disease in young children: application of a novel classification 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trafficking resulting from a spontaneous mutation in the surfactant protein c gene new surfactant protein c gene mutations associated with diffuse lung disease posttranslational processing of surfactant protein-c proprotein: targeting motifs in the nh(2)-terminal flanking domain are cleaved in late compartments structure of the human nkx2.1 gene stem/ progenitor cells in lung development, injury repair, and regeneration stem cells and their niches telomerase in alveolar epithelial development and repair mutations in dyskeratosis congenita: their impact on telomere length and the diversity of clinical presentation short telomeres are a risk factor for idiopathic pulmonary fibrosis progress and potential for regenerative medicine mammalian fetal organ regeneration role of ageing and coronary atherosclerosis in the development of cardiac fibrosis in the rabbit alterations in the tgfbeta signaling pathway in myogenic progenitors with age expression of fibroblast growth factors and their 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infantile chronic interstitial pneumonitis bronchoalveolar lavage in children. ers task force on bronchoalveolar lavage in children diagnostic value of hemosiderin-containing macrophages in bronchoalveolar lavage cd1a-positive cells in bronchoalveolar lavage samples from children with langerhans cell histiocytosis bronchoalveolar lavage cell analysis in a child with chronic lipid pneumonia value of bronchoalveolar lavage in lipidoses with pulmonary involvement lipid-laden macrophages in bronchoalveolar lavage fluid as a marker for pulmonary aspiration bronchoalveolar lavage fluid findings in children with hypersensitivity pneumonitis pulmonary infiltrates with eosinophilia syndromes in children expression profiles of hydrophobic surfactant proteins in children with diffuse chronic lung disease the diagnostic value of bronchoalveolar lavage in immunocompetent children with chronic diffuse pulmonary infiltrates the safety and efficacy of thoracoscopic lung biopsy for diagnosis and 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and surfactant proteins a and d in pediatric interstitial lung disease bronchoalveolar lavage fluid cellular characteristics, functional parameters and cytokine and chemokine levels in interstitial lung diseases pediatric environmental health. atlanta: us department of health and human services. agency for toxic substances and disease registry. division of toxicology and environmental medicine update in diffuse parenchymal lung diseases hypersensitivity pneumonitis in children bird fancier's lung: a series of 86 patients hypersensitivity pneumonitis in children: clinical features, diagnosis, and treatment computed tomography of diffuse interstitial lung disease in children interstitial lung disease associated with drug therapy interstitial lung disease induced by drugs and radiation the epidemiology of interstitial lung disease and its association with lung cancer cigarette smoking and diffuse lung disease cellular and connective tissue changes in alveolar septal walls in emphysema 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diffuse parenchymal lung disease a new missense mutation in the casr gene in familial interstitial lung disease with hypocalciuric hypercalcemia and defective granulocyte function langerhans cell histiocytosis: update for the pediatrician pulmonary langerhans cell granulomatosis pulmonary manifestations in a pediatric patient with ulcerative colitis: a case report primary biliary cirrhosis complicated with interstitial lung disease: a prospective study in 178 patients hepatitis c virus enhances incidence of idiopathic pulmonary fibrosis neurofibromatosisassociated lung disease: a case series and literature review viruses as co-factors for the initiation or exacerbation of lung fibrosis chronic lung disease in human immunodeficiency virus (hiv) infected children ferri c: mixed cryoglobulinemia alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: impact of chemokines and adhesion molecules hcv infection: pathogenesis, clinical manifestations 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interstitial pneumonia refractory to corticosteroid therapy pulmonary alveolar proteinosis in children diffuse neonatal haemangiomatosis interstitial lung diseases in children this work was supported by inserm, université pierre et marie curie-paris6, paris, assistance publique-hopitaux de paris, ministère de la santé (centre de référence des maladies respiratoires rares), and comité de soutien de belleherbe. the authors would like to especially thank malika malhoul, delphine michon, alexandra blondel, aurore coulomb and hubert ducou le pointe for all of their effort towards the creation of the reference center for rare lung diseases. authors' contributions ac and nn contributed equally to this work and should be considered as joint first authors. ac, nn and hc drafted the review. re and bf have been involved in revising critically the review. all authors read and approved the final manuscript. the authors declare that they have no competing interests. key: cord-276660-5yney7dh authors: allgaier, katharina; schmid, johanna; hollmann, karsten; reusch, pauline a.; conzelmann, annette; renner, tobias j. title: times are changing: digitalisation in child and adolescent psychotherapy date: 2020-07-31 journal: eur child adolesc psychiatry doi: 10.1007/s00787-020-01610-8 sha: doc_id: 276660 cord_uid: 5yney7dh nan hollis and colleagues [1] summarized 21 former meta-analyses and reviews from the beginning of the development of dhi in the 1990s until the end of 2015 in their meta-review and additionally updated a systematic review analysing 30 randomized controlled trials (rct) using dhi. their review represents an outstanding comprehensive approach and has recently been complemented by a systematic literature search of our own work group [2] , strictly following the criteria established in the preferred reporting items for systematic reviews and meta-analyses (prisma) statement. the work by hollis and colleagues and our own search revealed that most robust evidence exists for interventions for anxiety disorders and mild to moderate depression (especially computerized cognitive behavioural therapy (ccbt) approaches). rct for adhd in children and adolescents revealed rather heterogeneous results which might be explained by their highly heterogeneous approaches. the studies ranged from neurofeedback trainings to executive functioning trainings and interventions targeting everyday organization and planning skills. they show comparable (inconsistent) effects to nonpharmacological face-to-face therapy [1, 2] . increasing evidence emerges for dhi targeting autism spectrum disorders which include dhi for children from preschool age to adolescence and their parents [1, 2] . dhi for children and adolescents with asd involve parents more frequently than dhi for other diagnoses. studies investigating dhi for other diagnoses such as eating disorders, psychosis, obsessive compulsive disorders, dyslexia, coordination disorders, conduct disorders with disruptive behaviour, tic disorders, insomnia or trichotillomania in children and adolescents are rather scarce. but the few available studies show promising results, though more high-quality studies are needed for a profound evaluation of dhi for those disorders. looking at the technical aspects, most studies use personal computers, which offer the broadest range of applications, ranging from psychoeducation in serious games or in video or written modules over training of cognitive functions to video sessions [1, 2] . smartphone usage is on the rise, allowing ambulatory assessment of mood or experience in everyday life [1, 2] . tablets are mainly used for trainings to improve attention or social and communicative skills via apps [1, 2] . most published dhi studies were conducted in the western hemisphere and asia, with only few studies from south american and african countries [2] . due to the advantages of dhi in providing treatment over extensive distances and an increasingly evolving it-infrastructure for example in african countries, more use of dhi can be expected worldwide. implementing dhi in clinical practice requires careful consideration of a variety of prerequisites and precautions [3] . table 1 gives an overview of practical prerequisites, ranging from personal aspects over data security and regional legal frameworks to the relevance of instable therapeutic situations including suicidality. dhi provide unique benefits, as proven during the sars-cov2-19 lock-down, but also bring potential pitfalls. table 2 gives an overview on aspects regarding accessibility, the implementation of interventions itself, the evidence regarding interventions as well as economic aspects [4] . in summary, dhi are promising therapeutic interventions for children and adolescents with psychiatric disorders, with already robust data regarding depression and anxiety disorders. sars-cov2-19 catalyses the integration of dhi into the standard repertoire of child and adolescent psychiatry and psychotherapy. nevertheless, for using dhi in daily therapeutic work there are still challenges to overcome, ranging from technical aspects, e.g. general availability of the technical prerequisites, to the most demanding therapeutic tasks like the stabilisation of patients in acute crises. blended treatment formats using a combination of traditional face-to-face sessions with e.g. intermittent video conferences might be the silver bullet in integrating dhi and taking advantage of their strengths. fortunately, at least one partner in therapy, the children and adolescents, are often accustomed to and sometimes highly trained in digitally delivered communication. so, it increase of the frequency of synchronous communication e.g. via video conferencing as a tool to deliver support during vulnerable episodes at least one parent has to be present in the house during video therapy sessions therapist needs patient's/parents' contact information at hand to be able to initiate emergency services when needed cooperation with local professionals (paediatrician, psychiatrists) for emergency support is up to us to use our profound expertise in traditional psychotherapy to create the digital pathways for reaching out to them. times are changing. let's go. acknowledgements open access funding provided by projekt deal. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. annual research review: digital health interventions for children and young people with mental health problems-a systematic and meta-review the effects of human interaction on the outcomes of digital health interventions for children and adolescents with mental disorders: a systematic review and meta-analyses joint task force for the development of telepsychology guidelines for psychologists (2013) guidelines for the practice of telepsychology ethical issues in online psychotherapy: a narrative review key: cord-281248-z2gisufl authors: buonsenso, danilo; valentini, piero; moscato, umberto; ricciardi, walter; roland, damian title: a pediatric strategy for the next phase of the sars–cov-2 pandemic date: 2020-10-09 journal: front pediatr doi: 10.3389/fped.2020.582798 sha: doc_id: 281248 cord_uid: z2gisufl although the first wave of the sars–cov-2 pandemic relatively spared children, the next winter season will put a strain on health systems including pediatric services. clinical staff managing children will need to deal not only with suspected cases of covid-19, but also with the classic infectious agents that involve children during cold seasons. it will be necessary for physicians, institutions, policy makers, and families to prepare themselves for difficulties of this phase of the pandemic. otherwise, the same problems experienced during the first wave of sars–cov-2, including shortages of human resources, personal protective equipment, and uncertainty, will be exacerbated by significant issues in hospital capacity. here we highlight the potential role of improved vaccination services, school reorganization, home–outpatient–inpatients flows and telemedicine services in order to face the coming winter season. initially described in china, sars-cov-2 rapidly spread all over the world being declared as a pandemic by the world health organization on march 11, 2020. despite the virus causing millions of infections and thousands of deaths worldwide, the impact on children has been relatively mild. the number of infected children is much lower than in adults, and mortality is an extremely uncommon outcome in this age group (1) . although a more serious condition involving children has been recently described, the pediatric inflammatory multisystem syndrome temporally related with covid-19 (pims-ts), this is a rare post-covid-19 complication and in a minority of cases leads to death (2) . as a likely result of parents' fear of going to hospital, the impact of lockdown, and reduced circulation of infectious diseases, the number of sick children presenting to hospital has dropped significantly, and most pediatric wards have been relatively empty (3) . although we do not know yet if there will be a second wave of covid-19 in the next months, it is likely the pediatric practice will not be as unscathed as during the first wave of covid-19. during the coming autumn and winter seasons in europe, active surveillance will be necessary in order to understand if sars-cov-2 will circulate again and to prompt recognize new cases. this means that routine health care cannot be the same as in a pre-covid-19 era. importantly, the first covid-19 wave began at the end of the winter seasons when influenza and bronchiolitis were diminishing and school closures strongly contributed to the reduction of other infectious diseases. in the next autumn, children will be readmitted at school, and the autumn-winter seasons will figure 1 | summary of the most common signs and symptoms of sars-cov-2 infection in children and overlaps with other common infectious diseases in children. preventable diseases with active immunization strategies (or with immunoglobulins in case of respiratory syncytial virus) are highlighted. bring back the most common pathogens, such as influenza viruses, respiratory syncytial virus (rsv), pertussis, main bacterial pathogens (such as meningococcal and pneumococcal diseases, streptococcus, mycobacteria pneumoniae), gastroenteritis, and other relatively less common but important pediatric pathogens. considering that most of these conditions present several overlaps with sars-cov-2 (figure 1 ), this will pose challenges to pediatricians and health system to appropriately manage all these conditions and properly allocate resources, because covid-19 will need to be considered until exclusion, in order to reduce nosocomial transmission and new outbreaks. therefore, while the first wave relatively spared all services that see children, the next autumn/winter will be extremely difficult to be managed from a logistic and clinical point of view. timely preparedness is needed to be ready to face this new scenario unlike for the initial pandemic (3). in particular, pediatricians and policymakers should focus on prevention of communicable diseases in children and reorganization of pediatric care, improving the logistic of inpatient and outpatients services, the appropriateness of access to outpatient and inpatient settings, the interaction between families and general practitioners and between gps and hospitalists, and the role of telemedicine. in this article, we suggest a number of preventive strategies that pediatricians, institutions, medical societies, and policy makers should address in order to appropriately face the near future, whether or not a second wave of sars-cov-2 will come. among the possible preventive strategies aiming to reduce the rates of pediatric communicable diseases and indirectly reduce the overflow of children to outpatients/inpatients pediatric services, vaccinations would be the easiest, most effective, and fastest strategy available. infants and young children are typically at high risk of admission to hospital after respiratory tract infection with viruses such as rsv and influenza virus, probably due to immaturity of the respiratory tract and immune system in this age group (4, 5) . therefore, an active vaccination strategy supported by communication strategies is now a public health priority. the latest version of the recommended childhood and adolescent immunization schedules for 2020 has been released 1 . although several countries have different policies, in most places the obligatory vaccinations are those against diphtheria, tetanus, pertussis, haemophilus influenzae type b, and hepatitis b, whereas the others are recommended. however, this year will be of pivotal importance trying to achieve the highest immunization levels for all vaccinations, including measles, mumps, and rubella; meningococcal serogroups a, c, w, y, and b; pneumococcal vaccination; and, extremely important, influenza. the highest rates should be achieved not only in the pediatric population, but also vaccination services should focus on all the family members (including pregnant women) and health care workers, in order to update catch-up immunizations and reach high levels of influenza immunizations among the health care workers. currently, rates of influenza immunization are unacceptably low among health care providers. typically, fewer than 70% of health care providers receive influenza vaccine 2 . any of the mentioned preventable disorders has overlapping signs and symptoms with covid-19; therefore, reducing the burden of these disorders will allow a more sustainable care within inpatient and outpatient services. sustainable systems for vaccinating children, adolescents, and adults must be developed in the context of a changing health care system in the era of covid-19. families should understand that now, other than the known advantages of vaccinations on child deaths, immunizations have the indirect effect of reducing the workload for a resource-limited health system. most probably, a child with symptoms suggestive of an infectious disease will be considered possible covid-19 cases for the next 6 months at least. this means that each child will be isolated, that only one caregiver will be allowed to be with the child during the clinical evaluation or admission, and that bed capacity will not allow the isolation of all sick children until covid-19 is excluded with a high probability. a similar scenario will impair appropriate flows in the peds and admission wards, lengthen waiting times in the emergency departments, and ultimately impair or delay the appropriate care for children. importantly, high immunization rates cannot rest upon onetime or short-term efforts 2 . parents and patients need educating about each recommended vaccine, the disease it prevents, and the indirect effects on the health system. this step to achieve the highest immunization rates is now more necessary than ever. vaccine education and usefulness should be highlighted during each visit, via social media and official national communication channels, allowing parents to provide questions, receive answers, and discuss their concerns 3 . these strategies are neither novel or innovative communication strategies and therefore would require insignificant funds compared to the benefits to health system impact. multiple studies have shown serious consequences of covid-19 in children are relatively rare, and there is growing evidence that children themselves are more resistant to carriage and transmission compared with adults (6). somekh et al. (7) also confirmed these data examining the dynamics of covid-19 transmission within families. they demonstrated significantly lower rates of covid-19 positivity in children compared with adults residing in the same household. children 5-17 years of age were 61% and children 0-4 years of age were 47% less likely to have positive microbiological results (7) . although these results do not necessarily indicate that school reopening is safe, in any case children will need to be readmitted at school. instruction is a priority right of every child and a fundamental instrument for the growth of every society; therefore, children cannot continue a home-only education process, because this can be associated with reduction in socialization skills, poorer education outcomes, reduced activity, inappropriate nutrition, visual problems, increase in domestic accidents (8) , or violence. even assuming that children will need to be admitted back to school, there are no doubts that the school closure during this pandemic had an indirect benefit on the reduction of communicable diseases. french authors found a significant decrease (70%) of acute gastroenteritis, common cold, and acute otitis media compared to the expected values, and a 63.5% decrease in bronchiolitis. in general, a dramatic decrease in overall peds visits (−68.5%) and hospitalization (−44.7%) was observed (9) . however, the reduction of ped presentation can also be due to different parents' decision-making motives and reasoning on bringing their child to hospital or not. during these months of the covid-19 pandemic, an intense debate has started about possible late, belated, or "not-at-all" presentations in the ped related to the pandemic; however, strong evidences suggesting why the ped attendances have changed that much during the pandemic are still lacking (10) . although the assumption that children have higher risks of contagion within close communities, such as schools, is well known among pediatricians, this is the first time in the recent history that this finding has been methodologically demonstrated. although school closure aiming to reduce pediatric infectious disease burden is neither ethically feasible nor sustainable for families, the results from angoulvant et al. (9) and bressan et al. (3) provide unique evidence to implement new guidelines and new routines to provide child education at school. currently, most classrooms are overcrowded with 20 or more students per class, and lunch is usually served in large common spaces where students from all the schools are collected to eat. in light of new evidences and the need to reduce as much as possible the diffusion of infectious diseases among children during the next season (because this would lead to include all cases in the differential diagnosis with covid-19 because of similar symptoms), a reorganization of school environments should be a priority for policy makers. institution should plan to reduce the number of students in each room and practicing physical distance within the class, separating desks of 1 m from each other, and providing sanitizers at the entrance of each class. the reduction of students per class would also allow a better students-to-teacher ratio and potentially improve school outcomes. also, the figure of a school medical doctor/nurse might be considered (or implemented if already in place) in order to detect early cases of suspected infectious diseases to be sent home and to ensure catch-up immunizations are up-to-date. preparing schools will be a challenge both logistically and financially, and it is likely underlying inequities will be exacerbated with the most deprived settings likely to be disproportionately affected. however, given the importance of returning children to school, it may well be that governments prioritize education in a manner that they have not done so before. the sars-cov-2 pandemic has significantly altered health care systems with shortages of personal protective equipment (ppes) (3), human resources, and bed capacity not only related to intensive care unit ones. emergency departments and admission wards changed their assets, allowing dedicated flows for highrisk and low-risk covid-19 patients (11) . outpatient services have been postponed to the end of the peak unless necessary, and telemedicine services implemented in order to allow routine controls. in most countries, the peak of the sars-cov-2 arrived when the flu season was over or close to the end, and school closures determined a strong reduction of common pediatric infectious diseases. the reduction of common seasonal infections helped health systems focus most of their efforts on covid-19. however, the next autumn/winter will probably not be the same, no matter whether a second wave of sars-cov-2 infection begins or not. outpatient services cannot be postponed again, because a clear impact on other major contributors to mortality and morbidity, such as reduced number of new diagnoses of cancers and missed diagnosis, have been documented (12) . children will be back at school, and as discussed, the reoccurrence of common infections is expected. therefore, even though the direct clinical impact of the sars-cov-2 virus on children has been limited with a very low mortality rate, and the covid-19-related pediatric inflammatory multisystem syndrome remains a relatively rare consequence of the disease, pediatricians will still need to include sars-cov-2 in the differential diagnosis. this will be necessary to assess the reoccurrence of sars-cov-2 and to prevent the spread of the virus in the health facilities and communities. because parents/caregivers always accompany the child, they may need to be screened as well if the child needs hospital admission. in this context, a review of the necessity of regular outpatient follow-up, family education about the management of fever in children and recognition of red flags, implementation of technology, and more appropriateness in the access to emergency departments is needed (figure 2 ) (13) . ideally, parents of every sick child should be able to have relatively prompt access to their family pediatrician (fp) or general practitioner (gp) before bringing the child to medical attention, unless critical conditions that require immediate access to the hospital by ambulance (figure 2) . pediatricians should develop screening and telematics visit forms to perform a first evaluation of a child with telemedicine. this televisit should allow the pediatrician to discuss with both the mother and child, see how the child behave, and take an appropriate clinical history. at this moment, the fp/gp should decide if the child can be reassessed with telemedicine in 12-24 h or a real visit should be performed, at home or in the outpatient service. depending on the health system model of that country, the outpatient service and up-to-date fp/gp should be able to perform a comprehensive examination. this may include the use of point of care ultrasound, assessing major causes of diseases including pneumonia, appendicitis, intussusception, and pyloric stenosis, which can be easily diagnosed at point of care by trained physicians or other near patients testing interventions. only after this examination, the child should be sent to hospital if needed. this would be a radical change of service flow in some settings and may require significant shortterm investment in training and capacity. however, to not do this may confront services with an impossible capacity challenge. real-time platforms should allow the communication between the fp/gp and hospital pediatrician in order to share clinical decisions and agree with the most appropriate flow of the single patient. this last point will be necessary also for the follow-up of children with documented sars-cov-2 infection or known exposure that does not initially deserve admission because of their clinical condition. we now know that a minority of these children will develop pims-ts weeks after the initial exposure to the virus; therefore, family education, telemedicine daily updates, and proper interaction between family, fp/gp, and hospital will be of pivotal importance. the next winter season will put a strain on the health system, including all child health services. it is necessary that physicians, institutions, policy makers, and families all together prepare themselves on time to face in the best way the difficulties of the near future; otherwise, we will find ourselves facing the same problems experienced during the first wave of sars-cov-2, including shortages of human resources, ppes, and hospital capacity. in this context, improved vaccination services, school reorganization, a renewed concept of health system with appropriateness of the home-outpatient-inpatients flows, and strengthening of telemedicine services are public health priorities, right now. db and dr has the initial concept and wrote a preliminary draft. pv contributed to the writing of the clinical overview of the covid-19 in children. um actively work in immunizations and contributed in the writing of the immunization strategies. wr provided his expertise in the proposal of new future strategies to be prepared in facing the next phase of sar-cov-2 pandemic in children. the collaboration between experts in different fields from different countries was pivotal in writing a comprehensive manuscript on a particularly important topic on child health. all authors contributed to the article and approved the submitted version. coronavirus infection in pediatric emergency departments (confidence) research group. children with covid-19 in pediatric emergency departments in italy clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 preparedness and response to pediatric covid-19 in european emergency departments: a survey of the repem and peruki networks respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology covid-19 in children: the link in the transmission chain the missing link? children and transmission of sars-cov-2, don't forget the bubbles the role of children in the dynamics of intra family coronavirus 2019 spread in densely populated area lockdown: more domestic accidents than covid-19 in children covid-19 pandemic: impact caused by school closure and national lockdown on pediatric visits and admissions for viral and non-viral infections, a time series analysis arriving late, delayed, or not at all-presentations to paediatric emergency departments during covid-19 pandemic children's healthcare during corona virus disease 19 pandemic: the italian experience impact of the covid-19 pandemic on emergency department visits -united states covid-19 in children: develop solutions rather than look for problems key: cord-260459-7o1ob5fk authors: platt, vanessa borges; guedert, jucélia maria; coelho, elza berger salema title: violence against children and adolescents: notification and alert in times of pandemic date: 2020-10-28 journal: rev paul pediatr doi: 10.1590/1984-0462/2021/39/2020267 sha: doc_id: 260459 cord_uid: 7o1ob5fk objective: social isolation is currently identified as the best way to prevent the infection by the new coronavirus. however, for some social groups, such as children and adolescents, this measure carries a contradiction: the home, which should be the safest place for them, is also a frequent environment of a sad aggravation: domestic violence. this study aims to evaluate the notifications of interpersonal/self-inflicted violence available in the information system for notifiable diseases in the state of santa catarina (southern brazil), for the juvenile age group, before and during the new coronavirus pandemics. methods: cross-sectional, descriptive study of violence against children and adolescents (from 0 to 19 years) notified by health professionals by completing and entering the occurrence in the information system for notifiable diseases of the state of santa catarina in 11 weeks in which the social isolation measure was instituted as mandatory, comparing with the same period before this measure. results: during the study period, 136 municipalities in santa catarina made 1,851 notifications. there was a decrease of 55.3% of them in the isolation period, and the difficulties encountered in seeking protection and assistance institutions were listed. conclusions: the society needs to be aware of possible cases of violence in the children and adolescent population. it is important to provide accessible, effective, and safe ways for complaints and notifications, as well as a quick response to the cases, aiming at protecting victims and minimizing damages to prevent the perpetuation of the violence. on march 11, 2020 , the world health organization (who) recognized that covid-19 disease, caused by the new coronavirus (sars-cov-2), has taken pandemic proportions. 1 this unknown disease, with no possibility, until now, of pharmacological treatment or vaccine control, imposed the guidance, by the entity, of social isolation as the only way to contain its spread. since the first cases identified in brazil, the population has turned its attention to the devastating numbers of contaminated people and deaths, the adequacy with the ways to avoid contagion and the sanitary obligation of social isolation. as a result, daily activities of children and adolescents outside their home were prohibited, such as attending classes, circulating in public environments, and even hanging out with friends, restricting the social space of individuals to the home environment. despite laws and advances in the development of assistance and care strategies, the numbers on violence in pre-pandemic brazil were already worrying. data from the informatics department of the unified health system (datasus) reveal that in 2017 there were 126,230 cases of violence against children and adolescents up to the age of 19 (corresponding to 42% of the total cases reported that year). the record of 21,559 deaths from external causes, accidents, and violence up to the age of 19 shows that many did not resist the abuse. of these cases, a quarter died before the age of 10, and more than 10% (2,309 children) were up to 4 years old. 2 in 2019, the dial human rights (dial 100), a telephone tool provided by the brazilian government to receive, analyze, and forward complaints of human rights violations, including cases of violence, revealed 159,063 complaints of maltreatment -an increase of 15% compared to 2018. of these complaints, 86,837 were violence against children and adolescents (55%), distributed as follows: 38% linked to negligence, 23% to psychological violence, 21% to physical violence, 11% to sexual violence, 3% to exploitation/child labor, and 3% associated with other violent injuries. the most frequent place of occurrences was the victim's home. 3 in the state of santa catarina, from 2015 to 2019, 65,672 notifications were registered in the information system for notifiable diseases (sinan). of these, 38.4% occurred in the age group of children and adolescents. 4 intrafamily violence is difficult to unravel, as it occurs in the private sphere, in the domestic environment, within homes and is protected by the law of silence, by the fear, and impunity of its agents -people who should support and protect children and adolescents. this violence covers five types: physical, sexual, psychological, neglect, and specific forms, which are expressed in the forms of münchhausen syndrome, chemical violence, and filicide. 5 paradoxically, the home, the safest environment for people to be protected from contagion by the new coronavirus, while there is no vaccine available, can be the most unsafe place for many children and adolescents. 6 the concern about a regrettable and well-known wound in our society emerges from this situation: domestic violence against children and adolescentsoften at home and perpetrated by family members. this study aimed to present data on compulsory notifications on cases of violence against children and adolescents in the state of santa catarina, in the months after the emergence of the new coronavirus, and how the establishment of sanitary measures of social isolation influenced the increase in domestic violence against children and adolescents when comparing this information to that of the pre-pandemic, to alert health professionals, public institutions, and society to the need to reinforce actions to prevent injuries, protection, and adequate care for victims. this is a cross-sectional, descriptive, and analytical study of violence against children and adolescents (aged 0 to 19 years old) notified by health professionals, by filling out and inserting into the sinan the notification forms for individual investigation of interpersonal/self-inflicted violence, 7 between january and may 2020, in the state of santa catarina. the age limit is because the who defines this age range for children and adolescents. 8 santa catarina has 295 municipalities, distributed over 95,730,921km 2 . according to the brazilian institute of geography and statistics (ibge), in 2012, the brazilian state was the 11th in size of the population, with 6,248,436 inhabitants. the estimated population in 2019 was 7,164,788 inhabitants, with 971,034 being the population of children and adolescents. 9 the study analyzed the data using descriptive statistics. from january 1 to may 31, 2020, 136 of the 295 municipalities in santa catarina made 1,851 notifications in sinan of suspected or confirmed cases of interpersonal or self-inflicted violence in the 0 to 19 age group. these events were characterized as: neglect or abandonment, physical, psychological, sexual, and other violence, and child labor (table 1) . 10 at the time of data collection for this study, only 46% of the municipalities had included cases of violence in sinan. the data request was sent to all municipal health departments in the state of santa catarina. the response of less than half of them may be due to the need for restructuring health facilities and adapting their facilities to the service demands of the pandemic. table 2 shows the percentage differences in the number of notifications of child and adolescent violence accumulated in rev paul pediatr. 2021;39:e2020267 the weeks before and after the decree that established the measures of social isolation in santa catarina. for 30 years, the child and adolescent statute (eca), under law no. 8,069/90, made children and adolescents "subjects of law" in brazil. it delegates to society the duties to protect and care for these developing brazilian citizens and emphasizes the obligation to ensure full compliance with the rights necessary to promote their full potential, removing any form of oppression or discrimination. in its article 13, eca determines the obligation to report all cases of suspected or confirmed physical punishment, cruel or degrading treatment, and maltreatment of children to the local child protection councils, without damage to other legal measures. 11 in 2001, the notification of suspected or confirmed cases of abuse against children became mandatory and directed to municipal epidemiological surveillance and the child protection council. 12 in 2011, this notification became computerized, through compulsory filling for all health services, both public and private, of the sinan notification form/individual investigation of interpersonal/self-inflicted violence. 13 data from social organizations and non-governmental institutions published in the media report an increase in violence against children and adolescents in the pandemic, such as the 7.4% increase in the federal district, 14 8 .5% in paraná, 15 73% in rio grande do sul 16 , and 32% in pernambuco. 17 safernet, a civil association governed by private law, with national operations, focused on the promotion and defense of human rights on the internet in brazil, in partnership with the national committee to combat sexual violence against children and adolescents, registered a 108% increase in complaints on child pornography during the country's pandemic; in april 2020 alone, there were 9,995 complaints. 18 the state of santa catarina has provided data on the number of cases of domestic violence against children and adolescents since the emergence of the covid-19 pandemic. based on sinan notifications from 136 municipalities in santa catarina that released data (out of a total of 295) for 2020, there was a progressive decrease in the total number of notifications since the beginning of social isolation, the absolute numbers in january, february, march, april, and may are, respectively, 469, 506, 434, 273, and 169 ( table 2 ). 10 when comparing january with april, for example, we found a 42% decrease in the number of notifications of child and adolescent violence, the percentage of which is higher (64%), if we compare january to that of may. does this data mean that violence has decreased? we believe it has not. several factors can justify the significant reduction in notifications. the need for restructuring and adapting health services to the pandemic reality, directing employees and health units for the exclusive care of cases of acute respiratory syndromes, and overload of the teams of health workers due to the increased demand for care may have made it difficult for users to access services usually available to the population. added to this, we have the interruption of public transport services, which imposed difficulties in traveling and accessing health services. the fear of contamination, the social isolation imposed, the limitations for leaving home, added to the financial difficulties resulting from the pandemic, may have constituted barriers to reporting violence and seeking assistance and the consequent decrease in notifications. 14 for many women, the health measures adopted to cope with the new coronavirus demanded more domestic work, greater care for children, away from daycare centers and schools, besides greater assistance to the elderly and sick family members. it is inferred that movement restrictions, financial limitations, and generalized insecurity encourage abusers, giving them a greater sense of power and control. 19 confinement also brings different changes in the routine of family members, leading to stress, which, if not well conducted, can lead to consequences for the entire family dynamics. these consequences can affect the physical and mental health of children and adolescents, especially young children, who do not have the necessary tools to adjust to stress or to overcome it, which can make it especially harmful. family stress is closely associated with uncertainty/insecurity in the near future, the possibility of falling ill and experiencing the illness of a family member/loved one, fear of not getting adequate access to health, not promising news in the media, economic problems related to job loss and/or reduction of monthly family income. added to these facts is the increased time spent with children and adolescents, now almost 24 hours, both due to the need for social isolation and the closing of schools, parks, and leisure areas in the condominiums. stress is also associated with the absence of other components of the family support network, such as the interaction with grandparents, uncles, neighbors, domestic workers, and even institutions such as churches and social projects. this tension experienced and expressed by parents is reflected in children and adolescents, who start to adopt the same behavior: tension, demotivation, and aggression, which can be intensified by the excessive time on screen. this whole range of factors favors a violent domestic environment, which, associated with the distance from the protection agencies, the fear of losing the only provider of the family, of not being able to leave the house, for example, to stay at their parents' house (grandparents of the children), even because of the fear of rupturing the relationship, thus enabling the maintenance of the pact of silence inside the house, making everyone vulnerable to suffering violence. 20 family violence has a strong historical-cultural connotation: parents who were educated in a violent manner reproduce this form of education, resorting to physical and psychological violence, manifested by beatings, hair pulling, spanking, shouting, and the most diverse threats as a way to impose discipline to their children. the protective role of the school is recognized as paramount, identifying in the teacher often the confidant, the professional with a watchful eye on the students under their care, the one who can be the trigger for the protection and care network and guarantee the rights of children and adolescents. however, according to the united nations educational, scientific and cultural organization (unesco), about 1.5 billion children and adolescents worldwide are out of school because of the closure of educational institutions as an initiative to contain cases of covid-19. 21 therefore, children no longer have an important space to manifest and expose the violence suffered. still, much of the state's child protection structure, such as child protection councils and police stations, is providing virtual assistance only. additionally, public transport is absent in many regions and greater consumption of alcohol and other drugs, as well as psychoactive medications. 19 a recent publication was assertive when it was titled "the pandemic paradox", as this pandemic creates a paradox concerning security at home: a place where we should be protected and safe is where violence occurs for the most vulnerable groups. the authors emphasize that we must all pay attention to this issue: "governments around the world have asked all of us to participate in the fight against covid-19 by staying at home, but it is also important to pay critical attention to what this means for many women and children". 6 given this, specific and regional regulations were developed, initiatives to be thought and reproduced by states and municipalities, such as the national council for the rights of children and adolescents, dictating recommendations for the full protection of children and adolescents during the covid-19 pandemic, 22 and those of the state of minas gerais, through law no. 23,643, of 2020, 23 which requires residential condominiums to inform security agencies about episodes or signs of domestic violence in their common and private facilities, and the law no. 23,644, also from 2020, 24 which deals with the registration of this type of occurrence through the virtual police station system, during the pandemic. on june 10, the national council of justice and the association of brazilian magistrates launched the red flag against domestic violence campaign. the initiative focuses on helping women in situations of violence to ask for help in pharmacies in the country, offering a silent channel of communication and assistance: with a red x in the palm of the hand, which can be done with a pen or even lipstick, the victim indicates she is in a situation of violence. with the woman's name and address in hand, pharmacies and drugstore attendants who join the campaign should immediately call 190 and report the situation. at the time of its launch, the project had a partnership with 10,000 pharmacies and drugstores across the country. 25 in the same direction, the military police of santa catarina and the national council of general commanders of the military police and the military fire brigade joined forces, dispatched and disseminated, through the internal network, normative instruction with the addition of standard operating procedures for the specific handling of incidents involving domestic violence against women. 26 in the same state, technical note 012/2020, from the state department of health, dated may 19, 2020, deals with measures to combat domestic violence in the context of the covid-19 pandemic. it warns of the importance of notifying suspected or confirmed cases and referring them as soon as possible to protection agencies and multiprofessional care as recommended in the care protocols. the note also lists suggestions for protective actions for victims and informs contact phones of entities in the protection network. 27 law no. 14.022 was recently published in the federal official gazette of brazil (section 1, p. 3, of july 8, 2020), which ensures the full functioning, during the covid-19 pandemic, of entities assisting women, children, adolescents, the elderly, and citizens with disabilities who are victims of domestic or family violence. according to the law, assistance to victims is considered an essential service and cannot be interrupted while the state of public calamity caused by the new coronavirus lasts. 28 we chose to study data on domestic violence in children and adolescents under covid-19, considering the current concern of society for the risk of its intensification during home confinement imposed by the pandemic. the small number of municipalities that provided the notification data and the short period analyzed can be mentioned as limitations of this study. nonetheless, we understand that these limitations are minimized by the relevance and urgency of the topic. it is possible to conclude that the reduction in the number of complaints of violence against children and adolescents does not encourage, nor does it seem to reflect a decrease in the incidence of this condition. on the contrary, it can demonstrate difficulties that people may be facing in making the complaints and using existing social resources to care for the victims. initiatives, although specific, are understood as beneficial, which warn of the need for attention to the problem. in this pandemic moment, with the confinement of children in potentially violent homes and spaces, it is essential that their surroundings and the whole society be alert to the suspicion and evidence of cases of violence and that accessible, effective, and safe ways are provided so that complaints, notification, and prompt response to cases occur, aiming at protecting victims, minimizing damage and, thus, preventing the perpetuation of violence. this study did not receive any funding. folha informativa -covid-19 (doença causada pelo novo coronavírus) datasus: tecnologia da informação a serviço do sus. indicadores de saúde: causas externas da família e dos direitos humanos disque 100. relatório violência contra crianças e adolescentes. brasília, df: ondh informativo epidemiológico barriga verde ed especial) sociedade brasileira de pediatria. manual de atendimento às crianças e adolescentes vítimas de violência the pandemic paradox: the consequences of covid-19 on domestic violence secretaria de vigilância em saúde. departamento de vigilância de doenças e agravos não transmissíveis e promoção da saúde. viva: instrutivo notificação de violência interpessoal e autoprovocada. 2 nd relatório mundial sobre violência e saúde base de dados sobre covid-19 (coronavirus) superintendência de vigilância em saúde, diretoria de vigilância epidemiológica lei n. 8.069, de 13 de julho de 1990, e legislação correlate dispõe sobre a notificação, às autoridades competentes, de casos de suspeita ou de confirmação de maus tratos contra crianças e adolescentes atendidos nas entidades do sistema único de saúde viva: vigilância de violências e acidentes secretaria de saúde do distrito federal violência interpessoal e autoprovocada em tempos de covid-19. informe epidemiológico casos de violência doméstica no paraná aumentaram 8,5% no 1º trimestre de 2020, diz sesp. globo.com: g1 paraná rpc diário da manhã. notícias. segurança. passo fundo, rs; 2020 maio 11 violência contra crianças pode crescer 32% durante pandemia: levantamento de ong aponta aumento de denúncias em escala global. folha de pernambuco, agência brasil pandemia eleva risco de abuso a crianças e adolescentes cnj lança campanha nacional para incentivar denúncia de violência doméstica superintendência de planejamento em saúde, diretoria de atenção primária à saúde. nota técnica n. 012/2020 -daps/sps/ses/sc, de 19 de maio de 2020 the authors declare there is no conflict of interests.28. brazil -câmara dos deputados. lei nº 14.022, de 7 de julho de 2020. altera a lei nº 13.979, de 6 de fevereiro de 2020, e dispõe sobre medidas de enfrentamento à violência doméstica e familiar contra a mulher e de enfrentamento à violência contra crianças, adolescentes, pessoas idosas e pessoas com deficiência durante a emergência de saúde pública de importância internacional decorrente do coronavírus responsável pelo surto de 2019. brasília, df: diário oficial da união; 2020. key: cord-295260-te2jz2gn authors: leino, annamari; lukkarinen, minna; turunen, riitta; vuorinen, tytti; söderlund-venermo, maria; vahlberg, tero; camargo, carlos a.; bochkov, yury a.; gern, james e.; jartti, tuomas title: pulmonary function and bronchial reactivity 4 years after the first virus-induced wheezing date: 2018-10-08 journal: allergy doi: 10.1111/all.13593 sha: doc_id: 295260 cord_uid: te2jz2gn background: wheezing illnesses among young children are common, and are a risk factor for asthma. however, determinants of childhood bronchial reactivity, a key feature of asthma, are largely unknown. aim of this study was to determine how patient characteristics during the first severe virus-induced wheezing episode are associated with pulmonary function at pre-school age. methods: study consisted of 76 children presenting with their first wheezing episode at the ages of 3 to 23 months. at study entry, viral etiology, rhinovirus genome load, atopic and clinical characteristics, and standardized questionnaire were analyzed. at 4-year follow-up visit, impulse oscillometry with exercise challenge was performed. results: at study entry, the mean age of the children was 12 months (sd 6.0), 57 (75%) were rhinovirus positive and 22 (30%) were sensitized. at follow-up visit four years later, the mean age of the children was 60 months (sd 7.9) and 37 (49%) were using asthma medication regularly (discontinued before testing in 25 [68%] children). bronchial reactivity (≥35% change in mean crude values of resistance) after exercise challenge or bronchodilation was present in 9 (12%) children. children with atopic sensitization at the time of the first wheezing episode were more often likely to develop bronchial reactivity (odds ratio 8.8, p = .03) than the children without sensitization. no other significant associations were found. conclusions: atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at pre-school age. than the children without sensitization. no other significant associations were found. conclusions: atopic sensitization at the time of the first severe wheezing episode is an important early risk factor for increased bronchial reactivity at preschool age. bronchial reactivity, impulse oscillometry, pulmonary function, sensitization, wheezing previous studies have shown that early wheezing induced by rhinovirus and/or associated with sensitization is an important risk factor for recurrent wheezing and asthma. they are likely to reveal the underlying airway inflammation and the weaknesses in viral defense mechanisms. [1] [2] [3] however, the factors influencing bronchial reactivity in children are poorly characterized. previous studies have shown that early-life factors, such as early-onset atopy, 4-7 family history of asthma, 6, 8 maternal smoking, [4] [5] [6] 8, 9 exposure to traffic-related air pollution, 10, 11 preterm birth, [12] [13] [14] and low birth weight, 15 may be associated with decreased pulmonary function in later childhood. two studies have shown that wheezing at young age, induced by rhinovirus, may be associated with decreased pulmonary function or increased airway reactivity later in childhood. 8, 16 some 5,17,18 but not all 9, 19 studies have shown a comparable association between respiratory syncytial virus (rsv)-induced wheezing and reduced pulmonary function. however, these earlier studies mainly included older children, and there were no data from the first virus-induced wheezing episode. pulmonary function testing in young children is challenging. impulse oscillometry (ios) is a method for testing pulmonary function during tidal breathing. [20] [21] [22] [23] a key measurement in ios is respiratory resistance (rrs) which indicates the energy loss due to resistive forces to the airflow in the airways and is clinically interpreted as an indicator of obstruction. ios is child-friendly as it requires a minimum cooperation and has successfully been used from the age of 2-3 years forward. 21, 24 in finland, there are population-based reference values available for children aged 2-7 years. 20, 23 secondary strategies to prevent asthma can be initiated at the time of the first wheezing episode. [25] [26] [27] [28] however, it is not known which patient characteristics at the time of the first acute wheezing episode predict abnormal pulmonary function during the later childhood. thus, vinku2 is the first study to investigate the associations between the patient characteristics of the first acute severe virus-induced wheezing episode and the subsequent pulmonary function and bronchial reactivity. atopic sensitization diagnosed during the first acute severe wheezing episode was associated with increased bronchial reactivity and reduced lung function at preschool age. these results are important to consider for the design of early intervention trials for the secondary prevention of asthma. | 519 among children who had suffered from the first acute severe wheezing episode before the age of 2 years, we aimed to determine the pulmonary function at the age of 5 years and its reactivity to exercise or bronchodilation by ios. we also tested for early-life factors predicting the exercise or bronchodilation-induced bronchial reactivity. we hypothesized that patient characteristics, such as rhinovirus etiology and atopy at the time of the first severe wheezing episode, would be associated with the pulmonary function and increased bronchial reactivity measured by ios 4 years after the first wheezing episode. 2 | me th ods this study is a part of a larger vinku2 study which was carried out in the turku university hospital (recruitment june 2007 to march 2009). 3, 27, 29 the aim of the original study was to assess the effect of a 3-day course of oral prednisolone (first dose 2 mg/kg, then 2 mg/kg/ day in two divided doses, maximum dose 60 mg/day, prednisolon ® 5 mg tablets, leiras takeda, helsinki, finland) in children with the first acute rhinovirus-induced wheezing episode (79% hospitalized; 21% treated at emergency room of tertiary hospital) using a randomized double-blind placebo-controlled paralleled design. the inclusion criteria were age 3-23 months, first acute wheezing episode (confirmed by parental report and medical records), and delivery at ≥36 weeks. children with chronic nonatopic illnesses, need for intensive care unit treatment, or previous systemic or inhaled corticosteroid (ics) treatment were excluded from the study. the study was approved by the ethics committee of the turku university hospital and was commenced after obtaining written informed consent from guardians. the trial was double-blinded until the 12-month follow-up. at study entry, the guardian completed a standard questionnaire form, the child was physically examined, a nasopharyngeal aspirate sample was taken using a standardized procedure, 30 at study entry, multiplex (seeplex rv12 ace detection, seegene, seoul, korea) or in-house single pcr tests were used for detecting adenovirus, coronavirus 229e, nl63 and hku1, enteroviruses, human bocavirus, human metapneumovirus, influenza a and b viruses, parainfluenza virus types 1-3, rhinovirus types a, b, and c, and rsv a and b at the department of virology, university of turku. 29 rhinovirus sequencing has previously been described and analyzed in collaboration with the university of wisconsin-madison. 31, 32 human bocavirus-1 was also analyzed using serology, as previously described. 33 to analyze the virus genome load, a sterile flocked swab (catalog number 502cs01, copan, brescia, italy) was first dipped in the aspirate and then diluted with 1 ml of phosphate-buffered saline. the genome load was analyzed from rna of rhinovirus-positive samples by a quantitative rt-pcr, using known concentrations of rhinovirus-b14 plasmid. the plasmid was received from glyn stanway at the university of colchester (essex, uk) and has been described elsewhere. 34 serum levels of allergen-specific immunoglobulin e (ige, phadiatop combi ® , phadia, uppsala, sweden) and blood eosinophil counts (b the airway hyperresponsiveness and reversible airflow obstruction were measured using ios. [20] [21] [22] [23] the impulse oscillatory signals of 5-35 hz were used and output pressure and flow signals analyzed for their amplitude and phase difference, to determine the airway resistance (rrs, variable that reflects the energy loss due to resistive forces to the airflow) and the reactance (xrs, indicator of viscoelastic properties of the small airways). rrs and xrs both are components of total respiratory impedance (zrs, results from phase and pressure changes of the airflow). the frequency dependency of resistance (drrs/df) was determined using linear regression through resistance data points rrs5 and rrs10. during obstruction, rrs increases resulting in increased drrs/df. xrs decreases due to peripheral stiffening as a result of obstruction. the technical realization of ios is described in more detail in appendix s1. after the baseline measurements, a 6-minute exercise test was conducted. the children were urged to run 6-8 min at an exercise level where the heart rate was held at 85%-90% of their estimated maximum heart rate (205−1/2 × age), assessed with a heart rate monitor (polar sport tester ® , polar elektro ltd, kempele, finland). ios measurement was repeated 1, 5, and 10 min after the exercise testing. 23, 35, 36 finally, the reversible airflow obstruction was assessed with ios 15 min after the bronchodilation with inhalation of 400 micrograms of salbutamol (ventolin ® ) administered through a spacer (babyhaler ® ); both products are from glaxosmithkline (brentford, uk). 20 the results were proportioned by the height of the child. rrs at 5 hz was categorized as pathological if exercise-induced change in mean crude values was +35% or more 2 or if bronchodilator-induced change in mean crude values was −35% or more 23, 36 (malmberg 2008 , beydon 2007). children had atopic sensitization if they had a positive test (cutoff level ≥0.35 ku/l) for ige specific for any of tested allergens (codfish, cow's milk, egg, peanut, soybean, wheat, cat, dog, horse, birch, mugwort, timothy, cladosporium herbarum, and dermatophagoides pteronyssinus). 29 eczema at study entry was a physician-made diagnosis according to pruritus, typical morphology, and chronicity of disease and it was defined as atopic if any sensitization was diagnosed. (95%) children. exercise test was not conducted due to refusal of running in two (3%) children and due to severe asthma symptoms in one (1%) child. all the children with bronchodilation and/or exercise test (n = 76) were included in the analysis. the included (n = 76) and excluded (n = 48) participants did not differ from one another concerning the patient characteristics shown in table 1 (table s1 ). at study entry, the mean age of the 76 study subjects was 12 months (sd 6.0), 62 of them (82%) were hospitalized, and 50 in baseline ios measurements, one (1%) child had a pathological rrs table 2 were not associated with the baseline values of ios (table s3 ). baseline rrs 10 values were not associated with any of the factors shown in table 2 (data not shown). increased bronchial reactivity was diagnosed in 9/75 (12%) children. eight (11%) of these changes were diagnosed in the exercise test as a rrs 5 hz increase of ≥35%, and one (1%) of the children had a rrs likewise, other patient characteristics shown in table 1 were not associated with bronchial reactivity. the ocs treatment during the first wheezing episode did not affect the pulmonary function four years later. there were no significant differences in baseline ios parameters (all p ≥ 0.13) or in exerciseinduced bronchial reactivity (p ≥ 0.16) between the prednisolone and placebo groups. in the 12 children who were not able to discontinue the ics use, the exercise-induced change in rrs 5 hz was greater than that in non-ics users (β 0.70; 95%ci 0.080 to 1.3; p = 0.028), but this association did not remain in adjusted analysis ( table 2 , table s3 ). the results without the children using continuous ics treatment before the follow-up visit were not markedly different (data not shown). to our knowledge, this is the first study to investigate the associations between the patient characteristics of the first acute severe virus-induced wheezing episode and the subsequent pulmonary function and bronchial reactivity later in childhood. as a main finding, atopic sensitization, both aeroallergen and food sensitization, during the first wheezing episode was associated with increased bronchial reactivity at preschool age. we did not find any significant association between the rhinovirus or its genome load, other virus infections, or other patient characteristics at study entry and the later pulmonary function or bronchial reactivity. previous studies have reported that the early atopic sensitization previous studies have shown parental asthma and maternal smoking to be associated with baseline pulmonary function and/or bronchial reactivity. 5, 8 some studies have also found an association between these patient characteristics and decreasing pulmonary function during a follow-up until the age of 18 years. 6, 7 vitamin d has been found to be potential in preventing infectious diseases and atopic illnesses through both innate and adaptive immune responses. [38] [39] [40] in our study, patient characteristic data were carefully assembled and 25-oh-d levels were analyzed. however, we did not find associations between any of these patient characterisearlier studies have shown decreased baseline pulmonary function in 20%-29% of cases 6-8 years after virus-induced bronchiolitis. 8, 9, 19 in our study, the proportion of pathological pulmonary function at baseline was low (3%). our detection rate of exerciseinduced bronchial reactivity (11%) is also relatively low when compared to earlier studies (13%-62%). 8, 9, 19 in our study, twelve (32%) of the 37 children were not able to discontinue the ics medication for asthma, which may partly explain the low detection rate of increased bronchial reactivity. however, in majority (68%) of the children using ics, the medication was discontinued at least four weeks before the ios testing. according to the finnish guidelines, 41 strengths of our study include the prospective design, new focus on the first wheezing episode, comprehensive viral diagnostics, the use of ios for pulmonary function testing, good quality of the ios measurements, and discontinuation of regular asthma controller medication in majority of asthmatic children before testing. allergen-specific ige was used for characterization of atopic sensitization. the children were carefully examined by a physician, and the standard questionnaire was used which provided detailed characterization of the children. 42 however, our study has some limitations. most patients were hospitalized during the first acute wheezing episode, which makes these results only applicable for the most severe end of illness. the relatively small study population precluded analysis of rhinovirus species or the associations of other respiratory viruses with spirometry outcomes. reasonable challenge in exercise test was ensured by continuous heart rate monitoring, but ventilation was not measured for this purpose. in conclusion, atopic sensitization diagnosed during the first acute severe wheezing episode was associated with increased bronchial reactivity and reduced lung function at preschool age. clinically, these results suggest that testing for atopic sensitization at the time of first wheezing episode may have prognostic significance with respect to lung function. these results are also important to consider for the design of early intervention trials for secondary prevention of asthma. we thank mrs tiina peromaa for her valuable help in conducting the exercise tests, heidi jokinen, biomedical laboratory scientist for her help in laboratory analyses, dr pekka malmberg, phd, for his guidance into the ios methodology, and mr hans-jüergen smith (jaeger, würzburg, germany) for providing us with the ios device during this study. the authors have no conflict of interest in connection with this paper. role of viral infections in the development and exacerbation of asthma in children early life rhinovirus wheezing, allergic 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methodology, recommendations and future developments exercise-induced changes in respiratory impedance in young wheezy children and non-atopic controls reference values for respiratory system impedance by using impulse oscillometry in children aged 2-11 years prednisolone reduces recurrent wheezing after first rhinovirus wheeze: a 7-year follow-up sensitization at the first wheezing episode increases risk for long-term asthma therapy short-and long-term efficacy of prednisolone for first acute rhinovirus-induced wheezing episode prednisolone for the first rhinovirus-induced wheezing and 4-year asthma risk: a randomized trial the first wheezing episode: respiratory virus etiology, atopic characteristics, and illness severity respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children improve molecular typing assay for rhinovirus species a, b and c rhinovirus species and clinical characteristics in the first wheezing episode in children clinical assessment and improved diagnosis of bocavirus-induced wheezing in children the complete nucleotide sequence of a common cold virus: human rhinovirus 14 expert panel report 3 (epr3): guidelines for the diagnosis and management of asthma an official american thoracic society/european respiratory society statement: pulmonary function testing in preschool children basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection the vitamin d connection to pediatric infections and immune function latitude, sunlight, vitamin d, and childhood food allergy/anaphylaxis vitamin d and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials working group set up by the finnish medical society duodecim, the finnish respiratory society, finnish paediatric society, and finnish society of clinical physiology, helsinki: the finnish medical society duodecim international study of asthma and allergies in childhood (isaac): rationale and methods additional supporting information may be found online in the supporting information section at the end of the article. how to cite this article key: cord-006702-ekf6mja9 authors: nan title: abstracts for the 17th ipna congress, iguaçu, brazil, september 2016: oral presentations date: 2016-08-17 journal: pediatr nephrol doi: 10.1007/s00467-016-3466-6 sha: doc_id: 6702 cord_uid: ekf6mja9 nan 2 years was 67% for pbs and similar to cou (71%) and rhd (68%). age-adjusted death-censored risk of graft loss was not significantly different for pbs as compared to cou (hr 0.94; 95% ci 0.65-1.38) or compared to rhd (hr: 0.98; 95% ci 0.67-1.42). conclusions: in contrast to previous reports, we found encouraging outcomes in the largest cohort of pbs children on rrt reported so far, which were similar to those with renal dysplasia. the protective arm of the renin angiotensin system may counteract the intense inflammatory process in fetuses with posterior urethral valves t.r.r. prestes (1) , é.l.m. vieira (1) , f.m. bastos (1) , l.m. kangussu (1) , n.p. rocha (2) , a.c. simoes e silva (1) (1) ufmg, brazil, belo horizonte, brazil; (2) universiy of texas, houston, united states objectives: previous studies showed that cytokines, chemokines and components of the renin angiotensin system (ras) might take part in renal damage observed in other obstructive nephropathies. the aim of this study was to evaluate if molecules related to inflammation and components of the ras can be detected in the urine from fetuses with posterior urethral valve (puv) and if these biomarkers are associated with the pathogenesis of this congenital anomaly. methods: urine samples from 24 fetuses with puv at a mean gestational age of 22 weeks (16-33w) were collected and compared to urine samples from 37 healthy male newborns (control group). cytokines, chemokines and ras components levels were measured by cytometric bead array (cba) and enzyme-linked immunosorbent assay (elisa). results: in comparison to healthy male newborns, fetuses with puv had significantly increased urinary levels of il-2 (p<0,0001), il-4 (p<0,0001), il-6 (p=0,0022), il-10 (p<0,0001), ifn-γ(p<0,0001), eotaxin (p<0,0001), mcp-1 (p=0,005), soluble receptors of tnf type 1 (p=0,0002) and type 2 (p=0,0004). this intense elevation of inflammatory molecules was accompanied by significantly increased urinary levels of angiotensin i (p=0,0017), angiotensin-(1-7) (p<0,0001), and ace 2 (p<0,0001). on the other hand, ace concentrations were significantly reduced and angiotensin ii levels were similar when compared to control group. conclusions: the increased levels of cytokines and chemokines suggest that puv leads to a pro-inflammatory state that might be part of the pathophysiology of this anomaly. the observed activation of the protective arm of the ras, formed by ace2-angiotensin-(1-7)-mas receptor, may play a role in modulating the intense inflammatory process triggered by puv. objectives: to compare outcomes of patients (pts) with luto stratified by severity using a prenatal classification system. methods: retrospective chart review of luto cases evaluated at the texas children's hospital fetal center from 2012-2015. luto classification: stage i: normal amniotic fluid level (>18wks gestation), favorable fetal urinary indices*, absence of renal cysts or dysplasia; stage ii: oligohydramnios (>18wks), severe bilateral hydronephrosis, favorable urinary indices, absence of renal cysts or dysplasia; stage iii: oligohydramnios (>18wks), severe bilateral hydronephrosis, unfavorable urinary indices, presence of renal cysts or dysplasia. *favorable fetal urinary indices: na <100meq/l, chloride <90 meq/l, osm <200 mosm/l, β2-microglobulin <6mg/l results: 42 total luto cases were seen in the study period. five underwent termination of pregnancy and 1 had intrauterine fetal demise. therefore, 36 pts were evaluated: 6 stage i, 18 stage ii and 12 stage 3. no pts with stage i luto had fetal intervention, while 100% of stage ii and 25% of stage iii underwent vesicoamniotic shunting. gestational age at delivery and birth weight were similar between the groups. a greater percentage of neonatal deaths occurred in the stage iii group (67%) compared with stage ii (17%) or stage i (0%). 75% of surviving stage iii pts required dialysis as neonates, and 100% were dialysis dependent by 1yr of age. overall, 64% of pts were alive at 1 yr. five pts underwent neonatal dialysis with 80% 1 yr survival. for non-dialysis pts estimated gfr at 1 yr was not significantly different between stage i and ii. conclusions: prenatal luto staging is clinically useful as it is strongly associated with both neonatal survival and the need for neonatal dialysis. in addition, luto pts who survive the neonatal period, regardless of the need for dialysis, are likely to be alive at 1 yr of age. s5 -blood pressure: high to low fp-s05-1 abpm in children and adolescents with renovascular hypertension b. leite (1) , g. batista (2) , l. suzuki (1) , l. drager (2) , e. furusawa (1) , v. koch (1) , a. watanabe (1) (1) instituto da criança -hc -fmusp, sao paulo, brazil; (2) hospital das clínicas -fmusp, sao paulo, brazil objectives: to describe clinical presentation and ambulatory blood pressure monitoring (abpm) profile in a pediatric cohort with renovascular hypertension (rvh). methods: retrospective descriptive study of a cohort of pediatric patients (pts) with rvh including analysis of abpm profile. results: 27 pts with rvh are described. the initial clinical presentation was hypertensive encephalopathy in 6/27; congestive heart failure 6/27; abdominal pain 2/27; irritability 1/27; epistaxis 1/27 and asymptomatic in 11/27 pts. median age was 4 years. all pts had systemic arterial hypertension stage 2. fibromuscular dysplasia was diagnosed in 8/27 pts, takayasu arteritis in 8/27, williams syndrome in 5/27, neurofibromatosis in 4/27, 1 pt was diagnosed with renal artery compression by pheochromocytoma. the vascular lesion presented as mid aortic syndrome with bilateral renal artery stenosis (ras) in 12/27 pts, unilateral ras in 10/27 and bilateral ras in 5/27 pts. besides anti-hypertensive medication, angioplasty was performed in 12/27 pts, aortorenal surgery in 9/27, auto-transplantation in 1/27, excision of pheochromocytoma in 1 pt; 4/27 pts were managed exclusively with anti-hypertensive medication. left ventricular hypertrophy was diagnosed in 21/27 children. 29 abpm studies were performed in 16 pts at different treatment phases; 24 abpm recordings were analyzed (5 were excluded by failure of the measures). after therapeutic management, only 1/16 pt achieved bp control by abpm standards: systolic and diastolic (s/d) bp means < 95th percentile and bp load < 25%, with s/dnocturnal bp dipping of 8.7% and 14.2% respectively. the remaining 15 pts demonstrated severe ambulatory hypertension, with sbp/ dbp means values â'â'> 95th percentile and loads > 50%. s/d nocturnal bp dipping was present in 5/24 (range 10% -18.3%) and 19/24 (range 12.1% -26.6%) recordings respectively. conclusions: rvh in children presents with severe hypertension and high morbidity. abpm is fundamental for bp control evaluation. fp-s05-2 escort trial -effects of strict control of blood pressure in pediatric renal transplant recipients -final results from a randomized controlled trial t. seeman, j. dusek, n. simankova, k. vondrak, j. zieg university hospital motol, charles university prague, 2nd faculty of medicine, prague 5, czech republic objectives: the aim of this 3 year randomized controlled trial was to investigate whether strict bp control can protect kidney graft. we present the final results. methods: all 23 children who fulfilled the inclusion criteria were randomized to standard bp group (stand, target 24hr map 50-95 th percentile, n=11) or intensified bp group (intens, target 24hr map <50 th percentile, n=12). the primary endpoint is the yearly change in egfr (schwartz), the secondary bp, proteinuria and left ventricular mass. results: a total of 21 children completed the study (2 children withdrawn due to steroid-resistant or antibody mediated acute rejection). the results on bp and proteinuria are given in the table, the results on egfr will be presented at the meeting. & map = mean arterial pressure, map index = mean patient's map/95th perc. conclusions: this is the first randomized controlled trial on bp control and its effects on graft function. it demonstrates that strict bp control is possible in the majority of children and that proteinuria did not change significantly. the data on graft function will show, whether strict bp control can retard progression of chronic graft dysfunction. supported by grant azv of the ministry of health cze 15-31586a.. first evidence of progressive left ventricular mechanical dysfunction during four year follow-up in children with ckd: the 4c study. m. chinali (1) , m.c. matteucci (1) , a. franceschini (1) , c. esposito (1) , k. azukaitis (2) , a. doyon (2) , f. drago (1) , f. schaefer (2) (1) bambino gesù pediatric research hospital, rome, italy; (2) university of heidelberg, heidelberg, germany objectives: we have previosuly shown (cjasn 2015) that despite normal traditional markers of cardiac funtion, children with ckd exhibit mechanical systolic dysfuntion characterized by lower radial strain and transmural systolic gradient. objective of our study wars to analyze the evolution of cardiac mechcanics through repeated echocardiografic examination in a large sample of children with ckd. methods: one hundred patients from the 4c study with repeated echocardiographic examinations troughout four years of follow-up were included in the study. left ventricular (lv) hypertrophy was defined using the simplified approach recently described by our group (j peds 2016). advanced parameters of cardiac funtion included longitudinal epicardial and endocardial strain, circumferential epicardial and endocardial strain as well as radial strain. results: during four years of follow-up no significant changes in ejection fraction could be observed in the whole population. in contrast changes in cardiac mechcanics parameters could be observed during the study period in both endocardial circumferential strain (mean difference 6.05+/-2.02%) and longitudinal strain (mean difference 4.15+/-1.76%; p for both <0.05). no change in parameters of cardiac mechanics could be observed in children with normal lv mass at baseline (p=ns for all), while a significant reduction of cardiac systolic parameters was found in children with baseline lv hypertrophy in both endocardial circumferential strain (mean difference 9.12+/-4.14%) and longitudinal strain (mean difference 7.55+/-2.43%p for both <0.02). in time varying covariate analysis, main determinants of progressive reduction in cardiac mechaincs were the presence of lv hypertrophy and of lv concentric geometry. conclusions: despite parameters of traditional caridiac function remain normal during the years, in the presence of lv hypertrophy, progressive deterioration of cardiac mechanics can be observed in children with chronic ckd. objectives: to assess the prevalence of blood pressure abnormalities by ambulatory blood pressure monitoring (abpm) in a large european cohort of children with autosomal dominant polycystic kidney diseases (adpkd). methods: multicentric retrospective study. inclusion criteria: age < 18 years, abpm recording, basic anthropometric and laboratory data, adpkd diagnosis based on family history and renal cysts or on genetic test. results: 310 patients were enrolled in 22 european centers (m:f ratio 162:148; mean age 11.5 ± 4.2 years). when present, paternal and maternal inheritance were equally distributed (43% -44%). a minority of patients underwent genetic testing: pkd1 and pkd2 mutations were reported in 32% and 0% of patients, respectively. only 7 patients (2.2 %) had a egfr < 90 ml/min/1.73mq. overall, 34% of patients had 24h mean abpm values > 95th percentile or were treated with blood pressure medications. pre-hypertension was present in 10% of patients and borderline hypertension in 26% of patients. daytime heart rate was significantly lower in adpkd children compared to healthy controls (p<0.001). a significant proportion of patients had elevated nighttime blood pressure values: 35% were non-dippers and 19% had isolated nocturnal hypertension. as expected, the proportion of patients with enlarged kidneys increased with age; conversely, correlation between age and hypertension was weak. further rhythm analysis revealed a very high prevalence of circadian and ultradian rhytms in adpkd patients, including pre-pubertal children. these abnormalities exceeded those reported in children with chronic renal failure. conclusions: despite potential recruitment biases, this study shows very high prevalence of blood pressure abnormalities in children with adpkd, suggesting autonomic dysregulation and early onset of cardiovascular damage. fp-s06-1 detection of novel non-labelling biomarkers of progressive glomerulonephritis using fourier transform infrared spectroscopy m-c. yu (1) , r. peter (2) objectives: more reliable biological markers using near patient technology are desirable to improve early diagnosis of patients at risk of progressive kidney disease. over the past two decades, fourier transform infrared spectroscopy/microscopy has been increasingly applied to biomedical research such as cancer. however, thus far ftir methods have not yet been applied to detection of progressive kidney diseases. therefore, in the study, this technology was employed to analyze urine and plasma samples collected from rodent models of progressive glomerulonephritis (gn), with the aim of discovering more sensitive biomarkers of renal injury. methods: experimental gn: nephrotoxic nephritis (ntn) was induced in male wistar kyoto rats. urine and plasma were collected from nephritic rats on day 8, day 14, day 21 and day 28 and compared with samples from normal rats . corticosteroid treatment in experimental gn: (1) healthy control group (2) treatment group: ntn rats treated with 0.25 mg/ kg of dexamethasone (dxm), ip every 4 days, and (3) vehicle group : ntn rats treated with pbs, ip every 4 days. a series of urine was collected and plasma samples were taken at the time of cull. sample spectra were recored by ftir spectrometer and data was anayzed using origin 9.1. results: three spectral markers at 1668 cm -1 , 1545 cm -1 and 1033 cm -1 were identified in urine and their intensity changes were in accordance to acute renal injury, progressive renal injury and chronic renal failure, respectively. in particular, the intensity of urinary 1545 cm -1 marker was reduced in response to dxm treatment. besides, there were three potential plasma spectral markers identified at 1705, 1460 and 1240 cm -1 , respectively, showing that their intensity changes were parallel to the deterioration of renal injury. conclusions: the specific urinary/plasma ftir biomarkers can be the noninvasive and sensitive approach of early diagnosing and/or real-time monitoringprogressive kidney disease. objectives: although esi has been linked to peritonitis in pediatric pd, little data exists as to esi frequency and clinical factors influencing its manifestation. scope aims to reduce pd-associated infections through the systematic implementation of standardized care practices, including stipulated es care and an es-scoring tool. we sought to elucidate esi rates, predisposing clinical factors, and esi outcomes in children on pd. methods: scope data collected10/1/11-9/30/14 were analyzed, including demographic and infection detail. esi was defined as purulent drainage or exit site score >4 or treatment for esi. fp-s07-2 the role of peritoneal biopsy for the pediatric patients on peritoneal dialysis suspected of encapsulating peritoneal sclerosis. r. harada (1) , r. hamada (1) , h. satoh (1) , y. hamasaki (2) , k. ishikura (3) , h. hataya (1) , r. fukuzawa (1) , m. honda (1) (1) tokyo metropolitan children's medical center, fuchu-shi, japan; (2) toho university faculty of medicine, tokyo, japan; (3) national center for child health and development, tokyo, japan objectives: to evaluate the usefulness of peritoneal biopsy in japanese pediatric patients on peritoneal dialysis (pd) suspected of encapsulating peritoneal sclerosis (eps). methods: we retrospectively studied the data from children who underwent peritoneal biopsy from january 1979 to december 2014 at tokyo metropolitan children's medical center. all patients had at least one of the following characteristics, clinical symptoms of eps, poor ultrafiltration and a long period of pd (more than 5 years). the results were divided into an existing symptoms group and an asymptomatic group based on their clinical symptoms of eps such as vomiting and/or bloody ascites. we compared the pathological results and the treatment after biopsy of two groups. results: fifty-four cases were reviewed in this study. the median age at introduction of pd was 8.0 (range 0.0-25.9 years). ten cases were existing symptoms, while 44 were asymptomatic before peritoneal biopsy. at the biopsy, the median duration of pd continuation was 7.0 years (5.5-12.1) and 5.7 years (0.6-15.7) respectively. in both groups, most of the biopsy results showed mesothelial denudation, interstitial fibrosis, capillary angiogenesis and vascular sclerosis. after biopsy, all the patients in the existing symptoms group needed treatment for preserving peritoneum. while in the asymptomatic group, 33/44 (75%) required treatment, but 11/44 (25%) were able to see the progress without treatment. the biopsy results of the patients without treatment in the asymptomatic group were significantly fewer instances of mesothelial denudation and vascular sclerosis than those of the patients required treatment (p<0.01). there were two cases of peritonitis after biopsy as complications. conclusions: the peritoneal biopsy is useful for deciding treatment intervention for those who have no eps symptoms. the pd membrane microvasculature in uremia and pd -recent findings from the international pediatric pd biobank b. schaefer (1) , m. bartosova (1) , c. taylan (2) , j. vande walle (3) , u. querfeld (4) , r. krmar (5) , b.a. warady (6) , c.p. schmitt (1 results: the parietal peritoneum exhibits marked age dependent differences in vascular density, with highest blood capillary density and endothelial exchange area in infancy and lowest values in children aged 7-12 yrs. lymphatic vessel density is markedly lower, but again 70% higher in infants. omental blood capillary density correlates with parietal capillary density (r = 0.391; p = 0.03), small lymphatic vessels are few. uremia reduces omental but not parietal blood vessel density by 51%, angp-2 levels are 78% lower. the submesothelial 3 vessel layer structure dissipates with low gdp pd, blood vessel density increases 2-3 fold, as do tgf-ß/psmad, vegf, activated fibroblast and cd45/cd68+ macrophage abundance. mild lumen narrowing develops in 31% of blood vessels, lymphatic vessel density remains low. emt and profibrotic cd90+ fibroblast subpopulations appear more prevalent with high gdp pd-fluids. d/p creatinine ratios correlate with parietal peritoneal vessel density at baseline (r=0.49, p<0.05), and while on pd (r=0.57, p=0.08) but not with submesothelial thickness. conclusions: peritoneal vessel density defines peritoneal membrane transport function. despite low gdp fluid usage, progressive blood capillarisation develops with time on pd, while lymphatic vessel density remains low. fp-s08-1 pkhd1 mutation in autosomal recessive polycystic kidney disease (arpkd) : genotype-phenotype correlations from a series of 308 cases s. hamo (1) , j. bacchetta (2) , a. bertholet-thomas (2) , p. cochat (2) , l. calemard (3 objectives: arpkd is a recessive orphan disease due to pkhd1 mutations. the main objective of our study was to characterize the phenotypic variability of patients with pkhd1 mutations, according to the different types of mutations. methods: this study was performed in a cohort of 308 arpkd patients with a genetic diagnosis made in our genetic centre. we asked prescribing physicians to provide minimal clinical data, and sent them a questionnaire to retrospectively update the main outcomes. results: patients were divided into three genotypic groups: the first group (g1,n=65) consisted of patients with two truncating mutations, the second group ( g2, n=117) of patients with one truncating and one non-truncating mutation, and the third group ( g3, n=126) of patients with two non-truncating mutations. the proportion of severe arpkd (e.g. pregnancy termination or neonatal death) was significantly greater in g1: 94% in g1, 47% in g2 and 27% in g3 (p<0.05). 77 patients suffered from chronic kidney disease (ckd): g1 n=4, g2 n=28 and g3 n=45. notably, two patients from g3 developed ckd before the age of 3 months. renal transplantation was performed in 13 patients ( g1 n=0; g2 n=5; g3 n=8). portal hypertension occurred in 61 patients at a mean age of 13.9 years; oesophageal varices were present in 18 patients and complicated by bleeding in 14 patients (g1: n=0, g2: n=9, g3: n=5). three patients received a liver transplant (g2 n=2, g3 n=1, 23, 32 and 33 years), and one patients underwent combined kidney/liver transplantation (g2 ,23 yrs). seven patients died after the neonatal period, 2 from g1, 3 from g2 and 2 from g3 (p<0.05). the presence of two truncating mutations in pkhd1 is associated with a more severe perinatal and later-in-life phenotype. however, there is a phenotypic variability that requires great caution during prenatal councelling. fp-s08-2 3d-us with a correction factor is a good alternative in estimating total kidney volume in children with objectives: total kidney volume (tkv) has been shown in adult autosomal dominant polycystic kidney disease (adpkd) to be an independent and strong predictor for disease progression. in the current interventional clinical trials, tkv measurement by magnetic resonance (mr) imaging has been shown to be more accurate, reproducible and able to detect small changes over a short period of time compared to ultrasound (us). since future therapies in adpkd could be extended to include children, we aimed to examine whether the high-resolution 3d-us tkv measurements might be used as an alternative method to mr measurements in adpkd children methods: prospective evaluations of renal mr, 2d-and 3d-us were performed, whereby tkv was calculated by means of manual delineations (mr, 3d-us) or by the ellipsoid method (2d-us). correlations and differences between parameters were evaluated using pearson r and wilcoxon signed rank tests. after correction using the optimal linear regression, the variability of the measurements was examined using bland-altman plots results: we studied 29 patients (17 male, 12 female) with a median age (sd) of 14.0 (3.4) years and egfr 111 (17) objectives: mutations of the pkhd1 gene cause autosomal recessive polycystic kidney disease (arpkd). pkhd1 encodes fibrocystin (fpc), a ciliary type i membrane protein of largely unknown function, suggested to affect adhesion signaling of cells. contributions of epithelial cell adhesion and contractility to the disease process of arpkd are elusive. here, we establish a link between loss of fpc function and epithelial morphogenesis in 3d cell culture, cell contact formation and cytoskelal networks. methods: we analyze fpc function in madin-darby canine renal collecting duct epithelial cells (mdck) based on pkhd1 silencing. cells are studied on micro-pattered chips in 3d cell culture conditions allowing analysis of polarity, lumen formation and ciliogenesis in epithelial spheroids. quantitative automated image processing is applied to analyze z-stacks of 5-color fluorescence images. to determine critical differences in cell adhesion parameters, mdck cells are studied also on chips in their one and 2(4)-cell stages. activation of adhesion signaling is addressed based on phosphorylation of the fak/src axis. results: using defined adhesion conditions, we quantified the impact of fpc deficiency on size / density of adhesion sites, cell shape characteristics and initiation of an apical surface. effects on apicobasal polarity and lumen formation correlate significantly with positioning of centrosomes in 2(4)-cell stages and activation of adhesion signaling. in addition, fpc deficient cells reveal defects in the formation of correctly polarized epithelial spheroids. transient reduction of actomyosin contractility restores 70% of correct epithelial morphogenesis (p<0.01). conclusions: fpc silencing in mdck cells disturbs adhesion signaling and cell-cell interaction resulting in impaired epithelial morphogenesis. using a cell-based model system, we address molecular consequences of and analyze quantitatively rescue strategies for fpc deficiency in collecting duct epithelia. followed by those on hemodialysis (40.0, p=<0.0001) but even those with high score did not reach 50% of the score. on multinomial logistic regression and using those with high scores (>60) as referent group, dialysis patients had a significantly lower hct readiness score. conclusions: despite the socioeconomic difference in the populations served at both institutions, the sample's overall low score. patients who have a renal transplant had the greatest hct readiness scores, and this may reflect the more intense preparation and patient education prior to transplantation. three-year-pediatric peritoneal dialysis experience in benin: challenges and successes f. lalya (1) , y. tohodjede (1) , m. d'almeida (1) , a. hadonou (2) , p.c. hounkpe (3) , b. ayivi (1) objectives: nigeria has the largest burden of sickle cell anaemia (sca) in the world. kidney abnormalities are established findings in children with sca and are known to start early in childhood. the study objective was to determine the risk factors associated with microalbuminuria in children with sickle cell anaemia and the relationship between it and glomerular filtration rate methods: the study was descriptive and cross sectional involving 323 children with sickle cell anaemia in steady state and equal number with normal haemoglobin, age and sex matched as control. they were aged 6 months to 18 years and consecutively recruited from the paediatric outpatient department of the jos university teaching hospital between september and december 2013. anthropometric, demographic characteristics and clinical parameters of each child and the social status of the parents were obtained. spot urine and venous blood samples were obtained for determination of microalbuminuria, packed cell volume and serum creatinine respectively. results: the prevalence of microalbuminuria in children with sca was 26% in 84 children, compared to 1.85% in controls. of this, 87% were aged ten years or less and there was no sex difference. anaemia and elevated glomerular filtration showed strong positive correlation with microalbuminuria, however, age, low socio economic status, number of siblings with sca, did not. glomerular filtration rate was higher in subjects with sca than controls and as well in those with microalbuminuria compared to those without microalbuminuria (p<0.01). conclusions: the prevalence of microalbuminuria in children with sca in this study is high. the mean glomerular filtration rate is particularly higher in those with microalbuminuria compared with those without. this finding underscores the need for concerted effort at routine screening of sca children for microalbuminuria for the purpose of earlier detection of sickle cell nephropathy and appropriate therapeutic measure. s10 -global perspectives on registries fp-s10-1 congenital nephrotic syndrome of the finnish type, espn/era-edta registry data t. holtta (1) , m. bonthuis (2) , k. jager (2) , j. groothoff ( , and most of recipients were male (55.5%). the most common underlying renal etiologies were congenital anomalies of the kidney and urinary tract (46.7%) and glomerulopathy (33.5%). according to donor source, 1566 (69.3%) of transplants were performed with deceased donors (dd). graft survival rates according to donor source at 12, 60, and 120 months were 94%, 85%, and 72% for living donor (ld) and 91%, 76%, and 62% for dd, respectively (log rank test, p < .01). graft losses (20%) were most frequently caused by vascular thrombosis, chronic allograft nephropathy, death with functioning kidney, acute rejection, and recurrent renal disease. recipients of dd had 1.54 (95% confidence interval:1.04-2.30) times the hazard of graft loss compared with those of ld (p < 0.05). patient survival rates at 1, 5, and 10 years were 98%, 95 and 92% for ld and 97%, 93%, and 97% for dd, respectively. the mortality rate was 5.6%, mainly as the result of infection and cardiovascular disease. conclusions: the results of this collaborative pediatric transplant study are comparable to international registries. our effort has been able to maintain an exchange of information, both among the participating centers and with other international registries. fp-s10-3 turkish atypical hemolytic uremic syndrome registry: evaluation of long term prognosis a. soylu (1) , k. güllero?lu (2) , i̇. gökçe (3) , g. parmaks?z (4) , h. evrengül (5) , g. kaya aksoy (6) , m. hayran (7 esrd risk was increased in children >2 years of age at onset, while chronic renal disease was higher in the presence of extrarenal organ involvement, nephrotic range proteinuria at onset and cfh mutation. presence of hypocomplementemia was associated with lower risk of chronic renal disease. interestingly, proteinuria, hypertension and overall chronic renal disease rate was higher in those treated with eculizumab. conclusions: more than half of the children with ahus developed chronic renal disease. age over 2 years at onset, extrarenal organ involvement, nephrotic range proteinuria and cfh mutation were associated with poor renal prognosis. fp-s11-1 serum fractalkine (cx3cl1) is associated with abnormal carotid and femoral intimal medial thickness in pediatric chronic kidney disease. q.z. chee (1) , i.d. liu (1) , m. than (1) conclusions: cx3cl1, an inflammatory atherogenic chemokine, is associated with severe arteriopathy in children with ckd. fp-s11-2 novel method for the definition of left ventricular hypertrophy improves identification of risk phenotype in children with ckd m. chinali (1) , m.c. matteucci (1) , c. esposito (1) , a. doyon (2) , a. franceschini (1) , f. drago (1) , f. schaefer (2) , f. emma (1) (1) bambino gesù pediatric research hospital, rome, italy; (2) university of heidelberg, heidelberg, germany objectives: we have recently reported that traditional indexation of lv mass to the allometric power of 2.7, as curretly reccomended by current guidelines, may result in a significant overestimation of lv hypertrophy in younger children. accordingly we have suggested a simplified indexation approach to overcome this issue (j peds 2016). objective of the present study was to verify whether our proposed indexation improves risk stratification in ckd children. methods: overall 547 children with available echocardiographic data, from two multicenter european studies on ckd were included (237 from the escape trial and 310 from the 4c study). presence of lv hypertrophy was defined using partiction values suggested by currect guidelines (lvm>38g/m2.7) and by our recetluy suggested approach [lvm>(45g/m2.16)+0.09]. differences in the two methods in the identification of children with impaired systolic function were reported. results: using the traditional partition value lv hypertrophy (tlvh) could be identified in 217 children representing 39.6% of the total population. in contrast, our proposed method identified lv hypertrophy (nlvh) in 183 children, reporesenting 33.4% of the whole population. despite major accordance among methods (kappa score 0.78), tlvh was identified in 46 patients without nlvh, while nlvh identified 12 patients without tlvh. of note, children with tlvh, but not nlvh were significantly younger as compred to the rest of the population (8.12+/-3.45years vs 14.32+/-5.22years) and did not show any reduction in measures of chamber and or regional cardiac funtion (all p=ns). conclusions: traditional definition of lv hypertrophy significantly overestimates the prevalence of lvh in children with ckd. overestimation is more prominent in the very young children, in which no abnormalities in cardiac function are in fact found. our porposed simplified approach for the definition of lv hypertrophy reduces this overestimation and improves correct risk stratification in ckd children. fp-s11-3 very high resolution ultrasound reveals intimal and medial vascular remodelling in dialysis and transplant patients f. dangardt (1) , d. bhowruth (1) , a. rapala (1) , m. charakida (1) , d. thurn (2) , f. schaefer (2) , j. deanfield (1) , r. shroff results: at baseline, radial artery it and pedal mt were increased in patients compared to controls, most markedly in children on dialysis. children who had been on dialysis for more than one year had significantly greater carotid and dorsal pedal mt compared to those on dialysis for less than one year (p=0.007). in the ckd and dialysis cohort (n=39), higher carotid mt at baseline was associated with increased serum phosphate (p<0.001, r=0.42) and pth levels (p=0.03, r=0.27). no correlation was seen with 25hydroxyvitamin d, fgf23 or bmi on any vascular measures. higher carotid and radial it were associated with higher lipid levels (p=0.03, r=0.31) in all patients. at 1-year follow-up transplanted children had a 17% decrease in carotid mt (p=0.01) but not it. increased dorsal pedal it in transplanted patients was associated with a higher systolic bp z-score (p = 0.2, r = 0.22). the composite measure of cimt by cus did not reveal any significant changes in it at baseline and follow-up. conclusions: ckd patients have modifiable risk factors for intimal and medial vascular disease which were not detected by cus. our findings suggest vascular remodeling in response to a changing cardiovascular risk factor profile after transplantation and provides important information for effective cv risk stratification and treatment. fp-s12-1 x linked hypophosphatemia (xlh) and growth: gh and mapki treatments r. fuente (1) , h. gil-peña (2) , l. alonso (2) , o. hernández (1) , á. férnandez (1) objectives: to analyze the potential effect on growth and bone of p-erk1/2 inhibition (blocking of fgf23-mapkinase pathway) in comparison with gh treatment using young hyp-mice, a model of xlh. methods: 4 groups (n=6) of mice: wild-type (wt), control hyp (hyp), hyp treated with gh (hyp-gh, 3.33 mg/kg/day) and with p-erk1/2 inhibitor (hyp-mapki, 7.5 mg/kg/day). studies after 1 week: serum phosphate, kidney p-erk1/2 expression and napi-transporter function, tibia's growth plate histomorphometry, igf-1 expression, proliferation and apoptosis, bone mineralization and structure (uct and von-kossa) and osteoclastic activity (trap). results: both treatments improved hypophosphatemia (wt=7.65±0.37, hyp=3.16±0.22, hyp-gh=5.26±0.06, hyp-mapki=5.08±0.03 mg/dl; p<0.05) but not as a result of higher renal napi activity. nose-tail and tibia lengths were significally increased by these treatments. in growth plate ( figure) , gh as well as mapki increased the terminal chondrocyte' height, local igf1 expression and chondrocyte proliferation rate (table) . caspase signaling was negative for all hyp groups, indicating marked alteration of apoptosis. growth cartilage disorganization was only improved by mapk inhibition which also increased bone mineral density (wt:0.26±0.01;hyp:0.20 ±0.01;hyp-gh:0.23±0.02;hyp-mapk:0.26±0.018 cm3/g; p<0.05) and trabecular number (wt:5.9±0.3;hyp:5.4±0.1;hyp-gh:6.1±0.1;hyp-mapk:7.3 ±0.5; p<0.05). in contrast, gh enhanced cortical thickness to a greater extent (wt=0.14±0.004, hyp=0.07±0.03, hyp-gh=0.09±0.09 hyp-mapki=5.58 ±0.27 mm; p<0.02). trap and von-kossa staining fitted with micro-ct analysis, and disclosed lower amount of osteoid in treated mice (table) . conclusions: gh administration and blocking of mapk pathway improve hypophosphatemia, bone mineralization and body length in hyp mice, but only mapki is able to normalize growth plate structure and orientation. gh administration did not correct these alterations, which may imply an increased risk of bone deformities. fp-s12-2 progression of ckd and its determinants in children with ocrl mutations -retrospective analysis of a large international cohort d. böckenhauer (1) , m. zaniew (2) , a. bökenkamp (3) , m. ludwig (4) , m. konrad (5) , f. anglani (6) , m. addis (7) , h. il cheong (8 objectives: lowe syndrome (ls) and dent2 disease (dd2) are both ultrarare x-linked disorders associated with mutations in the ocrl gene and characterized by progressive chronic kidney disease (ckd). here, we aimed to investigate determinants of ckd and its progression in children with these tubulopathies. methods: retrospective, analyses of clinical and genetic data in a cohort of 106 boys (ls: 88 and dd2: 18). for genotype-phenotype analysis, we grouped mutations according to their type and localization. results: median egfr was lower in the ls group compared to dd2 (58.8 vs. 87.4 ml/min/1.73 m 2 , p<0.05). ckd stage ii-vwas found in 81% of all patients, of these 58% and 27% had moderate to severe ckd, in ls and dd2 respectively. esrd was found in three individuals with ls. trajectories of egfr showed a slow progression of ckd with a decline in egfr at the age of 10 years in the ls group, whereas in subjects with dd2, egfr remained stable throughout childhood. moreover, patients with mutations clustered in exons 21-24 had lower egfr and worse ckd progression. there was no significant association between type of mutation, presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and ckd. overall, 54% were treated with alkali therapy for acidosis. conclusions: this study shows worse ckd progression for children with ls compared to dd2. localization, but not type of mutation is associated with ckd progression. fp-s12-3 significant increase in urinary excretion of apolipoproteins and fatty acid-binding protein in children with nephrolithiasis and hypercalciuria l. kovacevic (1) , t. govil-dalela (1) , n. kovacevic (1) , h. lu (1) , j.a. caruso (2) , r. thomas (1) , y. lakshmanan (1) (1) children's hospital of michigan, detroit, united states; (2) institute of environmental health sciences, wayne state university, detroit, united states objectives: using a proteomic model and pooled samples, we have recently identified several urinary proteins involved in lipid transport and metabolism in children with nephrolithiasis and hypercalciuria (cal). in the current study, we aimed (1) to confirm these results in individual samples by performing enzyme-linked immunosorbent assay (elisa), and (2) to examine the relationship between the urinary excretion of selected proteins with demographic, dietary, blood, and urinary parameters. methods: prospective, controlled, pilot study comparing the urinary excretion of apolipoprotein a4 (apoa4), apolipoprotein c3 (apoc3), and fatty acid-binding protein 1 (fabp1) between cal (n=16, 9 females, mean age 11.8+/-4.1 years), and their age-and gender-matched healthy controls (hc)(n=14)(ttest). exclusion criteria included obese children (bmi>/= the 95th percentile for children of the same age and sex). results: statistically significant increase in the urinary excretion of apoa4, apoc3 and fabp1 in cal group vs hc was found (table) . apoa4 and apoc3 levels were higher in boys compared to girls. in the cal group, urinary apoa4 was positively correlated with urinary apoc3 (r=0.68, p<0.001), and intake of meat (r=0.65, p<0.011). 24-hour urinary calcium excretion significantly correlated with concentrations of apoc3 (r=0.77, p<0.001), and fabp1 (r=0.80, p=0.005). & apolipoprotein a4 (apoa4), apolipoprotein c3 (apoc3), and fatty acid-binding protein 1 (fabp1) conclusions: we found marked increase in urinary excretion of lipid metabolism/transport-related proteins in non-obese children with nephrolithiasis and hypercalciuria. these findings suggest that abnormalities in lipid metabolism may play an important role in nephrolithiasis. targeting these proteins may have preventive and therapeutic benefits. objectives: single center studies report neonatal acute kidney injury (aki) incidence of 12-70%; neonates with aki appear to have worse outcomes. these findings prompted the formation of the neonatal kidney collaborative (nkc) and the development and implementation of the awaken study. the objective of this study is to assess the incidence of neonatal aki and its association with outcomes in a large, multi-national cohort methods: nkc includes 24 institutions from 4 countries (usa, canada, australia and india). neonatal intensive care unit (nicu) admissions from jan 1 to mar 31, 2014 were screened. inclusion criteria need for intravenous (iv) fluids ≥48 hrs. exclusion criteria: 1) admission at > 2 weeks of age, 2) congenital heart disease requiring surgical repair at < 7 days of age, 3) lethal chromosomal anomaly, 4) death within 48 hours of admission, 5) severe congenital kidney disease. aki was defined as either urine output (uop) < 1 ml/ kg/hr during any 24 hour period from days 2-7 of life, a rise in serum creatinine (scr) of 0.3 mg/dl from previous lowest value and/or receipt of renal replacement therapy. (table) conclusions: our study demonstrated that at least 35.4% of infants admitted to nicu who required iv fluids develop aki. subjects with aki have worse increased risk of death and longer los. our data contribute to the growing evidence that neonatal aki is common, with significant impact on clinical outcomes. further analysis of this robust database is underway. fp-s13-2 the follow up and outcome of children requiring renal replacement therapy for acute kidney injury following cardiac surgery in new zealand c. chan, t. kara starship children's hospital, auckland district health board, auckland, new zealand objectives: to examine the characteristics, follow up and availability of long term outcome data in a cohort of new zealand children with acute kidney injury (aki) requiring renal replacement therapy (rrt) following cardiac surgery at starship hospital over a six-year period. methods: the cohort used was identified in the previously published "epidemiology and outcome of acute kidney injury in new zealand children". aretrospective review of medical records of all the children requiring rrt for aki following cardiac surgery from january 2001 to december 2006 was repeated to add further data regarding their cardiac history. patient characteristics were summarised. primary outcome was rates of renal surveillance. evidence of renal dysfunction and possible contributing factors were also studied. conclusions: this study suggests that a proportion of children who have had cardiac surgery have ongoing renal dysfunction at 5 years. the care of this group of children, and identification of others at risk, could be improved by increasing awareness. a standardised monitoring guideline could provide surveillance over time and enable collection of further data. fp-s13-3 hemodialysis in neonates and infants: a systematic review r. raina (1) , m.s. ascha (2) , j. darusz (1) , s.k. sethi (3) (1) akron children's hospital, cleveland, united states; (2) case western reserve university, cleveland, united states; (3) medanta, the medicity, gurgaon, india objectives: background: hemodialysis (hd) in neonates and infants can be both difficult to implement and to maintain. objectives: to determine the effectiveness, safety and feasibility of hemodialysis in infant population by a systematic review. methods: design: systematic review, 1990 onwards studies. pubmed/ medline search using the search term, "hemodialysis". the medical subject heading (mesh) term "infant" was used to return results that pertain to pediatrics. population: neonatal patients 0-12 months of age treated with hd for indications related to acute kidney injury (aki). selection criteria: retrospective reviews not including studies solely concerned with peritoneal dialysis or continuous renal replacement therapies, studies of economic or ethical issues in dialysis care, pharmacological studies, and articles not reporting data on a majority of patient's ages. of the 1310 returned results, only 9 studies were eligible for review. results: nine studies reported hd use in a total of 104 neonatal patients. a pooled mean age of 3.1 months (range: 2 days to 12 months) was calculated. among all subjects, there was 38% mortality, and a 33% rate of transplantation. 42% of patients presented with metabolic issues, 32% with acute kidney injury, and 17% with renal dysplasias. hd prescription vascular access was primary achieved via the internal jugular vein followed by the subclavian. the most common complications were mechanical catheter dysfunction and hemodynamic issues such as hypotension and anemia patient outcomes 39 of 104 total patients died, resulting in a mortality rate of 37.5%. conclusions: treating neonatal and infant patients with hd may pose many challenges, but it is a feasible treatment modality and when executed properly can quickly reverse pathology. such techniques such as blood priming, minimizing extracorporeal volume, and increased maintenance of vascular access can all potentially improve patient outcomes. s14 -therapies for difficult the nephrotic syndrome fp-s14-1 hyporesponsive t-cell activation subsets predict favorable rituximab response in patients with focal segmental glomerulosclerosis (fsgs) c.y. chan (1) , i.d. liu (1) , l.p. resontoc (1) , k-h. ng (1) , y-h. chan (1) , k-p. lam (2) , w-s. yeo (1) , h-k. yap (1) (1) national university of singapore, singapore, singapore; (2) agency for science, technology and research (a*star), singapore, singapore objectives: the use of rituximab in refractory idiopathic nephrotic syndrome especially fsgs has met with variable success. as b-cell depletion can impact t-cell function, this study aimed to characterize t-cell subsets in fsgs patients in order to identify an immunological signature predictive of favorable response to rituximab therapy. methods: 22 consecutive fsgs patients (median age 14.4 years, range 6.2-25.0 years) who received rituximab as third line therapy following steroids and calcineurin inhibitors (cni), were included in the study. clinical parameters including urinary protein excretion and serum albumin, as well as immunological subset monitoring were performed at baseline, 14-days, 1-month, and subsequently 3-monthly until relapse. baseline immunological subsets were compared between rituximab responders and non-responders, as well as 22 patients with minimal change nephrotic syndrome (mcns) in relapse and 30 healthy controls, using mann-whitney u test. paired comparison was done using wilcoxon signed rank test. results: 12 of 22 patients (54.5%) responded to rituximab therapy, defined as resolution of proteinuria and ability to wean off steroids and cni at 3 months following rituximab treatment. mitogen-stimulated t-cell activation subset expressions are shown in the table 1 below. mitogen-stimulated cd154 + cd4 + cd3 + expressions before rituximab were significantly lower in fsgs responders compared to non-responders and controls. ifn-γ + cd3 + and il-2 + cd3 + were similarly decreased in fsgs responders compared to nonresponders, mcns and controls. significant recovery of all 3 subsets in fsgs responders occurred 6 months post-rituximab treatment. using roc analysis, activated cd154 + cd4 + cd3 + (auc 0.81, 95% ci 0.61-1.01), ifn-γ + cd3 + (auc 0.90, 95% ci 0.75-1.05) and il-2 + cd3 + (auc 0.78, 95% ci 0.57-0.98) were good predictors of response to rituximab. & table 1 : t-cell activation subsets pre-rituximab and 6 months postrituximab in fsgs rituximab responders and non-responders compared to mcns patients in relapse and healthy controls. conclusions: t-cell subset hyporesponsiveness to mitogen stimulation predicted a favorable response to rituximab in fsgs patients. fp-s14-2 risk factors for relapse after b-cell recovery : a course after rituximab treatment in children with steroid-dependent nephrotic syndrome h. nagata (1) , k. kamei (1) , t. yoshikawa (1) , m. sato (1) , m. ogura (1) , s. ito (2) , k. ishikura (1) (1) national center for child health and development, tokyo, japan; (2) department of pediatrics, yokohama city university school of medicine, yokohama, japan objectives: rituximab is used for the treatment of refractory steroiddependent nephrotic syndrome (sdns) in children. we have previously reported that a history of steroid resistant nephrotic syndrome (srns) is a risk factor for early relapse after the treatment of single dose of rituximab followed by immunosuppressants (kamei k et al. pediatr nephrol 2016) . however, duration of b-cell depletion is different between each patient. here, we investigated the duration between b-cell recovery and first relapse and calculated risk factors for early relapse after b-cell recovery. methods: we retrospectively reviewed the medical records of children with refractory sdns who received a single dose of rituximab (375 mg/m 2 ) between june 2007 and november 2013. all patients continued immunosuppressants after rituximab treatment. b-cell recovery was defined as cd19>1% lymphocyte after rituximab treatment. kaplan-meier analyses for relapse after b-cell recovery were conducted. the differences between groups (history of srns (sr) vs. no history of srns(nsr)) were compared using the log-rank test. hazard ratio and 95% confidence interval (ci) for relapse after b-cell recovery was evaluated by the cox regression analysis. results: fifty-five patients (40 boys and 15 girls) received rituximab. the median follow-up period were 308 days (35-2,505 days). fifty-percent relapse free survival was significantly shorter in sr than in nsr (238 days vs. 1,001 days, p=0.014) ( figure 1 ). results of cox regression are shown in table 1 . controlling for age of onset, age at rituximab administration, gender and renal histology, the risk ratio of a history of srns for relapse after b-cell recovery was 2.96 (95% ci, 1.38-6.62; p=0.005). conclusions: a total of 71.2% of the children experienced ns relapse in 3 years after b-cell recovery. a history of srns was a significant risk factor for early relapse. intensified immunosuppressants with rituximab may be beneficial for these patients to prevent early relapse after b-cell recovery. fp-s14-3 effect of atorvastatin on lipid profile and carotid intima media thickness (cimt) in children with refractory nephrotic syndrome: a randomized double blind, placebo controlled, trial p. hari, a. satpathy, r. thergaonkar, p. khandelwal, s. hari, r. lakshmy, a. sinha, a. bagga all india institue of medical sciences, delhi, india objectives: role of statins for treatment of hyperlipidemia in children with nephrotic syndrome is unclear. we examined the lipid-lowering efficacy of atorvastatin and its effect on the cimt and brachial artery flow mediated dilatation (fmd) and safety in children with refractory nephrotic syndrome and hyperlipidemia. methods: children with refractory nephrotic syndrome and ldl-cholesterol (ldl-c) >130 mg/dl were randomized to receive atorvastatin (10 mg/day) or placebo for 1 year. lipid, creatinine phosphokinase (cpk), serum albumin, transaminase, c-reactive protein (crp) levels and estimated gfr were measured at baseline, 3, 6 and 12 months; cimt and brachial artery fmd was measured at baseline, 6 and 12 months. primary outcome was mean difference in reduction of lipid levels, cimt and brachial artery fmd. results: 30 children (mean age 11.4 yr) were included; 15 each were randomized to receive either atorvastatin or placebo ( figure 1 ). baseline characteristics were similar in both groups. at 12 months, median reduction in lipids in atorvastatin versus placebo was similar in total cholesterol, ldl-c, triglyceride, apolipoprotein a and high density lipoprotein (p>0.5; table 1 & study flow and outcome after 12 months of administration of atorvastatin conclusions: therapy with atorvastatin (10 mg/day) for a year significantly reduced apolipoprotein b levels but was ineffective in reducing other lipoproteins in children with refractory nephrotic syndrome; there was no beneficial effect on cimt and brachial artery fmd. serum albumin was a strong independent predictor of the lipid levels in these children. fp-s15-2 il-6 disruption improves anemia but not growth in developing mice with ckd v. dalal (1) , o. akchurin (1) , a. sureshbabu (1) , g. kaur (1) , s. cunninghamrundles (1) , m. choi (1) , s. rivella (2) (1) weill cornell medical college, new york, united states; (2) children's hospital of philadelphia, philadelphia, united states objectives: interleukin-6 (il-6), a major activator of hepcidin, is elevated in children with advanced ckd and in the adenine-based rodent model of ckd. anti-il-6 therapies improve anemia in many inflammatory disorders but it is unknown if il-6 blockade improves anemia in juvenile ckd. methods: ckd was induced by a 0.2% adenine diet given for 8 weeks to wild type (wa) and il6 knockout (il6a) male mice starting at 3 weeks of age. respective littermates fed a regular diet served as controls (wc and il6c). blood was obtained at sacrifice at 11 weeks of age and nose to tip of tail length was measured to assess linear growth. results: wa and il6a mice showed 3-fold elevated bun, serum creatinine and phosphorus, as compared with wc and il6c, respectively (p<0.001); il6 disruption did not improve these markers of ckd. all hematologic (cbc) parameters were similar between wc and il6c groups. adenine-induced ckd led to anemia in wa mice, as evidenced by significantly decreased hemoglobin, hematocrit, and mean corpuscular volume, compared to wc mice (p<0.001). these erythroid parameters, however, were similar between il6a and il6c groups. this was likely achieved in part via activation of erythropoiesis in il-6a group, as indicated by greater reticulocytosis in the il6a group as compared to wa group. body length, weight, and body mass index (bmi) were all significantly decreased in wa vs. wc mice and in il-6a vs. il6-c at the end of experimental period (p<0.001). there were no significant differences in these measurements between the wc and il-6c, nor between the wa and il-6a groups. conclusions: il6 disruption rescued the anemia phenotype in developing male mice with adenine induced ckd, thus suggesting that the efficacy of anti-il-6 therapies in anemia control should be tested in juvenile / pediatric ckd. the mechanism likely involves suppression of hepcidin, which is being validated in our ongoing experiments. in contrary to other inflammatory conditions, il6 disruption did not improve linear growth in this model. fp-s15-3 erythropoietin pathway dysregulation in anemia of chronic kidney disease d. landau (1) , l. london (2) , y. segev (2) (1) schneider children's medical center of israel, petach tikva, israel; (2) ben gurion university, beer sheva, israel objectives: anemia is a known driver for hypoxia inducible factor (hif) which leads to increased renal erythropoetin (epo) synthesis, resulting in inhibited apoptosis of bone marrow (bm) erythroid precursosrs, increasing back red cell mass. anemia of ckd is due to numerous factors, including impaired renal epo synthesis and intestinal iron absorption. epo resistance in ckd is a known clinical problem, but its mechanisms are poorly understood. epo receptor (epor) signals are transduced through a jak2-stat5 pathway. here we investigated the hif-epo-epor axis in kidney, bm and proximal tibia/epiphyseal growth plate (egp) in anemic juvenile ckd rats. methods: ckd was induced by 5/6 nephrectomy in young (20 d old) sd rats while c group was sham operated. an additional control group was daily bled for 7 days to induce iron deficiency anemia (c-a). rats were sacrificed after 4 weeks of ckd. a single bolus of iv rhepo (25 u/kg) was provided 5 minutes prior to sacrifice. results: hemoglobin levels were similarly reduced in ckd and c-a (11.7+/-0.4 and 10.8+/-0.2 vs 14.3+/-0.2 g/dl, p<0.001). serum iron and transferrin levels were unchanged in ckd. kidney hif2a was elevated in c-a but unchanged in ckd. remnant kidney epo protein and mrna levels were unchanged in both c-a and ckd. bm epo protein (which reflects circulating epo) was increased in c-a but unchanged in ckd. bm and egp epor were unchanged in c-a but decreased in ckd. egp phospho-stat5 was significantly increased in c but unchanged in ckd. conclusions: anemia in young ckd rats is associated with a multilevel inappropriate response: kidney hif2a and bm epo are not increased, contrary to what is normally seen after hemorrhage. in addition, bm and egp epor levels are reduced, as well as egp pstat5 response to epo, suggesting epo resistance as an additional mechanism. s16 -developmental nephrology: new concepts fp-s16-1 promotion of usp4 to tgf-β1-induced emt in renal tubular epithelial cells is regulated by akt through stabilizing tβri j. zhou, j. pu, y. zhang, z. huang, l. wang tongji hospital, tongji medical college, huazhong university of science and technology, wuhan, china objectives: we aimed to explore the role of ubiquitin-specific peptidase-4 (usp4) in tgf-β1 induced epithelial-mesenchymal transition (emt) during renal fibrosis, and investigated that if decreased activation of akt exerted a critical effect on emt via usp4/tβri pathway. methods: usp4, pakt and tβri proteins in the obstructed kidneys of unilateral ureteral obstruction (uuo) rats were detected by immunohistochemistry assay and western blot method. e-cadherin, α-sma, usp4 and pakt proteins in nrk-52e cells with different concentration tgf-β1 were detected at different time points. nrk-52e cells were transfected with usp4-specific sirna, and then stimulated with 10 ng/ml tgf-β1 for 24h to detect ecadherin and vimentin, e-cadherin and tβri by immunofluorescent double staining assay. we pre-treated nrk-52e cells with pi3k inhibitor ly294002 followed by tgf-β1 to detect pakt, e-cadherin, α-sma, vimentin and tβri protein expression level. meanwhile, the location of usp4 was visualized by immunofluorescent assay in nrk-52e cells. results: the usp4 expression was upregulated in the tubular epithelial cells of uuo rats. we also found that tgf-β1 upregulated usp4 expression in nrk-52e cells during their emt. importantly, depressed expression of usp4 inhibited tβri expression and partially reversed emt stimulated by tgf-β1. in the meantime, blunted phosphorylation of akt promoted the e-cadherin expression, and inhibited α-sma and vimentin expression in response to tgf-β1. however, inactivation of akt failed to induce usp4 to shuttle between the nucleus and the cytoplasm in nrk-52e cells and emt process stimulated by tgf-β1. conclusions: these data imply that usp4 is a harmless molecule induced by tgf-β1, regulated by akt activation and promotes tgf-β1-induced emt via tβri during renal fibrosis. fp-s16-2 exploring the mechanism of gen1 regulating the development of metanephros in mice and the association of gen1 x. wang (1) , h. wang (2) , q. shen (1) , y. zhang (1) , j. liu (1) , c. wang (1) , x. wu (2) , h. xu (1) (1) children's hospital of fudan university, shanghai, china; (2) institute of developmental biology and molecular medicine of fudan university, shanghai, china objectives: gen1 was recently identified as a holliday junction resolvase with a key role in repair of dna double-strand breaks. our previous research found that gen1mutant mice showed varied cakut phenotypes. our goal is to explore the underlying mechanism that gen1 may regulate the outgrowth and branching of ureteric bud (ub). methods: by whole mount in situ hybridization and real-time pcr, we identified the pattern and level of expression of gen1 in the developing kidney of mice. we analyzed the characters of varied phenotype of cakut in homozygous mice. using novel hoxb7/myr-venus transgenic mice, we observed the budding and branching of ub of wtand mutant mice, both in vivo and in vitro. by rna-seq techniques, we further investigate the different expression of related transcriptions after the disruption of gen1. results: 1) gen1 is ubiquitously expressed in the mesoderm of e10.5 embryos, including mm and ub regions. over 60% gen1 pb/pb newborn pups were detected different abnormalities of kidney and urinary tract, in which duplex kidney were the most common anomalies, hydronephrosis, renal agenesis, renal hypoplasia, vur and uvjo also were not rare. 2) over 50% gen1 pb/ pb mice grew supernumerary ectopic ub. the nd of e10.5d gen1 pb/pb mice cultured in vitro didn't show higher sensitivity to gdnf compared to wt mice. rna-seq analysis of e10.5 mm revealed grem1, a bmp4 antagonist that positively regulates ub formation, as the only gene that was significantly up regulated. in situ hybridization with an anti-sense rna probe confirmed grem1 up-regulation ingen1 pb/pb embryos. 3) the number of tips of branching ub was significantly reduced in gen1 pb/pb mice, bothin vivo andin vitro cultured explants. the suppression on branching in gen1 pb/pb mice may due to the consistently down-regulation of six2, which play an important role in the branching development. conclusions: this study reports good short-term renal allograft survival in kidneys that were initially declined for paediatric recipients and then subsequently transplanted. while most children who have a kidney declined on their behalf will eventually be transplanted, they wait more than 6 months on average to get a kidney transplant. in view of the advantages of timely transplantation in children, criteria for accepting kidneys for paediatric recipients could be reviewed. fp-s17-2 the effect of donor-recipient age-matching on graft survival in pediatric renal transplant recipients -an espn/era-edta registry study n. chesnaye (1) , k.j. van stralen (1) , m. bonthuis (1) , j.w. groothoff (2) , j. harambat (3) , f. schaefer (4) , k.j. jager (1 conclusions: we demonstrated a differential risk of graft failure dependent on recipient and dd age combinations. in the youngest recipients, dd agematching results in a higher risk of graft failure compared to the allocation of slightly older-than-recipient dd grafts. objectives: to characterise impact of complement abnormalities on phenotypes and outcomes of patients (pts) with atypical haemolytic uraemic syndrome (ahus) enrolled in the global ahus registry prior to eculizumab treatment. methods: all pts with ahus are eligible. demographics, medical history, and treatment outcomes data are collected at enrolment and then every six months. results: as of november 2015, 846 pts were enrolled (384 childhood, 462 adult onset). family history of ahus was positive in 16%. median age at first ahus manifestation was 7.2, 7.7, 18.5 and 34.3 years in pts with mcp, c3, cfh and cfi mutations, respectively, and 8.4 years for pts with cfh autoantibodies (fig 1) . for pts diagnosed since 2011, renal, gastrointestinal, cardiovascular, central nervous system and pulmonary tma manifestations occurred in the 6 months prior to baseline in 143 (68%), 80 (38%), 60 (28%), 45 (21%) and 24 (11%) paediatric pts, respectively and were least common in pts with mcp mutations. five years after disease onset, end-stage renal disease (esrd) had occurred in 26% of paediatric pts as compared with 46% of adults (fig 2) . overall, incidence of esrd was not significantly different in pts with or without any identified mutation. five-year renal survival was 43%, 46%, 57%, 64% and 92% in pts diagnosed with cfh, cfh autoantibodies, c3, cfi and mcp mutations, respectively, and 65% in pts with no identified complement abnormality. conclusions: we describe the phenotype and natural history of ahus in the largest cohort of pts to date, which includes pts of all ages. this is the first report to show extra-renal manifestations occur in >30% of paediatric patients and that pts with cfi mutations have later onset of ahus compared with other complement abnormalities. esrd occurred significantly less frequently in pts with childhood compared with adult-onset. renal outcomes were most favourable in pts with mcp mutations and least favourable in pts with cfh mutations and cfh autoantibodies. fp-s18-2 targeted exome sequencing in patients with atypical hemolytic uremic syndrome (ahus) and negative anti-complement factor h (fh) antibodies reveals multiple variations r. thergaonkar (1) , a. narang (2) & figure 1 : distribution of variants conclusions: genetic susceptibility in anti-fh antibody negative ahus is complex. our scheme of prioritization was useful in identification of diagnostic as well as background genetic variation. fp-s18-3 predictors of poor long-term renal prognosis in children with hemolytic uremic syndrome l. alconcher (1) , l. lucarelli (1) , m. rivero (2) , e. rodriguez (2) (1) hospital interzonal dr. jose penna, bahia blanca, argentina; (2) universidad nacional del centro de la provincia de buenos aires, tandil, argentina objectives: approximately 50% of hemolytic uremic syndrome (hus) patients evolved to different stages of chronic kidney disease (ckd). more days of anuria imply a worse long term renal prognosis. our aim was to look for predictors of poor renal outcome. methods: observational, longitudinal and retro-prospective study. postdiarrheal hus patients with at least 5 years of follow-up were included. to evaluate long term renal outcome, patients were divided in 3 groups: no sequelae, ckd stage 1 and ckd stage 2-5. predictors analyzed included: gender, age at onset (<1, 1-2, ≥ 2 years), neurological involvement (seizures and/or coma), maximum white blood cells (wbc) counts (≤20000 or >20000), days of dialysis (0, 1-9 and ≥10), initial hematocrit (≤23 or >23 %), and red blood cells (rbc) transfusion requirement. a bivariate and multivariate analysis were performed, a p<0.05 was considered significant. results: 180 patients (91 males) with a median follow-up of 11.9 years were included. gender, age at onset and neurological involvement were not associated with long term renal outcome. wbc count >20000 and hematocrit >23% were significant ckd predictors only in the bivariate analysis (p=0.04 and 0.0049). the risk to evolve to ckd stages 2-5 in patients who did not require dialysis was similar to those with < 10 days (p=0.31). ckd risk increased 8.8 and 3.2 times in patients with ≥ 10 days of dialysis and those not requiring rbc transfusions (ci 95% 4.1-18.5, p<0.0001 and ci 95% 1.6-6.3, p= 0.0009 respectively). considering only patients with ≥ 10 days of dialysis, 26% of those who received rbc transfusions were in ckd stage 2-5 vs. 61% of those who did not (p=0.0009, or 6.4 ci 95% 2-20). the association between ≥10 days of dialysis and no transfusion requirement was the most important predictor of long-term ckd. no transfusional requirement implies less hemolysis probably related to more severe vascular occlusion leading to more ischemia and poor long term renal outcome. fp-s19-1 the impacts of interdialytic weight gain on chronic hemodialysis in low weight children c. henriques, m.f.c. camargo, m.f.s. jardim, s. komi, s. vieira, p.c.k. nogueira hospital samaritano, sao paulo, brazil objectives: to assess the impacts of interdialytic weight gain (idwg) in low weight children undergoing chronic hemodialysis (hd). methods: prospective cohort of 30 patients (8f, 22m), with mean age of 2.4 years (20 days -6.8 years), mean weight of 8.4kg (2.8 -13.7) and median follow up of 231 days (iqr=120-334). the median number of hd sessions/week was 6 (only 1 child underwent conventional hd with 3 sessions/week). we evaluated the median of monthly idwg, defined as the difference between the weight pre hd sessions and the estimated dry weight and then tested its association with: a) z-score of left ventricle mass index, b)hemodynamic stability of the patient, assessed as the dose of vasoactive drugs needed to treat hypotension during the sessions and c) growth, assessed as the delta of repeated measurements of height/age z-score (last minus first measurement). results: perfoming univariate linear regression, we observed significant associations between the median idwg and: a) left ventricle mass, meaning that each 1% rise in the idwg is associated with an elevation 0.30 sds in the left ventricle mass index (p=0.048) and b) dopamine median dose during sessions, showing that each 1% increase in idwg is related to a dopamine dose increase of 0.87 mcg/kg/minute (p=0.020). with regard to growth, patients with idwg below the median of the sample (3.9%) showed an increase of 0.5 sds in height/age during follow-up, whereas patients with median idwg greater than 3.9 had a significantly smaller 0.1 sds increase (p=0.04). conclusions: in our series, idwg was associated with negative impacts such as augmented left ventricle mass, increased need for vasoactive drugs during hd and inferior growth. these facts reinforce the need for a strict control of idwg in dialysis of small children. fp-s19-2 predominance of central venous lines (cvl) in pediatric hemodialysis (hd) despite much higher complication rates -report from the international pediatric hemodialysis network (iphn) d. borzych-duzalka (1) , r. shroff (2) , y.n. lim (3) , s. testa (4) , h. xu (5) , b. warady (6) , f. schaefer (7) , c.p. schmitt (8 (1/57 mo.) , mainly including thrombosis (50%), puncture failure (15%) and insufficient flow (7%). in 11 cases an access revision was performed, while in 21 a new access was created. one, two and three year patency rates were significantly higher for avf/avg than cvl (0.92, 0.90, 0.81 and 0.84, 0.60, 0.30, respectively). the use of cvl increased the risk of access revision 4.8-fold (p<0.0001), as compared to avf/avg conclusions: this is the largest prospective pediatric report on vascular access in hd. cvl remain by far the first choice, despite much higher complication rates. infectious complications exclusively occurred in pts with cvl, and access dysfunction risk markedly increased with cvl use fp-s19-3 acute pancreatitis in children on chronic dialysis: incidence and clinical characteristic in a nationwide registry. e. vidal (1) , i. alberici (1) , m. martino (2) , s. picca (3) , c. pecoraro (4) , c. corrado (5) , i.m. ratsch (6) , e. verrina (7 objectives: the risk of acute pancreatitis (ap) is increased in patients (pts) with end-stage renal disease (esrd) on dialysis. to our knowledge, this hypothesis has never been explored in children. in this study we evaluated incidence, clinical characteristics and outcome of ap in a large pediatric chronic dialysis population. methods: ap cases were identified by reviewing files of all pts starting dialysis at <18 yrs of age recorded from jan 2000 to dec 2014 in a nationwide registry. results: 133 and 237 eligible pts were identified in the peritoneal dialysis (pd) and hemodialysis (hd) groups, respectively. 12 had ap, 7 were treated with hd and 5 with pd. the incidence rate of first-time ap was 9.5 per 1000 person-years for the overall cohort, 6.2/1000 pers./yrs for pd and 15.4/1000 pers./yrs for hd (p=0.04, fisher's test). the median age at ap diagnosis was 10 yrs (range 3-16) and median time on dialysis was 11 months (0.5-68). in 7 pts (58%) diagnosis leading to esrd was renal dysplasia and 6 patients (50%) were affected by motor-cognitive abnormalities. all pts were hospitalized for a median time of 25 days (2-180). median peak serum amylase and lipase was 1125 ui/l (234-3431) and 2885 ui/l (612-8140), respectively. instrumental diagnostic features at presentation included enlarged pancreas (80%) and peripancreatic fluid collections (33%). in 1 case, ap was diagnosed shortly after an abdominal surgery with exposure to propofol. at ap diagnosis, 4 pts were receiving valproic acid and 2 pts enalapril. in 3 cases, ap course was complicated by a pancreatic pseudocyst. one child required a shift from pd to hd because of abdominal pain. two pts experienced recurrent ap, while there were no deaths related to ap. conclusions: in our experience, children on dialysis show a significantly increased risk for ap compared with the general pediatric population (estimated incidence rate of 0.15/1000 pers./yrs). a higher incidence is observed in children on hd and in those with neurological co-morbidities. objectives: bartter syndrome (bs), a normotensive hypokalemic tubulopathy, has been clinically known for decades and genotypically characterized. as pediatric diagnosis and patient management improve, more patients survive to adulthood, potentially developing new complications. we summarized our experience with a group of 13 young adults with bs of 2 genotypic variants: type 2, due to mutations in romk (bs-2) and type 4, due to mutations in the barttin gene (bs-4). all bs-4 patients carry the same mutation and belong to an extended family of arab origin. methods: medical records were reviewed retrospectively. all patients have been treated since infancy with standard of care medications, including salts (nacl and kcl) supplementation. indomethacin was administered only when egfr was normal. results: patients (m:f=5:8; bs-4:bs-2 = 7:6) had an average age of 23.6 ±4.8 (range 18-37) years, without difference between the 2 groups. most of bs-4 vs none of bs-2 continue to need oral potassium supplementation, and their potassium concentration is lower (2.9±0.2 vs 3.7±0.3 meq/l in bs-2, p< 0.005). mean egfr was not different between groups (mean total: 95.5±43.9 ml/min), but 3 bs-4 (vs. no bs-2) patients had an egfr < 60 ml/min. mean uric acid level was higher in bs-4 (7.9±3 vs 5.1±0.7 mg/dl, p=0.05). two bs-4 patients had gouty attacks. no patient with bs-4 had hypercalciuria or nephrocalcinosis, compared to all bs-2 patients with these complications. three bs-2 also had symptomatic nephrolithiasis. serum pth levels were mildly increased in both groups (121±60.1 and 212±77.8 pg/ml in bs-4 and -2 respectively, p=0.057). conclusions: young adults with bs-4 and bs-2 display a phenotypic variability: decreased egfr was seen only in bs-4, in association with persistent hypokalemia, hyperuricemia and gout. bs-2 patients showed a preserved egfr and normal potassium levels (despite less need for drug therapy), but more significant hypercalciuria and nephrocalcinosis, with several cases of symptomatic nephrolithiasis. objectives: socio-economic disadvantage is increasingly recognised as an important risk factor for chronic disease, but the strength of the association with the development of chronic kidney disease (ckd) and the contribution of the various domains of disadvantage are uncertain. the aim of this study was to synthesise the evidence regarding the risk of ckd and end stage kidney disease (eskd) in the general population according to markers of socioeconomic disadvantage. methods: we performed a systematic review and meta-analysis with risk of bias was assessed using the newcastle ottawa scale and summary effects were estimated using random effects meta-analysis and meta-regression. we included published primary articles in medline, embase or cinahl (until december 2014) that were cohort studies conducted in the general population. we included studies investigating the risk of incident ckd (and stage) and any of the following social determinants: ethnicity, education, income, occupation and area level measures of socio-economic status. results: we identified 21 studies (n=12,987,147) -13 investigated risk by ethnicity, education (9), income (6), area level socio-economic status (4) and occupation (2). only two of the included studies were of high risk of bias. black americans have more than double the risk of eskd compared to white americans (hazard ratio 2.33, 95% confidence interval 2.02 to 2.63, i 2 59%). low income was found to increase risk of eskd in four of the six studies identified, however low education and low ses were not consistently identified as risk factors for ckd. conclusions: although there is a substantial body of evidence regarding the association between socioeconomic disadvantage and ckd, there appears to be an inconsistent relationship. this may be artefactual, due to difficulties in quantifying disadvantage, or reflect true underlying differences in the association across different settings. quality of life and its determinants of children on renal replacement therapy: a multicentre study l. tjaden (1) , a. splinter (2) , k. cransberg (3) , l. koster-kamphuis (4) , a. raes (5) , c. taylan (6) , m. grootenhuis (2) , j. groothoff ( objectives: to assess health-related quality of life (hrqol) across three renal replacement therapy modalities (preemptive transplant, non-preemptive transplant and dialysis) in comparison with the healthy norm and other chronic disease cohorts, and to explore which patient factors are related to hrqol. methods: all prevalent end stage renal disease (esrd) patients aged 8-18 years in the netherlands, belgium and part of germany were approached to complete the paediatric quality of life inventory 4.0 (pedsql™) questionnaire. we determined differences between groups on pedsql™ mean scores, and the proportion of children with an impaired hrqol (≥1 sd lower than the healthy norm). linear regression models were used to explore determinants of hrqol. conclusions: this is the first international study examining hrqol in the paediatric esrd population. we found important decrements in hrqol in this specific population, even after successful transplantation. physicians should be aware of the impact on social development and academic performance of paediatric renal transplant recipients and adjust their practice where possible in order to improve autonomy development. furthermore, to develop tailored interventions for children with esrd, qualitative studies are needed to gain more insight in the predictors of hrqol. disease (the k-cad study) m. didsbury (1) , j. craig (1) , a. van zwieten (1) objectives: poverty and social inequality are major barriers for achieving optimal health outcomes in children, but their impact on outcomes in children with chronic kidney disease (ckd) is unclear. the k-cad study is an australian and new zealand multicentre longitudinal cohort study that aims to describe the prevalence of economic hardship among caregivers and to determine the relationship between socioeconomic status of caregivers and self-rated health of children with ckd. methods: two hundred and ninety-three children aged 6-18 years with ckd [stage 1-2 (n=69), stage 3-5 (n=77), dialysis (n=35), transplant (n=112)] were recruited from four children's hospitals across australia. comparisons by quintile of socioeconomic status for nominal self-rated health outcomes among children with ckd were analysed using adjusted multinomial logistic regression. results: the mean ages of the caregivers and children were 43.5 years (sd: 8.0) and 12.5 (sd:3.9), respectively. more than 50% of all households earned less than $1250aud per week. only 20% (n=60) of caregivers engaged in fulltime employment and 30% (n=89) had completed tertiary education. across the cohort, carers who reported higher levels of financial difficulty were twice as likely to report that their child's health was poor than those with lower levels of financial difficulty ( conclusions: socioeconomic status of caregivers appears to have a profound impact on the self-rated health in children with ckd. longitudinal follow-up will help delineate the cause of socioeconomic disadvantage in these children and the long-term effects on disease progression and wellbeing outcomes. fp-s22-1 renal gene panels promote rapid diagnosis in paediatric renal disease of variable phenotype h. mccarthy (1) , a. mallett (2) , a. mallawaarachchi (1) , k. holman (1) , g. ho (1) , b. bennetts (1) , s. alexander (1 & table 1 . results per panel in nearly 50% of cases referred for diagnostic renal gene panels, a pathological result was found to explain the phenotype. certain panels are highly likely to reveal a useful result e.g. alport's panel and the tubular panel, whereas the panel for cakut remains low yield reflecting that previously described. prior to 2014, testing for renal genes within australasia was extremely limited. the arrival of diagnostic panels for a variety of renal conditions provides the referring clinician with an additional and important tool in the diagnostic pathway to be used in conjunction with imaging, serology and histology. this model has demonstrated the potential of genetic analysis in paediatric nephrology and suggests it will become mainstream practicein the next few years. objectives: at least 10% of adults who receive renal-replacement therapy (rrt) have an inherited kidney disease.we sought to determine the frequency of gene mutations in a heterogeneous population of children with end-stage renal disease. methods: this study used next generation sequencing to screen 4000 genes, including the 40 genes known to be associated with mitochondrial disease. the first 46 pediatric patients collected from department of nephrology and rheumatology, children's hospital of fudan universitywere chosen with comprehensive phenotypic detail. significant variants detected by next generation sequencing were confirmed by conventional sanger sequencing and segregation analysis was performed using parental dna samples. results: a total of 46 patients (females 16, males 30) with rrt(pd 38, hd 3, tx 5) were identified, with a mean age of 7.2 ± 6.4 years (range from 0.1 to 12.2 years). analysis revealed known and novel disease-associated variations in genes (nphs1, nphs2, plce1, wt1, slc12a1, ttc21b, agxt, scnn1g, coq2 and adck4) associated with inherited kidney diseasein 56.5% (26/46) of patients. of these 46 patients, 15 had compound heterozygous mutations, 6 had heterozygous mutations (de novo mutation), 5 had homozygous mutations. conclusions: more than half children who receive renal-replacement therapy haveknown and novel disease-associated variations in genes associated withinherited kidney disease. this study shows that next generation sequencing analysis of pediatric end-stage renal disease patients is accurate and revealing. this analysis should be considered part of the routine genetic workup of end-stage renal disease, where the proportion of genetic mutation is high but requires sequencing of multiple genes. conclusions: urinary metabolomic profiling is a feasible technology to help identify metabolites that can distinguish srns from ssns. can urinary proteomes be used as non-invasive markers for renal involvement in childhood febrile urinary tract infection (uti)? s.m. chao (1) , j. connolly (2) , y.h. ng (1) , i. ganesan (1) , l. bernett (2) (1) kk women's and children's hospital, singapore, singapore; (2) institute of molecular and cell biology, singapore agency of science and technology, singapore, singapore objectives: we hypothesized that proteomes expressed as downstream effectors of uti that are easily obtained from urine, can serve as early markers of acute pyelonephritis (apn) and predictors of renal scarring (rs). leveraging on advances in high throughput technologies and bioinformatics, we attempt to examine an extended range of urinary proteomes that may be implicated. methods: in this prospective cohort analytical study, patients aged 1 month or more with a clinical diagnosis of 1st febrile uti were recruited. apn and rs were diagnosed by dmsa scans done within 5 days of uti and at 6 months respectively. urine for proteomic study were collected at recruitment. us and mcu were done. using multiplexing bioassay, 57 cytokines, 14 soluble receptors and 8 kidney markers were measured and data analysed using bioinformatics software. conclusions: this prospective study of an extended repertoire of urinary proteomes during uti showed promising results esp.in the prediction of rs which can potentially be translated to clinical application of using urinary proteomes as early non-invasive markers and predictors of renal cortical involvement. larger cohort studies are needed to test the validity and reproducibility of these biomarkers. fp-s23-1 immunogenicity of human papillomavirus recombinant vaccine in children with ckd d. nelson (1) , a. neu (1) , a. abraham (2) , s. amaral (3) , d. batisky (4) , j. fadrowski (1) (1) johns hopkins university school of medicine, baltimore, united states; (2) johns hopkins university bloomberg school of public health, baltimore, united states; (3) university of pennsylvania school of medicine and the children's hospital of philadelphia, philadelphia, united states; (4) emory university school of medicine, atlanta, united states objectives: there is a disproportionate burden of human papillomavirus (hpv)related genital tract disease in patients with ckd and kidney transplantation, therefore the potential impact of the quadrivalent hpv vaccine (gardasil®) is profound. immune abnormalities associated with ckd and immunosuppression may prevent optimal vaccine response. our objective was to determine antibody response to the hpv vaccine in female adolescents with ckd. methods: cohort study conducted from 2008-2012 of 57 female patients age 9-21 years recruited from 2 pediatric nephrology clinics with ckd (n=25), on dialysis (n=9), or status post kidney transplantation (n=23) who received the standard 3-dose vaccine series of the hpv vaccine. antibody levels to hpv genotypes 6, 11, 16, 18 were measured prior to vaccine dose 1 (baseline), less than 12 months after vaccine dose 3 (blood draw 2), and 12 months or greater after vaccine dose 3 (blood draw 3). seropositivity was defined as antibody level above an established threshold for each hpv genotype. not all participants completed 3 blood draws. & bd, blood draw; v, vaccine results: antibody response to all 4 hpv genotypes was 100% in the ckd and dialysis groups with samples drawn at < 12 months and ≥12 months after dose 3 of the hpv vaccine. among the transplant patients, the percent of patients achieving seropositivity was significantly lower at blood draw 2 for hpv genotypes 6 (63.6%, p=0.003), 11 (63.6%, p=0.003) and 18 (72.7%, p=0.02) and blood draw 3 for hpv genotypes 6 (62.5%, p=0.02), 11 (50%, p=0.001), 16 (75%, p=0.04), and 18 (50%, p=0.001). & whiskers represent the 25th or 75th percentiles + (1.5x interquartile range) antibody levels in transplant patients compared to ckd patients and to dialysis patients for hpv genotypes 6, 11, 16, 18 . there was no statistically significant difference betw conclusions: antibody response to the quadrivalent recombinant hpv vaccine was robust and sustained in girls and young women with ckd and on dialysis. a less robust response to the vaccine was observed among those with a kidney transplant. further study is needed to determine if vaccination before kidney transplantation or an alternative vaccination regimen would benefit transplant recipients. chronic kidney disease can be identified reliably by urinary proteome analysis in children after orthotopic liver transplantation j. drube (1) , p. zuerbig (2) , h. mischak (2) , l. pape (1) (1) hannover medical school, hannover, germany; (2) mosaiques diagnostics gmbh, hannover, germany objectives: chronic kidney disease (ckd) is a common cause for morbidity and mortality not related to the primary disease inchildren after solid organ transplantation. a urinary proteome pattern publishedby good et al. was shown to identify adult patients with primary ckd with higher reliability than creatinine based methods. our study aimed to proof this pattern's reliability in pediatric patients following orthotopic liver transplantation (polt). in this population kidney function is usually over-estimated by creatinine based methods due to extreme low muscle mass of the patients. methods: the urinary proteome patterns of 25 children with biliary atresia followed by pediatric orthotopic liver transplantation were analyzed by capillary electrophoresis coupled to mass spectrometry and compared to the known proteome pattern of ckd. cystatin c based estimated glomerular filtration rate (egfr) was chosen as comparator. in addition, estimation of creatinine based gfr was also performed in all patients. results: thirteen children (f: 7; median age 7.9yrs.; range 0.6 to 15.4) had a reduced cystatin c gfr below 60 ml/min/1.73m 2 , 12 patients (f: 7, median age 6.0 yrs., range 2.0 to 11.9) showed no renal impairment. sensitivity to detect renal impairment using the ckd-pattern was 77% (95% ci 46-95%) and specificity was 92% (95% ci 62-99%). the area under the curve was 0.80 (95% ci 0.59-0.93; p=0.012). creatinine based estimation of gfr detected only 2/13 patients (15%) correctly resulting in a sensitivity of x %. using multiple testing corrections, 20 peptides were identified that significantly differentiated patients with renal impairment from those without. tandem mass spectrometry sequencing revealed 10 fragments of collagen alpha-1(i), 5 of collagen alpha-1(iii) and one fragment of collagen alpha-1 (xvi). the urine proteomics ckd-pattern can reliably identify children with secondary renal impairment after polt with a significantly better sensitivity as compared to standard creatinine based egfr. fp-s24-1 outcome and prognostic factors of nephropathic cystinosis: data from the eunefron cohort f. emma (1) , e. levtchenko (2) , g. ariceta (3) , m. greco (1) , w. van't hoff (4) , p. niaudet (5 . after modelling the hr, a nearly linear relationship was observed with the age at which cysteamine was started from 0.5 to 3.5 years and the risk of dialysis; correcting for leucocyte cysteine levels did not change significantly this relationship. over the same period of time, linear growth has improved. factors associated with improved outcome were the use of cysteamine, of indomethacin and of growth hormone. conclusions: this study represents one of the largest cohorts of nephropathic cystinosis patients assembled to date, and shows a gain of approximately 6 years in the median age to reach dialysis over a period of 30 years. early treatment with cysteamine and the use of indomethacin influenced positively renal outcome. fp-s24-2 a french cohort of patients with cystinosis: variability in the compliance to two formulations of cysteamine, use of electronic monitoring devices s. gaillard (1) , l. roche (1) , b. kassai (1) , g. deschenes (2) , d. morin (3) , c. acquaviva bourdain (1) , a. bertholet-thomas (1) , p. cochat (1) (1) hospices civils de lyon -chu lyon, lyon, france; (2) aphp -hôpital robert debré, paris, france; (3) chu montpellier, montpellier, france objectives: cystinosis is an inherited autosomal recessive disease. our objectives are (i) to describe the profiles of compliance to cysteamine treatment and white blood cell (wbc) cystine levels in cystinosis patients followed up for one year; and (ii) to explore the differences of compliance under delayedrelease or short-acting cysteamine. methods: crystobs is a french cohort of cystinosis patients. thirty patients are expected. all subjects receive oral cysteamine. four patients have received short acting cysteamine then delayed-release formulation. a descriptive analysis is performed on subjects followed-up for one year. compliance is described as a continuous variable, using an electronic monitoring system. levels of compliance (0: bad compliance; 1: correct compliance and 2: good compliance) are computed individually for the 17 patients: i) monthly; ii) quarterly; and iii) overall during the first year. mean compliance scores are summarized quarterly as median, 25 and 75 percentiles, minimum and maximum observed. the "number of hours covered by cysteamine" is generated per day. patients' self-evaluations of compliance are available at each visit. results: seventeen patients (mean age: 17.5 years; 58% female) were analyzed. seven patients were transplanted and 2 under dialysis. egfr remained stable over time. while wbc cystine levels remained under 1 μmol/ ½ cystine/g protein, there was a great variability among patients and over time in the mean quarterly compliance score (median: 1.9 at inclusion -1.6 at m12, min = 0.05 -max=2). however, subjects were globally well covered by their study treatment: 22 to 23 hours daily coverage. the compliance scores seemed improved under delayed-release formulation. conclusions: crystobs is the first study measuring objectively compliance to cysteamine in cystinosis patients. we observed a great variability among compliance profiles, and a trend towards improvement in compliance under delayed-release cysteamine. objectives: cystinosis is a lysosomal storage disorder characterized by accumulation and crystallization of cystine in different cell types. if not treated, renal failure invariably develops within the first decade of life. we have shown excessive number of podocytes and proximal tubular cells in urine of cystinosis patients. now, we hypothesized that in compensation for cell loss, ongoing regeneration might happen, and it could be reflected by the presence of kidney progenitor cells in urine of the patients. methods: we quantified the number of kidney progenitor cells in urine using qpcr analysis of mrna extracted of urine samples of healthy donors (n=10, age range 4-12 y.o) and cystinosis patients (n=8, age range 4-15 y. o). patients had no kidney graft. the expression of vimentin was correlated to calibration curves derived from known numbers of adult kidney progenitor cells and normalized to volume of urine. we cultured and characterized urinary cystinosis progenitors by qpcr, facs and immunofluorescence analysis. later we differentiated progenitor cells into functional podocytes and proximal tubular cells. results: we demonstrate a significant increased excretion of kidney progenitor cells in cystinosis patients (progenituria), while in controls no progenitors were found in urine. progenitor cells isolated from cystinotic urine expressed mesenchymal stem cell proteins and the kidney progenitor markers cd24 and cd133. the cells were positive for nephron progenitor markers, such as vimentin, pax2 and cited1 and were able to differentiate into functional podocytes and proximal tubular cells. conclusions: our data demonstrate the presence of kidney progenitor cells in urine of cystinotic patients, which might indicate a fast turnover of cells and the attempt of tissue regeneration to compensate cell loss. urinary cystinotic progenitor cells might have a therapeutic application in regenerative medicine once the correction of the genetic defect and consequent correction of the phenotype are successful. fp-s25-01 study of hierarchical management model of asymptomatic urine abnormalities in children in shanghai y. gong (1) , x. hong (1) , q. shen (1) , z. li (2) objectives: school urine screening can detect a great quantity cases with asymptomatic urine abnormalities. long-term follow-up is necessary for potential cases with kidney diseases. this project intends to explore the effective mode of school urine screening network in shanghai. methods: during 2013.9 to 2015.8, a hierarchical medical model in asymptomatic hematuria children was built in three districts in shanghai. the asymptomatic hematuria children were founded by school urine screening program. they were confirmed and diagnosed in the district central hospitals. tertiary referral needed in some patients. results: 1. model building1) the 3 level transferring system consisted of school urine screening agencies, local district cental hospital and children's hospital of fudan university (chfu), a tertiary pediatric nephrology center. 2) there were three models of school urine screening in accordance with three different screening agencies, community health service centers (chsc, model a), center for disease control and prevention (cdc, model b) and physical examination department (model c), respectively. 2. practical study 1) 40999 students were screened in this project, the prevalence of urine abnormalities was 1.06% in elementary school students and 1.44% in junior middle school students. 2) 80% of cases went to the district cental hospitals in model a, 100% in model b while only 24.6% in model c. totally 66 cases of asymptomatic hematuria, 2 of mass hematuria and 4 of proteinuria. of those, about 15% of cases met the criteria transferring to chfu and 90.9% completed the referral. all the 72 cases got followed up, 2 cases of alport syndrome and 1 of chronic interstitial nephritis. conclusions: hierarchical medical model for asymptomatic hematuria patients was feasible and helpful for the follow-up of potential patients with kidney disease. the complement system is highly activated in pd associated arteriolopathy b. schaefer (1) , m. bartosova (1) , j. lorenzo (2) , s. tarantino (3) , r. büscher (4) , c. aufricht (5) , k. kratochwill (3) , c.p. schmitt (1) (1) university of heidelberg, heidelberg, germany; (2) institute of medical biometry and informatics, university hospital heidelberg, heidelberg, germany; (3) zytoprotec gmbh, vienna, austria; (4) department of pediatrics ii, university hospital essen, essen, germany; (5) department of pediatrics and adolescent medicine, medical university of vienna, vienna, austria objectives: cardiovascular disease is the leading cause of death in children on peritoneal dialysis (pd), underlying mechanisms are still incompletely understood. methods: omental arterioles covered with fat, i.e. located beyond pd fluid penetration level were microdissected from non-uremic children, age and gender matched children at time of first pd catheter insertion and children treated with low gdp pd fluids [pd vintage 26; 2-72 months). children with diseases potentially affecting vessel integrity were excluded. 3-4 arterioles per patient with similar structural dimensions (as defined by aperio®automated image analysis after evg staining vessels) were selected, neighboured sections were used for whole transcriptome and proteome analysis. results: uremia induced up-regulation of 173 and down-regulation of 117 arteriolar genes (p<0.01) compared to age and sex matched healthy controls. in patients on low gdp pd, 88 genes were up-and 11 genes down regulated compared to respective uremic controls, while in children on high gpd pd 139 genes were up-and 17 genes downregulated.intima media thickness was comparable in all groups. gene ontology analyses demonstrated activation of various inflammatory, immunological and stress response cascades with uremia and even more with pd. in children treated with low gdp fluid the complement system and respective regulatory pathways were upregulated most significantly. 14 complement factors demonstrated comparable upregulation on rna and protein level, cd55 was suppressed. findings were validated immunohistochemically in an independent cohort of 15 children per group; c1q and c3c were 5 and 2.6 fold increased with low gdp pd compared to uremic controls. conclusions: omental arterioles are uniquely suited for global assessment of molecular pathomechanisms of uremia and pd associated arteriolopathy. we for the first time demonstrate specific activation of the complement cascade in arterioles from children on low gdp peritoneal dialysis, prior to overt arteriolopathy. objectives: chronic kidney disease (ckd) is a state of klotho deficiency and excess of the phosphaturic hormone fibroblast growth factor 23 (fgf23). although, both findings were shown to be associated with endothelial dysfunction in humans, direct vascular effects of fgf23 remain largely elusive. here, we investigated the effects of fgf23 in relation to its coreceptor klotho on nitric oxide (no) synthesis and reactive oxygen species (ros) formation and detoxification in human coronary artery endothelial cells (hcaec) in vitro. methods: hcaec were stimulated with fgf23 (10 ng/ml) in the presence or absence of a pan-fgf receptor (fgfr) or klotho inhibitor, and investigated by quantitative real-time pcr, immunoblotting, and flow cytometry. results: hcaec express fgfrs and membrane-bound klotho. fgf23 increases the expression of the klotho shedding protease adam17 and consequently the secretion of soluble klotho. fgf23 activates fgfr1, and stimulates no release via akt-dependent activation of endothelial no synthase (enos). both, ros formation via nadph oxidase 2 (nox2) as well as ros degradation via superoxide dismutase 2 (sod2) and catalase (cat) are stimulated by fgf23 treatment. the effects of fgf23 on no synthesis as well as on ros formation and degradation are fgfr-dependent. pre-incubation with a klotho inhibitor blunts the fgf23-stimulated akt-enos activation and no synthesis, decreases ros degradation by blocking sod2 and cat enzymes, whereas fgf23-stimulated ros synthesis via nox2 is unaffected, resulting in low no bioavailability and increased oxidative stress. in the presence of klotho, fgf23 induces no release in hcaec and its stimulating effects on ros production are counterbalanced by increased ros degradation. in the absence ofklotho, fgf23-mediated no synthesis is blunted and ros formation overrules ros degradation. our results suggest that in states of klotho deficiency, e.g. ckd, fgf23 excess may primarily promote oxidative stress and thus endothelial dysfunction. fp-s25-04 dysregulation of hepatic cholesterol transporter abcg5 in il13-induced hypercholesterolemia in a rat model of minimal change nephrotic syndrome (mcns) c.y. chan (1) , l.d. low (1) , j. chen (2) , k-h. ng (1) , h.h. yang (1) , h. yu (1) , m.r. wenk (1) , h-k. yap (1) (1) national university of singapore, singapore, singapore; (2) agency for science, technology and research (a*star), singapore, singapore objectives: our il13 gene overexpression rat model of mcns showed that hypercholesterolemia correlated significantly with serum il13, and appeared to precede the development of proteinuria. this study aimed to investigate the mechanism of il13-induced cholesterol dysregulation in our rat model of mcns. methods: hepatic transcriptome of il13-transfected nephrotic rats (late event) was studied using microarray and qpcr. this was compared with the gene expression profile of hepatic cholesterol metabolism at the onset of hypercholesterolemia in the pre-proteinuric phase (early event, hc rats). il13-mediated cholesterol effluxes via abcg5 and abca1 were measured using taurocholate and apoai as cholesterol acceptors respectively in rat primary hepatocytes. the role of lxra was validated using luciferase assay. results: 'abc transporters' was identified as the most relevant pathway in cholesterol metabolism, of which abcg5 expression showed the greatest downregulation in il13-transfected nephrotic rats (late event), and was associated with hmgcr upregulation. plasma cholesterol was significantly elevated from week 1 (hc rats) and preceded the onset of significant proteinuria at week 10. study of these hc rats (early event) also showed reduced abcg5, and was accompanied by downregulation of abca1 and lxra. similarly, il13-stimulated hepatocytes demonstrated downregulation of lxra, abcg5 and abca1, with reduced abcg5-and abca1-mediated cholesterol effluxes. moreover lxre-luciferase transfected il13-stimulated hepatocytes showed decrease in luciferase signal indicating reduced lxra activity. conclusions: hypercholesterolemia observed early in hc rats could be due to downregulation of lxra-abcg5/abca1 pathway with reduced cholesterol efflux into bile, resulting in increased intracellular free cholesterol, further inhibiting hepatic uptake of cholesterol. hepatic upregulation of hmgcr occurred secondarily as a late event following development of gross proteinuria exacerbating the hypercholesterolemia. autophagy is activated to protect podocyte from immune-mediated injury in membranous nephropathy y. zhang, f. yang, q. lv, .z. huang, h. yuan, j. zhou department of pediatrics, tongji hospital,tongji medical college, huazhong university of science and technology, wuhan, china objectives: autophagy is induced in podocytes during various kidney diseases, however, whether this is protective or injurious remains controversial. here, we address this question by pharmacologic blockade/activation of autophagy using in vivo and in vitro model of membranous nephropathy. methods: we studied female sd rats at day 21 after induction of passive heymann nephritis (phn) by injection of anti-fx1a. expressions of autophagy markers and apoptosis-associated proteins were analyzed . confocal microscopy was used to explore the expression patterns of f-actin and nephrin. attachment assay was used to assess the adhesion of podocyte. apoptosis and expression of integrin-α3 were measured by flow cytometry. results: first, autophagy was induced in vivo in podocytes of phn rats (shown by increased autophagosome number, conversion of lc3-i to lc3-ii, and beclin-1 expression). 3-methyladenine (3-ma) blocked autophagic flux and worsened renal injury in phn rats. compared with control littermates, the 3-ma-treated rats were markedly more sensitive to nephritis as indicated by increased urinary protein excretion, glomerular lesions, and podocyte apoptosis. subsequently, we utilized immortalized mouse podocytes (mpc5) to study the autophagy mechanisms involved in mn with sc5b-9 incubation in vitro. podocyte damage, apoptosis and deadhesion were demonstrated in the sc5b-9-incubated mpc5 cells. furthermore, sc5b-9 induced beclin-1 and lc3-ii expressions and autophagosome formation. inhibiting autophagy by 3-ma further promoted cellular lesions, apoptosis and actin reorganization-associated deadhesion in the sc5b-9-incubated mpc5 cells. in contrast, rapamycin, an autophagy inducer, promoted beclin-1 and lc3-ii expressions, which mitigated sc5b-9-induced changes in the injury-related morphology, apoptosis, and deadhesion of mpc5 cells. conclusions: our results establish a renoprotective role of podocyte autophagy in complement-mediated podocytopathy where it may interfere with cell killing and adhesion mechanisms. results: data on 61 children (32 male) from 12 centres were analysed. shortterm dialysis (<4 weeks) was required in 5 (8%) children (pd in 2, cvvh in 2 and hd in 1) at a median age of 11 (5-16) weeks for a median duration of 16 (8-18) days secondary to sepsis (n=2), acute fluid overload (n=2) or aki following acei (n=1). thirteen (21%) patients required long-term dialysis by the age of 6 months, 30 (50%) by 1 year, 38 (62%) by 2 years, 41 (67%) by final follow up at a median of 34 months. of those, 9 (22%) patients did not have nephrectomies, 29 (71%) had nephrectomies before and 3 (7%) after commencingdialysis. in 37 (90%) pd was the modality of choice. amongst those on pd, ccpd with a day exchange was the commonest prescription (43%). eleven (30%) patients needed to switch to hd due to pd catheter dysfunction (n=5), peritonitis (n=3), inadequate uf (n=2) or development of pleuro-peritoneal fistula (n=1). peritonitis rate was 0.95/12 patient months. none developed thrombosis on pd. all patients on hd received 3 sessions of 4 hours per week. no hd line infections and no development of thrombosis were reported. there was no difference in growth between pd and hd patients. twenty-five patients (61%) received a transplant at a median of 6.5 (0-47) months after start of dialysis of which 15 with living donor. one patient died whilst on pd (palliative treatment) and 2 patients died whilst on hd (hyperkalemia and candida peritonitis). the need for long-term dialysis in children with cns is very likely by the age of 1 year. pd is the modality of choice, however the peritonitis rate was higher than recommended, but may reflect the high percentage of infants in this study. a significant number switched between dialysis modalities. vascular access in children on hemodialysis: a report from the espn/era-edta registry m. boehm (1) , m. bonthuis (2) , m. noordzij (2) , j. harambat (3) , j. groothoff (4) , c. aufricht (1) , k. jager (2) , f. schaefer ( , showed lower hemoglobin levels (cvc: 9.1 (7.7-10.4) g/dl; avf: 10.4 (9.0-11.8) g/dl) and lower height-sds (cvc: -1.61 (-2.67; -0.50), avf: -1.35 (-2.09; -0.31) at start of hd. likelihood of receiving an avf was lower for children with glomerulonephritis (aor: 0.50, 95% ci: 0.32-0.76), vasculitis (aor: 0.13, 95% ci: 0.04-0.47) and missing or unknown diagnosis (aor: 0.38, 95% ci: 0.24-0.62). after two years 28.6% of avf patients and only 17.9% of cvc patients were still treated with their initial vascular access. the overall likelihood of receiving a renal transplant within two years was not different, children who received ld were more frequently started with cvc (ahr: 1.60, 95% ci: 1.19-2.14) . conclusions: in conflict with the kdoqi recommendations, cvc is the most often applied type of vascular access in children who start with hd, despite the significantly higher need for a second vascular access. the higher number of ld in cvc children suggests a conscious policy, which should be reconsidered, as the overall waiting time for transplantation is equal in both groups of patients. genetic and clinical characteristics of female x-linked alport syndrome : 267 cases study t. yamamura (1) , k. nozu (1) , k. nakanishi (1) , s. minamikawa (1) , t. ninchoji (1) , k. nakanishi (2) , n. yoshikawa (3) , k. iijima (1) (1) kobe university graduate school of medicine, kobe, japan; (2) department of pediatrics, wakayama medical university, wakayama, japan; (3) national center for children health and development, tokyo, japan objectives: the aims of this study are to clarify the genetic and clinical characteristics of the large number of female x-linked alport syndrome (xlas) patients in japan and the contribution of skewed x inactivation to disease severity. methods: we conducted a retrospective analysis for 267 female patients in 173 families who were genetically diagnosed with x-linked alport syndrome in our department. we analyzed clinical and laboratory data from medical records. the data included proportion of patients with proteinuria and the age at which proteinuria was detected, proportion of patients with end-stage renal disease (esrd) and the age at which they reached esrd, hearing loss and specific ocular changes, genotype-phenotype correlation. we also performed a x-inactivation analysis for the severe patients who reached esrd before age 60. results: the median age of our cohort was 24 years (age from 0 to 92 years). proteinuria was detected in 169 patients (72.2%) and the median age developing proteinuria was 7.0 years. 35 patients reached esrd and the median renal survival period in this study was 65.0 years and 15% patients reached esrd at the age of 40. specific ocular changes were detected in only 4 patients and hearing loss was 17 patients. no obvious genotype-phenotype correlation was observed. x inactivation analysis was held to 13 severe patients, but skewed x inactivation was detected in only one patient and its contribution to disease severity was unclear. conclusions: phenotype of female xlas patients is not always mild. therefore clinicians have to pay attention to their clinical course and treatment. there is no genotype-phenotype correlation and the contribution of xinactivation to disease severity is still unclear. it is assumed that the mechanism of determining severity of female xlas remain multifactorial. were excluded. following therapy of relapse, prednisone was tapered to 0.7 mg/kg ad. stratifying for dependence, patients were randomly assigned to prednisone at 0.2-0.3 mg/kg daily or 0.5-0.7 mg/kg ad for 12-months. relapses were treated with prednisone, followed by return to intervention. outcomes, based on intention-to-treat, included number of relapses, proportions with therapy failure (≥2 in 6-months or significant steroid toxicity) & sustained remission, time to first relapse & frequent relapses, cumulative prednisone received & adverse events. assuming that daily therapy will reduce relapses by 25% over ad treatment, 62 patients were required at power of 80% and two-tailed α of 0.05, with 10% attrition. results: of 62 patients, one did not return following randomization & was excluded from the analysis (fig. 1) . baseline features were similar in the two groups. patients receiving daily prednisone showed significantly less relapses than those on ad therapy (0.5±0.7 vs. 1.4±1.0 relapses; mean difference 0.8; 95%ci 0.3-1.3; p=0.0005). daily therapy was associated with higher proportion in sustained remission (60% vs. 29%; p=0.015), lower treatment failure (7% vs. 55%; p<0.0001), delayed time to first relapse (log rank p=0.0028) and to treatment failure (p<0.0001) (fig. 2) and lower prednisone use (0.3±0.7 vs. 0.4±0.2 mg/kg; p=0.0033). adverse events were similar. conclusions: in patients with frns, daily administration of low-dose prednisone was more effective than standard-dose alternate day therapy in sustaining remission and enabling steroid sparing. levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome: results of a multi-center, double-blind, placebo-controlled, randomized clinical trial m. gruppen (1) , j.c. davin (2) , a. bouts (2) (1) pediatrician, amc, amsterdam, netherlands; (2) pediatric nephrologist, acm, amsterdam, netherlands objectives: levamisole has been considered the least toxic and expensive drug for preventing relapses of steroid sensitive idiopathic nephrotic syndrome (ssins). however, evidence is limited, as previous randomized clinical trials (rcts) were found to have methodological limitations. this is why we conducted an appropriate rct to reassess its usefulness in prevention of ssins relapses in children. methods: the study was conducted in an international multi-center, placebo-controlled, double-blind rct for one year, in order to evaluate efficacy and safety of levamisole in children with ssins and frequent relapses. results: the intention to treat population (itt) consisted of 99 patients from 6 countries. time to relapse (primary endpoint) was significantly increased in the intervention group compared to placebo (p-value 0.22 [95% ci 0.11-0.43], p-value 0.001 after 100 days post-randomization). after 12 months of treatment, remission persistence was more frequent in levamisole than in the placebo group (26% vs 6 %: p = 0.012). the most frequent serious adverse event (sae) (4/50) possibly related to levamisole was asymptomatic moderate neutropenia (500-1000 cells/ μl), reversible spontaneously or after treatment interruption. rare, severe side effects of levamisole reported in treatment of ssins included hepatitis, convulsions or antineutrophil cytoplasmic antibody (anca) vasculitis were not observed in this study. however, anca-related arthritis was reversible with levamisole interruption, and reported in one patient. conclusions: in children with ssins and frequent relapses, levamisole prolongs time to relapse and also prevents recurrence for one-year of treatment in 20% of patients. regular blood controls are necessary for safety issues. defective complement inhibitor cd46mrna expression in peripheral mononuclear cells of patients with progressive iga nephropathy. r. coppo (1) , l. peruzzi (1) , e. loiacono (1) , m. bergallo (1) , m.l. russo (1) , a. krutova (2 objectives: report a case of vesicoureteral reflux degree iv in child treated conservatively methods: review of medical record provided by western paraná university hospital results: y.b.s. two years-old, reporting fever of 40°c, associated with chills, weakness for 3 days. it evolved with emesis, appetite loss, pain in hypogastric and discomfort when urinating, but the urine had normal color. gentamicin associated with ceftriaxone was started for pyelonephritis and used for seven days. after the end of therapy were requested two urine cultures and both came negative. urethrocystography was requested and showed a vesicoureteral reflux right degree iv. started using nitrofurantoin 5 mg once a day. the patient was discharged nine days after. six months after the episode, scintigraphy showed a slight tubular function impairment and cortical shrinkage in the right kidney. the current scan showed both kidneys with preserved tubular function and no cortical lesions; and indirect radionuclide cystography presented absence of bilateral vesicoureteral reflux. in october 2015, the patient was discharged from the pediatric nephrology not making more use of nitrofurantoin. conclusions: vesicoureteral reflux (vur) is a common urologic disease in childhood. the prevalence in patients presenting urinary tract infections (uti) ranges from 20% to 60%. uti and vur are risk factors for permanent kidney damage and renal scars, amongst them 5%-15% occur at the first itu. urological studies are recommended at the time of the first acute pyelonephritis in children of any age. despite of high prevalence, the treatment is still a discussion. surgery is curative about 98% of cases, however it is associated with a considerable risk. antibiotic prophylaxis to prevent damage is controversy because of low compliance rates and side effects. in a retrospective recent study, 63,3% of the patients with vur grade iv and v were conducted surgically. we present a case of uvr grade iv conservatively treated that evolved for complete cure. 6-2.6] . seventy-six percent of all tests were x-rays, and nuclear medicine studies accounted for 71% of cumulative radiation exposure. less than 5 children were exposed to a potentially toxic cumulative dose greater than 30 msv. longer duration of chronic kidney disease (ckd) before transplant was correlated with greater cumulative effective dose (table) . conclusions: children that receive kidney transplants undergo many imaging studies with radiation exposure predominantly from nuclear medicine studies, especially those that have longer ckd duration. greater awareness of cumulative ionizing radiation is needed to minimize exposure as children age into adulthood. & objectives: a short stature as a result of poor growth is common in pediatric esrd and has been associated with adverse psychosocial and clinical outcomes. through improved management of growth failure, its prevalence after kidney transplantation (kt) is supposed to have decreased over time. we aim to analyze longitudinal growth after kt, trends over time, and to identify potential determinants of height sds in a large cohort of transplanted children using data from the espn/era-edta registry. methods: a total of 3,492 patients from 23 european countries transplanted before 18 years of age between 1990 and 2012, with available longitudinal follow-up were included. height standard deviation scores (sds) were calculated using recent national growth charts or european growth charts for countries without recent reference data. we used generalized equation models to estimate the prevalence of growth retardation and linear mixed models to calculate adjusted mean height sds and its potential determinants. results: overall mean adjusted height sds post kt was -1.77 ± 0.04. 55% of children had a height sds within normal range, 28% showed moderate, and 17% severe growth retardation. girls were significantly shorter than boys. in multivariable analysis, living donor kt, steroid free immunosuppressive regimen, higher egfr, and not being hypertensive or anemic were associated with better post-kt height sds. patients with cakut and metabolic disorders were shorter compared to other primary renal diseases. catch-up growth by 5 years post kt was observed in both boys (+0.37) and girls (+0.33 sds). children <6 years were shortest at kt and showed the greatest increase (+0.8) in height sds, whereas there was no catch-up growth in children transplanted >12. post kt growth did not improve over time. conclusions: catch-up growth post kt remains limited, was mainly observed in the youngest recipients, and did not show substantial improvement over time, resulting in short stature in nearly half of transplanted children in europe. fp-s29-1 the global pediatric nephrology workforce: a survey of the international pediatric nephrology association d. glenn (1) , s. ocegueda (1) , m. nazareth (1) , y. zhong (1) , a. weinstein (2) , w. primack (1) , p. cochat (3) , m. ferris (1) (1) univeristy of north carolina at chapel hill, chapel hill, united states; (2) dartmouth hitchcock medical center, lebanon, united states; (3) hôpital femme mère enfant & université claude-bernard, lyon, france objectives: the global pediatric nephrology workforce is poorly characterized. the objectives of our study were to characterize the global pediatric nephrology workforce and training environments, assess pediatric nephrologists' perceptions of the adequacy of this workforce, and understand regional challenges to fellow recruitment and job acquisition. perceptions regarding optimal length of training and research requirements were also queried. conclusions: globally, there is a high level of perceived inadequacy in the pediatric nephrology workforce. regional variability exists in perceived workforce adequacy, ease of recruitment, and job acquisition. interventions to improve recruitment should be targeted to specific regional barriers. objectives: to evaluate an interinstitutional cooperation program between an experienced pediatric transplantation center and a developing center in other state, 600 km apart, and the count of kidney transplantation surgeries performed during the 3-year duration of the cooperation. methods: the cooperation consisted of short periods of fellowship (max 1 month) of pediatric nephrology residents, nurse and 2 physicians (one pednephrologist and 1 surgeon), along a 3-year period, as well as weekly teleconferences for case discussions once a week. the yearly count of pediatric kidney transplants (p-kt) in the developing center along the period was compared to the national mean as well to the state's mean. in total, 209 samples were taken from 11 patients before the eculizumab infusion in the induction (weekly), maintenance (2-weekly) and tapering (every 3, 4, and 5 weeks) phases of therapy. results: our newly-developed eculizumab assay had variation coefficients of 2.9 % (intra-assay, 352 μg/ml) and 5.2 % (inter-assay, 328 μg/ml) and detection limit of 8 μg/ml. the samples with >50 μg/ml demonstrated <6 % of complement activity in classical and alternative complement pathways. the eculizumab levels had ranges of 36-459 μg/ml and 40-772 μg/ml during induction and maintenance phases, respectively, with 3 samples from 2 patients <50 μg/ml, required for efficient complement inhibition. during tapering, ranges of 61-367 μg/ml, 11-256 μg/ml and 13-161 μg/ml were measured at 3, 4 and 5 week infusion intervals, respectively. conclusions: our data demonstrate large differences in attained eculizumab concentrations among patients at all treatment stages. in induction and maintenance, the detected concentrations were up to 9-15 fold higher than required for efficient complement inhibition (50 μg/ml), although 3 samples did not reach this target value. thus, eculizumab therapy should be adjusted to meet the needs of individual patients and monitoring of eculizumab concentration is useful to guide the treatment schemes. we have shown that target eculizumab values (>50 μg/ml) may be reached with extended intervals; extension of intervals for these patients may improve cost-effectiveness of therapy. outcomes from an observational clinical trial evaluating the long-term safety and effectiveness of eculizumab use in paediatric patients with atypical haemolytic uraemic syndrome (ahus) l. pape (1) objectives: to describe the long-term outcomes of paediatric patients (pts) with atypical haemolytic uraemic syndrome (ahus) treated with eculizumab (ecu). methods: pts with ahus who participated in a previous ecu clinical study were invited to continue to be monitored in this observational, multicentre, multinational long-term follow-up study (nct01522170). this analysis included paediatric pts (<18 years old at first ecu dose) who enrolled, including pts treated outside of the recommended regimen. change in renal function and targeted serious adverse events (tsaes: serious infections, meningococcal infection, sepsis, leukopenia, infusion reactions, renal or hepatic impairment and malignancy) were assessed. results: median age at first ecu dose was 8.0 (range 0-17) years and median follow-up from first ecu dose was 48.9 (range 35.1-78.5) months (n=35). at least 1 complement abnormality was identified in 21 (60%) pts, including mutations in factor h (9 pts), membrane cofactor protein (3 pts), factor i (2 pts) and c3 (2 pts). prior to first ecu dose, 11 (31%) pts were on dialysis and 5 (14%) had prior kidney transplantation. eight (23%) pts had experienced ≥2 thrombotic microangiopathy events prior to first ecu dose. median time from ahus diagnosis to first ecu dose was 3.1 (range 0-178.1) months. improvement in renal function (increase in estimated glomerular filtration rate) following ecu initiation, was maintained (figure 1), and dialysis was stopped in 9 (82%) pts. two (18%) pts remained on dialysis throughout the study. no new dialysis or kidney transplants occurred. during this follow-up study, no pts died, 7 (23%) pts experienced a total of 9 tsaes, including 2 meningococcal infections. both pts recovered and remained on ecu. & figure 1 . mean estimated glomerular filtration rate (+/-sd) over time, in pts with ongoing treatment with ecu conclusions: this is the first report to include paediatric pts with ahus treated with ecu for over 5 years. throughout this follow-up period, ecu was generally well tolerated and effective in paediatric pts. objectives: elevated intact parathyroid hormone (ipth) levels can contribute to morbidity and mortality in children with chronic kidney disease (ckd). the present studies evaluated the pharmacokinetics, efficacy, and safety of oral paricalcitol in the reduction of ipth levels in children with stages 3-5 ckd. methods: two phase 3 studies enrolled children aged 10-16 years with stages 3-5 ckd. the first study evaluated oral paricalcitol pharmacokinetics, efficacy, and safety in children with stage 3/4 ckd with an initial 12-week doubleblind period followed by a 12-week (minimum) open-label period wherein all children received paricalcitol. the second study evaluated the efficacy and safety of oral paricalcitol (no comparator) for 12 weeks in children with stage 5 ckd undergoing hemodialysis or peritoneal dialysis. results: in the stage 3/4 ckd study, 12 children received 3 μg paricalcitol and were assessed for intensive pharmacokinetics (mean c max , 0.13 ng/ml; auc 0−∞ , 2.87 ngâ'h/ml). population pharmacokinetic analysis showed that ckd stage does not influence the pharmacokinetics of paricalcitol in children. thirty-six children were randomized (baseline ipth, 150 mg/dl) and 27.8% of the paricalcitol group achieved two consecutive ipth reductions of ≥30% from baseline vs no childrenin the placebo group (p=0.045). adverse events were observed in a higher proportion of the placebo group compared with the paricalcitol group in the double-blind (88.9% vs 38.9%; p=0.005) portion of the stage 3/4 ckd study. in the stage 5 ckd study, 8 of the 13 (61.5%) children enrolled had two consecutive ipth reductions of ≥30% from baseline (baseline ipth, 884 pg/ml, n=13), and 5 (38.5%) had two consecutive ipth values between 150 and 300 pg/ml. clinically meaningful hypercalcemia occurred in 2 (15.3%) paricalcitol-treated children in the stage 5 ckd study. conclusions: oral paricalcitol dosing in children aged 10-16 years with stages 3-5 ckd reduced ipth levels and was well tolerated. fp-s31-2 calcimimetic (cinacalcet) and hemodiafiltration versus conventional treatment of secondary hyperparathyroidism in children with end-stage renal disease on regular hemodialysis r. galal (1) , f. fadel (1) , s. sabry (1) , m. farouk (1) , m. ghonim (2) , a. ismail (1) (1) cairo university, cairo, egypt; (2) ministry of health hospitals, cairo, egypt objectives: to compare the efficacy of 2 treatment strategies, namely cinacalcet-based regimen and hemodiafiltration modality, with conventional care (vitamin d and phosphate binders) for control of hyperparathyroidism and the high calcium phosphorus product in order to achieve the recommended targets of the nkf/doqi guidelines. methods: a case -control study was performed over 6 months on 33 children with esrd on regular hemodialysis. they were randomly divided into 3 groups: the first group (11 cases) on regular hemodialysis and received cinacalcet 30mg/day in addition to conventional care (vitamin d and phosphorus binders) as needed, the second group (13 cases) on hemodiafiltration for at least 6 months and received conventional care only, and the third group (9 cases) [control group] on regular hemodialysis received conventional care only. monthly follow up of serum calcium, phosphorus and alkaline phosphatase was done in addition to baseline and 3-monthly parathormone level (intact pth). results: the mean age of whole study population was 10.6 ± 3.9 years (range 3 -17 years), and the mean weight was 20.2 ± 7.3 kg (range 8 -39.1 kg). both groups i & ii, but not group iii, showed a statistically significant increase in hct level and a statistically significant decrease in alp and pth after the study period. there was a significant percent reduction of pth level in group i patients compared to those in group iii. there was no statistically significnat difference between percentage of achievement of the nfk-k/doqi recommended goals in the three groups. conclusions: in spite of the costs of cinacalcet and hemodiafiltration, patients with resistant hyperparathyroidism should use one of these modalities to avoid complications of the metabolic bone disease. the cost of cinacalcet and hdf should be calculated in the context that they will save in other items as decreasing the dose of erythropoietin and vitamin d analogues and decreasing the complications, and consequently therapy, of bone disease. objectives: vesicoureteral reflux (vur) is a common urological anomaly among children. the genetic correlations between gene mutations and some of the syndrome, which has vur phenotype, have been determined in recent years. however, the disease-causing genes of isolated vur were not well understood yet. methods: to determine the disease specific genes involving in isolated vur, the whole exon sequencing (wes) was performed in 37 vur patients. of these 37 patients, 28 were isolated vur.exon-enriched dna was sequenced by the illumina hiseq2500 platform following the manufacturer's instructions (illumina) . results: wes data shows 74 mutations (69 novel) in 28 genes in 32 patients (86.5%) from 37 families (table 1) . these genes include (number of mutations): tnxb (12), trap1 (7), kansl1 (6), ret (6), robo2 (6), upk3a (4), gene 1(4), xrn1 (3), sall1 (3), sall4 (3), bicc1 (2), eya1 (2), and other 16 genes shows one mutation. several mutations of ret and hnf1b genes consistent with previously investigation. further analysis by perniciousness of mutation demonstrated that the mutation of tnxb is significantly correlated with vur risk stratification. the staging of vur of patient harboring 4 or above mutations is much higher than the patient harboring 4 or bellowed (or score is 4) ( table 2 ). our findings may provide a clinical molecular marker in vur for risk stratification. finally, it is reported that c5orf49 mutation could cause meckel-gruber syndrome. in present study, we identified a run-on mutation were shared by 5 vur patients out of the 37 patients. although the maf in chinese thousand-genome project is around 4.7%, much higher than western population, it may be a susceptibility gene candidate in chinese population, which needs to be validated in a larger sample size. conclusions: our data demonstrated that the whole exon sequencing is a reliable approach to identify disease-causing genes in isolated vur, and c5orf49 may involve in the vur pathogenesis. fp-s32-2 a cost-consequence analysis of treatment of vesicoureteral reflux (vur): which children benefit from antimicrobial prophylaxis? n. shaikh (1) , v. rajakumar (1) , j. gorski (2) objectives: antimicrobial prophylaxis for children with vur reduces the risk of recurrences of uti, but requires daily administration of an antimicrobial for extended periods. repeated utis can rarely lead to long-term consequences such as hypertension, preeclampsia, and end stage renal disease. we used a cost-consequence model to evaluate whether the benefits of antimicrobial prophylaxis outweigh its risks, and if so for which subgroups of children prophylaxis may not be cost-effective. methods: we compared the costs and consequences of antimicrobial prophylaxis with trimethoprim-sulfamethoxazole to no antimicrobial prophylaxis in children aged <6 years diagnosed with vur grades i-iv after a first or second uti. we also examined the results in subgroups defined by grade of vur, presence of bladder bowel dysfunction (bbd), and presence of fever at the time of uti. costs and consequences were evaluated over the patient's lifetime. we included the following consequences in our model: hypertension, preeclampsia and end stage renal disease. results: average costs of treatment for patients who develop long-term sequelae is $46,708. treatment of all children with vur with antimicrobial prophylaxis would cost $191,396 per sequelae avoided. in contrast, treatment of children with both vur and bbd with antimicrobial prophylaxis would cost $42,799 per sequelae avoided. conclusions: antimicrobial prophylaxis is most cost-effective in children with both vur and bbd. screening children for bbd can help select those who would benefit the most from long-term antimicrobial prophylaxis. fp-s32-3 genetic discovery in vesicoureteral reflux (vur) using exome sequencing: a pilot study r. thergaonkar (1) , v. manchanda (2) , a. yadav (2) , b. varma (2) , d. dash (2) , m. mukerji (2) , a. bagga (1) , p. hari (1 in the family, autosomal dominant (ad), recessive (ar) and x-linked (xl) models were used. objectives: immunization with various vaccines is recommended for children with idiopathic nephrotic syndrome (ns) because of their high risk for severe infections. while vaccinations could precipitate ns relapses, there are no available data regarding influenza (flu) virus vaccines. methods: we retrospectively reviewed the medical records of pediatric patients with ns who had received flu vaccines between 2002 and 2015. the period from pre-vaccination days to post-vaccination days was defined as -x to +y. flu vaccines were given during except for the period administered 2 mg/kg/day of prednisolone or on relapses. comparison of ns relapse rates in pre-or post-flu vaccination periods was evaluated using poisson method. risk factors for ns relapses were evaluated using generalized linear mixed model about parameters such as pre-or post-flu vaccinations, sex, age at onset of ns, past history of steroid resistant, renal histology, being on various immunosuppressants or not. results: a total of 104 pediatric patients (73 boys and 31 girls) received 208 flu vaccines. mean age at onset of ns, mean age at first flu vaccinations, and mean observation period were 4.85 ± 3.87 years old, 7.76 ± 5.10 years old, and 2.64 ± 2.20 years, respectively. during -180 to +180, the total number of ns relapses and relapse rate were 274 episodes and 1.33 times/personï½¥year, respectively. compared with relapse rate in -180 to 0 (1.20 times/ personï½¥year), those in 0 to +30, 0 to + 60 and 0 to + 180 were 1.38 (risk ratio (rr): 1.14, 95% confidence interval (ci): 0.75-1. objectives: to evaluate the imaging results of childhood uti in a developing country setting, and examine if it would be appropriate to apply the recent guideline changes regarding imaging studies as routine practice in thailand. methods: medical records of children aged 0-15 years who had uti and were admitted at the department of pediatrics, prince of songkla university from january 2004 -december 2013 were reviewed. renal ultrasound (rus), cystogram and 99m tc dimercaptosuccinic acid (dmsa) renal scanresults to determine congenital anomalies of the kidney and urinary tract (cakut) and renal damage were evaluated. mild cakut was defined as primary vur grades i-iii or isolated hydronephrosis and all other abnormalities were defined as severe cakut. results: 142 boys and 129 girls had at least one imaging study after uti. their median (iqr) age was 1.0 (0.5 -2.7) year; 0.7 and 1.4 years for boys and girls, respectively (p=0.006).262 children had an rus performed, of which 99 (37.8%) were abnormal. cystograms were performed in 221 children, of which 83 (37.6%) cakuts were detected; 69 primary vurs, 3 posterior urethral valves, 5 neurogenic bladders with vur and 4 duplex kidneys and 2 urinary tract fistulas. 108 children had a dmsa performed, of which 53 (49.1%) were abnormal, including 30 scarred kidneys, 14 dysplastic kidneys, 4 with dysplasia and scarring in the contralateral kidney, 2 enlarged kidneys, 2 with generalized decreased uptake in one kidney and 1 with a non-functional kidney. overall, cakuts were detected in 148 (54.6%) children of which 43 were severe and 105 were mild. rus together with cystogram provided higher sensitivity (100% vs 88.9%) and specificity (53.8% vs 42.4%) to detect severe cakut than rus together with dmsa. conclusions: a cakut was detected in more than half of the children with first uti, with one third having severe cakut. there is no single optimal imaging study guideline after first uti, as patient settings and resources vary widely. an open labelled randomized control trial on the utility of antibiotic cover to prevent urinary tract infection in children undergoing voiding cystouretrogram b. maji (1) , r. sinha (1) , s. saha (2) (1) institute of child health, kolkata, india; (2) amri, kolkata, india objectives: to conduct an open labelled randomised controlled trial to assess the utility of antibiotics for preventing urinary tract infection (uti) in children undergoing voiding cystourethrogram (vcug). methods: children (2 month -5 year) referred for vcug were confirmed to have sterile urine and were thereafter randomized in 3:2 ratios to either undergo vcug under antibiotic cover (cotrimoxazole or cephalexin was started a day prior vcug and continued for a day post procedure) or without antibiotic cover. sample size was calculated at 120 for a power of 80% with alpha 0.05. urine routine and culture was done 4 days prior vcug to rule out underlying uti and repeated 2 days post vcug to diagnose post procedure uti. results: 120 children (69% male, age: median 10 month, range 2 to 60 months) were recruited. no significant difference was noted in the demographic criteria between those receiving antibiotic (n=72) and not receiving antibiotic (n=48). overall 13 children (11%) developed post vcug uti. incidence of uti was significantly lower among those receiving antibiotic (n= 4, 6%) when compared to those not receiving antibiotic (n=9, 19%), p=0.02. 21% (n=10) of children with abnormal ultrasound (n=48) developed uti post vcug when compared to 4% (n=3) of children with normal ultrasound (n=72) p = 0.004. the rct demonstrated that vcug performed under antibiotic cover results in significantly less uti. it also revealed that risk of post vcug uti is significantly higher among those with abnormal ultrasound. future studies are needed to explore whether using antibiotic only among those with abnormal ultrasound will reduce the usage of antibiotic without increasing the risk for post vcug uti. conclusions: the incidence of paediatric urolithiasis is rising in the uk, with increasing older children and females. metabolic abnormalities commonly predispose urolithiasis and recurrence rates are high, justifying the comprehensive screening of all children. objectives: we report preliminary observations from a first-in-human clinical trial of aln-go1, a subcutaneously administered investigational small interfering rna therapeutic for the treatment of primary hyperoxaluria type 1 (ph1). ph1 is a rare, inherited, life threatening condition characterized by end stage renal disease and multiple end organ damage. the disease results from an inherited defect in the hepatic peroxisomal enzyme, alanine glyoxylate aminotransferase (agxt), causing an overproduction of the toxic metabolite, oxalate. currently, liver transplantation provides the only definitive correction of the hepatic metabolic defect. aln-go1 is targeted to hepatocytes, where it inhibits glycolate oxidase (go), an enzyme upstream of agt, thereby reducing the substrate for oxalate production. in pre-clinical models, treatment with aln-go1 has demonstrated a dose-dependent increase in the non-toxic metabolite, glycolate, with a corresponding reduction in oxalate excretion, suggesting a potential for therapeutic benefit. methods: a placebo-controlled single-ascending dose phase 1/2 study of aln-go1 is ongoing in healthy adult volunteers. the primary endpoint is safety and tolerability. changes in plasma glycolate to determine selection optimum dosing regimens for patients with ph1 will also be evaluated. results: safety, tolerability and emerging dose-dependent pharmacodynamic data will be presented. the results of this phase 1/2 trial of aln-go1 will guide future stages of development of aln-go1 in patients with ph1. fp-s36-3 do patients diagnosed with primary hyperoxaluria through family screening have different characteristics compared with those diagnosed conventionally? d.j. sas (1) , f.t. enders (1) , r.a. mehta (1) , x. tang (2) , f. zhao (1) , b.m. seide (1) , d.s. milliner (1) , j.c. lieske (1) (1) mayo clinic, rochester, united states; (2) shanghai changzheng hospital, second military medical university, shanghai, china objectives: primary hyperoxaluria (ph) is an inherited disease characterized by excessive production of oxalate leading to recurrent nephrolithiasis, nephrocalcinosis and progressive kidney damage. most ph patients are diagnosed through evaluation initiated for clinical suspicion (cs) based on signs or symptoms. however, some are detected by family screening (fs) once an affected family member has been identified. we sought to characterize differences between these two groups. l. greenbaum (3) , g. ariceta united states; (3) emory school of medicine and children's healthcare of atlanta calcitriol treatment ameliorates fgf23/fgfr4-induced cardiac myocyte hypertrophy in vitro and in vivo m. leifheit-nestler (1) vitamin d deficiency and excess of fgf23 are contributors to cardiovascular mortality in ckd patients. fgf23 exclusively activates fgf receptor (fgfr) 4 to stimulate lvh, and cardiac expression of fgf23 correlates with the presence of lvh in ckd. 1,25-dihydroxyvitamin d (1,25d) is known to have cardioprotective properties, but may further stimulate fgf23 synthesis and thus lvh in ckd. here, we investigated the dose-and timedependent effects of calcitriol treatment on i) fgf23/fgfr4 system and lvh in 5/6 nephrectomized rats (nx), and ii) fgf23-induced hypertrophy of cardiac myocytes in vitro. methods: 5/6nx were treated with 1,25d (0-300 ng/kg bw/d) for 4 and 10 weeks, respectively. hearts were investigated for fgf23 signaling, cardiac remodeling, and lvh. isolated neonatal rat ventricular myocytes (nrvm) were stimulated with 1,25d and/or fgf23 and evaluated for myocardial hypertrophy. results: vehicle-treated 5/6nx rats show enhanced expression of fgf23 in bone and myocardium both bone and cardiac fgf23 gene expression, and total cardiac fgf23 protein levels are further stimulated by 1,25d, whereas full-length intact cardiac fgf23 protein, fgfr4, and calcineurin-nfat signaling are suppressed. expression of rcan1, trpc6, and pro-hypertrophic genes are increased in 5/6nx rats, and downregulated by 1,25d. in nrvm, 1,25d induces fgf23 and fgfr4 mrna levels, whereas the expression of rcan1 and bnp, and the size of cardiac myocytes remain unaffected. 1,25d treatment blunted fgf23-induced hypertrophy in nrvm. conclusions: 1,25d ameliorates lvh in 5/6nx rats and rescues fgf23-induced cardiac myocyte hypertrophy in vitro s32 -vesicoureteric reflux: what's new? fp-s32-1 whole exon sequencing (wes) reveals recurred germ line mutations in vesicoureteral reflux china & table 1: list of possible candidate genes results: median depth of coverage was 48x & target coverage 94% at 10x. mutations & cnvs in essential gene-sets are shown no mutation was shared. 1 mutation was noted in tmem67, a possible candidate gene that is also in a candidate cytoband & 0/2 patients with recurrent uti, worsening renal scarring, hypertension, proteinuria & voiding disorders, respectively. xl model identified 6 variants in arsd,located within a 187 bp intronic region; 3-6 of these were seen in all 9 boys but not the girl. ad model identified 2 mutations in aga and slit1 & table 2: variations in essential gene-sets and cnvs conclusions: exome sequencing using sharp phenotyping is a promising method for genetic discovery in vur. tmem67, aga, slit 1 & arsd are candidate genes. s33 -infections and the kidney fp-s33-1 examination of clinical relationship between influenza virus vaccine and relapse of nephrotic syndrome in children kamei (3) , s. ito (4) , k. ishikura (3) (1) department of pediatrics mycophenolate mofetil (mmf) as induction and maintenance therapy in childhood lupus nephritis (ln) f. nuzzi (2) , m.m. balletta (1) , g. malgieri (2) , m. d'armiento (1) histologic classes (weening) were: ii in 9 pts, iii in 7, iv in 18, v in 5. before mmf, methylprednisolone i.v. pulses were administered. hematuria was always present, proteinuria ranged from 1.7 to > 9 g/day, decreased c3 and increase in anti-dsdna ab were present. treatment outcome was monitored through assessment of sledai score, renal function, proteinuria, serological markers and side effects. mmf was administered twice daily at mean dose 29/mg/kg/day. oral prednisone (p) was associated to mmf. results: after a mean followup 4.5 yrs (0.5-8.3) all pts had sustained remission: proteinuria was absent or < 0.5g/day in 23, 0.5-1.0g/day in 15, > 1g in 3.; all but one of 9 children with renal failure at onset normalized; c3 mormalized in 25 (61%). a steroid sparing effect (p maintenance dose 0.3 mg/kg/alternate day in 27 pts). until now 6 pts are off therapy from 1.7 yrs mean period (0.8-3.2) after at least 4 yrs therapy, no flares from 3yrs, proteinuria < 1 g/day, normal pcreat, inactive urinary sediment. in 10 pts a second serial renal biopsy, after 2 yrs, showed decrease of activity indexes, chronicity indexes did not change. no hematological side effects were seen; because of gastrointestinal signs in 6 pts, mmf was shifted to gastroresistant formula; one pt had herpes zoster infection s35 -complications following renal transplantation fp-s35-1 post-transplant acute kidney injury (aki) predicts development of chronic kidney disease (ckd) in paediatric non-kidney transplant recipients c. williams (1) , k. borges (1) , t. banh (1) aki status (defined per international guidelines) was assessed at 3, 6 and 12 months post-transplant. patients were followed until ckd (creatinine-based estimated glomerular filtration rate (egfr) <60 ml/ min/m 2 for 6 months), end stage renal disease (esrd, initiation of dialysis or receipt of a kidney transplant) or last follow-up. those who received dialysis prior to transplant or were followed <90 days were excluded. risk of ckd as a function of aki and other covariates was evaluated in cox regression models. results: a total of 304 children were transplanted at a median age of 4.0 years (iqr:0.7-11.9); 55% were male. a total of 88 children developed aki with a mean of 1.3±0.6 aki episodes over the first year post-transplant and 24 developed ckd. less than 5 children developed esrd, all within 65 days posttransplant and thus were not included in subsequent analysis. in a cox regression model, those with 1 or more aki events versus no aki event by each of the pre-specified time points (3 months, 6 months, 1 year post-transplant) had a significantly greater risk for developing ckd over subsequent follow-up after controlling for age, sex, baseline egfr. conclusions: aki occurs commonly in the first year after transplant and more than 1 episode of aki is associated with 2-4 times greater risk of developing ckd fp-s35-2 focus on physical activity can improve cardiorespiratory fitness (vo2peak) in children after renal transplantation h. thorsteinsdottir (1) , a. lie (1) , t. tangeraas (1) , a. åsberg ) as well as all renal transplanted patients at the age of <16 yrs in the period 2010-2015 were invited to participate in this follow-up study. the participants were tested on the treadmill (vo 2,max ) and went through a thorough physical examination, including ambulatory blood pressure monitoring and measurements of plasma lipids. the present interim analysis is performed half way into the study. results: so far 12 out of 16 patients (8 girls) met the criteria for vo 2,max the median age at transplant was 9.6 years (iqr=4.7-12.8) and the median time on dialysis was 19 months (iqr=6.5-35.5). fifty-eight patients (76%) underwent kt with deceased donor, the median follow-up at the study time point was 3.4 years (iqr=2.2-4.7) and the median gfr was 63ml/min/1,72m 2 (iqr=48-81). only 1 child presented coronary calcification (1.3%) and with regard to echocardiography, multivariable linear regression revealed significant association between the lvm-sds and serum renalase (each 100 ng/ml increase in serum renalase is associated with 0.8 greater lvm-sds, p=0.005) and a trend of association with gfr (each 10 ml/min higher gfr is associated with -0.13 lower lvm-sds, p=0.062). conclusions: to summarize, our data showed relatively good heart health in the study sample. these results may be due to the young age of the patients and the short time of renal replacement therapy s36 -nephrocalcinosis & nephrolithiasis fp-s36-1 no stone unturned: the epidemiology and outcomes of paediatric urolithiasis in the united kingdom significant family history was strongly predictive of metabolic aetiologies (or 5.5:1 vs. no family history). 47% of children had multiple aetiological factors, complicating their investigation and management. 31% of children with ≥ 4 year follow-up experienced recurrence. critically, we report an association between paediatric urolithiasis and adverse long-term renal outcomes. 33 of 55 children that underwent dmsa scanning demonstrated abnormal results key: cord-290432-4dli5emd authors: o’grady, kerry-ann f.; hall, kerry k.; sloots, theo p.; anderson, jennie; chang, anne b. title: upper airway viruses and bacteria in urban aboriginal and torres strait islander children in brisbane, australia: a cross-sectional study date: 2017-04-04 journal: bmc infect dis doi: 10.1186/s12879-017-2349-1 sha: doc_id: 290432 cord_uid: 4dli5emd background: respiratory morbidity in australian indigenous children is higher than their non-indigenous counterparts, irrespective of urban or remote residence. there are limited studies addressing acute respiratory illness (ari) in urban indigenous children, particularly those that address the upper airway microbiome and its relationship to disease. we aimed to describe the prevalence of upper airway viruses and bacteria in symptomatic and asymptomatic urban-based australian indigenous children aged less than 5 years. methods: a cross-sectional analysis of data collected at baseline in an ongoing prospective cohort study of urban aboriginal and torres strait islander children registered with a primary health care service in the northern suburbs of brisbane, australia. clinical, demographic and epidemiological data and bilateral anterior nasal swabs were collected on enrolment. polymerase chain reaction was performed on nasal swabs to detect 17 respiratory viruses and 7 bacteria. the primary outcome was the prevalence of these microbes at enrolment. logistic regression was performed to investigate differences in microbe prevalence between children with and without acute respiratory illness with cough as a symptom (ariwc) at time of specimen collection. results: between february 2013 and october 2015, 164 children were enrolled. the median age at enrolment was 18.0 months (iqr 7.2–34.3), 49.4% were boys and 56 children (34.2%) had ariwc. overall, 133/164 (81%) nasal swabs were positive for at least one organism; 131 (79.9%) for any bacteria, 59 (36.2%) for any virus and 57 (34.8%) for both viruses and bacteria. co-detection of viruses and bacteria was more common in females than males (61.4% vs 38.6%, p = 0.044). no microbes, alone or in combination, were significantly associated with the presence of ariwc. conclusions: the prevalence of upper airways microbes in asymptomatic children is similar to non-indigenous children with ariwc from the same region. determining the aetiology of ariwc in this community is complicated by the high prevalence of multiple respiratory pathogens in the upper airways. study registration: australia new zealand clinical trial registry registration number: 12,614,001,214,628. retrospectively registered. electronic supplementary material: the online version of this article (doi:10.1186/s12879-017-2349-1) contains supplementary material, which is available to authorized users. acute and chronic respiratory illnesses are predominant causes of morbidity and mortality in aboriginal and torres strait islander (hereforth respectfully called indigenous) children in australia [1] . in some remote regions of australia, indigenous infants present on average at least once a fortnight to community clinics and acute respiratory illnesses (ari) are the most common reason for attendance [2] . indigenous children are 2.6 times more likely to present to emergency departments (ed) with ari [3] and twice as likely to be hospitalised for an ari than non-indigenous children [1] . however, respiratory research in indigenous children has predominantly focused on remote-based children [4, 5] , although the majority of indigenous children live in urban or inner regional areas of australia, with brisbane having the largest of those communities [6] . there is a conspicuous lack of current data on ari and related respiratory microbes in urban indigenous children at the community level and it is unknown whether it is similar to remote children or non-indigenous children in urban settings. further, cough is the most common symptom associated with health care utilisation amongst australian children [7] , including indigenous children and, if present in ari, is likely indicative of a lower ari particularly if wet. establishing the microbiological aetiology of ari with cough (ariwc) in children is complex, particularly if upper airway specimens are used [8] , given many organisms are also detected in the nasopharynx of healthy children. however upper airway microbial data obtained from the nasopharynx are still considered important because they can provide important epidemiological information on the prevalence of, and temporal trends in, organisms within and between different populations. knowing upper airway microbial epidemiology is particularly important to informing public health strategies such as vaccination. increasingly co-detection of viruses with bacteria is considered important and a recent south african study reported 5 different types of organisms per episode were found in the upper airways of young children [9] . yet, there are limited data on factors that are associated with virus and bacteria co-detection in indigenous children, particularly those in urban settings. thus, in 164 urban-based indigenous children presenting to an urban primary health care service, we described the prevalence of upper airway respiratory viruses and bacteria. we also sought to identify factors associated with virus-bacteria codetection. we hypothesised that virusbacteria codetection was more likely in children with ariwc than those without. we analysed data from a cohort of urban aboriginal and torres strait islander children aged less than 5 years collected at time of enrolment into a prospective study of ariwc. the full protocol of the prospective study has been previously published [10] . the study was conducted in a large primary healthcare clinic in the northern suburbs of subtropical brisbane which has a patient population of approximately 11,500 people. fifty-nine percent of the patients identify as being indigenous. an aboriginal research officer approached all children aged less than five years and their parent or guardian at time of presentation to the clinic for any reason (including well child checks and accompanying another person presenting for health care). children were eligible for inclusion in the primary cohort study [10] if they were: a) identified by the parent/guardian as being indigenous; b) a regular patient of the clinic; c) aged less than five years at time of enrolment, and; d) parents/guardians were willing and able to complete the study requirements. the reason for presentation and the presence of ariwc were not determined until after the child had been enrolled. for the analysis presented in this manuscript, only children who had a nasal swab performed were included. there were no exclusion criteria. at enrolment, detailed demographic, environmental, clinical and socio-economic data were collected, and an anterior bilateral nasal swab was performed. nasal swabs were collected using the virocult™ system (medical wire and equipment, corsham, uk) by inserting the tip at least 1 cm into each nare and turning the swab four times against the nasal mucosa. a child was considered symptomatic of ariwc if any of the following symptoms occurred within seven days prior to and including the day of enrolment: cough and other local or systemic symptoms suggestive of a respiratory illness (eg. runny nose, wheeze, dyspnoea and tachypnoea). children did not meet the case definition if cough was not present during that time. nasal swabs were stored refrigerated until they were transferred within one week to -80°c freezers. multiplex polymerase chain reaction (pcr) was used to test for adenovirus, respiratory syncytial virus (rsv) groups a and b, influenza virus types a and b, parainfluenza virus types 1-3, human metapneumovirus, human rhinoviruses, human coronaviruses (oc43, 229e,nl63 + hku1), human bocavirus, human polyomaviruses ki and wu, m. pneumoniae, c. pneumoniae, b. pertussis, s. pneumoniae, s. aureus, non-typeable haemophilus influenzae (nthi) and m. catarrhalis using previous established methods [11, 12] . descriptive analyses were performed with data expressed as proportions and/or means of the selected characteristics. where continuous data were not normally distributed, medians with accompanying interquartile ranges are presented. univariate analyses were performed to evaluate potential differences in child characteristics between swabs in which codetection of virus and bacteria did and did not occur. chi 2 statistics were used to assess differences in proportions and the wilcoxon rank sum test was used to compare differences in medians. given the lack of sufficient significant findings on univariate analyses, regression analyses were not performed. all analyses were performed in stata v14se (statacorp, college station, tx, usa). between february 2013 and november 2015, 403 children were screened and 180 indigenous children were enrolled. reasons for non-enrolment were 20 (4.9%) were non-indigenous, 72 (17.9%) declined, 43 (10.7%) were ineligible and 88 (21.8%) were not enrolled for other reasons. there were no differences in age and gender between children who were and were not enrolled. one child was withdrawn as a screen failure, 15 children/parents refused specimen collection and thus nasal swabs were collected from 164 children. of the 164 children, the median age at enrolment was 18.0 months (interquartile range (iqr) 7.2-34.3) and 49.4% were male; respiratory symptoms at time of enrolment were present in 56 children (34.2%). there were no differences in the median ages of children with and without ariwc (p = 0.432) nor any differences within and between age groupings (ie. < 6 months, 6 -<12 months, 12 -<24 months and 24+ months; p = 0.529). overall 133/164 (81%) nasal swabs were positive for at least one organism, 131 (79.9%) for any bacteria, 59 (36.2%) for any virus and 57 (34.8%) for both viruses and bacteria ( table 1 ). all but two swabs that were positive for one or more viruses also had bacteria detected. three or more organisms were detected in 33.1% of swabs. c. pneumoniae and m. pneumoniae were not detected in any specimens and are not considered further. there were no statistical differences in the prevalences of any virus or bacterium, alone or in combination, between children with and without ariwc (table 1) . even in children without ariwc, a virus was detected in 36.5% of children. virus-bacteria co-detection was more frequent in females than males (61.4% vs 38.6%, p = 0.044) and this was not age-dependent. no other characteristics were significantly different between children with and without codetection of viruses and bacteria ( table 2 ). the prevalences of specific bacteriumbacterium, virusvirus and virus-bacterium codetections are presented in the additional file 1: table s1 . the seasonal distribution of organisms detected is presented in fig. 1 ; influenza and b. pertussis are not included given each was only detected in one swab over the entire study. all other bacteria were detected across all seasons of the year however this did not occur for the parainfluenza viruses, adenovirus, polyomaviruses and coronaviruses. given the lack of microbiological data in the upper airways of urban-based indigenous children, we investigated this in a cohort of children aged <5 years attending a primary health care service with and without ariwc. irrespective of the reason for presentation to the clinic, a third of the children had ariwc symptoms at enrolment. the prevalence of upper airway respiratory viruses and bacteria were very high; at least one virus or bacteria was detected in 81% of children and ≥3 organisms were detected in a third. the detection of any upper airway viruses and/or bacteria, alone or in combination, was similar between children with and without ariwc and was not associated with age. the prevalence of any organism in children in this study of 81% is similar to children aged <15 years presenting acutely to a tertiary paediatric emergency department (ed) in the same geographical location with ariwc (91%), the majority of whom were non-indigenous [13] . the prevalence of co-detection of viruses and bacteria in the ed study was 51.8% [13] , higher than the 34.8% in this cohort. however, children in the ed study were all symptomatic for ariwc whilst the majority of children in this current study were asymptomatic. the two studies utilised the same specimen collection and laboratory methods and tested for the same organisms at the research laboratory. in both studies, s. pneumoniae followed by m.catarrhalis and nthi were the dominant bacteria and rhinoviruses were the most common virus. b. pertussis, m. pneumoniae and c. pneumoniae were rare and influenza was uncommon. respiratory syncytial virus was only observed in 4 % of children in this study but was detected in 17% of children in the ed study [14] . in that study, rsv was weakly associated with children being hospitalised [14] and its higher prevalence amongst ed children compared to community children possibly reflects the severity of illness if infected rather than community prevalence. the seasonal distribution of organisms was also similar to that identified in the ed study [13] , including a predominance of the autumn months for nthi and rsv and that virus-bacteria codetection occurred predominantly in autumn and winter. in a study of upper airway viruses and bacteria in central australian aboriginal children hospitalised for pneumonia [8] , a population with high rates of hospitalised lower ari [15] and nasal colonisation [16] , the [8] . that study differed from the two brisbane studies in that the nt study focused on children hospitalised with pneumonia rather than non-severe ariwc, different specimen collection techniques were used, the pcr for bacteria was performed at a different laboratory and the central australian study was undertaken prior to widespread implementation of pneumococcal conjugate vaccines. however, more recent community based studies of nasopharyngeal carriage of these bacteria in the northern territory in the 13-valent pneumococcal conjugate vaccine era identified prevalences of 77% for s. pneumoniae, 45% for m. catarrhalis and 63% for nthi [16] . viruses were not reported in that study. in a western australian study of asymptomatic rural aboriginal children that included testing for the same viruses as our study with the exception of bocavirus and the polyomaviruses [17] , viruses were detected in 41% of children (most commonly rhinoviruses: 23.6%). thus our data suggest that viral infection may be comparable between urban and remote indigenous children however bacterial carriage is likely to be higher in remote children. we identified only two swabs that were positive for viruses only (i.e. most had virus with bacteria codetection); one was a single isolation of a polyomavirus and the other was a co-detection of rhinovirus and bocavirus. the reasons why we found so few virus-only detections are uncertain, particularly given few data in the literature that have tested for the same spectrum of organisms by pcr that was undertaken in this study. both swabs were from children with ariwc at the time of testing but the clinical significance of virus only detections is unknown. a recent study of respiratory viruses (n = 15) detected by pcr in 560 paediatric episodes of ari reported 457 episodes were virus positive, of which 331 were single infections and 126 were multiple infections; testing was undertaken for only two bacteria (c. pneumoniae and m. pneumoniae) [18] . there was no difference in clinical severity and management between children with single infections and those with multiple infections. we found no relationship between the child characteristics and virus-bacteria codetection other than gender. notably there were no differences in codetection between children with and without ariwc, although the lack of difference may be attributable to a secondary analysis of data and hence lack of power to identify [19] . m. catarrhalis in the presence of viruses was also associated with rhinitis, nasal congestion and cough [19] . in 161 norwegian children attending two daycare centres over a 2-year period, nasopharyngeal swabs (nps) were collected over 4 time points and analysed by pcr for b. pertussis, m. pneumoniae, c. pneumoniae and 16 viruses [20] . overall 43% of 343 specimens were positive for at least one virus and none were positive for the three bacteria. in 331 swabs collected from 355 children who underwent a clinical examination, 70% of children with clear signs of respiratory tract infection were virus positive, compared to 41% with mild findings and 30% in those who were asymptomatic (p < 0.001), with rhinovirus the most common virus detected in all 3 groups [20] . in a study of respiratory viruses in alaska native children hospitalised with acute lower respiratory infections and age-matched community controls, viruses were detected by pcr in nps in 90% of 440 hospitalized children and 52% of 425 asymptomatic community controls, with rhinoviruses the most common in both groups [21] . bacteria were not reported in that study. while comparisons between children across studies are problematic given differences in demographics, geography and study methods, our study and those above emphasise the complexity in assigning ariwc causality based on nasal specimens in children given the high prevalence of multiple organisms in asymptomatic children. the probable exceptions are rsv, influenza virus and human metapneumovirus given their relatively strong association with severe ari in children and a low prevalence in asymptomatic children in several studies [22] . as these viruses were uncommon in our study it was not possible to examine their role in symptomatic respiratory infections. our study has limitations given the cross-sectional nature of the analyses, the relatively small number of children enrolled and that given this was single centre study, the children who were enrolled may differ to the general population of urban indigenous children in australia posing a risk of selection bias. our study children differed from national indigenous statistics with respect to the high prevalence of exposure to environmental tobacco smoke and other household characteristics such as the high number of single parent households, low total annual household income and low levels of attendance at childcare [23] . further, pcr detection of viruses and bacteria does not necessarily equate to active infection at the time of testing and simply provides an indication of recent exposure to the organism. next generation sequencing holds promise for the improved detection and differentiation of respiratory pathogens [24] . however the tests are costly which currently limits the use of the technology in population-based studies. our study is the first to report upper airway microbial in urban-based indigenous children with and without ariwc that includes the range of microbes we tested for. with the exception of rsv, the prevalence of upper airway respiratory viruses and bacteria in urban indigenous children is comparable to acutely unwell non-indigenous children from the same urban area but differs from remote indigenous children with respect to the latter having a higher prevalence of respiratory bacteria. given the high prevalence (82%) of organisms detected in children without ari, upper airway microbiology in urban-based indigenous children should be interpreted with caution. additional file 1: qld 4101, australia. 2 child health research centre, centre for children's health research australian institute of health & welfare. aboriginal and torres strait islander health performance framework 2014 report: detailed analyses. cat. no. ihw 167. canberra: australian government disease burden and health-care clinic attendances for young children in remote aboriginal communities of northern australia can linked emergency department data help assess the out-of-hospital burden of acute lower respiratory infections? a population-based cohort study diverging trends for lower respiratory infections in non-aboriginal and aboriginal children lower respiratory infections in australian indigenous children estimates of aboriginal and torres strait islander australians general practice activity in australia upper airway viruses and bacteria detection in clinical pneumonia in a population with high nasal colonisation do not relate to clinical signs aetiology of childhood pneumonia in a well vaccinated south african birth cohort: a nested case-control study of the drakenstein child health study the respiratory health of urban indigenous children aged less than 5 years: study protocol for a prospective cohort study successful application of a simple specimen transport method for the conduct of respiratory virus surveillance in remote indigenous communities in australia mailed versus frozen transport of nasal swabs for surveillance of respiratory bacteria in remote indigenous communities in australia prevalence, codetection and seasonal distribution of upper airway viruses and bacteria in children with acute respiratory illnesses with cough as a symptom upper airway viruses and bacteria and clinical outcomes in children with cough hospitalisation of indigenous children in the northern territory for lower respiratory illness in the first year of life general health, otitis media, nasopharyngeal carriage and middle ear microbiology in northern territory aboriginal children vaccinated during consecutive periods of 10-valent or 13-valent pneumococcal conjugate vaccines the interaction between respiratory viruses and pathogenic bacteria in the upper respiratory tract of asymptomatic aboriginal and non-aboriginal children single-and multiple viral respiratory infections in children: disease and management cannot be related to a specific pathogen role of nasopharyngeal bacteria and respiratory viruses in acute symptoms of young children respiratory virus detection and clinical diagnosis in children attending day care viral respiratory infections in hospitalized and community control children in alaska aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: a systematic review and meta-analysis australian institute of health & welfare. the health and welfare of australia's aboriginal and torres strait islander peoples: 2015. canberra: australian government unbiased detection of respiratory viruses by use of rna sequencing-based metagenomics: a systematic comparison to a commercial pcr panel the authors would like to thank the children and families who participated in this study and the staff of caboolture community medical for supporting the implementation of the study in their practice. we thank our indigenous research reference group for cultural oversight of the study throughout its duration. at the queensland paediatric infectious diseases laboratory, jane gaydon was instrumental in the processing and reporting of respiratory specimens. study data and materials may be made available on request with appropriate human research ethics committee approval and with the consent of the participating community as required by australian criteria for research with indigenous communities.authors' contributions kfo conceptualized the study, analysed the data and lead the production of the manuscript. kkh contributed to study design, had primary responsibility for recruitment and data collection and contributed to the manuscript. tps was responsible for the laboratory components of the study and interpretation of laboratory data. ja contributed to study design, managed the study at ccm and contributed to the manuscript. abc contributed to study design and implementation and provided significant input to the drafting of the manuscript.competing interests ja is the director of the clinic in which this study was conducted. she had no role in the recruitment and consent of participants and did not receive financial support for the study. not applicable. the study was approved by the human research ethics committees of the queensland children's hospital and health services (hrec/12/qrch/169), and the queensland university of technology (1300000741). informed consent was obtained from parents or guardians. an indigenous research reference group provided cultural oversight of the study. written informed consent was obtained from parents/guardians following provision of a plain language statement explaining the study. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. submit your next manuscript to biomed central and we will help you at every step: key: cord-022582-2e9i3m4b authors: potsic, william p.; wetmore, ralph f. title: otolaryngologic disorders date: 2012-03-21 journal: pediatric surgery doi: 10.1016/b978-0-323-02842-4.50055-3 sha: doc_id: 22582 cord_uid: 2e9i3m4b nan the ear is divided into three anatomic and functional areas: the external ear, the middle ear, and the inner ear. the external ear consists of the auricle, external auditory canal, and the lateral surface of the tympanic membrane. the auricle is a complex fibroelastic skeleton that is covered by skin and subcutaneous tissue that directs sound into the external ear canal. the external auditory canal is oval with the long axis in the superior to inferior direction. in neonates, the external canal is almost entirely supported by soft, collapsible cartilage. as the temporal bone grows over several years, the bony portion of the canal enlarges to comprise the inner one third, leaving the outer two thirds supported by firm cartilage. hair and cerumen glands are present in the outer two thirds of the external canal. the ear canal is lined by skin that is continuous with the lateral surface of the tympanic membrane, and it is innervated by cranial nerves v, vii, and x and cervical nerve iii. the tympanic membrane separates the external ear canal from the middle ear. it has three layers: an outer layer of skin; a middle layer of fibrous tissue that is attached to the malleus, the most lateral middle ear ossicle; and an inner layer of mucosa that is continuous with the mucosa lining the middle ear. the fibrous layer is also attached to a thick fibrous annulus that anchors it to the temporal bone. the middle ear is an air-filled space within the temporal bone of the skull that is lined by ciliated, columnar respiratory epithelium. the middle ear communicates with the mastoid air cell system posteriorly and is lined by the same mucosa. it also communicates with the nasopharynx anteriorly through the eustachian tube. the mucociliary transport system of the middle ear moves mucus and debris into the nasopharynx, where it is swallowed. secretory cells are not evenly distributed throughout the middle ear and mastoid complex and are more numerous anteriorly near the eustachian tube. three ossicles are present in the middle ear-the malleus, incus, and stapes-that transmit sound from the vibrating tympanic membrane to the stapes footplate. stapes movement creates a fluid wave in the inner ear that travels to the round window membrane and is dissipated by reciprocal motion to the stapes. there are two striated muscles in the middle ear. the tensor tympani muscle lies along the side of the eustachian tube, and its tendon attaches to the medial surface of the malleus. the stapedius muscle lies along the vertical portion of the facial nerve in the posterosuperior part of the middle ear. its tendon attaches to the head of the stapes. these muscles stiffen the ossicular chain in the presence of sustained loud noise. the facial nerve traverses the middle ear with its horizontal portion lying superior to the stapes. posterior to the stapes, the facial nerve turns inferiorly in a vertical fashion to exit the stylomastoid foramen deep to the tip of the mastoid. the chorda tympani nerve is a branch of the facial nerve that innervates taste to the anterior two thirds of the tongue. it exits the facial nerve in the vertical segment and passes under the posterosuperior surface of the tympanic membrane, crossing the middle ear lateral to the long process of the incus and medial to the malleus. the facial nerve lies within a protective bony canal throughout its course in the middle ear. however, the bony canal may be absent (in the horizontal portion) in as many as 30% of patients. cranial nerve ix supplies sensation to the floor of the middle ear. the inner ear consists of the cochlea, semicircular canals, and vestibule. the cochlea is a coiled fluid-filled tube consisting of 2 3 / 4 turns surrounded by dense bone. it contains the membranes that support the organ of corti and has hair cells that detect the fluid wave from vibration of the stapes footplate. the hair cells create the neural impulses that are transmitted from the auditory nerve (cranial nerve viii) to the brain, providing the sensation of hearing. the three paired semicircular canals (horizontal, superior, and inferior) are also fluid-filled tubes surrounded by dense bone. the semicircular canals each have a hair cell-containing structure (the ampulla) that detects motion. the utricle and saccule of the vestibule also have hair cell structures that detect acceleration. 26 the external ear develops during the sixth week of gestation and is completely developed by the 20th week. six hillocks fuse to form the basic units of the pinna. defects in the fusion of the hillocks lead to preauricular tags and sinuses. the external auditory canal develops from the first pharyngeal cleft. a solid epithelial plug forms during the beginning of the third month of gestation and canalizes in the seventh month to form the external auditory canal. the middle ear canal develops from the first pharyngeal pouch. the ossicles develop from the first and second pharyngeal arches. the inner ear arises from neuroectodermal tissue within the otic placode that forms the otic pit. 26 any combination of anomalies may occur. abnormalities of the development of the ear may create anomalies of the pinna, external auditory canal, middle ear structures, and inner ear. one of the anomalies that involves the external and middle ear is aural atresia (absence of the external auditory canal). absence of the external canal may occur with a deformed or normal external ear. the ossicles may be deformed and are usually fused to each other as well as the bony plate representing the undeveloped tympanic membrane. the facial nerve may also be altered in its course through the temporal bone. reconstruction of the atretic canal, removal of the bony tympanic plate, release of the fused ossicles, and reconstruction of a new eardrum is a complex surgical procedure that may improve hearing. rarely there is incomplete development of the inner ear structures. the most common of these is dysplasia of the cochlea, and it may vary in severity. dysplasia causes sensorineural hearing loss. 6, 14 the examination of the ear should always start with inspection of the outer ear and surrounding structures. deformities of the outer ear structure may suggest the presence of other anomalies, such as a first branchial cleft sinus. a first branchial cleft sinus usually presents below the ear lobe near the angle of the jaw. the sinus tract may connect to the ear canal or, rarely, the middle ear. the external auditory canal and tympanic membrane are best examined with a hand-held otoscope with a bright fiberoptic light source. the largest speculum that comfortably fits in the external canal should be used to maximize visualization and minimize pain. a very small speculum may be inserted deeply, but it might lacerate the ear canal as well as limit visibility of the tympanic membrane. the otoscope permits visualization of the ear canal and tympanic membrane. a translucent tympanic membrane will also permit visualization of the contents of the middle ear. cerumen may be encountered in the ear canal that obstructs the view of the tympanic membrane. removal of cerumen may be performed by using an operating otoscope head and an ear curet. however, the use of a headlight such as the lumiview (welch allyn, skaneateles, ny) or operating microscope permits the use of both hands and superior visualization. care should be taken to secure the child to prevent sudden movement, and the ear curet should be used gently to avoid causing pain and a laceration of the ear canal. examination of a child with an apparent or suspected ear condition often requires objective assessment of hearing by audiometry. current technology and expertise makes it possible to test a child at any age. behavioral audiometry can usually be accurately performed for a child who is older than 6 months of age by sound-field testing. older children are presented with a tone through insert earphones and a range of frequencies between 250 and 8000 hz for ear-specific testing. the hearing thresholds are recorded at each presented frequency; and this represents the air conduction threshold. the sound has to traverse the ear canal, tympanic membrane, and middle ear. the inner ear must respond by creating electrical impulses that are transmitted to the brain. normal thresholds are less than 20 db for children. bone conduction thresholds test the sensorineural component of hearing. a bone oscillator is used to test a range of frequencies by vibrating the skull, which stimulates the inner ear, directly bypassing the external and middle ear. normally, air conduction thresholds require less energy than bone conduction thresholds. if bone conduction thresholds require less sound intensity than air conduction to be heard, the child has a conductive hearing loss. if air conduction and bone conduction thresholds are elevated but the same, the child has a sensorineural hearing loss. most sensorineural hearing loss in children is a result of hair cell dysfunction in the organ of corti. hearing loss may be conductive, sensorineural, or mixed. electrophysical tests such as brainstem auditory evoked response and sound emission tests that measure the intrinsic sounds from the inner ear (otoacoustic emissions) may be employed in young infants and children who cannot participate in behavioral audiometry. a mechanical test of tympanic membrane compliance (tympanometry) may also be used for audiometric assessment. all of these tools are employed by pediatric audiologists. 23 for purposes of describing hearing loss, a threshold between 20 and 40 db is considered mild, 40 to 65 db is moderate, 55 to 70 db is moderately severe, 70 to 90 db is severe, and greater than 90 db is profound. four of 1000 children are born with a hearing loss, and 1 of those children is born with a severe to profound hearing loss. conductive hearing loss may be corrected with otologic surgery. hearing aids and fm systems may be helpful to children with both conductive and sensorineural hearing loss. assistance may be needed through auditory training, speech language therapy, and education to maximally develop communication skills. when a child has a sensorineural hearing loss that is too severe to be helped with hearing aids, a cochlear implant may be considered. a cochlear implant is an electrical device that is implanted under the scalp behind the ear. its processor converts sound to electrical impulses. a cable travels through the mastoid and facial recess to reach the middle ear, and the electrode array is inserted into the scala tympani of the cochlea through an opening that is made in the cochlea. cochlear implants stimulate the neural elements of the cochlea directly and bypass the hair cells. because the vast majority of sensorineural hearing loss in children is due to hair cell dysfunction, nearly all children get sound perception from a cochlear implant. rare conditions such as an absent auditory nerve or an absent cochlea preclude the use of a cochlear implant. a multidisciplinary evaluation by a cochlear implant team is required to evaluate a child and determine family expectations before performing a cochlear implant. a temporal bone computed tomographic (ct) scan and/or magnetic resonance imaging (mri) is performed to assess the cochlea and auditory nerves. children who are born deaf and are younger than the age of 3 years, as well as children who have already developed communication skills, language, and speech before losing their hearing, derive the greatest benefit from cochlear implants. cochlear implantation is approved for children 12 months of age or older by the u.s. food and drug administration. after a cochlear implant is performed, considerable auditory oral training is required to maximize a child's benefit to develop skills of audition, speech, and language. a child who has been deaf and without sound perception for several years is expected to benefit to a lesser degree. 33 otitis media with effusion is the most common chronic condition of the ear during childhood. all children are born with small eustachian tubes that may at times be unable to clear mucus that is secreted in the mastoid and middle ear. fluid may develop in the middle ear during an upper respiratory infection. it usually clears within a few weeks as the upper respiratory tract infection resolves. children with craniofacial anomalies such as cleft palate and down syndrome are also prone to middle ear effusions; there is no medication that is consistently effective in resolving such effusions. persistent effusion may cause a conductive hearing loss in the range of 20 to 40 db. a middle ear effusion may also function as a culture medium and predispose children to recurrent acute suppurative otitis media (asom). when fluid persists in the middle ear for 3 to 4 months, causing a hearing loss or is associated with asom, myringotomy and tympanostomy tube placement is helpful to resolve the hearing loss and reduce the frequency and severity of infection. myringotomy and placement of a tube is performed under general anesthesia using an operating microscope. a small incision is made in any quadrant of the tympanic membrane except the posterosuperior quadrant, where there would be risk of injuring the ossicles. the mucus is suctioned from the ear, and a silastic tube is placed in the myringotomy to provide prolonged ventilation of the middle ear. the tube will usually be extruded and the tympanostomy will heal in 6 months to 1 year. when the ear is no longer ventilated by a tube, the eustachian tube must ventilate the middle ear. if fluid recurs and persists, a repeat procedure may be needed. most children outgrow this problem as their eustachian tube grows. occasionally, adenoid tissue in the nasopharynx may contribute to the persistence of middle ear effusion and may also be removed at the time that a tube is placed. children who have had multiple sets of tubes are candidates for adenoidectomy. acute suppurative otitis media is the most common infection of childhood except for acute upper respiratory tract infections. it is the most common condition for which children seek medical care from their primary care physician. usual pathogens causing asom include streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis. 25 acute suppurative otitis media usually causes severe deep ear pain, fever, and a conductive hearing loss in the affected ear. the purulence in the middle ear is also present in the mastoid air cells because they are connected. asom is treated with broad-spectrum oral antibiotics; however, there is growing concern that indiscriminant use of antibiotics may result in antibiotic resistance. for this reason, accurate diagnosis by otoscopy should be made before initiating a course of antibiotics. occasionally, asom does not respond as expected to standard antibiotic therapy. when this occurs, culture and sensitivity testing can be obtained by tympanocentesis. after sterilizing the ear canal with alcohol, a 22-gauge spinal needle can be placed through the posterior or anterior inferior quadrant of the tympanic membrane and fluid can be aspirated with a small syringe. complications of asom are uncommon if appropriate antibiotic therapy is used. the conductive hearing loss resolves as the middle ear effusion clears. however, infection may necrose the tympanic membrane, causing a spontaneous perforation. small perforations usually heal in less than 7 days, but larger perforations may persist, cause a conductive hearing loss, and require a tympanoplasty for closure. the ossicular chain may also be disrupted by necrosis of the long process of the incus requiring ossicular reconstruction to restore hearing. acute coalescent mastoiditis occurs when infection erodes the bony mastoid cortex and destroys bony septa within the mastoid. a subperiosteal abscess may also be present. there is usually postauricular erythema and edema over the mastoid area. the auricle is displaced laterally and forward ( fig. 52-1 ). otoscopy reveals forward displacement of the posterior superior skin of the ear canal. in addition to antibiotics, treatment should include a wide field myringotomy from the anterior inferior quadrant to the posterior inferior quadrant, a tympanostomy tube placement for middle ear drainage, and a postauricular mastoidectomy to drain the subperiosteal abscess and the mastoid. facial nerve paralysis may occur from inflammation of that portion of the facial nerve that is exposed in the otolaryngologic disorders middle ear during asom. treatment with parenteral antibiotics, ototopical antibiotic drops applied in the ear canal, and a wide field myringotomy and tympanostomy tube placement almost always result in complete recovery of facial function. facial nerve recovery may take a few weeks to several months. intracranial complications of asom may include meningitis, epidural abscess, brain abscess, otitic hydrocephalus, and lateral sinus thrombosis. meningitis is the most common intracranial complication of asom and may be associated with profound sensorineural hearing loss and loss of vestibular function. treatment of the intracranial complications of asom is focused on appropriate treatment of the intracranial process, in addition to a wide field myringotomy and tympanostomy tube placement in the affected ear. 2 chronic otitis media is a descriptive term that refers to a persistent perforation of the tympanic membrane or the presence of a cholesteatoma of the middle ear. a cholesteatoma is a squamous epithelial-lined cyst that may be congenital or acquired. congenital cholesteatomas are caused by epithelial rests that persist in the middle ear during temporal bone development. they present behind an intact tympanic membrane and appear as a white, smooth mass in the middle ear. they expand over time and are filled with squamous debris and may erode the ossicular chain and extend into the mastoid. acquired cholesteatoma develops from skin entering the middle ear after a tympanic membrane perforation or a retraction pocket from eustachian tube dysfunction. cholesteatomas are usually painless, cause a conductive hearing loss, and, in acquired cases, often present as otorrhea. the otorrhea should be treated with ototopical antibiotic eardrops, but the only treatment of cholesteatomas is complete surgical excision by tympanomastoid surgery and ossicular reconstruction. 27[pp 18-59] the potential complications of cholesteatomas are the same as those for asom. objects stuck deeply into the ear canal such as a cottontipped applicator may perforate the tympanic membrane. this usually causes acute pain, bleeding, and a conductive hearing loss. if the ossicular chain is not disrupted, the vast majority of these perforations will heal spontaneously in about 2 weeks. if the tympanic membrane is perforated and the middle ear is contaminated with water, oral antibiotics should be given. lacerations of the auricle should be cleaned to prevent tattooing and repaired by careful approximation of the skin and soft tissue to restore the contours of the ear. the cartilage itself does not usually need to be sutured. partially or totally avulsed tissue should be replaced. if necrosis of tissue occurs, it can be dã©brided as needed. in severe injuries of the auricle, oral antibiotic treatment is helpful to prevent chondritis and loss of the cartilage framework. blunt trauma to the ear is commonly seen in wrestlers, in children with poor neuromuscular tone, or in children with self-injurious behaviors. blood or serum collects between the periosteum and the auricular cartilage. if the cartilage is fractured, the collection may occur on both sides of the ear. evacuation of the collection is required to restore the contours of the ear, prevent infection, and prevent scarring with formation of a "cauliflower ear." aspiration of the fluid and placement of a mastoid dressing for compression may be tried but is most often unsuccessful. incision and drainage provides for complete evacuation of the blood or serum. cotton dental rolls placed in each side of the auricle and held in place with bolster mattress sutures is the most effective management. the dental rolls should be left in place for 7 to 10 days while the patient also continues with a course of oral antibiotics. no outer dressing is required. 27[pp 106-109] blunt head trauma may disrupt the inner ear membranes causing sensorineural hearing loss and vertigo. no treatment is required, and the injury and symptoms may resolve spontaneously, but the sensorineural hearing loss may persist. severe head trauma may cause fracture of the temporal bone of the skull. temporal bone fractures can be classified as longitudinal, transverse, or mixed ( fig. 52-2 ) but are often complex and do not neatly fit into one category or another. a high-resolution, thin section ct scan of the temporal bone will define the extent of the fracture. the middle ear and mastoid are filled with blood when a fracture is present. the blood causes a conductive hearing loss that resolves when the ear clears. otoscopic evaluation of a child with a temporal bone fracture may reveal a laceration of the ear canal and tympanic membrane. blood is usually present in the ear canal, and the tympanic membrane appears to be dark blue because the middle ear is filled with blood. there is often ecchymosis of the mastoid area (battle's sign). it is important during evaluation of a skull and temporal bone fracture to note and record the function of the facial nerve if the patient is not unconscious. facial nerve paralysis may be immediate or delayed in onset. delayed facial nerve paralysis has a good prognosis for spontaneous recovery. immediate facial paralysis may indicate disruption of the nerve or compression by bone fragments. immediate facial nerve paralysis requires exploration and repair once the patient is stable and sufficiently recovered from any associated trauma. the facial nerve should be decompressed in the mastoid, middle ear, and middle cranial fossa. bone chips impinging on the nerve should be removed, and the nerve should be sutured or grafted if needed. all patients with temporal bone fractures should have an audiogram once their condition has stabilized. if the fracture disarticulates the ossicles, a conductive hearing loss will persist after the blood has cleared from the middle ear and mastoid. fractures of the temporal bone may transverse the cochlea and vestibular apparatus. these fractures usually cause a severe sensorineural hearing loss and loss of vestibular function on the affected side. a concussive injury of the cochlea may also simultaneously be present in the opposite ear in severe head trauma. temporal bone fractures may permit leakage of cerebrospinal fluid (csf) into the middle ear and mastoid. csf may also drain through the lacerated tympanic membrane, causing csf otorrhea. these leaks usually stop spontaneously, but persistent csf otorrhea may require a lumbar drain to reduce the pressure and permit healing. rarely, tympanomastoid exploration is required to close the leak. persistent csf leaks in the ear are associated with meningitis. benign and malignant tumors of the ear are rare. glomus tympanicum tumors and neuromas of the facial nerve may present in the middle ear. also, eosinophilic granuloma and rhabdomyosarcoma may involve the structures of the temporal bone. 5, 13 the nose can be divided into three anatomic sections. the bony vault is the immobile portion of the nose. it consists of the paired nasal bones, the frontal process of the maxillary bone, and the nasal process of the frontal bone. the cartilaginous vault is supported by the upper lateral cartilages and the cartilaginous nasal septum. the nasal lobule is supported by the lower lateral cartilages and the cartilaginous septum. the nasal septum is formed by the quadrilateral cartilage anteriorly. the posterior septum is composed of bone from the vomer, perpendicular plate of the ethmoid, nasal crest of the maxillary bone, and palatine bone. both the internal and external carotid artery systems supply blood to the nose. the roof and lateral wall of the internal nasal cavity are supplied by the anterior and posterior ethmoidal arteries, sphenopalatine artery, and greater palatine artery. the septum is supplied by the anterior and posterior ethmoidal arteries, palatine artery, and the superior labial artery. the convergence of these vessels in the anterior segment of the nose is referred to as kiesselbach's plexus or little's area. venous drainage is accomplished mainly by the ophthalmic, anterior facial, and sphenopalatine veins. the olfactory bulb is positioned high in the roof of the nasal cavity and is responsible for the sense of smell. sensory information is transported by nerves that penetrate the cribriform plate and traverse cranial nerve i (the olfactory nerve) to the brain. smell is also an important component of what is perceived as taste. bony projections, turbinates, form the lateral nasal wall and significantly increase the surface area of the nose, allowing for more efficient humidification and warming of the air to 36â°c. three turbinates are usually present (i.e., inferior, middle, and superior). a supreme turbinate, which is essentially a flap of mucosa, is occasionally present. the turbinates contribute to the turbulent airflow that creates approximately 50% of the total airflow resistance to the lungs. cleaning of air is accomplished through the nasal hairs (vibrissae) and the mucosal surface. anteriorly, the nose is lined with stratified squamous epithelium, which changes to respiratory epithelium immediately anterior to the turbinates. trapped debris is transported in a posterior direction into the nasopharynx by a mucociliary transport mechanism. speech is affected by nasal anatomy and pathologic conditions. hyponasality from nasal obstruction or hypernasality from an excessive air leak can affect voice quality and intelligibility of speech. the nose serves as a drainage port for the paranasal sinuses. the meati are spaces between the lateral aspect of the nasal turbinates and the medial aspects of the lateral nasal wall. each meatus is named for the turbinate that surrounds it. the maxillary, frontal, and anterior ethmoidal sinuses drain into the middle meatus. the posterior ethmoidal sinuses drain into the superior meatus. the sphenoidal sinus drains into an area known as the sphenoethmoidal recess that is located posterior and superior to the superior turbinate. the nasolacrimal duct drains into the inferior meatus. the nasal cavities develop from the nasal pits in the 4-week embryo. these pits deepen and move medially to form the nasal cavity. the oronasal membrane that separates the nose from the mouth resolves in the seventh week to permit communication between the nose and nasopharynx. the paranasal sinuses develop from an outpouching of the lateral nasal walls during the third and fourth months of development. the maxillary and ethmoidal sinuses are present at birth. the frontal and sphenoidal sinuses begin to develop several years after birth. the frontal sinus begins to develop at 7 years of age but is not fully aerated until adulthood. 1 viral rhinosinusitis (the common cold) accounts for the majority of nose and sinus infections. it is caused by many strains of viruses and is a self-limited infection. symptoms of fever, nasal congestion, headache, and clear rhinorrhea usually resolve over 5 to 7 days. treatment is symptomatic. acute bacterial rhinosinusitis may often follow an acute viral upper respiratory tract infection. the most common bacteria causing rhinosinusitis are streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis. acute rhinosinusitis causes malaise, headache, and nasal congestion. there may also be pain localized to the sinus region or pain on palpation over the maxillary or frontal sinuses. chronic sinus infection may persist after the acute phase and symptoms often last longer than 30 days. the "gold standard" for diagnosing sinusitis is a ct of the sinuses, but a thorough history and nasal examination is usually sufficient to diagnose acute rhinosinusitis. the nasal cavity can be visualized by using a large speculum on an otoscopic head. the posterior nasal cavity can be visualized with either a straight rod endoscope or a flexible fiberoptic nasopharyngoscope. the treatment of rhinosinusitis includes oral antibiotics, short-term use of topical nasal decongestants (e.g., oxymethazoline), and saline nasal sprays. topical nasal corticosteroid sprays may be helpful for the treatment of chronic sinusitis. chronic sinusitis in a child may be exacerbated by gastroesophageal reflux disease, immunodeficiencies, mucociliary dysfunction, and, more commonly, upper respiratory allergy. these predisposing conditions should be managed while treating the sinus infection. if the signs and symptoms of chronic sinus infection persist, a sinus ct is required to evaluate the condition of the sinus mucosa and the drainage pathways. endoscopic sinus surgery may be necessary to open the involved sinuses to provide drainage. chronic inflammation of the nasal and sinus mucosa may lead to nasal and sinus polyp formation that chronically obstructs the nose and sinuses. antrochoanal polyps are large polyps that originate from the walls of the maxillary sinus and extend through the nasal cavity into the nasopharynx. nasal polyps may be removed endoscopically, but a large antrochoanal polyp may require removal through an open maxillary sinus procedure. nasal polyps in a child should always prompt an evaluation for cystic fibrosis. the sinuses surround the orbit so a common complication of acute rhinosinusitis in children is orbital cellulitis with erythema and edema of the eyelids. chemosis (edema of the ocular conjunctiva) is usually absent. however, if a periorbital subperiosteal abscess forms adjacent to an infected sinus, there may be proptosis, chemosis, ophthalmoplegia, and loss of vision. infection in the ethmoidal sinuses most commonly results in this complication. subperiosteal periorbital abscess is demonstrated best by sinus ct. initial treatment should include intravenous antibiotics. endoscopic or external drainage may be required in some cases. intracranial complications of sinusitis include cerebritis, cavernous sinus thrombosis, as well as epidural, subdural, and brain abscess. treatment of intracranial complications or impending intracranial complications requires surgical drainage of the involved sinus and concurrent treatment of the intracranial lesion by a neurosurgeon. 30 fungal sinusitis may occur in immunocompromised children, specifically severe diabetics, children undergoing chemotherapy, and bone marrow transplant recipients. the treatment of fungal sinusitis involves surgical drainage and intravenous antifungal agents. however, a chronic form of fungal sinusitis is allergic fungal sinusitis. these patients usually have other signs of allergy, such as asthma. the treatment of this condition is corticosteroids and dã©bridement of the involved sinuses. the diagnosis is made by sinus ct findings and the presence of eosinophils as well as fungi in the sinus secretions that are removed at the time of surgery. 11 congenital stenosis of the anterior bony aperture causes partial nasal obstruction that may be severe enough to cause difficulty feeding, respiratory distress, and failure to thrive. anterior rhinoscopy demonstrates a very constricted nasal opening bilaterally. ct of the nose shows marked narrowing of the pyriform aperture. neonates are obligate nasal breathers, and severe stenosis must be surgically corrected. because the stenotic segment is very anterior and the remainder of the nasal cavity is normal, removal of the constricting bone with drills is done through a sublabial approach. the nasal openings are stented with 3.0-mm endotracheal tube stents that are sutured in place and removed after a few days. choanal atresia may be unilateral or bilateral. the obstructing tissue is usually a bony plate, but a few cases will have only membranous atresia. unilateral choanal atresia presents as chronic unilateral rhinorrhea. there is no significant respiratory distress. because neonates are obligate nose breathers, bilateral choanal atresia is associated with severe respiratory distress, difficulty feeding, and failure to thrive. the diagnosis is suspected if catheters cannot be passed through the nose and into the pharynx. the obstruction may be visualized with a narrow flexible nasopharyngoscope after the nasal cavity has been suctioned of mucus and the nasal mucosa has been constricted with a nasal decongestant (e.g., oxymetazoline). the diagnosis is best made with ct of the nasal cavity. ct will demonstrate the atresia, define the tissue (bony or membranous), and show the configuration of the entire nasal cavity. choanal atresia may be successfully treated by removing the obstructing tissue transnasally. curets, bone punches, and drills may all be effective to remove the atresia plate. however, when the bony plate is very thick and there is an extremely narrow posterior nasal cavity, a transpalatal repair is more direct. a transpalatal repair provides better access for more effective removal of the bony plate and posterior septum ( fig. 52-3 ). stents fashioned from endotracheal tubes are placed and secured with sutures to the septum. they are removed in several weeks. the stents must be moistened with saline and suctioned several times daily to prevent mucus plugging and acute respiratory distress. transpalatal repair of choanal atresia has a lower incidence of restenosis. 27[pp 196-205] nasal dermoid cysts or sinuses present in the midline of the nasal dorsum ( fig. 52-4 ). they usually appear as a round bump or a pit with hair present in the pit ( fig. 52-5 ). they also may become infected. nasal dermoid sinuses may extend through the nasal bones into the nasofrontal area and have an intracranial component. both ct and mri may be necessary to demonstrate the extent of the dermoid. surgical removal is required to prevent infection and recurrence. this may be done between ages 3 and 5 years if prior infection has not occurred. dermoids confined to the nose are resected completely using a midline incision with an ellipse around the sinus tract. otolaryngologic disorders the tract is followed to its termination, and the nasal bones may need to be separated to reach the end of the tract. 27[pp 188-191] if an intracranial component is present, a combined craniotomy and nasal approach with a neurosurgeon is recommended. a nasal glioma presents as an intranasal mass and may be confused with a nasal polyp. the mass contains dysplastic brain tissue and may have an intracranial connection. ct and mri are important to define the extent of the glioma and intracranial component as well as to plan the surgical approach. an encephalocele presents as a soft compressible mass and may also be confused with a nasal polyp. intranasal encephaloceles extend through a defect in the skull at the cribriform plate. ct and mri define the extent of the encephalocele and are necessary to design the surgical approach. surgical removal often includes a frontal craniotomy. nasal encephaloceles may be associated with csf rhinorrhea and meningitis. an infant may be born with the soft nasal bones and the septum deviated to one side either as a result of a difficult delivery or from persistent intrauterine compression of the nose. the nasal structures can most often be returned to the midline with digital manipulation. if the nasal deformity is partially reduced, the nose usually straightens with growth during the first year to 18 months of age. nasal bone and nasal septal fractures in older children usually occur from a blow to the face during sports. there is usually a brief period of epistaxis and deviation of the nasal dorsum to one side. swelling occurs rapidly, and the degree of the cosmetic deformity or the need for fracture reduction may not be easily determined. at the fourth to sixth day after injury, the edema subsides and the need for reduction can be determined. nasal bone radiographs are of little help in making this judgment, so the need for nasal fracture reduction is usually based solely on clinical examination. effective nasal fracture reduction may be done up to 2 weeks after the injury. closed reduction under general anesthesia is the method of choice. oral antibiotics prevent infection and are essential if nasal packing is used to support the nasal bone. although nasal fracture reduction is not urgent, a septal hematoma from a fractured septum should be excluded by the initial physician seeing the child. a septal hematoma that remains untreated may cause cartilage necrosis and loss of nasal support, with a resulting saddle-nose deformity. treatment of a septal hematoma is with incision and evacuation of the clot. the mucoperichondral flap should then be sutured in place by bolster sutures through the septum. a small rubber band drain should remain in place for 12 to 24 hours, and antibiotics should be given. epistaxis in children usually occurs in little's area of the anterior septum and frequently results from digital trauma (nose picking). the bleeding usually stops with pressure by squeezing the nasal ala. infrequently, cauterization of the vessels under general anesthesia is needed. children may be observed inserting a foreign body into their nose, or they may inform their parents of the event. most children, however, present with a foul-smelling unilateral purulent nasal discharge and deny putting anything into their nose. most nasal foreign bodies are painless and do no harm to the nose except cause a foul nasal discharge. disc batteries, on the other hand, cause very rapid alkali burns of the nasal cavity and pain. batteries must be removed from the nose quickly because the chemical burn occurs in minutes to hours. if extensive tissue necrosis occurs, it may cause a nasal stenosis. removal of a nasal foreign body is aided by decongesting the nasal mucosa and using a headlamp to visualize the foreign body. a variety of forceps or hooks may be used. if the object is deep in the nose, the removal is best performed under general anesthesia. the endotracheal tube prevents aspiration of the object into the tracheobronchial tree if it is pushed back into the nasopharynx. one must remember that multiple foreign bodies may be present. nasal lacerations should be closed with care to match edges and restore the contours of the nose. standard wound closure technique is employed. the nasal mucosa does not need to be sutured unless a large flap is displaced. rhabdomyosarcoma, lymphoma, squamous cell carcinoma, and esthesioneuroblastoma may occur in the nose and sinuses of children. fortunately, these malignant tumors are very rare in children. the treatment of children with malignant tumors of the nose and sinuses usually involves a multidisciplinary, multimodal approach. juvenile nasopharyngeal angiofibroma is a benign tumor of adolescent males that originates from the lateral wall of the nose and nasopharynx. the tumor may completely obstruct the nose and fill the nasopharynx. this type of angiofibroma may also extend intracranially through the base of the skull. patients with these tumors present with nasal obstruction, recurrent epistaxis, and rhinorrhea. the tumor may be seen with a flexible fiberoptic nasopharyngoscope or a rod lens telescope after decongesting the nasal mucosa. it appears as a smooth reddish mass. biopsy of the mass should be avoided because of the potential for severe bleeding. ct and mri define the extent and location of the tumor. mr angiography helps to delineate the blood supply, which may originate from both the internal and external carotid arteries. contrast angiography may be reserved for presurgical planning and embolization of the copious blood supply that is often present. the treatment of juvenile nasopharyngeal angiofibroma is complete surgical resection after preoperative embolization. depending on the material used, the embolization may be effective for days to weeks. a variety of surgical approaches may be used, including endoscopic resection of small tumors. extensive tumors may require a combined midfacial and craniotomy approach. 29 some authors have proposed radiation therapy as the primary treatment of juvenile nasopharyngeal angiofibroma, but many surgeons are concerned about the long-term effects of radiation in children, including the induction of malignant tumors. the boundaries of the oral cavity include the lips anteriorly, the cheeks laterally, and the palate superiorly. the posterior boundary is a plane that extends from the soft palate to the junction of the anterior two thirds and posterior one third of the tongue. the oral cavity is composed of the vestibule, the space between the lips and cheeks and alveolar ridges, and the oral cavity proper. the vestibule and oral cavity proper are separated by the alveolar ridge and teeth. the vestibule is divided in the midline by the labial frenula of the upper and lower lips. the alveolar ridge is contiguous superiorly with the hard palate. the parotid ducts (stensen's ducts) enter the vestibule opposite the second maxillary molars. the submandibular ducts (wharton's ducts) enter the floor of mouth near the lingual frenulum. the palate is formed by a fusion of the primary palate anteriorly and medial growth of the palatal processes that form the secondary palate. the hard palate divides the nasal and oral cavities and is formed by the premaxilla and the horizontal plates of the palatine bones. the soft palate is formed by a muscular aponeurosis of the tensor veli palatini tendon. five muscles insert into this aponeurosis and include the tensor veli palatini, levator veli palatini, palatoglossus, palatopharyngeus, and the musculus uvulae. defects in formation of the hard and/or soft palate result in clefting. the sensory and motor innervation of the palate is through the trigeminal nerve and pharyngeal plexus. the circumvallate papillae divide the tongue into the anterior two thirds that lies in the oral cavity and the posterior one third lying in the oropharynx. the innervation and vascular supply to the two major divisions of the tongue reflect their differences in origin-the anterior two thirds of the tongue being a first branchial arch derivative (trigeminal) whereas the posterior one third being a combination of third and fourth arch derivatives (pharyngeal plexus). the hypoglossal nerve supplies motor innervation to the intrinsic musculature. in addition to the intrinsic tongue musculature, the action of four extrinsic muscles combine to provide mobility. the genioglossus protrudes and depresses, the hyoglossus retracts and depresses, the styloglossus retracts, and the palatoglossus elevates. in addition to the circumvallate papilla, other taste buds on the tongue surface include conical, filiform, fungiform, and foliate papillae. the pharynx is a fibromuscular tube that extends from the skull base to the level of the cricoid cartilage of the larynx and can be divided into three levels. the nasopharynx extends from the skull base to the level of the soft palate, the oropharynx extends from the soft palate to the tongue base, and the hypopharynx extends from the tongue base to the cricoid cartilage. three muscular constrictors combine to form the muscular portion of the pharynx: superior, middle, and inferior constrictors. passavant's ridge is a muscular segment of the superior constrictor that is involved in velopharyngeal closure. lower fibers of the inferior constrictor help to form the upper esophageal sphincter. the motor and sensory innervation of the pharynx is from the glossopharyngeal and vagus nerves via the pharyngeal plexus. a collection of lymphoid tissue within the pharynx forms waldeyer's ring that includes the palatine tonsils, the adenoid (pharyngeal tonsil), and lymphoid follicles lining the lateral and posterior pharyngeal walls. in addition to the acute onset of sore throat, viral pharyngitis typically presents with fever and malaise. signs include erythema of the pharynx and cervical lymphadenopathy. depending on the viral agent, associated symptoms of nasal obstruction and rhinorrhea may also be present. rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, and influenza virus are agents responsible for viral pharyngitis. primary herpetic gingivostomatitis, caused by herpes simplex types 1 or 2, presents as fever, adenopathy, and vesicles and ulcers on the lips, tongue, buccal mucosa, soft palate, and pharyngeal mucosa. herpangina and hand-foot-and-mouth disease are viral infections that involve the oropharynx. epstein-barr virus (ebv) infection (infectious mononucleosis) presents as acute pharyngotonsillitis, fever, generalized adenopathy, malaise, and splenomegaly. although ebv infection is suspected by the appearance of 10% or more atypical lymphocytes on a complete blood cell count and the presence of a positive monospot test, the definitive diagnosis is confirmed by elevated titers of ebv. group a î²-hemolytic streptococcus (gabhs, i.e., s. pyogenes) commonly infects the pharynx. in addition to sore throat, associated symptoms include fever, headache, and abdominal pain. associated signs include pharyngeal erythema, halitosis, tonsillar exudates, and tender adenopathy. diagnosis may be confirmed initially with a rapid streptococcal antigen test. because rapid antigen testing is more sensitive than formal plating on blood agar, a negative test does not need confirmation, but positive rapid streptococcal tests should be confirmed with formal plating. other bacterial pathogens that cause acute pharyngitis include haemophilus influenzae and groups c and g î²-hemolytic streptococci. occasionally, concurrent infection with penicillin-resistant staphylococcus aureus may interfere with treatment of a gabhs infection. 28 although many cases of gabhs infections respond to treatment with penicillin v or amoxicillin, emerging resistance to oropharyngeal pathogens mandates treatment of recalcitrant cases with an antibiotic having known effectiveness against î²-lactamase-producing organisms. in cases in which a lack of compliance is suspected, intramuscular benzathine penicillin or ceftriaxone may be used. acute pharyngitis may also be associated with acute bacterial infections of the nose, nasopharynx, and sinuses. these infections may be caused by a variety of viral and bacterial pathogens; and in addition to sore throat, symptoms include fever, mucopurulent nasal drainage, nasal obstruction, and facial pain. recurrent infection of the pharynx may be either viral or bacterial. gabhs are the most worrisome bacterial organisms because recurrent infection may lead to complications such as scarlet fever, acute rheumatic fever, septic arthritis, and acute glomerulonephritis. in addition to a history of multiple positive cultures for s. pyogenes, elevated antistreptolysin-o (aso) titers may identify patients with chronic infection who are at risk for developing complications. some asymptomatic children may be chronic carriers of gabhs, and elevated aso titers may not be a reliable indicator for distinguishing between an active infection and the carrier state. treatment of recurrent streptococcal infection or the child who is a carrier should include a trial course of an antibiotic shown to reduce carriage (e.g., clindamycin, vancomycin, or rifampin). children with recurrent pharyngotonsillitis unresponsive to medical therapy or those who suffer a complication should be considered for surgical management. whereas treatment of each child should be individualized, suggested guidelines for surgical candidates include seven infections in 1 year, five or more infections per year for 2 years, or three or more infections per year for 3 years. 24 other factors to be considered in employing a surgical option include severity of infection, response to antibiotic therapy, loss of time from school, and need for hospitalization. the pharynx and specifically the tonsils may be the target of chronic infection. affected children complain of chronic throat pain, halitosis, and production of white particles or tonsilliths. signs include erythema of the tonsils, cryptic debris, and chronically enlarged cervical adenopathy. a variety of viral and bacterial agents can be blamed for chronic infection of the pharynx. cultures may or may not be positive in these patients, because surface cultures may be negative while core tissue is positive. antibiotic therapy directed at anaerobes or s. aureus may be helpful in resistant cases. children with infections unresponsive to medical management are candidates for tonsillectomy. localized extension of tonsillar infection may result in peritonsillar cellulitis. the same pathogens that cause acute pharyngotonsillitis are responsible for peritonsillar cellulitis. in addition to severe sore throat, symptoms and signs include drooling, trismus, muffled voice, ipsilateral referred otalgia, and tender lymphadenopathy. the affected tonsil is usually displaced in a medial and inferior position. peritonsillar cellulitis may progress to frank abscess formation (quinsy). early cases of peritonsillar cellulitis may respond to oral antibiotics, such as the penicillins, cephalosporins, erythromycins, or clindamycin. unresponsive cases of cellulitis or abscess should be treated with intravenous antibiotics. in children with suspected abscess formation, a variety of surgical drainage procedures can be performed. needle aspiration or incision and drainage have been shown to be equally effective. 15 in persistent cases or in those children who will require general anesthesia for drainage, consideration should be given to performing a tonsillectomy (quinsy tonsillectomy). signs and symptoms of deep neck space (retropharyngeal/ parapharyngeal) infections that involve the pharynx typically present as fever, drooling, irritability, decreased oral intake, torticollis, and/or trismus. often there is a history of a preceding viral illness. stridor or symptoms of upper airway obstruction may be seen in half of patients. 32 a neck mass or enlarged cervical nodes may be present depending on the location of the infection. usual pathogens include coagulase-positive staphylococci and gabhs. anaerobic bacteria have been found in as many as 50% of cases. 32 complications of deep neck space infections include airway obstruction, bacteremia, rupture of the abscess into the pharynx with aspiration, mediastinal extension of infection, jugular thrombosis, and carotid artery rupture. in suspected cases, the diagnosis of a retropharyngeal/parapharyngeal space infection is confirmed with either contrast medium-enhanced ct or mri. widening of the retropharynx on a lateral neck radiograph suggests a retropharyngeal infection. while ultrasound can detect the presence of an abscess cavity, ct or mri are most helpful in demonstrating the extent of infection and the location of surrounding structures of importance, specifically the great vessels. contrast medium-enhanced ct is particularly useful in distinguishing a phlegmon (cellulitis) from cases of frank suppuration. demonstration of a hypodense region with surrounding rim enhancement has been shown to correlate with an abscess in 92% of cases (fig. 52-6) . the initial management of a deep neck infection should begin with intravenous antibiotics, including oxacillin, clindamycin, cefazolin, î²-lactamase penicillins, or a combination thereof. surgical drainage should be reserved for those children who fail to show clinical improvement or progress to frank abscess formation on ct. the usual approach to surgical drainage is intraoral if the abscess points medial to the great vessels or extraoral if the infection points lateral to the great vessels. complications of deep neck infections should be treated aggressively. mediastinal spread requires prompt surgical drainage in most cases. an infected jugular thrombosis (lemierre's syndrome) can be a source of metastatic spread of infection as septic emboli. signs and symptoms include spiking chills and fever (picket-fence fevers) and a neck mass in spite of appropriate antibiotic therapy. ligature or excision of the infected thrombus may be required to eradicate the infection. in the past decade, the impact of sleep-disordered breathing (sdb) on the health of children has been well described, beginning with the report of normative sleep data by marcus and colleagues. 20 children appear to have briefer but more frequent episodes of partial (hypopnea) and complete (apnea) obstruction. because an apnea of less than 10 seconds may represent several missed breaths in a child, an apnea of any duration is abnormal. in most cases the site of obstruction during sleep is in the pharynx. in contrast to adults with this disorder in whom the pharyngeal impingement is due to adipose tissue surrounding the pharyngeal musculature, the major cause of airway obstruction in children results from adenotonsillar hypertrophy. the apnea index represents the number of apneas in an hour, with a normal value being less than 1 in children. because most children have an increased frequency of partial obstructions compared with adults, a measure of hypopneas may be more significant. a hypopnea is variably described as a reduction in airflow or respiratory otolaryngologic disorders effort or oxygen desaturation or combination thereof. respiratory disturbance index is a measure of both apneas and hypopneas in an hour and may be a better reflection of sdb in children. a respiratory disturbance index greater than 5 is abnormal. upper airway resistance syndrome represents obstructed breathing with normal respiratory indices but with sleep fragmentation and electroencephalographic arousals that indicate disordered sleep. the major group at risk for sdb includes children with adenotonsillar hypertrophy secondary to lymphoid hyperplasia (figs. 52-7 and 52-8). whereas the age of affected children ranges from 2 years through adolescence, the prevalence mirrors the age of greatest lymphoid hyperplasia, 2 to 6 years, the age the tonsils and adenoids are largest in size. other at-risk groups include syndromic children with down syndrome, children with craniofacial disorders, and patients with cleft palate or storage diseases (hunter's, hurler's syndromes). adverse effects of obstructive sleep apnea on children include poor school performance, failure to thrive, facial and dental maldevelopment, and, rarely, severe cardiac impairment, including systemic hypertension, cardiac arrhythmias, and cor pulmonale. daytime symptoms include noisy mouth-breathing, nasal obstruction and congestion, hyponasal speech, and dyspnea on exertion. in contrast to adults, hypersomnolence is uncommon in children because of the lower incidence of gas exchange abnormalities, specifically hypercarbia. children may complain of headaches, seem irritable, and perform poorly in school. nighttime symptoms are more obvious and include snoring, gasping and choking respirations, apnea, coughing, and a variety of other behaviors including sleepwalking, sleeptalking, rocking, head banging, and bruxism. enuresis may appear in children with airway obstruction and then resolve after surgical treatment. in addition to enlarged tonsils, signs include the presence of a posterior pharyngeal flap in cleft palate patients, a craniofacial disorder, adenoid facies, and, rarely, evidence of right-sided heart failure. the diagnosis of sdb is suggested by history and physical examination. confirmation of obstruction and apnea may be made with overnight pulse oximetry and video or audio monitoring of sleep. the "gold standard" in the diagnosis of obstructive sleep apnea remains formal polysomnography, including measures of nasal and oral airflow, chest wall movements, electrocardiography, extraocular muscle movements, and gastric ph monitoring in selected cases. depending on the suspected site of obstruction, adjuvant studies such as a lateral neck radiograph, mri of the head and neck, and flexible upper airway endoscopy might be helpful. the nonsurgical management of sdb consists of weight loss in obese patients and treatment of underlying allergies and gastroesophageal reflux. nasal and dental appliances to maintain airway patency that may be useful in adults are usually poorly tolerated in children. nasal continuous positive airway pressure, the mainstay of treatment in adults, is tolerated in many children and should be considered as a treatment option, especially in patients in whom other therapies have been exhausted or proven ineffective. the initial surgical treatment for most children with sdb remains a tonsillectomy and adenoidectomy, a therapy that is usually curative. in patients with documented sleep apnea or a sleep disorder, both procedures should be utilized even if the tonsils appear small. tonsillectomy and adenoidectomy techniques that have been standard for decades have been supplanted in some institutions by new technology including use of coblation, harmonic scalpel, and the microdebrider. efficacy of these newer techniques over established methods remains unproven. complications after tonsillectomy and adenoidectomy usually consist of respiratory compromise and acute or delayed bleeding. since the advent of modern pediatric anesthesia, respiratory complications such as aspiration with resultant pneumonia and lung abscess are rare. humidification, corticosteroids, and antibiotics have all been shown to improve the postoperative course after tonsil and adenoid surgery. young children are most vulnerable to complications, and in most institutions children younger than 4 years of age are observed overnight for signs of dehydration and respiratory compromise. adjuvant surgery in the management of sdb includes craniofacial repair or posterior flap revision surgery in appropriate patients. midface, mandibular, and hyoid advancement have proved useful in selected patients, along with nasal surgery such as septoplasty, partial inferior turbinectomy, or nasal polypectomy. tracheostomy remains the treatment of last resort in patients who fail to respond to other forms of therapy. ankyloglossia or tongue-tie is a common congenital disorder involving the lingual frenulum ( fig. 52-9 ). neonates with diminished tongue mobility due to a foreshortened frenulum may have problems in sucking and feeding. because the frenulum is thin and relatively avascular in neonates and young infants, it can often be incised as an office procedure. in older children the greatest effect of ankyloglossia is on speech. because the tip of the tongue curls under on extrusion and has limited lateral and superior movement, speech articulation may be affected. surgical treatment in these patients may require a short general anesthetic as the frenulum is thicker and more vascular, requiring surgical correction that includes either simple division with or without a z-plasty repair. macroglossia is uncommon. generalized macroglossia, as seen in association with omphalocele, visceromegaly, and adrenal and renal disorders (beckwith-wiedemann syndrome), with glycogen storage diseases (hunter's and hurler's syndromes) or hypothyroidism, is rare. relative macroglossia can be seen normally on occasion but is most common in down syndrome. the most serious complication of this condition is airway obstruction. in infants, macroglossia should be distinguished from focal enlargement of the tongue seen in patients with a lymphatic malformation or hemangioma. glossoptosis, posterior displacement of a normal-sized tongue, is seen in association with cleft palate and micrognathia in infants afflicted with the pierre robin sequence. infants with airway obstruction secondary to an enlarged or displaced tongue may require a tracheostomy. macroglossia in older children that affects cosmesis, interferes with speech, or causes drooling may be treated with a variety of tongue reduction techniques. epulis is a congenital granular cell tumor that typically presents as a soft, pink submucosal mass on the anterior alveolar ridge of the maxilla (fig. 52-10) . females are otolaryngologic disorders more commonly affected, and symptoms are usually confined to feeding problems. surgical excision is curative. ranula is a pseudocyst located in the floor of the mouth that may occur congenitally or result from intraoral trauma (fig. 52-11) . large ranulas may extend through the mylohyoid musculature and present in the neck as a "plunging ranula." treatment of ranulas is by excision or marsupialization of the pseudocyst, often in conjunction with excision of the sublingual gland. mucoceles are also pseudocysts of minor salivary gland origin and frequently rupture spontaneously. recurrent or symptomatic mucoceles respond to surgical excision. hemangioma is a proliferative endothelial lesion found commonly in the head and neck. their growth characteristics include enlargement during the first year of life, followed by spontaneous resolution. surgical excision or treatment with corticosteroids may be necessary in lesions that cause ulceration and bleeding, airway obstruction, cardiovascular compromise, or platelettrapping coagulopathy (kasabach-merritt syndrome). vascular malformations, including venous, arterial, or arteriovenous malformations, rarely occur in the oral cavity and pharynx and necessitate intervention only if they cause pain, bleeding, ulceration, or heart failure. management of complicated cases is by surgical excision or sclerotherapy for low-flow lesions (venous) and angiographic embolization for high-flow lesions. lymphatic malformation, formerly known as lymphangioma or cystic hygroma, is congenital and usually presents before 2 years of age. histologically, lymphatic malformations consist of multiple dilated lymphatic channels or may contain either capillary or venous elements (venolymphatic malformations). lymphatic malformations can occur anywhere in the neck and may cause extensive cosmetic deformity and functional problems in cases with involvement of the tongue, floor of mouth, mandible, or larynx. surgical resection of lymphatic malformations may be fraught with difficulty because they lack a capsule and are infiltrative. during surgical excision, care should be taken to avoid damaging nearby vital structures, and debulking is an acceptable option to total radical excision in many cases. postoperative suction drains can be helpful in preventing the recurrence of lymphatic drainage under skin flaps. carbon dioxide laser therapy has been employed in superficial lymphatic malformations of the tongue, and sclerotherapy of large cystic lesions may be an option. foregut cysts are true cysts, lined with respiratory epithelium, that present in the floor of mouth and should be distinguished from dermoid cysts, lined with stratified squamous epithelium and skin appendages, which may also be found in this location. a thyroglossal duct cyst may rarely present in the base of the tongue. likewise, aberrant thyroid tissue, lingual thyroid, presents as a purple mass in the tongue base. thyroid tissue in this location is usually hypofunctioning, and affected children require thyroid supplementation. other aberrant rests of tissue, choristomas, consist of gastric, enteric, or neural tissue of normal histology in an abnormal location. second branchial cleft derivatives will rarely present as a cystic mass near the superior pole of the tonsil. their extent and associated tracts can be demonstrated on mri. tornwaldt's cyst is a blind pouch in the nasopharynx that represents a persistence of an embryonic connection between the primitive notochord and the pharynx. other benign nasopharyngeal masses include nasopharyngeal teratomas, dermoid lesions (hairy polyp), and nasopharyngeal encephaloceles. most of these lesions are best evaluated by ct and/or mri to determine their extent and the presence of an intracranial connection. surgical excision is curative in most cases. squamous papillomas are benign slow-growing lesions typically found on the soft palate, uvula, and tonsillar pillars and are the result of infection with serotypes 6, 14, or 22 of the human papillomavirus (hpv). because of concern that these lesions could spread to the larynx or trachea, complete surgical excision is usually recommended. pleomorphic adenoma (mixed tumor) is a benign neoplasm of minor salivary glands with a predilection for the palate, although it may also be found in the lip and buccal mucosa. treatment is with surgical excision. rhabdomyosarcoma, the most frequent soft tissue malignancy of childhood, typically occurs in the 2-to 6-year age group and is derived from embryonic skeletal muscle. 4, 18 in the oral cavity and oropharynx it presents as a rapidly growing mass in the tongue, palate, and uvula or cheek. these tumors metastasize early to local nodes, lung, and bone. surgical therapy is limited to biopsy, excision of small lesions, or surgical salvage of treatment failures. the usual therapy includes a combination of chemotherapy and radiation therapy. lymphoma of the oral cavity and oropharynx typically involves the lymphoid tissue of waldeyer's ring and presents as a mass of the tonsil or in the nasopharynx. 8 the diagnosis may be suspected by evidence of involved adenopathy in the neck but is confirmed by surgical biopsy. treatment is with a combination of chemotherapy and radiation therapy. other rare malignant neoplasms of the oral cavity and pharynx include malignant salivary gland tumors (mucoepidermoid carcinoma) and epidermoid or squamous cell carcinoma. this latter tumor has been reported in organ transplant patients and adolescents who use snuff or chewing tobacco. 19 treatment is usually surgical depending on the site and extent of involvement. with the exception of the hyoid bone, the major structural framework of the larynx consists of cartilage and soft tissue. the hyoid bone lies superior to the larynx and is attached to it by the thyrohyoid membrane and strap muscles. the hyoid bone is derived from the second and third branchial arches. the cartilaginous structures of the larynx are composed of hyaline cartilage, with the exception of the epiglottis, which is composed of elastic cartilage. the cartilaginous structures of the larynx develop from the fourth, fifth, and sixth branchial arches. there are nine laryngeal cartilages, three that are single (thyroid, cricoid, and epiglottis) and six that are paired (arytenoid, cuneiform, and corniculate). the thyroid cartilage consists of two quadrilateral cartilages that form the anterior framework of the larynx. the cricoid cartilage is the only complete cartilaginous structure in the airway and provides posterior stability and a base of support for the cricoarytenoid and cricothyroid joints. the cricothyroid muscles are paired extrinsic laryngeal muscles that serve to tilt the larynx down and forward, tensing the vocal folds. paired intrinsic muscles-the thyroarytenoid, thyroepiglottic, and aryepiglottic muscles-act as a sphincter to close the larynx. the vocalis muscle comprises the internal fibers of the thyroarytenoid muscle and attaches to the vocal ligament. action of this muscle serves to regulate the pitch of the vocal ligament. the other set of paired muscles includes the posterior cricoarytenoid, lateral cricoarytenoid, and interarytenoid muscles. the posterior cricoarytenoid muscles serve to abduct the vocal folds, whereas the cricoarytenoid and interarytenoid muscles adduct the vocal folds. the quadrangular membrane is a connective tissue covering of the superior larynx that ends in a free margin along the vestibular ligament of the false cord. the conus elasticus is a membrane of elastic tissue that extends superiorly from the cricoid cartilage to form the paired vocal ligaments, the supporting structures of the vocal folds. the blood supply of the larynx arises from the superior and inferior laryngeal arteries. the former is a branch of the superior thyroid artery, whereas the latter is a branch from the thyrocervical trunk. the intrinsic muscles of the larynx are innervated by the recurrent laryngeal nerve, which also supplies sensory branches to the inferior larynx. the superior laryngeal nerve has two branches: the external branch innervates the cricothyroid muscle, while the internal branch supplies sensation to the superior larynx. the larynx has multiple functions within the upper airway. during respiration, it regulates airflow by opening during inspiration. the posterior cricoarytenoid muscle contracts with each inspiration to abduct the cords just before activation of the diaphragm. the protective function of the larynx produces two reflexes: cough and closure. cough is important to expel mucus and foreign objects. the closure reflex serves to prevent aspiration of foreign matter. in addition to closure, the larynx elevates during swallowing. both closure and elevation occur simultaneously along with relaxation of the cricopharyngeus muscle during the swallow of a bolus. finally, the larynx plays an important role in speech production by generating sound. vibration of the mucosa covering the vocalis structures produces sound whose pitch and register is altered by changes in tension, length, and mass of the underlying vocalis muscle and ligament. the larynx of an infant sits much higher than that of an adult. the cricoid is located at the level of c4, whereas the tip of the epiglottis is at c1. the close approximation of the epiglottis to the soft palate makes the infant an obligate nose breather. by 2 years of age, the larynx has descended to the level of c5 and reaches the adult level of c6 to c7 by puberty. the glottis of the newborn is 7 mm in the anteroposterior dimension and 4 mm in the lateral dimension. the narrowest area of the infant airway, the subglottis, is approximately 4 mm in diameter. symptoms of acute airway obstruction include dyspnea, cough, vocal changes, dysphagia, and sore throat. dyspnea and rapid or labored breathing are indications of inadequate ventilation and may be triggered by changes in pco 2 and po 2 . a stimulus anywhere in the airway may produce cough. it is difficult to localize the site of the stimulus from the quality of the cough. changes in the child's vocal character such as hoarseness or a muffled or weak cry may help in localizing the area of obstruction. dysphagia for solids and/or liquids is often associated with airway obstruction. depending on the cause of airway obstruction, affected patients may complain of sore throat. the child's overall appearance is the first sign to be assessed in airway obstruction, because airway status often dictates how quickly further evaluation and intervention need to be performed. the level of consciousness should be determined because the unconscious or obtunded patient may need immediate airway management. along with cyanosis in a patient without cyanotic heart disease, the presence of anxiety, restlessness, and diaphoresis are all ominous signs of impending airway compromise. other symptoms of airway obstruction include tachypnea and substernal retractions. the child with airway obstruction is often tachycardic. the presence of bradycardia is a otolaryngologic disorders late indicator of severe hypoxia. the presence of a muffled cry often suggests obstruction at the level of the pharynx, whereas a barking cough is associated with laryngeal inflammation and edema. stertor is a snorting sound whose origin is often in the pharynx. stridor is noise produced by turbulent airflow in the laryngeal or tracheal airway. inspiratory stridor suggests turbulence at or above the glottis. expiratory stridor results from turbulent airflow in the distal trachea or bronchi. biphasic stridor suggests a tracheal source. the degree and loudness of the sound is not always indicative of the severity of obstruction, because stridor can become softer just before complete obstruction. other important signs of airway obstruction include drooling and use of accessory respiratory muscles. in addition to determination of the child's physical status, assessment of the degree of airway obstruction should include an evaluation of the ventilatory status. pulse oximetry provides an immediate record of arterial oxygenation while transcutaneous monitoring of co 2 is a good indicator of ventilation. the lateral neck radiograph remains the best study for the initial evaluation of a child with airway obstruction because it demonstrates the anatomy from the tip of the nose to the thoracic inlet. the anteroposterior view of the neck is also helpful, specifically in defining areas of narrowing, such as a steeple sign associated with subglottic edema. a chest radiograph is also important in the initial assessment to identify foreign bodies or other conditions such as unilateral emphysema, atelectasis, or pneumonia that may account for the child's respiratory compromise. if time permits, a barium swallow or airway fluoroscopy may provide additional information. additional airway evaluation may include a brief flexible endoscopic examination. the nose is first sprayed with a combination of 2% lidocaine and oxymetazoline, and the child is gently restrained. the airway can be examined from the nares to the glottis. attempts to pass a flexible scope through the glottis in a child with airway obstruction should be avoided. likewise, flexible endoscopy should be avoided in a child with supraglottitis because of the possibility of precipitating complete obstruction. children with suspected airway pathology distal to the glottis or those in whom the possibility that flexible endoscopy could compromise the airway should undergo any airway examination in the operating room where rigid endoscopes and other airway equipment is immediately available to secure the airway if necessary. nonsurgical intervention in the child with acute airway obstruction may begin with just observation alone in a high surveillance unit. humidified oxygen administered by face mask will improve po 2 and clearance of secretions. racemic epinephrine administered by nebulizer acts to reduce mucosal edema and is useful in conditions such as laryngotracheobronchitis (infectious croup). because its length of action lasts 30 to 60 minutes, treated patients should be observed for signs of rebound for 4 to 6 hours after administration. corticosteroids have been shown to have value in the management of postintubation croup, adenotonsillar hypertrophy that results from ebv infection, allergic edema, and spasmodic croup. use of corticosteroids in infectious croup and in infants with a subglottic hemangioma remains controversial. 10, 16 other adjuvant therapies include antibiotics and inhalation of helium/oxygen mixture (heliox). although viral agents are often responsible for inflammation in the larynx and trachea, bacterial superinfection is also common. because of the prevalence of penicillin-resistant organisms, broad-spectrum antibiotics, including a higher-generation cephalosporin, penicillinase-resistant penicillin, or î²-lactamase penicillin, are useful in preventing or eradicating infection. heliox is a mixture of gas in which helium is used to replace nitrogen. the advantage of the helium-oxygen mixture is that its low density reduces air turbulence and gas resistance, allowing improved delivery of oxygen in patients with airway obstruction. nonsurgical airway management may include use of nasal or oral airways, endotracheal intubation, and, rarely, transtracheal ventilation. nasal airways of rubber or other synthetic material can be easily inserted into the nose of most children after adequate lubrication with a water-soluble lubricant. their best use is in cases where the pharynx is the site of obstruction. oral airways are not as readily tolerated by children and only serve as a brief solution to an airway problem. during the 1970s, endotracheal intubation with polyvinyl chloride tubes revolutionized the management of supraglottitis, and even today intubation remains the mainstay of initial airway therapy in most children with severe airway obstruction. the size of the endotracheal tube used correlates with the age of the child. the subglottis, the narrowest part of the infant airway, typically admits a 3.5-or 4.0-mm inner diameter tube. the tube used in children older than a year can be roughly estimated by using the following formula: tube size = (16 + age in years) ã· 4. once the airway has been established, the tube should be carefully secured and the child appropriately sedated and/or restrained if necessary to avoid accidental self-extubation. another method of airway management should be considered in children with an unstable cervical spine or in whom oral or neck trauma makes visualization difficult. transtracheal ventilation, insertion of a 16-gauge needle through the cricothyroid membrane for the delivery of oxygen, should be reserved for emergencies and used only until a more stable airway can be obtained. the surgical management of the child with acute airway obstruction should begin with endoscopy. the larynx can be visualized with one of a variety of pediatric laryngoscopes and the airway secured with a rigid pediatric ventilating bronchoscope of appropriate size. once the airway is secured, a more stable form of airway management can be utilized. rarely, in a child with acute airway obstruction, an airway cannot be established, and a cricothyrotomy may need to be performed. as in adults, this procedure avoids some of the risks of bleeding and pneumothorax inherent in a formal emergency tracheostomy. a small endotracheal or tracheostomy tube can be inserted through the incision in the cricothyroid membrane, but conversion should be made to a more stable airway as soon as possible. tracheostomy remains the preferred airway in cases of acute obstruction in which a translaryngeal approach is unsuccessful or must be avoided. the emergent tracheostomy should be avoided if at all possible to lessen complications of bleeding, pneumothorax, pneumomediastinum, subcutaneous emphysema, or damage to surrounding structures. the incidence of these complications can be reduced by careful attention to surgical technique, good lighting, and adequate assistance. laryngomalacia is the most common cause of newborn stridor and is caused by prolapse of the supraglottic structures (arytenoid cartilages, aryepiglottic folds) during inspiration ( fig. 52-12 ). symptoms typically appear at birth or soon thereafter and include inspiratory stridor, feeding difficulties, and, rarely, apnea or signs of severe airway obstruction. gastroesophageal reflux disease tends to worsen symptoms of laryngomalacia. the diagnosis is confirmed by flexible endoscopy of the larynx, and other airway pathology can be excluded with lateral neck, chest, and barium swallow radiography. in most cases, laryngomalacia is self-limited and resolves by 18 months of age. changes in positioning and feeding, treatment of reflux, and, in some neonates, use of monitoring may be necessary. in severe cases, surgical intervention with either a supraglottoplasy (surgical division of the aryepiglottic folds) or a tracheostomy may be necessary. tracheobronchomalacia is defined as collapse of the tracheobronchial airway. it may be congenital or acquired (from long-standing intubation and infection) and may be segmental or involve the entire tracheobronchial tree. depending on the extent and location, symptoms include low-pitched biphasic stridor and signs of respiratory compromise. the diagnosis is usually made with endoscopy, although fluoroscopy of the airway may often demonstrate it. treatment ranges from observation in most cases to airway management with a tracheostomy tube and positive-pressure ventilation in severe cases. vocal fold paralysis is the second most common congenital laryngeal anomaly (after laryngomalacia) and may be unilateral or bilateral. congenital vocal fold paralysis may be caused by neurologic abnormalities (hydrocephalus, arnold-chiari malformation), birth trauma, or rarely in association with neoplasms of the larynx or neck. neonates with bilateral involvement typically present with highpitched inspiratory or biphasic stridor but a good cry. respiratory compromise and feeding difficulties may accompany the stridor. in infants with unilateral involvement, the airway may be adequate although a few infants will show evidence of compromise, especially during feeding. the cry is often hoarse or breathy. acquired vocal fold paralysis may result from trauma or from neoplasms of the chest or neck or may be iatrogenic, typically after surgery of the neck or arch of the aorta. the diagnosis of unilateral or bilateral vocal fold paralysis is confirmed with endoscopy. additional studies in the evaluation of patients with vocal fold paralysis include lateral neck and chest radiography, barium swallow, and ct or mri of the head and neck. most cases of unilateral involvement can be observed, but infants with bilateral vocal fold paralysis often require a tracheostomy. in addition, infants with associated feeding difficulties may necessitate a gastrostomy. in older children (> 4 or 5 years of age) a more permanent solution such as a cordotomy or arytenoidectomy can be considered to improve the glottic airway. congenital subglottic stenosis is the third most common congenital laryngeal anomaly and is defined as a neonatal larynx that fails to admit a 3.5-mm endotracheal tube without a history of prior instrumentation or intubation ( fig. 52-13 ). the underlying abnormality is a cricoid cartilage that is either small or deformed. infants with congenital subglottic stenosis present with inspiratory or biphasic stridor, barking cough, and other symptoms of airway obstruction. the diagnosis is often suggested by narrowing of the subglottis on a lateral neck radiograph and confirmed by endoscopy. treatment depends on the severity of symptoms and ranges from observation to laryngeal reconstruction to tracheostomy. a child with a subglottic hemangioma presents with the onset of progressive stridor during the first few months of life (fig 52-14) . hemangiomas are proliferative endothelial lesions that can form in the submucosa of the posterior subglottis. occasionally, they may involve the subglottis in a circumferential pattern. associated cutaneous hemangiomas may be found in approximately 50% of patients. symptoms are dependent on the amount of airway compromise and include biphasic stridor, barking cough, difficulty feeding, and other symptoms and signs of airway obstruction. the diagnosis may be suggested on a lateral neck radiograph but is confirmed with endoscopy. nonsurgical management of infants with a subglottic hemangioma includes observation or treatment with systemic corticosteroids. surgical therapy includes laser excision, open excision through a laryngofissure, or a tracheostomy. a laryngocele is an air-filled dilatation of the saccule of the larynx that communicates with the laryngeal airway. it may present internally into the posterior superior false cord region or externally through the thyrohyoid membrane. a saccular cyst is fluid filled and protrudes between the true and false vocal folds. the diagnosis of this lesion is confirmed endoscopically, and ct of the larynx is helpful in assessing its extent and if it is fluid or air filled. treatment is with endoscopic marsupialization or excision through a laryngofissure. laryngotracheobronchitis (viral croup) is an inflammation of the subglottic airway caused by a variety of parainfluenza and influenza viral agents. the infection may involve the entire glottis and extend into the trachea and bronchi. affected children fall typically into the 1-to 3-year age group; males are more commonly affected than females. symptoms and signs of viral croup include biphasic stridor, barking cough, and hoarseness, often in association with a prodromal viral upper respiratory tract infection. the diagnosis of croup is made clinically, but endoscopic examination may help to exclude other pathologic processes. care should be taken not to instrument the subglottis, causing more swelling and inflammation and precipitating acute obstruction. lateral neck radiography demonstrates subglottic narrowing, whereas anteroposterior neck films show a "steeple sign," the result of subglottic edema. treatment of viral croup is typically supportive with humidification. use of corticosteroids remains controversial. treatment with nebulized racemic epinephrine in the emergency department or hospital setting often relieves symptoms; however, rebound of signs may occur several hours later and children should be monitored accordingly. severely affected children may require intubation for respiratory failure. a smaller than normal tube should be employed. in rare cases, a tracheostomy may be required if the inflammation fails to resolve. a child younger than 1 year of age with recurrent bouts of "croup" should be suspected of having either congenital subglottic stenosis or a hemangioma. spasmodic croup is the recurrence of croup-like symptoms in a child who is otherwise well. fever is rarely present, and the attacks frequently occur at night. gastroesophageal reflux disease has been suggested as a possible inciting process. treatment of spasmodic croup is usually observant, although corticosteroids or reflux medications may prove beneficial. supraglottitis (epiglottitis) is an infectious disease that involves the supraglottic larynx. in children the typical pathogen is type b haemophilus influenzae (hib). other pathogens have been implicated in adolescent and adult cases. the incidence of supraglottitis in children has diminished markedly since the introduction of the conjugated hib vaccine in the early 1990s. 17 affected children are somewhat older than those seen with croup-in the 3-to 6-year age group. symptoms and signs have a rapid onset, progress quickly to frank airway obstruction, and include stridor, dysphagia, fever, muffled voice, and signs of systemic toxicity. affected children frequently sit and assume the "sniffing" position in an attempt to maximize their airway. intraoral or endoscopic examination should be avoided in suspected patients because of concern for precipitating complete obstruction. lateral neck radiography demonstrates a classic "thumbprinting" of the epiglottis but should only be obtained if facilities are present in close proximity to secure the airway. prompt airway management is essential in children with supraglottitis. the child's airway should be secured in either the emergency department or operating room with team members who include a pediatrician, anesthesiologist, critical care physician, otolaryngologist, or pediatric surgeon or others familiar with the pediatric airway. after inducing the child with general anesthesia, the airway should be intubated. examination of the supraglottis may be made, and cultures of the larynx and blood are obtained. equipment to perform a tracheostomy should be readily available. the child should remain intubated for 24 to 72 hours and should be supported with intravenous fluids and antibiotics that treat antibioticresistant haemophilus (third-generation cephalosporins, chloramphenicol). bacterial tracheitis (membranous croup) often occurs as a complication of another infection, such as measles, varicella, or other viral agents. the most common organisms include s. aureus, gabhs, m. catarrhalis, or h. influenzae. it can occur in any age child and present with stridor, barking cough, and low-grade fever. symptoms and signs then progress to include high fever and increasing obstruction and toxicity. the diagnosis may be suspected by diffuse narrowing of the tracheal air shadow on chest radiograph but is confirmed by endoscopic examination in the operating room. purulent debris and crusts can be removed at this time. cultures of secretions and crusts may be helpful in guiding intravenous antibiotic therapy that should be aimed initially at the usual pathogens. the airway should be secured with an endotracheal tube or, rarely, a tracheostomy. repeat endoscopic examination of the airway may be warranted to continue dã©bridement and to determine the feasibility of extubation. the chronic management of subglottic stenosis and other prolonged airway disorders is discussed in chapter 63. recurrent respiratory papillomatosis is the most common benign neoplasm of the larynx in children. squamous papillomas involve the larynx and occasionally the trachea and lower respiratory tract as exophytic lesions. because of its recurrent nature, recurrent respiratory papillomatosis causes morbidity and, rarely, mortality due to malignant degeneration. patients may be almost any age, but the disease is more aggressive in children. human papillomavirus subtypes 6, 11, 16, and 18 have all been identified within papilloma tissue. the first two subtypes have been associated with genital warts, whereas the latter two have been associated with cervical and laryngeal cancers. the exact mechanism of human papillomavirus infection in the larynx remains unknown. transmission of virus to the child from a mother with genital warts is suspected in many cases, but there is no concrete evidence to support this route of infection. children afflicted with recurrent respiratory papillomatosis present initially with hoarseness but may also have symptoms and signs of airway obstruction, including stridor. lateral neck radiography may suggest laryngeal involvement, but the diagnosis is confirmed by direct laryngoscopy and biopsy (fig. 52-15 ). in addition to the trachea and bronchi, squamous papillomas may also be found in the oral cavity. surgical excision is the mainstay of therapy in patients with recurrent respiratory papillomatosis. in the past, papillomas were excised using the carbon dioxide laser. more recently, the laryngeal microdebrider has become the preferred method of excision in many centers. in aggressive cases with swift recurrence and accompanying airway obstruction, tracheostomy may be necessary for airway management, although tracheostomy has been implicated in the spread of disease to the trachea and lower respiratory tract. medical adjuvant therapy that has been employed with mixed results includes interferon, photodynamic therapy with dihematoporphyrin ether, indole-3-carbinol, or antiviral agents such as cidofovir. other benign laryngeal neoplasms are rare and include connective tissue tumors such as chondromas or fibromas, neurogenic tumors such as neurofibromas, or granular cell tumors and other cell types such as hamartomas or fibrous histiocytomas. malignant tumors of the larynx are also rare and include squamous cell carcinoma and a variety of epithelial and connective tissue malignancies such as spindle cell carcinoma, rhabdomyosarcoma, mucoepidermoid carcinoma, and chondrosarcoma. metastatic tumors and lymphoma may also rarely involve the larynx in children. diagnosis is suspected by the sudden appearance of stridor, hoarseness, and airway obstruction and confirmed by biopsy. treatment is dependent on cell type and may include surgical excision, radiation therapy, and/or chemotherapy. the surgical anatomy and embryology of the neck is discussed in chapter 56. the initial examination of a disease or disorder of the neck begins with a thorough history. a detailed history can often serve to focus the differential diagnosis of a neck disorder. the age of the child is an important otolaryngologic disorders first consideration. the appearance of a neck mass in an infant often suggests a congenital disorder, whereas the sudden appearance of a mass in an adolescent might suggest a malignant process. inflammatory diseases of the neck may occur in any age group but typically mirror the incidence of upper respiratory tract infections in children. growth and temporal relationships are often important clues to a diagnosis. neck masses that grow rapidly suggest either an inflammatory or malignant process, whereas slow-growing masses are typically benign. a history of systemic infection elsewhere in the body or recent travel or exposure to farm animals often points to an infectious origin. a history of trauma to the neck may explain the sudden appearance of a neck mass. likewise, changes in the size of a neck mass with eating may suggest a salivary gland origin. vascular lesions enlarge with straining or crying. finally, systemic symptoms of fever, weight loss, night sweats, or fatigue in association with the sudden development of a neck mass may indicate a malignant process. the physical examination of a child with a neck mass should begin with a comprehensive examination of the entire head and neck. because the vascular, neural, and lymphatic patterns of the head drain into the neck, the source of neck disorders may be found in the head. depending on the differential diagnosis, a physical examination of the entire body, including an assessment of lymph nodes in the groin and axillae and the presence of an enlarged spleen or liver, is essential. palpable lymph nodes in the neck of children are a common finding, but lymph nodes larger than 2 cm fall outside the range of normal hyperplastic nodes and should be either monitored or investigated. the sudden appearance of large nodes in either the posterior cervical or supraclavicular regions may suggest a malignancy. 31 the consistency of a neck mass is also important in narrowing the differential diagnosis. hard masses tend to be associated with either infection or malignancy. fixation of a neck mass to skin or nearby structures is also suggestive of a malignancy. cysts or abscesses tend to have a characteristic feel on palpation. depending on the differential diagnosis after a history and physical examination, radiologic studies may be useful. a lateral neck radiograph may demonstrate an abnormality of the nasopharynx, retropharynx, or cervical spine. likewise, a chest radiograph may identify a malignancy, sarcoidosis, or tuberculosis. infection or a neoplastic process in the sinuses may appear on a sinus series. ct and mri are useful in the evaluation of a neck mass. demonstration of hypodensity on ct suggests an inflammatory or necrotic process. ring enhancement of a hypodense region on a contrast ct scan is indicative of an abscess. mri is excellent for distinguishing fine detail within soft tissue and in the evaluation of vascular lesions of the neck. finally, ultrasound is helpful in distinguishing solid and cystic masses. use of ultrasound preoperatively in patients with a thyroglossal duct cyst is also a simple and economic way to assess the presence of normal thyroid tissue when it is not easily felt. ultrasound and thyroid scanning should be employed in the assessment of any thyroid mass. selected laboratory studies may be helpful in the evaluation of a child with a neck disorder. a complete blood cell count with differential may identify patients with either a malignancy or systemic infection. serologic testing for ebv or cytomegalovirus infection, toxoplasmosis, or cat-scratch disease may be diagnostic. thyroid function testing is essential in any child with a suspected thyroid disorder. finally, collection of urine for catecholamine metabolites (vanillylmandelic acid) may assist in the diagnosis of neuroblastoma. if the diagnosis remains in doubt at this point, incisional or excisional biopsy may be indicated. biopsy provides material for pathologic examination, culture, and other more sophisticated testing if necessary. fine-needle aspiration of a neck mass in children for suspected malignancy is not as reliable as in adults. congenital sinuses and cysts are discussed in chapter 56. viral adenitis is the most common infectious disorder to involve the neck in children. enlarged or hyperplastic lymph nodes are frequently the result of viral upper respiratory tract illnesses. common pathogens include rhinovirus, adenovirus, and enterovirus, but measles, mumps, rubella, varicella, ebv, and cytomegalovirus may also cause lymphadenopathy. the diagnosis is often suspected by other findings in the history or physical examination and can be confirmed by serologic testing. acute human immunodeficiency virus infection may present, as do other viral syndromes, with fever, headache, malaise, gastrointestinal symptoms, and a neck mass. the usual source of bacterial cervical adenitis is the pharynx. causative organisms are often streptococcal or staphylococcal species. patients present with systemic symptoms of fever and malaise in addition to a neck mass that is diffusely swollen, erythematous, and tender. in contrast to viral adenitis, which is frequently bilateral, bacterial infections of the neck are usually unilateral. ct with contrast medium enhancement may be helpful in the evaluation of large infectious neck masses that may contain an abscess cavity. needle aspiration of suspected infectious masses may provide material for culture and decompress the mass. broad-spectrum antibiotic therapy, administered either orally or intravenously, may be curative, although surgical drainage is usually necessary in extensive cases. cat-scratch disease is caused by bartonella henselae infection. the clinical picture includes the sudden appearance of unilateral lymphadenopathy after a scratch from a cat. fever and malaise may be accompanying symptoms in many cases. serologic testing for antibodies to bartonella is diagnostic. cat-scratch disease is usually self-limited, although some benefit has been described with the use of erythromycins and other antibiotics. 21 in the past most mycobacterial infections have been caused by atypical organisms such as mycobacterium avium-intracellulare, m. scrofulaceum, m. bovis, or m. kansasii. in the past decade or so, mycobacterial tuberculosis has made a resurgence as the pathogen responsible for a neck infection. atypical mycobacterial infections present as nontender nodes in the preauricular, intraparotid, or posterior triangle regions. the skin overlying the node typically assumes a violet color, and systemic symptoms are rare. a chest radiograph should be obtained if m. tuberculosis is suspected. the diagnosis is made by obtaining material for acid-fast stain and culture with needle aspiration, surgical drainage, or excision of involved nodes. surgical curettage or total excision is curative for atypical lesions. tuberculosis should be treated with appropriate antituberculin chemotherapy. rarely, the neck may be involved with infections such as tularemia, brucellosis, actinomycosis, plague, histoplasmosis, or toxoplasmosis. inflammatory disorders that may affect the neck include kawasaki syndrome, sarcoidosis, sinus histiocytosis (rosai-dorfman disease), kikuchi-fujimoto disease, and pfapa syndrome (periodic recurrent fever). thyroid malignancies are not uncommon in the adolescent age group, with 10% of thyroid carcinomas occurring in patients younger than 21 years of age. 3 welldifferentiated tumors, usually papillary carcinoma, make up the majority of tumors. follicular, mixed, and medullary tumors occur less commonly. most patients present with a painless midline neck mass. on presentation, cervical adenopathy can be palpated in a majority of patients, a finding that reflects the high incidence of papillary disease that metastasizes via the lymphatics. 9 other important symptoms and signs include a rapid rate of growth, pain, hoarseness, and dysphagia. children who have received prior radiation are at greater risk of thyroid malignancy. the occurrence of thyroid malignancy may be associated with iodine deficiency, hashimoto's thyroiditis, and graves' disease. 9, 22 preoperative assessment should include thyroid nucleotide scanning to distinguish between cold (hypofunctioning) and hot (hyperfunctioning) nodules. up to a third of cold nodules can be malignant, whereas hot nodules are rarely malignant. 12 ultrasonography can distinguish between solid and cystic lesions, and fine-needle aspiration is an alternative to surgical biopsy for diagnosis. surgical management includes near-total or total thyroidectomy, neck dissection if indicated, and postoperative 131 i ablation. lymphoma is a common pediatric malignancy and can present in the neck as painless lymphadenopathy. hodgkin's disease occurs most often in late adolescence and has four histologic subtypes: lymphocyte predominance, nodular sclerosing, mixed cellularity, and lymphocyte depletion. lymphocyte predominance and nodular sclerosing types make up most cases. staging of hodgkin's disease depends on the amount and location of nodal involvement and the presence or absence of systemic or b symptoms (fever, night sweats, weight loss). treatment is with multiple-agent chemotherapy and localized radiation therapy. non-hodgkin's lymphoma can be divided into low-, intermediate-, or high-grade subtypes. high-grade tumors may be further divided into large cell, lymphoblastic, and small cell types. staging of non-hodgkin's lymphoma is by location and extent. treatment is with multiple-agent chemotherapy. langerhans' cell histiocytosis (previously histiocytosis x) includes the disease entities known as eosinophilic granuloma, hand-schã¼ller-christian syndrome, and letterer-siwe disease. the exact nature of this entity remains an enigma: it may represent a neoplasm or a hyperimmune response. 7 symptoms and signs include lymphadenopathy, rashes, otorrhea, oral lesions, and hepatosplenomegaly. diagnosis is dependent on the identification of langerhan's cells on pathologic specimens. treatment ranges from curettage or excision to intralesional or systemic corticosteroids to chemotherapy and radiation therapy. two major categories of neural tumors may be found in the neck. neurofibromatosis is a benign disorder that in some forms (plexiform) may infiltrate surrounding tissues. for this reason, ct and/or mri are vital in the preoperative evaluation of these lesions. surgical resection is the mainstay of treatment. neuroblastoma is a malignancy that develops from neural crest cells and may present as a solitary tumor or as lymphadenopathy. clinical staging determines the mode of therapy that includes surgery, chemotherapy, and radiation therapy. rhabdomyosarcoma rarely presents as a primary tumor in the neck, more often being found as a primary tumor in the orbit, temporal bone, or nasopharynx. the diagnosis is made by biopsy, and patients are staged according to involvement. treatment includes surgery, chemotherapy, and radiation therapy. malignancies of almost any type and location in the body can metastasize to the neck. the most common are thyroid malignancies. in adolescents, carcinomas, especially those arising in the nasopharynx, may spread to the neck lymphatics. anatomy and embryology of the paranasal sinuses otitis media and eustachian tube dysfunction cancer of the thyroid in youth pediatric malignancies neoplasms of the ear and temporal bone congenital malformations of the temporal bone head and neck langerhans' cell histiocytosis otolaryngologic disorders lymphomas of the head and neck thyroid tumors in children corticosteroids in airway management allergic fungal sinusitis: pathophysiology, epidemiology and diagnosis solitary thyroid nodules in 71 children and adolescents glomus tympanicum in infancy grading system for the selection of patients with congenital aural atresia an evidence-based review of the treatment of peritonsillar abscess steroid treatment of laryngotracheitis: a meta-analysis of the evidence from randomized trials childhood epiglottitis in recent years is fetal cellular rhabdomyoma an entity or a differentiated rhabdomyosarcoma? a study of patients with rhabdomyoma of the tongue and sarcoma of the tongue enrolled in the intergroup rhabdomyosarcoma studies i, ii and iii squamous cell carcinoma of the tongue in a nine-year renal transplant survivor: a case report with a discussion of the risk of development of epithelial carcinoma in renal transplant survivors normal polysomnographic values for children and adolescents current knowledge of bartonella species thyroid carcinoma in children and adolescents pediatric audiology efficacy of tonsillectomy for recurrent throat infection in severely affected children: results of parallel randomized and nonrandomized clinical trials first-line treatment of otitis media structure and function of the temporal bone surgical pediatric otolaryngology influence of penicillin-producing staphylococci and the eradication of group a streptococci from the upper respiratory tract by penicillin treatments angiofibroma: changes in staging and treatment regional and intracranial complications of sinuses pediatric neck masses: guidelines for evaluation computed tomography in the evaluation of pediatric neck infections pediatric cochlear implantation key: cord-298551-ua90xoak authors: bennet, rutger; hamrin, johan; wirgart, benita zweygberg; östlund, maria rotzén; örtqvist, åke; eriksson, margareta title: influenza epidemiology among hospitalized children in stockholm, sweden 1998–2014 date: 2016-06-14 journal: vaccine doi: 10.1016/j.vaccine.2016.04.082 sha: doc_id: 298551 cord_uid: ua90xoak background: influenza remains a common reason for the hospitalization of children. there is a need for long term studies that are also population based. we describe the epidemiology of severe influenza in a defined population 1998–2014. method: retrospective study of annually collected data of virologically confirmed influenza in hospitalized children 0–17 years living in the catchment area (230,000 children). we gathered information about comorbidity and complications from case records, and compared influenza a, b and a(h1n1)pdm09 with respect to these factors. results: a total of 922 children with influenza were hospitalized. the mean rate remained unchanged at 22.5–24.2 per 100,000 children per year. there were two major outbreaks: influenza a(h3n2) in 2003–2004 and the a(h1n1) pandemic in 2009–2010. the proportion of children with influenza b increased from 8% during the first half of the study period to 28% during the second half. the highest admission rate was found in children <3 months of age, 169 per 100,000. children with influenza b were older than those with influenza a. comorbidity was found in 34%, complications in 41%, and 11% needed intensive care management. the mortality rate was 0.17/100,000 children. conclusion: influenza remains an important reason for the hospitalization of children, especially during the first years of life. the increasing proportion of influenza b may have to be considered when recommending influenza vaccines. influenza is common among children, especially before 5 years of age [1] . we here describe the influenza a, b and a(h1n1)pdm09 epidemiology in the 0-17-year-old population of northern stockholm during 17 seasons, 1998/99-2013/14, and its implications for the immunization of children. in stockholm, children with certain chronic diseases are eligible for free seasonal influenza immunization. this was introduced in 2004 and originally included children with chronic pulmonary or heart disease, but after the pandemic 2009 was expanded to include also chronic liver or renal diseases, immunosuppression, diabetes mellitus, extreme obesity (body mass index > 40), neuromuscular disease affecting breathing capacity, and children with multiple dysfunctions/handicaps. during the pandemic, adjuvanted monovalent h1n1 vaccine (pandemrix ® , glaxosmithkline biologicals, rixensart, belgium) was offered to all children from 6 months of age. however, except during the pandemic season, when 60% of all children accepted the offer, the vaccine uptake has been low (<5%), perhaps due to fear of side effects or unawareness of the severity of influenza [2] [3] [4] . in order to increase the knowledge base for vaccination recommendations, in addition to data that can be obtained from administrative databases, we here provide population-level influenza burden data based on observed, virologically confirmed hospitalizations. this is a retrospective study of annually gathered information about influenza in children (<18 years hospitalized at astrid lindgren children's hospital, stockholm, sweden during 1998-2014. the hospital is a tertiary referral center with surgery and a pediatric intensive care unit (picu) with resources for extracorporeal membrane oxygenation (ecmo), but only children resident in the catchment area were included in the study. we obtained population data from the stockholm area database at statistics sweden (www.scb.se). during the study period, the number of children in the primary catchment area increased by 17%, from 197,945 to 230,877. the number of person years for a specific age group during a certain year was considered equal to the number of children on december 31. we extracted information about risk factors, complications and intensive care management from the hospital charts. from 2009 we have also been able to extract information from the vaccine register in stockholm county [3] . risk factors were neuromuscular disease, chronic lung disease, immunosuppression, and chronic conditions such as kidney or liver disease, or inborn errors of metabolism. if a child had both neuromuscular and chronic lung disease, the factor judged most important for the clinical course was counted. recurrent wheezing/"asthma" in children younger than two years and uncomplicated preterm birth (>30 gestational weeks) were noted but not considered risk factors. we counted sinusitis, tracheitis and presumed bacterial pneumonia (with or without empyema), but not otitis media as focal complications. chest x-ray was always performed when pneumonia was suspected. if perihilar infiltrates and/or hyperinflation were present, a diagnosis of bronchitis or bronchiolitis was made. bacterial and viral pneumonia were differentiated mainly by c-reactive protein (crp) levels, with a cut-off value of 40 mg/l. neurologic complications were seizures; either primary or secondary (in children with underlying neurologic disease), and encephalitis confirmed by electroencephalography. other complications included a few rare conditions such as myocarditis. dehydration alone was not considered a complication. as a routine, children admitted from our pediatric emergency ward with respiratory symptoms or fever without localizing signs, including febrile convulsions, are examined for viral etiology. during the winter season samples are primarily investigated for respiratory syncytial virus (rsv) and influenza viruses. if they are found negative, viral investigation is extended to other respiratory viruses (adenovirus, bocavirus, coronavirus, enterovirus, human metapneumovirus, parainfluenza virus 1-3, and rhinovirus) [5] . all cases in this report were virologically confirmed by the laboratory. influenza virus was detected with immunofluorescence and viral isolation prior to october 2007, when these methods were replaced by real-time polymerase chain reaction (rt-pcr) [5, 6] . before the switch to rt-pcr the diagnostic sensitivity of the three methods was evaluated in 585 samples at our laboratory [5] . the rt-pcr analysis has since then been improved (in 2009 and 2011 by the inclusion of new probes for influenza a(h1n1)pdm09 and in 2014 by the redesign of the influenza b probe). rsv has since 2009 been diagnosed with a rapid point-of-care test, with negative specimens further investigated for both rsv and influenza with rt-pcr. the chi-square test, the mann-whitney u-test, and exact clopper-pearson binomial confidence intervals were employed as appropriate. for multivariate analysis, we used a generalized linear model with the logit function in statistica ® v. 10, with influenza subtype (non-pandemic a or b) as the dependent variable, and age and presence or absence of risk factors and complications as independent variables. there were 922 children (56% male) with confirmed influenza during the study period. 557 had non-pandemic influenza a, 179 had influenza b, and 186 had influenza a(h1n1)pdm09, out of whom 93 belonged to the 2009-2010 pandemic. during all winter seasons there were influenza epidemics with varying severity. all but two influenza epidemics occurred during rsv epidemics after january 1 and there were then always more children with rsv during a given week (fig. 1 ). the two largest outbreaks 2003-2004 and 2009-2010 peaked before january 1 and preceded the rsv epidemics. influenza b was present in all but two seasons and dominated during three seasons, all of which occurred during the second half of the study period. co-infections (with any simultaneously circulating respiratory virus) were identified in 11% of the patients. this is a minimum figure, since some children, for instance those with a positive point-of-care test for rsv, were not examined for additional viral etiology such as influenza. when the period comprising the first eight seasons was compared with the second period, excluding the pandemic and thus also comprising eight seasons, there were significantly more cases of influenza b during the latter period (p < 0.01). however, the overall rate of influenza cases in children <17 years remained unchanged at 22.5 (95% c.i. 20.1-24.9) and 24.2 (21.9-26.5) per 10 5 person years, respectively. the cumulative age distribution is shown in fig. 2 . children with influenza b were older (as also shown in table 1 ) than those with influenza a. influenza a(h1n1)pdm09 is presented separately for the pandemic year 2009-2010 and the post pandemic years, since the pandemic patients were significantly older (p < 0.001). the yearly incidence rates in different age groups varied considerably, with median (range) for children <5 years 59 (19previously known risk factors were found in 312/922 (34% , table 1 ), the most important being neuromuscular disease (131 cases) and chronic lung disease (40 cases). the frequencies of recurrent wheezing (not included among risk factors) and preterm birth were comparable to their occurrence in the general child population at 6% and 2.6% (24/922), respectively. complications were seen in 380/922 (41%). most were related to the respiratory tract where pneumonia dominated (117) out of which half (58) were considered bacterial in origin. other bacterial superinfections, such as sinusitis (including periorbital cellulitis) were diagnosed in 22 children. approximately 50% of the children had a blood culture taken, which was positive in 12 (6 streptococcus pneumoniae, 3 staphylococcus aureus, 2 streptococcus pyogenes and 1 neisseria meningitidis). neurological complication was the second most common with encephalitis (33) and primary or secondary seizures (104). risk factors and complications were more common among children with influenza b than in those with influenza a in the univariate analysis (p < 0.05), but when included with age in the multivariate model, only age remained significant (p < 0.001, table 2 ). children with recurrent wheezing had a low rate (1/59) of picu admission. their median duration of hospital stay was 2 days, which is equal to that of other children without risk factors. intensive care admission was required for 105/922 children (11%); 41/610 (6.7%) without risk factors and 57/171 (33%) with neuromuscular or chronic lung disease (p < 0.001). two children were treated with ecmo. six children (0.17/10 5 person years) died, 1 <1 year, 2 1-9 years, and 3 >10 years old. three of these were previously healthy, whereof two had an influenza b infection. the causes of death were encephalitis, myocarditis and bacterial pneumonia in the previously healthy children, and non-specific complications in the three children with co-morbidity. this is a report of children hospitalized for influenza a or b in a defined population in the northern stockholm area 1998-2014, covering the pre-pandemic period, including the 2003-2004 outbreak, the 2009 pandemic, and four post-pandemic seasons. there was a strong seasonal variation and the epidemiologic pattern was often in accordance with what has been seen in other countries, such as the large outbreak of a(h3n2) in 2003-2004 [7] . with the exception of the influenza a(h1n1)pdm09 pandemic with a peak in late autumn 2009, the epidemic peaks occurred during winter and coincided with rsv, with co-infections detected in 11%. as we have reported earlier, rsv and influenza co-infections do not have a more severe course or more late wheezing, but tend to follow the expected clinical course of the rsv infection [8] . most population based long-term studies are from the north american continent, but one study from finland covers a 16 year period up to 2004 [9] . there have been both single center and multicenter studies [10, 11] . some were population based whereas others represented tertiary centers without a defined population. many of these studies have covered the periods before the 2009 pandemic and have later been extended to also include the pandemic year [12, 13] . several studies described the pandemic and a few have included the first post pandemic season [14, 15] . no study has like ours covered both pre-and post-pandemic seasons, when the novel influenza a(h1n1)pdm09 continued to circulate. our findings are in accordance with these studies, all pointing to the fact that influenza in children is still a problem. neuromuscular disease and chronic lung disease were the dominating risk factors. in our setting recurrent wheezing/"asthma" and uncomplicated preterm birth were not important risk factors. bacterial superinfection, mostly pneumonia, was the most common complication. in most studies the distinction between bacterial and viral pneumonia has not been discussed. in our study 40% were considered to be viral [16] . neurologic complications, such as seizures and encephalitis, were the second most common category. intensive care was needed for 11% of all children, which is in agreement with most other studies [12, 13, 17] . the need for intensive care was highest (18%) in children with risk factors. the case fatality rate noted by us was similar to that reported from other western countries [18] . our age distribution and incidence rate calculations are similar to, although in the lower range, of what has previously been reported [19] . 30% of the children were below one year and 72% below five years of age, resulting in an incidence of 99/10 5 and 59/10 5 , respectively. the highest rate, 169/10 5 , was observed among the youngest (<3 months) infants, as in a recent study from the usa [17] . an important part of our study is the comparison of different influenza types. in several studies comparisons have been done between seasonal influenza and (h1n1)pdm09 [14, 15] . we studied influenza a(h1n1)pdm09 and the pandemic year separately from the following years, because of the marked difference of age distribution. during the pandemic, children were older in accordance with what has been presented from several other centers [12, 15, 20] . during the following seasons, however, the average age was actually somewhat lower than in children with other influenza a types. one contributing factor could be the high vaccine coverage (60%) with the adjuvanted vaccine (pandemrix) during the pandemic in sweden, which has been shown to give protection for at least two subsequent seasons [3] . in addition to the emergence of pandemic influenza, also the burden of influenza b has come into focus in recent years [21] . we found influenza b especially during the second half of the study period. previous epidemiologic studies used different methods for estimating the number of influenza cases, such as excess of cases with influenza-like illness during influenza seasons, virus isolation, and rapid methods like immunofluorescence and pcr [22] . at our laboratory immunofluorescence and viral isolation were replaced by the more sensitive pcr in october 2007. to what extent this has contributed to our observed increase of influenza b can be discussed. the initial pcr system had a higher sensitivity for influenza b compared to immunofluorescence and virus isolation, while the sensitivity for influenza a was lower. the influenza a pcr has since then been continually improved, and in a review by mahoney et al. it is stipulated that well optimized rt-pcr assays have 5-10% higher sensitivity than virus isolation [23] . one limitation of our study is its retrospective nature. however, the same pediatricians have been responsible for the care of the infected children during the entire period. the same level of care has been provided from the picu with availability of ecmo treatment during the entire period. furthermore, in our study "retrospective" means yearly reviews and documentation of the previous season as a preparation for planning of the following season. our study is a summary of these reviews. another important factor, as mentioned, is the introduction of new tests that could be more sensitive. on the other hand, the use of rapid tests precluded the detection of coinfections -found in more than 20% in an earlier study from our hospital [8] . the effect of influenza vaccine in children has been the subject of several reviews. in contrast to the known effect of trivalent influenza vaccine (the only one used during the studied period except for the pandemic year) in healthy children >18 months, less is known about its effect in younger children and in those with risk factors. during the 2009-2010 pandemic when 69% of the swedish childhood population was vaccinated with a monovalent adjuvanted vaccine an effect of 91% was demonstrated [2] . as also found in an english study, the protective effect was still present in children with comorbidity, albeit smaller than in children without risk factors [24] . even though the immunization of children with risk factors is free, few parents (<5%) take the opportunity to vaccinate their children. the reason for the low uptake of the vaccine is probably multifactorial. in a recent questionnaire study in the usa two factors were highlighted: fear of side effects and the belief that influenza is not a serious threat to children [4] . in conclusion, our population based study demonstrates that influenza in young individuals is still a major problem, especially but not exclusively in those with risk factors. we hope to be able to use this information to encourage more parents to immunize their children. there was a significant increase of influenza b during later years, primarily affecting older children with risk factors. the reason for this increase is probably multifactorial, but it points to the need for increased protection against influenza b, e.g. through the development of the quadrivalent vaccine. it may be important to note that in our study half of the children who died had no risk factors and that influenza b was the cause in 2/6 cases. none. global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis effectiveness of the monovalent as03-adjuvanted influenza a(h1n1)pdm09 vaccine against hospitalization in children because of influenza long term effectiveness of adjuvanted influenza a(h1n1)pdm09 vaccine in children pediatric provider vaccine hesitancy: an under-recognized obstacle to immunizing children development and implementation of a molecular diagnostic platform for daily rapid detection of 15 respiratory viruses respiratory virus infections in stockholm during seven seasons: a retrospective study of laboratory diagnosis multistate surveillance for laboratory-confirmed, influenza-associated hospitalizations in children wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza a in infancy incidence of influenza-related hospitalizations in different age groups of children in finland: a 16-year study incidence, complications, and risk factors for prolonged stay in children hospitalized with community-acquired influenza burden of seasonal influenza hospitalization in children comparison of children hospitalized with seasonal versus pandemic influenza a complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza the burden of seasonal and pandemic influenza in infants and children risk factors for mechanical ventilation in u.s. children hospitalized with seasonal influenza and 2009 pandemic influenza a influenza-associated pneumonia in children hospitalized with laboratoryconfirmed influenza the burden of influenza hospitalizations in infants from influenzaassociated pediatric deaths in the united states vaccination of healthy children against seasonal influenza: a european perspective children with asthma hospitalized with seasonal or pandemic influenza the burden of influenza b: a structured literature review influenza and the rates of hospitalization for respiratory disease among infants and young children molecular diagnosis of respiratory virus infections age-specific effectiveness of an oil-inwater adjuvanted pandemic (h1n1) 2009 vaccine against confirmed infection in high risk groups in england key: cord-282446-01lu7sce authors: stokholm, jakob; chawes, bo l; vissing, nadja h; bjarnadóttir, elín; pedersen, tine m; vinding, rebecca k; schoos, ann-marie m; wolsk, helene m; thorsteinsdóttir, sunna; hallas, henrik w; arianto, lambang; schjørring, susanne; krogfelt, karen a; fischer, thea k; pipper, christian b; bønnelykke, klaus; bisgaard, hans title: azithromycin for episodes with asthma-like symptoms in young children aged 1–3 years: a randomised, double-blind, placebo-controlled trial date: 2015-12-17 journal: lancet respir med doi: 10.1016/s2213-2600(15)00500-7 sha: doc_id: 282446 cord_uid: 01lu7sce background: bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting antibiotics as a potential treatment for such episodes. we aimed to assess the effect of azithromycin on the duration of respiratory episodes in young children with recurrent asthma-like symptoms, hypothesising that it reduces the duration of the symptomatic period. methods: in this randomised, double-blind, placebo-controlled trial, we recruited children aged 1–3 years, who were diagnosed with recurrent asthma-like symptoms from the copenhagen prospective studies on asthma in childhood 2010 cohort; a birth cohort consisting of the general danish population of zealand, including copenhagen. exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of ≥50 breaths per min; fever of ≥39°c; c-reactive protein concentration of ≥476·20 nmol/l [≥50 mg/l]). each episode of asthma-like symptoms lasting at least 3 days was randomly allocated to a 3-day course of azithromycin oral solution of 10 mg/kg per day or placebo after thorough examination by a study physician at the copenhagen prospective studies on asthma research unit. each episode was randomly allocated independently of previous treatment from a computer-generated list of random numbers in blocks of ten (generated at the pharmacy of glostrup). investigators and children were masked until the youngest child turned 3 years of age and throughout the data validation and analysis phases. the primary outcome was duration of the respiratory episode after treatment, verified by prospective daily diaries and analysed with poisson regression. analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). this trial is registered with clinicaltrials.gov, number nct01233297. findings: between nov 17, 2010, and jan 28, 2014, we randomly allocated 158 asthma-like episodes in 72 children (79 [50%] to azithromycin and 79 [50%] to placebo). the mean duration of the episode after treatment was 3·4 days for children receiving azithromycin compared with 7·7 days for children receiving placebo. azithromycin caused a significant shortening of the episode of 63·3% (95% ci 56·0–69·3; p<0·0001). the effect size increased with early initiation of treatment, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). we noted no differences in clinical adverse events between the azithromycin (18 [23%] of 78 episodes included in final analysis) and placebo (24 [30%] of 79) groups (p=0·30), but we did not investigate bacterial resistance patterns after treatment. interpretation: azithromycin reduced the duration of episodes of asthma-like symptoms in young children, suggesting that this drug could have a role in acute management of exacerbations. further research is needed to disentangle the inflammatory versus antimicrobial aspects of this relation. funding: lundbeck foundation, danish ministry of health, danish council for strategic research, capital region research foundation. childhood asthma is often preceded by recurrent episodes of troublesome lung symptoms in relation to airway infections in the fi rst years of life. 1,2 treatment of such episodes represents a major unmet clinical need; they are the most common cause of admission to hospital in young children, are a reason for stress and anxiety for families, and cause a major draw on health-care resources. [3] [4] [5] we discovered in our birth cohort, the copenhagen prospective studies on asthma in childhood 2000 (copsac 2000 ; a previous birth cohort of children born to mothers with asthma), that airway bacteria (haemophilus infl uenzae, streptococcus pneumoniae, and moraxella catarrhalis) and respiratory viruses (at least one of picornavirus, respiratory syncytial virus, coronavirus, parainfl uenzavirus, infl uenza virus, human metapneumovirus, adenovirus, or bocavirus) are equally closely associated with episodes of asthma-like symptoms in the fi rst 3 years of life. 6 bacteria and viruses occurred together in most cases, challenging the previous hypothesis that episodes with asthma-like symptoms in this age group are largely virally induced. [7] [8] [9] this fi nding suggested that bacteria might play an equal part in the pathogenesis of such episodes and that treatment with antibiotics might ameliorate symptoms. at present, guidelines do not recommend antibiotics for treatment of early asthma-like episodes, 10 yet they are widely used. 4 we did a randomised controlled trial (rct) of azithromycin for treatment of episodes of troublesome lung symptoms in young children who were followed up prospectively in our new unselected copenhagen prospective studies on asthma in childhood 2010 (copsac 2010 ) birth cohort. 11 in this randomised, double-blind, placebo-controlled trial, we recruited children from the copsac 2010 cohort, which is a single-centre, population-based birth cohort of 700 children recruited from the general danish population of zealand, including copenhagen, at 1 week of age and followed up prospectively at the copenhagen prospective studies on asthma in childhood (copsac) research unit (copenhagen and naestved, denmark) with deep clinical phenotyping. 11 children aged 1-3 years diagnosed with recurrent asthma-like symptoms (troublesome lung symptoms) as defi ned in the procedures section were eligible each time they had an episode of troublesome lung symptoms lasting at least 3 days. exclusion criteria were macrolide allergy, heart, liver, neurological, and kidney disease, and, before each treatment, one or more clinical signs of pneumonia (respiratory frequency of 50 breaths per min or higher, fever of 39°c or higher, or c-reactive protein [crp] concentration of 476·20 nmol/l [50 mg/l] or higher). most mothers from the copsac 2010 cohort also participated in other medical trials while pregnant and may have received dietary supplements or an infl uenza vaccination (nct00856947, nct00798226, and nct01012557). 11, 12 additional details of baseline characteristics of the cohort are outlined in the copsac 2010 cohort design report. 11 this trial was approved by the ethics committee for copenhagen (h-3-2010-065), danish data protection agency (2010-41-5023), and danish health and medicines authority (2612-4329). parents of children gave written and oral informed consent before enrolment of participants. the complete biobank is publicly available at the danish national biobank. the entire copsac dataset, including the rct-specifi c data, are currently being transferred to a publicly available database (the danish data archive). each episode of troublesome lung symptoms that occurred up to the age of 3 years or up to a maximum of seven treatments per child was randomised individually to either azithromycin or placebo. treatments were randomly allocated at the pharmacy of glostrup (copenhagen, denmark) with a computer-generated list of random numbers in blocks of ten. copies of the randomisation code were kept in sealed envelopes at the research site and the pharmacy. investigators and participating families were masked to treatment assignment until the youngest child turned 3 years of age and throughout the data validation and analysis phases. those assessing the primary outcome were masked; those doing subanalyses were not. evidence before this study findings from a publication from the copenhagen prospective studies on asthma in childhood showed that both bacteria and viruses are equally associated with the risk of acute episodes of asthma-like symptoms in young children, suggesting that antibiotics such as azithromycin could help in management of such episodes. we searched pubmed up to oct 15, 2010 , with no language limits, for various combinations of the search terms "rct", "childhood", "asthma", "wheeze", and "antibiotics". we identifi ed all previous randomised controlled trials of treatment with antibiotics for asthma and wheezy exacerbations, but focused mainly on childhood asthma. the search led us to new articles, but also identifi ed other relevant old publications for background material. investigators of two randomised trials concluded no benefi cial eff ect of β-lactam treatment for acute exacerbations, which has led to present guidelines not recommending antibiotic treatment for episodes of acute asthma-like symptoms. this study is, to our knowledge, the fi rst randomised controlled trial of azithromycin treatment of acute episodes of asthma-like symptoms in children aged 1-3 years with a history of recurrent episodes and its fi ndings show a clinically signifi cant shortening of symptom duration by 63% after intervention. present guidelines do not recommend antibiotics for treatment of episodes of asthma-like symptoms in young children, yet antibiotics remain among the most commonly prescribed drugs in these episodes. our fi ndings suggest that azithromycin might be benefi cial after medical assessment of an acute asthma-like episode in young children with a known history of such symptoms and without clinical signs of pneumonia. how the eff ect of azithromycin is compared with narrow-spectrum antibiotics and whether long-term eff ects are associated with recurrent use of azithromycin need to be investigated. troublesome lung symptoms, consisting of cough, wheeze, or dyspnoea, severely aff ecting the wellbeing of the child, were monitored using daily diary cards fi lled out by the parents from birth. 11 we defi ned an episode as at least 3 consecutive days of troublesome lung symptoms, at which point we requested that the parents brought the child to the copsac research unit for an acute visit. we used the composite score of troublesome lung symptoms to describe asthma-like symptoms in the children, a score previously validated 13, 14 and used in our clinical observational cohort studies of young children 13,15-17 and a randomised controlled trial. 19 at each acute visit, the diary cards were reviewed with the family by trained copsac paediatricians to validate symptom defi nitions and severity. additionally, the research paediatrician did a thorough physical examination, consisting of assessment of fever, tachypnoea, chest recessions, wheezing, and lung and heart auscultation, and examination of the skin, ears, nose, and throat. furthermore, we measured crp concentration (detection limit of 76·19-1523·84 nmol/l [8-160 mg/l]) in the peripheral blood with the quickread 101 instrument (orion diagnostica, espoo, finland). we collected a hypopharyngeal aspirate using a soft suction catheter passed through the nose into the hypopharynx, as previously described. 18 we cultured the samples and isolated the airway bacterial pathogens h infl uenzae, s pneumoniae, and m catarrhalis. we obtained a nasopharyngeal aspirate for viral identifi cation with pcr. the viral airway pathogens analysed were rhinoviruses, respiratory syncytial virus (rsv), and enteroviruses. we treated episodes of troublesome lung symptoms with the β2 agonist salbutamol (airomir; teva, kongens lyngby, denmark) inhaled from a pressurised metered dose inhaler delivered via a spacer (aerochamber; trudell medical international, london, on, canada) as needed. we added 4 mg of montelukast in the evening for 2 weeks in children who had previously benefi ted from this treatment. we added prednisolone 1-2 mg/kg per day for 3 days for severe episodes at the discretion of the attending paediatricians in the copsac research unit. recurrent troublesome lung symptoms were diagnosed if a child had: daily diary recordings of fi ve episodes of troublesome lung symptoms within 6 months; 4 weeks of continuous symptoms; or a severe acute episode needing oral prednisolone or hospital admission. this diagnosis algorithm had previously been validated in our at-risk copsac 2000 birth cohort. 19, 20 at diagnosis of recurrent troublesome lung symptoms, we gave children a 3-month course of 2 × 50 μg fl uticasone (flixotide; glaxosmithkline, uk) inhaled from a pressurised metered dose inhaler delivered via a spacer twice daily. if a second relapse of troublesome lung symptoms occurred after cessation of inhaled corticosteroids, we initiated a 6-month course of inhaled corticosteroids. children diagnosed with recurrent troublesome lung symptoms and participating in this trial were prescribed azithromycin or placebo at the copsac research unit when subsequent acute episodes of troublesome lung symptoms occurred after diagnosis. we gave azithromycin as an oral solution of 10 mg/kg per day in closed bottles (teva) for 3 consecutive days or a matching placebo of similar look and taste (pharmacy of glostrup). the primary outcome was diary-verifi ed duration of episodes of troublesome lung symptoms after initiation of treatment. secondary outcomes were the time from treatment to the next episode of troublesome lung symptoms, the number of episodes that turned into severe exacerbations (need for oral steroids or admission to hospital), and the duration of β2 agonist use after treatment. serious adverse events, any adverse events, gastrointestinal symptoms, or other infections were documented with daily diary cards and hospital records. we based our power calculations on the duration of episodes of troublesome lung symptoms at age 1-3 years in the children of the previous copsac 2000 cohort. 18, 19, 21 86 independent episodes were needed to detect a diff erence of 1 day duration of episodes with a power of 90%, a p value of 0·05, and an sd of the duration of an episode of 1·4 days. 18, 19, 21 we analysed the duration of an episode of troublesome lung symptoms and β2 agonist use after treatment with poisson regression with a log link. this type of regression is ideal for modelling counts because it captures both skewness and variance heterogeneity and provides an easy-to-interpret quantifi cation of eff ects as relative change in mean counts. the model includes fi xed eff ects of the categorical variable episode number and an eff ect of treatment. we included a random eff ect of child to account for heterogeneity between children. we analysed factors potentially modifying the treatment eff ect with robust poisson regression to account for within-child correlation. we obtained inference by means of the generalised estimating equations procedure with a working independence assumption. we analysed gap times between episodes with cox regression, including γ-distributed frailties shared by gap times within each child to account for between-child heterogeneity. we included fi xed eff ects of treatment at the preceding episode in the model and stratifi ed baseline hazards by episode number. we obtained estimates with maximum likelihood estimation with wald 95% cis and a 0·05 p value cutoff . we did analyses using r version 3.2.2 and the add-on package lme4. primary analyses were per protocol (excluding those without a primary outcome measure or who did not receive treatment). safety analyses included those without a primary outcome measure but who did receive the study treatment. this trial was monitored by the good clinical practice unit at copenhagen university hospital (copenhagen, denmark). this trial is registered with clinicaltrials.gov, number nct01233297. the funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. js, cbp, and hb had access to the raw data. the corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. 207 (30%) of the 700 children enrolled in the main cohort were diagnosed with recurrent troublesome lung symptoms during the fi rst 3 years of life; between nov 17, 2010, and jan 28, 2014, we randomly allocated 158 episodes for trial treatment (79 [50%] to azithromycin and 79 [50%] to placebo; fi gure 1) from 72 (35%) of these children. before analyses, we excluded ten (6%) episodes from the analysis (fi ve [6%] in each group), nine (6%) because of missing diary information (azithromycin four [5%]; placebo fi ve [6%]) and one (1%; in azithromycin group) because the treatment was never given to the child. mean age at randomisation was 2·0 years (sd 0·6). the mean number of randomisations for each child was 2·2 treatments (sd 1·5). in 121 (82%) of the 148 episodes analysed (62 [84%] in the azithromycin-treated episodes and 59 [80%] in the placebo-treated episodes), the child received concurrent treatment with inhaled corticosteroids. in 89 (60%) episodes, the child received concurrent treatment with montelukast (47 [64%] in the azithromycin-treated episodes and 42 [57%] in the placebo-treated episodes). treatment was complied with in 154 (97%) of 158 episodes: one (1%) azithromycin treatment was never given and three (2%) treatments were discontinued after initiation; one (1%) in the azithromycin group and two (1%) in the placebo group. 71 (99%) of 72 children had complete clinical followup from inclusion in the study until age 3 years. baseline characteristics did not diff er signifi cantly between participants in the trial and other children diagnosed with recurrent troublesome lung symptoms from the copsac 2010 cohort who did not participate in the ; table 1 ). the mean total duration of respiratory episodes was 13·7 days. the episode duration after randomisation was unrelated to sex, mother's smoking status, allergic sensitisation to inhalant or food allergens at 6 months or 18 months, atopic dermatitis, or 17q21 genetic risk variant (appendix). figure 2 shows the proportion of symptomatic children day-by-day during the 30 days after treatment, showing a shortening of the symptomatic period after treatment with azithromycin. the average number of symptom days after azithromycin treatment was 3·4 days versus 7·7 days after placebo, corresponding to a calculated reduction in episode length of 63·3% (95% ci 56·0-69·3; p<0·0001) within a child due to azithromycin treatment (table 2) . restriction of the analysis to the fi rst randomised treatment in each child substantiated a signifi cant reduction of symptom duration by 44·4% (30·9-55·2; p<0·0001) after treatment with azithromycin, corresponding to a mean duration of 4·0 days after azithromycin versus 7·1 days after placebo. the eff ect of azithromycin was increased when the duration of symptoms before treatment was shorter, showing a reduction in episode duration of 83% if treatment was initiated before day 6 of the episode compared with 36% if initiated on or after day 6 (p<0·0001). figure 3 shows the reduction of episode duration after azithromycin treatment as a function of episode duration before treatment (less than or more than the median value of 6 days). we noted no diff erential eff ect for episodes presenting with fever of ≥38°c or with increased crp concentration of ≥76·19 nmol/l (≥8 mg/l), and treatment was equally eff ective in episodes with and without objective wheeze during examination in the research clinic (table 2) . presence of any pathogenic bacteria did not signifi cantly modify the treatment eff ect compared with episodes without detection of bacteria, but azithromycin was more eff ective in episodes positive for h infl uenzae (table 2). presence of any virus did not modify the treatment eff ect of azithromycin. none of the detected viruses signifi cantly modifi ed treatment eff ects (table 2) . concurrent treatment with inhaled steroids (p value for interaction=0·57) or montelukast (p value for interaction=0·69) did not signifi cantly modify the treatment eff ect, and responses were equal (appendix). we noted no diff erences between treatment groups during the 30 days after treatment with respect to serious or any adverse events, gastrointestinal symptoms, or other infections, as documented by daily diary cards and hospital records (appendix). azithromycin signifi cantly reduced the duration of physician-verifi ed episodes of asthma-like symptoms in children aged 1-3 years with a history of recurrent asthma-like symptoms. the duration was decreased by about 63% after azithromycin treatment, with more improvement if treatment was started early in the episode. azithromycin had no long-term eff ect on risk of subsequent episodes. this study is substantially strengthened by the prospective, longitudinal, daily diary recordings of lung symptoms before development of attacks, validated by study paediatricians at 6-monthly and acute visits. copsac served as the primary health-care centre for the birth cohort, ensuring a standardised approach to diagnosis and treatment, which improves reliability of diagnoses compared with reporting from community doctors and retrospective information from parents. [18] [19] [20] 22 diagnosis was based on an algorithm of symptom quantity, which has been analysed and validated in detail 13 and applied in our previous rct 19 of inhaled corticosteroids in young children in the at-risk copsac 2000 birth cohort. such strict diagnostic procedure is paramount to clinical assessments, diagnoses, and treatments, which are otherwise poorly standardised in the community and more diffi cult in young children than later in life. 13 the in-depth clinical assessment of each respiratory episode by the study paediatrician before randomisation, including a thorough objective examination and crp concentration measurement in the research clinic, ensured validity and homogeneity of the primary outcome and exclusion of children with clinical signs of pneumonia. this assessment minimised the possibility of the azithromycin eff ect being driven by treatment of bacterial pneumonia misclassifi ed as an episode of asthmalike symptoms. another strength is the centralised longitudinal clinical follow-up of the cohort by a research team with a well established routine of doing clinical cohort studies. this routine ensured a high follow-up of the cohort, with 99% of the randomised children completing full followup until 3 years of age and only 6% of randomised treatments being unavailable. we obtained airway samples before treatment in 91% of episodes, with only 13 episodes missed. our results are generalisable to a similar group of children with a known history of recurrent asthma-like symptoms, with or without concomitant treatment with inhaled steroids and with an episode duration of at least 3 days. an important limitation is that our data pertain to children with a episode duration before treatment detailed clinical history and acute worsening judged by the study clinician. they cannot be generalised to a more liberal setting, such as initiation at home by parents or children with mild disease. this study is the fi rst, to our knowledge, to investigate and show an eff ect of azithromycin for treatment of acute respiratory episodes in young children with a history of recurrent asthma-like symptoms, in a cohort designed and powered to explore such eff ects. a third of all children will experience an episode of asthma-like symptoms in relation to airway infections before 3 years of age. 23 shortening of such episodes by 63% is therefore clinically signifi cant to the child, families, health-care user, and society. we noted that azithromycin had a marked eff ect in relation to any given type of episode independently of the trigger, clinical presentation, or symptom duration before the intervention, which suggests a broad application. the sensitivity analysis restricting episodes to the fi rst randomisation validated the primary fi nding. asthma-like episodes in young children probably represent a heterogeneous clinical syndrome. importantly, we excluded typical pneumonia based on predefi ned clinical criteria. furthermore, most children (more than 80%) had undetectable concentrations of crp and no fever at randomisation, and the treatment eff ect was similar in these children, strongly suggesting that the eff ect of azithromycin is not due to misclassifi cation of pneumonia. azithromycin treatment was particularly eff ective in children who were treated shortly after symptom debut. this fi nding makes us speculate that azithromycin is mainly acting on the acute infl ammatory 24 or infectious 6, 25 processes related to exacerbations, rather than a persistent underlying infl ammation. this hypothesis is supported by the absence of eff ect on time to next episode. alternatively, azithromycin acts by clearing bacterial pathogens indirectly responsible for the respiratory episode through subsequent co-infection by a viral trigger, and therefore the treatment was more eff ective when initiated early in the episode than when initiated late. 26 this study is based on our previous birth cohort study 6 in which we discovered that pathogenic airway bacteria and respiratory viruses are equally closely associated with acute episodes of asthma-like symptoms in young children and mostly occur together. our fi nding in this study that the treatment eff ect was strong, even in episodes for which no bacterial pathogen was detected, suggests that the eff ect of azithromycin is not only antibacterial. macrolide antibiotics are active against both common airway pathogenic bacteria and atypical bacteria, [27] [28] [29] but also have anti-infl ammatory activity 24 and, possibly, antiviral eff ects. 30 studies of macrolides in adults with severe asthma episodes are ambiguous, 31, 32 and macrolides reportedly reduce exacerbations in adults with an asthma type characterised by chronic neutrophilic infl ammation. 33, 34 indeed, recurrent asthma-like symptoms in young children are also characterised by neutrophilic infl ammation, 25, 35, 36 which, in particular, might be present for episodes triggered by h infl uenzae. 34 this corresponds with our fi nding of a stronger azithromycin eff ect in episodes triggered by h infl uenzae. viral infection in general did not predict an altered eff ect of azithromycin treatment. low numbers in some viral species groups limit the conclusions drawn about eff ect modifi cation by specifi c viruses. thus, the antibacterial, anti-infl ammatory, and antiviral pathways of azithromycin could have contributed to the shortening of episode length observed in this study. we cannot rule out that the eff ects noted are mainly anti-infl ammatory because episodes triggered by h infl uenzae induce neutrophilic infl ammation 34 and azithromycin also reduced episode duration in children without any evidence of bacterial infection. an rct 37 of treatment with azithromycin in rsv-positive children showed a reduction of the neutrophilic marker interleukin 8 at day 14 after azithromycin treatment. this fi nding could point towards an anti-infl ammatory eff ect as the primary mediator of our fi ndings and also explain why fi ndings from previous rcts 38, 39 have failed to show treatment eff ects of non-anti-infl ammatory antibiotics in acute exacerbations of childhood asthma. present guidelines do not recommend antibiotics for treatment of episodes of asthma-like symptoms in young children 10 and yet they are among the most commonly prescribed drugs for such episodes in both the usa and europe. 4 our data suggest an eff ect of azithromycin on acute asthma-like episodes and thereby identify a potential future treatment, but do not provide suffi cient evidence to recommend this treatment in clinical practice. how the eff ect of azithromycin compares with narrowspectrum antibiotics and whether any long-term eff ects are associated with recurrent use need to be investigated. we are keenly aware of the potential ecological issues relating to use of antibiotics in terms of bacterial ecology and resistance. macrolide resistance in organisms causing respiratory illness in children is already an issue. 40 future research should establish the choice of antimicrobial treatment and criteria for treatment, taking societal aspects into consideration. we did not identify strong eff ect modifi ers from the objective clinical measures, concomitant treatments, or the microbiological profi le other than the presence of h infl uenzae. our data suggest that the eff ect increases by starting early in the episode. future studies might help to identify specifi c disease phenotypes or biomarkers directing the treatment to specifi c groups of young children. the results of this study identify a potential treatment for a common childhood disease for which better treatment options are needed than are currently available. better treatments might help to alleviate a substantial disease burden for children, families, and society. hb conceived, designed, and carried out the study, acquired, analysed, and interpreted data, and wrote the report. js, blc, and kb contributed to design of the study. js acquired, analysed, and interpreted data and drafted the report. cbp did the statistical analyses. ss and kak cultured and identifi ed the bacteria. tkf identifi ed the viruses. blc, nhv, eb, tmp, rkv, a-mms, hmw, st, hwh, la, and kb collected and interpreted data and wrote the report. all coauthors have contributed substantially to the analyses or interpretation of the data and have provided important intellectual input and approval of the fi nal version of the manuscript. hb has received funds for research and for members of research staff and been paid as a consultant for chiesi. all other authors declare no competing interests. the global burden of asthma: executive summary of the gina dissemination committee report viruses and bacteria in acute asthma exacerbations-a ga² len-dare systematic review variations in pediatric asthma hospitalization rates and costs between and within nordic countries prevalence of asthma-like symptoms in young children practice imperfect-treatment for wheezing in preschoolers association of bacteria and viruses with wheezy episodes in young children: prospective birth cohort study viruses as precipitants of asthmatic attacks in children role of respiratory viruses in acute upper and lower respiratory tract illness in the fi rst year of life prevalence of viral respiratory tract infections in children with asthma a summary of the new gina strategy: a roadmap to asthma control deep phenotyping of the unselected copsac2010 birth cohort study altered response to a(h1n1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial endotyping early childhood asthma by quantitative symptom assessment to wheeze or not to wheeze': that is not the question neonates with reduced neonatal lung function have systemic lowgrade infl ammation increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates vegfa variants are associated with pre-school lung function, but not neonatal lung function childhood asthma after bacterial colonization of the airway in neonates intermittent inhaled corticosteroids in infants with episodic wheezing chromosome 17q21 gene variants are associated with asthma and exacerbations but not atopy in early childhood the copenhagen prospective study on asthma in childhood (copsac): design, rationale, and baseline data from a longitudinal birth cohort study elevated exhaled nitric oxide in high-risk neonates precedes transient early but not persistent wheeze asthma and wheezing in the fi rst six years of life. the group health medical associates eff ect of clarithromycin on cytokines and chemokines in children with an acute exacerbation of recurrent wheezing: a double-blind wheeze in preschool age is associated with pulmonary bacterial infection and resolves after antibiotic therapy nasopharyngeal bacterial colonization during the fi rst wheezing episode is associated with longer duration of hospitalization and higher risk of relapse in young children detection of viral, chlamydia pneumoniae and mycoplasma pneumoniae infections in exacerbations of asthma in children mycoplasma pneumoniae and asthma in children importance of acute mycoplasma pneumoniae and chlamydia pneumoniae infections in children with wheezing azithromycin induces anti-viral responses in bronchial epithelial cells eff ect of clarithromycin on acute asthma exacerbations in children: an open randomized study the eff ect of telithromycin in acute exacerbations of asthma azithromycin for prevention of exacerbations in severe asthma (azisast): a multicentre randomised double-blind placebo-controlled trial is there a role for macrolides in severe asthma? bronchoalveolar cells in children <3 years old with severe recurrent wheezing airway remodeling and infl ammation in symptomatic infants with reversible airfl ow obstruction randomized trial to evaluate azithromycin's eff ects on serum and upper airway il-8 levels and recurrent wheezing in infants with respiratory syncytial virus bronchiolitis double-blind study of the eff ectiveness of a broad spectrum antibiotic in status asthmaticus routine antibiotics in hospital management of acute asthma spreading us macrolide resistance copenhagen prospective studies on asthma in childhood (copsac) is funded by private and public research funds all listed on www.copsac.com. the lundbeck foundation, danish ministry of health, danish council for strategic research, and capital region research foundation have provided core support for copsac. we express our gratitude to the children and families of the copsac 2010 cohort for all their support and commitment. we likewise acknowledge and appreciate the unique eff orts and teamwork of the copsac research team. steff en lynge jørgensen is thanked for microbiological technical assistance. key: cord-293259-o51fnvuw authors: sinaei, reza; pezeshki, sara; parvaresh, saeedeh; sinaei, roya title: why covid-19 is less frequent and severe in children: a narrative review date: 2020-09-25 journal: world j pediatr doi: 10.1007/s12519-020-00392-y sha: doc_id: 293259 cord_uid: o51fnvuw background: despite the streaks of severity, severe acute respiratory syndrome-coronavirus-2 (sars-cov-2) infection is, in general, less frequent and severe in children than in adults. we searched for causal evidence of this mystery. data sources: an extensive search strategy was designed to identify papers on coronavirus disease 2019 (covid-19). we searched ovid medline, pubmed, embase databases, and cochrane library and carried out a review on the causes of this dilemma. results: our searches produced 81 relevant articles. the review showed that children accounted for a lower percentage of reported cases, and they also experienced less severe illness courses. some potential explanations, including the tendency to engage the upper airway, the different expression in both receptors of angiotensin-converting enzyme and renin–angiotensin system, a less vigorous immune response, the lower levels of interleukin (il)-6, il-10, myeloperoxidase, and p-selectin and a higher intracellular adhesion molecule-1, a potential protective role of lymphocytes, and also lung infiltrations might have protective roles in the immune system–respiratory tract interactions. finally, what have shed light on this under representation comes from two studies that revealed high-titer immunoglobulin-g antibodies against respiratory syncytial virus and mycoplasma pneumonia, may carry out cross-protection against sars-cov-2 infection, just like what suggested about the vaccines. conclusions: these results require an in-depth look. properties of the immune system including a less vigorous adaptive system beside a preliminary potent innate response and a trained immunity alongside a healthier respiratory system, and their interactions, might protect children against sars-cov-2 infection. however, further studies are needed to explore other possible causes of this enigma. the novel coronavirus infection spread rapidly, so that the world health organization (who) declared this epidemic as a pandemic on march 11, 2020 [1] . according to the preliminary data, the overall case fatality rate is about 2.3% and is significantly higher in older patients [2] . also, hospitalization rate increases with age, given the increased risk of nasal colonization and secondary infections [3, 4] . limited initial data exist on the burden of coronavirus disease 2019 in children [5] . thus far, only a small number of severe acute respiratory syndrome-coronavirus 2 (sars-cov-2) infection have involved children, so that they have accounted for only 1-5% of total patients [2, [6] [7] [8] [9] [10] . however, doubt has existed as to whether covid-19 is really less common in children, and some have believed that children are as likely as adults to become infected, but are less likely to be symptomatic or to develop severe symptoms [11] . some have attributed this to a lack of real epidemiological studies in children. however, the recent epidemiological studies have shown that although children are more likely to be affected than those reported previously, children are still less likely to be affected than adults. in iceland, researchers screened 6% of country's population and found that children under 10 years of age had a lower incidence of sars-cov-2 infection than adults [12] . although similar epidemiological results, especially those from serological investigations, are emerging in other countries, such as the netherlands, australia, and china, researchers in china found that children were less likely to catch the covid-19 within households from an affected family member [13] . similarly, of 806 close contacts in 15 schools in australia, only two students have been identified as secondary cases [14] . however, these are three ways that researchers have gauged whether children are less frequently infected by sars-cov-2 infection. the available data also suggest that sars-cov-2 is less severe in children. in a report, among 149,082 cases reported in the united states through april 2, 2020, children experienced less severe symptoms. fever, cough, or shortness of breath were in 73% of children compared to 93% of adults. also, myalgia, sore throat, headache, and diarrhea were less commonly reported by pediatric patients. three deaths were noted among the pediatric patients in this analysis. however, children aged less than 1 year accounted for the highest hospitalization [15] . dong et al. investigated epidemiological characteristics of 2143 suspected pediatric patients. infection was confirmed in 34% of these patients, whereas 94.1% of them were asymptomatic, or had mild to moderate courses, and 4.4% were asymptomatic [16] . these data were similar to previous findings that children with covid-19 may not have reported fever, cough, or sore throat as often as adults [17] . also, dong et al. revealed that the prevalence of severe and critical disease was 10.6% in children aged less than 1 year, 7.3% in those aged 1-5 years, 4.2% in those aged 6-10 years, 4.1% in those aged 11-15 years, and 3% in those aged 16-17 years [16] . however, some patients experienced severe courses of illness. severe sars-cov-2 infection is characterized by a hyperproinflammatory response or cytokine storm state that results to acute respiratory distress syndrome (ards) and multisystem inflammatory syndrome (mis). ards is characterized by hypoxemic respiratory failure with bilateral lung infiltrates often necessitating invasive respiratory support. in contrast, this situation occurs less frequently in pediatric patients [18, 19] . in a systematic review of 7480 pediatric patients with confirmed covid-19, only 2% were severe (e.g., dyspnea, central cyanosis, and hypoxemia), and 0.7% were critical (e.g., ards, respiratory failure, and shock) [20] . unexpectedly, there is now a growing cognizance of small reports of pediatric patients with a hyper inflammatory response termed as mis-c or kawasaki-like disease [21, 22] . nevertheless, these two entities are not so common, and the most children experience milder illness. for the first time, we reported two pediatric patients with reactive arthritis who presented with limping following sars-cov-2 infection [23] . the data on laboratory markers in children also revealed lower lymphocytopenia (3-3.5%) than adults (63%) in several studies. also, children generally had lower increased c-reactive protein and procalcitonin levels. thus, the overall prognosis of the disease in children is relatively good [15, 17, [24] [25] [26] . unfortunately, due to the high percentage of missing data, a real statistical evaluation and comparison could not be conducted [27] . however, it seems that symptoms in children are both less frequent and less severe. in this review, we comprehensively investigated the most likely causes of this enigmatic topic, although all the actual causes remain unclear. an extensive search strategy was designed to identify all relevant papers from beginning to august 23, 2020. we used ovid medline, pubmed, embase, and cochrane library and carried out a review on the causes of the lower prevalence and less severity of covid-19 in pediatric patients. the search strategy was constructed based on searching terms 2019 novel coronavirus, covid-19, sars-cov-2 with using and/or, also the terms of child, pediatric, newborn, infant, adolescence, adult, age, age groups, severity, epidemiology, prevalence, difference, immune system, etiology, reasons in title, abstract, and key words. the data were screened and extracted independently by two investigators (the first and corresponding authors) and by one highly experienced librarian; then we proceeded to cross check the results. in addition, we increased the references by using an additional snowballing method. after discussion and consensus, the article was written. the inclusion criteria were: (1) children and adolescents < 19 years of age; (2) all scientific papers and letters, about covid-19; and (3) description of the possible causes of lower prevalence and less severity of diseases. the exclusion criterion is that of ≥ 19 years of age. the search found 994 papers. after removing the duplications and less relevant papers, 81 scientific papers and letters (5-19, 24-69, 84-103) were included. however, several speculations were derived from pathophysiology of disease and defensive mechanisms. the results were categorized into two main groups of causes (immunological and non-immunological considerations), and each group included the six subsets described below. all causes are involved in the less severity of illness, but some (as * ) include the simultaneous and parallel causes of less frequency. the first results stem from some considerations that children have a less vigorous immune response to the virus than adults because the cytokine storm is thought to be important in the pathogenesis of severe sars-cov-2 infections [28] . these results have been suggested from several studies in which elevated inflammatory markers are less common in children, so they experience milder disease than adults [29] . children have a more active innate immune response * of course, this is not in conflict with another hypothesis that children have a more active innate immune response that can be one of the early stages of defense [11] . this can be attributed to the fact that children had more recurrences of recent viral infections [30] . however, if the disease went further extension, a less vigorous immune response may prevent them from the cytokine storm and help to reduce the severity. jeljeli et al. studied the ontogeny of cytokine production in the response of phytohemagglutinin by aging and found a rapid shift from enhanced interleukin (il)-10 secretion capacity at birth toward balanced il-10/t helper (th) 1/ th2/th17 cytokine levels early in life. this change appears to be an essential precondition to fight pathogens and also avoids overwhelming inflammatory reactions [31] . schouten et al. discovered an age-dependent difference in levels of biomarkers in the lungs of ards patients. levels of il-6, il-10, myeloperoxidase, and p-selectin were higher by aging; whereas intercellular adhesion molecule-1 was higher in neonates [32] . however, immunosenescence also may be explain covid-19 age variability. it refers to the gradual deterioration of the immune system (especially adaptive type) brought on by natural age advancement [33, 34] . some studies revealed that with aging, there is a gradual decrease of naïve t cell numbers related to the thymic changes, shrinkage in the collection of t cell clones generated in the thymus, and loss of costimulatory receptor cd28. all these factors may impair the immunological responses with age [35] [36] [37] . shortening of telomeres, especially t cells with cell divisions, might be associated with impaired immune response to new antigens along with increasing the production of proinflammatory cytokines [38, 39] . zhu et al. revealed that among 667 adolescents, the african and the girls had longer telomeres [40] . these findings along with those of other studies can justify the severity of covid-19 in males and also by aging [41] . some have suggested that the constitutional higher percentage of lymphocytes and natural killers (nk) in children may have a defensive role in covid-19 [42] . indeed, increasing proinflammatory cytokines associated with neutrophil function with age, associated with severity of ards and may explain, to some extent, the age-dependent difference [43] . in adult patients lymphocytopenia (especially cd4 + and cd8 + t lymphocytes) has been associated with increased severity or worse outcomes [44] . total leukocyte and neutrophil counts and the neutrophil/lymphocyte ratio can be used as follow-up parameters in covid-19 [45] . at least in three cohorts, the majority of pediatric patients had normal leukocytes and lymphocytopenia accounted for only 3-3.5% of cases [17, 24, 25] . given the central role of lymphocytes and monocytes in the induction of immune responses, their frequency in peripheral blood might be expected to reflect the state of an individual's immune response to infection [46] . in addition, since t cells are required for controlling exuberant innate immune responses, the absence of a potent antivirus t cell response in aged hosts could lead to an exuberant response and damage, which is not seen in children [47, 48] . wynn and colleagues found that 2360 genes in neutrophils, 965 in monocytes, and 109 genes in lymphocytes were up-or down-regulated in pediatric septic shock, referring the data that circulatory lymphocytes are not the main leukocytes population with altered gene profiles during septic shock [49] . other results for a milder disease in children are linked to a trained immunity that represents an immune memory after antigen exposure [26] . interestingly, what have shed light on this under representation comes from two studies that revealed multiple high-titer antibodies against respiratory syncytial virus (rsv) and mycoplasma pneumoniae (mp) in the blood of children appears to offer cross protection against sars-cov-2 infection [50, 51] . several studies have shown that children are more susceptible than adults to infection by rsv and mp [52] [53] [54] [55] . mp has been reported in 10-40% of community-acquired pneumonia cases, and children with 5-15 years age are the most susceptible groups. although, this was documented in children under 4 years by the report of 2010-2011 of european epidemic data [54] . also, rsv is more prevalent in infancy. the who has reported rsv as a causative pathogen for over 30 million new cases of lower respiratory infection episodes, including acute bronchitis in children less than 5 years age [52] . older siblings are a greater source of spreading infection than adults because they spend significant time in nurseries and schools [55] . these events can train the immunity of children so that neutralizing cross-reactive antibodies of mp and rsv may be more common in children than in adults. in a retrospective review of all covid-19 patients treated at wuhan union hospital until march 20, 2020, mi et al. evaluated the correlation between prior exposures to mp and better clinical response in covid-19 patients. the immunoglobulin g (igg) positive patients had a higher lymphocyte, monocyte and eosinophil counts and percentages (p < 0.05) than covid-19 patients without mp igg. in addition, thrombin time and lactate dehydrogenases were better in this group. furthermore, requirement and use of nasal catheter oxygen mask was significantly lower in covid-19 patients with mp igg positivity (p = 0.029). their findings indicate that mp igg positivity is a potential protective factor for sars-cov-2 infection [51] . orange et al. showed that the intravenous immunoglobulin (ivig) manufactured from a plasma pool derived from high-titer, anti-rsv plasma donors contains high titers of antibodies to several common respiratory viruses (influenza a, b, human metapneumovirus, parainfluenza 1, 2, and 3, covoc42 and v299e); this study found a direct correlation between antibody responder status of donors to rsv and their responder status to other viruses (p < 0.05). although, there are, however, a number of considerations, this could be due to higher humoral immune responders in general or especially against intercellular antigens, to diversity in major histocompatibility complex alleles, and finally to donors that might have experienced a greater diversity of viral infection. this can be generalized to the more infections in children and the potential protection effect that results from these infections [50] . cao and colleagues emphasized the role of trained immunity as a new immune model that represents a cross protection against various pathogens. it can be activated also by some vaccines, such as bacillle calmette-guerin (bcg), by generation of immune memory just like what is seen in mp [26] . miller and colleagues found that countries without universal policies of bcg vaccination (e.g., usa, italy) have been affected more severely as compared to countries with universal and long-standing bcg policies. also, countries that have a late start of universal bcg policy (e.g., iran in 1984) had a high mortality, consistent with the idea that bcg protects the vaccinated elderly population. in addition, they found that bcg vaccination reduced the number of reported covid-19 cases in the country. the combination of reduced mortality and morbidity makes bcg vaccine a potential new tool in the fight against covid-19 [56] . however, this cross-protection has been considered, and what argues against this anecdotal assumption is the higher mortality of covid-19 in countries where bcg vaccine is compulsory [47] . myśliwska et al. investigated the relationship between nk activity in the vaccinated population and specific immune protection against influenza virus. they concluded that nk cells activation, which was still significantly elevated after 1 month of vaccination, may allow protection against influenza and other respiratory viral infections [57] . indirect epidemiological analyses also have suggested a protective role of the measles, mumps, and rubella vaccine against covid-19 [58] . because the majority of vaccinated individuals had not protective igg titer against measles after 10 years, hanker et al. hypothesized that age-dependent decline in immunogenicity against measles vaccine could be an explanation for the higher occurrence of covid-19 in adults [59] . there are several issues at this setting. the results show at least six other considerations including some constitutional and behavioral reasons: (1) available data suggest that children may have more upper respiratory tract involvement than the lower. thereafter, viral interference in young children leads to a lower viral load [16] . however, several speculations have emerged at this setting. young children generally, have a healthier respiratory machinery due to their lower exposure to harmful environmental factors. in addition, children have fewer underlying chronic diseases, than what seen in adults [11] ; (2) possible reasons for the disparity in severity between adults and children may be related to the difference in distribution, maturation, and functioning of receptors of renin angiotensin system (ras), angiotensinconverting enzyme 2 (ace-2), and altered inflammatory response to virus [60] . zhu et al. have looked for reasons of this disparity in severity [61] . ace-2 is the receptor of viral endocytosis and also alters the ras activity from proinflammatory to anti-inflammatory response [62] . the ace levels may be altered by several underlying diseases [63] and by age [64] in a murine model, although schouten and colleagues found that there is no marked difference in ace and ace-2 among age groups [32] . however, this speculation should be investigated; (3) xie et al. believe that children are less likely to be exposed to the virus. this may be due to fewer outdoor activities and to less international travel. also, xie et al. considered an under-diagnosis of children that might have resulted from their milder symptoms and therefore yielded fewer laboratory tests [27] ; (4) in attili and colleague's investigation, age-stratified odds ratios showed that the nasal carriage was higher in adult rabbits [65] . this result suggested that the presence of the respiratory nasal bacterial colonization might have more impact in the adult population [49] . in contrast, it is possible that the presence of other viruses in the respiratory tract of young children limits the sars-cov-2 development by direct virus-virus interactions [66] . this hypothesis stems from the greater frequency of viral infection in children and also provides a link between the viral load and covid-19 severity [52] [53] [54] [55] 67] ; (5) in total, some results suggest that children have specific mechanisms that regulate the interaction between their immunological and respiratory systems, which could be contributing to milder disease. as a result, lymphocytes have participated in the inducible bronchus associated lymphoid structure after that respiratory insult has happened [68] ; (6) it was suggested that maturational changes in the axonal transport system may explain the relative resistance to immature mice to poliovirus induced paralysis [69] . this can be generalized to the issue as a complementary reason. knowledge about neonatal outcomes of sars-cov-2 infection is relatively limited. immaturity of both innate and adaptive immune systems make this group highly vulnerable to infection [70] . interestingly, the majority of neonates born to mother with covid-19 were not infected, and to date few reports have suggested that neonates have been affected by covid-19. the possible reasons might be related to surgical delivery and to rapid separation of neonate [71] . levy found that neonatal antigen presenting cells and plasmacytoid dendritic cells have impaired production of interferonand present a bias against the production of th1 cytokines [72] . however, the levels of il-6, il-10, myeloperoxidase, and p-selectin are higher by aging, whereas intercellular adhesion molecule-1 is higher in neonates [32] . therefore, unlike the infants under 1 year that are at higher risk of infection and hospitalization (17.6% of pediatric cases and 10.6% of critical cases) [16] , neonates are less likely to be infected. in contrast, two known ace-2 and transmembrane protease serine-2 receptors are widely spread in specific cell types of maternal-fetal interface and might be vulnerable to the neonate affecting by sars-cov-2 infection. however, on march 2020, the first case report of possible vertical transmission of sars-cov-2 infection was published [73] . dong et al. speculated the possibility of maternal fetal transmission of virus by demonstrating a higher igm level and abnormal cytokines 2 hours after birth [74] . however, two independent manuscripts described elevated sars-cov-2 specific igm and igg antibodies in the blood of newborns of affected mothers. to date, while maternal infections were observed in the late phase of pregnancy, there may not have been sufficient time for the generation of antibodies. thus, serological investigation for the diagnosis of neonate is still controversial. nevertheless, increased level of igg could be explained by trans-placental transferring from infected mother, while igm strongly indicates a selfimmune response of newborns [74, 75] . thus, the elevated igm might suggest that neonate was infected in utero. in any case, the possibility of vertical transmission has been raised. after birth, the neonates might be involved. zeng et al. reported a series of 33 infants from mothers with covid-19, while three of whom were symptomatic, with a radiological picture of pneumonia. the 31 weeks neonate developed coagulopathy, associated with sepsis. none of the newborns died. the clinical features of infected newborns might be nonspecific and include acute respiratory distress syndrome, temperature instability, gastrointestinal, and cardiovascular dysfunction [76] . however, the age-dependent pattern of immune reactions and other physiological elements may influence the response to sars-cov-2 in the neonatal subpopulation [73] . although covid-19 in children appears largely to present with mild features, a very small percentage of children with sars-cov-2 infection experience mis-c weeks later. however, the mis-c cases usually do not primarily affect the lungs [77] . the recent reports from european countries and the us followed by growing universal reports support the emergence of this novel phenomenon [18] . the clinical presentations of this entity are variable and include persistent fever, severe illness, and involvement of two or more organ systems, in combination with laboratory evidence of both inflammation and sars-cov-2 infection. however, some presentations of mis-c resemble kawasaki disease (kd), toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome [18, 19] . of the 191 potential cases reported across 191 hospitals in new york state, 95 patients were classified as confirmed mis-c. the peak in the number of mis-c cases followed the peak in the number of cases of laboratory-confirmed sars-cov-2 infection by 31 days. the researchers stated that based on molecular and serological results, mis-c is probably a post-infectious, inflammatory process related to covid-19 [78] . also, because the majority of patients have had positive serological results for sars-cov-2, with a lesser number of positive rt-pcr tests, this condition may be more a postinfection entity rather than one related to acute early infection state. this hypothesis seems to have emerged for two reasons. first, mis-c cases lagged in time compared with the peak of sars-cov-2 infection. second, children who were involved in mis-c, more often have igg than positive molecular tests. however, mis-c is a delayed immunological response associated with inflammation characterized by elevated levels of proinflammatory cytokines including il-6, il-1β, il-17, tnf-α, and granulocyte colony-stimulating factor. as a hypothesis, because the younger patients have increased number of naïve t cells in different sites to respond to new pathogens [43] , this may prevent severe respiratory disease in children. thus, a low-level, persistent infection in other sites may accumulate over time in some children, resulting in mis-c [19] . one compelling alternative hypothesis for this entity stems from the ability of coronaviruses to block type i and iii of interferon responses, that can result from delayed hyper-inflammatory response in whom that have a high viral load or cannot to control the infection [79, 80] . a mapping systemic inflammation and antibody (ab) responses in mis-c was conducted. they documented that all mis-c patients had igg against sars-cov-2 infection. they identified elevated signatures of inflammation (il-18, il-6), lymphocytic and myeloid chemotaxis and activation (ccl3, ccl4, and cub domain-containing protein-1), and mucosal immune dysregulation (il-17a, ccl20, ccl28). also, a reduction in m-dendritic cells, nk cells, and t cells in blood were seen, suggesting extravasation to affected tissues. also, some disease-associated autoantibodies (anti-la) were seen. these results suggest that autoreactivity secondary to sars-cov-2 infection and the inflammatory innate immune response may be crucial to the pathogenesis of mis-c [81] . interestingly, diorio et al. based on the clinical phenotype, hypothesized that children with mis-c are presenting with a syndrome that is distinct from both kd and severe covid-19 infection. the researchers found that the patients with mis-c had elevated levels of tnf-α and il-10, whereas patients with severe or mild covid-19 had no or minimally elevated levels of these cytokines. this profile for mis-c is distinct from what happens in kd, which is associated with mild elevations of other cytokines (il-1, il-2, and il-6) and not il-10. tnf-α appears to play key role in the pathogenesis of both mis-c and kd. viral cycle thresholds (cts) and burr cells on blood smears also differentiated between patients with severe covid-19 and mis-c. the high cts associated with mis-c support a postinfectious etiology phenomenon that has previously been postulated but not demonstrated [18, 82] . however, children with mis-c have no higher il-10 level, and this may be due to their higher lymphocyte counts hypothetically. in addition, they showed distinct ab responses as compared to adults with severe covid-19 causing ards, and to those who recovered from mild disease. patients with mis-c, often generate igg abs specific for spike (s) protein, while adults with covid-19 showed anti-s, igm, and iga abs, as well as anti-n igg abs. moreover, mis-c patients had reduced neutralizing activity compared covid-19 cohorts, indicating a reduced protective serological response [19] . these results suggest a distinct infection course and immune response in children and adults with severe disease. children appear to have a less severe pulmonary manifestation due to all previous reasons, especially a lower gene expression of the ace-2 receptor. in contrast, adults with severe respiratory failure syndrome due to sars-cov-2 infection, who typically deteriorate near one week later of illness onset, have a dysregulation of immune system as opposed to direct cellular injury from viral infection. the immune dysregulation in adults that experienced respiratory distress is characterized by lymphopenia and a sustained production of proinflammatory cytokines, such as tnf-α and il-6 [83] , giving the basis of immunomodulatory therapies like il-6 blockade at this situation. although, some suggest more conservative treatments, such as ivig or even corticosteroids for mis-c cases, empirical treatment with immunomodulators, such as anakinra or tocilizumab, as a substituted agent in refractory cases are promising [75, 81] . ards is the most severe manifestation of covid-19 in adults. the survival rate of covid-19 patients with ards who are admitted to an intensive care unit (icu) is approximately 25% [18] . in contrast, this situation is uncommon among pediatric patients and is called pards [18, 19] . why some children experience more severe illness? the reasons that children may experience a severe course have not yet been elucidated. here, we summarize some possible causes of this discrepancy. there are some suggestions that several conditions increase the risk of severe disease in children and include hospitalization, mechanical ventilation, congenital heart disease, neurologic, genetic and metabolic conditions [84] [85] [86] . other conditions are related to all ages and include: diabetes mellitus i and ii, immunocompromised due to solid organ transplant and other conditions, cerebrovascular accidents, chronic pulmonary disease (e.g., cystic fibrosis, moderate to severe asthma), chronic kidney disease, liver disease, pregnancy, obesity, smocking, sickle cell disease, thalassemia, and hypertension [87] . in two multicenter studies of children admitted to picu, 40 of 48 and 12 of 17 had an underlying condition [80, 81] . in a systematic review of 587 confirmed pediatric patients, 22% had an underlying condition. most of them were chronic pulmonary disease (45%), congenital heart disease (23%), immune suppression (12%), and hematological and oncological conditions (6%) [20] . it has an important role in development and worse outcome of severity, in both pediatric and adult patients. in the largest ards epidemiologic study of adults, 20.8% and in the pediatric acute respiratory distress syndrome incidence and epidemiology study, 13% of ards cases, had immunosuppression [88, 89] . the higher body mass index has been shown to be an independent factor associated with increased risk of ards development. as a paradox, the underweight patients with ards have higher mortality [90] . in adult population, cigarette smoking is associated with ards in patients with sepsis [91] . this can be generalized to pediatrics as both active and passive smokers. it seems that infants aged less than 1 year are at higher risk of infection and severity [15] . in the largest pediatric population-based study to date with 2143 patients, the proportion of severe and critical cases was 10.6% under 1 year, suggesting the higher risk of severe respiratory failure in infants. in addition to smaller airways, both immaturity of respiratory tract and immune system, alongside with relatively lower trained immunity might contributed to this severity [16, 68, 92] . pediatric studies have not always observed a marked association between ards and both race and ethnicity, perhaps due to limited sample size. however, african and hispanic ethnicity appears to be major risks in mis-c patients [81] . to date, several single-nucleotide polymorphisms have been identified by the increased risk of ards. the most significant variants are surfactant protein-b, ace, angiotensin-2, and il-1r antagonist [93] . the endothelial protein c receptor and thrombomodulin genes were independent factors associated with mortality [94] . il-1 pathway cytokines are associated with ards risk, although this association has not been found in pards studies [95] . the regulatory gene arylsulfatase-d was linked in 22 and 4% of ards cases and controls, respectively. also, xk kell blood group complex membr-3 was present in a minor allele frequency of 37 and 4% of ards cases and controls, respectively [96] . it has been shown that there are five variants of cystic fibrosis transmembrane conductance regulator splicing factor gens that independently are associated with pards in african american children without cystic fibrosis. another variant also was identified in caucasian children with cystic fibrosis, without higher risk of ards development [97] . interestingly, the cluster of mis-c patients in some countries after the peak incidence of coronavirus infection among adults by approximately one month and in contrast no statistically significant difference in japan and korea, suggest a genetic and ethnicity background for these severe cases [22] . however, at this time the extent to which genetics impacts the development of mis-c is unclear. considering the implications of host genes in the cell entry and replication of sars-cov-2 and in mounting the immune system response, it appears that several genes might be involved. the variations within ace-2 gene, the human leukocyte antigen locus, and the genes regulating toll-like receptor and complement pathways seem to influence susceptibility and subsequently the severity of covid-19 [98] . in addition to possible involvement of several other genes (e.g., abo blood type and mediterranean fever gene) [99] , genetic variations in these gateways might be influenced by the societies geographically. using a combinational analysis approach, taylor and colleagues identified 68 protein-coding genes that were highly associated with severe covid-19 [100] . ouyang et al. revealed that the number of differentially expressed genes (degs) increased by disease progression and decreased after initial treatment. all down-regulated degs in severe cases mainly involved th17 activation [101] . researchers identified the 3p21.31 gene cluster as a genetic susceptibility locus in severe covid-19 patients with respiratory failures. the results from comparing 1900 severe covid-19 patients and 1200 healthy blood donors indicated that people with blood group a had a 45% higher risk of infection than others. similarly, they found blood group o was associated with a lower risk of acquiring covid-19 [102] . unexpectedly, some children may have more viral loads without any other reasons. the higher exposure with or without high-risk behavior, alongside the more expression of ace-2 receptors due to the less immaturity, a less previous exposure to coronavirus, influenza and other viruses, not getting the flu vaccine and some other vaccines, a less simultaneous presence of other viruses in body, and a more bacterial nasal colonization, all can be generalized as involved factors at this setting. in addition, some children may have a weaker innate response; while the strong innate response can be due to more exposure to previous viruses and many other reasons. they also, may have a relatively greater adaptive response alongside memory cells like adults [30, 90] . there are several potential reasons that children have relatively milder illness. in addition to a fewer outdoor activity, children have a number of characteristics that protect them against sars-cov-2 infection. they have a healthier respiratory machinery alongside a different expression of receptors in the lower respiratory tract. also, we believe that the collection of immune system specifications including a less vigorous adaptive system beside a preliminary potent innate response, the constitutional higher level of lymphocyte counts, the trained immunity with cross-reactive neutralizing antibodies, the lack effects of aging, and the interaction between the immune system and respiratory tract might be protecting children against sars-cov-2 infection. although, these findings suggest that covid-19 is less common and somewhat milder in children compared to adults, there are now some reports of children presenting with severe types of infection such as mis-c. the exact incidence of mis-c following an asymptomatic or even a mildly symptomatic infection with sars-cov-2 is unclear. however, further investigations are needed to explore other possible causes of less severity of sars-cov-2 infection in the pediatric population. who. who director-general's opening remarks at the media briefing on covid-19 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention clinical course and outcomes of critically ill patients with sars-cov-2 pneumonia in wuhan, china: a single-centered, retrospective, observational study nasal colonization rate of community and hospital acquired methicillin resistant staphylococcus aureus in hospitalized children clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster diagnosis, 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(covid-19) and neonate: what neonatologist need to know innate immunity of the newborn: basic mechanisms and clinical correlates vertical transmission of covid-19-a systematic review possible vertical transmission of sars-cov-2 from an infected mother to her newborn antibodies in infants born to mothers with covid-19 pneumonia neonatal early-onset infection with sars-cov-2 in 33 neonates born to mothers with covid-19 in wuhan is it kawasaki shock syndrome, kawasaki-like disease or pediatric inflammatory multisystem disease? the importance of semantic in the era of covid-19 pandemic multisystem inflammatory syndrome in children in new york state type i and type iii interferons-induction, signaling, evasion, and application to combat covid-19 imbalanced host response to sars-cov-2 drives development of covid-19 mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (mis-c) pathogenesis of kawasaki disease: the central role of tnf-α complex 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opportunities association of common genetic variation in the protein c pathway genes with clinical outcomes in acute respiratory distress syndrome interleukin-1 receptor antagonist is associated with pediatric acute respiratory distress syndrome and worse outcomes in children with acute respiratory failure identification of novel single nucleotide polymorphisms associated with acute respiratory distress syndrome by exome-seq association of polymorphisms in genes of factors involved in regulation of splicing of cystic fibrosis transmembrane conductance regulator mrna with acute respiratory distress syndrome in children with pneumonia genetic gateways to covid-19 infection: implications for risk, severity, and outcomes differential expression of covid-19-related genes in european americans and african americans analysis of genetic host response risk factors in severe covid-19 patients down-regulated gene expression spectrum and immune responses changed during the disease progression in covid-19 patients genomewide association study of severe covid-19 with respiratory failure the authors thank the staff and participants of this key: cord-283440-8du0s33p authors: ciuca, ioana m title: covid-19 in children: an ample review date: 2020-06-25 journal: risk manag healthc policy doi: 10.2147/rmhp.s257180 sha: doc_id: 283440 cord_uid: 8du0s33p the aim of this review was to describe the current knowledge about coronavirus disease 2019 (covid-19, which is caused by severe acute respiratory syndrome coronavirus 2 [sars-cov-2]) in children, from epidemiological, clinical, and laboratory perspectives, including knowledge on the disease course, treatment, and prognosis. an extensive literature search was performed to identify papers on covid-19 (sars-cov-2 infection) in children, published between january 1, 2020 and april 1, 2020. there were 44 relevant papers on covid-19 in children. the results showed that covid-19 occurs in 0.39–12.3% of children. clinical signs and symptoms are comparable to those in adults, but milder forms and a large percentage of asymptomatic carriers are found among children. elevated inflammatory markers are associated with complications and linked to various co-infections. chest computed tomography (ct) scans in children revealed structural changes similar to those found in adults, with consolidations surrounded by halos being somewhat specific for children with covid-19. the recommended treatment includes providing symptomatic therapy, with no specific drug recommendations for children. the prognosis is much better for children compared to adults. this review highlights that covid-19 in children is similar to the disease in the adult population, but with particularities regarding clinical manifestations, laboratory test results, chest imaging, and treatment. the prognosis is much better for children compared to adults, but with the progression of the pandemic; the cases in children might change in the future. the recently declared coronavirus pandemic represents the "sword of damocles" in societies used to protocols and guidelines. it started at the end of 2019, when many adult patients with a new form of pneumonia that was frequently fatal were admitted to chinese hospitals; this illness was caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2). 1 in this time of modern medicine, when evidence-based medicine prevails, we find ourselves in the face of a difficult situation, where the necessary evidence is lacking; while there are some large studies for the adult population, for the pediatric population, the evidence is extremely limited. the new coronavirus was initially named 2019-ncov but was later renamed severe acute respiratory syndrome coronavirus 2 (sars-cov-2). 2 the virus is a single-stranded, zoonotic rna virus that is a member of the group of respiratory tract viruses. it is related to middle east respiratory syndrome coronavirus (mers-cov) and severe acute respiratory syndrome coronavirus (sars-cov). 3 the disease, known internationally as coronavirus disease 2019 (covid19) , affects a significant proportion of people, but it has been reported less frequently in children, especially in the initial studies, in which only 0.9% of the positive cases involved children <15 years. 4 the current transmission is from human to human, and both intra-family and intra-community spread occurs, although it is assumed that it was initially from bats and had an animal intermediate host. 5 the virus is excreted via the respiratory and digestive routes. 6 it has been found that the virus is excreted via the digestive route even at 4 days after a negative respiratory sample is obtained, which may be due to a longer time requirement for clearing the virus from the digestive route compared to the respiratory route. 7, 8 contamination occurs via pffluge drops (produced by coughing, sneezing, and talking) or by contact with contaminated surfaces, 9 with contamination of feces also occurring. 10 because having children (especially toddlers) follow sanitary practices is extremely difficult (depending on their age), it is expected that child carriers transmit the infection easily. major problems among children include the high degree of contagiousness, the healthy status of carriers of the virus (leading to an increased potential for transmission), and the lack of knowledge we have about the disease. not much is known about mother-to-child transmission, but there are studies reporting on positive newborns being born to positive mothers. in these cases, it is not clear whether infection occurred intranatally or perinatally (via secretions such as pflugge drops or milk), with no clear transmission route having been established. [11] [12] [13] this study aimed to review the current data on sars-cov-2 infection in children, from epidemiological, clinical, and laboratory perspectives, including data on the disease course, treatment, and prognosis. "covid-19" or "sars-cov-2" and "children" were used as the keywords in the search and the additional terms included epidemiology, diagnosis, clinic, laboratory, treatment, and outcome. the search period was january 1, 2020 to april 1, 2020. litcovid (the us national library of medicine's curated hub of scientific literature on sars-cov-2, https:// www.ncbi.nlm.nih.gov/research/coronavirus) was searched, along with searching for additional records in medline (pubmed interface), springer link and web of science. all retrieved records (including original articles, letters to editor, editorials, and case reports) in english and records with english translation were downloaded and evaluated. preprints, in-press articles, and accepted-for-publication studies were also evaluated, given the current scarcity of evidence. subsequently, the abstracts were evaluated for eligibility, duplicates were removed, and the data were analyzed. a total of 147 published papers were found on sars-cov-2 in general populations, 48 full-text articles that involved children were published between january 1, 2020 and april, 1 2020 and 44 considered relevant were reviewed for this study. epidemiology sars-cov-2 has triggered a significant number of illnesses; (as of 1st of april 2020), the world health organization (who) reported 1,133,758 confirmed cases, with 62,784 deaths. 14 although data on the pediatric population are currently limited, there are several studies that provide valuable information. based on the first published research, the disease was diagnosed in only 0.39% of children. 15 a later chinese study of 72,314 patients of all ages reported the virus in 1% of children. 16 a large-scale testing study in korea (involving children representing 18% of the country's population) reported that the proportion of children with covid-19 among the confirmed cases was 4.8%. 17 after the initiation of more widespread testing, lu et al conducted a recent study in china and reported that the incidence of confirmed covid-19 among children rose to 12.3% (171 out of the 1391 children assessed), with a mean an average age of 6.7 years. 18 dong et al studied 2143 cases of children with covid-19 in a large study in china (34.1% of cases were confirmed by laboratory testing and 65.9% were clinically diagnosed). the average age of these children was 6.7 years. there was no significant difference in the proportion of males (56%) and females, 19 but other research has shown a slightly higher prevalence in adult males. 17 it was presumed that children were infected via exposure to infected family members, 17, 19 without specifying from which family member the infection occurred, whether the infection was contracted simultaneously by all family members, or the incubation period in children. xia et al conducted a small study of 20 children with covid-19 and reported that 65% had clear contact with a family member, while the contact was indeterminate for the remainder of the children. 21 pediatric symptoms are variable, depending on the stage of the disease, the prior health status, and the presence of comorbidities and other individual features. the clinical picture in children includes fever, cough, dyspnea, and malaise, which is the tetrad of symptoms frequently reported in adults. 20 in children, fever is present in 41.5% 17 to 60% 21 of cases, being reported by most studies as a significant symptom, associated with both cough and common symptoms of rhinopharyngitis (such as sore throat and rhinorrhea). 18, 22 based on the who case definition, in the majority of countries, only patients (including children) with respiratory symptoms would be suspected of having covid-19. 23 however, dong et al reported that 4.4% of children were completely asymptomatic, while 55.3% had mild forms such as rhinopharyngitis. 19 digestive symptoms are also present in 8-10% of cases involving children, 24 including abdominal pain or discomfort, diarrhea, and vomiting; these symptoms may precede respiratory symptoms. 22 cardiac manifestations specific to myocarditis were also found in children: sinus tachycardia and minor right bundle branch block (rbbb); however, the prevalence was not significantly different from that in the general pediatric population. 21 depending on the affected organs, manifestations of the associated complications may be adjoining. the physical signs of covid-19 include rhinorrhea, pharyngeal congestion, 21 and pulmonary rales, 25 associated with pneumonia. compensatory signs such as polypnea, dyspnea, chest retractions, and other signs of respiratory failure have been observed, 26 but specific covid-19 signs were not highlighted. thus far, there have been no confirmed cases of hemoptysis or anosmia in children, unlike in adults, 27 but this might be because of the difficulty of describing the absence of smell by children. pediatric outcomes are usually excellent due to the mild forms of disease often present in children, although deaths have also been registered among children. 4 asymptomatic carriers among the pediatric population have been described, raising concerns, because infected children might be asymptomatic spreaders of the disease. 21 recently, the occurrence of a multisystemic inflammatory syndrome in children was reported. 28 it was initially named "kawasaki like-disease" and then renamed pediatric multisystem inflammatory syndrome (pims), and it is similar to the vascular multisystem inflammatory involvement in adults with covid-19.the disease onset is usually preceded by gastrointestinal symptoms, which are followed by systemic vasculitis with prolonged, nonresponsive fever associated with rash, palmar erythema, conjunctivitis, oral mucositis, and laterocervical lymphadenopathy, and sometimes complicated with myocarditis and/or severe coronaritis. pims has been reported in the uk, france, italy, and the usa but, fortunately, the treatment for kawasaki vasculitis has proven to be effective. 28 however, dong et al reported that 4.4% of children were completely asymptomatic, while 55.3% had mild forms such as rhinopharyngitis. 19 additionally, a recent study in china of 2143 children with covid-19 found that 94% of them had mild or moderate forms of the disease. 19 the clinical manifestations of the virus in children have been mild and less severe than those in adults, being linked to their age and development. 1, 4, 5, 8, 9 this needs to be kept under close supervision, and identifying the asymptomatic carriers is paramount for limiting the virus spread. although the clinical manifestations in children are more indistinct and less severe than in adults, this age category is distinct and must be considered with special care, particularly as early diagnosis influences the diseases outcome and, crucially, detecting asymptomatic carriers can limit the transmission of the disease. most studies suggest that the same risk factors in adults apply to children, including comorbidities such as diabetes, chronic pulmonary disease, and cardiac pathology, 4 and unfavorable outcomes are more frequent in adults with comorbidities such as hypertension, diabetes, kidney disease, immunosuppression (drug-induced immunosuppression and hiv), and chronic obstructive pulmonary disease (including asthma). 30 prompt diagnosis is vital, given the evolution of the disease, with ards potentially occurring at 1 week after symptom onset. 31 the most frequent complications observed in children with severe forms of covid-19 were septic shock, toxic encephalopathy, multiple organ dysfunction syndrome, disseminated intravascular coagulation, and status epilepticus. 26 fortunately, in a study that included 2173 children, only one child (aged 14 years) died, but the proportion of severe and critical cases was 10.6% among infected infants, and this decreased with increasing age to 3.0% for infected 16-18-year-olds. 19 more severe forms were more common in children < 3 year of age (10.6%) compared to in children aged 16-18 years (3%) infected with the virus, suggesting that younger children are more at risk of having severe forms than older children, but the study did not report if underlying diseases were pre-existent among any of the children. 19 another study reported the death of a 10-month-old baby with associated intestinal occlusion. 18 the comorbidities associated with severe cases in the study were leukemia (taking chemotherapy), intestinal occlusion, and hydronephrosis. 18 as of march 31, 2020, four deaths among children caused by covid-19 were reported in the international media. a 16-year-old died in france, and then a 12-year-old girl died in belgium and a 13-year-old boy died in the uk (https://www.euronews.com/2020/03/31/). the presence of clinical signs and symptoms in a relevant epidemiological context (eg, an endemic area) indicates a suspected case of covid-19, especially if contact with a confirmed covid-19 case is known. the diagnosis can be confirmed by viral detection laboratory tests. it is important to ascertain the timing of the onset of infection, based on the incubation period of 2-14 days, 9 with a mean of 3-7 days. 1 there may be suspicion of a case of covid-19 in a child if at least one of the following exists: 9 1. fever, specific respiratory symptoms, digestive symptoms, or fatigue 2. suggestive biological findings: normal leukocyte level, leukopenia, and increased c reactive protein (crp) and procalcitonin (pct) levels 3. specific imaging findings (based on chest x-ray [cxr] and ct scans) in a suspected case, the confirmation involves laboratory confirmation, although some clinicians would advocate that in the presence of clinical signs and symptoms and contact with a covid-19 case, a diagnosis can be made. 23 the laboratory diagnosis is performed by detecting a nucleic acid antigen (sars-cov-2 rna) from nasopharyngeal or pharyngeal secretions using reverse transcription polymerase chain reaction (rt-pcr). the tests involving nasopharyngeal secretions had a better sensitivity (65%) compared to the tests involving pharyngeal swabs (30%). 32 this is why the us centers for disease control and prevention (cdc) recommend screening involving nasal secretions or nasopharyngeal aspirate. 33 the timing of the sample collection 34 is very important: screening tests should ideally involve nasopharyngeal secretions collected at the beginning of the disease (when there are signs of rhinopharyngitis), as the viral load decreases in the upper airway and increases in the lower airways with the onset of lung disease; 35 thus, after the onset of lung disease, sputum samples are recommended. using nasopharyngeal secretions leads to a lower sensitivity than using bronchial secretions, but the required bronchoalveolar lavage for children without sputum excretion is invasive 35 and may increase the risk of infection among the medical personnel 36 and so is not indicated. screening tests based on the detection of specific immunoglobulin m, a, and g (igm, iga, and igg) in serum have been developed, but igm and iga only become positive from the fifth day from covid-19 onset, so the diagnosis is made retrospectively and the tests cannot be used for early diagnosis. 36, 37 igg levels can be detected after 14 days of disease evolution. 38 unfortunately, the number of screening tests is limited internationally due to the widespread nature of the pandemic, which makes it very difficult to establish precise diagnoses and to identify the healthy carriers acting as viral reservoirs. biological investigations are not specific, as expected in viral diseases. as in other viral infections, in covid-19, several hematological disorders have been reported. several studies have reported the presence of leukopenia in adults and children, associated with lymphopenia and neutropenia. 36, 39 another study reported normal leukocyte levels with leukopenia among children. 1 sun et al reported normal leukocyte levels (lymphocytes and neutrophils), platelets, and hemoglobin in some patients, but leukopenia with lymphopenia, thrombocytopenia, and anemia were linked with severe outcomes. 26 increased inflammatory markers such as crp, erythrocyte sedimentation rate, 1 and pct have been noticed in some children with covid-19, 40 signifying a bacterial coinfection and associated complications. 21, 25, 26 it has been shown that a large percentage (80%) of children had abnormal pct values, requiring antibiotics, but no deaths were registered among these children. 21 pct was normal in children with mild and moderate covid-19. 1, 21, 25 while studies involving adults revealed that pct and leukopenia were risk factors for increase mortality rates, this connection was not confirmed in children. increased troponin was present in adults with myocarditis, and myoglobin (also known as myohemoglobin) and muscle enzymes were increased in adults due to covid-associated muscular injury 1,40,41 but these findings were not reported in children. high crp and ferritin levels were associated with a poor prognosis in adults 42 as well as increased d dimers and thrombocytopenia. 21, 27, 30 other biological findings included idiopathic metabolic acidosis and increased serum levels of proinflammatory cytokines such as interleukin (il)-6. 42 increased transaminases, muscle enzymes, and lactic dehydrogenase 1, 21, 25, 43 can occur, depending on the affected organ, and alanine transaminase and direct bilirubin were associated with severe disease in children. 43, 44 chest imaging chest imaging, including chest xray (cxr), ct, and lung ultrasonography (lus), is often used for evaluation and monitoring of respiratory diseases. 45 therefore, it may be advisable to use one of the imaging techniques for covid-19 assessment. however, it would not be appropriate to use ct as a screening diagnosis tool for covid-19 diagnosis in children because of the lack of specificity of the lesions, which can occur in other viral lung diseases. 46 ai et al published a study on adults that concluded that ct scans should be considered for covid-19 diagnosis, 47 based on the good sensitivity of ct for detecting lung changes, which was biased by the fact that ct is the gold standard for the detection of morphological changes. a comprehensive report stated that chest ct scans would be normal in 35-50% of pediatric covid-19 patients with minor upper airway respiratory symptoms, which implies an unjustifiably high percentage of children, without injuries, who would be exposed to ct radiation if chest ct scans were used. to be used for screening, chest ct scans should detect lung changes in asymptomatic children as well as in symptomatic cases, but the median sensitivity of ct of 60% in pediatric patients with confirmed covid-19 is not sufficient to expose asymptomatic children to harmful radiation. as it is unusual to perform ct scans in cases of viral non-complicated pneumonia, there are currently no valid arguments for the use of ct scans as a screening tool in the pediatric population with asymptomatic sars-cov-2 infection. because ct scans lack specificity for covid-19, caution was recommended by an expert panel regarding imaging choices, especially when they necessitate patient transport. 48 in most cases of pneumonia, cxr is a key diagnostic tool, but its diagnostic utility for covid-19 is limited. the initial and mild stages of covid-19 can lead to a normal cxr image. 4, 27, 49 however, uni-or bilateral patchy or diffuse asymmetric airspace opacities, interstitial alterations, and nodularity can be detected in severe covid-19 cases. 50 nevertheless, cxr is neither an indispensable nor a mandatory covid-19 diagnostic tool due to its lack of specificity. ct is highly sensitive at detecting pulmonary lesions in all lung pathologies, including covid-19. however, many studies described covid-19 lesions on ct scans that are nonspecific and bear some resemblance to other lung pathologies. [49] [50] [51] ground-glass opacities were described, mostly subpleural 52 and predominantly in the lower lobes, while fine-mesh shadows occurred in the early stages of the disease. 21, 49, 51, 52 among children with moderate forms of covid-19, there was a bilateral multi-lobular distribution with diffuse ground-glass, crazy-paving pattern, and consolidation. 21, 47, 53 as the infection progressed, severe lesions and dense consolidation became more prevalent. 53 xia et al reported that consolidation surrounded by a halo was found in half of children with severe or moderate covid-19 lung disease, suggesting that there is some specificity regarding these lesions in children. 21 lesions such as ground-glass opacities and fine-mesh shadows were also described in children, while "patch-like shadows" and "white lung" have been found in severe cases. 26 a recently developed covid-19 ct score showed a reliable, sensitive association with decreased mortality risk in adults. 53 despite studies indicating that non-contrast chest ct scans could be used as an early diagnostic tool compared to rt-pcr 54 (ct being frequently delayed because of the high burden of cases during pandemics), ct is not recommended as a first-line diagnosis technique in children. this is due to irradiation risks, lack of specific lesions, and the potential increased contamination risk during patient transport. the results of a study by fang et al support the use of chest ct scans for screening in patients with clinical and epidemiological features compatible with covid-19, particularly when rt-pcr test results are negative. 55 various studies have demonstrated that lus is a valuable tool for identifying changes that can occur in covid-19 such as consolidations, pleural effusions, small subpleural consolidations, areas of white lung, and b lines in a variety of patterns including focal, multifocal, and confluent lesions. 56, 57 lus can indicate suggestive signs of interstitial-alveolar damage involving variable consolidations, irregularities of the pleura, nontranslobar consolidation, and consolidation with air bronchogram. 58 however, lus can detect lung artefacts that are not specific to covid-19, including consolidations with air bronchogram that occur in pneumonia, 58 subpleural consolidations that occur in pneumonia and bronchiolitis, 59 pleural line irregularities that occur in bronchiolitis, lung fibrosis, pleural malignancies, and copd, 60-62 and b-lines that occur in interstitial alveolar inflammation present in bronchiolitis and viral interstitial cases of pneumonia, 60 as well as in chronic lung pathologies such as fibrosis, 61 cystic fibrosis, 62 and bronchiectasis. 60 the limitations of lus is relied to the lesion localization, deeper lung lesions have no contact with the pleura and cannot be easily detected as the air is a very weak conductor of ultrasound. 63 however, in contrast to other methods of investigation, lus is easily available at the bedside 57 and portable probes that are easy to disinfect can be used, involving less exposure to infection among medical staff. 64 there are currently no etiological treatments or prophylactic for covid-19. 66 the treatment of mild cases addresses current symptoms, and isolation to prevent human-to-human transmission is the most important prophylactic treatment. 9, 67 for moderate and severe covid-19, the therapeutic recommendations involve supportive therapy, supplemental oxygen and, if bacterial infection (which is frequent in children) is suspected, empirical antibiotics. 1, 25, 29, 30 very severe cases involving refractory hypoxia and respiratory failure will need admission to an intensive care unit for mechanical ventilation; fortunately, children do not require this as often as adults. 19, 20, 26 non-invasive ventilation (niv) and high-flow oxygen therapy (hfot) are associated with a high risk of virus aerosolization, and the virus can be spread via mask leaks, so niv and hfot may only be used in specific cases and when the mask is precisely positioned, with an optimal fit. 67 retrospective studies on covid-19 suggest starting antiviral medication in the initial treatment window, when the evolution of the disease can still be changed, due to the lack of treatment efficiency once complications occur. 67 etiological treatment would require the administration of antivirals targeting rna viruses. so far, no antiviral has been shown to be effective for the treatment of covid-19 in humans, but there are multiple randomized clinical trials in progress. some antiretroviral drugs (such as lopinavir/ritonavir, darunavir/cobicistat, favipiravir, remdesivir, ribavirin, oseltamivir, tocilizumab, and umifenovir as well as angiotensin-converting enzyme [ace] inhibitors) have been indicated in adults. 1, 67 however, as there are no studies to demonstrate the benefit of any antivirals in children with covid-19, the use of this type of medication would not be recommended. chloroquine and its derivatives (including hydroxychloroquine and chloroquine phosphate) have been successfully used for sars-cov and ebola, and have also been shown to be effective in children with sars-cov-2. 68 co-administration of azithromycin increases the therapeutic success, according to a french study. 69 most of the therapeutic regimens for children include chloroquine (or derivatives) and lopinavir/ritonavir, which have been reported to show a degree of efficiency and a safety profile that is acceptable for children. 9 ribavirin has been reported to have been used to treat severe covid-19 in children. 25, 65 inhaled interferon-alpha has been used to treat covid-19 in children, but the efficiency and safety remain to be determined. 1, 65 non-specific immunity-boosting treatments such as immunoglobulins and intravenous interferon have been used to treat severe cases in adults, but additional consideration is required before it is used for children. 1, 9, 65 corticosteroids are recommended for the treatment of covid-19 complications such as ards, septic shock, encephalopathy, and bleeding disorders, and in other specific pathologies, steroids are required. the multicentric citris-ali trial demonstrated the effectiveness of high-dose ascorbic acid for treating ards due to other causes, lowering the mortality rate, 70 and this could be extrapolated to covid-19. antibiotics are recommended for secondary chest infections associated with covid-19. the majority of studies suggest using empirical broad-spectrum antibiotics until culture results become available. 1, 4 given the frequency of mycoplasma infections in children 9,21 and the well-described anti-inflammatory properties of azithromycin, this could be the antibiotic of choice in children with covid-19 and bacterial superinfection. further studies should be carried out to gather evidence on the best therapeutic options. prevention, aimed at reducing transmission in the community, remains the only proven efficient option to combat covid-19, until further discoveries are made. according to several studies, covid-19 has a milder clinical course with faster recovery and a better prognosis in children compared to in adults. 1, 9, 15 however, a recent study reported similarly severe forms of covid-19 in children with good outcomes. 40 the reasons for these particularities are still being investigated. some researchers have hypothesized that lung epithelial cells in children may express fewer or perhaps even differently shaped ace2 proteins, leading to a lower morbidity rate, 71 but further studies are needed to understand the mechanisms of the diverse manifestations of covid-19 in children. it has been shown that influenza virus, parainfluenza virus, respiratory syncytial virus (rsv), rhinovirus, or adenovirus, which are the most common viruses that cause acute lower respiratory infections in young children, might cross-react with coronavirus, 72 giving children partial protection against covid-19, 73 but co-infections were also reported. 9 the most common co-infections in children involved mycoplasma pneumoniae, influenza a and b, rsv, and cytomegalovirus. 21 children of all ages are predisposed to acquire covid-19, considering the human-to-human transmission, but the majority of them have mild forms of covid-19 and a favorable evolution. prognosis is much better in children compared to in adults, yet asymptomatic carrier transmission is presumed to be more common among the pediatric population. 73 nevertheless, with the progression of the pandemic, the cases in children might change in the future. this review highlights that even if covid-19 is rare in children, asymptomatic sars-cov-2 infection is more frequent than in adults. collecting further high-quality evidence is essential to understand covid-19 in children and to determine the most efficient case management strategies. infection prophylaxis through isolation of infected children is essential, involving proper monitoring, early detection of disease complications, and the opportunity for on-time treatment and limiting secondary spread. being caught up in a pandemic involving the "sword of damocles" and a "crown" of sars-cov-2 proteins, children might be a key element in the battle. risk management and healthcare policy is an international, peerreviewed, open access journal focusing on all aspects of public health, policy, and preventative measures to promote good health and improve morbidity and mortality in the population. the journal welcomes submitted papers covering original research, basic science, clinical & epidemiological studies, reviews and evaluations, guidelines, expert opinion and commentary, case reports and extended reports. the manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use. visit http://www.dovepress.com/testimonials.php to read real quotes from published authors. submit your manuscript here: 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this work. key: cord-016720-hgpnaoe7 authors: tremblay, richard e. title: disruptive behaviors: should we foster or prevent resiliency? date: 2005 journal: resilience in children, families, and communities doi: 10.1007/0-387-23824-7_3 sha: doc_id: 16720 cord_uid: hgpnaoe7 nan by scientists become buzz words, they can confuse more than clarify. sars and belly buttons appear to be concrete, objective observations, but what is "resilience"? my main area of research has been the development of disruptive behavior from childhood to adulthood, and i have focused more specifically on physical aggression. when i started to study the development of disruptive behavior, without being clearly conscious of the fact, i was somewhat following a social learning approach (e.g., bandura, 1973) . with a group of colleagues, i initiated a longitudinal study to understand how some kindergarten children from poor inner-city areas became "delinquents" while others did not. to use the term that became a buzz word in the late 1980s, i was looking for the factors that could explain the "onset" of delinquency (tremblay, pihl, vitaro, & dobkin, 1994) . i probably had in mind that some were "resilient" with regard to the bad influence of peers or to the surge of testosterone during adolescence (e.g., schaal, tremblay, soussignan, & susman, 1996; tremblay, mâsse, vitaro, & dobkin, 1995; vitaro, tremblay, kerr, pagani-kurtz, & bukowski, 1997) . it was certainly part of my thinking that parents could be both protective and risk factors, since a large part of the study was meant to assess the quality of the parent-child interactions throughout the elementary school years (e.g., . but i clearly had no idea of the conclusions i would come to 15 years later. in fact, when we started to see that things were not what we expected they would be, my reaction was far from open-minded. i still remember a meeting, probably in the fall of 1988, when my colleague marc leblanc, a criminologist who had never studied humans younger than 12 years of age, described the results of the analyses he had done of the self-reported delinquency questionnaire we had given to the 1,037 boys we had been following since their kindergarten year. we were asking them if they had ever exhibited any of 27 "delinquent" behaviors, and if they answered "yes," at what age that particular behavior had occurred for the first time. the boys' self-reports were indicating relatively high rates of "delinquency" in that sample from schools in low socioeconomic areas. we had started to ask these questions concerning "delinquent" acts at 10 years of age because we were hoping to catch them before they initiated (onset) their delinquent activities. there is in fact a law in canada that a child cannot be deemed a "delinquent" before 12 years old! we of course expected that some would break that law, but since they were only 10 years old, i was worried that they did not really understand the questions, or that they simply were having fun making us believe that they were doing the bad things that they were seeing their older brothers and neighbors doing. in other words, i had the impression that we were not getting reliable reports of their true behavior. with the 10-year-olds, we were using a questionnaire that had been designed to study delinquent behavior in adolescents, and i was saying to my criminologist colleague, who appeared to be coming from another planet, that he should not take these answers too seriously. it worried me even more when he showed us the results concerning the age at which the boys were saying they had started to commit these "delinquent" acts (the "age of onset" concept). the colleague who came from the world of adolescent and adult criminals was telling us that some 10-year-old boys were reporting that they had started, at age 4 and 5, to use weapons in fights, to steal goods worth more than $100, as well as to steal following breaking and entering. i distinctly remember my outrage. how could he be so naïve and believe that he was getting reliable answers? not only were we using with 10-year-olds an instrument created for adolescents, but we were asking them to recall when they had started to do these things that we expected would start later. how could 10-year-olds remember what they were doing at 4? there were few boys who were reporting onset of these "serious" "delinquent" behaviors at age 4, but this was proof that, at least some of them did not understand the questions we were asking them, and thus they were still much too young for that self-reported delinquency instrument. i strongly appealed to him not to report these data, especially the ones on age of onset, since it would discredit the whole study. well, at least a few reviewers and an editor of a serious scientific journal had a less sanguine reaction than i had, and the results were eventually published . but, as with most of our great scholarly publications, it did not get much attention (eight citations up to october 2003) , and thus my fear of the longitudinal study being discredited was, in hindsight, exaggerated. i certainly could not foresee at that time that 10 years later we would be publishing results that would be much more outrageous. the word "resilience" has spread in the world of psychology and psychiatry like an epidemic. we do not know exactly what it is, but it is a nice word, it appears to refer to something concrete that we would all like to have, and the epidemic process appears to be working, as people who have been in contact with it use the "resilience" word. the best sign that the "resiliency" epidemic knows no frontier is that france has been severely hit, although there is relatively little contact between french psychologists and anglo-saxon psychologists. as i write these words in september 2003, a large proportion of the inhabitants of france seem to be attributing their ups and downs in life to their "resilience," or lack of (tisseron, 2003) . books on "resilience" are instantaneous best sellers. every television and radio program dealing with human behavior uses the concept to explain all that goes well or goes wrong. every health-minded french citizen wants to know how he can increase his "resilience"; and every psychologist, psychiatrist, counselor, nutritionist, chiropractor, massage therapist, physiotherapist, osteopath, acupuncturist, and so on, is selling the magic formula. i agreed to write this chapter because i wanted to reflect on this fad, and thought that i could possibly help in understanding what we are talking about. however, i must admit that as i write these words i have not closely followed the debates concerning the concept of "resilience," and i am far from being certain what people mean when they are using the word. i read that werner and smith (1982, p. 36 ) used webster's new collegiate dictionary definition of resilience: 1. the capability of a strained body to recover its size and shape after deformation caused especially by compressive stress. 2. an ability to recover from or adjust easily to misfortune or change. according to murray (2003) , participants at the 2003 american psychological association annual meeting were being asked to take home the message that "resilience is not something we are born with-it's a set of learned behaviors, and it takes strategizing to build." intuitively, the concept appears to apply relatively well to some physical illnesses, and some mental illnesses. an illness appears at a certain point in time (onset), after the person has been attacked, for example, by a virus or a psychologically traumatic event. some individuals will become ill and others will not. those who do not become ill can be considered resilient. among those who become ill, some will not recover their healthy state, while others will. the "resiliency" label also appears to be applied to the latter. one can try to build resiliency with regard to some viruses and some trauma, for example, by taking vitamins and following the apa practice directorate's public education campaign "road to resilience"! these efforts to increase resiliency can be considered preventive interventions. however, it seems very likely that humans are born with individual differences in resilience regarding attacks from viruses and traumatic events. this developmental perspective concerning physical illnesses and some mental illnesses (e.g., depression) seems to work well. it is very obvious that health generally declines with age. overall, children and adolescents are much healthier than adults, and young adults are much healthier than older adults. thus, except for illnesses that we are born with, illnesses "onset" at a certain age. however, some humans are less ill than others throughout their lives, and some appear to simply die of old age, after a healthy life. although they live in the same environment as others who become miserably sick and die young, their bodies resist the invasions of bacteria, microbes, and viruses. some smoke like chimneys and die without a trace of cancer, others drink like sponges and celebrate their 100 th anniversary standing straight and tall while listening to the crowd sing "god save the queen." these fortunate people have been labeled "resilient" after the fact. in spite of the adversity that they had to endure, or that they brought upon themselves, they did not lose their health, or if they did, it was momentary, and they bounced back. like a resilient piece of rubber, they bounced back to their original healthy state after having been hit by an agent that creates an illness. how well does this perspective apply to disruptive behaviors? disruptive behavior generally refers to three sub-groups of behaviors: physical aggression, hyperactivity (intense motor activity) and oppositional behavior. i believe that most of the work on these three topics, until recently, was based on the idea that children start to exhibit these behaviors (onset) as they grow older. for example, the classic work of bandura, ross, and ross (1961; see also bandura, 1973) on aggression indicated that children learn to physically aggress others by imitation. the more they witness physical aggression, the more likely they are to learn to use it. this is why television would apparently be such a powerful cause of the physical aggression we see in our schools and our neighborhoods. it appears clear that physical aggression on television has substantially increased since television was made available to the public more than half a century ago, and each new generation of youth from industrialized countries has apparently been learning to physically aggress more than the previous one with the increase of physical aggression on television (eron, 1982; huesmann & eron, 1986; johnson, cohen, smailes, kasen, & brook, 2002) . obviously there are many who do not use much physical aggression, and those would be children who were either not exposed to violent television or who for some reason were resilient with regard to the social learning mechanisms of aggression through television viewing. since children would also learn to physically aggress from aggressive parents, peers, and neighbors, those who were exposed to these social learning factors and did not learn to physically aggress would also be considered resilient. the work on oppositional behavior indicates a similar developmental pattern. according to at least three decades of observational work on children's aversive behaviors, they learn to be oppositional because their parents use inappropriate parenting behaviors (patterson, 1982; patterson, reid, & dishion, 1992) . one would also expect that oppositional behavior is learned through social learning, and that peer influence and television play an important role, but i can't recall any empirical work done along these lines. on the other hand, although hyperactivity is strongly correlated to physical aggression and opposition (farrington, loeber, & van kammen, 1990; lahey, mcburnett, & loeber, 2000; nagin & tremblay, 1999) , i have not seen any theory linking hyperactivity to television content or peer imitation. because prescriptions for ritalin tend to reach a peak for 9-to10-year-old children (romano, baillargeon, wu, robaey, & tremblay, 2002) , one could hypothesize that, like aggression and opposition, hyperactivity is something you catch not long after you enter school. however, there have been suggestions that hyperactivity precedes antisocial behaviors such as aggression, and would even be one of the causes of antisocial behavior (e.g., farrington et al., 1990; moffitt, 1993) . thus, if the development of physical aggression, opposition, and hyperactivity was like an illness that starts at a given point in time following an exposure to specific causal factors, the "resiliency" model would posit that some who are exposed get it, while others who are also exposed do not get it. i would argue that we should talk of "resilience" only if most of those who are exposed get it. the resilient ones would be a minority. on the other hand, if it is only a minority of those who are exposed who get it, then the "in" word should be "vulnerable." unfortunately, the development of physical aggression does not appear to follow the traditional model of an illness. i believe that we now have enough evidence to confirm that physical aggression, opposition, and hyperactivity are behaviors that appear during infancy in all normally developing children. clearly, there is much inter-individual variability in the frequency of these behaviors, but infants do not appear to need to be exposed to violence on television, nor to be physically abused by their parents to initiate (onset) hitting, kicking, pushing, pulling, and biting others when angry or when they want to have something. these behaviors start at the end of the first year after birth, and humans appear to be at their peak in frequency of physical aggression between 24 and 42 months after birth (see tremblay, 2003; and figure 3-1) . the same process appears to apply to opposition and hyperactivity. children do not need to learn to say no nor learn to throw tantrums (e.g., goodenough, 1931; potegal, 2000) . data from a longitudinal study in belgium indicates that the developmental trajectories in temper tantrums are very similar to the physical aggression trajectories (sand, 1966; tremblay & nagin, in press ). children also do not need to learn to run. as soon as they start to stand firmly on their feet, they propel themselves on fast forward, using their legs and feet to keep going without stumbling, which they often do. if humans are at their peak in frequency of physical aggression and opposition during toddlerhood, they are also at their peak in frequency of running. this reminds me of an italian colleague who once came to my house and after having observed squirrels in the garden said in amazement that these animals never walk. indeed, young children are like squirrels, they run. and parents, rather than teaching them to run say many times a day "don't run, don't run." at the 2002 meeting of the international society for research on aggression, shaw, lacourse, and nagin (2002) presented trajectories of hyperactivity during early childhood that matched almost perfectly the trajectories of physical aggression during that period. in summary, disruptive behaviors such as physical aggression, opposition, and hyperactivity are at their peak in frequency during the toddler years. the expression "the terrible twos" probably stuck because it summarizes a phenomenon that all those who have spent some time with young children recognize. from the developmental trajectory work on these behaviors, which started only a few years ago (see nagin & tremblay, 1999) , it does not appear that there is any substantial increase in frequency later on in development for any statistically significant group of children (e.g., broidy et al., 2003; coté, tremblay, nagin, zoccolillo, & vitaro, 2002; shaw, gilliom, ingoldsby, & nagin, 2003) . thus, onset occurs in early childhood long before exposure to violent television, deviant peers, and demanding school performance. and if onset is universal, there are no "resilient" children (in the sense of children who would not exhibit onset of physical aggression, opposition, and hyperactivity) except possibly children who are physically sick to the point that they don't have the energy to do what normal children do. i have come to the conclusion that what we call disruptive problems are in fact resilience problems, but in the opposite meaning to the one given by "modern" psychology and psychiatry. in fact, after following the development of children for 20 years, i am simply saying what thomas hobbes (1641/1998) stated very clearly almost 400 years ago in his insightful treaty on social life and how humans become citizens: "an evil man is rather like a sturdy boy." disruptive school children, adolescents, and adults are resilient children, they have resisted the socialization process, they remain in their original form. in fact they all eventually become less physically aggressive, less oppositional, and less active, but compared to others they behave more like children, they have remained, more than others, in their "primitive" state. if in the physical illness domain a resilient individual is one whose physiology resists longer to the wear and tear of biological life, in the domain of disruptive behavior the resilient individual is one who is resistant longer to the socialization pressures. the socialization challenge lies in keeping the energy of the toddler years while channelling them so that they fit in the social fabric. some children are born with a biological makeup that will easily bend to the pressure of the environment. yes, they hit, and kick, and run, and say no, but they quickly learn to inhibit these behaviors when they realize that when you hit you may be hit back, when you run you fall and hurt your knees, and when you say no you get a frowning face rather than a smiling face. other children are born much more "resilient", that is, harder to mold into the social fabric. to use the analogy that steve porges uses, they are born with a turbo motor (e.g., porges, doussard-roosevelt, portales, & greenspan, 1996; suomi, in press ). when they want something they will cry until they get it, they will run until they catch you, and they will hit you if you don't comply. from day one they are those on the high-level trajectories of physical aggression, hyperactivity, and opposition. they need a very strong environment to get hold of themselves and learn that they must take into account those they are interacting with. helping these children learn to "self-regulate" and not disrupt their social environment will be more of a challenge. fortunately in most cases, and unfortunately in other cases, nature has evolved in such a way that children with turbo motors are more likely to have parents with turbo motors (e.g., caspi et al., 2002; dionne, tremblay, boivin, laplante, & pérusse, 2003; lahey, piacentini, mcburnett, & stone, 1988; rowe & farrington, 1997) . in the fortunate cases, these parents have learned to self-regulate and they will have both the energy and the skills to create an environment which will be appropriate for learning to self-regulate. in the unfortunate cases, the parents have not learned to self-regulate, and the environment they offer the child is so chaotic that the child will, like his parents, be "resilient" with regard to their erratic socialization pressures. however, although trajectories appear to be set early (see figure 3-1), we must realize that these trajectories are terrible simplifications of everyday behavior. the best analogy is the dow-jones index that investors look at everyday. if we had a daily index of a child's frequency of oppositional behavior or physical aggression, we would see that from day to day it goes up and down, as if it was completely unpredictable. you start seeing some kind of logic only when you step back and look at trends over months and years. the trajectories of disruptive behaviors must be seen in this perspective. children on the high trajectory of physical aggression are not getting up every morning and hitting everyone they meet during the day, and those on the low trajectory are not spending their days saying yes to all that is asked of them and never pushing others around. we are all born with a motor made to survive in the jungle, and to adapt somewhat to the social environment we are in. successful socialization provides a veneer over the jungle fabric. i am always amazed to see that this veneer is sufficient to generate a relatively peaceful environment on the street, in public transportation, at the job. but we are all made of that resilient fabric which will unleash the tiger in us if we feel that we are in danger, or if we are prevented from getting something we strongly desire. this is why, if we listen to all the news that can be heard in one day, we will hear daily that someone who has always been a peaceful citizen, a good employee, and a supporting spouse killed his wife and children, or his boss and fellow employees. this is also the reason why prevention by early intervention will have long-term impacts, but will not eradicate the risk of the appearance of disruptive behaviors. we need societies that are constantly aware of the importance of situational prevention. the social fabric needs constant lubrication, otherwise the veneer of some becomes scratched and the resilient fabric plays its role. if all adults are at risk of being at some point in time "robust children," as hobbes would say, we can imagine how difficult it is to "behave" for children who did not learn, or rather learned less well when they were young, how to behave in a socially accepted way. can we help these "resilient" children once they are in the school system? my usual answer to this question is why wait until they get to school? we know that the factors that handicap the socialization process are already being put in place during pregnancy. we know that there are interventions that start during pregnancy and that show long-term impacts (olds et al., 1998) . we know that some interventions during the preschool years have also shown long-term impacts (e.g., campbell, pungello, miller-johnson, burchinal, & ramey, 2001; campbell, ramey, pungello, sparling, & miller-johnson, 2002; schweinhart, barnes, & weikart, 1993) . why wait until they are in school? i guess the answer should be that we are not waiting, that we are providing programs during pregnancy and the preschool years, but that these programs are not reaching all the children that need them, or that these programs are not sufficient for the most "resilient" children. thus, support programs are needed during the elementary school years. the montreal longitudinal experimental study was designed to test to what extent a multimodal intervention for disruptive boys in kindergartens of low socioeconomic area schools would have a longterm impact. when the intervention was planned in the early 1980s, parent training and social skills training were perceived as the alternative to the traditional psychodynamic approach to treating disruptive children (e.g., meichenbaum, 1977; michelson, sugai, wood, & kazdin, 1983; patterson, reid, jones, & conger, 1975) . most experiments targeted either parenting skills or children's social-cognitive skills (e.g., lochman, nelson, & sims, 1981; patterson et al., 1975) . the interventions were also generally aimed at children older than 10 years of age and had a relatively short duration, usually less than 1 year, and often less than 6 months. to increase the chances of having a positive impact on the resilient fabric we decided to target younger children, as well as parents, to include well-adjusted peers, and to maintain the intervention for 2 years. the parent-training component was based on a model developed at the oregon social learning center (patterson, 1982; patterson et al., 1975) . the procedure involved (a) giving parents a reading program, (b) training parents to monitor their children's behavior, (c) training parents to give positive reinforcement for prosocial behavior, (d) training parents to punish effectively without being abusive, (e) training parents to manage family crises, and (f) helping parents to generalize what they had learned. having the professional who worked with a family meet the boy's teacher to discuss his adjustment and means of helping him complemented this component. teachers, however, were generally not able to spend much time discussing teaching strategies for one child, and resources to implement a structured teacher-training program were not available. work with parents and teachers was carried out by two universitytrained childcare workers, one psychologist, and one social worker, all working full-time. the professionals were trained for 10 months before the start of the program and received regular supervision for the duration of the experiment. each of these professionals had a caseload of 12 families. the team was coordinated by a fifth professional who worked on the project part-time. work with the parents was planned to last for 2 school years with one session every 2 or 3 weeks. the professionals, however, were free to decide that a given family needed more or fewer sessions at any given time. the maximum number of sessions given to any family was 46 and the mean number of sessions over the 2 years was 17.4, including families that refused to continue. the social skills training component was implemented in the schools. one or two disruptive boys were included in groups of three to five peers who were identified by teachers as highly prosocial. the same group of professionals who conducted the parent training offered the social skills training during lunchtime. to create a team approach, different professionals were responsible for the parent and child training with each family. the two professionals responsible for a given family met regularly to discuss treatment strategy. the multidisciplinary team of professionals also met weekly to study a few cases. this helped maintain a consistent treatment approach. for the social skills training component of our intervention, two types of training were given to the disruptive boys within the small group of prosocial peers in school. during the first year, a prosocial skills program was devised, based on other programs (cartledge & milburn, 1980; michelson et al., 1983; schneider & byrne, 1987) . nine sessions were given on themes such as "how to make contact," "how to help," "how to ask why ," and "how to invite someone in a group." coaching, peer modeling, role playing, and reinforcement contingencies were used during these sessions. the program was aimed at self-control during the second year. using material from previous studies (camp, bloom, hebert, & van doorminck, 1977; goldstein, sprafkin, gershaw, & klein, 1980; kettlewell & kausch, 1983; meichenbaum, 1977) , 10 sessions were developed on themes such as "look and listen," "following rules," "what to do when i am angry," "what to do when they do not want me to play with them," and "how to react to teasing." coaching, peer modeling, self-instructions, behavioral rehearsal, and reinforcement contingencies were also used during these sessions. from the 1,037 boys assessed in kindergarten, those above the 70 th percentile on the kindergarten teacher-rated disruptive behavior scale were randomly allocated to a treatment or control group. at the end of the 2-year intervention and up to the second year after the intervention, no significant differences were observed between the treated and the control groups. because of these disappointing results, it is likely that the follow-up of the preventive experiment would not have continued had it not been part of a longitudinal study. most preventive delinquency interventions have follow-up periods of less than 1 year (tremblay & craig, 1995; tremblay, lemarquand, & vitaro, 1999) . three years after the end of the intervention, when most of the boys were in their last year of elementary school, the annual assessments revealed statistically significant positive effects. the boys from the treatment group reported less delinquent behavior, they were rated by their teachers and their peers as being less disruptive, more of them were still in an age-appropriate classroom, and they tended to have less disruptive friends than the control group boys (mccord, tremblay, vitaro, & desmarais-gervais, 1994; tremblay et al., 1991 tremblay et al., , 1992 . assessments of the boys up to 17 years of age revealed that the intervention had long-term beneficial influences on the boys' development, but these depended on age, domain, and data source. with respect to global school adjustment, measured by being in an age-appropriate regular classroom, the intervention appeared to have a positive impact before the transition to high school and in the latter part of high school (tremblay, vitaro, nagin, pagani, & séguin, 2003) . the boys who remained in an age-appropriate regular classroom during elementary school were in a very different social and intellectual environment compared to those who were held back or placed in special classes or schools. the quality of that environment may have had beneficial effects upon other aspects of their development (e.g., self-esteem, attitudes toward school, antisocial behavior). this was confirmed by the school dropout data observed when the boys were 17 years of age: the school dropout rate for the control group was twice as high (21.6%) as the one for the treated group (10.5%) (vitaro, brendgen, & tremblay, 1999) . antisocial behavior was assessed both with self-reports and court records. the latter did not reveal any significant differences between the groups. one would have hoped that an intensive early intervention with disruptive boys would have reduced the number of boys who were officially treated by the courts as juvenile offenders. clearly, such a procedure is costly both in terms of social resources and human suffering for the boys and their families. thus, from the perspective of official delinquency, this type of intervention with these at-risk boys does not appear to have achieved its aim. however, from the perspective of selfreported antisocial behavior, the intervention reduced the number of antisocial behaviors from ages 13 to 17 vitaro, brendgen, & tremblay, 2001) . path analysis showed that reduction in disruptiveness and increase in parental supervision by age 11, as well as association with nondeviant peers by age 12, were part of a chain of events that was found to mediate the effect of the program on the initial level of antisocial behavior at 13 years. the analysis also showed that the program had an indirect effect through these variables on the growth of delinquency from 13 to 16 years of age. with developmental trajectory analyses we showed that disruptive kindergarten boys who did not participate in the preventive intervention were at higher risk of following a high-level antisocial trajectory, and less likely to be on a low-level antisocial trajectory . we also tested whether the 2-year (between 7 and 9 years of age) preventive intervention targeting the disruptive kindergarten boys and their families would deflect them to a low-level antisocial behavior trajectory during adolescence. results did confirm this hypothesis especially for physical aggression. boys from the intervention group, compared to those from the control group, were more likely to follow the lowest-level trajectory and less likely to follow high-level trajectories. we also did not observe any differences in the probability of following specific physical aggression trajectories between the boys from the intervention group and those who were not among the most disruptive in kindergarten. i believe this is the first demonstration of an intervention with disruptive elementary school children showing such a significant impact on the developmental course of physical aggression during adolescence. in fact, i have seen no evidence in the literature of any intervention with a long-term follow-up that showed a significant reduction in levels of physical aggression. these results are impressive because the intervention could have had a significant impact by simply deflecting some of the high-risk boys from a medium-level trajectory to a low trajectory. however, the results show that the disruptive boys who participated in the intervention were deflected from high-level trajectories to lowerlevel trajectories. interestingly, we did not observe a significant impact of the intervention on the developmental trajectories of theft. thus, the parent training and social skills training which was attempting to reduce disruptive behaviors such as physical aggression, opposition, and hyperactivity did not change an antisocial behavior which is considered "covert" rather than "overt" (loeber & schmaling, 1985) . taking away things from others is a behavior that starts as early as physically aggressing others (tremblay, japel, et al., 1999; tremblay, 2004) . in early childhood behavior is rarely covert, but as children become more cognitively sophisticated and learn to delay gratification, they will try to get others' possessions without confronting them directly. the best evidence of this transformation of open antisocial behavior to covert antisocial behavior is the development of indirect aggression (i.e., covert manipulative behaviors, such as spreading rumors, getting others to dislike a person, becoming friends with another person as a form of revenge, etc . . . ). as the frequency of physical aggression decreases with age, the frequency of indirect aggression increases vaillancourt, in press ). thus the socialization process does have some impact, but the resilience of the jungle fabric is such that more sophisticated ways are developed to achieve the old "primitive" goals. i have argued in this chapter that the "resilience" concept, which is possibly at the peak of its fashion, could not be applied to the development of disruptive behaviors unless we accept that it means the reverse of the meaning usually given to "resilience" by psychologists and psychiatrists, and sometimes by physical health specialists. this is because disruptive behavior is not an illness one catches and then attempts to get rid of in order to return to the initial state of health. disruptive behaviors are rather something you are born with, an initial state, and you have to work hard at getting rid of them. in fact these behaviors are so "resilient" that you never get rid of them, you simply keep them in check by constant self-regulation. if the word "resilient" is used to mean "to recover an original form or state, after having been submitted to forces that could make you lose that original state," then saying that a child who has learned not to physically aggress others is "resilient" does not make sense. the whole exercise of education and growing up is to get rid of your original state. children who do not learn not to cry and scream when they are angry are resilient, children who do not learn to talk are resilient, children who remain illiterate after having been taught to read and write are resilient. from this perspective, prevention of disruptive behavior problems should not be seen as an effort to prevent innocent young children from learning from parents, siblings, peers or television how to aggress against others or how to refuse to obey rules. prevention of disruptive behavior is, in fact, what used to be called "moral education": the process by which children learn how to behave in a way that will enable them to be accepted and even appreciated by their social environment. since children are not born socialized, it is not a state they risk losing, it is a state they need to acquire, and the later they receive the proper support (education), the less likely they are to master these very sophisticated and terribly important skills for a citizen. "i can say in my own favour that i was as a boy humane, but i owed this entirely to the instruction and example of my sisters. i doubt indeed whether humanity is a natural or innate quality." 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developmental trajectories of overt conduct problems and adhd from ages 2 to 10 trajectories leading to school-age conduct problems genetic and environmental factors influencing the expression of impulsive aggression and serotonergic functioning in rhesus monkeys résilience" ou la lutte pour la vie ( resilience or the fight for life) why socialization fails?: the case of chronic physical aggression the development of human physical aggression: how important is early childhood building a safer society: strategic approaches to crime prevention the developmental origins of physical aggression in humans early disruptive behavior, poor school achievement, delinquent behavior and delinquent personality: longitudinal analyses can disruptive boys be helped to become competent? predicting early onset of male antisocial behavior from preschool behavior the impact of friends' deviant behavior on early onset of delinquency: longitudinal data from 6 to 13 years of age do children in canada become more aggressive as they approach adolescence? the search for the age of "onset" of physical aggression: rousseau and bandura revisited the prevention of odd and cd the montreal longitudinal and experimental study: rediscovering the power of descriptions indirect aggression among humans: social construct or evolutionary adaptation impact of a prevention program on aggressive children's friendships and social adjustment disruptiveness, friends' characteristics, and delinquency: a test of two competing models of development prevention of school dropout through the reduction of disruptive behaviors and school failure in elementary school preventive intervention: assessing its effects on the trajectories of delinquency and testing for mediational processes vulnerable but invincible: a study of resilient children the author wishes to thank the following persons who have made important contributions to the research and ideas presented in this chapter: sylvana côté,éric lacourse, katia maliantovitch, daniel nagin, francisco quiazua, jean séguin, tracy vaillancourt, and frank vitaro. key: cord-274643-vjb2yt93 authors: kang, g. title: viral diarrhea date: 2008-08-26 journal: international encyclopedia of public health doi: 10.1016/b978-012373960-5.00571-2 sha: doc_id: 274643 cord_uid: vjb2yt93 viral gastroenteritis is among the most common illnesses affecting humans and has greatest impact at the extremes of age. the spectrum of disease can range from asymptomatic infections to severe disease with dehydration. intensive investigation of enteric infections in the past three decades has made it increasingly clear that viruses cause a significant proportion of enteric illnesses worldwide. in contrast to bacterial pathogens, enteric viruses cannot multiply outside their host; hence, the original inoculum into the common source determines infectivity. prevention of contamination of food and water will help control primary cases, whereas careful nursing and handwashing prevent secondary cases. acute gastroenteritis is among the most common illnesses affecting humans and has greatest impact at the extremes of age, severely affecting children and the elderly. the spectrum of disease can range from asymptomatic infections to severe disease with dehydration, which can be fatal. diarrheal disease continues to be a major cause of mortality in young children, particularly in developing countries. prior to 1972, the etiology of most episodes of gastroenteritis was unknown, and cases were attributed to a multitude of causes, including teething, weaning, diet, old age, drugs, and malnutrition, as well as infections. intensive investigation of enteric infections in the past three decades has resulted in the discovery of many new viral agents filling in the 'diagnostic gap' in diarrheal disease. with the identification of the norwalk virus, rotavirus, astroviruses, enteric adenoviruses, and other caliciviruses in the 1970s and subsequently, it has become increasingly clear that viruses cause a significant proportion of the enteric illnesses that did not earlier have a defined etiology. with improvements in sanitation and hygiene, and better standards of living, the proportion of diarrheal disease attributed to bacteria has decreased, resulting in an increase in the proportion of cases associated with viral infections. developments of new assays to identify viruses have also resulted in the ability to identify the viral etiology of episodes and epidemics of gastroenteritis. approximately 5 billion episodes of diarrhea occur worldwide annually, with virtually all children infected with the most common agents by the age of 3 years. widespread use of oral rehydration therapy in the past two decades has resulted in a significant decrease in mortality due to diarrhea, by about 50%, to 2.2 million annual deaths, occurring mainly in developing countries. infections with gastroenteritis viruses differ from bacterial enteric infections in that they affect children in both developing and developed countries, suggesting that they may also be transmitted by means unrelated to contaminated food or water. although feco-oral spread is the major route of transmission for all enteric viruses, transmission through contact, fomites, and a respiratory route has been suggested based on the recovery of these viruses from inanimate objects during outbreaks. the four distinct patterns of viral gastroenteritisendemic childhood diarrhea, outbreaks in closed communities, other food-or waterborne outbreaks among wider communities, and viral gastroenteritis in immunocompromised patients -reflect the differences in the pathogens, transmission, and host response. these have a direct bearing on strategies for prevention and control ( table 1) . the highest rates of viral gastroenteritis occur between 3 and 24 months of age. protection in early infancy is believed to be mediated by maternal antibodies, followed by acquisition of protective immunity through repeated exposure in early childhood. this pattern is seen with all viral enteropathogens. however, for the caliciviruses and astroviruses, immunity is not long-lasting, suggesting waning of immunity or lack of cross-protection between different viral strains. childhood diarrhea is best exemplified by the group a rotaviruses, but a similar pattern of infection and illness is seen with enteric adenoviruses, astroviruses, and sapoviruses. these agents infect children during the first few years of life, with first infections being symptomatic and protecting against subsequent disease. disease is caused by a limited number of specific serotypes and incidence decreases with increasing age. group a rotaviruses are the main cause of severe diarrhea in children under 5 years of age, and cause more than 130 million episodes per year throughout the world, and approximately 600 000 deaths annually. reports from europe, australia, and the united states indicate that rotavirus may be responsible for 20-60% of cases of gastroenteritis requiring hospitalization. recently, from asia, it has been estimated that 45% of gastroenteritis requiring admission is due to rotavirus, a higher percentage than previously recorded. of the 'non-group a' rotaviruses, group b rotavirus has been identified in epidemic outbreaks of severe diarrhea in adults in china and in symptomatic infections in children. outbreaks of diarrhea due to group c rotavirus have been identified in asia, europe, and south and north america, but are not common. human caliciviruses, consisting mainly of noroviruses and sapoviruses, are associated mainly with milder cases of gastroenteritis in children, causing greater than 20% of diarrheal disease in children in the community. in many studies, noroviruses are the second most common cause of gastroenteritis in children, following rotaviruses. enteric adenoviruses cause 10% of diarrheal disease in reports from developed countries and have a variable incidence of 2% to 30% depending on the region in developing countries. astroviruses were found in approximately 1% of cases, when electron microscopy was employed for detection, but with the availability of a commercial enzyme immunoassay and molecular techniques, the percentage of detection has increased in hospital and community settings to 5% to 10%. outbreaks in closed or semi-closed communities such as old-age homes, cruise ships, and hospitals are mainly due to caliciviruses. norovirus infections are a significant cause of outbreaks in adults in nursing homes and residential care facilities and can lead to an increased need for hospital care and increased mortality. nosocomial outbreaks occurring in hospitals have required the closure of wards in order to control infections. outbreaks due to noroviruses and to mixed viral infections have been reported among military personnel. outbreaks of norovirus gastroenteritis are also being recognized and are occurring with increasing frequency on cruise ships. attack rates as high as 30% have been observed among cruise ship passengers, and repeated outbreaks have continued even after cleaning and disinfection protocols were instituted on successive voyages. in addition to infections in adult patients, viral agents of gastroenteritis are an important cause of nosocomial infection in pediatric units. between 20% and 50% of cases of gastroenteritis caused by rotavirus in hospitals are considered to be of nosocomial origin, and nosocomial viral enteric infections have been documented in up to 6% of children admitted for more than 72 hours in both developed and developing countries. infections in older individuals are usually due to caliciviruses, although adenovirus infections have been documented. the prevalence and transmission of nosocomial infection may be explained by asymptomatic patients who excrete the virus and the relative resistance of these viruses to normal disinfectants. the microbiological contamination of food and water is a significant global problem. it is estimated that there are approximately 1.5 billion cases and over 3 million deaths worldwide annually. the microorganisms associated with about 50% of the foodborne disease outbreaks still go unrecognized, particularly those occurring in developing countries. the apparent failure to confirm a viral etiology in such outbreaks has been due largely to the lack of available tests, unavailability of food or water specimens, and the failure to report outbreaks of mild gastrointestinal disease. all of these factors have resulted in a drastic underestimate of the true scope and importance of foodor waterborne viral infection. the most common types of food-and waterborne viral disease are infectious hepatitis due to hepatitis a virus and acute viral gastroenteritis associated with the human caliciviruses. noroviruses, transmitted by the fecal-oral and the aerosol routes, are the most common cause of outbreaks of nonbacterial gastroenteritis in industrialized countries, but data from developing countries are lacking. noroviruses are responsible for an estimated 67% of all illnesses caused by known foodborne pathogens and for 96% of nonbacterial gastroenteritis in the united states. many outbreaks can be associated with the consumption of primarily or secondarily contaminated foods. shellfish and fruit implicated in outbreaks have been shown to be contaminated at the site where these foods are harvested or produced, whereas other foods, such as salads, cold foods, and sandwiches, have caused outbreaks after being contaminated by food handlers at the site of food preparation. shellfish, in particular oysters and clams that are raw or insufficiently cooked, is associated with noroviral outbreaks, frequently occurring because these shellfish filter contaminated seawater to feed and hence result in a concentration of virus. foodborne outbreaks due to rotaviruses, parvoviruses, and astroviruses are also occasionally reported. water is also a common source of outbreaks and may include water from municipal supplies, wells, recreational lakes, swimming pools, and ice machines. rotaviruses, caliciviruses, and some adenoviruses are important causes of waterborne disease outbreaks. post-recovery and secondary transmission are a particular concern in infections due to these agents. the main viral causes of severe gastroenteritis in immunosuppressed patients are cytomegalovirus (cmv) and epstein-barr virus (ebv), which mainly affect patients with aids and transplant recipients. cmv is a frequent pathogen in diarrhea associated with aids with cd4 counts under 100 cells/mm 3 . other viruses that produce hiv-associated gastroenteritis include astrovirus, picobirnavirus, calicivirus, and adenovirus. there is evidence of gastroenteritis due to astrovirus and adenovirus in both child and adult bone marrow transplant recipients. caliciviruses are now being increasingly recognized as a cause of chronic diarrhea in patients undergoing transplants. toroviruses have been found in association with diarrhea in immunocompromised children. criteria to define a virus as an etiologic agent of gastroenteritis include (1) the identification of the virus more frequently in study participants with diarrhea than in controls, (2) the demonstration of an immune response to the specific virus, and (3) the demonstration that the beginning and end of the illness correspond to the onset and termination of virus shedding, respectively. so far, these include human caliciviruses, rotaviruses, astroviruses, and the enteric adenoviruses. in immunocompromised patients, gastrointestinal cmv and ebv infections also cause significant morbidity. coronaviruses, toroviruses, the aichi virus, and picobirnaviruses have also been found to be associated with diarrhea in some studies, but definitive data are not yet available. similarly, in conditions such as hiv, it has been difficult to obtain definitive data on the role of enteric viruses in the causation of symptoms. the study of rotaviruses, enteric adenoviruses, and astroviruses has been facilitated greatly by the ability to propagate these viruses in cell culture, which has allowed the production of reagents for use in diagnostic studies, a better understanding of factors correlated with immunity to infection, and the elucidation of each virus's life cycle. although human caliciviruses have defied numerous attempts to propagate them in cell culture to date, recent developments in their study by using molecular biology techniques have increased our ability to diagnose and study infections due to these agents (see figure 1 ). rotaviruses are double-stranded rna viruses constituting a genus within the family reoviridae. the mature virus particles are triple layered, approximately 70 nm in diameter, and possess icosahedral symmetry. the rotavirus genome consists of 11 segments of doublestranded rna, which code for 6 structural viral proteins and 6 nonstructural proteins. of the nonstructural proteins, nsp4 is of particular interest, as it has enterotoxin-like activity and can induce diarrhea in mice. the classification of rotavirus into 7 different groups (a-g) is based on the antigenic specificity of the vp6 capsid proteins. of the 7 groups, only groups a, b, and c are known to infect humans. severe, life-threatening disease in children worldwide is caused predominantly by group a rotaviruses. variability in the genes encoding the two outer capsid proteins vp7 and vp4 forms the basis of the current strain typing of group a rotaviruses into g and p genotypes, respectively. all known g serotypes correspond with genotypes; more p genotypes than serotypes have been identified. the rapid evolution of rotaviruses by a variety of mechanisms provides one of the major challenges in epidemiological studies. these mechanisms include genetic drift, where an accumulation of point mutations generates genetic lineages leading to the emergence of antibody escape mutants, and genetic shift through gene reassortment during dual infection of a single cell. hence methods of virus typing need to be regularly monitored and updated to identify emerging novel strains of epidemiological importance. rotaviruses induce a clinical illness characterized by vomiting, diarrhea, abdominal discomfort, fever, and dehydration (or a combination of some of these symptoms) that occurs primarily in infants and young children and may lead to hospitalization for rehydration therapy. fever and vomiting frequently precede the onset of diarrhea. milder gastroenteric illnesses that do not require hospitalization are common. the highest attack rate is usually among infants and young children 6 to 24 months old. neonatal infections are largely asymptomatic. deaths from rotavirus gastroenteritis may occur from dehydration and electrolyte imbalance. the severity of diarrhea is measured by the vesikari score which includes duration and severity of diarrhea and vomiting, associated fever, and degree of dehydration. in older children and adults, rotavirus gastroenteritis occurs infrequently, although subclinical infections are common. rotaviruses also induce chronic symptomatic diarrhea in immunodeficient children. rotavirus infections can be severe and sometimes fatal in individuals of any age who are immunosuppressed for bone marrow transplantation. rotavirus infections have also been associated with necrotizing enterocolitis and hemorrhagic gastroenteritis in neonates in special-care units. recently, rotavirus antigenemia has been described early in infection in children requiring hospitalization and rna has been extracted from serum of antigenemic children and cerebrospinal fluid (csf) of children with seizures, but the clinical significance of these findings requires further investigation. rotaviruses infect the mature enterocytes on the tips of small intestinal villi, leading to villous atrophy with secondary hyperplasia of the crypts. it has been proposed that cellular damage is secondary to villous ischemia. the mechanism that induces the production of diarrhea is not well understood, although it appears to be mediated by the relative decrease of villous epithelium absorption in relation to the secretory capacity of the crypt cells, as well as the possible action of nsp4, the viral enterotoxin that has been shown to cause secretory diarrhea in rodents. there is a loss of intestinal permeability to macromolecules such as lactose, secondary to a decrease in disaccharidase in the intestine. the enteric nervous system is stimulated by this virus, leading to intestinal water and electrolyte secretion. the immunologic mechanisms responsible for protection against infection by rotavirus are still not well known. older children and adults usually have asymptomatic or mild infection unless an overwhelming infectious dose is delivered. several studies have shown that local intestinal immunity produced in response to infection protects against subsequent severe episodes of diarrhea. studies in children indicate that the antibody response in primary infection is homotypic with subsequent infections producing a broadening of the immune response. laboratory procedures for diagnosis of rotavirus include electron microscopy (em), passive latex agglutination assays (la), electropherotyping using polyacylamide gel electrophoresis (page), enzyme-linked immunosorbent assays (elisa), and reverse transcription-polymerase chain reaction (rt-pcr). in recent years, elisa has become the method of choice for screening. early studies on strain surveillance identified rotavirus serotypes using neutralization assays. monoclonal antibodies to specific serotypes were used. new methods have greatly improved data on circulating rotavirus strains and include multiplex rt-pcr based genotyping based on vp7 and vp4 genes, hybridization assays, and nucleotide sequencing. the term 'calicivirus' is derived from the latin calyx, meaning cup or goblet, and refers to the cup-shaped depressions visible by em. these cuplike depressions are more prominent in some strains, particularly the sapoviruses, leading to the characteristic star of david appearance from which caliciviruses get their name. caliciviruses (family caliciviridae) are a group of nonenveloped, icosahedral viruses with a single-stranded, positive-sense rna genome. the genome is 7.5 to 7.7 kilobases in length and has three open reading frames (orfs). noroviruses can be genetically classified into five different genogroups (gi, gii, giii, giv, and gv) which can be further divided into different genetic groups or genotypes. genogroup ii, the most prevalent human genogroup, presently contains 17 genotypes. genogroups i, ii, and iv infect humans, whereas genogroup iii is associated with bovine infections and genogroup v has recently been isolated in mice. noroviruses were named after the places where the outbreaks occurred. recently a numeric classification system has been proposed based on numbering genogroups with roman numerals and genotypes with numbers. for example, the genogroup ii norovirus, lordsdale virus, is a member of genotype 4, and therefore classified as a gii.4 norovirus. gii.4 viruses account for the majority of adult outbreaks of gastroenteritis and often sweep across the globe. sapoviruses, previously called the classical caliciviruses, based on their morphology, have 8 human genotypes in 5 genogroups, and have a similar system of strain designation as noroviruses. the incubation period for caliciviral infections is short, about 24 to 48 hours, and the mean duration of illness is 12 to 60 hours. nausea is prominent, with vomiting, nonbloody diarrhea, and abdominal cramps occurring in most cases. these symptoms are experienced by all age groups, but diarrhea is relatively more prevalent among adults, whereas a higher proportion of children experience vomiting. from 25% to 50% of affected persons also report headache, fever, chills, and myalgias. adults have died during illness caused by noroviruses, presumably from electrolyte imbalance. late sequelae have not been reported, but the elderly often report persistence of constitutional symptoms for up to several weeks. routes of transmission that have been documented include water, food (particularly shellfish and salads), aerosol, fomites, and person-to-person contact. infectivity can last for as long as 4 days after resolution of symptoms. presymptomatic shedding has been suspected on epidemiologic grounds but has not been proved in volunteer studies. other than a murine norovirus, noroviruses have not been grown in culture, making studies of pathogenetic mechanisms difficult. in studies carried out on volunteers, infection by calicivirus produces an expansion of the villi of the proximal small intestine. the epithelial cells remain intact with a shortening of the microvilli. the mechanism by which diarrhea is produced is unknown. in volunteer studies, infection by the norwalk virus induces a specific igg, iga, and igm serum antibody response, even in persons with preexisting antibodies. after norovirus infection, immunity appears to last for a few months but there is little or no evidence of long-term protection. volunteer studies conducted in the 1970s also suggest that some people are resistant to norwalk virus challenge. recently two host factors have been identified that may contribute to this resistance to infection. in volunteer studies homozygous recessives for the a (1,2) fucosyltransferases gene (fut2), who do not express h type-1 oligosaccharide were resistant to infection with norwalk virus (nonsecretors). there is also evidence to suggest that different norovirus strains bind to different blood group antigens. data on sapovirus infections and immune responses are not yet available. electron microscopy was initially used for identification of these viruses and continues to be used by many laboratories to screen stools for potential viral pathogens. this method is insensitive compared with molecular detection assays. currently, rt-pcr assays are the most common approach for establishing a diagnosis of norovirus infection. virus-specific primers are used to amplify conserved regions of the genome, usually in the polymerase or capsid genes. no single primer pair can detect all norovirus or sapovirus strains because of the high sequence diversity, but in most geographic regions, more than 90% of currently circulating strains can be detected using separate primer pairs for genogroups i and ii noroviruses and sapoviruses. antigen-detection elisa assays for noroviruses have been established in the last decade, but the first assays had a very narrow reactivity. more broadly reactive assays have been developed using monoclonal antibodies that recognize cross-reactive epitopes or multiple monoclonal antibodies, but are not widely used. serologic assays also have been developed to detect immune responses to infecting norovirus strains, but are used more in epidemiological studies than for diagnosis in individual patients. human astrovirus is the prototype of the astroviridae, a family of nonenveloped positive-sense rna viruses, measuring 38-41 nm. by direct em, astroviruses recovered from stool display a distinctive surface starlike appearance. the genome of astrovirus consists of positive-sense, single-stranded rna, 6.8 kb in length, organized in three orfs. all serotypes have at least three capsid proteins, p1, p2, and p3, with the p2 protein carrying the groupreactive epitopes and the p3 protein specifying serotype. astroviruses are classified into serotypes based on the reactivity of the capsid proteins with polyclonal sera and monoclonal antibodies. astroviruses can also be classified into genotypes on the basis of the nucleotide sequence of a 348-bp region of the orf2, and there is a good correlation with the serotypes. there are eight established genotypes. phylogenetic analyses have shown that it is common to find multiple astrovirus strains circulating in one region during a given period of time, and that there are also variations in the prevalent type with time, suggesting either a genetic shift or an introduction of new strains. serotype 1 is predominant in most studies, followed by 2, 3, 4, and 5. serotypes 6, 7, and 8 are rarely detected. clinically, these viruses cause similar symptoms to caliciviruses. like rotaviruses, astrovirus infections occur throughout the year with peaks in the winter months. infections have been shown to occur mainly in childhood. other studies showed that most of the cases of infection are detected in children under 5 years of age with the majority of the children being under 1 year of age. outbreaks of astrovirus infection involving children and elderly patients have been described and prolonged excretion documented in immunosuppressed, immunodeficient, and aids patients. significantly higher seroprevalence rates of astrovirus have been reported in adults exposed to contaminated water compared with a control group. the pathogenesis of the disease induced by astrovirus has not yet been established, although it has been suggested that viral replication occurs in intestinal tissue. in animal studies, atrophy of the intestinal villi is observed, as well as inflammatory infiltrates in the lamina propria leading to osmotic diarrhea. symptomatic astrovirus infection occurs mainly in small children and the elderly, which suggests both an acquisition of antibodies with increasing exposure and a reduction in antibodies with advancing age. studies in adult volunteers indicate that people with detectable levels of antibodies do not develop the illness, although epidemiological observations suggest that human astrovirus infections do not induce heterotypic immunity, as an episode of astrovirus diarrhea is not associated with a reduced incidence of a subsequent episode. em is an insensitive technique, because a high concentration of viral particles is required for detection and the typical five-or six-pointed star morphology is seen in less than 10% of particles. enzyme immunoassays have been developed including streptavidin-biotin assays for increased sensitivity of detection, and are used in most diagnostic laboratories. for epidemiological research, recently astrovirus-specific rt-pcr has been the screening method of choice. while some investigators have used highly sensitive primers targeted to conserved genomic regions coding for the nonstructural proteins and untranslated regions, others prefer to use primers from the capsid coding region which can be less sensitive but provide typing information. all adenovirus particles are nonenveloped, 60 to 90 nm diameter, with icosahedral symmetry easily visible in the electron microscope by negative staining, and are composed of 252 capsomers: 240 hexons and 12 pentons bearing fibers at the vertices of an icosahedron. the genome is linear, nonsegmented, double-stranded dna of 30 to 38 kbp. based on their immunologic properties, oncogenicity in rodents, genome, and morphology, adenoviruses are classified into six subgroups a through f with 51 serotypes. serotypes predominantly associated with human infections include h-40 and h-41, which belong to subgenus f, and occasionally h-31 in subgenus a. adenoviruses are widely recognized causes of respiratory, ocular, and genitourinary infections. however, serotypes 40 and 41 (previously called fastidious enteric adenoviruses) primarily affect the gut, contributing to 5% to 20% of hospitalizations for childhood diarrhea in developed countries. enteric adenoviruses have also been identified in pediatric gastroenteritis in developing countries. peak incidence is among children under 2 years of age, but older children and adults may be infected, with or without symptoms. incubation is between 3 and 10 days, with illness lasting 1 week or longer, longer than for other enteric viral pathogens. diarrhea is more prominent than vomiting or fever, and respiratory symptoms are often present. the lesions produced by serotypes 40 and 41 in the enterocytes lead to atrophy of the villi and compensatory hyperplasia in the crypts, with subsequent malabsorption and loss of fluids. a neutralizing antibody response made in response to infection results in control of disease and protection from reinfection with the same serotype. asymptomatic virus excretion can continue for prolonged periods even after an antibody response is documented in acute infection. although adenoviruses can be grown in culture, little data are available on the pathogenetic mechanisms of these agents of viral gastroenteritis. traditionally, adenoviruses have been detected and typed by em, virus culture, and neutralization assays. these assays are time-consuming, and more rapid serological assays including immunofluorescence, enzyme immunoassays, and latex agglutination have been developed. the rapid assays are useful in the diagnostic laboratory, but do not generally distinguish between serotypes. pcrbased techniques are more sensitive and relatively rapid, but have been shown to give discrepant results when compared with serotyping by neutralization. torovirus is a genus within the coronaviridae family, and toroviruses are known causes of diarrhea among cattle. these viruses have an envelope of 100-140 nm, with a helicoidal capsid and a single-stranded positive-sense rna genome. torovirus was detected for the first time in human gastroenteritis in 1984. they are associated with persistent and acute diarrhea in children, and may represent an important cause of nosocomial diarrhea. coronaviruses are well-established causes of diarrhea in animals and respiratory disease in humans. these viruses are between 60 and 220 nm, with helicoidal symmetry, a spiculated envelope which gives them the appearance of a crown, and a genome with positive-sense single-stranded rna. they have been identified in the stool of persons with gastroenteritis (usually children under 2 years of age), but human controls have been found to shed them with higher frequency, raising doubt about their etiologic role in human diarrhea. picobirnaviruses are small viruses, without an envelope, 30-40 nm in diameter, with an icosahedral capsid and a genome made up of two or three segments of bicatenary rna. reports from brazil documented human cases of diarrhea caused by picobirnavirus, which had been thought to be a cause of diarrhea only in animals. the importance of this pathogen is unknown, but it has been found in association with hiv and cryptosporidium-infected individuals. aichi virus, in the genus kobuvirus, was first recognized in 1989 in oyster-associated nonbacterial gastroenteritis in humans. aichi virus appears to morphologically resemble astroviruses when examined by em. recently aichi virus was isolated from pakistani children and from japanese travelers with gastroenteritis returning from tours of south-east asian countries. twenty-three percent of children under 2 years of age with gastroenteritis of unknown etiology were antigenpositive for pestivirus, compared with 3% of controls, in a study on an american indian reservation. no further studies have been done on the role of this agent in gastroenteritis. parvovirus-like particles have been identified by em in stool specimens of both well and ill persons in britain. the relationship of these particles to disease is unclear, but they have been associated with shellfish-related outbreaks of gastroenteritis. enteroviruses cause a wide spectrum of disease, in which gastroenteritis plays a minor role. although the entry of polio, coxsackie, echo, or other enteroviruses through the gut may cause incidental mild diarrheal symptoms, the spread of the virus through the bloodstream to other organs (e.g., central nervous system, heart, pleura, pancreatic islets) produces major disease manifestations. reports have linked some enteroviruses to illnesses in which diarrhea was the sole symptom; nevertheless, an outbreak or case of gastroenteritis should not be attributed to an enterovirus merely because it was isolated in the stool of an affected person. treatment of viral gastroenteritis is symptomatic, and its aim is to prevent or treat the dehydration secondary to the disease. dehydration is assessed using blood pressure, pulse, heart rate, skin turgor, fontanelle depression, mucous membranes, eyes, extremities, mental status and activity, urine output, and thirst. assessment of dehydration, particularly in children in community studies or by field workers, relies on lethargy, restlessness, appearance of eyes, skin turgor, and feeding/thirst. fluid and metabolic imbalances must be assessed and corrected. the most important factor predicting adverse outcome of viral gastroenteritis is delay in fluid and electrolyte therapy. clinically significant dehydration can occur within 6 hours of onset of illness, especially during primary infection in children. malnutrition, malignancy, and immunodeficient states predispose to a more severe episode of illness or unremitting diarrhea that can persist until the underlying condition is corrected. oral rehydration therapy is recommended for preventing and treating early dehydration and continued replacement therapy for ongoing losses. intravenous therapy is required in severe dehydration, shock, and decreased consciousness. in children, age-appropriate diet should be continued during oral rehydration and following intravenous rehydration. anti-emetics, anti-diarrheal agents, and antibiotics should not be given to children, although anti-emetics and anti-diarrheals may be used in adults. studies have shown that antirotavirus immunoglobulin as bovine hyperimmune colostrum or human milk may decrease the frequency and duration of rotavirus diarrhea. probiotics such as lactobacillus casei gg and saccharomyces boulardii reduce the frequency and duration of diarrhea. racecadotril, an enkephalinase inhibitor, has been shown in some studies to be useful in treating rotaviral diarrhea in children. zinc supplements have been suggested to reduce severity and duration of illness. preventive measures can limit the number of episodes of viral gastroenteritis both within the home and in institutions. diaper-changing areas should be separate from food preparation areas. diapers should be disposed of directly in the changing area and should be placed in closed bags. hands should be washed after contact with soiled diapers and clothing. interruption of transmission of the infection is extremely important, especially in hospitals and centers that care for small children. therefore, it is necessary to reinforce hygiene measures, such as handwashing, and clean all surfaces with suitable disinfectants. as viruses do not replicate outside a host, decreasing the potential inoculum is key to preventing further infection of susceptible hosts. further preventive measures in childcare facilities and hospitals include isolation and cohorting of ill children. asymptomatic infections probably also play an important role in the spread of infection. studies with vaccines against group a rotavirus began in 1982. the first vaccine developed was the tetravalent human-rhesus reassortant vaccine, which induces protection against the four main rotavirus serotypes, g1-g4. efficacy studies showed a reduction in the appearance of severe gastroenteritis caused by rotavirus in vaccinated children, and the vaccine was approved in the united states in 1998. however, the detection of an increase in the risk of intussusception after vaccination led to its suspension. in 2006, two licensed vaccines became commercially available. these are rotateq, a live oral attenuated pentavalent vaccine from merck which is recommended by the cdc advisory committee on immunization practices to be given at 2, 4, and 6 months with the last dose administered no later than 32 weeks, and rotarix from glaxosmithkline, a human strain derived monovalent live oral vaccine given in two doses at 2 and 4 months. rotateq is licensed in the united states and rotarix in many countries in europe and south america. these vaccines need to be evaluated in settings where there is marked diversity of rotaviruses and infection occurs at a younger age, as in developing countries. owing to the high cost of these vaccines, vaccine manufacturers in developing countries have initiated the process of formulating and testing vaccines based on local strains, which may address the issues of cost and heterotypic immunity in settings where different viruses circulate. dna-based and virus-like particle vaccines may also provide an alternate method of prevention in the future. studies on virus-like particle-based vaccines against norwalk virus have also been initiated with capsid proteins expressed in plants inducing an antibody response in experimental models. however, these potential vaccines are still in preclinical development. in summary, viral gastroenteritis is a major cause of morbidity in developed countries and mortality in developing countries. hygiene is the first preventive step in viral gastroenteritis and rehydration is the key to management of clinical illness. the range of organisms that can cause gastroenteritis is immense and vaccines will be important in reducing the impact of childhood gastroenteritis. also: adenoviruses; arboviruses; enteroviruses foodborne illnesses: overview infectious diarrhea in developed and developing countries viral gastroenteritis: perspectives in medical virology foodborne viruses: an emerging problem enteric viruses of humans and animals in aquatic environments: health risks, detection, and potential water quality assessment tools gastroenteritis viruses: an overview probiotics for children: use in diarrhea human astrovirus diagnosis and typing: current and future prospects norovirus disease: changing epidemiology and host susceptibility factors viral infections of the gastrointestinal tract probiotic therapy of intestinal inflammation and infections clinical trials of rotavirus vaccines in europe -national institute of diabetes and digestive and kidney diseases s h wedner and d a ross, london school of hygiene and tropical medicine, london, uk 2008 elsevier inc. all rights reserved. micronutrient deficiencies -most notably vitamin a, zinc, iodine, and iron deficiencies -are a major public health problem globally, with low-income countries in africa and asia carrying the highest burden of disease. young children and pregnant and breastfeeding women are the main groups affected, because their relative requirements for micronutrients are higher and thus the impact of deficiency is more severe than in other population subgroups. micronutrient deficiencies have also been described as hidden malnutrition, as subnormal levels of key: cord-272125-dez1nzg4 authors: jartti, t.; kuusipalo, h.; vuorinen, t.; söderlund‐venermo, m.; allander, t.; waris, m.; hartiala, j.; ruuskanen, o. title: allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children date: 2010-10-26 journal: pediatr allergy immunol doi: 10.1111/j.1399-3038.2010.01059.x sha: doc_id: 272125 cord_uid: dez1nzg4 jartti t, kuusipalo h, vuorinen t, söderlund‐venermo m, allander t, waris m, hartiala j, ruuskanen o. allergic sensitization is associated with rhinovirus‐, but not other virus‐, induced wheezing in children. pediatr allergy immunol 2010: 21: 1008–1014. © 2010 john wiley & sons a/s background: data on the link between atopy and viral wheeze are limited. aim: to evaluate the association between ige sensitization and viral infection in wheezing children. methods: this is an observational study in hospitalized wheezing children (n = 247; median age 1.6 ; interquartile range 1.1, 2.9). eighteen respiratory viral infections were studied using all available methods. a specific immunoglobulin e (ige) sensitization for common food and aeroallergens and other atopy‐related variables including total ige, blood and nasal eosinophils, exhaled nitric oxide, eczema and atopic eczema, parental allergy and asthma, number of wheezing episodes, positive asthma predictive index or asthma and use of inhaled corticosteroid were correlated with specific viral etiology. results: atopy was closely associated with sole rhinovirus etiology (n = 58) but not with sole respiratory syncytial virus, sole enterovirus, sole human bocavirus, sole other virus, mixed viral, or virus negative etiology. the number of sensitizations was particularly associated with sole rhinovirus etiology (odds ratio 4.59; 95% confidence interval 1.78, 11.8; adjusted to age and sex), followed by aeroallergen sensitization (respectively; 4.18; 2.00, 8.72), total ige level (2.06; 1.32, 3.21), food allergen sensitization (2.02; 1.08, 3.78), and nasal eosinophil count (1.52; 1.08, 2.13). conclusions: according to our data, allergic sensitization is positively linked to rhinovirus‐, but not other virus‐, associated wheezing and calls attention for studies to test rhinovirus‐associated wheezing as a part of asthma risk indices. atopy, especially aeroallergen sensitization, is an important risk factor for chronic childhood asthma (10) . aeroallergen sensitization, however, develops slowly, and it is rare during early life. thereby, it does not offer much help in the early identification of high-risk children (10, 11) . on the contrary, respiratory viral infections are common already in young infants (12) . the understanding of the link between atopy and respiratory viral infections is likely to give clinically highly relevant information that could help in designing early prevention and treatment strategies for asthma. therefore, in this observational analysis, we studied the link between allergic sensitization/several other atopy-related factors and respiratory viral infections (detected by all available modern molecular and conventional methods) in hospitalized wheezing children. we used a previously well-described cohort of 293 hospitalized wheezing children (13) . children aged 3 months to 16 years took part in a clinical trial (vinku-study) evaluating the efficacy of systemic corticosteroids for the treatment of virus-induced wheezing, which was the primary goal of the study (5, 11, 14) . the study was carried out in the department of pediatrics, turku university hospital (turku, finland) from september, 2000 to may, 2002 (study breaks were june-july, 2001 and christmas week 2001). to this analysis, we included all children (n = 247) with complete virology performed (fig. s1 ). the pre-defined inclusion criterion was acute wheezing necessitating hospitalization. pre-defined exclusion criteria included systemic corticosteroid treatment in the preceding 4 weeks, chronic disease (other than atopyrelated disease), intensive care unit treatment, or previous participation in this study. the study was commenced only after obtaining written informed consent from the parents. the study protocol was approved by the ethics committee of the turku university hospital. atopy was defined as positive immunoglobulin (ig) e antibodies to any of the common allergens (cut-off level 0.35 ku/l for codfish, cowõs milk, egg, peanut, soybean, wheat, cat, dog, horse, birch, mugwort, timothy, cladosporium herbarum, and dermatophagoides pteronyssinus; fluoro-enzyme immunoassay, cap feia, phadiatop combi ò , phadia, uppsala, sweden). aeroallergen sensitization was defined as positive ige antibodies to any of the latter 8 allergens. perennial aeroallergen sensitization was defined as positive ige antibodies to the dog, cat, or dermatophagoides pteronyssinus. birch, mugwort, timothy, and cladosporium herbarum were considered as seasonal aeroallergens. we slightly modified the asthma predictive index (api) according to the criteria for initiating daily long-term control therapy for asthma in children aged 0-4 as suggested by the heart, lung and blood institute of usa, i.e., ‡4 wheezing episodes within the past year of which at least one confirmed by a physician, or prolonged symptoms lasting ‡6 weeks and requiring symptomatic treatment >2 times per week, and in addition to either symptom criteria, ‡1 major risk factors (physician diagnosed atopic eczema or parental asthma) or ‡2 minor risk factors (allergic rhinitis, wheezing apart from colds or blood eosinophil count ‡0.40 · 10 9 /l) originally introduced by castro-rodriguez et al. (2000) (15, 16) . eczema (ever) was clinical diagnosis by a physician. it was defined as atopic eczema (ever) if specific sensitization (>0.35 ku/l) was found. data on clinical food allergies or food challenges were not collected. on admission, a nasopharyngeal aspirate sample was obtained using a standardized procedure (13) . blood samples were collected on admission and 2-3 weeks later. virus antigen detection and virus culture were analyzed using fresh samples by the department of virology, university of turku, and the samples obtained for polymerase chain reaction (pcr) assays were stored in )70°c before processing. blood counts and allergy tests were analyzed using fresh samples by the central laboratory or the turku university hospital. otherwise, sera were stored in )70°c before processing. virus culture was performed for adenovirus, influenza a and b viruses, parainfluenza virus (piv) types 1-3, rsv, enteroviruses, hrv, and human metapneumovirus (hmpv) (13) . viral antigens were detected for adenovirus, influenza a and b viruses, piv 1-3, and rsv. levels of igg antibodies specific for adenovirus, influenza a and b viruses, piv 1/3, rsv, and hbov were analyzed in paired serum samples, in addition to igm antibodies for enteroviruses and hbov (1, 2, 13, 17) . pcr was used for the detection of hrv, enteroviruses, rsv, coronaviruses (229e, oc43, nl63 and hku1), hmpv, hbov, influenza a and b viruses, adenovirus, piv 1-4, and wu-and ki-polyoma viruses. moreover, formerly non-typable picornavirus and enterovirus samples were reanalyzed by rt-qpcr with improved identification of hrv-c strains (18) . of available samples, 0/13 non-typable picornavirus samples and 1/19 (5%) enterovirus samples were hrv-c positive. hrv samples were not retested for hrv-c. non-typable picornavirus samples (rhino-enterovirus pcr positive samples that could not be typed by hybridization) were classified as rhinoviruses because all 12 such samples, which were available for sequence analysis, showed rhinoviruses. exhaled nitric oxide was measured as previously described (11) . the association analyses were performed by univariable and multivariable (adjusted to age and sex) logistic regression models. statistical significance was established at the level of p < 0.05. we used sas/stat(r) software (version 9.1.3 sp4 of the sas system for windows, sas institute inc., cary, nc, usa). of the 293 enrolled children, 247 had complete virology performed and were included in the analysis (fig. s1 ). the median age of the 247 children was 1.6 years (range 0.25, 15; 189 children were aged <3 ; 44 children were aged 3-6 ; and 14 children were aged >6 years). patient characteristics in sole virus, mixed virus, and virus-negative groups are partly shown in table 1 (full details are shown in table s1 ). allergen-specific ige sensitization was closely associated with sole hrv etiology (n = 58; fig. 1a ). log 10 number of sensitizations were particularly associated with sole hrv etiology (odds ratio 4.59; adjusted to age and sex), followed by aeroallergen sensitization (respectively, 4.18), total ige level (2.06), food allergen sensitization (2.02), and nasal eosinophil count (1.52) (p < 0.05 for all, fig. 1b , table s2 ). as allergic sensitization is rare during early life, we further tested these associations in children aged <1 (n = 57; 8 children had sole hrv infection) and <2 years (n = 146; 28 children had sole hrv infection). in children aged <1 years, the associations were either noncomputable because of small sample sizes or nonsignificant (data not shown). in children aged <2 years, total ige level (odds ratio 2.36; 95% confidence interval 1.23, 4.57; p = 0.010; after adjustments to age and gender, 2.01; 1.00, 4.05; p = 0.051), any sensitization (respectively, 3.14; 1.28, 7.71; p = 0.013), and food allergen sensitization (3.30; 1.34, 8.16; p = 0.010) were positively associated with sole hrv etiology. the latter two associations did not persist after adjustments to age and gender. no other significant associations were found. levels of eosinophils, exhaled nitric oxide, and total ige and number of wheezing episodes were negatively associated with sole rsv etiology (n = 35). log 10 exhaled nitric oxide level was particularly associated with sole rsv etiology (odds ratio 0.028; adjusted to age and sex), followed by blood eosinophil count (respectively, 0.046), number of wheezing episodes (0.095), nasal eosinophil count (0.13), and log 10 total ige level (0.37) (p < 0.05 for all, table s3 ). as allergic sensitization is rare during early life, we further tested these associations in children aged ‡1 (n = 190; 17 children had sole rsv infection) and ‡2 years (n = 101; 8 children had sole rsv infection). in children aged ‡1 year, any sensitization (odds ratio 0.14; 95% confidence interval 0.031, 0.63; p = 0.011; after adjustments to age and gender, respectively, 0.19; 0.039, 0.93; p = 0.040) and nasal eosinophil count (0.086; 0.013, 0.58; p = 0.012; after respective adjustments, 0.084; 0.012, 0.59; p = 0.013) were negatively associated with sole rsv etiology. in children aged ‡2 years, any sensitization was negatively associated with sole rsv etiology (0.087; 0.010, 0.76; p = 0.027; statistical significance did not persist after respective adjustments). otherwise, the associations were either non-computable because of small sample sizes or non-significant (data not shown). eosinophil counts and use of inhaled corticosteroid at study entry were positively associated with sole enterovirus etiology (n = 34). blood eosinophil count was particularly associated with sole enterovirus etiology (odds ratio 3.52; adjusted to age and sex), followed by nasal eosinophil count (respectively, 1.96) and use of inhaled corticosteroid at study entry (2.73) (p < 0.05 for all, table s4 ). in children aged <2 , there were 12 sole enterovirus infections. the sizes of sole hbov group (n = 12), sole other virus group (n = 8, which included: piv, n = 3; hmpv = 2; adenovirus, n = 1, influenza virus, n = 1, coronavirus, n = 1), and virus negative group (n = 13) were small. no significant associations were found between atopic characteristics and these groups (table s5-s7) . atopic characteristics were not associated with mixed viral group (i.e., >1 viruses found per patient; 87 patients; table s8 ). the following viruses were found in mixed viral infections: hrv (n = 41), hbov (n = 34), rsv (n = 31), enteroviruses (n = 30), piv (n = 18), adenovirus (n = 16), polyomaviruses (n = 10), influenza virus (n = 6), hmpv (n = 2), and coronavirus (n = 2). we show here that specific ige sensitization, particularly aeroallergen sensitization, is linked to hrv-induced acute wheezing, but not to acute wheezing induced by other viruses. this finding is in agreement with three previous studies that have connected hrv-associated wheezing to specific sensitization, nasal and systemic eosinophilia, and clinically diagnosed atopic eczema in separate reports (6, 8, 9) . moreover, hyva¨rinen et al. (2005) (19) found hrv infection to be dependent on atopy-related 7) found hrv-associated wheezing during the third year of life to be independent risk factor for asthma at age 6 , and hrv was eightfold stronger risk factor than aeroallergen sensitization. although rakes et al. (1999) (8) found link between eosinophils and hrv infection that they also reported that hrv-negative wheezing children had more often specific sensitization than hrv-positive wheezing children. hrv diagnostics are based almost exclusively on pcr. considering the tremendous sensitivity of pcr-based hrv assay, does it detect true acute infections or likely remnants from past distant infections? hrv has been detected in up to 40% in asymptomatic children (8) . it may represent a low-level infection without associated symptoms, although it is difficult to prove that a young child is totally asymptomatic. there is also evidence that positive hrv pcr finding may also represent the first sign of a developing clinical illness in about 14% to 38% of asymptomatic cases (12, 20) . there are three other arguments suggesting that hrv pcr is likely to detect true infections, whether symptoms are present or not, and argue against the suggestion that viruses detected by pcr are likely to be residual nucleic acids left over from distant infections. first, the proportion of persistent or recurrent viral infections with same hrv strain is <5% even in immunocompromised subjects (12, 21) . second, although hrv detection rates are high in asymptomatic subject, hrv, any virus and mixed viral etiology has correlated with illness severity (12) . third, hrv pcr findings have correlated with systemic cytokine responses (22) . there are several mechanisms that could explain the link between atopy and hrv infection. first, atopic inflammation may increase the expression of the major hrv receptor, icam-1 (intercellular adhesion molecule 1) (23). the increased receptor levels are likely to lead to more severe hrv infections. in agreement, atopic individuals have shown more severe illnesses after experimental hrv inoculation, although there are also contradictory reports (23, 24) . this mechanism does not apply to minor hrv group. second, t helper 2 (th 2 ) cell-polarized immune responses counteract th 1 responses such as interferon-gamma, which belongs to nonspecific defense mechanisms against viral infections (23, 24) . subjects with low interferon production have had greater susceptibility to hrv infections. third, a recent in vitro study showed that disrupted airway epithelium favoured hrv replication (25) . interestingly, damaged airway epithelium opened the way to deeper cell layers where hrv replicated the most and also increased the number of its own receptor icam-1. airway epithelium could be damaged by allergic inflammation, repeated respiratory infections, and/or by air pollution. fourth, high genetic diversity is a particular feature of hrv and makes it special from other viruses. today, 99-101 hrv serotypes and over 150 different hrv genotypes have been found (23, 26) . rhinoviruses elicit serotype-specific immunoresponses and are able to infect repeatedly with different strains. naturally, the high diversity and prevalence of hrv increase the odds that they could be associated with acute wheezing without causality. fifth, hrv-associated wheezing increases with age as does atopy. thus, the interaction between them is likely to be stronger by increasing age. therefore, we speculate that at young ages, when sensitization has not yet developed, the link may be more stronger between eosinophil levels and hrv infection. of note, the close association between enterovirus infection and eosinophilia may be explained by their phylogenetic similarity to hrv. the negative association between rsvinduced wheezing and certain atopy-related markers, such as nasal and blood eosinophils, exhaled nitric oxide, and total ige, is in agreement with three previous reports which have shown no association between rsv-induced bronchiolitis and sensitization status, eosinophil levels or presence of atopic eczema (6, 8, 9) . moreover, in two long-term follow-up studies, a history of rsv-induced bronchiolitis or lower respiratory tract infection has been unrelated to atopy status at ages 7, 11, and 18-20 (27-29) . one study even reported a reduction in skin prick test positivity at the age of 6-10 in children with a history of hospitalization for rsv-induced lower respiratory tract infection when compared to matched controls (30) . on the contrary, only one study has shown an increased association between rsv-induced bronchiolitis and sensitization to common allergens compared to matched controls at the age of 13 (31) . the negative/no association could be explained by several ways. first, rsv-affected children are typically young, median of 11 months in our study, and sensitization rates and eosinophil levels are very low during infancy. second, rsv may not be truly linked to atopy in contrast to hrv, because we did not find positive link between sole rsv infection and atopic characteristics even in older children. third, eosinophils may be protective against rsv infection as shown by domachowske et al. (1998) (32) . rsv and hrv were prominent viruses in the mixed virus group and probably had opposite effects within the group. the strength of the study was detailed virology and careful assessment of atopy status. there are also limitations. the power may not have been optimal for hbov etiology. the association between exhaled nitric oxide level and hbov showed an interesting positive tendency, and there were also wide confidence limits in the associations between sensitization variables and hbov infection. however, including also mixed viral infections (n = 46 for sole/mixed hbov infections), atopy was not associated with hbov infection (data not shown). statistical power was also low for the other sole virus and virusnegative groups. one could argue that many other factors that are associated with either wheezing or susceptibility viral infections could confound our results. however, passive smoking (p > 0.4), day-care attendance (p > 0.4), number of siblings (p > 0.2), or presence of pets (p > 0.3) did not confound the hrv-or rsvrelated results (data not shown). we have no data on the duration of breast feeding. in conclusion, susceptibility to the common cold virus, hrv, associated wheezing is likely to be an early manifestation of biased immune functions and atopic airway inflammation. as atopy was not associated with none of the other viral, non-viral nor mixed viral infections, our observations together with previous long-term follow-up studies strengthen the role of hrv infection in wheezing children as an important tool for early identification of asthma-prone children and call attention for studies to include rhinovirus as a part of asthma risk indices (33, 34) . additional supporting information may be found in the online version of this article: figure s1 . study flow chart. table s1 . the characteristics of hospitalized wheezing children with sole rhinovirus, sole respiratory syncytial virus (rsv), sole enterovirus, sole bocavirus, sole other virus, mixed viral and non-viral etiology. table s2 . the associations between atopic characteristics and sole rhinovirus infection (n = 58) in hospitalized wheezing children. table s3 . the associations between atopic characteristics and sole respiratory syncytial virus infection (n = 35) in hospitalized wheezing children. table s4 . the associations between atopic characteristics and sole enterovirus infection (n = 34) in hospitalized wheezing children . table s5 . the associations between atopic characteristics and sole human bocavirus infection (n = 12) in hospitalized wheezing children . table s6 . the associations between atopic characteristics and other sole virus infection than respiratory syncytial virus, rhinovirus, enterovirus, or bocavirus infection (n = 8) in hospitalized wheezing children. table s7 . the associations between atopic characteristics and non-viral etiology (n = 13) in hospitalized wheezing children. table s8 . the associations between atopic characteristics and mixed viral etiology (n = 87) in hospitalized wheezing children. please note: wiley-blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. any queries (other than missing material) should be directed to the corresponding author for the article. human bocavirus and acute wheezing in children clinical assessment and improved diagnosis of bocavirus-induced wheezing in children rhinovirusinduced wheezing in infancy-the first sign of childhood asthma? rhinovirus illnesses during infancy predict subsequent childhood wheezing prednisolone reduces recurrent wheezing after a first wheezing episode associated with rhinovirus infection or eczema earlylife respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma wheezing rhinovirus illnesses in early life predict asthma development in high-risk children rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. ige and eosinophil analyses rhinovirus-associated wheezing in infancy: comparison with respiratory syncytial virus bronchiolitis perennial allergen sensitisation early in life and chronic asthma in children: a birth cohort study evaluation of the efficacy of prednisolone in early wheezing induced by rhinovirus or respiratory syncytial virus serial viral infections in infants with recurrent respiratory illnesses respiratory picornaviruses and respiratory syncytial virus as causative agents of acute expiratory wheezing in children efficacy of prednisolone in children hospitalized for recurrent wheezing national heart, lung and blood institute. national asthma education and prevention program merkel cell polyomavirus dna in tumor-free tonsillar tissues and upper respiratory tract samples: implications for respiratory transmission and latency rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections teenage asthma after severe early childhood wheezing: an 11-year prospective follow-up persistence of rhinovirus and enterovirus rna after acute respiratory illness in children chronic rhinoviral infection in lung transplant recipients systemic t-helper and t-regulatory cell type cytokine responses in rhinovirus vs. respiratory syncytial virus induced early wheezing: an observational study rhinovirus and the initiation of asthma host immune responses to rhinovirus: mechanisms in asthma basal cells of differentiated bronchial epithelium are more susceptible to rhinovirus infection a diverse group of previously unrecognized human rhinoviruses are common causes of respiratory illnesses in infants respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years respiratory morbidity 20 years after rsv infection in infancy hospitalization for rsv bronchiolitis before 12 months of age and subsequent asthma, atopy and wheeze: a longitudinal birth cohort study association of an early respiratory syncytial virus infection and atopic allergy severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13 evolution of antiviral activity in the ribonuclease a gene superfamily: evidence for a specific interaction between eosinophil-derived neurotoxin (edn/rnase 2) and respiratory syncytial virus the clinical importance of rhinovirus-associated early wheezing inclusion of rhinovirus wheezing history in early life improves the sensitivity of the modified asthma predictive index (mapi) none. key: cord-023186-gqltd6u0 authors: nan title: poster sessions date: 2019-06-27 journal: pediatr pulmonol doi: 10.1002/ppul.24373 sha: doc_id: 23186 cord_uid: gqltd6u0 nan in this study. the near-fatal group accounted for 19%. the 12 months to 5 years age group accounted for 58%. female/male ≈ 1.2/1. sixtyone percent of children were from hồ chí minh city. admission to icu increased recently. dyspnea was the chief complaint, accounting for 88%. cough, wheezing, dyspnea were essential symptoms. fiftly-one percent had a history of asthma. preventer medication ownership was recorded in 34% of cases. the rate of impaired consciousness was 59.4%. 27% had a ph < 7.3% and 33% had a paco2 > 40 mm hg. chest x-rays showed hyperinflation, infiltrates and atelectasis. time of treatment was 7 days (6,11), days in icu was 2 days (2, 4). ten children were intubated, 43.5% received ncpap; 72.6% of children older than 1 year were given mgso4, 65% children were given diaphyllin, 20% children were given salbutamol and 6% children were given adrenaline subcutaneously. all intubated patients received pressure control ventilation. inspiratory pressure was 14 to 16 cmh2o to achieve tidal volume of approximately 6ml/kg, mean peep was 7 cmh2o, fio2 was approximately 80% and i/e was 1/2 -1/3. conclusions: appropriate treatment at first is crucial to lower the number of children to be intubated. mechanical ventilation still remains the last recourse in the treatment of near fatal exacerbations of asthma after mgso4, diaphyllin and salbutamol. a-132 | peanut and brazil nut sensitization profile among asthmatic patients in southern taiwan data on its importance in asian populations. the relevance of cdhr3 to childhood lung functions is also unknown. this cross-sectional study investigated the associations between cdhr3 and wheezing illnesses and lung function of preschool children in hong kong. methods: chinese children younger than 6 years of age were recruited from randomly selected nurseries and kindergartens throughout hong kong. the demographic, early-life exposures and allergy phenotypes of these preschool children were recorded by validated and modified isaac questionnaire. these children underwent incentive spirometry to measure their forced expiratory indices. their buccal swabs were collected for dna extraction and tagging single-nucleotide polymorphisms (snps) of cdhr3 were determined by taqman genotyping assays. genotypic and haplotypic associations between these snps and wheezing and lung function traits were analyzed by multivariable regression and r-package haplo.stats 1.7.7, respectively. results: the mean (sd) age of a total of 1341 children was 4.7 (1.0) years. forty-one percent of them had domestic exposure to cigarette smoking, whereas 17% and 11% had wheeze ever and current wheeze respectively. current wheeze was associated with rs6967330 and rs140154310 of cdhr3, with the respective odds ratios (ors) being 1.63 and 2.20. these two snps were also associated with frequency of wheezing illnesses over the past 12 months, with ors being 1.57 (p = 0.034) for rs6967330 and 2.14 (p = 0.024) for rs140154310. current wheeze was also associated with the 3-locus gac haplotype of cdhr3 (or, 1.54 and p = 0.048). two cdhr3, snps rs408223 and rs140154310 were associated with fev0.5, fvc and fev0.5/fvc, and the ggg haplotype was associated with fev0.5. a-174 | development and validation of an adherence questionnaire for adolescents with asthma on controller inhaled corticosteroids with asthma on ics at multiple hospitals and clinics in japan. adherence to ics medication was separately evaluated by "confidential" questions to ask frequency of "forgetting to take medicine" by nonmedical study staff. the best model to predict adherence was formed by multivariate logistic analysis. validation of the model was performed using answers to the questions from a separate group of ics-treated asthma patients of the same age. results: responses from 445 adolescents were used as development data set and those from separate 275 adolescents were used as validation data set. a 6-item logistic model was selected from the development data set. it showed good statistical fit and well discriminated poor adherence with auc at 0.814 and 0.759 in development and validation datasets, respectively. probability of adherence was calculated as propensity score in the logistic regression model and named as the pediatric asthma adherence questionnaire (paaq) score. the paaq scores for the physicians' ratings of adherence differed significantly in the hypothetical direction. the paaq may be a useful tool to evaluate adherence in adolescents with ics-treated asthma. a-208 | effect of long-term inhaled corticosteroid therapy on adrenal suppression growth and bone health in children with asthma years diagnosed as having asthma on inhaled corticosteroid therapy for more than 6 months were included as cases. children who were on oral steroids for exacerbations a week before the study, asthma with other chronic illnesses and children over 9 years old to avoid the confounding effects of pubertal growth acceleration seen at this age, were excluded. comparison group consisted of 70 age-matched children with asthma who were not on ics. heights were assessed according to their mid parental heights (mph). serum calcium, alkaline phosphatase and vitamin d levels were assayed in both groups. low dose short synacthen test was performed on cases and serum cortisol at 0, 30, 60 minutes of the test was performed to assess hpa axis function. peak cortisol level > 500nmol/l at 30 minutes was considered to have passed the test and exclude adrenal suppression. the average daily dose of ics was categorized as low, medium and high according to published literature. results: both the associations between long-term ics and growth (chi square value = 0.785, p = 0.376) and calcium levels (p = 0.88) were not statistically significant. a significant association was found between long-term inhaled corticosteroid therapy and alp level (p < 0.01) although the interquartile ranges of serum alp in both groups were within the normal range for the age. there was no statistically significant difference in vitamin d levels in both groups (p = 0.886), although vitamin d levels were deficient in 34% of cases and 41% of controls (< 50 nmol/l). interestingly suppressed cortisol levels were seen in 24% of cases. cumulative doses of ics in 70 cases were low, medium and high in 41%, 41% and 17% of children respectively. results: total antibiotic use appeared to have decreased 1 year after follow-up in a specialized asthma clinic. both the overall use (p 0.08) and the use of amoxycillin / clavulanate (p 0.01) were statistically significant. the use of amoxycillin, cephalosporins and macrolides was also found to be reduced. a statistically significant reduction was also found in the use of antihistamines (p 0.048). in terms of quality of life, a statistically significant improvement was found in the worry domain of asthma both in children (p 0.012) and their parents (p 0.013) as well as in the impact domain for parents (p 0.05). methods: in this prospective cross sectional study, we enrolled consecutive children between 5 to 15 years of age with poorly controlled asthma (partly controlled and uncontrolled as per gina guidelines) between july 2016 to march 2018. we excluded children with cystic fibrosis. the enrolled children were investigated for abpa that included total ige, aspergillus-specific ige, aspergillus-specific igg, skin prick test for aspergillus, serum precipitins, absolute eosinophil count (aec), chest x-ray, and chest ct (in selected patients). abpa was diagnosed as per recent criteria: if both of the following criteria were fulfilled: (1) total ige > 1000 iu/ml and positive skin prick test (spt) to aspergillus or aspergillus-specific ige > 0.35 kua/l; (2) at least of two of following three: presence of precipitating antibody or aspergillus-specific igg > 27 mg/l; chest radiology suggestive of abpa; and total eosinophil count > 500 cells/mm3. data were analyzed using stata 12.0. we used the receiver operating characteristic (roc) curve along with area under the curve (auc) to determine the utility of various parameters to differentiate children with abpa from those without. to determine best cut-offs, youden's index was used (sensitivity + specificity -1). results: we included 106 asthmatic children (male: female 72:34) with mean (sd) age of 10.2±2.6 years. the prevalence of abpa was 12/106 (11.3%; 95% ci, 5.2%, 17.5%). among baseline characteristics including spirometry of included children, only the presence of brownish sputum s88 | abstracts was greater in abpa children. among diagnostic criteria, all were significantly different between children with abpa and without abpa except aspergillus-specific igg and positive spt. the auc (95% ci) of rocs are shown in figure 1 . the difference between auc of total ige and aspergillus-specific ige vs. aspergillus-specific igg was significant. the sensitivity and specificity of total ige (>1000 iu/ml), aspergillus-specific ige (> 0.35 kua/l), aec (> 500/ mm3) and aspergillus-specific igg (> 27 mg/l) cut-offs as defined by diagnostic criteria was 100% and 65.9%, 75.0% and 79.8%, 91.7% and 57.0%, and 27.3% and 87.5% respectively. the best cut-off values as per youde's index of total ige, aspergillus-specific ige, aec, and aspergillus-specific igg were 1806 iu/ml, 0.63 kua/l, 786/mm3, and 16.8 mg/l, respectively with corresponding sensitivities and specificities of 75% and 76.6%; 75.0% and 88.3%; 83.3% and 74.2%; and 63.4% and 71.5%, respectively. conclusions: aspergillus-specific ige levels had the best discriminative value followed by total ige, aec, and aspergillus-specific igg for abpa in asthmatic children. the currently proposed cut-off values may not be appropriate for children. reflections and concrete proposals for action: there is need to develop childhood-specific diagnostic criteria for abpa. methods: this is a one-year retrospective study that was conducted in our pediatric intensive care unit (picu) comparing the intervention failure rate of three different noninvasive respiratory support modalities (bi-level positive airway pressure (bipap), continuous positive airway pressure (cpap) and hfnc) for infants and young children between the ages of 1 month and 2 years admitted with the diagnosis of bronchiolitis. a sample size of 137 patients was collected with a median age of 2 months. children who required hfnc were older (mean 4.5 months) than children who required bipap (2.7 months) while the mean age for children who required cpap was (2.8 months). results: hfnc carried a higher failure rate in comparison with the other two respiratory support modalities (50.6% for hfnc n39/77 vs. zero % for cpap n0/10% and 8% for bipap n4/50, p < 0.01). among the 39 patients who failed hfnc, (90%) were successfully shifted to bipap and weaned off later, while the other 4 were intubated and needed mechanical ventilation. on the other hand, all 4 patients who failed bipap were intubated and mechanically ventilated. no difference was found between the three groups in terms of gender or the causative virus. no respiratory complications or mortality was reported in the three groups. in the bipap group, oxygen requirement was significantly reduced at 24 hours from the start of the intervention and afterward in comparison with the hfnc group (p < 0.01 -0.02), although not statistically significant with the cpap group. no difference was observed in length of picu stay or hospital stay between the three groups. we did not observe any association between causative virus(es) and the number of er or pulmonology clinic visits for wheezing or recurrent bronchodilator use after discharge from the hospital. in the ba group, we found virus infection only in 25%, predominantly adenovirus, followed by rv and rsv. in 56% of the cases, streptococcus pneumoniae was confirmed in the throat swabs vs. only 33% for isolated moraxella catarrhalis. there were no other bacteria isolated in the ba group. in the cwc group, we found only in 10% of viral infections mainly hmpv, followed by adenovirus and rv. results: 105 children had been taking antibiotics before hospitalization while the remaining 180 patients were antibiotic naïve. in 44.9% of the cases, we could not prove etiological agent, while bacteria were confirmed in 41.6% and viruses in 16.2% (in 4.6%, we found combined virus and bacteria), and fungi were found in 2.5%. when dividing the cases according to prior antibiotic use, the distribution was: 38.8%, 48.3%, 15% and 2.2% for antibiotic naïve vs. 55.23%, 28.5%, 18.9% and 2.8% for the others respectively (p = 0.002). when looking at the bacterial isolates and prior antibiotic use, we did not find any significant difference regarding mycoplasma pneumoniae isolation (p = 0.36) although there was one for streptococcus pneumoniae (p = 0.015), mainly due to the standard guidelines to gps to start with penicillin antibiotic for pneumonia. as expected mycoplasma was isolated in older children, while streptococcus was mainly isolated in younger patients. mean age for children with bacterial pneumonia was 6.54 years, for those with viral pneumonia 4.34 years., for combined (viral+bacterial) 3.08 years. and for fungal pneumonia 10.42 years (p = 0.000). the values for crp were lower in cases with mycoplasma and in cases with non-compact infiltrate changes on x-rays (p = 0.002 and p = 0.000). almost 2/3 of the children have been immunized with pneumococcal vaccine (66%). the immunized patients had higher numbers of viral and lower numbers of bacterial isolates − 25.7% and 37.23% vs. non-immunized patients − 4.12% and 48.45%, respectively (p = 0.002). there was no difference in streptococcus pneumoniae isolation and vaccination status, but there was a major drop in mycoplasma isolates in vaccinated patients (6.9% vs. 32.98%, p = 0.000). for the patients with asthma only, we could not identify the microorganism in 14%, while in 48.5% and 51.2%, we found viruses and bacteria, respectively (co-infection was found in 23.26%). in 50% of children without asthma, we did not isolate the etiological agent and there was co-infection only in one case, while viral pneumonia and bacterial pneumonia was confirmed in 10.6% and 39.3% respectively (p = 0.008). all children but 3 were discharged healthy for mean 6.54 days in hospital stay. the mentioned 3 patients had severe complications and required surgical intervention. conclusion: in the future, we could expect more viral pneumonia with increasing vaccination coverage and maybe we should reevaluate our treatment guidelines. objective: to compare the need for pediatric critical care in a tertiary children's hospital with a diagnosis of community-acquired pneumonia (cap) or hospital-acquired pneumonia (hap). furthermore, we conducted a pilot study to evaluate the possible medical biomarkers which are associated with longer pediatric intensive care unit stay. methods: an observational, retrospective cohort analysis was conducted in children who were admitted to our tertiary children's hospital with a diagnosis of cap or hap. patient demographics, clinical characteristics, and comorbidity were collected between january 2012 and december 2013. the following prospective pilot study was conducted in children who were admitted to our pediatric intensive care unit (picu) due to pneumonia progression. we evaluated the clinical profiles and medical biomarkers. the primary endpoint was the duration of picu stay with associated predicting factors. results: a total of 548 patients with 598 episodes of pneumonia (310 males; 288 females) requiring admission to our children's hospital were included. the mean age at admission was 59.6 ± 1.95 months and the average length of stay was 11.4 ± 0.70 days. 530 episodes were identified as cap and the other 68 episodes were hap. patients with cap had significantly shorter lengths of hospital stay and duration of icu stay than those with hap (8.2±10.5 vs. 36.5±31.5 days, p < 0.001; 2±6.9 vs. 10±18 days, p < 0.001). the most common co-morbidities in cap were neurological diseases and atopy history. among the cap patients, 90 episodes (17%) led to icu admission during treatment course with the most common comorbidities being neurological diseases. however, in hap patients, cardiovascular diseases were the most common co-morbidities as well as those (38.2 %) who required picu care. the overall mortality rate was 3.8%, with the mortality rate being significantly higher in the hap group (p < 0.001). the pilot study included 8 children with the diagnosis of pneumonia in picu from jan 2015 to dec 2015. neither progressive ards mobility nor mortality occurred. the mean age at diagnosis was 37.5 ± 30.4 months. the average number of days of picu stay was 6.9 ± 4.7 days. the median duration of hospital stay was 14 days. patients were divided into two groups: picu stay more than 7 days and less than 7days. the values of pro-bnp, aado2, platelets, crp and ci in patients with picu stay more than 7 days showed a significant difference with those less than 7 days in the initial picu admission (p < 0.05). however, the values of thoracic fluid content (tfc) or even tfc corrected by cardiac output were not significantly different between the two groups. the levels of sputum 8-isoprostane and urinary 8ohdg revealed a trend of decreasing level after disease relief. conclusions: in this study, we found that (1) hap resulted in significantly longer lengths of hospital stay and picu stay than cap. the possible risk factors for the need of critical care are associated neurological disease in cap and heart disease in hap; (2) the possible biomarkers of pro-bnp, platelet, crp, ci, 8-isoprostane and 8ohdg may predict the duration of picu stay in our pilot study. these results not only help further our understanding of the risk of pneumonia in children who require critical care but also provide chances for better intensive respiratory care. background: pneumonia is a leading cause of respiratory morbidity and mortality in children younger than 5 years of age. 1 the incidence of severe cases of community-acquired pneumonia (cap) in low-and middle-income countries is still high. 2 although severe cap can be diagnosed by clinical features and chest x-ray, it could be useful to measure biomarkers to predict the outcome. the aim of the study was to determine the association between methods: ninety children aged between > 28 days to < 5 years hospitalized with diagnosis of severe cap in the pediatric department of west nusa tenggara province general hospital from january to october 2018 were enrolled. data on demographic and clinical characteristics, and laboratory examination were recorded. all subjects were treated in accordance with the hospital cap protocol and prospectively monitored until discharged. results: out of 90 subjects, 68% were ages < 1 year, 59% male, 87% passive smoke exposure, 56% lived in crowded environment, 62% came from low family income, 97% showed infiltrate on chest x-ray 81% with comorbidity and fe deficiency anemia was the most common (64%). c-reactive protein, esr, lc, and nlr were not significantly associated with hospital length of stay and duration of oxygen consumption (p > 0.05). after adjustment for crp, lc, nlr, and age, esr was found associated with mortality, with every increase in one log of esr decreasing the log odds of death about 3.3 (p = 0.043). conclusion: higher esr was associated with lower risk of death. however, none of the biomarkers were associated with hospital length of stay or duration of oxygen consumption. keywords: community-acquired pneumonia, outcome, children, biomarker. recurrent episode of bronchial obstruction were enrolled in this study. detailed history, physical examination, blood sample and nasopharyngeal aspirate (npa) collection were performed. the viral etiology of the respiratory tract infections was determined using polymerase chain reaction (pcr) and the concentration of ifn-γ in npa by elisa kits. results: the mean npa levels of ifn-γ in rsv (+) infants -4.3 (0-30.1) pg/ml was lower than rsv (-) infants -14.43(0-49) pg/ml, (p = 0.12). a gender difference in ifn-γ was detected with significant higher values in girls (or, 1.95; [ci] 0.85-4.26; p = 0.05). the cytokine ratio did not differ between infants with or without atopic status and family history of asthma. moderate-to-severe bronchiolitis in 7 cases (20%) was associated with lower ifn-γ level (or, 0.8; [ci] 0.64-1.13; p = 0.06), none of them required mechanical ventilation. decreased ifn-γ production correlated with the recurrent episodes of wheezing (p = 0.05). objectives: to test the hypothesis that high amplitude bcpap support after acute lung injury may have different effects on gas exchange efficiency and lung injury protection compared to high flow cpap (mimicking hfnc) support in rats with ali. methods: after normal saline lavage lung injury, all rats initially received high tidal volume mechanical ventilation (9 ml/kg) for 30 minutes, then were randomly divided into three groups: high amplitude bcpap group using the bubble technique with 135 degrees of expiratory limb (n = 8); standard bcpap group using the bubble technique with 0 degree of expiratory limb (n = 4); and high flow cpap (mimicking hfnc) group using the high flow technique (2 l/min, n = 8). all groups were killed 2.5 hours after bcpap or high flow cpap (mimicking hfnc) support. arterial blood gases, respiratory rate, peak inspiratory pressure (pip) and mean airway pressure (map) of rat lung during respiratory support, wetto-dry lung weight ratio, lung homogenate and/or bronchoalveolar lavage fluid tumor necrosis factor-α, macrophage inflammatory protein-2, interleukin-6 and total protein levels were measured and compared among groups after study completion. results: the high amplitude bcpap group exhibited a significantly higher pao2, lower paco2 and significantly lower alveolar protein, pip, map, wet-to-dry lung weight ratio and cytokine level compared to high flow cpap (mimicking hfnc) group. high amplitude bcpap group also exhibited a lower cytokine level compared to the standard bcpap group. no difference in gas exchange efficiency was observed between the two bcpap groups. conclusion: high amplitude bcpap support decreases lung inflammation, increases gas exchange efficiency and lung compliance compared to high flow cpap (mimicking hfnc) support in rats with ali, and may have a better lung protective effect than standard bcpap. keywords: bubble continuous positive airway pressure, high-flow nasal cannula, respiratory support, acute lung injury. nontraumatic chylothorax in children is rare and more difficult to treat than traumatic chylothorax. in some cases, they are refractory to conventional treatment, leading to severe morbidity and mortality. thus, the purpose of this study is to analyze the clinical features of chylothorax in pediatric patients in our hospital and seek appropriate therapeutic management. methods: a retrospective review was performed in 63 patients with chylothorax from january 2000 to december 2018 in the children's hospital of seoul national university. traumatic or postoperative chylothorax was excluded. a total of20 patients with nontraumatic chylothorax were included in our study. etiology, treatment, and outcome of chylothorax were analyzed. results: nontraumatic chylothorax was diagnosed in 20 patients. male patients (14/20 = 70%) were more frequently affected than female (6/ 20 = 30%) patients. eighteen patients were diagnosed before 1 year of age (90%), only two patients were diagnosed after 1 year of age (6 years old, 12 years old respectively). the most common cause of spontaneous chylothorax was idiopathic factors, constituting 45.5% (13), three cases were related to high central venous pressure due to venous thrombosis and recurrent sepsis, 2 cases were related to down syndrome, 1 case was noonan syndrome, and the remaining case was gorham stout syndrome. seventeen patients needed a respiratory support device, 6 of the latter received low flow oxygen supplementation, 11 patients received ventilator support. dietary modification (npo or mct base feeding), conventional medication (somatostatin or octreotide), sirolimus, surgical management were administrated to our patients. in the neonate and infant group, three patients who were related to venous thrombosis died because of recurrent septic shock before chylothorax management was administered. fifteen patients received a dietary modification (npo or mct base feeding) and nine patients improved by conservative management. one patient died due to heart failure before medical treatment. somatostatin or octreotide was used in 5 patients who failed dietary modification, but only one patient improved with octreotide. among the somatostatin or octreotide failure group, 4 patients received surgical management (pleurodesis or thoracic duct ligation). three of these patients improved, although one patient died after thoracic duct ligation operation because of post-op ards. two patients who were diagnosed after 1-year of age were refractory to nutritional modification and conventional medication such as somatostatin or octreotide. however, lymphatic intervention and surgical treatment were not suitable for these two patients. considering that their underlying disorder consisted of noonan syndrome and gorham stout syndrome, we used sirolimus to treat the refractory chylothorax. after administration of sirolimus, their chylothorax improved compared to before. conclusions: most of the nontraumatic spontaneous chylothorax in pediatric patients occur in newborns and the most common cause of chylothorax in the neonatal and infantile period is idiopathic. on the other hand, nontraumatic chylothorax in childhood is rare and tends more to be accompanied by the underlying syndrome. moreover, the treatment failure rate is higher in the childhood group. in such cases, sirolimus which is an mtor inhibitor, can be beneficial to patients who tend to be refractory and cannot be treated with lymphatic intervention or operation. purpose: specific genetic causes for childhood interstitial lung disease (child) in immunocompetent patients have been identified within the past decade. however, little is known about the pathogenesis of many forms of child, and treatment approach has not been standardized. a national survey was carried out by the japanese society of pediatric pulmonology (jspp) to identify the histopathology and response to current treatment, especially hydroxychloroquine, which is contraindicated for children younger than 6 years old in japan. methods: a questionnaire was sent to pediatricians who registered a child patient to the jspp. we conducted the survey over a period of 9 years, between 2010 and 2018. children (0-15 years) were included in the survey with persistent hypoxemia (pao2 less than 60 torr or spo2 less than 90%) for more than 2 weeks, diffuse infiltrates on ct scanning, and elevated serum markers such as kl-6, sp-a, or sp-d. immunodeficiency and other diseases which present with similar symptoms to child were excluded. the questionnaire included information on the patients' clinical symptoms, family history, pathological histology, clinical genetic findings, treatments and clinical outcomes. informed consent was obtained by all patients' guardians before participating in the survey. results: twenty-six cases were identified, including 15 males and 11 females. age of onset was between 0 months and 8 years. fourteen (53%) cases presented in the first year of life. lung biopsy was performed in 11 (42%) cases. five cases showed changes of nonspecific interstitial pneumonia (nsip), 1 case with desquamative interstitial pneumonia (dip), 1 case with cryptogenic organizing pneumonia (cop), 1 case with usual interstitial pneumonia (uip), 1 case with acute lung injury (ali), and 2 cases untagged. genetic testing was performed in 21 (80%) cases. mutation in sp-c gene (sftpc) was detected in 8 cases, atp binding cassette subfamily a member 3 (abca3) in 1 case, nk2 homeobox 1 (nkx2-1) in 1 case, coatomer associated protein subunit alpha (copα) in 1 case, and no mutation was detected in 10 cases. in the first half of the study period, only 5 out of 16 (31%) cases were diagnosed with genetic testing without lung biopsy, which increased to 8 out of 10 (80%) cases in the latter half. prednisolone was used in 24 (92%) cases and hydroxychloroquine in 20 (76%) cases with no onset of retinopathy. conventional treatment with prednisolone or hydroxychloroquine, monotherapy or in combination, resulted in a good response in 17 (65%) cases. three (11%) children died despite all therapies. in addition, it turned out that 1 case was diagnosed as juvenile idiopathic arthritis 4 years after registration. conclusions: this is the first nationwide prospective study regarding child in japan. the histopathology in this study is similar to that reported previously. there is increasing emphasis on genetic studies in the diagnosis of child as it can help avoid unnecessary lung biopsy. corticosteroid and hydroxychloroquine were the main therapeutic agents in our study. hydroxychloroquine therapy was tolerated in many cases, with no significant side effects. methods: twenty three children aged 11.8±4.9 years with bos after allogeneic hematopoietic cell transplantation were enrolled, and their clinical data were reviewed retrospectively. all subjects repeated the pulmonary function test at an interval of 1 month after occurrence of results: among 23 subjects with bos, 6 (25.0%) subjects expired due to respiratory failure, 4 (17.4%) subjects underwent lung transplantation, and 16 (69.6%) subjects needed o2 therapy. the mean value of fev1% predicted at the diagnosis of bos was 37.0±13.0%, and it rose after 12 months (47.0±24.9%). fev1 % predicted at diagnosis of bos tended to be lower in subjects with oxygen therapy (34.7±12.2) than in subjects without oxygen therapy (45.8±11.1), [yj1] although there was no statistical significance. the changes in fev1 % predicted at 3 months after bos diagnosis were significantly lower in the subjects with oxygen therapy (-19.4±24.3%) than in subjects without oxygen therapy (8.6±21.9%). however, there was no significant difference in the change over 3 months of fev1% predicted values between the two groups at 6, 9, and 12 months. in addition, the group with a negative slope of fev1% predicted change during the first 3 months had a higher likelihood of o2 therapy, compared to the group with a positive slope of fev1 change during the period (hr of 3.57, p = 0.059). the change in fev1 during the first 3 months after bos was significantly different between the subjects with and without oxygen therapy. these results suggest active intervention strategy is needed during the first 3 months after bos to improve the prognosis. this study is aimed to assess the effectiveness of hs nebulizations before physiotherapy over conventional physiotherapy in children with non-cf bronchiectasis. objectives: primarily to compare the change in fev1 from pretreatment phase to posttreatment phase between the two groups. method: we performed a retrospective cohort study of extremely preterm infants born before 28 weeks of gestational age in our nicu. study subjects were divided into two groups: auto group who underwent the automated control of inspired oxygen concentration (auto) with cpap, and manual group who underwent manual control of inspired oxygen concentration (manual) with cpap before introduction of auto in our nicu. we retrospectively investigated the patient characteristics and short-term outcome related to the respiratory system (reintubation rate, duration of cpap, introduction rate of home oxygen therapy) and retinopathy of prematurity (incidence, stage, and therapy rate). the mann-whitney u test and chi-squared test were used for statistical analysis, and logistic regression was used for multivariable analysis. result: a total of 47 infants were eligible for this study. there were 25 and 22 infants in the auto group and manual groups, respectively. in the auto and manual groups, the median (range) of their gestational age in weeks was 25.1 (23.3-27.9) and 25.5 (23.7-27.9, p = 0.25), birth weight in grams was 690 (461-990) and 789 (442-1178, p = 0.02), the rate of maternal steroid administration was 73% and 36% (p = 0.01), age at study entry in days was 2 (54-48) and 31 (2-67, p = 0.31). reintubation rate was 56% and 50% (p = 0.68), duration of cpap (day) was 28 (6-62) and 26 (3-38, p = 0.29), and introduction rate of home oxygen therapy was 20% and 27% (p = 0.56). the incidence of total retinopathy of prematurity (rop) was 64% and 77% (p = 0.32), the incidence of rop over stage ⅱ was 24% and 59% (p = 0.02), and therapy rate for rop was 8% and 14% (p = 0.53) in each group. there was a statistically significant association between the decreasing risk of rop over stage ⅱ and use of auto by multivariable analysis adjusted for confounding factors (odds ratio: 0.22 [95% ci: 0.06-0.76], p = 0.02). discussion: in this study, the incidence of rop over stage ⅱ was significantly decreased in extremely preterm infants who underwent auto with cpap. it is suggested that exposure to the excessive oxygen levels and the fluctuation of oxygenation are related to the incidence of rop. large studies indicate the strict spo2 target range. but in fact, the manual control of inspired oxygen concentration during respiratory support is not sufficient for the maintenance of spo2 within the latter. auto can maintain spo2 within the target range compared to the manual control of inspired oxygen concentration. auto has the potential to prevent rop by decreasing the exposure to excessive oxygen levels and the fluctuation of oxygenation. several limitations should be considered in our study. this was a retrospective, single-centered, non-randomized study; a further multi-centered prospective study is needed. since their pulmonary function is decreased, lower respiratory tract infections in this population may have a more severe clinical course. in our study, in addition to lung function measurement, we also wanted to see whether there is a connection between mental abilities and pulmonary function. methods: before the examination, a license was obtained from the ethical committee of the university of szeged. conclusions: we could also detect in our smaller population that vlbw patients at the age of 6 to 8 years have lung function test values in the lower normal region of the reference range. this may raise the presumption of the higher susceptibility of these children to respiratory tract diseases also in the later decades of life. bpd patients have lower pulmonary function test results than non-bpd patients. on the other hand, we could not find any connection between low raven test performance and lung function results. background: esophageal atresia (ea) and/or tracheoesophageal fistula (tef) is one of the rare congenital anomalies occurring in 1 out of 3,000-5,000 births. there has been improvement in the survival of these infants during recent decades. the diagnosis of tef with ea is commonly made during the first 24 hours after birth. preoperative flexible endoscopy (fe) is not yet routinely included in the diagnostic and postoperative assessment. this study aimed to evaluate the predictive factors that affected patients' prognosis and the role of flexible endoscopy application in managing infants with ea and/or tef in a tertiary medical center. methods: we enrolled patients who were admitted into our hospital due to suspected ea and/or tef and accepted an fe examination for one or more times between jan. 2000 and dec. 2017. all associated medical and surgical records were retrospectively reviewed. the analyzed data included basic characteristics, diagnosis, age of surgical repair, associated anomaly, timing of fe before and after surgical repair, and mortality. factors related to patient's mortality were analyzed. results: a total of 33 patients were enrolled, including 28 (84.8 %) cases referred from other hospitals. their mean birth weight was 2448 ± 603 gm, including 19 (57.6%) low-birth-weight infants, 17 (51.5%) cases with cardiac anomalies, 12 (36.4%) cases aged > 90 days, and 12 (36.4%) cases underwent fe before reconstruction. the most common classification of enrolled cases was type c (84.8%). additional other airway anomalies were found in 23 (69.7%) cases, including tracheomalacia, bronchostenosis, lung hypoplasia, and laryngeal cleft. one case underwent nasaltracheo-fistula-gastric catheter insertion before surgery. the mean age of receiving surgical reconstruction was 5 ± 7 days. the most common postsurgical complication was anastomotic stenosis (25, 75.8%) that required laser therapy (9, 27.3%), balloon dilatation (17, 51.5%), or stent implantation (2, 6.1%). gastroesophageal reflux was also commonly found in 21 (63.6%) cases. the overall 2-year survival rate was 72.7% (27/33). significant factors related to 1-year mortality were post-reconstruction referral (p = 0.004), age of reconstruction > 7 days (p < 0.001), and cardiovascular surgery requirement (p = 0.032). conclusions: in infants with ea and/or tef, fe is feasible for the early identification of associated airway and esophageal anomaly, as well as postoperative diagnosis and therapeutic interventions. postreconstruction referral, age of reconstruction > 7 days, and cardiovascular surgery requirement were significantly related to 1-year mortality of infants with ea and/or tef. background: patent ductus arteriosus (pda) is a common cardiovascular complication among premature infants and may be responsible for prematurity-related complications. surgical ligation is considered when medical treatment has either failed or was contraindicated. transcatheter occlusion, which was established in term infants, has recently been applied to premature population. previous reports stated that the complication and success rates were not statistically different between the transcatheter technique and surgical ligation. in this study, our aim was to compare the oxygenation status and oxygen dependence between these two techniques. the basic demographic data, fio2 change, pulmonary score, intubation days, ventilator-dependent days, oxygen-dependent days and mortality within 1 year were evaluated. results: the birth body weight, gestational age, post-menstrual age on procedure day, body weight on procedure day, pulmonary score and fio2 before procedure were not different between these two groups. the range of body weight on procedure day was from 478 to 1602gm in group a and from 551 to 1646gm in group b. the overall mortality within 1 year was similar (p = 0.360). the overall incidence of chronic lung disease was not significantly different (2/10 vs. 8/16, p = 0.218). when comparing the fio2 change before and 5 days after the procedure, the transcatheter closure group had a significant improveare rare disorders of which the incidence is not precisely known. this malformation might threaten the fetus, but it can also disappear spontaneously, or neonates can be asymptomatic with the malformation. according to previous studies, cpam may increase the risk for lung infections and lung malignancies, which is also the argument used when treating asymptomatic cpam-patients with surgery. purpose of the study: the purpose of the present study was to investigate whether there are differences between the treatment protocols between nordic countries. material and methods: a questionnaire was sent to 16 nordic centers dealing with pre-and postnatal management of patients with congenital lung malformation. this questionnaire was aimed to collect information on pre-and postnatal treatment protocols in the centers involved. results: the treatment protocols of this malformation vary largely in nordic centers. prenatal ultrasound was the primary examination in all centers. magnetic resonance imaging (mri) was used routinely as next prenatal examination in four centers for every cpam-patient with persistent finding in ultrasound during whole pregnancy (4 of 11). five centers (5 of 11) used mri if needed for differential diagnosis. various prenatal interventions were used in cases of fetal hydrops caused by cpam. shunting macrocystic lesion was used in 4 out of 11 centers, maternal cortisone in 9 out of 11. over half of the centers (7/11) consulted and co-operated with centers that performed fetal surgery and 3 out of 11 did consider ex utero intrapartum (exit) surgery. postnatally surgery was performed in every center (100%) for symptomatic cpam-patients. one center (14%) did not remove cpam but instead performed follow-up on asymptomatic patients. four infants used precision flow: three used single prong cannula (tip od1.9 mm), and the remaining infant used double prong, infant cannula (tip od1.9 mm). pharyngeal pressure tended to rise to flow rate dependence with any type of cannula. in patients managed with the optiflow junior, the mean pharyngeal pressure at the flow rates of 1, 2, 3, and 4 l/kg/min for premature size cannula were 2.3, 3.0, 3.1, and 3.6 cmh2o, respectively, and for neonatal size cannula were 0.5, 1.9, 3.0, and 3.7 cmh2o, respectively. in patients managed with precision flow, the mean pharyngeal pressure for each cannula at flow rates of 1, 2, 3, and 4 l/kg/min for single prong cannula were 1.8, 3.9, 4.7, and 5.0 cmh2o, respectively, and for double prong, infant size cannula were 2.6, 5.7, 6.0, and 7.0 cmh2o, respectively. background: even though it is considered as a screening test, sweat conductivity (sc) analysis seems to be an alternative diagnostic method to the coulometric quantitative test (cqt) for the diagnosis of cystic fibrosis (cf). it is widely accepted that coulometry requires specialized technicians, in addition to being performed only in referral centers. on the other hand, sc sweat analysis is a semiautomated procedure, simpler and faster than the conventional cqt. specially in poor-resource settings, it allows the decentralization of the diagnostic network and, consequently, a wider accessibility to cf diagnosis. to date, there are no studies comparing two concomitant conductivity tests performed in the same patient. objective: to assess the agreement between two sweat conductivity results performed concomitantly in young infants. methods: this was a prospective, cross-sectional study in which two sweat samples were obtained from the two arms among 100 consecutive patients, using the wescor macroduct collection system conclusion: since the strength of agreement was perfect, it reveals a high reliability of sc. apart from its role as a screening test, it seems that it has a place as a diagnostic tool in cf. background: because of frequent exacerbations and pulmonary deterioration in cystic fibrosis (cf), the radiological exposure to chest x-ray and ct scan is frequent in patients with cf, with subsequent potential secondary effect, although also required. lung ultrasound is, abstracts | s103 currently, a useful method of evaluation in multiples diseases such as: pneumonia, pleural effusion, interstitial syndrome or pulmonary fibrosis; therefore, the use of lus in cf would be of interest aim of the study: evaluation of thoracic ultrasound utility in cf exacerbations. methods: fifty cf patients were included in the study and monitored for 2 years of age. lung ultrasound was performed every 3 months, at clinical and biological evaluation. ct scan was performed during exacerbations and for stable patients, every 2 years timetable (aged over 8 years). ultrasound was performed using a linear high frequency 8 to 12 mhz probe, using a score based on specific artifacts which quantified the presence of consolidation, interstitial syndrome, saccular bronchiectasis and pleural effusion. ct was interpreted using the bhalla scoring system, independently of the lus score. pearson's correlation was used for the evaluation of the relationship between lus score and ct. results: median ct bhalla score was 14.3 + -4.5, and the average lus score = 5.13 + -2, consistent for moderate morphological lung injury. a good correlation was found in patients with increased lus (> 4) and ct score, r= 0.75, p < 0.001. there was no reliable correlation between the lung ultrasound score and ct, therefore, validation of the lus-cf score (r= 0.37, p = 0.26) was impossible with the currently identified artifacts. for patients in acute exacerbations, alveolarinterstitial syndrome described by multiple b-line artifacts and the presence of lake signs quantifying cystic bronchiectasis were accurately identified by lus and confirmed by ct. methods: we conducted a retrospective descriptive study at the university hospital of montpellier between 30/08/2000 and 30/08/2018. we collected the various respiratory disorders presented during the follow-up of these children. results: one hundred and two files were examined and 76 patients were included in our study. asthma concerned 26 patients in our cohort (34%) which is more frequent than in our general population (9% in occitania region, france). it was significantly related with atopy (p < 0.01). respiratory tract disorders were identified in 10 patients (13%). the most common were: tracheomalacia and laryngomalacia. lower respiratory infections were found in 18 patients (24%) and were significantly related to lymphopenia (p < 0.05) and swallowing disorders (p < 0.05). infants were tested for hiv using pcr and antibody testing. the association between hiv and arv exposure and lung function during 2 years was assessed using linear regression, adjusted for bmi for age z-score, sex, ethnicity, socioeconomic status (ses) abstracts | s105 quartile at enrolment and pre-and postnatal smoke exposure (based on urine cotinine). results: a total of 1036 infants had at least one lung function measurement and were followed over 2 years, 226 (22%) were heu; 535 (52%) male, 560 (54%) black african ancestry, 330 (33%) mothers smoked during pregnancy, 775 (71%) household tobacco smoke exposure. nine hundred and ten (88%) infants had lung function tested at 6 weeks and 743 (72%) children at 2 years. the majority of heu infants were black african (93% vs. 43% hu, p < 0.001), heu infants had less household smoke exposure (69% vs. 81%, p = 0.01), lower ses (p = 0.001) and had higher bmi zscore at 2 years (p = 0.001) compared to hu; other demographics were similar. at 6 weeks, heu infants had higher tidal volume compared to hu (1.1ml, ci, 0.02; 2.2, p = 0.045). amongst the heu infants, those whose mothers had triple therapy arvs had lower expiratory flow ratios, tptef/te, compared to those whose mothers had zidovudine (azt) only (-0.26, ci -0.4; -0.1, p < 0.001). at 2 years, tidal volume differences were no longer seen, but heu infants had a higher lung clearance index compared to hu (0.12, ci, 0.02; 0.23, p = 0.019). low antenatal maternal cd4 count was associated with an average 6.5ml lower tidal volume at 2 years compared to infants whose mothers had cd4 counts> 500 cells/ mm3 (ci, 1.0, 12.1; p = 0.02). background: chronic wet cough, which is prevalent in indigenous children, is the most common symptom of bronchiectasis and its precursors. early recognition of chronic wet cough leading to prompt and appropriate treatment may potentially prevent progression to bronchiectasis. therefore, timely health seeking for chronic wet cough by families, and its effective management by health practitioners is potentially important to prevent development of bronchiectasis. purpose: to identify the barriers to and enablers for timely health seeking for chronic wet cough by families, and optimal management by health practitioners, for chronic wet cough in aboriginal children. method: a qualitative study was conducted in two communities (one remote town and one very remote community) in the kimberley region of northern, western australia, of which 43% of the population is aboriginal. data were gathered through individual semi-structured in-depth interviews and focus groups to ascertain: the key enabler described was the provision of culturally appropriate health literacy information. all participants reported that they would seek help for chronic wet cough once they were informed that it could signify underlying disease. furthermore, families suggested that improved health practitioner knowledge of chronic wet cough database. complete monitoring data for the air pollutants (so2, no2, o3, co, pm2.5 and pm10) and meteorological factors (relative humidity, rainfall, and daily average temperature) were collected from 74 environmental protection agency monitoring stations of the taiwanese government. in the present study, each er visit for asthma ae was defined as case day. in bidirectional control samplings, the same weekdays 1, 2 or 3 weeks before and after er visit for asthma were defined as the control days. multiple correlation coefficients (r) (multiple regression analysis) were used to explain how much of the variance in the ed visits could be explained by a given set of air pollutants. result: as the study cases were divided as male and female, a 1 ug/m3 increase in the 48-h averages of pm2.5 and a 1℃ increase in temperature were associated with asthma er visit [or= conclusion: in taiwan, asthma ae is closely related to low temperature and indicated air pollution. there is an obvious bias if only a single air pollutant is being considered and neglects the influence of meteorological factors in studying the effects of the environment on asthma. with the result of this study, we can predict asthma exacerbation precisely according to individual age, gender and local air pollution/ meteorological conditions. in days with high risk for asthma exacerbation, patients with asthma should avoid/decrease outdoor activity, dress warmly and maintain inhaled corticosteroid therapy. however, while the path length of the right dorsum manus was not statistically significant, there was a significant difference in completion time between the two groups. the reason considered was that their left hand was their nondominant hand, while their dominant hand needed to be kept clean to touch an asepstic suction catheter. therefore, novice participants were unfamiliar with manipulating suctioning equipment with their left hand, which appeared as a difference in their proficiency. benefits of 3d cg were reported that the function of a virtual camera improved the accessibility to aois by screen transition, whereas operation was difficult, so they could not realize the effect of learning. advantages of 2d video was described that it is easy to concentrate because the device was familiar, while there was a negative impression that it was hard to observe aois compared to 3d cg. there was no significant difference between the groups who watched 2d video or 3d cg animation in the frequency distribution of fixation point movement speed analysis. however, considering the unignorable potential of 3d cg animation as a training tool, we concluded that defining visual criteria for assessing learning outcome of digital contents requires more research in the future. graduate school of nursing, the jikei university school of medicine -tokyo, japan the aim of this study is to compare the level of endotracheal suctioning proficiency between experts and novices, using an eyemark recorder. a head-mounted eye-tracking device (pupil, pupil lab, usa) was used to capture eye movement of the participants. twelve experienced nurses from three healthcare facilities who had more than 3 years of experiences of suctioning, and twelve nursing students from a university who had no experience of providing suctioning for real patients, participated in a simulation scenario of a patient with endotracheal intubation. we utilized cephalothorax realia with a simulated upper respiratory tract from mouth, nose, to a tracheal bifurcation, which did not represent any biological/patholoshowed that 57.3% of students are exposed to environmental tobacco smoke, which causes inflammation of respiratory tracts and a decrease in lung function. urinary cotinine can be used as a biomarker for cigarette smoke exposure. objectives: to examine the effects of environmental tobacco smoke exposure on urinary cotinine level and lung function test in children. methods: subjects were students aged 11 to 16 years-old in jakarta. data were obtained from questionnaire, spirometry and urinary cotinine test using elisa method. results: there were 92 subjects, consisting of 46 in the case group and 46 in the control group. urinary cotinine level > 10 ng/ml was found in 37.0% of the case group and 4.3% of the control group; p = 0.000; or= 8.50 (ci, 95% 2.08-34.71). there were significant differences between urinary cotinine level with number of smokers (p = 0.027) and number of cigarettes per day (p = 0.037). no association was found between cigarette smoke exposure and lung function test. there was a significant difference in school absenteeism between the case group and control group; p = 0.004; or= 6.00 (ci, 95% 1.42-25.33). conclusions: children exposed to environmental tobacco smoke there are relatively little data in healthy children and no data that compared these techniques. in 100 children without respiratory disease, we described (i) the bal differential cellular count and its correlation with age, and (ii) compared the differential cytology versus b-bal (10%, iqr 4-13%)). however, when adjusted for age using regression statistics, these differences were not significant. there was no significant difference in the total cell count (nb-bal 9.3x104/ml, iqr 4.5-15.3x104/ml versus b-bal 11.8x104/ml, iqr 8-22.1x104/ml) and neutrophil percentage (nb-bal 4.5%, iqr 2.8%-7% versus b-bal 3.5%, iqr 1.8-8%) between the two groups. there was no significant difference in the differential cytology with age in both b-bal and nb-bal. conclusion: nb-bal provides comparable information on the cellularity components of bal when compared to b-bal and should be considered an alternative. as age influences cellular differential count, age-matched data are required for comparative studies on bal in children. j-99 | spirometry assessment in children with congenital heart disease after open heart surgery in these spirometry assessments, obstructive type was more common than restrictive type (31.5% vs. 20.7%). however, in tof patients, restrictive type was slightly more common than obstructive type. j-115 | to squeeze or not to squeeze? can the raised -volume passive expiration flow-volume curve be used to estimate pulmonary functions in infants? background: spirometry is an essential tool for assessing patients with lung disease. however, it necessitates cooperation and thus, it cannot be performed in infants. one of the established alternative techniques in infants is the raised-volume rapid thoraco-abdominal compression technique (rvtct) which uses a compression vest to squeeze the chest forcedly after inflating the lungs to near total lung capacity (tlc). although it is an acceptable method, it is far from being perfect since it is not easy to perform. obtaining the raisedvolume passive expiration curve (rvpe) from passive deflation of the lungs from tlc is an easier technique (figure 1) . however, to our knowledge, data obtained from the rvpe curve were not assessed for their ability to estimate expiratory airway function in infants. tst was considered positive if induration > 10 mm and qft-git however, anesthetic choice as a risk factor for fever has not yet been reported. objectives: the aim of our study was to explore the role of sedative agents as a risk factor for fever during the 24 hours after the procedure. additional risk factors were investigated as well. multivariate analysis of the data (comorbidities, sedation choice, age, indication for performing the procedure, bal performed and its findings, post-prematurity, ftt, and medications) suggested that only sevoflurane and young age were statistically significant risk factors for fever. chronic treatment with montelukast was found to be a protective factor against fever. we conclude that post-bronchoscopy fever is probably an inflammatory noninfectious process. sevoflurane is a significant risk factor for developing post-bronchoscopy fever by generating such inflammation. the same mechanism may also explain why montelukst has a protective role. conditions were mostly present in young children less than 5 years old while obesity was more common in adolescents. of the treated patients, 75.6% had allergic rhinitis. comparing symptoms before and within 6 months after pap trial, there were significantly less patients with complaints of habitual snoring (95.6% vs. 8.9%, p < 0.01) and excessive daytime sleepiness (42.2% vs. 11.1%, p < 0.01). there was significant improvement in psg parameters with mean oahi decreasing from 21.5±18.5/hour tst to 1.6±1.9/hour tst (p < 0.05) and mean spo2 (oxygen saturation) nadir increasing from 80.6% ±10.4% to 90.9%±5.7% (p < 0.05) after pap therapy. within 6 months of follow up, 57.8% of the patients adhered to pap satisfactorily while the adherence dropped to 37.8% at the time of the latest follow-up. satisfactory usage established before 6 months was associated with favorable long-term outcomes of satisfactory usage or cessation of therapy due to improvement at the latest follow-up (chi square test p = 0.008). the commonest reported reason for non-adherence was due to nasal obstruction. results: forty-three bemss were placed in 26 infants. the mean bw and mean age were 4.0 ± 0.8 kg and 4.9 ± 2.7 months, respectively. there were 21, 9 and 13 stents located in trachea, carina and mainstem bronchi, respectively. seven infants with 13 stents died without obvious stent-related mortality. among them, 12 stents in 8 children were successfully retrieved by rigid endoscopy. at placement, the diameters of 30 tracheal and 22 bronchial stents were 7.5 ± 1.1 (4-10) and 5.4 ± 0.9 (4-8) mm, respectively. these implanted bemss could be gradually and significantly (p < 0.01) expanded. at the end of this study, all the remaining 18 stents in 12 infants could be kept functional. the diameters of the 11 remaining tracheal and 11 remaining bronchial stents were 9.7 ± 2.0 (8-14) and 7.0 ± 1.4 (4-10) mm, respectively. results: eithty -three children were included. males represented 48.5%, average age was 31.7 ± 4 months. the rate of ards was 39.8%. the mortality rate in children with this syndrome was 78.8%. septic shock with ards had a higher mortality rate than septic shock without this syndrome (26%). most children with this syndrome were in the moderate and severity range (78.8%); 81.8% were ventilated. the tidal volume was 8.3 ± 1.6 ml/kg and average peep was 8.6 ± 2.2 cmh2o, the medium fio2 was 90.7 ± 16.4 %; 36.4% of cases had a tidal volume of 8 to 10 ml/kg. there were no differences in tidal volume, peep and fio2 between survivor and non-survivor cases. conclusions: ards had a high prevalence in pediatric septic shock and the mortality rate among septic shock cases with this syndrome is still very high. according to the unit policy to transfer to icu which is based on idsa guidelines, 2% of the patients needed intensive care. hdu care was given for 38% of patients who required supplemental oxygen to maintain pulse oximetry above 92%. analysis of length of hospital stay indicated that 25% of the patients were discharged by the 4th day and 61% were hospitalized for 5 to 9 days. there was no mortality among the patients evaluated. conclusions: this retrospective analysis revealed that childhood community-acquired pneumonia is associated with significant morbidity and is an economic burden. the majority (65%) needed therapy beyond first line antibiotics which may indicate significant antibiotic resistance. central sleep apnea (csa) and periodic breathing are unusual findings described in pediatric patients with congestive heart failure. however, csa has not been reported in children with pulmonary hypertension. we hereby report on a 10-year-old girl with idiopathic pulmonary arterial hypertension (ipah) who had frequent central events in a periodic breathing fashion seen in her polysomnography, which was normalized following medical treatment leading to improvement of the pulmonary pressures. this case supports the importance of psg in pediatric patients with ipah, not only to exclude osa as a potential cause but also to assess for the presence of pb. we also show that the presence of pb might be a sign of disease severity and can be a marker of response to we present two children from a tb endemic region, with microbiologically confirmed tb presenting with parapneumonic effusion containing chyle, that were misdiagnosed initially as pleural empyema. tuberculous pleural effusion occurring with chylothorax is uncommon. the first case is a 12-year-old girl who presented with localized left-sided chest pain and parapneumonic effusion and a previous liver transplant and long-term intravenous catheter, who was on chronic immunosuppressive therapy. the second case was a 10-year-old boy who was hiv-exposed but uninfected and presented reports, to our knowledge, on using gastric lavage pcr to diagnose pjp. we report two cases in which p. jirovecii was identified by gastric lavage pcr and was treated appropriately. case 1 was a 1-year-old preterm, low-birth-weight male infant with down syndrome who had undergone operation for necrotizing enterocolitis and was being administered central venous nutrition. he was started on prednisolone for pericardial effusion because of postpericardiotomy syndrome when he was 7 months old and had been in an nicu for a year. on the day of onset of pjp, he required increased oxygen levels, and infiltrative shadows were observed in both lung fields on chest radiography. further, his (1→3)-d glucan (bdg) levels were elevated. p. jirovecii was detected on gastric lavage polymerase chain reaction (pcr), and trimethoprim-sulfamethoxazole was administered for 3 weeks, following which his condition improved. case 2 was an 8-month-old preterm, very-low-birth-weight male infant who was under central venous nutrition because of digestive tract disease. he was under treatment with hydrocortisone for 5 months because of refractory hypoglycemia and had been in an nicu. on the day of pjp onset, he showed increased oxygen demand, and chest radiography showed infiltration in both lung fields. further, his bdg level was elevated. p. jirovecii was detected on gastric lavage pcr, and trimethoprim-sulfamethoxazole was administered for 3 weeks, following which his condition improved. discussion: about 10%-30% of immunocompetent children carry p. jirovecii in their respiratory tract, and this percentage, depending on the underlying disease, is 60%-70% in immunosuppressed patients. therefore, when p. jirovecii is detected, it is important to distinguish infection from colonization. in these two cases, we suspected pjp on the basis of the clinical symptoms, backgrounds, bdg levels, and observations from image examination, and p. jirovecii was detected on gastric lavage pcr analysis. the patients' condition improved after definitive therapy. to our knowledge, there has been no report of pjp diagnosis by gastric lavage pcr to date, and this diagnostic technique may be useful if it is difficult to collect lower respiratory tract specimens. both patients had cellular immunodeficiency because of long-term steroid administration, although prophylactic treatment with trimethoprim-sulfamethoxazole for pjp had not been administered. this suggests the necessity of prophylaxis. we are reporting a 7-month-old boy, who was previously hospitalized with recurrent monthly pneumonia since birth until presentation to a regional tertiary center with pediatric respiratracheal agenesis (ta) is extremely rare and usually fatal. complete or partial absence of the trachea below the larynx can be found, and a tracheoesophageal fistula may exist. there is usually no prenatal symptom, but other congenital anomalies are commonly found. we present a low-birth-weight male infant (gestational age 36 weeks; birth weight 2100g) born with respiratory distress. physical and radiological examination disclosed single umbilical artery, bilateral malalignment of thumbs, sacral dimple, and hemi vertebra. difficult intubation was noted soon after birth. after being transferred to our center with an intubated endotracheal tube, flexible bronchoscopy was performed and found it was an esophageal intubation. a blind pouch at the subglottic level of the trachea without a fistula was observed. diagnosis by computed tomography (ct) with 3d-reconstruction revealed ta (floyd type ii) with a small esophago-bronchial (eb) fistula at the lower esophagus and linked to the right upper bronchus. at the age of 3 days, esophageal ligation and gastrostomy were performed. at the age of 21 days, with the assistance of 3dprinting simulation and veno-venous extracorporeal membrane oxygenation (ecmo) support, cervical esophagostomy and tracheoplasty were executed. the cervical esophagus was end-to-end anastomosed to the larynx. after dividing and excision of the eb fistula, the proximal end of the lower thoracic esophagus just above the fistula was end-to-side anastomosed to the right main bronchus. the distal end of the lower thoracic esophagus was ligated. however, pneumothorax, anastomosis dehiscence and repair, narrowing of anastomosis, collapse of esophageal-consisted airway, and bilateral pulmonary atelectasis developed in the following 2 weeks. flexible bronchoscopy aid balloon dilatation and stent implantation were planned. however, massive air-leak to mediastinum and peritoneum, shock and disseminated intravascular coagulation (dic) occurred. initially, nasal cpap (continuous positive airway pressure) was provided for respiratory support; however, intubation was finally performed with high-frequency oscillation use due to fluctuating respiratory condition. series of chest plain film showed progressive diffused infiltration, while high-resolution computed tomography showed bilateral ground glass appearance. in combination of her clinical features and image presentation, lung biopsy was performed due to the high suspicion of diffuse lung disease. oral steroid and azithromycin was administered but her improvement was poor. we did not administer hydroxychloroquine because of her g6pd (glucose-6-phosphate dehydrogenase) deficiency. recurrent ventilator-associated pneumonia was noted which needed several types of antibiotics. at 3 months of age, a tracheostomy was performed. lung transplantation was offered to the family but they decided to proceed with mechanical ventilation use. due to worsening of clinical condition and resistance to medication treatment, she received palliative extubation after full discussion with her family at the 5th month. a blood sample was collected for genetic testing before the patient passed away. revolutionized imaging of the "forgotten third circulation", improving our understanding of lymphatic diseases and paving the way for a new treatment modality, lymphatic embolization. we present a 7-year-old girl with kla whose pleural effusion stabilized following two lymphatic embolization procedures. case report: our patient presented at 2 years with recurrent severe non pulmonary infections. chest radiographs showed prominent diffuse reticular opacities despite the absence of respiratory symptoms or signs. comprehensive immunology and rheumatology investigations were normal, as were exhaled and nasal nitric oxide, ciliary biopsy, bronchoscopy and lavage, echocardiography and oxygen saturation at rest, on exertion and overnight. a chest ct showed thickening of interlobular septae with preservation of parenchymal architecture. a bone scan showed reduced uptake at l4, as well as t10 and the left clavicle in keeping with "vanishing bone disease". at has no effect on osa caused by ca, although rapid maxillary expansion (rme) is reported to be useful for it. objectives: herein, we report the case of a patient with osa likely due to ca that was successfully treated with rme. nights. respiratory event index (rei) were 24.2/h and 17.0/h on nights 1 and 2, respectively; nadir spo2 were 70% and 76%. as a result, severe osa was diagnosed. since his family did not wish for at, rme was performed. snoring and retractive breathing during sleep disappeared 3 weeks after the start of rme, and 8 months later, ocst was performed again on two consecutive nights. rei had improved to 5.7/h and 3.7/h on nights 1 and 2, respectively, and nadir spo2 had improved to 81% and 85%. no evidence on the usefulness of rme for osa in children has been established. however, rme was useful for osa likely due to moderate ath and ca in this patient, suggesting that tongue space expansion by rme can be a useful therapeutic method for osa. gorham-stout disease is also known as vanishing bone disease. it is a rare disease of unknown etiology characterized by progressive osteolysis and proliferation of lymphatic vessels. we report 2 cases of gorham-stout disease presenting with recurrent chylothorax and lytic bone lesion. we present a 2-month-old female infant with fever, cough, and vomit for 4 days. she was transferred to our medical center due to rapid progression to pards within 1 day, and her throat swab cmv pcr test revealed positive. her chest radiograph showed bilateral white-out, and very high ventilator settings were required to maintain oxygenation. cardiac disease was excluded by ultrasonography. intravenous ganciclovir, broad-spectrum antibiotics, and methylprednisolone were given, but the gas exchanges were still poor (oxygenation index= 31 at 38 hours after hospitalization). hfov was then applied (fio2 = 1.0, map= 20 cmh2o, amplitude = 30 cmh2o, frequency = 10, i time = 33%). after using hfov, the lungs were recruited and the settings could be weaned down gradually. intravenous immunoglobulin was given for suspected viral sepsis. case report: patient a was an 18-month-old girl with down syndrome, congenital hypothyroidism, small patent ductus arteriosus and anorectal malformation who presented with persistent fever and cough for 2 weeks post stoma closure. on examination, she was tachypneic with a respiratory rate of 50 breaths/minute and subcostal recessions. her breath sounds were reduced over the right lower zone with stony dullness. chest x-ray (cxr) showed right lower lobe consolidation with a loculated parapneumonic effusion. minimal thick stale blood-stained fluid was aspirated during an ultrasound guided thoracocentesis and an unusual mass was seen. hence the chest drainage was aborted and a contrast-enhanced ct angiography revealed a pulmonary pseudoaneurysm within the consolidated lung, adjacent to the right pleural collection. blood investigations showed a drop in hemoglobin from 12g/l to 8.8g/l. chest x-ray showed an extensive right pleural effusion and ultrasound described a right basal consolidation with a pleural effusion of 353ml. pleural fluid sample obtained by thoracentesis was purulent with exudate characteristics and a chest tube was inserted for drainage. due to these findings, a thoracic ct scan was performed and revealed atelectasis of the right lung and severe loculated pleural effusion with fluid-filled cavities in the right middle and lower lobes. since the patient was stable, a conservative management was preferred and empiric iv antibiotics, cefotaxime and clindamycin, were started. after 7 days of treatment, pleural fluid culture was positive for s. mitis. s. mitis was sensitive to ampicillin, thus treatment was completed with 10 days of ampicillin and 7 days of cefotaxime and clindamycin with a satisfactory outcome. considering that s. mitis is an innocuous commensal organism of the oropharynx, skin, and gastrointestinal and genitourinary tracts, we looked for primary infection sites. the origin of the infection was a cavity in the third lower molar that extended to the root. the patient had a history of a dental procedure 4 weeks before diagnosis. case report: a nine-month-old male preterm bpd infant with maternal premature rupture of membranes delivered by emergency caesarean section at 28 + weeks gestation due to fetal distress. apgar score was 4 at 1-minute and 7 at 5-minutes and birth weight was 1500 g. because of respiratory distress syndrome, endotracheal intubation was performed and the patient was transferred to the neonatal intensive care unit. after 3 months of mechanical ventilation support, the endotracheal tube was removed and the patient was treated under niv support. after 9 months of mechanical ventilation support since birth, we decided to make an assessment of the neurodevelopment of the patient by brain mri. conclusion: most of the time, preterm bpd infants with vd who are receiving niv support will be considered as high risk and follow-up for mri delayed because of two reasons: (1) need of oral intubation with endotracheal tube to guarantee the safety of the respiratory system; (2) the neonatal mri-ventilator which includes niv mode is too expensive and requires a well-trained respiratory therapist to operate the mri-ventilator. we believed that once we well-prepared the mri-ventilator, infants with vd who are receiving niv support could undergo mri more safely. by sharing this case experience, we hope the profession of neonatal respiratory therapy could receive more attention. we present two cases that were diagnosed after multiple consultations: case 1. a 2-year-old girl presented with a history of recurrent episodes of cyanosis during her first months of life, worsening respiratory symptoms and poor exercise tolerance. she was assessed on several occasions by a general practitioner (gp) who did not consider that further investigations were necessary. she also had recurrent epistaxis and was being followed by the local ent specialist who considered the episodes as normal. at the age of two, she was admitted to her local hospital with a lrti, cyanosis and persistent low oxygen saturation levels (70%). she was treated with antibiotics, but given her slow improvement she was referred to our center for further workup. on examination, she presented with failure to thrive, general cyanosis, multiple telangiectasia in oral cavity and nostrils, and clubbing fingers. initial chest x-ray showed abstracts | s139 ct angiography revealed an arteriovenous malformation (avm) in the middle segment of the right lower pulmonary lobe, multiple intraparenchymal small avms in both lungs and an aberrant artery from the descending aorta that irrigated the right upper lobe. embolization of the main pavm was proposed, however, it was not possible due to its large extension since there was no embolic device according to its size. further discussion in several international forums, a thoracotomy and pulmonary segmentectomy of the right lower lobe was suggested and then performed 7 months after presentation. since then, the patient has been asymptomatic, despite the fact that spo2 levels have not improved as expected. background: children with cystic fibrosis (cf) have frequent respiratory exacerbations, therefore the occurrence of cough and fever in a cf child raises the suspicion of an acute infectious event, while in a non-cf child this fever/cough association would suggest a pneumonia. what about the presence of tachycardia, which would suggest a different diagnosis, from myocarditis or hyperthyroidism. we herein present the case of a 3-year-old girl with cystic fibrosis with frequent acute cough, persistent fever and tachycardia attacks. a 3-year-old girl was diagnosed with cystic fibrosis in infancy, because of a pseudo-barterr syndrome. the child's evolution was very good, with good clinical and biological status, normal pulmonary lung function described by a normal lung clearance index and germ-free cough swab and negative induced sputum. she was monitored according to the national romanian guidelines every 3 months in the regional cf center and annually at the national center, by clinical and biological investigation. no ct or bronchoalveolar lavage was performed until age of 3 years. results: in evolution, her mother noticed episodes of tachycardia 5 months before the actual admission, supposed secondary to play or hospital anxiety, without any electrical ecg alteration. four months before admission, she had a mild exacerbation associated with insignificant chest x-ray findings and she received intravenous cephalosporin. after 1 month, she started to productively cough and fever, with a relatively strong persistence despite ains. her first sixteen emergency situations will be presented in detail using the above format. purpose: obstructive sleep apnea (osa) is a common disorder estimated at 1%-5% in school-aged children. with the obesity prevalence reaching staggering rates globally, osa in obese adolescents is estimated to be 4 to 5 fold higher than their lean peers. there is a paucity of data regarding obesity-related osa in children 6 years and less. this is particularly relevant as osa is associated with neurocognitive deficits. the aim of this study is to evaluate the prevalence of osa among obese toddlers and preschool children and further to determine what other factors may be associated with the presence of osa. methods: a retrospective study involving children < 6 years, identified from two canadian pediatric tertiary care centers who had an in-lab polysomnography (psg). obesity was defined by a bmi of > 95th percentile for age and gender or a z-score of > 2. osa was diagnosed if the obstructive apnea-hypopnea index (oahi) was greater than 2 events per hour. results: there were 60 participants included; the mean age was 4.4 years (standard deviation [sd] + 1.7), mean bmi z-score was 3.0 (sd + 1.2). of these, 22/60 (36.6%) had osa. compared with the non-osa group, the osa group had a higher epworth sleepiness score (p = 0.03) and were more likely to snore (p = 0.01). the present study "comparative study of nebulized beta 2 agonist, nebulized adrenaline and any added advantage of 3 % hypertonic saline in bronchiolitis" was undertaken to assess the efficacy. a total number of 150 patients (50 patients in each group) were examined below 24 months of age. group a was nebulized with salbutamol, group b was nebulized with adrenaline and similarly, group c was nebulized with 3% hypertonic saline. comparison of mean ± s.d. of rdai score before and after nebulization was performed in all 3 groups. in each patient from all groups (ie a, b and c), rdai scores were recorded at the time of admission (ie at 0 minutes), at 20 minutes and 40 minutes (after nebulization) and on subsequent days. the mean value of rdai score at admission and discharge was 10.78± 1.03 and 6.58±1.54 respectively in group a. in group b, rdai score at the time of admission and discharge was 11.20 ± 1.05 and 5.9 ± 1.61, respectively. similarly in group c, rdai score at the time of admission and discharge was 8.14 ± 1.80 and 3.18 ± 0.94, respectively. all the parameters before treatment had a p value > 0.05 (not significant at 0 minutes.) and at the time of discharge, the p value became < 0.0001 (extremely significant). mean differences in hr, rr, rdai score and spo2 were assessed after subsequent nebulization in all 3 groups. the post treatment values for group a (salbutamol), group b (adrenaline) and group c (3% hypertonic saline) were compared. all groups showed an increase in hr, but group b (mean difference of 14.80) showed a more increasing trend than group a (mean difference of 4.84) and group c (mean difference of 7.04) and had a p < 0.05. regarding rr, all 3 groups showed decreased rr, but group b (mean difference of 15.96) was more significant than group a (mean difference of 14.80) and group c (mean difference of 12.20) and had a p < 0.05. regarding rdai score, all 3 groups showed improved score, but group b (mean difference of 5.3) was more significant than group a (mean difference of 4.2) and group c (mean difference of 4.96) and had a p < 0.05. similarly, all 3 groups showed improved spo2 %, but group b (mean difference of 10.24) showed more improvement than group a (mean difference of 9.26) and group c (mean difference of 6.38) and had a p < 0.05. clinical parameters (heart rate, respiratory rate, rdai score and spo2 %) in both groups were comparable before nebulization. nebulized salbutamol was given to group a, nebulized adrenaline to group b and nebulized hypertonic saline to group c. different clinical parameters in the groups were compared before and after subsequent nebulization. mean respiratory rates, rdai scores and spo2 (%) significantly improved in all 3 groups. however, improvement was more significant in the adrenaline group. shorter length of hospitalization was noted in group c (hypertonic saline). no undesirable side effects were noted in all 3 groups. all 3 groups showed a transient increase in heart rate, although more so in the adrenaline group. objectives: endothelial dysfunction (ed) is one of the initial pathological changes ultimately leading to atherosclerosis and consequent cardiovascular disease. children with endothelial dysfunction are at higher risk of developing systemic and pulmonary hypertension, atherosclerosis and cardiac remodeling, with potential long-term adverse outcomes into adulthood. obstructive sleep apnea syndrome (osas) has been found to cause impaired endothelial function in adults. however, the evidence in pediatric osas is limited. the aim of the study is to evaluate endothelial function in a large cohort of children clinically referred for suspected osas, and to identify risk factors contributing to the presence of ed. methods: children aged 3 to 11 years old with habitual snoring (snoring ≥ 3 nights per week) were recruited to this study between june 1st 2015 -march 1st 2016. all subjects underwent an overnight polysomnography (psg), as well as endothelial function testing using peripheral arterial tonometry (pat) to derive the reactive hyperemic index (rhi). subjects were then divided into osas and primary snorers (ps) groups according to their obstructive apnea-hypopnea index (oahi). results: a total of 355 cases completed the study, with 248 children being diagnosed as osas, and 107 children assigned to the ps group. there were no differences in age, gender and bmi z-score between the two groups (all p > 0.05). the osa group had lower rhi than that of ps (p < 0.05). univariate correlation analysis showed that rhi was linearly correlated with age, gender, oahi, oxygen desaturation index, respiratory related arousal index, and oxygen saturation nadir. the relationship between bmi z-sore and rhi was quadratic. rhi and bmi z-sore were positively correlated when bmi z-score< 1. year follow-up, we regularly performed ekg, cardiac echogram, 6 minute walk testing (smwt) and monitoring of serum bun, bnp and creatinine. also, cardiac catheterization and hemodynamic studies, pet study with uptake of glucose analog 2-deoxy-2-﹝18f﹞fluoroglucose (18f-fdg) and pulmonary perfusion-ventilation scan were performed. we enrolled six patients with es including atrial septal defect type ii (3 cases), atrial septal defect type i (1case), right atrial isomerism after total cavopulmonary connection (tcpc) (1case) and ventricular septal defect (1case); the male:female ratio was 3:3. hemodynamic studies revealed that mean pulmonary arterial pressure was 52±7.3 mm hg; pulmonary vascular resistance index was 26.1±7.9 wu*m2, except the case receiving tcpc. in addition, three cases of intrapulmonary thrombus in right pulmonary artery, three cases of cerebral stroke and three cases of atrial fibrillation were found. the lung scan revealed that there were nonspecific findings noted in the es patients with or without intrapulmonary thrombus. very interestingly, an increased uptake of 18f-fdg in the right ventricle was noted in three cases. subsequently, there were two mortalities because of right ventricular failure. and pediatric settings which corresponds to a child of 15kg weight (tidal volume 150 ml, 25 breaths/min, ratio between inspiratory and expiratory 50/50 and peep 5 cm h2o). a filter was placed between the endotracheal tube and the test lung model (smartlung adult, imt medical, switzerland) to collect the drug. all components were tested for drug deposition. deposited doses were quantified by spectrophotometry. all measurements were performed five times. results: the percentages of the nominal dose of salbutamol deposited on the filter with the adult model after nebulization and aerosolization, were similar when the device was located before or after the y piece results: flow analysis. during inhalation, the pressure differential (y)/ flow rate (x) relationship was y = 0.1015x2 + 0.8343x (r2 = 0,9985). during exhalation, the pressure differential (y)/flow rate (x) relationship was y = -0.0106x2 + 0.0155x (r2 = 0,9873). this indicated that the flow rate closely followed the pressure differential (n = 5). furthermore, the ap was able to measure flow rate with great stability and reproducibility during all the experiments. results: valve resistance generated at low inspiratory flow rate (5 l/min) varied greatly between the different valves ranging from 9.5 to 0.27 cmh2o/l/s; however as the flow rate increased, variations were reduced (3.98 to 0.43 cmh2o/l/s at 60 l/min). the ability to close varied strongly from one valve to another: for some valves, expiratory flow did not pass through the inspiratory valve while for others, only partial closing could be achieved (85% of expiratory flow passed through the inspiratory valve). these results were confirmed by measuring the flow through the expiratory valve, maximum (100% of the initial flow rate) when inspiratory valves were completely closed. tilting the chamber did not seem to affect this result. ed measured with pediatric breathing parameters in coordinated and uncoordinated use was similar for four of the custom vhcs while with the other two vhcs, ed was lower. , and a high-speed camera (hxlink64,nac) and two different shapes of membrane models were used in this study. five catheter motions: 1) quiescent technique, 2) piston technique, 3) rolling technique, 4) twist technique, and 5) dynamic pressure technique, were performed 10 times each and the weight of secretion was measured by a digital scale. the negative pressure was set at 20kpa, suctioning time was counted 10 seconds. one-way anova and tukey test were used to analyze the obtained data. in experiment 1, the mean amount of secretion for 1) to 5) were 0.31, 0.48, 0.32, 0.43, and 0.45, respectively. there were significant differences between 1) quiescent technique and 2) piston technique (p = 0.025), 2) piston technique and 3) rolling technique(p = 0.039) on a flat membrane model with high viscous sputum. the high-speed camera showed that absorption was started when a catheter tip aperture and two side apertures were sealed with the high viscous sputum. as dynamic pressure technique, sputum was quickly absorbed right after the researcher released her thumb which bent the suctioning catheter. in experiment 2 with high viscous sputum on a tracheal membrane model, mean secretion weight 1) to 5) were 0.36, 0.31, 0.30, 0.42, and 0.43 respectively. there were no significant differences between these five techniques. in experiment 3 with low viscous secretion on a tracheal membrane model, mean amounts of suctioned secretion were 0.97, 0.76, 0.98, 1.01, and 1.15 respectively. there were significant differences between 2) piston technique and 4) twist technique (p = 0.042), 2) piston technique and 5) dynamic pressure technique (p = 0.000). in conclusion, the piston technique could absorb the most amount of secretion when a catheter tip was visible on a flat membrane model, however, the catheter motion which suctioned the most secretion was the dynamic pressure technique in a tracheal model despite the viscosity of the secretion. even though nurses had to carefully apply the level of negative pressure before their procedure, this result indicated that dynamic pressure technique is the most effective catheter motion to remove secretion on a tracheal model. background: respiratory syncytial virus (rsv) infection is the main cause leading to acute bronchiolitis in infants or children less than 2 years of age. children are more susceptible to rsv infection than adults, especially those who have hemodynamic-significant congenital heart disease or heart failure. in this study, we aimed to evaluate the possible risk factors leading to prolonged stay in the pediatric intensive care unit (picu) or hospital stay for chd children with rsv infection. methods: data were retrospectively retrieved of patients who had chd from jan 2011 to dec 2013. those patients who had concurrent rsv infections and underwent computed tomography imaging study were included as the study group. clinical presentations were recorded and classified. statistics used descriptive analysis and p < 0.05 was taken as significant. results: a total of 286 patients with associated congenital heart disease were included. the mortality rate was about 3% due to pulmonary edema, dysfunction or cyanosis. the total number of subjects whose age was below 1 year old was similar to those whose abstracts | s147 age was between 1 and 2 years old. there were 68 chd children with airway problems, including trachea-bronchomalacia, stenosis of the trachea or bronchus. patients aged less than 1 year old had longer hospital stay than those whose age was above 1 year old. the mean picu stay and the intubation period had a similar trend. in the comparison of groups without airway anomalies, the hospital stay in children who had hemodynamic-significant chd or heart failure (without associated airway anomalies) was 46.6 days compared to 11.6 days in children who did not have hemodynamic-significant chd or heart failure(without airway anomalies) (p < 0.05). in children with airway anomalies but did not fulfill the criteria of hemodynamic-significant chd or heart failure had longer hospital stay (22.8 days) than those without airway anomalies but with hemodynamicsignificant chd or heart failure (10.6 days) (p < 0.05). conclusions: patients with airway anomalies are not rare in children with chd, although the severity varies. lower airway anomalies were associated with longer hospital stay in chd children who were not hemodynamic-significant or heart failure. we found that airway problem is a risk factor for prolonged hospital or picu stay in chd children with rsv bronchiolitis. to achieve successful and sustainable outcome in chd children with rsv bronchiolitis, it is crucial to have early identification of concomitant airway anomalies in these children. childhood pneumonia and diarrhoea 1: global burden of childhood pneumonia and diarrhoea key: cord-276108-35rsrx3m authors: shulman, stanford t title: the history of pediatric infectious diseases date: 2004 journal: pediatr res doi: 10.1203/01.pdr.0000101756.93542.09 sha: doc_id: 276108 cord_uid: 35rsrx3m the history of pediatric infectious diseases closely parallels the history of pediatrics at least until the last century, because historically infections comprised the major causes of childhood morbidity and mortality, as they still do in the developing world. this history reviews developments in the field through the centuries and is writen so that it does not overlap the contribution to this series by baker and katz entitled ‘childhood vaccine development in the united states.' remarkable descriptions of selected pediatric infections existed long before the invention of printing, and early pediatric texts included many chapters devoted to various infections. coincident with the establishment of pediatric organizations in america in the late 19(th) and early 20(th) centuries, major attention was focused on diphtheria, infant diarrheal illnesses, tuberculosis, streptococcal infections and their complications, and other pediatric infections, and substantial progress was made. the american pediatric society (1888), the american academy of pediatrics (1930), the society for pediatric research (1931), and the american board of pediatrics (1933) all contributed to the evolution of the discipline of pediatric infectious disease, and numerous leaders of these organizations had significant infectious diseases interests. the establishment of the pediatric infectious diseases society, the pediatric infectious diseases sub-board, and an accreditation process for training programs, as well as sub-specialty textbooks and journal, further validated the development of this specialty, particularly in north america. the many remaining challenges related to infectious diseases in children (including hiv, emerging infections, antimicrobial resistance, opportunistic infections, and infections in the developing world) insure the future of the specialty. the genomic era of medicine and the tools of molecular biology will lead to new insights into pathogenesis, diagnosis, and treatment of infections. pediatric infectious diseases physicians can celebrate the past triumphs of the discipline and future achievements, all contributing to improved health for children. noted the complications of these illnesses; and the 11th century works of the prominent arab physician avicenna (ibn sina), who wrote on children's illnesses including tetanus, cough and catarrh, aphthae, ear drainage, seiriasis, fevers, pustules, throat inflammation, worms and diarrhea (flux) (1, 2) . for the next almost 500 y, there were virtually no pediatric writings. the invention of printing in the mid-15th century revived learning, and the first printed work on diseases of children was published in 1472 by the italian paolo bagellardo, including chapters on many common infections, including tinea capitis, otorrhea, ear abscess, cough, rheumatism and diarrhea (3) . two other similar books followed, that of metlinger (german) in 1473 and of roelans (belgian) in 1483. eucharius roesslin (german) opened the 16th century of pediatric texts with a text on midwifery and pediatrics, with reviews of the 35 most common ailments of children, including many infections, of course (2) . the book by leonellus faventinus de victoriis (italian) was published posthumously in 1544 and included a chapter on aphthae and another on measles and smallpox. the first english-language pediatric book was published in 1544 by thomas phaer, "the boke of chyldren" and included chapters on aposteme of the brayne (meningitis), scalles of the heed, styfnesse of the lymmes, bloodshoten eyes [kawasaki disease?], diseases in the eares, canker in the mouth, quynsye or swelling of throte, coughe, feblenesse of the stomacke and vomiting, fluxe of the belly (diarrhea), wormes, small pockes and measels, fevers, and consumpcion (1, 2) . in 1553 giovanne p. ingrassias (italian) differentiated scarlet fever (rossalia) from measles (1) . hieronymus mercurialis (italian) in 1583 published a pediatric text that mentioned the king's evil (scrofulous glands) and included 10 chapters on worms (1) . at the end of the 16th century, understanding of disease in children had barely advanced beyond the theories and observations of the greeks and romans, restated by the arab physicians, and clinical observation seemed of little value. significant advances, however, were made during the 17th century. the works of guillaume de baillou (french) published in 1640 were important for the first detailed description of whooping cough as a distinct entity, as he described an epidemic in 1578, as well as rubeola and scarlet fever. several important descriptions of diphtheria (morbo strangulatorio, angina puerorum) were made, with its epidemic nature highlighted by johannes sgambatus (italian) in 1620, its pathologic anatomy in 1646 by thomas bartholin (danish), who also commented on its contagious nature (1) , and its method of killing children (paedanchone or child-throttling) by marcus a. severinus (italian) in 1652. the second english language pediatric book, published by robert pemell in 1653, included chapters on lice, scab and itch, ulcers and sores in the head, pain and inflammation of the ears, oral ulcers, feavers, small pox and measels, rheums and cough, flux, worms, inflammation of the naval, and saint anthonie's fire (erysipelas or ergotism) (1, 2) . the third english book appeared in 1664, written by j. starsmare and included much the same topics but making the first mention in english of scrofula. franciscus sylvius de le boe (dutch) was a careful clinician and anatomist who published a book on diseases of infants in 1674 that included the usual topics. sylvius is remembered best for the aqueduct of sylvius and the sylvian fissure. thomas sydenham, the most respected english physician of the 17th century, deserves mention here for his careful description of chorea (1686), his very detailed description of measles (1670), and his account of scarlet fever (1675), which surprisingly failed to mention pharyngitis. thomas willis, who described the circle of willis, wrote a careful account of pertussis (chincough) in 1675 and said, "the plan of treatment which is usual in other varieties of cough is seldom of any use in this, which is the reason why old women and gypsies are consulted more often than doctors" (1) . near the end of the 17th century a small book on diseases of infants was published in london in 1689 by walter harris and became very popular, with 18 editions over 53 years. harris also wrote an essay on venereal diseases, a treatise on plague, and in 1721 strongly advocated inoculation against smallpox (4). his comments about summer diarrhea of infants are described below. in summary, the 17th century was associated with a rebirth of medicine, and for the first time since hippocrates clinical observations became important. anatomists laid a foundation for morbid anatomy/pathology, and there was initial rejection of some of the ancient theories of disease (1) . in the field of pediatric infectious diseases there was slow progress, but chorea, scarlet fever, scrofula, and pertussis had been recognized clearly as specific diseases. the history of pediatric infectious diseases (but not the medical specialty) in america predates the establishment of the united states. colonial children were afflicted by many epidemic contagious diseases, and a number of very graphic descriptions have been recorded, many referred to in thomas e. cone's history of american pediatrics (5) . smallpox that affected children was described in 1629 on the talbot, a ship en route from gravesend, england, to new england. during the voyage, the reverend higginson wrote an account of his children who became ill with smallpox, including his young daughter who died at sea. epidemics of smallpox, endemic in england through the 17th century, were described in massachusetts in 1633 and again in 1677, when about one-fifth of boston's population succumbed to this scourge (5) . the first american medical publication, a broadside on smallpox that discussed diagnosis and therapy, was written in 1677 by the pastor-physician reverend thomas thacher (1620 -1678) of boston, who practiced part-time pediatrics (6) . measles was recorded in boston and connecticut in 1657-1658 and again in 1687-1688, with many children afflicted but apparently relatively few deaths. diphtheria, which was often confused clinically with scarlet fever, was associated with great mortality. the first recorded north american epidemic of diphtheria occurred in 1659 in roxbury, ma, with subsequent probable outbreaks documented in 1686 in virginia and 1689 in new london, ct. scarlet fever, often mistaken for both measles and diphtheria, was first reported in the colonies by 164 shulman both john marshall and cotton mather, who wrote of an epidemic in boston from september to december, 1702. the next epidemic in new england did not occur until 1735. whooping cough caused an extensive epidemic in 1659 in young children, but there are no records of subsequent epidemics until 1738 (5) . summer diarrhea in infants was a very serious problem, with very high mortality rates. in england, walter harris (1647-1732), one of the earliest great "pediatrists" wrote in 1689 "from the middle of july to about the middle of september, the epidemical gripes of children are so rife every year, that more of them usually die in one month, than in three or four at any other time. . ." (4) in the colonies, john josselyn in 1674 and john marshall around 1700 wrote about children dying of bloody flux (dysentery) and fever (5) . the pace of progress regarding infectious diseases of children accelerated during the 18th century, particularly with respect to prevention of smallpox by inoculation or variolation. smallpox was an almost inevitable illness of childhood and was one of the most common causes of death because of its high mortality rate. it was reported, for example, to kill 10% of swedish children yearly. inoculation with matter from a smallpox subject was introduced into western europe from constantinople around 1720, with limited mortality from the procedure and resulting immunity (1). other advances were being made as well. richard wiseman (english) , surgeon to king charles ii, wrote extensively about the king's evil (scrofula) and mesenteric adenitis. jean astruc (french) in 1746 published an english edition of his lectures on diseases of children that included pertussis, infant diarrhea, worms, purulent lung disease, and scrofula. astruc was among the first to emphasize the importance of a thorough and methodical clinical exam of children. john fothergill (english) in 1748 published an important work on ulcerative pharyngitis, with descriptions of diphtheria and scarlet fever (1). the mid-18th century saw the identification of varicella as a disease distinct from smallpox. françois boissier de sauvages (french) in a 1760 book on diseases of children described what he thought was a variety of smallpox that he termed "la vérole volante" or the fleeting variola (smallpox). the description is of varicella, which was very clearly distinguished as a separate illness by william heberden the elder (english) in 1767 (1) (2) (3) . nils rosen von rosenstein (swedish) published a very important pediatric work in 1765, which was the most progressive and scientific book on pediatrics up to that time (1). it included a detailed description of a 1744 epidemic of scarlet fever, 14 varieties of infant diarrhea (obviously he was a splitter rather than a lumper), and also described varicella but considered it "the chrystalline or watery smallpox" (1). he described postscarletina dropsy with bloody urine (poststreptococcal nephritis) and had sufficient insight about pertussis to state that "the true cause of this disease must be some heterogeneous matter or seed which has a multiplicative power as is the case with smallpox. . . we find that it is communicated by infection and that a part of it is attracted by the breath down into the lungs." robert whytt (scottish) in 1768 published what some consider the finest clinical description of any disease to that time in his "observations on the dropsy in the brain," tuberculous meningitis, in which he detailed the three clinical stages of this disease as well as the autopsy findings (1) . around this time hugh smith (english) importantly focused public attention upon the staggeringly high mortality rates among children. he showed that from 1762 to 1771 about two-thirds of children born in london died before the age of five years and that about 75% of the deaths occurred before two years of age (1, 2) . at this time george armstrong founded the first dispensary for children in 1769, which ultimately led to the establishment of children's hospitals. he published a work on the diseases most fatal to infants in 1767, and he wrote in detail about the treatment of the chin-cough (pertussis). michael underwood (english) was probably the most advanced 18th century writer on the diseases of children (1) . his treatise, first published in 1784, was reprinted in 17 editions until 1848. he provided the first description of sclerema and poliomyelitis and wrote about coryza maligna, which was either congenital lues or nasal diphtheria. joseph clarke (irish) in 1789 described an outbreak of fatal "nine-day fits" among neonates (neonatal tetanus) at the lying-in hospital of dublin. hyacinthus andreas (spanish) had published an account of this condition at the end of the 17th century (1). it was in 1798 that edward jenner published his report of 23 years of observation and experimentation with the variolae vaccinae, or cowpox, to prevent smallpox. this proved much safer than the procedure of inoculation with smallpox matter (variolation) used earlier in the 18th century, as described above. at the end of the 18th century, pediatrics was characterized by increased awareness of the value of children's lives, the beginning of institutions to provide medical care for children and the beginning of instruction of medical students in children's diseases. additional important pediatric infectious diseases had been described, including tuberculous meningitis, varicella, neonatal tetanus, and poststreptococcal nephritis (1). jenner's studies provided the means to prevent the great morbidity and mortality related to the dreaded smallpox. epidemic diseases were better described during the 18th century in colonial america compared with the earlier period, and there was clear recognition of the impact of smallpox, diphtheria, scarlet fever, measles, influenza, tuberculosis and whooping cough, particularly upon children. a very severe new england epidemic of diphtheria in 1735-1740 killed more than 5000 individuals, mostly children, and was later called "the most horrible epidemic of a children's disease in american history" (7) . early accounts by jabez fitch (1736) of new hampshire and jonathan dickinson (1740) described these events (2) . samuel bard (8) . this work about diphtheria emphasized its infective etiology, "drawn in by the breath of a healthy child," and urged prevention by immediate removal of the young children in the family as soon as a first case appeared in a household. in 1736 william douglass (1691 -1752 of boston provided what is considered the earliest complete description of scarlet fever, terming it angina ulcusculosa (5) . in 1789, dr. benjamin rush (1745-1813) described a widespread epidemic of scarlet fever ("scarlatina anginosa") occurring in philadelphia in 1783 and 1784, while pertussis was described in detail in 1776 by lionel chalmers (1715 chalmers ( -1777 in an account of the weather and diseases of south carolina (9) . dysentery ("bloody flux") was emphasized as a serious and very common problem of children particularly in summer when benjamin rush wrote in detail about "cholera infantum" (and coined the term) in 1777 (10) . rush was the most influential american physician of his day and a signer of the declaration of independence, and he lectured and published regarding pediatric disorders, including cholera infantum and diphtheria (11) . cholera infantum, or summer diarrhea, appeared each year in epidemic form and emerged later as a particularly important problem for young children, as more crowded urban areas developed. in 1794 rush also described a major epidemic of yellow fever in philadelphia which killed about one-eighth of the population (5) . particularly severe epidemics of measles were noted in 1688, 1713, 1740, 1758, and 1772. more than 900 children in charleston, sc died in the 1772 epidemic alone (9) . cotton mather's diary in 1713 recorded the death of his wife, the maid, his neonatal twins, and another child in his family within a 12-d period (5) . this serves as a striking reminder about this now-preventable illness. other primarily pediatric illnesses including thrush, mumps, tinea capitis, and worm infestations also were clearly described in the colonies of the 18th century (5) . in contrast to europe, where smallpox was an endemic illness of childhood, in the colonies smallpox occurred in large epidemics with about 20-year periodicity and affected children as well as older susceptible individuals. this became an important issue during the revolutionary war, when the troops of the continental army (but not the british forces) were ravaged by smallpox until general george washington at valley forge decided to inoculate all susceptible troops. this act probably saved the war effort (12) . from 1800 to about 1870, the major causes of death in children were tuberculosis, diarrhea of infancy, bacillary dysentery, typhoid fever, and the highly contagious diseases of childhood, especially scarlet fever, diphtheria, and lobar pneumonia (5). significant fluctuations occurred. for example, for the first three decades of the 19th century, the severity of scarlet fever was less than observed previously but then around 1830 increased dramatically. by 1840 scarlet fever had become the leading cause of death among the infectious diseases of childhood in the u.s., great britain, and europe (13) . changes in the virulence of prevalent group a streptococcal strains would seem most likely responsible for such fluctuations, as seen in new york city, for example, where only 43 scarlet fever deaths were recorded from 1805-1822, but 4874 deaths by 1847 (14) . reports about other pediatric infections also exist. in 1813 nathan smith of lebanon, nh, founder of dartmouth medical school, successfully treated joseph smith (1805-1844), an unrelated 7-year-old boy, for osteomyelitis, removing bone from the left lower leg but avoiding amputation. long-term drainage apparently occurred with discharge of 14 additional pieces of bone, and crutches were used by the child for more than three years. joseph smith, who retained a slight limp, later founded the mormon church (11) . for a period of about 40 years, from 1813-1852, eli ives, the first u.s. medical school faculty appointee in pediatrics, lectured yale medical students on the diseases of children. the surviving lecture notes show that these lectures included a number of infectious diseases topics as they impacted children (11) . also in the first half of the 19th century, william potts dewees (1825), george logan (1825), and john eberle (1833) each published very early pediatric texts, each of which included sections on the infectious illnesses of children. dewees of philadelphia was an adjunct professor of midwifery, and his text, the first truly comprehensive american pediatrics book, has more than 60 pages devoted to infections, including not only epidemic illnesses but also abscesses of the hip joint and ear, worms, and whitlow (paronychia) (15) . epidemic spotted fever, or cerebrospinal meningitis, was described in detail by elisha north (1771-1843), who reported the 1807 connecticut outbreak of meningococcal infection (5) . in 1834 william wood gerhard (1809 -1872) provided the first american description of tuberculous meningitis (actually describing 30 children he saw in paris), and in 1836 and 1837 he distinguished typhus from typhoid in children at the pennsylvania hospital. gerhard also in 1834 was perhaps the first to record percussion and auscultation findings in pediatric pulmonary diseases (16) . his parisian training clearly exposed him to laennec's critically important invention, the stethoscope (5). very substantial advances were made in european pediatrics, particularly with respect to infectious diseases, throughout the 19th century. john cheyne (scottish, irish) published a number of important works, including "the pathology of the membranes of the larynx and bronchia" in 1809, a description of the 1817-1819 dublin fever epidemic, and three studies of cynanche trachealis (croup), and described cheyne-stokes respirations (3). pierre bretonneau (french) described the contagious nature of typhoid fever (1819 -1829) and of diphtheria (1826). he performed the first successful tracheostomy for diphtheria on july 1, 1825, on a child, elizabeth de puységur (3). in 1821 he distinguished typhoid from typhus clinically. the most important pediatric text of the early 19th century was by charles-michel billard (french). this 1828 work built upon that of bichat and laennec, who provided the initial scientific basis of 166 shulman medicine, and classified pediatric disorders (including infectious diseases) based not upon symptoms but upon pathologic lesions, i.e. upon autopsy findings (3) . armand trousseau (french) performed the first tracheostomy in paris (1831), described laryngeal tuberculosis, cutaneous and mucosal diphtheria, pediatric cholera, and he originated the technique of thoracentesis in pleurisy. frédéric rilliet (swiss) wrote on typhoid in children (1840), epidemic measles (1847), mumps (1850), and cholera (1856). his text (1838 -1843) with antoine-charles-ernest barthez (french) included classic descriptions of tuberculosis of the bronchial glands, bronchopneumonia, and chronic pleurisy. charles west (british) (1816 -1898) was considered the greatest english "pediatrist" of the second half of the 19th century. in 1852 he established the children's hospital in great ormand street, london. his pediatric text of 1848, which went through seven editions and numerous translations, included outstanding descriptions of infantile tuberculosis and poliomyelitis and emphasized the importance of breast feeding in the prevention of infantile diarrhea. johann rehn (german) studied epidemic jaundice (infectious hepatitis) in children (1869), while his countryman eduard heinrich henoch, a pupil of schönlein, described abdominal purpura (henoch-schönlein purpura) in 1874. nil f. filatoff (or filatow) (russian) published a series of lectures on the infectious diseases of children (1885-87), in which he described "scarlatinal rubella" termed "fourth disease" or filatoff-dukes disease (3). marie-jules parrot (french) described the pseudoparalysis of congenital syphilis (1872) that still bears his name (17) . jacques-joseph grancher (french) wrote extensively on tuberculosis (1872-1890) and pioneered isolation and antisepsis (infection control) at the hôpital des enfants malades, paris (1889 -1890), housing infectious patients in wire cages and using surgical gowns for staff (3) . bernard-jean-antonin marfan (french) wrote important works on pediatric typhoid (1894), peritonitis (1894), congenital infections (1897), infantile gastroenteritis (1900) and diphtheria (1905) . friedrich bezold (german) in 1877 provided the first clear description of mastoiditis (18) . henry ashby (british) was a pediatrician and public health officer who led the movement in britain to advocate for a pure milk supply during the 1890s and early 1900s. sir arthur newsholme (british) in the late 19th century and early 20th century provided extremely important data related to changes in infant, child, and maternal mortality primarily due to infectious diseases, particularly rheumatic fever (1895), epidemic diphtheria (1898) , and tuberculosis (1906) (3). before 1880, there was no organized group of physicians for children in the u.s. and, of course, no specific subspecialty fields within health care for children. the section of diseases of children of the american medical association was organized in 1880 at a meeting of the ama in richmond, va, with abraham jacobi chosen as president and thomas morgan rotch as secretary (7, 19 (3, 5) . he was the first to teach medicine at the bedside (3). jacobi is often called the "father of american pediatrics" and wrote extensively on a variety of pediatric problems, with his most frequent subjects related to infectious diseases, notably diphtheria. he advocated the use of boiled milk for infants (for nutritional reasons as well as to prevent the gastroenteritides). the inaugural issue of the ama's american journal of obstetrics and diseases of women and children in 1868, the first partially pediatric journal in the u.s., included an article on croup by jacobi. jacobi was an ardent social and political activist, striving to improve the circumstances of children. because the ama group began to flounder and the membership of the obstetrics and gynecology sections refused to allow pediatrics to form a separate section, a new group, the american pediatric society, the parent of organized pediatrics in the u.s., held an organizational meeting on september 18 -20, 1888, at the arlington hotel in washington d.c., with 14 physicians present (7, 19) . credit for forming the group is given to job lewis smith (1827-1897) of bellevue medical school and william booker (1844 -1921) of baltimore, the first clinical professor of the diseases of children at johns hopkins. jacobi was elected the first president, and there were 43 founding members, predominantly from the northeast, including william osler, who later served as the fourth aps president (20) . four papers were scheduled to be presented (although it is not clear from the minutes that any of them in fact was presented), including "treatment of whooping cough by antipyrin" by l. emmett holt, sr., of new york (21) . holt was professor of pediatrics at the new york polyclinic hospital and attending physician at babies hospital in new york. he was a founder of the american pediatric society and served as president in 1898 and then again in 1923. holt's presidential address in 1898 recapped his personal experiences with new york city children's hospitals, pointing out the discouraging 50% mortality for hospitalized infants and the very frequent nosocomial infections that occurred. he advocated care in the country, away from the crowded cities, during the summer months (21) . this theme was echoed by henry koplik of new york, aps president in 1900, who reported the continued problem of summer diarrhea and recommended ambulatory care and a "colony or camping system" with care provided by live-in mothers (21) . although it had improved somewhat compared with colonial times, the plight of children at the time of the founding of the american pediatric society in 1888 continued to be hazardous. coincident with the industrial revolution, mortality rates had climbed substantially from early in the 19th century to the later years of the 19th century as major crowded urban areas developed. life expectancy around 1888 was less than 50 years, infant mortality approached 200 per 1000 births, and neonatal mortality was about 50 per 1000 births (5, 21, 22) . the infant mortality rate in 1880 in new york city, a particularly crowded urban area, was 167 history of pediatric infectious diseases as high as 288 per 1000 live-born infants, primarily related to various infectious processes. infectious diseases such as diarrhea, diphtheria, scarlet fever and tuberculosis dominated as the major causes of morbidity and mortality among children, and they had yet to be impacted by the just-emerging scientific base of medicine. the science of bacteriology, founded on the landmark discoveries of louis pasteur in paris, robert koch in berlin, and others in the early 1880s, had not yet impacted child health. roentgen had not yet discovered x-rays. biochemical analyses were not available for infants and children. inadequate sanitation, impure water and unsafe milk supplies all contributed very significantly to the spread of infectious diseases among infants and children, and particularly to those living in the very crowded circumstances that promote transmission. the early years of organized u.s. pediatrics were marked by a number of landmark advances in the diagnosis and treatment of infectious diseases of children, with substantial reduction in infant mortality rates, to 189/1000 live births in new york city in 1900, with rates as low as 147 in chicago and as high as 311 in biddeford, me (5). the importance of infectious diseases to the relatively small number of founding members of the american pediatric society, a group of distinguished physicians who devoted much or all of their effort to the improvement of the health of children, is reflected by analysis of the topics of the papers presented at the early annual scientific meetings of aps. the first scientific meeting of the aps held in washington on september 20, 1889, and the next day in the then-new johns hopkins hospital included many presentations devoted to classic infectious diseases. these included two papers devoted to diphtheria, two elaborate bacteriologic studies of the stools in infant diarrhea (booker isolated 19 bacterial varieties and jeffries 28 different organisms), a paper on malaria in new york city, two papers related to infant feeding and prevention of infant diarrhea, and assorted case reports (7, 11) . at least 46 of the 87 papers delivered at the first five annual scientific meetings (1889 -1893) directly addressed infectious diseases topics, including diphtheria (8), diarrhea (7), scarlet fever and rheumatic fever (6), tuberculosis (6), pneumonia and empyema (6), typhoid fever (3), pertussis (2), lues (1), vulvo-vaginitis (1), malaria (1), and miscellaneous infections (5) (19). this dominance of the scientific agenda by infectious diseases topics attests to their extreme importance as the major causes of morbidity and mortality in childhood at the end of the 19th century. hippocrates had recognized the unfavorable implications of a sort of spiderweb (or membrane) in patients with tonsillar ulcers (2) , and both bard's 1771 contribution and the introduction of tracheostomy for laryngeal diphtheria in france in the 1820s have been noted (vide supra). diphtheria was of particular concern at the early american pediatric society meetings, as the laryngeal form of the disease in that era was almost invariably fatal, despite the use of tracheostomy. the few years just before the founding of the aps and the early years of the organization represented a period of landmark advances in understanding the etiology of this illness and in the development of markedly improved treatment modalities. in 1884 friedrich loeffler proved that a specific bacterium was the etiologic agent of diphtheria. the introduction of the o'dwyer intubation tube in 1885 received great attention because for the first time it enabled successful treatment of the suffocation that was associated with laryngeal diphtheria (23) . joseph o'dwyer (1841-1898), attending physician at the new york foundling hospital, a facility for unwanted children, was a founder of american pediatric society, and he served as president of aps in 1896 (19) . o'dwyer's 1896 presidential address reviewed his invention and experience with the intubation tube (7, 21) . at the 7th annual scientific meeting of the aps in 1895, papers from four groups regarding the dramatic, even revolutionary, effects of diphtheria antitoxin for therapy and prevention were presented. this led to the adoption of a formal resolution: "resolved, that, in the opinion of the society, the evidence thus far produced regarding the effects of diphtheria antitoxin, justifies its further and extensive trial" (7, 19) . a committee was apparently appointed, as the 1896 annual meeting included a report from the american pediatric society's collective investigation of the antitoxin treatment of diphtheria in private practice, chaired by l. emmett holt. this confirmed the spectacular results of the 1894 french report by roux, martin, and chaillou from the pasteur institute in paris. the 1897 meeting received a report from the committee on collective investigation of the antitoxin treatment of laryngeal diphtheria in private practice, chaired by william p. northrup (24) . these clinical studies of diphtheria equine antitoxin represented the first pediatric investigations in the u.s. of a national scope. the four committee members analyzed 1704 cases of laryngeal diphtheria treated with antitoxin who were submitted by aps members and concluded that antitoxin lowered the necessity for intubation from 90% to 39% and the mortality rate from 73% to 27% in this severest form of diphtheria (24) . the schick test to assess susceptibility to diphtheria was introduced by bela schick in 1913. emil von behring of germany, who initially discovered diphtheria toxin and developed the diphtheria antitoxin that was of such great interest and importance, was awarded the first nobel prize in medicine in 1901 for this work. tuberculosis and meningitis. tuberculosis was another very common and serious problem of childhood, and william osler was very actively involved in its study before moving to oxford, england, in 1905 to become the regius professor. osler's commitment to pediatrics is apparent from his frequent participation in the aps meetings to discuss tuberculosis, pertussis, chorea and carditis, croup, peritonitis and other topics, as well as from the 10% of his writings which are on pediatric subjects. he was particularly interested in tuberculosis of childhood and presented a paper at the third aps meeting in 1891 on pulmonary tuberculosis in children, in which he divided it into acute, subacute, and chronic or protracted forms (20, 25) , and another in 1893 that included autopsy findings (7) . papers on childhood tuberculosis were presented at virtually all of the aps scientific meetings during the early decades. 168 shulman particularly noteworthy milestones included walter carr's 1912 presidential address that reported a 71% decline in extrapulmonary tuberculosis, the 1927 report by the parisian armand-de lille of the diagnostic value of gastric aspirates in infants, the 1930 report by bela schick and colleagues on the bcg vaccination introduced three years earlier in france, detroit's joseph johnston's discussion in 1936 of the evolution of pediatric tb to the adult type by endogenous reactivation, and the exciting initial report in 1947 by john lyttle and colleagues from los angeles of the recovery of a patient with miliary tb after streptomycin treatment (7) . meningitis, including the invariably fatal tuberculous meningitis, was also a common affliction of children in the late 19th century. abraham jacobi wrote about meningitis that the u.s. "more than any other country has been invaded by this plague" (26) . at the 1896 meeting of aps, august caillé (1854 -1935) presented a paper on "tapping the vertebral canal in the lumbar region" and the following year a paper on "local treatment for tubercular meningitis" (19). these were the first reports to the aps of diagnostic lumbar puncture, after it had been introduced by quincke in 1891 as a treatment modality (2, 7) . two additional papers presented in 1896 discussed lumbar puncture in the subarachnoid space, which provided a scientific basis for studying meningitis, with measurement of sugar and protein, and a potential route of administering therapy, such as it was in the late 19th and early 20th centuries (7). summer diarrhea and the milk supply. in addition to the introduction of intubation techniques and diphtheria antitoxin, an exceptionally important advance during the late 19th century and early 20th century was the result of efforts by concerned pediatricians and others to secure a safe and sanitary milk supply for infants (5) . nonbreast-fed infants experienced particularly high mortality rates, because much of the cow milk supply was "swill milk," which came from cows fed only distiller's mash, housed in incredibly filthy conditions, without fresh air, exercise or hay, many of which were also infected by bovine tuberculosis (2, 5, 7, 22) . job lewis smith, who was one of the first to differentiate rubella from rubeola and wrote several papers on neonatal tetanus, served as the second aps president in 1890, 18 years after he had written in his textbook that more than half of new york's infants who were spoon-fed (i.e. not nursed or wetnursed) in the summer, died before fall (27) . he strongly urged milk sterilization and wrote and spoke about the dangers of artificial infant feeding. bacteriologic studies of milk began to establish a scientific basis for the association of impure milk with infant diarrheal illnesses, including the work of the pediatrician escherich in 1886, shiga in 1898, and flexner in 1900. the genera escherichia and shigella (as well as the species shigella flexneri) honor these pioneer bacteriologists. william d. booker's major area of interest was summer diarrhea of infancy. he presented a paper at the first aps scientific meeting in 1889 on that topic (7), and he devoted his presidential address in 1901 to the early history of summer diarrhea in america from colonial times (21) . the problem of summer diarrhea and its increasingly clear relationship to contaminated milk in the urban poor was highlighted by the report of 1500 infant deaths per week in new york city during the hot weather summer months that were associated particularly with bottle feeding (28) . considerable attention of organized pediatrics was focused on this issue, particularly by henry l. coit (1854 -1917) , smith, rotch, isaac abt, schick, and others, who advocated movement toward certified safe milk (5, 11) . coit began as early as 1887 to work tirelessly to ensure a safe milk supply for infants, after the death of his young son, by educating the public, lawmakers, and the medical community (5) . he coined the term "certified milk" and established the first medical milk commission in new jersey (19). henry koplik (president of aps in 1900) established the first american clean milk depot in new york in 1889 (called gouttes de lait), and thomas morgan rotch (a founder of aps and president in 1891) organized the walker-gordon farms that led to the first milk laboratory for preparing safe milk formulas. pasteurization of milk by heating was introduced in europe before 1890 (and had been used for wine since 1864!), and it was promoted particularly by jacobi in the u.s. during the 1890s for its ability to prevent milk-borne infections. many other academics preferred certification as an alternative to pasteurization, fearing that the latter would alter the chemical composition of milk and promote gastroenteritis. this proved wrong (29) . jacobi collaborated with the philanthropist nathan straus to establish pasteurization plants and milk stations for poor infants in new york beginning in 1893. a reduction in infant mortality of 65% was observed in just one year in the foundling hospital on randall's island after a pasteurization plant was established there by straus (2, 5). however, it was not until 1908 that chicago became the first city in the world to require pasteurization of milk, with many cities following thereafter (5) . controversy in this area was apparent early on, best exemplified perhaps by the resignation from the aps in 1892 of arthur v. meigs of philadelphia, who argued vehemently against milk sterilization and who continued to reject the germ theory of disease until his death in 1912 (6, 21) . thomas m. rotch (1849 -1914) was america's first full professor of pediatrics, appointed at harvard in 1893. rotch published a major textbook of pediatrics in 1896 as well as early reports of the value of the roentgen ray in pediatrics, in addition to his detailed studies of milk. although extremely focused on the biochemical composition of milk, calculating in minute detail the precise amounts of protein, fat and sugar content of milk for infants, he also recognized the importance of a safe milk supply and worked to achieve that goal. the improved milk supply was complemented by studies, primarily at johns hopkins, by holt, james gamble, w. mckim marriott, john howland, and others, that led to understanding the roles of acidosis and dehydration in contributing to the mortality of infants and children with acute diarrhea. this led directly to effective rehydration and correction of electrolyte imbalances in such children with improved outcomes (25) . scarlet fever. in the latter decades of the 19th century, case-fatality rates for scarlet fever were very high, particularly in the youngest children. holt's 1897 textbook, the diseases of infancy and childhood, indicated the case-fatality rate to be as high as 55% in those under one year and 7% to 22% in those under three years (30) . wide year-year fluctuations were some-169 history of pediatric infectious diseases times observed, with annual death rates during the decade of the 1850's, for example, from as low as 6/100,000 to a high of 272/100,000 population. representative case-fatality rates during the latter years of the 19th century were 12.3% in new york in 1889, 20% in 1886 -1888 in providence, ri, and 11.8% in philadelphia in 1897 (21.8% for those 1-5 years old) (5) . in addition to person-person spread of streptococcal infections including scarlet fever, contaminated milk was also shown to produce explosive epidemics of very acute streptococcal pharyngitis with high mortality. this provided an additional reason to support pasteurization of milk (7) . by the close of the 19th century, scarlet fever had overtaken diphtheria as a cause of death, occurring with great frequency and often with high case-fatality rates. the 1894 pediatric text of louis starr (1849 -1925) described scarlet fever as the most widely disseminated of the childhood exanthems and "the most dreaded of all the diseases of children." (31) poliomyelitis. poliomyelitis, which was initially described in underwood's first edition in 1784, was brought to general medical attention by jacob von heine (german). von heine was a pioneer of orthopedics who published a classic monograph on infantile paralysis and its resultant deformities in 1840, and he recognized the spinal cord localization of the pathology (3). the classic french pediatric text of rilliet and barthez (1838 -1843) provided an early account of polio, and guillaume-benjamin-amand duchenne (french) localized the lesion in polio to the anterior horn cells in 1855 (18) . later in the 19th century, oscar medin (swedish) first noted the epidemic character of polio when he observed an outbreak of 44 cases in stockholm in 1887 (18) . in 1894 a larger epidemic of 132 cases occurred in rutland county, vt (5). from the turn of the century until about 1915, the pediatric community focused particularly upon major public health and welfare issues that adversely affected children, working particularly hard to improve the milk supply. walter l. carr's 1912 presidential address to the aps very clearly spelled out the impressive improvements in the health of children that had occurred during the early years of the 20th century (7) . infant mortality in greater new york city declined 40% from 203/ 1000 live births in 1898 to 120 in 1911. as a consequence of the efforts to improve the milk supply, diarrheal deaths had declined 43%. mortality from measles, scarlet fever, pertussis, and diphtheria had declined 54%, while that from acute respiratory disease including pneumonia fell 32% (7) . during the period from 1881 to 1914, the etiologic agents of more than 30 infectious diseases were identified (32) . as microbiologic advances were made, american pediatric society meetings continued to include many papers related to epidemic infectious diseases including summer diarrhea, poliomyelitis, typhoid fever, gonococcal infection, and meningococcal meningitis. increasingly large u.s. poliomyelitis epidemics occurred, primarily affecting children, for example in new york city in 1907, with almost 3000 cases and up to 12% mortality (7) . this peaked in a 1916 epidemic in the northeast with almost 30,000 cases and 6,000 deaths, many in the new york city area, leading to massive public anxiety and aggres-sive public health measures including quarantine and travel restrictions (5) . progress in understanding the etiology and pathogenesis of polio was made early in the 20th century. in vienna in 1909 landsteiner and popper transmitted polio to monkeys by intraperitoneal injection of spinal cord material from a child who died early in the course of polio. also in 1909 simon flexner (of shigella flexneri fame) and paul lewis in new york extended those studies to show transmission to monkeys also after s.c., i.v., or intracerebral routes of inoculation and produced disease using filtrates of nasopharyngeal washes from polio patients (5) . additional flexner studies from 1910 -1917 showed that sera from monkeys that recovered neutralized the infectivity of polio material, that intrathecal injection of convalescent sera within 24 h of inoculation prevented paralysis, that recovered monkeys were protected against subsequent inoculation, and that recovered human patient sera contained antibodies to the infectious agent (5) . great effort was devoted by several groups to use intrathecal administration of convalescent polio sera to treat children with acute poliomyelitis but this proved unhelpful (5) . the development of the iron lung by philip drinker in the late 1920s was a noteworthy therapeutic advance for affected patients. during the period from 1900 to 1915, the application of serum therapy to the management of diphtheria, meningococcal and streptococcal infections served as topics for many aps presentations (19). jacobi's second aps presidential address, in 1906, was entitled "the tonsil as a portal for microbic and toxic invasion," while that of j. l. morse in 1913 reviewed the high mortality of pertussis, especially in infants, and proposed stringent isolation (21) . specific therapy for congenital syphilis with salvarsan, introduced by ehrlich two years earlier, was reported by lafétra in 1912, with dramatic benefit (7) . in his aps presidential address in 1923, l. emmett holt summarized the dramatic improvement in mortality in those less than five years old from infectious diseases in manhattan and the bronx from 1896 -1897 to 1921-1922 , with approximately an 80% decline in diarrheal deaths, diphtheria and croup, and 60% for pneumonia (33) . over the next 2 decades (~1915-1938), academic pediatricians and their research were focused particularly upon nutrition and the biochemistry of health and disease, which during this time somewhat eclipsed infectious disease concerns (21) . nevertheless, syphilis, tuberculosis, pertussis, measles, rheumatic fever, streptococcal infections, polio, and meningitis continued to interest those caring for children, as reflected by papers presented at the annual aps meetings. active immunization against diphtheria using toxin and antitoxin was introduced by alfred hess in the u.s. in 1916 (7) . at the end of this era, a particularly interesting paper was presented in 1937 by francis schwentker, who reported the treatment of meningococcal meningitis with s.c. and intrathecal para-aminobenzenesulfonamide (sulfanilamide) (7) . the first use of an antimicrobial agent in the u.s. was by future aps president a. ashley weech, whose unsuccessful treatment of a physician's child with h. influenzae meningitis with the sulfanilamidecontaining compound sulfachrysoidine in 1935 has been well documented (34, 35) . the actual administration of this agent was by the chief resident at babies hospital in new york, f. 170 shulman howell wright, who later served as chair of pediatrics at the university of chicago and president and executive secretary of the american board of pediatrics (35) . during this era, several aps presidential addresses concerned infectious disease issues, including that by linnaeus lafétra in 1918 regarding the need for preventive measures against infectious diseases and rheumatic fever in children two to six years old; by thomas s. southworth in 1920 on the communicability of acute pneumonia and the need for isolation of such patients, as was done for tuberculosis patients; by l. emmett holt in 1923 highlighting the decline in infectious diseases, particularly diarrhea, diphtheria and acute respiratory disease (as discussed above); and by henry f. helmholtz in 1937 on infections of the renal parenchyma and the importance of stasis in predisposing to urinary tract infection (7, 19) . during this period the first pediatric department with several identified subspecialists was developed by edwards a. park at johns hopkins beginning in 1926. under the previous leadership of john howland from 1912-1926, there had not been any special clinics or pediatric subdepartments at hopkins, with the exception of a clinic for the treatment of congenital syphilis. curiously it was lawson wilkins, later known as the father of pediatric endocrinology, who initiated and organized the congenital syphilis clinic as an intern (25) . as a discipline, infectious diseases did not figure as prominently as cardiology, endocrinology, neurology and other nascent subspecialty areas under park's leadership. this theme was replicated in most other academic departments as subspecialization began to develop. a few exceptions were pediatricians known for their expertise in contagious diseases, some of whom were particularly interested in vaccine development. these included bela schick at mt. sinai and at albert einstein in new york, hattie alexander and horace hodes at columbia university, joseph stokes at university of pennsylvania, russell blattner at baylor, william bradford at rochester, amos christie at vanderbilt, katherine dodd at vanderbilt and cincinnati, edith lincoln at new york university, louis sauer at evanston, il, and john zahorsky in st. louis. by 1938, when the american pediatric society was a halfcentury old, life expectancy had increased to over 60 years, infant mortality had declined to about 55/1000 and neonatal mortality to about 30/1000 (22) . sewage and sanitation had improved greatly, which along with much safer milk supplies had led to a marked fall in diarrheal illnesses of infancy. a few vaccines had been introduced, but antibiotic therapy was limited to the early use of sulfanilamide. at the 50th annual meeting of aps in 1938, the first held in conjunction with the young society for pediatric research (spr), important papers presented included that of trask and paul, reporting the isolation of poliovirus from nasal washes and stools of asymptomatic patients, several related to the pathogenesis of pertussis, that of lyttle showing elevated aso titers in acute glomerulonephritis, hodes' report of an irradiated rabies vaccine, and stokes' isolation of various strains of influenza virus. these works served as the prelude to the much more dramatic advances to come, related to the pathogenesis, diagnosis, and treatment of viral and bacterial infections of children (7). between 1930 and 1933, three new pediatric organizations emerged: the american academy of pediatrics in 1930, the society for pediatric research in 1931, and the american board of pediatrics in 1933. the eastern society for pediatric research, organized in 1929, became a national organization (also including mexico and canada) called the society for pediatric research (spr) in 1931, with the goals to foster research in pediatrics and to serve the younger pediatric faculty (ͻ45 years old), as the aps meetings were quite closed to junior investigators. the first meeting of the spr was held in may, 1932, and since 1938 the aps and spr have held joint meetings, with greater prominence of infectious diseases as a separate subspecialty in more recent years. presidents of spr who have been associated with a particular interest in infectious diseases are shown in table 1 . the american academy of pediatrics (aap) was founded in 1930 to promote the welfare of children. this occurred after the american medical association house of delegates severely chastised the pediatric section of the ama for taking pro-active stances favoring the sheppard-towner act, which supported maternal and child health. isaac abt of chicago became the first president of the aap, which had 304 charter members and held its first meeting in atlantic city, nj, on june 12-13, 1931 (7) . early in its existence, the aap declared its interest and involvement in infectious diseases issues. the aap established a special committee on prophylactic procedures against communicable diseases in 1933, chaired by edward b. shaw of san francisco and including j.e. gordon of detroit and j.a. toomey of cleveland. this committee was disbanded after its report "routine measures for the prophylaxis of communicable diseases" was published in the journal of pediatrics in april 1935 (36) . this six-page report dealt with diphtheria, scarlet fever, typhoid fever, whooping cough, measles, smallpox, polio (3 lines), epidemic meningitis (1 line), mumps and chickenpox (4 lines), rabies, and tetanus. the committee on immunization procedures was then established in 1936, with john a. toomey as chair. three years later the committee name was changed again to the committee on immunizations and therapeutic procedures for acute infectious diseases, in 1953 it was modified again to the committee on control of infectious diseases, and then in 1969 to the committee on infectious diseases, the current name, although it is now most commonly referred to as the red book committee. since 1938, this aap committee has published a report every one to five years (every three years for the past five editions), which because of the color of its binding has been known as the red book for many editions. after world war ii came the postwar boom, noteworthy for the expanded availability of federal research funds (especially from the national institutes of health), increasingly sophisticated research and technology, the development of vaccines against polio and measles, and the discovery of ever-moreactive antibiotics and other anti-infectives, with the initial emergence of antibiotic resistance, e.g. penicillin-resistant s. aureus. the period from 1945 to about 1965 heralded the era of modern infectious diseases and coincided with the increasing trend to subspecialization within pediatrics and the development of full-time pediatric departments. antimicrobial advances included the discoveries of streptomycin, isoniazid and then other agents to treat tuberculosis, as well as penicillin, chloramphenicol, streptomycin and other antibiotics for treatment of bacterial infections. virtually universally fatal infections such as bacterial meningitis and endocarditis became amenable to therapy. american pediatric society presidential addresses during this period that dealt with infectious diseases topics included that by jean v. cooke in 1949 discussing the impact of specific therapy including antimicrobials upon the common contagious diseases and reviewing mortality statistics (7). this era was associated with the virtual elimination of congenital syphilis, early studies of bacterial resistance to antibiotics, improved methods of viral cultivation, but also large poliomyelitis epidemics. the control of acute rheumatic fever and rheumatic heart disease was a consequence of the studies of floyd denny, lewis wanamaker, and others that proved that recurrent attacks could be prevented by antibiotic prophylaxis. edith in the period from 1966 to about 1985 has been termed the era of specialization and fragmentation of pediatrics by howard pearson (21) . at the onset of this era, the 1966 program of the society for pediatric research listed no infectious diseases subspecialty session per se but rather one session devoted to "microbiology/immunology" that included a handful of papers (out of the 101 in total that were presented) on topics that can be considered infectious diseases issues. several aps presidents during this era were closely linked to the emerging field of pediatric infectious diseases. (see table 2 ). warren wheeler in 1972 in his presidential address dis-172 shulman cussed the epidemics of enteropathogenic e. coli 0111 in the 1930s and 1940s and those of s. aureus 80/81 in the 1950s, recommending surveillance to detect emergent bacterial "hot strains" (21) . saul krugman, aps president in 1973, devoted his distinguished career to the field of infectious diseases, especially to the study of hepatitis viruses. fred robbins (1974) and horace hodes (1975) were each responsible for signal discoveries in virology, the former having received the nobel prize in 1954 with john enders and tom weller for the development of tissue culture technology that led to viral vaccine production, and the latter devoting his life to investigations of viral gastroenteritis of infants and vaccine development (21) . margaret h. d. smith (1977) worked tirelessly in the field of pediatric tuberculosis and advocated for social activism by organized pediatrics. c. henry kempe (1978) was instrumental in the eradication of smallpox, and floyd denny (1981) contributed to the understanding of group a streptococci and to the conquest of rheumatic fever. during this era, infections in the immunocompromised child began to emerge as an important clinical problem, as increasing numbers of cancer patients and other compromised patient populations were generated by improved treatment modalities (37) , and these were accompanied by increasing numbers of opportunistic viral, fungal and bacterial infections requiring expert management. it was during this time that many subspecialty organizations within pediatrics were born, including the pediatric infectious diseases club. formal organizations within the field of pediatric infectious diseases emerged gradually as the subspecialty became more clearly defined and differentiated from the rest of pediatrics during the 1960s and 1970s. in 1977 -1978 plotkin of philadelphia led the establishment of the pediatric infectious diseases club, which held its first election of officers in 1982-1983. this club evolved into the pediatric infectious diseases society (pids) in 1984, and it has grown into a very active organization to which the vast majority of those in the field belong. the modern era, from about 1986 to the present, is the period of modern molecular biology and genomics, with advances based upon new diagnostic modalities such as dna hybridization and sequencing, cloning, pcr, magnetic resonance imaging, pet scanning and many others. laboratory techniques for research related to pediatric illnesses have used these and other increasingly sophisticated molecular methods. the elucidation of the first bacterial genome, that of hemophilus influenzae, in 1995 heralded vast new opportunities to understand the pathogenesis of infectious diseases (38) . although many classic pediatric infectious disease disorders have virtually disappeared, new (or apparently new) clinical challenges such as opportunistic infections in the ever-increasing populations of immunocompromised patients, lyme disease, kawasaki disease, sars and hiv/aids have emerged. the onset of the aids epidemic in the early 1980s and the identification of hiv as its causative agent had a substantial impact upon the specialty of pediatric infectious diseases. identifying perinatal vertical transmission risk factors, dealing with transfusion-associated hiv infection (particularly in the hemophiliac population), and determining the clinical, virologic and immunologic parameters of pediatric aids occupied the first decade or so of the pediatric aids experience. the landmark 1994 report of the pediatric aids clinical trials group protocol 076 that demonstrated the marked effectiveness of zidovudine administered to pregnant women to prevent vertical transmission of hiv led to dramatic reduction in the number of perinatally infected children within several years in developed countries. in other areas of the world, where antiretroviral therapy during pregnancy is not being utilized, vertical transmission of hiv continues unabated. in recent years, in the u.s., the field of pediatric aids has focused increasingly upon prevention and treatment of adolescent hiv infection as well as upon the highly effective multi-drug therapies. table 2 provides a listing of presidents of aps with major interests in infectious diseases issues. recent aps presidents have included sam katz (1987), whose career has been devoted to vaccine development and implementation; paul quie (1988), a bacterial phagocytosis scholar; vince fulginiti (1992) , who advanced the fields of prenatal infections and viral vaccinology; and ralph feigin (1998), an authority on meningitis and many other aspects of pediatric infectious diseases. the american board of pediatrics (abp), which was founded in 1933, first certified general pediatricians in 1934. it then provided its first subspecialty certification in 1961 (cardiology). in may 1990 the abp approved a proposal from the pediatric infectious diseases society to certify individuals in pediatric infectious diseases, and the abp then applied to the american board of medical specialties (abms). abms approved this application on march 21, 1991 , and the abp established the sub-board of pediatric infectious diseases in 1991 (39) . the initial certifying examination in pediatric infectious diseases was offered on november 15, 1994 with 607 candidates taking the examination and 493 passing (39) . by 1998, after program applications were submitted and reviewed, a number of training programs for pediatric infectious diseases fellows were accredited by the accreditation council for graduate medical education (acgme). several publications have been developed within the field of pediatric infectious diseases, sponsored by various organizations. the aap's report of the committee on infectious diseases (the red book) is mentioned above. the pediatric infectious diseases society organized the establishment of the report on pediatric infectious diseases, published by churchill-livingstone ten times yearly, beginning in january 1991. in 1998 the report was changed to concise reviews of pediatric infectious diseases and was incorporated within the monthly pediatric infectious diseases journal. the latter journal had been the discipline of pediatric infectious diseases has a great many remaining challenges. these include the conquest of illnesses that affect children in the developing world, most notably hiv infection, tuberculosis and falciparum malaria, but also a wide array of other infections. opportunistic infectious diseases that affect immunocompromised children will also continue to demand attention, and this host population will likely increase. medicine has entered the genomic era, and the quantity of genomic data available, both microbial and mammalian, is increasing at a phenomenal pace. this has had, and will continue to have, profound implications for the study and practice of pediatric infectious diseases. since the elucidation of the h. influenzae genome with 1.8 million base pairs in 1995 (38) , almost 100 bacterial genomes have become available, including that of group a streptococcus (40) and other important human pathogens. the group a streptococcal genome work was led by joseph ferretti, who trained at the university of minnesota with elia ayoub and lewis wannamaker. additionally, the human genome project published drafts of the dna sequence of homo sapiens in 2001 (41, 42) . these developments unlock the potential for significant advances with impact on all aspects of the field of pediatric infectious diseases. pathogenesis of infections, new insights into the host-parasite relationship, mechanisms of host susceptibility and resistance, resistance to current and development of new anti-infective therapies, new vaccines, and the identification of new drug targets are some of the areas that will be impacted directly. utilization of dna microarray analysis as well as new methodologies of proteonomics will facilitate new insights into the characterization of gene expression during health as well as in disease states, with identification of new antimicrobial targets and identification of infectious disease risk factors for individuals. additionally, the field of pediatric infectious diseases will be impacted for the foreseeable future by issues related to the threat of bioterrorism and the public health response to this threat. this includes the renewal of smallpox immunization in the u.s. as well as focus upon prevention and treatment of anthrax and other potential bioterrorism threats. the unex-pected appearance of new infectious diseases (e.g. severe acute respiratory syndrome -sars) highlights the potential for previously unknown agents to emerge as major threats, and the discipline must learn whether they can cause congenital infection, transfusion-associated infection, and if they particularly target vulnerable populations such as children. pediatric infectious disease physicians can rightfully celebrate the past triumphs of their discipline and should anticipate future outstanding achievements, all of which contribute directly and indirectly to improved health for children. post-script. this history of the development of the field of pediatric infectious diseases in the united states has been written so that it does not overlap the contribution of baker and katz entitled "childhood vaccine development in the united states" (43) . therefore, it includes little if any information related to the highly successful development and implementation of vaccines for children that have been so instrumental in improving the health of children. rather, this history is focused upon infectious diseases of children per se and upon the development of the subspecialty. viral infections and vaccines hodes-viral vaccines viral infections robbins-viral vaccines rheumatic fever/streptococci steve kohl-herpes viruses hostetter-candidal infections fleisher-bacterial infections job lewis smith-diarrheal illnesses 1892 william osler-tuberculosis, etc walter carr-epidemic diseases other infections freeman-infectious diseases churchill-bacterial infections 1918 linnaeus lafétra-infection prevention viral infections bacterial infections fred robbins-viral vaccines horace hodes-viral vaccines kempe-smallpox eradication james cherry recipients for the distinguished service award the history of paediatrics nurturing children, a history of pediatrics abt-garrison history of pediatrics thacher t 1677 a brief rule to guide the common-people of new england how to order themselves and theirs in the small pocks or measles enquiry into the nature, cause and cure of the angina suffocativa or sore throat distemper an account of the weather and diseases of south carolina rush b 1777 an inquiry into the cause and cure of cholera infantum history of pediatrics in the united states pox americana: the great smallpox epidemic of 1775-1782 acute communicable diseases. in: wr bett (ed) the history and conquest of common diseases dewees wp 1825 a treatise on the physical and medical treatment of children on the pneumonia of children parrot's pseudoparalysis semi-centennial volume of the american pediatric society osler and children the centennial history of the american pediatric society infectious diseases and the last 100 years in the american pediatric society diphtheria and theories of infectious disease: centennial appreciation of the critical role of diphtheria in the history of medicine the american pediatric society's report of the collective investigation of the antitoxin treatment of laryngeal diphtheria in private practice the first full-time academic department of pediatrics: the story of the harriet lane home the history of cerebro-spinal meningitis in america smith jl 1872 a treatise on the diseases of infancy and childhood baker sj 1939 fighting for life save the babies: american public health reform and the prevention of infant mortality the diseases of infancy and childhood an american text-book of the diseases of children by american teachers kretchmer n (eds) 1991 history of pediatrics 1850 -1950 a retrospect and a forecast a historical note on chemotherapy of bacterial infections the first use of an antibiotic in america report of special committee on prophylactic procedures against communicable diseases 1935 routine measures for the prophylaxis of communicable diseases history of pediatric hematology oncology whole-genome random sequencing and assembly of haemophilus influenzae rd the first certifying examination in pediatric infectious diseases complete genome sequence of an m1 strain of streptococcus pyogenes the sequence of the human genome international human genome sequencing consortium 2001 initial sequencing and analysis of the human genome childhood vaccine development in the united states (1989) for rapid viral diagnostic methods, ann arvin (1992) for pathogenetic and immunologic studies of herpes viruses, margaret hostetter (1995) for studies of the pathogenesis of candidiasis, and elaine tuomanen table 3 . the first committee on rheumatic fever of the american heart association was organized in 1940, with t. duckett jones (famous for his jones criteria proposed in 1944) serving as the first chair. over the subsequent 63 years, this committee has expanded its scope to include infective endocarditis and kawasaki disease, and its membership has been weighted heavily to include pediatric infectious diseases experts as well as cardiologists. in contrast to many other organizations, world war ii actually accelerated the activities of this group because of the severity of rheumatic fever and rheumatic heart disease nobel laureates. four members of the american pediatric society (including one honorary member) have been awarded the nobel prize in physiology and medicine, and all of them were recognized for research related to infectious diseases and their prevention. in 1954, thomas weller, frederick robbins, and john enders received the nobel "for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissues." enders, a basic virologist, was elected to honorary aps membership in 1962, and weller and robbins are full members. additionally, d. carleton gajdusek received the 1976 nobel "for discoveries concerning new mechanisms for the origin and dissemination of infectious diseases," specifically for the study of kuru and slow virus infections.howland award. the john howland award of the american pediatric society "for distinguished service to pediatrics" was initiated in 1952, and a number of howland awardees have been honored particularly for contributions to the conquest of infectious diseases of childhood. these key: cord-279401-eehb5yny authors: haffejee, sadiyya; levine, diane thembekile title: ‘when will i be free’: lessons of covid-19 for child protection in south africa date: 2020-09-04 journal: child abuse negl doi: 10.1016/j.chiabu.2020.104715 sha: doc_id: 279401 cord_uid: eehb5yny background: covid-19 has highlighted and amplified structural inequalities; drawing attention to issues of racism, poverty, xenophobia as well as arguably ineffective government policies and procedures. in south africa, the pandemic and the resultant national lockdown has highlighted the shortcomings in the protection and care of children. children in alternative care are particularly at risk as a result of disrupted and uncoordinated service delivery. objective: the aim of this study was to explore the experiences and impact of the pandemic and the resulting social isolation on the wellbeing and protection of children living in a residential care facility. methods and participants: we used qualitative, participatory approaches – specifically draw-and-write methods – to engage with 32 children (average age = 13.5 years) living in a residential care facility in gauteng. findings: children in care demonstrated an awareness of the socio-economic difficulties facing communities in south africa, and shared deep concerns about the safety, well-being and welfare of parents and siblings. although they expressed frustration at the lack of contact with family members, they acknowledged the resources they had access to in a residential care facility, which enabled them to cope and which ensured their safety. discussion and conclusion: we focus our discussion on the necessity of a systemic response to child welfare, including a coordinated approach by policy makers, government departments and child welfare systems to address the structural factors at the root of inequality and inadequate, unacceptable care. this is essential not only during covid-19 but also in preand post-pandemic context. with care facilities either shutting down and releasing children prematurely or keeping children in-care, without access to family and friends. emerging reports from south africa confirm this, showing that key government departments responsible for vulnerable children in residential care have been severely hampered by the crisis (wolfson-vorster, 2020a). continuity of care as well as coordination of services between all essential service providers; key activities in ensuring the safety and protection of children, has been constrained (fallon et al, 2020) . in this exploratory study, we consider the impacts of covid-19 for children in one non-governmental organisation in johannesburg, south africa, which aimed to provide continuous and consistent care for children living in residential care. we ask 'what can the experiences and perspectives of south african children in care during lockdown tell us about the themes we should focus on to improve care moving forward? we focus on children's experience of the lockdown as well as covid-19; their concerns as well as the protective resources that enables them to cope. we frame the experiences of these children in care against a background of a crippled social system and reflect critically on what systemic changes are needed to support children. this study offers a way forward and contributes to an emerging body of research on the impact of pandemics on child well-being and protection. to address a global pandemic such as covid-19 requires inspired, informed leadership and co-ordination between all sectors of government and civil society. this has occurred to a limited extent in south africa. in comparison to the hesitancy that characterised some of the global responses to the pandemic, south africa's initial response was decisive. the complete national lockdown which began on the 26 th march 2020, saw trade, places of worship, and recreational activities shut down. a national curfew was mandated and movement between provinces prohibited. these stringent measures were considered necessary to flatten the curve and to ready the health system for a potential influx of cases. some rights groups and commentators however raised concerns about the impact and feasibility of such measures in a context with gross pre-existing and historic socio-economic inequalities (world bank, 2018) and a struggling economy (marais, 2020) . acknowledging these challenges and to mitigate against the worst impacts of the pandemic, the south african government introduced a number of temporary social and economic relief measures, which included increasing the health budget, economic support through the unemployment insurance fund, support for small business and tax relief measures. social relief support measures included the establishment of the special covid-19 social relief distress (srd) grant of r350 per month (£16/$20) as well as increases to existing social welfare grants, for example, the basic child support grant was increased by an additional r440 per month (£20/$26). the government, through the department of social development, also pledged to distribute food packages to communities most in need. as predicted however in a country with such disparate, intense needs these resources have simply not been enough, failing to buffer the majority of south africans from worsening j o u r n a l p r e -p r o o f social and economic conditions (van bruwaene, et al., 2020) . findings from the national income dynamics study-coronavirus rapid mobile survey (nids-cram), found that almost 3 million people lost their jobs during the most intensive lockdown period and during this time 1 in 7 children reported that they had gone hungry in the week before they were interviewed during may or june (nids-cram, 2020) . compounding, what is rapidly being seen as a humanitarian crisis, is the constrained leadership at national and provincial level and lack of co-ordination between government departments (thebus, 2020) . the department of social development (dsd), a key department in the care and protection of children and its minister, have been severely criticised for providing little leadership during this period (weiner, 2020) . for example, dsd's delivery of the much needed and promised food parcels have been hampered by reports of corruption and theft, cumbersome processes, lack of capacity to distribute food packages, lack of data on who needs this assistance and insufficient funds to meet the needs of the population (wolfson-vorster, 2020a). similarly, distribution of the covid srd grant has been challenged by complicated processes making it difficult to access. activists report that as at july 2020, approximately four months into lockdown, 74% of individuals eligible to receive the grant have not received it (thebus, 2020) . the department of basic education (dbe), another crucial department, took a decision, at the beginning of the lockdown period to also stop the national school nutrition programme (nsnp), as a result, the 9.6 million children who are dependent on this one meal a day have had to go without food. a number of child's rights groups instituted legal action against the minister of basic education as well as the provincial mec's, arguing that the failure of government to recommence this nutrition programme was a regression of the rights to education and to basic nutrition (see www.centreforchildlaw.co.za). on the 17 july 2020, dbe was ordered to reopen the nsnp, with the judge asserting that in closing the programme, the j o u r n a l p r e -p r o o f minister, and her mecs were in breach of their constitutional and statutory duties (wolfson-vorster, 2020b). to understand the impact that covid-19 has on the individual child we reference a multi-systemic framework; this framework situates the individual within broader systems and contextual factors, acknowledging the interconnectedness between physical, individual, relationships, community, and society. masten and motti-stefanidi (2020) note that risks to individuals span across all of these levels and as the pandemic unfolds, the challenges to these systems also change. similarly, factors that enable and support resilience are situated across levels. here we draw on a covid-19 specific explanation of systemic risks shared by the alliance for child protection in humanitarian action (2019) as well as that used by unicef (2020). from this perspective, individual level risks during a pandemic, include increased risks of child abuse, neglect, violence, exploitation as well as potential psychological distress and a negative impact on development. challenges also include adjusting to the changed circumstances, with school closures, disrupted routines, isolation from friends and peers and fear of the unknown and losing loved ones (ghosh, dubey, chatterjee & dubey, 2020; orgiles, morales, delvecchio, mazzeschi & espada, 2020 , zhou, 2020 . these changes may result in increased feelings of anxiety and distress or may exacerbate existing mental health issues and enhance the risk of developing psychological disorders (alliance for child protection in humanitarian action, 2019; wang, xiao, sun, wang & xu, 2020) . at the level of the family, risks may include family separation, reduced access to social supports, caregiver distress, heightened risk of violence/domestic abuse, disruption to family earnings as well as disrupted family connections and support and fear of the disease (spinelli, lionetti, pastore & fasolo, 2020) . community level risks may include distrust within communities, competition over j o u r n a l p r e -p r o o f limited resources, inadequate access to support services including educational resources and support (fischer et al., 2020; sekyere, bohler-muller, hongoro & makoae, 2020) . lastly societal level risks include corrosion of social capital and disrupted and inadequate access to basic services (fischer et al., 2020; scott, 2020; sekyere et al., 2020) . as discussed, within the south african context, these systemic risks are amplified by pre-existing challenges. present day south africa continues to be characterized by deeply embedded inequalities and structural violence, a legacy of colonialism and apartheid (loffell, 2008; tshishonga, 2019) . this inequality manifests in high levels of poverty, discrimination, poor access to education, health and social services, poor service delivery and exposure to high rates of communal and interpersonal violence (zizzami, schotte & leibbrandt al, 2019) . children in south africa are particularly vulnerable as a result of these structural challenges; for example, poverty creates food insecurity which impacts on a child's physical, mental and cognitive development (hall & sambu, 2014) . research suggests that prior to the pandemic a quarter of children in south africa were stunted, 12.5 million children were dependent on child support grants, 59% of children lived below the upper-bound poverty line, 30% of children were without access to water and 8% of children lived in overcrowded households (hall & sambu, 2014 , 2019 lake et al., 2020; van der berg & spaull, 2020) . poverty is recognized as a significant barrier to children's well-being, impacting on health and educational opportunities and increasing vulnerability to child maltreatment (fernandez, delfabbro, ramiac & kovacs, 2019; loffell, 2008; manyema & richter, 2019; meinck, cluver & boyes, 2015) . artz et al (2016) found that approximately 40% of young people in south africa have had direct experiences of abuse. fear and additional stressors caused by the pandemic provides an enabling environment that may exacerbate or trigger diverse forms of violence against children and women (peterman et al, 2020) . given the j o u r n a l p r e -p r o o f existing high levels of gender-based violence, sexual abuse and child abuse in south africa, of significant concern, during these exceptional times, is the safety of children, especially as many are in close, constant proximity to potential abusers. lack of income and employment opportunities and food insecurity are likely to increase conflict within families, thereby increasing risk to children (mathews, jamieson & makola, 2020 similarly, disruptions in education risks the wellbeing of children both in the short-term and may have significant long-term consequences. while some children have been able to access online learning, for the majority of children living in conditions of poverty, with no access to a phone, television or computer this has not been possible, further deepening the digital divide (fore, 2020) . van der berg and spaull (2020) report that by the beginning of august 2020, at least 4 million children will have missed more than half (57%) of the number of school days and they note that the education system in south africa is unlikely to make up this time. this has significant long-term consequences in a country with staggeringly high rates of illiteracy (howie et al., 2017) . j o u r n a l p r e -p r o o f (mamelani, 2013) . children identified as vulnerable includes a child who i) has been abandoned or orphaned and is without any visible means of support; ii) displays behaviour which cannot be controlled by the parent or care-giver; iii) lives or works on the streets or begs for a living; iv) is addicted to a dependence-producing substance and is without any support to obtain treatment for such dependency; v) has been or is at risk of serious physical or mental harm; or vi) has been abused, neglected, or exploited (mahery, jamieson & scott, 2011) . given the wide range of needs of children entering care, cyccs are mandated to not only provide for the basic needs of children in terms of food and shelter and access to education, but are required to make therapeutic programmes available. section 191 of the children's act provides a comprehensive list of programmes that should be offered. jamieson (2017) schmid & patel, 2014). historically, poor coordination between social and health systems in south africa during periods of health crises has meant that services to child and youth care centres have been inadequate (allende & khota, 2020) . the lockdown has intensified these. many children living in residential care come from disadvantaged communities and have been exposed to one or multiple traumas within the home or the community and some have pre-existing health problems (meintjies et al, 2007) . in this context, children may be safer in care where they have access to regular meals, shelter, protection and access to educational resources. the aim of this rapid exploratory, qualitative study was to understand how children residing in a care facility in south africa understood and experienced the lockdown measures imposed as a result of covid-19. we focus on the concerns that children in care experienced during this period as well as what helped them to cope. our decision to speak with children was informed by an acknowledgement that children are experts in their lives and capable of speaking on their own behalf. titi and jamieson (2020) found that only 10% of stories focus on children and less than half this number includes the voices of children, noting that such exclusion is in fact a violation of their rights. children residing at a child and youth care centre in gauteng, south africa (herewith referred to as cycc x) were invited to participate in the study. a cycc is defined as a facility that provides residential care for more than six children who are not living with their biological families (children's act, 2005) . cycc x is situated in gauteng (south africa) and was established by a social worker in 1992, in response to a growing number of mainly black south african children living on the streets. during this period, south africa was slowly transitioning out of apartheid and the country was characterised by uncertainty and ongoing hostility between various racial groups. the needs of disadvantaged, black children were often not acknowledged and services for this group was lacking or non-existent (loffell, 2008 for over 5000 children and is an active member in the child and youth care sector (newsletter, august 2020). the majority of children at cycc x have been exposed to one or more risk factors, including poverty, neglect, physical, emotional and/or sexual abuse and streetism. reasons for admission noted in the cycc's most recent progress report show that; 18% of children were admitted because of familial poverty, 5% of children were exposed to domestic violence, 23% reported parental neglect, 17% reported some form of abuse, 1% were placed in care for substance use, 8% were not attending school, 8% were street connected and 20% displayed uncontrollable behaviour prompting parents to request placement (progress report, 2020). as mandated in the children's act (children's act, 2005) , cycc x offers extensive programs to meet the physical, psychosocial, and trauma needs of these vulnerable children. this is delivered to children primarily through the in-care, residential programme and through a pre-care, prevention and early intervention programme and an after-care, transitory support programme. children in therapy consulted therapists online. although many of the schools that the children attended did not have an online teaching programme, educational activities continued throughout the period at the centre, with lessons delivered by teaching staff and online learning forums. information regarding the study was shared with children, who were then invited to participate in the study. participation was voluntary. a total of 32 children and youth chose to participate. the average age of participants was 13.5 years, 18 children identified as girls and 14 identified as boys. at the time of the study, all the participants were legally placed at the cycc. informed assent was obtained from the younger children and consent from the older children. to generate data, participants met in small groups, which were facilitated by a counsellor and a social worker, who both work at the centre. the decision to engage staff in j o u r n a l p r e -p r o o f facilitating groups was necessary during the initial, stricter levels of lockdown (when the data were generated) as non-essential staff were not allowed entry onto the premises. the first author has a working relationship with both the facilitators and provided information on the study aims and the methods. to guide the process, each participant was given a booklet with six open-ended questions related to covid-19 and the lockdown; each question had space allocated for participants to draw and/or write a response. the first question prompted participants to share something about themselves. the questions that followed included: -what are some of the things that are helping me cope? participants were then invited to share verbally in the groups what they had written, and what the drawing meant to them (angell et al., 2015) . this qualitative method, referred to as the draw, write and tell method of data generation, foregrounds the voice of the participants and is flexible and sensitive to the context and of the content (mitchell et al., 2011) . this method is particularly useful for use with children as it fun and non-threatening; it also gives children time to think through and structure thoughts before sharing and may also address linguistic difficulties (backett-milburn & mckie, 1999) . the method is, however, not without criticism with suggestions that it may undermine children's ability to adequately communicate their experiences, may be superficial and assumes that drawing is a fun activity for all children (angell et al., 2015; backet-milburn et al., 1999) . in our research, we gave children the option data comprised of the textual information generated by participants and was analysed following the six steps to inductive, thematic analysis described by braun and clarke (2006) . this method of analysis is used to identify, analyse and report themes within data (braun & clarke, 2006) . author 1 reviewed the data, becoming familiar with it and generated the initial codes and possible themes. these were then reviewed and refined by both authors and through a joint process, final themes were then defined and named. ethics approval for the study was granted by the university of leicester (9 april 2020). the director at cycc x, acting as legal guardian, granted consent and as mentioned above, informed assent was obtained for children younger than 12 and consent from those over 12. as well as delivering these fundamental ethical tasks, and aware of our positionality as researchers (both south africa, by birth, one indian and one white born during the apartheid era), our approach to ethics also accounted for four key dimensions accepted as important when delivering research in low resource settings experiencing chronic structural disadvantage j o u r n a l p r e -p r o o f association with cycc x and brought this experience to bear in ensuring a respectful approach was maintained throughout the data gathering process. author 2 visited the cycc x in 2019 and spent time with the staff team, with the intention of beginning to build a trusted working relationship. -risk-benefit ratioour exploratory project aimed to surface the key worries experienced by the participants, and had existing mechanisms in place to ensure they had adequate counselling and other support should significant issues arise. to ensure trustworthiness of the data, author 1 shared findings from the study with childcare staff and social workers based at cycc x; this group were in close contact with the children during the lockdown period and had engaged the children in similar conversations throughout the lockdown period. they were able to confirm the consistency of the findings. time constraints, for both children (including a demanding school schedule), staff (supporting online learning together with regular care duties) and ourselves, meant that, at the time of writing this, we were not able to share findings with the children. we used thick descriptions to describe the context and shared excerpts and images from the participants, ensuring we could begin to interpret the characteristics of each participant's contribution (schwandt, 2001) . findings from the study draws attention both to how the experiences and ways of coping for children in residential care are similar to that reported by children living in family contexts as well as how they differ. consistent with emerging literature on the impact of covid-19 on children's mental health, children in care reported experiencing a range of emotions ranging from frustration, anger and happiness and reported drawing on a host of resources to j o u r n a l p r e -p r o o f enable them to cope (ghosh et al, 2020) . children in care however differed with regards to their concerns, which centred primarily on worry for parents and siblings well-being. covid-19 as well as the variations in containment measures have raised concerns about the mental health and well-being of both adults and children (panchal et al., 2020) . for children in care, these feelings are exacerbated, as they are unable to have the normal contact visits with parents or extended family and tend to be under strict supervision, often grouped together with children with a variety of emotional and/or behavioural difficulties (lazzaro, 2020). children at cycc x similarly appeared to be experiencing a wide range of emotions in response to being under lockdown. fear, sadness and worry because of the virus, anger and frustration at having to be under lockdown away from family and school, as well as feelings of hopelessness and discomfort were mentioned. one of the participants aptly summarises the range of emotions she is experienced during this period, many of which were echoed by other the image (image 3) below by child 2 and her explanation reflects the complex relationship that children in care have with parents. for child 2, her concern for and attachment to her mum appears to override her mother's absence or potential parental neglect. speaking of her concern for her mum, [insert image 3: child 2 articulates her concern about her mother] in their concern, children and youth in care demonstrated an awareness of the 'i also think about school, when i will go back to school also if i will repeat a grade because i don't want to repeat.' these concerns are not unfounded, with child protection agencies asserting that many of the 1.5 billion children currently out of school worldwide will never return to school and will have limited future prospects (wolfson-vorster, 2020a). referring to the strict regulations that were of necessity imposed by the cycc, child 3 and child 32 both express frustration at not being able to leave the centre and go to school, in the image below (see image 4), child 3 draws attention to people that don't have homes. [insert image 4: child 3 expresses concern about those without homes.] the majority of children drew on internal, self-regulatory mechanisms to help them cope, this included exercise, reading, listening to music and watching television. this was accompanied by engaging with others through play and group sports. some of these resources, like television and radio, were easily accessible for children while in residential care. engaging with others through play was especially important for the younger participants, while for some of the older children helping staff with chores and younger children with homework appeared to give them a sense of purpose and stopped them from feeling bored. complaining. going to home work class and helping the staff with whatever they need help with.' sense of purpose has previously been identified as a potential protective factor in psychological resilience during adolescence (e.g. wang et al, 2017) . in addition to these internal mechanisms, structural resources provided by the cycc enabled children to cope. the ability to access education, through access to the online learning programme, 'doing my homework online' (child 4), alleviated some of the children's fears of falling behind and also kept them occupied, facilitating coping. it is important to note here that for the majority of children in south africa accessing education through online forums was not possible (van der berg and spaull, 2020). the awareness of being safe also helped children cope; 'we are very safe, we are in our homes and in our shelters because if we were outside we should have been dead or killed' (child 9). child 10 echoes this saying, 'by knowing i am safe.' as above, these statements suggest that participants in care are fully aware of the dangers present in communities; as mentioned above, approximately 45% have had exposure to some form of violence. the structure and support offered by the cycc enables them to feel safe. this sense of safety also enabled some children to focus 'on the positive side of life' (child 18). the following images (images 5 and 6) from participants captures this range of protective, resilience-enabling resources. [insert: image 5 and 6: participants share their protective, resilience-enabling factors] covid-19 has been referred to as an unprecedented event, unparalleled in its impact. in this global reach, it highlights more than any other event in recent times, our global inter-j o u r n a l p r e -p r o o f communities and societies are differentially impacted. in south africa, the social and economic disruptions caused by the pandemic and associated lockdown, combined with long-term structural social, economic and political inequality, and failures within government has impacted on service delivery, access to resources and availability of supportive networks, the absence of which increases vulnerability and heightens levels of anxiety and stress in children. in this exploratory study we aimed to address the research question 'what can the experiences and perspectives of south african children in care during lockdown tell us about the themes we should focus on to improve care moving forward?' as the findings emerged, we noted that there were a number of domains of concern that reflect the social ecologies in which our participants operated. in spite of being 'out' of community contexts, our findings show that children in care situate themselves firmly within their social-ecologies. they continue to express concern for families and for communities (some who may have rejected them). they acknowledged the resources that they have access to while at the cycc and through their concern for parents, siblings and wider society also acknowledged the prevalence of hunger, violence and food insecurity in south africa. for many south african children, pre-existing structural challenges heightens exposure to a multitude of risks. covid-19 has increased these risks factors. the majority of children admitted into care at cycc x have been exposed to poverty and child maltreatment. (jamieson, 2017) . cycc x, as many others, tries to provide an environment that is consistent, stable, and built on supportive relationships; studies show that access to this sort of environment provides a measure of protection in the face of multiple adversities (collishaw et al, 2016; mosavel et al, 2015) . many of the children acknowledged the protection and support offered to them and which helped them to cope. thus, even while in careoften thought of as the last possible resort for vulnerable children -in this protective context, they were also able to access their own internal resources and reach out to support others. research shows that child-level resources are most easily accessed within the context of a responsive, accessible ecology (ungar, 2011) , the absence of which may negatively impact on the child's well-being. the importance of self-regulation in mediating resilience pathways our findings showed that participants drew on a range of internal resources to help them cope, which was facilitated by caregivers that were available, access to therapeutic support as well as access to resources, like television, sports, books and online learning forums. of significant concern for the participants in our study, was the closure of schools. this experience is consistent with findings emerging from other studies, across diverse contexts. ghosh et al. (2020) note that being quarantined in homes and institutions presents a bigger psychological burden than that of the actual pandemic; adding that school closures, lack of physical activity and aberrant eating and sleeping habits may potentially promote monotony, distress, impatience, annoyance and varied neuropsychiatric manifestations. isolation and the absence of routines imposed by schools may also lead to psychological distress as schools provide stability and may be a coping mechanism for some children (lee, 2020). in the context of the residential care facility, the psychosocial support offered by schools, takes on further importance in that it represents an additional, external space away from the confines of the facility. in addition to the supportive role that schools play, for children at cycc x, absence from school was seen as a significant obstacle, potentially jeopardising future plans. south african research with youth exposed to structural adversity show that access to education and the presence of future oriented plans enable positive adaptation in contexts of risk and is regarded as a means to securing a better more economically stable future (lundgen & schekle, 2019; theron & van rensburg, 2018; walker & mkwanazi, 2015) . in the context of an emergency, such as this one, protecting the rights of children in residential care requires collaboration across multiple sectors, including government ministries (better care network, 2020). masten and motti-stefanidi (2020) suggest that every disaster brings with it lessons for future resilience planning at multiple levels. as such, learnings from this experience may be leveraged to repair and transform the child protection sector, strengthening system responses and building resilience. the findings of our study suggest that it is only through co-ordinated, holistic, and strategically sound collaboration that we will be able to protect children in care in south africa. some of the challenges experienced by children during lockdown particularly with regarding concern for family members, suggests a need for creative problem solving by care facilities to ensure that children have continued contact with families. digital technologies may j o u r n a l p r e -p r o o f offer new solutions using 'free at the point of use' services for families to stay in touch with cyccs, if not children themselves if access to technology is not universal. regional or national policy programmes facilitating solar chargers for communication devices in cyccs, and devices themselves in limited numbers, would overcome this barrier at a relatively low cost. beyond this emergency response planning, the pandemic has reinforced the need for broad scale systemic changes, necessary to protect and assist the most vulnerable communities in south africa. strengthening economic support for families is essential given the increasing levels of poverty, food insecurity and growing rates of unemployment. current calls for a universal, unemployment or basic income grant and general increase in child support grants are positive developments in the right direction. our findings on the significant role that parents play, even in their absence, suggest a need for positive parenting skills and family strengthening interventions that will ensure that children are cared for in family environments. combining social support grants that provides a measure of protection against the impacts of poverty with family strengthening interventions promotes greater child and youth development and well-being (cluver et al, 2016). families and communities should be safe spaces for children; the appallingly high prevalence of gender based violence and child abuse demands greater accountability from government and co-ordinated action from all departments, including justice, social development and health. the promotion of social norms that protect against adversity and violence through public education campaigns, legislative approaches that acknowledge and prioritise gender based violations and that develop and implement gender sensitive solutions is necessary (cdc, 2019). participants concerns regarding the interruption of their schooling highlighted the centrality of education in nurturing hope for children exposed to adversity. the importance of j o u r n a l p r e -p r o o f the schooling system has also been the subject of much discussion in the country throughout the pandemic. the role that education and educational systems have on youth development suggests a need for increased efforts in ensuring that these spaces are fully resourced and accessible. efforts must be to ensure that digital poverty is addressed, and that all children have equal access to adequate schooling. this study took place under unusual circumstances demanded by a global pandemic. as a result, there are limitations to the conclusions we can reasonably draw that could be mitigated by future research. our intention was to capture, in the most systematic way we could, the immediate experiences of our participants during the most intense period of south africa's lockdown, and our design reflects these priorities. the study has four key limitations to which we draw attention. 1. the size of the sample and length of the data-gathering period invite further investigation, in other alternative care settings in south africa and beyond. 2. qualitative research is dependent in part on the skill and experience of the person gathering the data. we mitigated the risk of poor data quality by ensuring the approach was closely structured and supported by author 1, and that a common prompt tool was used across the sample. 3. the qualitative nature of the study facilitates a rich and trustworthy understanding of the perspectives and experiences of our participants, but should not be read to imply causality. 4. in order to increase trustworthiness, our study relied on a well-tested method; arguably future research of this type should seek to take a more africa(n)-aligned approach to gathering data, which will bring with it additional strengths and some risks. our study with vulnerable children in care has provided a living example of the ways in which the covid-19 pandemic exposes and exacerbates the inherent structural inequalities that characterise south africa. this exacerbation of existing inequalities lies at the interface between public health, and societal and systemic structures. covid-19, devastating in its impact, urges accountability and provides multiple opportunities to learn from and build the capacity and resilience of individual, family, community and societal systems. caring for children in uncertain times principle 10: strengthen children's resilience in humanitarian action draw, write and tell': a literature review and methodological development on the 'draw and write'research method relationship between resilience and selfregulation: a study of spanish youth at risk of social exclusion a critical appraisal of the draw and write technique social dimensions of covid-19 in south africa: a neglected element of the treatment plan spike in child abandonments and the physical abuse of youngsters during lockdown technical note on the protection of children during the covid-19 pandemic: children and alternative care. retrieved from: review, 97 & yerkes. m. (2020) community, work, and family in times of covid-19 a wake-up call: covid-19 and its impact on children's health and wellbeing stronger together: community resilience and somali bantu refugees. cultural diversity and ethnic minority psychology the implications of covid-19 for the care of children living in residential institutions. the lancet impact of covid-19 on children: special focus on the psychosocial aspect long-term selfregulation moderates the role of internal resources for resilience in positive youth development in portugal income poverty, unemployment and social grants south african child gauge questionable correction: independent oversight of child and youth care centres in south africa pirls literacy 2016 progress in international reading literacy study 2016: south african children's reading literacy achievement. pretoria: centre for evaluation and assessment children and young people's right to participate in residential care in south africa developmental social welfare and the child protection challenge in south africa hope and future: youth identity shaping in post apartheid south africa children's act guide for child and youth care workers experiences and challenges related to residential care and the expression of cultural identity of adolescent boys at a child and youth care centre (cycc) in johannesburg. social work/maatskaplike werk transitional support: the experiences and challenges facing youth transitioning out of state care in the western cape adverse childhood experiences: prevalence and associated factors among south african young adults. heliyon, 5 (e03003) the crisis of waged work and the option of a universal basic income grant for south africa multisystem resilience for children and youth in disaster: reflections in the context of covid-19 our covid-19 strategy must include measures to reduce violence against women and children household illness, poverty and physical and emotional child abuse victimisation: findings from south africa's first prospective cohort study home truths: the phenomenon of residential care for children in a time of aids. cape town: children's institute drawings as research method residential care and beyond care south african urban youth narratives: resilience within a community immediate psychological effects of the covid-19 quarantine in youth from italy and spain six ways covid-19 is changing south africa. the new humanitarian the implications of covid-19 for mental health and substance use educational resilience among african survivors of child sexual abuse in south africa pandemics and violence against women and children the burden of disaster: part ii. applying interventions across the child's social ecology dictionary of qualitative inquiry the interaction of local and international child welfare agendas: a south african case what risks does covid-19 pose to society in the long-term? the impact of covid-19 in south africa children's act 38 of coronavirus rapid mobile survey (cram) overview and findings: nids-cram synthesis report wave parents' stress and children's psychological problems in families facing the covid-19 outbreak in italy giving voice to african thought in medical research ethics almost 80% of citizens eligible for social relief of distress grants kept waiting'. cape argus resilience over time: learning from schoolattending adolescents living in conditions of structural inequality include children's voice's on issues that concern them the legacy of apartheid on democracy and citizenship in post-apartheid south africa: an inclusionary and exclusionary binary? the social ecology of resilience: addressing contextual and cultural ambiguity of a nascent construct policy brief: the impact of covid-19 on children a critical review of south african child and youth resilience studies what are we doing to the children of south africa under the guise of covid-19 lockdown counting the cost: covid-19 school closures in south africa & its impacts on children positive academic emotions and psychological resilience among rural-to-urban migrant adolescents in china challenges in accessing higher education: a case study of marginalised young people in one south african informal settlement this study was made possible through seed funding from the leicester institute of advanced studies (lias), university of leicester. we wish thank our child and youth participants for sharing their knowledge with us as well the director at cycc x for granting us permission to conduct the study and staff cycc x for their assistance with data generation. key: cord-310534-ng6321hh authors: kaushik, ashlesha; gupta, sandeep; sood, mangla title: covid-19 in children: clinical approach and managementcorrespondence date: 2020-07-08 journal: indian j pediatr doi: 10.1007/s12098-020-03374-0 sha: doc_id: 310534 cord_uid: ng6321hh nan to the editor: we were pleased to read the well-written article in this journal entitled covid-19 in children: clinical approach and management by sankar j et al. [1] . we would like to commend the authors for a timely and succinct article on approach to management of pediatric covid-19, providing essential and practical guidance to clinicians, and would like to comment on the management of covid-19 in light of recent evidence, available studies and guidelines. we are in the midst of an unprecedented global covid-19 pandemic and though illness in children is usually mild, a small fraction can develop severe disease. the therapeutic approach for managing critically ill patients with acute respiratory distress syndrome (ards)/ respiratory failure centers around lung protection with low tidal volumes, high positive end-expiratory pressures and fluid restriction. anticoagulation is required in presence of high d-dimers or evidence of thromboembolism. a variety of therapeutic agents for covd-19 are under evaluation, with approximately 78 vaccine and 600 therapy related trials taking place worldwide. a recent study showed the antiviral remdesivir, a nucleoside-analog that acts by inhibiting viral replication, to be effective in the majority of treated critically ill adult patients [2] . a recent multicenter expert pediatric guidance panel has recommended remdesivir as the preferred antiviral agent in children if available [3] . another therapeutic alternative for management in children is hydroxychloroquine (hcqs), which can be used if remdesivir is not available [3] . hcqs has been shown to be effective against sars cov-2 in in-vitro studies, considered relatively safe in children, and is also suggested by authors in the management approach. of note, hcqs in combination with azithromycin has been associated with greater risk of cardiac adverse effects and qtc prolongation, therefore, this combination is not recommended in children [3] . other antivirals like 5-fluorouracil, ribavirin and favipiravir, in treating covid-19 by inhibiting the coronavirus' rna proteins from making genomic copies of the novel coronavirus, are being studied as well. although, lopinavir/ ritonavir was found to be of no benefit in one study as rightly noted by the authors [4] , results of the world health organization solidarity trial evaluating these are awaited [5] , and the pediatric panel neither recommends for /against its use [3] . the combination of lopinavir/ritonavir and ribavirin is not recommended, given concern for serious adverse effects [3] . convalescent plasma from recovered patients has been shown to be beneficial in critically ill patients [6] and given the accompanying cytokine storm with covid-19, il-6 (interleukin-6) inhibitors like tocilizumab are being increasingly utilized [7] . other drugs like famotidine are under study and low-dose steroids have been used in adults but studies pertaining to pediatric use are lacking. as noted by the authors, the vast majority of pediatric patients with covid-19 need only supportive care. as more scientific information becomes rapidly available, the decision to use therapeutic agents for critically ill children should be based on individual risk-benefit assessment, guided by the available evidence. to the editor: we thank kaushik et al. for interest in our article "covid-19 in children: clinical approach and management" [1] . the authors provided an excellent summary of status of specific therapies in covid-19 in children. as the disease is evolving and new evidence about drugs is published, management protocols are likely to evolve. we hereby summarize a few updates over our previously published article. though described as mild illness in children earlier, recently, a subset of children is seen to develop severe d i s e a s e w i t h m u l t i -o r g a n s i n v o l v e d t e r m e d a s "multisystem inflammatory syndrome in children" (mis-c). mis-c has clinical similarities to kawasaki disease and toxic shock syndrome. centers for disease control and prevention defined mis-c as patients (aged <21 y) with fever, laboratory evidence of inflammation, severe symptoms with multiorgan involvement, and confirmed sars-cov-2 infection, and no alternative diagnostic possibility [2] . common features described include gastrointestinal symptoms (diarrhea, abdominal pain), shock, myocardial dysfunction, coronary artery abnormalities, acute kidney injury, respiratory distress, and neurocognitive symptoms. timely diagnosis and management of mis-c with first-line therapy being immune modulation with human immunoglobulins or steroids is important, while some clinicians also administered aspirin and anticoagulants [2] . as pointed out by kaushik et al., despite in-vitro suppression of sars-cov-2 by various drugs, most clinical studies have not found significant benefit with therapy. as previously described, viral titers are highest in respiratory tract in initial phase of illness (flu like illness), antiviral therapies are likely to have maximum efficacy when started within first 1-2 d of illness [3] . remdesivir has been shown to decrease duration of hospitalization in adults with covid-19 [4] . among the options available, remdesivir could be the first choice drug for covid-19 in children. but in regions where remdesivir is not available, either lopinavir/ritonavir or hydroxychloroquine (or chloroquine) maybe used in children with severe disease (preferably as a part of clinical trial). recent evidence points towards lack of efficiency and significant arrhythmogenic side-effects of hydroxychloroquine and chloroquine (especially in combination with macrolides) in adults; these drugs should be used with caution [5] . but certain high-risk groups (infants and children with co-morbidities) could benefit from early anti-viral therapies (preferably as a part of clinical trial; remdesivir or lopinavir/ ritonavir or hydroxychloroquine, in that order of preference) [3] . understanding of the pathogenesis of respiratory failure is also evolving. though virus-induced diffuse alveolar damage is the major pathology, a recent report demonstrated frequent endothelialitis and thrombosis in alveolar capillaries in covid-19 autopsies in adults [6] . silent hypoxia is being observed in a fraction of patients, probably due to vascular involvement, pointing to need for routine oxygen saturation (spo 2 ) monitoring in patients who are apparently well [7] . also, covid-19 related acute respiratory distress syndrome (ards) has been classified as l-phenotype (low elastance, high compliance) and h-phenotype (high elastance, low compliance). l-phenotype usually has normal lung compliance, and can be managed with high flow, high fio 2 therapies (such as high flow nasal canula), non-invasive ventilation or mechanical ventilation (but lower positive end-expiratory pressure, peep). h-phenotypes should be managed with traditional ards protocols (high peep, low tidal volume) [8] . prone positioning in non-intubated patients may be beneficial in a subset of patients, but potential harm in infants due to risk of sudden infant death should be kept in mind [9] . we had suggested exclusive breastfeeding for all neonates born to covid-19 mothers [1] . recent american association of pediatrics guidelines suggest that breastmilk should be preferred feed for the baby while decision to directly breastfeed or feeding with expressed breastmilk should be based on choice of mother and family members. baby should preferably be nursed with a designated covid-19 negative care-giver, whenever feasible, till mother is non-infective [10] . regional guidelines regarding breastfeeding should be followed. department of pediatrics, aiims, new delhi, india. e-mail: rlodha1661@gmail.com covid-19 in children: clinical approach and management compassionate use of remdesivir for patients with severe covid-19 multicenter initial guidance on use of antivirals for children with covid-19/sars-cov-2 a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 race to find covid-19 treatments accelerates convalescent plasma as a potential therapy for covid-19 effective treatment of severe covid-19 patients with tocilizumab covid-19 in children: clinical approach and management experts shed more light on covid-19-related inflammatory syndrome in children pathophysiology of covid-19: why children fare better than adults? remdesivir for the treatment of covid-19 -preliminary report hydroxychloroquine or chloroquine with or without a macrolide for treatment of covid-19: a multinational registry analysis pulmonary vascular endothelialitis, thrombosis, and angiogenesis in covid-19 management of covid-19 respiratory distress use of prone positioning in non-intubated patients with covid-19 and hypoxemic acute respiratory failure breastfeeding guidance post hospital discharge for mothers or infants with suspected or confirmed sars-co v-2 infection publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-303451-66c2qobr authors: pelaez, martha; novak, gary title: returning to school: separation problems and anxiety in the age of pandemics date: 2020-07-15 journal: behav anal pract doi: 10.1007/s40617-020-00467-2 sha: doc_id: 303451 cord_uid: 66c2qobr the shift to the postpandemic school environment will cause dramatic changes and is likely to increase separation problems. in this article, we look at the anxiety problems that some parents and their children might experience when school reopens after the covid-19 lockdown. using a behavioral theory of development, we provide suggestions for how to handle the departure and separation problems that may emerge as parents drop their children off at school. many parents are unsure about how to handle anxiety or fear as their children return to school or have to visit other environments outside their homes. social distancing has caused families to develop stronger dependencies at home and to create new routines that vary, in many instances greatly, from their prepandemic routines. families are adjusting to the new “normal.” they are keeping their children busy with schoolwork as best they can. in particular, families have likely developed close attachment relationships. families have been struggling with an unprecedented lockdown, and for many parents and their children, this extended period of family confinement and severe restrictions has been especially stressful, and the timing for returning to school is uncertain. we emphasize here that parents can be responsive to their children’s needs, plan ahead, provide reassurance, and depart firmly without vacillating, and we provide other tips to avoid inadvertently shaping children’s negative or anxiety behaviors as they go back to school. we offer some specific advice for parents and teachers to follow to prevent the departure and separation problems that typically develop during challenging behavioral interactions in school settings. the covid-19 virus invasion and its impact on human behavior have been quick and unprecedented. it has abruptly produced a series of significant challenges and opportunities for those who study human behavior. in this article, we look at some special implications for understanding its impact on children and how we care for them. we also look specifically at one aspect of this situation: departure and separation protests in young children (although older children, adolescents, and parents themselves may also experience separation issues). we view separation anxiety from the perspective of behavioral developmental theory. further, we make suggestions for how to deal with the young child's protests after requirements for social distancing are over. many parents are unsure about how to handle their children's anxiety or fear as their children return to school or have to visit other environments outside their homes. social distancing has caused families to develop strict home routines as they have been struggling with an unprecedented lockdown. for many parents and their children, this extended period of family confinement and severe restrictions has been especially stressful. but some families have adapted by creating constructive routines and learning environments for their children, maintaining a positive attitude, and trying to balance work at home with family time. others have fallen into more problematic patterns of behavior, such as coercive interactions. editor's note this manuscript is being published as part of a series of emergency publications designed to help practitioners of applied behavior analysis take immediate action to adjust to and mitigate the covid-19 crisis. this article was submitted on april 20, 2020, and received final acceptance on may 20, 2020. the views and strategies suggested by the articles in this series do not represent the positions of the association for behavior analysis international or springer nature. in this article, we stay focused on the separation situation and its effects on parents and young children by using the lens of behavioral development theory (novak & pelaez, 2004) . our treatment of separation protests is uniquely based on behavior-analytic research (gewirtz & pelaez-nogueras, 1990 , 1991 , 1992 . we conclude by offering specific suggestions about how to handle the separation difficulties that will inevitably emerge in some families upon returning to school. the covid-19 crisis came on quickly in the us winter and in the spring of 2020, right in the middle of the school year. one of the immediate effects was the sudden disruption of the dynamic interactions among children and their care providers. in many communities, total social distancing was invoked with little warning. existing relations with teachers and peers were completely shut down, and families were left to scramble to find new ways to care for and educate their children as a replacement. our behavioral systems theory (bst; novak, 1996 novak, , 1998 novak & pelaez, 2004) incorporates developmental dynamicsystems concepts into behavior analysis. bst treats both schools and families as behavioral systems. in the case of schools, the ongoing reciprocal interactions among children and teachers and peers in the classroom develop into functioning systems that are highly efficient in producing reinforcers (both positive and negative). the same is true for the behavioral systems that children participate in at home with parents, grandparents, and siblings. these dynamic transactions take time to develop but become well attuned to the contingencies over time. a sudden and drastic change of conditions, as that which has occurred with the shutdown of schools in response to the covid-19 outbreak, means these well-adapted behavioral systems are thrown into chaos. that means many previously reinforced behaviors are no longer reinforced, establishing operations are no longer in effect, and once available cues for guiding the child (and parents) are now missing. consequently, the two systems have been disrupted quite decidedly. one way to look at the impact on behavioral development is to look at the disruptions they produce in all four terms of the behavioral contingency chain. in most u.s. households, time spent in school or preschool is a significant part of a child's everyday life. typical patterns of interaction emerged in the hours the child spent transacting with teachers and fellow peers. some of these interactions are primarily academic in nature, and nearly all of them involve social interactions. likewise, parents spent a significant part of the day at work, where they develop social interactions with coworkers and perhaps the public. in both the school and work environmental systems, participants develop strongly reinforced patterns of interactions based on behavioral contingencies and social rules. the new social-distancing rules in this age of pandemic have eliminated some of these former contingencies and created fresh ones. the conditions produced by the covid-19 pandemic serve as establishing operations or motivating operations for the development of attachment problems such as separation protest and anxiety. that is, the pandemic presents environmental variables that alter the effectiveness of stimuli, objects, or events as a reinforcer. among these possible motivational or setting conditions are the hospitalization of a parent or other family member, the unfortunate death of a parent or other family member, the worrisome tv news about the virus, the reports on job losses and a bad economy, and the negative reactions of others to the news. fear and anxiety can increase by watching continual updates on the covid-19 pandemic, and information directed at adults can cause anxiety and confusion, particularly in young children. all these experiences work to increase the general anxiety and fear of separation, leaving home and returning to school, and returning to a school environment that parents consider still unpredictable and uncontrollable. we offer some recommendations to parents on how to work with schools and teachers to cope with some of these emerging problems. although parent-child interactions were a part of wellestablished previrus family systems before and after school, with social-distancing policies, online virtual interactions have become nearly the sole source of social interactions outside the family. parental roles have also changed. no longer is the parent's role to support the child's learning in school. now, parents are the school. no longer do parents have to supervise their children for only a few hours before and after school. now they have daylong supervision responsibility. also, in cases where both parents are still working in essential jobs, stress is added to the situation by the need to secure childcare or education, with schools closed for half of the 2019-2020 school year and possibly the 2020-2021. furthermore, the pandemic has placed additional stress on families by eliciting fear of contracting the illness and producing job and huge economic losses. we predict that one initial effect of the changes the pandemic has triggered is increased variability in behaviors of individuals in the family and school systems. largely, this variability occurs when formerly reinforced patterns of behavior are no longer reinforced because old system participants (e.g., teachers and peers) are no longer present. because of physical-distancing rules, for example, a friend's touch or hug may no longer be available to reinforce as it had in the past. thus, increased emotional withdrawal and frustration are also likely to result from withholding some reinforcers (i.e., extinction), which in turn further fuels response intensity and even more variability. together, these withdrawing conditions and the loss of reinforcement may evoke bursts of novel child responses that produce parental reinforcement during coercive interactions. put simply, the child may start acting out in exaggerated ways to obtain reinforcement (e.g., proximity, attention). unfortunately, we have evidence that many of these aversive child responses can be shaped by inadvertent parental responses that wind up strengthening undesirable child-parent behavioral interactions through negative reinforcement traps, as detailed in patterson's coercive family process (patterson, debaryshe, & ramsey, 1989) . one of the hardest decisions parents are making is determining when is the right time for their children to return to the classroom (summer or fall). the postpandemic situation is unique due to its length. the family interactional systems that have been reorganized and will newly emerge will have had a far longer time for patterns to be established. the scope of daily interactions is much broader than summer break and encompasses new educational responsibilities in addition to supervisorial and recreational ones. attachment and dependency are likely to be even stronger than the previous norm. therefore, what we are likely to see is another significant move of virus disruption in a highly efficient family system in which both parents and children are strongly attached and will have more difficulty adapting to the "new normal" systems in a postvirus era in schools. in the remainder of this article, we will utilize a behavioral systems approach to address this important issue, as we anticipate increasing problems when children return to their school environments. we will describe some of the research on the variables leading to separation protests and suggest actions that may reduce the number and intensity of these. parents' behaviors are likely to reinforce their children's proximity, attention, and affection. when the child's proximityand security-regulating behaviors become organized around a parent or caregiver, we say the child has developed an attachment (bretherton, 1987 (bretherton, , p. 1063 . by "organized," we mean that more than just individual responses occur. child attachment is characterized by dynamic patterns of behaviors reinforced by proximity to the parent or main caregiver. parents' behaviors, too, are reinforced by proximity to their children, and parents may become "attached" to them. thus, behavioral systems are bidirectional and reciprocal. parents are also liable to have heightened feelings of attachment and, if severe, may need additional help to treat behaviors characteristic of separation anxiety disorder that are described in the diagnostic and statistical manual of mental disorders (american psychiatric association, 2013). however, the focus of this article is on the prevention and compassionate management of young children's separation protests in returning to school. visit nearly any childcare center or preschool at the beginning of a new academic year and you are certain to observe young children's separation protests. these young children's protests typically take the form of whining, crying, throwing tantrums, clinging to the parent when leaving, and refusing to detach. separation protests are commonly used to measure security or insecurity of attachment and separation anxiety (kagan, kearsley, & zelazo, 1978) . we have emphasized that there is a possibility that the child's separation protest might develop as learned responses during interactions with primary caregivers (gewirtz & pelaez-nogueras, 1990 , 1991 , 1992 . gewirtz and pelaez-nogueras (1990 , 1991 , 1992 conducted several intervention studies on how mother-infant interactions influence the development of separation protests and distress. they applied the results of those studies to provide guidance to parents. in light of the covid-19 crisis, when children return to school and separate from their parents after a months-long period of 24-hr-a-day interaction that occurred during a period of social distancing, we predict that high rates of protest and distress may emerge, as well as high rates of refusal to leave the parents. this is likely to produce heightened child separation-protest responses that can disrupt classroom settings the new physical distancing rules, and provoke anguish and anxiety in parents. thus, the way that the departures and separations are handled by parents and teachers may have positive or negative consequences for all-children, parents, and school settings. researchers have shown that contingent maternal responding to separation protests can shape children's behaviors, such as whining, crying, and throwing tantrums (gewirtz & pelaez-nogueras, 1991) . they have further shown that separation protests could be reduced if parents differentially reinforced behaviors other than protest behaviors, such as playing with toys. although the research demonstrates how the family is a system, and although the caregiver is likely to shape the child's behavior in separation protests, the interactions have reciprocal effects. that is, although mothers and teachers can "inadvertently" reinforce the child's separation protest, the caregiver's behavior is likely to be negatively reinforced by reducing or stopping (at least in the short run) the child's crying/protesting and anxious behavior. specifically, the caregiver's attachment behavior can be shaped by terminating or escaping the aversiveness of his or her child's separation protest; simultaneously, the child's protest behavior is being shaped by the contingencies (e.g., touching, hugging, vacillating, talking, and overreassuring the child) provided by the parent returning to the protesting child in the classroom. few parents know how to cope with the crying and tantrums of their children, especially in situations in which they are getting ready to leave their children at school for the first time or when they will return to school during or after the pandemic. this lack of knowledge is completely normal. at the beginning of school, children's protests and cries can delay their parents' departures and cause them to return to school after dropping their children off. the research we discussed earlier shows that, during departures and at separation, parents' responses to children's protests can encourage and reinforce more of this distressing behavior. even more problematic is that when parents intermittently reinforce protests, these protests may escalate and get worse. in this section, we offer some advice for parents to follow to prevent maladaptive behavior interactions. the behavior-analytic view is that parental responses in this situation can encourage and otherwise shape the child's behavior patterns. unfortunately, our responses as parents often make it more difficult for our children to separate in the long term. we often inadvertently provide "misplaced contingencies" under such commendable intentions as providing a secure base or loving attention to our children and their needs. let us provide observations of what happens when a parent provides the "goodbye cues." a child's separation protests are routinely cued by a parent's preparations to leave the child in school or other settings. the behavioral cues that signal parental departure and separation can involve a mother picking up her car keys and purse, placing her baby in the crib or playpen while saying goodbye, or the arrival of a babysitter or caregiver. these cues serve as discriminative stimuli for child protests, as well as stimuli that evoke emotional distress in both child and parent. a parent may fear that the young child may not be safe in the school in this era of covid-19. in older children, the cues would differ, and the parents may reason and provide explanations and a series of new instructions to the child. these new physical distancing rules may disrupt the existing family routine. we described this earlier as disruption and chaos in the dynamic system. departure-cued protests can include fusses, whines, whimpers, cries, and screams. in children with more advanced verbal and motor skills, protests may also involve grabbing the parent's body or clothes, clinging, pleading, or throwing a loud temper tantrum and refusal to leave the parent. these behaviors often cut short a separation from the parent. they also may further increase the emotional upset in the home setting. the parent's anguished responses to the child's protests can include delaying a departure, returning to hug the child, engaging in extensive reasoning with the child, vacillating during the departure, or hesitating to separate. the parent's anxious behavior may also include returning to school to pick up the child after having left the classroom in response to the teacher's call about a child's protest. often, parents return to touch, pick up, or hug and kiss the protesting child. these well-intended parental behaviors provide attention contingent on the child's protests, therefore strengthening them. in turn, during the transaction the child simultaneously trains the parent to behave this way, by stopping the protests contingent on the parent delaying departures, cutting short separations, or taking the child back home. thus, parents' behavior problems and anxiety responses can result from children's responses during the transactions. the serious situation of covid-19 virus transmission exacerbates all these scenarios, mainly because all the establishing operations or setting conditions it produces increase fear and anxiety of separation and the child getting infected. we discussed that parents' and teachers' attending reactions to infant protests during departures and after separations actually make recurrences of protests more likely in future situations. we also emphasized that intermittent reinforcement of protests will likely make them more resistant to extinction. the child's response bursts and variability are more likely to occur. parents with separation anxiety may have more fears and may want to check more frequently on their children. these parents may demand to know where their children are at all times by texting, making the teacher's job very difficult. in general, parents may have difficulties with separation from their children at all times, most specifically in light of the virus's risks of infection. to minimize separation distress, parents could program with teachers controlled visits to the child's classroom when the child has not recently protested and has remained there for varyingly longer periods. on each of these occasions, after parents drop off the child at school or classroom, the situation would be less stressful if the parent departs from the setting in a straightforward manner and is reassured by school personnel that the situation is under control. at the beginning of the separation episode, the classroom teacher in charge should provide reassurance to children that their parents will come back to pick them up at the end of the day. the new classroom routines and rules during and after the covid-19 pandemic should be established clearly and discussed ahead of time with parents and their children before they come back to school. some of the preliminary training can occur via virtual technology like zoom or telehealth techniques showing the new classroom arrangements and rules (e.g., handwashing routines, wearing face covers, physical distancing). it is important to keep in mind that parents and teachers should contact a professional if any child exhibits significant changes in behavior that suggest something else is amiss with the child that requires intervention from a child psychologist. going back to school after a prolonged and intense period locked down at home will require many adaptations to new environments, of which school is only one. in order to facilitate the shift from home to school, we offer several recommendations that parents can use to make parting less painful and anxious for their children. learn the new rules and routines of the classroom, and plan ahead. develop a plan for dealing with separation and new classroom routines and rules. involve the teacher's rules and plans in your own planning. discuss these with your child ahead of time. as a parent, you could write a description of your strategy for responding to your child's protests, e-mail it to the teacher, and invite the teacher to give input about how it fits into the classroom setting and how he or she may help you. at a minimum, this will keep the teacher informed of your intentions and concerns. listen carefully to the child. children give off verbal and nonverbal cues about their anxiety level. this will alert you to the likelihood of problems and may allow you to be especially reassuring and prepared for them. for younger children, while at home and talking to your child about returning to school, you might ask your child to make a drawing about his or her thoughts or concerns, and respond with truth and reassurance. model calm. be calm and relaxed. anticipate child protests and plan how to react calmly. model calm behavior during difficult situations, and "catch" your child being calm and richly reinforce it (see resources). create a less stressful environment. before your departure, ensure that your child is safe, relaxed, and positively engaged in an activity. use this to establish the conditions for a less stressful and safe departure. have the teacher greet your child in a warm and welcoming manner. check with the teacher about quickly providing a positive routine, such as helping prepare a snack or playing with a good friend. announce your departure. as soon as possible, follows physical distancing rules after arriving at the classroom, you should make sure the child follows physical distancing rules is welcomed into an activity (e.g., playing) and announce your departure to your child in a straightforward manner (e.g., by saying, "i'll be back for you later. i love you."). make the explanation clear and short. for younger children, you could simply say, "mommy has to go now, but i'll be back soon. have fun," give a kiss, and leave. for older children, you might also explain the departure ahead of time and indicate when you plan to return. reassure children that they are okay. however, once at school, such an explanation should be very short. do not negotiate. do not respond to protests with additional explanation or negotiation. negotiating runs the risk of reinforcing the child's protests. instead, focus on the positive. follow your plan, and leave without hesitating. depart without vacillating. you should leave the setting directly without hesitation. there is no need to appear rushed, but hesitating will only give the wrong cues and make it more difficult for you and your child. do not return. once you have left, you should not come back to pick up or talk to a protesting child. remember, occasional reinforcement of some protests will likely make the protests worse and make it harder for your child in the long term. behave consistently. have a routine that you continue to follow despite any protests. this predictability will make it easier for your child to learn that everything is normal. this will help your child integrate into the new daily postpandemic classroom routine. inconsistent experiences are likely only to produce more emotional upset and intermittently reinforce undesired behaviors. we would like to close our recommendations with a quote from the national association of school psychologists website: it is very important to remember that children look to adults for guidance on how to react to stressful events. acknowledging some level of concern, without panicking, is appropriate and can result in taking the necessary actions that reduce the risk of illness. teaching children positive preventive measures, talking with them about their fears, and giving them a sense of some control over their risk of infection can help reduce anxiety. this is also a tremendous opportunity for adults to model for children problem-solving, flexibility, and compassion as we all work through adjusting daily schedules, balancing work and other activities, getting creative about how we spend time, processing new information from authorities, and connecting and supporting friends and family members in new ways (nasp, 2020) . funding information the present study was not funded by any relevant grants or other funding sources. conflict of interest the authors declare that no relevant conflicts of interest influenced the nature of the present research investigation. ethical approval all procedures performed in studies involving human participants that participated in the studies cited that were conducted by pelaez et al. were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. informed consent this is a brief report, and no data were collected. informed consent in the studies cited in this article (by gewirtz & pelaez-nogueras, 1990 , 1991 , 1992 , 1993 was obtained from the parents of the infants who participated in those studies. specifically, if the parent's child met the characteristics for participation in the study and the parent provided consent-for-participation forms for both him-or herself and his or her child (via parental and child consent forms), the child would then begin the assessment procedures. the primary investigator was available and willing to answer any questions that the parent may have had regarding the study and his or her child's participation throughout every session. further, the consent form stressed that the parent may withdraw his or her child's participation at any time and that all participation was purely voluntary in nature. • coping with stress during infectious disease outbreaks: https://store.samhsa.gov/product/coping-with-stress-during-infectious-disease-outbreaks/sma14-4885 diagnostic and statistical manual of mental disorder patterns of attachment new perspectives on attachment relations: security, communication, and internal working models social-conditioning theory applied to metaphors like "attachment": the conditioning of infant separation protests by mothers the attachment metaphor and the conditioning of infant separation protests infants' separation difficulties and distress due to misplaced maternal contingencies leaving without tears: parents inadvertently train their children to protest separation helping children cope with changes resulting from covid-19 developmental psychology: dynamical systems and behavior analysis behavioral systems theory child and adolescent development: a behavioral systems approach a developmental perspective on antisocial behavior publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-009713-sxd4t2tz authors: nan title: poster presentations date: 2020-01-10 journal: dev med child neurol doi: 10.1111/dmcn.14411 sha: doc_id: 9713 cord_uid: sxd4t2tz nan what are the perspectives and understanding of healthcare professionals including occupational therapists on treatment and care of babies with infantile spasms and early-onset epilepsy? a qualitative design dm middleton university of roehampton-online, birmingham, uk objective: to explore the perspectives and understanding of allied healthcare professionals (occupational therapists, physiotherapists, speech & language therapists) that work with children and epilepsy in order to guide and advocate for this population group. methods: a qualitative study design using interpretive thematic analysis with the data from participants in 10 semi-structured interviews. results: the professionals had worked across acute and community settings and had previous experiences of working with children with epilepsy with some awareness of these needs. there were 5 themes that emerged: (1) housing and social needs, (2) epilepsy, psycho-social and mental health needs, (3) therapy approaches, (4) training for allied healthcare professionals, and (5) adolescents, young girls, women and epilepsy. conclusions: there are gaps in service provision for certain areas and will be shared within the presentation. epilepsy requires additional considerations for safety that other conditions may not require. it is crucial in the interests of public health for children and families with epilepsy to be able to advocate for resources and their specific needs. poster no. 004 time to onset of cannabidiol (cbd) treatment effect and resolution of adverse events in patients with dravet syndrome: pooled analysis of two randomised controlled trials solution) at 10mg/kg/day (cbd10; gwpcare2) or 20mg/ kg/day (cbd20; both trials) or placebo for 14 weeks. cbd treatment started at 2.5mg/kg/day and reached 10mg/kg/day on day 7 and 20mg/kg/day on day 11. percent reduction in cumulative convulsive seizure frequency for each treatment day (including previous treatment days) and timing of adverse events (aes) were assessed. results: overall, 194 patients were randomised to cbd and 124 to placebo. cbd led to significantly greater percent reductions in convulsive seizure frequency than placebo in gwpcare1 (cbd20 39% vs placebo 13%, p=0.0123) and gwpcare2 (cbd10 49%, cbd20 46% vs placebo 27%, p=0.0095 and p=0.0299). in the pooled data, treatment differences in seizure reduction emerged during titration and were maintained throughout the study, with nominal significance (p<0.05) achieved by day 13 for cbd10 and day 12 for cbd20. onset of the first reported ae occurred during titration in 60% of patients with aes. aes resolved within 4 weeks of onset in 40% of patients and by the end of the study in 60%. increases in alt/ast (>39 upper limit of normal) occurred in 3 (5%) patients for cbd10, 25 (19%) for cbd20, and 1 (1%) for placebo; all were on concomitant valproate. all elevations resolved, either spontaneously while continuing cbd, after discontinuing cbd, or after reducing cbd, valproate, and/or clobazam dose. conclusions: cbd treatment effect (seizure reductions and aes) may occur early, during titration. the majority of aes resolved during the study. poster no. 005 low dose fenfluramine hydrochloride oral solution provides long-term, clinically meaningful (≥50%) reduction in seizure frequency in dravet syndrome: interim analysis of a long-term openlabel extension study objective: to characterize long-term safety and durability of effect for adjunctive fenfluramine (ffa) in treating dravet syndrome (ds). methods: patients (2-18y) with ds entered a long-term openlabel extension (ole) (1503) after completing one of two phase 3 studies: study 1 (14wks; placebo or ffa 0.2 or 0.8mg/kg/d [max, 30mg/d] or study 1504 (15wks; placebo or ffa 0.5mg/kg/d [max, 20mg/d]) . stiripentol was excluded in study 1 but mandatory in study 1504. in 1503, patients received ffa 0.2mg/kg/d for month 1; dosing was titrated to effect thereafter. effectiveness and tolerability were assessed at months 1, 2, and 3, then at 3-month intervals. results: at interim analysis (13-mar-2018) , 158/187 patients continued into ole; 89% completed 12 months of ffa (mean dose, 15.2mg/d; median duration, 400d [range, 71-703d] ). during the entire ole, median percentage change in monthly convulsive seizure frequency (mcsf) for ffa vs pretreatment phase 3 study baseline was -63.6% (p<0.001); clinically meaningful (≥50%) and profound (≥75%) mcsf reduction from baseline were 63% and 41%. at month 12, median and mean longest interval between convulsive seizures were 26 and 60 days (range, 2-589d); 71% of caregivers and 83% of investigators rated patients 'much improved/very much improved'. the most common adverse events included appetite decrease, pyrexia, nasopharyngitis, and diarrhea. no valvular heart disease or pulmonary hypertension was observed in any patient. conclusions: treatment with ffa resulted in robust, sustained reductions in mcsf and was generally well tolerated. no valvular heart disease or pulmonary arterial hypertension was observed in any patient at any time. ffa may be an important, novel antiepileptic drug for long-term ds treatment. poster no. 006 zx008 (low dose fenfluramine hydrochloride oral solution) provides long-term, clinically meaningful reduction of convulsive seizure frequency in young (<6 years old) dravet syndrome participants: analysis from a long-term open-label study results: a total of 42 of 158 (26.6%) participants who enrolled in the ole were <6 years old upon entry into the phase 3 studies. the median baseline monthly convulsive seizure frequency (mcsf) before double-blind treatment was 10.7 seizures/month (range, 4.0-147.3 ) in this patient subgroup (<6y). at the time of the ole interim analysis, the median decrease in mcsf in the <6 years subgroup over the entire observation period compared to baseline was -75% (p<0.001) compared with -64% in the overall study population (2-18y). the most frequently reported adverse events included pyrexia, upper respiratory tract infections, decreased appetite, and diarrhea. no valvular heart disease or pulmonary arterial hypertension was observed. conclusions: treatment with zx008 provided sustained, clinically meaningful reduction in mcsf in ds participants <6 years old. importantly, effective control of seizures in this young age group might be expected to mitigate the negative neurodevelopmental outcomes reported to be associated with treatment-refractory seizures. the improving provision of epilepsy care for children in england and wales methods: all relevant health boards and trusts (hb/t) were invited to register to participate and identify a hb/t lead. a snapshot survey was completed via a bespoke online platform by the hb/t lead describing local provision as of april 2018. data was analysed by the rcpch including regional and national aggregates and longitudinal comparison to previous 2012, 2014 reports. results: 148 hb/t with a paediatric epilepsy service across england and wales registered to participate and submitted data. 94.6% (140/148) of hb/t employed a consultant paediatrician with expertise in epilepsy; 77.7% (115/148) had some epilepsy specialist nurse (esn) provision; 85.8% (127/148) had a defined epilepsy clinic seeing patients at secondary level. 92.6% (137/148) of hb/t had agreed referral pathways to tertiary paediatric neurology services. satellite paediatric neurology clinics were hosted in 77.0% (114/148) of hb/t. conclusions: there are improvements in the overall numbers of epilepsy nurse specialists, paediatricians with expertise and specific clinics for children and young people with epilepsies. the findings led to comprehensive recommendations to hb/ t and commissioners, informed updates to the epilepsy best practice tariff and themes within the nhs long term plan. poster no. 008 diagnosing and managing seizures on picu: an explanatory sequential mixed methods approach tonic clonic seizures. awake and sleep eeg showed temporal focal slowing. she was labelled as non lesional focal epilepsy after a normal mri scan and was discharged on keppra. she had multiple admissions with cluster of brief seizures at the age of 12, 16, 25, 26, 34, 38 and 46 months associated sometimes with febrile illness with poor response to intravenous aed's. she was diagnosed with autism at 42 months. 2nd child: 38 months old younger sibling had seizure onset at 9 months. seizures were tonic in nature, brief, multiple and in clusters over a period of 2 to 3 days. eeg's showed non-specific slowing during seizures. array cgh revealed chromosome 3p26.1 microdeletion. keppra was commenced and increased but recurrent cluster of seizures at the age of 15, 19 and 24 months required admission with poor response to iv aed's. family history revealed that half-sister (biological father's daughter who had epilepsy and global developmental delay) was diagnosed with pcdh 19 epilepsy. gene tests were requested on both siblings and both were heterozygous for pcdh 19 mutation. she had delayed social and communication skills from 2 years with a diagnosis of autism at 30 months. 3rd child: 1 year old half sibling (father's 4th child from 3rd relationship) has tested positive for pcdh 19. her development is normal and so far there have been no seizures. conclusions: pcdh 19 epilepsy is increasingly recognised as one of the early onset infantile encephalopathies. gene testing is likely to yield a diagnosis with a family history or with a typical phenotype. poster no. 010 seizure, developmental and cognitive outcomes in children post hemispherotomy tt tay 1 , dr reed 2 , vj josan 3 , sr rust 4 , jt tan 5 1 university of manchester, manchester, uk; 2 neuropsychology team, paediatric psychosocial service, royal manchester children's hospital, manchester, uk; 3 neurosurgery, salford royal nhs foundation, manchester, uk; 4 paediatric neuropsychology, royal manchester children's hospital, manchester, uk; 5 paediatric neurology, royal manchester children's hospital, manchester, uk introduction: patients with focal refractory epilepsy secondary to structural hemispheric changes have been shown in retrospective studies to have significantly improved seizure outcomes following hemispheric disconnection. the aim of this study was to report the seizure and cognitive outcomes in our cohort and investigate prognostic factors for seizure outcomes. methods: this was a single-centre retrospective study on children and adolescents who had hemispherotomy for refractory epilepsy in the royal manchester children's hospital between 2008 and 2017. results: twenty-two patients were included with median (range) age of seizure onset and of surgery of 4 (0-168) and 72 (13-217) months respectively. median (range) time from seizure onset to surgery was 38.5 (12-172) months. the most common aetiologies were antenatal/perinatal middle cerebral artery infarct (n=6) and malformations of cortical development (n=6). at 1 year after surgery and at last follow-up (median [range] 38 [2-107] months), 50% (10/20) and 32% (7/22) achieved complete seizure freedom. the number of anti-epileptic medications decreased for 10 (45%) at last follow-up. lateralisation of ictal and interictal eeg (p=1.00, p=0.11), aetiology (p=0.75), age of first seizure (p=0.45) were not associated with seizure recurrence. five who had formal neuropsychological testing using the wechsler intelligence scale for children (wisc) showed improvement in cognitive abilities across all subsets post-surgery. ten children showed reduction in median vineland adaptive behaviour score, from 58 to 49.5, indicating a failure to progress rather than regression of skills. nine (45%) had newly reported behavioural or psychiatric issues including sleeping problems, challenging behaviours, autistic spectrum disorder. sixteen (84%) were reported by parents/carers to show improved verbal abilities postoperatively while the rest had unchanged verbal abilities. conclusions: we present a cohort of children with early onset seizures who had hemispherotomy at a relatively early age. our cohort showed good seizure outcomes and cognitive improvements. there were no prognostic factors for seizure outcome identified in this small group. the mri phenotype of atp1a3-related disease contrast, all ahc patients with mri abnormalities (83%) had a hypoplastic corpus callosum. the only patient with normal mri was the patient carrying mutation p.g497r, associated with a mild clinical phenotype. of the patients with clinical ataxia (n=7), 5 (71%) had cerebellar atrophy on mri; 2 patients with cerebellar atrophy were not ataxic. two (67%) of the 3 patients with severe intellectual disability had cerebral atrophy. conclusions: atp1a3 mutations have subtle radiological findings, clustering around callosal dysmorphisms, as well as pontine and cerebellar abnormalities that seem to form distinctive mri phenotypes for ahc and capos. study of larger cohorts is required to more accurately define mutation-specific phenotypes and allow for quantitative analysis. poster no. 012 long-term safety and efficacy of adjunctive perampanel in paediatric patients (aged 4 to <12y) with partial-onset seizures (pos) or primary generalised tonic-clonic seizures (pgtcs) in study 311 r flamini 1 , a patten 2 , ly ngo 3 1 pediatric and adolescent neurodevelopmental associates, atlanta, ga, usa; 2 eisai ltd., hatfield, hertfordshire, uk; 3 eisai inc., woodcliff lake, nj, usa objective: study 311 (nct02849626) was a multicentre, openlabel, single-arm study of perampanel oral suspension (0.5mg/ ml) in paediatric patients (aged 4 to <12y) with pos (with/ without secondarily generalised seizures [sgs] ) or pgtcs. here, we report long-term (1y) safety and efficacy data of adjunctive perampanel in paediatric patients from study 311. methods: this analysis included cumulative data from all enrolled patients in the core study (23wks of treatment) and extension phase a (52wks of treatment). assessments included monitoring of treatment-emergent adverse events (teaes), median percent change in seizure frequency per 28 days from baseline, and 50% responder and seizure-freedom rates. results: of 180 patients enrolled in the core study (pos, n=149; sgs, n=54; pgtcs, n=31), 136 patients entered extension a. of these, 14 patients discontinued extension a; most common primary reasons for discontinuation were adverse events (3.7%) and inadequate therapeutic effect (2.9%). for all patients, mean (standard deviation [sd] ) time since diagnosis was 5.7 (2.9) years and mean (sd) duration of exposure was 41.5 (17.3) weeks. during baseline, 55.6% of patients received two concomitant anti-seizure medications. teaes were reported in 162 (90.0%) patients; somnolence was the most commonly reported (27.2%). median percent reductions in pos, sgs and pgtcs frequencies at weeks 1-13 were 43.0%, 57.9% and 79.3%, respectively; these were maintained at weeks 40-52 and were 69.4%, 73.8% and 100.0%, respectively. seizure-freedom rates for pos, sgs and pgtcs at weeks 40-52 were 13.0%, 24.4% and 38.5%, respectively. conclusions: long-term (1y) adjunctive perampanel is generally safe, well tolerated and efficacious in paediatric patients aged 4 to <12 with pos (with/without sgs) or pgtcs. poster no. 013 long-term adjunctive perampanel and healthrelated quality of life (hrqol) in paediatric patients (aged 4 to <12y) with partial-onset seizures (pos) or primary generalised tonicclonic seizures (pgtcs): study 311 ea portillo 1 , a patten 2 , g meier 3 , m malhotra 3 , ly ngo 3 1 paediatric neurology unit, department of paediatrics, hospital universitario virgen del roc ıo, sevilla, spain; 2 eisai ltd., hatfield, hertfordshire, uk; 3 eisai inc., woodcliff lake, nj, usa objective: study 311 (nct02849626) was a multicentre, openlabel study of adjunctive perampanel oral suspension in paediatric patients (aged 4 to <12y) with pos (with/without secondarily generalised seizures [sgs] ) or pgtcs. we report long-term (1y) hrqol data using the euroqol 5 dimensions-youth (eq-5d-y) scale from study 311. methods: this analysis included cumulative data from all enrolled patients in the core study and extension phase a (23 and 52wks of treatment, respectively). eq-5d-y was assessed at baseline, week 23 and week 52, and included five domains (mobility, self-care, doing usual activities, pain/discomfort, feeling worried/sad/unhappy). the eq-5d-y visual analogue scale (vas) was also assessed; increases in vas correspond with improvements. data are for observed cases. results: all 180 enrolled patients were included in the eq-5d-y analyses. the proportion of patients reporting 'a lot of problems' was similar during baseline vs week 52: mobility, 20/112 (17.9%) vs 13/68 (19.1); self-care, 44/112 (39.3%) vs 23/68 (33.8%); doing usual activities, 27/112 (24.1%) vs 18/68 (26.5%); pain/discomfort, 4/115 (3.5%) vs 2/70 (2.9%); feeling worried/sad/unhappy, 4/113 (3.5%) vs 1/70 (1.4%). outcomes were also similar for 'no problems' during baseline vs week 52: mobility, 64/112 (57.1%) vs 43/68 (63.2%); self-care, 42/112 (37.5%) vs 27/68 (39.7%); doing usual activities, 53/112 (47.3%) vs 34/68 (50.0%); pain/discomfort, 78/115 (67.8%) vs 50/70 (71.4%); feeling worried/sad/unhappy, 80/113 (70.8%) vs 52/70 (74.3%). mean (standard deviation) change in eq-5d-y vas from baseline at week 52 was 5.1 (16.6). conclusions: long-term adjunctive perampanel treatment (up to 1y) does not negatively affect hrqol (based on all eq-5d-y domains) in patients aged 4 to <12 years with pos (with/without sgs) or pgtcs. poster no. 014 efficacy and safety of adjunctive perampanel for partial-onset seizures (pos) in adult, adolescent and paediatric populations (studies 304, 305, 306, 311) . in study 311, 149 patients received perampanel ≤12mg/day (without enzyme-inducing anti-seizure medications [eiasms] ) or ≤16mg/day (with eiasms) (23-week treatment period). efficacy assessments included median percent change in seizure frequency/28 days from baseline, 50% responder rate and seizure-free rate. safety assessments included the incidence of treatment-emergent adverse events (teaes). results: the median percent reduction in seizure frequency/ 28 days was greater with perampanel at 4 (23.3%), 8 (28.8%) and 12mg/day (27.2%) vs placebo (12.8%; p<0.01) in adolescent/adult patients and was 40.1% in paediatric patients. the 50% responder rate during the maintenance period was greater with perampanel at 4 (28.5%), 8 (35.3%) and 12mg/ day (35.0%) vs placebo (19.3%; p<0.05) in adolescent/adult patients and was 46.6% in paediatric patients. seizure-freedom rates were greater with perampanel at 4 (4.4%), 8 (3.5%) and 12mg/day (4.1%) vs placebo (1.0%; p<0.05) in adolescent/ adult patients and was 11.5% in paediatric patients. teaes occurred in 61.7%-89.0% of adolescent/adult patients with perampanel 2-12mg/day (vs 66.5% in placebo patients), and in 89.9% of paediatric patients. teaes observed in pediatric patients were similar to those reported in adolescents and adults. conclusions: these studies suggest perampanel is efficacious and generally safe in paediatric, adolescent and adult patients with pos (with/without sgs). methods: patients who completed either of the rcts could enter this ole trial (gwpcare5/nct02224573). patients received gw pharmaceuticals' plant-derived highly purified cbd medicine (100mg/ml oral solution). the primary endpoint was safety. the secondary efficacy endpoints were median percentage change from baseline in drop and total seizure frequency. results: overall, 99% (366/368) of eligible patients with lgs entered the ole. median follow-up was 150 weeks (3d to 179wks); 119 patients (33%) withdrew. mean age: 16 years; 33% ≥18 years; 54% male. baseline median seizure frequency/28 days: 80 drop seizures; 168 total seizures. during the extended follow-up, the incidence of adverse events (ae) was 96%; serious aes 42%; aes leading to discontinuation 12%. most common aes (≥20%): diarrhoea, convulsion, pyrexia, somnolence, vomiting, upper respiratory tract infection, and decreased appetite. aes of alanine aminotransferase increased occurred in 8% of patients. there were 11 deaths; none deemed treatment-related by the investigator(s). median percentage reductions in seizure frequency (12-wk windows over 156wks) was 48-71% for drop seizures and 48-68% for total seizures. conclusions: long-term treatment with add-on cbd in patients with lgs produced sustained seizure reductions, with no new safety concerns. poster no. 016 management of status epilepticus in children with dravet syndrome jaa holland, u rajalingam paediatrics, hinchingbrooke hospital, huntingdon, uk objective: status epilepticus is reported to be the second greatest cause of mortality in children with dravet syndrome. we aimed to review the evidence on convulsive status management in children with dravet syndrome to guide local practice. methods: literature review. results: pubmed search using search terms 'dravet' or 'scn1a' and 'status epilepticus' returned 149 results, of which 8 were relevant. only one of these articles presented specific data on reported effectiveness of medications used in acute seizure management; this was based upon retrospective questionnaire data and defined status epilepticus as seizures lasting 30 minutes or longer. here, the most efficacious agents reported to terminate such seizures within 10 minutes were intravenous barbiturates (16 of 19 patients) and benzodiazepines (60 of 102 patients). rectal benzodiazepines, chloral hydrate and intravenous phenytoin or lidocaine were reported as less effective. the remaining articles presented expert and consensus opinion, all advising early administration (some at seizure onset) of buccal or intravenous benzodiazepines. provision of rescue medication for home use, with individualised plans, is recommended. one author advocated giving three doses of benzodiazepines sequentially. an article summarising a consensus panel described sodium valproate as a preferred second line option where benzodiazepines are ineffective, but there was no overall agreement on other possible medications. several articles advised caution in using phenytoin in acute seizure management. one source discusses possible harm from high dose barbiturates. conclusions: status epilepticus management for children with dravet syndrome should feature early, rapidly acting benzodiazepine administration. for second line treatment, phenytoin and barbiturates are commonly used in 'standard' status epilepticus management protocols, but there are potentially concerns around their use in this patient group. these concerns, however, appear largely theoretical. in the absence of evidence favouring a specific management protocol, individualised care plans should be designed with involvement of patients and their carers. poster no. 017 zx008 (low dose fenfluramine hydrochloride oral solution) significantly reduces frequency of generalized tonic-clonic seizures in dravet syndrome: pooled analysis from two phase 3 clinical trials jh cross 1 , a gil-nagel 2 , b gunning 3 , d battaglia 4 , k riney 5 , g farfel 6,7 , a mistry 6,7 , b galer 6,7 , g morrison 6,7 , a gammaitoni 6,7 , k pagano 6,7 1 great ormond street hospital, london, uk; 2 servicio de neurologia, hospital ruber internacional, madrid, spain; 3 stichting epilepsie instellingen, zwolle, the netherlands; 4 gemelli hospital, rome, italy; 5 mater children's hospital, brisbane, qld, australia; 6 zogenix, inc and int, emeryville, ca, usa; 7 zogenix, inc and int, maidenhead, uk objective: zx008 (low dose fenfluramine hcl oral solution) significantly reduced the frequency of convulsive seizures in patients with dravet syndrome (ds) in two phase 3 clinical trials. we conducted a pooled analysis of these trials to analyze the effect of zx008 on the frequency of tonic-clonic seizures (tcs), recently identified as a major risk factor for sudden unexpected death in epilepsy. methods: the frequency of generalized tcs and focal-to-bilateral tcs in patients with ds enrolled in one of two phase 3 clinical trials of zx008 added to current antiepileptic drug regimens were analyzed. results: 206 patients (55% male, mean age 9y) were enrolled and randomized to placebo (n=84), or zx008 0.8 (n=40), 0.5 (n=43), or 0.2 (n=39) mg/kg/day. the median baseline monthly frequency of generalized tcs ranged from 8.0 to 12.3/month in the four dose groups, and decreased during treatment by 80%, 64%, and 48% in the zx008 0.8, 0.5, and 0.2mg/kg/day groups, respectively, and by 10% in the placebo group. focal-to-bilateral tcs were experienced by fewer patients and had a median baseline frequency of 2.0 to 4.7/ month. during treatment, median percentage reductions in focal-to-bilateral tc frequency were 97%, 33%, and 69% in the zx008 0.8, 0.5, and 0.2mg/kg/day groups, respectively, and 39% in the placebo group. most common adverse events included decreased appetite, diarrhea, and fatigue. no valvular heart disease or pulmonary arterial hypertension was seen in any participant at any time. conclusions: zx008 substantially reduced the frequency of tcs. zx008 may be an important, effective new treatment option for ds patients. objective: mutations affecting tbc1d24 have been associated with an expanding spectrum of phenotypes including developmental delay, hearing impairment, doors syndrome and a range of epilepsies. a number of different movement disorders, including ataxia, spasticity and episodic paroxysmal dystonia have also been described. here we report two unrelated patients with biallelic tbc1d24 variants, in whom exerciseinduced dystonia was a major disease feature. methods: both patients were diagnosed through whole-exome sequencing. clinical information was obtained by a review of the medical notes, clinical correspondence and available video footage. results: both patients were found to have compound heterozygous mutations in tbc1d24, associated with an episodic dystonic/dyskinetic movement disorder reliably triggered by exertion. in the case of patient 1, exertion of specific body parts induced specific localised symptoms: for example, singing would precipitate orolingual dyskinesia. both girls experienced truncal dystoniaspecifically, lateral flexion of the trunkbrought on by prolonged walking. both girls also had epilepsy; of note, the exercise-induced movements and postures were captured on eeg and had no ictal correlate. conclusions: although tbc1d24 mutations are an established genetic cause of epilepsy, our study further confirms that not all paroxysmal events in people with tbc1d24 mutations are epileptic in nature. tbc1d24 should be included in the genetic differential diagnosis of patients with complex neurological syndromes associated with paroxysmal exercise-induced dyskinesia. objectives: heterozygous de novo rhobtb2 mutations have recently been reported in developmental and epileptic encephalopathy, but the associated movement phenotypes are not fully delineated. in order to better define the expanding phenotype and movement disorder in rhobtb2-related disease, we report a series of 9 unrelated patients presenting with complex movement disorders as well as epilepsy and developmental impairment. methods: cases were identified both in the uk (through the neurogenetic services at great ormond street hospital and the national hospital for neurology and neurosurgery, london), and from international collaborating centres. data were collected retrospectively by the patients' clinicians, using a standardised proforma. results: nine individuals were identified, aged from 2 to 55 years. 8/9 had epilepsy. of these, 4/8 had achieved seizure freedom at their last review. the commonest seizure types were focal onset with impaired awareness and/or focal to bilateral tonic-clonic seizures. 7/9 also had a paroxysmal movement disorder, which included hemiplegic or asymmetrical episodic weakness in 5/7, generalised dyskinesia in 4/7, episodic focal dystonia in 3/7 and episodic ataxia in 3/7. all individuals affected by a movement disorder had at least two different types of episodes. movement disorders improved significantly after treatment with carbamazepine in three children. cognitive ability varied from average to severe intellectual disability and in all but one case, developmental delay predated the onset of epilepsy. conclusions: rhobtb2 mutations cause a complex neurological phenotype associated with both epileptic and non-epileptic paroxysms. paroxysmal events occurring in people with known rhobtb2 mutation should therefore not be assumed always to be epileptic in nature. our study confirms that a wide variety of movement disorders are reported, including some which fall within the spectrum of alternating hemiplegia of childhood (ahc). rhobtb2 should thus be considered as a potential gene for ahc, other complex movement disorder phenotypes and epilepsy-dyskinesia syndromes. poster no. 020 evaluating seizure recognition and the use of electroencephalography in the paediatric intensive care unit objective: in the paediatric intensive care unit (picu), seizures are challenging to detect given patient complexity, comorbidity and sedation. this has led to both over-and under-treatment of seizures. there is growing literature on the use of continuous electroencephalography in picu, considered gold standard but not universally available, but little on standard electroencephalography (eeg). this study aims to investigate the indications for eeg requests, their efficacy and the use of antiepileptic drugs (aed) in picu, hypothesising a difficulty in clinically differentiating between epileptic and non-epileptic events and suboptimal use of aeds. methods: this retrospective study examined eeg reports over 2 years at a tertiary picu. data was collected on participant characteristics, eeg indications and findings and aed use. results: 185 eeg reports from 142 participants were included. median age was 6 months (iqr 1mo-3y 6mo). indications for eeg (often multiple per eeg) included suspected clinical seizures (64%), suspected subclinical seizures (21%), prognostication (28%) and suspected encephalopathy (8%). 63% of participants with suspected seizures were sedated and 43% of all participants were encephalopathic. clinical episodes suspected to be seizures were captured in 41/141 eegs. only 22% of these were eeg-confirmed seizures. captured movements shown not to be seizures are qualitatively described. 6% of patients with suspected seizures had electrographic seizures with no clinical correlate. most confirmed seizures were in participants without pre-existing epilepsy. antiepileptic(s) were changed prior to 25/35 captured events. seizures were present in 28% of these cases, while 60% had neither clinical nor electrographic seizure activity. 7/8 participants with confirmed clinical seizures had aeds changed. conclusion: it is challenging for clinicians to differentiate between seizure and non-seizure movements in picu. moreover, there are issues of over-medication and low event-capture rate with eeg. we propose a multidisciplinary education strategy and investment in ceeg to address these issues. introduction: glucose transporter 1 deficiency syndrome (glut1-ds) is a rare neurometabolic disorder causing impaired glucose transport into the brain. in the majority of patients, it is caused by an autosomal dominant heterozygous mutation in the scl2a1 gene. ketone bodies generated by a ketogenic diet (kd) provide the brain with an alternative energy source and is gold standard therapy. we report our experience for our cohort of patients at royal manchester children's hospital. methods: retrospective case note review of 14 patients with glut1-ds at royal manchester children's hospital from 2004 to 2019. results: 14 patients -8 male, 6 female. age range 3 to 19 years. average age at diagnosis was 6 years 3 months (range 4mo-9y). there was a history of seizures in 11 of 14 patients with average seizure onset of 2 years 6 months. seizures types were absences (5/11), generalised tonic-clonic (3/ 11), myoclonic (2/11), myoclonic astatic (1/11), tonic (1/11) and focal to bilateral tonic-clonic (1/11). ketogenic diet was used in all patients for a range of 4 months to 10 years 7 months. no significant adverse effects occurred that required discontinuation. six patients complying with kd are seizure free and not taking antiepileptic drugs (aeds). one of these patients had occasional tonic-clonic seizures with illness and loss of ketosis but has been seizure free for >18 months. five patients are non-compliant with kdtwo have good seizure control with aeds, potentially limiting motivation, and two (siblings) have a parent with glut1-ds and learning difficulties. learning difficulties were reported in 10 patients. other symptoms included ataxia (8/14), dysarthria (5/14), tremor (4/14) and dystonia (4/14). one patient presented with episodic hemiplegia. conclusions: patients with glut1-ds are a heterogeneous group leading to challenges in diagnosis, management and prognosis. ketogenic diet has been effective in managing this cohort but compliance was a limiting factor. objective: to conduct a survey regarding the management of relapse in children epilepsy in following weaning off aeds. methods: we conducted an online survey in the east of england (eoe) via the eastern paediatric epilepsy network (epen) regarding the management of relapse in children epilepsy after weaning aeds. epen is a network of paediatricians and nurse specialist with eoe who manage lead in management children with epilepsy within all the dgh's in the region. the questions in the survey asked about various aspects of management of patients after relapse, including the choice of anti-epileptic medication restarted, if started, any further investigations undertaken, and finally, the length of aed treatment before a second attempt at weaning might be considered. results: we received 17 responses from paediatricians in 16 dgh's across eoe. there was a large degree of variation in the responses to all of the questions in the survey. the frequency and semiology of seizures on relapse seemed to play a key role in decision making, as did the thoughts and views of the family and patient themselves. it was interesting to note there was a variation in response to whether any further investigations would be undertaken and if these were deemed necessary. most clinicians responded that they would continue aeds for another 2 years before attempting weaning again. conclusions: there is variability in the management of epilepsy relapse in the eoe and we suspect that this may also be the case nationally. to investigate this further, we would envisage extending the survey nationally, via open ukwhich is an organisation that links the various regional paediatric epilepsy networks across uk. this would enable establishing a standardized guideline for management of epilepsy relapse in the future. objective: de novo dominant mutations in dhdds were recently identified as a cause of developmental and epileptic encephalopathy. dhdds encodes dehydrodolichyl diphosphate synthase, which is essential for dolichol monophosphate synthesis and protein glycosylation. we report two half-siblings with a new pathogenic, maternally inherited dhdds missense variant, c.614g>a(p.arg205gln), identified through whole-exome sequencing. method: case note and literature review. results: sibling 1, aged 11 years, presented at 11 months with global developmental delay, hypotonia and frequent absences with eyelid myoclonia. from age 3, she developed atonic drop attacks, myoclonic seizures, tremor, ataxia and facial dyskinesia. dyskinesia and mobility deteriorated from age 7 and she is now largely non-ambulant. severe learning disability with possible cognitive deterioration and insatiable appetite are also features. sibling 2, aged 9 years, developed blank spells associated with eyelid flickering at 12 months and atonic drop attacks aged 5. development delay is present, but progress is greater than her sibling. dyskinesia, tremor, ataxia and deterioration in mobility are features. neither is dysmorphic. eegs on both showed bursts of irregular generalised spike wave associated with head nods and eyelid flutter. photosensitivity was not shown but both were treated with anti-epileptic medication. mri scans are normal. clobazam and zonisamide improved seizure control in both. mother has mild learning difficulties, tremor and dyspraxia. she had generalised tonic clonic seizures, from age 14 to 18 years, well controlled with lamotrigine. compared to the six known cases in the literature, our report confirms atonic seizures and dyskinesia as important features of this disorder, in addition to common characteristics of myoclonic component to seizures, hypotonia and tremor. learning disability is of variable severity. conclusions: this is the first report of familial inheritance of dhdds related developmental and epileptic encephalopathy and describes variable severity of the phenotype within family members. the features described are consistent with those previously observed. objectives: to evaluate whether the duration of treatment has an effect on the relapse rate in children with cae attending a paediatric neurology centre in cyprus, and whether the eeg can be used as a prognostic tool. methods: electronic patient database review of patients with cae, who have discontinued treatment attending the paediatric neurology clinic between years 2008-2017. results: fourteen patients with cae, off treatment were identified (7 male). age at presentation ranged from 3 to 9 years (median 6.5y). all patients underwent an eeg to confirm diagnosis and those who presented with seizures other than absences were excluded. twelve patients were treated with valproic acid (depakine) and 2 with ethosuximide (zarontin). in 10, absences resolved on first line monotherapy, whilst 4 were refractory requiring combination therapy. positive family history was present in 2 (non-identical twins), attention deficit in 2, and learning difficulties in 1 patient. all initial eegs were consistent with cae, patients also underwent an eeg post seizure control to confirm resolution. mean time to seizure cessation was 3.9 months, mean duration of treatment 2.2 years; 4 patients discontinued treatment after 1 year of seizure freedom. prior to withdrawing treatment all patients had an eeg (normal 6, mildly abnormal with brief generalised discharges 6, photosensitivity 1, brief electrographic absence 1). relapse occurred in 3 patients who required re-instigation of treatment. mild abnormalities on eeg prior to coming off treatment did not correlate with a higher relapse rate. there was no difference in relapse rate in patients on treatment for 1, 2 or more years. patients were followed up for a mean of 7.8 years. conclusions: treating patients with cae for less than 2 years does not affect relapse rate provided patients are seizure free, also confirmed by eeg normalisation, which may be used as an additional predictor. background: mutations in unc80, encoding part of the unc79-unc80-nalcn channel complex, causes autosomal-recessive severe infantile encephalopathy, this is a rare case of profound global developmental delay with psychomotor retardation. only 19 individuals have been reported to date. unc80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. the majority of individuals do not learn to walk. all individuals lack expressive language. additional features can include nystagmus, extremity hypertonia, a highpitched cry, repetitive and self-stimulatory behaviours, constipation, clubfeet, joint contractures, and scoliosis. there is no loss of skills suggestive of neurodegeneration. case presentation: 11-year-old, with a recent confirmed diagnosis of unc80 gene mutation and microcephaly. she had profound global developmental delay, learning disability, bilateral squint with cortical blindness, seizure disorder, sleep apnoea, head drops, movement disorders, feeding difficulty, scoliosis and constipation. term baby with normal anti-natal history. induction of labour for iugr. good apgar, at birth but developed respiratory distress with cardiac problems. birth weight 2050 g. neurologically: floppy with reduced muscle tone and microcephaly. had a short neonatal admission and discharged with cardiac, endocrine, neonatal and neurodevelopmental delay follow-up. she had no spoken words and communicated by crying. she was only able to sit transiently and never walked. she was wheelchair bound with gmfcs, macs, cfcs and edacs level 5 each, needing full 24-hour support from patents and carers. ddd study confirmed unc80 gene mutation, her cousin was also noted to have same gene mutation via exome sequencing and with similar clinical picture. conclusion: early diagnosis is key for genetic counselling for further children and ensuring global support as reported individuals span ages from birth to 15 year. the diagnosis is established in a pro-band with developmental delay and hypotonia by identification of bi-allelic pathogenic variants in unc80 on molecular genetic testing. poster no. 026 cognition and disease burden in scn1a positive dravet syndromea 10-year follow-up study development, disease burden and sleep profile of patients with dravet syndrome. methods: this is a follow-up to a 2009 study previously involving 141 ds patients with detailed developmental and clinical information available. participants completed a structured postal questionnaire on epilepsy severity and disease burden, the adaptive behavioural assessment system (abas-3), the sleep disturbances scale for children, pediatric quality of life inventory (pedsql) and the strength and difficulties questionnaire. results: 123/141 from the original cohort were contactable and 70 (57%) of carers completed the outcome measures. the developmental quotient at follow-up was significantly lower compared to the earlier study (p=0.001), and 89% of affected individuals had a severe or profound learning disability. we observed the steepest decline in cognitive functioning in those that were youngest (age 0-5y) at original study onset (p=0.001). poorer developmental quotients correlated with early onset of initial developmental concerns (rs=0.31; p=0.037), later mobility problems (rs=0.30; p=0.015), higher levels of behaviour problems (rs=0.26; p=0.043) and worse pedsql scores (rs=0.31; p=0.015). carers health and wellbeing was negatively affected in 98% of cases and in 90%, at least one of the two carers quit their job due to their child's illness. sleep problems as measured by total sleep scale score were reported in 40% of patients, whilst 71% had at least one abnormal sleep scale category. only 49% of individuals with abnormal sleep scores received treatment. rs=spearman rho correlation coefficient. conclusions: this study highlights the ongoing cognitive decline in ds, particularly affecting younger patients, alongside often untreated sleep problems and a significant disease burden on primary carers. with new therapeutic opportunities on the horizon, early interventions appear crucial to avert the observed severe cognitive decline. poster no. 027 forced normalisation as a factor in behaviour deterioration on the ketogenic diet e hassan 1 , vj whiteley 2,3 , hj tan 1 1 department of neurology, royal manchester children's hospital, manchester, uk; 2 therapy and dietetics, royal manchester children's hospital, manchester, uk; 3 school of health and society, university of salford, salford, uk introduction: there have been a number of reports that demonstrate a correlation between improved seizure management and deterioration of behaviour with psychosis in adults and children. forced normalisation is a concept where there is deterioration in behaviour when better seizure control is achieved with antiepileptic drugs (aeds) or epilepsy surgery. the ketogenic diet (kd) is a treatment option for children with refractory epilepsy with approximately 50 to 60% showing at least 50% reduction of seizures and 15% of those patients reaching seizure freedom 6 months after treatment. although forced normalisation has been discussed in literature following aeds and neurosurgical interventions, it has not been reported following the use of kd. cases: of the 195 children that have commenced on kd over the last 7 years at royal manchester children's hospital, 59.5% responded to the diet (at least 50% improvement in seizures) and 10.8% were non-compliant. we present 6 patients under the care of the kd service, whose behaviour deteriorated on kd when seizure reduction was >50%. the behaviour changes described by parents included poor sleep, unsettled, agitation, head-banging and shouting. five out of the six patients stopped kd treatment, with subsequent improvement in behaviour. conclusions: there are reports that patients on the ketogenic diet with seizure freedom show improvement in their behaviour, unlike our small cohort whose behaviour deteriorated. forced normalisation has been explored in paediatric patients as a cause for behaviour deterioration following surgical and medical management for intractable seizures. the associated factors of deteriorating behaviour have not yet been explored in depth with the ketogenic diet. objective: we wanted to determine how lacosamide was being used in children locally, and what their outcomes were at a year. methods: we undertook a registered, retrospective, clinical audit using hospital electronic records. we ascertained every patient aged <18 years who had been dispensed lacosamide january 2016-january 2018. the electronic health records were reviewed, and data collected using a standard proforma, including: patient demographics, age of seizure onset, seizure type, ecg and mri findings, baseline seizure frequency, seizure frequency 2, 6, and 12 months on lacosamide, maximum dose prescribed (mg/kg/day), and adverse effects at 2, 6, and 12 months. results: 20/42 (48%) patients were male, the median age was 9 years (range 2mo to 17y), with a mean age of onset of 3 years (range 2mo to 11y). 35/42 (83%) had epileptiform activity on eeg and 24/42 (57%) had an abnormal mri. 24/ 42 (57%) had focal seizures. 27/42 (64%) had a minimum of one seizure a week. 28/42 (66%) had previously tried 3 or more antiepileptic drugs (aeds), and 38/42 (90%) had drug resistant epilepsy prior to starting lacosamide (already failed 2 previous aeds). all patients had lacosamide alongside another aed. the mean daily dose of lacosamide was 7.3mg/kg/day (range 1.3-20.6). at 12 months, 15/42 (36%) of patients reported a >50% reduction in seizure frequency. 36/42 (86%) remained on lacosamide 1 year after starting, and 9/42 (21%) experienced an adverse side effect. conclusions: in this local audit, lacosamide was mostly prescribed for drug resistant epilepsies and was used in polytherapy. a third of patients saw a significant reduction in seizure frequency on lacosamide, although some were also started on other treatments during this period. most patients remained on lacosamide after 12 months, and about 1 in 5 experienced one or more adverse side effect. cacna1a is a large gene which encodes for the alpha subunit of a neuronal ion channel and it is expressed widely throughout the central nervous system (cns). pathogenic variants in this gene have been associated with many phenotypes. most commonly episodic ataxia type 2 (ea2) and spinocerebellar ataxia type 6 (sca6). rarer phenotypes include, familial hemiplegic migraine, paroxysmal tonic upgaze, epilepsy, and intellectual disability with autism. here we present the case of an 8 month old girl who presented with new onset paroxysmal abnormal eye movements during an intercurrent illness. the referring clinicians felt these episodes may be epileptic. however, an electroencephalogram (eeg) captured these movements which were non-epileptic downbeat nystagmus. all other initial investigations including cerebrospinal fluid glucose and neurotransmitters were normal as was her neuroimaging. over the next year her nystagmus became constant. she had otherwise normal development. at 16 months her gait was noted to be abnormally unsteady and broad based (even accounting for age). the nystagmus and ataxia changed in severity from day to day, she could have 4 to 5 more severe days followed by 4 to 5 better days, they never completely resolved. she had no family history of abnormal eye movements or ataxia. subsequent genetic testing revealed a cacna1a c.3787g>a p(glu1263lys) missense variant described only twice previously in ea2, both with very different phenotypes to our patient. neither of her parents carried the same genetic variant. this case is the first reported case of this cacna1a variant presenting as downbeat nystagmus followed by ataxia. both her age of presentation and her initial presenting features are very different to the typical phenotypes associated with this gene. it broadens the phenotype of cacna1a, and also broadens the differential diagnoses associated with abnormal eye movements in infancy. the importance of following up as yet undiagnosed patients who may go on to develop new and revealing symptoms is highlighted. objective: to undertake a questionnaire-based survey retrospectively exploring parents'/carers' recall of, and views on, the safety and risk advice given at the time of their child's epilepsy diagnosis. methods: questionnaires were distributed throughout scotland via scottish paediatric epilepsy network (spen). parents'/ carers' of 5 to 12-year-old children were asked to complete the questionnaire prior to their seizure clinic appointment. results: 178 questionnaires were suitable for inclusion. seizure burden was evenly distributed: 37% <1 seizure/month, 23% >1 seizure/month, 22% >1 seizure/week and 18% had absences only. respondents could recall post-diagnosis information being provided on: water safety (50%), taking medication regularly (91%), sports/activities (57%), seizures in sleep (62%), first aid (78%), prolonged seizures (53%) and/or sudep (45%). there was no statistically significant difference in the duration of epilepsy diagnosis between those who could recall information being given (m=3.77y, sd 2.747) and those who could not (m=4.138y, sd 2.84; t test p=0.42). the majority of information was given via clinic discussions (75%). 46% received written information, 28% directed to websites and/or independent search (12%). most information was 'just right' (71% water safety, 94% on taking aed regularly, 68% on sports/activities, 68% on seizures in sleep, 83% on first-aid for seizures). approximately 30% of respondents want more information on seizures in sleep, water safety and sports/activities. 46% of respondents felt worried following information about seizures in sleep, 57% about prolonged seizures and 67% regarding sudep. conclusions: a substantial proportion of parents'/carers' do not recall receiving safety information on epilepsy despite this being standard practice through spen. this appears to be unrelated to the duration of their child's epilepsy. repeated timely reinforcement may be of benefit. a high proportion of parents'/carers' felt concerned following information provided on nocturnal seizures, prolonged seizures and sudep. this should be recognised with support in place for further discussions. poster no. 031 seizure outcome in responsive vagus nerve stimulation therapy in children and young people v rasiah, n barnes, s carter, k das, r robinson, z tahir, s varadkar great ormond street hospital for children nhs foundation trust and ucl gosh institute of child health, london, uk aim: vagus nerve stimulation (vns) therapy is an established treatment for pharmacoresistant epilepsy. newer responsive-vns (rvns) systems use ictal-tachycardia detection as a biomarker of seizure onset and automatically deliver additional stimulation on detection to abort the seizure. we reviewed the seizure outcomes in children and young people (cyp) implanted with rvns at great ormond street between 2012 to 2018. methods: data were collected prospectively on 41 patients who had an aspiresr â rvns inserted during time period of 2012 to 2018. reduction in seizure frequency and severity, wean of medications and treatment complications or side-effects were assessed at time-points of 1 year, 18 months, 2 years and 3 years post-implantation. results: 41 cyp (mean age 11.9y) had rvns inserted. at 1 year, 34% (14/41) had a positive response graded as >50% reduction in seizure frequency or severity (i.e., duration), 32% (13) had benefit though <50% benefit, and 32% (13) of cyp were non-responders. this increased at 18 months to 41% (14/29) of children showing response >50%, a further 41% showed response 50% and only 17% (12/29) non-responders. response was over-all sustained, with response lessening in only 2 children between 18 months and 2 years. reduction of medication burden was achieved in 22% (9/41) (not attempted in all cyp). no patients achieved seizure freedom. replacement of vns from an older model to rvns showed further benefit. complications were infrequent: 12% (5/41). device removal for infection was required in one child of small body size; successful replacement was possible within the year. conclusions: vns is a useful treatment option for cyp with pharmacoresistant epilepsy. seizure outcomes with rvns in cyp are better than with standard vns. response is sustained. benefit may not be seen by 1 year; therapy should be continued until at least 18 months. in our patients who responded later than 1-year, further optimisations of duty cycle and current were made. replacement of older vns. devices with rvns led to additional benefit. these findings are consistent with reported outcomes from adult series, though seizure freedom is not seen in cyp. in our centre, cyp who seemed to benefit most were those whose epilepsy was of structural aetiology and those with focal seizures, although our numbers were not large enough to assess the significance of this. poster no. 032 atp1a3 mutation in twins presenting with apnoeic episodes, suspected seizures and possible dystonic events objective: we report the case of monochorionic diamniotic twins presenting at the age of 5 months with infantile seizures and apnoeic episodes. the eiee gene panel revealed a mutation in the gene atp1a3, supporting the clinical diagnosis of alternating hemiplegia of childhood (ahc). methods: case report. results: twin r presented with staring episodes, eye deviation and tonic posturing of limbs. episodes occurring mainly in clusters, affecting either side and requiring rescue medications for termination. profound apnoeic episodes needing resuscitation were also noted. twin s presented few weeks later with a very similar presentation. developmentally making satisfactory progress with twin r showing only very mild delay. the array cgh from twin r was normal. several investigations were performed including two normal standard eegs, a normal sleep eeg, a normal ecg, an echo showing a small pfo and an mri scan demonstrating a left sided mesial temporal lobe sclerosis. similar mri findings were reported in twin s. investigations such as urine organic acids and amino acids, plasma amino acids, carnitine, acylcarnitine, transferrin glycoforms, mucopolysaccharidosis screen, ammonia and lactate were all normal. pyridoxine was tried with no improvement, levetiracetam was added and afterwards changed to carbamazepine. sodium valproate was commenced eventually after an episode of prolonged clinical seizure. the eiee gene panel revealed a de novo atp1a3 mutation in both twins. flunarizine was commenced following this result. a video telemetry managed to capture both epileptic and non-epileptic episodes in twin r. the epileptic episode was characterised solely as apnoeic episode due to a left temporal seizure activity spreading onto the opposite hemisphere which is concordant with the imaging finding of left mesial temporal sclerosis. conclusions: knowledge of the atp1a3 mutation allowed clinical correlation of a diagnosis of ahc, matching the wide clinical spectrum of ahc including paroxysmal dystonia and epilepsy. poster no. 033 epilepsy in a child development centre population pc kenyon, njv cordeiro, gl duffy rainbow house child development centre, irvine, ayrshire, uk objective: to assess all the cases in a child development centre (cdc) population with epilepsy, to enable characterisation of the caseload. methods: all case notes of children with an epilepsy diagnosis coded on the cdc database were retrospectively reviewed for demographic, investigation and treatment data. results: 67 children were identified. 27% were diagnosed before a year of age, and over half before their third birthday. 84% of patients had an eeg, and of these, 70% had an abnormal eeg. 55% had genetic testing performed, and of these, 86% had a genetic cause of their epilepsy identified. 78% had an mri scan, and of these, 69% had a structural cause for their epilepsy identified. 90% had global developmental delay, and 90% had a diagnosis of learning disability. one third have a diagnosis of cerebral palsy, 16% have autism spectrum disorder, and 13% have a hemiplegia. 66% are seizure free, the majority of whom have their epilepsy controlled with one medication. 12% had adherence concerns identified. conclusions: compared to a general paediatric epilepsy clinic, this group of children were diagnosed earlier in life, had higher rates of genetic or structural causes identified, and were less likely to be seizure free. results: case 1. a 4-year-old with autism spectrum disorder (asd) developed hand waving in front of her face in bright light from 3 years. multiple myoclonic seizures occurred with screen use and her family live in complete darkness. eeg demonstrated photosensitivity, generalised spike-slow wave after hand waving and 3-3.5hz spike-wave with myoclonia. clonazepam has been commenced. case 2. a 10-year-old with learning difficulties and a family history of generalised seizures presented aged 6 years with forehead rubbing leading to loss of part of her eyebrow. eeg showed photosensitivity and the generalised spike-wave of absences and eyelid myoclonia (em). sodium valproate was used but replaced with lamotrigine due to weight gain. case 3. a 4-year-old with a family history of generalised seizures presented aged 2 years with hand waving in front of her face, requiring her nursery to provide a dimly-lit setting. eeg demonstrated generalised polyspikewave, 3-hz spike-wave and myoclonia with photic stimulation. lamotrigine was ineffective and replaced with sodium valproate. case 4. an 11-year-old with likely asd developed hand waving in front of her face in bright light aged 4 years, triggering generalised tonic convulsions (gtc). she had a non-induced gtc in dappled sunlight. there was on-going anxiety and thoughts of self-harm. eeg showed photosensitivity and bursts of spikes-polyspikes. lamotrigine was ineffective; seizures stopped with sodium valproate. conclusions: the self-induced seizures of sunflower syndrome are difficult to treat and are associated with physical, psychological and social impairments. sodium valproate is the most effective medication which may be problematic in this predominantly female patient group. what are the information needs of parents whose child is diagnosed with glutaric aciduria type 1 to help preserve neuro-developmental outcome? objectives: to assess the information needs and support of parents at the time of diagnosis of ga1 in their child, and how to support them in preventing metabolic decompensation and preserving neuro-developmental function. methods: a focus group with five parents was conducted using a topic guide to direct the discussion, which was recorded and fully transcribed. data were analysed using thematic analysis. two researchers were involved in initial coding of data and key analytic decisions. results: two main themes were identified. 'understanding the condition' explored parent's needs to understand the scientific complexity of ga1 and to be aware of the 'worst case scenario' associated with loss of metabolic control, and brain injury. parents reported clinicians did not give then enough information on the ga1, and were forced to use other information sources, sometimes seeking out scientific papers. information on managing crises was insufficient, with parents not understanding what the doctor meant about commencing the emergency regime when their child was 'sick'. parents reported living in terror of their child experiencing metabolic decompensation and permanent brain injury. 'managing the condition' explained how parents coordinated and controlled the involvement of other carers and outlined parents' need to be active partners in medical management to feel in control. parents wanted to know the results of regular biochemical tests for reassurance, but found they were not easily accessible. parents could not leave their child in the care of another adult because they did not have sufficient knowledgeable about ga1 or were known to 'cheat' by offering the child food they should not have. the transition into school was a particular challenge. conclusions: the study highlights the importance of addressing parents' initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic decompensation and permanent brain injury. poster no. 036 normal transferrin isoelectric focusing in a child with cog4 related congenital disorder of glycosylation objectives: congenital disorders of glycosylation (cdg) are a large group of rare multisystem diseases caused by defective linkage of oligosaccharides to newly synthesised proteins or lipids. several cdg subtypes are the result of mutations in subunits of the conserved oligomeric golgi (cog) complex. this includes cog4-cdg, an autosomal recessive disorder caused by pathogenic variants in the cog4 gene. in the two cases previously reported transferrin isoforms were abnormal, consistent with defective n-glycosylation. methods: we describe a 3-year-old female born to non-consanguineous parents. she presented with severe global developmental delay, dysmorphic features, postnatal progressive microcephaly, complex epilepsy, rhizomelia, spastic quadriplegia, and feeding problems from early infancy. results: mri brain showed global cerebral atrophy, predominantly supratentorial, with relative cerebellar sparing. trio exome sequencing and analysis identified compound heterozygous cog4 variants in the proband, a maternally inherited pathogenic splice site variant c.1061+1g>a and a paternally inherited likely pathogenic splice site variant c.1647+5g>a. messenger rna analysis showed that the c.1647+5g>a variant caused aberrant splicing, with skipping of exon 12 and the introduction of a premature stop codon in exon 13, likely to result in nonsense mediated decay. analysis of transferrin isoforms was normal (by both isoelectric focussing and mass spectrometry). since cog4-cdg also affects o-glycosylation apolipoprotein ciii (apociii) isoelectric focussing was undertaken, however this too was normal. conclusions: transferrin and apociii isoelectric focusing are screening tests for n-and o-glycosylation defects. however, both have their limitations and some cases of cdg have normal transferrin or apociii glycoforms escaping those screening tests. this is the first case of a patient with cog4-cdg with normal biochemical markers to be described. this case also demonstrates the diagnostic power of next generation sequencing for rare metabolic disorders, where the biochemical screening may be inconclusive. poster no. 037 developmental delay in a young infant with nonclassical combined malonic and methyl malonic aciduria (cmamma) caused by homozygous missense mutation in acsf3 gene kd dayasiri 1 , eg goh 1 , sk kodagali 1 , jb baruteau 2 , ga anand 1 1 oxford university hospitals nhs foundation trust, oxford, uk; 2 great ormond street hospital, london, uk introduction: acylcoa synthetase family member 3 (acsf3) activates malonylcoa and methymalonylcoa into their respective thioesters. acsf3 deficiency causes non-classical cmamma, a rare inborn error of metabolism characterised by presence of methyl malonic acid in higher concentrations than malonic acid in urine. the reversal is seen with classic cmamma caused by malonylcoa decarboxylase deficiency (mcd). case report: 5-and-a-half-month old male infant second born to consanguineous south asian parents presented with severe failure to thrive and recurrent vomiting. his older sibling who had failure to thrive and neuro-developmental delay died at 7 months without a genetic diagnosis. initial blood tests revealed metabolic acidosis, pancytopenia and coagulopathy. neuroimaging was unremarkable. subsequent evaluation revealed normal levels of methionine, homocysteine and red cell folate. significant methylmalonic aciduria with mild malonic aciduria without evidence of other abnormal metabolites (propionyl-coa metabolites: hydroxypropionate, and methylcitrate or tiglylglycine) in urine suggested the diagnosis of non-classic cmamma, confirmed by homozygous missense variants in acsf3 gene revealed by trio-exome sequencing. neurodevelopmental assessment at 8 months revealed global developmental delay with general hypotonia; gross motor (4-6mo); fine motor (4-6mo); speech (5-6mo) and social (under 6mo), and without any regression. carnitine was supplemented to avoid secondary depletion caused by the excretion of mma. parents were advised to avoid prolonged fasting and to provide emergency regimen (powdered carbohydrate drink mix) in the event of acute deterioration. conclusions: this report describes an unusual paediatric presentation of non-classic cmamma. urine organic acids allows identification of increased ma and mma excretion and highly suggestive of the diagnosis, thus avoiding additional investigations determination of urinary mma/ma ratio can help differentiating between classical and non-classical forms. methods: we conducted retrospective case note analysis of the five paediatric cases with confirmed diagnosis of the late onset pompe disease, referred to the highly specialised metabolic service. results: three of five patients (current age 14-22y) presented with delayed motor milestones in early childhood (mean age: 3.3y). one patient initially presented with episodes of thigh pain and high ck. in addition, when 10 years he re-presented with recurrent abdominal pain with high ck. the remaining one presented with muscle pain upon exercise with high ck. all apart from one had muscle weakness affecting limb girdle muscles and axial muscles. the remaining one presented with proximal muscle weakness by the age of 19 years. all patients remained ambulant, one developed scoliosis and two were on non-invasive ventilation. cardiac involvement as ventricular dysfunction requiring targeted treatment was observed in one. pathology showed vacuolated deposits in three patients and non-specific myopathic changes in one. four are on enzyme replacement therapy (ert) and tolerated well. conclusions: late onset pompe disease is a multisystem disease and should be considered in cases of isolated respiratory problems, lower back pain, rigid spine, and myopathy or exercise intolerance with elevated serum ck if these symptoms cannot be attributed to another disorder. poster no. 039 delay in diagnosis and misdiagnosis of ataxiatelangiectasia: a systematic review pubmed, scopus). the cochrane library was also searched. the search protocol is available. the inclusion criteria were: all dates, all languages, all ages, human participants and clinical relevance. the exclusion criteria were: no reference to ataxia-telangiectasia within the article, not an original article, animal studies, article not clinically relevant. results: search returned 184 541 articles; 13 868 titles and abstracts were reviewed after removing 170 673 duplicates. full text review includes 1106 articles of which 343 case series and 459 case reports were identified (12 518, exclusions; 244, articles not found or not accessible). mean age of first sign or symptom of a-t in 563 cases reviewed to date was 31.4 months (range -11d to 312mo). the mean age of diagnosis in 209 cases in which it has been reported was 81.4 months (range -22d to 624mo). there was a mean time of 34.9 months from presentation to clinician, to diagnosis of a-t (range -0 to 306mo, median 11mo) in the 71 cases in which this was reported. 20/563 (3.6%) cases had a documented alternative diagnosis prior to the diagnosis of a-t. 10/20 (50%) of these children were incorrectly diagnosed with cerebral palsy and 3/20 (15%) with hyper-igm syndrome. the mean delay from incorrect diagnosis to a diagnosis of a-t was 87 months with the longest delay 306 months. conclusions: this study is the first comprehensive systematic review of scientific literature on ataxia-telangiectasia. we aim to describe the natural history of the condition and, along with results from the natural history of a-t (n-hat) study, systematically define, where possible, the conditions presentation, course, and prognosis. (80%) people with a-t presented with gait ataxia or disturbance, and 13/751 (1.7%) with truncal ataxia. the most common presenting feature in cases without ataxia were developmental delay, or regression, and choreoathetoid movements. the second most common neurological presenting sign was dysarthria in 118/751 (15.7%) cases, and at least 2 of these had no associated ataxia. dystonia was a presenting sign in 37/751 (4.9%) cases, including 3/37 (8.1%) with no associated ataxia. 64/751 (8.5%) initially presented with no neurological signs or symptoms. conclusions: this study is the first comprehensive systematic review of scientific literature on ataxia-telangiectasia. these results show that 91.5% of people with a diagnosis of a-t presented initially with at least one neurological sign or symptoms. this completed review will lead into the natural history of a-t (n-hat) study, a longitudinal, retrospective and cross-sectional study. the role of serum oxysterol in the diagnosis of niemann pick c m alcheikh, g connolly, n cluskey, s osullivan royal hospitals belfast health and social care trust, belfast, uk introduction: neimann pick c is a neurovisceral disease that is caused by cellular cholesterol trafficking disruption. historically, the diagnosis of niemann pick c was made using filipin staining and skin fibroblast cultures. recently genetic testing of npc1 an npc2 genes are available. mutations of either gene also affect cellular trafficking of cholesterol and detecting oxidative cholesterol metabolities can also be diagnostic of nieman pick c. serum oxysterol can be used as a first line test with subsequent genetic confirmation and has a positive predictive value of >97%. methods: we present a case of an 11-year-old boy who was referred to genetics initially with absence of up gaze, severe restricted downward gaze, developmental delay, regression of skills and frequent falls. in the last 1 year his parents and school observed progressive deterioration of his symptoms with gelastic cataplexy, markedly decreased tone, increasing difficulty with memory loss and slurred speech. these symptoms are strongly suggestive of niemann pick c disease and oxysterols were requested which showed elevated oxysterol level of 128.7ng/ml (normal range 9.6-37). he was started on miglustat. genetics confirmed the diagnosis. results: overall the child's parents report that since commencing the miglustat he is more confident and they have recently seen him hop and skip which they haven't seen in quite a while. conclusions: oxysterol is suitable biomarker for neimann pick c disease and can be used as first line with the genetic confirmation of gene npc1 and npc2 at later stage. as modifying treatment with miglustat is available it is important to attempt diagnosing the condition as early as possible and oxysterol level can be used as screening test for neimann pick c when clinically suspected. introduction: biotinidase deficiency is a rare autosomal recessive inborn error of biotin metabolism. biotinidase catalyses biocytin to biotin, a deficiency of which can present with neurological symptoms including hypotonia, seizures, feeding difficulties, lethargy, optic atrophy, and sensorineural deafness. case: a 9-week-old female presented with a 4-week history of seizures and developmental delay. examination revealed generalised and axial hypotonia and delayed smile. she continued to have seizures despite initial treatments including levetiracetam and carbamazepine. mri brain was normal and initial interictal eeg on day 1 post admission revealed no significant abnormalities. ambulatory eeg on day 10 showed a focal onset epileptic seizure with sharp and slow wave activity originating predominantly from the left occipito-parietal region. normal investigations included paired plasma and csf glucose, lactate and culture, csf neurotransmitters, microarray and epilepsy gene panel. on day 11 post admission her biotinidase result was reported showing no activity. biotin was commenced at 10mg once daily and her seizures abruptly stopped. she was discharged home on day 14 and weaned off levetiracetam and carbamazepine. her development was normal at 12-month follow-up. genetic testing was declined by the family. discussion: biotinidase deficiency can present from the neonatal period up to 10 years of age with a mean age of 3.5 months. in recent years our understanding of pathogenic changes in the biotinidase gene has increased through sequencing for novel mutation. this has important implications for families and consideration should be given to offering affected families genetic counselling. treatment is available with oral biotin that rapidly improves symptoms, with seizures usually resolving within days and other symptoms showing improvement within weeks. objective: we present a previously well 16-year-old boy with a known m.3271t>c mutation experiencing 2 weeks of vomiting, lethargy and exercise intolerance. method: he was mildly dehydrated, fully consciousness but tachycardic and hypotensive. his ph was 7.28 with be -17.3, hco3 9.4 and lactate of 16.4. electrolytes, fbc and inflammatory markers were normal. he was admitted to picu for fluid management and sodium bicarbonate. tachycardia persisted during the first 24 hours though he remained stable. he had a good urine output, was on non-invasive monitoring and an echocardiogram was normal. his gas lactate ranged from 14.1 to 16.8. the following day he deteriorated with kussmaul respirations, tachypnoea, increased tachycardia and hypotension. venous blood revealed a ph 7.14, pco2 1.6 hco3 11.3 be -19 and lactate 18.5. he became unresponsive with refractory hypotension and multiorgan failure. arterial blood showed a ph 6.8, pco2 5.3 and a lactate >20 with indeterminable be or hco3. for over 24 hours he had a blood lactate level of >20. rhabdomyolysis and acute kidney injury occurred with a ck of >200 000 requiring haemofiltration. encephalopathy, with multiple white matter microhaemorrhages on mri brain, and acute liver failure, with thrombocytopenia and coagulopathy, ensued. multiple inotropes were required. the prognosis was very guarded. off sedation he was unresponsive, apnoeic and areflexic however an eeg showed an alpha rhythm which prompted on-going heroic efforts. he required prolonged haemofiltration, ventilation and inotropes with 26 days intensive care. results: the patient made an astounding recovery. he required 1 month of neurorehabilitation and returned to his cognitive baseline, achieving a grades at gcse 5 months later. liver and renal dysfunction resolved. conclusions: this case demonstrates that mitochondrial metabolic crises in melas can be severe and result in profound acid-base derangements. our patient was expected to not survive but uniquely did so without significant neurodisability. neuronal ceroid lipofuscinosis in children from central africa gl fisher, n shah, p watts, ja te water naude noah's ark children's hospital, university hospital wales, cardiff, uk objective: the effective and rapid diagnosis of neuronal ceroid lipofuscinoses (ncls) has become more relevant with the advent of disease-modifying treatments. some ncls have a more stereotyped clinical presentation: we describe two cases in a non-consanguinous family, originally from the democratic republic of the congo, with variant ncl. methods: retrospective case series. results: the index case was initially diagnosed with a focal epilepsy: on review this child had myoclonic seizures in the context of a slow developmental decline, with mild spasticity. ophthalmology was not diagnostically helpful, and a putative diagnosis of ncl was suggested by lymphocyte inclusions. neither enzyme nor dna analysis was available at that stage, although dna was retained. a brother presented with nystagmus and visual inattention in 2017: examination showed myoclonic jerks with a bull's eye maculopathy and an abnormal peripheral retinal vascular leak. mri imaging showed some element of cerebellar atrophy, which on review was also the case with his brother's scans. some lymphocytes (20%) contained fingerprint bodies, suggestive of variant ncl. this was confirmed by dna sequencing which was consistent with a diagnosis of mfsd8/cln7-related ncl. the identical dna alteration was also found in the index case. conclusions: ncl is not described in children from central africa: the presentation, investigations and laboratory findings and evolution are consistent with that for other children with variant ncl. obesity screening of patients affected by duchenne muscular dystrophy (dmd) in a tertiary paediatric neuromuscular centre and the effectiveness of metformin use in weight control in those with confirmed insulin resistance m neocleous 1 , s spinty 1 , r madhu 1 , p dharmaraj 1 , c degoede 2 , k cooke 1 , c greaves 1 1 alder hey hospital, liverpool, uk; 2 royal preston hospital, preston, uk objective: to assess whether patients affected by duchenne muscular dystrophy (dmd) who are currently followed up in alder hey hospital, uk are receiving obesity screening when clinically appropriate. to assess whether metformin use in those who are insulin-resistant, has been effective in controlling weight. methods: using the neurology department records, a list of patients with dmd currently under our services and those transitioned to adult services in the last 5 years, was generated. the patient record system, meditech, was used to collect patients' demographics, latest weight/height value and bmi. for patients classified as overweight/obese, completion of obesity screening was assessed as well as initiation of appropriate treatment (metformin). for patients on metformin, the following parameters were collected: weight pre and post-steroids, age of start of excessive weight gain, confounding variables and medications, weight/height/bmi at initiation of metformin and at 6-monthly intervals, side-effects, cessation of medication and reasoning. results: sixteen out of 90 patients were found to be above the 98th weight centile. in 38 patients, weight was at 3 or more centiles above height. using the non-dmd standardised bmi classification, 47 patients were identified as being overweight/ obese. 16 patients received obesity screening; 7 were found to be insulin resistant. 4 of those were started on metformin. 7 patients overall were started on metformin. 2 of those exhibited overall weight loss. 3 patients were found to have gained weight and 1 patient showed weight increase up to 18 months post-metformin initiation with subsequent weight loss. conclusions: there is a need for a validated and agreed bmi classification in dmd. screening for insulin resistance in this patient group should be considered for implementation as standard practice, especially if patient is classified as overweight/obese. a larger-scale study would be required to assess the effectiveness of metformin in this patient population. objective: niemann-pick disease (npd) is an autosomal recessive metabolic disorder with a prevalence of 0.4 to 0.6/100 000 worldwide, marked by varying degrees of lipid storage and foam cell infiltration in tissues, associated with hepatosplenomegaly, pulmonary insufficiency or central nervous system involvement. npd type a and b are allelic disorders caused by mutations in the sphingomyelin phosphodiesterase-1 gene, smpd1 (11p15.1-15.4), characterized by a primary deficiency of acid sphingomyelinase activity, resulting in an accumulation of sphingomyelin. in contrast to npd-a, npd-b is the milder, lateronset form, with no neurological involvement. in this paper, we report on three paediatric cases with npd-b who present an atypical phenotype marked by neurological involvement. methods: the three patients were diagnosed at the age of 1 with hepatosplenomegaly. the first is a girl who presented psychomotor regression at the age of 3 and epileptic seizures at the age of 10. she died at the age of 15. the second is an 8 years old girl who presented growth retardation, kyphosis and neurodevelopment regression since the age of 6. the third is a 15 years old boy with a mild phenotype marked by developmental delay and an aggressive behaviour. splenectomy was performed at the age of 8. results: genetic testing was performed, and all patients presented mutations of the smpd1 gene, confirming the diagnosis of niemann-pick type b. the c.1177t>g(p.trp393gly) mutation was common in all cases. in addition, heterozygous mutations c.573delt(p.ser192alafs*65) and del c.560_606del were found in the first and second case, respectively. conclusions: all cases present a complex phenotype, marked by psychomotor regression which is atypical for npd type b. the severity of the disease seems to be correlated to the genetic mutation-the most severe phenotype was associated with c.573delt. further work is necessary to more clearly delineate genotype-phenotype relationship in npd. objective: acute encephalitis syndrome (aes) is a group of symptoms and signs, which help diagnose encephalitis. since there is no definite treatment for most, role of fluids seems crucial. therefore, the objective of our study was to describe the association of low admission weight and weight loss in the hospital (as clinical marker of dehydration) with outcome of patients of acute encephalitis syndrome. to describe the association between changes in weight and blood lactate levels (at admission and discharge as indicators of hydration and acid base status) and outcome in children with acute encephalitis syndrome. methods: all children aged 1 month to 14 years with fever and altered sensorium and/or new onset seizures from september 2011 to september 2012 attending kanti children's hospital, kathmandu, nepal were recruited. weight-for-age (wfa) using z score and serum lactate were assessed at admission and discharge. total fluid input and output was monitored daily. results: of the 92 patients, 62% had low admission wfa or lost weight-after-admission (lwaa) (group a) and 38% no low wfa or didn't lwaa (group b). there was 19 times risk of death and 7 times risk of bad outcome (death or sequelae) in group a compared to b. bad outcome was significantly associated with less admission wfa, more fluid deficit, and trend for higher admission serum lactate. death was significantly more in those with low wfa, more lwaa, longer illness, more 5% dextrose and 0.5 normal saline, higher sodium and higher urea at admission. methods: we conducted a prospective cross-sectional study recruiting children aged between 1 month to 14 years attending kanti children's hospital, kathmandu, nepal with altered sensorium and two of the following: fever, seizure, focal neurological deficit, csf pleocytosis, electroencephalogram and computer tomography suggestive of encephalitis, over 1 year. in these patients, ve was if csf cell count was <1000cells/ mm 3 (lymphocyte predominance) and absence of non-viral pathogens in the csf or blood. bm was csf cell count >1000cells/mm 3 (polymorph predominance) and csf protein >0.45g/l and csf/plasma glucose <40%, and/or positive gram stain and/or bacterial culture. je was ve with ≥40units of anti je-igm in the csf and/or serum. all cns infections were defined as, suspected cases by treating clinician with or without fever with lp showing csf cells >4/mm3. results: out of 38, bm was found in 47%, je 21% and other causes in 32%. although who definition of aes was not significantly associated with all cns infections (p=0.069), it was significantly associated with ve (p<0.001, sensitivity 74%, specificity 93%, ppv 94%, npv 70%) and bm (p<0.001, sensitivity 30%, specificity 7%, ppv 33%, npv 6%). conclusion: we validate who aes definition of bm and ve as a significantly useful screening tool for children with these diseases specially in resource poor settings, endemic areas and where confirmatory tests were not easily available. objective: the aim of this case series is to raise awareness of this autosomal recessive encephalopathic syndrome that presents after birth in the multi-ethnic population in england. although aicardi goutieres syndrome (ags) is rare, its importance lies in the fact that that its presentation may be mistaken for other neurological conditions associated with congenital infections. results: all 6 of the patients were seen in our paediatric outpatient neurology clinic. the age of presentation ranged from the neonatal period to the first 20 weeks of life. all 6 patients were of pakistani origin and 5 were from consanguineous marriages. they all had an uneventful antenatal period with normal birth weight and head circumference. the initial presentation seems to be of poor feeding and irritability. further observations include truncal hypotonia, limb spasticity intermittent dystonic posturing coinciding with the onset of poor head growth and chilblains. 3 of our patients had abnormal movements with diffuse slow wave electroencephalogram activity. nystagmus with visual inattention and poor visual acuity were a typical finding in all of them by the age of 3 months. the ct scans showed cerebral calcification in all of them and mri suggested brain atrophy. the most striking abnormality was a raised level of csf interferon-alpha (infa) in an absence of other infection or metabolic disorder. csf inf a is a reliable diagnostic marker and can thus be used to differentiate patients with ags from other conditions. three of our patients had the same gene mutation, rnaseh2c. conclusions: ags is a rare disorder, however in patients from consanguineous marriages that depicts microcephaly, poor tone and global developmental delay, diagnosis of ags should be considered. as ags is a progressive neurological condition, early support and prognosis can be provided for affected families. t thomas 1 , ht yeo 1 , sv barron 1,2 1 paediatric neurology, kk hospital, kampong java, singapore; 2 university of newcastle, newcastle, uk objective: we report the association of mild encephalopathy with a reversible splenial lesion (mers) with a primary dengue virus infection. this case implies the existence of a wider spectrum of neurological involvement in dengue virus infections. case description: a 12-year-old girl presented with acute confusion, dysarthria and bilateral limb weakness following a 4-day history of fever. symptoms resolved after 2 hours; neurological examination was completely normal. she later experienced a second episode of slurred speech, dysphasia and right arm weakness which lasted an hour. a contiguous lesion involving the genu, body and splenium of the corpus callosum and bilateral posterior periventricular white matter was evident on the mri brain scan, with restricted diffusion and t2-hyperintensity. cerebrospinal fluid analysis showed no inflammation and polymerase chain reaction assay for respiratory viruses was negative. her clinical and radiological features were consistent with mild encephalopathy with a reversible splenial lesion (mers). on day 2 of admission, she developed a generalised maculopapular rash with leukopenia (white blood cell count 1.819109/l) and thrombocytopenia (platelets 1359109/l). serology (igm/igg) for dengue virus was negative and a positive dengue ns1 antigen was thus indicative of a primary dengue virus infection. she was given fluid rehydration and advised bedrest. at discharge (day 6 admission) she was well with no sequelae. conclusions: mers is a mild form of virus associated encephalopathy (vae), which are a spectrum of clinico-radiological syndromes associated with common childhood viral infections. the clinical and neurological symptoms in our patient occurred early in the course of illness (typical to vae) as opposed to after or late in the illness as is typical for postinfectious encephalopathy syndromes associated with dengue virus infections (e.g., acute disseminated encephalomyelitis). shouldering the burden of sepsis norfolk and norwich university hospital nhs trust, norwich, uk; 2 sheffield children's hospital, sheffield, uk aim: we report a case of a 15-year-old boy who presented with right brachial plexus neuritis secondary to meningococcal group b sepsis. brachial plexus neuritis or neuralgic amyotrophy (also known as parsonage -turner syndrome) is a rare disorder affecting the brachial plexus. it can be caused by various infectious agents and is characterized by acute onset of intense pain in the shoulder and arm followed by weakness, sensory loss and atrophy. methods: a 15-year-old boy, previously fit and well presented to the emergency department with an acute onset of excruciating pain in his right shoulder, radiating down his arm and hand with associated paresthesia. few hours later, he developed an evolving non-blanching purpuric rash to the chest, back, shoulder and right arm. he gradually developed weakness in the right arm and sensory loss over the ulnar aspect of the right hand. he then began to complain of headache, photophobia with subsequent vomiting. he was treated for meningococcal sepsis with intravenous ceftriaxone and received three fluid boluses for hypotensive shock with vitamin k correction for his associated coagulopathy. he received analgesia for right shoulder pain. results: blood cultures and blood pcr confirmed neisseria meningitidis group b type, nt subtype. mri of the shoulder showed inflammation consistent with brachial plexus neuritis with motor impairment affecting the right side c4 to t1 myotomes and sensory impairment involving the right c6 dermatome. the patient was treated with oral prednisone and gabapentin whilst receiving neurorehabilitation from physiotherapy and occupational therapy. he made a very pleasing recovery after few months and currently has no motor or sensory deficit of his right shoulder and arm. conclusion: brachial plexus neuritis should be considered in the differential when a child presents with sudden onset pain and weakness of the shoulder and arm. in review of literature, brachial plexus neuritis associated with meningococcal infection has not been described previously. to the best of our knowledge, this is the first reported case of its kind. introduction: previous cohort studies on paediatric multiple sclerosis (ms) have reported very low frequencies for a primary progressive ms course (ppms) ranging from 0 to 7%. an age-dependent increase in the rate of primary-progressive courses has been well described in the adult ms population. objectives and methods: we describe five patients presenting prior to the age of 18 years and fulfilling the 2017 mcdonald criteria for ppms. patients were identified from the national hospital for neurology and neurosurgery (nhnn) and the uk childhood inflammatory demyelination (uk-cid) network. results: patients presented at a median age of 15 years (range: 11-17y), with at least 1-year history of progressive deterioration of their balance (n=2) or progressive worsening of lower limb function (n=3). over time, all patients developed lower limb spasticity, three patients developed cognitive difficulties, three had visual problems, three had bladder involvement. median edss at 2 years was 5 (range: 4 to 7). cerebrospinal fluid (csf) oligoclonal bands were detected in all 4 patients tested. dissemination in space on first mri was seen in all patients with peri-ventricular (n=4), cortical juxtacoritcal (n=2), infratentorial and spinal cord (n=4) lesions. all patients showed new lesions on repeat mri imaging. contrast enhancement was present in 3 out of 4 (75%) during the disease course. three patients had genetic investigations to exclude other mimics. a trial of iv methylprednisolone was unsuccessful in 3 patients. all patients were on symptomatic treatment for spasticity and pain, including oral/intra-thecal baclofen, gabapentin and sativex. conclusions: given the rarity of primary progressive course in paediatric ms, presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes. nevertheless, our five patients presented with clinical, mri and immunological features consistent with a diagnosis of primary progressive multiple sclerosis. objective: clinical course in nmdar-antibody encephalitis is variable and difficult to predict. we aimed to identify clinical features in the presenting disease episode associated with worse functional outcome and/or relapsing disease course. methods: systematic review of the literature was conducted to identify published cases with individually reported data. clinical and treatment characteristics at first episode, outcome at ≥12 months, and monophasic vs. relapsing disease course were recorded. results: 1651 cases were identified from 693 articles (73% female; 48% ≤18 years old at onset). 91% received immunotherapy at first episode: corticosteroids in 81%, ivig in 66% and therapeutic apheresis in 33%. second-line immunotherapies were used in 32% at first episode, most frequently rituximab (17%), cyclophosphamide (5.1%), or both (7.2%); emerging second-line treatments (intravenous/intrathecal methotrexate, subcutaneous/intravenous bortezomib, intravenous tocilizumab) were used in 1.8%. life-threatening adverse events or death related to immunotherapy occurred in 1.9%. in a univariate analysis of 682 cases with ≥12 months follow-up data, poor final outcome (defined as modified rankin scale [mrs] score 3-6) occurred in 30% and was associated with very young or elderly age at onset, movement disorder, decreased consciousness, autonomic dysfunction, mechanical ventilation, higher mrs score in the acute phase, longer hospital stay, extreme delta brush on eeg, abnormal mri, csf pleocytosis and elevated csf protein (all p<0.05). a subset of 198 cases followed up for ≥36 months were analysed to identify associations with relapsing course, which occurred in 29%. in univariate analysis, factors protective against relapse were <30 days delay in first-line immune therapy, therapeutic apheresis, ivig, rituximab and other second-line treatments at first episode (all p<0.05). conclusions: worse functional outcome of nmdar-antibody encephalitis is associated with very young or elderly age at onset and worse disease severity in the acute phase. relapsing disease course is associated with delayed or insufficient early immunotherapy. objective: we describe three children with familial hemophagocytic lymphohistiocytosis (fhlh), who presented with an atypical chronic demyelinating illness. an initial working diagnosis of 'clippers' (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) was made in two cases. methods: retrospective case series. results: case 1: an 11-year-old girl presented with diplopia and squint with evolving ataxia. mri showed multiple enhancing white matter lesions in the pons, medulla and cerebellum raising the possibility of 'clippers'. her symptoms and neuroimaging responded only partially to treatment with ivig and steroids. genetic testing revealed a compound heterozygote mutation in the rab27a gene consistent with griscelli syndrome type 2 with fhlh. case 2: a 5-year-old boy had nocturnal headaches with a squint evolving over time. mri showed demyelination and swelling predominantly in the cerebellum. significant radiological resolution with steroids was followed by recurrence of demyelination on weaning steroids. a brain biopsy lesion was consistent with 'clippers'. genetic testing revealed a heterozygote variant in the stxbp2 consistent with fhlh v. case 3: a 9-year-old girl had a 7-month of intermittent fevers, deranged lfts and recurrent bilateral optic neuritis responsive to steroids/ivig. mri brain showed multiple areas of demyelination largely in the subcortical white matter. oligoclonal bands were positive in the csf. she developed a pleural effusion, high ferritin, deranged coagulation, lymphadenopathy and a rash found to be a cutaneous t-cell lymphoma. genetic testing revealed a homozygous mutation in the unc13 gene consistent with fhlh 3. all three children are awaiting stem cell transplantation. conclusions: fhlh can present with an isolated atypical demyelinating illness or with neuroimaging suggestive of 'clippers'. there may be no signs of systemic inflammation. we propose that all children with atypical recurrent cns inflammation and presentations consistent with 'clip-pers' undergo genetic panel testing for fhlh and natural killer cell functional testing. objective: the most common paediatric presentation of mog-ab disease is with acute disseminated encephalomyelitis (adem), or optic neuritis (on). with increasing recognition of the association of mog-abs with seizures in children, we present a case series of affected children. methods: retrospective anonymised case note review of affected children presenting between 2005-2019, from 5 uk paediatric neurology centres. patients were followed up for median of 6 years (range 0.5-16). results: 15 cases (7 female) of mog-ab-positive epilepsy patients were identified; median age at first presentation was 6 (range 2-14y). the most common preceding mog-ab disease was multiphasic adem (mdem 6; adem 3; adem-on 2; adem and transverse myelitis 1; nmosd 2; on 1). median time to recurrent seizure onset was 3 months (range 0-60). focal epilepsy/seizures were most common (12/15). eeg abnormalities were found in 14/15 patients, all demonstrated slowing/encephalopathy which was generalised or focal; epileptiform discharges were reported in 3 patients. brain mri was abnormal in all patients (8 with multifocal hazy/ poorly marginated lesions involving grey and white matter; 4 leukodystrophy-like pattern, 2 cortical encephalitis and 1 reported with subtle changes in brainstem). 8 patients received immunotherapy, all required at least 1 anti-epileptic drug (aed) and 8 children continue to have on-going breakthrough seizures. median mrs (modified rankin scale) at last follow-up was 1 (range 0-3), indicating no significant disabilities despite symptoms in clinical examination, age appropriate behaviour and development. conclusions: focal epilepsy is more common and more likely to follow an mdem presentation in children with mog-abs. with the relapsing nature of mog-ab disease there is a high risk of long-term cognitive impairment. further preclinical studies are urgently required to determine whether this epilepsy is due to ongoing inflammation or as a result of the mri changes commonly seen. this will help inform future management decisions regarding immunotherapy. poster no. 056 maternal mid-gestation cytokine dysregulation in mothers of children with autism spectrum disorder autism spectrum disorder (asd) is a developmental disorder characterised by a spectrum of deficits in social interactions/ communication combined with stereotypical, repetitive behaviours. recent evidence suggests maternal immune activation (mia) during pregnancy may predispose offspring to asd. the aim of this study was to examine the mid-gestation cytokine profile in mothers of children with a subsequent asd diagnosis. maternal-child dyads were recruited to a prospective population-based pregnancy study; the scope study, new zealand. children with confirmed diagnosis of asd at 6 years were enrolled in the nested cohort, along with matched neurotypical controls. cytokine concentrations (pg/ ml; mean [sem]) were examined in maternal serum samples taken at 15 and 20 weeks gestation using mesoscale discovery proinflammatory, cytokine and chemokine assays. of 2032 mothers recruited to the scope-nz study, 16 children completed follow-up and had reported asd at 6 years. these were analysed alongside 16 neurotypical matched controls. downregulation of il-17a occurred at 20 weeks gestation in cases when compared to controls (mean [sem]). 2-way anova revealed a relationship between il-17a concentration and weeks' gestation f(1,49)=4.183; p=0.0462, and also il-17a concentration and asd status f91,49)=7.801; p=0.0074. posthoc uncorrected fisher's lsd revealed a significant difference between cases (-0.3846 [0.1426] ) and controls (-0.1207 [0. 05068]) at 20 weeks gestation p=0.0160. ifnc is also downregulated at 20 weeks gestation in cases when compared to controls. 2-way anova revealed a relationship between ifny concentration and weeks gestation f(1,53) =5.692; p=0.0206. posthoc uncorrected fisher's lsd revealed a significant difference between cases (0.347 [0.0215] ) and controls (0.4345 [0. 1685]) at 20 weeks gestation p=0.0476. we have shown altered cytokine expression at 20 weeks gestation in mothers of children who progress to develop asd. this adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment. objective: acute disseminated encephalomyelitis (adem) is an immune mediated inflammatory cns disorder, predominantly affecting white matter, with a wide differential (1). here we describe a rare mimic of adem that is essential to consider in order to avoid a catastrophic outcome. case history: a 12-year old girl presented with a 2 day history of confusion, dysarthria, ataxia and left-sided squint, preceded by 2 weeks of general malaise and headache. examination confirmed encephalopathy and a left third cranial nerve palsy. mri brain was suggestive of adem and mri spine was normal. a recommended work up for adem was performed. rapid resolution of her symptoms occurred following intravenous methylprednisolone for 3 days. 2 years later she presented with acute left lower limb ischaemia and underwent emergency embolectomy of a popliteal arterial obstruction, with myxomatous material identified. preoperative echocardiogram confirmed a large atrial mass which was surgically removed. pathology confirmed an atrial myxoma (am). retrospective review of her initial mri images concluded that embolic phenomena from the am was the most likely explanation of her first presentation. conclusions: am is a very rare primary cardiac tumour and left sided am can embolise to the cerebrovascular system. early identification of am is important as, untreated, it can cause multiple embolic events and sudden cardiac death. 12% of adults with am present with neurological symptoms and this can mimic multiple sclerosis. am presenting with acute neurological symptoms masquerading as adem in paediatrics has not been previously reported. careful follow up is essential as late neurological complications (including cerebral arterial aneurysms) are recognised. this case highlights that adem is a diagnosis of exclusion and that mimics for acute focal neurology with encephalopathy and t2 hyperintensities on mri require careful consideration, including embolic phenomena. clinical examination alone does not exclude am and consideration of echocardiography is recommended. we describe an 8 year old boy with a rare demyelinating disorder: balo's concentric sclerosis. a routine optician review raised concerns about papilloedema in an asymptomatic child. a ct brain identified a well-demarcated high-density lesion in the left posterior frontal lobe with surrounding oedema. mri brain with contrast identified the lesion had central rim enhancement and slight diffusion restriction. alternating layers of high and low signal intensity gave it an 'onion bulb' appearance. the differential included balo's concentric sclerosis, a single demyelinating lesion, or a tumour. routine blood tests were unremarkable. csf oligoclonal bands were normal as were other csf indices. markers of immunology, including ana, anca, anti-mog, anticardiolipin, and aquaporin 4 antibodies were all negative, with normal complement levels. esr was mildly elevated when taken during an episode of acute tonsillitis. imaging 3 months later demonstrated an increase in the size of the lesion. a biopsy revealed inflammatory demyelinating pathology mediated by a perivascular and parenchymal t-and b-lymphocyte infiltrate and macrophage activity with associated demyelination lacking a perivenular distribution. there was no evidence of neoplasia, vasculitis, granulomas, or viral infection (including negative pcr testing). no treatment with corticosteroids was given, and the child remained asymptomatic. imaging, at 9 months from presentation, revealed the lesion had substantially reduced in size. there was still a rim of enhancement. as with all single demyelinating lesions, it is difficult to predict the clinical course. we opted to adopt a 'wait and see policy' and offer surveillance imaging and clinical review. balo's concentric sclerosis is a rare demyelinating disease, characterized by concentric lamella of alternating demyelinated and partially myelinated tissues. mri shows one or more concentrically mulitlayered ring-like lesions, usually in the cerebral white matter. most case reports describe cases predominantly in young adults, with few reports of cases in children. objective: cognitive and acquired neurodevelopmental deficits have been reported in children with opsoclonus-myoclonus syndrome (oms) and are associated with more severe and relapsing disease course. however, there is a paucity of data regarding cognitive dysfunction in children with stable neurological disease. we report on serial cognitive assessments of 4 children with oms demonstrating evolving cognitive dysfunction with milder disease course. methods: retrospective analysis of clinical features at presentation, investigations, treatments, clinical course including relapses and neuropsychological testing. results: four children (m:f 1:1) diagnosed with oms between 17 and 35 months were followed up for 4 to 10 years. neuroblastoma was identified in one child. oms severity scores ranged between 8 to 12/15 at presentation. patients underwent immunotherapy in accordance with european oms protocol. all patients were in remission by 7 months (range 4-13mo), with treatment maintained for 1 year. one child remained relapse free whilst 3 other children had one clinical relapse which was immunotherapy responsive again. in all cases, progressive cognitive dysfunction was reported despite being in remission and stable off treatment for 20 months (range of 12-31mo; 3 oms score 0/15 and one 2/15). sequential neuropsychological testing scores showed mean declines in fsiq of 16 (13-19) , viq of 24 (20-27) and piq of 17 (-2 to 30) between time of oms remission/stable disease and longer term follow-up time point (4-10y). conclusions: our cases demonstrate progressive cognitive dysfunction occurring in children with oms who have a milder disease and long after completion of treatment. children continued to develop but with a widening gap in comparison with peers. damage to cerebellar-cortical circuits at onset of the disease that becomes more apparent with time or indeed persistent ongoing low grade inflammation may explain this deterioration. the past decade has seen increasing cases of acute flaccid paralysis (afp) associated with enterovirus d68 (evd68) infection. it presents in clusters approximately every 2 years. we report three cases of afp due to evd68 that presented in november-december 2018. cases: two patients developed afp following a viral upper respiratory tract infection and one developed lower limb hypotonia and weakness during an inpatient admission with refractory epilepsy. two required admission to the paediatric intensive care unit for respiratory compromise and required tracheostomy ventilation. mri showed acute flaccid myelitis (afm) consistent with evd68 in 2/3 cases, consisting of central cord t2 hyperintensity in the cervical region over multiple segments with subsequent enhancement of the thalamus and cauda equina on follow-up imaging in one patient; and ventral surface enhancement of the conus and cauda equina in another. mri in the third patient was normal. electromyography and nerve conduction studies were normal in two patients but revealed a severe generalised motor axonal poly-neuronopathy in the third. two patients received intravenous immunoglobulin, corticosteroids or plasma exchange therapy and showed slow motor improvement in a distal to proximal pattern. the one patient without mri changes had received long-term oral corticosteroids but received no additional treatment and returned to baseline neurological function within 4 weeks. discussion: our cases demonstrate the range and clinical course of peripheral neurological presentations secondary to evd68 infection. we highlight the importance of sending repeat samples from multiple sites when the diagnosis is suspected, given that initial samples tested negative, and of sending samples to a national surveillance laboratory for confirmatory testing. ongoing national and multinational surveillance studies will hopefully continue to advance our understanding and treatment of this disease. poster no. 061 nmda receptor encephalitis a potential complication of biologic therapy for juvenile idiopathic arthritis? n abbassi 1 , t rossor 1 , r close 2 , a skippen 1 , k armon 2 , p bale 2 , g ambegaonkar 1 1 paediatric neurology, addenbrookes hospital, cambridge, uk; 2 paediatric rheumatology, addenbrookes hospital, cambridge, uk a 12-year-old girl presented with headaches, confusion and agitation, followed by seizures. she had presented at 20 months with polyarticular arthritis and was managed over subsequent years on methotrexate alone (2y) with added etanercept (anti-tnf alpha, 5y), tocilizumab (anti il-6, 2y) and abatacept (cd 80/86 t-cell modifier, 3y prior to presentation). flares of disease following a period of control necessitated the changes in monoclonal antibody therapy. at this presentation she was managed on methotrexate, abatacept and 5mg prednisolone for polyarticular rheumatoid factor negative juvenile idiopathic arthritis (jia). at presentation the patient was agitated, non-verbal and had one generalised seizure. examination demonstrated acute confusion, with increased tone, brisk reflexes and bilateral clonus in her lower limbs. iv ceftriaxone, acyclovir and clarithromycin were commenced. full blood count, liver function tests and inflammatory markers were unremarkable. infective serology was non-contributory. csf was unreactive with normal protein and jc virus pcr negative. mri brain 5 days after presentation showed increased t2 and flair signal intensity in the white matter of the right parietal lobe, in-keeping with an inflammatory process. eeg showed diffuse slowing with delta brush. she commenced iv methylprednisolone, followed by prednisolone. she continued to deteriorate and underwent plasmapheresis for treatment of presumed nmda receptor encephalitis, subsequently confirmed by anti-nmda receptor antibodies in serum and csf. she was commenced on rituximab (b-cell depletion, anti-cd 20), and continued to undergo plasmapheresis over the course of 4 weeks. she gradually improved and was discharged home after a 10-week inpatient stay. several adult and two paediatric cases of nmda receptor encephalitis are reported in patients on biologic therapy for autoimmune disease. autoimmune diseases are more common in those already affected by one autoimmune condition. it is unclear what contribution an autoimmune history or immunomodulation made on the development of this condition. introduction: the incidence of acute flaccid myelitis (afm) associated with enterovirus infection occurring in biennial clusters since 2012 has been reported in the us (bmj 2018, 18; 363:k5246) and recently in europe. previously, cases with transverse myelitis (tm) with anterior-horn cell or peripheral nerve involvement have been collectively termed tm-plus (neurology 2016; 87;s46-s52). we aimed to identify cases of tm-plus from a retrospective cohort of children to identify potential cases of 'undiagnosed' afm, and to evaluate the clinical and radiological features alongside long-term outcome. methods: consecutive cases of children (<16y of age) who presented to a large paediatric neurosciences centre from 2009 to 2016 fulfilling the transverse myelitis consortium working group criteria modified for the paediatric population (neurology 2015; 84:341-349) were retrospectively evaluated for additional features of anterior horn-cell involvement (fulfilling criteria for afm (current treat options neurol (2017) 19: 48)) or peripheral nervous involvement; and were collectively evaluated with the contemporary tm-plus cohort (2016) (2017) (2018) . results: 25 cases of tm were identified, 7 of which were excluded from further analysis; ms (n=6), adem (n=1). 8 cases of tm-plus were identified, 4 before 2016 and 4 after, all associated with a viral prodrome. flaccidity (n=8) and asymmetry (n=6) was noted at presentation, with corresponding nerve conduction studies revealing a motor axonopathy with sensory sparing (n=6) and anterior horn cell involvement confirmed in 3 cases. all cases with anterior horn cell involvement had poor outcomes while both cases with good outcomes had peripheral involvement and normal mri brains. conclusions: tm-plus was detected in our cohort from 2009 to 2016 with biennial clusters noted in 2016 and 2018. the clinical presentation, investigations and long-term outcomes appear consistent in both groups. acute necrotising encephalopathy is more severe when associated with influenza background and objective: acute necrotising encephalopathy (ane) is a rare but potentially life-threatening condition associated with viral infections. a familial and recurrent form (ane1) has been identified by mutations in the nuclear pore ran binding protein (ranbp2). we report the morbidity and mortality when associated with influenza infection. methods: we performed a review of paediatric ane cases from 1999 to 2019 evaluating the clinical, biochemical, microbiological and neuroimaging appearances as well as outcomes. results: the cohort comprised 6 children (2 boys), age ranging from 8 months to 3 years 9 months (<2y n=5), of which 4 had a confirmed genetic diagnosis and 2 were ranbp2 negative. there were 13 episodes of encephalopathy, with recurrences in 3 cases (2 ane1). 10 of these episodes had infectious aetiology identified: coronavirus n=2, parainfluenza n=1, adenovirus n=2, h influenzae n=1, influenza (h1n1 n=3, h3n2 n=1). clinical features of fever and encephalopathy were consistent (100%), and seizures and sixth nerve palsies prominent (50% each). csf revealed absent pleocytosis, normal-elevated protein and negative virology. symmetric involvement of the thalami bilaterally was present in all cases, and all ane1 cases were associated with haemorrhage and external capsule/claustrum involvement (100% specific and sensitive). the outcome following influenza infection was striking, death n=1, vegetative n=2, 4 limb motor and movement disorder n=1. 2 of these cases had previous episodes of encephalopathy with noninfluenza infection and did have recovery, albeit with moderate to severe disability. all 3 cases were never immunised against influenza infection and suffered grave outcomes. conclusions: influenza infection in ane has the poorest outcome therefore vaccination should be a mandatory consideration for the known cases of ane. introduction: acute flaccid paralysis (afp) is characterized by a rapid onset of limb weakness. we describe six cases of afp in children aged 9 months to 3 years of age who presented to a tertiary paediatric neurology service in the east of england over a 5-year period from november 2013-november 2018. retrospective analysis of the six cases was performed, reviewing their clinical course and management, as well as their radiological, electrophysiology and laboratory results. results: case 1, a 9-month-old boy, presented in november 2013 with a viral urti requiring escalation of care to picu due to a significant respiratory compromise. only on subsequent recovery was the child found to have a unilateral upper limb flaccid paralysis. this child was positive for enterovirus serotype d68. cases 2 and 3 in our series presented in 2016 with acute weakness of the lower limbs with an mri brain and spine showing enhancement of the lumbar spinal roots. both have made a good recovery. enterovirus was not detected in either case. the final three children in our series presented in autumn 2018 with weakness of a unilateral upper limb following a viral urti, with all three being positive for enterovirus. unfortunately, they have shown minimal recovery of motor function of the affected upper limb. one child, a 3year-old girl, showed a more severe clinical course involving a prolonged period of intensive care and a tracheostomy for long-term ventilation. she has undergone neurorehabilitation and an upper right arm nerve transfer. conclusions: in our case series, four patients presented with an acute viral urti associated with an upper extremity weakness, and subsequently all four were positive for enterovirus. clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (afm). objective: to present an interesting case of recurrent anti-mog demyelinating disease and provoke discussion regarding possible immunomodulatory therapy. methods: a 14 year old girl presented, initially at 5 years of age, with headache and vomiting. she was initially treated as atypical tuberculosis meningitis based on csf cell counts, but later developed a 6th nerve palsy and was diagnosed with optic neuritis. anti-mog antibodies were positive and they were commenced on iv methylprednisolone. she clinically improved and was discharged on weaning oral prednisolone, antibodies were negative following treatment. results: a few months later she had her first relapse, with an acute decline in visual acuity. an mri showed new lesions in her optic chiasm and both optic nerves with associated bilaterally reduced visual evoked potentials. she was again treated with iv methylprednisolone, with rapid improvement, followed by a switch to weaning oral prednisolone. anti-mog antibodies were negative following treatment. she was symptom free for 7 years until her second relapse, when she presented with facial palsy, swallowing difficulties and slurred speech. mri showed brainstem and periventricular white matter demyelination, with positive anti-mog antibodies. she was again treated with iv methylprednisolone, followed by oral prednisolone, but was maintained on low dose prednisolone as her anti-mog antibodies remained weakly positive despite being symptom free. these were stopped at patient request due to low mood and abdominal pain in february 2019, with no recurrence of symptoms as yet. repeat mog antibodies have been sent and are awaited. conclusions: this case shows an interesting relapsing/remitting pattern of anti-mog demyelinating disease, which appears to be very steroid responsive, however on her second relapse her anti-mog antibodies remained weakly positive despite steroid therapy. discussion is welcomed on whether prophylactic immune modulation therapy should be considered with this child, such as azathioprine, mycophenolate mofetil or rituximab. objective: to highlight the utility of early mr imaging in children presenting with acute severe encephalopathy and to consider whether there might be a subgroup of children with myelin oligodendrocyte glycoprotein antibody (mog-ab)associated demyelination who might be candidates for early intense immunomodulation. methods: we report two cases with mog-ab-associated acute demyelination who relapsed with new neurological symptoms after initial steroid therapy had been discontinued. results: two toddlers were initially admitted to intensive care with acute encephalopathy and acute symptomatic seizures. both had an initial ct head during picu admission; one was reported normal; the other was suggestive of diffuse cerebral oedema. both children improved with supportive care only and were discharged home within a week. both children presented again over the following 2 to 4 weeks with new neurological symptoms but without encephalopathy. mr imaging demonstrated demyelination and they were treated with steroids. both children relapsed as steroids were being weaned and/or stopped. repeat mr imaging at this stage demonstrated new enhancing lesions. it was subsequently found that both children were mog-ab positive. conclusions: reliance on cranial ct imaging in the context of a young child with acute encephalopathy and seizures can be misleading. prediction of the severity of mog-ab-associated demyelinating syndrome at onset is challenging. mr imaging in the acute phase with early follow up imaging may identify this subgroup. case: hb is a 7 year old boy who presented with sudden onset diplopia and painful ophthalmoplegia, following a 12 day history of frontal headache. on examination, he had a left vith nerve palsy, partial left iiird nerve palsy and normal right eye movements. the remainder of his neurological and general systems examination was normal. his initial ct head scan and pre-contrast mri of the brain were normal. he was discharged from the local hospital following normal blood tests and imaging. clinical course: nine days later, his symptoms worsened including severe vomiting, worsening frontal headache and photophobia. he was treated for a possible underlying infective cause with ceftriaxone and acyclovir. given the broad underlying differential diagnoses, hb had extensive infectious and immunological blood workup which was unremarkable. a repeat mri brain scan with contrast revealed a lesion in the left cavernous sinus, possibly of vascular origin. differentials included cerebrovascular venous sinus thrombosis, tumour and inflammatory causes such as tb, sarcoid and zoonoses. hb continued to be conservatively managed and completed his course of ceftriaxone and acyclovir. repeat mri imaging 2 months later showed some resolution of the lesion and a diagnosis of tolosa-hunt syndrome was provisionally made. hb's symptoms continued to improve and further repeat mri scan 6 months later showed ongoing resolution of the lesion. discussion: according to the ichd-3 beta classification of tolosa-hunt syndrome, hb fulfilled the diagnostic criteria given his presentation of unilateral headache, granulomatous inflammation of the cavernous sinus on mri, palsies of ipsilateral iiird, ivth and vith cranial nerves. steroid use has been reported to be beneficial although more evidence is required in the paediatric population, refractory cases may respond to azathioprine and methotrexate. objective: we present a case of internuclear ophthalmoplegia unresponsive to steroid treatment which clinically improved with folinic acid supplementation. method: a retrospective chart review. results: our patient presented with acute internuclear ophthalmoplegia, ataxia and bilateral ptosis. she had a background of hypoplasia of the corpus callosum and optic atrophy with visual impairment, learning difficulties and asd. mri brain demonstrated symmetrical high signal intensity in the region of the medial longitudinal fasciculus and periaqueductal grey matter. she was investigated to exclude an inflammatory cause and was treated with high dose steroids. follow up mri did not show any improvement post steroids and there was no clinical improvement. subsequent csf investigations showed a low level of 5-methyltetrahydrofolate of 35nmol/l (normal range 72-172nmol/l). she was commenced on folinic acid 15mg once daily and her symptoms improved. on follow up her eye movements had significantly improved as had her ptosis. follow up mri brain showed partial resolution of the areas of abnormal signal in the periaqueductal grey matter. conclusion: internuclear ophthalmoplegia is a sign usually associated with an inflammatory or demyelinating cause. our case did not respond to steroid treatment but has associated low levels of 5-methyl tetrahydrofolate and has responded to treatment with folinic acid. this is sometimes associated with underlying mitochondrial disorders but muscle biopsy in this case did not show any evidence of mitochondrial disease. mri brain has shown partial resolution of the abnormal signal in the periaqueductal grey matter. introduction: paediatric intracranial aneurysms are rare. the pattern of disease is different to that in adults and there is far less literature available. i provide a case as an example of the presentation and progress of a child with a dissecting vertebrobasilar artery aneurysm. presentation: 11-year-old boy presented to his local hospital with sudden-onset headache, photophobia and vomiting. bloods and observations were normaldischarged. symptoms recurred more severely the following day. managed as meningitis. 4 lumbar punctures were 'bloody' and considered failed. mri brain 2 days post-admission demonstrated a vertebrobasilar aneurysm. transferred to the regional neurosurgical centre. transfer to neurosurgical/neurovascular centre: cerebral angiography revealed dissecting vertebrobasilar aneurysm (1298910mm). fusiform component extending beyond aici/ pica origins. wide-necked saccular component. procedure and progress: loaded with aspirin and clopidogrel. underwent endovascular procedure the following daycoil embolization, flow-diverting stent to the aneurysm. ongoing low dose dual anti-platelet therapy. made an excellent recovery with no neurological deficits. further imaging -x-ray cervical spine for possible arcuate foramen or atlantoaxial instability, normal. ultrasound liver/spleen, normal. discharged home 10 days post-transfer. patient background: past medical historyunder the gp for 18 months of headaches. traumasignificant fall from bicycle 2 years before with forced lateral flexion of the neck. posited that this may have been a contributing factor in aneurysm development. no significant family history. lifestylean active boy, enjoys weightlifting and motocross. weightlifting also posited as a contributing factor. conclusions: i provide a case which i hope will raise awareness of paediatric intracranial aneurysms and stimulate discussion concerning their management and aetiology. poster no. 070 cavernoma in children: cddft experience of two cases d jayachandran, s chandraiah darlington memorial hospital, cddft, darlington, uk aim: to report two cases of congenital cavernoma diagnosed in children presenting with neurological symptoms. cases: case 1: 10-year-old female presented with multiple left facial focal seizures in the form of twitches with full awareness. there was no family history of epilepsy. a typical event was captured lasting 70 seconds during the awake eeg and was reported as focal seizure arising from right hemisphere. an mri brain scan showed 2 popcorn balls lesions within the frontal/fronto parietal lobes, one on each side (right>left) with evidence of bleeding. she remains seizure free on carbamazepine. ccm gene results are awaited and neurosurgeon opinion was not for intervention and for local follow up. case 2: 12-year-old male had presented with confusion at 7 years of age. he also had transient loss of vision, vomiting, headaches with a few minutes unresponsive episode during admission. with a diagnosis of migraine, he had an mri brain scan as op that showed multiple cavernous haemangiomas in the cerebrum and cerebellum with the largest demonstrating a fluid level in the left parieto-occipital region. family history revealed that father had seizures secondary to brain cavernomas. he was positive for krit1 (ccm1) mutation. neurosurgeons advised active monitoring and he presented again at 12 years with focal onset seizures with impaired awareness. eeg was normal but mri showed a new cavernoma in the left temporal horn with bleeding. he remains well on carbamazepine with a plan for yearly mri scans. conclusions: congenital cavernomas of brain can be sporadic or familial, can be multiple and in any location including brain stem and can result in physical disability secondary to bleeding. in the majority of cases bleeding is spontaneous and diagnosed on mri scans after a neurological event. objective: foxp1-related intellectual disability syndrome is characterised by developmental delay, variable physical features and autism. diagnosis has increased with better access to broad genetic testing. we present a case report of a child with foxp1 mutation whose presentation was notable for significant cerebral venous ectasia. case: child s presented aged 1 year with gross motor delay (not sitting or weightbearing) along with relative macrocephaly (91st-99th centile), strabismus and prominent superficial forehead veins. intracranial imaging was arranged in which ct angiogram raised a possibility of an arteriovenous fistula. subsequent catheter angiography excluded this but demonstrated extensive tortuous cerebral venous ectasia. the venous ectasia was not felt to explain her developmental difficulties. initial genetic testing including microarray and pik3ca and pten analysis was normal. s made some developmental progress but remained globally delayed compared with her peers. reanalysis of her dna against a panel of genes associated with intellectual disability identified a de novo heterozygous pathogenic variant in the foxp1 gene, c.1507c>t, p.(arg503ter) (east anglian medical genetics service). discussion: foxp1 acts as a transcription factor and is likely to be involved in the development of many different tissue types. a wide range of genetic aberrations affecting foxp1, including point mutations and large structural anomalies, lead to overlapping clinical phenotypes. this patient demonstrates many relevant clinical features including developmental delay with autistic traits, relative macrocephaly with a prominent forehead, strabismus and early gross motor developmental delay. however, descriptions of associated neurovascular anomalies in foxp1 syndrome are scarce, with a single case report recording a venous angioma and none of cerebral venous ectasia to our knowledge. foxp1 follow up studies and whole exome or genome sequencing may help determine whether there is an additional genetic cause for this child's cerebral venous ectasia or whether it is foxp1 related. objective: a 2017 rcpch guideline was published to increase awareness of stroke in children and standardize best practice. the need for urgent (within 1h) ct angiography in children presenting with suspected stroke and criteria for thrombolysis were set out. we aimed to review the acute management and investigation of pais in children (1mo to 16y) since the introduction of the guideline with an emphasis on identifying candidates for thrombolysis. methods: retrospective notes review in a single regional neurology centre over a 20-month timeframe. results: eighteen cases were identified (8f:10m) with two mortalities. age range 2 months-13 years (mean 4.8y). 10/ 18 presented in peripheral hospitals and 8/18 in the regional centre. no cases had pednihss score documented on presentation. 9/18 had dedicated vascular imaging (cta/ mra) on initial imaging. 12/18 presented with a hemiparesis, 2/18 with seizures, 2/7 dysphasia, 1/7 headache, 1/7 ataxia. 5/18 cases had a stroke post cardiac surgery, 5/18 idiopathic stroke, 3/18 post varicella angiitis, 2/18 arterial dissection, 2/18 cardiomyopathy and 1/18 embolic stroke as a complication of central line insertion. 5/18 presented with an acute hemiparesis with a clear time of onset. no cases received thrombolysis. 1/5 was imaged within 1 hour of presentation. 1/5 had vascular imaging (mra or cta) on presentation. 1/5 cases was discussed acutely with paediatric neurology; this case was not suitable for thrombolysis due to cardiomyopathy. in retrospect the other 4/5 cases were suitable candidates for thrombolysis. conclusions: the results highlight the continued need for enhanced awareness of paediatric stroke as a medical emergency. most acute strokes will present to peripheral hospitals. therefore, there is a need for regional multidisciplinary integrated pathways amongst emergency department physicians, paediatricians and radiologists to ensure prompt vascular neuroimaging and discussion with a paediatric neurologist about the possibility of thrombolysis in suspected pais. poster no. 073 'a nudge, a fall and a weakness'a common but missed cause of paediatric stroke r shyam 1 , r bahri 1,2 , a kumar 1 , v jain 1 1 department of paediatric neurology, santokba durlabhji hospital and medical research institute, jaipur, india; 2 norwich medical school, university of east anglia, norwich, uk objective: this study retrospectively analysed paediatric strokes with further evaluations and outcomes of strokes related to minor injury, to isolate characteristic features and outcomes in these patients. methods: paediatric patients (6mo to 15y age), presenting with acute stroke between january 2015 to january 2019 were retrospectively recruited from a tertiary care hospital in north india. from this cohort, strokes following minor injury were analysed for clinical profile, investigations and outcomes (measured by international paediatric stroke study scoring system, ipss). results: of the total 114 cases, 50 (43.8%) were post-minor injury (m: f 2.5:1; mean age 14.2ae3.4mo). of the remaining (n=64; mean age 5ae4.5y) most common aetiologies were moya-moya disease (n=10, 15%) and transient unilateral arteriopathy (n=8, 12%). the post-minor injury group revealed a median time of 60 minutes from trauma to stroke onset. more than 1/3rd (36%; n=18) had transient episodic hemi-dystonia on the hemi-paretic side after a median of 4 days of symptoms onset. 90% (18/20) of children where results were available had anaemia. ct head in all (n=50) showed calcification of the lenticulo-striate vessels. subsequent brain mri (n=20) confirmed ct findings of basal ganglia ischaemia. mr angiogram and thrombophilia screen (n=6) done in the first few patients were normal and hence not pursued subsequently. follow ups of 44/50 (6-48mo; median=12mo) showed good recovery in the majority (66%; n=29/44). the median ipss score for these children was 0.5. conclusions: trivial injury leading to basal ganglia stroke was the most common cause of paediatric stroke, occurring exclusively in less than 2 year-olds. ct head was diagnostic (calcification in lenticulo-striate blood vessels and ischemia) with no further information revealed from vascular imaging or thrombophilia work-up. children were commonly anaemic, a potential causative association. often transient episodic hemidystonia of the hemiparetic side after a few days was witnessed. neurological outcomes in most children with this entity is good. introduction: rcpch launched guidance on paediatric stroke in march 2017. we present a series of paediatric patients who presented with stroke following this publication. we audited this group of patients against the key standards of the rcpch guidance. methods: we retrospectively analysed cases between april 2017 and april 2019. we identified cases from a neurology database and audited acute management using rcpch guidance 2017 as standard. results: we identified 11 children with stroke in the last 2 years. ages ranged from 21 months to 16 years with a mean age of 8 years at presentation. 7 children had haemorrhagic stroke and 4 had ischaemic stroke. the majority involved the anterior cerebral circulation (10/11). underlying aetiology was identified in 6 patients, 5 of whom had haemorrhagic stroke. 2 of the patients died. only 2 out of 11 patients had brain imaging within an hour of presentation. only one patient was eligible for thrombolysis, however due to contraindication she underwent thrombectomy. discussion: stroke pathways are well developed in adult services. due to the rarity of stroke in childhood and challenges with recognising symptoms, treatment is often delayed. symptoms in children need a high index of suspicion. the findings of this audit support the development of an all wales paediatric stroke pathway. we aim to facilitate activation of the stroke pathway when children present with the fast symptoms. we also hope to increase awareness of stroke in childhood. withdrawn. objective: stroke is a common childhood neurological disorder, affecting at least 400 children in the uk each year. the majority of children have residual sequelae across a wide domain of functions, with significant personal and societal consequences. recent rcpch guidelines have proposed criteria for hyperacute treatments; this would require rapid recognition of the potential diagnosis by clinicians. here we describe the acute care pathway of a group of children with confirmed arterial ischaemic stroke (ais). methods: parents of children aged >28 days and <18 years referred to gosh (ais) (2015-2019) were approached and sent a questionnaire exploring their experience of navigating through the healthcare system on initial presentation. responses were tabulated where possible and reported as frequencies; qualitive results were thematically coded and categorised for analysis. results: 41/90 eligible parents responded. 999 and the gp were the first port of call for the majority (n=12 for each). ten parents stated they had 'no idea' what initial symptoms might represent. when directly asked if they had suspected a stroke, nearly 2/3 stated 'no'. f.a.s.t features (f: face a: arm s: speech t: time) were noted in a third of patients and only 10 patients were given a diagnosis of stroke at first presentation. on initial discharge, a correct diagnosis of stroke was provided to 21 patients. notably, the need for improved education of paediatric stroke, for healthcare providers was raised by nearly 50% of parents surveyed. conclusions: the study demonstrates the need for further education to be delivered in pre-hospital, primary and secondary healthcare settings for recognising acute stroke in children. this will be an essential step in the delivery of hyperacute treatments. background: hereditary spastic paraparesis refers to a heterogeneous group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. there is marked genetic heterogeneity in hsp with all modes of inheritance described for the different loci and causative genes implicated up to now. we present a case of a child with a complex diagnosis of hsp with a homozygous missense mutation in nt5c2 underlying hereditary spastic paraplegia spg45. case presentation: this child had initially been diagnosed as having bilateral cerebral palsy with diplegic pattern and gmfcs ii. he had gross motor and speech and language delay. there was a family history of consanguinity. mri scans had initially been described as showing evidence of periventricular leukomalacia and he had been referred for consideration of sdr. following tertiary assessment there were clinical concerns that the overall diagnosis may need to be reexplored. review of his mri scans demonstrated similarities to a case series of hsp with a rarer form of hsp (spg45). he subsequently tested positive for spg45 nt5c2. a second case with similar clinical findings has now been identified in our region. mri scan findings will be presented. summary: spg45 is a rare but important cause of a cerebral palsy phenotype and testing for nt5c2 should be considered in the differential diagnosis and investigation of patients presenting with cp. recommendations on patient suitability for sdr has focused on children functioning at gmfcs level ii or iii. sdr has been considered for gmfcs levels iv and v however the decision to progress can be challenging. the goals in these children are significantly different with the focus being around comfort and pain relief rather than mobility. we describe the case of a boy with a mixed pattern movement disorder involving 4 limbs which had initially been managed with oral medications baclofen, trihexiphenidyl and intramuscular botulinum toxin. due to the child having a vp shunt the family didn't wish to consider itb pump. despite optimisation of oral medications and intramuscular botulinum toxin spasticity was a significant issue adversely impacting on quality of life. escalation of baclofen was unsuccessful due to loss of head control and duration of action of botulinum toxin injections appeared to be limited to 4 to 6 weeks before tone increased again. this resulted in significant difficulties with moving and handling. in view of this the option of selective dorsal rhizotomy was explored. the goal was to improve ease of personal care and sleep. post-operative outcomes greatly exceeded the family expectations. along with a reduction in tone in the lower limbs they were delighted to report several unexpected improvements. these included: improved functional ability with the left upper limb which facilitated switch access; improved truncal control making moving and handling easier; a reduction in extension posturing which had been particularly problematic pre-operatively; significant improvement in sleep; improved mood. this resulted in the local team exploring eye gaze technology with him. these functional benefits have significantly improved the quality of life for not only the patient but his family. further research into the benefit of sdr in this group of patients should encompass care and comfort outcomes, sleep assessment and measurement of pain. introduction: clonidine has become increasingly repurposed for the management of childhood dystonia. one potential advantage of clonidine is the availability of patches for transdermal delivery. we aimed to review the use of transdermal clonidine patches in our institution. methods: a retrospective notes review of children and young people (cayp) with dystonia issued transdermal clonidine patches as identified from pharmacy records. results: a total of 45 cayp were identified, median age at initiation of clonidine of 7 years 5 months (range 10mo to 14y and 5mo). prior to initiation of patches 43/45 cayp were already receiving clonidine, including 5 acutely receiving iv clonidine infusions. one child with difficult iv access experiencing an acute deterioration of dystonia was lost to follow up following transfer to local services. the commonest indications for transdermal clonidine were concerns about 'on/off' effect of enteral doses (n=23) and concerns about enteral absorption (n=17). transdermal clonidine was discontinued by 5/44 cayp (3 as patches wouldn't adhere, 1 receiving patches as a temporary bridge from iv to enteral clonidine and 1 due to severe local cutaneous reaction). one additional clonidine naive child experienced significant hypotension with a 0.75µg/kg/hour transdermal dose but tolerated a reduced dose of 0.25µg/kg/hour. follow up for the remaining 39/44 children ranged from 2 months to 6.5 years (median 1y). the median transdermal dose was 1.67µg/kg/hour (range 0.25-8.05µg/kg/h). additional enteral clonidine was used by 25/44 cayp. efficacy of transdermal clonidine was difficult to determine, but 18/44 cayp retrospectively scored 2 on the clinical global improvement-scale, suggesting significant improvement. conclusions: in cayp receiving enteral clonidine switching to transdermal clonidine patches appears to be well tolerated, with 88.6% of cayp continuing with longer term use. further prospective work is required to determine the efficacy and safety profile of transdermal clonidine. objective: to review the indications for and outcomes following itb for children and young people (cayp) at our centre. methods: 42 patients were identified undergoing itb pump insertion from 2006 to 2015. 35 had reports available. a retrospective note review was performed, with data extracted using a standardised data collection proforma. results: median age at itb pump insertion was 9 (range 4 to 18). hypertonia was described as dystonia, spasticity and/or dyskinesia. median length of follow up was 3 years (range: 1mo to 9y). choice of outcome measure was dependent upon the goals identified for surgery. care provider child health index living with disability (cpchild) data was available for 23 cayp at baseline and 18 cayp at 1 year. cpchild improved from a median score of 45.5 to 58.2 at 1 year (p=0.03, wilcoxon signed rank test). burke-fahn-marsden dystonia rating scale (bfmdrs) data was available for 12 cayp at baseline (median: 92.5 for motor, 30 for disability), 10 cayp at 1 year (median 98.25 for motor, median 28 for disability), all with a clinical picture of dystonia. gross motor function measure (gmfm) was available for 9 cayp at baseline (median=40), 8 cayp at 1 year (median 47) and 7 cayp beyond 1 year (median=43.1). gmfm and bfmdrs were not statistically significant. pain was measured with paediatric pain profile, available for 14 cayp at baseline, 6 cayp in 1 year and 3 cayp beyond 1 year. median of most troublesome pain improved from 29 at baseline to 17 in 1 year. conclusions: for a heterogeneous cohort of cayp with motor disorders, itb appeared to improve ease of care and comfort, indicated by change in cpchild. multiple measures are required to fully capture benefits seen in this cohort, which should be focused on their individual needs for intervention. objective: to evaluate neurosurgical interventions and outcomes in the management of hemidystonia. methods: the pubmed database was searched including terms 'hemidystonia', hemi-dystonia', 'unilateral dystonia', 'dystonia and (pallidotomy or thalamotomy)', 'dystonia and (dbs or 'deep brain stimulation')' and 'dystonia and (itb or 'intrathecal baclofen')', up to may 2019. papers were included if written in english and presenting outcome data for human participants undergoing a neurosurgical intervention for management of hemidystonia. reference lists of included papers were also reviewed. individualised patient data was extracted. to facilitate comparison across patients with and without validated dystonia scale scores individual patient outcomes were categorised on a 6-point scale ranging from 'worsened compared to baseline' to 'very marked improvement'. results: we identified 53 reports meeting inclusion criteria, describing 144 unique patients (20 <18y of age). ablative methods (85/144 cases) most commonly targeted the thalamus, and dbs (59/144 cases) the gpi. in recent years dbs is reported far more commonly then ablative surgery. reported follow up ranged from 6 months to 10 years. one patient underwent itb but no further individual data was available. out of the 144 cases 82 had individual outcome data. objective measures were available in 38 dbs and 7 ablation cases, most commonly the bfmdrs. reported outcomes in dbs patients were 2/47 worsening compared to baseline, 4/47 no change, 13/47 slight improvement, 10/47 moderate improvement, 9/47 marked improvement and 9/47 very marked improvement. for the ablative cases 0/35 worsened, 12/35 no change, 6/35 slight improvement, 10/35 moderate improvement, 3/35 marked improvement and very marked improvement. complications were reported in 2 dbs cases (1 shielded battery syndrome, one infection) and 7 ablative cases (2 depression and 5 transient hemiplegia). conclusions: available evidence for the neurosurgical treatment of hemidystonia is of low quality, but suggests generally positive results, with few complications reported. introduction: acute flaccid myelitis (afm) is a recently characterised condition causing multiple muscle paralysis and life-changing disability in children. no medical treatment is effective. however, recovery of denervated muscle function is possible via nerve transfer surgery. such treatment is complex, specific to the individual and should be carried out by specialist teams. objective: to describe the clinical features, management and outcomes of nerve transfer surgery following the 2018 afm outbreak. methods: retrospective analysis of patients with afm treated with nerve transfer surgery in 2019. surgical criteria: persistent motor deficits (paralysis) 6 months post onset with neurophysiologic signs of denervation and donor nerve availability. results: eight patients (m=f, aged 26-75 months; mean 40) were referred between march and july 2019. at initial onset/ infection: 6/8 had involvement of all four limbs and trunk and 4/8 had involvement of the phrenic nerve. mean date of initial assessment within specialist centre was 10.5 months post onset (range 4-38). at this time 7 had upper limb paralysis (4 right, 3 left) and 1 had bilateral lower limb paralysis. following consultation, 1 declined surgical intervention and 2 are awaiting surgery. 5/8 patients have proceeded to surgery: 4/5 cases presented with three-or-more nerve root involvement. 10 nerve-transfers have been performed (median 2 per patient). no surgical complications were encountered. early clinical functional outcomes from this cohort following surgery are currently being collated and evaluated and will be presented in full at conference. conclusion: this study supports international experience that nerve transfer surgery can improve functional outcomes in afm. the delivery of care in the nhs requires coordination and referral to specialist centres. experiences with this cohort will inform decision making and improve patient outcomes and family expectations during the next outbreak of afm. poster no. 083 a catastrophic case of acute flaccid myelitis t chakrabarty 1 , c lundy 1 , g doherty 1 , d bhattacharya 2 , p moriarty 1 , d peake 1 1 royal belfast hospital for sick children, belfast, uk; 2 royal victoria hospital, belfast, uk objective: acute flaccid myelitis (afm) is a rare but serious neurological condition characterised by acute onset of flaccid weakness in one or more limbs with distinct abnormalities of the spinal cord grey matter on magnetic resonance imaging (mri) and without any features suggesting an upper motor neuron disorder. in recent years, there has been a global increase in the incidence of afm associated in some cases with a non-polio enterovirus, ev-d68. the long-term prognosis in most cases remain poor. we present a severe case of afm in a 3-year-old boy with catastrophic consequences. method: retrospective review of clinical course, neuroimaging, treatment and neurorehabilitation. results: a 3-year-old boy presented with clinical encephalitis. he deteriorated over 24 hours and developed an encephalopathy, multiple cranial nerve deficits, and complete flaccid paresis requiring picu support. csf 2 weeks apart showed a resolving lymphocytic pleocytosis with increased protein (0.5 to 0.92 g/dl). serial mri brain and spinal cord showed extensive signal abnormality involving thalamus, dorsal pons, medulla, cervical cord, conus along with cauda equina. nerve conduction studies were consistent with a severe acute motor axonal neuropathy. eeg showed a posterior dominant encephalopathy. infective (including edv-68), metabolic, immunological (aqp4 and mog abs) and genetic (ranbp2) tests were negative. immunomodulation therapies (methylprednisolone, ivig, and plasma exchange) resulted in no clinical improvement. resolution of signal changes in the thalami, brainstem and spinal cord along with mild generalised cerebral atrophy was noted in repeat mri after 3 months. 10 months following presentation he remains fully ventilated with no significant motor improvement despite intensive rehabilitation including use of passive range of movement devices and functional electrical stimulation. conclusion: this is one of the most severe cases of afm, representing the wider spectrum of afm involving encephalopathy, dominant bulbar signs and quadriparesis. mirror movement disorder (mmd) is a rare movement disorder with a prevalence of less than 1 in a million in which involuntary symmetrical movement is observed in the limb contralateral to the voluntary limb movement. we report 2 children with an mmd. case 1: a 15-year-old girl following an uneventful pregnancy and normal delivery, born to nonconsanguineous parents presented with difficulties with fine motor activities like writing. parents noticed from age of eight that her left hand would make similar movements to her right hand in activities like writing, combing etc. maternal grandfather has mmd. case 2: a 9-year-old girl following an eventful pregnancy and normal delivery to non-consanguineous parents presented with an mmd at age of 5 years first noticed whilst writing and this continues affect her activities of daily living. there is no family history of mmd. both children are neurodevelopmentally normal and have normal mri brain and spine. mmd have been described congenitally due to prenatal insult before 28 weeks gestation, kallman syndrome and klippel-feil syndrome or as an acquired due to hemiplegic stroke and parkinson's disease in adults. pathogenesis is thought to be due to lesions in supplementary motor area, corpus callosum or cervical lesions. mutations in dcc and rad51 gene are present in 35% of the cases. the multimodal mri and neurophysiological studies have revealed that the motor system is completely disorganised with abnormal crossing at brain stem level and abnormal communication between both brain hemispheres in these children. there is a positive family history in some cases. the upper limbs are commonly involved. diagnosis is usually clinical and treatment is symptomatic with support at school and limiting repeated complex and sustained movements involving both hands. poster no. 085 acute spinal cord infarction in children: a review of the presentation, aetiological investigations and outcomes in 6 children m shehata, ar hart, cd rittey, e davies department of paediatric neurology, sheffield children's hospital nhs foundation trust, sheffield, uk aims: acute spinal cord infarction is poorly understood in the paediatric population. we reviewed cases presenting to a single paediatric neurology centre in uk between 2010 and 2019 to explore common themes of presentation, aetiology and outcome. material and methods: cases of spinal cord infarction presenting to a single centre were identified from our spinal database and medical records were reviewed to determine clinical presentation, aetiological investigations, management and outcomes. results: six children/young people were identified, 2 male, 4 female, age range 3 to 14 years. 4 participants presented with symptoms after seemingly trivial movements or trauma, including: being kicked in the back whilst playing football, bending forwards to tie hair up, getting up to walk in the garden, and performing a crab gymnastic movement. 2 had no obvious precipitants. initial presentation was neck or back pain in all patients, progressing to bilateral lower limbs weakness, sensory deficit, lost reflexes, and urinary/bowel involvement. mri imaging failed to reveal the diagnosis when performed early in 1 participant. the level of lesions for each participant were: t2-3; t2-6; t2-t12; c2-t6; c1-t8; and isolated to the conus. aetiological investigations, including thrombophilia screens, failed to reveal a cause in any participant. 2 initially received steroids because the differential diagnosis included an inflammatory disorder. 2 patients received aspirin, 5/6 gained motor improvement but none returned to normal. all had residual bladder problems, 5 had bowel sequelae. conclusions: spinal cord infarction may be related to minor trauma or movements. the association with a chiari 1 malformation is previously described in adults. outcome is poor. although motor improvement can be seen, children do not return to normal functionally. aetiological investigations and treatments vary within a single centre. national recommendations are required to standardise practice. cost of care for long-term ventilation patients r belderbos, v kumar, l alkhalidi east lancashire nhs trust, lancashire, uk background: advances in neonatal and paediatric intensive care have increased the survival of children with life threatening or life limiting conditions. there has been a significant rise in children on long-term home invasive ventilation. high profile cases have been in the media recently with debate on whether such interventions should be implemented focussing on ethics but without evidence of cost benefit analysis. children on long-term invasive ventilation are a high cost group with complex and varying underlying medical conditions requiring input from multiple teams, including 24 hour carers, medical and multidisciplinary team input as well as recurrent hospital and picu admissions. in addition, the cost of equipment and drugs makes this a costly intervention. in any limited healthcare system rationing decisions have to be made: drug and other therapies are subject to health economic analyses. this study aims to assess cost per annum for ltv and a cost benefit analysis. objective: identify patients on ltv including comorbidities. assess cost of ltv to quantify cost-benefit analysis. measure outcomes: death/admissions/recovery. methods: review of patients requiring home long-term invasive ventilation july 2009-july 2019. analysis of costs: clinic visits, hospital admissions, costs of equipment; cost of medication. outcomes and quality of life: mortality, admissions and length of stay; decannulation, ability to communicate and mobility analysis; ability of parents to work. results: 9 patients: 3 died (aged 1, 7 and 15y), 4 decannulated, 3 ongoing ltv (aged 15mo, 19 and 22y), 5 night package £140 000 pa, accessories £12 000 pa, replaceables/service £92 000, average cost home ltv around £350 000 pa. conclusions: ltv ventilation is an expensive treatment: its use should be analysed on a cost benefit analysis in a similar way to other available treatments. objective: to assess the feasibility of recruiting to a study, performing and interpreting aeeg in preterm infants, and to assess family and staff members' views. methods: a prospective feasibility study. 7 preterm neonates between 26 and 30 weeks postmenstrual age were recruited for continuous aeeg monitoring using adhesive electrodes whilst receiving nicu care. we studied optimal methods of attaching leads, impedance data, number of electrode changes, and preliminary aeeg findings. staff and parents were asked for feedback on the process and their involvement. results: we recruited 36.8% of eligible babies. nuprep and sorbaderm were the most effective combination for skin preparation. the aeeg recording was good quality if staff were engaged and knew when electrodes needed to be changed. four of the seven (57.1%) babies showed seizure activity on aeeg, none of which were diagnosed clinically. babies with seizures were born earlier, had lower birthweights, and had more complications than babies without seizures. feedback showed parents and staff were positive, although staff reported caring for the baby was harder. 75.0% of parents and 87.5% of staff would 'definitely' recommend the study to parents with a premature baby. conclusions: the use of continuous aeeg in preterm neonates in feasible, with similar recruitment rates to other studies in the department, and a positive experience for parents and staff. a high rate of electrical seizures was detected. background: the 'magnetic resonance imaging (mri) to enhance the diagnosis of fetal developmental brain abnormalities in utero' (meridian) study showed improved diagnostic accuracy and confidence for detecting fetal neurological abnormalities compared to ultrasound. the additional information provided by in utero mri altered prognosis in 44% of women. the meridian study did not report whether the neuro-developmental prognoses given to women varied between clinicians or were accurate. objectives: to assess the variation in prognosis given to pregnant women by clinicians in feto-maternal units for 5 different fetal brain abnormalities. methods: we contacted one clinician at each of the meridian feto-maternal units and asked what percentage chance of normal neuro-developmental outcome they would give pregnant women for 5 fetal neurological abnormalities: isolated ventriculomegaly 10 to 12 mm; unilateral hypoplasia of the cerebellar hemisphere, isolated hypoplasia of the cerebellar vermis, isolated cisterna magna, and isolated blake's pouch cyst. respondents were asked to give a percentage chance of normal outcome, although some used free text to answer. results: responses were received from 14 senior obstetricians in 14 feto-maternal units. there was general agreement for isolated mild ventriculomegaly with respondents replying that 90 to 95% would have normal developmental outcome. wider variation was seen for posterior fossa abnormalities, with the suggested chance of normal outcome for one condition ranging from 10 to 90%. conclusion: estimating long-term neuro-developmental outcome based on antenatally detected neurological abnormalities is challenging due to limited high-quality data. our data highlights there is high variation in outcomes offered by different clinicians for the same abnormality. further work is needed to determine what advice is given by obstetricians on the potential developmental outcomes of a wide range of fetal brain abnormalities in current practice, how well these agree with published evidence, and whether the involvement of paediatricians with experience in neuro-developmental disorders improves prognostication. background: in-utero mri (iumri) detects fetal brain abnormalities more accurately than ultrasonography (uss) and provides additional clinical information in around half of pregnancies. there is little published data on whether postnatal neuroimaging beyond 6 months of age changes the diagnostic accuracy of iumri nor its ability to predict developmental outcome. methods: families enrolled in the meridian study whose child survived to 3 years of age were invited to have a case note review and assessment of developmental outcome with either the bayley scales of infant and toddler development, the ages and stages questionnaire or both. a paediatric neuroradiologist, blinded to the iumri results, reviewed the postnatal neuroimaging if the clinical report differed from iumri findings. diagnostic accuracy was recalculated. a paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iumri and uss to predict developmental outcome were assessed. results: 210 participants had case note review, of whom 81 (38.6%) had mri after 6 months of age. the diagnostic accuracy of iumri remained higher than uss (absolute differ-ence=25%, 95% ci 21% to 29%, p<0.0001). developmental outcome data was analysed in 156 participants: 111 (71%) were normal, of whom 56 (51%) had a normal or favourable prognosis on uss and 76 (69%) on iumr (difference in speci-ficity=18%, 95% ci 7% to 29%, p=0.0008). no statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity=4%, 95% ci -10% to 19%, p=0.727). conclusions: iumri remains the optimal tool to identify fetal brain abnormalities. it is less accurate at predicting developmental outcome, although iumri is better at identifying children with normal outcome than uss. further work is needed to determine how the prognostic abilities of iumri can be improved. poster no. 090 introducing hypothermia or not decision algorithm (honda) guideline in the assessment of neonates following hypoxic insult at birth in a district general hospital a sproule, j courtney, m mcgowan ulster hospital, belfast, uk introduction: hypoxic-ischaemic encephalopathy (hie) accounts for up to 30% of cases of cerebral palsy. hie can be caused by multiple events and occurs in 2/1000 births. hypoxic insult at the time of birth can result in an encephalopathic state characterised by: need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. the toby study demonstrated that induction of moderate hypothermia within 6 hours of birth for 72 hours duration in infants who had perinatal asphyxia resulted in improved neurologic outcomes in survivors. therapeutic hypothermia is the only proven neuroprotective treatment for hie. an assessment tool was required as there was no standard proforma for neurological assessment for babies with a low cord ph (<7.1) in our district general hospital (dgh). this was to ensure that all infants who met the toby criteria received the appropriate treatment within the recommended timeframe. methods: the honda assessment tool was developed for use in the tertiary neonatal intensive care unit. this assessment tool was adapted to use in a dgh as a guideline. the honda included the criteria from the toby study with a user-friendly flow chart. a comprehensive neurological examination is outlined with text and images to ensure reliable and repeatable findings by different clinicians over time. results: the honda tool ensured a standard algorithm was used to assess those infants who had a hypoxic insult at birth. it has standardised record keeping and repeated neurological examination of at-risk infants. conclusions: the honda is a comprehensive and userfriendly algorithm to ensure those infants who meet requirement for therapeutic hypothermia are being appropriately identified and treated. poster no. 091 foetal exposure to misoprostol and mobius syndrome s tilib-shamoun, a siddiqui, v ramesh king's college hospital, london, uk background: mobius syndrome is a rare condition comprising a collection of specific congenital anomalies, usually congenital lower motor neuron 6th and 7th cranial nerve palsies. hydrocephalus, cerebellar hypoplasia, orofacial and limbs deformities have been reported in some. the literature links mobius syndrome to early foetal exposure to misoprostol, a synthetic prostaglandin e analogue widely used for medical termination of pregnancy. for abortions it is used by itself or with the anti-progestogen mifepristone; the combination is 97% effective during the first trimester of pregnancy. the mechanism by which misoprostol disrupts brainstem development resulting in hypoplasia or absence of central brain nuclei is not elucidated as yet. suggested mechanisms include selective vulnerability to hypo-perfusion and ischaemic injury of the foetal brain stem due to direct disruption of the foetal vasculature or to global foetal hypoxia because of uterine contractions and placental ischaemia. clinical case: we report a case of an infant with known exposure to misoprostol from failed medical termination of pregnancy (top) at 12 weeks gestation, who presented with an abnormally increased head circumference, multiple lower motor neuron cranial nerve palsies (7, 11 and 12th cranial nerves). his mri scan showed hydrocephalus due to cerebral aqueduct stenosis, inferior vermian hypoplasia and loss of bulk of the right facial collculus of the pons. conclusions: it is vitally important to counsel expectant mothers following exposure to misoprostol and failed top of possible congenital anomalies if the woman elects to continue with the pregnancy. poster no. 092 neurological examination in unwell neonates: health care professionals' perspectives a fadilah, ar hart department of paediatric neurology, sheffield children's hospital, sheffield, uk objective: to explore health care professionals' opinions of neurological examination in unwell neonates. methods: a questionnaire designed to assess views on examining unwell neonates neurologically was distributed to all uk neonatal and paediatric neurology units. questions included likert scales, with scores ranging from 0 to 6. scores of 4 to 6 were taken to be positive, 1 to 3 negative or equivocal. answers were compared between consultants and other staff members using chi-squared testing, with p<0.05 assumed statistically significant. results: 192 responses were received, although not every question was answered. 106/192 (55.2%) responders were based in general paediatrics, 60/192 (31.3%) in tertiary neonatal units, and 18/192 (9.4%) in paediatric neurology. 92/192 (47.9%) were consultants. 59/192 (30.7%) performed a neurological examination in all unwell neonates, 114/191 (59.7%) in most. 84.8% of consultants felt confident performing a neurological examination, compared to 57.0% of other health care professionals (p<0.05). consultants were also more confident at interpreting the results and using them to formulate management and prognosis (all p<0.05). 140/192 (72.9%) did not find a high-quality neurological examination documented routinely in medical notes of half or more unwell neonates. 86/167 (51.5%) reported using the classical neurology examination adapted for neonates, 22 (13.3%) used the hammersmith neonatal neurological examination or an adapted version. the most difficult aspects were fundus and cranial nerve examination. the most frequently cited challenges were: effect of medication; difficulties in interpretation; equipment and lines; experience; time limitations; and risks of handling unwell neonates. 124/171 (72.1%) wanted a new standardised neurological examination for unwell neonates; 9 (5.2%) did not. conclusions: non-consultant grade health care professionals feel less confident performing a neurological examination in unwell neonates. all responders highlighted a number of challenges to performing and interpreting the results. around three-quarters of responders want a new, standardised neurological examination for unwell neonates, which could address these challenges. use of re-standardised griffiths scales of child development (3rd edition) in a healthy cohort at 4 to 5 months of age objective: the griffiths scales of child development (gscd) is an established tool for the developmental assessment of children from birth to 6 years. in 2016, the gscd underwent significant revisions, and was re-standardised using contemporary cohorts. to date, no studies have reported on its use in healthy children post-marketing. our aim is to examine the use of the gscd-iii in a healthy population of infants aged 4 to 5 months and to provide the first published data on the use of the revised griffiths-iii. methods: in a prospective observational study of healthy, fullterm infants, participants were recruited into a randomized controlled trial of infant massage. griffiths iii assessments were performed by aricd-trained practitioners across 5 subscales and a general development quotient (gd) at 4 to 5 months. results: 178 children were considered in the analysis, male: female ratio 101/77. mean (sd) birth weight was 3.53 (0.46) kg and mean birth gestational age was 39.8 weeks (sd 1.22). mean (sd) age at assessment was 4.5 (0.3) months, with 98 (55.1%) children being assessed according to 4/12 rounded norms, and 80 (44.9%) to 5/12 norms. no difference was found in either arm of the study in any subscale. scores were considerably greater than average (dq 90-109) in all subscales but particularly subscales b, d and gd. mean (sd) developmental quotients (dq) in a=121.0 (15.9); b=130.7 (11.6); c=119.0 (9.7); d=127.0 (8.4); e=123.3 (11.1) and in gd=128.3 (10.1). using the published cutoffs, we found that 97.2% (n=173) of our cohort scored 'above average' or greater in gd. conclusions: we have provided the first data on the use of griffiths-iii in a healthy cohort. scores were higher than expected across all sub-scales. this may be due to the characteristics of our cohort but raises concern that griffiths-iii may overestimate ability in young infants. objective: metabolic investigations are important in the investigation of children with disordered development. the aim of this audit was to determine if paediatric metabolic investigations were ordered as per current best practice evidence at tallaght university hospital, dublin, republic of ireland. methods: we used recommendations from seven publications to guide this audit and identified indications for performing metabolic investigations. we reviewed metabolic investigations sent on paediatric patients at tallaght university hospital from 1 january 2018 to 31 december 2018. we identified the clinical indication for investigating patients by reviewing dictated clinic letters available on the hospital intranet and confirmed investigation results by reviewing scanned copies available on the hospital intranet. we compared the indications for metabolic investigations with published expert guidelines. results: metabolic investigations were performed on 254 patients from 1 january 2019 to 31 december 2018. six patients had inconclusive results and were referred to the metabolic team at temple street children's university hospital dublin for further assessment. there have been no metabolic diagnoses made to date as per tallaght university hospital dictated letters. of the 254 patients, 104 had a diagnosis of autism spectrum disorder (asd). of those with asd, 33 had a confirmed or suspected intellectual disability. 158 patients (62%) met best practice recommendations for metabolic investigations. of the 96 patients who did not fulfil recommendations, 71 (74%) were for children with asd. conclusions: we identified two areas that could improve patient care by optimising diagnostic yield and improving resource utilisation at the hospital. first, we recommend clinicians send targeted investigations and avoid blanket investigations for children with disordered development, including asd. second, we recommend clinicians include relevant clinical details on request forms to improve diagnostic yield. finally, we question the value of metabolic investigations for intellectual disability in the absence of other clinical risk factors or comorbidities and suggest this requires further study. the early developmental course of babies with sturge-weber syndrome n thapa 1 , t fosi 2,3 , v siyani 3 , j sloneem 3 , h richardson 3 , s aylett 2,3 1 university college london medical school, london, uk; 2 ucl great ormond street institute of child health, london, uk; 3 neurodisability, great ormond street hospital, london, uk background: sturge-weber syndrome (sws) is a rare neurocutaneous condition which arises from a mutation in g protein subunit alpha q. the hallmark is leptomeningeal angiomas often associated with a facial port-wine birthmark. seizures, stroke-like episodes and hemiplegia are common clinical presentations. objective: to describe clinical features of infants with sws under 3 years and their developmental trajectory in relation to seizure onset. methods: a retrospective case note review was conducted on 90 children aged below 3 years with sws under clinical review at our centre. the medical history and standardised developmental test results (language, cognition, motor and visuospatial skills) contained in patients' assessment reports were analysed. results: common clinical features of children with sws aged under 3 years were: seizures in 81 patients (90%), hemiplegia in 52 patients (57.8%) and glaucoma in 42 patients (46.7%). their developmental trajectory was a decrease in the mean percentiles (for language, cognition and motor skills) and mean developmental quotients (for visuospatial skills) over the first 36 months. infants with unilateral brain involvement had significantly higher cognitive percentiles than those with bilateral brain involvement (p<0.01), but both groups showed the aforementioned pattern. children with epilepsy had worse language (p=0.039) and cognitive outcomes (p=0.004) than children without seizure onset. there was seizure onset in the first year in 62 infants (78.5%). in these patients, earlier seizure onset was associated with a higher language percentile (p=0.041) at age 36 months or at the time of seizure onset. conclusions: following treatment of early seizures in sws language recovery appears to occur over time relative to cognition. the functional plasticity of language might account for these observations. it is proposed that seizure prevention and optimal seizure control in the crucial first year of life will benefit cognitive and language development in patients with sws. objective: rett syndrome (rtt) is a rare neurodevelopmental disorder primarily affecting females, characterized by loss of speech, stereotypies, abnormal hand movements, motor and cognitive impairment. diagnosing rtt before regression occurs remains a challenge and there is an increasing interest in early diagnosis, due to the ongoing gene therapy clinical trial in rtt. methods: retrospective case notes review. the patient was born at term after induction of labour for reduced movements, with meconium-stained liquor, but was well. poor crying and suck noted at birth with gradual deterioration of feeding, with frequent chest infections, necessitating peg-feeding at 6 months. peripheral/axial muscle weakness and hypotonia were noted at this time. mri brain showed mild underopercularisation of sylvian-fissures; thin corpus-callosum. mrs, mri spine, echocardiogram, and eeg were normal. vitamin b12 deficiency was found, treated with hydroxycobalamin. sleep study showed hypoventilation with frequent apnoeas and low respiratory rate, leading nocturne bipap. emg was myopathic. muscle biopsy showed marginal loss of complex-i activity in the respiratory-chain-enzymes analysis. results: videofluoroscopy showed delayed swallow and disorganised pharyngeal stage leading to peg feeding. over the following months, no regression noted but only minimal motor progression seen; she was interactive and smiled. at 12 months, regression in her motor abilities was notedshe stopped fixing, following and smiling with progressive microcephaly and hand writhing movements. eeg showed epileptic encephalopathy with tonic/myoclonic jerks. whole-exomesequencing showed a de-novo pathogenic mutation in the mecp2 gene (nm_004992.3:c.1157_1200del,p.[leu386fs] ) and the diagnosis of rtt was confirmed. after 3 months, she restarted smiling and fixing/following and making motor progress but continues to have seizures. conclusions: this case illustrates early-onset features in atypical rtt with central breathing abnormalities, bulbar insufficiency, generalized hypotonia before regression. evidence of mitochondrial dysfunction is in keeping with recent reports suggesting neuronal redox imbalance in rtt as one of the disease pathogenic contributors. objective: neurodegeneration with brain iron accumulation (nbia) comprises a group of rare genetic disorders characterized by progressive extrapyramidal and other neurological symptoms due to focal iron accumulation in the basal ganglia.1 b-propeller protein-associated neurodegeneration (bpan) is the most recently identified subtype of nbia caused by heterozygous variants in wdr45 at xp11.23. we report a new subtype of bpan caused by a de novo wdr45 variant in a 6-year-old girl. methods: case report on a new subtype of b-propeller proteinassociated neurodegeneration (bpan) caused by a de novo wdr45 deletion in a 6-year-old girl and review of the literature. results: we report a 6 year old girl with bpan due to a large (5824 bp) de novo chrx:g.48,930,034_48,935,858del (hg19) deletion in wdr45, presenting with early-onset global developmental delay, hypotonia, seizures, and speech apraxia. the patient presented at the age of 10 months with hypotonia and motor developmental delay, following a normal birth history, and at 14 months developed complex partial seizures and later on steroid-responsive electrical status epilepticus of slow-wave sleep (eses). she has made minimal developmental progress and has remained profoundly globally developmentally delayed and cognitively impaired, and has still not achieved independent ambulation. conclusion: we have described the clinical, neurophysiological and neuro-imaging findings in a 6-year-old girl, the unique combination of which may assist in the diagnosis of further similar cases. bpan is an exceedingly rare, severe and debilitating disorder with a broad spectrum of clinical heterogeneity and variable age at presentation with early-onset symptoms. early detection and diagnosis are very important in order to offer proper genetic counselling to affected families and provide symptomatic treatment to patients. next-generation broad-spectrum genetic analyses will enable early detection of bpan in the paediatric age group in order for patients to be diagnosed prior to reaching adulthood. introduction: how to measure the effectiveness of an early intervention program in low resource setting. can assessments lead to interventions? and with improvements leads to new interventions, can new assessment lead to new interventions? can this system be measured for its effectiveness and improved based on feedbacks and results? an attempt to set up child development centres in low resource countries using software, apps and e-learning. method: 5 years of data in early interventions was analysed in lucknow, india. in phase 1, 527 children with non-progressive neurological problems were given best available local interventions. only 8% compliances and improvement were seen. based on the feedback algorithms were written to create individual profile of children based on their skills (uk curriculum of excellence), disability score, information processing preference, educational and behaviour problems. based on the score each child generates an individualised profile and an intervention plan delivered by app for parents (p-bac-drv) and app (t-bac-drv) at child development centres. the assessment is repeated every 2 months and new individualised profile is generated with new set of intervention. in total more than 2000 interventions are developed, and the algorithm helps in deciding which main areas to target at one time. result: the current system in low resource settings have either no service or results are close to 10% prevent disability in non-progressive neurological problems. our system has shown to prevent disability in about 60% of children. supported by government start up initiative the program has won in top 40 data innovations in india. conclusion: use of technology to provide training, exams and support professionals in the low resources areas is the solution to provide effective services. pattern recognition is the key delivered by software and auto audits has been placed to measure and improve the system. introduction: medical advances in the treatment of cns tumours has enhanced survival but also impacted on levels of residual morbidity and participation. service provision has not increased alongside the improvement in survival, with many patients not being able to return to their previous level of activity and participation following their oncology treatment. nice cancer services for children and young people 2014 state: 'children and young people who have had a central nervous system malignancy should receive a specialist neuro-rehabilitation care package'. robbie's rehab, a charity funded physiotherapy service embedded within the southampton children's hospital therapy service, launched june 2017, provides supplementary physiotherapy for children diagnosed with brain and spinal tumours under the care of southampton children's hospital. objective: to accurately identify and quantify the need for this service. method: prospective data was collated and reviewed june 2017-may 2019. results: year 1: 30 patients; year 2: 32 patients. 94 new episodes of physiotherapy (average 3.9 per month), 303 direct clinical contacts. reasons for accessing the service: need for enhanced intensity of rehabilitation on discharge (n=23), enhanced inpatient rehabilitation (n=18), bridge the gap whilst awaiting community services (n=11), change in symptoms (n=12), pre-op assessment (n=5), support for palliative care planning (n=7), support for complex social and emotional needs (n=8), disease progression (n=7), higher level rehabilitation not fulfilling community criteria (n=12), facilitate access to local exercise facilities (n=13), within oncology clinic for assessment/one-off treatment (n=8), post-op assessment (n=11), individualised goal orientated participation (n=4). 8 patients had an estimated 2 weeks reduction in acute bed days. conclusions: robbie's rehab referrals are for a variety of multifactorial reasons with rereferral often needed within their pathway. it has enabled earlier discharge, improved transition to community services and opportunities for therapy access previously not available. results: our proband presented at 5 weeks with marked stridor and bulbar weakness after a normal pregnancy. he subsequently developed respiratory failure requiring nocturnal bipap and was found to have a type i laryngeal cleft. initially he met developmental milestones but at 5months developed features of axial weakness with further regression at 9months with limb weakness and loss of deep tendon reflexes. emg confirmed denervation in genioglossus, as well as proximal and distal limb muscles without evidence of neuropathy. genetics for smn1 gene and smard were negative. inherited peripheral neuropathy 56 gene panel testing identified a heterozygous missense variant c. 631t>c, p.(cys211arg) in exon 5. the variant is predicted to alter a highly conserved amino acid, has not been reported before and has not been identified in control databases. in silico prediction tools supports the pathogenicity of the variant. mutagenesis of the equivalent amino acid in mice produces impaired motor control and denervation. conclusions: the gars gene encodes an ubiquitously expressed glycyl trna synthetase which has an integral role in protein synthesis in all eukaryotic cells. missense gars mutations can lead to distal hereditary motor neuropathy as well as a sensorimotor neuropathy phenotype (cmt2d) typically with adolescent or early adulthood onset. objective: to discuss sma, which is one of the differentials in a hypotonic child and bring to light the diagnosis is not always cerebral palsy (cp). method: descriptive case report. results: case 1: 4-month-old girl admitted to icu with severe pneumonia. case 2: 9-month-old boy, both admitted to the intensive care unit with severe pneumonia. case 3: 15-month-old girl, presented to outpatient with progressive 'floppy' limb weakness and swallowing and breathing difficulties. case 4: attended opd with worsening respiratory distress, difficulty feeding, difficulty managing secretions. all 4 had perinatal histories of uncomplicated deliveries but subsequent early respiratory distress and oxygen requirement for the first few days of life. all had been 'floppy' since birth, with severe gross motor delay, feeding difficulties, poor weight gain and recurrent chest infections. cases 2, 3 and 4 had been diagnosed with cp despite having normal neuroimaging. examination of all 3 children was similar and consistent with clinical diagnosis of sma. findings included an alert, interactive child; frog-legged posture; 4-limb hypotonia and weakness with legs more affected than arms; absent deep tendon reflexes; bell-shaped chest; and tongue fasciculation. genetic testing for all confirmed homozygous deletion of exon 7 of the smn1 gene. in all the cases creatinine kinase levels were normal, ruling out myopathy. conclusions: the incidence of sma is 1/10 000 livebirths. it can be diagnosed clinically from pathognomic features when genetic testing is unavailable and should be considered in any hypotonic child, irrespective of perinatal history. a wide clinical spectrum that ranges from early death to near-normal adult life exists. families must be counselled regarding implications of this genetic diagnosis. correct early diagnosis and multidisciplinary intervention can vastly improve outcomes. poster no. 102 syros studylong-term reduction in rate of respiratory function decline in patients with duchenne muscular dystrophy (dmd) treated with idebenone l servais 1 , c lawrence 2 , oh mayer 3 , cm mcdonald 4 , u schara 5 , t voit 6 , e mercuri 7 , gm buyse 8 respiratory function decline in dmd is caused by the underlying weakness and degeneration of the respiratory muscles leading to impaired inspiratory and expiratory effort and associated complications. idebenone reduced the rate of respiratory function decline over 52 weeks in the phase iii delos trial. syros is a long-term study in former delos patients who transitioned to idebenone under expanded access programs following a variable untreated period. here, we aimed to characterize the long-term effects of idebenone on respiratory function. patients were managed according to routine clinical practice. respiratory function was assessed by calculating the annualized decline in forced vital capacity (fvc) and peak expiratory flow (pef), expressed as percent predicted (%p). comparisons were made between treated and untreated periods and to matched external controls. data on bronchopulmonary adverse events (baes) and hospitalizations were collected. data from 18/64 former delos patients were available. at delos baseline, mean (sd) age and fvc%p were 13.3 (2.7) years and 58.7% (17.6%); all patients were glucocorticoid non-users and 83.3% were non-ambulatory. patients were treated for an average (min-max) of 4.2 (2.4-6.1) years compared to an average untreated period of 2.1 (1.1-5.5) years. the annual rate of fvc%p decline was almost halved (3.8% vs 7.4%) when comparing these periods. for the external comparisons, declines remained lower across all treatment years (up to 6y) compared to the matched group of untreated patients. comparable results were seen for pef%p. the risk of baes was reduced by 68% during longterm idebenone treatment versus untreated periods, leading to fewer hospitalizations due to respiratory causes (0.06 vs 0.15 events per year). long-term treatment with idebenone results in a consistent and sustained reduction in the rate of respiratory function decline for up to 6 years. two placebo-controlled trials of 52-week duration (phase ii delphi, phase iii delos) showed that idebenone consistently reduced respiratory function decline rate in patients with advanced dmd. long-term data from the delphi-extension (delphi-e) study and syros (delos patients who transitioned to idebenone under an expanded access program) are now presented. the aim was to assess the consistency of the long-term effect of idebenone on respiratory function across both placebo-controlled trials and their respective long-term data collections. 11 delphi-e and 18 syros patients with abnormal (<80%) forced vital capacity (as percent predicted, fvc%p) were treated with idebenone for an average of 2.0 and 4.2 years respectively. annualized fvc%p decline rates were compared to untreated patients from syros or matched external controls (matched for baseline fvc%p) from the cinrg duchenne natural history study (cinrg-dnhs). mean (sd) baseline age was 13.6 (2.3) and 13.3 (2.7) years in delphi (n=11) and delos (n=18), respectively, and fvc%p was 47.2% (19.7%) and 58.7% (17.6%). for the first 2-year period, where data were available for both studies, the average annual decline rate was comparable in treated patients (4.5% and 5.4% in delphi-e and syros) and lower than in untreated syros patients and external controls (7.9% untreated and 8.1% in cinrg-dnhs). during years 3 to 6, the annual decline rate was consistently lower than for matched controls. treatment with idebenone resulted in a sustained reduction in the rate of decline in respiratory function across both placebo-controlled 52week studies and across both long-term data collections, with follow-up time of up to 6 years. the consistency observed across 2 independent datasets adds to the robustness of the treatment effect of idebenone and its potential to modify the course of respiratory function decline in dmd. poster no. 104 a rare mutation in dync1h1 causing a mixed clinical phenotype of spinal muscular atrophy with lower extremity predominance and hereditary spastic paraplegia: a case series in a family el goh 1,2 , s jayawant 3 , g anand 1 objective: to describe the identification of a rare mutation in the dync1h1 gene as a cause of a mixed clinical phenotype of spinal muscular atrophy with lower extremity predominance (sma-led) and hereditary spastic paraplegia (hsp). methods: case series of three family members (father and two sons) across two generations. results: there was a history of early childhood-onset, progressive lower limb muscle weakness and atrophy. no relevant family history of neuromuscular disorders was reported on both the paternal and maternal sides of the family. examination revealed markedly diminished tone and power in the lower limbs, with wasting and a positive crossed adductor reflex. there were no abnormalities detected in the upper limbs and sensation was preserved throughout. neurophysiological testing showed moderate to severe chronic denervation of the lower limb muscles with sparing of the peripheral sensory nerves. hsp panel was negative but charcot-marie-tooth (cmt) panel demonstrated a heterozygous sequence change in the dync1h1 gene: c.1808a>t p.(glu603val), which was present in all affected family members. discussion and conclusions: mutations in the dynein gene are typically associated with sma-led or cmt. a mixed sma-led and hsp phenotype has previously been shown to be caused by mutations in bicd2. bicd2 encodes a golgin, which is a component of dynein-based transport, and plays a key role in mrna transport during oogenesis and embryogenesis. we present the first case series of a mixed clinical phenotype of sma-led and hsp occurring due to a mutation in dync1h1. this was the first observation of the c.1808a>t p.(glu603val) variant at our laboratory and was not listed in the genome aggregation database, suggesting an extremely rare variant. opening the lid on unilateral ptosis in paediatric nf1 e hassan 1 , e witter 1 , z mughal 2 , l robinson 3 , d weisburg 3 , sa roberts 4 , e hupton 3 , j eelloo 3 , e burkitt wright 3,5 , s garg 3 , l lewis 3 , dg evans 3,5 , sm stivaros 3,6,7 , g vassallo 1,3,5 introduction: neurofibromatosis type 1 (nf1) is a genetic disorder with a birth incidence of 1 in 2-2700 individuals and prevalence of around 1 in 4000 worldwide. ptosis is a welldocumented feature in this condition and is known to be associated with plexiform neurofibromas or in the noonan phenotype, with bilateral ptosis. unilateral ptosis in the absence of a plexiform neurofibroma is not a common feature in nf1. we describe a number of patients with nf1 who demonstrated unilateral ptosis. methods: a retrospective cohort study was carried out using the patient database within the nf1 service based in st mary's hospital, manchester, uk. children and young adults aged 2 to 18 years with nf1 were identified via the patient database and patients with a presentation of ptosis were identified. results: six children with unilateral ptosis were identified, four females and two males (ages 2-18, mean=9.5y). five had unilateral ptosis affecting the right and one the left, with no differences observed between sporadic or familial disease. five patients had complex disease; however, none had any other associated complication to account for the unilateral ptosis apart from nf1. they did not meet the diagnostic criteria for noonan syndrome, and none had plexiform neurofibromas in the orbital or peri orbital area. discussion: it is unclear why there is an increased incidence of unilateral ptosis in our cohort of nf1 patients, in the absence of plexiform neurofibromas and noonan's syndrome. ptosis in nf1 has been associated with a noonan syndrome phenotype in nf1 patients. the general hypotonia and myopathy observed in these patients could also factor into the causes for ptosis. further research is necessary to investigate the aetiology of increased unilateral ptosis in nf1 patients. objective: sma is a severe neuromuscular disorder characterised by progressive muscle atrophy and weakness. scoliosis is a highly prevalent complication and surgery is almost invariably required in 'sitters'. data on secondary outcomes are limited, and this study investigates post-surgical respiratory (fvc%) and motor function, weight gain, pain and satisfaction. methods: we retrospectively reviewed the notes of 33 patients who never walked or lost ambulation (sma type ii/iii) who successfully underwent scoliosis surgery at great ormond street hospital: spinal fusion (25), magnetic (4) or traditional (4) growth rods. we performed phone interviews and run a focus group for families on pre and post-surgical satisfaction. results: median follow-up before and after surgery was 3.9 (0.9-12.3) and 3.7 (0.4-10.5) years respectively. mean annual rate of fvc% decline improved post-surgery in sma ii: -2.8 versus -7.4 (p<0.001), with similar trajectories in sma iii. mean annual rate of hammersmith functional motor scale's scores decline did not change significantly (-1.2 vs -1.6, p<0.001), while the revised upper limb module's scores showed a less progressive deterioration (-1.3 vs -2.3, p=0.07). a negative deviation from previous weight curve after surgery was observed in 17/33 requiring food supplements (5); one/4 with significant weight loss (>5% of total weight) needed gastrostomy. pain was frequently documented, especially hip pain (13/33) requiring painkillers (8), intra-articular steroids (2) and surgery (1). nine/10 families participating in the phone interview reported major improvements in posture, physical appearance, self-image; all rated the procedure as very successful. however, 7/10 did not report significant improvements in quality of life due to reduced mobility and increased unmet care needs. five families attended the focus group reporting on both positive and negative aspects of their experiences. conclusions: this study provides relevant data and suggestions to improve the current multidisciplinary approach of scoliosis surgery in children with sma. poster no. 107 sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (rg7916) treatment in patients with type 2 or 3 spinal muscular atrophy (sma) objective: spinal muscular atrophy (sma) is a severe, progressive neuromuscular disease caused by reduced levels of survival of motor neuron (smn) protein due to deletions and/or mutations of the smn1 gene. while smn1 produces fulllength smn protein, a second gene, smn2, produces only low levels of functional smn protein. risdiplam (rg7916/ ro7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates smn2 pre-mrna splicing to increase smn protein levels. sunfish (nct02908685) is an ongoing, multicentre, double-blind, placebo-controlled study (randomised 2:1, risdiplam:placebo) in patients aged 2-25 years, with type 2 or 3 sma. methods: sunfish part 1 (n=51) is a dose-finding study assessing the safety, tolerability and pk/pd of risdiplam; pivotal part 2 (n=180) assesses the safety and efficacy of the risdiplam dose level that was selected based on results from part 1. sunfish part 1 included patients of broad age ranges and clinical characteristics (functional level, scoliosis and contractures). an interim analysis of part 1 (data cut-off, 06 july 2018) showed a sustained, >2-fold increase in median smn protein versus baseline after 1 year of treatment. adverse events were mostly mild, resolved despite ongoing treatment and reflective of the underlying disease. despite not being designed to detect efficacy, risdiplam improved motor function measures over 12 months versus natural history. results: safety, tolerability and pk/pd will be reported from all patients in part 1 who have received treatment with risdiplam for a minimum of 18 months. updated part 1 exploratory efficacy data, including motor outcome measures, will also be presented. the clinical benefit of risdiplam is being assessed in part 2, which is ongoing worldwide. objective: ryr1 encodes the skeletal muscle ryanodine receptor, an intracellular calcium-release channel that is crucial to excitation-contraction coupling in muscle. gene variants can cause heterogeneous myopathies, including dominantly inherited central core disease. both autosomal dominant (ad) and autosomal recessive (ar) pattern of inheritance have been reported. methods: retrospective case notes review. results: sibling 1: female, presented during the first year of life with motor developmental delay. at 4 years of age she is able to sit unsupported and crawl but not stand or walk. she has facial weakness, but no feeding difficulties or ophthlamplegia. she has axial and proximal weakness with antigravity power in neck flexors and hip flexors (mrc 3/5) and sub-gravity power in hip abductors/extensors and knee flexors/extensors (mrc 2/5). there are severe hip, knee and ankle fixed contractures. power and joint range is normal in upper limbs. muscle biopsy showed type-1 fibre predominance and core-like structures. sibling 2: female, presented at birth with feeding difficulties. at 3 months of age she is fully nasogastric fed. there is no facial weakness or ophthlamplegia. she has good head control with active head lift in prone, and antigravity power in hips, knees and ankles. she has mild hip and knee contractures and shoulder girdle weakness. both siblings have been confirmed to be heterozygous for a ryr1 pathogenic frameshift variant (c.12063_12064dupca p.(met4022fs)) inherited from father and a likely pathogenic missense variant (c.14598g>c p.(lys4866asn)) inherited from mother. both parents are asymptomatic. conclusions: the clinical and pathological features of ad ryr1-related myopathy are well recognized but much less is known about ryr1-related disorders secondary to an ar pattern of inheritance. we report two siblings with ar ryr1related myopathy with similar genotypes but different phenotypic features demonstrating intra-familial variability and expanding current knowledge on this disorder. results: our probands were the second and third children of consanguineous irish parents who were fourth cousins. antenatally, reduced fetal movements and amniotic fluid was noted with both probands. at birth, both had arthrogryposis and the second sibling required prolonged intubation at birth. both had significant developmental delay; a more severe phenotype in the younger. on examination, both had myopathic facies, inability to bury eyelashes, full eye movements, high arches palates, drooling, a weak cry, micrognathia but a preserved suck. they both had long thin fingers, with thumbs held adducted and dimpling of elbows and hands. peripheral reflexes were absent but there were good anti-gravity movements of the lower limbs. both were noted to have pectus excavatum and progressive scoliosis. muscle biopsies showed dystrophic features of fibrosis, hypertrophy and atrophy of fibres and variation in fibre size with increased fibrous connective tissue. occasional central cords and multiple mini cords were also seen in the second proband. whole exome sequencing identified the compound heterozygote mutation (ttn c.95076delc in combination with ttn c22226c>tp. (ser7409leu) and ttn c.40405g >a p. (asp13469asn)). conclusions: mutations in the titin gene (ttn) have been implicated in several skeletal and or cardiac phenotypes to date. each individual variant of the compound heterozygote has not been reported as pathogenic mutations and have been detected in the general population at 0.7% frequency. however, the presence of the triple count may certainly account for the severe phenotype of our probands. poster no. 110 gene-replacement therapy (grt) in spinal muscular atrophy type 1 (sma1): long-term follow-up from the onasemnogene abeparvovec phase 1/2a clinical trial objective: sma1 is a rapidly progressing neurologic disease caused by biallelic survival motor neuron 1 gene (smn1) deletion/mutation. the smn grt onasemnogene abeparvovec (formerly avxs-101; approved in us) treats the genetic root cause of sma and is designed for immediate, sustained smn protein expression. in a phase 1/2a trial (start [cl-101]; nct02122952), sma1 patients received a one-time onasemnogene abeparvovec infusion at low dose (cohort 1, n=3) or high dose (cohort 2, n=12), and demonstrated improved outcomes versus natural history. no patients in start received nusinersen during the 24-month follow-up after dosing. sma1 patients in start could rollover into a long-term follow-up study (study lt-001; nct03421977). primary objective: long-term safety. methods: sma1 patients have annual visits (5y), then phone contact (additional 10y). patient record transfers are requested. safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. efficacy assessments include developmental milestone evaluation to determine maintenance of the highest achieved milestone in the parent study. results: as of 8 march 2019, 13 patients (cohort 1, n=3; cohort 2, n=10) had enrolled in study lt-001 and had a baseline visit. for patients in cohort 2, the mean (range) age and time since dosing were 3.9 (3.4-4.8) years and 3.7 (3.3-4.3) years, respectively. all patients in cohort 2 (10/10) were alive. no developmental milestones achieved in start were lost, and new milestones have been achieved, supporting the durability of onasemnogene abeparvovec. updated data will be presented. conclusions: one-time onasemnogene abeparvovec administration at the high dose continues to provide prolonged and durable efficacy with milestone development in lt-001. poster no. 111 micu1-myopathy: a mitochondrial disorder that mimics a congenital muscular dystrophyreport of 2 siblings with variable phenotypes m fernandez, m sa, v gowda evelina london children's hospital, london, uk objective: micu1 encodes a selective calcium-channel subunit within mitochondrial inner membrane whose function is essential for buffering cytosolic ca2+ transients and activating atp production. mutations in micu1 have been reported in 20 different families with muscle weakness, fatigability and developmental delay, with normal lactate despite being a mitochondrial disorder and persistently elevated creatine kinase (ck) usually in the range of congenital muscular dystrophies (cmd). the phenotypic spectrum is highly variable and keeps expandingother features include progressive extrapyramidal signs, learning disabilities, nystagmus and cataracts. we report the clinical features of 2 siblings from a consanguineous family with the homozygous c.1078-1g>c splicing mutation in micu1. methods: retrospective case notes review. results: sibling 1: boy, older sibling, presented aged 7 years. he had short stature which was investigated when found to have ck of 13 000iu/l. he complained of occasional cramps. muscle biopsy showed mild dystrophic changes with reduced alpha-dystroglycan that indicated a possible congenital disorder of glycosylation. his mri brain was normal. he was diagnosed with autism. sibling 2: girl, diagnosed antenatally with cerebellar hypoplasia, confirmed postnatally as inferior-vermis hypoplasia. presented at 5 years with occasional cramps, mild tightness of tendo-achilles, and ck of 3500iu/ l. her height and weight were on 2nd centile. muscle mri showed a small area of high signal in the left adductor magnus related to a group of normal vascular structures. neurophysiology studies were normal. no other systemic involvement was seen in either of them. next generation sequencing revealed the micu1 mutation described. conclusions: our work expands the phenotypical spectrum of micu1 deficiency and highlights the variability in patients within the same family. targeted analysis of the micu1 gene in patients with high ck levels resembling a cmd picture may be warranted, even in the absence of prominent muscle features. the role of dystrophin brain isoforms on early motor development and motor outcomes in young children with duchenne muscular dystrophy half of patients have central nervous system (cns) manifestations. two dystrophin isoforms, dp140 and dp71, play an important role in cns function. those lacking dp140 have a more severe cns phenotype, most marked in those lacking dp140 and dp71. our objective is to determine whether lack of dp140 and dp71 also has an adverse impact on early motor development. methods: the northstar ambulatory assessment (nsaa) is a scale of motor function. clinical information for 320 dmd participants was classified by dmd mutation location and effects on isoform expression as follows: dp140+_dp71+ (dp427 absent, dp140/dp71 present), dp140-_dp71+ (dp427/dp140 absent, dp71 present) and dp140-_dp71-(dp427/dp140/dp71 absentall isoforms affected). results: amongst 4 to 6 year olds, median total nsaa scores were lower in the dp140-_dp71+ (p=0.0088) and dp140-_dp71-groups (p=0.0001) than the dp140+_dp71+ group, most markedly in the dp140-_dp71-group. for example, for 6-year olds, median total nsaa scores were 26 (dp140+_dp71+), 23 (dp140-_dp71+) and 17 (dp140-_dp71-). amongst 4 to 6 year olds, a lower percentage of participants achieved a full score of 2 (normal, achieves goal without assistance) for the nsaa sub-items in the dp140-_dp71+ (p<0.0001) and dp140-_dp71-(p<0.0001) groups than in the dp140+_dp71+ group, most markedly in the dp140-_dp71-group. for example, amongst 4-year-olds, percentage of visits for which a full score was recorded for jump were as follows: 56% (dp140+_dp71+), 19% (dp140-_dp71+) and 0% (dp140-_dp71-). conclusions: in addition to the known cns phenotype, young dmd patients lacking dp140 also exhibit lower median total nsaa scores and greater early motor delay, most markedly seen in those lacking both dp140 and dp71 (lacking all dystrophin brain isoforms). this has important implications for patient prognostication and clinical trial design. background: most commonly known as a rare subtype of guillain-barr e, miller fisher syndrome (mfs) has evolved since it was first described in 1956. the syndrome is characterised by a triad of ophthalmoplegia, ataxia and areflexia but clinical variations do occur. it occurs more often in men than woman (ratio 2:1) with the average age of onset 43.6 years. mfs is associated with positive anti gq1b antibodies, which is concentrated in cranial nerves iii, iv and viexplaining the link with ophthalmoplegia. clinical case: we present an unusual case of a 2-year-old boy with background of macrocephaly and pre-existing developmental delay with a previous mri which showed mild signal change in periventricular white matter bilaterally. he was admitted with a subacute history of proximal muscle weakness and fatiguability. he had no obvious focal neurological signs apart from intermittent lid hopping and ptosis. differential diagnosis included myasthenia, demyelinating disorders or an underlying pre-existing luecodystrophy. anti gq1b antibodies were checked along with extensive metabolic investigations, lumbar puncture, muscle biopsy, anti-cholinesterase and antimusk antibodies along with repeat mri. all investigations were negative including mri which showed no significant change from previous. the only findings were strongly positive anti gq1b antibodies. in the interim, the patient was started on trial with pyridostigmine with significant clinical improvement. conclusion: atypical variants of mfs should be a differential in children with subtle eye signs without ophthalmoplegia. lid hopping and fatiguability should raise the suspicion of mfs and anti gq1b antibodies should be tested. pyridostigmine has been reported to be effective in mfs. potential utility of muscle mri in congenital myasthenia syndrome secondary to agrn mutation found on whole exome sequencing (wes) congenital myasthenia syndromes (cms) are caused by genetic defects affecting neuromuscular transmission, resulting in muscle weakness and fatigability. agrin, an extracellular matrix molecule released by the nerve is essential at the neuromuscular junction. the large coding gene agrn, has a number of exons and with increasing variants found on wes, it is time consuming and complex to undertake functional studies to define pathogencitiy. previous reports of agrn mutations have a phenotype with prominent distal leg weakness and changes in the soleus on mri. we describe a differing presentation and striking changes on mri, especially in the posterior compartment of the thigh. a 10-year-old presented with deterioration in his gait and difficulty climbing the stairs. he was born at term, via a normal vaginal delivery. his parents were consanguineous, and he had three well siblings. he was reported to walk by 2 years. on examination he had a waddling gait and was unable to run or hop. he had proximal weakness with a positive gowers sign, together with weak eye closure. muscle biopsy showed non-specific myopathic features, however an mri of the lower leg found widespread fatty muscle atrophy of the thigh and calf with relative preservation of the adductor longus, rectus femoris and semitendonosis. wes revealed an agrn mutation (c.5952_5963del) and a homozygous mutation in the nebulin gene (not felt to be clinically relevant). single fibre emg confirmed electrodecrement on repetitive nerve stimulation. the patient has been commenced on treatment with salbutamol. our patient had very distinctive changes on mri and nonspecific muscle biopsy changes. muscle mri changes prompted further genetic testing when symptoms fitted a clinical diagnosis of a congenital myasthenic syndrome. with increasing variants found of unknown significance in these patients, collation of mri imaging to try and elucidate patterns of changes will be important. mcardle disease (glycogen storage disease type v) is an autosomal recessive condition caused by pathogenic mutations in both copies of the muscle glycogen phosphorylase (pygm) gene encoding the muscle-specific isoform of glycogen phosphorylase, 'myophosphorylase' exclusively affecting skeletal muscle. it is the commonest form of glycogenosis. mcardle disease shows significant clinical variability, with symptoms ranging from mild discomfort during exercise to marked muscle weakness and rhabdomyolysis with myoglobinuria. the second wind phenomenon is unique to mcardle disease and consists of improved exercise tolerance with a decrease in heart rate after a rest. despite the majority of patients recalling symptoms during the first years of life, mcardle is infrequently diagnosed in children, 66% of patients being diagnosed after 20 years of age according to a recent review. here we report two patients diagnosed with mcardle disease at the age of 11 and 6 years respectively. case one presented with fatigue and inability to increase pace of walking from the age of 4. hills lead to earlier fatigue. she was able to participate in gymnastics and dancing. presentation was with fluctuating ck levels (700 to 28 000). she had no second wind phenomenon or myoglobinuria. case two presented at 6 years with a history from 18 months of reduced exercise tolerance and myalgia after low intensity physical activity with no evidence of myoglobinuria or second wind. on formal assessment there was no evidence of muscle weakness or functional impairment. ck was persistently raised ranging from 650 to 4000. in the light of symptoms and ck levels a rhabdomyolysis panel was requested in both cases leading to diagnosis. objectives: to explore characteristics of anxiety experienced by young males with duchenne muscular dystrophy (dmd) using: 1. qualitative analysis of focus group discussions with dmd boys and their parents. 2. parent-report scales of anxiety/emotional problems. methods: eight boys aged 7 to 18 years with dmd and 14 dmd parents participated in separate child and parent focus groups. perspectives on anxiety were elicited using semi-structured discussions, and framework analysis was applied to identify themes. scores on five parent-report scales were determined and scales were compared for content and sensitivity. results: from group discussions, six characteristics of anxiety were recurrently reported: catastrophic conclusions; rigidly held anxieties; extreme distress; unexpected/unfamiliar; social anxieties; physical changes and needs. many features echo the anxiety phenotype in autism spectrum disorder (asd). four further themes described relevant contextual factors: individual, family, social and environmental responses. from parent-report scales, younger dmd boys (7-11y; n=12) had significantly higher total, general and social anxiety scores compared to population means on at least two scales (p<0.01; p<0.01; p<0.05). the older dmd group (12-18y; n=6) trended towards higher scores in total, general and separation anxiety (p=0.10; p=0.06; p=0.051) compared to population norms. different scales varied in their diagnostic sensitivity and item content, which may influence their utility in dmd. conclusions: anxiety can be a pervasive and impactful issue in dmd. it appears to have some shared traits with anxiety in asd and may be influenced by situational factors, such as living with a disabling, life-limiting condition. screening with standard anxiety scales may not accurately capture the full spectrum of the phenotype in dmd, therefore further evaluation to determine optimal screening instruments in dmd is warranted. however, multi-modal assessments tailored to dmd are key to identifying those in need of support to optimise the mental well-being of young people with dmd. objective: as part of the clinical psychology service in paediatric neurology we developed a tic management group to support young people and their parents to develop positive coping in relation to their tics. the group combined psychoeducational, emotional regulation and habit reversal therapy (hrt) components. this evaluation aimed to establish the effectiveness of these groups in reducing tics and associated distress. method: twenty-eight children, aged 9 to 13 years and their parents attended one of seven tic management groups facilitated between february 2015 and november 2018. these children had been referred to the clinical psychology for support with tics. each group consisted of 5 weekly, 1-hour sessions with a review session 4 weeks later. a parent group was held in parallel. both the young persons and parent groups were facilitated by the clinical psychology team. homework tasks were provided to support hrt skill practice and consolidation of learning of the group content between sessions. the following pre and post group measures were completed by the young people and their parents: the paediatric index of emotional distress, the yale global tic severity scale, the parent tic questionnaire and session rating scales. measures were collated and descriptive data reviewed. results: 96% of children found the group was helpful in the management of tics. 57% of children were 'less bothered by their tics'. 70% of children felt more confident in controlling their tics. parents reported a greater understanding of tics and a reduction in the severity of their child's tics. conclusions: results indicate the tic management group is effective in building young peoples' understanding of tics, confidence in tic management whilst providing peer support. the findings also indicate that parents found the groups informative and valued the opportunity to share experiences with others. background: patients with epilepsy often have deficits in cognitive, physical, psychological and social functioning, and treatment should aim to alleviate these deficits. epilepsy surgery is considered for medication refractory epilepsy with aims to improve patient quality of life. a recent study highlighted the importance of a multidisciplinary workup prior to epileptic surgery, including a neuropsychiatric assessment. part of this assessment should identify patient expectations of epilepsy surgery, so that these can be addressed peri-operatively. at king's college hospital (kch), london, these assessments are routinely performed by the paediatric liaison service as part of the children's epilepsy surgery service (cess). aim: to analyse retrospective data of pre-operative patient and carer expectations between october 2018 -september 2019 at kch. methods: a record of patient and carer expectations is routinely recorded as part of kch cess neuropsychiatric assessments. the responses were compiled and analysed using qualitative content analysis. results: a preliminary survey of 12 cases with an average age of 11 (range 5-15) identified 15 responses that were grouped into broader classifications (cognitive, seizure experience, social process, school experience, mental state and general improvements). simple analysis showed carers most often expected surgery to reduce the need for medications (42%), ablate seizures (33%), increase school performance (25%), independence (25%) and overall quality of life (25%). this compared to child responses, where the most common expectations were a reduction in lifestyle restrictions (42%), a cure for epilepsy (33%), decrease in medications (25%) and increased independence (25%). conclusion: consideration of both child and carer expectations during pre-epilepsy surgery neuropsychiatric assessments is important in order for services to manage each individual's expectations. unmanaged unrealistic expectations may lead to a negative psychological outcome for either child or carer. expectations should be weighed up against an individual's clinical profile. poster no. 119 neural correlates of conversion hemianaesthesia in an adolescent: a novel fmri case study m ray, a zaman, t alam leeds teaching hospital nhs trust, leeds, uk aim: to highlight the novel functional magnetic resonance imaging (fmri) findings in an adolescent with rare conversion hemianaesthesia. methods: we hereby report a right-handed 14y old boy who presented with inability to perceive sensations on the right half of body without any motor weakness causing him to have frequent injuries on his right leg as well as burns on his right hand without realizing. when he wore a jacket, he felt warm on one side of the body more than the other. his birth and developmental history were non-contributory. neurological examination was unremarkable except for right hemisensory disturbance. the mri of brain and spine, peripheral nerve conduction studies and somatosensory evoked potentials did not show any evidence of dysfunction were normal. he underwent fmri on a 3t philips achieva. the paradigm consisted of stimulating both the right and left hands and feet with three dissimilar stimuli (cold, brushing, pin-prick-pain) . the order of the stimuli was pseudorandomised and after each stimuli delivery, feedback was obtained. results: both the hand and foot sensory motor cortices were successfully stimulated. irrespective of which hand was being stimulated, there was left hemisphere sensory motor cortex dominance (with the brushing and cold stimuli), however selfreport from the participant confirmed detection of stimuli on the left-side only. there was more sensory-motor activation when the stimuli were delivered to the right hand. pain stimuli successfully activated parts of the 'pain matrix', furthermore enhanced attention effects (frontal pole activations) were observed with right-sided stimulation (supports lack of stimuli detection ability). the pain stimuli were more effective on the hands than foot, reflected by increasing activation and also self-report from the participant. conclusions: the fmri findings are unique and support the evidence of neuroplasticity and the current study paves the way for future studies investigating conversion hemianaesthesia. poster no. 120 chronic paroxysmal hemicrania presenting as facial pain in a child with autism and bipolar disorder: diagnostic challenges case presentation: a boy diagnosed with disintegrative psychosis aged 3, revised to autism with bipolar disorder, had been on carbamazepine with risperidone for poor mood control. withdrawal of risperidone produced tardive oromotor diskinesia responsive to clonidine. aged 11, when mood improved on aripiprazole, carbamazepine was withdrawn. he then presented with episodes of distress preceded by withdrawal, unilateral but not side-locked facial flushing, with additional flushing of neck, back and wrists. behaviours included hitting wrists off walls, chewing of hard objects and requesting pressure to his head. episodes occurred 8-9 times/ day, lasting 2-60 minutes. he showed rhinorrhea and tearing, attributed to crying, during events. the attacks self-terminated. results: mri and electroencephalogram were normal. failed pharmacological trials included paracetamol, amitriptyline, gabapentin and oxcarbazepine. diclofenac provided mild pain relief and morphine reduced the incidence of attacks. reintroduction of carbamazepine resulted in improvement at 30mg/kg/day but did not eliminate pain. sequencing of scn9a was normal. a plan to wean morphine alongside a trial of indometacin, initially at 25mg twice-daily was successful at 50mg twice-daily. episodes ceased, including all autonomic features. exacerbation at 4 weeks occurred in context of an intercurrent illness and was managed with an additional dose of indometacin. conclusions: cph is underreported in the paediatric age group. in our case, the patient's inability to describe events, and an additional psychiatric diagnosis added complexity. the possibility of pain as a cause for early psychotic breakdown in a developmentally vulnerable child cannot be excluded. criteria emphasising side-locked headache and autonomic features, and not recognising associated symptoms elsewhere may also delay recognition in children. objectives: piih can be a challenging condition to diagnose and manage with risks of misdiagnosis, permanent sight loss and frequent comorbidities. we aimed to review our practice to identify areas of uncertainty to help formulate important questions to address within a clinical guideline. methods: a single centre retrospective case notes review of all cases referred to neurology with suspected piih (papilloedema confirmed by a consultant ophthalmologist in all cases) during an 18-month period. results: 14 (12f: 2m) cases were identified. age range 8 to 15 years. mean 13 years. 8/12 had a bmi >98th centile. one case was referred to an obesity service. 6/14 had a comorbid headache disorder and 4/14 had anxiety/depression. all cases had neuroimaging (13 mri, 1 ct) with 4/14 having dedicated venography. in 2/14 cases lumbar punctures (lp) were conducted under general anaesthesia (ga). in 4/14 cases lp was not done; 2 due to presence of a chiari malformation and 2 due to procedural failure related to body habitus. intracranial pressure (icp) monitoring was done in one of these four cases. all children were treated with acetazolamide as first line therapy. frusemide, zonisamide and topiramate were also used in single cases. 5/14 children had repeat lps due to failure of resolution of symptoms. 2/14 cases had sight threatening piih with permanent visual loss in one case. 5/14 cases were discussed with neurosurgery. one child with evolving visual failure had an emergency ventriculo-peritoneal shunt. conclusions: important questions raised were: should all obese children with piih have access to a specialised obesity service? should all children have dedicated venographic imaging? how reliable is measuring csf opening pressure under ga? where lp is not possible should icp monitoring always be done? should repeat lps be done for persistent symptoms? should csf diversion surgery be restricted to cases of sight threatening piih only? objective: to describe a case of revesz syndrome due to a de novo missense variant in tinf2. case report: a male infant was born at 35 weeks gestation by emergency lscs due to maternal hypertension and reduced amniotic fluid. from 32 week's gestation, reduced fetal growth was identified. the proband was born by at 35 weeks. birth weight was 1.7kg (0.4th-2nd centile) and occipitofrontal circumference (ofc) was 31.7cm (2nd-9th centile). he spent 15 days in the scbu. he developed thrombocytopenia (nadir: 679109/l), which resolved pre-discharge. periventricular calcifications on cranial ultrasound prompted torch screen and ophthalmology review. a right pre-retinal haemorrhage with overlying organised vitreous haemorrhage was identified, which remained stable on subsequent reviews. aged 8 weeks, he was smiling, fixing and following with good head control. aged 5 months, he developed new wobbly eye movements and was no longer fixing or following. bilateral retinal detachments were identified. ct and subsequent mri showed diffuse calcification within the thalami, posterior limb of the internal capsule, deep white matter, cerebellar atrophy and thin corpus callosum. findings on examination included ofc of 0.4th centile, rotatory nystagmus and central hypotonia. whole-exome sequencing identified a pathogenic de novo variant in tinf2 (c.845g>a, p.arg282his). he subsequently developed thrombocytopenia and anaemia and is transfusion dependent. discussion: trf1 interacting nuclear factor-2 (tinf2), protein regulates telomerase and prevents telomere shortening. revesz syndrome is a severe form of dyskeratosis congentia, with multi-system involvement and early onset in-utero. revesz syndrome is characterised by intrauterine growth retardation (iugr), microcephaly, cerebellar hypoplasia, bilateral exudative retinopathy, intracranial calcifications and progressive bone marrow failure. revesz syndrome is distinguished from hoyeraal-hreidarsson syndrome by the presence of retinopathy. telomere disorders should be considered in infants with a background of iugr, thrombocytopenia, retinopathy and intra-cranial calcifications with a negative torch screen, as early features mimic congenital infection. objective: currently the most commonly reported neurological complication of sca is overt stroke. reversible cerebral vasoconstriction syndrome may be more frequent in patients with sickle cell anaemia than reported at present. the scarcity of prevalence studies however makes it difficult to improve diagnostic accuracy in these patients. methods: a 16-year-old ghanaian female was rushed to the paediatric emergency room with first episode of sudden severe global headaches initially started 8 hours prior to arrival. the headache was so excruciating that she described it as her heart was beating in her head. there was associated neck pain, back pain, dizziness, and vomiting. there was no fever or dark urine. she was first diagnosed with sickle cell anaemia (genotype ss) at 2 years of age after she was treated for dactilitis. she had since then been in her usual state of health with no history of blood transfusions or surgeries or admissions. she was compliant with her medications (folic acid 5 mg daily). a physical examination and all investigations were also normal. on day six of admission patient had a generalized tonic clonic seizure with some degree of left sided weakness after having her bath. this was aborted with intravenous diazepam and a magnetic resonance imaging (mri) of the brain was requested. the mri of the brain revealed diffuse narrowing of the cerebral arteries with no areas of bleeding or oedema. reversible cerebral vasoconstriction syndrome was therefore suspected. results: the headache rapidly improved after starting nimodipine and repeat angiography at 3 months showed no vasoconstriction, confirming the diagnosis. on follow up she is doing well academically with no neurological deficits. conclusions: the true incidence of rcvs in patients with sickle cell is uncertain, thus sensitizing medical practitioners is important. introduction: status dystonicus (sd) is a life-threatening disorder of generalised, painful dystonic movements and muscular spasm in patients with severe neurodisability. while rare, it may be complicated by rhabdomyolysis, multi-organ dysfunction, and death. infection, pain, gord, and medication failure are common triggers, but in approximately one-third of cases, sd is idiopathic. mordekar et al. (2017) identified a series of 11 patients in whom sd occurred secondary to gi dysfunction. assisted feeding (e.g., via gastrostomy), and aberrant bowel peristalsis may trigger the onset of sd. this was a retrospective analysis which aimed to estimate an incidence rate for feed-induced sd (fisd). methods: patients presenting to sheffield children's hospital over a 5-year period with sd were identified. episodes were studied to assess for the nature of the onset of sd and as to the likelihood that the trigger was feed related. incidence of fisd as a proportion of total sd was calculated and or calculation performed to explore relative risk of sd between individual trigger factors. results: twenty-four individual episodes of sd were identified. 13 (54%) arose from non-feed-related sources (nfisd), and 11 were felt to be fisd (46%). 6 additional patients were entered into a feed-induced dystonia (fid) group, whom showed clinical evidence of dystonia in relation to gi sources, but not sd. with the exception of infection, the relative risk of sd secondary to gi dysfunction was significantly higher than pain/gord and medication failure combined (or 0.11 (95% ci 0.02-0.56) and 0.05 (95% ci 0.01-0.44) respectively). conclusion: gi dysfunction coupled with severe neurodisability could serve as a trigger in a number of previously idiopathic sd cases through disruption of the neuro-enteric axis. however, overlap between triggers for fisd and nfisd, and significant variation between groups is evident, in addition to a lack of statistical study power. large, prospective studies are needed in the future to corroborate with these findings. poster no. 125 dystonia can twist the patient, physician and the scans: hypermanganesemia, a rare cause of dystonia in children r kumar, s ali liaqat national hospital, karachi, pakistan introduction: manganese (mn) is a chemical element with symbol mn and atomic number 25. mn in the environment can cause toxicity with dystonia and other movement disorders. waterborne mn has a greater bioavailability than dietary manganese. according to results from a 2010 study, higher levels of exposure to mn in drinking water are associated with increased intellectual impairment and reduced intelligence quotients in school-age children. we have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental mn exposure. the rarity of the disease can become a challenge for the physicians to recognize this as a cause of dystonia in children. it also has a characteristic finding on mri with t1 hyperintensity in basal ganglia rather than on t2. case report: we present a case of a 6-year-old girl with dystonia who was previously healthy. she has been suffering from this for the last 6 months and currently one of her 4 years old sister started showing similar symptoms. physical examination revealed marked dystonia (score of 24 on baryalbright dystonia scale) and polycythemia (haematocrit 65). magnetic resonance imaging (mri) brain showed basal ganglia hyperintensity on t1 weighted images. hypermanganesemia was suspected and samples send for serum level which came out to be high. water samples were tested, which came out to be normal. chelation was done and the dystonia improved. conclusions: dystonia in children should be thoroughly investigated and rare, treatable causes should not be ignored. objectives: sodium valproate is used primarily for the treatment of epilepsy in children. it is a well-established teratogen, with 4 in 10 babies at risk of developmental disorders and 1 in 10 babies at risk of birth defects. this risk has been known since the 1970s and yet it is estimated that since then 20 000 children in the uk have been left with disabilities as a result. in 2016, the medicines and healthcare products regulatory agency released guidance for its use, which included a risk acknowledgement form. patient safety alerts were issued in 2017 asking all organisations to identify females taking this medication. we aimed to identify all girls taking sodium valproate in the south eastern trust under paediatrics requiring annual risk assessment; patients under the additional care of a neurologist; patients receiving an annual review. methods: patients were identified through paediatric epilepsy nurse records and data collected through the electronic care record and medical notes from august 2018 to december 2018. results: 24% (n=30) of girls with epilepsy currently taking sodium valproate, 73% under the age of 10 years, 37% profound learning difficulties/disability and considered to be at low risk of pregnancy, 7% (n=2) potentially currently at risk, 81% were under the additional care of a neurologist, 87% reviewed in the past year. conclusions: sodium valproate must not be considered first line treatment in girls with epilepsy and >75% of girls in our trust are not receiving it. of those receiving it, the majority are felt to be low risk due to young age and/or profound disability. we identified two patients at risk and steps were taken to ameliorate this. we have demonstrated good awareness; however lifelong education of families is crucial to reducing the burden of fetal valproate syndrome. rett syndrome (rtt) is neurodevelopmental disorder affecting approximately 1 in 10 000-15 000 live female births, most commonly associated with mutations in the mecp2 gene. hand stereotypies and gait disturbance, as well as spasticity and dystonia, have been noted in rtt since the first descriptions of the syndrome. objective: this review aimed to explore the prevalence of reported movement disorders in rtt. data sources and extraction: pubmed and embase databases for papers describing features of movement disorders in rett syndrome. papers were selected for inclusion to be reviewed if they included description of case report, cohort or case-series of patients with rtt which included a description of clinical features of their movement disorder. selected papers were divided into 3 epochs: (i) pre-1999, (ii) 2000 to 2009, and (iii) 2010 onwards. results: 32 studies (13 in the first epoch, 10 in the second epoch and 9 in the third epoch) reported on movement disorders including stereotypies in rtt patients. hand stereotypies were almost universal in reported cases, diminishing but not disappearing over time. gait disturbance and ataxia/tremor were also very common (>50% cases). elements of hypertonia were also common, increasing with age. in earlier descriptions spasticity was commonly described, with more frequent reference to dystonia/rigidity in more recent reports. myoclonus and choreoathetosis are uncommonly reported in rtt. conclusions: movement disorders beyond hand stereotypies are common in rtt, most notably tremor. hypertonia is a common feature seen in rtt, increasing in prevalence with age, and with an apparent change in nomenclature over time, (i.e., early epoch spasticity, late epoch dystonia). dystonia was specifically reported in 229/417 cases. further work is required to explore the relative contribution of dystonia and rigidity to hypertonia in rtt, as well as the impact of these impairments when present. introduction: headache is the common complaint in children, and the source of it, a great deal of worry for general practitioners and parents. one of the commonest causes of headache in paediatrics is migraine. methods: a prospective study was conducted to evaluate the demographic data, clinical spectrum and grading the child with migraine by using the paediatrics migraine disability assessment (ped-midas) questionnaire and to start prophylactic treatment for those with the higher grades in the department of paediatrics in tertiary care hospital. all children with migraine from age 5 to 18 years were included while all other types of headache cases were excluded. results: total 112 children with migraine were studied. approximately 80% children complained of bilateral frontotemporal headache in which 69.64% presented with throbbing type. other associated features were photophobia, phonophobia, nausea and vomiting. 75% had skipped meal, followed by altered sleep and exam stress as aggravating factors. 94.6% required medication for headache relief. headache duration and frequency was approx. 17 days and 9 days/month. 57.1% cases were diagnosed migraine without aura and 42.9% cases were diagnosed as migraine with aura. loss of full school days due to headache was approx. 2 days for period of 3 months. based on ped-midas score, 50% of children with migraine had grade i disability while 42.9% and 7.10% cases had grade ii and grade iii disability respectively. correlation of ped-midas score with frequency and severity were significant (p<0.001) while with duration of headache was insignificant (p<0.245). conclusions: all patients with higher ped-midas grade are warranted prophylactic treatment. both ped-midas scores and grading can be successfully used for assessing the migraine disability and its easier, less time consuming, bedside diagnostic tool, can be used widely in routine clinical evaluation and management. objective: to review the cases referred to this uk-wide study of children with possible variant creutzfeldt-jakob disease (vcjd) and report the differential diagnosis in children presenting age 10 years or older. methods: children meeting the case definition for progressive intellectual and neurological deterioration (pind) were identified via the british paediatric surveillance unit. details were obtained by standard questionnaire. results: between april 1997 and august 2019, 4589 children had been notified to the study. 2068 were found not to meet the pind case definition. 2006 had an underlying diagnosis to explain their deterioration, with over 210 different disorders including 6 vcjd cases (the last identified in 2000). there were 104 children who presented to clinicians when aged 10 years or over, including all the 6 vcjd cases. of the other disorders in this age group the commonest were: mitochondrial cytopathy 16, adrenoleukodystrophy 9, lafora body disease 8, huntington's disease 7, neuronal-ceroid lipofuscinoses 6, niemann-pick type c 6, metachromatic leukodystrophy 4, sspe 4, wilson's disease 4. when reviewed in 2017 there was no underlying diagnosis in 225 pind cases; 108 of them had diedonly 14 underwent autopsy. the recent identification of the first patient with vcjd who was mv heterozygous at prnp codon 129 reinforces the need for continued vcjd surveillance, particularly as a study of archived appendix samples from uk hospitals published in 2013 indicated that approximately 1 in 2000 of the uk population is carrying abnormal prion protein in the gastrointestinal tract. in the absence of a validated vcjd screening test the pind study remains the only means of performing systematic surveillance of the neurodegenerative diseases that make up the differential diagnosis of vcjd. objective: transient lesions in the splenium of corpus callosum (scc) are rare findings in mri brain in paediatrics. in literature, it has been described as reversible splenial lesions syndrome (resles) and mild encephalitis/encephalopathy with reversible splenial lesions (mers). the condition has diverse aetiology and widely variable neurological presentation but the prognosis is usually favourable. we present two cases of resles with predominantly expressive dysphasia but varying causal associations. method: retrospective review of resles case series exploring clinical course, investigations, neuroimaging, treatment and recovery. result: case 1: a 15 year-old-girl presented with confusion, fever and low oxygen saturation. she had alagille syndrome and partially corrected tetralogy of fallot. her neurological manifestations were expressive dysphasia, dysarthria and difficulties with spatial awareness. interestingly she was able to use occasional words that were abusive in nature. mri showed prominent focus of abnormal signal and restricted diffusion in scc. her blood culture grew staphylococcus aureus and echo revealed infected shunt. treatment involved shunt replacement and prolonged iv antibiotics. repeat mri showed resolution of splenial lesions. she continued to improve neurologically. case 2: a 9 year-old-girl presented with paroxysmal episodes of head turning, head drop and staring for a few seconds. she refused to feed. she showed emotional lability with expressive dysphasia but preservation of expletives. neurologically she was intact. mri brain showed high signal with restricted diffusion in scc. her blood and csf investigations including mog, aquaporin, nmdar, lyme antibodies were negative except asot was 400. her eeg was normal. she received a course of ivig and azithromycin. her repeat mri showed resolution of the lesion in splenium. she made complete recovery over next few months. conclusion: splenial lesions are rare but clinically significant but not 'non-specific'. expressive dysphasia is a prominent symptom. awareness of resles/mers will avoid unnecessary investigations and assist in the prognostication. background: the evidence-base on managing paediatric-headaches is sparse resulting in wide variation in practice with nice guidelines commencing over 12 years of age. this study aims to evaluate outpatient management of paediatric headaches. objective: to investigate paediatric headache referrals to a tertiary hospital over a 1-year period, exploring patient demographics, headache type, role of neuroimaging, management and outcome. methods: this prospective study reviewed headache referrals for the year 2018-2019. the data was collected following weekly emails to relevant clinicians. the patient demographics, headache classification, imaging, management and outcome were collated on a proforma from the electronic patient-records. results: there were 99 patients. the median age of patients at first outpatient appointment was 12 years (range 3-17y); 63.6% were female. incidence of headaches increased with age. female preponderance of headaches existed in all age groups and was most substantial post-puberty with a 2.4:1 female-to-male ratio in patients aged 13 to 17 years. migraine was the most common diagnosis, affecting 46.5% of patients. 51% of referred patients underwent a brain mri scan, all of whom had a normal neurological examination. no mri scans found pathology contributing to headache presentation. 91% of patients were discharged from neurology clinic after first or second neurology appointment. non-pharmacological management was the most common intervention and consisted of: headache diary, lifestyle advice, education, relaxation techniques. the most common medications prescribed bar simple analgesia were sumatriptan (12%), propranolol (9%) and pizotifen (9%). conclusions: a multidisciplinary and biopsychosocial approach to managing paediatric headaches, consisting of non-pharmacological and pharmacological methods resulted in a positive outcome, with majority discharged from tertiary care after first appointment. prescription of sumatriptan and propranolol first line for acute and prophylactic management respectively, was in accordance with current clinical recommendations. the role of mri scanning for paediatric headaches requires further exploration and perhaps more stringent guidelines. objective: the head-up tilt test (hutt) is the gold standard autonomic function test for identifying disorders of blood pressure (bp) and heart rate (hr) regulation, specifically with excessive falls in bp and or hr, as well as excessive postural tachycardia (pt). the 10 minute active standing test (ast) is quicker and easier to apply, e.g., in an outpatient clinic, and may be more sensitive in demonstrating pt. we aimed to compare the yield of these abnormalities when using ast vs hutt. methods: this was a retrospective, clinical notes review, and registered clinical audit of unselected consecutive children and young people undergoing hutt immediately preceded by an ast. results: data was available on 86 children and young people, 56 (67%) female, aged 3 to 18 years (median 14). 12/84 (14%) with complete data sets for the first 10 minutes of hutt and the ast had abnormally large drops in bp and or hr on hutt. only 1/12 positive on hutt was also positive on ast. however, an additional 6/84 (7%) were positive on ast but not on hutt, giving 18/84 (21%) positive in total. 8/86 (9%) with hr data sets for 10 minute hutt and ast had abnormally large rises in hr on hutt. only 3/8 positive on hutt were also positive on ast. however, an additional 10/86 (12%) were positive on ast but not on hutt, giving 18/86 (21%) positive in total. while hutt yielded more cases with significant falls in bp and or hr than ast (14% vs 8%), combining the tests gave the highest yield (21%). while ast yielded more cases with significant rises in hr than hutt (15% vs 9%), combining the tests gave the highest yield (21%). conclusions: we recommend routinely undertaking a 10 minute ast prior to the 45 minute 60°hutt, in children and young people. objective: the aim of our work is to describe the respiratory function trajectories and their correlation with motor function in a cohort of spinal muscular atrophy type 2 and non-ambulant sma3 paediatric patients. methods: this is a retrospective 9-year study in patients recruited in the ismac natural history study (uk, italy, us). the following respiratory data were collected: lung function data (forced vital capacity absolute (fvc) and fvc% predicted, non-invasive ventilation (niv) requirement. recumbent or ulnar length were used as surrogate for height in fvc%pred. calculation. comorbidities affecting lung function such as aspiration were collected. anthropometrics and motor function scores as hammersmith functional motor scale (hfms), revised performance of upper limb (rulm) were noted. we excluded patients in interventional clinical trials and nusinersen therapy. results: data were available for 437 patients: 348 sma2, 89 sma3. mean age at first visit was 6.9 (ae4.4) and 11.1 (ae4) years for sma2 and 3. 180/215 (84%) sma2 and 39/49 of significant lesions. a review of practice of asking routine or non-urgent mri requests should be considered in view of an unlikely significant result. retrospective review of brain magnetic resonance imaging referrals in children less than 12 years (r[20] ) is an ultrarare disease characterised by drug-refractory epilepsy, cognitive impairment and behavioural problems. non-pharmacological treatments should be considered alongside antiepileptic drugs (aeds) early after diagnosis to benefit prompt seizure control and preserve cognitive function. we aimed to understand the use and experience of ketogenic diet therapy (kdt) in r(20) by patients families carers (pfcs) and healthcare professionals (hcps), assessing its efficacy and safety, and contrasting nhs kdt service provision with patient demand. methods: literature searches were conducted on use of kdt in r(20) and similar complex epilepsies. two surveys were developed to gather demographic, diagnostic and clinical care information. surveys were qualitative and descriptive with patient and expert collaborators assessing content accuracy and readability. responses were discussed at a patient and expert workshop. results: the number of responses (42 pfcs, 23 hcps) was considered significant given the ultra-rare status of r(20). 50% of pfcs had tried kdt. seizure activity, behaviour and cognitive outcomes were ranked equally important by hcps and pfcs. significant improvement in seizure activity, cognition and alertness were reported; side-effects were typically mild but with one report of increased seizure frequency. the high rate of comorbidities, older age at presentation, behavioural problems and cognitive impairment can make implementing kdt in r(20) challenging. pfcs report quality of life would be most improved with reduced aed side-effects; hcps report they would consider reducing or withdrawing aeds where kdt is successful. conclusions: kdt may not be suitable for every r(20) patient, but there is a strong consensus that it should be considered as an early intervention. in the uk, nhs kdt services are predominantly available for paediatric patients, with very limited adult access. a detailed health economic analysis illustrating reduced acute care costs and improved quality of life may encourage more widespread kdt implementation. objectives: whole exome sequencing (wes) with a 2-week result turnaround time has become available on the nhs for children in an intensive care setting. we aimed to determine the diagnostic utility and impact on clinical care of wes in a regional paediatric neurology centre. methods: retrospective case notes review. results: six cases (4m, 2f) were identified. three patients were dependent on long-term respiratory support. a pathogenic mutation was detected on wes in 5/6 cases (83%). one case required 'reverse phenotyping' with an abnormal transferrin glycoform electrophoresis confirming that two heterozygote variants of the rtf1 gene were consistent with a congenital disorder of glycosylation (cdg). no other variants of unknown significance were found. three children presented with neonatal onset epileptic encephalopathy (two cases had scn2a, one case wwox), one child with intractable epilepsy from 2 months of age (rft1 mutation associated with cdg) and one child with hypotonia and ventilator dependence after a respiratory infection at 4 months of age (ighmbp2 mutation associated with spinal muscular atrophy with respiratory distress). wes found no pathogenic mutation in a 3-year-old with intracranial calcification, microcephaly, epileptic encephalopathy and severe developmental regression. in 5/6 cases other single genes/panels had been sent prior to initiation of wes with multiple single genes/panels sent in 3/6 cases. in 3/6 cases wes detected the gene thought most likely based on clinical phenotyping on the request form. conclusions: wes has a high diagnostic yield in this cohort of patients. reaching a prompt diagnosis facilitated withdrawal of care in one case (ighmbp2) and helped to exclude an epilepsy surgery hypothesis in four cases as well as guide prognosis in all cases. wes should be considered as a cost-effective alternative when multiple single genes and/or genetic panels are being sent off in parallel due to clinical urgency. objective: the care provided in the time surrounding the death of a child shapes long-term memories and has potential to impact on the grieving process. there are no specific guidelines for picu staff in relation to what good care looks like at this time. we sought insight into practice across the uk to build an evidence base, improve care provided and share good practice. conclusions: from the survey feedback, we found this was an area that all units believe can be improved. in relation to acps, we hope this will be more widely introduced. we know that 60% of patients admitted to picu are life limited. these difficult conversations with family help guide management, understand wishes, and formal documentation ensures all staff are aware. several units with higher uptake of hospice/home care found early conversations with families beneficial. units with a dedicated palliative nurse stated this allowed more time with families. we believe this should become a standard of care. staff training is limited in most units. for something so difficult and frequently encountered, it is vital we equip staff better. prioritising children with epilepsy in the first seizure clinic cp white, s brown, ka hapgood, s tuohy children's epilepsy service, morriston hospital, swansea, uk objective: rising demand for limited first seizure clinic appointments was leading to increasing waiting times and the feeling that children with epilepsy were waiting too long for their first assessment. concern was also expressed that families were not receiving our first seizure leaflet or given instructions about capturing any further episodes either on video or by making a written record when initially seen. methods: from april 2018 all families were sent a letter acknowledging the referral and asking them to contact the specialist epilepsy nurse if they had any concerns prior to the appointment. later modifications included a seizure information leaflet and a seizure record document. we have analysed the results of the first year of using this system. patients were identified from the clinic database and further information was obtained by reviewing clinic letters. results: our initial concern that the specialist nurse would be inundated with phone calls from worried parents were not realised as only 13% (14/104) of parents contacted the service before their appointment. these were invariably parents whose children had had a second episode (10/14). 8 had had further generalised tonic clonic seizures. 11 children had eegs performed before their first appointment. this included all the children given a diagnosis of epilepsy. 71% of these children (10/14) were given a diagnosis of epilepsy made compared to 19.5% of other referrals (p<0.01). although a higher percentage of families who were reminded about videoing any further episodes did so the difference between the two groups was not statistically significant. unfortunately, overall waiting times were not affected. conclusions: a simple change to the way in which the service is delivered has led to earlier identification of those children with epilepsy. we are looking at other ways of improving the accuracy and timeliness of the appointments. introduction: paediatric idiopathic intracranial hypertension (iih) is an uncommon disorder and presentation is varied with children presenting to paediatricians, paediatric neurologist, and ophthalmologists. there are many areas of diagnosis and management where evidence is limited. a national adult evidence and consensus-based guideline was published in 2018. no national paediatric guideline exists to aid the further investigations and management of the cases. the iih meeting at the bpna conference in 2017 and january 2019 set the scene for collaborative work on this topic. aim: to develop a national paediatric iih guideline based on the available literature such as modified dandy criteria, friedman 2013 classification and icdh-3 classification and consensus amongst various members of bpna chan group, members of rcpch, ophthalmology, neurosurgery and radiology, and patients. methods: a core children's headache iih guideline development group was established and has met at four national special interest group meetings between november 2017 and september 2019. topics discussed include incidence of papillioedmea, csf dynamics in iih, bpnsu iih data, ophthalmology good practice, regional iih pathways in uk and setting up of the delphi process. the paediatric iih study day in september 2019 with invited patient/parent representatives highlighted the impact on families with the disorder with need for better communication about the disorder, clear guidelines and sharing of good practice amongst clinicians. an email list of bpna chan group, rcpch members, ophthalmologists interested in the guideline was created. results: a set of 55 statements were drafted for delphi consensus work. these are currently being reviewed by the core guideline development group prior to being circulated to the wider working group. conclusions: goal setting for the next process with the delphi process to work with the core committee and a wider working group will be presented at the bpna conference 2020. objective: nhs england's marginal rate emergency threshold (mret) and readmission fund funded the chameleon project 2018 (twitter account: @chameleonproje1), to improve children's end of life care. this funded a lead disability paediatrician with expertise in paediatric palliative care (10h/wk), a children's palliative care nurse (3d/wk) a network administrator (2d/wk), and additional hours for paediatricians in the critical care, oncology, and neonatal units, and in each of the local district general hospitals (total 18h/wk). methods: tools were developed to aid identification of children in the last year of life and to support anticipatory care planning. the team attended ward rounds and provided teaching sessions, advice and support. children who died an expected death in the 12 months of the project were ascertained from the child death review teams. non-elective admissions, bed days, and costs were tabulated. we also evaluated the documentation of care plans and post bereavement family feedback questionnaires. results: 29 children died an expected death. the same number died during the previous 12 months. the median number of non-elective admissions reduced from 2 to 1 per child, specialist ward bed days reduced from 504 to 251 (50% reduction). for children admitted to picu in the last 12 months of life, the total picu bed days reduced from 342 to 184 (46% reduction), the median length of stay reduced from 21 days to 11 days, and the maximum length of stay reduced from 141 days to 38 days. the percentage of children who died an expected death who had documented anticipatory care plans rose from 50% to 72%. conclusions: the network of clinicians with expertise in paediatric palliative care working together across a region improved anticipatory care planning and reduced admissions and bed days for children in their last year of life: better care with reduced costs. child a, a boy with speech and language delay, presented at 2 years of age with self-resolving episodes of floppiness, ataxia, and disorientation. there was associated muscle weakness and drooling. these unusual episodes occurred 3 to 4 times per week and were often triggered by excitement, especially physical and emotional overstimulation. they lasted from a few minutes to an hour, with no residual deficit. episodes could also be triggered by having late meals (fasting episodes). investigations including an mri/mra brain, eeg, sleepdeprived eeg and video telemetry did not reveal any significant abnormalities. metabolic and endocrine tests were normal. as his presenting symptoms were consistent with episodic ataxia, possibly a periodic paralysis spectrum, a trial of acetazolamide was given, which showed some improvement in the number and severity of the episodes. at 8 years of age, genetic sequencing results revealed child a has a recessive 23kb deletion within the long arm of chromosome 22, band q11.21. this is a homozygous intragenic deletion within the tango2 gene. tango2 is a 'transport and golgi organization 2' homolog. the function of tango2 is unknown; however, in previous studies, depletion in drosophila s2 tissue culture cells was observed to cause fusion of the golgi with the er. a recent study of 14 individuals with tango2, illustrated that child a has a clinical phenotype which is consistent with those previously reported in the literature. although seizures are present in 75% of individuals with tango2, child a has not had any seizures to date. although no effective treatments for this rare condition are known, early diagnosis is important so that individuals and their families are aware of the potential encephalomyopathic crises and arrhythmias which occur. further research in elucidating the structure and function of the tango2 protein may lead to effective therapies in the future. objective: hie affects around 1.68/1000 live births. prognostication relies on clinical progress, neurophysiology, neurological examination, and magnetic resonance imaging (mri). there is limited information on the relationships between mrs brain results and visual appearances of the brain on mri and clinical features. this work studied the use of mrs in this cohort. methods: mrs is used routinely in all neonates with hie in our unit, so approval for this service evaluation was obtained from our clinical governance department. we identified neonates with hie between jan 2010 and march 2016 who had mri and mrs in the first 7 days of life. medical notes were reviewed, and mri results categorised as normal or abnormal. mrs results and clinical features were compared between mri groups using parametric or non-parametric testing. correlation and regression analyses studied relationships between clinical features and mrs results. p-values of <0.05 were assumed to be significant. results: 82 participants were identified, 19 were excluded because they did not meet our inclusion criteria. data from a total number of 63 neonates were analysed using r studio. babies with abnormal mri scans had significantly lower birth weight (p=0.018), gestational age (p=0.037), and higher scores in the sarnat staging scale (p=0.04). the analysis of the mrs data also revealed that these babies had lower levels of n-acetylaspartate (naa) in their parieto-occipital region (p=0.006), as well as higher levels of lactate and lactate to choline both in the parietooccipital region (p=0.032 and p=0.007 respectively). finally, these significant mrs variables were significantly correlated with time to normalisation of lactate in single linear regression. background: more children and young people are surviving with an acquired central nervous system injury (traumatic or non-traumatic). the first nhs england (nhse) specialist specification for paediatric neurorehabilitation services was written in 2013. evidence for benefits of early neurorehabilitaion after adult stroke are compellingevidence for early neurorehabilitation in cyp is emerging. methods: service information was collected from all england and wales pnr units in 2019. results: 15/17 units contributed. activity is increasing (464 (2012/13); 530 (2013/14); 595 (2014/15). 10/17 (60%) are major trauma units (50%) have dedicated coordinators. several units cannot offer daily therapy. most units discharge cyp home. conclusions: considerable neurorehabilitation in-patient activity is taking place but there remains an absence of secure funding, adequate staff, dedicated beds, key members of the mdt, protected time for pro-active patient specific discharge planning. neurorehabilitation is an integral part of the neuroscience clinical pathway and our children deserve a fully resourced service as described in the service specification. tuberculosis/sarcoidosis (1). out of the sub-categories, the group of refractory seizures/status epilepticus were most likely to have repeated imaging with either ct or mri within 3 years (80%), followed by the group of ventriculo-peritoneal shunt blockage (77%), space occupying lesion (20%) then head injury (14%). out of 5 patients with refractory seizures/ status epilepticus, 4 were already known to have epilepsy. also, most repeated imaging included a subsequent head mri. conclusions: most common indications for ct head were head injury and shunt blockage (as this was a neurosurgical centre). the groups most likely to have repeated imaging were refractory seizures/status epilepticus and shunt blockage. with children presenting with known epileptic seizures in the emergency department, it is important to consider clinical data and seek to devolve decision to image. poster no. 150 isolated radial nerve palsy, a rare presentation of congenital wrist drop c duggan, n mcsweeney cork university hospital, cork, ireland isolated congenital radial nerve palsies are a rare phenomenon and typically spontaneously recover within 6 months. the true incidence is not known, but in a recent study 2.6% of infants presenting to a brachial plexus injury clinic had an isolated congenital radial nerve palsy. patient a is a 10-week-old male who presented at birth with a left sided wrist drop following a non-traumatic elective caesarean section at 38+5/40. his birthweight was 4.23kg (91st centile). movement of the wrist and digits were impaired to absent with preservation of function at the shoulder and elbow. there was a nodule noted in the left upper limb, anatomically superficial to the radial nerve. it was a normal pregnancy with no antenatal or postnatal issues. he attended physiotherapy and occupational therapy who provided a splint. on examination at 10 weeks, there was weakness of the extensors of the left wrist. the 3rd, 4th and 5th digits remained fully flexed at rest and could be extended passively but not actively. extension of the thumb and index finger had recovered at 10-week review. function at the shoulder and elbow joints were preserved with normal flexion of the wrist and digits. a scar was noted superficial to the radial nerve at the same location as the lesion described at birth. the remaining systemic and neurological examinations were normal with typical development and appropriate growth. the working diagnosis at present is an isolated radial nerve palsy likely caused by in-utero compression. the nodule and scar noted above are consistent with lesions described in a previous case series. these were hypothesised to be areas of fat necrosis secondary to compression; resulting in the palsy. patient a's lack of further neurology such as a generalised brachial plexus palsy makes a birth injury less likely. further investigations and follow-up are awaited. background: valproate is an effective antiepileptic medication. if a woman becomes pregnant while taking valproate, her baby is at risk of congenital malformations (1 in 10) and developmental disorders (4 in 10). furthermore, it is associated with an increased risk of autism spectrum disorder and adhd. in 2018, the nhs/hse recommended new restrictions on the use of valproate, including a national pregnancy prevention program (prevent) and avoidance in prescribing to female patients of childbearing potential unless other treatments are ineffective or not tolerated. objective: to review the use of valproate in a well-defined population of at risk females with moderate to profound intellectual disability (id). identify the patients at risk and imbed the guideline into our practice. methods: a retrospective chart review was carried out of all girls aged between 6 and 18 years, attending the daughters of charity disability service (doc) in dublin, ireland. data such as diagnosis, valproate use, degree of id/gross motor function classification system (gmfcs), documentation of menarche and discussion regarding risk of valproate use were recorded. results: in total 9 females aged between 6 and 18 years where identified as currently using valproate out of 73 charts reviewed (12%). of the 9 patients identified, 2/9 had moderate id (gmfcs iii) and 7/9 had severe to profound id (gmfcs iv-v). 3/9 had menarche documented. 2/9 had the risk of valproate discussed. conclusions: in our cohort, a significant number of girls remain on valproate. 22% complied with new guidelines regarding discussions around the risks of valproate; highlighting the 78% of patients in need of counselling. an annual risk acknowledgement form was placed in their charts to prompt discussion next visit. in children with intellectual disability, conversations regarding contraception are difficult but essential. if valproate is used, then the risks must be fully understood by parents and carers. evaluation of the management of children up to age of 10 years with cerebral palsy in southend university hospital large district university general hospital against nice guidelines (nice guidelines ng62). methods: clinic notes of all 42 registered children with cerebral palsy (cp) up to 10 years of age as of june 2019 were included in the study. this was because there was no early data on children above 10 years age. results: 22 patients were age 0 to 5 years and 20 patients age 6 to 10 years. 15 were male and 27 females. 11 had hemiplegic, 3 quadriplegic, 18 diplegic and 10 dystonic cp. only 27 (64%) had gmfcs levels recorded. 11 (26%) were <28 weeks, 18 (42%) were 29 to 36 weeks and 13 (31%) were term. mri head findings: white matter changes including pvlin 29 (69%), 3 (7%) hie changes, 3 (7%) basal ganglia changes, 3 (7%) congenital brain malformation, 2 (4%) infarction. 1 migrated to area with no mri report. all the children received multidisciplinary team (mdt) input including physiotherapy. comorbidities werechildren on medications for gastro-esophageal reflux -9 (with 6 peginsertions). for epilepsy -5, for dystonia/spasticity -5, for constipation -12, for poor salivary control -2. behavioral issues noted in 7 and 1 was on adhd medications. 8 had botulinum toxin injections and 4 had selective dorsal rhizotomy for spasticity. documented discussion of diagnosis with family was in 28 (66%) patients and none in 14 patients (31%). only 50% patients had vitamin d levels checked. conclusions: management was in line with nice guidelines. they all had mdt input. there is a need to improve documentation of -evidence of discussion with parents, gmfcs level by age 2 ½ years plus, hip surveillance from age 2 years for gmfcs level iii to v and annual vitamin d levels especially for gmfcs level iii to v, peg fed and children on multiple anti-epileptic medications. poster no. 153 intracranial hypertension in children: an updated systematic review l di genova 1 , n desai 2 , s esposito 1 , p prabhakar 3 1 pediatric clinic, department of surgical and biomedical sciences, universit a degli studi di perugia, perugia, italy; 2 department of paediatric neurology, great ormond street hospital nhs foundation trust, london, uk; 3 neurosciences, great ormond street hospital nhs foundation trust, london, uk objective: our goal is to provide an overview on paediatric intracranial hypertension. methods: given that the last update of the diagnostic criteria of idiopathic intracranial hypertension was published in 2002, a thorough medline search of all english articles was conducted between 2002 and 2019. results: intracranial hypertension may be primary, with a paediatric annual incidence ranging between 0.63 and 0.71 per 100 000 children or arise from a secondary cause. misdiagnosis or delayed intervention can lead to poor quality of life and morbidity. in 2013, this condition was reconsidered, due to new accepted values for opening pressure and advances in neuroimaging; the importance to develop effective therapeutic strategies in order to prevent blindness was thus highlighted. to date, the main strategies described involved both medical and surgical approaches; nevertheless, there have been no paediatric intervention studies. disease monitoring plays a key role in the definition of the best timing and modality of treatment. recently, a risk stratification has been proposed with the aim to facilitate an adequate evaluation and proper care of children with intracranial hypertension: visual monitoring could represent an objective tool to manage these patients. in recent years, important evidence for the efficacy of acetazolamide emerged in the idiopathic intracranial hypertension treatment trial. surgical treatment is the modality of choice in children with worsening vision impairment, intractable headaches despite maximal medical management or in case of intolerance to medical therapy. conclusions: there are poor evidences about paediatric intracranial hypertension's outcomes. unfortunately, children's quality of life is heavily influenced by pain and permanent vision loss. standardized therapeutic strategies remains uncertain, highlighting the need for longitudinal studies to identify the best treatment in childhood. in order to alleviate symptoms and prevent permanent chronic sequelae, careful clinical evaluation and ophthalmological monitoring could be a useful guide to better manage this medical condition. objective: cerebral sinovenous thrombosis in childhood is a life-threatening neurological entity with uncertain epidemiology, potentially complicated by secondary intracranial hypertension. in the literature, there is a lack of evidence supporting the main strategies to approach both these medical conditions. our objective is to highlight the value of a prompt diagnosis aiming to define a tailored management approach based on children monitoring. methods: we review the main findings regarding cerebral sinovenous thrombosis and intracranial hypertension in children through illustration of a case with otogenic sinus thrombosis and secondary intracranial hypertension. results: a 7-year-old boy developed a local venous sinus thrombosis because of the spreading of a primary infective process from his middle ear into the sigmoid sinus complex, facilitated by anaemia and dehydration. the venous outflow disturbances led to secondary intracranial hypertension. the management aimed to treat cerebral thrombosis with anticoagulants and intracranial hypertension through medical and surgical strategies. the insertion of the lumbar-peritoneal shunt was necessary when medical approached failed and visual function deterioration was evident. careful clinical evaluation and ophthalmological monitoring helped us in the tailoring of the best treatment with the aim to alleviate symptoms and prevent sequelae of increased intracranial pressure. in the literature, no paediatric intervention studies regarding the main strategies to reduce intracranial pressure have been published. moreover, there is a lack of evidence supporting the safety of anticoagulation therapy, reducing the possibilities to safely manage cerebral thrombosis in childhood. conclusions: in children, a multidisciplinary approach is essential to manage both cerebral thrombosis and intracranial hypertension and ensure an optimal follow-up, aiming to prevent visual and therapy-related complications, possible relapses and their early diagnosis. from our perspective, monitoring our patient with clinical manifestations and visual status helped us to plan the best timing and modality of treatment and intervention. yearly rate of progression of fvc% predicted (available in n=260) was 3.6% in sma2 and 3.5% in sma3. in sma2, fvc% predicted declined steeply from 5 to 15 years of age, followed by a levelling. conversely, in sma3 patients fvc% predicted declined slower but steadily from 10 years of age. 136/298 (46%) sma2 and 8/71 (11%) required non-invasive ventilation due to respiratory infections or hypoventilation conclusions: the results of this ongoing collaborative work suggests that in sma2 and 3 lung function declines from age 5 and 10 respectively. lung and motor function correlate well in both sma2 and 3. this data will help the assessment of the long-term efficacy of new treatments for sma this review aims to study the appropriateness of mri brain referrals following implementation of local changes to improve compliance to the nice cg150 standard. methods: following an earlier survey (es; 01/06/16 -30/06/ 17) of mri brain referrals for headaches in children over 12 years, key recommendations included adding pop-ups in the neuroimaging request system (ice) of nice cg150 and headsmart clinical guideline v2 as well as verbal consent obtained from senior paediatrician before request was made. following these implementations, requests for mri brain were analysed during 01/06/2018 -31/12/2018 in the same district general hospital. referral was deemed compliant if the nice guideline cg150 standard were met. results: 50 children were referred for mri brain scan (mean 7/ month vs 10/month in es). 43 (86%) referrals were compliant (vs 67% compliance in es). 13 (26%) referrals were 'urgent' (vs 30% urgent es) and 37 (74%) 'routine' or non-urgent (vs 68% routine es). 12 (92%) of urgent referrals (vs 35% es) and 31 (84%) of routine referrals (vs 65% es) were compliant mri brain guidelines for neuroimaging in less than 12 years exist (headsmart clinical guideline v2 and nice epilepsy qs27) but are limited. this study aimed to assess current practice of mri brain referrals in children under 12 years. methods: retrospective review of mri brain referrals in children under 12 years performed between mri brain scans were done (m:f 1.1:1) 92 (43%) referrals under headsmart and 33 (36%) of these were urgent requests; significant brain abnormality was seen in 26 (79%) in urgent and 1 (0.01%) in nonurgent cases. 45 (21%) referrals under epilepsy qs27 and 12 (27%) were urgent requests; significant brain abnormality in 2 (17%) in urgent and 2 (6%) in non-urgent cases. 78 (36%) were miscellaneous requests and 24 (31%) were urgent; significant brain abnormality in 8 (33%) in urgent and 13 (24%) in non-urgent cases. overall mri brain showed significant abnormality in urgent requests (52%) compared to non-urgent requests (11%) poster no. 147 investigating factors that influence unplanned admissions and a&e attendances in those with pre-existing neurological conditions in childhood s dowsell 1 , k kananaviciute 1 , r parslow 1 , am childs 2 1 university of leeds, leeds, uk; 2 paediatric neurology, leeds general infirmary, leeds, uk objective: previous papers have shown increasing demands and costs to the nhs in relation to the inpatient care of children with neurological conditions. unplanned admissions may reflect a lack of effective care and have been shown to correlate with high outpatient clinic did not attend (dna) rates 2. the aim of this study was to determine factors underlying unplanned admissions and accident & emergency (a&e) attendances in a cohort of patients under the care of the leeds regional paediatric neurology service over a 3-year period. methods: all children <18 years who had paediatric neurology outpatient appointments in 2013 were identified using hospital databases. clinical and demographic data was extracted from electronic case notes. those without a definitive neurological diagnosis or who had moved to adult services during the study period were excluded. the cohort was cross referenced to a&e databases and admission records from 2015 to 2018. poisson regression was used to identify any correlation between specific predetermined factors to assess their influence on a&e attendance and admission rates. results: a cohort of 291 patients was established and 53 had a total of 82 unplanned admissions during the study period. 183 patients had a&e attendances with a total of 570 attendances. higher dna rates, younger age and certain diagnostic categories correlated with increased rates of unplanned admissions. the role of emergency care plans in preventing admission was unclear as only 27/147 patients with epilepsy had care plans in place. conclusions: this study confirms the association between increased rates of a&e attendances and unplanned admissions in children with specific neurological disorders and high dna rates. this is relevant for service planning as it highlights the need to target scarce resources towards 'higher' risk patients with more complex diagnoses where more integrated care and support may prevent or reduce unplanned hospital attendances.poster no. 148 audit comparing great ormond street hospital headache clinic diagnoses and management of patients aged 12 to 17 years to nice clinical guidelines a ward 1,2 , p prabhakar 1 1 neurology, great ormond street hospital, london, uk; 2 university of glasgow, glasgow, uk introduction: between 16/4/18 and 15/4/19 the gosh headache clinic saw 85 new patients aged 12 to 17 years. the nice clinical guideline 150 (cg150) on the diagnosis and management of headaches in over 12s covers tension-type headache, migraine, cluster headache and medication overuse headache. this audit aims to compare gosh diagnosis and management to those of the cg150. methods: using the patient list from the headache clinic data was gathered by accessing outgoing clinic letters via epic. raw data was collected on; age, gender, description of headache (pain location, quality, intensity, duration and frequency) and associated symptoms, triggers, previous imaging, previous and current treatments. the management data collected include: diagnosis and treatments offered, as well as whether gosh offered lifestyle advice, psychology, occipital nerve block or riboflavin. this data was then compared to cg150. results: 37 (62.7%) of diagnoses made by gosh matched the cg150 diagnosis. 22 (37.3%) diagnoses differed, with 14 of these due to discrepancy between chronic/episodic and/or presence of aura and 6 due to the vague diagnoses of migraine-type, new daily persistent, migrainous etc. fitting the cg150 definition of chronic migraine. all but one patient was managed in line with the guidelines. 76.9% of patients had brain imaging prior to attending the clinic, with 21.7% of these reporting positive findings. discussion: despite 22 patients' diagnosis differing between gosh and cg150, all but one patient was managed in line with the guidelines. this is likely due to nice recommended management being the same for any type of migraine. improvements could be made in documentation of frequency and duration of headache and aura, as well as more routinely offered lifestyle advice, psychology and riboflavin recorded in outgoing clinic letters. objective: to review the purpose of ct head requests from emergency department of a busy tertiary hospital as part of quality improvement. due to increasing evidence of ct scan radiation predisposing to leukaemia and brain tumours, it is best to keep ct scans to the minimum if clinically indicated. this project reviewed the indications for ct head and also looked at patients who had repeated ct or mri head scans within 3 years. methods: data was collected retrospectively looking at a snapshot period of 3 months between september-november 2018. patients were <18 years of age and they had a ct head from emergency department at king's college hospital, london. trauma patients were excluded. data was collated with aid of the neuro ct department 'cris' system. results: out of 56 patients, reasons for ct included: head injury (29), ventriculo-peritoneal shunt blockage (13), refractory seizures/status epilepticus (5), space occupying lesion (5), orbital cellulitis (1), intracranial haemorrhage (1) objectives: mutations in kif1a are associated with a wide range of neurological disorders, ranging from hereditary spastic paraparesis (hsp) to sensory neuropathies to a severe infantile neurodegenerative disorder. collectively, they are extremely uncommon but likely to be under-recognised. we aim to report the spectrum of kif1a-related disorders from a single tertiary neurology centre, with a view to improving understanding and awareness of these rare conditions. methods: affected individuals known to great ormond street hospital were identified through liaison with consultants involved in the care of children and young people with movement disorders. clinical information was collected through a retrospective review of case notes. results: twelve individuals in 9 families were identified. all had heterozygous kif1a mutations including three previously unreported variants. severity ranged from a fatal neonatalonset disorder with contractures, absence of visual development, and agenesis of the corpus callosum on mri to hsp with preservation of ambulation into the second or third decade of life and entirely normal mri. upper motor neuron signs were found in 10/12 children and a primarily sensory neuropathy was present in 9/11 children assessed. 3/12 children also had extrapyramidal signs (dystonia). some degree of learning difficulties and/or disorders of mood or behaviour were present in all children. optic atrophy, mr brain white matter changes and epilepsy were also common, especially in those children who were more severely affected overall. conclusions: kif1a related disorders are so diverse that it is arguably misleading to consider them as a single disease entity. features common to the majority of affected patients include upper motor neuron involvement, and neuropathy (even in the absence of an obvious sensory deficit), with high risk of other neurological and neurobehavioural comorbidities. objective: ataxia with oculomotor apraxia type 2 (aoa2) is a slowly progressive, autosomal recessive disease characterised by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy that results from mutations in the gene encoding senataxin (setx), a dna/rna repair protein essential for genomic stability. we investigated a 16-year old male with a history of unsteady gate for genetic and molecular changes associated with aoa2. in this report we describe a case of aoa2 with two clear pathogenic setx mutations, one of which is novel, as well as two further setx changes likely to be in cis polymorphisms that have previously been reported as pathogenic. methods: two independent lymphoblastoid cell lines obtained from the patient were used for western blotting of senataxin and protein markers of other autosomal recessive cerebellar ataxias. the setx gene was sequenced to identify possible disease-causing mutations. results: western blotting showed reduced levels of senataxin. serum afp level was elevated at 15lg/l (normal 0.0-7.0lg/l). genetic sequencing revealed two clear pathogenic setx mutations. one of these was a novel mutation, c.2990delg; p.(cys997phefster32), a deletion causing a reading frameshift resulting in truncation and loss of expression of senataxin protein from this allele. the other, c.6638c>t; p.(pro2213leu) was a missense mutation within the helicase domain which has previously only been reported in the homozygous state in a japanese aoa2 patient. two further sequence changes, c.1807a>g; p.(asn603asp) and c.1957c>a; p.(gln653lys), were also identified in our patient. conclusions: the reduced senataxin expression and elevated afp levels support a diagnosis of aoa2 in our patient. genetic analysis found a novel pathogenic mutation and documented the first case of another pathogenic mutation in the helicase domain outside of japan. the case contributes to the growing diversity of setx mutations known to be responsible for aoa2. key: cord-024981-yfuuirnw authors: severin, paul n.; jacobson, phillip a. title: types of disasters date: 2020-05-14 journal: nursing management of pediatric disaster doi: 10.1007/978-3-030-43428-1_5 sha: doc_id: 24981 cord_uid: yfuuirnw disasters are increasing around the world. children are greatly impacted by both natural disasters (forces of nature) and man-made (intentional, accidental) disasters. their unique anatomical, physiological, behavioral, developmental, and psychological vulnerabilities must be considered when planning and preparing for disasters. the nurse or health care provider (hcp) must be able to rapidly identify acutely ill children during a disaster. whether it is during a natural or man-made event, the nurse or hcp must intervene effectively to improve survival and outcomes. it is extremely vital to understand the medical management of these children during disasters, especially the use of appropriate medical countermeasures such as medications, antidotes, supplies, and equipment. skeleton as a result of incomplete calcification and active bone growth centers. protected organs, such as the lungs and heart, may be injured due to overlying fractures. cervical spine injuries can also be pronounced, as in patients with head trauma. in fact, spinal cord injury may be present without any radiographic abnormalities of the spine. finally, vital signs will vary based on the pediatric patient's age. this may be a pitfall during rapid evaluation by any nurse or hcp not accustomed to the care of children. younger pediatric patients have higher metabolic rates and, therefore, higher respiratory rates and heart rates. this can be a distinct disadvantage versus older pediatric patients when encountering similar diseases. an example is inhaled toxins (e.g., nerve agents and lung-damaging agents). infants and children will suffer greater toxicity since they inhale at a faster rate due to higher metabolic demands and thus, distribute the toxin more rapidly to various end-organs. understanding respiratory differences is essential to the management of the acutely ill pediatric patient. the most common etiology for cardiorespiratory arrest in children is respiratory pathology, typically of the upper airway. most of the airway resistance in children occurs in the upper airway. nasal obstruction can lead to severe respiratory distress due to infants being obligate nose breathers. their relatively large tongue and small mouth can lead to airway obstruction quickly, especially when the neuromuscular tone is abnormal such as during sedation or encephalopathy. in infants, physiologic (i.e., copious secretions) and pathologic (i.e., edema, vomitus, blood, and foreign body) factors will exaggerate this obstruction. securing the airway in such events can be quite challenging. typically, the glottis is located more anterior and cephalad. appropriate visualization during laryngoscopy can be further hampered by the prominent occiput that causes neck flexion and, therefore, reduces the alignment of visual axes. the omega or horseshoeshaped epiglottis in young infants and children is quite susceptible to inflammation and swelling. as in epiglottitis, the glottis becomes strangulated in a circumferential manner leading to dangerous supraglottic obstruction. children also have a natural tendency to laryngospasm and bronchospasm. finally, due to weaker cartilage in infants, dynamic airway collapse can occur especially in states of increased resistance and high expiratory flow. along with altered pulmonary compensation and compliance, a child may rapidly progress to respiratory failure and possibly arrest. cardiovascular differences are critical in the pediatric patient. typical physiological responses tend to allow compensation with seemingly normal homeostasis. with tachycardia and elevated systemic vascular resistance, younger pediatric patients can maintain normal blood pressure despite decreased cardiac output and poor perfusion (compensated shock). since children have less blood and volume reserve, they progress to this state quickly. in pediatric patients with multiorgan injury or severe gastrointestinal losses, these compensatory mechanisms are pushed to their limits. the unaccustomed hcp may be lulled into complacency since the blood pressure is normal. all the while, the pediatric patient's organs are being poorly perfused. once these compensatory mechanisms are exhausted, the patient rapidly progresses to hypotension and, therefore, hypotensive shock. if not reversed expeditiously, this may lead to irreversible shock, ischemia, multiorgan dysfunction, and death. pediatric patients with altered mental status pose significant problems. the differential diagnosis will be very broad in the comatose patient based on development alone. for example, younger pediatric patients can present with nonconvulsive status epilepticus (ncse) instead of generalized convulsive status epilepticus (gcse). in fact, ncse is more common among younger pediatric patients than gcse, especially in those from 1 to 12 months of age. furthermore, many of them are previously well without preexisting diseases such as epilepsy. other disease states may include poisoning, inborn errors of metabolism, meningitis, and other etiologies of encephalopathy. using the modified pediatric glasgow coma scale (gcs) is the cornerstone when evaluating the young pediatric patient when they are preverbal. pupillary response, external ocular movements, and gross motor response may be challenging to evaluate in a developmentally young or delayed pediatric patient. pediatric traumatic brain injury is extremely devastating. whether considered accidental (motor vehicle crash) or nonaccidental (abusive head trauma), evaluation of the neurological status of the acutely injured pediatric patient can be problematic, especially the gcs. some prefer to use the avpu system (alert, responds to verbal, responds to pain, and unresponsive). due to the disproportionately larger head and weaker neck muscles, there is more risk of acceleration-deceleration injuries (fall from a significant height, vehicular ejection, and abusive head trauma). furthermore, the softer skull, dural structural differences, and vessel supply will place the pediatric patient at risk for brain injury and intracranial hemorrhage. finally, due to pediatric brain composition, the risk of diffuse axonal injury and cerebral edema is much higher. although spinal cord injury is rare in young pediatric patients, morbidity and mortality are significant. in pediatric patients less than 9 years of age, the most commonly seen injuries are in the atlas, axis, and upper cervical vertebrae. in young pediatric patients, spinal injuries tend to be anatomically higher (cervical) versus adolescents (thoracolumbar). furthermore, congenital abnormalities, such as atlantoaxial abnormalities (trisomy 21), may exaggerate the process. the clinical presentation of spinal cord injury varies in young pediatric patients due to ongoing development. laxity of ligaments, wedge-shaped vertebrae, and incomplete ossification centers contribute to specific patterns of injuries. finally, spinal cord injury without radiographic abnormality (sciwora) may result. because of the disproportionately larger head, weaker neck muscles, and elasticity of the spine, significant distraction and flexion injury of the spinal cord may occur without apparent ligament or bony disruption (hilmas et al. 2008; jacobson and severin 2012; severin 2011). motor skills develop from birth. gross and fine motor milestones are achieved in a predictable manner and must be assessed during each hcp encounter. cognitive development will follow a similar pattern of maturation. the development of these skills can often predict injuries and their extent. for example, consider a house fire. a young infant, preschooler, and adolescent are sleeping upstairs in house when a fire breaks out in the middle of the night. the smoke detectors begin to alarm. each child is awoken by the ensuing noise and chaos. based on the development, the adolescent will most likely make it out of the house alive. he will comprehend the threat, run down the stairs, and exit the house without delay. smoke inhalation may be minimal. if it is a middle adolescent, an attempt may be made to jump out of the window leading to multiple blunt trauma with or without traumatic brain injury. the preschooler most likely will be too scared and not understand how to escape. tragically, he may hide under a bed or in a closet. when the firefighters arrive and search the house, the preschooler may remain silent because of fear, especially of strangers in the house. he will most likely succumb to thermal injuries along with the effects of carbon monoxide and die. as far as the infant, he cannot walk, climb, crawl, or run. furthermore, he cannot scream for help or know how to escape. as the smoke engulfs the room, he will most likely suffer severe smoke inhalation injury including extensive carbon monoxide toxicity along with thermal injuries and die. this example also points out another important difference in pediatric patients: their dependence on caregivers. when considering neonates, for example, their entire existence depends on the caregiver, including feeding, changing of diapers, nurturing, and environmental safety. these dynamics are essential to the pediatric patient's health and survival, especially during a disaster. another aspect of development is the attainment of language skills. this, too, develops over time in a predictable fashion. one of the biggest challenges in pediatrics is the lack of the patient's ability to verbally convey complaints. as described above, verbal milestones vary among the different age ranges of the pediatric patient. hcps are often faced with a caregiver's subjective assessment of the problem. although it can be revealing and informative, this may not be available in an acute crisis situation. it will take the astute hcp to determine, for example, if an inconsolably crying infant is in pain from a corneal abrasion or something more life-threatening such as meningitis. this can also be a challenging task in a teenager, especially during middle adolescence. an hcp will have to determine, for example, if the seemingly lethargic middle adolescent is intoxicated with illicit drugs or has diabetic ketoacidosis. finally, the hcp will have to address developmental variances among their pediatric patients and any comorbid features. young pediatric patients can regress developmentally during any illness or injury. this is especially seen in patients with chronic medical conditions (cancer) or during prolonged hospitalization with rehabilitation (multisystem trauma). furthermore, those pediatric patients with developmental and intellectual disabilities, for example, will be difficult to evaluate based on the effects of their underlying pathology. these pediatric patients typically have unique variances in their physical exams (jacobson and severin 2012; severin 2011) . please refer to chap. 7 for more detailed information on pediatric development. pediatric patients will often reflect the emotional state of their caregiver. they take verbal and physical cues from their caregiver. at times, this may also occur in the presence of a nurse or hcp. the psychological impact of illness will vary greatly with the child's development and experience. children tend to have a greater vulnerability to post-traumatic stress disorder especially with disaster events. furthermore, they are highly prone to becoming psychiatric casualties despite the absence of physical injury to themselves. and as any pediatric hcp can tell you, the younger pediatric patients tend to also have greater levels of anxiety, especially while preparing for invasive procedures such as phlebotomy and intravenous line placement (hilmas et al. 2008; jacobson and severin 2012; severin 2011) . please refer to chap. 12 for more detailed content on mental health. the world health organization and the pan american health organization define a disaster as "an event that occurs in most cases suddenly and unexpectedly, causing severe disturbances to people or objects affected by it, resulting in the loss of life and harm to the health of the population, the destruction or loss of community property, and/or severe damage to the environment. such a situation leads to disruption in the normal pattern of life, resulting in misfortune, helplessness, and suffering, with adverse effects on the socioeconomic structure of a region or a country and/or modifications of the environment to such an extent that there is a need for assistance and immediate outside intervention" (lynch and berman 2009 ). types of disasters usually fall into two broad categories: natural and man-made. natural disasters are generally associated with weather and geological events, including extremes of temperature, floods, hurricanes, earthquakes, tsunamis, volcanic eruptions, landslides, and drought. naturally occurring epidemics, such as the 2009 h1n1, 2014 ebola, and 2019 novel coronavirus outbreaks, are often included in this category. man-made disasters are usually associated with a criminal attack such as an active shooter incident, or a terrorist attack using weapons such as explosive, biological, or chemical agents. however, man-made disasters can also refer to human-based technological incidents, such as a building or bridge collapse, or events related to the manufacture, transportation, storage, and use of hazardous materials, such as the 1986 chernobyl radiation leak and the 1984 bhopal toxic gas leak. even though disasters can be primarily placed into any of these two categories, they can often impact each other and compound the magnitude of any disaster incident (united states department of homeland security, office of inspector general 2009). a prime example is the march 2011 tohoku earthquake leading to a tsunami (natural) that triggered the fukushima daiichi nuclear disaster (man-made). disasters can also be characterized by the location of such an event. internal disasters are those incidents that occur within the health care facility or system. employees, physical plant, workflow and operations of the clinic, hospital, or system can be disrupted. external disasters are those incidents that occur outside of the health care facility or system. this impacts the community surrounding the facility, proximally or distally, but does not directly threaten the facility or its employees. as with natural and man-made disasters, internal and external disasters can impact each other. for example, an overflow of patients during a high census period may lead to the shutdown of the hospital to any new patients (internal disaster). this will place the hospital on bypass and possibly stress other hospitals in the community beyond their means (external disaster). a terrorist event, such as the release of sarin in a subway system during a busy morning commute, can lead to massive disruption in the community (external disaster). all the victims of the attack will seek medical care at nearby hospitals, possibly overwhelming the health care staff and depleting critical resources (internal disaster). characterization of disasters by geography (local, state, national, and international) can also be used. again, no matter the site of the incident, a disaster in one area could easily create a disaster in another geographical region. for example, a factory and its community could be ravaged by a hurricane (local disaster). if this is the only factory in the world to produce a certain medication, this could lead to critical shortages to hospitals all around the world (international disaster). the term "disaster preparedness" has been used over the years as a way to describe efforts to manage any disaster event. however, preparedness is only one aspect of the process. the use of the term disaster planning is more appropriate. it considers all aspects needed for an effective effort and is dependent on additional phases, not just preparedness. national preparedness efforts, including planning, are now informed by the presidential policy directive (ppd) 8 that was signed by the president in march 2011 and describes the nation's approach to preparedness (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013; united states department of homeland security 2018b). a recommended method for disaster preparedness efforts is the utilization of an "all-hazards" model of emergency management (adini et al. 2012; waugh 2000) . the four overlapping phases of the model include mitigation, preparedness, response, and recovery. the mitigation phase involves "activities designed to prevent or reduce losses from a disaster" (waugh 2000) . examples include land use planning in flood plains, structural integrity measures in earthquake zones, and deployment of security cameras. the preparedness phase includes the "planning of how to respond in an emergency or a disaster, and developing capabilities for more effective response" (waugh 2000) . examples include training programs for emergency responders, drills and exercises, early warning systems, contingency planning, and development of equipment and supply caches. up to this point, all planning efforts are proactive and not reactive. often times, a hazard analysis is conducted to delineate areas of strengths and identify potential risks. it helps in "the identification of hazards, assessment of the probability of a disaster, and the probable intensity and location; assessment of its potential impact on a community; the property, persons, and geographic areas that may be at risk; and the determination of agency priorities based on the probability level of a disaster and the potential losses" (waugh 2000) . after a disaster or emergency incident occurs, the response phase, or "immediate reaction to a disaster", (waugh 2000) begins. examples include mass evacuations, sandbagging buildings and other structures, providing emergency medical services, firefighting, and restoration of public order. in some situations, the response period may be a short (e.g., house fire), intermediate (e.g., bomb detonation), or extended (e.g., pandemic influenza) duration. after a period of time, the recovery phase follows. these are "activities that continue beyond the emergency period to restore lifelines" (waugh 2000) . examples include the provision of temporary shelter, restoration of utilities such as power, critical stress debriefing for responders, and victims, job assistance and small business loans, and debris clearance. recovery always seems to be the most unpredictable; it may take days to months to years. as demonstrated with recent hurricanes harvey, irma, and maria in 2017, the most affected regions are still in the phase of recovery and may be along a prolonged track as hurricane katrina in 2005. as mentioned, the early phases of planning (mitigation and preparedness) truly hinge upon the environment or community surrounding the health care site (e.g., clinic, hospital, or long-term care facility). identification of potential hazards and risks is a key step in disaster planning. using a hazard vulnerability assessment (hva) or a threat and hazard identification and risk assessment (thira) can provide a basis for mitigation and prevention tasks. an hva/thira emphasizes which types of natural or man-made disasters are likely to occur in a community (e.g., tornado, flood, chemical release, or terrorist event). they further highlight the impact those disasters may have on the community and any capabilities that are in place that may lessen the effects of the disaster (illinois emergency medical services for children 2018). a basic principle of the hva methodology is to determine the risk of such an event or attack occurring at a given hospital or hospital system. simply, the risk is a product of the probability of an event and the severity of such an event if it occurs (risk = probability ã� severity). however, there are many complexities in quantifying terrorism risk (waugh 2005; woo 2002) . it is important to note that in some circumstances, exposure may need to be included in the equation (risk = probability ã� severity ã� exposure), but usually for operational risk management applications (mitchell and decker 2004) . at any rate, issues to consider for the probability of an event occurring include, but are not limited to, geographic location and topography, proximity to hazards, degree of accessibility, known risks, historical data, and statistics of various manufacturer/vendor products. severity, on the other hand, is dependent on the gap between the magnitude of an event and mitigation for the given event (severity = magnitude -mitigation). magnitude varies upon the impact of the event to humans, property, and/or business. mitigation varies upon the development of internal and external readiness before a disaster strikes. as one can surmise, if the magnitude of the event outstrips the mitigation, the event is considered a threatening hazard. once the hva is completed, the health care site should immediately prioritize planning efforts for the top 5-10 hazards and develop plans accordingly. all other identified hazards must also be addressed to ensure a broad and robust disaster plan. it is important to realize that local and regional entities also perform comprehensive hvas. a concerted analysis among a hospital and key community stakeholders is optimal for a coordinated plan. an hva/thira contains both quantitative and qualitative components. specific tools have been developed through private and public organizations (e.g, fema) that can help in the analysis (united states department of homeland security, federal emergency management agency 2001). using these tools as a guide, the entity can determine what types of hazards have a high, medium, or low probability of occurring within specific geographic boundaries. typically, these tools do not have components specific to children or other at-risk populations. however, the tools can be adapted either directly by adding children to specific hazards or ensuring considerations specific to children are incorporated into the hva/thira calculations. the hva/thira should be reviewed and updated minimally on an annual basis to identify changing or external circumstances. this includes conducting a pediatric-specific disaster risk assessment to identify where children congregate and their risks (e.g., schools, popular field trip designations, summer camps, houses of worship, and juvenile justice facilities) (illinois emergency medical services for children 2018). of note, hva techniques have been utilized for pediatric-specific disaster plans. having a separate pediatric hva (phva) is crucial to a well-rounded and robust health care disaster plan. first, it demonstrates the extent of the pediatric population in the community. it is estimated that 25% of the population fits within the age range of pediatric patients. in some situations, it may be more. during the performance of a phva, it was demonstrated that 29% of the community was less than 19 years of age (jacobson and severin 2012) . second, a phva increases the situational awareness of those tasked to plan for disasters that involve children and adolescents. often times, children and adolescents are excluded from local and regional disaster plans. the unique vulnerabilities of pediatric patients will demand appropriate drills, exercises, equipment, medications, and expertise. thirdly, identifying pediatric risks in a community will help prioritize efforts of planning, especially in those hospitals not accustomed to caring for pediatric patients. finally, a phva helps to develop a framework for global pediatric disaster planning. this can extend beyond a local community and actually advance city, state, regional, and national disaster planning efforts. there has been a development of web-based tools to simplify and enhance the phva process (jacobson and severin 2012) . after an hva/thira has been completed, the results should be used to help direct and plan drills/exercises based on high impact and high probability threats. it is advised to conduct an hva/thira on an annual basis to assess specific threats unique to your organization's physical structure as well as the surrounding geographic environment. it will also provide insight into whether there is an improvement in previous planning efforts. completion of a population assessment that provides a demographic overview of the community with a breakdown of the childhood population is strongly recommended in conjunction with the hva/ thira. collaborating with other community partners, such as local health departments and emergency management agencies, can assist an organization with the conduction of a comprehensive hva/thira (illinois emergency medical services for children 2018). please see chap. 13 for further information on hospital planning. pediatric supplies, equipment, and medications will be scarce during a disaster. it will become more of an issue if the health care facility is not accustomed to caring for acutely ill pediatric patients. this will be further exacerbated by a massive surge of acutely ill pediatric patients, a widespread or prolonged disaster, and supply line disruptions. to protect the health security of children and families during a public health emergency, the assistant secretary for preparedness and response (aspr) manages and maintains the strategic national stockpile (sns), a cache of medical countermeasures for rapid deployment and use in response to a public health emergency or disaster (fagbuyi et al. 2016) . various pediatric-specific supplies and countermeasures are included in the sns. maintaining a supply of medications and medical supplies for specific health threats allows the stockpile to respond with the right product when a specific disease or agent is known. if a community experiences a large-scale public health incident in which the disease or agent is unknown, the first line of support from the stockpile is to send a broad-range of pharmaceuticals and medical supplies. place and martin 2012) . the emergency equipment and supply lists can easily be adapted for any pediatric disaster emergency (place and martin 2012) or incident requiring pediatric mass critical care (desmond et al. 2011) . ageappropriate nutrition, hygiene, bedding, and toys/distraction devices should also be available (illinois emergency medical services for children 2013) (tables 5.3 and 5.4). endotracheal tubes â�¢ uncuffed: 2.5 and 3.0 mm â�¢ cuffed or uncuffed: 3.5, 4.0, 4.5, 5.0, and 5.5 mm â�¢ cuffed: 6.0, 6.5, 7.0, 7.5, and 8.0 mm feeding tubes (5f and 8f) laryngoscope blades curved: 2 and 3; straight: 0, 1, 2, and 3 laryngoscope handle magill forceps (pediatric and adult) nasopharyngeal airways (infant, child, and adult) oropharyngeal airways (sizes 0-5) stylets for endotracheal tubes (pediatric and adult) suction catheters (infant, child, and adult) tracheostomy tubes (sizes 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, and 5.5 mm) yankauer suction tip bag-mask device (manual resuscitator), self-inflating (infant size: 450 ml; adult size: 1000 ml) clear oxygen masks (standard and nonrebreathing) for an infant, child, and adult masks to fit bag-mask device adaptor (neonatal, infant, child, and adult sizes) nasal cannulas (infant, child, and adult) nasogastric tubes (sump tubes): infant (8f), child (10f), and adult (14f-18f) laryngeal mask airway a vascular access arm boards (infant, child, and adult sizes) catheter over-the-needle device (14-24 gauge) intraosseous needles or device (pediatric and adult sizes) intravenous catheter-administration sets with calibrated chambers and extension tubing and/or infusion devices with ability to regulate rate and volume of infusate umbilical vein catheters (3.5f and 5.0f) b central venous catheters (4.0f-7.0f) intravenous solutions to include normal saline, dextrose 5% in normal saline, and dextrose 10% in water fracturemanagement devices extremity splints, including femur splints (pediatric and adult sizes) spine-stabilization method/devices appropriate for children of all ages c (continued) laryngeal mask airways could be shared with anesthesia but must be immediately accessible to the ed b feeding tubes (size 5f) may be used as umbilical venous catheters but are not ideal. a method for securing the umbilical catheter, such as an umbilical tie, should also be available c a spinal stabilization device is one that can stabilize the neck of an infant, child, or adolescent in a neutral position when a pediatric disaster victim presents acutely ill to the hospital, various emergency interventions will be needed to stabilize the patient. evaluation of the pediatric patient should include a primary survey (abcde), secondary survey (focused sample history and focused physical examination), and diagnostic assessments (laboratory, radiological, and other advanced tests). this will guide further therapeutic interventions. particular attention should be given to the identification of respiratory and/or circulatory derangements of the child, including airway obstruction, respiratory failure, shock, and cardiopulmonary failure. interventions will be based on physiologic derangements of the pediatric patient and determined by the scope of practice and protocols, such as standard resuscitation algorithms for neonatal (american academy of pediatrics and american heart association et al. 2016) and pediatric (american heart association 2016) victims. the hcp must be knowledgeable of various emergency medications (table 5 .1) used for children, the appropriate dosages and their mechanism of action, any potential side effects, and drug/drug interactions. other medications, such as antibiotics, antidotes, or countermeasures, may be needed as well. pharmacologic therapy should be initiated immediately based on clinical suspicion and not delayed due to pending laboratory tests (e.g., antibiotics for presumed infection/sepsis or antidotes for suspected nerve agents). dosages should be based on the patient's weight or a length-based weight system. (montello et al. 2006) or hard copy countermeasure manuals may be more practical, especially during a disaster incident when computer service or internet access may be unreliable. in 1988, the centre for research on the epidemiology of disasters (cred) launched the emergency events database (em-dat). em-dat was created with the initial support of the world health organization (who) and the belgian government. the main objective of the database is to serve the purposes of humanitarian action at national and international levels. the initiative aims to rationalize decision-making for disaster preparedness as well as provide an objective base for vulnerability assessment and priority setting. em-dat contains essential core data on the occurrence and effects of over 22,000 mass disasters in the world from 1900 to the present day. the database is compiled from various sources, including united nation agencies, nongovernmental organizations (ngos), insurance companies, research institutes, and press agencies (cred 2019). as described in the cred report entitled natural disasters 2017: lower mortality, higher cost, a disaster is entered into the database if at least one of the following criteria is fulfilled: 10 or more people reported killed; 100 or more people reported affected; declaration of a state of emergency; and/or call for international assistance (cred 2018). in economic losses, poverty and disasters 1998-2017: cred/unisdr report, the cred defines a disaster as "a situation or event which overwhelms local capacity, necessitating a request at national or international level for external assistance; an unforeseen and often sudden event that causes great damage, destruction and human suffering" (cred 2018). the cred em-dat classifies disasters according to the type of hazard that triggers them. the two main disaster groups are natural and technological disasters. there are six natural disaster subgroups. geophysical disasters originate from the solid earth and include earthquake (ground movement and tsunami), dry mass movement (rock fall and landslides), and volcanic activity (ash fall, lahar, pyroclastic flow, and lava flow). lahar is a hot or cold mixture of earthen material flowing on the slope of a volcano either during or between volcanic eruptions. meteorological disasters are caused by short-lived, micro-to meso-scale extreme weather and atmospheric conditions that last from minutes to days and include extreme temperatures (cold wave, heat wave, and severe winter conditions such as snow/ice or frost/ freeze), fog, and storms. storms can be extra-tropical, tropical, or convective. convective storms include derecho, hail, lightning/thunderstorm, rain, tornado, sand/dust storm, winter storm/blizzard, storm/surge, and wind. derecho is a widespread and usually fast-moving windstorm associated with convection/convective storm and includes downburst and straight-line winds. hydrological disasters are caused by the occurrence, movement, and distribution of surface/subsurface freshwater and saltwater and include floods, landslides (an avalanche of snow, debris, mudflow, and rockfall), and wave action (rogue wave and seiche). flood types can be coastal, riverine, flash, or ice jam. climatological disasters are caused by longlived, meso-to macro-scale atmospheric processes ranging from intraseasonal to multidecadal climate variability and include drought, glacial lake outburst, and wildfire (forest fire, land fire: brush, bush, or pasture). biological disasters are caused by the exposure to living organisms and their toxic substances or vectorborne diseases that they may carry and include epidemics (viral, bacterial, parasitic, fungal, and prion), insect infestation (grasshopper and locust), and animal accidents. extraterrestrial disasters are caused by asteroids, meteoroids, and comets as they pass near-earth, enter earth's atmosphere, and/or strike the earth, and by changes in the interplanetary conditions that affect the earth's magnetosphere, ionosphere, and thermosphere. types include impact (airbursts) and space weather (energetic particles, geomagnetic storm, and shockwave) events (cred 2019). there are three technological disaster subgroups. industrial accidents include chemical spills, collapse, explosion, fire, gas leak, poisoning, radiation, and oil spills. a chemical spill is an accidental release occurring during the production, transportation, or handling of hazardous chemical substances. transport accidents include disasters in the air (airplanes, helicopters, airships, and balloons), on the road (moving vehicles on roads or tracks), on the rail system (train), and on the water (sailing boats, ferries, cruise ships, and other boats). miscellaneous accidents vary from collapse to explosions to fires. collapse is an accident involving the collapse of a building or structure and can either involve industrial structures or domestic/nonindustrial structures (cred 2019). technological disasters are considered man-made, but as suggested by their subgroup, they are accidental and not intentional. the united nations office for disaster risk reduction (unisdr) and cred report, economic losses, poverty, and disasters 1998-2017, reviews global natural disasters during that time period, their economic impact, and the relationship with poverty. between 1998 and 2017, climate-related and geophysical disasters killed 1.3 million people and left a further 4.4 billion injured, homeless, displaced, or in need of emergency assistance. although the majority of fatalities were due to geophysical events, mostly earthquakes and tsunamis, 91% of all disasters was caused by floods, storms, droughts, heatwaves, and other extreme weather events. the financial impact was staggering. in 1998-2017, disaster-hit countries reported direct economic losses valued at us$ 2908 billion, of which climate-related disasters caused us$ 2245 billion or 77% of the total. this was up from 68% (us$ 895 billion) of losses (us$ 1313 billion) reported between 1978 and 1997. overall, reported losses from extreme weather events rose by 151% between these two 20-year periods. in absolute monetary terms, over the last 20-years, the usa recorded the biggest losses (us$ 945 billion), reflecting high asset values as well as frequent events. china, by comparison, suffered a significantly higher number of disasters than the usa (577 vs. 482) but lower total losses (us$ 492 billion) (cred 2018) (figs. 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8 and 5.9 in 2018, 281 climate-related and geophysical incidents in the world were estimated with 10,733 deaths and over 60 million people impacted. indonesia recorded approximately half of the deaths with india accounting for half of those impacted by disasters. notable features of 2018 were intense seismic activity in indonesia, a series of disasters in japan, floods in india, and an eventful year for both volcanic activity and wildfires. however, an ongoing trend of lower death tolls from previous years continued into 2018 (centre for research on the epidemiology of disasters (cred) and united nations office for disaster risk reduction (unisdr) 2019) (tables 5.5, 5.6, 5.7, 5.8, 5.9, 5.10 and 5.11 there are no specific deviations when medically managing children after a natural disaster. according to sirbaugh and dirocco (2012) "small-scale mass casualty incidents occur daily in the united states. few present unusual challenges to the local medical systems other than in the number of patients that must be treated at one time. except in earthquakes, explosions, building collapses, and some types of terrorist attacks, the same holds true for large-scale disasters. sudden violent disaster mechanisms can produce major trauma cases, including patients needing field amputations or management of crush syndrome. for the most part, medicine after a disaster is much the same as it was before the disaster, with more minor injuries, more people with exacerbations of their chronic illnesses, and number of patients seeking what is ordinarily considered primary care. this is true for children and adults." it should be noted, however, that children have a predisposition to illness and injury after natural disasters. the hcp must be able to identify any health problems and treat the child effectively and efficiently while utilizing standard resuscitation protocols as indicated. traumatic injuries may be seen after any natural disaster. the injuries can range from minor scrapes and bruises to major blunt trauma or traumatic brain injury. children are at increased risk for injury since adults are distracted by recovery efforts and may not be able to supervise them closely. the environment may not be safe due to environmental hazards, such as collapsed buildings, sinkholes, and high water levels. dangerous equipment used during relief efforts may be present, such as heavy earth moving equipment, chainsaws, and power generators. hazardous chemicals, such as gasoline and other volatile hydrocarbons, may be readily accessible or taint the environment. without suitable shelter, children are also exposed to weather, animals, and insects (sirbaugh and dirocco 2012) . infectious diseases may also pose a problem to children after a natural disaster. infectious patterns will persist during a disaster based on the season and time of year. there may be outbreaks or epidemics of highly contagious infections (e.g., influenza, respiratory syncytial virus, streptococcus pyogenes) due to mass sheltering of children and families. poor nutrition or decreased availability of food may lower their resistance against infections. various water-borne or food-borne diseases may cause illnesses in children. poor hygiene and mass shelter environments may exacerbate these illnesses. immunized children should be protected against common preventable diseases after a natural disaster but still could be a problem in mass groups that are not completely or appropriately immunized. after the 2010 haiti earthquake, there were increased cases of diarrhea, cholera, measles, and tetanus in children months after the earthquake despite some level of vaccination (sirbaugh and dirocco 2012) . children are at risk for various environmental emergencies. austere environments will impact children greatly. heat exposure coupled with minimal access to drinkable water may lead to severe dehydration. exposure to the cold may lead to frostbite or hypothermia. children are at risk for carbon monoxide toxicity due to generator use or natural gas poisoning due to disrupted gas lines. there is always a risk for thermal injury due to the use of candles and other flame sources. exposure to animals (snakes) and insects (spiders) may increase the risk of envenomation. submersion injury and drowning incidents may escalate. this will be due to lack of supervision of children around storm drains, newly formed bodies of water, or rushing waters of storm diversion systems (sirbaugh and dirocco 2012) . mental health issues are often seen in children after natural disasters. even though a child may not be injured, they may become "psychiatric casualties" due to the horrific sights they have seen during or after the disaster. children and adolescents with behavioral or psychiatric problems may experience worsening symptoms and signs due to stress, trauma, disruption of routines, or availability of medications. this is often exacerbated if the parent, guardian, caregiver, or hcp is also having difficulty coping with the stress of the disaster. in general, the most common mental health problem in children is a post-traumatic stress disorder. however, separation anxiety, obsessive-compulsive symptoms, and severe stranger anxiety can also be seen in children after a traumatic event (sirbaugh and dirocco 2012) . see chap. 12 for more detailed information. terrorism impacts children and families all around the world (tables 5.12 and 5.13). after the events of 9/11, much attention has been given to the possibility of another mass casualty act of terrorism, especially with weapons of mass destruction, that include chemical, biological, nuclear, radiological, and explosive devices (cbnre), or other forms of violence such as active shooter incidents and mass shootings (jacobson and severin 2012) . since then, other incidents, both foreign and domestic, have involved children and complicates the concept of and the response to terrorism. johnston (2017) said it best in his review of terrorist and criminal attacks targeting children: "one of the more accepted defining characteristics of terrorism is that it targets noncombatants including men, women, and children. however, terrorist attacks specifically targeting children over other noncombatants are uncommon. this is for the same reason that most terrorists have historically avoided mass casualty terrorism: the shock value is so great that such attacks erode support for the terrorists' political objectives. the 9/11 attacks represent an increasing trend in mass casualty terrorism. at the same time, policymakers are examining this evolving threat, they must increasingly consider the threat of terrorist attacks targeting children." based on historical events, it is clear infants, toddlers, children, and adolescents have been victims of terrorism. this global trend of terrorists targeting children seems to be escalating (johnston 2017) . therefore, it is imperative to understand terrorism and ways it impacts the children and families served by the health care community. combs (2018) defines terrorism as "an act of violence perpetrated on innocent civilian noncombatants in order to evoke fear in an audience". however, she goes on to argue that to become an operational definition, there must also be the addition of a "political purpose" of the violent act. therefore, "terrorism, then, is an act composed of at least four crucial elements: 1) it is an act of violence, 2) it has a political motive or goal, 3) it is perpetrated against civilian noncombatants, and 4) it is staged to be played before an audience whose reaction of fear and terror is the desired result." (combs 2018) . there are different typologies of terrorism. at least five types of terror violence have been suggested by feliks gross: "mass terror is terror by a state, where the regime coerces the opposition in the population, whether organized or unorganized, sometimes in an institutionalized manner. dynastic assassination is an attack on a head of state or a ruling elite. random terror involves the placing of explosives where people gather (such as post offices, railroads, and cafes) to destroy whoever happens to be there. focused random terror restricts the placing of explosives, for example to where significant agents of oppression are likely to gather. finally, tactical terror is directed solely against the ruling government as a part of a 'broad revolutionary strategic plan'" (combs 2018 ). an additional typology offered is "lone wolf terror which involves someone who commits violent acts in support of some group, movement, or ideology, but who does stand alone, outside of any command structure and without material assistance from any group" (combs 2018) . martin (2017) reviews eight different terrorism typologies in the ever shifting, multifaceted world of modern terrorism. the new terrorism "is characterized by the threat of mass casualty attacks from dissident terrorist organizations, new and creative configurations, transnational religious solidarity, and redefined moral justifications for political violence" (martin 2017) . state terrorism is "committed by governments against perceived enemies and can be directed externally against adversaries in the international domain or internally against domestic enemies" (martin 2017) . dissident terrorism is "committed by nonstate movements and groups against governments, ethno-national groups, religious groups, and other perceived enemies" (martin 2017) . religious terrorism is "motivated by an absolute belief that an otherworldly power has sanctioned and commanded the application of terrorist violence for the greater glory of the faithâ�¦[it] is usually conducted in defense of what believers consider to be the one true faith" (martin 2017) . ideological terrorism is "motivated by political systems of belief (ideologies), which champion the self-perceived inherent rights of a particular group or interest in opposition to another group or interest. the system of belief incorporates theoretical and philosophical justifications for violently asserting the rights of the championed group or interest" (martin 2017) . international terrorism "spills over onto the world's stage. targets are selected because of their value as symbols of international interests, either within the home country or across state boundaries" (martin 2017) . criminal dissident terrorism "is solely profit-driven, and can be some combination of profit and politics. for instance, traditional organized criminals accrue profits to fund their criminal activity and for personal interests, while criminalpolitical enterprises acquire profits to sustain their movement" (martin 2017) . gender-selective terrorism "is directed against an enemy population's men or women because of their gender. systematic violence is directed against men because of the perceived threat posed by males as potential soldiers or sources of opposition. systematic violence is directed against women to destroy an enemy group's cultural identity or terrorize the group into submission" (martin 2017) . the all-hazards national planning scenarios are an integral component of dhs's capabilities-based approach to implementing homeland security presidential directive 8: national preparedness (hspd-8). the national planning scenarios are planning tools and are representative of the range of potential terrorist and natural disasters and the related impacts that face the nation. the federal interagency community has developed 15 all-hazards planning scenarios for use in national, federal, state, and local homeland security preparedness activities. the objective was to develop a minimum number of credible scenarios to establish the range of response requirements to facilitate disaster planning (dhs 2006) (table 5 .14). twelve of the scenarios represent terrorist attacks while three represent natural disasters or naturally occurring epidemics. this ratio reflects the fact that the nation has recurring experience with natural disasters but faces newfound dangers, including the increasing potential for use of weapons of mass destruction by terrorists. the scenarios form the basis for coordinated federal planning, training, exercises, and grant investments needed to prepare for all hazards. dhs employed the scenarios as the basis for a rigorous task analysis of prevention, protection, response, and recovery missions and identification of key tasks that supported the development of essential all-hazards capabilities (united states department of homeland security, federal emergency management agency 2019) (table 5 .15). each of the 15 scenarios follows the same outline to include a detailed scenario description, planning considerations, and implications. for each of the 12 terrorismrelated scenarios, fema national preparedness directorate (npd) partnered with dhs office of intelligence and analysis (i&a) and other intelligence community and law enforcement experts to develop and validate prevention prequels. the prequels provide an understanding of terrorists' motivation, capability, intent, tactics, techniques and procedures, and technical weapons data. the prequels also provide a credible adversary based on known threats to test the homeland security community's ability to understand and respond to indications and warnings of possible terrorist attacks (united states department of homeland security, federal emergency management agency 2019). a chemical agent of terrorism is defined as any chemical substance intended for use in military operations to kill, seriously injure, or incapacitate humans (or animals) through its toxicological effects. chemicals excluded from this list are riot-control agents, chemical herbicides, and smoke/flame materials. chemical agents are classified as toxic agents (producing injury or death) or incapacitating agents (producing temporary effects). toxic agents are further described as nerve agents (anticholinesterases), blood agents (cyanogens), blister agents (vesicants), and lung-damaging agents (choking agents). incapacitating agents include stimulants, depressants, psychedelics, and deliriants (banks 2014; departments of the army, the navy, and the air force, and commandant, marine corps 1995). nerve agents are organophosphate anticholinesterase compounds. they are used in various insecticide, industrial, and military applications. military-grade agents include tabun (ga), sarin (gb), soman (gd), cyclosarin (gf), venom x (vx), and the novichok series. these are all major military threats. the only known battlefield use of nerve agents was the iraq-iran war. however, other nerve agent incidents, such as the 1995 tokyo subway attack (sarin), the chemical attacks in syria (chlorine, sarin, mustard), and the attempted assassination of sergei skripal in salisbury, uk (novichok), support that civilian threats also exist. nerve agents are volatile chemicals and can be released in liquid or vapor form. however, the liquid form can become vapor depending upon its level of volatility (e.g, g-agents are more volatile than vx). the level of toxicity depends on the agent, concentration of the agent, physical form, route and length of exposure, and environmental factors (temperature and wind) (tables 5.16 and 5.17). nerve agents exert their effects by the inhibition of esterase enzymes. acetylcholinesterase inhibition prevents the hydrolysis of acetylcholine. the clinical result is a cholinergic crisis and subsequent overstimulation of muscarinic and nicotinic receptors throughout the body including the central nervous system. clinical muscarinic responses include sludge (salivation, lacrimation, urination, defecation, gastrointestinal distress, and emesis) and dumbels (diarrhea, urinary incontinence, miosis/muscle fasciculation, bronchorrhea/bronchospasm/bradycardia, emesis, lacrimation, and salivation). nicotinic responses vary by site. preganglionic sympathetic nerve stimulation produces mydriasis, tachycardia, hypertension, and pallor. however, stimulation at the neuromuscular junction leads to muscular fasciculation and cramping, weakness, paralysis, and diaphragmatic weakness. central nervous system presentations range from anxiety and restlessness to seizures, coma, and death (banks 2014; rotenberg and newmark 2003; rotenberg 2003b ). pediatric manifestations (table 5 .19) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. 2008 ): â�¢ children may manifest symptoms earliest and possibly more severe presentations. â�¢ could be hospitalized for similarly related illnesses and diseases. â�¢ smaller mass. â�¢ lower baseline cholinesterase activity. â�¢ tendency to bronchospasm. â�¢ pediatric airway and respiratory differences. â�¢ altered pulmonary compensation. â�¢ lower reserves of cardiovascular system and fluids. â�¢ isolated central nervous system signs (stupor, coma). â�¢ less miosis. â�¢ vulnerability to seizures and neurotransmitter imbalances (excitability). â�¢ immature metabolic systems. differential diagnoses include upper or lower airway obstruction, bronchiolitis, status asthmaticus, cardiogenic shock, acute gastroenteritis, seizures, and poisonings (carbon monoxide, organophosphates, and cyanide). diagnostic tests include acetylcholinesterase levels, red blood cell cholinesterase levels, and an arterial blood gas. treatment (tables 5.20 and 5.21) includes decontamination (reactive skin decontamination lotion â® [potassium 2,3-butanedione monoximate], soap and water, and 0.5% hypochlorite solution), supportive care, and administration of nerve agent antidotes (atropine, pralidoxime chloride, and diazepam). atropine is a competitive antagonist of acetylcholine muscarinic receptors and reverses peripheral muscarinic symptoms. it does not restore function at the neuromuscular junction nicotinic receptors. it does, however, treat early phases of convulsions. pralidoxime chloride separates the nerve agent from acetylcholinesterase and restores enzymatic function. it also binds free nerve agent. the major goal is to prevent "aging" of the enzyme (e.g., gd). diazepam provides treatment of nerve agent-induced seizures and prevents secondary neurologic injury. typically, associated seizures are refractory to other antiepileptic drugs. the antiseizure effect of diazepam is enhanced by atropine (banks 2014; cieslak and henretig 2016; messele et al. 2018) . potential medical countermeasures include trimedoxime (tmb4), hi-6 (an h-series oxime), obidoxime, "bioscavengers" (butyrylcholinesterase, carboxylesterase, organophosphorus acid anhydride hydrolase, and human serum paraoxonase), novel anticonvulsant drugs, n-methyl-d-aspartate (nmda) receptor antagonists (ketamine, dexanabinol), and common immunosuppressants such as cyclosporine a (jokanovic 2015; merrill et al. 2015 ; national institutes of health 2007; united states department of health and human services 2017). all patients should be observed closely for electroencephalographic changes and neuropsychiatric pathologies. polyneuropathy, reported after organophosphate insecticide poisoning, has not been reported in humans exposed to nerve agents and has been produced in animals only at unsurvivable doses. the intermediate syndrome has not been reported in humans after nerve agent exposure, nor has it been produced in animals. muscular necrosis has occurred in animals after high-dose nerve agent exposure but reversed within weeks; it has not been reported in humans (banks 2014). on march 4, 2018, sergei skripal, a former russian double agent, and his daughter, yulia skripal, were found unresponsive on a park bench in salisbury, uk. they were brought to a nearby hospital and treated for signs consistent with a cholinergic crisis due to a nerve agent exposure. analysis of the skripals found the presence of a secret nerve agent called novichok. further testing found high concentrations of the agent on the front-door handle of his home. one of the investigating police officers, detective sergeant nick bailey, unknowingly touched the door-handle and also became ill. all three survived due to rapid recognition of the nerve agent exposure by hospital personnel. four months later, two other people, dawn sturgess and charlie rowley, became ill with identical symptoms in the town of amesbury, 7 miles from salisbury. they were later confirmed to have high concentrations of novichok on their hands from a perfume bottle found in a recycling bin. both were immediately treated, but dawn sturgess later died. charlie rowley survived. it was believed the discarded perfume bottle contained novichok and was discarded by the assailants after the attempt on sergei skripal. on september 5, 2018, the uk government revealed that their investigation uncovered two suspects from closed circuit television (cctv) footage near the skripal's home. the suspects entered the uk on russian passports using the names alexander petrov and ruslan boshirov, stayed in a london hotel for 2 days, visited salisbury briefly, and then returned to moscow. minute traces of novichok were also found in the london hotel where they had stayed. the uk prime minister, teresa may, said that the suspects are thought to be officers from russia's military intelligence service the glavnoye razvedyvatel'noye upravleniye (gru), and that this showed that the poisoning was "not a rogue operation" and was "almost certainly" approved at a senior level of the russian state. the two suspects later appeared on russian tv denying the accusations and saying they were just "tourists" who had traveled all the way from moscow to salisbury just to see the "famous cathedral". however, cctv of the cathedral area found no evidence of the two men visiting the cathedral, although they were captured on cctv near the skripal's home. in a development in september 2018, one of the men was revealed as actually being a russian intelligence officer named colonel anatoliy chepiga and was a decorated veteran of russian campaigns in chechnya and ukraine. and later in october, the second man was named as dr. alexander mishkin, a naval medical doctor allegedly recruited by the gru (chai et al. 2018; may 2018) . novichok (ð�ð¾ð²ð¸ñ�ð¾ñ�: russian for "newcomer") is a highly potent nerve agent developed from the russian classified nerve agent program known as foliant. almost everything known about these agents is due to a russian defector, vil mirzayanov (2009) who was an analytical chemist at the russian state research institute of organic chemistry and technology (gosniiokht). he has described the details of the novichok program in his book "state secrets: an insider's chronicle of the russian chemical weapons program". the first three nerve agents of the novichok series developed in the program were substance-33, a-230, and a-232 (table 5 .18). they were synthesized as unitary agents, like vx, tabun, soman, and sarin. unitary means that the chemical structure was produced at its maximum potency. however, the novichok agents were developed as binary agents: maximum potency when two inert substances are combined together prior to deployment to create the active nerve agent (cieslak and henretig 2003) . very little is known about the chemistry of these weaponized organophosphate agents. however, they appear to be more potent than current nerve agents. for example, the ld 50 of novichok agents is reported 0.22 î¼g/kg similar to 2-(dimethylamino)ethyl n,n-dimethylphosphoramidofluoridate (vg), a novel fourth generation nerve agent. furthermore, novichok-5 is 8ã� more effective than vx and novichock-7 is 10ã� more effective than soman (cieslak and henretig 2003; hoenig 2007) . clinically, they behave like other organophosphates by binding to acetylcholinesterase preventing the breakdown of acetylcholine thereby leading to a cholinergic crisis. there appears to be a similar "aging" process as seen with other nerve agents. in addition, the novichok agents binding to peripheral sensory nerves distinguishes this class of organophosphates. prolonged or high-dose exposure results in debilitating peripheral neuropathy. exposure to these agents is fatal unless aggressively managed (cieslak and henretig 2003) . decontamination is essential to prevent ongoing exposure to the patient and medical personnel. clothing should be removed and quickly placed in a sealed bag (prevents ongoing exposure to the emission of vapors) followed by thorough washing with soap and water. application of dry bleach powder should be avoided as it may hydrolyze nerve agents into toxic metabolites that can produce ongoing cholinergic effects. supportive care is essential. antidote therapy should be given as usual for nerve agents, including atropine, diazepam, and pralidoxime chloride (united states department of health and human services, office of the assistant secretary for preparedness and response, national library of medicine 2019; united states department of health and human services, chemical hazards emergency medical management (chemm) 2019). of note, the toxicity of the novichok agents may not rely on anticholinesterase inhibition. some have suggested that reactive oximes like potassium 2,3-butanedione monoximate are preferred oximes for antidotal therapy (cieslak and henretig 2003) . cyanide is a naturally occurring chemical. it can be found in plants and seeds. it is also used in many industrial applications and is a common product of combustion of synthetic materials. typical cyanogens include hydrogen cyanide (ac) and cyanogen chloride (ck). low levels of cyanide are detoxified by a natural reaction in the human body using the rhodanese system. there is reversible metabolism with vitamin b12a to vitamin b12 (cyanocobalamin). an irreversible reaction occurs with sulfanes to produce thiocyanates and sulfates. the former is excreted via the urinary tract. when cyanide overwhelms this natural process, cyanide binds to (1990) a vx = venom x (cieslak and henretig 2003) cytochrome oxidase within the mitochondria and disrupts cellular respiration. cyanide has an affinity for fe+3 in the cytochrome a3 complex and oxidative phosphorylation is interrupted. cells can no longer use oxygen to produce atp and lactic acidosis ensues from resultant anaerobic metabolism. when inhaled, cyanide produces rapid onset of clinical signs. findings include transient tachypnea and kussmaul breathing (from hypoxia of carotid and aortic bodies), hypertension and tachycardia (from hypoxia of aortic body), and neurologic findings such as seizures, muscle rigidity (trismus), opisthotonus, and decerebrate posturing. other findings include cherry red flush, acute respiratory failure/ arrest, bradycardia, dissociative shock, and cardiac arrest. venous blood samples exhibit a bright red color. arterial blood gas may demonstrate a metabolic acidosis with an increased anion gap due to lactic acid (banks 2014; cieslak and henretig 2016; rotenberg 2003a) . pediatric manifestations (table 5 .19) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. 2008 ): â�¢ thinner integument leading to shorter time from exposure to symptom development. â�¢ higher vapor density (ck) and concentration accumulation in living zone of children, â�¢ higher minute ventilation and metabolism. â�¢ abdominal pain, nausea, restlessness, and giddiness are common early findings. â�¢ cyanosis mostly noted other than classic cherry red flushing of the skin. â�¢ resilient with recovery even when just using supportive measures alone. differential diagnoses include meningitis, encephalitis, gastroenteritis, ischemic stroke, methemoglobinemia, and poisonings (nerve agents, organophosphates, methanol, hydrogen sulfide, and carbon monoxide). diagnostic tests include arterial blood gas, lactic acid, and thiocyanate levels. treatment (tables 5.20 and 5.21) includes decontamination, supportive care, and administration of cyanide antidote kit (nitrites and thiosulfate). the nitrites facilitate the production of methemoglobinemia (fe+3) which attracts cyanide molecules forming cyanmethemoglobin. amyl nitrite pearls are crushed into gauze and placed over the mouth/nose or in a mask used for bag/mask ventilation. sodium nitrite is given parenterally and dosed according to the patient's estimated hemoglobin so as to prevent severe methemoglobinemia. since the formation of cyanmethemoglobin is a reversible reaction, and sodium thiosulfate is given to extract the cyanide. dosing is also dependent upon estimated hemoglobin. along with the naturally occurring rhodanese enzymatic system, the irreversible reaction forms thiocyanate. thiocyanate is water soluble and is excreted harmlessly via the kidneys (banks 2014; cieslak and henretig 2016). potential medical countermeasures (national institutes of health 2007; united states army medical research institute of infectious diseases (usamriid) 2014) include hydroxocobalamin, cobinamide (a cobalamin precursor), dicobalt edetate, cyanohydrin-forming compounds (alpha-ketoglutarate and pyruvate), s-substituted crystallized rhodanese, sulfur-containing drugs (n-acetylcysteine), and methemoglobin inducers (4-dimethylaminophenol and others). blistering agents, or vesicants, promote the production of blisters. typical examples include sulfur mustard (hd), nitrogen mustard (hn), and lewisite (l). these agents, especially sulfur mustard, are considered capable chemical weapons since illness may not occur until hours or days later. vesicants are alkylating agents that affect rapidly reproducing and poorly differentiated cells in the body. however, they can also produce cellular oxidative stress, deplete glutathione stores, and promote immature cognitive function unable to flee emergency immature coping mechanisms inability to discern threat, follow directions, and protect self high risk for developing ptsd bbb blood-brain barrier, bsa body surface area, cns central nervous system, ptsd post-traumatic stress disorder (hilmas et al. 2008) intense inflammatory responses. clinical findings are initially cutaneous (erythema, pruritus, yellow blisters, ulcers, and sloughing), respiratory (hoarseness, cough, voice changes, pneumonia, respiratory failure, acute lung injury, and acute respiratory distress syndrome), and ophthalmologic (pain, irritation, blepharospasm, photophobia, conjunctivitis, corneal ulceration, and globe perforation) in nature. after exposure through these primary portals of entry, other sites are affected, including the gastrointestinal tract (nausea, vomiting, and mucosal injury), the hematopoietic system (bone marrow suppression), the cardiovascular system (l), reproductive system (hd, hn) , and the central nervous system (lethargy, headache, malaise, and depression) (banks 2014; yu et al. 2003) . pediatric manifestations (table 5 .19) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. 2008 ): â�¢ thinner integument leading to shorter time from exposure to symptom development. â�¢ higher vapor density and concentration accumulation in the living zone. â�¢ higher minute ventilation and metabolism. â�¢ greater pulmonary injury. â�¢ ocular findings more frequent (less self-protection and more hand/eye contact). â�¢ gastrointestinal manifestations more prominent. â�¢ unable to escape and decontaminate. â�¢ unable to verbalize complaints (i.e., pain). treatment (tables 5.20 and 5.21) includes decontamination and supportive care. currently, there are no antidotes for mustard toxicity (cieslak and henretig 2016) . agents under investigation include antioxidants (vitamin e), anti-inflammatory drugs (corticosteroids), mustard scavengers (glutathione, n-acetylcysteine), and nitric oxide synthase inhibitors (l-nitroarginine methyl ester). other therapeutics under investigation include the use of british anti-lewisite (bal), reactive skin protectants, and ocular therapies (national institutes of health 2007; usamriid 2014). lung-damaging agents are toxic inhalants and potentially can affect the entire respiratory tract. typical examples include chlorine (cl 2 ), phosgene (carbonyl chloride), oxides of nitrogen, organofluoride polymers, hydrogen fluoride, and zinc oxide. since many of these chemicals are readily available and have multiple industrial applications, they are considered terrorist weapons of opportunity. toxicity is dependent upon agent particle size, solubility, and method of release. large particles produce injury in the nasopharynx (sneezing, pain, and erythema). midsize particles affect the central airways (painful swelling, cough, stridor, wheezing, and rhonchi). small particles cause injury at the level of the alveoli (dyspnea, chest tightness, and rales). highly soluble agents, such as chlorine, dissolve with mucosal moisture and immediately produce strong upper airway reactions. less soluble agents, such as phosgene, travel to the lower airway before dissolving and subsequently causing toxicity. it is important, however, to realize that very few lungdamaging agents affect only the upper or lower airway (e.g., cl 2 ). if the agent is aerosolized, solid or liquid droplets suspend in the air and distribute by size. if it is a gas or vapor release, there is uniform distribution throughout the lungs and toxicity will be based on solubility and reactivity of the agent (banks 2014; burklow et al. 2003; cieslak and henretig 2016) . pediatric manifestations (table 5 .19) may vary from the classic clinical responses due to their unique vulnerabilities (hilmas et al. 2008 ): â�¢ pediatric airway and respiratory tract issues (obligate nose breathers, relatively small mouth/large tongue, copious secretions, anterior/cephalad vocal cords, omega or horseshoe-shaped epiglottis, tendency of laryngospasm and bronchospasm, and anatomically small, "floppy" airways). â�¢ high vapor density and concentration accumulation in the living zone. â�¢ unable to verbalize or localize physical complaints. â�¢ rapid dehydration and shock secondary to pulmonary edema. â�¢ increased minute ventilation and metabolism. differential diagnoses include smoke inhalation injury, cardiogenic shock, heart failure, traumatic injury, asthma, bronchiolitis, and poisoning (cyanide). treatment (tables 5.20 and 5.21) includes decontamination and supportive care. currently, there are no antidotes for lung-damaging agent toxicity (cieslak and henretig 2016) . potential countermeasures include novel positive-pressure devices, drugs to prevent lung inflammation, and treatments for chemically induced pulmonary edema (beta agonists, dopamine, insulin, allopurinol, and ibuprofen). in addition, drugs are being investigated that act at complex molecular pathways of the lung the centers for disease control and prevention (cdc) has delineated bioterrorism agents and diseases into three categories based on priority. category a agents include organisms with the highest risk because the ease of dissemination or transmission from person-to-person, result in high mortality rates, have the potential for major public health impact, promote public panic and social disruption, and require special action of public health preparedness. these agents/diseases include smallpox (variola major), anthrax (bacillus anthracis), plague (yersinia pestis), viral hemorrhagic fevers (filoviruses [ebola, marburg] and arenaviruses [lassa, macupo]), botulinum toxin (from clostridium botulinum), and tularemia (francisella tularensis). category b agents, the second highest priority, include those that are moderately easy to disseminate, result in moderate morbidity and low mortality rates, and require specific enhancements of diagnostic capacity and enhanced disease surveillance. these agents/diseases include ricin toxin (ricinus communis), brucellosis (brucella species), epsilon toxin of clostridium perfringens, food safety threats (salmonella species, escherichia coli o157:h7, shigella), glanders (burkholderia mallei), meliodosis (burkholderia pseudomallei), psitticosis (chlamydia psittaci), typhus fever (rickettsia prowazekii), q fever (coxiella burnetii), staphylococcal enterotoxin b, trichothecenes mycotoxin, viral encephalitis (alphaviruses, such as eastern equine encephalitis, venezuelan equine encephalitis, and western equine encephalitis), and water safety threats (vibrio cholera, cryptosporidium parvum). category c agents have the next priority and include emerging pathogens that could be engineered for mass dissemination because of availability, ease of production and dissemination, and have the potential for high morbidity and mortality rates and major health impact. recognition of a biologic attack is essential. there are various epidemiologic clues to consider when determining whether the outbreak is natural or man-made (markenson et al. 2006; cieslak 2018; usamriid 2014) : â�¢ the appearance of a large outbreak of cases of a similar disease or syndrome, or especially in a discrete population. â�¢ many cases of unexplained diseases or deaths. â�¢ more severe disease than is usually expected for a specific pathogen or failure to respond to standard therapy. â�¢ unusual routes of exposure for a pathogen, such as the inhalational route for disease that normally occur through other exposures. â�¢ a disease case or cases that are unusual for a given geographic area or transmission season. â�¢ disease normally transmitted by a vector that is not present in the local area. â�¢ multiple simultaneous or serial epidemics of different diseases in the same population. â�¢ a single case of disease by an uncommon agent (smallpox, some viral hemorrhagic fevers, inhalational anthrax, pneumonic plague). â�¢ a disease that is unusual for an age group. â�¢ unusual strains or variants of organisms or antimicrobial resistance patterns different from those known to be circulating. â�¢ a similar or identical genetic type among agents isolated from distinct sources at different times and/or locations. â�¢ higher attack rates among those exposed in certain areas, such as inside a building if released indoors, or lower rates in those inside a sealed building if released outside. â�¢ outbreaks of the same disease occurring in noncontiguous areas. â�¢ zoonotic disease outbreaks. â�¢ intelligence of a potential attack, claims by a terrorist or aggressor of a release, and discovery of munitions, tampering, or other potential vehicle of spread (spray device, contaminated letter). one should know the cellular, physiological, and clinical manifestations of each biologic agent. furthermore, knowledge of distinct presentation patterns of children will be helpful to diagnosis. in any event, the ten steps in the management of biologic attack victims, pediatric, or otherwise, should be applied (cieslak and henretig 2003; cieslak 2018; usamriid smallpox is caused by the orthopoxvirus variola and was declared globally eradicated in 1980. the disease is highly communicable from person-to-person and remains a threat due to its potential for weaponization. the only stockpiles are at the cdc and at the russian state centre for research on virology and biotechnology. however, clandestine stockpiles in other parts of the world are unknown. since the cessation of smallpox vaccination, the general population has little or no immunity. the three clinical forms of smallpox include ordinary, flat, and hemorrhagic. another form, modified type, occurred in those previously vaccinated who were no longer protected. the asymptomatic incubation period is from 7 to 17 days (average 12 days) after exposure. a prodrome follows that lasts for 2-4 days and is marked by fever, malaise, and myalgia. lesions start on the buccal and pharyngeal mucosa. the rash then spreads in a centrifugal fashion, and the lesions are synchronous. initially, there are macules followed by papules, pustules, and scabs in 1-2 weeks. other clinical features include extensive fluid loss and hypovolemic shock, nausea, vomiting, diarrhea, bacterial superinfections, viral bronchitis and pneumonitis, corneal ulceration with or without keratitis, and encephalitis. death, if it occurs, is typically during the second week of clinical disease. variola minor caused a mortality of 1% in unvaccinated individuals. however, the variola major type caused death in 3% and 30% in those vaccinated and unvaccinated, respectively. flat (mostly children) and hemorrhagic (pregnant women and immunocompromised) types caused severe mortality in those populations infected. the differential diagnoses for smallpox include chickenpox (varicella), herpes, erythema multiforme with bullae, or allergic contact dermatitis. varicella typically has a longer incubation period (14-21 days) and minimal or no prodrome. furthermore, the rash distributes in a centripetal fashion and the progression is asynchronous (images 5.1 and 5.2). diagnosis of smallpox is mostly clinical (centers for disease control and prevention 2019a). if considered, contact public health immediately. laboratory confirmation (cdc or who) can be done by dna sequencing, polymerase chain reaction (pcr), restriction fragment-length polymorphism (rflp), real-time pcr, and microarrays. these are more sensitive and specific than the conventional virological and immunological approaches (goff et al. 2018) . generally, treatment is largely supportive (table 5 .23). fluid losses and hypovolemic shock must be addressed. also, due to electrolyte and protein loss, replacement therapy will be required. bacterial superinfections must be aggressively treated with appropriate antibiotics. biologic countermeasures and antivirals against smallpox are under investigation, including cidofovir, brincidovir (cmx-001), and tecovirimat (st-246). these agents have shown efficacy in orthopoxvirus animal models and have been used to treat disseminated vaccinia infection under emergency use. cidofovir has activity against poxviruses in animal studies (in vitro and in vivo) and some humans (eczema vaccinatum and molluscum contagiosum). brincidovir is an oral formulation of cidofovir with less nephrotoxicity and has recently been announced as an addition to the strategic national stockpile (sns) for patients with smallpox. tecovirimat is a potent and specific inhibitor of orthopoxvirus replication. a recent study found that treatment with tecovirimat resulted in 100% survival of cynomolgus macaques challenged with intravenous variola virus. the disease was milder in tecovirimat-treated survivors and viral shedding was reduced compared to placebo-treated survivors. prophylaxis comes in the form of the smallpox vaccine (vaccinia virus), acam2000 â® , which replaced wyeth dryvaxâ�¢ in 2007. safety profile of the two vaccines appears to be similar. side effects of vaccination range from low-grade fever and axillary lymphadenopathy to inadvertent inoculation of the virus to other body sites to generalized vaccinia and cardiac events (myopericarditis). rare, but typically fatal complications include progressive vaccinia, eczema vaccinatum, postvaccination encephalomyelitis, and fetal vaccinia. modified vaccinia ankara (mva) smallpox vaccine (bavarian nordic's imvamune â® ) is a live, highly attenuated, viral vaccine that is under development as a future nonreplicating smallpox vaccine (greenberg et al. 2016; kennedy and greenberg 2009 ). passive immunoprophylaxis exists in the form of vaccinia immune globulin (vig) and is used for primarily treating complications from smallpox vaccine. limited information suggests that vig may be of use in postexposure prophylaxis of smallpox if given the first week after exposure and with vaccination. monoclonal antibodies may represent another form of immunoprophylaxis. postexposure administration of human monoclonal antibodies has protected rabbits from a lethal dose of an orthopoxvirus. as mentioned, smallpox is highly communicable person-to-person (table 5 .25). contact precautions with full personal protective equipment (ppe) are required. airborne isolation with the use of an n-95 mask is needed for baseline protection. an n-95 mask or powered airpurifying respirator (papr) is recommended for protection during high risk procedures (beigel and sandrock 2009; goff et al. 2018; rotz et al. 2005; pittman et al. 2018 ; usamriid 2014). anthrax is caused by the aerobic, spore-forming, nonmotile, encapsulated gram-positive rod bacillus anthracis. it is a naturally occurring disease in herbivores. humans contract the illness by handling contaminated portions of infected animals, especially hides and wool. infection is introduced by scratches or abrasions on the skin. there is concern for potential aerosol dispersal leading to intentional infection through inhalation: it is fairly easy to obtain, capable of large quantity production, stable in aerosol form, and highly lethal. anthrax spores enter the body via skin, ingestion, or inhalation. the spores germinate inside macrophages and become vegetative bacteria. the vegetative form is released, replicates in the lymphatic system, and produces intense bacteremia. the production of virulence factors leads to overwhelming sepsis. the main virulence factors are encoded on two plasmids. one produces an antiphagocytic polypeptide capsule. the other contains genes for the synthesis of three proteins it secretes: protective antigen, edema factor, and lethal factor. the combination of protective antigen with lethal factor or edema factor forms binary cytotoxins, lethal toxin, and edema toxin. the anthrax capsule, lethal toxin, and edema toxin act in concert to drive the disease. three clinical syndromes occur with anthrax: cutaneous, gastrointestinal, and inhalational. cutaneous anthrax is the most common naturally occurring form. after an individual is exposed to infected material or the agent itself, there is a 1-12 day (average 7 days) incubation period. a painless or pruritic papule forms at the site of exposure. the papule enlarges and forms a central vesicle, which is followed by erosion into a coal-black but painless eschar. edema surrounds the area and regional lymphadenopathy may occur. gastrointestinal anthrax is rare. typically, it develops after ingestion of viable vegetative organisms found in undercooked meats of infected animals. the two forms of gastrointestinal anthrax, oropharyngeal and intestinal, have incubation periods of 1-6 days. the oropharyngeal form is marked by fever and severe pharyngitis followed by ulcers and pseudomembrane formation. other findings include dysphagia, regional lymphadenopathy, unilateral neck swelling, airway compromise, and sepsis. the intestinal form begins with fever, nausea, vomiting, and abdominal pain. bowel edema develops which leads to mesenteric lymphadenitis with necrosis, shock, and death. endemic inhalational anthrax (woolsorters' disease) is also extremely rare and is due to inhaling spores. therefore, any case of inhalational anthrax should be assumed to be due to intentional exposure until proven otherwise. the incubation period is 1-5 days but can be up to 43 days. there is a prodrome of 1-2 days consisting of fever, malaise, and cough. within 24 h, the disease rapidly progresses to respiratory failure, hemorrhagic mediastinitis (wide mediastinum), septic shock, multiorgan failure, and death. patients with inhalational anthrax may also have hemorrhagic meningitis. mortality is greater than 80% in 24-36 h despite aggressive treatment of inhalational anthrax. the differential diagnoses of ulceroglandular lesions include antiphospholipid antibody syndrome, brown recluse spider bite, coumadin/heparin necrosis, cutaneous leishmaniasis, cutaneous tuberculosis, ecthyma gangrenosum, glanders, leprosy, mucormycosis, orf, plague, rat bite fever, rickettsial pox, staphylococcal/ streptococcal ecthyma, tropical ulcer, tularemia, and typhus. the differential diagnoses of ulceroglandular syndromes include cat scratch fever, chancroid, glanders, herpes, lymphogranuloma venereum, melioidosis, plague, staphylococcal and streptococcal adenitis, tuberculosis, and tularemia. the differential diagnoses for inhalational anthrax include influenza and influenza-like illnesses from other causes. the differential diagnoses of mediastinal widening include normal variant, aneurysm, histoplasmosis, sarcoidosis, tuberculosis, and lymphoma. the diagnosis of anthrax is by culture and gram stain of the blood, sputum, pleural fluid, cerebrospinal fluid, or skin. specimens must be handled carefully, especially by lab personnel and those performing autopsies. elisa and pcr are available at some reference laboratories. the chest radiograph of inhalational anthrax shows the classic widening of the mediastinum. additional findings include hemorrhagic pleural effusions, air bronchograms, and/or consolidation (purcell et al. 2018 ). supportive treatment is indicated, including mechanical ventilation, pleural effusion drainage, fluid and electrolyte support, and vasopressor administration. for inhalational anthrax, antibiotic treatment is unlikely to be effective unless started before respiratory symptoms develop. treatment (table 5 .22) includes ciprofloxacin (or levofloxacin or doxycycline), clindamycin, and penicillin g. raxibacumab, a monoclonal antibody, was approved by the fda in 2012 for the treatment of inhalational anthrax in combination with recommended antibiotic regimens and prophylaxis for inhalational anthrax when other therapies are unavailable or inappropriate. it works by inhibiting anthrax antigen binding to cells and, therefore, prevents toxins from entering cells (kummerfeldt 2014) . the adult dose is 40 mg/kg given iv over 2 h and 15 min. the dose for children is weight based; â�¤15 kg: 80 mg/kg; >15-50 kg: 60 mg/kg; >50 kg: 40 mg/kg. premedication with diphenhydramine iv or po is recommended 1 h before the infusion. it can also be used as postexposure prophylaxis in high risk spore exposure cases (cieslak and henretig 2016; migone et al. 2009 ; the medical letter 2013). obiltoxaximab (anthim) is a recently approved monoclonal antibody treatment for inhalational anthrax in combination with recommended antibiotic regimens and prophylaxis for inhalational anthrax when other therapies are unavailable or inappropriate. adults and children >40 kg should receive a single obiltoxaximab dose of 16 mg/kg. the recommended dose is 24 mg/kg for children >15-40 kg and 32 mg/kg for those weighing â�¤15 kg. premedication with diphenhydramine is recommended to reduce risk of hypersensitivity reactions (the medical letter 2018). in patients with inhalational anthrax, intravenous anthrax immune globulin (anthrasil) should be considered in addition to appropriate antibiotic therapy (mytle et al. 2013 ; the medical letter 2016; usamriid 2014). postexposure prophylaxis includes ciprofloxacin (or levofloxacin or doxycycline) for 60 days plus administration of vaccine; since spores can persist in human in addition to appropriate antibiotic regimen, monoclonal antibody therapy (see text for dosing) and intravenous anthrax immune globulin should be administered for inhalational anthrax c levofloxacin or ofloxacin may be an acceptable alternative to ciprofloxacin d rifampin or clarithromycin may be acceptable alternatives to clindamycin as a drug that targets bacterial protein synthesis. if ciprofloxacin or another quinolone is employed, doxycycline may be used as a second agent because it also targets protein synthesis e ampicillin, imipenem, meropenem, or chloramphenicol may be acceptable alternatives to penicillin as drugs with good cns penetration f assuming the organism is sensitive, children may be switched to oral amoxicillin (40-80 mg/kg/d divided q8 h) to complete a 60-day course. the first 14 days of therapy of postexposure prophylaxis, however, should include ciprofloxacin or levofloxacin and/or doxycycline regardless of age. vaccination should also be provided; if not, antibiotic course will need to be longer g according to most experts, ciprofloxacin is the preferred agent for oral prophylaxis h ten days of therapy may be adequate for endemic cutaneous disease. a full 60-day course is recommended in the setting of terrorism, however, because of the possibility of concomitant inhalational exposure tissues for a long time, antibiotics must be given for a longer period if vaccine is not also given. the anthrax vaccine adsorbed (ava biothraxâ�¢) is derived from sterile culture fluid supernatant taken from an attenuated strain of bacillus anthracis and does not contain any live or dead organisms. the vaccine is given 0.5 ml intramuscularly at 0 and 4 weeks then at 6, 12, and 18 months followed by yearly boosters (pittman et al. 2018; usamriid 2014) . consult with cdc for current pediatric recommendations. anthrax is not contagious in the vegetative form during clinical illness (table 5 .25). contact with infected animals increases likelihood of spread. therefore, contact should be limited and the use of appropriate ppe in endemic areas is indicated (beigel and sandrock 2009; purcell et al. 2018; usamriid 2014) . plague is caused by yersinia pestis, a nonmotile, nonsporulating gram-negative bacterium. it is a zoonotic disease of rodents. it is typically found worldwide and is endemic in western and southwestern states. humans develop the disease after contact with infected rodents, or being bitten by their fleas. after a rodent population dies off, the fleas search for other sources of blood, namely humans. this is when large outbreaks of human plague occur. pneumonic plague is a very rare disease and when it is present in a patient, it may be highly suspicious for intentional dispersal of this deadly agent. three clinical syndromes occur with plague: bubonic plague (85%), septicemic plague (13%), and primary pneumonic plague (1-2%). bubonic plague occurs after an infected flea bites a human. after an incubation period of 2-8 days, there is onset of high fever, severe malaise, headache, myalgias, and nausea with vomiting. almost 50% have abdominal pain. around the same time, a characteristic bubo forms which is tender, erythematous, and edematous without fluctuation. buboes typically form in the femoral or inguinal lymph nodes, but other areas can be involved as well (axillary, intraabdominal). the spleen and liver can be tender and palpable. the disease disseminates without therapy. severe complications can ensue, including pneumonia, meningitis, sepsis, and multiorgan failure. pneumonia is particularly concerning since these patients are extremely contagious. mortality of untreated bubonic plague is 60%, but 5% with efficient and effective treatment. septicemic plague is characterized by acute fever followed by sepsis without bubo formation. the clinical syndrome is very similar to other forms of gram-negative sepsis: chills, malaise, tachycardia, tachypnea, hypotension, nausea, vomiting, and diarrhea. in addition to sepsis, disseminated intravascular coagulation can ensue leading to thrombosis, necrosis, gangrene, and the formation of black appendages. multiorgan failure can quickly follow. untreated septicemic plague is almost 100% fatal versus 30-50% in those treated. pneumonic plague is very rare and should be considered due to an intentional aerosol release until proven otherwise. the incubation period is relatively short at 1-3 days. sudden fever, cough, and respiratory failure quickly follow. this form produces a fulminant pneumonia with watery sputum that usually progresses to bloody. within a short period of time, septic shock and disseminated intravascular coagulation develop. ards and death may occur. mortality rate of pneumonic plague is very high but may respond to early treatment. plague meningitis is a rare complication of plague. it can occur in 6% of patients with septicemia and pneumonic forms and is more common in children. usually occurring a few weeks into the illness, it affects those receiving subtherapeutic doses of antibiotics or bacteriostatic antibiotics that do not cross the blood-brain barrier (tetracyclines). fever, meningismus, and other meningeal signs occur. plague meningitis is virtually indistinguishable from meningococcemia. the differential diagnoses of bubonic plague include tularemia, cat scratch fever, lymphogranuloma venereum, chancroid, scrub typhus, and other staphylococcal and streptococcal infections. the differential diagnoses of septicemic plague should include meningococcemia, other forms of gram-negative sepsis, and rickettsial diseases. the differential diagnosis of pneumonic plague is very broad. however, sudden appearance of previously healthy individuals with rapidly progressive gram-negative pneumonia with hemoptysis should strongly suggest pneumonic plague due to intentional release. diagnosis can be made clinically as previously described. demonstration of yersinia pestis in blood or sputum is paramount. methylene blue or wright's stain of exudates may reveal the classic safety-pin appearance of yersinia pestis. culture on sheep blood or macconkey agar demonstrates beaten-copper colonies (48 h) followed by fried-egg colonies (72 h). detection of yersinia pestis f1-antigen by specific immunoassay is available, but the result is available retrospectively. chest radiograph of patients will demonstrate patchy infiltrates (centers for disease control and prevention 2018a; worsham et al. 2018) . treatment includes mechanical ventilation strategies for ards, hemodynamic support (fluid and vasopressor administration), and antimicrobial agents (table 5 .23). gentamicin or streptomycin is the preferred antimicrobial treatment. alternatives include doxycycline or ciprofloxacin or levofloxacin or chloramphenicol. in cases of meningitis, chloramphenicol is recommended due to its ability to effectively cross the blood-brain barrier. streptomycin is in limited supply and is available for compassionate use. it should be avoided in pregnant women. postexposure prophylaxis includes doxycycline or ciprofloxacin. no licensed plague vaccine is currently in production. a previous licensed vaccine was used in the past. it only offered protection against bubonic plague but not aerosolized yersinia pestis. the plague bacterium secretes several virulence factors (fraction 1 (f1) and v (virulence) proteins) that as subunit proteins are immunogenic and possess protective properties. recently, an f1-v antigen (fusion protein) vaccine developed by usamriid provided 100% protection in monkeys against high-dose aerosol challenge. there is no passive immunoprophylaxis (i.e., immune globulin) available for pre-or postexposure of plague (usamriid 2014). use of standard precautions for patients with bubonic and septicemic plague is indicated. suspected pneumonic plague will require strict isolation with respiratory droplet precautions for at least 48 h after initiation of effective antimicrobial therapy, or until sputum cultures are negative in confirmed cases. an n-95 respirator should be used for baseline protection (table 5 .25). it is also recommended to use an n-95 respirator or papr for high risk procedures (beigel and sandrock 2009; ; centers for disease control and prevention 2017; centers for disease control and prevention 2018b; pittman et al. 2018; usamriid 2014) . in a mass casualty setting, parenteral therapy might not be possible. in such cases, oral therapy (with analogous agents) may need to be used b ofloxacin (and possibly other quinolones) may be acceptable alternatives to ciprofloxacin or levofloxacin; however, they are not approved for use in children c concentration should be maintained between 5 and 20 î¼g/ml. some experts have recommended that chloramphenicol be used to treat patients with plague meningitis, because chloramphenicol penetrates the blood-brain barrier. use in children younger than 2 may be associated with adverse reactions but might be warranted for serious infections d ribavirin is recommended for arenavirus or bunyavirus infections and may be indicated for a viral hemorrhagic fever of an unknown etiology although not fda approved for these indications. for intravenous therapy use a loading dose: 30 kg iv once (max dose, 2 g), then 16 mg/kg iv q6 h for 4 days (max dose, 1 g), and then 8 mg/kg iv q8 h for 6 days (max dose, 500 mg). in a mass casualty setting, it may be necessary to use oral therapy. for oral therapy, use a loading dose of 30 mg/kg po once, then 15 mg/kg/day po in 2 divided doses for 10 days viral hemorrhagic fever has a variety of causative agents. however, the syndromes they produce are characterized by fever and bleeding diathesis. the etiologies include rna viruses from four distinct families: arenaviridae, bunyaviridae, filoviridae, and flaviviridae. the filoviridae (includes ebola and marburg) and arenaviridae (includes lassa fever and new world viruses) are category a agents. based on multiple identified characteristics, there is strong concern for the weaponization potential of the viral hemorrhagic fevers. specifically, there has been demonstration of high contagiousness in aerosolized primate models. there are five identified ebola species, but only four are known to cause disease in humans. the natural reservoir host of ebola virus remains unknown. however, on the basis of evidence and the nature of similar viruses, researchers believe that the virus is animal-borne and that bats are the most likely reservoir. four of the five virus strains occur in an animal host native to africa. marburg virus has a single species. geographic distribution of ebola and marburg is africa (fitzgerald et al. 2016 ). both diseases are very similar clinically. incubation period is typically 5-10 days with a range of 2-16 days. symptoms may include fever, chills, headache, myalgia, nausea, and vomiting. there is rapid progression to prostration, stupor, and hypotension. the onset of a maculopapular rash on the arms and trunk is classic. disseminated intravascular coagulation and thrombocytopenia develops with conjunctival injection, petechiae, hemorrhage, and soft tissue bleeding. there is a possible central nervous system and hepatic involvement. bleeding, uncompensated shock, and multiorgan failure are seen. high viral load early in course is associated with poor prognosis. death usually occurs during the second week of illness. mortality rate of marburg is 25-85% and for ebola 50-90%. in a retrospective cohort study of children during the 2014/2105 ebola outbreak in liberia and sierra leone (all less than 18 years with a median age of 7 years with one-third less than 5 years of age), the most common features upon presentation were fever, weakness, anorexia, and diarrhea. about 20% were initially afebrile. bleeding was rare upon initial presentation. the overall case fatality rate was 57%. factors associated with death included children less than 5 years of age, bleeding at any time during hospitalization, and high viral load (smit et al. 2017) . in another retrospective cohort study of children at two ebola centers in sierra leone in 2014 (all less than 5 years of age), presenting symptoms included weakness, fever, anorexia, diarrhea, and cough. about 25% were afebrile on presentation. the case fatality rate was higher in children less than 2 years (76%) versus 2-5 years of age (46%) and 9 times more likely to die if child had a higher viral load. signs associated with death included fever, emesis, and diarrhea. interestingly, hiccups, bleeding, and confusion were only observed in children who died (shah et al. 2016) . lassa virus and new world viruses (junin, machupo, sabia, and guanarito) are transmitted from person-to-person. the vector in nature is the rodent. the incubation period is from 5 to 16 days. the geographical distribution is west africa and south america, respectively. the south american hemorrhagic fevers are quite similar but differ from lassa fever. the onset of the south american viruses is insidious and results in high fever and constitutional symptoms. petechiae or vesicular enanthem with conjunctival injection is common. these fevers are associated with neurologic disease (hyporeflexia, gait abnormalities, and cerebellar dysfunction). seizures portend a poor prognosis. mortality ranges from 15% to over 30%. on the contrary, lassa viruses are mild. less than 10% of infections result in severe disease. signs include chest pain, sore throat, and proteinuria. hemorrhagic disease is uncommon. other features include neurologic disease such as encephalitis, meningitis, cerebellar disease, and cranial nerve viii deafness (common feature). mortality can be as high as 25%. differential diagnoses include malaria, meningococcemia, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and typhoid fever. diagnosis is through detection of the viral antigen testing by elisa or viral isolation by culture at the cdc. no specific therapy is present and generally involves supportive care, especially mechanical ventilation strategies for ards, hemodynamic support, and renal replacement therapy. for the arenaviridae and bunyaviridae groups, ribavirin may be indicated ( (pittman et al. 2018) . there is no current vaccine for ebola that is licensed by the fda. an experimental vaccine called rvsv-zebov was found to be highly protective against ebola virus in a trial conducted by the world health organization (who) and other international partners in guinea in 2015. fda licensure for the vaccine is expected in 2019. until then, 300,000 doses have been committed for an emergency use stockpile under the appropriate regulatory mechanism in the event and an outbreak occurs before fda approval is received (centers for disease control and prevention 2019b; henao-restrepo et al. 2015) . another ebola vaccine candidate, the recombinant adenovirus type-5 ebola vaccine, was evaluated in a phase 2 trial in sierra leone in 2015. an immune response was stimulated by this vaccine within 28 days of vaccination and strict contact precautions (hand hygiene, double gloves, gowns, shoe and leg coverings, and face shield or goggles) and droplet precautions (private room or cohorting, surgical mask within 3 ft) are mandatory for viral hemorrhagic fevers. airborne precautions (negative-pressure isolation room with 6-12 air exchanges per h) should also be instituted to the maximum extent possible and especially for procedures that induce aerosols (e.g., bronchoscopy). at a minimum, a fit-tested, hepa filter-equipped respirator (e.g., an n-95 mask) should be used, but a battery-powered papr or a positive pressure-supplied air respirator should be considered for personnel sharing an enclosed space with, or coming within 6 ft of, the patient. multiple patients should be cohorted in a separate ward or building with a dedicated airhandling system when feasible (table 5 .25). environmental decontamination is accomplished with hypochlorite or phenolic disinfectants (beigel and sandrock 2009; radoshitzky et al. 2018; usamriid 2014; won and carbone 2005) . francisella tularensis, a small aerobic, nonmotile gram-negative coccobacillus, causes tularemia (rabbit fever). clinical disease is caused by two isolates, biovars jellison type a and b. this organism can be stabilized for weaponization and delivered in a wet or dry form. the incubation period is usually 3-6 days (range 1-21 days). initial symptoms are nonspecific and mimic the flu-like symptoms or other upper respiratory tract infections. there is acute onset of fever with chills, myalgias, cough, fatigue, and sore throat. the two clinical forms of tularemia are typhoidal and ulceroglandular diseases. typhoidal tularemia (5-15%) occurs after inhalational exposure and sometimes intradermal or gastrointestinal exposures. there is abrupt onset of fever, headache, malaise, myalgias, and prostration. it presents without lymphadenopathy. nausea, vomiting, and abdominal pain are sometimes present. untreated, there is a 35% mortality rate in naturally acquired cases (vs. 1-3% in those treated). it is higher if pneumonia is present. this form would be most likely seen during an aerosol release of the agent. ulceroglandular tularemia (75-85%) occurs through skin or mucus membrane inoculation. there is abrupt onset of fever, chills, headache, cough, and myalgias along with a painful papule at the site of exposure. the papule becomes a painful ulcer with tender regional lymph nodes. skin ulcers have heaped up edges. in 5-10%, there is focal lymphadenopathy without an apparent ulcer. lymph nodes may become fluctuant and drain when receiving antibiotics. without treatment, they may persist for months or even years. in some cases (1-2%), the primary entry port is the eye leading to oculoglandular tularemia. patients have unilateral, painful, and purulent conjunctivitis with local lymphadenopathy. chemosis, periorbital edema, and small nodular granulomatous lesions or ulceration may be found. oropharyngeal tularemia with pharyngitis may occur in 25% of patients. findings include exudative pharyngitis/tonsillitis, ulceration, and painful cervical lymphadenopathy. the differential diagnosis is antibiotic unresponsive pharyngitis, infectious mononucleosis, and viral pharyngitis. pulmonary involvement (47-94%) is seen in naturally occurring disease. it ranges from mild to fulminant. various processes include pneumonia, bronchiolitis, cavitary lesions, bronchopleural fistulas, and chronic granulomatous diseases. left untreated, 60% will die. differential diagnoses include those for typhoidal (typhoid fever, rickettsia, and malaria) or pneumonic (plague, mycoplasma, influenza, q-fever, and staphylococcal enterotoxin b) tularemia. diagnosis should be considered when there is a cluster of nonspecific, febrile, systemically ill patients who rapidly progress to fulminant pneumonitis. tularemia can be diagnosed by recovering the organism from sputum (pcr or dfa) or serology at a state health laboratory. chest radiograph is nonspecific with possible hilar adenopathy. treatment is streptomycin or gentamicin (table 5 .23). alternatives include doxycycline, ciprofloxacin, or chloramphenicol. a live-attenuated vaccine (ndbr 101) exists and typically used for laboratory personnel working with francisella tularensis. there is no passive immunoprophylaxis. ciprofloxacin or doxycycline can be given as pre-and postexposure prophylaxis (beigel and sandrock 2009; hepburn et al. 2018; pittman et al. 2018; usamriid 2014) . botulinum neurotoxins (bont) are produced from the spore-forming, gram-positive, obligate anaerobe clostridium botulinum. it is the most potent toxin known to man. a lethal dose is 1 ng per kilogram. it is 100,000 times more toxic than sarin (gb). there are seven serotypes of botulinum toxin (a through g). a new serotype (h) has been tentatively identified in a case of infant botulism but has not been fully investigated. most common are serotypes a, b, and e. the toxin acts on the presynaptic nerve terminal of the neuromuscular junction and cholinergic autonomic synapses. this disrupts neurotransmission and leads to clinical findings. there are three forms of botulism: foodborne, wound, and intestinal (infant or adult intestinal). botulinum toxin can also be released as an act of bioterrorism via ingestion or aerosol forms. incubation can be from 12 h after exposure to several days later. clinical findings of botulism include cranial nerve palsies such as ptosis, diplopia, and dysphagia. this is followed by symmetric descending flaccid paralysis. however, the victim remains afebrile, alert, and oriented. death is typically due to respiratory failure. prolonged respiratory support is often required (1-3 months). differential diagnoses include guillain-barre syndrome, myasthenia gravis, tick paralysis, stroke, other intoxications (nerve gas, organophosphates), inflammatory myopathy, congenital and hereditary myopathies, and hypothyroidism. diagnosis is mostly clinical. laboratory confirmation can be obtained by bioassay of patient's serum. other assays include immunoassays for bacterial antigen, pcr for bacterial dna, and reverse transcriptase-pcr for mrna to detect active synthesis of toxin. cerebrospinal fluid demonstrates normal protein (unlike guillain-barre syndrome). emg reveals augmentation of muscle action potential with repetitive nerve stimulation at 20-30 hz. treatment (table 5 .23) is mainly supportive including intubation and ventilator support. tracheostomy may be required due to prolonged respiratory weakness and failure. antibiotics do not play a role in treatment. botulism antitoxin heptavalent [a, b, c, d, e, f, g]-equine (bat) was approved by the fda in 2013. bat was developed at usamriid as one of two equine-derived heptavalent bont antitoxins. bat is approved to treat individuals with symptoms of botulism following a known or suspected exposure. it has the potential to cause hypersensitivity reactions in those sensitive to equine proteins. the safety of bat in pregnant and lactating women is unknown. evidence regarding safety and efficacy in the pediatric population is limited. in 2003, the fda approved botulinum immune globulin intravenous (babybig), a human botulism immune globulin derived from pooled plasma of adults immunized with pentavalent botulinum toxoid. it is indicated for the treatment of infants with botulism from toxin serotypes a and b. immediately after clinical diagnosis of botulism, adults (including pregnant women) and children should receive a single intravenous infusion of antitoxin (bat or, for infants with botulism from serotypes a or b, babybig) to prevent further disease progression. the administration of antitoxin should not be delayed for laboratory testing to confirm the diagnosis. the pentavalent toxoid vaccine (previously for protection against a, b, c, d, and e; but not f or g) is no longer available as of 2011. no replacement vaccine is currently available. standard isolation precautions (table 5 .25) should be followed (beigel and sandrock 2009; dembek et al. 2018; pittman et al. 2018; timmons and carbone 2005; usamriid 2014 ). ricin is a potent cytotoxin derived from the castor bean plant ricinus communis. it is related in structure and function to shiga toxins and shiga-like toxin of shigella dysenteriae and escherichia coli, respectively. it consists of two glycoprotein subunits, a and b, connected by a disulfide bond. the b-chain allows the toxin to bind to cell receptors and gain entrance into the cell. once ricin enters the cell, the disulfide chemical linkage is broken. the free a chain then acts as an enzyme and inactivates ribosomes thereby disrupting normal cell function. cells are incapable of survival and soon die. ricin has a high terrorist potential due to it characteristics: readily available, ease of extraction, and notoriety (maman and yehezkelli 2005) . three modes of exposure exist: oral, inhalation, and injection. four to eight hours after inhalation exposure, the victim develops fever, chest tightness, cough, dyspnea, nausea, and arthralgias. airway necrosis and pulmonary capillary leak ensues within 18-24 h. this is followed quickly by severe respiratory distress, ards, and death due to hypoxemia within 36-72 h. injection may cause minimal pulmonary vascular leak. pain at the site and local lymphadenopathy may occur. however, it may be followed by nausea, vomiting, and gastrointestinal hemorrhage. ingestion leads to necrosis of the gastrointestinal mucosa, hemorrhage, and organ necrosis (spleen, liver, and kidney). diagnosis is suspected when multiple cases of acute lung injury occur in a geographic cluster. serum and respiratory secretions can be checked for antigen using elisa. pulmonary intoxication is managed by mechanical ventilation. gastrointestinal toxicity is managed by gastric lavage and use of cathartics. activated charcoal has little value due to the size of ricin molecules. supportive care is indicated for injection exposure. in general, treatment is largely supportive, especially for pulmonary edema that can result from the capillary leak. there is no vaccine available or prophylactic antitoxin for human use. however, there are two ricin vaccines in the development that focus on the ricin toxin a (rta) chain subunit. a mutant recombinant rta chain vaccine, rivax, has been shown to be safe and immunogenic in humans. the other vaccine is another recombinant rta chain vaccine, rvec . it has shown effectiveness in animal models by producing protective immunity against aerosol challenge with ricin in animal models. standard precautions are advised for health care workers (pittman et al. 2018; roxas-duncan et al. 2018; traub 2005 ; usamriid 2014). recent events which include the nuclear reactor meltdown at fukushima and international tension between nuclear powers, spark concern over potential devastation from nuclear catastrophes. there are numerous examples of radiation disasters in history. sixty-six thousand people were killed in hiroshima and thirty-nine thousand people were killed in nagasaki from nuclear bombs detonated over these cities in 1945 (avalon project-documents in law, history and diplomacy n.d.). many other people suffered from long-term consequences of radiation poisoning. in 1986, 21,000 square kilometers of land in russia, ukraine, and belarus were contaminated with radiation from a meltdown at a nuclear power plant in chernobyl, ukraine. one hundred and thirty-five thousand people were permanently evacuated from their homes (likhtarev et al. 2002) . long-term health consequences included many children who developed thyroid cancer several years later. many of these children died. a tsunami pummeled the east coast of japan in march of 2011. the power outage that ensued at the fukushima power plant led to a failure of the cooling system of the fuel rods, leading to a meltdown of four of the reactors at the plant. a massive quantity of radiation was released into the atmosphere, forcing people to evacuate their homes indefinitely. creative thinking and heroic actions by the tokyo fire department prevented entire populations of cities from being poisoned with radiation. terrorism experts are concerned that terrorist organizations will produce and detonate a radiological dispersion device (rdd), sometimes referred to as a dirty bomb. this is a conventional explosive, loaded with radioactive material which would be dispersed upon detonation. this would likely involve only one radioisotope. fewer people would be exposed and a smaller area would be contaminated than what would transpire with the detonation of a nuclear weapon. spreading fear and panic would be the primary purpose of such a device (mettler jr and voelz 2002) . radiation is the emission and propagation of energy through space or through a medium in the form of waves. radiation can be ionizing or nonionizing depending on the amount of energy released. most radiation that people encounter is low energy and, therefore, nonionizing with no biological effects. ionizing radiation emits enough energy to strip electrons from an atom, which provokes cellular changes and thereby, results in biological effects. radiation emitted from nuclear decay is always ionizing (radiation emergency assistance center/training site (react/s-cdc) 2006). atomic nuclei are held together by a very powerful binding energy despite positively charged protons repelling each other. this energy is released from unstable nuclei in the form of electromagnetic waves or particles. when ionizing radiation reaches biological tissue, chemical bonds are disrupted, free radicals are produced, and dna is broken. electromagnetic waves are of two types, x-rays and gamma rays. x-rays are relatively low energy and less penetrating. gamma rays have a shorter wavelength and contain relatively higher energy, making them more penetrating of biological tissue. ionizing radiation in the form of particles consists of alpha particles, beta particles, and neutrons. alpha particles are the largest of the forms of particulate radiation. they are composed of two neutrons and two protons. they do not easily penetrate solid surfaces, including clothes and skin. however, they can cause severe damage to an organism if internalized. in 2006, in the united kingdom, alexander litvienko, an ex kgb agent was poisoned with a radioactive element called polonium (mcphee and leikin 2009). a small amount of polonium was sprinkled into his food. polonium releases alpha particles when it decays. it was relatively safe for the assassin to carry this element with him because of the relatively poor ability of alpha particles to penetrate clothing and skin. once it is ingested, however, alpha particles have profound biological effects. mr. litvienko became very ill, and ultimately died. beta particles are high energy electrons discharged from the nucleus and are highly penetrating. neutrons emitted from a nucleus are also highly penetrating. in general, neutrons are only released by the detonation of a nuclear weapon. ionizing radiation of any form cannot be detected by our senses. it is not smelled, felt by touch, tasted, or seen. it is possible to be exposed to a lethal dose of radiation without realizing it. in goiania, brazil, in 1987, children found a canister of radioactive cesium ( 137 cs) that had been looted from a medical center and left in the street. the children liked the appearance of the substance but were not able to sense any abnormalities or danger with it. they began to rub it on their bodies because they liked the way it made them glow in the dark. the children all became ill. ultimately, 250 people were exposed to this radioisotope. it took 10 days before physicians recognized that the people had radiation poisoning. four people died of acute radiation syndrome. four factors determine the severity of exposure to ionizing radiation: time, distance, dose, and shielding. time is the time of exposure to the radiation source. distance is the distance from the radiation source. based on the inverse square law, exposure is reduced exponentially with increasing distance from the radiation source. dose is measured by the amount of energy released by the source and is numerically described by how many disintegrations per second occur, in curies (ci) or becquerels (bq). shielding is the efficacy of the barrier to the radioactive source. lead is well-known to be a very effective shield to x-rays. in a radiation exposure, injury to skin from trauma or burns may cause a greater degree of contamination because of loss of the shielding of the skin. there are four important principles for the nurse or hcp to understand with regard to exposure to ionizing radiation: external exposure, external contamination, internal contamination, and incorporation. external contamination occurs when radioactive material is carried on a person after exposure. this person can then contaminate others. removing contaminated clothing eliminates 90% of the toxin. others are then less vulnerable to exposure. internal contamination is when a radioactive substance enters the body through inhalation, ingestion, or translocation through open skin. incorporation is internalization of the toxin into body organs. incorporation is dependent on the chemical and not the radiological properties of the radioactive toxin. radioactive iodine, 131 i, is taken up by the thyroid gland because iodine enters the gland as part of normal physiology (advanced hazmat life support (ahls) 2003). ionizing radiation can damage chromosomes directly and indirectly, causing ravaging biological effects. indirect damage comes from the production of h + and oh â�� . free radical formation upsets biochemical processes and causes inflammation. these effects can take anywhere from seconds to hours to be expressed. clinical changes can take from hours to years to be realized (zajtchuk et al. 1989 ). immediately after a major radiation exposure, the clinical matters of most concern are those related to trauma from blast and thermal injuries. these injuries may be life-threatening and must be addressed first. after thermal and traumatic injuries are addressed, attention should be paid to the severity of radiation exposure. severe exposure can cause acute radiation syndrome. "the acute radiation syndrome is a broad term used to describe a range of signs and symptoms that reflect severe damage to specific organ systems and that can lead to death within hours or up to several months after exposure" (national council on radiation protection (ncrp) and measurements 2001; national council on radiation protection (ncrp) and measurements 2009). the mechanism of cell death from toxic radiation exposure is related to the inhibition of mitosis. organs with the most rapidly dividing cells are the most susceptible. the gastrointestinal and the hematopoietic are the organ systems most notably affected. the organs of pediatric patient have a higher mitotic index, in general, to those of adults and are more vulnerable to injury from radiation poisoning. the time of onset and the severity of acute radiation syndrome are controlled by the total radiation dose, the dose rate, percent of total body exposed, and associated thermal and traumatic injuries. there is a 50% death rate (ld 50 ) within 60 days for people exposed to a dose of radiation of 2.5-4.0 gy. the ld 50 is lower for the pediatric population. the acute radiation syndrome is composed of four phases: prodromal, latent, manifest illness, and death or recovery. inflammatory mediator release during the prodromal phase causes damage to cell membranes. this phase occurs during the first 48 h after exposure to radiation. nausea and vomiting and fever can occur during this time. if these symptoms occur during the first 2 h after exposure, there is a poor prognosis. the onset of the latent phase is usually in the first 4 days post exposure but can ensue anytime during the first 21 days thereafter. all cell lines of the hematopoietic system are affected. lymphocytes and platelets, the most rapidly dividing cells of the bone marrow, are most severely affected. the illness phase manifests after 30 days since radiation exposure. infection, impaired wound healing, anemia, and bleeding occur during this time of illness. the hematopoietic, gastrointestinal, central nervous, and integumentary are the organ systems affected. there is a marked reduction of cells from all cell lines of the bone marrow. there is a direct correlation with the drop in absolute lymphocyte count with the dose of radiation received. the absolute lymphocyte count is commonly used to estimate the dose of radiation received. the gastrointestinal (gi) epithelial lining, one of the most rapidly dividing cell lines of the body is the second most vulnerable to radiation poisoning. the radiation dose required to affect the gi system is 8 gy. vomiting, diarrhea, and a capillary leak syndrome for gi tract are common manifestations. hypovolemia and electrolyte instability ensue. translocation of bacteria into the bloodstream, combined with the diminished immunity caused by the decimation of the hematopoietic system, place victims at high risk for septic shock. another organ system affected by the acute radiation syndrome is the central nervous system. this requires a large dose of at least 30 gy. manifestations include cerebral edema, disorientation, hyperthermia, seizures, and coma. acute radiation syndrome that involves the central nervous system is always fatal. the integumentary system is frequently affected by the acute radiation syndrome, especially if the skin is in direct contact with a radioisotope. epilation, erythema, dry desquamation, wet desquamation, and necrosis occur respectively with increasing severity associated with increasing doses of radiation. radiation burns can be distinguished from thermal or chemical burns by their delayed onset. it can take days to weeks for radiation burns to affect victims. thermal and chemical burns cause signs and symptoms more acutely. hospitals that anticipate victims of radiation should prepare areas of triage with decontamination supplies and techniques ready to be deployed. an emergency department (ed) should be divided into "clean" and "dirty" areas. the dirty area is created for the purpose of decontamination to prevent the spread of radioisotopes. all health care personnel should wear ppe including surgical scrubs and gowns, face shields, shoe covers, caps, and two pairs of gloves. the inner pair of gloves is taped to the sleeves of the gown. each health care worker should be monitored for the exposure of the radiation and its dose with a dosimeter worn underneath the gown. the radiation safety officer of the hospital should take a leadership role in health care worker protection and decontamination procedures. consultation from the radiation emergency, assistance center (react/ts) is imperative. react/ts is a subsidiary of the u.s. department of energy. its contact information is as follows: phone number during business hours is 865-576-3131. the phone number is 865-576-1005 after business hours. the react/ts website is http://orise.orau. gov/reac/ts/. as victims arrive, triage protocols of mass casualty scenarios should be implemented. it should be noted that radiation exposure is not "immediately" lifethreatening. initial clinical management should focus on the abcde (airway, breathing, circulation, disability, and exposure) of basic trauma protocol. the "d" in the above acronym can also be a symbol for decontamination. after airway, breathing, and circulation are addressed, initial phase of decontamination entails careful removal of potentially contaminated clothing. caution should be exercised to remove the clothing gently, while rolling garments outward to prevent the release of dust of radioactive material that could contaminate people in the treatment area. further decontamination procedures take place after initial stabilization. skin decontamination procedures are identical to those of toxic chemical exposure with the following exceptions: â�¢ ppe are slightly different as described above. â�¢ gentle skin rubbing is done to prevent provocation of an inflammatory response and further absorption of the radioactive toxin. â�¢ only soap and water are used. rubbing alcohol and bleach should be avoided. it is advisable to shampoo the hair first, because it is usually the site of the highest level of contamination of the body, and runoff onto the body can then be cleansed during skin decontamination (radiation event medical management (remm) of the u.s. dept. of health and human services n.d.). it should be noted that health care workers are not at risk for contamination if they wear proper ppe during the resuscitation and decontamination process. the lack of knowledge of this point may lead to reluctance to treat patients and increase morbidity and mortality for victims. "no hcp has ever received a significant dose of radiation from handling, treating, and managing patients with radiation injuries and/or contamination."(react/s-cdc 2006). when initial resuscitation and decontamination have been completed, attention should be paid to ongoing support of ventilation, oxygenation, the management of fluid and electrolytes, and treatment of traumatic and burn injuries. infection control procedures are important due to the impending immunocompromised state of the victims. it is important to ascertain the details of the catastrophic event. data on the nature and size of the exposure and the types of radioactive agents involved are vital for ongoing management and decontamination. after the details of the nature of the exposure are uncovered, diagnostic tests should be done, including serial cbc and cytogenetic analysis of lymphocytes, otherwise known as cytogenic dosimetry (react/s-cdc 2006). measurements of change in lymphocyte counts and cytogenetic dosimetry are sensitive markers for the dose of radiation received by a victim. measurements of internal decontamination are done by the sampling and analysis of nasal and throat swabs, stool, and 24 h urine. wound samples and irrigation fluid should also be sampled. after initial stabilization, external decontamination, and diagnostic testing, internal decontamination is performed. external decontamination involves removal of clothes and cleaning the skin and hair. internal decontamination removes radioisotopes that are internalized via inhalation, ingestion, and entry into open wounds. because ionizing radiation is being released inside the body, internal decontamination must be performed promptly after initial resuscitation. since radioisotopes behave identically to their nonradioactive counterparts, antidotes are chosen based on the chemical, and not the radiological properties of the element. basic strategies of internal decontamination include chelation, competitive inhibition, enhanced gastrointestinal elimination, and enhanced renal elimination. specific agents are used for chelation of different radioisotopes. dtpa (diethyenetriaminepentaacetic acid) is administered for the elimination of heavy metals such as americium, californium, curium, and plutonium. dtpa comes in two forms, calcium dtpa (ca-dtpa) and zinc-dtpa (zn-dtpa). ca-dtpa is ten times more effective than zn-dtpa. for adults and adolescents, administration is as follows: â�¢ 1 g of ca-dtpa iv initially in the first 24 h, followed by 1 g zn-dtpa iv daily for maintenance. â�¢ for children less than 12 years of age administer: â�¢ fourteen mg/kg ca-dtpa iv initially, followed by fourteen mg/kg of zn-dtpa iv daily thereafter (national council on radiation protection (ncrp) and measurements 2009). â�¢ the initial dose of dtpa may be administered via inhalation to adolescents and adults if the contamination occurred via inhalation. this method of administration is not approved for pediatric use. chelation with dimercaprol (bal) is used to eliminate polonium. bal is a highly toxic drug and should be administered with caution. the dose is 2.5 mg per kg im four times a day for 2 days, then twice a day on the third day and once a day for 5-10 days, thereafter (national council on radiation protection (ncrp) and measurements 2009). alkalinization of the urine is renal protective during administration. a less toxic alternative to bal, dimercaptosuccinic acid (dmsa), otherwise known as chemet â® is also available. the dose of dmsa is ten mg per kg po every 8 h for 5 days. the same dose is given every 12 h for 14 days, thereafter (national council on radiation protection (ncrp) and measurements 2009). another mechanism for internal decontamination is competitive inhibition. the radioisotope, 131 i, is released during a meltdown of a reactor at a nuclear power plant. potassium iodide (ki) is widely recognized as a competitive inhibitor to its radioactive counterpart, 131 i, from being incorporated into the thyroid gland. ki blocks 90% of 131 i uptake into the thyroid gland if ki is given within the first hour of exposure. it will block 50% of incorporation if given within 5 h of exposure. its protective effect lasts for 24 h. with administration of this drug, thyroid function should be monitored closely. dosing guidelines (table 5 .26) are included in the table below (u.s. food and drug administration n.d.). gastrointestinal elimination is another mechanism of internal decontamination (table 5.27 ). an ion exchanger, prussian blue, (ferric ferrocyanide), binds elements that circulate through the enterohepatic cycle. since it is not absorbed through the gastrointestinal tract, prussian blue carries the toxins into the stool. it is highly effective in the elimination of 137 cs or thallium and was used during the 137 cs incident in goiania, brazil. the dosing of prussian blue is as follows: â�¢ infants: 0.2-0.3 mg per kg po three times a day (not fda approved). â�¢ children 2-12 years of age: 1 g po three times a day. â�¢ children â�¥12 years of age: 3 g po three times a day. â�¢ prussian blue is administered for at least 30 days, and can be adjusted based on the degree of poisoning (national council on radiation protection (ncrp) and measurements 2009). urinary elimination is another useful method of internal decontamination. tritium can be eliminated with excess fluid administration. uranium is eliminated by alkalinizing the urine to a ph of 8-9. sodium bicarbonate is given at a dose of 1 meq/kg iv every 4-6 h and is titrated to effect. if renal injury occurs, dialysis may be required. the basic approach to treating acute radiation syndrome is supportive therapy. gi losses from gastrointestinal difficulties are treated with iv fluids and electrolyte replacement. 5-ht3 antagonists can be used to suppress vomiting and benzodiazepines for anxiety. a patient suffering from acute radiation syndrome may be severely immunocompromised and requires a room with positive pressure isolation. colony stimulating agents for granulocytes and erythrocytes can be used for bone anemia and leukopenia. bone marrow transplant may be required for severe cases. a patient with skin contamination with radiation should be decontaminated with soap and water. a geiger counter can be helpful to identify areas of contamination. scrubbing is performed in a concentric matter, beginning at the outer layers of contamination and moving into the center since the area of greatest contamination is in the center. in this way, the area of contamination remains contained. attention should be paid to good nutrition and pain control. burn and plastic surgery service should also be consulted. more details on decontamination can be found in chap. 9. the psychological impact of a radiation catastrophe on the pediatric victims is likely to be devastating (american academy of pediatrics (aap) 2003). sleep disturbances, social withdrawal, altered play, chronic fear and anxiety, and developmental regression can occur. a correlation between the parent's psychological response and that of the child would occur as with other types of disaster. mental health professionals should be consulted in the event of this type of situation. please refer to chap. 12 for more information. a lot of concern has been expressed over the possibility of terrorist attacks involving explosive devices in recent years (depalma et al. 2005) . explosive devices are relatively simple to manufacture and easy to detonate. they can injure and kill many people and spread fear over large populations. victims of bomb blasts sustain more body regions injured, have more body injury severity scores, and require more surgeries than victims of nonexplosive trauma incidents. victims of explosives also have a higher mortality (kluger et al. 2004) . these observations are also true of pediatric victims (daniel-aharonson et al. 2003) . many factors influence the number of people injured and the severity of the injuries in an explosion. the magnitude of the explosion and its proximity to people and the number of people in the area affect the severity and number of injuries. other factors include the collapse of building or structure from the blast, promptness of the rescue operation, and the caliber and proximity of medical resources in the vicinity. victims who experience explosions in closed spaces are especially vulnerable to more severe injuries. twenty-nine case reports of injuries from terrorist bombings were reviewed (arnold et al. 2004a) . the investigators compared the injury severity of victims of explosions who sustained injuries from structural collapse, closed space explosions without structural collapse, and open space explosions. the mortality rate for these victims was 25%, 8%, and 4%, respectively. hospitalization rates were 25%, 36%, and 15%, respectively. ed visits were 48%, 36%, and 15%, respectively. victims of closed space explosions without structural collapse experienced greater hospitalizations rates than those involved in a structural collapse, because many of the victims involved in the structural collapse experienced immediate death. an explosion is defined as a rapid chemical conversion of a liquid or solid into a gas with energy release. substances that are chemically predisposed to explosion, called explosives, are characterized as low or high order, depending on the speed and magnitude of energy release. low-order explosives release energy at a relatively slow pace and explosions from these substances tend not to produce large air pressure changes or a "blast." the energy release is caused by combustion, producing heat. the involved material "goes up in flames." gunpowder, liquid fuel, and molotov cocktails are examples of low-order explosives (centers for disease control and prevention 2010). explosions from high-order materials cause a blast with a pressure wave in addition to causing the release of heat and light. the blast pressure wave causes compression of the surrounding medium which is physically transformed in all directions from the exact point of explosion. when an explosion occurs on land, air is the surrounding medium compressed. in bodies of water, the surrounding medium is water. the degree of medium compression and the distance that the energy wave travels is determined by the magnitude of the explosion. the power of the blast is measured in pounds per square inch (psi). the pressure blast wave has distinctive characteristics. the amplitude of the wave reaches its highest point immediately after the blast. the blast wave then rapidly decays as it travels through space. as the blast wave propagates, and compresses the surrounding medium, it leaves a vacuum because of displaced molecules in the surrounding medium and a negative phase of the wave ensues. in a land explosion, air molecules are displaced by the initial positive pressure, after which a negative pressure occurs in the vacated space. a wave that propagates through a confined space rebounds off of the wall and reverberates. it may interact with victims in the confined space many times, causing more severe injuries (stuhmiller et al. 1991) (fig. 5.10 ). four kinds of injury occur in high energy explosions. primary blast injuries occur directly from the pressure wave of the blast. secondary injuries occur from being struck by flying objects from the blast. these injuries can be blunt or penetrating. tertiary injuries occur when victims are displaced from a location and strike other objects or surfaces. all other injuries related to the blast are called quarternary. they include burns, inhalational injuries, toxic exposures, and traumatic injuries from structural collapse. primary injuries from blast waves affect bodily tissues with a tissue gas interface. when a pressure wave enters the body, tissue of gas filled organs compress slower than the air inside the tissue, causing stress in the tissue, possibly damaging it. this baseline positive phase originally described by friedlander, a blast wave consists of a short, high-amplitude overpressure peak followed by a longer depression phase. injury potential depends on the wave's amplitude as well as the slopes of its increase and decrease in pressure. x-axis refers to time and y-axis refers to pressure. (jacobson and severin 2012) also known as the "spalling effect." as the negative pressure phase of the blast wave propagates through, it causes more stress on the tissue and further damage. in addition to damaging tissues with an air tissue interface, pressure blasts can cause injury to the brain and can lead to limb detachments. despite the fact that primary blast injuries can be ravaging, they are less common than other types of injury from blasts. the tympanic membranes, lungs, and gastrointestinal tract are the most common organs sustaining injury from pressure waves. the tympanic membrane is the most vulnerable of these three organ systems (depalma et al. 2005; garth 1997) . five psi, which is considered a weak blast, will rupture 50% of tympanic membranes. to put this in perspective, c4, a commonly used explosive generates a pressure of four million psi. otoscopy can reveal ruptured tympanic membranes. neuropraxia, deafness, tinnitus, and vertigo are symptoms that can be experienced. severe blast injuries of the ear can result in damage to the organ of corti, resulting in permanent hearing loss. the second most common organ injured from a blast wave is the lung. fifteen psi are required to cause injury to this organ. lung injuries are more likely to occur from a blast within a closed space, or when victims sustain burns (burns commonly cause acute lung injury from release of inflammatory mediators). direct alveolar damage, blood vessel with bleeding, and inflammation are the three different manifestations of lung injury from blasts. alveolar damage can cause pneumothorax and pulmonary interstitial emphysema. when air dissects along the bronchovascular sheath, pneumomediastinum, pneumopericardium, and subcutaneous emphysema can occur. air that enters the pulmonary venous system can result in a systemic arterial air embolism, and possibly, a stroke. inflammation of the lungs from direct pressure damage to the tissue, cause acute lung injury and possibly, disseminated intravascular coagulation. clinical signs of lung injury include tachypnea, chest pain, hypoxia, rales, and dyspnea. if there is vascular disruption, hemoptysis can occur. air leaks from alveolar injury can result in diminished breath sounds, subcutaneous crepitance, increased resonance, and tracheal deviation. hemodynamic compromise will occur with tracheal deviation. alveolar damage, leading to air in the pulmonary venous system, can lead to a systemic arterial air embolism. air in the coronary arteries can lead to coronary ischemia with st and/or t waves changes on ecg. air embolism to cerebral arteries leads to cerebral vascular accidents (strokes) with focal neurological deficits. other manifestations of systemic air embolism include mottling of the skin, demarcated tongue blanching, and/or air in the retinal vessels (the most common sign of arterial air embolus). rapid death after initial survival is most often caused by arterial air embolus. initiation of positive pressure ventilation may trigger this event (ho and ling 1999) . a lung injury from a blast can also precipitate a vagal reflex resulting in bradycardia and hypotension. it is postulated that this occurs from the stimulation of c fibers in the lungs (guy et al. 1998 ). the gastrointestinal system is the third most common organ system affected by primary blast injury. physical stress and/or mesenteric infarct leads to weakening of the bowel wall with possible rupture. hemorrhage can also occur (paran et al. 1996; sharpnack et al. 1991) . the most common site of injury is the colon. injury to the bowel can be delayed and occur up to several days after the inciting incident. solid organs are spared because of their homogeneity and lack of air tissue interface. brain injury is becoming increasingly recognized as a result of primary blast. shearing injuries of the brain occur as a result of wave reverberation in the skull. hippocampal injury causing cognitive impairment has been shown in animal studies (cernak 2017; cernak et al. 2001; singer et al. 2005) . observations in humans have revealed electroencephalographic abnormalities and attention deficit disorder (born 2005) . human autopsies have revealed punctate hemorrhages and disintegration of nissl substance in victims who sustained blast injury without direct head trauma (guy et al. 1998) . research involving yucatan minipigs revealed that the brain sustains neuronal loss in the hippocampus after being subjected to primary blast injury. brain injury also occurred from the inflammation that ensued post blast (goodrich et al. 2016) . novel therapeutic approaches may be on the horizon for treatment of traumatic brain injury, including that caused by primary blast. intranasal insulin administered to rats subjected to traumatic brain injury resulted in enhanced neuronal glucose uptake and utilization, and subsequently improved motor function and memory. decreased neuroinflammation and preservation of the hippocampus were also noted (brabazon et al. 2017) . in a different investigation, a neuroprotective nucleotide, guanosine, was administered to rats subjected to traumatic brain injury. the treatment group of rats had better locomotor and cognitive outcomes than did the placebo group. programmed cell death and inflammation were also attenuated in the treatment group (gerbatin et al. 2017) . the leading cause of death from blast is from flying objects striking victims (secondary blast injury). eyes are particularly vulnerable. injuries resulting from displacement of the victims who strike objects are known as tertiary injuries. lighter weight children are particularly susceptible to this type of injury. burns, toxic exposures, and crush injuries constitute quaternary injuries. crush injuries commonly occur in explosions with structural collapse. the "crush syndrome" can occur when a trapped limb sustains prolonged compromise to the circulation, leading to rhabdomyolysis. tissue destruction and inflammatory response then occur. lifethreatening electrolyte abnormalities including hyperkalemia, renal failure, hyperuricemia, metabolic acidosis, acute respiratory distress syndrome, disseminated intravascular coagulation, and shock can result from crush syndrome (gonzalez 2005) . the crush syndrome is commonly seen in natural disasters that result in a lot of structural collapse. structural collapse and fires can cause the release of toxic materials such as carbon monoxide and cyanide. knowledge of the details of a blast can greatly enhance the ability of nurses and hcps to care for victims of a blast in a hospital setting. knowledge of whether a blast occurred in a closed or open space, whether structural collapse occurred, or if a victim was rescued from a collapsed area are details that can alert nurses and hcps as to what kind of injuries that they may anticipate. if toxic substances are released with a blast, nurses and hcps can prepare for decontamination techniques and antidote therapies. it would be advantageous for a hospital to be aware of the number of victims that are arriving for care. a mass casualty incident will stress the resources of the institution. hospital personnel should take stock of the resources that are available. the number of available ventilators and o-blood are examples of finite resources that should be considered. advanced trauma life support (atls) principles should be applied to all blast injury victims. abcd of initial resuscitation is applied. the "d" stands for disability as well as decontamination. decontamination techniques should be deployed if there is uncertainty about toxic exposure as described elsewhere in this chapter. on completion of abcd of initial resuscitation a secondary survey is performed, as described by atls protocol. attention should be paid to potential injuries that occur with blast injuries. ruptured tympanic membranes should alert the nurse or hcp of problems from primary blast injury. impaled objects should remain in place and removed in the operating room by surgical staff so that bleeding may be controlled. a thoracoscopy tube should be placed with an open three point seal over a wound on the side of the chest with an open pneumothorax. a hemothorax is also treated with a thoracoscopy tube. an autotransfusion setup can be applied to recirculate the blood from the pleural cavity of a hemothorax (wightman and gladish 2001 ) that would help preserve donor blood for other victims. for severe respiratory distress and/or impending respiratory failure, endotracheal intubation should be performed and positive pressure ventilation should be instituted. because lung tissue could be weakened from primary blast injury, caution should be exercised because of a high risk of pneumothorax, hemorrhage, or arterial air embolus. gentle application of positive pressure ventilation should be applied to avoid these complications. if only one lung is injured unilateral lung ventilation can be considered for larger children and adults. this technique is not suitable for babies and small children. supplemental oxygen with an fio 2 of 100% should be administered to patients suspected of having an arterial air embolus. hyperbaric oxygen therapy could even be considered to help accelerate the removal of air from the arteries. placement of the patient in the left lateral recumbent position may reduce the likelihood of the air lodging in the coronary arteries. victims of blast injuries should be treated identically to those of other types of trauma after initial resuscitation is completed. if primary blast injury occurred, frequent chest and abdominal x-rays should be performed in consideration of the possibility of lung or gastrointestinal injuries. limbs with open fractures should be immobilized and covered with sterile dressings. systemic, broad spectrum antibiotics should be administered to patients with open limb injuries. eyes that sustained chemical injury should be irrigated with water for an hour. all injured eyes should be covered. most ruptured tympanic membranes will heal spontaneously. victims with tympanic membrane injury should be advised to avoid swimming for some time. topical antibiotics are prescribed if dirt or debris is seen in the ear canal. oral prednisone is prescribed for hearing loss. victims with crush injuries should be treated with large volumes of iv fluids to treat inflammatory shock and possibly rhabdomyolysis. electrolytes should be monitored carefully as these patients are at risk for hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and acidosis. smoke inhalation, burns, and toxic exposures should be treated according to guidelines of burn, trauma, and toxicology protocols. mass casualty incidents (i.e. mass shootings, active shooter events, bombings, and other multifatality crimes) often attract extensive media coverage as well as the attention of policy makers. many agencies and organizations record and publish data on these incidents. the measurement and reporting does vary based on the absence of a common definition. however, it is clearly evident that mass casualty incidents (mcis) continue to increase in both number and scope (federal bureau of investigation 2017; office for victims of crime, office of justice programs, u.s. department of justice 2019). in the u.s., mass shootings are the most common and most closely tracked. the congressional research service (crs) defines mass shootings as events where more than four people are killed with a firearm "within one event, and in one or more locations in close proximity." congress uses the term mass killings and describes these events as "three or more killings in a single incident." the federal bureau of investigation (fbi) uses the term active shooter, which it defines as "an individual actively engaged in killing or attempting to kill people in a populated area." it is important to realize that nongovernmental ( ranking third of all locations for 2016 and 2017, seven of the 50 incidents occurred in educational environments resulting in five killed and 19 wounded. two incidents occurred in elementary schools, resulting in two killed (including a firstgrade student) and eight wounded (one teacher shot, three students shot, and four wounded from shrapnel). one incident occurred in a junior/senior high school, resulting in none killed and four wounded (two from shrapnel, all students). four incidents occurred at high schools (one outside a school during prom), resulting in three killed (all students) and seven wounded (all students). fortunately, no incident occurred at institutions of higher learning during 2016 or 2017 (advanced law enforcement rapid response training (alerrt) center, texas state university and federal bureau of investigation, u.s. department of justice 2018). notably, two of the 50 incidents occurred in houses of worship, resulting in 27 killed and 27 wounded. one of these incidents occurred at the first baptist church in sutherland springs, texas, and had the third highest number of casualties (26 killed and 20 wounded) in 2017. the dead included 10 women, 7 men, 8 children (7 girls and 1 boy), and an unborn child (goldman et al. 2017) . a summary report has also been developed for all 250 active shooter incidents from 2000 to 2017, including incidents per year (fig. 5.11 ), casualties per year (fig. 5.12) , and location ( fig. 5.13 ) categories (federal bureau of investigation 2017; federal bureau of investigation 2018). overall, there was an increase in number of active shooter incidents and casualties per year. location categories with number of incidents and statistics of their contribution were provided: areas of educational environments account for a large portion of locations for active shooter incidents, ranking only second to commercial areas. of the 37 incidents (14.8%) occurring at schools, one took place at a nursery (pre-k) school and one incident occurred during a school board meeting that was being hosted on school property but no students were involved (neither perpetrator or victim). the remainder (35 incidents) were perpetrated by or against students, faculty, and/or staff at k-12 schools (federal bureau of investigation 2018). finally, 15 active shooter incidents (6%) did occur at institutions of higher learning. as a reminder, no incident occurred at institutions of higher learning during 2016 or 2017. table 5 .31 provides a detailed summary of educational environment incidents from 2000 to 2017. since the beginning of 2018, other tragic active shooter attacks have occurred in the u.s. and greatly impacted children and adolescents. two of these such events have occurred in educational environments (united states secret service national threat assessment center 2018). on february 14, 2018, a gunman opened fire at marjory stoneman douglas high school. fourteen students and three staff members were killed while fourteen others were injured (follman et al. 2019) . twelve victims died inside the building, three died just outside the building on school premises, and two died in the hospital. the shooter was a former student of the school. another active shooter event occurred on may 18, 2018 at santa fe high school in santa fe, texas. the shooter killed ten individuals including eight students and two teachers while injuring 13 others. the shooter was an enrolled student at the school (follman et al. 2019) . based on the statistics of active shooter incidents, casualties, and locations, it is vital to prepare schools and plan for such events. national preparedness efforts, including planning, are now informed by the presidential policy directive (ppd) 8 that was signed by the president in march 2011 and describes the nation's approach to preparedness. this directive represents an evolution in our collective understanding of national preparedness based on the lessons learned from terrorist attacks, hurricanes, school incidents, and other experiences. ppd-8 defines preparedness around five mission areas and can be applied to school active shooter incidents. on march 21, 2005, at 2:49 p.m., jeffery james weise, 16, armed with a shotgun and two handguns, began shooting at red lake high school in red lake, minnesota. before the incident at the school, the shooter fatally shot his grandfather, who was a police officer, and another individual at their home. he then took his grandfather's police equipment, including guns and body armor, to the school. a total of nine people were killed, including an unarmed security guard, a teacher, and five students; six students were wounded. the shooter committed suicide during an exchange of gunfire with police campbell county comprehensive high school (education) on november 8, 2005, at 2:14 p.m., kenneth s. bartley, 14, armed with a handgun, began shooting in campbell county comprehensive high school in jacksboro, tennessee. before the shooting, he had been called to the office when administrators received a report that he had a gun. when confronted, he shot and killed an assistant principal and wounded the principal and another assistant principal. the shooter was restrained by students and administrators until police arrived and took him into custody pine middle school (education) on march 14, 2006, at 9:00 a.m., james scott newman, 14, armed with a handgun, began shooting outside the cafeteria at pine middle school in reno, nevada. no one was killed; two were wounded. the shooter was restrained by a teacher until police arrived and took him into custody essex elementary school and two residences (education) on august 24, 2006, at 1:55 p.m., christopher williams, 26, armed with a handgun, shot at various locations in essex, vermont. he began by fatally shooting his ex-girlfriend's mother at her home and then drove to essex elementary school, where his ex-girlfriend was a teacher. he did not find her, but as he searched, he killed one teacher and wounded another. he then fled to a friend's home, where he wounded one person. a total of two people were killed; two were wounded. the shooter also shot himself twice but survived and was apprehended when police arrived at the scene orange high school and residence (education) on august 30, 2006, at 1:00 p.m., alvaro castillo, 19, armed with two pipe bombs, two rifles, a shotgun, and a smoke grenade, began shooting a rifle from his vehicle at his former high school, orange high school in hillsborough, north carolina. he had fatally shot his father in his home that morning. one person was killed; two were wounded. the shooter was apprehended by police weston high school (education) on september 29, 2006, at 8:00 a.m., eric jordan hainstock, 15, armed with a handgun and a rifle, began shooting in weston high school in cazenovia, wisconsin. one person was killed; no one was wounded. the shooter was restrained by school employees until police arrived and took him into custody west nickel mines school (education) on october 2, 2006, at 10:30 a.m., charles carl roberts, iv, 32, armed with a rifle, a shotgun, and a handgun, began shooting at the west nickel mines school in bart township, pennsylvania. after the shooter entered the building, he ordered all males and adults out of the room. after a 20-min standoff, he began firing. the shooter committed suicide as the police began to breach the school through a window. five people were killed; five were wounded on april 2, 2012, at 10:30 a.m., su nam ko, aka one l. goh, 43, armed with a handgun, began shooting inside oikos university in oakland, california. he then killed a woman to steal her car. seven people were killed; three were wounded. the shooter was arrested by police later that day on august 27, 2012, at 10:45 a.m., robert wayne gladden jr., 15, armed with a shotgun, shot a classmate in the cafeteria of perry hall high school in baltimore, maryland. the shooter had an altercation with another student before the shooting began. he left the cafeteria and returned with a gun. no one was killed; one person was wounded. the shooter was restrained by a guidance counselor before being taken into custody by the school's resource officer sandy hook elementary school and residence (education) on december 14, 2012, at 9:30 a.m., adam lanza, 20, armed with two handguns and a rifle, shot through the secured front door to enter sandy hook elementary school in newtown, connecticut. he killed 20 students and six adults, and wounded two adults inside the school. prior to the shooting, the shooter killed his mother at their home. in total, 27 people were killed; two were wounded. the shooter committed suicide after police arrived taft union high school (education) on january 10, 2013, at 8:59 a.m., bryan oliver, 16, armed with a shotgun, allegedly began shooting in a science class at taft union high school in taft, california. no one was killed; two people were wounded. an administrator persuaded the shooter to put the gun down before police arrived and took him into custody new river community college, satellite campus (education) on april 12, 2013, at 1:55 p.m., neil allen macinnis, 22, armed with a shotgun, began shooting in the new river community college satellite campus in the new river valley mall in christiansburg, virginia. no one was killed; two were wounded. the shooter was apprehended by police after being detained by an off-duty mall security officer as he attempted to flee santa monica college and residence (education) on june 7, 2013, at 11:52 a.m., john zawahri, 23, armed with a handgun, fatally shot his father and brother in their home in santa monica, california. he then carjacked a vehicle and forced the driver to take him to the santa monica college campus. he allowed the driver to leave her vehicle unharmed but continued shooting until he was killed in an exchange of gunfire with police. five people were killed; four were wounded sparks middle school (education) on october 21, 2013, at 7:16 a.m., jose reyes, 12, armed with a handgun, began shooting outside sparks middle school in sparks, nevada. a teacher was killed when he confronted the shooter; two people were wounded. the shooter committed suicide before police arrived arapahoe high school (education) on december 13, 2013, at 12:30 p.m., karl halverson pierson, 18, armed with a shotgun, machete, and three molotov cocktails, began shooting in the hallways of arapahoe high school in centennial, colorado. as he moved through the school and into the library, he fired one additional round and lit a molotov cocktail, throwing it into a bookcase and causing minor damage. one person was killed; no one was wounded. the shooter committed suicide as a school resource officer approached him berrendo middle school (education) on january 14, 2014, at 7:30 a.m., mason andrew campbell, 12, armed with a shotgun, began shooting in berrendo middle school in roswell, new mexico. a teacher at the school confronted and ordered him to place his gun on the ground. the shooter complied. no one was killed; 3 were wounded: 2 students and an unarmed security guard. the shooter was taken into custody (continued) on june 5, 2014, at 3:25 p.m., aaron rey ybarra, 26, armed with a shotgun, allegedly began shooting in otto miller hall at seattle pacific university in seattle, washington. he was confronted and pepper sprayed by a student as he was reloading. one person was killed; 3 were wounded. students restrained the shooter until law enforcement arrived reynolds high school (education) on june 10, 2014, at 8:05 a.m., jared michael padgett, 15, armed with a handgun and a rifle, began shooting inside the boy's locker room at reynolds high school in portland, oregon. one student was killed; 1 teacher was wounded. the shooter committed suicide in a bathroom stall after law enforcement arrived marysville-pilchuck high school (education) on october 24, 2014, at 10:39 a.m., jaylen ray fryberg, 15, armed with a handgun, began shooting in the cafeteria of marysville-pilchuck high school in marysville, washington. four students were killed, including the shooter's cousin; 3 students were wounded, including one who injured himself while fleeing the scene. the shooter, when confronted by a teacher, committed suicide before law enforcement arrived florida state university (education) on november 20, 2014, at 12:00 a.m., myron may, 31, armed with a handgun, began shooting in strozier library at florida state university in tallahassee, florida. he was an alumnus of the university. no one was killed; 3 were wounded. the shooter was killed during an exchange of gunfire with campus law enforcement. umpqua community college (education) on october 1, 2015, at 10:38 a.m., christopher sean harper-mercer, 26, armed with several handguns and a rifle, began shooting classmates in a classroom on the campus of umpqua community college in roseburg, oregon. nine people were killed; 7 were wounded. the shooter committed suicide after being wounded during an exchange of gunfire with law enforcement. madison junior/ senior high school (education) on february 29, 2016, at 11:30 a.m., james austin hancock, 14, armed with a handgun, allegedly began shooting in the cafeteria of madison junior/senior high school in middletown, ohio. he shot two students before fleeing the building. no one was killed; four students were wounded (two from shrapnel). the shooter was apprehended near the school by law enforcement officers antigo high school (education) on april 23, 2016, at 11:02 p.m., jakob edward wagner, 18, armed with a rifle, began shooting outside a prom being held at his former school, antigo high school in antigo, wisconsin. two law enforcement officers, who were on the premises, heard the shots and responded immediately. no one was killed; two students were wounded. the shooter was wounded in an exchange of gunfire with law enforcement officers and later died at the hospital townville elementary school (education) on september 28, 2016, at 1:45 p.m., jesse dewitt osborne, 14, armed with a handgun, allegedly began shooting at the townville elementary school playground in townville, south carolina. prior to the shooting, the shooter, a former student, killed his father at their home. two people were killed, including one student; three were wounded, one teacher and two students. a volunteer firefighter, who possessed a valid firearms permit, restrained the shooter until law enforcement officers arrived and apprehended him on january 20, 2017, at 7:36 a.m., ely ray serna, 17, armed with a shotgun, allegedly began shooting inside west liberty salem high school, in west liberty, ohio, where he was a student. after assembling the weapon in a bathroom, the shooter shot a student who entered, then shot at a teacher who heard the commotion. the shooter shot classroom door windows before returning to the bathroom and surrendering to school administrators. no one was killed; two students were wounded. school staff members subdued the shooter until law enforcement arrived and took the shooter into custody freeman high school (education) on september 13, 2017, at 10:00 a.m., caleb sharpe, 15, armed with a rifle and a pistol, allegedly began shooting at freeman high school in rockford, washington, where he was a student. one student was killed; three students were wounded. a school employee confronted the shooter, ordered him to the ground, and held him there until law enforcement arrived and took him into custody rancho tehama elementary school and multiple locations in tehama county, california (education) on november 14, 2017, at 7:53 a.m., kevin janson neal, 44, armed with a rifle and two handguns, began shooting at his neighbors, the first in a series of shootings occurring in rancho tehama reserve, tehama county, california. after killing three neighbors, he stole a car and began firing randomly at vehicles and pedestrians as he drove around the community. after deliberately bumping into another car, the shooter fired into the car and wounded the driver and three passengers. the shooter then drove into the gate of a nearby elementary school. he was prevented from entering the school due to a lockdown, so he fired at the windows and doors of the building, wounding five children. upon fleeing the school, the shooter continued to shoot at people as he drove around rancho tehama reserve. law enforcement pursued the shooter; they rammed his vehicle, forced him off the road, and exchanged gunfire. the shooter's wife's body was later discovered at the shooter's home; the shooter apparently had shot and killed her the previous day. in total, five people were killed; 14 were wounded, eight from gunshot injuries (including one student) and six from shrapnel injuries (including four students). the shooter committed suicide after being shot and wounded by law enforcement during the pursuit aztec high school (education) on december 7, 2017, at approximately 8:00 a.m., william edward atchison, 21, armed with a handgun, began shooting inside aztec high school in aztec, new mexico. the shooter was a former student. two students were killed; no one was wounded. the shooter committed suicide at the scene, before police arrived a in a study of active shooter incidents in the united states between 2000 and 2013, the fbi identified 11 locations where the public was most at risk during an incident. these location categories include commercial areas (divided into business open to pedestrian traffic, businesses closed to pedestrian traffic, and malls), education environments (divided into schools [prekindergarten through 12th grade] and institutions of higher learning), open spaces, government properties (divided into military and other government properties), residences, houses of worship, and health care facilities. in 2018, the fbi added a new location category, other location, to capture incidents that occurred in venues not included in the 11 previously identified locations (federal bureau of investigation 2017). this table only includes educational environments. an entire list of all incidents from 2000 to 2017 at all locations can be found at https://www.fbi.gov/file-repository/activeshooter-incidents2000 .pdf/view (federal bureau of investigation 2018 prevention means the capabilities necessary to avoid, deter, or stop an imminent crime or threatened/actual mass casualty incident. prevention is the action schools take to prevent a threatened or actual incident from occurring. protection means the capabilities to secure schools against acts of violence and man-made or natural disasters. protection focuses on ongoing actions that protect students, teachers, staff, visitors, districts, networks, and property from a threat or hazard. mitigation means the capabilities necessary to eliminate or reduce the loss of life and property damage by lessening the impact of an event or emergency at the school. it also means reducing the likelihood that threats and hazards will happen. response means the school's or school district's capabilities necessary to stabilize an emergency once it has already happened or is certain to happen in an unpreventable way, establish a safe and secure environment, save lives and property, and facilitate the transition to recovery. recovery means the capabilities necessary to assist schools affected by an event or emergency in restoring the learning environment. it also means teaming with community partners to restore educational programming, the physical environment, business operations, and social, emotional, and behavioral health. the majority of prevention, protection, and mitigation activities generally occur before an incident, although these three mission areas do have ongoing activities that can occur throughout an active shooter incident. response activities occur during an incident, and recovery activities can begin during an incident and occur after an incident (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013; united states department of homeland security 2018b; united states department of homeland security 2018). in the k-12 school security guide, the u.s. department of homeland security (dhs) focuses on prevention and protection since the activities and measures associated with them occur prior to an incident (2018). effective preventative and protective actions decrease the probability that schools (or other facilities) will encounter incidents of gun violence or should an incident occur, it reduces the impact of that incident. the guide emphasizes that the level of security at a facility will be based on hazards relevant to the facility, people, or groups associated with it. it also warns that as new or different threats become apparent, the perception of the relative security changes and insecurity should drive change to reflect the level of confidence of the people of groups associated with the facility. the dhs utilizes a hometown security approach that emphasizes the process of connect, plan, train, and report (cptr) with the objective to realize effective, collaborative outcomes (united states department of homeland security 2018b). the initial phase is connect and occurs by a school or district reaching out and developing relationships in the community, including local law enforcement. having these relationships before an incident or event can help speed up the response when something happens. each school must begin with identification or development of a security team, group, or organization. this phase also emphasizes outreach, collaboration, and building of a coalition. there should be coalition members from within a school and may include district/school administrators, teachers, aides, facility operations personnel, human resources, administrative, counseling, and student groups. external groups directly related to the school might include boards of education, parent organizations, mental health groups/agencies, and teacher and bus driver unions. external groups indirectly related to the school include all responder organizations such as police and fire departments, sheriff's office, emergency medical services, emergency management, and the local dhs protective security advisor (psa). other tangential groups such as volunteer organizations, utility providers, and facilities in close geographic proximity should also be considered. core and advisory members of the coalition are established. a coalition champion is also identified and is the person who owns the majority of the responsibility for achieving a school's security goals. the champion organizes the coalition as it grows and matures (united states department of homeland security 2018b). the next phase is plan. this will bring the coalition together. the guide for developing high quality school emergency operations plans (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013) is an excellent resource for the coalition. a school security survey for gun violence can be completed and the coalition or user can quickly and effectively determine a facility's security proficiency (united states department of homeland security. 2018). specific portions of or topics within a school plan should be assigned to individuals, committees, or working groups most qualified to address them. the planning process must be sustainable. the amount of time spent in the planning phase should be commensurate with the amount of effort expended on the other phases (united states department of homeland security 2018b). the next phase of the process is to train on the plan developed by the coalition. determining who is responsible for what and how it should be done is the basic function of planning. in fact, telling various members of the team what is expected of them and when to do that activity is the function of training. it is vital to utilize the curricula development expertise possessed by the k-12 community. school administrators should take advantage of this skill set and find creative ways to address difficult topics, such as gun violence. it should be carried out in an effective and nontraumatic way. presenting the training in pieces or steps allows for a more comprehensive learning experience. it is important to validate training through exercises and drills, all of which should include the students. the training event should be followed by the completion and implementation of an after-action improvement plan with adjustment of the cptr as indicated (united states department of homeland security 2018b). the final phase in the process is report. the reporting phase is arguably the most important of all the phases. reporting principles underlie the other three phases and have profound prevention and protection impacts by driving forward information. dhs models the reporting phase using the "if you see something, say something â® " campaign (u.s. dhs, 2018) and the nationwide suspicious activity reporting (sar) initiative (nationwide suspicious activity reporting initiative (nsi) 2019). "if you see something, say something â® " focuses on empowering anyone who sees suspicious activity to do something about it by contacting local law enforcement, or if an emergency to call 9-1-1 (united states department of homeland security 2018a). this is a compelling capability when well organized and managed. a good plan for reporting, especially for a k-12 school, involves training staff and students on what is considered suspicious. there are many methods in which schools can employ to facilitate this, such as dedicated telephone numbers, websites for anonymous reporting, email or text messaging, and mobile phone applications. conducting simple drills for reporters and receivers keeps skills sharp and reinforces the importance of the effort with the goal to save lives. if the plan includes sharing all suspicious activity calls with the local fusion center then the probability of higher fidelity reporting increases (united states department of homeland security 2018b). when making changes to a school's plans, procedures, and protective measures, it is imperative the needs of individuals with special health care needs be addressed throughout the process. planning, training, and execution should always consider accessible alert systems for those who are deaf or hard of hearing; students, faculty, and staff who have visual impairments or are blind; individuals with limited mobility; alternative notification measures; people with temporary disabilities; visitors; people with limited english proficiency; sign cards with text-and picture-based emergency messages/symbols; and involving people with disabilities in all planning (united states department of homeland security, interagency security committee 2015). it is important to understand that no "profile" exists for an active shooter (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013). however, research indicates there may be signs or indicators. o'toole (2000) presents an in depth, systematic procedure for school shooter threat assessment and intervention. the model was designed to be used by educators, mental health professionals, and law enforcement agencies. its fundamental building blocks are the threat assessment standards, which provide a framework for evaluating a spoken, written, and symbolic threat, and the fourpronged assessment approach which provides a logical, methodical process to examine the threatener and assess the risk that the threat will be carried out. schools should learn the signs of a potentially volatile situation that may develop into an active shooter situation and proactively seek ways to prevent an incident with internal resources, or additional external assistance (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013). potential warning signs of a school shooter may include increasingly erratic, unsafe, or aggressive behaviors; hostile feelings of injustice or perceived wrongdoing; drug and alcohol abuse; marginalization or distancing from friends and colleagues; changes in performance at work or school; sudden and dramatic changes in home life or in personality; pending civil or criminal litigation; and observable grievances with threats and plans of retribution (united states department of homeland security 2018b). at a minimum, schools should establish and enforce policies that prohibit, limit, or determine unacceptable behaviors and consequences of weapons possession/use, drug possession/use, alcohol/tobacco possession/use, bullying/harassment, hazing, cyber-bullying/harassment/stalking, sexual assault/misconduct/harassment, bias crimes, social media abuse, and any criminal acts (united states department of homeland security 2018b). in addition to policies and positive school climates, school districts and administrators should establish dedicated teams to evaluate threats, such as a threat assessment team (tat). the team should include mental health professionals (e.g., forensic psychologist, clinical psychologist, and school psychologist) to contribute to the threat assessment process (united states department of homeland security 2018b). it is the responsibility of the tat to investigate and analyze communications and behaviors to make a determination on whether or not an individual poses a threat to him/herself or others (united states department of education, office of elementary and secondary education, office of safe and healthy students 2013). as well as tats, some schools have even opted to establish social media monitoring teams which look for keywords that may indicate bullying or other concerning statements. if a school opts to create such a team, it should work very closely with the tat to ensure that applicable privacy, civil rights and civil liberties, other federal, state and local laws, and information sharing protocols are followed. please refer to chap. 14 for further information. after an active shooter incident, field triage (e.g., jumpstart) must commence and the patient must be evaluated by an experienced emergency medicine or trauma surgeon, preferably by a pediatric specialist in those disciplines. if an active shooter incident is coupled with detonation of an explosive device, the child must be screened and decontaminated for radiation exposure ("dirty bomb"). triage tags are extremely helpful when multiple victims present in a short period of time. medical response to an active shooter event will focus on control of external hemorrhage along with circulatory stabilization. operative emergencies will be common and receive the highest priority. severe extremity injuries may be controlled with tourniquet application or other forms of hemorrhage control. re-evaluation is paramount to prevent ischemia to distal regions. however, thoracic or abdominal (truncal) injuries will need immediate surgical exploration and intervention. penetrating trauma will cause more vascular injuries than blunt trauma, and vascular surgical trays may be in short supply at a hospital. major procedure or surgical trays may become short in supply based on the increased operative demand. resuscitative blood transfusion therapy may utilize a massive blood transfusion protocol. since whole blood may be short in supply, some will simply use the 1:1:1 rule (administer one unit of packed cells: one unit of fresh frozen plasma: one unit of platelets). a unit for children may be substituted as an aliquot based on size of the patient (e.g., administer 10 ml/kg of packed cells: 10 ml/kg of fresh frozen plasma: 10 ml/kg of platelets). calcium must also be replaced when there is a large volume transfusion. due to extensive blood product utilization, there may be a heavy impact on institutional or regional blood supplies. plans should be in place to address these problems, including the implementation of allocation of scarce resources. mental health support and staff debriefs are essential and should be included after an active shooter event (hick et al. 2016 ). in conclusion, all forms of disasters, whether man-made or natural, impact infants, children, and adolescents throughout the world. effective and efficient interventions remain the cornerstone of sustaining a child's well-being while reducing untoward complications due to all forms of disasters. having a deep understanding of pediatric physiology and pathophysiology is crucial to all levels of disaster diagnostics and therapeutics. all nurses and hcps have an obligation to understand these principles and deliver excellent, compassionate care to the pediatric disaster victim. advanced law enforcement rapid response training evidence-based support for the all-hazards approach to emergency preparedness ahls advanced hazmat life support provider manual active shooter incidents in the united states in 2016 and 2017 radiation disasters and children-committee on environmental health apls: the pediatric emergency medicine resource textbook of neonatal resuscitation american college of emergency physicians, pediatric committee, and emergency nurses association pediatric committee american college of emergency physicians, national association of ems physicians, pediatric equipment guidelines committee emergency medical services for children (emsc) partnership for children stakeholder group handbook of emergency cardiovascular care for healthcare providers pediatric advanced life support provider manual mass casualty terrorist bombings: a comparison of outcomes by bombing type committee on pediatric emergency medicine and task force on terrorism. the pediatrician and disaster preparedness mass casualty terrorist bombings: a comparison of outcomes by bombing type assistant secretary for preparedness and response, united states department of health and human services avalon project-the atomic bombings of hiroshima and nagasaki 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glycoprotein: interim results from the guinea ring vaccination cluster-randomised trial committee on drugs. preparing for pediatric emergencies: drugs to consider health and medical response to active shooter and bombing events: a discussion paper medical management of chemical toxicity in pediatrics systemic air embolism after lung trauma nerve agents. in: compendium of chemical warfare agents caring for non-injured and non-ill children in a disaster: a guide for non-medical professionals and volunteers pediatric disaster preparedness guidelines for hospitals current concepts of pediatric critical care. mount prospect, il: society of critical care medicine terrorist and criminal attacks targeting children pyridinium oximes in the treatment of poisoning with organophosphorus compounds imvamuneâ®: modified vaccinia ankara strain as an attenuated smallpox vaccine the special injury pattern in terrorist bombings raxibacumab: potential role in the treatment of inhalational anthrax 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the united states pediatric acute care: a guide for interprofessional practice inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two ebola management centres in sierre leone, 2014: a retrospective cohort study the pathology of primary blast injury conventional terrorism and critical care apls: the pediatric emergency medicine resource characteristics and outcomes of pediatric patients with ebola virus disease admitted to treatment units in liberia and sierra leone: a retrospective cohort study the physics and mechanisms of primary blast injury guidance potassium iodide as a thyroid blocking agent in radiation emergencies. n.d.. w.fda.gov/downloads/drugs/guidancecomplianceregulatory information/guidances/ucm080542 medical response to terrorism: preparedness and clinical practice medical response to terrorism: preparedness and clinical practice usamriid's medical management of biological casualties handbook guide for 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homeland security. k-12 school security survey understanding your risks: identifying hazards and estimating losses fema fact sheet: national planning scenarios united states department of homeland security. national planning scenarios. version 21.3 final draft fema's progress in all-hazards mitigation enhancing school safety using a threat assessment model: an operational guide for preventing targeted school violence living with hazards, dealing with disasters: an introduction to emergency management terrorism and the all-hazards model explosions and blast injuries medical response to terrorism: preparedness and clinical practice quantitative terrorism risk assessment medical aspects of biological warfare vesicant agents and children medical consequences of nuclear warfare (textbooks of military medicine) safety and immunogenicity of a recombinant adenovirus type-5 vector-based ebola vaccine in healthy adults in sierra leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial key: cord-289861-i6bfuvq1 authors: macdonald-laurs, emma; koirala, archana; britton, philip n.; rawlinson, william; hiew, chee chung; mcrae, jocelynne; dale, russell c.; jones, cheryl; macartney, kristine; mcmullan, brendan; pillai, sekhar title: csf neopterin, a useful biomarker in children presenting with influenza associated encephalopathy? date: 2018-09-28 journal: eur j paediatr neurol doi: 10.1016/j.ejpn.2018.09.009 sha: doc_id: 289861 cord_uid: i6bfuvq1 purpose: neurological complications of influenza cause significant disease in children. central nervous system inflammation, the presumed mechanism of influenza-associated encephalopathy, is difficult to detect. characteristics of children presenting with severe neurological complications of influenza, and potential biomarkers of influenza-associated encephalopathy are described. methods: a multi-center, retrospective case-series of children with influenza and neurological complications during 2017 was performed. enrolled cases met criteria for influenza-associated encephalopathy or had status epilepticus. functional outcome at discharge was compared between groups using the modified rankin scale (mrs). results: there were 22 children with influenza studied of whom 11/22 had encephalopathy and 11/22 had status epilepticus. only one child had a documented influenza immunization. the biomarker csf neopterin was tested in 10/11 children with encephalopathy and was elevated in 8/10. mri was performed in all children with encephalopathy and was abnormal in 8 (73%). treatment of children with encephalopathy was with corticosteroids or intravenous immunoglobulin in 9/11 (82%). in all cases oseltamivir use was low (59%) while admission to the intensive care unit was frequent (14/22, 66%). clinical outcome at discharge was moderate to severe disability (mrs score > 2) in the majority of children with encephalopathy (7/11, 64%), including one child who died. children with status epilepticus recovered to near-baseline function in all cases. conclusion: raised csf neopterin was present in most cases of encephalopathy, and along with diffusion restriction on mri, is a useful diagnostic biomarker. lack of seasonal influenza vaccination represents a missed opportunity to prevent illness in children, including severe neurological disease. severe neurological complications from seasonal influenza, including influenza-associated encephalopathy/encephalitis (iae), cause considerable morbidity and mortality in healthy children, and those with pre-existing neurological disease. 1e3 recent estimates indicate the annual incidence of iae in australia is 2.8 per 1,000,000 in children under 14 years, with around 1% of hospitalized influenza cases associated with iae. 4 other populations show similar or higher incidence, with japan's annual incidence of iae recorded as 6e11/ 1,000,000. 2, 5 neurological complications attributed to influenza range from a mildly altered mental state, vertigo and brief febrile seizures to life threatening complications such as status epilepticus, meningitis, stroke, and demyelinating disease. 1 antiviral agents, predominantly neuraminidase inhibitors, and immunomodulatory treatments (corticosteroids, intravenous immunoglobulin), are used to treat patients with influenza-associated neurological disease but there is limited evidence on their efficacy. 6 while it is thought that more extensive changes on mri correlate with disease severity 7 there are no other available biomarkers that predict outcome. the australian influenza season typically occurs between july and october. the 2017 season saw the highest levels of influenza reported since the 2009 pandemic year. 8 the authors of this report noted an apparent increase in iae and other severe neurological complications during 2017. here, we describe the clinical presentation, laboratory testing, neuroimaging, treatment and short-term outcome of these cases. in addition, we observed elevated cerebrospinal fluid (csf) neopterin e a marker of central nervous system (cns) inflammation e amongst children with iae that has not previously described. we compared the frequency of iae during the 2017 influenza season with previously published incidence estimates. materials and methods we identified children aged 0e14 years, with evidence of influenza and associated severe neurological disease including status epilepticus or moderate to severe encephalopathy, admitted to two paediatric hospitals which comprise the sydney children's hospital network, the largest paediatric network in australia. cases were ascertained between april 1st and october 31st, 2017. at the children's hospital at westmead, cases were identified from those recruited under pre-existing surveillance studies: the australian childhood encephalitis study (ace), and the influenza complications network (flucan) surveillance study. 4, 9 at sydney children's hospital, children were identified from neurology consultation databases. children were included if they required hospital admission and consultation from a paediatric neurologist for a neurological complication or worsening of a pre-existing neurological condition due to proven influenza. all children included either presented with status epilepticus (for 30 min or longer) or reached level 2 diagnostic certainty on the brighton encephalopathy score. 10 children were excluded if: influenza was not confirmed, neurological symptoms were mild, hospital admission was not required, and when an alternative diagnosis could better explain the presentation. data were retrospectively collected from electronic medical records. we collected demographic data, presenting clinical characteristics, intensive care unit (icu) admission, and length of stay, laboratory results including csf testing, and influenza testing. csf analysis included cell count, protein, glucose, microscopy, lactate, oligoclonal bands, neopterin and influenza pcr. an elevated csf neopterin result was defined as >30 nmol/l. 11 electroencephalogram reports and brain magnetic resonance imaging (mri) (t2 weighted, flair and diffusion weighted imaging) were assessed by a neurologist (s.p.) and neuroradiologist (c.c.h.). the neuroradiologist was blinded to diagnosis during review of the mri. influenza was most commonly acutely diagnosed through the detection of influenza rna in respiratory samples. both hospitals used multiplex pcr assays (seegene, south korea) which detected up to 16 respiratory viruses. the assay has targets for both influenza a and b and was performed daily with a turnaround time of 1e2 days. at sydney children's hospital, the assay also had targets for subtypes of influenza a: h3 strains and the pandemic strain h1n1/09. when influenza serology was requested to diagnose a recent influenza illness, this was performed using a complement fixation assay (virion, germany). treatment given including oseltamivir, empiric aciclovir, or 3rd generation cephalosporins, ivig, corticosteroids, and e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 3 ( 2 0 1 9 ) 2 0 4 e2 1 3 plasmapheresis were recorded. time from admission to commencement of oseltamivir was recorded. each case was assigned a modified rankin scale (mrs) based on the examination at presentation and discharge from hospital. 12 the mrs ranges from 0 (no symptoms) to 6 (death). a poor outcome was an mrs score of >2 which indicates at least moderate disability requiring assistance. the relation between categorical variables was investigated using the two tailed fisher exact test. the mannewhitney u test was used to determine the relation between continuous variables. ethics approval was granted by the sydney children's hospitals network ethics committee (lnr/17/schn/497). twenty two children were included in this case series; 59% (13/22) were female. the median age at presentation was five years (range: 1.25e14 years). eight children (36%) had preexisting epilepsy and/or developmental delay. one child had an immunodeficiency (hypogammaglobulinemia) and receives monthly ivig. this child, who presented with status epilepticus, was the only child recorded as having received the seasonal influenza vaccination. eleven children (50%) met level 2 brighton criteria for encephalitis and were designated as influenza associated encephalopathy/encephalitis (iae). 10 two children with iae had previous episodes of acute disseminated encephalomyelitis (adem) with complete clinical and radiological recovery ( table 3 cases 1&2). one child had mosaic tetrasomy x, while another had epilepsy and developmental delay. the remaining 11 children in our series had status epilepticus. in contrast to the children with iae, over half of this group (n ¼ 6) had preexisting neurological disease including two children with refractory genetic epilepsies (dravet syndrome and cdkl5). the majority of children had a fever (82%) and two-thirds had respiratory symptoms. half presented with neurological symptoms within two days of onset of their influenza illness. sixteen children (73%) presented with an altered level of consciousness. seizures occurred in 19 children (86%) at any stage of illness and status epilepticus was frequent (n ¼ 17, 77%). other neurological findings at presentation were weakness (n ¼ 9, 41%), pyramidal signs (n ¼ 8, 36%), movement disorder (n ¼ 7, 32%) and ataxia (n ¼ 6, 27%). hallucinations, meningism, cranial neuropathy and pupillary changes were infrequent (<20%). the majority of children (n ¼ 18, 82%) had influenza a. of those sub-typed (n ¼ 8) half were h1 (2009) and half were h3. four children had other respiratory pathogens co-identified on npa (rhinovirus, coronavirus, mycoplasma pneumoniae). enterovirus was detected in the npa of one child but was absent in csf. one blood culture was positive for staphylococcus epidermidis, and this was assessed to be a contaminant. lumbar puncture was performed in 14 children where it was considered clinically indicated ( table 2) . of those who did not have a lumbar puncture performed most were children who presented with status epilepticus alone, usually with known pre-existing epilepsy. one case, with acute necrotising encephalopathy (ane), who was deemed to be too unwell to undergo a second lumbar puncture for measurement of neopterin. where sampled, csf showed pleocytosis and elevated protein in only a third (each n ¼ 5). influenza pcr on csf was positive in 1 of 5 children tested, in an immunocompetent previously well 10 year old. the csf neopterin was elevated in 9 of 11 children tested; in seven children it was considerably elevated ranging from 74 to 669 nmol/l (normal < 30 nmol/l), one had a borderline result (34 nmol/l). csf neopterin was measured in one child presenting with status epilepticus and was 31.75 nmol/l (borderline result). while most children with iae had a raised csf neopterin (8/10, 80%), only three had csf pleocytosis (10, 18, 19 cells/mm 3 ) and two had an elevated csf protein (0.7 g/l and 7.0 g/l). oligoclonal bands were measured on serum and/or csf in 10/11 children with iae and were not present in any. some children with iae had anti-neuronal antibodies testing performed on serum and/or csf, usually nmda and vgkc (table 3 ). these were negative apart from two cases with mildly elevated anti-thyroid antibodies. other routine laboratory data were normal or only mildly abnormal in most children (table 1) . mri brain was performed in 15 children and showed new abnormalities in eight (53%), all with iae. the common acute mri abnormalities were the presence of t2-flair hyperintensities, diffusion restriction (each, n ¼ 8), and gadolinium enhancement (n ¼ 4). the spectrum of radiological features are shown in fig. 1aei . diverse clinico-radiological syndromes were diagnosed including: ane (n ¼ 1), acute encephalopathy with biphasic seizures (aesd) (n ¼ 2), posterior reversible encephalopathy (pres) (n ¼ 1), hemiconvulsion hemiplegia syndrome (hhs) (n ¼ 1), and cerebellitis. genetic testing of ran-binding protein 2 (ranbp2) was performed in the child with ane (table 3 case 2) and the child who died from an ane-like illness ( table 3 , case 1). both were negative. one child who met criteria for iae was subsequently found to have a mutation in the polymerase gamma (polg) gene (table 3 , case 11). fourteen (66%) children were admitted to the icu and nine (41%) required mechanical ventilation. thirteen (59%) children received oseltamivir. median time to commencement of oseltamivir from presentation was 1 day (mean 5.6 days, iqr 0e9 days), but >3 days in five cases. two icu ventilated children were commenced on oseltamivir nine days after admission. in contrast, nineteen (86%) children were treated with a 3rd generation cephalosporin, while 14 (64%) received aciclovir. nineteen (86%) received anticonvulsants and 16 (73%) continued these on discharge. first-line e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 3 ( 2 0 1 9 ) 2 0 4 e2 1 3 immunomodulatory treatment (corticosteroids and/or ivig, plasmapheresis) was given to nine children with iae (corticosteroids (n ¼ 9), ivig (n ¼ 7) and plasmapheresis (n ¼ 1)) but none of those with status epilepticus alone. the median length of icu and hospital stay was four days (range 1e37) and 8 days (range 2e108 days) respectively. children with iae were more likely to have both longer hospital (mean 33.5 days vs 4.8 days; p ¼ 0.001) and picu admissions (mean 7.7 days vs 2 days; p ¼ 0.03) compared to children with status epilepticus. one child with iae died following an ane-like illness, although mri findings were atypical (table 3 , case 1). her post-mortem was inconclusive: showing generalised cerebral oedema and some features of acute hemorrhagic leucoencephalitis. ten out of 11 children with iae had an mrs score of 0 (normal) at baseline. at discharge from hospital 7/11 (64%) of children with iae had a higher in mrs score (mrs > 2; moderate disability) compared to those with status epilepticus. the change in mean mrs was significant between the two groups: children with iae had a change in mrs of 3.1 points while those in the status epilepticus group had a mean increase of mrs of 0.4 points (p-value: 0.001). nearly all children (7/8, 88%) with mri diffusion restriction had a poor outcome. the child with mri diffusion restriction and a good outcome had posterior reversible encephalopathy syndrome (pres). among the 7 children with iae and a considerably elevated neopterin, four had an mrs > 2 while three had mild deficits (mrs 1, 2 and 2). there was a mean increase in the mrs of 2.8 points the seven children with highly elevated csf neopterin (74e669 nmol/l). in this case series we observed two groups of children who presented with severe influenza related neurological disease. one group of children fulfilled criteria for iae, while the other group, most often with pre-existing neurological disease, presented with status epilepticus but otherwise did not fulfill criteria for iae. amongst cases of iae, elevated csf neopterin appeared to correlate with the presence of diffusion restriction on mri brain and adverse outcome. use of oseltamivir was infrequent among all cases, although use of antibiotics occurred in the majority. only one child had documented influenza vaccine, even amongst those with pre-existing neurological co-morbidity, despite the fact that this is recommended in australia. 13 influenza associated neurological complications are thought to occur due to an inflammatory or immunemediated response to influenza infection rather than direct viral invasion. 14,15 among those with iae we observed, similar to previous authors 2,6,16 that csf pleocytosis and detection of influenza in the csf occurred in a minority (n ¼ 5; 35%, and n ¼ 1/4; 25%). 3, 7, 17, 18 however csf neopterin, a biomarker of inflammation, was elevated in most children with iae (n ¼ 9, 81%). neopterin, a catabolic product of guanosine triphosphate (gtp), is synthesized by human macrophages upon stimulation from interferon gamma and can be measured in urine, serum and csf. 19 while serum neopterin levels are useful in the diagnosis and monitoring of systemic infectious or inflammatory diseases, such as hiv, 20 csf neopterin, reflecting intrathecal production by microglial cells, more accurately detects cns inflammatory diseases (infectious or immune mediated). 11, 19 a recent review assessing biomarkers of csf inflammation found, among clinically available tests, that csf neopterin performed better than the presence of oligoclonal bands or csf pleocytosis in detection of cns inflammation. 21 there is limited data regarding prognostically significant biomarkers in iae. pro-inflammatory cytokines may impair the blood brain barrier and induce apoptosis of neurons. 14 elevated cytokines such as interleukin-6 (il-6) and tumour necrosis factor alpha have been demonstrated in children with iae and correlates with poorer outcome. 14, 22, 23 testing csf il-6 outside the research setting is currently unavailable. clasmatodendrosis, abnormal morphological changes in astrocytes, occurring presumably due to the effect of proinflammatory cytokines, has recently been suggested to be a pathological feature of iae on autopsy. 24 clasmatodendrosis was found in the cerebral white matter, thalamus, corpus callosum, cerebellum, thalamus and hippocampus of children with iae and may correlate mri changes commonly seen. 24 previous authors have associated abnormalities on mri brain with poorer outcome. 7 in our cohort mri brain abnormalities were diverse and common, particularly diffusion restriction in the subcortical white matter. diffusion restriction correlated with a poor outcome, apart from in the child who had pres, and was associated with an elevated csf neopterin in most cases. further studies of iae are required to evaluate whether significant elevations of csf neopterin, particularly in combination with diffusion restriction and other mri changes, could predict short and long-term outcome. oseltamivir, a neuramidase inhibitor which prevents release of influenza virus from infected cells 25 has been shown to reduce influenza symptoms in otherwise healthy children by 29 h (95% ci 12e47 h,p ¼ 0.001). 26 only 59% (13 children) were treated with oseltamivir and there was a significant delay in commencement in 5 cases (>3 days in hospital). in contrast, empirical 3rd generation cephalosporin (86%) and aciclovir use (64%) was more frequent. this may be related to the perception among practitioners that antiinfluenza therapy has little benefit. we suggest in accordance with local guidelines, 8 that children with encephalitis should be empirically treated with oseltamivir during the influenza season (may to october). the evidence for use of immunotherapy (ivig, corticosteroids) in iae, is limited 27, 28 however, in our case series, most children with iae were treated with first-line immunotherapy with uncertain benefit. no serious side effects were reported. in 2017, the burden of influenza in australia (particularly the eastern states) was the highest seen since the 2009 pandemic. 8 based on iae incidence estimates published by britton et al. 2 from the 2013e15 influenza seasons in australia and the population coverage of our hospitals, we calculated that we would expect 5.2 (1.3e14.5) cases of iae in children (<14 years) per year. the iae case frequency observed in our cohort was twice the expected point estimate based on these previous incidence estimates but within the 95% confidence interval, 2 and so contribute to validating the estimates from britton et al. 2 the short-term outcome of our cohort, particularly those with iae, was alarming with 64% having a poor outcome. while there was a significant rate of icu admission among the group of children with status epilepticus (45%) this was not as high as children with iae (82%) and, most often, non-iae children did not experience a significant change in their mrs. this supports previous observations that survivors of iae during the 2009 h1n1 pandemic, and in more recent nonpandemic influenza seasons in australia, experienced significant ongoing disability. 29, 30 we have previously shown in a large retrospective encephalitis cohort study that icu admission, mri diffusion restriction and status epilepticus and were risk factors for a long-term abnormal outcome. 31 these risk factors were common (82%, 73%, 45%) in children with iae from our cohort. the medium and long-term outcome in our cohort should be assessed including formal neuropsychological testing. further research is required to understand and modulate the cns inflammatory cascade present in iae in order to modulate long term neurodisability. the overall influenza immunisation rate during 2017 in australia was low at 33%, 32 however a recently observed rate of vaccine receipt among children was even lower at 17.1%. 33 four age-specific quadrivalent influenza vaccines containing two strains of influenza a (h1n1 [michigan] and h3n2 [hong kong]) and two strains of influenza b (brisbane and phuket) were available in 2017. children older than six months were eligible to be vaccinated and the vaccine was provided free to children with neurological disease. 34 in our cohort just one child had a documented influenza vaccination, although a third of children were eligible for free immunisation and the remainder could have received an immunisation at the cost of around $20e50 aud. we emphasise that the severe syndromes and adverse outcomes observed here should be considered preventable. following high rates of influenza related morbidity in 2017(including these cases), new south wales and other australian states have introduced universal funded seasonal influenza immunisation to all children aged 6 months to 5 years. 35 our series has limitations. we describe children with severe influenza-associated neurological complications but did not include children with mild neurological complications. children with pre-existing epilepsy may not have always been tested for influenza and may be under-represented. the collection of clinical data was retrospective, and some electronic data were incomplete. seasonal influenza immunisation status was not always clearly recorded, although we reviewed the australian immunisation register to verify vaccination status where possible. influenza sub-typing from npa samples and csf influenza pcr testing was not routinely performed. in the se group, csf studies, including csf neopterin were performed infrequently and mri brain infrequently requested. due to this we were unable to use this group as a direct control for the finding of elevated csf neopterin the iae group. serial csf neopterin to assess treatment and clinical progress were not performed. this is the first series to demonstrate that elevation of csf neopterin, a marker of cns inflammation, occurs commonly in children with iae. csf neopterin may be a useful diagnostic marker for iae while its role as a prognostic marker e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 3 ( 2 0 1 9 ) 2 0 4 e2 1 3 requires further evaluation. mri diffusion restriction was associated with a poor outcome in iae. short-term outcomes of children with neurological complications of influenza, especially within the iae group, were alarming, with nearly two-thirds of children having a poor outcome despite receipt of icu support, anticonvulsants, first-line immunotherapy and, in some, anti-viral treatment. given the severity of influenza associated neurological complications, we recommend a "treat and test" approach to the use of oseltamivir in children presenting with acute encephalopathy/encephalitis during the influenza season. finally, seasonal influenza vaccination should be universally provided to children and those at risk of severe influenza, with better education and awareness to increase uptake in the paediatric population. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. neurological manifestations of influenza infection in children and adults: results of a national british surveillance study the spectrum and burden of influenza-associated neurological disease in children: combined encephalitis and influenza sentinel site surveillance from australia neuroinfluenza: evaluation of seasonal influenza associated severe neurological complications in children (a multicenter study pilot surveillance for childhood encephalitis in australia using the paediatric active enhanced disease surveillance (paeds) network encephalitis and encephalopathy associated with an influenza epidemic in japan national paediatric hnsg. neurologic manifestations and complications of pandemic influenza a h1n1 in malaysian children: what have we learnt from the ordeal? clinical and mri features of neurological complications after influenza a (h1n1) infection in critically ill children influenza season in australia. a summary from the national influenza surveillance committee paediatric active enhanced disease surveillance: a new surveillance system for australia encephalitis, myelitis, and acute disseminated encephalomyelitis (adem): case definitions and guidelines for collection, analysis, and presentation of immunization safety data cerebrospinal fluid neopterin in paediatric neurology: a marker of active central nervous system inflammation recovery of motor function after stroke atagi) atagoi. the australian immunisation handbook australian government department of health acute encephalopathy and encephalitis caused by influenza virus infection evidence for influenza virus cns invasion along the olfactory route in an immunocompromised infant neurological and muscular manifestations associated with influenza b infection in children influenza virus and cns manifestations central nervous system manifestations in pediatric patients with influenza a h1n1 infection during the 2009 pandemic neopterin in the diagnosis and monitoring of infectious diseases csf fluid neopterin: an informative biomarker of cns immune activity in hiv-1 infection utility of csf cytokine/chemokines as markers of active intrathecal inflammation: comparison of demyelinating, anti-nmdar and enteroviral encephalitis h1n1 encephalitis with malignant edema and review of neurologic complications from influenza influenza-associated neurological complications clasmatodendrosis is associated with dendritic spines and does not represent autophagic astrocyte death in influenzaassociated encephalopathy prevention and treatment of influenza oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments immunomodulatory therapies in neurologic critical care intravenous immunoglobulin for the treatment of childhood encephalitis national survey of pandemic influenza a (h1n1) 2009-associated encephalopathy in japanese children influenza-associated encephalitis/encephalopathy identified by the australian childhood encephalitis study 2013e2015 infectious and autoantibody-associated encephalitis: clinical features and long-term outcome influenza season in australia. a summary from the national influenza surveillance committee influenza epidemiology, vaccine coverage and vaccine effectiveness in children admitted to sentinel australian hospitals in 2017: results from the paeds-flucan collaboration influenza vaccine effectiveness against pediatric deaths seasonal influenza vaccination the authors have stated that they had no interests, which might be perceived as posing a conflict or bias. this manuscript has been contributed to, seen, and approved by all the authors. all the authors fulfill the authorship credit requirements. no honorarium grant or other form of payment was received for the preparation of this manuscript. supplementary data to this article can be found online at https://doi.org/10.1016/j.ejpn.2018.09.009. r e f e r e n c e s key: cord-283667-jqlz7yt8 authors: katz, sophie e.; williams, derek j. title: pediatric community-acquired pneumonia in the united states changing epidemiology, diagnostic and therapeutic challenges, and areas for future research date: 2018-03-31 journal: infectious disease clinics of north america doi: 10.1016/j.idc.2017.11.002 sha: doc_id: 283667 cord_uid: jqlz7yt8 community-acquired pneumonia (cap) is one of the most common serious infections in childhood. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. pneumonia is an infection of the lower airways (distal bronchi and alveoli) caused by both viruses and bacteria. community-acquired pneumonia (cap) specifically refers to clinical signs and symptoms of pneumonia acquired outside a hospital setting. 1 it is one of the most common serious infections in childhood, accounting for more than 900,000 deaths among children younger than 5 years of age in 2015. 2 although the rate of mortality due to cap is much lower in the developed world compared with the developing world, cap continues to account for a significant proportion of health care visits and hospitalizations in high-income countries. this review focuses on pediatric cap in the united states and other industrialized nations, specifically highlighting the changing epidemiology of cap, diagnostic and therapeutic challenges, and areas for further research. in the united states, cap accounts for approximately 2 million outpatient visits annually 3 and is among the most common causes for hospitalization, with approximately 124,000 pediatric hospitalizations annually (annual incidence of 15.7-22.5 hospitalizations per 100,000 children). [4] [5] [6] the highest rate of health care utilization occurs in children younger than 2 years of age and decreases with increasing age in the pediatric population. 4 children with pneumonia most often present with fever, tachypnea, and other signs of respiratory distress ( table 1) . signs and symptoms may include tachypnea, cough, dyspnea, retractions, grunting, hypoxemia, abdominal pain, or lethargy, and physical examination findings of decreased breath sounds, crackles, rales, or wheezing on auscultation of lung fields. many of these findings overlap with other acute lower respiratory tract diseases (eg, asthma and viral bronchiolitis), and identifying children with pneumonia based only on clinical signs and symptoms is sometimes difficult. as a result, chest radiographs are commonly used to confirm the diagnosis. even when a chest radiograph reveals an infiltrate, however, it is sometimes difficult to differentiate between consolidation representing pneumonia and atelectasis commonly seen in children with asthma or bronchiolitis. as a result, variation in chest radiograph interpretation is common and may contribute to antibiotic overuse. 7, 8 for this reason, the guideline developed by the pediatric infectious diseases society (pids) and infectious diseases society of america (idsa) discourages use of chest radiographs in children with suspected uncomplicated pneumonia in an outpatient setting. 7 chest radiographs are recommended in children who are hospitalized with hypoxemia or respiratory distress and in those with suspected complications, such as parapneumonic effusions, necrotizing pneumonia, or pneumothorax ( fig. 1) . chest ultrasound is most often used for evaluating local complications, such as parapneumonic effusion and empyema, but recent studies have demonstrated high sensitivity (92%-98%) and specificity (92%-100%) for detecting lung consolidation compared with chest radiography. [9] [10] [11] [12] [13] additional benefits of chest ultrasound include a lack of ionizing radiation and availability in most emergency department settings. an important limitation of ultrasound is that evaluation and interpretation are highly operator dependent. thus, despite these promising early studies, large-scale, pragmatic studies are needed to better evaluate the effectiveness of this imaging technique versus standard chest radiography. pneumonia is a heterogeneous disease caused by a variety of pathogens, including viruses and bacteria. historically, cap was largely considered a bacterial process, most often due to streptococcus pneumoniae, haemophilus influenzae, streptococcus pyogenes, and staphylococcus aureus. [14] [15] [16] [17] [18] the introduction of routine childhood vaccination against both streptococcus pneumoniae and h influenzae, however, has dramatically reduced disease caused by these pathogens. at the same time, highly sensitive molecular diagnostics for viral respiratory pathogens have heightened awareness of the impact of viruses as a cause of cap. a 2004 study by michelow and colleagues 15 exemplifies pre-pneumococcal conjugate vaccine (pcv) era etiology studies. that study used traditional culture methods, pneumolysin-based polymerase chain reaction (pcr) assays, viral direct fluorescent antibody tests, and serologic tests for viruses, mycoplasma spp, and chlamydia spp to identify pathogens in 154 hospitalized children with radiographically confirmed lower respiratory infections at a single institution. a majority of patients (60%) were noted to have infection with typical respiratory bacteria (most commonly, streptococcus pneumoniae, detected in 73% of children with documented bacterial disease), with viruses identified in 45% of children. a 7-valent pcv (pcv7) targeting the most common clinically important pneumococcal serotypes was introduced into the united states childhood immunization schedule in 2000. rates of invasive pneumococcal disease caused by pcv7 serotypes in children less than 5 years of age plummeted from an average of 95.2 cases to 22.6 cases per 100,000 population within 4 years after the introduction of pcv7. 19 by 2006, hospitalization rates for cap and pneumonia-associated complications among young children decreased by 39% and 36%, respectively. 5, 20 despite these declines, disease caused by nonvaccine serotypes soon emerged, and rates of complicated pneumonia increased, prompting introduction of an expanded, 13-valent pct (pcv13) into the us childhood immunization program in 2010. 21 since that time, hospitalization rates decreased from 53.6 per 100,000 admissions in the pre-pcv13 era to 23.3 per 100,000 admissions in the post-pcv13 era, and rates of complicated pneumococcal pneumonia decreased significantly. 22 pneumonia etiology in the post-pneumococcal conjugate vaccine era the multicenter centers for disease control and prevention (cdc) etiology of pneumonia in the community (epic) study was a prospective, population-based surveillance study of greater than 2300 pediatric cap hospitalizations in the united states conducted from 2010 to 2012. 4 this study used serology and nasopharyngeal pcr to identify 8 different viruses, culture-based methods and whole-blood pcr (pneumococcal lyt-a) to identify typical bacteria, and nasopharyngeal pcr to identify atypical bacterial pathogens. viruses were identified in greater than 70% of children, whereas bacteria were identified in only 15% of children (fig. 2) . 4 the most common viral pathogens included respiratory syncytial virus (rsv), human rhinovirus, human metapneumovirus, and adenovirus, all detected in greater than 10% of children. rsv, adenovirus, and human metapneumovirus were more commonly identified in children younger than 5 years of age compared with older children. bacteria were identified in approximately 15% of children in the cdc epic study, although streptococcus pneumoniae was only identified in 4% of children, further underscoring the impact that pcv has had on the epidemiology of pediatric cap. 4 mycoplasma pneumoniae was the most frequently identified bacterial pathogen, detected in 8% of children, including 19% of school-aged children, but only 3% of children younger than 5 years of age. other bacteria were identified in 1% or less of children. importantly, 19% of children in the cdc epic study had no pathogen identified, highlighting the continued need for enhanced diagnostics and novel pathogen discovery techniques. other pathogens that are less commonly seen among us children include mycobacterium tuberculosis, fungi, burkholderia cepacia, aspergillus fumigatus, and pseudomonas aeruginosa and usually occur in patients with underlying risk factors, such as immunocompromising conditions; chronic conditions, such as cystic fibrosis and spinal muscular atrophy; or history of international travel ( table 2) . these pathogens should also be suspected in patients who experience treatment failure for more common etiologic agents. the 2011 pids/idsa cap guideline recommends obtaining blood cultures in children hospitalized with cap. 7, 23, 24 in this setting, however, blood cultures identify a pathogen in only 2% to 7% of children with cap. [24] [25] [26] [27] blood cultures are more often positive in children with parapneumonic effusion, ranging from 10% to 35%. 25, 26, 28 in the outpatient setting, blood cultures are not routinely recommended, because positivity rates are low and results are unlikely to change management. regardless, despite group b streptococci neonatal pneumonia and sepsis. neonatal pneumonia and sepsis. gram-negative enterics neonatal pneumonia and sepsis. potential pathogens in aspiration pneumonia. cause of afebrile pneumonia in young infants <3 mo of age. anaerobes (oral flora) potential pathogens in aspiration pneumonia. legionnaires' disease. rare in children but associated with community outbreaks. exposure to contaminated artificial freshwater systems. coxiella burnetti q fever. exposure to wild and domesticated herbivores or unpasteurized dairy (eg, cattle, sheep, and goats). also potential bioterrorism agent. psittacosis. bird (eg, pet birds and pigeons) exposure. tularemia. rabbit exposure. yersinia pestis pneummonic plague. rodent flea exposure. anthrax. woolsorter's disease. wild and domesticated herbivore (eg, cattle, sheep, goats) exposure. also potential bioterrorism agent. leptospirosis. exposure to urine of wild and domestic animals carrying the bacterium. rare in us children. usually associated with high-risk exposures. brucellosis. exposure to wild and domesticated animals or unpasteurized dairy (eg, cattle, sheep, pigs, goats, deer, and dogs). histoplasmosis. exposure to bird or bat droppings (eg, poultry/ bird roosts and caves). endemic to eastern and central united states. blastomycosis. environmental exposure to fungal spores (wooded areas). endemic to southeastern and midwestern united states. cryptococcosis. exposure to soil contaminated with bird droppings. significant pathogen nearly exclusively among immunocompromised. their low yield, blood cultures currently provide the best opportunity to identify typical bacterial pathogens in most children with cap. diagnostic yield of blood cultures can be optimized by restricting their use to those patients with increased pretest probability of having a positive culture, such as those who are severely ill or have parapneumonic effusion. [29] [30] [31] isolation of pathologic organisms occurs significantly less frequently in patients exposed to antibiotics before specimen collection. 32, 33 studies have also demonstrated increased yield of blood cultures with each additional milliliter of blood drawn. [34] [35] [36] obtaining adequate weight-based blood volumes is also associated with lower rates of blood culture contamination, for reasons yet unknown. 35, 37 contamination rates can also be minimized by adhering to proper sterile collection methods. 32, 35, 37 cultures of the lower respiratory tract pleural fluid cultures are positive in up to 35% of cases and should be performed whenever pleural fluid is obtained. 7, 25, 26, [38] [39] [40] the invasive methods associated with sampling the pleural space, however, make it impractical to obtain pleural fluid specimens except when dictated for clinical care. bronchoalveolar lavage is rarely indicated in cap, except in instances of lack of response to therapy, very severe pneumonia, or immunocompromised hosts in whom opportunistic pathogens are suspected. 41 sputum cultures are of low diagnostic yield in children, due to the inability of most young children with pneumonia to produce an adequate sputum sample. pretreatment with antibiotics further hinders diagnostic yield. induced sputum has been explored as an opportunity to collect sputum samples in young children, although utility is limited by frequent detection of upper respiratory tract bacteria and similar rates of recovery of pathogens in pneumonia cases compared with children without pneumonia. 42, 43 molecular diagnostics pneumococcal urinary antigen testing is often used in the evaluation of pneumonia in adults. in children, however, detection of streptococcus pneumoniae urinary antigen is associated with false-positive results due to high rates of nasopharyngeal colonization. 44, 45 more recently, a serotype-specific urinary antigen detection method has been developed and validated in adults with pneumonia 46 ; whether or not this test could prove useful in children remains to be determined. although not widely used in clinical settings, whole-blood pneumococcal pcr (lyt-a) has been used in epidemiologic studies, including epic and pneumonia etiology research for child health (perch). potential benefits include improved sensitivity, rapid turnaround time, and less influence of antibiotic pretreatment compared with culturebased methods. 47, 48 in the epic study, 2.5% of children tested were pcr-positive for streptococcus pneumoniae, whereas blood cultures were positive for pneumococcus in only 1% of children (p<.001). 4 in the perch study, 291 children with pneumonia (7.3%) were pneumococcal pcr-positive, whereas only 44 children (denominator not provided) had a positive blood culture for streptococcus pneumoniae. 49 moreover, although prior studies demonstrated 100% specificity of lyt-a pneumococcal pcr from the blood, 50 the perch study also identified pneumococcal dna in the blood of 273 control children (5.5%). 49 thus, although pneumococcal pcr may increase rate of detection over blood culture, suboptimal test specificity hampers interpretation. pcr also increases yield for pleural fluid specimens. in a study evaluating archived pleural fluid specimens from 63 pediatric patients with cap, a pathogen was detected in 84% of samples using pcr compared with only 35% of samples when using conventional culture methods (p<.001). 28 the most frequent pathogen detected using pediatric community-acquired pneumonia both methods was streptococcus pneumoniae, 71% using pcr and 24% using conventional culture. the next most frequent pathogens identified were streptococcus pyogenes (11% using pcr and 5% using conventional culture) and s aureus (8% using pcr and 6% using conventional culture). this study also highlighted the potential for bias with respect to pathogen identification introduced when relying on culture alone for epidemiologic studies, because penicillin-resistant pneumococcal isolates and s aureus were more likely to be positive in culture, whereas other serotypes of streptococcus pneumoniae and bacterial pathogens commonly susceptible to penicillins were more commonly identified by pcr. up to two-thirds of children younger than 5 years are colonized in the upper respiratory tract with common bacterial pathogens known to cause pneumonia, 51 and pcr from the upper respiratory tract is not a reliable method for ascertaining bacterial etiologies of pneumonia. a possible exception is m pneumoniae, which has not previously been considered a frequent colonizer of the upper respiratory tract. consistent with this theory, the cdc epic study demonstrated that although m pneumoniae was detected in 8% of children with pneumonia, fewer than 1% of controls had evidence of m pneumoniae. 4 in contrast, a cross-sectional, observational study in the netherlands of asymptomatic children and children with symptoms of upper and lower respiratory tract infection detected m pneumoniae dna not only in 16% of symptomatic children but also in 21% of asymptomatic children. 52 given the conflicting results of these 2 studies and the increasing commercial availability of m pneumoniae pcr tests, caution is warranted when interpreting test results in the clinical setting. in contrast to bacteria, pcr testing for viruses from upper respiratory samples has largely replaced culture and serology-based methods to investigate pneumonia etiology, owing to superior sensitivity, rapid turnaround time, and ability to identify viruses that are difficult to grow in culture. a major concern, however, is whether lower respiratory tract disease can be attributed to a viral pathogen detected in the upper airway. the scope of the problem is well illustrated in a study conducted by self and colleagues 53 that compared pcr detections of 13 viruses from the upper respiratory tract among 1024 children with cap and 759 healthy, asymptomatic children enrolled in the cdc epic study. overall, approximately 25% of asymptomatic children had 1 or more viruses detected compared with approximately 65% of children with cap. detection of most viruses was higher among children with cap compared with asymptomatic controls, including influenza (3% vs 0%), rsv (27% vs 2%), and human metapneumovirus (15% vs 2%), with attributable fractions greater than 90% for all. conversely, rhinovirus was detected at a similar frequency in both children with cap and asymptomatic children (22% vs 17%; attributable fraction 12%; 95% ci, 18% to 34%). attributable fractions for other viruses studied ranged from 44% to 68%. thus, although some viruses detected in the upper airway likely reflect lower airway disease (eg, rsv, influenza, and human metapneumovirus), detection of other viruses must be interpreted with caution. as proposed for adults, investigating viral loads may further help to differentiate disease versus asymptomatic colonization. 54 because sensitive methods of diagnosing viral infections have become more widely available, the recognition of viral and bacterial coinfection has also increased. it is well known that upper tract disease with respiratory viruses often precedes the development of bacterial pneumonia. [55] [56] [57] although it is not always clear if a virus detected in the upper airway represents prior or concurrent infection in a subject with bacterial pneumonia, studies suggest that viral-bacterial codetections are associated with a more severe clinical course compared with single viral or bacterial detections. [58] [59] [60] the association between influenza and coinfection with pneumococcal or staphylococcal pneumonia is perhaps the best described of these viral and bacterial coinfections. 61, 62 elevated leukocyte count was traditionally considered to be associated with serious bacterial infection, but the specificity of leukocyte count in making the diagnosis of bacterial pneumonia in children is poor, and the degree of elevation does not reliably distinguish between viral and bacterial pneumonia. 7,63-65 as such, routine measurement of leukocyte count is likely not beneficial. more recent biomarkers used in the detection of pneumonia include c-reactive protein (crp) and procalcitonin (pct). these biomarkers may perform better than leukocyte count for identifying bacterial infections, 64, 66, 67 although identifying relevant clinical cutpoints remains a challenge. to evaluate the impact of crp in the etiologic diagnosis of pneumonia, a meta-analysis of 8 studies with more than 1200 children with viral or bacterial causes of cap demonstrated that crp levels greater than or equal to 40 mg/l to 60 mg/l were associated with only a 64% positive predictive value for identifying children with bacterial pneumonia. 68 pct is a peptide precursor of calcitonin and is produced by c cells in the thyroid gland and by neuroendocrine cells in the lung and intestine. levels are usually undetectable in healthy individuals but increase in response to systemic inflammation. cytokines typically associated with bacterial infection enhance pct release, whereas interferons, which are more often associated with viral infections, inhibit pct release. 69, 70 thus, much interest has been directed at pct as a potential biomarker for bacterial disease. among 532 hospitalized children enrolled in the cdc epic study, a pct cutoff value of 0.25 ng/ml demonstrated a sensitivity of 85% and specificity of 45% for cap caused by typical bacterial pathogens. 71 the study also found that higher pct levels were associated with more severe disease. multiple studies have shown utility in using pct levels to guide antibiotic initiation and duration. [71] [72] [73] [74] [75] [76] biomarker studies using transcriptomics show promise for enhancing diagnostic capabilities by using host responses to identify possible pathogens and study disease severity. [77] [78] [79] [80] transcriptomics uses gene expression profiling to measure the activity or expression of thousands of genes at once, thereby creating a global picture of cellular activity. profiles of peripheral blood leukocytes in patients with lower respiratory tract infection can accurately distinguish influenza viral infection from bacterial infection and predict disease severity. 81 host transcriptional profiling has also been shown useful in distinguishing symptomatic rhinovirus infection from incidental detection in children. 80 these promising studies will likely add much to the understanding of pneumonia etiology and outcomes, although much work remains prior to translating these new technologies to the bedside. several prognostic models are available for adults with pneumonia, 82, 83 and their application has been shown to contribute to improved outcomes. unfortunately, no analogous models have been validated in children, a recognized key knowledge gap. 7 recently, williams and colleagues 84 derived 3 prognostic models to identify risk for severe outcomes among children with cap; each model demonstrated good predictive accuracy (concordance index 0. 78-0.81) . in that study, extremes of age, vital signs, chest indrawing, and radiographic infiltrate pattern ranked among the most important predictors of disease outcomes. although these models require further validation, their use could reduce variability and improve care for children with pneumonia. although viruses are a major cause of childhood pneumonia, a majority of children with pneumonia receive antibiotics. pneumonia is associated with more antibiotic use in us pediatric hospitals than any other condition. 85 when antibiotics are indicated, amoxicillin or ampicillin is recommended as first-line therapy in most children 7 (table 3) . prior to release of the national guideline, however, broader-spectrum third-generation cephalosporins and macrolides were commonly used. to date, the impact of the national guideline on prescribing has been mixed. approximately 4 years after guideline publication, penicillin use increased approximately 27.6% and cephalosporin use decreased approximately 27.8% across 48 tertiary care children's hospitals in the united states, although substantial variability was noted across institutions. 86 similar variability persists in the outpatient setting. 87 antimicrobial stewardship programs, local clinical practice guidelines, and quality improvement methods all play important roles in raising awareness of these recommendations and reducing unnecessary and inappropriate antibiotic use. 86, 88, 89 current practices for treatment of uncomplicated cap generally use 7-day to 10-day antibiotic courses, although 2 large pediatric randomized controlled studies are currently evaluating the safety and efficacy of shorter courses of antibiotics, a united kingdom community-acquired pneumonia study (cap-it) and the us phase iv double-blind, placebo-controlled, randomized trial short course outpatient therapy of community acquired pneumonia (scout-cap). 90, 91 consideration of alternative etiologies, such as s aureus, is warranted in children with severe or rapidly progressive disease, extensive local complications, or poor treatment response. s aureus is an uncommon cause of cap, detected in only 1% of children hospitalized with pneumonia. 4 thus, to preserve the effectiveness of antistaphylococcal antibiotics, care must be taken when considering when to use these agents empirically, and efforts to de-escalate therapy whenever possible should be emphasized. although m pneumoniae is a frequent cause of cap in children, it is impossible to reliably distinguish this pathogen from other common causes of pneumonia. questions regarding the utility of currently available pcr tests for m pneumoniae, as outlined previously, further complicate treatment considerations. moreover, azithromycin use is associated with the development of multidrug resistance. 92, 93 perhaps the most important consideration governing when to use macrolide therapy, however, is that currently available studies have failed to consistently demonstrate their benefit in children with pneumonia. 94 despite advances in recent years, cap continues to cause significant morbidity and mortality and poses diagnostic and therapeutic challenges. vaccination against haemophilus influenzae type b and streptococcus pneumoniae has greatly reduced invasive disease rates caused by these pathogens, and the introduction of molecular diagnostics has highlighted the important role that respiratory viruses play in disease pathogenesis while also introducing new challenges. this updated understanding brings into question whether all children with cap would benefit from antibiotic therapy, and if so, which therapies might be most effective. limitations of current diagnostics, however, impede advances toward addressing these important questions. biomarkers and host responses to infection are current areas of intense study that may facilitate a deeper understanding of pneumonia etiology and disease outcomes. as this important work progresses, future epidemiologic studies using state-of-the-art diagnostics will continue to serve an important role in informing understanding of the changing epidemiology of cap. british thoracic society guidelines for the management of community acquired pneumonia in children: update 2011 world health organization ambulatory visit rates and antibiotic prescribing for children with pneumonia community-acquired pneumonia requiring hospitalization among u.s. children national hospitalization trends for pediatric pneumonia and associated complications healthcare cost and utilization project (hcup) the management of communityacquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america disagreement in the 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randomized controlled trial procalcitonin measurements for guiding antibiotic treatment in pediatric pneumonia whole blood gene expression profiles to assess pathogenesis and disease severity in infants with respiratory syncytial virus infection superiority of transcriptional profiling over procalcitonin for distinguishing bacterial from viral lower respiratory tract infections in hospitalized adults association of rna biosignatures with bacterial infections in febrile infants aged 60 days or younger rhinovirus detection in symptomatic and asymptomatic children: value of host transcriptome analysis gene expression patterns in blood leukocytes discriminate patients with acute infections a prediction rule to identify low-risk patients with community-acquired pneumonia smart-cop: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia predicting severe pneumonia outcomes in children identifying targets for antimicrobial stewardship in children's hospitals impact of a national guideline on antibiotic selection for hospitalized pneumonia variability in antibiotic prescribing for community-acquired pneumonia effectiveness of antimicrobial guidelines for community-acquired pneumonia in children quality improvement methods increase appropriate antibiotic prescribing for childhood pneumonia cap-it: efficacy, safety and impact on antimicrobial resistance of duration and dose of amoxicillin treatment for young children with community-acquired pneumonia (cap): a randomised controlled trial placebo-controlled, randomized trial to evaluate short course vs. standard course outpatient therapy of community acquired pneumonia in children (scout-cap) active bacterial core surveillance team. outpatient antibiotic prescribing and nonsusceptible streptococcus pneumoniae in the united states mycoplasma pneumoniae infections-does treatment help? treatment of mycoplasma pneumonia: a systematic review the authors thank kathryn edwards, md, and ritu banerjee, md, phd, vanderbilt university medical center, for their critical review and input during article preparation.pediatric community-acquired pneumonia key: cord-264651-cqxmpxyq authors: lee, shawna j.; ward, kaitlin p.; chang, olivia d.; downing, kasey m. title: parenting activities and the transition to home-based education during the covid-19 pandemic date: 2020-10-13 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105585 sha: doc_id: 264651 cord_uid: cqxmpxyq this study reports on parent-child dynamics following covid-19 related school closures, based on cross-sectional analyses of a survey that utilized a convenience sampling approach. data were collected approximately five weeks after the world health organization declared that the coronavirus was a pandemic. participants (n = 405) were adults recruited throughout the u.s. this study examines data from parents (69% mothers and 31% fathers) with at least one child 0-12 years of age. the majority were white (71%) and 41% had at least a bachelor’s degree. 78% of parents said they were educating their child at home due to covid-19. most (77.1%) reported use of online tools for at-home education, including educational apps, social media, and school-provided electronic resources. more than one-third (34.7%) of parents said their child’s behavior had changed since the pandemic, including being sad, depressed, and lonely. most parents were spending more time involved in daily caregiving of their children since covid-19. two out of every five parents met the phq-8 criteria for major depression or severe major depression (40.0%) and the gad-7 criteria for moderate or severe anxiety (39.9%). multivariate analyses indicated that, compared to non-depressed parents, parents who met criteria for probable major or severe depression (b = -.16, 95% ci = [-.29, -.02], p = .021) and parenting stress (b = -.37, 95% ci = [-.47, -.27], p < .001) were negatively associated with parents’ perceived preparation to educate at home. compared to parents with minimal or mild anxiety, parents with moderate or severe anxiety reported higher child anxiety scores (b = .17, 95% ci = [.06, .28], p = .002). parenting stress was also positively associated with higher child anxiety scores (b = .40, 95% ci = [.32, .48], p < .001). content analyses of open-ended questions indicated that school closures were a significant disruption, followed by lack of physical activity, and social isolation. overall, study results suggested that parents’ mental health may be an important factor linked to at-home education and child wellbeing during the pandemic. experienced declines in academic achievement, and many families relocated to other states, in part to obtain better educational opportunities for their children (peek & richardson, 2010) . during previous global health crises, such as severe acute respiratory syndrome (sars) and influenza a (h1n1), research documented issues related to school closures such as conflicts between parental work responsibilities and child care needs, lack of effective communication between parents and schools, and a lack of inclusive procedures to provide students access to needed resources and services (boon et al., 2011; braunack-mayer et al., 2013; o'sullivan et al., 2009 ). past public health emergencies and natural disasters underscore the potential for a number of challenges for parents' ability to support their children's schooling during covid-19. the widespread shift from in-person education to at-home education is unprecedented in recent american history. during covid-19, school closures were estimated to have impacted approximately 55.1 million students in 124,000 public and private schools across the u.s. (education week, 2020) . worldwide, the united nations estimated that about 463 million children were cut off from educational altogether, due to their inability to access remote learning (united nation's children's fund, 2020) . in addition, in the u.s., most after-school activities (e.g., school-based after school care, sports, clubs and other extracurricular activities) and specialized programs (e.g., services provided to children with developmental disabilities) were cancelled or significantly disrupted. homeschooling is the provision of educational activities in the home, usually by the child's parent. homeschooling is not new in the u.s., and reflects a small portion of education delivery for american children. prior to covid-19, approximately 1.7 million u.s. children were homeschooled. homeschooling was on the rise, from 1.7% of all u.s. students between the ages of 5 and 17 in 1999, to 3 .3% of all u.s. students between the ages of 5 and 17 in 2016 (national center for education statistics, 2019) . homeschooling appears to be more common among religious parents, politically conservative parents, two-parent families, and rural families (lines, 2001; hartman, stotts, ottley, & miller, 2017) . homeschooling parents use a variety of tools, and one study indicated that 41% of parents use online education for homeschooling (davis, 2011) . there is little research on the outcomes of children who are homeschooled. one study suggested that children who are homeschooled score above or at grade level (lines, 2001) . in this study, we distinguish homeschooling, a deliberate decision by the parent to deliver an educational curriculum in a home-based setting, with the situation immediately following covid-19, in which educational activities were delivered by or supervised by the parent at home because of the suspension of in-person educational activities and the closure of school buildings. with in-person educational activities disrupted, many schools turned to resources and strategies that are used by homeschooling parents. for example, schools used online resources to facilitate the delivery of educational activities at home. however, initially after covid-19, most schools made the transition with little to no preparation, and solutions were spotty at best (nuñez, stuart-cassel, & temkin, 2020 ). many families were not able to adequately access online education due to numerous factors. one report documented that 14.5 million u.s. households do not have access to the internet or personal computers; thus, online education is not a readily available option for children in these households (institute for children, poverty, & homelessness, 2020) . not all households that lack internet access are those in rural areas. children who are homeless or socioeconomically disadvantaged may lack reliable access to the internet or electronic tools (computer and tablets), and thus may not be able to fully participate in online education. in new york city, one region hit particularly hard by covid-19, as many as 300,000 students did not have internet-connected devices at home (institute for children, poverty, & homelessness, 2020) . to the best of our knowledge, to date there are no national estimates of how many parents were able to use online resources to provide at-home education for their children during the time period examined in the current study (april 2020). in addition to challenges related to accessing online educational resources, another challenge in the shift to at-home education is the considerable burden that is placed on parents. at a minimum, at-home education requires parental supervision at times when children would have otherwise been supervised by school personnel in school buildings. in many cases, at-home education necessitates greater involvement and support from parents to ensure that children understand and complete educational activities. this may be especially true for parents of young children and children with disabilities. parents in single-parent headed households, which comprise 11 million american families with children under 18 years old (u.s. department of labor, 2017), likely face even more difficult conditions as they struggle to balance work, child care and homeschooling during the pandemic, without the benefit of a second parent to "tag team" responsibilities. this raises the question of how parents, most of whom work in order to provide for their families, have adjusted to supervising at-home education. in addition to the challenges of balancing work responsibilities with at-home education and child care, most parents were not educators. lack of preparation and lack of skill set, as well as mental health concerns, worries, and parenting stress, are factors that may impede parents' ability to support their children's educational needs. during covid-19, parents in particular were reporting significantly greater levels of stress when compared to adults without children (apa, 2020) and parents were reporting worsening mental health overall (patrick et al., 2020) . more than 7 in 10 parents reported that managing distance/online learning for their children and routine disruptions/adjusting to new routines were a significant source of stress (apa, 2020). a high level of food insecurity, loss of health insurance, and child care disruptions are common stressors that are impacting parental wellbeing during the pandemic (patrick et al., 2020) . there is relatively little data on the mental health of children during the pandemic (lee, 2020) . one study noted that parents were reporting worsening behavioral health for their children (patrick et al., 2020) . the lack of in-person school activities has disrupted children's access to caring adults such as teachers, coaches, and school social workers (sacks & jones, 2020) and has consequences for children's wellbeing. given the extent of these disruptions, it is reasonable to anticipate that millions of children will suffer elevated anxiety, worries, and trauma, depending on their ability to understand and comprehend the changes around them. the worsening of parental mental health (apa, 2020; patrick et al., 2020) -such as increased levels of depression and anxiety -are likely to have negative consequences for child wellbeing. this study captures a snapshot of parent-child activities and wellbeing in the first six weeks after the world health organization (who) announced that covid-19 was a pandemic (who, 2020a; who, 2020b) . we examine a variety of factors related to parent-child interactions during the pandemic. we describe parents' involvement with their children in daily caregiving activities, parents' daily schedule disruptions, and the types of resources parents were using to provide at-home education to their children. in multivariate models, we examine parenting risk factors associated with parents' perceived preparation to provide education athome. we also examine how parental wellbeing may influence parents' perception of their children's anxiety. we present qualitative analyses using thematic content coding to examine parents' responses to open-ended questions about common daily disruptions, the use of technology for children's education, parents' perceived changes in child behavior, and parents' perceptions of what children need during the pandemic. data for the current study were collected via an online survey that was administered through prolific, a company that conducts survey research. the survey was launched on april 2, 2020, nearly five weeks after the who declared that the coronavirus was a pandemic, and four weeks after the white house issued social distancing guidelines to slow the spread of covid-19. survey participants were recruited from geographic locations throughout the u.s.; however, it is important to note that the survey procedures utilized a convenience sampling approach and the sample is not nationally representative. participants who met study criteria were sent an email from prolific regarding their eligibility to participate in the survey. participants were provided with a brief description of the survey via the prolific website. in order to be eligible, individuals had to have u.s. nationality and be age 18 or older. if they chose to participate in the survey, they were linked through the prolific platform to a qualtrics survey designed and managed by the research team. the research team set a predetermined target enrollment number, and when that number was reached, the survey automatically closed. we do not have information on individuals who might have viewed the study details on the prolific platform but decided not to participate, or on individuals who decided to participate after enrollment for the survey was already closed. it took less than 24 hours for the survey to reach its target enrollment number. after reviewing the study information and providing informed consent, participants completed the online survey and received $6.00 in payment, which was administered directly to participants via prolific. the average completion time was 40 minutes long (range: 13 to 147 minutes). to ensure the quality of the data, three attention checks were embedded throughout the survey. none of the participants failed more than one of the attention checks. all data provided to the research team were anonymous and contained no identifying information. this study was reviewed and deemed exempt from oversight by the university of michigan institutional review board. a total of 654 adults residing in the u.s. completed the survey. the analytic sample for the current study included parents with at least one child living at home between the ages of 0-12 years (n = 405, or 61.9% of the total sample), of which 69% were mothers and 31% were fathers. 78% of participants said they were currently educating their child at home due to covid-19. as seen in table 1 , the average age was 34 years. approximately 41% of participants had at least a bachelor's degree and the majority of participants identified as white (71%). average household income in the prior year was between $40,000 and $50,000. approximately 24% of participants indicated their employment status had changed due to covid-19. parental perceived preparation to educate at home. three items assessed parents' perceived feelings of preparation to educate their children at home. items were only given to parents who indicated they were currently educating their child(ren) at home (n = 315). items included, "i feel prepared to educate my child at home," "i do not have the resources i need to education my child at home" (reversed), and "i have felt overwhelmed by responsibilities to educate by child at home" (reversed), which were rated on a scale from 1 (strongly disagree) to 5 (strongly agree). the internal reliability of the scale was good (⍺ = .82). participants who did not wish to respond typed "no response" or left the text box blank. resources to educate at home were measured by asking parents to indicate how much they agreed with three statements: "i have support from my child's school to educate my child at home," "i have collaborated with other parents to provide resources for educating my child at home," and "i have used online or social media resources to educate my child at home" (1=strongly disagree, 5=strongly agree). these questions were only given to parents who indicated they were currently educating their child(ren) at home (n = 315). parents' use of technology for child education and entertainment was assessed using an open-ended question, "what online resources have been the most helpful in educating your child at home?" in a text box below the question, participants provided words or phrases to respond. participants who did not wish to respond typed "no response" or left the text box blank. child anxiety. child anxiety was measured using the child anxiety subscale of the child behavior checklist/4-18 (achenbach, 1992) . participants were asked, "since approximately 2 weeks ago, my child(ren):" and were presented with 14 items that were rated on a 3-point scale (0=not true, 1=true, 2=often true). sample items include, "(he/she) worries," "is too fearful or anxious," and "is nervous, high strung, or tense." items were averaged to create a scale which demonstrated good internal consistency (⍺ = .87). parents were asked, "in your opinion, has your child(ren)'s behavior changed in the past 2 weeks, during the coronavirus/ covid19 global health crisis?" those who responded "yes" (n = 140; 34.7%) to this question were subsequently asked to provide responses to an open-ended question that examined parents' perceived changes in their child's behavior, "how has your child(ren)'s behavior changed in the past 2 weeks, since the coronavirus/covid-19 global health crisis?" in a text box below the question, participants provided words or phrases to respond. participants who did not wish to respond typed "no response" or left the text box blank. asked an open-ended question, "what do you think your child(ren) need during this global health crisis?" participants provided words or phrases to describe their response in a text box below the question. participants who did not wish to respond typed "no response" or left the text box blank. questionnaire (phq-8; kroenke et al., 2008) . the phq-8 is a valid diagnostic tool to measure severity of depressive disorders in the general population. participants were asked, "over the last 2 weeks, how often have you been bothered by any of the following problems?" sample items include, "little interest or pleasure in doing things," "feeling down, depressed, or hopeless," and "feeling tired or having little energy." items were assessed on a 4-point response scale from 0 = not at all, 1 = several days, 2 = more than half the days, and 3 = nearly every day, resulting in a score range from 0-24. a score of 9 or under indicates the participant is not depressed; a score between 10-19 indicates the participant has probable major depression; and a score between 20-24 indicates the participant has probable severe major depression. we created a dichotomous variable to reflect whether the participant met the phq-8 criteria for major depression or severe major depression, in which scores of 9 or less were coded "0" and scores of 10 or above were coded "1" (0=not depressed, 1=probable major depression or severe major depression). parental anxiety. anxiety was measured using the generalized anxiety disorder, 7item scale (gad-7; spitzer, kroenke, williams, & lowe, 2006) . the gad-7 is a widely used and well validated diagnostic tool to measure anxiety symptoms in the general population. participants were asked, "over the last 2 weeks, how often have you been bothered by the following problems?" sample items include, "feeling nervous, anxious, or on-edge," "not being able to stop or control worrying," and "trouble relaxing. items were assessed on a 4-point response scale from 0 = not at all, 1 = several days, 2 = more than half the days, and 3 = nearly every day, resulting in a score range from 0-21. a score of 4 or under indicates the participant has minimal anxiety; a score between 5-9 indicates the participant has probable mild anxiety; a score between 10-14 indicates the participant has probable moderate anxiety; and a score between 15-21 indicates the participant has probable severe anxiety. we created a dichotomous variable to reflect whether the participant met the gad-7 criteria for moderate or severe anxiety, in which scores of 9 or less were coded "0" and scores of 10 or above were coded "1" (0=minimal or mild anxiety, 1=moderate or severe anxiety). parenting stress. parenting stress was measured by the four-item aggravation in parenting scale ( that was utilized in the fragile families and child wellbeing study (ffcws). this measure has been widely used as a benchmark measure of child and family wellbeing (ehrle & moore, 1997) including in the child development supplement of the panel study of income dynamics (hofferth, davis-kean, davis, & finkelstein, 1997) . parents were asked whether they: 1) felt that their child(ren) are harder to care for than most children, 2) felt that there are things that their child(ren) do that bother them a lot, 3) find themselves giving up more of their lives to meet their children's needs than they ever expected, and 4) felt angry with their child(ren) on a scale from 1 (never true) to 4 (always true). the internal consistency of the scale in our sample was good (⍺ = .83). . total household income in the last year before taxes was treated as a continuous variable: 1=$10-20k, 2=$20-30k, 3=$30-40k, 4=$40-50k, 5=$50-70k, 6=$70-90k, 7=$90k or more. parent age was continuous and measured in years. the number of days spent social distancing and number of days spent in "lockdown" were continuous. we measured these factors to control for social isolation that may impact both the independent and dependent variables in the study models. a dichotomous variable indicated whether participants had experienced an employment change due to covid-19: "has your employment status changed (e.g., laid off, furloughed) because of the coronavirus/covid-19 global health crisis?" (0=no, 1=yes). our analyses included quantitative analysis of close-ended questions and qualitative analysis (content coding) of open-ended questions. for quantitative analyses, data cleaning and descriptive analyses were run in stata version 15.1. all regression analyses were run in mplus version 8 (muthén & muthén, 1998 using the maximum likelihood estimator. for descriptives of parental involvement in child caregiving activities and daily schedule disruptions, parents who answered "na/i don't engage in this behavior" were coded as missing so that we could examine the percentage of parents who engaged in these behaviors more often than they normally do. for parental at-home education resources, rated from 1 to 5, we calculated the percentage of parents who indicated they "agreed" or "strongly agreed" (i.e., rated a 4 or 5). missing data on our key independent variables of interest-including depression, anxiety, and parenting stress-were <3%. regarding our key dependent variables, because the home preparation items were only presented to parents who were educating their children from home (n = 315), the home preparation had 22.2% missing data (notably, for the 315 parents who were given this question, there were no missing data). child anxiety did not have any missing data. to handle missing data, analyses were conducted using full-information maximum likelihood estimation (fiml), which uses all available data. to examine whether our independent variables were associated with missingness on the home preparation scale, we ran a logistic regression analysis where all of our independent variables predicted whether participants were missing data (0=not missing, 1=missing) on the home preparation scale. the only variable that predicted missingness on the home preparation scale was parental age (odds ratio: 0.92, se = .02, p < .001). compare responses, thus establishing inter-rater reliability. overall, inter-rater reliability was good, and ranged from 80% to 95%. descriptive results. descriptive statistics of participant characteristics can be found in table 1 . notably, 40.0% of the parents in this sample met the phq-8 cutoff score for major depression, and 39.9% met the gad-7 cutoff score for moderate or severe anxiety. more than one-third (34.7%) of parents said their child's behavior had changed since the pandemic. descriptive results for changes in parental involvement in caregiving after covid-19, daily schedule disruptions, and resources to educate at home are presented in table 2 . in terms of parental involvement, parents said that they were engaging in most caregiving activities more often since covid-19, specifically parents were playing games with child(ren) more often (68.7%), watching tv or other media with child(ren) more often (65.1%); and playing with toys with child(ren) more often (56.9%). regarding daily schedule disruptions, 97.1% of parents indicated public schools were closed and over half of parents who typically utilize free/reduced meal services indicated they were unable to receive free or reduced cost breakfast or lunch. the questions related to parental at-home education resources were asked of the 78% of participants who said they were educating their child at home. the majority of these parents endorsed that they were using online or social media resources to educate their child(ren) at home (77.1%) and agreed they had support from their child(ren)'s school to educate their child(ren) at home (71.3%). however, only 22.5% had collaborated with other parents to provide resources to educate their child(ren) at home. multivariate results (table 3) . compared to non-depressed parents, parents who met the phq-8 criteria for probable major depression or major severe depression reported that they were less prepared to provide at-home education their child(ren) (b = -.16, 95% ci = [-.29, -.02], p = .021). in other words, compared to being a non-depressed parent, being a parent who met criteria for major depression was associated with a .16 standard deviation decrease in at-home education preparation score. parents with mild or minimal anxiety did not differ from parents with moderate or severe anxiety in their preparation to conduct at-home education for their child(ren) (b = .06, 95% ci = [-.07, .19], p = .380). parenting stress was negatively associated with parents' at-home education preparation (b = -.37, 95% ci = [-.47, -.27], p < .001)-in other words, a one standard deviation increase in parenting stress score was associated with a .37 standard deviation decrease in the at-home education preparation score. in addition to these parenting risk factors, the results indicated that parents' report of an employment change (i.e., job loss) in the past 2 weeks was not associated with parents' perceived preparation to provide at-home education in any of the models. in fact, it seems that parental mental health factors were the only statistically significant predictor of parents' perceived preparation to provide at-home education to their children following covid-19. as a robustness check, we ran these models again, but only among parents who stated they were currently homeschooling their children (n = 315). standardized coefficients and p-values were all unchanged. in analyses examining the predictors of child anxiety scores following covid-19, nondepressed parents did not differ from parents with major depression in reporting child anxiety about other disruptions to your child's schedule because of the coronavirus/ covid-19 global health crisis"; 2) "what online resources have been the most helpful in educating your child at home?"; 3) "how has your child(ren)'s behavior changed in the past 2 weeks, since the coronavirus/covid-19 global health crisis?"; and 4) "what do you think your child(ren) need during this global health crisis?" are presented in tables 4, 5 with regard to daily schedule disruptions due to covid-19, school and/or daycare closure and lack of physical activity emerged as the most consistent disruptions reported by parents (28.3%). this is consistent with the close-ended questions which showed that the majority of parents reported school closures. another prominent disruption that parents noted was social isolation from generalized others and relatives (245.7% and 24.8%, respectively). additionally, 7.5% of parents reported a disruption in their child's basic routine (e.g., changes to eating and sleeping patterns). although reported relatively infrequently, it is worth noting that 4.0% of children experienced a schedule disruption due to an inability to obtain their usual special education resources, and 4.9% of parents reported canceled doctor appointments as an important daily schedule disruption to their child. with regard to the use of technology for child education during covid-19, we asked parents to tell us about the online tools that they were using to support at-home educational activities. programs such as abc mouse and khan academy ranked as the most commonly reported tools parents were using to support at-home education. approximately 59.9% of participants to this question indicated some form of online educational tool. furthermore, schoolbased technological resources were common, and 28.5% of participants generated a tool that was school-based. school-based tools were provided by the school, and were differentiated from standalone online tools such as abc mouse and khan academy (prior category) that were used to supplement classroom based activities but are not generated by the school setting. the school based programs included seesaw and google classroom, and school-based websites. about 26.1% of parents reported using social media (e.g., youtube, facebook mom groups) to supplement their child's at-home education. only about 7.0% of parents reported utilizing live remote technological resources (e.g., zoom, online meetings) to educate their children. about 7.4% of parents reported lack of use of online resources to educate their child at home or they included resources that the researchers determined were outside of other coding categories, such as amazon.com. with regard to parents' perceived changes in child behavior during covid-19, increased externalizing problems was the most common behavior change reported by parents (48.4%). following externalizing problems, parents reported increased internalizing problems, namely, anxious and depressive symptoms (27.8% and 18.3%, respectively). additionally, 15.1% of parents reported their child becoming bored during covid-19. interestingly, although reported relatively infrequently, 7.9% of parents reported observing a positive change in their child's behavior (e.g., expressing gratitude, feeling more relaxed) during the pandemic. [ insert table 6 here] in the context of the covid-19 pandemic, we asked parents to tell us what they think their children need. the majority of parents (50.1%) reported that during the pandemic children needed general emotional support, such as love, care, and attention. socialization (14.0%), entertainment (12.7%), and physical activity (10.7%), were indicated as important needs of children by participants. approximately 9.7% reported that during the covid-19 global health crisis, students needed access to education, including going back to school and having access to better educational resources at home. 9.2% emphasized the need for children to feel safe and protected. furthermore, 7.7% of parents that responded reported that their children needed access to basic needs, such as toilet paper, food, and housing. only about 7.2% reported that they felt that their children needed guidance and information about covid-19 during the pandemic. parental stability/security referenced the specific needs of children from their parents, and were differentiated from general emotional needs. about 6.5% of parents specifically indicated that children needed support from their parents (e.g., security from parents, even-tempered parenting). finally, a small portion (3.0%) indicated that children needed to not be told about covid-19 (e.g., to avoid scaring children). this study provides a snapshot in time of how families with young children were adapting to the covid-19 in the early days of the pandemic (april 2020). the results suggest that parents were engaging in higher levels of nearly all child caregiving activities following covid-19, such as playing more often, reading more often, and watching tv more often with their children. given the ramifications of social distancing measures and school closures due to covid-19, it is perhaps not surprising that parents were more involved in everyday caregiving activities during this time. notably, 53.6% of parents said they were hugging and showing physical affection toward their child more often following covid-19. the increase in everyday caregiving activities occurs in the context of numerous stressors. for example, 1 in 4 parents reported an employment change related to covid-19. over half of the parents who said they received free and reduced cost school meals indicated that lack of access to this resource was a disruption to their daily life. this study documents very high levels of parental depression, parental anxiety, and parenting stress (apa, 2020; patrick et al., 2020) . two out of every five parents (40.0%) met the phq-8 criteria for probable major depression or severe major depression. similarly, 39.9% met the gad-7 criteria for moderate or severe anxiety. though the rates of anxiety and depression among this sample of parents of young children were very high, they were consistent with the census bureau's household pulse survey. the nationally representative household pulse survey indicated that during april 23 -may 5 2020, about 31% of american adults had symptoms of anxiety disorder; 23.5% had symptoms of depressive disorder; and about 36% had symptoms of anxiety or depressive disorder (cdc, 2020; u.s. census bureau, 2020). notably, the rates in the current study as well as those reported by the cdc are more than double those shown prior to covid-19. during january to june 2019, 8.2% of adults had symptoms of anxiety disorder; 6.6% had symptoms of depressive disorder; and 11.0% had symptoms of anxiety disorder or depressive disorder (centers for disease control and prevention [cdc], 2020; fowers & wan, 2020). the high rates of parental mental health problems are also supported by recent research showing that parents are experiencing more stress and declines in mental health during the pandemic (apa, 2020; patrick et al., 2020) . there is reason to be concerned about the mental health of american parents (brooks et al., 2020; panchal et al., 2020) , with the results of this study suggesting an alarmingly high rate of anxiety and depression among parents. at the point this survey was administered, in mid-april 2020, 97% of parents reported that public schools were closed, and a majority of parents (78%) were educating their child at home. the apparent disconnect between the report of school closures (97%) and parents saying they were educating their children at home (78%) can be explained by several factors. some parents may have been relying on the child's other parent or another caregiver to provide athome education; thus, they themselves were not providing the education, and responded "no" to this question. in addition, some parents may not have been able to provide at-home education to their children, due to work and other responsibilities. another potential explanation is that, although most parents (71.3%) felt supported by their child's school to provide at-home education, those that did not feel supported or well prepared may have been less likely to engage in at-home education with their child. nonetheless, the gap between school closures and parents' report of at-home education is notable, and may be an area for concern as likelihood of continuing school closures or partial at-home education seems likely to continue for the 2020-2021 school year. further research is needed to understand how schools can support parents to deliver or support at-home education. multivariate analysis indicated that parental depression and parenting stress were significantly negatively associated with parents' perceived preparation to provide at-home education. it may be that the stresses experienced during the pandemic interfered with some parents' ability to educate their children at home. because our data are cross-sectional, it is also important to note the possibility that parents who felt more prepared to provide at-home education may have had a better mental health in the wake of school closures. in other words, we cannot determine the direction of the association between parents' mental health and at-home education. over one-third of the parents in this study said that their children were experiencing behavior changes since the pandemic. in content coding of open-ended questions, parents reported that their children were lonely, sad, and afraid. multivariate analysis indicated that parental mental health -specifically, parental anxiety and parenting stress -were associated with higher levels of child anxiety. parental employment changes were also linked to higher levels of child anxiety. to date, there is little empirical data on how children are faring during covid-19. these results may suggest that, like their parents, children are suffering from anxiety that is associated with the disruptions to life from the pandemic. however, it is important to note that we do not have a baseline measure of child anxiety, and thus cannot infer that child anxiety levels have increased because of covid-19. future longitudinal research is needed to document whether children's anxiety increased as a result of the pandemic. given that, prior to covid-19, homeschooling was relatively rare, there is little data on how socioeconomically disadvantaged children, children without access to the internet, abused and neglected children, or children with learning disabilities or other developmental delays may fare during a widespread national shift to at-home education and/or parents supplementing online education. a limitation of the current study is that it does not encompass the challenges and experiences of marginalized children. children who faced disadvantages prior to covid-19 are going to be disproportionately impacted by lack of access to education and schooling (united nations children's fund, 2020). one vulnerable group is children with physical and learning disabilities. over seven million children with special needs, including those with autism spectrum disorder, thrive on routines and tend to also be reliant on in-school therapists and other services for individualized education programs (national center for education statistics, 2020). disruptions to routines, as well as lack of access to school-provided therapists and educational activities, may result in frustration and acting out behaviors (lee, 2020) . in anticipation of the possibility of additional in-person education closures, it is critical to address solutions to provide services to children with special needs. this may include telehealth-based interventions or other strategies (frederick, raabe, rogers, & pizzica, 2020; hinton, sheffield, sanders, & sofronoff, 2017) . research on the effects of the covid-19 disease demonstrate that the impacts of covid-19 have disproportionately impacted communities of color, socioeconomically disadvantaged individuals, as well as those with underlying health conditions and others who faced health inequalities before covid-19. it is clear that the impacts of covid-19 are exacerbated by underlying socioeconomic and racial inequalities in the u.s. (ebor, loeb, & trejo, 2020; fortuna, tolou-shams, robles-ramamurthy, & porche, 2020) . children in socioeconomically disadvantaged contexts are also likely to be disproportionately impacted by lack of access to in-person education, and special attention should be given to programs to support their educational and mental health needs. in addition, at least 1.5 million american children are homeless (national center for homeless education, 2020) and homelessness is associated with lower educational outcomes for children (manfra, 2019) . there are 146,000 child victims of maltreatment who are in foster care in the u.s. (u.s. department of health and human services, 2020), and research shows children in foster care have poorer educational outcomes when compared to other children (morton, 2015; zetlin, weinberg, & kimm, 2004) . abused and neglected children are particularly vulnerable, given that they have already been traumatized by maltreatment. lack of access to caring adults such as school personnel, who can check on their welfare and provide support, as well as lack of access to much-needed resources, such as school meals, are especially problematic for these youth (herd et al., 2020) . further research is needed to better understand the experiences of at-home education and online education among parents and children who are homeless, in foster care, or who face other barriers to equal educational access (herd et al., 2020) . most schools do not offer mental health treatment services, and rely on teachers and nonclinical staff to support children's mental health (fulks & stratford, 2020) . trauma-based interventions to help children cope with the aftereffects of covid-19 may be especially effective when students return to in-person school activities. trauma-based care in schools have been shown to be effective to support students' wellbeing. the best evidence for whole-school or classroom approaches delivered by teachers or non-clinical school staff. one promising approach is training school staff on the use of trauma-informed approaches that are implemented in a way that is specific to the unique needs of marginalized youth (stratford et al., 2020) . another promising model to support children during the closure of in-person education is the youthconnect program model, which is a partnership of youth-serving organizations that supported students during the pandemic (sacks & jones, 2020) . community-based organizations may be able to provide children with meaningful connections to caring adults during a time of crisis. furthermore, linkages with community-based organizations may help parents and youth connect to resources to address issues such as food insecurity and mental health needs. this study speaks to the experiences of mostly white (70%), middle-income parents. minority parents were underrepresented in the sample. the data were collected using a convenience sampling approach, thus, the study results are not nationally representative and are not generalizable to all parents in the u.s. all study analyses reported herein are cross-sectional in nature. we cannot infer causality in the results, nor can we conclusively determine whether the patterns of associations documented in this study are the result of covid-19. for example, we do not have baseline measures of child anxiety; thus, it is not possible to determine whether the child anxiety levels found in this study reflect an increase in child anxiety due to the pandemic. all measures in this study were reported by parents; thus, all the study results are parents' perceptions. we do not have data from third parties to verify or validate study results. all of the study results should be interpreted with these caveats in mind. the current study provides a one-time snapshot of parent and child wellbeing during the covid-19 pandemic, in particular, some of the dynamics as families adjusted to in-person education closures and shifted to at-home educational options. parents were engaged in more everyday activities with their child and most parents were hugging and showing physical affection more often, even while 1 in 4 parents were affected by changes to employment. parents reported high levels of daily schedule disruptions, as well as stressors such as lack of access to free and reduced price school meals. high levels of parental depression and parenting stress have implications for parents' perceived ability to provide at-home education. as the pandemic continues into the 2020-2021 school year, parents and children are clearly in need of more mental health intervention to reduce mental health problems, as well as assistance in carrying out at-home educational activities. innovative solutions that utilize telehealth as well as partnerships with community-based organizations may help to meet these challenges. used online or social media resources 314 77.1 support from child(ren)'s school 315 71.3 collaborated with other parents 315 22.5 note: n reflects the total number of individuals who responded to the question. only parents who were currently educating their child at home (n = 315) were asked the "resources to educate at home" items. individuals who answered "not applicable" were not included in percentage calculation. phq-8 criteria for probable major depression or severe major depression). parental anxiety is coded as (0=minimal or mild anxiety, 1=meets gad-7 criteria for probable moderate or severe anxiety). parenting stress is a continuous scale that ranged from 0-3. †p < .10, *p < .05, **p < .10, ***p < .001 manual for the child 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during the coronavirus (covid-19) pandemic the national evaluation of the welfare-to-work strategies news release: unemployment insurance weekly claims ted: the economics daily, employment in families with children in 2016 department of health & human services, administration for children and families improving education outcomes for children in foster care: intervention by an education liaison parents were hugging/ showing affection to child more often during pandemic note: n reflects the total number of individuals who responded to the question. individuals who answered "not applicable" or left the response box blank (n = 179) were not included in percentage calculation. table 5 . type of technology frequency (%) online educational tools 59.9% "abc mouse", "study island", "khan academy", "wikipedia", "pbs", "prodigy", "epic"school-based 28.5% "the school has provided a website for lessons and homework", "seesaw", "google classroom", "resources provided by the course coordinator", "the schools app", "teacher has mailed and emailed assignments i can work with my child"social media 26.1% "youtube", "the mom groups on facebook", "pinterest" miscellaneous 7.4% "i don't use online resources", "amazon" live remote 7.0% "online meetings with teacher", "zoom meetings with tutors"paper-based 5.3% "printing out worksheets from k5 learning website" note: n reflects the total number of individuals who responded to the question. individuals who answered "not applicable" or left the response box blank (n = 121) were not included in percentage calculation. 27.8% "worries more", "anxious", "afraid and hesitant to leave the house", "stressed"depressive symptoms (internalizing problems) 18.3% "less energetic", "sad", "depressed", "sleeps a lot", "less desire to interact with peers", "lonely" , "cries a lot" bored 15.1% "bored", "they aren't as motivated as usual", "often complain of being bored"positive 7.9% "more thankful and helpful", "hasn't been as cranky", "more excited to spend time with the family", "more relaxed"miscellaneous 7.9% "i don't use online resources", "amazon" note: n reflects the total number of individuals who responded to the question. of the total sample, 140 parents indicated that they had observed change in their child's behavior and were prompted to answer this question. individuals who answered "not applicable" or left the response box blank (n = 14) were not included in percentage calculation. table 7 . type of need frequency (%) general emotional needs 50.1% "love", "support", "attention" socialization 14.0% "friends to communicate with", "socialize with kids their own age", "a way to interact with another child" entertainment 12.7% "convenient access to pastime that isn't on a screen", "new and interesting ways of being entertained", "things to keep them busy" physical activity 10.7% "play outside with other kids", "better kid workout videos", "better weather so we can be outside", "more exercise"school 9.7% "to go back to school", "more formal education", "better schooling resources", "more educational engagement"feel safe/protected 9.2% "reassured that they will be safe", "clarity and plan from trustworthy adults", "understand as long as they do the right thing they will be ok" basic needs 7.7% "food and toiletries", "cleaning supplies", "housing", "money"share covid-19 guidance 7.2% "lots of safety and precautions", "take responsibility for themselves", "someone to clarify the situation", "guidance"parental stability/security 6.5% "good parenting", "her parents to be eventempered", "for us to be as calm and rational as possible", "security from parents" miscellaneous 6.2% "alone time", "wake up from day dreaming and the usual grind"withhold covid-19 guidance 3.0% "they need to not be told about this because it would terrify them unnecessarily", "they need the restrictions to be lifted… the flu kills more"note: n reflects the total number of individuals who responded to the question. individuals who answered "not applicable" or left the response box blank (n = 4) were not included in percentage calculation. shawna j. lee conceptualized the study, collected the data, conducted data analysis, reviewed data analysis, and prepared the first draft of the manuscript. kaitlin p. ward contributed to the selection of study variables, conducted data analysis, created tables, and contributed to writing the study manuscript. olivia d. chang conducted qualitative content coding and contributed to writing the study manuscript. kasey m. downing conducted qualitative content coding and contributed to writing the study manuscript. the authors confirm that they have no conflicts of interest to report related to this study. key: cord-294772-nma7w7of authors: de oliveira collet, giulia; campagnaro, ricardo; podadeiro de andrade, mariana; pedro da silva lopes salles, joão; de lourdes calvo fracasso, marina; lopes salles scheffel, debora; maria salvatore freitas, karina; cristina santin, gabriela title: covid-19 pandemic and pediatric dentistry: fear, eating habits and parent’s oral health perceptions date: 2020-09-15 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105469 sha: doc_id: 294772 cord_uid: nma7w7of background: severe measures have been implemented around the world to reduce covid-19 spread with a significant impact on family dynamics. aim: to assess the impact of the pandemic on fear, dietary choices and oral health perceptions of parents. design: questionnaire containing 19 questions was remotely applied to 1,003 parents of children aged 0-12 years. the questions addressed topics regarding changes in daily routine, dietary habits, fear level, oral health, and variation of income during the pandemic. data analysis included the description of the relative and absolute frequencies of the variables. association tests were performed using fisher's exact and kruskal-wallis tests. results: 73% of respondents reported income loss. five hundred sixty-eight people denied seeking medical or dental care. 61.5% of respondents revealed changes in the dietary pattern; most of them mentioned an increase in food intake. most parents (66.6%) would only seek urgent dental care. there was an association between parents’ willingness to take their children to dental appointments with the fear level (p<0.001). conclusions: most families have experienced changes in daily routine and eating habits during the pandemic. parents fear covid-19 and it impacts their behavior regarding seeking dental care for their children. on march 11 th 2020, the world health organization (who) characterized the coronavirus disease 2019 as a pandemic. the disease was first reported in december 2019 to who china office as pneumonia of unknown cause. in january 2020, a novel coronavirus (sars-cov-2) was identified, and its genome sequencing was released (world health organization, 2020c) . by september 07 th , the world had registered 27,150,797 covid-19 cases and 889,256 deaths (european centre for disease prevention and control, 2020), numbers widely higher than those reported during the two outbreaks with coronaviruses in the recent past. during 2002 during -2003 ,098 cases of the severe acute respiratory syndrome (sars) and 774 deaths were registered (world health organization, 2003) , while 2,519 laboratory-confirmed cases of the middle east respiratory syndrome (mers) were reported between 2012-2020 with 866 deaths (world health organization, 2020a). covid-19 has high contagiousness and rapid spread (sanche et al., 2020) , mainly through small droplets from the nose and mouth expelled when an infected person speaks, coughs or sneezes (world health organization, 2020b) . even patients with no symptoms seem to be able to transmit the virus (world health organization, 2020b) . the majority of the infections are mild or asymptomatic (80%), while about 5% are critical infections (world health organization, 2020b) . governments have established policy responses to combat the coronavirus pandemic, including measures to restrict people's transit, business operations, social distancing, cancellation of services, reservations and events (coulthard, 2020; ministry of economics; peloso, ferruzzi, et al., 2020) . those measures have led to stay-at-home orders, social distancing, lockdowns, job losses, insecurity, concerns, fears, and a decrease in the quality of life of families worldwide (ornell et al., 2020) . the suspension of school programs and sports activities during the pandemic has led children and adolescents to spend longer periods at home. the new routine may result in an increase in food intake, including ultra-processed and calorie-dense foods (creswell et al., 2020; di renzo et al., 2020) . pietrobelli et al. (2020) suggested that potato chips, red meat, and sugary drink intakes significantly increased in italy during the lockdown. high-carbohydrates diets may lead to several health issues, such as obesity, diabetes, as well as poor oral health. frequent sugar intake favors dental biofilm accumulation and contributes to the development of caries lesions and periodontal disease (colombo & tanner, 2019) . meanwhile, the pandemic has challenged health professions such as dentistry. concerns regarding dentist's and patient's safety pushed to the reduction of routine dental care (cotrin et al., 2020a; coulthard, 2020; faccini et al., 2020; pereira et al., 2020) , compromising preventive appointments. brazil is the second country in the number of confirmed cases of covid-19, with one of the fastest growing coronavirus epidemics in the world (candido et al., 2020) . the increasing number of cases has divided opinions regarding the economy reopening and resumption of once-routine daily life. it has directly affected habits, bringing concerns toward the future in general. the changes in diet, economic issues, general concerns, fear, added to the lack of preventive dental care, could impact the oral health of children during the enforced stay-at-home orders. thus, this study aimed to assess the fear level, dietary choices and parent's oral health perceptions during the stay-at-home orders period in brazil. a cross-sectional study was carried out using non-probabilistic sampling, with parents of children aged 0 to 12 years, from all 5 geographic regions of brazil (north, northeast, southeast, south, and center-west) . this study was conducted after approval by the research ethics committee of _______________ (protocol # __________). the representative sample size was estimated using a 95% confidence level and margin of error of 5%. the sample calculation considered 35.5 million children aged 0-12 years in brazil in 2018 (ibge, 2018) . the sample size was estimated at a minimum of 385 respondents. a structured questionnaire was developed according to the cherries recommendations (eysenbach, 2004) . a pilot study was performed to verify the functionality of the questionnaire. for the pilot study, 38 parents (10% of the sample size calculation) were randomly selected from the files of the patients of a single private dental office and they were not included in the final sample. the questionnaire contained 19 mandatory questions about socioeconomic and demographic dates, fear income variability, eating habits and parent's oral health perceptions. the original questionnaire was an open survey, written in brazilian portuguese using the google forms platform and forwarded to parents and caregivers of children aged 0-12 years through social media and message apps from may 12 th to june 9 th , 2020. it was available for 29 days. all parents who fit the criteria of having children under 12 years of age could answer the questionnaire. the translated questionnaire is shown in table 1 . all the respondents had access to the consent statement and requested to agree with it before being included in the present study. the informed consent included the object of the study, the responsible researchers and their contact information. the approximate time for the answer to the questionnaire was informed, being about five minutes. the answers and data obtained were stored by the researchers and used only for this study. to ensure the anonymity of each respondent, no identifying information was collected. before sending the questionnaire, participants could change their answers many times as they wish. no duplicate response control tool was used, but if identical responses in sequence were observed, one was excluded. the answers obtained were tabulated in excel (microsoft corp., redmond, usa), and the statistical analysis was performed using the ibm-spss 22.0 software. for statistical analysis, some variables were categorized. the 'state' variables were scored according to the number of cases per 100,000 inhabitants, according to national data at the time of the study, being 'up to 100,000 cases', '101,000 to 300,000 cases', '301,000 to 500,000 cases' and 'over 500,000 cases'. the fear level was categorized into '0 to 2', '3 to 5', '6 to 8' and '9 to 10'. fear levels 6-8 and 9-10 were considered moderate and high fear, respectively. data analysis included the description of the relative and absolute frequencies of the variables. association tests were performed using fisher's exact and kruskal-wallis tests for ordinal variables. a total of 1,003 questionnaires were filled in by people from 25 states and the federal district. no response was obtained from the state of acre (north). the great majority of respondents (97.2%) were parents (mother/father), with an average age of 36.6 years (s.d.= ±6.97). most families (73%) disclosed a reduction in income, with 52.9% reporting a slight reduction and 20.1% drastic reduction or total loss of income. regarding the number of people living in each house, 82.6% of the households had three to four people, and 94.1% of respondents had 1 or 2 children aged 0 to 12 years. no association was found between these variables and the reported presence of caries lesions, dental pain or dental trauma (p>0.05). only 1.8% of respondents had confirmed covid-19, and 6.9% had symptoms but were not tested. five hundred sixty-eight people declared not leaving their houses for medical or dental appointments, and 876 were not doing leisure activities. forty-three percent said they were leaving their houses only when necessary, and 52.8% stated leaving their houses to work. 61.5% of respondents reported changes in eating habits during the pandemic; most of them revealed an increase in food intake ( figure 1 ). of those who claimed changes in eating habits, only 33.1% said they were choosing healthier foods, while the others increased the consumption of processed foods, pasta and snacks ( figure 2 ). families with drastic or total loss of income are eating less than before or opting for cheaper food (p<0.001) ( table 2) . no association was found between the caries perception of parents and changes in food consumption (p=0.53). regarding their children's oral hygiene, 83.5% of parents reported brushing their children's teeth during the pandemic, 14.7% brushed sometimes and only 1.8% did not brush. there was no significant association between brushing the teeth and the variables tooth pain, presence of dental caries and change in dietary pattern. regarding oral health, 24.4% of parents/caregivers reported their children were undergoing dental treatment before the pandemic. however, only 17.8% of total respondents are willing to take their children to dental care regardless of the procedure; 66.6% would only seek urgent care, and 15.1% would not seek dental care at all. the frequency of distribution of dental pain reports, the presence of caries lesions and dental trauma are shown in table 3 . fifty-one people declared their children experienced dental trauma during the pandemic. however, 86% of them did not seek dental care. association was found among parents/caregivers' willingness to take their children to dental appointments, fear level (p<0.001), and the local number of covid-19 cases (p<0.001) ( table 4) . when the fear level was assessed, 49.2% of respondents reported a level of fear between 6 and 8, while 16.1% said their fear level is between 9 and 10. for billions of people across the world, daily life has changed dramatically in the past months. the coronavirus pandemic has required adaptations from adults, youth and children in the way they study, work and interact with others. the new routine may impact family wellbeing by reducing its income, raising fears, increasing anxiety, stress, and instability (cotrin et al., 2020b; ornell et al., 2020; parsons, 2020; peloso, pini, et al., 2020) . in the course of the present work, brazil recorded an increasing number of daily cases of covid-19, reaching its highest number of new confirmed cases (54,771) on june 19 th . this compelled the extension of stay-at-home orders, social distancing and restrictions, exacerbating the risk of an economic recession. this study found that 73% of the participants from 25 states and the federal district of brazil lost income during the pandemic, 20.1% of them reported drastic reductions in family income. in a single-hit scenario, brazil's gdp is expected to fall by 7.4%, while a decrease by 9.1% may be experienced if a second wave of the pandemic imposes further lockdowns. financial instability, unemployment, economic crises, social distancing, self-isolation, and potentially life-threatening diseases are impacting people's concerns and mental health around the world (knipe et al., 2020) . in the present study, over 65% of respondents reported fear levels equal to or higher than 6 when the likert scale was applied, while 16.1% declared fear levels 9 or 10. fear is present since the early stages of human development (papalia & feldman, 2013) . it is a non-pathological emotion, consequence of real or imagined threat (burnham & gullone, 1997) and results from risk assessments (papalia & feldman, 2013) . however, high levels of fear may produce negative health outcomes and ultimately may cause emotional and physical damage, as it impedes people from naturally performing daily activities (balan et al., 2019) . a significant association was found between the level of fear, the local number of contaminated and seeking dental care. families living in areas with higher numbers of covid-19 cases fear more for safety than those living in less affected areas. it results in greater precaution regarding the seek for dental treatments since parents with higher levels of fear are also those who would either take their children to the dentist only in dental urgencies (66.6%) or would not take them at all (15.1%) . the concerns of parents/caregivers regarding covid-19 may be especially high when it comes to children since its sign and symptoms are not well established at young ages (mallineni et al., 2020) . adverse manifestations of covid-19 have been reported in children, such as the kawasaki disease-like illness related to the infection by sars-cov-2 observed in europe and the united states (choi, 2020) . however, ludvigsson (2020) found, in a systematic review, that infected children presented milder symptoms of covid-19 and also a better prognosis than adults. studies have shown that people have postponed medical treatments due to the fear of contracting covid-19, which may increase the risk of serious health issues in the near future (karacin et al., 2020; omarini et al., 2020; teoh et al., 2020) . a similar trend was observed in the present study regarding oral health. about 56% of respondents said they are not leaving their houses to attend to medical or dental appointments, and 86% of those who reported that their children were victims of dental trauma during the pandemic did not seek dental care. besides that, 24.4% of the children had their dental treatment temporarily suspended. the lack of preventive and curative care may negatively impact the oral health of children all over the country and trigger the need for future public actions to address those impacts. the new routine, work-at-home for parents, remote classes for children and economic instability have contributed to changes in dietary habits (di renzo et al., 2020) . about 77% of respondents said they increased the intake of high-carb foods. pietrobelli et al. (2020) correlated the social distancing period to the summer vacation, when children's carbohydrate intake considerably increases, with a direct impact on childhood obesity. families with drastic or total income loss reported eating less or choosing cheaper foods during the pandemic. more affordable foods may include pasta, sandwiches, snacks, and other foods with low nutritional value and high sugar content. those diet changes not only affect general health but also increases the risk of caries development. in addition to the damage caused by the change in dietary pattern to oral health, this change can cause an increase in obesity, nutritional deficiencies, among others. at the same time, there are the psychological effects of the pandemic on children (spinelli et al., 2020) , which are somehow linked to the changes in food intake patterns and oral hygiene routine. although this study found no association between parents' perception of caries lesions, food intake and oral hygiene, one has to consider that the questionnaire was filled in a relatively early stage of the pandemic in brazil. the effects of dietary habits and decreased care with oral hygiene may become more evident in the next months. the present study concluded that the covid-19 pandemic has negatively impacted the eating habits and dental care of children in brazil. furthermore, it has trigged moderate and high levels of fear among parents/caregivers. as an alternative to offer dental assistance during these unusual times, future studies should evaluate the effectiveness of 'teledentistry'. it has been approved in brazil by the federal council of dentistry (2020) and allows parents and children to have video or phone appointments, with dentists providing a safe triage, sharing information on oral hygiene and health (aziz & ziccardi, 2009) . there are no fundings to declare. no potential conflict of interest was reported by the author(s). the data are available from the authors upon request. 6. on a scale of 0 to 10, where 0 is no fear and 10 is terror, indicate the option that best describes your fear of the pandemic. 0; 1; 2; 3; 4; 5; 6; 7; 8; 9; 10 7. which alternative best describes the impact of the pandemic on your family income. family income not impacted; slightly reduced; drastically reduced; total loss of income; increased during the pandemic. 8. there has been any change in food consumption in your home during the pandemic? yes, we are eating cheaper foods; eating less than before; eating more than before; there was no change in food intake; other (the volunteer could write the answer). 9. there has been any change in eating habits at your home during the pandemic? (volunteer could select one or more options). we are consuming more processed food with sugar such as soft drinks, sweets and cookies; consuming more pasta and carbohydrates; consuming more healthy food such as fruits and vegetables; consuming more snacks and/or frozen food; nothing has changed. 10. how is your family's daily routine during the pandemic? we are not leaving the house for anything; leaving the minimum necessary (pharmacy, supermarket, etc.); leaving just to work; leaving the house as usual. 11. do you or anyone in your household have had symptoms of covid-19? yes, but the person was not tested; yes, the test was negative for covid-19; yes, the test was positive for covid-19; no one has had kruskal-wallis test telemedicine using smartphones for oral and maxillofacial surgery consultation, communication, and treatment planning fear level classification based on emotional dimensions and machine learning techniques the fear survey schedule for children--ii: a psychometric investigation with american data evolution and epidemic spread of sars-cov-2 in brazil. science, eabd2161 can we get a clue for the etiology of kawasaki disease in the covid-19 pandemic? the role of bacterial biofilms in dental caries and periodontal and peri-implant diseases: a historical perspective urgencies and emergencies in orthodontics during the coronavirus disease 2019 pandemic: brazilian orthodontists' experience impact of coronavirus pandemic in appointments and anxiety/concerns of patients regarding orthodontic treatment dentistry and coronavirus (covid-19) -moral decision-making research review: recommendations for reporting on treatment trials for child and adolescent anxiety disorders -an international consensus statement eating habits and lifestyle changes during covid-19 lockdown: an italian survey covid-19 situation update worldwide improving the quality of web surveys: the checklist for reporting results of internet e-surveys (cherries) dental care during covid-19 outbreak: a web-based survey resolution cfo continuous national household sample survey (pnad how does covid-19 fear and anxiety affect chemotherapy adherence in patients with cancer mapping population mental health concerns related to covid-19 and the consequences of physical distancing: a google trends analysis systematic review of covid-19 in children shows milder cases and a better prognosis than adults coronavirus disease (covid-19): characteristics in children and considerations for dentists providing their care brazil's policy responses to covid-19 cancer treatment during the coronavirus disease 2019 pandemic: do not postpone, do it! pandemic fear" and covid-19: mental health burden and strategies psychosocial development in second childhood in human development covid-19, children and anxiety in 2020 notes from the field: concerns of health-related higher education students in brazil pertaining to distance learning during the coronavirus pandemic. evaluation and the health professions how does the quarantine resulting from covid-19 impact dental appointments and patient anxiety levels? biological and social aspects of coronavirus disease 2019 (covid-19) related to oral health lockdown on lifestyle behaviors in children with obesity living in high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 parents' stress and children's psychological problems in families facing the covid-19 outbreak in italy a global survey on the impact of covid-19 on urological services summary of probable sars cases with onset of illness from 1 mers situation update q&a on coronaviruses (covid-19) were any of your children (0-12 years old) undergoing dental treatment before the pandemic? (volunteer could select one or more options). no; yes, orthodontic treatment; yes, caries treatment; yes, because of toothache; yes the pandemic? yes, for any procedure; yes, but only for urgent treatments if not, for what reason? risk of contracting covid-19; the dental treatment is not urgent; my child/i has/have symptoms of covid-19 have you been able to brush your children's teeth during the pandemic? yes; no; sometimes has any of your children experienced dental trauma during the pandemic? no; yes, i sought care right after the trauma and my child was assisted; yes, but i did not seek care; yes, i sought care other (the volunteer could write the answer) have you noticed any cavities/caries in your children's teeth during the pandemic? no; yes, i sought care and my child was assisted yes, but i did not seek care; yes, i sought care has any of your children experienced toothache during the pandemic? no; yes, i sought, and my child was assisted yes, but i did not seek care; yes, i sought care key: cord-295575-zgta5ah8 authors: howard, evin; orhurhu, vwaire; huang, lisa; guthrie, barbara; phipatanakul, wanda title: the impact of ambient environmental exposures to microbial products on asthma outcomes from birth to childhood date: 2019-11-28 journal: curr allergy asthma rep doi: 10.1007/s11882-019-0890-2 sha: doc_id: 295575 cord_uid: zgta5ah8 purpose of review: asthma is a chronic respiratory condition with increasing domestic and worldwide prevalence that burdens individuals and the healthcare system with high costs associated with long-term treatments and acute emergency room (er) visits. it can be triggered by ambient microbes, including bacteria, viruses, and fungi. in this review, we examine the outcomes of asthma patients in relation to environmental exposures to ambient microbe products, focusing on whether exposure leads to asthma development from birth to childhood and if particular microbes are associated with worsened asthma exacerbations. recent findings: bacterial endotoxin is more prominent in homes with pets and may cause cytokine cascades that lead to asthma exacerbation. however, some studies have demonstrated a protective effect with early exposure. patients with positive aspergillus skin testing are more prone to moderate-severe or severe-uncontrolled asthma. fungal sensitization is also associated with earlier onset of asthma and demonstrates a dose-dependent relationship of symptom severity and duration. among viruses, rhinovirus has the greatest association with decreased lung function, severe asthma, and asthma-related hospital admissions. distribution of microbial products and associated asthma symptoms depends on the geographical climate. genetic variations among individuals also mitigate the effects of microbial products on asthma development and symptom severity. summary: microbial products of bacteria, fungi, and viruses are associated with the development of asthma, more severe asthma symptoms, and worse outcomes. however, some early exposure studies have also demonstrated a protective effect. bacterial and fungal products are related to decreased lung function and earlier onset of asthma. viral products are related to asthma-associated hospital admissions; and the climate and patient genetics can also temper or intensify the relationships between microbial products, asthma development, and asthma symptom severity. further research should focus on the effects of early microbe exposure and its interaction with human immune systems and asthma-related outcomes. every day, 10 people in the usa die from asthma [1] . in 2017 alone, there were 3,564 asthma-related deaths [1, 2] . within the usa, the prevalence of asthma is 1 in 13 people, producing annual economic costs of over $81.9 billion, related to missed school and work, medical costs, and asthma-related mortality [1] [2] [3] . ambient microbes have been shown to trigger asthma attacks [4] [5] [6] . the most common microbes are bacteria, viruses, and fungi [7] . though the literature has clearly demonstrated that microbes and allergens can trigger asthma exacerbations, controversy still remains whether or not microbes promote the development of asthma with early-life exposure or if they have a preventative effect against asthma symptoms in an individual with established disease [4] [5] [6] . many longitudinal studies have demonstrated that early this article is part of the topical collection on allergies and the environment exposure to ambient microbial products increases the risk of the development of asthma [8•, 9, 10, 11•] . whereas, other studies, particularly related to human contact with animal microbes, have shown protective effects against the development of asthma [8•, 12, 13] . with over 1.8 million asthma-related er visits each year, which may be potentiated by exposure to various ambient microbial products in the environment, earlylife exposure to microbial products and its effect on the respiratory system later in childhood warrants further investigation [2, 6, 14, 15] . the purpose of this literature review was to specifically examine asthma outcomes related to environmental exposures to microbial products, pertaining to endotoxin from bacteria-(1,3)-β-d-glucan and ergosterol from fungus, and common viruses associated with worsening asthma morbidity (rhinovirus, respiratory syncytial virus (rsv), enterovirus, and the influenza virus) during infancy, and to assess the risk of asthma development later in childhood [15] [16] [17] [18] (see table 1 ). while other reviews have focused on common routes of exposure and the concentration of microbial products (endotoxin, fungal spores, virus, etc.) in urban vs. suburban regions [19, 20] , this review investigates if the exposure to microbial products during infancy leads to the development of asthma during childhood, and whether particular microbes have a higher severity for triggering asthma exacerbations over others. primary questions for this review consisted of the following: what microbes are associated with asthma severity and outcomes? what microbial products are known for triggering asthma symptoms and/or exacerbations? does the exposure of microbial products in the environment lead to the development of asthma? for this review, we selected original manuscripts in english, published in peer-review journals on the basis of bacterial, fungal, and viral products within the environmental matrix with children exposed to these microbial products. thus, we selected articles examining health outcomes for the development of asthma related to microbial product exposure during the time of infancy until childhood. however, we also highlighted factors in the literature that contribute to microbial exposure and their effect on asthma for people with an established diagnosis of asthma. only journal articles within the last 5 years were chosen; however, there were no restrictions pertaining to specific populations or geographical locations. exclusion criteria consisted of animal studies, investigative procedures using only in vitro methods, studies not translated into english, articles focusing on the measurement of microbial products without their effect on asthma outcomes, and articles not assessing microbial exposure from the time of infancy. with this thought process in mind, the following word criteria was applied using pubmed as the primary search engine: ( the search returned a total of 2999 articles. after the removal of 2924 studies, consisting of reviews, duplicates, mouse studies, and irrelevant articles to asthma health outcomes, this then left 76 studies. 65 studies were pertaining to adults, which left a total of n = 11 studies (see fig. 1 ). the majority of the studies had a prospective cohort design (9/11), while the other two studies were retrospective cohort designs. environmental sampling consisted of different locations in participants' homes (living room, kitchen, bedroom, mattress), outside air, and settled dust in classrooms. all of the studies included examined asthma health outcomes related to ambient exposure to bacterial, fungal, and viral microbial products. considering bacterial products and asthma outcomes, the literature has discussed endotoxin, β-glucan, and lipopolysaccharide (lps). of these microbial products, when bacteria are destroyed or lysed, lps is dispersed into the environment or blood as endotoxin, which can lead to a cascade of inflammatory cytokines (il-6, il-12, il1β, and tnf-α) and exacerbation of asthma symptoms [22, 23] . the main route of contact to endotoxin is via inhalation, which has been demonstrated in multiple studies [5, 14, 21, 22] . of the 11 studies selected for review, there were two that specifically discussed endotoxin exposure from infancy [8•, 24 ••] (see table 2 ). tischer et al. conducted a prospective longitudinal study examining whether early exposure to microbial products in dust was associated with allergy and asthma later in childhood for children in suburban areas using the following three birth cohort studies for children born between 1996 and 1999: [24••] , dust samples were collected from children's mattresses, bedroom floors, and living room floors; and showed no association between endotoxin nor the fungal membrane lipid ergosterol in the development of asthma with exposure from birth to 7 years of age. previous research has shown that endotoxin levels tend to be higher in homes with a pet such as a cat or dog in addition to homes of families that are low-income and/or may be in community projects that contain cockroaches [5, 31] . similar results were seen in children by a study conducted by mendy et al. [32] who found that overall for people who had a cat or dog, endotoxin levels were higher in the household with a pet and was associated with wheeze (or = 1.30; 95% ci (1.04-1.62)) but not with asthma [32] . co-exposure with dog and cat allergens modified the association with asthma, increasing the risk when exposed to endotoxin (or = 2.00; 95% ci (1.04-3.83)) [32] [5] demonstrated that endotoxin exposure is associated with wheeze with exercise, office or er visits, and use of prescription medication for wheezing [5] . studies have indicated that lung function and capacity can be decreased due to continuous exposure to endotoxin in patients with atopic asthma [22, 33] . lipopolysaccharide has also been shown to promote eosinophil airway inflammation in patients with asthma despite maintenance treatment with inhaled corticosteroids (ics) [34] . besides having a pet, there are other factors that could have contributed to the varying results between the cohorts within the tischer et al.'s study. the climate also plays a role in the concentration of endotoxin in the surrounding environment [14, 31] . researchers have found a positive correlation between log 10 -endotoxin and current asthma (or = 1.56, 95% ci (1.11-2.18), p = 0.046) for hot-humid regions and a higher incidence of exercise-induced wheeze (or = 1.48, 95% ci (1.22-1.80), p = 0.009) for subarctic/very cold/cold regions [31] . high levels of endotoxin, regardless of being inside or outside the home environment, are associated with severe asthma [14, 35] . a study conducted in japan by khan and colleagues showed that asthma-related visits to the er for patients 15-years-old or older was highest during the seasons of autumn and spring, when the environmental endotoxin was highest in the air [14] . oluwole et al. [35] showed that for 7 to 17-year-olds, high concentrations of endotoxin within households, including mattresses, are associated with an elevated risk of moderate or severe asthma (adjusted or = 11.40, 95% ci (1.45-89.43)). tischer et al. [8•] also supported these • sleeping with animal fur was inversely associated with early wheezes at age 4 and current asthma at age 6 • sleeping on animal fur during the first 3 months of life was associated with persistently stimulated interferon-γ response until age 3 • animal fur exposure might act as an immune system stimulant and offer protective mechanisms against asthma and allergy, as observed in farm/rural environments not able to determine the microbial profile of the animal fur nor the intensity of the exposure. lifestyle factors also play a role in developing asthma bonnelykke et al. • after adjusting for total respiratory episodes and number of episodes per pathogen, only the total number of episodes were significantly associated with asthma development • risk factor for development is asthma is the number of respiratory episodes, not the specific viral trigger assumed that children who did not present to clinic did not have clinically significant respiratory episodes • maternal history of asthma and depression were associated within higher risk of asthma by age 7. • bacterial species kocuria, bifidobacterium, alloiococcus, and acinetobacter were found in homes of children without asthma, but not in homes of children with asthma. • endotoxin and ergosterol were not found to be associated with the development of asthma gastrointestinal and airway microbiome were not measured during early childhood results for children from infancy to 6 years of age. in addition, these findings are also in accordance with previous investigations in the early 2000s [36] [37] [38] [39] . non-environmental patient characteristics can also impact the development or severity of asthma. mendy et al.'s [40] study determined that the combination of high levels of endotoxin exposure and low vitamin d levels are associated with an asthma diagnosis or recurrent wheeze (or = 1.88, 95% ci (1.33-2.66), p = 0.02), current asthma (or = 1.97, 95% ci (1.09-2.23), p = 0.03), wheeze over the last 12 months (or = 1.72, 95% ci (1.10-3.7), p = 0.002), and recurrent wheeze (or = 1.97, 95% ci (1.0-4.0), p < 0.001) [40] . nevertheless, this study was conducted in adults and the effect from infancy to childhood, regarding vitamin d levels in combination with endotoxin exposure, would need to be assessed. no studies on fungal spore exposure were found for the time period from birth to childhood to assess the development of asthma. [8•] . sensitization to fungal antigens is a key component to understanding asthma severity. chopra and colleagues showed that asthma patients with skin reactivity to the aspergillus skin test (ast) had more cases of moderate and severe asthma versus nonreactive ast patients (98.6% vs. 3.2%, p < 0.001) in a cohort of 282 adult asthma patients over a 1-year period. sensitization to aspergillus has been found to have a more significant impact on asthma outcomes compared to other species of fungus [41, 42] . for instance, vincent et al. [41] demonstrated that adult asthma patients who were sensitized to penicillium chrysogenum, [41] . masaki and colleagues' study in japan implicates a different species; their study investigated sensitization to candida and found that out of 124 adults with asthma, more people had sensitization to candida than aspergillus (16 vs. 11%) [6] . the researchers also found that fungal sensitization leads to a higher rate of early-onset asthma (< 16 years of age) compared to those without sensitization (45% vs. 25%) and sensitization increases with age [6, 43] . however, further investigation is needed to examine early exposure of various fungal species during infancy and its effect on the development of asthma during childhood. the fungal genus alternaria has also provided more insight into fungal sensitization and asthma outcomes. recently, baxi and colleagues conducted a study in 37 inner-city schools in new england with school-aged children with asthma and observed that children sensitized to alternaria had an association with asthma symptom days (or = 3.61, 95% ci (1.34-9.76), p = 0.01); however, this did not apply to children not sensitized to alternaria (or = 1.04, 95% ci (0.72-1.49), p = 0.85) [44] . researchers found that asthmatic children who were sensitized to alternaria and exposed to high levels had 3.2 more symptom days per 2week period when compared to asthmatic and sensitized children exposed to lower levels of alternaria. this suggests a dose-dependent relationship between mold exposure and asthma severity [44] . this finding is supported by oluwole et al. [45] , who demonstrated that high mold levels in children's play areas are associated with current asthma (adjusted or = 3.0, 95% ci (1.11-8.0)). furthermore, additional studies have demonstrated that sensitization to alternaria increases with higher mold concentration exposure and may lead to a risk of hospitalization, especially in the urban setting [46] [47] [48] [49] . fungal exposure also impacts lung function [41] . asthma patients with sensitization to aspergillus fumigatus have been found to have higher total serum ige levels and an increased degree of broncho-obstruction (as measured by fev 1 /fvc), compared to asthmatic patients without sensitization [41, 50] . the impact of fungal exposure on lung function has been evaluated in adults; however, this has not been thoroughly evaluated in infants and young children. the fungal product (1,3)-β-d-glucan has been shown to have a low association with severe asthma (or = 0.55, 95% ci (0.24-1.26), p = 0.003) in children [51, 52] . ergosterol has also demonstrated a low affinity for the development of asthma [52] . however, exposure to fungal spores has been shown by multiple studies in adults to be associated with asthma exacerbations; yet, there are very few studies involving children [53] [54] [55] . in a study analyzing the fungal microbiome in exhaled breath condensate (ebc) of patients with asthma in italy, carpagnano et al. [53] found that in 47 adults with asthma, 94% of the people were colonized in the ebc by cladodosporium species, 21% by alternaria, and 24% by penicillium species [53] . fungal colonization tended to be higher in asthmatics with severe and uncontrolled asthma with sensitization to fungal species such as alternaria [53] [54] [55] . the differing levels of fungal species, with cladosporium being the most abundant, and alternaria and penicillium in lower quantities, was also found in manitoba, canada, by polyzoi and polyzois, examining mold within the bedrooms and basements of 3424 school-aged children [56] . cladosporium was the most common mold found in homes (98.2% of bedrooms and 97.8% of basements), followed by alternaria (82.4% of bedrooms and 77% of basements), and penicillium (35.4% of bedrooms and 48.8% of basements). in addition, visible mold in bedrooms and basements in participants' homes were associated with persistent asthma and colds (16.8%, p < 0.0001). other fungal studies conducted in europe, canada, and australia have also found similar results [45, 57, 58] . viral exposure also plays a critical role in the development of asthma and asthma morbidity [9, 11•] . two studies were found that were conducted on early-life exposure to rhinovirus and asthma outcomes: one by rubner et al. [9] and another by lukkarinen et al. [11•] . rubner et al. [9] conducted a prospective cohort study with 217 children, examining early-life rhinovirus exposure from birth to 13 years of age. the researchers observed that wheezing with rhinovirus was associated with asthma at age 13 (or = 3.3, 95% ci (1.5-7.1), p = 0.02) and sensitization to allergens increased with age [9] . fev 1 % predicted has also been shown to be lower in asthmatic patients admitted to the hospital with an asthma exacerbation with concurrent rhinovirus infection, compared to children with asthma admitted for an exacerbation but negative for rhinovirus [29, 59] . lukkarinen et al. [11• ] performed a 7-year long prospective cohort study following 127 finnish children from birth to 7 years of age and found that the risk factors for atopic asthma at study entry were sensitization to common allergens (dust, mold, etc.), and wheezing with rhinovirus infection (aor 4.8, p < 0.014) [11•] . zheng et al. [15] conducted one of the numerous studies that demonstrated that human rhinovirus (hrv) was the most common viral microbe to induce an asthma exacerbation in children [60] [61] [62] . zheng and colleagues collected data from 143 inpatient children with asthma exacerbations, 131 outpatients, including 88 patients with asthma exacerbations, and 43 controls with stable asthma [15] . researchers tested for common viruses including hrv, respiratory syncytial virus (rsv), parainfluenza virus type 3 (piv3), influenza virus (ifv), human bocavirus (hb0v 1 ), atadenovirus (adv), human coronavirus (hcov), and hepatitis e virus. of all the viruses, hrv was the most prominent among inpatients with severe asthma exacerbations at 50.3% and hcov was the least at 0% [15] . the researchers found three variants of the hrv: hrv-a, hrv-b, and hrv-c, with hrv-c being the most virulent for severe asthma exacerbations [15] . other studies conducted in japan, france, and australia have also identified rhinovirus as the most common viral culprit for asthma exacerbations [28, [60] [61] [62] . white blood cells and neutrophil counts were significantly higher in patients with all hrv variants versus those who were negative for hrv ( [15] . thymic stromal lymphopoietin (tslp), a cytokine that impacts t cell maturation, also plays a role in asthma severity in patients with viral illnesses. it has been demonstrated to have a positive outcome on patients during viral infections in patients with asthma [60] . bjerregaard et al. [60] performed a study in australia with 44 virus-positive adolescent and adult patients (including rhinovirus, human coronavirus, parainfluenza virus, and human metapneumovirus) and 44 controls. the researchers found that patients with tslp expression had lower levels of sputum eosinophils, lower fractional exhaled nitric oxide, higher blood neutrophils, lower asthma control questionnaire scores, and higher fev 1 in comparison to patients with low tslp expression levels [60] . again, these types of studies are rare for examining variances in lung function and asthma development from birth to childhood. in total, four studies were found on respiratory syncytial virus (rsv) that followed children from birth to childhood for the development of asthma [10, [28] [29] [30] . two of the rsv studies showed that males from infancy to childhood have a high tendency of developing asthma after an infection, compared to females [28, 29] (see table 2 ). two out of the four studies were retrospective cohort studies and the other two were prospective cohort studies [10, [28] [29] [30] . one of the retrospective studies showed that peak time for rsv-related hospitalizations was during autumn [29] . the rsv studies showed a high risk for asthma with rsv infection and that the cytokines il-6, il-1β, and il-8 are elevated during infection, which leads to respiratory inflammation [10, 28] . kitsantas et al. [30] conducted a 6-year long study from birth to 6 years of age, examining the risk of the development of asthma by 6 years with early exposure of rsv infection during infancy. results showed that exposure to rsv did increase the risk of asthma by age 6 (or = 1.99, 95% ci (1.06-3.74)). however, children who had a parent with a history of asthma posed a higher risk for childhood asthma by age 6 (or = 3.86, 95% ci (2.61-5.71)) [30] . a maternal history of asthma has also been demonstrated by o'connor et al. [24••] to increase the likelihood of asthma in childhood by age 7 (or = 1.79, 95% ci (1.18-2.74)). similar to what was discussed about fungi, asthma patients can also be colonized by viruses. nguyen-thi-dieu et al. [63] conducted a cohort study in hanoi, vietnam, on 115 hospitalized children under the age of 15 with a diagnosis of asthma exacerbation and a control group of healthy children under the age of 15. patients underwent a clinical examination, blood analysis for a cytokine profile, pediatric asthma score (pas) for severity of asthma exacerbation, and nasopharyngeal aspirates to determine viral infection using real-time polymerase chain reaction (pcr). of the 115 children diagnosed with an asthma exacerbation, there were 18.2% with a mild pas, 37.4% with a moderate pas, and 44% with a severe pas [63] . nguyen-thi-dieu and colleagues found that 54.8% of the asthmatic children were positive for hrv [63] . the high number of asthma patients with a severe pas score (44%) was associated with a high number of children diagnosed with hrv [63] . the researchers also found that the percentage of leukocytes in asthmatic children with hrv was significantly higher, compared to children without hrv (76.2% vs. 59.6%, p < 0.05) [63] . no enterovirus longitudinal studies from birth to childhood were available, assessing asthma development; however, studies have been done in children with a diagnosis of asthma [64] . smith-norowitz et al. [64] studied patients in ireland, examining the levels of ige and igm antibodies (ab) for enterovirus 71 with a mix of 77 children and adolescents, and found that asthmatic children have higher ige ab levels, compared to non-asthmatic children, who have higher igm levels of ab (p < 0.001). the levels of enterovirus ige ab were shown to increase with age especially among the asthmatic group [64] . another study analyzed data on a 16-year longitudinal study with 36,935 children from infancy to 18 years of age in taiwan and found that children were diagnosed with asthma within 2.77 years after an enterovirus infection [16] . there was also a higher incidence of asthma associated with enterovirus infection (hr = 1.65, 95% ci (1.60-1.71), p < 0.0001) [16] . overall, the literature suggests that the rate of hospitalization due to enterovirus infection is low and does not increase asthma severity or length of hospital stay for asthma-related admissions [65, 66] . the influenza virus is a major cause of acute exacerbation of bronchial asthma (aeba); however, rhinovirus has still been shown to be the number one viral cause of asthma exacerbations [67] . yoshi et al. and other researchers have shown that obtaining the flu vaccine reduces aeba morbidity significantly when compared to individuals who are unvaccinated for the influenza virus (20.5% vs. 0%), p = 0.047 [67, 68] . influenza can worsen asthma morbidity; however, it has yet to be determined if there is a relationship pertaining to the development of asthma in association with an influenza infection [69] . recent studies have found that certain bacteria play a role in preventative effects against the development of asthma. den hollander et al. [27] performed a population-based prospective cohort study of pregnant women and their children in rotterdam, netherlands, and followed the children from pregnancy to 6 years of age for evaluation of asthma. colonization of a european child with a cytotoxin-associated protein a (caga)-negative-helicobacter pylori (h. pylori) strain at age 6 was associated with an increased prevalence of asthma overall (or = 2.11, 95% ci (1.23-3.60)) but was different for european children (or = 3.64, 95% ci (1.97-6.73)) and significantly less for non-european children (or = 0.52, 95% ci (0.14-1.89)) [11•] . there are also common bacteria within the environmental matrix that have been shown to have an effect on the development of asthma in children. teo et al. [26] found that early childhood nasopharynx (np) colonization typically involved staphylococcus or corynebacterium, which was later replaced by moraxella or alloiococcus. staphylococcus was the dominant colonizing bacteria in the early healthy np microbiomes, but its presence declined rapidly with age. these researchers found that early asymptomatic colonization with streptococcus increased the risk of developing asthma [26] . most infants were initially colonized with staphylococcus or corynebacterium before stable colonization with alloiococcus or moraxella [26] . transient incursions of streptococcus, moraxella, or haemophilus marked virus-associated acute respiratory infections (aris) [26] . o'connor et al. [24••] found supporting results in a study examining early-life exposure to environmental factors, including dust, fungal products, bacterial taxa; cockroach, mouse, and cat allergen; from infancy to 7 years of age. staphylococcus, haemophilus (pasturellaceae), several sphingomonas species members, and corynebacterium were among the taxa found in children's homes who had asthma [24••] . however, for children who did not have asthma, there was a prevalence of alloiococcus (aerobacteriaceae), kocuria (micrococcaceae), acinetobacter (moraxellaceae) species, and bifidobacterium [24••] . more research is needed to investigate the mechanism of transition of bacteria from one species to another in the infant microbiome and how this may possibly contribute to the development of asthma. in addition to the microbiome, children's genes affect how their bodies will react to their environment. like most illnesses, symptoms and severity can vary at the individual level based on unique genetic differences. carnes et al. [22] found that there is a gene-by environment interaction for cd14 variant rs2569190 (p interaction = 0.16) but not for the tlr4 variants rs4986790 and rs4986791. this research is also supported by an older study conducted by kljaic-bukvic et al. [70] , who found that there are two genetic variants related to cd14 and endotoxin signaling that are highly related with asthma exacerbation hospital admissions. for cd14 single nucleotide polymorphism (snp) rs5744455, carriers of the t-allele in children 5 to 18 years old had a decreased risk of repeated hospital asthma-related admissions, compared to homozygotes for the c-allele (or = 0.42, 95% ci (0.25-0.88), p = 0.01) [70] . c-allele carriers were at lower risk of asthmarelated hospitalizations in comparison with t-allele homozygotes (or = 0.59, 95% ci (0.38-0.90), p = 0.01) [70] . a human interleukin 4 receptor alpha chain gene (il4r) variant that results in a glutamine to arginine substitution at amino acid residue 576 (il4rα-q576r polymorphism) has previously been associated with asthma diagnosis and severity [71] . lai et al. [72] have demonstrated that there is a gene-byenvironment interaction between the il4rα-q576r polymorphism and environmental endotoxin exposure in school-aged children with asthma. higher classroom endotoxin levels were associated with fewer asthma symptoms for children with the q/q genotype (or = 0. 76 [72] . in addition to genetics, exposure to animals, especially within the farm setting, has shown to play a role in asthma. the environment of a farm is a great example of exposure to all of the microbes and microbial products discussed in this review. carnes et al. [22] found that high concentrations of endotoxin exposure at homes of people not born on a farm have a risk for the development of asthma (or = 1.67, 95% ci (1.26-2.20), p = 0.05), compared to individuals who were born on a farm (or = 1.18, 95% ci (1.02-1.37), p = 0.05). in addition, lampi et al. [12] found that people born on a farm had a higher fev 1 , compared to those not raised on a farm. the limitation here is that these participants in the lampi study could be more physically fit having to do the chores of farm work, compared to people not living on a farm. prior studies have attributed farm-specific protection from the development of asthma from endotoxin exposed in utero and during early childhood [13, 73, 74] . an older study conducted on amish and hutterite communities whom participate in farming activities has revealed two very different results [75, 76] . the amish farm children of indiana were found to have a lower prevalence of asthma and allergen sensitization (5.2% vs. 21.3% and 7.2% vs. 33.3%, respectively), compared to the hutterite farm children of south dakota [75, 76] . the difference between these two farming communities was that the amish have constant direct contact with animals to do all of their farming traditionally, and the hutterite community relies on machinery and maintains the animals in one localized area away from the community homes [75, 76] . this finding brings up a few questions. why is early farm exposure to endotoxin related to protective effects against the development of asthma and asthma symptoms; whereas, non-farm house endotoxin exposure is generally associated with asthma and asthma exacerbations? are there different microbes related to farm animals versus household pets, which are associated with increasing asthma symptoms [5, 31] ? in a different study, tischer et al. [25] examined the german lisaplus birth cohort and found that children who slept on animal fur during the first 3 months of life had higher exposure to endotoxin in their mattress, compared to children who did not sleep on fur. more importantly, the researchers found a decrease in the risk of asthma development by age 6 for children who slept on animal fur during the first 3 months of life (aor = 0.56, 95%, ci (0.31-1.01). in addition, for tnf-α, il-2, and il-4 producing t cells, there were no significant changes found in blood levels associated with sleeping on animal fur the first 3 months of life [25] . this review has shed light on several different findings within the literature. based on the information provided, sensitization within the non-farming community for bacterial, fungal, and viral products increases with ige ab expression and over time with age [43, 64, 77] . in terms of the fungal species, aspergillus fumigatus has shown to induce one of the highest sensitizations for moderate/severe asthma [54, 78] . in addition, human colonization of the genera cladosporium, alternaria, and penicillium have been associated with severe asthma and their ambient environmental concentration is similarly proportional in various parts of the world [41, 45, 53, [56] [57] [58] . for viruses, rhinovirus has been shown to be one of the most common triggers of a viral source for an asthma exacerbation [9, 11•, 15, 63, 79, 80] . early exposure to endotoxin at a young age within the farm setting with direct animal contact may reduce the chances of developing asthma later in life [12, 22, 75, 76] . for children not living on a farm, growing up with a cat or dog may have a protective effect against asthma symptoms [8•, 24••] . the mechanism of this effect is yet to be understood and it appears that genetics plays a role in asthma severity especially among ethnic minorities [72] . further research is needed to investigate the difference in microbes between farm animals and household pets and how early exposure effects the human microbiome and the immune system's response to inflammatory triggers. in addition, since studies have shown that people with severe asthma may be colonized with various genus of fungi, it would be worthwhile to further investigate the treatment of moderate/severe asthmatics colonized with fungi with other methods not associated with toxic side effects related to current medications for anti-fungals. in addition, more studies are needed examining the mechanism(s) for the transition of bacteria in the microbiome during childhood and how this may effect asthma outcomes. biomarkers such as dimethylamine, a metabolite produced by bacteria within the gastrointestinal tract, may pose a clue as it has been demonstrated to decrease in concentration from higher to lower levels with the development of asthma in children [81] . further advances are also being made with dupilumab, a monoclonal antibody that blocks a common receptor for interleukin-4 (il-4) and interleukin-13 (il-13), involved in type 2 inflammation [82] . in adult patients with atopic asthma, it has been shown to reduce severe asthma exacerbations [82] . this medication has recently been approved for children 12 years old and up for the treatment of severe asthma [83] . continued exploration of the human microbiome and its interaction with the environment hopefully may lead to more discoveries. all reported studies/experiments with human subjects performed by the authors have been previously published and compiled with all applicable ethical standards (including the helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines). the authors declare no conflicts of interest relevant to this manuscript. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. most recent national asthma data the economic burden of asthma in the united states airway microbiota in severe asthma and relationship to asthma severity and phenotypes endotoxin exposure: predictors and prevalence of associated asthma outcomes in the united states characteristics of severe asthma with fungal sensitization harrison's principles of internal medicine ,3)-β-d-glucan, and lps on each cohort from different geographical regions for the development of asthma in children from birth to age 6 [8]. it has been demonstrated that the climate and geographical region can affect asthma outcomes [14, 25]; and this was observed as high endotoxin levels were associated with asthma at age 6 for the piama cohort (dutch); an inverse relationship with the inma cohort (spanish), and no association with the lisaplus cohort (german). also, other studies have shown that early constant animal exposure reduces the risk of asthma early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence association between respiratory infections in early life and later asthma is independent of virus type previous studies have demonstrated that early infant exposure to human rhinovirus (hrv) is associated with triggering asthma attacks this study demonstrated that early childhood exposure to rhinovirus significantly increased the risk for the development asthma, and found clinical markers that could be used to predict the development of atopic and non-atopic asthma in children [11]. this study was different from previous studies farm environment during infancy and lung function at the age of 31: a prospective birth cohort study in finland exposure to farming in early life and development of asthma and allergy: a cross-sectional survey association of airborne particles, protein, and endotoxin with emergency department visits for asthma in kyoto epidemiological analysis and follow-up of human rhinovirus infection in children with asthma exacerbation association between enterovirus infection and asthma in children: a 16-year nationwide population-based cohort study ev-d68 infection in children with asthma exacerbation and pneumonia in mexico city during 2014 autumn. influenza other respir viruses high fractional exhaled nitric oxide and sputum eosinophils are associated with an increased risk of future virus-induced exacerbations: a prospective cohort study the indoor environment and inner-city childhood asthma environmental exposure to endotoxin and its health outcomes: a systematic review house dust endotoxin levels are associated with adult asthma in a u.s. farming population endotoxin tolerance: new mechanisms, molecules and clinical significance this study not only demonstrated this concept, following patients from birth to 7 years of age, but also found that the bacterial species kocuria, bifidobacterium, alloiococcus, and acinobacter are found in the home of children without asthma furthermore, a previous study has demonstrated that the microbiome of infants' nasopharynx is initially colonized with alloiococcus when healthy and declines with acute respiratory infections and the development of asthma thus, this study shows key bacteria may have the potential to suppress or trigger the development of asthma from early childhood exposure sleeping on animal fur is related to asthma outcomes in later childhood the infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development helicobacter pylori in children with asthmatic conditions at school age, and their mothers predictors of asthma following severe respiratory syncytial virus (rsv) bronchiolitis in early childhood association between respiratory syncytial viral disease and the subsequent risk of the first episode of severe asthma in different subgroups of high-risk australian children: a whole-ofpopulation-based cohort study effects of respiratory syncytial virus infection in infancy on asthma and respiratory allergy in 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chest dis rhinoviruses significantly affect day-to-day respiratory symptoms of children with asthma absence of back to school peaks in human rhinovirus detections and respiratory symptoms in a cohort of children with asthma longitudinal urinary metabolomic profiling reveals metabolites for asthma development in early childhood dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma targeted therapy for severe asthma in children and adolescents: current and future perspectives publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-304437-ezqghyid authors: palmieri, tina l. title: children are not little adults: blood transfusion in children with burn injury date: 2017-08-15 journal: burns trauma doi: 10.1186/s41038-017-0090-z sha: doc_id: 304437 cord_uid: ezqghyid blood transfusion in burns larger than 20% total body surface area (tbsa) are frequent due to operative procedures, blood sampling, and physiologic response to burn injury. optimizing the use of blood transfusions requires an understanding of the physiology of burn injury, the risks and benefits of blood transfusion, and the indications for transfusion. age also plays a role in determining blood transfusion requirements. children in particular have a different physiology than adults, which needs to be considered prior to transfusing blood and blood products. this article describes the physiologic differences between children and adults in general and after burn injury and describes how these differences impact blood transfusion practices in children. children and adults have different physiologic and hematologic systems, which impacts therapeutic interventions and their efficacy. in addition, children of different ages have different physiology and anatomy, which further complicates treatment. for example, an infant has a higher metabolic rate than an 8-year-old, a larger body surface area to mass ratio, and a markedly smaller blood volume. hence, different strategies need to be employed when treating children of different ages. these differences are accentuated in burn injury, which further alters metabolism, anatomy, and physiology. understanding the differences among children of different age groups is essential to optimize the use of blood transfusion in children. this article will discuss how differences in the physiologic, hematologic, metabolic, and immunologic systems in burned children impact blood transfusion requirements. although this article describes how children differ from adults in terms of factors with impact on blood transfusion, the unique primary aim of this article is to understand how burned children are impacted by blood transfusion and describe optimal transfusion practices in burned children (table 1) . children and adults have differences in hematologic and physiologic characteristics children clearly have a smaller stature than adults, yet their requirements may actually exceed those for adults on a kilo per kilo basis. for example, young children have a greater body surface area per mass than an adult, and the distribution of that mass is different than in adults. this impacts burn size determination, intravenous fluid requirements, and blood transfusion requirements. even the most essential body systems are impacted by the differences between children and adults. heart rate measurement is simple, yet there are important differences between children and adults that should be considered when instituting burn treatment. the baseline heart rate in a child is higher than that in an adult and varies with age [1] . burned children have a higher cardiac output and heart rate than unburned children, which can predispose them to heart failure. cardiac function also differs with age. as a baseline, a newborn child's myocardium is at near maximum function; hence, the newborn may not be able to compensate for decreased oxygen carrying capacity by increasing cardiac output after injury [2] . in other words, an infant increases heart rate rather than contractility to increase cardiac output. in the burned child, whose hypermetabolic rate adds further demand to an already stressed system, tachycardia is increased. hence, burned infants are at particular risk for heart failure after injury. beta blockade will be problematic, as lowering the heart rate will also lower cardiac output. finally, myocardial ischemia could occur due to decreased oxygen delivery capacity in the newborn or very young infant, which may in part contribute to the increased mortality of burned children less than 2 years. a second difference between adults and children is in blood volume. a child's mean blood volume approximates 70 ml/kg, which exceeds adult blood volume/ weight calculation. this increased blood volume/unit mass impacts a variety of body functions. as indicated above, oxygen consumption in children is higher; in addition, cardiac output to blood volume ratio is also higher in children than in adults [3, 4] . normal hemoglobin levels in children are agedependent and also differ from adults. children are born with a hemoglobin level approximating 19 g/dl and have a nadir of 11.2 g/dl at approximately 2-3 months of age. eventually, a child's hemoglobin stabilizes at approximately 13 g/dl [5] . in infants, fetal hemoglobin can play a role in oxygen delivery, thus decreasing the efficacy of the at-birth oxygen delivery. at birth, fetal hemoglobin constitutes 70% of the child's hemoglobin. at 6 months of age, however, only a trace of fetal hemoglobin remains [6, 7] . in fetal hemoglobin, red blood cell life span is decreased by 30 days (from 120 to 90), causing the oxygen-hemoglobin dissociation curve to be shifted to the left, which may impact tissue ischemia in the face of inadequate erythropoiesis. clearly, the presence of fetal hemoglobin should be considered in children less than 1-2 months of age who sustain burn injury, as younger infants (<6 months) thus have lower oxygen carrying capacity. this is exacerbated by a decreased production of erythropoietin in response to hypoxia or anemia in critically ill infants with sepsis or polytrauma [8] . burned children clearly fall into this category. children who sustain severe burns at birth or shortly after birth due to bathing rituals are at particular risk. the higher blood transfusion/unit volume ratio in children increases their risk for metabolic perturbation with blood transfusion. both the red blood cells themselves and the substances used to help preserve red blood cells contribute to these effects. risks related to transfusion include hyperkalemia, hypomagnesemia, hypothermia, acidosis, and hypothermia. hyperkalemia associated with blood transfusion poses a significant risk in children, and potassium levels should be monitored in children receiving >20 ml/kg transfusion volume (or lower if the patient has renal dysfunction or hyperkalemia at the onset of transfusion). hyperkalemia has been associated with cardiac arrest during large blood volume transfusions intraoperatively in children and infants receiving exchange transfusions [9, 10] . children with small blood volumes are at particularly high risk of hyperkalemia due to both volume/ size considerations and the developing renal function of infants and small children. potassium levels differ among blood products. whole blood, irradiated units, and units nearing the expiration date (i.e., "old blood") contain the largest amounts of potassium [11, 12] . practices that decrease hyperkalemic cardiac arrest risk include using "young" blood (packed red blood cell (prbc) <7 days in age), washing erythrocytes prior to transfusion, and avoiding whole blood transfusion in small infants. the life-threatening arrhythmias associated with rapid large volume can be ameliorated by administering calcium [9, 12] . administration of calcium treats hyperkalemic arrhythmias by opposing the effects of hyperkalemia on the heart's electrical conduction system. additional measures, such as intravenous glucose, insulin, albuterol, and kayexelate, may be needed to resolve the hyperkalemia. in addition to ameliorating hyperkalemia, ionized calcium is an important cofactor in infant coagulation and myocardial contractility [13] . citrate, used in blood storage to prevent clotting, prevents clot formation by chelating calcium. as such, transfusion may induce hypocalcemia. the type of blood product transfused, the rate of the transfusion, and the patient hepatic function all influence the extent of hypocalcemia [5, 14] . whole blood and fresh frozen plasma (ffp) contain the highest concentration of citrate/unit volume of product; hence, they have the highest hypocalcemia risk. hypocalcemia has been reported after the transfusion of ffp [15] . the neonate is at a particular risk of cardiac dysfunction with hypocalcemia due to the relative lack of neonatal cardiac sarcoplasmic reticulum. this reduction makes the table 1 summary of transfusion considerations in burned children 1 . despite a smaller stature, burned children have a greater body surface area per mass than adults. 2. cardiac function, mean blood volume, and normal hemoglobin levels are age-dependent in children; hence, children have a higher blood transfusion/unit volume ratio. 3. the optimal hemoglobin threshold for initiating a blood transfusion in burned children has not yet been defined. 4. hyperkalemia associated with blood transfusion poses a significant risk in children, and potassium levels should be monitored in children receiving >20 ml/kg transfusion volume. 5. the maximal allowable blood loss (mabl), i.e., the volume of blood that can be lost in an operation without transfusing blood, can be calculated from the following (hct = hematocrit, ebv = estimated blood volume): mabl = [(hct start − hct target )/hct start ] × ebv. neonate myocardium dependent on ionized calcium for both normal contraction and relaxation. transfusing blood at a rate of less than 1 ml/kg/min may ameliorate the hypocalcemic effect of the blood. correction of hypocalcemia can be accomplished with administration of either calcium chloride (5-10 mg/ kg) or calcium gluconate (15-30 mg/kg) intravenously. in general, the dose of calcium gluconate required to achieve the same effect is three times that of calcium chloride. because calcium may result in clot formation when in contact with blood, calcium should never be administered in a blood line. magnesium, which is often altered in association with calcium, must also be considered. hypomagnesemia may also occur after massive transfusion, and if a patient is hypocalcemic, magnesium levels should be obtained. magnesium stabilizes resting membrane potential; hence, hypomagnesemia may cause lifethreatening arrhythmias. if ventricular fibrillation or ventricular tachycardia develops after transfusion and does not respond to calcium administration, intravenous magnesium sulfate, in a dose of 25-50 mg/ kg, may be helpful. environmental issues also impact transfusion effects. hypothermia in burned children, in particular, requires special consideration. children, due to their large surface area to volume ratio, are at increased risk for hypothermia. not only do children with burn injury lose skin integrity, and hence the key temperature regulating mechanism, they also actively lose heat through convection and conduction through wet wounds and exposed tissue. hypothermia will increase oxygen consumption and exacerbate coagulopathy and is associated with increased mortality [16, 17] . hypothermia may be exacerbated during periods of rapid transfusion utilizing cold blood products, especially during episodes of massive transfusion in the operating theater. hypothermia may be ameliorated using several different methods, including the use of blood warmers during transfusion, increased ambient room temperature, external warming devices, and potentially warming central venous catheters. hypothermia frequently accompanies another significant complication of transfusion in children: acidosis. hypovolemia in the operating room during massive excision is of particular concern with respect to the development of acidosis. as such, life-threatening acidosis may occur during rapid transfusion for massive blood loss in a hypovolemic patient. because stored blood cells continue to metabolize, lactic acid increases in stored blood, making acidosis more likely. it is also notable that metabolic alkalosis may occur several days after massive transfusion from the metabolism of the citrate in the blood products administered. although transmission of infectious diseases due to blood transfusion has decreased over time, the transmission of infectious diseases remains an important problem in children requiring blood transfusion [2] . parents, understandably, are worried about hepatitis and human immunodeficiency virus from blood transfusion. blood products in different countries differ in the frequency of transmission of infectious organisms. current blood screening tests include hepatitis b surface and core antigen, hepatitis c virus antibody, hiv-1 and hiv-2 antibody, htlv-i and htlv-ii antibody, nucleic acid amplification testing for hiv-1 and hcv, syphilis, and west nile virus [18] . in addition to these commonly measured viral infections, bacteria can also infect blood products. the incidence of bacterial contamination is highest for platelets [19] [20] [21] . other potential infections that could be transmitted via transfusion that are not tested for include htlv, west nile virus, babesiosis, chagas disease, lyme disease, malaria, creutzfeldt-jakob disease, and severe acute respiratory syndrome (sars). screening for zika and ebola virus has recently been released by the food and drug administration [22] . hemolytic transfusion reactions continue to occur despite the careful application of compatibility testing. blood mismatch transfusions is due primarily to clerical error. particularly important is the verification of blood products prior to transfusion by physician and nurse with the patient's identification to make sure that the unit is truly intended for that patient. this simple, inexpensive procedure can prevent a life-threatening transfusion reaction. strict adherence to transfusion protocols is important to avoid this iatrogenic complication. acute hemolytic reactions generally occur due to abo incompatibility and causes immunologic destruction of red cells. however, this complication can also occur due to minor antigens not detected by current screening techniques [23, 24] . anaphylactic reactions rarely occur. transfusion-related graft-versus-host reaction, in which the lymphocytes in the transfused blood cause host cell destruction, occurs primarily in immunocompromised patients and has been reported in neonates and immunocompromised children [25] [26] [27] [28] . this condition occurs primarily in premature infants or children with rapid acute blood loss, cardiopulmonary bypass, cancer, or severe systemic illness [29] . burned children are immunosuppressed and require massive transfusions in the operating room, thus putting them at risk for this complication. transfusion-related graft-versus-host disease can be reduced by using irradiated units, which effectively decrease the lymphocyte count. however, since irradiated blood has a higher potassium content than nonradiated blood, potassium levels must be monitored closely. the child's blood volume varies with age and weight; hence, the amount of blood required in times of acute blood loss varies markedly among children of different ages. the highest blood volume per unit weight is for a premature infant (90-100 ml/kg), while the lowest is for a very obese child (65 ml/kg). a term infant has an 80-90 ml/kg blood volume until age of 3 months, after which the total blood volume drops to 70 ml/kg [2] . the difference in total blood volume in an infant compared to that in an adult is an important consideration in determining how much blood to transfuse in a child. as such, formulas have been developed to guide clinicians during massive blood loss (blood loss greater than 1 blood volume) in a child without preexisting anemia. the blood loss at which transfusion should be considered in a child (or an adult) without preexisting anemia (maximal allowable blood loss (mabl)) can be estimated from the following formula [30] : theoretically, blood loss amounting to the mabl can be replenished by crystalloid or colloid, with blood transfusion reserved for higher blood losses. in general, the hematocrit in prbc approaches 70%; hence, approximately 0.5 ml of packed rbcs should be transfused for each milliliter of blood loss beyond the mabl. although this formula provides a framework for blood transfusion, it is merely an estimate. ultimately, blood transfusion requires careful consideration of patient condition, local resources, and severity of illness. a burned child poses a particular challenge, due to the increased red cell destruction and decreased red cell production that accompanies major burn injury. surgical excision of the burn wound results in major blood loss; a child loses 5% of a blood volume per percent face burn excised and 2% of a blood volume per percent burn excised on other areas [31] . thus, an infant having burn excision of the entire head could potentially lose 90% of total blood volume (body surface area of the head of 18 percent × 5 percent blood volume lost per percent excision of the head). sufficient units of blood products should be ready prior to the onset of surgery. the optimal transfusion threshold for critically ill children has been evaluated in a multicenter trial in pediatric intensive care units [32] . this study reported that a restrictive transfusion strategy, which transfused at a hemoglobin <7 g/dl, had mortality and outcomes comparable to a liberal strategy (maintain hemoglobin >10 g/dl). this study evaluated stable, critically ill children without acute blood loss; hence, its applicability to burn patients is limited. a recently completed randomized prospective trial in adult burn patients with burn size >20% tbsa demonstrated no outcome difference between different transfusion strategies (palmieri, in press). massive blood transfusion may result in the lethal triad: hypothermia, acidosis, and coagulopathy. hypothermia in the operating room, as discussed above, is more prevalent in the infant due to the larger surface area per unit mass. hypothermia is further exacerbated by exposure to the cold operating room suite and anesthetic agents which decrease shivering. acidosis due to hypovolemia and hypothermia develops if patients are under-resuscitated. coagulopathy, the final link in the triad, occurs during massive blood transfusion as a result of depletion of clotting factors. currently, prbcs are the predominant form of red cell transfusion. since 80% of coagulation factors are separated from prbcs during processing, clotting factor deficiency generally occurs at approximately 1 blood volume [33] . however, if whole blood is used, all clotting factors except for labile factors v and viii will be transfused at normal levels. thus, coagulation abnormalities tend to occur later (>3 blood volumes) when using whole blood [34] . however, whole blood carries substantial risks as well, including hyperkalemia, transfusion reactions, and transfusion-related circulatory overload. thrombocytopenia may be caused by dilution of platelets during transfusion. in general, a patient will lose 40% of the starting platelet count in the first blood volume loss, with loss of an additional 20% of the starting count at a second blood volume [33] . it is thus important to record the platelet count prior to an anticipated massive blood loss, such as happens with major burn excision. a child with sepsis and a low starting platelet count is far more likely to require platelet transfusion than a child with a high or normal platelet count. the optimal ratio of fresh frozen plasma to packed red blood cells in massive bleeding associated with extensive surgical burn excision has not been definitively defined; however, a prospective trial in burned children suggests that a 1:1 ffp/prbc strategy may improve outcomes. the use of prbc and other transfusion products also predisposes patients to other potential complications, including transfusion-related immunomodulation (trim), transfusion-related acute lung injury (trali), and transfusion-related circulatory overload (taco). as blood is stored, it releases a variety of agents, including toxic oxygen radicals, cytokines, soluble hla class i antigens, histamine, plasminogen activator inhibitor-1, and leukocyte elastase [35] . older blood may increase infection risk in multiple different patient populations [36] . blood transfusion in general impact the immune system by increasing suppressor t lymphocyte and natural killer cell function, depressing monocyte and macrophage phagocytic activity, inducing immune cell anergy and clonal deletion, decreasing macrophage antigen presentation, suppressing lymphocyte blastogenesis, decreasing delayed-type hypersensitivity, and suppressing mitogen-stimulated human t cell proliferation [37] . trim involves both immune activation (such as transfusion reactions, trali, alloimmunization, autoimmune diseases, and transfusion-associated graft-versus-host disease) as well as immune tolerance and immunosuppression (infection, cancer recurrence, microchimerism, enhanced allograft survival). trali, first described in 1983, is characterized by respiratory distress, hypoxemia, pulmonary edema, hypotension, and fever after receiving blood transfusion. a recent study in canada estimated that the incidence of trali in children is 1.8/100,000 population, much less than in adults [38] . the incidence of trali in burn injury is unknown. taco consists of pulmonary edema that develops within 6 h of transfusion due to increases in hydrostatic pressure. the incidence of taco is <11% in adults and carries a 5-15% mortality [39] . the incidence of taco in burned children and adults has not been determined. multiple strategies can be employed to decrease the immunologic and storage-related impact of blood. the first strategy is to decrease the amount of blood lost due to testing and surgery. for example, reducing volume and frequency of blood draws, adopting a restrictive transfusion policy, and utilizing tourniquets and tumescence during surgical burn excision will all decrease the volume of blood removed from the patient. the second strategy is to minimize the volume of blood administered. this entails using leukoreduced blood, transfusing blood one unit at a time, and investigating alternatives to transfusion. the fewer units of blood the patient receives, the less likely the patient is to have a transfusionrelated complication. children, due to their age-dependent physiology, alterations in body mass ratio, and immature cardiac and immunological status, have variable and complex transfusion needs after burn injury. optimizing the treatment of burn-injured children requires knowledge of these issues and careful consideration of the impact of transfusion on patient outcomes. fastidious attention to the sometimes subtle differences between children and adults is needed to optimize blood utilization in children with major burn injury. normal ranges of heart rate and respiratory rate in children from birth to 18 years: a systematic review of observational studies intraoperative pediatric blood transfusion therapy: a review of common issues the gaseous metabolism of the newborn infant breathing 15% oxygen oxygen consumption in normal newborn infants during moderate hypoxia in warm and cool environments pediatric resuscitation in the operating room physiologic anemia of infancy: normal red-cell values and physiology of neonatal erythropoiesis nathan and oski's hematology of infancy and childhood blunted erythropoietic response to anemia in multiply traumatized patients hyperkalaemia during rapid blood tansfusion and hypovolaemic cardiac arrest in children hyperkalemia following exchange transfusion hyperkamemia after irradiated blood tansfusion hyperkalemia after irradiation of packed red blood cells: possible effects with intravascular fetal transfusion anesthesia for pediatric orthotopic liver transplantation ionized hypocalcemia after fresh frozen plasma administration to thermally injured children: effects of infusion rate, duration, and treatment with calcium chloride functional equivalence of hypothermia to specific clotting factor deficiencies hypothermia in trauma victims: an ominous predictor of survival bacterial contamination of blood components cost-effectiveness of transfusion of platelet components prepared with pathogen inactivation treatment in the united states apheresis platelets: emerging issues related to donor platelet count, apheresis platelet yield, and platelet transfusion dose revised recommendations for reducing the risk of zika virus transmission by blood and blood components unexpected red blood cell antibody distributions in chinese people by a systematic literature review the kidd (jk) blood graoup system transfusion practices in infants receiving assisted ventilation dna polymorphism analysis in transfusion-associated graft-versus-host disease transfusion-associated graft versus host disease (tagvhd)-with reference to neonatal period nonlethal, attenuated, transfusionassociated graft-versus-host disease in an immunocompromised child: case report and review of the literature changes in lymphocyte subpopulations as a result of cardiopulmonary bypass. the effect of blood transfusion intraoperative pediatric blood transfusion therapy: a review of common issues. part ii: transfusion therapy, special considerations, and reduction of allogenic blood transfusions a prospective study of blood loss with excisional therapy in pediatric burn patients transfusion strategies for patients in pediatric intensive care units changes in serial platelet counts following massive blood transfusion in pediatric patients complications of massive blood transfusions red cell changes during storage addressing the question of the effect of rbc storage on clinical outcomes: the red cell storage duration study (recess) duration of red cell storage influences mortality after trauma transfusion-related acute lung injury in the canadian paediatric population incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients none. the authors received no funding for this work.availability of data and materials not applicable. ethics approval and consent to participate not applicable. not applicable. the author declares that she has no competing interests. submit your next manuscript to biomed central and we will help you at every step: key: cord-298807-67psjrt3 authors: morris, peter s.; leach, amanda j. title: acute and chronic otitis media date: 2009-12-31 journal: pediatric clinics of north america doi: 10.1016/j.pcl.2009.09.007 sha: doc_id: 298807 cord_uid: 67psjrt3 otitis media (om) is a common illness in young children. om has historically been associated with frequent and severe complications. nowadays it is usually a mild condition that often resolves without treatment. for most children, progression to tympanic membrane perforation and chronic suppurative om is unusual (low-risk populations); this has led to reevaluation of many interventions that were used routinely in the past. evidence from a large number of randomized controlled trials can help when discussing treatment options with families. indigenous children in the united states, canada, northern europe, australia, and new zealand experience more om than other children. in some places, indigenous children continue to suffer from the most severe forms of the disease. communities with more than 4% of the children affected by chronic tympanic membrane perforation have a major public health problem (high-risk populations). higher rates of invasive pneumococcal disease, pneumonia, and chronic suppurative lung disease (including bronchiectasis) are also seen. these children will often benefit from effective treatment of persistent (or recurrent) bacterial infection. peter s. morris, mbbs, fracp, phd a,b,c, *, amanda j. leach, phd a,b upper respiratory tract infections (including otitis media) are the most common illnesses affecting children. 1 the term ''otitis media'' (om) covers a wide spectrum of disease, and is used to describe illnesses with predominantly middle ear symptoms (including acute otitis media, otitis media with effusion, and chronic suppurative otitis media). children can expect to experience around 6 to 8 upper respiratory infections (urtis) each year. 2 nearly all children will experience at least one episode of om during childhood. on average, they experience around one episode of acute otitis media (aom) per year in the first 3 years of life. 3 the initial cause of respiratory mucosal infections (including om) is most commonly a viral infection but can be bacterial ( table 1) . 4 of importance is that many infections involve both viruses and bacteria. 5 most commonly, an initial viral infection is complicated by a secondary bacterial infection. in developed countries, both viral and bacterial infections are likely to be self-limited. persistent symptomatic disease is an indication that the child has an ongoing bacterial infection. by understanding the evidence available from high quality studies, the clinician is in a position to advise the families on appropriate action. 6 well designed randomized controlled trials (rcts) provide the most reliable evidence of effect ( table 2) . 7 the aim of this article is to support clinicians in answering the following questions: (i) what happens to children with these conditions when no additional treatment is provided? (ii) which interventions have been assessed in well-designed studies? (iii) which interventions have been shown to improve outcomes? (iv) if an intervention is considered appropriate, how large is the overall benefit? there is a long list of potential interventions for the different forms of om. many families have strong personal preferences about their treatment options. the challenge for the clinician is to make an accurate diagnosis and then to match the effective treatment options to the preferences of the family. in this article, the authors have initially considered the effects of an intervention compared with no intervention. their focus on trial evidence means that the authors may not review all the relevant information to an individual decision. the overall effects of an intervention may need to be adjusted with this in mind. it is hoped that clinicians using this article should be able to determine which interventions have been rigorously assessed and the overall findings of these assessments. the grade working group has described the steps required to review evidence. [8] [9] [10] the grade working group proposes that a recommendation should indicate a decision that the majority of well-informed individuals would make. for self-limited conditions with low risk of complications, even well-informed individuals may reach different conclusions. therefore, the authors have tried to provide an evidence summary that will assist discussions with families ( table 3) . the authors' own approach (informed by the best available evidence) is described in box 1. the self-limiting nature of modern om in developed countries is of the utmost importance in determining which treatments are indicated. in this article, groups of children with low rates of suppurative complications of om are categorized as low-risk populations. communities where more than 4% of children experience chronic tympanic membrane perforation secondary to suppurative infection are high-risk populations. 35 in low-risk populations, om is generally a condition that resolves without treatment or complications. unfortunately, tympanic membrane perforation remains a common occurrence for many indigenous groups. the outcomes considered important in this article are: (i) persistent disease (short term %14 days, medium term >2 weeks to 6 months, long term >6 months); (ii) time to cure; and (iii) complications arising from progressive disease. the authors considered interventions to have very large effects if they were associated with a relative reduction in the outcome of interest of more than 80%; large effects were associated with a reduction in outcome of at least 50%. 36 reductions of between 20% and 50% were considered modest and reductions less than 20% were considered slight (or small). because only a proportion of children with om experience bad outcomes, even large relative effects may have modest absolute benefits. the search targeted evidence-based guidelines, evidence-based summaries, systematic reviews, and rcts of interventions for otitis media (see box 2) . this simple strategy identified over 1600 hits using pubmed alone. to be included as an evidence-based guideline, summary, or systematic review, one needed to provide an explicit search strategy and criteria for study inclusion. to be included as a clinical trial, randomization needed to be used. four primary sources to identify relevant information were used: clinical evidence (issue 1 2009), 36 the cochrane library (issue 2 2009), 37 evidence-based otitis media 27 and medline (last accessed via pubmed on 26 june, 2009). the evidence-based summaries in clinical evidence have links to major guidelines and use the grade working group approach to assess quality of evidence and strength of recommendations. 36 pubmed was also searched to identify publications specifically addressing om in indigenous populations. the search identified over 50 evidence-based guidelines, evidence summaries, and systematic reviews (and many more additional rcts) published since 2000. in this the impact of the conjugate pneumococcal vaccine on om in navajo and apache children. 43 although they were not identified by a search strategy, the authors were also aware of an additional systematic review and evidence-based clinical guidelines developed specifically to assist in the care of australian aboriginal children with om. 44, 45 otitis media (om) is an acute upper respiratory tract infection that affects the respiratory mucosa of the middle ear cleft. om is a common illness in young children (and occurs much less frequently in children >6 years). 24, 46 in developed countries, om is the commonest indication for antibiotic prescribing and surgery in young children. in the united states, annual costs were estimated to be $3 to $5 billion in the 1990s. 46 the costs per capita are likely to be considerably greater in high-risk populations. otitis media is best regarded as a spectrum of disease. the most important conditions are ome, acute otitis media without perforation (aomwop), acute otitis media with perforation (aomwip), and csom. ome is usually the mildest form of the disease and csom the most severe. children who end up with csom usually progress through the stages of ome, aom without perforation, aom with perforation, and finally to csom. unfortunately, there is currently a lack of consistency in definitions of different forms of om (especially aom). 47 this can lead to confusion when you need to describe the progress of a child over time. ome is usually defined as the presence of a middle ear effusion without symptoms or signs of an acute infection. ome is by far the most common form of om in all populations. brief periods of ome (often in association with upper respiratory tract infections) should be regarded as a normal phenomenon in early childhood. aom is usually defined as the presence of a middle ear effusion plus the presence of the symptoms (especially pain) or signs (especially bulging of the tympanic membrane or fresh discharge). the diagnostic criteria used in studies of aom vary. some use symptomatic criteria, some use otoscopic criteria, and some require both symptomatic and otoscopic criteria to be met. csom is usually defined as discharge through a perforated tympanic membrane for greater than 2 to 6 weeks. if the duration of the discharge is uncertain, perforations box 2 a simple pubmed search strategy to identify evidence-based guidelines, evidence-based summaries, systematic reviews, and rcts on otitis media and additional studies involving indigenous children that are easily visible (covering >2% of the tympanic membrane) are more likely to be associated with csom. children with immunodeficiency or craniofacial abnormalities (cleft palate, down syndrome, and so forth) are at increased risk of om. other risk factors that have been identified in epidemiologic studies include recent respiratory infection, family history, siblings, child care attendance, lack of breast feeding, passive smoke exposure, and use of a pacifier. 48 high rates of severe otitis media have been described in indigenous children for over 40 years. the first publication identified by the authors' search was published in 1960, 49 and publications have appeared regularly from 1965 on. 50 in the recent past, indigenous children from the united states, canada, northern europe, australia, and new zealand have all been affected. [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] the rates of tympanic membrane perforation in these populations remain among the highest ever described in the medical literature. 61 many investigators have puzzled over the high rates of severe disease and wondered whether ear discharge was a new illness that occurred during the transition from a nomadic lifestyle typical of many of these indigenous groups. the search reported here did not identify any studies that were able to answer this question. the rates of tympanic membrane perforation vary enormously, even with indigenous groups within the same region. furthermore, discharging ears as described in indigenous children (''the running ear are the heritage of the poor'') 62 were common in disadvantaged children living in developed countries in the pre-antibiotic era. 63 for these reasons, the authors believe the most important underlying causes of severe ear infections are likely to be environmental. indigenous populations at high risk of severe om also have high rates of rhinosinusitis, bronchitis, pneumonia, invasive pneumococcal disease, and chronic suppurative lung disease (including bronchiectasis). [64] [65] [66] [67] [68] [69] [70] [71] it is likely that the same risk factors contribute to the excessive frequency of all of these conditions. early exposure to otitis media pathogens has been demonstrated in australian aboriginal infants, and this is the most important determinant of subsequent om (fig. 1) . [72] [73] [74] of importance is that in this high-risk population, children usually have multiple pathogens (and often multiple types of each pathogen) and their total bacterial load is high. international comparisons show that a similar early onset of carriage of the pneumococcus is seen in other populations with high rates of invasive pneumococcal disease (fig. 2) . 75 although genetic factors are known to contribute to the risk of om, their importance in high-risk populations has not been determined. some investigators have proposed that genetic susceptibility is linked to poor eustachian tube function. 52 however, this does not explain the associated high rates of other bacterial respiratory infection. children with om will usually present with features related to either: (i) pain and fever (aom); (ii) hearing loss (ome); or (iii) ear discharge (aom with perforation or csom). in some children, om will be detected as part of a routine examination. making an accurate diagnosis is not easy. in general it requires a good view of the whole tympanic membrane, and the use of either pneumatic otoscopy or tympanometry (to confirm the presence of a middle ear effusion). 47, 76 studies of diagnostic accuracy in aom have found ear pain to be the most useful symptom (but not very reliable on it is own). presence of bulging, opacity, and immobility of the tympanic membrane are all highly predictive of aom. normal (pearly gray) color of the tympanic membrane makes aom unlikely. 77 the commonest form of om is ome. the point prevalence in screening studies is around 20% in young children. 46 ome can occur spontaneously, as part of rhinosinusitis, or following an episode of aom. the same respiratory bacterial pathogens associated with aom have been implicated in the pathogenesis. most children with ome will improve spontaneously within 3 months, and complications from this illness are uncommon. 46 the average hearing loss associated with ome is around 25 db. 46 despite large numbers of studies, a causal relationship between ome and speech and language delay has not been proven. 27, 78 most children will experience at least one episode of aom. 46 the peak incidence of infection occurs between 6 and 12 months. although the pathogenesis of aom is multifactorial, both viruses and bacteria are implicated. 46 bacterial infection with the common respiratory pathogens (streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis) is often preceded by a viral infection. viruses (especially respiratory syncytial virus and influenza) can cause aom without coinfection with bacteria. 46 the pain associated with aom resolves within 24 hours in around 60% and within 3 days in around 80%. 24 young children with aom (<2 years) are less likely to experience spontaneous resolution. 22 complications of aom include csom, mastoiditis, labyrinthitis, facial palsy, meningitis, intracranial abscess, and lateral sinus thrombosis. 27 mastoiditis was the most common life-threatening complication in the pre-antibiotic era. mastoiditis occurred in 18% of children admitted to hospital with aom in one study. 23 mastoiditis (and all other complications) is now rare in developed countries. csom is the most severe form of om. 79 although there is a lack of well-designed longitudinal studies, csom is the type of om most likely to persist without treatment. in developing countries, csom occurs as a complication of aom with perforation and can be a major health issue. the range of bacterial pathogens associated with csom is considerably broader than those seen in aom. pseudomonas, staphylococcus, proteus, and klebsiella species are most commonly isolated, and mixed infections are common. 79 multidrug antibiotic resistance is often seen in pseudomonas infections. the associated hearing loss is usually more than that seen in ome (and csom represents the most important cause of moderate conductive hearing loss [>40db] in many developing countries). 31 in developed countries, csom is now very uncommon. a recent risk factor study in the netherlands found that most cases of csom are now occurring as a complication of tympanostomy tubes insertion. 80 children with immunodeficiency and some indigenous populations are also at greatly increased risk. in rural and remote communities in northern australia, more than 20% of young children are affected. 71 ome affects all children but is usually asymptomatic. 46 a small proportion of children have persistent ome with associated hearing loss. there is evidence on the effects of screening to identify young children with ome (or hearing loss associated with ome), and this is not effective in developed countries. 81 there is also evidence on treatment effects of antibiotics, insertion of tympanostomy tubes, autoinflation devices, antihistamines and decongestants, and antibiotics plus steroids (see table 3 ). [14] [15] [16] [17] [18] [19] [20] 22, 23, 82 of these interventions, early insertion of tympanostomy tubes (compared with watchful waiting and option of insertion later) is proven to improve hearing at 6 and 12 months, but the beneficial effect is modest. [14] [15] [16] this improvement in hearing has not been associated with improvement in language development or cognitive assessment scores. 16 tympanostomy tubes usually last 6 to 12 months, and there is no evidence that there is any ongoing benefit after they have been extruded. antibiotics have also been shown to be an effective treatment, but the beneficial effects are slight and do not seem to persist over the long term. 14, 15, 27 there seem to be additional shortterm benefits when antibiotics are combined with steroids, but again the beneficial effect is modest. 14, 20 there is some evidence that autoinflation devices are effective. 14, 19 the benefits are modest and have only been documented to be short term. antihistamines and decongestants provide no benefit (see table 3 ). 14, 15, 18 given the available evidence from rcts on ome, most well-informed individuals in low-risk populations would choose a course of watchful waiting initially. for those children with persistent ome in both ears associated with hearing loss despite watching and waiting for 6 to 12 months, a trial of antibiotics is reasonable. insertion of tympanostomy tubes is most appropriate in children for whom the primary concern is the conductive hearing loss and communication difficulties. children with the most severe conductive hearing loss are most likely to benefit. families should be informed that a small proportion of children will suffer recurrent persistent ome when the tympanostomy tubes are extruded, and may need a second operation. in these children, tympanostomy tubes plus adenoidectomy is a reasonable option. 14, 82 children who experience frequent suppurative infections (including those with immunodeficiency or persistent bacterial rhinosinusitis) are at greatest risk of developing csom as a complication of tympanostomy tubes. indigenous children in high-risk populations would fall into this group. none of the rcts assessing interventions for ome were conducted with indigenous children. however, one rct of prophylactic antibiotics in australian aboriginal children enrolled only infants with ome. none of the children in the placebo group had resolution of their ome within 6 months. around 10% of children in the antibiotic group had resolution of their ome. 40 this result suggests that ome is a persistent condition that does not respond well to established treatment options. although no reliable evidence from rcts was found, strategies that aim to improve hearing and communication in those with moderate hearing loss might provide most benefit in high-risk populations. although not a primary outcome measure, pneumococcal conjugate vaccine reduced the number of children who received tympanostomy tube insertion by around 20%. it is possible that some of this effect was mediated through a reduction in chronic bilateral ome with hearing loss. consistent with this, substantial declines in this procedure have been described in the united states in recent years, but not amongst alaskan native children. 83 most children with aom will improve spontaneously within 14 days, and complications from this illness are uncommon. when considering the onset of the illness, there is evidence on the preventive effects of pneumococcal conjugate vaccine and influenza vaccine (see table 3 ). [11] [12] [13] 24 both of these vaccines have been shown to be effective, but the beneficial effects in terms of overall rates of infection are slight. the beneficial effects of the pneumococcal conjugate vaccine are modest in terms of reductions in the insertion of tympanostomy tubes. 84 most children in low-risk populations will not meet the criteria for tympanostomy tube insertion. there is also evidence on the treatment effects of antihistamines and decongestants, antibiotics, myringotomy, and analgesics (see table 3 ). 21, [23] [24] [25] 27 regular analgesics (paracetamol or ibuprofen) provide a benefit (assessment on day 2), and the beneficial effects were large. 24 antibiotics are also proven to be effective. 22, 23 the short-term beneficial effects are slight in most children. the beneficial effects are modest in children younger than 2 years with bilateral aom, and large in those with aom with perforation. studies of initial treatment with antibiotics have not documented a long-term effect. if antibiotics are to be used, there is evidence that a longer course of treatment (r7 days) is more effective but the beneficial effects are modest (persistent aom reduced from 22% to 15%). 85 there is no evidence to support the belief that any one of the commonly used antibiotics is more effective than the others. the use of antihistamines and decongestants has not been shown to be beneficial, and myringotomy seems to be harmful compared with no treatment or antibiotics (see table 3 ). 21, 24, 27 given the available evidence from rcts on aom, most well-informed individuals in low-risk populations would choose symptomatic relief with analgesics and either watchful waiting or antibiotics. antibiotics would be most appropriate in children younger than 2 years with bilateral aom, those with aom with perforation, children with high risk of complications, and those who have already had 48 hours of watchful waiting. if the child is not in a high-risk group but the family prefers antibiotic treatment, the clinician should discuss ''wait and see prescribing.'' provision of a script for antibiotic along with advice only to use it if the pain persists 48 hours will reduce antibiotic use by two-thirds (with no negative impact on family satisfaction). [86] [87] [88] a small proportion of children with aom will experience recurrent aom (3 episodes in 6 months or 4 episodes within 12 months). 46 there is evidence on the treatment effects of prophylactic antibiotics, adenoidectomy, and tympanostomy tube insertion. 24, [26] [27] [28] [29] [30] antibiotics are proven to be effective but the beneficial effects are modest. the rates of aom also reduce spontaneously without treatment so that absolute benefits are less impressive than anticipated. two of the rcts assessing prophylactic antibiotics have been conducted in indigenous children. 39, 40 these studies demonstrate that prophylactic antibiotics will prevent perforation of the tympanic membrane. the size of the benefit is similar to prevention of any aom. insertion of tympanostomy tubes also seems to reduce rates of aom, and the effect is similar to antibiotics. either of these options could be considered in those children from low-risk populations with very frequent infections (especially if occurring before the peak of respiratory illness in winter). however, children with tympanostomy tubes may develop a discharging ear, so this is not a good option in children at increased risk of suppurative infections (including those with immunodeficiency or persistent bacterial rhinosinusitis). for indigenous children in high-risk populations, prophylactic antibiotics or prompt antibiotic treatment of infections are probably the more appropriate treatment options. adenoidectomy does not seem to be an effective treatment. [27] [28] [29] because indigenous children in high-risk populations are known to have high rates of pneumococcal diseases, there was hope that introduction of the pneumococcal conjugate vaccine would have a greater impact on om in these populations. one rct in navajo and apache children assessed the impact on om and could not demonstrate substantially improved outcomes. 43 of note, comparison of longitudinal cohorts before and after the introduction of the pneumococcal conjugate vaccine found a reduction in om visits for american indian children but not for alaskan native children. 83 in australia, comparison of longitudinal cohorts of aboriginal infants before and after the introduction of the vaccine did not document substantial reductions in severe om. 43, 89 a small proportion of children with aom with perforation go on to develop csom. in developed countries, csom most commonly occurs as a complication of tympanostomy tube placement. there is evidence on the treatment effects of topical antibiotics, topical antiseptics, systemic antibiotics, and ear cleaning. [31] [32] [33] [34] 79 interpretation of a large number of small studies is challenging, but topical antibiotics are proven to be effective and the beneficial effects vary from large to modest. most studies have not documented a long-term effect. topical antibiotics also seem to be more effective than antiseptics and systemic antibiotics. 31 the role of topical antibiotics plus systematic antibiotics is unclear. 90 cleaning the middle ear discharge has not been proven to be effective in rcts but is generally regarded as necessary before insertion of topical antibiotics (at least in children with profuse discharge). although not seen in rcts, there is also a very small risk of ototoxicity associated with most topical antibiotics (except topical quinolones) and topical antiseptics. 27 for children who fail to respond to prolonged courses of topical antibiotics, 2 small studies (85 participants) have documented high cure rates and large beneficial effects associated with 2 to 3 weeks of intravenous antipseudomonal antibiotics (such as ceftazidime). 91, 92 given the available evidence from rcts on csom, most well-informed individuals would choose topical antibiotic treatment. however, even though this is an effective treatment, prolonged or repeated courses of treatment are often required. if this is the case, topical quinolones will provide a slight benefit in terms of risk of ototoxicity. even in high-risk indigenous populations there is a considerable difference in the likely response to treatment. two rcts comparing ciprofloxacin drops with framycetingramycidin-dexamethasone drops in australian aboriginal children with csom have been conducted. one trial found most children could be effectively treated within 9 days, whereas the other reported most children with persistent csom despite 6 weeks of treatment. 41, 42 although not the subject of rcts, the outcomes of tympanoplasty in indigenous children and adults have been described. these studies usually report effective surgical repair of the tympanic membrane in around 50% to 70% and a modest improvement in hearing. 57, 93, 94 these results are not as good as those seen in other populations, where effective repair is usually achieved in 80% to 90%. this operation is probably most appropriate for indigenous children with bilateral large, dry tympanic membrane perforations associated with a moderate hearing loss or frequent episodes of discharge. om is one of the most common illnesses affecting children. in low-risk populations, most illnesses are mild and will resolve completely without specific treatment. unfortunately, this is not always the case for indigenous children in high-risk populations. multiple interventions have been assessed in the treatment of om. none of the interventions have had substantial absolute benefits for the populations studied. therefore, for low-risk children symptomatic relief and watchful waiting (including education of the parents about important danger signs) is the most appropriate treatment option. antibiotics have a role in children with persistent bacterial infection, or those at risk of complications. even today, many indigenous children will often fall into these high-risk groups. epidemiology of viral respiratory infections the common cold otitis media in infants and children textbook of pediatrics incidence of acute otitis media and sinusitis complicating upper respiratory tract infection: the effect of age smart health choices: making sense of health advice statistics notes. treatment allocation in controlled trials: why randomise? grading quality of evidence and strength of recommendations grade: an emerging consensus on rating quality of evidence and strength of recommendations systems for grading the quality of evidence and the strength of recommendations ii: pilot study of a new system pneumococcal vaccines for preventing otitis media vaccines for preventing influenza in healthy children the efficacy of influenza vaccine for healthy children: a meta-analysis evaluating potential sources of variation in efficacy estimates including study quality otitis media with effusion american academy of pediatrics subcommittee on otitis media with effusion. otitis media with effusion grommets (ventilation tubes) for hearing loss associated with otitis media with effusion in children grommets in otitis media with effusion: an individual patient data meta-analysis antihistamines and/or decongestants for otitis media with effusion (ome) in children autoinflation for hearing loss associated with otitis media with effusion oral or topical nasal steroids for hearing loss associated with otitis media with effusion in children decongestants and antihistamines for acute otitis media in children antibiotics for acute otitis media: a meta-analysis with individual patient data antibiotics for acute otitis media in children otitis media in children (acute) a randomized, double-blind, multicentre controlled trial of ibuprofen versus acetaminophen and placebo for symptoms of acute otitis media in children antibiotics for the prevention of acute and chronic suppurative otitis media in children evidence-based otitis media. hamilton: b.c prevention of otitis media by adenoidectomy in children younger than 2 years adenoidectomy does not significantly reduce the incidence of otitis media in conjunction with the insertion of tympanostomy tubes in children who are younger than 4 years: a randomized trial grommets (ventilation tubes) for recurrent acute otitis media in children chronic suppurative otitis media topical antibiotics without steroids for chronically discharging ears with underlying eardrum perforations systemic antibiotics versus topical treatments for chronically discharging ears with underlying eardrum perforations interventions for chronic suppurative otitis media report of a who/ciba foundation workshop. prevention of hearing impairment from chronic otitis media. geneva: world health organisation oxford: wiley interscience a systematic review of clinical research addressing the prevalence, aetiology, diagnosis, prognosis and therapy of otitis media in australian aboriginal children otitis media in alaskan eskimo children. prospective evaluation of chemoprophylaxis compared to placebo, long-term antibiotics resolve otitis media with effusion (ome) and prevent acute otitis media with perforation (aomwip) in a high-risk population: a randomized controlled trial effectiveness of ototopical antibiotics for chronic suppurative otitis media in aboriginal children: a community-based, multicentre, double-blind randomised controlled trial topical ciprofloxin versus topical framycetingramicidin-dexamethasone in australian aboriginal children with recently treated chronic suppurative otitis media: a randomized controlled trial randomized, controlled trial efficacy of pneumococcal conjugate vaccine against otitis media among navajo and white mountain apache infants systematic review of existing evidence and primary care guidelines on the management of otitis media in aboriginal and torres strait islander populations. canberra: office of aboriginal and torres strait islander health recommendations for clinical care guidelines on the management of otitis media in aboriginal and torres strait islander populations. canberra: office of aboriginal and torres strait islander health otitis media american academy of pediatrics subcommittee on management of acute otitis media. diagnosis and management of acute otitis media a meta-analytic review of the risk factors for acute otitis media prophylaxis for otitis media in an indian population draining ears and deafness among alaskan eskimos patterns of ear disease in the southwestern american indian eustachian tube function in an american indian population early otitis media among minnesota american indians: the little ears study an overview of twenty years of observation concerning etiology, prevalence, and evolution of otitis media and hearing loss among the inuit in the eastern canadian arctic high rate of nasopharyngeal carriage of potential pathogens among children in greenland: results of a clinical survey of middle-ear disease prevalence of otitis media in a survey of 591 unselected greenlandic children outcome of mobile ear surgery for chronic otitis media in remote areas otitis media in australian aboriginal children: an overview the prevalence of hearing impairment amongst maori schoolchildren prevalence and natural history of otitis media with perforation in maori school children epidemiology and pathogenesis of chronic suppurative otitis media: implications for prevention and treatment middle-ear disease in indians of the mount currie reservation, british columbia childhood morbidity and mortality in newcastle-upon-tyne. further report on the thousand family study bronchiectasis in alaska native children otitis media in inuit children in the eastern canadian arctic-an overview 1968 to date bronchiectasis in alaska native children: causes and clinical courses lower respiratory tract infections among american indian and alaska native children and the general population of u.s. children invasive pneumococcal disease caused by nonvaccine serotypes among alaska native children with high levels of 7-valent pneumococcal conjugate vaccine coverage invasive pneumococcal disease in central australia bronchiectasis in indigenous children in remote australian communities the burden and outcome of respiratory tract infection in australian and aboriginal children bacterial colonization of the nasopharynx predicts very early onset and persistence of otitis media in australian aboriginal infants carriage of multiple ribotypes of nonencapsulated haemophilus influenzae in aboriginal infants with otitis media measuring nasal bacterial load and its association with otitis media report from a who working group: standard method for detecting upper respiratory carriage of streptococcus pneumoniae evidence assessment of the accuracy of methods of diagnosing middle ear effusion in children with otitis media with effusion does this child have acute otitis media? otitis media and speech and language: a meta-analysis of prospective studies chronic suppurative otitis media: a review predictors of chronic suppurative otitis media in children identification of children in the first four years of life for early treatment for otitis media with effusion surgical prevention of otitis media trends in otitis media and myringtomy with tube placement among american indian/alaska native children and the us general population of children impact of the pneumococcal conjugate vaccine on otitis media short course antibiotics for acute otitis media delayed antibiotics for respiratory infections wait-and-see prescription for the treatment of acute otitis media: a randomized controlled trial pragmatic randomised controlled trial of two prescribing strategies for childhood acute otitis media pneumococcal vaccination and otitis media in australian aboriginal infants: comparison of two birth cohorts before and after introduction of vaccination effectiveness of trimethoprim/sulfamethoxazole for children with chronic active otitis media: a randomized, placebo-controlled trial medical treatment of chronic suppurative otitis media without cholesteatoma in children-a two-year follow-up outpatient management of chronic suppurative otitis media without cholesteatoma in children outcomes of myringoplasty in australian aboriginal children and factors associated with success: a prospective case series myringoplasty: a post-operative survey of 90 aborigine patients key: cord-296141-h1h18ek6 authors: hoekstra, pieter j. title: suicidality in children and adolescents: lessons to be learned from the covid-19 crisis date: 2020-06-02 journal: eur child adolesc psychiatry doi: 10.1007/s00787-020-01570-z sha: doc_id: 296141 cord_uid: h1h18ek6 nan suicide is the second most prevalent cause of death worldwide overall and the third leading cause of death in 15-19-year-olds. the most frequent suicide method worldwide is hanging, followed by poisoning by pesticides for females and firearms for males [1] . for every suicide, there are many more people who attempt suicide every year. a prior suicide attempt is the single most important risk factor for suicide in the general population [2] . mortality and sociodemographic factors data from the swiss national cohort (involving the whole swiss resident population) indicated a clearly increasing suicide rate with increasing age, from none per 100,000 at age 10 years to 14.8 per 100,000 at 18 years in boys, and 5.4 per 100,000 in girls [3] . other risk factors, apart from male sex, were living in a single parent household, being an only or middle-born child, and living in rural regions. prevalence of suicide in children and adolescents was remarkably stable over the years 1991-2003, in contrast to a decreasing trend in adults [4] . in this month's issue of european child and adolescent psychiatry, figures from a general population cohort of 1035 junior high-school students (mean age of 13.2 years) from taiwan showed that suicidal ideation was observed in 20.3%, suicide plans in 5.7%, and actual suicide attempts in 4.7% during the course of one year [5] . students with suicidal behaviors were more likely to be females and to be living in highly urbanized areas. perceived stress as measured by the ten-item perceived stress scale appeared a major predictor of suicidality. although a measure of resilience did indicate protective effects, the effect sizes of protective factors were smaller than those of risk factors. in a previous study, conducted in a large population cohort of seventh and tenth grade students from korea, family conflict, being exposed to violence, and being victim of bullying were associated with an increased risk of suicidal ideation [6] . a systematic review into psychosocial risk factors for suicidality in children and adolescents, also in the current issue of european child and adolescent psychiatry [7] , substantiate the role of stressful life events (in interaction with vulnerability factors), most notably family conflicts, academic stressors (including bullying or exam stress), trauma, and other adverse life events (peer conflict, legal problems, physical abuse, worries about sexual orientation, romantic breakups, exposure to suicide/suicide attempts, and physical and/or sexual violence). temperament and character are also an important factor; of note, 50% of adolescents have only started thinking about self-harm less than an hour before the act itself. apart from psychosocial stressors, also the presence of mental disorders clearly increases the risk of suicide attempts. based on data from a 10-year prospective study of 3021 community subjects (14-24 years of age), almost all mental disorders were associated with an elevated risk of suicide attempts [8] ; the more mental disorders a subject had, the higher the risk of a suicide attempt. the highest risks of suicide attempts were associated with posttraumatic stress disorder, dysthymia, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, agoraphobia, and nicotine dependence. as the authors rightly noticed, most of these disorders are well treatable and may thus form promising early intervention targets to decrease suicidality. the recent measures imposed on families in the current covid-19 pandemic is unprecedented. an important question is if and how they affect suicide rates in children and adolescents. a higher risk of being exposed to physical and/or sexual violence at home and the economic damage caused by the crisis may well lead to increased suicide rates. there is, however, still a lack of empirical data on the consequences of the covid-19 crisis on children with mental disorders. an early study in china showed that children's adhd behaviors worsened related to lowered mood of the children and their parents [9] . another study found almost doubled rates of anxiety and depression in adults from the general population who were affected by quarantine [10] . lower household income, lower education level, being more worried about being infected, having no psychological support, and lower self-perceived health were significantly associated with higher levels of anxiety and depression. on the other hand, one may argue that school closures have led to less academic and social pressure, and less peer conflict and bullying. this may have a substantial positive impact on the wellbeing of some vulnerable children and perhaps lead to lessened suicidality rates. it will be of utmost importance to learn lessons how schools may use the benefits of online teaching to decrease psychosocial risk factors associated with suicidality and to improve the mental health for large groups of children. it is too early to tell how suicide rates have developed during lockdown measures, but some countries have reported remarkable decreases (japan [11] , the netherlands [12] , north rhine-westphalia in germany [13] , and new zealand [14] ). the impact of the covd-19 crisis on child and adolescent practice has also been substantial, with many outpatient assessments and treatments now delivered through videoconferencing. for some families this may lower the barrier of seeking treatment, especially for those with suicidality, depression, and anxiety [15] . telepsychiatry is also well suited for providing pharmacotherapy in accordance with evidence-based treatment protocols for children with attention-deficit hyperactivity disorder [16] . it is important that there will be an increase in well-powered randomized controlled trials into the effects of telepsychiatry in comparison to conventional modes of treatment delivery. better use of online treatment delivery could have a lasting positive effect on reaching vulnerable families and on delivering more effective services. suicide methods in children and adolescents fact sheet of suicide suicide in adolescents: findings from the swiss national cohort suicide trends diverge by method: swiss suicide rates effects of perceived stress and resilience on suicidal behaviors in early adolescents the impact of psychological problems and adverse life events on suicidal ideation among adolescents using nationwide data of a school-based mental health screening test in korea psychosocial risk factors for suicidality in children and adolescents mental disorders and the risk for the subsequent first suicide attempt: results of a community study on adolescents and young adults acute stress, behavioural symptoms and mood states among school-age children with attention-deficit/hyperactive disorder during the covid-19 outbreak comparison of prevalence and associated factors of anxiety and depression among people affected by versus people unaffected by quarantine during the covid-19 epidemic in southwestern china suici de-rate-plumm etsdurin g-coron aviru s-lockd own-while -other -count ries-repor t-incre ase-in-distr ess-calls so-hat-sich-die-suizi drate -in-deuts chlan d-waehr end-der-coron a-krise -entwi ckelt -id573 32446 telehealth increases access to care for children dealing with suicidality depression, and, anxiety in rural emergency departments telepsychiatrists' medication treatment strategies in the children's attention-deficit/hyperactivity disorder telemental health treatment study key: cord-277805-b3hizdmz authors: catassi, giulia n.; vallorani, martina; cerioni, federica; lionetti, elena; catassi, carlo title: a negative fallout of covid-19 lockdown in italy: life-threatening delay in the diagnosis of celiac disease date: 2020-05-16 journal: dig liver dis doi: 10.1016/j.dld.2020.05.016 sha: doc_id: 277805 cord_uid: b3hizdmz nan the contact/movement restrictions imposed by the current covid-19 pandemic had a deep impact on primary health care, with possible negative fallouts on even common and usually benign gastrointestinal disorders, as clearly illustrated by the clinical history we briefly summarize herein. on covid-19 day-19 lockdown in italy (march 31, 2020), a 17-month-old girl presented at our pediatric academic medical center for evaluation of abdominal pain and distention, and widespread edema. during the first year of life, the patient's medical history had been unremarkable. the child had been breastfed for 4 months and then baby-led weaned with formula, cereals, meat and vegetables. poor appetite, constipation, stunting growth and abdominal distention gradually manifested after the first 12 months. at age 15 months (end of february 2020), the parents consulted the family pediatrician by phone, but the doctor was unable to visit the child because of the first contact/movement restrictions imposed by the covid-19 emergency in italy. during the following weeks, clinical worsening manifested with walking refusal and progressive swelling of face and lower limbs. at this time, the child was brought to the local hospital and then immediately transferred to our academic regional center. on admission, ileocecal intussusception and mesenteric lymphadenitis were diagnosed by abdominal ultrasound and barium enema, and laparotomy was needed for reduction of involved intestinal segments. the day after surgery, on clinical examination the child was markedly irritable and showed edema on the face, hands, abdomen and legs (fig. 1 ). vital signs were normal. a reduced lower limbs motility was noted but the neurological examination was normal. weight and height were 8.0 kg (below 3 rd centile) and 70 cm (below 3 rd centile), respectively. congestive heart failure, as a cause of widespread edema, was first excluded by a normal echocardiography. first-level laboratory investigations were normal, including urinalysis and liver function tests, except for low serum albumin (2.8 g/dl) and total calcium (8 mg/dl). since the clinical history suggested celiac disease (cd), serum cd autoantibodies were checked, as recommended by the european society for pediatric gastroenterology, hepatology and nutrition (espghan) diagnostic guidelines, 1 and a gluten-free diet (gfd) was started before getting the results, due to the severity of symptoms. diagnosis of cd was strongly suggested by high-level positivity (> 10x upper normal limit -unl) of igg anti-deamidated gliadin peptide (dgp) and borderline levels (1x unl) of iga antitransglutaminase (ttg). the daily caloric intake was gradually increased to avoid a refeeding syndrome. after 10 days of gfd, edema had disappeared and the child lost 1 kg of retained fluids (14% of body weight). at that time, the clinical picture of typical cd became even more noticeable than before (fig. 2) . in young children, delayed cd diagnosis may be responsible for life-threatening manifestations, such as the celiac crisis and intestinal intussusception observed in our patient. celiac crisis is a potentially fatal complication of cd, characterized by hypoproteinemia, edema, and profound metabolic and nutritional abnormalities. 2 during the first half of the 20 th century, when pediatric cd was associated with a high mortality (on average 15%) in western countries, a celiac crisis was often the precipitating cause of death. 4 nowadays, the celiac crisis has nearly disappeared in europe and north america, due to improved infant nutrition, decreased infection rate, and reduced lag time between cd development and diagnosis, but is still reported from developing countries. [5] [6] treatment of celiac crisis requires gradual increase of daily caloric intake (as we managed in this case) to avoid the risk of a refeeding syndrome. 5 intestinal intussusception is another complication that can be associated with untreated cd. according to recent data from india, intussusception is frequently seen in children with newly diagnosed cd (up to 25% of cases), it is generally asymptomatic and resolves spontaneously on gfd. interestingly, hypoalbuminemia and abdominal distention are more common in cd children with intussusception. 7 in our patient, the delay in medical referral, caused by the covid-19 related restrictions in italy, was clearly responsible of the previously described life-threatening presentation of cd. another interesting feature of our case was the pattern of cd serological markers found at diagnosis, with nearly normal values of ttg-iga (1x) and very high values of dgp-igg (10x). several studies have shown that dgp-igg may be the first positive marker of cd in children aged less than 2 yrs. 3 for this reason it is advisable to include dgp-igg determination in the first-level serological screening for cd in young children. this recommendation was included in the 2012 espghan guidelines for cd diagnosis, 8 but has been removed from the 2020 revision. 1 in conclusion, the history of this patient highlights a potentially life-threatening delay in the diagnosis and treatment of cd, a disorder usually characterized by a benign presentation in europe, that was apparently related to the negative impact of covid-19 lockdown on clinical practice in italy. european society paediatric gastroenterology, hepatology and nutrition guidelines for diagnosing coeliac disease 2020 celiac disease and nonceliac gluten sensitivity: a review the anti-deamidated gliadin peptide antibodies unmask celiac disease in small children with chronic diarrhoea diagnosis of gluten-related enteropathy in a newborn: how and when? celiac crisis/refeeding syndrome combination: new mechanism for an old complication refeeding syndrome in children in developing countries who have celiac disease celiac crisis in children in serbia intussusception in celiac disease: is it a common feature in children? european society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease gnc had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.no funding was used in generating this work. design and conduct of the study: gnc, cc collection, management, analysis, and interpretation of the data: gnc, mv, fc, el preparation, review, and approval of the manuscript: gnc, mv, fc, el, cc decision to submit the manuscript for publication: cc key: cord-271814-a2vlkwce authors: brough, helen a.; kalayci, omer; sediva, anna; untersmayr, eva; munblit, daniel; rodriguez del rio, pablo; vazquez‐ortiz, marta; arasi, stefania; alvaro‐lozano, montserrat; tsabouri, sophia; galli, elena; beken, burcin; eigenmann, philippe a. title: managing childhood allergies and immunodeficiencies during respiratory virus epidemics – the 2020 covid‐19 pandemic: a statement from the eaaci‐section on pediatrics date: 2020-05-31 journal: pediatr allergy immunol doi: 10.1111/pai.13262 sha: doc_id: 271814 cord_uid: a2vlkwce while the world is facing an unprecedented pandemic with covid‐19, patients with chronic diseases need special attention and if warranted adaptation of their regular treatment plan. in children, allergy and asthma are among the most prevalent non‐communicable chronic diseases, and healthcare providers taking care of these patients need guidance. at the current stage of knowledge, children have less severe symptoms of covid‐19, and severe asthma and immunodeficiency are classified as risk factors. in addition, there is no evidence that currently available asthma and allergy treatments, including antihistamines, corticosteroids, and bronchodilators, increase the risk of severe disease from covid‐19. most countries affected by covid‐19 have opted for nationwide confinement, which means that communication with the primary clinician is often performed by telemedicine. optimal disease control of allergic, asthmatic, and immunodeficient children should be sought according to usual treatment guidelines. this statement of the eaaci section on pediatrics puts forward six recommendations for the management of childhood allergies and immunodeficiencies based on six underlying facts and existing evidence. viruses interact with most living organisms, mostly in a symbiotic way. nevertheless, this equilibrium can be disturbed in many occasions and lead to outbreaks of disease. in the case of the delicate interaction between viruses and human beings, many significant epidemic outbreaks of viral disease are linked to respiratory symptoms. while all humans are at risk of being infected regardless of age, gender, or health, vulnerable populations at higher risk of developing a severe form of covid-19 disease have been identified. among them, older age is a major risk factor. since the beginning of the pandemic, it has become rapidly apparent that children less often present symptoms and that these are less often severe. the only systematic review bringing together data on children has been published recently and concluded that children account for 1%-6% of the diagnosed covid-19 cases often have milder disease than adults, and mortality rates are extremely low. 3 however, with hundreds of papers published on covid-19 in the past few months, the problem of reporting the same patients in different manuscripts was raised 4 ; duplicate reporting may lead to inaccurate scientific record and thus potentially misleading results in any systematic review and meta-analysis. the first reliable data came from more than 72.000 case reports reviewed by the chinese center for disease control and prevention showing that less than 1% of cases were younger than 10 years of age. 5 however, as discussed in the paper and outlined in an accompanying editorial one should bear in mind that in this study testing for other viruses was not standardized, and two-thirds of cases were control of allergic, asthmatic, and immunodeficient children should be sought according to usual treatment guidelines. this statement of the eaaci section on pediatrics puts forward six recommendations for the management of childhood allergies and immunodeficiencies based on six underlying facts and existing evidence. allergy, asthma, biologics, children, coronavirus, corticosteroids, covid-19, immunodeficiency, sars-cov-2, treatment clinically diagnosed, but not virologically confirmed. 9 in addition, more of the severe and critical cases were in the suspected than the confirmed group which suggests that some suspected cases might be caused by other respiratory infections. the cdc in the united states recently published a review of laboratory-confirmed covid-19 in children between february 12 and april 2, 2020. 10 among 149 082 (99.6%) reported cases for which age was known, 2572 (1.7%) were among children aged <18 years. the majority of pediatric cases (57%) were male, and male predominance persisted even in infants. among 345 pediatric cases with information on underlying conditions, 23% (n = 80) had at least one underlying condition, most commonly chronic lung disease (including asthma) (n = 40), followed by cardiovascular disease (n = 25), and immunosuppression (n = 10). information on hospitalization status for children was available for only 745 (29%) cases. infants accounted for the highest percentage of hospitalizations; of the 95 infants with known hospitalization status, 62% (n = 59) were hospitalized, including five who were admitted to intensive care. there was little variation in the percentage hospitalized among children >1 year of age. limitations of this study included substantial missing data; thus, statistical comparisons were not possible and need to be interpreted with caution. however, similarly to the wuhan review of pediatric cases, children were less severely affected than adults, and infants were more likely to be hospitalized. of note, given the higher percentage of asymptomatic children in the population, the real percentage of pediatric subjects with severe or critical disease may be even lower. the reason for the relatively milder clinical presentation in children is mostly unknown. as outlined in the chinese study, several factors in relation to the exposure and host factors may account for this observation; in addition, since the children's immune system is still developing, it may react to pathogens differently than do adults. 11 angiotensin-converting enzyme ii (ace-2) which acts as the receptor for coronaviruses may be structurally and functionally less mature in the airways of children. [12] [13] [14] as children attend daycare/ schools, they are exposed to a variety of viruses including other types of coronaviruses, and they may be better equipped with general antiviral defense mechanisms of the immune system. another potential hypothesis 14 suggested that the simultaneous presence of other viruses in the respiratory tract mucosa, which is very typical for young children, may limit the growth of sars-cov-2 by direct virus-to-virus interactions and competition. 15 similar to the observation made in children with sars, 16 the children with covid-19 infection may not be mounting a generalized cytokine storm but rather may be responding with elevation of specific cytokines. in a recent study with clusters of adults with pneumonia cases in wuhan, china, the cytokine profile associated with covid-19 disease severity was characterized by increased interleukin (il)-2, il-7, granulocyte colony-stimulating factor, interferon-γ-inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumor necrosis factor-α. 11 it is also possible that children have less severe disease because they have fewer chronic health conditions. it is important to note that although children have less severe covid-19 disease, they are still able to pass on the virus, even while asymptomatic. 17 in addition to age, chronic health conditions such as renal failure, diabetes, hypertension, and heart disease are major risk factors for developing more severe symptoms of covid-19. 18 patients with asthma (particularly severe or uncontrolled asthma) and immunodeficiency have also been classified to be at increased risk of developing more severe covid-19, based more on common sense rather than mounting evidence. 19 however, recently, the cdc in the united states released a morbidity and mortality weekly report which suggested that adults with a history of asthma were more likely to be hospitalized with covid-19; those hospitalized with covid-19 had a higher rate of a history of asthma (17.0%) than the general population (7.7%). while public policy is majorly focusing on "flattening the curve," that is, preventing a too rapid spread of covid-19 and on providing adequate health care for patients with severe respiratory symptoms in this very aggressive disease, many health providers are faced with questions about safe management of their patients with chronic health conditions. many elective face-to-face hospital services have been discontinued, in favor of remote consultations that have also been substantially scaled back, which provides its own challenges. the care of children with allergies or immune conditions is being adapted to the current situation, with more remote working and providing guidance to children to reduce likelihood of infection in children who would be deemed at higher risk of severe covid-19 disease. guidance is strongly needed on how to manage children with allergic diseases during the pandemic, particularly, as the pandemic is hitting the northern hemisphere during the tree and grass pollen pollination season. how to run a clinic under the condition of the covid-19 pandemic is reviewed in the eaaci position paper. 21 although the current covid-19 pandemic may fade away and hopefully eventually a vaccine may be available, it is unavoidable that new respiratory viruses will appear and that similar questions will arise again in the future. hopefully, these recommendations will be helpful also in future similar events. it became rapidly evident that severe covid-19 infections were particularly prevalent in specific risk groups. a retrospective cohort involving 191 adults hospitalized in wuhan at the early onset of the disease identified pre-existing comorbidities in 48% of the patients. 18 hypertension was most common followed by diabetes, and by coronary heart disease. chronic obstructive lung disease was a pre-existing condition in only 6 patients with 4 of them having a fatal outcome due to covid-19. asthma or allergy was not mentioned as a risk factor in this population. older age was associated with increased odds of in-hospital death; this observation has now been confirmed during the course of the disease in europe and north america. evaluating asthma and allergy more specifically as potential risk factors, a retrospective study based on electronic medical records from 140 hospitalized covid-19 adult patients investigated pre-existing asthma or allergic diseases. 22 in this adult population, drug hypersensitivity was self-reported in 11.4% and urticaria in 1.4%. however, asthma or other allergic diseases were not reported by any of the patients. even though there are no data specifically addressing this question, cdc states that people of all ages with chronic lung disease including moderate to severe asthma are listed as having high risk. 19 pre-existing allergies have not been classified as risk a factor. concerns have also been raised regarding a more severe course of there are no data regarding whether the treatment with inhaled corticosteroids (ics) modifies the susceptibility to or severity of covid-19. previous studies have shown that ics especially when used at high doses may be associated with an increased risk of pneumonia in adult patients with chronic obstructive pulmonary disease. in this regard, one should keep in mind that children have different phenotypes of asthma than adults. in children, however, a recent meta-analysis has shown that regular use of ics may not increase the risk of pneumonia or other respiratory infections in children with asthma. 30 early childhood is a time associated with frequent infections due to common respiratory viruses such as respiratory syncytial virus (rsv) or rhinovirus. in children with increased bronchial hyperactivity, recurrent viral infections predispose to episodes of bronchoconstriction. in order to prevent this, these patients are frequently treated with ics. during such treatments, increased severity or frequency of viral infection has not been observed. 31 since asthma itself may be a risk factor for the severity of covid since primary immunodeficiencies (pid) are congenital disorders, patients with pid might represent a potential group-at-risk in the current pandemic of covid-19. from the very onset of the pandemic, a special focus was given to this patient group predisposed to infections with respiratory viruses. an international consensus recently summarized how to best manage patients with pid during the pandemic. 33 according to current knowledge in april 2020, it is not yet known whether any specific form of immunodeficiency poses a particular threat to patients. as a joint project, questionthe current covid-19 pandemic might also pose a risk to pediatric patients with secondary immunodeficiencies, such as patients on immunosuppressive therapy for autoimmune or severe allergic diseases. it is recommended to continue the treatment, including immunosuppressants. in the case a secondary deficiency is treated by immunoglobulin substitution, continuation is recommended. the use of convalescent plasma might be considered in these cases in the future, when this now emerging covid-19 treatment option is scientifically established. 35 precautionary recommendations for patients with immunodeficiencies follow the national guidelines for the general population and include strict hygiene and social distancing measures to limit exposure. a general consensus has been reached to continue established therapies for the immune disorder, even immunosuppressive therapy for autoimmune complications of the underlying disease. 36 however, the current pandemic poses an exceptional challenge and safety concern for patients treated with cellular therapies, not only limited to the field of pid. 37 the main drawback to define tailored safety recommendations for patients with immunodeficiencies arises from our lack of knowledge regarding immune mechanisms during covid-19. cytotoxic lymphocytes, essential to control viral infections, were described to be markedly decreased in total cell numbers, and nk and cd8 + t cell function was exhausted in patients with covid-19 infection. 38 moreover, toll-like receptor 7 activation associated with alpha-interferon and tnf-alpha as well as il-12 and il-6 production seem to play an essential role in the control of the viral infection. 39 to increase our knowledge in disease mechanisms, we need to learn from clinical and immunologic characteristics of patients with severe in contrast to moderate disease. 40 in children and young adults, covid-19 mainly occurs mildly and without life-threatening complications. if covid-19 causes severe to lethal disease as observed in sporadic cases in these age groups without other comorbidities, it is tempting to speculate that severity is due to a defect in defense against the infection. therefore, a targeted search for possible monogenic immunodeficiencies by next generation sequencing and further advanced methods was launched in these patients, 41 which will greatly advance our understanding of immune protection against covid-19. there has been no scientific evidence that allergy treatments either increase susceptibility to sars-cov-2 or the severity of covid-19 disease. pediatric allergists should treat patients with allergic asthma, allergic rhinitis, or other allergy conditions according to usual guidelines, 24 without restricting the use of any specific medication. one exception to this is the advice to withhold biologics during acute covid19 disease. in addition, there is also reason to believe that proper treatment of these diseases might prevent unnecessary visits to physicians and hospitals and thus reduce the risk of being exposed to the sars-cov-2 virus. of note, the global initiative for asthma (gina) recommends avoiding the use of nebulizers for asthma attacks due to the increased risk of disseminating covid-19 (to other patients and to physicians, nurses, and other personnel); thus, pressurized metered-dose inhaler (pmdi) via a spacer is the preferred treatment during severe attacks. 28 a novel coronavirus from patients with pneumonia in china genomic epidemiology of novel coronavirus -global subsampling systematic review of covid-19 in children shows milder cases and a better prognosis than adults editorial concern-possible reporting of the same patients with covid-19 in different reports characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention sars-cov-2 infection in children detection of covid-19 in children in early epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china covid-19 in children: initial characterization of the pediatric disease cdcmmwr. coronavirus disease 2019 in children -united states clinical features of patients infected with 2019 novel coronavirus in wuhan are children less susceptible to covid-19? cleavage of the sars coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro why is covid-19 so mild in children? acta paediatr virus-virus interactions impact the population dynamics of influenza and the common cold inflammatory cytokine profile in children with severe acute respiratory syndrome a well infant with coronavirus disease 2019 with high viral load clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study cent dis control prev most recent national asthma data clinical characteristics of 140 patients infected with sars-cov-2 in wuhan clinical evidence does not support corticosteroid treatment for 2019-ncov lung injury cal-manag ement -of-sever e-acute -respi rator y-infec tion-when-novel -coron aviru s-(ncov)-infec tion-is-suspe cted a multicenter, randomized, controlled trial of dexamethasone for bronchiolitis dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal covid-19: gina answers to frequently asked questions on asthma management bts advice for healthcare professionals treating patients with asthma inhaled corticosteroids and respiratory infections in children with asthma: a meta-analysis preventing exacerbations in preschoolers with recurrent wheeze: a meta-analysis considerations on biologicals for patients with allergic disease in times of the covid-19 pandemic covid 19_world wide_ joint _ st ate ment _ 2020 0 311_120 0 c e t_final .pdf. accessed deployment of convalescent plasma for the prevention and treatment of covid-19 covid-19: pandemic contingency planning for the allergy and immunology clinic impact of covid-19 and future emerging viruses on hematopoietic cell transplantation and other cellular therapies. stem cells dev functional exhaustion of antiviral lymphocytes in covid-19 patients why the immune system fails to mount an adaptive immune response to a covid -19 infection clinical and immunologic features in severe and moderate coronavirus disease parenting in a time of covid-19 shielding advice for very high-risk groups american college of allergy, asthma & immunology position paper on the use of telemedicine for allergists managing childhood allergies and immunodeficiencies during respiratory virus epidemics -the 2020 covid-19 pandemic: a statement from the eaaci-section on pediatrics key: cord-281948-xv7vuypd authors: hoang, ansel; chorath, kevin; moreira, axel; evans, mary; burmeister-morton, finn; burmeister, fiona; naqvi, rija; petershack, matthew; moreira, alvaro title: covid-19 in 7780 pediatric patients: a systematic review date: 2020-06-26 journal: eclinicalmedicine doi: 10.1016/j.eclinm.2020.100433 sha: doc_id: 281948 cord_uid: xv7vuypd background: studies summarizing the clinical picture of covid-19 in children are lacking. this review characterizes clinical symptoms, laboratory, and imaging findings, as well as therapies provided to confirmed pediatric cases of covid-19. methods: adhering to prisma guidelines, we searched four medical databases (pubmed, litcovid, scopus, who covid-19 database) between december 1, 2019 to may 14, 2020 using the keywords “novel coronavirus”, “covid-19” or “sars-cov-2”. we included published or in press peer-reviewed cross-sectional, case series, and case reports providing clinical signs, imaging findings, and/or laboratory results of pediatric patients who were positive for covid-19. risk of bias was appraised through the quality assessment tool published by the national institutes of health. prospero registration # crd42020182261. findings: we identified 131 studies across 26 countries comprising 7780 pediatric patients. although fever (59·1%) and cough (55·9%) were the most frequent symptoms 19·3% of children were asymptomatic. patchy lesions (21·0%) and ground-glass opacities (32·9%) depicted lung radiograph and computed tomography findings, respectively. immunocompromised children or those with respiratory/cardiac disease comprised the largest subset of covid-19 children with underlying medical conditions (152 of 233 individuals). coinfections were observed in 5.6% of children and abnormal laboratory markers included serum d-dimer, procalcitonin, creatine kinase, and interleukin-6. seven deaths were reported (0·09%) and 11 children (0·14%) met inclusion for multisystem inflammatory syndrome in children. interpretation: this review provides evidence that children diagnosed with covid-19 have an overall excellent prognosis. future longitudinal studies are needed to confirm our findings and better understand which patients are at increased risk for developing severe inflammation and multiorgan failure. funding: parker b. francis and pilot grant from 2r25-hl126140. funding agencies had no involvement in the study. in december 2019, an unprecedented number of pneumonia cases presented in adult individuals from wuhan, china [1] . despite rapid action by the chinese government and health officials, the number of similar presenting cases continued to rise at an alarming rate [2] . by january 2020 an emerging zoonotic agent, known as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was identified in respiratory samples in patients diagnosed with pneumonia who subsequently developed respiratory failure [1] . the spread of sars-cov-2 from human to human, through respiratory droplets, has now resulted in a worldwide outbreak, now classified as a pandemic by the world health organization [3] . as of june 3rd, 2020, there has been more than 6¢4 million confirmed cases worldwide and >380,000 fatalities [4] most symptomatic cases have occurred in the adult population, characterized by fever, cough, malaise, and frequent hospitalization [1] . accordingly, most of the published data is derived from adults with coronavirus disease 2019 (covid19) who were hospitalized in china [5] . as the pandemic continues, we are now observing numerous reports describing the clinical presentation and hospital course of children with confirmed covid-19 [5] . what is currently known is that children have milder symptoms and are less likely to be hospitalized when compared to adults [6] . however, on may 14th, 2020 the united states centers for disease control and prevention (cdc) released a health advisory reporting a multisystem inflammatory syndrome in children (mis-c) associated with covid-19 [7] . this statement stemmed from a subset of pediatric patients manifesting with severe inflammation, multi-organ failure, and testing positive for sars-cov-2 [8, 9] . data extraction was performed by all investigators and compared by at least two investigators for consistency. data collected included the type of article (e.g., case series), country of origin, number of pediatric patients, demographic information, and all clinical symptoms (e. g., fever, cough), laboratory values (e.g., cbc, lfts, bmp), imaging studies (e.g., chest x-ray, ct, mri), clinical outcomes (e.g., icu admission), and treatments provided (e.g. antivirals). the risk of bias for observational studies was appraised through the quality assessment tool published by the national institutes of health [10] . we opted to use this guide as the development of the assessment tool was conducted rigorously by researchers in the agency for healthcare research and quality evidence-based practice centers, the cochrane collaboration, the united states preventive services task force, the scottish intercollegiate guidelines network, the national health service centre for reviews and disseminations, and consulting epidemiologists. moreover, it was a preferred tool in a systematic review on risk of bias assessments used in prospero-registered protocols [11] . risk of bias was assessed independently by at least two investigators and disagreements were resolved by a third researcher (am). furthermore, the level of evidence was assessed according to sackett [12] . all laboratory data were converted to similar units and presented as mean with standard deviation (sd). laboratory information presented as median (iqr) were converted to mean (sd), and denoted when unable to convert [13] . publications that provided multiple timepoints (e.g., hospital course of individuals) for laboratory results were gathered and averaged. if the symptom was present anytime during the hospitalization, it was considered positive and characterized as a count with percent. a similar approach was taken for imaging information. means, standard deviations, and proportion ratios were calculated using microsoft excel. statistical analyses between covid-19 pediatric patients with/ without mis-c was conducted on stata v¢13. all statistical tests were two-sided, and significance was defined as a p value <0¢05. continuous data was summarized as mean (standard deviation) or median (interquartile range) and assessed by student's t-test or wilcoxon rank sum. categorical data was summarized as counts (percent) and analyzed by fisher's exact test. the funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. the search yielded 1,142 studies. after removing 237 duplicates, 905 articles were reviewed by abstract and title. after initial screening, only 319 articles met inclusion criteria and underwent full text evaluation. publications that were retracted, or consisted of editorials, reviews, or commentaries that did not meet our criteria were removed, generating a final list of 131 articles (see fig. 1 ). studies included in this review were published between january 24th to may 11th, 2020. eight studies were cross sectional, 75 were case series, and 48 were case reports (refer to table 1 ). twenty-six countries were represented with the largest data derived from 2572 children from the united states. china comprised 64¢1% of the studies included in this review. appendix 1 displays publications by the country of origin. twenty of the publications pertained to the neonatal population and the ages extended from an extremely premature neonate at 26 weeks gestation to 20 years of age. the level of evidence for all of the studies was 5 (1 is highest, 5 is lowest) and the risk of bias scores were between 2 to 7 (1 is lowest, 9 is highest, refer to appendix 2). a total of 7780 covid-19 positive children were included. fifty six percent of the individuals were male ( table 2 ). the mean age was 8¢9 years (sd 0¢5) and 75¢6% of patients were exposed to a family member who was diagnosed with covid-19. the most common method for detection of the virus was through nasopharyngeal or throat swab (86¢5%). need for intensive care unit observation or treatment was low (3¢3%). twenty studies (n=655 individuals) reported an underlying medical condition; covid-19 positive children who were immunosuppressed or had a history of a respiratory or cardiac condition comprised the majority (65¢%). moreover, influenza and mycoplasma were the most common co-infections (see table 3 ). table 4 summarizes clinical symptoms and imaging findings in covid-19 confirmed pediatric patients. no symptoms were described in 456 of 2367 patients (19¢3%), while the two most common symptoms were fever (59¢1%), and cough (55¢9%). while upper respiratory symptoms were characteristic of covid-19, some patients presented with mild or often overlooked symptoms such as fatigue, abdominal pain, or decreased appetite [14à16] . table 4 also summates imaging findings. according to chest x-ray and computed tomography (ct), 23¢6% and 18¢9% had normal results, respectively. patchy lesions were observed in 105 of 501 patients on chest radiography and bilateral ground glass opacities were the most frequent ct abnormality. complete blood counts were the most common laboratory results described (see table 5 ). overall, leukocytes were within normal values (7¢1 £ 10 3 /ml), whereas neutrophils were mildly decreased (44¢4%) while lymphocytes were marginally elevated (39¢9%). markers of liver and renal function were normal. four serum inflammatory markers were above the mean: d-dimer, procalcitonin, creatine kinase, and interleukin-6. sixty-six studies (n=614 individuals) provided information regarding treatments. interferon was the most commonly administered drug (41¢0%), followed by empiric antibiotics (20¢2%). of note, glucocorticoids, and intravenous immunoglobulin was used in 4¢1% and 3¢1% of patients, respectively. complications we evaluated were rare and only described in 21 studies. there were 7 cases of kidney failure (0¢09%), 19 cases of shock (0¢24%), and 42 children were intubated (0¢54%). more details on treatments provided and complications can be found in table 6 . asymptomatic ( abbreviations: abg-arterial blood gas; asa-aminosalicylate; alt-alanine aminotransferase; ast-aspartate aminotransferase; bun-blood urea nitrogen; bnp-brain natriuretic peptide; cbc-complete blood count; ck-creatine kinase; cpap-continuous positive airway pressure; cr-creatinine; crp-c-reactive protein; ct-computed tomography; cxr-chest radiograph; esr-erythrocyte sedimentation rate; hgb-hemoglobin; ig-immunoglobulin; il-interleukin; ivig-intravenous immunoglobulin; ldh-lactate dehydrogenase; lfts-liver function tests; lus-lung ultrasound; nk-natural killer cell; nr-not reported; pct-procalcitonin; plts-platelets; pt-prothrombin time; ptt-partial thromboplastin time; rsv-respiratory syncytial virus; tnf-tumor necrosis factor. *one patient met our inclusion, but the publication was a case series. eleven patients (0¢14%) met the cdc's criteria for mis-c [7] . compared to control (n=14), children with severe inflammation were more likely to present with dyspnea (72¢7% vs 28¢6%), vomiting (45¢5% vs. 7¢1%), and diarrhea (45¢5% vs. 21¢4%). white blood cell counts were comparable between the groups; however, patients with mis-c have significant lymphopenia (11¢1% vs. 41¢8%). no difference was noted in platelets or liver function markers. serum lactate dehydrogenase and d-dimer were higher in children with mis-c (p<0¢05, details provided in table 7) . also, patients with mis-c had lower expression of circulating cd16 + cd56 + natural killer cells. imaging findings and treatments were comparable in mis-c and non-mis-c patients. over the last 6 months, there have been over 6¢4 million worldwide cases of sars-cov-2 infection and our knowledge of the disease and its epidemiologic and clinical characteristics continue to evolve [4]. however, since it was first reported in wuhan city in december 2019, most studies have focused on symptomatic adults. in the presence of this rapidly emerging, novel infection, identification of clinical and laboratory characteristics in the pediatric population is essential to guide clinical care, predict disease severity, and determine prognosis. in this context, we performed the largest and most comprehensive systematic review of published studies involving pediatric patients with known covid-19. our systematic review summarized the clinical, laboratory and radiologic features of covid-19 in neonates, children, and adolescents. our review also supports the findings by a recent systematic review by castagnoli et al. [17] their study included a total of 1,065 covid-19 infected children and concluded that, by and large, the prognosis for children was excellent, demonstrated by only one death. compared to that review and other covid-19 pediatric systematic reviews, [18à21] this manuscript has several key advantages: (1) we summarize 131 studies that includes 7780 children from 26 different countries, (2) this report synthesizes underlying pediatric medical conditions and delineates bacterial and viral coinfections, (3) we quantitatively describe clinical symptoms and imaging findings, (4) herein, we conglomerate the mean and standard deviation of frequently used laboratory analytes in covid-19 positive children, (5) our report presents antiviral therapies by specific agents, and (6) our systematic review offers a preliminary comparison of patients with/without mis-c. although sars-cov-2 infection was first identified in china, the united states has now amassed the highest number of confirmed cases [18] . calculations made on june 4th, 2020 from the covid-19 dashboard by the center for systems science and engineering at johns hopkins university indicate that china has 4¢5% of total confirmed covid-19 cases compared to the united states [4] . as expected, the most common vector for childhood infection is close contact to an affected family member or residing in an area with a high population of cases. our findings align with the results of an april 2020 report by dong et al, in which there was a clear trend that the disease spread rapidly from a chinese province to surrounding provinces and cities in children from december to february [22] . furthermore, qiu and colleagues studied 36 pediatric covid-19 positive patients in which ten patients (28%) were asymptomatic latent cases identified secondary to an adult family member who was infected, symptomatic, or traveled to an endemic area [23] . this lends concern that children, who may be asymptomatic, may play a role in community transmission of the virus. continuous data presented as mean § sd. np-nasopharyngeal. results from this systematic review echo findings describing milder symptoms in pediatric cases of sars-cov-2 infection [17, 21] . for instance, the most common clinical manifestations we found were fever (59¢1%), cough (55¢9%), rhinorrhea (20¢0%) and myalgia/fatigue (18¢7%). unlike adults, children rarely progressed to severe upper respiratory symptoms requiring intensive care unit admission [24, 25] . although transmission rates for sars-cov-2 are high, symptoms are less severe than sars/middle east respiratory syndrome (mers) infection [26] . serum inflammatory markers, specifically d-dimer, procalcitonin, creatine kinase, and interleukin-6, were consistently abnormal in the studies included in this review. alterations to acute-phase infectionrelated biomarkers are corroborated in adult case series and metaanalyses [27, 28] . however, we must take caution when interpreting these outcomes and await more robust, longitudinal laboratory analyses. again, these blood analyses are non-specific and may merely represent a pro-inflammatory state induced by the virus [26] . in terms of imaging findings, we found that most patients had normal chest x-rays, a finding that is not surprising as most pediatric patients did not present with respiratory symptoms. paralleling this review, a meta-analysis of ct features for covid-19, showed that diffuse bilateral ground-glass opacities were the most common finding at all stages of disease [29, 30] . despite these promising associations, it is important to consider that radiologic manifestations from various pathogens may have a similar impression and should be ruled out. co-infections with other respiratory illnesses including influenza and mycoplasma were described in 72 patients. as elegantly described by cox and colleagues, most fatalities from the 1918 influenza outbreak were secondary to bacterial infection [31] . thus, future reports should not only describe coinfections but also detail pertinent negatives. at present, our study had a low rate of reporting the infectious workup (26¢7) of patients. illustrating the importance, one of two patients that died in the study by shekerdemian et al was due to gram negative sepsis in a child with comorbidities who developed end organ failure [32] . although most children have an uneventful course, a present concern is an inflammatory cascade in pediatric patients with covid-19 [8, 9] . clinical presentation includes an unremitting high fever, and includes systemic signs such as rash, conjunctivitis, and/or gastrointestinal symptoms. the case series of eight children from london required respiratory assistance, whether it was oxygen support (n=1), noninvasive ventilation (n=2) or intubation and mechanical ventilation (n=4) [8] . one patient was so ill that he required mechanical ventilation and extracorporeal membrane oxygenation. in addition, all required vasopressor support and demonstrated elevated levels of ferritin, d-dimers, troponin, procalcitonin, and c-reactive protein (crp). additionally, cardiac imaging showed ventricular dysfunction in five children. in another article, italian investigators describe ten patients with mis-c. correspondingly, they describe patients manifesting with fever, diarrhea (n=6), and abnormal echocardiograms (n=6). laboratory specifics showed elevated crp, lymphopenia, thrombocytopenia, and elevated ferritin levels [9] . we found evidence of mis-c features in 11 children who also presented with fever (n=11), dyspnea (n=8), and diarrhea (n=6). according to riphagen and verdoni, lymphopenia was marked in our cohort of patients, as well as increased levels of lactate dehydrogenase, crp and d-dimer [8, 9] . despite low numbers we did observe an interesting lower level of cd16 + cd56 + natural killer (nk) cells in patients with mis-c. both lymphopenia and a reduced number/activity of nk cells in adults has correlated with a more severe covid-19 disease progression [33à36] . little is known about the perinatal aspects of covid-19, and there have been several reported cases of neonatal infection, suggesting a possible perinatal or vertical transmission during pregnancy [37] . however, in a report by chen et al., all nine neonates born to covidgiven that the mean (sd) in our pediatric population was 8.9 § 0.5 years we provide the lowest to highest numbers presented in children with a similar age range when possible (data from nelson textbook of pediatrics 2019). *gregory's pediatric anesthesia 2012 5 th edition. y mayo clinic laboratories. 19 positive mothers tested negative for the virus after cesarean delivery [38] . in another study by zhang et al., 10 neonates from covid-19 positive mother all tested negative for the infection [39] . moreover, this is further supported by analysis of breast milk and placental pathologic specimens from covid-19 positive mothers, which have returned negative for the virus [40, 41] . lastly, vertical transmission was not observed with either sars-cov-1 or in mers-cov; [41] therefore, it is unlikely that maternal vertical transmission during third trimester occurs, or is likely very rare. however, from the limited data published, we cannot determine the consequences of sars-cov-2 infection in early pregnancy and if it can be transmitted to the fetus and hinder organ development, malformations, growth abnormalities, or even lead to premature labor or spontaneous abortions [42, 43] . also, dong et al communicated an alarming finding in which the proportion of severe and critical cases were higher in neonates when compared to the >16-year-old age group (10¢6% vs. 3¢0%) [44] . as a community, we must stay vigilant, practice social distancing, hand wash frequently, and be especially careful with our children who are at potentially higher risk for critical disease (e.g. multiple comorbidities, weakened immune systems, etc.). there are several limitations to this review. first, many of the included studies were case reports or cases with low patient numbers. second, the level of evidence for all the studies was low. next, we unified the laboratory data to mean and standard deviation. there are inherent issues when using averages including the impact of outliers. we did not include suspected cases, which would allow for a direct comparison of symptoms, labs, imaging, and outcome data. of concern, many of the studies were incomplete and did not include a comprehensive picture of the patients. future studies should not generalize data ("cbc was normal"), or categorize laboratory values (i.e., number of patients with elevated crp), or group therapies (i.e., patient received "antiviral therapy"), or display aggregate data between adults and children. if feasible, divide the symptoms, laboratory markers, and imaging characteristics by children vs. adults. a better understanding of covid-19 requires access to data, even if it is provided in the appendix or supplementary section of the article. in this way, we will be able to identify the best biomarkers that can stratify disease severity and potential short-and long-term outcomes. another limitation, is that we had a small number of patients that fit the criteria for mis-c. reasons for the small number of patients includes a lack of reporting all of the signs, symptoms, and laboratory markers necessary to make the diagnosis (especially duration of fever). missing information for laboratory markers (d-dimer, interleukins, and cd%) hinders our preliminary findings. lastly, the table 7 comparison between covid-19 children with and without multisystem inflammatory syndrome in children (mis-c). mis-c data are presented as mean (sd) or median (iqr). student's t test, wilcoxon rank sum, or fisher's exact was conducted as appropriate. * denotes limited data was in at least one group (d-dimer in mis-c=3; interleukins and cds had 4 in non-mis-c group vs. 4-5 in mis-c). literature focusing on covid-19 is very dynamic and growing rapidly and we expect the rates, especially for mis-c, of our outcomes to change. ansel hoang-literature search, study design, data collection, data analysis, data interpretation, manuscript writing, risk of bias, tables. kevin chorath-literature search, study design, data collection, data interpretation, manuscript writing, risk of bias. axel moreira-literature search, study design, data collection, manuscript writing, data interpretation, risk of bias. mary evans-data collection, verifying data integrity, risk of bias. finn burmeister-morton-data collection, verifying data integrity. fiona burmeister-data collection, verifying data integrity, risk of bias. rija naqvi-data collection, verifying data integrity, risk of bias. matthew petershack-data collection, risk of bias. alvaro moreira-literature search, study design, data collection, data analysis, data interpretation, manuscript writing, figure, tables, oversight. none. creatine kinase (u/l) 77 risk for transportation of coronavirus disease from wuhan to other cities in china the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19 who declares covid-19 a pandemic who. coronavirus disease 2019 (covid-19): situation report-28 covid-19 in children: an epidemiology study from china resources for emergency health professionals hyperinflammatory shock in children during covid-19 pandemic lancet2020 an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study quality assessment tool for observational cohort and cross-sectional studies. nhlbi. nih.gov/health-topics/study-quality-assessment-tools risk of bias tools in systematic reviews of health interventions: an analysis of prospero-registered protocols rules of evidence and clinical recommendations on the use of antithrombotic agents estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range coronavirus disease 2019 in children -united states, 2020. mmwr morb mortal wkly rep 2020february 12àapril 2 sars-cov-2 infection with gastrointestinal symptoms as the first manifestation in a neonate neonatal early-onset infection with sars-cov-2 in 33 neonates born to mothers with covid-19 in wuhan, china severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review clinical manifestations of children with covid-19: a systematic review clinical characteristics of covid-19 infection in newborns and pediatrics: a systematic review characterisation of covid-19 pandemic in paediatric age group: a systematic review and meta-analysis systematic review of covid-19 in children shows milder cases and a better prognosis than adults epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang. china observat cohort study lancet infect dis clinical, laboratory and imaging features of covid-19: a systematic review and meta-analysis clinical features of patients infected with 2019 novel coronavirus in wuhan middle east respiratory syndrome coronavirus in children elevated interleukin-6 and severe covid-19: a metaanalysis clinical characteristics of 3,062 covid-19 patients: a metaanalysis clinical and ct features in pediatric patients with covid-19 infection: different points from adults a systematic meta-analysis of ct features of covid-19: lessons from radiology co-infections: potentially lethal and unexplored in covid19 characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units nkg2a and covid-19: another brick in the wall immunology of covid-19: current state of the science lymphopenia predicts disease severity of covid-19: a descriptive and predictive study prognostic value of leukocytosis and lymphopenia for coronavirus disease severity. emerg infect dis possible vertical transmission of sars-cov-2 from an infected mother to her newborn clinical characteristics, and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records clinical characteristics of children with coronavirus disease 2019 in hubei coronavirus disease 2019 (covid-19) and pregnancy: what obstetricians need to know perinatal aspects on the covid-19 pandemic: a practical resource for perinatal-neonatal specialists epidemiology of covid-19 among children in china funding sources: parker b. francis; pilot grant 2r25-hl126140. funding agencies had no role in the writing of the manuscript or the decision to submit. supplementary material associated with this article can be found in the online version at doi:10.1016/j.eclinm.2020.100433. key: cord-274834-24v2b509 authors: lima, rosiane; gootkind, elizabeth f.; de la flor, denis; yockey, laura j.; bordt, evan a.; d’avino, paolo; ning, shen; heath, katerina; harding, katherine; zois, jaclyn; park, grace; hardcastle, margot; grinke, kathleen a.; grimmel, sheila; davidson, susan p.; forde, pamela j.; hall, kathryn e.; neilan, anne m.; matute, juan d.; lerou, paul h.; fasano, alessio; shui, jessica e.; edlow, andrea g.; yonker, lael m. title: establishment of a pediatric covid-19 biorepository: unique considerations and opportunities for studying the impact of the covid-19 pandemic on children date: 2020-09-11 journal: bmc med res methodol doi: 10.1186/s12874-020-01110-y sha: doc_id: 274834 cord_uid: 24v2b509 background: covid-19, the disease caused by the highly infectious and transmissible coronavirus sars-cov-2, has quickly become a morbid global pandemic. although the impact of sars-cov-2 infection in children is less clinically apparent, collecting high-quality biospecimens from infants, children, and adolescents in a standardized manner during the covid-19 pandemic is essential to establish a biologic understanding of the disease in the pediatric population. this biorepository enables pediatric centers world-wide to collect samples uniformly to drive forward our understanding of covid-19 by addressing specific pediatric and neonatal covid-19-related questions. methods: a covid-19 biospecimen collection study was implemented with strategic enrollment guidelines to include patients seen in urgent care clinics and hospital settings, neonates born to sars-cov-2 infected mothers, and asymptomatic children. the methodology described here, details the importance of establishing collaborations between the clinical and research teams to harmonize protocols for patient recruitment and sample collection, processing and storage. it also details modifications required for biobanking during a surge of the covid-19 pandemic. results: considerations and challenges facing enrollment of neonatal and pediatric cohorts are described. a roadmap is laid out for successful collection, processing, storage and database management of multiple pediatric samples such as blood, nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine. using this methodology, we enrolled 327 participants, who provided a total of 972 biospecimens. conclusions: pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the multisystem inflammatory syndrome in children. the specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to sars-cov-2 infection and disease abnormalities. the successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies. conclusions: pediatric biospecimens will be key in answering questions relating to viral transmission by children, differences between pediatric and adult viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the multisystem inflammatory syndrome in children. the specimens in this biorepository will allow necessary comparative studies between children and adults, help determine the accuracy of current pediatric viral testing techniques, in addition to, understanding neonatal exposure to sars-cov-2 infection and disease abnormalities. the successful establishment of a pediatric biorepository is critical to provide insight into disease pathogenesis, and subsequently, develop future treatment and vaccination strategies. keywords: covid-19, sars-cov-2, multisystem inflammatory syndrome in children (mis-c), viral transmission, viral susceptibility, biorepository, biobank, pediatric the global pandemic of covid-19, caused by the highly infectious and transmissible coronavirus, sars-cov-2, has become a leading cause of death in older adults [1] . while adults can develop life-threatening complications such as pneumonia, acute respiratory distress syndrome (ards), and sepsis from sars-cov-2 infection, its impact on children is less clinically apparent and needs to be studied. collecting high-quality biospecimens from infants, children and adolescents in a standardized manner during the covid-19 pandemic is essential for understanding the biologic consequences of sars-cov-2 infection in children. specific questions that must be addressed revolve around the role children play in viral transmission, differences in pediatric viral susceptibility and immune responses, which could guide potential therapies for adults, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the development of severe hyperinflammatory shock and cardiac damage seen in multisystem inflammatory syndrome in children (mis-c). outlined here is a roadmap for establishing a biorepository of specimens obtained from infants, children and adolescents during the covid-19 pandemic. special attention is provided to pediatric-specific considerations in the establishment of a biorepository during the covid-19 pandemic. the goal is to enable pediatric centers world-wide to collect samples in a standardized manner to drive forward our understanding of covid-19. the impact of sars-cov-2 infection on infants and children is not well-defined. children are typically asymptomatic or mildly symptomatic during the acute infection, although some can develop significant complications requiring intensive care. in order to capture the full range of sars-cov-2 infection in the pediatric population, a covid-19 biospecimen collection study was designed and implemented, including patients seen in urgent care clinics and hospital settings, neonates born to sars-cov-2-infected mothers, and asymptomatic children. each study population required specific tailoring of study conduct to effectively and efficiently collect critical samples. cornerstones of the biorepository included open dialogue between research and clinical team members, a sensitivity to procedures required for specimen collection in children, and clear documentation of study participation and sample collection. close communication and collaborations with the adult covid-19 biorepository enable paralleled recruitment efforts and processing procedures and ensured consistency and harmonization across patient cohorts, facilitating high-quality comparisons between patient groups and with adult cohorts. central to the operation, physician-scientists in pediatrics, neonatology, medicine-pediatrics, and obstetrics-gynecology harmonized sample collection protocols, established clinical connections and provided clinical and scientific context to covid-19-related research in the neonatal and pediatric population. to establish a pediatric covid-19 biorepository during the surge of covid-19 cases locally, protocols were rapidly submitted to our institutional biosafety committee (ibc, mgh ibc#2020b000061) and the institutional review board (irb, mgh irb#2020p000955) for approval. during this initial wave of the covid-19 pandemic in late march 2020, covid-19 research proposals were prioritized by the ibc and irb. a biosafety protocol was submitted to the ibc to transition from a biosafety level 2 (bsl2) to an enhanced bsl2+ laboratory environment, allowing collection, processing, and storage of sars-cov-2-infected samples. ibc approval was obtained within 2 weeks. an expedited irb review facilitated irb approval 2 days following submission. figure 1 displays a timeline of study activity relative to the community surge of covid-19 cases in massachusetts. eligible participants in all cohorts were identified by screening outpatient clinic schedules or hospital admission lists, then discussing potential patients with care team members. if appropriate, parents/guardians or patients (if > 18 years of age) were called by phone to introduce the study and, if interested in participation, an informed consent was completed by phone. participants or their parent/guardian also selected which biospecimens they would provide to the biorepository. assent was completed by phone, when possible, with parents/ guardian present for children 7-17 years of age. inperson consent/assent was waived by the irb to avoid close contact between patients and research staff and to abide by the social distancing measures implemented by the state. witness requirements were also waived as a result of the restricted visitor hospital policy due to the pandemic. one copy of the signed consent form, and assent form if appropriate, was emailed to enrolled patients or parents/guardians, and another was uploaded into the electronic medical record flagging the patient as a research participant, clearly documenting research participation for the clinical care teams facilitating sample collection. paper copies were not provided to participants due to the covid-19 restrictions. upon enrollment, participants were assigned a unique study id number using redcap, a secure, centralized online database platform that allows simultaneous recruitment at multiple sites without risking assigning the same number to multiple patients. in order to include pediatric and neonatal patients from a range of clinical presentations for covid-19, we established 4 cohorts of patients from ages 0-25 years, reflecting the ages of patients cared for by the pediatric teams during the surge of covid-19 cases locally: 1) pediatric patients with mild-moderate covid-19, presenting to the mgh covid-19 urgent care clinics, 2) pediatric patients with severe covid-19 or mis-c requiring hospitalization, 3) newborns born to mothers infected with sars-cov-2 at any point during their pregnancy and infants born to non-infected mothers, and 4) asymptomatic children presenting to their wellvisits during the pandemic. each cohort presented unique challenges and required tailored strategies for a successful recruitment. in the pediatric urgent care units, challenges in enrollment included variability in patient volume and frequent rotation of nurses, medical assistants, and physicians. research coordinators had to be flexible to adapt to the frequently changing workflow within the clinic. for enrollment in the hospitalized cohort, the research team remained attentive to new admission lists and promptly completed enrollment protocols in order to obtain specimens prior to the initiation of treatment, as interventions such as intravenous immunoglobulin or steroids would interfere with the natural immune responses to sars-cov-2 infection. specimen collection from the hospitalized cohort was coordinated with clinical laboratory collections to minimize blood draws and collection procedures. for enrollment of newborns, the research coordinators coordinated with maternal arm of the adult covid-19 biorepository to allow simultaneous enrollment of mother and newborns prior to birth facilitating the recruitment process and limiting non-clinical interactions with the mother during the perinatal period. additionally, blood volumes collected for newborns were minimized to < 1 ml obtained by heal stick and coordinated with blood collection for newborn screening. enrolling well-visits was challenging as blood draws are not routinely obtained in all ages and children are often unwilling to undergo voluntary venipuncture. in each cohort, the research staff was mindful of the physical and [2] emotional stress the care teams were enduring while caring for patients with covid-19 and therefore sought to minimize disruptions in clinical care. figure 2 provides a schematic of the recruitment strategy. pediatric patients with mild-moderate covid-19 as most children did not require hospital-level care, significant efforts were made to enroll patients in the outpatient setting. covid-19 screening clinics, called respiratory infection control clinics, were established at massachusetts general hospital. as covid-19 symptoms are non-specific and current diagnostic reporting is time-delayed, all patients presenting to the pediatric covid-19 screening clinics were eligible to participate in the biorepository. during the surge of covid-19 cases locally, young adults up through 25 years of age were seen in the pediatric covid-19 clinics. for patients seen in the respiratory infection control clinics, the crc called eligible participants via telephone after acquiring approval from the lead physicians in the clinics. after acquiring verbal consent over the telephone, the crc alerted the clinical team of patient enrollment and the clinical teams obtained specimens for research. participants who provided informed consent could give nasopharyngeal, oropharyngeal swabs, and/or blood. stool and urine were not collected given time limitations of clinic visits and patient flow patterns established to minimize potential covid-19 exposures to clinical staff. blood was collected into one tube with an edta anticoagulant (edta tube) (bd), one serum separator tube (sst) (bd), and a paxgene rna tube (bd). blood volumes varied, depending on the age and weight of the patient, in accordance with limits established by the irb. the aerosolizing procedure of collecting nasopharyngeal and oropharyngeal swabs into 15 ml falcon tubes, containing 3 ml phosphate buffered saline (pbs) (gibco), was performed by clinical team members wearing n95 mask, face shield, protective outer gown, and disposable gloves. patients with severe covid-19 or multisystem inflammatory syndrome in children requiring hospitalization pediatric patients who were hospitalized with suspicion of sars-cov-2 exposure and/or symptoms concerning for sars-cov-2 infection or mis-c were identified by members of the research team, who subsequently requested approval from the clinical team to approach the patient. a member of the research team contacted the patient and family via phone to obtain informed consent, as described above, and coordinated with both the clinical and tcrc teams for specimen collection. sample collection was pre-planned with the clinical teams via emails and occurred every 2-3 days for this cohort of patients. hospitalized patients could opt to provide urine, stool, sputum, or if intubated, tracheal aspirates, in addition to blood, nasopharyngeal and oropharyngeal swabs. phlebotomy was aligned with clinical blood draws, when feasible, although participants had an option to undergo a separate venipuncture for research purposes. blood was collected into an edta tube, an sst tube, and a paxgene rna tube. repeat samples were collected on alternating days, as feasible. based on daily coordination between the research and clinical teams, discarded blood from clinical labs were also obtained from hospitalized patients. pregnant women with confirmed sars-cov-2 infection followed in the mgh obstetrics practice, presenting to the labor and delivery (l&d) unit, or hospitalized for sars-cov-2 illness, were approached to enroll their infant in the pediatric covid-19 biorepository following birth in collaboration with the maternal arm of the adult covid-19 biorepository. when universal screening for sars-cov-2 infection was initiated on all pregnant women admitted to l&d, asymptomatic sars-cov-2 positive patients were identified and offered enrollment. women who tested negative for sars-cov-2 were also approached as a control group. the pregnant mothers were simultaneously offered enrollment in the companion obstetric covid-19 biorepository, which included collection of placental biopsies, umbilical cord blood, and other maternal samples. the clinical team assessed the patient's interest in the biorepository, then a member of the research staff contacted the patient via telephone to obtain informed consent. parents could opt to have newborn blood, nasopharyngeal and oropharyngeal swabs, urine, stool, and (if intubated) tracheal aspirates collected. all samples were collected in the clinical setting by the clinical team members to accommodate covid-19 infection control guidelines, minimizing the risk of sars-cov-2 transmission and limit personal protective equipment (ppe) use. blood was collected via heel stick between 24 and 36 h of life, simultaneously with the heel stick for clinical newborn screening, into two edta microtainer tubes (bd). research nasopharyngeal and/or oropharyngeal swabs were obtained after 24 h of life, batched at the time of the nasopharyngeal swab for sars-cov-2 testing, if performed clinically. stool and urine were collected on day of life 0 and 2. stool was collected directly from the diaper. urine was collected by placing cotton balls in the diaper, then transferring the urine-soaked cotton balls into a specimen cup for transport. if the recruited newborn was intubated for clinical indications, tracheal aspirates were collected at the time of clinical suctioning. asymptomatic children presenting to their well-visit during the covid-19 pandemic children presenting for their 2-, 3-, or 4-year annual well-child visit with their pediatrician for planned phlebotomy were eligible to participate in this cohort. eligible patients were identified by study staff and clinicians. if appropriate, researchers contacted the parents via telephone prior to their visit to explain the research and obtain informed consent. blood and saliva were collected during their clinical phlebotomy. saliva collection is not considered an aerosolizing procedure; thus, these specimens could be collected in clinic without the need for n95 mask use. the specimens were immediately transported to the laboratory for processing. redcap databases were used to record all study data, including: 1) an enrollment log serving as the decoding log -study id numbers were assigned consecutively across all four patient groups; 2) a laboratory processing database with pertinent processing and freezer storage location information; 3) a chart review database, with demographic and clinical data, including covid-19 exposures, sars-cov-2 polymerase chain reaction (pcr) results, symptoms, and outcomes; 4) a questionresponse database about covid-19 exposures and risk factors, specifically for the well-visit cohort. in accordance with specimen transport guidelines, specimens were sealed in a leak-proof container labeled with subject's study id, then placed in a tight-sealed, biohazard-labeled, secondary container with a rigid outer container and lockable lid (e.g. igloo cooler) for transport to the laboratory. the entire research team was properly trained on bsl2+ procedures, as required for handling sars-cov-2 specimens. a coordinated effort by research personnel enabled successful and efficient troubleshooting, and processing of high influx of samples to the lab during the acute rise of covid-19 cases in the months of april-june 2020 (fig. 1) . scheduled shifts were implemented throughout the week to ensure the safety of all research staff and sample processing efficiency. three laboratory roles were created: 1) blood processing technician with extensive technical skill required for blood cell isolation, 2) biospecimen processing technician fully trained in bl2+ enhancement protocols, and 3) specimen labeling, quality control, and sample storage staff. these roles optimized processing workflow, safety precautions, and resources (including staff resource). paramount to the success of this biorepository included open communication via emails and the use of mobile group messaging outlets, frequent quality checks between staff regarding data and sample collection and processing, accessible leadership, and coordination with patients' clinical care teams. blood samples were processed following bsl2 safety guidelines, with a lab coat, nitrile/latex gloves, and a face shield or safety goggles. all other samples, including nasopharyngeal and oropharyngeal swabs, sputum, saliva, tracheal aspirates, stool, and urine were processed following bsl2+ safety guidelines. bsl2+ safety precautions require all samples to be processed in a certified biosafety cabinet (bsc), class ii a2, with intake airflow. well-trained laboratory personnel handling infectious specimens were required to wear closed-front water impermeable gowns, double nitrile/latex gloves, sleeve covers, and a face shield. outer gloves were removed when moving away from the bsc and replaced with a new glove when returning to work in the bsc. blood samples collected in tubes with an edta anticoagulant were stored at room temperature until processed, within 24 h of collection. tubes were spun at 1000 g for 10 min with brake activated. plasma was then collected, aliquoted, stored at − 80°c, and logged in the redcap database (fig. 3b) . immediately following the removal of plasma, samples with greater than 2 ml initial volume were processed for pbmc isolation using a ficoll density gradient [3] . briefly, blood was transferred into a 50 ml conical tube, then diluted 1:1 with hanks' balanced salt solution without calcium or magnesium (hbss minus) (gibco). this diluted blood was then gently layered on top of ficoll-paque plus (ge healthcare) at 2:1 ratio (2 volumes of blood diluted with hbss minus to 1 volume ficoll). careful attention was made to avoid any mixing of blood with the ficoll layer. the conical tube was then centrifuged at 1000 g for 30 min at room temperature with brake inactivated to allow adequate layering of cellular components. the cloudy ring below the plasma and above the ficoll (i.e. the pbmc layer) was collected and transferred to a new 15 ml conical tube, with hbss minus added to bring the volume to 15 ml (fig. 3a) . this tube was then centrifuged at 330 g for 10 min, with high brake activated. the supernatant was removed, the pbmc pellet was again washed with hbss minus, and then resuspended in 10 ml hbss minus for counting. cell count was obtained by diluting 10 μl of sample with 90 μl of trypan blue, mixed, and sampled on a hemocytometer. cells were then frozen in freshly-prepared freezing medium (rpmi 1640 medium with 1% penicillin-streptomycin, l-glutamine, 1% sodium pyruvate, 1% non-essential amino-acids, and 20% fetal bovine serum (fbs) (sigma)) with 10% dmso (sigma) for a goal concentration range of 5-10 million cells/vial, placed in a chilled mr. frosty filled with isopropanol, then immediately placed at − 80°c. final concentration (5-10 million cells per 1 ml of freezing medium) and number of aliquot vials were logged. the following day, pbmc cryovials were moved to a liquid nitrogen freezer for long term storage, and location was recorded in specimen log. pbmcs were isolated within 24 h of phlebotomy, although higher cell counts were obtained if isolated within 3-4 h of collection. if less than 5 ml blood was collected, a 15 ml conical tube, rather than a 50 ml conical tube could be used for ficoll layering. fresh freezing media were made throughout the day for each sample batch. neutrophils were extracted from the red blood cell layer that remained following the collection of pbmcs (fig. 3a) . neutrophils were isolated using easysep direct human neutrophil isolation kit (stemcell technologies). the remaining blood layer was incubated with easysep direct rapidspheres and easysep direct human neutrophil isolation cocktail, fig. 3 overview of laboratory blood processing procedures following bsl2 containment guidelines depicting steps for a) collection of plasma, isolation of pbmc and pmn, from blood collected into an edta tube and b) collection of serum from an sst blood tube (created with biorender.com) then diluted in easysep buffer. neutrophils were isolated by successive negative magnet selection using easysep magnets, then counted using a hemocytometer and aliquoted into eppendorf tubes for rna extraction (1 × 10 5 cells/tube) or dna analysis (5 × 10 6 cells/tube). neutrophils designated for rna extraction were resuspended in 100 μl of rna lysis buffer (tcl) (qiagen) with 1% β-mercaptoethanol (sigma), immediately stored at − 80°c and logged. neutrophils planned for dna analysis were pelleted then directly stored at − 80°c and logged. for rna extraction steps, a cleaning agent, such as rna-sezap should be used to remove rnase from the working surface. rna lysis buffer should be newly made for each sample using a 10:1 tcl to β-mercaptoethanol ratio. serum samples were collected from blood drawn into serum separator tubes without any anticoagulant (bd). blood was kept at room temperature, standing upright for 30-60 min, then spun at 1200 g for 10 min with brake activated. serum was then collected, aliquoted, stored, and logged (fig. 3b) . swab samples were delivered in phosphate buffered saline (pbs) [4] . samples were directly aliquoted into 1 ml aliquots, then immediately stored at − 80°c and logged (fig. 4a) . samples collected into a collection cup were mixed well at 1:1 ratio with 500 mm dl-dithiothreitol (dtt) (sigma)/pbs solution according to cdc recommendations. diluted samples were then divided into 1 ml aliquots, volume permitting, immediately stored at − 80°c and logged (fig. 4b) . aspirates collected into a sterile collection cup were divided into 1 ml aliquots (1 ml/vial), immediately stored at − 80°c and logged (fig. 4c) . stool samples collected from a diaper or specimen cup were divided using a micro spatula, volume permitting, into cryovials with 1 ml rnalater (invitrogen), empty cryovials without any additive/reagent, up to the 1.5 ml tube mark, and cryovials with 1 ml buffered glycerol saline (fisher). stool samples were fully submerged in rnalater or glycerol solution prior to immediate storage at − 80°c. samples were logged onto database (fig. 4d) . urine samples collected with cotton balls placed inside baby diapers were transferred using forceps, to a 10 ml syringe to dispense at most 1 ml of fluid into cryovials and immediately stored at − 80°c. samples collected into a tube or a sterile collection cup were aliquoted into cryovials (at 1 ml at most/vial) and immediately stored at − 80°c (fig. 4e) . supplies required for specimen collection and processing are listed in supplemental table 1 . sample labels, logging, storage, and quality control were performed by assigned lab #3 personnel. the pediatric covid-19 biorepository enrolled 327 pediatric and neonatal patients from a range of clinical presentations, including 178 patients from the urgent care/respiratory infection control clinic, 48 hospitalized children, 85 newborns born to mothers with or without sars-cov-2 infection, and 16 asymptomatic children presenting for their well-visits. the average age was 11 (± 8) years for enrolled children and adolescents and 1.3 (±1.3) days for newborns. equal gender distribution was seen, except more males were enrolled in the hospitalized cohort (60%, n = 29). sixty-four participants were positive for sars-cov-2 by clinical testing, most of whom were seen in the respiratory infection control clinic, while 21 patients were diagnosed with mis-c, all of whom were hospitalized. the one patient presenting to the respiratory infection control clinic with mis-c was ultimately hospitalized. table 1 characterizes total enrollment number, age, gender, sars-cov-2 infection status, and mis-c diagnosis within each enrollment site. a total of 972 biospecimens were collected. these biospecimens included 295 blood samples, 181 nasopharyngeal swabs, 145 nasopharyngeal swabs, 172 stool samples, 154 urine samples, 4 tracheal aspirate samples, and 21 sputum/saliva samples. hospitalized patients and newborns had the option of providing subsequent sampling. table 2 depicts the sample collection from each enrollment site. the goal of the biorepository is to provide high quality biospecimens for studies understanding how infants and children are impacted by and contribute to covid-19 pandemic. establishing a standardized biorepository collection protocol facilitates comparison of samples across institutions and with adult biorepositories. key neonatal and childhood factors of interest that will be studied using this biorepository focus on: 1) informing pediatric contribution to viral transmission, 2) teasing apart the dichotomy between pediatric and adult immune responses to covid-19, 3) ascertaining the impact of maternal sars-cov-2 infection on child fetal development, and 4) elucidating factors driving the mis-c. in this study, nasopharyngeal and oropharyngeal swabs were collected from pediatric patients presenting with symptoms concerning for sars-cov-2 infection in both the outpatient and hospitalized setting, from newborns born to mothers infected with sars-cov-2, and from healthy controls. additionally, saliva was collected from young children presenting for their annual well-visit. blood, tracheal aspirates, stool, and urine were also collected from the hospitalized patients and newborns for assessment of viral load. questions relating to the role of viral carriage in the pediatric population can be addressed using these samples. case reports and recent research studies suggests that asymptomatic children carry high viral loads despite lack of symptoms [5] [6] [7] . in adults, severe infection is not necessarily associated with a significant increase in viral loads by nasopharyngeal swab [8] , and asymptomatic individuals appear to have equal viral loads as symptomatic individuals [9] . the potential correlations between viral load, symptoms, and exposures have yet to be clarified in the pediatric population. age-stratification within adults show no differences in viral load across age-groups, although younger patients were less likely to develop severe disease [8] , thus a similar comparison among children would be informative. additional questions remain as to whether there are risk factors affecting viral load density in children, including household contacts or other environmental factors. viral studies are also needed to determine accuracy of viral testing techniques within the pediatric population. including infants born to covid-19 infected mothers will allow assessment of viral exposure in the airway, and through the meconium, giving important insight into neonatal exposure to sars-cov-2 infection. understanding how children are infected with sars-cov-2 will provide critical insight into how viral loads may impact disease severity in children, and how children may contribute to viral transmissibility driving this pandemic. these data will be critical to making decisions about risk factors for re-opening of schools and childcare as the pandemic progresses. covid-19 results in a major apparent dichotomy of immune response between children and adults [10] . children often develop mild infections whereas adults more commonly develop severe disease associated with high levels of mortality [11] . neonates appear to be unaffected, even when born to covid-19 positive mothers [12] . it has been postulated that children are less impacted by viral infection because they have fewer angiotensin-converting enzyme 2 (ace2) viral binding sites [7, 13] , although the research thus far remains conflicted. in this study, rna obtained from nasopharyngeal and oropharyngeal swabs, and/or saliva collected from neonates, children, and young adults, can be used to characterize ace2 expression, and potentially shed light on the availability of viral binding sites across the age span. further, prior research has shown immunosenescence in aged individuals, which affects t cell and b cell function, and cytokine production by innate immune cells [14] . it is yet to be evaluated as to whether this plays a central role in the age differences in the morbidity and mortality from covid-19. additionally, mis-c is shown to be driven by a cytokine storm and macrophage activation [15] . peripheral blood monocytes, plasma, serum, and neutrophil rna collected as part of this biorepository can be used to answer these questions. understanding the disease abnormalities may provide key insight into therapeutic targets. this study collects plasma, serum, pbmcs, and neutrophil rna from sars-cov-2 infected and uninfected children with a range of symptoms for comparison. neonatal development intimately depends on maternal health. prior infections and disease states causing maternal inflammatory activation and cytokine storm have resulted in increased risk of autism spectrum disorder, schizophrenia, cerebral palsy, cognitive delay, depression, and bipolar disorder in exposed children [16] [17] [18] . the effect of the sars-cov-2 hyperinflammatory milieu on the developing fetus is yet to be seen. this biorepository, partnered with the obstetric covid-19 biorepository will obtain placental tissue, cord blood, maternal and neonatal biospecimens to address these critical questions. following a mild or symptomatic infection of covid-19, children can develop a severe, post-infectious inflammatory response syndrome, termed multisystem inflammatory syndrome in children (mis-c), which is characterized by hyperinflammatory shock [19] , "kawasaki-like" cardiac damage, and possible death [20] . risk all enrolled participants provided clinical and demographic data. enrolled subjects had the option of selecting which biospecimens they would like to provide. stool and urine were not collected from participants enrolled in the urgent care and well-visit cohorts for logistic reasons, unless these individuals were later hospitalized for covid-19-related illness. enrolled subjects could also consent to provide specimens, then later decline any or all specimen collection. repeat biospecimen collection could occur if participants re-presented to care, or if hospitalized for multiple consecutive days factors for developing mis-c and biomarkers predicting severe complications need to be identified. these specimens collected through this pediatric covid-19 biorepository will be used to characterize the immune responses driving mis-c in hopes of mitigating this lifethreatening complication. although children were initially felt to be spared from covid-19, it has become clear that much needs to be learned as to how children and newborns are impacted by the pandemic. research is needed to address viral transmission by children, differences in pediatric viral susceptibility and immune responses, the impact of maternal sars-cov-2 infection on fetal development, and factors driving the mis-c. this pediatric covid-19 biorepository will serve as an important resource providing critical insight into disease pathogenesis, covid-19susceptibility, and future treatment and vaccination strategies. supplementary information accompanies this paper at https://doi.org/10. 1186/s12874-020-01110-y. additional file 1 supplemental table 1 . list of supplies required for specimen collection, processing, and storage in the pediatric covid-19 biorepository commonwealth of massachusetts covid-19 reporting isolation of lymphocytes, granulocytes and macrophages evaluation of swabs, transport media, and specimen transport conditions for optimal detection of viruses by pcr a well infant with coronavirus disease 2019 (covid-19) with high viral load viral rna load in mildly symptomatic and asymptomatic children with covid-19 pediatric sars-cov-2: clinical presentation, infectivity, and immune responses association of viral load with serum biomakers among covid-19 cases sars-cov-2 viral load in upper respiratory specimens of infected patients insight into the pediatric and adult dichotomy of covid-19: age-related differences in the immune response to sars-cov-2 infection coronavirus disease 2019 in children -united states vertical transmission risk of sars-cov-2 infection in the third trimester: a systematic scoping review nasal gene expression of angiotensinconverting enzyme 2 in children and adults immunosenescence: emerging challenges for an ageing population multisystem inflammatory syndrome related to covid-19 in previously healthy children and adolescents long-term risk of neuropsychiatric disease after exposure to infection in utero the fetal origins of mental illness schizophrenia and influenza at the centenary of the 1918-1919 spanish influenza pandemic: mechanisms of psychosis risk hyperinflammatory shock in children during covid-19 pandemic multisystem inflammatory syndrome in u.s. children and adolescents publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations we are incredibly grateful for the selfless contributions by the entire pediatric and obstetrics covid19 received: 13 july 2020 accepted: 30 august 2020 we also acknowledge funding from the national heart lung and blood institute (5k08hl143183 to ly), the cystic fibrosis foundation (yonker18q0 to ly), and the eunice kennedy shriver national institute of child health and human development (1r01hd100022-01 to age). the funder/sponsor did not participate in the work.availability of data and materials a variety of pediatric samples collected during the covid-19 pandemic may become available to other researchers upon reasonable request to the correspondent author and compliance with the partners innovations office. the study received ethics approval from the partners/massachusetts general hospital institutional review board (irb#2020p000955) and the partners/ massachusetts general hospital institutional biosafety committee (ibc#2020b000061). verbal consent to participate was obtained from the participants or from parents/guardians (for children under 18 years of age). verbal assent was obtained, when possible, from children ages 7-18 years of age. all participants signed an irb-approved informed consent prior to participating. not applicable. the authors declare no competing interest. key: cord-284145-7le8303x authors: taylor, johanna; booth, alison; beresford, bryony; phillips, bob; wright, kath; fraser, lorna title: specialist paediatric palliative care for children and young people with cancer: a mixed-methods systematic review date: 2020-05-02 journal: palliat med doi: 10.1177/0269216320908490 sha: doc_id: 284145 cord_uid: 7le8303x background: specialist paediatric palliative care services are promoted as an important component of palliative care provision, but there is uncertainty about their role for children with cancer. aim: to examine the impact of specialist paediatric palliative care for children and young people with cancer and explore factors affecting access. design: a mixed-methods systematic review and narrative synthesis (prospero registration no. crd42017064874). data sources: database (cinahl, cochrane database of systematic reviews, embase, medline, psycinfo) searches (2000–2019) identified primary studies of any design exploring the impact of and/or factors affecting access to specialist paediatric palliative care. study quality was assessed using the mixed methods appraisal tool. results: an evidence base of mainly lowand moderate-quality studies (n = 42) shows that accessing specialist paediatric palliative care is associated with less intensive care at the end of life, more advance care planning and fewer in-hospital deaths. current evidence cannot tell us whether these services improve children’s symptom burden or quality of life. nine studies reporting provider or family views identified uncertainties about what specialist paediatric palliative care offers, concerns about involving a new team, association of palliative care with end of life and indecision about when to introduce palliative care as important barriers to access. there was evidence that children with haematological malignancies are less likely to access these services. conclusion: current evidence suggests that children and young people with cancer receiving specialist palliative care are cared for differently. however, little is understood about children’s views, and research is needed to determine whether specialist input improves quality of life. • • specialist paediatric palliative care is promoted as an important component of children and young adult cancer services, but there is uncertainty about the factors that affect access and the benefits for children who receive this specialist input. • • three reviews, which have aggregated evidence for children with all life-limiting conditions, suggest that the benefits of specialist palliative care include less time in hospital and improvements in quality of life and symptom management. • • the growing number of studies investigating the role of specialist palliative care for children with cancer report mixed results and varying provision, and there is a need to aggregate this evidence to inform future policy and practice. • • accessing specialist paediatric palliative care is associated with less intensive care at the end of life, more advance care planning and fewer in-hospital deaths for children and young people with cancer, but there is no robust evidence to tell us whether these services lead to improvements in quality of life or symptom management. • • children with haematological malignancies are less likely to receive specialist palliative care than children with other cancers. • • uncertainty about when to introduce palliative care services to families, what it comprises and the added value of specialist input was identified as a key barrier to access, as were perceptions that paediatric oncology teams already meet the palliative care needs of their patients. • • evidence is still needed to determine whether specialist paediatric palliative care improves the quality of life and symptom management for children and young people with cancer. • • exploration of why children with certain cancers are less likely to receive specialist palliative care at the end of life may help address this inequality in access. • • a core outcome set study including the views of children and families would help improve future aggregation of evidence in this area. approximately 20% of children and young people diagnosed with cancer do not survive despite significant medical advances in recent decades. 1, 2 the majority of deaths are due to the malignancy, with some attributable to anticancer treatments. 3 distress from symptoms and suffering during the end-of-life phase can be significant, [4] [5] [6] impacting on the child and their family's quality of life. 7, 8 in addition, many children and young people who die from cancer continue to have high-intensity treatments towards the end of life, 9, 10 with nearly half dying in the acute care setting, 11 despite preferences from the majority of children and their parents for being at home during the end-of-life phase. 12, 13 palliative care, defined by the world health organization (who) as 'the active total care of the child's body, mind and spirit . . . [that] begins when illness is diagnosed, and continues regardless of whether or not a child receives treatment directed at the disease', 14 is recognised as an important component of children and young people's cancer services. 15, 16 in addition, and over the last 30 years, specialist paediatric palliative care services for children and young people have been developing in many countries including the united states, canada, united kingdom and across europe. 17 the english national health service (nhs) defines specialist paediatric palliative care as 'a consultant-led multi-professional specialist palliative care team . . . led by a medical consultant working at paediatric palliative care competency level 4'. 16 in practice, however, the models of providing specialist palliative care vary within and between countries, including, for example, hospital-and community-based teams which support all children with life-limiting conditions, 18 teams embedded within paediatric oncology departments, joint working with, or hospice-led provision, and specialist nurse-led teams as well as services led by a paediatric palliative care consultant. 17, 19, 20 even within the developed world, the availability, referral and uptake of specialist palliative care among children and young people with cancer remains low and variable between and within countries and settings, and it is not clear to what extent these services are addressing all aspects of palliative care as defined by who. 17, [21] [22] [23] [24] [25] for children with cancer, referral to palliative care also often occurs late in the trajectory of illness, sometimes only days before death. 26, 27 recent systematic reviews suggest that access to specialist palliative care services is associated with improvements in quality of life, symptom control, perceived support, reduced time in hospital, less invasive treatment and greater advance care planning. 19, 28, 29 however, these reviews have aggregated the results for children and young people across conditions, and the evidence for those with cancer remains unclear because of conflicting results between individual studies 28 and the lack of work exploring condition-specific factors that may influence access to and benefit from specialist palliative care services. 30, 31 a rigorous review of the evidence on the impacts of specialist paediatric palliative care for children and young people with cancer and their families is both crucial to informing debates within paediatric oncology regarding the positioning and role of these specialist services and for future service development. this mixed-methods systematic review synthesises the existing evidence on the benefits, drawbacks, facilitators and barriers associated with referral to and uptake of specialist paediatric palliative care for children and young people with cancer and their families. the review questions are as follows: 1. what are the reported benefits and drawbacks of referral to specialist paediatric palliative care for children and young people with cancer and their families? 2. what are the factors (e.g. barriers, facilitators) affecting referral to and uptake of specialist paediatric palliative care for children and young people with cancer? the protocol registration number is crd42017064874. 32 primary studies of any design (e.g. experimental, observational, surveys, consensus and qualitative studies) examining either the impact of or factors affecting specialist paediatric palliative care access for children and young people (age 0-24 years) with cancer were included. studies of a mixed population were included if (1) the majority of the participants were children and young people with cancer and/or (2) data were reported separately. we defined specialist paediatric palliative care as care provided by multidisciplinary teams or palliative care services which included clinicians (e.g. oncologists, paediatricians, nurses) with paediatric palliative care training, or services who self-identified as providing specialist paediatric palliative care. we included services delivered in different settings (e.g. inpatient, community or home settings) and both liaison services (e.g. supporting the child's usual care team) and services directly supporting children and their families. although broad, this reflects the varying provision of specialist palliative care for children within and between different countries and so enabled us to synthesise the evidence about these specialist services. to understand the different perspectives on referral to specialist palliative care services, studies that included the following participant groups were eligible: children and young people; parents (including bereaved); other family members and health and social care staff. no comparator was required. we excluded case studies, review articles, descriptive, theoretical or clinical opinion articles, conference abstracts and articles not published in the english language. we also restricted the eligibility to studies conducted in highincome countries (defined as oecd (organisation for economic co-operation and development) 33 member countries) because of the very different healthcare infrastructure and status of specialist paediatric palliative care in developing countries. 17 electronic databases (cinahl, cochrane database of systematic reviews (cdsr), embase, medline, psycinfo) were searched on 27 june 2017 (from 2000, in line with increasing availability of specialist paediatric palliative care services internationally 19 ). the search strategy consisted of terms and synonyms for [ titles and abstracts were screened in covidence, 34 and relevant full-text articles were retrieved and independently assessed for eligibility by two reviewers with disagreements resolved via a third reviewer. 35 reasons for exclusion at full text were recorded. data on study characteristics, methods, study focus (e.g. impact and/or factors affecting access) and quantitative outcome data were extracted into microsoft excel using a pre-piloted data extraction template. qualitative data, including author-reported results, direct quotations and results tables, were imported into nvivo version 11 36 for analysis. data extraction was carried out by one reviewer and checked by a second. the mixed methods appraisal tool (mmat) 37,38 was used to appraise the methodological quality of all included studies. mmat comprises two generic screening questions and an additional four criteria for use with specific study designs. criterion assessments (e.g. is the sample representative of the population under study?) are categorised 'yes', 'no' or 'can't tell'. an overall quality score (of 0%, 25%, 50% or 100%) based on how many study design specific criterion were met (those categorised as 'yes') was calculated for each study. the quality assessment was undertaken independently by two reviewers and informed the synthesis methods and reporting of the review results, along with identifying needs for future research. we did not exclude studies based on quality assessment. an integrative narrative synthesis was planned drawing on interpretative review methodology 39 with thematic analysis as the principal method of synthesis. 40 the synthesis plan outlined in the protocol 32 was modified following an assessment of the potential for aggregation, configuration and integration of study findings. the final method involved separate syntheses of data reporting the impact of specialist paediatric palliative care and factors affecting access (both included quantitative and qualitative data). each comprised the following steps: data reduction. this involved reviewing and summarising extracted data and identifying recurring categories from across the studies, and distinct service types. each synthesis included quantitative and qualitative data and all numerical and statistical findings were converted to descriptive summaries. for qualitative data, 'meaning units' (comprehensible segments of text which contain one idea or piece of information) were identified and named (or 'coded') drawing both on author-reported results and participant quotes to capture the full range of concepts or themes across the studies. 41 data display. using the method of constant comparison, 39 descriptive summaries of quantitative data and coded qualitative data were compared to ensure that similar data were grouped together to develop a thematic coding matrix consisting of descriptive themes and overarching categories which grouped similar themes together. this was performed by one reviewer with regular input from the wider review team for sense checking and validation. data from each study were then synthesised into the coding matrix, retaining reference to the service type and critical appraisal score to facilitate greater interpretation. data display techniques were used to illustrate the spread of themes across studies and specialist paediatric palliative care models, and narrative weaving describes the results of each synthesis. 42 a total of 8549 unique records were screened by title and abstract, 626 full-text articles were retrieved and reviewed, and 49 articles describing 42 studies 23, were included in the review (see figure 1 ). of the 42 included studies, 11 examined the impact of specialist paediatric palliative care, 44, 48, 57, 58, 62, 64, 66, 70, 73, 74, 88 14 explored factors affecting access 23, 43, 45, 56, 65, 68, 71, 75, 76, [78] [79] [80] [81] [82] [83] 89 and 17 studies investigated both 46, 47, [49] [50] [51] [52] [53] [54] [55] [59] [60] [61] 63, 67, 69, 72, 77, [84] [85] [86] [87] 90 (see table 1 for study characteristics). using the mmat, 25 studies were categorised as quantitative non-randomised, 12 as quantitative descriptive and 5 as qualitative studies. the majority of studies were conducted in the united states (n = 28). others were in the united kingdom (n = 3), 23, 47, 76 canada (n = 3), 50, 51, 63, 72 germany (n = 3), 57, 73, 90 france (n = 1), 87 switzerland (n = 1), 79 israel (n = 1) 49 and two in multiple countries. 65, 71 study populations thirty-one studies (all quantitative) examined the impact of and/or characteristics of children receiving specialist palliative care; 24 included a comparator group of children not receiving this, 23,43-51,54-64,78,86-88, 90 1 compared children receiving late and early specialist input, 52, 53, 84, 85 and 6 used a single-group study design. 66, 67, 69, 70, 73, 74 of the remaining 11 studies (6 quantitative and 5 qualitative), 10 explored the views of healthcare staff 65, 71, 72, [75] [76] [77] [79] [80] [81] [82] [83] 89 and 1 the views of parents and young people. 68 of the 31 studies examining outcomes and/or characteristics of children, the majority (n = 21) drew their sample of children and young people from a single centre. several studies used the same or potentially overlapping samples as other included studies (see figure 2 ). in total, data for 7933 children and young people, 4289 of whom had received specialist palliative care compared to 3644 who did not, were included. while the majority (n = 23) included children and young people with any cancer, eight studies concerned children and young people with particular diagnoses or treatments (see table 1 for details). 44, 56, 61, 62, 66, 67, 69, 78 overall, these 31 studies address diagnoses from infancy to young adulthood, with only three studies focused on young adults, which included any malignancy. 54, 58, 86 five studies included some children and young people with conditions other than cancer. 61, 67, 70, 73, 88 of the 11 studies exploring stakeholder views, 3 recruited paediatric oncology staff from single hospitals 75, 77, 82, 83 and 1 from multiple hospitals, 79,80 1 recruited staff involved in providing palliative care to children with cancer from primary, tertiary and community settings, 76 4 recruited paediatric oncologists via professional organisations 65,71,72,81 and 1 recruited parent and young person dyads from three hospitals. 68 in total, these studies represented the views of 1133 physicians, 986 other healthcare professionals (mainly nurses, social workers and other staff working in paediatric oncology, but also in palliative care and other settings), 129 parents and 129 young people. we identified five broad service types from the included studies: hospital-based palliative care teams with referral triggering an initial consultation 46, [50] [51] [52] [53] 58, [61] [62] [63] [64] 67, 69, [73] [74] [75] 77, [82] [83] [84] [85] 87, 88 (n = 17), hospice services 23, 45, 47, 55, 56, 59, 60, 65, 86 (n = 8), home-based services 48, 57, 70, 90 (n = 4), integrated oncology services 44,66 (n = 2) and an integrated oncology inpatient unit 49 (n = 1). three studies referred to palliative care consultation only, 43, 54, 78 and three a palliative care team, 68, 79, 81 although it is likely that these were all referring to hospital-based teams. of the remaining four studies, three included a range of models 71, 72, 89 and one referred to specialist paediatric palliative care explicitly but did not define this. 76 very few studies provided specific details about the team or service providing palliative care in terms of skills mix, role and the extent of provision. there were also some anomalies between studies; for example, five studies used hospice discussions or enrolment as an outcome of specialist palliative care, 46, 61, 62, 64, 90 whereas in other studies hospices were defined as the source of specialist intervention. not all studies investigating hospice settings specified the characteristics (e.g. adult vs children's hospice), and it was difficult to determine what 'home-based services' might comprise. among the studies exploring stakeholder views, three offered only 'hypothetical models' for participants to consider 68, 75, 76 and three focused primarily on views about early integration of specialist palliative care, which was defined as close to the time of diagnosis. 68, 75, 81 only two studies accounted for the timing of the initial palliative care consult/enrolment when deciding which children to classify as having received specialist intervention; one only included children who had received specialist palliative care for more than 30 days 63 and the second for more than 1 day. 54 a third study, which compared early and late interventions, included all children receiving specialist palliative care but defined early provision as that received for more than 30 days. 52, 53 only two studies explored how the duration of specialist paediatric palliative care exposure affected outcomes. 61, 70 study quality the quality and reporting of studies varied greatly among the 37 quantitative studies, with scores ranging from 0% to 100% (see table 2 ). there were concerns about the representativeness of samples in 14 of the quantitative studies, due to the single-site design of many studies, long study period and inappropriate participant selection or recruitment methods. 44, 46, [48] [49] [50] [51] 54, 57, 61, 62, 64, 70, 72, 86, 89 assessment of representativeness was not possible in another seven studies because of poor reporting. 66, 68, 73, 78, 81, 89, 90 in eight studies, there were concerns about the comparability of groups (e.g. use of historical cohorts, different participant characteristics), which were not accounted for in the analysis. 44, 50, 51, 54, 55, 57, 58, 62, 90 although inappropriate measures were identified in only three studies, 50, 51, 56, 66 wider concerns about measurement were evident across studies. these included how receipt of specialist palliative care was determined (e.g. from day of initial palliative care consultation); whether outcomes could be attributed to specialist provision or care from the primary oncology team; potential recall problems in studies using bereaved parent-reported outcomes and failure to take account of the chronology of variables. for example, having a do-not-resuscitate (dnr) order was a predictor of specialist palliative care in some studies 46, 59, 60 and an outcome in others. 54, 58 determining the extent of these limitations was hindered by poor reporting of study methods. the five qualitative studies 75-77,79,83 used appropriate methods for sampling, data collection and analysis. however, there were limitations to the transferability of findings due to the single-site design in three studies, [75] [76] [77] 83 and for the third, the time period elapsed since the study was conducted (published in 2001 when specialist paediatric palliative care for children with cancer was at an early stage of development). 76 the impact of specialist paediatric palliative care a total of 17 distinct outcome domains were identified and these were categorised under one of six overarching categories: advance care planning (n = 9 studies), end-oflife care provision (n = 16), location of death (n = 18), child's quality of life (n = 6), family support (n = 3) and service satisfaction (n = 7). the synthesis of results by category and outcome domain is summarised below and in detail in table 3 . the outcome domains were of end of life discussions and decisions about attempting resuscitation (dnr orders), and the timing of these. provision of specialist palliative care was found to be associated with an increased likelihood of end-of-life discussions being documented in all six studies that measured this, 50, 54, 61, 62, 64, 74 with evidence from two studies that these occurred earlier in the child's illness in those receiving specialist palliative care. 61, 64 six studies found that dnr orders occurred earlier in care trajectories in those receiving specialist palliative care. 46, 54, 55, 58, 62, 64 however, the evidence about whether a dnr order was more likely was mixed. 46, 54, 55, 61, 62, 64 end-of-life care provision there was evidence from the seven studies which measured treatment intensity 54, 58, 61, 63, 64, 87, 88 that children who received specialist paediatric palliative care were less likely to receive high-intensity treatments and to spend less time in an intensive care unit (icu) during the end-of-life phase, compared to children who did not receive this. there was also evidence from the five studies which assessed hospital admissions (either the duration of stay or the number of admissions) that children who received specialist palliative care spent less time in the hospital than those who did not. 44, 47, 55, 70, 90 only one study compared the types of admission; here specialist palliative care was only found to decrease the number of planned admissions. 47 two studies examined the cost of care, also focusing on hospital admissions, but did not find any significant differences between before and after specialist input, 70 or between those who received specialist palliative care and those who did not. 54 there was no evidence to suggest that hospice care, either enrolment or utilisation, changed as a result of specialist involvement from the four studies that explored this. 46, 61, 62, 90 outpatient care, 90 home-based care 57 and preferred location of care 51 were each assessed by a single study so no conclusions can be drawn about these. a total of 17 studies examined differences in location of death between children receiving and not receiving specialist palliative care. a consistent finding across studies was that children who received this were less likely to die in icu. 49, 52, 54, 57, 58, 61, 64, 84 however, studies varied in whether or not they found differences in the proportion of home or hospital deaths. 46, 48, 57, 59, 60, 62, 64, 73, 90 for example, the study comparing early and late involvement of a hospital team found that 'late access' children were nearly five times more likely to die in icu than at home or in a hospice, but observed no differences in terms of non-icu hospital versus home/hospice deaths. 52 however, they did find lower odds of hospital deaths when comparing hospice and no hospice involvement. 84 just four studies investigated the impact of specialist palliative care on whether children died in their/families preferred location of death, 48, 51, 57, 90 three of which found that congruence between preferred and actual place of death increased with specialist involvement. 48, 51, 90 satisfaction with the information received, medical care and pc, rated on a likert-type scale (1 = very good, 6 = unsatisfactory) overall satisfaction across the items was very good, with a mean rating of 1.6 (1 = very good, 6 = unsatisfactory). there were no significant differences in satisfaction ratings between parents whose child died at home (which was preferred by most families) or in hospital szymczak et al. 77 paediatric oncology providers were asked about their perceptions of sppc service and how these may influence timing of referral the sppc service was highly regarded by oncology providers, who identified the following impacts: the sppc team being able to spend time with families and provide emotional support and explore wider needs, expertise in pain and symptom management, supporting transition from hospital to home, around-theclock support, support for parents and siblings, and helping families to clarify goals ql 100 all sppc models wentlandt et al. 72 paediatric oncologists asked about the quality of sppc services in a survey more than 83% of participants agreed or strongly agreed that they were satisfied with the quality of sppc services this theme included three outcome domains: quality of life, comfort and symptoms. data were primarily from parent-reported measures collected after a child had died. two studies measured quality of life but did not use validated measures; one found that children receiving specialist paediatric palliative care had more fun and more events adding meaning compared to children not receiving this, but found no differences in how afraid or peaceful they felt. 48 in the second, 70% of parents strongly agreed that these specialist services improved their child's quality of life, but there was no comparator group. 66 the study which measured comfort, also with no comparator, found an increase in comfort levels over time reported by parents but no change reported by children. this was the only study that used a child-reported measure. 67 although three studies suggested that treatment of symptoms increased with specialist involvement, 57, 74, 90 there was little evidence that the extent of symptom control/suffering from physical and emotional symptoms differed between children receiving and not receiving specialist palliative care. indeed, high levels of suffering from symptoms were described by the four studies which assessed this. 48, 57, 64, 90 family support only three studies investigated whether specialist paediatric palliative care affected provision of support to family members, or the impact of that support. one study found that use of bereavement support for parents and siblings was more likely if a child had received specialist input. 62 two studies found that specialist palliative care increased parent preparedness for the end-of-life phase of care. 64,66 all seven studies (six surveys 66, 67, 69, 72, 73, 90 and one qualitative 77 ) assessing this reported high levels of family and professional satisfaction with specialist palliative care, with reported benefits including expertise in pain and symptom management, time to plan end-of-life care with families and meeting psychosocial and family needs. none of these studies included a comparator group, although one reported increasing parental satisfaction in line with increasing provision of specialist services. the synthesis of studies exploring factors affecting specialist paediatric palliative care access identified four overarching categories each containing several linked themes: sociodemographics (n = 14 studies), disease profile (n = 22 studies), end-of-life care characteristics (n = 18 studies) and acceptability of specialist paediatric palliative care (n = 17 studies). the synthesis of results by category and theme are summarised below and presented in detail in table 4 . multiple quantitative studies which investigated the sociodemographic profile of children and/or their families receiving and not receiving specialist palliative care consistently showed that access was not associated with a child's gender 47 out of 12 studies examining type of cancer, 10 found that children with solid tumours were more likely to receive specialist palliative care than children with haematological malignancies. 46, 47, 49, 50, [53] [54] [55] 59, 61, 63, 78, 86 six studies investigated whether disease status (e.g. prognosis, relapse) was associated with access; no consistency was found across these, with some studies reporting conflicting resu lts. 46, 49, 50, 54, 55, 61 in contrast, all the studies investigating staff-reported practices consistently identified children with a poor prognosis as those most likely to be refer red. 65, 71, 72, 75, 77, 79, 81, 83, 89 staff in two studies believed that this could result in referrals that were too late for children to benefit from specialist input. 71, 79 uncertainty about a child's prognosis and about the benefits of introducing specialist palliative care earlier in the disease trajectory (e.g. around diagnosis) were identified as key barriers to a timely referral, 65, 71, 75, 77, 79, 81, 83, 89 although non-physician professionals 75, 81 and families 68 were more receptive to early integration than physicians. automatic referral triggers were used by the majority of providers in one study. however, in line with reported practice, most encouraged referrals for children during the end-of-life phase of care. 71 the end-of-life care provided to children was found to influence whether or not children received specialist palliative care. four studies consistently found that advance care planning (e.g. documented advance directives or dnrs, hospice referrals) was associated with an increased likelihood of specialist involvement, or earlier compared to late involvement. 46, 53, 55, 59 provision of palliative care by the oncology team (we already do palliative care) was also reported by oncology staff to influence referral practices 65, 71, 72, 75, 79 and to impede oncologists' abilities and willingness to identify needs for specialist input in their patients and practice, something that was reported to encourage referrals. 65, 71, 72, [75] [76] [77] 79, 89 similarly, young people were more likely to accept specialist input if they had specific unmet needs, for example, pain and poor quality of life, 68 although staff in one study were concerned that parents might not discuss their child's palliative care needs during active treatment. 81 there was conflicting evidence about whether treatment intensity (e.g. phase 1 trial enrolment) influenced access to specialist palliative care, 43, 46, 50, 53, 56, 61 and this mirrored varying beliefs among oncology staff and families about whether children receiving active treatments should or could be referred. 65, 68, 71, 72, 75 acceptability of specialist paediatric palliative care staff acceptability of specialist palliative care was reported to influence access in 16 studies. family acceptability was identified in 13, although families' views were sought in only three of these. [67] [68] [69] eight studies measured intervention uptake to explore acceptability. 23, 46, 61, 63, 67, 69, 89, 90 these reported varying rates of referral and uptake of specialist palliative care, but provided evidence of increasing involvement over time. staff uncertainties about the benefits of specialist palliative care, and about how a specialist service differs from care provided within oncology (the added value of specialist paediatric palliative care), were identified as key barriers to referral. 68, [75] [76] [77] 79, 81, 83, 89 concerns that bringing in a new team could undermine continuity of care and impact on relationships with families were also reported to influence referral practices, 68, 72, [75] [76] [77] 79, 89 as were perceptions about availability and capacity of specialist palliative care services (perceived availability). 65, 71, 72 staff in eight studies identified the association of palliative care with end of life (what specialist paediatric palliative care symbolises) as a barrier to access. 72, [75] [76] [77] 79, 81, 83, 89 a clinician's emotion about a family and their readiness to accept a child's prognosis and discuss this were identified as additional challenges, 75, 77, 79, 81, 83, 89 and contributed to what was described as the emotional labour associated with introducing a service which staff participants referred to as 'death nurses', 76 'the death team' 77 and 'the death squad'. 75 a perception that oncologists need to control patient care ('clinical ownership') was identified as a further barrier to specialist palliative care referral and could deter others involved in a child's care from recommending this for a family. 75, 81, 83, 89 oncology staff reported that family readiness 75, 77, 81, 83 and family resistance 65, 71, 72, 79, 89 could affect access, although views on this varied. for example, 60% of paediatric oncologist respondents in one survey believed that their patients had negative perceptions of specialist palliative care, but very few (4%) reported that patients refused a referral. 72 in another study, only 38% of staff participants identified family resistance as a barrier, 89 and the study that explored young people and parents' attitudes found mainly positive views, and very few participants (2% and 8%, respectively) believed that referral was associated with the loss of hope for a cure, 68 which was a fear commonly reported by staff. 72, [75] [76] [77] 79, 83, 89 this systematic review found evidence that children and young people with cancer who receive specialist paediatric palliative care are more likely to be engaged in advance care planning, receive less intensive care at the end of life and are less likely to die in hospital, compared to those who do not receive this. some of the included studies also indicate that these differences may be more marked when children receive specialist input for a longer duration before they die. the review did not find that receipt of specialist palliative care is associated with improved quality of life or symptom control; however, no conclusions can be drawn because of the significant methodological limitations of the seven studies investigating this. 48, 57, 58, 64, 66, 67 importantly, only one study sought young people's views about the impact of these specialist services across the 28 studies which examined this, and this was a feasibility study with no comparator group. 67 the review also found that the type of cancer and whether or not paediatric oncology teams themselves engage in palliative care practices may affect access to specialist palliative care services. thus, studies reported fewer children with haematological malignancies receiving specialist palliative care, and involvement more likely where the oncology team were proactively addressing palliative care needs (e.g. evidence of advance care planning). there was no indication from the studies included about why children with certain cancers are less likely to receive specialist palliative care, and a recent review of barriers to access did not explore this. 31 evidence from adult cancer 91 indicates that the remitting and relapsing trajectories of haematological malignancies, a more aggressive approach to treatment and greater difficulties predicting prognosis may contribute to the observed inequity of specialist palliative care involvement. 92 evidence from our review regarding clinician uncertainty about when to involve specialist palliative care, combined with the commonly reported practice of referring children with a poor prognosis, 27 suggests this might be the case. clinicians' views regarding the need for specialist palliative care input for their patients and their acceptability of specialist palliative care services were also consistently reported as affecting referral practices. more specifically, views on how these specialist services differ to palliative care provided by the oncology team, perceived drawbacks associated with involving a new team, readiness to accept a change in prognosis and the negative connotations associated with the term 'palliative care' were identified as barriers to referral. concerns among clinicians about how families might react to the offer of a referral was a common theme in several studies, and although the study that explored young people and parents' views runs counter to this, wider work on this issue reports mixed opinions among young people 93, 94 and parents 73,74 about palliative care and how this should be introduced. 95 this review is the first to systematically synthesise the available evidence about specialist paediatric palliative care for children and young people with cancer. strengths of the review include a published protocol, robust search, independent screening and data extraction by two reviewers, and the use of appropriate mixed-methods techniques to synthesise the results. there are, however, limitations in the conclusions which can be drawn from this review due to the heterogeneity of study populations and interventions. this, and the substantial risk of potential bias identified in some of the studies and inconsistency of measurement across studies, meant it was inappropriate to aggregate the results statistically, or to compare results between the different approaches to providing specialist palliative care. in addition, the descriptions of specialist services and the palliative care provided by oncology teams were typically very poor, making interpretation of the differences between these challenging. our finding that end-of-life care is different for those who receive specialist paediatric palliative care compared to those who do not broadly aligns with three recent reviews about children with all life-limiting conditions. 19, 28, 29 two of these reviews 19, 29 concluded that specialist intervention appears to offer benefit in terms of improved quality of life. by focusing only on children and young people with cancer, our review highlights the lack of robust evidence pertaining to both quality of life and symptom burden in this population. although the broader literature implies that other differences we observed, such as reduced hospital stays and more advance care planning, are indicative of better care, 63 there is no evidence that these changes in the delivery of care reflect family preferences, 48, 51, 57 or lead to reduced symptom burden, which studies continue to show is significant for children with cancer. 5, 90, 97 the integration of findings from evaluation studies and those which have explored factors affecting access tells us that while end-of-life care may be different for children who receive specialist palliative care, children who receive this are also different to those who do not, particularly in terms of their disease profile and care processes. synthesis of the qualitative studies go some way to explaining these differences, highlighting in particular the central role of clinicians' emotions, beliefs and attitudes in shaping referral practices, and the ongoing uncertainty about when to initiate palliative care and whether this should be provided by a specialist service or the oncology team. it also reveals that, in practice, decisions and discussions about no longer pursuing curative treatments and introducing specialist palliative care go hand in hand, and that families who are comfortable discussing an uncertain future or families cared for by clinicians who have this confidence may be more likely to receive specialist palliative care. 75, 77, 83 interventions that support clinicians to initiate palliative care with families and improve clinical acceptability of specialist palliative care services therefore offer the potential to address these key barriers to access. 82, 98 although there are various initiatives to support the delivery of palliative care within oncology services (e.g. palliative care training, 99,100 communication tools, 101,102 early integration models 26,67,69 ), we know very little about whether these are being implemented in practice and how they might influence referral to specialist palliative care. there is also little available evidence about whether families play an active role in the initiation of palliative care, or whether clinicians' concerns about how families will respond to a referral are warranted. 68 future research should therefore investigate the effectiveness, delivery and acceptability of the different models of delivering palliative care for children and young people with cancer, particularly outside of north america. future research also needs to examine factors affecting uptake from families' perspectives and to explore the role of socioeconomic factors. this conclusion is supported by the recent priority setting partnership results for teenagers and young adults with cancer, 103 which includes how best to support young people who have incurable cancer and their families. in order to undertake this research, we must first determine what outcomes are the most important to measure and develop appropriate tools to measure them. 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scoping review health-related quality-of-life outcome measures in paediatric palliative care: a systematic review of psychometric properties and feasibility of use symptoms and concerns among children and young people with life-limiting and life-threatening conditions: a systematic review highlighting meaningful health outcomes how do professionals assess the quality of life of children with advanced cancer receiving palliative care, and what are their recommendations for improvement? core outcome set-standards for development: the cos-stad recommendations the authors would like to acknowledge the input of members of the martin house research centre family advisory board, who helped with interpretation of the review findings. data are reported fully in the included tables and figures and are derived from published sources only. the author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. this review contains data derived from published sources only. the author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: this article presents independent research partly funded by the wellcome trust https://orcid.org/0000-0001-5898-0900alison booth https://orcid.org/0000-0001-7138-6295 supplemental material for this article is available online. key: cord-312835-a60bkohc authors: kohli, utkarsh; meinert, elizabeth; chong, grace; tesher, melissa; jani, priti title: fulminant myocarditis and atrial fibrillation in child with acute covid-19 date: 2020-10-18 journal: j electrocardiol doi: 10.1016/j.jelectrocard.2020.10.004 sha: doc_id: 312835 cord_uid: a60bkohc covid-19 has manifested with ventricular dysfunction and cardiac arrhythmias, most commonly atrial fibrillation (afib), in adults. however, very few pediatric patients with acute covid-19 have had cardiac involvement. afib, an exceedingly rare arrhythmia in otherwise healthy children, has not been reported in children with covid-19. we report a 15 year-old girl with acute covid-19, fulminant myocarditis and afib. serum pro-nt bnp, inflammatory markers and high sensitivity troponin concentration were all markedly elevated (supplement 1). she was initially treated with intravenous immune globulin (1g/kg), intravenous methylprednisolone 60mg every 12 hours and subcutaneous low molecular weight heparin (supplement 1). epinephrine infusion was discontinued within 12 hours. milrinone (0.7 mcg/kg/min) was continued until her ventricular function normalized (day 4). hypotension recurred 24 hours post-admission, and immunomodulatory therapy was therefore intensified via addition of the il-1 receptor antagonist, anakinra (100 mg subcutanous every 12 hours). she did not require any respiratory support though her chest radiograph showed minimal vascular engorgement. atrial fibrillation with rapid ventricular conduction (ventricular rate 140s to 190s) developed 27 hours after admission and she was successfully cardioverted (50j, synchronous) ( figure 1 ). post-cardioversion, an amiodarone infusion was initiated and 12 hours later, transitioned to an oral regimen. our patient denied a history of drug or alcohol abuse and the family history was negative for channelopathy, cardiomyopathy or early onset afib. her following initiation of amiodarone, she has done well without any recurrence. her cardiac and inflammatory biomarkers continue to trend downwards (supplement 1). covid-19 antibody test (roche elecsys anti-sars-cov-2 antibody test, roche labs, basel, switzerland) was obtained on day 2 of admission and was positive. covid-19 pcr assay (cepheid genexpert system, sunnyvale, california, usa) was repeated on post-admission days 8 and 9 and was negative. while ventricular dysfunction and the whole gamut of arrhythmias have been reported in adults with acute covid-19 [1] , pediatric patients have either been asymptomatic or have mostly manifested with mild respiratory illness [2] . rare pediatric patients with covid-19 have presented with ventricular dysfunction [3] ; however, arrhythmias such as afib, which are exceedingly rare in otherwise healthy children, have not been reported in children with acute covid-19 [4] [5] [6] [7] [8] [9] . a broad range of electrocardiographic abnormalities and arrhythmias such as t wave alterations, st segment elevation, si, qiii, tiii pattern, high degree atrioventricular block, atrial tachycardia, atrial flutter, ventricular tachycardia or fibrillation and pulseless electrical activity have been reported in adults with covid-19 [10] . the pediatric data however remains somewhat limited. in a recently published single center pediatric series (n=36), nonsustained ventricular tachycardia (n=5) and sustained atrial tachycardia (n=1) were noted in approximately 17 % of children with acute covid-19. of note, all of these arrhythmias self-resolved. however, half of the children in this series were started on an anti-arrhythmic therapy. the electrocardiographic parameters like corrected qt interval was no different between children with and without cardiac arrhythmias [4] . one of these patients was on high dose epinephrine and nor-epinephrine infusions and the other patient had dyselectrolytemia (hypokalemia, hypomagnesemia and hypocalcemia). in addition, abnormal echocardiographic findings such as left ventricular dysfunction, left ventricular dilation and pericardial effusion were noted in twothirds of the patients. afib in young patients (<18 yrs) is exceedingly rare and is usually associated with alcohol or drug abuse [5] , an inherited channelopathy such as brugada syndrome, long qt syndrome, short potential effects of coronaviruses on the cardiovascular system: a review systematic review of covid-19 in children shows milder cases and a better prognosis than adults pediatric life-threatening coronavirus disease 2019 with myocarditis atrial fibrillation in long qt syndrome by genotype atrial fibrillation in young patients a kcnq1 mutation causes a high penetrance for familial atrial fibrillation cardiac involvement in children with covid-19 international society of electrocardiology young community (ise-yc). value of electrocardiography in coronavirus disease 2019 (covid-19) life-threatening event risk in children with wolff-parkinson-white syndrome: a multicenter international study the follow-up evaluation of electrocardiogram and arrhythmias in children with fulminant myocarditis impact of extracorporeal membrane oxygenation on acute fulminant myocarditis-related hemodynamic compromise arrhythmia in children cardiac and arrhythmic complications in patients with covid-19 inflammatory activation and carbohydrate antigen-125 levels in subjects with atrial fibrillation splenectomy exacerbates atrial inflammatory fibrosis and vulnerability to atrial fibrillation induced by pressure overload in rats: possible role of spleen-derived interleukin-10 treatment ameliorates high-fat diet-induced inflammatory atrial remodeling and fibrillation outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (optime-chf) investigators. short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial relation of milrinone after surgery for congenital heart disease to significant postoperative tachyarrhythmias milrinone use is associated with postoperative atrial fibrillation after cardiac surgery key: cord-275578-9y90uj5h authors: han, aixi; chai, li; liao, xiawei title: demographic scenarios of future environmental footprints of healthy diets in china date: 2020-07-30 journal: foods doi: 10.3390/foods9081021 sha: doc_id: 275578 cord_uid: 9y90uj5h dietary improvement not only benefits human health conditions, but also offers the potential to reduce the human food system’s environmental impact. with the world’s largest population and people’s bourgeoning lifestyle, china’s food system is set to impose increasing pressures on the environment. we evaluated the minimum environmental footprints, including carbon footprint (cf), water footprint (wf) and ecological footprint (ef), of china’s food systems into 2100. the minimum footprints of healthy eating are informative to policymakers when setting the environmental constraints for food systems. the results demonstrate that the minimum cf, wf and ef all increase in the near future and peak around 2030 to 2035, under different population scenarios. after the peak, population decline and aging result in decreasing trends of all environmental footprints until 2100. considering age-gender specific nutritional needs, the food demands of teenagers in the 14–17 year group require the largest environmental footprints across the three indicators. moreover, men’s nutritional needs also lead to larger environmental footprints than women’s across all age groups. by 2100, the minimum cf, wf and ef associated with china’s food systems range from 616 to 899 million tons, 654 to 953 km(3) and 6513 to 9500 billion gm(2) respectively under different population scenarios. this study builds a bridge between demography and the environmental footprints of diet and demonstrates that the minimum environmental footprints of diet could vary by up to 46% in 2100 under different demographic scenarios. the results suggest to policymakers that setting the environmental constraints of food systems should be integrated with the planning of a future demographic path. to ensuring food security is commonly recognized as a global challenge, the united nations has set "ending hunger, achieving food security and improved nutrition, and promoting sustainable agriculture" as the second of its seventeen sustainable development goals for the year 2030 [1]. by 2050, the world needs to feed nine billion people with food demand being 60% higher than it is today [2] . with the largest population in the world, china's food security plays an important role in underpinning its social and economic development. to ensure food security, china set a goal of complete self-sufficiency for grains and basic self-sufficiency for meat, eggs, milk, and vegetables as early as 1996 [3] . 2014's 16.87 million births [29] . the comprehensive effect of the "universal two-child" policy was gradually released, and china's population structure will change further. therefore, the impact of future population changes in chinese society caused by population policies on the environmental impact of the food system deserves further study. furthermore, china's food systems are facing increasing environmental challenges. first, china has committed to cutting its carbon intensity by 40-45% from 2005 levels by 2020 and reaching the peak levels before 2030 [30] ; secondly, climate change is expected to aggravate water scarcity in some regions by changing water regimes, both in terms of availability and variability; last but not least, rapid urbanization is shifting an increasing amount of arable land to urban areas, which is set to constrain the available land resources for food production. the previous studies have proved that adopting a healthier diet is able to significantly reduce environmental footprints. it is informative for policymakers to determine how much environmental pressure would be posed at minimum by food consumption when aiming at human health goals. this minimum environmental pressure can be quantified according to the dietary guidelines; however, this is uncertain and strongly depends on demographic characteristics. in this study, we reveal how the minimum environmental footprint of diet varies with demographic characteristics by integrating the demographic study with the environmental footprint assessment. this study has enlightenments (1) for further researches that demographic characteristics need to be considered when studying the environmental footprints of diet, and (2) for policymakers that demographic characteristics needs to be considered when setting future environmental constraints and redlines for food systems. results in this study are of global significance because, while china has the world's largest population to feed, it has also overtaken the us in 2006 as the largest carbon emitter in the world. maximizing the carbon reduction potentials of china's food sector will be indispensable to reach global climate change mitigation targets. furthermore, china is one of the 17 mega-biodiversity countries in the world and harbors nearly 10% of all plant species and 14% of animals on earth [31] . land and water conservation in china are important for global biodiversity conservation efforts. we use padis-int software in this study to predict china's population size and structure from 2020 to 2100. the padis-int software is developed based on the queue element method, which is a commonly used method to predict the population [32] . we do not consider migration in this study as the overall net migration rate is low in china [10, 33] . the padis-int software is developed based on the cohort-component method, which is a commonly used method to predict the population [32] . the cohort-component method looks at the changes in the population of different death, fertility, and migration risks during the forecast period. simulating this change requires corresponding death, fertility and migration parameters. here, we do not consider migration in this study as the overall net migration rate is low in china [10, 33] . for the age and gender structure of the starting population, which is the most important factor in predicting the overall situation, interpolation techniques are used to make reasonable predictions. padis-int provides a linear interpolation method for assignment in the main age group. that is, given any two points, an interpolation method can be used to calculate and specify the value of the middle year between the two points. the interpolation method follows the following formula: where i means single-year-old group; a represents the age group with a mantissa of 2 or 7 that is slightly less than the age of the single-year group (that is, the middle age group in the five-year group (i -a) foods 2020, 9, 1021 4 of 18 actually refers to the age difference between the two); j represents the five-year-old group where a is located; and p represents the corresponding population. when using padis-int to predict the population by age and sex, the key is to set the fertility level, life expectancy, death pattern and sex ratio at birth [33, 34] . this article is based on the data of the sixth national census, combined with the analysis of previous census data and the analysis of social and population development trends, the basic parameters are set as follows: tfr: the total fertility rate refers to the average number of children born to each woman during childbearing age in a specific country or region. although scholars still find a lot of controversy about the actual fertility level, it is generally believed that the total fertility rate is about 1.5-1.6 [10] . in 2016, the "universal two-child" policy was launched, aiming to ease the pressure of aging. this policy has had a profound impact on the chinese population size and structure since it allows every family to have two children, which may influence the fertility rate of china. zhai et al. have pointed that the "universal two-child" policy will bring about a relatively significant rebound in china's tfr and the highest tfr may exceed 1.8 but will not exceed 2 [35] . after the cumulative effect is released, the tfr will be in 1.6-1.7. it was also believed that raising the tfr closer to the intergenerational replacement level of 2.1through policy adjustments, such as 1.77 to 1.94, is the most optimistic assumption [34] . the national population development strategy research report proposed that if the total population peak is controlled at about 1.5 billion people, the national total fertility rate should be maintained at about 1.8 over the next 30 years, and a value higher or lower than this number is not conducive to the coordinated development of the population and society [36] . therefore, we propose three scenarios for setting tfr parameters to predict all possibilities from the influence of the "universal two-child" policy. before that, we set the tfr of 2018, the starting year, to 1.637 according to wpp (world population prospects) [28] . in the first scenario we set the "universal two-child" policy as having not caused changes in fertility levels, so the tfr maintains its current level with slight fluctuations. it fell to 1.5 in 2030, which is the current range of fertility levels, and remained unchanged from then. in the second scenario, we considered that the "universal two-child" policy had some impact on tfr but one that was not so influential. because the goal of china's family planning rate is to be stable at 1.8 by 2020, it is reasonable to set the tfr as rising to 1.8 in 2030 and then slowly dropping to 1.6 in 2099 [29] . in the third scenario, we consider that the "universal two-child" policy can significantly increase the chinese population, so it is assumed that china's tfr will reach 2.0 in 2030, close to the intergenerational replacement level of 2.1, and this assumption is regarded in the literature as the greatest possibility of china's total factor productivity [37] . life expectancy: the population division of the national bureau of statistics points out that in the process of increasing the average life expectancy of china's population, women have increased faster than men, and the difference between the two has also further expanded. the law of change is consistent [34] . according to the who 2019 population life expectancy ranking, the average life expectancy of females in china was 77.6 years in 2018 and 74.6 years for males. we set the life expectancy of men to increase by 1.26 every five years, reaching 82.46 by 2050; the life expectancy of women to increase by 0.17 every year, to reach 85.38 years by 2050. death pattern: the core element of the population forecasting method based on the cohort element method is to calculate the survival ratio according to age, which needs to be supported by the life table. the basic calculation formula is: where n t1 (x) represents the population in age x at time t1; n t2 (x+n) represents thepopulation in age (x + n) at time t 2 ; and l is the survival probability in the specific age. [38, 39] . among them, the western model was built on the data of 130 actual life tables, which mainly come from countries in africa and asia, such as israel, japan, the taiwan province of china, and south africa. there is no obvious systematic deviation in their death data. therefore, when applied to chinese population predictions, this group of models is more widely representative than the other groups and is regarded as the standard model life table. so we adopt the coale-demeny mortality table in this study to perform age shift and to use is a as death pattern. sex ratio at birth: the sex ratio at birth refers to the ratio of the total number of male babies born to a total number of female babies in a certain period, usually expressed as the number of male babies per 100 female babies. the "universal two-child" policy is expected to alleviate the imbalance of sex ratio at birth in china. while the data of the sixth census (2010) shows that the sex ratio at birth in china is 118.06, the normal range identified by the united nations is from 102 to 107 [40] .zhang, a former director of the national population and family planning commission, pointed out that the implementation of the "universal two-child" policy could alleviate the imbalance in the sex ratio at birth in china, and it shows a downward trend within a certain range [10] .wang pointed out that the "inflection point" of the sex ratio of the birth population in china has emerged and is continuing to strengthen comprehensive governance. under the conditions, the sex ratio at birth will enter a declining process [41] . therefore, we assume that the sex ratio will reduce to 107 in 2030 and will remain unchanged after that. table 1 summarizes key parameters used in this study to predict china's future population size and structure until 2100. the environmental footprint coefficients were obtained from a database for the double food-environmental pyramid (dfep) model [42] . table 2 shows these coefficients. the dfep database has been adopted and works reliably in recent studies assessing the environmental footprint of china's food system [7, 8] . the lifecycle footprint assessment based on this database is in a boundary "from cradle to gate", i.e., the stages of transportation, storage, and retailing are not included. three types of footprints are considered in this study to examine environmental impacts, namely water footprint, carbon footprint, and ecological footprint. the water footprint is an indicator of water use based on consumption. it measures the total water demand for all products and services produced by the residents of that country or region. three water footprints are considered here, namely green water, blue water, and grey water. green water refers to the evaporation of water during food production [43] . blue water refers to surface runoff and groundwater [44] . grey water is the fresh water needed to dilute sewage [45] . the carbon footprint measures the total amount of greenhouse gas (ghg) caused by an activity (or accumulated in the life cycle of a product) [46] . the intergovernmental panel on climate change (ipcc) has proposed global warming in terms of co 2 equivalents to assess greenhouse gas emissions [47] . the ecological footprint assesses human impact on ecosystems by measuring how much humans today use nature to sustain themselves. it covers all land (including foods 2020, 9, 1021 6 of 18 arable land, forests, construction sites, etc.) and converts it into the same unit of measurement, that is, hectares of production land [48] . the scope of this study is focusing on the environmental footprint embodied in the diet rather than the whole food system, so we did not consider the impact of international trade. importing food indeed can reduce the internal environmental footprint for a country, and therefore the global trade model is encouraged to be integrated into and extend this study in future research. for this study, ignoring the imports is acceptable as china currently has a very high self-sufficient rate of over 85% [36] . this ratio is expected to elevate more in the future, especially after covid-19. although the nutrient group item can more accurately assess the quality of the diet, it also lacks operability to a certain extent, so the use of the food group can make the index tool more acceptable and easier to operate. therefore, we use the food group data given in the dietary guidelines, that is, the recommended daily dietary intake measured by grams per day. we have selected different guide data for different age groups: the 0at the same time, we divided the food group into 11 categories and unified them with the previous data for environmental footprint: (1) cereals and tubers,(2) vegetables,(3) fruits,(4) red meats and poultry,(5) eggs,(6) aquatic products,(7) dairy products,(8) soybeans and nuts,(9) oils, (10) salt, and (11) sugars. from dietary guidelines, we can get a detailed energy recommended intake (i.e., eer) for each age group and the caloric amount of different food items. the optimal dietary structures of different foods 2020, 9, 1021 7 of 18 age groups can be obtained based on such information. furthermore, based on the environmental footprint coefficients of the consumption of different food items, the environmental footprints of food consumption of people in different age groups can be calculated, which can be used as an indicator of the minimum environmental footprints of food consumption that meet the lowest nutritional requirements of different age groups. similar to the previous prospective study, we assume that environmental footprint intensities of food consumption will remain the same into the future [50] . our analyses focus on the impacts of two prospective changes in china's future food system: (i) the dietary guidelines are used to understand the impacts of future age-and gender-specific dietary patterns; (ii) scenario analyses are conducted to show the impacts of demographic changes. the research route and framework is summarized in figure 1 below. figure 2 shows the changing trend of the total population with time in three scenarios. under all scenarios, china's population in the future generally demonstrates a trend of first rising and then declining, with peaks at different times. under the first scenario with the lowest tfr, china's population will first grow and reach 1.45 billion in 2028 and will then gradually decline to 1.351 billion and 820 million by 2050 and 2100 respectively. similarly, the second scenario projects china's population to grows to 1.46 billion by 2034 and then decline to 1.406 billion and 979 million by 2050 and 2100 respectively. assuming that the "universal two-child" policy has a significant effect on population growth, the chinese population is expected to peak at 1.48 billion in 2038 and then gradually decline to 1.45 billion and 1 billion by 2050 and 2100 respectively. therefore, although the "universal two-child" policy offers the potential to stimulate population growth in the short term, china's population is expected to decrease eventually, and people's willingness to have children is expected not to meet expectations, and the cumulative effect of adjustment and release of fertility policy can only last for a short time period. figure 2 shows the changing trend of the total population with time in three scenarios. under all scenarios, china's population in the future generally demonstrates a trend of first rising and then declining, with peaks at different times. under the first scenario with the lowest tfr, china's population will first grow and reach 1.45 billion in 2028 and will then gradually decline to 1.351 billion and 820 million by 2050 and 2100 respectively. similarly, the second scenario projects china's population to grows to 1.46 billion by 2034 and then decline to 1.406 billion and 979 million by 2050 and 2100 respectively. assuming that the "universal two-child" policy has a significant effect on population growth, the chinese population is expected to peak at 1.48 billion in 2038 and then gradually decline to 1.45 billion and 1 billion by 2050 and 2100 respectively. therefore, although the "universal two-child" policy offers the potential to stimulate population growth in the short term, china's population is expected to decrease eventually, and people's willingness to have children is expected not to meet expectations, and the cumulative effect of adjustment and release of fertility policy can only last for a short time period. therefore, although the "universal two-child" policy offers the potential to stimulate population growth in the short term, china's population is expected to decrease eventually, and people's willingness to have children is expected not to meet expectations, and the cumulative effect of adjustment and release of fertility policy can only last for a short time period. under the first scenario, the existing fertility level being kept unchanged gradually results in an aging society, while the "universal two-child" policy that is considered in the second and third scenario is expected to alleviate such a trend to different extents. foods 2020, 9, x for peer review 8 of 18 figure 3 shows that china's population pyramid shows a slow bottom-shrinking phenomenon. under the first scenario, the existing fertility level being kept unchanged gradually results in an aging society, while the "universal two-child" policy that is considered in the second and third scenario is expected to alleviate such a trend to different extents. the optimal dietary patterns that meet the eer by chinese dietary guidelines of different age groups are demonstrated in figure 4 . it can be seen that the population aged 0-0.5 (six months) mainly depends on breast milk, so there is no specific food consumption. after the age of 0.5, with the growth of age, the total food consumption gradually increases, reaching the peak at the age of 14-17, and then slowly decreases. on the other hand, the difference between the food consumption of men and women begins to emerge after the age of 6, because under normal circumstances, gender the optimal dietary patterns that meet the eer by chinese dietary guidelines of different age groups are demonstrated in figure 4 . it can be seen that the population aged 0-0.5 (six months) mainly depends on breast milk, so there is no specific food consumption. after the age of 0.5, with the growth of age, the total food consumption gradually increases, reaching the peak at the age of 14-17, and then slowly decreases. on the other hand, the difference between the food consumption of men and women begins to emerge after the age of 6, because under normal circumstances, gender differences in food consumption among preschoolers are not considered. considering gender differences, after the age of 6, men consume a higher amount of food than women in general [51] . in terms of dietary pattern, dairy products and vegetables account for the largest proportions. take the population of 14 to 17 years for example, dairy products account for about 16.9%, and vegetable consumption accounts for about 28.2%. environmental footprint coefficients of different food items used in this study are summarized in table 2 below. water footprint coefficient (wfc), carbon footprint coefficient (cfc), and ecological footprint coefficient (efc) respectively represent water consumed, carbon emitted, and land resources used throughout the life cycle of certain food products. it can be seen from table 2 that animal products have much higher environmental footprint coefficients than vegetable products; therefore, the increasing consumption of animal products is set to exert increasing pressures on natural resources and the environment. figure 5 demonstrates the environmental footprints of age-gender specified dietary requirements according to the national nutritional dietary guidelines. it can be seen that people's food consumption's environmental footprints have gradually increased since 0.5-year-olds in general, and people in the 14-17 age group, require the largest environmental footprint to meet their dietary needs. men require higher environmental footprints for their food requirements than women, with the gap peaking from 14 to 17. dairy products, fruits and cereals and tubers require the largest water footprints throughout their life cycles, occupying 45%, 12%, and 11% respectively on average. dairy products, vegetables and cereals and tubers require the largest carbon footprints throughout their life cycle, occupying 33%, 18%, and 13% respectively on average. in terms of ef, on average, dairy products, aquatic products and meats require the largest ef, occupying 50%, 17%, and 7% respectively on average. it can be seen that dairy products account for the largest environmental footprints, and that the food requirements of the 14~17 age group has the largest environmental footprint. specifically, fruits, environmental footprint coefficients of different food items used in this study are summarized in table 2 below. water footprint coefficient (wfc), carbon footprint coefficient (cfc), and ecological footprint coefficient (efc) respectively represent water consumed, carbon emitted, and land resources used throughout the life cycle of certain food products. it can be seen from table 2 that animal products have much higher environmental footprint coefficients than vegetable products; therefore, the increasing consumption of animal products is set to exert increasing pressures on natural resources and the environment. figure 5 demonstrates the environmental footprints of age-gender specified dietary requirements according to the national nutritional dietary guidelines. it can be seen that people's food consumption's environmental footprints have gradually increased since 0.5-year-olds in general, and people in the 14-17 age group, require the largest environmental footprint to meet their dietary needs. men require higher environmental footprints for their food requirements than women, with the gap peaking from 14 to 17. all three indicators of environmental footprints first increase, then peak around 2030-2035 and then decrease toward 2100. under scenario 1 where the population trend remains unchanged, wf, cf, and ef first increase and peak in 2029 at 1181 km 3 , 1113 million tons co2eq and 11,809billion gm 2 respectively. under scenario 2 and 3 where the "universal two-child" policy effect is to different extents, wf, cf, and ef all peak in a later year, in 2032, at 1190 km 3 , 1120 million tons co2eq and 11,901 billion gm 2 respectively under scenario 2 where the "universal two-child" policy's effect is conservative and around 2035 at 1199 km 3 , 1128 million tons co2eq and 12,000 billion gm 2 under scenario 3 where the "universal two-child" policy's effects are substantial. after the peaks, dietary pattern change offsets the impacts brought by population increase and leads to environmental footprints decreasing until 2100. by 2100, the minimum cf, wf, and ef associated with china's food systems range from 616 to 899 million tons, 654 to 953 km 3 and 6513 to 9500 billion gm 2 respectively under different population scenarios. it can be seen from figure6 that the impacts of the different fertility rates applied in the three population scenarios are negligible until 2030, but gradually become visible from 2050 and are substantial toward 2100. two observations worth notice from figure 7 , are that the differences resulted from different population scenarios are most visible in lower aged groups under 2050 and 2100, this is because the "universal two-child" policy of today mainly has impacts on the population size of under 30 by 2050 and under 70 by 2100. therefore, apparent discrepancies can be observed in environmental footprints of the population under 30 in 2050 and of the population under 70 in 2100. furthermore, figure 7 further demonstrates that male members of the society require larger environmental footprints to meet their food demands than their female counterparts since all the figures in figure 6 have a fatter left part. dairy products, fruits and cereals and tubers require the largest water footprints throughout their life cycles, occupying 45%, 12%, and 11% respectively on average. dairy products, vegetables and cereals and tubers require the largest carbon footprints throughout their life cycle, occupying 33%, 18%, and 13% respectively on average. in terms of ef, on average, dairy products, aquatic products and meats require the largest ef, occupying 50%, 17%, and 7% respectively on average. it can be seen that dairy products account for the largest environmental footprints, and that the food requirements of the 14~17 age group has the largest environmental footprint. specifically, fruits, vegetables, and aquatic products, which share in wf, cf, and ef, respectively, all peak at the 14-17 age group, at 16%, 22%, and 22%. furthermore, food requirements environmental footprints of males have been consistently higher than those of females, with the difference increasing significantly after age 6. all three indicators of environmental footprints first increase, then peak around 2030-2035 and then decrease toward 2100. under scenario 1 where the population trend remains unchanged, wf, cf, and ef first increase and peak in 2029 at 1181 km 3 , 1113 million tons co 2 eq and 11,809billion gm 2 respectively. under scenario 2 and 3 where the "universal two-child" policy effect is to different extents, wf, cf, and ef all peak in a later year, in 2032, at 1190 km 3 , 1120 million tons co 2 eq and 11,901 billion gm 2 respectively under scenario 2 where the "universal two-child" policy's effect is conservative and around 2035 at 1199 km 3 , 1128 million tons co 2 eq and 12,000 billion gm 2 under scenario 3 where the "universal two-child" policy's effects are substantial. after the peaks, dietary pattern change offsets the impacts brought by population increase and leads to environmental footprints decreasing until 2100. by 2100, the minimum cf, wf, and ef associated with china's food systems range from 616 to 899 million tons, 654 to 953 km 3 and 6513 to 9500 billion gm 2 respectively under different population scenarios. it can be seen from figure 6 that the impacts of the different fertility rates applied in the three population scenarios are negligible until 2030, but gradually become visible from 2050 and are substantial toward 2100. foods 2020, 9, x for peer review 11 of 18 two observations worth notice from figure 7 , are that the differences resulted from different population scenarios are most visible in lower aged groups under 2050 and 2100, this is because the "universal two-child" policy of today mainly has impacts on the population size of under 30 by 2050 and under 70 by 2100. therefore, apparent discrepancies can be observed in environmental footprints of the population under 30 in 2050 and of the population under 70 in 2100. furthermore, figure 7 further demonstrates that male members of the society require larger environmental footprints to meet their food demands than their female counterparts since all the figures in figure 6 have a fatter left part. being constrained by limited planetary boundaries, there is a growing consensus that all anthropogenic activities should take into account and strive to minimize their environmental impacts. with the largest population and unprecedented economic growth, china is facing emergent challenges to meet its demands in a sustainable way. among all the demands for different commodities, food demand poses the foremost challenge due to its fundamental importance. while food provision processes require large amounts of water consumption, carbon emission and land occupation, china's food system is posing increasing pressure on its environment and natural resources. in 2009, china pledged to peak its carbon emissions by 2030 in copenhagen, which is further reiterated in china's intended national determined contribution. furthermore, china is also facing stringent finite water and land limitations. china is not abundant in water, with the country's national average water resources amounting to only one third of the global average at around 1900 being constrained by limited planetary boundaries, there is a growing consensus that all anthropogenic activities should take into account and strive to minimize their environmental impacts. with the largest population and unprecedented economic growth, china is facing emergent challenges to meet its demands in a sustainable way. among all the demands for different commodities, food demand poses the foremost challenge due to its fundamental importance. while food provision processes require large amounts of water consumption, carbon emission and land occupation, china's food system is posing increasing pressure on its environment and natural resources. in 2009, china pledged to peak its carbon emissions by 2030 in copenhagen, which is further reiterated in china's intended national determined contribution. furthermore, china is also facing stringent finite water and land limitations. china is not abundant in water, with the country's national average water resources amounting to only one third of the global average at around 1900 m 3 . moreover, the scarcity of arable land is a defining feature of chinese agriculture [52] . in 2015, china fed 18.9 percent of the world's population with only 8.5 percent of the world's arable land [36] . such challenges are further aggravated by the spatially uneven distribution of china's natural resources. for example, with merely 2 percent of china's renewable water resources, the yellow river basin contributes to 8 percent of the national gdp and supports nearly 9 percent of the national population, 13.3 percent of the arable land. it is therefore of paramount importance to examine the environmental impact of the future food system in exploring a sustainable path meeting both environmental and social objectives. according to china's dietary guidelines, we evaluate the environmental benefits of food pattern change of the chinese population and demonstrate that while population growth may play the primary role in driving the increasing environmental footprints associated with the food system in the near future, food pattern change offers potentials to offset such impacts and result in net decreases of food system's environmental impacts after the 2030s.it should be noted that although the guidelines represent the minimal energy and nutrition intakes that are recommended for age and gender-specific groups, the average chinese person's current diet has not reached the recommended levels and therefore may have a smaller environmental footprint than our results. however, as recognized by the 2nd sdg (sustainable development goals), nutritious diet plays a fundamental role in sustaining human lives, fostering healthy human capital, and underpinning other aspects of social economic development, results in this study represent the minimal environmental footprints that are required to meet the sdg2 (sustainable development goals) under which scenario every person has access to nutritious food as recommended by the guidelines. as recognized by previous studies, optimizing food diets helps to contribute to the global climate change mitigation agenda [53] [54] [55] . china pledged to peak its carbon emissions by 2030, and while its food system makes up 25% of global carbon emissions, our results show that carbon emissions associated with the food system in china will likely peak between 2030 and 2035, which is in line with china's national efforts to comply with the paris agreement [30] . different age and gender groups have different dietary needs, therefore using dietary pattern of one single group, normally adults, as a proxy results in overestimation of the food systems' impacts on the environment. adopting age-gender specified dietary patterns, results in this study demonstrate that teenagers aged between 14 and 17 require the largest environmental footprint for their food requirements. dairy products require the largest wf, cf and ef across all age and gender groups. this raises alarms for people's increasing livestock-based food consumption with a bourgeoning lifestyle. the environmental footprint for food systems could be reduced from both producer and consumer's sustainable practices. from the producer's perspective, low environmental-impact farming practices should be encouraged. for example, dripping irrigation is useful in reducing agricultural water consumption. from the consumer's perspective, environmentally responsible food choices should be promoted. for instance, the increasing consumption of avocado by urbanites is imposing increasing water pressure along the life cycle supply chain. environmental information disclosure and raising awareness such as via environmental labeling could be a useful way to change people's consumption behaviors. furthermore, organic agricultural and husbandry has gained increasing appreciation worldwide, its application in china merits cautions as organic farming require larger amount of water and land inputs as well as greenhouse gas emissions per calorie of food products [56] . while most of the existing studies have examined china's food systems' environmental footprints until 2050, it is shown in this study that the population policy's effects only become significant after that because that's most new-born become adults whose food requirements reaching the maximum environmental impacts. it is therefore important to look beyond 2050. our results offer three particular novel insights: (1) by adopting different population scenarios, our results have shown that the food system's environmental footprints may reach the peak several foods 2020, 9, 1021 14 of 18 years later delaying from 2030 to 2035 due to population effects resulted from loosening policies. such effects may cause conflicts with other existing policies, for example, as the food system is a major contributor to the society's total carbon emissions, the delaying peak of carbon emissions associated with the food system can impede the achievement of china's carbon emission targets by 2030. while the "universal two-child" policy is expected to generate positive impacts on the shrinking workforce and aging society, its environmental implications need further studying and corresponding policies should be formulated [57] . enhanced technology advancement should be promoted to reduce the food system's environmental intensities to mitigate the effects of a growing population. for instance, nitrogen optimization and manure management may be effective in reducing the lifecycle greenhouse gas emission intensity of live-stock consumption [58] . (2) secondly, our results highlight the importance of adopting a longer-term view in both academic research and policy formation. while most existing studies have examined china's food systems' environmental impacts until 2050, our results have shown that the population policy's effects only become significant after 2050 because that is when most new-born become adults whose food requirements reaching the maximum environmental impacts. while many non-structural environmental policies, such as raising environmental awareness and promoting healthy diet patterns, take decades to be effective, many structural policies, such as irrigation infrastructure, are at risk being locked-in [59] .therefore, it is important for policymakers to look beyond the mid-term and adopt longer term perspectives. (3) last but not least, by adopting the national age and gender-specific dietary guidelines, our results determine the minimal environmental impacts of the food system in china, which lays the foundation for future studies and for policymakers to evaluate the trade-offs with other sector policies as well as to explore potential synergies. there are certain limitations embodied in this study that merit future studies. first, we estimate the residents' dietary structures based on the 2016 chinese dietary guidelines. while the current dietary guidelines did not take environmental sustainability into consideration, we recommend future dietary guidelines to be further updated upon environmental considerations. therefore, future studies are recommended to consider optimized dietary structures. second, water consumption and land occupation have different impacts in different places due to different levels of water and land scarcity. for instance, water consumption in china's arid northern regions generated higher impacts on water consumption in china's water-abundant southern regions [60] . therefore, upon place-specific trade data available, it is meaningful to take into account such considerations to evaluate the lifecycle scarce water and scarce land use by food systems. food products that are produced from water-abundant and land-abundant regions should be preferred over food produced from where water and land are scarce. thirdly, environmental-friendly diet modes not only depend on a reasonable diet structure but also on the need to reduce food waste and losses. garcía-herrero et al. pointed out that reducing food loss is considered to be an important means to improve food security and reduce the pressure on natural resources [61] . according to research by chai et al., the dietary patterns of vegetarians, non-vegetarians, and omnivores have different effects on the environment [62] . therefore, in the following discussion, combined with demographic scenario analysis and different diet patterns, it is more scientific to judge which diet has the least impact on the environment of our planet, so as to make reasonable adjustments to the improvement of the dietary structure. at the same time, china is increasingly playing a significant role in the global food market. willett et al. have reported that the global food system may have an important impact on human health and environmental sustainability. providing a healthy diet for the growing global population from a sustainable food system is an urgent challenge [63] . it is therefore recommended to link china's food system with the global food system in future studies, while combining population scenario analysis with global food allocation, to explore an ideal dietary structure satisfying both health and environmental sustainability. we evaluated the minimum environmental footprints, including the carbon footprint (cf), water footprint (wf), and ecological footprint (ef), of china's food systems into 2100 under different demographic scenarios and using the national age-gender specified energy and nutrition intake requirements. our results show that food consumption's environmental impacts peak for the 14-17 age group, the environmental footprint of china's food system is expected to peak around 2030 to 2035. under different population scenarios, the peaks of wf, cf, and ef are expected to range from 1181 km 3 , 1113million ton co 2 eq and 11,809billion gm 2 respectively to 1199 km 3 , 1128 million tons co 2 eq and 12,000 billion gm 2 . higher fertility rates under less strict population policies are also expected to delay those peaks by at most five years. after the peak, environmental footprints of the food system are expected to continuously decline until 2100 and reach 616 to 899 million tons (cf), 654 to 953 km 3 (wf), and 6513 to 9500 billion gm 2 (ef) under different population scenarios. the minimum environmental footprints that are required to meet the healthy 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omnivorous diets the anthropocene: the eat-lancet commission on healthy diets from sustainable food systems the authors declare no conflict of interest. key: cord-285459-fph03r22 authors: patel, ami b; clifford, andrea; creaden, julie; kato, kimberly; malakooti, marcelo r; muller, william j; o’donnell, anna; reynolds, sally; richey, karen; rippe, jason; wheeler, derek s; kociolek, larry k title: sars-cov-2 point prevalence among asymptomatic hospitalized children and subsequent healthcare worker evaluation date: 2020-08-28 journal: j pediatric infect dis soc doi: 10.1093/jpids/piaa102 sha: doc_id: 285459 cord_uid: fph03r22 asymptomatic sars-cov-2 carriage among hospitalized children and the risk of transmission to healthcare workers (hcw) was evaluated through a point prevalence survey. we estimated a low, 1-2%, prevalence of sars-cov-2 among children without symptoms of covid-19 and there were no secondary transmission events among hcw exposed to these patients m a n u s c r i p t 3 asymptomatic sars-cov-2 carriage has been reported during the covid-19 pandemic 1,2 , but prevalence data are lacking, especially in hospitalized children. the risk of transmission 3 from asymptomatic children remains unknown. we conducted a point prevalence survey for sars-cov-2 among hospitalized children around the time of predicted peak community covid-19 activity in chicago. our objectives were to characterize: 1) prevalence of sars-cov-2 in hospitalized children without symptoms of covid-19; 2) the frequency of secondary infection among healthcare workers (hcw) exposed to asymptomatic children with sars-cov-2; and 3) environmental contamination in rooms of asymptomatic children with covid-19. ann & robert h. lurie children's hospital of chicago is a 364-bed free-standing academically affiliated children's hospital. all inpatient children were offered testing for sars-cov-2 over a 2-day period, regardless of clinical concern for covid-19 in these patients. on day 1, children in the intensive care units (icu) were tested. on day 2, children in acute care units were tested. all inpatient children were included with the following exceptions: children known to be sars-cov-2-positive; children tested within the previous 72 hours because of clinical suspicion for covid-19 and were sars-cov-2-negative; contraindications to obtaining a nasopharyngeal sample; or parents declined participation. two nurses per unit obtained all specimens on their unit. nurses participated in an orientation and sample collection competency session to review optimal nasopharyngeal specimen collection. each child had one nasopharyngeal specimen collected sampling both nares via one synthetic fiber flocked swab. the swabs were stored in viral transport media at room temperature until processed by the laboratory within 12 hours of collection. a c c e p t e d m a n u s c r i p t 4 an exposure workup was conducted for all hcw who had significant contact with any patient who tested positive for sars-cov-2 on our point prevalence. a significant exposure was considered as being within 6 feet of the patient for at least 10 minutes without appropriate personal protective equipment (ppe). for patients who tested positive for sars-cov-2, appropriate ppe would have been a standard facemask, eye protection, gown and gloves for routine care and n95 (instead of standard facemask) if an aerosol generating procedure was performed. universal masking for hcw and visitors with a level 1 procedure facemask provided by the hospital was ongoing at the time of this study. family members were asked to wear a level 1procedure mask provided by the hospital when hcw entered patient rooms, but patients were not masked in their inpatient room. of note, universal eye protection for hcw was not in place at the time of this survey so although masks were required at all times for hcw, eye protection was not. to evaluate contamination of hospital rooms of children with covid-19, we sampled the environment of children identified on this point prevalence survey as well as the inpatient rooms of known covid-19 positive children for comparison. samples were collected with pre-moistened synthetic fiber flocked swabs with viral transport media. samples were analyzed in a clia-certified laboratory using a qualitative fdaapproved rt-pcr assay (abbott realtime™ sars-cov-2, abbott molecular inc., illinois). this assay is intended for detection of nucleic acids from the sars-cov-2 virus from individuals suspected of covid-19 by their healthcare provider and was applied identically to both symptomatic and asymptomatic patients. environmental samples were processed similarly to nasopharyngeal swab samples for the purpose of this study, however environmental sampling is not validated for this assay. a c c e p t e d m a n u s c r i p t 5 we performed sars-cov-2 rt-pcr on nasopharyngeal swabs collected from 148/197 hospitalized children (97 icu and 51 acute care unit) after a median (interquartile range) length of stay of 33 (6-73) days. we excluded 49/197 inpatients because: clinically suspected covid-19 but tested negative in the prior 72 hours (n=35); known covid-19 positive (n=2); parental declination (n=10); and medical contraindication (n=2). table 1 summarizes clinical characteristics. only 2/148 (1.4%; 95% confidence interval 0.4-4.8%) patients, both on acute care units, tested positive. child 1, tested on day 2 of a 2-day hospital stay, is a school-aged child with an endocrinopathy who was admitted from the emergency department after one episode of emesis thought to be related to the child's underlying condition. this child was under contact isolation (gowns, gloves) because of the emesis. upon further history, the child had mild sore throat the day prior to admission but had resolved by the day of admission. this child had no known ill household contacts.. child 2, tested on day 4 of a 4-day hospital stay, is a school-aged child with leukemia who was admitted for chemotherapy. this child was not on isolation. the child had a respiratory illness about one month prior. sars-cov-2 testing was not performed at that time, but respiratory viral pcr panel was positive for rhinovirus/enterovirus. other household members also had a respiratory illness at that time but were not tested for sars-cov-2. at the time of the point prevalence study, the child's symptoms had significantly improved; only a very mild lingering cough was present. the child underwent an aerosol generating procedure (intubation for procedural anesthesia) two days prior to testing. we identified 68 hcws with significant exposure (being within 6 feet of the patient for at least 10 minutes during the child's admission) to at least one of the children, 18 related to child 1 and 50 related to child 2 (hcw roles listed in supplemental table 1 ). hcws were actively monitored for covid-19 symptoms for 14 days post exposure. additionally, 28 (41%) and 40 (59%) hcws agreed to sars-cov-2 rt-pcr testing between days 5-7 and day 10-14 after exposure, respectively. four hcws who developed respiratory symptoms, and the asymptomatic hcws who agreed to testing, all tested negative for sars-cov-2. this included six hcws exposed to the child during an aerosol generating procedure; all 6 remained asymptomatic and 5/6 agreed to testing and were negative. thus, we did not identify any secondary transmission events related to the two children with covid-19 identified by point prevalence. seventeen total environmental samples were collected from high-touch surfaces in rooms of patients identified with covid-19 by point prevalence survey. for child 1, ten samples were collected at the time of result notification prior to any room cleaning. the child had been admitted for about 30 hours. for child 2, seven samples were collected at the time of result notification, which was 6 hours after patient was discharged and after the room had undergone a routine discharge clean with a quaternary ammonia disinfectant. (surfaces samples are listed in supplemental table 2 ). all swabs from these patients identified by point prevalence survey were negative for sars-cov-2. for comparison, we swabbed ten high in summary, we estimated sars-cov-2 point prevalence among hospitalized children without clinical suspicion of covid-19 to be very low, approximately 1-2%, when performed around the time of predicted peak community covid-19 activity. there was no detection of sars-cov-2 environmental contamination of inpatient rooms of these children and there were no secondary transmission events among hcw exposed to these patients. this suggests the infection control and occupational health implications for care of these children with undetected sars-cov-2 shedding were minimal to hcws who were universally masked. limitations to asymptomatic detection include point-prevalence design and duration of hospital stay. many children had relatively long length of stays (i.e., >14 days), often beyond the sars-cov-2 incubation period related to community exposure. however, we received anecdotal reports from staff that parents sometimes circumvented visitation policies (i.e., not completing or omitting details from their daily symptom screening, not wearing their universal mask while in the inpatient room), so children may remain at risk of sars-cov-2 exposure even while hospitalized. lack of compliance with daily symptom screening and universal masking by hcw has not been observed. there was a small number of asymptomatic positive patients limiting a broader evaluation of hcw exposures and transmission. in addition, although all hcw were monitored for symptoms, not all agreed to testing. environmental sampling was limited by lack of a standard protocol for test collection and lack of validation of our hospital sars-cov-2 pcr assay for this purpose. although this surveillance was limited to the inpatient setting of one children's hospital, these data may guide isolation precautions and testing strategies during this pandemic. m a n u s c r i p t 9 clinical characteristics of 24 asymptomatic infections with covid-19 screened among close contacts in nanjing presumed asymptomatic carrier transmission of covid-19 transmission of 2019-ncov infection from an asymptomatic contact in germany key: cord-293136-lfwqzf8m authors: escosa‐garcía, luis; aguilera‐alonso, david; calvo, cristina; mellado, maría josé; baquero‐artigao, fernando title: ten key points about covid‐19 in children: the shadows on the wall date: 2020-08-13 journal: pediatr pulmonol doi: 10.1002/ppul.25025 sha: doc_id: 293136 cord_uid: lfwqzf8m the pandemic of the new coronavirus disease (covid‐19) caused by the severe acute respiratory syndrome coronavirus 2 (sars‐cov‐2), initially described in china, is challenging the healthcare systems of all countries. every emerging disease raises many questions with a scarcity of answers since all its characteristics are still being discovered. in the case of sars‐cov‐2, most of the literature comes from adult patients. children seem to be less affected. pediatric patients diagnosed with covid‐19 disease usually suffer a mild illness, with low risk of complications or mortality. defining the role of children in the transmission of sars‐cov‐2 is critical as some national infection control decisions involving children, such as school closures or social distancing, will probably impact the dynamics of the virus. to aid in the knowledge on covid‐19 in children, this work presents an expert review of the literature published from january 1 to april 20, 2020, including peer‐reviewed and pre‐print non‐peer‐reviewed studies, along with some relevant articles afterwards, summarizing ten key points that characterize the disease in children. this article is protected by copyright. all rights reserved. the average age reported of covid-19 confirmed cases in most countries is around 50 years old, with small differences depending on the demographic characteristics of each country (figure 1 ). most of the data from several countries place the prevalence of confirmed cases in children around 1-2% of all diagnosed cases 4 5 , which is strikingly low compared to infections caused by other respiratory viruses. the most recent official report on the epidemiology of covid-19 in spain (may 18, 2020), describes among the total notified cases only 0.3% cases in the groups under 10 years-old and 0.3% cases in the group 10-19 years-old 6 . subsequent studies in a late stage of the epidemic in china have suggested a similar transmission in children 7 8 . the data from iceland offer an accurate view of the age distribution, because the screening included the asymptomatic population 9 . this study describes a lower prevalence in population screening in children under 10 years of age compared to adolescents and adults (0/848 [0%] vs 100/12,232 [0.8%], respectively). targeted diagnosis also showed a parallel trend: 6.7% vs 13.7% confirmed cases among children <10 years old and those 10 years of age or older, respectively. this has been similarly reported in a screening study carried out in vo, a small population next to padua (italy) 10 . seroprevalence studies are being performed in different countries and settings. a preprint study conducted in geneva (switzerland) showed an increasing seroprevalence throughout april, from 6.1% to 9.7% 11 . the seroprevalence in the 5-19 year old group (6.1%) did not differ (p=0.12) from that in the year old group (8.4%). however the first group did not include children under 5 years old, and it included a broad range of ages. a similar study conducted in spain (ene-covid19 study) between abril 27 to may 10, coordinated by the spanish ministry of health, has shown a global seroprevalence of 5% 12 . one of this article is protected by copyright. all rights reserved. the most interesting aspects of this study is the low seroprevalence among children: the younger the age group, the lower the percentage of seroprevalence (1.1% in <1 years old; 2.2% in 1-4 years old; 3% in 5-9 years old; 3.9% in 10-14 years old and 3.8% in 15-19 years old). in several contact-tracing studies, children do not seem to be the usual source of infection in most cases 13 14 . based on the data currently published, it seems that children have not been a major vector for transmission in the current pandemic, but further information is needed to draw clear conclusions. whether this lower propensity to acquire and transmit the infection is due to biological resistance or due to less exposure is still a question to be answered. to evaluate the real impact of covid-19 among children, screening strategies, including serological studies, are essential, since children usually have nonsevere symptoms or are even asymptomatic, which implies that they are underdiagnosed in studies following targeted diagnosis strategies. these data will be key to determining the role of children in the transmission of sars-cov-2 and, as a consequence, adopting decisions regarding non-pharmacologic preventive approaches. to summarize, the prevalence of covid-19 disease in children is lower than in adults. although initially children were supposed to have a relevant role in the transmission of the infection, several studies suggest that they do not have such an important position. clinical features seem to be mild in comparison with adults 15 . at the time of writing, at least 3473 covid-19 cases had been reported in children (table 1) , but detailed data remain scarce. the best established features are presence or absence of fever and cough, but these have only been recorded in 31% of children in case reports. fever is the most frequent symptom (58.3%), followed by cough (47.3%) and sore throat (18.3%). rhinorrhea (15.9%) and gastrointestinal symptoms (12.7%) are also frequent. some data in adults have established fever (71-83%) and cough (65-80%) as the most commonly reported symptoms 16 15 . other symptoms in adults, such as headaches or myalgia, are not usually reported in children. non-mild disease (defined as pneumonia or this article is protected by copyright. all rights reserved. need for hospitalization) or a more severe illness accounted for 33.3% and 9.1% of all the cases reported, respectively, in this review. notably, some singular presentations that could be associated with sars-cov-2 infection have been described in children, such as infection-induced chilblains 17 in adolescents and young adults. by mid-april an increase in episodes similar to kawasaki disease and/or toxic shock syndrome were reported in several countries (e.g., uk, us, france, italy or spain). it was initially named pediatric multisystem inflammatory syndrome (pims) temporally associated with covid-19 by the royal college of paediatrics and child health (rcpch) 18 to date, some cases of neonatal sars-cov-2 infection have been reported 27 28 . most were asymptomatic or had mild symptoms, but some cases progress to a severe infection 29 30 . the earliest diagnosed patient using molecular diagnosis from a nasopharyngeal specimen was a 36-hour-old newborn 31 . breastfeeding has not been discouraged by most scientific societies (e.g., who, unicef, spanish society of neonatology or academy of breastfeeding medicine). to note, recently the detection of sars-cov-2 in human breast milk by rt-pcr has been published, which deserves further studies 32 . some questions about vertical transmission have been raised after the publication of three newborns born to mothers with sars-cov-2 infection who presented positive igm against sars-cov-2 at birth, but a negative sars-cov-2 pcr 33 34 , and the detection of sars-cov-2 rna in the placenta of pregnancies with covid-19 35 . however, these data should be interpreted with caution. in summary, pediatric patients with a sars-cov-2 infection usually develop a mild disease. however, the increasing number of patients with pims, who usually have a severe presentation, deserve a detailed analysis in order to establish the best definition and treatment. regarding the vertical transmission, currently there is not enough information and further studies are needed. typical covid-19 laboratory markers in adults are not prevalent in children, but the vast majority (table 1) do not document information about laboratory tests, so inaccurate extrapolation from adult literature is frequent. leukocyte counts are often normal, but lymphocytosis is frequent (44%) in children with covid-19. lymphocytopenia has been reported as the most common sign in blood count for adults 36 37 , but it is only present in 17.5% of children. it has been related to poorer prognosis in adults, so perhaps the low prevalence in our review might be explained by a high frequency of mild cases (66.7% in this review). procalcitonin levels seem to be greater (37.1%) than adults but reference ranges were not clearly defined. c-reactive protein is within normal range in about 74.8% of children, but in contrast it remained normal in only 37.5% (3/8 cases) of children requiring intensive care 38 . liver enzymes are frequently normal in pediatric patients 39 40 41 , in contrast to adults. remarkably, 50% of children in a case series of severe and critically ill patients presented abnormal liver function 38 . other typical markers in adults such as high lactate dehydrogenase, ferritin, d-dimer or interleukin-6 are not evident in children but may be altered in severe and critical patients. in our experience, from 43 confirmed pediatric cases who underwent a blood test, 30% presented lymphocytes below 1200/mm3 and 70% a d-dimer above 700 mg/dl 42 . so, some analytical markers to take into account when evaluating a child with confirmed or suspected covid-19, are lymphocyte count, d-dimer, c-reactive protein, procalcitonin and liver enzymes. however, their cut-off points in covid-19 and the association with severe disease is not as well defined as in adults. most data in children are provided by computed chest tomography (cct) studies from china (table 1) . from our perspective, it is surprising that cct has become the covid-19 gold standard in radiology diagnosis in children in some regions as radiation concerns might exist with doubtful medical benefit. in spain, cct is not recommended by pediatric guidelines in mild and moderate covid-19 43 . few data are available from chest radiographs in children with covid-19. no abnormalities in radiographs are shown in 48.1% of cases. unilateral or bilateral infiltrates in cct are found in 60.9% of children. bilateral ground glass opacities are the most prevalent findings. in addition, patchy shadows and consolidations are frequent. accurate and reliable diagnosis of sars-cov-2 infections remains the cornerstone of the public health strategy for disease containment. the virus nucleic acid real time-polymerase chain reaction (rt-pcr) test has become the current standard diagnostic method, using specimens collected via nasopharyngeal swab 31 . most patients have high viral loads in upper respiratory specimens soon after symptom onset which peak in the first few days before declining 32 . a study including 57 children showed that symptomatic infants had higher nasopharyngeal sars-cov-2 viral loads (measured as cycle threshold) than older children 33 . recent data from a german study indicate that viral loads in the very young (age group 0-6 years) do not significantly differ from those of adults 44 to put it briefly, sars-cov-2 pcr of nasopharyngeal swab is considered the gold standard diagnostic test for acute covid-19 disease. however, due to its suboptimal sensitivity, retest of the same specimen or even invasive specimens may be considered for non-confirmed cases. on the other hand, sars-cov-2 serology has a relevant diagnostic role in the late stages of the disease, including pims, or for seroprevalence studies. mycoplasma (1/2) 48 . in contrast, other case series did not document coinfections with respiratory viruses such as influenza, parainfluenza or rsv 39 40 . the clinical relevance of co-infections is an issue that may have important implications. this article is protected by copyright. all rights reserved. at the time of writing this article, 12 studies have recorded information on underlying conditions, which is less than 26% of the total patients in this review. among patients with reliable information, 26.4% had at least one comorbidity. the cdc in an april 6, 2020 report established that chronic lung disease (including asthma) is the most prevalent pre-existing condition (50%), followed by cardiovascular disease (31%) and immunosuppression (12.5%). additionally, a study highlighted that 40/48 (83%) patients <21 years old admitted to picu had significant preexisting comorbidities 49 . of note, immunosuppressive therapy has not been linked to poorer prognosis in small pediatric case series. d'antiga et al. in summary, comorbidities in children does not appear to be a relevant risk factor among children with covid-19 in studies focused on cohorts of children with specific chronic conditions. however, as is shown below, a relevant percentage of children with covid-19 admitted to picu have some comorbidity. anyway, due to the vulnerability of patients with chronic conditions, a special caution seems to be recommended when attending these children during sars-cov-2 epidemics. the vast majority of symptomatic children recover from covid-19 within 1-2 weeks. in contrast to adults, severe covid-19 infection in children is not frequent. some of the proposed hypotheses as to why there is different severity among children compared to adults are 57 58 : 1) different angiotensinconverting enzyme 2 expression in cell membranes 59 ; 2) better control of viral replication through innate immunity; 3) different inflammatory signaling pathways; 4) pre-existing immunity to common coronaviruses 60 ; 5) differences in clotting function; and 6) lower comorbidities. however, none of these hypotheses has been validated. a study from china included 2143 children with microbiology-confirmed (34%) or clinically suspected covid-19 (66%). severe (defined as hypoxic) or critical cases were documented in 5.8% and 2.8% of the total sars-cov-2 confirmed patients, respectively. children aged <1 year had the highest prevalence of severe and critical disease (10.6%), and 53% of children in pediatric intensive care units (picu) were infants. however, as a limitation, this group had the highest proportion of clinically suspected disease, so other viruses may have led to severe disease. of note, children aged 1-5 years might have a poorer prognosis (7.3% had severe and critical disease) compared to children >5 years and adolescents (3-4.2%). the cdc report included prognostic information, but hospitalization status was declared in only 29% of children 15 . hospitalization was more frequent among children aged <1 year and 5.2% of infants required intensive care admission. in addition, 33% of children in intensive care units were aged <1 year. patients this article is protected by copyright. all rights reserved. with underlying conditions also required more frequent hospitalization than healthy children. out of hospitalized patients, 77% were children with chronic conditions which stands in contrast to 12% of non-hospitalized covid-19 infected children. information on children with covid-19 requiring intensive care is scarce and incomplete. deterioration starts typically after 7-10 days of clinical course. currently, the main treatment for covid-19 disease is supportive care, ensuring adequate oxygenation and nutritional support for the patient. the specific treatment has focused on two different strategies 64 (table 3) 43 . regarding the antiviral treatments proposed, they target different stages of the viral replication cycle 66 . among antimicrobials 64 (e.g., lopinavir/ritonavir, chloroquine/hydroxychloroquine or ivermectin), only remdesivir has proved to this article is protected by copyright. all rights reserved. be of clinical benefit in a clinical trial including patients ≥18 years old 67 . in terms of anti-inflammatory drugs, some guidelines have included systemic steroids to be considered for covid-19 disease 68 . tocilizumab, an anti-il-6 antibody, is being evaluated in several studies 69 severe hypoxemia, severe distress or hemodynamic disfunction signs of lung infection. supportive care (1) hospital admission. consider compassionate use of remdesivir (2) . consider systemic steroids and/or tocilizumab. a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review pediatric characteristics of 2019 novel coronavirus: review of available published literature clinical characteristics of 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retrospective study of the clinical characteristics of covid-19 infection in 26 children novel coronavirus infection in children outside of wuhan, china clinical characteristics of a case series of children with coronavirus disease clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study the different clinical characteristics of corona virus disease cases between children and their families in china -the character of children with covid-19 covid-19 -service evaluation and audit on the care needs of children admitted to hospital (england) | rcpch children with covid-19 in pediatric emergency departments in italy multicentre italian study of sars-cov-2 infection in children and adolescents we thank megan yoder for kindly reviewing the manuscript, césar garcía-vera for guiding authors on statistical work, and alasdair munro and don't forget the bubbles team for inspiring this review. figure 1 . age distribution of sars-cov-2 confirmed cases in different countries. percentages are calculated from the total of confirmed cases in each country. in the case of the uk, the group aged 80-89 includes >89 years old. in the case of iceland, the 0-9 group includes 0-12 years old; the 10-19 group includes [13] [14] [15] [16] [17] chest x-ray treatment management consider compassionate use of remdesivir (2) . key: cord-310998-zchtu6cm authors: kalash, danny a. title: how covid-19 deepens child oral health inequities date: 2020-05-23 journal: j am dent assoc doi: 10.1016/j.adaj.2020.05.015 sha: doc_id: 310998 cord_uid: zchtu6cm abstract the fallout from covid-19 will reveal the depth and range of social, economic, and political disparities faced by u.s. families and children. those same injustices, magnified and worsened by covid-19, are also responsible for perpetuating child oral health disparities. s covid-19 reaches every part and level of the united states (u.s.), our society's widespread inequalities will be intensely highlighted and further exacerbated. the outbreak's impact will also be acutely felt by disadvantaged and underprivileged children. 1 those effects will prominently emerge in our oral healthcare system, where they will further widen glaring child oral health disparities. well before the coronavirus, u.s. children in poverty, from low-income families, or racial and ethnic minorities, overrepresented our national dental disease burden. 2 dental decay has unfairly and unjustly persisted and concentrated among this relatively small part of the u.s. population. and while the national prevalence of dental decay appears to be decreasing among all children, it continues to stagnate or worsen among this demographic. 2 as a result of dental decay, children's health, development, and quality of life markedly suffer. 3 when compounded with social barriers, the chronic and cumulative consequences of child oral disease contribute to wider health inequities through the life course. 4 a earlier in march, the centers for disease control and prevention (cdc) recommended all elective surgeries, non-essential medical, surgical, and dental procedures be delayed during the coronavirus outbreak. as a result, dental clinics across the country have temporarily closed to children, triaging patients for only urgent and emergency procedures. while this is a necessary precaution, closures will disproportionally harm children in poverty, from low-income families and racial and ethnic minority groups, since they carry the greatest extent and severity of dental disease. in fact, these groups already represented the highest proportion of all u.s. children with unmet dental needs. 5 by abruptly pausing the provision of child dental care, covid-19 adds delays to time-sensitive treatment, worsens the status of already significant decay, and further overburdens our previously strained dental safety net including community health centers, federally qualified health centers, and hospitals. here, the pandemic agonizingly reminds us that poor outcomes resulting from our past oral health policies and approaches will continue unless an equity and justice framework is utilized. children live in families, and as families struggle through instability, it becomes increasingly difficult to maintain a child's oral health. a growing body of evidence now shows a close link between a family's social and economic conditions and child oral health outcomes. 6 covid-19's spread refocuses our attention to those social inequities, perpetuated by deficient federal and state policies, which carry both direct and unintended consequences for child oral health. covid-19 has dramatically led to unprecedented job loss in america. regrettably, employment status in the u.s. plays a critical role in meeting eligibility requirements to qualify or maintain health and dental insurance. parental job loss can trigger loss of child dental insurance, and while there are options for keeping or renewing coverage, transitions can result in coverage gaps or changes in benefits and affordability. without dental insurance, most families are unable to afford out-of-pocket expenses for dental care. [7] [8] [9] fear of affordability dissuades parents from taking their children to the dentist, and therefore leaves children without a dental home or with unmet dental needs. policy reform should prioritize strategies which safeguard vulnerable american's oral health care by increasing state flexibility to expand coverage, and streamlining enrollment to ensure uninterrupted coverage. it should also take meaningful steps to end involuntary work-eligibility requirements which discriminate against naturally volatile jobs, and thus penalize parent and child oral health coverage. tied to covid-19's cascade of unemployment is a sudden and inescapable fall in family income. but well before the coronavirus, many american households lived paycheck to paycheck, carried large debt, were unable to cope through emergencies, and lacked disposable income or savings. furthermore, unjust power relations which stagnate worker salaries result in unlivable minimum wages and strangle family livelihoods. for these families, even slight work disruptions are devastating. as covid-19's economic stress becomes overwhelming, it jeopardizes a family's ability to afford basic needs. this forces families to prioritize only absolute necessities -like food, shelter, and utilities -and neglect or delay other expenses, including parent or child oral health care or hygiene supplies. by delaying or neglecting preventive dental services, dental decay can result or progress, and opportunities for minimally invasive approaches or early interventions are missed. all of which necessitates more advanced treatment options, requiring added time and expense unavailable to many families. this self-reinforcing cycle is accelerated by covid-19, putting further financial stress on already strained parents and their children. policy reform should ease provision of health care by shifting cost burdens away from families. it should also weigh how financial burdens of care can negatively influence healthcare systems decisions, both by parents who are unable to enter or engage in the system, as well as by providers who are unable to freely practice in the system. lastly, covid-19 has completely disrupted the us education system, keeping over 55 million students home -nearly half of which rely on free or reduced-price school meals. with unprecedented school shutdowns, school meal programs are now at serious risk of failing to meet the needs of eligible children. as a vital source of healthy and balanced nutrition, school-based meal options are especially important for children living in food deserts, with a scarcity of healthy food options. covid-19 provides a stark window into u.s. child food insecurity where families are forced into cheap, convenient, and unhealthy alternatives, including highly processed foods with significant salt, fat, and added sugars. added sugars are of course the leading and primary cause of dental caries. 10 the frequency and volume consumed is a major risk factor for development and progression of dental decay among young children. 11 policy reform should support states with flexibility to implement school-based meal programs which ensures continuity and avoids disruptions. it should also aid system and environmental strategies to improve access to healthy food options and eating habits for all children, and, take meaningful regulatory steps -particularly around advertising and food labels -to discourage the consumption of added dietary sugars. social policy has wide-ranging and disparate effects on child health and oral health, whether direct or indirect, intentional or unintentional. only by solutions which thoughtfully target the roots of social and economic inequity -through discriminatory practices and unjust power relations -can we meaningfully address the center of child oral health disparities. coronavirus heartbreakingly teaches america many important lessons: our interconnectedness and dependence on one another; our individual and collective responsibility for social welfare, and most importantly, our shared humanity. how we collectively address the social conditions of our most marginalized and weak after coronavirus is critical, and, will shape whether we truly find meaningful, sustainable, and just solutions for the health and oral health of all children. mitigating the impacts of the covid-19 pandemic response on at-risk children two decades of persisting incomedisparities in dental caries among us children and adolescents pediatric oral health research and policy center a life course health development perspective on oral health handbook of life course health development prevalence of total and untreated dental caries among youth: united states social determinants of pediatric oral health oral health for all: policy for available, accessible, and acceptable care barriers to care-seeking for children's oral health among lowincome caregivers the effect of health and dental insurance on us children's dental care utilization for urgent and non-urgent dental problems-2008 sugars and dental caries sugar restriction for caries prevention: amount and frequency. which is more important? disclosure. dr. kalash did not report any disclosures. key: cord-006050-rwayc7lr authors: das, rashmi ranjan; sami, abdus; lodha, rakesh; jain, richa; broor, s.; kaushik, s.; singh, b. b.; ahmed, m.; seth, rachna; kabra, sushil k. title: clinical profile and outcome of swine flu in indian children date: 2010-08-01 journal: indian pediatr doi: 10.1007/s13312-011-0085-y sha: doc_id: 6050 cord_uid: rwayc7lr objective: to describe the clinical characteristics and outcome of indian children infected with 2009 h1n1 influenza virus. study design: retrospective chart review. setting: outpatient department and hospitalized patients in a tertiary care hospital. methods: clinical details of 85 children (positive for the 2009 h1n1 virus infection tested by real-time reverse-transcriptase-polymerase-chain-reaction assay) were analyzed from medical charts. results: of the 85 (55 boys) children positive for 2009 h1n1 virus infection, 64.7% were between 5 years to 16 years, and 35.3% were below 5 years age. the mean age of these children was 7.5±3.5 yr. contact history was positive only in 22 (26%) cases. high grade fever was the most common symptom, followed by cough and rhinorrhea. twenty-nine (34%) patients had an underlying co-morbid condition. of the 34 patients who underwent chest radiography during evaluation, 18 children (52.9%) had findings consistent with lower respiratory tract infection. antiviral therapy was initiated in 76 patients. hospitalization was required in 30 (35.3%) children. risk factors for hospitalization included underlying co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph. mean length of hospitalization was 131±76 hours, irrespective of underlying disease. three children developed acute respiratory distress syndrome and died. conclusions: clinical features and routine laboratory investigations in children with swine origin influenza were non-specific. children with co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph were at higher risk of hospitalization. of the 85 (55 boys) children positive for 2009 h1n1 virus infection, 64.7% were between 5 years to 16 years, and 35.3% were below 5 years age. the mean age of these children was 7.5±3.5 yr. contact history was positive only in 22 (26%) cases. high grade fever was the most common symptom, followed by cough and rhinorrhea. twenty-nine (34%) patients had an underlying co-morbid condition. of the 34 patients who underwent chest radiography during evaluation, 18 children (52.9%) had findings consistent with lower respiratory tract infection. antiviral therapy was initiated in 76 patients. hospitalization was required in 30 (35.3%) children. risk factors for hospitalization included underlying co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph. mean length of hospitalization was 131+76 hours, irrespective of underlying disease. three children developed acute respiratory distress syndrome and died. clinical features and routine laboratory investigations in children with swine origin influenza were non-specific. children with co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, hypotension and infiltrates/consolidation on chest radiograph were at higher risk of hospitalization. key words: acute lung injury, ards, h1n1 influenza, pandemic influenza, swine origin influenza. the epidemic of 2009 h1n1 influenza is spreading rapidly in the indian subcontinent with more than 23727 cases and 782 deaths [6] . there have been sporadic reports about swine flu in pediatric population [7] [8] [9] . we hereby share our experience with 2009 h1n1 influenza in children seen between august and december 2009. [10] . in children presenting with mild symptoms, the medication was administered if the rt-pcr assay confirmed the diagnosis. in children who were admitted with a suspicion of swine flu, medication was started after sending the sample for the rt-pcr test for 2009 h1n1 influenza; it was continued in those who tested positive. the study was conducted as a retrospective analysis of de-identified data. we obtained demographic, clinical, laboratory, epidemiologic, and radiologic data from a chart review. hypoxemia was defined as an oxygen saturation of less than 93% while the patient was breathing ambient air. the data were managed on microsoft excel and analyzed on stata 9.0 (stata inc, college station, tx). the chi-square test or fisher's exact test was used to assess the statistical significance of differences in categorical variables, and the wilcoxon ranksum test was used to compare continuous variables. a p value of less than 0.05 was considered to indicate statistical significance. of the 260 children tested, a total of 85 (55 boys) children were found to have 2009 h1n1 infection during study period (august to december 2009) ( table i) . twenty-nine (34%) patients had significant pre-existing disorders including asthma (9) , chronic respiratory illness (6), neurological problems (4), malignancy (2), immunodeficiency (1), disseminated tuberculosis (1), chronic liver disease (1), chronic kidney disease (1), and restrictive cardiomyopathy (1). after fever, cough and coryza were the most common symptoms. other symptoms included sorethroat, vomiting, headache, diarrhea, respiratory distress, myalgia, lethargy, decreased oral accep-tance, hypotension, wheezing, croup, flushed face. mean (± sd) duration of symptoms was 3.9 (± 2) days and median duration was 5 days (range, 1-15). antiviral therapy (oseltamivir) was initiated in 76 (89%) patients at a mean of 5.3 ± 1.8 days after the onset of illness. fifty two patients (68%) started showing response to oseltamivir (in form of being afebrile and improved subjective wellbeing) within 24 hours. out of 85 children, 9 recovered without administration of oseltamivir or antibiotic. in 44 (51.8%) children, antibiotics were started either due to severe upper respiratory or chest symptoms or possible infection/sepsis. twenty six children received oseltamivir alone for recovery. thirty (35.3%) children required hospitalization for various reasons. among 20 children having respiratory distress, 17 children were hypoxic at admission and required oxygen therapy. of these 17 children, 6 children required mechanical ventilation three children developed ards and succumbed to the illness, all other children recovered. of the 3 children who died, one (12 years old) had underlying steroid resistant nephrotic syndrome with chronic kidney disease and he was admitted with diagnosis of severe pneumonia and tested positive for h1n1 influenza infection; the child died within 24 hours of admission. another (age 9 years) had diagnosis of refractory epilepsy with developmental delay and he was admitted with severe pneumonia. the third child (2.5 years) who died had diagnosis of tuberous sclerosis with lennoux-gastaut syndrome and presented with ards with refractory shock and died of refractory hypoxemia. mean (sd) total leukocyte count was 7915 (3908)/mm 3 and mild leucopenia (<5000/mm 3 ) was observed in 35% children (includes 2 children with febrile neutropenia). mean (sd) hemoglobin level (n = 41) was 10.9 (1.3) g/dl with low level (<10 g/dl) observed in 8 children. mean (sd) platelet count (n=41) was 2.01 (1.09) lakh/mm 3 with thrombocytopenia (platelets <150000/mm 3 ) being observed in 37.5% children (15/41) . four children (out of 30) had elevated total serum bilirubin (>1mg/dl) and among these 2 had underlying chronic liver disease. fourteen children (out of 30) had elevated alt and ast, with 10 children having elevation of both alt and ast >2 times upper normal limit (0-40 iu/l). abnormalities in chest radiography were detected in 18 (out of 34) children on presentation/admission or during hospitalization. the most common features were infiltrates either unilateral or bilateral (41.2%) followed by consolidation patch involving one or both lung fields (11.8%). few bacterial co-infections were detected as bacterial diagnostic tests were not performed in all patients; blood samples for cultures were taken only in hospitalized children. only one of the hospitalized children had blood culture positive sepsis (klebsiella pneumoniae). table ii . the mean age of children who required hospitalization was lower than those who received ambulatory care. the risk factors for hospitalization were: children with underlying co-morbid condition, and children with symptoms like-respiratory distress, vomiting, wheezing, or diarrhea. children having infiltrates/consolidation patch on chest radiograph were also more prone for hospitalization. children who were hospitalized had a longer duration of symptoms and also a longer interval between onset of symptoms and initiation of oseltamivir. as of 10 january 2010, worldwide more than 208 countries and overseas territories or communities have reported laboratory confirmed cases of pandemic influenza (h1n1) 2009, including at least 13554 deaths [11] . but in the indian subcontinent, there are more than 23727 laboratory confirmed cases with more than 782 (3.3%) deaths [6] . our experience of the pediatric 2009 h1n1 influenza infection in new delhi, india, shows that presentations can be atypical, severity is associated with underlying disease, and rates of secondary bacterial infection are low. the proportion of children who had an underlying condition in our study (38%) was similar to that reported in children with seasonal influenza (31-43%) [12] [13] [14] . as in patients with seasonal influenza, asthma was the most common underlying conditions in our patients [12] . antiviral drugs were administered to most patients (89.4%), but such therapy was started more than 48 hours after the onset of illness in a majority of the patients. the interval between the onset of symptoms and the initiation of oseltamivir was longer in children who were hospitalized than those who received ambulatory care. this is similar to that reported in other series [15, 16] . due to non-specific symptomatology children who had not received oseltamivir timely had high probability of hospitalization, thus adding to the impression of delayed administration of oseltamivir in hospitalized children. secondly, being a tertiary care hospital, children referred from outside with severe illness (without obvious cause) were tested only after getting admitted to our hospital; there was a time gap for administration of oseltamivir after onset of illness. while the risk factors/groups are not well defined for the 2009 h1n1 influenza, they are likely to be similar to those for seasonal influenza. patients susceptible to severe disease are -those younger than five years and over sixty five years of age, pregnant women, those with systemic illnesses, adolescents on aspirin, residents of nursing homes and immune suppressed. among these, children younger than 4 years have the highest complication and death rates [16] . pediatric data for severe disease include: chronic respiratory illness including asthma, neuromuscular disorders, cerebral palsy, developmental delay, immunodeficiency, heart disease, and prematurity [7, 9, 16] . majority of children with underlying disease fully recovered, which may be explained by seeking medical attention before serious complications as many were children of parents who are employed in our hospital, this group also includes children in follow up clinics for major illnesses. hospitalized children were more likely to receive antibiotics in view of possible sepsis/infection or complications. patients who expired came to hospital in an advanced stage of illness. out of three deaths, two occurred in children who presented with serious complication of acute lung injury and one had • the clinical features of the ongoing swine origin influenza pandemic are non-specific and are similar to other viral infections. • clinical features and routine laboratory investigations in children with swine origin influenza were non-specific. • risk factors for hospitalization include: underlying co-morbid condition, respiratory distress, vomiting, wheezing, diarrhea, or hypotension, infiltrates/consolidation on chest radiograph. • majority of the children with swine origin influenza had a benign course and a good outcome. volume 48 __ may 17, 2011 we found history of contact in only 26% children; this suggests that h1n1 flu was widespread in the community. travel history was also not significant now as only two children had history of foreign travel. clinical features and routine laboratory investigations were non-specific and also could not be distinguished from other viral infections, as described previously. the clinical features of patients who were hospitalized with 2009 h1n1 influenza were generally similar to those reported during peak periods of seasonal influenza and past pandemics with an acute onset of respiratory illness [17] [18] [19] [20] . whereas diarrhea or vomiting have occasionally been reported in children during peak periods of seasonal influenza [18] , these symptoms were reported in 10-27% of patients in our study. incidence of diarrhea was reported to be between 8-20% and vomiting in 10-40% in children infected with swine origin h1n1 infection [9, 16] . in one report incidence of diarrhea or vomiting was reported to be in 42% of children [15] . as found in other studies, occasional case may present without respiratory symptoms. recovery was very fast in all the patients irrespective of underlying illness, which is in contrast to other studies. some patients recovered without complications even without antiviral therapy, so antiviral therapy may not be required in all cases. few complications in the patients including those with underlying high risk illness tells that majority of children will have a benign course. our study has several limitations. in this retrospective chart review, majority of the patients we evaluated were children of hospital employees, who may seek early evaluation and treatment. the number of children evaluated was also small (though it is the largest data on pediatric h1n1 flu from a single centre). we evaluated only patients with confirmed 2009 h1n1 influenza virus infection, so the group may not be representative of patients who may not have been tested. finally, despite the use of a standardized data-collection form, not all information could be collected for all patients. clinicians should consider h1n1 influenza in the differential diagnosis of children with pre-existing disorders who present acutely to health services even if there are no classic flu like symptoms or an alternative diagnosis is suspected, especially if there are severe symptoms or underlying disease. it is imperative that further data are collected prospectively on the clinical presentations and predictors of severity in h1n1 influenza. to conclude, h1n1 infection should be considered in the differential diagnosis for patients presenting with fever and respiratory illness or pneumonia. majority will have a benign course. as the 2009 h1n1 pandemic evolves, continued investigation is needed to better define the clinical spectrum of disease and risk factors for an increased severity of illness, which will allow for improvements in treatment guidance. novel swine-origin influenza virus a (h1n1): the first pandemic of the 21st century emergence of a novel swine-origin influenza a (h1n1) virus in humans antigenic and genetic characteristics of swine-origin 2009 a (h1n1) influenza viruses circulating in humans the persistent legacy of the 1918 influenza virus clinical management of human infection with new influenza a (h1n1) virus: initial guidance. world health organization: global alert and response ministry of health and family welfare, government of india swine-origin influenza virus h1n1, seasonal influenza virus, and critical illness in children surveillance for pediatric deaths associated with 2009 pandemic influenza a (h1n1) virus infection -united states clinical characteristics of paediatric h1n1 admissions in birmingham directorate general of health services, ministry of health and family welfare, government of india. pandemic influenza a h1n1-clinical management protocol and infection control guidelines pandemic (h1n1) 2010 -update 83. geneva: world health organization multistate surveillance for laboratory confirmed, influenza-associated hospitalizations in children neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection epidemiology, complications, and cost of hospitalization in children with laboratory -confirmed influenza infection hospitalized patients with 2009 h1n1 influenza in the united states pediatric hospitalizations associated with 2009 pandemic influenza a (h1n1) in argentina clinical features of influenza surveillance for influenza admissions among children hospitalized in canadian immunization monitoring program active centers studies on influenza in the pandemic of 1957-1958. ii. pulmonary complications of influenza key: cord-277315-e26oc883 authors: dhiman, sapna; sahu, pradeep kumar; reed, william r.; ganesh, g. shankar; goyal, ramesh k.; jain, shilpa title: impact of covid-19 outbreak on mental health and perceived strain among caregivers tending children with special needs date: 2020-10-06 journal: res dev disabil doi: 10.1016/j.ridd.2020.103790 sha: doc_id: 277315 cord_uid: e26oc883 background: while covid-19 outbreak has had adverse psychological effects in children with special needs, the mental state and burden on their caregivers during this pandemic has yet to be reported. aims: the objectives of this study were to describe the mental health status and the change in perceived strain among caregivers during the covid-19 outbreak. methods and procedures: two hundred sixty four caregivers completed an online survey that assessed demographics, use and perspective on tele-rehabilitation, homecare therapy, caregiver’s strain and mental health. outcomes and results: the prevalence of depression, anxiety and stress symptoms were found to be 62.5 %, 20.5 % and 36.4 % respectively. a significant difference in caregiver strain (p < 0.001, effect size = 0.93) was observed during the outbreak compared to levels pre-outbreak (pre-outbreak strain was measured retrospectively). caregivers not using tele-rehabilitation along with a perception of it being a poor medium for rehabilitation were at greater risks for poor mental health whereas a negative perception on homecare therapy were strongly associated with higher psychological symptoms and strain. conclusions and implications: this study identified a high prevalence of depression and significant change in strain displayed by caregivers during the covid-19 outbreak. we identified several factors associated with poor mental health and perceived strain that can be used to help safeguard caregivers. this was a survey conducted in collaboration with rehabilitation professionals working in pediatric clinics across india. a network of physiotherapists and occupational therapists known to the investigators were contacted and the study explained in detail. the contact information of caregivers having children with special needs satisfying the inclusion criteria were collected from the professionals networks and reconfirmation on their understanding of english was done by the authors before participating in the survey. an online questionnaire was created to conduct data collection without risking participant exposure to the virus. a link containing the questionnaire was sent through emails, whatsapp and other social media to caregivers. data was collected from april 29, 2020 to may 22, 2020. in this online survey participants older than 18 years of age and primary caregivers of children with special needs were allowed to participate. other inclusion criteria included the ability to read and comprehend english along with their willingness to provide informed consent. the study and protocol was approved by the institutional ethical committee, school of physiotherapy, delhi pharmaceutical sciences and research university (10/876/acad/dpsru/2018, dated 27.04.2020) and was conducted in accordance with the declaration of helsinki guidelines. electronic informed consent was obtained from each participant prior to starting data collection. the questionnaire was developed by the investigators and contained several sections (appendix a). the initial section was information on demographics including child's age, relation with child, occupation of caregiver, diagnosis, and any elder (> 60 years) living at home. then questions regarding presence of steady financial status, current workload, relationship between workload and care and whether the primary caregiver worked from home or the workplace were asked. in this section, the child's independent functioning in eating, dressing, hygiene and mobility were assessed. the response for eating, dressing, hygiene function were dichotomized in to independent or dependent status where-as mobility were categorized to 5 levels. apart from this, the caregiver's perception about homecare therapy and tele-consulation and rehabilitation were also assessed. to assess mental health symptoms during the pandemic outbreak, depression anxiety stress-21scale (dass-21) was used (lovibond & lovibond, 1995) . participants responded to a 21 item depression anxiety stress scale . the scale is divided in to three subsets (stress, anxiety and depression) and each domain contains 7 items. dysphoria, hopelessness, devaluation of life, self-deprecation, lack of interest / involvement, anhedonia and inertia were evaluated by the depression subscale. the anxiety subscale assessed autonomic arousal, skeletal muscle effects, situational anxiety, and the subjective experience of anxious affect. to assess difficulty in relaxing, nervous arousal, and being easily upset / agitated, irritable / over-reactive and impatient the stress subscale was used. the respondent scored the response on a 4 item linkert rating scale with 0 "denotes did not apply to me at all" to 3 "applied to me very much or most of the time". scores for depression, anxiety and stress symptoms were calculated by summing the scores for the relevant items. finally this short version dass-21 scores were multiplied by 2 to find the severity of depression, anxiety and stress symptoms. the depression subscale is categorized as mild (10-13), moderate (14-20), severe (21-27) and extremely severe (28+). the anxiety subscale is classified in to mild please cite this article in press as: s. dhiman (8-9), moderate (10-14), severe (15) (16) (17) (18) (19) and extremely severe (20+) to note the severity of anxiety symptoms. finally, the severity of stress was assessed on mild (15-18), moderate (19-25), severe (26-33) and extremely severe (34+). the validity of this scale measuring depression, anxiety and stress symptoms was previously tested (ng et al., 2007) . caregiver's strain during and before the covid-19 outbreak were enquired by using a validated caregiver strain index (csi) questionnaire (robinson, 1983) . to observe the impact of the covid-19 outbreak on caregiver strain, participants were asked to retrospectively note the strain they perceived one month before the pandemic. this is a 13 item questionnaire measuring strain perceived by caregivers related to the childcare provided. this questionnaire contains at least one item related to domains such as employment, financial, physical, social and time. items were dichotomized in to yes/no response and the total possible score ranges from 0 to 13 (0 -no, yes -1). a score 7 or above indicates a greater level of strain. this scale was developed and validated to measure strain perceived due to care of children with various neurological conditions such as cerebral palsy, duchene muscular dystrophy and other serious illnesses (byrne et al., 2011; pangalila et al., 2012; sharan et al., 2012) . data were analysed with spss version 26.0. descriptive statistics were used to find the prevalence of depression, anxiety, stress symptoms and demographics of factors. the impact of covid-19 outbreak on csi was analysed using a paired t-test. bivariate pearson correlation testing was conducted to find the relationship among depression, anxiety, stress symptoms and csi. multivariate anova (manova) was conducted to analyse the demographic, social and care related factors associated with dass indices (depression, anxiety and stress symptoms). to test the demographic, social and care related factors associated with csi, analysis of covariance (ancova) was used where the csi score one month before the pandemic outbreak (retrospective data) was considered as a covariate. contact information of 307 caregivers of children with special needs satisfying the inclusion criteria were received from the rehabilitation professional network and then participants were reconfirmed by the authors for knowledge in reading, understanding english and access to internet. five caregivers denied participating because of various reasons and two were excluded because of lack of understanding english. the 300 participants fitting study criterion were asked to complete the online form. finally, data from 264 respondents were recorded (response rate 88 %, no missing data) and analysed. all respondents had a minimum bachelor degree qualification and 85 % of our sample had above bachelor level education. approximately, 80 % of caregivers were the mother, 16 % were the father and only 4% provided care as other family member ( table 1 ). the mean age of children was 6.20 ± 3.05 (mean ± sd) years and participants were from 9 major cities of india. overall, the prevalence of depressive symptoms was 62.5 % whereas prevalence of anxiety and stress symptoms were 20.5 % and 36.4 % respectively. the prevalence of psychological symptoms with their severity is presented in table 2 and to evaluate the impact of covid-19 on csi, the csi during the outbreak was compared with the retrospectively reported csi score 1 month before the outbreak by a paired t-test. table 3 and fig. 2 indicates there was a statistical significant change (p < 0.001) with large effect size (0.93) from before to during the outbreak and a mean difference of 2.98±3.83. please cite this article in press as: s. dhiman, p.k. sahu, w.r. reed et al. impact of covid-19 outbreak on mental health and perceived strain among caregivers tending children with special needs. research in developmental disabilities (xxxx), https://doi.org/10.1016/j.ridd.2020.103790 table 3 impact of covid-19 outbreak on caregiver strain index analysed by paired t-test. before outbreak (mean ± sd) graph showing mean change in csi score before the outbreak (retrospectively reported) to during the outbreak. the results of correlation analysis are shown in table 4 . bivariate correlation testing was done among depression, anxiety, stress symptoms and csi. the results showed a weak but statistically significant correlation between depression (r = 0.25, p < 0.001) and anxiety symptoms (r = 0.21, p < 0.001) with csi, while a moderate, statistical significant correlation (r = 0.40, p < 0.001) was found between csi and stress symptoms. moreover, a statistical significant and strong correlation were observed between depression, anxiety symptoms (r = 0.64, p < 0.001), depression, stress symptoms (r = 0.61, p < 0.001) and anxiety, stress symptoms (r = 0.73, p < 0.001). to explore the demographic, social and care related factors associated with dass indices (depression, anxiety and stress symptoms), manova was used. the assumptions for manova such as absence of outliers, linear relationship between each dependent variables and each group of independent variable, multivariate normality and absence of multi-collinearity (correlation coefficient 0.2 to 0.9 between each dependent variables) were met and the independent factors satisfying the assumptions were selected to be tested. one way manova analysis with wilk's lamda ( ), p value and effect sizes (partial eta squared) are presented in table 5 , which shows the difference across levels in various factors when depression, anxiety and stress symptoms considered together as a dependent variable. analysis of variance (anova) was conducted to test association of each independent factor on depression, anxiety and stress symptoms separately ( table 6 ). the mean and standard deviation score of all psychological symptoms of each independent factor across levels is presented in appendix b. to estimate the strength of associations estimates (b) is used. finally, a series of post-hoc analyses (scheffe's test used because of unequal sample sizes) were performed to examine differences across three levels of perception on difficulty of home care therapy, five levels of mobility and three levels of work from home pattern during lock-down. the mean differences and p value are presented in table 7 . univariate ancova was performed to test the demographic, social and care related factors associated with csi during the outbreak among caregivers tending children with special needs. after meeting the assumptions, csi score before the pandemic outbreak was considered as a covariate in the model. the mean and standard deviation score of csi during the outbreak of each independent factor across levels is presented in appendix b. the ancova results including estimates (b), p value and effect sizes (partial eta squared) after controlling csi score before the outbreak, is presented in table 8 . the overall result of the study shows a high prevalence of depressive symptoms among caregivers tending children with special needs during the covid-19 pandemic outbreak. a significant difference in caregiver strain was observed during the outbreak when the strain was retrospectively noted one month before the pandemic. apart from it, we found several demographic, social factors and services related to care of child are associated with depression, stress, anxiety symptoms and perceived strain. the study observed a high prevalence of depressive symptoms (62.5 %) among caregivers whereas 20.5 % and 36.4 % were indicated for anxiety and stress symptoms respectively. our study reported a significantly high prevalence of depressive symptoms among caregivers in contrast to 37.1 % and 20.1 % reported by two chinese studies conducted during the initial period of lockdown among the general population huang & zhao, 2020) . it was also noted that an extended period of outbreak was not associated with a change in depression score among the general population (wang, pan et al., 2020; wang, hu et al., 2020) . caregivers of children with special needs face unique challenges in family, social life and are stigmatized in society because of their children's disability. behavioral issues are also very common in this population (martin et al., 2019; vadivelan et al., 2020) . however, in comparison to a low prevalence of depression reported by previous studies among caregivers of asd (43 %), cp (26 %), intellectual and developmental disabilities (idd) (29 %) children, a higher prevalence in our study was possibly because of the added burdens after the outbreak (al-farsi et al., 2016; sajedi et al., 2010; singer, 2006) . thus, we assume the high prevalence in our sample may be due to the combined effect of lock-down and the particular nature of their occupation. moreover, the impact of the increase in death rate in india and the amount of pandemic media coverage during the time of data collection may have contributed to increased depression level. the low prevalence of anxiety symptoms in the present study is similar to the data reported by past research on parents of intellectual disabled (18.33 %) and idd (31 %) (tak et al., 2018; scherer et al., 2019) . although the chinese and iranian general population observed a high prevalence of anxiety during the pandemic, the lower prevalence in our caregivers might be related to the timing of the individual studies moghanibashi-mansourieh, 2020) . fear of disease contagiousness, knowledge on safety measures are usually the main causes of anxiety apart from financial and social issues (roy et al., 2020) . by the time this study was conducted, caregivers may have been more aware and better informed about the disease, the precautionary measures to be followed, and had partially adapted to the situation. furthermore, during the lockdown, living with the family members and increased interpersonal communication might have had a direct effect on anxiety scoring. the same factors probably attributed to stress levels unlike to the previous study results ( *csi before the outbreak (retrospective) as co-variate in the model. note: p ≤ 0.05*, p ≤ 0.01**, p ≤ 0.001*** ; a -referent factor. b = estimates; áp 2: partial eta squared. mobility level 1: can walk on their own without using a walking aid, including fairly long distances, outdoors and on uneven surfaces. level 2: can walk on their own without using a walking aid, but has difficulty walking long distances or on uneven surfaces. level 3: can walk on their own using a walking aid (such as a walker, rollator, crutches, canes, etc.). level 4: can sit on their own but does not stand or walk without significant support and adult supervision. level 5: has difficulty sitting on their own and controlling their head and body posture in most position. 2016; masulani-mwale et al., 2018) . recent research also identified a strong relationship between psychological and physical symptoms in the general population and among health workers during the covid-19 pandemic (chew et al., 2020; wang, pan et al., 2020; wang, hu et al., 2020) . these common symptoms such as throat pain, headache, migraine and fatigue are often confused with associated symptoms of viral infection and may further aid in deteriorating mental health. caregivers not continuing tele-rehabilitation during the lockdown are associated with a high anxiety level and a strong association was found between a caregiver's perception on tele-consultation as an alternate medium for rehabilitation and psychological symptoms. we found that subjects who responded with a perception against tele-consultation were at greater risk for depression, anxiety and stress symptoms. with the advancement in technology, tele-rehabilitation is considered as an alternative medium in health care. moreover, to provide solutions to global disease and to better battle against this current pandemic, tele-rehabilitation should have a greater emphasis wherever feasible. poor utilization and acceptance of tele-health service was also observed in another indian study (khanna et al., 2018) . the overlooked barriers in a developing country such as poverty, confidentiality, privacy and cross-cultural acceptance of tele-rehabilitation strategies are the probable factors for the negative perception of tele-rehabilitation warrant future exploration (khan et al., 2015) . moreover, caregiver's knowledge on the importance of tele-rehabilitation, patient and therapist bonding, communication between participants play a major role in creating acceptance of tele-rehabilitation and a positive perception in caregivers (kairy et al., 2013; mair et al., 2005) . thus, the present work encourages greater urgency for policy makers and care providers to implement and strengthen greater use of tele-rehabilitation approaches and to provide better education on the benefits of tele-rehabilitation as a means to reduce depression, stress and anxiety symptoms among caregivers tending children with special needs. parents/caregivers participation and engagement are major components in rehabilitation of children with disability as they spend more time with them (phoenix et al., 2020) . thus, it is advisable that the caregivers should strive to learn homecare treatment techniques from the therapists to enhance their overall functional ability. however, due to a sudden declaration of lockdown many caregivers were unable to learn homecare techniques in an appropriate manner that might have resulted in wrong perception about difficulties encountered during homecare therapy. caregivers who did not learn homecare therapy were associated with depression and who held a perception that homecare therapy is moderate to difficult was strongly associated with stress symptoms. these findings indicate either lack of education on the importance of homecare therapy or ineffective home care training was provided to caregivers deserves greater consideration. we also found that certain immediate non-modifiable factors such as dependency in eating, dressing and hygiene were risk factors for depression, anxiety and stress symptoms similar to that reported in a previous study (batool & khurshid, 2015) . we observed that both caregivers of children who could walk long outdoor distances without difficulty (mobility level 1) and with difficulty (level 2) were associated with poor mental health compared to those caregivers with children having only independent sitting ability (level 4). most of the participants in level 1 and 2 were asd and ld while in level 4 cp were the majority. therefore, we can assume that sensory and behavioral issues of children are the main contributors to poor psychological health in their caregivers. working from home during the lockdown is also found to be a risk factor for poor mental health. the reason could be by being at home they have to care the child in addition to their job schedule at home. caregivers of older children were less prone for depression, anxiety and stress symptoms because they are likely to be more autonomous, independent in function and less demanding for caregivers. this data was confirmed by the positive association between dependency in eating, dressing, hygiene and higher depression, anxiety and stress symptoms. moreover, coping strategies learnt by parents over time might have aided in reducing the poor psychology associated with the children's disability. health is defined as a state of complete physical, mental and social well-being and to observe all the three dimensions of caregiver's health, the csi questionnaire was used (who definition of health, 2020). one month before the covid-19 pandemic lockdown a mean perceived strain of 4.30 was observed in our sample (when asked to score it retrospectively) which significantly increased to 7.29 post-lockdown. this level of increase demands that greater attention to be paid to effectively alleviate this added strain. relationship between caregiver strain and functional limitation of the child remain inconclusive. we noticed children with indoor mobility with orthotic devices and lack of independent sitting ability groups were strongly associated with increased caregiver strain. this finding is corroborated by the previously published indian study (prakash et al., 2017) . on the other hand, a lower level of strain among caregiver's of children with dependency in dressing indicates it should not be an immediate primary goal by care providers to reduce strain in the caregivers during this pandemic. caregivers continuing tele-rehabilitation and homecare therapy scored these types of therapies to be physically strained and confining in csi questionnaire. this was supported by the findings that the strain was more in caregivers whose perception of homecare therapy was moderate to difficult. thus, better communication between rehabilitation professionals and caregivers is needed to teach the strategies in an efficient manner to reduce strain. furthermore, there should be a call for greater attention among rehabilitation care providers and policy makers for increasing education in this area. family adjustments, keeping a fixed work schedule and simulating office conditions may help to decrease strain associated with care giving as a strong association was noted between working from home and perceived strain similar to mental health. beside this, a higher strain in caregivers living with elder may be due to the burden related to additional care to them. this study has several limitations. first of all, to ensure safety of participants, psychological testing and caregiver strain were self administered, and not recorded by health professionals. second, a causal relationship between covid-19 and psychological outcome is difficult to obtain because of the cross-sectional nature of study. moreover, covid-19 for some participants in itself may have contributed to levels of mental health symptoms, and this was not controlled for. third, because of the online nature questionnaire structure, and location of rehabilitation centres, the study was limited to participants in major cities who had adequate english comprehension skills. thus, the results may not be generalizable to all caregivers tending children with special needs. fourth, the study had not scrutinized the severity of the illness of the child and past history of mental symptoms in caregivers which likely contribute to the strain and mental health of caregivers. this aspect should be addressed in future studies. finally, due to the time-constraint of pandemic outbreak, user involvement in instrument development was not solicited but this could be incorporated in future studies. the study represented the initial use of an on-line questionnaire that could possibly be further refined and used in future pandemics. future investigations should longitudinally assess the mental health and strain on caregivers whenever an outbreak persists for a sufficient duration of time. this study identifies a high prevalence of depressive symptoms displayed by caregivers tending children with special needs. the covid-19 outbreak has had a significant impact on caregiver strain when the perceived strain one month before the outbreak was measured retrospectively. lack of tele-rehabilitation and its negative perception were found to be associated with caregiver's anxiety symptoms and poor mental health respectively whereas continuing tele-rehabilitation added more strain to the caregivers. caregivers who had not learned homecare therapy were more depressed, while those who learned homecare therapy methods experienced more strain. moreover, a perception of homecare therapy as being moderate to difficult medium were significantly associated with higher stress and strain compared to those who perceived it as easy. older children (≥ 6 years), with better self-care abilities were protective factors against caregiver's poor mental health. finally, working from home during the lockdown was associated with poor psychological health and elder living at home poses greater stress to the caregivers. therefore, greater communication among service providers and caregivers regarding removal of barriers associated with an unfavorable perception of tele-rehabilitation, increasing education on the homecare therapy, and provision of psychological interventions/services may help to diminish mental health issues and strain associated with care-giving. ultimately, by these caregiver implementations, children with special needs can receive better care during current (covid-19) and future outbreaks. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. all data relevant to the study are included in the article or are available as supplementary files. the authors report no declarations of interest. please cite this article in press as: s. dhiman, p.k. sahu, w.r. reed et al. impact of covid-19 outbreak on mental health and perceived strain among caregivers tending children with special needs. research in developmental disabilities (xxxx), https://doi.org/10.1016/j.ridd.2020.103790 3 age of the child-4 what is the diagnosis of the child? (e.g., cerebral palsy, autism, adhd, attention deficit hyperactive disorder, learning disability, spina bifida etc.) 5 detail address of caregiver 6 do you have a steady financial income after the covid19 outbreak?-yes/no 7 do any elderly member (above 60) live with you in your family-yes/no 8 occupation: 9 are you working from home during covid-19 outbreak? yes/no/not applicable 10 if yes, does working from home affects the care you provide to your child? yes/no 11 what are your child's functioning abilities in the following areas? a eating: dependent/independent b dressing: dependent/independent c hygiene: dependent/independent 12 please read the following and mark only one box beside the description that best represents your child's movement abilities. a has difficulty sitting on their own and controlling their head and body posture in most positions b can sit on their own but does not stand or walk without significant support and adult supervision c can walk on their own using a walking aid (such as a walker, rollator, crutches, canes, etc.) d can walk on their own without using a walking aid, but has difficulty walking long distances or on uneven surfaces e can walk on their own without using a walking aid, including fairly long distances, outdoors and on uneven surfaces 13 have you learned homecare therapy of your child? yes/no 14 if yes, how you find homecare therapy? easy / moderate / difficult. 15 are you able to do tele-rehabilitation with your rehabilitation service provider during this lockdown? yes/no 16 do you find tele-rehabilitation as an alternate option for rehabilitation? yes/no two caregiver strain index questionnaire are attached. answer the following questions according to your experience one month before and during the covid-19 pandemic outbreak in yes or no format. below is a list of things which other people have found to have difficulty with when helping care for a relative /friend. please answer yes or no by placing a √ in the appropriate column yes no sleep is disturbed becauseis in and out of bed or wanders around at night 2. it is inconvenient because (e.g. helping takes so much time or its long drive over to help.) 3. it is a physical strain(e.g. because helping in and out of a chair, effort or concentration required) 4. it is confining (e.g. helping restricts free time or cannot go visiting) 5. there have been family adjustments (e.g. because helping has disrupted routine, there has been no privacy) 6. there have been changes in personal plans (e.g. had to turn down a job; could not go on vacation) 7. there have been other demands on my time (e.g. from other family members) 8. there have been other emotional adjustments (e.g. because of severe arguments) 9. some behaviour is upsetting ( e.g. because of incontinence;has trouble remembering things; oraccuses people of taking things) 10. it is upsetting to findhas changed so much from his/her formal self (e.g. he/she is a different person than he/she used to be) 11. there have been work adjustments (e.g. having to take time off) 12. it is a financial strain 13. feeing completely overwhelmed (e.g. because of worry about . . .. . .. . .. . .. . ...: concerns about how you will manage.) 1. are you not experience any positive feeling a. 1 (s) i found it hard to wind down 0 1 2 3 2 (a) i was aware of dryness of my mouth 0 1 2 3 3 (d) i couldn't seem to experience any positive feeling at all 0 1 2 3 4 (a) i experienced breathing difficulty (e.g. excessively rapid breathing, breathlessness in the absence of physical exertion) 0 1 2 3 impact of covid-19 outbreak on mental health and perceived strain among caregivers tending children with special needs guidance for the treatment and management of covid-19 among people with intellectual disabilities stress, anxiety, and depression among parents of children with autism spectrum disorder in oman: a case-control study factors associated with stress among parents of children with autism parent 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utility of tele-neurorehabilitation service in india: experience from a quaternary center an estimation of the prevalence of intellectual disabilities and its association with age in rural and urban populations in india living alone among older adults in canada and the adoption of telerehabilitation in a developing country before and during the covid-19 pandemic factors associated with parents' adherence to different types of exercises in home programs for children with disabilities manual for the depression anxiety & stress scales patient and provider perspectives on home telecare: preliminary results from a randomized controlled trial associations between parenting stress, parent mental health and child sleep problems for children with adhd and asd: systematic review prevalence of psychological distress among parents of children with intellectual disabilities in malawi utilization of institutional rehabilitation service in pediatric patients with disability in southwest rajasthan 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anxiety & perceived mental healthcare need in indian population during covid-19 pandemic depression in mothers of children with cerebral palsy and its relation to severity and type of cerebral palsy living arrangements and health of older adults in india preparing children for pandemics depression and anxiety in parents of children with intellectual and developmental disabilities: a systematic review and meta-analysis the human rights of children with disabilities during health emergencies: the challenge of covid-19 coronavirus immunoreactivity in individuals with a recent onset of psychotic symptoms musculoskeletal disorders in caregivers of children with cerebral palsy following a multilevel surgery meta-analysis of comparative studies of depression in mothers of children with and without developmental disabilities loneliness among older europeans prevalence of psychiatric morbidity among parents of children with intellectual disability intensive training of motor function and functional skills among young children with cerebral palsy: a systematic review and meta-analysis the covid-19 pandemic and people with disability burden of caregivers of children with cerebral palsy: an intersectional analysis of gender, poverty, stigma, and public policy a longitudinal study on the mental health of general population during the covid-19 epidemic in china clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan acute stress, behavioural symptoms and mood states among school-age children with attention-deficit/hyperactive disorder during the covid-19 outbreak we acknowledge mr. priyabrata kalikinkar ojha, junior research fellow, department of pediatrics, all india institute of medical sciences (aiims), new delhi, india for helping in collecting data. questionnaire during covid-19 parents/caregivers of children with special needs are facing unique challenges. though social distancing has been widely promoted as the best strategy to avoid transmission that advice may not be realistic for people who care for children and youth with special needs and who may require therapy or assistance with daily tasks. parents/caregivers are struggling to balance work, child care and self-care while keeping worries of both children's and own under control, which further adding to parents/caregiver stress.hence this survey intends to find out impact of covid-19 on parents/caregivers mental health and caregiver strain. participation is totally voluntary. information provided by the participant shall be kept confidential and will be used only by the researcher for research purpose.consent: i have understood the details of the study. i allow using information provided by me for research purpose by researchers.agree to participate in the study disagree note: sd = standard deviation. key: cord-301022-0q2ertja authors: mims, james w.; veling, maria c. title: inhalant allergies in children date: 2011-04-29 journal: otolaryngol clin north am doi: 10.1016/j.otc.2011.03.013 sha: doc_id: 301022 cord_uid: 0q2ertja children with chronic or recurrent upper respiratory inflammatory disease (rhinitis) should be considered for inhalant allergies. risk factors for inhalant allergies in children include a first-degree relative with allergies, food allergy in infancy, and atopic dermatitis. although inhalant allergies are rare in infancy, inhalant allergies are common in older children and impair quality of life and productivity. differentiating between viral and allergic rhinitis can be challenging in children, but the child's age, history, and risk factors can provide helpful information. allergic rhinitis is a risk factor for asthma, and if one is present, medical consideration of the other is warranted. james w. mims, md a, *, maria c. veling, md b most otolaryngologists see pediatric patients and treat disorders associated with chronic upper respiratory inflammation (rhinitis, otitis, pharyngitis, and laryngitis) as a routine part of their practice. in 2009, otolaryngologists were surveyed by telephone as part of the pediatric allergies in america survey. otolaryngologists estimated that they saw 43 patients aged 4 to 17 years per week and that 41% were diagnosed with ar. 1 pillsbury and colleagues 2 noted that ar was the most common international classification of diseases-9 code used by otolaryngologists in a workforce study conducted in 2000. because allergy is a common contributor of upper airway inflammation, a working knowledge of pediatric allergy is beneficial in the evaluation and treatment of children presenting to otolaryngologists. upper and lower airway inflammation is linked epidemiologically and physiologically. 3 therefore, considering and appropriately identifying coexisting lower respiratory inflammation (eg, asthma) is also logical. identifying asthma in otolaryngology patients is especially compelling because unmanaged asthma impairs quality of life and can be fatal. it is also likely that asthma is underdiagnosed and undertreated. 4 this article informs the otolaryngologist about the development, manifestations, and treatment of allergy in pediatric patients. atopy is the predisposition to develop allergic diseases. the phenotype of allergy seems to have a complicated and variable genetic contribution. gene-environment interactions have been identified, 5 and add another layer of variability to the development of allergic disease. there is no single genetic test to identify if an individual is likely to be atopic. genetic studies looking at single nucleotide polymorphism have focused primarily on allergic inflammatory cells and mediators. although hundreds of associations have been identified, each alone tends to be difficult to reproduce or represents only a small percentage of allergic individuals. 6 large genome-wide association studies use a hypothesis-independent strategy to identify which genes are statistically different between an affected and nonaffected population. in asthma, genome-wide association studies have identified a small number of genes, such as ormdl3, 7, 8 of which the functions remain unclear. currently, the allergy phenotype probably represents multiple and variable combinations of genetic predispositions many of which require a specific environmental interaction to be manifested. so far, the genes identified suggest alterations in both innate and adaptive immunity play a significant role in allergic disease. 9 as suggested by the complicated genetics, family history of allergy is a risk factor, but inheritance does not follow a simple pattern. for ar, family history of atopy is one of several risk factors that include cigarette exposure; higher socioeconomic class; first-born or only child; and elevated total ige (>100 iu/l) before age 6 years. 10 in the danish twin study of asthma by skadhauge and coworkers, 11 the proban-wise concordance of monozygotic males to develop asthma was 0.51 (0.39-0.63), whereas dizygotic opposite sex twins was only 0.07 (0.03-0.11). another study showed that of those with one asthmatic parent, 26% developed asthma. of note, maternal history was more predictive. 12 although not definitive, asking about allergies in first-degree relatives is useful in the evaluation of a child with chronic upper or lower respiratory inflammation. there have been multiple studies investigating if variables in pregnancy affect the later development of allergies including the time of year the child is born, maternal diet, or route of delivery. one study suggested that north american children born in the late fall have a higher risk of developing asthma. 13 this is attributed to the role of winter respiratory viruses, such as respiratory syncytial virus, occurring in the first few months of life increasing the risk of asthma. however, the authors are not aware of any recommendations advising timing of pregnancy based on allergy risk because studies are conflicting and the overall evidence insufficient. restricting maternal diet in pregnancy from proallergic foods has been shown not to affect the development of atopy in the child. 14 some studies have shown some protection from atopy in children delivered vaginally compared with those delivered by cesarean section. 15 the affect is attributed to the "hygiene hypothesis," which is discussed later. ige in cord blood has also been of interest. nonspecific ige is produced in utero starting around 11 weeks gestation, but specific ige is first identified after birth. initial reports of ige levels in cord blood predicting atopy have not been supported in later prospective studies. 16 difficulties in identifying children at high risk for allergy beyond parental allergic history complicates research aimed at attempting to prevent the development of allergic disease. although inhalant allergy is not prevalent during the first 2 years of life, there are clues in infancy as to the risk of later developing inhalant allergic disease. knowledge of these risk factors can be useful when trying to determine if an older child's rhinitis may be allergic. many studies have also examined if there are ways to prevent or reduce the development of allergic disease in children. a basic knowledge of the infant's developing immune system places the risk factors context. in the atopic child, the bias of the immune system toward an allergic response is at least partially influenced by lymphocytes. attention has been focused on t-helper cell lymphocytes because they direct much of the immunologic response to antigens. stimulated t-helper lymphocytes produce different cytokine profiles that are broadly classified as th1 or th2 (a th3 phenotype has also been described). 17, 18 th1 cytokines primarily influence the immune system to act against bacteria and include interleukin (il)-2 and interferon-g. th2 cytokines direct activity more appropriate toward parasites. the th2 influence toward ige and eosinophils also occurs in allergic inflammation. th2 cytokines include il-4, il-5, and il-13. at birth, t-helper lymphocytes are th2 biased (or allergy biased), and as the immune system develops the t-helper cells change to a th1 bias. the "hygiene hypothesis" suggests that challenges to the immune system early in life facilitate the shift to a th1 bias, which protects against allergy. infections early in life, 19 or increased risk of infections represented by exposure to siblings or by early entry into daycare, 20 have been associated with a decreased risk of later developing allergic disease. some studies of t lymphocytes from infants at high risk for atopy have shown not only bias toward th2, but also a decreased production of both th1 and th2 cytokines. it may be that the greater reduction of stimulated th1 cytokines accounts for most of the imbalance compared with controls. 21 paradoxically, as infancy has become more sanitized in developed countries, atopy has become more prevalent. the reason for the increase in allergy is likely to be more complicated than the "hygiene hypothesis" alone and multiple competing theories from changes in exposures, to nutrition, to air pollution exist. manifestations of allergy in infancy include food allergy and atopic dermatitis, which are both risk factors for the later development of inhalant allergy. food allergy is commonly seen in infants and is frequently the first identifier of the atopic child. 22 ten percent of 1 year olds have an elevated ige to a food, most commonly milk or egg. 23 infants with milk or egg food allergy are at increased risk for developing ar and asthma. 23, 24 atopic dermatitis is another marker of atopy in infancy. atopic dermatitis in infancy frequently presents as pruritic eczema of the cheeks and flexural surfaces of the elbows and knees. infants with atopic dermatitis have a 30% risk of developing asthma and a 35% risk of developing ar. 25, 26 early sensitization to inhalant allergies in infancy occurs, but infrequently. herr and colleagues 27 used a standardized questionnaire in 1850 infants at their 18th-month examination to identify children with ar-like symptoms defined as runny nose, blocked nose, and sneezing apart from a cold. of the 1850 infants, 9.1% were found to have ar-like symptoms. all children were then assessed with a specific inhalant ige screen, total ige, and eosinophilia. there was no difference in eosinophilia or total ige in the "ar-like symptoms" group compared with the "no ar-like symptoms" group. inhalant-specific ige was elevated in 5.5% with ar-like symptoms versus 2.7% (p 5 .04) of those without symptoms. however, the allergic rhinitis and its impact on asthma (aria) guidelines include both specific ige sensitization and symptoms in the definition of ar. 28 only 9 of the 1850 children had both ar-like symptoms and elevated inhalant-specific ige. in comparison, there were 43 of 1850 infants with elevated inhalant-specific ige that were identified in the "no ar-like symptoms group." this suggests that ar is rare at 18 months of age and that screening infants for elevated specific ige would lack specificity in identifying infants with clinical symptoms. of interest, five of the nine infants with both ar-like symptoms and inhalantspecific ige elevation were sensitized to dust mite. 28 although ar is uncommon in infancy, viral rhinitis is prevalent. children less than 6 years old average six to eight "colds" annually with symptoms lasting 10-14 days. 29 rhinovirus accounted for 46% of childhood upper respiratory infections in one study. 30 distinguishing between ar and viral rhinitis is clinically significant because a physician might reasonably treat an infant with ar with antihistamines, but antihistamines have been demonstrated as ineffective compared with placebo in viral rhinitis. 31 lower respiratory inflammation in infants has a similar clinical dilemma in differentiating viral bronchiolitis from asthma. viral bronchiolitis (wheezing and tachypnea) accounts for outpatient visits in 15% of infants and 3% are hospitalized. 32 the common causes include respiratory syncytial virus, rhinovirus, metapneumovirus, and coronaviruses. viral-triggered asthma and bronchiolitis are difficult to distinguish from each other, but viral-triggered asthma tends to occur in children who have multiple wheezing episodes, are older than 2 years, and have a family history of atopy. 33 once children are older than 2 years, an association between viral-induced wheezing and asthma risks (elevation in inhalant-specific ige, maternal asthma history) becomes significant. 34 the clinical distinction between bronchiolitis and asthma affects pharmacologic treatment. although bronchodilators and corticosteroids are mainstays of asthma treatment, neither bronchodilators 35,36 nor corticosteroids 37 have been shown to be effective in uncomplicated viral bronchiolitis (discussed later). attenuating the development of allergy through environmental manipulation has not been very successful. a substantial number of studies have investigated restriction of food antigens or environmental controls to prevent inhalant sensitization, but these have yielded conflicting and often paradoxic results. because food allergy is frequently the first allergic manifestation in the atopic child and the prevalence of food allergy is increasing, multiple studies have investigated if restricting allergenic foods (eg, peanut products) from the infant's diet would reduce the development of allergic disease. dietary avoidance of highly allergenic foods was supported by a 1990 study of 1200 infants that correlated the number of solid foods introduced by age 4 months with eczema at age 10 years. 38 however, dietary antigen avoidance has not proved to be effective in most studies and a 2008 review in pediatrics states, "for infants at high risk of developing atopic disease, there is evidence that exclusive breastfeeding for at least 4 months compared with feeding intact cow milk protein formula decreases the cumulative incidence of atopic dermatitis and cow milk allergy in the first 2 years of life." 39 beyond this, whether exposure to antigenic foods early in life promotes sensitization or tolerance is unclear. the effect of breastfeeding in the development of asthma is controversial and studies conflict. 39 in a large cohort, breastfeeding seemed to reduce wheezing episodes in children less than 4 years, but in infants who had a family history of maternal asthma breastfeeding increased the risk of developing asthma after age 6 years. 39, 40 however, a 2009 isaac ii study of 54,000 children found no association between breastfeeding and allergy. 41 this type of disparity between study results is common in research examining the development of atopic diseases, but perhaps not unexpected given allergy's complicated genetics and multiple environmental influences. preventing the development of inhalant allergies with environmental modifications has also yielded inconsistent results. studies have looked at whether cat exposure in infancy might increase the risk of allergic sensitization to cat. in sweden, most children with allergic asthma are sensitized to cat. unexpectedly, a large study reported that having a cat in the home during infancy was associated with a decreased risk of developing asthma. 42 however, the influence of cat exposure seems to be opposite in high-risk groups. in a high-risk population defined by maternal asthma, having a cat in the home during infancy was associated with an increased risk of asthma. 43 attempts to reduce house dust mite exposure to prevent atopic disease in high-risk infants have yielded mixed results. 44, 45 in the manchester asthma and allergy study wheezing was reduced with early intervention against dust mites. 44 the isle of wight study also found dust mite precautions reduced the development of allergy and asthma. [46] [47] [48] however, three other large studies showed no effect: the piama study in the netherlands, 49 the space study in europe, 45 and the caps study in australia. 50 effective interventions to prevent development of allergic disease seem to vary by geographic location, ethnicity, socioeconomic class, and risk factors. genetic tests may one day identify populations where allergic risk and effective prevention strategies are better matched. although preventing allergy through environmental control has shown mixed results, two controlled studies have shown that treating young children who have atopic dermatitis with antihistamines decreases the risk of developing asthma. bustos and colleagues 51 treated children with atopic dermatitis, age 1 to 36 months, with daily antihistamine in a randomized, placebo-controlled trial. they reported 25% fewer diagnoses of asthma in the antihistamine group. the etac study treated 817 atopic dermatitis infants with either placebo or cetirizine. fifty percent developed asthma in the control group, but 25% less in the cetirizine group when they had sensitization to dust or grass. 52 infants with food allergy or atopic dermatitis are at risk for later developing inhalant allergies, but inhalant allergies are uncommon in infancy. successful prevention of inhalant allergy has remained elusive, but treating atopic dermatitis with antihistamines may have a modest but significant benefit. asking about a family history of allergies, food allergy, and atopic dermatitis is likely helpful when considering if allergies contribute to upper or lower respiratory inflammation encountered in the older child. inhalant allergy sensitivities generally develop after the third birthday. 23 there is rarely a need to test for allergies in children less than 4 years of age. total and specific ige increases rapidly in children from 3 to 6 years and peaks in the teenage years. 23 prevalence and spectrum of inhalant ige sensitization increase with age. allergies in children play a well-defined role in nasal and conjunctival inflammation. however, the role of allergy in adenoid hypertrophy and eustachian tube function is less clear. for this section, allergic disease is separated by the different anatomic sites. allergic rhinitis ar is defined by the aria guidelines of 2008 as a chronic disorder of the upper airways that is induced by ige-mediated inflammation after exposure of the nasal membranes in sensitized patients to a specific allergen. 27 the symptoms include nasal congestion, rhinorrhea, sneezing, nasal itching, and postnasal drainage. ar has been traditionally categorized as seasonal or perennial depending on allergen sensitivity. the more recent aria guidelines of the world health organization include a classification that uses duration of symptoms and impact on quality-of-life parameters. 53 the duration of symptoms is either "intermittent" (symptoms for <4 days per week or for a duration of <4 weeks per year) or "persistent" (symptoms that occur >4 days per week and are present for >4 weeks per year). the effect on quality of life is subdivided into either "mild disease" (no impairment of daily activities, no sleep interruption, and no troublesome symptoms) or "moderate to severe disease" (one or more of the previously mentioned symptoms). other guidelines (and the food and drug administration [fda]) divide ar into seasonal and perennial. 54 ar is estimated to affect 60 million people in the united states, and its prevalence is increasing. 55 the prevalence of ar in children is possibly as high as 40%, 56 making it the most common chronic disease in the pediatric population. however, whether ar is self-described, physician diagnosed, or includes allergy testing affects the reported incidence and prevalence. 27 additionally, there is profound geographic variability. 57 most individuals develop symptoms of ar before 20 years of age, with 40% of patients becoming symptomatic by age 6 years. in adults diagnosed with ar, 40% have perennial ar and 20% have seasonal ar; an additional 40% have perennial ar with seasonal flare-ups. 10 the recently published pediatric allergies in america survey suggests that children are more likely to have seasonal allergies compared with perennial ar. 1 the most common triggers of nasal symptoms in the allergic children were pollen, dust, and animal dander. the single most frequently experienced nasal allergy symptom reported by parents was nasal congestion (52%), which was said to occur either every day (25%) or most days (27%) each week during their children's worst month for allergy symptoms. in addition to parental responses, the children 10 to 17 years of age were asked which nasal allergy symptoms they experienced every day or most days during their worst allergy month in the past year. nasal congestion or stuffedup nose (39%), repeated sneezing (36%), runny nose (35%), and watering eyes (20%) were frequently reported as occurring either every day or on most days of the worst month. 1 although ar is not life-threatening, it can be associated with significant morbidity through loss of productivity, 58 cognitive functioning, 59 missed school, 60 and impaired quality of life. 61 many of these health-related quality-of-life issues seem to stem in part from sleep disturbances associated with ar. 62 in addition to impaired quality of life that ar elicits in patients, it can have a substantial economic impact including both direct costs to patients and indirect costs that include patient absenteeism and inefficient performance at school. 60 walker and colleagues 63 compared national examination test performance in winter (practice) and summer (final) in grass-allergic and nonallergic students. compared with controls, grass-allergic students were found to have a significantly increased risk to unexpectedly fail a test section in the summer (grass pollen season) that they had previously passed in the winter. the diagnosis of ar in children is based on clinical evaluation and allergy testing. allergy testing in the absence of clinical likelihood of allergic disease yields unacceptable false-positive rates illustrated by a positive skin prick test in 53.9% of 10,509 americans randomly sampled in third national health and nutrition survey. 64 the differential diagnosis of ar in children differs from adults. children are more likely to have adenoid hypertrophy, nasal foreign body, or choanal atresia contributing to their nasal obstruction than adults. polyps, deviated septum, and neoplasia are more likely causes of nasal obstruction in adults than children. treatment of ar in children is similar to adults. 27 environmental control, pharmacologic therapy, and desensitization are the three main options for treating ar. although counseling about environmental control of ar is recommended, clinical efficacy in controlled studies is often disappointing. terreehorst and colleagues 65 performed a randomized placebo-control trial of dust mite mattress covers in 279 subjects allergic to dust mite. although they did demonstrate decrease in dust mite counts, no clinical improvement in ar was detected between the groups. a recent cochrane review suggested an extensive bedroom-based program including acaracides may "be of some benefit" in ar symptoms. 66 pharmacotherapy for ar consists of antihistamines, decongestants, intranasal corticosteroids, and leukotriene antagonists. the use of first-generation antihistamines should be limited in children because of drowsiness, impaired learning, 67 and paradoxical hyperactivity. pediatric formulations of second-generation antihistamines are found in table 1 , and although appropriate for allergy they have not shown benefit in viral rhinitis or otitis media. topical antihistamines have indications starting at age 5 years for azelastine and age 6 years for olopatadine but compliance in children can be hampered by taste in the authors' experience. decongestants and over-thecounter cough and cold preparations are not currently recommended in children under 2 years of age because of lack of proved efficacy and an association with rare cardiac fatalities in infants. 68, 69 intranasal corticosteroids are indicated down to age 2 years. concerns of reduced growth and adrenal axis suppression have led to differences in the lowest indicated age listed for different steroid molecules ( table 2) . paired papers published in pediatrics in 2000 measured a 0.9-cm reduction in annual height gained with intranasal beclomethasone 70 and no difference in height with intranasal mometasone. 71 the fda has recommended using the lowest effective dose and monitoring growth in children when prescribing intranasal steroids. nasal steroids seem to reduce adenoid size and can be considered for moderate adenoid hypertrophy. however, it is unclear how long the nasal steroids have to be maintained to sustain the reduced adenoid size. 72 other allergy medications for children include pseudoephedrine, chromolyn, ipatropium, and montelukast ( table 3) . montelukast is indicated for perennial ar in children down to age 6 months and may also have a beneficial effect on lower respiratory inflammation. desensitization by subcutaneous immunotherapy in children has been shown to be effective. 73, 74 risk, time, and expense of subcutaneous immunotherapy needs to be carefully matched to severity and ability to control allergic disease. desensitization is unique in its beneficial effect on allergies after the treatment is discontinued, its affect on reducing additional sensitizations, and reduction in the development of allergic asthma. 73 data on sublingual immunotherapy in children have been less convincing than adults. roder and colleagues 74 published a systematic review of sublingual immunotherapy in children that identified seven high methodologic studies of which only one of seven showed efficacy. however, in 2009 and 2010 three large studies showed statistical results for sublingual immunotherapy for grass ( table 4) . [75] [76] [77] each of these three studies showed similar percentages of symptom although ocular disease is not part of the respiratory system, the overlap between ar and allergic conjunctivitis is so great that it is often considered one disease: rhinoconjunctivitis. bielory 78 summarizes several epidemiologic studies to estimate that there is 80% overlap, with 10% having ar alone and 10% having allergic conjunctivitis alone. the large isaac studies looked at rhinoconjunctivitis as single diagnosis and reported symptoms in 8.5% of 6 to 7 year olds and 14.6% in 13 to 14 year olds. 57, 79 as such, children with ar should be assessed for allergic conjunctivitis and topical antihistamine or cromolyn eye drops considered. the relationship between otitis media and allergy has been the focus of several studies with a discrepancy of findings 80 suggesting either large regional differences or bias in associating otitis and allergic disease. the relationship between allergy and otitis media likely varies with the age of the children studied. in the authors' experience, inhalant allergy plays a smaller role in acute recurrent otitis media during infancy compared with chronic otitis media with effusion in 5-or 6-year-old children, especially when there is no infant history of eustachian tube dysfunction. there is very little evidence that acute recurrent otitis media in infancy is associated with inhalant allergies. in 3549 case-controlled pairs, no increased risk of ar at age 6 81 however, the melbourne atopy cohort study of 448 children identified at high risk by having an atopic first-degree relative found an association with asthma. they showed that of the 59% who had at least one episode of acute otitis media when less than 2 years old there was a small to moderate increased risk for physician-diagnosed asthma at age 6 years (relative risk, 1.3; 95% confidence interval, 1.15-1.81). 82 allergic rhinitis may occur more frequently in children with chronic otitis media with effusion, 80 but common pharmacologic therapy for ar (antihistamines, decongestants, and nasal steroids) has not been shown to be effective. 83 one study found 89% of children aged 3-8 years with "glue ear" also had ar diagnosed by symptoms and either nasal eosinophilia or a positive skin prick test 84 ; however, some of these children may have had nonallergic rhinitis with eosinophil syndrome and there may have been a referral bias. in contrast, another study showed a lower but statistically significant association of 16.3% versus 5.5% between chronic otitis media with effusion and ar defined by nasal symptoms independent of a "cold" and positive skin prick test compared with a control group. interestingly, 16.3% would not be characterized as an elevated rate of ar in some epidemiologic studies of children. 56 this underscores how regional differences, age of subjects, and different definitions of ar make comparing outcomes across studies difficult. the american academy of otolaryngology head and neck surgery's 2004 practice guidelines for chronic otitis media with effusion specifically made no recommendation about allergies as a causal agent or effective treatment of chronic otitis media with effusion because of insufficient evidence. 83 the relationship between adenoid hypertrophy and ar is also unclear and there is little evidence linking adenoid hypertrophy with allergy. nuhoglu and coworkers 85 compared adenoid size in ar and non-ar, finding that non-ar was more significantly associated with adenoid hypertrophy in a retrospective study of 108 children (p 5 .0001). marchisio and colleagues 86 found that the poor correlation between adenoid size and clinical nasal obstruction was worse in allergic children, presumably because of turbinate hypertrophy playing a larger role. however, adenoids from atopic children may be different pathologically and have showed increased ige-positive macrophages and plasma cells compared with controls. 87 if turbinate hypertrophy is more frequently the cause of nasal obstruction in allergic children relative to adenoid hypertrophy, nasal steroid sprays or other management of the child's allergies should be carefully considered in the treatment of their nasal obstruction. although there are many causes of inflammation in the lower airway including infections, asthma is the archetypal disease of chronic lower respiratory inflammation in the allergic child. however, not all asthmatic children have allergies. like many other complex chronic diseases, asthma is a single name for a spectrum of disease. hundreds of genes likely influence the pathogenesis of asthma, many of which are influenced by environmental interactions. 88 asthma varies clinically in onset, severity, triggers, and response to therapy. asthma comprises a range of heterogeneous phenotypes that differ and overlap in presentation. although we may be on the cusp of tailoring the diagnosis and treatment of asthma using genetic markers, in 2011 asthma is approached clinically by selecting treatment based primarily on severity and triggers (eg, exercise-induced asthma or allergic asthma). awareness of asthma is important for otolaryngologists because of the epidemiologic link between chronic upper and lower airway inflammation. 27 asthma is underdiagnosed, impairs quality of life, and even mild persistent asthma is potentially life threatening. 4 the ability to identify asthma, initiate treatment, and ensure appropriate continued care should be the goal of every specialist who cares for children that are known to be at increased risk of this common disease. asthma is influenced by both genetic and environmental factors. family and twin studies have indicated that genetics play an important role in the development of allergy and asthma. twin studies suggest that approximately 60% of asthma susceptibility is caused by genetic factors, with indicators of allergic sensitization, such as serum ige levels, also demonstrating heritability. 89 genome-wide linkage studies and case-control studies have identified 18 genomic regions and more than 100 genes associated with allergy and asthma. 9 recently, the gene ormdl3 has been identified as exhibiting a highly significantly association with asthma, a finding that has been replicated in several populations. 90 although genetic predisposition is clearly evident, environmental factors also play a large role in asthma susceptibility and are likely to underlie the increases that have occurred in recent decades. 91 observations of migrating populations and of germany after unification have strongly supported the role of local environmental factors in determining the degree of expression of asthma within genetically similar populations. 92 during early childhood, certain viruses have been associated with the development of the asthmatic phenotype. in a landmark 2008 study, jackson and colleagues 93 showed that wheezing with rhinovirus at age 3 years was more predictive of asthma at age 6 years (or, 25.6) than aeroallergen sensitization (or, 3.4). respiratory syncytial virus, rhinovirus, influenza, and parainfluenza are among viral pathogens associated with wheezing in the first few years of life. 94 in contrast, exposure of an infant to a substantial number of infections, as suggested by the hygiene hypothesis, is seen as protective against the development of the asthma phenotype. 95 although this theory has been supported by some studies of allergy prevalence, 96 it has been partially refuted by recent studies of asthma prevalence suggesting that although large family size (more than four children) is associated with a decreased risk of asthma, birth order is not involved. 97 wheezing and asthma are not synonymous in children. although some 50% of preschool children have wheezing with viral respiratory infections, only 10% to 15% have a diagnosis of asthma by the time they reach school age. 98 wheezing in early infancy and childhood has been divided into three courses: (1) transient wheezing, (2) persistent wheezing, and (3) late-onset wheezing. 99 transient wheezing in early infancy has been well characterized, with decreased airflow rates on pulmonary function testing at birth, onset of wheezing within the first year, and resolution by mid-childhood with no lasting effects on pulmonary function. 98 transient wheezing is the most prevalent form of early wheezing and accounts for 60% of the children who wheeze in infancy. it has no significant relationship to atopy but maternal smoking during pregnancy has been identified as a variable significantly associated with this phenotype. 100 it is suspected that these children have smaller airways, which seems to be associated with maternal smoking, and as they grow the episodic narrowing of the already small airway by viral-induced inflammation becomes asymptomatic. 98 children with persistent wheezing can be subdivided into nonatopic and atopic. nonatopic persistent wheezing comprises 20% of wheezy children under the age of three years and is associated with the first episode of wheezing occurring less than 1 year of age. 98 it is believed that this phenotype may be caused by an alteration in the regulation of airway tone leading to viral-induced wheeze. 101 the atopic persistent wheezing phenotype is found in 20% of children who wheeze during the first 3 years of life and symptoms typically present after age 1 year. risk factors associated with atopic wheeze include male gender, parental asthma, atopic dermatitis, eosinophilia at 9 months, and a history of wheezing with lower respiratory tract infections. 101 this phenotype is also associated with early sensitization to food or inhalant allergens 102 and reduced lung function at age 6 years (compared with children with no history of wheezing with lower respiratory illnesses). 98 late-onset wheezing (wheezing absent before age 3 years, but present at age 6 years) seems to represent another phenotype. these children are more likely to be male, have mothers with asthma, be sensitized to allergens, and have early rhinitis than children who never wheezed. late-onset wheezing represented 15% of children in one cohort. 98 wheezing may also have less common noninflammatory causes, such as an airway foreign body, subglottic cyst, hemangioma, or vascular ring. the most common cause of asthma symptoms in children less than 5 years old is viral infections. there is no single test or risk factor that predicts who will progress to asthma. instead, a predictive index may be used based on the cohort data that separated transient wheezing from persistent and late-onset wheezing. castro-rodriguez and colleagues 103 created a predictive index for ages 2 to 3 years that conferred a 76% chance of asthma by age 6 and a greater than 95% chance of not having asthma by age 6 if negative. guilbert and colleagues 104 modified these criteria for the peak study for clinical use. the index used in the peak study was recommended by the 2007 national institutes of health (nih) asthma guidelines and is as follows: children between ages 2 and 4 years who have had more than three episodes of wheezing (one physician diagnosed) within 1 year and who have met either one major criteria (parental asthma, physician-diagnosed atopic dermatitis, or inhalant allergen sensitization) or two minor criteria (wheezing unrelated to colds, food sensitization, or eosinophilia >4%). children positive for this index had fewer asthma exacerbations and decreased burden of disease if treated with inhaled corticosteroids compared with placebo, but early inhaled corticosteroids failed to prevent asthma development. 105 because atopic children with rhinitis are well represented in otolaryngology clinics and at increased risk for asthma, asking about recurrent wheezing and considering treatment in children who meet the index's criteria would benefit these patients. a check list is provided in table 5 . other important risks for childhood asthma include sensitization to the smaller inhalant allergens by age 6 to 8 years and maternal history of asthma. smaller inhalant allergen travel preferentially to the lungs by virtue of their size and include cat, alternaria, dust mite, and cockroach. the 2007 nih asthma guidelines divides asthma into age groups of 0 to 4 years, 5 to 11 years, and older than age 12 years. asthma is classified into intermittent and persistent disease. persistent asthma is stratified into mild, moderate, and severe. children can be classified based on frequency of wheezing, night time awakenings, frequency of inhaled b2 agonist use, and exacerbations lasting greater than a day. once classified, simple charts recommend the initial treatment for each age group. 4 asthma is a heterogeneous disease and response to treatment needs to be assessed. in most children, optimally managed asthma should result in no missed school, rare use of rescue inhalers, no emergency room visits, and no hospitalizations. treating asthma also reduces asthma mortality. the number of corticosteroid inhalers used annually is inversely proportionally to the chance of death in those with asthma. 106 the 2007 nih asthma guidelines, including charts for classifying severity, stepwise approach to management, and recommendations for altering therapy based on standardized assessment of the control of asthma control, are available free online. the nih asthma guidelines are written to improve the diagnosis and management of asthma by primary care physicians and can be easily incorporated by otolaryngologists. children with rhinosinusitis and rhinoconjunctivitis are at risk for inhalant allergies. allergies often contribute to upper and lower chronic respiratory inflammation. this population of children is likely well represented among otolaryngology patients. inhalant allergies are uncommon in infancy, but food allergy, atopic dermatitis, and allergic disease in a first-degree relative are 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prevention of early asthma in kids study: design, rationale and methods for the childhood asthma research and education network long-term inhaled corticosteroids in preschool children at high risk for asthma inhaled corticosteroids: impact on asthma morbidity and mortality table 5 asthma risk checklist for pediatric otolaryngology patients with rhinitis or allergies has your child had greater than four episodes of wheezing in the last year?has a physician diagnosed wheezing in your child in the last year?did your child have wheezing in absence of a "cold" in the last year?has the child's father ever been diagnosed with asthma?has the child's mother ever been diagnosed with asthma?has your child ever been diagnosed with atopic dermatitis?does your child have a food allergy or did they have a food allergy?has your child tested positive for allergies?does your child use an inhaler or nebulizer sometimes?did your child wake up with coughing or difficulty breathing in the last month when they did not have a "cold"? does your child wheeze or become abnormally short of breath with exercise? key: cord-309095-ka9abe0c authors: idoiaga, nahia; berasategi, naiara; eiguren, amaia; picaza, maitane title: exploring children’s social and emotional representations of the covid-19 pandemic date: 2020-08-12 journal: front psychol doi: 10.3389/fpsyg.2020.01952 sha: doc_id: 309095 cord_uid: ka9abe0c covid-19, a new emerging infectious disease (eid), has spread throughout the world, including europe. spain, in particular, has witnessed a significant outbreak of the pandemic. all classes have been canceled, and the government has declared a state of emergency, ordering the lockdown and confinement of the entire population. all children in the country have been confined to their homes since march 13 and are not allowed to leave at any time. this population is thus facing the harshest restrictions. given the vulnerable situation of children, the aim of this research is to understand how they represent and emotionally cope with the covid-19 crisis. a free association exercise elicited by the word “coronavirus” was completed by 228 children (age range: 3–12 years) from the north of spain. to analyze the content, we employed the reinert method with iramuteq software for lexical analysis. the results revealed that children represent the covid-19 as an enemy that is being fought by the doctors. children are afraid and worried about catching the virus, but mainly because they think they can infect their grandparents, and this makes them feel guilty. moreover, the lockdown situation has produced conflicting emotions in the children. on the one hand, they are scared, nervous, lonely, sad, bored, and angry, but they also feel safe, calm, and happy with their families. these results indicate the need for governments to also consider children in their management of the current situation by placing greater emphasis on social and inclusive policies to help alleviate the possible effects that they may suffer as a consequence of the pandemic and the lockdown. in short, there is a need to address the psychological, educational, social, health, and well-being needs of children. children represent only a small percentage of covid-19 cases (hamzelou, 2020; pavone et al., 2020) , and the majority of infected children might appear asymptomatic (cai et al., 2020) or present mild clinical manifestations (jiao et al., 2020) . it might therefore be tempting to assume that, in comparison with adults, children are less vulnerable to this pandemic (pavone et al., 2020) . however, from the beginning of the pandemic, health authorities and politicians have repeatedly pointed out that because of this mild symptomatology, children may play a significant role in spreading the infection. consequently, in most countries of the world, schools have been closed (united nations educational, scientific and cultural organization, 2020) with children confined to their homes. nevertheless, each country has imposed its own specific rules for children in the frontiers in psychology | www.frontiersin.org 2 august 2020 | volume 11 | article 1952 lockdown; while in some countries they are allowed to leave their homes to exercise, play sports, or take walks with their parents, in other countries these activities are prohibited (garcia, 2020) . spain is currently one of the european countries most affected by . cases began to multiply exponentially and uncontrollably in early march. in view of this situation, all the schools in the country were closed (sánchez, 2020a) , with the spanish prime minister declaring a state of emergency on 14th march 2020, ordering a mandatory lockdown for all citizens (royal decree 462/2020 . in the same speech, the prime minister stated that the rules of this lockdown were very drastic, possibly the most stringent in europe and even the world (merino, 2020; sánchez, 2020b) . in that speech, there was not a single mention of children, even though the rules of the lockdown are particularly harsh for them. children were forbidden to leave their homes, with spain along with italy, being the only european countries where children were not allowed to go out at all (granda, 2020; grechyna, 2020) . on the 18th of march, however, the government clarified a detail of this law, which permitted single parents (specifically those unable to leave their children in the care of another adult) to leave their homes accompanied by children to purchase groceries and essential items. further, children were not allowed to use the communal spaces within their buildings, such as a shared terrace or garden (royal decree 465/2020 . in spain, this absolute lockdown for the children lasted 6 weeks, and then, from april 26, they were allowed to go outside, but only for 1 h a day. pediatricians, psychologists, and educators have warned of the serious threats that this confinement may pose to children from both a physical and emotional perspective (grechyna, 2020; jiloha, 2020; léon, 2020; the spanish children's rights coalition, 2020) , stressing that it is essential that children understand what is happening in order to mitigate the damage that this situation may cause them (dalton et al., 2020; wang et al., 2020) . however, no research has yet been conducted to explore the ways in which children integrate this coronavirus outbreak into their everyday thinking and how they are coping with the psychosocial impact of the crisis. during the 1980s and 1990s, a considerable body of research focused on children's understanding of illness (myant and williams, 2005) . most of this research was based on piaget's theory of development, essentially demonstrating that children have different perceptions of the disease depending on their age and stage of development (bibace and walsh, 1980; banks, 1990; gillis, 1990; hergenrather and rabinowitz, 1991; carson et al., 1992; simeonsson et al., 1993; kury and rodrique, 1995; moss-morris and paterson, 1995) . however, these cognitive studies, even in their most modern versions (vacik et al., 2001; koopman et al., 2004; myant and williams, 2005; piko and bak, 2006) , have failed to address how children understand specific diseases from a common sense standpoint or the ways in which they deal with illnesses on an emotional level. in contrast, the present study is theoretically framed within the social representations theory (srt; moscovici, 1961 moscovici, , 1984 because this theory provides a framework for embracing the symbolic meaning that is assigned to diseases in everyday thinking (joffe, 2003) . although relatively little work has been conducted with children from the perspective of social representations (galli and nigro, 1987; galli and fasanelli, 1995; cagnin et al., 2004; goodwin et al., 2004) , srt offers an innovative point of view since the function of social representations is to make familiar the things that are unknown or unfamiliar to us (such as the new covid-19 pandemic; galli and nigro, 1987) . thus, a key concern of this theory relates to how knowledge about a new risky phenomenon is transformed from scientific discourse into the common understanding of lay people (joffe, 2003) . consequently, extensive research has been carried out with regard to specific emerging infectious diseases (eids) within this framework (joffe and haarhoff, 2002; joffe and bettega, 2003; joffe and lee, 2004; washer, 2006; idoiaga et al., 2017a,b) . however, this work has always been conducted from the perspective of adults. in recent years, social representation research on several eids (wagner-egger et al., 2011; idoiaga et al., 2017a) , including the covid-19 pandemic (eiguren et al., 2020; idoiaga et al., 2020 a,b 1,2 ) , has revealed that recurring emotional patterns can be observed when it comes to dealing with pandemics. first, eids are usually represented in terms of heroes, victims, and villains (wagner-egger et al., 2011) . the heroes are typically the scientific and medical experts who work to beat the disease, while villains are the media and governments (washer, 2010) . the victims are represented as the infected people, particularly those who are defenseless to face the epidemic (idoiaga et al., 2017b) . however, the representation of risk is not homogeneous throughout society. the srt also states that in these moments of crisis specific shared ideas emerge among different groups, and also, of course, among children (wagner and hayes, 2005; washer, 2006) . social representations are important in these contexts because they are constructed based on the particular experiences that each group is living through during the pandemic and the information they receive both from the media and through social interactions (moscovici and duveen, 2000) . moreover, research in the field of social representations (smith and joffe, 2013) and eids highlights the role played by the emotional context in symbolic thought and its relevance for making a topic recognizable and understandable (höijer, 2010) . in fact, the work carried out so far has revealed that in modern societies there are recurring emotional patterns that emerge in response to the threat of eids, with fear being very prominent, along with anger and emotional fatigue (joffe, 2011; sherlaw and raude, 2013; idoiaga et al., 2017a,b) . in the case of children, it has been warned that the lockdown imposed in response to covid-19 could generate feelings of fear, worry, sadness, or stress (jiao et al., 2020; jiloha, 2020; wang et al., 2020) and that understanding children's reactions and emotions is essential to properly address their emotional needs (jiao et al., 2020; jiloha, 2020) . frontiers in psychology | www.frontiersin.org given these considerations, it is of critical importance to identify how children understand this health crisis in order to develop strategies and tools that, by taking into account their concerns, will ultimately help them to overcome these unprecedented circumstances. thus, the main goal of this article is to study how children understand or represent the covid-19, while observing their emotional response to the coronavirus pandemic in spain. a total of 250 children participated in this study between 30th march and 13th april 2020. the sample was recruited in the basque country region located in northern spain. of the sample, 52.21% were girls and 47.79% were boys. the mean age of the participants was 7.14 years (sd = 2.57) with an age range of 3-12 years. as additional information on participating families and with regard to the economic status of the families, most of them (85.7%) have a medium economic status, the rest 8.9% have a low economic status, and the remaining 5.4% have a high economic status. moreover, most of the parents have a university education 71.2% or a bachelor's degree 23.2%. and, only 2.8% have a secondary education and the 2.8% have a primary education. besides, with regard to children care, most of the parents, 46% said that they shared the childcare tasks, 32.4% said that it is the mother who takes care of the children, 18.0% said that it is the father, and 3.2% said that other people take care of their children. finally, 36.6% of the families had no outside space (such as a balcony, terrace, or garden) in their homes. due to the confinement situation, we decided to access the children through their parents. questionnaires were sent to all schools in the basque country region and the schools were asked to forward these questionnaires to the families. in that email, a document was sent explaining how the study should be carried out and a link to do so. in the explanatory document, it was specified to the parents that this was a free association exercise for their children and that they, the parents, would take the role of interviewers. to carry out the exercise, they had to ask to their children two specific questions: (1) these days we are talking a lot about the coronavirus. when you hear the word coronavirus, what comes to mind, or what do you think? (2) how are you feeling these days because of the coronavirus? the parents were then encouraged to transcribe the exact responses given by their children. the document gave two practical examples of how the exercise should be done and how it should not be done (specifying that no suggestions should be made or that the children's words should not be paraphrased). all children participated on a voluntary basis, received information about the procedure of the investigation, and their parents gave their consent before participating in the study. this research has obtained the approval of the ethics committee of the upv/ehu [m10/2020/055]. the reinert method using iramuteq software for lexical analysis (reinert, 1983 (reinert, , 1990 ) was employed to analyze the corpus of text. this method has frequently been used for the study of social representations (lahlou, 2001; klein and licata, 2003; kalampalikis, 2005) , confirming that the results obtained agree with those of other methods used in this field of research (lahlou, 1996) . iramuteq software eliminates problems of reliability and validity in text analysis (reinert, 1996; klein and licata, 2003) . using this method, which follows a descending hierarchical analysis format, the analyst obtains a series of classes and statistical cues in the form of typical words and typical text segments (see idoiaga et al., 2017a) . specifically, the software identifies the words and text segments with the highest chi-square values, that is, those words and text segments that best identify each class or idea that the participants have repeatedly mentioned. once these "classes" have been identified, they are associated with "passive" variables (independent variables). in the present case, the passive variable was the age range, that is, young children (3-5 years), middle-aged children (6-9 years), or old children (10-12 years). in accord with previous research using the reinert method (camargo and bousfield, 2009) , the raw data were entered into the iramuteq software, and the most significant items of vocabulary in each class were selected on the basis of three criteria: (1) an expected value of the word greater than 3; (2) proof of association of the chi-square, tested against the class [χ 2 ≥ 3.89 (p = 0.05); df = 1]; and (3) the word appears mainly in that class, with a frequency of 50% or more. reinert method operations are statistical, transparent, and reproducible until the final stage of interpretation, where the analyst assigns a label to each specific vocabulary set that the software had identified as a lexical world on the basis of co-occurrences and distribution patterns (schonhardt-bailey, 2013) . finally, as a complementary analysis, iramuteq also conducts a lexical similarity analysis. this analysis presents in a graphical format the structure of a corpus, distinguishing between the shared parts and the specificities of coded variables. this allows the link between the different forms in the text segments to emerge. that is, this analysis allows to identifying the words' co-occurrences, providing information on the words connectivity, and thus helping to identify the structure of a text corpus content. it also allows to identify the shared parts and specificities according to the descriptive variables identified in the analysis (marchand and ratinaud, 2012) . the full corpus contained 12,892 words, of which 1,515 were unique words. specifically, the descending hierarchical analysis divided the corpus into 211 segments and five classes. the results of this analysis can be observed in figure 1 . the analysis identified the main ideas held by children regarding covid-19, elicited through the free association procedure. each issue or idea is represented by a set of typical words and text segments, which is referred to as a class. first, the results revealed two main branches or themes (composed of different classes), which are referred to as main clusters frontiers in psychology | www.frontiersin.org and labeled as "coronavirus" and "lockdown". the first main cluster is composed of classes 3 (our enemy the virus) and 2 (fear of coronavirus). the second main cluster is composed of classes 4 (safe at home), 1 (emotions regarding lockdown), and 5 (when is this going to end?). following the hierarchical clustering dendrogram, within the first main cluster describing the coronavirus, the first class to emerge was class 3, with a weight of 15.6%, which has been labeled as "our enemy the virus". within this class, it can be observed how children describe the covid-19 with words such as bug, bad, or enemy but they also mention words such as doctors, win, brave, balcony, or clap, praising the work of the doctors to tackle the virus and stressing that what they must do is to stay at home, as can be seen in the characteristic text segments: "it's a virus but we don't really know what it is. we have to stay home and beat it because it's bad and it's a bug or something that gets into our tummy. in the street the doctors, who are heroes and brave, are going to beat it and that's why we go out every afternoon to the balcony to clap for them" (x 2 = 157.75, boy, 4 years); "it's a bad bug, but we're going to beat it and the doctors are going to kill it! and get it out of here now!" (x 2 = 153.59, boy, 5 years); and "it travels by plane and has come here and will not leave. that's why we have to beat it and to beat it we have to help the doctors and stay home and that's it, and then everything will be fine" (x 2 = 145.03, girl, 5 years). this class was mainly elicited by young children (2-5 years; p < 0.02). within the same "coronavirus" main cluster, the second class emerges, labeled as "fear of coronavirus" with a weight of 19.7%. this class describes the emotions of fear, concern, sadness, nervousness, or fright created by this health crisis. however, children are more afraid of infecting their grandparents than themselves, even mentioning that they would feel guilty if that happened. the most significant text discourses are: "it's a virus but since it's new we're all a little scared and they talk about it on the radio, on television and everywhere else. it doesn't hurt children but we can infect our grandparents and that scares me and that's why we can't go to their house" (x 2 = 148.60, girl, 6 years); "older people say they are afraid but then they go out and buy bread four times a day! i don't care about those people! i am worried and afraid that something will happen to my grandmother! that's why i don't go to her house because if she gets sick i will feel guilty" (x 2 = 115.88, girl, 12 years); and "the coronavirus is a virus that makes you feel a little afraid but not for yourself, for older people (x 2 = 98.60, boy, 10 years). this class was mainly elicited by middle-aged children (6-9 years; p < 0.01) and old children (10-12 years; p < 0.05). in the second main cluster, classes related to the lockdown situation emerged, including the fourth class (20.5%), which has been labeled as "safe at home. " with words such as safe, protected, calm, home, parents, or mother, children describe how they feel safe and protected at home and are happy with their family, as revealed in the most characteristic segments: "the virus can't figure 1 | the hierarchical clustering dendrogram of the free association exercise, showing the most frequent words and the words with the greatest association χ 2 (1), p < 0.00. frontiers in psychology | www.frontiersin.org get into my house so i am safe here and i don't want to go out. besides, i am happy to play with my family a lot" (x 2 = 84.83, boy, 7 years) and "i am happy and calm because i like to be with my father and mother and we do many things that i like, and at home we are safe" (x 2 = 67.64, girl, 5 years). within the same main cluster, the first class emerges, labeled as "emotions regarding lockdown" (23.8%). in this class, it is emphasized that children have conflicting emotions during these times. on the one hand, they say they are bored, angry, overwhelmed, tired, and even lonely because they have to stay at home without being able to go out. on the other hand, they also say that they are happy and cheerful being with their family, as can be seen in the characteristic text segments: "bored because i have to do a lot of homework, sad, and a little lonely because i don't see my friends or my dog. but also happy because at home we spend more time with my father, mother, and sister and because we clap our hands at the window" (x 2 = 140.07, boy, 10 years); "i am happy and cheerful but sometimes i get angry because i want to go out and see my friends. it's a virus that makes me feel angry because it's a pain in the ass and i can't decide about anything" (x 2 = 94.36, girl, 8 years); and "i feel happy when i play with my family. sometimes i get angry and sometimes i get bored too. if i get angry, i yell and then my mother gets angry" (x 2 = 74.20, girl, 4 years). finally, the fifth class emerges, labeled as "when is it going to end?" (20.5%). children are very explicit about wanting to know when they will be able to return to school and to their normal life. in addition, many of them are also worried about whether they will still be in confinement on significant dates, for example, on their birthdays. the following are some of the most significant text segments of this class: "i have doubts because i don't know when this boring confinement is going to end. i want to go back to school and play with my friends" (x 2 = 144.85, boy, 12 years); and "i want to know when i will go back to school. april 17th is my birthday, i will be 11 and i will have to be at home, and i don't like it. " (x 2 = 84.18, girl, 10 years). this class was mainly elicited by the oldest children (10-12 years; p < 0.001). given the wide range of emotions that emerged in the different classes, and in order to analyze these in more depth, we decided to create a tgen with all the words reflecting emotions and a sub-corpus with these and the associated text segments. this sub-corpus was subjected to a lexical similarity analysis (see figure 2 ). the similarity analysis is interesting to observe the words interconnection as well as the level of relation between them, which rate of co-occurrences between them may be stronger or weaker (chi-squared test). based on this analysis, it can be seen more clearly that the coronavirus evokes feelings of fright -and even terror and fear -in the children. this fear is mainly associated with the possibility of infecting their grandparents, along with feelings of guilt. infants are also concerned about whether the doctors will manage to kill the bad bug (the covid-19). moreover, the children are also nervous, sad, and afraid of having to leave their house and are worried about falling ill outside. therefore, they feel happy, cheerful, calm, and safe at home with their family. however, at the same time, being at home also bores and tires them, particularly when it comes to schoolwork. finally, this lockdown situation also makes them feel angry. the findings of this research offer important clues for identifying how children integrate covid-19 into their everyday thinking. from the voices of the children, the issues that have arisen can be classified into two categories: the coronavirus itself, and the lockdown that has been implemented to control the spread of the virus. first, coronavirus is represented not only as an enemy, but also as something that could be contagious. specially from the youngest children's standpoint, the virus is viewed as something that is very bad and they represent it as a serious bug that is clearly their enemy. in the research carried out so far on covid-19, and in other work on previous eids, other populations (adults and young people) also showed representations of enemies, but interestingly, this enemy or villain was never the disease itself, but the media, the government, or even the citizens who were perceived as behaving in an uncivilized way (idoiaga et al., 2020b 2 ). however, there is agreement regarding the heroeswhich are the doctors and healthcare professionals -and also the victims, who are the people most vulnerable to infection (wagner-egger et al., 2011; idoiaga et al., 2020b 2 ) . moreover, older children (the ones from 6 to 12 years) are quite concerned because they know that covid-19 is highly contagious. in fact, these children expressed their fear, concern, sadness, nervousness, and fright when they were asked about coronavirus. however, they understand the situation well, and most of them are more worried about infecting their grandparents than being infected themselves. however, some of them have expressed that they would feel guilty if someone close to them became infected. this emotion of guilt should be particularly taken into account since in china these feelings have been found to be intrinsically linked to post-traumatic stress (vidal, 2020) . therefore, it is of vital importance to make it clear to children that they will in no way be blamed if someone close to them becomes infected. second, and in relation to the lockdown, we observed the emergence of a sense of security on account of being made to stay at home. they express the idea that for them their house is a safe place and they feel protected at home. however, it should be borne in mind that along with this sense of security, children also express fear of going outside. it is true that at the time at which this research was conducted, children were not allowed to leave their homes under any circumstances. even so, the street should not be represented as something dangerous or scary because this could have undesirable consequences when the children are eventually permitted to go outside, turning those initial exits into the outside world into traumatic events (pakpour and griffiths, 2020) . returning to the confinement situation, the counter-emotions expressed by the children are remarkable. on the one hand, they are bored, angry, overwhelmed, tired, and even lonely because they have to stay at home without being able to go out. previous research conducted in china also found that similar negative emotions arise in children regarding the coronavirus lockdown (jiao et al., 2020; wang et al., 2020) . however, loneliness is a new and striking feeling to emerge in our study. in research with other age groups on covid-19, loneliness was only aroused in the case of older people (aged over 60; eiguren et al., 2020) . loneliness is an exceedingly painful experience that is the sum of an unfulfilled need for intimacy and social relationships that are felt to be insufficient or not entirely satisfactory (berger and poirie, 1995) . therefore, the emergence of this feeling indicates that peer interaction is extremely important to children (howes, 2020) . that is, they need contact with others such as friends and classmates, and the fact that they feel lonely indicates that they are not receiving the opportunity for such interaction, or at least, not to the extent that is required. given the importance of relationships in this growth stage, different strategies must be developed for children to cope with these feelings of loneliness until they have the opportunity to become re-acquainted with friends and classmates. for example, it would be useful to promote socialization strategies from within schools. in other words, in "real life" educational institutions are much more than places, where academic skills are developed; indeed, in terms of socialization in children, the school environment is the space par excellence (wentzel and looney, 2007) . therefore, in this situation, emphasis should also continue to be placed on promoting active relationships, with schools playing a primary role in the development and well-being of children. further, the children also report feeling happy and cheerful being at home with their family, because now they have more options to spend time and play with their parents, brothers, and sisters. this indicates the great work that families are doing to create safe and pleasant spaces, even in adverse situations like this, particularly in nurturing resilience in children exposed to epidemics (jiao et al., 2020) . resilience is an attribute that helps children to manage everything from minor disappointments to major life traumas (goldstein and brooks, 2005) . amid the current covid-19 crisis, research from china suggests that resilience should be nurtured by public health programs implemented by healthcare professionals, schools, and families in order to help children to overcome conditions of distress, and prospectively provide them with emotional and psychological support (pettoello-mantovani et al., 2019; dalton et al., 2020; jiao et al., 2020) frontiers in psychology | www.frontiersin.org further, given the results of our lexical similarity analysis, it is worth noting that we again observed the appearance of the emotions of fear, nervousness, sadness, happiness, calmness, boredom, and anger. some of these emotions, particularly those linked to fear, sadness, worry, or nervousness, have already been identified in other studies (jiloha, 2020) , but new emotions have also emerged here. in particular, emotions of anger and boredom need to be considered as they have been noted as risk factors for mental health during lockdown (brooks et al., 2020) and have already appeared in previous lockdown experiences during the sars epidemic (cava et al., 2005) . in addition, the fact that these emotions are represented in relation to schoolwork should be analyzed more carefully, since it might need to be considered whether this work is an additional source of conflict for families, as certain pedagogues point out (tonucci, 2020) . finally, there appears to be one particular question that repeatedly comes to the minds of the children, especially to the oldest ones, that is, when is this situation going to finish? it is clear that this question cannot be answered by anyone at this time, but this call for answers also makes it obvious that children need to be considered in communications regarding covid-19. in fact, several academics have argued that communication about the epidemic in both family and institutional networks is essential for mitigating its effects and is also one of the best tools for fostering resilience (dalton et al., 2020; jiloha, 2020; weaver and wiener, 2020) . it is worth noting that this research also has some limits that should be mentioned. first of all, the main limitation refers to the way in which data were collected, that is through parents. although this choice was due to lockdown circumstances, the presence of parents may have altered some responses, especially those of younger children. secondly, the sample of this research includes a range of children of very varied ages, from 3 to 12 years. and although the results have pointed to some differences among the responses of children from different ages, their understandings for an epidemic disease and for their own cognitions and feelings probably will vary quite differently. in short, we are experiencing an unprecedented and rapidly changing situation. understanding the emotional patterns linked to the current pandemic from the voice of those that are most vulnerable i.e., children, and identifying how they cognitively represent and emotionally face this new situation could help to lay bare the strategies that could be developed in order to help them deal with the crisis from a psychological, emotional, and social sphere. to begin with, this research has shown that, contrary to popular belief, children are not impervious to covid-19. they are experiencing this health crisis and its consequences first-hand, and they are feeling the considerable effects of these unprecedented circumstances at different levelsnot only emotionally, but also in physical and social terms. special attention must also be paid to the emotions of fear, worry, guilt, loneliness, boredom, and anger, with an emphasis on strengthening resilience and offering psychological support to parents and children, a point that has already been emphasized by a number of scholars during this crisis (coyne et al., 2020) . in this regard, it will be essential for governments and local authorities to develop social and inclusive policies that address the psychological, social, health, and well-being needs of children, which could help to mitigate the possible effects that they could suffer as a consequence of this crisis. the data that support the findings of this study are available on 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a social representations approach el comité de los derechos del niño de nnuu advierte del grave impacto físico, emocional y psicológico del coviden los niños y pide a los estados que tomen medidas [the un committee on the rights of the child warns of the serious physical, emotional and psychological impact of covid on children and calls on states to take action franceso tonucci: "no perdamos un tiempo precioso dando deberes covid-19 educational disruption and response children's understanding of illness: students' assessments todo el mundo en wuhan padece un trauma everyday discourse and common sense: the theory of social representations lay perceptions of collectives at the outbreak of the h1n1 epidemic: heroes, villains and victims mitigate the effects of home confinement on children during the covid-19 outbreak emerging infectious diseases and society applying palliative care principles to communicate with children about covid-19 socialization in school settings" in handbook of socialization: theory and research all authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. key: cord-311393-e82jy629 authors: giménez-dasí, marta; quintanilla, laura; lucas-molina, beatriz; sarmento-henrique, renata title: six weeks of confinement: psychological effects on a sample of children in early childhood and primary education date: 2020-10-08 journal: front psychol doi: 10.3389/fpsyg.2020.590463 sha: doc_id: 311393 cord_uid: e82jy629 spain has been one of the countries most affected by the health crisis derived from covid-19. within this country, the city of madrid has registered the highest number of infections and deaths. this circumstance led to the adoption of strict confinement measures for a period of 6 weeks. the objective of the present study was to investigate the psychological effects that this confinement has had on the psychological well-being of a sample of children from madrid. a total of 167 families with children aged between 3 and 11 years participated in this study. the parents evaluated the children through the system of evaluation of children and adolescents (sena) scale in the month of february and refilled part of the same scale after the children had spent between 4 and 6 weeks confined. the comparison between the two measures showed no change among the 3-year-old children. however, change was observed among the 6–10-year-old. children in primary education obtained lower scores in dimensions related to self-regulation (emotional, attentional, and behavioral) and in willingness to study. the results are discussed in light of the situation experienced between the months of march and may 2020. spain has been one of the countries most affected in the world by the health crisis caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2). within this country, madrid has been the city where more confirmed cases of contagion and more deaths have occurred. this situation makes the city of madrid one of the places in the world most affected by this health crisis and where the restrictions have been the harshest. the entire population of this autonomous community and this city (around 6 million inhabitants, ine, 2019) has suffered strict confinement measures for 2 months, which have also affected children. on the 11th of march, all educational centers in madrid closed, from early childhood education to university levels. on the 14th of march, the state of alarm was declared and people were prohibited from leaving their homes except for essential supply services (real decreto 463/2020 . for children, this confinement lasted until the 25th of april frontiers in psychology | www.frontiersin.org 2 october 2020 | volume 11 | article 590463 (real decreto 492/2020 . after 6 weeks and 3 days at home, children were allowed to go outside for an hour a day. this outing regime was maintained until the 25th of may, date on which meetings with friends and family in private homes up to a maximum of 10 people were authorized (real decreto 537/2020 . thus, the most demanding isolation measures for the children of madrid extended over a period of 6 weeks and the measures with a partial relief of 1 h of outing per day for an additional 4 weeks. in total, the children of madrid have lived confined or with only 1 h a day of outing for a total of 10 weeks. this novel situation in our world, due to the unexpectedness of the measure and its duration, may have had some effect on the psychological well-being of children. previous research shows that social isolation can cause some difficulties such as depression, anxiety, emotional problems, or sleep disorders (holt-lunstad et al., 2015; urbina, 2020) . some studies have found alterations related to an increase in anxiety in between 16 and 30% of the population in the face of health crises already experienced, such as sars, ebola, or swine flu (rubin et al., 2010; shultz et al., 2016; satcher and kenned, 2020) . other very recent studies have shown that the duration of confinement and the associated emotions can generate significant psychological stress, as well as anxiety, delusional thinking, obsessions, or rumination in vulnerable people (brooks et al., 2020; mucci et al., 2020) . similarly, previous research on the effects of social isolation in children shows important effects on aspects, such as feelings of sadness, anger, frustration, and apathy (biordi and nicholson, 2013; brooks et al., 2020) . other indicative aspects of wellbeing and regulation during childhood have also been found to be altered, such as sleep patterns, potty training, or challenging behaviors (simon and walker, 2018) . changes have also been observed in the levels of anxiety (increased fear, worry, obsession, or rumination) and depression (depressed mood, lack of interest and motivation, or sadness; teo et al., 2013; urbina, 2020) . a study evaluating the psychological effects of pandemics in children and adults found that the risk of posttraumatic stress was four times higher for children who had suffered confinement measures compared to those who had not (sprang and silman, 2013) . there are very few published studies on the effects of confinement derived from the sars-cov-2. jiao et al. (2020) report a study with families of 320 chinese children aged between 3 and 18 years. the families evaluated the frequency of clinical symptoms through an online questionnaire. the results showed that the most frequent symptoms in the entire sample were inattention, irritability, and clinging. more specifically, the older children (6-18) showed greater inattention and persistent inquiry, while the younger ones (3-6) showed more clinging and fear that family members could contract the illness. in europe, a study prior to ours among italian children showed a significant impact on the psychological wellbeing of children (pisano et al., 2020) . italy and spain have been two comparable cases in confinement measures, number of infections, and deaths. pisano et al. (2020) designed a questionnaire for parents to assess the perceived changes in children aged between 4 and 10 years during the 1st month of confinement. the sample consisted of 5989 participants. between 20 and 30% of parents said that their children showed more symptoms, such as irritability, excessive demands, sleep problems, mood changes, or fear. around 43% indicated that their children seemed more apathetic when performing their usual activities. some positive effects were also found. in fact, 92% stated that their children had been able to adapt to the restrictions imposed by the pandemic, 49% indicated that their children seemed more reflective, and 31% indicated that they were calmer. in spain, we also found a study, prior to ours, in which a group of sociologists designed a questionnaire for children to answer online (martínez muñoz et al., 2020) . this questionnaire was available between the 21st of march and the 7th of april for boys and girls aged between 8 and 17 years. it is important to note that the questionnaire was completed during the most difficult days of the crisis, when the number of daily deaths was close to a 1,000 people. a total of 425 boys and girls answered the questionnaire, the majority aged between 10 and 14 years. the sample was made up of children residing in different communities in spain. most of the sample expressed a high level of satisfaction and well-being in their daily lives. this result suggests that the sample was made up of children belonging to normalized environments and without problems of social exclusion, poverty, etc. the results of this work are interesting and show, according to previous studies, some of the psychological effects that confinement and the health crisis had at that time on the children. thus, the most frequent feeling that the participants said they experienced every day or quite a lot was boredom (61% of the sample), followed by worry (36%), sadness (28%), and fear (16%). the main concern of the children was that a member of their family would fall ill or die (83%). a very relevant fact has to do with the relationship between subjective well-being and academic performance. there was a negative relationship between perceived well-being and the feeling of being overwhelmed by academic tasks. in this sense, 26% of children said they felt overwhelmed by the amount of academic work sent by their teachers and 60% said they felt tired from working so much. these two results show that, on the whole, 85% of children perceived the work demanded by their teachers as exaggerated or inadequate and this perception affected their sense of well-being. finally, children expressed joy during these weeks for being able to spend more time with the family (45%), having more time to play (23%), having free time (8%), and not having to get up early and not go to school (4%). these results clearly show that spanish children overwhelmingly demand more time for their family life, for themselves, and for resting. these previous results lead us to think that spanish children were able to experience negative changes and, perhaps, also positive changes derived from the absence of school, the greater availability of time, and family life. however, one of the main problems of the studies that began to evaluate once the crisis had started is the absence of a previous measure with which to compare the changes experienced. frontiers in psychology | www.frontiersin.org 3 october 2020 | volume 11 | article 590463 the objective of the present study is to evaluate the changes that the confinement situation experienced between the 11th of march and the 25th of april could have caused on a sample of children residing in the community of madrid. our study is the result of a particular circumstance that has allowed us to compare the changes between a previous measure of adaptation and psychological well-being, collected during the month of february, and a subsequent measure taken during the most restrictive period of confinement. in this sense, we believe that we can provide a reliable assessment of the effects that the health crisis and confinement has had on children in madrid after 6 weeks of restrictive measures. a total of 167 families with children aged between 3.2 and 11.1 years (42% girls, mean age of 7 years and 2 months, sd = 2.64, and range = 3.2-11.1) participated in the study. the sample was divided into two age groups: preschool families (m = 3.9, sd = 0.6, range = 3.2-6.2) and primary families (m = 8.6; sd = 1.7, range = 6-11.1). from this sample, 113 families completed a questionnaire before and during confinement (75 from primary education). the rest of the participants (54) only completed the questionnaire during confinement (42 from primary education). the convenience sample was obtained thanks to the fact that the schools were participating in a research project related to the promotion of emotional skills when the pandemic struck. children went to two public schools of the northern area of madrid (spain) and resided in middle and upper middle class neighborhoods. the questionnaire used was the system of evaluation of children and adolescents (sena, fernández-pinto et al., 2015) , validated and scaled for the spanish population. this instrument offers a comprehensive assessment of emotional and behavioral problems for ages between 3 and 18 years. as it is a very broad questionnaire, with more than 100 items, answering it fully during the confinement involved a too demanding task for parents with school-age children. for this reason, those dimensions of the questionnaire that evaluated aspects related to psychological adjustment were selected. the selected scales were attentional problems, depression, challenging behaviors, emotional regulation, hyperactivity, and willingness to study (the latter only for the primary education version). the score for each item ranged from 1 (never or almost never) to 5 (always or almost always). for all dimensions, except for willingness to study, the lowest scores indicate absence of problems and scores above 3 indicate the presence of some type of difficulty. for the willingness to study scale, a score lower than 3 indicates a problem. to the selected scales of the questionnaire, we added an open-ended question, so that the families could comment on any aspect that had not been included in the questionnaire. the instruction was "comment here on anything you have observed, any change you have noticed in your child since the confinement began that seems significant to you and has not been included in the previous questions (for example, eats too much, has nightmares, complains of headaches, is very afraid, etc.). " as a consequence of the confinement caused by covid-19 and the closure of the educational centers in madrid decreed on the 11th of march 2020, the research project in which we had been working with the two educational centers in the northwestern area of madrid had to be discontinued. however, according to the schedule of our research project, before the closing of the educational centers we had carried out assessments on different aspects of the participating children. the families had completed the assessment tests related to the children during the month of february. based on these previous assessments, a month and a half later and after having spent between 4 and 6 weeks of confinement, we again asked the families to fill out a part of the questionnaire. all the questionnaires were answered by the parents between the 8th and the 25th of april 2020, granting their consent to participate in the study. both the pretest and posttest questionnaires were answered online. this research was approved by the deonthological committee of the faculty of psychology of the complutense university of madrid. the principals and the families of the participating schools were informed of the purpose of the study by the research team. parents signed the appropriate consent forms. both the university and the schools followed the protocols for applying the ethical procedures that regulate research in spain. as we mentioned before, the families had answered the questionnaire during the month of february, a few weeks before confinement. this situation could sensitize parents when answering the questionnaire in the second round. on the other hand, some families did not answer the pretest (t1) but did answer the questionnaire during confinement (posttest/t2). to control the possible sensitivity to the test of the participants with pretest, the scores of both groups were compared -with and without prior assessment in the t2 measure. to do so, we used a manova in which the main factor was whether or not the assessment was carried out before confinement. with this analysis, we wanted to rule out that the t1 measure had interfered with the t2 measure in that group. to assess whether there were differences in the psychological adjustment between before and during confinement, we carried out a repeated-measures (rm) anova in which the psychological adjustment was contrasted in the two measures, observing the possible differences in age and sex. given that the sena questionnaire has different items for children in early childhood education (3-6 years) and primary education (6-12 years), we carried out the statistical analysis for each group separately. we used spss 24 for these analyses. the open-ended question was coded into broad categories of change, that is, if the change reported by the family indicated a worsening of the child's condition, an improvement, or an absence of change. likewise, the symptoms described by the families were grouped into several categories. subsequently, the percentage of responses was calculated for both the early childhood and primary education groups. the objective of this open-ended question was to obtain a more accurate description of the families' perception of their children's changes during confinement. the preliminary analysis carried out to verify whether previously applying the questionnaire had sensitized the participants indicated that the difference between the groups with and without prior assessment was not significant, either for the primary education ]. this result allowed us to consider with greater guarantee that the possible differences between the pretest and the posttest assessment were not biased. comparison between the pretest and posttest scores for the early childhood education group indicated very little variation in the mean scores of the five dimensions (see table 1 on the contrary, for the primary education group of children, some differences were observed between the mean scores obtained before and during confinement (see table 1 ). in general terms, the scores suggest that there was normality regarding the dimensions evaluated. in the pretest evaluation, the scores were mostly rather low, while some mean scores increased during confinement and willingness to study decreased. the statistical analysis indicated that there were no significant differences due to gender [f(6, 55) = 1.49, p = 0.23, h p ] scales did not vary. the qualitative analysis of the responses was carried out on the voluntary comments of the parents. it should be noted that only 62% of the participants answered this open-ended question. the comments were classified into three categories: those that indicated an improvement in the child's general condition, those that indicated a worsening, and those that did not show any significant change. figure 1 shows the percentage of responses for each category in each age group. families reported a higher percentage of children whose psychological state worsened, both in early childhood (55%) and in primary education (64%). however, this result was higher in primary education, where only 36% of families indicated that children did not change (17%) or had improved (19%) . when comparing early childhood and primary education, it is observed that in early childhood, the percentage of children who did not experience changes was higher (28%) and the percentage of children who improved their psychological state (19%) was similar. taken together, these results are consistent with those obtained through the questionnaire, showing, on the one hand, that although children were affected by the situation of confinement, those in primary education suffered this situation more than those in early childhood education, and on the other, that a significant percentage of children in both cycles improved their psychological state. in addition to these percentages, the behavior or type of symptomatology described by families in the open-ended question was also classified. table 2 lists the percentages of the types of behaviors that parents perceived in their children. in the early childhood group, families reported overall greater difficulties in emotional regulation (he/she is more irritable, has more mood swings, etc.), in sleeping and eating patterns (he/she does not want to sleep alone, has trouble falling asleep, has nightmares, eats more, etc.) and in potty training (he/she wets the bed again at night, has had a potty accident during the day, etc.). in the primary education group, families also mentioned these three types of behaviors or symptoms, but they also mentioned attentional difficulties and, above all, school difficulties. finally, some families indicated positive changes, referring to improvements in mood (he/she is happy, is calmer, etc.) and to the positive effect of the greater availability of free time (he/she has more time to play, has more time for him/herself, etc.) and family time (he/she is delighted to be with us, enjoys playing with his/her sibling very much, has strengthened the bond with his/her siblings, etc.). the objective of the present study was to verify whether the situation of 6 weeks of strict confinement experienced in madrid as a consequence of the sars-cov-2 health crisis had caused a change in the psychological well-being of children. the results show significant changes in most of the indicators evaluated in the older children of the sample (6-11 year-old). these changes, however, were not observed in the younger children of the sample (3-year-old). more specifically, children aged between 6 and 11 scored higher in emotional regulation difficulties, attentional difficulties, hyperactivity, and impulsivity. willingness to study was the scale on which the worst result was obtained. in this dimension, the greatest difference was observed between the pretest and posttest scores. on the contrary, no changes were found in the depression or challenging behaviors scales. in general, the results obtained are congruent with those found in previous studies on the effects of social isolation on children and also with the few studies that have been carried out on the particular situation of confinement during sars-cov-2 health crisis (jiao et al., 2020; pisano et al., 2020) . despite this coincidence, it is necessary to highlight that the two previous studies mentioned found a significant increase in symptoms in children aged from 3 to 4 years, respectively; in our case, this difference was delayed until the age of 6 years. it is possible that the sample size may have influenced these differences. one of the most striking results of the present study is the greater difficulties that primary school children seem to experience when carrying out school tasks. this result coincides with the school difficulties expressed by the children in study of martínez muñoz et al. (2020) . despite the fact that the mean age of the sample in this study was 12 years, it should be highlighted that 85% of children expressed difficulties in adequately performing school tasks as well as excessive demand on behalf of teachers. our results also show that the dimension in which primary children obtained worst results was related to academic performance. in this sense, it is necessary to take into account the difficulties that online teaching may pose for primary children. as rogero-garcía (2020) points out, distance learning can become a fiction in which no one can fulfill their role, but in which frustration and stress of teachers, students, and families will grow. the difference observed in the present study between early childhood and primary education children shows that, in some way, young children are more protected from reality than older children. this protection comes, on the one hand, from the family and, on the other, from the cognitive system of young children. in this sense, the care that young children receive from their families should facilitate the continuity of their lives, turning confinement into a time similar to that of holiday time spent at home or periods of illness that are so frequent in young children. furthermore, the toddler's cognitive system operates largely within the framework of fiction (harris, 2000) . fiction is a fundamental element for development and learning that in this age group has a very relevant role. it is possible that the time and cognitive effort that children dedicate to fiction constitutes a protective element of psychological well-being in this circumstance. it is also possible that these two protective factors have been less present in the lives of children aged 6, 8, and 10 years during confinement and that part of their psychological deterioration may be due to the progressive decrease in pretend play that is experienced from the age of 7, the more conscious perception of reality, and the lesser need for constant attention from the adults. despite the fact that early childhood children did not show a significant worsening, when the families described the observed changes, they mentioned similar symptomatology to that manifested by primary education children. these changes have to do mainly with regulatory skills and are manifested in behaviors related to executive functions (i.e., emotional regulation, attentional control, hyperactivity, and impulsivity). likewise, despite the fact that families pointed out regulation problems, around 40% of families observed that children were not affected or had even improved during the situation of confinement. this improvement situation, in which around 20% of the children are, together with the comments of the families that noted that children were happy to be able to have more time and enjoy family life constitutes a call of attention on the impact that school days and daily activities can have on the well-being of children. although the children who were not affected by or even appreciated the situation of confinement were not a majority, they constitute a significant percentage and it would be desirable to make the appropriate adjustments to optimize their development. finally, keeping in mind the reality we will probably have to face this following academic year, with the difficulties that online teaching can pose for children of these ages, the decrease in the willingness to study that has been observed in these 6 weeks of confinement, and the stress that the academic burden can pose for children, it would be necessary for the responsible authorities in education to design an academic course focused on the essential contents, adapting the demands to the real working and learning abilities of the children, in which the workload is reduced, the stress is decreased, and the psychological well-being is promoted. the impact that this health crisis may have on the psychological well-being of future generations is still unknown, but the first studies carried out in spain coincidentally indicate an increase in academic difficulties. the design of the next course can be a very relevant variable. education managers, school directors, and teachers have an important role to play in the coming months (jansen et al., 2020) . this study has some limitations that need to be considered. firstly, the sample size is small and it is a convenience sample. in the future, it will be necessary to design studies with representative populations and larger samples in order to generalize the results. likewise, it would be necessary to carry out studies with vulnerable populations. secondly, the instrument applied is relatively small. it would have been desirable to be able to obtain broader assessments that consider other dimensions. thirdly, it would also be necessary to carry out medium-and long-term follow-up studies to understand the scope and maintenance of the changes observed in these 1st week of confinement. moreover, the long-term impact on mental health together with the need to monitor children and adolescents' well-being are important issues to consider for future research (lee, 2020) . the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by comisión deontológica, facultad de psicología, ucm. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. mg-d designed the study. mg-d and lq have collected the data. lq has analyzed data. mg-d and lq have written the first draft. bl-m and rs-h have reviewed and completed the manuscript. mg-d did the submission. all authors contributed to the article and approved the submitted version. this work has been funded by the spanish ministry of science and innovation (rti2018-098631-b-i00). social isolation the psychological impact of quarantine and how to reduce it: rapid review of the evidence the work of the imagination loneliness and social isolation as risk factors for mortality: a meta-analytic review anuario estadístico de españa. madrid: instituto nacional de estadística child and adolescent health needs attention now, and in the aftermath of the covid-19 pandemic behavioral and emotional disorders in children during the covid-19 epidemic mental health effects of school closures during covid19 infancia confinada. ¿cómo viven la situación de confinamiento niñas, niños y adolescentes? madrid: infancia confinada y enclave de evaluación. frontiers in psychology | www.frontiersin.org 7 lockdown and isolation: psychological aspects of covid-19 pandemic in the general population a qualitative report on exploratory data on the possible emotional/behavioral correlates of covid-19 lockdown in 4-10 years children in italy de 14 de marzo, por el que se declara el estado de alarma para la gestión de la situación de crisis sanitaria ocasionada por el covid-19 de 24 de abril, por el que se prorroga el estado de alarma declarado por el real decreto 463/2020, de 14 de marzo, por el que se declara el estado de alarma para la gestión de la situación de crisis sanitaria ocasionada por el covid-19 de 22 de mayo, por el que se prorroga el estado de alarma declarado por el real decreto 463/2020, de 14 de marzo, por el que se declara el estado de alarma para la gestión de la situación de crisis sanitaria ocasionada por el covid-19 la ficción de educar a distancia the impact of communications abouts wine flu (influenza a h1n1v) on public responses to the outbreak: results from 36 national telephone surveys in the uk failure to address coronavirus mental health issues will prolong impact the role of fear-related behaviors in the 2013-2016 west africa ebola virus disease outbreak sleep loss causes social withdrawal and loneliness posttraumatic stress disorder in parents and youth after health-related disasters the role of social isolation in social anxiety disorder: a systematic review and meta-analysis young children's mental health: impact of social isolation during the covid-19 lockdown and effective strategies we are grateful to the principals, the teachers, the children, and the families that have participated. key: cord-282868-yd7pzcbz authors: shelmerdine, susan c.; lovrenski, jovan; caro-domínguez, pablo; toso, seema title: coronavirus disease 2019 (covid-19) in children: a systematic review of imaging findings date: 2020-06-18 journal: pediatr radiol doi: 10.1007/s00247-020-04726-w sha: doc_id: 282868 cord_uid: yd7pzcbz background: covid-19 is a novel coronavirus infection that can cause a severe respiratory illness and has been declared a pandemic by the world health organization (who). because children appear to be less severely affected than adults, their imaging appearances have not been extensively reported. objective: to systematically review available literature regarding imaging findings in paediatric cases of covid-19. materials and methods: we searched four databases (medline, embase, cochrane, google scholar) for articles describing imaging findings in children with covid-19. we included all modalities, age <18 years, and foreign language articles, using descriptive statistics to identify patterns and locations of imaging findings, and their association with outcomes. results: twenty-two articles were included, reporting chest imaging findings in 431 children, of whom 421 (97.7%) underwent ct. criteria for imaging were lacking. at diagnosis, 143/421 (34.0%) had a normal ct. abnormalities were more common in the lower lobes and were predominantly unilateral. the most common imaging pattern was ground-glass opacification (159/255, 62.4%). none of the studies described lymphadenopathy, while pleural effusions were rare (three cases). improvement at follow-up ct imaging (3–15 days later) was seen in 29/100 (29%), remained normal in 25/100 (25%) and progressed in 9/100 (9%). conclusion: ct chest findings in children with covid-19 are frequently normal or mild. lower lobes are predominantly affected by patchy ground-glass opacification. appearances at follow-up remain normal or improve in the majority of children. chest ct imaging adds little to the further management of the patient and should be reserved for severe cases or for identifying alternative diagnoses. electronic supplementary material: the online version of this article (10.1007/s00247-020-04726-w) contains supplementary material, which is available to authorized users. a novel strain of coronavirus (referred to as 2019-ncov or sars-cov-2), which causes the sometimes severe respiratory infection covid-19, was first identified in wuhan city, china, toward the end of 2019 [1] . by 12 march 2020, covid-19 was declared a global pandemic by the world health organization (who), and at the time of writing it had spread to 187 countries, with almost 3.5 million confirmed cases, and had claimed more than 244,000 lives [2] . epidemiological studies originating from china have shown that children are less likely to be clinically affected than older adults, with one study finding only 0.9% of those affected being younger than 15 years old [3] . a different chinese study, which included 731 confirmed paediatric cases, found that the majority (84.1%) sustained either mild or moderate symptoms, with <3% described as being severely or critically affected [4] . only one study reported a death in a child, a 10-month-old with multiorgan failure and intussusception [5] . in the united states, data published on 2 april 2020 [6] showed that only 1.7% (n=2,572) of people affected by covid-19 were younger than 18 years, with 0.58-2% of children requiring intensive care admission. given the low number of paediatric cases, keeping abreast of the latest information and assimilating the combined knowledge of radiographic findings in infected children is challenging. whilst several systematic reviews of imaging findings in covid-19 cases have been performed for adults [7, 8] , none has specifically focused on children. the overall objective of this study was therefore to assimilate the available information on imaging features of covid-19 disease in children. particular points of interest include identifying typical imaging findings during diagnosis and follow-up stages of the infection, and whether any features might be used as prognostic markers to determine patient outcome. where knowledge gaps exist, we intend to highlight these and suggest potential future avenues for research. ethics approval was not required for this retrospective review of published data. we followed preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines for transparent reporting of systematic reviews. this study was registered in prospero, an international prospective register of systematic reviews (registration id: crd42020175945 [9] ). a systematic literature search was performed of medline (ovid), embase and the cochrane library databases for the latest articles published between 1 january 2015 and 17 march 2020 (5-year range), using database-specific boolean search strategies with key terms and word variations relating to all three categories: (1) "coronavirus", "covid-19", "sars-cov-2" or "2019-ncov"; (2) "paediatrics", "children", "neonate", "infant" or "adolescent"; (3) "radiology", "imaging", "ultrasound", "ct", "mri" or "radiography." full search terms are shown in the supplementary material (tables s1, s2 and s3). to include as many recent articles as possible, we also performed a grey literature search (i.e. literature not formally published in sources such as books or journal articles [10] , such as government white paper articles and guidelines) using the same keywords on google scholar and for any who global library publications. additional articles were retrieved by manual screening of the reference lists of included studies and relevant review articles/editorial pieces. the initial search was conducted on 17 march 2020. a repeat search was conducted on 23 march 2020, and again on 30 april 2020 for any further eligible manuscripts. inclusion criteria encompassed all studies investigating and describing imaging findings of confirmed covid-19 infection in children, using reverse transcriptase polymerase chain reaction (rt-pcr) testing. studies were limited to human subjects, including foetuses (any gestation) and children (ages 0-18 years). no restrictions were placed on type of imaging modality, number of cases described or type of clinical setting. to widen our search and include as many cases as possible, we included case reports. no language restrictions were used given that many early articles on imaging findings have been published in chinese. where this was the case, we sought online translation services and advice from native-speaking colleagues to interpret reported findings. exclusion criteria included studies reported as editorials, opinion articles or multimedia files (online videos, podcasts). suspected but unconfirmed cases of covid-19 were not included. studies relating to other coronavirus-related illnesses, such as middle east respiratory syndrome (mers) or severe acute respiratory syndrome (sars) were excluded. we also excluded any articles reporting on a mixed adult and paediatric cohort where imaging results for the paediatric cohort could not be extracted. all articles were independently searched by two reviewers (s.c.s. and s.t. with 7 years and 10 years of paediatric radiology experience, respectively). they examined abstracts of suitable studies and obtained full papers according to the eligibility criteria. disagreements were resolved by consensus. the same two reviewers (s.c.s., s.t.) independently extracted data from the full articles into a database (excel; microsoft, redmond, wa), which included the following factors: study design, study setting/country, population demographics (e.g., gender, age, underlying comorbidities), sample size, patient outcomes (number of mortalities), imaging modality and imaging findings (pattern and location of involvement of disease) and results of any follow-up imaging. missing data were recorded as "not recorded" or "not stated". authors of published studies were not contacted because of the tight time constraints involved in the completion of the systematic review during the unprecedented time of need for this information. the quality for each included study was assessed using the national institutes of health quality assessment tool for case series studies [11] by two reviewers (s.t. and j.l, with 17 years of paediatric radiology experience). disagreements were resolved by consensus review. any that could not be resolved by consensus was arbitrated by a third reviewer (s.c.s.). we planned a meta-analysis to assess association of imaging findings with patient outcomes and demographic data; however, we omitted this because of a lack of sufficient data, with many cases being incompletely reported. therefore, we used descriptive statistics to determine frequency and percentages of imaging appearances across different articles. during the initial literature search, after removing duplicates, we identified 146 unique records. after screening titles and abstracts, we excluded 100 studies and checked 46 full-text articles. reasons for exclusions included insufficient description regarding imaging results (n=8), opinion pieces (n=7), adult population only (n=5), no confirmed (only suspected) covid-19 cases (n=3), retracted article (n=2) and no full text available (n=1). after the second and third searches of the databases, we found eight more records that met our inclusion criteria and reviewed them. although it was not explicitly stated in the articles, we found that a small case series of 8 children [12] and a larger one of 115 children [13] appeared to describe a subset of a larger case series already published of 171 children with covid-19 [5] (included in our review). all three articles originated from wuhan city, china. we therefore excluded the two smaller studies from further qualitative or quantitative analysis. we have provided the reference and summary results from the smaller articles in our supplementary appendix (tables s4 and s5 ; [5, ) to alert readers to this overlap and show why we reached this conclusion. most articles were given an overall scoring of "fair" (17/26, 65.4%), with 5/26 (19.2%) described as "good". four of 26 (15.4%) articles were scored as "poor"; these were excluded from further analysis, mainly for poor descriptions of radiographic findings in non-representative cohorts [35] [36] [37] [38] . methodological quality assessment of the studies is presented in table 1 [5, 13-22, 24-34, 36-38] . we therefore analysed 22 studies overall in this systematic review (19 case series, 3 case reports), including 431 children with imaging (241 male, or 55.9%) [5, 12, 14, 15, [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] 39] . two (2/22, 9.1%) articles were in chinese [18, 34] , the remainder in english. all articles were published in 2020, over a 4-month period from january to april. the demographics of the children and their presenting complaints are summarised in table 2 [5, and expanded upon in the supplementary material (table s4 ). all children were confirmed covid-19 cases on rt-pcr testing. the studies mainly originated from china (20/22, 91.0%), with 1/22 (4.5%) from south korea [25] and 1/22 (4.5%) from iran [29] . of the chinese studies, 4/22 (18.2%) described cases from wuhan city [5, 23, 27, 28] . the youngest child in our cohort was 36 h old; the oldest was 17 years old. ninety-eight (98/431, 22.7%) children were asymptomatic upon admission to hospital, being assessed for having recent travel to a covid-19 endemic area or close contact with an infected individual. of those with symptoms, fever (120/333, 36.0%) and coughing (139/333, 41.7%) were the more common presenting complaints. the majority of the imaging modalities described in the studies were chest ct (21/22, 95.5%), of which only 1/21 (4.8%) utilised intravenous contrast agent for imaging [25] . in one study (1/22, 4 .5%) only chest radiography findings were described [14] . in 5/22 (22.7%) studies, a combination of both chest radiography and ct imaging findings were described [25-27, 29, 32] . none of the studies described mri, nuclear medicine or chest ultrasound findings (see supplementary material for full details, table s5 [5, ). in only 5/22 (22.7%) studies were the ct vendor and scanner model described [18, 22, 23, 28, 34] . of these, four articles provided detailed imaging acquisition parameters [18, 22, 28, o v e r a l lr a t i n g cai j et al. [14] 1 one study did not report on the ct scanner model but did report upon the imaging parameters [17] . details on imaging protocols and parameters are provided in the supplementary material, table s6 [5, [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] . in only 10/22 (45.5%) articles was a radiologist identified as a co-author. detailed indications for performing ct imaging were lacking in all studies. where ct imaging was used, 143/421 (34.0%) cases did not have any radiographic findings despite being covid-19 positive. in the one study where only chest radiography was used, 6/10 (60%) of the imaged cases were normal [14] . in a case report from south korea, the admission chest radiography was normal, although the ct demonstrated patchy nodular consolidation with ground-glass opacification [25] . throughout all studies, there was significant heterogeneity in terminologies used with reference to radiographic findings, many of which included well-known terms (e.g., ground-glass opacifications) as well as non-standard descriptive terminologies (e.g., "thickened lung texture" [27] ). in addition, missing information regarding imaging findings made summarising these difficult. despite this, available findings are summated tables 3 and 4 [5, . it should be acknowledged that the percentage of cases for the various descriptors is less important than their relative frequencies to one another, given the missing information. from the reports where location of pathology was stated, this was identified in the upper lobe in 31/90 (34.4%), middle lobe in 15/90 (16.7%) and the lower lobe of the lung in 40/90 (44.4%) children. diffuse/multifocal disease was described in 4 patients (4.4%). pathology was unilateral in 78/146 (53.4%) and bilateral in 68/146 (46.6%) children. subpleural disease (i.e. peripheral in location) was specifically described in 13 cases across three studies [19, 25, 26] . where a specific pattern was described, the most characteristic pattern on ct was ground-glass opacity, reported in 159/255 (62.3%) children. patchy consolidations were seen in 14/255 (5.5%) patients. a so-called halo sign (of ground-glass opacification) around areas of consolidation was reported in 24/255 (9.4%) children across four studies [18, 28, 29, 34] . nonspecific terminologies of "lung infiltrates/shadows" were reported in 111/255 (43.5%) and interstitial lesions in 5/255 (1.9%) children. not all articles had case-specific individual descriptions of chest radiography and ct findings, which were frequently described together. several findings were either not reported or only rarely reported. for example, none of the articles described significant mediastinal lymphadenopathy or cavitation on imaging, although only one study performed a contrast-enhanced ct. in only 3/255 (1.2%) children there were pleural effusions. of these, one was a neonate also infected with respiratory o v e r a l lr a t i n g (9) were the results well-described? [22] . the underlying conditions of the other cases were not reported [23] . in 11/22 (50%) studies, repeat ct imaging results were described, representing a total of 100 children. the ct was performed 3-15 days after admission, with a quarter of imaging studies remaining normal (25/100, 25%) or showing some improvement from previously detected abnormalities (29/100, 29%). in a minority of cases the abnormalities had progressed (9/100, 9%) or new findings developed (4/100, 4%). findings were stable in 18/100 (18%) cases, and a complete resolution of previous abnormalities was seen in 15/100 (15%) ( table 5) [ 16-19, 21-23, 27, 28, 31, 34] . for one study where only chest radiography follow-up was performed, findings remained normal [25] . 1 consolidation only; 1 ggo only) 1 (11.1%) pleural effusion 3 (33.3%) halo sign distribution 4 (50%) bilateral 4 (50%) unilateral location 6 (75%) upper lobe 6 (75%) lower lobe 5 (62.5%) middle lobe a initial timing of imaging might be days since onset of symptoms or days since admission to hospital b imaging patterns described are as written in the publications ct computed tomography, cxr chest radiography, ggo ground-glass opacification, lll left lower lobe, lul left upper lobe, nc non-contrast, ns not stated, rll right lower lobe, rml right middle lobe, rt-pcr reverse transcriptase polymerase chain reaction, rul right upper lobe, us ultrasound given the small number of cases and the heterogeneous nature of case reporting, we could not to determine whether differences in imaging presentations varied significantly with patient age group, gender or presenting symptoms. given the lack of available rt-pcr testing kits in many countries, there has been interest in using ct to identify early pulmonary findings suggestive of covid-19, particularly where children are asymptomatic but at risk of disease because of infected co-habitants. in a subset of 30 children across 10 publications, we extracted imaging findings from asymptomatic children (table s7) [5, 15, 16, 18, 19, 21, 23-27, 30-32, 34] . of these, 11/30 (36.7%) had normal ct findings, 14/30 (46.7%) reported the more typical pattern of ground-glass opacification and 4/30 (13.3%) described nonspecific, consolidative changes, or "patchy shadowing". regarding differences with adults, ma et al. [23] found that children in their cohort (compared to a published adult cohort of 1,099 cases [3] ), were more likely to demonstrate the findings correspond to readily available reported imaging findings within the relevant publications. only covid-19 confirmed cases by reverse transcriptase polymerase chain reaction (rt-pcr) are included. because of the heterogeneous and occasionally incomplete reporting of these findings (e.g., some without pathology location, some using different terminologies), not all features are mutually exclusive, nor total to the combined number of patients; therefore, percentages are not provided for features that were only reported by a small number of publications (e.g., segmental involvement and subpleural distribution), and the denominator for lobe affected and laterality is derived for total number of studies where these findings were stated at time of publication, 296/431 (68.7%) children had been discharged from the hospital, 72/431 (16.7%) were in a stable condition in a hospital, 3/431 (0.7%) had been admitted to intensive care units. one child admitted to intensive care reportedly later died at 4 weeks post hospital admission; this was a 10-month-old with multiorgan failure, septic shock and intussusception [5] . the outcome of the remainder of cases was unclear from the published reports (60/431, 13.9%). one study performed subgroup analysis to determine the relationship between patient outcomes and ct imaging results [23] . the authors reviewed a subset of 23/50 (46.0%) children in their cohort who had been discharged, whose symptoms had resolved and who had negative rt-pcr testing on two separate occasions. the majority of these children 17/23 (73.9%) still demonstrated lung abnormalities, and in 2 cases these had progressed. a cox regression analysis did not find any statistically significant association between differences in imaging findings during treatment and likelihood of discharge. this was supported in part by findings by xia et al. [28] , who stated that ct findings appeared to lag behind resolution of clinical symptoms and two sets of negative nucleic acid testing. chest ct imaging findings in children with covid-19 are frequently normal or mild, with lower lobes most commonly descriptors refer to those stated within the relevant publications. because of the heterogeneous, non-standard terminologies, we included descriptions of "shadows/infiltrates" together and interpret these to mean nonspecific opacities. in many articles, there was incomplete reporting of findings; therefore, not all features are mutually exclusive, nor total to the combined number of children within the study. the column titled "pattern described" is therefore included to demonstrate how many of the reported abnormal ct cases for which the study provided the abnormalities. the relative frequencies of findings are provided (with the "total pattern described" as denominator, rather than total abnormal ct), which is the more important indicator than the absolute numbers summated ct computed tomography, ggo ground-glass opacification affected, demonstrating patchy ground-glass opacification or, less frequently, areas of consolidation. imaging appearances at follow-up remain normal or improve in the majority of children. these findings raise important clinical implications for paediatricians and radiologists. given the mild and sometimes absent findings on chest radiography and ct, it is unlikely that imaging will provide an increased confidence in the diagnosis for covid-19, nor can it provide reassurance for the absence of infection if imaging is normal. this finding is supported by a recent study of 24 asymptomatic carriers of covid-19, of whom 6 were children (5-15 years old) and all had normal chest ct findings [19] . similar results have also been supported by work in adults [40, 41] . whilst it is well known that chest radiography can underplay the chest ct findings, the identification of mild to moderately severe imaging appearances in the majority of children, with little subsequent change in management, is unlikely to justify the ct imaging. conversely, even when ct findings are present, we have found that these can be heterogeneous and nonspecific, and in the adult literature it has been reported that differentiation between covid-19 and other viral infections based on imaging findings is difficult [42] . research on this topic in paediatric radiology is currently unavailable, although qiu et al. [30] compared clinical findings between children with covid-19, h1n1 influenza and severe acute respiratory syndrome (sars) and found that children with covid-19 had a much milder course of illness than with sars, but were more likely to develop pneumonia than those with h1n1 influenza. future studies that focus on attempting to differentiate imaging findings among these viral illnesses in children should be mindful to account for co-existing viral infections given that one publication in this study demonstrated covid-19 in a child with co-infection of rsv [22] . in recent publications, it has been shown that some paediatric patients might be "super spreaders" (i.e. high viral shedding) [43] and more likely to demonstrate early symptoms. whether they also display earlier ct changes, which could be used to screen for individuals prior to available rt-pcr testing, remains unknown. therefore, given the lower severity of disease and additional radiation burden, ct imaging should not be routinely conducted for diagnosis, but rather reserved for those with severe or deteriorating symptoms, or in the search for an alternative diagnosis to aid management. the fact that imaging appearances frequently resolve, improve or remain normal at follow-up imaging is reassuring because it suggests that long-term pulmonary damage is unlikely, although at present there is insufficient evidence to confirm this. it is also important to bear in mind that the persistence of pulmonary findings does not necessarily imply ongoing infection, given that one study found persisting ct findings in 17/23 (73.9%) children who had been treated, with resolution of their symptoms and two negative rt-pcr tests. therefore, follow-up ct imaging would also be better guided by clinical symptoms rather than being performed as a matter of routine. these recommendations have recently been incorporated into newly published guidelines for imaging in [44] , which encourages a pragmatic approach based on patient symptom severity using chest radiography for initial workup and only for follow-up in moderate to severe cases, reserving an initial chest ct only where a clinical change in management is anticipated and for the post-recovery stages. useful advice regarding general staff protection and departmental organisation for imaging of covid-19 cases has also been recently provided by the european societies of radiology (esr) and thoracic imaging (esti) [45] . it is worth noting that although our inclusion criteria were not set to review infected pregnant women, there was one case in this review of an infected newborn, diagnosed at 36 h of age from a covid-19-positive mother [27] . the authors proposed the possibility for vertical transmission as a route of infection; however, several subsequent articles reviewing outcomes of infected pregnant women have now suggested this to be unlikely [39, [46] [47] [48] . a recently published rapid review of coronavirus in pregnancy [49] found that of the 32 infected women identified in the literature, there was 1 stillbirth (34 weeks of gestation) and 15/32 (47%) pre-term deliveries. in the 15/32 (47%) neonates who were tested for covid-19, all were negative. the latest guidance from the royal college of obstetricians and gynaecologists [50] has therefore recommended against routine separation of affected mothers and their babies and has not found any evidence to suggest intrauterine fetal infection or teratogenic effects from the novel coronavirus. clinicians should thus remain alert to alternative, more common diagnoses in newborns presenting with respiratory symptoms (e.g., respiratory distress syndrome, aspiration, pneumonia from alternative organisms), even if the mother is covid-19 positive [48] . although we performed a comprehensive systematic review, there are still several gaps in our radiologic knowledge regarding covid-19 in children. in this article we included manuscripts relating to radiographic or ct appearances of lung pathologies in children, although information on other modalities is lacking. there is sparse literature on the use of portable point-of-care ultrasound (pocus) for adult covid-19 patients in italy [51] and in children [52, 53] . in adults, pocus has been reportedly used to triage more severe cases for urgent management by helping to identify areas of groundglass opacification (so-called b lines) as well as areas of necrotic lunga marker of the more advanced stages of infection [54] . nevertheless, given that severe disease in children is less likely, the extent to which pocus might be helpful is questionable, although it has been recommended as one of several potential options for lung assessment by a chinese expert consensus review for neonatal management in covid-19 [55] . two adult publications have reported the use of [f-18]2-fluoro-2-deoxyglucose (fdg) positron emission tomography (pet)/ct in covid-19 [56, 57] , and suggested that it could help monitor disease progression and treatment outcomes, particularly by detecting residual activity in mediastinal lymph nodes. this modality has not been reported in infected children, and adult studies have only included a small number of cases (4 patients or fewer). the added value is thus still undetermined [58] and should not be first studied in children, particularly given the increased radiation burden. our review also did not find many articles reporting imaging findings in immunocompromised children, so it is undetermined whether these features might differ from those without health conditions. it has been well documented that more severe infections are found in immunocompromised children with other strains of coronavirus [59] and that these infections can spread to other parts of the body, such as the brain, causing encephalitis [60] . whether this also occurs with covid-19 remains to be seen. it is interesting that the only child death reported in this review was also suffering from an intussusception. whether this was triggered by the underlying viral infection is unclear, but it is worth noting that gastrointestinal complaints can be the first and more prominent symptom of covid-19 in some people and has been reported in an adult series [61] . there are several limitations to this work. given the widespread public health interest, several manuscripts on the topic of covid-19 are emerging each week, many bypassing usual peer review processes. it is likely that some information might be missing but later included, or in certain cases articles retracted (as for two articles during our screening process). nevertheless, where possible, we have tried to mitigate this by conducting our literature review thrice in order to provide the most up-to-date information from reliable sources. whilst not all imaging findings in all cases were reported in the studies, we described all available findings to give a general overview of the imaging pathology. future works on the study of covid-19 imaging findings could be improved by the use of standardised detailed descriptors for imaging findings (i.e. stating both the pattern and localisation of findings), in line with rsna guidance [44] , with clearly stated indications for imaging where possible. second, because of the origin of the virus in china, some articles have been published in a language other than english, or in english by non-native speakers. this might have hampered our understanding and interpretation of the data, although we used online translation services where required. whilst other systematic reviews on the topic of covid-19 have excluded articles not written in english, we thought it was important to review as many foreign-language articles where possible to increase our collective knowledge base, particularly given the few reported paediatric cases. finally, the majority of articles have included children from china, in particular wuhan city. it is unclear whether some of these paediatric cohorts overlap, although we did identify three papers where there was clear similarity in many of the patients described, and we avoided repetition of findings in summary results. it is also important to highlight that differences in indications for ct imaging in children might also exist (which could explain why ma et al. [23] found slightly more abnormalities on ct in children than adults), but unfortunately these indications were not made clear in the publications. chest imaging findings in children with covid-19 are frequently normal or mild, with unilateral changes that include patchy ground-glass opacification, commonly affecting the lower lobes. imaging appearances at follow-up frequently remain normal or improve in the majority of children. chest ct imaging adds little to the further management of the child and should be reserved for severe cases or for identifying alternative diagnoses. further areas of research should include information on imaging and clinical characteristics in immunocompromised children with covid-19, and information on long-term follow-up, particularly in the more severely affected children. we should therefore be prudent with the usage of ct, particularly at a time where resources are stretched, and only use it in the more vulnerable populations. a novel coronavirus from 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covid-19 pneumonia characteristics and outcomes of coronavirus infection in children: the role of viral factors and an immunocompromised state fatal encephalitis associated with coronavirus oc43 in an immunocompromised child covid-19: gastrointestinal manifestations and potential fecal-oral transmission publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. key: cord-295792-hajvtzj9 authors: álvez, fernando title: sars-cov2 coronavirus: so far polite with children. debatable immunological and non-immunological evidence date: 2020-07-03 journal: allergol immunopathol (madr) doi: 10.1016/j.aller.2020.05.003 sha: doc_id: 295792 cord_uid: hajvtzj9 abstract the reasons for the relative resistance of children to certain infections such as that caused by coronavirus sarscov2 are not yet fully clear. deciphering these differences can provide important information about the pathogenesis of the disease. regarding the sars-cov2 virus, children are at the same risk of infection as the general population of all ages, with the most serious cases being found in infants. however, it has been reported that the disease is much less frequent than in adults and that most cases are benign or moderate (even with high viral loads), provided there are no other risk factors or underlying diseases. it is not clear why they have lower morbidity and virtually no mortality. a series of findings, relationships and behavioral patterns between the infectious agent and the child host may account for the lower incidence and a greatly attenuated clinical presentation of the disease in children. it is not just a question of the infectious agent. the reasons for the relative resistance of children to certain infections such as that caused by coronavirus sars-cov2 (which causes covid-19 disease), are still not fully clear. many infectious processes in this age group occur differently from what is seen in adults, and deciphering these differences can provide important information about the pathogenesis of the disease. regarding the sars-cov2 virus, children are at the same risk of infection as the general population of all ages, with the most serious cases being found in infants (1) . however, it has been reported that the disease is much less frequent than in adults and that most cases are benign or moderate (even with high viral loads), provided there are no other risk factors or underlying diseases. the condition may even be asymptomatic. of note in this regard is the documentation of 12 asymptomatic children with mild pneumonias (2) (3) (4) (5) . however, knowing the evidence on the "benignity" of this infection caused by such a novel virus in the childhood population should not generate a feeling of complacency or relaxation towards the disease (6) . recently, the national health service and the paediatric intensive care society of the united kingdom have alerted clinicians about a small number of children admitted with symptoms of toxic shock syndrome and kawasaki disease (kd), and their possible association to covid-19 (not all cases being positive) (7) . without ruling out a new type of presentation of covid-19, such a relationship has not been definitively confirmed. these are most likely presentations of kd coinciding in time with the viral pandemic and having an incidence not higher than in previous years. it is worth pointing out that toxic shock syndrome is associated to bacterial toxins and has nothing to do with a rare complication: kawasaki shock syndrome in the context of also rare kd. lastly, several studies have described associations of kd with different viruses that are common in children. are all children well protected from acquiring the infection or only from the risk of becoming ill after being infected? children are also infected but it is not clear why they have lower morbidity and virtually no mortality. a series of findings, relationships and behavioral patterns between the infectious agent and the child host may account for the lower incidence and a greatly attenuated clinical presentation of the disease in children. data on the immune response to the sars-cov2 virus are still not entirely conclusive, although information on its sars-cov and mers-cov congeners is known and can serve to make an approximate or potentially comparative assessment. the respiratory epithelial cells (recs) form a major line of defense in the human body against microorganisms present in inhaled air. this first barrier from the nasopharynx to the alveolar epithelium is a constituent of the innate immune response (iir) formed by many different cells: epithelial cells, alveolar macrophages, and innate lymphoid and dendritic cells. the most common respiratory viruses that reach and invade the lungs in children are rhinoviruses (rvs), respiratory syncytial virus (rsv), influenza, and coronavirus. they share a common rna genome that plays an important role in the set of sensors (pattern recognition receptors) present in the iir, and which are responsible for identifying these viruses when they target respiratory cells. these sensors generate cascades of specific inter-and intracellular molecular signals that, -with integrity of the cellular defensive barrier mentioned above, -play a key role as the first line of defense to ensure the establishment of antiviral protection in the lungs (8) . the first elements encountered by sars-cov2 are alveolar macrophages -the most numerous pulmonary leukocytes in the first years of life -with the contribution of antiviral proteins produced mainly by recs and neutrophils (9) . the response of these viruses, and in particular of sars-cov2, is to activate mechanisms to evade or suppress the iir, and thus be able to open a gate to replicate and cause the disease. it can be argued that the iir is more important in the first years of life when adaptive processes are less developed (9) . considering the differences in the iir between children and adults, it has been hypothesized that this non-specific response occurring after the first encounter with the virus is more robust and active in children (3) . in this regard, it could be asked whether the mentioned response is particularly diligent against sars-cov2, for it is already known that against other viruses such as rsv, this desired protection does not occur as effectively in infants. moreover, infants are characterized by a respiratory tract that is healthier and less punished by extensive exposure to inhalants, pollution and other respiratory processes as seen during adulthood. to achieve this protection, the infected person must be in an optimum state of health and with an adequate genetic background (for example, the hla system which ensures the immune response with some determined anti-sars-cov2 immune locus), favoring specific antiviral immunity. when this protective response is altered, viral expansion will be greater, increasing damage to the lung, where there is a strong expression of angiotensin converting enzyme (ace2) receptors. initial good health is no longer an advantage once the lung is damaged (10) . the iir is considered to be more delayed and weakened with aging and when viral attack occurs. in an effort or as a replica update (reset), it reacts with an excessive and out-of-control inflammatory response, and pulmonary dysfunction also occurs due to altered o 2 exchange, resulting in further damage to both tissue and lung function and capacity (11, 12) . in short, the purpose of this first defensive barrier for early control during the incubation period and the first symptoms of sar-cov2 infection is to inhibit viral replication, promote elimination of the virus, induce tissue repair and trigger a specific adaptive immune response (air) (12) . this next defensive activity is slower in developing, and it is not clear whether it is stronger in children than in adults with regard to the clearance of sars-cov2. studies of sars-cov-infected mice have shown the t lymphocyte response to be particularly important, particularly that of helper cd4+ t lymphocytes, which stimulate b lymphocytes (in charge of humoral antibody response) -all of which are essential for disease protection and viral clearance. a subpopulation of cd4+ t cells, the regulatory t lymphocytes (tregs), are relatively abundant in pediatric tissues, and possibly have a greater suppression capacity than in adults (8) . likewise, cd8+ t cells account for 80% of the inflammatory cells in the lung interstitium, and play a vital role in eliminating the virus and also in inducing immune damage. the response of these t lymphocytes to s protein and other structural proteins of the coronaviruses is persistent and longlasting (12) (13) (14) . in the event of sars-cov2 infection, the t lymphocyte pattern that predominates in the first few years of life could be considered more effective in rejecting the virus. it is still premature to know how long this antibody response will last, with long-term serological studies being needed to monitor the immune status of the patients. evidence from other particularly virulent coronaviruses (sars-cov, mers-cov) shows that defensive immunity can last up to three years, and that reinfection with the same strain is highly unlikely during the next winter season (15). the sars-cov2 coronavirus, as was previously verified with sars-cov and mers-cov, initiates the attack due to its interrelationship and affinity with the reninangiotensin system (ras) ( figure) , through a key enzyme in this system -ace2which in addition to its known physiological contribution has been shown to be the receptor for these viruses and to facilitate access to the target cells that will become their reservoir. the virus, by means of the spicules on its surface (with the s-protein) as a key, invades the cells expressing ace2 and the serine protease tmprss2 to replicate and reproduce. this interaction is a powerful conditioning factor of the virulence of the virus (16) . the expression of ace2 is very high on the apical surface of well-differentiated epithelial cells lining the airways, and especially in the alveoli of the lung -precisely the main target of the virus and where it causes the greatest damage. strong expression has also been demonstrated in the mouth and tongue, indicating that the oral cavity is a potential route of infection (17) . furthermore, this enzyme also plays an important role in the immune response, especially in inflammation, and is involved in the defensive mechanisms of the lung -protecting it from severe injury induced by respiratory viruses (11, 18) . following cell damage induced by the virus, the expression of messenger rna (mrna) (responsible for transporting genetic information) and the enzymatic activity of ace2, in an intimately related pattern, are significantly reduced (16, 19, 20) . this reduction partly explains the poor ability to slow down the inflammatory response, as a consequence of advancing age. the expression of ace2 does not seem to play an essentially harmful role in the body, especially in children, rather quite the opposite. on the one hand, under normal conditions, ace2 is involved in the ras cascade through activation of the mas receptor, and the function of this ace2/mas pathway is crucial due to its beneficial effects: vasodilatation, with anti-fibrotic, anti-proliferative and anti-inflammatory actions, thereby counteracting the actions of the ace-angiotensin ii-at1r axis (figure) . however, as previously mentioned, it is the lock which the virus skillfully recognizes and uses to penetrate and damage the alveolar epithelial cells. since the virus first needs to attach and gain access to the cell before it can replicate, the state of cell differentiation with surface location of ace2 can have a strong impact upon the disease (19) . considering this state of cell differentiation in childhood and that the distribution of ace2 receptors is uneven in different organs and populations, are there differences in the extent and function of ace2 in the alveolar tissue of children and adults? some studies report that the number and function of ace receptors is not as robust in children as it is in adults (3). however, definitive information is not available, as it is very difficult to obtain lower airway samples from healthy children. the existing data are therefore based on studies in murine or other animal models. studies in mice have shown that eca2 protein expression increases with age, and that mrna/eca2 activity is not only regulated during development but is also impacted by aging (19, 21) . in extrarenal tissues such as the lung, mrna/eca2 expression is low during pregnancy, increases in the perinatal period and peaks in adulthood (22) . an analysis of thousands of lung tissue samples from patients of different ages with a variety of lung tumor processes investigated the determinants of ace2 expression from the cancer transcriptome data. the activity and amount of ace2, not affected by carcinogenesis, was found to increase from 40 years of age, with peak expression between 60-80 years of age (21) . ideally, by demonstrating a more precise number and distribution of epithelial cells expressing ace2 in cohorts such as age, it could be determined whether the pediatric population is potentially less susceptible. common human coronaviruses (covh), not sars or mers, have been detected in respiratory secretions of a significant percentage of healthy children during the winter months. one feature to note is that in children over four years of age, the infection rates were relatively consistent, when it is well known that the pathogens that cause respiratory infections are less prominent above that age (23, 24) . like other respiratory viruses, covh can infect people of all ages, and the infection only generates relative immunity -although the type of specific protection has not been completely defined. the usual co-circulation of covh types and co-infection in people suggests that protection is unlikely to be of high cross-reactivity, and also that the greater incidence of sars-cov2 infection in adults points to poor cross-immunity with previous covh infections (24) . however, serological studies evaluating the immune response to respiratory infections including covh have shown steadily increasing seroprevalence of antibodies to covh in both children and young adults, as well as cross-reactivity, such as between antibodies to the previous sars-cov and covh (25) (26) . the extent to which this antibody response may mean cross-immunity to sars-cov2 remains unclear. the respiratory system constitutes a reservoir for a group of microorganisms -both commensal and pathogenic. children are especially prone to many viral infections, with a high burden of respiratory viruses in the upper respiratory tract (urt) mostly (approximately 90%) in infants and toddlers, and with a prominent participation of respiratory syncytial virus (rsv) and rhinoviruses (rvs) (27) . in addition to these two well-known viruses, molecular techniques have allowed more viruses to be identified in the urt coexisting in the same periodalthough this does not imply that there will be a greater tendency towards more serious processes. according to the available data, the number of viruses involved and the related symptoms are variable and not always similarthis being a peculiar aspect in the pediatric population. in a recent series of adults hospitalized with covid-19 in germany, no viral co-infection was demonstrated in any patient (28) . in relation to covh, four are endemic in many populations and have been involved in upper and lower respiratory tract infections in healthy children, as commented above. current studies preceding the present pandemic showed that children carrying covh in their respiratory tract become co-infected in up to two thirds of all cases (23) . under these conditions of co-infection, there is some evidence of synergistic and antagonistic interactions among the coexisting viruses that can play a key role in acute respiratory infection. an example is rsv growth blocked by the activity of the influenza a virus. studies on the dynamics of these viral respiratory co-infections have observed that if a given virus initiates colonization and infection in the nasopharynx first, it is able to block or reduce the growth of a second arriving invader. that is, the level of viral load (fastest growing virus) determines which virus will be dominant. in particular, the presence of rvs recognized as the fastest growing is able to reduce the growth of the remaining viruses during a state of co-infection (29, 30) . the clinical course in coinfection scenarios will be determined by specific combinations of the virus involved. if the amount of more than one virus in the urt of children is usually higher in winter and early spring (rvs and rsv being the most frequent), the question that arises is whether in the current pandemic the activity and virulence of sars-cov2 virus is blocked or somehow reduced by other viruses already often present in the urt of this age group. it is possible that such repeated and continuous viral exposure also sustains and keeps the immune system active when it needs to respond to sars-cov2 infection, added to the fact that enzyme eca2 is more immature in this age group (31). melatonin is a hormone involved in a wide range of cellular, neurophysiological and neuroendocrine processes. it does not exert a specific direct antiviral effect but indirectly possesses anti-inflammatory and anti-oxidative action, thus improving the immune response (32) . all these effects afford potential mitigation of covid-19 disease. this is a benefit to be considered not only preventively but also as an adjuvant to treatment when the disease is already established. respiratory viruses such as covh and, as was demonstrated with sars-cov1 in its day (the molecular biology of sars-cov2 is still not completely documented) in its attack upon the lung, trigger oxidative stress and activation of the nlrp3 inflammasome (multiprotein complex of the innate immune system), activating a cytokine avalanche -specifically il-1β and il-18 -which will play a critical role. melatonin has been shown to inhibit coronavirus-induced cell death; exert an antioxidative and inhibitory effect upon the cytokine complex; and also prevent secondary pulmonary fibrosis (33) (34) (35) . it is noteworthy that nocturnal melatonin blood levels are much higher in children aged 1-3 years and under 15 years compared to adults, with a significant drop after age 70. there is a definite negative relationship between age and melatonin secretion between the ages of 20 and 90 years (35) . in fact, children typically exhibit significantly greater secretion and activity of melatonin than their grandparents, an age group characterized by more frequent and more severe covid-19 disease. of course, the pneumococcal vaccine does not provide any protection against coronaviruses. children over 12 months of age have theoretically completed pneumococcal vaccination and have a robust anti-pneumococcal antibody response. previous studies on the benefits of vaccination with heptavalent and nine-valent conjugate vaccines have shown a significant reduction in both children and adults not only of invasive pneumococcal disease but also of influenza episodes and admissions due to viral pneumonia compared to pre-vaccination years (36) (37) (38) . furthermore, lower influenza morbidity has been reported during a 2-3 year period in people over 60 years of age who have been vaccinated with the pneumococcal polysaccharide vaccine (39) . the most recent direct beneficiaries of the pneumococcal vaccine besides children are people over 65 years of age. during this pandemic, given the high mortality rate in individuals over age 65, and in order to investigate any possible indirect effects of the vaccine such as those reported for influenza virus, it could be important to know the proportion of individuals that died due to covid-19 in this age group and who were vaccinated against pneumococcus with conjugate and polysaccharide vaccine administered five years prior to death. the range and type of activities in children is generally relatively minor, with a more attenuated exposure to the virus, considering the main routes and risks of transmission common in adults. children are usually infected through contact with their adult family members, with more limited exchanges than is usual for adults, and the majority -being asymptomatic or presenting only very mild symptoms -are not tested for the presence of the virus. one of the characteristics of an rna virus such as sars-cov2, is its tendency to make mistakes in replication and mutation. this allows it to survive without being well recognized by the immune system, and also results in attenuation of its virulence (3) . assuming that children as secondary cases become infected in second, third or even fourth order after the initial case, would their clinical manifestations be more attenuated? to better appreciate potential infectivity in patients infected by sars-cov2 with mild disease (as usually happens in children), in general the concentrations of rna and viral replication are higher in the first seven days when the viral load is greater and more active (28) . after the first few days of symptoms, the viral load drops uniformly and infectivity is also significantly reduced, and the virus might not be isolated from respiratory samples after one week from symptoms onset (40) . so what is the chance of transmission of active virus from the respiratory tract of the child? some data indicate that the positivity time of the polymerase chain reaction (pcr) test is longer than in adults (3). in mild processes (such as in children), after the first 7-8 days the detection of viral rna in the urt does not necessarily imply the presence of an infecting virus, as this depends on the threshold level of the viral load under which infectivity (virus isolation) is less likely. in this regard, a study in adult patients has shown that the virus was not detected in throat and sputum samples containing < 10 6 copies/ml (28) . ideally, but impractical and chimerical as a widespread test, the determination of viral load would be an interesting resource to have an indirect but more concrete estimate of infectivity in the current circumstances. concerning the importance of the pediatric population as a transmitter, children infected with symptoms or asymptomatic, as well as adults, can potentially spread the infection. one concern, considering the significance which the disease can have, is that elderly people may become infected. as in the case of influenza, there is a high possibility of spread from children to grandparents, but with the difference that the latter are protected by a vaccine in the case of influenza. the role which children play in spreading the infection is unclear, but there are obviously no children in nursing homes for the elderly. so far, most reported children with infection have been part of a household outbreak, living with symptomatic or very subtly infected adults (almost all sick with symptoms before the children were infected) -suggesting that children are not an important reservoir (41) . in the current situation with day-care centers and schools closed, it is very unlikely that children will become index cases in households. the true hazard of the asymptomatic child as a transmitter to its environment is probably being overestimated. among over two thousand children diagnosed in china, 13% of those virologically confirmed had asymptomatic infection (1) -a rate that obviously minimizes the true number of asymptomatic infections, since many of them are not tested. although theoretically they can be as infectious as adults, asymptomatic children do not spread the virus by coughing, and generate a smaller volume of expired air than adults. in contrast, however, they have a lot of physical activity and closer social interaction. it is therefore prudent to remain cautious. the reasons for the relative resistance of children to some infections remain unclear. in relation to the very benevolent behavior of the sars-cov2 virus, several reasons have been proposed that are not free from argumentation and controversy, and which demand more studies, more time, and a greater notion of the magnitude and biology of this virus. the immunological interrelationship between the virus and its pediatric host has not been well recognized yet. the sars-cov2 virus discovered that children are not the "fishing grounds" to cast their nets, since the chances of abundant fishing -ace2 -are unfavorable. probably, and given the extraordinary research in progress, in the time remaining until publication of this paper, light will have been shed on the questions now raised. in these months of pandemic, the observation that the incidence and severity are much lower in children does not necessarily mean that they are less susceptible to infection. the number of infected and sick children may increase in future, and with some concerns especially in children with special needs or underlying illnesses. the relevance of the childhood population in relation to the spread of infection is uncertain and no more accentuated than in adults. epidemiology of covid-19 among children in china severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review the different clinical characteristics of corona virus disease cases between children and their families in china -the character of children with covid-19 coronavirus disease 2019 in children-united states systematic review of covid-19 in children shows milder cases and a better prognosis than adults covid-19 in children in the united states: intensive care admissions, estimated total infected, and projected numbers of severe pediatric cases in 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covid-2019 in vitro growth profiles of respiratory syncytial virus in the presence of influenza virus coinfections of the respiratory tract: viral competition for resources systematic review of covid-19 in children shows milder cases and a better prognosis than adults impact of melatonin on immunity: a review. cent covid-19: melatonin as a potential adjuvant treatment melatonin alleviates acute lung injury through inhibiting the nlrp3 inflammasome can melatonin reduce the severity of covid-19 pandemic? impact of pneumococcal conjugate vaccine and the severity of influenza-like illnesses on invasive pneumococcal infections in children and adults a role for streptococcus pneumoniae in virus-associated pneumonia the impact of pneumococcal vaccination on bacterial and viral pneumonia in western australian children: record linkage cohort study of 469589 births does pneumococcal vaccine reduce influenza morbidity in humans? temporal dynamics in viral shedding and transmissibility of covid-19 coronavirus infections in children including covid-19.: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children key: cord-308493-3fsn7awq authors: günther‐bel, cristina; vilaregut, anna; carratala, eduard; torras‐garat, sonia; pérez‐testor, carles title: a mixed‐method study of individual, couple and parental functioning during the state‐regulated covid‐19 lockdown in spain date: 2020-07-17 journal: fam process doi: 10.1111/famp.12585 sha: doc_id: 308493 cord_uid: 3fsn7awq during the recent covid‐19 outbreak in spain we explored the individual and relational wellbeing of people confined together with their partners and/or children during the first three weeks of state‐regulated lockdown. adults 18 years or older (n=407) completed an online survey that included demographic, household, and employment information along with standardized measures of psychological distress (state‐trait anxiety, beck depression) and relationship functioning – either the dyadic adjustment scale if there were no children in the household or a basic family relations evaluation questionnaire (cerfb) measuring conjugal, parental, and co‐parental functions. qualitative analyses of responses to an open‐ended question about perceived changes in couple or family dynamics during lockdown revealed 9 specific themes comprising two overarching categories: relational improvement and deterioration. the overall prevalence of improvement themes (61.7%) exceeded deterioration themes (41.0%), with increased (re)connection and conflict atmosphere cited most often. quantitative analyses found elevated levels of state anxiety but not trait anxiety or depression during lockdown. consistent with the qualitative results, couples having no children at home reported high levels of dyadic adjustment, but with children present cerfb parental functioning exceeded conjugal functioning, a pattern sometimes associated with child triangulation into adult conflicts. although correlates of psychological distress (e.g., unemployment, perceived economic risk) were relatively stable across sub‐groups, predictors of relationship functioning varied substantially with household/parental status (e.g., telecommuting and employment facilitated conjugal functioning only for couples with children). according to the world health organization (who, 2020a), a pneumonia of unknown cause was first detected in wuhan, china in december 2019. after rapid escalation, the who (2020b) declared the novel coronavirus disease (covid-19) a global pandemic. in the context of this outbreak, governments around the world have taken measures to prevent and control the covid-19 infection. starting in china, one such measure has been to place entire cities under mass quarantine. spain has been one of the worst affected european countries. the virus spread to all spanish regions, with the communities of madrid and catalonia suffering the highest number of cases. on march 14th 2020, the spanish government formally declared a state of alarm over covid-19 and ordered a state-regulated lockdown defined as home confinement, in which everyone, including those who were asymptomatic, had to stay confined at home for the next two weeks. the only exceptions were for basic activities like buying food or medicine, attending medical centers, or commuting to work (boe, 2020) . schools, universities and other education institutions were also on lockdown, going online in most cases. one week into the state of alarm, as covid-19 taxed the country's oversaturated health care system, spain's government tightened quarantine even further, ordering all non-essential workers to stay home for two additional weeks with the possibility of extending the emergency measures until outbreak remission. in addition to the biomedical and epidemiological benefits of mandatory mass quarantine, it is prudent to consider possible psychological and behavioral impacts (rubin & wessely, 2020) . in a prompt and clarifying article, brooks, webster, smith, woodland, et al. (2020) have reviewed scientific literature relevant to effects of quarantine on individual mental health, aiming to facilitate decision making in the current global crisis. based on 24 quantitative and qualitative studies across 10 countries where quarantines involved direct or potential exposure to sars, ebola, h1n1 influenza pandemic, middle east respiratory syndrome, or equine influenza, brooks et al. (2020) conclude that quarantine often has negative psychological effects, including anxiety, depressed mood, irritability, insomnia, symptoms of post-traumatic stress, and emotional exhaustion. indeed, a recent large-scale survey during the covid-19 pandemic in china found that well over a third of the general population experienced significant psychological distress, though it is unclear how much of this was related to lockdown (qiu, this article is protected by copyright. all rights reserved shen, zhao, wang, et al., 2020) . in may of this year a similar proportion of american adults reported clinical anxiety or depression according to the u.s. census bureau (fowers & wan, 2020) . the literature cites many factors that could have negative mental health consequences during or after quarantine including fear of infection (bai, lin, lin, chen, et al., 2004; desclaux, badji, ndione, & sow, 2017) , boredom and isolation (cava, fay, beanlands, mccay, & wignall, 2005; digiovanni, conley, chiu, & zaborski, 2004) , financial insecurity (jeong, yim, song, min, et al., 2016; mihashi, ostubo, yinjuan, nagatomi, et al., 2009) , limited access to basic supplies (jeong et al., 2016) , and confusing public information (blendon, benson, desroches, raleigh & taylor-clark, 2004; jeong et al., 2016) . another factor particularly relevant to the present study is quarantine duration (hawryluck et al., 2004; marjanovic, greenglass, & coffey, 2007; reynolds, garay, damond, moran, et al., 2008) . for example, hawryluck et al. (2004) found significantly more symptoms of posttraumatic stress among people locked down for more than 10 days compared with those in quarantine less than 10 days. in spain we collected data through the first three weeks of intensive covid-19 lockdown. although the literature emphasizes psychological effects of quarantine on individuals, there are good reasons to consider implications for couple and family relationships as well (sprang & silman, 2013) . for example, a global times (2020) newspaper article reported unprecedented divorce rates in some districts of xi'an, the capital of northwest china's shaanxi province, as a direct repercussion of covid-19. similarly, in qualitative studies, participants described ebola containment measures in liberia as creating mutual distrust, even between family members (pellecchia, crestani, decroo, van den bergh, & al-kourdi, 2015) ; and toronto health care workers quarantined following exposure to sars reported disruptions in parental roles and routines, "creating stress for the entire family" (robertson, hershenfield, grace, & steward, 2004, p.404) . from our interpersonal-systems perspective, a more general reason to widen the lockdown lens is that individual and family functioning are inextricably interwoven, especially for children and adolescents but also for adults. in fact, an enormous body of research links family conflict and dysfunction to psychological distress, physical health symptoms, and a wide variety of behavior problems (e.g., cummings, koss & davies, 2015; repetti, taylor & seeman 2002) . similarly, cohesive and supportive family processes not only protect individuals from accepted article negative effects of life stress (hobfoll & spielberger, 1992) but also generate a variety of positive outcomes (e.g., conger & conger, 2002; joel wong, uhm & li, 2012) . relevant to the covid-19 pandemic, disruptions of family functioning in the wake of widespread socioeconomic stress such as the great recession of 2007-09 (forbes & krueger, 2019; margerison-zilko et al., 2016) , as well as natural disasters such as floods and earthquakes (cao, jiang, li, lo & li, 2013; mcdermott & cobham, 2012) , have had multiple negative impacts on survivors' behavioral health just as stable and cohesive family relations protect against these. while the quarantine literature emphasizes mainly deleterious effects, it is possible that positive as well as negative repercussions of lockdown could occur at the level of intimate relationships. on the one hand, home confinement can easily create conditions for conflict or estrangement as household members readjust work, school, and recreational activities; face possible contagion and financial strain; and spend virtually all of their time together in limited physical space. on the other hand, such proximity might also create opportunities for increased closeness, communal problem solving, and deeper personal relationships. the title of a may 24th new york times article -"the virus has wrecked some families. it has brought others closer" (wilson, 2020)essentially captures this mixed picture. as couples and families face the demands of a new (crisis) situation, interactional discontinuities may sometimes lead to more resilient as well as deteriorated functioning (patterson, 2002; walsh, 2007) . soon after covid-19 disrupted spain we were able to organize a sizable on-line study of repercussions for individuals, couples, and families. although the sample of convenience did not rigorously represent the spanish population, we hoped to gain preliminary information about the individual and relational wellbeing of people confined together with their partners and/or children during the first three weeks of state-regulated lockdown. in addition to demographic, household, and covid-related employment information, the survey included standardized spanish-language measures of psychological distress and relationship functioning: the former were the state-trait anxiety inventory (stai; spielberger, gorsuch & lushene, 2008; buela-casal, guillen-riquelme & seisdedos-cubero, 2015) and the beck depression inventory (bdi; beck, steer & brown, 1996; sanz & vazquez, 2011 this article is protected by copyright. all rights reserved important qualitative (mixed-method) component of the study is that participants also responded to an open-ended question about perceived changes in couple or family dynamics since the beginning of home confinement. the relationship aspects of the study were of special interest to us as couple and family therapists, and including the cerfb followed naturally from our involvement in a research and development project ("family relational diagnosis in mental health") funded by the spanish government (ministerio de economía, industria y competitividad, 2017). the cerfb attempts to operationalize central constructs in linares' (1996 linares' ( , 2002 linares' ( , 2012 basic family relations theory, where partially orthogonal conjugal functions and parenting functions converge to create optimal (or sub-optimal) conditions for relational nurturing, a crucial determinant of child mental health. according to the theory, combining the bi-polar conjugal (harmony-disharmony) and parenting (preservation-deterioration) dimensions yields four prognostically significant quadrants: functionality (both dimensions high) allows for mature and balanced child development; triangulation (parenting high, conjugal low) facilitates child involvement in couple conflicts; deprivation (conjugal high, parenting low) sustains satisfactory couple relations at the expense of child nurturing; while chaotization (both dimensions low) maximizes conditions for child psychopathology (linares, 2002) . because the cerfb scales apply only with children present, we used the das to assess conjugal relationship quality when parents had no children (couple only) or when children were no longer at home (empty nest). more specific aims of the study were to (a) compare lockdown responses from the pandemic convenience sample to benchmarks for established measures of individual, couple and parental functioning; (b) describe via qualitative analysis the ways in which participants felt their couple and family relationships had improved and/or deteriorated during the first few weeks of lockdown; (c) identify demographic, household, and employment-related correlates of pandemic relationship functioning and psychological distress with special attention to variations across couples with children at home, couples with no children, and couples with empty nests; and (d) explore possible changes in relationship functioning over time during the first three weeks of lockdown. this article is protected by copyright. all rights reserved a total of 407 participants recruited through facebook and other social media platforms completed our online survey between 24 march and 7 april 2020, weeks 2 and 3 of the stateregulated home confinement. inclusion criteria were: (a) aged 18 or higher, (b) currently living in spain, (c) living with one's romantic partner and/or one's children (including divorced parents currently living with children in a shared custody arrangement). the participants were predominantly female (77.0%) and ranged in age from 22 to 77 years (m = 42.7; sd = 12.7). most were also well-educated (76.7% had university degrees) and resided in cities (67.2%) rather than smaller urbanized towns (27.5%) or rural areas (5.1%). the crucial variable of household-parental status governing which relationship measure(s) they would complete distributed as follows: partnered parents living with children (47.4%), partners in couples without children (37.3%), partners in couples whose children were not at home (9.6%), and divorced parents (5.7%). children's ages ranged from 5 months to 51 years, and 49.7% of parents had more than one child at home. a majority of participants (69.9%) were at least partly employed at the time of the survey, with 54% telecommuting, 7.3% working entirely on site, and 8.8% doing both. while only 7.1% had experienced covid-related job loss, 17.0% of the sample was currently unemployed and 5.9% had retired. occupations varied widely, with 33.4% of the sample in some way affiliated with the health professions, 11.3% working in an educational capacity, and 47.2% in general commerce or self-employed. some participants (14.0%) reported that a member of their household was experiencing a health problem at the time of the survey, and 11.8% indicated they were currently receiving psychological or psychiatric treatment for problems such as anxiety, depression, substance abuse, adhd, relationship issues, or wanting "personal growth." the project received ethics approval from the ethics research committee of the school of psychology, education, and sports sciences, blanquerna, ramon llull university (certificate # 1920005p). before beginning the online survey, each participant reviewed information about the study's purpose and procedures, including assurance of confidentiality, and provided her or his informed consent. responses to an initial question about household and parental status distributed participants according to which standardized relationship measures they would complete later in this article is protected by copyright. all rights reserved the survey. while all 407 participants completed the stai and bdi, those in couples with no children or all children away from home completed the das (n=191); partnered parents with a child in the household did the full cerfb (n=193); and divorced parents completed the cerfb parenting and co-parenting scales but not the conjugal function scale (n=23). although a common measure of couple functioning for participants with and without children at home would have been ideal, allocating scales as we did made the online survey more time efficient. fortunately, previous validation research has found high correlations between cerfb conjugal functioning and the das (e.g., r = .74 in ibañez, 2016) . the sequence of survey questions proceeded from demographic, household, and current employment information (including perceived economic risk) to the standardized measures of psychological distress and relationship functioning. instructions throughout the survey reminded participants to focus on the lockdown period in considering their responses. a final, open-ended question eliciting data for qualitative analysis asked, "what changes have you perceived in your couple or family dynamics since the beginning of home confinement (march 14th 2020)?" accompanying this was an apology for not conducting a face-to-face interview and a request to answer in as much written detail as possible: "the more information you provide, the better." we discontinued the survey on 8 april 2020, when state-regulated restrictions first began to ease. the state-trait anxiety inventory (stai; spielberger et al., 2008) , validated for use in spain by buela-casal, et al. (2015) , is a 40-item self-report instrument that assesses anxiety as both a state (20 items) and a trait (20 items). with items in a 0-3 response format, state and trait anxiety scores range from 0-60, and benchmark cut points for adult spanish men and women provide a basis for classifying subscale scores from "very high" to "very low" (buela-casal et al., 2015) . internal consistency coefficients for the current lockdown sample were α = .93 and .84 for state and trait anxiety, respectively. the beck depression inventory (bdi; beck et al., 1996) , validated in spanish by sanz & vázquez (2011), consists of 21 self-report items measuring the presence and severity of this article is protected by copyright. all rights reserved depression. as with the stai, benchmark cut points for the spanish population permit classifying bdi scores as reflecting minimal, mild, moderate or severe depression (sanz & vázquez, 2011) . reliability for the lockdown sample was α = .85. participants with no children at home completed the spanish version of the dyadic adjustment scale (das; spanier, 1976, 2017), a 32-item questionnaire measuring general couple relationship quality. the das also has consensus, satisfaction, affectional expression, and cohesion subscales, but because these were highly intercorrelated we used only the das total score (α = .94) in the main analyses. although clinical cut points for the das are not participants with children at home completed the basic family relations evaluation questionnaire (cerfb; ibáñez et al., 2012; vilaregut et al., 2019) , a 25-item parent-report instrument inspired by linares' (2002 linares' ( , 2012 theoretical ideas about relational nurturing. the original cerfb includes a 14-item parenting function scale (α = .92), measuring the quality of parent-child relations (e.g., "i feel that my children return my affection"), and an 11-item conjugal function scale (α = .91) reflecting the quality of how parents relate to each other as a couple (e.g., "my partner knows how to treat me"). responses are on 5-point likert scales ranging from 1 (never) to 5 (always). to further assess collaboration between the two parents with regard to childrearing, we included 16 additional items from a preliminary co-parenting scale (α = .85) currently undergoing validation (e.g., "we make a good team as parents"). clinical norms for cerfb scales are not yet available but, as with the spanish das, descriptive statistics from validation studies provide tentative benchmarks for evaluating levels of parental and conjugal functioning in the lockdown sample (campreciós, 2015; ibáñez et al., 2012; roca et al., 2020; vilaregut et al., 2019) . interpretation may be complicated, however, because identifying linares' patterns of functional and dysfunctional parenting requires taking both dimensions (and ideally the views of both parents) into account. this article is protected by copyright. all rights reserved given the exploratory nature of the study, we approached the research aims with the basic premise that combining qualitative and quantitative forms of evidence provides a better understanding than either method does by itself (creswell & plano clark, 2011) . indeed, both qualitative and quantitative data figure prominently in the resultsand despite homage to validated quantitative measurement methods (above), our most direct evidence of actual lockdown "effects" on couple and family functioning came from participants' qualitative (written) descriptions of what had changed. in the spirit of mixed-method research, we then used dichotomous variables representing the presence or absence of specific qualitative themes in participants' responses to explore quantitative associations with other study variables. after dropping 23 written responses reporting no couple/family change (e.g., "everything continues as usual") and 53 blank responses, we used braun & clarke's (2006) method of thematic analysis, assisted by atlas.ti software for mac (v. 8), to code 329 descriptions of change. the total qualitative data set consisted of 13,226 words, with individual responses ranging from 2 words (e.g., "closer now") to 353 words. the thematic analysis involved identifying interesting data features, or codes; clustering codes and searching for potential themes; and finally, naming and defining the themes. to facilitate accuracy and trustworthiness, two authors served as co-coders in an ongoing consensual review process, and the full team reviewed emerging results to reach on the final thematic configuration. on the quantitative side (using spss statistics, v. 20), preliminary analyses justified creating two composite variables that would simplify later examination of psychological distress and couple relationship functioning: composite distress was a z-score combination of stai state, stai trait, and bdi scores, which intercorrelated highly with all r s > .66. similarly, the composite measure of couple functioning combined z-transformations of das total scores and cerfb conjugal function scores, which were not available for the same participants here but had correlated highly in previous research. as dependent variables, the two composites helped clarify multivariate and moderated influences on central study constructs. we approached the main study aims by first examining descriptive statistics for psychological distress (stai, bdi) and relationship functioning (das, cerfb) in the lockdown sample with an eye toward areas of possible discrepancy and/or alignment with benchmarks for the broader population. in light of sampling limitations both here and in the standardization studies, however, such comparisons can only be approximate, with conclusions about lockdown this article is protected by copyright. all rights reserved effects necessarily tentative. next, having defined qualitative change themes (as described above) and coded their presence/absence across participant responses, simple tabulations and cross-tabulations illuminated the prevalence of various improvement and deterioration themes in the full sample and across the four main participant groupings: partnered parents with children at home, partners in couples with no children, parents with all children away from home, and divorced parents. finally, we employed a variety of univariate, multivariate, and moderation analyses to identify demographic, household, and employment-related correlates of pandemic relationship functioning and psychological distress, again with attention to variations across household/parental subgroups. in addition to cerfb scores, das scores, and the two composites, these correlational explorations included the qualitative change themes and a rough approximation of the linares cerfb parenting styles (functionality, triangulation, etc.). also of interest were possible changes in relationship functioning over time as the lockdown progressed, including system-symptom links between relationship quality and individual distress. 13.4% of lockdown participants but only 4.6% were in the moderate or severe range. when asked about their perception of economic risk, just over half of the respondents were at least moderately concerned with economic risk during the pandemic (53.5%) but less than a quarter were very concerned (15.7%) or extremely concerned (6.6%). in general, the lockdown experience appeared to generate moderate to high levels of situational anxiety and uncertainty but not much chronic distress among the adults who completed the on-line survey. this article is protected by copyright. all rights reserved cerfb norms provide no firm basis for locating parenting styles in the linares' quadrants, a rough comparison of lockdown means with standardization data suggests that at least half of the reports in our sample would be most consistent with the triangulation style, where parents tend to maintain harmony by involving children in their conflicts. such classification is approximate at best, however, especially without reports from both parents or confirmation from a child. to summarize, with no children in the household, the quality of couple relationships during the covid-19 lockdown appeared no worse and possibly better than would have been the case without lockdown. with children present, however, our data raise the possibility that preservation of family harmony may have sometimes occurred at the expense of relational nurturing. two overarching thematic categoriesperceived improvement and perceived deteriorationemerged from our qualitative analysis of participants' free-form descriptions of how family and couple dynamics had changed during the lockdown. table 2 shows the prevalence of these themes in the subsample of 329 respondents who indicated that some degree of lockdown-related family change had occurred. (note that a given response could include more than one theme; in fact, 24 cited both improvement and deterioration.) interestingly, the overall prevalence of improvement themes (61.7%) exceeded the prevalence of deterioration themes (41.0%), with increased connection/cohesion (44.7%) and conflict (21.9%) cited most often. relative to the das and cerfb data above, this appears more consistent with the dyadic adjustment of couples having no children at home than with the cerfb parenting picture. table 2 also indicates (via chi-square comparisons) that some themes distributed less evenly than others across subgroups defined by household composition and parental status. for example, the theme of family (re)connection was more prevalent for parents with no children and those with children at home than for parents who were divorced or had children not at home. the most striking differences, however, involved deterioration themes such as couple/family distance (most common with children away and negligible with children at home), conflict atmosphere (less frequent with emancipated children) and unbalanced needs (most likely with children with children at home). overall, participants tended to use more words when describing deterioration themes than improvement themes, with unbalanced needs (r = .24, p < .01), negative expectations (r = .21, p < .001), and conflict atmosphere (r =.14, p = .01) entailing the thickest descriptions. on the improvement side, longer responses were associated with balanced needs (r = .26, p < .001) and teamwork spirit (r = .16, p = .003). as noted above, we created two composite dependent variables representing psychological distress and couple functioning to facilitate identifying correlates of individual and relational wellbeing during lockdown. the distress composite is available for the full sample while the latter includes all participants except 19 who had divorced. the couple composite is useful because the survey entailed different (though highly correlated) measures of couple functioning depending on whether or not the respondent had a child at home. thus, although it was not possible to compare these subgroups directly, the z-score composite permits examining differential (moderated) prediction of conjugal functioning. this article is protected by copyright. all rights reserved table 3 provides an overview of predictor variables associated with various measures of individual, couple, and parental functioning. point bi-serial correlations in the first few rows, where dichotomous dummy variables represent household/parental subgroups, reveal few group differences in composite individual or couple functioning apart from the small group of divorced parents and parents with a preschool-age child reporting more psychological distress. a strikingly different picture of couple functioning emerges in relation to pandemicrelated employment, where stronger associations appear when respondents have children at home (cerfb conjugal function) compared to when they do not (das total score). of particular interest is how couple adjustment relates to telecommuting and (un)employment. general linear model (glm) moderation analyses examining these association across three groups of couples (no children, child at home, empty nest) found significant group x telecommute (f = 5.23, p = .006) and group x employed (f = 4.44, p = .012) interaction terms, with group means suggesting that telecommuting and employment were positively related to couple functioning when respondents were parents (regardless of whether children were at home or emancipated) but in the opposite direction when they were not. table 3 also highlights correlates of individual distress and relationship functioning that did not vary appreciably (interact) with household/parental status: psychological distress was generally higher among women, recipients of psychological treatment, unemployed respondents, those in business professions or perceiving economic risk, and those with a health problem at homebut lower among health professionals. among the cerfb family relationship measures, parental functioning showed significant correlations with some of the same predictors and was positively related to education; and if anything, marital and co-parental functioning was better among younger couples. the last two rows in the top panel of table 3 show potentially important associations involving lockdown duration, couple functioning, and psychological distress. first, marital functioning for couples with children at home systematically improved with days in lockdown, which was not the case for parenting functions, psychological distress, or for couples without children at home. this cross-sectional temporal trend remained after statistically controlling for parallel changes over days in other demographics such as urban location, employment status, or having a preschool child at home. note also that effective marital functioning with a child at home correlated positively with telecommuting and having a job but not with psychological this article is protected by copyright. all rights reserved distress. in this way, couple functioning in the context of active parenting during lockdown was unique among the relationship measures. the strong associations between relationship quality and individual distress in table 3 are consistent with a large couple and family relations literature, but we do not know if they are in any way unique to quarantine. an indirect way to approach this is to ask whether the linkage between relationship quality and individual functioning systematically changed over the course of quarantine, as would be indicated by statistical interactions involving lockdown days. glm analyses along these lines, with psychological distress as the dependent variable, did in fact show suggestive relationship-quality x lockdown-duration interaction terms for das total dyadic adjustment (f = 5.37, p = .022) and cerfb co-parenting (f = 4.50, p = .035) in the direction of system-symptom linkages strengthening as the lockdown progressed. the lockdown study period was relatively short, however, so this intriguing evidence is tentative at best. finally, because the cerfb results in table 3 do not speak directly to the linares model of relational nurturing that guided development of the instrument, we were interested in how parenting styles representing functionality, triangulation, deprivation and chaotization might have operated during the lockdown. this seemed important because the apparent parentalconjugal discrepancy in our sample suggests that some degree of triangulation may have been in play. although the cerfb standardization data offers no cut points for defining linares quadrants with any precision, we attempted to approximate the quadrants in a relative manner by splitting the conjugal and parental distributions at their medians. interestingly, participants in the high-parenting/low-conjugal (triangulation) quadrant reported less distress and fewer deterioration themes than other participants (supplementary table s1 , online). triangulation represented in this manner was also more common among university graduates and health professionals. because the most direct evidence of lockdown effects on family relationships comes from participants' free-form reports of improvement and deterioration, we were interested in which qualitative themes were most and least likely to come from which participants. the bottom panel of table 3 shows strong associations between perceptions of relational improvement/deterioration and some but not all of the standardized individual, couple, and parental functioning measures. in particular, the qualitative reports aligned most solidly with this article is protected by copyright. all rights reserved psychological distress and with the dyadic adjustment of partners with no children in the household. with children at home there were no significant correlations for cerfb conjugal functioning and only marginal ones for parenting and co-parenting. of the specific qualitative themes, family (re)connection dominated criterion connections on the improvement side while conflict and distance did so on the deterioration side. table s2 , online) indicate that respondents reporting improvement were more often employed and had no emancipated children or preschoolers at home. deterioration themes, on the other hand, were associated with receiving psychological treatment, the presence of preschoolers, and coping with health problems in the household. as for markers of specific qualitative theme categories, improvements in (re)connection were more prevalent among health professionals and respondents with no preschoolers; education and employment predicted improved communication; expressiveness themes correlated with telecommuting and low perceived economic risk; city dwellers were high on teamwork; younger participants described more conflict and fewer distance themes; females reported more conflict; health professionals described fewer negative expectations; an empty nest predicted more distance and less conflict; health problems in the household portended distance themes; and having children at home meant less distance and more unbalanced family member needs as noted above. this mixed-method exploration of the recent covid-19 lockdown in spain adds depth and complexity to the quarantine literature by highlighting repercussions for relationships as well as individuals in the direction of improved as well as compromised functioning. although survey respondents experienced moderate to high levels of situational anxiety during the first three weeks of state-regulated lockdown, they also reported high dyadic (couple) adjustment relative to a norm group and cited more instances in which their couple and family dynamics had improved rather than deteriorated. this contrasts with previous studies that have emphasized predominantly negative psychological effects of mass quarantine on individuals (brooks et al., 2020) , and occasionally also on couple and family relations. the results also suggest that quarantine ramifications for couples and families are more complex than those for individual children and adults. one aspect of this complexity is that positive as well as negative forms of change appear more likely at the level of close relationships this article is protected by copyright. all rights reserved (with opportunities for collective coping, interpersonal need satisfaction, etc.) than at the level of individual adjustment. positive individual change (e.g., post-traumatic growth) is certainly possible, of course, but the quarantine literature has not emphasized this. another indication of greater complexity is that measures of couple and parental functioning varied with household composition and parental status in ways that measures of individual wellbeing (psychological distress) did not. for example, conjugal relations during lockdown appeared more harmonious when there were no children in the household, and moderation analyses indicated that covidrelated employment variables (e.g., telecommuting) predicted successful couple functioning in different ways depending on parental status. in general, the relationship implications of lockdown were clearer for participants with no children at home than for those actively engaged in parenting. for the former, dyadic adjustment scores were higher than those from a benchmark comparison group and correlated highly with both the absence of psychological distress and the presence of improvement themes in participants' descriptions of how relationship dynamics had changed. for active parents, on the other hand, benchmark cerfb comparisons were more ambiguous, with parenting quality tending to exceed conjugal quality, and qualitative improvement/deterioration themes did not map so clearly onto relationship functioning. although tentative, the apparent prevalence in our sample of a parenting style linares (2002) associates with triangulation raises the possibility of a subtle downside to family relations during lockdown. if greater appreciation of parent-child than parent-parent (conjugal) bonds does in fact invite triangulation of children into adult conflicts, this could undermine child development in ways that would not be apparent without direct assessment of child functioning. the fact that provisional triangulation correlated with less psychological distress and fewer family conflict themes seems also to underscore the subtlety of this ultimately dysfunctional pattern. as noted earlier, however, the cerfb norms as yet provide no firm basis for identifying linares parenting styles, so without converging reliability and validity evidence we must offer this interpretation cautiously. if nothing else, the possibility of increased risk for triangulation during lockdown provides a hypothesis for future research. what might it mean that participants without children at home more often reported increased couple cohesion during lockdown? from an interpersonal-systems perspective, the relative absence of third-party involvements with children, relatives, friends, or colleagues, this article is protected by copyright. all rights reserved coupled with sustained proximity and more time for shared conjugal activities, provides a plausible explanation. a more psychological explanation, from the author of a recent survey of u.s. couples conducted around the same time as ours, is that people simply want more closeness in their important relationships and turn to partners for support under covid-19 stressso in effect they are getting what they want (g. lewandowski, as cited in bonos, 2020) . the current data are cross-sectional and can only indirectly address any changes that may have occurred over time during the relatively brief (two-week) study period. such change was of interest because at least one prior study found increased symptoms of psychological distress among individuals quarantined at least 10 days (hawryluck et al., 2004) . this was not the case in the present study, where stai, bdi and composite measures of individual distress did not changeyet the cerfb measure of conjugal functioning actually showed an opposite trend of improvement over lockdown days. in other words, participants challenged by managing children at home, whose conjugal relations were probably not as good on average as those of other participants, nonetheless tended to report more couple-level resilience in the third week of lockdown than in the second. our rough indicator of triangulation decreased over days as well, implying the possibility of positive spillover for children. intriguingly, moderation results also suggest that the correlation or linkage between individual distress and couple relationship functioning may have strengthened as the lockdown progressed. the direction of influence in this would be ambiguous, however. in addition to supplementing quantitative analyses, the qualitative themes add texture and detail to how participants experienced relational improvement and deterioration during lockdown. on the deterioration side, some of the themes echo aspects of previously identified stressors linked to quarantine at the individual level. for example, experiencing loneliness and couple/family distance connects to boredom and isolation (cava et al., 2005; digiovanni et al., 2004) ; and negative expectations incorporates fear of the disease (bai et al., 2004; desclaux et al., 2017) , economic uncertainty (jeong et al., 2016; mihashi et al., 2009) , and information overload (blendon et al., 2004) . although a few participants cited instances of both improvement and deterioration, most followed one of the two paths in ways that sometimes resonated with our clinical experiences during the first few months of the pandemic. as if to illustrate the improvement pathway, a stayat-home mother who had come to therapy distressed by a disobedient, disrespectful and this article is protected by copyright. all rights reserved occasionally violent child reported that she, her husband, and the difficult son had been having "so much fun together" (for a change) since the lockdown began, adding that "while we were playing, several picture frames fell of the wall and broke without even bothering me!" more often, however, we encountered deterioration themes in the form of a lockdown family crisis. here a useful strategy has been to contextualize the current problem situation by exploring how family members had (successfully) handled similar situations or had more satisfying relations before the lockdown began. the qualitative improvement themes suggest possible areas to explore. our study has many limitations, with sample representativeness foremost among them. the self-selected sample of convenience was predominantly female, well educated, employed, interested in the topic at hand (family relationships), and probably more functional and economically advantaged than the adult spanish population at large. it is entirely possible that different results (e.g., more evidence of individual distress or relational deterioration) would obtain in other sectors of the population or in other countries or cultures. another limitation is that time-limited, cross-sectional survey data shed little light on enduring effects of quarantine, on how adaptations to lockdown changed or evolved over time, or on what happened during reopening, when home-confinement restrictions began to ease. we plan to address these and other questions through follow-up interviews with study participants. finally, it is difficult to obtain reliable and valid representations of family functioning from the self-reports of only one family member, and shared method variance (e.g., positive or negative response set) could account for some of the quantitative association between individual and couple/family variables. despite these limitations, our exploratory study of the recent state-regulated covid-19 lockdown in spain helps to break new ground by looking beyond the individual to understand psychosocial impacts of quarantine experiences. the ramifications of these experiences for couples and families are clearly important and probably more complex than for individuals. notes. table entries are pearson or point-biserial correlation coefficients reflecting associations between predictor variables and measures of individual, couple and parental functioning. left-most column includes prevalence proportions for dichotomous predictors and qualitative themes. a z-score composite of stai state and trait anxiety measures and bdi depression available for all participants. b z-score composite of total dyadic adjustment (das) and cerfb marital functioning scores, excluding divorced parents. c dyadic adjustment scale (das) total score. d family relations (cerfb) scores for parents with at least on child at home. two-tailed significance levels: *** p < .001, ** p < .01, * p < .05, † p < .10. survey of stress reactions among health care workers involved with the sars outbreak bdi-ii. beck depression inventory-second edition. manual the public's response to severe acute respiratory syndrome in toronto and the united states real decreto 463/2020, de 14 de marzo, por el que se declara el estado de alarma para la gestión de la situación de crisis sanitaria ocasionada por el covid-19 our relationships are relationships are actually doing well during the pandemic, study finds using thematic analysis in psychology the psychological impact of quarantine and how to reduce it: rapid review of the evidence cuestionario de ansiedad estado-rasgo validación y aplicabilidad clínica del cuestionario de evaluación de las relaciones familiares básicas (cerfb) en los trastornos de la conducta alimentaria (doctoral dissertation) family functioning and its predictors among disasterbereaved individuals in china: eighteen months after thewenchuan earthquake. plos one, e60738 the experience of quarantine for individuals affected by sars in toronto resilience in midwestern families: selected findings from the first decade of a prospective, longitudinal study designing and conducting mixed methods research prospective relations between family conflict and adolescent maladjustment: security in the family system as a mediating process accepted monitoring or endured quarantine? ebola contacts' perceptions in senegal factors influencing compliance with quarantine in toronto during the 2003 sars outbreak the great recession and mental health in the united states a third of americans now show signs of clinical anxiety or depression, census bureau finds amid coronavirus pandemic. the washington post chinese city experiencing a divorce peak as a repercussion of covid-19. global times sars control and psychological effects of quarantine accepted article this article is protected by copyright. all rights reserved family stress: integrating theory and measurement validación del cuestionario de evaluación de las relaciones familiares básicas (doctoral dissertation) propiedades psicométricas del cuestionario de evaluación de las relaciones familiares básicas (cerfb) mental health status of people isolated due to middle east respiratory syndrome asian americans' family cohesion and suicide ideation: moderating and mediating effects identidad y narrativa. la terapia familiar en la práctica clínica del abuso y otros desmanes. el maltrato familiar, entre la terapia y el control terapia familiar ultramoderna. la inteligencia terapéutica health impacts of the great recession: a critical review the relevance of psychosocial variables and working conditions in predicting nurses' coping strategies during the sars crisis: an online questionnaire survey family functioning in the aftermath of a natural disaster accepted article this article is protected by copyright. all rights reserved predictive factors of psychological disorder development during recovery following sars outbreak propuesta de resolución provisional del procedimiento de concesión de ayudas a proyectos de i+d+i construcción del cuestionario de evaluación de relaciones familiares básicas y coparentalidad (cerfb-cop). poster session presented at xix jornades anpir understanding family resilience social consequences of ebola containment measures in liberia a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations risky families: family social environments and the mental and physical health of offspring the authors appreciate the assistance of dr. michael rohrbaugh in preparing the manuscript for publication. key: cord-297241-ajy2wi51 authors: katz, carmit; noa, cohen title: invisible children and non-essential workers: child protection during covid-19 in israel according to policy documents and media coverage date: 2020-10-06 journal: child abuse negl doi: 10.1016/j.chiabu.2020.104770 sha: doc_id: 297241 cord_uid: ajy2wi51 background: the protection of children from maltreatment has become extremely challenging during the covid-19 pandemic. the public's gaze is focused on the urgent health crisis, while many children are at risk due to social isolation and reduced social services. objective: examine child protection in israel during covid-19, as portrayed in mainstream news media and government policy documents. participants and setting: the study analyzed all policy documents and mainstream media reports published in israel from march to may 2020, during the initial mandatory nationwide quarantine. methods: (1) search of relevant articles in mainstream news websites; (2) search of documents in official websites of relevant government ministries and agencies. results: 28 government policy documents and 22 media articles were found relevant. when examined chronologically, what stood out was the initial decision to shut down social services, including some of the residential care units for youth at risk, and declare social workers “non-essential”. these decisions were revoked a few weeks into the quarantine, following persistent media pressure by child advocates, resulting in minor changes in policy. conclusion: children were initially invisible to israeli policymakers facing the pandemic, highlighting the centrality of advocates promoting children's rights and of mainstream news media in disseminating the discourse of protecting children from maltreatment, especially in times of crisis. moreover, the study points to the heightened threat to at-risk children due to inadequate policies, and to the urgent need to develop child protection policies in order to avoid further risk in future global crises. over the past few months, the covid-19 disease has dramatically affected many aspects of life. since march 11, when the world health organization (2020) declared it worldwide pandemic, it has been clear to policymakers around the world that many concerns will arise following this outbreak. the united nations framework for the immediate socio-economic response to covid 19 (united nations, 2020) highlights that the pandemic is not only a health crisis, but is also greatly affecting economies and societies. in addition, scholars worldwide argue that children are particularly at risk of maltreatment due to increased rates of poverty, food insecurity, unemployment, and inequalities (fore, 2020; van der berg, & spaull, 2020) . it has also been suggested that child maltreatment (cm) would increase as children are isolated from adults who provide care and support and from those responsible for reporting maltreatment (humphreys et al., 2020) . in israel, the wide impact of covid-19 is due mainly to social distancing regulations, which included a nationwide mandatory quarantine in march to may 2020. social services, including residential care for youth at risk, were initially forced to reduce their workforce, with many social workers declared "non-essential" and forced to go on leave without pay. the consequences of this initial policy decision on the response capabilities of the local child protective service (cps) are still unknown. the current study examines this question by j o u r n a l p r e -p r o o f in a recent analysis of the israeli cps policy (weiss-dagan & cnaan, 2020) , the researchers developed a framework for addressing changes in israel policy through the years, and concluded that protecting children in israel was almost solely the responsibility of social workers. the current study examines the protection of israeli children from maltreatment during . through an analysis of official government policy documents as well as media coverage, the current study seeks to answer the following questions: (1) what were the government's policies with respect to protecting children from maltreatment during covid-19? (2) what was the mainstream news media's stance in relation to these policies and to cm in general? (3) what key lessons can be learned from the challenges that face the protection of children from cm during covid-19? the sample included two data sources: policy documents of the israeli government and mainstream israeli news media coverage of cm-related issues, published between march and may 2020. this period was chosen as it included the initial responses to covid-19, mainly nationwide mandatory quarantine. mainstream media coverage was relevant as major news websites are familiar to most if not all israelis (katz et al., 2019) . note that there are additional news websites relevant to various subgroups in israel, such as those serving the ultra-orthodox jewish community, but they were assessed in the current study due to language barriers. policy documents were identified in two ways. first, we reviewed all policy and legislative documents published in the various government websites during the general j o u r n a l p r e -p r o o f quarantine. second, we conducted a google search to ensure no relevant document was excluded, using the following keywords: child maltreatment, abuse, physical abuse, sexual abuse, emotional abuse, neglect, children, children at risk, youth at risk, domestic violence. thematic analysis was carried out on all the documents in several interrelated stages (braun & clarke, 2006) . first, preliminary ideas were identified: the authors read the documents and broke each down into textual segments representing distinct units of meaning, later grouped into initial themes. in the second stage, some codes and categories were removed or revised, and others added. a research assistant used the codes identified at this stage to analyze the remaining data in consultation with the authors. next, the authors reviewed themes and subthemes, classified and reclassified them as required (strauss & corbin, 1998) . in the fourth stage, the authors refined and named the final themes and suggested interrelationships (braun & clarke, 2006) . the authors also referred back to the transcripts to retrieve any information needed to further develop the categories (maykut & morehouse, 1994) . marginalized children in heightened risk. the discussion of each of these themes addressed a timeline that was identified within the analysis of the texts, including the initial government response to covid-19 and its impact on cps; the media's role in raising awareness to cm and its pressure on policymakers; and policy revisions by the government. israel initially responded to covid-19 by a nationwide quarantine that included shutting down the cps immediately and forcing social workers to go on unpaid leave, including other employees officially designated as "non-essential". some cps workers were maintained as emergency workers in the welfare departments of several municipalities and were instructed to provide material support for families and the elderly in need. this policy characterized the period between march 3 and april 8, 2020. policy updates were published periodically through the circulars of molsa director general (hereafter, executive circulars) until the end of the shutdown in may. policy documents published during this time by molsa completely neglected to address the issue of cm, instead focusing on work regulations in services that were to remain open and instructions for reducing the risk of covid-19 contamination (see molsa 2020bk; presented in chronological order). as a result, israeli residential care was partially shut down, with hundreds of at-risk children forced to return to their abusive homes, while those with no homes to return to remained in residential care (note that there are no reliable data on how many children were affected by this policy). during this time, a document published by the knesset outlined the risks of domestic violence during covid-19 and various plans to address j o u r n a l p r e -p r o o f them (almagor lotan, 2020). however, no emergency protocol was created for protecting children. parallel to the neglect of children in published policy documents, child protection advocates led a media campaign targeting the public and policymakers, which highlighted the need to provide children and families at risk with services. this campaign intensified upon the murder of six israeli women by their husbands during the quarantine, which drew attention to the potential risks to children (levi & katz, 2020) . many identified media items addressed specific struggles of at-risk youth (n=10; bagno, 2020; ilan, 2020). in general, the rise in cm risks was at least partially attributed to the government's neglect of cm and at-risk youth during covid-19. these were discussed with respect to the shutdown of educational institutions; as one article stated, "children who were not at risk might now become at risk" (kabir, 2020) due to the pressure in the household reaching a "boiling point" (surkes, 2020) . additional criticism in the media focused on the government's neglect of cm in official policies, manifested in the lack of resources directed towards mental health services (yitschaki, 2020) , and the aforementioned initial categorization of social workers as "non-essential" (rotlevy, 2020; surkes, 2020) . this was related to welfare services' diminished ability to accommodate domestic violence victims due to lack of shelter capacity (yaron, 2020b) and services being forced to operate through remote interventions with no resources allocated to facilitate this urgent adaptation (kol-hair, 2020a). the struggles of youth at-risk in residential care were covered in four newspaper articles, one of which reported that approximately 7,000 children aged 6-18 did not lose just their school, but their home (gamliel, 2020). due to the initial total shutdown of residential care, many youth at risk were forced to return to an unsafe home, which was "more dangerous than covid-19" (kol-hair, 2020a). social workers interviewed talked about these children's j o u r n a l p r e -p r o o f struggles, including hunger, substance abuse and lapses in their mental health (yaron, 2020a) . others, with no home to return to, spent the entire quarantine period in residential care (gamliel, 2020) . as stated in one article, the government was "preoccupied" with reducing the spread of covid-19, but "nobody is talking about the children's struggles" (rotlevy, 2020) . minister's office, 2020c; serphos et al., 2020a,b) . this initiative focused on policies regarding children and youth at risk and outlined proposals for reforming the cps and moving from a reactive to a proactive approach (prime minister's office, 2020b). the team's work and recommendations throughout the quarantine were summarized in a document published on june 1 (prime minister's office, 2020). crucially, this was to remain a dead letter, without being translated into any official policy document or disseminating the recommendations. a major change in the published policy documents was the shift from focusing on logistics and reducing contamination to the welfare of families and youth. first, social workers were declared "essential workers" and returned to work after several weeks of unpaid leave. on may 2, prevention of domestic violence was declared a top priority (molsa, 2020b) and on may 10, instructions were released as to ways social workers should contact and support j o u r n a l p r e -p r o o f families (weisberg nakash et al., 2020) . additionally, residential care facilities for youth at risk were reopened (prime minister's office, 2020b). the analysis of the policy documents throughout the identified timeline reveals that even when policies were adapted to the harmful consequences of covid-19, the focus was on families, not children, illustrating a regression in terms of protecting children's rights. several importantly, although at this third stage, following the media coverage, adaptations to the policy instructions were made, there was still significant imbalance in the policy documents, with most of those focusing on domestic violence and supporting families in the community discussing mainly support for parents. considerably fewer documents were dedicated to the protection of children from maltreatment and no policies from other relevant ministries such as health and education addressed this issue. through all identified policy documents and the entire identified timeline, policy documents did not address the protection of children from marginalized groups, which can potentially result in intensified risk. one particularly disadvantaged group in israel is preschoolers. some of the news websites (e.g. katz, april 2020) stressed that preschoolers had always been one of the most overlooked groups of children during routine times, a situation that intensified during the covid-19 pandemic. in israel, preschoolers from the age of 3 months to 3 years of age do not have standardized, subsidized childcare arrangements. parents must find their own childcare, which means that it is sometimes expensive and unsafe. from the age of 3 to 6 children are supposed to be cared for in kindergartens, but these are not monitored or supervised by the ministry of education. this means that during the covid-19 pandemic, infants and toddlers continued to be "undocumented" residents in israel. another group of children completely neglected by policy documents and received little attention in the media (katz, april 2020) was children with developmental disabilities. in israel, during the covid-19 pandemic there was no standardized support for children with developmental disabilities and their families. additionally, their routine support was taken j o u r n a l p r e -p r o o f away from them, often leading to regression in these children's conditions, resulting in intensive stress for their parents and families. in addition to preschoolers and children with developmental disabilities, the situation of several other disadvantaged groups worsened during covid-19. palestinian-arabs in israel are routinely disadvantaged and excluded, including in terms of cps resources. this situation was exacerbated during covid-19 with more racism and fewer resources targeted towards them. finally, ultra-orthodox jews experienced considerable hate and racism, including blaming them for spreading the virus (surkes, 2020) . the media (e.g. katz, april 2020) suggested that this group's social isolation and internal competition for limited resources contributed to community alienation. the aim of the current study was to examine how the protection of children from maltreatment was officially handled in israel during the covid-19 mandatory quarantine. our analysis of both policy documents and media coverage paints a worrisome picture. policymakers' automatic response to covid-19 neglected to address child maltreatment (cm). they overlooked the crucial role of the cps and declared social workers to be "non-essential", which reveals a blind spot regarding the needs of children, especially those who are already at risk. consequently, during the first few weeks of quarantine in israel, the protection of children was not addressed in policies despite elevated risks for children and youth. mainstream news media coverage appears to have been critical of the government's handling of cm during the covid-19 crisis. various websites have repeatedly stated the risks for cm and the alarming rate of abuse reports. at the same time, a special roundtable committee operating from the prime minister's office has both monitored and criticized the initial policies and advocated for children's rights. these actions by child advocates might explain the mild j o u r n a l p r e -p r o o f growth in the awareness of policymakers to cm and the importance of the cps detected a few weeks into the quarantine. however, children have never become a top priority, and most of the policymakers' attention and resources remained devoted to supporting families, while neglecting direct coping with cm and abandoning the discourse of children's rights. the findings from the current study can be discussed through a recent framework offered for understanding the evolution of cps-related policies (weiss-dagan & cnaan, 2020). the first aspect of the framework is a socialist/collectivist-capitalist/individualistic continuum, which presents the country's commitment to welfare. although focusing on cm, the analysis presented in the current study illustrates more generally that the israeli government is far from socialist. in their initial response to covid-19, policymakers did not take the welfare of the israeli population into consideration, particularly not that of the children. this is surprising given the response of other countries considered highly individualist and capitalist. for example, the us cpss were not shut down and were provided with greater resources, thus acknowledging the challenges that covid-19 posed to welfare (guerrero et al., 2020) . the second aspect of the framework is transitionfrom denial of cm to recognition of its existence. based on the current study's findings, it is clear that the phenomenon of cm was initially ignored by policymakers. during march, the policies published by molsa and the ministry of health focused on logistics and guidelines to reduce the spread of covid-19. in april and may, updates were released, instructing social services on ways to work with families. updated policies published in may recognized prevention of domestic violence as a top priority (molsa, 2020b). the emphasis was, however, on working with families, and cm was not mentioned explicitly (weisberg et al., 2020) . it seems that during covid-19, all the progress presumably achieved in israel with respect to cm was brought to a complete halt, and that in fact, a regression occurred. in direct contradiction to the foregoing critical assessment of the government's response to the crisis as arising from the policy documents, the current study results points to the central role played by media coverage during this time. the media have a central role in promoting discussions among the public and policymakers regarding issues relating to public health. the media are the main channel for the language, communication, and contexts of the social structures of modern society (mccartan, 2015) . given that cm, like all social concepts, is only partially understood by society, media representations have the potential to influence policymakers and the public with regard to this social issue (weatherred, 2015) . a recent study on media coverage and public perceptions of cm in israel painted a worrisome picture in which most of the coverage was episodic, addressing individual incidents rather then addressing cm in its social framework (katz et al., 2019) . not only that but the discussion in both the news items themselves and in the public comments to them tended to put the blame and responsibility for the abuse on the victims and their families for not educating them better. conversely, the current findings illustrate how the active involvement of child advocates can make a difference, through the government and media coverage, as most of the media coverage during the crisis stressed the responsibility of the government and policymakers for protecting children from maltreatment. this shift is extremely important and needs to be maintained and further encouraged in future efforts to advance cm policies in israel. the third aspect refers to the professionalization of care. this includes the training and appointment of professional practitioners to serve populations in need. a disturbing picture arises from the current findings regarding the policymakers' lack of recognition of society's need for professional welfare services during covid-19. policymakers ignored the need for frontline practitioners, mainly cps social workers, to protect children from maltreatment. no financial support was given and while guidelines were disseminated to social services on j o u r n a l p r e -p r o o f reducing covid-19 contamination, they failed to promote child protection. moreover, the current results stress the fact that the social work profession in israel exclusively charged with protecting children, with no identified policies by other professionals (from the health and education ministries, for example) referring to the protection of children from maltreatment during covid-19. this imbalance in responsibility is a source for concern and must to be a focus for change. the fourth aspect in the framework is the transition from out-of-home placement to community solutions. indeed, when solutions were provided in the third stage of the timeline, they mainly targeted community-based services with no relocation of resources and support to professionals or to children and youth in out-of-home placements. the impact of this neglect of children and youth in residential care needs to be further explored, and it is also necessary to examine thoroughly the impact of the short-notice closure of some residential care facilities on both the children and their family. the fifth aspect is the transition from punishing to protecting and providing rights. our findings clearly show that during the initial covid-19 outbreak, children overall and at-risk children more particularly were invisible to israeli policymakers, and that even after a media campaign children were still not a top priority. this attests to an extremely worrisome lack of a children's rights discourse in israel. although israel ratified the united nations convention on the rights of the child (unicef, 1989) in 1991, several documents attest to its lack of implementation, including its failure to create a government-appointed commission on children's rights or to adopt a national children's rights strategy or program in order to implement various israeli laws addressing children's rights (katz & kosher, 2020) . this general disregard of children's right to live and to be protected, and as made painfully apparent during the pandemic, is cause for concern, suggesting the urgent need to advance the visibility of children's rights in the israeli policy. the assumption that was the starting point of the current study was that the issues that had characterized the israeli cps in routine would become intensified during covid-19. indeed, our findings clearly showed that cm was neglected and overlooked by policymakers and that even after the media campaign the resources were directed towards supporting families with no clear focus on child protection, maltreatment prevention, and children's rights. adding to this worrisome picture, certain groups of children that deserve even greater support in times of pandemic were not addressed at all in the identified policies, such as preschoolers, children with developmental disabilities, and children from closed or extremely peripheral communities in israel, such as asylum seekers. more generally, the impact of the quarantine and competition over limited resources generated a context of not only social isolation but more specifically, social alienation in israeli society (levi & katz, 2020) . this social context could have a severely adverse impact on all citizens, but mainly those from disadvantaged groups. one such group, palestinian-arabs, is routinely disadvantaged and excluded, including from cps resources. this situation was intensified during covid-19 with more racism and fewer resources targeted towards them. another disadvantaged group, ultra-orthodox jews, was the target of hatred and racism during the crisis, with many blaming them for spreading the virus. the impact of racism has adverse effects on all involved: children and their families from such traditional groups might become more isolated and suspicious of others, which might affect their tendency to seek help and disclose cm. finally, research indicates rampant racism in israeli society against non-jewish immigrants (birger et al., 2020; tsfati et al., 2020) , which manifests itself in policy documents in the lack of clear policies targeting their children (kagan et al., 2019) . on the ground, they are supported and protected almost exclusively by cash-strapped ngos (tsfati et al., 2020) . the findings of the current study and the conclusions that can be drawn from them should be carefully discussed in light of the study's limitations. the first limitation relates to the fact that the media coverage analyzed was limited to hebrew-language, mainstream news websites. this means that the media coverage directly is relevant to various disadvantaged groups discussed above were not studied. the second limitation of the current study is in its focus on written policy documents. in a retrospective discussion on protecting children from maltreatment during covid-19 (levi & katz, 2020) , the way municipalities initiated and led efforts to provide children and families with support was worth mentioning, as was the way the cps found innovative ways to support children and families remotely. these initiatives were not addressed in formal policy documents or in mainstream media. accordingly, to fully capture the phenomenon of protecting children from maltreatment during covid-19, information should be gathered from other important informants such as practitioners from various disciplines as well as interviews with child advocates. finally, the perceptions of children and parents are of crucial importance in order to better understand the israeli policy and its outcomes during covid-19. to conclude, the results of the current study indicate the potentially harmful impact that lack of policy with respect to protecting children from maltreatment during the pandemic might have. it involves overlooking not only child protection and rights but also their exposure to elevated risks. the disturbing picture portrayed in the current study stresses the urgent need to better establish children's rights in israeli laws and policies, which hopefully would improve their protection during global crises such as the current one, and in normal times as well. on a they are essential workers now, and should continue to be: social workers and home health care workers during covid-19 and beyond increased risk for family violence during the covid-19 pandemic ninety thousand at-risk youth and 50 thousand special education children are left without a care setting children in israel: statistical abstract. author (h) children who were not at risk might now become at risk due to the ministry of education's shutdown. calcalist (h) no policies and no politics: israeli teachers, asylum seeker pupils, and remobilized strategies of avoidance and depoliticization it's final: the gradual return to school will commence next sunday protecting children from maltreatment during covid-19 child maltreatment in the media: analyses of media coverage and reader comments on child maltreatment in israel executive circular: the government's preparation for dealing with the covid-19 crisis: circular 14 executive circular: the government's preparation for dealing with the covid-19 crisis: circular 15 executive circular: the government's preparation for dealing with the covid-19 crisis: circular 16 executive circular: the government's preparation for dealing with the covid-19 crisis: circular 17 executive circular: the government's preparation for dealing with the covid-19 crisis: circular 18 executive circular: the government's preparation for dealing with the covid-19 crisis: circular 17 update when home is more dangerous than covid-19: a rise in domestic violence complaints emergency regulations (legal procedures in rabbinic courts in a unique emergency state) founding of the ministry for community strengthening and promotion and an amendment of the government decision list of participants -team for children and youth at risk the sub-table of the intersectorial table on children and youth at risk during the covid-19 crisis: interim summary, recommendations and takeaways for the future nobody talks about the covid-19 children's crisis a summary of the intersectorial roundtable for children and youth at risk. prime minister's office outline for the continued work of the secondary roundtable on children and youth at risk. prime minister's office covid-19, anxiety, sleep disturbances and suicide basics of qualitative research techniques challenges in the transition to adulthood of young-adult arabs who graduated from residential facilities in israel a rise in violence towards women: bibi and sarah were shocked, a committee was formed, and nothing changed %d7%94%d7%a9%d7%aa%d7%a0%d7%94/ar-bb13yya0?li=bbqrn0z doubling from the heart: giving up the government grant for a good cause ethnocentrism, universalism, and refugees' social rights: the israeli perspective united nations convention on the rights of the child children at increased risk of harm online during global covid-19 pandemic -unicef newly released technical note aims to help governments a un framework for the immediate socio-economic response to covid-19 counting the cost: covid-19 school closures in south africa & its impacts on children berg-spaull-2020-counting-the-cost-covid-19-children-and-schooling-15 child sexual abuse and the media: a literature review instructions for implementing a program for covid-19 understanding the evolution of national child welfare policies: the case of israel the quiet outcry of abused children is not heard. maariv (h) mental health and psychosocial considerations during the covid-19 outbreak voices of distress: the michal sela hackathon initiatives for a sharp rise in domestic violence due to quarantine, and shelters are filling up the invisible graph of mental health. news1 (h) from youth in haifa to the neighbors in bnei brak to the volunteers in kiryat gat: the communities that are not waiting for government assistance. globes (h) number of children in boarding schools and their characteristics: trends in the years key: cord-313258-luiw46zj authors: kim, joon hwan; choi, ji-yeon; kim, na yeon; kim, jin woo; baek, ji hyeon; baek, hye sung; yoon, jung won; jee, hye mi; choi, sun hee; kim, hyeung yoon; kim, ki eun; shin, youn ho; han, man yong title: clinical risk factors associated with the development of wheezing in children less than 2 years of age who required hospitalization for viral lower respiratory tract infections date: 2015-07-22 journal: korean j pediatr doi: 10.3345/kjp.2015.58.7.245 sha: doc_id: 313258 cord_uid: luiw46zj purpose: wheezing following viral lower respiratory tract infections (lrtis) in children <2 years of age is an important risk factor for the development of asthma later in life; however, not all children with viral lrtis develop wheezing. this study investigated risk factors for the development of wheezing during viral lrtis requiring hospitalization. methods: the study included 142 children <2 years of age hospitalized for lrtis with at least one virus identified as the cause and classified them into children diagnosed with lrtis with wheezing (n=70) and those diagnosed with lrtis without wheezing (n=72). results: there were no significant differences in the viruses detected between the two groups. multivariate logistic regression analysis showed that, after adjusting for potentially confounding variables including sex and age, the development of wheezing was strongly associated with parental history of allergic diseases (adjusted odds ratio [aor], 20.19; 95% confidence interval [ci], 3.22-126.48), past history of allergic diseases (aor, 13.95; 95% ci, 1.34-145.06), past history of hospitalization for respiratory illnesses (aor, 21.36; 95% ci, 3.77-120.88), exposure to secondhand smoke at home (aor, 14.45; 95% ci, 4.74-44.07), and total eosinophil count (aor, 1.01; 95% ci, 1.01-1.02). conclusion: past and parental history of allergic diseases, past history of hospitalization for respiratory illnesses, exposure to secondhand smoke at home, and total eosinophil count were closely associated with the development of wheezing in children <2 years of age who required hospitalization for viral lrtis. clinicians should take these factors into consideration when treating, counseling, and monitoring young children admitted for viral lrtis. lower respiratory tract infections (lrtis) are common in early childhood and are mostly caused by respiratory viruses. wheezing caused by viruses is considered an important risk factor for the development of asthma later in life [1] [2] [3] [4] [5] . although the same virus may cause lrtis, only those who develop wheezing during lrtis are more likely to develop asthma 1, 5) . thus, upon infection with a virus, children less than 2 years of age with and without wheezing may differ with regard to the development of recurrent wheezing and/or asthma. children diagnosed with lrtis with wheezing would be more likely to develop recurrent wheezing and/or asthma in late childhood than those with lrtis without wheezing, even though they are infected with the same virus. in this regard, previous studies have reported risk factors for young children who are more likely to have wheezing during or following a viral lrti 6, 7) . however, there are relatively small data focusing on the clinical risk factors related to the development of wheezing in young children with lrtis who require hospitalization. this study was designed to determine clinical risk factors associated with the development of wheezing in infants and young children less than 2 years of age who require hospitali zation for viral lrtis. we conducted a cross-sectional study of all infants and children admitted to the cha bundang medical center from august 2006 through july 2007 with signs and symptoms of lrtis. inclusion criteria were as follows: (1) children less than 2 years of age; and (2) children with a positive nasopharyngeal washing aspirate confirming infection with at least one of the 12 respi ratory viruses. a total of 400 children were admitted with lrtis during the study period. all had signs and symptoms of lrtis: i.e., cough, tachypnea, respiratory distress, and breathing difficulties with grunting or wheezing sounds with rales 8) . after a complete physical examination by an experienced pediatrician, children who developed wheezing on auscultation at admission and/or during hospitalization were defined as the lrtis with wheezing and those who did not develop wheezing were defined as the lrtis without wheezing. infants and young children were excluded if (1) they were infected with mycoplasma pneumoniae, defined as an initial indirect microparticle agglutinin method (serodia-myco ii, fujirebio, japan) (titer of >1:320) or a fourfold rising titer in double-checking samples and positivity for anti-mycoplasma igm 9) , (2) no virus was detected, (3) their parents or guardians did not respond to questionnaires regarding the patient's past and parental history at admission, (4) they were born prematurely (i.e., less than 37 weeks gestational age), or (5) they had a cardiac anomaly. clinical factors recorded at admission included sex; age; the presence of fever; laboratory findings; patient's and parental history of allergic diseases, including asthma 10) , allergic rhinitislike symptoms 11) , and atopic dermatitis 12) ; previous hospitalization for respiratory illnesses; and smoking by any member of the house hold during the previous year, with the latter defined as exposure of the patient to secondhand smoke. at admission, blood samples were obtained from the antecubital vein of each subject and laboratory tests, including complete blood count, absolute neutrophil count, total eosinophil count, c-reactive protein (crp), and erythrocyte sedimentation rate (esr), were performed and recorded for each subject. the study protocol was reviewed and approved by the institutional review board of cha university medical center, seongnam, korea, and written informed consent was obtained from the parents/guardians of each patient. nasopharyngeal aspirates were obtained upon admission by gently flushing the children's nostrils with 4 ml of sterile saline solution. all nasopharyngeal aspirates were tested within 24 hours of collection for respiratory syncytial viruses (a and b), human metapneumovirus, human rhinovirus, influenza a and b viruses, parainfluenza (a, b, and c) virus, coronavirus (a and b), and adenovirus. total viral rna was extracted from nasopharyngeal aspirates (300 μl) using viral gene-spin viral dna/rna extraction kits (intron, seongnam, korea) and stored at -80°c. first-strand cdna was synthesized using revert aid first strand cdna synthesis kits (fermentas inc., burlington, on, canada), followed by polymerase chain reactions using seeplex respiratory viruses detection kits-1 (seegene, seoul, south korea) and the geneamp pcr system 9700 (applied biosystems, waltham, ma, usa). each 20 μl reaction mixture included 3 μl of cdna, 4 μl of 5× rv1a or 5× rv1b primer, and 10 μl of 2× multiplex master mix. briefly, 2.5 μl of extracted rna was mixed with 5× buffer, 0.2mm of each dntp, 0.5μm of each primer [13] [14] [15] [16] , 1 μl of enzyme mix, and depc-treated ultrapure water to a final volume of 25 μl. after incubations at 50°c for 30 minutes and at 94°c for 15 minutes, the reactions were subjected to 40 cycles of denaturation for 30 seconds at 94°c, annealing for 90 seconds at 60°c, and extension for 90 seconds at 72°c, followed by a final extension at 72°c for 10 minutes. the ampli fied products were analyzed on 2% agarose gels containing 0.5 g/ml ethidium bromide. data are expressed as mean±standard deviation unless otherwise indicated. between-group differences were compared using independent student t tests, mann-whitney u tests, or chi-square tests, as appropriate. multivariate logistic regression analysis was used to identify clinical risk factors for the development of wheez ing caused by viruses, with adjusted odds ratios (aors) and 95% confidence intervals (cis) calculated; age and total eosinophil count were used as continuous variables and the other factors were used as categorical variables. all statistical analyses were performed using ibm spss statistics ver. 21.0 (ibm co., korean j pediatr 2015;58 (7):245-250 armonk, ny, usa). all statistical tests were two-sided, with a p value of <0.05 indicating statistical significance. the demographic and clinical characteristics of the study population are shown in table 1 . the study population consisted of 142 children aged <2 years, 70 children with lrtis with wheezing and 72 children with lrtis without wheezing (fig. 1) . the mean ages of the children with the lrtis with and without wheezing were 7.0±5.4 and 8.3±5.9 months, respectively. approximately 70% of the children in each group were male. there were no between-group differences in sex, age, absolute neutro phil count, crp concentration, and esr. the children with the lrtis with wheezing were more likely to have parents with a history of allergic diseases than the children with the lrtis without wheezing ( to secondhand smoke at home (aor, 14.45; 95% ci, 4.74-44.07), and total eosinophil count (aor, 1.01; 95% ci, 1.01-1.02) ( table 3 ). the present study showed that past and parental history of allergic diseases, past history of hospitalization for respiratory illnesses, exposure to secondhand smoke at home, and serum total eosinophil count were independently associated with the development of wheezing in children <2 years of age who had viral lower respiratory infections requiring hospitalization. our findings are in good agreement with those of previous studies, which reported that the development of childhood wheezing is closely associated with parental history of allergic disease 17) and a personal history of allergic diseases 18) . a recent study from the paris (pollution and asthma risk: an infant study) birth cohort focusing on the determinants of wheezing severity in infants found that the risk of severe wheezing was mainly ascribed to the atopic status of the child 17) . this study corresponds well with our findings that the children included in the present study had signs and symptoms severe enough to require hospitalization and that the children diagnosed with lrtis with wheezing had a higher incidence of parental and past history of allergic diseases than those with lrtis without wheezing. viral lower respiratory infection is a major risk factor for development of wheezing. these illnesses are thought to interact with allergic inflammation, altering airways by damaging lower epithelial cells, increasing the release of mast cell mediators, and amplifying allergic inflammation 19) . several viruses, including respiratory syncytial virus [20] [21] [22] , human rhinovirus 20, 23, 24) , and human metapneumovirus 20, 25) , have been associated with the development of wheezing in children. in contrast, we observed no differences in the incidence of each virus in the children diagnos-cantly more likely to have past history of allergic diseases than those diagnosed with the lrtis without wheezing ( table 2 shows the comparison of viruses identified in the study subjects diagnosed with lrtis with and without wheezing. respiratory syncytial virus was detected in 39 subjects (55.7%) in the children diagnosed with lrtis with wheezing and 37 (51.4%) in those diagnosed with lrtis without wheezing; human metapneu movirus in 14 (20.0%) and 9 (12.5%), respectively; and human rhinovirus in 12 (17.1%) and 11 (15.3%), respectively. there were no between-group differences in the incidence of each virus (p>0.05 each). we utilized multivariate analysis to determine the relationships between the development of wheezing and clinical variables in the study subjects. multivariate logistic regression analysis showed that after adjusting for potential confounding variables including sex and age, the development of wheezing was strongly associated with parental history of allergic diseases (aor, 20.19; 95% ci, 3.22-126.48), past history of allergic diseases (aor, 13.95; 95% ci, 1.34-145.06), past history of hospitalization for respiratory illnesses (aor, 21.36; 95% ci, 3.77-120.88), exposure korean j pediatr 2015;58 (7):245-250 ed with and without wheezing, suggesting that, at least in this cohort of children, the development of wheezing was not associated with specific viral agents causing lrtis requiring hospitalization. previous studies have suggested the hypothesis that susceptibility to viral bronchiolitis may be an early manifestation of biased immune responses, which associates with both diminished viral defense and atopic airway inflammation 26) . furthermore, viral infection in infancy may alter subsequent th1/th2 immune responses and enhance th2 sensitization to inhalant allergens, resulting in the development of an asthmatic phenotype 27, 28) . although we did not look into the long-term outcome of the children with lrtis with wheezing, we speculate that the development of wheezing in these young children may be an early manifestation of th2-biased immune response to viral respiratory infections. therefore, the interaction between age at initial infection, genetic susceptibility, and virus will determine the outcome of respiratory virus infection and airway disorders. one clinically important finding in the present study is that the children diagnosed with lrtis with wheezing showed a lower incidence of temperature >38℃, a lower wbc count, and a higher total eosinophil count when compared with those with lrtis without wheezing. this may be due to the notion that upon viral lrti, the children with wheezing may demonstrate th2-type response, whereas those without wheezing demonstrate th1-type response; this is also supported by the higher incidence of past and parental history of allergic diseases in children with wheezing. it is well-known that blood eosinophil count reflects systemic eosinophilic inflammation and associates with having wheeze. a recent cross-sectional study examining the value of blood eosinophil count in a random population sample of 12,408 subjects found that a higher blood eosinophil count was closely associated with having asthma, wheeze, and asthma attacks 29) , a finding that corresponds well with our results. the harmful effects of exposure to secondhand smoke on the development of wheezing in infants and toddlers are well established 17, [30] [31] [32] [33] . in line with previous studies, we found that exposure to secondhand smoke was a risk factor for development of wheezing in children with viral lrtis requiring hospitalization. the severity of bronchiolitis in early life has been shown to be altered by postnatal exposure to maternal tobacco smoke, and by atopy and age of the infant 34) . thus, children exposed to secondhand smoke are at risk of airway infiltration by small particles, making these children more susceptible to develop wheezing when infected with a respiratory virus. we speculate that contrary to the other clinical risk factors, exposure to secondhand smoke at home is a modifiable environmental risk factor for young children in terms of preventing the development of wheezing when inflicted with viral lrtis. the present study had some limitations. first, it was of cross-sectional design; therefore, we were unable to determine predictive factors for recurrent wheezing in late childhood. second, we did not classify familial smoking into smoking during pregnancy and/or after delivery or into paternal and/or maternal smoking. third, the infants were not subjected to pulmonary function tests; therefore, wheezing and lung function were not measured in an objective manner. fourth, the present study yielded high odds ratios for clinical factors such as past and parental history of allergic diseases with regard to the development of wheeze in the study subjects. this may be ascribed to the fact that they are the most likely sensitizers to wheezing in children hospitalized for lrtis. finally, we did not determine allergic sensitization of the study subjects, which is considered to play a role in the development of wheezing 35) . in conclusion, we found that past and parental history of allergic diseases, past history of hospitalization for respiratory illnesses, exposure to secondhand smoke at home, and total eosinophil count were closely associated with the development of wheezing in children less than 2 years of age who required hospitalization for viral lrtis. clinicians should take these clinical factors into consideration in treating, counseling, and monitoring young children hospitalized for viral lrtis. early-life respiratory viral infections, atopic sensitization, and risk of subsequent development of persistent asthma respiratory syncytial virus bronchiolitis in infancy is an important risk factor for asthma and allergy at age 7 severe respiratory syncytial virus bronchiolitis in infancy and asthma and allergy at age 13 rhinovirus illnesses during infancy predict subsequent childhood wheezing wheezing rhinovirus illnesses in early life predict asthma development in high-risk children lower respiratory tract infections associated with rhinovirus during infancy and increased risk of wheezing during childhood. a cohort study comparison of viral load in individuals with and without asthma during infections with rhinovirus circulation of different rhinovirus groups among children with lower respiratory tract infection in kiremba the relationship between serum endothelin (et)-1 and wheezing status in the children with mycoplasma pneumoniae pneumonia the global initiative for asthma. gina report, global strategy for asthma management and prevention the global initiative for asthma; c2011 does allergic rhinitis exist in infancy? findings from the paris birth cohort diagnostic features of atopic dermatitis development of three multiplex rt-pcr assays for the detection of 12 respiratory rna viruses direct diagnosis of human respiratory coronaviruses 229e and oc43 by the polymerase chain reaction human coronavirus nl63 detection of the new human coronavirus hku1: a report of 6 cases influence of host and environmental factors on wheezing severity in infants: findings from the paris birth cohort risk factors for wheezing, eczema and rhinoconjunctivitis in the previous 12 months among six-year-old children in himeji city, japan: food allergy, older siblings, day-care attendance and parental allergy history the role of pulmonary infection in pediatric asthma a molecular epidemiological study of respiratory viruses detected in japanese children with acute wheezing illness determinants of asthma after severe respiratory syncytial virus bronchiolitis association between respiratory syncytial virus hospitalizations in infants and respiratory sequelae: systematic review and meta-analysis rhinoviruses are a major cause of wheezing and hospitalization in children less than 2 years of age rhinovirus infections in infancy and early childhood role of emerging respiratory viruses in children with severe acute wheezing viral infections and the development of asthma in children association between antenatal cytokine production and the development of atopy and asthma at age 6 years differential immune responses to acute lower respiratory illness in early life and subsequent development of persistent wheezing and asthma exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in national health and nutrition examination survey subjects prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis maternal smoking affects lung function and airway inflammation in young children with multiple-trigger wheeze household environmental tobacco smoke and risks of asthma, wheeze and bronchitic symptoms among children in taiwan prevalence of asthma and wheeze in relation to passive smoking in japanese children severity of respiratory syncytial virus bronchiolitis is affected by cigarette smoke exposure and atopy early-life risk factors for childhood wheeze phenotypes in a high-risk birth cohort no potential conflict of interest relevant to this article was reported. key: cord-310543-2ly18d15 authors: clemens, vera; deschamps, peter; fegert, jörg m.; anagnostopoulos, dimitris; bailey, sue; doyle, maeve; eliez, stephan; hansen, anna sofie; hebebrand, johannes; hillegers, manon; jacobs, brian; karwautz, andreas; kiss, eniko; kotsis, konstantinos; kumperscak, hojka gregoric; pejovic-milovancevic, milica; christensen, anne marie råberg; raynaud, jean-philippe; westerinen, hannu; visnapuu-bernadt, piret title: potential effects of “social” distancing measures and school lockdown on child and adolescent mental health date: 2020-05-23 journal: eur child adolesc psychiatry doi: 10.1007/s00787-020-01549-w sha: doc_id: 310543 cord_uid: 2ly18d15 age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. as the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. the management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. therefore, management in this age group should be based on a patient’s functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. however, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. as the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. the management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. therefore, management in this age group should be based on a patient’s functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. however, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes.age-related metabolic and renal changes predispose older people to an increased risk of diabetes mellitus and diabetic kidney disease, respectively. as the prevalence of the ageing population is increasing, because of increased life expectancy, the prevalence of older people with diabetic kidney disease is likely to increase. diabetic kidney disease is associated with an increased risk of adverse outcomes and increased costs to healthcare systems. the management includes promotion of a healthy lifestyle and control of cardiovascular risk factors such as hyperglycaemia, hypertension and dyslipidaemia. older people are a heterogeneous group of people from a community-living fit and independent person to a fully dependent individual residing in a care home. therefore, management in this age group should be based on a patient’s functional level adopting tight metabolic control in the fit individual and relaxed targets in the frail person. however, despite the maximum available therapy, a significant number of patients with diabetic kidney disease still progress to renal failure and experience adverse cardiac outcomes. therefore, future research is required to explore methods of early detection of diabetic kidney disease and to investigate novel therapeutic interventions to further improve the outcomes. so-called "social distancing" and measures of hygiene have proven to be effective reactions to the threat of increasing numbers of covid-19 cases and fatalities. however, there is no such thing as a free lunch. as medical doctors, we know very well that the majority of our most effective treatment methods unfortunately have chance of provoking severe side effects. in every day practice, we are used to balanced and shared decision-making based on national or international guidelines on an individual level together with our patients and their families and caregivers. in the battle we are all fighting against covid 19, at the moment there is no balancing or shared decision-making at an individual level. rather, at the population level, within their national borders, countries all over the world aim to reduce contact among humans to prevent infection with covid-19 1 . this has a positive effect on protecting health, especially for the elderly and ill people. children, adolescents and their parents are usually at a much lower risk for severe illness, even if there have been rare deaths in this age range as well. political measures that aim to achieve social distancing hit their age groups particularly although the efficacy of school closures is of equivocal evidence [1] . this calls for further reflection on the effects on their mental health. over the past few weeks, an estimated 90% [2] or more of children and adolescents have faced the effects of school closures. in addition, most other social and out-of-home activities for children and adolescents have been canceled. they no longer enjoy positive interactions with their sport coaches, music teachers, friends and peers. children and their families have to share a restricted space at home with limited resources and have to change their daily life and routines to cope with numerous new challenges. children are supposed to get home schooling, supervised by parents. however, some parents are expected to work as much as possible at home office or, due to the nature of their job, are confronted with daycare problems. support and the help of grandparents and other family members fall away, as they should avoid contact. all family members struggle with their own anxieties in this situation and for many families, economic pressure further increases stress. when a family member dies, the child has to deal with their grief. quite often, a combination of challenges clusters in families with limited space, job loss, and other known risk factors such as mental illness/disabilities of family members or single parenting. together, all of this can erupt in interpersonal violence and there is a series of reports on increased domestic violence and increased child abuse during this first phase of the pandemic (an overview is given by fegert et al. 2020 [3] ). in brief, children and adolescents are at home with their families, experience an increase in stress and a reduction in support and coping resources. as a result, on the spectrum from healthy-coping-struggling to unwell, many children can expect to suffer, though some will do better. as with most other stressors, resilience and coping are bound to play their role for most individuals. special attention is needed for those who were already struggling or unwell before home quarantine. anecdotally, in clinical practice, we see three emerging patterns. a first group of children seem to prosper. they are at home in a quieter environment; they thrive with the structure and support their parents provide; they enjoy online learning and they are not exposed to bullying nor find themselves socially excluded. a second group seems to be mildly adversely affected. their developmental opportunities are paused as they may have too few resources available for online education, are unable to interact with others to practice social skills and no longer have access to practice what they were learning in social/ emotional-treatment. the third group includes children and young people who find themselves in families with increasing negative interactions and who are deprived of the safe haven offered by their schools. to make matters worse, services and help may be temporarily less available. for those who are in need of professional help, the outreach of mental health services has been reduced. families avoid consultations due to fear of covid-19. the activity of child protection services and currently existing programs of support or supervision by youth welfare agencies is reduced or interrupted. this is a result of re-organization of services, with provisional care (including re-assigning doctors and nurses not usually involved in critical care), (partial) closures of facilities to avoid the risk of infection and in some services illness among personnel. the lack of access to the support services can be particularly harmful for vulnerable children and/or families who experience increased stress. thus, school closures exacerbate inequities, disproportionately affecting already disadvantaged children [4] . a small group of youth and children who were previously in residential centers are in a mental health crisis after they went back to their dysfunctional families. in inpatient treatment, infections among staff and/or patients can lead to isolation and separation of patients and sub-groups developing a cohort immunity. a first screening of patients via helplines may help to avoid infections; while in some places, strict rules to avoid infections with distancing and quarantine are abandoned to maintain the functioning of the clinical units. if inpatients have reduced access to their families due to hygiene restrictions, this makes it difficult to adhere to the un convention of children's rights. units should maintain their child patient's contact with their family as much as possible. how are we, as european child and adolescent psychiatrists (cap), supposed to deal with this situation? first, in our clinical practices, we need to continue to provide services for children and adolescents with mental health disorders. cap institutions should keep contact with patients who have special needs and those patients who are missing out on specialized education systems both to avoid disrupting current treatment programs and to offer support to caregivers. parents and patients should be informed not to stay away from private practices and hospitals when mental health care is needed. to avoid a concentration of the most severe cases in hospitals on wards with reduced staff and difficult or unsuitable care conditions, outpatient and inpatient facilities must be kept open as much as possible; they need to follow all the necessary protocols to prevent transmission of the virus. crisis interventions must be accessible at all times. for patients with new onset of child psychiatric disorders, appointments should be arranged and they should be directed to adequate care. digital communication with the patient's family should be used wherever possible to support parents on how to deal with the current challenges. europeans generally have smart phones but those in very poor families may not. they may have no opportunity for a safe, confidential space at home. support regarding how to address anxiety and stress in children is important (for information on these issues see, e.g., recommendations of escap [5] ). in many places, there are adverse consequences for training and for the workforce. recruitment is not possible because of home working and the difficulty of ensuring equity of opportunity. this is compounded by staff being redeployed to care for covid-19 patients. cap is an understaffed discipline already. on the positive side, we see an acceleration in switching to online training and supervision, development of e-learning. there are newly emerging networks of international information exchange about the effects of corona on mental health and to share lessons learned. the further development of an international network of cap trainers as well as the development of courses on an international level and moocs may prove to be crucial to maintain training [6] . after the crisis, it will be important to avoid delays in training caused by the crisis. there should be regulations that acknowledge training experiences in child and adolescent psychiatry and psychotherapy even though the normal functioning of training courses, personal supervision, etc., have been interrupted. in a broader scope, in many hospitals, we are sharing what we have learned about mental health advice with other health care professionals. this may well prove to have an additional long-term effect on the awareness of the importance of (child) mental health and on recruitment for future mental health care professionals. last but not least, mental health professionals should take precautions to safe-guard their own mental health; minded has recently provided front line staff in the nhs and care services with recommendations for management of mental health, whilst looking after others during the covid-19 crisis (https ://covid .minde d.org.uk); child and adolescent mental health care professionals, too, may well profit from such recommendations. turning to the role of cap in research, it is not an empty plea that more research is urgently needed on both the shortterm and the long-term effects on child mental health to better inform policy makers. even though numerous reviews on mental health effects of covid-19 are being published (just to name some examples: [7] [8] [9] [10] ), they are based on the existing literature that only partly mirrors the current situation. prospective assessment of the effect of covid-19-related mental health effects in children and adolescents is needed. international collaborations in the eu seem key to both detect general as well as specific mechanisms at play in each culture and country. in addition, it is important to analyze the tele-psychiatric interventions to determine measures of quality control and ask patients, parents and therapists through questionnaires about the usefulness of online therapy to help maintain such services in the future. the question of data-protection and the use of user friendly, easy to handle systems are challenges that are not fully solved yet. however, based on the old medical ethical position that the health of the patients is the primary issue (aegroti salus suprema lex), many child and adolescent psychiatrists and psychologists and social workers have managed to stay in contact with their patients by new technical means. taken together, cap faces numerous challenges. however, to maintain emergency and regular treatments, training and research wherever possible must be a priority for all cap professionals. in the long term, child mental health is the basis for future adult mental health which is closely associated with general health and is, thus, related to productivity and well-being in our society. although measures that aim for "social distancing" are important to protect the health of our society, political decision makers have to keep in mind that it does not come without side effects and that children, adolescents and their families bear a major burden of these measures. in medicine, treatment decisions are never made on the potential benefit alone-the risk of side effects always has to be taken into account. likewise, in the current situation, risk-benefit analyses are urgently needed based on the effects of "social distancing" including importantly for children and adolescents school closures. although current knowledge about the risks is based on studies with limited comparability or on just emerging novel results, this information has to be taken into account. instead of "social distancing", measures that enable "physical distancing" with maintained "social connectedness" should be aimed. effective alternatives for school closures may be "physical distancing" measures such as to keep students in classrooms and to decrease the number of students per class and to increase space between students [1, 11] . as a result of governments taking their own national measures, the return of border controls and the financial risks inherent to the covid-19 pandemic, this crisis carries the risk of reduced solidarity across europe. as is the case for all other international families, we, too, as the european cap-family, find ourselves physically separated. this should not stop us from trying to remain emotionally close. advocacy of european cap to policy makers from a mental health perspective should be based on the principle: first, do no harm (primum non nocere). school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review covid-19 educational disruption and response covid-19 pandemie: kinderschutz list systemrelevant considering inequalities in the school closure response to covid-19 dealing with children and adolescent mental health during the coronavirus pandemic training for child and adolescent psychiatry in the twenty-first century the psychological impact of quarantine and how to reduce it: rapid review of the evidence the outbreak of covid-19 coronavirus and its impact on global mental health mental health effects of school closures during covid-19 coronavirus disease 2019 (covid-19) and mental health for children and adolescents school practices to promote social distancing in k-12 schools: review of influenza pandemic policies and practices acknowledgements the authors of this editorial come from europe; the contents should be interpreted accordingly. authors include representatives/board members from the union of european medical specialists, section of child and adolescent psychiatry (uems-cap) and the european society of child and adolescent psychiatry (escap). the core author group consists of the first three authors (vc, pd and jf). vera clemens 1,2 · peter deschamps 3,4 · jörg m. fegert 2,5 · dimitris anagnostopoulos 5,6 · sue bailey 3,7 · maeve doyle 5,8 · stephan eliez 5,9 · anna sofie hansen 3,10 · johannes hebebrand 5,11 · manon hillegers 5,12 · brian jacobs 3,13 · andreas karwautz 5,14 · eniko kiss 5,15 · konstantinos kotsis 5,16 · hojka gregoric kumperscak 3,17 · milica pejovic-milovancevic 5,18,19 · anne marie råberg christensen 5,20 · jean-philippe raynaud 5,21 · hannu westerinen 3,22 · piret visnapuu-bernadt 3,23 key: cord-269716-x3b0qphd authors: hopper, lydia m.; jacobson, sarah l.; howard, lauren h. title: problem solving flexibility across early development date: 2020-08-26 journal: j exp child psychol doi: 10.1016/j.jecp.2020.104966 sha: doc_id: 269716 cord_uid: x3b0qphd cognitive flexibility allows individuals to adapt to novel situations. however, this ability appears to develop slowly over the first few years of life, mediated by task complexity and opacity. we used a physically simple novel task, previously tested with nonhuman primates, to explore the development of flexible problem solving in 2-, 3-, and 4-year-old children from a developmental and comparative perspective. the task goal was to remove barriers (straws) from a clear tube to release a ball. the location of the ball, and therefore the number of straws necessary to retrieve it, varied across two test phases (four of five straws and two of five straws, respectively). in test phase 1, all children retrieved the ball in trial 1 and 83.61% used the most efficient method (removing only straws below the ball). across phase 1 trials, 4-year-olds were significantly more efficient than 2-year-olds, and solve latency decreased for all age groups. test phase 2 altered the location of the ball, allowing us to explore whether children could flexibly adopt a more efficient solution when their original (now inefficient) solution remained available. in phase 2, significantly more 4-year-olds than 2-year-olds were efficient; the older children showed greater competency with the task and were more flexible to changing task demands than the younger children. interestingly, no age group was as flexible in phase 2 as previously tested nonhuman primates, potentially related to their relatively reduced task exploration in phase 1. therefore, this causally clear task revealed changes in cognitive flexibility across both early childhood and species. flexibility allows individuals to nimbly react to novel situations, playing an important role in adaptive responses to environmental changes and finding optimum solutions to problems. humans are particularly adept at flexible thinking, potentially due to complexity in their environment and social relationship structure (gökçen, petrides, hudry, frederickson, & smillie, 2014) . such flexibility is important because it is linked to our innovative ability and tool use (keen, 2011; neldner, mushin, & nielsen, 2017) . previous research has shown that, as compared with younger children, older children can more flexibly react to environmental or task changes (but see gopnik et al., 2017) . for example, children over 4 years of age can quickly alter sorting techniques on the same objects when given different verbal cues (e.g., ''find the ones that look like a ____" vs. ''find the one that is the same kind as ____"; deák & bauer, 1995) or game rules (e.g., ''sort the red ones" vs. ''sort the small ones"; frye, zelazo, & palfai, 1995; zelazo, frye, & rapus, 1996) , whereas children under age 4 often perseverate on the first cue or rule with which they are provided, making switch errors on 50-100% of trials . indeed, children's flexibility appears to develop slowly over the first few years of life and may be mediated by a child's understanding of the task (karmiloffsmith, 1990; spensley & taylor, 1999) . these findings, and others, suggest that cognitive flexibility might be linked to children's biological age (zelazo, muller, frye, & marcovitch, 2003) , although some evidence finds that children as a whole may also be more flexible than adults in certain situations (lucas, bridgers, griffiths, & gopnik, 2014) . in addition to biological maturation across one's lifespan, we can explore cognitive flexibility from a comparative perspective, for example, by studying nonhuman primates (sneve et al., 2018) . although there appears to be much variability across and within primate species with regard to their flexible or conservative responses to novel tasks (reviewed in brosnan & hopper, 2014) , nonhuman primates do exhibit cognitive flexibility in relation to both physical and social understanding (e.g., amici, call, watzek, brosnan, & aureli, 2018; pope et al., 2020) . in certain cases, and as compared with adult humans, nonhuman primates (e.g., macaques, capuchin monkeys) have been found to be significantly better at quickly and flexibly altering their behavior in response to changing task demands (e.g., avdagic, jensen, altschul, & terrace, 2014; stoet & snyder, 2007; watzek, pope, & brosnan, 2019) . thus, an exploration both across human development and across species might prove to be particularly insightful for understanding the ontogeny and evolutionary development of cognitive flexibility. research with humans and nonhuman primates has revealed that other important factors, including task complexity, opacity, and cognitive demands, influence cognitive flexibility. zelazo, carter, reznick, and frye (1997) proposed that individuals' ability to evaluate their own success in a task (i.e., error detection and correction) is a key component of problem solving as related to executive function. as such, tasks that make error detection easier are more likely to elicit adequate task switching from children. for example, when 3-year-olds are asked to repeat game rules before task switching, they are much more likely to succeed than when they are asked to simply complete the task without this verbal reminder (kirkham, cruess, & diamond, 2003) . whereas understanding the rules of a task can enhance children's success, causally clear tasks are also more efficiently solved by children and nonhuman primates (jacobson & hopper, 2019) . for example, 2-year-olds are more successful at an inhibition task if the actions required of them are obviously causal (e.g., pull a lever to get an object) as opposed to unclear or arbitrary (e.g., answer a phone to get an object) (mcguigan & núñez, 2006) . in this way, causal understanding may allow for solutions to be found and errors to be identified as well as flexibility in response to changes in task demands (hopper, kurtycz, ross, & bonnie, 2015; jacobson & hopper, 2019) . research has suggested that differences in response flexibility also likely depend on the cognitive demands inherent in the task. for example, less demanding lookingtime paradigms often show much earlier evidence for cognitive flexibility than tasks that require children to act on objects (e.g., smith, thelen, titzer, & mclin, 1999) . given this, (davis, schapiro, lambeth, wood, & whiten, 2019) proposed that perseveration is likely mediated by response prepotency (how familiar an action is) and working memory load (how demanding the task is). here, we sought to explore how children's cognitive flexibility (i.e., set shifting; ionescu, 2012) changes across early development and how their strategies compare with those of nonhuman primates (chimpanzees and gorillas tested previously using a comparable task and testing protocol). specifically, research with nonhuman primates has shown that they are less likely to adopt a novel solution after learning one successful one (hrubesch, preuschoft, & van schaik, 2009) but that this is mediated by task transparency, such that individuals tested with a causally clear task appear to be more flexible (jacobson & hopper, 2019) . therefore, unlike many previous studies on early cognitive flexibility, we used a paradigm that was both physically and causally clear and asked children to switch strategies without a large memory demand (e.g., remembering an abstract rule; zelazo et al., 1996) . specifically, we used a novel puzzle that was a clear vertical tube with five paper straws threaded through it at equal intervals. a small ball was placed in the tube such that it rested on a straw, and to retrieve the ball children needed to pull out all the straws below the ball so that it could fall down the tube and out the bottom. each time children retrieved the ball, they could exchange it with the researcher for a sticker. thus, this clear task relied on participants' basic understanding of gravity and support, did not necessitate the use of arbitrary actions, and did not require participants to retain information across trials. in the first configuration of the task, four straws were below the ball and one was above it. this was to test children's spontaneous understanding of the causal mechanics of the task and to verify that it was causally clear to children. research shows that even infants appear to have a basic understanding of gravity (baillargeon & hanko-summers, 1990; needham & baillargeon, 1993) , looking longer at and interacting more with objects if they appear to magically float in space when their support is removed (e.g., stahl & feigenson, 2015) . infants also appear to understand that a solid barrier will stop an object from falling or rolling in a downward trajectory even when that object is behind an opaque occluder (spelke, breinlinger, macomber, & jacobson, 1992) . although 2-year-olds struggle with more cognitively demanding physical adaptation of these looking-time studies, by 3 years of age children are able to track a falling object behind an occluder, correctly select a door to open, and reach for the fallen object (berthier, deblois, poirier, novak, & clifton, 2000) . thus, with this first configuration of our task, we could test whether children would remove only straws below the ball and ignore the straw above it or whether they would ''blindly" pull out all straws, in turn revealing whether they understood the task rules (without explanation or guidance). furthermore, by testing 2-, 3-, and 4-year-olds, we could observe whether their understanding and success differed by age. to examine whether the children could adopt a new solution strategy after repeated experience with the task in the first configuration, we subsequently presented a new configuration where only two straws were below the ball and three straws were above it. in this new configuration, the most efficient solution was to remove two straws instead of four, although the previously efficient strategy remained viable (albeit a less efficient solution). in this way, our paradigm allowed us to test individuals' flexibility in the face of possible conservatism and the interplay between causal understanding and cognitive flexibility across children of different ages and across (primate) species. our previous research with nonhuman primates using the same task revealed that chimpanzees and gorillas showed flexible problem solving when task demands changed, likely due to the apes' causal understanding of the task (jacobson & hopper, 2019) . therefore, we predicted that if children understood the task mechanics, they would respond flexibly when task demands changed. specifically, we predicted that if children solved the task using the most efficient strategy in the first task configuration, they would also be able to adopt a new efficient strategy when the configuration was changed. however, we also predicted that the younger children may be less likely to master the task (i.e., understand the solution and so be less likely to use efficient responses) and, accordingly, may be less flexible than the older children (if task understanding relates to flexibility in response patterns). thus, with our study, we wanted to see how young children responded to changing task demands, how their efficiency and flexibility differed with age, and how their responses compared with those of nonhuman primates. we tested 61 children representing three age groups: 20 2-year-olds (m = 30.0 months, range = 24.0-34.7; 10 girls), 22 3-year-olds (m = 40.6 months, range = 36.0-47.8; 12 girls), and 19 4-yearolds (m = 53.4 months, range = 49.0-59.6; 6 girls). from parental reporting, we determined that 81% of participants were caucasian, 5% were african american, 2% were hispanic, 2% were asian american, and 10% were multiracial (2% of parents opted out of answering questions concerning their child's race/ethnicity). in addition to the 61 children described above, we tested 9 children who were not included in the final sample due to refusing to participate in the given tasks (n = 7), failure to obtain video-recording consent (n = 1), or experimenter error (n = 1). this study received approval from the franklin & marshall institutional review board. after entering the testing room, children sat in a chair placed directly in front of experimenter 1 and the testing apparatus. the apparatus (modeled from the design previously used to test problem solving flexibility in apes; jacobson & hopper, 2019) was a clear pvc tube (approximately 2.5 cm in diameter and 63.5 cm long) affixed to a stand with equally spaced holes for up to five straws to be slotted through the tube (fig. 1 ). experimenter 2 sat on a small chair perpendicular to children. parents sat in a chair opposite from the apparatus, facing children and the experimenters, and were asked to remain quiet and to not intervene in the task or guide children's responses. sessions were videorecorded for later coding, with the camera located diagonal to the testing area (focused on experimenter 1, the testing apparatus, and children's hands. testing comprised a familiarization phase followed by two experimental phases. in the familiarization phase, experimenter 1 introduced children to the test apparatus, saying, ''this is my toy. look what this toy can do. when i put a ball in, it comes out the end." the experimenter then proceeded through 3 familiarization trials to acquaint children with the general mechanics of the tube. during these trials, the experimenter dropped a ball into the tube to show how a ball could fall down the apparatus when no obstructions (straws) were present. with each trial, experimenter 1 verbally prompted children to retrieve the ball that came out of the tube (''can you get the ball?") and told children that they would be rewarded with a sticker by experimenter 2 when they obtained the ball (''every time you give the ball to our friend [experimenter 2], you get a sticker!"). the sticker provided an incentive for children to quickly retrieve the ball by removing the straw obstructions (in the previous study with chimpanzees and gorillas using this task, a food reward was used in place of the ball here, which was inherently rewarding; see jacobson & hopper, 2019) . in test phase 1, participants completed 10 trials whereby they were asked to retrieve the ball from the test apparatus. for each trial, experimenter 1 baited the test apparatus out of view of children (behind a 122 by 91-cm tri-fold display board). experimenter 1 inserted a straw through each of the five holes in the shaft of the tube, with the ball placed into the apparatus such that there were four straws below the ball and one straw above it (configuration 1 in fig. 1 ). in this configuration, children needed to remove the four straws below the ball to obtain it; the fifth straw could also be removed, but doing so was causally irrelevant to obtaining the ball. the experimenter ensured that the straws were aligned equally to avoid any visual cuing that might encourage participants to select specific straws (e.g., one straw sticking out from the apparatus farther than another straw). then, the experimenter removed the tri-fold board so that children could view the tube. a test trial began as soon as the experimenter verbally prompted children to interact with the apparatus (''can you get the ball?"). participants were then given a chance to remove any of the straws (below or above the ball) in whatever manner they wished. if children were hesitant to initiate an interaction with the straws or the apparatus, the experimenter further prompted them with encouraging but noninformative cues (e.g., ''it's okay, you can come up and touch it"; ''the ball is stuck. how do you think you could get it out?"; ''if you get the ball, you'll get a sticker!"). throughout the trial, the experimenter retained a neutral facial expression and a neutral tone of voice to prevent children from receiving any external cues that would interfere with their interaction with the apparatus. similar to the familiarization trials, participants received a sticker whenever they acquired the ball and handed it to experimenter 2. after completing 10 trials with the apparatus in configuration 1, phase 2 commenced. in test phase 2, participants completed test trials with the new task configuration. these trials were run as in phase 1, changing only the apparatus configuration; in phase 2, the experimenter baited the apparatus such that there were only two straws below the ball and three straws above it (configuration 2 in fig. 1) . thus, the total number of straws that could be removed (five) was the same across test phases, but the number of straws that needed to be removed to obtain the ball differed (four in phase 1 and two in phase 2). importantly, the experimenter never highlighted the change in task configuration, or the new location of the ball at the start of the trial, either verbally or via pointing. as with phase 1, the experimenter made statements only to encourage children's engagement (e.g., ''can you get the ball?"). in phase 2, children completed 4 trials. there were two reasons why we ran fewer trials in this second phase. first, our primary interest was assessing children's ability to switch response strategies when the task configuration changed. for this, we were predominantly interested in assessing their the configuration both in phase 1 (four straws below the ball and one straw above it) and in phase 2 (two straws below the ball and three straws above it) and a photograph of one participant completing a trial in phase 1. in either task configuration, participants were free to pull out as many straws us they chose and in any order. thus, although the most efficient strategy would be to only remove straws below the ball, in either configuration children could also adopt inefficient strategies and remove straws both above and below the ball. importantly, the efficient solution for phase 1 (removing straws 1-4) remained viable in phase 2, although a different solution was the most efficient one (removing straws 1 and 2). responses in the first trial post-configuration change (i.e., to see whether they adopted a new solution and whether they adopted the most efficient solution possible with their first response in phase 2). second, although we also wanted to evaluate children's repeated responses in phase 2 with multiple trials (to see whether their responses increased in efficiency over time if they did not make a strategy switch with their first trial of phase 2), we did not want to give children too many opportunities to interact with the task because we wanted to test their spontaneous responses. this is in contrast to phase 1, where we wanted to assess their spontaneous understanding of the task (trial 1) and also wanted to give them repeated experience with the task across multiple trials both to assess their exploration of the task and to generate a modal response (''remove four straws") that would be more likely to be conserved and potentially harder to deviate from in phase 2 (in the sense of jacobson & hopper, 2019) . a trained researcher coded all the test trials from video. a second independent research assistant coded 25% of participants' trials, with the two coders agreeing on approximately 99.9% of total behavioral scores. when there was a coding disagreement, we used the primary coder's scoring for a given trial. for each trial, the coder recorded four elements and associated information: the total number of straws participants removed, the order in which participants removed the straws, the length of each trial (i.e., latency to remove straws), and any comments participants made during the first trial of test phase 2 when they were presented with a new configuration of the task (i.e., the ''switch trial"). for each trial, we coded for the total number of straws removed by children (out of a possible five for each trial) and the order in which children removed each straw. if participants retrieved the reward by pulling only the straws below the ball (four straws for test phase 1 or two straws for test phase 2), we coded the trial as ''efficient," but if participants pulled one or more straws above the ball (thereby pulling straws that were not causally necessary to receive the reward), we coded the trial was as ''inefficient" (as per jacobson & hopper, 2019) . we coded the time at which participants removed each straw within a given trial. thus, we could calculate the latency for participants to complete each of their trials. the start time for each trial began as soon as the experimenter uttered the introductory prompt (''can you get the ball?") and ended once children indicated they were done removing straws by explicitly stating such or moving to experimenter 2 to retrieve a sticker for ball retrieval (typically as soon as the ball fell from the tube). during the first trial of phase 2 (the ''switch trial" when the configuration of the apparatus was altered), we transcribed any verbal comments participants made that might indicate that they noticed a change and/or were seeking information related to the change (i.e., ''why" questions; legare, sobel, & callanan, 2017) . for instance, some participants would recognize the change of the tube arrangement and say, ''why is the ball all the way down there?" or ''how did you do that?" we provide a descriptive summary of these in the results section. to explore participants' spontaneous understanding of the task and their flexibility in response to changing task demands, we analyzed four key aspects of the coded data using r version 3.5.2 (core, 2018): (a) participants' spontaneous understanding of the task, (b) any apparent learning across trials, (c) participants' flexibility and efficiency across and within phases, and (d) the verbal responses participants made, if any. for clarity, the specific analytical approaches that we used for each analysis are reported within that section of the results. for all pairwise comparisons, a bonferroni correction was applied (i.e., a .017). with a .017 and an effect size of .80, our power analysis revealed a value of .63. (to achieve a power value of .80, we would need to have included 29 children per condition, but with the current covid-19 pandemic, additional testing was not feasible.) we plotted all data using the ggplot2 package (wickham, 2016) and beeswarm package (eklund, 2016 ; see also wilkinson, 1999) in r version 3.5.2 (core, 2018). all 61 children tested were able to retrieve the ball from the apparatus in their first trial of phase 1. furthermore, 15 of the 20 2-year-olds (75.00%), 18 of the 22 3-year-olds (81.82%), and 18 of the 19 4year-olds (94.74%) used the most efficient method to do so in trial 1 of phase 1 (i.e., they removed only the lower four of the five straws from the tube) (fig. 1) . we compared children's spontaneous ability to solve the task across the three age groups. to do so, we used first trial efficiency (efficient or inefficient) as our outcome variable and participant id as a random factor. given the binary response variable, we analyzed our data using a binomial generalized linear mixed model (glmm) in r version 3.5.2 (core, 2018). we fit this model using the laplace approximation method via the ''glmer" function in the lme4 package (bates, maechler, & bolker, 2012) to test the relative effect of our predictor variable age group (family = ''binomial"). this revealed that there was no significant difference across the three age groups of children in their likelihood to use the most efficient method in their first trial of phase 1 {z = 0.34, p = .733, 95% confidence interval (ci) [à3.80, 5.41]}. not only were the three age groups equally likely to use an efficient response with their first trial, but of those children who responded efficiently in the first trial of phase 1, there was strong consistency in the action sequence (i.e., straw removal order) that they used: 93.33% of the 2-year-olds who responded efficiently used the 4,3,2,1 action sequence, as did 100.00% of the 3-year-olds and 94.44% of the 4-year-olds who responded efficiently (i.e., they sequentially removed the straw directly below the ball) (fig. 1 ). on average across all their trials in phase 1, 2-year-olds used an efficient action sequence in 60.56% (sd = 27.75) of trials, whereas 3-year-olds were efficient in 71.90% (sd = 32.19) of trials and 4-yearolds were efficient in 86.32% (sd = 24.99) of trials (fig. 2) . using a glmm, we explored the proportion of all the participants' trials in phase 1 that were efficient (family = ''poisson") and used independent t tests, using the ''t.test" function to compare children's efficiency across age groups. this revealed that there was a significant effect of age on the percentage of trials in which children made efficient responses in phase 1 (z = 2.80, p = .005, 95% ci [0.53, 0.30]). specifically, 4-year-olds made significantly more efficient responses than 2-year-olds, t(34.13) = à2.96, p = .006, 95% ci [à4.34, à0.81], but there was no significant difference in the percentages of trials in which 2-and 3-year-olds made efficient responses, t(36.99) = à1.18, p = .245, 95% ci [à3.08, 0.81] or in the percentages of trials in which 3and 4-year-olds made efficient responses, t(37.19) = à1.59, p = .120, 95% ci [à3. 28, 8.63] . when first presented with the task in phase 1, the average latency for 4-year-olds to complete their first trial was 23.05 s (sd = 10.43). the 4-year-olds were significantly quicker to complete their first trial than the 2-year-olds (average latency = 80.35 s, sd = 71.98), t(19.84) = 3.52, p = .002, 95% ci [23.34, 91.26] and the 3-year-olds (average latency = 61.95 s, sd = 70.03), t(22.08) = 2.57, p = .017, 95% ci [7.55, 91.26 ]. there was no significant difference, however, between the 2-and 3-year-olds in the time it took them to complete their first trial, t(39.38) = 0.84, p = .407, 95% ci [à26.00, 62.79]. to test whether children's trial completion times became quicker across trials, as a proxy for learning, we correlated participants' trial latency with trial number using the ''rmcorr" function (bakdash & marusich, 2017) . this takes into account repeated samples from participants to determine whether their trial latency decreased over time. this revealed that there was a significant negative correlation between the trial completion latency and trial number for all three age groups, such that children became quicker to complete trials across the 10 trials in phase 1: 2-year-olds (r = à.385, p < .001), 3-year-olds (r = à.297, p < .001), and 4-year-olds (r = à.232, p = .002). the weaker negative relationship between trial number and latency for 4-year-olds is likely because they completed their first trial faster than the younger children and there is likely a limit to how quickly any children can complete a trial, creating a floor effect. indeed, 4-year-olds' average trial completion latency delta from trial 1 to trial 10 was only 14.89 s (average trial 10 latency = 8.16 s, sd = 23.05), whereas the delta for 3-year-olds was 47.90 s (average trial 10 latency = 14.05 s, sd = 15.51) and for 2-yearolds was 64.35 s (average trial 10 latency = 16.00 s, sd = 10.83). to evaluate children's cognitive flexibility, we assessed their efficiency in the first trial of phase 2 when they were presented with the new task configuration (fig. 1 ). only 7 (11.48%) of the children used the same action sequence (straw removal order) in the first trial of phase 2 as they had used in their last trial of phase 1. specifically, 4 2-year-olds and 2 3-year-olds used the 5,4,3,2,1 action sequence in both trials, whereas 1 4-year-old used the 4,3,2,1 action sequence in the last trial of phase 1 and the first trial of phase 2. thus, the majority of children (88.52%) used a different action sequence across these trials. for all children and action sequences used, in the first trial of phase 2, 7 of the 20 2year-olds (35.00%), 14 of the 22 3-year-olds (63.64%), and 13 of the 19 4-year-olds (68.42%) used the (newly available) most efficient method (i.e., they removed only the lower two of five straws from the tube), highlighting their recognition of the changed task demands. as with test phase 1, we used the ''glmer" function in the lme4 package (family = ''binomial") to compare the numbers of children across the three age groups whose first trial in phase 2 was efficient, and we used independent t tests using the ''t.test" function for post hoc pairwise comparisons across age groups. our analyses revealed that there was a significant effect of age on children's efficiency in the first trial of phase 2 (z = 2.74, p = .023, 95% ci [0.11, 1.51]). in spite of this, after correcting for multiple comparisons, post hoc pairwise comparisons revealed no significant difference across age groups when comparing the numbers of children whose responses in the first trial of phase 2 responses were efficient: 4-year-olds versus 2year-olds, t(35.92) = à2.41, p = .021, 95% ci [à0.68, à0.06]; 4-year-olds versus 3-year-olds, considering all 4 trials that children completed in phase 2, on average children removed significantly fewer straws per trial in phase 2 than they did in phase 1, highlighting their understanding of the changed task demands. this was true for all three age groups of children tested: 2-year-olds, t(21.45) = 3.81, p = .001, 95% ci [0.49, 1.68]; 3-year-olds, t(25.10) = 6.20, p < .001, 95% ci [1.04, 2.08]; 4-year-olds, t(20.65) = 7.55, p < .001, 95% ci [1.21, 2.13]. although children removed fewer straws in phase 2 as compared with phase 1, did they consistently remove the fewest possible number (i.e., two straws)? on average across all trials in phase 2, 2-year-olds used an efficient action sequence in 42.50% (sd = 39.82) of their trials, whereas 3-year-olds used an efficient solution in 68.18% (sd = 41.68) of trials and 4-year-olds were efficient in 81.58% (sd = 32.10) of trials. using a glmm (family = ''poisson"), we found that there was a significant effect of age on the proportion of phase 2 trials in which children made efficient responses (z = 3.04, p = .002, 95% ci [0.11, 0.51]). specifically, 4-year-olds made significantly more efficient responses than 2-year-olds, t(36.07) = à3.38, p = .002, 95% ci [à2.50, à0.63], but there was no significant difference in the proportions of trials in which 3-and 4-year-olds made efficient responses, t(38.54) = à1.16, p = .253, 95% ci [à1.47, 0.40], or in the proportions of trials in which 3-and 2-year-olds made efficient responses, t(39.89) = à2.04, p = .048, 95% ci [à2.04, à0.01]. to further explore children's causal understanding of the task and their ability to flexibly shift strategies across the phases in response to the change in task configuration, we compared children's latency to complete trials across the two phases as a proxy for flexibility (i.e., removing two straws should take less time than removing four straws). across all children tested, they were significantly faster to complete trials in phase 2 (average trial completion latency = 12.03 s, sd = 13.36) compared with phase 1 (average trial completion latency = 17.44 s, sd = 11.45), r(60) = à.426, p < .001. there was also a significant effect of age on children's latency to complete a trial. within phase 2, the average latency for 2-year-olds to complete a trial was 17.40 s (sd = 16.70), whereas the average trial completion latencies for 3-and 4-year-olds were 11.82 s (sd = 13.63) and 6.63 s (sd = 4.61), respectively. the 4-year-olds completed trials significantly faster than both the 2-year-olds, t(49.82) = 4.74, p < .001, 95% ci [7.10, 17.57] and 3-year-olds, t(63.56) = 3.31, p = .002, 95% ci [2.65, 10.68]. in contrast, there was no significant difference between the 2-year-olds' and 3-year-olds' trial completion latency, t(73.10) = 1.88, p = .056, 95% ci [à0. 35, 11.69 ]. in addition to comparing children's understanding of the task and flexibility across ages, we were also interested in how consistently proficient each child was. to examine this, we compared children's efficiency in phase 1 with their efficiency in phase 2. we found that, for all three age groups, children showed intra-individual consistency in their efficiency across phases; that is, the proportion of trials that children solved efficiently in phase 1 was significantly correlated with the proportion of trials that children solved efficiently in phase 2: pearson's product-moment correlation, 2-year-olds, t(18) = 5.066, p < .001, 95% ci [.49, .90]; 3-year-olds, t(20) = 3.635, p = .002, 95% ci [.28, .83]; 4-year-olds, t(17) = 6.093, p < .001, 95% ci [.60, .93]. as reflected by children's responses in the first trial of phase 1, the action sequence most commonly used by children across all trials in phase 1 was repeatedly removing the straw directly below the reward (i.e., 4,3,2,1) ( figs. 1 and 3) . this action sequence represented 53.78% of 2-year-olds' trials, 64.84% of 3-year-olds' trials, and 73.82% of 4-year-olds' trials in phase 1. in addition, and as can be seen in fig. 3 , the modal inefficient action sequence for all three age groups in phase 1 was 5,4,3,2,1 (i.e., pulling out all the straws from top to bottom). not only was there consistency across children in their modal action sequence (4,3,2,1) in phase 1, there was also intra-individual consistency such that some children perseverated in their response phenotype and used an action sequence in multiple successive trials. indeed, 14 children (1 2-yearold, 5 3-year-olds, and 8 4-year-olds) used the same efficient action sequence for every response they made in phase 1, and 2 2-year-olds used the same inefficient sequence in each of their 10 trials. therefore, we explored children's conservatism in this regard. for each child, we calculated the longest run of consecutive trials in which the child used the same action sequence in phase 1, where 2 consecutive trials was the shortest possible run length and 10 consecutive trials was the longest possible run length. in addition, we coded whether each run was efficient or inefficient, and we calculated each child's average efficient run length as a proportion of total possible responses. from this, we found that 4-year-olds made significantly longer efficient runs (average proportion of trials = .63, sd = .41) than 2-year-olds (average = .30, sd = .27), t(25.32) = à2.752, p = .011, 95% ci [à.57, à.08] (fig. 4) . however, there was no significant difference in the average efficient run length made by 4and 3-year-olds (average = .53, sd = .36), t(30.03) = à 0.778, p = .443, 95% ci [à.36, .16] or in the average efficient run length made by 2-and 3-year-olds, t(38.31) = à2.315, p = .026, 95% ci [à.43, à.03]. in spite of the aforementioned conservatism shown by some children to perseverate on an action sequence across multiple trials, there was variation in the action sequences used by the children across trials. thus, even after discovering the 4,3,2,1 solution, children sampled other action sequences. collectively, children used 27 different action sequences in phase 1 (120 were possible) (fig. 3) . they used 12 (50.00%) of the 24 possible action sequences that were efficient, removing straws 1, 2, 3, and 4 first (e.g., 1,3,2,4 and 4,3,2,1), but used only 15 (15.63%) of the 96 possible action sequences that were inefficient in which they pulled out the irrelevant straw before releasing the reward (e.g., 5,4,3,2,1 and 3,5,4,2,1). in addition, 2 (33.33%) of the 6 different action sequences that 2-year-olds used were efficient ones, whereas 6 (50.00%) of the 12 action sequences used by 3year-olds and 10 (45.45%) of the 22 action sequences used by 4-year-olds were efficient. to determine the diversity of action sequences children used, we calculated the diversity index of their responses (shannon & weaver, 1949) . if participants repeatedly used the same action sequence (i.e., developed a habit), their diversity index would be lower than those who did not. we used wilcoxon tests (''wilcox.test") to compare participants' ''h-index" diversity index across age groups and across test phases. children's individual h-index scores in phase 1 ranged from 0.00 to 2.03, where an index score of 0 means that only one action sequence was used and an index score of 2.30 would mean that a different action sequence was used for each of the 10 trials, although this never occurred, as indicated by children's maximum score of 2.03. in phase 1, there was no significant difference in children's h-index scores across the three age groups: 2-year-olds versus 3-year-olds, t(39.12) = 0.443, p = .661, 95% ci [à.22, .34]; 3-year-olds versus 4-year-olds, t(27.40) = à 0.258, p = .799, 95% ci [à.46, .36]; 2-year-olds versus 4-year-olds, t(28.93) = 0.047, p = .963, 95% ci [à.41, .43 ]. in spite of this, we found differences across the three age groups in the relationship between their phase 1h-index score and the proportion of trials in which they used an efficient action sequence. specifically, for 4-year-olds, there was a significant negative correlation between their h-index score and their proportion of trials that were efficient {pearson's product-moment correlation: t(17) = à6.469, p < .001, 95% ci [à.94, à.63]}, and this was also the case for 3-year-olds, t(20) = à3.373, p = .003, 95% ci [à.82, à.24], but not 2-year-olds, t(18) = à1.137, p = .271, 95% ci [à.63, .21] . in contrast to phase 1, children needed to complete only 4 trials in phase 2, so there was a higher probability that they would use the same response in all trials. indeed, whereas only 16 children (26.23%) used the same response across all trials in phase 1 (described above), 29 children (47.54%) used the same response across all trials in phase 2, and 24 of these children used an efficient response for every trial (no 4-year-olds used the same inefficient action sequence repeatedly across trials). reflecting this intra-individual consistency, there was also inter-individual consistency in the specific action sequence that children used in phase 2. as in phase 1, the action sequence most commonly used by children in phase 2 was repeatedly removing the straw directly below the reward (i.e., 2,1) (fig. 5) . this action sequence represented 41.25% of 2-year-olds' trials, 62.50% of 3-year-olds' trials, and 75.00% of 4-year-olds' trials, and as in phase 1 the modal inefficient response for 2-and 3-year-olds was to remove all the straws from top to bottom (i.e., 5,4,3,2,1) (fig. 5) . in spite of children's preference for the 2,1 action sequence in phase 2, they still explored other solution phenotypes, including the alternative efficient action sequence (1,2) and an additional 25 different inefficient action sequences (fig. 5) . in addition to the 2 efficient strategies, 2-year-olds used 17 inefficient action sequences (22.22% of their action sequences were efficient), whereas 3-year-olds used 11 inefficient sequences and 4-year-olds used 10, meaning that 15.38% and 16.67% of the action sequences they used were efficient, respectively. children's individual h-index scores in phase 2 ranged from 0.00 to 1.39, where an index score of 0 means that only 1 action sequence was used and an index score of 1.39 would mean that a different action sequence was used for each of the 4 trials. as in phase 1, in phase 2 there was no significant difference in children's h-index scores across the three age groups: 2-year-olds versus 3-year-olds, t(37.42) = 1.768, p = .085, 95% ci [à.04, .60]; 3-year-olds versus 4-year-olds, t(39.00) = 0.089, p = .930, 95% ci [à.26, .29]; 2-year-olds versus 4-year-olds, t (34.79) = 1.894, p = .067, 95% ci [à.02, .61]. however, as with their responses in phase 1, we found that the older children's diversity of responses (h-index score) was negatively correlated with efficiency. specifically, for 4-and 3-year-olds, there was a significant negative correlation between their hindex score and their proportion of trials in phase 2 that were efficient {4-year-olds: t(17) = à3.101, p = .006, 95% ci [à.83, à.20]; 3-year-olds: t(20) = à2.623, p = .016, 95% ci [à.76, à.11]}, but this was not the case for 2-year-olds, t(18) = à1.776, p = .093, 95% ci [à.71, .07]. during the first trial of phase 2, when children were first presented with the novel configuration of the task (i.e., the ''switch trial"), none of the 2-year-olds made any verbal comment in relation to the task. however, 36.36% of the 3-year-olds did, as did 47.37% of the 4-year-olds. most 3-year-olds' comments reflected the change in task configuration (e.g., ''why did it go down to this one?"; ''it's not up there anymore"), whereas other comments highlighted the configuration change but also flagged the experimenter's agency in causing that change (e.g., ''why did you put two?"; ''how did you do that?"). like 3-year-olds, 4-year-olds' comments referred to the change of task configuration (e.g., ''there's only two straws"; ''hey, it's now down there") and the experimenter's causation of the change (e.g., ''how did you do that?"), but 4-year-olds also commented on how this change affected their own behavior and success (e.g., ''i only had to get two"; ''that was super fast-that's because there were only two straws"). both 3-and 4-year-olds commented on the configuration change in 46.67% of their first trials in phase 2 in which they made an efficient response (i.e., removing only the bottom two straws). in the trials in which children made an inefficient response (i.e., removing three or more straws), 14.29% of 3-year-olds commented on the change, whereas a quarter (25.00%) of 4-yearolds commented on the change. for both age groups, there was no significant difference in the numbers of efficient first trial responses in which children made a comment on the task configuration (fisher's exact test: 3-year-olds, p = .193; 4-year-olds, p = .399). in our study, we explored 2-, 3-, and 4-year-old children's ability to flexibly switch between response patterns as task demands changed. as jacobson and hopper (2019) found previously for nonhuman primates, all the children easily mastered the task and retrieved the ball from the tube. however, 4-year-olds were consistently more efficient than the younger children in terms of both the time it took them to complete trials and the number of straws they removed. this developmental trajectory in children's responses reflects previous research showing that children's problem solving and tool making skills increase with age (gönül, takmaz, hohenberger, & corballis, 2018) . indeed, the cognitive complexity and control theory proposes that ''executive function can be understood in terms of agerelated increases in the maximum complexity of the rules children can formulate and use when solving problems" (zelazo et al., 2003, p. 274) . in spite of this, there was no significant difference across the three age groups of children in their likelihood of using the newly available efficient solution when it was presented in the first trial of phase 2. we also identified intra-individual consistency in children's success such that their efficiency in phase 1 correlated with their efficiency in phase 2. given the general success of children in all age groups, it is likely that this causally clear task facilitated children's success and flexibility (in the sense of davis et al., 2019) , as has been found in chimpanzees and gorillas tested using the same task (jacobson & hopper, 2019) . our aim was to provide a task that was accessible for children in all three age groups to allow us to make meaningful across-age comparisons (as well as comparisons with nonhuman primates' responses). supporting our goal, all children spontaneously solved the task and there was no difference across the three age groups in their initial understanding of the task, as evidenced by their comparable likelihoods to use the most efficient method in their first trial of phase 1 (83.61% of children used an efficient solution in the first trial of phase 1). however, 4-year-olds showed sustained efficiency across trials in phase 1; significantly more of their trials were solved via the efficient method than those of 2-year-olds. although the 4-year-olds were not more likely to spontaneously use the most efficient solution in their first trial of phase 1 than the younger children, they were more likely to stick with it and were significantly quicker to complete their first trial, suggesting enhanced physical dexterity, potentially in combination with a better understanding of the task demands. however, and in spite of 4-year-olds' greater use of efficient solutions, within phase 1 all three age groups showed an improvement in task proficiency over time, as demonstrated by the negative correlation between trial latency and trial number. although the vast majority of children spontaneously used an efficient solution when first presented with the task, when we changed the task demands and introduced the possibility of a new efficient solution in phase 2, only 57.73% of children spontaneously used the most efficient solution with their first attempt (removing only two straws). as with the first trial of phase 1, however, there was no effect of age on children's likelihood to use an efficient solution for the first trial of phase 2. thus, nearly half of the children, irrespective of age, did not switch strategies in the first trial of phase 2. in certain situations, humans react in remarkably fixed ways even when their environment does not necessitate such rigidity (bilalić , mcleod, & gobet, 2008; gopnik, griffiths, & lucas, 2015) . for example, adults often sit in the same seat during classes or meetings even without seat assignment and when there are no repercussions for moving (costa, 2012) . the limited flexibility we observed cannot be explained by pure conservatism (in the sense of hrubesch et al., 2009) ; of the 26 children who used an inefficient solution for the first trial of phase 2, only 7 (26.92%) were inefficient because they used the exact same action sequence as they had used in the previous trial (i.e., the final trial of phase 1). we also note that a large subset of 3-and 4-year-olds remarked on the change in task configuration. although children often verbally seek out information to understand causal elements of their environment (legare et al., 2017) , our experimenters were instructed not to answer children's questions and were not useful as informants (and, anecdotally, children almost never explicitly asked for help). therefore, it is possible that children were describing the changes they observed to help themselves make sense of the changes and respond to the new task demands (winsler, fernyhough, & montero, 2009) . we had predicted that greater exploration of the task (i.e., using a range of action sequences) would protect children against conservatism and allow them to more flexibly respond when task demands changed. paradoxically, although 4-year-olds were the most efficient in their responses, they were also the most conservative; fully 73.82% of their trials in phase 1 were solved using the same action sequence (4,3,2,1), and we saw similar patterns in their responses in phase 2 (when they preferentially used the 2,1 action sequence). indeed, the older children's preferred responses (whether efficient or inefficient) were to remove straws sequentially rather than in a random pattern (although they did this on occasion). reflecting this, of the 14 children who used the same action sequence for every trial in phase 1, 8 were 4-year-olds (only 1 2-year-old used the same action sequence in every trial in phase 1). indeed, for 3-and 4-year-olds, but not 2-year-olds, there was a significant negative correlation between their h-index score and proportion of trials that were efficient. thus, for the older children, decreased diversity was associated with increased efficiency, reflecting the results of their likelihood to display longer runs of efficient action sequences (this was also seen in their phase 2 responses). in this way, the younger children's greater exploration did not benefit them either within phases or in their flexibility across phases. although conservatism is often seen as a sign of reduced cognitive flexibility, because the older children struck on and then stuck with an efficient solution from the start, they were able to sustain their efficiency (i.e., ''if it ain't broke, don't fix it"). furthermore, the older children's apparent flexibility in switching strategies from phase 1 to phase 2 might not reflect a switch but rather a continuation of the same strategy (''pull the straw below the ball"). without further controls, it is difficult to discern whether this is an insightful solution or a rigid response-sticking with the first reinforced pattern used-but we would argue the former given that the younger children also used this solution early on but did not stick with it. the increased exploration in the younger children aligns with some of the ideas outlined in the overlapping waves theory, which states that children do not simply progress from ignorance to full comprehension across development but rather proceed through cognitive waves involving data collection, mapping, strengthening, and refinement when attempting to effectively solve problems (e.g., chen, siegler, & daehler, 2000) . however, although this exploration might be viewed favorably with respect to cognitive flexibility, it is actually counter to maximizing efficiency. in phase 2, there were fewer possible action sequences that were efficient as compared with phase 1, and so we might expect that children with a strong causal understanding of the task, and a desire to be efficient, would use fewer different action sequences in phase 2 than in phase 1. indeed, this is what we saw with 4year-olds. the 4-year-olds used fewer action sequences in phase 2 (12) than in phase 1 (22), whereas the 3-year-olds used a comparable number of action sequences in both phases (12 vs. 13). although our a priori goal for this task was to remove the ball by removing as few straws as possible, we never explicitly shared this goal with the children. therefore, for the younger children, rather than maximizing efficiency, play and exploration might have been stronger drives, which can be advantageous (greve & thomsen, 2016) . a drive to play might explain why the younger children used more action sequences in phase 2, although this could also be explained by a reduced understanding of the task mechanics or could be related to young children's tendencies to be more exploratory when events are surprising (stahl & feigenson, 2017) . in addition to exploring ontogenetic changes in children's cognitive flexibility, we were also interested in comparing children's behavior in this task with that of chimpanzees and gorillas tested previously with the same task under comparable protocols. when first presented with the task, all children spontaneously retrieved the ball and 83.61% used the most efficient method with their first attempt. as noted above, the apes we tested previously were equally successful, with 84.62% of them using the most efficient method when first presented with the same task (jacobson & hopper, 2019) . however, in spite of the seeming similarities across species, there were differences in the way in which the children and apes solved the task. for example, whereas the children used 12 different efficient action sequences collectively in phase 1, the apes deployed 21. furthermore, the children used fewer action sequences on average across the first 10 trials of phase 1 as compared with the apes (see fig. s1 in the online supplementary material). the increased exploration by the apes may be due to differences in experimental protocol (children completed all 10 trials within a single session, whereas apes completed trials over one or more sessions; see jacobson & hopper, 2019, for details) . however, it is notable that whereas the 2-and 3-year-old children never used more than 4 different action sequences each, the 4-year-old children used up to seven and eight different sequences each, revealing exploration rates more similar to that of the apes. a greater percentage of the apes were flexible in adopting a more efficient response in the first trial of phase 2 as compared with the children even when comparing apes with the oldest child age group. as discussed, within phase 1 and across all three age groups, the children predominantly solved the task by repeatedly removing the straw directly below the ball (i.e., 4,3,2,1). this was also the predominant strategy used by the chimpanzees tested previously, but not by the gorillas, whose preferred strategy was to remove straws sequentially from the bottom up (i.e., 1,2,3,4) (cf. fig. 3 here with fig. 2 in jacobson & hopper, 2019) . the strategy of consistently moving the straw that the ball rests on could potentially represent a simple association that was learned by the children rather than a holistic understanding of the task mechanism, but what explains these apparent species differences is not clear at this time. the observed species differences may be a result of methodological elements between this study and that of jacobson and hopper (2019) . namely, we gave the children 10 trials in phase 1 before changing the task configuration, whereas the apes received more than 20 trials spread over multiple sessions before the task was changed. the apes' increased experience with the task may have afforded them greater experience with the task, which may have allowed them to be more flexible or simply gave them more opportunities to explore alternative action sequences. indeed, this might be why the apes' average run length was shorter than that of the children (average proportion of apes' first 10 trials that were runs = .21, sd = .13; cf. with fig. 4 here) ; however, unlike the children, the apes never performed a run of inefficient action sequences in their first 10 trials of phase 1 (see table 2 in jacobson & hopper, 2019) . future work is needed to tease apart the influences of experience, causal understanding, and conservatism on the apparent species differences we identified. from our results, we propose that causal understanding of a task not only promotes problem solving but also reduces the likelihood of conservative perseveration (see also jacobson & hopper, 2019) . however, humans are inherently social, and although we may sometimes solve problems by ourselves, we also often seek out information from others. in a landmark study, bonawitz et al. (2011) found that children were much less flexible when they were directly trained on how to use a certain object. termed the ''double-edged sword of pedagogy," children who observed someone interacting with the object were more likely to explore and learn its multiple functions, whereas those who were directly given instructions did not stray from the singular function they were taught. this effect has now been seen in a number of other contexts, such as children learning to flexibly solve new math problems (loehr, fyfe, & rittle-johnson, 2014) , and may explain children's proclivity for overimitation (lyons, young, & keil, 2007; over & carpenter, 2013; whiten, mcguigan, marshall-pescini, & hopper, 2009 ). thus, although direct social instruction can help children to quickly learn how to complete a task, it might also unnecessarily cause behavioral perseveration. conversely, nonhuman primates appear to be less influenced by social norms as compared with children (e.g., haun, rekers, & tomasello, 2014; horner & whiten, 2005 ; but see hopper, schapiro, lambeth, & brosnan, 2011) . future research could explore the role of individuals' causal understanding and their reliance on social information on cognitive flexibility (e.g., burdett, mcguigan, harrison, & whiten, 2018) from both a comparative perspective and an ontogenetic perspective (e.g., horner & whiten, 2005; pope, fagot, meguerditchian, washburn, & hopkins, 2019; stengelin, hepach, & haun, 2020; wood, kendal, & flynn, 2013) . here, we found that although all three age groups of children were successful in solving the task, 4year-olds were more efficient and more flexible in their approach to solving the task and responding to changing task demands than 2-year-olds. we previously tested apes on the same task and concluded that their ability to alter the solution strategy they used when we changed the task configuration was likely linked to their causal understanding of the task (jacobson & hopper, 2019) . unfortunately, procedural differences in testing protocols across species prevents us from making too many inferences about the apparent species differences we observed or what might drive these differences. however, we note that research using different tests of cognitive flexibility has also identified differences across human and nonhuman primates' responses to matched tasks (e.g., avdagic et al., 2014; pope et al., 2020; watzek et al., 2019) , although typically such research has tested adult humans, not young children as we did. future work exploring the interplay among social information, causal understanding, and cognitive flexibility is needed. social inhibition and behavioural flexibility when the context changes: a comparison across six primate species rapid cognitive flexibility of rhesus macaques performing psychophysical task-switching is the top object adequately supported by the bottom object? young infants' understanding of support relations repeated measures correlation lme4: linear mixed-effects models using s4 classes where's the ball? two-and three-year-olds reason about unseen events inflexibility of experts-reality or myth? quantifying the einstellung effect in chess masters the double-edged sword of pedagogy: instruction limits spontaneous exploration and discovery psychological limits on animal innovation the interaction of social and perceivable causal factors in shaping 'over-imitation across the great divide: bridging the gap between understanding of toddlers' and older children's thinking. monographs of the society for research in child development territorial behavior in public settings behavioral conservatism is linked to complexity of behavior in chimpanzees (pan troglodytes): implications for cognition and cumulative culture the effects of task comprehension on preschoolers 0 and adults 0 categorization choices beeswarm: the bee swarm plot, an alternative to stripchart theory of mind and rule-based reasoning sub-threshold autism traits: the role of trait emotional intelligence and cognitive flexibility the cognitive ontogeny of tool making in children: the role of inhibition and hierarchical structuring when younger learners can be better (or at least more open-minded) than older ones changes in cognitive flexibility and hypothesis search across human life history from childhood to adolescence to adulthood evolutionary advantages of free play during childhood children conform to the behavior of peers; other great apes stick with what they know captive chimpanzee foraging in a social setting: a test of problem solving, flexibility, and spatial discounting chimpanzees' socially maintained food preferences indicate both conservatism and conformity causal knowledge and imitation/emulation switching in chimpanzees (pan troglodytes) and children skill mastery inhibits adoption of observed alternative solutions among chimpanzees (pan troglodytes) exploring the nature of cognitive flexibility hardly habitual: chimpanzees and gorillas show flexibility in their motor responses when presented with a causally-clear task the development of problem solving in young children: a critical cognitive skill constraints on representational change: evidence from children's drawing helping children apply their knowledge to their behavior on a dimensionswitching task sorting between theories of perseveration: performance in conflict tasks requires memory, attention and inhibition causal learning is collaborative: examining explanation in social contexts wait for it delaying instruction improves mathematics problem solving: a classroom study when children are better (or at least more open-minded) learners than adults: developmental differences in learning the forms of causal relationships the hidden structure of overimitation executive functioning by 18-24-month-old children: effects of inhibition, working memory demands and narrative in a novel detour-reaching task intuitions about support in 4.5-month-old infants young children's tool innovation across culture: affordance visibility matters the social side of imitation enhanced cognitive flexibility in the seminomadic himba optional-switch cognitive flexibility in primates: chimpanzees' (pan troglodytes) intermediate susceptibility to cognitive set r: a language and environment for statistical computing the mathematical theory of communication knowing in the context of acting: the task dynamics of the a-not-b error high-expanding regions in primate cortical brain evolution support supramodal cognitive flexibility origins of knowledge the development of cognitive flexibility: evidence from children's drawings observing the unexpected enhances infants' learning and exploration expectancy violations promote learning in young children cross-cultural variation in how much, but not whether, children overimitate task-switching in human and nonhuman primates: understanding rule encoding and control from behavior to single neurons capuchin and rhesus monkeys but not humans show cognitive flexibility in an optional-switch task emulation, imitation, over-imitation and the scope of culture for child and chimpanzee ggplot2: elegant graphics for data analysis dot plots. the american statistician private speech, executive functioning, and the development of verbal selfregulation copy me or copy you? the effect of prior experience on social learning early development of executive function: a problem-solving framework an age-related dissociation between knowing rules and using them the development of executive function in early childhood. monographs of the society for research in child development a portion of this study was funded by the franklin & marshall college hackman scholars program award to lhh, and lmh received support from the lincoln park zoo's women's board. in addition, we thank the following individuals for their assistance with data collection, coding, and methods preparation: lauren hein, natalie hutchins, enya meade, you jin park, ayla saferstein, tian tian, ellen verry, fiona waters, and peiru yu. supplementary data to this article can be found online at https://doi.org/10.1016/j.jecp.2020. 104966. key: cord-023767-rcv4pl0d authors: o’ryan, miguel l.; nataro, james p.; cleary, thomas g. title: microorganisms responsible for neonatal diarrhea date: 2009-05-19 journal: infectious diseases of the fetus and newborn infant doi: 10.1016/b0-72-160537-0/50022-0 sha: doc_id: 23767 cord_uid: rcv4pl0d nan at the beginning of the 1st century, diari..eal disease continues to be a significant cause of morbidity and mortality worldwide. during the period of 1986 to 2000, an estimated 1.4 billion children younger than 5 years suffered an episode of acute diarrhea every year in developing countries; among these, 123.6 million required outpatient medical care, and 9 million required hospitalization. approximately 2 million diarrhea-associated deaths occurred in this age group annually, primarily in the most impoverished areas of the world.' these estimates are somewhat lower than the more than 3 million annual deaths from diarrhea reported in the prior 10 years? indicating progress in prevention and treatment of acute diarrhea. in the united states, approximately 400 childhood deaths per year were reported during the late 1 9 8 0~,~*~ although the actual number may be higher: accurate incidence rates for acute diarrhea in neonates from different populations are not readily available. the relative sparing of the newborn probably results from low exposure to enteropathogens and protection associated with brea~t-feeding.~-' after the first few months of life, increasing interaction with other individuals and the environment, including introduction of artificial feeding, increases the risk of exposure to enteropathogens. for most pathogens, the incidence of acute diarrhea peaks in children between 6 months and 4 years old? neonatal diarrhea is more common in underdeveloped areas, where low educational levels, crowding, and poor standards of medical care, environmental sanitation, and personal hygiene favor early contact with enteropathogens. as the incidence of neonatal gastroenteritis rises, there is a proportional increase in neonatal deaths because medical care for the poor often is inadequate.'0*" for very low birth weight infants (<1500g), the death rate from diarrhea is 100-fold greater than for higher-birth-weight infants. 12 this chapter discusses the pathogenesis, diagnosis, treatment, and prevention of gastroenteritis based on the available knowledge about pathogens that can cause neonatal diarrhea. pathogens that rarely or never cause acute diarrhea in neonates are not discussed. after an overview of host defense mechanisms and protective factors in human milk, the remainder of the chapter is devoted to specific pathogens that cause inflammatory or noninflammatory diarrhea. the neonate is a host that is uniquely susceptible to enteric infections. neonates have not had the opportunity to develop local or systemic immune responses, and in the first few days of life, they have not acquired the highly important enteric flora that protects the normal adult gastrointestinal tract.i3-" still less is known about the barrier effect of the neonate's gastric acidity," intestinal mucus,z0 or each of which provides protection against gastrointestinal tract infections in older infants, children, and adults. the gastric acid barrier appears to be least effective during the first months of life. the average gastric ph level of the newborn is high (ph 4 to 7; mean, 6).23,24 although the ph falls to low levels by the end of the first day of life (ph 2 to 3),23 it subsequently rises again; by 7 to 10 days of life, the hydrochloric acid output of the neonatal stomach is far less than that of older infants and ~hildren.~~.'~ the buffering action of frequent milk feedings and the short gastric emptying interpose additional factors in the neonate that would be expected to permit viable ingested organisms to reach the small intestine. the intestinal epithelium serves as a nutrient absorptive machine, barrier to pathogen entry, and regulator of inflammation. intestinal epithelial cells have receptors for bacterial products and produce chemokines (e.g., interleukm [ il]-8, monocyte chemotactic protein type 1 [ mcp-1 1, granulocyte macrophage-cell stimulating factor [ gm-csf] ) and proinflammatory cytokines (e.g., il-6, tumor necrosis factor-a [tnf-a], il-1) in response to invasion by enteropathogens." the gut epithelium orchestrates the immune response. however, in the newborn, phagocytic, chemotactic, and complement functions are immature. b and t lymphocyte functions are impaired, resulting in a preferential igm production in response to antigenic stimulation. igg is actively transferred from mother to infant across the placenta at about 32 weeks' gestation and peaks by about 37 weeks; premature neonates, especially those born before 28 weeks' gestation, are deficient in these maternally derived serum antib~dies.~' h e 2 6 -2 9 the importance of breast-feeding infants for the prevention of diarrheal disease has long been e m p h a s i~e d .~~~~* -~~ published studies reporting the association between breastfeeding and diarrhea are extensive and suggest that infants who are breast-fed suffer fewer episodes of diarrhea than those who are not. this protection is greatest during a child's first 3 months of life and declines with increasing age, during the period of weaning, partial breast-feeding confers protection that is intermediate between that gained by infants who are exclusively breast-fed and that by those who are exclusively bottle-fed. a striking demonstration of the protection afforded by breast-feeding of newborns has been provided by mata and urrutiai3 in their studies of a population of infants born in a rural guatemalan village. despite extremely poor sanitation and the demonstration of fecal organisms in the colostrum and milk of almost one third of diarrheal disease did not occur in any newborns. the incidence of diarrhea rose significantly only after these infants reached 4 to 6 months old, at which time solids and other fluids were used to supplement the human milk feedings. at that time, escherichia coli and gram-negative anaerobes (e.g., bacteroides) were found to colonize the intestinal tract.i3 in contrast, urban infants of a similar ethnic background who were partly or totally artificially fed frequently acquired diarrheal disease caused by enteropathogenic e. coli (epec) . multiple mechanisms by which breast-feeding protects against diarrhea have been postulated. breast-feeding confers protection by active components in milk and by decreased exposure to organisms present on or in contaminated bottles, food, or water. many protective components have been identified in human milk and generally are classified as belonging to the major categories of cells, antibody, antiinflammatory factors, and glycoconjugates and other nonantibody f a~t o r s .~~-~' examples of milk antibodies are summarized in table 20-1. for any given pathogen, multiple milk factors may help protect the infant. human milk typically targets a major pathogenic mechanism using multiple, redundant strategies. redundancy of milk protective factors and targeting of complex virulence machinery have created a formidable barrier to enteropathogens. despite the fact that pathogens can rapidly divide and mutate, milk continues to protect infants. for example, human milk has secretory antibodies to shigellu virulence antigens and lipopoly-saccharide^,^^.^^ neutral glycolipid gb3 to bind shiga and lactoferrin to disrupt and degrade the surface-expressed virulence antigen^.^^-^^ in a similar way, milk contains antibodies directed toward the surface expressed virulence antigens of epec,5' oligosaccharides that block cell attachment?9 and lactoferrin that disrupts and degrades the surface expressed epec antigens6' human milk can initiate and maintain the growth of bifidobacterium and low ph in the feces of newborn infants, creating an environment antagonistic to the growth of e. ~o l i . ' the protective effect of human milk antibodies against enteropathogen-specific disease has been described for vibrio cholerae,62 campylobacter j e j~n i , ~~ epec,59 enterotoxigenic e. coli (etec),64965 shigella,66'67 and giardia lamblia68,69 and for bovine milk concentrate against etec,70 rota~irus,~' and shigella. 72 in 1933, the nonlactose carbohydrate fraction of human milk was found to consist mainly of oligosa~charides.~~ in 1960, montreuil and mullet74 determined that up to 2.4% of colostrum and up to 1.3% of mature milk are oligosaccharides. human milk contains a larger quantity of the oligosaccharides than does milk from other mammals, and its composition is singularly complex.75 the metabolic fate of the oligosaccharides is of interest. only water, lactose, and lipids are present in greater amounts than the oligosaccharides. despite the fact that substantial energy must be expended by the mother to synthesize the many hundreds of different milk oligosaccharides, the infant does not use them as food. most of the oligosaccharides pass through the gut undigested.76377 it is thought that they are present primarily to serve as receptor analogues that misdirect enteropathogen attachment factors away from gut epithelial carbohydrate receptors. likewise, enteropathogens use the oligosaccharide portion of glycolipids and glycoproteins as targets for attachment of whole bacteria and toxins. evidence is emerging that these glycoconjugates may have an important role in protection of the breast-fed infant from disease. 48 human milk protects suckling mice from the heat-stable enterotoxin (st) of e. coli; on the basis of its chemical stability and physical properties, the protective factor has been deduced to be a neutral fucosyloligosaccharide. 79~80 experiments have shown that epec attachment to hep-2 cells can be inhibited by purified oligosaccharide fractions from human milk.59 oligosaccharides also may be relevant to protection from norwalk virus and other caliciviruses, because these viruses attach to human abo, lewis, and secretor blood group antigens.80'81 human milk contains large amounts of these carbohydrates. the ganglioside fraction in human milk has been shown to inhibit the action of heat-labile toxin (lt) and cholera toxin on ileal loops more effectively than secretory iga.82s83 lactadherin in human milk has been shown to bind rotavirus and to inhibit viral replication in vitro and in v~v o . ~~ a study of infants in mexico showed that lactadherin in human milk protected infants from symptoms of rotavirus infection.72 e. coli organisms promptly colonize the lower intestinal tracts of healthy infants in their first few days of life85-88 and constitute the predominant aerobic coliform fecal flora throughout life in humans and in many animals. the concept that this species might cause enteric disease was first suggested in the late 19th and early 20th centuries, when several veterinary workers described the association of diarrhea (i.e., in 1905, m0r0'~ observed that bacterium (now escherichia) coli was found more often in the small intestines of children with diarrhea than in children without diarrhea. adam96*97 confirmed these findings and noted the similarity with asiatic cholera and calf scours. he further extended these observations by suggesting that e. coli strains from patients with diarrhea could be distinguished from normal coliform flora by certain sugar fermentation patterns. although he called these disease-producing organisms dyspepsicoli and introduced the important concept that e. coli could cause enteric disease, biochemical reactions have not proved to be a reliable means of distinguishing nonpathogenic from pathogenic e. coli strains. there are now at least six recognized enteric pathotypes of e. ~oli.'~ the pathotypes can be distinguished clinically, epidemiologically, and pathogenetically (table 20 -2) .98104 etec organisms are defined by their ability to secrete the lt or the st enterotoxin, or both. lt is closely related to cholera toxin and similarly acts by means of intestinal adenylate c y c l a~e , '~~~'~~ prostaglandin s y n t h e~i s , '~~~'~~ and possibly platelet activating f a c t~r . '~~' '~~ st (particularly the variant sta) causes secretion by specifically activating intestinal mucosal guanylate cyclase.' "-' l3 the stb toxin causes noncyclic, nucleotide-mediated bicarbonate secretion and appears to be important only in animals.1'4-"6 enteroinvasive e. coli (eiec) has the capacity to invade the intestinal mucosa, thereby causing an inflammatory enteritis much like shigellosi~.'~~~''~ epec elicits diarrhea by a signal transduction m e~h a n i s m~~~'~~~~~'~'~~ which is accompanied by a characteristic attaching-and-effacing histopathologic lesion in the small intestine.12' enterohemorrhagic e. coli (ehec) also induces an attaching-and-effacing lesion, but in the colon?' ehec also secretes shiga toxin, which gives rise to the sequela of hemolytic-uremic syndrome (hus). diffusely adherent e. coli122 executes a signal transduction effect, which is accompanied by the induction of long cellular processes. 123 enteroaggregative e. coli (eaec) adheres to the intestinal mucosa and elaborates enterotoxins and a major problem in the recognition of etec, eiec, epec, and ehec strains of e. coli is that they are indistinguishable from normal coliform flora of the intestinal tract by the usual bacteriologic methods. serotyping is of value in recognizing epec serotypes'26 and eiec, because these organisms tend to fall into a limited number of specific serogroups (see table 20 -2).'263'27 eiec invasiveness is confirmed by inoculating fresh isolates into guinea pig conjunctivae, as described by sereny. 12' the ability of organisms to produce enterotoxins (lt or st) is encoded by a transmissible plasmid that can be lost by one strain of e. coli or transferred to a previously unrecognized although the enterotoxin plasmids appear to prefer certain serogroups (different from epec or invasive serogro~ps),'~~ etec is not expected to be strictly limited to a particular set of serogroups. instead, these strains can be recognized only by examining for the enterotoxin. this is done in ligated animal or by enzyme-linked immunosorbent assay (elisa)'36 for lt or in suckling mice for st. 137, 138 specific dna probes also are available for lt and st.98 whether there are other mechanisms involved in the ability of the versatile e. coli species to cause enteric disease, such as by producing other types of enterotoxins"' or by fimbriate adherence traits a l~n e , '~~. '~' remains to be elucidated. cytoto~ns.98~103,125 in tissue although early work on the recognition of e. coli as a potential enteric pathogen focused on biochemical or serologic distinctions, there followed a shift in emphasis to the enterotoxins produced by previously recognized and entirely "new" strains of e. coli. beginning in the mid-1950s with work by de and colleague^'^^^'^^ in calcutta, e. coli strains from patients with diarrhea were found to cause a fluid secretory response in ligated rabbit ileal loops analogous to that seen with v; cholerue. work by taylor and associate^'^"^^ showed that the viable e. coli strains were not required to produce this secretory response and that this enterotoxin production correlated poorly with classically recognized epec serotypes. in sho paulo, trabulsi'& made similar observations with e. coli isolated from children with diarrhea, and several veterinary workers demonstrated that etec was associated with diarrhea in piglets and cal~es.'~~-'~o a similar pattern was described in 1971 with acute undifferentiated diarrhea in adults in bengal from whom e. coli could be isolated from the upper small bowel only during acute i l l n e~s . '~' "~~ these strains of e. coli produced a nondialyzable, lt, ammonium sulfate-precipitable enterotoxin.'53 analogous to the usually short-lived diarrheal illnesses of e. coli reported by several workers, a short-lived course of the secretory response to e. coli culture filtrates compared with the secretory response of cholera toxin was de~cribed."~ however, like responses to cholera toxin, secretory responses to e. coli were associated with activation of intestinal mucosal adenylate cyclase that paralleled the fluid secretory r e~p o n s e . '~~. '~~ the two types of enterotoxins produced by e. have been found to be plasmid-encoded traits that are potentially separable from each other and from the equally important plasmid-encoded adherence traits for patho-st causes an immediate and reversible secretory whereas the effects of lt (e.g., cholera toxin) follow a lag period necessitated by its intracellular site of a~t i o n . '~~' '~' '~~ only lt appears to cause fluid secretion by activating adenylate cyclase, which is accomplished by toxininduced adp-ribosylation of the gsa signaling p r~t e i n .~' "~~ the activation of adenylate cyclase by lt and by cholera toxin is highly promiscuous, occurring in many cell types and resulting in development of nonintestinal tissue culture assay systems such as the chinese hamster ovary (cho) cell assay'34 and y1 adrenal cell assay.'35 the antigenic similarity of lt and cholera toxin and their apparent binding to the monosialoganglioside gm, have enabled development of elisas for detection of lt and cholera t~x i n . '~~, '~' -'~~ st is a much smaller molecule and is distinct antigenically from lt and cholera t~x i n . '~~, '~'~'~' al though it fails to alter camp levels, st increases intracellular intestinal mucosal cyclic guanosine monophosphate (cgmp) concentrations and specifically activates plasma membrane-associated intestinal guanylate cy~lase."'-"~ like camp analogues, cgmp analogues cause intestinal secretion that mimics the response to st."' the receptor for sta responds to an endogenous ligand called guunylin, of which sta is a structural homologue.'" because the capacity to produce an enterotoxin may be transmissible between different organisms by a plasmid or even a bacteri~phage,''~-'~' interstrain gene transfer genesis. [129] [130] [131] 160 may be expected to be responsible for occasional toxigenic non-e. coli. enterotoxigenic klebsiella and citrobacter strains have been associated with diarrhea in a few reports, often in the same patients with etec.'65,'66 likewise, certain strains of salmonella appear to produce an lt, cho cellpositive toxin that may play a similar role in the pathogenesis of the watery, noninflammatory diarrhea sometimes seen with salmonella enteritidis i n f e c t i~n . '~~"~ at least equally important as enterotoxigenicity for e. coli to cause disease is the ability of these organisms to colonize the upper small bowel, where the enterotoxin produced has its greatest effect. a separable, plasmid-encoded colonization trait was first recognized in porcine e. coli. veterinary workers demonstrated that the fimbriate k-88 surface antigen was necessary for etec to cause disease in piglets.16' an autosomal dominant allele appears to be responsible for the specific intestinal receptor in piglets. in elegant studies by gibbons and c o -~o r k e r s , '~~ the homozygous recessive piglets lacked the receptor for k-88 and were resistant to scours caused by etec. at least 15 analogous colonization factors have been described for human e. coli isolate^^^"^'"^^ against which local iga antibody may be produced. these antigens potentially may be useful in vaccine development. data on the epidemiology and transmission of etec remain scanty for the neonatal period. in the past 2 decades, these strains have been recognized among adults with endemic, cholera-like diarrhea in calcutta, india, and in dacca, banglade~h,''~*'~' and among travelers to areas such as mexico and central a f r i~a . '~~-'~~ the isolation of etec is uncommon in sporadic diarrheal illnesses in temperate climates where sanitation facilities are good and where winter viral patterns of diarrhea predominate. etec is commonly isolated from infants and children with acute watery summer diarrhea in areas where sanitary facilities are less than optimal.35-165*'75-'87 these include areas such as afria,165 ~~~il,35,175,181,186,187 gentir~a,'~~ bengal,'78''79 mexico,'8o and native american reservations in the southwestern united state^."^"'^ in a multicenter study of acute diarrhea in 3640 infants and children in china, india, mexico, myanmar, and pakistan, 16% of cases (versus 5% of 3279 controls) had etec.le4 a case-control study from northwestern spain showed a highly significant association of etec with 26.5% of neonatal diarrhea, often acquired in the ho~pital.''~ although all types of etec (lt and/or st producers) are associated with cholera-like, non inflammatory, watery diarrhea in adults in these areas, they probably constitute the major cause (along with rotaviruses) of dehydrating diarrhea in infants and young children in these areas. in this setting, peaks of illnesses tend to occur in the summer or rainy season, and dehydrating illnesses may be life threatening, especially in infants and young ~h i l d r e n . 3~~'~'~'~ humans are probably the major reservoirs for the human strains of etec, and contaminated food and water probably constitute the principal vector^.''^"^^ although antitoxic immunity to lt and asymptomatic infection with ltproducing e. coli tends to increase with age, st is poorly immunogenic, and st-producing e. coli continues to be associated with symptomatic illnesses into adulthood in endemic area~.l'~>l'~ the association of etec with outbreaks of diarrhea in newborn nurseries is well documented. ryder and colleagues'g0 isolated an st-producing e. coli from 72% of infants with diarrhea, from the environment, and in one instance, from an infant's formula during a 7-month period in a prolonged outbreak in .a special care nursery in texas. another st-producing e. coli outbreak was reported in 1976 by gross and a~sociates'~~ from a maternity hospital in scotland. etec and epec were significantly associated with diarrhea among infants younger than 1 year in bang1ade~h.l~ ' an outbreak of diarrhea in a newborn special care nursery that was associated with enterotoxigenic organisms that were not limited to the same serotype or even the same species has been reported.lg3 the short-lived etec, klebsiella, and citrobacter species in this outbreak raised the possibility that each infant's indigenous bowel flora might become transiently toxigenic, possibly by receiving the lt genome from a plasmid or even a bacteriophage. the clinical manifestations of etec diarrhea tend to be mild and self-limited, except in small or undernourished infants, in whom dehydration may constitute a major threat to life. in many parts of the developing world, acute diarrheal illnesses are the leading recognized causes of death. there is some suggestion that the diarrheal illnesses associated with st-producing etec may be particularly severe.'79 most probably the best definition of the clinical manifestations of etec infection comes from volunteer studies with adults. ingestion of 10' to 10'' human etec isolates that produce lt and st or st alone resulted in a 30% to 80% attack rate of mild to moderate diarrheal illnesses within 12 to 56 hours that lasted 1 to 3 days.'17 these illnesses, typical for traveler's diarrhea, were manifested by malaise, anorexia, abdominal cramps, and sometimes explosive diarrhea. nausea and vomiting occur relatively infrequently, and up to one third of patients may have a low-grade fever. although illnesses usually resolve spontaneously within 1 to 5 days, they occasionally may persist for 1 week or longer. the diarrhea is noninflammatory, without fecal leukocytes or blood. in outbreaks in infants and neonates, the duration has been in the same range (1 to 11 days), with a mean of approximately 4 days. as in cholera, the pathologic changes associated with etec infection are minimal. from animal experiments in which thiry-vella loops were infected with these organisms and at a time when the secretory and adenylate cyclase responses were present, there was only a mild discharge of mucus from goblet cells and otherwise no significant pathologic change in the intestinal tract.lo6 unless terminal complications of severe hypotension ensue, etec organisms rarely disseminate beyond the intestinal tract. like cholera, etec diarrhea is typically limited to being an intraluminal infection. the preliminary diagnosis of etec diarrhea can be suspected by the epidemiologic setting and the noninflammatory nature of stool specimens, which reveal few or no leukocytes. although the ability of e. coli to produce enterotoxins may be lost or transmitted to other strains, there is a tendency for the enterotoxin plasmids to occur among certain predominant serotypes, as shown in table 20 -2."' these serotypes differ from epec or invasive serotypes, but their demonstration does not prove that they are enterotoxigenic. the only definitive way to identify etec is to demonstrate the enterotoxin itself by a specific gene probe for the toxin codon, by a bioassay such as tissue culture or ileal loop assays for lt or the suckling mouse assay for st, or in the case of lt, by immunoassay such as elisa. however, even these sensitive bioassays are limited by the unavailability of any selective media for detecting etec by culture. even though substantial improvements have been made in enterotoxin assay (particularly for lt), the necessary random selection of e. coli from a relatively nonselective stool culture plate resulted in a sensitivity of only 43% of epidemiologically incriminated cases in an outbreak when 5 to 10 isolates were randomly picked and tested for enter~toxigenicity."~ by also examining paired serum samples for antibody against lt, only 36% demonstrated significant serum antibody titer rises, for a total sensitivity of etec isolation or serum antibody titer rises of only 64%. some have suggested that isolates may be pooled for lt or st assay. the capacity to prove with radiolabeled or enzyme-tagged oligonucleotide gene sequences for the enterotoxins (lt or st) further facilitates the identification of enterotoxigenic organisms.'94s195 a novel method of combining immunomagnetic separation (using antibodycoated magnetic beads) followed by dna or polymerase chain reaction (pcr) probing may enhance the sensitivity of screenin fecal or food specimens for etec or other the mainstay of treatment of any diarrheal illness is rehydration."' this principle especially pertains to etec diarrhea, which is an intraluminal infection. the glucose absorptive mechanism remains intact in e. coli enterotoxininduced secretion, much as it does in cholera, a concept that has resulted in the major advance of oral glucose-electrolyte therapy. this regimen can usually provide fully adequate rehydration in infants and children able to tolerate oral fluids, replacing the need for parented rehydration in most cases .199,200 its use is particularly critical in rural areas and developing nations, where early application before dehydration becomes severe may be lifesaving. the standard world health organization solution contains 3.5 g nacl, 2.5 g nahco,, 1.5 g kcl, and 20 g glucose per liter of clean or boiled drinking water.i9' this corresponds to the following concentrations: 90 mmoyl of sodium, 20 mmovl of potassium, 30 mmoyl of bicarbonate, 80 mmol/l of chloride, and 1 10 mmol/l of glucose. a variety of recipes for homemade preparations have been described?" but unless the cost is prohibitive, the premade standard solution is preferred. each 4 ounces of this solution should be followed by 2 ounces of plain water. if there is concern about hypertonicity, especially in small infants in whom a high intake and constant direct supervision of feeding cannot be ensured, the concentration of salt can be reduced.'02 a reduced osmolality solution with 60 mmol/l of sodium and 84 mmoyl of glucose and a total osmolality of 224 (instead of 311) mosm/kg has been found to reduce stool output by 28% and illness duration by 18% in a multicenter trial involving 447 children in four countries.203 commercially available rehydration solutions are increasingly available ~orldwide.'~' pathogens. lf6,197 the role of antimicrobial agents in the treatment or prevention of etec is controversial. this infection usually resolves within 3 to 5 days in the absence of antibacterial therapy.198 moreover, there is concern about the potential for coexistence of enterotoxigenicity and antibiotic resistance on the same plasmid, and co-transfer of multiple antibiotic resistance and enterotoxigenicity has been well d~cumented."~ widespread use of prophylactic antibiotics in areas where antimicrobial resistance is common has the potential for selecting for rather than against enterotoxigenic organisms. the prevention and control of etec infections would be similar to those discussed under epec serotypes. the use of breast-feeding should be encouraged. eiec causes diarrhea by means of shigella-like intestinal epithelial invasion (discussed later).117s11' the somatic antigens of these invasive strains have been identified and seem to fall into 1 of 10 recognized 0 groups (see table 20 -2). most, if not all, of these bacteria share cell wall antigens with one or another of the various shigelza serotypes and produce positive reactions with antisera against the cross-reacting antigen."* however, not all strains of e. coli belonging to the 10 serogroups associated with dysentery-lke illness are pathogenic, because a large (140 mda) invasive plasmid is also required.205 additional biologic tests, including the guinea pig conjunctivitis (sereny) test or a gene probe for the plasmid, are used to confirm the property of inva~iveness."~ although an outbreak of foodborne eiec diarrhea has been well documented among adults who ate an imported cheese,"' little is known about the epidemiology and transmission of this organism, especially in newborns and infants. whether the infectious dose may be as low as it is for shigella is unknown; however, studies of adult volunteers suggest that attack rates may be somewhat lower after ingestion of even large numbers of eiec than would be expected with shigella. the outbreak of eiec diarrhea resulted in a dysentery-like syndrome with an inflammatory exudate in stool and invasion and disruption of colonic mucosa."' descriptions of extensive and severe ileocolitis in infants dying with e. coli diarrhea indicate that neonatal disease also can be caused by invasive strains capable of mimicking the pathologic features of shigellosis. 206 the immunofluorescent demonstration of e. coli together with an acute inflammatory infiltrate2" in the intestinal tissue of infants tends to support this impression, although it has been suggested that the organisms may have invaded the bowel wall in the postmortem ~e r i 0 d . l '~ there is still little direct evidence concerning the role of invasive strains of e. coli in the cause of neonatal diarrhea.175 the infrequency with which newborns manifest a dysentery-like syndrome makes it unlikely that this pathogen is responsible for a very large proportion of the diarrheal disease that occurs during the first month of life. the diagnosis should be suspected in infants who have an inflammatory diarrhea as evidenced by fecal polymorphonuclear neutrophils or even bloody dysenteric syndromes from whom no other invasive pathogens, such as campylobacter, shigella, salmonella, vibrio, or yersinia, can be isolated. in this instance, it may be appropriate to have the fecal e. coli isolated and serotyped or tested for invasiveness in the sereny test. plasmid pattern analysis and chromosomal restriction endonuclease digestion pattern analysis by pulsed-field gel electrophoresis have been used to evaluate strains involved in outbreaks. 208 the management and prevention of eiec diarrhea should be similar to those for acute shigella or other e. coli enteric infections. the serologic distinction of e. coli strains associated with epidemic and sporadic infantile diarrhea was first suggested by goldschmidt in 1933209 and confirmed by dulaney and michelson in 1935. 205 these researchers found that certain strains of e. coli associated with institutional outbreaks of diarrhea would agglutinate with antisera on slides. in 1943, bra?" isolated a serologically homogeneous strain of e. coli (subsequently identified as serogroup 0111) from 95% of infants with summer diarrhea in england. he subsequently summarized a larger experience with this organism isolated from only 4% of asymptomatic controls but from 88% of infants with diarrhea, one half of which was hospital this strain (initially called e. coli-gomez by varela in 1946) also was associated with infantile diarrhea in a second type of e. coli (called beta by giles in 1948 and subsequently identified as 055) was associated with an outbreak of infantile diarrhea in aberdeen, s~o t l a n d .~'~*~'~ from this early work primarily with epidemic diarrhea in infants has developed an elaborate serotyping system for certain e. coli strains that were clearly associated with infantile these strains first were called enteropathogenic e. coli by neter and colleagues219 in 1955, and the association with particular serotypes can still be observed.220 as shown in table 20 -1, these organisms are distinct from the enterotoxigenic or enteroinvasive organisms or those that inhabit the normal gastrointestinal tract. they exhibit localized adherence to hep-2 cells, a phenotype that has been suggested to be useful for diagnosis and pathogenesis research. 'i9 epec is an important cause of diarrhea in infants in developing or transitional c~u n t r i e s .~"~~' -~~~ outbreaks have become rare in the united states and other industrialized countries, but they still 0ccur.2~~ some have attributed the rarity of this recognition of illness in part to the declining severity of diarrheal disease caused by epec within the past 30 years, resulting in fewer cultures being obtained from infants with relatively mild symptom^.^^^^^^ however, several other variables influence the apparent incidence of this disease in the community. a problem arises with false-positive epec on the basis of the nonspecific cross-reactions seen with improper shortening of the serotyping p r o c e d~r e .~~~,~~~ because of their complexity and relatively low yield, neither slide agglutination nor hep-2 cell adherence or dna probe tests are provided as part of the routine identification of enteric pathogens by most clinical bacteriology laboratories. failure to recognize the presence of epec in fecal specimens is the inevitable consequence. the apparent incidence of epec gastroenteritis also varies with the epidemiologic circumstances under which stool cultures are obtained. the prevalence of enteropathogenic strains is higher among infants from whom cultures are obtained during a community epidemic compared with those obtained during sporadic diarrheal disease. neither reflects the incidence of epec infection among infants involved in a nursery outbreak or hospital epidemic. epec gastroenteritis is a worldwide problem, and socioeconomic conditions play a significant role in determining the incidence of this disease in different populations.22s for instance, it is unusual for newborn infants born in a rural environment to manifest diarrheal disease caused by epec; most infections of the gastrointestinal tract in these infants occur after the first 6 months of conversely, among infants born in large cities, the attack rate of epec is high during the first 3 months of life. this age distribution reflects in large part the frequency with which epec causes crossinfection outbreaks among nursery populations'9'~230~237; however, a predominance of epec in infants in the first 3 months of life also has been described in community epidemic^^^'-^^^ and among sporadic cases of diarrhea acquired outside the h~s p i t a l . '~' -~~~ the disparity in the incidence of neonatal epec infection between rural and urban populations has been ascribed to two factors: the trend away from breast-feeding among mothers in industrialized societies and the crowding together of susceptible newborns in nurseries in countries in which hospital deliveries predominate over home d e l i~e r i e s . 5 '~~~'~~ although the predominant serogroup can vary from year to year,239,242,243,z46.249~250 the same strains have been prevalent during the past 40 years in great britain?51 puerto r~c o ?~~ guatemala: panama, 205 newfoundland,240 indonesia,244 thailand,254 and south when living conditions are poor and overcrowding of susceptible infants exists, there is a rise in the incidence of neonatal diarrhea in general257 and epec gastroenteritis in p a r t i c~l a r .~'~~~~~~~~~ a h igher incidence of asymptomatic family carriers is found in such situations.238b239 newborn infants can acquire epec during the first days of life by one of several routes: (1) organisms from the mother ingested at the time of birth; ( 2 ) bacteria from other infants or toddlers with diarrheal disease or from asymptomatic adults colonized with the organism, commonly transmitted on the hands of nursery personnel or parents; (3) airborne or droplet infection; (4) fomites; or (5) organisms present in formulas or solid food supplements.259 only the first two routes have been shown conclusively to be of any real significance in the transmission of disease or the propagation of epidemics. most neonates acquire epec at the time of delivery through ingestion of organisms residing in the maternal birth canal or rectum. stool cultures taken from women before, during, or shortly after delivery have shown that 10% to 15% carry epec at some time during this period.85~s6~88~260~26' use of fluorescent antibody techniquesz6' or cultures during a community outbreak of epec gastroenteritis" revealed twice this number of persons excreting the organism. virtually none of the women carrying pathogenic strains of e. coli had symptoms referable to the gastrointestinal tract. many of the mothers whose stools contain epec transmit these organisms to their infant~,8~*~' resulting in an asymptomatic infection rate of 2% to 5% among newborns cultured at random in nursery surveys.85~86~19'~262 these results must be considered conservative and are probably an artifact of the sampling technique. one study using 150 0 antisera to identify as many e. coli as possible in fecal cultures showed a correlation between the coliform flora in 66% of motherinfant pairs?63 of particular interest was the observation that the 0 groups of e. coli isolated from the infants' mucus immediately after delivery correlated with those subsequently recovered from their stools, supporting the contention that these organisms were acquired orally at the time of birth. in mothers whose stools contained the same 0 group as their offspring, the mean time from rupture of membranes to delivery was about 2 hours longer than in those whose infants did not acquire the same serogroups, suggesting that ascending colonization before birth also can play a role in determining the newborn's fecal flora. the contours of the epidemiologic curves in nurse$38264-269 and communi@38-240 outbreaks are in keeping with a contact mode of spread. transmission of organisms from infant to infant takes place by way of the fecal-oral route in almost all cases, most likely on the hands of persons attending to their care.86*267,269,270 ill infants represent the greatest risk to those around them because of the large numbers of organisms found in their stools271-274 and crossinfection also has been initiated by infants who were healthy at the time of their admission to the nursery.264,2723278-280 a newborn exposed to epec is likely to acquire enteric infection if contact with a person excreting the organism is intimate and prolonged, as in a hospital or family setting. stool culture surveys taken during outbreaks have shown that between 20% and 50% of term neonates residing in the nursery carry epec in their intestinal tracts.'02,230,231'm despite descriptions of nursery outbreaks in which virtually every neonate or low-birth-weight infant became infected,26232643281 there is ample evidence that exposure to pathogenic strains of e. coli does not necessarily result in greater likelihood of illness for premature infants than for term infants.261,272*279,282 any increased prevalence of cross-infections that may exist among premature infants can be explained more readily by the prolonged hospital stays, their increased handling, and the clustering of infants born in different institutions than by a particular susceptibility to epec based on immature defense mechanisms. the most extensive studies on the epidemiology of gastroenteritis related to e. coli have dealt with events that took place during outbreaks in newborn nurseries. unfortunately, investigations of this sort frequently regard the epidemic as an isolated phenomenon and ignore the strong interdependence that exists between community-and hospital-acquired ~~~~~~2 8 0 , 2 8 3 , 2 8 4 n ot surprisingly, the direction of spread is most often from the reservoir of disease within the community to the hospital. when the original source of a nursery outbreak can be established, frequently it is an infant born of a carrier mother who recently acquired her epec infection from a toddler living in the home. cross-infection epidemics also can be initiated by infected newborns who have been admitted directly into a clean nursery unit from the surrounding d i s t r i~t~~~~~~~*~~~ or have been transferred from a nearby hospital. 27832803286 after a nursery epidemic has begun, it generally follows one of two major patterns. some are explosive, with rapid involvement of all susceptible infants and a duration that seldom exceeds 2 or 3 months.264*265,276*287 the case-fatality rate in these epidemics may be very high. other nursery outbreaks have an insidious onset with a few mild, unrecognized cases; the patients may not even develop illness until after discharge from the hospital. during the next few days to weeks, neonates with an increased number of loose stools are reported by the nurses; shortly thereafter, the appearance of the first severely ill infants makes it apparent that an epidemic has begun. unless oral antimicrobial therapy is instituted (see "therapy"), nursery outbreaks like these may continue for months266-269 or with cycles of illness followed by periods of relative quiescence. this pattern can be caused by multiple strains (of different phage or antibiogram types) sequentially introduced into the nursery?78*288.289 the nursery can be a source of infection for the community. the release of infants who are in the incubation stages of their illness or are convalescent carriers about to relapse may lead to secondary cases of diarrheal disease among young siblings living in widely scattered areas.238,239,243 these children further disseminate infection to neighboring households, involving playmates of their own age, young infants, and mothers.23832393242 as the sickest of these contact cases are admitted to different hospitals, they contaminate new susceptible persons, completing the cycle and compounding the outbreak. this feedback mechanism has proved to be a means of spreading infantile gastroenteritis through entire ~o~n t i e s , 2~~~~~~,~~~ and even provinces.240 one major epidemic of diarrhea related to epec 01 11:b4 that occurred in the metropolitan chicago and northwestern indiana region during the winter of 1961 involved more than 1300 children and 29 community hospitals during a period of 9 months.240,291 almost all of the patients were younger than 2 years old, and 10% were younger than 1 month, producing an age-specific attack rate of nearly 4% of neonates in the community. the importance of the hospital as a source of cross-infection in this epidemic was demonstrated through interviews with patients' families, indicating that a minimum of 40% of infants had direct or indirect contact with a hospital shortly before the onset of their illness. it has been suggested, but not proved, that asymptomatic carriers of epec in close contact with a newborn infant, such as nursery personnel or family members, might play an important role in its t r a n s m i~s i o n .~~~'~"~~~ stool culture surveys have shown that at any one time about 1% of and 1% to 5% of young who are free of illness harbor epec strains. higher percentages have been recorded during community epidemics?38*239s243 be cause this intestinal carriage is transitory:383280 the number of individuals who excrete epec at one time or another during the year is far higher than the 1% figure recorded for single specimens.2803293 nursery personnel feed, bathe, and diaper a constantly changing population of newborns, about 2% to 5% of whom excrete epec.238*280 despite this constant exposure, intestinal carriage among nursery workers is surprisingly low. even during outbreaks of diarrheal illness, when dissemination of organisms is most intense, less than 5% of the hospital personnel in direct contact with infected neonates are themselves excreting pathogenic strains of e. coli.29',294,295 although adult asymptomatic carriers generally excrete fewer organisms than patients with acute illness large numbers of pathogenic bacteria may nevertheless exist in their stools?42s274 however, no nursery outbreak and few family cases24o have been traced to a symptomless carrier. instead, passive transfer of bacteria from infant to infant by the hands of personnel appears to be of primary importance in these outbreaks. cities,238.239,242 epec can be recovered from the throat or nose of 5% to 80% of infants with diarrheal illness275p2949295 and from about 1% of asymptomatic the throat and nasal mucosa may represent a portal of entry or a source of transmission for epec. environmental studies have shown that epec is distributed readily and widely in the vicinity of an infant with active diarrheal disease, often within 1 day of admission to the ~a r d . '~' , '~~ massive numbers of organisms are shed in the diarrheal stool or vomitus of infected e. coli organisms may survive 2 to 4 weeks in dust243.296 and can be found in the nursery air when the bedding or diapers of infected infants are disturbed during routine nursing procedure^^^^^^^ or on floors, walls, cupboards, and nursery equipment such as scales, hand towels, bassinets, incubators, and oxygen tents of other infant^?^,'^^,'^^ documentation of the presence of epec in nursery air and dust does not establish the importance of this route as a source of cross-infection. one study presented evidence of the respiratory transmission of epec; however, even in the cases described, the investigators pointed out that fecal-oral transmission could not be completely ruled additional clinical and experimental data are required to clarify the significance of droplet and environmental infection. coliform organisms have also been isolated in significant numbers from human mi1k,46~297~298 prebottled infant f0rmulas,2~~ and formulas prepared in the home.292 epec in particular has been found in stool cultures obtained from donors of human milk and workers in a nursery formula room.26o in one instance, epec 01 11:b4 was isolated from a donor, and subsequently, the same serogroup was recovered in massive amounts in almost pure culture from her milk.260 pathogenic strains of e. coli have also been isolated from raw cow's milk3'' and from drinking ~a t e r .~" likewise, epec has been isolated from flies during an epidemic, but this fact has not been shown to be of epidemiologic significance.211'220 infection of the newborn infant with epec takes place exclusively by the oral route. attempts to induce disease in adult volunteers by rectal instillation of infected material have been unsuc~essful.~~ there are no reports of disease occurring after transplacental invasion of the fetal bloodstream by enteropathogenic or nonenteropathogenic strains of e. coli. ascending intrauterine infection after prolonged rupture of the membranes has been reported only once; the neonate in this case suffered only from mild diarrhea.86 bacterial cultures of the meconium and feces of newborns indicate that enteropathogenic strains of e. coli can colonize effectively the intestinal tract in the first days of although e. coli may disappear completely from stools of breast-fed children during the ensuing weeks, this disappearance is believed to be related to factors present in the human milk rather than the gastric secretions.5~302~303 the use of breast-feeding or expressed human milk has even been effective in terminating nursery epidemics caused by epec 0 11 1:b4, probably by reducing the incidence of crossinfections among infants.3033304 although dose-effect studies have not been performed among newborns, severe diarrhea has occurred after ingestion of 10' epec organisms by very young the high incidence of cross-infection outbreaks in newborn nurseries suggests that a far lower inoculum can often effect spread in this setting. the role of circulating immunity in the prevention of gastrointestinal tract disease related to epec has not been clearly established. virtually 100% of maternal sera have been found to contain hemaggl~tinating,2'~~~''~~'~ or bacteriostatic2'0~3'2 antibodies against epec. the passive transfer of these antibodies across the placenta is extremely inefficient. titers in blood of newborn infants are, on average, 4 to 100 times lower than those in the corresponding maternal sera. group-specific hemagglutinating antibodies against the 0 antigen of epec are present in 10% to 20% of cord blood samp1es,219~307~308 whereas b a~t e r i c i d a l~'~~~~~ or bacterio-static3" activity against these organisms can be found much more frequently. tests for bacterial agglutination, which are relatively insensitive, are positive in only a small percentage of neonate^.'^^'^" the importance of circulating antibodies in the susceptibility of infants to epec infection is unknown. experiments with suckling mice have failed to demonstrate any effect of humoral immunity on the establishment or course of duration of intestinal colonization with e. coli 0127 in mothers or their infants.313 similar observations have been made in epidemiologic studies among premature human infants using enteropathogenic (01 27:b8)310 and nonenteropathogenic (04:h5)269 strains of e. coli as the indicator organisms. in a cohort of 63 mothers and their infants followed from birth to 3 months old, cooper and associate^'^ were able to show a far higher incidence of clinical epec disease in infants of epec-negative mothers than in infants born of mothers with epec isolated from stool cultures. this finding suggested to the investigators the possibility that mothers harboring epec in their gastrointestinal tracts transfer specific antibodies to their infants that confer some protection during the first weeks of life. protection against enteric infections in humans often correlates more closely with levels of local secretory than serum antibodies. although it is known that colonization of newborns with e. coli leads to the production of coproantibodies against the ingested the clinical significance of this intestinal immunity is uncertain. the previously mentioned experiment with mice showed no effect of active intestinal immunity on enteric col~nization.~'~ in human infants, the frequency of bacteriologic and clinical relapse related to epec of the same and the capacity of one strain of epec to superinfect a patient already harboring a different train^^^,^^^,^^^ also cast some doubt on the ability of mucosal antibodies to inhibit or alter the course of intestinal infection. studies of the protective effects of orally administered epec vaccines could help to resolve these question^.'^' the mechanism by which epec causes diarrhea involves a complex array of plasmid and chromosomally encoded traits. epec serotypes usually do not make one of the recognized enterotoxins (lt or st) as usually measured in tissue culture or animal r n~d e l s ,~'~~~'~ nor do these serotypes cause a typical invasive colitis or produce a positive sereny test only uncommonly do epec strains invade the bloodstream or disseminate.288 nevertheless, epec strains that test negative in these tests are capable of causing diarrhea; inocula of 10'' e. coli 0142 or 0127 organisms caused diarrhea in 8 of 10 adult volunteers.320 some epec strains may secrete weak enterot~xins,~~''~'~ but the consensus opinion is that the attaching and effacing lesion constitutes the critical secretory virulence pheno-clinical pathologic reports reveal the characteristic attachin and effacing lesion in the small intestine of infected infants? the lesion is manifested by intimate (about 10 nm) apposition of the epec to the enterocytes plasma membrane, with dissolution of the normal brush border and rearrangement of the cyto~keleton.'''~~~~ in some instances, the bacteria are observed to rise up on pedestal-like structures, which are diagnostic of the infection.i2' villus blunting, crypt hypertrophy, histiocytic infiltration in the lamina propria, and a reduction in the brush border enzymes may also be ~bserved.~'~'~'~ two major epec virulence factors have been described; strains with both factors are designated as typical epec.98*99*3'3 one such factor is the locus of enterocyte effacement (lee), a type 111 secretion system encoded by the lee chromosomal pathogenicity i~land.~'~-~'* the lee secretion apparatus injects proteins directly from the cytoplasm of the infecting bacterium into the cytoplasm of the target enter~cytes.~'~ the injected proteins constitute cytoskeletal toxins, which together elicit the close apposition of the bacterium to the cell, cause the effacement of microvilli, and most likely give rise to the net secretory one critical secreted protein, called towinterleukin-1 receptor (tir),"' inserts into the plasma membrane of the epithelial cell, where it serves as the receptor for a lee-encoded epec outer membrane protein called intimin.'" animals infected with attaching and effacin pathogens mount antibody responses to intimin and t i r ! 9 and both are considered potential immunogens. the lack of protection from epec reinfection suggests that natural antibody responses to tir and intimin are not protective. the second major virulence factor of typical epec is the bundle-forming pilus (bfp),330 which is encoded on a partially conserved 60 mda virulence plasmid called epec adherence factor bfp, a member of the type iv pilus family, mediates aggregation of the bacteria to each other and probably to enterocytes themselves, thereby facilitating mucosal colonization.332 a bfp mutant was shown to be attenuated in adult volunteers.333 the principal pathologic lesion with epec is the focal destructive adherence of the organism, effacing the microvillous brush border with villus blunting, crypt hypertrophy, histiocytic infiltration of the lamina propria, and reduced brush border enzymes. rothbaum and colleagues324 described similar findings with dissolution of the glycocalyx and flattened microvilli with the nontoxigenic epec strain 0119:b14. there has been a wide range of pathologic findings reported in infants dying of epec gastroenteritis. most newborns dying with diarrheal disease caused by epec show no morphologic changes of the gastrointestinal tract by gross or microscopic examination of tiss~es.~'~'~'' bra?" described such "meager" changes in the intestinal tract that "the impression received was that the term gastroenteritis is incorrect." at the other extreme, extensive and severe involvement of the intestinal tract, although distinctly unusual among neonates with epec diarrhea, has been discussed in several reviews of the pathologic anatomy of this disease.247v3 19,334 changes virtually identical to those found in infants dying with necrotizing enterocolitis have been reported.334 drucker and c o -~o r k e r s~'~ found that among 17 infants who were dying of epec diarrhea, "intestinal gangrene, and/or perforation, andlor peritonitis were present in five, and intestinal pneumatosis in five." the reasons for such wide discrepancies in epec disease pathology are not clear. the severity of intestinal lesions at the time of death does not correlate with the birth weight of the patient, the age of onset of illness, the serogroup of the infecting strain, or the prior administration of oral or systemic antimicrobial agents. the suggestion that the intensity of inflammatory changes may depend on the duration of the diarrhea3'' cannot be corroborated in autopsy s t~d i e s~'~*~"~~~ or small intestinal it is difficult to reconcile such a thesis with the observation that a wide range of intestinal findings can be seen at autopsy among newborns infected by a single serotype of epec during an epidemic. the nonspecific pathologic picture described by some researchers includes capillary congestion and edema of the bowel wall and an increase in the number of eosinophils, plasma cells, macrophages, and mononuclear cells in the mucosa and submucosa.262,319,335 villous patterns are generally well preserved, although some flattening and broadening of the villi are seen in the more severe cases. almost complete absence of villi and failure of regeneration of small bowel mucosa have been reported in an extreme case.338 edema in and around the myenteric plexuses of auerbach, a common associated finding, has been suggested as a cause of the gastrointestinal tract dilatation often seen at autopsy in infants with epec infection^.^^^'^^^'^^^ in general, the distal small intestine shows the most marked alterations; however, the reported pathologic findings may be found at all levels of the intestinal tract. several complications of epec infection have been reported. candidal esophagitis accounted for significant morbidity in two series collected before'" and the antibiotic era. oral thrush has been seen in 50% of epecinfected infants treated with oral or systemic antib i o t i c~. '~~,~~"~~ some degree of fatty metamorphosis of the liver has been reported by several investigators"0i2'5 335; however, these changes are nonspecific and probably result from the poor caloric intake associated with persistent diarrhea or vomiting. some degree of bronchopneumonia, probably a terminal event in most cases, exists in a large proportion of newborns dying of epec i n f e~t i o n .~" " '~'~~~ in one reported series of infant cases, epec was demonstrated by immunofluorescent staining in the bronchi, alveoli, and interalveolar septa. mesenteric lymph nodes are often swollen and congested with reactive germinal centers in the lymphoid f o l l i~l e s . 2 '~~~~, '~~ severe lymphoid depletion, unrelated to the duration or severity of the antecedent illness, also has been de~cribed.'~~ the kidneys frequently show tubular epithelial toxic changes. various degrees of tubular degeneration and cloudy swelling of convoluted tubules are common finding^.^'^,'^^,^^^ renal vein thrombosis or cortical necrosis may be observed in infants with disseminated intravascular coagulation in the terminal phases of the illness. the heart is grossly normal in most instances but may show minimal vacuolar changes of nonspecific toxic myocarditis on microscopic examinati0n.3~~'~~' candidal abscesses of the heart339 and kidneys'85,335,339 have been described. with the exception of mild congestion of the pia arachnoid vessels and some edema of the meninges, examination of the central nervous system reveals few changes?153262 despite the observation of braf l1 that "inflammation of the middle ear [is] exceptional," strains of epec have been isolated from a significant number of specimens of the middle ear in case series in which dissection of the temporal bone has been performed.2093215 exposure of newborns to epec may be followed by one of several possible consequences: no infection, infection without illness, illness with gastroenteritis of variable severity and duration, and rarely, septicemia with or without metastatic foci of infection accompanying gastroenteritis. when infants are exposed to epec, a significant number become colonized as temporary st00185,888231 or pharyngeal238 carriers with no signs of clinical disease. although l a~r e l l~~' showed that the percentage of asymptomatic infections rises steadily as age increases, this observation has not been confirmed by other investigator^.^'^.^^^ similarly, the suggestion that prematurity per se is associated with a low incidence of inapparent epec infection has been documented in several clinical but refuted in others.252,279 most neonates who acquire infection with epec eventually show some clinical evidence of gastroenteritis. the incubation period is quite variable. its duration has been calculated mostly from evidence in outbreaks in newborn nurseries, where the time of first exposure can be clearly defined in terms of birth or admission dates. in these circumstances, almost all infants show signs of illness between 2 and 12 days after exposure, and most cases show signs within the first 7 days.215,231,264 in some naturally and experi-menta1306 infections with heavy exposure, the incubation period may be as short as 24 hours; the stated upper limit is 20 days.2323343 the first positive stool culture and the earliest recognizable clinical signs of disease occur simultaneously in most although colonization may precede symptoms by 7 to 14 days.265,2663344 th e gastroenteritis associated with epec infection in the newborn is notable for its marked variation in clinical pattern. clinical manifestations vary from mild illness manifest only by transient anorexia and failure to gain weight to a sudden explosive fulminating diarrhea causing death within 12 hours of onset. prematurity, underlying disease, and congenital anomalies often are associated with the more severe forms of illness.214,233,345,346 experienced clinicians have observed that the severity of epec gastroenteritis has declined markedly during the past 3 decades.225 the onset of illness usually is insidious, with vague signs of reluctance to feed, lethargy, spitting up of formula, mild abdominal distention, or even weight loss that may occur for 1 or 2 days before the first loose stool is passed. diarrhea usually begins abruptly. it may be continuous and violent, or in milder infections, it may run an intermittent course with 1 or more days of normal stools followed by 1 or more days of diarrhea. emesis sometimes is a prominent and persistent early finding. stools are loose and bright yellow initially, later becoming watery, mucoid, and green. flecks or streaks of blood, which are commonly seen with enterocolitis caused by salmonella, campylobacter, or shigella, are rarely a feature of epec diarrheal disease. a characteristic seminal smell may pervade the environment of infants infected with epec 0 1 1 1:b34,232,262, 347 and an odor variously described as "pungent," "musty," or "fetid" often surrounds patients excreting other strains in their stool^.^^','^^ because the buttocks are repeatedly covered with liquid stools, excoriation of the perianal skin can be an early and persistent problem. fever is an inconstant feature, and when it occurs, the patient's temperature rarely rises above 39" c. convulsions occur infrequently; their occurrence should alert the clinician to the possible presence of electrolyte disturbances, particularly hypernatremia. prolonged hematochezia, distention, edema, and jaundice are ominous signs and suggest an unfavorable p r o g n o~i s .~'~,~~~*~*~ m ost infants receiving antimicrobial agents orally show a cessation of diarrhea, tolerate oral feedings, and resume weight gain within 3 to 7 days after therapy has been those with mild illness who receive no treatment can continue to have intermittent loose stools for 1 to 3 weeks. in one outbreak related to epec 0142:k86, more than one third of the untreated or inappropriately treated infants had diarrhea for more than 14 days in the absence of a recognized enteric pathogen on repeated culturing.267 recurrence of diarrhea and vomiting after a period of initial improvement is characteristic of epec e n t e r i t i~. '~'~~~~~~~ though seen most often in newborns who have been treated inadequately or not treated at all, clinical relapses also occur after appropriate therapy. occasionally, the signs of illness during a relapse can be more severe than those accompanying the initial attack of illness.215,232,285 not all clinical relapses result from persistent infection. a significant number of relapses, particularly those that consistently follow attempts at reinstitution of formula fee ding^?^^.^^^ are caused by disaccharide intolerance rather than bacterial proliferation. intestinal superinfections, caused by another serotype of epecz8393479348 or by completely different enteric pathogens, such as salmonella or shigella,245 also can delay the resolution of symptoms. rarely, infants suffer a "relapse" caused by an organism from the same 0 group as the original strain but differing in its h antigen. unless complete serotyping is performed on all epec isolates, such an event easily could be dismissed as being a recurrence rather than a superinfection with a new ~r g a n i s m . '~~*~~~ antimicrobial agents to which the infecting organisms are susceptible often may not eradicate epec:45,265,267 which may persist for weeks264,283,344 or months349 after the acute illness has subsided. although reinfection cannot always be excluded, a significant number of infants are discharged from the hospital with positive rectal dehydration is the most common and serious complication of gastroenteritis caused by epec or a toxin-producing e. coli. virtually all deaths directly attributable to the intestinal infection are caused by disturbances in fluids and electrolytes. when stools are frequent in number, large in volume, and violent in release, as they often are in severe infections with abrupt onset, a neonate can lose up to 15% of body weight in a few h o~r s .~~~,~~~ rarely, fluid excretion into the lumen of the bowel proceeds so rapidly that reduction of circulating blood volume and shock may intervene before passage of even a single loose before the discovery of the etiologic agent, epidemic diarrhea of the newborn was also known by the term cholera infantum. mild disease, particularly when aggravated by poor fluid intake, can lead to a subtle but serious deterioration of an infant's metabolic status. sometimes, a week or more of illness elapses before it becomes apparent that an infant with borderline acidosis and dehydration who seemed to be responding to oral fluids alone requires parenteral therapy for impr~vement?~~ it is incumbent on the clinician caring for small infants with gastroenteritis to follow them closely, with particular attention to serial weights, until full recovery can be confirmed. there are few other complications, with the possible exception of aspiration pneumonia, directly related to epec gastroenteritis. protracted diarrhea and nutritional failure may occur as a consequence of functional damage to the small intestinal mucosa, with secondary intolerance to dietary necrotizing enterocolitis, which occasionally results in perforation of the bowel and peritonitis, has not been causally related to infection with epec.247,264,266 a review of most of the large clinical series describing epec disease in infants who ranged in age from neonates to children aged 2 years revealed only three proven instances of ba~teremia:~~**~~ one possible urinary tract infection:65 and one documented case of meningitis in an infant of unspecified age.351 focal infections among neonates were limited to several cases of otitis and a subcutaneous abscess294 from which epec was isolated. additional complications include interstitial pneumonia,319 gastrointestinal bleeding with or without disseminated intravascular coagulatio11,3~.~~~ and methemoglobinemia caused by a mutant of epec 0127:b8 that was capable of generating large quantities of nitrite from proteins present in the gastrointestinal tract.353 the gold standard of epec diagnostics is identification in the stool of e. coli carrying genes for bfp and lee. identification of these genes can be accomplished by molecular methods (discussed later), but lack of access to these methods has led many labs to rely on surrogate markers, such as serotyping." classic epec has been recovered from the vomitus, stool, or bowel contents of infected newborns. isolation from bile233 and the upper respiratory t r a~t~~~~~~*~~~ ha s been described in those instances in which a specific search has been made. less commonly, epec is isolated from ascetic fluid'" or purulent exudates209*2157294* , occasionally, the organism has been recovered from blood c u l t~r e s ?~~,~~~ urine:65 and cerebrospinal fluid. stool cultures generally are more reliable than rectal swabs in detecting the presence of enteric pathogens, although a properly obtained swab should be adequate to demonstrate epec in most cases.2'7,296*354 specimens should be obtained as early in the course of the illness as possible because organisms are present in virtually pure culture during the acute phase of the enteritis but diminish in numbers during convalescence. because of the preponderance of epec in diarrheal stools, two cultures are adequate for isolation of these pathogens in almost all cases of active disease. studies using fluorescent antibody methods for identification of epec in stool specimens have demonstrated that during the incubation period of the illness, during convalescence, and among asymptomatic carriers of epec, organisms can be excreted in such small numbers that they escape detection by standard bacteriologic methods in a significant proportion of as many as 3 to 10 specimens may be required to detect epec using methods that identify individual epec isolates in the ~t 0 0 1 . 8~~~ after a stool specimen is received, it should be plated as quickly as possible onto noninhibiting media or placed in a preservative medium if it is to be held for longer periods. deep freezing of specimens preserves viable epec when a prolonged delay in isolation is necessary?" no selective media, biochemical reactions, or colonial variations permit differentiation of pathogenic and nonpathogenic strains. certain features may aid in the recognition of two important serogroups. cultures of serogroups 0 1 11:b4 and 055:b5, unlike many other coliforms, are sticky or stringy when picked with a wire loop and are rarely hemolytic on blood whereas 0 1 11:b4 colonies emit a distinctive evanescent odor commonly described as "~e m i n a l . ' '~~~,~~~ this unusual odor first led b r a y to suspect that specific strains of e. coli might be responsible for infantile gastroenteritis. because serotyping is simpler than molecular detection and because epec have long been known to belong to certain highly characteristic serotypes, serotyping can be used to identify likely epec strains, especially in outbreaks?16 e. coli, like other enterobacteriaceae members, possesses cell wall somatic antigens (o), envelope or capsular antigens (k), and if motile, flagellar antigens (h). many of the 0 groups may be further divided into two or more subgroups (a, b, c), and the k antigens are divisible into at least three varieties (b, l, a) on the basis of their physical behavior. organisms that do not possess flagellar antigens are nonmotile (designated nm). the epec b capsular surface antigen prevents agglutination by antibodies directed against the underlying 0 antigen. heating at 100°c for 1 hour inactivates the agglutinability and antigenicity of the b antigen. slide agglutination tests with polyvalent 0 or ob antiserum may be performed on suspensions of colonies typical of e. coli that have been isolated from infants with diarrhea, especially in nursery outbreaks. however, because of numerous false-positive "cross-reactions:' the 0 and k (or b) type must be confirmed by titration with the specific a n t i~e r a .~~~ the presence of epec does not prove that epec is the cause of diarrhea in an individual patient. mixed cultures with two or three serotypes of epec have been demonstrated in 1% to 10% of patients.244*245*352 this need not mean that two or three serotypes are causative agents. secondary infection with hospital-acquired strains can occur during convalesand some infants may have been asymptomatic carriers of one serotype at the time that another produced diarrheal disease. a similar explanation may pertain to mixed infections with epec and salmonella or shigella.217*2203358 nelson245 reported the presence of these pathogens in combination with epec in 14% of infants who were cultured as part of an antibiotic therapy trial. salmonella and shigella that had not been identified on cultures obtained at admission were isolated only after institution of oral therapy with neomycin. the investigator postulated that the alteration in bowel flora brought about by the neomycin facilitated the growth of these organisms, which had previously been suppressed and obscured by coliform overthe importance of seeking all enteric pathogens in primary and follow-up cultures of infantile diarrhea is apparent, particularly when the specimen originates from a patient in a newborn nursery or infants' ward. although epec gastroenteritis was once considered to be synonymous with "summer diarrhea," community outbreaks have occurred as frequently, if not more frequently, in the colder seasons.133,160*172 it has been suggested that the increased incidence at that time of year might be related to the heightened chance of contact between infants and toddlers cence,l 73,281,283,380 that is bound to occur when children remain indoors in close contact.z94 nursery epidemics, which depend on the chance introduction and dissemination of epec within a relatively homogeneous population and stable environment, demonstrate no seasonal prevalence. average relative humidity, temperature, and hours of daylight have no significant effect in determining whether an outbreak will follow the introduction of enteropathogenic strains of e. coli into a ward of infants.243 there are no clinical studies of the variations in peripheral leukocyte count, urine, or cerebrospinal fluid in neonatal enteritis caused by epec. microscopic examination of stools of infants with acute diarrheal illness caused by these organisms usually has revealed an absence of fecal polymorphonuclear l e~k o c y t e s~'~~~~~~~~~*~~~ although data on fecal lactoferrin in human volunteers suggest that an inflammatory process may be important in epec diarrhea.360,361 stool ph can be neutral, acid, or alkaline.617341 serologic methods have not proved to be useful in attempting to establish a retrospective diagnosis of epec infection in neonates. rising or significantly elevated agglutinin titers rarely could be demonstrated in early investigation^^'^"'^^^'; hemagglutinating antibodies showed a significant response in no more than 10% to 20% of cases.245,297 fluorescent antibody techniques have shown promise for preliminary identification of epec in acute infantile diarrhea. this method is specific, with few false-positive results, and it is more sensitive than conventional plating and isolation t e c h n i q~e s .~~~,~~' .~~~ the rapidity with which determinations can be performed makes them ideally suited for screening ill infants and possible carriers in determining the extent and progression of a n~r s e r f '~,~~~ or om mu nit$^^^^'' outbreak. because immunofluorescence does not depend on the viability of organisms and is not affected by antibiotics that suppress growth on culture plates, it can be used to advantage in following bacteriologic responses and relapses in patients receiving oral the rap^.^","^ the use of fluorescent antibody techniques offers many advantages in the surveillance and epidemiologic control of epec gastroenteritis. immunofluorescent methods should supplement but not replace standard bacteriologic and serologic methods for identification of enteric pathogens. specific gene probes and pcr primers for the bfp adhesin, the intimin-encoding gene (eue) and for a cryptic plasmid locus (eaf) are a~ailable.~~ detection of bfp or eaf are superior to detection of eue, because many non-epec, including nonpathogens, carry the eae gene.98b364 pcr and gene probe analysis can be performed directly on the stools of suspect infants. however, confirmation of infection by the identification of the organism in pure culture should be pursued. before widespread use of molecular methods, the hep-2 cell adherence assay was proposed for epec diagnosis."' the presence of a focal or localized adherence (la) pattern on the surface of hep-2 or hela cells after 3-hour coincubation is a highly sensitive and specific test for detection of epec. 365 the requirement for cell culture and expertise in reading this assay limits its utility to the research setting. an elisa for the bfp has been described but is not readily available?66 the capacity of la + epec to polymerize f-actin can be detected in tissue culture cells stained with rhodamine-labeled phall~idin.~~' this fluorescence-actin staining (fas) test is cumbersome and impractical for routine clinical use. the mortality rate recorded previously in epidemics of epec gastroenteritis is impressive for its variability. during the 1930s and 1940s, when organisms later recognized as classic enteropathogenic serotypes were infecting infants, the case-fatality ratio among neonates was about 50%. 2099210 during the 1950s and 1960s, many nursery epidemics still claimed about one of every four infected infants, but several outbreaks involving the same serotypes under similar epidemiologic circumstances had fatality rates of less than 30h.23424131 in th e 1970s, reports appeared in the literature of a nursery epidemic with a 40% neonatal mortality rate285 and of an extensive outbreak in a nursery for premature infants with 4% fatalities265; another report stated that among "243 consecutive infants admitted to the hospital for epec diarrheal disease, none died of diarrheal disease per se."368 a significant proportion of the infants who died during or shortly after an episode of gastroenteritis already were compromised by preexisting disease233,283,330 or by congenital m a l f~r m a t i o n s~'~,~~'~~~~ at the time they acquired their illness. these underlying pathologic conditions appear to exert a strongly unfavorable influence, probably by reducing the infant's ability to respond to the added stresses imposed by the gastrointestinal tract infection. although prematurity is often mentioned as a factor predisposing to a fatal outcome, the overall mortality rate among premature infants with epec gastroenteritis has not differed significantly over the years from that recorded for term the management of epec gastroenteritis should be directed primarily toward prevention or correction of problems caused by loss of fluids and electr01ytes.i~~ most neonates have a relatively mild illness that can be treated with oral rehydration. infants who appear toxic, those with voluminous diarrhea and persistent vomiting, and those with increasing weight loss should be hospitalized for observation and treatment with parenteral fluids and careful maintenance of fluid and electrolyte balance and possibly with antimicrobial therapy. clinical studies suggest that slow nasogastric infusion of an elemental diet can be valuable in treating infants who have intractable diarrhea that is unresponsive to standard modes of therapy. 369 there is no evidence that the use of proprietary formulas containing kaolin or pectin is effective in reducing the number of diarrheal stools in neonates with gastroenteritis. attempts to suppress the growth of enteric pathogens by feeding lactobacillus to the infant in the form of yogurt, powder, or granules have not been shown to be of value.370 a trial of cholestyramine in 15 newborns with epec gastroenteritis had no effect on the duration or severity of the diarrhea.265 the use of atropine-like drugs, paregoric, or loperamide to reduce intestinal motility or cramping should be avoided. inhibition of peristalsis interferes with an efficient protective mechanism designed to rid the body of intestinal pathogens and may lead to fluid retention in the lumen of the bowel that may be sufficient to mask depletion of extracellular fluid and electrolytes. the value of antimicrobial therapy in management of neonatal epec gastroenteritis, if any, is uncertain. there are no adequately controlled studies defining the benefits of any antibiotic in eliminating epec from the gastrointestinal tract, reducing the risk of cross-infection in community or nursery outbreaks, or modifymg the severity of the illness. proponents of the use of antimicrobial agents have based their claims for efficacy on anecdotal observations or comparative studies.245 nonetheless, several clinical investigations have provided sufficient information to guide the physician faced with the dilemma of deciding whether to treat an individual infant or an entire nursery population suffering from epec diarrheal disease. it should be emphasized, however, that these guidelines must be considered tentative until rigidly controlled, double-blind studies have established the efficacy of antibiotics on a more rational and scientific basis. oral therapy with n e o m y~i n ,~'~'~~' ~olistin,'~~or chloram-phenic01~~~ appears to be effective in rapidly reducing the number of susceptible epec organisms in the stool of infected infants. studies comparing the responses of infants treated orally with ne~mycin?~' gentamicin:65 p~l p y x i n :~~ or kanamy~in'~' with the responses of infants receiving supportive therapy alone have shown that complete eradication of epec occurs more rapidly in those receiving an antimicrobial agent. in most cases, stool cultures are free of epec 2 to 4 days after the start of therapy.2459363 bacteriologic failure, defined as continued isolation of organisms during or after a course of an antimicrobial agent, can be expected to occur in 15% to 30% of patients?45s265 such relapses generally are not associated with a recurrence of ~y m p t~m~.~~i *~~~*~~~ the effectiveness of oral antimicrobial therapy in reducing the duration of epec excretion serves to diminish environmental contamination and the spread of pathogenic organisms from one infant to another. breaking the chain of fecal-oral transmission by administering antimicrobial agents simultaneously to all carriers of epec and their immediate contacts in the nursery has appeared to be valuable in terminating outbreaks that have failed to respond to more conservative m e a s~r e s .~'~,~~,~~~ the apparent reduction in morbidity and mortality associated with oral administration of neomycin,230.233,234 colistin,246.267.285 p o l y m y x i r~,~~~ or gentamicin2& during nursery epidemics has led to the impression that these drugs also exert a beneficial clinical effect in severely or moderately ill infants. reports describing bacteriologic:65 or histopathol~gic~'~ evidence of tissue invasion by epec have persuaded some investigators to suggest the use of parenteral rather than oral drug therapy in debilitated or malnourished infants. on the basis of these data, there appears to be sufficient evidence to recommend oral administration of nonabsorbable antibiotics in the treatment of severely or moderately ill newborns with epec gastroenteritis. the drug most frequently used for initial therapy is neomycin sulfate in a dosage of 100 mg/kg/day administered orally every 8 hours in three divided doses.24s in communities in which neomycin-resistant epec has been prevalent, treatment with colistin sulfate or polymyxin b in a dosage of 15 to 20 mglkglday orally and divided into three equal doses may be appropriate. however, it is rarely necessary to use this approach. treatment should be continued only until stool cultures become negative for epec.245 because of the unavoidable delay before cultures can be reported, most infants receive therapy for 3 to 5 days. if fluorescent antibody testing of rectal swab specimens is available, therapy can be discontinued as soon as epec no longer is identified in smears; this takes no more than 48 hours in more than 90% of cases.245 after diarrhea and vomiting have stopped and the infant tolerates formula feedings, shows a steady weight gain, and appears clinically well, discharge with outpatient follow-up is indicated. bacteriologic relapses do not require therapy unless they are associated with illness or high epidemiologic risks to other young infants in the household. because the infecting organisms in these recurrences generally continue to show in vitro susceptibility to the original drug, it should be reinstituted pending bacteriologic re~ults.2~~ when clinical judgment suggests that a neonate may be suffering from bacterial sepsis and epec diarrheal disease, parenteral antimicrobial therapy is indicated after appropriate cultures have been obtained. the routine use of systemic therapy in severe cases of epec enteritis is not appropriate on the basis of current clinical experience. antimicrobial susceptibility patterns of epec are an important determinant of the success of therapy in infections with these organism^.^^',^^'^^^ these patterns are unpredictable, depending on the ecologic pressures exerted by local antibiotic and on the incidence of transmissible resistance factors in the enteric flora of the particular population served by an i n s t i t~t i o n .~~~"~~ for these reasons, variations in susceptibility patterns are apparent in different n~r s e r i e s~~~, '~~ and even from time to time within the same institution.247,248,250 sudden changes in clinical response may even occur during the course of a single epidemic as drugsusceptible strains of epec are replaced by strains with multidrug r e~i s t a n c e .~~~'~~' ,~~' because differences can exist in the susceptibilities of different epec serogroups to various antimicrobial agents, regional susceptibility patterns should be reported on the basis of ob group or serotype rather than for epec as a whole.250 knowledge of the resistance pattern in one's area may help in the initial choice of antimicrobial therapy. the prevention of hospital outbreaks of epec gastroenteritis is best accomplished by careful attention to infection control policies for a nursery. all infants hospitalized with diarrhea should have a bacteriologic evaluation. if the laboratory is equipped and staffed to perform fluorescent antibody testing, infants transferred from another institution to a newborn, premature, or intensive care nursery and all infants with gastroenteritis on admission during an outbreak of epec diarrhea or in a highly endemic area can be held in an observation area for 1 or 2 hours until the results of the fluorescent antibody test or pcr are received. because of the difficulty in diagnosing epec infection, reference laboratories, such as those at the centers for disease control and prevention (cdc), should be notified when an outbreak is suspected. infants suspected to be excreting epec, even if healthy in appearance, then can be separated from others and given oral therapy until the test results are negative. some experts have suggested that when the rapid results obtainable with fluorescent antibody procedures are not available, all infants admitted with diarrhea in a setting where epec is common may be treated as if they were excreting epec or some other enteric pathogen until contrary proof is obtained.372 stool cultures should be obtained at admission, and contact precautions should be enforced among all who come into contact with the infant. additional epidemiologic studies are needed to establish the advantages of careful isolation and nursing techniques, particularly in smaller community hospitals in which the number of infants in a "gastroenteritis ward may be small. the use of prophylactic antibiotics has been shown to be of no value and can select for increased r e~i s t a n c e .~~~"~~ unfortunately, it can be difficult to keep a nursery continuously free of epec. specific procedures have been suggested for handling a suspected outbreak of bacterial enteritis in a newborn nursery or infant care ~n i t .~~~l~~~*~~~ evidence indicating that a significant proportion of e. coli enteritis may be caused by nontypeable strains has required some modification of these earlier recommendations. the following infection control measures may be appropriate: 1. the unit is closed, when possible, to all new admissions. 2. cultures for enteric pathogens are obtained from nursing personnel assigned to the unit at the time of the outbreak. 3. stool specimens obtained from all infants in the nursery can be screened by the fluorescent antibody or another technique and cultured. identification of a classic enteropathogenic serotype provides a useful epidemiologic marker; however, failure to isolate one of these strains does not eliminate the possibility of illness caused by a nontypeable epec. 4. antimicrobial therapy with oral neomycin or colistin can be considered for all infants with a positive fluorescent antibody test or culture result. the initial drug of choice depends on local patterns of susceptibility. depending on the results of susceptibility tests, subsequent therapy may require modification. 5. if an identifiable epec strain is isolated, second and third stool specimens from all infants in the unit are reexamined by the fluorescent antibody technique or culture at 48-hour intervals. if this is not practical, exposed infants should be carefully followed. 6. early discharge for healthy, mature, uninfected infants is advocated. 7. an epidemiologic investigation should be performed to seek the factor or factors responsible for the outbreak. a surveillance system may be established for all those in contact with the nursery, including physicians and other health care personnel, housekeeping personnel, and postpartum mothers with evidence of enteric disease. a telephone, mail, or home survey may be conducted on all infants who were residing in the involved unit during the 2 weeks before the outbreak. 8. when all patients and contacts are discharged and control of the outbreak is achieved, a thorough terminal disinfection of the involved nursery is mandatory. above all, personnel and parents should pay scrupulous attention to hand hygiene when handling infants.38' since a multistate outbreak of enterohemorrhagic colitis was associated with e. coli 0157:h7,382 shiga toxin-producing e. coli (stec) have been recognized as emerging gastrointestinal pathogens in most of the industrialized world. a particularly virulent subset of stec, ehec, causes frequent and severe outbreaks of gastrointestinal the most virulent ehec belong to serotype 0157:h7. ehec has a bovine reservoir and is transmitted by undercooked meat, unpasteurized milk, and contaminated vegetables such as lettuce, alfalfa sprouts, and radish sprouts (as occurred in more than 9000 schoolchildren in japan).3849387 it also spreads directly from person to the clinical syndrome is that of bloody, noninflammatory (sometimes voluminous) diarrhea that is distinct from febrile dysentery with fecal leukocytes seen in shigellosis or eiec infection^.^^ most cases of ehec infections have been recognized in outbreaks of bloody diarrhea or hus in daycare centers, schools, nursing homes, and c o m m~n i t i e s .~~~-~~~ although ehec infections often involve infants and young children, the frequency of this infection in neonates remains unclear; animal studies suggest that receptors for the shiga toxin may be developmentally regulated and that susceptibility to disease may be age related. 391 the capacity of ehec to cause disease is related to the phage-encoded capacity of the organism to produce a vero cell cytotoxin, subsequently shown to be one of the shiga toxins.392-394 shiga toxin 1 is neutralized by antiserum against shiga toxin, whereas shiga toxin 2, although biologically similar, is not neutralized by anti-shiga toxin.395,396 like shiga toxin made by shigella dysenteriae, both e. coli shiga toxins act by inhibiting protein synthesis by cleaving an adenosine residue from position 4324 in the 28s ribosomal rna (rrna) to prevent elongation factor-1-dependent aminoacyl transfer rna (trna) from binding to the 60s rrna.3923393 the virulence of ehec also may be determined in part by a 60-mda plasmid that encodes for a fimbrial adhesin in 0157 and 026.397,398 this phenotype is mediated by the lee pathogenicity island, which is highly homologous to the island present in epec strains. 328 ehec and other stec infections should be suspected in neonates who have bloody diarrhea or who may have been exposed in the course of an outbreak among older individuals. because most cases are caused by ingestion of contaminated food, neonates have a degree of epidemiologic protection from the illness. diagnosis of stec diarrhea is made by isolation and identification of the pathogen in the feces. e. coli 0157:h7 does not ferment sorbitol, and this biochemical trait is commonly used in the detection of this s e r~t y p e .~~. '~~ because some nonpathogenic e. coli share this characteristic, confirmation of the serotype by slide agglutination is required. these techniques can be performed in most clinical laboratories. however, detection of non-0 157 serotypes is problematic and relies on detection of the shiga toxin; available methods include shiga toxin elisa, latex agglutination, and molecular method^.^^,^^^ these should be performed by a reference laboratory. hus in infants is not necessarily caused by stec infection. even in older patients, however, the stool is typically negative for stec at the time the that hus develops.400340' serum and fecal detection of cytotoxin has been performed in such patients, but no diagnostic modality is definitive once hus has s~pervened!~~,~~~ antimicrobial therapy should not be administered to patients who may have stec infection, although their role in inducing hus remains c o n t r o~e r s i a l .~~~'~~~ management of the diarrhea and possible sequelae is supportive, with proper emphasis on fluid and electrolyte replacement. aggressive rehydration is helpful in minimizing the frequency of serious sequelae. the hep-2 adherence assay is useful for the detection of epec, which exhibit a classic la pattern."' two other adherence patterns can be discerned in this assay: aggregative (aa) and diffuse (da). these two patterns have been suggested to define additional pathotypes of diarrheogenic e. coli." strains exhibiting the aa pattern (i.e., eaec) are common pathogens of infants.lz5 eaec cause diarrhea by colonization of the intestinal mucosa and elaboration of enterotoxins and c y t o t o~i n s .~~~~~ many strains can be shown to elicit secretion of inflammatory cytokines in vitro, which may contribute to growth retardation associated with prolonged otherwise asymptomatic colonization.io3 several virulence factors in eaec are under the control of the virulence gene activator aggr.404 presence of the aggr regulator or its effector genes has been proposed as a means of detecting truly virulent eaec strains (called typical eaec),404,405 and an empirical gene probe long used for eaec detection has been shown to correspond to one gene under aggr the mode of transmission of eaec has not been well established. in adult volunteer studies, the infectious dose is high (> lo8 colony-forming units [ cfu] ), suggesting that in adults at least, person-to-person transmission is unlikely.408.m several outbreaks have been linked to consumption of contaminated f~o d . "~~,~'~ the largest of these outbreaks involved almost 2700 schoolchildren in japan4"; a contaminated school lunch was the implicated source of the outbreak. some studies have demonstrated contamination of condiments or milk, which could represent vehicles of foodborne transmission. several nursery outbreaks of eaec have been 0bserved,4~'~~'~ although in no case has the mechanism of transmission been established. the fist reported nursery outbreak involved 19 infants in nis, serbia, in 1995. because these infants did not ingest milk from a common source, it is presumed that horizontal transmission by environmental contamination or hands of health care personnel was possible. most of the infants were full term and previously well, and they were housed in two separate nursery rooms. the earliest epidemiologic studies of eaec implicated this organism as a cause of endemic diarrhea in developing c o~n t r i e s .~'~-~'~ in this setting, eaec as defined by the m pattern of adherence to hep-2 cells can be found in upward of 30% of the population at any one time>l7 newer molecular diagnostic modalities have revised this figure downward, although the organism remains highly prevalent in many areas. several studies from the indian subcontinent implicated eaec among the most frequent enteric pathogen^.^'^.^'^.^^^ other sites reproducibly reporting high incidence rates include and bra~il."~'*~~' there is evidence that eaec may be emerging in incidence. a study from spo paulo, brazil, implicated eaec as the prevalent e. coli pathotypes in infants4i9; epec had previously been shown to be the most common pathogen in this community. many other sites in developing countries of africa:" asia,4°5~422 and south america4" have described high endemic rates. several studies have suggested that eaec is also a common cause of infant diarrhea in industrialized c~u n t r i e s . "~~~~~~ using molecular diagnostic methods, a large prospective study in the united kingdom implicated eaec as the second most common enteric bacterial pathogen after cumpylob~cter.~~~ a similar study from switzerland found eaec to be the most common bacterial enter~pathogen.~'~ studies from the united states also have demonstrated a high rate of eaec diarrhea in infants; using molecular diagnostic methods, eaec was implicated in 11% and 8% of outpatient and inpatient diarrhea cohorts, respectively, compared with less than 2% of asymptomatic control infants (p < .05). 427 although epidemiologic studies have shown that eaec can cause diarrhea in all age groups, several studies suggest that the infection is particularly common in infants younger than 12 months 01d.405*420 descriptions from outbreaks and volunteer studies suggest that eaec diarrhea is watery in character with mucus but without blood or frank pus.4o834o93412 patients typically are afebrile. several epidemiologic studies have suggested that many infants may have bloody diarrhea,4i6 but fecal leukocytes are uncommon. the earliest reports of eaec infection suggested that this pathogen may be particularly associated with persistent diarrhea (>14 days).414-416 however, later studies suggest that persistent diarrhea may occur in only a subset of infected infants!" in the serbian outbreak of 19 infected infants, the mean duration of diarrhea was 5.2 days4''; diarrhea persisted more than 14 days in only three patients. infants in this outbreak had frequent, green, odorless stools. in three cases, the stools had mucus, but none had visible blood. eleven babies developed temperatures in excess of 38oc; only one had vomiting. despite a lack of clinical evidence suggesting inflammatory enteritis, several clinical studies have suggested that eaec is associated with subclinical inflammation, including the shedding of fecal cytokines and la~toferrin.'~~.~'~ studies in fortaleza, brazil, suggest that children asymptomatically excreting eaec may exhibit growth shortfalls compared with uninfected peers.lo3 a study from germany reported an association between eaec isolation and infant colic in infants without diarrhea.4z5 this observation has not been repeated. eaec should be considered in the differential diagnosis of persistent diarrhea and failure to thrive in infants. diagnosis of eaec requires identification of the organism in the patient's feces. the hep-2 adherence assay can be used for this purpose"'; some reports suggest that the adherence phenotype can be observed using formalin-fixed cell^^^'^^^' thereby obviating the need to cultivate eukaryotic cells for each assay. pcr and gene probe for typical eaec are available. successful antibiotic therapy has been reported using fluoroquinolones in adult although preliminary studies suggest that a~ithrornycin~~~ or r i f a~i m i n~~~ also may be effective. therapy in infected infants should be guided by the results of susceptibility testing, as eaec frequently is antibiotic re~istant.~" additional e. coli pathotypes have been described, including diffusely adherent e. coli (daec), 434 and cytodetaching e. c 0 1 i .~~~ daec has been specifically associated with diarrhea outside of infancy, as infants may have some degree of inherent resistance to infection. 436 cytodetaching e. coli represent organisms that secrete the e. coli hem~lysin.~~' it is not clear whether these latter organisms are true enteric pathogens. there are differences in invasiveness of salmonella strains related to serotype. s. typhi, s. choleraesuis, salmonella heidelberg,439p440 and salmonella dub1inm1 are particularly invasive, with bacteremia and extraintestinal focal infections occurring frequently. salmonella species possess genes closely related to those for the shigella invasion plasmid anti ensthese genes are probably essential to intestinal infection. virulence plasmids, which increase invasiveness in some serotypes, have been recognized, although the precise mechanisms of virulence remain to be elucidated; resistance to complement-mediated bacteriolysis by inhibition of insertion of the terminal c5b-9 membrane attack complex into the outer membrane may be laboratory studies have demonstrated dramatic strain-related difference in the ability of s. typhimurium t o evoke fluid secretion, to invade intestinal mucosa, and to disseminate beyond the production of an enterotoxin immunologically related to cholera toxin by about two thirds of salmonella strains may be related to the watery diarrhea often seen. 447 part because of the properties of their lipopolysaccharide~~~~~~~~ persistence of the organism within phagolysosomes of phagocytic cells may occur with any species of salmonella. it is not completely clear how the organisms have adapted to survive in the harsh intracellular environment, but their survival has major clinical significance. it accounts for relapses after therapy. it explains the inadequacy of some antimicrobial agents that do not penetrate phagolysosomes. it perhaps is the reason for prolonged febrile courses that occur even in the face of appropriate therapy. although humoral immunity and cell-mediated immunity are stimulated during salmonella infections, it is believed that cell-mediated immunity plays a greater role in eradication of the ba~teria.4'~ t cell activation of macrophages appears to be important in killing intracellular salmonella. 454 defective interferon-y production by monocytes of newborns in response to s. typhimurium lipopolysaccharide may explain in part the unusual susceptibility of infants to salmonella infection. 455 studies in mice suggest that helper t cell (th1) responses in peyer's patches and mesenteric lymph nodes may be central to protection of the intestinal m~c o s a .~~~ humans who lack the il-12 receptor and therefore have impaired th1 responses and interferon-y production are at increased risk for salmonella infe~tion.~~' in typhoid fever, presence of an envelope antigen, vi, is known to enhance virulence. patients who develop classic enteric fever have positive stool cultures in the first few days after ingestion of the organism and again late in the course after a period of bacteremia. this course reflects early colonization of the gut, penetration of gut epithelium with infection of mesenteric lymph nodes, and reseeding of the gut during a subsequent bacteremic pha~e.4~' studies of s. typhimurium in monkeys suggest similar initial steps in pathogenesis (e.g., colonization of gut, penetration of gut epithelium, infection of mesenteric lymph nodes) but failure of the organism to cause a detectable level of ba~teremia.4~~ although both salmonella and shigella invade intestinal mucosa, the resultant pathologic changes are different. shigella multiplies within and kills enterocytes with production of ulcerations and a brisk inflammatory response, whereas salmonella passes through the mucosa and multiplies within the lamina propria, where the organisms are ingested by phagocytes; consequently, ulcer formation is less striking,446 although villus tip cells are sometimes sloughed. acute crypt abscesses can be seen in the stomach and small intestine, but the most dramatic changes occur in the colon, where acute diffuse inflammation with mucosal edema and crypt abscesses are the most consistent findings.460v461 with s. typhi there also is hyperplasia of peyer's patches in the ileum, with ulceration of overlying tissues. salmonella strains, with the exception of s. typhi, are well adapted to a variety of animal hosts; human infection often can be traced to infected meat, contaminated milk, or contact with a specific animal. half of commercial poultry samples are contaminated with salmonella. 462 definition of the serotype causing infection can sometimes suggest the likely source. for example, s. dublin is closely associated with cattle; human cases occur with a higher-than-predicted frequency in people who drink raw milk.@' for s. typhimurium, which is the most common serotype and accounts for more than one third of all reported human cases, a single source has not been established, although there is an association with cattle. despite the 1975 ban by the u.s. food and drug administration (fda) on interstate commercial distribution of small turtles, these animals continue to be associated with infection, as illustrated by a series of cases in puerto ~i~~.~~~ various pet reptiles are an important source of a variety of unusual salmonella serotypes such as salmonella marina, salmonella chameleon, salmonella arizonae, salmonella java, salmonella stanley, salmonella poona, salmonella jangwain, salmonella tilene, salmonella pomona, salmonella miami, salmonella manhattan, salmonella litchfield, salmonella rubislaw, and salmonella w a~s e n a a r .~~-~~ salmonella organisms are hardy and capable of prolonged survival; organisms have been documented to survive in flour for nearly a year?67 salmonella tennessee has been shown to remain viable for many hours on non-nutritive surfaces (i.e., glass, 48 hours; stainless steel, 68 hours; enameled surface, 114 hours; rubber mattress, 119 hours; linen, 192 hours; and rubber tabletop, 192 infection with salmonella is, like most enteric infections, more common in young children than in adults. the frequency of infection is far greater in the first 4 years of life; roughly equal numbers of cases are reported during each decade beyond 4 years of age. although the peak incidence occurs in the second through sixth months of life, infection in the neonate is relatively common. researchers at the cdc have estimated the incidence of salmonella infection in the first month of life at nearly 75 cases per 100,000 infants?69 adult volunteer studies suggest that large numbers of salmonella ( lo5 to lo9) need to be ingested to cause di~ease.4~' however, it is likely that lower doses cause illness in infants. the occurrence of nursery ~u t b r e a k s~"~~~~~ and intrafamilial spread497 suggests that organisms are easily spread from person to person; this pattern is typical of low-inoculum diseases transmitted by the fecal-oral route. the neonate with salmonella infection infrequently acquires the organism from his or her mother during delivery. although the index case in an outbreak can often be traced to a mother,474-477,495 subsequent cases result from contaminated objects in the nursery e n~i r o n m e n t~~"~~~ serving as a reservoir coming in contact with hands of attending p e r~o n n e l .~~.~'~ the mother of an index case may be symptomatic479~480i500~501 or asymptomatic with preclinical infecti0n,4'~ convalescent infedon,477,48 1,502 or chronic carriage. 503 the risk of the newborn becoming infected once salmonella is introduced into a nursery has been reported to be as high as 20% to 27%,487,493 but the frequency of infection may be lower because isolated cases without a subsequent epidemic are unlikely to be reported. gastric acidity is an important barrier to salmonella infection. patients with anatomic or functional achlorhydria are at increased risk of developing salmonellosis.504~505 the hyp~chlorhydria'~ and rapid gastric emptying typical of early lifez8 may in part explain the susceptibility of infants to salmonella. premature and low-birth-weight infants appear to be at higher risk of acquiring salmonella infection than term whether this reflects increased exposure because of prolonged hospital stays or increased susceptibility on the basis of intestinal or immune function is unclear. contaminated food or water is often the source of salmonella infection in older patients; the limited diet of the infant makes contaminated food a less likely source of infection. although human milk?06-508 raw milk?09 powdered milk,510-512 formula:93 and cereal5i3 have been implicated in transmission to infants, more often fomites, such as delivery room resu~citators,4~' rectal thermometer~,4'~>~'~ oropharyngeal suction device^,^^^'^^' water baths for heating formula?17 soap dispenser^,^" " clean" medicine airconditioning mattresses, radiant and serve as reservoirs. one unusual outbreak involving 394 premature and 122 term infants was traced to faulty plumbing, which caused massive contamination of environment and personnel.493 after salmonella enters a nursery, it is difficult to eradicate. epidemics lasting 6 to 7 week^,'@^,^^' 17 weeks,& 6 months,485b490 1 year:' " and 27 to 30 months487b493 have been reported. spread to nearby pediatric wards has the incubation period in nursery outbreaks has varied widely in several studies where careful attention has been paid to this variable. in one outbreak of salmonella oranienburg involving 35 newborns, 97% of cases occurred within 4 days of in an outbreak of s. typhimurium, each of the ill infants presented within 6 days of birth.477 these incubation periods are similar to those reported for salmonella newport in older children and adults, 95% of whom have been reported to be ill within 8 days of e~p o s u r e .~'~'~~' conversely, one outbreak of salmonella nienstedten involving newborns was characterized by incubation periods of 7 to 18 days.488 the usual incubation period associated with fecal-oral nursery transmission is not found with congenital typhoid. during pregnancy, typhoid fever is associated with bacteremic infection of the fetus. the congenitally infected infants are symptomatic at birth. they are usually born during the second to fourth week of untreated maternal illness.522 usually, the mother is a carrier; fecal-oral transmission of s. typhi can occur with delayed illness in the newborn.523 several major clinical syndromes occur with nontyphoidal salmonella infection in young infants. colonization without illness may be the most common outcome of ingestion of salmonella by the neonate. such colonization usually is detected when an outbreak is under investigation. most infected infants who become ill have abrupt onset of loose, green, mucus-containing stools, or they have bloody diarrhea; an elevated temperature is also a common finding in salmonella gastroenteritis in the first months of life.44o grossly bloody stools are found in the minority of patients, although grossly bloody stools can occur in the first 24 hours of life. hematochezia is more typically associated with noninfectious causes (e.g., swallowed maternal blood, intestinal ischemia, hemorrhagic diseases, anorectal fissures) at this early age.524 there appear to be major differences in presentation related to the serotype of s. enteritidis causing infection. for example, in one epidemic of s. oranienb~rg~'~ involving 46 newborns, 76% had grossly bloody stools, 11% were febrile, 26% had mucus in their stools, and only 11% were healthy. in a series of s. newport infections involving 11 premature infants;74 90% of infants with gastroenteritis had blood in their stools, 10% had fever, 10% had mucus in their stools, and 9% were asymptomatic. in an outbreak of s. typhim~rium~~' involving 11 ill and 5 healthy infants, none had bloody stools; all of the symptomatic infants were febrile and usually had loose, green stools. of 26 infants infected by salmonella virchow, 42% were asymptomatic; the rest had mild diarrhea!82 seals and colleagues488 described 12 infants with s. nienstedten, all of whom had watery diarrhea and low-grade fever; none had bloody stools. in a large outbreak in zimbabwe of s. heidelberg infection reported by bannerman,485 38% of 100 infants were asymptomatic, 42% had diarrhea, 16% had fever, 15% had pneumonia, and 2% developed meningitis. an outbreak of salmonella worthington was characterized primarily by diarrhea, fever, and jaundice, although 3 of 18 infants developed meningitis and 17% died. 515 in dramatic contrast to these series, none of 27 infants with positive stool cultures for s. tennessee had an illness in a nursery found to be contaminated with that organism.469 a few infants with salmonella gastroenteritis have developed necrotizing e n t e r o c o l i t i~, 4~~~~~~ but it is not clear whether salmonella was the cause. although gastroenteritis is usually self-limited, chronic diarrhea has sometimes been attributed to s a l r n~n e l l a .~~~~~~~ whether chronic diarrhea is caused by salmonella is uncertain. although some infants develop carbohydrate intolerance after a bout of salmonella and salmonella is typically listed as one of the causes of postinfectious protracted diarrhea,529 it is difficult to be sure that the relationship is causal. the prolonged excretion of salmonella after a bout of gastroenteritis may sometimes cause non-specific chronic diarrhea to be erroneously attributed to salmonella. major extraintestinal complications of salmonella infection may develop in the neonate who becomes bacteremic. extraintestinal spread may develop in infants who initially present with diarrhea and in some who have no gastrointestinal tract signs. bacteremia appears to be more common in the neonate than in the older a study of more than 800 children with salmonella infection showed that extraintestinal infection occurred significantly more often (8.7% versus 3.6%) in the first 3 months of life.531 several retrospective studies suggest that infants in the first month of life may have a risk of bacteremia as high as 30% to 50%. 440 one retrospective suggests that the risk is not increased in infancy and estimates that the risk of bacteremia in childhood salmonella gastroenteritis is between 8.5% and 15.6%. prospective studies of infants in the first year of life suggest that the risk of bacteremia is 1.8% to 6.0%.532*533 although selection biases in these studies limit the reliability of these estimates, the risk is substantial. the salmonella species isolated from infants include some serotypes that appear to be more invasive in the first 2 months of life than in older children or healthy adults (s. newport, s. agona, s. blockley, s. derby, s. enteritidis, s. heidelberg, s. infantis, s. javiana, s. saint-paul, and s. typhimurium) and serotypes that are aggressive in every age group (s. choleraesuis and s. dublin). other serotypes appear more likely to cause bacteremia in adults (s. typhi, s. paratyphi a, and s. paratyphi b). 530 virtually any salmonella serotype can cause bacteremic disease in neonates. a few infants with salmonella gastroenteritis have died with e. coli or pseudomonas aeruginosa sepsis;94 but the role of salmonella in these cases is unclear. unlike the situation in older children in whom bacteremic salmonellosis often is associated with underlying medical conditions, bacteremia may occur in infants who have no immunocompromising conditions.534 salmonella bacteremia is often not suspected clinically because the syndrome is not usually d i s t i n~t i v e . 4~~~~~ even afebrile, well-appearing children with salmonella gastroenteritis have been documented to have bacteremia that persists for several days.535 although infants with bacteremia may have spontaneous resolution without therapy:36 a sufficient number develop complications to warrant empirical antimicrobial therapy when bacteremia is suspected. the frequency of complications is highest in the first month of life. meningitis is the most feared complication of bacteremic salmonella disease. between 50% and 75% of all cases of nontyphoidal salmonella meningitis occur in the first 4 months of life.537 the serotypes associated with neonatal meningitis (s. typhimurium, s. heidelberg, s. enteritidis, s. saint-paul, s. newport, and s. panama)497 are serotypes frequently associated with bacteremia. meningitis has a high mortality rate, in part because of the high relapse rates. relapse has been reported in up to 64% of ca~es.5~' in some studies, more than 90% of patients with meningitis have died,539 although more typically, 30% to 60% of infants die.540*541 the survivors suffer the expected complications of gram-negative neonatal meningitis, including hydrocephalus, seizures, ventriculitis, abscess formation, subdural empyema, and permanent neurologic impairment. neurologic sequelae have included retardation, hemiparesis, epilepsy, visual impairment, and a t h e t o~i s .~~~ in large nursery outbreaks, it is common to find infants whose course is complicated by pneum~nia?'~ osteo-myeliti~,5">~~~ or septic arthriti~.4'~,~'~ othe r rare complications of salmonellosis include p e r i~a r d i t i s ,~~ p y e l i t i~,~~ peritonitis:77 otitis media:77 mas ti ti^,^^^ chole~ystitis,~~' endophthalmiti~,~~~ cutaneous abscesses,492 and infected cephal~hematoma?~' other focal infections seen in older children and adults, such as endocarditis and infected aortic aneurysms, rarely or never have been reported in neonates.537,549 altho ugh the mortality rate in two reviews of nursery outbreaks was 3.7% to 7.0%,"959496 in some series, it reached 18%. 485 enteric fever, most often related to s. typhi but also occurring with s. paratyphi a, s. paratyphi b, s. paratyphi c, and other salmonella species, is reported much less commonly in infants than in older patients. infected infants develop typical findings of neonatal sepsis and meningitis. current data suggest that mortality is about 30y0.~~' in utero infection with s. typhi has been described. typhoid f e~e r~" *~~' and nontyphoidal salmonella infections552 during pregnancy put women at risk of aborting the fetus. premature labor usually occurs during the second to the fourth week of maternal typhoid if the woman is untreated.522 in a survey of typhoid fever in pregnancy during the preantibiotic era, 24 of 60 women with well-documented cases delivered prematurely, with resultant fetal death; the rest delivered at term, although only 17 infants survived. 553 the outlook for carrying the pregnancy to term and delivering a healthy infant appears to have improved dramatically during the antibiotic era. however, one of seven women with typhoid in a series still delivered a dead fetus with extensive liver necrosis. 554 in the preantibiotic era, about 14% of pregnant women with typhoid fever died.555 with appropriate antimicrobial therapy, pregnancy does not appear to put the woman at increased risk of death. despite these welldescribed cases, typhoid fever is rare early in life. of 1500 cases of typhoid fever that osler and m~c r a e~~~ reported, only 2 were in the first year of life. in areas where typhoid fever is still endemic, systematic search for infants with enteric fever has failed to find many cases. the few infections with s. typhi documented in children in the first year of life often present as a brief nondescript "viral syndrome" or as p n e~r n o n i t i s ?~~*~~' fever, diarrhea, cough, vomiting, rash, and splenomegaly may occur; the fever may be high, and the duration of illness may be many weeks.522 the current practice of early discharge of newborn infants, although potentially decreasing the risk of exposure, can make recognition of a nursery outbreak difficult. diagnosis of neonatal salmonellosis should trigger an investigation for other cases. other than diarrhea, signs of neonatal salmonella infection are similar to the nonspecific findings seen in most neonatal infections. lethargy, poor feeding, pallor, jaundice, apnea, respiratory distress, weight loss, and fever are common. enlarged liver and spleen are common in those neonates with positive blood cultures. laboratory studies are required to establish the diagnosis because the clinical picture is not distinct. the fecal leukocyte examination reveals polymorphonuclear leukocytes in 36% to 82%359. 559 of persons with salmonella infection, but it has not been evaluated in neonates. obviously, the presence of fecal leukocytes is consistent with colitis of any cause and therefore is a nonspecific finding. routine stool cultures usually detect salmonella if two or three different enteric media (i.e., macconkey's, eosin-methylene blue, salmonella-shigella, tergitol 7, xylose-lysine-deoxycholate, brilliant green, or bismuth sulfite agar) are used. stool, rather than rectal swab material, is preferable for culture, particularly if the aim of culture is to detect carriers.560 on the infrequent occasions when proctoscopy is performed, mucosal edema, hyperemia, friability, and hemorrhages may be seen.*' infants who are bacteremic often do not appear sufficiently toxic to raise the suspicion of b a~t e r e m i a .~~~ blood cultures should be obtained as a routine part of evaluation of neonates with suspected or documented salmonella infection. ill neonates with salmonella infection should have a cerebrospinal fluid examination performed. bone marrow cultures also may be indicated when enteric fever is suspected. there are no consistent abnormalities in the white blood cell count. serologic studies are not helpful in establishing the diagnosis, although antibodies to and flagellar antigens487 develop in many infected newborns. if an outbreak of salmonellosis is suspected, further characterization of the organism is imperative?64 determination of somatic and flagellar antigens to characterize the specific serotype may be critical to investigation of an outbreak. when the serotype found during investigation of an outbreak is a common one (e.g., s. typhimurium), antimicrobial resistance testing475,565 and use of molecular techniques such as plasmid chara~terization~~~ can be helpful in determining whether a single-strain, common-source outbreak is in progress. and ampicillin or amoxicillin versus placebo.572 in contrast to these studies, data suggest that there may be a role for quinolone antibiotics in adults and ~h i l d r e n ,~~~,~~~ but these drugs are not approved for use in neonates, and resistance has been en~ountered.~'~ because these studies have few data as to the risk-benefit ratio of therapy in the neonate, it is uncertain whether they should influence treatment decisions in neonates. studies that have included a small number of neonates suggest little benefit from antimicrobial therapy.477*487*56835773578 however, because bacteremia is common in neonates, antimicrobial therapy for infants younger than 3 months who have salmonella gastroenteritis often is recommended,532v533v561 especially if the infant appears toxic. premature infants and those who have other significant debilitating conditions also should probably be treated. the duration of therapy is debatable but should probably be no more than 3 to 5 days if the infant is not seriously ill and if blood cultures are sterile. if toxicity, clinical deterioration, or documented bacteremia complicates gastroenteritis, prolonged treatment is indicated. even with antimicrobial therapy, some infants develop complications. the relatively low risk of extraintestinal dissemination must be balanced against the well-documented risk of prolonging the carrier state. for infants who develop chronic diarrhea and malnutrition, hyperalimentation may be required; the role of antimicrobial agents in this setting is unclear. the infant with typhoid fever should be treated with an antimicrobial agent; relapses sometimes occur after therapy. colonized healthy infants discovered by stool cultures during evaluation of an outbreak ought to be isolated but probably should not receive antimicrobial therapy. such infants should be discharged from the nursery as early as possible and followed carefully as outpatients. antimicrobial treatment of neonates who have documented extraintestinal dissemination must be prolonged. bacteremia without localization is generally treated with at least a 10-day course of therapy. therapy for salmonella meningitis must be given for at least 4 weeks to lessen the risk of relapse. about three fourths of patients who have relapses have been treated for three weeks or less?37 similar to meningitis, treatment for osteomyelitis must be prolonged to be adequate. although cures have been reported with 3 weeks of therapy, 4 to 6 weeks of therapy is recommended. in vitro susceptibility data for salmonella isolates must be interpreted with caution. the aminoglycosides show good in vitro activity but poor clinical efficacy, perhaps because of the low ph of the phagolysosome. aminoglycosides have poor activity in an acid environment. the stability of some drugs in this acid environment also may explain in vitro and in vivo disparities. the intracellular localization and survival of salmonella within phagocytic cells also presumably explains the relapses encountered with virtually every regimen. resistance to antibiotics has long been a problem with salmonella i n f e c t i~n .~~,~~~,~~' there has been a steady increase in resistance to salmonella in the united states over the last 20 years.581 with the emergence of typhimurium type dt 104, resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline has increased from 0.6% in 1979 and 1980 to 34% in 1996. 582 resistance plasmids have been selected and transmitted, partly because therapy has been given for mild illness that should not have been treated566 and partly because of use of antibiotics in animal feeds. resistance to chloramphenicol and ampicillin has made trimethoprim-sulfamethoxazole increasingly important for the treatment of salmonella infection in those patients who require therapy. however, with increasing resistance to all three of these agents in asia?83 the middle e~r o p e ,~~~,~'~ ar gentina,580 and north america,5793588,589 the third-generation cephalosporins and quinolones represent drugs of choice for invasive salmonellosis. the quinolones currently are not approved for persons younger than 18 years. cefotaxime, ceftriaxone, and cefoperazone represent acceptable alternative drugs for typhoidal and nontyphoidal salmonellosis when resistance is e n c o~n t e r e d .~~"~~~ because the second-generation cephalosporins, such as cefuroxime, are less active in vitro than the third-generation cephalosporins and are not consistently clinically effective, they should not be data suggest that cefoperazone may sterilize blood and cause patients with typhoid fever to become afebrile more rapidly than with chl~ramphenicol,~~~ perhaps because cefoperazone is excreted into bile in high concent r a t i o n~.~~~ the third-generation cephalosporins may have higher cure and lower relapse rates than ampicillin or chloramphenicol in children with salmonella meningitis. 595 the doses of ampicillin, chloramphenicol, or cefotaxime used in infants with gastroenteritis pending results of blood cultures are the same as those used in treatment of sepsis. because of the risk of gray baby syndrome, chloramphenicol should not be used in neonates unless other effective agents are not available. trimethoprim-sulfamethoxazole, although useful in older children and adults, is not used in neonates because of the risk of kernicterus. nosocomial infection with strains of salmonella resistant to multiple antibiotics, including third-generation cephalosporins, has emerged as a problem in south america. 580 nonantibiotic interventions are important in the control of salmonella infections. limited data suggest that intravenous immune globulin (igiv) (500 mg/kg on days 1,2,3, and 8 of therapy) along with antibiotic therapy may decrease the risk of bacteremia and death in preterm infants with salmonella ga~troenteritis.~~~ early recognition and intervention in nursery outbreaks of salmonella are crucial to control. when a neonate develops salmonellosis, a search for other infants who have been in the same nursery should be undertaken. when two or more cases are recognized, environmental cultures, cultures of all infants, cohorting and contact isolation of infected infants, rigorous enforcement of hand hygiene, early discharge of infected infants, and thorough cleaning of all possible fomites in the nursery and delivery rooms are important elements of control. if cases continue to occur, the nursery should be closed to further admissions. cultures of nursery personnel are likely to be helpful in the unusual situation of an s. typhi outbreak in which a chronic carrier may be among the caretakers. culture of health care personnel during outbreaks of salmonellosis caused by other salmonella species is debatable, although often recommended. data suggest that nurses infected with salmonella rarely infect patients in the hospital setting.597 the fact that nursing personnel are sometimes found to be colonized during nursery outmay be a result rather than a cause of those epidemics. the potential role of vaccines in control of neonatal disease is minimal. for the vast number of non-s. ryphi serotypes, there is no prospect for an immunization strategy. multiple doses of the commercially available oral live attenuated vaccine (ty2la; vivotif, berna), has been shown in chilean schoolchildren to reduce typhoid fever cases by more than 70%.598,599 however, the vaccine is not recommended for persons younger than 6 years, in part because immunogenicity of ty2la is age dependent; children younger than 24 months fail to respond with development of immunity!" vi capsular polysaccharide vaccine is available for children older than 2 years and is effective in a single dose. whether some degree of protection of infants could the virulence of shigellae has been studied extensively since their recognition as major pathogens at the beginning of the 20th century. the major determinants of virulence are encoded by a 120-to 140-mda p l a~m i d .~~~.~~~ this plasmid, which is found in all virulent shigellae, encodes the synthesis of proteins that are required for invasion of mammalian cells and for the vigorous inflammatory response that is characteristic of the d i s e a~e .~~*~~ shigellae that have lost this plasmid, have deletions of genetic material from the region involved in synthesis of these proteins, or have the plasmid inserted into the chromosome lose the ability to invade eukaryotic cells and become aviru1ent6o7; maintenance of the plasmid can be detected in the clinical microbiology lab by ability to bind congo red. the ability to invade cells is the basic pathogenic property shared by all ~h i g e l l a e~~'~~~~ and by the shigella-like invasive e. coli, which also possesses the shigella virulence plasmid.205~605~606~610~611 in the laboratory, shigella invasiveness is studied in tissue culture (hela cell invasion), in animal intestine, or in rabbit or guinea pig eye, where instillation of the organism causes keratoconjunctivitis (sereny test)."' animal model studies have shown that bacteria penetrate and kill colonic mucosal cells and then elicit a brisk inflammatory response. in addition to the virulence plasmid, several chromosomal loci enhance virulence.612v613 this has been best studied in s. flexneri in which multiple virulence-enhancing regions of the chromosome have been defined.604s612-614 the specific gene products of some of the chromosomal loci are not known; one chromosomal virulence segment encodes for synthesis of the 0 repeat units of lipopolysaccharide. intact lipopolysaccharide is necessary but not sufficient to cause virulence.6129615 at least two cell-damaging cytotoxins that also are chromosomally encoded are produced by shigellae. one of these toxins (shiga toxin) is made in large quantities by s. dysenteriae serotype 1 (the shiga bacillus) and is made infrequently by other shigellae.616 shiga toxin is a major virulence factor in s. dysenteriae, enhancing virulence at the colonic mucosa and also giving rise to sequelae similar to those caused by stec (discussed earlier). this toxin kills cells by interfering with peptide elongation during protein ~y n t h e s i s .~'~-~'~ additional toxins may also be secreted by shigellae, although their roles in virulence are not established.620 although much of the epidemiology of shigellosis is predictable based on its infectious dose, certain elements are unexplained. shigellae, like other organisms transmitted by the fecal-oral route, are commonly spread by food and water, but the low infecting inoculum allows person-to-person spread. because of this low inoculum, shigella is one of the few enteric pathogens that can infect swimmers. 621 the dose required to cause illness in adult volunteers is as low as 10 organisms for s. dysenteriae serotype 1,6" about 200 organisms for s. f l e~n e r i ,~~~ and 500 organisms for s. ~o n n e i .~'~ personto-person transmission of infection probably explains the continuing occurrence of shigella in the developed world. enteropathogens that require large inocula and hence are best spread by food or drinking water are less common in industrialized societies because of sewage disposal facilities, water treatment, and food-handling practices. in the united states, daycare centers currently serve as a major focus for acquisition of shigell~sis.~'~ numerous outbreaks of shigellosis related to crowding, poor sanitation, and the low dose required for diseases have occurred in this setting. given the ease of transmission, it is not surprising that the peak incidence of disease is in the first 4 years of life. it is, however, paradoxical that symptomatic infection is uncommon in the first year of life.626-629 the best data on the age-related incidence of shigellosis come from mata'~~'~ prospective studies of guatemalan infants. in these studies, stool cultures were performed weekly on a group of children followed from birth to 3 years old. the rate of infection was more than 60-fold lower in the first 6 months of life than (fig. 20-1) . 626 the same age-related incidence has been described in the united states629 and in a rural egyptian village. 628 this anomaly has been explained by the salutary effects of brea~t-feeding.~~'-~~' however, it is likely that breast-feeding alone does not explain the resistance of infants to shigellosis. a review of three large case series633-635 suggests that about 1.6% (35 of 2225) of shigellosis cases occur in infants in the neonatal period. the largest series of neonatal ~higellosis~~~ suggests that the course, complications, and etiologic serogroups are different in neonates than in older children. although newborns are routinely contaminated by maternal feces, neonatal shigellosis is rare. other aspects of the epidemiology of shigellosis elude simple explanation. the seasonality (summer-fall peak in the united states, rainy season peak in the tropics) is not well explained. the geographic variation in species causing infection likewise is not well understood. in the united states, most shigella infections are caused by s. sonnei or, less commonly, s. flexneri. in most of the developing world, the relative importance of these two species is reversed, and other shigella serotypes, especially s. dysenteriae serotype 1, are identified more frequently. as hygiene improves, the proportion of s. sonnei increases and that of s. flexneri decreases.636 data from bangladesh suggest that s. dysenteriae is less common in neonates, but s. sonnei and s. boydii are more c0mmon.6~~ there appear to be some important differences in the relative frequencies of various complications of shigella infection related to age. some of these differences and estimates are based on data that are undoubtedly compromised by reporting biases. s. dysenteriae serotype 1 characteristically causes a more severe illness than other shigellae with more complications, including pseudomembranous colitis, hemolysis, and hus. however, illnesses caused by various shigella serotypes usually are indistinguishable from each other and conventionally are discussed together. the incubation period of shigellosis is related to the number of organisms ingested, but in general, it is between 12 and 48 hours. volunteer studies have shown that after ingestion, illness may be delayed for a week or more. neonatal shigellosis seems to have a similar incubation period. more than one half of the neonatal cases occur within 3 days of birth, consistent with fecal-oral transmission during parturition. mothers of infected neonates are sometimes carriers, although more typically they are symptomatic during the perinatal period. intrauterine infection is rare. in the older child, the initial signs are usually high fever, abdominal pain, vomiting, toxicity, and large-volume watery stools; diarrhea may be bloody or may become bloody. painful defecation and severe, crampy abdominal pain associated with frequent passage of small-volume stools with gross blood and mucus are characteristic findings in older children or adults who develop severe colitis. many children, however, never develop bloody diarrhea. adult volunteer studies have demonstrated that variations in presentation and course are not related to the dose ingested because some patients develop colitis with dysentery but others develop only watery diarrhea after ingestion of the same i n o c u l~m .~~~ the neonate with shigellosis may have a mild diarrheal syndrome or a severe ~o l i t i s .~~~~~~~-~~ fever in neonates is usually low grade (<102" f) if the course is uncomplicated. the neonate has less bloody diarrhea, more dehydration, more bacteremia, and a greater likelihood of death than the older ~h i l d . 6~~ physical examination of the neonate may show signs of toxicity and dehydration, although fever, abdominal tenderness, and rectal findings are less striking than in the older complications of shigellosis are common.646 although the illness is self-limited in the normal host, resolution may be delayed for a week or more. in neonates and malnourished children, chronic diarrhea may follow a bout of shigello~is.6~',~~ between 10% and 35% of hospitalized children with shigella have convulsions before or during the course of usually, the seizures are brief, generalized, and associated with high fever. seizures are uncommon in the first 6 months of life, although neonates have been described with seizures.6399649 the cerebrospinal fluid generally reveals normal values in these children, but a few have mild cerebrospinal fluid pleocytosis. the neurologic outcome generally is good even with focal or prolonged seizures, but fatalities do occasionally occur, often associated with toxic encephalpa thy.^^' although the seizures had been postulated to result from the neurotoxicity of shiga toxin, this explanation was proved to be incorrect because most shigellae make little or no shiga toxin and the strains isolated from children with neurologic symptoms do not produce shiga t~x i n .~'~,~~' hemolysis with or without development of uremia is a complication primarily of s. dysenteriae serotype 1 infection. 652 sepsis during the course of shigellosis may be caused by the shigella itself or by other gut flora that gain access to the bloodstream through damaged mucosa.632'653*654 the risk of sepsis is higher in the first year of life, particularly in neo-nates,632.637-639,649,656 in malnourished children, and in those with s. dysenteriae serotype 1 infection.654 sepsis occurs in up to 12% of neonates with given the infrequency of neonatal shigellosis, it is striking that 9% of reported cases of shigella sepsis have involved infants in the first month of life.657 one of the infants with ba~teremia~~' reportedly had no discernible illness. disseminated intravascular coagulation may develop in those patients whose course is complicated by sepsis. meningitis has been described in a septic neonate. colonic perforation has occurred in n e o n a t e~, 6~"~~~ older children,@' and adults.661 although this complication of toxic megacolon is rare, it appears to be more common in neonates than in older individuals. bronchopneumonia may complicate the course of shigellosis, but shigellae are rarely isolated from lungs or tracheal secretions."2 the syndrome of sudden death in the setting of extreme toxicity with hyperpyrexia and convulsions but without dehydration or sepsis (i.e., ekiri ~yndrome)~~'"~ is rare in neonates. in the nonbacteremic child, other extraintestinal foci of infection, including ~a g i n a~~~. "~ and eye,"' rarely occur. reiter's syndrome, which rarely complicates the illness in children, has not been reported in neonates. although infection is less common in infants than in toddlers, case fatality rates are highest in infant^.^^'^^' the mortality rate in newborns appears to be about twice that of older children.632 in industrialized societies, less than 1% of children with shigellosis die, whereas in developing countries, up to 30% die. these differences in mortality rates are related to n~t r i t i o n . 6~~ availability of medical care, antibiotic resistance of many shigellae, the frequency of sepsis, and the higher frequency of s examination of stool for leukocytes as an indication of colitis is useful in support of the clinical suspicion of shigellosis. the white blood cell count and differential count also are used as supporting evidence for the diagnosis. leukemoid reactions (white blood cells > 50,000/mm3) occur in almost 15% of children with s. dysenteriae serotype 1 but in less than 2% of children with other ~h i g e l l a e .~~~ leukemoid reactions are more frequent in infants than in older ~hildren.6~' even when the total white blood cell count is not dramatically elevated, there may be a striking left shift. almost 30% of children with shigellosis have greater than 25% bands on the differential cell few reports address the white blood cell count in newborns, but those that do suggest that normal or low rather than elevated counts are more common. although serum and fecal antibodies develop to lipopolysaccharides and the virulence plasmid-associated polypeptide~,6~~ serologic studies are not useful in the diagnosis of shigellosis. pcr can identify shigella and eiec in feces.678 colonoscopy typically shows inflammatory changes that are most severe in the distal segments of therapy because dehydration is particularly common in neonatal shigellosis, attention to correction of fluid and electrolyte disturbances is always the first concern when the illness is suspected. although debate continues over the indications for antimicrobial therapy in the patient with shigellosis, the benefits of therapy generally appear to outweigh the risks. the chief disadvantages of antimicrobial therapy include cost, drug toxicity, and emergence of antibiotic-resistant shigellae. because of the self-limited nature of shigellosis, it has been argued that less severe illness should not be treated. however, children can feel quite ill during the typical bout of shigellosis, and appropriate antimicrobial therapy shortens the duration of illness and eliminates shigellae from stool, decreasing secondary spread. complications are probably decreased by antibiotics. given the high mortality rates of neonatal shigellosis, therapy should not be withheld. the empirical choice of an antimicrobial agent is dictated by susceptibility data for strains circulating in the community at the time the patient's infection occurs. multiresistant shigellae complicate the choice of empirical therapy before availability of susceptibility data for the patient's isolate. plasmid-encoded resistance (r factors) for multiple antibiotics has been observed frequently in s. dysenteriae serotype 1 outbreaks682 and with other ~higellae.~'~.~'~ antimicrobial resistance patterns fluctuate from year to year in a given locale.686 however, despite the guesswork involved, early preemptive therapy is indicated when an illness is strongly suggestive of shigellosis. in vitro susceptibility does not always adequately predict therapeutic responses. cefa~lor,6~~ furazolidone,688 ~ephalexin,6'~ amo~icillin,6~' kanam~cin,6~' and ~e f a m a n d o l e~~~ all are relatively ineffective agents. the optimal duration of therapy is debatable. studies in children older than 2 years and in adults suggest that singledose regimens may be as effective in relieving symptoms as courses given for 5 days. the single-dose regimens generally are not as effective in eliminating shigellae from the feces as are the longer courses. a third-generation cephalosporin, such as ceftriaxone, may be the best empirical choice. optimal doses for newborns with shigellosis have not been established. trimethoprim at a dose of lomg/kg/day (maximum, 160 mg/day) and sulfamethoxazole at a dose of 50 mg/kg/day (maximum, 800 mg/day) in two divided doses for a total of 5 days are recommended for the older child if the organism is s~s c e p t i b l e . 6~~-~~~ if the condition of the infant does not permit orally administration, the drug usually is divided into three doses given intravenously over 1 ampicillin at a dose of 100 mg/kg/day in four divided doses taken orally for 5 days may be used if the strain is susceptible. 676 for the rare newborn who acquires shigellosis, appropriate therapy often is delayed until susceptibility data are available. this occurs because shigellosis is so rare in newborns that it is almost never the presumptive diagnosis of the child with watery or bloody diarrhea. although a sulfonamide is as efficacious as ampicillin when the infecting strain is sus~eptible,6~~ sulfonamides are avoided in neonates because of concern about the potential risk of kernicterus. the risk of empirical ampicillin therapy is that shigellae are frequently resistant to the drug; 50% of shigellae currently circulating in the united states are ampicillin resistant.6963697 for the neonate infected with ampicillin-resistant shigella, there are few data on which to base a recommendation. ceftriaxone is generally active against shigellae, but in the neonate, this drug can displace bilirubin-binding sites and elicit clinically significant cholestasis. data on children and adults suggest that clinical improvement occurs with c e f t r i a x~n e .~~~*~~~ quinolones, such as ciprofloxacin and ofloxacin, have been shown to be effective agents for treating s h i g e l l o s i~~~~~~~~ in adults, but they are not approved for use in children younger than 18 years. other drugs sometimes used to treat diarrhea pose special risks to the infant with shigellosis. the antimotility agents, in addition to their intoxication risk, may pose a special danger in dysentery. in adults, diphenoxylate hydrochloride with atropine has been shown to prolong fever and excretion of the ~rganism.~" the response to appropriate antibiotic therapy is generally gratifying. improvement is often obvious in less than 24 hours. complete resolution of diarrhea may not occur until a week or more after the start of treatment. in those who have severe colitis or those infected by s. dysenteriae serotype 1, the response to treatment is somewhat delayed. for most of the developing world, the best strategy for prevention of shigellosis during infancy is prolonged breastfeeding. specific antibodies in milk appear to prevent symptomatic shigellosis6'68; nonspecific modification of gut flora and the lack of bacterial contamination of human milk also may be important. breast-feeding, even when other foods are consumed, decreases the risk of shigellosis; children who continue to consume human milk into the third year of life are still partially protected from in the united states, the best means of preventing infection in the infant is good hand hygiene when an older sibling or parent develops diarrhea. even in unsanitary environments, secondary spread of shigellae can be dramatically decreased by hand hygiene after defecation and before meals.704 spread of shigellae in the hospital nursery can presumably be prevented by the use of contact isolation for infants with diarrhea and attention to thorough hand hygiene. although nursery personnel have acquired shigellosis from infected newborns,685 further transmission to other infants in the nursery, although is rare. in contrast to salmonella, large outbreaks of nosocomial shigellosis in neonates are rare. unfortunately, good hygiene is a particularly difficult problem in daycare centers. the gathering of susceptible children, breakdown in hand hygiene, failure to use different personnel for food preparation and diaper changing, and difficulty controlling the behavior of toddlers all contribute to daycare-focused outbreaks of shigellosis. immunization strategies have been studied since the turn of the 20th century, but no satisfactory immunization has been developed. even if immunizations are improved, a role in managing neonates seems unlikely. campylobacter was first recognized in an aborted sheep fetus in the early 19o0s7o6 and was named vibrio fetus by smith and taylor in 1919. 707 this organism subsequently was identified as a major venereally transmitted cause of abortion and sterility and as a cause of scours in cattle, sheep, and goats.70s3709 it was not until 1947, when it was isolated from the blood culture of a pregnant woman who subsequently aborted at 6 months' gestation, that the significance of campylobacter as a relatively rare cause of bacteremia and perinatal infections in humans was a~preciated.~l'-~'~ during the 1970s, campylobacter was recognized to be an opportunistic pathogen in debilitated in 1963, v fetus and related organisms were separated from the vibrios (such as v cholerae and v parahaemolyticus) and placed in a new genus, campylobacter (greek word for "curved rod"). 715 since 1973, several campylobacter species have been recognized as a common cause of e n t e r i t i~~l~.~~~ and, in some cases, extraintestinal infections. the genus campylobacter contains 15 species, most of which are recognized as animal and human pathogens. the most commonly considered causes of human disease are campylobacter fetus, campylobacter jejuni, campylobacter coli, campylobacter lari, and campylobacter upsaliensis (table 20 -5),'30-732 although campylobacter mucosalis has been isolated from stool of children with diarrhea.733 dna hybridization studies have shown that these species are distinct, sharing less than 35% dna homology under stringent hybridization ~o n d i t i o n s .~~~,~~~ helicobacter pylori was originally named campylobacter pylori, but because of differences in dna, it was reclassified and is no longer considered in the campylobacter genus. strains of c. fetus are divided into two subspecies: c. fetus subsp. fetus and c. fetus subsp. venerealis. the first subspecies causes sporadic abortion in cattle and sheep7369737; in by far the most common syndrome caused by a campylobacter species is enteritis. c. jejuni and c. coli cause gastroenteritis and generally are referred to collectively as c. jejuni, although dna hybridization studies show them to be different. in the laboratory, c. jejuni can be differentiated from c. coli because it is capable of hydrolyzing hippurate, whereas c. coli is not. most isolates that are associated with diarrhea (61% to 100%) are identified as c. jejuni,751-754 and in some cases, individuals have been shown to be simultaneously infected with c. jejuni and c. ~o l i . ~~~ because of the fastidious nature of c. jejuni, which is difficult to isolate from fecal flora, its widespread occurrence was not recognized until 1973.716-732 previously called related vibrios by this organism had been associated with bloody diarrhea and colitis in infants and adults only when it had been associated with a recognized b a~t e r e m i a .~~~-~~~ in the late 1970s, development of selective fecal culture methods for c. jejuni enabled its recognition worldwide as one of the most common causes of enteritis in persons of all ages. it is an uncommon infection in neonates who generally develop gastroenteritis when i n f e~t e d .~'~-~~~-~~' bacteremia with c. jejuni enteritis also is uncommon.718~759,76l*769*772-778 maternal symptoms considered to be related to c. jejuni infection generally are mild and include fever (75%) and diarrhea (30%). in contrast to the serious disease in newborns that is caused by c. fetus, neonatal infections with although meningitis occurs in rare third trimester infection related to c. fetus or c. jejuni may results in abortion or stillbirth. pathogenesis c. fetus does not produce recognized enterotoxins or cytotoxins and does not appear to be locally invasive by the sereny instead, these infections may be associated with penetration of the organism through a relatively intact intestinal mucosa to the reticuloendothelial system and blo~dstream.~'~ whether this reflects a capacity to resist serum factors or to multiply intracellularly remains to be determined. c. jejuni is capable of producing illness by several mechanisms. these organisms have been shown to produce an lt enterotoxin and a c y t o t o x i r~.~~~~~~~ this enterotoxin is known to be a heat-labile protein with a molecular mass of 60 to 70 mda.7793782 it shares functional and immunologic properties with cholera toxin and e. coli lt. c. jejuni and c. coli also elaborate a cytotoxin that is toxic for a number of mammalian cells.783-785 the toxin is heat labile, trypsin sensitive, and not neutralized by immune sera to shiga toxin or the cytotoxin of clostridium dificile. the role of these toxins as virulence factors in diarrheal disease remains unpr~ved.'~~,~~ several animal models have been tested for use in the study of this pathogen.786 potential models for the study of c. jejuni enteritis include dogs, which may acquire symptomatic infection787; 3-to 8-day old ~h i c k s~~' -~~; chicken embryo cells, which are readily invaded by c. jejuni7"; rhesus monkeys791; and rabbits by means of the removable intestinal tie adult rabbit technique. an established small mammal model that mimics human disease in the absence of previous treatment or surgical procedure has not been successful in adult mice.792 an infant mouse mode1793,794 and a hamster of diarrhea appear promising. c. jejuni is negative in the sereny test for invasivenes~,~~~ and most investigators report no fluid accumulation in ligated rabbit ileal loops. the pathologic findings of c. fetus infection in the perinatal period include placental necrosis7'' and, in the neonate, widespread endothelial proliferation, intravascular fibrin deposition, perivascular inflammation, and hemorrhagic necrosis in the brain. 797 the tendency for intravascular location and hepatosplenomegaly in adults infcctcd with c. fetus has been the pathologic findings in infants and children infected with c. fetus can include an acute inflammatory process in the colon or rectum, as evidenced by the tendency for patients to have bloody diarrhea with numerous fecal leukocytes. 798 there also can be crypt abscess formation and an ulcerative colitis or pseudomembranous colitis-like or a hemorrhagic jejunitis or ileitis.717b725,801,802 mesenteric lymphadenitis, ileocolitis and acute appendicitis also have been described. infection with campylobacter species occurs after ingestion of contaminated food, including unpasteurized milk, poultry, and contaminated water.'26,803-812 m any farm animals and pets, such as chickens,813 dogs,814s815 and cats (especially young animals), are potential sources. the intrafamilial spread of infection in h o~s e h o l d s ,~~~,~~~ the occurrence of outbreaks in and the apparent laboratory acquisition of c. jejuni818 all suggest that c. jejuni infection may occur after person-to-person transmission of the organism. outbreaks of c. jejuni in the child daycare setting are not common. volunteer studies8i9 have shown a variable range in the infecting dose, with many volunteers developing no illness. the report of illness after ingestion of lo6 organisms in a glass of milk728 and production of illness in a single volunteer by 500 organisms8i9 substantiate the variation in individual susceptibility. the potential for low-inoculum disease has significant implications for the importance of strict enteric precautions when infected persons are hospitalized, particularly in maternity and nursery areas. when diarrhea in neonates caused by c. jejuni has been r e p~r t e d ,~~~-~~' maternal-infant transmission during labor has generally been documented.758~763*765~768p770~771 the lior serotyping system, restriction length polymorphism, and pulse-field gel electrophoresis have been used to confirm the identity of the infant and maternal isolates. most mothers gave no history of diarrhea during pregnancy.7623763*765,766 outbreaks have occurred in neonatal intensive care units because of person-to-person spread.8z0 the frequency of asymptomatic carriage of c. jejuni ranges from 0% to 1.3%7'6,717 to as high as 13% to 85%.716,717,732,821-823 in a cohort study in mexico, 66% of all infections related to c. jejuni were asymptomatic.732 infected children, if untreated, can be expected to excrete the organisms for 3 or 4 weeks; however, more than 80% are culture negative after 5 ~e e k s .~~~,~~~a~ ymptomatic excreters pose a significant risk in the neonatal period, in which acquisition from an infected mother can be clinically important.718,760s762,766 c. jejuni has increasingly been recognized as a cause of watery and inflammatory diarrhea in temperate and tropical climates throughout the world. it has been isolated from 2% to 11% of all fecal cultures from patients with diarrheal illnesses in various parts of the world.716-724,728*824-829 there is a tendency for c. jejuni enteritis to occur in the summer in countries with temperate climates. 825 the reservoir of campylobacter is the gastrointestinal tract of domestic and wild birds and animals. it infects sheep, cattle, goats, antelope, swine, chickens, domestic turkeys, and pet dogs. c. fetus often is carried asymptomatically in the intestinal or biliary tracts of sheep and cattle. during the course of a bacteremic illness in pregnant animals, c. fetus organisms, which have a high affinity for placental tissue, invade the uterus and multiply in the immunologically immature fetus. the infected fetuses generally are aborted. whether this organism is acquired by humans from animals or is carried asymptomatically for long periods in humans, who may then transmit the organism through sexual contact as appears to occur in animals, is unclear. it is believed that this subspecies rarely is found in the human intestine and that it is not a cause of human enteriti~?'~ c. fetus infections predominantly occur in older men with a history of farm or animal exposure and in pregnant women in their third trimester.710~71 1,716,717 symptomatically or asymptomatically infected women may have recurrent abortions or premature deliveries and are the source of organisms associated with life-threatening perinatal infections of the fetus or newborn infant.710,739-7483830 in several instances of neonatal sepsis and meningitis, c. fetus was isolated from culture of maternal cervix or vagina.712,747s795 a n osocomial nursery outbreak has been associated with carriage in some healthy infants.83' other outbreaks have been associated with meningitis 832, 833 cervical cultures have remained positive in women who have had recurrent abortions and whose husbands have antibody titer elevations. 738 the most commonly incriminated reservoir of c. jejuni is poultry.808,s12,834,835 m ost chickens in several different geographic locations had a large number (mean, 4 x 106/g) of c. jejuni in the lower intestinal tract or feces. this occurred in some instances despite the use of tetracycline, to which the campylobacter was susceptible in vitro, in the chicken feed.828 the internal cavities of chickens remain positive for carnpylobacter even after they have been cleaned, packaged, and fr0zen.8~~ however, unlike salmonella, c. jejuni organisms that survive usually do not multiply to high concen-tration~?~' domestic puppies or kittens w i t h c. jejuni diarrhea also can provide a source for spread, especially to infants or c. jejuni enteritis also has been associated in a number of outbreaks with consumption of unpasteurized in retrospect, the first reported human cases of c. jejuni enteritis were probably in a milk-borne outbreak reported in 1 946. 842 because campylobacter infections of the udder are not seen, milk is probably contaminated from fecal shedding of the organism. these organisms are killed by adequate heating. fecally contaminated water is a potential vehicle for c. jejuni infections.843 several phenotypic and genotypic methods have been used for distinguishing c. jejuni strains from animals and humans involved in epidemics. 844 clinical manifestations of infection caused by campylobacter depend on the species involved (see table 20 -5). human infections with c. fetus are rare and generally are limited to bacteremia in patients with predisposing condition^^^^.^^^ or to bacteremia or uterine infections with prolonged fever and pneumonitis that lasts for several weeks in women during the third trimester of pregnancy. unless appropriately treated, symptoms usually resolve only after abortion or delivery of an infected infant?10j12,739-748*750 these infected neonates, who are often premature, develop signs suggesting sepsis, including fever, cough, respiratory distress, vomiting, diarrhea, cyanosis, convulsions, and jaundice. the condition typically progresses to meningitis, which may be rapidly fatal or may result in serious neurologic ~equelae.~" additional systemic manifestations include pericarditis, pneumonia, peritonitis, salpingitis, septic arthritis, and abscesses.823 c. jejuni infection typically involves the gastrointestinal tract, producing watery diarrhea or a dysentery-like illness with fever and abdominal pain and stools that contain blood and ~u c u s .~~~~~~'~~' " ' older infants and children generally are affected, but neonates with diarrhea have been reported. infection in neonates generally is not clinically apparent or is mild. stools can contain blood, mucus, and pus712p721*762*763; fever often is ab~ent.7~~"~' the illness usually responds to appropriate antimicrobial which shortens the period of fecal shedding.845 extraintestinal infections related to c. jejuni other than bacteremia are rare but include cholecystitis,846 urinary tract and meningitis.761 bacteremia is a complication of gastrointestinal infe~tion,8~' especially in malnourished children. 849 meningitis that appears to occur secondary to intestinal infection also has been reported in premature infants who have had intraventricular needle aspirations for neonatal hydrocephalus.'i2 complications in older children and adults that have been associated with c. jejuni enteritis include reiter's syndrome, 850 guillain-barre ~y n d r o m e , 8~~~~~* and reactive persistent c. jejuni infections have been described in patients infected with human immunodeficiency extraintestinal manifestations generally occur in patients who are immunosuppressed or at the extremes of age.'14 campybbacter zari has caused chronic diarrhea and bacteremia in a neonate!% most important in the diagnosis of campylobacter infection is a high index of suspicion based on clinical grounds. c. fetus and c. jejuni are fastidious and may be overlooked on routine fecal cultures. isolation of campylobacter from blood or other sterile body sites does not represent the same problem as isolation from stool. growth occurs with standard blood culture media, but it may be slow. in the case of c. fetus infecting the bloodstream or central nervous system, blood culture flasks should be blindly subcultured and held for at least 7 days or the organism may not be detected because of slow or inapparent the diagnosis of c. fetus infection should be considered when there is an unexplained febrile illness in the third trimester of pregnancy or in the event of recurrent abortion, prematurity, or neonatal sepsis with or without meningitis. a high index of suspicion and prompt, appropriate antimicrobial therapy may prevent the potentially serious neonatal complications that may follow maternal c. fetus infection. campylobacter is distinguished from the vibrio organisms by its characteristics of carbohydrate nonfermentation and by its different nucleotide base omp position.^^^^^^^-^^^*^^^ campylobacter is 0.2 to 0.5 fm wide and 0.5 to 8.0 long. it is a fastidious, microaerophilic, curved, motile gram-negative bacillus that has a single polar flagellum and is oxidase and catalase positive, except for c. upsaliensis, which is generally catalase negative or weakly positive. c. jejuni and c. fetus are separated by growth temperature (c. fetus grows best at 25' c but can be cultured at 37' c; c. jejuni grows best at 42' c) and by nalidixic acid and cephalosporin susceptibilities, because c. jejuni is susceptible to nalidixic acid and resistant to cephalosporins. c. jejuni grows best in a microaerobic environment of 5% oxygen and 10% carbon dioxide at 42' c. it grows on a variety of media, including brucella and mueller-hinton agars, but optimal isolation requires the addition of selective and nutritional supplements. growth at 42' c in the presence of cephalosporins is used to culture selectively for c. jejuni from fecal specimens. in a study of six media, charcoal-based selective media and a modified charcoal cefoperazone deoxycholate agar were the most selective for identification of campylobacter species. extending the incubation time from 48 to 72 hours led to an increase in the isolation rate regardless of the medium its typical darting motility may provide a clue to identification, even in fresh fecal specimens, when viewed by phase-contrast microscopy. 72 when the organism has been cultured, it is presumptively identified by motility and by its curved, sometimes sea gulllike appearance on carbolfuchsin stain. polymorphonuclear leukocytes are usually found in stools when bloody diarrhea occurs and indicate the occurrence of ~o l i t i s .~~~*~~* to avoid potentially serious c. jejuni infection in the newborn infant, careful histories of any diarrheal illnesses in the family should be obtained, and pregnant women with any enteric illness should have cultures for this and other enteric pathogens. detection of c. jejuni and c. coli by pcr has been reported859 and in the future may be useful for the rapid and reliable identification of this organism. the differential diagnosis of c, fetus infections include the numerous agents that cause neonatal sepsis or meningitis, especially gram-negative bacilli. diagnostic considerations for inflammatory or bloody enteritis include necrotizing enterocolitis, allergic proctitis, and salmonella; rarely shigellu, and other infectious agents occur. agglutination, complement fixation, bactericidal, immunofluorescence, and elisa tests have been used for serologic diagnosis of c. jejuni infection and to study the immune response, but these assays are of limited value in establishing the diagnosis during an acute infection.731 the prognosis is grave in newborn infants with sepsis or meningitis caused by c. fetus. in infants with c. jejuni gastroenteritis, limited data suggest that appropriate, early antimicrobial therapy results in improvement and rapid clearance of the organism from stool.845 campylobacter species are often resistant to p-lactams, including ampicillin and cephalosporins.860v861 mo st strains are susceptible to erythromycin, gentamicin, tetracycline, chloramphenicol, and the newer quinolones, although resistance to these agents has been r e p~r t e d .~~' ,~~~ it appears that a parenteral aminoglycoside is the drug of choice for c. fetus infections, pending in vitro susceptibility studies. in the case of central nervous system involvement, cefotaxime and chloramphenicol are potential alternative drugs. depending on in vitro susceptibilities, which vary somewhat with locale, erythromycin is the drug of choice for treating c. jejuni e n t e r i t i~.~~~~~"~~' ' if erythromycin therapy is initiated within the first 4 days of illness, a reduction in excretion of the organism and resolution of symptoms occur.845 although data regarding treatment of asymptomatic or convalescent carriers are not available, it seems appropriate to treat colonized pregnant women in the third trimester of pregnancy when there is a risk of perinatal or neonatal infection. the failure of prophylactic parenteral gentamicin in a premature infant has been documented, followed by successful resolution of symptoms and fecal shedding with erythromycin. because there appears to be an increased risk of toxicity with erythromycin estolate during pregnancy and other forms of erythromycin should probably be used in these settings. azithromycin appears to be effective if the organism is susceptible.865 strains that are erythromycin resistant often are resistant to azithromycin.866 cumpylobucter tends to have higher minimal inhibitory concentrations for clarithromycin than for a~ithromycin.~~~ furazolidone has been used in children and ciprofloxacin in nonpregnant patients older than 17 years. contact precautions should be employed during any acute diarrheal illness and until the diarrhea has subsided. hand hygiene after handling raw poultry and washing cutting boards and utensils with soap and water after contact with raw poultry may decrease risk of infection. pasteurization of milk and chlorination of water are critically important. infected food handlers and hospital employees who are asymptomatic pose no known hazard for disease transmission if proper personal hygiene measures are maintained. ingestion of human milk that contains anti<. jejuni antibodies has been shown to protect infants from diarrhea due to c. j e j~n i .~~,~~~ c. dificile is a spore-forming, gram-positive, anaerobic bacillus that produces two toxins. in the presence of antibiotic pressure, c. dificile colonic overgrowth and toxin production occur. the virulence properties of c. dificile are related to production of an enterotoxin that causes fluid secretion (toxin a) and a cytotoxin detectable by its cytopathic effects in tissue culture (toxin b).869*870 both the usual manifestations of c. dificile disease in older children and adults include watery d&rhea, abdominal pain and tenderness, nausea, vomiting, and low-grade fever. grossly bloody diarrhea is unusual, although occult fecal blood is common. leukocytosis is present during severe illness. diarrhea usually begins 4 to 9 days into a course of antimicrobial therapy but may be delayed until several weeks after completion of the therapeutic course. usually, the illness is mild and self-limited if the offending drug is discontinued. severe colitis with pseudomembranes is less common now than in previous years because the risk of diarrhea developing during antimicrobial therapy is recognized and the antimicrobial agent typically is stopped. it is unclear whether this organism causes disease in newborns. one study from a newborn intensive care unit suggests that toxin a in stools is associated with an increased frequency of abnormal stools.893 endoscopic findings of pseudomembranes and hyperemic, friable rectal mucosa suggest the diagnosis of pseudomembranous colitis. pseudomembranes are not always present in c. dificile colitis; mild cases are often described as nonspecific colitis. several noninvasive techniques are used to establish the diagnosis, including enzyme immunoassay (eia) for toxin detection and pcr.893-896 isolation of c. dificile from stool does not distinguish between toxigenic and nontoxigenic isolates. if c. dificile is isolated, testing for toxin by cell culture or eia should be performed to confirm the presence of a toxigenic strain. there are multiple commercially available eias that detect either toxin a or both toxins a and b.893-895 these assays are sensitive and easy to perform. other assays are available for epidemiologic investigation of outbreaks of disease due to c. d i f i~i l e .~~~ in older children and adults, the diagnosis is confirmed by culture of c. dificile and demonstration of toxin in feces. in neonates, these data are inadequate to prove that an illness is related to c. dificile. when the clinical picture is consistent, the stool studies are positive for c. dificile and no other cause for illness is found, a diagnosis of "possible" c. dificile is made. a favorable response to eradication of c. dificile is supportive evidence that the diagnosis is c0rrect.8~~ because of the uncertainty implicit in the ambiguity of neonatal diagnostic criteria, other diagnoses must be considered. when the decision is made that a neonate's illness might be related to c. difjcile, the initial approach should include fluid and electrolyte therapy and discontinuation of the offending antimicrobial agent. if the illness persists or worsens or if the patient has severe diarrhea, specific therapy with r n e t r o n i d a z~l e~~~*~~~ should be instituted. metronidazole is considered to be the treatment of choice for most patients with c. difjcile ~olitis.8~' rarely is there a need to consider orally administered vancomycin or bacitracin in after initiation of therapy, signs of illness generally resolve within several days, titers decrease, and fecal toxins disappear eventually. recurrence of colitis after discontinuation of metronidazole or vancomycin has been documented in 10% to 20% of adults.g01 relapses are treated with a second course of metronidazole or vancomycin. drugs that decrease intestinal motility should not be administered. neutralizing antibody against c. dificile otoxin has been demonstrated in human colostrum.' secretory component of siga binds to toxin a to inhibit its binding to receptors 903 data show that there are nonantibody factors present in milk that interfere with the action of toxin b in addition to secretory iga directed at toxin a. 904 breast-feeding appears to decrease the frequency of colonization by c. d i f j~i l e .~'~ in addition to standard precautions, contact precautions are recommended for the duration of illness. meticulous hand hygiene techniques, proper handling of contaminated waste and fomites, and limiting the use of antimicrobial agents are the best available methods for control of c. dificile infection. b! cholerue is a gram-negative, curved bacillus with a polar flagellum. of the many serotypes, only enterotoxin-producing organisms of serotype 01 and 0139 cause epidemics. b! cholerue 01 is divided into two serotypes, inaba and ogawa, and two biotypes, classic and el tor; the latter is the predominant biotype. nontoxigenic 0 1 strains and non-01 strains of v cholerae can cause diarrhea and sepsis but do not cause outbreaks?06~90a pathogenesis b! cholerue 0 group 1 is the classic example of an enteropathogen whose virulence is caused by enterotoxin production. cholera toxin is an 84-mda protein whose five b subunits cause toxin binding to the enterocyte membrane ganglioside gm, and whose a subunit causes adenosine diphosphate ribosylation of a guanosine triphosphate-binding regulatory subunit of adenylate cy~lase."~~~'~ the elevated camp levels that result from stimulation of enterocytes by cholera toxin cause secretion of salt and water with concomitant inhibition of absorption. two other toxins are also encoded within the virulence cassette that encodes cholera toxin. these toxins, zona occludens toxin (zot) and accessory cholera toxin (ace), are consistently found in illness-causing strains of 0 1 and 0139 but not usually in v; cholerae organisms that are less virulent. since 1960, v cholerae 01, biotype el tor, has spread from india and southeast asia to africa, the middle east, southern europe, and the southern, western, and central pacific islands in the aquatic environment. the usual reported vehicles of transmission have included contaminated water or ice; contaminated food, particularly raw or undercooked shellfish; moist grains held at ambient temperature; and raw or partially dried fish. the usual mode of infection is ingestion of contaminated food or water. boiling water or treating it with chlorine or iodine and adequate cooking of food kill the organism.907 asymptomatic infection of family contacts is common but direct person-to-person transmission of disease has not been documented. persons with low gastric acidity are at increased risk for cholera infection. cholera acquired during pregnancy, particularly in the third trimester, is associated with a high incidence of fetal miscarriage can be attributed to a fetal acidosis and hypoxemia resulting from the marked metabolic and circulatory changes that this disease induces in the mother. it is not surprising that the likelihood of delivering a stillborn child is closely correlated with the severity of the maternal illness. the inability to culture v; cholerue from stillborn infants of infected mothers, together with the usual absence of bacteremia in cholera, suggests that transplacental fetal infection is not a cause of intrauterine death. neonatal cholera is a rare disease. this generalization also applies to the new 0139 strains, although mild9'* and severe forms of illness have rarely been described in newborns. 919 among 242 neonates admitted to a cholera research hospital in dacca, bangladesh, there were 25 infants ill with ~holera.~" even infants born to mothers with active diarrheal disease may escape infection, despite evidence that rice-water stools, almost certain to be ingested during the birth process, may contain as many as lo9 organism~/ml.~~~ the reason for this apparently low attack rate among newborns is not certain; however, it probably can be attributed in large part to the protection conferred by breast-feedingg2' human milk contains antibodies62 and receptor-like glycoprotein that inhibit adherence of v choleraeu and gangliosides that bind cholera toxin.65 the role of transplacentally acquired vibriocidal maternal antibodies has not been determined.922 because v cholerae causes neither bacteremia nor intestinal invasion, protection against illness is more likely to be a function of mucosal rather than serum additional factors that may reduce the incidence of neonatal cholera include the large inoculum required for infection925 and the limited exposure of the newborn to the contaminated food and water.229 clinicians should request that appropriate cultures be performed for stool specimens from persons suspected of having cholera. the specimen is plated on thiosulfate citrate bile salts sucrose agar directly or after enrichment in alkaline peptone water. isolates of v cholerae should be confirmed at a state health department and then sent to the cdc for testing for production of cholera toxin. a fourfold rise in vibriocidal antibody titers between acute and convalescent serum samples or a fourfold decline in titers between early and late (>2 months) convalescent serum specimens can confirm the diagnosis. probes have been developed to test for cholera toxin.926*927 the most important modality of therapy is administration of oral or parented rehydration therapy to correct dehydration and electrolyte imbalance and maintain h y d r a t i~n .~~ antimicrobial therapy can eradicate vibrios, reduce the duration of diarrhea, and reduce requirements for fluid replacement. one cholera vaccine, which is administered parenterally, is licensed in the united states but is of very limited value. several experimental oral vaccines are being t e~t e d ? *~-~~' i.: enterocolitica is a major cause of enteritis in much of the industrialized enteritis due to this organism primarily occurs in infants and young children, and infections in the united states are reported to be more common in the north than in the s o~t h .~~~-~~~ h i m als, especially swine, have been shown to serve as the reservoir for y. enterocolitica. a history of recent exposure to chitterlings (i.e., pig intestine) is common. transmission has also occurred after ingestion of contaminated milk and infusion of contaminated blood p r o d~c t s .~~~,~~~ virulence of y. enterocolitica is related primarily to a virulence plasmid, which is closely related to the virulence plasmids of yersinia pseudotuberculosis and yersinia p e s t i~.~~'~~~~ an st enterotoxin, which is closely related to the st of etec,943 may also be important. infection with y. enterocolitica is recognized as one of the causes of bacterial gastroenteritis in young children, but knowledge of neonatal infection with this organism is fragmentary. even in large series, isolation of yersinia from newborns is rare?313932, 944 the youngest infants whose clinical course has been described in detail were 11 days to several months old at the onset of their illness.932,944-952 there were no features of the gastroenteritis to distinguish it from that caused by other invasive enteric pathogens such as shigella or salmonella. infants presented with watery diarrhea or with stools containing mucus with streaks of blood. sepsis was common in these infants particularly in the first 3 months of life when 28% of enteritis was complicated by sepsis.948,949,953,954 fever is not a consistent finding in children with bacteremia, and meningitis is rare. in older children, fever and right lower quadrant pain mimicking appendicitis are often found.940 diagnosis y enterocolitica can be recovered from throat swabs, mesenteric lymph nodes, peritoneal fluid, blood, and stool. because laboratory identification of organisms from stool requires special techniques, laboratory personnel should be notified when yersinia is suspected. because avirulent environmental isolates occur, biotyping and serotyping are useful in assessing the clinical relevance of isolates. pcr has been used to detect pathogenic strain^.^^^'^^^ the effect of antimicrobial therapy on the outcome of gastrointestinal infection is uncertain. it has been recommended that antibiotics be reserved for sepsis or prolonged and severe gastroenteritisg3'; however, there are no prospective studies comparing the efficacy of various antimicrobial agents with each other or with supportive therapy alone. most strains of y. enterocolitica are susceptible to trimethoprimsulfamethoxazole, the aminoglycosides, piperacillin, imipenem, third-generation cephalosporins, amoxicillin-clavulanate potassium, and chloramphenicol, and resistant to amoxicillin, ampicillin, carbenicillin, ticarcillin, and m a c r o l i d e~.~~~-~~~ therapy in individual cases should be guided by in vitro susceptibility testing, although cefotaxime has been successfully used in bacteremic infants?54 aerornonas hydrophila is widely distributed in animals and the environment. although wound infection, pneumonia, and sepsis (especially in immunocompromised hosts) represent typical aeromonas infections, gastroenteritis increasingly is being recognized. the organism is a gramnegative, oxidase-positive, facultatively anaerobic bacillus belonging to the family vibrionaceae. like other members of this family, it produces an enter~toxin~~' that causes fluid secretion in rabbit ileal loops.%' some strains cause fluid accumulation in the suckling mouse model,"' whereas other strains are i n~a s i v e~~~ or cytotoxic. 964 the enterotoxin is not immunologically related to cholera toxin or the heat lt of although volunteer studies and studies with monkeys have failed to provide supportive evidence for enteropathog e n i~i t y ?~~,~~ there is good reason to believe that a. hydrophila does cause diarrhea in children. the earliest description of aeromonas causing diarrhea was an outbreak that occurred in a neonatal unit. 968 although several studies have failed to show an association with diarrhea,%9-974 most studies have found more aeromonas isolates among children with gastroenteritis than among ~o n t r o l s ?~~-~~~ part of the controversy may be caused by strain differences; some strains possess virulence traits related to production of gastroenteritis, whereas others do not. 970, 977 the diarrhea described in children is a disease of summer, primarily affecting children in the first 2 years of life. in one study, 7 (13%) of 55 cases of aeromonas detected during a 20-month period occurred in infants younger than 1 month. typically, watery diarrhea with no fever has been described; although there are descriptions of watery diarrhea with fever?78 however, in 22%, a dysentery-like illness occurred. dysentery-like illness has been described in the neonate. 979 in one third of children, diarrhea has been reported to last for more than 2 ~eeks.9~' there may be species-related differences in clinical features of aeromonas-associated gastroenteritis in children. 980 organisms that were formerly classified as a. hydrophila are now sometimes labeled as aeromonas sobria or aeromonas ~a v i a e .~~'~~~' fever and abdominal pain appear to be particularly common with a. sobria. one series of a. hydrophila isolates from newborns in dallas showed more blood cultures than stool cultures positive for a e r o m o n a~.~~~ diagnosis of enteric infection associated with aeromonas often is not made because this organism is not routinely sought in stool cultures. when the organism is suspected, the laboratory should be notified so that oxidase testing can be performed. the organism is usually susceptible to aztreonam, imipenem, meropenem, third-generation cephalosporins, trimethoprim-sulfamethoxazole, and chloramphenicol.q84~986 plesiomonas shigelloides is a gram-negative, facultative anaerobic bacillus that, like aeromonas, is a member of the vibrionaceae family. it is widely disseminated in the environment; outbreaks of disease are usually related to ingestion of contaminated water or seafood. 987 although it has been associated with outbreaks of diarrheal disease988 and has been found more commonly in ill than well controls, the role of i? shigelloides in diarrheal disease has remained contro~ersial.~~~ if it is a true enteropathogen, the mechanism by which it causes disease is ~n c l e a r . 9~~'~~' the role of this organism in neonatal diarrhea has not been extensively investigated. infections of neonates have been r e p~r t e d ?~' .~~~ but most cases of enteric disease currently reported in the united states are in adults.987 typical illness consists of watery diarrhea and cramps; sometimes, fever, bloody stools, and emesis occur and last for 3 to 42 days. diagnosis is not usually made by clinical microbiology laboratory testing because, as with aeromonas, coliforms can be confused with l ? shigelloides unless an oxidase test is performed. 996 the true frequency of infection is unknown. the organism has antibiotic susceptibilities similar to those of a e r~m o n a s .~~~'~~~ proving that an organism causes diarrhea is difficult, particularly when it may be present in large numbers in stools of healthy persons. bacteria that have been associated with acute gastroenteritis may be considered causative when the following criteria are met: 1. a single specific strain of the organism should be found as the predominant organism in most affected infants by different investigators in outbreaks of enteric disease in different communities. 2. this strain should be isolated in a significantly lower percentage and in smaller numbers from stool specimens of healthy infants. 3. available methods must be used to exclude other recognized enteropathogens, including viruses and parasites, enterotoxigenic agents, and fastidious organisms such as ca mpylobacter. 4. demonstration of effective specific antimicrobial therapy and specific antibody responses and, ultimately, production of experimental disease in volunteers are helpful in establishing the identity of a microorganism as a pathogen. optimally, the putative pathogen should have virulence traits that can be demonstrated in model systems. most bacteria that have been suggested as occasional causes of gastroenteritis in neonates fail to fulfill one or more of these criteria. their role in the cause of diarrheal disease is questionable. this is particularly true of microorganisms described in early reports in which the possibility of infection with more recently recognized agents could not be excluded. much of the clinical, bacteriologic, and epidemiologic data collected earlier linking unusual enteropathogens to infantile diarrhea must be reevaluated in light of current knowledge and methodology. several reports of acute gastroenteritis believed to have been caused by klebsiella suggest that, rather than playing an etiologic role, these organisms had probably proliferated within an already inflamed b~w e l .~~~-' '~' the recovery of klebsiella-enterobacter in pure culture from diarrheal stools has led several investigators to suggest that these bacteria may occasionally play a causative role in infantile gastroenteritis and enterocoliti~.'~~~~'"~ ingestion of infant formula contaminated with enterobacter sakazakii has been associated with development of bloody diarrhea and sepsis.'oo8 however, klebsiella species also may be isolated in pure culture from stools of newborns with no enteric s y m p t o m~. '~~~~'~' ' in one study, certain capsular types of klebsiella were more often isolated from infants with diarrheal disease than from normal infants.ioo2 later work has shown that klebsiella pneumoniae, enterobacter cloacae, and citrobacter species are capable of isolation of citrobacter species, such as those of klebsiella species, describe associations with enteric illnesses in up to 7% of cases.1014-1016 there is inadequate evidence to define the roles of klebsiella, enterobacter, and citrobacter species as etiologic agents of enteric illnesses. listeria monocytogenes, one of the classic causes of neonatal sepsis and meningitis (see chapter 14), has been linked to outbreaks of febrile diarrheal disease in immunocompetent adults and ~h i l d r e n . '~'~~'~~' seventy-two percent of ill individuals have had fever.ioz2 outbreaks have been related to ingestion of contaminated foods. listeria has rarely been described as a cause of neonatal gastroenteriti~.'~~~-~~~~ infection with enterotoxin-producing bacteroides fragilis has been associated with mild watery diarrhea.'027 these infections have a peak incidence in 2-to 3-year-old infants.1028 these toxin-producing organisms cannot be detected in routine hospital laboratories. a variety of organisms has been isolated from infant stools during episodes of diarrhea. most of these reports have failed to associate illness with specific organisms in a way that has stood the test of time. for example, i? aeruginosa 1029-1034 and have been associated with diarrhea, but proteus 1017, [1035] [1036] [1037] [1038] [1039] [1040] [1041] there are few convincing data suggesting that either is a true enteropathogen. these organisms generally are recovered as frequently from healthy infants as from infants with diarrheal disease, suggesting that their presence in stool cultures is significant.273,1042-1046 an association between providencia and neonatal enteritis has been substantiated largely by anecdotal reports of nursery outbreaks.215.27131016~1@'7 these bacteria are rarely isolated from infants with sporadic or community-acquired diarrheal disease.'042~'0m"04b~1050 candida albicans usually is acquired during passage through the birth canal and is considered a normal, although minor, component of the fecal flora of the neonate (see chapter 33).'05' intestinal overgrowth of these organisms frequently accompanies infantile gastroenteriti~,2"~~~~~'~~~*'~~~ particularly after antimicrobial therapy.233,247,'0521055 the upper small gut may become colonized with candida in malnourished children with diarrhea1056; whether the presence of the organism is cause or effect is unclear. stool cultures obtained from infants with diarrheal disease are therefore inconclusive, and although candida enteritis has been reported in adults,'057 the importance of this organism as a primary cause of neonatal gastroenteritis has been difficult to prove. clinical descriptions of nursery epidemics of candidal enteritis are poorly documented, generally preceding the recognition of epec and rotaviruses as a cause of neonatal diarrhea. even well studied cases of intestinal involvement add little in the way of substantive proof because secondary invasion of candida has been shown to be a complication of coliform enteritis.21 1,2333247 producing e n~e r o~o~n s~1 3 9~~~~1 6 7~1 7 5~1 9 3 ' " 0 1 2~1 0 1 3 reports of although diarrhea has sometimes been described as a finding in neonatal disseminated candidiasis, more typically, gastrointestinal tract involvement with disseminated candida is associated with abdominal distention and bloody stools mimicking necrotizing enterocoliti~.~~~"~~~-~~~~ typically, affected infants are premature and have courses complicated by antibiotic administration, intravascular catheter use, and surgical procedures during the first several weeks of life. a trial of oral anticandidal therapy may be helpful in neonates suffering from diarrhea in the presence of oral or cutaneous candidiasis. if the therapy is appropriate, a response should be forthcoming within 2 to 5 days. diarrhea sometimes occurs as a manifestation of systemic infection. patients with staphylococcal toxic shock syndrome, for example, often have diarrhea. loose stools sometimes occur in sepsis, but it is unclear whether the diarrhea is a cause or an effect. the organisms isolated from blood cultures in a group of bangladeshi infants and children with diarrhea included staphylococcus aureus, haemophilus inpuenzae, streptococcus pneumoniae, r aeruginosa, and various gramnegative enteric bacilli.'062 it is unknown whether the bacteriology of sepsis associated with diarrhea is similar in the well-nourished infants seen in industrialized countries. acute diarrhea associated with intestinal parasites is infrequent during the neonatal period. in areas with high endemicity, infection of the newborn is likely to be associated with inadequate maternal and delivery care, insufficient environmental sanitation, and poor personal hygiene standards. the occurrence of symptomatic intestinal parasitic infection during the first month of life requires acquisition of the parasite during the first days or weeks; the incubation period for e. histolytica and g. larnblia is 1 to 4 weeks, and for cryptosporidium parvum, it is 7 to 14 days. the newborn can be infected during delivery by contact with maternal feces,1o63 in the hospital through contact with the mother or personnel, or in the household through contact with infected individuals in close contact with the child. contaminated water can be an important source of infection for g. lamblia and c. parvum. organisms formerly identified as e. histolytica have been reclassified into two species that are morphologically identical but genetically distinct: e. histolytica and e. dispar. the former can cause acute nonbloody and bloody diarrhea, necrotizing enterocolitis, ameboma, and liver abscess, and the latter is a noninvasive parasite that does not cause disease. early acquisition of disease tends to be more severe in young infants; rarely, amebic liver abscess and rapidly fatal colitis have been reported in infant^."^^-'^^^ for example, a 19-dayold child from india who presented with 10 to 12 episodes of watery and mucous diarrhea, lethargy, jaundice, and mildly elevated liver enzymes has been described; the child recovered completely after 10 days of intravenous o m i d a~o l e . '~~~ however, asymptomatic colonization of neonates with various species of ameba is common in areas of high endemi~ity."~~ diagnosis can be established by stool examination for cysts and trophozoites and by serologic studies.'072 through the use of pcr, isoenzyme analysis, and antigen detection assays, e. histolytica and e. dispar can be differentiated.10733'074 serum antibody assays may be helpful in establishing the diagnosis of amebic dysentery and extraintestinal amebiasis with liver involvement. the efficacy of treatment with metronidazole for colitis or liver abscess has not been established for the newborn period, although this therapy has been used with success.1o65 patients with colitis or liver abscess caused by e. histolytica are treated also with iodoquinol, as are asymptomatic carriers. g. lamblia is a binucleate, flagellated protozoan parasite with trophozoite and cyst stages. it is spread by the fecal-oral route through ingestion of cysts. child-care center outbreaks reflecting person-to-person spread have demonstrated high i n f e~t i v i t y . "~~~'~~~ foodborne transmission and waterborne transmission also occur. infection is often asymptomatic or mildly symptomatic; cases of severe symptomatic infection during the immediate newborn period have not been reported. symptoms in giardiasis are related to the age of the patient, with diarrhea, vomiting, anorexia, and failure to thrive typical in the youngest children. seroprevalence studies have demonstrated evidence of past or current infection in 40% of peruvian children by the age of 6 months.io8' in a study of lactating bangladeshi mothers and their infants, 82% of women and 42% of infants excreted giardia once during the study; in some infants, this occurred before they were 3 months old.'o82 of these infected infants, 86% had diarrhea, suggesting that the early exposure to the parasite resulted in disease. in a prospective study of diarrhea conducted in mexico, infants frequently were infected with giardia from birth to 2 months, with a crude incidence rate of first giardia infection of 1.4 infections per child-year in this age group.6 the symptom status of these children was not reported but this study strongly suggests that g. lamblia may be more common than currently recognized among newborns living in developing areas. the diagnosis of giardiasis can be made on the basis of demonstration of antigen by eia or by microscopy of feces, duodenal fluid or, less frequently, duodenal b i~p~y . ' '~~~' '~' breast-feeding is believed to protect against symptomatic g i a r d i a~i s .~-~~* '~~~ this protection may be mediated by cellular and humoral i1nrnunity6~~"~~*"~~ and nonspecifically by the antigiardial effects of unsaturated fatty acids.iob6 giardia infections causing severe diarrhea may respond to metronidazole or furazolidone.'080 c. parvum is a coccidian protozoon related to toxoplasma gondii, lsospora belli, and plasmodium species. 1087s'088 the life cycle involves ingestion of thick-walled oocysts; release of sporozoites, which penetrate intestinal epithelium; and development of merozoites. there is asexual and sexual reproduction, with the latter resulting in formation of new oocysts that can be passed in stools. cryptosporidium species are ubiquitous. infection often occurs in persons traveling to endemic areas.'o89 because cryptosporidium infects a wide variety of animal species, there is often a history of animal contact among infected individ~als."~' person-to-person spread, particularly in household c~n t a c t s '~~'~' '~~ and daycare center^,"^^"'^^ is well documented and suggests that the organism is highly infectious. waterborne outbreaks of cryptosporidiosis occur and can be of massive proportion^."^^ the clinical manifestations of illness in immunocompetent persons resemble those of giardia infection but are somewhat shorter in d~ration'"~; asymptomatic carriage is rare. symptoms and signs include watery diarrhea, abdominal pain, myalgia, fever, and weight loss.1089*1090~1095~'096"098~'09 infection in the first month of life has been described.""~"" because symptoms resolve before excretion of oocysts ceases, a newborn whose mother has been ill with cryptosporidiosis in the month before delivery might be at risk even if the mother is asymptomatic at the time of the child's birth."'* with the increasing frequency of human immunodeficiency virus infection, it is likely that women with symptomatic cryptosporidiosis occasionally will deliver an infant who will become infected. infants infected early in life may develop chronic diarrhea and maln~trition."'~ the diagnosis of cryptosporidiosis is most typically made by examination of fecal smears using the giemsa stain, ziehl-neelsen stain, auramine-rhodamine stain, sheather's sugar flotation, an immunofluorescence procedure, a modified concentration-sugar flotation method, or an eia.' io4,1 lo5 nitazoxanide is effective therapy of immunocompetent adults and children ill with cryptosporidiosis.'io6 because illness is usually self-limited in the normal host, attention to fluid, electrolyte, and nutritional status usually suffices. enteric isolation of hospitalized infants with this illness is appropriate because of the high infectivity. several studies suggest that the risk of infection early in life may be decreased by breast-feeding. ' '"j viruses that infect the intestinal mucosa and cause primarily gastroenteritis are referred to as enteric viruses; they should not be confused with enteroviruses, members of picornaviridae family that are associated primarily with systemic illnesses. enteric viruses include rotaviruses, enteric adenoviruses, human caliciviruses, and astroviruses. other viruses such as coronaviruses, breda viruses, pestiviruses, parvoviruses, toroviruses, and picobirnaviruses have been sporadically associated with acute diarrhea but are currently considered of uncertain relevance. extensive reviews on the role of enteric viruses in childhood diarrhea can be found elsewhere."08-"" all four enteric viruses could conceivably infect the newborn, but the extent of exposure and clinical manifestations are largely unknown for astrovirus, enteric adenovirus, and human caliciviruses. rotavirus is the most extensively studied enteric virus. neonatal rotavirus infections have similar virologic and clinical characteristics to infection in older children, although some differences exist. rotavirus is a 75-nm, nonenveloped virus composed of three concentric protein shells: a segmented genome (1 1 segments), an rna-dependent polymerase, and enzymes required for messenger rna synthesis are located within the inner core. each segment codes for at least one viral protein (vp). the vp can be part of the structure of the virus, or it may be a nonstructural protein (nsp) required for replication, viral assembly, budding, determination of host range, or viral pathogenesis."" six distinct rotavirus groups (a through f) have been identified serologically based on common group of which three (a, b, and c) have been identified in humans.'io8 because group a rotaviruses represent more than 95% of isolated strains in humans worldwide, further discussion focuses on this group. group a rotaviruses are subclassified into serotypes based on neutralization epitopes located on the outer capsid. both rotavirus surface proteins, vp4 and vp7, can induce production of neutralizing antibodies.111431115 at least 10 vp7 types (g serotypes: gi to g6, g8 to g10, and g12) and nine vp4 types (p serotypes: pia, plb, p2a, p3, p3b, p4, p5, p8, and p12) have been detected among human r o t a v i r u~e s .~~~~-~~~~ by sequencing the vp4-coding gene, eight genomic p types (genotypes) have been identified that correspond to one or more of the described p antigenic types (genotype 8 to antigenic type pla, 4 to plb, 6 to p2a, 9 to p3,13 to p3b, 10 to p4,3 to p5, and 11 to p8)."" combining g antigenic with p antigenic and genetic typing, a specific rotavirus strain can be identified p antigenic type (p genetic type), g type. as an example, the human neonatal m37 strain is described as p2a[6], gi. from newborn nurseries, some of which seem to be endemic to the newborn units with high rates of asymptomatic infe~tion,"~~-"~' and less commonly, outbreaks of symptomatic infection.iiz8 these findings suggest that specific conditions of the newborn environment (e.g., child, nursery, personnel) may increase the possibility of reassortments between human strains; such strains may persist in these settings possibly through constant transmission involving asymptomatic newborns, adults, and contaminated surfaces. rotavirus primarily infects mature enterocytes located in the mid and upper villous e p i t h e l i~m .~~~~-"~~ lactase, which is present only on the brush border of the differentiated epithelial cells at these sites, may act as a combined receptor and uncoating enzyme for the virus, permitting transfer of the particles into the cell.1137 perhaps for this reason, infection is limited to the mature columnar enterocytes; crypt cells and crypt-derived cuboidal cells, which lack a brush border, appear to be resistant to rotaviral i n f e~t i o n . "~~' "~~ this concept also may explain why rotavirus infection is less common in infants younger than 32 weeks' gestational age than in more mature infants1139; between 26 and 34 weeks' gestational age, lactase activity is approximately 30% of that found in term infants. 1140 the upper small intestine is most commonly involved, although lesions may extend to the distal ileum and rarely to the ~0 l 0 n .~~~~7~~~~ interaction between intestinal cell and rotavirus structural and nonstructural proteins occurs, resulting in death of infected villous enter~cytes."~~ once infected, the villous enterocyte is sloughed, resulting in an altered mucosal architecture that becomes stunted and flattened. the gross appearance of the bowel is usually normal; however, under the dissecting microscope, scattered focal lesions of the mucosal surface are apparent in most cases. light microscopy also shows patchy changes in villous morphology, compatible with a process of infection, inflammation, and accelerated mucosal renewal. the villi take on a shortened and blunt appearance as tall columnar cells are shed and replaced by less mature cuboidal entero-ischemia may also play a role in the loss and stunting of villi"45 and activation of the enteric nervous system; active secretion of fluid and electrolytes may be another pathogenic mechanism.1146 during the recovery phase, the enteroblastic cells mature and reconstruct the villous structure. because of the loss of mature enterocytes on the tips of the villi, the surface area of the intestine is reduced. diarrhea that occurs may be a result of this decrease in surface area, disruption in epithelial integrity, transient disaccharidase deficiency, or altered countercurrent mechanisms and net secretion of water and electrolytes.1'33~1140~1142~1146~1147~1148 nsp4 has been found to induce age-dependent diarrhea in cd1 mice by triggering calcium-dependent chloride and water secretion.1149 the potential role of this "viral enterotoxin" in human disease is not yet clear.1150,1151 infants with asymptomatic rotavirus infections in the nursery are less likely than uninfected nursery mates to experience severe rotavirus infection later in life1152-1153; this finding suggested protective immunity and supported vaccine development. most studies have indicated that serum and intestinal antirotavirus antibody levels are correlated with protection against i n f e~t i o n "~~-"~~ although this correlation has not been ~n i v e r s a l .~~~~-~~~~ breast-feeding protects against rotavirus disease during the first year of life,57 probably including newborns. 1146 the high prevalence of antirotaviral antibodies in colostrum and human milk has been demonstrated by numerous investigators in widely diverse geographic areas.8 maternal rotavirus infection or immunization is accompanied by the appearance of specific antibodies in milk, probably through stimulation of the enteromammary immune between 90% and 100% of women examined in london, bangladesh, guatemala, costa rica, and the united states had antirotaviral iga antibodies in their milk for up to 2 years of rotavirus-specific igg antibodies have been found during the first few postpartum days in about one third of human milk samples a~s a y e d ,~~@~"~~ whereas i@ antibodies were detectable in about one half.1167 glycoproteins in human milk have been shown to prevent rotavirus infection in vitro and in an animal model."70 the concentration of one milk glycoprotein, lactadherin, was found to be significantly higher in human milk ingested by cytes.l 133, 1135, 1144 infants who developed asymptomatic rotavirus infection than in milk ingested by infants who developed symptomatic infe~tion.4~ rotaviruses probably infect neonates more commonly than previously recognized, although most infections seem to be asymptomatic or mildly symptomatic. 1128" 1 3 0 9 1 1 3 1~1 172-1 in a prospective study, the prevalence of rotavirus infection among neonatal intensive care unit patients was 18.4%. rotavirus has a mean incubation period of 2 days, with a range of 1 to 3 days in children and in experimentally infected adults. fecal excretion of virus often begins a day or so before illness and maximal excretion usually occurs during the third and fourth days, and generally diminishes by the end of the first week, although low concentrations of virus have been detected in neonates for up to 8 weeks.1140, [1186] [1187] [1188] [1189] rotavirus infections are markedly seasonal (autumn and winter) in many areas of the world, although in some countries seasonality is less striking; the reason for this is u n~l e a r .~~~" '~~ in nurseries in which persisting endemic infection has permitted long-term surveillance of large numbers of neonates, rotavirus excretion can follow the seasonal pattern of the community but can also show no seasonal it is not clear how units in which infection remains endemic for months or years differ from those with a low incidence of rotavirus. some nurseries are free of rotavirus infection' or minimally a f f e~t e d~~"~" whereas others have rotavirus diarrheal disease throughout the year or in outbreaks that involve 10% to 40% of low birth weight does not seem to be an important factor in determining the attack rate among infants at risk but may be important in rn0rta1ity.i~~~ infants in premature or special-care nurseries, despite their prolonged stays and the increased handling necessary for their care, do not demonstrate a higher susceptibility to infection; data regarding shedding of the virus are inconsi~tent!~*~~~~ after infection is introduced into a nursery, rotavirus probably will spread steadily and remain endemic until the nursery is closed to new admissions or nursing practices permit interruption of the cycle.1205 exactly how the virus is introduced and transmitted is uncertain, although limited observations and experience with other types of enteric disease in maternity units suggest several possibilities. the early appearance of virus in stools of some neonates indicates that infection probably was acquired at delivery. virus particles can be detected on the first45v11s6 or second"98 day of life in a significant number of infected infants. by day 3 or 4, most infected infants who will shed virus, with or without signs of illness, are doing so.117431186,1198 the large numbers of virus particles e x~r e t e d "~~,~~~~ suggest a fairly large and early oral inoculum. it is unlikely that contamination from any source other than maternal feces could provide an inoculum large enough to cause infection by the second day. transfer of particles from infant to infant on the hands of nursing and medical staff is probably the most important means of viral spread. with 10' to 10" viral particles usually present in 1 g of stool, the hands of personnel easily could become contaminated after infection is introduced into a nursery. there are numerous reports of nosocomial and daycare center rotavirus gastroenteritis outbreaks that attest to the ease with which this agent spreads through a hospital or institutional setting.'io8 admission of a symptomatic child usually is the initiating event, although transfer of a neonate with inapparent infection from one ward to another also has been incriminated. the most important factors influencing the incidence of rotavirus diarrhea in a nursery are the proximity to other newborns and the frequency of handling.1187 during a 4-month study, infants cared for by nursing staff and kept in communal nurseries experienced three epidemics of diarrhea with attack rates between 20% and 50%. during the same period, only 2% of infants rooming in with their mothers became ill, even though they had frequent contact with adult relatives and siblings. there is no clear evidence of airborne or droplet infection originating in the upper respiratory tract or spread by aerosolization of diarrheal fluid while diapers are changed. indirect evidence of airborne transmission includes the high infection rate in closed settings, the isolation of the virus from respiratory secretions,izo6 and the experimental observation of transmission by aerosol droplets in mice.'207 however, the respiratory isolation achieved by placin an evidence indicates that transplacental or ascending intrauterine infection occurs. transmission of virus through contaminated fomites, formula, or food is possible but has not been documented in newborns. rotavirus particles have not been found in human milk or c o l o~t r u m .~~~~~~~~ exposure of a newborn to rotavirus can result in asymptomatic infection or cause mild or severe gastro-outbreaks with high attack rates as measured by rotavirus excretion have been described but the extent of symptomatic infection severe rotavirus infection is seldom reported during the newborn period1203 but the extent of underreporting of severe disease, especially in the less developed areas of the world, has not been evaluated. it has been hypothesized that asymptomatic infections during the newborn period are the result of naturally attenuated strains circulating in this environment. rna electrophoretic patterns of rotaviruses found in certain nurseries have shown uniform and it has been suggested that these strains may be attenuated. the presence of unusual antigenic types such as the p2a[6] type within nurseries also suggests "less virulent strains." at least 10 rotavirus strains were documented to co-circulate in a tertiary care center during a 2-month period12" and in a different setting the same rotavirus strains by electropherotype produced asymptomatic infection in neonates and symptomatic infection in older infants.1183 newborns within a nursery exposed to a given rotavirus strain can develop symptomatic or asymptomatic infection. 130~1 2 1 0~1 2 i because newborns routinely have frequent relatively loose stools, it is possible that mild diarrhea episodes caused by rotavirus are being wrongly labeled as asymptomatic episodes. no clinical feature is pathognomonic of rotaviral gastroenteritis. early signs of illness, such as lethargy, irritability, vomiting, and poor feeding, usually are followed in a few hours by the passage of watery yellow or green stools free of blood but sometimes containing mucus.1187,1212-1214 diarrhea usually decreases by the second day of illness and is much infant in a closed incubator is not fully protective.118 s no enteritisel 129. 1130.1 173.1 179,1196,l 197,1201,1208 varies. 1 175.1 177.1 186.1 198,1203 improved by the third or fourth day. occasionally, intestinal fluid loss and poor weight gain may continue for 1 or 2 weeks, particularly in low-birth-weight infants. 1175 although reducing substances frequently are present in early fecal ~a m p l e s "~~~'~~~' 176~1187 this finding is not necessarily abnormal in neonates, particularly those who are breast-fed.1215 nevertheless, infants with prolonged diarrhea should be investigated for monosaccharide or disaccharide malabsorption or intolerance to cow's milk protein or in a prospective 49% of newborns with gastrointestinal symptoms in a neonatal intensive care unit had rotavirus detected in their stools. frequent stooling (present in 60%), bloody mucoid stool (42%), and watery stools (24%) were risk factors for a rotavirus infection. bloody mucoid stools, intestinal dilatation, and abdominal distention were significantly more common in preterm infants, but severe outcomes such as necrotizing enterocolitis and death did not differ among infected term and preterm infants. longitudinal studies in newborn nurseries and investigations of outbreaks among neonates rarely describe a severe adverse outcome or death.1139,1168,1187 because these infants are under constant observation, early detection of excessive fluid losses and the availability of immediate medical care are probably major factors in determining outcome. rotavirus gastroenteritis causes almost 400,000 deaths of infants every year,i2i7 concentrated largely in the poorest regions of the world. it is likely that in places where hospital-based care is uncommon, rotavirus causes neonatal deaths secondary to dehydration. group a rotavirus has been associated with a wide array of diseases in infants and children; reye syndromes, encephalitis-aseptic meningitis, sudden infant death syndrome, inflammatory bowel disease, and kawasaki syndrome have been described but not systematically studied. 1108 case reports and small case series have associated neonatal rotavirus infection with necrotizing e n t e r o c~l i t i s .~~'~"~~~ rotavirus infection may play a role in a small proportion of cases of necrotizing enterocolitis, although it probably represents one of many potential triggering factors. a significant association between neonatal rotavirus infection and bradycardia-apnea episodes was detected in one prospective study.1220 the possible association between natural rotavirus infection and i n t u s s u~c e p t i o n~~~~~~~~~ gained support after the association was made between the human-simian reassortant vaccine and intussusception in infants older than 2 months (attributable risk = 1: 10,000). 1224 intussusception is extremely uncommon in the newborn; it is highly unlikely that rotavirus triggers this disease in neonates. there are many methods used for detection of rotavirus in stool specimens, including electron microscopy, immune electron microscopy, elisa, latex agglutination, gel electrophoresis, culture of the virus, and reverse transcriptasepolymerase chain reaction. elisa and latex agglutination currently are the most widely used diagnostic techniques for detection of rotavirus in clinical samples. many commercial kits are available that differ in specificity and ~e n s i t i v i t y . '~~~-'~~~ in general, latex agglutination assays are more rapid than elisas but are less sensitive. the sensitivity and specificity of the commercially available elisas surpass 90%. checking of the elisa by another method such as gel electrophoresis or pcr amplification may be desirable if there is concern about false-positive results. fecal material for detection of rotavirus infection should be obtained during the acute phase of illness. whole-stool samples are preferred, although suspensions of rectal swab specimens have been adequate for detection of rotavirus by rotavirus are relatively resistant to environmental temperatures, even tropical temperatures, 1232 although 4°c is desirable for short-term storage and -70°c for prolonged storage.'io8 excretion of viral particles may precede signs of illness by several days' 190; maximal excretion by older infants and children usually occurs 3 to 4 days after onset of symptoms.1233 neonates can shed virus for 1 to 2 weeks after onset of symptoms. the primary goal of therapy is restoration and maintenance of fluid and electrolyte balance. despite the documented defect in carbohydrate digestion with rotavirus diarrhea, rehydration often can be accomplished with glucoseelectrolyte or sucrose-electrolyte solutions given orally .199,1234-1236 intravenous fluids may be needed in neonates who are severely dehydrated, who have ileus, or who refuse to feed. persistent or recurrent diarrhea after introduction of milkbased formulas or human milk warrants investigation for secondary carbohydrate or milk protein i n t~l e r a n c e . '~~~~~~" disaccharidase levels and xylose absorption return to normal within a few days1144 to weeks after infe~tion."~~ intractable diarrhea related to severe morphologic and enzymatic changes of the bowel mucosa is possible although rare in the newborn; it may require an elemental diet or parenteral nutrition. efficacy of anti-rotavirus antibodies (e.g., hyperimmune colostrum, antibody-supplemented formula, human serum immunoglobulin) and of probiotics has been p~s t u l a t e d , '~~~~'~~' although not convincingly shown1242; the widespread clinical use of these measures seems remote. one study suggests that use of lactobacillus during the diarrheal episode may decrease the duration of rotavirus-associated hospital stays, especially when used early in the course of the disease, although more studies are needed before recommending widespread use. 1241 hand hygiene before and after contact with each infant remains the single most important means of preventing the spread of infection. because rotavirus is often excreted several days before illness is recognized, isolation of an infant with diarrhea may be too late to prevent cross-infection unless all nursing personnel and medical staff have adhered to this fundamental precaution. infants who develop gastroenteritis should be moved out of the nursery area if adequate facilities are available and the infant's condition permits transfer. the use of an incubator is of value in reducing transmission of disease only by serving as a reminder that proper hand-hygiene and glove techniques are required, but is of little value as a physical barrier to the spread of encouraging rooming-in of infants with their mothers has been shown to be helpful in preventing or containing nursery epidemics.'243 temporary closure of the nursery may be required for clinically significant outbreaks that cannot be controlled with other measures.1128 development of rotavirus vaccines began in the early 1980s. candidate vaccines included bovine and rhesus monkey elisa. 1230, 1231 attenuated strains, human attenuated strains, and bovinehuman and rhesus-human reassortant strains."" in august 1998, the first licensed rotavirus vaccine, rotashield, an oral formulation of a simian-human quadrivalent reassortant vaccine, was recommended for use in children when they were 2, 4, and 6 months old. after approximately 500,000 children were vaccinated with more than 1 million doses, a significantly increased risk of intussusception was observed among vaccinated children, with an overall odds ratio of 1.8.iz4 use of this vaccine was terminated. two new vaccine candidates are undergoing phase i11 clinical trials: a "pentavalent" bovine-human reassortant vaccine including g types gl-g4 and p type pla[8] and a monovalent human attenuated pla[ 8]g1 vaccine. the epidemiology of rotavirus infection will change significantly if one or both candidates become widely available in the future. the impact on neonatal infection will depend on the effect of herd immunity in decreasing circulation of rotavirus strains. stools from breast-fed neonates are typically watery and yellow, green, or brown. the frequency of stooling can vary from one every other day to eight evacuations per day. in an active, healthy infant who is feeding well, has no vomiting, and has a soft abdomen, these varied patterns of stooling are not a cause for concern. physicians need to consider the child's previous frequency and consistency of stools and establish a diagnosis of acute diarrhea on an individual basis. close follow-up of weight increase in infants with nonformed stools can help confirm the clinical impression. a normal weight gain should direct medical action away from stool exams or treatment. diarrhea during the neonatal period is a clinical manifestation of a wide variety of disorders (table 20-6). the most common initiating factor is a primary infection of the gastrointestinal tract that is mild to moderate in severity, chapter 20 self-limited, and responsive to supportive measures. acute diarrhea can also be an initial manifestation of a systemic infection, including bacterial and viral neonatal sepsis. infants with moderate to severe diarrhea require close monitoring until the etiologic diagnosis and the clinical evolution are clarified. there are noninfectious diseases leading to chronic intractable diarrhea that may result in severe nutritional disturbances or even death unless the specific underlying condition is identified and treated appropriately. the differential diagnosis of a diarrheal illness requires a careful clinical examination to determine whether the child has a localized or a systemic process. lethargy, abnormalities in body temperature, hypothermia or hyperthermia, decreased feeding, abdominal distention, vomiting, pallor, respiratory distress, apnea, cyanosis, hernodynamic instability, hypotension, hepatomegaly or splenomegaly, coagulation or bleeding disorders, petechiae, and exanthemas should lead to an intense laboratory investigation directed at systemic viral or bacterial infection. if the process is deemed a localized intestinal infection, initial evaluation can be focused on differentiating an inflammatory-invasive pathogen from those that cause a noninflammatory process. for this, stool examination for fecal leukocytes, red blood cells, and lactoferrin can be a helpful indicator of the former. inflammatory diarrhea can be caused by shigella, salmonella, carnpylobacter, v parahaemolyticus, k: enterocolitica, eiec, eaec, c. difjcile, necrotizing enterocolitis, antibioticassociated colitis, and allergic colitis (i.e., milk or soy intolerance). noninflammatory causes of diarrhea include etec, epec, rotaviruses, enteric adenoviruses, calicivirus, astrovirus, g. larnblia and cryptosporidium. although supportive fluid therapy is mandatory for all types of diarrhea, the brief examination for fecal leukocytes and red blood cells can direct the diagnostic and therapeutic 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in infants the irritable colon of childhood (chronic nonspecific diarrhea syndrome) gut transit time and lactose malabsorption during phototherapy. i, 11 neonatal diagnosis of familial dysautonomia familial enteropathy: a syndrome of protracted diarrhea from birth, failure to thrive, and hypoplastic villous atrophy lethal familial protracted diarrhea infantile gastroenteritis due to water with high sulfate content diarrhea, red diapers, and child abuse management of children with infection-associated persistent diarrhea key: cord-281844-c0uhcatg authors: costa, lusmaia d.c.; costa, paulo sucasas; camargos, paulo a.m. title: exacerbation of asthma and airway infection: is the virus the villain? date: 2014-12-31 journal: jornal de pediatria doi: 10.1016/j.jped.2014.07.001 sha: doc_id: 281844 cord_uid: c0uhcatg abstract objective to review the available literature on the association between acute viral respiratory tract infection and the onset of asthma exacerbations, identifying the most prevalent viruses, detection methods, as well as preventive and therapeutic aspects. sources a search was conducted in pubmed, lilacs, and scielo databases, between the years 2002 and 2013, using the following descriptors: asthma exacerbation, virus, child, and acute respiratory infection. summary of the findings a total of 42 original articles addressing the identification of respiratory viruses during episodes of asthma exacerbation were selected, mostly cross-sectional studies. there was a wide variation in the methodology of the assessed studies, particularly in relation to the children's age and methods of collection and viral detection. the results indicate that, in up to 92.2% of exacerbations, a viral agent was potentially the main triggering factor, and human rhinovirus was the most frequently identified factor. the pattern of viral circulation may have been responsible for the seasonality of exacerbations. the association between viral infections and allergic inflammation appears to be crucial for the clinical and functional uncontrolled asthma, but few studies have evaluated other triggering factors in association with viral infection. conclusions respiratory viruses are present in the majority of asthmatic children during episodes of exacerbation. the involved physiopathological mechanisms are yet to be fully established, and the synergism between allergic inflammation and viral infection appears to determine uncontrolled disease. the role of other triggering and protective agents is yet to be clearly determined. asthma is a chronic, genetically-determined disease, whose prevalence in the pediatric population ranges between 19 .0% and 24.3% among brazilian adolescents and schoolchildren, respectively. 1 from the physiopathological viewpoint, it is characterized by chronic inflammation with the involvement of several cell types, associated with airway hyperresponsiveness, with episodes of reversible airflow limitation. it is clinically manifested by recurrent exacerbations, also called ''asthma attacks'' or, more appropriately, acute asthma, characterized by progressive worsening of dyspnea, coughing, wheezing, chest tightness, or a combination of these. 2 the loss of clinical and functional asthma control usually occurs gradually, but it can occur abruptly in a subgroup of patients. 2 it is one of the main causes of emergency consultations, having been responsible, in 2007, for 195 deaths in children younger than 19 years in brazil. 3 public policies have been developed to promote both scientific knowledge about the disease and its management, as well as to organize assistance programs in public health, which include, among others, the dispensing of medications. however, exacerbations continue to represent a significant number in statistics, with great impact on public and private healthcare systems. 2 the multifactorial origin of the clinical-functional lack of disease control is well known; since the early 1970s, respiratory viruses have been associated with the triggering of asthma exacerbations in adults and children. 3 in the 1990s, the development of more sensitive and specific molecular techniques allowed for the increase in respiratory virus detection and therefore, ways to better explain this association. studies using reverse transcriptase polymerase chain reaction (rt-pcr) as the detection technique, isolated or combined with traditional methods, observed positivity for respiratory viruses in up to 92.2% of episodes of acute asthma exacerbation in children. 4 considering the possibility of a causal relationship between respiratory virus infection and the triggering of asthma attacks in children, the implications of this association, as well as the possibility of specific prophylaxis and therapy for these agents, special attention to this subject is justified. therefore, this literature review aimed to analyze articles, published between 2002 and 2013, assessing the association between asthma exacerbation and acute viral airway infection. a search was conducted in the pubmed, lilacs and scielo databases, using the descriptors: ''asthma exacerbation'', ''viral infection'', and ''child'', resulting in a total of 283 references for that period. after selecting the articles published in portuguese, english, spanish, or french, 195 articles remained. after reading the titles and abstracts, 42 original articles that assessed respiratory tract viral infection in asthmatic children during exacerbation were selected. some articles of historical importance or review articles that included the three descriptors were added to generate the bibliography of this review. the list of references was inserted into endnote x6 (thompson corp., ca, usa), a bibliographic citation management software. the most frequently identified respiratory viruses in association with asthma exacerbation were human rhinovirus (hrv), respiratory syncytial virus (rsv), human adenovirus (hadv), influenza (flu), parainfluenza (pflu), human metapneumovirus (hmpv), and human coronavirus (hcov). of the listed viruses, most have rna as the nucleic acid; their biological characteristics and taxonomy 5 are described in table 1 . the main transmission methods for these viruses are through contaminated fomites, droplets, aerosols, or direct contamination. by infecting the nasal epithelium cells, these agents trigger an immune response, which involves mainly the dendritic cells and natural killer (nk) cells, inducing the release of a number of pro-inflammatory cytokines and chemokines by the infected epithelial cells, such as interferon (ifn-1) and tumor necrosis factor alpha (tnf␣), among others ( fig. 1) . in asthma patients, the viral infection causes an imbalance in the immune homeostasis of the respiratory system. several mechanisms related to viral infection and allergic inflammation, as well as their role in triggering acute asthma, have been proposed; among them, the deficient function of the epithelial barrier caused by the virus, which has been implicated as a predisposing factor by some. 6 however, both asthma and atopy are associated with epithelial damage, which may contribute to increased susceptibility to infections, including viral diseases and sensitization by aeroallergens. 7 another evaluated factor was mucus production as an airway defense mechanism; in mice studies, it was demonstrated that allergic inflammation and viral infection act synergistically increasing mucus production, which can lead to airway impaction and obstruction in asthma patients. 8 virus-induced alterations in interferon production have also been observed. for instance, in vivo and in vitro studies in epithelial cells from healthy adults and asthma patients infected with hrv demonstrated a decreased production of type i interferon (␣ and ␤) in the latter, making them more susceptible to infection associated with viral exacerbation. 6, 9 similar results were obtained in studies performed with children, where the production of interferon and th2 cytokines by bronchial epithelial cells was assessed after hrv-16 infection. lower interferon production and higher concentrations of viral rna have been demonstrated in children with asthma, regardless of their atopic status, and in atopic children without asthma, suggesting that an impaired immune response to viral infection occurs not only in asthma patients, but in children with other disorders associated with th2 lymphocytes. 10 however, other studies failed to demonstrate the same reduction in interferon production; others even found an increase in its production in exacerbated asthma. 11, 12 the bronchial epithelium produces some cytokines, including interleukin 25 and 33, as well as thymic stromal lymphopoietin, which promotes the differentiation of innate lymphoid cells into th2. the latter can be induced by viral infection, and its production can be increased by interleukin-4 (il-4), suggesting that the interaction between viruses and allergic airway inflammation may enhance the inflammatory th2 response and potentially reduce the antiviral response. 11, 13 collection and viral detection methods viral detection is highly dependent on the quality of the collected sample, on the time of symptom onset to the time of collection (ideally within 72 hours), and on transportation and storage of the sample before testing. the analysis for respiratory viruses should be performed in material from the airways. upper airway secretion is used in most cases, and several methods are employed for this collection, such as nasopharyngeal aspirate (npa), nasopharyngeal swab (nps), nasopharyngeal lavage, and the combined nasal-oral swab; the first technique is considered the gold standard. 14 recently, new flocked swabs (copan, brescia, italy) were developed, and presented better performance during data collection. recent studies using this type of swab presented a sensitivity comparable to that of npa when the detection is performed by pcr, suggesting that this swab can be used in epidemiological research and surveillance studies, due to its greater technical simplicity. 15, 16 there are few data to support the use of combined oralnasal swabs for virus detection, and its sensitivity is lower than that of the nasopharyngeal swab or aspirate, which can be explained by the lower viral load in the oropharynx than in the nasopharynx. the collection can also be performed on material from the lower airways, such as induced sputum and bronchial lavage. 17 the methods for detection of respiratory viruses are varied and include rapid tests for antigen detection, culture, direct and indirect immunofluorescence, and nucleic acid amplification reactions, such as rt-pcr, which can detect a single agent (monoplex) or perform multiple detections (multiplex). the sensitivity of the latter is higher, and it was used in most recent studies. 18, 19 immunofluorescence reactions have lower cost, are faster to perform, and are also able to detect multiple viruses. a panel of seven viruses (iflu a and b, pflu 1 to 3, hadv, and rsv) is generally used. some viruses, such as hrv and bocavirus, can only be detected through nucleic acid amplification reactions. 17 several authors have performed studies aiming to detect viruses in respiratory secretions of exacerbated asthma patients, showing a prevalence of viral identification that varies with several factors, such as patient age, time of the year, method of sample collection, and method of viral detection. table 2 presents the original articles that demonstrate results of viral testing in children with exacerbated asthma. most studies found prevalence rates between 36.0% 20 and 92.2%; 5 in these cases, the most frequently identified virus was hrv. an investigation of respiratory viruses in 209 children aged between three and 16 years hospitalized for asthma exacerbation was performed over a period of 12 months in buenos aires, argentina. due to the possibility of other diagnoses for wheezing episodes in infants, the definition immune process involved in response to respiratory viruses and their association to allergic inflammation. respiratory viruses infect bronchial epithelial cells (becs) through tool-like receptors (tlrs). during replication, they trigger an inflammatory process with induction of cytokine and chemokine production by becs, among them interferon (ifn-1), tumor necrosis factor alpha (tnf-␣), interleukins (il-33, il-25), and thymic stromal lymphopoietin (tslp). the dendritic cells (dcs), components of the innate immunity, are directed to secondary lymphoid organs after capturing viral antigens, where they stimulate the lymphoid cells, the protagonists of the specific immune response. in asthma patients, the production of ifns is reduced, allowing for greater viral replication and under stimulation of tslp, there is a deviation from lymphoid profile to helper t lymphocyte 2 (th2), promoting lower antiviral response and increased allergic inflammation, with bronchial hyperreactivity and increased production of mucus, causing bronchial obstruction and asthma exacerbation. of asthma was based on the criteria of castro-rodriguez for children younger than 3 years, and on the global initiative for asthma (gina) criteria for those older than 3. immunofluorescence and pcr were performed in nasopharyngeal secretions of the children and showed a positive rate of 78.0% for viruses in general; hrv and hrsv were the most frequently identified types. there was also 20.0% of dual detection, with the involvement of all analyzed viruses. 21 in méxico, the frequency of the viral positivity at the immunofluorescence was higher in children with asthma (75.0%) than in a control group of wheezing children without asthma (44.0%). hrv was not included in that study, and iflu, pflu, and hadv were the most frequently identified virus in the group of asthma patients. 22 in japan, respiratory viruses were detected by multiplex pcr in 86.1% of 115 children with exacerbated asthma, with a mean age of 20.8 months. the hrsv was related to a single episode of wheezing (p < 0.05). 23 hrv was more frequently observed in patients with a history of asthma (p < 0.05). a group of 82 french children with exacerbation treated at home was compared to 27 stable asthmatic children. immunofluorescence, pcr, and serology for viruses (mycoplasma pneumoniae and chlamydophila pneumoniae) detected a pathogen in 45.0% of samples, with significantly higher frequency in cases than in controls (3.7%). viral detection tests were positive in 38% of cases, and hrv was the most common (12.0%). in 10.0% of cases, the serologic tests were positive for both atypical pathogens. 24 another series of 104 children with exacerbation, compared to 31 stable children, was studied by turkish authors and showed positivity of 53.8% in the cases and 22.6% in controls, through rt-pcr reaction. hrv was the most commonly found virus in 35.6% of the samples. 25 in japan, 174 children with acute asthma were compared to 79 stable asthmatic children and 14 children without asthma. using an antigen detection kit and rt-pcr, respiratory viruses were detected in 79.0% of nasal aspirate samples in exacerbated asthmatic children, and hrv was the most common (33.9%). in parallel, the assessment of inflammatory markers showed a significant elevation (p < 0.01) of interleukins il-1, 5, 6, and 10 in serum and in the nasal aspirates of patients in exacerbation, as well as an increase in serum eosinophilic cationic protein (ecp) levels (p < 0.01). 26 flu, although less frequently associated with these episodes, appears to be responsible for increased morbidity in patients with an underlying chronic disease, including asthma. of 2,165 children aged 2 to 17 years admitted with a diagnosis of infections by fluv-a and b between 2003 and 2009 in the united states, 44.0% were asthma patients, and complications were more significantly associated with fluv-a (p < 0.01). other viruses were not assessed in that population. 27 another study compared exacerbated children treated in hospitals (n = 232) with those treated at home (n = 107). immunofluorescence for flu, hadv, hrsv, and piv was performed, as well as pcr for bocavirus. a 36.0% rate of viral detection was obtained, but no difference was observed regarding the viral profile between inpatients and outpatients. the most frequently observed viruses were rsv (15.0%) and bocavirus (12.0%), but hrv was not included in the viral panel of this study. 20 a group of 179 australian children aged up to 16 years had their nasal secretions collected in three periods between 2000 and 2002, and were compared with a control group of non-asthmatic children with upper respiratory tract infection (urti) in the same period and another group of 28 children with controlled asthma, assessed during routine consultations. hrv and hmpv were screened by rt-pcr and a panel of seven viruses (fluv-a and b, piv-1 to 3, hadv, and hrsv) was studied by immunofluorescence. hrv infection accounted for 50.0% of the urti of non-asthmatic children, and co-infection was common, especially with the hrsv, especially in children younger than 2 years. children with symptomatic asthma had the highest rates of hrv infection (79.0% vs. 52.0% among all children). finally, children with controlled asthma had the lowest rates of hrv identification (17.0% vs. 79.0%). 19 studies conducted in 2007 28 and 2009 29 aimed to the identification of hrv in exacerbated asthmatic patients through rt-pcr, found an overall frequency of viral identification of 37.0% and 15.9%, respectively. the first study used a group of comparison consisting of stable asthma patients, in which the identification rate was lower (18.0%) than in the case group (60.0%). both studies found a greater association between exacerbations and the presence of hrv c. another important issue in the complex association between viruses and asthma is related to the intensity of the association of exacerbations with viral infection. in this sense, several studies 4,30---34 presented inconclusive results, although hrv was associated with increased severity or worse response to treatment. 30, 33, 34 the association between viral infection and acute asthma severity was evaluated in 128 children aged 2 to 16 years. a positivity rate of 92.2% for the presence of virus was observed by direct immunofluorescence (dif) and multiplex pcr; hrv was detected in 87.5% of cases, and type c was observed in half the cases and was associated with greater severity. 4 fifty-eight asthmatic children aged 6 to 8 years were monitored for a period of five weeks between april and september of 2009. they had nasal lavage samples collected weekly for multiplex pcr analysis, in addition to a symptom diary, peak expiratory flow, and notes on rescue medication use. a virus was detected in 36.0% to 50.0% of the specimens; hrv was identified in 72.0% to 99.0% of the positive samples, and was associated with greater symptom severity. 30 nonetheless, viral testing by multiplex pcr for 20 pathogens in 209 children with exacerbated asthma compared with 77 controlled asthma patients, performed in hong kong between 2007 and 2008, showed no association between the presence of the virus and exacerbation severity. one virus was identified in 51.0% of cases, and this detection was, in general, more associated with exacerbations (or 2.77; 95% ci: 1:51 to 5:11; p < 0.01). when analyzed individually, no virus was associated with exacerbation, although hrv was the most frequent, being identified in 26.2% of exacerbated and in 13.0% of controlled asthma patients, but with no significant difference (p = 0.27). 31 nasopharyngeal aspirate samples of 201 asthmatic children aged between 2and 15 years collected during episodes of exacerbation were referred for viral identification by pcr. the positivity rate was 53.8%;the most frequently observed were hrv (41.0%), followed by hrsv (9.0%). there was no association with exacerbation severity. 32 a study compared the response to treatment with bronchodilators between exacerbated children with viral respiratory infection symptoms (n = 168) and a group without such symptoms (n = 50). the mean age was 6.6 years, and exacerbation severity did not differ between groups. children with viral symptoms had poor response to bronchodilators, requiring more doses of beta-agonists after 6, 12, and 24 hours. the viral screening was conducted in 77.0% of cases; hrv was the most frequently found virus (61.4%). 33 in another study, 78 exacerbated children were treated at the hospital and compared to 78 asymptomatic adults. multiplex pcr reactions for eight respiratory viruses and monoplex pct for enterovirus, hrv, and bocavirus detected the presence of respiratory viruses in 65.4% of cases; hrv was once again the most frequently observed virus (52.6%). genotyping showed a higher frequency (56.0%) of type c hrv and association with type a showed a worse clinical outcome. 34 asthma exacerbations have seasonal distribution, occurring cyclically in both adults and children, and can be explained by the viral circulation pattern or change in the level of pollutants and aeroallergens. one example is what occurs in temperate countries, where a higher rate of occurrence is more likely to be observed in the fall and spring among schoolchildren. 35 a combination of factors may explain this phenomenon, such as increased circulation of hrv in late summer and early autumn, increased circulation of pollutants and aeroallergens, and the return to school after the summer vacations. the influence of the return to school activities may be explained by lower adherence to maintenance treatment during the vacation period. the circulation of other viruses has been reported in other countries in the northern hemisphere, especially hrsv during autumnwinter, flu in winter, piv-1 and 2 in the fall, and piv-3 in the spring. 36, 37 in brazil, data on viral circulation were collected from the brazilian system of epidemiological surveillance on flu viruses and their counterparts in the period between 2000 and 2010. samples obtained from nasopharyngeal swabs of patients in different sentinel units distributed throughout the country were analyzed by immunofluorescence. they showed a predominance of fluv and hrsv, with circulation throughout the year, with peaks for the latter between march and june, and between may and august for fluv. 38 no data were located concerning the movement of hrv in brazil. few published data regarding the seasonality of exacerbations were found. to make a parallel to virus circulation and the occurrence of exacerbations, the authors analyzed data obtained in some studies, such as the study conducted in the federal district, which observed a higher frequency in the month of march. 39 still in the midwest region, in the state of goiás, an increased frequency of respiratory symptoms, not specified as asthma, was observed in winter. 40 an observation regarding the distribution of the occurrence of asthma in the state of minas gerais also showed higher concentrations in fall-winter, between may and july, 41 indicating a predominance of respiratory and/or asthma symptoms in the brazilian fall-winter seasons. in addition to the seasonal variation of the virus, other factors involved in the genesis of asthma exacerbation may explain this variation, such as aeroallergens and pollutants, which also vary throughout the different seasons. it is likely that the combination of these and other factors result in the observed seasonal peaks in exacerbations. in the month of april of the years 2006 and 2008, a study was conducted in korea aiming to monitor viral infection and to identify sensitization to aeroallergens in 58 children with acute asthma or diagnosis of a cold, whose mean age was 6.5 years. children with allergic sensitization presented the same number of viral infections, but with more symptoms than those nonsensitized. 30 in another study, conducted in manchester, england, 84 children hospitalized for exacerbation were compared to children with stable asthma and children hospitalized for non-respiratory disease. the authors concluded that the association between viral infection and allergen exposure increased the risk of hospital admission by 19.4-fold. 42 in brazil, camara et al. 43 investigated the role of viral infections, sensitization, and exposure to aeroallergens as risk factors for wheezing in children aged up to 12 years. in those younger than 2 years, the frequency of viral positivity was significantly higher in cases (60.8%) than in controls (13.3%). in older children, there was no significant difference: 69.7% of cases and 43.4% of the positive controls. they concluded that in children younger than 2 years, the risk factors associated with wheezing were viral infection and a family history of atopy; among older children, sensitization to inhalant allergens was the most important event for the onset of crises. the effect of air pollutants is usually disregarded in the presence of viruses or allergens. however, there is evidence that acute exposure to specific pollutants may contribute to the symptoms and severity of exacerbations. for instance, cigarette smoke induces a model of non-eosinophilic inflammation with relative resistance to corticosteroids. 44 passive smoking is quite common in homes of asthmatic children, causing a negative impact on disease control. in scotland, the 2006 legislation that banned smoking in public places reduced hospitalizations for asthma by 18.2%. 45 other pollutants appear to contribute to asthma exacerbations, such as those resulting from the combustion of natural gas and engine oil, such as nitrogen dioxide (no 2 ). children spend most of their time outside and breathe in a greater amount of pollutants per kilogram of weight when compared to adults, and the increased levels of no 2 are associated with the severity of virus-induced exacerbations. this emphasizes a potential synergism between these two inflammatory stimuli. 44 moreover, controlled exposure in asthma patients demonstrated that no 2 increases the response to inhaled allergens. a cohort of 114 asthmatic children aged between 8 and 11 years were monitored for symptoms, measurement of peak expiratory flow, measurement of exposure to no 2 , and presence of virus in nasal secretion during a period of 13 months. one or more viruses were detected in 78% of the reported episodes of respiratory symptoms; it was demonstrated that exposure to high concentrations of no 2 in the week before the onset of a viral respiratory infection was related to the exacerbation severity. 46 a longitudinal study conducted in the united states measured exposure to cigarette smoke in 1,444 children with asthma and no 2 in a subset of 663 of them, over a period of nine months. they demonstrated increased symptoms in those exposed to no 2 , but only among non-atopic children, with a relative risk of 1.8 (95% ci: 1.1 to 2.8). there was no association between symptoms and increased cigarette smoke exposure. 47 two cross-sectional studies compared children exposed to different levels of cigarette smoke and showed that those exposed to high levels had higher symptom scores (p < 0.01), nocturnal symptoms (or 3.4; 95% ci: 1.3 to 8.8), and need for relief (p = 0.03) and control (p = 0.02) medications. 48 a study in which 937 children aged between 5 and 11 years were randomized to intervention with environmental education guidelines aimed at reducing exposure, showed a reduction in exposure in the group that received instructions for a period of 14 months. the intervention group had fewer days with symptoms (p < 0.01) after one year of followup, in addition to a decrease in the levels of dust mites (dermatophagoides pteronyssinus and dermatophagoides farinae) and cockroach antigens in the home environment. 49 fungal sensitization is prevalent in children with asthma, although few studies have addressed this issue, compared to studies related to dust mites. one study demonstrated that children with a positive skin test for fungi had more days of symptoms when compared to those with negative tests (6.3 vs. 5.7 for two weeks, p = 0.04). during the study period, fungi were grown from the intra-and extra-domestic environment; increased exposure to fungi was associated with increased days of symptoms and unscheduled physician visits for asthma. 44 the preponderance of virus participation among the infectious agents in exacerbations makes the indiscriminate prescription of antibiotics in this situation pointless in most cases. previous studies suggest that chest radiography is improperly and unnecessarily used in children and adults with acute asthma treated in emergency rooms. 50 due to the alterations that are usually found in patients during asthmatic crises, such as hyperinsufflation, fluid extravasation, and atelectasis associated with hypoxemia, 51 the misinterpretation of these findings as a sign of pneumonia is common and, consequently, unnecessary prescription of antibiotics. a multicenter study of 734 asthmatic patients treated in emergency rooms evaluated the request for additional tests, in this case, chest radiography and blood tests. severely ill patients, those under 1 year, and those with a comorbidity were excluded. a total of 302 (41.0%) children underwent additional tests, such as chest radiography (27.0%) and blood tests (14.0%). after excluding febrile or hypoxic patients, 32.0% were still subjected to at least one of the exams. 50 despite the lack of brazilian data, the routine of pediatric emergency care services in the country appears to adhere to this rule. in order to prevent the dissemination of viral agents, due to the high capacity of viral spread through droplets and fomites, hand washing, and the use of respiratory masks are simple strategies that have been proven to be effective. 52 staying away from situations that favor clusters of people during periods of increased viral circulation has been recommended, although there are no studies that proved the effectiveness of this strategy. 52, 53 the use of substances such as herbal preparations including echinacea and vitamin c has been evaluated, but double-blind, placebo-controlled studies failed to demonstrate their benefit. 54 the prevention of viral infections through vaccines has been the most effective way to control diseases caused by viruses. in the case of respiratory viruses, the only vaccine available is for flu, although there are ongoing studies for the development of vaccines for other respiratory viruses, especially hrv. however, their great antigenic diversity hinders research success; recent studies have tried to establish a more adequate antigenic target in the viral structure. 54, 55 specific rsv immunoglobulin has been successfully used in reducing hospitalizations for viral bronchiolitis, and new perspectives for the treatment of exacerbations triggered by viral infections have emerged from studies directed to synthetic agonists of tlr3 receptor, ifn-␤ agonist, and il33and il25-antagonists, among others. 56, 57 there is no specific treatment for most respiratory viruses. some antivirals have been successfully used, as in the case of flu infection, such as amantadine, rimantadine, oseltamivir phosphate, and zanamivir; the latter is not indicated for patients with asthma. ribavirin is indicated for the treatment of severe infections caused by rsv. other antiviral agents are being studied and have not yet been approved for clinical use, such as pleconaril, vapendavir, pirodavir, and rupintrivir. 54 glucocorticoids have potent anti-inflammatory effects and have been successfully used in maintenance treatment in patients with persistent asthma, controlling inflammation and preventing exacerbations. some studies have assessed its effect on virus-induced asthma. the suppression of the release of pro-inflammatory mediators induced by hrv infection in vitro in bronchial epithelial cells, such as ccl5, ccl10, cxcl8, and il6, as well as the reduction of factors associated with remodeling, was achieved after the use of budesonide. 58 other in vitro studies documented the action of other corticosteroids alone or in combination with bronchodilators or leukotriene antagonists in reducing the release of several inflammatory molecules, with potential modulation of the deleterious effects of viruses on the asthmatic population. 51, 59 despite the proven benefits of inhaled corticosteroids in the control of asthma triggered by multiple factors, their action on virus-induced exacerbations is unclear. the use of low-to-moderate doses of inhaled corticosteroids as maintenance therapy cannot prevent intermittent viral-induced wheezing. 60, 61 however, better results have been obtained with the intermittent use of inhaled corticosteroids at high doses. 62 the use of viral detection techniques with high sensitivity and specificity has increased the identification of some respiratory viruses in children with asthma exacerbation. the direct or indirect immunofluorescence reactions still have great practical importance, as they can detect a panel of seven viruses (fluv-a and b, piv-1-3, hadv and hrsv), being an affordable and fast method, with good sensitivity, especially in children. 18 it is currently used by the brazilian ministry of health for the screening of respiratory viruses in the diagnosis of severe acute flu-like illness and flu-like illness in sentinel units. the techniques for nucleic acid amplification (rt-pcr) are more expensive, but more sensitive; thus, they are used in research and by the brazilian ministry of health for the identification and genotyping of flu. 38 furthermore, it allows for the identification of some viruses with significant clinical and epidemiological importance, such as hrv and bocavirus, not identified by immunofluorescence. 17, 54 as for the method used to obtain the sample, it is worth mentioning the controversial issue of nasopharyngeal swab in viral research. although its use has been consolidated for bacterial infections (s. pneumoniae and s. aureus), its role in viral infections still deserves some consideration. the authors agree that, from the practical point of view, it is more feasible, eliminating the use of suction systems, probes, and more specialized training, when compared to aspirate or lavage samples. however, only those with more advanced technology (flocked swab), which provides best capture and release of cells and, therefore, of the virus, are equivalent to the aspirate in terms of sample quality. nevertheless, this swab is not routinely used in services and researches in brazil. 38 regarding the association between viral infection and asthma exacerbation, a wide variation was observed concerning the methods of studies that assessed viral infection in exacerbated asthmatic children in the studies included in this review. for instance, sample size varied from 58 to 1,052 cases and the age ranged from 0 to 17 years. this finding is important, given the difficulty in defining asthma in children younger than 3 years, which should be considered in case selection. 2, 21 moreover, it is known that there is a considerable difference between the age groups and the most prevalent viruses, such as the hrsv. 60 regarding the methods of respiratory secretion collection in the included studies, there was no uniform means of collection; the aspirate was used in 43.8% of studies, the swab in 31.6%, both in 25%, and the flocked swab was not used. there was a wide variation regarding the detection methods and in relation to some outcomes. in addition to the differences in sample collections, all these studies were cross-sectional, which does not allow for the establishment of a cause-effect association between viral infection and the onset of exacerbation, but suggest such an association. in relation to other factors known to be associated with uncontrolled asthma, such as allergens and irritants, most studies did not include these variables in the evaluation. when the inflammatory process typical of asthma is associated with a viral respiratory infection, there is a tendency to greater severity and duration, as well as a poorer response to conventional treatment of the acute episode. 32, 33 the involved mechanisms still need to be fully elucidated, evidencing the synergistic effect between viral infection and allergic airway inflammation in the pathogenesis of exacerbations. 30, 43 another pertinent issue is the role of inhaled corticosteroids in attenuating the inflammation triggered by the virus, also seldom mentioned in these studies. its action in the control and reduction of morbidity associated with asthma is well established, 2 but it is still a controversial subject regarding the prevention of viral-induced wheezing. its effectiveness in the inflammatory process triggered by a virus has been demonstrated in in vitro studies, 51, 58, 59 but studies evaluating its clinical benefit have yet to reach conclusive results. 61, 62 regardless of the direction of virus-allergen interaction, the present findings strongly suggest that an adequate strategy to prevent virus-induced exacerbations should focus on two courses, namely the improvement of antiviral response and the reduction of allergic sensitization or inflammation. the latter can be achieved with appropriate treatment of the asthma patient at risk with medications that reduce airway inflammation. conversely, the preventive measures for viral infection acquisition and its timely diagnosis allow for a proper management of exacerbations, and reduction of the number of hospitalizations and unnecessary additional tests, especially in children who are febrile at the time of assessment. the association between viral infection and asthma in childhood still has several points that need clarification, especially the actual role of viruses in triggering exacerbations and that of inhaled corticosteroids in its attenuation. fundação de amparo à pesquisa do estado de goiás (n • 20120267001128). the authors declare no conflicts of interest. prevalência de sintomas de asma, rinite e eczema atópico entre crianças e adolescentes brasileiros identificados pelo international study of asthma and allergies (isaac): fase 3 global strategy for asthma management and prevention. global initiative for asthma (gina) 2012 proceedings: the role of viral infection in asthma and bronchitis association between human rhinovirus c and severity of acute asthma in children microbiologia médica de jawetz role of deficient type iii interferonlambda production in asthma exacerbations epithelium dysfunction in asthma respiratory syncytial virus in allergic lung inflammation increases muc5ac and gob-5 viruses and bacteria in acute 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inflammatory chemokine expression by fluticasone propionate respiratory viral infections in children with asthma: do they matter and can we prevent them? the impact of infection control upon hospital-acquired influenza and respiratory syncytial virus human rhinoviruses rhinovirus vaccination: the case against asthma exacerbations: origin, effect, and prevention use of toll-like receptor 3 agonists against respiratory viral infections budesonide and formoterol inhibit inflammatory mediator production by bronchial epithelial cells infected with rhinovirus budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses epidemiological and genetic characteristics associated with the severity of acute viral bronchiolitis by respiratory syncytial virus effect of continuous treatment with topical corticosteroid on episodic viral wheeze in preschool children preemptive use of high-dose fluticasone for virusinduced wheezing in young children to the laboratory of virology of the instituto de patologia tropical e saúde pública of the universidade federal de goiás. key: cord-022084-hap7flng authors: arruda, eurico; cintra, otavio a.l.; hayden, frederick g. title: respiratory tract viral infections date: 2009-05-15 journal: tropical infectious diseases doi: 10.1016/b978-0-443-06668-9.50064-8 sha: doc_id: 22084 cord_uid: hap7flng nan acute respiratory infections (aris) are prevalent worldwide 1 and rival diarrhea as the leading cause of death in developing countries. 1, 2 in some impoverished urban populations in south america, ari symptoms may be present on an almost continuous basis, making it difficult to determine symptom-free days and estimate attack rates. 3, 4 children from these areas may spend 40% to 75% of their time with respiratory symptoms, 1,5 mostly caused by upper respiratory infections (uris). the most striking disparity between developing and developed countries with regard to ari epidemiology is the case-fatality rate of lower respiratory infection (lri), mainly pneumonia, bronchiolitis, and influenza, 6, 7 in children under 5 years of age, which may reach 16% in some areas. 1, 8 several community-based studies have established the importance of common respiratory viral infections in tropical countries 5 (table 59-1) . in impoverished populations, these common viral infections may occur simultaneously with measles, diarrhea, and malnutrition, resulting in complex interactions of pathologic conditions that carry the potential to become life-threatening diseases. 1, 9 unlike certain pathogens restricted to tropical areas, the respiratory viruses have worldwide distribution, efficient person-to-person transmission, and an impact on all age groups. except for a few agents (e.g., adenoviruses, severe acute respiratory syndrome [sars] coronavirus) and rare cases of extrapulmonary dissemination with other respiratory viruses, replication is generally restricted to the respiratory mucosa of humans. in most health-care facility-based studies of acute lri (alri) conducted in tropical countries (table 59 -2), respiratory syncytial virus (rsv) is the virus most frequently detected (11% to 33%), followed by parainfluenza viruses (1% to 13%), adenoviruses (2% to 34%), and influenza viruses (1% to 4%). with few exceptions, human rhinovirus (hrv) and human coronaviruses (hcov) have not been reported frequently in studies in tropical countries, 5 probably because of difficulties in their detection. although previous studies have shown that attending daycare centers can be a risk for ari, 10 providing day care for children has become an important economic issue in developing countries, where mothers must join the workforce to contribute to the family income. consistent with studies in the united states and elsewhere, a study found a high burden of ari in young, low-income children attending day care in salvador, brazil. 11 few specific interventions are available to reduce the impact of respiratory viruses, 2 and the application of these interventions may be further hampered by epidemiologic patterns in ari and socioeconomic differences in temperate, developed countries compared with equatorial regions. for example, housing conditions and crowding pose challenges for optimizing health-care strategies in the tropics. while the incidences of some respiratory viruses, particularly rsv and influenza, show seasonal trends in some tropical areas, the association of seasonal peaks of respiratory viruses in general may be less apparent where fluctuations in temperature are smaller. 12 nutritional and educational interventions, such as reinforcing breast-feeding, 13 vitamin a supplementation for measles, 14 and facilitation of access to oral rehydration therapy, 15 may have significant effect on the morbidity and mortality due to lri alone or in association with diarrhea. in this chapter we focus attention on the most common viral respiratory infections, whose main features are summarized in table 59 -3, and try to highlight features unique to the developing world. in tropical countries influenza activity may occur yearround as well as in outbreaks more typical of temperate regions. these infections cause serious disease in populations weakened by malnutrition, with limited access to medical care. 16 of note, the predisposition induced by influenza to superimposed bacterial infections, mainly streptococcus pneumoniae, may greatly affect morbidity and mortality, mainly among impoverished populations. 17 in addition, influenza viruses can reassort or sometimes cross species barriers to generate emergent strains that may cause localized outbreaks or potentially pandemics with enormous impact for health on a global scale. 18 influenza viruses are pleomorphic, enveloped, with segmented negative-strand rna genomes and belong to the family orthomyxoviridae. influenza viruses are distributed in three genera-a, b, and c-based on the antigenicity of the nucleoprotein (np) and matrix protein. influenza a virus is further classified in subtypes based on its two surface glycoproteins: hemagglutinin (ha) and neuraminidase (na). 19 among the 15 ha and 9 na subtypes recognized in nature, 6 ha (h1, h2, h3, h5, h7, and h9) and three na (n1, n2, and n7) subtypes have now been identified in human isolates of influenza a viruses. 18 however, only three subtypes of ha (h1, h2, and h3) and two of na (n1 and n2) have caused pandemics and sustained circulation in human populations in recent years. 20 the genomes of influenza viruses contain eight rna segments in influenza a and b viruses, and seven rna segments in influenza c. 19 the glycoprotein ha is responsible for the attachment of the virus to sialic acid-containing cell receptors, and it mediates fusion and penetration. proteolytic cleavage of ha by cellular serine proteases exposes hydrophobic fusion domains that mediate membrane fusion. the na cleaves terminal sialic acid from glycoconjugates present on respiratory mucins, cells, and progeny virions. this action destroys receptors recognized by ha and allows budding virus to be released from infected cells and to spread within the respiratory tract. influenza c virus contains a single surface glycoprotein that binds to receptor, promotes fusion of membranes, and also cleaves sialic acid. 19 virus binding to receptor is followed by internalization into endosomes, fusion of viral and endosomal membranes, and release of the genome to the cytoplasm, from where it is transported to the nucleus. in influenza a viruses, the m2 protein serves an ion channel function that facilitates dissociation of the rna segments from the virion interior. transcription of the negative-strand genomic rna into positive-strand messenger rna (mrna) and complementary rna (crna) is mediated by a viral rna polymerase complex in the nucleus. crna serves as a template for the synthesis of negative-strand virion rna genome segments, and mrna directs viral protein synthesis. newly assembled nucleocapsids acquire an envelope as they bud through the cell surface. only viruses with a full complement of genome segments are infectious. 19 influenza a viruses are primarily viruses of aquatic birds, particularly ducks and shore birds, which harbor all subtypes recognized to date. selected subtypes naturally infect a range of terrestrial (swine, horses, humans) and aquatic (seals) mammals; influenza b virus infects humans and uncommonly seals, dogs, cats, and swine, and influenza c virus is primarily a virus of humans. depending on the virus type and subtype, experimental infection can be induced in mice, ferrets, chickens, swine, and primates, and the viruses can be propagated in primary cultures of kidney cells, continuous cell lines (mdck, vero, per.c6, and llc-mk2), and also in embryonated hen' s eggs. 20 the biologic property of influenza viruses to bind erythrocytes is exploited for early detection of the virus in cell culture and for the development of serologic assays by hemagglutination inhibition. 20 influenza viruses are inactivated by temperatures above 50°c and by lipid solvents, acid, formaldehyde, ionizing radiation, and ultraviolet (uv) light. 20 influenza viruses occur throughout the world, causing highly contagious respiratory infections with high morbidity and excess mortality (in seasonal peaks), particularly in infants and the elderly. in developing tropical countries, influenza has been associated with an average of 5% of aris leading to physician contact. 6, 21 this apparently low proportion probably represents only the most severe cases, since 30% to 50% of children under 5 years of age in tropical africa have been found to seroconvert in one outbreak. 21 previously healthy children younger than 1 year of age are hospitalized for influenza at rates similar to those for adults at high risk for influenza, and influenza accounts for a great number of outpatient visits and courses of antibiotics in children of all ages. 22 when human influenza virus is introduced into a malnourished population with limited access to care, high morbidity and mortality rates can occur, as was observed in madagascar in 2001 where a conventional influenza a/h3n2 subtype virus was associated with case-fatality rates of approximately 3%. contrary to the remarkably sharp seasonality of influenza a outbreaks in temperate countries, seasonal patterns in tropical countries have varied between studies. in southern india 23 and thailand 24 influenza has occurred throughout the year with sporadic outbreaks, whereas there have been consistent outbreaks in june-july and november-january, coinciding with the winter seasons in the southern and northern hemispheres, but with no apparent association with meteorologic factors. 12 in the philippines influenza has been more frequent between november and january, 25 while in senegal, nigeria, and taiwan there has been clear association with increased rainfall. 12 in southeastern brazil, 26 argentina, 27 as well as in south africa, 28 seasonal outbreaks of influenza a have occurred annually from may through august (mid autumn through winter) in association with cooler temperatures but not with rainfall. influenza b outbreaks occur periodically, yet less frequently than influenza a, in both temperate and tropical regions, 12, 20 whereas influenza c is generally nonseasonal. 20 minor changes in antigenicity, called antigenic drift, are caused by accumulation of point mutations in the genes coding for influenza ha and na, generating new strains that spread in annual epidemics. influenza viruses b and c are less prone to antigenic drift. major antigenic changes in influenza a are called antigenic shift and result in the emergence of a novel ha subtype with or without new na to which humans lack significant immunity. 18 this may be caused by the acquisition of new gene segments through genetic reassortment in a host infected simultaneously by a human and an animal (typically avian) virus, or by reappearance of a subtype from reservoir. swine are susceptible to both avian and human influenza viruses and may be hosts for reassortment or serve as the mammalian species in which avian viruses can adapt. novel influenza virus subtypes generated by shift have caused catastrophic pandemics, including three in the last century. the h1n1 "spanish flu" pandemic of 1918 is estimated to have caused up to 100 million deaths worldwide, 18 while the h2n2 "asian flu" in 1957 and the "hong kong flu" in 1958 caused an estimated 1 to 3 million deaths. recent clusters of human infections due to avian influenza, particularly h5n1 subtype viruses in asia, have raised concerns about new pandemic threats. in 1997 a highly pathogenic avian influenza h5n1 virus resulting from reassortment among several avian viruses caused lethal outbreaks in domestic poultry and severe illness with 6 deaths among 18 human cases in hong kong. the outbreak was due to exposure to infected poultry in live poultry markets and was later contained by their slaughter. this virus was transmitted inefficiently from person to person. 18, 20 in february 2003 an h5n1 virus caused deaths in a family visiting fujian province in china. since late 2003 wide-scale poultry outbreaks due to h5n1 virus have occurred in at least 10 asian countries. interspecies transmission to humans occurred in at least two countries, causing over 45 cases and 32 deaths in vietnam and thailand. 29 these h5n1 viruses have continued to reassort, evolve antigenically, and extend their host range with documented infections in swine and felids. prolonged nonsymptomatic excretion in ducks and detection in migratory birds indicate that this virus has become endemic in southeast asia. 18, 30 an avian h9n2 virus with human receptor specificity has also spread throughout asia in domestic poultry and pigs and caused mild disease in humans in hong kong and china. 18 an avian h7n7 virus caused conjunctivitis in at least 82 people and one fatal pneumonia in the netherlands in 2003; the outbreak was contained by culling and quarantine of poultry. in february 2004 a highly pathogenic h7n3 virus emerged in domestic poultry in british columbia with two documented human cases of conjunctivitis and mild "flulike" illness. 18, 29 influenza virus is transmitted from person to person by large droplets and small-particle aerosols, as well as possibly by fomites with hand contamination and subsequent selfinoculation. the relative importance of these routes is uncertain for natural influenza. ingestion of infected birds has led to infection by avian viruses in cats. secondary attack rates may reach over 70% in semiclosed populations, especially among schoolchildren and patients debilitated by underlying conditions who live in relative confinement, such as nursing home residents. 20 children play a major role in influenza outbreaks with respect to propagation of the epidemic virus in families and communities. 20 classic influenza starts abruptly after an incubation period of 1 to 2 days, with fever, chills, malaise, headache, myalgia, and prostration, often accompanied by nonproductive cough, sore throat, and mild rhinorrhea. systemic complaints last 3 to 5 days, whereas sore throat, hoarseness, and cough, with substernal discomfort, may increase in severity as the systemic symptoms subside. cough and asthenia often persist for 2 weeks or longer. respiratory symptoms may be minimal or absent initially, especially in the elderly or infants. in frail elderly persons, lassitude, lethargy, confusion, lowgrade fever, and sometimes gastrointestinal complaints may be the primary findings. influenza b tends to be milder than influenza a, and influenza c typically causes colds or bronchitis. 20 influenza may also present as unexplained fever, croup (laryngotracheobronchitis), vomiting, diarrhea, and neurologic manifestations in young children. 31 up to 50% of influenza virus infections in adults are subclinical. 20 influenza causes a variety of viral respiratory complications, including otitis media, sinusitis, tracheobronchitis, pneumonia, and, in young children, bronchiolitis and croup. secondary bacterial infections, especially pneumonia caused by staphylococcus aureus, streptococcus pneumoniae, and haemophilus influenzae, are common complications and should be suspected in relapses of fever, chest pain, and cough. 20 influenza is also associated with invasive meningococcal infections. other complications include exacerbations of asthma, chronic bronchitis, and congestive heart failure. myositis, myoglobinuric renal failure, meningoencephalitis, transverse myelitis, polyneuritis, parotitis, myocarditis, arthritis, and disseminated intravascular coagulation rarely occur after influenza. reye' s syndrome occurs in fewer than 1 per 100,000 cases of influenza in patients under 18 years of age following the use of salicylates. pregnant women, human immunodeficiency virus (hiv)-infected patients, and other immunocompromised hosts are at higher risk for severe disease and complications. 20 the virus infects the respiratory mucosa, where it causes lytic infection of cells and desquamation of the respiratory epithelium, mononuclear cell infiltrates in the lamina propria, and altered mucociliary clearance. tracheobronchitis is a typical feature and often associated with prolonged abnormalities in small airway pulmonary function and airway hyperreactivity. primary influenza viral pneumonia results in diffuse alveolar damage, alveolar hemorrhage and exudate, hyaline membranes, and later reactive fibrosis. fatal cases show pathologic changes in nonrespiratory organs, such as brain congestion and swelling, myocardial inflammation, and fibrinoid changes in arterioles. 20 viral replication in the upper respiratory tract generally peaks within 1 or 2 days of symptom onset and, depending on age and prior immunologic experience, continues for about 3 to 8 days. the severity of illness broadly correlates with upper respiratory tract viral levels. constitutional symptoms with influenza are due in part to the release of proinflammatory cytokines and chemokines. levels of interferon (ifn-α and ifn-γ), tumor necrosis factor (tnf-α), interleukins and chemokines (il-1β, il-6, il-8, il-10, mcp-10, mip-1α and mip-1β) are increased in nasal secretions, and ifn, il-6, and tnf-α are increased in blood in human influenza. 20 the tissue tropism of a strain of influenza virus depends, among other factors, on a combination of susceptibility of its ha to be cleaved by, and tissue availability of proteases with specificity to cleave it, thus rendering the virus infectious. 32 extrapulmonary dissemination of virus has been uncommonly documented in humans, but systemic spread is a regular feature of highly pathogenic avian viruses in chickens and sometimes in rodents or other mammalian hosts. serum and secretory antibodies directed to ha and na appear about 10 days after infection. protection against reinfection by the homologous strain is durable following natural infection and is correlated with serum and nasal neutralizing antibody levels, principally directed against ha. vaccine-induced protection may last for up to 2 to 3 years against homotypic virus. infection also induces cell-mediated immunity, which is detectable 3 to 6 days after infection and seems to be important for recovery. 30 cytotoxic t-lymphocyte responses against internal proteins may provide some degree of heterosubtypic immunity. the diagnosis of influenza is frequently made on the basis of clinical and epidemiologic information. a higher index of suspicion and laboratory diagnostics is needed outside the season, particularly in sporadic individual cases or unexplained outbreaks of febrile respiratory illness. viral isolation from respiratory specimens can be done in several types of cells (e.g., prmk, mdck, llc-mk2) and remains the current standard. 20 the presence of virus may be detected in cell cultures by hemadsorption with guinea pig erythrocytes before or after cytopathic effect (cpe) is visible. blind hemadsorption is positive 3 days after inoculation in almost all positive samples. 20 confirmation of isolates can be done by hemagglutination inhibition or immunofluorescence with typespecific antisera. diagnosis can also be made in 1 to 2 days by immunofluorescence of monolayers of mdck cells inoculated by centrifugation (shell-vial). 33 conserved influenza antigens (m or np) directly in clinical samples can be detected by one of several techniques (e.g., immunofluorescence [if], enzyme immunoassay [eia]), and multiple point-of-care kits are commercially available with turnaround time of 15 to 30 minutes. one commercial assay is based on detection of influenzaspecific na activity. the sensitivities of these assays are higher in children (up to 90%) than in adults (generally 50% to 70%) and depend on duration of illness and sample type. 20 several formats of reverse transcription-polymerase chain reaction (rt-pcr) assays have been used for the detection of influenza a and b rnas in clinical samples, with the advantage of detecting genomes of noninfectious virus. 20 the time to perform rt-pcr is longer but the cost may be lower than for commercial rapid antigen detection kits, especially in developing countries. real-time rt-pcr has enabled the development of assays that provide rapid quantitative detection of influenza a and b with high sensitivity. 34, 35 these assays have great potential to replace other methods, because they are simultaneously rapid, highly sensitive, quantitative, and amenable to being used in multiplex format, which might include probes for several different respiratory pathogens. 35 however, the costs are still prohibitive for most laboratories in developing nations. serologic diagnosis of influenza using paired acute and convalescent serum can be done retrospectively by a variety of techniques but mainly for serologic survey purposes. 20 amantadine and rimantadine are m2 ion channel blockers that inhibit influenza a virus replication at the uncoating step. 20 in uncomplicated influenza a in adults without underlying diseases, treatment with either drug can reduce the duration of influenza illness by approximately 1 to 2 days if started early, within 48 hours from the onset of symptoms. amantadine is excreted in an unchanged state in the urine, while rimantadine is extensively metabolized after absorption and less than 10% of the dose is excreted unchanged in the urine. elderly persons need only half the dose to achieve similar plasma levels. amantadine or rimantadine may cause gastrointestinal upset and central nervous system side effects. central nervous system (cns) intolerance is more common with amantadine and, when severe, can be manifested as agitation, psychosis, seizures, and coma. mild complaints including insomnia, dizziness, anxiety, dry mouth, anorexia, and nausea are reversible upon discontinuation. amantadine and rimantadine are marketed as 100-mg tablets and 10-mg/ml syrup. the recommended dose is 100 mg twice daily for adults older than 65 years of age (100 mg/day for patients ≥65 years of age). for children under age 10 years, a rimantadine dose of 5 mg/kg/day (maximum, 150 mg/day) has been suggested. 20 dose reductions proportional to the creatinine clearance (clcr) are suggested for patients with renal insufficiency (amantadine for clcr <60 to 80 ml/min/1.73 m 2 ; rimantadine for clcr <10 to 20 ml/min/1.73 m 2 ). influenza virus resistant to amantadine-rimantadine emerges in approximately one third of treated patients; such viruses are transmissible to close contacts and cause typical influenza illness. resistance to these drugs renders them ineffective and is sometimes present naturally, including in recent human isolates of h5n1 virus. 20 the neuraminidase inhibitors zanamivir and oseltamivir inhibit both influenza a and b viruses by blocking the active site of the enzyme for cleavage of sialic acid, thus inhibiting virus release from infected cells and spread within the respiratory tract. 36 in adults and children older than 5 years, inhaled zanamivir (10 mg twice daily for 5 days) provides 1to 2.5-day reduction in illness 37 and reduces antibiotic use for lower respiratory complications by 40%. zanamivir is generally well tolerated but may uncommonly induce bronchospasm, particularly in those with influenza and pre-existing airway disease. 20 oseltamivir (75 mg orally twice daily for 5 days) reduces illness severity, time to resumption of daily activities by 1 to 3 days, and rates of complications leading to antibiotic prescription and hospitalization by about 50% in adults. in children 1 to 12 years of age, oseltamivir reduces the frequency of otitis media and, consequently, antibiotic prescriptions. side effects include mild-to-moderate nausea or emesis. dosage of neuraminidase inhibitors does not need to be adjusted for the elderly. 20 resistance emergence is uncommon with both drugs, 20 although a recent study of children treated with oseltamivir detected drug-resistant viruses in 18%, often in association with prolonged viral excretion, and showed that children can be a source of viral transmission, even after 5 days of treatment. 38 antipyretic-analgesic drugs may be used for influenzainduced fever and aches. aspirin should be avoided because of its association with reye' s syndrome. immunization with formalin-inactivated or live-attenuated multivalent influenza virus vaccines and chemoprophylaxis for influenza virus a are the methods available for preventing influenza. influenza vaccine is used prior to the influenza season and currently includes one strain of influenza b and two strains of subtypes h3n2 and h1n1 of influenza a virus, chosen by the world health organization (who) surveillance network among the viruses most likely to circulate in the next influenza season. 20, 39 the inactivated vaccine has an approximate 70% to 90% efficacy in preventing illness in healthy children and adults. 39 it also reduces influenza-related hospitalizations and mortality in elderly and high-risk patients. the centers for disease control and prevention (cdc) recommends the immunization of persons aged 50 years and older; residents of nursing homes; children and adults with chronic cardiovascular or pulmonary disease, including asthma; persons chronically ill with diabetes mellitus, renal dysfunction, or hemoglobinopathies; immunosuppressed patients including those with hiv infection; children and adolescents on chronic aspirin therapy who may develop postinfluenza reye' s syndrome; women who will be pregnant during the influenza season; children aged 6 to 23 months; those who can transmit influenza to persons at high risk, such as health-care workers and household contacts of those at high risk including children 0 to 23 months of age; crew members of cruise ships; providers of essential services; and unimmunized travelers to areas where influenza may be circulating, including the tropics, the southern hemisphere between april and september, and those traveling in large organized tourist groups. in addition, vaccine is made available to anyone interested in reducing the likelihood of becoming ill with influenza. 20, 39 the inactivated vaccine, administered as a single intramuscular (im) dose shortly before influenza season (two doses in previously unimmunized children <9 years of age), is safe during pregnancy but should be avoided in persons with history of anaphylactic reactions to eggs. 39 vaccine safety and efficacy in children has been extensively evaluated and has shown a favorable safety profile with efficacy in 1-to 15-year-old children of 77% to 91%. inactivated vaccine is not currently recommended for children younger than 6 months, but vaccination of household contacts and caregivers should reduce the risk of these high-risk children contracting influenza. healthy people aged 5 to 49 years who are not contacts of immunosuppressed patients can receive either inactivated or intranasal live-attenuated vaccines. 39 influenza inactivated vaccine has been recently introduced in many tropical areas of the world, with a composition based on influenza viruses circulating in the southern hemisphere. the vaccine is given prior to the influenza season, which for most countries in the southern hemisphere is between may and july. 40 in south america, annual vaccination of the elderly has reduced hospitalizations and mortality for respiratory diseases. 41 continuous surveillance has already shown that regional variations of circulating influenza virus strains should be taken in consideration in the formulation of influenza vaccines with compositions more appropriate for south america. 42 live-attenuated, cold-adapted vaccines administered intranasally are well tolerated, genetically stable, and rarely transmissible and have the advantage of inducing local secretory immunoglobulin a (iga) responses. because of potential interference between components, two doses may be required in young children. 20 this vaccine was licensed in the united states in 2003, where it has become an option for healthy persons aged 5 to 49 years, including those in close contact with groups at high risk and those wanting to avoid influenza. 39 this vaccine is not recommended for persons with asthma and other chronic disorders of the pulmonary or cardiovascular systems; persons with underlying medical conditions, including diabetes, renal dysfunction, and hemoglobinopathies; persons with known or suspected immunodeficiency diseases or who are receiving immunosuppressive therapies; children or adolescents receiving aspirin or other salicylates; persons with a history of guillain-barré syndrome; pregnant women; and persons with a history of hypersensitivity to eggs. 39 cold-adapted trivalent influenza vaccine is highly effective (92% in phase 3 studies) in preventing cultureconfirmed influenza in healthy children and has provided protection against drift variant strains in some studies. in young and middle-aged adults, efficacy is generally comparable to that of inactivated vaccine. 39 other investigational approaches have been explored in influenza vaccine development, including recombinant ha produced in insect cells, virosomes incorporating surface glycoproteins, m2 protein conjugated with hepatitis b virus core, and naked dna encoding influenza virus nucleoprotein or ha. 20 cell culture-based vaccines (mdck, vero) have been approved in europe and may offer an alternative to the limitations of the current egg-grown vaccines. the technique of reverse genetics has been used to rapidly produce candidate vaccines against potential pandemic threat viruses. amantadine and rimantadine are approved for use, and are 70% to 90% effective in the prophylaxis of influenza a during outbreaks. unvaccinated elderly persons, immunodeficient patients, patients in chronic care institutions experiencing outbreaks, persons who could not be vaccinated, and those who received a vaccine strain different from the outbreak strain may receive prophylaxis with amantadine or rimantadine. prophylaxis should be started as early as possible at doses equivalent to those used for therapy, and continued until 1 week after the end of the outbreak for a total of at least 2 weeks. 39 amantadine-and rimantadine-resistant mutants of influenza a virus occur in up to 30% of treated patients and may be associated with failure of drug prophylaxis. 43 both oseltamivir (75 mg twice daily) and inhaled zanamivir (10 mg/dose twice daily) are more than 80% effective in the prophylaxis of influenza during outbreaks, but only oseltamivir has been approved for this indication in the united states. 20, 39 antiviral agents, especially the neuraminidase inhibitors, could significantly help in the control of a future influenza pandemic by reducing lower respiratory complications and hospitalizations as well as potentially person-to-person transmission. however, supply limitations 44 pose a real difficulty. therefore, policies to ensure a reasonable supply of these drugs, as well as directions to optimize the use of limited supplies, are important issues to be considered. 18 respiratory syncytial virus (rsv) is the single most important viral cause of lower respiratory disease and a major cause of morbidity and mortality in children worldwide. rsv is the leading cause of hospitalization in young children in developed and developing countries. 45 in tropical areas, rsv has been the most frequently isolated virus in hospital-based ari studies of children. 5 agent rsv, the only known human pathogen of the genus pneumovirus in the family paramyxoviridae, is a pleomorphic rna virus with helical nucleocapsid and lipid-containing envelope. antigenic differences in the surface glycoprotein g permit the classification of rsv into groups a and b, each with antigenic subgroups. 46 the interaction of rsv envelope glycoprotein g with glycosaminoglycans enables adherence to the cell surface. however, g protein-independent mechanisms of attachment must exist, since mutants devoid of g protein can also enter host cells. rsv enters the cell by fusion of viral envelope with cell membranes, a process mediated by binding of the viral f protein to the cell gtpase rhoa. 46 the syncytia resulting from fusion of the infected cells to adjacent ones are the major feature of the cytopathic effect of paramyxoviruses. once in the cytoplasm, the negative-strand rna is transcribed by viral transcriptase into mrnas, which then direct viral protein synthesis. an intermediate positivestrand full-length crna serves as a template for the synthesis of progeny negative-strand rna. as they bud through the cell membrane, the virions acquire a glycoprotein-containing envelope. 46 rsv causes asymptomatic infection in a variety of experimental animals, but natural infection occurs only in humans and chimpanzees. 47 rsv grows well in several human heteroploid cell lines, such as hep-2, hela, and a549, and is sensitive to ether, chloroform, detergents, and a ph less than 5. rsv is inactivated at 55°c, survives poorly on porous surfaces, and loses infectivity significantly by slow freezing and storage at temperatures above 4°c. 46 rsv occurs worldwide and causes annual outbreaks in temperate climates in the winter and early spring, with sporadic cases throughout the year. 47 in tropical regions, where temperature fluctuations are smaller and the only significant seasonal variable is often rainfall, rsv outbreaks tend to occur in the rainy seasons. such has been the case in malaysia, hong kong, india, papua new guinea, colombia, kenya, and the gambia. 12 interestingly, in singapore rsv peak activity occurs from march to august, a period of higher temperature, higher day-to-day temperature variation, and lower relative humidity. 48 in southeast brazil, rsv occurs seasonally, within a broader range of months from february through july, after the rainy season and when temperatures tend to be cooler, with slight variations from year to year. 49 in regions where average winter temperatures are colder, such as in são paulo city and the southernmost parts of brazil, as well as in argentina, rsv peak activity tends to occur in july and august. [50] [51] [52] most children have specific serum rsv antibody by age 2 years, but reinfections occur throughout life. more than one subtype of either rsv group may cocirculate in one season, with group predominance changing from year to year, without apparent correlation with clinical or epidemiologic characteristics of the illness they cause. 49,53 rsv transmission requires close contact and occurs either by large-particle aerosols or by contamination of hands and inoculation into the eye or nose. secondary infections in family contacts of an index case are common, after an average incubation period ranging from 2 to 8 days. 45 it is estimated that 30% of all infants will have rsv infection that requires medical attention and that 2% of them will be hospitalized. 45 an estimated 10% of children will have bronchiolitis in their first year of life, with 60% to 90% of those infections caused by rsv. 54 in southeast brazil, rsv is the leading cause of lower respiratory tract infections in children younger than 1 year of age and is responsible for up to 85% of hospitalizations in this age group during peak months. 52 the spectrum of illnesses caused by rsv ranges from mild uri to severe lri, including pneumonia, bronchiolitis, tracheobronchitis, and croup. 45 in infants and young children, uri with fever and otitis media is common. during outbreaks, rsv rna has been detected in up to 75% of middle ear effusions in children with rsv infection and acute otitis media. 55 the most frequent lri caused by rsv in infants is bronchiolitis, usually preceded by 2 to 3 days of uri symptoms, and progressing to lower respiratory tract involvement characterized by tachypnea, dyspnea, cough, expiratory wheezing, air trapping, and in more severe cases, intercostal muscle retractions and cyanosis. fever is present in only 50% of infants. chest radiographs may show hyperaeration of the lungs and sometimes segmented atelectasis. 45 blood counts usually show lymphocytosis, and an increase in neutrophils with a left shift could be associated with bacterial superinfection. the most frequent bacterial superinfection in children with rsv infections is acute otitis media, which may be found in up to 60% of children with brochiolitis. 56 however, more serious bacterial infections that may require sepsis work-up is uncommon in previously healthy infants with rsv infections. 57 this may be different, however, in developing tropical areas, where rsv frequently causes infections in children previously debilitated by other diseases and malnutrition. infants with congenital heart disease, premature infants, or infants with underlying pulmonary conditions, such as cystic fibrosis and bronchopulmonary dysplasia, as well as immunocompromised hosts of any age, are at risk for severe and fatal rsv infections. hiv-infected children with rsv infections have a higher rate of pneumonia and prolonged illness and virus shedding, but the general severity of the rsv disease is not increased. 45 differential diagnosis of acute bronchiolitis includes asthma, pneumonia, congenital heart and lung diseases, and cystic fibrosis. particular clinical signs are generally not accurate predictors of specific viral causes, but in a study conducted in the philippines, wheezing was a significant predictor of viral lri, while manifestations of higher severity, such as chest indrawing and cyanosis, were more often associated with bacterial lri. 58 the most frequent rsv illness in children over 3 years of age and adults is uri with coryza and cough, sore throat, and hoarseness, often accompanied by low-grade fever. exacerbations of chronic pulmonary diseases and wheezing can also be seen in adults with rsv infection. 45 the role of rsv infections in causing wheezing and asthma exacerbations in infants is well established in studies conducted in temperate areas. 59 similar observations have been made in an emergency room study conducted in southeast brazil, which found that infection with respiratory viruses, especially rsv, and a family history of allergy were independently associated with wheezing. 60 similar findings have been observed in urban nigerian preschool children. 61 rsv has been increasingly recognized as a cause of lri in the elderly, mainly characterized by interstitial pneumonia, prolonged cough, and dyspnea in persons with chronic pulmonary conditions, and it should be considered in the differential diagnosis of flulike illnesses. 62 rsv replicates in respiratory epithelium to reach titers as high as 10 6 tcid 50 /ml in nasal secretions of infected babies, and virus shedding may be as prolonged as 3 weeks after the symptoms disappear. 46 rsv spreads from cell to cell and may involve the entire respiratory tree, reaching bronchioles in 1 to 3 days after the onset of rhinorrhea. replication in the bronchiolar epithelium causes necrosis of ciliated cells, syncytia formation, peribronchiolar inflammation with abundant lymphocytes and macrophages, and impairment of secretion clearance, resulting in small airway obstruction and the hyperinflation characteristic of bronchiolitis. pneumonia frequently coexists, evidenced by interstitial mononuclear infiltrate, eosinophilic cytoplasmic inclusions in epithelial cells, and multinucleated giant cells. the most severe rsv disease occurs in young babies, whose immature airways may be unable to compensate for the pathologic changes. 46 naturally acquired immunity to rsv is incomplete and short-lived, but the severity of illness tends to decrease with reinfections. local secretory iga correlates better with protection than does serum antibody level and age, and pre-existing virus-specific maternal antibodies influence the development of neutralizing antibodies. cell-mediated immune response is central to recovery from rsv infection, and patients with suppressed cell-mediated immune response are at risk of severe rsv pulmonary disease and fatal outcome. 45, 46 the type of immune response to the virus is probably a major factor in the development of wheezing and asthma exacerbations. a bias toward a th2 cytokine response seems to be associated with more severe disease, whereas a th1 response leads to effective viral clearance and milder illness. the virus itself generally triggers a th1 response, but a preexisting th1 deficiency may be associated with disease severity in some children. it has been suggested that rsv bronchiolitis may be a marker of predisposition to wheezing or asthma later in life. 46, 63 children vaccinated with a formalin-inactivated rsv vaccine developed in the 1960s had severe disease when exposed to natural infection, apparently as a consequence of an imbalance between protective and immunopathologic t-cell responses elicited by previous parenteral immunization with inactivated rsv. this would favor a cd4+ th2 cytokine pattern in response to subsequent rsv infections, whereas a previous natural infection would favor a cd4+ th1 pattern in response to reinfection. 64 nasopharyngeal aspirates or swabs, nasal washings, and lower respiratory samples are all appropriate specimens for rsv isolation. this is usually accomplished in cultures of hep-2 cell line, in which rsv induces syncytia in 3 to 5 days. rsv antigen detection by eia, including membrane-based eia, is sensitive and specific and requires virtually no equipment, making it ideal for field studies. rapid rsv detection by if of exfoliated respiratory cells may be even more sensitive than eia-based methods. 45, 46 the increasing use of rapid tests has facilitated the assessment of rsv in tropical areas. 1 ideally, a combination of a rapid method with viral isolation should be used for maximal rsv detection, but the cost may still be prohibitive for the meager resources available in some tropical areas. detection of rsv rna by conventional rt-pcr has shown suboptimal sensitivity, especially when compared with easy-to-perform, more sensitive rapid methods. 45 however, more recently developed assays based on real-time rt-pcr are proving to be more sensitive than conventional rt-pcr assays, with the added conveniences of being rapid, quantitative, and amenable to simultaneous detection and subtyping of rsv directly from clinical specimens. 65 rsv serology has limited value for case management but may be useful for epidemiologic surveys. 45 treatment uri caused by rsv requires no specific treatment, and antibiotics are needed only when bacterial otitis media or sinusitis are present. 45 the supportive treatment of infants with rsv bronchiolitis consists basically in preventing hypoxemia and electrolyte imbalance, in addition to aerosolized bronchodilators. the lack of obvious correlation between radiologic findings and disease severity suggests that a chest film should be recommended only for severely ill or deteriorating infants. 54 to prevent hypoxemia, requirements may vary from simple removal of respiratory secretions and proper positioning of the infant to mechanical respiratory assistance and even extracorporeal membrane oxygenation (ecmo). pulse oximetry has been advocated to assess oxygen needs, but in tropical developing areas, where oximeters may not be available, serial clinical assessment is essential to monitor disease progression. for this purpose, crackles and cyanosis seem to correlate better with hypoxemia than tachypnea and intercostal retraction. 54 correction of hypoxemia can be accomplished with 40% or lower oxygen concentrations. 45 oxygen should be humidified with saline and delivered by mask if head boxes or tents are unavailable. the role of corticosteroids remains unclear with some evidence that they are not beneficial. 54 the only antiviral drug currently approved for the treatment of infants with rsv is the synthetic nucleoside ribavirin, delivered by small-particle aerosol via a mist tent, mask, oxygen hood, or ventilator. it is recommended only for infants and young children with an underlying condition, such as congenital heart disease, cystic fibrosis, or immunosuppression. premature infants, infants younger than 6 weeks of age, and severely ill infants may also be considered for therapy. 66 aerosolized ribavirin is well tolerated, but it is expensive and its prolonged administration requires facilities that may not be available in impoverished tropical areas. passive immunotherapy with rsv immunoglobulin, in combination with aerosolized ribavirin, improved the outcome of rsv pneumonia in bone marrow transplant patients. 67 the use of rsvintravenous immunoglobulin (ivig) or humanized monoclonal antibody against rsv has shown no benefit for the treatment of rsv infections in infants. 45 no vaccine is currently available for rsv prophylaxis. the disease enhancement caused by formalin-inactivated vaccine in the 1960s plus results of more recent unsuccessful trials of live-attenuated vaccines, have significantly slowed progress toward an rsv vaccine. 2 purified fusion protein vaccine has been tested for safety and immunogenicity in seropositive children older than 18 months, and was associated with reduction of lower respiratory tract illness, but not of rsv infection rates, in children with cystic fibrosis. 45 these and other candidate subunit vaccines, as well as intranasal liveattenuated vaccines, should be tested in high-risk children with underlying bronchopulmonary diseases. passive immunization of high-risk infants with monthly infusions of rsv immunoglobulin during the rsv season reduced the incidence and severity of rsv infections in highrisk children. 68 this costly intervention is the only available means of protecting high-risk children against serious rsv lri. monthly intramuscular injections of humanized monoclonal antibody should be considered for passive immunoprophylaxis during rsv season for high-risk infants such as preterm infants less than 6 months old, children with congenital heart disease, and children less than 2 years of age with bronchopulmonary dysplasia. 45 hospitalized infants with rsv infection should be isolated or grouped to prevent cross-infection. hand washing; use of eye-nose goggles, gowns, and gloves; and decontamination of surfaces and fomites are additional nosocomial infection control measures. 45 human parainfluenza viruses (hpivs) are the single most frequent cause of croup in infants and children worldwide and are second only to rsv as cause of lri in infants. 45, 69 little is known about the epidemiology of hpivs in tropical countries, but these viruses have been detected in up to 13% of children in hospital-based ari studies in developing countries. 5,21 hpivs are distributed in two genera of the family paramyxoviridae, sharing the structural and biological characteristics already mentioned in the rsv section. hpivs are classified antigenically into types 1 to 4, and hpiv-4 has subtypes a and b. hpiv types 1 and 3 are classified in the genus respirovirus, while hpiv types 2 and 4 are in the genus rubulavirus. hpiv-1 and -3 are the types most frequently associated with lri in children, the immunocompromised, the chronically ill, and the elderly, whereas piv-4 causes mostly uri in both children and adults. 69 binding of hpiv to sialic acid in the cell membrane is mediated by the glycoprotein hn, which contains hemagglutinin and neuraminidase activities. fusion of viral and cell membranes is mediated by the viral f protein, which is cleaved by cellular proteolytic enzymes. 45 once inside the cell, the cycle is similar to other paramyxoviridae, as summarized in the rsv section. hpivs can be propagated in primary simian or human kidney cells and in several cell lines, such as hep-2, vero, mdck, llc-mk2, bhk, and hela. 69 a variety of experimental animals undergo asymptomatic infection with piv, but only higher primates develop symptoms. 45, 69 epidemiology primary hpiv infection occurs early in childhood, and by age 5 virtually all children are seropositive. 19 an estimated one third of all viral lris in children in the united states are caused by hpiv-1 and -3. 69, 70 in most temperate regions, hpiv-1 and -2 cause epidemics in the fall of alternate years, either in co-circulation or alternating with one another. the biennial pattern of hpiv-1 is found in both hemispheres. 69 hpiv-1 causes most croup epidemics, whereas hpiv-2 more frequently causes illness with milder manifestations, although it can also cause croup. 69 hpiv-3 occurs endemically throughout the year, with sporadic spring outbreaks mainly among infants, and hpiv-4 occurs sporadically throughout the year in children and adults. 45, 69, 70 in tropical areas hpivs may account for up to 15% of child hospital admissions due to lri. 21 community-based ari studies in children under age 5 years show higher hpiv activity during rainy seasons in tropical countries. 3, 24 hpivs were the most frequent viruses detected in school-aged children with bronchial asthma exacerbations in urban nigeria. 61 hpivs spread mainly within families and closed communities, such as nurseries, day-care centers, and pediatric wards, with high secondary attack rates. in a longitudinal study conducted with children less than 2 years of age with ari in a day-care center for low-income families in northeast brazil, hpivs represented 11% of the viruses detected. 11 the virus does not persist long in the environment and is transmitted mainly by large droplets and fomites. 45 viral shedding usually lasts 3 to 10 days, but shedding of hpiv for months has been reported in very young children and immunosuppressed hosts. 71 primary hpiv infection may cause rhinitis, pharyngitis, laryngotracheobronchitis (croup), bronchiolitis, or pneumonia. approximately two thirds of all piv infections in children result in febrile uri with associated otitis media in 10% to 34%. the remaining one third of piv infections are cases of croup, bronchiolitis, or pneumonia. 61, 63 hpivs, mainly of types 1 and 2, cause up to 74% of all cases of croup. 69 croup is the most striking clinical presentation of hpiv infection and is most common between the ages of 6 and 36 months. 72 croup is manifested by inspiratory stridor, barking cough, and hoarseness caused by subglottic edema, preceded by rhinorrhea, mild cough, and low-grade fever. 45, 72 most children recover in 2 to 5 days, but some may develop bronchiolitis and pneumonia and present with a bronchopneumonia-croup syndrome. 45, 69, 72 since immunity to hpivs is incomplete, infections tend to occur throughout life, but little is known about hpiv infections in adults. in general, adults have only nonspecific uri, commonly with hoarseness. 45 hpivs can cause particularly severe diseases in immunocompromised hosts, especially children with severe combined immunodeficiency and bone marrow transplant patients. mortality in bone marrow transplant patients with hpiv infection varies from 10% to 20% in most series. 45, 69 hpivs replicate in ciliated epithelial cells, causing cytolysis of the respiratory mucosa. the infection begins in the upper respiratory tract and tends to disseminate down the respiratory tree. the larynx and trachea are mostly involved in the croup syndrome, and extensive involvement of the lower respiratory tree may be present in tracheobronchitis, bronchopneumonia, and bronchiolitis. 69, 71, 72 similar to influenza, factors determining the extent of hpiv infection include the susceptibility of the viral f protein to be cleaved and tissue-specific differences in the production of proteases to cleave it. 45 host immunity is largely mediated by humoral immunity to the two surface proteins hn and f. virtually all children by the age of 3 years will have seroconverted to hpivs, generally first to hpiv-3 but later also to hpiv-1 and -2. at school age, a significant proportion of children will have seroconverted also to hpiv-4. secretory antibody targeted to the hn glycoprotein is the best marker of protection against piv, 71 but the protection conferred by antibodies is limited, and repeated infections will develop. t-cell immune response seems to be involved in the clearance of virus and additionally in the development of inflammatory infiltrate, edema, and excess mucus secretion, 69 and immunocompromised hosts may develop progressive and even lethal disease. 73 like rsv, pivs cause mononuclear interstitial infiltrate, epithelial necrosis, inflammatory exudate into the alveoli, and hyaline membrane formation in the lungs. 45 piv is present in respiratory secretions until about 8 days from the onset of symptoms and can be isolated in monkey kidney primary cells and several continuous cell lines. virus can be detected in the monolayers by hemadsorption with guinea pig erythrocytes in around 3 days after inoculation and confirmed by if. 69, 71 shell-vial assays have been developed for hpiv detection but with mixed results. 69 if of exfoliated respiratory epithelial cells has produced conflicting and sometimes disappointing results, with most studies reporting sensitivities between 50% and 75% at best. 69 detection of viral rna by rt-pcr, including commercially available multiplex assays for several respiratory viruses, has enhanced the sensitivity of detection of hpiv from clinical samples. 69, 74 real-time pcr for respiratory viruses in multiplex format is sensitive and specific for hpiv. 35 at present, only supportive and symptomatic treatment is available for piv infections. management of croup includes supplemental oxygen and racemic epinephrine nebulization in hospitalized patients. mist therapy, although traditional, has no proven value. 72 short-term, high-dose systemic corticosteroids may reduce the need for intubation, and nebulized budesonide has a rapid effect and is as safe and efficacious as nebulized epinephrine in moderately severe croup. 72 several antiviral agents have in vitro activity against hpivs, but none has reached clinical testing. 69 there have been anecdotal reports of reduced hpiv shedding in immunocompromised patients treated with ribavirin, but this finding has not resisted scrutiny. 69 future possibilities include the bcx 2798 and bcx 2855 compounds, whose design is based on the threedimensional structure of the hn protein, which inhibit the hemagglutinin and neuraminidase activities of the protein and were effective in vitro and in an animal model against hpiv-1, -2 and -3. 75 no interventions are available for the prevention of hpiv infections. early trials with inactivated hpiv vaccine in the 1960s were unsuccessful. 69 recently, a live-attenuated, coldadapted hpiv-3 vaccine was found to be immunogenic for children as young as 1 month of age and holds promise for further development. 69 the same vaccine was tested in combination with a live-attenuated rsv vaccine candidate, showing that this approach is feasible and deserves further study. 76 characterization of hpiv proteins hn and f has led to development of subunit immunogens that showed efficacy in animal models. 69 human rhinoviruses (hrvs) are the most frequent respiratory pathogens of humans. 77 they were the most frequently isolated viruses in children under 5 years of age with ari in an urban slum in northeast brazil. 3 human rhinoviruses are small, nonenveloped, positivestrand rna viruses in the family picornaviridae, with over 100 identified serotypes. 77 hrv serotypes have been classified according to receptorspecificity into three groups. the major group includes 91 serotypes whose receptor is intercellular adhesion molecule-1 (icam-1); the minor group contains 10 serotypes whose receptor is the low-density lipoprotein receptor (ldlr); and the remaining serotype, hrv-87, utilizes a sialoprotein as cell receptor. unlike other picornaviruses, hrvs are acid-labile, a property that distinguishes them from enteroviruses. 77 the hrv genome is a monocistronic single-stranded rna, packed in an icosahedral capsid composed of 12 pentamers. surrounding the fivefold vertex, each pentamer contains a 1.2-to 3.0-nm-wide canyon that contains the receptor binding site. following receptor binding, the viral positivestrand rna is released into the cytoplasm and directs the synthesis of a polyprotein, whose cleavage products include an rna polymerase. this enzyme will produce an expanding pool of positive-strand rna using as a template an intermediate negative-strand rna. the positive-strand rna can be either translated into virion proteins or packaged as a genome into newly assembled virions. the hrv replication cycle takes place in the cytoplasm, and mature virions are released when the host cell is lysed. 77 hrvs are resistant to ethanol, ether, chloroform, and nonionic detergent but are sensitive to uv light; to ph lower than 5 and higher than 9; and to halogens such as chlorine, bromine, iodine, and phenolic disinfectants. they are stable for days on environmental surfaces and for years at minus 70°c. 77 hrv infects only higher primates and causes illness only in humans. several cell lines of primate origin support hrv propagation, but certain strains of hela cells and human embryonic fibroblasts provide higher sensitivity for hrv isolation from clinical specimens. 78 the optimal growth temperature for hrv is 33°c to 35°c. 77 hrv infections occur in people from all continents, including remotely located population groups, such as bushmen from the kalahari desert, native alaskans, and an isolated amazon indian tribe. 79 hrv has been estimated to cause up to 80% of all autumn colds in temperate climates. 80 in tropical countries, very few community-based studies of viral ari have used adequate hrv detection methods, 5 and this has limited the assessment of the actual impact of hrv in those areas. however, available evidence indicates that hrv is frequently associated with ari in children in brazil. in fortaleza, a city in northeast brazil, hrv detected by isolation in cell culture represented 46% of the viruses in children under 5 years of age with ari. 3 in salvador, another city in the same region, hrv represented 52% of the viruses detected by rt-pcr in association with ari in children younger than 2 years of age attending a day-care center for the underprivileged. 11 data on the frequency of hrv among adults in tropical countries are even more scarce. in singapore, hrv was detected in 20% of the samples obtained from adults with ari symptoms attending primary care centers. 81 hrv transmission requires close exposure and occurs mainly by hand-to-hand contact, followed by self-inoculation into the eye or nose, but also by airborne spread. once hrv reaches the nasal cavity, infection occurs in virtually 100% of susceptible subjects, and approximately 75% of those infected develop illness after a 1-to 2-day incubation. 77 children play a central role in spreading the virus in the household. evidence suggests that indoor hrv transmission is favored by high relative humidity and crowding of young children, as occurs in the united states at the beginning of the school term, which may explain the autumn seasonal peak of hrv. 77 in tropical northeastern brazil, however, where relative humidity remains above 70% reaching 90% during the rainy season, longitudinal studies have found no obvious hrv seasonality. 3, 11 hrv colds are indistinguishable from colds of other viral causes and consist of nasal discharge, nasal obstruction, sneezing, sore or scratchy throat, hoarseness, cough, and headache. facial and ear pressure may be present. fever and malaise are uncommon. these symptoms last approximately 7 days but may persist for up to 2 weeks in 25% of cases. infants and toddlers may display only nasal discharge and be otherwise asymptomatic. 77 the majority of patients have obstruction and mucosal abnormalities of the sinus cavities, eustachian tubes, and middle ear, which predispose to secondary bacterial sinusitis and otitis media, each complication found in approximately 2% of all colds. 82 hrv rna may be detected by rt-pcr in maxillary sinus brushings in 40% of adults presenting with acute sinusitis, 83 and in 24% of the samples of middle ear fluid from children less than 7 years of age with diagnosis of acute otitis media. 84 hrv is frequently associated with exacerbations of chronic obstructive pulmonary disease and asthma attacks in children over 2 years of age and in adults. 59, 77, 85 hrv replication is restricted to the respiratory epithelium, taking place in scattered ciliated cells of the nose and in nonciliated cells of the nasopharynx. 86 this tropism seems to be a consequence of receptor availability. infection of a limited number of cells triggers the release of cytokines, chemokines, and inflammatory mediators, which together with stimulation of the local parasympathetic nerve endings, results in the cold symptoms. kinins, prostaglandins, and proinflammatory cytokines and chemokines may contribute to vasodilation, increased vascular permeability, influx of polymorphonuclear leukocytes, exocrine gland secretion, and nerve ending stimulation, resulting in nasal obstruction, rhinorrhea, sneezing, cough, and sore throat. 77 serotype-specific neutralizing igm, igg, and iga antibodies develop in most infected persons in 7 to 21 days and persist for years. protection from infection is partially attributed to the presence of iga antibody in nasal secretions, and recovery from illness is more dependent on cell-mediated immunity. hrv-induced blastogenesis, natural killer cell activity, mitogen-stimulated cell production of il-2 and ifn-γ have been documented during hrv infection. 77, 87 hrv induces the expression of human β-defensin 2 (hbd-2) in the respiratory epithelium, which supports a role for hbd-2 in host defense to hrv infection. 88 hrv can be detected in respiratory secretions by isolation in cultures of susceptible cell lines. 78 hrv shedding peaks around 48 hours after infection and declines rapidly, but may remain at low levels for up to 3 weeks. 77 cultures should be kept at 33°c to 35°c in a roller drum and examined for 10 to 14 days. the presence of hrv, indicated by the typical cpe, is confirmed by the acid sensitivity of the isolate. rapid immunocytochemical methods are not available because of the large number of serotypes. rt-pcr in clinical samples is more sensitive and less tedious than hrv isolation, 83 and the recently introduced real-time pcr-based assay is more sensitive than conventional rt-pcr. 89 pcr-based assays have been useful in studies to assess the impact of hrv in different settings. the homotypic nature of hrv antibodies restricts serology to experimental settings. 77 trials of antiviral agents for hrv have been conducted, but no specific treatment suitable for routine use has yet been identified, mainly because of lack of potency, untoward side effects, and drug delivery problems. 90 ruprintrivir, a selective inhibitor of hrv 3c protease, has potent, broad-spectrum anti-hrv activity in vitro. a double-blind, placebo-controlled clinical trial of intranasal ruprintrivir in experimental hrv infection reduced symptoms by 33% and also decreased viral titers and nasal discharge. 91 symptomatic relief from cold symptoms can be obtained with a broad variety of nonprescription medications. systemic sympathomimetic decongestants, such as pseudoephedrine, may reduce nasal obstruction, first-generation antihistamines may reduce sneezing and rhinorrhea, and nonsteroidal antiinflammatory drugs such as naproxen or ibuprofen may reduce headache, cough, and systemic symptoms. 77 the large number of hrv serotypes with minimal crossantigenicity has hampered the development of an hrv vaccine. it may be possible to reduce exposure to hrv by hand washing after contact with a cold sufferer or after handling objects that may have been contaminated with respiratory secretions. 77 studies in experimentally infected volunteers show that application of the virucidal agents salicylic acid or pyroglutamic acid to the hands reduced recovery of rhinovirus from the hand skin of treated persons as compared with controls. 92 this result suggests that rhinovirus transmission can be prevented by virucidal hand treatments. short-term, postexposure prophylaxis by intranasal ifn-α significantly reduced the incidence of hrv colds in household contacts of an index case. 93 however, the cost and difficulty of making the drug available to homes in a timely fashion reduce the utility of this approach for extended use by populations, especially in tropical countries. ruprintrivir has also been evaluated for prophylaxis of hrv colds starting 6 hours prior to inoculation of human volunteers. this approach reduced the proportion of subjects with positive viral cultures and viral titers but did not affect the frequency of colds. 91 respiratory infections caused by adenoviruses are among the most frequent illnesses that these viruses cause, particularly in children under age 5 years. 94 adenoviruses have been frequently isolated in ari studies in tropical countries. 5 in the south cone of south america, adenoviruses were the second most frequent virus recovered from children hospitalized for ari. 95 adenoviruses are nonenveloped, icosahedral dna viruses of the genus mastadenovirus in the family adenoviridae. 94 adenoviruses are distinguished antigenically by group-specific (a through f) and type-specific (1 through 49) antigens and by genomic subtypes identified by restriction site mapping. 93, 94 the adenovirus capsid consists of three morphologically, antigenically, and functionally distinct types of capsomers: hexons, penton bases, and fibers that project from the penton bases. the hexon and penton bases contain complementfixing, group-specific antigens common to all human adenoviruses, whereas the fibers have primarily neutralizing and hemagglutination-inhibiting, type-specific antigens. adenoviruses are commonly accompanied by small, singlestranded dna parvoviruses known as adenoassociated viruses, which do not seem to cause any specific disease. most people have antibodies to at least one of the four serotypes of adenoassociated virus by age 10 years. 96 the fiber protein binds to the host cell, through the protein coxsackie and adenovirus receptor (car) of the immunoglobulin superfamily, which serves as a high-affinity receptor for adenoviruses. the class i major histocompatibility complex (mhc) also may serve as receptor for adenovirus 5. 94 ligand-receptor interaction facilitates interaction of the penton base with cell surface integrins, which triggers entry. after endocytosis, the double-stranded linear genomic dna is transported to the nucleus, where "early" and "late" sets of viral genes are transcribed, resulting in mrnas coding for structural and nonstructural proteins. virus assembly takes place in the nucleus, and the infectious cycle is completed by the release of up to 1 million virions upon cell lysis. 94 adenoviruses replicate well in continuous cell lines of epithelial origin, such as hep-2, hela, and a549, and can be adapted to grow in human embryonic lung fibroblasts. they are stable over a wide ph range (5 to 9), resistant to isopropyl alcohol, ether, and chloroform, stable for weeks at room temperature and for years at approximately 20°c or colder, and can be lyophilized. they are inactivated by sodium hypochlorite and a temperature of 60°c for 2 minutes. 97 respiratory transmission of adenoviruses occurs at all ages but is of prime importance during epidemics among military recruits. ocular transmission has been associated with swimming pools and physician offices where sterilization or hand washing has been inadequate. asymptomatic infection and a prolonged carrier state are common. 94 low-number adenovirus serotypes (1, 2, 3, and 5) are more frequent before age 5 years and account for 5% to 20% of cases of uri and approximately 5% of cases of lri in children. 98 in adults, adenoviruses occur sporadically and cause mostly uri. infections by adenoviruses types 4 and 7 are usually epidemic, with attack rates of 6% to 16% per week in newly assembled military recruits, whose adenovirus carriage rate may be as high as 18%. 94 in this group, the adenoviral syndromes vary from mild colds to severe lri, but overall attack rates may reach 80%, with 20% to 40% of the individuals needing hospitalization. 94 in temperate climates, adenoviral infections are more frequent in late winter, spring, and early summer, whereas in northeast brazil they seem to occur year-round. 5 in salvador, also in northeast brazil, adenoviruses were detected in 11% of children younger than age 2 years with ari in a day-care center. 11 in tropical areas the incidence of adenovirus infections in military recruits is lower, and different serotypes may be involved. 98 pharyngoconjunctival fever, commonly caused by adenoviruses types 3 and 7, may be epidemic or endemic among children during the summer in temperate climates. inadequate chlorination or filtration of swimming pools and lakes has been associated with epidemics. 99 the incubation period of adenovirus infections averages 10 days. 98 adenovirus respiratory diseases may involve all parts of the respiratory tract, and up to 50% of nonepidemic infections are asymptomatic. in fact, adenoviruses were discovered because of their propensity for latency in adenoidal tissue. 94, 98 in southeast brazil, adenoviruses were detected with equal frequency in wheezing young children and asymptomatic controls. 60 most adenoviral illnesses consist of febrile colds, and in children the fever may be high and long-lasting. pharyngitis is common and may be associated with fever, pharyngeal exudate, granular appearance of the mucosa, and anterior cervical adenopathy, similarly to streptococcal pharyngitis. 94 adenoviruses can be recovered from up to 20% of cases of pharyngitis in small children. pharyngitis may be concurrent with pharyngoconjunctival fever, a syndrome caused by adenovirus types 3 and 7 and characterized by conjunctivitis, frequently unilateral, which may last for 1 to 2 weeks, preauricular adenopathy, cough, rhinitis, malaise, and fever. 99 the most frequent complication of adenoviral colds is acute otitis media, which occurs in up to 30% of cases. 100 adenovirus lris consist mainly of bronchitis and pneumonia, and may make up over 10% of childhood lris in temperate areas. 101 adenoviruses may cause permanent lung parenchymal damage, especially when concurrent with measles. 101 epidemic adenoviral infections in military recruits have a spectrum of clinical manifestation ranging from colds to severe pneumonia. typically, however, the manifestations are fever, pharyngeal symptoms, cough, chest pain, headache, and malaise. 98 overwhelming pneumonitis may be part of disseminated adenoviral infections in newborn infants and patients with immunodeficiencies, including acquired immunodeficiency syndrome (aids). however, the frequent concomitance of other respiratory pathogens in aids patients and the high prevalence of asymptomatic adenovirus infection shed doubt on the causal role of the adenovirus in these patients. 102 adenoviruses are also an important cause of epidemic keratoconjunctivitis. 94, 98 while most adenoviral aris are self-limited and uncommonly associated with death or permanent sequelae, 94 adenoviruses alone or associated with other pathogens have been recovered from 20% of fatal cases of lri in argentina. 103 adenoviral respiratory disease results from necrosis of cells of airway epithelia, and viremia may result in disseminated infection in immunocompromised persons. bronchiolitis, interstitial pneumonitis, and mononuclear cell infiltrates are part of the inflammatory process in the lungs. it remains unclear why certain strains are more virulent than others. for example, the genomic variant b7h was associated with the majority of fatal lower respiratory disease in south america. 95 in addition to lytic infection, adenoviruses may become latent in epithelial and lymphoid cells, which is probably important to maintaining the virus in populations. 94 a possible role of latent adenovirus in the pathogenesis of chronic airway inflammation has been suggested. 94, 96, 104 protection from adenovirus infection and disease is mainly due to type-specific neutralizing antibody, but reinfections, mostly asymptomatic, may occur. a long-lived t-cell immune response develops in most infected immunocompetent persons and is not only responsible for recovery but also is involved in tissue pathologic changes. 94 adenoviruses can be detected in respiratory, ocular, or ear secretions, but clinical correlation is required, because asymptomatic virus shedding is common. isolation of adenoviruses in cell culture with identification by if constitutes the standard diagnostic method, but direct detection of viral antigens or viral dna by pcr in clinical samples is an attractive rapid alternative. 94 rapid antigen detection by immunochromatography is around 95% sensitive in comparison with cell culture, and easily can be used in point-of-care diagnosis of adenovirus. however, both conventional and real-time pcr are more sensitive than cell culture is. 105 positive results by pcr should be interpreted with caution, given the propensity of adenoviruses to cause latency. adenoviruses cause a characteristic cpe in a variety of cell lines of human origin, and maintenance of cultures for 2 weeks combined with blind passage (i.e., passage of cells even without obvious cpe to see if it develops after passage) may increase adenovirus recovery. 3, 94 inoculation of cells by centrifugation followed by immunostaining may shorten the detection time. 106 several serologic tests can detect antibodies to the common hexon antigen. 94 however, their clinical utility is restricted. at present, there is no routine effective antiviral treatment for adenovirus infections. successful therapy of severe adenoviral infections in immunocompromised patients with iv ribavirin has been reported. 107 cidofovir has shown some efficacy in the rabbit ocular model of adenoviral infection. iododeoxyuridine and adenine arabinoside were unsuccessful in the treatment of adenoviral keratoconjunctivitis. 94 a live vaccine consisting of wild-type adenovirus packaged in enteric-coated capsules induces immunity by ensuring enteric infection without infection of the respiratory tree. this approach has been used successfully to vaccinate military recruits against adenoviruses types 4 and 7. 98 proper sterilization, hand washing, and chlorination can prevent adenovirus spread via tonometers, hands, and swimming pools. coronaviruses are enveloped viruses with distinct virion morphology, displaying widely spaced, long petal-shaped spikes at the surface, that confer a crownlike appearance, the origin of the name corona. the envelope contains a long helical nucleocapsid with single, positive-stranded rna, 27 to 32 kb in size, which is the largest known viral rna genome. 108 until very recently, only three human coronaviruses (hcovs) were known to exist: hcov-229e, hcov-oc43, and the cov associated with severe acute respiratory syndrome (sars-cov). recently, two groups in the netherlands almost simultaneously published studies that resulted in the identification of two new strains of hcov: hcov-nl63 109 and hcov-nl. 110 in addition, pcr primers directed to conserved replicase 1a sequences of animal covs led to the identification of yet another hcov detected in 8.8% of children from new haven, connecticut with symptoms of ari. this agent was designated hcov-nh and is likely to represent the same species of hcov-nl and -nl63. 111 on the basis of antigenic and genetic studies, the known human coronaviruses are distributed in three of the four coronavirus groups so far identified. hcov-229e, -nh, -nl, and -nl63 belong to group i, hcov-oc43 belongs to group ii, and sars-cov is the only known constituent of group iv, while group iii contains no known human viruses and consists only of the avian infectious bronchitis virus. coronavirus rna synthesis occurs in the cytoplasm via a negative-strand rna intermediate. the viral rna possesses a 5′ cap followed by a leader sequence and an untranslated region, with another 3′ terminal untranslated region followed by a poly(a) tail. the genome is polycistronic and the synthesis of subgenomic negative-sense rnas is done by discontinuous transcription to originate a nested set of subgenomic mrnas that share the 5′ leader sequence and overlap at the 3′ end. the envelope contains the structural proteins s (spike), m (membrane), e (envelope), and only in the case of some group ii coronaviruses, ha (hemagglutinin). the s glycoprotein contains neutralizing and t-cell epitopes and functions as the cell receptor ligand, thereby determining tissue tropism. the m protein is embedded in the envelope and interacts with the n (nucleocapsid) protein during maturation. in addition to the nucleocapsid and envelope proteins, a replicase is present in cells infected by all coronaviruses. new virions assemble by budding through intracellular membranes and are released through vesicles of the secretory pathway. 108 hcov-229e and -oc43 are considered to be second only to rhinoviruses as agents of common colds, causing infections with variable frequency, depending mainly on the detection method and season of the study. up to 35% of mild upper respiratory tract infections in adults have been attributed to hcov-229e. 112 while hcov-229e and -oc43 are documented causes of colds in temperate regions, their impact as causes of respiratory infections in tropical regions has not been defined. human coronaviruses were first isolated in england, almost 40 years ago, in human organ cultures of tracheal and nasal tissues. there have been relatively few field studies based on hcov isolation in cell culture, likely because these viruses are too fastidious to be propagated, but most respiratory isolates obtained so far have been antigenically similar to either hcov-229e or -oc43. 112 these agents have the same structural features as the other members of the family. the s protein of hcov-229e binds to the metalloprotease human aminopeptidase n at the cell surface, and entry is independent of enzymatic activity of the receptor. the hemagglutinin of hcov-oc43 binds to sialic acid present in glycoproteins on the cell surface and this interaction facilitates infection, but to the best of our knowledge, a specific receptor has not been identified for this agent. 108 hcovs have been found throughout the world and are considered to be the second most frequent cause of common cold, accounting for an average rate of 15% of respiratory illnesses in the general population in the united states. however, the rates may be quite variable from year to year, ranging from 1% to 35% in years of peak activity. hcov infections occur mainly in the winter and spring months, but summer activity has also been documented. during the autumn peak of rhinovirus activity, 8% of the adults with a cold negative for rhinovirus were positive for hcov by rt-pcr in charlottesville, va. 80 hcov-229e has caused well-documented winter outbreaks at 2-to 4-year intervals in temperate regions. 112, 113 similarly, winter outbreak of hcov-oc43 has also been detected in europe. 114 in contrast, little is known about the prevalence of hcov-229e and -oc43 in tropical countries. in brazil, the activity of hcov-229e as cause of respiratory infections in nonhospitalized children was first documented by serology in the early 1970s, with a seropositivity rate of 26% in adults by complement fixation assay. 115 the usual manifestations of hcov infection are typical common colds. the incubation period tends to be 1 day longer that that for rhinovirus colds, with illness duration of 6 to 7 days. low-grade fever may occur in up to 20% of the patients, and in addition to nasal symptoms, cough and sore throat occur frequently. more serious infections of the lower respiratory tract caused by hcov have also been documented, either sporadically in infants with pneumonia and immunocompromised patients, or in up to 33% of previously healthy marine corps recruits with pneumonia. 112, 113 in addition, hcov-229e and -oc43 have been recognized in association with influenza-like illnesses in frail elderly patients. eight of 100 (8%) nasopharyngeal swabs from older patients hospitalized for cardiopulmonary illnesses during the influenza seasonal outbreak in rochester, n.y., were positive for hcov (five for hcov-229e). 116 respiratory hcov infections have been associated with exacerbations of asthma, chronic bronchitis, and recurrent wheezing in children. 112, 113 hcov was detected by rt-pcr in 38 of 292 (13%) episodes of asthma in children 9 to 11 years old in england. 117 in brazil, hcov was detected in respiratory samples from 3 (2 oc43 and 1 229e) of 73 (4%) children younger than 2 years of age who came to the er with wheezing. 60 similarly to hrv, hcov infections have been frequently recognized in association with otitis media and maxillary sinusitis in children and adults. hcov was detected by rt-pcr in the middle ear effusion or nasopharyngeal aspirate from 16 of 92 (17%) children with acute otitis media in finland 84 and in nasal swabs from 3 of 20 adults with acute maxillary sinusitis. 83 there is no convenient small animal model to study the pathogenesis of hcov, and humans naturally or experimentally infected are the only source of information obtained in vivo. hcovs are transmitted by the respiratory route, and experimentally infected volunteers shed virus for approximately 5 days, beginning 48 hours after infection, which is approximately the time of onset of symptoms. 112, 113 the peak of symptoms occurs 2 to 4 days postinoculation. 112 hcov-229e is known to infect airway epithelial cells from the apical surface, where the receptor is constitutively expressed, and to exit productively infected cells through the same route. 118 ultrastructural studies of nasal epithelium of volunteers experimentally infected with hcov-229e revealed significantly greater epithelial cell damage, ciliary loss, and cytolysis in virus-inoculated subjects than in sham-inoculated ones on day 3 postinfection. 119 in the united states, seropositivity to hcov-oc43 and -229e rises during the first 5 years of life, and around 40% of adults are seropositive. symptomatic reinfections are possible, despite the presence of antibodies, suggesting rapidly waning immune response or circulation of closely related but antigenically different viruses. 113, 120 several studies indicate that respiratory hcovs are able to reach the central nervous system. 112, 113, 120 the recently reported temporal association between hcov-nh infection and kawaski disease 121 awaits confirmation. laboratory diagnosis in clinical samples by isolation is tedious, because the two best characterized strains of hcov are difficult to grow in routine cell cultures. since primers can be developed for relatively constant parts of the genome, rt-pcr-based assays for hcov-229e and -oc43 have recently become the best alternative to other methods of detection. 80 more recently, a quantitative real-time pcr-based assay for hcovs has been developed, providing a faster means for detection and determination of viral load with potential applications in clinical studies. 122 serologic diagnosis of hcov by eia is sensitive and specific and has been useful in epidemiologic surveys. 113 intranasal interferon protects against experimental infection with hcov-229e, 123 but no specific antiviral therapy is available, and treatment of hcov-induced colds remains largely symptomatic. no vaccines are currently available for hcov. the hcov that fulfills koch`s postulates as the causative agent of sars 127 shares structural features and genome organization of the family coronaviridae ( fig. 59-1) . the prompt recognition of the peculiar morphology of a coronavirus in the electron microscopic studies of vero e6 cells inoculated with oropharyngeal material from a patient was the initial finding that resulted in the identification of sars-cov. 128 the viral genome is 29,727 nucleotides in length, with more than 11 open reading frames coding for 23 putative proteins, some of which have unknown functions. sars-cov is phylogenetically different and equidistant from all previously known coronaviruses, but isolates from different origins are relatively homogeneous genetically. genome analysis reveals that sars-cov is neither a host-range mutant nor a recombinant of respiratory tract viral infections ■ 651 previously known coronaviruses but rather an independently emerged virus. sars-cov seems to have evolved from an animal sars-like virus, acquiring greater fitness in humans during the course of the outbreaks, probably through the appearance of nucleotide deletions in open reading frame 8. 129 it is also noteworthy that genetic signatures present in the genomes allow for differentiation of isolates obtained from different clusters. 129 the replicative cycle of sars-cov is thought to follow the same main steps as other coronaviruses. sars coronavirus (sars-cov) probably emerged around november 2002 in the province of guangdong, china, where there was no serologic evidence of infection caused by this virus in sera of healthy humans sampled prior to that time. 130 at the beginning of the outbreak, many affected individuals in guangdong were directly or indirectly involved with game trade, and indeed, palm civets and raccoon dogs from wildgame markets in the area were later found to harbor a cov 99% homologous to sars-cov at the nucleotide level. this suggests that animal-to-human interspecies transmission was involved in the outbreak, providing the source of an agent that later adapted to efficient human-to-human transmission. 131, 132 interestingly, shortly after the lifting of a wildlife trade ban that originally had been imposed to control the sars outbreak, new cases were again detected in guangdong, all of them caused by viruses newly introduced from animals. since the ban was reinstalled, there have been no further naturally acquired human cases of sars in guangdong. 131 remarkably, 1.8% of 938 serum samples from adults recruited in 2001 in hong kong tested positive for sars-cov antibodies, suggesting that a small proportion of healthy people from hong kong, as opposed to guangdong, china, had been exposed to sars-related viruses at least 2 years before the outbreak. 133 it is probable that sars-cov precursors previously crossed the species barrier and may even have caused subclinical human infection, but perhaps only occasionally this event generated strains adapted to successful human-to-human transmission. 131 sars-cov is mainly transmitted between humans by the deposition of infected droplets or aerosols on the respiratory epithelium. the number of confirmed secondary cases generated by one index case of sars is relatively low, ranging from 2.2 to 3.7, suggesting relatively inefficient transmission. in addition, transmission is infrequent during the first 5 days of illness, partly because of the low viral load in respiratory secretions during that phase. for reasons not completely understood, some sars patients, identified as superspreaders, disproportionately contribute to the generation of a high number of secondary cases. 131 excretion of sars-cov in sputa and stools may average 21 and 27 days, respectively, after symptom onset, but an excretion period as prolonged as 126 days has been documented in stools. 134 such prolonged shedding of virus in feces raises the possibility of oral-fecal transmission and, in fact, one outbreak of sars was attributed to a faulty sewage system. 131 case-fatality rates estimated based on cases admitted to hospital have been around 13% for patients younger than age 60 and 43% for those older than age 60 years. however, it is likely that case-fatality rates based on all infections occurring in the community would be lower. 135 transmission of sars-cov among health-care workers and between patients in the hospital setting played a pivotal role in outbreak propagation. analysis of data from initial outbreaks indicates that close contact is the most important factor leading to nosocomial transmission of this agent. despite the lack of complete studies on the sensitivity of sars-cov to different environmental conditions, there have been reports of sars-cov persisting for up to 2 days on environmental surfaces and 4 days in diarrheal stools. 136 the median incubation period of sars is 4 to 6 days. clinical symptoms and signs of sars appear 2 to 10 days after exposure, and systemic symptoms, such as fever, chills, myalgia, and malaise, usually appear first. respiratory symptoms appear 2 to 7 days later, represented most frequently by nonproductive cough, dyspnea, chest pain, headache, and sore throat. diarrhea and vomiting may occur. chest radiograms frequently reveal infiltrates consistent with viral pneumonitis, consisting mostly of consolidations and ground-glass opacifications. computed tomography (ct) scans in patients with normal or equivocal chest radiograms may show unilobar or multilobar abnormalities. fever generally subsides in 48 hours, but one or two relapses within 8 to 15 days are frequently observed. lymphopenia with reduction of both cd4+ and cd8+ cells, slight decrease in platelet counts, prolonged coagulation profile, and elevated serum enzymes (lactic dehydrogenase [ldh], creatinine kinase [ck], and c-reactive protein [crp]) are often observed. around one third of patients may have cd4+ lymphocyte counts below 200 cells/mm 3 and higher susceptibility to secondary infections. watery diarrhea with an average of six evacuations per day is common. 130, 131, 137 radiologic worsening of the pulmonary lesions seen at admission, with or without appearance of new lesions, is a frequent observation, with development of diffuse groundglass changes frequently heralding the development of acute respiratory distress syndrome (ards). hypoxemia is noted in approximately half of the patients at around 9 days after the onset of symptoms, and a high proportion of those admitted to the intensive care unit (icu), especially older males, require mechanical ventilation around day 13. development of spontaneous pneumomediastinum during follow-up is not uncommon, probably as a consequence of ruptured peripheral lung lesions into the pleural space. 130 prognosis is related to the level of viral replication in tissues, and patients with high viral loads in serum, nasopharyngeal aspirates, or feces, as well as those in whom virus can be detected from multiple sites, tend to have poor clinical outcome. 131 in addition to old age and severe underlying diseases, ck and crp levels have been identified as predictors of poor outcome. 138 the n-terminal portion of the spike glycoprotein is needed for virus attachment to the virus receptor, identified as the metallopeptidase angiotensin-converting enzyme homolog (ace-2), 139 but it is unclear whether the mechanism of entry is contingent on ph-dependent endocytosis. 131 some inconsistencies between ace-2 and sars-cov tissue distribution suggest that ace-2 may not be the only receptor, or that a coreceptor molecule may be needed for cell infection. sars-cov spike protein can also bind the dendritic cell-specific c-type lectin intercellular adhesion molecule 3-grabbing nonintegrin (dc-sign), which does not result in dendritic cell infection by the agent but allows for sars-cov to be transported to susceptible target cells elsewhere. 140 sars-cov has been detected in studies using different combinations of immunohistochemistry, in situ hybridization, and electron microscopy in pneumocytes and on the apical surface of enterocytes. marked inflammatory infiltrates and mucosal atrophy have not been observed in the intestine, and the pathogenesis of the sars-cov-related diarrhea remains largely unknown. 131 sars-cov viral load in the upper airways is low in the 4 initial days, with the peak at day 10 of illness. quantitative rt-pcr for sars-cov in nasopharyngeal aspirates from patients who tested positive at admission revealed viral loads around 10 5 copies/ml on days 5 and 15 after clinical onset, and peak 10 7 copies/ml on day 10. 130 higher viral loads can be detected in the lower respiratory tract than in the upper airways. pulmonary tissue shows diffuse alveolar damage, mixed infiltrate, lung edema, hyaline membrane, abundant macrophages in alveoli and interstitium, and syncytia formation. besides respiratory secretions and stools, sars-cov can be detected in urine in up to 30% of patients, with titers averaging 10 4.4 copies/ml, in association with abnormal urinalysis results. 141 the effect of sars-cov infection on the immune system is highlighted by pronounced t-cell lymphopenia and elevation of several inflammatory cytokines (il-1β, il-6, and il-12) and chemokines (mcp-1 and ip-10) observed in sars patients. while mcp-1 is likely to be involved in the lung monocytic/macrophagic infiltrate, its role is not firmly established, since other viral diseases that are associated with elevated mcp-1, such as influenza, do not include such prominent histologic features. in addition, since immunologic markers in the peripheral blood may not reflect what happens in the microenvironment of the lung, the pathogenic importance of these findings is not clear. co-inheritance of hla-b*0703 and -b60 is higher among sars patients than in the general population, favoring a role for the genetic background in susceptibility to sars-cov. 131 the pathogenesis of the t-cell lymphopenia remains unknown. seroconversion has been documented in 93% of the patients at around 20 days and the rise in igg titers correlates with decrease in viral load. 130 paradoxically, clinical worsening also occurs during this phase, suggesting that, rather than unchecked viral replication, immunopathologic factors may be responsible for the lung lesions. 130 while infection in experimental animals, such as cynomolgus macaques, ferrets, cats, golden syrian hamsters, mice, and african green monkeys, does not induce disease that mimics that in humans, these models are important for studies of pathogenesis and development of vaccines and therapy. 129 in addition, the development of an infectious cdna clone of sars-cov should permit reverse genetics experiments and may help elucidate determinants of viral pathogenesis. 142 low viral loads in the upper respiratory tract in the first few days of illness account for the relatively poor sensitivity (35% to 65%) of first-generation rt-pcr for diagnosis in that period. sars-cov is detectable by rt-pcr in nasopharyngeal aspirates in only one third of patients at presentation and in two thirds at day 14. rt-pcr may be positive for sars-cov in stools from as much as 97% of patients at day 14, and in urine in 42% of samples at day 15. 130 testing multiple nasopharyngeal, serum, and fecal samples increases the sensitivity of the diagnosis by rt-pcr. 143, 144 to overcome the low sensitivity of conventional rt-pcr, quantitative real-time pcr-based assays for sars-cov have been developed that improve sensitivity and turnaround time, allow for amplification and analysis to be done in a closed system, and thus reduce cross-contamination. in addition, the capability of the assay to quantitate viral load has contributed not only to understanding viral pathogenesis but also to predicting outcome, since high viral loads are associated with poor prognosis. 143 the ability to grow sars-cov in vero e6 cell cultures was critical to identifying the agent. sars-cov can be recovered by isolation from respiratory secretions, feces, and urine in the first 3 weeks of illness, but the overall sensitivity is relatively low and recovery is more likely to be successful from respiratory secretions than from stools and urine. 143 recent small outbreaks of sars-cov originating in laboratories 143 have heightened concern about laboratory safety issues regarding sars specimens. the who guidelines for biosafety in the diagnosis of sars (updates available at the who web site) recommend that propagation of sars-cov in cell culture for isolation or for preparation of viral stocks and cell slides be performed in biosafety level 3 (bsl3) laboratories, whereas handling serum and blood specimens for routine tests and serology can be performed in bsl2 laboratories. nucleic acid extraction procedures, inoculation of bacterial or mycologic cultures, and preparation of sample smears can be done in bsl2 laboratories, observing bsl3 work practices (use of safety cabinets, sealed centrifuges, protective equipment, 5% bleach spillage decontamination, and proper waste disposal). although not useful for early diagnosis, seroconversion determined by ifa or eia remains the gold standard for confirming sars diagnosis. igg seroconversion is detectable in over 90% of patients at around day 28. 130 antibody crossreaction with other human coronaviruses, however rare, remains a possibility; therefore, confirmation of positive serology by an independent neutralization assay should be performed if available. 143 the main component of treatment of sars patients is supportive therapy, chiefly the management of hypoxemia and ards. during the 2003 outbreak, treatment included a broadspectrum antiviral agent (ribavirin) and immunosuppressive doses of corticosteroids, aimed at reducing the immunopathologic damage to the lungs. the use of high-dose steroid therapy is controversial and for the most part supported by anecdotal evidence, whereas the use of ribavirin is based on the broad antiviral spectrum of the drug. however, sars-cov is only modestly susceptible to ribavirin in vitro, and therapeutic doses are difficult to achieve clinically. since it became possible to grow sars-cov in culture, many potential antiviral compounds have been evaluated in vitro, but just a few have been tested in animal models and even fewer are in clinical testing. 131 interferons (ifn-αn1/n3, leukocytic ifn-α, ifn-β) and hiv protease inhibitors were consistently active in vitro and may be considered for animal testing and clinical trials. 131 the resolution of the structure of sars-cov principal protease has prompted studies of the inhibitory capacity of known anti-hiv protease inhibitors for treatment of sars. in one open-label study, a combination of hiv protease inhibitor (lopinavir plus pharmacokinetic booster ritonavir) and ribavirin was used to treat sars patients and the outcomes were compared with historical controls treated with ribavirin alone. at day 21 after onset of symptoms, development of ards or death was significantly less frequent in the group treated with the combination (2.3%) than in historical controls (28.8%). in addition, peak viral loads in respiratory samples and stools were reduced in the group treated with the combination as compared with controls. 145 however, since there were differences in outcome predictors, such as sex, platelet counts, and ldh levels, between the two groups, these results should be interpreted with caution. a preliminary open-label study found that a restricted number of patients treated with subcutaneous interferon alfacon-1 in association with corticosteroids showed reduced oxygen-saturation impairment and faster resolution of radiographic chest findings than those treated with corticosteroids alone. 146 convalescent plasma has also been tested in the treatment of sars patients. in one preliminary uncontrolled study, convalescent plasma may have reduced the frequency of poor outcome when given before 14 days of illness. 147 it is impossible to predict whether naturally reemerging sars-cov would be likely to cause a global outbreak. nevertheless, a vaccine for this agent would be relevant for high-risk individuals, such as workers in laboratories, hospitals, and game-animal farming. therefore, considerable effort has been directed at developing such a vaccine. it has been shown that sars-cov spike protein produced in bacteria and expressed on chimeric parainfluenza virus, as well as spike protein-encoding dna, induced neutralizing antibodies and protected experimental animals from challenge with live virus. at present, no sars-cov vaccine is available for human use. therefore, in the absence of person-to-person transmission of sars-cov worldwide, prevention of future outbreaks of sars requires careful surveillance. the goal is to maximize early detection of new cases of sars to implement control measures, thereby minimizing social disruption. 131 to reach this goal, the cdc recommends testing for sars-cov in patients who require hospitalization for radiographically confirmed pneumonia or ards without identifiable etiology and who have one of the following risk factors in the 10 days before the onset of illness: (1) travel to mainland china, hong kong, or taiwan, or close contact with an ill person with a history of recent travel to one of these areas, or (2) employment in an occupation associated with a risk for sars-cov exposure (e.g., health-care worker with direct patient contact; worker in a laboratory that contains live sars-cov), or (3) belonging to a cluster of cases of atypical pneumonia without an alternative diagnosis (updates on these recommendations are made available at the cdc web site http://www.cdc.gov/ncidod/sars). during times of overt sars activity, prevention of humanto-human transmission is pivotal to curtailing outbreaks. although sars infectiousness relative to the onset and termination of clinical symptoms has not been accurately determined, it is clear that shortening the time from onset to hospital admission and isolation reduces the risk of transmission, thus contributing substantially to curtailing of outbreaks. identification of new cases through contact tracing played an important role in the control of the outbreaks registered so far. stringent isolation procedures must be adopted for confirmed and suspected cases, which require a high level of alertness among health-care workers for early identification of sars cases. the scenario may be further complicated in situations in which other diseases such as influenza and hantavirus pulmonary infections may occur simultaneously. 135 rates of transmission of sars-cov among health-care workers vary, depending on stringency of control measures adopted, presence of so-called superspreaders in the hospital, and kind of activities carried out by personnel, especially as related to proximity to the index case. assisting during intubation, suctioning, and manipulating ventilatory apparatuses seem to be high-risk activities. while studies conducted in different settings have produced conflicting results, one study in toronto found that up to 25% of the nurses who cared for sars patients in critical care units became infected. 148 the presence of severe watery diarrhea may add to the challenge for the infection control team. 130 an updated set of recommendations for health-care and laboratory personnel is available at the cdc web site (http://www.cdc.gov/ncidod/sars). a new paramyxovirus was described in the netherlands in 2001, in association with respiratory illness in children. the agent was first detected by analysis of previously unidentifiable viral isolates that induced cytopathic effect in llc-mk2 cell cultures. the isolates were recovered over a 10-year period in respiratory secretions from 28 children with ari occurring in the winter time. electron microscopy of cell culture isolates revealed paramyxovirus-like particles, and rna sequencing revealed genome sequences and organization consistent with a paramyxovirus of the subfamily pneumovirinae, most closely related to avian pneumovirus of the genus metapneumovirus. rather than an avian virus that can also infect humans, this agent is now recognized as a primarily human pathogen, and thus has been named human metapneumovirus (hmpv). 156,157 hmpv antibodies detected in sera collected in 1958 in the netherlands indicate that this agent has been in circulation for at least 4 to 5 decades. 156 agent hmpv particles are enveloped, pleomorphic, spherical, and filamentous particles, with a mean diameter of about 209 nm. 156,157 complete genome sequences of hmpv are available and, in contrast to the genomic organization of pneumoviruses, metapneumoviruses have different positioning of the genes between m and l and lack ns1 and ns2 genes. 156,158 similar to hrsv, genetic and antigenic studies indicate that hmpv isolates cluster into two main serotype named a and b, with n gene sequences 83% to 85% similar at the nucleotide level, each subgroup including two genetic lineages (a1, a2, b1, and b2). 156, 159, 160 both are globally distributed. there have been no detailed studies of the hmpv replication cycle, but it is likely to be similar to that of other human paramyxoviruses. hmpv is a frequent cause of community-acquired ari in children and adults in all continents, although with variable incidence in different settings. 157, 159, [161] [162] [163] [164] [165] [166] [167] [168] [169] in the united states, hmpv has been reported in up to 20% of lower respiratory tract illnesses whose etiology would have been unidentifiable prior to the development of assays for the detection of hmpv. 170 in canada, during the 2001-2002 winter season, hmpv was detected in 15% of patients of all age groups from four different provinces. 167 similar to hrsv, hmpv infections are more frequent in the colder months in temperate regions, and different strains of both subgroups a and b cocirculate during the same year. 157, 162 however, only limited knowledge is available about hmpv seasonality in more tropical climates. peaks of hmpv activity have been documented in the spring/summer in hong kong, 171 while in south africa hmpv has been detected in 6% to 9% of children with ari admitted to hospitals in the winter season. 161 ,165 hmpv was detected alone or simultaneously with rsv in 24% of children younger than 3 years of age admitted to health-care facilities in aracaju, northeast brazil, in the months of april and may, 2002. 164 interestingly, hmpv was not detected by the same methods in that same city, in the following year. 166 this apparent variability in hmpv incidence from year to year has also been observed in studies conducted in argentina 168 and italy, where hmpv frequencies varied from 7% to 43% in three consecutive annual respiratory virus seasons. 172 long-term prospective studies will be needed to establish whether there is a seasonal pattern in hmpv circulation in tropical regions of the world. clinically, hmpv infections resemble closely those caused by hrsv, ranging from mild upper ari to severe bronchiolitis and pneumonia. the median age of children hospitalized with hmpv infection is older than those with hrsv. hrsv in hospitalized infants and young children may require intensive care and mechanical ventilation, 156,173,174 and dual infection with hmpv and hrsv appears to increase the likelihood of severe illness. 175, 176 the most frequent symptoms in all age groups are fever, dyspnea, cough, wheezing/stridor, rhinitis, and sore throat. 162, 173 all infected children in one study had either pneumonia or bronchiolitis, frequently accompanied by otitis media. 162 hmpv may cause more serious infections in patients with comorbid or immunosuppressive conditions, as well as in the very young and the elderly. 162, 167 in one study, all individuals older than 65 with lower respiratory infection caused by hmpv had at least one underlying chronic or debilitating condition, including lymphoma, leukemia, or neurologic or cardiovascular diseases. 162 hmpv infection in adults may present as influenza-like illness, acute bronchitis, or common cold. 162 in england, in the winter of 2000-2001, hmpv was detected by rt-pcr in association with 2.2% of samples taken from patients in all age groups with influenza-like illnesses negative for hrsv and influenza viruses. 159 hmpv has been increasingly recognized as cause of acute wheezing in children. one study conducted in finland found hmpv in 8% of wheezing children, who presented significantly higher levels of il-8 in nasal secretions as compared to children with hrsv-associated wheezing. 174 a study conducted in brazil found that 47% of the children with hmpv had wheezing and 31% had chest indrawing. 164 previous history of asthma has been more frequently associated with hmpv than with hrsv infection and hmpv-infected patients are more often treated with bronchodilators and corticosteroids than hrvs-infected patients. 173 little is known about specific mechanisms of pathogenesis and host immune response in hmpv infections. hmpv is a pathogen of both the upper and lower respiratory tracts. 162 hmpv replicates efficiently in the respiratory tract of monkeys, with virus shedding peaking between days 2 and 8 following infection. 156 serologic data indicates that hmpv infects young individuals, and by the age of 5 virtually all children have become seropositive for the agent; reinfections at later ages are common. 156, 157, 159 interestingly, coinfection with hmpv has been reported to correlate with increased severity of hrsv infections. a study conducted in the united kingdom found that this coinfection caused a tenfold increase in the relative risk of admission to the icu for mechanical ventilation in children under 2 with hrsv bronchiolitis. 173 a similar finding was also reported in germany. 176 hmpv can be isolated in llc-mk2 cells from nasal aspirates or nasopharyngeal swabs. the cytopathic effect, characteristically negative on hemadsorption testing, develops usually late after inoculation (up to 23 days). 160 sensitive rt-pcr assays for this agent have been developed in many different laboratories and have rapidly become standard for hmpv diagnosis. 159,169 a real-time pcr assay for hmpv showed to be more sensitive than conventional rt-pcr, even when hybridization was used to increase sensitivity of the detection of amplicons generated by the conventional method. 169 using real-time pcr, hmpv was detected in 10% of 329 samples collected from patients with ari in australia from march to october 2001 that were negative for other pathogens. 169 other than supportive measures, oxygen therapy, bronchodilators, corticosteroids and mechanical ventilation, there is no specific antiviral treatment for this agent. 173 ribavirin is inhibitory for hmpv in vitro. 176 although a hmpv vaccine is not available at this time, the demonstration that hamsters, ferrets, and 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metapneumovirus and human respiratory syncytial virus is strongly associated with severe bronchiolitis prospective study of human metapneumovirus infection in children less than 3 years of age identification of small animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hmpv) and implications for hmpv design were protected from challenge with either a or b hmpv serotypes opens possibilities for hmpv vaccine design. 176 humanized neutralizing monoclonal antibody to f protein is active in experimentally infected animals. 177 key: cord-303741-1ou0cy5k authors: stafstrom, carl e.; jantzie, lauren l. title: covid-19: neurological considerations in neonates and children date: 2020-09-10 journal: children (basel) doi: 10.3390/children7090133 sha: doc_id: 303741 cord_uid: 1ou0cy5k the ongoing worldwide pandemic of the novel human coronavirus sars-cov-2 and the ensuing disease, covid-19, has presented enormous and unprecedented challenges for all medical specialists. however, to date, children, especially neonates, have been relatively spared from the devastating consequences of this infection. neurologic involvement is being increasingly recognized among adults with covid-19, who can develop sensory deficits in smell and taste, delirium, encephalopathy, headaches, strokes, and peripheral nervous system disorders. among neonates and children, covid-19-associated neurological manifestations have been relatively rare, yet reports involving neurologic dysfunction in this age range are increasing. as discussed in this review, pediatric neurologists and other pediatric specialists should be alert to potential neurological involvement by this virus, which might have neuroinvasive capability and carry long-term neuropsychiatric and medical consequences. severe and at times fatal symptoms caused by the novel human coronavirus, severe acute respiratory syndrome (sars)-cov-2, and the associated coronavirus disease 2019 (covid19) , are ravaging the world. while symptoms of covid-19 are primarily pulmonary (fever, dry cough, fatigue, pneumonia), it is becoming increasingly recognized that multiple organ systems can be affected, including the brain, with neurological involvement affecting up to~36% of patients [1] [2] [3] [4] [5] . information gained from studies of related coronaviruses in recent epidemics of severe acute respiratory syndrome (sars, 2002) and middle east respiratory syndrome (mers, 2012) suggests that all three coronaviruses might have neurologic consequences [6, 7] , though the relative severity and frequency of neurologic involvement caused by coronaviruses varies and thus the extent to which sars and mers epidemics inform our understanding of covid-19 remains unclear [5] . nevertheless, the possibility has been raised that sars-cov-2 could invade the brain and cause neurological disease [2, 8] . while appealing conceptually, data supporting the idea that the sars-cov-2 virus can infect the peripheral and central nervous systems (pns, cns) are limited, as discussed below. table 1 lists definitions of relevant terms that are often used in the literature. neurotropic viruses vary in their invasiveness, virulence, and propensity to cause inflammation [9] . the purpose of this review is twofold: (1) to discuss the available data about covid-19 infections in neonates and children, and (2) to provide a perspective about potential neurologic involvement in neonates and children with covid-19 infections, in view of neurobiological development. a few points need clarification up front. first, data about the virus and its effects are accumulating rapidly and our understanding of its consequences will evolve over time. second, much of the literature about covid-19 currently exists as case reports or small series; obviously, the impact of such publications is limited, and greater understanding will emerge only as large, rigorous studies are published. third, we must be mindful that a positive test for sars-cov-2 in a patient with a neurological symptom does not necessarily imply that the virus caused the symptom. the covid-19 epidemic has escalated rapidly and spread widely across the globe, with cases continuing to accrue at an alarming rate. the first case was reported from wuhan, china in mid-december 2019 and three months later, in march 2020, the world health organization declared covid-19 a pandemic. as of this writing (late august, 2020), more than 23 million cases of covid19 have been documented worldwide (with many more mildly symptomatic cases likely not reported), with over 800,000 deaths, and more than 175,000 deaths in the united states alone (www.cdc.gov, accessed 24 august 2020). documentation of the numerous clinical presentations, manifestations, and disease course have proliferated in the medical literature. a pubmed search (23 july 2020) using the keyword covid-19 revealed an astounding number of published reports already (34, 310) , over the course of only a few months. of those citations, only 501 reports (1.5%) also included the keyword neonate, attesting to the low published incidence in newborns. when searching pubmed with the key terms covid-19, neonate and neurological or brain, fewer than 10 articles emerged. therefore, at least so far, covid-19 does not seem to be affecting neonates very often from a neurological point of view; pubmed counts probably underestimate the occurrence of neurological involvement in children, being biased toward areas of the world with greater medical resources. these observations do not preclude the potential for neonatal brain involvement in covid-19 nor exclude the possibility of long-term medical, neurodevelopmental, and psychosocial consequences of the disease. indeed, as time goes on, a wider spectrum of neurologic manifestations will likely emerge with as yet undetermined long-term sequelae. as the covid-19 pandemic continues, certain trends are becoming evident. first, while the number of cases and deaths continue to rise, the disease does not affect infants and children nearly as frequently as adults [9, 10] . to date, approximately 2-5% of cases of covid-19 involve children, who appear to be less severely affected than adults, mainly with pulmonary symptoms [11] [12] [13] . second, disease severity in children who develop covid-19 is usually milder than in adults, and children with severe disease often have an underlying co-morbidity such as immunosuppression [10, 14] . indeed, there is accumulating evidence that adults with covid-19 infection manifest with multiple organ system involvement, including the cns and pns, and that older and sicker individuals carry a higher risk for neurologic problems [1, 4, 15] . these age-dependent differences in disease expression and severity have clear implications for healthcare professionals who deal with the pediatric population because children remain at risk for incurring and spreading the virus, yet many remain asymptomatic. several hypotheses have been posited as to why children are less affected by covid-19, including age-related differences in immune responses [16] , a neutralizing antibody response due to prior exposure to coronaviruses [17] , lower prevalence of co-morbidities in children, and age-specific differences in sars-cov-2 receptor function [18] , neurovirulence, intrinsic biological protective mechanisms, and other host factors [19] . none of these hypotheses is supported compellingly by extant data at present. while the number of affected neonates and children remains small, pediatric practitioners cannot become complacent about the potential for neurologic involvement in covid-19. furthermore, the recently described multisystem inflammatory syndrome-children (mis-c), raises the specter that covid-19 or its after-effects also target children (see section 4) [20, 21] . as data from china, europe and other areas affected early by the covid-19 pandemic are reported, some patterns are emerging regarding pregnant women and neonates. first, it is clear that vertical transmission covid-19 from a pregnant mother to her fetus occurs quite rarely. more than a dozen publications attest to this observation, together encompassing over 100 patients (table 2 lists a few relevant publications, selected from the largest available series and omitting small series and single case reports). none of these reports documents unequivocal vertical transmission. in many of the babies, onset of symptoms occurred in the neonatal period but not immediately at birth, so the exact timing of infection remains uncertain. overall, the data does not support robust transplacental transfer of sars-cov-2, but recent case reports are providing proof-of-principle that the virus can be transmitted intrauterine from infected mother to fetus [22, 23] . an especially apropos case demonstrated maternal viremia, placental infection shown by immunohistochemistry, and high placental viral load with subsequent neonatal viremia, implying transplacental transfer of sars-cov-2 from pregnant mother to fetus [24] ; this newborn presented with neurological symptoms as discussed in section 3. of all the infants reported during the first month of life, most had documented exposure to affected family members [13, 32] which emphasizes the importance of controlling horizontal virus transmission from affected family members to the neonate [33] . while this trend may need revision [27, 34] , so far, it is encouraging that most covid-19-positive pregnant women do not transmit the disease to their unborn children. similarly, there is no evidence that covid-19-positive pregnant women incur covid-19 or develop more severe disease than similar-aged women who are not pregnant. however, the impact of chronic inflammation caused by maternal viral infection on fetal development, pregnancy outcomes and long-term neurodevelopment is unknown. similarly, the timing of maternal viral infection with respect to major milestones of in utero neurodevelopment (i.e., second trimester vs. late third trimester) is an unknown and critical consideration for further research and long-term neurodevelopmental followup. there is legitimate concern about the impact of acute and chronic stress during the pandemic (i.e., worry about the medical complications of sars-cov-2 infection, family disruption, job loss, economic pressures, educational uncertainties, food availability, etc.) on the pregnant patient and developing fetus [35] [36] [37] [38] . furthermore, it is reassuring that there is no definitive evidence that the virus is present or can be transmitted in the breast milk of covid-19-positive women [28, 39, 40] . the current american academy of pediatrics recommendation is that covid-19-positive mothers can breast feed directly while wearing a mask or feed expressed breast milk, using appropriate breast and hand hygiene [41] . extensive guidelines are available regarding principles of management of pregnant women with covid-19 and their newborns [40] [41] [42] . again, all of these observations are preliminary and subject to modification over time. although covid-19 primarily affects the pulmonary system, it is a multisystem infection (e.g., gastrointestinal tract, kidneys, liver, heart) and involvement of the pns and cns are increasingly recognized [43] [44] [45] [46] . data on neurological signs and symptoms are limited but increasing, with a wide spectrum of acute and chronic manifestations becoming apparent [47] . in a series of 214 hospitalized adults with covid-19, 88 of whom had "severe" infections, 36.4% of the entire group was reported to manifest some neurologic involvement, including alteration of consciousness, encephalopathy, headache, cerebrovascular disease, and skeletal muscle injury (myalgia, weakness) [1] . ischemic strokes, many affecting young adults with large vessel occlusions, have garnered considerable concern that the etiology may be a prothrombotic state caused by virus-induced inflammation of the vascular epithelium [48, 49] . many of the young adult stroke victims had other vascular risk factors such as diabetes or hypertension, which emphasizes the importance of comorbidities with systemic inflammatory conditions in disease manifestations and severity. stroke has not been reported in children with covid-19 [50] . the occurrence of encephalitis remains controversial, as virus has not been recovered from cerebrospinal fluid (csf) [51] and overall, a surprisingly small number of covid-19 patients develop classic encephalitic symptoms. autopsy studies are beginning to be published. the wide spectrum of postmortem findings include mostly secondary changes to the cns such as hypoxemia and ischemia, rarely localized perivascular and interstitial neuroglial activation with neuronal loss and axonal degeneration [52, 53] , and no other major cns abnormalities [54] . no pediatric autopsy cases have reported neuropathological involvement. clearly, more data are needed before this issue can be clarified. in the chinese series [1] , only 2 out of 214 patients had seizures (1%), which is not greater than the general population, so it is uncertain whether infected patients are at higher risk. the few patients with seizures are reported mainly in case reports [55, 56] . the lack of frequent seizures is rather curious, especially if encephalopathy is indeed a frequent complication of covid-19; this data may be related to sampling bias rather than actual non-occurrence. a few reports of seizures have appeared in adults using electroencephalography (eeg) [57, 58] , but a more concerted effort to evaluate the brain electrophysiology of children with covid-19 would be informative. the examples of seizures in children with covid-19 described in section 3.6 appear to be largely anecdotal. many additional cases are necessary to conclude whether there is increased seizure susceptibility in the pediatric population. other cns symptoms include headache, dizziness and delirium, all of which can occur as a nonspecific consequence of systemic infection or inflammation of the respiratory tract as well as via a cns mechanism. although headaches are reported frequently, the pain often appears to be nonspecific or associated with inflammation or migraine exacerbation rather than meningeal irritation [59] . the most commonly reported symptoms related to the pns are decreased taste (hypogeusia or ageusia) and smell (hyposmia or anosmia) [60, 61] . a neural mechanism is suspected for hyposmia in covid-19, because decreased smell is often the first symptom experienced and occurs in mild disease in the absence of significant local inflammation or mucosal congestion that are typical of the more benign coronavirus or non-coronavirus nasal infections [62] . a few adolescents with covid-19 have been reported with decreased taste or smell [63] ; these symptoms appear to be very uncommon in children but deserve a more concerted ascertainment effort. several cases of guillain-barré syndrome (gbs) have been reported in adults with covid-19, raising the possibility of post-infectious autoimmune responses against the pns [64, 65] . two case reports of children with gbs who developed covid-19 symptoms about 3 weeks later confirms that gbs can occur with covid-19, though this association remains quite rare given the widespread prevalence of covid-19 [66, 67] . finally, the possibility of central demyelination has been raised, e.g., in the form of multiple sclerosis (ms), among patients with covid-19 [68] ; this concern is relevant in that various disease-modifying agents used to treat ms could theoretically exacerbate ms symptoms [69] . fortunately, there is no evidence that covid-19 triggers central demyelinating disease in children [50] . the lack of unequivocal reports of sars-cov-2 being recovered from the csf of individuals affected with presumed neurological involvement nor in brain tissue from the limited number of autopsied cases strengthens the possibility that the virus does not often directly cause the symptoms but rather, that the neurological sequelae are secondary to hypoxia, cytokine involvement, or some other non-direct mechanism (see section 6). it is appropriately concerning that chronic neurologic diseases such as epilepsy, amyotrophic lateral sclerosis, multiple sclerosis, etc., might be exacerbated during concurrent covid-19 infection or that covid-19 may unmask preexisting cns pathology that might have been unrecognized or asymptomatic. as just discussed, neurologic involvement in children, and in particular neonates, with covid-19 appears to be scarce but may be under reported [70] . a few selected examples of case reports of neurologic involvement in neonates and children are presented in table 3 ; such case reports have limited generalizability, and many lack sufficient details to ascribe causality between sars-cov-2 and neurologic symptoms. most children were assumed to have contracted covid-19 from a family member and some children had concurrent infection with other viruses, confounding any argument for causality. importantly, csf was negative for sars-cov-2 in all children on whom spinal fluid was obtained. all children recovered within a few days or weeks, contrasting with the severe and prolonged courses in many adults. available evidence does not allow distinction between a direct effect of sars-cov-2 causing neurologic dysfunction, versus the symptoms instead being secondary to an over activated immune response (see section 5) . in summary, case reports of neurological involvement in babies and children are rare but accumulating, and the recovery of most infants with early neurologic symptoms implicates some virus-or host-related factors that minimize massive neurological devastation. this newly recognized kawasaki syndrome-like hyperinflammatory disorder presents with acute hypotension and cardiogenic shock and is proliferating across the globe. it is likely a post-infectious syndrome or inflammatory reaction following asymptomatic or mildly symptomatic covid-19 [76] . children can develop toxic shock-like symptoms, hypoxia-ischemia, and significant end organ damage to the heart, kidneys, and other organs. while definitive data is not available, there is concern that the inflammation that hallmarks mis-c may have adverse consequences on the developing brain. while no consistent neurologic picture has emerged, several mis-c patients have had cns involvement as part of their course. in a small series of 6 children with mis-c, 4 patients had neurologic symptoms, including headache, altered mental status, and aseptic meningitis [77] . headache was the most common symptom in a series of 58 children with mis-c associated with sars-cov-2, affecting 26% of patients [78] . a series 21 children from france notes that 57% of patients were "irritable" and another 29% had "other neurological features", though these were not specified [79] . in a larger survey of 186 children, 5-11% had neurologic involvement, depending on age, including encephalitis, seizures or mental status alteration, but details are not provided [80] . finally, 4 of 27 children with covid-19 associated mis-c developed new neurologic symptoms including encephalopathy, headache, weakness, ataxia, and dysarthria [81] ; two patients had lumbar punctures and csf was negative for sars-cov-2 in both. three of the four patients had an eeg; each showed diffuse slowing. brain mri scans of all four children showed abnormal signal intensities of the splenium of the corpus callosum (a finding seen in previous cases of encephalopathy and thought to indicate inflammation-induced focal myelin edema [81, 82] . a recent systematic review of eight studies notes neurological symptoms in~25-50% of children with mis-c, depending upon inclusion criteria [83] . a putative impact on the immature cns and developing immune system, including neural-immune maturation, cannot be overlooked, and the long-term neurologic impact of both covid-19 and mis-c on the developing brain need urgent elucidation. sars-cov-2 is a highly contagious and pathogenic rna virus that is transmitted via droplet, contact, or aerosol routes. the virus gains entry into epithelia of the pulmonary system (upper or lower respiratory tracts), digestive tract, or nasopharynx. the virus is composed of single-stranded rna enveloped by surface proteins (s, e, m, n). the spike (s) glycoprotein serves as the attachment site onto angiotensin converting enzyme type 2 (ace-2) receptors on epithelial membranes. the normal function of ace-2 receptors is to provide protection against pulmonary and endothelial injury [84] . sars and sars-cov-2 share~79% genome sequence identity and both viruses infect epithelium by the binding of spike proteins to ace-2 receptors. while most prevalent on airway and pulmonary epithelium [85] , ace-2 receptors are also reportedly present to a lesser degree on neurons and perhaps glia [2] . binding of the s protein to ace-2 receptors leads to proteolytic cleavage of s by the transmembrane protease tmprss2 [5] . viral rna then enters the epithelial cell and replicates rapidly, translating viral proteins and inducing a host immune response. this immune response can be adaptive, attacking and inactivating the virus. by contrast, the immune response can be maladaptive and induce a massive immune reaction, accompanied by a hyper-inflammatory response hallmarked by excessive cytokine secretion and signal transduction (cytokine storm), and robust cellular immune activation and recruitment [86] . the large-scale cytokine storm consists of a massive release of pro-inflammatory humoral agents such as interleukin-6 (il-6), interferon gamma (ifn-y), mcp-1/ccl2 (monocyte chemoattractant protein 1/chemokine ligand 2), il-1, il-12, il-8, tnfα (tumor necrosis factor alpha), and cxcl 10 (c-x-c motif chemokine ligand 10) that exacerbate the underlying pathophysiology [87, 88] . this cytokine release subsequently feeds forward an overactive and dysregulated cellular immune response defined by macrophage, monocyte, neutrophil, and t-cell hyperactivation and recruitment [89] . the impact of this systemic cytokine storm on neurodevelopment is under investigation in preclinical models [90] and should be the focus of future prospective studies. subsequently, the replicated viruses exit the cell, leading to further infection. it is unknown why children, and neonates in particular, seem to be relatively resistant to covid-19 and its severe symptoms, including neurological manifestations. the cytokine response to coronavirus infection appears to be less robust in young children although the recognition of mis-c may suggest host-dependent genetic susceptibility to enhanced cytokine and/or inflammatory responses [91] , but other mechanisms are also plausible [19] . it remains controversial whether ace-2 inhibitors would provide symptomatic relief or prevent the covid-19 disease, and evidence for the effectiveness of these agents in children and neonates is not yet available [92] . the cellular and molecular basis of sars-cov-2 neurotropism, neuroinvasiveness, and neurovirulence are poorly understood [9] : does the virus get into the brain and if so how, and what does it do in the cns once there (e.g., infects neural cells? causes disease?). neurological involvement in covid-19 might be associated with at least four potential mechanisms: 1. a direct neurotropic or neuroinvasive effect of sars-cov-2 (e.g., anosmia, encephalopathy), 2. a secondary effect of the systemic inflammatory responses triggered by the viral infection (e.g., encephalopathy), 3. a secondary effect associated with the vascular and prothrombotic effect of the viral infection on the cns or pns vasculature (e.g., strokes, necrotizing leukoencephalopathy), 4. an immune-mediated para-infectious or post-infectious autoimmune effect in response to the viral infection (e.g., gbs, acute disseminated encephalomyelitis). figure 1 summarizes, in schematic fashion, some hypothetical possibilities about how the virus may infect the brain directly, whether the neurological symptoms and signs may be related to systemic or hyperactivation of immune responses, or both [87] . it is important to consider the mechanisms associated with neurological manifestations of covid-19, with an aim toward developing therapeutic options. the possibilities of direct neurotropism and hyper-responsiveness to immune activation (cytokine storm) are considered separately below, though these mechanisms might work synergistically. the sars-cov-2 virus attaches to olfactory epithelium using the ace-2 receptor. after cell entry, the virus replicates and induces a massive immune response leading to excessive cytokine release, comprising a maladaptive immune response. theoretically, virus particles may reach the cns retrogradely via cranial nerve pathways: v from corneal epithelium or oropharyngeal cutaneous sensory receptors; i via the cribiform plate, infecting olfactory sensory neurons; vii and ix from tongue chemoreceptors; x via pulmonary mechanoreceptors. once reaching cns nuclei including brainstem and cortex, a variety of neurologic signs and symptoms are possible. however, it must be noted that the virus has not been recovered from csf or brain tissue, making all of these pathways hypothetical at this point. abbreviations: np, nasopharynx; gi, gastrointestinal; ace-2, angiotensin converting enzyme type 2 receptor; pns, peripheral nervous system; cns, central nervous system; ich, intracranial hemorrhage; gbs, guillain-barre syndrome; bbb, blood-brain barrier. definitive demonstration of direct viral invasion would require a positive csf reverse transcriptase-polymerase chain reaction (rt-pcr) for sars-cov-2, recovery of infective virus from the csf as demonstrated by viral cultures or "plaque assay" [93] , intrathecal synthesis of antibodies to sars-cov-2, or autopsy-demonstrated sars-cov-2 antigen or rna in brain tissue [5] . current published evidence meeting these strict criteria is minimal. while it is plausible that the virus infects the brain through one of the anatomical pathways discussed below, the lack of viral recovery from the cns gives pause to that notion. neuroinvasion has been demonstrated for the related sars and mers viruses [94] , but sars-cov-2 has not been recovered from the csf or brain tissue. animal models of sars and mers have shown that the virus can enter through epithelium of the nasopharynx and travel retrogradely to the cns [95, 96] . interestingly, wild type mice are not vulnerable to infection and disease by human coronaviruses, but transgenic mice with human ace-2 receptors do develop respiratory and neurological symptoms when infected [95, 97] . in such transgenic mice, intranasal exposure to sars or mers leads to brain infection. one of the proposed portals of entry is via olfactory sensory neurons, crossing the cribiform plate into the olfactory bulb, with subsequent retrograde travel along the olfactory nerve (cranial nerve i) to the brainstem, thalamus, and basal ganglia, all areas that are connected to the olfactory cortex. please note that it has yet to be proven that sars-cov-2 infects olfactory sensory neurons. emerging animal models may clarify whether sars-cov-2 is similarly neuroinvasive as sars and whether this isage dependent the sars-cov-2 virus attaches to olfactory epithelium using the ace-2 receptor. after cell entry, the virus replicates and induces a massive immune response leading to excessive cytokine release, comprising a maladaptive immune response. theoretically, virus particles may reach the cns retrogradely via cranial nerve pathways: v from corneal epithelium or oropharyngeal cutaneous sensory receptors; i via the cribiform plate, infecting olfactory sensory neurons; vii and ix from tongue chemoreceptors; x via pulmonary mechanoreceptors. once reaching cns nuclei including brainstem and cortex, a variety of neurologic signs and symptoms are possible. however, it must be noted that the virus has not been recovered from csf or brain tissue, making all of these pathways hypothetical at this point. abbreviations: np, nasopharynx; gi, gastrointestinal; ace-2, angiotensin converting enzyme type 2 receptor; pns, peripheral nervous system; cns, central nervous system; ich, intracranial hemorrhage; gbs, guillain-barre syndrome; bbb, blood-brain barrier. definitive demonstration of direct viral invasion would require a positive csf reverse transcriptase-polymerase chain reaction (rt-pcr) for sars-cov-2, recovery of infective virus from the csf as demonstrated by viral cultures or "plaque assay" [93] , intrathecal synthesis of antibodies to sars-cov-2, or autopsy-demonstrated sars-cov-2 antigen or rna in brain tissue [5] . current published evidence meeting these strict criteria is minimal. while it is plausible that the virus infects the brain through one of the anatomical pathways discussed below, the lack of viral recovery from the cns gives pause to that notion. neuroinvasion has been demonstrated for the related sars and mers viruses [94] , but sars-cov-2 has not been recovered from the csf or brain tissue. animal models of sars and mers have shown that the virus can enter through epithelium of the nasopharynx and travel retrogradely to the cns [95, 96] . interestingly, wild type mice are not vulnerable to infection and disease by human coronaviruses, but transgenic mice with human ace-2 receptors do develop respiratory and neurological symptoms when infected [95, 97] . in such transgenic mice, intranasal exposure to sars or mers leads to brain infection. one of the proposed portals of entry is via olfactory sensory neurons, crossing the cribiform plate into the olfactory bulb, with subsequent retrograde travel along the olfactory nerve (cranial nerve i) to the brainstem, thalamus, and basal ganglia, all areas that are connected to the olfactory cortex. please note that it has yet to be proven that sars-cov-2 infects olfactory sensory neurons. emerging animal models may clarify whether sars-cov-2 is similarly neuroinvasive as sars and whether this isage dependent [97, 98] . however, since mice are not naturally susceptible to the clinical and immunopathological manifestations of coronaviruses affecting humans, translational studies of pathogenic mechanisms and vaccine development become complicated. extensive efforts to modify mice with transgenic approaches have begun to provide informative models. as mentioned, the olfactory epithelium has been touted as a potential site of viral entry into the brain, and hence explain hyposmia [99] .detailed genetic and immunohistochemical examinations of cell types of the olfactory system reveal that ace-2 and tmprss2 are present on olfactory epithelial cells (especially supporting or "sustenacular" cells) but not on olfactory sensory neurons themselves [54, 85, 100] . moreover, there is some evidence of virus-induced cell death in other coronavirus infections but not yet for sars-cov-2 [84, 101] . likewise, the virus might enter via the sensory system of the tongue that mediates taste, with transmission via cranial nerves vii, ix, and x to the nucleus tractus solitarius, thalamus and eventually, brain. finally, trigeminal nociceptors via cranial nerve v from either the corneal epithelium or buccal epithelium could theoretically reach the cns. these potential pathways could explain the symptoms of hypogeusia and altered vision. however, sars-cov-2 has not been recovered from the brain. transynaptic transport from lower respiratory tract mechano-and chemoreceptors to the brainstem medullary cardiorespiratory centers has been proposed as a hypothetical mechanism that could exacerbate brainstem dysfunction and perhaps even worsen respiratory effort [102] ; however, this hypothesis lacks objective validation and remains controversial. other potential routes for virus to enter the cns are through the bloodstream (hematogenous) or via disruption of the blood brain barrier (bbb). from the systemic circulation, the virus might travel to the cerebral circulation where it can damage capillary epithelium and access the brain. interestingly, there is scant evidence that sars-cov-2 produces a significant or sustained viremia [103] . the bbb is essential for transport of molecules into the brain and exclusion of pathogens and overall maintenance of cerebral homeostasis [104] . the bbb is a dynamic structure, consisting of several cell types and proteins, each with its own maturational profile-astrocyte foot processes, pericytes, tight junction proteins, and extracellular matrix, providing structural and functional support. virus attachment to ace-2 receptors at the bbb might facilitate trafficking of the virus into the cns, facilitating endothelial damage and edema [89] . notably, while the bbb is structurally complete at birth and is sufficiently functional in the neonate to provide protection against many pathogens, its full physiological maturation may take several months [105] . in the context of covid-19 infection, the bbb may be dysfunctional, disrupted either by inflammatory response or the virus itself, allowing transmission of the virus or activated immune cells from the circulation into the cns [8, 84] . the release of inflammatory cytokines by activated glia and neural mast cells exacerbate the inflammation [89] . similarly, flow of the virus through lymphatic channels of the interstitial space of the brain could breach the blood-csf barrier and permit virus entry [106] . to date, there is no evidence for the presence of the virus in pathological specimens of the pns or cns, in part due to the dearth of comprehensive autopsies [52] [53] [54] . obviously, patient care has focused on critical pulmonary and life-support measures so neuropathologically-focused autopsy studies have been uncommon. animal studies of covid-19 will be crucial to complement information gained from prior studies of the other coronaviruses. such animal models will provide more information about mechanisms of virus entry into the nervous system and how the virus affects neural function, neural-immune maturation and neurodevelopment, as well as the critical and yet unanswered question of long-term neurological sequelae of covid-19 [107] . that is, if there is predilection of the virus for certain neural structures or chronic neuroinflammation, long-term consequences may arise in various neural functions such as learning, memory, cognition, seizure predisposition, and other functions. all of this is speculative at present. another essential question, alluded to above, is whether cns disease contributes to the respiratory failure seen in covid-19 patients. ongoing or severe hypoxia can exacerbate ongoing symptoms in other organs. in particular, cns respiratory control centers in the brain stem, nearby the vagus nerve, has been speculated to play a role in respiratory failure [102, 108] . at present, there is some reason for guarded optimism for young patients within the devastating covid-19 pandemic. children, particularly neonates, are less likely to become infected and develop severe symptoms, and their propensity to spread the virus is controversial [109] . there is at best slight evidence for vertical transmission of sars-cov-2 or covid-19 disease from pregnant mother to fetus; rather, neonates are more likely incur the disease by exposure to affected individuals postnatally, and breast milk transmission has not been shown (table 4) . a variety of practical guidelines have been developed for the care of pregnant women who have or are suspected to have covid-19 positivity. analogous guidelines for the care of adult covid-19 patients with neurologic problems are also available and need to be developed for children [110] . table 4 . summary of covid-19 infections in children. severe infection caused by the novel coronavirus, sars-cov-2, has predominant pulmonary involvement but can also affect multiple other organ systems, including the cns and pns. symptoms are less frequent and usually less severe in children and particularly in neonates. vertical transmission of sars-cov-2 from pregnant mother to fetus is rare but anecdotal case reports support this possibility. most cases of covid-19 in early life are due to exposures to infected patients (horizontal transmission). there is no reported transmission of sars-cov-2 via breast milk. regarding neurologic involvement in covid-19, there are plausible mechanisms by which the virus can gain entry into the cns and subsequently incur acute neurologic symptoms, either directly or through immune dysfunction ( table 5 ). the occurrence of long-term medical and neuropsychiatric sequelae is unknown. children can be resilient and yet remain vulnerable to coping with the challenges of covid-19 in the context of other acute and chronic diseases. youngsters may not understand the need for social distancing, prolonged quarantine, and other preventative measures, and it is anticipated that stress-related post-traumatic symptoms will develop in some young people, whether or not they actually acquire symptoms. in children with comorbid chronic conditions and developmental disabilities, the challenges are even more profound. therefore, neuropsychological surveillance and studies of the long-lasting effects of this pandemic on neurodevelopment are critical [111] . finally, the emergence of the hyper-inflammatory multisystem syndrome (mis-c) supplants any conclusion that covid-19 is benign or negligible in the pediatric age range. therefore, it behooves neurologists and other pediatric specialists who deal with neonates and young children to be aware of the potential neurologic involvement of this novel, potentially devastating virus. future animal models should evaluate the impact of sars-cov-2 on maternal infection, inflammatory signal transduction through the maternal-placental-fetal axis, and brain development. the importance of large-scale immunization should a vaccine become available, cannot be over emphasized as should the role of systemic inflammation, neuroinflammation, and neural-immune interactions in novel pathophysiology and symptomology. additionally, mechanism-specific targeted therapies could emerge from basic science studies of sars-cov-2 infection. table 5 . neurological involvement in covid-19. acute neurological involvement in adults with covid-19 can include decrease taste/smell, headache, confusion, peripheral nerve dysfunction, strokes, and encephalopathy. neurological involvement of covid-19 in neonates and children is still quite rare but recent case reports warrant vigilant surveillance. neurological involvement of covid-19 in neonates and children is still quite rare but recent case reports warrant vigilant surveillance. sars-cov-2 has not been recovered from 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transmission for severe acute respiratory syndrome coronavirus 2 development, maintenance and disruption of the blood-brain barrier review: the blood-brain barrier; protecting the developing fetal brain sars-cov2 entry and spread in the lymphatic drainage system of the brain in vitro and animal models for sars-cov-2 research is the collapse of the respiratory center in the brain responsible for respiratory breakdown in covid-19 patients covid-19 super-spreaders: definitional quandaries and implications child neurology society; in collaboration with the neurocritical care society ethics committee aan position statement neurotropic mechanisms in covid-19 and their potential influence on neuropsychological outcomes in children this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license research in the laboratory of stafstrom is supported by the mathias koch memorial fund, the sandra and malcolm berman foundation, and the paine foundation. research in the laboratory of jantzie is supported by the national institutes of health (1r01hl139492) and the department of defense (w81xwh-18-1-0167) . we thank carlos pardo-villamizar for his insightful comments and critique of the manuscript. the authors declare no conflict of interest. key: cord-314390-q36ye9ff authors: kang, gagandeep title: viral diarrhea date: 2016-10-24 journal: international encyclopedia of public health doi: 10.1016/b978-0-12-803678-5.00486-0 sha: doc_id: 314390 cord_uid: q36ye9ff viral gastroenteritis is among the most common illnesses affecting humans and has greatest impact at the extremes of age. the spectrum of disease can range from asymptomatic infections to severe disease with dehydration. in contrast to bacterial pathogens, enteric viruses cannot multiply outside their host; hence, the original inoculum into the common source determines infectivity. prevention of contamination of food and water control primary cases, whereas careful nursing and handwashing prevent secondary cases. effective vaccines are available and widely used to prevent rotaviral gastroenteritis, but vaccines for other causes of viral gastroenteritis are not yet available. acute gastroenteritis is among the most common illnesses affecting humans and has greatest impact at the extremes of age, severely affecting children and the elderly. the spectrum of disease can range from asymptomatic infections to severe disease with dehydration, which can be fatal. diarrheal disease continues to be a major cause of mortality in young children, particularly in developing countries. prior to 1972, the etiology of most episodes of gastroenteritis was unknown, and cases were attributed to a multitude of causes, including teething, weaning, diet, old age, drugs and malnutrition, as well as infections. intensive investigation of enteric infections in the past three decades has resulted in the discovery of many new viral agents filling in the 'diagnostic gap' in diarrheal disease. with the identification of the norwalk virus, rotavirus, astroviruses, enteric adenoviruses and other caliciviruses in the 1970s and subsequently, it has become increasingly clear that viruses cause a significant proportion of the enteric illnesses that did not earlier have a defined etiology. with improvements in sanitation and hygiene, and better standards of living, the proportion of diarrheal disease attributed to bacteria has decreased, resulting in an increase in the proportion of cases associated with viral infections. developments of new assays to identify viruses have also resulted in the ability to identify the viral etiology of episodes and epidemics of gastroenteritis (desselberger and gray, 2003) . approximately, 5 billion episodes of diarrhea occur worldwide annually, with virtually all children infected with the most common agents by the age of 3 years. widespread use of oral rehydration therapy in the past two decades has resulted in a significant decrease in mortality due to diarrhea, by about 70% to approximately 1.4 million annual deaths, occurring mainly in developing countries (lozano et al., 2012) . infections with gastroenteritis viruses differ from bacterial enteric infections in that they affect children in both developing and developed countries, suggesting that they may also be transmitted by means unrelated to contaminated food or water (cheng et al., 2005) . although feco-oral spread is the major route of transmission for all enteric viruses, transmission through contact, fomites and a respiratory route is likely based on epidemiology and the recovery of these viruses from inanimate objects during outbreaks. the four distinct patterns of viral gastroenteritis, endemic childhood diarrhea, outbreaks in closed communities, other food or waterborne outbreaks among wider communities and viral gastroenteritis in immunocompromised patients, reflect the differences in the pathogens, transmission and host response (glass et al., 2001) . these have a direct bearing on strategies for prevention and control ( table 1) . the highest rates of viral gastroenteritis occur between 3 and 24 months of age. protection in early infancy is believed to be mediated by maternal antibodies, followed by acquisition of protective immunity through repeated exposure in early childhood. this pattern is seen with all viral enteropathogens. however, for the noroviruses and astroviruses, immunity is not long-lasting, suggesting waning of immunity or lack of cross-protection between different viral strains. childhood diarrhea is best exemplified by the group a rotaviruses, but a similar pattern of infection and illness is seen with enteric adenoviruses, astroviruses and sapoviruses. these agents infect children during the first few years of life, with first infections being symptomatic and protecting against subsequent disease. disease is caused by a limited number of specific serotypes and incidence decreases with increasing age. group a rotaviruses are the main cause of severe diarrhea in children under 5 years of age, and resulted in an estimated 450 000 deaths in 2008 (tate et al., 2012) . prior to vaccine introduction, reports from europe, australia, and usa indicate that rotavirus was responsible for 20-60% of cases of gastroenteritis requiring hospitalization. in other parts of the world, approximately 40-45% of gastroenteritis requiring admission is due to rotavirus. of the 'non-group a' rotaviruses, group b rotavirus has been identified in epidemic outbreaks of severe diarrhea in adults in china and in symptomatic infections in children. outbreaks of diarrhea due to group c rotavirus have been identified in asia, europe, south, and north america, but are not common. human noroviruses are associated mainly with milder cases of gastroenteritis in children, causing >20% of diarrheal disease in children in the community. after introduction of rotavirus vaccines, noroviruses have become the most common cause of gastroenteritis in children (koo et al., 2013) . enteric adenoviruses cause 10% of diarrheal disease in reports from developed countries and have a variable incidence of 2-30% depending on the region in developing countries. astroviruses were found in approximately 1% of cases, when electron microscopy was employed for detection, but with the availability of a commercial enzyme immunoassay and molecular techniques, the percentage of detection has increased in hospital and community settings to 5-10%, and several new types of astroviruses have recently been described. outbreaks in closed or semi-closed communities such as old-age homes, cruise ships and hospitals are mainly due to noroviruses. norovirus infections are a significant cause of outbreaks in adults in nursing homes and residential care facilities and can lead to an increased need for hospital care and increased mortality. nosocomial outbreaks occurring in hospitals have required the closure of wards in order to control infections. outbreaks due to noroviruses and due to mixed viral infections have been reported in military personnel and on cruise ships. attack rates as high as 30% have been observed among cruise ship passengers, and repeated outbreaks have continued even after cleaning and disinfection protocols were instituted on successive voyages (ahmed et al., 2014) . in addition to infections in adult patients, viral agents of gastroenteritis are an important cause of nosocomial infection in pediatric units. between 20% and 50% of cases of gastroenteritis caused by rotavirus in hospitals are considered to be of nosocomial origin, and nosocomial viral enteric infections have been documented in up to 6% of children admitted for >72 h in both developed and developing countries. infections in older individuals are usually due to noroviruses, although adenovirus infections have been documented. asymptomatic patients who excrete the virus and the relative resistance of these viruses to normal disinfectants may explain the prevalence and transmission of nosocomial infection. the microbiological contamination of food and water is a significant global problem. it is estimated that there are approximately 1.5 billion cases and over 3 million deaths worldwide annually (duizer and koopmans, 2004) . the microorganisms associated with about 50% of the foodborne disease outbreaks still go unrecognized, particularly those occurring in developing countries. the apparent failure to confirm a viral etiology in such outbreaks has been due largely to the lack of available tests, unavailability of food or water specimens and the failure to report outbreaks of mild gastrointestinal disease. all of these factors have resulted in a drastic underestimate of the true scope and importance of food-or waterborne viral infection. the most common types of food-and waterborne viral disease are infectious hepatitis due to hepatitis a virus and acute viral gastroenteritis associated with the human noroviruses. noroviruses, transmitted by the fecal-oral and the aerosol route, are the most common cause of outbreaks of nonbacterial gastroenteritis in industrialized countries, and emerging data indicates that they are also prevalent in developing countries. many outbreaks can be associated with the consumption of primarily or secondarily contaminated foods. shellfish and fruit implicated in outbreaks have been shown to be contaminated at the site where these foods are harvested or produced, whereas other foods, such as salads, cold foods, and sandwiches, have caused outbreaks after being contaminated by food handlers at the site of food preparation. shellfish, in particular, oysters and clams, which are raw or insufficiently cooked, are associated with noroviral outbreaks, frequently occurring because these shellfish filter contaminated seawater to feed and hence result in a concentration of virus. foodborne outbreaks due to rotaviruses, parvoviruses, and astroviruses are also occasionally reported. water is also a common source of outbreaks and may include water from municipal supplies, wells, recreational lakes, swimming pools, and ice machines. rotaviruses, noroviruses and some adenoviruses are important causes of waterborne disease outbreaks. post-recovery and secondary transmission is a particular concern in infections due to these agents (kapikian, 1994) . the main viral causes of severe gastroenteritis in immunosuppressed patients are cytomegalovirus (cmv) and epstein-barr virus (ebv), which mainly affect patients with aids and transplant recipients. cmv is a frequent pathogen in diarrhea associated with aids with cd4 counts <100 cells mm à3 . other viruses that produce hiv-associated gastroenteritis include astrovirus, picobirnavirus, calicivirus and adenovirus. there is evidence of gastroenteritis due to astrovirus and adenovirus in both child and adult bone marrow transplant recipients. noroviruses are now being increasingly recognized as a cause of chronic diarrhea in patients undergoing transplants. toroviruses have been found in association with diarrhea in immunocompromised children (krones and hogenauer, 2012) . criteria to define a virus as an etiologic agent of gastroenteritis include (1) the identification of the virus more frequently in subjects with diarrhea than in controls, (2) the demonstration of an immune response to the specific virus, and (3) demonstration that the beginning and end of the illness correspond to the onset and termination of virus shedding, respectively (glass et al., 2001) . so far, these include human caliciviruses, which are noroviruses and sapoviruses, rotaviruses, astroviruses and the enteric adenoviruses. in immunocompromised patients, gastrointestinal cmv and ebv infections also cause significant morbidity. coronaviruses, including the sars coronavirus, toroviruses, the aichivirus, certain non-polio enteroviruses and picobirnaviruses have also been found to be associated with diarrhea. similarly, in conditions such as hiv, it has been difficult to obtain definitive data on the role of enteric viruses in the causation of symptoms (thomas et al., 1999) . the study of rotaviruses, enteric adenoviruses, and astroviruses has been facilitated greatly by the ability to propagate these viruses in cell culture, which has allowed the production of reagents for use in diagnostic studies, a better understanding of factors correlated with immunity to infection, and the elucidation of each virus's life cycle. although human noroviruses have defied numerous attempts to propagate them in cell culture to date, the ability to culture murine norovirus has informed pathogenesis and the use of molecular tools has increased our ability to diagnose and study norovirus infections ( figure 1 ). rotaviruses are double stranded rna viruses comprising a genus within the family reoviridae. the mature virus particles are triple layered, approximately 70 nm in diameter, and possess icosahedral symmetry. the rotavirus genome consists of 11 segments of double-stranded rna that code for 6 structural viral proteins and 6 non-structural proteins. of the non-structural proteins, nsp4 is of particular interest, since it has enterotoxin-like activity and can induce diarrhea in mice. the classification of rotavirus into 7 different groups (a-g) is based on the antigenic specificity of the vp6 capsid proteins. of the 7 groups, only groups a, b and c are known to infect humans. severe, life-threatening disease in children worldwide is caused predominantly by group a rotaviruses. variability in the genes encoding the two outer capsid proteins vp7 and vp4 form the basis of the current strain typing of group a rotaviruses into g and p genotypes respectively. all known g serotypes correspond with genotypes; more p genotypes than serotypes have been identified. at least 15 g genotypes and >30 p genotypes have been identified to date. the strains most commonly reported include g1p , and more recently g12 strains in combination with different p types. unusual g and p types have been reported from different parts of the world. the temporal changes in circulating strains and the rapid evolution of rotaviruses by a variety of mechanisms provide challenges in epidemiological studies. these mechanisms of evolution include genetic drift, wherein accumulation of point mutations generates genetic lineages leading to the emergence of antibody escape mutants, and genetic shift through gene reassortment during dual infection of a single cell. hence methods of virus typing need to be regularly monitored and updated to identify emerging novel strains of epidemiological importance (parashar et al., 2013) . rotaviruses induce a clinical illness characterized by vomiting, diarrhea, abdominal discomfort, fever, and dehydration (or a combination of some of these symptoms) that occurs primarily in infants and young children and may lead to hospitalization for rehydration therapy. fever and vomiting frequently precede the onset of diarrhea. milder gastroenteric illnesses that do not require hospitalization are common. the highest attack rate is usually among infants and young children 6-24 months old. neonatal infections are largely asymptomatic. deaths from rotavirus gastroenteritis may occur from dehydration and electrolyte imbalance. the severity of diarrhea is measured by the vesikari score that includes duration and severity of diarrhea and vomiting, associated fever and degree of dehydration. in older children and adults, rotavirus gastroenteritis occurs infrequently, although subclinical infections are common. rotaviruses also induce chronic symptomatic diarrhea in immunodeficient children. rotavirus infections can be severe and sometimes fatal in individuals of any age who are immunosuppressed for bone marrow transplantation. rotavirus infections have also been associated with necrotizing enterocolitis and hemorrhagic gastroenteritis in neonates in special-care units. rotavirus antigenemia has been described early in infection in children requiring hospitalization, and rna has been extracted from serum of antigenemic children and csf of children with seizures, but the clinical significance of these findings require further investigation. rotaviruses infect the mature enterocytes on the tips of small intestinal villi, leading to villous atrophy with secondary hyperplasia of the crypts. it has been proposed that cellular damage is secondary to villus ischemia. the mechanism that induces the production of diarrhea is not well understood, although it appears to be mediated by the relative decrease of villous epithelium absorption in relation to the secretory capacity of the crypt cells, as well as the action of nsp4, the viral enterotoxin that has been shown to cause secretory diarrhea in rodents. there is a loss of intestinal permeability to macromolecules such as lactose, secondary to a decrease in disaccharidase in the intestine. the enteric nervous system is stimulated by this virus, leading to intestinal water and electrolyte secretion (parashar et al., 2013) . recent studies indicate that lack of specific carbohydrates in the enteric mucosa may influence the ability of rotaviruses to infect and cause disease (lependu et al., 2014) , but the immunologic mechanisms responsible for protection against infection by rotavirus are still not well known. older children and adults usually have asymptomatic or mild infection unless an overwhelming infectious dose is delivered. several studies have shown that local intestinal immunity produced in response to infection protects against subsequent severe episodes of diarrhea. it was believed that the antibody response in primary infection was homotypic with subsequent infections producing a broadening of the immune response, but the basis of strain-specific immunity is less clear now that it has been shown that two doses of a monovalent vaccine can present infection with multiple strains as well as a multivalent vaccine (parashar et al., 2013) . laboratory procedures for diagnosis of rotavirus include electron microscopy (em), passive latex agglutination assays (la), electropherotyping using polyacylamide gel electrophoresis (page), enzyme-linked immunosorbent assays (elisa) and reverse transcriptionpolymerase chain reaction (rt-pcr). in recent years, elisa has become the method of choice for screening. early studies on strain surveillance identified rotavirus serotypes using neutralization assays. monoclonal antibodies to specific serotypes were used. new methods have greatly improved data on circulating rotavirus strains and include multiplex rt-pcr based genotyping based on vp7 and vp4 genes, nucleotide sequencing for specific genes and whole genome sequencing. the name calicivirus is derived from the latin calyx, meaning cup or goblet, and refers to the cup-shaped depressions visible by electron microscopy. these cup-like depressions are more prominent in some strains, particularly the sapoviruses, leading to the characteristic star of david appearance from which caliciviruses get their name. caliciviruses (family caliciviridae) are a group of nonenveloped, icosahedral viruses with a single-stranded, positive sense rna genome. the genome is 7.5-7.7 kb in length and has three open reading frames (orfs). noroviruses can be genetically classified into six different genogroups (gi-gvi) which can be further divided into different genetic groups or genotypes. genogroups i, ii and iv infect humans, while genogroup iii is associated with bovine infections and genogroup v has been isolated in mice. noroviruses were initially named after the places where the outbreaks occurred, but a numeric classification system based upon numbering genogroups with roman numerals and genotypes with numbers is now used. for example the genogroup ii norovirus, lordsdale virus is a member of genotype 4, and therefore classified as a gii.4 norovirus. gii.4 viruses account for the majority of adult outbreaks of gastroenteritis and often sweep across the globe, with the sydney 2012 virus the most recent gii.4 to cause multi-country outbreaks (ramani et al., 2014) . sapoviruses, previously called the classical caliciviruses based on their morphology, have a similar system of strain designation as noroviruses and have 8 human genotypes in 5 genogroups, although up to 14 genogroups have been proposed with the inclusion of sapoviruses from other hosts (scheuer et al., 2013) . the incubation period for caliciviral infections is short, about 24-48 h, and the mean duration of illness is 12-60 h. nausea is prominent, with vomiting, non-bloody diarrhea, and abdominal cramps occurring in most cases. all age groups experience these symptoms, but diarrhea is relatively more prevalent among adults, whereas a higher proportion of children experience vomiting. from 25-50% of affected persons also report headache, fever, chills, and myalgias. adults have died during illness caused by noroviruses, presumably from electrolyte imbalance. late sequelae have not been reported, but the elderly often report persistence of constitutional symptoms for up to several weeks. routes of transmission that have been documented include water, food (particularly shellfish and salads), aerosol, fomites, and person-to-person contact. infectivity can last for as long as 4 days after resolution of symptoms. presymptomatic shedding has been suspected on epidemiologic grounds but not proven in volunteer studies. human noroviruses have not been grown in culture, making studies of pathogenetic mechanisms difficult. in studies carried out on volunteers, infection by calicivirus produces an expansion of the villi of the proximal small intestine. the epithelial cells remain intact with a shortening of the microvilli. the mechanism by which diarrhea is produced is unknown. in volunteer studies, infection by the norwalk virus induces a specific igg, iga and igm serum antibody response, even in persons with pre-existing antibodies. after norovirus infection, immunity appears to last for a few months but there is little or no evidence of long-term protection. volunteer studies conducted in the 1970s also suggested that some people were resistant to norwalk virus challenge. human blood group antigens (hbgas) have been shown to serve as cell attachment factors for noroviruses and thus determine susceptibility to certain human noroviruses. reduced infection and illness is observed in persons with serum antibodies that block strain-specific binding to hbgas hbga expression on cell surfaces is affected by the abo, secretor and lewis genotypes of an individual. in general, because gii.4 viruses can bind a larger range of hbgas in comparison to other genotypes, they have a larger susceptible population pool for infection (ramani et al., 2014) . data on sapovirus infections and immune responses is not yet available. electron microscopy was initially used for identification of these viruses, but is insensitive compared with molecular detection assays. currently, rt-pcr assays are the most common approach for establishing a diagnosis of norovirus infection. virus-specific primers are used to amplify conserved regions of the genome, usually in the polymerase or capsid genes. no single primer pair can detect all norovirus or sapovirus strains because of the high sequence diversity, but in most geographic regions, more than 90% of currently circulating strains can be detected using separate primer pairs for genogroup i and ii noroviruses and sapoviruses. real-time pcr assays have greater sensitivity and are increasingly used. antigen-detection elisa assays for noroviruses have been established in the last decade, but the first assays had a very narrow reactivity. more broadly reactive assays have been developed using monoclonal antibodies that recognize cross-reactive epitopes or multiple monoclonal antibodies, but not widely used. serologic assays also have been developed to detect immune responses to infecting norovirus strains, but are used more in epidemiological studies than for diagnosis in individual patients. human astrovirus is the prototype of the astroviridae, a family of non-enveloped positive sense rna viruses, measuring 38-41 nm. by direct electron microscopy, astroviruses recovered from stool display a distinctive surface star-like appearance. the genome of astrovirus consists of positive-sense, single stranded rna, 6.8 kb in length, organized in 3 orfs. all serotypes have at least three capsid proteins, p1, p2 and p3, with the p2 protein carrying the group-reactive epitopes and the p3 protein specifying serotype. astroviruses are classified into serotypes based on the reactivity of the capsid proteins with polyclonal sera and monoclonal antibodies. astroviruses can also be classified into genotypes on the basis of the nucleotide sequence of a 348-bp region of the orf2, and there is a good correlation with the serotypes. there are eight established genotypes. phylogenetic analyses have shown that it is common to find multiple astrovirus strains circulating in one region during a given period of time, and that there are also variations in the prevalent type with time, suggesting either a genetic shift or an introduction of new strains. serotype 1 is predominant in most studies, followed by 2, 3, 4 and 5. serotypes 6, 7 and 8 are rarely detected. new astroviruses have been described recently, based on sequencing of samples from children with diarrhea and controls. clinically, these viruses cause similar symptoms to caliciviruses. like rotaviruses, astrovirus infections occur through the year with peaks in the winter months. infections have been shown to occur mainly in childhood. other studies showed that most of the cases of infection were detected in children less than 5 years of age with the majority of the children being under 1 year of age. outbreaks of astrovirus infection involving children and elderly patients have been described and prolonged excretion documented in immunosuppressed, immunodeficient and aids patients. significantly higher seroprevalence rates of astrovirus have been reported in adults exposed to contaminated water compared with a control group. the pathogenesis of the disease induced by astrovirus has not been established, although it has been suggested that viral replication occurs in intestinal tissue. in animal studies, atrophy of the intestinal villi is observed, as well as inflammatory infiltrates in the lamina propria leading to osmotic diarrhea. symptomatic astrovirus infection occurs mainly in small children and the elderly, which suggests both an acquisition of antibodies with increasing exposure and a reduction in antibodies with advancing age. studies in adult volunteers indicate that people with detectable levels of antibodies do not develop the illness, although epidemiological observations suggest that human astrovirus infections may not induce heterotypic immunity, as an episode of astrovirus diarrhea is not associated with a reduced incidence of a subsequent episode. electron microscopy is an insensitive technique, because a high concentration of viral particles is required for detection and the typical five or six pointed star morphology is seen in less than 10% of particles. enzyme immunoassays have been developed including streptavidin-biotin assays for increased sensitivity of detection, and are used in most diagnostic laboratories. for epidemiological research, recently astrovirus-specific rt-pcr has been the screening method of choice. while some investigators have used highly sensitive primers targeted to conserved genomic regions coding for the nonstructural proteins and untranslated regions, others prefer to use primers from the capsid coding region, which can be less sensitive but provide typing information (guix et al., 2005) . all adenovirus particles are non-enveloped, 60-90 nm diameter, with icosahedral symmetry easily visible in the electron microscope by negative staining and are composed of 252 capsomers: 240 hexons and 12 pentons bearing fibers at the vertices of an icosahedron. the genome is linear, non-segmented, double-stranded dna of 30-38 kbp. based on their immunologic properties, oncogenicity in rodents, genome and morphology, adenoviruses are classified into six subgroups a-f with 51 serotypes. serotypes predominantly associated with human infections include h-40, h-41, which belong to subgenus f and occasionally h-31 in subgenus a. adenoviruses are widely recognized causes of respiratory, ocular, and genitourinary infections. however, serotypes 40 and 41 (previously called fastidious enteric adenoviruses) primarily affect the gut, contributing to 5-20% of hospitalizations for childhood diarrhea in developed countries. enteric adenoviruses have also been identified in pediatric gastroenteritis in developing countries. peak incidence is among children less than 2 years of age, but older children and adults may be infected, with or without symptoms (glass et al., 2001) . incubation is between 3 days and 10 days, with illness lasting greater than or equal to 1 week, longer than for other enteric viral pathogens. diarrhea is more prominent than vomiting or fever, and respiratory symptoms are often present. the lesions produced by serotypes 40 and 41 in the enterocytes lead to atrophy of the villi and compensatory hyperplasia in the crypts, with subsequent malabsorption and loss of fluids. a neutralizing antibody response made in response to infection results in control of disease and protection from reinfection with the same serotype. asymptomatic virus excretion can continue for prolonged periods even after an antibody response is documented in acute infection. although adenoviruses can be grown in culture, little data is available on the pathogenetic mechanisms of these agents of viral gastroenteritis. traditionally, adenoviruses have been detected and typed by electron microscopy, virus culture and neutralization assays. these assays are time-consuming and more rapid serological assays including immunofluorescence, enzyme immunoassays and latex agglutination have been developed. the rapid assays are useful in the diagnostic laboratory, but do not generally distinguish between serotypes. pcr-based techniques are more sensitive and relatively rapid, but have been shown to give discrepant results when compared to serotyping by neutralization. torovirus is a genus within the coronaviridae family, and toroviruses are known causes of diarrhea among cattle. these viruses have an envelope of 100-140 nm, with a helicoidal capsid and a single-stranded positive sense rna genome. torovirus was detected for the first time in human gastroenteritis in 1984. they are associated with persistent and acute diarrhea in children, and may represent an important cause of nosocomial diarrhea. coronaviruses are well-established causes of diarrhea in animals and respiratory disease in humans. these viruses are between 60 and 220 nm, with helicoidal symmetry and a spiculated envelope that gives them the appearance of a crown and a genome with positive sense single stranded rna. they have been identified in the stool of persons with gastroenteritis (usually children less than 2 years of age), but human controls have been found to shed them with higher frequency, raising doubt about their etiologic role in human diarrhea. diarrhea also occurs as part of the syndrome seen with the sars coronavirus and is likely to play a role in transmission. picobirnaviruses are small viruses, without an envelope, 30-40 nm in diameter, with an icosahedral capsid and a genome made up of two or three segments of bicatenary rna. reports from brazil documented human cases of diarrhea caused by picobirnavirus, which had been thought to be a cause of diarrhea only in animals. the importance of this pathogen is unknown, but it has been found in association with hiv and cryptosporidium infected individuals. aichivirus, in the genus kobuvirus, was first recognized in 1989 in oyster-associated non-bacterial gastroenteritis in man. aichivirus appears to morphologically resemble astroviruses when examined by electron microscopy. recently aichivirus was isolated from pakistani children and from japanese travelers with gastroenteritis returning from tours of southeast asian countries. pestivirus antigen was found in 23% of children less than 2 years of age with gastroenteritis of unknown etiology compared with 3% of controls in a study on an american indian reservation, but further studies on the role of this agent in gastroenteritis have been lacking. parvovirus-like particles have been identified by electron microscopy in stool specimens of both well and ill persons in britain. the relationship of these particles to disease is unclear, but they have been associated with shellfish-related outbreaks of gastroenteritis. enteroviruses cause a wide spectrum of disease, in which gastroenteritis plays a minor role. although the entry of polio, coxsackie, echo, or other enteroviruses through the gut may cause incidental mild diarrheal symptoms, the spread of the virus through the bloodstream to other organs (e.g., central nervous system, heart, pleura, pancreatic islets) produces major disease manifestations. although reports have linked some enteroviruses to illnesses in which diarrhea was the sole symptom, an outbreak or case of gastroenteritis should not be attributed to an enterovirus merely because it was isolated in the stool of an affected person, but attempts should be made to evaluate the amount, duration of shedding and relation to symptoms and antibody response to establish a causal relationship. treatment of viral gastroenteritis is symptomatic, and its aim is to prevent or treat the dehydration secondary to the disease. dehydration is assessed using blood pressure, pulse, heart rate, skin turgor, fontanelle depression, mucous membranes, eyes, extremities, mental status and activity, urine output and thirst. assessment of dehydration, particularly in children in community studies or by field workers relies on lethargy, restlessness, appearance of eyes, skin turgor and feeding/thirst. fluid and metabolic imbalances must be assessed and corrected. the most important factor predicting adverse outcome of viral gastroenteritis is delay in fluid and electrolyte therapy. clinically significant dehydration can occur within 6 h of onset of illness, especially during primary infection in children. malnutrition, malignancy, and immunodeficient states predispose to a more severe episode of illness or unremitting diarrhea that can persist until the underlying condition is corrected. oral rehydration therapy is recommended for preventing and treating early dehydration and continued replacement therapy for ongoing losses. intravenous therapy is required in severe dehydration, shock and decreased consciousness. in children, age-appropriate diet should be continued during oral rehydration and following intravenous rehydration. anti-emetics, anti-diarrheal agents and antibiotics should not be given to children, although anti-emetics and anti-diarrheals may be used in adults. studies have shown that antirotavirus immunoglobulin as bovine hyperimmune colostrum or human milk mat decrease the frequency and duration of rotavirus diarrhea. probiotics such as lactobacillus casei gg and saccharomyces boulardii reduce the frequency and duration of diarrhea (guandalini, 2006) . racecadotril, an enkephalinase inhibitor has been shown in some studies to be useful in treating rotaviral diarrhea in children. zinc supplements have been suggested to reduce severity and duration of illness. preventive measures can limit the number of episodes of viral gastroenteritis both within the home and in institutions. diaper-changing areas should be separate from food preparation areas. diapers should be disposed of directly in the changing area and should be placed in closed bags. hands should be washed after contact with soiled diapers and clothing. interruption of transmission of the infection is extremely important, especially in hospitals and centers which care for small children. therefore, it is necessary to reinforce hygiene measures, such as handwashing and clean all surfaces with suitable disinfectants. since viruses do not replicate outside a host, decreasing the potential inoculum is key to preventing further infection of susceptible hosts. further preventive measures in child care facilities and hospitals include isolation and cohorting of ill children. asymptomatic infections probably also play an important role in the spread of infection. studies with vaccines against group a rotavirus began in 1982. the first vaccine developed was the tetravalent human-rhesus reassortant vaccine, which induces protection against the four main rotavirus serotypes, g1-g4. efficacy studies showed a reduction in the appearance of severe gastroenteritis caused by rotavirus in vaccinated children, and the vaccine was approved in the usa in 1998. however, the detection of an increase in the risk of intussusception after vaccination led to its suspension. in 2006, two new licensed vaccines became commercially available. these were rotateqô, a live oral attenuated pentavalent vaccine from merck which is recommended by the cdc advisory committee on immunization practices to be given at 2, 4 and 6 months with the last dose administered no later than 32 weeks, and rotarixô from glaxosmithkline, a human strain derived monovalent live oral vaccine given in two doses at 2 and 4 months. both vaccines are licensed and used in over one hundred countries and the number continues to grow. the vaccines have lower efficacy in low and middle-income countries than in more industrialized countries. nonetheless, use of the vaccine has shown a dramatic effect on diarrheal hospitalizations in countries where the vaccines are widely used and a reduction in all cause diarrheal mortality in middle-income countries. a lower level of risk of intussusception of about one case in 20 000-50 000 vaccines has been identified in several countries with both vaccines, but overall, the benefits and lives saved by the vaccine are much greater than the risk and sequelae of intussusception (parashar et al., 2013) . owing to the high cost of these vaccines, vaccine manufacturers in developing countries have initiated the process of formulating and testing vaccines based on local strains which will address the issue of cost. dna based, subunit protein based and virus like particle vaccines may also provide an alternate method of prevention in the future. studies on virus-like particle based vaccines against norwalk virus were initiated with capsid proteins expressed in plants inducing an antibody response in experimental models. more recently, a monovalent genogroup i norovirus virus-like particle (vlp) vaccine was evaluated in secretor positive individuals and showed proof-of-concept efficacy. studies on a bivalent formulation including gii.4 vlps, given intramuscularly are now underway (ramani et al., 2014) . in summary, viral gastroenteritis is a major cause of morbidity in developed countries and mortality in developing countries. hygiene is the first preventive step in viral gastroenteritis and rehydration is the key to management of clinical illness. the range of organisms which can cause gastroenteritis is immense and vaccines will be important in reducing the impact of childhood gastroenteritis. global prevalence of norovirus in cases of gastroenteritis: a systematic review and meta-analysis infectious diarrhea in developed and developing countries viral gastroenteritis foodborne viruses: an emerging problem gastroenteritis viruses: an overview probiotics for children: use in diarrhea human astrovirus diagnosis and typing: current and future prospects viral infections of the gastrointestinal tract noroviruses: the most common pediatric viral enteric pathogen at a large university hospital after introduction of rotavirus vaccination diarrhea in the immunocompromised patient host-pathogen co-evolution and glycan interactions global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study diagnosis, management, and prevention of rotavirus gastroenteritis in children epidemiology of human noroviruses and updates on vaccine development prevalence of porcine noroviruses, molecular characterization of emerging porcine sapoviruses from finisher swine in the united states, and unified classification scheme for sapoviruses estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis enteric viral infections as a cause of diarrhoea in the acquired immunodeficiency syndrome key: cord-318965-0mxv8h06 authors: mastnak, wolfgang title: psychopathological problems related to the covid‐19 pandemic and possible prevention with music therapy date: 2020-06-01 journal: acta paediatr doi: 10.1111/apa.15346 sha: doc_id: 318965 cord_uid: 0mxv8h06 covid-19 is having a profound effect on societies worldwide and the impact that it is having on children cannot be underestimated. although brodin (1) stated that the disease tends to be mild in children, psychopathological considerations allow us to assume that the pandemic will have a high risk of long-term paediatric psychiatric sequelae and interdisciplinary preventative measures are needed. covid-19 is having a profound effect on societies worldwide and the impact that it is having on children cannot be underestimated. although brodin 1 stated that the disease tends to be mild in children, psychopathological considerations allow us to assume that the pandemic will have a high risk of long-term paediatric psychiatric sequelae and interdisciplinary preventative measures are needed. psychopathological sample analyses 2 show that experiencing natural disasters has an impact on the mental health of children and increases their risk of mental disorders in adulthood. children's awareness of disasters is affected by how their parents react and interact with them, as well as social factors. 3 given that the covid-19 pandemic is a global disaster, public health, education and social systems need to work together to minimise the mental sequelae in the younger generation. comparative analyses and considerations based on inferential reasoning suggest that this pandemic will involve four substantially different phases with regard to child mental health. the first is the acute phase, when children become aware of national and local cases and steps are taken to limit the spread of the disease. changes like lockdowns and school closures can trigger acute stress reactions and adjustment issues and children can exhibit insomnia, paranoid traits and disruptive behaviour as they attempt to cope with the strain. they can also be very scared and experience suicidal feelings. this is followed by the subacute phase. it has been suggested 4 that the global impact of covid-19 is likely to last for several years. our lives need to adapt to changed social circumstances, and this could result in pathological habituation, ongoing anxiety and delusional ideas. children could suffer post-traumatic stress disorders that adversely affect developmental processes, personal growth and cognitive factors, such as concentration and reduced motivation to achieve goals. next comes the post-traumatic phase, which the author estimates to last for about three years. depending on children's resilience and/or susceptibility to stress, this could give rise to self-protective attitudes and personality features, as well as mental health issues such as post-traumatic stress disorders or depressive and avoidant personality traits. finally, there is the effect phase. in common with other traumata resulting from disasters, adverse experiences with covid-19 could come back to haunt individuals after several relatively symptom-free decades, and this could affect their minds and harm their quality of life. the effect phase mainly concerns adult psychiatry and psychogeriatrics. it is critical to understand the complex way that a child's mind responds to acute and persistent calamities, by interacting with developmental factors and personality traits. this can manifest in various positive and negative phenomena such as creative acts or nightmares. 5 according to differential pathopsychology, we have to take children's psychopathological susceptibility and specific dispositions to mental disorders into account. covid-19 measures need to be carefully designed to avoid adverse psychosocial experiences that can lead to severe symptoms. this calls for adequate screening by public health bodies and educational systems. we can expect positive and negative attitudes to emerge and these will depend on many factors. these include cultural backgrounds, children's personalities, environmental changes and their perceptions of the lack or harmony between the life they had before the pandemic and their changing self-image and life plans. some children may regard the new situation as a challenging opportunity, while others will see it as a destructive blow of fate that may even induce suicidal ideation. from a cognitive psychological point of view, particularly vulnerable children will need support to modify the way they think and to how they fit in with changes to their culture and society. it is also important to look out for communication apprehension and schizoid-schizotypal patterns. through consolidation and habituation, experiences with forced isolation could lead to social phobias and self-imposed withdrawal. these psychopathological developments may even lead to new diagnoses. these could include intertwined characteristics of schizotypal and schizoid personality disorders, which manifest as emotional coldness and detachment, discomfort in social situations and inappropriate paranoid fears of being contaminated by others. there is some evidence of structural similarities between anxiety and obsessive-compulsive disorders and the covid-19 pandemic could lead to fears that restrict children's behaviour. these could include phobias about getting infected, compulsive hand-washing and disinfection, the need to escalate self-control and avoiding contact with others. some children will display conscientious behaviour that is in line with relevant hygiene guidelines, but others will demonstrate compulsive self-protection and self-isolation and an excessive fear of getting infected. owing to possible interdependencies between acute behavioural reactions and individual features, these phenomena could turn into strikingly irritating personality traits. issues of pseudo-adjustment and self-abandonment may also emerge. from the perspective of cognitive behavioural psychology, vulnerable children are at risk to experience covid-19 regulations as correctional means or punishment. related adjustment processes are likely to cause adverse impacts on the child's will and self-determination or even result in self-abandonment. the experience of such measures can cause disorientation, learned helplessness and dependence that go way beyond the intentions of the public health messages. it is vital that children are educated about the risks, and how to manage them, in a way that makes them feel empowered and in control and avoids irrational panicking. distinction between reality and imagination will also play a role. child psychiatry and child psychotherapy provide efficient means to treat the psychopathological sequelae of covid-19, but these will not reach all children who are susceptible to those threats and/or, those with unreported issues or subclinical symptoms. in-service-training for teachers. we have to consider the pandemic may also affect developing countries without advanced education and paediatrics, hence the need of international support. although the whole spectrum of school subjects is being considered by these universities, there is an explicit focus on educational models that are tailored to the specific issues associated with covid-19. these include physical and arts education, with a particular emphasis on music, including music therapy and music-oriented medical sciences. music has been chosen for a number of reasons. there is some medical evidence that music has a positive influence on the immune system, which has direct implications for life during the pandemic. experiences in other medical disciplines suggest that even being aware that this can work can boost the immune system. singing therapy is already used to improve respiratory issues, like asthma, and this could alleviate symptoms if children are infected and experience breathing issues. inner calmness, activation of autotherapeutic potential and psychosomatic rebalancing are key issues in music therapy. various music therapy can help children who are socially shy or hostile, as it can enhance their empathy and readiness to communicate. creativity is also a driving force behind the individual therapeutic solutions used in child psychotherapy. from a neuroscientific perspective, creative processes are interdependently linked to the brain's default mode network, hence the both artistic and neuro-psychological value of music. furthermore, neuro-aesthetic and cultural-anthropological findings suggest therapeutic and health-promoting effects of 'beauty'. community music therapy may also be useful for self-help groups dealing with the immune system in health and disease. interdisciplinary collaboration will be required and should include mindfulness, which has become a psychiatric standard. these approaches are all designed to help children regulate their own emotions and take care of their immunological health. improving adjustment and resilience in children following disasters 6 call for immediate and interdisciplinary research. multi-modal approaches need to combine prospective and meta-synthetic research, cross-sectional and culturally sensitive studies, quantitative evidence-based medical and qualitative in-depth investigations. there also needs to be collaboration between schools of thought, such as cognitive behavioural and psychoanalytic approaches. since covid-19 and its psychopathological sequelae are a global concern, both western medicine and ethno-medical approaches are called into play. none declared. the author has no conflicts of interest to declare. https://orcid.org/0000-0003-4632-5639 why is covid-19 so mild in children? are natural disasters in early childhood associated with mental health and substance use disorders as an adult? children's disaster reactions: the influence of family and social factors projecting the transmission dynamics of sars-cov-2 through the postpandemic period contributing factors predicting nightmares in children: trauma, anxiety, dissociation, and emotion regulation improving adjustment and resilience in children following a disaster: addressing research challenges key: cord-310840-h49dx92d authors: eslamy, hedieh k.; newman, beverley title: pneumonia in normal and immunocompromised children: an overview and update date: 2011-09-30 journal: radiologic clinics of north america doi: 10.1016/j.rcl.2011.06.007 sha: doc_id: 310840 cord_uid: h49dx92d pneumonia is an infection of the lung parenchyma caused by a wide variety of organisms in pediatric patients. the role of imaging is to detect the presence of pneumonia, and determine its location and extent, exclude other thoracic causes of respiratory symptoms, and show complications such as effusion/empyema and suppurative lung changes. the overarching goal of this article is to review cause, role of imaging, imaging techniques, and the spectrum of acute and chronic pneumonias in children. pneumonia in the neonate and immunocompromised host is also discussed. normal and immunocompromised children: an overview and update hedieh k. eslamy, md, beverley newman, md* pneumonia is an infection of the lower respiratory tract, involving the lung parenchyma. the world health organization estimates that there are 150.7 million cases of pulmonary infection each year in children younger than 5 years, with as many as 20 million cases severe enough to require hospital admission. 1 in north america and europe, the annual incidence of pneumonia in children younger than 5 years is estimated to be 34 to 40 cases per 1000, and decreases to 7 cases per 1000 in adolescents 12 to 15 years of age. 2, 3 the mortality in pediatric patients caused by pneumonia in developed countries is currently low (<1 per 1000 per year). 3 however, pneumonia is still the number one cause of childhood mortality in developing countries. 1, 4 the overarching goal of this article is to review cause, current role of imaging, imaging techniques, and the spectrum of acute and chronic pneumonias in children. pneumonia in the neonate and immunocompromised host is also discussed. infectious agents causing pneumonia in children include viruses, bacteria, mycobacteria, mycoplasmas, fungi, protozoa, and helminths. etiologic diagnoses of pneumonia are not so easy to determine or so accurate as is sometimes implied. in addition, proof of the cause of pneumonia is not obtained in most cases. there is a great deal of overlap in the radiographic appearance of pneumonias caused by different organisms. imaging is usually poor at predicting the broad category (eg, bacterial vs viral) of infectious agent, let alone the specific agent. preexisting lung disease may not only predispose to pulmonary infection but also modify the appearance of pulmonary consolidation. furthermore, because the lungs can respond to a diverse disease processes in only a limited number of ways, it is common for the radiographic features of both acute and chronic infectious pneumonia to overlap considerably with many noninfectious lung diseases. such noninfectious lung diseases are identified as pneumonia mimics in this article. viral pneumonia is rare in the neonatal period, because of conferred maternal antibody protection, whereas bacterial pneumonia is most frequently caused by pathogens acquired during labor and delivery, and is more prevalent in premature babies. with decreasing maternal antibody levels, viral pneumonia occurs at a peak between 2 months to 2 years of age. bacterial infections become relatively more common in older children from 2 years to 18 years of age. 5 the lung response to an infective antigen seems to be more agespecific than antigen-dependent (ie, bacteria vs viral). therefore, lobar and alveolar lung opacities are more common in older children and are more frequently caused by bacterial infections, whereas interstitial opacities are seen in all age groups, and are relatively nonspecific as to the type of causative organism. 6, 7 the role of imaging, including chest radiographs, ultrasound (us) and computed tomography (ct), is to detect the presence of pneumonia, determine its location and extent, exclude other thoracic causes of respiratory symptoms, and show complications such as parapneumonic effusion/ empyema and suppurative lung complications. 5 although magnetic resonance (mr) imaging is not routinely used for evaluating pneumonia in children, it is a promising imaging modality particularly for children with chronic lung conditions who require repeat imaging studies. frontal and lateral chest radiographs are the mainstay, and often the only, imaging needed in pediatric pulmonary infection. this imaging can be supplemented with other views such as lateral decubitus or other imaging modalities as the circumstances warrant. decubitus views are not useful when an entire hemithorax is opacified because layering fluid cannot be identified without any adjacent air. the main use of us is to identify, quantify, and characterize a parapneumonic effusion/empyema, as well as provide image guidance for drainage and identify residual collections after treatment. 8, 9 operator availability and expertise are important factors in making us a useful tool for evaluating pulmonary infection. although intrapulmonary fluid-filled cavities and even lung abscesses within consolidated lung can be identified on us, ct provides a more global view of the disease process. ct is often used to further evaluate: (1) suppurative lung complications and to differentiate these from parapneumonic effusion/empyema; (2) patients with recurrent or chronic pneumonia and concern for an underlying lesion; and (3) immunocompromised children with noncontributory or confusing chest radiographs and clinical findings that could be secondary to lung infection. 5 close attention to ct technique is crucial for imaging evaluation of pneumonia in pediatric patients. ct with low radiation dose technique should be carefully performed in all cases. eighty to 120 kvp with weight-based low milliampereseconds coupled with radiation dose modulation techniques is appropriate in most children for evaluation of pneumonia. multiple ct image acquisitions are usually not needed and the scan field of view should be tailored to the area of interest (especially if following a specific lesion serially over time) to further decrease the overall radiation dose. 10 occasionally, it may be useful to acquire additional expiratory scans to assess air trapping, which is an early imaging finding associated with small airway disease. in this situation, often at least 1 or both ct acquisitions can be obtained using a high-resolution ct (hrct) gap technique. to obtain optimal ct imaging at peak inspiration and close to expiratory residual volume, controlled ventilation (cvict) in infants and young children ( 5 years old) or spirometer-controlled ct in older children may be needed. 11 young children have little intrinsic tissue contrast. therefore, intravenous contrast is almost always needed for ct imaging of infection especially if mediastinal delineation is required. the exception is when hrct is used only for evaluating lung parenchymal and airway disease. breath-holding is usually desirable but can be adapted on a case-by-case basis depending on the needs of the study and the ability of the child to cooperate. however, for the study to be interpretable, gross patient motion should be absent. sedation or anesthesia may be required in infants, young children, or children with intellectual disability. delays between induction of anesthesia and scanning need to be minimized to prevent the potential for lung atelectasis with anesthesia. the anesthesiologist needs to pay close attention to techniques for preventing atelectasis or recruiting lung before the ct imaging. 12 peltola and colleagues 13 recently published their experience with mr imaging of lung infections in children using free-breathing t2-weighted, short tau inversion recovery, and t1-weighted with fat saturation precontrast and postcontrast sequences. their study showed that lung parenchymal, pleural, and lymph node inflammatory abnormalities can be characterized by mr imaging in children with lung infection. therefore, mr imaging might potentially be used to further evaluate suspected, acute complications of pneumonia. 13 children with chronic lung conditions and recurrent infection, such as cystic fibrosis, who are often subjected to substantial radiation exposure from repeated ct studies, would benefit the most from mr imaging evaluation of the lungs instead of ct. although mr imaging may not provide as much detail compared with ct especially with early, small or subtle changes ( fig. 1) , there are promising indications of a role for mr imaging in pulmonary infection. [13] [14] [15] there are several different descriptions of basic patterns of lung diseases on chest radiographs. in this review article, we adopt the one described by hansell and colleagues. 16 almost all of these are seen as part of the spectrum of infectious lung disease ( table 1) . pneumonia and bronchiolitis are both common in infants and have overlapping clinical and imaging features. many studies, particularly those in the developing world, use the term acute lower respiratory tract illness and make no attempt to differentiate pneumonia from bronchiolitis. 17 bronchiolitis occurs in children less than 2 years of age, who typically present with cough, coryza, and wheezing. bronchiolitis is a major cause of morbidity and mortality in infants. 18 respiratory syncytial virus (rsv) is the most common cause 2) . such imaging findings are related to diffuse airway inflammation and partial (air trapping) or complete (atelectasis) airway obstruction. 19 similar changes are seen in older children (>2 years of age) with bronchitis although the features of diffuse small airway obstruction are less common in these older children with larger airways. pneumonia can be divided into several syndromes based on clinical presentation, imaging appearance, underlying predisposition, and cause. pneumonia syndromes that are discussed in this article include acute focal pneumonia, atypical pneumonia, miliary or nodular pneumonia, progressive or fulminant pneumonia, aspiration pneumonias, pulmonary infiltrates with eosinophilia (pie), and chronic or recurrent pneumonia. 20 neonatal pneumonia is briefly highlighted separately. pneumonia in immunosuppressed individuals is included in the general discussion of pneumonia syndromes and then specifically reviewed with regard to the different infections associated with various types of immunodeficiency. acute and chronic complications of pneumonia are also reviewed. characteristics that are typical for acute focal pneumonia include fever more than 38.8 c (102 f), a toxic appearance, and a focal opacity on chest radiographs. pleuritic chest pain in lower-lobe pneumonia is sometimes referred to the abdomen and may be mistaken clinically for an acute abdominal condition. acute focal pneumonia is most often caused by bacterial infection with streptococcus pneumonia. other causes of acute focal pneumonia are summarized in box 1. the chest radiograph of acute focal pneumonia usually shows a dense, typically more peripheral airspace opacity, which may appear segmental, lobar, or spherical ( figs. 3 and 4) . [21] [22] [23] in a febrile child with a spherical density on a chest radiograph, the most likely diagnosis is a round pneumonia but the possibility of an underlying neoplasm may be considered. round pneumonias tend to be solitary, have well-defined borders, and are often located in the perihilar region or posteriorly in the lungs. the radiograph should be carefully scrutinized for features of consolidation such as air bronchograms as opposed to those of a mass such as vascular/airway displacement or bony erosion. a second view such as a lateral radiograph may be helpful because a round pneumonia is often less masslike in appearance on an orthogonal view. this is one of the few scenarios in which radiologic follow-up after about 2 weeks may be useful to document interval resolution of acute pneumonia. 22 acute respiratory distress may be secondary to an intrathoracic mass causing airway or lung compression, especially when there is complete opacification of a hemithorax on radiographs (fig. 5) . intrapulmonary masses including both benign and malignant entities may present clinically with acute superinfection. in addition, other conditions or anatomic variants may be mistaken for pneumonia when a chest radiograph is obtained in a child with a fever and respiratory symptoms. atypical features in pneumonia include prominent extrapulmonary features (eg, headache, sore throat, and pharyngeal exudates), minimal or disparate chest signs on physical examination, subacute onset, nonfocal lung opacity on chest radiographs, lack of clinical response to antibiotics, lack of substantial leukocytosis, and a slow disease course. common infectious causes of atypical pneumonia are summarized in box 2. on chest radiographs, the pulmonary opacity is seen as either airspace, reticular (linear), or bandlike opacities in a nonfocal, patchy, or mottled distribution, with various degrees of density, usually without a single dense area of consolidation (fig. 6 ). most patients with atypical pneumonia can be classified into one of the following subgroups or a combination of two of them based on findings on chest radiographs: 20 acute interstitial pneumonia chest radiographs show a patchy, nonfocal reticular pattern. causes of acute interstitial pneumonia include self-limited viral infections and other pathogens. subacute minimal patchy pneumonia chest radiographs show 1 or more patches of minimal foci of airspace opacity. the most common causes of subacute minimal patchy pneumonia are mycoplasma pneumoniae, chlamydia pneumoniae, and adenoviruses. chest radiographs show a dense focal airspace opacity that is segmental or subsegmental. most of the other features of acute focal pneumonia are absent. tuberculosis needs to be excluded in these patients. most children exposed to mycobacterium tuberculosis do not develop active disease but can have latent foci that may reactivate at a later date particularly if they become immunosuppressed or debilitated. primary infection of mycobacterium tuberculosis is more likely in infants with local spread from the initial parenchymal/lymph node complex to form larger single or multifocal parenchymal lesions, typically with prominent hilar and mediastinal lymph node involvement ( fig. 7) and occasional pleural or pericardial disease. the primary focus as well as involved nodes may cavitate with liquefaction of the caseous material and ultimately calcification (see fig. 7 ). enlarged lymph nodes may encroach on adjacent bronchi and cause bronchial narrowing with resultant air trapping or collapse in the distal lung (fig. 8) . distant spread to other organs may occur either via lymphatics or hematogenously (including military lung involvement). 24, 25 infections with more than 1 organism may cause the atypical pneumonia pattern, resulting in confusing persistence of the illness or prominent findings in another organ system. an example of this situation is influenza infection with superimposed typical or atypical pneumonia (see fig. 6b ). the more common mimics that simulate the appearance of atypical pneumonia syndromes are summarized in box 3. miliary or nodular pneumonia is characterized by chest radiographic findings of multiple miliary or larger nodular opacities. miliary pneumonia in pediatric patients is seen most commonly in tuberculous and fungal infections (fig. 9 ). nodular pneumonia (including reticular and reticulonodular patterns) in pediatric patients is seen in septic emboli, viral pneumonia, lymphocytic interstitial pneumonia associated with epstein-barr virus (ebv) infection with underlying human immunodeficiency virus (hiv) infection, and some fungal and bacterial infections (box 4; figs. 10 and 11). 25, 26 septic pulmonary emboli usually occur secondary to a focal staphylococcus aureus infection (eg, right-sided bacterial endocarditis, septic thrombophlebitis, osteomyelitis, soft tissue infection, or urinary tract infection). the pulmonary nodules in septic emboli may cavitate (see fig. 11 ). 27 mimics of the pattern of miliary or nodular pneumonia are summarized in box 5. pneumonia is deemed progressive when it becomes radiologically and clinically worse despite antibiotic therapy that should be effective against the presumed cause. in this situation, the cause is often nonbacterial pathogens and mimics should also be carefully considered. fulminant pneumonia is defined as a severe bilateral pneumonia with an unusually rapid progression clinically or radiologically, over 24 to 48 hours after initial presentation. a common cause of progressive or fulminant pneumonia is the influenza virus during an epidemic. uncommon infectious causes of this pattern and mimics are summarized in boxes 6 and 7, respectively ( fig. 12 ). 20 aspiration pneumonia refers to the pulmonary consequences of abnormal entry of fluid, particulate matter, or endogenous secretions into the lower airways. aspirated material can be relatively inert, toxic, or oropharyngeal secretions. the most commonly aspirated materials in children include oropharyngeal secretions, gastric contents, water, hydrocarbon, lipid, and foreign bodies. radiographic pulmonary opacities related to aspiration may have an upper rather than lower lobe distribution when the child aspirates in the supine position. bacterial aspiration pneumonia is an infectious process caused by the inhalation of oropharyngeal secretions that are colonized by pathogenic bacteria. the basic defect leading to bacterial aspiration pneumonia is failure of the normal oropharyngeal defense mechanisms. the patient typically has a depressed state of consciousness, abnormal swallowing, a neuromuscular defect that prevents adequate coughing, or an abnormal connection between the airway and esophagus (such as an h-type tracheoesophageal fistula). acute lung aspiration (mendelson syndrome) is an acute chemical injury caused by inhalation of gastric contents. in neurologically normal children, gastric aspiration usually occurs as a complication of anesthesia. the diagnosis of acute aspiration is mainly clinical and usually involves witnessed inhalation of vomitus or tracheal suctioning of gastric contents. 28, 29 chronic lung aspiration (cla) is repeated passage of food, gastric reflux, or saliva into the subglottic airways that causes chronic or recurrent respiratory symptoms. cla may present with chronic cough, wheeze, noisy breathing, choking during feeding, recurrent episodes of pneumonia or bronchitis, and failure to thrive. chronic aspiration often results in progressive lung disease, recurrent pneumonia, chronic airway inflammation, bronchiectasis, and respiratory failure. it is a major cause of death in children with severe neurologic disorders (fig. 13) . pulmonary aspiration may occur as a result of swallowing dysfunction, gastroesophageal reflux, and inability to adequately protect the airway from oral secretions or a combination of these. anatomic conditions that predispose to aspiration lung disease include esophageal stricture or obstruction (eg, vascular ring, foreign body, achalasia), cleft palate, tracheoesophageal fistula (fig. 14) , laryngeal cleft, and bronchobiliary fistula. 28, 29 aspiration related to near-drowning occurs when fluid enters the lungs without being prevented by laryngospasm. it typically manifests as pulmonary edema radiographically. 30 in a recent series of 83 children, secondary infections from aspiration related to near-drowning were rare. 31 hydrocarbon pneumonia is an acute, intense chemical pneumonitis after unintentional aspiration of volatile hydrocarbon compounds. most cases of hydrocarbon pneumonia occur in children. chest radiographs typically show bilateral, scattered pulmonary densities with middle and lower zone predominance. such densities may become confluent and progress to acute respiratory distress syndrome (ards) and respiratory failure. they typically worsen over the first 72 hours and then clear over the next few days. however, occasionally radiographic changes may take weeks to months to be cleared. obstructive emphysema, pneumatoceles, subsegmental, or segmental atelectasis may also be seen. 32 lipoid pneumonia is a rare form of pneumonia caused by inhalation or aspiration of a fatty substance. oral administration of various oils is a common cultural practice, including mineral oil, olive oil, shark liver oil, cod liver oil, coconut oil, and ghee. such oily materials can readily slide into the airway even in normal infants and young children without eliciting a cough reflex and are poorly removed by cilia. lipoid pneumonias are typified by mild, subacute, or chronic clinical findings with accompanying marked radiographic changes. chest radiographs of children with lipoid pneumonia typically show bilateral parahilar illdefined, airspace opacities. in a series of 7 pediatric patients, ct showed dense consolidation surrounded by ground-glass opacity with a geographic lobular distribution. 33 within the dense consolidations, areas with relatively low attenuation were identified in only 1 patient. therefore, low-density consolidation in the posterior lungs is an infrequent ct finding in the diagnosis of lipoid pneumonia in children (fig. 15 ). interlobular septal thickening in areas of ground-glass opacity (ie, crazy paving pattern) has also been described in children with lipoid pneumonia. 33 lipoid pneumonias may be complicated by superimposed infection especially with atypical mycobacteria. slow recovery usually takes place with cessation of the oil administration. there may be residual scarring/fibrosis especially with animal rather than vegetable oils. 34, 35 foreign body aspiration can also result in pneumonia. accidental aspiration of both organic and nonorganic foreign bodies is a cause of childhood morbidity and mortality, requiring prompt recognition and early treatment to minimize the potentially serious and sometimes fatal consequence. eating is the most common circumstance during which it occurs, with small food items being the most common foreign bodies aspirated. coughing, choking, acute dyspnea, and sudden onset of wheezing are the most common symptoms. clinical signs of foreign body aspiration have low positive predictive values. chest radiographs are the initial imaging modality for patients with clinically suspected tracheobronchial aspiration of a foreign body. chest radiographs may show air trapping, atelectasis, a radiopaque foreign body (rare), or be normal (fig. 16) . 36 when the routine inspiratory chest radiograph is unhelpful or confusing, inspiratory and expiratory radiographs (in a cooperative child) or bilateral decubitus views (in a younger child unable to follow breathing instruction) are useful in confirming focal or unilateral air trapping. in selected cases, ct (possibly integrated with virtual bronchoscopy) may be considered to exclude a foreign body. ct evaluation may avoid bronchoscopy or provide the exact location and postobstructive complications of the foreign body before bronchoscopy. 37 an underlying chronic unrecognized airway foreign body should be considered among other causes of recurrent or chronic pneumonia, particularly in the pediatric population (see fig. 16 ). pie syndrome comprises a group of heterogeneous disorders having the common findings of lung disease and eosinophilia in the peripheral blood, bronchoalveolar lavage fluid, or pulmonary interstitium. pie syndrome is rare in children. a subclassification for the pie syndromes in children is summarized in box 8. 38, 39 infectious causes of pie syndrome are uncommon and include chlamydia trachomatis (especially in infants less than 3 months of age), allergic bronchopulmonary aspergillosis (in asthmatics and cystic fibrosis), parasitic larvae in lungs (toxocara, ascaris, and others), and fungi (eg, cryptococcus, candida species). 20 the radiographic findings in pie syndromes tend to be nonspecific. chest radiographs may show interstitial, alveolar, or mixed (interstitial and alveolar) infiltrates, which tend to be bilateral and diffuse. certain pie syndromes may be associated with more specific findings. the classic radiographic appearance of chronic eosinophilic pneumonia is characterized by peripheral infiltrates with sparing of the central lung zones. this radiographic appearance has been described as the "photographic negative of pulmonary edema." 40 bronchiectasis with mucoid impaction is generally present on chest radiographs or ct in patients with allergic bronchopulmonary aspergillosis (fig. 17) . 41 acute eosinophilic pneumonia is frequently associated with small bilateral pleural effusions. imaging is often helpful in determining the extent of disease, localizing the potential sites for lung biopsy, and in assessing response to therapy once treatment has begun. 38 chronic pneumonia is defined as a pulmonary opacity that does not improve within 1 month. it is best classified from the anatomic pattern, as focal, interstitial, with hilar lymphadenopathy, or with cysts, cavities, or spherical masses. spherical masses, with or without cavitations, are often features of an infectious cause. infectious causes and mimics of this pattern are summarized in boxes 9 and 10 (see fig. 16 ; figs. [18] [19] [20] . 42 obstructive atelectasis may both mimic and predispose to chronic pneumonia. it may have many underlying causes, including foreign body, mucoid impaction, narrowed bronchus, and extrinsic bronchial compression by cardiovascular anomalies, lymphadenopathy, tumor, or postpneumonic inflammatory changes. anomalies of the lung, mediastinum, and diaphragm that may mimic an acute or chronic pneumonia pattern include atypical thymus, diaphragmatic eventration and hernia, tracheal bronchus, lung hypoplasia, and congenital bronchopulmonary malformations (bpms). 20 several of these lesions, such as the bpms, predispose to recurrent or chronic infection but differentiating an infected from uninfected lesion may be difficult or impossible on imaging. sometimes having previous imaging for comparison is helpful in terms of features such as the new presence of fluid in a previously air-filled cavity or perilesional consolidation. recurrent pneumonia is defined as more than 1 episode within a 1-year period or more than 3 episodes in a lifetime. many children with a chronic pulmonary lesion (especially a congenital anomaly) are believed to have recurrent pneumonias if chest radiographs are taken only during a febrile illness. recurrent pneumonias may be either focal or interstitial (linear). underlying abnormalities that may predispose to recurrent focal pneumonia include chronic aspiration (see section on aspiration pneumonia), congenital heart disease, bronchopulmonary foregut malformations (including bpms with enteric-respiratory tract fistula), airway abnormalities (foreign body, stenosis, bronchiectasis, cystic fibrosis, immotile cilia disease), paralysis or eventration of the diaphragm, and congenital, acquired, and iatrogenic immune deficiencies. 43, 44 recurrent interstitial pneumonia may be secondary to asthma, hypersensitivity pneumonitis, or pneumonias in children with aids (including pneumocystis jiroveci pneumonia, lymphoid interstitial pneumonitis, and recurrent streptococcus pneumoniae infection) (see fig. 10 ). 20 neonatal lung infections can be generally classified into 3 types depending on the initial source of neonatal infection: transplacental, perinatal, and postnatal (including nosocomial) infections. transplacental infections enter the fetus hematogenously via the umbilical cord. most infants affected with transplacental infections typically recurrent aspiration caused by tracheoesophageal fistula without esophageal atresia in a 6day-old girl who presented with recurrent episodes of apnea, cyanosis, and choking desaturations. barium esophagram shows an oblique connection (red arrow) coursing anterosuperiorly from the esophagus to the trachea at the level of the thoracic inlet. contrast has opacified the central tracheobronchial airways. inferior to the fistula, there is a focal mild narrowing of the esophagus (blue arrow), raising concern for a congenital esophageal stricture. manifest systemic and multiorgan disease rather than a primary lung infection. the most common transplacental infection is caused by cmv, which manifests as a diffuse reticulonodular pattern. 45 other less common, transplacentally acquired pneumonias include rubella, syphilis, listeria monocytogenes, and tuberculosis. perinatal infections can be acquired via ascending infection from the vaginal tract (most commonly group b streptococcus or escherichia coli), transvaginally during the birth process, or nosocomially in the neonatal period. 46 radiographic findings in neonatal pneumonia are nonspecific in differentiating between various etiologic pathogens, as well as differentiating pneumonia from other causes of respiratory distress (eg, transient tachypnea of the newborn, surfactant deficiency disease, and meconium aspiration). the most common radiographic manifestation of neonatal pneumonia is bilateral coarse perihilar reticular densities with possible scattered airspace opacities (fig. 21) . solitary lobar consolidations are uncommon. 47 there is an association between group b streptococcal pneumonia and an ipsilateral diaphragmatic hernia. 48 chest radiographs in group b streptococcal sepsis can mimic the diffuse ground-glass opacity seen in surfactant deficiency disease. however, the presence of this finding in a full-term infant or the presence of cardiomegaly or pleural effusions may help to differentiate group b streptococcal infection from surfactant deficiency disease. 49 pneumonia caused by chlamydia trachomatis occurs in about 10% of infants born to women who carry this organism in their genital tract and becomes symptomatic more than 2 to 3 weeks after birth. chlamydia pneumonia is characterized by hyperinflation and bilateral diffuse reticular perihilar densities that are disparate with relatively mild clinical symptoms. 50 concomitant conjunctivitis, which used to be a useful clue to the cause, is prevented by the routine instillation of antibacterial eye drops at birth. neonates with chlamydia pneumonia frequently have accompanying eosinophilia. bordetella pertussis has recently resurfaced to produce epidemics of infection, probably related to waning community immunity. the clinical presentation of pertussis in the newborn may lack some features (characteristic whooping cough and fever) typical of the disease in older children. the clinical presentation of the most severely affected newborns may be dominated by marked respiratory distress, cyanosis, and apnea. mortality caused by pertussis usually results from secondary pneumonia, encephalopathy, cardiac failure, or pulmonary hypertension. a suggested mechanism for pulmonary hypertension that may develop in newborns with bordetella pertussis infection is formation of leukocyte thrombi in pulmonary venules secondary to hyperleukocytosis. 51, 52 the classic radiographic appearance in pertussis is the shaggy heart with diffuse peribronchial cuffing related to airway inflammation. however, chest radiographic findings such as hyperaeration, atelectasis, segmental consolidation, and lymphadenopathy are usually nonspecific. recurrent pulmonary infection, with bacterial, viral, or occasionally fungal pathogens, are frequent problems in neonates undergoing prolonged hospitalization and complex treatments, especially in premature infants with chronic lung disease. radiographic alterations caused by infection may be subtle when superimposed on chronic lung changes. 47 pneumonia is a common disease in the immunocompromised host. immunocompromise may be congenital (congenital immunodeficiencies), acquired (hiv/aids, malnutrition) or iatrogenic (during chemotherapy for cancer or after tissue transplantation). immunodeficient states can result in: (1) humoral immunodeficiency (hypogammaglobulinemia, functional b-lymphocyte deficiency accompanying hiv infection); (2) cellular immunodeficiency (severe malnutrition, late stages of aids, some congenital immunodeficiencies such as digeorge syndrome); and (3) neutrophil dysfunction and neutropenia (chronic granulomatous disease, pure neutropenia). iatrogenic immunodeficiencies may be a combination of neutropenia or neutrophil dysfunction, innate or drug-induced defective lymphocyte function, and drug-induced breaks in the oral and intestinal mucosal barriers. 53 the causes of pneumonia in the immunocompromised host consist not only of the same agents that cause pneumonia in the normal host but also of several opportunistic agents depending on the type and severity of immunodeficiency as well as temporal pattern after chemotherapy or transplant. in an immunocompromised child with a noncontributory chest radiograph and clinical findings that could be attributed to a lung infection, chest ct is often required for evaluation of a possible lung infection. in this situation, there are 4 major advantages of chest ct over chest radiographs. first, the presence, pattern, and extent of the disease process are better visualized. second, more than 1 pattern of abnormality may be detected, suggesting dual pathologic entities. third, invasive diagnostic procedures (eg, bronchoscopy or needle aspiration) can be more precisely planned. fourth, ct also allows for increased sensitivity in assessment of the response to treatment. 54, 55 although the radiographic or ct appearance might not be specific for a pathogen, knowledge of the clinical setting in combination with the type and severity of immunodeficiency and imaging pattern may narrow the differential diagnosis. a commonly encountered clinical issue is the possibility of fungal infection in immunocompromised children. the hallmark ct finding of fungal infections is the presence of pulmonary nodules. such pulmonary nodules are often clustered peripherally and can show poorly defined margins, cavitation, or a surrounding halo of ground-glass opacity (ct halo sign) (fig. 22) . the ct halo sign is a nonspecific finding and represents either hemorrhage around a nodule or neoplastic or inflammatory infiltration of the lung parenchyma. in the immunocompromised host, the ct halo sign can be seen most commonly with fungal infections (eg, aspergillosis, mucormycosis, or candida) but also in viral infections (eg, cmv infection, herpes infection), organizing pneumonia, and pulmonary hemorrhage. 54, [56] [57] [58] [59] [60] [61] microorganisms associated with severe pneumonia in immunodeficiency states are summarized in box 11. lip is a form of subacute pneumonia seen in several states of immunologic dysregulation, particularly in children with hiv infection. lip is characterized by micronodules of proliferating lymphoid tissue associated with infection by ebv. chest radiographs in lip show a characteristic diffuse, bilateral nodular, or reticulonodular pattern 19 . wegener granulomatosis mimicking chronic cavitary pneumonia in a 15-year-old male who presented with hemoptysis and respiratory distress. initial chest radiograph showed bilateral confluent airspace opacities secondary to diffuse pulmonary hemorrhage (not shown). contrast-enhanced ct obtained 9 days after initial presentation shows multifocal consolidation with cavitation (arrow), ground-glass opacities, and a right pneumothorax. (see fig. 10 ). other recognized associated imaging findings of lip include consolidation, mediastinal adenopathy, and bronchiectasis. 26, 58, 62 radiologic features in common hiv-associated infections in pediatric patients are summarized in table 2 . in pediatric patients with iatrogenic deficiencies of the immune system, pneumonia is commonly caused by opportunistic bacteria and fungi, acquired nosocomially or from resident mucosal flora (fig. 23) . in addition, after solid-organ transplantation although total immunoglobulin levels are normal, children and adolescents may be susceptible to encapsulated bacteria (eg, streptococcus pneumoniae, haemophilus influenzae). viruses that commonly cause pneumonia in healthy hosts (eg, rsv, influenza, parainfluenza viruses, human axial contrast-enhanced ct shows multiple bilateral pulmonary nodules, some have rims of groundglass opacity (arrow), which is also known as the ct halo sign. microorganisms associated with severe pneumonia in immunodeficiency states in pediatric patients metapneumovirus, and adenovirus) display greater virulence in both children and adults after solid-organ or human stem cell transplantation, particularly when cellular immunity is profoundly suppressed. in the posttransplant setting, ebv can cause progressive pulmonary disease in the form of posttransplantation lymphoproliferative disease. 53 in 2 studies of hrct in bone marrow transplant recipients, the most useful distinguishing feature was the presence of large nodules and visualization of the halo sign, suggestive of fungal infection. 63, 64 after solid-organ transplantation, nosocomially acquired bacteria predominate as a cause of pneumonia in the first month. later, viruses, especially cmv and adenovirus, as well as listeria, nocardia, and aspergillus, may be the cause. after more than 6 months after solid-organ transplantation, community-associated bacterial pneumonia becomes more common. 53 a variety of noninfectious pulmonary processes can present with acute or subacute clinical findings mimicking pulmonary infection. 54 these findings include alveolar hemorrhage, pulmonary edema, drug reaction, idiopathic interstitial pneumonia, benign and malignant lymphoproliferative disorders, constrictive bronchiolitis, bronchiolitis obliterans with organizing pneumonia, and chronic graft-versus-host disease. the ct findings of many of these entities are nonspecific. 54, [57] [58] [59] [60] [61] abbreviations: alveolar, focal of diffuse alveolar pattern; interstitial, focal or diffuse interstitial pattern; ln, lymphadenopathy; 1 and 11, refer to relative frequency of radiographic finding with each organism/disease. acute complications of pneumonia can be categorized as suppurative lung parenchymal complications and pleural complications. suppurative lung parenchymal complications span a spectrum of abnormalities and include cavitary necrosis, lung abscess, pneumatocele, bronchopleural fistula (bpf), and pulmonary gangrene. the name given to the suppurative process depends on several factors including the severity and distribution of the process, condition of the adjacent lung parenchyma, and temporal relationship with disease resolution. 65, 66 cavitary necrosis cavitary necrosis represents a dominant area of lung necrosis associated with a variable number of thin-walled cysts. characteristic findings on ct for cavitary necrosis include loss of normal lung architecture, poor parenchymal enhancement, loss of the lung-pleural margin, and multiple thin-walled fluid-filled or air-filled cavities (fig. 24) . cavitary necrosis is seen earlier in chest us or ct compared with chest radiography because these cavities need to be filled with air to be visible on chest radiographs. such cavities filled with air are accomplished only after communication with bronchial airways. most pediatric patients can be managed successfully with conservative treatment. follow-up chest radiographs typically show complete or near-complete resolution of the cavitary necrosis (see fig. 24 ). 65, 66 lung abscess lung abscess is a severe complication of pneumonia in children, mostly occurring in the presence of predisposing factors, such as congenital or acquired lung abnormalities, or immunodeficiency. lung abscess represents a dominant focus of suppuration surrounded by a well-formed fibrous wall. the predominant pathogens isolated from primary lung abscesses in children include streptococcal species, staphylococcus aureus and klebsiella pneumoniae. children with a lung abscess have a significantly better prognosis than adults with the same condition. 67 lung abscesses are uncommon in immunocompetent children. on contrast-enhanced ct, a lung abscess appears as a fluid-filled or airfilled cavity with a thick definable, enhancing wall (fig. 25) . 65, 66, 68 although lung abscess in children has been managed successfully for many years with prolonged courses of intravenous antibiotics, the evolution of interventional radiology has seen the accelerated use of percutaneously placed pigtail drainage catheters using us and ct guidance. 67 pneumatocele pneumatocele is a term given to thin, smoothwalled air-filled cysts seen at imaging and may represent a later or less severe stage of resolving or healing lung necrosis (see fig. 24 ). pneumatoceles are most often caused by severe lung infection from staphylococcal pneumonia. however, they may be seen with other bacterial infections including streptococcus pneumonia and after hydrocarbon aspiration. on ct, thin-walled small or large cysts containing air with or without fluid are identified. the wall of a pneumatocele does not enhance. the surrounding lung may be opacified but does not typically show findings of lung necrosis. 65, 66 pneumatoceles usually resolve spontaneously over time although pneumatoceles may be atypically persistent in children with hyper-ige syndrome. large pneumatoceles containing fluid can be a source of ongoing infection and may occasionally require drainage. bronchopleural fistula bpf is defined as a communication between the lung parenchyma or airways and the pleural space. central bpfs (ie, main or lobar bronchi communicating with the pleural cavity) most often develop after traumatic injury to large airways or leak from the bronchial stump after pneumonectomy or lobectomy. the main causes for peripheral bpfs (ie, segmental or more distal airways or lung parenchyma communicating with the pleural cavity) are necrotizing pulmonary infection (ie, cavitary necrosis), trauma, lung surgery, and malignancy. 69, 70 presence of air in the pleural space before aspiration or drainage attempts is suggestive of either a peripheral bpf or infection with a gas-producing organism. multidetector ct with thin-section axial and multiplanar reformation images may show a fistulous tract between the pleural space and peripheral airway or lung parenchyma in peripherally located bpfs (fig. 26) . 70 pulmonary gangrene pulmonary gangrene is a rare complication of severe lung infection with devitalization of lung parenchyma and secondary infection. 71 the primary feature that distinguishes pulmonary gangrene from necrotizing pneumonia and lung abscess is the extent of necrosis and the fact that thrombosis of large vessels plays a prominent role in the pathogenesis. chest imaging shows lobar consolidation with bulging fissures and is followed by tissue breakdown to form many small cavities, which subsequently coalesce into a single large cavity occupying the entire lobe. such a large cavity is filled with fluid and irregular pieces of sloughed lung parenchyma. however, these findings are not invariably present. surgical resection of necrotic tissue is often necessary for proper management of children with pulmonary gangrene. [71] [72] [73] [74] the differential diagnosis of suppurative lung complications includes an underlying cystic axial contrast-enhanced t1-weighted mr image of the brain shows a rim-enhancing brain abscess in the right occipital lobe. the patient underwent right lower lobectomy and craniotomy for resection of these lesions. congenital bpm that has become secondarily infected. prior and follow-up imaging may aid in the distinction. the presence of large, welldefined cysts early in the course of the illness or a systemic arterial supply to the lung may be helpful in suggesting an underlying bpm, although a chronic inflammatory process in the lower lobe can acquire some systemic vascular supply from diaphragmatic vessels. pleural complications from acute pneumonia include parapneumonic effusion and empyema. parapneumonic effusion is defined as a pleural effusion in the setting of a known pneumonia. it may be simple or complicated based on the absence or presence of the infecting organism within the pleural space, respectively. 75 empyema is defined as thick purulent pleural effusion. it may be free-flowing or loculated. progression of a pleural effusion to empyema occurs through 3 stages: exudative, fibrinopurulent, and organization. parapneumonic effusions complicate pneumonia in 36% to 56% of cases in pediatric patients. 76 empyema complicates an estimated 0.6% of all childhood pneumonias. 77 chest radiographs can often detect a parapneumonic collection, although some fluid, especially in a subpulmonic location, may not be visible and is often seen better on a decubitus film. in cases with complete or almost complete opacification of a hemithorax with or without contralateral mediastinal shift, additional erect or decubitus views are unhelpful in defining the quantity or nature of the pleural fluid. us is most helpful in this situation because it can readily distinguish a parapneumonic collection from extensive consolidation or an underlying mass. the us determination of the echogenicity of the pleural collection (anechoic or echogenic) and showing fibrin strands, septations, loculations, or fibrinous pleural rind is helpful in determining appropriate therapy (see fig. 26 ). treatment options for parapneumonic effusions/ empyemas include antibiotics alone, simple tube drainage, chest drain insertion with fibrinolytics, or surgery (eg, video-assisted thoracoscopic surgery or open thoracotomy with decortication). although imaging techniques are used as a guideline, they do not always accurately stage empyema, predict outcome, or guide decisions regarding surgical versus medical management. 75 ct provides a more global overview of pleural and pulmonary abnormality from acute pneumonia, but is poor at differentiating parapneumonic effusion from empyema in pediatric patients. findings on ct, in patients with parapneumonic effusion/ empyema, include: (1) enhancement and thickening of visceral and parietal pleura; (2) thickening and increased density of extrapleural subcostal tissues; and (3) increased attenuation of extrapleural subcostal fat. 78 loculation can be inferred by the presence of a lenticular fluid collection or nondependent air. septations are usually not appreciated on ct (see fig. 26 ). pleuropulmonary infection may occasionally spread to involve the chest wall, including soft tissues and adjacent bones. mycobacterium tuberculosis, aspergillus, and actinomyces are the most common organisms in this scenario. chronic complications or consequences of pneumonia include parenchymal scarring, bronchial wall thickening, bronchiectasis, a predisposition to asthma, constrictive bronchiolitis, fibrothorax and a trapped lung, fibrosing mediastinitis, constrictive pericarditis, and pleural thickening. for practical purposes, bronchiectasis, constrictive bronchiolitis, fibrothorax and trapped lung, and fibrosing mediastinitis are discussed in the following sections. bronchiectasis is defined by the presence of permanent and abnormal dilation of the bronchi. this condition usually occurs in the context of chronic airway infection causing inflammation. bronchiectasis is nearly always diagnosed using hrct. the main diagnostic features of bronchiectasis on hrct are: (1) internal diameter of a bronchus that is wider than its adjacent pulmonary artery; (2) failure of the bronchus to taper peripherally; and (3) visualization of bronchi in the outer 1 to 2 cm of the lung zones (see fig. 17 ; figs. 27 and 28). a wide variety of factors predisposing to the development of bronchiectasis have been identified, including hereditary (cystic fibrosis, ciliary dyskinesia), infective, immunodeficiency (antibody deficiency), obstructive (intrabronchial foreign body), and systemic causes. causes most commonly associated with bronchiectasis are childhood infections, including pneumonia, pertussis, complicated measles, and tuberculosis (eg, mycobacterium tuberculosis and mycobacterium avium complex). [79] [80] [81] constrictive bronchiolitis (bronchiolitis obliterans) constrictive bronchiolitis (bronchiolitis obliterans) is characterized by the presence of concentric narrowing or obliteration of the bronchioles caused by submucosal and peribronchiolar fibrosis. a common cause of constrictive bronchiolitis is previous childhood infection, resulting in the so-called swyer-james syndrome, identifiable as asymmetric hyperlucent lung on chest radiographs. whereas the process may appear unilateral on chest radiographs, there is usually bilateral but asymmetric abnormality on ct (see fig. 28 ). central bronchiectasis and a characteristic mosaic appearance with patchy expiratory air trapping are seen on hrct. causes and associations of constrictive bronchiolitis include previous infections (viral including adenovirus, rsv, influenza, parainfluenza; mycoplasma and pertussis), collagen vascular diseases, previous transplant, toxic fume exposure, ingested toxins, drugs, and cryptogenic constrictive bronchiolitis. 82 pleural fibrosis can result from a variety of inflammatory processes (box 12). the development of pleural fibrosis follows severe pleural inflammation, which is usually associated with an exudative pleural effusion. fibrothorax and trapped lung are 2 uncommon consequences of pleural fibrosis (see fig. 27 ). 83 fibrothorax represents the most severe form of pleural fibrosis. with a fibrothorax, there is dense fibrosis of the visceral and parietal pleural surfaces, leading to fusion of these membranes, contracture of the involved hemithorax (and ipsilateral mediastinal shift), and reduced mobility of the lung and thoracic cage (see fig. 27 ). decortication is the only potentially effective treatment of fibrothorax in patients with severe respiratory compromise. 83, 84 a trapped lung is characterized by the inability of the lung to expand and fill the thoracic cavity because of a restrictive, fibrous, visceral pleural peel (see fig. 27 ). restriction of lung parenchymal expansion and subsequent negative pressure in the pleural space result in filling of the pleural space with pleural fluid (usually a transudate). the diagnosis of a trapped lung implies chronicity, stability over time, and a purely mechanical cause for the persistence of a fluid-filled pleural space. patients with a trapped lung usually do not experience improvement in dyspnea after thoracentesis. in symptomatic patients, decortication should be considered. the underlying lung parenchyma should be assessed before decortication. if the trapped lung is severely diseased and fibrotic, decortication is unlikely to result in lung reexpansion and the procedure does not provide symptomatic benefit. in contrast, lung entrapment is the result of an active inflammatory process or malignancy in the pleural space, leading to a restricted pleural space. pleural fluid from lung entrapment is an exudate, and symptoms in patients with lung entrapment typically improve after thoracentesis. 83, 85 fibrosing mediastinitis fibrosing mediastinitis is a rare condition characterized by proliferation of fibrous tissue within the mediastinum. symptoms are related to compression of the central airways, superior vena cava, pulmonary veins, pulmonary arteries, and esophagus. the most common cause of this disorder is fungal infection, especially histoplasma capsulatum in the united states. 86 pneumonia is an infection of the lung parenchyma caused by a wide variety of organisms in pediatric patients. imaging evaluation plays an important role in children with pneumonia by detecting the presence of pneumonia and determining its location and extent, excluding other thoracic causes of respiratory symptoms, and showing complications such as effusion/empyema and suppurative lung changes. clear understanding of the underlying potential cause, current role of imaging, proper imaging techniques, and characteristic imaging appearances of acute and chronic pneumonias can guide optimal management of pediatric patients with pneumonia. who child health epidemiology reference group. global estimate of the incidence of clinical pneumonia among children under five years of age pneumonia: an eleven-year study in a pediatric practice incidence of community-acquired pneumonia in the population of four municipalities in eastern finland pneumonia: the leading killer of children what imaging should we perform for the diagnosis and management of pulmonary infections? differentiation of bacterial and viral pneumonia in children aetiology of community-acquired pneumonia in children treated in hospital ultrasound of the chest in children (mediastinum excluded) us in the diagnosis of pediatric chest diseases multidetector ct in children: current concepts and dose reduction strategies computed tomography scanning techniques for the evaluation of cystic fibrosis lung disease increased inspiratory pressure for reduction of atelectasis in children anesthetized for ct scan magnetic resonance imaging of lung infections in children follow-up of acute pulmonary complications in cystic fibrosis by magnetic resonance imaging the role of advanced imaging techniques in cystic fibrosis follow-up: is there a place for mri? basic patterns in lung disease the epidemiology of acute respiratory tract infection in young children: comparison of findings from several developing countries susceptibility to bronchiolitis in infants the chest radiograph in acute bronchiolitis moffet's pediatric infectious diseases: a problem-oriented approach the many radiologic facies of pneumococcal pneumonia round pneumonia: imaging findings in a large series of children review of new and newly discovered respiratory tract viruses in children. pediatr emerg care tuberculosis in children: an update tuberculosis in children: an update chest radiographic features of lymphocytic interstitial pneumonitis in hiv-infected children clinical and radiographic spectrum of septic pulmonary embolism aspiration lung disease recurrent pneumonia in children: clinical profile and underlying causes chest radiographs of near-drowned children respiratory complications of accidental drownings in children hydrocarbon pneumonitis squalene aspiration pneumonia in children: radiographic and ct findings as the first clue to diagnosis lipoid pneumonia in children following aspiration of mineral oil used in the treatment of constipation: highresolution ct findings in 17 patients lipoid pneumonia presenting as non resolving community acquired pneumonia: a case report foreign body inhalation in children: an update utilization of low dose multidetector ct and virtual bronchoscopy in children with suspected foreign body aspiration pulmonary infiltrates with eosinophilia syndromes in children parasitic pulmonary eosinophilia peripheral opacities in chronic eosinophilic pneumonia: the photographic negative of pulmonary edema eosinophilic lung diseases: state of the art juvenile laryngeal papillomatosis with pulmonary parenchymal spread. case report and review of the literature recurrent pneumonia in children: a case report and approach to diagnosis assessment of the child with recurrent chest infections radiological imaging of the neonatal chest intra-amniotic infection and premature rupture of the membranes imaging of medical disease of the newborn lung neonatal radiology. acquired diaphragmatic hernia with group b streptococcal pneumonia radiographic findings in early onset neonatal group b streptococcal septicemia chlamydia trachomatis in children pertussis with severe pulmonary hypertension in a newborn with good outcome-case report malignant pertussis in the pediatric intensive care unit principles and practice of pediatric infectious diseases revised reprint fungal pulmonary infections after bone marrow transplantation: evaluation with radiography and ct investigation and management of a child who is immunocompromised and neutropoenic with pulmonary infiltrates ct halo sign: the spectrum of pulmonary diseases thoracic mycoses from opportunistic fungi: radiologic-pathologic correlation thoracic disease in children with aids childhood leukemia: diagnostic accuracy of bedside chest radiography for severe pulmonary complications acute lung disease in the immunocompromised host: ct and pathologic examination findings cytomegalovirus pneumonia in transplant patients: ct findings pulmonary infections in hiv-positive children pulmonary infections after bone marrow transplantation: high-resolution ct findings in 111 patients pulmonary infections following bone marrow transplantation: high-resolution ct findings in 35 paediatric patients pneumonia in children: decreased parenchymal contrast enhancement-ct sign of intense illness and impending cavitary necrosis cavitary necrosis complicating pneumonia in children: sequential findings on chest radiography lung abscess in children lung abscess in a child with mycoplasma pneumoniae infection peripheral bronchopleural fistula: ct evaluation in 20 patients with pneumonia, empyema, or postoperative air leak multi-detector row computed tomographic evaluation of bronchopleural fistula: correlation with clinical, bronchoscopic, and surgical findings gangrene of the lung: treatment in two stages massive pulmonary gangrene pulmonary gangrene. a complication of bacterial pneumonia pulmonary gangrene complicating bacterial pneumonia imaging of parapneumonic pleural effusions and empyema in children therapy of parapneumonic effusions in children: videoassisted thoracoscopic surgery versus conventional thoracostomy drainage management of empyema in children ct appearance of parapneumonic effusions in children: findings are not specific for empyema an investigation into causative factors in patients with bronchiectasis the pathophysiology of bronchiectasis bronchiectasis: an update bronchiolar disorders: a clinical-radiological diagnostic algorithm pleural fibrosis physiological evaluation of results of pulmonary decortication trapped lung sclerosing mediastinitis mimicking anterior mediastinal tumor key: cord-305786-06dpjik8 authors: sandora, thomas j.; harper, marvin b. title: pneumonia in hospitalized children date: 2005-07-09 journal: pediatr clin north am doi: 10.1016/j.pcl.2005.03.004 sha: doc_id: 305786 cord_uid: 06dpjik8 pneumonia is one of the most common infections in the pediatric age group and one of the leading diagnoses that results in overnight hospital admission for children. various micro-organisms can cause pneumonia, and etiologies differ by age. clinical manifestations vary, and diagnostic testing is frequently not standardized. hospital management should emphasize timely diagnosis and prompt initiation of antimicrobial therapy when appropriate. issues of particular relevance to inpatient management are emphasized in this article. pneumonia is one of the most common infections in the pediatric age group and one of the leading diagnoses that results in overnight hospital admission for children. in 2001, 198 ,000 patients younger than 15 years were discharged from hospitals in the united states with a primary diagnosis of pneumonia [1] . in north america, the annual incidence of pneumonia in children younger than 5 years is 30 to 45 cases per 1000; in children aged 5 years and older, the annual incidence is 16 to 22 cases per 1000 [2, 3] . in developing countries, which account for more than 95% of episodes of clinical pneumonia worldwide, researchers estimate that more than 150 million new cases occur annually in children younger than 5 years [4] . pneumonia can be classified as either community-acquired pneumonia (cap) or nosocomial pneumonia; hospital-acquired pneumonia may be ventilatorassociated pneumonia or may be acquired in the absence of mechanical ventilation. ventilator-associated pneumonia differs in several respects from cap and is addressed separately in this article. although no precise definition is universally applied, cap is generally defined as an infection of the lungs that is marked by symptoms of acute infection (ie, fever, cough, or dyspnea) and is typically associated with abnormal auscultatory findings (eg, rales or altered breath sounds) or the presence of an acute infiltrate on chest imaging in an 0031 individual not hospitalized or residing in a long-term care facility for at least 14 days before onset of symptoms [5] . a large number of micro-organisms can cause pneumonia in children. table 1 lists the most frequent etiologic agents that are identified in each age group. overall, viruses are responsible for a large percentage of cases of cap in the pediatric age group, and they are particularly common in children aged 3 weeks to 4 years [6] . in a recent us study of children aged 2 months to 17 years who were hospitalized for pneumonia, 45% were found to have a viral etiology [7] . in general, the most frequently isolated respiratory viruses are respiratory syncytial virus, parainfluenza viruses, influenza a and b, and adenovirus, although other viruses may occur in specific settings (eg, cytomegalovirus or herpes simplex infection in neonates). most cases of viral pneumonia can be managed without invasive diagnostic testing, and aside from supportive care, no specific antimicrobial therapy is generally required. for these reasons, the remainder of this article focuses on bacterial pneumonia, although important distinctions related to viral etiologies are highlighted when appropriate. the epidemiology of bacterial cap differs by age and has been impacted by vaccine strategies. from birth to 3 weeks of age, the most common causes of pneumonia are group b streptococci and gram-negative rods (particularly enterics such as escherichia coli). although viruses predominate from 3 weeks to 3 months of age, bacterial pneumonia can occur in this age group. afebrile pneumonia at this age is frequently caused by chlamydia trachomatis; this agent rarely requires hospital admission unless found in combination with another respiratory tract pathogen, such as respiratory syncytial virus or pertussis. streptococcus pneumoniae is the most common bacterial cause of febrile pneumonia among children aged 3 weeks to 4 years. a recent study from texas found that 60% of children between 2 months and 17 years of age who were admitted with pneumonia had a bacterial pathogen isolated, and s. pneumoniae was confirmed in 73% of those cases [7] . other less commonly isolated bacteria include haemophilus influenzae (historically type b before widespread vaccine use, but currently includes nontypable h. influenzae), streptococcus pyogenes, staphylococcus aureus, and other streptococcal species (including the streptococcus milleri group). in children aged 5 years and older, the most common bacterial pathogens are mycoplasma pneumoniae and chlamydophila pneumoniae (previously known as chlamydia pneumoniae). these atypical agents account for nearly one fourth of all cases of bacterial pneumonia among school-aged children and adolescents [7] . pneumococcus remains high on the list of agents identified table 2 provides a list of these less frequent pathogens and the risk factors or clinical situations that should prompt consideration of more unusual infections. finally, it is important to remember that a significant proportion of cases of pediatric pneumonia represents a mixed infection [8] . pathogen, host, and environmental factors all play a role in the development of pneumonia, which typically begins with tracheal colonization by the infecting micro-organism [9] . the initial line of defense against the establishment of a respiratory pathogen is the barrier defenses of the airway, namely the mucosal barrier of respiratory epithelium and the mucociliary apparatus that is responsible for clearing foreign material and micro-organisms from the airway [10] . once the lower respiratory tract is inoculated with a sufficient burden of bacteria, the normal inflammatory response that fights infection (which includes components such as antibodies, complement, phagocytes, and cytokines) also results in damage to functioning lung tissue [11] . the bacteria that commonly cause pneumonia also possess specific virulence factors that enhance their survival and propagation while concurrently resulting in injury to the pulmonary host. for example, s. pneumoniae contains pneumolysin, a pore-forming protein that enables the bacterium to kill host cells, which results in complement activation and a vigorous inflammatory response [12] . pneumonia also may result from direct seeding of the lung tissue after bacteremia, which may be a particularly important mechanism for bacteria such as pneumococcus and s. aureus. several studies have evaluated the use of various clinical symptoms and signs in children with pneumonia. tachypnea widely has been shown to be the most sensitive indicator [13] [14] [15] [16] . the world health organization defines tachypnea as a respiratory rate (rr) of more than 60 breaths/min in infants younger than 2 months of age, rr of more than 50 breaths/min from ages 2 to 12 months, and rr of more than 40 breaths/min in children older than 12 months [17] . several studies have found that cutoffs of more than 50 breaths/min in children younger than 12 months and more than 40 breaths/min in children aged 12 to 35 months provide the greatest combination of sensitivity and specificity in identifying children with lower respiratory infections [18] [19] [20] , although one study showed that a single value of 50 breaths/min for all ages was equally useful [21] . the precise predictive value depends on the underlying prevalence of disease [22] , but a diagnosis of pneumonia in the industrialized world rarely would be made based solely on the presence of tachypnea (which is present in many other childhood illnesses, including bronchiolitis and asthma). fever and cough are also frequently present in children with pneumonia, and clinical signs may include retractions or abnormal auscultatory findings, such as rales or decreased breath sounds, which tend to be more specific as indicators of lower respiratory tract infection [23] [24] [25] [26] . other less specific indicators that may be seen in children include malaise, emesis, abdominal pain, and chest pain (which is particularly suggestive of bacterial pneumonia as opposed to viral etiologies, especially when pleuritic in nature). wheezing may be seen in children with bacterial pneumonia [25] but is more suggestive of bronchiolitis or viral lower respiratory tract infection. the diagnosis of pneumonia is likely in patients who present with fever, cough, and tachypnea and who have infiltrates on chest radiography. various other diseases can present with a similar constellation of signs and symptoms, however. the differential diagnosis may include upper respiratory tract infection, bronchiolitis, congestive heart failure, pulmonary embolism, thoracic tumors, or inflammatory disorders (such as systemic vasculitis), among other entities [27] . table 3 reviews diseases that should be considered when infiltrates are present on chest radiography. several laboratory studies may be helpful in establishing a diagnosis of pneumonia in children. leukocytosis may be present; in one study, 26% of children who presented to the emergency department with fever and a white blood cell count of more than 20,000/mm 3 were found to have occult pneumonia on chest radiography [26] . pneumonia also has been shown to be the most common diagnosis in children with white blood cell counts of 25,000/mm 3 or more and even in children with white blood cell counts of 35,000/mm 3 or more [28] . other inflammatory markers, such as c-reactive protein and the erythrocyte sedimentation rate, are generally elevated. one study found that patients with an elevated c-reactive protein were more likely to have pneumonia of proven or probable bacterial cause as opposed to viral or mycoplasma pneumonia [29] . cultures of the blood for bacteria traditionally have been recommended in consensus guidelines for the diagnosis and management of pneumonia, particularly when a bacterial cause is suspected [30] [31] [32] . this recommendation stems from previous work, which suggested that the rate of bacteremia in adults hospitalized for pneumonia was in the range of 10% to 30%. several more recent studies have attempted to evaluate the use of blood cultures in the diagnosis of pneumonia, however. in these studies, the yield of blood cultures has been lower-generally ranging from 3% to 11%-and the management of pneumonia is rarely altered [33] [34] [35] . various organisms may be detected, but s. pneumoniae has been the most frequently isolated pathogen in these studies. it is likely that the current rate of bacteremia will be lower because of the introduction of the pneumococcal conjugate vaccine in the routine childhood immunization schedule. with increasing resistance to antimicrobial agents and limited available data regarding the use of cultures of the blood among children with pneumonia since the widespread use of the conjugate pneumococcal vaccine, we feel that patients with disease severe enough to require hospital admission and parenteral antimicrobial therapy generally should have cultures of blood sent before therapy. although it is uncommon to identify a pathogen, the identification of a specific organism (such as s. pneumoniae or s. aureus) and its associated antimicrobial susceptibilities can be helpful (especially in more severe cases or when pleural effusions are present). several other microbiologic tests can be considered as diagnostic aids. culture of the sputum has had variable use in published studies, with yields ranging from 5% to 34% [34, 36] . to be considered reliable (ie, bronchial in origin as opposed to oropharyngeal), a sputum sample should contain fewer than ten epithelial cells per low-powered field [37] . it is difficult to obtain a good sputum sample from children, who often have a nonproductive cough. in general, a valuable sample of expectorated sputum is difficult to obtain from a preschoolaged child. although a sputum gram stain with a single predominant organism, leukocytes, and few epithelial cells can be helpful, a negative gram stain result never should exclude pneumonia as a possible diagnosis. pneumococcal urinary antigen testing is generally not recommended as a diagnostic modality in pediatric pneumonia; despite good sensitivity, the specificity of this test is low (because it is frequently positive in individuals with nasopharyngeal colonization, particularly young children) [38, 39] . viral diagnostics (either culture or antigen detection using direct fluorescent antibodies) are not necessary in most routine pneumonia cases, but they can be useful in certain circumstances (including cases that involve immunocompromised patients or to help guide infection control precautions). mycoplasma infection can be identified using serology (a positive igm is an indicator of acute infection); polymerase chain reaction testing is also available and has higher sensitivity and specificity [40] , but it is rarely necessary outside of the research setting. c. pneumoniae may be detected rapidly by direct fluorescent antibodies from a nasopharyngeal specimen or diagnosed by serology. legionella urinary antigen is the diagnostic modality of choice when legionella pneumophila infection is suspected, and the test can remain positive for weeks after acute infection. it is important to remember that the urinary antigen is negative in cases that involve other species of legionella. the decision to perform a skin test with purified protein derivative in patients who present with pneumonia should be based on the presence of risk factors that would increase the likelihood of tuberculosis or when specific radiographic findings suggest mycobacterial disease (such as the presence of mediastinal adenopathy). the diagnosis of pneumonia frequently is made or confirmed by the presence of consolidation or infiltrates on chest radiography. the presence of respiratory signs (eg, cough, tachypnea, and rales) increases the likelihood of a positive chest radiograph, and one meta-analysis suggested that infants younger than 3 months of age with a temperature of 100.58 f or higher but with no clinical findings of pulmonary disease (defined as rales, ronchi, retractions, wheezes, tachypnea, coryza, grunting, stridor, nasal flaring, or cough) do not require routine chest radiography, because the probability of a normal chest radiograph in the absence of these findings is at least 98.98% [41, 42] . when chest radiographs are obtained in patients who have pneumonia, various patterns may be seen. alveolar infiltrates are seen more frequently in bacterial pneumonia, whereas viral infection is more frequently associated with an interstitial pattern [43] . these distinctions are not universal, however, and studies have confirmed that patients with viral pneumonia can present with infiltrates that have a lobar or alveolar appearance [44] . interobserver agreement among radiologists about the pattern of infiltrates (alveolar versus interstitial) or the presence of air bronchograms also has been demonstrated to be poor [45] . one interesting study showed that radiologists' readings of chest radiographs in febrile children aged 3 to 24 months were biased by the reading of the treating physician (when compared with radiologists who did not have access to that information) [46] . mycoplasma pneumonia appears most commonly as unilateral or bilateral areas of airspace consolidation and can include reticular or nodular opacities. on high-resolution ct, ground-glass opacities, airspace consolidation, nodules, and bronchovascu-lar thickening are common [47] . when children exhibit persistent or progressive symptoms despite seemingly adequate therapy, contrast-enhanced chest ct can be useful in detecting suppurative complications, such as empyema or necrosis, that may require further intervention [48] . for adults with cap, a prediction rule (the pneumonia severity index) was developed and validated to identify patients who are at low risk for death and other adverse outcomes and who might be treated successfully as outpatients [49] . a score is created using various criteria that can be assessed at initial presentation, including demographic factors (eg, age, sex, and nursing home residence), coexisting illnesses (eg, neoplastic disease, congestive heart failure, cerebrovascular disease, renal disease, and liver disease), physical examination findings (eg, mental status, rr, heart rate, blood pressure, and temperature), and laboratory and radiographic findings (eg, arterial ph, blood urea nitrogen, sodium, glucose, hematocrit, partial pressure of arterial oxygen, and pleural effusion). patients are placed into specific risk classes to guide decisions about the need for hospitalization. a similar tool for pediatric patients would be useful, but no such validated scoring system has been established. although specific admission criteria for children may vary among institutions, several criteria for admission are widely used, including ill appearance or septic physiology, hypoxia that requires oxygen administration, moderate or severe respiratory distress, inability to tolerate oral fluids or medications, and social factors, such as the absence of a telephone or the inability to follow-up with a pediatrician or return to the emergency department if disease worsens. neonates with febrile pneumonia generally should be managed as inpatients, although one field study in india suggested that infants could be treated safely in the community after the first month of life [50] . patients with underlying conditions that could affect their clinical course adversely and children with complicated pneumonias should be admitted for initiation of therapy. because the most likely etiologic agents depend on the age of the child, it is logical to select initial empiric antibiotic regimens according to age. in neonates from birth to 3 weeks of age, in whom group b streptococcus and gramnegative rods predominate, the initial coverage should be intravenous (iv) ampicillin and gentamicin in most cases; if disease is severe, a third-generation cephalosporin (eg, cefotaxime) may be added (while continuing the ampicillin to cover listeria monocytogenes, another pathogen in this age group). from age 3 weeks to 3 months, if the infant is afebrile, erythromycin (40 mg/kg/d iv divided every 6 hours) is the drug of choice for treatment of c. trachomatis. if fever is present or if a child seems ill, ceftriaxone (50 mg/kg/d every 24 hours) should be given. for patients aged 4 months to 4 years, when viral pneumonia (the most common cause) is suspected, no antibiotic therapy should be administered. if bacterial pneumonia is suspected, iv ampicillin (200 mg/kg/d divided every 6 hours) can be used. if the child appears ill, ceftriaxone may be chosen instead to provide broader coverage. finally, among children aged 5 years or older, azithromycin (one dose of 10 mg/kg, followed by 5 mg/kg/d) or erythromycin can be used in routine cases to provide coverage of atypical organisms (particularly mycoplasma); ampicillin may be added if there is strong evidence of a bacterial etiology, and ceftriaxone (with or without a macrolide) may be used in children who are more ill. in all ages, if features that suggest s. aureus are present, oxacillin or vancomycin should be added, depending on the prevalence of methicillin-resistant staphylococcus in the community [6] . once a specific pathogen has been identified, coverage can be narrowed accordingly. for chlamydia and mycoplasma infections, a macrolide (at the doses described previously) is the drug of choice. in patients with suspected pneumococcal pneumonia, therapeutic choices are driven by local antimicrobial susceptibility patterns. when s. pneumoniae has been recovered from an appropriate patient specimen, the antibiotic susceptibility pattern can be used to guide therapy. for isolates that are fully susceptible to penicillin (minimal inhibitory concentration b 0.1 mg/ml), ampicillin should be administered (because of its easier dosing schedule as compared with penicillin). even for isolates with intermediate susceptibility to penicillin (minimal inhibitory concentration 0.1-1 mg/ml), high-dose ampicillin (200 mg/kg/d) provides excellent coverage. when fully nonsusceptible isolates are encountered (minimal inhibitory concentration 2 mg/ml), ceftriaxone should be used. unlike the treatment of meningitis, vancomycin is rarely necessary in the treatment of pneumococcal pneumonia, even when a penicillin nonsusceptible strain is the etiologic agent. it should be added only if ceftriaxone resistance (defined for pneumonia as a minimal inhibitory concentration of 4 mg/ml) is demonstrated. a recent study from spain suggested that the combination of a beta-lactam plus a macrolide may be superior to a beta-lactam alone for the treatment of pneumococcal pneumonia in adults, but no randomized trial addressing this hypothesis has been published to date [51] . when h. influenzae is considered a likely pathogen (such as in children with underlying lung disease), ceftriaxone or ampicillin-sulbactam is preferred rather than ampicillin because of the presence of beta-lactamasemediated ampicillin resistance among many h. influenzae isolates. the optimal length of antimicrobial therapy for the treatment of uncomplicated or complicated pneumonia has not been well established for most pathogens. there are data to suggest that a 7-to 14-day course of therapy (or a 5-day course of azithromycin) is adequate for the treatment of c. pneumoniae [30, 52] . for pneumococcal pneumonia, treatment probably should continue until the patient has been afebrile for 72 hours, and the total duration of therapy probably should not be less than 10 to 14 days (or 5 days if using azithromycin because of its long tissue half-life). fevers may persist for several days after initiation of appropriate therapy, which reflects the resultant inflammatory cascade and tissue damage. no good data are available to support prolonged treatment courses for patients without underlying conditions (eg, cystic fibrosis) who have uncomplicated pneumonia. some data suggest that shorter courses of therapy may be equivalent to current standards, although more controlled studies are needed before this practice can be recommended routinely [53, 54] . several groups have published practice guidelines for the management of cap in adults [5, 30, 32] . no analogous clinical practice guideline for pediatric pneumonia has been accepted universally, although several suggested guidelines have been published [8, 31] . despite the differences among various recommendations, these guidelines serve as excellent compilations of the existing evidence regarding multiple aspects of the treatment of pneumonia. the differences in recommended management strategies contribute to variation in care for this diagnosis, however [55] . published studies of adult patients with cap have shown that adherence to a treatment guideline results in improvement in several outcomes, including lower costs, decreased length of stay, more appropriate antibiotic usage, and lower mortality rates [56] [57] [58] [59] [60] [61] . even when guidelines are used, physicians' impressions of their adherence to clinical practice guidelines do not always match their actual adherence to the recommendations contained therein, which suggests that awareness does not guarantee familiarity [62] . the causative organism in cases of pneumonia is frequently not identified by sputum examination or blood culture. when symptoms persist despite empiric antibiotic therapy, bronchoscopy with bronchoalveolar lavage (bal) is a diagnostic option. several studies have shown that culture of bal fluid in children with pneumonia can be useful in making a microbiologic diagnosis [63, 64] . although bronchoscopy is not necessary in routine cases, it should be considered when patients fail to improve with standard therapy or when concern about antibiotic resistance or unusual organisms is high and recovery of the causative agents will change management. early bronchoscopy may be critical for immunocompromised patients, for whom the selection of empiric therapy is difficult because of the expanded list of potential causes. no single set of criteria defining clinical stability for inpatients with pneumonia has gained widespread acceptance, which introduces variability in decisions about discharge. the combination of normalization of vital signs, ability to take oral nutrition, and clear mental status has been shown to predict a low risk of subsequent clinical deterioration among hospitalized adults with pneumonia [65] . time to clinical stability and 30-day post-admission mortality have been suggested to be the most reliable clinically based outcome measures for cap (along with process-of-care measures, such as admission-to-antibiotic time, proportion of patients receiving guideline-based antibiotic therapy, and percentage of patients switched from iv to oral therapy within 24 hours of reaching clinical stability) [66] . follow-up of children with pneumonia after discharge from the hospital should include involvement from their pediatrician or other primary care provider to ensure that clinical stability continues and that antibiotic therapy is completed as prescribed. in otherwise healthy children, follow-up radiographic studies are not necessary after a single episode of pneumonia. consolidation on chest radiographs can persist for up to 10 weeks, regardless of clinical improvement [67] . children with m. pneumoniae infection have been found to have detectable abnormalities on high-resolution ct scans more than 1 year after the episode [68] . follow-up radiographs should be reserved for children with underlying conditions, recurrent or persistent symptoms, or recurrent episodes of pneumonia. in these cases, a period of at least 2 to 3 weeks is recommended before obtaining a follow-up radiograph [69] . although rates of hospitalization for pneumonia among children have been rising, mortality rates from childhood pneumonia in the united states declined by 97% between 1939 (24,637 deaths from pneumonia) and 1996 (800 deaths) [70] . case fatality rates (not adjusted for underlying comorbidities) from 1995 to 1997 have been estimated to be 4% in children younger than 2 years of age and 2% in children aged 2 to 17 years [71] . although antibiotic use probably accounted for much of the decrease in mortality rates during the early part of this time period, recent declines are likely attributable in part to improved access to care for poor children [70] . improvements in critical care medicine also may reduce mortality, which is highest in children with underlying medical conditions. most children who develop pneumonia do not have any long-term sequelae. some data suggest that up to 45% of children may have symptoms of asthma 5 years after hospitalization for pneumonia, however, which may reflect either unrecognized asthma at the time of presentation with cap or a propensity to develop asthma after cap [72] . parapneumonic effusions are not uncommon with pneumonia and can occur in conjunction with most etiologic agents. whereas s. pneumoniae accounts for most cases with parapneumonic effusions, s. aureus and s. pyogenes are associated with particularly high rates of effusion and empyema [73] . tuberculosis is also a common cause in geographic areas with a high prevalence of disease and should be considered in the differential diagnosis of selected patients [74] . traditionally, the classification of such effusions as transudative versus empyema has been based on laboratory analysis of the pleural fluid. characteristics that suggest empyema include ph less than 7.1, lactate dehydrogenase more than 1000 iu/ml, and glucose less than 40 mg/dl [75] . additional data that may be obtained include an elevated pleural fluid white blood cell count (ie, n 50,000/mm 3 ) or a positive microbiologic study (including gram stain, culture, or other diagnostic tests, such as stains or polymerase chain reaction). pleural fluid cell count has limited predictive value, however [76] , and a positive microbiologic diagnosis is made from pleural fluid analysis in less than one third of cases [77] . ct scan findings (such as pleural thickening or enhancement, among others) have been shown to be inaccurate in predicting which effusions meet laboratory criteria for empyema [78] . several therapeutic options are available for the management of parapneumonic effusions. antibiotic therapy alone may result in resolution in some cases. drainage of the fluid by thoracentesis or placement of a drainage tube (large-bore chest tube or pigtail catheter) can remove the effusion. one study found that either needle aspiration alone or catheter drainage resulted in similar complication rates and lengths of stay, but children who underwent primary aspiration without catheter placement had a higher reintervention rate than children who had catheter placement at the time of initial drainage [79] . lower ph (especially b 7.2) and presence of loculations also were independent predictors of reintervention in this study. the natural history of parapneumonic effusions follows several stages, beginning with an exudative phase, during which the fluid is free-flowing and of low cellularity. this stage is followed 24 to 48 hours later by a fibropurulent phase, during which the accumulation of fibrin and neutrophils may result in loculation. finally, an organizing phase occurs, with fibroblast activity resulting in the formation of a ''peel.'' thoracoscopy with surgical dã©bridement may be necessary when the effusion has been longstanding enough to have allowed the development of septations, which reduce the fea-sibility of tube drainage. surgery has been shown to reduce the length of stay for hospitalized children whose effusions were considered high grade (defined as containing sonographic evidence of organization such as fronds, septation, or loculation) [80] . in particular, video-assisted thoracoscopic surgery has been shown to have numerous advantages compared with open thoracotomy, including fewer lung resections, fewer associated blood transfusions, less postoperative analgesia, shorter length of stay, faster resolution of fever, and shorter time to removal of chest drains [81] . an alternative option for managing loculated parapneumonic effusions is the use of intrapleural fibrinolytic agents (such as tissue plasminogen activator, streptokinase, or urokinase). these agents are used when inadequate drainage is obtained after chest tube insertion. recent reports of fibrinolytic therapy in children demonstrate that 60% to 70% of effusions in the fibropurulent phase can be drained completely and another 20% to 30% can be drained partially using the technique of daily instillation of streptokinase or urokinase through a chest tube with a dwell time of 4 hours. this technique is ineffective in draining effusions that already have reached the organizing phase, however [82, 83] . increased drainage also has been demonstrated using a 1-hour dwell of tissue plasminogen activator [84] . one randomized trial in children showed that children who received intrapleural urokinase treatment had a shorter length of stay compared with a placebo group [85] . fibrinolytic therapy has been associated with several rare complications, including allergic reactions (particularly with streptokinase), hemorrhage, and bronchopleural fistula formation. a large, prospective, randomized trial is needed to define better several aspects of this treatment option, including precise indications, optimal dosing and duration of therapy, and complication rates. failure to improve despite appropriate antimicrobial therapy should raise the suspicion of complications, such as parenchymal necrosis or abscess. these complications may be identified on contrast-enhanced ct scan when plain films do not reveal the findings [48] . decreased parenchymal enhancement may herald the development of cavitary necrosis and a prolonged and more intense illness [86] . most children who develop cavitary necrosis eventually demonstrate resolution of the pulmonary abnormality on follow-up radiography, however, even in the absence of surgical intervention [87] . interventional procedures (eg, percutaneous catheter placement) should be avoided in children with necrotizing pneumonia, because such procedures may increase the likelihood of complications, such as bronchopleural fistula formation [88] . lung abscess is an uncommon complication that more frequently occurs in older children. abscesses may be primary or secondary. experts have recommended that therapy routinely should include coverage of gram-positive organisms (s. aureus and streptococci) and anaerobes, although gram-negative coverage may be required in selected circumstances. most patients can be treated medically; needle aspiration or percutaneous catheter drainage of an abscess is safe and often provides diagnostic and therapeutic value in cases that fail to resolve on antibiotic therapy alone, without the associated complication rate seen in necrotizing pneumonia [88] [89] [90] . in general, percutaneous drainage should be considered if a patient's condition worsens or when clinical status fails to improve after 72 hours of antibiotic therapy. at least 3 weeks of iv antibiotic therapy should be delivered before lobectomy is considered [91] . recurrent pneumonia is generally defined as two episodes in 1 year or more than three episodes in a lifetime. most children with recurrent pneumonia have an identifiable underlying predisposing factor. in one pediatric study, the most common of these factors was aspiration secondary to oropharyngeal muscular incoordination (eg, in cerebral palsy); other identified illnesses included immune disorders (generally related to malignancy or abnormalities of the humoral immune system, including hiv infection), congenital heart disease, asthma, congenital or acquired anatomic abnormalities (eg, tracheoesophageal fistula), gastroesophageal reflux, and sickle cell anemia [92] . evaluation of a child with recurrent pneumonia should include a detailed history that focuses on possible indicators of these underlying illnesses combined with a targeted diagnostic evaluation that may include tests such as swallowing studies, serum immunoglobulins, hiv testing, echocardiography, pulmonary function tests, sweat testing, or radiographic studies, such as chest ct. several underlying abnormalities may result in a predisposition to the development of pneumonia. patients with endotracheal tubes or tracheostomies are at risk of lower respiratory tract infection because aspiration of contaminated secretions from the oropharynx or stomach is enhanced by several factors, including pooling of secretions above the cuff with subsequent leak and prolonged supine positioning [9] . intubated patients in an intensive care unit may have fever or respiratory compromise unrelated to lung infection, and distinguishing bacterial colonization in tracheal aspirates from pneumonia can be difficult. ventilator-associated pneumonia is best identified using a combination of diagnostic modalities. in one study, 90% of ventilated children with bacterial pneumonia met one of the following three criteria: (1) bronchoscopic protected specimen brush culture with 10 3 or more colony-forming units/ml, (2) intracellular bacteria in 1% or more of cells retrieved by bal, (3) bal fluid culture with 10 4 or more colony-forming units/ml [93] . patients with gastroesophageal reflux and patients who are unable to control their secretions because of neurologic impairment (underlying or drug induced) or anatomic disruption are at risk of aspiration pneumonia. aspiration of oropharyngeal contents may produce a chemical pneumonitis, but it is frequently difficult to assess whether the introduction of oral bacteria has resulted in the establishment of a lower respiratory tract infection. antibiotic therapy is routinely prescribed for presumed aspiration pneumonia, and the administration of either penicillin or clindamycin (which provide reasonable coverage for oral anaerobes) has been shown to be equally effective therapy for this indication [94] . in children who experience an aspiration event after hospitalization or in others in whom infection with pseudomonas or other gram-negative organisms is suspected (eg, patients with cystic fibrosis), a combination agent such as ampicillin or piperacillin and a beta-lactamase inhibitor should be considered. any abnormality in the host immune system may predispose a child to develop pneumonia. some of the more common scenarios seen in hospitalized patients include malignancy (either hematologic or solid tumors), solid organ or stem cell transplant, congenital or acquired immunodeficiencies, and autoimmune disorders or immunosuppressive medications used to treat systemic illnesses. regardless of cause, the immunocompromised host should be considered high risk for infection and merits a more aggressive diagnostic and therapeutic approach. table 4 reviews micro-organisms that may be pathogens in immunocompromised patients with pneumonia. in particular, viral infections (especially cytomegalovirus) and fungal infections (including candida and aspergillus) must be considered [95] along with unusual organisms such as pneumocystis jaroveci (formerly known as pneumocystis carinii) or cryptococcus neoformans. results of chest radiographs in patients with neutropenia may be negative [96] , although findings that suggest an infectious cause (such as nodules) may be visible on plain films [97] . chest ct scan may demonstrate abnormalities that are not detected on routine radiograph and may help localize lesions (particularly nodules) that are amenable to biopsy to aid in diagnosis [98] . mr imaging is another alternative diagnostic modality and may be more sensitive for the detection of necrotizing pneumonia than ct scan [99] . flexible bronchoscopy can establish a diagnosis in many cases, and several sampling methods are available. in one study of immunocompromised patients, the diagnostic yield was highest using a combination of bal and transbronchial biopsy (70%), as compared with bal alone (38%), transbronchial biopsy alone (38%), or protected specimen brush sampling (13%) [100] . finally, lung biopsy may be considered to assist in making a diagnosis in patients with a concerning clinical status in whom noninvasive testing has failed to uncover an etiologic agent [101] . in general, decisions regarding diagnostic testing may need to be accelerated in this population of patients to permit any interventions to be performed before clinical status deteriorates and a patient is unable to tolerate invasive procedures and to allow appropriate therapy to be initiated earlier in the course of disease. the differential diagnosis of pneumonia in patients who have been hospitalized for any prolonged period should include routine infectious etiologies and hospital-acquired organisms. failure to improve with appropriate empiric therapy should raise the concern for antimicrobial resistance. organisms of particular importance in these situations may include methicillin-resistant s. aureus, vancomycin-resistant enterococci, and gram-negative rods with resistance to third-generation cephalosporins, among others. empiric coverage for pneumonia in patients in the intensive care unit or others at risk for nosocomial infections should include broad-spectrum agents that provide coverage for these antibiotic-resistant organisms (and any organisms known to be a frequent cause of hospital-acquired infections in the institution) until a specific diagnosis can be made and antimicrobial susceptibilities are available. the infection control staff and the hospital microbiology laboratory are invaluable resources in determining which organisms should be considered in these circumstances. isolation precautions are a topic of particular interest to hospitalists who manage patients with pneumonia, particularly when a specific etiologic agent has not been identified. because pneumonia can be caused by a wide variety of agents, several different infection control precautions may be appropriate. the single most important procedure to prevent the spread of infection in the hospital is hand hygiene (performed either with soap and water or a waterless alcoholbased hand sanitizer). table 5 reviews the correct precautions for specific organisms that may be encountered in the hospital setting. two infections that merit specific mention are pertussis and influenza. these organisms are highly infectious, and exposure among hospital staff may require chemoprophylaxis. patients with pertussis or influenza should be admitted to a single room whenever possible. staff also should wear masks when entering the room of patients with influenza (despite the fact that droplet transmission precautions usually only require masks within 3 feet), because several reports have suggested a role for airborne transmission [102] [103] [104] . when pulmonary tuberculosis is suspected, strict attention to airborne precautions must be followed. in addition to the use of respirators and negative-pressure isolation rooms, visitation should be limited when possible; at our institution, two primary visitors may undergo screening chest radiography to ensure that they do not have active pulmonary infection. special organism precautions a contact refers to gown and gloves; droplet refers to mask within 3 feet; airborne refers to n95 respirator to enter room; special organism precautions refers to gown and gloves and dedicated patient equipment. as medical care for complex patients increasingly shifts from the inpatient to the outpatient arena, a greater number of infections are being treated by continuing the delivery of parenteral antibiotic therapy in the home or at stepdown facilities [105] [106] [107] . outpatient parenteral antimicrobial therapy (opat) is a reasonable option for patients with pneumonia who have stabilized clinically in the hospital but are judged to require prolonged parenteral treatment. the treatment of lower respiratory tract infections using opat has resulted in excellent clinical outcomes and high levels of patient and physician satisfaction [108, 109] . eligibility for opat requires a suitable home environment and the selection of an antimicrobial agent with appropriate pharmacokinetic parameters and drug stability to allow a reasonable dosing schedule at home [110] . an infectious diseases specialist (or a physician knowledgeable about the use of antimicrobial agents in opat) and a hospital pharmacist should be involved before discharge in planning for the administration of opat. the involvement of discharge planning services in the hospital also can facilitate contact with visiting nurse associations, which can arrange to instruct families in the proper techniques for iv infusions in the home. these agencies can make home visits to observe caregivers and answer questions and obtain blood for laboratory monitoring of disease or medication toxicities. the use of these services, in conjunction with careful follow-up by primary care physicians, provides the best continuity of care from the hospital to the outpatient setting and helps to ensure that patients with pneumonia receive the highest quality of care across the health care spectrum. national hospital discharge survey the tucson children's respiratory study. ii. lower respiratory tract illness in the first year of life pneumonia: an eleven-year study in a pediatric practice global estimate of the incidence of clinical pneumonia among children under five years of age practice guidelines for the management of community-acquired pneumonia in adults: infectious diseases society of america community-acquired pneumonia in children epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children guidelines for the management of community acquired pneumonia in childhood role of different routes of tracheal colonization in the development of pneumonia in patients receiving mechanical ventilation acute respiratory infections diagnosis and interventions in lower respiratory tract infections the role of pneumolysin in pneumococcal pneumonia and meningitis assessment of clinical criteria for identification of severe acute lower respiratory tract infections in children diagnostic value of tachypnoea in pneumonia defined radiologically acute lower respiratory infection in argentinian children: a 40 month clinical and epidemiological study clinical predictors of pneumonia as a guide to ordering chest roentgenograms standardized diagnosis of pneumonia in developing countries evaluation of simple clinical signs for the diagnosis of acute lower respiratory tract infection clinical signs of pneumonia in infants under 2 months establishing clinically relevant standards for tachypnea in febrile children younger than 2 years clinical signs of pneumonia in children respiratory rate greater than 50 per minute as a clinical indicator of pneumonia in filipino children with cough characteristics of streptococcus pneumoniae and atypical bacterial infections in children 2-5 years of age with community-acquired pneumonia decision rules and clinical prediction of pneumonia: evaluation of low-yield criteria clinical characteristics and outcome of children with pneumonia attributable to penicillin-susceptible and penicillin-nonsusceptible streptococcus pneumoniae occult pneumonias: empiric chest radiographs in febrile children with leukocytosis principles and practice of pediatric infectious diseases. 2 nd edition. philadelphia7 churchill-livingstone extreme leukocytosis in patients presenting to a pediatric emergency department value of the c-reactive protein test in the differentiation of bacterial and viral pneumonia update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults a practical guide for the diagnosis and treatment of pediatric pneumonia guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy the contribution of blood cultures to the clinical management of adult patients admitted to the hospital with community-acquired pneumonia: a prospective observational study initial microbiologic studies did not affect outcome in adults hospitalized with community-acquired pneumonia utility of blood cultures in pediatric patients found to have pneumonia in the emergency department nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia rejection criteria for endotracheal aspirates from adults evaluation of rapid assay for detection of streptococcus pneumoniae urinary antigen among infants and young children with possible invasive pneumococcal disease usefulness of urinary antigen detection by an immunochromatographic test for diagnosis of pneumococcal pneumonia in children detection of mycoplasma pneumoniae by two polymerase chain reactions and role of m. pneumoniae in acute respiratory tract infections in pediatric patients is a chest radiograph necessary in the evaluation of every febrile infant less than 8 weeks of age? the futility of the chest radiograph in the febrile infant without respiratory symptoms comparison of radiological findings and microbial aetiology of childhood pneumonia chest x-ray appearances in pneumonia and bronchiolitis: correlation to virological diagnosis and secretory bacterial findings interobserver reliability of the chest radiograph in community-acquired pneumonia: port investigators bias and overcall in interpreting chest radiographs in young febrile children mycoplasma pneumoniae pneumonia: radiographic and high-resolution ct features in 28 patients the yield of ct of children who have complicated pneumonia and noncontributory chest radiography a prediction rule to identify low-risk patients with community-acquired pneumonia pneumonia in neonates: can it be managed in the community? addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia safety and efficacy of azithromycin in the treatment of community-acquired pneumonia in children 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guidelines in treating community-acquired pneumonia bilateral fiberoptic bronchoalveolar lavage in acute unilateral lobar pneumonia the diagnostic utility of bronchoalveolar lavage in immunocompetent children with unexplained infiltrates on chest radiograph time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines evaluation of outcomes in community-acquired pneumonia: a guide for patients, physicians, and policy-makers the radiographic resolution of streptococcus pneumoniae pneumonia late abnormal findings on high-resolution computed tomography after mycoplasma pneumonia maximizing the usefulness of imaging in children with community-acquired pneumonia mortality from pneumonia in children in the united states mortality from invasive pneumococcal pneumonia in the era of antibiotic resistance, 1995-1997 asthma after childhood pneumonia: six year follow up study complicated parapneumonic effusions in children caused by penicillin-nonsusceptible streptococcus pneumoniae the etiology of pleural effusions in an area with high incidence of tuberculosis parapneumonic effusions parapneumonic effusions and empyema in hospitalized children: a retrospective review of 227 cases value of thoracentesis in the diagnosis and management of infectious pleural effusions ct appearance of parapneumonic effusions in children: findings are not specific for empyema outcomes of primary image-guided drainage of parapneumonic effusions in children implications of early sonographic evaluation of parapneumonic effusions in children with pneumonia experience with video-assisted thoracoscopic surgery in the management of complicated pneumonia in children intrapleural fibrinolytic treatment of multiloculated postpneumonic pediatric empyemas intrapleural fibrinolytic treatment of multiloculated pediatric empyemas effectiveness and safety of tissue plasminogen activator in the management of complicated parapneumonic effusions randomised trial of intrapleural urokinase in the treatment of childhood empyema pneumonia in children: decreased parenchymal contrast enhancement. ct sign of intense illness and impending cavitary necrosis cavitary necrosis complicating pneumonia in children: sequential findings on chest radiography lung abscess versus necrotizing pneumonia: implications for interventional therapy tube drainage of lung abscesses percutaneous catheter drainage of tension pneumatocele, secondarily infected pneumatocele, and lung abscess in children lung abscess in infants and children underlying causes of recurrent pneumonia in children blind protected specimen brush and bronchoalveolar lavage in ventilated children a randomized controlled trial of penicillin vs clindamycin for the treatment of aspiration pneumonia in children pneumonia in allogenic and autologous bone marrow recipients: a retrospective study the yield of chest radiography in febrile and neutropenic patients acute lung disease in the immunocompromised host: diagnostic accuracy of the chest radiograph acute lung disease in the immunocompromised host: ct and pathologic examination findings mr imaging of pneumonia in immunocompromised patients: comparison with helical ct role of flexible bronchoscopy in immunocompromised patients with lung infiltrates lung biopsy in immunocompromised children: when, how, and who? an outbreak of influenza aboard a commercial airliner airborne infection transmission of influenza: implications for control in health care settings outpatient parenteral antimicrobial therapy (opat) for the treatment of osteomyelitis: evaluation of efficacy, tolerance and cost outpatient parenteral antimicrobial therapy for central nervous system infections the management of skin and soft tissue infections: outpatient parenteral antibiotic therapy in the united kingdom efficacy and safety of intravenous cefotaxime for treating pneumonia in outpatients treatment of lower respiratory tract infections in italy: the role of outpatient parenteral antibiotic therapy practice guidelines for outpatient parenteral antimicrobial therapy: idsa guidelines key: cord-312615-q333qgps authors: knobbe, rebecca b; diallo, abdallah; fall, amary; gueye, aida d; dieng, assane; van immerzeel, tabitha d; ba, abou; diop, amadou; diop, abdoulaye; niang, mbayame; boye, cheikh sb title: pathogens causing respiratory tract infections in children less than 5 years of age in senegal date: 2019-12-30 journal: microbiol insights doi: 10.1177/1178636119890885 sha: doc_id: 312615 cord_uid: q333qgps introduction: while acute respiratory tract infections are the main cause of paediatric mortality and morbidity worldwide, pathogen patterns shift due to factors such as hygiene, vaccinations, and antibiotic resistance. knowledge about current cause of respiratory infections is lacking, particularly in lowand middle-income countries. the aim of this study was to identity the various respiratory pathogens causing acute respiratory tract infections in children below 5 years of age visiting a sub-urban primary care clinic in senegal. methods: a case-control study was performed in september and october 2018. oropharyngeal swabs were collected from cases; infants with fever and respiratory symptoms, and controls; children involved in the vaccination programme. viral identification was conducted by polymerase chain reaction for 21 different viruses; bacteria were identified by culture studies. associations between microorganisms, acute respiratory infection and severity of disease were calculated by multivariate regression adjusting for confounders such as age, sex, and living area. results: overall, 102 cases and 96 controls were included. microorganisms were detected in 90.1% of cases and 53.7% of controls (p < .001). influenza virus a (including h1n1), influenza virus b, respiratory syncytial virus (rsv), and streptococcus pneumoniae were independently associated with acute respiratory tract infections. co-detection of two or more pathogens was present in 49.5% of cases; 31.7% of cases had a pneumonia and 90.2% was treated with antibiotics. conclusions: this case-control study in a primary care setting in sub-saharan africa found influenza virus a and b, rsv, and s pneumoniae to be the main causes of acute respiratory tract infections in children below 5 years of age. we recommend evaluation of antibiotics prescription behaviour in this setting. worldwide, the leading cause of paediatric mortality and morbidity in the postneonatal period remains lower respiratory tract infections (lrtis). the who (world health organization) estimated that more than 800 000 of the 5.6 million total deaths in children less than 5 years old were caused by lrtis in 2016. 1 a meta-analysis found a hospital-based case-fatality ratio of 6.1% in children in lowincome countries with severe lrti, compared with 3.9% in high-income countries. 2 children with lrti can present with a highly variable package of symptoms including cough, tachypnoea, dyspnoea, fever, rhinitis, chest pain, abdominal pain, vomiting, diarrhoea, headache and lethargy. the who guidelines states tachypnoea as the main diagnostic criterion for pneumonia requiring an antibiotic. 3 however, distinction from upper airway infections and other illnesses such as asthma/bronchiolitis, anaemia or malaria can be challenging when minimal diagnostic tools are available. 4 furthermore, in many low-and middle-income countries, treatment policies are empiric or based on foreign guidelines, due to a lack of local causal studies. 5 these could be reasons why research has discovered an overdiagnosis and overprescription of antibiotics to treat pneumonia in low-income countries. 6 one of the biggest public health problems of this century is antimicrobial resistance. it threatens the effective treatment of major infections and is induced by an overuse and inappropriate usage of antibiotics. 7 this phenomena has major consequences: higher health-related costs because of the necessity of more expensive antibiotics, rising mortality rates due to pathogens causing respiratory tract infections in children less than 5 years of age in senegal 2 microbiology insights untreatable infections and an increasing danger for the immunosuppressed patient. 7, 8 moreover, viral causes of lrtis have become seemingly more important. 9 ancient studies in mostly western countries frequently described haemophilus influenza b (hib), streptococcus pneumoniae, and moraxella catarrhalis as major causative pathogens of lrtis. 10, 11 nonetheless, while in 2000, s pneumoniae was responsible for 600 000 deaths in children, in 2015, this number dropped to 294 000 children. 12 recent developments, such as the implementation of the pneumococcal conjugate vaccine and the hib vaccine, are responsible for a reduction in the burden of these respiratory bacteria but may also have induced a shift in the pathogens causing lrtis. 9, 13 recent research in senegal indicated viruses as main pathogens of all acute respiratory tract infections (artis), both upper and lower. the frequency of virus detection was even higher than those found in several other countries. 14,15 viruses most commonly found in senegal were respiratory syncytial virus (rsv ), adenovirus, rhinovirus, influenza virus a, enterovirus, human bocavirus, and parainfluenza viruses. 16 furthermore, there are indications that nowadays artis are more often caused by the sequential or concurrent interaction of different pathogens and that the presence of multiple organisms is linked with the existence of a lrti and with severity of disease. 17, 18 to reduce paediatric mortality caused by lrti, while fighting antibiotic resistance, more knowledge about the cause of respiratory infections, especially in low-and middle-income countries, is essential. case-control studies have been conducted in africa, investigating the association between different pathogens and pneumonia. these studies found strongest associations for s pneumoniae, bordetella pertussis, rsv, influenza virus a, and human metapneumovirus. [19] [20] [21] [22] [23] [24] however, these studies were conducted in hospitalized settings while most children with lrti are treated in primary care clinics. to the best of our knowledge, no case-control studies investigating artis in primary care have been conducted in sub-saharan africa. therefore, the aim of this case-control study was to investigate the prevalence of the different viruses and bacteria colonizing the airways and their association with the occurrence of artis and severity of disease in children less than 5 years of age, visiting a sub-urban primary care clinic in dakar, senegal. an unmatched case-control study was performed at the institute de pédiatrie sociale (ips), a primary care clinic in dakar, senegal, during september and october 2018. institute de pédiatrie sociale is a free government health care clinic for children and pregnant women based in pikine, a sub-urban area. children with respiratory infections were enrolled using convenience sampling at the paediatric outpatient ward. controls were enrolled during the vaccination programme, which took place once a week. exclusion criteria for controls were fever and respiratory symptoms. standardized forms were used to prospectively gather information concerning patient demographics, medical history, clinical signs, and symptoms at enrolment and treatment. oropharyngeal swabs and bloods samples were taken in cases. one week after enrolment, symptoms and signs were evaluated by phone call in all cases. every case was called a minimum of 3 times when parents did not respond. when a child had to be admitted to a hospital, daily follow-up of signs and symptoms was conducted. data were imported in the data management software, excel. databases were anonymized. this study has been approved by the ethics committee for research of the cheikh anta diop university of dakar. data were gathered after an informed consent statement had been signed by parents or a legal guardian. children aged less than 5 years old with an acute respiratory infection defined as (antecedents of ) fever and at least one respiratory symptom were found suitable for inclusion. cases were excluded if the symptoms began >10 days before enrolment and/or if antibiotics were taken within 48 hours before enrolment. exclusion criteria for controls were signs of fever or respiratory symptoms. fever was defined as a rectal or ear temperature of ⩾38.0°c or an axillary temperature of ⩾37.5°c. antecedents of fever had to occur within 24 hours before enrolment. respiratory symptoms included cough, thoracic pain, sore throat, dyspnoea, chest indrawings, tachypnoea, cyanosis, and rhinorrhoea. tachypnoea was defined using the who definition of a respiratory rate >60 breaths/min in children <2 months of age, >50 breaths/min in children 2 to 12 months of age, and >40 breaths/minute in children ⩾1 year of age. 3 tachycardia was defined as >160 beats per minute (bpm) for infants <2 years of age and >140 bpm for children 2 to 12 years of age. 25 elevated c-reactive protein (crp) suggestive for severity of disease was defined as ⩾50 mg/l. 26, 27 leucocytosis was present if leucocytes are increased to more than 11 000/mm 3 . pneumonia was defined using the who guidelines as tachypnoea with cough and/or dyspnoea. 3 alarming signs were defined as tachypnoea, chest indrawing, or hypoxemia. in all cases and controls, oropharyngeal samples were collected. all samples were analysed by the biotechnology unit of the laboratory of bacteriology of university hospital aristide le dantec and by the virology unit of pasteur institute. the samples were stocked and transported following the protocols. for bacterial samples, bacteria were isolated from appropriate culture media. morphological, cultural, and biochemical or antigenic characters were studied. strains were determined and knobbe et al 3 considered for infection if the bacterial load was at least 10 5 cfus/ml. all samples were tested using polymerase chain reaction (pcr) with a bio-ras cfx-96 thermo cycler and the ftd respiratory pathogens 33 (fast-track diagnostics), capable of detecting 21 viruses and 12 bacteria (supplement 1). in addition, blood samples were collected in cases and crp and leucocytes were determined by the laboratory of ips. c-reactive protein was determined using the crp latex kit 850a (lorne laboratories, berkshire, uk). based on g*power 3.1.9.2 version, a sample size of 182 was yielded, when using logistic regression, an alpha of .05, and a small-to-medium effect size with an odds ratio (or) of 1.60. 28 therefore, a sample size of 198 is sufficient to detect microorganisms as a predictor of acute respiratory infection. baseline characteristics were compared between cases and controls. continuous variables were expressed as medians and ranges. they were compared using the mann-whitney u test. categorical variables were expressed as frequencies and proportions and were compared using the chi-square test. to identify potential predictive factors, a univariable logistic regression was used. thereafter, established predictors of the outcomes (occurrence of respiratory infection and severity of disease) (p < .1) were included in multivariable logistic regression. data were presented as ors and 95% confidence intervals (ci). p < .05 was considered significant. epi info was used for analysis of the data. of 208 eligible children, 102 cases and 96 controls were analysed ( figure 1 ). ten cases were excluded from analysis, due to an onset of disease of more than 10 days before enrolment, missing month of birth, or an age of more than 60 months. approximately 5% of all assessed controls declined to participate in the study, mainly based on fear of discomfort for their child or possible disapproval of the other parent. none of the cases declined. overall, 96 (48.5%) children were male, and the mean age was 18.0 (±12.4) months. overall vaccination coverage was 97.7%. table 1 shows a summary of baseline characteristics of the included cases and controls at enrolment. a significant difference of means was found in mean age among case and control group, respectively, 23.5 (±13.2) and 12.2 (±8.0) with a p value of <.001. furthermore, cases more often lived in other areas in and outside of dakar, whereas more controls than cases lived in the neighbourhood near the pikine clinic, respectively, 36 (35.3%) and 63 (65.6%) with a p value of <.001. among all cases, 31.7% had a pneumonia based on who criteria. the main respiratory symptoms were rhinitis and cough, in 90 (88.2%) and 89 (87.3%) of cases, respectively. in all, 19.8% had a tachycardia and 32.7% a tachypnoea. none of the children had a hypoxemia during consultation. on physical examination, 52 (51.0%) cases had abnormal lung sounds of which rhonchi were the main type. an elevated crp was seen in 72.8% of cases with a mean crp of 47.2 (±41). in all, 46.2% had a leucocytosis with a mean number of leucocytes of 11 527.8 (±5654.5). malaria rapid diagnostic tests were performed on only 32 cases, but all were negative. data on treatment were available in 92 cases. antibiotics were prescribed in 90.2% of those. data on follow-up were only available in 51 cases. in 78.1% of those, symptoms had passed within 1 week. none of the children had to be hospitalized. table 2 shows a summary of clinical signs and symptoms and management of cases. for detection of bacteria, only culture was used, because when using pcr, equal amounts of bacteria were found in cases and controls. the reason for this is that a better differentiation between bacterial colonization and infection can be made using cultures. 29 at least 1 pathogen was detected in 90.1% of cases and 53.7% of controls. bacteria were detected in 62.8% of cases and 25% of controls, of which s pneumoniae (73.6%) and h influenzae b (24.6%) were the most prevalent. viruses were detected in 75.3% of cases and 42.1% of controls and influenza virus a (28.9%), rsv (17.8%), and influenza virus b (10.4%) were most common. in 49.5% of cases, 2 or more pathogens were detected. univariate analysis shows that s pneumoniae, rsv, influenza virus a (including h1n1) and b were significantly associated with the occurrence of arti (table 3) (continued) 3.0, ci: 1.2-7.4). respiratory syncytial virus was only significantly related to illness in children less than 2 years of age. likewise, the prevalence was higher in this age group. legionella pneumophila, b pertussis, chlamydia pneumoniae, coronavirus 229, coronavirus oc43, coronavirus hkui, piv (parainfluenza virus) 1, piv 3, piv 4, human metapneumovirus, and influenza virus c were investigated, but not detected in cases or controls. the prevalence of pathogens in cases and controls is illustrated in figure 2 . table 4 shows the prevalence of different co-detections. streptococcus pneumoniae was found in most of the co-detections (76.0%). it was most frequently found in combination with influenza virus a, in 17 cases. associations between all possible specific co-detections and illness were analysed, but no additional relationship was found, other than a cumulative association of the present pathogens. analysis of cases. treatment with antibiotics was not significantly related to alarm signs: tachypnoea (or: 3.9, ci: 0.5-33.0), withdrawals (or: 0.2. ci: 0.0-1.1), and hypoxemia (or: undefined). none of the pathogens was significantly associated with those alarm signs or an elevated crp or leucocytosis. no difference in elevated crp or leucocytosis was found between bacteria and viruses. this case-control study investigates the prevalence of the different viruses and bacteria colonizing the airways and their 6 microbiology insights association with the occurrence of artis in children visiting a sub-urban primary care clinic in senegal. dieng et al studied pathogens in children with arti in senegal and found a total of 78 bacteria in 162 children. they found a lower prevalence of s pneumoniae (18% of cases) in comparison with our study (48% of cases) and a prevalence of m cattharalis of 15% where we did not detect this pathogen. dieng et al used different swab sampling techniques (bronchoalveolar lavage, sinus fluids, and throat swab) depending on the site of infection. moraxella cattharalis causes otitis media and sinusitis rather than lrti, possibly explaining the higher detection rate. 30 furthermore, their study covered a full year, including all seasons. although our study was conducted during 2 months, it covered the rainy season, which is known for its respiratory infections. 15 streptococcus pneumoniae was the most prevalent bacteria in our sample. recent case-control studies in low-income countries found similar prevalence in cases and controls, even though those countries have lower vaccination coverages. 19, 21, 24, 31 in western countries with a similar vaccination coverage to senegal, s pneumoniae rates in children with arti are evidently lower than we detected. 32 possibly, disease burden of s pneumoniae is high in senegal due to serotype replacement following the introduction of the pneumococcal vaccine, as has occurred in many other countries. 33 staphylococcus aureus is a bacteria frequently detected in these studies. 19, 21, 24 they used nasal/nasopharyngeal swabs, but the literature does not mention major differences in detection of s aureus between nose or throat. 34 another explanation is the use of pcr for detection of bacteria. numerous studies in sub-saharan africa have been conducted studying the prevalence of viruses in children with an arti. equal total amounts of viruses and a similar prevalence of rsv and influenza viruses were detected when comparing with our results, but these studies, including some recent senegalese studies, found significantly higher percentages of adenovirus, enterovirus, and rhinovirus. 14, 15, 35, 36 results from case-control studies conducted in low-and middle-income countries show a similar prevalence of all viruses in healthy children, except that the average prevalence of rhinovirus in those studies is approximately 30%, whereas we found rhinovirus in 7.4% of controls. 19, [21] [22] [23] [24] the most obvious possible reason for the differences in virus prevalence is our short study period, given that virus prevalence is highly seasonal. 37 this study did not find an association between different pathogens and alarm signs (tachypnoea, tachycardia, hypoxemia, or an elevated crp). concordant to our findings, no association was found between alarming signs and specific pathogens in previous research. 38 both viral and bacterial infections can cause either mild or severe infections in children. other studies found an association between viral or bacterial aetiology and an elevated crp too weak to rule out bacterial infection in clinical practice. 26, 39, 40 we did not find this association, presumably because of a small number of severely ill children. colonization by more than one pathogen is believed to influence the occurrence and severity of illness, by stimulating each other's adherence and decreasing clearance. 41 co-detections were seen in 49.5% of cases and 17.7% of controls. most of the co-detections in our study were caused by s after adjusting for pathogens significantly related to illness, no relation was detected between the presence of a co-detection and illness in our study, which means that we did not detect a synergic effect in co-infection, possibly due to a small sample size. in investigating the cause of arti in low-income countries, most studies are done in hospital setting and case-control methods are rarely used. nevertheless, in these studies, similar pathogens were found with similar significant associations with illness compared with our study. [19] [20] [21] [22] [23] [24] 42, 43 this could mean that the same pathogens are responsible for both upper and lower artis. furthermore, it confirms a generally shifting pattern towards viruses of pathogens causing artis. some pathogens were more prevalent in other settings, such as human metapneumovirus, piv, and mycoplasma pneumoniae. 19, 22, 24, 42, 43 low prevalence of these pathogens was found in our study, possibly due to seasonality or their possible higher prevalence in severe infections. notable is the overprescription of antibiotics in our population. approximately 90% of cases have been treated with antibiotics, whereas only 31.7% had a pneumonia and should have been treated as such following who criteria. moreover, most of the antibiotic treatments concerned broad-spectrum antibiotics, whereas a narrow-spectrum penicillin is recommended in the primary care setting. literature confirms that practices are similar in other low-income countries. [44] [45] [46] the main strength of this study is the inclusion of all artis within a primary care clinic. this gives insight into the pathogens causing the infections. other strengths are the large number of pathogens tested for, with pcr and culture testing for bacteria, and the inclusion of treatment methods. an additional strength is that all data were gathered by one researcher, hereby decreasing the risk of variation in swabbing technique. there are also limitations to be mentioned. we could not properly adjust for some factors such as social status due to few data on these subjects. furthermore, selection bias could have occurred, because no matching was done. the average age of controls is lower than the average age of children with a respiratory infection, probably due to the young age of children enrolled in vaccination programmes. however, we did not discern significant heterogeneity regarding pathogens in different age groups (except for the mentioned differences in prevalence of rsv ) or living areas. another limitation is the use of only throat swabs. the nasopharyngeal swab is found to be superior in detecting influenza virus, s pneumoniae, and moraxella species, but oropharyngeal swabs are superior for the detection of m pneumoniae and h influenzae. [47] [48] [49] [50] it is preferable to use both techniques, but limited resources inhibited that. there was a lack of a gold standard such as chest x-ray for pneumonia. by taking a clinical definition of arti, there is possible overlap with other feverish diseases such as malaria and gastrointestinal illnesses. other limitations are the short duration of the study and a lack of follow-up data of patients due to nonresponse to phone calls. we might have missed data on severity of illness and hospitalizations. this case-control study conducted in senegal investigates the cause of artis in children less than 5 years of age in a primary care setting. in this population, illness was mainly caused by influenza virus a and b, rsv, and s pneumoniae, which confirms a generally shifting pattern towards viruses in pathogens causing artis. we suggest continuation of this case-control study for a full year, and further research on serotypes and resistance patterns of bacteria present in children with arti. these findings could lead to improvement of vaccinations against respiratory pathogens. we recommend reduction of antibiotics prescription, especially broad-spectrum antibiotics, for children with an arti visiting a primary care clinic. rbk, adg, ad and tdvi contributed to the design and implementation of the research. samples were analyzed by af, adg, amb, abd and mn. rbk analyzed the data and wrote the manuscript with consultation from all authors. adiallo supervised the project at the clinic. csbb supervised the study. rebecca b knobbe https://orcid.org/0000-0002-5562-3569 amary fall https://orcid.org/0000-0002-6890-7915 tabitha d van immerzeel https://orcid.org/0000-0001 -8809-3886 abou ba https://orcid.org/0000-0003-1216-0813 estimates developed by the un inter-agency group for child mortality estimation estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for 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using clinical predictors, c-reactive protein, and pneumococcal pcr viral bacterial co-infection of the respiratory tract during early childhood the contribution of viruses and bacteria to community-acquired pneumonia in vaccinated children: a case-control study aetiological role of common respiratory viruses in acute lower respiratory infections in children under five years: a systematic review and meta-analysis care seeking behaviour and aspects of quality of care by caregivers for children under five with and without pneumonia in ibadan the effect of rapid diagnostic testing for influenza on the reduction of antibiotic use in paediatric emergency department an under-recognized influenza epidemic identified by rapid influenza testing a comparison of nasopharyngeal and oropharyngeal swabbing for the detection of influenza virus by real-time pcr comparison of the prevalence of common bacterial pathogens in the oropharynx and nasopharynx of gambian infants comparison of four different sampling methods for detecting pharyngeal carriage of streptococcus pneumoniae and haemophilus influenzae in children comparison of oropharyngeal and nasopharyngeal swab specimens for the detection of mycoplasma pneumoniae in children with lower respiratory tract infection key: cord-312971-r9sggqh8 authors: mancino, enrica; cristiani, luca; pierangeli, alessandra; scagnolari, carolina; nenna, raffaella; petrarca, laura; di mattia, greta; la regina, domenico; frassanito, antonella; oliveto, giuseppe; viscido, agnese; midulla, fabio title: a single centre study of viral community-acquired pneumonia in children: no evidence of sars-cov-2 from october 2019 to march 2020 date: 2020-04-29 journal: j clin virol doi: 10.1016/j.jcv.2020.104385 sha: doc_id: 312971 cord_uid: r9sggqh8 pneumonia is an important cause of morbidity and mortality in children. we described viral aetiologies, with particular interest in detecting sars-cov-2, in hospitalized pneumonia children. human rhinovirus was the most frequently detected agent. no children tested positive for sars-cov-2. our findings suggest that sars-cov-2 infection is rare in children and it was not circulating in rome before covid-19 outbreak. rhinovirus was the most frequently detected agent. no children tested positive for sars-cov-2. our findings suggest that sars-cov-2 infection is rare in children and it was not circulating in rome before covid-19 outbreak. key words: community acquired pneumonia, sars-cov-2, covid-19, virus community acquired pneumonia (cap) remains the leading cause of mortality and morbidity in children worldwide [1] . cap aetiology is difficult to establish and it is often multifactorial: viral and bacterial. a considerable number of childhood pneumonias is caused by viruses; in particular, viral infections appear to occur mostly in younger patients [1] . commonly identified viruses in children with cap include respiratory syncytial virus (rsv), influenza (flu) a and b, parainfluenza viruses (piv), adenovirus (adv), human rhinovirus (hrv), human metapneumovirus (hmpv) and human coronavirus (hcov) [2] . ample evidence describes that rsv is the most commonly detected virus in hospitalized children less than 5 years old, both as single virus and as coinfection [2] . varghese l. et al. characterized epidemiology and clinical features of hcovs (hcov 229e, hku1, nl63, and oc43) in children and they found that the proportion of all identified hcovs was highest among 1-5 years old. they detected hcovs both in a community cohort and in hospitalized children and they reported an increased clinical severity in hospitalized children with young age and comorbidity; however, the clinical severity was not associated with hcovs type [3] . several papers demonstrated that the spread of pneumococcal and haemophilus influenzae type b vaccinations reduced the global incidence of children pneumonia [4] . however, mycoplasma j o u r n a l p r e -p r o o f pneumoniae and other atypical bacterial associated pneumonias showed a significant increment, even among pre-school children [5] . in december 2019, a novel coronavirus (sars-cov-2) was identified as the cause of a new infectious disease, the coronavirus disease 2019 (covid-19). covid-19 became a pandemic and it has affected hundreds of thousands of people worldwide. surprisingly, only a small number of cases of covid-19 has been described in children, suggesting that sars-cov-2 infection in the paediatric population is unusual [6] . analysing clinical features of covid-19 hospitalized paediatric patients, chinese preliminary studies reported polypnea, fever and cough as the most common symptoms; a high rate of these patients presented unilateral or bilateral pulmonary lesions on chest computed tomography [7] . streptococcus pneumoniae and haemophilus influenza type b. the aim of the present study was to examine viral aetiologies in children less than 14 years old hospitalized with pneumonia from october 1, 2019 to march 31, 2020. in particular, the most interesting aspect was to test the sars-cov-2 presence and its diffusion among our paediatric population. hmpv and human bocavirus (hbov), as described [8] . real-time pcr reactions targeting the rdrp and the e-genes of sars-cov-2 were developed in-house following the protocols described by corman et al [9] . mycoplasma pneumoniae was detected by real-time pcr reactions on dna extracted from oropharyngeal swabs, as described [10] . demographic, epidemiological, clinical and laboratory data were systematically collected. on hospital admission, we assigned each child a clinical severity score (from 0 to 8) according to respiratory rate, oxygen saturation in room air, presence of retractions and ability to feed [8] . a chest x ray was obtained in all children and radiological findings were classified as single pulmonary consolidation, multiple pulmonary consolidations or interstitial findings. table 1) . our aim was to describe viral aetiologies, with particular interest in detecting sars-cov-2, in hospitalized pneumonia children under 14 years of age. in contrast to a plenty of papers declaring rsv the main cause of children's cap [2] , in our study hrv was more frequently associated with pneumonia. however, the clinical severity score was higher in rsv patients and hrv was found in 9/17 cases (53%) in coinfection, consistent with the notion that hrv is very frequently detected in respiratory infections j o u r n a l p r e -p r o o f during childhood. according to previous studies, no significant laboratory and radiological differences between children hospitalized for pneumonia were observed. since the enrollment period partially overlapped with covid-19 peak infection in italy, we investigated also sars-cov-2 distribution in children hospitalized with cap in a tertiary university hospital in rome. kelvin aa et al. suggest that children are susceptible to sars-cov-2 infection, but frequently they do not have notable disease, raising the possibility that they could be facilitators of viral transmission [11] . in our population, we detected two cases of hku1, an hcov belonging to the same genus beta of sars-cov-2, but no children with cap tested positive for the novel cov. these results seem consistent with several recent papers who have demonstrated that children appear to be less susceptible to severe sars-cov-2 infection [6, 12] . reasons remain unclear [12] . despite some evidences describing pneumonia as the most frequent clinical manifestation among covid-19 hospitalized children [7] , in our population, in rome, no children tested positive for covid-19, even picu admitted ones. another interesting aspect was the hospitalization rate, spanning from 13 (31%) in february to 3 (7%) in march. environmental risk factors such as household crowding and air pollution, as well as virulence factors, play a fundamental role in developing lower respiratory infection [13] and particularly pneumonia [14] . accordingly, the lockdown that italian authorities established to confine covid-19 and the resulting decrease in social interactions (schools and day nurseries closure) were likely determinant in reducing cap which required hospitalization. the major limitation of our study was the small size of the sample. however, to our knowledge, no reports about sars-cov-2 detection in children admitted for cap before and during covid-19 outbreak are available. in conclusion, in this small study, we demonstrated that no children tested positive for sars-cov-2 over october 2019-march 2020 period, confirming sars-cov-2 is very rare in children and it was not circulating in rome the months before the italian covid-19 outbreak. we community-acquired pneumonia in children -a changing spectrum of disease childhood pneumonia: the role of viruses epidemiology and clinical features of human coronaviruses in the pediatric population the effect of haemophilus influenzae type b and pneumococcal conjugate vaccines on childhood pneumonia incidence, severe morbidity and mortality detection of mycoplasma pneumoniae in children with lower respiratory tract infections systematic review of covid-19 in children shows milder cases and a better prognosis than adults clinical and ct features in pediatric patients with covid-19infection: different points from adults respiratory syncytial virus, human bocavirus and rhinovirus bronchiolitis in infants detection of 2019 novel coronavirus (2019-ncov) by real-time rt-pcr detection of mycoplasma pneumoniae, chlamydia pneumoniae, and legionella spp. in clinical specimens using a single-tube multiplex real-time pcr assay covid-19 in children: the link in the transmission chain will children reveal their secret? the coronavirus dilemma risk factors for virus-induced acute respiratory tract infections in children younger than 3 years and recurrent wheezing at 36 months follow-up after discharge risk factors for severe acute lower respiratory infections in children: a systematic review and meta-analysis key: cord-016783-8x05oh5q authors: arruda, l. karla; solé, dirceu; naspitz, charles k. title: early interventions in allergic diseases date: 2010 journal: allergy frontiers: therapy and prevention doi: 10.1007/978-4-431-99362-9_23 sha: doc_id: 16783 cord_uid: 8x05oh5q atopy has been defined as the genetic predisposition to develop ige antibody responses to a variety of common environmental allergens. clinically, atopy is expressed by asthma, allergic rhinoconjunctivitis and atopic dermatitis. it has been recognized that the “atopic march” evolves from food allergy and atopic dermatitis in the first 2 years of life, followed by asthma and allergic rhinitis. over the past 30 years, the prevalence of allergies and asthma has increased significantly in developed countries, and asthma is one of the most common chronic diseases in children. evidence indicates that environmental factors acting early in life, including respiratory viral infections, exposure to pets and microbial products, day-care attendance, breast feeding, and exposure to allergens, tobacco smoke and other pollutants, are key events for establishment of sensitization and development of chronic, persistent symptoms of allergic diseases [1]. it is thought that gene—environment interactions play a crucial role in these processes. therefore, attempts to successfully prevent development of allergic diseases should be a priority. at present, there are no genetic markers for atopy or asthma which could be used routinely in clinical practice and family history of atopy has been used to identify children genetically at-risk of developing allergic diseases. these children from high-risk families have been the focus of most of the intervention studies. atopy has been defined as the genetic predisposition to develop ige antibody responses to a variety of common environmental allergens. clinically, atopy is expressed by asthma, allergic rhinoconjunctivitis and atopic dermatitis. it has been recognized that the "atopic march" evolves from food allergy and atopic dermatitis in the first 2 years of life, followed by asthma and allergic rhinitis. over the past 30 years, the prevalence of allergies and asthma has increased significantly in developed countries, and asthma is one of the most common chronic diseases in children. evidence indicates that environmental factors acting early in life, including respiratory viral infections, exposure to pets and microbial products, day-care attendance, breast feeding, and exposure to allergens, tobacco smoke and other pollutants, are key events for establishment of sensitization and development of chronic, persistent symptoms of allergic diseases [1] . it is thought that gene-environment interactions play a crucial role in these processes. therefore, attempts to successfully prevent development of allergic diseases should be a priority. at present, there are no genetic markers for atopy or asthma which could be used routinely in clinical practice and family history of atopy has been used to identify children genetically at-risk of developing allergic diseases. these children from high-risk families have been the focus of most of the intervention studies. in this chapter, we discuss risk factors for development of sensitization and allergic disease, focussing on preventive strategies for allergies and asthma at an early age. infections with respiratory viruses, particularly human rhinovirus (hrv) and respiratory syncytial virus (rsv) are leading causes of lower respiratory tract (ltr) illnesses associated with wheezing in children. although acute wheezing episodes may be severe enough to require hospitalization, majority of children presenting wheezing illnesses early in life will no longer wheeze by the age of 6 [2] . however, in a proportion of these children, early-life-wheezing is a clinical manifestation of asthma. respiratory viral infections have been implicated in the pathogenesis of asthma in several ways: during infancy, certain viruses have been linked to inception of the asthma phenotype; in children with established asthma, viral respiratory infections play a significant role in triggering acute exacerbations that might lead to hospitalizations and frequent outpatient visits; in children with repeated infections due to day-care attendance or contact with older siblings, respiratory viruses may have a paradoxical effect of reducing long-term risk of allergy and asthma, through alterations of cytokine response profiles. in the first 3 years of life, most lrt illnesses with wheezing are associated with infection by rsv. in the northern hemisphere, rsv accounts for 60-80% of wheezing episodes in children younger than 2 years of age [3] . it has been shown that children who wheeze with rsv infection in early life have lower level of lung function prior to infection [2] . most children have serum rsv antibody by the age of 2, yet reinfections are common. although risk of subsequent wheezing after rsv may decrease significantly with age, recurrent episodes of wheezing due to active rsv infections may occur throughout childhood. transmission requires close contact, and occurs either by large-particle aerosols or by contamination of hands and inoculation into the eye or nose, with an average incubation period of 2-8 days [4] . more recently, the role of hrvs in causing acute wheezing has been appreciated. hrvs are small, nonenveloped, positive-strand rna viruses in the family picornaviridae , with over 100 identified serotypes with minimal cross-antigenicity [5] . hrv infects only higher primates, and causes illness only in humans, with replication restricted to the respiratory epithelium [6] . in temperate climates, hrv has been estimated to cause up to 80% of autumn colds [5, 7] . in tropical countries, available evidence indicates that hrv is frequently associated with acute respiratory illnesses (ari). hrv transmission requires close exposure and occurs mainly by hand-to-hand contact, followed by self-inoculation into the eye or nose. it can also be transmitted by airborne spread. once hrv reaches the nasal cavity, infection occurs in virtually 100% of susceptible subjects; and approximately 75% of those infected develop illness after 1-2 days incubation [5] . sensitive pcr-based assays have established the importance of hrv as the cause of lrt illnesses, in addition to upper respiratory tract symptoms. a recent study with in situ hybridization applied to lower airway biopsy specimens has demonstrated presence of hrv in the ltr of 45% of a group of children 3-26 months of age with recurrent respiratory symptoms [8] . other viruses have also been associated with wheezing lrt illnesses in children at lower frequencies, including influenza, human parainfluenza viruses, human coronavirus, adenovirus, human metapneumovirus, and the recently identified human bocaviruses (hbov) -however at a lower frequency [9] . in keeping with observations made in temperate climates, it has been shown that infection with respiratory viruses and family history of allergy, were independently associated with wheezing among infants [10] . results of this case-control study carried out in ribeirão preto, a city in southeast brazil, revealed that, in the group of children under 2 years of age, respiratory viruses were detected in 60.8% of wheezing infants versus 13.3% of controls, and rsv was detected in 39% wheezing children and none of the controls. rhinovirus rna was found in 20.2 and 10% of the wheezing and control children, respectively, though this difference was not significant ( p = 0.21). the frequency of rsv was lower than that reported in temperate regions (39% versus 60-80%). however, considering the subgroup of infants 0-6 months-old, 61% tested positive for rsv antigen. rsv infections were predominantly found in the months of february to may, corresponding to late summer and early to midfall, indicating that the virus occurs in a different seasonal pattern as compared to that of the northern hemisphere. in the group of children 2-12 years of age, respiratory viruses were not significantly associated with wheezing [10] . in the united states, heymann et al have shown that viral infections, especially hrv, were the dominant risk factor for wheezing among children hospitalized before the age of 3 [11] . in their study, 84% of wheezing children p = 3 years-old were positive for virus, compared to 54% of controls ( p < 0.001); rsv was the dominant pathogen in the winter months among children 2 years-old or younger; however, rhinovirus was detected more often among wheezing children hospitalized in the other months of the year (58%) as compared to controls (26%, p < 0.04) [11] . one important issue would be whether infections with respiratory viruses particularly rsv and hrv occurring early in life could function as triggers or "adjuvants" for subsequent development of sensitization and persistent symptoms of allergic diseases. the rational for this hypothesis would be the potential of these infections to induce significant damage to the airways which might facilitate penetration of allergen(s) and/or trigger events related to airway remodeling. rsv enters the cell by fusion of the viral envelope with the cell membrane, and causes syncytia formation as a result of fusion of the infected cells to adjacent ones. replication in the bronchiolar epithelium causes necrosis of ciliated cells, peribronchiolar inflammation with abundant lymphocytes and macrophages, and impairment of secretion clearance, resulting in small airway obstruction and the hyperinflation characteristic of bronchiolitis. clinically, involvement of the lrt is characterized by tachypnea, dyspnea, cough, expiratory wheezing, air trapping, hyperaeration of the lungs on chest x-rays, and intercostal muscle retractions and cyanosis [4] .the pathogenesis of hrv infection is based on the release of cytokines, chemokines, and inflammatory mediators triggered by productive viral replication in a limited number of cells. a number of chemokines, particularly cxcl8 (il-8), ccl3 (macrophage inflammatory protein 1 a ) and ccl5 (rantes) are major mediators released during respiratory viral infections, which could recruit virus-specific t-cells as well as allergen-specific t-cells that in turn could augment any ongoing allergic response in the lung [12, 13] . it has been speculated that the contemporaneous occurrence of cycles of viral-induced and allergen-induced inflammation in the airways during the period of rapid lung growth and remodeling in infancy interacts synergistically to disrupt underlying tissue differentiation programs. this interaction could result in deleterious changes in ensuing respiratory functions, which may then manifest as persistent wheeze and/or asthma [14] . studies have shown association of rsv bronchiolitis and other early respiratory tract infections with recurrent wheezing or symptomatic asthma during the first 4-7 years of life [15, 16] . a long-term study carried out in tucson, arizona, revealed an association of ltr infection caused by rsv early in life with persistent wheezing at 3 and 6 years of age; however, this effect was lost at age 13 [17, 18] . besides rsv, hrv [19] may be potentially implicated in the subsequent development of childhood asthma. lemanske et al. have shown that, in a group of 285 children at high risk of asthma, studied during the first 3 years of life, infection with hrv in the first year was the greatest risk factor for persistent wheezing in the third year [20] . the authors showed that 63% of children who wheezed during rhinovirus season continued to wheeze in the third year, as compared to only 20% of all other infants (or = 6.6). a study in finland revealed that infants hospitalized for rhinovirus-induced wheezing presented a fourfold higher risk of asthma in school age, as compared to wheezing infants from whom no rhinovirus was identified. children with atopic dermatitis were especially likely to develop wheezing during hrv infections [21] . these studies highlight the previously unrecognized potential role of rhinovirus infection occurring in early life in the onset of asthma. follow-up of children 0-2 years of age who participated in the emergency room study in brazil [22] revealed that, after 2 years, 52% presented persistent wheezing. in contrast to studies carried out in temperate regions, viral infections were not a risk factor for persistent wheezing. on the other hand, early sensitization particularly to mites and cockroach, at 2-4 years of age, and exposure to high levels of cockroach allergen in the home in the first 2 years of life were both strong and independent risk factors for persistence of wheezing. it has been consistently shown that early allergen sensitization becomes a major risk factor for wheezing exacerbations and hospitalizations for wheezing after age 3 [17, [22] [23] [24] [25] . it is thought that ige-mediated inflammation found in most children with persistent symptoms of asthma is a key factor in causing lung function impairment and airway remodeling. previous studies in brazil have shown that day-care centers and schools, in addition to homes, are sources of significant exposure to mite and cockroach allergens, which might contribute to sensitization [26, 27] . heymann et al have demonstrated that sensitization to house dust mites and other aeroallergens was an important risk factor for hospital admissions for wheezing and adverse responses to viral infections, particularly those caused by rhinovirus, in 3-18 years old children [11] , highlighting the synergistic effect of sensitization, allergen exposure, and concomitant viral infection in augmenting inflammatory responses in the airways [28] . the possibility that viral and atopy-associated inflammation may interact synergistically to drive asthma pathogenesis has been raised recently by kusel et al. [14] . results of this community-based cohort, involving 198 children followed from birth to 5 years, revealed that acute ltr infection caused by rhinovirus or rsv in the first year of life interacted with atopy in infancy (sensitization £ 2 years-old) to promote later asthma [14] . it is well recognized that exacerbations of asthma, in patients with established disease, are often triggered by respiratory viral infections, particularly those caused by rhinovirus. in asthmatic patients, persistence of hrv up to 6 weeks following infection or exacerbation of asthma, has been reported [29, 30] , suggesting that an aberrant immune response to hrv may be involved in the development of acute exacerbations in atopic individuals with asthma. also, coexistence of atopy enhances the clinical effect of hrv infection, increasing intensity and duration of bronchial hyperreactivity [31] . finally, it has been suggested that repetitive viral infections might confer protection to development of asthma, based on their ability to skew the immune system away from the th2-type response [13, 15] . day-care attendance and/or siblings significantly increased the likelihood of occurrence of rsv or rhinovirus infections, and increased the risk of rhinovirus-induced wheezing at an early age. neonatal interferon (ifn)-g responses were lower in infants with high frequency of respiratory infections; conversely, frequent infections were associated with a smaller decline of ifn-g responses during the first year of life, indicating that preexisting immunologic factors may influence the expression of viral infections in infancy [15] . exclusive breast feeding for at least 4 months has been associated with protection against development of asthma or atopic diseases [32, 33] , but other studies have failed to demonstrate protection by breast milk [34] . bottcher et al. [35] found no relationship in levels of cytokines (il-4, il-5, il-6, il-8, il-10, il-13, il-16, ifn-g , tgf-b 1, tgf-b 2), chemokines (rantes, eotaxin) or secretory iga in breast milk, and development of sensitization or allergic symptoms, or levels of salivary iga during the first 2 years of life. endotoxin is a constituent of the outer membrane of gram-negative bacteria, found ubiquitously in nature, being present in most indoor environments as a component of house dust. endotoxin stimulates the release of potent proinflammatory cytokines. exposure to high levels of endotoxin in dust is associated with induction of asthma in sensitive patients [36, 37] . it has been demonstrated that bacterial endotoxin is capable of producing th1associated cytokines, ifn-g , and il-12 and therefore, has the potential to decrease allergen sensitization. chronic endotoxin exposure, before polarized t-cell responses are established, might be expected to protect against allergen sensitization by continuously enhancing th1-type lymphocyte development [38] . this assumption has been partially confirmed by studies in humans showing that exposure to high levels of endotoxin in early life was associated with protection against allergic sensitization [39, 40] . an experimental study with pregnant balb/c mice has shown that combined exposure to endotoxin during prenatal and postnatal phases suppressed allergenspecific sensitization (ige production), eosinophilic airway inflammation (reduced numbers of eosinophils in bronchoalveolar lavage fluids), and in vivo airway reactivity in response to methacholine. the suppression of allergen-mediated inflammatory responses was associated with increased toll-like receptor and t-bet expression by lung tissues and a shift toward predominantly th1 immune responses [41] . similar results were observed by wang and mccusker [42] . the relationship of exposure to microbial agents (endotoxin, fungal agents, and other microbial contaminants) early in life (3 months of age) and the development of atopic sensitization and physician-diagnosed asthma and wheeze in the first 4 years of life, in children of atopic mothers, was investigated in the prevention and incidence of asthma and mite allergy (piama) birth cohort study. a significant reduction in the development of asthma was associated with early exposure to these substances [43] . children who were born and raised in a farm environment and exposed to poultry and livestock were reported to have lower prevalence of asthma and/or allergic diseases in comparison to those living in urban area [44, 45] . until recently, exposure to high levels of endotoxin was associated with exposure to farm animals, presence of pets in home, number of people living in the house, and cleaning habits [46] . however, results of a study carried out on children from rural areas in europe, evaluating farm-related exposures and health outcomes, revealed that levels of endotoxin and extracellular polysaccharides were associated with health outcomes independent of farm exposures [47] . it has recently been shown by simpson et al. that the impact of endotoxin may be genetically determined [48] . in the setting of a birth cohort study, increasing endotoxin exposure was associated with reduced risk of allergic sensitization and eczema, and increased risk of nonatopic wheeze, only in children with the cc genotype at −159 of the cd14 gene [48] . several prospective birth cohort studies have raised the issue of whether keeping of pets , particularly keeping of dogs or cats, might decrease the risk of developing sensitization to those allergens and have confirm these results in part [49] [50] [51] . a systematic review of the scientific literature concerning keeping of pets within the first 2 years of life and prevalence of asthma has shown that exposure to pets was associated with increased risk of asthma and wheezing in children older than 6 years of age and a tendency for protection in those aged below 6 years [52] . in a recent study, a protective effect of early exposure to cat was documented [53] ; however it hasn't happened unanimously and some bias of selection may have accounted for the results. so, the protective effect observed might be attributable to allergen or other exposures associated with pet ownership (eg. endotoxin), but may in part be due to the prior removal of pets in families where children are sensitized or symptomatic or in families with a positive history for atopy at the time the child was born [49] . platts-mills and colleagues [54] while evaluating the immune response among 226 children, 47 of whom had asthma and airway hyperresponsiveness, have demonstrated that increasing the exposure to house dust mites was associated with an increase in frequency of sensitization to dust mite allergen. the highest category of exposure to cat allergen though was associated with decreased frequency of sensitization and higher prevalence of igg antibody to fel d 1. however, the occurrence of sensitization to dust mite or cat allergens was the strongest independent risk factor for asthma (mite or = 4.2; cat or = 6.1). maternal tobacco smoking during gestation is an important avoidable risk factor associated with elevated levels of ige in cord blood, subsequent asthma and allergic diseases in childhood [55] [56] [57] , and reduction of pulmonary function in children [58] . increased production of il-13 by cord blood cells has been found in newborns whose mothers had smoked during gestation as compared with those who never smoked [56] . macaubas et al. [59] reported a direct relationship of maternal tobacco smoking with both low concentrations of il-4 and ifn-g in cord blood and increased risk of wheezing by age 6 years. a recent experimental study on balb/c mice has shown that daily in utero exposure to maternal tobacco smoking was associated with exacerbation of subsequent adult responses to initial allergen exposure [60] . there is a strong body of evidence to support the role of exposure of children to environmental tobacco smoke (ets) in increasing the incidence of asthma, wheeze, cough, bronchitis, bronchiolitis, pneumonia, and impaired pulmonary function. ets increases both the prevalence and severity of asthma, as judged by increases in the frequency of attacks, the number of emergency room visits, and the risk of intubation [55, 57] . the risk associated with parental smoking seems to be greater at younger ages. although a dose-response relationship between ets exposure and respiratory outcomes has been demonstrated, at present there is no threshold dose of ets exposure below which an effect will not occur, and therefore active intervention measures and policies to reduce or eliminate children's exposure to ets should be strongly encouraged [55] . polymorphisms in the proinflammatory cytokine genes tumor necrosis factor-a (tnf) and lymphotoxin-a (lta) have been associated with asthma and atopy in some studies. secondhand smoke and ozone both stimulate tnf production. in a recent study, wu et al. genotyping six tagging single nucleotide polymorphisms (snps) in tnf and lta have observed that genetic variation in tnf may contribute to childhood asthma and that association may be modified by parental smoking [61] . a home-based, individualized, intervention study [62] carried out among inner city children with atopic asthma which included education and remediation for exposure to both allergens and ets, resulted in reduction of asthma associated morbidity. few specific interventions are available to reduce the impact of respiratory viruses. no vaccine is currently available for rsv prophylaxis. the disease enhancement caused by formalin-inactivated vaccine in the 1960s plus results of more recent unsuccessful trials of live-attenuated vaccines, have significantly slowed progress toward an rsv vaccine. passive immunization/immunoprophylaxis with monthly infusions of rsv immunoglobulin or monthly intramuscular injections of humanized monoclonal antibody, during the rsv season, reduced the incidence and severity of rsv infections in high-risk children including those preterm babies less than 6 months-old, children with congenital heart disease, and children less than 2 years with bronchopulmonary dysplasia [4] . the large number of hrv serotypes with minimal cross-antigenicity has hampered the development of an hrv vaccine. it may be possible to reduce exposure to hrv by washing of hands after contact with a cold sufferer or after handling objects that may have been contaminated with respiratory secretions [5] . immunization with formalin-inactivated or live-attenuated multivalent influenza virus vaccines and chemoprophylaxis for influenza virus a are the methods available for preventing influenza. influenza vaccine is used prior to the influenza season. the inactivated vaccine has an approximate 70-90% efficacy in preventing illness in healthy children and adults. in summary, there are virtually no effective strategies targeted at the respiratory viruses for treatment or prevention of viral-induced wheezing illnesses in children. however, evidence indicates that treatment of lung inflammation with inhaled corticosteroids or blocking viral-induced overproduction of leukotrienes with leukotriene-receptor antagonist montelukast may be effective in decreasing severity and frequency of viral-induced wheezing in young children with recurrent or persistent symptoms [63, 64] . a double-blind, controlled trial (previa study) investigated the effect of treatment with montelukast for 12 months in 2-5 years-old children with intermittent asthma. approximately half of these children were positive for at least one respiratory virus, including hrv, coronavirus, and rsv in their nasal aspirates during exacerbations of symptoms. the results showed that montelukast had a beneficial effect, decreasing frequency of exacerbations, increasing time between acute wheezing episodes, and reducing the need for inhaled corticosteroids during exacerbations [64] . preventive strategies have focused on manipulating the environment of high-risk individuals as an attempt to reduce the prevalence of allergies and asthma in children. at present, six primary prevention controlled studies are in progress [65] . the longest follow-up reported has been from the isle of wight study [66] . in this randomized, controlled study, a group of 120 high-risk infants was recruited prenatally, and development of allergic diseases and sensitization to common allergens was assessed at ages 1, 2, 4 and 8 years. intervention included strict elimination of common food allergens (dairy products, egg, wheat, nuts, fish, and soy) to the age of 12 months. lactating mothers followed the same restriction diet (except wheat) for the duration of breast feeding. extensively hydrolyzed formula was given as a supplement to the child from birth, or when breast feeding was discontinued before 9 months. stringent allergen avoidance measures were also instituted at birth, aimed at reducing exposure to house dust mites. repeated measurement analysis showed a sustained preventive effect of allergen avoidance on asthma, atopic dermatitis, and sensitization to allergens over the period of the first 8 years of life, and on allergic rhinitis at age 8 [67] . therefore, the conclusion was that stringent avoidance of mite and food allergens applied to high-risk children in infancy were beneficial and resulted in reduction of allergic sensitization and clinical manifestations of allergy, beyond the period of avoidance [67] . likewise, outcome of the canadian primary prevention study on high risk infants has been reported at age 7 years, showing that intervention during the first year of life, comprising avoidance of mite, pet allergens and ets, as well as dietary regimen, resulted in reduction of asthma symptoms and asthma diagnosed by a pediatric allergist in the intervention group. in the canadian study, no significant effect of intervention was observed for bronchial hyperreactivity, allergic sensitization, allergic rhinitis, or atopic dermatitis at age 7 years [68] . initial results from other cohorts look promising; however further follow-up will be necessary before any recommendations can be made [65] . results of the manchester asthma and allergy study (maas) have been reported up to the age of 3, and showed that stringent mite and pet allergen avoidance measures starting during gestation, resulted in decrease in severe wheezing and exercise induced wheezing at age 1, and improved pulmonary function in the intervention group at age 3. however sensitization to mites was increased at 3 years of age [69] . in the study of prevention of allergy in children in europe (space), environmental control measures aimed at reducing exposure to dust mite allergens at birth and education failed to prevent sensitization at age 2 [70] . another study looking at the effects of mite avoidance measures during gestation and education. the piama study, showed a modest benefit of reduction of cough apart from colds at 2 years of age [71] . the results of the childhood asthma prevention study (caps), carried out in australia, revealed that house dust mite allergen avoidance in conjunction with supplementation of diet with omega-3 fatty acids (abundant in fish and canola-based oils), applied to children with high risk of asthma, resulted in decrease in cough and sensitization to mites at 3 years of age , with no significant differences in wheeze [72] . the conclusion of these prospective studies so far is that environmental measures taken to decrease exposure to dust mite allergens, even if started during gestation, appear to have limited beneficial effects. however, dust mite avoidance in conjunction with stringent dietary avoidance measures applied to high-risk infants of highly motivated families, may result in prevention of sensitization and clinical manifestations of allergy up to 8 years. follow-up of some of the studies is still too short to allow more definitive recommendations. the prophylactic treatment with an antihistamine, ketotifen, in atopic dermatitis patients was followed by a fourfold reduction in incidence of asthma related symptoms, mainly in those with high levels of serum total ige [73] . similar results were observed among children with high risk of developing asthma. the incidence of asthma in preasthmatic patients treated with ketotifen was 9% versus 31% in the placebo group [74] . warner et al. have evaluated long-term treatment with cetirizine as a preventive tool for the onset of asthma in children aged less than 2 years with atopic dermatitis and without asthma, in a double-blind, randomized, placebo-controlled trial (the early treatment of the atopic child, etac study). at the end of 18 months of active treatment, they observed a significant reduction in the onset of asthma among grass pollen-sensitized infants and dust mite-sensitized infants. these differences were sustained only for the grass pollen-sensitized infants after 18 months of treatment interruption. they concluded that cetirizine truly delays or, in some cases, prevents the development of asthma in a subgroup of infants with atopic dermatitis sensitized to grass pollen and, to a lesser extent, to house dust mite [75] . more recently, preliminary results of the early prevention of asthma in atopic children (epaac) study, shows that the use of levocetirizine daily for 18 months was safe among atopic children 12-24 months of age [76] . on the whole, these studies indicate that the antihistamines ketotifen, cetirizine, and levocetirizine are safe for use in very young atopic children, and that they may have a role in preventing development of asthma in some of these children, particularly those with atopic dermatitis, and those allergic to house dust mite and grass pollen at an early age [76] . the hypothesis that early introduction of inhaled corticosteroids in young children at high risk of developing asthma could change the natural history of the disease has been investigated. a recent study in preschool children at high risk of asthma revealed that 2 years of treatment with inhaled corticosteroid was highly effective in reducing symptoms and asthma exacerbations, though the benefit was no longer present during a third treatment-free year, indicating that corticosteroids may not have disease modifying effects [63] . in this trial, the prevention of early asthma in kids (peak), 285 children aged 2-3 years were randomized to receive either 88 mcg fluticasone twice daily for 2 years or placebo, and at the end of the second year, treatments were interrupted. clinical and functional differences favoring the children treated with inhaled fluticasone disappeared a few weeks after discontinuation of regular treatment. recently, two other studies carried out in the united kingdom and denmark [77, 78] reached similar conclusions as the peak trial: very early treatment of asthma with inhaled corticosteroids, even before the persistent form of the disease has become evident, does not change the natural clinical course of the disease, and does not seem to affect the level of lung function attained at the end of follow-up, despite the fact that this form of treatment is very effective in controlling asthma symptoms while in use [79] . specific immunotherapy (sit) administered by the subcutaneous route is an efficient treatment for ige-mediated disease to defined allergens [80] . beneficial effects of sit in children have been demonstrated in preventing new sensitizations in children monosensitized to mites [81, 82] and in slowing the progression to asthma in those with seasonal allergic rhinitis, sensitized to pollen allergens (the pat study) [83] . follow-up of children with allergic rhinitis sensitized to birch or grass pollens, who underwent sit for 3 years [83] showed that the effect of sit in preventing development of asthma was still evident 2 years after sit was discontinued [84] . concerns regarding the use of sit in asthma include the possibility of severe anaphylaxis; however guidelines have been developed to minimize risks of reaction [80] . sublingual immunotherapy (slit) is increasingly being regarded as an efficient tool for the treatment of patients with asthma and/or rhinitis, as indicated by results of meta-analysis of studies carried out in children and adults [85] . the increased safety and ease of administration of slit makes this strategy very attractive as a form of early intervention in young children with ige-mediated disorders, which could modify the natural course of allergic diseases. studies addressing the use of slit in young children however have not been reported. issues including standardization of the vaccines, establishment of effective doses and schedules for administration, compliance, and better understanding of mechanisms of action and magnitude of efficacy need further research [85] . evidence suggests that events taking place between 2 and 3 years of age might be crucial determinants in the development of allergies and asthma [86] . strategies to prevent development of sensitization and progression to disease or to elicit long lasting remission of symptoms are strongly desirable. however, current environmental interventions and treatment modalities with pharmacotherapy do not meet these expectations. according to the recent published world allergy organization project report and guidelines on prevention of allergy and allergic asthma document [87] , some evidence-based recommendations can be highlighted (tables 1 and 2 ). acknowledgments dr. l. karla arruda's research on risk factors for asthma in children in brazil is supported by fapesp and cnpq, instituto de investigação em imunologia, l.k.a. and d.s. are recipients of cnpq scholarships. table 1 recommendations based on the world allergy organization project report and guidelines on prevention of allergy and allergic asthma -primary prevention infants without a special risk for allergic diseases exclusive breast feeding for 6 months is recommended by the who: if a supplement is needed, a conventional cow-milk-based formula is recommended (b) no special maternal diet during pregnancy or lactation (a) avoidance of solid foods until 6 [4] months of age (b) avoidance of exposure to tobacco smoke (also during pregnancy) (b) infants with a high risk for allergic diseases exclusive breast feeding for at least 6 months: if a supplement is needed, a documented hypoallergenic formula is recommended for the first 4 months of life; after the age of 4 months, high-risk children can receive the same nutrition as nonhigh-risk children (a) no special maternal diet during pregnancy or lactation (a) avoidance of solid foods until 6 [4] months of age (b) environmental measures avoidance of tobacco smoke (also during pregnancy) (b) reduction of allergen exposure early in life (house dust mites, furred pets, cockroaches) (b) avoidance of damp housing conditions (c) avoidance of pollutants (c) table 2 recommendations based on the world allergy organization project report and guidelines on prevention of allergy and allergic asthma -secondary prevention avoidance of tobacco smoke (b) patients who have perennial asthma, rhinitis, or eczema and who are allergic to house dust mites or animal dander should try to reduce their exposure to the relevant allergens (a, b). recommended measures include: removal of relevant pets reduction of indoor relative humidity 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earlier onset of the persistent childhood asthma phenotype? preventive measures: early interventions key: cord-315860-9j667c03 authors: jullien, sophie; pradhan, dinesh; tshering, tashi; sharma, ragunath; dema, kumbu; garcia-garcia, selene; ribó, jose luis; muñoz-almagro, carmen; bassat, quique title: pneumonia in children admitted to the national referral hospital in bhutan: a prospective cohort study date: 2020-04-10 journal: int j infect dis doi: 10.1016/j.ijid.2020.04.017 sha: doc_id: 315860 cord_uid: 9j667c03 objectives: the study aim was to describe the etiological profile and clinical characteristics of pneumonia among children hospitalized in thimphu, bhutan. methods: this prospective study enrolled children aged 2–59 months admitted to the jigme dorji wangchuck national referral hospital with world health organization (who)-defined clinical pneumonia. demographic and clinico-radiological data were collected through questionnaires, physical examination, and chest radiography. blood samples and nasopharyngeal washing were collected for microbiological analysis including culture and molecular methods. results: from july 2017 to june 2018, 189 children were enrolled, of which 53.4% were infants. pneumonia-related admissions were less frequent over the winter. chest radiographies were obtained in 149 children; endpoints included pneumonia in 39 cases (26.2%), other infiltrates in 31 (20.8%), and were normal in 79 children (53.0%). non-contaminated bacterial growth was detected in 8/152 (5.3%) blood cultures, with only two cases of streptococcus pneumoniae. viral detection in upper respiratory secretions was common, with at least one virus detected in 103/115 (89.6%). the three most-commonly isolated viruses were respiratory syncytial virus (52/115; 45.2%), rhinovirus (42/115; 36.5%), and human parainfluenza virus (19/115; 16.5%). a third of patients with viral infections showed mixed infections. case fatality rate was 3.2% (6/189). conclusion: respiratory viral infections predominated among this cohort of who-defined clinical pneumonia cases, whereas bacterial aetiologies were uncommon, highlighting the epidemiologic transition that bhutan seems to have reached. pneumonia is the single largest cause of mortality in children aged under five years, causing an estimated 15.5% of all deaths in children under five years of age, and over 800,000 paediatric deaths annually (liu et al., 2016; un igme, 2018) . most of these lives could be saved through more effective and equitable health system interventions, combining prevention, early and accurate diagnosis, and treatment (walker et al., 2013; rambaud-althaus et al., 2015) . the main pneumonia burden remains disproportionately concentrated in low-and middle-income countries (lmics) in southeast asia and sub-saharan africa (walker et al., 2013) . pneumonia deaths are decreasing, but more slowly than for other major causes of mortality, and too slowly to achieve the sustainable development goal ambition of "ending preventable child deaths" by 2030 (united nations, 2018) . risk factors and causative pathogens of childhood pneumonia differ across the world. obtaining reliable local data, including the burden of the disease, epidemiological trends, and the determination of the main pathogens involved, is imperative to help develop targeted interventions. therefore, adequate surveillance systems are required to monitor the effectiveness of national strategies implemented towards the reduction of the disease burden. however, the lack of local data and weak surveillance systems in many lmics hamper an adequate knowledge of the epidemiology and aetiology of childhood pneumonia in those settings where reliable data are most needed. one country that exemplifies the dearth of data regarding childhood pneumonia is the kingdom of bhutan (jullien et al., 2020) , a small country locked in the himalayas, with an estimated population of 779,666 in 2017 (department of information technology, 2016; ministry of health, 2018) . in this predominantly mountainous country, elevation rises from around 100 m in the southern foothills to over 7500 m in the northern himalayan range, with the capital, thimphu, standing at 2334 m (central intelligence agency, 2019). the climate varies with the altitude, from tropical in the southern plains to alpine with very cold winters in the north. in thimphu, the temperature ranges from à3 c in winter to 22 c in summer on average, coinciding with the monsoon that brings precipitations of around 350 mm in july (climate-data org, 2019). bhutan is classified as a lower-middle income country as of 2020 (the world bank, 2020) . essential health services in both modern and traditional medicines are free for bhutanese citizens, based on a primary healthcare approach (world health organization, 2017) . we conducted this prospective hospital-based observational study to describe the epidemiology, aetiology, and clinical and radiological presentation of world health organization (who)defined pneumonia among children aged between 2 and 59 months admitted to the jigme dorji wangchuck national referral hospital in thimphu. this was a prospective hospital-based study conducted for 12 consecutive months at the jigme dorji wangchuck national referral hospital (jdwnrh) in thimphu. the hospital has 38 paediatric beds, including five in the paediatric intensive care unit (picu). all children aged 2-59 months hospitalized with who-defined pneumonia (irrespective of severity) were eligible for recruitment (world health organization, 2014) (see box 1). children admitted in the preceding seven days or with evidence of a foreign body in the respiratory tract were excluded. potential participants were identified during day and night by the study co-investigators with the collaboration of paediatricians, paediatric residents, and nurses from the outpatient department, the emergency room, the picu, and the paediatric ward. if an eligible participant was missed during the night, the child was assessed and recruited the following morning. all eligible children were recruited provided parent(s) or guardian(s) consented to study participation. on study admission, a study identification number was assigned and a comprehensive physical examination was performed, including anthropometric measurements, vital signs, axillary temperature, and peripheral oxygen saturation in room air. demographic and clinical data were collected from the medical records and through family interviews. sample collection upon enrolment, or as soon as possible after enrolment, included blood samples and nasopharyngeal washing (npw). all the nurses in the picu and paediatric ward were trained at the beginning of the study by the lead investigator on how to collect these samples. when a child was identified for recruitment but blood had already been collected, no further blood sampling was conducted. however, if another blood analysis was clinically indicated, additional blood was obtained for the specific purpose of the study. fluid from pleural effusion was collected when clinically indicated. all recruited patients underwent a postero-anterior chest radiography upon admission. additional information of potential diagnostic interest, such as computed tomography scans, ultrasound, or cerebrospinal fluid investigation available throughout admission, was also collected. children were clinically managed and discharged as per existing hospital protocols and discretion of the treating paediatricians, and were followed-up by one study investigator in terms of outcome determination. all data were collected using digitalized and standardized forms (see supplementary material for clinical definitions and details of variables measured). the who protocol used in clinical trials of pneumococcal conjugate vaccines (pcv) was followed to interpret chest radiographs (cherian et al., 2005) . in brief, readers first judged the box 1. who definitions of pneumonia and severe pneumonia used as inclusion criteria (world health organization, 2014) . history of cough or reported breathing difficulty, and increased respiratory rate (rr) or chest indrawing. severe pneumonia: history of cough or reported breathing difficulty and at least one of the following: oxygen saturation <90% or central cyanosis, severe respiratory distress (e.g. grunting, very severe chest indrawing), signs of pneumonia with a general danger sign: inability to breastfeed or drink, lethargy or reduced level of consciousness, convulsions. increased rr is defined according to age as follows: rr ! 50 breaths per minute in children aged two months or more and less than 12 months. rr ! 40 breaths per minute in children aged 12 months or more and less than 60 months. quality of the film (uninterpretable or interpretable, the latter stratified as suboptimal or adequate) and then classified findings for all interpretable radiographs. significant pathology was defined as the presence of consolidation, other infiltrates, and/or pleural effusion. endpoint radiologically confirmed pneumonia was defined as consolidation, pleural effusion, or both on any hemithorax. initially, two paediatricians independently interpreted the radiographs. discordant results were read by a third reader, trained in who criteria for interpretation of chest radiographs. an additional external quality control measure was included in the study protocol, whereby a paediatric radiologist would read a random sample of 10% of the chest radiographs. however, as substantial discordance was observed between the two primary readers, all chest radiographs were again independently interpreted by the paediatric radiologist using the who criteria. this last reading was accepted as final interpretation for analysis. blood was collected under aseptic conditions following the hospital's validated standardized procedures. blood for haematology, biochemistry, and culture was processed following standard procedures. blood was cultured using an automated blood culture system (bact/alert 1 ). bacterial isolates were identified by colony morphology, growth requirements, and basic biochemical tests. antibiotic susceptibility was determined using disk diffusion in accordance with the guidelines of the clinical laboratory standard institute (clsi, 2015) . additionally, real-time polymerase chain reaction (rt-pcr) for lyta gene of streptococcus pneumoniae in dried-spot collected blood, and host-response biomarkers in additional blood (2 ml, edta tube) were investigated (findings reported elsewhere) (brotons et al., 2017) . the blood samples were centrifuged at 3000 â g for three minutes, and the serum was separated and stored at à80 c. npw samples were homogenized and aliquots frozen at à80 c and subsequently shipped to barcelona, spain, where they were subjected to molecular screening (multiplex rt-pcr qiastat respiratory panel, qiagen, for 17 viral targets and four bacterial targets). npw were also subjected to detection of pneumococcus and capsular typing (findings reported elsewhere). rapid influenza diagnostic tests (alere binaxnow 1 ) were performed as per discretion of the treating clinicians and nurses, independently of the current study. investigations for active tuberculosis included mantoux test and gastric aspirates for microscopy and genexpert 1 . the lead investigator entered data into a computerized password-protected database (odk 1 ) with study identification number. errors in data entry were limited by pre-defined ranges for every value. stata 15.1 was used for data analyses (statacorp, 2017) . mean with standard deviation (sd) and median with interquartile range (iqr) were used to summarize normally and non-normally distributed variables respectively. between 1st july 2017 and 30th june 2018, 1591 children were admitted to the paediatric department of jdwnrh. among them, 286 (18.0%) were children aged 2-59 months with respiratory symptoms, of which 189 (66.1%) were recruited ( figure 1 ). the baseline characteristics of the 189 children are presented in table 1 . median age was 10.8 months; over half of the children were infants. most children were adequately immunized according to age. there was no known case of hiv infection. children were mainly from the district of thimphu, although the study included patients from 16 out of the 20 districts in bhutan. on average, families reported that it had taken around 15 min to reach the closest healthcare facility. twenty-seven children (14.3%) were referred from another health centre. summer, fall, and spring each comprised around 30% of the recruited cases, while winter had the lowest number of pneumonia admissions (10.1%). october was the month with the highest number of cases (37; 19.6%) ( figure 2 ). clinical characteristics upon admission are presented in tables 2 and 3 . wasting (waz à2 sd) was detected in 17 children (9.0%). on admission, 77 children (41.2%) presented with fever, half of the children were breathing fast according to age, and three-quarters were hypoxemic. median basal oxygen saturation was 85% (iqr 80-90) among the 173 children with available measurement in room air without oxygen therapy. on auscultation, typical lung consolidation-related sign (crackles) was most common (57.5%), followed by rhonchi (45.2%) and wheezing (25.0%). on admission, 35.8% of the children were anaemic, 36.9% had leucocytosis, and 25.3% had neutrophilia. two common inflammatory markers were tested at jdwnrh: c-reactive protein (crp) with a mean of 2.06 mg/dl (sd 2.09), and erythrocyte sedimentation rate (esr) with a mean of 24.89 mm (sd 28.02). twenty-five (sanders et al., 2008; bruel et al., 2011) . only four children presented with both high crp and esr. chest radiography was performed in 178/189 children (94.2%). images were available for interpretation by the study investigators in 150 of them (84.3%). in 28 cases, children were discharged before investigators could interpret the radiography findings and the radiograph was missing. one film was judged uninterpretable. among the final 149 readable chest radiographs, 79 (53.0%) were normal, 39 (26.2%) were classified as primary endpoint pneumonia, and 31 (20.8%) as other infiltrates. while hiv infection was not suspected in any child by the treating physicians, active tuberculosis was suspected in 10 children (5.3%) but was not confirmed by the laboratory tests in any of them. blood culture was performed in 148/189 children (78.3%), of which 45 (30.4%) had received antibiotics prior to sample collection (table 4) . thoracocentesis was performed in one child with pleural effusion. six different pathogens were isolated among the eight non-contaminated positive blood cultures: s. pneumoniae (two cases), pseudomonas sp. (two cases), escherichia coli, acinetobacter sp., salmonella typhi, and serratia rubidaea (one case each). drug sensitivity results are shown in supplementary table 2. s. pneumoniae was isolated in the only sample of pleural fluid that was collected, which corresponds to the same child with positive blood culture, subsequently also confirmed by rt-pcr in blood. npw was collected in 129/189 children (68.3%). the npw sample was too scarce or of bad quality to run the test in 14 children (10.9%). among the remaining 115 children, 52 (45.2%) had received antibiotics prior to sample collection. bordetella pertussis was detected in three (2.6%) children, and mycoplasma pneumoniae in one (0.9%) child; chlamydophila pneumoniae and legionella pneumophila were not detected among respiratory samples. at least one virus was identified in 103/115 npw samples (89.6%) ( coronavirus were detected in two children (1.7%). routine rapid flu test was performed under the influenza national surveillance programme in 32/189 children (16.9%), being positive for influenza a in seven cases, for influenza b in one case, and for co-infection of influenza a and b in one case. analysis by rt-pcr confirmed the detection of influenza virus in 4/9 children with positive rapid flu test, and detected 10 additional cases with influenza virus. among children with at least one virus detected, 4/86 (4.6%) had a positive blood culture for bacteria and 24/89 (27.0%) had radiological endpoint pneumonia. among children with no virus detected, 3/9 (23.3%) had a positive blood culture and 4/11 (36.4%) had radiological endpoint pneumonia (supplementary table 3) . no children with influenza had a positive blood culture. however, 6/15 (40.0%) children with influenza identified in their nasopharynx had radiological endpoint pneumonia. lumbar puncture was not indicated in any of the children. children were hospitalized for a median of four days (iqr 2-6) ( table 5) . thirty children required picu admission, with a median stay of 72 h (iqr 24-96). three-quarters of the children were put on oxygen therapy, of which half for at least three days. most children (72.0%) received antibiotics during admission. antibiotics were stopped in the first two days of admission in 10 children (7.4%) and advised to be continued after discharge in 90 (66.2%). main diagnoses given by the treating physician at discharge are shown in supplementary table 4 . half of the children were discharged with a diagnosis of pneumonia or bronchopneumonia. in terms of the seasonal variability of the most common clinical syndromes given by the treating physician at discharge, bronchopneumonia was mainly in fall (50.0%), bronchiolitis in spring (43.6%), and pneumonia did not show a clear seasonal pattern (supplementary figure 1) . six children had a fatal outcome (case fatality rate 3.2%); all had been referred from other centres in critical condition. npw was not collected in three children due to the severity of their illness upon arrival. of the other three children, one child presented a triple co-infection by b. pertussis, parainfluenza virus, and influenza virus. four fatal cases were diagnosed as suffering of pneumonia, and two of bronchiolitis. two deaths occurred within the first 24 h of admission to our centre. a summary of the main characteristics of these six children is presented in supplementary table 5 . abbreviations: gcs: glasgow coma scale; na: not applicable; waz: weight-for-age z-score. a two children presented with convulsions. one was diagnosed as febrile convulsion, while the other child was a severe case of pneumonia which led to a fatal outcome. b some children who presented with non-severe pneumonia developed hypoxemia during their hospitalization, which is a sign of severity as per the who definition. c twenty children (10.6%) did not strictly meet the who definition of pneumonia at the time of admission but were admitted to the paediatric ward with suspected pneumonia or bronchiolitis as per the clinical discretion of the treating paediatricians. four of them developed hypoxemia during hospitalization requiring oxygen therapy and were therefore classified as severe pneumonia. none of the remaining 16 children were admitted to picu or presented other signs of severity, and were classified as nonsevere pneumonia (supplementary table 1 ). d increased respiratory rate (rr) according to age is defined as rr ! 50 bpm in children aged 2-12 months and rr ! 40 bpm in children aged !12 months. this is the first published series of comprehensive epidemiological, clinical, and microbiological data describing bhutanese children under five years of age hospitalized with who-defined clinical pneumonia. mortality related to pneumonia was 3.2%, similar to other studies from lmics (jroundi et al., 2014; lazzerini et al., 2016; bénet et al., 2017; chen et al., 2018; o'brien et al., 2019) . nevertheless, this remains high for bhutan in spite of the country offering free and easily accessible healthcare services. the six children who died were referred from other health centres and reached the study hospital in critical condition. the high proportion of infants in our study highlights that infants are particularly vulnerable and prone to hospitalization due to severe pneumonia (fancourt et al., 2017; chen et al., 2018; jakhar et al., 2018 ). there was no child known or suspected to be infected with hiv, which is consistent with the very low number of underfive year old children infected with hiv in bhutan (unaids, 2018). abbreviations: crp: c-reactive protein; esr: erythrocyte sedimentation rate; hb: haemoglobin; wbc: white blood cells. a leucocytosis was defined as white blood cells greater than 15 â 10 9 cells/l for children aged between 2 and 11 months and greater than 13 â 10 9 cells/l for children aged between 12 and 59 months. abbreviations: npw: nasopharyngeal washing; pcr: polymerase chain reaction; rsv: respiratory syncytial virus; rt-pcr: real-time polymerase chain reaction. a vials for blood culture were out of stock at the hospital for few weeks during the study period, leading to blood culture not being performed in 12 participants, although molecular screening in bloodspots in filter paper was conducted for all 10 of these children. b coagulase-negative staphylococci, and bacillus spp were considered contaminants, as per our protocol. c bacterial growth was detected in 22 blood cultures, but it was attributed to contamination in 14 cases. d seven children had positive rapid flu test for influenza a, one child for influenza b, and one child for influenza a and b. out of the seven children with rapid flu test positive for influenza a, detection of influenza a by rt-pcr in npw was also positive in four cases, but negative in one case, and "failed/inhibited" in the remaining two cases. for the child with rapid flu test positive for influenza b and for the child with rapid flu test positive for both influenza a and b, rt-pcr in npw was negative for both influenza a and b in both children. e parainfluenza viruses 1, 2, 3, and 4 were detected in 2 (1.7%), 1 (0.9%), 14 (12.2%), and 3 (2.6%) children respectively. f fourteen were influenza a, and two were influenza b. winter, which is the coldest season in bhutan, surprisingly showed the lowest number of cases (10.1%); this finding differs from what is commonly seen in other settings, whereby hospitalization of childhood pneumonia tends to peak during the coldest season (murdoch et al., 2014; ben-shimol et al., 2015) . however, this finding is consistent with those reported by the national sentinel surveillance programme for severe acute respiratory infections, and with the proportion of all-cause paediatric admissions, lower during winter (royal centre for disease control, 2018). this could be partially explained by the fact that winter coincides with the school break in bhutan, with less contact among children; and families moving from the capital to the villages with lower population density. hypoxemia is a well-established predictor of severity in children with pneumonia (duke et al., 2001; lozano, 2001) . a high proportion of children in this study (74.9%) presented with hypoxemia, which is much higher than reported in other settings (subhi et al., 2009; o'brien et al., 2019) . we defined hypoxemia as spo2 < 90%, which is considered appropriate for altitudes under 2500 m, as is the case with thimphu (2334 m). this characteristic might therefore not be generalizable to bhutanese children who live at different altitudes than that of thimphu. while bacterial aetiology was infrequent, viruses were identified in a considerable proportion of children. these microbiological findings coincide more with the etiological profile of pneumonia in children from high-income countries, highlighting the advanced stage of the epidemiologic transition that bhutan seems to have reached (omran, 2005; prayle et al., 2011) . the findings from the perch study, conducted in seven lmics with routine use of pcv, are similar (o'brien et al., 2019) . even in the absence of a deployed pcv in bhutan (pcv was introduced only in january 2019), the burden of pneumococcal invasive disease appears to be low in children. the low proportion of confirmed bacterial cases could be explained by several reasons. first, vaccination coverage was high, which is representative of the rest of the country, although the pcv was not in routine use during the recruitment period (who, 2016) . second, almost one-third of the children had received antibiotics prior to collection of blood sample, which reduces the yield of blood culture by around 45% (berkley et al., 2005; rhodes et al., 2010; driscoll et al., 2017; o'brien et al., 2019) . small blood volume is another factor known to compromise the sensitivity of blood culture (berkley et al., 2005; bouza et al., 2007; driscoll et al., 2017) . blood collection is challenging in children, especially in infants. blood volumes collected for each child were not recorded in this study but, in practice, around 1 ml was dedicated for blood culture in most cases, despite the 2-3 ml recommended in the protocol. nevertheless, these findings confirm the low yield of blood culture in hospitalized children with pneumonia and question both the need of blood culture for uncomplicated cases of pneumonia and using blood culture as the preferred screening tool for invasive bacterial disease in children with pneumonia. molecular methods have been found to be more sensitive than blood culture to detect pneumococcal invasive disease (muñozalmagro et al., 2011; selva et al., 2013; o'brien et al., 2019) . this was not the case in this study. b. pertussis was isolated in respiratory samples of three children. this is similar to the detection rate of around 1% of hospitalized pneumonia cases in similar studies (jroundi et al., 2014; barger-kamate et al., 2016) . one of these three children, aged five months, had a fatal outcome. this underlines the high fatality ratio of pertussis-infected pneumonia, especially in infants who are unvaccinated, and suggests the need of intervention such as maternal vaccination to reduce morbi-mortality associated with pertussis in vulnerable populations. viral detection was common. the use of pcr techniques has increased the ability to detect respiratory viruses (ruuskanen et al., 2011) . however, evidence of the detection of viruses in asymptomatic individuals has raised concern about the clinical significance of these positive findings. attribution of causality is not straightforward, as viruses can commonly be found both in symptomatic but also asymptomatic individuals (jartti et al., 2008; ruuskanen et al., 2011; rudan et al., 2013; o'brien et al., 2019) . while the causative role of rsv, influenza, adenovirus, human metapneumovirus, and bocavirus in childhood pneumonia is wellestablished, the pathogenic role of other viruses such as rhinovirus is still questioned (fry et al., 2007; caracciolo et al., 2008; ruuskanen et al., 2011; shi et al., 2017; jayaweera et al., 2018; o'brien et al., 2019) . using molecular methods, rhinovirus has been shown to be the most frequent respiratory pathogen isolated in children, and its detection in asymptomatic children is significantly higher than other respiratory viruses (kusel et al., 2006; jartti et al., 2008; ruuskanen et al., 2011) . nevertheless, clinical relevance of rhinovirus has been proven by the association of this virus with respiratory symptoms in children, mainly wheezing (kusel et al., 2006; khetsuriani et al., 2007) . in our series, 27.5% of the children with rhinovirus presented with wheezing. infection with coronavirus (cor229e, corhku1, cornl63, coroc43) was low in the present study. similarly, the new coronavirus (sars-cov-2) seems to cause a low infection rate in children (world health organization, 2020). the reason why coronavirus infection rate in children is low is unknown. in addition, the interpretation of positive viral findings is challenging due to the identification of multiple co-existing viral infections (jartti et al., 2008; ruuskanen et al., 2011) . co-infections were common in the present study, which is consistent with the existing literature (ruuskanen et al., 2011; jroundi et al., 2014; jiang et al., 2017) . considering radiological pneumonia endpoint as a proxy for bacterial pneumonia, 27.0% of children with positive npw findings had a viral-bacterial co-infection, and 40.0% of children with influenza detected in npw had an influenzabacterial co-infection. the contribution of viral-bacterial coinfections is well-acknowledged in the aetiology of childhood pneumonia, particularly the interaction between influenza virus and s. pneumoniae (o'brien et al., 2000; kwofie et al., 2012; brealey et al., 2015) . the combined effect of bacteria and viruses was shown to increase the severity of the disease, and bidirectional interactions have been described: respiratory viruses leading to bacterial superinfection, and bacteria pathogens promoting respiratory viral superinfections (brealey et al., 2015) . however, there is still a lack of robustness supporting these findings. this study has several limitations. most children in the present study lived in thimphu, and the microbiological findings may not be generalized to the rest of the country. bhutan is very diverse: comprised of cities, such as thimphu, and isolated households in very remote areas, leading to different lifestyles and environmental exposures; and also diverse in terms of altitude, with different climates and precipitations. the burden of pneumonia requiring hospitalization was highest among infants. respiratory viruses were detected in a considerable number of children, although a clear pathogenic role cannot be established. together with the relatively low proportion of children presenting a likely bacterial pneumoniaaround a quarter as per positive blood culture and radiological findingsthese findings emphasize the advanced stage of the epidemiologic transition that bhutan seems to have reached. this study is the first step to better understand the aetiology and clinicopathological characteristics of pneumonia in bhutanese children. henceforth, the development of targeted pneumonia interventions and hypothesis-driven research is encouraged to reduce the morbidity and mortality associated with this disease. fostering a robust pneumonia aetiology surveillance in children under five years of age appears important and would allow the assessment of the impact of the recently introduced pcv in reducing the burden of pneumonia. funding sj received a pre-doctoral fellowship from the secretariat of universities and research, ministry of enterprise and knowledge of the government of catalonia and co-funded by european social fund. this work was supported by a scholarship from the spanish society of paediatric infectology (sociedad española de 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infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study usa: college station the prevalence of hypoxaemia among ill children in developing countries: a systematic review world bank country and lending groups united nations interagency group for child mortality estimation country fact sheets bhutan sustainable development goals global burden of childhood pneumonia and diarrhoea world health organization. revised who classification and treatment of childhood pneumonia at health facilities. geneva: evidence summaries world health organization. the kingdom of bhutan health system review world health organization. coronavirus disease (covid-19) outbreak we thank all the children and their parents or caregivers who participated in this study, as well as the paediatric department of jdwnrh including paediatricians, residents in paediatrics, and interns who contributed to identifying eligible cases for the study. we are very grateful to all nurses who participated in the collection of biological samples and contributed to the success of this study, especially those in the paediatric ward. we thank dr. kinley tshering, paediatrician, who read and interpreted all the chest radiographies; the radiological and microbiological departments of jdwnrh for their support; and laia blanco lopez for contributing to the microbiological analysis of viruses in npw. we are very grateful to gaurav kwatra and laura puyol for their assistance in the shipment of the biological samples.we are grateful to the spanish society of paediatric infectology (sociedad española de infectología pediátrica, seip) for their financial support, which contributed to the shipment and testing of biological samples. we acknowledge support from the spanish ministry of science and innovation through the "centro de excelencia severo ochoa 2019-2023" program (cex2018-000806-s), and support from the generalitat de catalunya through the cerca program. cism is supported by the government of mozambique and the spanish agency for international development (aecid). no conflict of interest to declare. supplementary material related to this article can be found, in the online version, at https://doi.org/10.1016/j.ijid.2020.04.017. key: cord-314196-1go07yi6 authors: bondy, andy; horton, catherine; frost, lori title: promoting functional communication within the home date: 2020-05-12 journal: behav anal pract doi: 10.1007/s40617-020-00439-6 sha: doc_id: 314196 cord_uid: 1go07yi6 functional communication skills are essential for all learners and must be promoted within all environments, including the home. during this time of home confinement, many families will need to look at opportunities for their children to use existing functional communication skills or even to acquire new skills. this article describes a set of 9 critical communication skills and provides a variety of examples of how families can improve the use of these important skills. some of these involve speaker (expressive) skills, whereas others involve listener (receptive) skills. to ensure success in the home environment, functional communication skills are essential. functional communication is defined as a behavior that is directed to another person who in turn provides either direct or social rewards. nine critical communication skills will be described. these skills are critical because, if children cannot calmly and effectively engage in each skill, then they will most likely try other means to obtain the same outcome. typically, these other means are challenging-crying, fussing, shouting, hitting, and so on. we have identified nine such skills, of which some are skills to be used as a speaker and some are to be used as a listener, as outlined in table 1 . editor's note this manuscript is being published on a highly expedited basis, as part of a series of emergency publications designed to help practitioners of applied behavior analysis take immediate action to adjust to and mitigate the covid-19 crisis. this article was submitted on april 4, 2020, and received final acceptance on april 7, 2020. the journal would like to especially thank dr. cynthia anderson for her expeditious review of the manuscript. the views and strategies suggested by the articles in this series do not represent the positions of the association for behavior analysis international or springer nature. it is helpful to assess each of these critical skills for each learner. it is important to complete a checklist involving these skills in addition to other measures used to assess a child's language skills. that is, knowing that a child has a language age equivalent of a 9-year-old will not necessarily indicate whether the child can accomplish each skill independently. see the appendix table 2 for a suggested template to assess these critical communication skills. for each skill, it will be helpful to think about how a child currently handles a particular situation. for example, when a child sees a toy or something else he or she wants, what does the child do? is his or her response appropriate or problematic? if a 2-year-old pointed to a book on a shelf that the child wanted to look at, that might be considered appropriate for that skill and age level. on the other hand, if the child stood and stomped his or her feet and screamed until someone gave him or her the book, that would be something you would want to work on. after completing the form regarding all nine skills, rate each of the problem areas and note how difficult each problem is. that is, prioritize the severity of the problems to help determine which ones will be worked on first. for example, if a child requests help by handing a parent items that do not work, but the aim is to have the child say the word "help," that would not be as important as working on screaming when the child cannot get toys that are out of reach. given the current mandates for social distancing, behavior analysts are urged to guide caregivers through the completion of the checklist using a telehealth model. through interviews with the caregivers, the behavior analyst can guide the discussion to help determine if the learner's current communicative repertoire is effective. behavior analysts should also lead the analysis to determine priorities to help achieve two goals. one goal helps develop crucial communication skills in anticipation of problems and stresses that may arise in a child's life in the near future. the other goal helps to ensure that specific critical communication skills will serve as functionally equivalent alternative behaviors to any identified challenging behavior in the home setting. to begin, review routines and activities that are problematic for the child and be sure to consider what role expressive or receptive communication plays in the problem. for children with autism spectrum disorder (asd), a paucity or lack of appropriate communication skills is often among the biggest impediments to smooth family functioning. when a child is having difficulties with a family activity or routine, determine whether a problem with one or more of these specific communication skills is contributing to the difficulty. after completing the critical communication skills checklist to pinpoint what areas of communication are posing the biggest problem for the child and family, the next step is to figure out what the child can learn to do instead of what he or she is doing now. the following sections give many examples of potential problems with communication that children with asd have, together with some potential solutions. once an alternative skill is identified, add it to the list of teaching goals. as these skills are acquired, review the prioritization of all nine communication skills to help determine which new skills should be addressed. asking for a desired item is an essential and fundamental communication skill. requesting (i.e., manding in applied behavior analysis jargon) allows people to get access to items and activities that are essential for day-to-day living or promotes enjoyment and greater interactions with others. it is important to begin teaching requesting by having children ask for items that are highly preferred or needed to complete an important task or routine. prior to starting these lessons, identify several people, places, and/or things that are important from the child's perspective. there are many resources to help conduct preference assessments in and around the home. it also is recommended to distinguish what a child likes or prefers from what a child needs when assessing motivating items and activities. for example, mary enjoys eating vanilla pudding but does so only with a spoon, never with her fingers. it is fair to say that she likes pudding, but it would be unusual transitioning (going from one activity to another) asking for a break following directions (spoken and/or visual instructions) accepting ("yes!") following a schedule rejecting ("no!") to declare that she likes spoons. mary does not have a collection of spoons, and when asked to name things she likes or enjoys, she never mentions spoons. therefore, parents are advised to list both things their children like and things they may need within a context. furthermore, many traditional approaches to preference assessment attempt to compare individually offered items for the purpose of ranking them within a hierarchy. although it may be true that a child prefers a ball in comparison to a napkin, this strategy places too much emphasis on individually presented rewards as opposed to combinations. simply put, imagine how most children would respond if asked, "do you want peanut butter or jelly?" adults rarely simply order coffee from a barista. therefore, parents are advised to investigate combinations of items or activities in order to enhance their effectiveness: cookies and milk, french fries and ketchup, music and dancing, and so on. & problem: three-year-old derek wants to play his favorite game, but his father has put the ipad on the top shelf above the television where derek cannot reach it. he tries to climb on top of the television but cannot quite make it. he begins whimpering and jumping up and down. when his mother comes into the room, not knowing that derek's father put the ipad out of reach, she cannot figure out what he wants. -potential solution: teach derek to exchange a picture to ask for the ipad. & problem: eight-year-old sam wants some juice, and the juice carton is empty. he goes to his mother and says, "sam, say you want some juice." -potential solution: re-create the situation by giving sam just a little juice, and as he finishes it, guide him to say, "i want some juice." & problem: fourteen-year-old darlene is about to do some homework. she looks at her sister who is on the computer and screams, "get off now!" -potential solution: do not try to teach a new skill while darlene is screaming. re-create the situation with her sister, and as darlene approaches her, prompt her to say, "i have homework to do. can i use the computer soon?" the key to teaching this type of lesson is to create situations involving the use of moderately rewarding items or activities when the child is relatively calm. use these types of items at first to minimize the potential for an emotional reaction to not getting the most powerful potential reward. in the midst of a tantrum or meltdown, it is very difficult to teach a new skill. instead, re-create the situation and be prepared to prompt or guide the new or replacement skill at the right time and context. teach the new form of communicating the request without requiring a big change in performance-a single picture before a series of pictures, a single spoken word before a full sentence, and so on. asking for help is universally important because everyone at some time will be in a situation where the solution to a problem must come from someone else. & problem: joey is playing with his favorite electric train set. he has learned to set the track up on his own; connect the train engine, cars, and caboose; and put the train on the track and start the train. today when the train rounds the first corner, it falls off the track. joey tries several times to restart the train but does not notice that the track is not properly connected at the first corner. after several attempts to get the train going, each time ending with a derailed train, joey screams and throws the train across the room. -potential solution: re-create the situation by intentionally misaligning part of the track. before joey gets upset, teach him to bring the train to his sister and gesture for help. over time, create other more challenging problems for joey to encounter. & problem: amanda is working on her math homework at the kitchen table along with her brother. she carefully adds the numbers for each problem, reciting the problem aloud as she works. ("seven plus eight equals fifteen.") when her pencil lead breaks, she grabs her brother's pencil. -potential solution: re-create the situation by giving amanda a pencil with a broken nib and teach amanda to point to her brother's pencil and say, "can i use that for now?" in teaching a child to request help, identify many activities and times during the day when it is natural for the child to ask for help. the key to teaching this skill is to set up help situations that are easy to solve at first and then to gradually make the situation more challenging. if the situation rapidly leads to challenging behaviors, then re-create the problem at a less intense level. for example, once joey has calmly handled the singletrack problem, we should not immediately add 10 broken tracks and hope for the best; instead, we should gradually introduce new problems to solve. we are the ones creating the "problem" so we can modulate the severity from opportunity to opportunity. everyone has been in situations where the demand is too high or fatigue has set in due to the length of the task at hand. in these cases, asking for a break is appropriate to gain some time to recuperate. requesting a break effectively leads to avoiding or escaping from certain events in a socially acceptable manner. although parents may be able to "read" when their children need a break, children also need a calm way to ask for a break on their own. as with learning to ask for help, the key will be for the child to ask for a break before having a tantrum. & problem: maria has started distance learning and is listening to her teacher sing a song. shortly after the singing begins, maria brings her hands to her ears, starts to scream, and backs away from the computer. -potential solution: teach maria to use a break card when she is overwhelmed by a situation. in the future, maria can hand her father a card that says "break" and walk to a neutral break area. & problem: reggie's math assignment includes 50 longdivision problems. reggie is generally accurate with his math equations and can work for up to 15 min independently. after 15 min pass, reggie breaks his pencil, throws it across the room, and yells, "i hate math!" -potential solution: teach reggie to say "i need to chill for a minute" when he has worked for 15 min but before he screams or breaks his pencil. when teaching this skill, try to create the opportunity to request a break before the breaking point. once a tantrum has begun, it is too late to calmly request a break. if a child can handle 10 min of a task but not 15, try to stretch to 11 or 12 before pushing for the full 15 min of work. rejecting offers from other people allows participation in interactions with communicative partners who are determining what, specifically, may be wanted in the situation. when someone cannot politely or calmly reject something that is not liked, trouble usually ensues. & problem: jacqui, 19 years old, is having dinner with her parents. she has learned to sit with her family at mealtimes, and virtually all meals at her house involve mom or dad handing her a plate of her favorite foods. tonight, jacqui's mother tries to pass jacqui the bowl of broccoli. jacqui will not take it from her, and when her mother tries to spoon some broccoli onto jacqui's plate, jacqui forcefully pushes the bowl away, knocking over her water glass. -potential solution: teach jacqui to shake her head no when she is offered foods she does not like. & problem: jamie wants to watch a movie. her sister tries to help and puts on the frozen video because it is one of jamie's favorite movies. jamie screams, "thomas! thomas! thomas!" -potential solution: jamie learns to say "no, thanks" and give her sister a picture of the video she wants to watch. for this lesson to be successful, the rejection must work. that is, if a child communicates no to the offered item, that item must be removed. as with the other lessons, the first lessons should involve items that are mildly or moderately unwelcomed and should not involve items that are deeply feared. for example, use broccoli with jacqui because it is something she mildly dislikes, as opposed to bananas, the mere smell of which makes her gag and throw up. present a small amount of the item or activity to be rejected before gradually increasing how much of the item or activity is offered. we all can remember times when we have played 20 questions with a child in order to figure out what was wanted. when holding out a preferred item and asking, "do you want this?" most often children will simply take it. however, many items cannot be held or even shown, such as when asking, "do you want to go to the swimming pool?" so children need to indicate "yes!" & problem: eight-year-old sierra is in the kitchen with her older brother, sam. sam is trying to help his sister get a snack and is pulling one food after another out of the snack cupboard, asking, "is this what you want?" he thinks it is the blue corn chips she wants, but he has not been able to reach them yet. so, without showing them to her, he asks, "do you want the blue corn chips?" sierra does not answer. finally, he reaches them in the back of the cupboard, and when he holds them out to sierra, she takes them from him. -potential solution: when sam asks, "is this what you want?" sierra nods her head. & problem: fourteen-year-old alexis is helping her mother make cookies. when it is time to stir the dough, her mother asks, "do you want the big spoon?" alexis answers, "big spoon." -potential solution: when asked whether she wants something, alexis learns to say, "yes!" it is important to distinguish answering a question from repeating part of the question, as alexis did in the previous big-spoon example. it is suggested that teaching no versus yes should involve separate opportunities before trying to alternate between the two. furthermore, answering "do you want . . . ?" questions leads to very different outcomes than when asking, "is this a . . . ?" questions. when a ball is held up while asking, "do you want the ball?" a yes results in receipt of the ball. when a ball is held up while asking, "is this a ball?" a yes merely results in praise, and not the ball itself. responding to "wait" or "no" when we say "wait" to a child, the full message is actually complex: "i know what you want, and you are going to get it, but only after some more time passes." being told to wait is not the same as being told no because in the wait situation, the item or activity will eventually occur. learning to wait is a crucial skill for everyone and requires providing more details on several issues. there are three key elements to teaching someone to wait: first, there must be full control over access to whatever it is the child is waiting for. essentially, saying wait is equivalent to a promise that must be fulfilled if we expect the child to heed the statement the next time it is made. if the provision of the item is not guaranteed, then the lesson will be very difficult to learn. therefore, start with something that the child wants but that can be given to him or her at any time. second, there must be control over how long the child must wait. start with a time interval that is so short-1 or 2 s-that it virtually guarantees that there will be no failure. then, begin to gradually increase the time interval over a series of opportunities. if too much time is added and there is a problem, simply readjust the next interval to something shorter. highlight that it is time to practice waiting with a visual cue, such as a large, brightly colored card that has "wait" written on it. third, as the wait intervals become 1 min or longer, help the child select something easy to do while waiting. the point is, do not expect someone to simply wait while doing nothing-that remains very hard for all of us. instead, pick some easy activities such as looking at a picture book or listening to music (as long as the child is not waiting to listen to music). here are some more common situations that all families face and their suggested solutions: & problem: mark's mother is on the telephone trying to schedule an appointment. mark comes up to her and begins tugging on her, trying to get her to move with him. she resists and whispers to mark, "just a minute. i'm almost done." mark falls to the floor and begins screaming. -potential solution: mark's mother teaches him to use a "wait" card. for example, mom hands mark a card that says, "wait," and mark calmly stands next to her for 1 min. mom then pays attention to mark. (note that if mark cannot yet read, he can learn to associate this visually unique card with waiting.) & problem: sue's family is planning on having food from her favorite restaurant delivered for dinner. during the early afternoon, sue begins asking her parents when the food will arrive, and they answer, "not for several hours," "later," or "at 6:00." sue does not know how to tell time and continues to ask every 15 or 20 min, which begins to annoy her parents. by the time the food finally arrives, everyone is frustrated. -potential solution: her parents place a picture of the restaurant on sue's picture schedule, which she quietly checks several times during the afternoon. & problem: marshall has finished his homework and a bowl of ice cream that he had earned. he asks his father if he can have another bowl of ice cream. his father says, "no, one is enough." marshall ignores his father and heads for the freezer for more ice cream. his father blocks his path, and they start to yell and shout at each other. -potential solution: marshall's parents teach him "the no game." they tell marshall that sometimes they will say no to him, but if he responds calmly, they will provide other types of rewards-special time with them when he can pick which game to play. they give marshall an index card with five open circles and tell him that he will earn a token each time he calmly responds when they say no. when all five circles are filled, he can pick a game to play. at first, marshall's parents arrange to say no at times when it does not seem highly important to marshall. for instance, he is about to sit on one chair at the dinner table, and they say, "no, please sit on that chair." when he follows through, he earns a token. after several weeks of this type of practice, marshall asks once again for more ice cream. when his father says no, marshall calmly walks out of the kitchen, and his father praises him while giving him a token. no one is perfect, so it is likely that when time is added to this lesson, the next change may lead to a failed opportunity. it is not the learner who has failed; it is the teacher who set too high a level. therefore, cope with the reaction as best you can, and then reset the opportunity at an interval that is more likely to succeed. responding to directions is viewed as a critical communication skill because of the potential risks associated with failing to understand a message. for example, when mom shouts to her son, "don't walk in front of the swings!" failure to respond could result in injury. it is important to first teach children to respond to directions that will produce meaningful and desired outcomes from the children's point of view. & problem: angela's parents report that angela sometimes looks toward them when they call her name. if she is engaged in a favorite activity, however, she does not respond when they say, "come here." she seems to follow directions some of the time, but not always. for example, yesterday when her father told her to put her shoes away, she did not do so. but this morning, as he was getting on his coat so they could go to the park, he told angela to get her shoes, and she ran right to them. -potential solution: angela's parents can teach her to listen for her name paired with "come here" by rewarding her with favorite items (e.g., toys, snacks) for coming over. behavior analysts readily distinguish between requests and comments because of the important differences in the outcomes. asking for a ball yields the ball, whereas saying "that's a ball" leads to praise. this analysis should extend to following directions. "get the ball" leads to the ball, whereas "point to the ball" leads to praise. it is suggested that directions at home should initially result in a child receiving items and activities in a direct fashion before lessons that only lead to social outcomes are introduced. just as children must eventually learn to request and comment, so too should children learn to respond to what others are communicating about for both types of outcomes. most adults keep track of all the important things needed to be done today, this week, or this month by using some type of written calendar system. that is, whatever our level of vocal communication, most adults rely on a visually mediated system to help them navigate their schedules. children also need to know what is expected of them and when activities will occur. therefore, they should be taught how to use systems that contain information about their future schedules of activities. schedules can come in many shapes and forms. if a child can read, then using words may be helpful, but children with asd can learn to use pictures or other three-dimensional items to keep track of their schedules. when pictures are used within a schedule, it is a good idea to first teach what the pictures mean (i.e., what to do when one sees a picture) and only then teach the child how to use the schedule itself. teach one lesson at a time, and avoid mixing them together. the pictures used should refer to important objects, activities, or areas of the home or neighborhood. the child should respond to the picture without someone telling him or her what the picture means-otherwise, why use the pictures? for example, when shown a picture of a spoon, the child should get the spoon and go to the area or start the activity shown without someone saying, "right! get the spoon!" one strategy involves arranging the pictures in a top-down fashion to show the sequence of events, whereas other strategies involve notebooks that can be used to show a single activity on each page. more complex systems can be developed over time. & problem: mary wants to play a game on her smart tablet right now. her mother wants mary to complete her online lesson that her school has assigned. mary throws a tantrum while screaming, "now! now!" -potential solution: mary's mother introduces a visual schedule of the important activities of the day. when mary wants to play her game, her mother puts the picture of the tablet on the schedule after the "school lesson" picture. & problem: on weekdays, david's parents maintain a very predictable routine in the household. david seems content to follow along with the family's activities. on weekends, though, when the schedule is more unpredictable or loosely structured, david has frequent tantrums. on days when any kind of "surprise" occurs (e.g., an anticipated trip to the park is canceled when it storms), david is inconsolable. -potential solution: david's parents introduce a "surprise" card on his schedule during weekdays. initially, they make sure the surprise is something that david enjoys, such as time on the computer. later, these good surprises are intermixed with surprise activities that david feels neutral about. finally, his parents intersperse some surprises concerning things that david does not enjoy. then his parents begin to use a visual schedule and the surprise card for weekends as well. a visual schedule contains information about activities and their sequence. it is difficult to assure that the plan for the day will remain intact-life happens. children should be encouraged to cope with the normal variations that occur by introducing choice (i.e., "do you want to read or do math work first?") or even the surprise lesson taught to david. everyone must deal with transitions-between locations, activities, and from person to person. the use of a schedule can help a child cope with what is going to happen at different times of the day. however, some children respond to transitions as if their lives were being turned upside down! although improving information about the upcoming event may reduce the magnitude of the ensuing tantrum, providing more information (even visually based) is not always sufficient. some transitions involve changes from activities that are highly rewarding to those that are less rewarding-and no one looks forward to leaving pleasant activities. some children become upset even when they are asked to change from a less rewarding activity to one that is more rewarding. this reaction may be because the transition involves both leaving something behind and changing to a new activity. many children respond better when provided with information about the next reward rather than information about the next activity. when the next activity is not inherently rewarding, then adding a separate reinforcer may be necessary. & problem: maryjane has just finished her breakfast and is coloring on a sheet of paper in the kitchen. her mother tells her that it is time to play in the family room. maryjane throws the crayons on the floor and screams while her mother physically guides her to the family room. within a few minutes, maryjane is calm once more and contentedly playing with her toys. then her mother tells her that it is time to water the plants-something that maryjane usually enjoys. maryjane screams and throws the toys around while her mother coaxes her to get the watering can. this pattern cycles many times each day. -potential solution: maryjane's mother shows maryjane what her reward will be for making a transition before asking her to change activities. for example, while maryjane is coloring, her mother brings her one of her favorite toys from the family room. she shows the toy to her daughter, who immediately reaches for it. then her mother says, "let's play with the toys in the family room . . . but first we need to put away the crayons." maryjane puts away the crayons and runs to play with the toy. later, while maryjane is still playing with the toy, her mother shows her a picture of the watering can. while she is looking at the picture, her mother says, "let's go water the plants . . . but first we need to clean up the toys." throughout the day, maryjane's mother shows her the next available reward before indicating that maryjane needs to stop what she is currently doing. whereas adults often consider transitioning from activity to activity, most children appear focused on the current reward. this transition strategy aims to provide functional information about the next reward before signaling to the child the removal of the current reward. it is extremely important to teach children to continue to use and expand their repertoires of functional communication skills. we have noted several key skills and the strategies to promote them. when these critical skills are weak or missing, behavior problems are often seen in their place. because all families are unique, it is crucial that each child's communication skills are assessed in his or her home environment, and then a plan to help improve each of the critical skills described in this article can be mapped out. communication is something that should be worked on during all activities-we do not suggest having a special time to practice communication. it's 10:00 a.m.-we need to do a pecs lesson!" that would most likely lead to something arbitrary and nonfunctional. instead, look for opportunities to work on these skills throughout the day and across all activities pyramid educational consultants, inc.; catherine horton behavior analyst certification board. (2014) . professional and ethical compliance code for behavior analysts. littleton, co: author.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-326277-dwyvics9 authors: thakur, kalpna; kumar, naveen; sharma, novrattan title: effect of the pandemic and lockdown on mental health of children date: 2020-05-12 journal: indian j pediatr doi: 10.1007/s12098-020-03308-w sha: doc_id: 326277 cord_uid: dwyvics9 nan to the editor: in response to covid-19 outbreak, indian government recently announced lockdown of 21 d which surely is going to reduce the transmission rate of sars-cov-2. however, this lockdown has restricted people to stay at home which is likely to impact their physical as well as mental health. especially vulnerable to this are children. particularly those whose parents are either affected by covid-19 or are rendering their services in hospitals or those who are affected or had exposure to this virus and quarantined therefore. it has been found that children staying at home due to lockdown spend more time in front of tv and internet which can lead to psycho-social problems, like lower selfesteem [1] . excess use of internet can lead to internet addiction disorder. some can also experience cyberbullying which can affect their mental health. moreover, spending more time inside the house makes children vulnerable to effects of indoor pollution which can affect their brain development leading to limited development of cognitive abilities [2] . liu et al. suggests that children who are separated from their parents/ caregivers due to their infections or their parents being affected or their parents serving in hospitals are more susceptible to psychological problems. their vulnerability to depression, stress, anxiety, avoidance behavior, and post-traumatic stress disorder have been reported [3] . infant's development of attachment to their caregivers can be affected by their separation which is crucial for the child psychological wellbeing in the adulthood [4] . though, great efforts have been made by indian government to combat this pandemic, however, this will lead india half way only as we need to focus on holistic health of children and not focusing only on providing basic care. for this we suggest, the parents of children staying at home should reduce their use of internet and tv by engaging them in physical activities. children who are separated from their parents should be given special care. their nutritional needs should be taken care of. their communication with parents should be increased via phone and their access to mental health services should be improved. for this, throughout india, various psychological associations have come forward to provide counselling services through telephone. we suggest efforts like these should be encouraged. health threats associated with children lockdown in spain during indoor air quality and respiratory health of children mental health considerations for children quarantined because of covid-19. lancet child adolesc health future directions in the study and treatment of parent child separation publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations conflict of interest none. key: cord-323742-rt0g0ufe authors: carter, michael j.; gurung, pallavi; jones, claire; rajkarnikar, shristy; kandasamy, rama; gurung, meeru; thorson, stephen; gautam, madhav c.; prajapati, krishna g.; khadka, bibek; maharjan, anju; knight, julian c.; murdoch, david r.; darton, thomas c.; voysey, merryn; wahl, brian; o'brien, katherine l.; kelly, sarah; ansari, imran; shah, ganesh; ekström, nina; melin, merit; pollard, andrew j.; kelly, dominic f.; shrestha, shrijana title: assessment of an antibody-in-lymphocyte supernatant assay for the etiological diagnosis of pneumococcal pneumonia in children date: 2020-01-17 journal: front cell infect microbiol doi: 10.3389/fcimb.2019.00459 sha: doc_id: 323742 cord_uid: rt0g0ufe new diagnostic tests for the etiology of childhood pneumonia are needed. we evaluated the antibody-in-lymphocyte supernatant (als) assay to detect immunoglobulin (ig) g secretion from ex vivo peripheral blood mononuclear cell (pbmc) culture, as a potential diagnostic test for pneumococcal pneumonia. we enrolled 348 children with pneumonia admitted to patan hospital, kathmandu, nepal between december 2015 and september 2016. pbmcs sampled from participants were incubated for 48 h before harvesting of cell culture supernatant (als). we used a fluorescence-based multiplexed immunoassay to measure the concentration of igg in als against five conserved pneumococcal protein antigens. of children with pneumonia, 68 had a confirmed etiological diagnosis: 12 children had pneumococcal pneumonia (defined as blood or pleural fluid culture-confirmed; or plasma crp concentration ≥60 mg/l and nasopharyngeal carriage of serotype 1 pneumococci), and 56 children had non-pneumococcal pneumonia. children with non-pneumococcal pneumonia had either a bacterial pathogen isolated from blood (six children); or c-reactive protein <60 mg/l, absence of radiographic consolidation and detection of a pathogenic virus by multiplex pcr (respiratory syncytial virus, influenza viruses, or parainfluenza viruses; 23 children). concentrations of als igg to all five pneumococcal proteins were significantly higher in children with pneumococcal pneumonia than in children with non-pneumococcal pneumonia. the concentration of igg in als to the best-performing antigen discriminated between children with pneumococcal and non-pneumococcal pneumonia with a sensitivity of 1.0 (95% ci 0.73–1.0), specificity of 0.66 (95% ci 0.52–0.78) and area under the receiver-operating characteristic curve (aurocc) 0.85 (95% ci 0.75–0.94). children with pneumococcal pneumonia were older than children with non-pneumococcal pneumonia (median 5.6 and 2.0 years, respectively, p < 0.001). when the analysis was limited to children ≥2 years of age, assay of igg als to pneumococcal proteins was unable to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia (aurocc 0.67, 95% ci 0.47–0.88). this method detected spontaneous secretion of igg to pneumococcal protein antigens from cultured pbmcs. however, when stratified by age group, assay of igg in als to pneumococcal proteins showed limited utility as a test to discriminate between pneumococcal and non-pneumococcal pneumonia in children. pneumonia is the leading cause of childhood mortality after the neonatal period, yet the pathogen-specific etiology of childhood pneumonia remains poorly defined (liu et al., 2016; feikin et al., 2017b) . using data from randomized controlled vaccine trials, vaccine-probe studies help reveal the pathogen-specific burden of disease by estimating the difference in disease between vaccinated and unvaccinated individuals (feikin et al., 2014) . results from these studies estimate that approximately one third of children with pneumonia and radiographic consolidation have pneumococcal pneumonia in settings prior to the introduction of vaccines that prevent etiology-specific pneumonia, regardless of geography (o'brien et al., 2009; wahl et al., 2018) . however, microbiological data to support this prevalence estimate are lacking. accurate diagnostic tests for the etiology of pneumonia are needed to assess the etiology of pneumonia in changing epidemiological contexts, notably following vaccine implementation (feikin et al., 2017b) . direct aspiration of infected (lung) tissue is rarely used due to perceived safety concerns (ideh et al., 2011; howie et al., 2014) , while culture of broncho-alveolar lavage samples is only possible on samples from children requiring mechanical ventilation. culture of bacteria from blood is therefore the most widely used test for bacterial pneumonia in children admitted to hospital. however, estimates of yield from "true positive" bacterial pneumonia cases are <20% (cutts et al., 2005) , depending on prior antibiotic exposure, sample volume and culture technique (driscoll et al., 2017) . in the recent pneumonia etiology research for child health (perch) casecontrol study, quantitative (q)pcr of lyta to determine whole blood pneumococcal load (deloria , and density of nasopharyngeal (np) colonization with s. pneumonia , demonstrated only moderate ability to discriminate between pneumococcal pneumonia and agematched community children. an alternative approach to the diagnosis of pneumococcal pneumonia is to assess the immune response to the pathogen. unfortunately, serological assays have limited specificity in the acute phase, or require convalescent samples to discriminate from past infections (tuerlinckx et al., 2013; andrade et al., 2016) . we hypothesized that we could combine the etiological specificity of serological assays to a time-specific population of b cells (plasmablasts), that circulate during active infection (carter et al., 2017) , using the antibody-in-lymphocyte supernatant (als) assay. the als assay was originally developed to assess vaccineinduced serological responses, and has since been developed for the diagnosis of enteric fever and tuberculosis (chang and sack, 2001; sheikh et al., 2009; darton et al., 2017b; sariko et al., 2017) . this assay is based upon testing the secretions of lymphocytes that are incubated in vitro following sampling from an unwell patient (without ex vivo stimulation). following incubation, harvested supernatant can be tested for pathogenspecific antibodies using standard serological techniques. we assessed the diagnostic performance of the als assay for the diagnosis of pneumococcal infection in a prospective study of childhood pneumonia in nepal, a low income country in south asia with a high burden of childhood pneumonia (ministry of health population (mohp) et al., 2012) . we used five pneumococcal proteins as target antigens (choline binding protein a, cbpa; protein for cell wall separation of group b streptococci, pcsb; pneumococcal histidine triad d, phtd; pneumolysin, ply; serine threonine kinase protein c, stkpc). these antigens are thought to be expressed by all pathogenic pneumococci, are specific to pneumococci or closely related species, and have been used to assess the serological response to pneumococcal pneumonia (andrade et al., 2014 borges et al., 2016) . this prospective study was carried out in accordance with the protocol and the international conference on harmonization good clinical practice standard. literate parents/legal guardians all gave informed written consent prior to enrolment. nonliterate parents/legal guardians gave verbal and thumbprint consent in the presence of a literate (non-hospital/research staff) witness who could attest to the explanation of the patient information leaflet and the agreement of the signatory. the study protocol was approved by the nepal health research council (286/2014) and the oxford tropical research ethics committee (09/15). patan hospital is in the lalitpur sub-metropolitan district of nepal, contiguous with the city of kathmandu. it is one of the largest hospitals in the country, and one of few with inpatient pediatric and pediatric critical care facilities. during the study period, the primary infant vaccination schedule included diphtheria-tetanus-pertussis, bacille-calmette-guérin, hepatitis b, haemophilus influenzae type b (from 2009), oral and inactivated poliovirus and measles, rubella and japanese encephalitis antigens, with 83% coverage for all antigens in 2011 in the central development region of nepal (including lalitpur) [ministry of health population (mohp) et al., 2012] . tenvalent pneumococcal conjugate vaccination (10-valent pcv) was introduced to the infant immunization schedule in lalitpur in august 2015 at 6 and 10 weeks, and 9 months of age. there was a limited pcv catch-up campaign among infants. children were enrolled for this study between 22nd december 2015 and 30th september 2016. children were eligible for enrolment if ≥60 days of age and <15 years of age and being admitted to patan hospital with a clinical diagnosis of pneumonia. a small number of patients were diagnosed with pneumonia, enrolled, and then discharged directly before admission; their data are included here (figure 1) . the diagnosis of pneumonia was made by admitting pediatricians, reviewed by a consultant (attending) pediatrician, and was typically prior to results from radiographs or blood tests becoming available. children who did not have a clinical diagnosis of pneumonia were excluded from the study. a digitalized radiograph was obtained on all children on study enrolment. all radiographs were independently interpreted using standardized who criteria (liu et al., 2016) as endpoint consolidation, other infiltrate, or no consolidation/effusion/infiltrate by two specific readers (a pediatrician, and a radiologist). a second specific radiologist arbitrated upon all discordant results, and 10% of other radiographs. radiographic findings were not used to exclude children from the study. child healthy controls were enrolled from a vaccine clinic at 10 months of age, and all controls had been vaccinated with three doses of 10-valent pcv (most recent dose received ≥28 days prior to sampling). enrolled cases and controls all had 2 ml of blood sampled into heparinized and sterile centrifuge tubes for this study by peripheral venepuncture within 48 h of admission. in addition all enrolled children had full blood count, plasma (for storage) and inoculation of blood into bactec peds plus culture bottles (becton dickinson, bd; usa) for automated incubation (bactec, bd), subculture and identification of isolated organisms. heparinized blood was immediately taken to the microbiology laboratory and processed within 4 h of sampling as described below. c-reactive protein (crp) concentrations were measured following shipment of plasma to oxford at oxford university hospitals nhs foundation trust. a single flocked swab (thermo fisher scientific, uk) was used to sample the nasopharynx, and a digital chest radiograph was taken, at admission. the np swab was immediately and aseptically placed into skim-milk-tryptone-glucose-glycerin media and transported to the on-site microbiology laboratory, cultured for pneumococci, and subjected to quellung serotyping. np swabs in stgg media were subsequently stored at −80 • c before transport to the uk on dry ice and further storage at −80 • c. all chest radiographs underwent blinded review for radiographic endpoint consolidation by two clinicians (a pediatrician and a radiologist) according to world health organization criteria (cherian et al., 2005) , with quality control and discordant readings arbitrated upon by a second radiologist. np swabs were defrosted and dna was extracted from 200 µl stgg media using the qiagen dneasy 96 kit (qiagen, uk) using a modified protocol. extracted dna was subsequently transported to micropathology ltd (warwick, uk) where samples (40 µl extracted dna) were analyzed using the nxtag luminex respiratory pathogen panel (luminex corp, usa) (tang et al., 2016) according to manufacturer's instructions for: influenza a, influenza a h1, influenza a h3, influenza b, rsv a, rsv b, parainfluenza 1-4, coronaviruses 229e/nl63/oc43/hku1, human metapneumovirus, rhinovirus/enterovirus, adenovirus, human bocavirus, chlamydophila pneumoniae, legionella pneumophila, and mycoplasma pneumoniae. results were reported as positive or negative for each pathogen. we considered rsv (any group), influenza virus (any serotype) or any of the parainfluenza viruses 1-4 as pathogenic, since these were highly associated with case status in the perch study, and were prevalent (≥5 cases for each virus) in our cohort. samples of fresh, heparinized, whole blood were separated by centrifugation over ficoll media with a density of 1.077 g/ml (histopaque 1077, sigma-aldrich, usa) at 400 g for 20 min with minimal acceleration and deceleration. this yielded plasma, peripheral blood mononuclear cells (pbmcs) and a sediment of red cells and polymorphonuclear cells. the pbmc layer was manually aspirated and washed by resuspension and centrifugation twice into rpmi culture media plus penicillin (500 u/l), streptomycin (0.25 mg/l), and l-glutamine (10 mmol/l; all sigma-aldrich; "r0 medium"). following manual counting and calculation of the total number of pbmcs, the cells were resuspended into r0 medium plus 10% fetal bovine serum (heatinactivated and sterile-filtered, sigma-aldrich; "r10 medium"), and incubated in a sterile cell culture plate (greiner, germany) at 37 • c and 5% co 2 for 48 h. following incubation the cell suspension was separated by centrifugation with the resulting supernatant (als) preserved with 40x protease inhibitors (25 µl per ml of als) and stored immediately at −80 • c before shipping to oxford and helsinki on dry ice for further analyses. figure 1 | classification of children by likely etiology of pneumonia into comparator groups (definite pneumococcal, probable pneumococcal, probable bacterial, unknown, influenza/parainfluenza virus, rsv, and definite other bacterial) and by diagnosis of "pneumococcal pneumonia" and "non-pneumococcal pneumonia". a fluorescent multiplexed bead-based immunoassay (fmia) to detect igg als to five pneumococcal proteins (cbpa, pcsb, phtd, ply, and stkpc) was used for this study as previously described (andrade et al., 2014 . in brief, samples of als were diluted to 1/25 in phosphate buffered saline containing 10% fetal bovine serum, with the fmia performed as a 5plex assay with 1,200 beads per region per well. igg in als were detected using rpe-conjugated goat anti-human igg (jackson immunoresearch, usa). pneumococcal reference standard serum 007sp (nibsc, uk) was used as the reference with an arbitrary assigned concentration of 100 units/ml for each anti-pneumococcal antibody. we classified children by comparator groups based on likely etiology of pneumonia (where these comparator groups are used in the text, they are italicized for clarity.) this classification scheme is described in figure 1 . specifically, we classified children into comparator groups as definite pneumococcal pneumonia (s. pneumoniae cultured from blood or pleural fluid), probable pneumococcal pneumonia (crp concentration ≥60 mg/l and np carriage of serotype 1 pneumococci), probable bacterial pneumonia (crp concentration ≥60 mg/l only), unknown pneumonia (crp concentration <60 mg/l only), influenza/parainfluenza viral pneumonia (crp <60 mg/l and influenza/parainfluenza viruses detected by qpcr from np specimen), rsv pneumonia (crp <60 mg/l and rsv detected by qpcr from np specimen), and definite other bacterial pneumonia (other bacterial pathogen cultured from blood or pleural fluid). these were ordered by hypothesized probability of pneumococcal infection from definite pneumococcal pneumonia to definite other bacterial pneumonia (left to right, figure 1 ). to assess the utility of acute igg als to pneumococcal proteins to identify pneumococcal pneumonia we compounded definite pneumococcal pneumonia and probable pneumococcal pneumonia into a single category (pneumococcal pneumonia); and we combined influenza/parainfluenza virus pneumonia, rsv pneumonia and definite other bacterial pneumonia into a single category (non-pneumococcal pneumonia). the classification scheme was modified from similar schemes for the development of novel diagnostic tests to discriminate between bacterial and viral infection (herberg et al., 2016; kaforou et al., 2017) . recent data have estimated a threshold to discriminate between bacterial and viral pneumonia at a crp concentration of ∼50-60 mg/l in children in south asia and in low and middle-income countries in the perch study (lubell et al., 2015; higdon et al., 2017b) . we chose np carriage of pneumococcal serotype 1 (by culture) as a predictor of pneumococcal infection. the association of np carriage of serotype 1 pneumococci in cases compared with controls, has been previously established in unvaccinated populations (scott et al., 1996) . np carriage of serotype 1 was also associated with cases in comparison with controls in 938 children with pneumonia at patan hospital between 2014 and 2015 (prior to 10-valent pcv introduction) and 3,202 age-stratified control (non-pneumonia) children (odds ratio for case status of 5.0, 95% confidence interval, ci, 1.7-14.0; figure s1 ). this was supported by unpublished data from childhood invasive pneumococcal disease at patan hospital from 2005 to 2016, where 58/124 (47%) isolated pneumococci were of serotype 1. similar findings have been reported from other epidemiological settings (scott et al., 1996; johnson et al., 2010) . we chose np carriage (as detected by pcr) of influenza or parainfluenza virus, and rsv to represent viral pneumonia since carriage of these viruses was associated with radiographically-confirmed pneumonia in the perch study (feikin et al., 2017a) . while we used np carriage of serotype 1 pneumococci as a predictor of pneumococcal pneumonia, we also subsequently investigated for an association of np carriage of pneumococci with increased igg als to pneumococcal proteins. to avoid confounding with undetected pneumococcal infection, we limited this analysis to children with non-pneumococcal pneumonia (i.e., definite other bacterial pneumonia, influenza/parainfluenza pneumonia or rsv pneumonia). continuous variables were compared using student's t-test, following appropriate transformation (log transformation of age distribution; and taking the reciprocal of als concentrations to pneumococcal protein for the comparison of als concentrations to pneumococcal proteins between probable bacterial pneumonia and unknown pneumonia). assay signals that were undetectable were assigned a value below the threshold of detection. fisher exact tests, wilcoxon rank sum tests, and χ 2 test were used as indicated. kruskal-wallis tests were used to assess for confounding of acute igg als to pneumococcal proteins with age, and length of illness. formal statistical testing for an interaction between age (grouped, due to a non-normal distribution) and acute igg als to pneumococcal proteins stratified by comparator group was not possible due to small numbers and tied als values. analyses were prespecified, with the exception of a post-hoc analysis of the effects of age on igg als to pneumococcal proteins. we used best subsets regression analysis to investigate optimal combinations of pneumococcal protein antigens for igg als to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia and assessed for multiple co-linearity. one thousand nine hundred four children were admitted to patan hospital during the study period. of admitted children, 356 (19%) children had a clinician diagnosis of pneumonia, as had an additional 37 children who were diagnosed with pneumonia, but not admitted, totaling 393 children. 369 children were enrolled to the study, with data on als to pneumococcal proteins available on 348 of these children (figure 2) . of 348 children, 122 (35%) had endpoint consolidation/effusions on chest radiograph, 32 (9%) had infiltrates, 178 had neither consolidation/effusions or infiltrates, 2 (<1%) were uninterpretable and 14 (4%) children did not have a chest radiograph. of 304 children <5 years of age, 217 (71%) met the who criteria for pneumonia (fast breathing or chest indrawing) and 87 (29%) did not. in addition, 48 healthy infants (controls) aged 10 months of age were enrolled, on whom als was analyzed on a random subset of 20 infants. all healthy infant controls had received three doses of 10-valent pcv, with the most recent dose ≥28 days prior to enrolment to this study. the clinical characteristics of children with pneumonia are described in table 1 by comparator group (and table s1 by other classifications). we classified eight children as definite pneumococcal, four children as probable pneumococcal (totaling 12 as pneumococcal pneumonia), 66 children as probable bacterial, 214 children as unknown, 23 children as parainfluenza/influenza virus, 27 children as rsv, and six children as definite other bacterial pneumonia. this totaled 56 children as non-pneumococcal pneumonia. on comparison of children with pneumococcal pneumonia vs. children with non-pneumococcal pneumonia, there were significant differences in age (median 6.3 years, interquartile range 4.2-8.3 and 0.8 years, iqr 0.5-2.2, t-test following log transformation of age distribution, p < 0.001), sex (females 8 and 46%, fisher exact test, p = 0.02), length of illness (3 days, iqr 2-3.3 and 4.5 days, iqr 3-7, wilcoxon rank sum test, p < 0.001), and proportion with radiographic endpoint consolidation (92 and 23%, χ 2 test, p < 0.001). the youngest child with pneumococcal pneumonia was 3.8 years of age. igg als to pneumococcal proteins was detected and quantifiable in 348 acute samples from children with pneumonia. acute igg als was higher in children with pneumococcal pneumonia than children with all other pneumonia (including possible cases of undiagnosed pneumococcal pneumonia within the comparator groups probable bacterial pneumonia, unknown, influenza/parainfluenza pneumonia, rsv pneumonia, definite other bacterial pneumonia) for 4/5 pneumococcal proteins (figure 3) . assay of acute igg als to pneumococcal proteins discriminated between pneumococcal pneumonia and all other pneumonia with good accuracy for cbpa, pcsb and phtd, but not ply or stkpc: auroc curve was 0.81 (95% ci 0.73-0.89) for cbpa, 0.77 (95% ci 0.65, 0.89) for pcsb, 0.78 (95% ci 0.67-0.89) for phtd, 0.59 (95% ci 0.42-0.76) for ply, and 0.66 (95% ci 0.50-0.81) for stkpc. acute igg als was higher in children with pneumococcal pneumonia than with non-pneumococcal pneumonia for all five pneumococcal proteins (figure 4) . acute igg als to pneumococcal proteins discriminated between pneumococcal pneumonia and non-pneumococcal pneumonia in children enrolled to the study with good sensitivity and specificity, with auroc curve ranging from 0.60 (95% ci 0.42-0.79) for ply, to 0.85 (95% ci 0.75-0.94) for cbpa, using thresholds derived from the youden index (table 2) . there was a high degree of colinearity between acute igg als to all five pneumococcal proteins measured with pneumococcal pneumonia (and non-pneumococcal pneumonia) in best subsets logistic regression analysis. discriminating between pneumococcal pneumonia patients and healthy controls, acute igg als had an auroc curve ranging from 0.68 for ply (95% ci 0.49-0.87) to 0.98 for cbpa (95% ci 0.94-1.0; figure s2 , table s2 ). among children with pneumococcal pneumonia, there was no significant increase in acute igg als to any of the pneumococcal proteins measured with increasing length of illness (simple linear regression, p > 0.5 for all five proteins; figure s3 ). there were too few female cases with pneumococcal pneumonia to investigate sex differences. among children with non-pneumococcal pneumonia, there was no significant difference in acute igg als to pneumococcal proteins between children with viral pneumonia (influenza/parainfluenza, rsv) or definite other bacterial pneumonia (cbpa, p = 0.06; pcsb, p = 0.50; phtd, p = 0.28; ply, p = 0.92; stkpc, 0.93). children with probable bacterial pneumonia had higher concentrations of acute igg als to cbpa, pcsb, phtd, ply, and stkpc than children with unknown pneumonia (wilcoxon rank sum test, p < 0.001 for all). the proportion of children with acute igg als concentrations greater than the threshold derived from roc curve analysis differed significantly for cbpa (71% of probable bacterial pneumonia and 32% of unknown pneumonia, χ 2 test, p < 0.001), pcsb (55 and 35%, p = 0.007), phtd (45 and 25%, p = 0.002), but did not differ for ply and stkpc (threshold lines not applicable to figure 5 ). pneumococcal pneumonia was only diagnosed in children ≥2 years of age. we therefore undertook a post-hoc analysis of acute igg to pneumococcal proteins in children ≥2 years of age for the etiological diagnosis of pneumonia. children ≥2 years of age known to have a qualitatively different humoral immune response to pneumococcal polysaccharide antigens, although not pneumococcal protein antigens, in comparison with young infants (clutterbuck et al., 2007; borges et al., 2016; ramos-sevillano et al., 2019) . the clinical characteristics of children ≥2 . p-values were not calculated for variables that were entered into the classification scheme in figure 1 . values are expressed as the percentage of n for each column (excepting continuous variables). years of age with pneumococcal pneumonia or non-pneumococcal pneumonia from the cohort are described in table 3 . restricting the analysis to children ≥2 years of age reduced the ability to discriminate between pneumococcal pneumonia (12 children) and non-pneumococcal pneumonia (16 children) for all pneumococcal proteins to non-significance in this smaller number of samples (wilcoxon rank sum tests; cbpa, p = 0.12; pcsb, p = 0.10; phtd, p = 0.17; ply, p = 0.13; stkpc, p = 0.26; figure 6 and table 4 ). a visual examination of data points did not suggest that children with definite other bacterial pneumonia had different acute igg als to pneumococcal proteins than other children with non-pneumococcal pneumonia (red crosses and black crosses, figure 6 ). among all children enrolled, those with np carriage of pneumococci had higher acute igg als than those without np carriage of pneumococci (wilcoxon rank sum tests, p < 0.001 for all five pneumococcal proteins). among children with non-pneumococcal pneumonia (i.e., not "confounded" by definite pneumococcal or probable pneumococcal or probable bacterial or unknown pneumonia), those with np carriage of pneumococci had higher acute igg als to all five pneumococcal proteins than those without np carriage (wilcoxon rank sum tests; cbpa, p < 0.001; pcsb, p < 0.001; phtd, p < 0.001; ply, p < 0.001; stkpc, p < 0.001; figure 7) . among children ≥2 years of age with non-pneumococcal pneumonia, there were no significant differences in acute igg als to any pneumococcal protein detected between those with (n = 19) and without (n = 49) np carriage of pneumococci (wilcoxon rank sum tests, p > 0.5 for all comparisons, figure s4 ). stratification of this age group to those who had not received antibiotics prior to np sampling did not significantly affect these results. we used acute igg als to pcsb as the most parsimonious approach to investigate acute igg to pneumococcal proteins in children ≥2 years of age across the cohort. the number of children (proportion) that had acute igg als greater than, or equal to, the optimum threshold to discriminate between pneumococcal pneumonia and non-pneumococcal pneumonia was: definite pneumococcal pneumonia 5/8 (0.63), probable pneumococcal pneumonia 4/4 (1.0), probable bacterial pneumonia 20/44 (0.45), unknown pneumonia 23/55 (0.42), influenza/parainfluenza pneumonia 3/8 (0.38), rsv pneumonia 1/5 (0.2), definite other bacterial pneumonia 2/3 (0.67; figure 8 ). the development of novel diagnostic tests for the etiology of pneumonia is partly driven by the need to assess the impact of vaccination strategies on the total, and pathogen-specific burden of pneumonia in diverse settings. we have chosen to focus our work on pneumococcal pneumonia, during the introduction of 10-valent pcv to the infant immunization schedule in nepal. currently available diagnostic tests for pneumonia etiology lack sensitivity or specificity in children. culture of pneumococci from blood or pleural fluid from children with pneumonia is presumed to be highly specific for pneumococcal pneumonia but lacks sensitivity (o'brien et al., 2009; wu et al., 2016) . theoretically, sampling infected tissue (the lung) might improve sensitivity. a review of studies using lung biopsy followed by culture for the diagnosis of pneumonia etiology identified an increase in yield of bacterial pathogens from 14 to 47% of children tested (ideh et al., 2011) . however, lung biopsy requires peripheral radiographic consolidation, and was therefore not possible in approximately three quarters of patients with clinically severe pneumonia in a recent prospective cohort (howie et al., 2014) . this, in addition to safety concerns, has prevented lung biopsy for diagnostic sampling from becoming a widespread technique (ideh et al., 2011) . interpretation of samples from the nasopharynx of children is limited by poor specificity, with many pathogens detected at similar prevalence in children with pneumonia and in community controls . culture or molecular detection of pathogens from of broncho-alveolar lavage samples is only possible on samples from children receiving mechanical ventilation. we hypothesized that analysis of the immune response to pneumococci may be useful as a diagnostic approach to pneumonia etiology in children. we evaluated a new diagnostic strategy, assay of als, based on quantification of antibodies against pneumococcal proteins that are spontaneously secreted by transiently circulating lymphocytes from children with pneumonia. we were able to detect, and quantify, igg als to five specific pneumococcal proteins (cbpa, pcsb, phtd, ply, and stkpc) from children with pneumonia using a multiplexed immunoassay (fmia). concentrations of als igg to these antigens were significantly higher in supernatants from pbmcs obtained from children with pneumococcal pneumonia than table 2 | diagnostic accuracy, using thresholds derived from the youden index, for acute igg als to pneumococcal proteins to discriminate between pneumococcal pneumonia and non-pneumococcal pneumonia in children with pneumonia in nepal (all age groups). from children with non-pneumococcal pneumonia. for children of all ages, acute igg als to the best-performing antigen (cbpa) appeared highly sensitive, and moderately specific, with an auroc curve of 0.85, for the discrimination of pneumococcal pneumonia from non-pneumococcal pneumonia. this is considerably higher than previously reported approaches, including quantification of pneumococcal dna in blood, or in np specimens by qpcr deloria knoll et al., 2017) , to discriminate between children with microbiologically confirmed pneumococcal pneumonia and non-pneumococcal pneumonia, or between pneumococcal pneumonia and healthy controls. despite this reasonable performance, we observed a statistically significant association between acute igg als and age, independent of diagnostic comparator group. the limited overlap in ages between children with pneumococcal pneumonia and non-pneumococcal pneumonia made adjustment for this important confounding variable infeasible. the age distribution of children with pneumococcal pneumonia in this study was consistent with unpublished data from long-term surveillance of childhood invasive pneumococcal disease at patan hospital, but is in contrast to other sites in south asia where 50% or more of confirmed pneumococcal pneumonia is detected in infants (baqui et al., 2007; arifeen et al., 2009; saha et al., 2015; manoharan et al., 2017) . we therefore undertook post-hoc analysis in children ≥2 years of age. in this age group, als assay to the best-performing antigen (pcsb) was unable to discriminate between children with pneumococcal pneumonia and non-pneumococcal pneumonia with an auroc curve of 0.69 (with wide confidence intervals in these data). our experience suggests that this is insufficiently sensitive or specific for clinical use. assay of acute igg als may be informative for the etiological diagnosis of childhood pneumonia in epidemiological studies, but future studies will need careful accounting for age between comparator groups. we also described the effect of np carriage of pneumococci on acute igg als in children with non-pneumococcal pneumonia. previous work has shown specific igg and iga responses can be induced through stimulation of ex vivo child adenoidal mononuclear cells with pneumococcal protein antigens. these als responses were found to be positively associated with age and serum antibody concentrations, and were higher from cells from adenoids colonized by pneumococci (zhang et al., 2002 (zhang et al., , 2006 . our data suggest that np carriage of pneumococci in pneumonia-without apparent pneumococcal disease (palkola et al., 2012 (palkola et al., , 2016 )-also induces igg secretion from antibodysecreting cells, thus confounding the utility of an als-based diagnostic approach. strengths of this study include the unselected cohort, and the breadth of clinical and microbiological data used to classify the likely etiology of pneumonia by comparator group. in april and may 2015 central nepal (including the kathmandu valley) experienced earthquakes that led to the deaths of ∼8,000 people in the central region of nepal, and large population movements (hall et al., 2017) . in addition, a severe fuel shortage and increased construction from september 2015 to february 2016 may have contributed to severe pollution in the kathmandu valley through the increased burning of biofuels (budhathoki and gelband, 2016) . both earthquakes and increased pollution may have affected pneumococcal pneumonia incidence at patan hospital during the study period. despite the lack of additional selection, our cohort was enriched for invasive pneumococcal disease (ipd) in comparison to similar cohorts within south asia. our cohort included 8 children bacteremic for the pneumococcus from 369 children (2.2%). in comparison, separate studies of pneumonia in rural bangladesh [7 cases of ipd from 840 children, 0.8% (baqui et al., 2007) ], severe febrile illness [25 cases of ipd from 6,925 children, 0.4% (arifeen et al., 2009)] , and 220 cases of ipd from a meta-analysis of 26,258 blood cultures from children (0.1%) across south-east asia between 1990 and 2010 (deen et al., 2012) , were identified. the recently published perch study isolated the pneumococcus in 19 cases from 4,232 children (0.4%) with pneumonia (o'brien et al., 2019) . our cohort had a similar prevalence of ipd as among rural gambian or rural kenyan children with pneumonia [2.5% (cutts et al., 2005) and 1.7%, respectively (berkley et al., 2005) ] prior to introduction of pcv. any test for pneumonia etiology should identify children in whom there is pneumococcal infection, but no bacteremia. for this reason, and to increase the number of children available for comparator standards, we defined four children with pneumonia, high crp and np carriage of serotype 1 as pneumococcal pneumonia (figure 1) . all of these children also had consolidation on chest radiograph. we chose np carriage of serotype 1 due to its high odds ratio for carriage in pneumonia vs. community controls ( figure s1 ) in our unpublished data from kathmandu, and in published data from israel (greenberg et al., 2011) , the uk, and south america (scott et al., 1996) . of 128 children with ipd admitted to patan hospital between 2005 and 2016, 58 (45%) had serotype 1 pneumococci identified. we therefore believe that class of children with np carriage of serotype 1 and high crp as pneumococcal pneumonia has biological relevance, and internal and external validity. we focused our analysis on comparisons between children with pneumococcal pneumonia and non-pneumococcal pneumonia, rather than on discriminating between children with pneumococcal pneumonia and age-matched community controls. this substantially reduced the measured diagnostic accuracy of acute igg als to pneumococcal proteins that we present in the main text (in this study: optimum antigen auroc curve 0.98 for pneumococcal pneumonia and healthy controls; 0.84 for pneumococcal pneumonia and non-pneumococcal pneumonia in all ages; 0.69 for pneumococcal pneumonia and non-pneumococcal pneumonia in children ≥2 years of age). however, testing acute igg als to pneumococcal proteins for the diagnosis of pneumococcal pneumonia, in the context of an unselected cohort of pneumonia patients (as presented here), rather than in healthy controls gives a meaningful representation of accuracy in the context in which the test would be potentially implemented. assay of als for the etiological diagnosis of pneumonia might be optimized to yield more accurate diagnostic information. reviews of b cell responses to vaccination (mitchell et al., 2014) and to infection (carter et al., 2017) suggest that the optimum time for sampling transiently circulating plasmablasts from peripheral blood is 7-10 days following the onset of illness. there are difficulties defining length of illness in children with pneumonia. nevertheless, the median length of illness prior to blood sampling in our study was 4 days. a delay in sampling until 7 days of illness may improve test specificity. an additional method to improve specificity of the als assay would be to sort recently activated plasmablasts for incubation using flow cytometry. however, separation, washing, and incubation of pbmcs to generate and store als requires reagents (ficoll-paque) and equipment (centrifuges, incubators with co 2 , and −80 • c freezers) that are not readily available in routine microbiology laboratories. the use of flow cytometry would limit the potential availability of this test further. finally, although we described a high degree of co-linearity in acute igg als to the pneumococcal proteins measured, a larger array of pneumococcal antigens might be considered to optimize als cognate antigens using variable selection methods (zou and hastie, 2005; darton et al., 2017a) . quantification of als to pneumococcal capsular polysaccharides may also enable serotype-specific measure of pneumococcal pneumonia burden to inform vaccination strategies (tuerlinckx et al., 2013) . a major limitation of any study of pneumonia etiology is the lack of a "gold standard." blood culture is presumed to be specific, but insensitive, for bacterial pneumoniaa "silver standard" (wu et al., 2016) . we used a series of comparator groups ("standards") against which to test the als assay. in this cohort, the low prevalence and different age distribution of confirmed pneumococcal pneumonia cases, in comparison to other pneumonia cases, limited our measures of the diagnostic accuracy of als between comparator groups. assay of als was also confounded by the association of acute igg als with np carriage of pneumococci. diagnostic accuracy of als assay may be better in studies of pneumonia of other etiology (notably rsv pneumonia), where reasonably accurate diagnostic tests already exist with a high positive and negative predictive value for disease, as a point of comparison. despite the high prevalence of pneumococcal pneumonia in the cohort relative to other studies (baqui et al., 2007; arifeen et al., 2009; deen et al., 2012; o'brien et al., 2019) , the majority of children in the study (81%) were designated as probable bacterial pneumonia or unknown pneumonia. in a cohort that were largely unvaccinated with pcv, only 8 children had invasive pneumococcal disease, with a further 4 children with probable pneumococcal pneumonia. many comparisons were therefore underpowered. although this limits the ability to fully assess assay of igg als for the diagnosis of pneumococcal pneumonia, at a minimum, a clinically useful test should be "positive" in cases of ipd (the silver standard). our data show that this was not the case, with low igg als assay in 3 of 8 children with pneumococcal bacteremia (figure 8) . in summary, we detected spontaneously secreted antibodies to pneumococcal proteins from pbmcs isolated from a figure 8 | acute igg als to pcsb by comparator group in children ≥2 years of age. the dotted horizontal line represents a threshold of 0.08 units/ml, the threshold derived from the youden index. the proportion of children with acute igg als to pcsb concentration greater than, or equal to, the threshold derived from roc curve analysis to discriminate pneumococcal pneumonia from non-pneumococcal pneumonia is annotated. proportion of children with pneumonia in nepal using the als assay. concentrations of igg als to the pneumococcal proteins cbpa, pcsb and phtd were higher in children with pneumococcal pneumonia than non-pneumococcal pneumonia, with good ability to discriminate between groups. however, these results were confounded by different age distributions of children with pneumococcal pneumonia and non-pneumococcal pneumonia. assay of als to pneumococcal proteins did not discriminate between these groups when stratified by ≥2 years of age. our data suggest that assay of igg als to pneumococcal proteins is not sufficiently accurate as a diagnostic test for clinical utility. alternative new diagnostic tests for the cause of childhood pneumonia should be sought. the datasets generated for this study are available on request to the corresponding author. the studies involving human participants were reviewed and approved by nepal health research council and the oxford tropical research ethics committee. written informed consent to participate in this study was provided by the participants' legal guardian/next of kin. consortium (https://www.perform2020.org/) supported pcr identification of np viruses. we also thank reviewers for helpful comments. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcimb. 2019.00459/full#supplementary-material figure s1 | odds ratios for nasopharyngeal carriage of pneumococcal serotypes contained within 13-valent pcv and non-typeable (nt) pneumococci in pneumonia and community control children, adjusted for age and sex, prior to introduction of the vaccine into the kathmandu valley. error bars show 95% confidence intervals. figure s2 | acute igg als to pneumococcal proteins by children with pneumococcal pneumonia and healthy infant controls. dashed horizontal lines represent represent thresholds derived from the youden index, p-values were derived from the wilcoxon rank sum test. for all box and whisker plots: the solid line represents the median value, lower hinge 25th centile, upper hinge 75th centile, and whiskers represent 1.5 times the interquartile range. all data points have also been plotted. figure s3 | linear regression analysis of length of illness with acute igg als to pneumococcal proteins (grey colouring represents 95% confidence intervals about the regression line; p-value > 0.5 for all proteins). figure s4 | acute igg als to pneumococcal proteins in children with non-pneumococcal pneumonia by nasopharyngeal carriage of pneumococci. 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pneumococcal conjugate vaccine evaluation of the antibody in lymphocyte supernatant assay to detect active tuberculosis serogroup-specific epidemiology of streptococcus pneumoniae: associations with age, sex, and geography in 7000 episodes of invasive disease salmonella enterica serovar typhi-specific immunoglobulin a antibody responses in plasma and antibody in lymphocyte supernatant specimens in bangladeshi patients with suspected typhoid fever clinical evaluation of the luminex nxtag respiratory pathogen panel evaluation of a who-validated serotype-specific serological assay for the diagnosis of pneumococcal etiology in children with community-acquired pneumonia burden of streptococcus pneumoniae and haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000-15 partially latent class models for case-control studies of childhood pneumonia aetiology serum and mucosal antibody responses to pneumococcal protein antigens in children: relationships with carriage status immune responses to novel pneumococcal proteins pneumolysin, pspa, psaa, and cbpa in adenoidal b cells from children regularization and variable selection via the elastic net we thank all of the children, and their parents, who participated in this study; and the clinical teams at patan hospital who gave unstinting help. phtd was kindly supplied by sanofi pasteur key: cord-300371-6ja5o3sa authors: maloney, susan a.; weinberg, michelle title: prevention of infectious diseases among international pediatric travelers: considerations for clinicians date: 2004-11-24 journal: semin pediatr infect dis doi: 10.1053/j.spid.2004.05.002 sha: doc_id: 300371 cord_uid: 6ja5o3sa an estimated 1.9 million children travel overseas annually. infectious disease risks associated with international travel are diverse and depend on the destination, planned activities, and baseline medical history. children have special needs and vulnerabilities that should be addressed when preparing for travel abroad. children should have a pretravel health assessment that includes recommendations for both routine and special travel-related vaccination; malaria chemoprophylaxis, if indicated; and prevention counseling regarding insect and animal exposures, food and water safety, and avoiding injuries. special consideration should be given to children with chronic diseases. families should be given anticipatory guidance for management of potential illnesses and information about the location of medical resources overseas. susan a. maloney, md, mhsc,* and michelle weinberg, md, mph* an estimated 1.9 million children travel overseas annually. infectious disease risks associated with international travel are diverse and depend on the destination, planned activities, and baseline medical history. children have special needs and vulnerabilities that should be addressed when preparing for travel abroad. children should have a pretravel health assessment that includes recommendations for both routine and special travelrelated vaccination; malaria chemoprophylaxis, if indicated; and prevention counseling regarding insect and animal exposures, food and water safety, and avoiding injuries. special consideration should be given to children with chronic diseases. families should be given anticipatory guidance for management of potential illnesses and information about the location of medical resources overseas. semin pediatr infect dis 15:137-149. t he volume of international travel has increased tremendously during the past decade. nearly 26.9 million u.s. residents traveled overseas in 2000. approximately 50 percent of u.s. residents traveled to destinations other than europe; these destinations included almost 5 million trips to asia, more than 2.2 million trips to south and central america, 1.3 million trips to the middle east, and 500,000 trips to the african continent. 1 an estimated 15 percent to 70 percent of adult travelers report health problems during international travel; 1 percent to 5 percent of travelers seek medical care during travel, 0.1 percent to 1 percent are hospitalized abroad, 0.01 percent to 0.1 percent require emergency evacuation, and 1 in 100,000 die. 2, 3 infectious diseases are a major cause of morbidity among international travelers. [3] [4] [5] [6] [7] an estimated 40 percent of persons traveling annually from industrialized to developing countries develop travelers' diarrhea. [3] [4] [5] [6] [7] [8] [9] malaria is a less frequent but potentially life-threatening problem for travelers; an estimated 30,000 north american and european travelers contract malaria annually. 10 other infectious diseases reported in travelers include hepatitis a and b, sexually transmitted diseases, animal bites with risk of rabies, typhoid, cholera, legionellosis, human immunodeficiency virus (hiv) infection, and meningococcal disease. 3, [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] less specific information is available on the number of children traveling internationally or living abroad. extrapolating from overseas travel data for u.s. residents, one can estimate conservatively that at least 1.9 million children travel overseas annually (ie, 7% of the 26.9 million u.s. residents traveling internationally in 2000 reported traveling with children). information on the causes of serious morbidity and mortality among pediatric travelers is more limited. [28] [29] [30] [31] available data include a 1-year prospective hospital-based study in the united kingdom of children evaluated for fever who had traveled recently to the tropics. 30 in this study, 31 children with a median age of 4 years (range, 5 months to 15 years) met the study entry criteria. fourteen of these children had nonspecific, self-limited illnesses of presumed viral origin, and 17 children had conditions requiring hospital management and antimicrobial therapy. conditions requiring hospital management included four cases of malaria (3 of plasmodium falciparum, and 1 of plasmodium vivax malaria), three cases of bacillary dysentery, two cases each of dengue and typhoid fever, and one case each of acute hepatitis a infection, pneumonia (unspecified), pneumocystis carinii pneumonia (in a child with newly diagnosed hiv infection), bacterial lymphadenitis, streptococcal throat infection, and acute myeloid leukemia; no deaths occurred. in another retrospective study of travelers' diarrhea among swiss children who had visited the tropics or subtropics, pitzinger and coworkers found incidence rates of 40 percent, 8.5 percent, 21.7 percent, and 36 percent in children aged 2 years or younger, 3 to 6 years, 7 to 14 years, and 15 years and older, respectively. 31 other authors have reported substantial health risks for pediatric travelers from noninfectious causes such as injuries, including automobile accidents and drowning. 29 children have special needs and vulnerabilities that should be considered when preparing for travel abroad, and all children should have a pretravel health assessment performed. depending on the destination and the vaccinations needed, this assessment should be conducted up to 6 months before travel. the pretravel assessment should include an evaluation of the child's medical history and immunization status, as well as a detailed review of the trip itinerary, including travel destinations, planned activities, type of accommodations (eg, hotel chains, residing with local families, camping), extent of contact with the local populations, and exposure to animals. special consideration should be given to children who have chronic diseases, such as diabetes, cardiac abnormalities, or immunocompromising conditions, in terms of vaccine recommendations and travel risks and precautions. parents should be advised to carry a summary of their child's medical history, treatment record, and all required prescription medications. during the assessment, the caregiver should ensure the following: 1) the child has received up-to-date and appropriate vaccinations (both routine and special travel-related vaccines); 2) the child has received appropriate malaria and other chemoprophylaxis regimens tailored for use in pediatric travelers; 3) prevention counseling, particularly in the areas of insect barriers, food and water safety, and injury avoidance, has been given; and 4) anticipatory guidance for managing potential illnesses (eg, diarrhea and dehydration) and seeking medical resources overseas has been provided. vaccination for international travel is among the most critical and complex components of the pretravel health assessment for children, and a careful review of both recommended routine childhood vaccinations and required and recommended travel-related vaccinations should be undertaken. pediatric travelers must have their routine immunizations brought up-to-date, as many vaccine-preventable diseases (vpds) are more prevalent in developing countries than in the united states. for example, diphtheria and pertussis are prevalent in eastern europe and many developing countries, and measles still is endemic in much of the developing world. hepatitis b, haemophilus influenzae type b, streptococcus pneumoniae, and varicella also are endemic in many developing countries. further, although worldwide polio eradication efforts have decreased the number of countries where travelers are at risk for acquiring polio (with most poliovirus transmission now occurring in 2 large endemic areas in south asia and sub-saharan africa), polio outbreaks still occur; in july 2000, outbreaks of vaccine-derived poliovirus type 1 were reported in the dominican republic and haiti. 32, 33 trip activities also may increase the risk of contracting infectious diseases such as measles; in both 2001 and 2004, epidemiological investigations identified numerous cases of serologically confirmed measles among internationally adopted children and their new parents and siblings, who had traveled to china to accompany them home. 34, 35 in addition, travel in large groups on conveyances such as cruise ships can facilitate transmission of vpds. 36 parents should check their own immune status because travel with children can increase risk of exposure to vpds. if travel to developing countries is planned, assuring immunity is imperative, and accelerated schedules should be considered. depending on the travel destination and itinerary, routine vaccinations may need to be accelerated to maximize protection, particularly against polio, diphtheria/tetanus/pertussis, and measles (for example, measles vaccination may be recommended for children younger than 12 months of age). 37 guidelines for standard and accelerated schedules for routine childhood immunizations and special precautions and recommendations for immunocompromised children are available in the american academy of pediatrics, "red book: 2003 report of the committee on infectious diseases," and on web sites of the centers for disease control and prevention (cdc). 37 common travel-related vaccines for children the most recent requirements and recommendations for travel-related vaccinations by specific geographic destinations can be obtained from cdc, "health information for international travelers" (the "yellow book"), and from cdc travelers' health internet and other travel-related web sites 32 (see also table 1 , international travel health information resources for web sites). the united states does not require arriving travelers to have any vaccinations for entry or return into the united states. some other countries may require proof of vaccination against yellow fever for entry, especially if the traveler is arriving from a country where yellow fever is endemic. yellow fever vaccine is available only from certified yellow fever vaccination centers; providers can refer to the following cdc yellow fever vaccine registry to locate certified centers in their areas: http://www2.ncid.cdc.gov/travel/yellowfever. saudi arabia requires meningococcal vaccine for travelers to the hajj in mecca. some countries have required previous vaccination for cholera, but currently no countries require it, and the vaccine is not available in the united states. table 2 provides general guidelines and indications for use of selected common travel-related vaccines, based on u.s. recommendations; world health organization (who) recommendations may differ. 32, 38 hepatitis a is endemic in most of the world, and travelers are at risk in any area where sanitation is poor. vaccination is recommended for pediatric travelers aged 2 years or older who will be visiting countries with intermediate to high endemicity (areas other than the united states, canada, australia, new zealand, western europe, and scandinavia). studies have demonstrated that protective antibody titers 2 weeks after the patient has received the first dose of hepatitis a vaccine range from 69 percent to 98 percent; after 4 weeks, protective antibody titers were present in 95 percent to 100 percent of vaccinees. intramuscular immunoglobulin is recommended for immunoprophylaxis against hepatitis a in children younger than 2 years of age. in addition, for children 2 years of age or older who are departing less than 4 weeks after receiving a vaccination, immunoglobulin and vaccine can be given concurrently at different sites to ensure optimal protection. meningococcal disease occurs sporadically worldwide. epidemic disease has been reported in india, saudi arabia, and sub-saharan africa; indeed, recurrent epidemics of meningococcal disease occur in sub-saharan africa, mainly from december to june (the dry season). serogroup a is the most common cause of epidemics outside the united states, but serogroup c and other serogroups have been associated with epidemics. serogroup w-135 meningococcal infections among travelers returning from saudi arabia after visiting mecca during the hajj also have been reported recently. [13] [14] [15] the meningococcal vaccine available in the united states is the quadrivalent polysaccharide a/c/y/w-135, which is recommended for pediatric travelers 2 years or older who are visiting sub-saharan africa during the dry season, or any country where an epidemic caused by a vaccine serogroup is occurring. the vaccine can be administered to children younger than 2 years of age, but their immunologic response may be limited to serogroup a only. 37 yellow fever occurs year-round in predominately rural areas of sub-saharan africa and south america; in recent years, outbreaks have been increasing. recently, yellow fever has reemerged in brazil, raising concern about increased risk in other areas of latin america and raising the possibility of transmission of yellow fever in urban areas. 39 although a rare occurrence, yellow fever continues to be reported among travelers, particularly unvaccinated travelers, and can be fatal. prevention measures against yellow fever should include the use of personal protection measures against mosquitoes and vaccination. yellow fever vaccine is considered a relatively safe and effective vaccine. however, the vaccine has been found to be associated with an increased risk of developing encephalitis and other severe reactions in young infants. 37 the vaccine should not be used in children younger than 6 months of age. it should be used with caution in children 6 to 9 months of age, and after discussion with a travel medicine expert to weigh risks and benefits. 37 medical waivers can be given to children who are too young for vaccination and to those who have other contraindications to vaccination, such as immunodeficiency. recently, reports have raised concern about possible rare instances of yellow-fever vaccine-associated neurotropic and viscerotropic disease, and these adverse events are being investigated. [40] [41] [42] [43] in the interim, cdc has stated that given the risk of serious illness and death caused by yellow fever, evidence of increasing transmission of the disease, and the known effectiveness of the vaccine, clinicians should continue to use yellow fever vaccine to protect travelers. however, cdc recommends that healthcare providers carefully review travel itineraries to ensure that yellow fever vaccine be given to only people traveling to areas where yellow fever is endemic or areas where there is reported yellow fever activity. 42, 43 japanese encephalitis (je) is a viral infection transmitted by culex mosquitoes, which bite from dusk to dawn. je occurs year-round in tropical regions, and primarily from may through october in temperate zones. risk is greatest for travelers to rural asia, where the mosquito breeds in rice fields and other agricultural areas. je is associated with a high casefatality rate and severe neurological sequelae, especially among young children and the elderly. vaccination should be considered for pediatric travelers who are 1 year of age or older and who will visit and reside in areas where je is endemic or epidemic, especially during transmission season, or for pediatric travelers whose activities include trips to rural farming areas. short-term travelers (ͻ30 days) who visit only major urban areas are at lower risk for acquiring je and generally do not need to be vaccinated. 32 rabies occurs worldwide. in certain areas of the world, including parts of brazil, bolivia, colombia, ecuador, el salvador, guatemala, india, mexico, nepal, peru, the philippines, sri lanka, thailand, and vietnam, canine rabies remains highly endemic. rabies also occurs in other wild animals, including bats. rabies vaccine should be considered for children visiting rabies-endemic countries for longer than 1 month; undertaking extensive outdoor activities, such as backpacking or camping; or traveling to areas where access to health care is limited. to reduce the risk of acquiring rabies, children and their families should be counseled to stay away from stray dogs and other animals, especially if traveling to latin america, asia, or africa. 32 typhoid vaccine is recommended for pediatric travelers visiting developing countries, especially for prolonged peri-ods of time, or traveling outside the usual tourist destinations. parents should be cautioned, however, that vaccination is not 100 percent effective, and safe food and water precautions should be followed. influenza vaccine should be considered for children with chronic diseases and others at increased risk for developing complications of influenza if they are traveling to the tropics or to the southern hemisphere from april through september. in addition, influenza risk has been shown to be increased in destinations and on conveyances having large groups of tourists and in destinations with influenza outbreaks occurring, and, therefore, vaccination also should be considered in these circumstances. 44 lastly, bacille calmette-guerin (bcg) vaccine is a live vaccine prepared from attenuated strains of mycobacterium bovis; bcg is used primarily in young infants to prevent disseminated and other forms of life-threatening diseases caused by tuberculosis (tb), such as tuberculous meningitis. bcg is recommended by the who for administration at birth; in the united states, bcg is recommended only in limited circumstances, such as unavoidable risk of exposure to m. tuberculosis. vaccination of a young pediatric traveler (non-hiv-infected and with negative tb skin test) might be considered, therefore, if travel is planned for a long-term stay in a country with high tb prevalence and prolonged contact with active tb cases is considered a potential problem. 37,45 bcg vaccine can be obtained from the canadian subdivisions of aventis pasteur or organon. more generally, children traveling to countries with high prevalence of tb should be given a skin test before and after travel to document possible exposure to tb. u.s. children who had traveled within the previous 12 months to countries with a high prevalence of tb were reported to be 3.9 times more likely to have positive tb skin tests than were children who lived in the same u.s. areas but had not traveled. 46 47 a recent review of malaria cases among u.s. civilians (adults and children) reported that the largest percentage of cases (38.5%) occurred among persons who were visiting friends or relatives in malarious areas. 48 retrospective reviews of malaria in children also have found that a substantial proportion of cases occurred among recent immigrants and among children of former immigrants who had traveled to visit their family's country of origin. 28, 49 preventing malaria in pediatric travelers young children and nonimmune persons of any age are at greater risk for the development of severe complications from malaria; the substantial proportion of u.s. malaria cases reported in children underscores the importance of having strategies for the prevention of malaria. the prevention of malaria in pediatric travelers depends first on obtaining current and accurate information about the risk of contracting malaria in proposed travel destinations and determining if planned activities and season of travel place the traveler at increased risk of exposure. information on geographic and country-specific risks regarding malaria is available from multiple sources (see table 1 , international travel health information resources). prevention strategies for pediatric travelers are two-fold: personal protection measures against mosquitoes and antimalarial chemoprophylaxis. the first mainstay of prevention is appropriate and effective use of personal protection measures to avoid being bitten by anopheles mosquitoes, which typically are evening and nighttime feeders. these measures include wearing clothing that reduces the amount of exposed skin (such as long-sleeved shirts, long pants tucked into socks, and hats) and, whenever possible, remaining in wellscreened or enclosed air-conditioned areas. travelers staying overnight in facilities without air conditioning or screens should use insecticide-treated mosquito nets over the beds. 50 during the evening, insecticide also can be sprayed inside rooms. another important measure of personal protection is appropriate use of insect repellent, such as n,n-diethylmetatoluamide (deet), on exposed skin. the american academy of pediatrics has recommended using repellents with less than 30 percent deet for infants and children. 51 deet should not be used in children younger than 2 months of age or applied to hands, mouth, or near the eyes of young children. despite the demonstrated efficacy of these measures, studies have found only 17 percent of adult travelers with malaria reported using insect protection methods, and only 11 percent took recommended chemoprophylaxis. 52 the second mainstay of preventing the acquisition of malaria is chemoprophylaxis. the selection of the appropriate drug for antimalarial chemoprophylaxis must be based on numerous factors, including the most recent information available about the prevalence of malaria in the proposed travel destinations; trip itinerary; age, weight, and medical history of the traveler; personal preference regarding frequency of dosing and duration of chemoprophylaxis on trip return; and cost of medication. cdc provides resources with guidance on appropriate use and recommended regimens for antimalarial chemoprophylaxis (see table 1 , international travel health information resources). figure 1 outlines an algorithm for determining appropriate antimalarial chemoprophylaxis regimens for pediatric travelers. because the distribution of drug-resistant malaria is evolving constantly, clinicians should obtain the most recent information about the risk of malaria and zones of drug resistance before prescribing chemoprophylaxis for malaria. the first decision point in selecting appropriate antimalarial chemoprophylaxis is whether travel is occurring in a region of chloroquine-sensitive or -resistant malaria. for travel to areas with chloroquine-sensitive malaria, chloroquine is the drug of choice for antimalarial chemoprophylaxis. plasmodium ovale, plasmodium malariae, and most p. vivax are widely sensitive to chloroquine; however, chloroquine-resistant p. vivax is an emerging problem and has been reported from guyana, new guinea, india, myanmar (burma), and areas of indonesia. 53 in addition to chloroquine-resistant p.vivax, chloroquine-resistant p. falciparium has been reported from these areas, and, consequently, chloroquine would not be recommended for chemoprophylaxis for travelers to these regions. if the traveler is visiting a region with chloroquine-resistant malaria, the next decision point is whether travel will include regions with chloroquine-resistant malaria only or both chloroquine-and mefloquine-resistant malaria. chloroquine-resistant p. falciparium is widespread and exists in all malaria-endemic areas except mexico, the caribbean, central america west of the former panama canal zone, argentina, and parts of the middle east and china. 32 in some regions, p. falciparum may be resistant to both chloroquine and mefloquine; these areas currently are limited to the borders of thailand with myanmar (burma) and with cambodia, in the western provinces of cambodia, and in the eastern states of myanmar. 32, 53 for travel to areas with chloroquine-resistant malaria, currently the three antimalarial chemoprophylaxis options are: mefloquine (lariam; hoffman-laroche, nutley, nj), atovaquone-proguanil (malarone; glaxo wellcome, research triangle park, nc), or doxycycline. cdc no longer recommends the use of chloroquine/proguanil for chemoprophylaxis for chloroquine-resistant areas. for travel to areas with chloroquine-and mefloquine-resistant malaria, either atovaquone-proguanil or doxycycline can be used. when antimalarial chemoprophylaxis options are being evaluated, each medication should be reviewed for contraindications and weight and age restrictions (see table 3 , antimalarial chemoprophylaxis regimens for pediatric travelers). chloroquine is relatively well tolerated in children. in the united states, chloroquine is available in tablet form; in europe and other countries, it also is available as a syrup. mefloquine can be used safely in children weighing less than 15 kilograms and may be useful for longer trips because it is administered once weekly. however, it must be continued for 4 weeks after leaving the malarious area, and no liquid preparation is available. doses for children are one-quarter, one-half, and three-quarters of a tablet, depending on weight. few data are available on the use of atovaquone-proguanil in children weighing less than 11 kilograms; however, studies are in progress. for children weighing more than 11 kg at risk for acquiring chloroquine-resistant p. falciparum infection, atovaquone-proguanil can be advantageous for short trips because it is started 1 to 2 days before the trip and can be stopped 7 days after the trip. it is available in pediatric tablet form. doxycycline is contraindicated in children younger use in areas with chloroquine-resistant and mefloquine-resistant malaria gi symptoms, photosensitivity may decrease the effectiveness of oral contraceptives *despite the use of chloroquine as an antimalarial chemoprophylaxis agent for decades and the use of high-dose chloroquine for certain chronic diseases, the literature is inconclusive regarding the potential risk of retinopathy associated with long term use of chloroquine for antimalarial prophylaxis. retinopathy rarely has been reported in patients on weekly prophylaxis. retinopathy appears to be related to dosage and accumulated dosage. than 8 years of age because of concerns about the propensity of tetracycline to stain growing teeth or potentially to affect developing bones. for older children, doxycycline must be administered daily and continued for 4 weeks after departing the malarious area. primaquine may be used as an option for primary prophylaxis in special circumstances. clinicians should contact cdc malaria branch for additional information (see table 1 ). primaquine also can be used for terminal prophylaxis to decrease the risk of occurrences of relapses of p. vivax and p. ovale. 32, 54 another aminoquinoline, tafenoquine, which is a long-acting primaquine analog, is undergoing investigation and may become approved for malaria chemoprophylaxis indications in the future. 53 the importance of recommending appropriate antimalarial chemoprophylaxis regimens for travelers cannot be overemphasized. a review of malaria cases among u.s. civilians in 1998 found that close to 60 percent had not taken any chemoprophylaxis and another 13 percent had not taken the cdc-recommended drug for the area visited. 48 in retrospective reviews of pediatric malaria cases, between 75 and 100 percent of cases had received no or inadequate chemoprophylaxis. 49, 55 indeed, the inappropriate use of antimalarial chemoprophylaxis has been shown to be an important cause of mortality and serious morbidity among travelers. from 1992 through early 2001, cdc received reports of seven u.s. travelers who died from malaria after using inappropriate chemoprophylaxis. all these travelers had received prescriptions for chloroquine for travel to areas with widespread chloroquine resistance. among 4685 cases of imported malaria with information about chemoprophylaxis during 1992 through early 2001, 2616 (56%) took no chemoprophylaxis, and 893 (19%) took an inappropriate chemoprophylaxis regimen. 56 in addition to being given preventive therapy, parents should be counseled in signs and symptoms of malaria infection in children, such as fever, headaches, vomiting, diarrhea, and myalgias. delays in recognition and treatment of malaria are associated directly with increases in morbidity and mortality rates; therefore, prompt and appropriate initiation of effective therapy is paramount. because the epidemiology of many diseases is evolving, prevention hinges on clinicians' knowledge about current information regarding risks and outbreaks in travel destinations. a variety of pathogens are being recognized increasingly as emerging infectious diseases among travelers. in addition to malaria, other vector-borne infectious diseases are among the important diseases for consideration in travelers. dengue is one of the most important vector-borne viral infections worldwide and is endemic in asia, the south pacific, africa, latin america, and the caribbean. epidemics of dengue hemorrhagic fever, the more severe clinical form of dengue fever, occur every 3 to 5 years in southeast asia and are an emerging problem in latin america. recently, outbreaks of dengue fever occurred in hawaii and along the u.s. and mexico border. [57] [58] [59] worldwide, an estimated 50 to 100 million cases of dengue fever occur annually; of these cases, 200,000 to 500,000 are dengue hemorrhagic fever. every year, cases of dengue fever among u.s. travelers are reported to cdc. dengue is transmitted primarily by day-biting aedes aegypti mosquitoes, which breed in flower vases, barrels, and discarded tires that collect water. transmission occurs in rural and urban areas, but the risk is greatest in urban areas. prevention should focus on protection against mosquito bites. travelers to risk areas should be counseled to apply repellent during the day, even while visiting cities. no vaccine is available, and prior infection with one of the four serotypes does not protect against infection with another serotype. the risk of developing dengue hemorrhagic fever actually may increase with subsequent infection with a different serotype. 60 infections with african trypanosomiasis (sleeping sickness), a parasitic infection transmitted by the bite of a tsetse fly, occasionally have been reported among travelers. infection can result in severe neurological sequelae and is 100 percent fatal if untreated. in 2001, significant increases in the number of cases were reported among u.s. and european travelers to game parks in tanzania and kenya. between 1967 and 2000, an imported case occurred on average every 1 to 2 years; however, in 2001, seven cases were reported among u.s. travelers. 61, 62 schistosomiasis, another parasitic infection caused by flukes that live part of their life cycle in fresh water snail hosts, affects more than 200 million people worldwide. schistosomiasis has been reported among travelers to endemic areas of the africa, asia, south america, and the caribbean who participated in high-risk activities, such as swimming or wading in fresh water. 32, 63, 64 children and their families should be counseled against swimming or wading in fresh water in risk areas. tick-borne encephalitis is transmitted primarily by the bite of ixodes ticks. it also can be transmitted by ingestion of unpasteurized dairy products from infected livestock. transmission occurs during summer months in western and central europe, scandanavia and parts of the former soviet union. persons who will be traveling for longer than 3 weeks in endemic rural areas or travelers who will be engaging in high-risk activities, such as camping, should be considered for vaccination. the vaccine is not available in the united states but can be obtained in europe. 32 examples of recent outbreaks or cases of unusual pathogens affecting travelers include fungal organisms (such as histoplasmosis and coccidioidomycosis), leptospirosis, and leishmaniasis. histoplasmosis is a fungal infection acquired by inhalation of spores, usually through exposure to bat, bird, or chicken droppings in barnyards and caves. the organism is endemic in the united states, latin amer-ica, eastern asia, parts of europe, africa, and australia. coccidioidomycosis, a fungal infection associated with inhalation of soil from high-risk areas, is endemic in the southwestern united states and latin america. both infections can cause a spectrum of illnesses from asymptomatic infection to acute pulmonary infection to severe, disseminated disease, especially in immunocompromised persons. several outbreaks of histoplasmosis have been reported among groups of u.s. visitors who entered a cave with bats in costa rica (cdc, unpublished data), 65 ecuador, 66 peru, 67 and nicaragua. 68 recently, more than 200 college students became infected with histoplasmosis during a spring break trip to acapulco, mexico. 69 two outbreaks of coccidioidomycosis have been reported among youth missionary groups involved in construction work in mexico. 70, 71 most of these fungal outbreaks have two common features: high-risk, group activities and high attack rates, even in young, nonimmunocompromised individuals. because no vaccine is available, prevention involves counseling travelers to avoid exposure or to use special masks for high-risk individuals who cannot avoid exposure. 72 leptosporosis is a zoonotic infection that is transmitted by exposure to water or soil contaminated with organisms excreted by domestic and wild animals. outbreaks have been reported among whitewater rafters in costa rica and among athletes from 26 countries who participated in the eco-challenge multisport expedition race in borneo, malaysia in 2000. 73 because no vaccine against leptospirosis exists, persons engaging in high-risk activities should be counseled to avoid exposure to water that may be contaminated or to wear protective clothing. leishmaniasis, a parasitic infection transmitted by the bite of a sand fly, can lead to cutaneous or visceral infection. it has been reported among students who traveled to the rain forest in costa rica and among other travelers. 74 the appropriate use of insect repellent and other personal protection measures against sand fly bites is the only prevention tool that is available. in 2003, we experienced the global spread of a novel coronavirus, sars cov, which causes severe acute respiratory syndrome (sars); in many locations, the introduction of disease by ill travelers was followed by spread to healthcare workers and household contacts. 75 during the course of approximately 6 months, more than 8000 persons were infected with the virus and more than 800 persons died. the majority of cases occurred in adults, and pediatric patients appeared to have a milder clinical course. 76, 77 the united states was relatively spared during the outbreak, reporting a total of 75 suspect or probable cases, with only eight laboratory-confirmed cases and no attributable deaths. however, during the sars outbreak, at least 17 suspect or probable sars cases were investigated in the united states among children recently adopted from china and their family members. although none of these cases ultimately was laboratoryconfirmed, these findings demonstrate unique risks for pediatric travelers and their families and highlight the need for clinicians to be knowledgeable of emerging infectious diseases and recommended travel precautions. one of the most difficult tasks faced by international travelers of any age is ensuring the safety of food and water. travelers' diarrhea, caused by ingestion of contaminated food and water, affects between approximately 20 to 50 percent of adult travelers, and it is the most frequent health problem reported by travelers to developing countries. 8 in terms of children, a retrospective study conducted by pitzinger and coworkers among swiss children who had visited the tropics or subtropics reported similar incidence rates of traveler's diarrhea in children: 40 percent, 8.5 percent, 21.7 percent, and 36 percent in children aged 0 to 2 years, 3 to 6 years, 7 to 14 years, and 15 years and older, respectively. 31 in this study, the authors also found that small children (0 to 2 years) most frequently were affected with travelers' diarrhea and that the clinical course tended to be more severe and prolonged when compared with older pediatric age groups. overall, children were found to have longer-lasting illness than that in adults, with an average duration of 11 days for all children combined and 29 days for small children. enteric pathogens typically are isolated from approximately 50 to 75 percent of stool specimens from adult travelers with diarrhea; in the remainder, usually no pathogen is isolated. escherichia coli, especially enterotoxigenic e. coli (etec), is the most common overall cause of travelers' diarrhea (although incidence can vary by destination), followed by camplobacter spp., salmonella spp., and shigella. other etiologic agents include pathogenic bacteria such as aeromonas and plesiomonas, protozoa (eg, giardia lamblia, entamoeba histolytica, crypotospiridium spp., and cyclospora cayetanensis), viruses such as rotavirus or norwalk-like viruses, and rarely helminthes. 78 numerous risk factors for traveler's diarrhea also have been identified and include the consumption of certain high-risk foods (raw foods such as meats, seafood, and vegetables, unpasteurized dairy products, and ice and tap water) and travel to certain destinations. 6, 8 destinations generally considered to have a high risk for travelers' diarrhea include latin america, africa, asia, and the middle east; low-risk travel destinations include north america, northern europe, australia, and new zealand. 32 location of food preparation also is a recognized risk factor for traveler's diarrhea, with a higher risk shown for travelers eating from street vendors and in local restaurants and a lower risk for those eating in luxury hotels and private homes. counseling about food and water precautions to prevent traveler's diarrhea and anticipatory guidance to assure successful management of diarrhea are important parts of the pediatric pretravel assessment. in areas where access to bottled water is poor, water may be boiled for 1 minute (or for 3 minutes at altitudes greater than 2000 m [6562 feet]). these procedures will kill bacterial, parasitic, and viral pathogens. chemical disinfection with iodine is an alternative method for water treatment when it is not possible to boil water; however, this method cannot be relied on to kill cryptosporidium unless the water stands for 15 minutes before drinking. chlorine also can be used for chemical disinfection, but its germicidal activity varies with ph, temperature, and the organic content of the water; it can, therefore, provide less consistent levels of disinfection in many types of water. portable filters are available and provide various degrees of protection against microbes. parents of pediatric travelers also should be counseled on the importance of advance planning for food and beverage items, especially for infants and young children. breast-feeding infants are considered relatively safe from travelers' diarrhea; for infants receiving formula, formula concentrate and powdered forms are the most convenient for travel, but a clean water supply must be available, or water must be boiled or chemically disinfected before preparation. for feeding toddlers and for older children, the travel adage of "boil it, cook it, peel it, or forget it" applies. travelers should avoid eating dairy products, including cheese and ice cream, because they often are unpasteurized. when a pediatric traveler develops diarrhea, oral rehydration solution to maintain hydration is the treatment of choice. parents also should be educated about the signs of mild, moderate, and severe dehydration and instructed in management of diarrhea, especially oral rehydration therapy. antimotility agents, such as lomotil (active ingredient, diphenoxylate; pfizer inc, new york, ny) and imodium (active ingredient, loperamide; mcneil-ppc, inc., ft washington, pa), are not recommended in children because of potential toxic megacolon and toxicity (extrapyramidal symptoms with diphenoxylate). empiric treatment of traveler's diarrhea with antimicrobial agents, typically ciprofloxacin, because of resistance to other agents such as trimethoprim-sulfamethoxazole, is used for adults. few studies of empiric antimicrobial treatment have been performed in children, and it is not a routinely recommended intervention for children. parents should be advised that severe diarrhea requires urgent medical attention, especially in younger pediatric travelers. prophylaxis for travelers' diarrhea with medications such as bismuth subsalicylate (the active ingredient in pepto-bismol; proctor & gamble, cincinnati, oh) is not recommended because of the potential accumulation of salicylate. prophylactic regimens with antimicrobial agents also are not recommended in children; the benefits usually are outweighed by potential risks, including allergic drug reactions, antimicrobial-associated colitis, and emergence of antibiotic-resistant strains. moreover, limited information is available about destination-specific antimicrobial resistance patterns. 37 clinicians need to provide pediatric travelers and parent(s) with up-to-date and accurate international travel health information and recommendations for preventing illness. increasingly, the internet and computer-based travel resources are being used by practitioners and consumers alike because they provide current information that can be used to counsel and treat international travelers appropriately and effective-ly. 79 a summary of some selected travel health resources that can be useful for providing information on health risks in specific travel destinations and current travel health recommendations (including immunizations and chemoprophylaxis) is provided in table 1 . in addition, if health care provided overseas is not covered by a family's health insurance company, insurance can be purchased from several companies and can include airlift/medical evacuation. the u.s. embassy or consulate can provide names and addresses of english-speaking healthcare providers in the travel destination if medical evaluation is needed abroad. this information can be obtained before departure from embassy internet sites or by calling the embassy. in addition, names of physicians abroad also can be obtained from some worldwide directories, including those of the international society of travel medicine, at www.istm.org. travelers' and immigrants' health health problems after travel to developing countries a cumulative review of studies on travelers, their experience of illness and the implications of these findings illness associated with travel travelers' diarrhea: epidemiology, microbiology, prevention, and therapy health risks abroad: general considerations travelers diarrhea: approaches to prevention and treatment epidemiologic studies of travelers diarrhea, severe gastrointestinal infections, and cholera update on prevention of malaria in travelers pre-exposure rabies prophylaxis for travellers: are the benefits worth the cost legionnaires' disease on a cruise ship linked to the water supply system: clinical and public health implications -135 meningococcal disease among travelers returning from saudi arabia-united states update: assessment of risk for meningococcal disease associated with hajj absence of neiserria meningitidis w-135 electrophoretic type 37 during the haj hiv-1 and hiv-2 infections among u.s. peace corps volunteers returning from west africa hiv infections, needlesticks and sexual behavior among dutch expatriates in sub-saharan africa meningococcal disease in travelers: vaccination recommendations risk of infection and other sexually transmitted diseases in travelers reported cholera in the united states memish z: meningococcal disease and travel typhoid fever in the united states, 1985-1994 group a meningococcal carriage in travelers returning form saudi arabia should travellers in rabies endemic areas receive pre-exposure rabies immunization febrile illness in successive cohorts of tourists to a hotel on the italian adriatic coast: evidence of a persistent foci of legionella infection risk of hepatitis b for travelers epidemiology and prevention of hepatitis a in travelers imported malaria in children in the uk epidemiology of travel-related morbidity and mortality in children prospective, hospital based study of fever in children in the united kingdom who had recently spent time in the tropics incidence and clinical features of traveler's diarrhea in infants and children prevention: health information for international travel update: outbreak of poliomyelitis-dominican republic and haiti centers for disease control and prevention: measles outbreak among internationally adopted children arriving in the united states, february centers for disease control and prevention: multistate investigation of measles among adoptees from china investigation and management of infectious diseases on international conveyances (airplanes and cruiseships redbook: 2003 report of the committee on infectious diseases world health organization: international travel and health: vaccination requirements and health advice. world health organization aedes aegypti, dengue and re-urbanization of yellow fever in brazil and other south american countries: past and present situation and future perspectives fever and multisystem organ failure associated with 17d-204 yellow fever vaccination: a report of four cases centers for disease control and prevention: fever, jaundice, and multiple organ system failure associated with 17d-derived yellow fever vaccination centers for disease control and prevention: yellow fever vaccine information statement cruise ships: a travel destination for high-risk passengers and the global spread of new influenza viruses prevention: the role of bcg vaccine in the prevention and control of tuberculosis in the united states: a joint statement by the advisory council for the elimination of tuberculosis and the advisory committee on immunization practices mycobacterium tuberculosis infection after travel to or contact with visitors from countries with a high prevalence of tuberculosis malaria surveillance-united states malaria surveillance-united states pediatric malaria in insecticide-treated bednets reduce mortality and severe morbidity from malaria among children follow safety precautions when using deet on children imported malaria: prospective analysis of problems in diagnosis and management malaria chemoprophylaxis in the age of drug resistance. i. currently recommended drug regimens delayed onset of malariaimplications for chemopropylaxis in travelers pediatric imported malaria in new york: delayed diagnosis prevention: malaria deaths following inappropriate malaria chemoprophylaxis-united states centers for disease control and prevention: travelers' health notice: dengue fever dengue surveillance in texas risk factors in dengue shock syndrome african trypanosomiasis in u.s. travelers: american society of tropical medicine and hygiene 50th annual meeting tropneteurop: outbreak of african trypanosomiasis among travelers to the serengeti national park in tanzania schistosomiasis in lake malawi schistosomiasis in travelers and expatriates control and prevention: cave-associated histoplasmosis-costa rica bat-associated histoplasmosis in returning travelers: case presentation and description of a cluster acute histoplasmosis in spelunkers returning from mato grosso an outbreak of acute febrile illness among travelers to nicaragua centers for disease control and prevention. outbreak of acute respiratory febrile illness among college students outbreak of coccidioidomycosis in washington state residents returning from mexico coccidioidomycosis in travelers returning from histoplasmosis: protecting workers at risk, revised guidelines for preventing histoplasmosis centers for disease control and prevention: outbreak of acute febrile illness among participants in ecochallenge sabah 2000 -malaysia lesion on the arm of a returning traveler a novel coronavirus associated with severe acute respiratory syndrome children hospitalized with severe acute respiratory syndrome-related illness in toronto infants born to mothers with severe acute respiratory syndrome travelers' diarrhea: epidemiology and clinical aspects information sources in travel medicine key: cord-314190-fvdock94 authors: florin, todd a; plint, amy c; zorc, joseph j title: viral bronchiolitis date: 2017-01-01 journal: the lancet doi: 10.1016/s0140-6736(16)30951-5 sha: doc_id: 314190 cord_uid: fvdock94 viral bronchiolitis is a common clinical syndrome affecting infants and young children. concern about its associated morbidity and cost has led to a large body of research that has been summarised in systematic reviews and integrated into clinical practice guidelines in several countries. the evidence and guideline recommendations consistently support a clinical diagnosis with the limited role for diagnostic testing for children presenting with the typical clinical syndrome of viral upper respiratory infection progressing to the lower respiratory tract. management is largely supportive, focusing on maintaining oxygenation and hydration of the patient. evidence suggests no benefit from bronchodilator or corticosteroid use in infants with a first episode of bronchiolitis. evidence for other treatments such as hypertonic saline is evolving but not clearly defined yet. for infants with severe disease, the insufficient available data suggest a role for high-flow nasal cannula and continuous positive airway pressure use in a monitored setting to prevent respiratory failure. acute bronchiolitis, a viral infection of the lower respiratory tract, is one of the most substantial health burdens for infants and young children worldwide. 1 respiratory syncytial virus is the most prevalent viral cause of bronchiolitis in infants. estimates suggest that about 34 million new cases of lower respiratory infection due to respiratory syncytial virus occur globally in children younger than 5 years, with 3·4 million admissions to hospitals and about 199 000 deaths per year, predominantly in the developing world. 2 in developed countries such as the usa, bronchiolitis is the most common reason for admission to hospital in the fi rst 12 months of life, 3 accounting for approximately 100 000 infant admissions annually. although admissions to hospital have declined from 2000 to 2010, emergency department visits have increased, in addition to increased use of mechanical ventilation and hospital charges. 4, 5 the clinical management remains challenging despite the frequency, global reach, economic cost, and morbidity and mortality associated with bronchiolitis. several treatment strategies (including bronchodilators and corticosteroids) showed no eff ect in pooled metaanalyses, making supportive care the hallmark of current therapy. in this seminar, we aim to summarise the current evidence for the epidemiology, pathophysiology, diagnostic approach, and management of acute viral bronchiolitis. bronchiolitis is a seasonal infection, with the season typically beginning in late october in the temperate northern hemisphere, peaking in january or february, and ending in april. 6 globally, independent of region, respiratory syncytial virus infection peaks consistently during annual or biannual epidemics. although the peak and duration of these epidemics vary worldwide, they are consistent year-to-year within a country. 7 some data suggest that climate might also be associated with prevalence of respiratory syncytial virus infection, with global surveillance suggesting that infection peaks during wet months in areas with high precipitation and during cooler months in hot regions. 7 indoor crowding in population-dense areas during rainy seasons or cooler months might be one factor that facilitates viral transmission. 8 additionally, weather-related factors, such as inhalation of cold and dry air that might impair ciliary function, the airway mucosa, and inhibition of temperature-dependent antiviral responses, might infl uence both disease transmission and severity. 9, 10 altitude, climate, and meteorological conditions (such as wind speed and dew point) have been shown to have a modest association with bronchiolitis. 11, 12 furthermore, air pollutants, such as ozone and traffi c pollutants, have been associated with exacerbations of respiratory infections in children younger than 5 years. [13] [14] [15] environmental tobacco smoke has been associated with increased risk for respiratory syncytial virus-attributable admission to hospital and disease severity in those admitted. 16, 17 as with other respiratory viral infections, the risk of severe respiratory syncytial virus bronchiolitis might be greater in boys than in girls. 18, 19 this diff erence might be due to diff erences in lung and airway development, and by genetic factors. 8, 20 pathophysiology bronchiolitis is characterised by extensive infl ammation and oedema of the airways, increased mucus production, and necrosis of airway epithelial cells. 21 respiratory syncytial virus binds to epithelial cells and replicates, resulting in epithelial necrosis and ciliary destruction. 21, 22 the cell destruction triggers an infl ammatory response with proliferation of polymorphonuclear cells and lymphocytes. the submucosa and adventitial tissues become oedematous with increased mucus secretion. 22 plugs composed of cellular debris and mucus form in the bronchiole lumens leading to bronchiolar obstruction, air trapping, and diff erent degrees of lobar collapse. 21 microbiology molecular testing has led to an improved understanding of the viruses associated with bronchiolitis. respiratory syncytial virus remains the most commonly identifi ed virus, detected in 41-83% of patients. [23] [24] [25] [26] [27] [28] other viruses associated with bronchiolitis include rhinovirus, metapneumovirus, coronavirus, human bocavirus, infl uenza virus, adenovirus, and parainfl uenza virus. 24, 25, 27, 29, 30 studies have investigated whether severity of illness, as measured by need for hospital admission, length of hospital stay, intensive care unit admission, repeated emergency department visits, and apnoea, is associated with specifi c viral infections or co-infections, but the evidence is confl icting. data from some studies have shown that in infections involving a single virus, respiratory syncytial virus is associated with a more severe course compared with other viruses. 31, 32 up to 30% of children with bronchiolitis are found to have co-infections with two other viruses, 29 with the combination of respiratory syncytial virus and rhinovirus being the most commonly reported. 29 some evidence suggests that co-infection in bronchiolitis, particularly respiratory syncytial virus in combination with rhinovirus or metapneumovirus, could be associated with a more severe disease course compared with infection by a single virus. 25, 30, 31, 33, 34 however, other studies do not confi rm this association. 24, 26 furthermore, although use of nucleic acid amplifi cation tests has greatly improved our ability to detect viruses present in respiratory infections, studies using these technologies have also found at least one respiratory virus in up to 30% of children younger than 6 years with no respiratory symptoms. [35] [36] [37] these viruses might be detected because of asymptomatic colonisation, incubation before clinical infection, or prolonged viral shedding post-infection. the confl icting evidence and high prevalence of respiratory viruses in asymptomatic children suggest no indication at this time that management should vary based on presumed viral cause and presence, or absence of viral co-infections. the diagnosis of bronchiolitis is clinical and thus requires a clinician to recognise signs and symptoms of viral lower respiratory tract infection in young children. peak incidence occurs between 3 months and 6 months of age. 38 since the early clinical defi nition by court, and as noted in recent practice guidelines, the most specifi c defi nition is in infants. [38] [39] [40] although the same physiology can occur in toddlers older than 12 months, many clinical trials have excluded these children or have included them as a small subgroup of patients. bronchiolitis in toddlers can overlap with other conditions such as viral-induced wheezing and asthma, and application of evidence from trials predominantly assessing infants might not be appropriate. further eff orts to focus the defi nition might assist eff orts to standardise care. the classic clinical presentation of bronchiolitis starts with symptoms of a viral upper respiratory infection, such as nasal discharge, that progress to the lower respiratory tract over several days (fi gure 1). timing of symptom progression can vary, and young infants can present with apnoea. lower respiratory tract symptoms of bronchiolitis include persistent cough, tachypnoea, and increased work of breathing, as shown by intercostal or supraclavicular retractions, use of abdominal muscles, grunting, or nasal fl aring. auscultatory fi ndings include crackles and wheeze. a hallmark characteristic of bronchiolitis is the minute-to-minute variation in clinical fi ndings, as mucus and debris in the airways are cleared by coughing or as the child's state changes from sleep to agitation. this variation can confound assessment, and often requires several examinations over a period of observation. nasal congestion can also confound the clinical assessment. nasal suctioning might help to ascertain which fi ndings are truly from the lower airways. fever can be present in about a third of infants with bronchiolitis, but it is usually present early in the illness with a temperature less than 39°c. 38 the median duration of symptoms is about 2 weeks, with 10-20% of infants still having symptoms at 3 weeks after onset. 38, 41 various clinical scores have been shown in studies and clinical protocols to correlate with disease severity and improvement. 42, 43 although documentation of a score can be useful as an objective measure, individual scores are not highly predictive, and they should be repeated and combined with other measures of severity for a universal assessment to guide decision making. the diff erential diagnosis for bronchiolitis includes considerations of various infectious and non-infectious causes. absence of upper respiratory symptoms should raise suspicion of other causes of respiratory distress in young infants, including cardiac disease, congenital airway abnormalities such as a vascular ring, or foreign body aspiration. other infections can resemble or complicate bronchiolitis. pertussis should be considered in infants with severe or paroxysmal cough, or with known exposure. bacterial infections complicating viral bronchiolitis, including otitis media or pneumonia, might present as a new fever or worsening status later in the course of illness. various risk factors have been associated with progression to severe bronchiolitis. those supported by the strongest evidence include presence of chronic lung disease of prematurity and haemodynamically important congenital heart disease, with immunodefi ciency and neuromuscular disorders also considered as high risk in practice guidelines. 38, 39 young infants (aged <2-3 months) and those with a history of premature birth (especially <32 weeks' gestation) are also at high risk for progression and can present with apnoea without other clinical fi ndings. studies assessing the risk for further apnoea in hospital have found it to be limited to infants less than 1 month for full-term infants, 48 weeks postconceptional age for preterm infants, or those with apnoea observed before admission. 44 bronchiolitis is a clinical diagnosis based on history and physical examination, according to consensus across national guidelines. for infants with a typical presentation of bronchiolitis, routine imaging or laboratory testing is not recommended, as they increase costs without evidence for benefi t (table). appropriate use of pulse oximetry monitoring and initiation of oxygen for bronchiolitis have received increasing attention in studies and practice guidelines. findings suggest that arbitrary thresholds for oxygen administration might drive hospital admissions and prolong hospital length of stay. these outcomes represent only part of the morbidity of bronchiolitis, but developing evidence suggests that intermittent hypoxaemia might occur commonly in otherwise stable infants with bronchiolitis and raises questions as to whether this factor should be used as a sole indication for admission to hospitals. a canadian randomised trial found reduced admissions to hospital from the emergency department without any increase in revisits when pulse oximeters displayed values 3% higher than the actual value, suggesting that arbitrary pulse oximetry thresholds result in unnecessary admissions. 51 a similar trial in the uk in the hospital setting found that reduction of the oxygen threshold from 94% to 90% resulted in earlier discharge from the hospital without any evidence of adverse outcomes. 52 a us trial comparing intermittent versus continuous pulse oximetry in non-hypoxaemic infants in hospitals found similar outcomes between the groups. 53 this us trial and other evidence supports recommendations in us practice guidelines that clinicians use a threshold of 90% for initiation of oxygen, whereas uk guidelines recommend 92%. 38, 39 as the child improves, reduction in intensity of monitoring to intermittent checks is appropriate. a recent study using blinded oximetry at home showed that a substantial proportion of infants with bronchiolitis who are otherwise doing well have oxygen desaturations less than 90%, particularly during sleep, further calling into question arbitrary thresholds for hospital admissions and initiation of oxygen. 54 this evidence will probably lead to eff orts to reduce continuous monitoring in children without other indications for monitoring. the majority of children with bronchiolitis have either normal radiographs or radiographic fi ndings consistent with simple bronchiolitis, 55-58 including peribronchial thickening, hyperinfl ation, and atelectasis. one prospective study 58 of routine radiographs as part of the assessment for bronchiolitis in the emergency department reported airspace disease in 17 (7%) of 246 patients. despite the low prevalence of radiographic pneumonia, this and other studies have reported an increase in antibiotic prescription after radiographs are performed, because of non-specifi c fi ndings that infl uence clinicians' decisions. 58, 59 factors that have been associated with defi nite focal infi ltrates consistent with pneumonia include hypoxia (oxygen saturation <92%), [56] [57] [58] 60 grunting, persistently focal crackles, and fever (especially >39°c). 38 chest radiographs should only be considered in patients when the presentation is not classic for bronchiolitis. these situations include when another diagnosis (such as foreign body aspiration) is high on the diff erential diagnosis, when a child is severely ill and respiratory failure is imminent, and when symptoms are progressing or not resolving according to the typical disease course expected for bronchiolitis. lung ultrasound is increasingly used to assess cardiopulmonary conditions in adults and children. several studies have investigated the use of lung ultrasound in the diagnosis of bronchiolitis. two small studies found that ultrasound fi ndings in infants with bronchiolitis correlate with clinical fi ndings, and might be more specifi c than chest radiography, 61,62 but further studies are needed to establish whether there is a role for ultrasound in diagnosis or assessment of severity. with the development of pcr to detect respiratory viruses in the nasopharynx, interest in the use of viral testing for causative diagnosis in bronchiolitis has increased. virological testing, however, does not generally assist in management and is insuffi cient to predict outcomes. 30, 63 many national guidelines therefore recommend against routine virological testing in bronchiolitis (table). recent studies suggest that higher respiratory syncytial virus genomic load, measured using quantitative pcr, might be associated with increased length of stay, use of respiratory support, and need for intensive care, in addition to recurrent wheezing, compared with lower viral loads. 28, 31, 32, 64 further study is warranted to confi rm this association and clarify whether viral load measurement improves understanding of disease pathophysiology and severity. several guidelines recommend using respiratory syncytial virus testing to guide cohorting of patients; however, the viruses most likely to cause bronchiolitis are all transmitted in a similar fashion (close contact with large-particle aerosols or direct contact with contaminated fomites). [65] [66] [67] thus, infection control might not be dependent on the identifi cation of specifi c viruses, but rather on following strict precautions including hand hygiene, separating infants in shared hospital rooms by more than 1 m, and other infection control procedures. 65 additionally, given the sensitivity of pcr testing, results should be interpreted with caution. certain viruses, such as rhinovirus, might be detected because of viral shedding from an unrelated illness or colonisation; whereas certain other viruses, such as respiratory syncytial virus and metapneumovirus, are almost always associated with an acute infection. blood and urine testing is not routinely recommended as part of standard practice in the diagnostic work-up of bronchiolitis (table) . a blood gas measurement should not be routinely obtained in infants with bronchiolitis, unless there are signs of impending respiratory failure or severe distress. proportions of serious bacterial infections, especially bacteraemia and meningitis, are very low in infants with bronchiolitis. 68 abnormal white blood cell count is rarely useful in predicting serious bacterial infections in children infected with respiratory syncytial virus. 69 guidelines universally do not recommend complete blood counts in infants with bronchiolitis unless blood count is part of assessment for a fever in infants younger than 1-2 months. similarly, given that bacteraemia is exceedingly rare (with cited proportions of <0·1% in the post-pneumococcal vaccine era), blood cultures should not be routinely performed, except in the septic work-up of infants younger than 1-2 months, 70, 71 or in those with severe illness and signs of sepsis. hydration status is an important consideration in infants with bronchiolitis and should be determined by clinical examination. routine measurement of serum electrolytes is of little value in the majority of infants. urinary tract infections in infants with bronchiolitis occur with greater frequency than do bacteraemia and meningitis, with proportions ranging from 1% to 7%. 68, 71, 72 it is reasonable to obtain a urinalysis and urine culture for infants aged less than 60 days with fever and for older febrile infants who have risk factors for urinary tract infections, 73 but urine should not be routinely obtained in all infants with bronchiolitis. current recommendations for management of bronchiolitis focus on agents to treat the patho physiological eff ects of viral lower respiratory infection (eg, bronchodilators and hypertonic saline). specifi c antivirals such as ribavirin to treat respiratory syncytial virus infection are not recommended in practice guidelines for typical cases of bronchiolitis because of challenging delivery methods, high cost, and potential health risks to caregivers. multiple new agents for prevention and treatment are under investigation and might become available in the future, including immunoglobulins, small interfering rna interference, fusion inhibitors, and small molecules. 74 numerous studies have assessed the role of bronchodilators for the treatment of bronchiolitis, and systematic reviews have found no consistent benefi t. a 2014 cochrane collaboration systematic review identifi ed 30 studies assessing bronchodilators, predominantly salbutamol and excluding epinephrine, and 21 studies that looked specifi ally at clinical scores found no evidence of benefi t in any outcomes for infants admitted to hospitals. 75 in outpatients, oxygen saturation, admission to hospital, or time to resolution of symptoms did not improve with bronchodilator usage compared with placebo. for outpatient studies assessing short-term change in pooled clinical scores, the reviewers found a small signifi cant diff erence in mean score (z=2·26; p=0·024) that was of small eff ect with minimal clinical importance (fi gure 2). outpatient studies were heterogeneous (i²=81%; p<0·00001), and those showing benefi t in scores tended to include older children and children with recurrent wheezing. nebulised epinephrine was assessed in another cochrane collaboration systematic review. 76 this review found no benefi t for epinephrine compared with placebo for inpatients in hospital length of stay or other outcomes. a multicentre scandinavian study published after this cochrane review found that inpatients receiving standing doses of epinephrine had longer length of stay compared with inpatients receiving as-needed epinephrine or placebo. 77 for outpatients, the cochrane review found a diff erence in the numbers of admissions associated with epinephrine treatment during the time of an emergency department visit, but not during the overall course of illness when assessed at 1 week. clinical practice guidelines including those from the usa, uk, and canada do not recommend treatment with bronchodilators for bronchiolitis because of this evidence (table) . 38 nebulised hypertonic saline is thought to reduce airway oedema, decrease mucus plugging, improve mucociliary clearance, and rehydrate the airway surface liquid in infants with bronchiolitis. 78 these physiological changes are extrapolated from the cystic fi brosis literature, 79, 80 and the pathophysiological processes in acute bronchiolitis are diff erent. therefore, the theoretical benefi ts of hypertonic saline seen in cystic fi brosis might not be present in infants with acute viral bronchiolitis. although initial trials demonstrated some ability of hypertonic saline to decrease hospital length of stay and transiently improve clinical severity score, 81-83 more recent trials demonstrated confl icting results. [84] [85] [86] [87] [88] [89] [90] the trials that showed the largest benefi t were done in hospitals with lengths of stay more than 72 h; thus, hypertonic saline for infants in countries and institutions in which the length of stay approaches or exceeds 72 h might be benefi cial at reducing length of stay. the confl icting results are test for heterogeneity in the inpatient studies demonstrated low inconsistency between the nine studies (i²=36%; p=0·13) and the summary eff ect was not signifi cant (z=1·06; p=0·29), the outpatient studies demonstrated very high inconsistency between the 12 studies (i²=81%; p<0·00001) and the summary eff ect was signifi cant (z=2·26; p=0·024), and the overall heterogeneity of the meta-analysis demonstrated high inconsistency between the 21 studies (i²=73%; p<0·00001) and the overall summary eff ect was signifi cant (z=2·4; p=0·016). ipr=ipratropium. sal=salbutamol. neb=nebulised. reproduced from gadomski and scribani, 75 refl ected in the diff erences in recommendations across national guidelines (table), with some countries not recommending hypertonic saline, some recommending use for all inpatients, and some recommending use only in moderate to severe illness. the largest systematic review and meta-analysis, published in 2015, examined 24 trials and 3209 patients. 91 infants receiving hypertonic saline had a signifi cant diff erence in hospital length of stay of -0·45 days (95% ci -0·82 to -0·08; p=0·01) compared with those receiving 0·9% saline or standard care. in seven trials, hypertonic saline reduced the risk of admission to hospital by 20% (risk ratio 0·8; 95% ci 0·67-0·96) compared with 0·9% saline. no substantial adverse eff ects of hypertonic saline were noted in this systematic review. although the results of this meta-analysis were signifi cant, attention should be paid to the outer limits of the confi dence intervals, which approach no diff erence, and to the clinical relevance of these diff erences. a second 2015 meta-analysis of 15 trials and 1922 patients found a smaller, but signifi cant, decrease in length of stay by -0·36 days (95% ci -0·5 to -0·22; p<0·001) in those who received hypertonic saline (fi gure 3). 92 this study found a discrepancy between the overall combined eff ect of all studies on length of stay and the negative results from the largest trials, allowing the authors to conclude that neither individual trials nor pooled estimates provide a strong evidence-based foundation for the use of hypertonic saline. both meta-analyses showed substantial heterogeneity across studies (i²=82·1%, p<0·001; 91 and i²=77·8%, p=0·029 92 ). a recent reanalysis of the fi rst 2015 meta-analysis removed two outlying chinese studies and accounted for imbalances in day of illness at presentation. 93 these analyses resolved the heterogeneity and found that hypertonic saline does not reduce length of stay in infants admitted to hospitals with bronchiolitis (mean diff erence in length of stay removing outliers -0·21 days; 95% ci -0·43 to 0·02; mean diff erence in length of stay accounting for day of illness imbalance 0·02 days; 95% ci -0·14 to 0·17). large trials have not demonstrated benefi t for hypertonic saline and this meta-analysis found no eff ect of hypertonic saline on length of stay after adjustment for outliers and imbalances. the decision to undertake future trials is controversial given the positive results of some metaanalyses and negative results of others. multiple studies have examined the role of corticosteroids in the management of children with bronchiolitis. data from two large multicentre trials have shown no benefi t to corticosteroids alone in reducing admissions to hospital, 94, 95 and a 2013 cochrane collaboration review supports the results of these studies. 96 this review included only studies that enrolled children younger than 24 months with a fi rst episode of wheezing and signs of a viral illness. among the included eight outpatient studies (1824 participants) comparing corticosteroids with placebo there was no reduction in admission at day 1 (z=1·05; p=0·3) or day 7 (z=1·38; p=0·17) after enrolment (fi gure 4), clinical scores, length of stay in the emergency department, or length of time to resolution of symptoms. among the nine inpatient studies (772 participants), length of hospital stay was not reduced. 96 on the basis of this evidence, multiple clinical practice guidelines recommend against the use of corticosteroids for infants with bronchiolitis (table) . although clinicians report considering a family or personal history of atopy when deciding whether to treat infants with bronchiolitis with corticosteroids, 41 there is no evidence that such infants receive any benefi t from corticosteroid treatment. [94] [95] [96] evidence for the presence or absence of respiratory syncytial virus infection in these infants being associated with a response to corticosteroids is also unavailable. 94, 95 authors from a large study with a factorial design have suggested, in an unadjusted analysis, that high-dose corticosteroids in combination with nebulised epinephrine might reduce admissions for outpatients with bronchiolitis by day 7, 95 but these results are considered exploratory. 39, 45 high-fl ow oxygen and respiratory support non-invasive technologies to improve oxygenation and ventilation for bronchiolitis include humidifi ed high-fl ow nasal cannula oxygen and continuous positive airway pressure. 97 high-fl ow nasal cannula allows delivery of high fl ows (usually 1-2 l/kg per min) with humidifi cation and a cannula designed to improve patient tolerance. it has been used widely in premature infants, but the mechanisms of action are unclear, in particular whether it might deliver positive end-expiratory pressure in some conditions. evidence for effi cacy of high-fl ow nasal cannula is predominantly observational, with studies documenting corneli (2007) goebel (2000) kuyucu (2004) plint (2009) improved respiratory parameters and reduced intubation rates after implementation. 97 one small randomised trial compared high-fl ow nasal cannula with hypertonic saline and found no diff erence in change in respiratory score. 98 concerns about high-fl ow nasal cannula include the potential for rapid deterioration if the infant is not closely monitored and costs associated with overuse. continuous positive airway pressure has been studied in intensive care settings in observational studies and several small trials, with some evidence of improved respiratory parameters. 97 the uk guidelines recommend considering continuous positive airway pressure in children with impending respiratory failure from bronchiolitis. antibiotic overuse in children with bronchiolitis probably occurs because of concerns about the presence of fever, the young age of aff ected patients, diffi culty diff erentiating atelectasis from infectious consolidation on chest radiograph, and concern for undetected secondary bacterial infection. bronchiolitis, however, has a clear viral cause and the occurrence of secondary bacterial infections is low, with a risk of bacteraemia or meningitis of less than 1%. 99 a detailed review of randomised clinical trials found that routine use of antibiotics did not improve duration of symptoms, length of hospital stay, need for oxygen therapy, or hospital admission. 38 overuse of antibiotics is known to result in unnecessary adverse eff ects on the patient, and the development of antimicrobial resistance. routine use should be avoided unless there is clear evidence of a secondary bacterial infection (table) . acute otitis media has been documented in up to 60% of infants with bronchiolitis. 100, 101 antibiotic use for acute otitis media in bronchiolitis should follow established evidence and guidelines for acute otitis media. 102 macrolide antibiotics have anti-infl ammatory properties that might have potential benefi t in mitigating the infl ammation present in bronchiolitis. two randomised trials found that there was no diff erence between azithromycin and placebo in hospital length of stay, need for oxygen, or hospital re-admission. 103, 104 another randomised trial found that azithromycin lowered nasal interleukin-8 concentrations, prolonged time to subsequent wheezing episodes, and resulted in fewer days with respiratory symptoms in the year following the bronchiolitis episode compared with placebo. 105 finally, a us multicentre study found that in children aged 12-72 months with a history of recurrent severe lower respiratory tract infections, early administration of azithromycin during a lower respiratory tract infection reduced the likelihood of progression to a severe infection, but it is not clear whether the underlying disease in these children was bronchiolitis or some other disease process. 106 given the current evidence, routine use of macrolides is not recommended in bronchiolitis and more research is needed to clarify any potential role it might have in the future. hydration, suctioning, and chest physiotherapy have been suggested as supportive therapies. infants with bronchiolitis might have diffi culty feeding because of nasal congestion and increased work of breathing; thus, hydration remains a cornerstone of therapy. a multicentre study of 759 infants younger than 12 months admitted to hospital with bronchiolitis showed no benefi t of intravenous fl uids compared with administration of fl uids by nasogastric tube in mean length of stay, admission to the intensive care unit, need for ventilatory support, and adverse events. this trial also found that a nasogastric tube might be easier to place than an intravenous line in these infants. 107 most guidelines recommend either nasogastric or intravenous fl uids to maintain hydration, with the uk and scottish guidelines preferring nasogastric or orogastric hydration in those that can tolerate it compared with intravenous hydration (table). if intravenous fl uids are used, isotonic fl uids are preferred to avoid risk of hyponatraemia. 38 because infants are obligate nasal breathers, nasal suctioning has been suggested to help with clearing of the nares, improve the work of breathing, and improve feeding; however, suctioning might irritate the nasal mucosa and result in oedema. no randomised controlled trials have examined the role of nasal suctioning in bronchiolitis. the insuffi cient available evidence includes a retrospective cohort study of 740 infants 108 and a small observational study of 40 infants. 109 these studies suggest that deep suctioning might increase length of stay for inpatients, 108 infrequent suctioning is associated with an increased length of stay, 108 and oxygen saturation might increase after suctioning. 109 to draw conclusions about causality from these observational studies is diffi cult, because the potential for confouding by indication exists (eg, sicker children might be more likely to receive deep suctioning). evidence suggests that oxygen saturation increases after nasal irrigation even without suctioning. 110 current guidelines give diff ering recommendations with regard to suctioning; those that support its use recommend only superfi cial suctioning rather than deep suctioning (table) . 38, 39, 45 chest physiotherapy use in bronchiolitis appears to vary by country. 111, 112 a recent cochrane collaboration review of 12 studies (1249 participants) demonstrated no evidence of benefi t to any type of chest physiotherapy among inpatients in length of stay, oxygen saturation, or respiratory parameters. 113 no published guidelines routinely recommend chest physiotherapy for the management of uncomplicated bronchiolitis in otherwise healthy children without respiratory comorbidities (table) . 38, 39, 45 prognosis much work has been published about the risk of developing recurrent wheezing and asthma following bronchiolitis in infancy. [114] [115] [116] studies have followed birth cohorts to determine the risk of subsequent wheezing after lower respiratory tract infection in young childhood, and cohorts of children admitted to hospital with bronchiolitis. [114] [115] [116] [117] overall, admission to hospital with bronchiolitis at a young age is associated with an increased risk of recurrent wheezing. studies report that 17-60% of children with bronchiolitis might develop recurrent wheezing in the years following their initial admission to hospital. a large study from taiwan that followed up 1981 children admitted with bronchiolitis before age 3 years found that by age 10 years, 351 (17·7%) of 1981 children with bronchiolitis had a diagnosis of asthma compared with 2159 (11·7%) of 18 527 controls (hazard ratio 1·58; 95% ci 1·41-1·71). 118 one small cohort study of 138 patients has suggested that 18 (39%) of 46 children admitted with bronchiolitis before 12 months have asthma by 18 years compared with eight (9%) of 92 controls. 115 however, another study that followed a birth cohort of 1246 children found that although lower respiratory tract infection in childhood was associated with an increased risk of recurrent wheezing, this association decreased with age and was not signifi cant by age 13 years. 116 most children in this cohort had mild illness not requiring hospital admission, and severity of illness might be associated with the increased risk of asthma. 119 the question remains whether respiratory infection at a young age itself predisposes children to asthma through damage or alteration of lung function, or whether children with severe bronchiolitis might have individual risk factors (such as altered immune response or airway function) that predisposes them to both severe bronchiolitis and recurrent wheezing. 8 substantial knowledge gaps and controversies exist in the management of acute bronchiolitis. the role of nebulised hypertonic saline in acute management is not clear, resulting in confl icting recommendations across clinical guidelines (table) . although meta-analyses suggest a small reduction of length of stay, these analyses are limited by heterogeneity, not accounting for duration of illness, and not considering the role of outlying study populations. 91 two large multicentre trials do not support a clinically signifi cant diff erence in length of stay for inpatients and there is no clear evidence of cost benefi t. 4, [89] [90] [91] 120 while the same meta-analysis suggests a possible reduction in admissions for outpatients, the confi dence intervals were wide and the studies were also heterogeneous. 91 no multicentre studies of nebulised hypertonic saline have been completed in outpatients. although the evidence is increasing that hypertonic saline has little role in meaningfully reducing the length of stay, its role in outpatients is less clear. a large outpatient multicentre study could clarify whether there is any benefi t. evidence also suggests that combined therapy with nebulised epinephrine and corticosteroids might reduce admissions to hospital. 95 synergy between corticosteroids and β2 agonists is well documented in clinical trials of asthma management. [121] [122] [123] [124] basic science literature also shows that β2 agonists and corticosteroids enhance each other's eff ectiveness, particularly with regard to antiinfl ammatory gene expression. 125, 126 because of the economic burden of bronchiolitis and the plausible basic and clinical evidence for synergy, a large and multicentre trial is needed to ascertain whether combined therapy with epinephrine and corticosteroids is benefi cial. oxygen saturation and the use of pulse oximetry play an important role in the decision to admit infants with bronchiolitis to hospital and in the length of their hospital stay. [51] [52] [53] [54] [55] [56] [57] [58] [59] clinical practice guidelines also give confl icting guidance on the level of oxygen saturation at which admission should be considered. furthermore, a substantial proportion of discharged infants have episodes of transient desaturation. 54 again, in view of the large health-care costs associated with hospital admission in bronchiolitis, further research is needed to clarify the level of oxygen saturation requiring admission, the role of continuous and spot measurements of oxygen saturation, and the clinical importance of transient desaturations in otherwise stable young infants. taf contributed to the design and coordinated the writing of this manuscript. all authors contributed to the literature search and writing of this manuscript. we declare no competing interests. taf, acp, and jjz have participated in trials of bronchiolitis funded by unrestricted public or academic institutional funding sources that had no infl uence on the conception 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beta(2)-adrenoceptor agonists enhance the clinical effi cacy of inhaled corticosteroids long-acting beta 2-adrenoceptor agonists synergistically enhance glucocorticoiddependent transcription in human airway epithelial and smooth muscle cells beta 2-adrenoceptor agonist-induced rgs2 expression is a genomic mechanism of bronchoprotection that is enhanced by glucocorticoids taf receives funding from the national institutes of health-national institute of allergy and infectious diseases (grant 1k23ai121325-01). the nih had no role in the writing of this manuscript, and in the decision to submit the paper for publication. we would like to thank kerry aicholtz for her administrative support. key: cord-318012-bg9y2nsp authors: cantais, aymeric; mory, olivier; pillet, sylvie; verhoeven, paul o.; bonneau, julie; patural, hugues; pozzetto, bruno title: epidemiology and microbiological investigations of community-acquired pneumonia in children admitted at the emergency department of a university hospital date: 2014-05-22 journal: j clin virol doi: 10.1016/j.jcv.2014.05.006 sha: doc_id: 318012 cord_uid: bg9y2nsp background: the management of children with community-acquired pneumonia (cap) is largely influenced by the development of new molecular diagnostic tests that allow the simultaneous detection of a wide range of pathogens. objectives: evaluation of a diagnostic approach including multiplex pcr assays for revisiting the epidemiology and etiology of cap in children at hospital. study design: children of all ages consulting at the emergency department of the university hospital of saint-etienne, france, during the 2012–2013 winter period were included. in addition to bacterial cultures, the following pathogens were detected using biplex commercially-available rt-pcr tests: adenovirus, respiratory syncytial virus, human metapneumovirus, bocavirus, rhinovirus/enterovirus, coronavirus, influenza viruses a and b, parainfluenza viruses, mycoplasma pneumoniae and chlamydophila pneumonia. results: from 85 patients with cap, at least one pathogen was identified in 81 cases (95.3%), including 4 bacterial exclusive infections (4.7%), 53 viral exclusive infections (62.4%) and 24 mixed infections (28.2%). coinfection by at least two viruses was observed in 37 cases (43.5%). mean age was higher in the case of documented bacterial infection (p < 0.05). in the subgroup of viral exclusive infection, the mean age of severe cases was 2.0 years vs 3.8 years in mild and moderate cases (p < 0.05). conclusions: these findings highlight the huge proportion of cap of viral origin, the high number of co-infection by multiple viruses and the low number of bacterial cap, notably in children under 5 years, and address the need to re-evaluate the indications of empiric antimicrobial treatment in this age group. community-acquired pneumonia (cap) is the leading cause of death in children under five years of age in the world [1] . in developed countries, the systematic prescription of antimicrobial drugs to patients with cap has led to a dramatic reduction in mortality linked to this pathology [2, 3] . however, a bacterial origin of cap has not been documented in a large proportion of cases despite extensive aetiological investigations. the current recommendations [4] [5] [6] encourage pediatricians to prescribe a probabilistic antimicrobial treatment, even when no bacterial infection is documented, which results in prolonged use of antibiotics and in the possible selection of resistant strains within the endogenous flora [7] . until the beginning of the current century, the absence of documented bacterial infection was attributed to the difficulty in obtaining deep respiratory specimens that are not contaminated by bacteria from the local flora [8] together with the lower sensitivity of blood cultures in proving bacterial sepsis [9] . at this time, most of the epidemiological data from pediatric cap relied on traditional bacteriological cultures. with the occurrence of new diagnostic tools and notably of multiplex pcr assays able to simultaneously detect a large panel of viruses and atypical bacteria, it now appears that a large proportion of cap could be related to viral infection [10] [11] [12] . many studies have evaluated these new tools but most of them were limited to subgroups of children notably to the young [13, 14] , to hospitalized children [11, [13] [14] [15] [16] [17] , or for selected pathogens [10, 12, 18, 19 ]. the aim of the present study was to document the presence of a large variety of pathogens in respiratory specimens from children attending the pediatric emergency department of the university hospital of saint-etienne, france, during a six-month period and presenting a cap based on clinical and radiological evidence. the microbiological diagnostic approach combined bacterial cultures and biplex commercially available rt-pcr tests detecting a wide range of respiratory pathogens. a single center epidemiological observational study was conducted over a six-month period (november 2012 to april 2013) on children aging from one month to 16.5 years and presenting with cap at the pediatric emergency department of the university hospital of saint-etienne, france. the study was submitted for approval to the local ethics committee. after oral information was given together with a form explaining the content of the research, a consent form was signed by a parent or legal tutor before inclusion of each patient. a cap case was defined [6] as a subject with fever of at least 38.5 • c, an age-corrected polypnea [20] and a chest radiograph showing images of acute pneumonia confirmed by a second examiner (a pediatric radiologist for ambulatory children or a pediatrician for hospitalized patients). a few subjects were excluded after this second reading, notably in the case of associated bronchiolitis. the data collected at inclusion comprised the demographic characteristics of the child, their vaccine status, the smoking habits of parents, the date of the beginning of the current respiratory episode and the drugs, including antimicrobials, that they received during this period. according to the current guidelines [4] [5] [6] , a pneumonia was defined as severe for this study if the patient presented at least one of the following criteria: respiratory rate above 70 per minute in infants less than 1 year of age and above 50 per minute for older children, a tachycardia adjusted to age, a capillary refill time >3 s and an oxygen saturation <92%. a control visit was systematically carried out at days 2 and 5 either by phone call for ambulatory-treated children or after a physical examination in the service of hospitalization for children admitted to hospital. a number of biological parameters were recorded systematically, including c reactive protein (crp), procalcitonin (pct), white blood cell count and natremia. nasopharyngeal secretions obtained by sputum induction [21, 22] were sampled at entry for all the participants. the following tests were performed at inclusion: standard detection of conventional bacteria by culture, detection of five different viruses (respiratory syncytial virus (rsv), influenza viruses a and b, parainfluenza viruses, metapneumovirus and adenovirus) by indirect immunofluorescence (ifi) assay and detection of atypical bacteria by pcr as previously described [23] . in parallel, blood cultures and pneumococcal antigenuria were tested if prescribed by the clinician, notably in the case of hospitalization. in addition to the test listed above that were performed at the time of hospital attendance, a rtpcr assay was performed at the end of the study on an aliquot fraction kept frozen at −80 • c for the whole panel of nasopharyngeal aspirates, as previously described [24] . briefly, 200 l of aspirate was extracted on nuclisens ® easymag tm (biomérieux, marcy l'etoile, france). the respiratory multi well system (mws) r-gene tm (chla/myco pneumo, influenza a/b, rsv/hmpv, ad/hbov, hcov/hpiv, and rhino&ev/cc) from biomérieux was used for molecular testing. it consists of a series of biplex assays detecting either a couple of pathogens or a single pathogen and a cell control (cc) attesting for the presence of cellular nucleic acids within the specimen. the following pathogens were tested: mycoplasma pneumoniae and chlamydophila pneumoniae, influenza viruses a and b, rsv and human metapneumovirus (hmpv), adenovirus (adv) and bocavirus (bov), parainfluenza viruses and coronaviruses, rhinovirus/enterovirus (hrev) and a cell control. an univaried analysis was performed to compare the cases documented as probably related to a bacterial infection (threshold of 10 7 cfu/ml for conventional cultures [25, 26] or the presence of atypical bacterium by pcr in nasopharyngeal aspirates), and the others. comparisons adjusted for age, severity of pneumonia and mono/multiple infection were also performed. the chi-square test or the fisher exact test was used to compare qualitative variables whereas the student t test was used for quantitative variables. a p value of 0.05 was considered as statistically significant. a multivariate analysis of factors independently associated with detection of bacterial was secondarily performed; the parameters included in the logistic regression model were those with p < 0.10 by univaried analysis. over the six-month period of the study, 95 children thought to have cap were included; 10 of them were excluded secondarily, comprising 7 cases with non-cap infection, 2 cases without nasopharyngeal aspirate and one case of cap whose inclusion was not consented by the child's family. with reference to the total number of cases of cap recorded over the same period in the pediatric emergency department (n = 97), the representation rate was of 87.6% (85/97). the demographic and clinical characteristics of the 85 included cases together with the mode of management (ambulatory or hospital) and the probabilistic antimicrobial treatment are listed in table 1 . apyrexia was observed in 85.9 and 98.8% of cases at day 2 and 5, respectively. from the 35 children hospitalized at entry, 33 (94.3%) and 5 (14.3%) were still hospitalized at day 2 and 5, respectively. only one child needed intensive care within the pediatric intensive care unit. the antimicrobial treatment was modified in only three cases. neither fatal cases nor immediate sequelae were observed during the study. twenty-six cases (30.6%) were classified as severe cap. the general biological characteristics of the included cases were as follows: the median count of leukocytes was 14.7 10 9 per liter (interquartile range 10.84-20.08), with 66.5% of neutrophils; the crp median rate was of 64.5 mg/l (interquartile range: 19-163), the pct median rate was of 0.87 g/l (interquartile range: 0.17-5.14); an hyponatremia (<135 meq/l) was observed in 23 cases (27%). by using ifi prospectively, only 26 of the 85 nasopharyngeal aspirates (30.6%) were found positive, including 17 rsv, 9 adv and 4 influenzavirus b; all of these infections were confirmed by the retrospective rt-pcr assay. the pneumococcal antigenuria, available in 60 cases, was positive in 13 patients, 3 of them exhibiting a threshold of 10 7 cfu/ml by conventional culture. in the three other pneumococcal infections, no antigenuria was available. blood culture, performed in 38 cases (44%), was found positive for streptococcus pneumoniae in only one case. by combining bacterial culture and retrospective rt-pcr assays, at least one pathogen was identified in 81 cases (95.3%). the number of detected pathogens was of 0, 1, 2, 3, 4 and 5 in 4 (4.7%), 30 table 2) . from the 85 cases of cap, 4 bacterial exclusive infections were observed (4.7%), 24 infections with at least one bacterium and one virus (28.2%) and 53 viral exclusive infections (62.4%). coinfection by at least two viruses was observed in 37 cases (43.5%). table 3 displays the distribution of the identified pathogens and specifies the various associations, the most common being adv/rsv (10 cases), haemophilus influenzae/adv(8 cases) and hrev/bov (8 cases). the monthly distribution of microbiological infections is depicted in fig. 1. as shown in table 4 , none of the variables tested was statistically correlated to the presence of a bacterial pathogen by univaried analysis, with the exception of age that was higher in the case of documented bacterial infection (mean age of 5.45 vs 3.49 years; p < 0.05 by student t test) and the presence of abdominal pain at clinical examination at entry (p = 0.02). concerning biological parameters, no correlation was observed between bacterial and non-bacterial cases for the most of them, notably for crp and pct, with the exception of the white blood cell count that was higher in case of viral infection. severity was statistically associated neither to the bacterial or non bacterial etiology of cap, nor to a younger age, except in the subgroup of viral exclusive infection (n = 53), in which the mean age of severe cases was 2.0 years vs 3.8 years in mild and moderate cases (p < 0.05 by student t test). coinfection was not associated to a younger age or a more severe disease, even if the number of detected pathogens tended to be related to the severity of cap (2.1 infected agents in severe cases vs 1.7 in non-severe cases, p = 0.09 by student t test). by multivariate analysis, none of the tested variables was independently associated with bacterial infection. the demographic characteristics of the included patients were coherent with those of the literature [6] in terms of age (median age of 2.8 years; interquartile range: 1.5-5.7 years) and sex ratio (1.18 to the benefit of males). those patients with cap were shown to exhibit different risk factors as illustrated by a lower vaccination coverage as compared to that of the french population, an elevated rate of previous hospitalization (17/85, 20 .0%), a history of frequent respiratory disease (26/85; 30.6%) and a high level of smoking habits in parents (table 1) . approximately 4 children out of 5 reached hospital without having consulted another physician; most of them had already received an antipyretic treatment, mainly acetaminophen but also non-steroidal anti-inflammatory drugs (nsaid), despite the fact that the use of nsaid may be harmful [27] . at entry, 95.3% (81/85) of children had received an antimicrobial treatment. in most cases, the first choice for antimicrobial drug was amoxicillin, as currently recommended [4] [5] [6] . despite the limited size of the present study and its restriction to a single center, its originality lies in the diversity of the included table 3 detailed presentation of cases of community-acquired pneumonia exhibiting an infection with at least 2 pathogens. gray boxes indicate the total number of positive cases for each pathogen. white boxes corresponds to the cases with co-infection. from a microbiological point of view, it is first useful to justify the definition of what level of detection constitutes a causative agent in children with cap included in this study. concerning bacterial loads, the threshold of 10 7 cfu/ml was retained as recommended by european experts when induced sputum specimen are used [25] . it helps the discarding of pneumococcal colonization with prevalence of up to 57-65% in children of less than 5 years old [28, 29] from true infection. by contrast, "the asymptomatic carrier state of viruses is rather uncommon for most respiratory viruses [12, 30] , apart from the post active phase of respiratory virosis" [25] , which justifies to consider the detection of viral genome in respiratory specimens as a marker of probable viral infection. in the more exhaustive studies performed earlier, the percentage of elucidated cases from a microbiological point of view ranged from 72% to 86% [6, 11, 30] whereas it was of 95.3% in the present study detecting a wide spectrum of infectious agents with respiratory tropism. as reported earlier [30] , viral infections were shown to be predominant in children under 5 years of age and only 32% of all cap were found to be of bacterial origin. eighteen children received antimicrobial therapy before emergency consultation, which could be considered as a source of false-negative culture. however, all of them were always symptomatic at entry, which implies that a bacterium, if present, had a significant opportunity to be recovered by culture. an interesting finding of this study is the large proportion of viral coinfection (43.5%), much higher than that previously reported [10, 12, 30] , notably for bocavirus, metapneumovirus and adenovirus that were detected in association with at least one other virus in more than 80% of the cap cases involving these agents ( table 2 ). it has been suggested that infection by several viruses could enhance the severity of cap [12, [30] [31] [32] . in the present study, a trend was observed in the association between the mean number of infectious agents and the severity of cap as defined above (p = 0.09); a larger effective size would have been needed to determine a statistically significant difference. in terms of clinical evolution, neither death nor major complications were reported in this study, despite rates of 30.6% for severe pneumonia and 42.4% for hospitalization. there was no statistical difference in the severity of cap between viral and bacterial infections. almost all of the children received antibiotics, which was unnecessary in a large proportion of cases (62.4%) for which only viruses were detected. this finding raises the question of the systematic use of antimicrobials to treat childhood cap, which is still recommended in different guidelines [4] [5] [6] . the present findings, together with those of others, allowed the identification of a subpopulation of children less than 5 years of age with mild or moderate symptoms for which a viral etiology of cap is highly probable. this situation represents half of the cases recorded in this study: 62 children (72.9%) were less than five-years old, and 40 of them presented a mild or moderate cap, which corresponds to 47.1% of all cases. the use of a rapid molecular test detecting a large set of viral and bacterial pathogens within 2 or 3 hours, such as that described in [33] , would allow an improvement in the management of the antimicrobial treatment. in the case of positive result, it would be recommended to avoid the use of amoxicillin as a first-intent therapy (or to prescribe erythromycin in the case of detection of an agent of atypical pneumonia) and to reconsider the use of antimicrobial treatment 24-48 h later according to the clinical evolution and to the results of bacterial cultures. conversely, the negativity of the rapid test would lead to the empiric prescription of amoxicillin, as currently recommended [4] [5] [6] . it is obvious that this attitude would be dedicated to cap with mild or moderate symptoms and that cap with severe presentation at entry should include a systematic probabilistic antimicrobial therapy, whatever the results of pcr assay. the present results are indicative that this strategy could dramatically reduce the proportion of unnecessary antimicrobial treatments in mild or moderate child cap. wider studies are needed to prospectively evaluate the benefits of this approach in terms of patient recovery, prevention of antibiotic resistance and medical economy. the reagents used for the retrospective analysis were funded by a grant from the medical association of pediatricians of the university hospital of saint-etienne for research and studies (aderps), france. from the medical association of paediatrician of the university-hospital of saint-etienne for research and studies (aderps). who estimates of the causes of death in children global, regional, and national causes of child mortality in 2008: a systematic analysis epidemiology and etiology of childhood pneumonia the management of community-acquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america japanese guidelines for the management of respiratory infectious diseases in children 2007 with focus on pneumonia british thoracic society guidelines for the management of community acquired pneumonia in children: update antibiotic therapy for pediatric community-acquired pneumonia: do we know when, what and for how long to treat? breathing new life into pneumonia diagnostics blood culture is poor method of confirming pneumococcus as cause of childhood pneumonia association of human metapneumovirus with radiologically diagnosed community-acquired alveolar pneumonia in young children comprehensive detection of causative pathogens using real-time pcr to diagnose pediatric community-acquired pneumonia viruses in community-acquired pneumonia in children aged less than 3 years old: high rate of viral coinfection etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections etiology of community-acquired pneumonia in hospitalized children based on who clinical guidelines community acquired pneumonia -a prospective uk study epidemiology and clinical characteristics of community-acquired pneumonia in hospitalized children human metapneumovirus and community-acquired pneumonia in children development of three multiplex rt-pcr assays for the detection of 12 respiratory rna viruses role of mycoplasma pneumoniae and chlamydia pneumoniae in children with community-acquired lower respiratory tract infections diagnostic value of tachypnoea in pneumonia defined radiologically comparing nose-throat swabs and nasopharyngeal aspirates collected from children with symptoms for respiratory virus identification using real-time polymerase chain reaction induced sputum in the diagnosis of childhood community-acquired pneumonia development and evaluation of chlamylege, a new commercial test allowing simultaneous detection and identification of legionella, chlamydophila pneumoniae, and mycoplasma pneumoniae in clinical respiratory specimens by multiplex pcr comparative evaluation of six commercialized multiplex pcr kits for the diagnosis of respiratory infections european manual of clinical microbiology pneumonia methods working group, et al. laboratory methods for determining pneumonia etiology in children prevalence and risk factors of suppurative complications in children with pneumonia indirect effect of 7-valent pneumococcal conjugate vaccine on pneumococcal colonization among unvaccinated household members the descriptive epidemiology of streptococcus pneumoniae and haemophilus influenzae nasopharyngeal carriage in children and adults in kilifi district impact of viral infections in children with community-acquired pneumonia: results of a study of 17 respiratory viruses human bocavirus: a novel parvovirus epidemiologically associated with pneumonia requiring hospitalization in thailand unsolved problems in the approach to pediatric community-acquired pneumonia comparison of the idaho technology filmarray system to real-time pcr for detection of respiratory pathogens in children the authors are indebted to the patients' families who gave their consent for participating to this study. philip lawrence is warmly acknowledged for his careful checking of english language. the reagents used for the retrospective analysis were funded by a grant the authors declare that they have no conflict of interest regarding the object of this study. the study was submitted for approval to the local ethics committee. key: cord-323859-rkxgtyoq authors: patel, khushboo title: mental health implications of covid-19 on children with disabilities date: 2020-07-02 journal: asian j psychiatr doi: 10.1016/j.ajp.2020.102273 sha: doc_id: 323859 cord_uid: rkxgtyoq nan teaching children with visual impairments or those who are hard-of-hearing (hills, 2020) . challenges of online learning coupled with a lack of recreational activities that can be done at home can prove to be frustrating for children with such physical disabilities. furthermore, developing social skills and social interaction has been one of the hardest issues for children with autism spectrum disorder (asd). the current situation of social distancing and having no access to outdoor activities deteriorates their development. a lack of routine and the attached uncertainty can make children with autism spectrum disorder (asd) feel more anxious, grumpy, restless, and develop unpleasant feelings. tandon (2020), in their work has rightly pointed out the relation between covid-19 and psychiatry, and vice versa. experiencing negative emotions, changes in moods, and changes in the sleeping and eating patterns of children put them at a greater risk of experiencing relapse of mental illness as well as exacerbating existing mental health issues. with medical care being prioritized for those affected by the pandemic along with closure of mental health clinics serves as a source of stress, anxiety, and fear. for instance, in india, 7.8 million children between 0-19 years of age have a physical or mental disability, and one fourth of them do not attend any educational institute (unesco, 2019). this becomes a cause of concern as there is already a lack of physical infrastructure, inclusive education, and assistive technologies in countries like india. coupled with this, being confined to home during the pandemic leads to an elevated level of frustration and helplessness in such children. on the other hand, united states has seven million children between 3-21 years of age who have been receiving special education classes at school (national center for education statistics, 2020). shifting classes online leads to a dearth of providing special education assistance to children as parents cannot replace special education teachers and there exists a lack of assistive technologies. this impacts development of children as effective communication about sensitive information has long-term effects of psychological wellbeing for a child (dalton, rapa, & stein, 2020) . fear along with insufficient knowledge about the pandemic also leads to a lack of understanding leading to incorrect decision making (tandon, 2020) . thus, caregivers should aim to spend quality time with their children. a system of online clinics and volunteer based psychological interventions should be set up as immediate priority to mitigate effects of covid-19 on children with mental health issues (holmes et al., 2020) . conducting international research on mental health consequences on children with physical and mental disability is of utmost importance to seek long-term solutions to combat this issue. as an immediate remedy, guidelines by unicef providing resources on children with disability during covid-19 can be effectively followed (unicef, 2020). in conclusion, everyday lives for individuals across the globe have been severely affected due to covid-19. amidst this, it becomes important to keep children with physical and mental disability not only physically safe, but also look after their psychological and emotional wellbeing. in particular, social distancing and its effects are extremely novel and difficult to understand for children, especially those experiencing developmental and intellectual delays. this affects their wellbeing and places them at a higher risk for clinically significant mental j o u r n a l p r e -p r o o f resources for supporting children's emotional wellbeing during the covid-19 pandemic protecting the psychological health of children through effective communication about covid-19 the pandemic is a crisis for students with special needs. the atlantic multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science children and youth with disabilities the covid-19 pandemic, personal reflections on editorial responsibility state of the education report for india 2019; children with disabilities leaving no child behind during the pandemic: children with disabilities and covid-19 key: cord-296434-tok2nvyd authors: sakellaropoulou, afroditi; hatzistilianou, maria; eboriadou, maria; athanasiadou-piperopoulou, fanni title: hyponatraemia in cases of children with pneumonia date: 2010-09-07 journal: arch med sci doi: 10.5114/aoms.2010.14471 sha: doc_id: 296434 cord_uid: tok2nvyd introduction: hyponatraemia is the most common electrolyte imbalance seen in clinical practice, and a common laboratory finding in children with community-acquired pneumonia (cap). this study aimed to identify the incidence of hyponatraemia in cases of cap, to find predictive tools in order to classify the severity and outcome of cap and to explore possible differences of clinical importance between the two sexes. material and methods: the medical files of 54 children (66.4% males), 4.67 ±2.88 years old, were retro-prospectively reviewed. results: 35/54 (64.8%) children with pneumonia had normal values of sodium at admission, 18/54 (33.3%) had mild hyponatraemia and 1 child (1.9%) moderate hyponatraemia. increased heart rhythm and tachypnoea at admission were correlated with lower values of sodium (z= −2.664, p = 0.007 and z = −1.705, p = 0.089 respectively). no differences were found between the two sexes concerning the characteristics of pneumonia or the range of sodium in serum at admission. a correlation was found between sodium admission values and: a) c-reactive protein (p = 0.000), and b) leukocyte count (p = 0.006). sedimentation rate (p = 0.021) was also considered as a possible risk factor affecting the value of sodium at admission to hospital. finally, a negative association was also observed between the degree of hyponatraemia and the duration of hospitalization (z = −3.398, p = 0.001). conclusions: although studies in larger population groups are needed, in our study increased heart rhythm, tachypnoea, leucocyte count, c-reactive protein, and also erythrocyte sedimentation rate could be considered as possible risk factors influencing the degree of hyponatraemia, and thus the outcome of hospitalized children with cap. hyponatraemia (hn, serum sodium < 135 meq/l) is the most common electrolyte imbalance seen in clinical practice, and also in critically ill children [1] . it is present in approximately 3% of hospitalized patients [2] . mild to moderate hn and severe hyponatraemia are found in 15-30% and 1-4% of hospitalized patients, respectively [3] . pathophysiologically, hns are classified into two groups: hn due to nonosmotic hyper-secretion of vasopressin (hypovolaemic, hypervolaemic, euvolaemic) and hn of non-hypervasopressinaemic origin (pseudohyponatraemia, water intoxication, cerebral salt wasting syndrome) [3] . first, in 1920 it was shown that many children with pneumonia retain water [4] , which has been found to be associated with an increased blood volume and a low plasma chloride value [5] . these findings are explained by the syndrome of inappropriate secretion of anti-diuretic hormone (siadh), which has been described in children with pneumonia [6] , and meningitis [7] . it was found that hn frequently accompanies pulmonary diseases, infectious and also neoplastic [8] . hyponatraemia is considered a common laboratory finding in children with communityacquired pneumonia (cap), which can be defined clinically as the presence of signs and symptoms of pneumonia in a previously healthy child due to an infection which has been acquired outside hospital [9] . few studies, though, explore the correlation of hn and pneumonia in children [10] . based on the published studies, the severity of cap and hn due to cap are associated with the need of hospitalization, the presence of prolonged and high fever, and elevated serum non-specific inflammatory markers, such as serum c-reactive protein (crp) and serum procalcitonin [9] . moreover, lower respiratory infections (lris), including acute lower respiratory tract infections, pneumonia, atypical pneumonia, bronchitis, bronchiolitis, and severe acute respiratory syndrome (sars), continue to threaten the health of children worldwide and especially in developing countries, where poor nutrition prevails and access to health care is scarce [11] . therefore, the purpose of this study was to identify the incidence of hyponatraemia in children with cap, to find predictive tools in order to classify the severity and outcome of cap and also to explore possible differences of clinical importance between the two sexes. the files of children hospitalized due to pneumonia in the 2 nd department of paediatrics, medical school, aristotle university of thessaloniki, were retroprospectively reviewed. participants in the study were chosen randomly from those that were hospitalized from january 2008 to may 2009. information on sociodemographic variables including child's age and gender, and also clinical features of pneumonia, such as the presence and duration of fever, cough, nasal congestion, thoracic or abdominal pain and the duration of hospitalization were also recorded. moreover, laboratory examinations, including nonspecific markers of inflammation, such as white blood cells (wbc), erythrocyte sedimentation rate (esr), crp, and also biochemical exa minations (including electrolytes, liver and kidney function) were performed in order to find possible predictors of pneumonia's severity and outcome. in order to be more specific sodium (na), potassium (k), urea (ur), creatinine (cr), glucose (glu), serum glutamic oxaloacetic transaminase (sgot) and serum glutamate pyruvate transa minase (sgpt) were measured. moreover, laboratory examinations were done at the admission of the child to the hospital, irrespective of the time of admission. since there was no control group to correlate our findings, the study group was subdivided into two groups based on patients' gender. hyponatraemia was defined as a sodium level of < 135 mmol/l in serum [12, 13] . the severity of hn was determined by the reports of ellison and berl [8] . serum concentration of 131-135 mmol/l means mild hn, 126-130 mmol/l means moderate hn, and ≤ 125 mmol/l means severe hn [2] . hypernatraemia was defined as a serum sodium concentration > 145 mmol/l [2] . the statistical analysis was performed using spss 12.00 for windows (spss inc, chicago il). frequencies and descriptive statistics were used primarily in order to describe the sample's overall attitudes. the distribution of the population in various groups was described by mean value ± standard error (se). χ 2 test and fisher's exact test were used for qualitative variables in order to calculate p values, while regression analysis was used for quantitative variables. student's t-test or one-way analysis of variance (anova) was used for normally distributed variables, while the mann-whitney test was used for variables not normally distributed. values of p < 0.05 were considered as significant. the study population consisted of 54 children, 0.20-12.0 years old (mean ± se: 4.67 ±0.39 years). there were 32 males (59.25%) and 22 females (40.75%). the duration of their hospitalization was 2.0-15.0 days (mean ± se: 5.42 ±0.42 days). the majority of them presented cough (44/54, 81.50%), and fever (53/54, 98.15%). admission body temperature was variable, ranging between 36.2°c and 41.0°c (mean ± se: 37.96 ±0.17°c). fever was present for 0-15 days (4.24 ±0.43 days) before entrance to the hospital, and lasted for 0.0-11.0 days (2.75 ±0.27 days) after admission day. moreover, cough was present 0.0-10.0 days before hospitalization (mean ± se: 4.10 ±0.43 days) in children with pneumonia. nasal congestion and abdominal pain were described in about one third of them (16/54, 29.60% and 17/54, 31.50% respectively). thoracic pain and vomiting were recorded only in 9/54 (16.70%) and 5/54 (9.25%) of them respectively. one third of the children with pneumonia had previously received antibiotics (18/54, 33.33%). seven children developed pleural effusion. the outcome of all patients was favourable. laboratory values of both sexes are presented in table i. there were no statistically significant differences between age of hospitalized children with pneumonia and their sex (p = 0.25) or the presence of abdominal pain (p = 0.27). however, older children (mean age ± se: 6.93 ±1.11 years) more often (p = 0.01) present thoracic pain compared with younger ones (mean age ± se: 4.22 ±0.38 years). moreover, there was no statistically significant difference between the duration of hospitalization and the presence of thoracic (r = -0.96, p = 0.33) or abdominal pain (z = -1.04, p = 0.29). a correlation was found between the duration of hospitalization: a) and the duration of fever after admission (p = 0.004), and b) the value of crp at admission (p = 0.00). there was also a correlation between the value of serum sodium at admission and erythrocyte sedimentation rate (p = 0.02). furthermore, crp value and leukocyte count were correlated with admission value of sodium in serum (p = 0.00 and p = 0.006 respectively). finally, there was a negative association between the degree of hyponatraemia and the length of hospitalization (z = -3.39, p = 0.001). correlations were also performed between the two sexes concerning their age, days of hospitalization, body temperature at admission (°c), duration of fever before and after admission, duration of cough, respiratory and heart rate at admission, sato 2 (%) and the value of serum sodium at admission. no statistically significant differences between the two groups were found (table ii) . hyponatraemia could result from a sodium deficit, or surplus of water. primary illness, impaired water excretion, "inappropriate" release of vasopressin, use of hypotonic fluids, redistribution of sodium and water, sickle cell syndrome, and several drugs may contribute to hyponatraemia [3, 14] . hyponatraemia is a frequent finding in children with pneumonia. usually, it comprises part of the syndrome of inappropriate siadh [10, 15, 16] . secretion of anti-diuretic hormone typically results in water retention with minimal weight gain, usually with no oedema formation, and normal blood pressure [10] . according to studies, siadh occurs in about one third of children hospitalized for pneumonia, and was associated with a more severe disease and a poorer outcome [10] . few studies exist concerning the correlation of hn and pneumonia in children. it was first described by stormont and waterhouse in 1962 [17] . since then and during the past 35 years, only case reports and a few relevant studies on the association between hn and pneumonia have been published, of which only three concern children [10, 18, 19] . community-acquired (cap) and nosocomial pneumonias contribute substantially to morbidity and hospital resource utilization [20, 21] . hyponatraemia, occurring in more than 1/4 of patients with cap, is associated with greater disease severity and worsened outcomes [20] . in the present study, only 33.33% of children had mild hyponatraemia and 1 child (1.90%) moderate hn. moreover, children with more severe hn had a longer duration of hospitalization (z = -3.40, p = 0.001), findings that are consistent with previously published data [20] . hyponatraemia is usually mild in children with cap [9] . it seems that high atrial natriuretic peptide levels (anp) may play a role [15] . atrial natriuretic peptide is a member of the family of natriuretic peptides, and regulates a variety of physiological parameters, such as diuresis and natriuresis, and reduces systemic blood pressure. it is synthesized and secreted from cardiac atria [15] . increased levels of anp were found in diseases affecting the lungs. over-secretion of anp is correlated with hypoxia, which leads to pulmonary vasoconstriction, pulmonary hypertension, and right-heart overload [22, 23] . severe hn is rare in children with cap, as in our study where only one child presented a moderate degree of hn (1%). this can be explained by the observations of haviv et al. [15] . according to them, the anp through its natriuretic, diuretic and vasodilatatory effects may contribute in maintaining water and electrolyte balance in children with pneumonia and siadh. gerigk et al. [24] found that adh may cause hn that may originate by a nonosmotic, cardiovascular mechanism in acutely ill children, including children with pneumonia. based on studies, symptoms and signs indicative of severe pneumonia were two to three times more frequent and the mean duration of tachypnoea, chest wall retraction and hospital stay about 50% longer in children with hn [10] . in the present study, children with increased heart rhythm and tachypnoea at admission presented lower values of sodium (z = -2.66, p = 0.007 and z = -1.70, p = 0.089 respectively). the analysis of non-specific inflammatory markers (crp, wbc, esr) has shown a significant association between the presence of hn and elevated levels of wbc [9] . a significant association also exists between hn and fever, increased wbc count and crp levels and the need for hospital treatment. all these parameters reflect the severity of pneumonia, but without taking into consideration the radiological pattern of pneumonia or the length of hospital stay and the aetiological agent [9, 25] . in our study there was also a correlation between leukocyte count (z = -2.010, p = 0.04), sedimentation rate (z = -2.42, p = 0.01), crp (z = -3.76, p = 0.00), and levels of sodium at admission to hospital. it should be pointed out that no statistical associations were analysed between pct and other factors/markers, since only in a few children with pneumonia (fewer than ten) was pct measured at admission to the hospital. hyponatraemia, the most common frequent electrolyte derangement identified among hospitalized patients, is associated with worsened outcomes in patients with pneumonia, heart failure and other disorders [26] . hyponatraemia is common among hospitalized patients with pneumonia and is associated with worsened clinical and economic outcomes and indicates a poor prognosis [20, 25] . a recent single-centre cohort study found the incidence of hn at hospital admission among cap patients to be 28% [26] . it is important to emphasize that the presence of hn was associated with not only prolongation of hospitalization (hlos), but also with an increase in hospital mortality [20] . in our study, children with hn at admission had longer hos pitalization times and a prolonged duration of fever, although their final outcome was favourable, including cases that developed pleural effusion. although no differences were found in our study between the two sexes concerning the characteristics of pneumonia or the range of serum sodium at admission (table ii) , it is important to emphasize the originality of our study since no data exist as far as we could find by checking electronic resources on this topic. in conclusion, our findings further confirm the fact that mild hn is common among hospitalized patients with pneumonia and influences hospital length of stay. thus, it contributes to increased morbidity rates and probably adds to the costs of care. however, a limitation of the study was the relatively small size of our study group, since only one child with pneumonia had moderate hn. thus, studies in larger population groups are needed in order to evaluate whether the degree of hn could impact the outcome of hospitalized children with cap and whether sex is a risk factor for the development of hn in cases of children with pneumonia. the evaluation of the severity of cap should include clinical markers, such as heart rate and respiratory rate, and also biochemical indexes, such as leukocyte count, esr, crp and serum levels of sodium. re f e r e n c e s hyponatremia: a prospective analysis of its epidemiology and the pathogenic role of vasopressin disorders of water metabolism in children: hyponatremia and hypernatremia diagnostics and therapy of hyponatremias water retention in pneumonia chemical changes occurring in the body as a result of certain diseases. iv. primary pneumonia in children inappropriate secretion of anti-diuretic hormone in infants with respiratory infections the syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis clinical practice. the syndrome of inappropriate antidiuresis hyponatremia in pediatric community-acquired pneumonia hyponatraemia and the inappropriate adh syndrome in pneumonia coronaviruses oc43 and 229e lower respiratory tract coinfections: a clinical report of two cases pathogenesis and diagnosis of hyponatremia the syndrome of inappropriate antidiuresis atrial natriuretic peptide in children with pneumonia the syndrome of inappropriate secretion of antidiuretic hormone severe hyponatraemia associated with pneumonia hyponatraemia associated with pneumonia or bacterial meningitis hyponatremia in community-acquired pneumonia hyponatremia and hospital outcomes among patients with pneumonia: a retrospective cohort study pulmonary abscesses -aetiology and treatment. ten-year experience of the department of general and thoracic surgery in lodz, poland natriuretic peptides, respiratory disease, and the right heart the natriuretic-peptide family arginine vasopressin and renin in acutely ill children: implication for fluid therapy hyponatremia in community-acquired pneumonia epidemiology, clinical and economic outcomes of admission hyponatremia among hospitalized patients key: cord-034340-3ksfpaf7 authors: nan title: proceedings of the 26th european paediatric rheumatology congress: part 2: virtual. 23 26 september 2020 date: 2020-10-28 journal: pediatr rheumatol online j doi: 10.1186/s12969-020-00470-5 sha: doc_id: 34340 cord_uid: 3ksfpaf7 nan introduction: juvenile idiopathic arthritis (jia) represents the most common pediatric chronic rheumatic disease. children with jia present an increased risk of infections, due to the immune-regulatory effects of disease modifying antirheumatic drugs (dmards); many of these infections are vaccine-preventable. nevertheless, suboptimal vaccinations rates are reported in children with jia. objectives: to evaluate vaccination coverage in a population of children with jia and to describe the prevalence of the adverse events following immunization (aefis) in our cohort. methods: a single-centre retrospective study was conducted by reviewing medical records of all jia patients, diagnosed according to ilar criteria, admitted to the pediatric rheumatology unit of university of naples federico ii from january to december 2019. parents were asked to provide the vaccinations records in form of the vaccination booklet. the occurrence of aefis was explored by telephone interviews. introduction: intrarticular corticosteroid injections (iaci) are widely used in the management of patients with juvenile idiopathic arthritis (jia). general anesthesia can be avoided in case of a small number of joints to inject or in older children. however, pain and anxiety may reduce the patient compliance to iaci, and may compromise the accuracy of the procedure. in order to overcame such problems, the use of appropriate methods of pain and anxiety control is advisable. objectives: to assess the effectiveness and satisfaction of patients undergoing iaci with the use of topical numbing agent or under minimal sedation. methods: patients with jia who underwent an iaci of up to 3 joints were recruited. depending on age and number of joints to treat, a group of patients (group a) were injected with the application 30 minutes prior the procedure of a topical numbing agent (prilocaine+lidocaine) to the skin over the injection site. another group of patients (group b) were treated under minimal sedation (ketorolac/tramadol or morphine + midazolam). the physician was asked to record the degree of motion and pain of the patient during the procedure and the patient (or parents for patients aged less than 4 years) was asked to report the degree of pain and satisfaction on a visual analogue scale (vas) from 0 to 10. results: twenty-seven patients were enrolled for a total of 30 procedures, 17 and 13 of them in group a and b, respectively. the median age at the procedure was 10 years for group a and 11 years for group b. for group a median pain scores for patients, parents and physicians were 2, 2 and 1.5, respectively. in patients of group b who underwent the iaci under ketorolac/tramadol the median pain scores for patients, parents and physicians were 3, 5.25 and 2.5, whereas in patients treated with morphine median pain scores were 6, 6 and 2, respectively. overall, we found that pain as reported by the patient/parent were higher with increase in the number of sites injected (and, consequently, duration of procedure) and age of patient. amount of motion during procedures was overall negligible. the majority of patients/parents was satisfied for the procedures. only 2 patients treated with midazolam had psychomotor agitation during the iaci. conclusion: iaci in a small number of sites without the use of general anesthesia is well tolerated by patients. the level of pain perceived from patients is irrespective of the power of the painkiller used, but seems to correlate with the duration of the procedures. it is possible that, in the paediatric age, the psychoemotional component seems to be decisive, with a progressive loss of tolerance with the increase in the number of injected joints. for gc-ms analysis of the steroid hormone metabolites age and sexmatched healthy controls were matched to each patient. patients were excluded if they were treated with corticosteroids in the preceding 3 months. results: of the 35 metabolites measured, 23 were significantly lower in jia patients before the etanercept treatment compared to the healthy control group. one day after the injection only 5 metabolites were still significantly lower in the jia patients and all the other 30 metabolites normalized and were similar to the control group. urine metabolite ratios reflecting cyp21 and 11β-hsd2 enzymatic activity indicate that these two enzyme activities were lower in jia patients. the slowest recoveries noted were for metabolites of dheas and 17 oh pregnenolone. conclusion: prior to etanercept treatment almost all urine adrenal metabolites were significantly lower mainly due to the active inflammatory process. immediately after the treatment many metabolites raised to normal values as in the control group. the two adrenal enzymes that were found to be affected in jir are cyp21 and 11β-hsd2. blocking tn alpha immediately restore adrenal function in jia. introduction: patients with juvenile idiopathic arthritis (jia) receive adalimumab treatment. adalimumab is a monoclonal antibody that blocks tnf-α and is structurally and functionally similar to human igg 1 . nevertheless, there are reports of the development of anti-drug antibodies. the production of these antibodies may be associated with treatment failures (a decrease in the effectiveness of therapy or drug inefficiency that developed over time) and hypersensitivity reactions. to our knowledge, there is currently limited information on the availability of adalimumab antibodies (aaa) in patients with jia. objectives: to evaluate the prevalence rate and the clinical significance of aaa in patients with jia on adalimumab treatment. methods: 26 patients with jia were examined, 17 of whom had the oligoarticular form of the disease, 7 of them with uveitis, and 9 patients had the polyarticular form of the disease, 3 of them with uveitis. among them, there were 13 (50%) girls and 13 (50%) boys. the mean age was 11.0 ± 3.4 years; the mean disease duration was 4.1 ± 2.2 years. patients received adalimumab (at least 1 year before the study) with concomitant administration of methotrexate (mtx) or adalimumab only -13 children who did not receive mtx for at least 3 months prior to the study as a result of either adverse events of mtx administration (5 patients) or permanent drug remission (8 patients). before starting adalimumab therapy, all participants were treated with mtx. the mean duration of adalimumab treatment for these patients was 1.8 ± 1.0 years. the serum aaa level of antibodies was determined using the enzyme immunoassay (eia) method. this method determines both free and bound antibodies to adalimumab at reference values less than 10 au/ml. a and was used every 2 weeks for 3 months. the values were presented as mean ± standard deviation. data processing and analysis were carried out using pearson's chi-squared test and spearman's correlation test. results: 8 (31%) of the 26 patients enrolled in the study had aaapositive results. the mean aaa level in positive patients was 40.8 ± 20.1 au/ml. further disease relapses tended to occur significantly more often in aaa-positive patients than in aaa-negative ones (χ2 = 5.46, p = 0.019). thus, 5 of 8 (62.5%) aaa-positive children had at least 1 exacerbation of the disease within 3 months, compared with 3 of 18 (16.7%) in aaa-negative ones. 7 out of 8 (87.5%) aaapositives did not take mtx for at least 3 months compared to 6 out of 18 (33.3%) in aaa-negative ones. thus, aaas are found to be significantly more frequent without concomitant administration of mtx in the treatment of jia (χ2 = 6.5, p = 0.01). there were no observed adverse events or side effects during adalimumab therapy. no significant correlation was found between the presence of aaa and sex, introduction: advances on molecular medicine, illumination of the cytokine network and the immune pathways shed light on the etiopathogenesis for a better understanding of juvenile idiopathic arthritis (jia). however, the fact that the course of the disease differs individually strongly suggests the effect of external factors. objectives: the current study was undertaken to evaluate sociodemographic and sociocultural features, parent behavior, the gestation and breastfeeding period, nutritional status of early childhood in our patients with jia, and to determine their relationship with disease activity, damage index, remission time, and relapse rate. methods: the study was conducted with a face-to-face questionnaire method with the parents of 171 patients with jia and 183 healthy children. the medical patient records were reviewed. juvenile arthritis disease activity score (jadas) 27, wallace clinical inactive disease criteria, juvenile arthritis damage index (jadi), and relapse rates were used to assess the general medical condition of each patient. results: the median age of jia patients (n = 171) was 13 (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) , with a female ratio of 59,1%. age at disease onset was 7 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) years. the first remission time was 5(1-17) months. the patients were evaluated according to disease subtypes and treatment modalities. there was no difference in the duration of breastfeeding according to the distribution of the subtypes (p = 0,97). when the breastfed and formula-fed patients were compared, there was a marginally significant difference in terms of first remission time (p = 0,05), whereas there was a significant difference in relapse rate in patients who introduced to cow milk early (<12 months) (p = 0,019). the early risk factors and their relationship with the disease are presented in table 1 . both breastfeeding durations and maternal literacy levels showed a significant difference in terms of relapse rates (p = 0,01; p=0,03, respectively). there was no significant difference in breastfeeding durations and gestational risks between the patients and the healthy group (p = 0,1; p= 0,65), respectively. however, the smoking rate among family members was significantly higher in the patient group (p = 0,03). conclusion: in patients with juvenile idiopathic arthritis, breastfeeding rate and duration did not differ when compared to healthy controls. however, breastfeeding duration, cow's milk commence age, and maternal literacy appeared to be relevant to the relapse rates. going to preschool both influence the remission time and relapse rate. these findings suggest a role for parental attitude and nutritional status during early childhood in the course of jia. none declared introduction: immunogenicity and low trough concentrations have been associated with adalimumab treatment failure in several studies of paediatric inflammatory diseases, indicating the possible value of therapeutic drug monitoring (tdm). adalimumab efficacy may be improved by changing dose or treatment intervals based on drug concentrations. however, lack of standardization, assay heterogeneity, and paucity of research hinder the implementation of tdm in clinical practice. objectives: to assess the relationship of trough concentrations, immunogenicity and adalimumab response in paediatric patients with jia. methods: monocentric cohort study of patients ≤18 years with jia treated with adalimumab due to active arthritis. clinical data and plasma samples were collected during routine follow-up. adalimumab trough concentrations were measured by liquid chromatographytandem mass spectrometry (lc-ms/ms). anti-adalimumab antibodies were measured in samples with trough concentrations <5mg/l. disease activity was evaluated using the clinical juvenile arthritis disease activity score with 71 joint count (cjadas71). response to adalimumab was defined as at least 50% reduction of disease activity within 3 months of therapy followed by clinical inactive disease or minimal disease activity after 6 months. the latter was defined as cjadas71 ≤1.5 and ≤2.5, for oligoarthritis and polyarthritis, respectively, or an active joint count equal to zero when cjadas71 was unavailable. results: 36 adalimumab trough samples were available from 35 jia patients. although there was no significant difference in median adalimumab dose, trough concentrations were significantly lower in patients with secondary failure compared to primary failure or an adequate adalimumab response (p-values <0.01). in addition, there were 11 samples with trough concentrations <5mg/l, 9 in the group with secondary failure and 2 in the group with adequate adalimumab response (table 1) . conclusion: adalimumab trough concentrations were significantly lower in jia patients with secondary failure compared to primary failure or an adequate response to adalimumab. anti-adalimumab antibodies were present in 8 out of 11 samples with trough concentrations <5mg/l. adalimumab trough concentration measurements may identify jia patients that would benefit from increased doses or shorter treatment intervals. in addition, jia patients with primary failure and adequate adalimumab trough concentrations may respond better to biologic agents with other therapeutic targets. although biologic agents have improved disease outcome of patients with jia, concentration measurements using reliable and cost-effective methods, such as lc-ms/ms, could further improve efficacy of biologic agents and guide treat-to-target strategies. introduction: most studies of physical fitness (pf) in juvenile idiopathic arthritis (jia) have shown decreased levels of maximal oxygen consumption (vo 2 max) compared to healthy peers. in jia, boys have higher pf-levels than girls and younger children have higher levels than adolescents, congruently with data of healthy peers. previously, we have shown that more than half of jia-patients had below normative average of vo 2 max. however, monitoring physical activity (pa) using accelerometry, 68% of boys and 39% of girls with jia fulfilled the recommendations of who of ≥1 hour of pa per day, which was comparable to normative values (61%/39%). moreover, patients reporting engagement more than 7 hours per week in club-sports exceeded accelerometry values of healthy peers. objectives: to explore the association between pf and specific sport habits in 10 to 16-year-old jia-patients, related to gender, bmi, disease activity, and pain, and comparing the most fit quartile (q4) of patients (respectively boys and girls) to the least fit quartile (q1). methods: sixty patients with jia performed an indirect ergometertest of vo 2 max (watt max test) and answered the physical activity and sport questionnaire (pasq). objective pa-monitoring for one week was conducted using the gt1m accelerometer. cut-offs for moderate-high and high intensity pa were set to >1000 and >2500 counts per minute, respectively. disease activity was assessed with the jadas-27, current pain and worst pain last week were measured on visual analogue scales (vas) and in a one-week pain diary using the faces pain scale-revised (fps-r). results: girls with jia (n=36) had lower mean pf than the boys (n= 24) (36.5±8.2/43.4±6.73 ml/kg/min), being below normative values, respectively. in both genders the most fit boys and girls (q4; 49.3-57/ 40.9-54) had average to well-above normative average pf. the least fit boys (q1; 33.5-37.4) all had pf-levels well-below normative average. in girls q1-levels (18.7-30.9) were well-below to below normative average. we found significant differences between most fit (q4) and least fit (q1) patients regarding patient´s global wellbeing (p=0.040) and pain diary (p=0.026). these differences were not significant when separating genders, though differences were more pronounced in girls. the least fit girls (q1) had significantly higher disease activity (jadas-27) than the most fit girls (q4)(p=0.019). the most fit boys and girls (q4) engaged equally in high intensity sports (soccer: 3/24; 2/36, handball: 0/24; 2/36, gymnastics: 2/24; 4/ 36, rowing: 1/24; 0/36). however, more boys than girls played soccer (11/24; 3/36), whereas more girls preferred sports of lower intensity (riding: 8/36; 0/24). eight of 11 boys in soccer and 2 boys in gymnastics or rowing had below average to well-above normative average of pf (q3+q4: 41.6-57). three girls in gymnastics, 2 girls in soccer, and 2 girls in handball were in q4 (40.9-54) with levels of average to well-above average pf. the third girl in soccer was in q2 (31-36.3) with levels of well-below to below normative average. none of the riding girls were in q4 and only 1 was in q3 (36.3-40.8) (below to average normative pf). comparing accelerometer-monitored values of pa-intensity in girls with low (q1) and high (q4) pf, pavalues of q1 were significantly lower than in q4. the same tendency was observed in boys, but not to significance. conclusion: our results are in accordance with most other studies of pf in jia, adding to the knowledge of gender-specific differences in pf and type and behavior in sport activities. it emphasizes the need of regular pf-testing and guidance in high intensity pa and sport in order to improve pf and avoid the risks of inactivity and lifestyle diseases in jia. pg/ml), which also showed the highest the frequency of detection of its increase. it was absent in sjia (7.52±4.74 pg/ml). the highest values of il-17r (1849836.4±176751 pg/ml) were in the middle age group. the data obtained suggest the compensatory value of increasing il-17r and the simultaneous initiation of inflammatory and anti-inflammatory processes during exacerbation of jia. assessment of the ratios of stimulating and inhibiting cytokines showed in patients with uveitis, the ratio of ifn-γ/il-1β (4379.29 ±476.83) was higher than with other jia (from 60.84 ± 14.92 in ojia to 105.20± 66.01 in pjia) and ifn-γ/il-17r (4474.01 ±3899.19 versus from 20.14± 11.48 in ojia to 934.55±931.37 in sjia). an increase of il-1β/il-17r ratio was characteristic only for sjia (34.12±26.17). all of these ratios increased with disease activity (r=0.22-0.37) & they did not reflect the unpleasant course of the disease. methods: in this multicenter, case-control study, 113 fecal samples were collected from 91 children with jia, with 72 of these samples collected from untreated children (67 of whom were treatment-naïve children). samples from 28 children with jia were collected during treatment with mtx as single treatment and samples from 13 children during treatment with etn. of those 13 children, four were treated with etn as single treatment and nine had a combination of etn and mtx. we compared 28 children on single treatment with mtx with 57 untreated children (52 treatment-naïve), and 13 children on treatment with etn (nine in combination with mtx) with 62 untreated children (57 treatment-naïve). we also did pairwise comparisons of samples taken before any medication was given (n = 22) and samples taken during ongoing treatment with mtx (n = 14) or etn (n = 8, four in combination with mtx). the microbiota was characterized by sequencing amplicons from the v3 and v4 regions of the 16s rrna gene. alpha diversity of the fecal samples was measured using the chao-1 index and the shannon diversity index. to compare these indices between treated children and untreated children, we used a logistic regression model with age at sampling as a covariate. for pairwise analyses, we used the wilcoxon signed-rank test. to analyze the community composition of the microbiota, principal coordinate analysis (pcoa) plots based on bray-curtis distances were generated for visual comparisons, and analysis of similarity (anosim) was used to test for differences. analyses for relative abundances of taxa were performed at three taxonomic levels (phyla, families, and genera), and logistic regression with age as a covariate was used for calculations of differences between treated and untreated children, while the wilcoxon signedrank test was used for pairwise comparisons. significance was set to p < 0.05 and corrections for multiple comparisons were made using the benjamini-hochberg method. results: analyses showed no significant differences in α-diversity between children treated with mtx or etn and untreated children, and pairwise comparisons of samples before and during treatment with mtx or etn also showed no differences. pcoa plots for children treated with mtx or etn, in comparison with untreated children, did not show any clustering. anosim showed no significant differences between treated and untreated children. pcoa plots were also made for the pairwise comparisons of children sampled before and during treatment, and according to that analysis the community compositions of microbiota did not change in any uniform way during treatment with either mtx or etn. furthermor, analyses of relative abundances of specific taxa did not reveal any significant results in any of the comparisons, after adjustment for multiple analyses. conclusion: treatment with mtx or etn did not alter the composition of fecal microbiota in children with jia. introduction: juvenile idiopathic arthritis (jia) is the most common rheumatic disease in childhood and an important cause of shortterm and long-term disability if patients are not treated appropriately. by definition, jia clinically presents with peripheral joint inflammation of unknown origin, persisting for at least six consecutive weeks and starting before the age of 16 years. the predominant subtypes, i.e. oligoarticular (oligo) and polyarticular (poly) jia, have long been assumed autoimmune diseases caused by dysregulation of the adaptive immune system, with a central role for autoreactive t cells belonging to the th1 and th17 lineages and autoantigens that may include aggrecan, fibrillin, matrix metalloproteinase (mmp)-3 and heat shock proteins. nevertheless, the original t cell-centered hypothesis has been challenged since it does not cover nor completely explain the full spectrum of immune-pathological phenomena observed in patients. lien.desomer@uzleuven.b objectives: emerging evidence suggests a potentially important role for neutrophils in jia pathogenesis. here, we investigated extensively the phenotypical features of neutrophils present in the peripheral blood and inflamed joints of jia patients. methods: synovial fluids and parallel blood samples from patients with oligo-or polyjia and blood samples from healthy children were collected. multicolor flow cytometry panels allowed for in-depth phenotypical analysis of neutrophils, focusing on the surface expression of adhesion molecules, activation and maturation markers, chemoattractant-and toll-like receptors. multiplex technology was exploited to quantify pro-and anti-inflammatory cytokines in plasma and synovial fluids. results: the vast majority of synovial fluid neutrophils displayed a strongly activated, hypersegmented phenotype with decreased lselectin (cd62l) expression and increased numbers of nuclear lobes, upregulation of adhesion molecules cd66b, cd11b and cd15 and downregulation of chemokine receptors cxcr1/2. an elevated percentage of cxcr4-expressing aged neutrophils was detected in synovial fluids from patients. strikingly, significant percentages of synovial fluid neutrophils showed a profound upregulation of atypical neutrophil markers, including cxcr3, icam-1 and hla-dr. conclusion: our data indicate that neutrophils present in inflamed joints of jia patients are strongly activated cells with elevated proinflammatory and antigen presenting potential. this detailed molecular analysis supports the notion that a complex intertwining between these innate immune cells and adaptive immune events drives jia. none declared the main factors, associated with incomplete vaccination againts measels, parotitis, rubella and diphtheria in 170 juvenile idiopathic arthritis patients n. lyubimova 1 , i. objectives: the aim of our study was to evaluate the rate and the main factors of incomplete vaccination against measels,parotitis, rubella (mmr) and diphtheria in jia patients. methods: in the present study were included data 170 jia(55 boys and 115 girls)aged from 2 to 17 years,who received scheduled vaccination before the age of 2 years and before jia onset against measles,parotitis,diphtheria and rubella.incomplete vaccination means the reduced number of vaccine to age.in all patients the ig g anti-vaccine antibodies levels were detected with elisa.jia categories were:oligoarthritis -73,polyarthritis -61,systemic-16 and enthesitisrelated arthritis-20.data presented with median and 25%>75% results: incomplete vaccination against mmr was in 50 (42%)diphtheria in 85 (50%) of the jia patients. the main differences in the studied groups are in the table.there were no differences in sex,jia categories and treatment, except biologics compare to complete and complete vaccination in all vaccines.no differences in antimeasels(p=0.18),antiparotitis (p=0.1) and anti-rubella(p=0.17)vaccination between complete and incomplete vaccination group.number of patients with protective level of anti-vaccine antibodies was similar, except parotitis(70% vs 84.2%, p=0.035).the anti-diphtheria antibodies igg level was lower in the patients with incomplete vaccination group (0.07 iu/ml [95%ci:0.03; 0.22] vs 0.2 [95%ci:0.06; 0.4], p=0.001)as well as number of patients with protective level(34% vs 54%, p=0.002). in the multiple regression model only jia onset age(p=0.00001)and methotrexate treatment duration(p=0.003) were predictors of incomplete vaccination against mmr and methotrexate treatment duration(p=0.005) and biologic treatment(p=0.05) for diphtheria incomplete vaccination.incomplete mmr vaccination influence on the maintenance of the protective anti-parotitis level(p=0.036)in regression model.in correlation analysis the number of vaccination influences on anti-diphtheria antibodies level(p=0.017)and number of patients with protective level of anti-diphtheria antibodies(p=0.017). the main predictors in logistic regression for incomplete vaccination for mmr were:onset age<6 years(or=7. 8 conclusion: younger onset of jia age, longer duration of jia and methotrexate treatment, biologics and more than 1 biologics are the main predictors of incomplete vaccination againt mmr and diphtheria. introduction: the prevalence of autoimmune thyroid disorders (aitd) has been reported to be higher in patients with juvenile idiopathic arthritis (jia) in comparison to the general population. nevertheless, there is a lack of studies investigating risk factors for aitd development in children with jia. objectives: to investigate the co-occurrence of jia and autoimmune thyroiditis in southern italy and to identify potential predisposing factors to anti-thyroid antibodies (ata) positivity in a jia population. methods: a single-centre retrospective study was conducted. all jia patients admitted to the pediatric rheumatology unit of the university of naples federico ii, from january 2001 to december 2019, tested for ata at least once and with a minimum of 6-months follow-up, were included. for each patient, demographic, clinical and laboratory data were extracted from clinical charts. differences between patients affected by jia with or without ata were analyzed. results: three hundred thirty jia patients (247 females; median age 12.5 years, iqr 9.1-16.1) were included in study. median age at jia onset was 4 years (iqr: 2.2-7.8). twenty-three patients [7% (95% ci 4.5-10. 3)] presented ata positivity. twenty-one of them (91.3%) were females. anti-thyroperoxidase was positive in 18/23 patients (78.2%) while 12 patients presented anti-thyroglobulin positivity (52.1%). both antibodies were present in 8/23 (34.8%). 19 patients showed the typical ultrasound findings of autoimmune thyroiditis, resulting in a prevalence of hashimoto's thyroiditis of 5.7% (95% ci 3.5-8.8) in our cohort. three female patients developed subclinical hypothyroidism, whereas one male patient presented subclinical hyperthyroidism. the remaining 19 patients were euthyroid. no statistically significant difference was observed in regard to age of jia onset, follow-up duration and jia subtype between the patients with or without ata. the proportion of females was marginally significantly higher (p=0.059) in the group with ata positivity compared to children without thyroid antibodies (91.3% vs 73.6%, respectively). 56.5% of patients with ata showed ana positivity compared to 37.5% of patients without ata (p=0.07). family history for aitd was significantly higher in children with thyroid antibodies positivity (p= 0.01). anti-tnf-alpha inhibitors were administered in only 3 children (13%) with thyroid antibodies before their detection compared to 35 .5% of patients without thyroid antibodies (p=0.028). multivariate regression analysis showed that patients with a family history for aitd were about four times more likely to develop ata (or 3.75, 95% ci 1.401-10.017, p=0.008) and confirmed that ata positivity is less likely to occur in patients undergone anti-tnf-alpha therapy (or 0.127, 95% ci 0.031-0.518, p=0.004). conclusion: a high prevalence of ata positivity and hashimoto's thyroiditis in patients with jia was found in our wide southern italian cohort. as expected, a positive family history of aitd was found to be associated with a higher risk to ata development during the follow-up. this finding supports the usefulness of an active screening for aitd in jia children, in particular in patients with relatives affected by thyroid disorders. notably, patients treated with tnf-alpha inhibitors resulted less likely to develop thyroid antibodies. further studies are needed to investigate the effect of anti-tnf-alpha therapy on thyroid autoimmunity in jia. introduction: the knee is considered by far the joint most frequently affected at jia onset. nonetheless, jia onset may present with unusual musculoskeletal involvement, eventually leading to a delay in the diagnosis and treatment. objectives: to identify the type and number of musculoskeletal sites affected at jia onset in consecutive patients seen at the study center in an 8 years period. methods: records of patients with new diagnosis of jia from june 2012 to may 2020 available information in the medical history and standardized joint assessment at diagnosis, were retrospectively reviewed. systemic jia subtype according to ilar classification criteria were excluded. demographic and clinical features, including the type and number of joints at disease onset and diagnosis, were registered. data were analyzed through descriptive statistics. results: of a total of 333 caucasian patients included in the study (75.7% females), 241 patients (72.4%) had oligoarthritis, 79 (23.7%) rf-negative polyarthritis, 7 (2.1%) rf-positive polyarthritis, 1 (0.3%) psoriatic arthritis, 5 (1.5%) enthesitis-related arthritis (era). antinuclear antibody (ana) were positive in 188 patients (56.5%). the median age at onset was 4.8 years (iqr 2.3-9.3). at diagnosis 103 (30.9%) patients had only 1 active joint, 143 (43.0%) had 2-4 active joints, 87 (26.1%) had ≥ 5. as expected the knee, the tibiotalar and the wrist were the most frequently affected joints (77.2%, 41.1%, 21.0%, respectively); cervical spine was involved only in patients with polyarthritis (n=13). notably, of 103 patients with monoarthritis at diagnosis 98 presented with large joints involvement, among which n=2 isolated elbow and n=2 isolated wrist, and 5 with small joints involvement (table 1) . no sufficient data were available regarding the involvement of tendons and bursae, since the standard joint assessment form did not include them. nonetheless, additional 4 patients, not included in the sample analysis, had isolated tenosynovitis involvement at diagnosis (n=1 both-sided ulnar extensor tendons; n=2 isolated tenosynovitis of the flexor digiti proprius; n=1 tenosynovitis of 2 flexors digiti proprii). conclusion: our study confirms the knee, the tibiotalar and the wrist as the most frequently affected joints at jia diagnosis. on the other hand, musculoskeletal sites, such as small joints of hands and feet, the hip and the shoulder, usually involved in polyarticular jia, can be the site of disease presentation in oligo-and also mono-articular jia. further, jia may present with isolated tendon involvement. our results foster not to delay jia diagnosis in persistent synovitis occurring in infrequent joints and to include musculoskeletal sites, other than joints, in the standard articular evaluation. this could be realized by merging clinical and imaging (i.e. ultrasound) musculoskeletal examinations in the same assessment. none declared introduction: treatment response in jia is currently viewed as a binary outcome: response or non-response. however, jia is a heterogeneous disease and it is likely that different, identifiable subgroups of children and young people (cyp) may demonstrate different patterns of disease following treatment. identifying these response subgroups can assist the tailoring of stratified treatment approaches in jia. objectives: to identify subgroups of cyp defined by different trajectories of juvenile arthritis disease activity score (jadas) components following methotrexate (mtx) initiation for jia. methods: mtx-naïve cyp with jia were selected if enrolled prior to january 2018 in the bspar etanercept cohort register or the biologics for children with rheumatic diseases study at point of starting mtx. jadas components (active joint count, physician's global assessment (pga, 0-10cm), parental global evaluation (pge, 0-10cm) and standardised esr (0-10) were calculated based on data collected in the year following mtx initiation. multivariate group-based trajectory models were used to explore mtx response clusters across the different jadas components, which were log1p transformed for analysis. optimal models were selected based on a combination of model fit (bic, relative entropy, average posterior probabilities), parsimony and clinical plausibility. clinical and demographic characteristics and achievement of acr pedi 30/90 by six months were compared across identified groups. results: of 658 cyp selected, the majority were female (68%) and of white ethnicity (86%), with rf-negative jia the most common disease category (35%). six subgroups of cyp were identified with differing patterns of disease activity following mtx initiation. two groups improved across all jadas components: fast improvers (11%), and slow improvers (16%). persistent pga (8%), and persistent pge (13%) groups maintained one persistent disease feature but otherwise improved. one group relapsed (7%) and a final group had persistent disease overall (44%). there were no differences in active joint counts at mtx initiation between subgroups and all ilar categories were represented across each subgroup. however, cyp in persistent disease and slow improver groups had higher chaq, pga and pge scores at mtx initiation. those with persistent disease were also older at mtx initiation. the majority of cyp fulfilled acr pedi 30 response (>60% across every group). acr pedi 90 achievement was low at 6 months for slow improvers (30%) and high in the relapse group (68%). between 41% and 73% achieved acr pedi 90 response in groups with persistent disease in one jadas component. we identify different patterns of disease activity within cyp initiating mtx, suggesting a simple responder/non-responder analysis at a set point may be over-simplistic. commonly used response measures did not adequately describe these heterogeneous response patterns. understanding both clinical factors associated with, and biological mechanisms underpinning, these subgroups would aid stratified medicine in jia. introduction: despite modern treatment and improved disease control, pain is the most common complaint in juvenile idiopathic arthritis (jia). knowledge about pain thresholds and pain sensitivity among young adults with jia is sparse. objectives: to study pressure pain thresholds (ppts) in young adults with jia, 16 years after disease onset compared with controls. methods: consecutive newly diagnosed children with jia and a disease onset between 1997-2004 from central norway, were included in this prospective population-based long-term follow-up study. children with onset 1997-2000 were part of the nordic jia cohort 1,2 . age-and sex-matched controls were drawn from the national population register of norway. inactive disease and remission were defined according to wallace 3, 4 . at the follow-up between 2015-17, data from a clinical examination and blood tests were included in addition to an investigator-blinded quantification of ppts. a digital algometer was used to manually apply pressure three times with an even rate at the upper and lower limb. ppts from jia and controls, and from subgroups of jia defined by disease status, were compared with multilevel models in stata. results: among the 96 participants with jia, 71% were female, median age was 22.7 (iqr 18.7-26.2) years, median disease duration was 16.1 (iqr 14.2-17.1) years, 47% had an oligoarticular disease (persistent or extended), and 45% were in remission off medication. in the control group, 71% were female and median age was 23.5 (iqr 20.2-26.7) years. results from the multilevel regression model showed significantly lower ppts among participants with jia compared to controls (table 1 ). in the jia group, participants with inactive disease had lower ppts than both jia in remission off medication and jia with active disease ( table 1 ). the results were consistent for both upper and lower limb. conclusion: in this long-term follow-up study of young adults with jia, we found significantly lower ppts compared to controls. this may indicate that young adults with jia have altered pain sensitivity possibly due to accumulated earlier pain experiences. introduction: juvenile idiopathic arthritis (jia) represents the most common chronic rheumatic disease in childhood. non-steroidal antiinflammatory drugs (nsaids) and intra-articular steroids are the first line treatment for jia. systemic steroids, disease modifying antirheumatic drugs (dmards) and biologic drugs are used in children with severe disease. it is not possible at onset of disease to predict when a child can suspend pharmacological treatment, so children affected from jia have to continue pharmacological treatment for several months or years. anecdotal reports showed that rarely jia could present renal involvement due to uncontrolled inflammation or to long exposure to drugs. objectives: because no cohort studies investigating renal injury in children with jia are available, we designed this kind of study in our population. methods: we retrospectively evaluated 110 patients suffering from jia. jia diagnosis was made according to ilar criteria, treatment was assigned with acr recommendations. for each patient we recorded the type and the duration of pharmacological treatment and the presence of renal injury. renal injury was defined by the presence of hypertension (systolic and/or diastolic blood pressure >95 th percentile for age, sex and height), proteinuria (persistentconfirmation within 3 months-urinary protein/creatinine ratio>0.5 mg/mg for children <2 years old and >0. 2 introduction: juvenile idiopathic arthritis (jia) is a pediatric rheumatic disease with partially unknown etiology and pathogenesis. neutrophils are the most common immune cell present in synovial fluid from inflamed joints in oligoarticular jia, but the role of neutrophils in the immunopathogenesis of oligoarticular jia has not been investigated. objectives: to characterize neutrophil phenotypes and effector functions in the circulation and in the inflamed joint during active arthritis in children with oligoarticular jia. methods: paired samples of blood and synovial fluid from 17 children with oligoarticular jia were investigated regarding surface markers, phagocytic ability and oxidative burst. healthy blood neutrophils exposed to cell-free jia synovial fluid and healthy oral cavity neutrophils were studied as controls for synovial fluid exposure and transmigration respectively. results: synovial neutrophils had a shifted phenotype, characterized by high surface levels of neutrophil activation markers cd11b and cd66b, and mannose receptor cd206 and decreased levels of adhesion molecule cd62l compared to circulating neutrophils. in comparison to oral cavity neutrophils, synovial neutrophils had higher levels of cd11b and a different overall phenotype, suggesting that the phenotype shift in synovial compared to circulating neutrophils is not dependent on transmigration alone. jia synovial fluid in itself induced activation of healthy blood neutrophils, measured as increased cd11b levels. synovial fluid neutrophils had impaired ability to phagocytose opsonized e. coli and to produce oxygen radicals upon neutrophil activation with phorbol-myristateacetate (pma) compared to circulating neutrophils. the impaired effector functions in synovial neutrophils was not dependent on the synovial fluid alone, as addition of cell-free synovial fluid to blood neutrophils did not alter phagocytosis and oxidative burst. conclusion: jia synovial fluid neutrophils are activated, have a "polarized" phenotype and impaired effector functions compared to neutrophils in the circulation. this study will help bridge the current knowledge-gap regarding the role of neutrophils in the immunopathogenesis in oligoarticular jia. methods: a case report is described. data was extracted from the medical chart of the patient and a literature review was undertaken. results: a 7-year-old girl was transferred to our tertiary center after being admitted for prolonged intermittent fevers, abdominal pain, fatigue and polyarthralgias. on examination, there was symmetrical proximal muscle weakness, a vasculitic lower limb rash, facial erythema with eyelid edema (fig. 1 ) and oral mucositis. initial laboratory exams revealed pancytopenia, high muscle enzymes, increased erythrocyte sedimentation rate with moderately elevated reactive c-protein, and hypocomplementemia. she also had non-nephrotic proteinuria, without hematuria.further investigations showed a positive direct antiglobulin test, antinuclear antibodies, antidouble-stranded dna, anti-mi 2 and anti-ku. serositis (pericardial and pleural effusions, ascitis) and hepatosplenomegaly were present. lower limb mri documented diffuse muscle edema. the diagnosis of an overlap syndrome of jsle and iim was established. while being treated for concomitant bacteremia, the patient became ill-appearing, with persistent fevers, worsened cytopenias, low fibrinogen and high ferritin and triglycerides, and a macrophage activation syndrome (mas) diagnosis was assumed. the patient received antibiotics and intravenous immunoglobulin, followed by methylprednisolone pulses, iv cyclosporine (cyc), hydroxychloroquine and supportive therapy with progressive improvement. due to hypertension (possibly related to cyc) and persistent proteinuria a renal biopsy was performed showing class iv lupus nephritis. after achieving clinical stability, cyc was switched to mycophenolate mofetil as an induction treatment, which is ongoing. conclusion: imm with sle os is uncommon, and has seldom been described in children. in addition to fulfilling sle criteria, our patient had clinical, laboratory and imagiologic evidence of imm. the presence of myositis specific antibodies (especially anti-mi 2) further supports the diagnosis of an os rather than an atypical presentation of a lupus myopathy. juvenile dermatomyositis appears to be the imm subtype -it is associated with anti-mi 2, and mild heliotrope and eyelid edema are compatible. facial rash sparing the nasolabial folds is more suggestive of sle. mas is a rare but life-threatening condition that should be suspected in rheumatologic conditions and might be triggered by infections or disease flares. its identification may be particularly challenging at presentation, especially in sle where cytopenias are common. the reported prevalence in adult sle ranges from 0.9% to 4.6%; disease-specific criteria have been proposed. mas has occasionally been described in iim. in a patient with a predisposing condition, persistent fevers and illappearance must always prompt a mas workup, since early diagnosis and treatment are paramount. due to an early referral to a pediatric rheumatology center, the patient received a prompt diagnosis and treatment, which probably improved her prognosis. results: four of the five patients were female (80%) and all aged between 6 and 10 years. four of them had calcinosis at the time of diagnosis, although they may have had symptoms for 12 to 18 months prior to diagnosis. skin involvement was severe requiring multiple systemic and topical therapeutic agents in four out of the five patients -significantly more affected than the muscles. one patient had amyopathic subtype with normal childhood myositis assessment score (cmas) throughout. none of them had cardiac involvement. all had weakly positive anti-nuclear antibodies (ana); but were negative for myositis antibodies except the patient with most severe skin involvement and calcinosis (patient 2), who was positive for anti-tif1gamma antibodies. two of the three patients with calcinosis at onset had cyclophosphamide as the second line agent (chosen due to calcinosis) following systemic corticosteroids with complete resolution of the lesions after six cycles at 500mg/m2. one patient responded to infliximab, which failed to work after 20 months, following which cyclophosphamide was tried with good response. the other two patients were given cyclophosphamide after they failed to respond to rituximab, which did work for muscle disease. one patient had recurrent episodes of calcinosis needing surgical curettage despite initial response to cyclophosphamide and later ivig. introduction: systemic juvenile idiopathic arthritis (sjia) is a unique form of childhood arthritis. according to current understanding sjia is primarily driven by innate immune mechanisms at disease onset, but can progress towards chronic destructive arthritis, which can involve t cellular immunity. for yet incompletely understood reasons, sjia can be complicated by macrophage activation syndrome (mas), a severe hyperinflammatory condition characterized by a catastrophic cytokine storm resulting in multiple organ failure and high mortality. objectives: the sjia/mas working party (wp) aims to promote knowledge and international multidisciplinary collaboration among experts in the field of mas and sjia and to foster translational research in order to improve the care and outcome of these patients methods: currently 60 pres members participate to the mas/sjia wp. the wp arranges an annual meeting during the pres congress, open to all members activities. the mas/sjia wp core team frequently report about ongoing activities by email. results: several studies are currently ongoing. a project aimed to establish and validate a risk score for mas in sjia patients using routine laboratory parameters of disease activity and severity has already completed the construction phase. recently, building of a validation cohort comprising data form 182 patients from 10 paediatric rheumatologic centers has been accomplished and is awaiting analysis (claudia bracaglia). a second project focused on mas patients with systemic thrombotic microangiopathy (tma) has just completed the collection of 27 patients with mas and tma from 18 centers in 9 countries and results will soon be published (francesca minoia). furthermore, the mas/sjia wp participated in the data collection phase of a project on the development of new criteria for primary hlh (jan-inge henter and annacarin horne introduction: hemophagocytic lymphohistiocytosis (hlh) is an immunological disorder characterized by clinical signs and symptoms of severe uncontrolled inflammation, due to massive release of inflammatory cytokines. a delay in diagnosis is common, and is one of the factors that determine the poor outcome. hlh is classified into primary (phlh) and secondary (shlh). it is important to differentiate between the two as management differs. objectives: to describe the clinical and laboratory profile of hlh in infancy. methods: the electronic case files of children (age<1 year) diagnosed with hlh at the aims, kochi, kerala, between january 2012 and december 2019, was retrospectively reviewed and described. results: eight infants, with age range 1.5 months to 7 months, were clinically diagnosed with hlh. all were immunised and had normal development for age. none had a family history suggestive of hlh. third degree consanguinity was present in parents of patient no.5 and second degree for patient no.7. duration of symptoms before presentation ranged from 2 days to 68 days. duration of follow up with us ranged from 12 days to 192 days, for those who expired. all, eight of them, had fever, anemia, thrombocytopenia, hyperferritinemia, transaminitis, raised ldh and crp. lymphadenopathy was present only in patient no.4. before starting specific treatment patient no. 7 had pseudomonas sepsis, patient no.5 had roseomonas gilardii infection; patient no.3 and 4 were igm cmv positive but their pcr was negative. both of them had received prior blood transfusion. before making a definitive diagnosis of hlh patients were treated for puo, sepsis ? cause and acute liver failure. there was a delay in diagnosis for all patients except patient no.7. all of them were treated with hlh 2004 protocol with modification according to clinical status of the patient. later, broad spectrum antibiotics, antifungals and antivirals were used for all. anakinra was tried for patient no.5. five patients (phlh) succumbed to sepsis and mods and three (one phlh and two shlh) are continuing follow up. hsct was not done in any of them. other clinical features are shown in table 1 . conclusion: making a timely diagnosis of hlh is difficult. differentiating phlh from shlh is very important as the management differs. genetic testing should be done for all infants with hlh. negative genetic study doesn't rule out phlh. the only curative treatment for phlh is hsct. shlh infants, once their primary condition is treated, can have normal survival. hyperbilirubinemia, splenomegaly, neutropenia, hepatomegaly, tissue hemophagocytes and hypertriglyceridemia were more common in phlh. health, kolkata diagnosed as having mas, admitted between july 2008 and april 2020 was tabulated and retrospectively analyzed . objectives: to evaluate the clinical features, laboratory findings and outcomes in pediatric mas, assess the response to different pharmacological therapies, and finally to identify possible factors associated with an unfavourable outcome. methods: the data of patients diagnosed with mas over the study period was analyzed for the clinical and laboratory features, treatment details, response to therapy and outcome. results: 35 patients were diagnosed as having mas. primary illness was sjia in 29 (82%), sle in 5 (14%) and kawasaki disease (kd) in 1(4%). all had fever with varying degrees of multi systemic involvement. hyperferritinemia was universally present. in the absence of anakinra in india, pulse methylprednisolone with cyclosporine was used for treating the majority.10 patients (28.5%) expired. patients on biologics and steroids can present with a silent mas which may be difficult to diagnose. conclusion: mas is a near fatal complication with protean manifestations and multi organ dysfunction. hyperferritinemia is characteristic, higher values being associated with increased mortality. patients resistant to steroids and cyclosporine had a poor prognosis. early recognition with aggresive management forms the backbone of a successful outcome as reflected by improved prognosis over successive years. late presentations with multiorgan dysfunction are associated with the poorest outcomes. methods: case report's description results: a two-year-old boy presented with one month history of fever associated with limping gait, cervical lymphadenopathy and skin rash. laboratory tests showed elevation of inflammatory markers and ferritin. by exclusion criteria, sjia was diagnosed and steroid therapy started. after a soft tissue bacterial infection, fever relapsed and laboratory tests were consistent with mas (day 1): hb 8.5 g/dl, plt 44000/mm3; fdp 1522 ug/l, crp 100 mg/l, ferritin 2200 ug/l. high doses intravenous metilprednisolone and oral cyclosporin a (csa) were started. on day 2 he presented a systemic capillary leak syndrome and acute myocarditis. he was admitted into the pediatric intensive care unit (picu) where intravenous immunoglobulin and subcutaneous anakinra (ana) were added. on day 4, due to an introduction: sjögren's syndrome is a systemic autoimmune disease characterized by dry syndrome and lymphocytic infiltration of the exocrine and extraglandular glands. pulmonary involvement in primary sjögren's syndrome occurs in 9-20% of patients, with very heterogeneous manifestations, and occasionally as an initial mani-festation¹. diffuse interstitial lung involvement is one of the most characteristic pulmonary manifestations and the most frequent subtypes in lung biopsy are interstitial lymphocytic pneumonia and nonspecific interstitial pneumonia². objectives: 14-year-old girl presented to our hospital because of bilateral interstitial involvement with ground glass areas in lower lobes of both lungs on thorax and abdominal ct scan after for kidney stones follow-up. the patient had grade 1 mmrc dyspnoea and dry cough but denied having symptoms of arthralgia or arthritis, photosensitivity, oral and genital ulcers, raynaud's phenomenon or episodes of dry mucosa. she had no history of autoimmune disease nor family antecedents of any autoimmune disease. a physical examination disclosed no finger clubbing or swollen superficial lymph nodes but indicated crackles on pulmonary auscultation. laboratory work showed elevated acute phase reactants, positive rheumatoid factor, positive antinuclear antibodies (1/ 40), positive cytoplasmic antineutrophil antibodies (1/320) and igg and iga hypergammaglobulinemia. an examination for autoantibodies were negative for anti-ss-a, anti-ss-b, anti jo-1, anticentromere and anti-scl-70 antibodies. iontophoresis with pilocarpine and 6-minute walk test was also normal. pulmonary function tests demonstrated a mild restrictive impairment and a reduced percent diffusion capacity for carbon monoxide of 55%. fibreoptic bronchoscopy showed acute inflammation in bronchial mucosa. flow cytometry of bronchoalveolar lavage and cytology showed lymphocytosis with a 15% of cd4 and 85% of cd8 lymphocytes in bronchoalveolar lavage fluid. finally, a transbronchial lung biopsy lead to a definitive diagnosis, showing mixed interstitial inflammation and lymphocytic follicular hyperplasia with formation of germinal centers, suggestive of a lymphoid interstitial pneumonia of unreleased autoimmune etiology. throughout time, the patient reported progression of her symptoms with increasing dyspnoea, persistent dry cough, xerostomia and arthralgia. schirmer and rose bengal dye test were negative, and a salivary gland biopsy showed interstitial plasmacytosis and no igg4 plasma cells expression which suggested sjogren's disease. a high resolution computerized axial tomography was requested, suggesting organizing pneumonia in the context of sjogren's disease. methods: several studies indicate that lung involvement in sjögren is more frequent in advanced stages of the disease and rarely as an initial manifestation. sjögren's syndrome in paediatric age is rare and the subtype of secondary sjogren's is the most common. the course is longer, and the symptoms are more heterogeneous than in adulthood 5 . the diagnosis in children is delayed, because children less frequently report dryness and frequently present with extraglandular clinical features suggestive of other autoimmune diseases. a systematic review on primary sjögren's syndrome in male and paediatric population reported a 2.4% of pulmonary involvement in paediatric patients. 6 pulmonary involvement is associated with an increase in the mortality of patients with sjögren's, therefore, it is essential to periodically monitor patients with respiratory symptoms, making an early diagnosis and treatment of the disease. results: -conclusion: we present a case of a patient with childhood sjögren's disease with atypical onset of disease with lung involvement. introduction: sarcoidosis is a multi-system disorder. little is known about its pathogenesis. in children, the early onset sarcoidosis phenotype including blau syndrome is more often seen. 1, 2 the diagnosis of sarcoidosis is confirmed by demonstrating a typical non-caseating granuloma on a biopsy specimen. other granulomatous diseases should be excluded, in particular mycobacterial infections, crohn's disease and immunodeficiencies. the clinical presentation may vary depending on the organs involved and the age of the patient. 3, 4 objectives: we are reporting the case of a boy with a presentation of bone sarcoidosis at a young age. this is a rare phenotype in children. methods: clinical details were retrospectively collated using routine clinical records. confirmation of diagnosis was confirmed with bone biopsy. results: a 5 year old non-identical twin boy of ghanaian descent born in the uk had a slowly growing, painless frontal bone mass which started to develop from 7 months of age. he was developmentally normal, with no history of fever, rashes or joint pains. examination findings revealed frontal bossing while the remainder of the musculoskeletal examination was normal. there was no evidence of rashes, hepatosplenomegaly and ocular examination was normal. the patient was initially referred for neurosurgical review with suspected fibrous dysplasia, after an initial mri scan of the head revealed abnormal marrow signal and expansion of the frontal bone, with no soft tissue swelling. however, the ct scan of the calvarium was not suggestive of fibrous dysplasia. consequently, bone biopsy was performed demonstrating inflammation with granuloma formation. he was referred to infectious diseases and rheumatology. there was no travel history and no tb contact. quantiferon tb was negative. infectious work-up was negative especially for mycobacterial infections. rheumatology work-up identified on skeletal survey another bone location: a well-defined lytic lesion in the right distal fibula that was biopsied. infection cultures and pcr were negative. histopathology identified fibrous tissue and poorly formed granulomas. laboratory investigations revealed a mild microcytic anaemia with iron deficiency and eosinophilia. he had normal serum calcium and vitamin d and his esr was 25 mm/hr. ana, anca and rheumatoid factor were negative, and complement c3 and c4 were normal. his serum angiotensin converting enzyme (ace) level was raised at 125 nmol/ ml/min (normal <40 nmol/ml/min). investigations revealed mild renal impairment with normal urinary tests including normal calcium, protein and tubular proteins. ultrasound of the kidneys was normal. chest x-ray was normal. lung function was performed and was normal. dlco couldn't be performed due to low lung volume. vascular and inflammation genetic panel identified a variant in the nemo gene. functional studies excluded nemo deficiency and patient did not display any of the clinical features. however, a pattern of dysregulated t cells response was identified. he was treated with oral steroids and methotrexate. the oral steroids were successfully weaned off. he has been successfully treated with methotrexate 10mg s/c to initially stabilise disease with no bone growth, and had no significant side effects. repeat mri 2 years later showed increased burden of disease with other newly affected sites however, including the right femoral diaphysis and signal changes in the left tibial metaphysis. based on the mri and increasing musculoskeletal pain, decision was made to escalate to anti-tnf (adalimumab) with good clinical response. conclusion: bone sarcoidoisis is rare in children but this should be considered in the differential diagnoses when granulomatous inflammation is identified on histopathology. response to steroids and methotrexate is usually good but some patients will need escalation to anti-tnf. the most worrisome non-rheumatic condition causing persistent night pain in children which closely mimics arthritis is malignancy 1, 4 . it is vital to pick up subtle clues at an early stage especially in absence of hematological manifestations , organomegaly and lymphadenopathy. to reveal early clinical clues in pediatric patients with predominant musculoskeletal (msk) night pains who were initially diagnosed as suffering from some form of chronic arthritis but ultimately turned out to be affected by malignancy. methods i gathered a data of five pediatric patients fulfilling above mentioned criteria who were seen at dev children's hospital between january 2019 and march 2020. it included demographics, clinical presentation and laboratory results. all above cases reemphasize the need for an extremely detailed history pertaining to characteristics of pain & pattern recognition in pediatric rheumatology. prolonged fever , persistent msk night pain, persistent limp, upper limb and hip joint involvement which is unlikely for jia at onset are proven to be the earliest subtle clues which should not be missed. 1 other constitutional symptoms, respiratory, cardiovascular, ophthalmologic or osteoarticular involvement were absent. growth was unaffected. auditory tests were normal. systemic antibiotic treatment and local steroids were ineffective. laboratory findings were unremarkable, with only mild elevation of esr (28mm/1 st hr). ana and anca were absent in repeat meausrements (3 months intervals). cardiovascular disease was excluded. abdominal us was normal. on the basis of relapsing bilateral auricular chondritis and confirmatory histological findings revealing inflamed cartilage from the pinna of the ear with chondrocyte degeneration, perichondrial infiltrates of lymphocytes, plasma and polymorphonuclear cells and replacement of cartilage with fibrous tissue perivascular infiltrates of polymorphonuclear cells and lymphocytes, relapsing polychondritis was diagnosed. one month nsaids trial, pending histology results was ineffective. methotrexate sc and steroids 1mg/kg/d gradually tapered over a 3-month period were given with significant improvement of auricular inflammation and normalization of markers of inflammation. auricular chondritis worsened after steroid withdrawal and adalimumab was added to treatment with significant improvement of auricular inflammation in 2 months. in the following 8 months auricular chondritis relapsed during uris with mild elevation of esr (25mm 1st hr) and crp (13 mg/l). after 15 months of treatment, in an effort to prolong the intervals of adalimumab administration, bilateral auricular chondritis relapsed. after 24 months of mtx and 21 months of adalimumab administration inflammation was put in complete remission. the following year no flares or involvement of other systems were observed, under methotrexate and adalimumab treatment. conclusion: in this patient isolated auricular relapsing polychondritis was unresponsive to nsaids. steroids and methotrexate greatly improved inflammation but did not induce complete remission. complete remission was achieved by addition of adalimumab to methotrexate treatment, which also allowed for steroids discontinuation. none declared first ever single center study revealing spectrum of rheumatic diseases in 114 children from an indian state of gujarat d. b. pandya, on behalf of dr mehul mitra, pankaj buch, sonal shah, there is very limited information and awareness about pediatric rheumatic and immunodeficiency diseases amongst primary physicians 1, 2, 3 in gujarat and to make this matter even worse, we are not having a single exclusive pediatric rheumatology and immunology centre for a population of around 60 million. to guesstimate a status of children with rheumatic and immunodeficiency diseases in gujarat and spectrum of these diseases at dev children's hospital. methods i gathered a retrospective data of 174 patients who attended dev children's hospital between january 2019 and january 2020. out of these, 114 children with confirmed diagnosis of inflammatory rheumatic diseases and suspected primary immunodeficiencies were included. patients with non-inflammatory musculoskeletal(msk) pains and non-rheumatic diseases causing msk pains were excluded. my collected data included referral details, demographics, clinical presentation, laboratory results and diagnosis. majority of the cases were referred by pediatricians, orthopedicians, hemato-oncologist and general physicians. main reasons for referral were joint involvement , undiagnosed fever , multisystem disease and elevated inflammatory markers. many physicians had put a diagnosis like rheumatoid/rheumatic arthritis, autoimmune disease or connective tissue disease. almost 80% of patients had been evaluated with rf, aso titer, ana and joint imaging irrespective of clinical pattern by their primary physicians before referral. fever , msk involvement, extreme fatigue, constitutional symptoms, skin and mucosal involvement were prominent complaints noted by me. family history of rheumatic, primary immunodeficiency (pid) or consanguinity was found in 1/3 of patients. anemia of chronic disease, elevated esr and thrombocytosis were almost universal laboratory findings in our cohort. rheumatic diseases in children are not anymore rare but due to lack of expertise and awareness , these children are not getting diagnosed. many cases were advised unnecessary rheumatological investigations even before referral. results: a 10-year-old female patient was referred to the rheumatology clinic at our hospital with a previous history of fever of 39°c (102.2ºc), loss of appetite, and acute polyarthritis of wrist, knees, and ankles. at that time, laboratory exams revealed a hemoglobin of 11.1 g/dl, c reactive protein 78.6 mg/l, and antistreptolysin o titers of 400 ui/ml (normal range <200ui/ml. clinical symptoms were relieved only after using nsaids. after 6 months, the patient returned to our hospital with a 7-month history of weight loss and claudication related to pain and daily morning stiffness (15 minutes) on her right ankle. new laboratory findings demonstrated positive antinuclear antibodies 1:320, negative rheumatoid factor, and alpha-1-acid glycoprotein of 171 mg/dl (normal range: 44-113mg/dl). clinical signs suggestive of chronic arthritis with exuberant swelling of the ankles were observed on physical examination (figure a). she was screened for tuberculosis (tb) and had a positive (18mm) tuberculin skin test (figure b). chest ct revealed infiltrative soft tissue mass in the posterior mediastinum, with homogeneous contrast enhancement (figure c). magnetic resonance imaging of both ankles was performed and demonstrated bilateral and symmetrical tibiotalar arthritis and prominent tenosynovitis of extensors, flexors, and fibularis tendons (figure d). right ankle synovial biopsy revealed no granulomas and joint fluid culture was negative for mycobacterium tuberculosis, confirming reactive arthritis (poncet's) and tenosynovitis, that may follow mycobacterial infection with no infective agent in the joints. conclusion: to our knowledge, there is no report of poncet's disease associated with inflammatory tenosynovitis, showing the particularity of this case. the patient's symptoms resolved after two months of anti-tb therapy. introduction: cacp is characterized by congenital or early-onset camptodactyly (usually bilateral); non-inflammatory arthropathy (more frequently in the wrists, knees, ankles, elbows, and hips); coxa vara (reduction of the angle between the neck and shaft of the femur); and non-inflammatory pericardial effusion (a late manifestation, less frequently reported). recognizing the radiological aspects of this syndrome and differentiating it from jia is crucial since cacp has no effective treatment and jia is usually treated with nsaids and methotrexate (2, 3) . objectives: to report a rare case of cacp syndrome mimicking jia. methods: case report and literature review. results: a 5-year-old male patient presented with arthropathy characterized by painless progressive swelling and restricted movement of the hands, hips, knees, and ankles since the first year of life. he had a family history of camptodactyly from his paternal grandfather. on physical examination, symmetric camptodactyly of the hands and feet was observed (a). he had no history of rash or weight loss and inflammatory markers were unremarkable. the echocardiogram was normal. the pelvic radiograph showed a widening of the joint space and bilateral coxa vara. magnetic resonance imaging (mri) of the hips (b) and knees (c) was performed and depicted large joint effusions (arrows, b and c) with normal synovial thickness and mild synovial enhancement in all joints, without bone marrow edema-like signal. a synovial biopsy of the knee was performed and revealed mild synovial hyperplasia without inflammatory cells. the patient was diagnosed with camptodactyly-arthropathy-coxa vara-pericarditis syndrome (cacp -omim 208250), a recently described genetic disorder with no gender predominance identified to date (1). conclusion: an important differential diagnosis of cacp is juvenile idiopathic arthritis (jia), a painful inflammatory chronic arthritis that can cause not only joint effusions due to synovial inflammation, but arthritis was the most frequent extraglandular manifestation. renal tubular acidosis represented the typical expression of renal involvement (19 cases). neuromyelitis optica and aseptic meningoencephalitis (6 and 9 cases, respectively) were the most typical neurologic manifestations. two cases of interstitial lung disease and one of pulmonary hypertension were reported. almost all patients had autoantibodies, mostly ana (200/224 patients) and anti-ssa/ro (170/208 patients). the schirmer test was performed in less than half of the patients, of whom 62% tested positive. a positive result of minor salivary biopsy was reported in 129/140 cases with available data. juvenile idiopathic arthritis was the most frequently associated disease, followed by systemic lupus erythematosus (16 and 8 cases, respectively). no significant differences between patients with or without parotitis were found except that patients with parotitis showed increased levels of crp more frequently than those without it (p= 0.00). patients with anti-ssa/ro had more frequently a positive schirmer test (p= 0.04). the presence of rf was significantly associated with dry mouth (p= 0.00), arthritis (p= 0.00), and rash (p= 0.04). a positive minor salivary biopsy was more common in children with dry eyes than in those without this clinical feature (p= 0.02). arthritis was more frequent in patients with other diseases than in those with primary ss (p= 0.00). we further investigated ss features according to the age groups (≤ 6 years, 7-11 years, ≥ 12 years). parotid involvement was inversely proportional to the age and occurred more frequently in younger patients (79% of those ≤ 6 years; p= 0.03). interestingly, the rate of anti-ssa/ro positivity increased with age (97% of those ≥ 12 years; p= 0.00). conclusion: even though parotitis was the most frequently reported feature, a wide range of clinical manifestations in children with ss has been reported so far. a better knowledge of css features will help to pave the way for the development of css specific diagnostic criteria. none declared introduction: pachydermodactyly (pdd) is a rare benign fibromatosis, characterized by progressive painless swelling of soft tissue of proximal interphalangeal (pip) joints without inflammation signs. generally pdd affects pip joints of the fingers, rarely of the thumb. the involvement is typically symmetrical, in few cases unilateral. it usually occurs more frequently in young males. etiology is unknown, but it arises from mechanical stimulation of periarticular skin (i.e repetitive rubbing, interlacing, and cracking of fingers). pdd has to be considered in the differential diagnosis of arthritis (i.e. juvenile idiopathic arthritis, jia) and many syndromes (i.e. progressive pseudorheumatoid dysplasia). prognosis is good with cessation of mechanical stimulation 1 the recurrent paroxysmal appearance of inflammatory lumps (local erythematous tender swellings, which partially respond to antiinflammatory agents), accompanied by elevated inflammatory markers during flares, suggest that fop may be an autoinflammatory disease. the episodic formation of bone, often following a trivial injury, suggests that innate immune-related triggers induce tissue transformation through the bmp pathway. moreover, interleukin-1β (il-1β), a well-known mediator of the innate immune system, has been linked to ho and mineralization in mesenchymal stem cell cultures derived from human bone marrow. we hypothesized that treating fop patients with anti-il-1 agents could help ameliorate the progression of this devastating disease. we report our experience treating two fop patients with anakinra and canakinumab. objectives: to decrease the frequency of fop paroxysms, and/or limit the symptoms and extent of residual lesions, by using anti-il-1 agents. methods: patients' data and blood il-1 levels were analyzed to characterize the efficacy of anti-il-1 treatments in ameliorating the natural progression of fop. results: a 13.5 year old boy and a 5 year old girl were diagnosed with fop, both clinically and genetically (the typical r206h mutation was found). various treatments, including high-dose corticosteroids, pamidronate infusions, celecoxib, monteleukast and sirolimus, did not change the course of the disease. both patients are receiving canakinumab (the male patient was initially treated with anakinra). the male patient has been treated for over 2 years. flare rate was markedly reduced from one new lump every 8 days to approximately one every 25 days ( figure 1 ). the lumps involved in almost all of these flares are the same: at the left scapular base and within the sternocleidomastoid muscle. the female patient has been treated for a year, and has not experienced any ho flares during canakinumab treatment. temporarily withholding canakinumab in both patients, led to serious flares 8 weeks after the last dose. notably, while undetectable levels of il-1β (<0.125 pg/ml) were found in the three plasma samples obtained from the male patient during treatment with anakinra or canakinumab, high levels (up to 21.52 pg/ml, about 90-fold higher compared to average levels measured in healthy controls) were found in his plasma samples collected during the flare ( figure 2 ). in contrast, il-18 and il-6 plasma levels, measured before, during and after withholding treatment, were comparable or slightly higher than those observed in healthy controls ( figure 3a , b). conclusion: we report here, for the first time, that anti-il-1 agents were found efficacious in treating two fop patients. we also found markedly increased il-1β levels during flares, which normalized following the treatment. we suggest a role for il-1β in the pathogenesis of this disease. although it is too soon to conclude whether fop may be included under the umbrella of auto-inflammatory syndromes, anti-il-1 agents can be effective in ameliorating the natural progression of fop. introduction: musculoskeletal symptoms are one of the common reasons for applying to rheumatology departments in general practice 1 . although inflammatory causes are generally considered in the foreground, it is known that non-inflammatory causes including genetic diseases may also be responsible. the absence of signs of inflammation (morning stiffness, redness, tenderness) and normal inflammatory markers in laboratory findings may support nonrheumatologic diseases 2 . objectives: to present genetic disorders that can mimic rheumatologic symptoms and to answer when genetic diseases should be considered in the differential diagnosis in patients presenting with rheumatological complaints. methods: we retrospectively evaluated 60 patients who applied to hacettepe university pediatric rheumatology department with musculoskeletal compliants between january 2015 and december 2019 and had been consulted to genetics departmant. the rate and degree of consanguinity, clinical diagnosis, indication for consultation, accompanying musculoskeletal and other findings had been recorded. the diagnosis of genetic diseases were based on physical examination, radiological evaluations and genetic analysis. results: a total of 60 patients, 19 boys (31.6%), with a mean age 12.46 ± 1.41 years were included in the study. the rate of consanguinity was 25.0%. the most frequent referral to the genetic department was the presence of skeletal anomalies (n:12) such as camptodactyly, clinodactyly, and bone shortness accompanying joint findings. other causes include short stature (n:4), joint deformity (n:5), joint hyperlaxicity (n:10), dysmorphic findings such as atypic facial appearance (n:9), accompanying diseases that may be part of a syndrome (n:11), genetic diagnosis suspicion according to the results of radiological examination (n:4) and joint findings without clinical and laboratory signs of inflammation (n:5). distribution of joint involvement in 20 patients with genetic disease were hands, knees, and hips respectively. in the laboratory evaluation of patients presenting with joint swelling and arthralgia, acute phase reactants (erythrocyte sedimentation rate and c-reactive protein concentrations) were within normal reference values. one third of the patients (33.3%) had a final diagnosis of a genetic disease. the diagnoses of these patients were as follows; cacp (camptodactyly, arthropathy, coxa vara deformity and pericarditis) syndrome (n:3), trichorhinophalangeal syndrome (n:1), progressive pseudoromatoid dysplasia (n:2), lig4 syndrome (n:1), 3m syndrome (n:1), h syndrome (n:1), spencd (spondyloenchondrodysplasia, n:3), and nonspecific connective tissue disease (n:8). conclusion: genetic syndromes with musculoskeletal findings are often unrecognized and misdiagnosed as rheumatologic diseases leading to unnecessary procedures and treatments. summarizing the genetic diagnosis spectrum that can be detected in these patients will increase the awareness of physicians. results: according to the results of observation, the disease was more common in the age group of 7-11 years (65%), to a lesser extent among children in the group of 12-15 years (35%), less often in the group of 3-7 years (5%). when examining infectious agents, zoonotic infection was detected in 41% (listeria monozytogenes, yersinia enterocolitica). clinical course of nodular erythema in this group was characterized by an expressed activity of the inflammatory process with multiple elements in the lower and upper extremities, joint syndrome, increased esr to 45± 3.8 mm per hour, crp 28± 2.5 mg\l. the disease was preceded by an episode of acute infection with an increase in body temperature, intoxication, in some cases with short-term intestinal syndrome, pharyngitis. the rashes were persistent and recurrent, with a slow regression of laboratory activity. streptococcal etiology of nodular erythema was detected in 37% of cases. there was an increase in esr to 25±3.8 mm per hour, crp 15± 2.7 mg/l, a significant increase in antistreptolysin on average 480± 34% iu / ml. with an increase in individual cases to 870 iu/ml. in 13% of cases, erythema nodosum developed after an intestinal infection. among the pathogens were identified sh. disenteria, e. coli, yersinia enterocolitica, enterovirus. the disease was characterized by moderate activity, a good response to etiological therapy and a short course of nsaids . an interesting fact was the development of nodular erythema in 4% of cases caused by the epstein-barr virus in groups of children from 3 to 7 years and 7-9 years. they had clinic picture with normothermia, no symptoms of intoxication, periodically occurring elements of nodular erythema on the shins, no blood changes. therapy aimed at eliminating the virus gave a positive result and did not require specific anti-rheumatic therapy. in 5% of cases, the etiology of nodular erythema was not defined. the clinical course of nodular erythema in children depends on the infectious agent that was the trigger of the pathological process. the higher activity and duration of the disease is caused by zoonotic infection, which requires more active antiinflammatory therapy with corticosteroids, which may be associated with the activation of autoimmunity. this group of children was taken for further observation as a group at risk of developing systemic connective tissue disease. changes in the etiological structure of nodular erythema and treatment tactics require further study. introduction: sjögren syndrome (ss) is a chronic autoimmune disorder characterized by inflammation of the lacrimal and salivary glands leading to oral and ocular dryness. childhood ss is rare and poorly defined and underdiagnosed owing to the lack of childspecific diagnostic or classification criteria. objectives: the purpose of this study is to describe 12 cases with pediatric ss in order to better clarify the characteristics of the disease in the pediatric age. methods: we retrospectively reviewed medical records of patients (pts) with pediatric ss referring to three italian pediatric rheumatology centers. due to lack of childhood validated ss-specific criteria, physician diagnosis was the only inclusion criteria. results: we collected data on 12 pts (9 females). the mean age of disease onset is 10.0 yrs (median 10.2, range 4-17). the mean age of diagnosis is 11.83 (median 11.45, range 6-18). the follow up period varied from 0.1 to 9.3 yrs (mean 3.95, median 5.0). the most common manifestations were articular involvement (mainly with arthralgia) (9/12 pts) and parotid/salivary glands swelling (8/12 pts). xerostomia and xerophthalmia were found in 6/12 pts and in 4/12 respectively. vaginal dryness was reported only by one pt. fever and fatigue occurred in 3/12 and 7/12 pts respectively. we also recorded 3 cases of circulating immune complexes manifestations in 3 pts, purpura (n=2) and glomerulonephritis (n=1). we observed an endocrine involvement in 3 pts (1 metabolic syndrome, 2 autoimmune thyroiditis). abdominal pain was found in 4/12 pts. all pts were positive for autoantibodies (positivity for ana or anti-ssa or anti-ssb or fr) at presentation. rf test results were available in 8 pts, all positive. positive ana (titer>1/320) and anti-ssa were present in 10/12 pts and in 9/12 respectively. hypergammaglobulinemia (range 1,6-8.04 g/dl) was found in 8/11 pts (1 na). abnormal schirmer test was observed in the half of cases (6/12). minor salivary gland biopsy was performed in 10 pts resulting in histological evidence of focal lymphocytic sialadenitis in 9/10. sonographic evaluation of salivary glands was abnormal in all of the patients (10/10). with regard to treatment, 6/12 pts received corticosteroids and eight were also treated with one or more dmards such a hydroxychloroquine (n=8), methotrexate (n=3), azathioprine (n=1), leflunomide (n=1). biological therapy was used in 3 patients for systemic involvement: 1 received belimumab and then rituximab, while the other patients received rituximab. conclusion: xerostomia and keratoconjunctivitis sicca were not common in our series while recurrent parotid swellings were more frequent than what reported in adults. pediatric recurrent parotitis should increase the suspicion for sjögren syndrome. current diagnostic criteria for ss do not include parotitis and therefore, the incidence of ss may be under-recognized in childhood. the disease is not always benign and patients with severe course may need second line treatment including immunosuppressant and biologics. introduction: improving our understanding of pediatric rheumatological (pr) patient population is crucial for pediatric rheumatologists to know rheumatic disease epidemiology and to raise awareness leading to early detection. we didn't find studies of pr disorders presenting in the first year of life. objectives: the aim of this study is to assess the prevalence of pr disorders with onset in the first year of life. methods: we retrospectively studied patients observed in our pediatric rheumatology unit between january 1 st of 1987 and december 31 st of 2019. we defined acute (<2 weeks), subacute (≥2 and <6 weeks) and chronic (≥6 weeks). results: a total of 3751 patients were observed in 32 years. diseases' onset occurred in the first decade of life in 2290 patients (61%) and in the first year of life in 158 (4,2%). among the latest group, chronic inflammation was the most frequent group of diagnosis (30%), followed by recurrent inflammation (23%), acute inflammation (11%), infection (9%), infiltrative/ degenerative disorders (8%) and subacute inflammation (3%). the remaining patients (16%) were diagnosed with other disorders classified as miscellaneous. among chronic inflammation group, 14 patients were diagnosed with juvenile idiopathic arthritis (4 systemic); 14 had neonatal lupus and one patient had polyarteritis nodosa. among recurrent inflammation group, 13 patients were later diagnosed with pfapa (periodic fever, aphthous stomatitis, pharyngitis and adenitis), 8 were diagnosed with behçet disease and 6 had an autoinflammatory disorder. acute vasculitis was diagnosed in 13 patients (9 kawasaki disease and 4 acute hemorrhagic edema of infancy). among infectious diseases group, there were two cases of congenital syphilis with arthritis and two cases of osteomyelitis secondary to bcg vaccination. conclusion: rheumatological diseases presenting in the first year of life are not exceptional. although many patients didn't have a definitive diagnosis at the beginning of the symptoms, many of them were later diagnosed with rheumatic disorders, mostly chronic inflammation (30%), which requires early diagnosis, specific treatment and long-term follow-up. rheumatic diseases must be considered as differential diagnosis in the first year of life in order to avoid delayed intervention and long term disabilities and sequelae. (1), on the other side measles-induced mas has rarely been reported (2). objectives: we present the case of a child known to have sjia in remission, who presented a measles primary infection and a secondary kd complicated by mas. methods: a 5 years old girl, not fully vaccinated and known to have sjia in remission under methotrexate, presented for frequent high grade fever of 3 days duration associated with flat flash red spots on the face and trunk as well as the palms and soles. a koplik's spot was identified. conjunctivitis and coryza were also present. initial viral serology, including measles, returned negative. fever persisted and on day 7, edema of both hands and feet appeared with bilateral cervical adenopathy, erythematous tonsils, gingivitis, cracked lips and hepatomegaly was noted. all cultures were negative and chest x-ray was normal. inflammatory markers rose up. viral serology was repeated and measles igm came back positive. cardiac ultrasound ruled out coronary aneurism and the ophthalmic exam showed no uveitis. kd criteria were met and 2g/kg of intravenous immunoglobulins (ivig) were administered. after 48 hours of clinical improvement, fever reappeared and the patient returned to be ill looking although the rash regressed. we noted high ferritine(2016 ng/ml) together with low c3, decrease in platelets(170 x10 3 /ml) and elevation of hepatic enzymes, ldh and cpk, without increase in the inflammatory biomarkers. mas was suspected and a bone marrow aspirate showed the presence of mild macrophage hemophagocytosis. antibodies for lupus and auto-immune myositis were all negative. steroids were given, fever disappeared, and spectacular clinical and biological improvements were objected. 2 weeks later, desquamation of all extremities was noted. sars-cov-2 was not investigated because historically this case presented 1 year earlier than the pandemic. results: we hereby report, for the first time, kd and mas triggered by measles infection in a child with sjia in remission. the exact mechanism involved in kd-induced mas and measles-induced mas has not yet been defined but a defective immune response is suspected (3). conclusion: significant similarities and overlap between measles, kd, sjia and mas make an early diagnosis very challenging (1)(3). the recent covid19 pandemic emphasizes how a viral illness can be responsible of kd and sometimes degenerating in mas. we report this clinical case as an example of a systemic inflammatory syndrome (sis) taking place after a viral infection to measles. in the era of covid19 pandemic and secondary sis in children, an additional challenge is present in regions lacking measles vaccine coverage. none declared the musculoskeletal manifestations of scurvy: a diagnostic challenge for the rheumatologist p2 was a 5-year-old boy, with autism spectrum disorder, malnutrition and severe food selectivity, admitted to our unit for refusal to bear weight and bruises in lower limbs. the auxological evaluation showed a strongly dystrophic aspect. coagulation profile and main organ function markers were normal. at nutritional biochemical parameters evaluation, iron and vitamin c deficiencies were detected (vitamin c: 2 μmol/l). oral vitamin c therapy was started, with prompt clinical response. p3 was a 7-year-old boy with autism spectrum disorder, admitted to our unit for lameness and difficulty in walking for a month. at clinical examination, a mottled skin at lower limbs was noted. joint examination was normal. auxological parameters and main blood tests were adequate for age. given the presence of food selectivity, he underwent serum vitamin c dosage (11 μmol/l); hence he started oral vitamin c therapy, with rapid clinical improvement. p4 was a 2 years old boy who was referred for coxalgia and fever. at clinical examination, pale skin, gingival hyperemia, and pain in mobilization of the left hip were present. microcytic anemia was detected, but main organ and inflammatory markers were normal. no evidence of infection was present. x-ray of femur and knee showed morpho-structural alteration of the distal metaphysis bilaterally. a low intake of fruit and vegetables was reported; hence, dosage of vitamin c was performed, resulting reduced (2.5 μmol/l). he started vitamin c oral therapy with clinical response. p5 was a 13-year-old girl with behavioral disorder and intellectual disability, admitted for fever and right knee swelling which appeared two days after a right leg burning. c-reactive protein and esr were elevated and ultrasound exam confirmed intra-articular knee effusion. suspecting a septic arthritis, antibiotic therapy was started with laboratory normalization and partial clinical improvement. considering the persistence of knee swelling after nine days of intravenous antibiotic therapy, the presence of gingival hyperemia and history of food selectivity, vitamin c dosage was practiced (12 μmol/l). oral vitamin c was administered with complete clinical resolution. conclusion: although scurvy is considered a disease of the past, it still occurs nowadays. food selectivity associated to autism is a major risk factor for vitamin c deficiency in childhood. rheumatologists should take into account the diagnosis of scurvy in the diagnostic approach of musculoskeletal disorders in children, especially when development disorders are present. 15.4%), juvenile dermatomyositis (n=1), sarcoidosis (n=1), granulomatous polyangiitis (gpa) (n=1), sting-associated vasculopathy with onset in infancy (savi) (n=1), and oligoarticular jia (n=1). respiratory symptoms were present in 6 (46.2%) patients at the time of primary diagnosis. in other patients, the time period between the diagnosis of the rheumatic disease and the onset of the respiratory symptoms ranged from 1 to 12 years. cough, the most common symptom, was present in 10 (76.9%) patients. six patients manifested with cough and sputum. six (46.2%) patients had shortness of breath and one patient had hemoptysis. on the physical examination of one patient, rales and clubbing were detected. high resonance computerized tomography (hrct) was performed in all patients. hrct findings were as follows; lymphadenopathy in 8 patients (61.5%), ground glass appearance in 10 patients (76.9%), consolidation in one patient, pleural effusion in one patient, pulmonary nodule in 4 patients (30.8%), fibrosis in one patient, cystic lesions in 3 patients (23.1%), septal thickening in 5 patients (38.5%), bronchiectasis in one patient, and reverse halo sign in one patient. in echocardiographic examination, only one patient had pulmonary hypertension. three patients underwent open lung biopsy, and diagnosis was made with pathological examination of the lung tissue. of these three patients, two (15.4%) had lymphocytic interstitial pneumonia (lip), and one patient had chronic inflammation and focal fibrosis. infectious lung disease was not detected in any patient. ten patients (76.9%) had interstitial lung disease associated with rheumatic disease, one patient had pulmonary hemorrhage, one patient had pulmonary involvement of gpa, one patient had pulmonary involvement of sarcoidosis. there was no statistically significant difference between the first and last spirometry and dlco values during the follow-up period. mortality was 7.5% (1/ 13) in this cohort. active disease was significantly associated with abnormal tc, hdl, and tg levels (p=0.04*), (p=0.03*) and (p=0.04*) respectively. multivariate analysis of the factors affecting abnormal cholesterol level revealed that sle is a significant predictor of abnormal cholesterol level . presence of jsle increase risk of abnormal cholesterol 9 times more than cases without jsle. the overall percent predicted was 80%. active disease is a significant risk factor for abnormal tg with increased risk of abnormal tg by 3.2 among cases with active disease than cases with inactive disease. the overall percent predicted was 75.6%. conclusion: children with rheumatic diseases showed significant lipid profile abnormalities. abnormal tc, hdl and tg are significantly associated with active disease. presence of jsle increase risk of abnormal cholesterol. active disease is a significant risk factor for abnormal tg. therefore, lipid levels should be monitored regularly and managed in patients with paediatric rheumatic diseases to minimize the longterm risk of cvd. methods: non-experimental, cross-sectional and descriptive study. a confidential survey was conducted online, aimed at residents and attendings who deal with musculoskeletal pain. were addressed with the definitions of arthralgia, arthritis, myalgia, allodynia and hyperesthesia (between five to seven options) with only one correct answer. correct definitions: arthralgia (pain localized to the joint or periarticular structures, as a only manifestation); arthritis (criterion one or criterion two: 1 -joint swelling or intra-articular effusion / 2 -limitation of joint mobilization associated with at least one of the following: a) pain b) tenderness c) swelling d) heat); myialgia (pain with muscular origin or referred to muscle, regardless of its etiology); allodynia (pain resulting from usually non-painful stimulus); hyperesthesia (coexistence of allodynia plus hyperalgesia -exaggerated responses to tactile and thermal nociceptive and nonnociceptive stimuli the association of pure red cell aplasia (prca) with thymoma led to the discovery of the autoimmune mechanisms involved in the pathogenesis of this rare disease. till date many adult case reports have revealed a strong link between prca and autoimmune diseases, endocrine disorders, rheumatic diseases, autoinflammation and immune dysregulation. [1] [2] [3] [4] [5] objectives to stimulate a search for the genetic and immunological roots for a 2.5 years old girl with syndromic face, pure red cell aplasia, type 1 diabetes and polyarthritis. methods this is a story of a 2.5 years old girl with pure red cell aplasia, type 1 diabetes and polyarthritis. she was normal till 7 months of age. at the age of 8 months, she was diagnosed with type 1 diabetes. she was evaluated by her paediatrician in view of generalized hypotonia, deformed pinna, low set ears, midfacial hypoplasia, blue sclera, umbilical hernia and retracted eyelids. she had multiple episodes of seizures during next few months. to me, she was presented with one year history of polyarthritis with severe pallor requiring frequent blood transfusions. family history was inconclusive. musculoskeletal examination showed polyarthritis involving right knee, bilateral ankles, fingers and toes. further examination revealed haemolytic facies and hepatosplenomegaly. i was not able to make out any facial dysmorphism mentioned earlier by her paediatrician. results: table 1 conclusion early age of onset, pure red cell aplasia, autoimmune and endocrine manifestations with some doubtful facial dysmorphism inspired me to suspect some known or unknown immune dysregulation syndrome in this child. genetic analysis would be the best possible option in this scenario if financial condition permits. introduction: galactosialidosis (gs) is a rare inherited lysosomal storage disorder (lsd) which is characterized by a defect in the lysosomal glycoprotein catabolism. here we report, for the first time, a case of a child affected by gs who presented with recurrent episodes of extensive joint inflammation in both knees. knowledge on gs related inflammatory joint pathology is lacking, which hampers evaluation of possible mechanisms that could give an explanation for the significant arthritic joint abnormalities as observed in our patient. objectives: the aim of this study is to describe the clinical presentation as well as the laboratory, radiologic and microscopic features of this extremely rare presentation of gs. furthermore, we conduct a literature review on lsd's complicated by arthritis in order to evaluate potential mechanisms that could explain the extensive inflammatory joint swelling observed in our patient. methods: in this study we present a 12-year-old turkish boy who was diagnosed with gs (late infantile form) at 17 months of age. from the age of 8 years, the boy presented with episodes of inflammatory joint pathology of the knee. informed consent was obtained. alongside the case report, a literature review using medline was conducted. an extensive list of known lsd's was combined with the terms: "arthritis", "joint inflammation", "synovitis" and "synovial inflammation". cases in which joint inflammation was based on a probable cause other than the underlying lsd were excluded. results: in the present case, owing to comprehensive examinations (i.e. laboratory tests, imaging and microscopic examination) multiple possible causes for the recurrent inflammatory joint pathology could be rejected (i.e. no signs of infectious arthritis, reactive arthritis, osteoarthritis, arthritis secondary to a malignancy or crystal induced arthritis). a diagnosis which could explain the clinical picture is the jia subtype: ana negative oligo-articular jia. however, microscopic examination showed numerous foamy macrophages with extensive vacuolization in the synovial tissue of the inflamed joint, which is not associated with jia. given the evidence of storage products within the macrophages of the inflamed synovial tissue and no conclusive diagnosis, gs itself should be considered as the primary cause for the recurrent arthritis. an in-depth literature review using medline for data on inflammatory joint pathology in lsd's showed that 7 lsd subtypes (i.e. fabry disease, farber lipogranulomatosis, gaucher disease type 1, mucopolysaccharidosis ix, a-mannosidosis, fucosidosis and cystinosis) could present with disease related arthritis. multiple potential arthritic mechanisms secondary to storage product accumulation in lsd's have been described, such as: dysregulation of innate immunity and increased upregulation of numerous pro-inflammatory proteins. conclusion: given the evidence of storage products within macrophages of the inflamed synovial tissue and the absence of other etiological clues, our hypothesis is that gs itself is the primary cause for the inflammatory joint pathology in our patient. although, gs cannot be linked directly to joint inflammation, lysosomal defects have been associated to pro-inflammatory effects that possibly could result in arthritic disease. future identification of other patients with gs is required to support the hypothesis of an arthritic clinical phenotype of gs and to assess underlying pathophysiology. introduction: joint pain (jp) is a relatively common complaint among children and adolescents. a painful joint in children for many years continues to maintain the status of the most common symptom of juvenile arthritis. however this symptom should not always be interpreted as a manifestation of rheumatic diseases. objectives: the aim of current review is to debate of the structure in children with the chief complaint of jp. methods: we retrospectively analysed our series of 600 children which attending outpatient department with complaint about pain lasting longer than two months in one or more joints. the clinical, instrumental and laboratory pictures were collected. special attention was paid to certain aspect of medical complaints, a complete and accurate history and physical examination. different categories as possible etiologies of jp in children were systematize and detailed. results: all children were divided into several groups based on their anatomical and physiological characteristics of osteoarticular system: the first group consisted of 240 children under 6-7 years old, the second group -220 children 7-12 years old, the third group -140 children over 12 years old. research suggests that more preschool children were experience bilateral lower extremity pain by "post-walk genesis" due to natural hypermobility, immaturity of sensory innervation of the joints and imbalance of the leg muscles (e.g. growing pains). the second most common cause of jp was associated with intra -or postinfectious factor (viral, streptococcal and chronic focal of infection). the frequency of juvenile arthritis and other rheumatic diseases in children of this age group did not exceed 10%. special attention was paid to fever, chills, malaise, nightpain and constitutional symptoms with changes in blood lab tests to exclude osteomyelitis (inc specific cause), malignancies manifestation and other bone tumors (less 5%). the most common causes of joint pain of school-age children were hypermobility syndrome and enthesopathy (primary, secondary). secondary enthesopathy were result of changes in nutrition, rapid growth and excessive exercise. also enthesopathy were manifestation of endocrine, gastrointestinal or infectious diseases. the proportion of children with the onset of chronic inflammatory arthropathy also did not exceed 10%. hypermobility child's syndrome was characterized by harmless pain (inc low back pain), linked to physical activity (less morning stiffness). over the past decade, we've seen a gradual increase in the number of children (95% were girls) with knee pain by diagnosed patellofemoral and mediopatellar plica syndromes, patellar tendinitis or idiopathic cause. in most cases children was complicated by syndrome of increased anxiety. the share of true chronic inflammatory arthropathies, including spondylitis, in children of this age group did not exceed 10%. fibromyalgia were diagnosed less 5%. introduction: a significant part of patients in rheumatologist's practice is children and teenagers with complaints of pain. the further volume of examination and the choice of treatment course depends on the capability of the rheumatologist to define the inflammatory and non-inflammatory genesis of pain. that makes the problem of differential diagnosis very important. objectives: to conduct a comparative analysis of patients with a principal pain complaint to determine if there are significant differences in the groups with the inflammatory and noninflammatory pain genesis. methods: the retrospective study included children who consulted a rheumatologist in the outpatient clinic in the period 2018-2020 without preliminary selection (n = 176). of them there were selected children with principal pain complaint (n = 120). according to the diagnosis, the children were divided into 2 groups: those who have inflammatory genesis of pain (a, n =59) and those with noninflammatory genesis of pain (b, n =61). the group a included children with such diagnoses as: reactive, poststreptococcal and juvenile idiopathic arthritides. the group b included children with arthralgia, chronic pain syndrome, orthopedic pathology, fibromyalgia. results: 1. groups a and b differ in the average age of the first complaints onset (t-criterion for equality of means) with a high degree of statistical significance (group a = 7,4 years; group b = 9,3 years; p = 0.019). which means that in group a more often than in group b first complaints appear in the age between 1 to 10 while in group b more often than in group a it happens in the age between 11 to 16. 2. there was a statistically significant difference in the means between groups a and b in time between the onset of first complaints and the first visit to a rheumatologist (p = 0.03) also in favor of this conclusion speaks the fact that in group a the number of visits to a rheumatologist in the same year when the first complaints appear is almost 2 times higher than in group b. 56% of cases in group a consulted the rheumatologist the same year when the first complaints appeared in comparison to group b where only 31% of patients did the same. below is the table with distribution of cases by the number of years between the first complaints onset and the first visit to a rheumatologist in both groups: conclusion: in children with arthritides, the first pain complaints appear at an earlier age (an average of 7.4), and in group b (an average of 9.3). patients with arthritis more often visit a rheumatologist earlier (within 1 year after the first complaints) than those with non-inflammatory genesis of pain complaints. the most common cause of recurrent musculoskeletal pain is growing pain (gp) in children. differential from rheumatic diseases could be challenging in some cases since there are no diagnostic criteria for gp. objectives: to analyze gp characteristics in a large cohort of patients in comparison with other non-inflammatory and inflammatory diseases causing limb pain, and to simplify the gp's diagnosis process by using machine learning (ml) techniques. methods: this is a multicenter cross-sectional study. introduction: it is a well-known fact that the period of intensive growth in children is associated with the processes of active bone mass accumulation and coincides with them in time. one of the most distinctive indicators of an increase in the disease incidence among children for the recent decade (+105,3%) can be found in the skeletal disorders resulting from disrupted calcium metabolism and vitamin d deficit. the latter is widespread in ukraine as it is observed in 92% of schoolers. objectives: establish the specifics of the structural and functional status of the bone tissue in children during the growth spurt, taking account of the degree of vitamin d3 sufficiency. methods: the examination covered 147 children aged 9-17 who were divided into three groups depending on the presence of the growth spurt (gs) and its intensity: group 1 -35 children who had become 8-12 cm taller for the year in question; group 2 -32 children who had become taller by 12 cm or more, group 3 -80 children who had experienced no growth spurt. inclusion criteria were the following: no chronic somatic or endocrine pathologies, no musculoskeletal disorders or mineral homeostasis disruptions; physical exertion corresponding to their age; the children had not been taking any complexes of vitamins and minerals, including vitamin d 3 for 6 months before the examination. conclusion: children aged 9-17 showed deficiency of vitamin d 3 reaching 100% which had no correlation with the presence or intensity of the growth spurt. in children who experienced growth spurt, a reduced bmd proved more frequent and correlated with the spurt intensity, however, it did not depend on sufficiency of vitamin d 3. therefore, during the growth spurt, disrupted mineralization of the bone tissue was influenced not only by the vitamin d deficit but also by the correlation between the bone tissue mineralization rate and intensity of growth in the children. methods: a self-reported 25 question online survey on qol of patients with sjia and aosd was developed by the non-profit organizations, the autoinflammatory alliance, kaisz/vaisz, enca and sjia foundation in english and translated to dutch. respondents were recruited by convenience sampling through online social media posts. data on flares, triggers, family history, and correlation of symptoms with labs were collected in addition to detailed information on qol during and in-between flares. results: between 2017 and 2019, there were 109 responses; 54 were from parents of children with sjia, 18 from adults with sjia, and 37 from adults with aosd. interestingly, adults (whether diagnosed with sjia or aosd) were more likely to report pain, fatigue, joint swelling or arthritis, nausea & vomiting, and diarrhea during flares than children. adults were also more likely to describe flares >one month. 80% of patients reported being "greatly" or "severely" limited during flares. between flares, 20% reported being "greatly" or "severely" limited while 59% were "somewhat" limited. 80% felt their condition affected their studies, job, and career, including 66% of children with sjia, 100% of adults with sjia, and 92% with aosd. respondents were asked open-ended questions regarding their experience with disease flares and impact on their lives, and specifically how sjia and aosd affected work, career and schooling. responses regarding the disease experience were classified into 7 theme areas: 1) experience with disease onset and process of diagnosis; 2) health care access, quality, and drug safety concerns; 3) physical impact of the disease including pain and chronic fatigue; 4) social impact of the disease; 5) mental health and emotional impact of the disease; 6) impact on work, career, and employment; and 7) broad impact on life and lifestyle. responses regarding effect on work, career, and schooling were categorized into 3 theme areas: 1) physical impact negatively influencing school/work productivity; 2) lost work and wages, including unemployment and needing disability benefits, and parents missing work to care for the child; and 3) the socialemotional impact as well as negative effects on mental health. about half of patients regardless of age reported the name sjia did not represent well the disease, specifically that it did not emphasize the systemic symptoms, and that the disease gets confused with other types of arthritis. adult patients with sjia did not like to have juvenile in the name. conclusion: children and adults with sjia and aosd report high levels of qol limitation and effect on school, work, and career, both during and between flares. our qualitative data emphasizes the importance of multidimensional evaluation of disease with ongoing input from the patients, which will provide a foundation for asking more relevant research questions to foster better care and improve qol. results: in total 111 participants were included in the study : 62 juvenile idiopathic arthritis (jia) patients, and 49 their parents. the mean age of the patients was 13.7 ± 2.3 years. significant differences were found between patients and healthy children in such hrqol survey categories like "autonomy" and "financial resources" (p < 0.05). although quality of life in children's with juvenile idiopathic arthritis was lower than in healthy children in hrqol survey category "self perception" (p < 0.05). after analyzing data no significantly differences were found between patients and parents' assessment scores in hrqol survey categories (p > 0.05). conclusion: juvenile idiopathic arthritis has a moderate negative influence on hrqol survey categories "self perception", "autonomy" and "financial resources" (p < 0.05) according kidscreen-52 queationnaire. introduction: juvenile dermatomyositis (jdm) is often first identified by parents and carers as the red facial rash develops. the rash can progress and lead to young people being misdiagnosed with eczema, scarlet fever or psoriasis. however, over time the obvious signs of jdm can become "invisible" as treatment calms the rashes and masks the outward signs of jdm, until a flare occurs, when the rashes can be a marker for disease activity or progression. as part of a larger study, children around the united kingdom were asked to discuss their views on whether they wanted people to be able to see their jdm. objectives: to understand the implications for children and young people from having a disease that has visible and invisible phases and whether they want others to see their jdm, or not. methods: children and young people around the united kingdom who were already consented and enrolled into the uk juvenile dermatomyositis cohort and biomarker study were asked to complete a bespoke questionnaire. there was a mix of open and closed questions, and it was administered in paper format to all children and young people between the ages of 8 and 19 years of age for self-completion, either on the paper forms, or via a secure web-based software system. the questionnaires were administered at the end of 2018. numeric data were described and qualitative data were analysed using standard content analysis. results: 246 questionnaire packs were sent out, with 127 (52%) being returned. of these 4 could not be used due to practical reasons, such as only demographic data being completed, which left a sample of 123. 98 (80%) of the 122 who responded said other people could not see their jdm, with only 11 (9%) saying it was visible and 13 (11%) saying they did not know if others can see it. 1 did not respond to the question as said their jdm has gone away. they were then asked whether it was a good or bad thing for others to be able to see their jdm or for others not to be able to see it. 41 young people left comments as to why it was a good thing, 36 left comments as to why it was a bad thing and 14 left comments to why they said don't know, table 1 presents the top ranking response for the three multichoice answers. conclusion: this study has highlighted the disparity between young people wanting others to see their jdm so that they gain more understanding and empathy from those around them, but equally, wanting their jdm to be invisible, so that they feel the same as their peers. whilst many paediatric rheumatic conditions are in fact invisible, our data illustrate that jdm often gives children and young people a taste of both visible and invisible phases of disease activity. as one young person said "it's not good, nor badit's good that it's invisible sometimes so i can blend in without the disabled stereotype. however, sometimes it needs to be seen so i can be understood and not challenged". disclosure of interest: none declared multidimensional assessment report (j-fimar) which includes comprehensive patient self-report questionnaire and numerical rating scales to measure pain, fatigue, headache, sleep quality, physical function, psychological state, health-related quality of life, satisfaction with illness course. the j-fimar has been devised according to the outcome measure in rheumatology (omeract) guidelines. discriminant ability of the multidimensional tool was evaluated by testing it in a control group including healthy controls and patients affected by active juvenile idiopathic arthritis (jia). the psychosocial consequences of chronic pain were evaluated by using the children depression index (cdi) and the multidimensional anxiety scale for children (masc). the objective sleep quality was measured by overnight polysomnography. results: table 1 shows characteristics and the most represented somatic symptoms in our cohort of jfs patients at the study enter. polysomnography was performed in 21 patients with sleep disturbance; 8/21 (38.1%) showed an electroencephalographic pattern of alpha wave intrusion in slow wave sleep (sws). the presence of objective sleep disorders was significantly correlated to cdi score rs -0,775 (p≤0,0001) and masc 0,61 (p=0,005). from november 2016 to april 2020 j-fimar was completed by 43 jfs patients (f 35 (81.4%), median age 14.7 years [7.1-17.6], median disease duration 1.9 years [0.1-7.8]) in 125 visits. all patients filled out the questionnaire in a short time (<15 minutes) and considered it simple and easy to understand. jfs patients showed significantly higher score for pain, fatigue, poor physical function and measure of psychological distress than healthy controls and jia patients (p<0.05 for each item). conclusion: jfs patients presented significantly higher pain experience, functional disability, and impaired quality of life than patients with active jia. a relevant percentage of jfs patients experience sleep disturbances, which were correlated with mood and anxiety disorders. our multidimensional tool was feasible and able to quantify global jfs severity. this multidimensional tool, by measuring the main domains affected by the disease, could be promising to individualize treatment strategy and to test its efficacy. disclosure of interest: none declared introduction: fatigue is a subjective state of overwhelming, sustained exhaustion and decreased physical and mental capacity, which is not relieved by rest. fatigue is the most common complaint in children and teens with an autoinflammatory disease, besides the disease related flares. the purpose for this study was to show that fatigue is a serious issue for children and young people with autoinflammatory diseases. we hypothesized that age, gender and/ or the type of autoinflammatory disease could have differing effects on the fatigue experience. objectives: we aimed to investigate fatigue in children and young people (cyp) with autoinflammatory disease, including how this affected them on a daily basis. methods: cyp with autoinflammatory diseases were invited to complete an online survey, providing details about their fatigue and how it affected them. the survey was developed by the non-profit organizations autoinflammatory alliance and kaisz/vaisz, in english. respondents were recruited by convenience sampling through online social media posts. data on age, gender and disease were collected in addition to information on their experience of fatigue on school and social interaction. a total of 114 cyp (age range 7-18 years) with an autoinflammatory disease responded to the survey (52% female). results: the majority of respondents (81%) reported experiencing both mental and physical fatigue. respondents were asked how much their fatigue affected them, on a scale of 0 to 10; overall, the mean fatigue score was 6.6. however, young people aged 15 or over reported a significantly higher impact than those aged 11-14 years (mean 7.5, p=0.012). different autoinflammatory diseases were surveyed: crmo 25%, caps 20%, pfapa 12% also unclassified said (usaid) with 23%. in the open-response portion of the survey, 81% of respondents reported that fatigue was physical, as well as mental, in their experience. most (89%) reported that someone had doubted their fatigue in the past; 29% had found their teachers had doubted them, 26% had friends who doubted them, and 24% reported that they felt their doctors had doubted them. children and young people also felt a number of activities made their fatigue worse (table 1) ." conclusion: cyp with autoinflammatory diseases experience physical and mental fatigue. health professionals and teachers should listen to patients reporting fatigue, validate their experience, and help find ways to support them. identifying resources to help the patients with fatigue, and referrals to therapy and mental health resources as needed may help the patients to better cope and manage their chronic disease. further studies will include patient engagement in designing questionnaires about all aspects of life and autoinflammatory disease will help our understanding of these complex conditions and how they affect patients. introduction: scleromyositis is the most common overlap syndrome but is rarely observed in childhood. this disorder involves two different autoimmune diseases: systemic scleroderma (ssc) and polymyositis (pm). objectives: to describe the clinical course of a ssc/pm syndrome in a young girl. methods: case report results: an 11-year-old female was admitted to the neurological unit of our hospital for creatine phosphokinase (cpk) increase and hypertransaminasemia associated to sporadic episodes of right calf pain. familiarity for muscular dystrophy was reported in the maternal branch. muscle tone and trophism were preserved at initial neurological evaluation. laboratory investigation confirmed increased muscle enzyme levels, including cpk (x70) (ck-mm 94.5%, ck-mb 5.5%), aldolase (x7), cardiac troponin (x10) and myoglobin (x10). suspecting a primary muscle disease, she underwent a total body stir-mri which showed a diffuse edema of gluteus medius bilaterally and a muscle biopsy revealing a marked muscle damage with dystrophic aspects and normality of the tested proteins. a genetic extended panel for congenital myopathies resulted negative. after 4 months, a new clinical examination showed the occurrence of general skin induration, sclerodactyly and tightening of the face skin. appearance of dysphagia was also reported, and muscle enzyme increase persisted. in suspicion of an ssc/pm overlap syndrome, she was referred to our unit. nailfold capillaroscopy showed capillary dilatation and branching, megacapillaries and diffuse microhemorrhages. reduction of esophageal contractions amplitude and hypotensive lower esophageal sphincter pressure were observed at esophageal manometry test. high-resolution ct of lungs and pulmonary function testing were normal. skin biopsy showed sclerodermiform findings. immunological studies revealed a positivity of antinuclear antibody (1:320) and anti-ku. anti-pm-scl resulted negative. an oral corticosteroid therapy (prednisone, 1.5 mg/kg/day) was started in association with subcutaneous methotrexate (15 mg/m 2 /week) and intravenous immunoglobulins (ivig) (2gr/kg every two weeks). improvement of skin manifestation, joint mobility, as well as normalization of serum cpk levels were observed. over 3 months, prednisone and ivig were slowly discontinued up to the ongoing dosage of 0.9/mg/day and 2 gr/kg every 4 weeks, respectively. mtx is still ongoing at the same dosage. conclusion: the diagnosis of overlap connective tissue disease syndromes may be challenging in pediatric age. different symptoms may be prevalent at different stages throughout the course of the disease. in our patient, a localized myositis preceded the ss onset by about four months. even though the use of high dose of corticosteroids is associated to a higher incidence of renal crisis in patients with css, a combined therapy with high doses of oral steroids, ivig and mtx was safe and effective in skin, muscle and joint symptoms in our patient. results: a total of 336 images were obtained from 118 healthy children included in the study and 708 capillary measurements were made. capillary density was significantly higher in group 4 than in groups 1 and 2. arterial width was significantly lower in group 1 as compared to group 3 and 4, and in group 2 as compared to group 4. apical loop width and capillary distance were significantly lower in group 1 compared to group 2 and 3 and 4. there was no significant difference between the age groups in terms of capillary length and venous width. there was no difference between the groups in terms of capillary morphology. in total 336 image evaluations, capillary tortuosity was <50% in 67.8%, and > 50% in 4.2%, and capillary crossing were <50% in 52.5% and> 50% in 3.4%. while the enlarged capillary was 4.7% and the avascular area was 4.2%, capillary branching, capillary meandering, microhemorrhage, and giant capillary were not detected in any case. there was a good level of agreement between the researchers, as 20 cases with 120 capillaries were evaluated with a good level of agreement (table 1) . conclusion: this is the first study to evaluate capillary morphology in healthy turkish children. this study also adds that some special forms such as enlarged capillary and avascular area, which is always named as pathological in adult age, can be seen in healthy children. these data will be guiding in capillaroscopic studies in various patient groups, particularly in children with collagen vascular diseases. methods: 308 patients with jia were tested for hla-b27. they were divided into 2 groups: 1) hla-b27 positive and 2) hla-b27 negative. results: 100 patients (32,5%) were hla-b27 positive and all of them are fulfilled the eular criteria of entesitis-related arthritis (era). the group 2 consists of 208 patients (67.5%). there's no statistical difference between both groups in active joint count, ana-positivity and uveitis frequency, the rate of use methotrexate and time before biologics. no difference in axial cervical spine 12 (12.0%) vs 21 (10.1%) (p=0.613) and sacroiliac joints 18 (18.0%) vs 23/207 (11.1%) (p=0.097) involvement was observed. hla b27(+) patients often received pulse therapy with methylprednisolone due to increased inflammatory activity and severe arthritis (22% vs 11.1%, p=0.011). other parameters are listed in table1. conclusion: patients with hla-b27 positivity were characterized by male predominance, more often hip involvement, higher laboratory activity and the need for more frequent use biologics. the rate of axial involvement wasn't different in hla-b27 positive and negative patients, that needs further study and creating more accurate classification criteria for jsa. disclosure of interest: none declared introduction: although gut is increasingly recognized as origin and/or target of inflammation in adult onset spondyloarthritis (spa), the incidence of gut involvement in juvenile spa (jspa) patients is still largely unknown, mostly due to the lack of reliable non-invasive tests. objectives: we performed a cross-sectional study of fecal calprotectin (fcal), a surrogate marker of gut inflammation, in patients with jspa, other forms of juvenile idiopathic arthritis (jia) and noninflammatory (ni) conditions. methods: fcal was measured by commercially available assay in stool samples of enthesitis related (era), psoriatic (psa) and patients with other jia subtypes (oligo-and poly-articular) who fulfilled ilar criteria, as well as in children with ni causes of musculoskeletal pain (ni-msd), regardless of the gastrointestinal (gi) symptoms (table 1 ). fcal was compared among different groups of patients and correlated with demographic data, clinical characteristics, treatment modalities and disease activity measured by jspada. the values were also dichotomized to <50 mg/kg, 50-200 mg/kg, and >200 mg/kg, which was regarded as normal, slightly increased and increased, respectively. ileocolonoscopy was performed in one patient. our study has shown that fcal levels are significantly higher in era patients compared to other jia (p=0.03) and/or ni-msd (p=0.03) patients. moreover, almost a third of patients with era had levels of fcal above the range regarded as normal, which adds to the number of evidences for a gut inflammation in this particular type of jia. besides, the fcal levels were higher in those with axial involvement, which further suppots the association of gut and axial inflammation in children with era. although endoscopy remains a gold standard for the diagnosis of gut inflammation, fcal can help to select children with era who might benefit from this invasive procedure, regardless of the gi symptoms, as shown in one patient with the highest fcal concentration in our study. moreover, fcal levels seems not to be influenced by disease characteristic and/or concomitant therapy intake. therefore, fcal should be a part of diagnostic workup in children with any type of jia, but most importantly in those with era. evaluate potential predictor variables of magnetic resonance imaging (mri) sij remission methods: retrospective review of prospectively collected data. we included patients with era (according to ilar criteria) continuously treated with anti-tnf agents for ≥ 12 months who had at least two mris of the sacroiliac joints performed before starting anti-tnf therapy (baseline) and during the follow up ( > 12 months after anti-tnf treatment). si joints were examined using t1-weighted images, t2 fastsuppressed and short-tau inversión recovery. the sparcc-sis was scored by two pediatric radiologists. sparcc-sis assessed the presence, depth and intensity of bone marrow edema (bme) on consecutive six slices in the iliac and sacrum bones . scoring is composed by: bme (0-48), bm intensity (0-12), bm depth (0-12 introduction: several paediatric patients manifest conditions commonly misdiagnosed as spider bites, which however, can include other arthropods bites; bacterial, viral, and mycotic infections; vasculitis; dermatological diseases; miscellaneous conditions as drug reactions, chemical injuries. objectives: in italy, spiders which are likely to be associated with severe toxin mediated tissue damage are uncommon, especially in urban zones. however, a minor trauma may be a precipitating factor for pyoderma gangrenosum particularly over the legs, in association with inflammatory bowel disease, haematologic diseases and juvenile idiopathic arthritis (jia). methods: we describe a 11-years old boy with pyoderma gangrenosum complicated spider bite in association with systemic jia (sjia). the patient was in clinical remission after the start of the sjia, occurred two months before, still treated with tapering doses of steroids and canakinumab, with the normalization of inflammatory parameters (crp, esr, saa, ferritin) and clinical manifestations. only a mild arthritis of the knee persisted and for this reason he was still treated with steroids. furthermore, he developed hyperglycemia, requiring insulin treatment. the first dermatological manifestation which he referred was a red dot of the leg skin. in a few days, the erythema enlarged, involving an area of 7 x 7 cm, with oedema, pain, and blisters, evolving in a necrotic lesion, with purulent exudate, surrounded by a haemorrhagic zone. results: haematological controls revealed neutrophilic leucocytosis, increased crp and procalcitonin. he started treatment with intra venous administration of teicoplanin plus ceftriaxone, with no resolution of the clinical manifestations and the reduction of leukocytosis, crp, procalcitonin. a culture swab was performed and was positive for pseudomonas aeruginosa, confirmed by pcr on the culture. he started ciprofloxacin and surgical curettage of the lesion, with the resolution of the lesion and the normalization of biochemical parameters. conclusion: the aspect of the lesion and its evolution were evocative of a spider bite suggested by anamnestic records, complicated by a pyoderma gangrenosum secondary to pseudomonas aeruginosa. the underlying disease, the immune suppressive treatment, with steroids and biological drugs, the hyperglycaemic pattern of the patient allowed the severe evolution of the spider bite. children in treatment with immune suppressive and/or biologic drugs are at high risk of infections. skin lesions, as arthropods bites, can be a facility for superinfection, with possible haematological and systemic diffusion. the strict application of the ilar 1 requirement for the presence of documented arthritis for the diagnosis of sjia, early in the disease course, may result in unnecessary delays in initiating appropriate treatment. in preliminary printo 2 classification criteria for sjia, this mandatory requirement of documented arthritis has been modified. to measure performance of preliminary printo classification criteria for sjia in our indian cohort. methods i gathered a data of seven sjia patients who attended dev children's hospital between jan 2019 and jan 2020. my data included demographics,clinical presentation, laboratory parameters and outcome of these patients. all these patients were diagnosed at an early stage by clinical judgement irrespective of fulfilment of ilar criteria. i applied preliminary printo classification criteria for all. average age of selected children (4 girls and 3 boys) was 5.1 years. conclusion a preliminary printo classification criteria for sjia has been validated in our cohort. there are many raised inflammatory markers in most of these patients other than wbc count. these markers should be considered to be added in supportive laboratory criteria to be more specific towards the diagnosis. it is important to add pid in exclusion list especially in a case of sjia with mas at onset. 3 trial registration identifying number leningrad's regional children' two patient stopped treatment within 6 months from therapy start: due to primary inefficiency (1) and allergic reaction (1). five (5/11) patients were-co-administered with cdmards, other 5with oral gc, and 6 subjects had been previously exposed to other biologic drugs. whole 5 patients stopped therapy due to secondary inefficiency: 2 patients were switched on toc, other children were switched on eta (1) introduction: systemic juvenile idiopathic arthritis (sjia) is a rare, complex auto-inflammatory disease with significant morbidity including fever, rash, serositis and articular problems. with the availability of interleukin-1 (il-1) and il-6 inhibitor treatment, morbidity has significantly reduced and the outcome for sjia patients has improved. however, differences in access to care and differences in treatment strategies between countries in and outside of europe remain a concern. objectives: the single hub and access point for paediatric rheumatology in europe (share) consortium aimed to develop best practices for paediatric rheumatic diseases in order to decrease differences in care between european countries. here, we present the final results of the literature review and a series of consensus meetings on defining overarching, diagnostic and therapeutic recommendations for diagnosis and treatment of sjia. methods: the share methodology has been previously published, including the use of the eular standardized operating procedure for developing best practice recommendations. as per these guidelines, a methodologist provided supervision during the process and consensus meetings. conclusion: hscore seems to perform slightly better than ms-score for the diagnosis of mas in our cohort. early inhibition of il-1 is discussed to play an important role in the disease course of sjia 1 . assuming that pretreatment with other dmards leads to a later start of therapy with canakinumab, this analysis evaluates the effectiveness of canakinumab as first-line vs. second-line dmard. to evaluate the effectiveness of canakinumab as first used biological dmard in sjia compared to canakinumab in sjia-patients pretreated with other dmards. methods sjia-patients documented in the german biologic registry for pediatric rheumatology (biker), who were exposed to canakinumab, were identified. for the first-line (fl) group dmard naïve patients were selected, prior treatment with corticosteroids and/or nsaids was allowed. patients receiving any dmard prior to canakinumab entered the second-line (sl) group. both groups were compared in a retrospective intention-to-treat-analysis. effectiveness canakinumab treatment showed good effectiveness in sjia both as first-and second-line dmard. after 6 months the use of canakinumab as first-line dmard is associated with higher response rates compared to second-line use. our data support the hypothesis that early treatment with canakinumab is associated with good therapeutical response and a positive effect on the disease course of sjia. results: a total of 11 children (9 girls) with sle were identified. median age of symptom onset and diagnosis was 14 years(range 8-17 years) and 11 years respectively. the presenting manifestations were fever(5), oral ulcers(3), alopecia(3), malar rash(4), photosensitivity(5), renal involvement (5), seizures(1) and gastrointestinal complaints (1) apart from some unusual manifestations of isolated peripheral arthritis(1), isolated bilateral pleural effusion(1), macrophage activation syndrome(2). laboratory investigations: hemogram revealed anemia in 8 children and thrombocytopenia in 5. urine examination showed nephrotic range proteinuria in 1 child and subnephrotic proteinuria in 2. microscopic hematuria was noted in 2 pateints. renal function tests were deranged in 2 cases. ana, anti dsdna positivity and hypocomplimentemia were present in all. renal biopsy was done in 4 patients, 2 had class iv, one class iii and one had class v lupus nephritis. all patients were initiated on hydroxychloroquine and photoprotection. children with renal involvement were given pulse methylprednisolone followed by tapering doses of oral prednisolone and intravenous, monthly cyclophosphamide. azathioprine was used as maintenance therapy in all. subcutaneous weekly methotrexate was used in 2 patients. one child (mas) died during disease course. disease continues to be in remission in rest. conclusion: we found a significant female preponderance in our study group. renal involvement was the commonest presentation. some unusual presentations were also seen. early recognition of sle is critical for timely initiation of appropriate treatment. this is the first report of a cohort of pediatric sle from this part of india. introduction: autoantibodies in ahai may be igg/igm/iga. ahai can be divided into primary or secondary (e.g. sle, lymphoproliferative diseases, infections, medications). it is also classified based on the temperature at which the antibody reacts to erythrocytes, and can be warm (igg or iga) or cold (igm or c3). in warm ahai, the antibodies react at temperatures ≥37ºc, not activating the complement system and not undergoing agglutination in vitro. in cold ahai, antibodies react at temperatures below 37ºc, activating the complement system with in vitro agglutination.mixed aiha (warm and cold) is rare and occurs in <10% of aiha cases and can occur at any age, but is extremely rare in children. the prevalence of the mixed form is less than 1/1,000,000 patients with ahai. objectives: to report a rare case of mixed ahai and idiopathic intracranial hypertension(iih) in a 15-years old female patient with a previous diagnosis of sle and aps. methods: case report and literature review. results: a 15-years old female adolescent previously diagnosed with sle/aps since 2017 was in remission on hydroxychloroquine(400mg);azathioprine(150mg);aspirin(100mg);vitamind3(1.000iu);calcium(1g), and sunscreen. in april 2020 , she had a relapse presenting with fatigue, myositis, headache, hypocomplementemia, and severe autoimmune hemolytic anemia (hb of 4g/dl) (sledai-2k=18 points). mixed ahai was diagnosed base on a direct/indirect coombs test 4/4+;directantiglobulintesting showing anti-iga(weak),anti-igm(3+/4+),anti-igg(3+/4+),anti-c3c(weak),anti-c3d (3+/4+);igg1/3subclasses with a reaction of 1:100(2+/4+);an eleven cell antibody panel positive revealing a cold and warm antibody, and adsorption technique revealing a cold and warm autoantibody. chest ct showed bibasilar subsegmental atelectasis, head ct/mri was normal and lp showed a high opening pressure of 45cmh2o with a normal cell count. after the procedure, the patient reported improvement in the pain and was diagnosed with iih. the patient was screened for secondary causes for ahai (table 1) due to the unusual mixed type pattern and serology was positive for chlamydia trachomatis (igm) and mycoplasma pneumoniae (indeterminate-igm/positive-igg) suggesting a recent infectious trigger causing reactivation of the underlying disease with a probable cross-reactivity. the patient treated with 10-days of clarithromycin. before the infectious screening came back negative, ahai was treated with a single dose of ivig(1g/kg) and then, with 3-days of methylprednisolone(1g/day). azathioprine was replaced by mycophenolate mofetil. due to headache recurrence, acetazolamide(500mg/day) was started, and the patient referred no pain. the patient was discharged with a resolution of the symptoms. objectives: to our knowledge, the association of gbs and bbe has been described in adults only. methods: we here describe a child presenting at sle disease-onset with an overlap of peripheral (gbs) and central (bbe) nervous system manifestations, highlighting the possible association between these two entities in children. results: an 11-year-old healthy girl presented with acute ataxia, ophtalmoparesis and altered level of consciousness, rapidly followed by areflexia, facial paresis, swallowing difficulties, sensory deficits, paresis in all four limbs and respiratory insufficiency. these symptoms were accompanied by pleuro-pericardial serositis, proteinuria and hypertension. immunological investigations revealed the presence of positive ana and ds-dna antibodies. the renal biopsy showed a stage iii lupus nephritis. hence, the clinical, laboratory findings and biopsy report led to the diagnosis of psle. brain and spine mri did not show any abnormalities; diffuse slowing compatible with nonspecific encephalopathy was seen on eeg. nerve conduction studies (ncs) confirmed the clinical suspicion of acute polyradiculoneuropathy with proximal interruption of motor nerve conduction, compatible with guillain-barré-like syndrome. csf analysis (performed twice) remained normal. the patient was treated with glucocorticoids, intravenous immunoglobulins, cyclophosphamide as well as plasmapheresis. the neurological and physical symptoms improved gradually with complete neurological recovery four months after onset. conclusion: overlapping forms of bbe/gbs have never been described in association to sle in children. our patient's presentation and evolution fulfilled the criteria for such an overlap, occurring at psle onset. although sle and bbe/gbs are rare entities, our case suggests that there may be a common underlying immune background. this association should be recognized early for rapid and appropriate treatment initiation. infantile antiphospholipid antibody syndrome: acquired and de novo apl appearance in four infants t. giani 1 , g. ferrara 2 , a. mauro 3 , r. cimaz 4 introduction: antiphospholipid syndrome (aps) is a rare condition in the neonatal age. in most cases it is considered a passively acquired autoimmune disease, due to a transplacental passage of maternal antiphospholipid antibodies (apl). exceedingly unusual is the de novo production of apl in newborns and infants. objectives: to describe four infants who developed an early brain stroke with increased and persistent levels of apl, even after six months of life. methods: we reviewed the clinical charts of four such infants, followed from diagnosis up to two years after the disappearance of apl. conclusion: common characteristics of these four children are the development of brain stroke and the increased and persistent apl levels even after six months of life. this opens the window on a gray zone related to the origin of these antibodies (maternal or neonatal) and on their role in the pathogenesis of the infantile brain stroke. patients had over 20% of their monitoring completed but only 2 had over 80%. aspects of monitoring that were more time intensive or were required less regularly were most frequently overlooked. there was a statistically significant increase in the percentage of completed monitoring in those patients for whom the lupus checklist was used compared to patients where a checklist was not used (p=0.00). conclusion: there is significant room for improvement in the monitoring of these patients with jsle in the rheumatology clinic. this audit illustrates that more diligent use of the lupus checklist and an overall improvement in sustained use of the checklist will help to improve monitoring of these patients. evidence suggests that checklists are underutilised in medicine and wider implementation of this simple tool could improve patient outcomes. 3, 4, 5 interventions such as in person or electronic reminders, or audits with feedback to physicians could improve usage over time. the application of the lupus checklist or a similar document in other paediatric clinics is important for comprehensive monitoring of a condition as complex as jsle and has the potential to prevent ongoing damage and medication toxicity in this high-risk population. juvenile onset and this cluster have may more severe kidney, neuropsychiatric or hematological involvement. objectives: the aim of this study was to assess the clinical and laboratory characteristics, disease activity, and treatment response of patients with juvenile sle (jsle). methods: this is a retrospective study involving patients between 1 july 2016 and 1 january 2020. the data of patients diagnosed with jsle and followed up for a minimum of 6 months, were collected. the sledai-2k scores at initiation and at the follow-up (1st, 3rd, 6th, and 12th months of treatment) were examined. the sledai-2k score was considered to be ≤4, for disease remission status. results: a total of 49 children were included in to the study. the female/male ratio was 4.4/1 and the median age of the patients at the diagnosis was 13 (iqr: 11.1-15.2) years. the median follow-up of patients was 19 (iqr: 12-25) month. four of the patients were diagnosed with monogenic sle. two siblings were diagnosed with c3 deficiency and two were diagnosed with familial chilblain lupus. the most common clinical findings were found musculoskeletal complaints (69.4%), malar rash (51%), oral ulcers (38.8%), and fever (30.6%), respectively in over all the group. the frequency of involvement of the system and organs was as follows; mucocutaneous 77.6%, musculoskeletal 69.4%, renal 44.9%, hematological 34.7%, serous membranes 16.3%, neuropsychiatric 12.2%, respectively. all patients had anti-nuclear antibody positivity, while 46.9% had anti-ds dna, 14.3% had anti-sm and 8.2% had antiphospholipid antibody positivity. while all patients received hydroxychloroquine treatment, 22.4% of the patients were received were mycophenolate mofetil, 22.4% were azathioprine, 14.3% cyclophosphamide, 12.2% methotrexate and 10.2% were rituximab. the median sledai-2k score was 14 (iqr: 10-18.5) at admission, besides it was found to 6 (iqr: 4-12), 4 (iqr: 2-6), 2 (iqr: 0-6) in the 1st, 6th and 12th months of treatment, respectively. while 98% of the patients had active disease at admission, 67.3% at 1 months, 32.7% at 6 months and 22.4% at 12 months still had active disease (sledai-2k >4). patients with initially high sledai-2k scores had significantly lower remission rates in the first month (p=0.003). it was observed that patients with high sledai-2k scores in admission were more resistant to conventional immunosuppressive treatments and the use of rituximab was more frequent in these patients. at least one major organ (renal, hematological, neurological) were affected in 57% of patients. the remission rate of these patients at 6 months was found significantly decreased compared to the others (p <0.005). renal biopsy was performed in 21 patients (42.9%). 12 of them had type 4 lupus nephritis (ln), 5 had type 2, 2 had type 3, and 1 had type 5. it was observed that patients with renal involvement were the group that reached remission latest. conclusion: the presence of high initial sledai-2k scores and the major organ involvement have poor predictive value to achieve inactive disease. a two year old girl of consanguineous parents presented to hospital at 13 months of age with fever and erythematous macular rash on her cheeks which spread to her nose, chin, and ears. the rash started a month prior, and progressed over her entire body. a skin swab grew staphylococcus aureus but the rash didn't respond to topical antibiotics. review of systems was unremarkable except for longstanding oral thrush and diaper rash. birth and family history were unremarkable. on exam she had a diffuse, erythematous, morbilliform eruption over her face and body. she had facial swelling, orbital edema and vasculitic oral ulcers. she had leukopenia mainly neutropenia, low hemoglobin, with normal platelets. her liver enzymes and erythrocyte sedimentation rate (esr) were high while c-reactive protein, immunoglobulins, c3 and c4 were normal. cultures were negative, however she was positive for adenovirus, mycoplasma and ebv (ebv load was 6000 iu/ml ). autoimmune hepatitis work up was negative. the direct coombs test, antinuclear antibodies (1:640), ro, rnp and smd were positive. ch50 came low as well as c1q level of 4 mg/dl (normal range 12-22 mg/dl). lymphocyte subsets showed reduced cd4 and nk cells. bone marrow aspiration showed active marrow. skin biopsy showed chronic non-specific inflammation (immunofluorescence and electron microscopy were not available). echocardiogram showed dilatation of the left coronaries. she was treated with intravenous immunoglobulin (ivig) for kawasaki disease with no improvement. therefore pulse steroid 30mg/kg followed by 2 mg/kg was initiated. her rash, facial swelling and abnormal blood counts improved dramatically. whole exome sequence showed homozygous variant c.469g>t p.g157c at the c1qa gene. while tapering steroids she flared so subcutaneous methotrexate was started. unfortunately, she continued to have rash, leukopenia and high liver enzymes, so treatment was switched to mycophenolate mofetil and hydroxychloroquine. however she did not improve and started to have recurrent bacterial and viral infections that included cellulitis, gastroenteritis and upper respiratory tract infection. we started her on regular ivig, which helped with infections and allowed for weaning of steroids. however she developed alopecia and lower limb spasticity with delayed walking. mri brain and spine was normal. upon reanalysis of the wes, two other homozygous mutations at kif1c and apg7 were identified and associated with spastic paraplegia, but reported as variants of unknown significant. fresh frozen plasma (ffp) transfusions were started, initially weekly, then every two weeks and subsequently every four weeks. the rash disappeared, leukopenia and esr improved and we were able to discontinue steroids conclusion: early-onset sle with a severe course of disease raises the possibility of a genetic etiology. we are reporting, for the first time, a rare missense mutation g>t in exon 3 of the c1qa gene that resulted in an amino acid substitution that is pathogenic. interestingly, she had other mutations associated with neurological manifestation that never reported together before and altered her phenotype. she has responded well to ffp as has been reported in a few case reports results: a total of 148 psle under the age of 13 years were included, 30% (n = 44) were males. the overall mean age at diagnosis was 7.6 ± 3.5 years and median disease duration was 9.5 (5-13) years. huv was diagnosed in 34.5% (n = 51) of psle cohort. psle with uv were more likely to be males (57% vs 15%; p < 0.001), diagnosed at a younger age (5.9 vs 8.5 years; p < 0.001), have a family history of sle (53% vs 36%; p = 0.044) and have conjunctivitis more frequently (32% vs 5.3%; p < 0.001) than psle without uv. psle with uv were also less likely to have cns involvement (7.6% vs 20%; p = 0.045) and hematological manifestations such as leukopenia (9.4% vs 24%; p = 0.028) and thrombocytopenia (5.7% vs 18%; p = 0.045). in addition, psle with uv were more likely to be associated with low c3 complement count (94% vs 66%; p < 0.001) and positive cytoplasmic anca (11% vs 0%; p = 0.022).however, the psle with uv cohort were less likely to be associated with ana (65% vs 83%; p = 0.016), dsdna (56% vs 72%; p = 0.042) and perinuclear anti-neutrophil cytoplasmic antibodies (33% vs 55%; p = 0.047). conclusion: we report a high occurrence of huv in psle cohort (34.5%) associated with unique demographic, clinical features and laboratory features. the debate regarding whether huv is a rare subset or unusual type of sle, or is a separate entity altogether, continues. however, the overlap in clinical, laboratory and genetic mutation supports the notion that huv and sle fall into the same spectrum of autoimmune disease with similar disease pathogenesis. however, further studies are needed to reach clear conclusions regarding the relationship between huv and sle. introduction: the last decade has brought a lot to the approaches to the diagnosis and treatment of juvenile arthritis. in russia, the actualization of the problem of diagnosis and treatment of jia required the development of federal standards, which provide the most detailed algorithms for medical care, both at the stage of inpatient and outpatient care. in the regions of the russian federation, the effective use of these documents required a whole range of additional educated activities, both with students of medical universities, as well as with the medical and nursing community, in addition, a set of work was carried out to create a regional regulatory framework. in the total biological therapy pool, 67% of patients receive tnf-alpha inhibitors, antibodies to il-6 receive 27% of patients, antibodies to il-1 -6,25%. it is worth noting that when using biological agents in 60% of cases, the criterion of an inactive disease was achieved by 4-5 months, which was characterized by the absence of acute inflammatory symptoms, normalization of esr and crp. monitoring of patients with jia receiving biological agents required the conduct of a number of educational activities for medical personnel, the creation of an additional methodological base. for further training of young specialists at the regional medical university, a program of an additional educational course in pediatric rheumatology was developed and introduced. a regional patient organization was established and also required a set of information activities by the medical community. conclusion: in the saratov region of the russian federation, about 20% of patients with jia receive biological therapy, which corresponds to the average indicators according to the literature. in the structure of the biological drugs used, the group of tnf-alpha inhibitors is preserved -67%. the introduction of modern methods of treatment using biological agents in jia has significantly increased the effectiveness of treatment, but it required the organization of additional information support for medical personnel. disclosure of interest: none declared introduction: immunogenicity and development of anti-drug antibodies have been associated with treatment failure and adverse events during biologic treatment. anti-drug antibodies (adas) have been reported in 21% of juvenile idiopathic arthritis patients treated with adalimumab. however, their role in reducing adalimumab efficacy is still debated due to conflicting results. no study has been directed toward identification of neutralizing adas in paediatric rheumatic disorders. objectives: aim of our study was to detect adas, along with their clinical relevance, using a new theranostic peptide-base assay in a cohort of children with inflammatory chronic diseases on adalimumab treatment. methods: six candidate adalimumab derived peptide antigens (hc-cdr1, hc cdr2, hc cdr3, lc cdr1, lc cdr 2, lc cdr3) have been developed and optimized to be tested. their performance has been compared with commercial elisa kit and a spr-based optical assay (biacore®). assays have been performed in sera of a cohort of children receiving adalimumab due to an inflammatory chronic disease. mean age, disease duration, concomitant treatment with methotrexate (mtx), ana positivity, disease activity parameters and scores at the time of ada determination have been recorded. chisquare, and fisher exact test were used to compare data. pearson's and spearman's correlation tests were used to determine correlation coefficients for entered variables. results: eighteen (14 f, median age 12.6, range 3.8-16, yrs) patients were enrolled: 16 affected by juvenile idiopathic arthritis, 7 of whom complicated by jia -associated chronic uveitis, and 2 patients affected by chronic idiopathic uveitis. peptide assay revealed adas in 8 children, biacore in 6, commercial elisa in 5. of note, we found total concordance among the 3 tests just in 2 patients. no significant correlation has been proven among the 3 ada determinations. biacore and elisa determination showed significant concordance (r s : 0.72, p<0.006). the presence of hc cdr3 and lc cdr 3 resulted significantly correlated with disease activity (r s : 0.57, p<0.05), and, inversely, with disease remission on treatment (r s = -0.523, p<0.05). no patient experienced severe adverse events and no correlation with adas has been revealed conclusion: in chronic rheumatic disorders, novel reliable methods are urgently required to guide clinical decision and support decisions about switching within or between drugs in refractory children. the 3 different methods, since based on different antigenic probes, detect different antibody populations. the present peptide-based assays might contribute to identify neutralizing adas in patients treated with adalimumab. further validation in larger cohort is required. introduction: non-bacterial multifocal osteomyelitis (nbo) is a rare polygenic autoinflammatory disease, which is difficult to diagnose and treat. because of combination of bone lesions with arthritis and/ or axial skeleton damage in most cases the diagnosis of juvenile idiopathic arthritis (jia) or juvenile ankylosing spondylitis (jas) may be establish as a concurrent diagnosis, so this allows to legal use of biologics (ba) for the treatment. objectives: to analyze the single center experience of clinical and laboratory features of multifocal nbo in patients (pts) who were treated by ba for the last 8 years. methods: the study involved a retrospective cohort of multifocal nbo pts treated by different ba in our clinic from 2013 to 2020. all of them underwent standard rheumatological examination. in order to examine all localizations of the bone damage, a scintigraphy and/ or "whole body" mri scan was performed. results: among the whole group of pts with nbo (n=40) we identified 13 pts treated by ba (tnf-inhibitors only). the majority were girls (n=9, 69 %). age at disease onset was 10.2 years in average (me 10.2 range 1.3-16.5). for legal reason of ba administration, we classified our patients according to rheumatological features as jia or jas. 7 pts had jia (5 girls), 6 pts had jas (4 girls). among 13 pts 9 had oligoarthritis (69%), 4 had polyarthritis of low limbs (hip, knee, ankle). axial involvement was represented by active erosive sacroiliitis with deep bone marrow edema on mri scan in 9 pts (69%), active spondylitis of several bodies in thoracic spinein 2; erosive arthritis with partial ankyloses of facet joints of neck in 3 pts, multiple syndesmophytes in 1 girl. we found that definite axial lesions in nbo developed in very young children (in 2 y.old at minimum), much earlier than in "idiopathic" jas. hla b27 was presented in 5 pts (39%), 5 pts had ana in high titer (all of those hla b27-negative). the pts had bone lesions in different parts of skeleton: vertebral bodies -5 pts, clavicle -1, sternum, ribs -1, extremities bones, metaphysic mostly (tibial, fibular -7 pts), sacroiliac region -4 pts. extraskeletal manifestations were observed in 3 pts, one in each condition -uveitis, psoriasis pustulosus, acnae conglobate. in a girl with very severe course of disease, not responded to any therapy nbo was combined with familial mediterranean fever. high level of laboratory activity were detected before biologics in 10 pts (77%): esr acceleration up to 60 mm/h, increase of crp up to 80 mg/l. treatment included nsaids (all), methotrexate (7 pts), sulfasalazine (6 pts, but it was withdrawn in all pts), bisphosphonates (1 pt), prednisolone (3 pts). because of high activity of nbo with appearance of new bone lesions and persistent arthritis tnf inhibitors were administrated: etanercept in 10 pts, adalimumab -4 (2 as first line, 2second line), golimumab -1. at the start of ba the average age was 13.7 years (range 7.2-17.9); mean disease duration was 3,4 years (range 0.3-8.1). there were 2 cases of withdrawals. due to inefficacy etanercept was switched to adalimumab. disease activity decreasing was reached in the most of the patients (12 from 13). among them 2 pts developed the whole remission with resolving of active arthritis and bone marrow edema spots. skin lesions (psoriasis pustulosis and acnae conglobate) were significantly improved. there were no adverse events during the tnf therapy. conclusion: our experience of the therapy with tnf inhibitors in patients with high nbo activity has shown that this is a good and safe therapeutic option that is expected to prevent progression and bone destruction. . ae were reported for 71.7% of patients, most within 24 to 48 hours after the first or second injection: flu-like symptoms (57.5%), hypocalcaemia (37.5%) and hypophosphatemia (20%). underweight patients (body mass index < 18.5 kg/m²) accounted for 50% of hypocalcaemia. the frequency of all the ae not significantly decreased with the reduction of the first dose. only one serious hyponatremia occurred corresponding to a patient with renal failure before treatment. conclusion: our results were similar to those previously published: bisphosphonates are safe for osteoporosis in children. in the literature, sae are very rare in children, being limited to anecdotal osteopetrosis in cases of higher doses and long-term treatment, and delayed bone healing. anecdotal osteonecrosis of the jaw in adults has never been described in children. the use of bisphosphonates beforehand requires dietary measures (vitamin d and calcium supplementation). furthers systematic collection on efficacy and safety parameters for each bisphosphonates drug should confirm these data. introduction: the use of biosimilars in rheumatology has increased significantly over the last 5 years and has resulted in considerable cost savings. objectives: to assess the effectiveness and tolerability of the adalimumab biosimilar abp 501 in patients with jia. methods: a database of patients prescribed adalimumab in our service has been screened to identify patients with jia, who switched from the originator to the biosimilar. only patients who had a clinical review since they had started the biosimilar were included. a paired-samples t-test was conducted to compare the number of active joints at the clinic appointment before and after the initiation of the biosimilar treatment. the frequency and type of side effects, the clinical response and the number of patients who switched back to the originator have been collected. results: sixty-one patients who switched to the biosimilar abp 501 between february 2019 and february 2020 were included. they were comprised of 30 enthesitis-related arthritis (era), 13 polyarthritis, 9 oligoarthritis, 6 psoriatic and 3 systemic jia patients. their baseline characteristics and outcomes are summarised in table. the mean duration of follow-up after the switch to biosimilar was 10 months (range 2-23). eleven patients (18%) reported side effects; the most common side effect (n=7, 63.6%) was injection site reactions and the remaining 4 consisted of anaphylaxis, druginduced lupus, dizziness and bone pain, respectively. seven patients (11.5%) reverted to the adalimumab originator, 4 as a result of side effects, 3 because of ineffectiveness and one patient for both reasons. in addition, 3 patients were changed to a different biologic, one patient due to allergy to both the originator and biosimilar and the other two patients had active disease on the originator and biosimilar adalimumab. two patients stopped the biosimilar and remained off any biologic, in the first case this was due to a side effect and in the second case it was patient's choice. on the whole, 78.7% of patients had remained on abp 501 at their last visit. there was no significant difference in the active joint count before the biosimilar was started (mean 0.55+/-1.11) and after the switch (mean 0.6+/-1.59), (p= 0.855). introduction: golimumab (gol) is approved for polyarticular juvenile idiopathic arthritis (pjia) in patients of ≥2years but long-term safety data are limited. objectives: prospective monitoring of long-term safety and effectiveness of gol in routine care using the biker-registry. methods: baseline demographics, clinical characteristics, disease activity and safety parameters were compared to a contemporary 1:2 matched control cohort using alternative tnf inhibitors or methotrexate without exposure to a biologic. efficacy outcomes were jadas10, joint counts and functional status. safety assessments were based on adverse events (ae) reports. results: in this ongoing study, 65 pts initiating gol were matched to 130 with alternative tnfi and 65 biologic-naïve pts. pts starting gol had a longer disease duration (p<0.0001) and use of gol was significantly more often second line (84.6% vs 22.3%, p< 0.0001) and thus disease activity was lower at baseline. pts in the gol cohort used less corticosteroids, otherwise patients were comparable with pts treated with other tnfi (table 1 ). in gol treated ps a marked clinical response was noted at 6 months and beyond, indicating the effectiveness of gol in the treatment of pjia. a significant decrease of the mean jadas 10 11.3 to 5.3 (p= 0.0008) after 6 months of treatment was observed, as well as jia acr 30/50/70/90 response rates of 61/59/42/29%. jadas remission and minimal disease activity was observed in 27% and 53.7% after 6 months and in 39% and 54% after 12 months of treatment. rates of ae, sae and infectious ae were comparable in the gol cohort (87.5/100py, 3.4/100py and 11.1/100py), the alternative tnfi cohort (92.3/100py, 2.9/100py and 9.7/100py) and the mtx only cohort (121.2/100py, 2.1/100py and 18.5/100py). sae reported in the gol cohort were flares of uveitis and of jia (each 1) and fibromyalgia syndrome (1) . sae reported in the alternative tnf cohort was two serious infections (both influenza), one knee ligament injury, one flare of arthritis and one hyperventilation . no case of pregnancy, malignancy or death was reported. conclusion: golimumab seems an effective in treatment of pjia. tolerability was acceptable and comparable to alternative tnfi or mtx. recruitment to the project is ongoing. disclosure of interest none declared introduction: methotrexate (mtx) is one of the most commonly used disease-modifying anti-rheumatic drug in rheumatology practice. it has some side effects that can impair quality of life. the most common of them is associated with the gastrointestinal tract. objectives: the aim of the study is to evaluate and compare the frequency of methotrexate intolerance in adult and pediatric patients. methods: patients with rheumatologic diseases followed in hacettepe university pediatric rheumatology and rheumatology departments who used oral or parenteral methotrexate for at least 3 months were included in the study. methotrexate intolerance was assessed using 'methotrexate intolerance severity score (miss) questionnaire. the miss questionnaire consisted of 5 parts: abdominal pain, nausea, vomiting, fatigue and behavioral symptoms. the patients scored the severity of each symptom separately; 0: no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe symptoms. a total score of 6 or more was defined as mtx intolerance. visual analogue scale (vas) ranging from 0 cm to 10 cm was performed to each patient concurrently with the miss questionnaire. in the pediatric patient group, miss questionnaire and vas assessment were applied to both patients and families. results: a total of 100 patients, 50 of whom were children, enrolled in the study. the mean age for children and adults were 11.78 (± 3.4) and 52.9 (± 11.8) respectively. the most frequent diagnosis of patients was juvenile idiopathic arthritis (78.0%) in children and rheumatoid arthritis in adults (68.0%). the mean mtx dose in adults and pediatric group was 12.5 (±3) mg vs 14.5 (± 3.6) mg (p: 0.004). the prevalence of mtx intolerance in children and adults were 66.0% (n:33) and 14.0% (n:7) respectively. the mean miss score in the pediatric group was higher compared with the adults (12.4±9.4 vs 1.84±4.5, p<0.001). similarly, the mean vas scores were higher in pediatric group (1.2±2.4 vs 4.2±3.2 (p<0.001)). there was a strong correlation between miss and vas scores between family and child evaluations (p <0.01, r = 0.95 / p <0.01, r = 0.94). abdominal pain, nausea, vomiting and behavioral symptoms were observed more frequently in children compared to adults. results: 3(4%) out of 73 patients were diagnosed with psoriasis denovo. one patient was treated with ada (a girl with undifferentiated arthritis who had positive hla-b 27, anf and family history of psoriasis -her grandmother had psoriasis), 2 patients were treated with eta (both female, one patient had undifferentiated arthritis, the other had enthesitis-related arthritis; both patients had positive hla -b 27 and anf negative). 2 patients achieved significant improvement after changing tnfalpha inhibitor (1-ada, 1-eta), 1 patient (was treated with eta) had significant improvement after discontinuation of biological therapy. conclusion: this single-center observational study demonstrates the possibility of developing psoriasis de-novo in patients with jia receiving tnf-alpha inhibitors. although more extensive research is needed, our data suggest that discontinuing the tnf-alpha inhibitor or switching to another tnfalpha inhibitor in patients with psoriasis de-novo should be considered as a treatment strategy in such cases. objectives: long-term surveillance of patients newly initiating toc treatment for at least 5 years compared to a cohort of patients newly initiating a comparator biologic using the biker-registry. methods: baseline demographics, clinical characteristics and disease activity, efficacy and safety parameters were compared. efficacy outcomes were jadas10, joint counts and functional status safety was assessed by adverse events (ae) reports. results: 161 patients with 161 matched controls have been recruited. patients starting on toc were older at treatment start (12.1 vs. 10.1 years (y); p<0.0001) and had a longer disease duration (p< 0.0001). toc was significantly more often a second line biologic (p< 0.0001). baseline jadas10 (17+/-10 vs 15+/-6), chaq-di (0.63+/-0.63 vs 0.65+/-0,64), esr 18+/-15 mm/h vs. 21+/-21 mm/h and active joint counts (7+/-7 vs. 6+/-5) were comparable. upon toc a substantial response with a significant reduction in jadas 10 from 16.8 to 3.4 (p<0.0001) after 12 months of treatment was observed. there were no significant differences between patients from the toc cohort and their matched controls in the jia acr 30/50/70/90 criteria, jadas 10, jadas remission and minimal disease activity was reached by comparable numbers (toc 37% and 58%; control cohort 37% and 60%). the total number of ae was comparable (toc cohort n=201 ae; (77/ 100py); control cohort n=207; (65/100py; rr 1.2; 95%ci 0.99-1.4). more serious ae (sae) were reported with toc. serious infections were documented at lower frequency with toc. uveitis events were documented at significantly higher frequency with tnf inhibitors most likely due to a selection bias (table 1) . sae with toc were depression (n=3) in 2 with suicidal intent, exacerbation of jia (n=2), septic arthritis, gastrointestinal infection, abdominal pain, colitis, paronychia and fracture. sae in the control cohort were depression, osteomyelitis, gastrointestinal infection and disease flare. no significant differences regarding cytopenias and elevated transaminases were observed. no gastrointestinal perforation, no vascular events and no deaths occurred. conclusion: toc was effective and comparable to treatment with alternative biologics. tolerability was acceptable. as toc was given as a second-line biologic in the vast majority of patients comparisons between the 2 cohorts have to be interpreted carefully. observation is ongoing. conclusion: in this retrospective cohort study in pediatric patients on rtx-treatment, we found undetectable low drug levels in adapositive patients, indicative for their neutralizing capacity. consequently, the lack of b-cel depletion leads to reduced treatment efficacy. patients with sle seem more susceptible to develop ada. if ada are detected, continuation of treatment seems non-effective and changing medication is advised. certainly when considering that, in this study, anaphylactic reactions only occurred in ada-positive patients. none declared objectives: the aim of this study was to evaluate retrospectively the long-term efficacy and safety of adalimumab in patients with jiaassociated uveitis. methods: we have retrospectively analysed nineteen jia patiens data with associated uveitis from our centre registry between 2010 and 2020, treated with adalimumab after failure of treatment with corticosteroids and metotrexate. demografic data and blood samples were collected at different time points while uveitis activity was evaluated by slit-lamp biomicroscopy. adverse events were recorded. results: registry records provided 10 years follow up of 19 jia patients data with associated uveitis. eleven patients were females (57.90 %) diagnosed as oligo/extended oligoarticular jia while eight (42.10 %) were males diagnosed as enthesitis related arthritis (era). before adalimumab was prescribed, all patients were previously treated with metotrexate during 3.5 years in avarage dose of 10 mg/ m 2 weekly. the mean uveitis duration, before adalimumab administration was 9 months. ten years long follow up period have showed that there were no new relapsis of uveitis while patients were receiving adalimumab and metotrexate. all of our patients were able to gradually tapper and stop treatment with topical steroids two months after adalimumab commencing. seven patients were able to stop biological treatment after 4.3 years of adalimumab usage. uveitis relapsed three monts after the adalimumab discontinuation only in one patient. two patient were lost to follow up during the transitional period. no serious adverse events were recorded. conclusion: during the long term follow up period adalimumab have shown good efficacy and safety profile in jia patients with active inflammatory ocular disease. introduction: post-streptococcal syndrome is a systemic immunemediated complication of beta-haemolytic streptococci infection, mostly seen as post-streptococcal arthritis, rheumatic fever or glomerulonephritis. uveitis is an uncommon manifestation of this syndrome. objectives: case report methods: case report results: a previously healthy 7-year-old female was admitted at the emergency department with prolonged fever, arthritis and red eye. she had a 4-month history of febrile episodes every two weeks, with axillary temperature ranging from 37,8 to 39ºc. migratory arthralgia affecting both knees and tibiotarsal joints showed up two months after the fever onset and worsened in the previous week, with refusal to walk. non-painful bilateral red eye for several weeks was mentioned. other symptoms were absent. recent infections were denied and family history was irrelevant. physical examination revealed lower limb muscular atrophy, knees pain and impaired function and bilateral tibiotarsal arthritis with inability to walk. ophthalmological observation showed a bilateral non-granulomatous anterior uveitis. sequential laboratory work up revealed a maximum eritrocitary sedimentation rate of 135 mm/h, maximum c-reactive protein of 5,3 mg/dl, microcytic hypochromic anemia, positive antistreptolysin o titer (asot) (initial result of 1250 that increased to 2500 in 4 weeks and later decreased to 500) and negative anti-nuclear antibodies. cardiac involvement was excluded. the diagnosis of rheumatic fever with concomitant poststreptococcal uveitis was assumed and the patient was treated with oral and topical ophthalmic corticosteroids with prompt clinical resolution of fever, acute polyarthritis and uveitis. no relapse occurred in a 5-year follow-up. conclusion: juvenile idiopathic arthritis (jia) is the most common cause of uveitis in childhood. although our patient clinical course could initially raise the possibility of systemic jia (sjia), the criteria that define this entity weren't all present and clinical and laboratory findings were more supportive of rheumatic fever. besides, uveitis occurs exceptionally in sjia, which turned this diagnosis even less reasonable. in our rheumatology unit, among 563 patients diagnosed with jia in 32 years, 89 had uveitis. however, in the group of 51 patients with sjia only one had ocular involvement, a boy with isolated vitritis. post-streptococcal uveitis (psu) typically presents as bilateral, non-granulomatous anterior uveitis, as described in this case. as streptococcal infection is very common among children and many patients may experience subclinical infection. psu should be considered in all patients with uveitis along with positive asot and negative routine investigations for other causes. although psu has been described in literature, to the best of our knowledge, this is the first reported case of concomitant rheumatic fever and psu. . ada was first tapered to every 3 weeks by 76% of the responders and then to every 4 weeks by 49% before discontinuing. fewer respondents used or tapered ifx, toc or aba. around 65% tapered the interval and 20% tapered the dose and interval for aba, 26% for toc and 37% ifx there were differences in the duration of tapering prior to discontinuation of specific medications. for ada it was 6 months in 62%, 12 months in 36% ,and 24 months in 10%. for ifx it was 6 months in 27%, 12 months in 45%, and 24 months in 33%. for toc it was 40% after 4 weeks, 87% after 6 weeks and 53% after 24 weeks. for aba i.v. it was 30% after 8 weeks, and 90% after 12 weeks. if combination therapy was used, 36% tapered the bdmard first, 62% csdmard first, and 12% both simultaneously. conclusion: this is the first survey to describe "real world" medication tapering and discontinuation practices of pediatric rheumatologists and ophthalmologists globally. most physicians start to taper medication after 24 months of remission on medication and discontinue after the 6 to 12 months of tapering. we would like to thank all the participating colleagues, who took time to fill out our surve introduction: jia-associated uveitis (jia-u) occurs in 10-20% of children with juvenile idiopathic arthritis (jia) and typically asymptomatic, and sight-threatening complications occur in 50% of children, (i.e. cataracts, vision loss). frequent ophthalmic examinations are important for early diagnosis and monitoring of uveitis activity. even after uveitis is controlled, risk of disease exacerbation still exists. therefore, frequent ophthalmic screening and monitoring is important for detection and management of jia-associated uveitis (jia-u). s100 proteins, cytokines, and chemokines detected in aqueous humor of patients with uveitis are also detected in tears. biomarker discovery using tears is promising since collection is noninvasive, feasible, well-tolerated, and close to the target organ. objectives: we aim to determine if s100 proteins, cytokines, and chemokines levels differ in tears of children with jia and jia-u and in children with jia-u by uveitis activity. methods: tears were collected using schirmer strips from children ≥5 years old with oligo-or polyarticular rf negative jia with (jia-u) and without uveitis (jia-no-u), and in children with jia-u at time of active and inactive eye disease. activity was defined by standardization of uveitis nomenclature (sun) criteria. active uveitis was anterior chamber inflammation grade ≥0.5+ cells. s100a8, a9, and a12 were measured by elisa, and il-18, il-8, ip-10, mcp-1, rant es, and sicam-1 by luminex assays. biomarker levels were compared in children with 1) jia-no-u (n=8) to active jia-u (n=8), and 2) jia-u (n=8) at time of active and inactive uveitis. results: children with jia-no-u and jia-u were matched by jia subtype and arthritis activity. they had primarily oligoarticular jia (63%), active arthritis (25%), and were on systemic medication (75%). at time of active uveitis, 75% had grade 0.5+, and 25% had 1+ and mean interval between time of active and inactive disease was 11 months. we found that levels of biomarkers in tears of children with jia-no-u compared to active jia-u were similar. although not statistically significant, levels of s100a12 (mean difference 12,190 pg/ml [95% ci -4847 to 29,227], p= 0.14) and sicam-1 (5329 pg/ml [95% ci -5372 to 16,031], p=0.28) were higher when uveitis was active compared to inactive. conclusion: our results suggest that s100a12 and sicam-1 are potential biomarkers of uveitis activity in jia-u, but not uveitis diagnosis. thus, neutrophils may play a role in the pathogenesis of anterior uveitis which has been reported in an animal model of acute anterior uveitis. identifying biomarkers using tears provides a noninvasive and objective method of monitoring uveitis. limitations are our heterogeneous cohort that varied by arthritis severity and immunosuppression, and minimally active uveitis. we were underpowered to detect statistically significant differences and continue to collect tears prospectively in children with jia-u with goal of n=28. despite low uveitis activity, we were still able to detect differences. further studies in larger and diverse cohorts are necessary to assess the role of s100a12 and sicam-1 in jia-u. objectives: to report an extremely rare presentation of gpa in a 12 year old with acute digital ischemia. a 12 year old boy, with a background of poorly controlled type 1 diabetes and hypothyroidism, initially presented to hospital unwell with diabetic ketoacidosis. treatment was initiated promptly with good response. furthermore, he was found to have weight loss, productive cough and hearing loss over the past 3 months. he was haemodynamically stable, but very pale and cachectic. he had reduced air entry and crackles on the right. there was hypertonia and clonus in his lower limbs. blood tests showed microcytic hypochromic anaemia (hb 82g/l), normal white cell count, thrombocytosis and raised inflammatory markers (crp 138mg/l and esr 68 mm/hr). his chest x-ray showed enlargement of the right hilum with consolidation/ atelectasis extending into the middle and lower lobes. mri scans of head and spine were normal apart from fluid opacification in the paranasal sinuses. he was screened for infections including tuberculosis and started on intravenous antibiotics. on day 13, he developed painful bluish discolouration of his left hand, particularly his thumb, index and middle fingers. his left radial and brachial pulses weren't palpable. a heparin infusion was started. a doppler scan showed occlusion of radial and ulnar arteries proximal to the wrist with no clear thrombus. he had a ct thoracic aorta with contrast which showed proximal left radial artery occlusion and distal ulnar artery occlusion with no evidence of proximal embolic source or vasculitis. it showed multiple perihilar masses (lymph nodes) in the right lung and peripheral parenchymal masses in both lungs, suggestive of atypical infection or connective tissue disease. blood tests still showed raised inflammatory markers(crp 107mg/l, esr 86 mm/hr and platelets 658 10 9 /l). an autoantibody screen showed positive anca with strongly positive anti pr3(>100 u/ml); other autoantibodies, including ana, ds dna and anti-phospholipid antibodies, were negative. he developed further ischaemia with bluish, painful discoloration of his right foot, especially right great toe, with a weakly palpable dorsalis pedis pulse. doppler scan revealed occlusion/narrowing of the posterior tibial artery 6cm proximal to the ankle. following vascular team advice, he was started on ilioprost infusion to aid reperfusion of the extremities involved, with good results. based on clinical and lab features of systemic inflammation, evidence of upper airway involvement(bilateral conductive hearing loss and sinusitis on mri scan), parenchymal lesions on ct chest and strong pr3 positivity, a diagnosis of gpa was made. results: our patient responded well to therapy including multiple pulses of high dose methylprednisolone and cyclophosphamide, with improvement of all organs involved and no further digital ischemia. conclusion: although gpa is very rare in children, it is associated with high morbidity and mortality. many studies show that the spectrum of paediatric gpa is not vastly different from adults, except for higher gender bias towards female, more constitutional and musculoskeletal symptoms and higher risk of subglottic stenosis. although there are a handful of case reports of digital ischaemia in adults with gpa, to our knowledge this is the first case report of acute digital ischaemia in paediatric gpa. early diagnosis and prompt treatment with a multidisciplinary team approach is paramount for good outcome. introduction: adenosine deaminase-2 deficiency (dada2) is a monogenic vasculitis syndrome whose presentation ranges from recurrent fevers and livedo reticularis to systemic vasculitis, hematologic and immunologic abnormalities, and early-onset stroke. it is characterized by biallelic loss-of-function mutations in the encoding gene of ada2 protein and low levels of ada2 enzymatic activity in the peripheral blood. the genotype and phenotype features of dada2 has a wide spectrum. treatment with anti-tnf inhibitors is effective in controlling vascular inflammation and reducing strokes. objectives: to describe two sisters with different presentations of dada2 and a deletion mutation on exon 7 of the ada2 gene. methods: medical data was used to describe the clinical manifestations of two siblings. parental informed consent was obtained. results: patient 1: a 10-year-old female had presented with fever, rash, arthralgia, hepatosplenomegaly, and coombs positive autoimmune hemolytic anemia (aiha) at the age of 7 years. she had been followed with a suspected diagnosis of systemic lupus erythematosus (sle) and steroids, azathioprine, mycophenolate mofetil had been used. her ana and complement levels were normal. because of unmet classification criteria of sle, genetic testing had been done, and no mutation found in the ada2 gene. cranial mr and mr angiography was normal. she was referred to our clinic after 2.5 years of the first manifestation. physical examination revealed raynaud phenomenon on both hands and feet, livedo reticularis, arthritis, and splenomegaly. laboratory tests indicated an increase in acute phase reactants, cd19, cd20, and switched memory b cell lymphopenia, and hypogammaglobulinemia. because of prolonged fevers, a thorax ct was obtained and aneurisms of the renal artery were seen. abdominal ct angiography indicated multiple aneurysms of both renal, intercostal, and hepatic arteries. repeated genetic analysis of the ada2 gene showed a homozygous deletion mutation on exon 7. she has been followed on anti-tnf and iv immunoglobulin without severe symptoms for a year. patient 2: the older sister had been followed with a diagnosis of familial mediterranean fever with e148q heterozygous mutation because of recurrent fever, abdominal pain, erysipelas-like erythema, elevated acute phase reactants, and splenomegaly. she did not have any other cutaneous or systemic findings. because of parental consanguinity, the ada2 gene was analyzed and a homozygous deletion mutation on exon 7 was found. she has been followed without any symptoms after anti-tnf treatment. throat swab was negative. abdomen ultrasound showed bowel wall thickening, testis ultrasound was normal. hsp diagnosis was confirmed. methylprednisolone iv was administered for three days, then oral prednisone was started. purpuric lesions, abdominal pain persisted, so we decided to add mmf (600mg/ m 2 /day) and prednisone was tapered in a month. results: thanks to mmf vasculitis lesions and abdominal symptoms disappeared in few days. mmf was continued for a month, tapered in 6 months. there was no evidence of relapse in a 6 months follow up. conclusion: these cases suggest that mmf may be useful to induce and maintain remission of recurrent hsp with gastrointestinal involvement. multicenter clinical trials with long-term follow up to confirm the efficacy of mmf in the treatment of hsp with gastrointestinal involvement are needed. introduction: henoch-schönlein purpura (hsp), the most common childhood vasculitis. cholecystitis is extremely rare in patients with hsp. this is the first case of a libyan child presenting with hsp complicated by calculus cholecystitis hsp nephritis. objectives: our aim is to present an unusual case of gall bladder involvement in an 8-year-old libyan female affected by hsp. methods: a case reports study results: : we report an unusual case of gall bladder involvement in an 8-year-old libyan female with hsp. she was referred to a rheumatology clinic due to hsp with chronic calculus cholecystitis and distended small bowel with fluid-like fecal material with no evidence of intussusception on an abdominal ultrasound. the patient had a one-month history of abdominal pain, purpuric lesion on lower limbs and swelling in both feet. she was admitted 3 times to another hospital before being referred to the rheumatology clinic. an abdominal sonography revealed a distended small bowel with fluid-like fecal material with no evidence of intussusception and chronic calculus cholecystitis; they treated her with urosdoxycholic acid tab at 250mg per day and ibuprofen syrup. then referred to our rheumatology clinic. after 40 days, she showed a purpuric rash over her lower extremities, mainly over her thighs and buttocks, microscopic hematuria, no arthritis, no fever, no abdominal pain; her blood pressure was normal at90\55mmhg, and she had normal laboratory tests (cbc, wbc 7.7, hgb 10.8, platelets 356 esr 20ml\hour, crp 1mg\dl was negative, c3 was 150mg\dl within normal range 90-180mg\dl, c4 was 35.4 mg\dl within normal range 10-40, anca, ana, as well antidsdna ab yielded negative, antistreptolysin-o (aso) titer was 250 todd , lft included total bilirubin , direct , indirect gpt,got, u�, creatinine ) except urine routine showed mild microscopic hematuria rbc 100 hpf , protein was nil ) urine for pro-tein disclosure of interest none declared p161 correlation of serum neopterin levels with disease activity and moneta 1 1 division of rheumatology, irccs, ospedale pediatrico bambino gesù, roma; 2 university of genova a multinational study of thrombotic microangiopathy in macrophage syndrome clinical impact of a targeted next-generation sequencing gene panel for autoinflammation and vasculitis laboratory biomarkers to facilitate differential diagnosis between measles and kawasaki disease in a pediatric emergency room: a retrospective study a rare case of measles-associated hemophagocytic lymphohistiocytosis in an infant. cureus children's interstitial and diffuse lung disease respiratory complications of the rheumatological diseases in childhood on behalf of dr nishant dharsandiya and dr j.p. keshrani paediatric rheumatology & immunology, dev children's hospital arthritis care res (hoboken) disclosure of interest: none declared development and initial validation of the ms score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis development and validation of the hscore, a score for the diagnosis of reactive hemophagocytic syndrome double-blind, placebo-controlled study of anakinra in pediatric and adult patients with still's disease l. schanberg 1 , p. nigrovic 2 duke children's hospital & health center, durham; 2 boston children's hospital, boston; 3 children's mercy kansas city, kansas city; 4 university of alabama at birmingham, birmingham; 5 nationwide children's hospital, columbus; 6 university of iowa hospitals and clinics children and adolescents with sle: not just little adults severe disease presentation and poor outcomes among pediatric systemic lupus erythematosus patients in south africa the checklist manifesto: how to get things right clinical review: checklists -translating evidence into practice the who surgical safety checklist: a review pehlivanoğlu 3 p283 gastrointestinal henoch-schönlein purpura treated with mycophenolate mofetil: description of two case reports venous vessel wall thickness in lower extremity is increased in male patients with behcet's disease increased vein wall thickness in behçet disease polyarteritis nodosa: a contemporary overview eular / printo / pres criteria for henoch -schönlein purpura , childhood polyarteritis nodosa , childhood wegener granulomatosis and childhood takayasu arteritis : ankara six patients were treated with canakinumab and 2 patients with anakinra. conclusion: it is known that excessive production of il-1β can cause inflammatory bone loss and abnormality. vitamin d deficiency and osteopenia/ osteoporosis may cause additional musculoskeletal problems besides arthritis and joint destruction in caps. we think that ca metabolism and bone mineral density measurements should be a part of routine controls in patients with caps. disclosure of interest none declared ab007 clinical and genetic features of patients with periodic syndrome associated with mutation of the tumor necrosis factor receptor gene and juvenile arthritis having mutations in tnfrsf1a gene m active arthritis in 8/9, it was poly in 2, oligo in 6. when assessing the clinical symptoms and laboratory activity of patients with jia, it was revealed that in the onset of the disease, systemic manifestations were observed in 8/12: fever in 8/12, rash in 4/12, hepatosplenomegaly in 5/ 12, pneumonitis in 2/12, carditis in 1/12 and lymphadenopathy in 5/12. high laboratory activity was recorded in 11/12. active arthritis in 10/12, it was polys in 4, oligo in 6. in all 100% of patients, the nucleotide variants of the tnfrsf1a gene were identified in the study. 9/21 of patients were diagnosed with traps. the most frequent heterozygous variant of tnfrsf1a gene with nucleotide substitution of c.362g>a was found in 7/9 of patients, in 1/9 of patients it was found homozygous variant with nucleotide substitution of c.362g>a, in 1/9 of children it was found heterozygous variant with deletion of c.337_339del. all of these variants are pathogenic. 12/21 of patients were diagnosed with ja: juvenile arthritis with a systemic onset was in 7/12, paucarticular arthritis was in 2/12, in 1/12 it was poly rf-and in 1/12 it was psoriatic arthritis. it is worth noting to note that in 6/12 a heterozygous version of the tnfrsf1a gene was detected with a nucleotide substitution c.362g> a, however, considering the absence of clinical manifestations of autoinflammatory disease and active articular syndrome in these patients, children were diagnosed with ja. in addition dvoryakovskaya: none declared, a. mamutova speaker bureau of: novartis, k. isayeva: none declared, r. denisova speaker bureau of: novartis covid-19 and relapsing kawasaki disease: a case report during the pandemia m. c. maggio ab009 introduction: the pandemia of covid-19 remains a global health alarm with high incidence of lethality, especially in older age groups who suffer from underlying medical conditions. however, children are less likely to manifest severe conditions. objectives: covid-19 was correlated to a higher incidence and a suspected increased risk of kawasaki disease (kd) in children anamnestic records revealed a previous kd, without coronary artery lesions (cal), 1 year before. results: he was treated with antibiotics, intravenous infusion of immunoglobulins (ivig) (2 gr/kg), acetylsalicylic acid (asa) (50 mg/kg in 4 doses/day) and reached defervescence into 2 days. echocardiography excluded cal. the nasopharyngeal swab for sars-cov-2 was doubt. the second throat swab done the day after ivig infusion, was negative; however, the third nasopharyngeal swab for sars-cov-2, done 4 days after ivig infusion, was positive. chest x-ray showed a significant lung interstitial thickening. il-6 levels were < 6.25 pg/ml (n.v. < 6.25 pg/ml). he continued treatment with antibiotics, asa (5 mg/kg/day), with the progressive resolution of the clinical symptoms and of the normalization of laboratory findings. conclusion: the peculiar outcome of the patient is the correlation of covid-19 with kd, recently reported as associated. kd is considered as a multifactorial autoinflammatory disease, induced by a cytokine hypersecretion with a systemic vasculitis. covid-19 is considered a cytokine storm syndrome, with a severe systemic vasculitis. sars-cov-2 infection could be the trigger that could lead to hyperinflammation of kd. the ivig infusion could explain the transient negative swab for sars-cov-2, with the successive positive relieve lasting 7 days, and the normal levels of il-6, detected after ivig infusion. relapsing kd is rare (1.7-3.5%); in our patient this event could be triggered by the documented sars-cov-2 infection. disclosure of interest none declared disclosure of interest none declared ab012 spectrum of systemic inflammatory syndrome in children during covid 19 pandemic in india d. b. pandya, on behalf of dr haresh dobariya pediatric rheumatology & immunology, dev children's hospital ab025 rituximab for treatment of resistant paediatric mctd v. paisal, s. compeyrot-lacassagne paediatric rheumatology the diagnosis and classification of of mixed connective tissue disease mixed connective tissue disease in children -case series the value of rituximab treatment in primary sjögren's syndrome juvenile idiopathic arthritis a multifaceted approach is essential for robust rehabilitation m methods: in a retrospective study 92 children (89% girls) aged median (iqr) 4,2 (1,6 -7,6) years with oligoarticular onset jia without extra-articular manifestations (oligo-ja) who did not received dmards were monitored. all children were met ilar criteria. ttriamcinolone acetonide (ta) was administered intra-articular at a dose of 20-40 mg with an injection interval of 3-6-12 months which was depended on the activity of the disease. the maximum allowable number of consecutive isolated intra-articular injections (is-iai) was 3-4. a total of 218 active joints were injected with ta: knees -156 injections, ankles -62 injections. all children were divided into two groups: active / inactive arthritis based on the effectiveness of local corticosteroid treatment. the average follow-up was 48 and physicians' assessment of jia disease activity efficacy is-iai of ta was no associated significantly with number of active joint of onset oligo-ja, cjadas10, serum level of crp mg/ml, esr mm/h, il6 pg/ml and tnf-α pg/ml, titer of anf. the mean inflamed synovial fluid of il6 levels 2208 abstracts from conferences and relevant studies were added. rcts were included if (i) patients were aged ≤ 20 years, (ii) patients had a previous defined pediatric rheumatic diagnosis and (iii) rct met predefined outcomes. studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤ 5 patients. study design, location, duration, treatment, population, sample size, age criteria, gender, concomitant treatments and primary outcome was extracted. results: out of 550 screened references, 62 references reporting 35 unique rcts in pird. all 35 rcts reported efficacy while 34/35 rcts provided safety outcomes and 15/35 rcts provided pk data. ten of 17 reviewed bdmards are approved for pirds by the food and drug administration (fda). of these, seven had ≤ 2 rcts. the most common intervention was tnf inhibitors (63%) treatment with intravenous immunoglobulin (ivig) significantly reduces the risk of caas. however, up to 20% of cases are ivig resistant with a higher risk of cardiovascular complications. currently several second-line treatments are available for refractory kd. nonetheless, the existing literature is still unable to identify which treatment is the most effective. recent studies suggest that a il-1 receptor antagonist (anakinra) may be an effective therapy in refractory kd. objectives: we report the case of a 3 year-old boy diagnosed with kd refractory to conventional treatment, who developed giant caas successfully treated with subcutaneous (sc) anakinra. methods: case report. results: a 3 year-old boy was referred to our pediatric rheumatology unit 18 days after the onset of a typical refractory kd. he had been previously treated at a local hospital with two doses of ivig (2 g/kg), infused respectively 8 and 11 days after the onset of the fever. afterwards, given the persisting fever, doses of pulse intravenous (iv) methylprednisolone (mpdn 30 mg/kg/day) have been used for 3 days followed by oral prednisone (2 mg/kg/day). treatment with acetylsalicylic acid (60 mg/kg/day q8h) was also started. following a transient defervescence the day after the first iv pulse mpdn, fever relapsed and the echocardiography showed caas of left main coronary artery (lmca), left anterior descending (lad) and right coronary artery (rca) rationale and study design for a phase i/iia trial of anakinra in children with kawasaki disease and early coronary artery abnormalities (the anakid trial) the use of interleukin 1 receptor antagonist (anakinra) in kawasaki disease: a retrospective cases series there are few reports of acute kidney injury (aki) in kd, defined as serum creatinine level elevation to more than 1.5 times of baseline level. objectives: to describe the case of kawasaki disease complicated by aki methods: a 5-year-old female was admitted to our rheumatology unit with persistent fever (6 days), widespread polymorphous exanthema, change in lips and in oral mucosa. family history was unremarkable. she had no chronic underlying disease nor history of previous hospitalization. at admission, she appeared stable. body temperature was 38.9°c, o2 saturation was 96% in ambient area, blood pressure was 118/75 mm hg, heart rate was 90 bpm, respiratory rate was 21 breaths per minute. on examination she presented widespread polymorphous exanthema, changes in lips and in oral mucosa, cervical lymphadenopathy and bilateral conjunctival injection. results: exams revealed: white blood cells 11980/μl, hb 10.4 g/dl, platelets 389.000/μl, albumin 2.5 g/dl, serum sodium 126 meq/l, serum chloride 90 meq/l. transaminases were in normal range. creatinine was 1.5 mg/dl disclosure of interest none declared ab041 paediatric extra-pulmonary large vessel arteritis, a forme fruste of pediatric behcet's disease? we presented two siblings from a consanguineous marriage with different clinical presentations of dada2. further, we emphasize that genetic testing should be repeated in the presence of clinical suspicion. introduction: there are several scoring systems developed in japan that are clinically used to stratify high risk kd patients and thus identify the ones that may benefit from early adjunctive therapy. there are increasing reports from all over the world on poor performance of these scores in other ethnic populations. objectives: the aim of our study was to evaluate the kobayashi, egami, sano and kawamura scores in our population which is homogenous caucasian. methods: hospital database was retrospectively searched for code m30.3 of the international classification of diseases, 10th revision, clinical modification code: mucocutaneous lymph node syndrome [kawasaki] , over the period from january 2006 to december 2019. all patients who were seen in this period for the first time for complete or incomplete kawasaki disease, as defined by the american heart association, were included. we applied ivig resistance prediction scores (kobayashi, sano, egami and kawamura scores) to our cohort. only patients who received 2g/ kg ivig within the first 10 days of the disease were included in this analysis. the scores of prediction models were calculated for each patient and patients were assigned to high-or low-risk group accordingly. results: during the study period a total of 169 children were diagnosed with kd (61.5 % males, median age 3.28 years). all of them were caucasian except one child who was biracial (caucasian and african american). among them, 158 children were hospitalized in the acute phase of the disease and 11 children were seen in the subacute phase of the disease. 151 children were followed-up for at least one year to evaluate persistent coronary artery aneurysms (caa), which were observed in 8 (5.3 %) patients. among them, 2 were not treated with ivig and 2 received ivig after 10 days of illness. 125 patients were treated with ivig within first 10 days of illness and were included in the calculation of ivig resistance prediction scores. 24 (19.2 %) were ivig resistant. sensitivity of kobayashi, sano, egami and kawamura scores were 0.53, 0.47, 0.61and 0.58, respectively. specificity of those scores were 0.77, 0.87, 0.75 and0.58, respectively. we found no difference in demographic or clinical characteristics between ivig resistant and ivig responsive patients. patients with ivig resistance had significantly higher alt (p = 0.025), neutrophil-to-lymphocyte ratio (p = 0.036) and lower serum sodium (p = 0.009). conclusion: by applying the japanese scores to our population, we were able to identify most of the low-risk, but missed many of the high-risk patients. our results are consistent with caucasi n based population studies available to date. introduction: varicella zoster virus (vzv) related arterial ischemic stroke (ais) has been described in literature in pediatric age. however, the long-term course of post-vzv vasculopathy need to be inquired: clear information about prevalence of recurrence and severity of clinical outcome are lacking, even if a favorable evolution was initially described, and therapeutic protocols are not currently standardized. objectives: we aimed to describe the clinical, laboratory and neuroradiologic features of children affected by ais due to post-vzv referred to our institute and to present our experience in their therapeutic management. methods: we selected 22 pediatric patients (6 females) with ais and a cns confirmed vzv reactivation and/or with a vzv history in the previous 12 months. other causes of pediatric stroke (systemic disease, cardiac disease, trauma, major thrombophilia) were excluded. clinical, neuroimaging, laboratory and treatment data were reviewed, focusing on pediatric score outcome measure (psom) and executive functions final outcome. results: average age of ais onset, vzv primary infection and interval between infection and ais were: 4 years 10mo (range: 1 year and 8 mo-9 years and 11 months), 4 years and 5 months (range 8 months-9.4 years), and 7 months (range 10days-34 months), respectively. the ais involved the nucleo-capsular region in 18 cases, the cerebral cortex in 9 cases, the thalamus in 4 cases, and the pons in 3 subjects. seventeen patients had inflammatory focal cerebral arteriopathy (ifca). virological confirmation (vzv-dna or anti-vzv igg in the cerebrospinal fluid) was obtained in 11 patients. three patients were treated with trombectomy and one with rtpa. thirteen patients were treated with antiviral agents associated with steroids in 8 cases, with different administration schedules. only in one case steroid treatment was given without association with antiviral agents. one patient received a short course of steroid and antiviral treatment at the time of the stroke and then a more prolonged course after six months at the time of the virological diagnosis. prophylactic antiaggregants were administered to all patients. mean follow-up was 2 years and 5 months (range 6 mo -10 years) ; ifca was persistent in 12 cases and transient in 5 subjects. four patients presented a recurrence of post vzv arteriopathy, two of them presenting new stroke events. twelve patients presented a variable motor deficit at last follow up. the mean psom score of the cohort at the last visit was 1 (range 0-2). executive functions were evaluated at last follow up in twelve patients, showing no deficit in seven patients, a mild deficit in two patients and a severe deficit in the last three. conclusion: albeit a favourable evolution was initially described, our experience suggests that vzv-related ais may result in persistent fca and significant neurological impairment in the majority of cases. therapeutic approach, particularly involving steroid administration, still need to be validated. introduction: iga vasculitis/ henoch schönlein purpura (igav/hsp) is the most common vasculitis of childhood and renal involvement is the most serious long-term complication. a better understanding of the pathophysiology of the progression to kidney disease is required for better treatment to be achieved and current biomarkers of ig a vasculitis with nephritis (igavn) lack the predictive value. objectives: in this study, an untargeted metabolomics approach was performed to reveal the underlying molecular mechanism of disease pathogenesis and to find potential biomarkers of plasma samples from patients with igav and igavn.methods: igav was diagnosed according to the ankara criteria in 2008 (1). forty-five patients, including 39 active igav patients (h), 6 igavn (n), and 6 age-and gender-matched healthy controls (c), were enrolled in the study. plasma samples from subjects were collected on the same day of igav(hsp) diagnosis and before steroid or other immunosuppressive treatment initiated. this study has utilized liquid chromatography-mass spectrometry (lc-ms/ q-tof) to investigate the alterations in plasma metabolomic profiles. three separate pools, health controls, active igav , and igavn were created. peak picking, grouping, and comparison parts were performed (metabolite profiling) via xcms (https://xcmsonline.scripps.edu/) software. results: totally 2618 peaks were detected for group h, n and c. among them 355 peaks were found to be statistically significant and reliable (p< 0.05) and 155 of these peaks were found to be changed (fold change >1.5) between the groups c and h. on the other hand, 66 peaks were found to be changed (fold change >1.5) between the groups h and n. the number of the peaks on the intersection of the peaks found to be changed between the groups (c and h) and (h and n) was 39. based on putative identification results, 15 peaks were matched with 11 metabolites. we found an up-regulated level of dhap(18:0), prostaglandin d2/i2, 5methyltetrahydrofolic acid, porphobilinogen and n-acetyl-4-o-acetylneuraminic acid/n-acetyl-7-o-acetylneuraminic acid, 5-aminopentanamide /5-aminopentanoic acid, glycocholic acid, saccharopine, n2-succinyl-l-ornithine, gamma tocopherol, and galactosylsphingosine /glucosylsphingosine in igav patients. in conclusion, we have identified a number of metabolites that may be associated with the pathogenesis of igav. we also suggest that dhap (18:0), prostaglandin d2/i2, porphobilinogen, 5-methyltetrahydrofolic acid and n-acetyl-4-oacetylneuraminic acid/n-acetyl-7-o-acetylneuraminic acid may serve as biomarkers for predicting kidney disease since they were increased only in the patients who developed renal involvement at follow-up. children were divided into four groups: those with jia who didn't receive mtx yet (group 1); those who received mtx less than one gram during whole treatment (group 2); those who received mtx from 1 to 3 grams (group 3); children, received more than 3 grams of mtx (group 4). the autoimmune inflammatory process in jia can cause formation of pathological changes in the liver, even before the start of treatment. it is confirmed by a statistically significant correlation of bfgf level in 1st group with liver steatosis according to ultrasound examination (r = 0.8) and the level of c-reactive protein (r = 0.7). this indicates a close relationship between the intensity of the inflammatory process and collagen synthesis activation, which can further provoke liver fibrosis. alterative processes in the liver associated with autoimmune inflammation, as evidenced by the presence of a positive correlation between the level of alt and bfgf (r = 0.5). upon reaching mtx dose 1 gram and 3 grams, it is possible that compensatory processes in the liver are triggered, as evidenced by the negative correlation between the content of bfgf and hgf (r = -0.6).conclusion: the use of modern markers with routine laboratory and instrumental studies is appropriate for the timely determination of the risks of developing irreversible pathological changes in the liver during jia treatment with mtx. objectives: the aim of our study is to evaluate the efficacy of (iag) injections in hip in children with (jia) and to assess the factors predicting the improvement of this management. methods: this is a retrospective study, between 2006 and 2009, including patients with jia diagnosed according to the ilar criteria. the socio-demographic data were collected as well as the parameters of the disease. the activity was evaluated by jadas. the functional impact was assessed by the lequesne score. the treatments taken have been specified as well as the infiltrations received. the improvement after infiltration was assessed by jadas and lequesne score.results: fourteen patients were included, with mean age 17.21 +6.8 . the mean age at the onset of symptoms was 11 +0.5 [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] . subtypes of jia according to the ilar were: enthesitis-related arthritis in 7 cases, seropositive polyarticular jia in 2 cases, seronegative polyarticular jia in 2 cases, oligoarticular jia in 2 cases and juvenile psoriatic arthritis in one case. all the patients had hip arthritis, inaugural in 90% of the cases. of these, 92.8% had a flexion deformity and lower limb inequality. the average lequesne index was 8.5 +4.6. the treatments taken were methotrexate in 57.14% of the cases, sulfasalazine in 14.28% of the cases, and the combination of the two in 21.4% of the cases. eleven patients underwent hip infiltration, and three of them required more than one. eighty one percent improved thereafter. the number of infiltrations was not statistically associated with the lequesne index (p = 0.069). improvement after infiltration was negatively associated with the prior existence of an inequality of the lower limbs (p = 0.04). the existence of a flexion deformity was not associated with good results after infiltration (p = 0.476, r=-0,624). ten patients (90%) among those who had an infiltration did not have to resort to surgery. conclusion: iag injection is an adjunct therapy in aji with hip involvement offering a good results and delay surgery in the majority of cases. the presence of lower limb inequality is associated with less improvement of iag. conclusion: synovial rice bodies are rarely described in juvenile idiopathic arthritis, even less at disease onset. their presence has not been associated to a worse disease prognosis or joint outcome but awareness of the existence of this particular form of intraarticular loose bodies may encourage the clinician to use lower gauge needle during arthrocentesis procedure; this can prevent arthroscopy, as occurred in our case 1. arthroscopy may be necessary in some cases to achieve full drainage of the joint. in our series the duration of arthritis correlated with the size of rice bodies and the number and agressiveness of procedures needed to evacuate them. objectives: we described a case of liver involvement in sle presenting with emphasis on the differential diagnosis with autoimmune hepatitis. methods: case report study results: : an 8-year-old female patient was referred to the rheumatology clinic with complaints icteric sclera for 10 months anorexia, malaise, pain in the both knees, ankles joints and both wrists accompanied by swelling, and remarkable motion limitations. laboratory revealed t bilirubin 4.9 mainly direct 3.9 with elevated liver enzymes got 401, gpt 189, alkp 520, high glutamyl transpeptidase 56u\l her wbc 7.4 hgb 10, ptl 317, except very high esr 105ml\hr, crp was positive 190mg\dl, viral screen (hcv, hbsag, hiv) was normal, serology tests ana was positive with high titer 1280, anti ds-dna ab was positive 320, anti-sm was negative, anti lkm1 antibodies negative, anti smooth muscle ab negative soluble liver antigen were negative, antimitohondrial ab( m1,m2,m3). ultrasound abdomen revealed mild enlarged spleen, abnormal diffused increased liver echogenicity with early stage of liver cirrhosis treated her by fresh frozen plasma 5 times, vit k 10mg once\ day then was referred to rheumatology clinic regarding her serology tests & developed arthritis of her joints suspected psle! she was performed liver biopsy showed lesions necrotic inflammatory portal and lobular severe in eosinophilic polynuclear with cirrhosis evoking a syndrome of overlap associating a primary biliary cirrhosis and an autoimmune hepatitis. laboratory data revealed liver dysfunction and liver biopsy suggesting autoimmune hepatitis, and she underwent treatment for hepatitis (prednisolone with azathioprine), urosdoxycholic acid with fat-soluble vitamins k, d&a, e. however, with the elimination of jaundice and decreased hepatic enzyme levels, the prednisolone dose was tapered within 2 months and stopped before they were referred to rheumatology clinic. on her review of systems, she has malar rash, generalized fatigability. on physical examination, we found malar rash, levidoreticularis of her skin, swelling and limitation of movement in the knees, ankles, wrists joints. there was hepatosplenomegaly. laboratory data revealed liver treatment for hepatitis, ana still high titer 1:1280, antids dan positive with titer 307 iu\ml, antisma was negative .wbc 4.5, hgb 11.8, plt 268, esr 68ml\hr, her ultrasound abdomen: revealed slightly heterogeneous liver with coarse echotexture without focal lesion with liver span 14 cm.these paraclinical results together with the clinical findings strongly suggested systemic lupus erythematosus (sle) as the definitive diagnosis. indeed, in this case, aih was associated with sle, prednisolone orally for 2 months, after that dose was tapered and continued, rapid clinical improvement in arthritis, malaise, and general condition. azathioprine was continued. in addition, daily hydroxycholoquine sulfate overlapping of sle and aih should be suspected when aih patients present with a malar or other skin rash. the prompt diagnosis and adjustment of further treatment plans can improve disease outcomes and prevent liver disease progression. introduction: juvenile systemic lupus erythematosus (sle) is a chronic autoimmune disease characterized by multi-visceral involvement with an unpredictable prognosis. the diagnosis is usually made in young women aged between 20 to 40years, however, it can affect people at any age and it is classified as a juvenile illness when it starts before the age of 16. objectives: we are reporting the epidemical, clinical, therapeutical and evolutional characteristics of a series done in the pediatric pole in setif with 13 girls and 1 boy. methods: the average age of onset is 13 years. the average time limits of the diagnosis is 7 months. the clinical features is done with cutaneous, articular manifestations and fever respectively in 100% 71% and 57% of the cases ,followed by kidney damage in 42% of the cases , the cardiac, pulmonary and ophthalmological participations are reported with low percentage. haematological involvement was detected in 85% of the patients and the inflammatory syndrome was almost constant. a positive titer of anti-nuclear antibodies and anti-dna is objectified, as well as a reduction in the complement rate. antibodies anti gp 2 and anti cardiolopine are positive in 57% of cases. kidney damage was diagnosed in 42% of the cases , and only one case of overlap syndrome with dermatomyosits was reported. concerning the neurological form it was present in only one addolecent girl ,and only one case of familial lupus.results: the diagnosis is based on the classification of the american college of rheumatology (acr) 1982 revised on 1997 and the new criteria slicc"systemic lupus international collaborating clinics" . the clinical characteristics of our series relies on global data of literature with the predominance of cutaneous and articular involvement. with however some specific characteristics which are individualized by a more advanced age of onset, 13 years on average in our study versus 10 years and 12 years, the rarity of familial forms (1 case), a lower percentage of kidney damage (42% versus 63% and 80%).the therapeutic management was based on corticosteroid therapy and hydroxychloroquine in the majority of cases, the use of immunosuppressants has been reserved for severe forms. conclusion: lupus is an autoimmune disease with protean clinical manifestations, the prognosis of which is dominated by renal, neurological and thrombotic disorders. cortisonic treatments and immunosuppressants have significantly improved the prognosis for life . trial registration identifying number: lupus is an autoimmune disease with protean clinical manifestations, the prognosis of which is dominated by renal, neurological and thrombotic disorders. cortisonic treatments and immunosuppressants have significantly improved the prognosis for life . onset of inactive and active oligo-ja were not significantly differ. the analysis revealed a correlation between a short phase of beneficial effect after is-iai of ta and risk of activity disease (with an inactive phase of arthritis less than 3 months, the risk activity was or = 2.09, p <0.001; with an inactive phase less than 2 months -or = 8.9, p < 0.001). rtx was administered to patients who had received high-dose cs with 2-3 dmards; in all cases combined pulse therapy cs № 2-10 was preliminarily used. rtx 500 mg № 2 was applied after 6mo-2y from the debut of the disease. in all 5 cases, its use led to clinical improvement after 1-5 mo with normalization of laboratory activity indicators, in 4 cases a decrease in the level of b cells to 0-0.56 in μl was noted (3 with agammaglobulinemia). after 2 months 3 patients had severe infectious complications, 2 of them ended fatally. 2 another patients had a second stroke. the 1st patient survived, had a kidney allotransplantation, there is no disease activity. the 2nd patient, in connection with the development of the demyelinating process of cns, attempted to continue therapy using golimumab with ivig. it led to an increase in the infectious syndrome, therefore, we decided to refrain from continuing with itnf as well. the patient died after 2 years from the administration of rtx due to the progression of neurological disorders. 2 cases with auto-inflammatory syndromes were: chronic infantile neurologic cutaneous and articular syndrome received tcz; it was unsuccessful (hyperthermia and rash persisted, eye lesions progressed, there were no increase in height), later switched to anakinra. family mediterranean fever, received adalimumab (ada). the 1-year-course of ada leaded to the disappearance of articular and abdominal syndrome while maintaining persistent increased levels of esr and crp and periodic fever. the use of tcz in 2 patients with ssd was more successful. the first patient received it subcutaneously for 1 year, cs&dmards (3 were used) had already been canceled, lung and kidney lesions were contained, blood pressure normalized, escsg-ai decreased from 7 to 1, mrss decreased from 18 to 14. in the second case, the patient received tcz for 6 months i/v, decrease of escsg-ai 6.5 to 1, mrss 33 to 21 were noted, the dose of cs was halved, he also continued treatment with cyclophosphamide. we introduce a 13-year-old girl patient who has been admitted to our clinic with suspicion of an erythema nodosum. she had painful subcutaneous nodules for 4 weeks, especially on the lower extremities and her face. macroscopically, central necrotizing skin rashes could be seen. she had frank arthritis of both knee and ankle joints. the comprehensive serological diagnosis (including hepatitis serology and anti-streptolysin titer) were normal except for a slight increase in crp 0,9 mg/dl and esr 36 mm/h. the patient also complained of abdominal pain and bloody stools. calprotectin was 3613 μg/g. a gastro-coloscopy revealed a small mariske and a minimal inflammation of the ileocecal valve, without signs of vasculitis or chronic bowel disease. a skin biopsy revealed leukocytoclastic vasculitis of the small arteries. angiography of the intestinal arteries was rejected by the family. initially we started a treatment with methylprednisolone pulses followed by oral prednisolone. the patient showed a very good response with quick resolution of the skin symptoms and abdominal pain. the medication could be quickly tapered and discontinued at full remission after one month results: pan is classified as a cutaneous pan (cpan) when there are exclusive skin manifestations, besides arthralgia or arthritis. a systemic pan must be diagnosed with the involvement of internal organs. however, cutaneous pan may evolve into systemic pan. in our patient, the skin and joints were primarily affected. if the existing gastrointestinal complaints are part of a systemic pan or chronic bowel disease could not be cleared yet, due to refusal of further investigations. conclusion: cpan must be considered as a suspected diagnosis in patients with necrotizing skin nodules. as transition of the cutaneous into the systemic form cannot be predicted regular monitoring is mandatory. introduction: prevalence of behcet's disease in children is not known, but is probably very low. extra-pulmonary large vessel arteritis in these cases is even rarer as a presenting manifestation. objectives: to report two cases of paediatric extrapulmonary large vessel arteritis with a 'behcet like disease'. methods: we present case reports of two cases who presented to paediatric rheumatology opd to our department. ms. f, a 16 year old girl was referred to us with history of short duration of fever, generalized lymphadenopathy, neutrophilic leucocytosis, thrombocytosis, hyperglobulinemia and high inflammatory markers. on detailed history and examination she was found to have a healed palatal ulcer and her maternal aunt was found to have a history of recurrent oral ulcer, genital ulcer and enthesitis. patient's montoux test was positive but the gene expert for mtb was negative. md-ct showed a circumferential thickening of aorta, subclavian and bilateral renal artery with stenosis at origin of both renal arteries indicating a vasculitis. few necrotic nodes were also noted in lungs. lymph node biopsy suggested a reactive hyperplasia. tissue typing showed presence of hla b 44, b 51. she improved clinically with oral prednisolone and mycophenolate mofetil and had no recurrence till her recent follow up visit. second case, master fkn an 11 year old child was referred to us with a background of 2 week history of fever, non migratory arthritis, raised inflammatory markers and a symptomatic severe aortic regurgitation with pandiastolic flow reversal on 2d echo. his evaluation showed negative montoux, normal igg4 levels and hla b35 b 51 on tissue typing. his aortic wall thickness resolved with 1 mg/kg oral prednisolone and mycofenolate mofetil. results: both these cases have features similar to behcet's disease. these cases do not fulfil isg, icbd 2014 or icbd criteria for pediatric behcet's disease. however, the aortitis and other clinical features responded well to the treatment in both cases.conclusion: paediatric case with extra-pulmonary large vessel arteritis that do not meet criteria for behcet's disease but have specific clinical or laboratory features do respond well to immunosuppression. therefore, after ruling out other causes of the large vessel vasculitis, a possibility of form fruste of behcet's disease should be under consideration. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. these abstracts have been published as part of pediatric rheumatology, volume 18, supplement 2, 2020: proceedings of the 26th european paediatric rheumatology congress (pres 2020). the full contents of the supplement are available at https://ped-rheum. biomedcentral.com/articles/supplements/volume-18-supplement-2. please note that this is part 2 of 2. key: cord-323473-e2pgjynr authors: cevey-macherel, manon; galetto-lacour, annick; gervaix, alain; siegrist, claire-anne; bille, jacques; bescher-ninet, béatrice; kaiser, laurent; krahenbuhl, jean-daniel; gehri, mario title: etiology of community-acquired pneumonia in hospitalized children based on who clinical guidelines date: 2009-02-24 journal: eur j pediatr doi: 10.1007/s00431-009-0943-y sha: doc_id: 323473 cord_uid: e2pgjynr community-acquired pneumonia (cap) is a major cause of death in developing countries and of morbidity in developed countries. the objective of the study was to define the causative agents among children hospitalized for cap defined by who guidelines and to correlate etiology with clinical severity and surrogate markers. investigations included an extensive etiological workup. a potential causative agent was detected in 86% of the 99 enrolled patients, with evidence of bacterial (53%), viral (67%), and mixed (33%) infections. streptococcus pneumoniae was accounted for in 46% of cap. dehydration was the only clinical sign associated with bacterial pneumonia. crp and pct were significantly higher in bacterial infections. increasing the number of diagnostic tests identifies potential causes of cap in up to 86% of children, indicating a high prevalence of viruses and frequent co-infections. the high proportion of pneumococcal infections re-emphasizes the importance of pneumococcal immunization. which both pneumonia and viral lower respiratory tract infections are common conditions. the world health organization (who) has defined pneumonia and subsequent treatment on strict clinical signs (table 1) [1, 7, 17] . a prospective study showed that the who guidelines can also be applied in developed countries, as recommended by the guidelines of the british thoracic society (bts) [2, 11] . the second difficulty is to identify the causative agent of pneumonia in children. this remains challenging for a number of reasons: endo-tracheal aspirates cannot be obtained routinely, nasopharyngeal swabs (ns) only show colonization by normal flora including the bacteria most commonly causing pneumonia, and bacteremia is demonstrated in less than 10% of bacterial cap. therefore, the etiology of cap remains often unknown, with the consequence that many children get an antibiotic treatment for non-bacterial infections, contributing to the increase of bacterial resistance to antibiotics [9, 41] . the aims of this study, performed before the routine implementation of the heptavalent pneumococcal vaccine in switzerland, were to define, as strictly as possible, the causative agents of pneumonia among children aged from 2 months to 5 years hospitalized for cap on the basis of who clinical criteria, and to determine which factors could help clinicians to discriminate bacterial from viral pneumonia. participation to this prospective and descriptive study was offered to all consecutive children aged 2 months to 5 years old presenting with cap according to the who criteria (table 1 ) consecutively admitted to the children's unit of the university hospitals of lausanne and geneva between march 2003 and december 2005. they were classified according to initial severity. children with actively treated asthma, an underlying chronic disease, immunosuppression, or wheezing were excluded. children with wheezing were specifically excluded because wheezing is considered to be a symptom of asthma and/or viral bronchiolitis and not of pneumonia, and therefore these children are not treated with antibiotics. cough and fever, associated signs and symptoms, the use of antibiotics in the month before admission, and the main features of the clinical course were recorded. the ethical committees of both institutions approved the study protocol. signed consent was obtained from informed parents. on admission, a blood sample was taken for total white blood cell count (wbc) with manually verified differential count. serum crp and pct (lumitest®, brahms, berlin, germany) were measured. a senior radiologist, blinded to clinical and laboratory findings, reviewed all chest radiographs and assigned a standardized description of the x-ray as proposed by the who working group [5] : the presence of consolidation or pleural effusion with parenchymal infiltrate defined pneumonia. on admission, before starting an antibiotic treatment, peripheral blood cultures, and during the winter epidemic, a rapid antigen detection test for rsv (coris or becton dickinson), were performed. within 8 h after admission, nasopharyngeal aspirates (npa) were obtained after respiratory physiotherapy for viral and bacterial culture, pcr analysis, and viral antigen detection. pcr analysis was performed for mycoplasma pneumoniae and chlamydia pneumoniae. rt-pcr assays were performed for 13 viruses including influenza a and b, rsv a and b, rhinovirus, parainfluenza 1-3, enterovirus, human metapneumovirus, coronavirus oc43, e229, and nl 63 as previously described [15, 16, 25] . in the present study, all the assays were used as qualitative tools. pcr for m. pneumoniae and c. pneumoniae were done by a multiplex real-time pcr according to welti et al. [44] . viral antigen detection was performed for adenovirus, para-influenza 1-3, rsv, and influenza a and b by indirect immunofluorescence (argene antibodies) or elisa. serum samples were taken at admission and approximately 3 weeks after hospitalization, then stored at −20°c and subsequently transported on dry ice to the laboratories. the laboratory was unaware of clinical data. antibodies for influenza a and b; parainfluenza 1, 2, and 3; rsv; adenovirus; and m. pneumoniae were detected by the complement fixation method. paired samples were tested in the same run. acute infection was defined by a fourfold rise or a titer higher than 1/80. serologic tests for c. pneumoniae were done by using a micro-immunofluorescence test (mrl diagnostics). a fourfold rise between the acute and convalescent sera or an initial titer higher than fourfold the positive cut off value (1:16) were considered as indicative of a recent infection, as previously described [26] . serum igg antibodies to pneumolysin were measured by indirect elisa on antigen-coated immulon plates (thermo labsystem), following 60 min incubation at 37°c. results were compared to a pool of purified human immunoglobulins (endobulin, baxter) used as standard and expressed in elisa units/ml. samples with a rise greater than twofold between acute or convalescent sera and/or acute serum antibody titers greater than 300 eu/ml were scored positive. these limits have been previously demonstrated to be a reliable method for the serological diagnosis of pneumococcal exposure [22, 35] . the blood samples were taken at the time of admission and sera were frozen at −70°c in order to be analyzed in a second phase. the detection of s. pneumoniae was performed by real-time pcr with the taqman method. the specific target was the pneumolysin gene. briefly, 200 µl of blood specimen were pre-lysed with 80 μl of lysis buffer (bacterial lysis buffer, roche diagnostics) and with 30 μl of a cocktail of enzymes (lyt030 enzymmix, roche diagnostic). after an incubation period of 30 min at 37°c, the sample was automatically extracted with a magna pure compact instrument using the magna pure compact isolation kit i. five microliters of the eluted dna were then amplified in triplicate with a taqman abi prism 7700 sequence detector (applied biosystems). any significant curve before the cycle 40, was considered as a positive signal, the positive cut off was defined as 1,000 copy/ml [8, 27, 43] . the criteria for viral infection were a positive viral culture, viral antigen, positive viral serology, or viral pcr. a bacterial infection was considered if a blood culture, a pleural fluid culture, a pneumococcal pcr, or a serologic assay was positive. atypical and typical bacteria were grouped together. subjects with criteria of both viral and bacterial infections were considered to have infections of mixed etiology. patients were treated with a course of parenteral antiobiotics first (cefuroxime (n = 46), ceftriaxone (n =22), amoxiclavulanic acid (n=38), floxapen (n=1)), followed by oral antibiotics (amoxiclavulanic acid or cefuroxime) for a total duration of 2 to 25 days. parenteral cefuroxime was initially associated with clarithromycin in four patients or switched for vancomycin and amoxyclavulanic acid or for amoxycillin and clindamycin in two patients with pleural effusion. data were analyzed using epi info 6.04d (center for disease control and prevention, atlanta, ga, usa). standard parametric and non-parametric statistical tests were done according to distribution and variance of studied variables. the level of statistical significance was defined as p≤0.05. kappa statistics were computed using pairs module, version 1.33, of pepi for windows software. a total of 111 children were eligible during the study period. ninety-nine children were finally enrolled (six patients were excluded because of the impossibility to obtain samples and, after initial consent, five parents decided to interrupt the study). among these patients, 51 were females (52% although there was a large variation in the number of monthly hospitalizations, no clear seasonal pattern was observed. the average duration of hospitalization was 2 days ranging from a few hours to 25 days. twenty-six children (26%) required supplemental oxygen therapy, nine patients (9%) needed a gastric feeding tube, and nine (9%) a thoracic drainage. three patients were transferred to the pediatric intensive care unit, two of them requiring noninvasive assisted ventilation (table 2) . overall results table 3 shows the number of samples obtained for each test. viral and atypical bacterial serology, were the most difficult to obtain (follow-up blood sample), as well as nasopharyngeal aspirates (npa), notably in children without upper respiratory tract involvement. a potential causative agent was detected in 85 (86%) of the 99 patients. evidence of bacterial infection alone was demonstrated in 19 patients (19%) and viral infection alone in 33 (33%) cases. mixed bacterial-viral infection was found in 33 (33%) patients (fig. 1) . only one patient had a positive blood culture (s. pneumoniae), while three other blood cultures were contaminated by a coagulase-negative staphylococci. one patient had a group a β-hemolytic streptococcus in pleural fluid culture. overall, bacteria with or without co-infecting pathogens were identified in 53% of the cases (52 patients). pneumococcal pneumonia was diagnosed in 45 patients (table 4 ). overall, 66 among the 99 children (67%) had evidence of an acute viral infection ( fig. 2 ; table 4 ). pcr was very sensitive to detect several viruses. in no patient with a negative viral pcr, could a viral infection be detected using another method. there was a significant relationship between age and etiological category ( table 2) . excluding patients with undetermined etiology, univariate analyses showed that dehydration was the only clinical sign significantly more represented in the bacterial group of pneumonia. indeed, 47% of children with bacterial pneumonia, while only 24% in the mixed group and 6% in the viral pneumonia group (p=0.003), showed signs of dehydration, ( table 2 ). other symptoms were not significantly associated with etiology. in particular, urs were not significantly more frequent in the viral group. the proportion of patients in each clinical severity category (who stages) did not differ significantly according to etiology (p=0.698). analysis of laboratory data showed that children with bacterial pneumonia overall had higher inflammatory parameters: crp and pct values were significantly higher in the bacterial pneumonia group when mixed and bacterial pneumonia were analyzed together (table 2 ). however, inflammatory indices were not statistically associated with clinical severity. for a cut off level of 60 mg/l the sensitivity of crp was 88% but the specificity was low (44%). for a cut off level of 5 ng/ ml the sensitivity of pct was 72% and the specificity 58%. total white blood cell count and band forms were not significantly associated with etiology. the proportion of children treated with antibiotics before hospitalization, did not differ according to the etiological category (chi square, p=.33). the average duration of hospitalization was related to clinical severity. on admission, breath sounds were described as completely normal in 21 (21%) patients. in 78 patients with abnormal auscultation, the most constant sign was diminished breath sounds (59 patients). chest x-ray was abnormal in 97 of 98 patients (99%). radiological consolidation was present in 77 (79%) patients. overall percent agreement between the presence of diminished breath sounds and radiological consolidation was 60.2% with a kappa coefficient of 0.11 (95% ci-0.07 to 0.29), confirming very poor agreement. there was no association between radiological description and severity or etiology of pneumonia. one hundred and eleven immunocompetent children, aged between 2 months and 5 years old, hospitalized for pneumonia, were studied prospectively to elucidate the [23, 24, 31, 39] . evidence of bacterial infection was demonstrated in 53% of patients. s. pneumoniae was documented in 45% of the cases, corroborating previous reports such as the one by michelow et al. [32] . a virus was found in 67% of the children. in 33% of the cases, a concurrent bacterial and viral infection was found. antibiotic treatment before hospitalization doesn't seem to be a factor of misdiagnosis. our study showed that in children fulfilling the who clinical definition of pneumonia and severity criteria, diagnosis was confirmed by radiological consolidation in 78% of cases. the poor agreement between auscultation and radiological consolidation confirms the poor sensitivity and specificity of auscultation to diagnose pneumonia in young children [11] . as previously described [14, 28] chest x-ray and blood cultures were not helpful in discriminating etiological categories of pneumonia. duration of hospitalization was correlated with clinical severity essentially because who criteria define children with stage iii pneumonia as requiring oxygen supplementation. pain was the only clinical sign significantly associated with bacterial pneumonia. acute-phase surrogate markers such as crp and pct, were significantly higher in bacterial infection regardless of the presence or absence of co-infecting viruses, corroborating several previous analyses [20, 33, 37] even if these findings are controversial in recent literature [13] . further analysis is needed to determine the exact utility of these tests, as the sensibility and specificity with a bacterial cut off level were quite low. finally, our data could not show a significant correlation between clinical severity and etiology of pneumonia [24] . as reported previously [12, 21, 40, 42] , our data confirm the high prevalence of viruses and showed the frequent occurrence of co-infection in childhood cap. the viruses most commonly found were rhinovirus (30%) and hmpv (20%), confirming the recent findings that these viruses frequently involved in pediatric cap [3, 11, 36, 38] . rsv was less represented than in other reports [6] , probably because all patients with typical bronchiolitis were strictly excluded. several points still have to be elucidated: whether viruses are the direct cause of pneumonia, whether they the main limitation to our study is the lack of validation and standardization of all microbiological cut off values, especially those concerning s. pneumoniae [4] . one of the major obstacles to improve the understanding of cap is probably that we are still underdiagnosing pneumococcal and possibly other bacterial pneumonia. the use of a single antigen (pneumolysin) for the serological diagnosis of pneumococcal pneumonia may be a limitation, as well as the difficulty, in our study, to obtain convalescent serum samples (available for only 73% of the children). therefore, it remains difficult to distinguish a real acquired infection from a recent colonization. as recently described by nakayama et al. [34] , the use of pcr to detect bacterial pneumonia could be a useful additional diagnostic method. however, the fact that 46% of young children with cap requiring hospitalization demonstrated evidence of an acute pneumococcal infection, is in accordance with the demonstrated impact of pneumococcal immunization [10, 18, 29, 30] . finally, our results do not support the hypothesis that clinical severity depends on the causal agent. however, for ethical and practical reasons we chose to study only hospitalized children. therefore, we have a limited number of patients with stage i pneumonia whom we usually treat in the ambulatory setting. a further study should include this group in order to confirm, with a greater number of patients, the non-association between clinical severity at admission and etiology. in conclusion, this study used strict who clinical criteria to select suitable subjects to undergo an extensive microbiological etiological workup using a complete set of modern diagnostic tools. our data confirm a high prevalence of viruses and the frequent occurrence of co-infection in childhood cap. dehydration and surrogate markers of inflammation such as crp and pct were significantly higher in children with bacterial pneumonia. therefore, further analyses should be performed in order to find out which children should be treated with antibiotics and in which children antibiotics could be withheld safely. the high proportion of s. pneumoniae in severe cap reemphasized the importance of pneumococcal immunization and antibiotics for treatment of cap in young children. other studies should also be performed to evaluate the epidemiology of moderate to severe bacterial pneumonia after introduction of pneumococcal immunization. case management of childhood pneumonia in developing countries guidelines for the management of community acquired pneumonia in childhood role of rhinovirus in hospitalized infants with respiratory tract infection in spain evaluation and 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of community-acquired pneumonia: serological results of a paediatric survey efficacy of serum procalcitonin in evaluating severity of community-acquired pneumonia in childhood community acquired pneumonia: a prospective uk study a prospective hospital-based study of the clinical impact of non-severe acute respiratory syndrome (non-sars)-related human coronavirus infection lower respiratory viral illnesses: improved diagnosis by molecular methods and clinical impact integrated management of childhood illness by outpatient health workers: technical basis and overview. the who working group on guidelines for integrated management of the sick child effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than 5 years of age for prevention of pneumonia: updated analysis using world health organization standardized interpretation of chest radiographs epidemiology and bacteriology of bacterial pneumonias procalcitonin and c-reactive protein levels in community-acquired 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characteristics of communityacquired pneumonia in hospitalized children procalcitonin in children admitted to hospital with community acquired pneumonia rapid optimization of antimicrobial chemotherapy given to pediatric patients with community-acquired pneumonia using pcr techniques with serology and standard culture bacterial antibody assays in the diagnosis of acute lower respiratory tract infection in children clinical effects of rhinovirus infections procalcitonin, c-reactive protein and leukocyte count in children with lower respiratory tract infection a recently identified rhinovirus genotype is associated with severe respiratory-tract infection in children in germany pneumonia in childhood: etiology and response to antimicrobial therapy viral pneumoniae in children: incidence and aetiology community-acquired pneumonia: a review and recent advances etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections a quantitative lightcycler pcr to detect streptococcus pneumoniae in blood and csf development of a multiplex real-time quantitative pcr assay to detect chlamydia pneumoniae, legionella pneumophila and mycoplasma pneumoniae in respiratory tract secretions estimates of world-wide distribution of child deaths from acute respiratory infections acknowledgments this study was supported in part by glaxo-smithkline. we thank dr. b. vaudaux, infectious disease pediatrician at the university hospital of lausanne, for his advices. we are grateful to mrs. j. bersier and her laboratory staff, to dr. wunderli and his collaborators for the viral serology test, to dr. k. jaton and her collaborators for the m. pneumoniae and c. pneumoniae pcr tests, to s. grillet for the pneumococcal serology analyses, to prof. j. schrenzel for pneumococcal pcr, and to sabine nobs-grunenwald for viral pcr analysis.conflicts of interest all the authors certify that they have no financial relationship with the organization that partly sponsored the research and no conflicts of interest. key: cord-320438-9j41eyw3 authors: daltro, pedro; santos, eloá n.; gasparetto, taísa d.; ucar, maria e.; marchiori, edson title: pulmonary infections date: 2011-04-27 journal: pediatr radiol doi: 10.1007/s00247-011-2012-8 sha: doc_id: 320438 cord_uid: 9j41eyw3 this paper reviews the most common imaging findings of pulmonary infection in children. pneumonia is a leading cause of mortality in children in developing and industrialized countries. while the imaging findings usually are nonspecific, correlation with the patient’s age, immune status and pertinent history can limit the differential diagnoses. the paper will review the common and unique features of pneumonia caused by specific organisms and in specific patient populations. pneumonia is defined as an acute or chronic disease that causes inflammation of the lungs. it is one of the most common infections in the pediatric population and a leading cause of mortality in children in developing countries. it is usually acquired through inhalation of infected upper airway secretions, although hematogenous routes or contiguity can occur [1] [2] [3] [4] . viruses, bacteria, fungi and other microorganisms are the main etiological agents. though pneumonia from any organism can occur at any age, certain age groups are at higher risk for particular types of pneumonia. the vast majority of pneumonia in infancy and early childhood is of viral origin and accounts for 50% of pneumonia in children younger than 5 years [2] . the most common bacterial organism in children older than 5 years is s. pneumoniae. mycoplasma is the most frequent cause of pneumonia in those older than 5 years of age group [2, 4, 5] . the immunological status of the child and the infectious agent also have an important role in the clinical and radiological aspects of the disease [5, 6] . this paper reviews the most common causes of pulmonary infection in children, emphasizing the imaging findings. viral infections occur after the inhalation of infected aerosols. usually the infection begins in the nasopharynx and upper respiratory tract and migrates to the small airways and alveoli. the clinical presentation of viral pneumonia varies greatly depending on the infecting agent, the age and the immune status of the host [4, 5] . influenza virus, respiratory syncytial virus (rsv), adenovirus and parainfluenza are common causes of viral pneumonia in children. in premature-born infants with lung disease, rsv can be devastating. recently, human metapneumovirus has been recognized as a pathogen. its ubiquity suggests that it is as important as rsv, and studies suggest its incidence is as high as that of rsv. nearly 100% of children ages 5-10 years are seropositive [7] . herpes simplex virus is rare, affecting mostly newborns. patients with immunodeficiency syndromes are also at risk of pneumonia caused by other pathogens such as cytomegalovirus [5] . influenza virus and rsv infect the pneumocytes, causing diffuse alveolar damage. the alveoli are infiltrated with neutrophils, and mononuclear cells with fibrin and edematous fluid [1, 4] . in addition, the submucosa presents with hyperemia with focal hemorrhage and edema. the small bronchial diameters and poorly developed airways of the smallest children combined with their abundant mucus production cause the characteristic abnormalities revealed by chest radiograph [4, 5] . ct is sometimes indicated in complicated cases of diffuse disease [2] . the most common chest radiographic findings are bilateral symmetrical parahilar and bronchial opacities with or without atelectasis and air trapping (figs. 1 and 2). focal and asymmetrical disease are not uncommon. lymph node enlargement can occur, but pleural effusion is rare. recently viral infection has been recognized as a cause of severe pneumonias leading to respiratory failure and death. higher mortality rates are associated with coronavirus a (sars, severe acute respiratory syndrome), and influenza virus type a h5n1 (bird flu) and type a h1n1. as with other viral infections, focal or diffuse interstitial opacities are the initial chest radiograph presentation, but they can progress rapidly to bilateral areas of consolidation (fig. 3 ). in children with type a h1n1 initial radiographs were often normal, and a trend to more severe disease was seen in children with diffuse ground-glass opacities [2] . early recognition of the epidemic and an increased index of suspicion in patients with asthma and chronic lung diseases will help in identifying these pneumonias. the most common complication of viral pneumonia is a secondary bacterial pneumonia. damage to the respiratory tract mucosa harms local defense mechanisms and leaves the lung vulnerable to bacterial superinfection [1, 4, 6] . postinfectious bronchiolitis obliterans (bo) is a chronic obstructive disease of the lower airways that affects mainly male infants after an episode of acute viral bronchiolitis. adenovirus is the most common agent. the virus infects the epithelial cell surface and initiates intracellular replication, resulting in squamous metaplasia of the bronchial mucosa and necrosis of the bronchiolar wall with destruction of the ciliated epithelium. peribronchiolar inflammatory opacities, edema of the submucosa and connective tissue, and increased mucus secretion cause obstruction of the bronchioles, resulting in air trapping and atelectasis. ct performed in children because of progressive disease shows mosaic perfusion, peribronchial thickening, atelectasis, bronchiectasis, air trapping and sometimes lung volume reduction (fig. 4) [8, 9] . swyer-james-macleod syndrome is a postinfectious bo with characteristic radiological features that are virtually pathognomonic. typically involvement is unilateral, affecting the entire lung, lobe or segment. the changes observed on chest radiography are hyperlucency, mainly because of pulmonary hypoperfusion; reduction of vascular and hilar markings; volume reduction of the affected lung or lobe, and air trapping on radiographs made at expiration. ct demonstrates these features with more detail and might demonstrate bronchiectasis (fig. 5) . bronchiolitis obliterans organizing pneumonia (boop) is now called cryptogenic organizing pneumonia and should not be confused with postinfectious bronchiolitis obliterans. it shares many of the clinical features of pneumonia but is not of infectious etiology [10, 11] . bacterial pneumonia is generally characterized by consolidation and filling of alveolar air spaces with exudate, inflammatory cells and fibrin. the first phase is characterized by active hyperemia and engorgement of the arterial blood vessels. edematous fluid, which might be seen in the alveoli, contains few exudative cells. in the next stage, neutrophils and fibrin material fill the alveoli, and massive extravasation occurs through interalveolar pores (pores of kohn), producing a homogeneous opacity. fibrin and exudative cells accumulate, appearing on radiographs as a clear zone adjoining the alveolar and acinar cells [9, 12, 13] . if the process extends to the pleural space, associated pleural effusion is present. bronchopneumonia is a form of bacterial pneumonia that begins as a peribronchiolar inflammation involving many lobes and spreads to the adjacent parenchyma, causing patchy nodules and consolidation. streptococcus pneumoniae is a common infectious agent but pathogens like haemophilus influenzae, staphylococcus aureus and gram-negative enteric bacteria can cause similar clinical syndromes. the typical chest radiograph reveals homogeneous or fluffy lobar consolidation, but diffuse bilateral inhomogeneous opacities extending peripherally also can be seen, both with and without associated pleural fluid (fig. 6) . as opposed to the other bacterial pneumonias, round pneumonia has an atypical radiographic appearance of pulmonary bacterial infections. it is caused most often by s. pneumoniae. it is rare in adults and occurs in less than 1% of children (usually younger than 8 years of age) but is seen more frequently in the young because of the underdeveloped pores of kohn and the absence of canals of lambert characteristic of this age group. the radiographic finding usually occurs early in the disease course, and for this reason cough and respiratory symptoms can be absent in the initial presentation. the usual presentation is an area of focal nodular consolidation, often solitary, with well-defined borders and mass effect. it frequently occurs in the lower lobes, posteriorly (>80%) and inferiorly (>70%) [14] (fig. 7) . pneumonias have been classified as atypical based largely on the observation of clinical (low white count, little or no fever, etc.) and imaging findings disproportionate to the clinical condition. legionella species, mycoplasma pneumoniae and chlamydia pneumoniae are the most common etiologies of atypical pneumonias. reticulonodular infiltrate in one lobe is a usual presentation of mycoplasmal pneumonia. other radiographic features are lobar consolidation or pseudoconsolidation (fig. 8) , atelectasis, bilateral parahilar peribronchial opacities that resemble butterfly wings, bilobar reticular pattern, pleural and pericardial effusion and hilar lymphadenopathy [12, 13] . many of these features can be seen in viral pneumonia as well. to distinguish these pneumonias one needs to recognize the clinical features that don't appear to match the radiograph, such as the degree of respiratory distress or the unusual laboratory findings. for example, chlamydia trachomatis (or chlamydophila) affects young infants in the first 4 months, and frequently a history of conjunctivitis and a staccato cough are observed. the history will reveal a vaginal delivery and a mother with vulvovaginitis. chest radiograph shows bilateral reticular interstitial involvement, hyperinflation and bronchial wall thickening. the three most common complications of bacterial pneumonia are pulmonary necrosis, pulmonary abscess and empyema. children who have complicated pneumonias might require an imaging evaluation by us or chest ct [15, 16] . necrotizing lobar lesions result from thrombotic occlusion of alveolar capillaries associated with adjacent inflammation, resulting in ischemia and eventually necrosis. the typical ct findings of necrotizing pneumonia are cystic heterogeneous areas of necrosis within solid consolidation and non-enhancing lung parenchyma ( fig. 9 ) [17] . pulmonary abscess is a necrotic parenchymal cavity filled with pus. ct imaging shows a cystic area within consolidated lung parenchyma but with contrast rim enhancement (fig. 10 ). chest ct with intravenous contrast administration can be very useful in atypical, complicated pneumonia presentations, although it should not be performed routinely. ct is better than chest radiograph for detecting lobar lesions such cavitary necrosis, early abscess formation, chest tube placement, fluid loculation, empyema, bronchopleural fistulas and pericardial effusions. ct also helps define lesions that might require early surgical intervention [15, 16] . chest sonography, however, is mainly used to demonstrate the internal echogenicity of pleural pneumatoceles and bronchiectasis are the most common postinfectious sequelae of bacterial pneumonia. pneumatoceles are thin-walled cystic lucencies with or without septations that develop within the lung parenchyma, occurring after an acute pneumonia most often caused by s. aureus (fig. 11 ). bronchiectasis is an abnormal irreversible dilation of the proximal and medium-size bronchi caused by weakening or destruction of the muscular and elastic components of the bronchial walls. the more commonly acquired forms occur in older children after destructive pulmonary infections that cause impaired clearance of bronchial secretions, or in cases of superimposed bacterial infections in children with previous conditions such as cystic fibrosis. bronchiectasis can be observed as thickening of the bronchial walls and marked dilatation of the bronchial channel on both radiographs and chest ct. mycobacterium tuberculosis causes tuberculosis, and its incidence is increasing worldwide. sixty percent of new childhood infections occur in children younger than 5 years old [2] . pulmonary tuberculosis in infancy and childhood is classically related to an inhaled innoculum. there is a small, peripheral primary focus that leads to lymphadenopathy asymmetrically distributed in paratracheal, hilar and/or subcarinal areas. the right side is more commonly affected than the left because of the usual pattern of lymphatic circulation within the lungs [1, [18] [19] [20] . enlarged lymph nodes with lobulated, sharp or ill-defined borders can be partially or completely calcified. ct is reserved for complicated cases, not those with a positive skin test. lymph nodes on ct are dense soft-tissue masses with homogeneous or ring-like enhancement and lowattenuation centers. inflamed nodes sometimes erode the bronchial wall and discharge caseous material into the bronchus (fig. 12) . this results in bronchogenic spread, characterized as centrilobular or branching centrilobular opacities. coalescence of the centrilobular opacities results in focal areas of bronchopneumonia [1, 21] . sporadically, the primary parenchymal lesion continues to enlarge, resulting in focal pneumonitis or lobar pneumonia with thickening of the overlying pleura without distinct hilar lymphadenopathy. it is helpful to divide the disease into subtypes. primary tuberculosis, which sometimes progresses to a symptomatic infection, is often indistinguishable from other forms of bronchial pneumonia. enlarged in cases of tuberculosis, progressively destructive liquefaction of lung parenchyma leads to formation of a primary cavity or more extensive pulmonary necrosis (fig. 13) . hematogenous spread can also develop with a miliary pattern of small, well-defined nodules of up to several millimeters in diameter uniformly distributed through the lungs [1, 22] . it is important as well to recognize healed tb as latent infection can reactivate. the immune response to the initial infection leads to calcification of the healing lung as well as infected lymph nodes. this observation is important, as the child's immune function can change. in children who have newly diagnosed hiv infection or are undergoing chemotherapy for malignancy or transplantation, it might be important to treat latent tb before it reactivates [22] [23] [24] . histoplasmosis and aspergillosis are the most common fungal pneumonias in children, most often in the immunesuppressed group (see below) [25, 26] . histoplasmosis is a systemic mycosis caused by a small fungus, histoplasma capsulatum, whose natural habitat is soil contaminated by bat or bird excrement. it is endemic in some geographical regions, such as the ohio river valley. human infection occurs when airborne spores of h. capsulatum are inhaled. the most common imaging features are diffuse reticulonodular opacities with small and diffuse pulmonary nodules (fig. 14) . usually it affects both lungs as well as hilar and mediastinal lymph nodes. this miliary pattern can be identical to miliary tuberculosis and blastomycosis [25] . pulmonary nodules heal, leaving residual granulomata that undergo central calcification. mediastinal lymph nodes can also exhibit central caseation, peripheral enhancement and, frequently, calcification as in tuberculosis. another uncommon but severe complication of histoplasmosis is mediastinal fibrosis, which not only causes mass effect in the mediastinum, it can compress major blood vessels or occlude bronchi (fig. 15) [26, 27] . aspergillosis refers to any infection caused by several species of aspergillus: a. fumigatus, a. flavus, a. niger and a. terreus. the fungus is ubiquitous, and asymptomatic colonization is common. three factors are important to the development of active infection: the virulence of the fungus, the type and amount of exposure, and the immune status of the child. the spectrum of lung diseases ranges from allergic reactions, colonization of a preexisting lung cavity, or invasion and destruction of lung tissue, to progressive vascular invasion with involvement of the brain, skin and other organs [28] [29] [30] . allergic bronchopulmonary aspergillosis (abpa) affects children with asthma or cystic fibrosis. the disease is a hypersensitivity reaction to the fungus; the findings are secondary to the reaction to the allergen. this form of the infection occurs most frequently in children with cystic fibrosis. it is important to recognize that prompt therapy can prevent progression of the child's bronchiectasis. abpa should be considered in cf patients with new asthma symptoms and when any new chest radiograph airspace changes are found and when ige titers increase [30] . the most common ct findings are proximal and segmental bronchiectasis with or without mucous plugs and fleeting consolidations. aspergilloma, in which the fungus colonizes a preexisting lung cavity, occurs in individuals with chronic lung disease and pulmonary sequelae such as tuberculosis, bronchiectasis and pulmonary fibrosis. invasion to lung parenchyma, pleura and fibrosis is minimal, and a fungus ball might be present. neither fungal vascular invasion nor spread to other organs is observed. the disease can persist for months or years. chest ct usually reveals a consolidation with an interposed cavitation and an ovoid intracavitary mass (fungus ball, or mycetoma) consisting of fungal hyphae, mucus and cellular debris [28] [29] [30] . this infection is often associated with underlying pathologies and other infections. it is not uncommonly found in cavities from tb infection or in congenital bronchopulmonary malformations, such as sequestrations. angioinvasive aspergillosis is one of the most common forms of fungal infection among immunocompromised and neutropenic children. the lesions seen on conventional chest radiograph include single or multiple nodules, cavities, and subsegmental or segmental consolidation. in the initial phase, the most characteristic image seen on ct is the halo sign, an area of low attenuation around the centrilobular nodules that represents edema or hemorrhage (fig. 16) . in later stages, ct might show areas of necrotic tissue and pulmonary sequestration within the surrounding parenchyma, resulting in the air crescent sign [31] . ascaris lumbricoides can lead to an acute inflammatory lung process caused by the host immunological response to parasite migration. this is called loeffler syndrome, or acute allergic eosinophilic pneumonia. chest radiograph and ct often show transient nonsegmental airspace opacification, which can be unilateral or bilateral, usually with predominantly peripheral distribution. the features are not specific for this etiology of allergic eosinophilic pulmonary infiltration. echinococcosis is a parasitic disease usually caused by echinococcus granulosus, which affects humans through accidental ingestion of parasite eggs released in the feces of definitive, carnivorous hosts, such as sheep, dogs and cats. especially in children, infection can also occur through direct contact with infected domestic animals. echinococcus eggs hatch into larvae in the duodenum, then migrate through the portal system to the liver and to pulmonary alveolar lung capillaries, where they develop into spherical or oval cysts. the liver is the primary site of infection in 75% of patients. the ct scan might show single or multiple cysts, which can present as daughter cysts or floating cysts with internal membranes (water lily sign) (fig. 17 ) [32] . in addition amebiasis, malaria and protozoa infections along with toxoplasmosis are well recognized to cause pulmonary disease. the increase in hiv/aids as a cause of immunosuppression has increased the incidence of parasitic infection and pulmonary complications worldwide. the radiographic diagnosis is not specific for any of these diseases and their recognition relies upon an astute clinician and serological evaluation with polymerase chain reaction (pcr) testing. pulmonary infections are one of the most significant causes of morbidity and mortality in immunocompromised children. regardless of the immunodeficiency cause, the most common complications are infections caused by bacterial, viral or opportunistic pathogens [5, [33] [34] [35] . immunodeficiency can be divided into major groups of primary and secondary. a simple model of the immune system is that it is mediated by two major mechanisms: humoral and cellular. defective development of b cells results in humoral immunity abnormalities, while defective development of t cells causes cellular immunity problems. children with impairment of cellular or humoral immune mechanisms or both experience a higher propensity for specific infections. humoral immune impairments usually result in bacterial infections, while cellmediated immune impairments make children more prone to opportunistic, viral and mycobacterial infections [34] . this applies to children with primary immunodeficiency syndromes and secondary immunodeficiency diseases, including aids. most primary immunodeficiencies are humoral deficiencies, with iga deficiency, x-linked agammaglobulinemia and common-variable immunodeficiency the best known examples. these children are prone to repeated bacterial infections with associated pneumonia leading to postinfectious bronchiectasis (fig. 18) . a much smaller group of primary immunodeficiencies is caused by changes in cellular immunity (digeorge syndrome and severe combined immunodeficiency) or in phagocyte activity like chronic granulomatous disease. digeorge syndrome, which is also called thymic aplasia or hypoplasia, is a typical example of a primary t cell deficiency with abnormal development of the thymus, parathyroid glands and heart. children with this syndrome are susceptible to opportunistic organisms and to graft-versus-host disease from blood transfusions [34] . chronic granulomatous disease is a genetic syndrome characterized by an abnormality in an oxidative metabolic response during phagocytosis and resulting in bacterial and fungal infections. children with chronic granulomatous disease develop recurrent infections resulting in granuloma formation. these granulomatous lesions are seen in the skin, lungs, liver and lymph nodes. the onset of symptoms usually occurs early in life. chest radiograph and ct findings show fig. 16 axial ct shows the typical halo sign in an immunocompromised child with invasive aspergillosis chronic or recurrent pneumonia, usually by aspergillus or candida organisms. hilar and mediastinal adenopathy, pleural reaction and chest wall invasion can be also present [5, 36] . hyper-ige syndrome (hies, job syndrome) is a complex primary immunodeficiency disorder characterized by a spectrum of abnormalities related to the immune system, bones, connective tissue and teeth. hies was initially defined as a triad of clinical problems involving skin boils, severe episodes of pneumonia and very high serum ige levels. recurrent staphylococcal cutaneous lesions and pneumonia beginning in infancy and resulting in lung cyst formation with variable persistence and expansion are the typical findings [37] [38] [39] (fig. 19) . secondary immunodeficiency affects a mixed group of neutropenic children with previous chemotherapy or radiotherapy, immunosuppressed hosts after an organ or bone marrow transplant, and children with hiv/aids [2, 5, 40, 41] . in the second group, the deficiency occurs to a greater extent than in cellular immunity. however, humoral immunity can also be compromised in neutropenic and severely malnourished children. children who are predominately neutropenic as a result of chemotherapy or who are in the early phase after a bone marrow transplant with or without incipient graft-versus-host disease are at risk for infection by gram-negative bacteria such as pseudomonas aeruginosa or by gram-positive bacteria such as s. aureus. fungal pneumonias caused by aspergillus or candida species can also occur. pulmonary nodules are the most frequent finding of candidiasis lung infection on chest ct. these nodules might present the halo sign or excavation. centrilobular lesions or a mixed pattern can also occur [40, 41] . aids is caused by a retrovirus whose main characteristic is the development of immunosuppression and subsequent opportunistic infections and malignancies. vertical transmission is the usual form of infection in the pediatric population. lung infection is the leading cause of morbidity and mortality, causing 50 percent of deaths. viral and bacterial pneumonia are the most frequent infections at diagnosis [3, 42] . the most frequent agents are streptococcus pneumoniae, haemophilus influenzae, respiratory syncytial virus and adenovirus. children are prone to having severe presentations, and bacterial pneumonias are usually associated with cavitations, abscesses and empyema [40] . children with aids are also susceptible to fungal and mycobacterial infections. pneumocystis jirovecii is the most common opportunistic infection in infected babies without prophylaxis. p. jirovecii has a high mortality rate during the initial episode. the most common chest radiograph and ct findings are diffuse reticular interstitial opacities that can progress to massive alveolar consolidations resulting in acute respiratory distress syndrome in infants (fig. 20) . postinfection cavitations and bronchiectasis are typical after recurrent infections. cryptococcus neoformans infection is rare and has unusual presentations in hiv-infected children. the spectrum of disease ranges from asymptomatic pulmonary lesions to disseminated infection with necrotizing pneumonia, pleural effusion and meningoencephalitis [43] (fig. 21) . mycobacterium tuberculosis infection can mimic infections seen in immunocompetent children, but more severe c an older child with a right hyperlucent lung with small cavitations and incipient bronchiectasis and a left lung with ground-glass pattern after previous recurrent infections disseminated and miliary presentations of tuberculosis are becoming more frequent among children and even adolescents affected by aids (fig. 22) . the main reason is that m. tuberculosis, like hiv infection, also decreases cellular immunity. mycobacterium avium-intracellulare complex is also encountered in children with aids. imaging findings are nonspecific and similar to those of other forms of mycobacterial infections [2, 41] . pulmonary infection is also the most common cause of death after bone marrow transplantation. after engraftment (during the first 30 days) profound neutropenia and mucosal injury lead to severe immune suppression. children at this time are very susceptible to all organisms fungal, bacterial and viral. as the child's neutropenia recovers the immune suppression related to antirejection medication leads to impairment of humoral and cellular immunity (days 30 to 100). these children have a high incidence of cytomegalovirus and rsv. after 100 days the children have near normal immune function and pneumonia is less common. fungal organisms are associated with very high mortality, with aspergillus and candida the most common. it should be noted that children might not demonstrate fever or an elevated white blood cell count. ct is frequently used to monitor these children when there is a high index of suspicion for disease. fungal infections in particular demonstrate small, ill-defined nodules with or without surrounding ground-glass opacity. bacterial infections have features similar to those found in the immunecompetent child [44] . the role of the radiologist is to help recognize the presence of pneumonia and help guide therapy. the identification of a specific organism is almost never possible from imaging alone. however, by combining imaging and clinical information, the differential diagnoses can be generated. chest radiographs remain the mainstay of pneumonia imaging, supplemented with sonography and ct for specific indications. investigation of specific organisms using image-guided sampling and serological determinations is important in designing therapy. during treatment the radiologist can recognize complications such as cavitation, abscess and empyema. the role of image-guided intervention is beyond the scope of this paper, but in many centers the radiologist might be asked to address each of these complications. pediatric chest imaging: chest imaging in infants and children in: slovis tl (ed) caffey's pediatric diagnostic imaging, 11th edn thoracic disease in children with aids viral vs. bacterial pulmonary infections in children (is roentgenographic differentiation possible?) thoracic disorders in the immunocompromised child differentiating bacterial from viral pneumonias in children human metapneumovirus: a ubiquitous and long-standing respiratory pathogen post infectious bronchiolitis obliterans in children radiographic follow-up of pneumonia in children high-resolution ct of peripheral airway diseases bronchiolitis obliterans in children: clinical presentation, therapy and longterm follow-up spectrum of clinical and radiographic findings in pediatric mycoplasma pneumonia mycoplasma pneumoniae pneumonia: ct features in 16 patients round pneumonia: imaging findings in a large series of children cavitary necrosis complicating pneumonia in children: sequential findings on chest radiography the yield of ct of children who have complicated pneumonia and noncontributory chest radiography imaging of parapneumonic pleural effusions and empyema in children tuberculosis in children: where do we go now? modern imaging of tuberculosis in children: thoracic, central nervous system and abdominal tuberculosis cavitating pulmonary tuberculosis in children: correlating radiology with pathogenesis high resolution ct of the lung an update on primary care management for tuberculosis in children hiv in children: take a moment to make a difference pulmonary infections in hiv-positive children chapter 4 histoplasmosis imaging of pediatric mediastinal histoplasmosis imaging of chronic granulomatous disease in children spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings the radiological spectrum of invasive aspergillosis in children: a 10-year review diagnosing allergic bronchopulmonary aspergillosis in children with cystic fibrosis angioinvasive pulmonary aspergillosis after allogeneic bone marrow transplantation: clinical and high-resolution computed tomography findings in 12 cases radiological characteristics of pulmonary hydatid disease in children: less common radiological appearances primary immunodeficiency disorders in pediatric patients: clinical features and imaging findings the primary immunodeficiencies non-infective pulmonary disease in hiv-positive children chronic granulomatous disease hyperimmunoglobulinemia e syndrome: radiographic observations hyperimmunoglobulinemia e syndrome: pulmonary imaging considerations primary immunodeficiencies: a pictorial immunology primer for radiologists chest imaging in the immunocompromised child pulmonary disease in patients with aids: high-resolution ct and pathologic findings cryptococcosis in children risk factors for the development of bronchiectasis in hiv-infected children pulmonary infections after bone marrow transplantation: high-resolution ct findings in 111 patients key: cord-315436-8qrlc5sf authors: corona, laura l.; weitlauf, amy s.; hine, jeffrey; berman, anna; miceli, alexandra; nicholson, amy; stone, caitlin; broderick, neill; francis, sara; juárez, a. pablo; vehorn, alison; wagner, liliana; warren, zachary title: parent perceptions of caregiver-mediated telemedicine tools for assessing autism risk in toddlers date: 2020-06-02 journal: j autism dev disord doi: 10.1007/s10803-020-04554-9 sha: doc_id: 315436 cord_uid: 8qrlc5sf telemedicine tools have potential for increasing access to diagnostic services for children with autism spectrum disorder (asd). past work has utilized tele-assessment procedures in which remote psychologists observe administration of interactive screening instruments by trained, on-site providers. although promising, this approach relies on two clinicians, limiting its efficiency and scalability. the present study examined the use, acceptability, and parents’ perceptions of two caregiver-mediated tools for assessing asd risk in toddlers, in which remote clinicians guided parents to complete interactive screening activities with their children. most parents found tele-assessment to be comfortable, and many reported liking the parent-led nature of these tools. parents also offered constructive feedback, which was used to modify the tele-assessment process for future study. as the prevalence of autism spectrum disorder (asd) has increased, so too have needs for screening, diagnosis, and intervention access for young children. current prevalence estimates indicate that one in 54 children has asd (maenner 2020) . to maximize early identification and intervention, american academy of pediatrics guidelines recommend combining routine developmental surveillance at all pediatric visits with standardized autism-specific screening for all children at 18 and 24 months of age, as well as at any point that caregivers report concerns (hyman et al. 2020 ). however, universal screening remains aspirational (guthrie et al. 2019; zwaigenbaum and maguire 2019) , and many children are not diagnosed with asd until after four years of age even when developmental concerns are present during their toddler years (maenner et al. 2020) . although reasons for these diagnostic delays are likely multifaceted (bishop-fitzpatrick and kind 2017; mazurek et al. 2014 ), a lack of qualified diagnostic professionals (hyman and johnson 2012; kalkbrenner et al. 2011 ) as well as socioeconomic, geographic, and linguistic barriers (antezana et al. 2017; durkin et al. 2010; khowaja et al. 2015 ) make it difficult for families to access care. telemedicine tools may reduce this care disparity by increasing access to diagnostic and treatment services for individuals with asd, particularly in rural and underserved communities where access to qualified professionals is limited. emerging research has examined the feasibility and acceptability of telemedicine procedures in the assessment and diagnosis of asd, using video technologies to allow clinicians to remotely observe child behavior and converse with caregivers (juárez et al. 2018; kanne et al. 2018; reese et al. 2015; stainbrook et al. 2019) . for example, juárez et al. (2018) compared a tele-assessment procedure in which a remote psychologist observed administration of the screening tool for autism in toddlers and young children (stat; stone et al. 2000 ) by a trained, on-site early intervention provider and found that remote psychologists correctly identified approximately 80% of children later diagnosed with asd via comprehensive evaluation. in the second phase of this work, juárez et al. (2018) investigated feasibility and parent perceptions of the telemedicine assessment procedures. they found that parents reported high levels of satisfaction with the tele-assessment process, indicating that the process was convenient, private, and saved them an average of four hours of travel time from rural regions. most parents (90%) indicated that, if they had not received the telemedicine evaluation, they would have waited for an appointment at the more distant diagnostic center, resulting in later diagnosis and potentially delayed access to early intervention services. although a promising method for increasing access to diagnostic care, this work did not address a key barrier to care regarding the human resource requirements of assessment. this approach to tele-assessment of asd relies on the availability and dedicated time of two expert providers (i.e., stat administrator and observing clinician), which ultimately limits its efficiency and scalability. another novel approach to tele-assessment has been the involvement of parents or caregivers in completing structured activities with their children, under the verbal guidance of a clinician observing remotely. this type of in-the-moment remote coaching has long been used in parent training interventions, such as parent-child interaction therapy (funderberk and eyberg 2011), in which a therapist coaches parents from another room using a wireless microphone and earpiece. the use of telemedicine for remote coaching is increasingly common in parent-mediated interventions for children with asd (lindgren et al. 2016; pickard et al., 2016; vismara et al. 2012) , but this modality has been less often studied for the purpose of asd assessment. in one initial parent-guided approach to asd assessment (reese et al. 2015) , a remote clinician guided parents through a modified administration of the autism diagnostic observation schedule, second edition (ados-2; lord et al., 2012) . the assessment procedure included observation of the child's free play, interview questions with parents, and a modified ados-2 administration. parents were guided through evaluation procedures by a psychologist, who was either in the room with the family or interacting via video conference technology. parent guidance was completed through a description and orientation to ados-2 activities, as well as viewing a 16-min video modeling the activities parents would complete. additional research clinicians observed the visits, both in-person and via video technology, to provide data on inter-rater agreement. children later received interdisciplinary comprehensive assessments within 60 days of participating in the tele-assessment visit. when comparing diagnostic impressions based on the parent-guided procedure to diagnoses assigned following comprehensive evaluation, remote clinicians achieved diagnostic accuracy for 86% of participants. in an earlier study using this procedure, parents reported high levels of satisfaction with the process and noted that they felt comfortable during the assessment (reese et al. 2013) . there are several benefits to, as well as precedence for, the active involvement of parents during asd assessments (head and abbeduto 2007; huerta and lord 2012; luyster et al. 2009 ). many modules of the ados-2 involve the presence and scripted involvement of parents or caregivers . for example, caregivers may be asked to call their child's name, demonstrate what makes their child smile, or participate in a play routine with their child. clinicians also observe how a child initiates and responds to interactions with his or her parent or caregiver. this type of observation is valuable, as it is expected that young children behave differently with familiar caregivers than with unfamiliar adults. furthermore, observing a child interact with a close, familiar caregiver may provide insight into that child's best and/or most typical social interactions. though parents and caregivers play an essential role in asd assessment, both in providing information about their children and through interacting with their children, little is known about parents' perspectives on their involvement in the assessment process. parents often report dissatisfaction with the process of receiving an asd diagnosis and describe it as stressful (crane et al. 2016; howlin and moore 1997) . parent satisfaction with the diagnostic process is impacted by factors including the wait time for receiving a diagnosis, the manner in which providers share an asd diagnosis, and the amount of help and support parents receive during and following the diagnosis (crane et al. 2016; howlin and moore 1997; osborne and reed 2008) . absent from the literature on parent perceptions of the diagnostic process is information regarding parents' role and active involvement during the diagnostic evaluation. in contrast, parent involvement in asd intervention approaches has been well studied (meadan et al. 2009; wetherby et al. 2014) , with parents often reporting satisfaction with and benefit from parent-implemented interventions (mcconachie and diggle 2007; stahmer et al. 2017) . there is also some indication that interventions requiring a high level of parent involvement are associated with high levels of parent stress (kasari et al. 2015) . similarly, it is possible that parents may benefit from and appreciate being involved directly in asd assessment procedures. however, it is also possible that parents may experience direct involvement in assessment activities as stressful. from a telemedicine perspective, involving parents in the administration of assessment activities may reduce or eliminate the need for a second trained examiner in addition to a remote clinician. however, no formal tools or procedures have been thoroughly evaluated for use in caregivermediated asd assessment. as reese et al. (2015) described, initial attempts to coach parents to correctly administer ados-2 activities involved detailed descriptions of activities, explanations of multiple social bids and presses, and viewing of video models. further, it may be challenging to score and interpret the ados-2 using this modified approach. a goal of the present study was to determine whether assessment tools specifically created or adapted for teleassessment of asd could be used by parents in a comfortable, efficient way, while allowing clinicians to remotely observe child behavior and possible symptoms of asd. as part of a larger project evaluating the diagnostic accuracy and clinical utility of two novel, parent-guided screening tools either developed (tele-asd-peds) or adapted for (tele-stat) the remote assessment of asd in young children, we conducted preliminary evaluations of parent perceptions and feedback regarding these telemedicine tools. this critical parent feedback on the telediagnostic process was collected to understand parents' experience and perceptions, as well as to provide data to further adapt the tele-asd-peds and tele-stat for use in this manner. we hypothesized that parents would generally provide data regarding the acceptability of the tele-screening process, but would also offer key qualitative feedback for enhanced use over time. the data included in the present study are part of the initial feasibility and optimization component of a larger, ongoing clinical trial (clinicaltrials.gov, 2019, nct03847337) investigating the accuracy and limits of telediagnostic assessment in children with concerns for asd. participants were recruited from two sources: from an existing large clinical research database consisting of children with asd and developmental delay (dd) (n = 35) and from a clinical waitlist for evaluation of developmental concerns related to asd (n = 16). eligibility criteria included children being 18-36 months of age and having a primary caregiver that spoke english. participants were excluded if children had significant sensorimotor differences (e.g., visual impairment, motor impairment) that would have impacted ability to complete assessment activities. of 97 eligible families contacted about study participation, 51 consented to enroll. participants included 51 children (36 boys, 15 girls) between 1.63 and 3.01 years of age (m = 2.49 years, sd = 0.35 years) and their caregivers (see table 1 ). of these, 35 children were diagnosed with asd, 10 had developmental delays, and six were typically developing. caregivers included 45 mothers and eight fathers. of the participants recruited from a clinical research database, 22 children had a prior diagnosis of asd; eight children had a prior diagnosis of developmental delay; and five children were typically developing. prior diagnostic evaluations for children with asd or dd were completed by clinical psychologists (n = 23), pediatricians (n = 3), or developmental pediatricians (n = 3) between 26 and 391 days (m = 178.65, sd = 119.23) prior to completing tele-screening. given (a) the study's preliminary emphasis on understanding parent perceptions of the telediagnostic process rather than validation of tools themselves and (b) that children recruited from this registry were evaluated by a range of providers at various intervals of time prior to participation in the study, data regarding current cognitive, opted not to answer 11 (31%) 2 (20%) 2 (33%) household income ($) < 10,000 1 (3%) 1 (10%) 1 (17%) 10,000-20,000 2 (6%) 1 (10%) -20,000-30,000 -3 (30%) 1 (17%) 30,000-40,000 4 (11%) 1 (10%) -40,000-50,000 1 (3%) --50,000-60,000 5 (14%) --60,000-70,000 1 (3%) -1 (17%) 70,000-80,000 6 (17%) 2 (20%) -80,000-90,000 3 (9%) 1 (10%) -90,000-100,000 3 (9%) --> 100,000 7 (20%) -2 (33%) opted not to answer 2 (6%) 1 (10%) -adaptive, and ados-2 scores are not available for these participants. families recruited from the clinical waitlist completed telehealth screening on the same day that they received a full diagnostic evaluation by a clinical psychologist or licensed senior psychological examiner. for these participants, tele-screening was completed immediately prior to full diagnostic evaluations, and clinicians who completed diagnostic evaluations were not aware of remote assessors' clinical impressions. of these children, 13 received diagnoses of asd, two received diagnoses of developmental delay, and one was typically developing. cognitive, adaptive, and ados-2 scores for this subset of participants are presented in table 2 . remote assessors (n = 7) were licensed clinical psychologists and licensed senior psychological examiners with expertise in diagnosing asd in young children. all remote assessors were research reliable on the ados-2 and engaged in active clinical practice focused on asd diagnosis. remote assessors were blind to children's clinical diagnoses. the tele-stat was adapted from the stat for the purpose of tele-screening. the stat is a play-based level 2 asd screening tool designed and validated for use with children between 14 and 47 months of age (stone et al. 2004 (stone et al. , 2008 . it includes 12 clinician-led activities intended to elicit child behavior in four different domains: play, requesting, directing attention, and imitation. specific activities include encouraging the child to roll a ball or car back and forth with the examiner, presenting a snack and waiting for the child to make a request, and presenting motor activities for the child to imitate. each activity is scored as a "pass" (score of 0), indicating that the behavior or skill was observed, or a "fail" (score or 0.25, 0.5, or 1 depending on domain) indicating that the child did not demonstrate the behavior in question. scores across all activities are summed, resulting in a total score between 0 and 4, with scores greater than 2 indicating autism risk. in the tele-stat, adaptations included a brief introduction to communicate to parents that the remote assessor would ask them to provide specific prompts and complete specific activities with their child. remote assessors also asked parents for clarification where necessary regarding parent impression of child eye contact. otherwise, remote assessors used the stat standardized script to coach parents through implementation. remote assessors completed the stat standardized scoring following each activity. stat scores are presented in table 3 . the tele-asd-peds is a novel tool developed specifically for remote assessment of young children. it is derived from the application of machine learning technology to a database containing gold standard diagnostic tool data from several hundred individuals with and without asd (adiani et al. 2019) . the most predictive items for young children were derived and then applied to interactive, parent-led tasks with guidance from expert clinicians (i.e. 2 ados-2 trainers and 5 ados-2 research reliable psychologists). the tele-asd-peds includes 12 discrete social activities or social bids, including opportunities for free play, opportunities for physical play routines (e.g., peekaboo, tickling), and activities (e.g., bubbles, snack) that may prompt a child to request. following administration, clinicians rate child behavior on seven items (e.g., socially directed speech and sounds, use of eye contact, atypical vocalizations, unusual or repetitive play), allowing for dichotomous (yes/no) as well as likert (3 = behaviors characteristic of asd clearly present; 2 = possible atypical behavior; 1 = behaviors characteristic of asd not present) scoring regarding presence and severity of predictive symptoms. specific behaviors coded and associated likert-style asd-peds scores are presented in table 3 . immediately after the evaluation, parents answered seven questions related to pacing of the visit, content of the procedures, and usability of the materials, as well as their comfort with the process. each question was scored along a likert-type scale (1 = not true, 2 = somewhat true, 3 = very true). parents were also asked to provide openended feedback, including suggestions for changes to the process and whether there were aspects of tele-screening participants were randomized to receive one of two telescreening procedures: the tele-stat (n = 24) or tele-asd-peds (n = 27). randomization occurred prior to consent and assent. group assignments were issued after consent and assent were obtained. all procedures were approved by the institutional review board. no adverse events occurred. participants were escorted to the tele-screening room by a research assistant who oriented them to the technology and the space, including the test materials (e.g., toys, bubbles, snacks) on wall-mounted shelves. the research assistant established a connection with the remote assessor using the video conference technology and ensured that both the clinician and family could see and hear each other. the tele-screening visit began after the research assistant left the room. during the tele-screening process, parents interacted with a remote assessor via a wall-mounted monitor, speakers, and a hipaa-compliant video platform (cisco systems 2015) . this configuration allowed for two-way audiovisual communication and camera control by the remote assessor. remote assessors followed scripts and guided parents through structured interactions with their children, following the specific procedures described above for either the tele-stat or tele-asd-peds. the tele-screening procedure took an average of 23 min (sd = 5.00), with no significant difference between the two screening tools. each measure was coded according to its instructions regarding behaviors that the clinician observed. remote assessors then documented their diagnostic impressions (asd vs. no asd) immediately following screening. diagnostic impressions were not shared with participants but were used to provide preliminary information about remote assessors' agreement with clinical diagnoses. immediately following the telescreening, parents completed the parent questionnaire to provide feedback on the process. of participants who completed tele-screening immediately prior to full diagnostic evaluations (n = 16), parents provided their feedback on tele-screening after the tele-visit but prior to the diagnostic evaluation. they completed a second brief questionnaire comparing the two visits immediately after the diagnostic evaluation. survey responses from parents indicated that many found tele-assessment procedures to be acceptable and comfortable (see table 4 ). most parents reported that they felt comfortable playing with their children during the tele-screening, found the spoken instructions easy to follow, and believed that the screening lasted about the right amount of time. a minority of parents (12%) indicated that screening activities did not elicit the child behaviors about which they were most concerned. nonparametric analysis using mann-whitney u tests yielded no significant differences (p values > 0.05) on these items between parents who completed the tele-stat and those who completed the tele-asd-peds. similarly, mann-whitney u tests indicated no differences (p values > 0.05) in parent ratings of these items as a function of whether children received full evaluation on the same day as tele-screening or on a previous date. finally, mann-whitney u tests indicated no significant differences (p values > 0.05) in parent ratings as a function of remote assessors' diagnostic agreement (i.e., whether remote assessors' impressions were consistent or inconsistent with children's clinical diagnoses). overall, when asked whether they would prefer to play with their child as part of screening or observe a psychologist play with their child, 19% of parents indicated that they would prefer to play with their child by themselves, 4% would prefer to observe a psychologist interact with their child, and 77% would prefer to both play and observe. examination of parents' qualitative responses provided additional information about aspects of tele-assessment that parents enjoyed, as well as constructive feedback on suggested changes to tele-assessment procedures. in total, 45 parents participants responded to each item using a likert scale, with 1 representing "not true," 2 representing "somewhat true," and 3 representing "very true." participant ratings on these items did not differ across any comparisons run (p's greater than .05) total asd (n = 35) dd (n = 10) td (n = 6) examples technology 25 (22%) "the video kept cutting in and out making it hard to hear and understand what was being said." parent-led nature of screening 21 (18%) "my child interacted with me rather than people he didn't know" "i enjoyed being a part of the process but worried my interaction was too much or too little" comparing diagnostic evaluations to tele-screening 16 (14%) "it feels like if the screening tool was just that-a screening, it would be good. but maybe a full evaluation is still needed? for whatever reason, [my child] often performs well at these type of things-like today, he didn't get frustrated or have a meltdown. i wonder if he would have been overlooked if he had only received this screening instead of the full evaluation he got." "i like the telemedicine as it included me as a parent but i also like the full evaluation as it allows me to see what happens when someone else is working with my child." time 11 (9%) "i feel like a screening should last a little longer. maybe 30-45 min." "it was fast and was able to hold his attention with all the different task." comfort/convenience 8 (7%) "really easy screening. very comfortable for both baby and i." screening space and activities 7 (6%) "i would change to have toys out of eyesight for child. maybe in a box next to parent." clinician and staff communication 9 (8%) "i appreciated the questions about eye contact and the doctor's patience." other 19 (16%) "it was about the same play wise" "never had a visit like this for her." provided 116 written comments (see table 5 ), including comments about technology (n = 25), the parent-led nature of the screening process (n = 21), comparisons between full evaluation and tele-screening (n = 16), and the convenience of the process (n = 8). when asked about changes they would make to the screening visit, 19 parents provided comments. most comments (n = 13) focused on technology, including concerns related to audio quality, the small size of the screen, and their children's interest in accessing or touching the screen and camera. parents also commented on the screening activities (n = 4), including suggestions for adding more or different activities. two parents suggested extending the amount of time for screening. as noted above, screening visits lasted 23 min, on average. one parent wrote that a screening visit of 30-45 min would be preferable. when asked what they liked more about the tele-screening, compared to their child's full diagnostic evaluation, 32 parents provided a total of 35 comments. the majority of these comments (n = 14) emphasized the parent-led nature of the screening process. parents commented that they liked being involved and that their children were more comfortable or better able to pay attention when interacting with a parent rather than an unfamiliar clinician. other comments focused on the shorter time of the screening as compared to a full diagnostic evaluation (n = 6), the convenience of the screening process (n = 4), and that the screening purpose and instructions were easy to understand (n = 3). when asked what they liked less about the tele-screening process, 15 parents provided a total of 16 comments. three parents wrote that there was nothing they liked less. four parents commented on technology issues. four parents indicated that the full evaluation had gone into more detail, or that the behaviors they were most concerned about were not apparent during the tele-screening. three parents noted that the tele-screening process was less personal than the full evaluation, and one parent voiced concern that they were not administering the activities correctly. finally, when asked for other comparisons between the screening and full evaluation or other general comments, 36 parents provided a total of 46 comments. these comments addressed many of the topics described above, including technology, parent and child comfort, and parents' role in the process. some parents (n = 8) commented that they thought that tele-screening may be useful as an initial step in the evaluation process, but also wanted face-to-face interaction with a provider or an opportunity for a provider to interact with their child as well (e.g., "i feel it was a comfortable tool for parent child but because it's not in person, it might be easier to miss something, for that reason maybe should have more than one screening"). preliminary diagnostic agreement information is presented in table 3 . remote clinicians accurately identified 33 children with clinical asd diagnoses and accurately identified 11 children who did not have asd. five children with developmental delays were inaccurately identified as having asd, and two children with asd were not identified as such by remote assessors. although a relatively small proportion of the sample, none of the typically developing children were incorrectly identified as having asd. overall diagnostic agreement was 86%. analysis of diagnostic agreement and characteristics of children who were accurately vs. inaccurately identified is ongoing. this work evaluated parent perceptions of two promising tools either adapted for or designed intentionally for the use of telemedicine to improve access to services for children with asd and their families. results provide initial information on parent perceptions of these novel telemedicine tools used to guide parents through administration of asdscreening activities with their toddlers. overall, parents rated tele-screening to be acceptable and comfortable. parents' qualitative feedback offered important insight into potential modifications to tele-screening procedures. some parents also described limitations of tele-screening, highlighting the importance of creating procedures that capture parent concerns and child behavior as comprehensively as possible. together, these parent comments provide important guidance regarding the development and modification of teleassessment processes. a preliminary question in considering tele-assessment of children with concerns for asd has been whether parents find this approach to asd identification to be acceptable, comfortable, and useful. results of the present study indicate that the majority of parents found the clinician's instructions to be easy to follow, understood what they were asked to do, and felt comfortable playing with their child as part of the screening. qualitatively, parents provided positive feedback on many aspects of the tele-assessment process. several parents appreciated the parent-led nature of the tele-assessment, noting that their children may feel more comfortable playing with a parent than an unfamiliar clinician. some parents reported satisfaction with clinician communication during the assessment, particularly when clinicians asked questions to better understand the child's behavior or to clarify how the child was interacting with his or her parent. this positive feedback from parents is in keeping with past work on parents' responses to being involved in providing intervention to their children (mcconachie and diggle 2007; stahmer et al. 2017) . this is also important information for clinicians interacting with families during both in-person and telemedicine-based assessments, as there has been limited research on parents' perceptions of their own involvement in the diagnostic evaluation process (head and abbeduto 2007) . parents also provided feedback highlighting areas in which tele-assessment procedures and technology can be improved. many parent comments addressed difficulty hearing or seeing the clinician, concern about what the clinician could and could not see, and problems with internet connections. these comments highlight the challenges inherent in telemedicine. existing research and guidelines for telepractice stress the barriers associated with technological challenges and emphasize the importance of technical support (boisvert et al. 2010 ; joint task force for the development of telepsychology guidelines for psychologists 2013). future work should continue to gather iterative feedback from stakeholder parents that will inform the development of tools and resources delivered via telehealth. within this work, feedback allowed us to take practical steps to address several parent concerns in the next phase of work. these include changes to the technological set-up, such as using a larger video screen, providing a portable speaker that parents can hold next to them, and using a wired internet connection rather than relying on a wireless network. it also included several adjustments to the tele-evaluation rooms and materials. specifically, child-friendly art and noise-canceling panels were added to walls, a larger wallmounted monitor was utilized, audio issues were resolved, and materials used in assessment activities were placed into labeled boxes for ease of access. in addition to feedback on technology challenges, some parents commented on potential limitations of the telescreening process. a minority of parents reported concern that the tele-screening tools did not allow clinicians to observe the full range of children's behavior, including some behaviors about which parents were most concerned. others expressed concern that the brief nature of the screening may result in their child's vulnerabilities being overlooked. finally, some parents provided comments referencing the value of face-to-face evaluation with an experienced clinician. some noted that they found it valuable to watch someone else work with their child. others indicated that perhaps tele-screening may be a first step in a process that ultimately includes in-person diagnostic evaluation. further, when all parent participants were asked whether they preferred to play with their child, observe a clinician playing with their child, or both, most parents indicated that they preferred to both play and observe. this feedback suggests that while parents appreciated the opportunity to be directly involved in their child's assessment, some families may continue to prefer traditional, in-person visits with clinicians, either in addition to or instead of tele-screening. parents' concerns highlight a key limitation of any brief screening or assessment procedure, which provide clinicians only a glimpse of a child's behavior and may or may not be representative of that child's behavior in other settings. for this reason, best clinical practice in asd evaluation has long stressed the importance of caregiver interviewing combined with observation of child behavior (huerta and lord 2012) . in subsequent phases of this ongoing clinical trial, remote assessors supplement use of the tele-stat or tele-asd-peds with a clinical interview to obtain developmental history, parents' current concerns, and presence or absence of asd-related symptoms in other settings. given the stress frequently associated with the diagnostic process for parents (crane et al. 2016) , any novel assessment modality must be responsive to parents' concerns. for tele-assessment of asd to be an acceptable and scalable clinical model, it is essential that parents and clinicians view the process as comprehensive and capable of capturing the child behaviors about which parents are specifically concerned. though tele-assessment presents a promising avenue for delivering services to children and families in a convenient and efficient manner, not all families will prefer or be appropriate for tele-assessment. a tele-assessment model of asd identification is meant to serve families whose needs can be met with a distance consultation and assessment approach. stainbrook et al. (2019) described a set of decision rules used to determine which families would be most successfully served by a telemedicine assessment. children considered most appropriate for this model were those between the ages of 18 and 33 months without significant medical complexity, who were not yet speaking in sentences, and for whom specific concern for asd had been raised by parents, caregivers, or medical or early intervention providers. children with higher levels of diagnostic complexity, medical comorbidities, or more advanced language, as well as families who preferred to travel for in-person assessment, were referred for comprehensive evaluations (stainbrook et al. 2019 ). this type of triage approach may help to decrease wait times both for families who can access telemedicine assessment as well as those who prefer or likely require an in-person or lengthier evaluation. this approach also allows families an opportunity to choose which type of care they receive. this study has several key limitations that warrant further investigation. first, the present study has a relatively small sample size and an unequal distribution of children across diagnostic status. participants in this study were from families who spoke english as a primary language, limiting our ability to understand how tele-screening may operate for non-english speaking families. our sample is also made up of families who elected to participate in research on telehealth. as such, it is possible that these families already have positive views of telemedicine as a healthcare modality. as telehealth becomes increasingly common throughout medical and psychological fields, it will be important for future research to understand how patients who opt for telemedicine visits are different from those who do not. an additional limitation is that psychometric properties are not yet available on the tele-stat and tele-asd-peds, limiting our ability to comment on their ultimate utility. ultimately, understanding diagnostic agreement in relation to characteristics of family and child is of critical importance, but beyond scope of the present study. the first phase of this clinical trial was focused on acceptability of these tools and sought parent feedback for the purpose of optimizing tele-screening procedures, laying the groundwork for further rigorous evaluation of these procedures. it is promising to note that initial diagnostic agreement in this study was 86%, similar to diagnostic agreement reported in other research on tele-assessment of asd (juárez et al. 2018; reese et al. 2015) . further analysis of the diagnostic accuracy of tele-assessment procedures that combine parent-led activities with clinical interviewing is ongoing and will be submitted for publication separately. though acceptability and parent feedback are important first steps in developing tele-screening procedures, it will be important to understand how and for whom these tools can be most useful. the current study presents several fruitful directions for ongoing research. within our ongoing clinical trial, immediate future directions include investigation of the psychometric properties of the tele-stat and tele-asd-peds. we intend to examine child and family factors impacting diagnostic accuracy and clinician diagnostic certainty. we also intend to investigate provider and caregiver perceptions of tele-assessment for asd within a community sample, particularly in the context of covid-19 as many providers explore telemedicine-based models of care. as telemedicine services expand, it will be important to continue seeking and responding to stakeholder feedback in collaborative, familycentered ways. in addition, it will be essential to understand for whom and under what circumstances telemedicine is most appropriate and effective. continuing to assess factors impacting family preference for telemedicine versus in-person visits, as well as understanding barriers to telemedicine, will allow for the creation of models that best meet patients' and families' needs. in conclusion, parent-led, clinician-guided asd screening represents a promising approach to the use of telemedicine in early asd assessment. while prior approaches to tele-assessment have relied on multiple expert providers or detailed coaching sessions with parents, the tele-stat and tele-asd-peds allow a remote clinician with expertise in asd to guide caregivers through a set of activities with their toddlers in real time, creating opportunities to observe toddlers' independent play, response to social bids, and interaction with caregivers. the feedback provided by parents in the current study both highlights the preliminary acceptability of these procedures, as well as presents key opportunities for further optimizing these procedures to best meet families' needs. ultimately, leveraging telemedicine for the purpose of asd assessment may address barriers families face in accessing early assessment and diagnosis of asd, including geographic barriers, long wait times, and limited availability of expert providers to complete diagnostic evaluations. in turn, this increased access can facilitate early access to interventions, resources, and family support, promoting long-term developmental outcomes and family functioning. usability enhancement and functional extension of a digital tool for rapid assessment of risk for autism spectrum disorders in toddlers based on pilot test and interview data rural trends in diagnosis and services for autism spectrum disorder a scoping review of health disparities in autism spectrum disorder telepractice in the assessment and treatment of individuals with autism spectrum disorders: a systematic review cisco jabber can novel telemedicine tools reduce disparities related to early identification of autism. identifier nct03847337 experiences of autism diagnosis: a survey of over 1000 parents in the united kingdom socioeconomic inequality in the prevalence 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perceptions of communication with professionals during the diagnosis of autism a mixed-method evaluation of the feasibility and acceptability of a telehealth-based parent-mediated intervention for children with autism spectrum disorder brief report: use of interactive television in identifying autism in young children: methodology and preliminary data evaluating interactive videoconferencing for assessing symptoms of autism measuring the service system impact of a novel telediagnostic service program for young children with autism spectrum disorder parent perceptions of an adapted evidence-based practice for toddlers with autism in a community setting brief report: screening tool for autism in two-year-olds (stat): development and preliminary data psychometric properties of the stat for early autism screening use of the screening tool for autism in two-year-olds (stat) for children under 24 months: an exploratory study telehealth for expanding the reach of early autism training to parents parent-implemented social intervention for toddlers with autism: an rct autism screening: where do we go from here? the authors wish to acknowledge and thank the parents and children who participated in this research, as well as the research staff at the vanderbilt kennedy center treatment and research institute for autism spectrum disorders. author contributions asw, jh, an, nb, apj, av, zw contributed to the study conception and design. all authors were involved in aspects of study preparation, data collection, and analysis. the first draft of the manuscript was written by llc, and substantial edits were made by asw. jh and zw also provided edits. all authors reviewed previous versions of the manuscript. all authors approved the final manuscript.funding the study was funded by nih/nimh (grant number 1r21mh118539-01). conflict of interest all authors declare that they have no conflict of interest. all procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. the study was approved by the institutional review board at vanderbilt university medical center. key: cord-302863-9e5ajbgq authors: alhabdan, yazeed abdullah; albeshr, abdulhameed ghassan; yenugadhati, nagarajkumar; jradi, hoda title: prevalence of dental caries and associated factors among primary school children: a population-based cross-sectional study in riyadh, saudi arabia date: 2018-11-30 journal: environ health prev med doi: 10.1186/s12199-018-0750-z sha: doc_id: 302863 cord_uid: 9e5ajbgq background: dental caries is a preventable childhood disease, but public health efforts are hampered due to limited information on associated factors in vulnerable populations. our study was aimed at estimating the prevalence of dental caries and identifying key associated factors in four major risk domains, including socioeconomic factors, child oral health behavior and practices, child feeding practices, and dietary habits among primary school children in saudi arabia. methods: a cross-sectional study design was used to recruit 578 male saudi primary school children, aged 6–8 years, from 12 primary schools in five different regions of riyadh. children were clinically screened to detect carious lesions in primary teeth according to world health organization’s criteria. structured self-administered questionnaire was used to collect information on social and individual factors from the parents. the odds ratios and 95% confidence intervals of associated factors for dental caries were computed using logistic regression models; key factors were identified by systematic selection process that accounted for multicollinearity and bias correction. results: dental caries was prevalent among children (83%, 95% confidence interval 79.7–86.0%). individual factors, including irregular brushing, late adoption of brushing habit, consulting dentist for symptomatic treatment, lack of breast feeding, sleeping with a bottle in mouth, habit of snacking between meals, low consumption of fruits, and frequent consumption of soft drinks and flavored milk, were predominantly associated with dental caries in children, instead of socioeconomic factors (p < 0.05, adjusted r-square 80%). conclusion: dental caries were prevalent in school children, and individual factors were predominantly associated with the disease. electronic supplementary material: the online version of this article (10.1186/s12199-018-0750-z) contains supplementary material, which is available to authorized users. dental caries is a major oral health problem affecting 2.43 billion people (35. 3% of the population) worldwide in the year 2010 [1] . a high burden of dental caries was evident among children in saudi arabia with an estimated prevalence of approximately 80% [2] ; other high-risk areas include latin america, middle east, and south asia [3] . the world health organization (who) emphasizes the need to reduce global burden of dental caries in attaining optimal health. consequently, in the year 2003, who and fédération dentaire internationale (fdi) world dental federation set global goals for oral health in 2020 to guide planners and policy makers to improve the status of oral health in their populations [4] . unfortunately, knowledge gaps with respect to the availability of baseline data on oral health and population-specific key modifiable factors of dental caries restrict the ability of many developing nations and semi-developed countries, including saudi arabia to attain the goals set by who. in addition, competing interests in health care funding warrant prioritizing the associated factors to better direct public health mitigation efforts. although factors, such as occupational status, family income, and level of education of parents [5] [6] [7] [8] [9] that affect the socioeconomic status of populace, have been associated with dental caries, their relative impact on dental caries compared to individual factors is unclear. moreover, modification of socioeconomic factors requires time-consuming macro level changes. in contrast, individual factors, such as child oral health behaviors, child feeding practices, and dietary habits that play a role in cariogenesis, could be targeted for modification by directing the limited resources to primary school children. prior evidence illustrates the importance of adopting good oral health behaviors such as regular brushing of teeth, using mouthwash, and flossing teeth in reducing the disease burden and attaining optimal oral health [10] . similarly, the role of sugary foods (e.g., candies) in cariogenesis was also well established [11] . however, the relative significance of aforementioned oral behavioral factors on cariogenesis compared to other host factors could vary significantly in different populations owing to cultural and behavioral practices. in our globalized world, constant migration of individuals and transfer of certain behaviors or practices (e.g., favoring flavored milk over plain milk among children) [12] is the prevailing norm. therefore, the knowledge of associated factors for dental caries in saudi children not only benefit saudi populace but also international organizations such as who and health authorities in directing the mitigation efforts at vulnerable populations (e.g., children). this study aimed at estimating the prevalence of dental caries in primary teeth and identifying key associated factors in 6-8-year-old school children in riyadh city of saudi arabia would contribute towards the knowledge of dental caries by enriching the baseline data and determining population-specific risk factors of such a highly prevalent and preventable condition. our analysis is the first in saudi arabia to comprehensively evaluate and prioritize factors encompassing all four major risk domains for dental caries, including parental socioeconomic status, children oral health behavior and practices, child feeding practices, and dietary habits. in addition, the relative importance of individual factors (over socioeconomic factors) as determinants of dental caries was assessed using extensive modelling techniques. a population-based cross-sectional study design was employed to determine the burden of dental caries in primary teeth and key associated factors among 6-8-year-old male primary school children recruited from 12 government primary schools for boys located in 5 geographical regions (southern, northern, eastern, western and central) in riyadh city, saudi arabia. the study included only saudi nationals, whose parents were able to fill the self-administered questionnaire and provide informed consent for their child's dental examination at school. non-saudi children or children with non-saudi care givers or parents were excluded. this study was conducted in the year 2015 between september 1 and november 30. sample size was calculated using single proportion formula based on 95% confidence level, expected prevalence of 80% [2] , precision of 0.05, and design effect of 2. the recommended sample size was 492 children with one of their parents as a single unit. we anticipated low response rate owing to the outbreak of middle east respiratory syndrome-corona virus (mers-cov) in riyadh city during the study period. therefore, a total of 1130 questionnaires were distributed to parents and we received 578 completed questionnaires at a response rate of 51% from 12 out of 15 schools considered for recruitment among 513 government primary schools for boys in riyadh region. our study sample was obtained by a multistage random sampling technique. briefly, up to three primary schools in riyadh were randomly selected from each of the five geographical locations in riyadh city based on the list of primary schools obtained from the ministry of education. a maximum of 80 students were randomly selected from each of these schools. each of the five regions in riyadh city contributed a fifth of the total study sample. children underwent a simple dental examination based on the world health organization diagnostic criteria for oral health surveys [13] . the basic oral assessment of every child was performed by a single, well-trained professional dentist by seating each subject on a chair in a good day light using mouth mirror and dental probes. this simple oral examination poses no harm to children. the intra-examiner reliability was good based on re-examination of 30 children prior to the study (kappa value = 0.98). caries status in the crown of primary teeth was assessed using decayed (d), missing (m), and filled (f) teeth (dmft) index [2, 13] ; teeth missing (m) or filled (f) contributed to the overall dmft score only if they were missing or filled because of caries. a dmft score above null indicates the presence of caries, whereas a null score indicates the absence of caries [13] . a structured self-administered parental questionnaire was developed by relying on previous studies [13] [14] [15] [16] [17] [18] [19] [20] and accounting for cultural sensitivities of the study population. the questionnaire was translated into arabic and then back to english to ensure accuracy. face validity, feasibility, and construct validity of the questionnaire was established prior to study. the questionnaire responses provided data on age of the child, demographic and socioeconomic factors such as father's education level, mother's education level, parental occupation as health care provider, monthly income of the family, region of residence, type of residence, and availability of medical insurance with dental coverage. parents also provided information on oral health behavior and practices of children, such as frequency of brushing teeth with toothpaste in a day; age at which children started brushing; use of dental floss; use of mouthwash; frequency of fluoride application; recent visit to the dentist; habit of eating after brushing teeth in night; and child feeding practices, such as type of milk feeding practice (breast-fed only/children mixed-fed with both breast milk and powdered milk/powdered milk only), age of child when breast feeding was stopped, age of child when bottle feeding was stopped, child sleeping with bottle in mouth, number of meals per day, number of snack items consumed between meals, and snack time corresponding to main meals (ate snacks with main meals only/ate snacks in between main meals or with main meals). dietary information included use of multivitamin supplementation (no/yes) and consumption of fresh fruits, fresh vegetables or salads, fast food, candy, potato chips, sweetened chewing gum, fresh juice, flavored juices, soft drinks, fresh milk, and flavored milk at least twice a week (no/yes). some of the original variable categories were combined to create meaningful new groups, and facilitate appropriate analyses. in particular, the 'frequency of brushing teeth' variable was classified in to 3 categories (children brushing less than once daily/once daily/two times or more daily. all analyses of study data were performed using sas software version 9.4 (sas institute inc., cary, nc, usa). categorical variables were described as counts and percentages, whereas means and standard deviations (sd) were computed for continuous variables. the 95% confidence intervals for proportions were constructed using clopper-pearson exact tests. the independence of characteristics of study sample by caries status (presence or absence) was assessed using pearson's chi-squared test (or fisher's exact tests for smaller samples) and p values. missing data were analyzed as a separate category (unknown or other) in corresponding variables. the main associated factors for dental caries in our study were determined in three steps. in the first step, the association between each characteristic of study sample and the presence of dental caries was evaluated using univariate logistic regression analyses; all the variables that were significant at p value less than or equal to 0.05 were selected for second step of analyses. in the second step, the associated factors for dental caries among each of the four broader determinants of health, including socioeconomic factors, child oral health behavior and practices, child feeding practices, and dietary factors, were identified based on four separate stepwise logistic regression analyses. subsequently, the covariates that were significant (p ≤ 0.05) in each of the four analyses were selected for further analysis. in the final step, a stepwise multivariate logistic regression analysis was performed on covariates selected from step two and variable age group of the child (6 or 7 or 8 years) to determine key associated factors for dental caries. in addition, multicollinearity was assessed using collinearity indices, eigenvalues, and variable decomposition proportions for all the multivariate models. one of the highly collinear variables was removed giving precedence to children oral health behavior and practice covariates. in addition, firth's bias correction was applied to the final multivariate model to address potential issues due to small sample size, and complete or quasi-complete separation. the measures of association were reported as unadjusted odds ratios (uor) and adjusted odds ratios (aor) along with their corresponding 95% confidence intervals (95% ci). the discrimination, calibration and overall performance of the final multivariate model was assessed using concordance statistic, hosmer and lemeshow goodness-of-fit test, and adjusted cox and snell r-square, respectively. the performance of final model with and without socioeconomic factors was compared based on adjusted cox and snell r-square, which indicates the proportion of variation explained by the covariates in the model. statistical analyses that yielded a p value less than or equal to 0.05 were considered significant. a total of 578 primary school boys aged 6 to 8 years in riyadh, saudi arabia, were analyzed in this study. the prevalence of dental caries in our sample was 83% (95% ci 79.7-86.0%). about 17% (95% ci 14.0-20.3%) of children had no carious lesions. the age-specific prevalence of dental caries among children aged 6, 7, and 8 years was 87.6% (95% ci 82.4-91.6%), 72.9% (95% ci 65.9-79.1%), and 88.4% (95% ci 82.7-92.8%), respectively. the mean age and dmft score in our sample was 6.92 (sd ± 0.82) and 4.20 (sd ± 2.96), respectively. table 1 provides the frequencies, percentages, and differences (by caries status) for various characteristics of study population. a significant number of fathers (65.7%, 95% ci 61.7-69.6%) and mothers (73.9%, 95% ci 70.1-77.4%) did not attend a college or university, and their children experienced high prevalence of dental caries. majority of the children came from low-income families (59.7%, 95% ci 55.6-63.7%), and approximately 99% of them experienced dental caries. most of the study subjects lived in rental homes, and 77% had no dental coverage in medical insurance. in general, the children had poor oral health behavior and practices as most of them started brushing at a late age (5 or more years) and brushed less than once daily (55%) in any given week. the use of dental floss and mouthwash was negligible, and most of the children visited a dentist for symptomatic treatment. although the practice of breast feeding is common, most of the children were weaned by the first year. the practice of mixed feeding was common in our sample; approximately 81% of mixed-fed children experienced dental caries compared to 93% of children that were exclusively fed with either breast milk or powdered milk. the practice of sleeping with a bottle in mouth and frequent consumption of sugary snacks between meals was also common. the consumption of fresh fruits and fresh juice was less prevalent in our sample. the summary of variables selected during different steps of selection process is illustrated in table 2 . barring few exceptions, almost all the factors were significantly associated with dental caries' experience in univariate analyses (step 1). in the ensuing step 2 multivariate analysis, a limited number of factors were associated with dental caries in each of the four risk domains with more concessions observed among dietary factors. in the final step of model selection, the highly collinear child feeding covariate (i.e., age of the child when breast feeding was stopped) was excluded to address multicollinearity. our model selection process yielded 12 variables that were significant at p < 0.05 for inclusion in the final model. although association measures were not provided in table 2 to avoid confusion, interested readers could find these details in additional file 1. the unadjusted and adjusted odds ratios along with their 95% confidence intervals (based on firth's bias correction) for the variables, representing all four risk domains, in the final model are reported in table 3 . it should be noted that factors representing low socioeconomic status, such as low level of maternal education, low family income, and lack of dental insurance, were associated with a minimum of fourfold increased dental caries experience. child oral health practices, such as failure to brush teeth at least once a day, failure to start brushing on or before a child attained 2 years of age, and visiting dentist for symptomatic treatment, were associated with dental caries experience in children. children habituated to sleeping with bottle in mouth experienced 4.4-fold higher dental caries compared to children not practicing this habit (aor = 4.4, 95% ci 1. 4-13.4 ). in addition, lack of mixed feeding and consuming two or more sugary snack items between meals were predominantly associated with dental caries experience (p < 0.05). dietary habits, such as less consumption of fresh fruits and frequent consumption of soft drinks and flavored milk, were significantly associated with dental caries with an odds ratio of 11.6, 5.3, and 7.7, respectively. the final model was well calibrated (p = 0.7667; hosmer and lemeshow goodness-of-fit test) with very high discriminatory power (c-statistic = 99%) and high overall performance (adjusted r-square of 88%). subsequent exclusion of three variables representing socioeconomic status from the final model also resulted in a well-calibrated model (p = 0.3502; hosmer and lemeshow goodness-of-fit test) with very high discriminatory power (c-statistic = 98%). however, a slight reduction in overall performance from 88 to 80% was noted, signifying the influence of individual or personal factors (represented in the remaining three risk domains) on dental caries experience in children; the overall performance of model with variables representing socioeconomic status was 59%. in addition, the higher magnitude of adjusted odds ratios of individual factors (ranging from 4.4 to 38.4) compared to aors of socioeconomic factors (ranging from 4.2 to 28.2) and the lower confidence limits that were consistently above 1.5 lend further support to the predominant flavored milk x x x *the variables selected in the step were marked with an "x," and variable excluded is marked as "-." the variables selected were significant at p value less than or equal to 0.05 †the variable "age of the child when breast feeding was stopped" was excluded to address the issue of collinearity in the final model influence of individual factors on dental caries' experience in children. dental caries was prevalent among 6-to 8-year-old primary school children in saudi arabia (83%, 95% ci 79.7-86.0). we identified individual factors, encompassing three major risk domains (children oral health behavior and practices, child feeding practices, and dietary habits) that were predominantly associated with dental caries' experience in our study. especially, child oral health behavior and practices, such as brushing teeth at least once daily, starting the practice of brushing earlier than 2 years, and visiting a dentist regularly, were significantly associated with dental caries. in addition, children mixed-fed with both breast milk and powdered milk, children sleeping with bottle in mouth, and the practice of snacking two or more items between meals were linked to dental caries experience in children. dietary habits, such as less frequent consumption of fresh fruits (once a week or less) and more frequent consumption of soft drinks and flavored milk (more than once a week), were significantly associated with dental caries in our study. in our sample, socioeconomic factors (less-educated mothers, low family income, and lack of dental insurance coverage) were less influential than individual factors in determining dental caries' experience in 6-8-year-old male primary school children. the high prevalence of dental caries observed among primary school children in our sample was consistent with previous studies in saudi arabia [14, [21] [22] [23] [24] and uae [25] . a recent meta-analysis of various dental caries studies in different regions of saudi arabia determined the prevalence to be 80% [2] . furthermore, the observed prevalence of dental caries among children in the present study was substantially higher than the target established for the year 2000 (50%) by who/fdi [26] . the collective evidence from our study and previous studies confirm the endemic nature of dental caries in middle eastern population and signify the burden on public health. it is interesting to note that dental caries' experience among primary school children was better explained by individual factors (80%) rather than socioeconomic factors (59%) in our study, which is consistent with weaker role of socioeconomic factors observed in developed nations [6, 15] . this notion was further supported by the relatively stronger associations observed between individual factors and dental caries experience in our study. in contrast, several cross-sectional and longitudinal studies from developing nations demonstrated the dominant role of socioeconomic factors in dental caries' experience [18, [27] [28] [29] . the risk profile of dental caries among children in saudi arabia appears to follow the theme in developed world, where oral health behavioral practices and dietary habits were relatively more important [30] . however, efforts directed at improving socioeconomic status should be continued, owing to evidence from the present study and prior studies that identified maternal education and family income as consistent associated factors for dental caries [16, 17, 27, 28] . in addition, the availability of dental coverage in medical insurance was associated with dental caries. although literary evidence was inconsistent in saudi arabia [16] , the alarming proportion of children (77%) that lacked dental coverage in medical insurance warrant further attention. our results were consistent with previous studies on dental caries that reported an association between dental caries and good oral health behaviors in general [10, 19] , and tooth brushing habits in particular [31, 32] . a recent meta-analysis identified a 1.5-fold higher risk of dental caries among people brushing less than once daily compared to those brushing regularly (odds ratio (or) = 1.56; 95% ci 1.37-1.78) [33] . an overwhelming majority of children started brushing after 2 years (82%, 95% ci 78.6-85.1%) in the present study, consistent with late adoption of brushing observed in previous studies in saudi arabia [20, 34] and in philippines [35] . however, the higher risk of dental caries observed uniquely among children who started brushing late at 3 or 4 years, in our sample, warrant further investigation. particularly, future studies could evaluate the possible table 3 unadjusted odds ratios (uor), adjusted odds ratios (aor), and their respective 95% confidence intervals (95% ci) of the key associated factors for dental caries in primary school children aged 6-8 years (continued) role of cultural habit of using chewing stick (miswak) for cleaning teeth on better outcome observed among children starting brushing at ages 5-6 compared to those starting brushing at 3 or 4 years in saudi arabia. given the importance of brushing teeth regularly and mouthwash use in maintaining good oral hygiene and preventing dental caries [10] , and lower prevalence of these habits observed in our study, detailed investigation of various brushing practices (e.g., use of fluoridated/non fluoridated toothpaste, and use of chewing stick for cleaning teeth), and other oral hygiene practices (e.g., use of fluoride containing mouthwash) among primary school children in saudi arabia is necessary. furthermore, interventions aimed at encouraging good oral health behaviors among children should be undertaken. the negative attitude or apprehension towards visiting a dentist was clearly evident in our study, where only 21.1% (95% ci 17.8-24.7%) of children visited a dentist for regular check-up, while the others visited for symptomatic treatment (e.g., toothache). the problem was even worse among younger children in saudi arabia; a mere 11% of children visited dentist for regular checkup on their first visit [20] . this dangerous trend might have prevented patients from availing sound advice on preventive oral health practices, thereby contributing to high prevalence, delayed recognition, and management of dental caries in saudi arabia. therefore, saudi children would benefit from publicly funded school-based dental screening programs that aid in timely detection and management of dental and other oral health problems. in addition, regular dental screening programs targeted at school children have an added benefit of realizing cost savings due to reduced need for advanced dental care [36] . the present study found a 4.5 (or = 4.5, 95% ci 1.5-13.8)-fold higher risk of dental caries among children falling asleep with the bottle in their mouth, which was consistent with literary evidence [37] [38] [39] . however, the magnitude of risk among australian children sleeping with a bottle in mouth was much lower (or = 1.5, 95% ci = 1.1-2.2) [39] . it was suggested that decreased salivary flow and reduced swallowing reflex as the child gets drowsier would allow carbohydrates to remain in the mouth and pool around the teeth priming the area for bacterial attack [40, 41] . the practice of frequently consuming sugary snacks between meals was associated with dental caries in our study. however, current evidence has been inconsistent with some studies indicating a positive association [42, 43] , while others failed to observe such a relationship [44] . therefore, further evaluation and confirmation of this globally relevant predictor is warranted. although breast feeding is commonly practiced in western countries [45, 46] , the practice of mixed feeding or partial breast feeding (with breast milk and powdered milk) was predominant in saudi arabia [47, 48] . children in our study that were never breast-fed had higher risk of caries, which was consistent with existing literature [49] [50] [51] . breast milk by itself was not cariogenic [52] , but the reported cariogenicity of certain infant formulas [53] and a higher risk associated with practice of breast feeding until late infancy (> 12 months -or = 1.99; 95% ci 1.35-2.95) [54] should not discourage the practice of mixed feeding until the emergence of new evidence. interestingly, children in our study that were exclusively breast-fed also experienced higher risk of caries, rendering support to the practice of mixed feeding. as noted in previously published literature [54] , it is possible that the practice of breast feeding until late infancy could have played a role in excess risk observed in saudi children; however, further research based on a larger sample is warranted to confirm our findings and determine the role of duration of exclusive breast feeding on caries risk among children in saudi arabia. furthermore, our study identified that eating patterns and food choices play an important role in dental caries experience in children. interestingly, the observed association between flavored milk and dental caries in this study could be a result of evolving trends in milk consumption practices in saudi arabia. although prior observational studies [55, 56] contrast our findings, a moderate cariogenic potential of flavored milk observed in a recent animal experiment and the possibility of developing nations adopting this new trend warrant further evaluation [57] . incidentally, our study contributed towards ever increasing evidence for the association between dental caries and sodas (or soft drinks) [58] [59] [60] . the acidic content of these soft drinks combined with sugars were known to reduce oral ph and increase the cariogenic potential of tooth [61] . it is noteworthy that low consumption of fresh fruits (less than twice a week) was associated with increased risk of dental caries among primary school children in this study. in contrast, the literary evidence did not provide a clear benefit of eating fresh fruits in preventing cariogenesis [62, 63] . however, certain fruit extracts (e.g., morinda citrifolia) have been associated with inhibiting the growth of cariogenic bacteria [64] , indicating the need to further evaluate the relevance of fresh fruit consumption to dental caries experience. in general, our findings were consistent with studies that linked intake of foods with high sugar content and dental caries in saudi arabia [19, 65] and other places [58] [59] [60] 66] . the strengths of this study are multi-fold. information from various risk domains was systematically analyzed to aid in prioritizing the modifiable factors associated with dental caries experience in children. unlike several prior studies in this area [10, 14, 16, 19, 34] , this study addressed the issue of multicollinearity and corrected potential bias from small sample in the analysis. the comprehensive nature of information collected encompassing various risk domains enabled us to evaluate the relative importance of individual factors over socioeconomic factors, a component seldom addressed in previous studies. our study provides much needed baseline statistics on several population characteristics to aid not only local authorities, but also international organizations (e.g., who) to evaluate and improve the health programs aimed at mitigating the burden of dental caries in children. however, certain limitations of this study should be considered while interpreting the results. a self-administered questionnaire was used as the main study instrument, which is subjected to recall bias. however, we do not expect our results to be grossly affected by recall, owing to recurrent and current themes tested in the questionnaire. for example, we would expect a more accurate recollection of tooth brushing habits and child feeding practices that were routine activities performed in the recent past; collection of information on flavored milk, a recent trend in saudi arabia, serves as an example for current themes. the study sample was restricted to 6-8-year-old male primary school children in riyadh city of saudi arabia, which warrants caution in generalizing the results to the entire country; however, given the cultural homogeneity and urbanity of the area, we would expect our estimates to be relevant to general population. our study does not support generalizing the results to girl children, as our sample was restricted to boys to comply with school regulations and cultural sensitivities of saudi population. although some of our findings could be relevant to girls owing to shared cultural practices, future research should evaluate and confirm gender-related differences. moreover, the cross-sectional nature of this study warrants against drawing causal inferences. the burden of dental caries is high in saudi arabia with eight out of ten primary school children aged 6-8 years suffering from this preventable condition. several individual factors encompassing three risk domains, including oral health behaviors and practices, child feeding practices, and dietary habits, were found to be more relevant factors associated with dental caries than socioeconomic factors. our results were consistent with findings in developed world where poor brushing habits, lack of dental coverage in health insurance, and high consumption of sodas were predominantly associated with dental caries. future research should focus on confirming some of the unique or globally relevant associated factors for dental caries identified in our study, including late adoption of brushing, frequent consumption of sugary snacks between meals, and consumption of fresh fruits and flavored milk. our results support the development and implementation of public awareness campaigns or health education programs targeted at primary school children to promote good oral health behaviors, feeding practices, and dietary habits. additional file 1: table s1 . unadjusted odds ratios (uor), adjusted odds rations for variables selected within each risk domain (dor), and adjusted odds ratios (aor) for variables selected from all four risk domains at different steps of model selection process*. (docx 34 kb) abbreviations 95% ci: 95% confidence interval; aor: adjusted odds ratio; dmft index: decayed, missing and filled teeth index; fdi: fédération dentaire internationale; mers-cov: middle east respiratory syndrome-corona virus; or: odds ratio; sd: standard deviation; uor: unadjusted odds ratio; who: world health organization years lived with disability (ylds) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the global burden of disease study a systematic review of population-based dental caries studies among children in saudi arabia the world oral health report 2003: continuous improvement of oral health in the 21st century--the approach of the who global oral health programme global goals for oral health 2020 evaluating dental awareness and periodontal health status in different socioeconomic groups in the population of sundernagar socio-economic inequalities and oral health in canada and the united states access to care, health status, and health disparities in the united states and canada: results of a crossnational population-based survey department of health and human services. oral health in america: a report of the surgeon general caries experience and its relationship with parent's education, occupation and socio economic status of the family among 3-6 years old preschool children of sri ganganagar city, india. open journal of dentistry and oral medicine oral hygiene practices, dental knowledge, dietary habits and their relation to caries among male primary school children in al hassa, saudi arabia sugar consumption and dental caries: evidence from 90 countries the consumption of flavored milk among a children population. the influence of beliefs and the association of brands with emotions world health organization. oral health surveys: basic methods. 5th ed. geneva: world health organization prevalence of dental caries in primary and permanent teeth and its relation with tooth brushing habits among schoolchildren in eastern saudi arabia socioeconomic status and selected behavioral determinants as risk factors for dental caries can socioeconomic status indicators predict caries risk in schoolchildren in saudi arabia? a cross-sectional study. oral health prev dent prevalence of dental caries and associated social risk factors among preschool children in riyadh, saudi arabia risk indicators and risk predictors of dental caries in schoolchildren use of sweet snacks, soft drinks and fruit juices, tooth brushing and first dental visit in high dmft 4-6 year olds of riyadh region oral hygiene practices and first dental visit among early childhood caries children in riyadh. pakistan oral & dent jr prevalence of caries in primary school children in saudi arabia caries prevalence in saudi primary school children of riyadh and their teachers' oral health knowledge, attitude and practices caries experience of children aged 6-9 years in jeddah, saudi arabia prevalence of dental caries, severity, and pattern in age 6 to 7-year-old children in a selected community in saudi arabia the relationship between diet and dental caries in 2 and 4 year old children in the emirate of abu dhabi caries experience of 5-year-old children in alkharj, saudi arabia prevalence and severity of dental caries are associated with the worst socioeconomic conditions: a brazilian cross-sectional study among 18-year-old males low maternal schooling and severity of dental caries in brazilian preschool children oral health status among 6-and 12-year-old jordanian schoolchildren. oral health prev dent dental caries predictors in countries with different human development index: a review of articles fluoride toothpaste and toothbrushing; knowledge, attitudes and behaviour among swedish adolescents and adults factors related to dental health in 12-year-old children: a cross-sectional study in pupils effect of toothbrushing frequency on incidence and increment of dental caries: a systematic review and metaanalysis caries prediction model in pre-school children in riyadh, saudi arabia early childhood caries in northern philippines world health organization. oral health promotion: an essential element of a health-promoting school: world health organization breastfeeding duration and childhood caries: a cohort study dietary habits and early childhood caries intensity among young children pattern and severity of early childhood caries biological mechanisms of early childhood caries causes, treatment and prevention of early childhood caries: a microbiologic perspective the relationship between snacking habits and dental caries in school children caries risk assessment in an educational environment role of dietary habits and diet in caries occurrence and severity among urban adolescent school children breastfeeding trends in canada infant feeding practices and the decline of breast feeding in saudi arabia breast feeding in a saudi arabian community. profile of parents and influencing factors feeding practices of greek children with and without nursing caries breast feeding, bottle feeding and dental caries in kuwait, a country with low-fluoride levels in the water supply early childhood caries and feeding practices in kindergarten children investigation of the role of human breast milk in caries development cariogenicity of different types of milk: an experimental study using animal model breastfeeding and the risk of dental caries: a systematic review and meta-analysis influence of cocoa and sugar in milk on dental caries incidence milk, flavoured milk products and caries evaluating the cariogenic potential of flavored milk: an experimental study using rat model medically administered antibiotics, dietary habits, fluoride intake and dental caries experience in the primary dentition dental caries and beverage consumption in young children carbonated soft drinks and dental caries in the primary dentition dental erosion and severe tooth decay related to soft drinks: a case report and literature review dietary pattern of finnish children with low high caries experience diet, nutrition and the prevention of dental diseases role of aqueous extract of morinda citrifolia (indian noni) ripe fruits in inhibiting dental caries-causing streptococcus mutans and streptococcus mitis dental caries, sugar consumption and restorative dental care in 12-13-year-old children in riyadh, saudi arabia oral health knowledge, attitudes and behaviour of children and adolescents in china we would like to thank the administration of the schools, parents, children, and dental professionals who participated and provided assistance in our study. we also thank king abdullah international medical research center (kaimrc) for partially funding our research. king abdullah international medical research center (kaimrc) partially funded our research (grant number sp15/081). the funders had no role in the study design; collection, analysis, and interpretation of data; decision to publish; and preparation of the manuscript. please contact the author for data requests.authors' contributions ya and hj conceived the project idea. ya, aa, ny, and hj designed the study and approved the methodology. ya, aa, and hj participated in the data collection. ya, ny, and hj managed the study data and conducted the formal data analysis. all authors contributed extensively towards the preparation of this manuscript and approved the version submitted to the journal. all authors read and approved the final manuscript.ethics approval and consent to participate ethics approval for this study, including oral examination of the children, was provided by the institutional review board (irb) at king abdullah international medical research center (kaimrc) in riyadh under protocol number sp15/081. informed consent was obtained from the parents. not applicable. the authors declare that they have no competing interests. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-327284-j6cg7nf0 authors: meireles, andré luís ferreira; de meireles, louisiana carolina ferreira title: impact of social isolation due to the covid-19 pandemic in patients with pediatric disorders: rehabilitation perspectives from a developing country date: 2020-08-17 journal: phys ther doi: 10.1093/ptj/pzaa152 sha: doc_id: 327284 cord_uid: j6cg7nf0 nan the novel coronavirus appeared in wuhan, china, in december 2019. it quickly spread across the globe and was declared a worldwide pandemic by the world health organization (who) 3 months later. covid-19 can lead to acute respiratory distress syndrome, pneumonia, and other important complications, including death, especially in high risk groups. 1 among pediatric patients, according to the literature, covid-19 appears to be less severe than in adults and the elderly, and approximately 90% of pediatric patients are diagnosed with asymptomatic, mild, or moderate disease. 2, 3 even so, 6.7% of cases may be severe in children with serious underlying conditions such as neurologic and neurodevelopmental disorders. 4 respiratory complications are a major cause of death in the chronic neuropediatric population. 5 moreover, covid-19 treatment may be more challenging in these children. for instance, prone ventilation, which is often practiced in patients with covid-19, 6 is difficult to perform in individuals with cerebral palsy and advanced neuromuscular conditions. hydroxychloroquine and azithromycin are being indicated in treatment protocols of countries such as brazil; however, a case report on an adult patient taking chloroquine for presumable reticular erythematous mucinosis indicated that the drug induced myasthenic syndrome, suggesting that the drug might affect neuromuscular junction transmission and might adversely affect children with myasthenia. 7 considering the absence of vaccines and effective antiviral therapies, the only strategies that have been shown to be effective in the reduction of cases and deaths in most countries are rigid public health measures such as social distancing. 8, 9 despite its importance in the control of the pandemic and in the protection of groups who are at risk, social distancing seems to impact the lives of patients with neuropediatric conditions in a biopsychosocial manner. analyzing this issue from a social perspective, 3 children with disabilities in social isolation, especially in developing countries, may have problems in accessing the necessary therapies. panda and sharawat 10 mentioned that due to strict isolation measures in some countries, children with epilepsy and neuromuscular disease may be deprived of their drug treatment. 10 in addition, economic damage caused by pandemic has a negative impact on household income, which is already limited in these families due to the high costs of medication, support technologies, and physical therapies. unfortunately, this vulnerable population has not received any special economic or sociopolitical support in most developing and underdeveloped countries. other important negative effects of social isolation in children and adolescents during a pandemic are in the area of mental health. 11, 12 school closures and lack of access to day care centers and parks may exacerbate children's feelings of loneliness, depression, and anxiety. 13 most schools have adopted the recommendation of united nations educational, scientific, and cultural organization (unesco) and are using distance learning programs and open educational opportunities that can connect teachers and students remotely and limit the disruption of education; however, in most cases, this is not a reality for children with disabilities. physical health is also negatively impacted by social isolation. evidence shows the importance of physical rehabilitation for pediatric patients with chronic neurological conditions 14, 15 ; however, these activities must be interrupted during a pandemic. rehabilitation staff, such as speech-language pathologists and physical therapists, are at increased risk of self-contamination and may contaminate others, because they are exposed directly to respiratory droplets from patients with neurological conditions. the absence of rehabilitation may lead to soft tissue contractures, bone deformities, regression in motor milestones, dysphagia, and respiratory difficulties in addition to other complications. pediatric patients with neurological conditions also may experience declines in motor function. one modality of rehabilitation assistance that has been discussed and adopted in this period of social isolation is telerehabilitation, wherein rehabilitation professionals' interactions with patients take place at a distance, through telecommunications devices, to provide rehabilitation assistance. 16 in contrast to countries such as the united states, united kingdom, japan, and canada, the use of telerehabilitation in brazil was prohibited by the national council of physiotherapy and occupational therapy (coffito) and national council of speech therapy (cffa); however, in march 2020, due to the pandemic, both institutions published resolutions authorizing professionals to assist the population via telerehabilitation. for brazilian rehabilitation therapists, and for many of the world's physical therapists, the possibility of telerehabilitation was something extremely new and challenging. telerehabilitation particularities, such as data privacy, prior programming of the session environment and material, internet quality, specific applications for telerehabilitation, and legal aspects of this type of service are being discussed strongly among regional councils and associations representing different specialties in brazil. the treatments and interventions for rehabilitation of children and adolescents with neuromuscular disabilities comprise techniques that involve touch, handling, performing of specific tasks, correction of activities during execution, and use of machines or apparatuses, such as treadmills, suit therapy protocols, and virtual reality. 14,17 thus, the adoption and performance of attendance by telerehabilitation in neuropediatric patients may be a complex process. in addition, we still need to know more about the effects of telerehabilitation effects in the neuropediatric population. in a systematic review, dos santos et al 18 discusses 9 studies about telerehabilitation in children and teenagers; 6 of the studies looked at asthma management, but none examined rehabilitation for pediatric neurological disorders. 18 a recent systematic review with similar scope reported 17 studies, 4 of which explored telerehabilitation use in children and adolescents with neurological conditions (unilateral cerebral palsy and acquired brain injury). 19 even though this systematic review showed some benefits in rehabilitation for children with physical disabilities, the clinical outcomes evaluated were not clearly relevant for clinical practice, and the diseases and outcomes evaluated did not reflect the complexity of neuropediatric rehabilitation. we live in a unique time, and its real impact will be perceived only after the pandemic resolves. until then, rehabilitation professionals, policy makers, and families of children with neuromotor disabilities should discuss and direct their attention to some key points: 3. to provide psychological and social support to families and help them to deal with this hard time of pandemic and social isolation. in this context, some measures may be adopted, such as maintaining regular routines and programs as much as possible or creating new ones (eg, regular exercising, daily chores, singing, painting, keeping in regular contact with friends and colleagues via telephone, e-mail, social media, or video calls). these strategies might reduce boredom and also help family members integrate themselves. additionally, low-cost specific psychological support can be provided via teleconsultation from psychology faculty at local universities or nongovernmental organizations or even supported by the local public health system. although we will probably will not be able to see the real impact of social isolation on health of children with disabilities until after covid-19 is gone, pediatric physical therapists must adapt in order to provide the best possible care during this complex social moment that our patients and families are enduring. there is no funding to report. the authors completed the icmje form for disclosure of potential conflicts of interest and reported no conflicts of interest. covid-19 will severely impact older people's lives, and in many more ways than you think! braz novel coronavirus disease (covid-19) in children epidemiology of covid-19 among children in china covid-19 in children in the united states: intensive care admissions, estimated total infected, and projected numbers of severe pediatric cases in 2020 survival and mortality in cerebral palsy: observations to the sixth decade from a data linkage study of a total population register and national death index is the prone position helpful during spontaneous breathing in patients with covid-19? myasthenic syndrome caused by direct effect of chloroquine on neuromuscular junction only strict quarantine measures can curb the coronavirus disease (covid-19) outbreak in italy covid-19 (sars-cov-2 infection) and children: pediatric neurologist's perspective multidisciplinary research priorities for the covid-19 pandemic: a call for action for mental health science covid-19 and mental health: a review of the existing literature covid-19) pandemic for child and adolescent mental health: a narrative review to highlight clinical and research needs in the acute phase and the long return to normality trends in neuropediatric physical therapy. front public health let's make pediatric physical therapy a true evidence-based field! can we count on you? physical rehabilitation using telemedicine state of the evidence traffic lights 2019: systematic review of interventions for preventing and treating children with cerebral palsy telehealth application on the rehabilitation of children and adolescents diversity of practices in telerehabilitation for children with disabilities and effective intervention characteristics: results from a systematic review world health organization. disability considerations during the covid-19 outbreak key: cord-299781-9d5g5xaw authors: hrusak, ondrej; kalina, tomas; wolf, joshua; balduzzi, adriana; provenzi, massimo; rizzari, carmelo; rives, susana; del pozo carlavilla, maría; valerio alonso, maria eli; domínguez pinilla, nerea; bourquin, jean-pierre; schmiegelow, kjeld; attarbaschi, andishe; grillner, pernilla; mellgren, karin; ten bosch van der werff, j.; pieters, rob; brozou, triantafyllia; borkhardt, arndt; escherich, gabriele; lauten, melchior; stanulla, martin; smith, owen; juh yeoh, allen eng; elitzur, sarah; vora, ajay; li, chi-kong; ariffin, hany; kolenova, alexandra; dallapozza, luciano; farah, roula; lazic, jelena; manabe, atsushi; styczynski, jan; kovacs, gabor; ottoffy, gabor; felice, marisa; buldini, barbara; conter, valentino; stary, jan; schrappe, martin title: flash survey on sars-cov-2 infections in pediatric patients on anti-cancer treatment date: 2020-04-07 journal: eur j cancer doi: 10.1016/j.ejca.2020.03.021 sha: doc_id: 299781 cord_uid: 9d5g5xaw abstract introduction since the beginning of covid-19 pandemics, it is known that the severe course of the disease occurs mostly among elderly, whereas it is rare among children and young adults. comorbidities, in particular diabetes and hypertension, clearly associated with age, besides obesity and smoke are strongly associated with the need of intensive treatment and a dismal outcome. a weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. along the same line, anecdotal information from wuhan, china mentioned a severe course of covid-19 in a child treated for leukemia. aim and methods we made a flash survey on covid19 incidence and severity among children on anticancer treatment. respondents were asked by email to fill in a short web based survey. results we received reports from 25 countries, where approximately 10,000 patients at risk are followed. at the time of the survey, over 200 of these children were tested, nine of whom were positive for covid-19. eight of the nine cases had asymptomatic to mild disease and one was just diagnosed with covid-19. we also discuss preventive measures that are in place or should be taken as well as treatment options in immunocompromised children with covid-19. conclusion thus, even children receiving anti-cancer chemotherapy may have a mild or asymptomatic course of covid-19. while we should not underestimate the risk of developing a more severe course of covid-19 than observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment. since the beginning of covid-19 pandemics, it is known that the severe course of the disease occurs mostly among elderly, whereas it is rare among children and young adults. comorbidities, in particular diabetes and hypertension, clearly associated with age, besides obesity and smoke are strongly associated with the need of intensive treatment and a dismal outcome. a weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. along the same line, anecdotal information from wuhan, china mentioned a severe course of covid-19 in a child treated for leukemia. we made a flash survey on covid19 incidence and severity among children on anticancer treatment. respondents were asked by email to fill in a short web based survey. we received reports from 25 countries, where approximately 10,000 patients at risk are followed. at the time of the survey, over 200 of these children were tested, nine of whom were positive for covid-19. eight of the nine cases had asymptomatic to mild disease and one was just diagnosed with covid-19. we also discuss preventive measures that are in place or should be taken as well as treatment options in immunocompromised children with covid-19. the outbreak of severe acute respiratory syndrome coronavirus-2 (sars-cov-2) causing the coronavirus disease (covid-19) pandemic in 2020 was identified in december, 2019. by march 17, 2020 it has affected 200,000 cases in 163 countries and in several foci the numbers rise exponentially [world health organization, "rolling updates on coronavirus disease (covid-19)" https://www.who.int/emergencies/diseases/novel-coronavirus-2019/events-as-they-happen]. in spite of high mortality rate, the spectrum of covid-19 includes asymptomatic infection, upper respiratory tract infection, lower respiratory tract infection through severe respiratory failure, as well as other problems such as myocarditis, sepsis 1 , and diarrhea (pan et al, am. j. gastroenterol., in press). the age distribution of the more severe course of the disease is strikingly skewed towards older patients, especially those over 65 years of age 1,2 . in contrast, pediatric patients rarely develop critical illness. [3] [4] [5] [6] [7] in one study, only 5% and 0.6% of 2141 evaluable children with confirmed covid-19 had severe or critical illness respectively. 7 the biology underlying this disparity in severity is unknown. the possibility that more severe disease associated with immunosenescence, along with an increased risk of severe disease in adults with cancer, and a single case report of a critically ill child who developed covid-19 during myelosuppressive chemotherapy, has raised the concern that covid-19 among immunosuppressed children might be a much more severe illness than is seen in otherwise healthy children. 2, [8] [9] [10] this is consistent with data for other coronaviruses, which do cause more severe infections in immunocompromised children. 11 to evaluate this, we used a flash survey to determine whether there was current evidence that pediatric patients with cancer in sars-cov-2 affected areas had been tested for this virus or had developed severe covid-19 disease. on march 16, 2020, we circulated a simple survey on covid-19 incidence and diagnostic and preventative measures. a web-based form was sent by email to 89 addressees, who work in pediatric hematology/oncology (ph/o) departments in many countries. data was collected one day later. in total, 32 centers or countries provided data on covid-19 incidence in children treated with chemotherapy or intensive immunosuppression in their institutions or countrywide ( table 1) . the results are shown together with the covid-19 incidences in general population. briefly, of more than 200 patients who were tested for sars-cov-2 in these ph/o departments, which care for close to 10,000 at-risk patients, only eight cases of proven infection were identified. given that there is no general recommendation regarding testing of asymptomatic individuals, many centers only tested symptomatic patients, so the true rate of infection is not known. none of the reported cases required intensive care because of covid-19. case 1 was a febrile adolescent after mediastinal radiotherapy for osteosarcoma, no information was available regarding prior chemotherapy. case 2 was a 16year girl with febrile neutropenia after adjuvant chemotherapy for hepatoblastoma. she received azithromycin and granulocyte colony stimulating factor (g-csf), no pulmonary involvement was present and after 5 days she was free of both neutropenia and fever. also case 3 had febrile neutropenia, after chemotherapy for a cervical rhabdoid tumor. there were no radiologic signs of pulmonary involvement but she required oxygen for nightly desaturations. she received g-csf and azithromycin and after 10 days she was dismissed from hospital. case 4 was a 6-year boy admitted in a hospital for a cisplatin cycle for hepatoblastoma, with a covid-19-positive swab after the end of therapy; he was discharged without therapy and remained in a good condition. cases 1-4 were also mentioned elsewhere (balduzzi et al, submitted). case 5 was a child with metastatic ewing sarcoma who developed febrile neutropenia after their 5 th cycle of chemotherapy. case 6 was a child with wilms' tumor who presented with fever and diarrhea after 6 weeks of chemotherapy; this child did have lymphopenia but not neutropenia. none of these two patients had respiratory symptoms, and both became afebrile within 12-24 hours. both received hydroxychloroquine, and case 5 also received lopinavir-ritonavir (lpv/r). two more cases were reported two days after the survey responses were collected. one of them (case 7) was in febrile neutropenia treated for all and no data on outcome is available yet. the other one (case 9) was on maintenance treatment for all without typical symptoms, tested because his parents were covid-19-positive; the anti-leukemic maintenance treatment was interrupted until two negative results will be obtained. to our knowledge, this is the first survey of pediatric oncology centers in sars-cov-2 affected areas. we found that the number of infected patients appears to be low, and that the few who were identified had mild and possibly self-limited infection. the low rate of identified infection is somewhat surprising, as it is reasonable to assume that the pediatric patients with cancer would be at least as susceptible to infection with sars-cov-2 infection as their healthy peers. the sars-cov-2 does infect children in general, although lower severity of the infection makes children prone to be underreported 3, 6 . thus, at least in the countries with high covid-19 incidence, either the transmission of sars-cov-2 was prevented by standard infection prevention measures, or cases remained undiagnosed as the course of the infection did not raise a suspicion of covid-19. in some areas, the devastating overall situation made the diagnostics of mild cases a low priority. the mild disease experienced by the three children in this study is in direct contrast to the only previously published case of which we are aware. an 8 year old child undergoing myelosuppressive chemotherapy for t-cell acute lymphoblastic leukemia in all in a wuhan hospital developed respiratory failure over the course of 3 weeks, eventually requiring mechanical ventilation; the patient had not recovered at the time of the report 8 (and included in 3, 9 ) . during the course of that patient's disease, crp and il-6 were only mildly elevated but ferritin levels were high (6417-15,758 ug/l). this is reminiscent of features of hemophagocytic lymphohistiocytosis, which has been previously described to co-occur with infections 12 . possible correlation between the severity of infection and the composition and intensity of chemotherapy should be studied in larger cohorts. the participating countries are gradually strengthening general preventative measures, usually aiming at social distancing, quarantines for the infected and contacts, clean hands and surfaces and cautious checking for possible symptoms -similarly to measures successfully applied in hong kong during the sars epidemic in 2003 13 . in ph/o departments, precautions are always taken to protect patients from any infections. the degree of these precautions typically depends on the severity of immunosuppression and differs among hospitals 14 . although our study portrays symptomatic covid-19 as a rare finding among heavily immunocompromised children, at least in the first weeks of pandemics, other viruses do occasionally infect these patients in hospital wards despite these precautions 15 . the responders to this survey recommend taking additional measures during the covid-19 epidemic to protect patients and staff from being either infected or in quarantine. as the epidemiological situation develops, only scientifically supported measures should remain in place, not to cause unwanted delays in the treatment of the underlying malignancies. the overall experience with daily life in hospitals during the peak covid-19 epidemics has been thoroughly described by italian physicians (balduzzi et al, submitted). there are large differences among countries regarding the specific measures recommended. most commonly, social contact is being minimized in the general population during high epidemic risk. whole hospitals or hospital areas in italy and spain are designated as "dirty" (suspected or proven sars-cov-2 infection) and "clean" (no suspicious symptoms or sars-cov-2 test is negative) areas. facial masks are recommended for all care givers and, if possible, for patients any time during personal contacts. health professionals taking care of immunocompromised patients are separated into teams without mutual physical contact, to avoid simultaneous infection or preventative quarantine in the entire staff. this can be done by working on alternate days (unless the workload forbids it) or weeks and not sharing offices and common areas. fewer or no in-person conferences take place. children with respiratory symptoms are screened for sars-cov-2 before entering ph/o units. outpatient visits for long-term surveillance patients are postponed. immunosuppressed children are recommended to be isolated from general pediatric patients, where possible. although these infection prevention measures might reduce the risk of sars-cov-2 transmission, they can also directly or indirectly complicate patient care. it can cause a shortage of clinical doctors, nurses, diagnosticians, and technical supportive staff, drug shortages, higher stress in accompanying parents, logistic problems with transfusion and transplant products, and organizational inaccuracies in clinical decision making process due to lack of meetings. in conclusion, heavily immunocompromised patients in the ph/o wards remain at high potential risk of acquiring infectious diseases, including covid-19. in a striking contrast, the current number of reported cases of covid-19 among these patients is limited to a single previously reported case from china plus the four cases reported here. more research is needed to better understand the epidemiology of sars-cov-2 infection and covid-19 in pediatric patients with cancer or other immunocompromised children. more cases are expected as the pandemic is only just unfolding in many countries. this flash survey, although providing a very early picture of covid-19, shows that the disease may have a mild course even in children receiving anticancer chemotherapy. the risk of severe disease with covid-19 in profoundly immunocompromised children is still unknown, and predictors of asymptomatic infection, mild disease or severe and life-threatening infection would help support the development of approaches to prevent as well as to optimize treatment of covid-19 in this vulnerable patient population. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china. intensive care med sars-cov-2 infection in children novel coronavirus infection in hospitalized infants under 1 year of age in china a case series of children with 2019 novel coronavirus infection: clinical and epidemiological features detection of covid-19 in children in early epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china clinical features of severe pediatric patients with coronavirus disease 2019 in wuhan: a single center's observational study korean society for antimicrobial therapy, korean society for healthcare-associated infection control and prevention characteristics and outcomes of coronavirus infection in children: the role of viral factors and an immunocompromised state hemophagocytic syndromes -an update impact of sars on development of childhood acute lymphoblastic leukaemia differences in infection prophylaxis measures between paediatric acute myeloid leukaemia study groups within the international berlin-frankfürt-münster (i-bfm) study group detection, control, and management of a respiratory syncytial virus outbreak in a pediatric hematology-oncology department key: cord-319286-xbf4zhnr authors: howie, erin k.; mcnally, shelley; straker, leon m. title: exploring the reliability and validity of the techu-q to evaluate device and purpose specific screen use in preschool children and parents date: 2020-08-05 journal: j child fam stud doi: 10.1007/s10826-020-01787-1 sha: doc_id: 319286 cord_uid: xbf4zhnr young children are increasingly using mobile technology, with potential for positive and negative developmental consequences. parents are responsible to guide children in their use of technology based on recommendations and guidelines. guidelines for screen use in young children have been based on little empirical information on contemporary screen use. this study surveyed parents of young children (n = 96, mean child age 3.0, sd 1.0 years) from three settings (australia, united states) to test the reliability and validity of a new tool to capture richer data on technology use within a techno-microsystem. the techu-q demonstrated reasonable test-retest reliability and face and construct validity. young children averaged more than 60 min per day of total technology use, mostly using tv, tablet computers, and mobile phones. the primary purposes for child use were educational and watching videos. parental attitudes towards technology and parent use were associated with their child’s use. future guidelines should utilize detailed descriptions of technology use by device and purpose to provide more relevant advice on technology use for young children. governments and national agencies, including the american academy of pediatrics, the canadian paediatric society and the australian department of health have issued public health guidelines for screen use by young children (canadian society for exercise physiology 2017; council on communications and media american academy of pediatrics 2016; department of health 2017), while an understanding of contemporary screen use by young children and its impacts lags behind. these guidelines are created to help parents and families navigate technology use practices of their children. previous guidelines have been revised due to the changing nature of screens in families (przybylski and weinstein 2017) , childcare, and educational needs (commonwealth of australia 2009), including the increasing availability of mobile touch screen devices (mtsd) such as smartphones and tablet computers. in 2017, adult smartphone ownership in australia was at 88% (drumm et al. 2017) , and in the us in 2018, adult smartphone ownership was at 95% (pew research center 2018). smartphone use is becoming ubiquitous with a recent australian study reporting 70% of adults use their phones during mealtimes with family and friends (drumm et al. 2017) . increasingly, mtsd are also being used by children, even young children. in 2017 children in the usa under the age of 8 were reported to spend close to an hour per day using a mtsd (howard 2017) and in 2014 75% of 4-year olds owned their own mobile device (kabali et al. 2015) . a study of 3-5 year-olds in the usa published in 2018 found parents reported more than 3 h of mobile device use by their children . parents report that there are large differences in weekday and weekend screen use and by device due to differences in schedules and parental regulations (solomon-moore et al. 2018 ). there have been limited endeavors to validate measures of screen use (saunders and vallance 2017) . in order to create and implement applicable screen use guidelines, policymakers should have an understanding of the complex screen use behavior of young children and their families. anecdotal evidence suggests that parents are providing tablets and smartphones for their young children for a mix of educational and recreational use. observations of young children suggest they are drawn to the fun aspects of tablet and smartphone use, with the intuitive gesture-based touch screen interface enabling even very young children to be independent in playing games, watching videos, etc. research has found that children from ages 2 to 4 in india were able to scribble and draw using a smartphone app (yadav and chakraborty 2017) . they are also being given to children by parents as a way to calm children (radesky et al. 2016) . further, anecdotal evidence shows mass media are encouraging parents to give children an advantage at school by providing them with a tablet and educational apps. early childhood educators are also being encouraged to teach young children to be competent users of technology (commonwealth of australia 2009; paciga and donohue 2017). however, little empirical evidence on the purpose of use of mtsd by young children currently exists in the literature. the recent screen use guidelines have been prompted by a growing concern about the effects of mtsd use on physical and mental health, well-being and general development including musculoskeletal discomfort (toh et al. 2017) , family interactions (carlson et al. 2017) , and learning (domingo and gargante 2016) . whilst much of this interest has been focused on adults, adolescents and older children (vernon et al. 2018) , there are now growing concerns from parents and professionals for young children's physical, social and cognitive development (anderson and subrahmanyam 2017; straker and howie 2016; zabatiero et al. 2018) . laboratory evidence suggests use of tablet computers may have physical effects on young children's activity and posture , and tablet use by preschoolers has been associated with sleep disturbances . parents are reported to have both positive and negative attitudes about young children using screens (kostyrka-allchorne et al. 2017; mccloskey et al. 2018; zabatiero et al. 2018) . positive ideas relate to interactive child games potentially encouraging positive parent-child interactions (skaug et al. 2017 ) and potentially enhancing learning (radesky et al. 2015) but increased screen use may have negative effects on social interactions (hinkley et al. 2018) . similarly early childhood educators have both positive and negative attitudes about screen use by young children, recognizing the potential to enhance learning and the potential for harm . evidence from earlier generations of technology suggest that it is not just the total time of use that is important, but that different devices may result in different effects (straker et al. 2008) and that the effect of technology use can depend on the purpose of use (council on communications and media american academy of pediatrics 2016; radesky et al. 2015) . this growing use and potential consequences for children's social, emotional, mental, and physical development have resulted in the recent updates to screen technology use recommendations from national health organizations (canadian society for exercise physiology 2017; council on communications and media american academy of pediatrics 2016; department of health 2017). however, these authorities have had to meet the real world need for guidance with very limited evidence regarding the current patterns and purposes of use by children and their parents and also very limited evidence on the impacts of this mtsd use. research on the techno-microsystem has found that internet use of specific types, within specific contexts was associated with children's social, emotional, physical and cognitive development (johnson 2010) . the techno-microsystem is an ecological model that highlights the reciprocal interactions of child characteristics, technologies, and the environment. it specifies multiple uses of technologies including communication, information and recreation across multiple settings such as school, home and community. to better understand the developmental implications of technology use in young children, it is important to better understand the use and context, including family use, that contribute. an important step to better understand the implications of mtsd use, and thus provide evidence to inform health and education guidelines , is the development of a reliable, valid, and feasible measure to capture family screen technology use (saunders and vallance 2017) . given the potential differential effects of device and purpose of use as proposed by the technomicrosystem (johnson 2010) , exposure assessment needs to be at this detailed level. currently, to our knowledge, there is no such measure that can be used to assess comprehensive screen technology use including the access, duration, frequency and purpose of use for multiple devices including mtsds, television, computers, and electronic games. in summary, to provide better information to families and others supporting families with young children regarding appropriate use of mtsd it is important to understand the contemporary use of these devices within the family context, including details on the devices used and the purposes of use. to develop such an understanding, a reliable and valid tool is required to capture details of screen use in families. therefore, the objectives of the study were: 1. to evaluate the reliability and face, content and construct validity of the technology use questionnaire parent report version (techu-q(parent)) and technology use questionnaire adult version (techu-q(adult)). it was hypothesised that the techu-q would have face and content validity confirmed by users and an expert panel. in relation to construct validity, it was hypothesised that parents' technology use would be higher among those with sedentary occupations, children's outdoor play would be associated with lower technology use, and more positive parent perceptions would be associated with higher technology use in their children. 2. to provide a detailed description of technology use among young children and their parents including by device and purpose of use. it was hypothesised that the technology use of young children would be positively related to the technology use of parents. the convenience sample consisted of parents of young children attending participating childcare settings between january 2016 and january 2018. three settings were selected to represent a range of factors potentially contributing to children's technology use and parental understanding of questionnaires. settings: (1) a private not-forprofit childcare organization catering for predominantly low ses families in metropolitan perth, western australia, (2) a university childcare center in metropolitan perth and, (3) a university childcare center in a town in central united states. parents completing the survey had to be english speaking, 18 years or older, and be a primary caregiver to a child from 0 to 5 years of age. participating parents completed the techu-q(adult) for their own technology use and the techu-q(parent) for the technology use of their child (ren). the study was approved by curtin university and university of arkansas institutional review boards. information on the study was distributed to all parents with a child attending the participating childcare settings. the online baseline survey was distributed to all parents through an email link sent by the childcare setting. informed consent was obtained as the first part of the questionnaire, before entering personal information and beginning the questionnaire content. hard copy surveys were available as an alternative, upon request. during initial survey completion, parents were asked to provide their email address and a unique name to enable matching to the repeated survey. no complete names or further identifying information were collected. the technology use questionnaire (techu-q) was developed utilizing 20 years of experience collecting parent and child reports of technology use (harris and straker 2000; harris et al. 2017 ) and existing published surveys of child technology use (hinkley et al. 2012; houghton et al. 2015) . initial construction of the techu-q was conducted through an iterative process involving technology use experts and pilot tests with users. versions were prepared for parentproxy report of young children's (birth to 5 years) use (techu-q parent), children's (8-17 years) self-report (techu-q childsee straker et al. for reliability and validity evaluation details ) and adult parent self-report (techu-q child). the techu-q was pilot tested for feasibility in a sample of over 150 parents of young children (coenen et al. 2015) . techu-q includes questions on frequency, duration and purpose of weekday and weekend day use of multiple technology devices (television, computers, tablet computers, mobile phones, and electronic games). for young children, parents were asked to report the amount of time using each device for each purpose: educational activities, social networking, watching videos, playing games, and other general use. parents were asked about the proportion of their own use of each device for each purpose: occupation, social networking, watching videos, playing games, and other general use. an example question from the parent-proxy questionnaire is "over a typical monday to friday period, on how many days does your child use screen devices?" (drop down menu for number of days) followed by "on each of these weekdays, for about how long does your child use screen devices per day?" (drop down menu from 5 min to 12 h or more). total technology use and device specific use was tabulated by multiplying duration of use by frequency of use for both weekdays and weekend days. the survey was administered using the qualtrics (qualtrics, provo, utah, usa) platform. the complete online version of the questionnaire is available by request from the authors. demographic information including date of birth, gender, postcode, parent education, and occupation were obtained for both the adult and (where relevant) their child (ren) as per prior studies . to provide estimates of test-retest reliability, the same questionnaire was re-distributed directly using the provided email address to participants 2 weeks following the date of the initial baseline completion in settings 1 and 2 only. face validity was explored with parents. qualitative methods were used to assess the face validity of the techu-q (parent) and techu-q(adult) among end-users. questionnaire comments were provided and semi-structured interviews were conducted with a convenience sample of parents of young children. the interviewer asked prompted questions on feasibility, comprehension, comprehensiveness and accuracy. additionally, the interviewer checked comprehension by asking the participants to elaborate on answers to the questionnaire. questions were asked separately for techu-q(adult) and techu-q(parent). the interviewer completed detailed field notes during the interviews. to further establish the content validity, 10 experts in research of technology use by children, measurement and activity and task behaviors, and childcare professionals were sent the questionnaire along with a brief description of the intended constructs to measure. experts were asked to respond to the following questions as well as to provide any additional comments: (1) were the exposure categories appropriate for technology use by young children, adolescents and adults to capture meaningful duration and frequency of use and (2) were any common technology devices not included? construct validity was explored through associations with parental use, parental perceptions and children's physical activity. additional questions on perceived risk, benefits and concerns of parents regarding technology use were collected. these questions assessed parents' perceptions of educational, social, physical and overall risk of mtsd use. it was hypothesized that more positive parent perceptions would be associated with higher technology use in their children. parents were also asked about their child's level of outdoor play as an indicator of overall physical activity level, as it was hypothesized that outdoor play would be negatively associated with technology use. total outdoor play, weekly outdoor play, and weekend outdoor play during both warmer and cooler months was calculated. the outdoor play questions have been related to objectively measured physical activity and total weekly outdoor play with a one week intraclass correlation (icc) of 0.41 in children reported (cleland et al. 2008 ). to assess the test-retest reliability, intraclass correlations (icc) were calculated for total technology use volume for young children and adults separately, and separately for each device. icc's ≥ 0.9 were considered excellent, between 0.75 and 0.9 was good, between 0.5 and 0.75 was moderate and <0.5 was poor (koo and li 2016) . face validity was assessed by analysis of the interviews with parents. content validity was assessed by analysis of expert review comments. construct validity was assessed using cronbach's alpha, principal components analysis and correlations with hypothesized convergent and divergent constructs. cronbach's alpha was calculated on the volume of use (product of duration of use of each device and frequency of use) separately for children and parent technology use, standardized as rank order questions to determine if the questions for multiple devices are measuring a single construct. it was hypothesised that the techu-q would have low internal consistency, thus providing evidence that multiple device questions need to be asked. a principal components analysis was conducted on the frequency-duration products, separately for children and parents, to further assess the construct differences between devices. eigen values, factor loadings, variance explained and conceptual interpretation were used to determine the number of factors retained. for children, spearman correlations were determined between children's technology use and parent attitudes towards technology. it was hypothesized that parents with higher perceived risks and lower perceived benefits of technology use would report less use by their children. spearman correlations were also determined between children's technology use and total weekly outdoor play. it was hypothesized that children with lower levels of outdoor play would have higher levels of technology use. for adults, overall technology use was compared by occupation type using krusak-wallis tests. it was hypothesised that adults with an office job would have higher computer use compared to physical labor occupations. descriptive statistics were calculated on the overall use, device-specific use, and purpose-specific use for both young children and adults and for parental attitudes of technology use. means and standard deviations are presented in the text, however the same pattern existed across devices when medians and 25th-75th intervals were examined. technology use distribution was found to be non-normal, thus appropriate non-parametric tests were used. findings were compared across the three settings using kruskal-wallis tests. spearman correlations were used to test the associations between child technology use and parent technology use. due to the nested structure of the data within settings, data was group-mean centered to account for effect of setting (meinck and rodriguez 2013) . table 1 shows the characteristics of the participants (n = 96 reporting on total technology use, mean age = 3.0 years, range 5.5-64.3 months) at the three settings. as expected, parents in setting 1 had lower educational achievement, less sedentary work and more children. the test-retest reliability of parent-reported child technology use ranged from an icc of 0.20 for laptop use on weekdays to 0.96 desktop use on weekends, as seen in table 2 . fifteen of the 18 iccs were moderate to excellent. iccs could not be calculated for electronic game device use due to minimal reports of use. test-retest reliability of parent self-report of technology ranged from and icc of 0.39 for tablet use on weekdays to 0.91 for total laptop use. thirteen of the 18 iccs were moderate to excellent, again excluding electronic game use due to low numbers. parents found the questions appropriate and no major changes were suggested based on parent feedback. experts commented on the content validity and made suggestions to wording and question structure. all the comments of the experts were summarized, reviewed and survey questions were modified prior to distributing survey through childcare centers based on substantial and consensus comments. overall, experts agreed with the measured constructs and questions. no major changes were suggested based on expert feedback. cronbach's alpha was 0.26 for children suggesting low consistency between devices. principal components analysis suggested three principal components consisting of (1) tv, (2) tablet and mobile, and (3) desktop, laptop and electronic games, as seen in table 3 . parent attitudes to technology use were typically associated with their children's technology use, with negative attitudes associated with less use and vice versa. children's technology use was not associated with outdoor play time (total technology rho = 0.16, p = 0.147; tv r = 0.20, p = 0.074; tablet r = −0.08, p = 0.505; mobile r = −0.07, p = 0.550). cronbach's alpha was 0.80 for parents suggesting high consistency between devices. in the principal components analysis all items loaded on two principal components: (1) tv, desktop, laptop, tablet, mobile, and (2) technology use by young children was dominated by tv on both weekdays (m = 53.6 min per day, sd = 86.6) and weekend days (m = 74.3, sd = 72.8), with tablet and mobile used less as seen in table 4 . there were no differences in children's technology use on weekdays between settings. on weekends, there were differences between settings in children's tv use (p = 0.018), tablet use (p = 0.040), and total technology use (p = 0.044) with higher reported tv and total technology use for children in setting 3 and lower tablet use in setting 1. of children less than 2 years of age, 7 out of 22 (32%) were reported to have zero technology use. of children 2 years of age or older, 59% were reported to accumulate more than 60 min of technology use per day. both educational and videos were the dominant purpose of use on both weekdays and weekend days for tablets and mobiles and a comparison of purposes for tablets and mobiles can be seen in fig. 1 . in contrast, for parents, desktop computers dominated use on weekdays (m = 234.2, sd = 221.4 min per day), with substantial use of tv, laptop, mobile and tablets. on weekends, mobile phone (m = 150.1, sd = 186.7) and tv (m = 133.7, sd = 125.0) dominated for parents. social purposes dominated for parents' use of tablets and mobiles, with substantial use for work and general use as seen in fig. 1 . parents reported diverse attitudes to technology use by their children with a range from strongly agree to strongly disagree for 9 out of 11 items as seen in fig. 2 and complete results compared between settings. parents reported the highest agreement (1-5 scale with 1 being strongly disagree and 5 strongly agree) with the statements "using mobile technology will increase the amount of time my child spends sitting" (m = 4.3, sd = 0.8) and "using mobile children's tv (total technology use rho = 0.49, p < 0.001), tablet (r = 0.31, p = 0.006), and mobile (r = 0.36, p = 0.002) use was positively associated with their parents' use of each device respectively for total use and weekday use. on weekends, children's use was positively correlated with tv (weekend rho = 0.39, p < 0.001), mobile (r = 0.25, p = 0.03) and total technology (r = 0.27, p = 0.01) use by parents. negative associations were found between child and parent reported use of mobiles on weekends (r = −0.39, p < 0.001), and active video games on weekdays (r = −0.26, p = 0.01), weekends (r = −0.24, p = 0.03) and total (r = −0.26, p = 0.01). the current study aimed to establish face, content and construct validity of the techu-q and then to use this measure to explore the device-and purpose-specific use of technology in young children and their parents. the findings support the utility of the techu-q with reasonable testretest reliability and evidence of face, content and construct validity. while the reliability for individual devices was sometimes low, such as for laptop use by young children, this may reflect the low frequency and potentially sporadic nature of use. proxy-or self-report of technology use is less desirable than objective measures for both participant burden and accuracy reasons. however, no valid, low-cost objective method of logging technology device use across the whole day and multiple devices appears to exist. prior studies have used direct observation (ciccarelli et al. 2011 played sitting, not actively moving e.g. xbox, wii, ps3 c played actively and moving about e.g. xbox kinect, wii, ps3 move but this is very research resource intensive and having an observer nearby may alter parent or child behavior. thus proxy-and self-report remains the only viable option for many studies, and has prior evidence of reasonable validity in comparison to direct observation by a researcher (ciccarelli et al. 2011) . the current study only captured parent informed child use, however the techu-q could also be used by childcare staff to report on use during childcare in order to capture the whole exposure of children. total daily technology use by young children in this study was over an hour per day with more than half of children 2-5 years participating in more than 1 h a day of screen use. this is less than in a recent study where children under 5 were reported to watch over 75 min of tv per day and other screens for an additional half hour (waisman et al. 2018) , however it is possible that parents are underreporting children's technology use due to social desirability biases. thus, it is likely that the majority of young children are not meeting current guidelines of less than 1 h per day of screen use for children in this age group (canadian society for exercise physiology 2017; council on communications and media american academy of pediatrics 2016; department of health 2017). this substantial exposure in young children to screens reinforces the need for a better understanding of potentially important impacts on physical, psychological and social development and the contextual information within the technomicrosystem influencing developmental outcomes (johnson 2010). when examining which devices young children are using, tv is still the dominant technology used by these children. as much of the previous research on developmental effects of screens is based on television viewing, those findings are still relevant today (boulos et al. 2012; lillard et al. 2015; marinelli et al. 2014) . television may be a unique exposure compared to other devices as it is primarily passive and also can include a large amount of advertising, e.g. unhealthy foods, targeted towards children (boulos et al. 2012) . passive viewing of tv has been shown to decrease energy expenditure compared to resting, which may contribute to energy balance dysregulation (klesges et al. 1993) . however, the current findings suggest mtsd use is a significant exposure (approximately half as much time spent as watching tv) justifying the importance of assessing exposure to this new generation of technology. both tablets and desktop/laptop computers are being provided to young children for a range of purposes, as reported by parents, with education a common purpose. the high percentage of educational use likely reflects the perceptions of parents that screen use is important for children's education. whilst parents reported this use to be educational, it is unknown if the content was actually educational. many apps claim to be educational but actually offer low quality learning opportunities that are solely rote memorization and do not take advantage of the interactive potential of technology (hirsh-pasek et al. 2015) . educational apps can and should be further classified in varying quality for educational purposes (cherner et al. 2014) . future studies should ask about specific educational app usage for app content analysis. for practitioners, future research is needed to determine if young children 2-5 years of age who use "educational apps" are more or less successful when they transition to formal school. although a high-quality early childhood curriculum currently does not necessarily include screen use, there may be intentionally planned uses for devices that could benefit children. as practitioners prepare children to be successful in formal schooling, understanding and knowing current technology uses has the potential to improve teaching practices. parents reporting a high use of screens for passive video viewing in addition to educational purposes may be more worrisome. earlier research on tv has suggested passive consumption of screens can have detrimental effects on physical (klesges et al. 1993 ) and cognitive development (lillard et al. 2015) . however, active engagement with screens may be more likely to lead to aggressive behavior compared to passive consumption (polman et al. 2008) . social interaction, whether live or by video, may improve the influence of screen use on child development (roseberry et al. 2014) . together these data suggest that parents need applicable and specific guidance in using mtsd in ways which promote positive outcomes for children whilst minimising the potential for harm. the results of the current study emphasize the important role parents play in their young children's technology use. firstly, parent and child use was positively associated for tv, tablet, mobiles and total technology use. the negative associations for active video games and laptop use on weekends was likely due to very small reported use and correlations being driven by outliers. thus, strategies aimed at altering young children's use may also need to target parent modeling of screen behaviors. childcare facilities are poised to implement strategies that alter children's use by offering parent education events on the effects of screen use. secondly, parent attitudes were associated with reported child technology use, with parents having positive attitudes reporting higher use by their child and those with negative attitudes reporting less use by their child. educating parents on the benefits and risks of technology use in young children may be a useful strategy, as part of a larger strategy, to promote appropriate use of technology in young children. overall, parents reported generally neutral attitudes towards young children's technology use, including use in childcare settings, which reflects the previously reported moral dilemma parents have around their children's technology use (solomon-moore et al. 2018) . parents have knowledge of needing to limit screen use, and yet see the educational and practical benefits of it. thus, there may be a need to reconcile current recommendations of strict limitations on screen use in young children with more practical advice of how to supervise "wise use". similarly, as childcare settings are deciding whether or not to incorporate technology into their curriculums, they may encounter a range of parent opinions. childcare providers must be aware of current practices and changing guidelines in order to decide how to intentionally incorporate technology and communicate to parents how technology can be used with children appropriately. regardless, childcare settings are a key opportunity to influence parent attitudes and to teach children, and their families, about wise use of mtsds, as parents may have limited prior experience with evolving technologies as a unique developmental phenomena (yan 2018 ). the current sample is not a representative sample and represented a higher socioeconomic status overall. previous research suggests that the amount of technology use is similar across sociodemographic backgrounds, however the purpose and quality of use may differ . large, representative samples that capture weekly duration, frequency, and purpose of use by device are needed to understand technology use across populations and identify groups who may be in most need of education and intervention to improve the quantity and quality of technology use to achieve better outcomes for children. as previously mentioned, while there are limitations of self-or proxyreported technology use, few alternatives exist as observation is labor intensive and technology tracking apps are limited to single devices. the current study provides for the utility of an instrument to assess technology use of young children and their parents. this may be useful for childcare providers to better understand family screen use contexts to inform areas for family education around screen use or technology skill instruction in children. researchers can utilize the techu-q to further explore technology use, including monitoring changes in screen use over time, better understanding the context influences of screen use, determining the effects of various devices and purpose of use on child development, and ultimately evaluating interventions to modify screen use. it is important for both childcare practitioners and researchers to evaluate technology use within the family environment, as parent and child use are associated. whilst the data in this study were collected prior to the social disruptions associated with covid-19, these changes emphasized the importance of understanding how to use technology wisely. lockdowns enforced to reduce covid-19 transmission had implications for the physical, mental and social development of children. for example, physically active play opportunities were often reduced, education was often delivered through screen technologies, and children were often unable to visit their grandparents. the sudden reliance on mtsds to support children in isolation exposed the limitations of guidelines that are time-based, and reinforced the need for more useful guidance about how to use these devices wisely. mobile touch screen device use is now a substantial exposure for many young children. parents and professionals interested in child health, well-being and development need support on wise ways for young children to use this new generation of technology as they disentangle the complex techno-microsystem. the evidence to support such guidance requires reliable and valid assessments of child (and parent) technology use, by device and purpose, which the techu-q now provides. future guidelines will be able to provide more informative and relevant advice to parents and professionals involved in childcare, health and development based on a better understanding of the nature of use and associated outcomes. conflict of interest the authors declare that they have no conflict of interest. publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. digital screen media and cognitive development electronic media use and sleep among preschoolers: evidence for time-shifted and less 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devices by young children effects of television on metabolic rate: potential implications for childhood obesity a guideline of selecting and reporting intraclass correlation coefficients for reliability research touchscreen generation: children's current media use, parental supervision methods and attitudes towards contemporary media television and children's executive function hours of television viewing and sleep duration in children: a multicenter birth cohort study parent perceptions of mobile device use among preschool-aged children in rural head start centers considerations for correlation analysis using clustered data: working with the teacher education and development study in mathematics (teds-m) and other international studies. large-scale assessments in education the relation between use of mobile electronic devices and bedtime resistance, sleep duration, and daytime sleepiness among preschoolers technology and interactive media for young children: a whole child approach connecting the vision of fred rogers with research and practice mobile fact sheet experimental study of the differential effects of playing versus watching violent video games on children's aggressive behavior digital screen time limits and young children's psychological well-being: evidence from a population-based study use of mobile technology to calm upset children: associations with social-emotional development mobile and interactive media use by young children: the good, the bad, and the unknown skype me! socially contingent interactions help toddlers learn language screen time and health indicators among children and youth: current evidence, limitations and future directions parent-child interactions during traditional and interactive media settings: a pilot randomized control study examining the challenges posed to parents by the contemporary screen environments of children: a qualitative investigation a comparison of posture and muscle activity during tablet computer, desktop computer and paper use by young children mobile technology dominates school children's it use in an advantaged school community and is associated with musculoskeletal and visual symptoms conflicting guidelines on young children's screen time and use of digital technology create policy and practice dilemmas rationale, design and methods for the 22 year follow-up of the western australian pregnancy cohort (raine) study young children and screen time: it is time to consider healthy bodies as well as healthy minds the associations of mobile touch screen device use with musculoskeletal symptoms and exposures: a systematic review mobile phones in the bedroom: trajectories of sleep habits and subsequent adolescent psychosocial development screen use among young children in a city of argentina. archivoes argentinos de children aged two to four are able to scribble and draw using a smartphone app child and adolescent use of mobile phones: an unparalleled complex developmental phenomenon young children and digital technology: australian early childhood education and care sector adults' perspectives key: cord-308916-6p2qutc5 authors: le roux, david m.; zar, heather j. title: community-acquired pneumonia in children — a changing spectrum of disease date: 2017-09-21 journal: pediatr radiol doi: 10.1007/s00247-017-3827-8 sha: doc_id: 308916 cord_uid: 6p2qutc5 pneumonia remains the leading cause of death in children outside the neonatal period, despite advances in prevention and management. over the last 20 years, there has been a substantial decrease in the incidence of childhood pneumonia and pneumonia-associated mortality. new conjugate vaccines against haemophilus influenzae type b and streptococcus pneumoniae have contributed to decreases in radiologic, clinical and complicated pneumonia cases and have reduced hospitalization and mortality. the importance of co-infections with multiple pathogens and the predominance of viral-associated disease are emerging. better access to effective preventative and management strategies is needed in lowand middle-income countries, while new strategies are needed to address the residual burden of disease once these have been implemented. pneumonia has been the leading cause of death in children younger than 5 years for decades. although there have been substantial decreases in overall child mortality and in pneumonia-specific mortality, pneumonia remains the major single cause of death in children outside the neonatal period, causing approximately 900,000 of the estimated 6.3 million child deaths in 2013 [1] . substantial advances have occurred in the understanding of risk factors and etiology of pneumonia, in development of standardized case definitions, and in prevention with the production of improved vaccines and in treatment. such advances have led to changes in the epidemiology, etiology and mortality from childhood pneumonia. however in many areas access to these interventions remains sub-optimal, with large inequities between and within countries and regions. in this paper we review the impact of recent preventative and management advances in pneumonia epidemiology, etiology, radiologic presentation and outcome in children. the overall burden of childhood pneumonia has been reduced substantially over the last decade, despite an increase in the global childhood population from 605 million in 2000 to 664 million in 2015 [2] . recent data suggest that there has been a 25% decrease in the incidence of pneumonia, from 0.29 episodes per child year in low-and middle-income countries in 2000, to 0.22 episodes per child year in 2010 [3] . this is substantiated by a 58% decrease in pneumonia-associated disability-adjusted life years between 1990 and 2013, from 186 million to 78 million as estimated in the global burden of disease study [1] . pneumonia deaths decreased from 1.8 million in 2000 to 900,000 in 2013 [1] . these data do not reflect the full impact of increasingly widespread use of pneumococcal conjugate vaccine in low-and middle-income countries because the incidence of pneumonia and number of deaths are likely to decrease still further as a result of this widespread intervention [4] . notwithstanding this progress, there remains a disproportionate burden of disease in low-and middle-income countries, where more than 90% of pneumonia cases and deaths occur. the incidence in high-income countries is estimated at 0.015 episodes per child year, compared to 0.22 episodes per child year in low-and middle-income countries [3] . on average, 1 in 66 children in high-income countries is affected by pneumonia per year, compared to 1 in 5 children in low-and middle-income countries. even within low-and middleincome countries there are regional inequities and challenges with access to health care services: up to 81% of severe pneumonia deaths occur outside a hospital [5] . in addition to a higher incidence of pneumonia, the case fatality rate is estimated to be almost 10-fold higher in low-and middle-income countries as compared to high-income countries [3, 5] . childhood pneumonia can also lead to significant morbidity and chronic disease. early life pneumonia can impair longterm lung health by decreasing lung function [6] . severe or recurrent pneumonia can have a worse effect on lung function; increasing evidence suggests that chronic obstructive pulmonary disease might be related to early childhood pneumonia [7, 8] . a meta-analysis of the risk of long-term outcomes after childhood pneumonia categorized chronic respiratory sequelae into major (restrictive lung disease, obstructive lung disease, bronchiectasis) and minor (chronic bronchitis, asthma, abnormal pulmonary function) groups [9] . the risk of developing at least one of the major sequelae was estimated as 6% after an ambulatory pneumonia event and 14% after an episode of hospitalized pneumonia. because respiratory diseases affect almost 1 billion people globally and are a major cause of mortality and morbidity [10] , childhood pneumonia might contribute to substantial morbidity across the life course. chest radiologic changes have been considered the gold standard for defining a pneumonia event [11] because clinical findings can be subjective and clinical definitions of pneumonia can be nonspecific. in 2005, to aid in defining outcomes of pneumococcal vaccine studies, the world health organization's (who) standardized chest radiograph description defined a group of children who were considered most likely to have pneumococcal pneumonia [12] . the term "end-point consolidation" was described as a dense or fluffy opacity that occupies a portion or whole of a lobe, or the entire lung. "other infiltrate" included linear and patchy densities, peribronchial thickening, minor patchy infiltrates that are not of sufficient magnitude to constitute primary end-point consolidation, and small areas of atelectasis that in children can be difficult to distinguish from consolidation. "primary end-point pneumonia" included either end-point consolidation or a pleural effusion associated with a pulmonary parenchymal infiltrate (including "other" infiltrate). widespread use of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination has decreased the incidence of radiologic pneumonia. in a review of four randomized controlled trials and two case-control studies of haemophilus influenzae type b conjugate vaccination in high-burden communities, the vaccination was associated with an 18% decrease in radiologic pneumonia [13] . introduction of pneumococcal conjugate vaccination was associated with a 26% decrease in radiologic pneumonia in california between 1995 and 1998 [14] . in vaccine efficacy trials in low-and middle-income countries, pneumococcal conjugate vaccination reduced radiologic pneumonia by 37% in the gambia [15] , 25% in south africa [16] and 26% in the philippines [17] . the who radiologic case definition was not intended to distinguish bacterial from viral etiology but rather to define a sub-set of pneumonia cases in which pneumococcal infection was considered more likely and to provide a set of standardized definitions through which researchers could achieve broad agreement in reporting chest radiographs. however, despite widespread field utilization, there are concerns regarding inter-observer repeatability. there has been good consensus for the description of lobar consolidation but significant disagreement on the description of patchy and perihilar infiltrates [18, 19] . in addition, many children with clinically severe lung disease do not have primary end-point pneumonia: in one pre-pneumococcal conjugate vaccination study, only 34% of children hospitalized with pneumonia had primary end-point pneumonia [20] . a revised case definition of "presumed bacterial pneumonia" has been introduced, and this definition includes pneumonia cases with who-defined alveolar consolidation, as well as those with other abnormal chest radiograph infiltrates and a serum c-reactive protein of at least 40 mg/l [21, 22] . this definition has been shown to have greater sensitivity than the original who radiologic definition of primary end-point pneumonia for detecting the burden of pneumonia prevented by pneumococcal conjugate vaccination [23] . using the revised definition, the 10-valent pneumococcal conjugate vaccine (pneumococcal conjugate vaccination-10), had a vaccine efficacy of 22% in preventing presumed bacterial pneumonia in young children in south america [22] , and pneumococcal conjugate vaccination-13 had a vaccine efficacy of 39% in preventing presumed bacterial pneumonia in children older than 16 weeks who were not infected with human immunodeficiency virus (hiv) in south africa [21] . thus there is convincing evidence that pneumococcal conjugate vaccination decreases the incidence of radiologic pneumonia; however there is no evidence to suggest that pneumococcal conjugate vaccination modifies the radiologic appearance of pneumococcal pneumonia. empyema is a rare complication of pneumonia. an increased incidence of empyema in children was noted in some high-income countries following pneumococcal conjugate vaccination-7 introduction, and this was attributed to pneumococcal serotypes not included in pneumococcal conjugate vaccination-7, especially 3 and 19a [24] . in the united states, evidence from a national hospital database suggests that the incidence of empyema increased 1.9-fold between 1996 and 2008 [25] . in australia, the incidence rate ratio increased by 1.4 times when comparing the pre-pneumococcal conjugate vaccination-7 period (1998 to 2004) to the post-pneumococcal conjugate vaccination-7 period (2005 to 2010) [26] . in scotland, incidence of empyema in children rose from 6.5 per million between 1981 and 1998, to 66 per million in 2005 [27] . these trends have been reversed since the introduction of pneumococcal conjugate vaccination-13. data from the united states suggest that empyema decreased by 50% in children younger than 5 years [28] ; similarly, data from the united kingdom and scotland showed substantial reduction in pediatric empyema following pneumococcal conjugate vaccination-13 introduction [29, 30] . several national guidelines from high-income countries, as well as the who recommendations for low-and middleincome countries, recommend that chest radiography should not be routinely performed in children with ambulatory pneumonia [31] [32] [33] . indications for chest radiography include hospitalization, severe hypoxemia or respiratory distress, failed initial antibiotic therapy, or suspicion for other diseases (tuberculosis, inhaled foreign body) or complications. however, point-of-care lung ultrasound is emerging as a promising modality for diagnosing childhood pneumonia [34] . in addition to the effect on radiologic pneumonia, pneumococcal conjugate vaccination reduces the risk of hospitalization from viral-associated pneumonia, probably by reducing bacterial-viral co-infections resulting in severe disease and hospitalization [35] . an analysis of ecological and observational studies of pneumonia incidence in different age groups soon after introduction of pneumococcal conjugate vaccination-7 in canada, italy, australia, poland and the united states showed decreases in all-cause pneumonia hospitalizations ranging from 15% to 65% [36] . in the united states after pneumococcal conjugate vaccination-13 replaced pneumococcal conjugate vaccination-7, there was a further 17% decrease in hospitalizations for pneumonia among children eligible for the vaccination, and a further 12% decrease among unvaccinated adults [28] . a systematic review of etiology studies prior to availability of new conjugate vaccines confirmed s. pneumoniae and h. influenzae type b as the most important bacterial causes of pneumonia, with staphylococcus aureus and klebsiella pneumoniae associated with some severe cases. respiratory syncytial virus was the leading viral cause, identified in 15-40% of pneumonia cases, followed by influenza a and b, parainfluenza, human metapneumovirus and adenovirus [37] . more recent meta-analyses of etiology data suggest a changing pathogen profile, with increasing recognition that clinical pneumonia is caused by the sequential or concurrent interaction of more than one organism. severe disease in particular is often caused by multiple pathogens. with high coverage of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination, viral pathogens increasingly predominate [38] . in recent case-control studies, at least one virus was detected in 87% of clinical pneumonia cases in south africa [39] , while viruses were detected in 81% of radiologic pneumonia cases in sweden [40] . in a large multi-center study in the united states, viral pathogens were detected in 73% of children hospitalized with radiologic pneumonia, while bacteria were detected in only 15% of cases [41] . a meta-analysis of 23 case-control studies of viral etiology in radiologically confirmed pneumonia in children, completed up to 2014, reported good evidence of causal attribution for respiratory syncytial virus, influenza, metapneumovirus and parainfluenza virus [42] . however there was no consistent evidence that many other commonly described viruses, including rhinovirus, adenovirus, bocavirus and coronavirus, were more commonly isolated from cases than from controls. further attribution of bacterial etiology is difficult because it is often not possible to distinguish colonizing from pathogenic bacteria when they are isolated from nasal specimens [43] . another etiology is pertussis. in the last decade there has also been a resurgence in pertussis cases, especially in highincome countries [44] . because pertussis immunity after acellular pertussis vaccination is less long-lasting than immunity after wild-type infection or whole-cell vaccination, many women of child-bearing age have waning pertussis antibody levels. their infants might therefore be born with low transplacental anti-pertussis immunoglobulin g levels, making them susceptible to pertussis infection before completion of the primary vaccination series [45] . in 2014, more than 40,000 pertussis cases were reported to the centers for disease control and prevention in the united states; in some states, population-based incidence rates are higher than at any time in the last 70 years [44] . in contrast, most low-and middleincome countries use whole-cell pertussis vaccines and the numbers of pertussis cases in those countries were stable or decreasing until 2015 [46] . however recent evidence from south africa (where the acellular vaccine is used) shows an appreciable incidence of pertussis among infants presenting with acute pneumonia: 2% of clinical pneumonia cases among infants enrolled in a birth cohort were caused by pertussis [39] , and 3.7% of infants and young children presenting to a tertiary academic hospital had evidence of pertussis infection [47] . similarly, childhood tuberculosis is a major cause of morbidity and mortality in many low-and middle-income countries, and mycobacterium tuberculosis has increasingly been recognized as a pathogen in acute pneumonia in children living in high tuberculosis-prevalence settings. postmortem studies of children dying from acute respiratory illness have commonly reported m. tuberculosis [48, 49] . a recent systematic review of tuberculosis as a comorbidity of childhood pneumonia reported culture-confirmed disease in about 8% of cases [50] . because intrathoracic tuberculosis disease is only culture-confirmed in a minority of cases, the true burden could be even higher; tuberculosis could therefore be an important contributor to childhood pneumonia incidence and mortality in high-prevalence areas. childhood pneumonia and clinically severe disease result from a complex interaction of host and environmental risk factors [37] . because of the effectiveness of pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination for prevention of radiologic and clinical pneumonia, incomplete or inadequate vaccination must be considered as a major preventable risk factor for childhood pneumonia. other risk factors include low birth weight, which is associated with 3.2 times increased odds of severe pneumonia in low-and middle-income countries, and 1.8 times increased odds in high-income countries [51] . similarly, lack of exclusive breastfeeding for the first 4 months of life increases odds of severe pneumonia by 2.7 times in low-and middle-income countries and 1.3 times in highincome countries. markers of undernutrition are strong risk factors for pneumonia in low-and middle-income countries only, with highly significant odds ratios for underweight for age (4.5), stunting (2.6) and wasting (2.8) . household crowding has uniform risk, with odds ratios between 1.9 and 2.3 in both low-and middle-income countries and high-income countries. indoor air pollution from use of solid or biomass fuels increases odds of pneumonia by 1.6 times; lack of measles vaccination by the end of the first year of age increases odds of pneumonia by 1.8 times [51] . it is estimated that the prevalence of these critical risk factors in low-and middle-income countries decreased by 25% between 2000 and 2010, contributing to reductions in pneumonia incidence and mortality in low-and middle-income countries, even in countries where conjugate vaccines have not been available [3] . the single strongest risk factor for pneumonia is hiv infection, which is especially prevalent in children in sub-saharan africa. hiv-infected children have 6 times increased odds of developing severe pneumonia or of death compared to hiv-uninfected children [52] . since the effective prevention of mother-to-child transmission of hiv, there is a growing population of hiv-exposed children who are uninfected; their excess risk of pneumonia, compared to hiv unexposed children, has been described as 1.3-to 3.4-fold higher [53] [54] [55] [56] [57] . the pneumococcal conjugate vaccination and haemophilus influenzae type b conjugate vaccination have been effective tools to decrease pneumonia incidence, severity and mortality [58, 59] . however, equitable coverage and access to vaccines remains sub-optimal. by the end of 2015, haemophilus influenzae type b conjugate vaccination had been introduced in 73 countries, with global coverage estimated at 68%. however, inequities are still apparent among regions: in the americas coverage is estimated at 90%, while in the western pacific it is only 25%. by 2015, pneumococcal conjugate vaccination had been introduced into 54 countries, with global coverage of 35% for three doses of pneumococcal conjugate vaccination for infant populations [60] . to address this issue, the who's global vaccine access plan initiative was launched to make life-saving vaccines more equitably available. in addition to securing guarantees for financing of vaccines, the program objectives include building political will in low-and middle-income countries to commit to immunization as a priority, social marketing to individuals and communities, strengthening health systems and promoting relevant local research and development innovations [61] . maternal vaccination to prevent disease in the youngest infants has been shown to be effective for tetanus, influenza and pertussis [62] . influenza vaccination during pregnancy is safe, provides reasonable maternal protection against influenza, and also protects infants for a limited period from confirmed influenza infection (vaccine efficacy 63% in bangladesh [63] and 50.4% in south africa [64] ). however as antibody levels drop sharply after birth, infant protection does not persist much beyond 8 weeks [65] . recently respiratory syncytial virus vaccination in pregnancy has been shown to be safe and immunogenic, and a phase-3 clinical trial of efficacy at preventing respiratory syncytial virus disease in infants is under way [66] . within a decade, respiratory syncytial virus in infancy might be vaccine-preventable, with further decreases in pneumonia incidence, morbidity and mortality [67] . improved access to health care, better nutrition and improved living conditions might contribute to further decreases in childhood pneumonia burden. the who integrated global action plan for diarrhea and pneumonia highlights many opportunities to protect, prevent and treat children [68] . breastfeeding rates can be improved by programs that combine education and counseling interventions in homes, communities and health facilities, and by promotion of baby-friendly hospitals [69] . improved home ventilation, cleaner cooking fuels and reduction in exposure to cigarette smoke are essential interventions to reduce the incidence and severity of pneumonia [70, 71] . prevention of pediatric hiv is possible by providing interventions to prevent mother-to-child transmission [72] . early infant hiv testing and early initiation of antiretroviral therapy and cotrimoxazole prophylaxis can substantially reduce the incidence of community-acquired pneumonia among hiv-infected children [73] . community-based interventions reduce pneumonia mortality and have the indirect effect of improved-careseeking behavior [58] . if these cost-effective interventions were scaled up, it is estimated that 67% of pneumonia deaths in lowand middle-income countries could be prevented by 2025 [58] . case management of pneumonia is a strategy by which severity of disease is classified as severe or non-severe. all children receive early, appropriate oral antibiotics, and severe cases are referred for parenteral antibiotics. when implemented in highburden areas before the availability of conjugate vaccines, case management as part of integrated management of childhood illness was associated with a 27% decrease in overall child mortality, and 42% decrease in pneumonia-specific mortality [74] . however the predominance of viral causes of pneumonia and low case fatality have prompted concern about overuse of antibiotics. several randomized controlled trials comparing oral antibiotics to placebo for non-severe pneumonia have been performed [75] [76] [77] and others are ongoing [78] . in two studies, performed in denmark and in india, outcomes of antibiotic and placebo treatments were equivalent [76, 77] . in the third study, in pakistan, there was a non-significant 24% vs. 20% rate of failure in the placebo group, which was deemed to be non-equivalent to the antibiotic group [75] . furthermore, because who-classified non-severe pneumonia and bronchiolitis might be considered within a spectrum of lower respiratory disease, many children with clinical pneumonia could actually have viral bronchiolitis, for which antibiotics are not beneficial [79] . this has been reflected in british [33] and spanish [31] national pneumonia guidelines, which do not recommend routine antibiotic treatment for children younger than 2 years with evidence of pneumococcal conjugate vaccination who present with non-severe pneumonia. the united states' national guidelines recommend withholding antibiotics in children up to age 5 years presenting with non-severe pneumonia [32] . however, given the high mortality from pneumonia in low-and middle-income countries, the lack of easy access to care, and the high prevalence of risk factors for severe disease, revised world health organization pneumonia guidelines still recommend antibiotic treatment for all children who meet the who pneumonia case definitions [80] . use of supplemental oxygen is life-saving, but this is not universally available in low-and middle-income countries; it is estimated that use of supplemental oxygen systems could reduce mortality of children with hypoxic pneumonia by 20% [81] . identifying systems capacity to increase availability of oxygen in health facilities, and identifying barriers to further implementation are among the top 15 priorities for future childhood pneumonia research [82] . however, up to 81% of pneumonia deaths in 2010 occurred outside health facilities [5] , so there are major challenges with access to health services and health-seeking behavior of vulnerable populations. identifying and changing the barriers to accessing health care is an important area with the potential to impact the survival and health of the most vulnerable children [82] . much progress has been made in decreasing deaths caused by childhood pneumonia. improved socioeconomic status and vaccinations, primarily the conjugate vaccines (against haemophilus influenzae and pneumococcus), have led to substantial reductions in the incidence and severity of childhood pneumonia. stronger strategies to prevent and manage hiv have reduced hiv-associated pneumonia deaths. however, despite the substantial changes in 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children consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach. world health organization community-acquired pneumonia in hivinfected children: a global perspective effect of pneumonia case management on mortality in neonates, infants, and preschool children: a metaanalysis of community-based trials does 3-day course of oral amoxicillin benefit children of non-severe pneumonia with wheeze: a multicentric randomised controlled trial antibiotic treatment of pneumonia and bronchiolitis. a prospective randomised study comparison of oral amoxicillin with placebo for the treatment of world health organizationdefined nonsevere pneumonia in children aged 2-59 months: a multicenter, double-blind, randomized, placebo-controlled trial in pakistan a double blind communitybased randomized trial of amoxicillin versus placebo for fast breathing pneumonia in children aged 2-59 months in karachi, pakistan (retapp) antibiotics for bronchiolitis in children under two years of age integrated management of childhood illness: chart booklet. world health organization an evaluation of oxygen systems for treatment of childhood pneumonia setting research priorities to reduce global mortality from childhood pneumonia by acknowledgments h.j.z. acknowledges grants for studies on childhood pneumonia from the bill and melinda gates foundation (opp 1017641); from the national institutes of health, united states (h3africa 1u01ai110466-01a1); from the mrc south africa; and from the national research foundation, south africa. key: cord-324786-8k81jetq authors: chang, anne b; grimwood, keith; robertson, colin f; wilson, andrew c; van asperen, peter p; o’grady, kerry-ann f; sloots, theo p; torzillo, paul j; bailey, emily j; mccallum, gabrielle b; masters, ian b; byrnes, catherine a; chatfield, mark d; buntain, helen m; mackay, ian m; morris, peter s title: antibiotics for bronchiectasis exacerbations in children: rationale and study protocol for a randomised placebo-controlled trial date: 2012-08-31 journal: trials doi: 10.1186/1745-6215-13-156 sha: doc_id: 324786 cord_uid: 8k81jetq background: despite bronchiectasis being increasingly recognised as an important cause of chronic respiratory morbidity in both indigenous and non-indigenous settings globally, high quality evidence to inform management is scarce. it is assumed that antibiotics are efficacious for all bronchiectasis exacerbations, but not all practitioners agree. inadequately treated exacerbations may risk lung function deterioration. our study tests the hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo at improving resolution rates of respiratory exacerbations by day 14 in children with bronchiectasis unrelated to cystic fibrosis. methods: we are conducting a bronchiectasis exacerbation study (best), which is a multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel group trial, in five centres (brisbane, perth, darwin, melbourne, auckland). in the component of best presented here, 189 children fulfilling inclusion criteria are randomised (allocation-concealed) to receive amoxicillin-clavulanic acid (22.5 mg/kg twice daily) with placebo-azithromycin; azithromycin (5 mg/kg daily) with placebo-amoxicillin-clavulanic acid; or placebo-azithromycin with placebo-amoxicillin-clavulanic acid for 14 days. clinical data and a paediatric cough-specific quality of life score are obtained at baseline, at the start and resolution of exacerbations, and at day 14. in most children, blood and deep nasal swabs are also collected at the same time points. the primary outcome is the proportion of children whose exacerbations have resolved at day 14. the main secondary outcome is the paediatric cough-specific quality of life score. other outcomes are time to next exacerbation; requirement for hospitalisation; duration of exacerbation; and spirometry data. descriptive viral and bacteriological data from nasal samples and blood markers will also be reported. discussion: effective, evidence-based management of exacerbations in people with bronchiectasis is clinically important. yet, there are few randomised controlled trials (rcts) in the neglected area of non-cystic fibrosis bronchiectasis. indeed, no published rcts addressing the treatment of bronchiectasis exacerbations in children exist. our multicentre, double-blind rct is designed to determine if azithromycin and amoxicillin-clavulanic acid, compared with placebo, improve symptom resolution on day 14 in children with acute respiratory exacerbations. our planned assessment of the predictors of antibiotic response, the role of antibiotic-resistant respiratory pathogens, and whether early treatment with antibiotics affects duration and time to the next exacerbation, are also all novel. trial registration: australia and new zealand clinical trials register (anzctr) number actrn12612000011886. compared to the early 20th century, the prevalence of bronchiectasis has fallen substantially. although regarded as an 'orphan disease' in affluent countries, reports of prevalence of bronchiectasis are increasing [1, 2] . bronchiectasis remains a major contributor to chronic respiratory morbidity [2, 3] and mortality [1, 4] in both indigenous [5] and non-indigenous populations [6] . in our recently completed multicentre study of children newly referred for chronic cough and managed in accordance to a standardised protocol [7] , 31 (9%) of the 346 children had bronchiectasis proven on radiology [8] . in the northern territory in australia, the incidence of bronchiectasis in the first year of life is 118 in 100,000 [9] . the estimated prevalence of bronchiectasis is 1,470 per 100,000 in central australian indigenous children aged below 15 years [10] and 1,600 per 100,000 in alaskan native children [11] . in the united states, reported prevalence in adults range from 4.2 to 271.8 per 100,000 [6] . however, any reported prevalence is likely to be an underestimate as many cases are misdiagnosed or coexist with other diseases like asthma [12] [13] [14] and chronic obstructive pulmonary disease (copd) [15] . even without accounting for these unrecognised cases, globally there are far more patients with bronchiectasis than cystic fibrosis (cf), which has a prevalence of 7.4 to 7.9 per 100,000 in the european union and the united states [14] . effective clinical management reduces both short-and long-term morbidity (and likely mortality) associated with bronchiectasis [16] [17] [18] . there is increasing evidence that intensive treatment of children who either have bronchiectasis or are at risk of developing severe bronchiectasis prevents poor lung function in adulthood [17] [18] [19] [20] . cohort data have shown that approximately 80% of newly diagnosed adults (non-smokers) with bronchiectasis reported symptoms dating back to childhood and that the duration of chronic cough (the most common symptom of bronchiectasis [21] ) was related (r = −0.51, p < 0.001) to lung function at diagnosis [22] . arguably, appropriate overall management and treatment of exacerbations (leading to reduction of persistent symptoms) potentially prevents or reduces deterioration of chronic respiratory disease [23] . determinants of accelerated lung function decline in adults with bronchiectasis are the frequency of hospitalised exacerbations, increased systemic inflammatory markers and pseudomonas aeruginosa infection [24] . amongst other factors, increased mortality risk is associated with the degree of lung function impairment [25] . no prospective data exist in children. our study and a london-based retrospective study found that, with appropriate treatment in specialised centres, lung function improves and can be maintained [18, 20] . however, those with poor lung function at diagnosis, although substantially improved, were likely to still have poor lung function five years later [20] . we also found that the only significant predictor of a decline in forced expiratory volume in one second (fev 1 ) was frequency of hospitalised exacerbations [20] . forced expiratory volume in one second (fev 1 )% predicted decreased by 1.95% with each previous hospitalised exacerbation [20] . as airway injury in children is superimposed upon the physiological changes involving lung growth and development [26, 27] , improvement in childhood bronchiectasis may impact favourably upon future adult lung function. early and effective management of bronchiectasis exacerbations in children may lead to reduced hospitalisations, better quality of life (qol) and improved future adult lung function. antibiotics are one of the key interventions used to treat acute respiratory exacerbations of bronchiectasis [21, 28] . however, it is biologically plausible that antibiotics are not useful for treating some respiratory exacerbations triggered by viral infections. our retrospective study found that 34% of exacerbations were preceded by a viral-like illness [29] . while most respiratory physicians will treat exacerbations intensively (with antibiotics and airway clearance), other doctors do not. those choosing not to use antibiotics routinely argue that most episodes of exacerbations and cough are caused by viral infections and hence do not require antibiotic therapy. this may be appropriate but viral-bacterial interactions in the airways risk prolonged endobronchial bacterial infection that, with the associated inflammatory cascade, may cause further lung injury [23, 30] . better evidence to guide the management of exacerbations in people with bronchiectasis is needed. there are two components of best; here we present the study protocol of the first phase (best-1). the second phase of best (best-2) will address the question "is daily azithromycin non-inferior (within 20% margin) to amoxicillin-clavulanic acid in achieving resolution of exacerbations on day 21?" the protocol for best-2 will be the subject of a later paper. this first phase of our proposed national multicentre double-blind double-dummy randomised controlled trial (rct) is designed to answer our primary questions, as follows. amongst children with non-cf bronchiectasis, does azithromycin improve the resolution of respiratory exacerbations by day 14 compared with placebo, and does amoxicillin-clavulanic acid improve the resolution of respiratory exacerbations by day 14 compared with placebo? our secondary aims are to: 1. determine the effect of azithromycin or amoxicillinclavulanic acid on the qol, systemic inflammation, time to next respiratory exacerbation, and duration of exacerbations; 2. explore factors that predict response to antibiotics, including respiratory pathogens (viruses, bacteria, macrolide-resistant bacteria) present in respiratory secretions and blood markers; and 3. describe the point prevalence and diversity of respiratory viruses, mycoplasma pneumoniae and chlamydia species during exacerbations using sensitive molecular detection techniques. our study tests the primary hypothesis that both oral azithromycin and amoxicillin-clavulanic acid are superior to placebo in improving the resolution rate of respiratory exacerbations by day 14 in children with non-cf bronchiectasis. we are conducting a multicentre, parallel group, double-blind placebo rct (with concealed allocation) to assess the impact of treatment with antibiotics (azithromycin or amoxicillinclavulanic acid) in children with an exacerbation of bronchiectasis. our study plan is summarised in figure 1 . the inclusion criteria are age below 18 years at time of study enrolment; diagnosed with bronchiectasis by a respiratory physician following high resolution computed tomography in the five years immediately prior to study entry or, if diagnosed earlier, have been followed regularly by a respiratory physician for treatment of bronchiectasis; and has experienced two or more respiratory exacerbations in the 18 months prior to study entry. exclusion criteria are current severe exacerbation of bronchiectasis (dyspnoea, hypoxia or hospitalisation), recent (in last 8 weeks) in the entry; cf; liver dysfunction; allergy or sensitivity to penicillin or macrolides; current or recent lower airway infection by a member of the pseudomonas genus group of gram-negative bacteria (in the four months prior to study enrolment); has received antibiotics belonging to the macrolide or penicillin class of antibiotics within three weeks immediately prior to study entry; or is currently receiving oncological treatment. eligible children will be identified from clinics in our centres (brisbane, perth, darwin and melbourne in australia and auckland in new zealand). parents will be approached and informed consent obtained. baseline pre-exacerbation data will be collected ( figure 1 ), parents contacted monthly and children reviewed every three months. parents will be educated specifically on symptoms of exacerbations and asked to contact the research nurse at the onset of an exacerbation. a double-dummy design is planned. if eligibility is fulfilled and after informed consent has been obtained, the child is randomised to one of three arms. at the start of the exacerbation, the child will receive amoxicillinclavulanic acid with placebo-azithromycin, azithromycin with placebo-amoxicillin-clavulanic acid or placeboazithromycin with placebo-amoxicillin-clavulanic acid. amoxicillin-clavulanic acid dose is 22.5 mg/kg/dose (up to 40 kg) twice a day (max 900 mg/dose). azithromycin dose is 5 mg/kg/day, max of 200 mg daily. equivalent volumes in placebo will be given in all arms. all treatments will continue for 14 days. an exacerbation is defined as an increase in sputum volume or purulence, or three or more days of change in cough (> 20% increase in cough score [31] or type (dry to wet) [32] ). we validated this definition in our prospective study and found that the kappa values (between clinicians) of these symptoms and signs were excellent (> 0.75) [33] . daily diaries will also be collected during exacerbations until the scores for two or more days reflect the child's 'baseline' state, which for each child will be established at enrolment, prior to any exacerbations. this assessment consists of a combination of symptoms (daily cough (yes/no), cough quality (wet/dry/none) and cough score [31] averaged over two consecutive days) and signs (sputum colour (if any present) using a colour chart card (bronkotest ltd, london, uk), crackles on chest auscultation). children will be reviewed on days 7 and 14 and at resolution of the exacerbation. the exacerbation is considered 'resolved' when symptoms and signs are the same as 'baseline' state. post exacerbation, the children will be followed-up and clinically evaluated every three months for 18 months or until their next figure 1 overall schematic study design. amox-clav: amoxicillinclavulanic acid; azithro: azithromycin. exacerbation. 'time to next exacerbation' will be determined by the number of days from 'resolution of current exacerbation' to beginning of the next exacerbation. upon enrolment, the child is assigned to the next unique number on the appropriate stratified list. the allocation will be performed by the trial pharmacist at the royal children's hospital in brisbane. randomisation is stratified by site (brisbane, perth, darwin, melbourne, auckland), age (≤ 5 or > 5 years) and underlying aetiology (idiopathic/post-pneumonia or all other causes). the randomisation sequence was computer generated and used permuted blocks. the allocation sequence is concealed at all times throughout the study. the computer generated allocation sequence was prepared by a statistician external to the study team. the placebo medications, specifically manufactured by the institute of drug technology australia limited (melbourne, victoria), have a similar taste and colour to their respective antibiotics. both active medications (amoxicillin-clavulanic acid and azithromycin) are repackaged by the institute of drug technology. thus both the amoxicillin-clavulanic acid and azithromycin and their respective placebos are in identical opaque bottles. for both types of trial medications, equal volumes of water are added using a syringe and needle by punching the seal. adherence will be assessed by parent report and return of empty bottles. all data will be recorded on standardised forms. on enrolment, demographic information (age, gender, ethnicity, household size, and so on), birth history, breast feeding history, prior illness and in utero and household smoke exposure will be recorded, and a physical examination will be performed by a study physician. the primary and secondary outcome measures (see below) are collected at the time points specified above. serious and non-serious adverse effects (nausea, vomiting, diarrhoea, rash) will also be documented and monitored. safety exit points are discussed in end points below. at enrolment (baseline), all children will have a deep nasal swab (ns) specimen collected. in a subset, additional specimens will be collected at baseline and during exacerbations depending on feasibility (some children are unable to attend the study centre at the onset of the exacerbation) and willingness of parents to allow additional venipuncture. these specimens are: a deep ns specimen for respiratory viruses, respiratory bacterial pathogens (with antibiotic susceptibility testing) and other potentially important respiratory pathogens (m. pneumoniae, chlamydia spp) at baseline and at the beginning and resolution of an exacerbation. the technique used is identical to previous studies [34] [35] [36] where the specimens were described as nasopharyngeal swabs. the nss are handled as per our research laboratory protocol (see below). bloods at baseline and at the beginning and end of each exacerbation for c-reactive protein (crp), neutrophilic marker of inflammation (il-6) [37] , serum amyloid a (saa) [33, 38] and markers of viral infection (interferon gamma-inducible protein 10 (ip-10) and il-10). sputum at baseline and at the beginning and end of each exacerbation (when possible) for lower airway microbiology and antibiotic sensitivity. the verbal categorical descriptive score is a validated daily diary score of cough rated on a six-point scale (0 = no cough to 5 = severe cough and cannot perform activities) with increasing scores reflecting greater interference with usual activities. this rating was validated against an objective cough meter measure [31] and changes in cough scores have been shown to reflect changes in objective cough counts [39] . the parent chronic cough quality of life (pc-qol) is a 27-item questionnaire designed to assess the level of frequency of feelings (15 items) and worry (12 items) related to their child's cough. it uses a seven-point likert-type scale with higher scores reflecting less frequency and fewer worry concerns (that is, greater qol) [40, 41] . the minimal important difference is 0.62 determined by the distribution method and 0.9 determined by the anchor method [42] . oropharyngeal sampling under estimates streptococcus pneumoniae carriage by approximately 50% when compared with ns [43] . thus, ns are the preferred method when evaluating the presence of antibiotic-resistant bacteria. culturing, identifying and, when appropriate, serotyping common respiratory bacteria are established techniques at our research laboratory [36, 44] . swabs are stored in skim milk tryptone glucose glycerol broth medium at −80°c before being batch processed for typical respiratory bacterial pathogens, notably haemophilus influenzae (including strains of non-typeable h. influenzae), moraxella catarrhalis and s. pneumoniae. batches of swabs are thawed and 10-μl aliquots cultured overnight on selective media at 37°c in 5% carbon dioxide. growth of s. pneumoniae, h. influenzae and m. catarrhalis is recorded and confirmed by standard techniques [36, 45] . four isolates each of s. pneumoniae and h. influenzae and two isolates of m. catarrhalis per positive swab are tested for antimicrobial resistance and stored [36, 45] . s. pneumoniae isolates are serotyped using the quellung method (antisera from statens serum institute, copenhagen,denmark). in addition to routine susceptibility testing using the calibrated dichotomous susceptibility disc diffusion method, azithromycin minimum inhibitory concentration (mic) will be determined by etests (ab biodisk, solna, sweden) if the azithromycin disc annulus is <6 mm. for s. pneumoniae, the penicillin mic is determined for penicillin non-susceptible isolates (oxacillin and/or penicillin disc annulus < 6 mm) and for h. influenzae, the ampicillin mic is determined for isolates if the ampicillin disc annulus is < 6 mm. interpretive criteria (clinical and laboratory standards institute breakpoints) used for s. pneumoniae are penicillin non-susceptible mic > 0.12 μg/ml, azithromycin resistance mic ≥ 2 μg/ml; and for h. influenzae, ampicillin resistance mic ≥ 4 μg/ml, azithromycin resistance mic > 4 μg/ml. a nitrocephin-based test will identify beta-lactamase activity in h. influenzae and m. catarrhalis isolates. we will use our previous methods [46, 47] . nucleic acids will be extracted from the media using the high pure viral nucleic acid kit (roche diagnostics, sydney, new south wales, australia), according to the manufacturer's instructions. real-time polymerase chain reaction assays will be used to detect respiratory syncytial viruses (a and b), adenoviruses, influenza viruses (a and b), parainfluenza, human metapneumovirus, human coronaviruses (oc43, hk1, 229e, nl63), enteroviruses, rhinoviruses (and subtypes [48] ) and the more recently described human viruses (human bocavirus 1, parechoviruses, human polyomaviruses k1 and wu) and m. pneumoniae and chlamydia species [49] . serum crp (threshold 5 mg/l) are standard tests that will be analysed locally (diagnostic laboratory of each participating centre). saa, il-6 (threshold < 3 pg/ml), il-10 (threshold < 0.5 pg/ml) and ip-10 (threshold 2.8 pg/ml) will be performed using elisa commercial kits (r&d systems, minneapolis, mn, usa) at our research laboratory. spirometry (in children aged ≥ 5 years) will be performed using american thoracic society criteria and the fev 1 % predicted recorded. we elected not to use oscillatory measures as we found no difference in airway resistance between steady and exacerbation states [33] . thus we will use conventional spirometry although we do not expect to detect significant differences. participation is complete when the child's clinical state returns to baseline and the 'time to next exacerbation' has been obtained. other exit points are if the child is clinically worse prior to day 14 or intolerance to the trial medications requiring withdrawal from the study (as determined by the treating clinician). the primary outcome is the proportion of children whose exacerbations have resolved by day 14. exacerbations will be considered resolved when symptoms and signs are the same as the baseline state. children who are withdrawn from the study or receive additional antibiotic treatment will be categorised as non-resolved. the main secondary outcome is the pc-qol score. other outcomes are the time to next exacerbation; requirement for hospitalisation; duration of exacerbation (persistence of symptoms till 'return to baseline state') and fev 1 % predicted. serum markers (crp, saa, il-6, il-10, ip-10) and data on viruses and respiratory bacterial pathogens, including antibiotic susceptibility patterns to penicillin and azithromycin, will be the secondary laboratory outcomes. we plan to enrol 189 children (63 per arm), providing 84% power (α = 0.0245, two-sided) to detect a halving of the number of children in the active arm achieving resolution by day 14 (that is, azithromycin or amoxicillinclavulanic acid: 60% resolved by day 14, compared with placebo: 30% resolved). this is a conservative estimate when compared with our prospective data of persistent symptoms in 24% of children based on the same diary card [50] . as the primary outcome will be obtained in all enrolled children, a drop-out has not been factored in for the intention-to-treat analysis. with 20% drop-out rate, data from 153 children (51 per arm) for 'per protocol' analysis provides a study power of 75%. both treatment arms are compared with the same placebo arm. while the maximum efficiency is attained by allocating more children to the placebo arm (that is, using an allocation ratio of 1:1:√2), we chose to use a 1:1:1 allocation due to ethical concerns of deviating from standard care in respiratory centres. in the main secondary outcome (pc-qol), based on a between-group difference of 0.9 (minimum important difference [42] ) (sd 0.9), our sample size provides power of 100% (α = 0.05) for data from at least 147 children (that is, assuming at least 80% retention of the 189 children enrolled). for secondary aim 2 (exploring factors that predict response to antibiotics), we will be examining eight main factors and thus a sample size of 147 exceeds the recommended minimum (n = 10 per factor) [51] . the eight factors are smoking, age, underlying aetiology, detection of virus (any versus none, then single versus multiple viruses), presence of azithromycin resistance and blood markers (il-6, il-10, ip-10 levels). data will be reported and presented in accordance with the updated consort criteria [52] . children will be analysed according to allocation status (regardless of subsequent management). an interim analysis is planned and a data safety and monitoring committee will determine if the study should be ceased should superiority of any antibiotic be identified after 50% of sample size is achieved. for our primary aim, the main effects of the interventions will be determined by comparing the primary outcome (resolution of exacerbation) between groups ((azithromycin versus placebo) and (amoxicillin-clavulanic acid versus placebo)). children who exit the study as clinically worse or drop-outs prior to the end point will be considered non-resolved. those who exit the study as 'returned to baseline' will be considered resolved. odds ratios will be calculated and, if appropriate, number needed to treat (for benefit) will be expressed. tests of a treatment arm versus placebo at the end of the study for the primary outcome will be performed at the 2.45% significance level to account for spending some alpha at the interim analysis. per protocol analysis will be an a priori secondary analysis. for clinical secondary outcomes (secondary aim 1), t-tests or mann-whitney will be used for continuous variables (according to normality of data distribution). a kaplan-meier curve will be constructed for each group for 'time to resolution' and 'time to next exacerbation' as done previously [53] . for secondary aim 2 (factors that predict response to antibiotics), univariate analysis will be used to examine the biological factors listed above. factors that have a p-value < 0.2 will be included in a logistic regression model. potential interactions (for example, virus with bacteria) will be examined in the model. descriptive data will be used for secondary aim 3 (point prevalence of respiratory pathogens). a data safety monitoring committee has been established and has met prior to commencement of this study. it was determined that, when 50% of the sample size has been achieved, the stopping rules are as detailed below. if superiority between each antibiotic arm and the placebo arm is shown at significance level of 0.001, the study will cease. if superiority of only one antibiotic is shown, we will continue recruiting children to the other antibiotic arm and to the placebo arm but not to the superior antibiotic arm. if the serious adverse events (related to the medications) in each antibiotic arm outnumber the adverse events in the placebo arm at significance level of 0.01 or less, the study will cease. if increased adverse events of only one antibiotic is shown, we will continue recruiting children to the other antibiotic arm and to the placebo arm but not to the antibiotic arm related with increased adverse events. however, the study is not powered to detect between-group differences in total adverse events. the protocol has received ethical approval from the re despite the considerable global burden, bronchiectasis services receive disproportionately fewer allocated resources (clinical and research) when compared with other chronic respiratory diseases [3, 54, 55] . the marked paucity of rcts [21, 55] is reflected in the existence of only a single (small) published placebo-controlled rct in children with bronchiectasis [21, 56] . that study described a reduction in sputum purulence and airway hyper-responsiveness in children receiving roxithromycin (n = 13) [57] . there are no rcts on the management of bronchiectasis exacerbations in children [58] . almost all current recommendations are based on cf management [21, 28] . such extrapolation can, on occasions, be detrimental for those with non-cf bronchiectasis. for example, a large rct found that deoxyribonuclease (efficacious for cf) increased exacerbations and decline in fev 1 in adults with bronchiectasis [59] despite prior case reports advocating its use [60] . the importance of exacerbations in most chronic respiratory diseases is generally accepted. unfortunately, data on triggers, definitions and effective treatment of bronchiectasis exacerbations in both children and adults are scarce [56, 61, 62] . although viral triggers of acute exacerbations are well described in asthma [46] and copd [63, 64] , no such data exist for bronchiectasis. whether other potential respiratory pathogens (m. pneumoniae and chlamydia species) trigger exacerbations has never been examined. our retrospective study found that 34% of exacerbations were preceded by a viral-like illness [29] . thus, for the first time in this population, we will determine the nature and diversity of respiratory viruses m. pneumoniae and chlamydia species associated with bronchiectasis exacerbations. our study addresses a large knowledge gap in an under-researched area [55] . if the intervention is successful, it would lead to improved short-term (and possibly long-term) health benefits. conclusive results would produce changes to evidence-based standard treatment guidelines. in our retrospective data of 115 respiratory exacerbations [29] , we found that 35% of exacerbations failed to respond to oral antibiotic therapy (duration could not be determined) and required hospital admission. in our prospective cohort of 69 children followed for 900 childmonths (156 exacerbations), 36 exacerbations (23%) were treated with intravenous antibiotics following persistence of symptoms, that is, non-resolution of the exacerbation episode. generally, hospitalisation began three to five weeks following the initiation of oral antibiotics and 'return to baseline' occurred within two weeks of hospitalisation. based on our data that 24% of otherwise well children in the community still have a cough associated with a viral infection at day 14 [50] , we chose day 14 as the time point for this rct. we also asked parents and clinicians about their willingness to use placebo for a period of time; 14 days was the limit with a safety exit point at day 7. adult bronchiectasis studies show that qol measures, particularly cough-specific qol, are valid and important outcome measures [62, 65] . likewise, we have shown the utility of a paediatric chronic cough qol (the pc-qol) score in children with bronchiectasis [66] . in summary, our double-blind, double-dummy rct that examines the superiority of azithromycin and amoxicillin-clavulanic acid (compared with placebo) for exacerbations of bronchiectasis in children has the 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pulmonary disease identifying viral infections in vaccinated chronic obstructive pulmonary disease (copd) patients using clinical features and inflammatory markers assessing response to treatment of exacerbations of bronchiectasis in adults the burden of disease in pediatric non-cystic fibrosis bronchiectasis submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution we thank the research staff (lesley versteegh, clare wilson, sophie anderson-james, joanne tuppin, stacey spencer, carol willis) for facilitating the study, robert ware for generating the randomisation sequences and anita champion for allocating the children and dispensing the medications. we are also grateful to members of the indigenous reference group of the child health division at menzies for supporting this study and for overseeing the cultural aspects. we also thank professor alan isles, professor craig mellis and associate professor chris blyth for voluntarily providing their time in their participation as members of the data safety monitoring committee. the authors declare that they have no competing interests.authors' contributions ac conceived the study, and participated in its design and coordination and drafted the manuscript. pm, cr, kg, pva, aw, ko, pt and ts participated in its design and submission to the national health and medical research council. eb and gm participated in initiating the project and imm in the viral analysis plan. ibm, cb and hb will assist in recruitment and assessment of the children. mdc advised on statistical issues. all authors read and approved the final manuscript.authors' information abc, cfr, acw, ppva, cab, ibm and hmb are paediatric respiratory physicians, kg is a paediatric infectious disease physician, pjt is an adult respiratory physician, kfo is an epidemiologist, tps and imm are virologists, mdc is a statistician, ejb and gbm are research nurses and pm is a general paediatrician. key: cord-314597-1q3osgk7 authors: hill, holly a.; yankey, david; elam-evans, laurie d.; singleton, james a.; pingali, s. cassandra; santibanez, tammy a. title: vaccination coverage by age 24 months among children born in 2016 and 2017 — national immunization survey-child, united states, 2017–2019 date: 2020-10-23 journal: mmwr morb mortal wkly rep doi: 10.15585/mmwr.mm6942a1 sha: doc_id: 314597 cord_uid: 1q3osgk7 immunization has been described as a "global health and development success story," and worldwide is estimated to prevent 2-3 million deaths annually.* in the united states, the advisory committee on immunization practices (acip) currently recommends vaccination against 14 potentially serious illnesses by the time a child reaches age 24 months (1). cdc monitors coverage with acip-recommended vaccines through the national immunization survey-child (nis-child); data from the survey were used to estimate vaccination coverage at the national, regional, state, territorial, and selected local area levels† among children born in 2016 and 2017. national coverage by age 24 months was ≥90% for ≥3 doses of poliovirus vaccine, ≥3 doses of hepatitis b vaccine (hepb), and ≥1 dose of varicella vaccine (var); national coverage was ≥90% for ≥1 dose of measles, mumps, and rubella vaccine (mmr), although mmr coverage was <90% in 14 states. coverage with ≥2 doses of influenza vaccine was higher for children born during 2016-2017 (58.1%) than for those born during 2014-2015 (53.8%) but was the lowest among all vaccines studied. only 1.2% of children had received no vaccinations by age 24 months. vaccination coverage among children enrolled in medicaid or with no health insurance was lower than that among children who were privately insured. the prevalence of being completely unvaccinated was highest among uninsured children (4.1%), lower among those enrolled in medicaid (1.3%), and lowest among those with private insurance (0.8%). the largest disparities on the basis of health insurance status occurred for ≥2 doses of influenza vaccine and for completion of the rotavirus vaccination series. considering the disruptions to health care provider operations caused by the coronavirus disease 2019 (covid-19) pandemic, extra effort will be required to achieve and maintain high levels of coverage with routine childhood vaccinations. providers, health care entities, and public health authorities can communicate with families about how children can be vaccinated safely during the pandemic, remind parents of vaccinations that are due for their children, and provide all recommended vaccinations to children during clinic visits. this will be especially important for 2020-21 seasonal influenza vaccination to mitigate the effect of two potentially serious respiratory viruses circulating in the community simultaneously. children enrolled in medicaid or with no health insurance was lower than that among children who were privately insured. the prevalence of being completely unvaccinated was highest among uninsured children (4.1%), lower among those enrolled in medicaid (1.3%), and lowest among those with private insurance (0.8%). the largest disparities on the basis of health insurance status occurred for ≥2 doses of influenza vaccine and for completion of the rotavirus vaccination series. considering the disruptions to health care provider operations caused by the coronavirus disease 2019 (covid-19) pandemic, extra effort will be required to achieve and maintain high levels of coverage with routine childhood vaccinations. providers, health care entities, and public health authorities can communicate with families about how children can be vaccinated safely during the pandemic, remind parents of vaccinations that are due for their children, and provide all recommended vaccinations to children during clinic visits. this will be especially important for 2020-21 seasonal influenza vaccination to mitigate the effect of two potentially serious respiratory viruses circulating in the community simultaneously. the nis-child is conducted annually as a random-digitdialed telephone survey § of parents and guardians of children § the nis-child used a landline-only sampling frame from 1995 through 2010. from 2011 through 2017, the survey was conducted using a dual-frame design, with both mobile and landline sampling frames included. in 2018, the nis-child returned to a single-frame design, with all interviews conducted by mobile telephone. aged 19-35 months. sociodemographic information is collected during the telephone interview, and the respondent is asked to identify all providers who administered vaccines to the child. when consent is obtained, a survey is mailed to each provider requesting the child's vaccination history. if survey responses from multiple providers are returned for a given child, the information is synthesized into a single, comprehensive vaccination history, which is then used to calculate vaccination coverage estimates. nis-child data from survey years 2017-2019 were combined to identify 25,970 children with adequate provider data ¶ who were born in 2016 and 2017. for survey year 2019, the household response rate** ¶ children with at least one vaccination reported by a provider and those who had received no vaccinations were considered to have adequate provider data. "no vaccinations" indicates that the vaccination status is known because the parent or guardian indicated that there were no vaccinations, and the providers returned no immunization history forms or returned them indicating that no vaccinations had been given. ** the council of american survey research organizations (casro) household response rate is calculated as the product of the resolution rate (percentage of the total telephone numbers called that were classified as nonworking, nonresidential, or residential), screening completion rate (percentage of known households that were successfully screened for the presence of age-eligible children), and the interview completion rate (percentage of households with one or more age-eligible children that completed the household survey are not yet available). § includes children who might have been vaccinated with diphtheria and tetanus toxoids vaccine or diphtheria, tetanus toxoids, and pertussis vaccine. ¶ includes children who might have been vaccinated with measles, mumps, rubella, and varicella combination vaccine. ** hib primary series: receipt of ≥2 or ≥3 doses, depending on product type received; full series: primary series and booster dose, which includes receipt of ≥3 or ≥4 doses, depending on product type received. † † one dose hepb administered from birth through age 3 days. § § statistically significantly different from zero at p<0.05. ¶ ¶ includes ≥2 doses of rotarix monovalent rotavirus vaccine (rv1), or ≥3 doses of rotateq pentavalent rotavirus vaccine (rv5); if any dose in the series is rotateq or unknown, a 3-dose series was assumed. the maximum age for the final rotavirus dose is 8 months, 0 days. *** doses must be ≥24 days apart (4 weeks with a 4-day grace period); doses could have been received during two influenza seasons. † † † the combined 7-vaccine series (4 coverage with all vaccines except the hepb birth dose was lower among uninsured children and those insured by any medicaid plan (with or without another type of insurance) than among privately insured children ( table 2) . differences in coverage between uninsured children and those with private insurance ranged from 9.5 percentage points (≥3 hepb) to 33.9 percentage points (≥2 doses of influenza vaccine). disparities between children insured by any medicaid and those with private insurance tended to be smaller, ranging from 2.7 percentage points (≥1 var) to 20.3 percentage points (≥2 doses of influenza vaccine). the proportion of children who had received no vaccines was higher among uninsured (4.1%) and medicaid-insured children (1.3%) than those privately insured (0.8%). disparities in coverage were also observed by race/ethnicity (supplementary (figure) . for most acip-recommended childhood vaccines, coverage was stable by year of birth from 2011 to 2017. ¶ ¶ the percentage of children who received no vaccinations ranged from 0.9% for those born in 2011 and 2017 to 1.5% for those born in 2016; the linear relationship between the prevalence of children receiving no vaccinations and birth year was not statistically significant.*** more recent increases have been observed for ≥2 doses of influenza vaccine, the hepb birth dose, completion of the rotavirus vaccination series, ≥1 dose of hepa, and the combined 7-vaccine series. however, not all children have benefited from the high and increasing national-level coverage. coverage among uninsured children and those insured by medicaid is lower than that among privately insured children. the lowest coverage and largest insurance-related disparities were associated with ≥2 doses of influenza vaccine; increasing influenza vaccination coverage is particularly important this season, given the likely cocirculation of influenza virus and sars-cov-2, the virus that causes covid-19. children aged 6-59 months are at increased risk for severe illness and complications from influenza and for influenza-related outpatient, emergency department, or hospital visits (2) . most children are recommended to receive 3 doses of influenza vaccine by age 24 months, depending on their month of birth and the months considered as the seasonal influenza vaccination period (2) . thus, the percentage of children fully vaccinated by age 24 months per acip recommendations is lower than the estimates for receipt of ≥2 influenza vaccine doses in this report, which are based on criteria from the healthcare effectiveness data and information set (hedis). † † † current efforts to increase influenza vaccination coverage are especially important, given that sars-cov-2 and influenza virus are likely to be circulating in the population simultaneously during the fall and winter of 2020-21. both viruses are associated with significant morbidity and mortality, and together they could impose considerable strain on the public health and medical systems in the united states (3, 4) . coverage with influenza and most other vaccines was lower for children with medicaid or no health insurance. the ¶ ¶ https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/ pubs-presentations/nis-child-vac-coverage-2016-2017-tables. html#supp-figure-01. *** https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/ pubs-presentations/nis-child-vac-coverage-2016-2017-tables. html#supp-figure-02. † † † https://www.ncqa.org/hedis/measures/childhood-immunization-status/. are not yet available). § children's health insurance status was reported by parent or guardian. "other insurance" includes the children's health insurance program (chip), military insurance, coverage via the indian health service, and any other type of health insurance not mentioned elsewhere. ¶ includes children who might have been vaccinated with diphtheria and tetanus toxoids vaccine or diphtheria, tetanus toxoids, and pertussis vaccine. ** statistically significant (p<0.05) difference compared with the referent group. † † includes children who might have been vaccinated with measles, mumps, rubella, and varicella combination vaccine. § § hib primary series: receipt of ≥2 or ≥3 doses, depending on product type received; full series: primary series and booster dose, which includes receipt of ≥3 or ≥4 doses, depending on product type received. ¶ ¶ one dose hepb administered from birth through age 3 days. *** includes ≥2 doses of rotarix monovalent rotavirus vaccine (rv1), or ≥3 doses of rotateq pentavalent rotavirus vaccine (rv5); if any dose in the series is rotateq or unknown, a 3-dose series was assumed. the maximum age for the final rotavirus dose is 8 months, 0 days. † † † doses must be ≥24 days apart (4 weeks with a 4-day grace period); doses could have been received during two influenza seasons. children aged 6 months to 8 years should receive 2 doses separated by ≥4 weeks if they did not receive ≥2 doses during the previous flu season. § lower among children living in poverty. although this could indicate challenges accessing vfc, for which many of these children likely qualify, lower family income has also been associated with more parental vaccine hesitancy (5) . strategies for responding to vaccine hesitancy and other barriers to vaccination are described in a framework newly developed by cdc and its partners called vaccinate with confidence (6), which outlines activities designed to increase vaccination coverage by helping to protect communities, empower families, and stop vaccination-related myths. the findings in this report are subject to at least two limitations. first, the low response rate and exclusion of phoneless and landline-only households creates the possibility for bias if study participants are not representative of u.s. children of the corresponding age. second, coverage could be underestimated as a result of an incomplete list of vaccination providers identified by parents or providers not returning the vaccination history survey. a recent assessment of total survey error ¶ ¶ ¶ has shown that nis-child estimates might slightly underestimate true coverage for mmr and ≥4 dtap, and by as much as nine percentage points for the combined 7-vaccine series. evidence for a change in survey accuracy from 2018 to 2019 was not apparent.**** estimates of coverage with ≥2 influenza vaccine doses by age 24 months might differ from other cdc estimates that are specific to each influenza season or based on parent report of their child's vaccination status (7) . by the early spring of 2020, the covid-19 pandemic was rapidly expanding in the united states, and as the number of cases increased over the subsequent weeks and months, state ¶ ¶ ¶ https://www.cdc.gov/vaccines/imz-managers/nis/downloads/nis-puf18-dug.pdf. **** https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/ pubs-presentations/nis-child-vac-coverage-2016-2017-tables. html#supp-table-01. what is already known about this topic? the national immunization survey-child monitors coverage with vaccines recommended for children age <24 months to protect against 14 potentially serious illnesses. what is added by this report? national coverage with many recommended vaccines has remained high and stable, with recent increases for several vaccines for children born during 2016-2017 compared with those born during 2014-2015. large coverage disparities by health insurance and poverty status persist. what are the implications for public health practice? the covid-19 pandemic has disrupted routine medical care. extra effort will be required to achieve and maintain high levels of coverage with recommended childhood vaccinations. this is especially important for seasonal influenza vaccination to mitigate the effect of cocirculation of two serious respiratory viruses. and local governments increasingly imposed stay-at-home orders in an effort to slow the spread of disease. † † † † although cdc continued to emphasize the importance of well child exams and immunization during the pandemic, disruptions occurred in nearly all parts of society, including routine medical care such as vaccination (8) . extra effort to ensure that children continue receiving life-saving vaccines, especially uninsured children and those insured by medicaid, is critical. many providers' ability to deliver routinely recommended childhood vaccines has likely recovered following the initial impact of the pandemic (9,10). health care and public health authorities can communicate with families about how vaccinations can be provided safely during the pandemic, remind parents of vaccinations that are due or overdue for their children, and administer all recommended vaccinations to children during clinic visits. providers should use every opportunity to safely administer recommended vaccines to children during the covid-19 pandemic, with particular attention to influenza vaccination during fall and winter. § § § § advisory committee on immunization practices recommended immunization schedule for children and adolescents aged 18 years or younger-united states prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices-united states, 2020-21 influenza season covid-19 and the next influenza season parental vaccine hesitancy and childhood influenza vaccination a call to action: strengthening vaccine confidence in the united states trends in childhood influenza vaccination coverage effects of the covid-19 pandemic on routine pediatric ordering and administration-united states provision of pediatric immunization services during the covid-19 pandemic: an assessment of capacity among pediatric immunization providers participating in the vaccines for children program-united states notes from the field: rebound in routine childhood vaccine administration following decline during the covid-19 pandemic key: cord-316356-xq9bw349 authors: ross, kristie r.; redline, susan title: is it time to head home for the night? home sleep testing in young children date: 2020-10-17 journal: ann am thorac soc doi: 10.1513/annalsats.202008-970ed sha: doc_id: 316356 cord_uid: xq9bw349 nan the gold standard for the diagnosis of obstructive sleep apnea (osa) in children is in-laboratory polysomnography (psg), and the american academy of pediatrics recommends that polysomnography be performed in children with snoring and symptoms or signs of osa (1) . the field's focus on this tool for evaluating osa (as well as evaluating other sleep disorders) reflects the ability of psg to comprehensively collect physiological data on respiration, sleep, heart rate, and leg movements in controlled settings where issues of sensor loss can be readily addressed. however, there are key limitations to use and interpretation of such data from single-night laboratory assessments. these include the cost and burden of testing and representativeness of data collected in the laboratory compared with what is typically experienced at home. when ordering an attended in-laboratory psg, the response from caregivers is rarely enthusiasm. instead, parents are concerned about the ability of the child to sleep in a strange place, the logistics of finding childcare for other children who cannot accompany the patient, and out-of-pocket expenses related to testing. in the era of coronavirus disease (covid19) , concerns about bringing children into a sleep laboratory environment now include not just comfort but also safety. although firstnight effects and night-to-night variability in osa severity estimates are wellrecognized limitations to single-night in-laboratory psg (2, 3), additional concerns are the early termination of studies by technicians working fixed shifts (that end before the child awakens), losing data for the last rem period when osa may be most severe. although home-based sleep apnea testing is widely used in adults to diagnose osa, its use in children has been much more limited, reflecting concerns about the safety and feasibility of collecting multiple respiratory signals in this population. in this issue of annalsats, vézina and colleagues (pp. 1238-1246) present data on use of home sleep cardiorespiratory monitoring in a large sample (n = 562) of very young children using a novel pilot sleep scoring algorithm (4) . notably, with technicians setting equipment up and activating the study in the children's homes and providing families with audio and video equipment to self-monitor potential safety issues (tangled and/or misplaced sensors), 91% of studies were deemed acceptable and no safety issues were reported. importantly, the average duration of sleep monitored was 573 minutes, a period likely to provide representative sleep data for young children, and substantially longer than total sleep time reported from attended psgs (5, 6) . although these data support the feasibility of home sleep studies in young children, there are important questions regarding the extent to which this protocol can generalize to other samples (older children, diverse households), is broadly acceptable to families, or can be simplified such that caregivers can be trained to set up equipment. the primary objective of their study was to provide normative data in a historically understudied population-a worthwhile endeavor that provides data critical to age-specific psg interpretation. the data reported in this sample on distributions of such parameters as the obstructive and central apnea index, oxygen desaturation index, apnea-hypopnea index, and average oxygen saturation levels are needed for understanding the variation of these parameters in a community sample of children. notably, the frequency of central apneas exceeded that of obstructive apneas, supporting the relatively high frequency of central events in young children. the mean oxygen desaturation index exceeded 5 (a level generally considered abnormal) and no association was seen between objective parameters and elevated scores on the pediatric sleep questionnaire subscore, underscoring the discordance between objective and caregiver-reported information. further research testing the ability of statistically defined thresholds for sleep-disordered breathing (sdb) metricsand their association with subjective reports-to predict clinical morbidity is needed to further inform the utility of sleep studies for clinical decision-making. a unique aspect of the study by vézina was the use of a scoring algorithm for classifying sleep state from heart rate and movement data in infants. such data are readily available not only from cardiorespiratory monitors but also from many wearable health devices used in older children and adults, which similarly use those types of data for noninvasively estimating sleep state. nonburdensome collection of data for estimating sleep state in real-world settings, including over multiple nights, holds tremendous promise for elucidating the role of sleep in health, including how sleep changes with interventions. further research that defines the role of non-electroencephalogramdefined sleep states in characterizing sleep physiology across the populationincluding children-could inform a myriad of clinical and research applications, including elucidating longitudinal changes in sleep and sleep disorders with growth and development. whether such data are best extracted with manual, expert-directed approaches, as done by vézina and colleagues (4), or can be done more efficiently and objectively using artificial intelligence is a central question as the sleep field adopts advanced technologies. as the pediatric sleep medicine field also evaluates newer measurement approaches, it is useful to remember the often-quoted refrain "children are not small adults" when considering multiple aspects of sleep and polysomnography in young children and the implications for adapting home sleep testing in this population. unattended portable monitoring is recommended for use in adults with a high pretest probability of osa when performed in conjunction with a comprehensive evaluation by a medical provider (7, 8) . in addition to addressing safety concerns about sleeping with sensors attached, and the need for parental oversight/involvement, we need to consider the indications for testing, accuracy of testing, and approach to sensor placement, all of which distinguish pediatric home-based sleep testing from standard adult protocols. the data presented by vézina and colleagues suggest we can, and perhaps should, view these considerations not as barriers but as opportunities to innovate to study children where they and their parents are most comfortable. innovations in technology demonstrated by vézina and colleagues and many others (9) should do much to assuage concerns about safety and feasibility. although further research is needed to validate these approaches in children, even the gold standard attended psg-derived apneahypopnea index has limitations in terms of assigning severity and predicting long-term consequences. finally, as in many areas of health care, disparities in diagnosis, access to care, and treatment outcomes in children with sdb are a significant public health problem (10) . sdb is more common in black children than white children (11) , and black children are less likely to have spontaneous resolution of sdb (12) . higher poverty rates and percentage of children living in singlefemale-headed households are associated with higher apnea-hypopnea indices (13) . what role does the reliance on in-lab psg play in long-term health disparities related to sdb? in a study of more than 200 children referred from primary care physicians for evaluation of sdb, of whom 87% had public insurance, half of them were lost to follow-up (14) . among those referred for polysomnography, more than threequarters were lost to follow-up. these parents are voting with their feet-the barriers to bringing their children to a sleep laboratory for an attended psg are too high for most of them to overcome. in a separate study, it took twice as long for children with public insurance to be treated with adenotonsillectomy following psg than their peers with private insurance (15) . delay in treatment is likely to have longterm consequences. treatment of sleep disorders in young children improves outcomes (16) , but complete response is the exception rather than the rule (17, 18) , suggesting there are critical windows of exposure that have lifelong consequences. race and poverty adversely affect response to treatment (16, 19) . we owe it to children and their families to leverage technology to make it easier to be diagnosed and receive treatment for sdb and other sleep disorders. because of the complexities of successfully studying sleep in young children, is it time to challenge ourselves that the default approach of laboratorybased attended sleep studies provides the best care? we have seen an unprecedented rate of change in healthcare delivery in 2020 and a groundswell of support to address health disparities. using that momentum, as well as advances in technology, to improve comfort and access to care for children with sleep disorders is the right thing to do. n author disclosures are available with the text of this article at www.atsjournals.org. diagnosis and management of childhood obstructive sleep apnea syndrome first night effect in children and adolescents undergoing polysomnography for sleep-disordered breathing first night effect for polysomnographic data in children and adolescents with suspected sleep disordered breathing cardiorespiratory monitoring data during sleep in healthy canadian infants night-to-night variability of polysomnography in children with suspected obstructive sleep apnea polysomnography reference values in healthy newborns portable monitoring task force of the american academy of sleep medicine. clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients clinical use of a home sleep apnea test: an updated american academy of sleep medicine position statement towards patient-centered diagnosis of pediatric obstructive sleep apnea-a review of biomedical engineering strategies racial/ethnic and socioeconomic disparities in the diagnosis and treatment of sleep-disordered breathing in children risk factors for sleep-disordered breathing in children: associations with obesity, race, and respiratory problems childhood adenotonsillectomy trial. prognosis for spontaneous resolution of osa in children associations among neighborhood, race, and sleep apnea severity in children: a six-city analysis follow-up and time to treatment in an urban cohort of children with sleep-disordered breathing public insurance and timing of polysomnography and surgical care for children with sleep-disordered breathing childhood adenotonsillectomy trial (chat). a randomized trial of adenotonsillectomy for childhood sleep apnea sleep-disordered breathing, behavior, and cognition in children before and after adenotonsillectomy long-term changes in neurocognition and behavior following treatment of sleep disordered breathing in school-aged children growth velocity predicts recurrence of sleep-disordered breathing 1 year after adenotonsillectomy although tracheomalacia is a widely recognized cause of respiratory morbidity, diagnosis of the condition remains difficult, and prevalence is likely underestimated because of limitations in noninvasive testing (1) . flexible bronchoscopy has long been the gold standard diagnostic test, but because of its invasive nature and because it requires a careful anesthetic approach (i.e., balancing depth of anesthesia that maximizes patient safety and comfort while allowing spontaneous, unobstructed breathing), it has typically been employed for select patients with moderate to severe symptoms to establish initial diagnosis and less so for subsequent evaluation of disease. importantly, visual assessment of tracheal collapse via flexible bronchoscopy is subject to significant intra-and interrater variability, even at a qualitative level (2) . confounding these limitations, there is a lack of clarity regarding the "normal" degree of tracheal collapse that is present in healthy infants during inspiration and expiration as well as a lack of data that objectively characterize age-dependent variations.a noninvasive diagnostic modality that can reliably and quantitatively assess tracheal collapse has long been elusive, with earlier methods, including airway fluoroscopy, contrast tracheobronchography, and computed tomography, falling short in one or more of these parameters. recently, hysinger and colleagues validated ultrashort echo time magnetic resonance imaging (ute mri) as a means to noninvasively assess tracheomalacia in neonates without sedation or ionizing radiation, thereby offering an unprecedented opportunity to objectively characterize tracheal dynamics as well as assess changes over time and in response to potential therapies (3) . in an editorial accompanying the hysinger and colleagues manuscript, we noted our optimism with this technology, but we also lamented that ute mri "fails to measure the magnitude of force required to produce that collapse," which is necessary to objectively assess tracheal compliance and determine whether the airway collapse is due to inherent defect in the trachea or excessive forces imposed on it by obstruction in the small airways (4) . though this has yet to be accomplished, an exciting new approach adds a functional component to this structural assessment.in this issue of annalsats, gunatilaka and colleagues (pp. 1247-1256) demonstrate the utility of ute mri to quantify tracheal resistance in infants with tracheomalacia (5). using computational fluid dynamics (cfd), the authors extracted clinically relevant physiological data from this noninvasive imaging modality, allowing calculation of work of breathing attributed to the defect. this three-dimensional key: cord-320868-a9yegebb authors: senthilkumaran, subramanian; meenakshisundaram, ramachandran; shah, sweni; thirumalaikolundusubramanian, ponniah title: coronavirus disease (covid-19) in children: indian perspectives date: 2020-04-26 journal: indian pediatr doi: 10.1007/s13312-020-1869-8 sha: doc_id: 320868 cord_uid: a9yegebb nan balasubramanian, et al. [1] have concisely described various aspects related to coronavirus disease in children in the indian setting. we would like to address additional issues related to epidemiology of covid-19, reasons for uneventful clinical course in children, and the contributions of indian judiciary to the health of children during the pandemic. from the point of epidemiology, reporting and testing of children for covid-19 are less, which lead to undersampling and under-reporting of the disease [2]. decreased illness severity and an overall resilience to this disease in children facilitate transmission of the organism by rendering children as carriers. moreover, children can shed covid-19 virus through stools for a longer time. this is attributed to increased viral load through the act of swallowing the virus containing sputum or saliva [3] and the expression of angiotensin converting enzyme 2 (ace2) in the intestine. from a physiological perspective, a higher frequency of beating lung cilia [4] in children hinders the virus entry into lung pneumocytes. apart from that, they have low risk for covid-19 associated acute respiratory distress syndrome (ards) due to decreased generation of thrombin, and fibrin formation [5, 6] . the other reasons for the protection of lungs and airways are lack of comorbidities and less exposure to particulate matter and pollutants [7] , as also mentioned by balasubramanian, et al. [1] . in addition, increased expression of ace2 in pediatric lungs and other tissues gives additional protection and contributes to uneventful clinical course [4] . moreover, they escape from cytokine storm [6, 8] and hence, fatal complications are rarely observed [8, 9] . in addition, exposure of pediatric population to various vaccines [10] carried out as per the universal immunization program in india enhance the activation of the immune system [11, 12] , and contribute to uneventful clinical course. further, we think that the relative lack of physical and mental stress in children likely gives additional protection via psychoneuroimmunology. understanding the gravity of the current and emerging situations of covid-19, the supreme court of india has given directions [13] and measures to child welfare committee, juvenile justice boards, children's courts, child care institutions and state governments across india towards the care and attention of children in conflict with law and those kept in various types of homes including those under foster and kinship care. thus, indian judiciary is the first in the globe to look into the needs of marginalized children and give specific directions for their care in this pandemic. over all, we believe that indian children will withstand the outbreak of the novel coronavirus pandemic, but may be a link in transmission due to possibility of underreporting of cases, sub-clinical syndrome and longer shedding period of virus. we have to urgently address these through effective public health approach, including possible vaccination against covid-19, as and when available [14] . differences in the mechanism of blood clot formation and nanostructure in infants and children compared with adults the influence of pm2.5 on lung injury and cytokines in mice inflammatory cytokine profile in children with severe acute respiratory syndrome induction of neutralising antibodies and cellular immune responses against sars coronavirus by recombinant measles viruses immune responses in covid-19 and potential vaccines: lessons learned from sars and mers epidemic the burden of seasonal and pandemic influenza in infants and children a small jab -a big effect: nonspecific immunomodulation by vaccines supreme court issues directions for prevention of children from covid-19 coronavirus vaccines: light at the end of the tunnel transmission? [6] . extrapolating the same logic even a crying and screaming child should produce aerosol super-emission. although an operational definition for agp is in place, the relation to crying and its possible effects of increased aerosol generation has so far not been stressed.in a pandemic situation, we need to ponder on some points: even infants and toddlers who come for routine vaccinations or non-respiratory complaints can be asymptomatic carriers or in pre-symptomatic period of transmission; implementing source control measures like face mask and social distancing in this age group practically difficult; crying, a common occurrence in this age group, also increases the risk of aerosol generation and transmission; and, proximity of these kids to caregivers and their attenders along with sustained crying either due to anxiety or fear might further increase the risk and load of aerosol.in view of the yet unknown increased risks posed by expected or unexpected crying of asymptomatic children in the transmission of covid-19, it may be prudent to make every effort to avoid examining a crying child without adequate precautions. it is established that even loud speaking results in increased aerosol generation i.e. aerosol super-emission key: cord-321949-s1qu3odd authors: anderson, evan j; weber, stephen g title: rotavirus infection in adults date: 2004-01-28 journal: lancet infect dis doi: 10.1016/s1473-3099(04)00928-4 sha: doc_id: 321949 cord_uid: s1qu3odd rotavirus has been recognised for 30 years as the most common cause of infectious gastroenteritis in infants and young children. by contrast, the role of rotavirus as a pathogen in adults has long been underappreciated. spread by faecal-oral transmission, rotavirus infection in adults typically manifests with nausea, malaise, headache, abdominal cramping, diarrhoea, and fever. infection can also be symptomless. rotavirus infection in immuno-compromised adults can have a variable course from symptomless to severe and sustained infection. common epidemiological settings for rotavirus infection among adults include endemic disease, epidemic outbreak, travel-related infection, and disease resulting from child-to-adult transmission. limited diagnostic and therapeutic alternatives are available for adults with suspected rotavirus infection. because symptoms are generally self-limiting, supportive care is the rule. clinicians caring for adults with gastroenteritis should consider rotavirus in the differential diagnosis. in this review we intend to familiarise clinicians who primarily provide care for adult patients with the salient features of rotavirus pathophysiology, clinical presentation, epidemiology, treatment, and prevention. infective gastroenteritis causes substantial morbidity and mortality worldwide. although various bacterial species have long been associated with gastrointestinal disease, 1 specific viral causes of these infections were not delineated until the early 1970s. however, with the discovery of norwalk virus in 1972 2 and rotavirus in 1973, 3 the causative agents for most non-bacterial gastroenteritis infections were identified. almost immediately, the spectrum of viruses causing gastrointestinal infection in adults was recognised as differing from that in children. among children younger than 2 years, nearly half of all cases of diarrhoea requiring admission to hospital can be attributed to rotavirus infection. 4 by contrast, among adults most non-bacterial outbreaks of gastroenteritis can be linked to the norwalk-like viruses. 5 the important part played by viral pathogens besides the norwalk-like viruses in adults with gastroenteritis is not yet fully appreciated. specifically, the contribution of pathogens that typically affect children is not recognised by most clinicians who take care of adults. such is the case for adult infections caused by the common paediatric pathogen rotavirus. here we review important features of rotavirus microbiology and pathophysiology, along with relevant clinical and epidemiological features of rotavirus infection. in 1973, bishop and colleagues 3 described unique viral particles obtained from the duodenal mucosa of children with gastroenteritis. viruses with similar morphological appearance had been seen in 1963 in the intestinal tissue of mice with diarrhoea. 6 under the electron microscope, the 70 nm diameter viral particles first described in these reports had a wheel-like appearance, prompting the name rotavirus, from the latin rota (figure). 7 rotavirus is a non-enveloped virus now classified within the reoviridae family. 11 segments of doublestranded rna reside within the core. the rna encodes six viral proteins (vp) that make up the viral capsid, and six non-structural proteins (nsp). the core is surrounded by an inner capsid, composed mostly of vp6, the primary group antigen, 1, 8 and includes the epitope detected by most common diagnostic assays. other structural proteins also seem to confer some degree of group specificity. 9 the outer capsid is primarily composed of vp4 and vp7. 10 vp4 contributes the spoke-like projections to the wheel-shaped appearance of rotavirus. this vp is cleaved by trypsin in vitro to yield vp5* and vp8*, which appear to play an important part in cellular attachment. 9 the inner and outer capsids give the viral particle the double-layered icosahedral structure visualised on negative-stain electron microscopy. 10 seven distinct groups of rotavirus (named a to g) have been shown to infect various animal species. of these, only groups a, b, and c have been reported as human pathogens. 9 group a is the primary pathogen worldwide and is the group detected by commercially available assays. additional subgroups and serotypes can be identified by further characterisation of vp4, vp6, and vp7 antigens. 10 group b seems to be limited to causing epidemic infection in asia and the indian subcontinent, whereas group c rotavirus causes endemic infections that frequently go unrecognised. rotavirus spreads from person to person, mainly by faecaloral transmission. although rotavirus has been detected in urine and upper-respiratory samples, 11, 12 these body fluids are not believed to be commonly associated with transmission. after ingestion, rotavirus particles are carried to the small intestine where they enter mature enterocytes 13 through either direct entry or calciumdependent endocytosis. 14 after cytolytic replication in the mature enterocytes of the small intestine, new rotavirus particles can infect distal portions of the small intestine or be excreted in the faeces. more than 10 10 -10 11 viral particles per gram of faeces are excreted by children during infection. 8, 15 the amount of rotavirus excreted by adults might be more variable. in at least one study shedding was 10-100-fold lower in travellers' diarrhoea. 16 symptom-free adults can shed rotavirus in quantities so low as to be undetectable by most routine assays. 17 the mechanism by which rotavirus induces diarrhoea is poorly understood. few investigations have incorporated the study of human mucosal samples. the reports that are available describe various findings: villous shortening, flattening, and atrophy, denudation of microvilli, mitochondrial swelling, distension of the endoplasmic reticulum, depressed disaccharidase concentrations, and infiltration of mononuclear cells. 14, 18, 19 additional hypotheses about the pathophysiology of rotavirus gastroenteritis have been generated from animal studies. in one review the diminished ability of the intestinal epithelium to absorb fluid and nutrients, 14 stimulation of the enteric nervous system, 20 and local villous ischaemia and shortening resulting in impaired nutrient absorption were noted. a murine model of rotavirus infection suggests that rotavirus nsp4 acts as an enterotoxin, potentially by increasing calcium-dependent signalling of chloride secretion. 21, 22 the diarrhoea induced by rotavirus is unlikely to be completely explained by any one process, rather that several mechanisms contribute simultaneously. 14 these mechanisms are summarised in panel 1. 3, 13, 14, [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] resolution of rotavirus gastroenteritis depends greatly on the immunological response of the host. in a normal host, rotaviral antigens are transported to peyer's patches, undergo processing by b cells, macrophages, or dendritic cells and are presented to helper t cells. this cascade culminates in stimulation of rotavirus-specific b cell and cytotoxic t-lymphocyte-precursor expansion. 29 bernstein and colleagues 30 noted that stool rotavirus iga concentrations peaked 14-17 days after infection and persisted for longer than 1 year, but at declining concentrations. the researchers suggested that serum rotavirus iga is a more consistent marker of rotavirus immunity than other antibody measurements. 30 however, rotavirus-specific iga is frequently undetectable in duodenal fluid or faeces in the first week of infection, although symptoms might resolve within that time. 29 this pattern suggests a mechanism independent of humoral immunity. offit 29 notes that infected mature villous epithelial cells are steadily replaced by less-mature enterocytes, which may be less susceptible to rotavirus invasion. increased peristalsis improves clearance of viral particles and the non-specific activity of interferons can prevent vp translation. 29 de bouissieu 31 has reported that interferon ␣ concentrations correlate with a trend towards shorter duration of diarrhoea among patients who have rotavirus infection. although many physicians presume that rotavirus infection will confer lifelong immunity, multiple investigations show that re-infection can occur. bishop and colleagues 32 noted that infection with rotavirus during the neonatal period did not protect against developing rotavirus infection during the first 3 years of life but did lessen the severity of such infections. in a prospective study of 200 mexican infants followed up from birth, valazquez and colleagues 33 noted that by age 2 years 96% of infants had experienced a primary rotavirus infection. during the same period, nearly 70% of the infants experienced a second infection. more than 10% of the children studied had five or more rotavirus infections during the first 2 years of life. yolken and colleagues 34 had previously noted that by age reduced absorptive surface denudation of microvilli; shortening, flattening, and atrophy of villi; invasion of villi by rotavirus causing ischaemia and shortening 3, 18, 19 functionally impaired absorption depressed disaccharidase concentrations; impaired co-transport of glucose and sodium; decreased sodium-potassium atpase activity impairing electrochemical gradient 3, 18, 19, [23] [24] [25] cellular damage impairing absorption mitochondrial swelling; distension of endoplasmic reticulum; mononuclear cell infiltration 3, 13, 18, 19 enterotoxigenic effects of rotavirus protein nsp4 induces increased intracellular calcium concentrations; in murine models, acts like a toxin to induce diarrhoea 21, 22 stimulation of enteric nervous system stimulation of intestinal secretion of fluid and electrolytes; stimulation of intestinal motility resulting in decreased intestinal transit time 14, 20 altered epithelial permeability increased paracellular permeability by weakening tight junctions between cells [26] [27] [28] 2 years, more than 85% of children had antibodies to two different rotavirus serotypes. therefore, although nearly all adults have antibodies to rotavirus, 35 they might still be susceptible to infection. rotavirus can elude host defences and induce repeat infection through several mechanisms. there are multiple groups, subgroups, and serotypes of rotavirus. initial antibody response to infection is serotype specific, with limited production of cross-reactive antibodies. 36 subsequent rotavirus infections increase antibodies that cross-react with multiple serotypes. 36 additionally, certain elements of the rotavirus-specific immune response are short-lived. rotavirus-specific secretory iga is sometimes not detectable in faeces as early as 1 year after infection. 37 elias 38 reported that rotavirus fluorescent antibody titres peaked in children at age 1-3 years but subsequently fell to almost undetectable concentrations in individuals older than 70 years. 38 in a review of multiple studies, jiang and colleagues 36 an appreciation of the typical presentation of rotavirus infection in children is critical to understanding the spectrum of disease among adults. primary infection with rotavirus typically occurs in infants between ages 6 months and 2 years, although infection in neonatal intensive-care units and severe infection in infants younger than 6 months are well documented. 51, 52 in all age-groups, the classic presentation of rotaviral infection is fever and vomiting for 2-3 days, followed by non-bloody diarrhoea. 53 the diarrhoea may be profuse, and 10-20 bowel movements per day are common. when examined, the stool from affected patients is generally devoid of faecal leucocytes. especially when associated with vomiting, the diarrhoea of rotavirus infection can precipitate severe and even life-threatening dehydration. infants with repeat rotavirus infections are generally less-severely affected than those with primary disease. 33 among adults, rotavirus infection has been associated with a wide spectrum of disease severity and manifestations. as such, it is difficult to provide a concise description of a typical clinical presentation. nevertheless, prospective studies of voluntary rotavirus ingestion have provided some insight, although the participants in these studies were primarily young healthy adults. data from several such trials are summarised in the table. 35, [46] [47] [48] 54 for these volunteers, illness most frequently began 2-6 days after ingestion and continued for 1-4 days. about two-thirds of study participants had an antibody response, with more than half of all participants eventually shedding rotavirus. symptoms were less common than evidence of infection, but most frequently included diarrhoea, fever, headache, malaise, nausea, or cramping. one participant passed 11 stools in 1 day. 35 among the volunteers, rotavirus particles were detectable in the stool from the start of symptom onset and persisted for more than 10 days in some. three studies document rotavirus readministration to volunteers, noting that symptoms and antibody response were much less common. 35, 47, 54 in several reports of rotavirus outbreaks among adults similar symptoms have been described. in a prospective study of 98 families with neonates followed up from shortly after birth, only 17 of 43 adults who had serological evidence of rotavirus infection were symptomless. 55 14 had diarrhoea and 11 had abdominal cramping. none had symptoms that necessitated medical care or absence from work. in a separate study, 14 parents of children with rotavirus gastroenteritis developed serological evidence of infection, but only three had diarrhoea. 56 grimwood and colleagues 57 found, in a study of children with rotavirus in 28 families, that 18 of 54 adult family members exposed to rotavirus developed evidence of infection, and all but four were symptomatic. in a study of college students during a rotavirus outbreak, of the 83 individuals who met the criteria for rotavirus infection, 93% had diarrhoea, 90% abdominal pain or discomfort, 83% loss of appetite, 81% nausea, and more than 50% had fatigue, vomiting, headache, chills, subjective or low-grade fever, or myalgia. 58 patients with underlying immunodeficiency are at risk of sustained symptoms and rotavirus dissemination, a phenomenon already recognised among children. this pattern was first described in 1980 when two of four children with underlying primary immunodeficiency who had rotavirus infection developed chronic diarrhoea that at least temporarily responded to administration of human milk containing a high titre of rotavirus antibodies. 59 a geriatric patient with impaired naturalkiller-cell activity and impaired cellular and humoral immunity had rotavirus shedding for at least 35 days. 60 gilger and colleagues 61 noted that in four children who had various immune deficits and chronic diarrhoea from rotavirus, rotavirus was identified in the liver and kidney. whether the involvement of liver or kidney was important is unclear. natural infection quantity of cross-reactive neutralising antibody responses against multiple serotypes, 40-42 of virus-specific secretory iga at intestinal mucosa surface, 37, 43 and of virus-specific iga and igg in serum 41, 44 challenge studies serum serotype specific neutralising antibody; 35, 45 intestinal neutralising antibody; 46,47 serum rotavirus igg, but not necessarily with large doses; [46] [47] [48] and raised prechallenge titres of antibody to specific epitope of rotavirus vp7 49 vaccine-induced serum antibodies might be important in protection from natural infection, but interpretation is complicated because of differences in methods of existing studies; 36 and heterotypic antibody response to rotavirus vaccination might be protective against usual infecting serotypes 36, 50 other investigators have assessed the course of rotavirus infection in patients with malignant disease. a wide spectrum of clinical manifestations and severity of illness have been reported. bolivar 62 screened 90 adults who had various solid tumours and leukaemia, with and without diarrhoea. he noted that two patients had rotavirus infection, both of whom had undergone bone-marrow transplantation and had developed graft-versus-host disease. diarrhoea lasted for 10 days before resolution. in three subsequent studies in bone-marrow-transplant patients results varied. yolken and colleagues 63 prospectively assessed patients undergoing bone-marrow transplantation for infectious gastroenteritis and found that rotavirus occurred less frequently than clostridium difficile or adenovirus, but still occurred in nine of 78 patients. in one patient, adenovirus occurred concomitantly with rotavirus infection. of the eight remaining patients, all developed vomiting, seven had abdominal cramps, six had respiratory illness (infiltrates on chest radiography with appropriate clinical signs and symptoms) and four had diarrhoea. five of the eight rotavirus-infected patients eventually died. troussard and colleagues 64 also prospectively assessed patients undergoing bone-marrow transplantation and noted rotavirus infection in eight of 94 patients. adenovirus occurred concomitantly in two patients. seven of the patients had isolates positive for rotavirus in the winter months, with acute onset, vomiting, and diarrhoea. in a later study of the same topic, rotavirus was noted in four of 60 adult asymptomatic stem-cell-transplant patients followed up prospectively. 65 no patient with gastroenteritis had rotavirus isolated. rotavirus infections in adult patients infected with hiv-1 frequently present as a chronic diarrhoea with sustained viral shedding in stools. albrecht and colleagues, 66 between 1987 and 1991, detailed a retrospective assessment of 106 samples from 66 patients infected with hiv-1 who had otherwise unexplained diarrhoea. 35 samples from patients without diarrhoea served as controls. 13 samples from nine case patients were positive for rotavirus; two of these samples were rotavirus recurrences 6 months after the initial episode. no symptom-free patients had rotavirus infection. rotavirus was associated with diarrhoea of 2-8 weeks' duration in all patients and with abdominal cramping in eight patients. thomas and colleagues 67 looked prospectively at 862 samples from 377 uk hiv-1-positive patients with diarrhoea. rotavirus was third in frequency to adenovirus and coronavirus, occurring in 11 (2·4%) samples. the median cd4 count of patients with rotavirus infection was nine. hrdy 68 described five typical settings for rotavirus infections in adults. we propose modification of these classifications to the following: endemic disease, epidemic outbreaks, travelrelated gastroenteritis, and infections transmitted from children to adults. although substantial overlap exists between the groups, our classifications clarify separate risk factors and clinical features. rotavirus infection in children is seasonal, with peak incidence in winter months in temperate climates. iturriza-gomara and colleagues 69 noted that, in the uk between 1995 and 1998, notable numbers of infections began in december or january, peaking in march or april and falling to almost zero by july. in the usa, kapikian and colleagues 56 found that rotavirus cause 59% of diarrhoea cases necessitating admission to hospital in children between november and april, but could not be linked to cases from may to october. in several studies findings suggest that adult disease is not as season-specific as childhood disease. cox ffu=focus forming unit. nr=data not recorded in original paper and taken as not having occurred in calculation of summary percentages. *data included when >50% infectious dose ingested (>9 ffu). †15 of 38 patients had mild illness (including one patient with no antibody response or shedding). ‡one of four volunteers experienced illness but no specific symptoms were recorded. §summary percentages after rotavirus ingestion calculated only from data from studies in which full clinical syndrome of illness described. all percentages have been rounded to the nearest whole percentage point. adult serum in routine hospital samples are present throughout the year. igm concentrations increased with older age, and antibodies reached 20% in march and fell to 10-11% during the summer months. cox and medley attributed the high rates to igm persistence, igm crossreactivity, or possibly to non-seasonal high infection rates in adults. other researchers have also found that rates of adult disease do not mirror the winter seasonality of infection in paediatric patients. 71 these studies suggest that endemic disease in adults may not arise solely from unrecognised transmission of rotavirus from children to adults. the contribution of rotavirus as a cause of endemic gastrointestinal disease varies according to geographic distribution and characteristics of patients. in a small prospective study in the uk, rotavirus caused 4·1% of acute diarrhoea in adults admitted to hospital. 72 similarly, 3% of acute diarrhoea in switzerland, 73 3% of infectious diarrhoea pathogens in a swedish clinic for infectious diseases, 74 5% of adults with gastroenteritis requiring admission in thailand, 75 2-4% of adults older than 15 years with gastroenteritis presenting to their family physician in the netherlands, 76 and nearly 4% of individuals older than 45 years in michigan 77 were due to rotavirus. in studies in other geographic areas even higher rates of infection have been seen. in japan, nakajima and colleagues 71 reported that group a rotavirus had a role in 14% of patients with diarrhoea. pryor and colleagues 78 noted that rotavirus was second only to campylobacter spp as a cause of diarrhoea among australian adults, accounting for 17% of all cases. in indonesia, 42% of patients presenting with diarrhoea had rotavirus-positive stools compared with 11% of control samples. 79 in a study of mexican adults, 63% of patients presenting with acute gastroenteritis during winter months were positive for rotavirus. 80 even these results might underestimate the true prevalence of endemic rotavirus infection. group c rotavirus is not routinely detected by commercial assays but it does contribute to endemic rotavirus infection worldwide. in a study in the uk, 43% of patients were seropositive for group c rotavirus. 81 among adults, clusters of rotavirus infections most frequently occur in communities that are otherwise sheltered from more routine exposure to rotavirus-infected children. 82 one of the largest outbreaks involved nearly 3500 people in 1964, in an isolated area of micronesia. 83 since then, other outbreaks have occurred among closed communities, including a finnish military base, 84 an israeli kibbutz, 85 and an isolated south american indian community. 86 outbreaks of rotavirus infection have also occurred in long-term health-care facilities, particularly those with close living quarters; compromised host immunity and multiple comorbid disorders might help facilitate the spread of infection. 87-91 cubitt and colleagues 88 described an epidemic of rotavirus among staff and patients in an extended-stay geriatric hospital, in which 15 of 39 residents developed symptoms and seven had confirmed rotavirus infection. halvorsrud and orstavik 92 described an outbreak of 92 cases of acute gastroenteritis among nursing-home patients with identification of rotavirus by comparing acute and convalescent antibody titres. rotavirus has been suggested as the causal pathogen in 5% of diarrhoea outbreaks in a study of institutions caring for elderly residents. 93 among adults, rotavirus outbreaks are not confined to geriatric populations. group a rotavirus was associated with an outbreak of gastroenteritis among college students in the district of colombia. 58 rotavirus also caused a waterborne outbreak of gastroenteritis in 1981 in eagle-vail and avon, co, usa in which severity of symptoms correlated with the amount of tap water consumed. 94 finally, griffin and colleagues 95 screened 263 outbreaks of gastroenteritis in the usa between 1998 and 2000 and found that rotavirus was implicated in three outbreaks. uniquely affecting asia, group b rotavirus has been associated with outbreaks affecting large numbers of adults in broad geographic distributions of china and india. 96, 97 rotavirus has been implicated as an important contributor to travellers' diarrhoea among adults, especially among those visiting central america and the caribbean. in a study of travellers returning from jamaica, rotavirus was identified in 9% of individuals with diarrhoea, making the virus second only to enterotoxigenic escherichia coli as a cause. 98 in two studies of us students travelling in mexico, electron microscopy identified rotavirus in about 25% of patients who had diarrhoea, compared with 3% and 15%, respectively, of symptom-free patients. 99, 100 in a third study, a substantial rise of antibodies to rotavirus was seen in 17% of two student groups travelling to mexico. 101 by contrast, only 5-6% seroconverted to norwalk virus. 101 ryder and colleagues 102 found rotavirus in 26% of panamanian travellers to mexico who had diarrhoea. sheridan and colleagues 103 similarly found that 36% of us peace corps volunteers and 30% of panamanian travellers visiting mexico had at least a four-fold increase in rotavirus antibody titres. adult travellers with rotavirus shed 10-100 times less rotavirus than do paediatric patients. 99, 100 although rotavirus can be linked to adult gastroenteritis in each of the other settings, adults who are in contact with children are at particularly high risk of infection. transmission of rotavirus within families from children to parents seems to be a common event. wenman and colleagues 55 showed prospectively that rotavirus infection occurred in 36 of 102 adults caring for children with rotavirus infection. by contrast, only four of 86 adults whose children had no documented rotavirus infection became infected. 55 grimwood and colleagues 57 confirmed this finding in a report that a third of adult family members in new zealand developed evidence of rotavirus infection. the same phenomenon has been seen among parents of more severely ill children. kim and colleagues 104 found evidence of rotavirus infection in 55% of adult contacts of children who were admitted to hospital with rotavirus, compared with 17% of adult contacts whose children were not infected. more casual contact might also be sufficient to facilitate rotavirus transmission from children to adults. rodriguez and colleagues 105 reported that nine of 12 adults experienced illness after exposure to children infected with rotavirus in a playgroup. although substantial evidence is lacking, child-to-adult transmission of rotavirus is accepted to occur with some frequency on paediatric wards. many paediatric nurses, medical students, and house officers experience symptoms of gastroenteritis during the winter months when most paediatric rotavirus infections are encountered. von bonsdorff and colleagues 106 described paediatric nurses at several different locations with acute gastroenteritis caused by rotavirus. among seven hospital staff that developed diarrhoea after direct contact with children with diarrhoea staying in hospital, a rise in antibody titres was detected in three. 104 interestingly, in the same study, six of 45 medical students reported gastroenteritis. three of the students had rotavirus particles present on electron microscopy and were noted to be more ill than the parents of the children who were infected. all had diarrhoea for 3-6 days and two of the three had low-grade fever and vomiting. another case report supports transmission of rotavirus from children to hospital caretakers. 107 electron microscopy, which permits visualisation of the pathognomonic wheel-like appearance, was initially used for diagnostic purposes, but elisa or eia have become more commonly used. commercial assays are reliable, convenient, and inexpensive, but require at least 10 4 -10 7 virions to generate a positive result. 108, 109 the false-positive rate of commercial assays is 3-5%. 69 one of the biggest limitations of most commercial assays is that they do not detect non-group-a rotavirus. 68, 110 other more sensitive and newer methods are being used in research. one such method is pcr, which is up to 1000 times more sensitive than immunoassays. 109 in one study using pcr, 30% of otherwise healthy children shed virus for 25-57 days after symptoms developed. 111 although stool cultures are routinely tested for bacterial pathogens, the low frequency of detecting a positive result calls the usefulness of this practice into question. rotavirus infection can occur in a similar number of patients to some bacterial pathogens. sending a sample of rotavirus antigen for testing by elisa or eia could potentially cut costs if by doing so either hospital stay or procedures could be avoided. such a cost-benefit analysis in adult patients has not been published. one limitation is that adults might shed less rotavirus in faeces than do children, further hampering diagnosis. 100 we suggest that obtaining rotavirus antigen testing for patients admitted to hospital with risk factors for rotavirus infection will be cost effective if additional inpatient studies can be avoided. determination of rotavirus infection may also be beneficial if infectious patients can be isolated to prevent nosocomial spread. a positive rotavirus antigen test might also allow physicians to avoid prescribing antibiotics for travel-related rotavirus infections. treatment of rotavirus infections is primarily directed at symptom relief and restoration of normal physiological function. oral rehydration should be attempted initially. in most developing countries, oral rehydration salt solutions are used extensively in children. most adults can be managed by encouraging them to drink fluids. an additional intervention that has been used is administration of lactobacillus spp bacteria to shorten the duration of diarrhoea. 112, 113 although seldom used in children, codeine, loperamide, and diphenoxylate can help with symptom relief and control of the volume of diarrhoea. 114 bismuth salicylate, in a placebo-controlled double-blinded trial, was efficacious in treating the symptoms of rotavirus diarrhoea. 115 trial use of bismuth salicylate can be considered in adults when other coexistent infectious causes have been ruled out. if symptoms cannot be controlled and the patient becomes dehydrated, administration of intravenous fluids and hospital admission might be necessary. rarely, extraordinary measures have been attempted to help resolve rotavirus infections. for example, human breastmilk has been provided to immunodeficient infected children to help resolve chronic diarrhoea. 59 this option, however, is not practical in adults. several groups report oral administration of human serum immunoglobulins possessing antirotavirus activity to bind free rotavirus antigen. guarino and colleagues 116 noted a mean duration of diarrhoea of 76 h in children who received one oral dose of 300 mg/kg human serum immunoglobulin, compared with 131 h in children who did not. in a study involving three immunocompromised children with chronic rotavirus diarrhoea, oral administration of human serum immunoglobulins (igg 150 mg/kg) cleared rotavirus antigen in all three, but rotavirus antigen recurred in two. 117 among adults, oral immunoglobulin administration of 5-6 g daily for 5 days to bone-marrow-transplant recipients has been successful. 118 prevention of rotavirus infection can be facilitated by avoiding exposures and faecal-oral spread. contact with sick children and potentially contaminated food and water should be avoided. since 43% of rotavirus virions placed on human fingers survive for 60 min, thorough hand washing is critical in prevention. 119 contact isolation for patients diagnosed with rotavirus infection is necessary, generally for the duration of hospital stay, because of sustained faecal shedding of low concentrations of virus. 120 gloves, gowns, isolation, and rigorous hand washing should be used in the care of individuals infected with rotavirus. 121 sattar and colleagues 122 reported that rotavirus survives best in low humidity on non-porous surfaces at room temperature or cooler. phenolic disinfectants do not inactivate rotavirus; instead hypochlorite or sodium dichloroisocyanurate tablets with a free chlorine concentration of at least 20 000 parts per million are recommended. 110 a 70% ethanol solution is also effective in inactivation of rotavirus and can help to prevent environmental spread. 120 rotavirus infection in adults has been successfully prevented by use of a commercially available review disinfectant spray on rotavirus contaminated fomites under experimental conditions. 123 given the substantial disease-related morbidity and mortality associated with rotavirus, the development of an effective vaccine is a priority. although multiple vaccines were under development, the tetravalent rhesus-human reassortant rotavirus vaccine (rrv-tv) seemed to produce the best results. the rrv-tv vaccine prevented about half of rotavirus infections, but was much more effective in preventing severe disease. 124, 125 shortly after the vaccine was approved, the vaccine adverse-event monitoring system noted by mid-1999 an excess of cases of intussusception among recently vaccinated infants, eventually prompting the vaccine to be withdrawn. two sharply differing perspectives on the risk and benefits of the rrv-tv vaccine and the advisory committee on immunization practices' confirmation of its decision to withdraw its recommendation for the vaccine have been put forward. 126, 127 other vaccines are under development. vaccines have been primarily developed to attempt to decrease the severity of rotavirus infections in children. although vaccines seem to be fairly safe in adults from the vaccine trials, we are unaware of any plan to consider vaccination in adult patients. vaccination could theoretically be used in adult patients considering travel to central america or the caribbean or among immunocompromised patients to prevent or lessen the severity of rotavirus diarrhoea. despite recognition as an important cause of gastroenteritis in children, rotavirus's role in adult gastroenteritis is underappreciated. immunity to rotavirus is incomplete and most people have multiple infections over their lifetime. adults with rotavirus can be asymptomatic, but the most common symptoms are nausea, malaise, headache, abdominal cramping, diarrhoea, and fever. adults at particular risk of rotavirus infection are travellers, adults exposed to infected children, and immunocompromised people. group a rotavirus, the most common human pathogen, can be diagnosed with many different commercial assays, but all have limited sensitivity. rotavirus testing might be beneficial in certain clinical settings if detecting rotavirus would change management of patients or prevent nosocomial spread. treatment is primarily symptomatic. rotavirus should be considered in the differential diagnosis of adult infectious gastroenteritis. we have no conflicts of interest. we identified sources for this review by searches of medline with use of the key words "rotavirus infection" and "adult." the search strategy and selection criteria included all english and human studies from the year 1970 until the present. we further reviewed the abstracts for relevance before inclusion. review of the references of the papers retrieved by the initial search allowed for additional studies to be identified and considered for inclusion. visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis viral gastroenteritis molecular epidemiology of "norwalk-like viruses" in outbreaks of gastroenteritis in the united states epizootic diarrhea of infant mice: identification of the etiologic agent relationship between viruses from acute gastroenteritis of children and newborn calves rotavirus infections: guidelines for treatment and 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rotavirus survival on human hands and transfer of infectious virus to animate and nonporous inanimate surfaces red book: 2003 report of the committee on infectious diseases infection control for hospitalized children institutional outbreaks of rotavirus diarrhoea: potential role of fomites and environmental surfaces as vehicles for virus transmission prevention of surface-to-human transmission of rotaviruses by treatment with disinfectant spray randomised placebo-controlled trial of rhesushuman reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in venezuela reappraisal of the association of intussusception with the licensed live rotavirus vaccine challenges initial conclusions the first rotavirus vaccine and intussusception: epidemiological studies and policy decisions for personal use. only reproduce with permission from the lancet. a 73-year-old woman presented with a 2-year history of persistent ulcerous nasal injury that had progressed slowly and without fever, respiratory, or any general symptoms, until the upper lip was affected. a painless ulcero-vegetating injury was seen but the patient was otherwise normal; chest radiographs did not show abnormalities. further examination showed soft tissue attenuation and an ulcered mass lesion in the nasal cavity (figure). the definitive diagnosis was made by isolating mycobacterium tuberculosis from tissue removed during biopsy and antituberculous therapy was started. the lesion had resolved at completion of treatment.tuberculosis of head and neck occurs infrequently and involvement of the nose is rare. granulomatous lesions within the nasal cavity may represent either local disease or a manifestation of a systemic disorder and the differential diagnosis must include tuberculosis. although almost forgotten in industrialised countries, this unusual form of tuberculosis can appear mainly in females and the elderly. it is not thought to be contagious, or to produce noticeable symptoms or physical signs. key: cord-337037-xpj17vn4 authors: weigel, ralf; krüger, carsten title: global child health in germany time for action date: 2020-10-09 journal: global health action doi: 10.1080/16549716.2020.1829401 sha: doc_id: 337037 cord_uid: xpj17vn4 child health is central to the sdg agenda. universities in the uk and other european countries provide leadership in research and education for global child health to inform related policy and practice, but the german contribution is inadequate. german paediatricians and other child health professionals could make more substantial contributions to the debate at home and internationally, but lack opportunities for scholarship and research. we argue, that there is a momentum to advance global child health in academia and call on german universities to realise this potential. 'viruses don't need visas, pathogens don't need passports' -the world health organization (who) director-general's urgent message to the participants of the world health summit in berlin in 2017 is more relevant today than ever [1] . the impact of the sars-cov-2 pandemic on children is a powerful reminder in this regard [2] and other threats are looming [3, 4] . germany, like other highincome countries, is a beneficiary of globalisation. however, benefits come with responsibilities: as a signatory of the sustainable development goals (sdg) 2016-2030, germany committed to advance health globally [5] . child health and well-being are central to the sdg agenda illustrating our responsibility for future generations [6, 7] . unfortunately, global child health in germany is somewhat neglected in research and education. we need a major effort to improve the situation. in germany, global child health institutions and the scientific debate are still in their infancy compared to other european countries. in the uk (uk), the centres at the university college london, the london school of hygiene and tropical medicine, the liverpool school of tropical medicine, and other universities have active research groups in global child health as an integral part of maternal, newborn, child and adolescent health. the royal college of paediatrics and child health annual meetings regularly devote entire days to global child health research and training. global child health topics regularly feature in the college's scientific journal. universities in italy, the netherlands, norway and sweden have institutes dedicated to international maternal and child health. at the universities in utrecht, london and liverpool, under-and postgraduates can attend various courses on global child health. in sweden, the institute for global health transformation initiated a multidisciplinary forum hosted by the royal swedish academy of sciences, which resulted in a roadmap on global child health with five priority areas in the context of the sdgs [8] . although germany has successful research groups in maternal and child public health that collaborate internationally, for example at the universities in hamburg, heidelberg and munich, there is no such overarching forum to share ideas, to develop strategies and to provide direction. it is the private witten/ herdecke university that has the only professorship for global child health, funded by the friede springer foundation [9] . the german society for tropical paediatrics and international child health (gtp) is a professional society established almost 40 years ago with about 400 current members which brings together paediatricians with different backgrounds at its annual meetings and offers a range of trainings, but its mandate for research is limited [10] . the academic global child health landscape in germany is fragmented, without a dedicated chair at a statefunded university and with little collaboration between different actors. however, there are also deeper and more systemic reasons why german global health research and education as a whole are underdeveloped [11, 12] . for contact ralf weigel ralf.weigel@uni-wh.de friede springer endowed professorship for global child health, witten/herdecke university, witten 58448, germany example, the abuse of public health by the nazi regime for their racial hygiene policies and atrocities descredited the field and left a stain that still affects perceptions today [13, 14] . currently, public health research is concentrated at several federal institutions, such as the robert koch institute (rki) and the federal centre for health education (bzga). but, compared with universities, their scholarly role is limited. at the local level, public health interventions are implemented by public health offices that have no formal academic role [15] . furthermore, global health policy programmes in germany are distributed over six ministries and international health programmes are funded to a large degree not by the ministry of health but the federal ministry for economic cooperation and development. its main implementers, the society for international cooperation (giz) and the kreditanstalt für wiederaufbau (kfw), a promotional bank owned by the state, have little focus on academic research and education. thus, the historical heritage, and the policy and funding structure appear to be barriers that may have contributed to the slow development of an academic base in global health in general [16] and global child health specifically. within this historical and structural context and with weakly organised public or global health institutions, it is not surprising that german paediatricians are hard to find in scientific landmark publications, guidelines and reports of global relevance. in the 108page global strategy 2016-2030 for the health of women, children and adolescents [17] , a groundbreaking document for the global health of mothers and children, no german name is found in the recognition and author lists, similar to the 16 review articles in the bmj special issue 2015, which provides the scientific background for the strategy [18] . of the 471 organisations that contributed to the development process of the strategy, only five came from germany [19] . the same applies to the who publications 'standards to improve the quality of care for mothers and newborn babies in health care institutions' from 2016 [20] and 'standards to improve the quality of care for children and adolescents in health care institutions' from 2018 [21] . among the authors from more than 100 institutions, only three and seven, respectively, are from germany, and only in one case from a paediatric professional society. similarly, of the institutions involved in 'the 2019 report of the lancet countdown on health and climate change: ensuring that the health of a child born today is not defined by a changing climate', 10 come from the us, 11 from the uk, five from other european countries, including one from germany, and five from other, non-european countries [4] . although this lack of representation is not necessarily a sign of a lack of participation in the international scientific debate, the few opportunities german researchers have to engage in global child health research and education at universities suggest that this is, in fact, the case. without academic leadership, a lively exchange of ideas, a research agenda and funding, it is hard to participate and to be heard. without global child health institutes, students and young researchers have few opportunities and academic career prospects, preventing them from engaging in research and applying for funding. our research and educational institutions need to provide a better environment for child health professionals that they can move the global scientific and policy debate forward and contribute more substantially to the global research agenda. many opportunities exist for paediatricians and other health workers caring for children to engage with the realities of global child health in research and education. for example, in 2015/2016, some 350,000 children and their families came to germany to seek refuge, many of them vulnerable with multiple risks and in urgent need of health care [22, 23] . their physical and mental health needs and strategies to meet them are important to share [24, 25] . what are the enablers and barriers to their integration in the health care and education system, viewed from a child rights perspective [26] ? germany's development cooperation focus on health systems strenghtening offers further opportunities. the initiative 'hospital partnerships -partners strengthen health' financed by the federal ministry for economic cooperation and development and the else kröner-fresenius foundation, supports 181 projects with institutions from 51 low-and middle-income countries, several of them focusing on mother and child health [27] . the german academic exchange service (daad) has helped to establish 28 cooperations between universities in germany and low-and middle-income countries with its 'partnership for health care in developing countries' programme [28] , some addressing maternal and child health. rigorous evaluation of the short and long term effects of interventions implemented within these partnerships, for example on human resources or on child health outcomes, would also make a substantial contribution to the field. it is time for german universities to use this potential to strengthen research and education in global child health -there is momentum to realise this. the sars-cov-2 pandemic has fuelled a debate of how social determinants, such as access to education, affect health, well-being and development of children in germany and elsewhere [29, 30] . children are leading in advocacy for their own for their right to health in the context of climate change, holding world leaders accountable in the fridays-for-future movement. the experiences of families while educating their children at home during lock-downs due to the pandemic as well as the voices of children concerned about climate change are making headlines in the media [31, 32] . this may represent an opportunity to leverage global child health concepts, such as social and environmental determinants of health and child rights, higher on the policy and research agenda. as germany is updating its global health strategy, receiving valuable advice from various professional organisations [33, 34] , global child health has to become a core element of this strategy, building on and developing further existing initiatives. a recent discussion paper, published by the commission for global child health of the german academy for child and adolescent medicine (dakj), listed several recommendations for improving the landscape of global child health research and education [35] . in addition, the german society of tropical paediatrics and international child health and the named dakj commission will continue to lobby for the inclusion of global child health into the planned german centre for child health, funded by the federal ministry of education and research [36] . and the recently founded global health hub germany [37] and the german alliance for global health research [38] are also prime opportunities for building institutional capacity. to date, the global child health agenda has had limited visibility in germany. we call on the academic leadership of paediatric professional societies in germany to provide a forum for the scientific and political aspects of global child health, to provide leadership and to lobby for funding from the government. paediatric researchers should respond more actively to calls from multilateral agencies like who [39, 40] and make public their positions on issues such as child rights [41] . medical faculties need to strenghten their academic base by offering under-and postgraduate education in global child health through institutes and chairs so that students and young researchers see a path for their careers. we must now seize the opportunities unfolding for urgently needed engagement in this important field in research and education. german universities can and should play a much more active part in advancing the health and well-being of children throughout the world. viruses don't need visas, pathogens don't need passports early estimates of the indirect effects of the covid-19 pandemic on maternal and child mortality in low-income and middle-income countries: a modelling study climate change and global child health: what can paediatricians do? the 2019 report of the lancet countdown on health and climate change: ensuring that the health of a child born today is not defined by a changing climate united nations department of economic and social affairs. the sustainable development goals report placing children and adolescents at the centre of the sustainable development goals will deliver for current and future generations a future for the world's children? a who-unicef-lancet commission swedish institute fo global health transformation. a new roadmap on global child health germany's expanding role in global health german society for tropical paediatrics and international child health global health education in germany: an analysis of current capacity, needs and barriers global health research and education at medical faculties in germany results presented of the research project confronting the past: contemporary german paediatric response to medical practice in the third reich statutory health insurance in germany: a health system shaped by 135 years of solidarity, self-governance, and competition germany's expanding role in global health every women every child. the global strategy for women's, children's and adolescents health towards a new global strategy for women's, children's and adolescents' health participating organizations: fhi360 standards for improving quality of maternal and newborn care in health facilities geneva standards for improving the quality of care for children and young adolescents in health facilities accumulated environmental risk in young refugees-a prospective evaluation recommendations for the diagnosis and prevention of infectious diseases in pediatric and adolescent refugees in germany: statement of the german society of pediatric infectious diseases, the society of tropical pediatrics and international child health mental health needs of refugee children in specialized early education and care programs in germany immunization coverage among refugee children in berlin unaccompanied refugee minors in germany: attitudes of the general population towards a vulnerable group else kröner fresenius-stiftung. initiative hospital partnerships pagel -partnerships for the health sector in developing countries covid-19 and its impact on child and adolescent psychiatry -a german and personal perspective children and adolescents in the covid-19 pandemic: schools and daycare centers are to be opened again without restrictions. the protection of teachers, educators, carers and parents and the general hygiene rules do not conflict with this after two years of school strikes, the world is still in a state of climate crisis denial we swallowed our misgivings'; 2020 statement of the international advisory board on global health: global health centre, the graduate institute of international and development studies deutsche gesellschaft für public health deutschland und sein engagement für die gesundheit der kinder weltweit federal ministry of education and research. startschuss für zwei neue deutsche zentren der gesundheitsforschung deutsche gesellschaft für internationale zusammenarbeit (giz) gmbh. global health hub germany berlin charité global health. german alliance for global health research berlin who hospital care for children guidelines: what do users need? new who standards for improving the quality of healthcare for children and adolescents the budapest declaration for children and youth on the move-comment in the lancet child and adolescent health we thank william christopher buck for proofreading the manuscript. rw wrote the draft manuscript, which ck reviewed. both authors read and approved the final version. rw holds the friede springer endowed professorship for global child health at the witten/herdecke university. ck is currently the chairperson of the german society of tropical paediatrics and international child health and the spokesperson of the committee of global child health of the german academy of child and adolescent medicine. not applicable. the authors have no funding to report. this call to action addresses child health professionals and stakeholders to engage in research and education for global child health at germany's higher education institutions. universities should realise the momentum and recognise the importance of global child health to enable substantial contributions to the scientific and policy debate at the national and global levels. http://orcid.org/0000-0001-9034-2634 carsten krüger http://orcid.org/0000-0001-7936-7689 key: cord-032363-86ovid90 authors: gerson, william t. title: “who are we?” common pediatric orthopedic disorders and the primary care clinician date: 2020-09-20 journal: curr probl pediatr adolesc health care doi: 10.1016/j.cppeds.2020.100885 sha: doc_id: 32363 cord_uid: 86ovid90 nan "who are we?" common pediatric orthopedic disorders and the primary care clinician william t. gerson, md* i have no name i am but two days old.-what shall i call thee? i happy am joy is my name,-sweet joy befall thee! pretty joy! sweet joy but two days old, sweet joy i call thee; thou dost smile. i sing the while sweet joy befall thee. -william blake "infant joy" 1789 once there was a way to get back homeward once there was a way to get back home sleep pretty darling do not cry and i will sing a lullaby. -the beatles (paul mccartney), "golden slumbers," 1969 bent, stork, and nemeth speak to the soul of children's healthcare in their superb summary on common childhood orthopedic disorders. 1 theirs is an understated goal: to provide a framework to the approach to some of the most common orthopedic conditions in children. however, the result speaks not only to what we do or strive to do as primary care clinicians but to why. the exposure of the murky underbelly of our healthcare system during the current covid-19 pandemic gives us a unique opportunity for reflection. a call-out from our specialty colleagues unexpectedly prodding us for self-definition is most welcome à "who are we?" we find the soul of children's healthcare in our exam rooms in our consultations with patients and families. that soul is grounded in our expertise over a body of knowledge whose roots travel through developmental biologic turf. our professional soul's origin lies in the notion of childhood; its poems and lullabies; in our children's hospitals whose own origins derive, in part, from the treatment of orthopedic conditions; and in the breadth of our training and experience in the principles and practice of children's healthcare. the first encounter with a child and her/his family is often in the newborn nursery à and that evaluation sets the standard for all that follow. families most remember our touch and our words during those moments à and much of our exam is orthopedic. some may wonder why parents are so concerned about the curve of the lower legs or feet when the medical focus is on the heart and lungs' transition. the reason, of course, is not difficult to understand. the true meaning of infancy and childhood underpins this critical encounter. in the newborn exam, the juxtaposition of the promised joy of childhood, often perceived as that of play -the walking, running, jumping, climbing of innocent times, is never far from a feared image of difference or even of crippling disorders. every primary care clinician should read this paper, not just because musculoskeletal illness represents a large portion of all childhood office visits. it provides a concise synopsis of the most common orthopedic concerns presenting to primary care clinicians, beginning with the newborn exam, and often resulting, not necessarily appropriately, in referral to pediatric orthopedic surgeons. the authors present a developmentally-based approach to infant, childhood, and adolescent musculoskeletal complaints. they highlight the range of normal variation that drives much of parental concerns and emphasize the critical role of reassurance with periodic reevaluation. it emphasizes the principles of anticipatory guidance and education and a welcome, careful approach to diagnostic imaging. there is also a clear delineation of pathologic conditions and the importance of timely referral. the authors acknowledge a limited scope; they do not review fractures, sports-related concerns, bone tumors, or infectious processes. bent, stork, and nemeth present their topic in an easy to read style that belies its comprehensive content. they achieve the conceit of the addition of a wise consultant in the exam room, walking through the encounter, assisting in the physical exam, and answering patient and parental concerns. for each topic there is a bolded question of "what is . . ." followed by "how do i evaluate," "risk factors," and ending in "treatment and when to refer." the authors place all topics in a developmental context, and their description of both angular variants (bow legs and knock knees) and rotational/torsional variants are extensive. pearls and pitfalls are frequent and sometimes bold-faced or capitalized, jargon and acronyms are minimal, unmistakable figures and extensive references round out their work. the authors artfully weave the importance of the physical exam into the context of the age-appropriate and longitudinal general office exam. critical thinking and placing important but unlikely etiologies of common variants in proper perspective (e.g., cerebral palsy and in-toeing, hypothyroidism and scfe) are abundant. the section on the causes of foot pain without injury is also excellent. our strength as child health clinicians is our knowledge base of growth and development and our ability to recognize and appropriately manage disorders and health promotion. the popular chronologic model of childhood office visits has limitations. better is a developmental model based on the needs, risks, and vulnerabilities of individual children and their families. bent, stork, and nemeth offer such a wellness-focused, developmentally driven, and vulnerability-defined timeline. our pediatric orthopedic colleagues have well documented the deficiencies in our medical school and residency pediatric education. their paper could be a model for child health education and it should be included in every educational packet for students and trainees regarding children's healthcare and pediatric orthopedics. let us embrace the power of poem, lullaby, or song to enable a better future rooted in the best of the past where the art and practice of medicine are valued, education in children's health is developmentally sensitive, and the pursuit of excellence is an unwavering commitment to children, their families and our profession. the accompanying paper is an affirmation of all that is best in education and the clinical care of our young patients. the diagnosis and management of common childhood orthopedic disorders: an update key: cord-330780-lmntovs5 authors: simacek, jessica; elmquist, marianne; dimian, adele f.; reichle, joe title: current trends in telehealth applications to deliver social communication interventions for young children with or at risk for autism spectrum disorder date: 2020-10-12 journal: curr dev disord rep doi: 10.1007/s40474-020-00214-w sha: doc_id: 330780 cord_uid: lmntovs5 purpose of review: early, intensive, and high-quality interventions can often improve social communication outcomes for children with autism spectrum disorder (asd). many children experience barriers to intervention, resulting in significant delays to intervention onset or missed opportunities for intervention altogether. with constant advances in technology, the field is experiencing a rapid increase in investigation of telehealth applications to intervention delivery. this article highlights the current trends in social communication intervention via telehealth used in early intervention practices for children with asd over the past 5 years, including a brief review of studies (from 2014 to january 2020) and our team’s experiences in this area. recent findings: based on our experience and the 22 studies we identified in this area, we describe the current trends in telehealth applications used and how interventions were delivered. we also provide recommendations, limitations, and future directions on this topic. summary: telehealth offers innovative intervention delivery options by increasing intervention access, overcoming barriers such as geography and costs of service delivery for young children with asd. early intervention represents a critical factor in improving social communication acquisition for children with asd [1] [2] [3] . unfortunately, many children encounter barriers to accessing early intervention [4] . these barriers include a shortage of qualified providers of early intervention for this population, geographic areas without adequate service availability, challenges in funding for intervention, and systems that are underprepared to meet the needs of children from culturally and linguistically diverse populations [5, 6] and children from disadvantaged socioeconomic backgrounds [7] . with a growing prevalence in asd [8] , this trend is not likely to reverse without changes in service delivery systems. since the covid-19 pandemic, intervention and special education services have been significantly curtailed. timely solutions are needed to ensure that all children receive access to high-quality early intervention. telehealth applications represent a potential social communication intervention innovation to address these issues. the use of telecommunications technology in health care, telehealth, originated and is more prevalent in the medical, psychiatric, and psychological fields. the transition to using telehealth to support intervention activities with children with developmental disabilities emerged somewhat later. early applications of telehealth in this area include providing intervention and support for students [9] , educators [10, 11] , therapists [12] , and parents [13•, 14-16] . clearly, the evidence of the successful use of telehealth applications in early intervention for children with developmental disabilities is growing. given current service needs, telehealth applications seem a this article is part of the topical collection on communication disorders we begin by briefly describing telehealth applications including synchronous and asynchronous (i.e., store-and-forward) connections, followed by a brief discussion of the potential benefits of each. we also discuss online learning modules and a learning app. as telehealth includes interaction between an intervention provider and a recipient, standalone modules and apps are often not considered to be telehealth. however, telehealth-delivered interventions are often "packaged" with online modules, which warrants discussion of this modality in this article. each of the applications discussed can be (and often are) packaged together or combined with in-person intervention delivery. in early intervention for children with asd, synchronous connection often occurs between an intervention provider, educator, or clinician (herein referred to as "tele-provider") and someone receiving the intervention via telecommunications technology, such as a child or, more often, a caregiver, interventionist, educator, or clinician who is interacting with the child (herein referred to as the "end-user"). in our review, synchronous applications were the most frequently used (12 studies, or 54.5% of studies used synchronous telehealth alone). synchronous telehealth can be a standalone intervention delivery method when families are not receiving in-person intervention with a provider or it can augment a program (e.g., a child receives therapy in a center-based environment and in-home sessions are added to the model via telehealth). for example, subramaniam et al. provided intervention initially at a clinic with in-person visits from the parents [19•] . the in-person visits were combined with video-conferencing with parents in their homes, to give the parent time to learn the targeted intervention skills before implementing the strategies with their child in their homes. a clear advantage to synchronous telehealth is that it allows "live" intervention to be conducted easily in homes, often forgoing travel requirements for both parties. the majority of studies (18 studies, 81.8%) from our sample were conducted at least partially in homes. access to technology and the necessary infrastructure can impose limitations to the advantages of telehealth (e.g., reliable internet connection); however, successful implementation of telehealth intervention has been demonstrated in rural locations with families with lessthan-optimal internet connectivity [20•] . synchronous telehealth can also virtually link clinics or satellite sites (often a community location) with a tele-provider. a potential benefit of this type of connection is to build specialist capacity in an area that typically lacks those resources (e.g., rural location). it can also provide families with a site that has been prepared to receive telehealth connection, which may help avoid some technological barriers [21•] . teleconnection between sites occurred in a smaller subset of included studies (4 studies; 18%). examples of interventions delivered clinic-to-clinic or clinic-to-satellite site included training interventionists in clinics [22•, 23•] ; training parents at local sites including a primary care clinic, a hospital, and a school site [21•] ; and training early childhood personnel to provide parent training at a local community clinic [24•] . regardless of location, synchronous connection allows for immediate instructions, feedback, and consultation to be delivered. this can facilitate supervision and fidelity monitoring from a professional (e.g., licensed psychologist) while an interventionist is implementing the intervention directly with a child. this can also enable interdisciplinary service delivery by connecting professionals for wraparound service provision, such as allowing intervention providers working with the child in the home to virtually attend an individualized education plan meeting at the child's school. while these activities can also occur in-person, telehealth may make them more feasible. finally, whether telehealth is a reimbursable service modality varies by state, payer, provider type, and the type of service being rendered. historically, synchronous applications have been more frequently covered than asynchronous applications (center for connected health policy, https://www. cchpca.org). asynchronous applications rely on the transmission of audio/ visual or related health information (e.g., imaging) to a teleprovider, who can then review and respond. for example, a tele-provider may ask a parent to record a video of their child communicating during mealtimes and then upload it to a secure online portal. once uploaded, the tele-provider would view the video to monitor the child's progress and provide feedback to the parent. in our review, asynchronous applications were used less as the only telehealth mode in fewer studies (3 studies, 13.6%). studies more frequently included a combination of telehealth approaches (7 studies, 31.8%). benefits to asynchronous applications include that caregivers can often complete intervention sessions and record them during convenient times. it can also provide a window into times of the day when scheduling live intervention sessions is not feasible, such as bedtime. likewise, tele-providers can collect multiple "video/audio samples" from end-users simultaneously, without scheduling limitations from the provider. online learning modules and apps our review includes online learning modules that were combined with other forms of telehealth. we also describe a study that used an online learning app, therapy outcomes by you (toby), that contained activities and lessons for parents to implement with their children, as apps like these could be used asynchronously by tele-providers [ [26•] . in this example, the modules were combined with asynchronous video viewing by teleproviders; however, the authors noted that the asynchronous video viewing was for research purposes only. benefits to online learning include that parents/trainees can complete at a convenient time [27• ]. this may be essential for families with multiple children, single parents, or other challenges. however, whether parents are likely to complete standalone modules without ongoing contact with a teleprovider is less clear. for example, in the previously mentioned study, mcgarry et al. reported a low completion rate for the full sequence of the online learning modules [26•] . in this study, when parents did complete the modules, children's vocalizations, eye contact, and positive affect increased. social communication skills targeted in the recent telehealth literature primarily focused on child requests (16 studies; 72.7%). many studies also targeted multiple social communication skills (9 studies; 40.9%). for example, guðmundsdóttir et al. demonstrated an increase in social communication skills, including child requests and social attending, language modifiers (e.g., adjectives), and the overall number of words used [20•] . one form of intervention strategy frequently represented in the synchronous telehealth literature has been functional communication training or fct [16] . researchers have continued to replicate and refine fct delivered via telehealth, with this format largely represented (8 studies; 36%, including [5, 18•, 28 •, 29•, 30•, 31•, 32•, 33•]). fct was implemented to increase a communicative alternative to challenging behavior [28•] and to increase more recognizable communicative alternatives to idiosyncratic responses [18•] . clearly, fct appears to be a suitable instructional format for telehealth service delivery for children who are beginning communicators and/or experience challenging behavior. naturalistic developmental behavioral intervention (ndbi) models were another instructional format that appeared multiple times in this review (7 studies, 31.8%). particularly relevant for younger children, ndbis combine behavioral principles with developmental and naturalistic approaches (e.g., less structured, more play-based, and child-led approaches to intervention than is commonly associated with behavioral interventions) [34] . for example, vismara training began with parents attending visits in-person at a clinic; then moved to twice per week with parents in their homes via synchronous telehealth visits; then faded to weekly visits; and finally, faded to biweekly visits. throughout this gradual fading, parents maintained fidelity. one of the best-documented uses of telehealth applications is training parents to implement intervention strategies to support their child's social communication development (18 studies; 81.8%). parents received training to deliver intervention with their children through various telehealth applications and various parent-coaching procedures. for example, several studies compared self-directed and therapist-assisted interventions delivered via telehealth. ingersoll et al. compared a selfdirected and a therapist-assisted group using the impact online training and found that both groups experienced gains in child communication, but only the therapist-assisted group experienced gains in child social skills [35• ]. pickard et al. made a similar comparison and found that both groups reported similar increases in their child's social communication skills [36•] . however, the parents reported that the therapist assistance was (or would have been) helpful. applying these findings to recommendations for coaching parents includes that interventionists should consider how to balance the convenience of self-directed online training components, with the importance of opportunities to practice and receive feedback from a tele-provider in a therapist-directed type of format. telehealth has also been used to train and provide supervision to interventionists (3 studies; 13.6%), including a study that involved teaching interventionists on how to coach parents [ [23•] . a tele-provider ("specialist") provided training to coaches with an online module; teleproviders (and coaches) viewed recorded videos of the coaches implementing the targeted incidental teaching strategies and provided feedback meetings via videoconferencing between the specialist and the coaches. the program resulted in high levels of fidelity to the teaching strategies and increased requests of the children. extending the reach of intervention, to rural locations and across the globe another significant trend we observed was the extensive reach of telehealth, with many studies actively recruiting children who resided in rural regions and through intercontinental training of interventionists and families. multiple studies recruited and included families who resided in rural areas [19•, 20•, 21•, 22•, 37•] . for example, rubi asd network parent training was delivered through synchronous video-conferencing between a clinic and a satellite site clinic [22•] . parents located in rural areas came to the site and received coaching via video-conferencing focused on the core and supplemental lessons. internationally, multiple studies included families from different countries (highlighted in fig. 1 ). often, families were recruited who resided in rural areas or did not otherwise have access to specialists in early intervention. barkaia these accumulated findings demonstrate that telehealth is a tool to innovate intervention delivery for providers to reach children in further areas. it is also a tool for researchers to develop and test interventions that include participant samples from diverse geographic locations, potentially reaching populations of participants whom do not reside near university campus locations. based on our experience and the available evidence, recommendations for parent-mediated interventions with their young children should be family-centered and routine-based. first, tele-providers can provide assessment for intervention planning and for onboarding a family to telehealth by helping them prepare, troubleshoot, and acclimate to the technology and the intervention. in our previous studies, our protocols have begun with a combination of telephone interviews and structured observations [18•, 29•] . examples of interviews include the functional assessment interview [39] , the inventory of potential communicative acts [40] , and the vineland adaptive behavior scales [41] . in our first sessions with families, we conduct "free play" sessions (approximately 3 to 5 min of preferred activities available to the child without any demands or restrictions aside from ensuring safety), a strategy we adopted from wacker et al. [15, 16] . we find that free play helps the child and family adjust to the telehealth and intervention arrangement. currently, we continue to begin and end most intervention periods with a brief free play session. we also conduct a structured descriptive assessment [42] by implementing several repeated antecedent conditions and routines (e.g., snack time) and measuring the child's potential communicative acts during these times. we compile the assessment information to determine the skills to target and the specific intervention strategies with each child and their parent. second, parent education strategies can introduce new concepts to the parent. parents can receive planning information via email, phone, online modules, or mail, such as providing a list of simple steps that will be implemented or providing instructions on how to prepare for the session (e.g., what items to have available). another helpful element can be video examples of intervention implementation for parents to view [43•] , although this requires video release permission from families. third, parents need hands-on experience with implementing strategies with feedback while providing the child with numerous opportunities to respond. while this phase can seemingly occur in different ways, providing some elements of live coaching or closely timed asynchronous feedback can be helpful. fourth, the parent should be given opportunities to expand on their use of intervention strategies to support increasingly complex skills for their children [45] . interventionists should prioritize skills that are important to the family and that promote critical points of social communication development for the child. some pivotal social communication skills that are foundational for later learning include initiations, imitation, the ability to make requests and choices, naming, responding to requests, and joint attention [46] . as children progress in communication competence, fluency and expansion of communication skills should occur, such as conversational skills. due to the covid-19 pandemic, some government agencies have temporarily relaxed certain requirements to allow providers to use telehealth to connect with patients. however, providers should still consider existing requirements and the importance of security of protected health information. for guidance, regulating agencies release recommendations, policies, and resources for adherence to the health insurance portability and accountability act [47] and the family educational rights and privacy act (ferpa; 20 u.s.c. § 1232g; 34 cfr part 99) [48] , as well as ethical considerations on the use of telehealth. regional telehealth resource centers provide a broad range of telehealth resources (e.g., national consortium of telehealth resource centers) https://www. telehealthresourcecenter.org/). many video-conferencing platforms are successfully used for telehealth implementation. examples from the reviewed studies included gotomeeting®, vsee®, and vidyo®. when selecting a synchronous platform, consider security, hipaa and/or ferpa, compliance, and features of the platform that enhance usability for the end-user. the use of a virtual private network provides another layer of secure connection [21•] . capturing high-quality sound during video sessions is another area of consideration. external microphones can enhance the quality of sound, particularly when targeting child communication (e.g., vocalizations) that may be difficult to hear when the child is not close to the computer or telehealth device [20•] . synchronizing sound and volume during video recordings of telehealth sessions is one area in particular that has been challenging for our team, at times. we have remedied these problems through troubleshooting sound settings outside of intervention sessions with taking test videos of telehealth calls. we then use a dedicated computer with the sound settings set to these tested adjustments and clearly posted instructions not to adjust the sound settings for interventionists who use the computer to run telehealth sessions. despite the clear benefits of providing parent-mediated intervention via telehealth, it is vital that parents alone are not responsible for their children's intervention. sole reliance on this type of model poses several potential issues: (a) low intervention intensity, (b) a high level of commitment with the potential of additional stress on families, and (c) missed opportunities for the child to receive intervention from professionals with greater levels of expertise and experience and to generalize skills with people outside of their family. resultantly, many experts caution that telehealth interventions based on parent implementation should be viewed to improve and augment an intervention while in combination with intervention delivered by professionals [13•, 23•] . appropriately for an emerging area of research, the majority of the studies in the current review focused on feasibility, including measures such as fidelity, acceptability, and early efficacy data [43•] . overall, the majority of studies yielded promising results. this conclusion is consistent with another recent review related to asd and telehealth [49] . in this previous review, the authors concluded that while results were promising, there was a lack of randomized control trial (rct) designs [49] . thus, they indicated a need to move towards studying effectiveness. in the current review, three studies (13.6%) used rcts. results of these studies were positive, yet mixed. parsons et al. found an increase in expressive language for a group of children who received the therapy outcomes by you app [25• ]. vismara et al. did not find a treatment effect on child social communication skills when comparing a parent-training version of the early start denver model with a group in a community sample (both groups improved); however, parents' fidelity and ratings of satisfaction improved more in the treatment group [13•] . as previously discussed, ingersoll et al. found a treatment effect on some, but not all, child measures and an impact on parent measures in a therapist-assisted telehealth intervention compared to a self-directed intervention [35•] . it is important to consider how telehealth can integrate into established intervention models to address barriers and to optimize outcomes for children and families. the short-and longterm cost-effectiveness of telehealth to deliver social communication intervention for young children with asd warrants further investigation. there are no clear cost-benefit measures in the studies in our current review. however, previous research indicates a comparable level of efficacy of functional analysis and fct delivered via telehealth as with other inperson settings, with cost savings reported in the settings that included telehealth and the most substantial cost savings when families were supported in-home via telehealth [14] . cost analysis needs to be applied to other models of telehealth. for example, the time lag that typically follows after a child is identified as potentially having asd to when the child receives a diagnosis and then begins intervention is often fraught with delays. this often results in children waiting for long periods of time prior to beginning intervention. in minnesota, with a cohort of medicaid-enrolled children, for example, this gap was estimated at 8.99 months of delay [4] . our research team focuses on investigating parent-mediated intervention via telehealth coaching as a supplement to bridge these delays. if future studies examined the potential cost savings of this type of model, the short-term impact on the cost of the treatment may initially be higher, as more families could access intervention when they historically have not. however, in cost-effectiveness studies of comprehensive (and seemingly expensive) early intervention models, the long-term cost savings far offset the costs of the interventions themselves [50, 51] . piccininni et al. estimated that if wait times to accessing early intervention were eliminated in ontario, canada, the lifetime savings would be $267,000 per individual [50] . supplemental models of telehealth to enhance and improve early intervention should be a continued area of future research and should include cost-benefit comparisons that take into account the potential for long-term cost savings. there is a similar potential for expansion of telehealth into early childhood education. to embed telehealth into this model potentially allows for home visits to occur more frequently or for expanding center-based programs to include a home connection component. these examples could increase the dosage of the interventions, allowing educators to see children multiple times per week and to serve children across multiple settings. meadan et al. demonstrated feasibility of coaching an early childhood specialist based in an early childhood center to coach families in their homes [43•] . however, this model would need to be tested at a larger scale to inform its impact on feasibility and effectiveness for children, families, and educators. researchers are incorporating new technological developments into novel intervention delivery approaches. when reviewing the recent literature, we screened a large number of studies that included keywords based on virtual reality. these studies did not meet our inclusion criteria due to a missing interaction between a tele-provider and a tele-user or including participants in the wrong age range. however, examples in the literature are beginning to emerge, such as the use of virtual reality in facial affect recognition of adolescents with asd [52] . there are two other telehealth applications that did not emerge in our search of the literature: (a) remote monitoring, in which technology allows a tele-provider to monitor the tele-user via technology (e.g., wearable technology to collect heart rate data [44] , and (b) mhealth, the use of mobile technology to share health and public health information (e.g., text alerts to notify tele-users with a chronic condition to refill a medication). there may be particular relevance for future exploration of remote monitoring to monitor speech samples for children with asd or other home-based measures. we anticipate that over the next 5 years, there will be a greater focus in these areas. conflict of interest the authors declare that they have no conflicts of interest. please note that we opted to include an additional article from our team [18• ] that was not located in the initial search but does meet the inclusion criteria. we used examples from this work to report experience in interventions delivered via telehealth from our team. we also included a study from january, 2020 (suess et al., 2020) particular interest, published recently, have been highlighted as: • of importance council on children with disabilities, section on developmental and behavioral pediatrics. identification, evaluation, and management of children with autism spectrum disorder using participant data to extend the evidence base for intensive behavioral intervention for children with asd applied behavior analytic intervention for asd in early childhood: meta-analysis, meta-regression and dose-response meta-analysis of multiple outcomes delay to early intensive behavioral intervention and educational outcomes for a medicaidenrolled cohort of children with autism disparities in diagnosis and access to health services for children with autism: data from the national survey of children's health access to diagnosis and treatment services among latino children with autism spectrum disorders sociodemographic disparities in intervention service utilization in families of children with autism spectrum disorder prevalence of asd spectrum disorder among children aged 8 years-asd and developmental disabilities monitoring network, 11 sites training teachers to assess the challenging behaviors of students with asd using video tele-conferencing using telemedicine to conduct behavioral assessments using desktop videoconferencing to deliver interventions to a preschool student with autism dissemination of evidence-based practice: can we train therapists from a distance? this study compared to the effects of parent training on the early start denver model delivered via telehealth with a group receiving community intervention. the study used both synchronous and asynchronous modalities to coach parents to increase child spontaneous utterances telehealth and autism: treating challenging behavior at lower cost conducting functional analyses of problem behavior via telehealth conducting functional communication training via telehealth to reduce the problem behavior of young children with autisms american psychiatric association. diagnostic and statistical manual of mental disorders (dsm-5®) teaching communicative responses with a speech-generating device via telehealth coaching this study evaluated the effects of training parents in discrete trial training through a combination of in-person and synchronous telehealth modalities on maintenance of the parent implementation and targeted child skills this study used telehealth to deliver a parent-training program for families living in rural areas with low-speed internet access. parents were coached with synchronous methods to increase child social attending and requesting feasibility of parent training via telehealth for children with asd spectrum disorder and disruptive behavior: a demonstration pilot interventionist acquisition of incidental teaching using pyramidal training via telehealth this study used telehealth to train clinicians in implementing incidental teaching targeted to child requests this study used telehealth to train early childhood special education behavior specialists to support parent-implemented behavioral procedures and interventions a randomised controlled trial of an information communication technology delivered intervention for children with autism spectrum disorder living in regional australia brief report: a pilot online pivotal response treatment training program for parents of toddlers with autism spectrum disorder this study used telehealth to train parents to implement powr to increase child communication this international study investigated a training model of telehealth to coach parents on functional analysis and fct across multiple countries to decrease challenging behavior and to increase child requests this study examined the effects of parent-implemented functional communication training delivered via synchronous telehealth coaching on child requests during routines this study coached parents synchronously via telehealth to implement assessment and intervention (functional communication training) procedures to reduce self-injurious behaviors and to increase child requests evaluating the treatment fidelity of parents who conduct inhome functional communication training with coaching via telehealth this study examined the use of parent-implemented functional analyses and functional communication training with synchronous coaching via telehealth this study examined the use of telehealth to coach parents synchronously to implement functional analyses and fct to decrease challenging behavior and to increase child requests naturalistic developmental behavioral interventions: empirically validated treatments for autism spectrum disorder comparison of a self-directed and therapist-assisted telehealth parent-mediated intervention for children with asd: a pilot rct a mixedmethod evaluation of the feasibility and acceptability of a telehealth-based parent-mediated intervention for children with autism spectrum disorder this international study examined the use of telehealth to train parents on implementation of a sequence of naturalistic steps for child communication initiations and responses intercontinental telehealth coaching of therapists to improve verbalizations by children with autism functional analysis of problem behavior: a practical assessment guide: sycamore publishing company identifying potential communicative acts in children with developmental and physical disabilities vineland adaptive behavior scales, (vineland-3). antonio: psychological corporation use of a structured descriptive assessment methodology to identify variables affecting problem behavior this study examined the effects of parent-implemented naturalistic intervention delivered with telehealth coaching on their child teaching social communication to children with autism: a practitioner's guide to parent training and a manual for parents pivotal response intervention ii: preliminary long-term outcome data health insurance portability and accountability act of 1996. public law the family educational rights and privacy act of 1974. student records management: a handbook a systematic review of telemedicine in autism spectrum disorders cost-effectiveness of wait time reduction for intensive behavioral intervention services in ontario assessing the utility of a virtual environment for enhancing facial affect recognition in adolescents with asd cost comparison of early intensive behavioral intervention and special education for children with asd remote patient monitoring a comprehensive study publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-326532-2ehuuvnx authors: götzinger, florian; santiago-garcía, begoña; noguera-julián, antoni; lanaspa, miguel; lancella, laura; calò carducci, francesca i; gabrovska, natalia; velizarova, svetlana; prunk, petra; osterman, veronika; krivec, uros; lo vecchio, andrea; shingadia, delane; soriano-arandes, antoni; melendo, susana; lanari, marcello; pierantoni, luca; wagner, noémie; l'huillier, arnaud g; heininger, ulrich; ritz, nicole; bandi, srini; krajcar, nina; roglić, srđan; santos, mar; christiaens, christelle; creuven, marine; buonsenso, danilo; welch, steven b; bogyi, matthias; brinkmann, folke; tebruegge, marc title: covid-19 in children and adolescents in europe: a multinational, multicentre cohort study date: 2020-06-25 journal: lancet child adolesc health doi: 10.1016/s2352-4642(20)30177-2 sha: doc_id: 326532 cord_uid: 2ehuuvnx background: to date, few data on paediatric covid-19 have been published, and most reports originate from china. this study aimed to capture key data on children and adolescents with severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection across europe to inform physicians and health-care service planning during the ongoing pandemic. methods: this multicentre cohort study involved 82 participating health-care institutions across 25 european countries, using a well established research network—the paediatric tuberculosis network european trials group (ptbnet)—that mainly comprises paediatric infectious diseases specialists and paediatric pulmonologists. we included all individuals aged 18 years or younger with confirmed sars-cov-2 infection, detected at any anatomical site by rt-pcr, between april 1 and april 24, 2020, during the initial peak of the european covid-19 pandemic. we explored factors associated with need for intensive care unit (icu) admission and initiation of drug treatment for covid-19 using univariable analysis, and applied multivariable logistic regression with backwards stepwise analysis to further explore those factors significantly associated with icu admission. findings: 582 individuals with pcr-confirmed sars-cov-2 infection were included, with a median age of 5·0 years (iqr 0·5–12·0) and a sex ratio of 1·15 males per female. 145 (25%) had pre-existing medical conditions. 363 (62%) individuals were admitted to hospital. 48 (8%) individuals required icu admission, 25 (4%) mechanical ventilation (median duration 7 days, iqr 2–11, range 1–34), 19 (3%) inotropic support, and one (<1%) extracorporeal membrane oxygenation. significant risk factors for requiring icu admission in multivariable analyses were being younger than 1 month (odds ratio 5·06, 95% ci 1·72–14·87; p=0·0035), male sex (2·12, 1·06–4·21; p=0·033), pre-existing medical conditions (3·27, 1·67–6·42; p=0·0015), and presence of lower respiratory tract infection signs or symptoms at presentation (10·46, 5·16–21·23; p<0·0001). the most frequently used drug with antiviral activity was hydroxychloroquine (40 [7%] patients), followed by remdesivir (17 [3%] patients), lopinavir–ritonavir (six [1%] patients), and oseltamivir (three [1%] patients). immunomodulatory medication used included corticosteroids (22 [4%] patients), intravenous immunoglobulin (seven [1%] patients), tocilizumab (four [1%] patients), anakinra (three [1%] patients), and siltuximab (one [<1%] patient). four children died (case-fatality rate 0·69%, 95% ci 0·20–1·82); at study end, the remaining 578 were alive and only 25 (4%) were still symptomatic or requiring respiratory support. interpretation: covid-19 is generally a mild disease in children, including infants. however, a small proportion develop severe disease requiring icu admission and prolonged ventilation, although fatal outcome is overall rare. the data also reflect the current uncertainties regarding specific treatment options, highlighting that additional data on antiviral and immunomodulatory drugs are urgently needed. funding: ptbnet is supported by deutsche gesellschaft für internationale zusammenarbeit. in late december, 2019, who was notified of an unusual cluster of pneumonia cases in wuhan, china. the disease, later termed covid-19, spread quickly beyond the borders of china, with the first cases in europe being recorded on jan 25, 2020. 1 subsequent investigations identified a novel betacoronavirus now designated as severe acute respiratory syndrome coronavirus 2 (sars-cov-2). 2 currently, there are no antiviral treatment options with proven efficacy, but several randomised controlled trials are investigating agents such as hydroxychloroquine, lopinavir-ritonavir, favipiravir, and remdesivir (eg, nct04336904, nct04328285, and nct04280705). other trials are focusing on immunomodulators, including tocilizumab and anakinra (eg, nct04317092 and nct04330638). to date, data on covid-19 in children and adolescents remain scarce, despite the number of confirmed covid-19 cases now exceeding 8 million globally. 3, 4 most published data originate from china, which cannot necessarily be extrapolated to children in europe and elsewhere. [5] [6] [7] [8] [9] [10] [11] [12] also, existing papers from china contain very few clinical data on children, and most lack details regarding supportive measures required by children with covid-19. similarly, recent epidemio logical reports from europe and north america contain little clinically relevant information. 13, 14 determining the level of support required by children is essential for paediatric service planning during the ongoing covid-19 pandemic. by use of a well established research network, predominately comprising paediatric infectious diseases specialists and paediatric pulmonologists, the aim of this study was to rapidly capture key data on covid-19 in children in europe on a large scale, to aid physicians in europe and in other geographical locations with service planning and allocation of resources. for this cohort study, european members of the paediatric tuberculosis network european trials group (ptbnet)-which currently includes 304 clinicians and researchers, most of whom are based at tertiary or quaternary paediatric infectious diseases or paediatric pulmonology units, across 128 paediatric health-care institutions in 31 european countries [15] [16] [17] [18] [19] [20] -were invited to contribute cases of confirmed sars-cov-2 infection that had been managed at or managed remotely by their health-care institution (including individuals admitted to other hospitals or identified during community screening) before or during the study period. any individual aged 18 years or younger with sars-cov-2 infection confirmed by rt-pcr was eligible for inclusion. a standardised data collection spreadsheet was used by collaborators to record data from their centre. all data were reviewed by three of the investigators (fg, bs-g, and mt), and any inconsistencies and other data queries were clarified with the reporting collaborators. units that did not see any cases before or during the study period were asked to report the absence of cases fulfilling the inclusion criteria at the end of the study period. the study was done over a 3·5-week period, from april 1 to april 24, 2020. the study was reviewed and approved by the ptbnet steering committee, and the human research ethics committees of the university of bochum, germany (19-6545-br), the hospital gregorio marañon, spain (ceim hgugm-177/20), and the city of vienna, austria (ek 20-071-vk). the study was conducted in accordance with the declaration of helsinki and its subsequent evidence before this study we searched medline on may 7, 2020, through the pubmed interface to identify publications describing clinical studies in children with covid-19. to ensure a broad search, the search terms used were "(child or children or pediatric or paediatric) and covid-19". no additional limits were set. this search yielded 809 papers: 104 case reports or case series; 38 epidemiological reports; 66 guidelines and consensus statements; 184 reviews, perspectives, or editorials without original data; and 53 letters; 332 were unrelated to children with covid-19. 22 papers presented original data, but exclusively in adults. only ten papers reported clinical studies in children with covid-19: eight papers originated from china, one from spain, and one from italy. the study by tagarro and colleagues was reported in letter format, and only included 41 children with confirmed severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in madrid. the study from italy by parri and colleagues was also reported as a letter and included 100 cases across several italian hospitals. however, the study only featured a single patient who required mechanical ventilation, and consequently very few data on children with covid-19 at the severe end of the disease spectrum. to our knowledge, this study is the first multinational, multicentre study in children with covid-19, and provides a detailed overview on sars-cov-2 infection in children in europe during the initial peak of the pandemic, which was facilitated by a collaboration of 82 units across 25 european countries. the study has several key findings. first, the data show that covid-19 is generally a mild disease in children, including infants. second, the study found that a substantial proportion (8%) of children develop severe disease, requiring intensive care support and prolonged ventilation. several predisposing factors for requiring intensive care support were identified. third, the study confirms that fatal outcome is rare in children. there was considerable variability in the use of drugs with antiviral activity as well as immunomodulatory medication, reflecting current uncertainties regarding specific treatment options. this study confirms previous reports from china suggesting that the case-fatality rate of covid-19 in children is substantially lower than in older adult patients. however, some children develop severe disease and require prolonged intensive care support, which should be accounted for in the planning of health-care services and allocation of resources during the ongoing pandemic. finally, the findings highlight that data on antiviral and immunomodulatory drugs are urgently needed from well designed, randomised controlled trials in children, to enable paediatricians to make evidencebased decisions regarding treatment choices for children with severe covid-19. amendments. no personal or identifiable data were collected during the conduct of this study. a confirmed case was defined as a patient in whom sars-cov-2 was detected in any clinical sample (respiratory tract, blood, stool, or cerebrospinal fluid) by rt-pcr. pcr testing was done as part of routine clinical care, and therefore done according to local testing guidelines in place at the time. date of symptom onset was defined as the day when the first symptom or sign occurred, and date of diagnosis as the day when sars-cov-2 was first detected. pyrexia was defined as a body temperature at least 38·0°c. the index case was defined as the most likely source case based on history; if multiple family members were affected, the person who displayed symptoms first was recorded. diagnosis of upper respiratory tract infection was based on clinical signs and symptoms, encompassing any of the following: coryza, pharyngitis, tonsillitis, otitis media, or sinusitis. lower respiratory tract infection was based on clinical signs and auscultation findings. inotropic support was defined as administration of dopamine, dobutamine, epinephrine, or norepinephrine by continuous infusion. non-parametric two-tailed mann-whitney u tests were used to compare continuous variables and χ² or fisher's exact tests to compare categorical variables, as appropriate. in children younger than 2 years, age was calculated as fraction of a whole year (365 days); from 2 years of age, age was rounded to the nearest year. the 95% ci around the case-fatality rate (cfr) was calculated with the wald method. normality of data distribution was assessed with the shapiro-wilk test. the clinical endpoint was the need for admission to an intensive care unit (icu; either neonatal or paediatric intensive care). the association of baseline characteristics and clinical findings with icu admission was initially evaluated using univariable logistic regression. subsequently, multivariable logistic regression analysis with the backward stepwise method was used to explore variables that were independently associated with icu admission. only variables that were significant in univariable analyses were introduced into the model. factors associated with drug treatment for covid-19 were also explored with univariable analysis. all probabilities are two tailed. p<0·05 was considered statistically significant. all analyses were done with prism (version 8.0; graphpad, la jolla, ca, usa) and spss (version 25.0; ibm, armonk, ny, usa). the funders had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript. the corresponding author had full access to all the data and had the final responsibility for the decision to submit for publication. 585 cases of sars-cov-2 infection were reported from 77 health-care institutions located in 21 european countries: austria, belgium, bulgaria, croatia, denmark, estonia, germany, greece, hungary, ireland, italy, lithuania, norway, portugal, slovakia, slovenia, spain, sweden, switzerland, turkey, and the uk (figure 1). three cases did not meet the inclusion criteria (one 21-year-old individual and two individuals diagnosed with covid-19 based on serological testing, but pcr negative). five participating units in the netherlands, moldova, ukraine, and russia reported not having encountered any cases. 582 individuals with pcr-confirmed sars-cov-2 infection were included in the final analyses. 454 (78%) were contributed by tertiary or quaternary health-care institutions, whereas 54 (9%) had been diagnosed in secondary and 74 (13%) in primary health-care settings. the median age of the study population was 5·0 years (iqr 0·5-12·0), ranging from 3 days to 18 years (table) . age was non-normally distributed (w=0·8710; p<0·0001), with 170 (29%) participants younger than 12 months (figure 2). the sex ratio was 1·15 males to every female. the most common source of infection was a parent, considered the index case in 324 (56%) individuals; for 24 (4%) individuals, the most probable index case was a sibling. in the remaining 234 (40%) individuals, the index case was a person outside of the immediate family or unknown. 363 (62%) individuals were admitted to hospital and 48 (8%) required admission to an icu for additional support, corresponding to 13% of those admitted to hospital. 437 (75%) individuals had no pre-existing medical conditions. among the remaining 145 (25%) individuals, the most common conditions were chronic pulmonary disease (29 individuals, of whom 16 had asthma and six bronchopulmonary dysplasia), followed by malignancy (27 individ uals, of whom 14 had leukaemia or lymphoma and 11 had solid tumours), neurological disorders (26 individuals, of whom nine had epilepsy and eight had cerebral palsy), congenital heart disease (25 individuals), chromosomal abnormalities (ten individuals, of whom eight had trisomy 21), and chronic kidney disease (nine individuals; table). 17 (3%) individuals had two or more pre-existing medical conditions. 29 (5%) individuals were receiving immunosuppressive medication at the time of covid-19 diagnosis (table) . three (1%) had a previously diagnosed immunodeficiency, comprising common variable immunodeficiency, congenital neutropenia, and schimke immuno-osseous dysplasia. 25 (4%) individuals were receiving chemotherapy at the time of their diagnosis or had received chemotherapy in the preceding 6 months. three (1%) had previously undergone human stem cell transplant. pyrexia was the most common sign at presentation, observed in 379 (65%) individuals (table). approx imately half had signs or symptoms of upper respiratory tract infection and approximately a quarter had evidence of lower respiratory tract infection; 128 (22%) had gastrointestinal symptoms. 40 (7%) individuals with gastrointestinal symptoms had no respiratory symptoms; the majority (65%; n=26) of these individuals had pyrexia. 92 (16%) individuals were asymptomatic. dates when sars-cov-2 infection was confirmed by rt-pcr in the study population are summarised in figure 3 . the median interval between symptom onset and diagnosis was 2 days (iqr 1-4; range 0-23); in the baseline characteristics in the entire cohort and by requirement of icu admission majority (n=391; 67%) of cases, the interval was no more than 3 days. in eight cases, sars-cov-2 infection was confirmed before any signs or symptoms were presentmainly neonates born to sars-cov-2-positive mothers and household members of symptomatic adults with confirmed covid-19. a chest x-ray was done in 198 (34%) patients. of those, 93 (47%) had changes consistent with pneumonia (table). ten (5%) had changes suggestive of acute respiratory distress syndrome (ards), all of whom required mechanical ventilation. in 29 (5%) patients, additional viruses were detected in respiratory samples, comprising enterovirus or rhinovirus (n=18), influenza virus (n=5), parainfluenza virus (n=3), adenovirus (n=3), respiratory syncytial virus (rsv; n=2), bocavirus (n=2), and coronavirus nl63, coronavirus hku1, coronavirus oc43, and human metapneumovirus (n=1 each). in 22 patients one virus was detected in addition to sars-cov-2; in six patients, two additional viruses were detected simultaneously; and in one patient, three were detected. patients with one or more viral co-infections were more likely to have signs or symptoms of upper or lower respiratory tract infection at presentation compared with those in whom no additional viral agent was identified (appendix p 1). furthermore, individuals with viral co-infection were significantly more likely to require icu admission, respiratory support, or inotropic support. 507 (87%) individuals did not require respiratory support at any stage. 75 (13%) patients required oxygen support: 31 (5%) were started on continuous positive airway pressure (cpap) and 25 (4%) on mechanical ventilation (including 14 who had been managed with cpap initially). the median duration of mechanical ventilation was 7 days (iqr 2-11; range 1-34). one (<1%) patient was started on extracorporeal membrane oxygenation. 19 (3%) patients required support with inotropes. when comparing individuals by their requirement of icu admission, we found that patients who required icu admission were younger than those who did not (ie, individuals in the community and those admitted to hospital but not needing icu support), but this was not statistically significant (table; figure 2 ). in univariable analysis, being younger than 1 month of age, male sex, pre-existing medical conditions, pyrexia, signs or symptoms of lower respiratory tract infection, radiological changes suggestive of pneumonia or ards, and viral coinfection were associated with icu admission (table) . in multivariable analysis, the factors that remained associated with icu admission were being younger than 1 month (odds ratio [or] 5·06, 95% ci 1·72-14·87; p=0·0035), male sex (2·12, 1·06-4·21; p=0·033), signs or symptoms of lower respiratory tract infection at presentation (10·46, 5·16-21·23; p<0·0001), and presence of pre-existing medical conditions (3·27, 1·67-6·42; p=0·0015). the most commonly used drug with antiviral activity was hydroxychloroquine, used in 40 (7%) patients, followed by remdesivir, which was used in 17 (3%) patients. lopinavir-ritonavir was used in six (1%) patients and oseltamivir in three (1%), two of whom had influenza virus co-infection. three (1%) patients received two drugs with antiviral activity and one (<1%) patient received three; all four patients had ards on chest x-ray. no patient received chloroquine, favipiravir, zanamivir, or ribavirin. with regard to immunomodulatory medication, 22 (4%) patients received systemic corticosteroids, seven (1%) intravenous immunoglobulin, four (1%) tocilizumab, three (1%) anakinra, and one (<1%) siltuximab. in univariable analysis, factors associated with treatment initiation of drugs with antiviral or immunomodulatory activity comprised pre-existing malignancy (or 6·3, 95% ci 2·8-14·2), cardiac disease (4·2, 1·8-10·0), or respiratory disease (6·5, 3·0-14·2); immuno suppressive therapy at presentation (6·5, 3·0-14·2) or recent chemo therapy (6·1, 2·6-14·1); radiological findings suggestive of pneumonia (4·5, 2·3-8·6) or ards (22·3, 2·7-180·5); and viral coinfection (5·5, 2·5-12·2; all p<0·0001; appendix p 2). four patients, all older than 10 years, had a fatal outcome (cfr 0·69%, 95% ci 0·20-1·82), with death occurring at 3, 9, 11, and 17 days after symptom onset. two patients had no known pre-existing medical conditions; one had a cardiorespiratory arrest before arrival at the hospital and resuscitation was unsuccessful and the other died while being mechanically ventilated in icu. the third patient had undergone human stem cell transplant 15 months earlier. the fourth patient was managed palliatively (without intubation), due to the severity of their pre-existing medical conditions. the remaining 578 patients were alive when the study closed. 93 (16%) individuals never developed clinical symptoms. in 460 (80%) individuals, all symptoms had resolved without apparent sequelae, whereas 25 (4%) were still symptomatic or were requiring respiratory support when the study closed. to our knowledge, this is the first multinational, multicentre study on paediatric covid-19, and also the largest clinical study in children outside of china to date. the inclusion of such a substantial number of cases was made possible by involving a large number of specialist centres across europe via a well established collaborative paediatric tuberculosis research network, allowing this study to provide one of the most detailed accounts of covid-19 in children and adolescents published to date. it is important to highlight that this study has primarily captured data from children and adolescents who were seen or managed within the hospital setting, and that the majority of participating units were part of tertiary or quaternary health-care institutions. consequently, the study population is likely to primarily represent individuals at the more severe end of the disease spectrum. notably, a recent letter summarising 171 pcr-confirmed cases in wuhan suggests that close to 20% of children and adolescents with sars-cov-2 infection are asymptomatic. 10 at the time our study was conducted, testing capacity for sars-cov-2 in many european countries was lower than clinical demand, and therefore many children with symptoms consistent with covid-19 in the community were not tested and consequently not diagnosed. nevertheless, our data indicate that children and adolescents are overall less severely affected by covid-19 than adults, particularly older patients. previous, large-scale data suggest that the cfr in adults older than 70 years is close to 10%, 6 potentially due to immuno senescence. 21 it is reassuring that our data show that severe covid-19 is uncommon in young children, including infants, despite their immune maturation being incomplete, 22, 23 with only few requiring mechanical ventilation. it was striking that all children who died in our cohort were older than 10 years. the centers for disease control and prevention (cdc) reported 2572 confirmed cases of covid-19 in individuals younger than 18 years in the usa as of april 2, 2020, representing only 1·7% of the total number of recorded cases (n=149 760). 14 the australian health protection agency has reported that children accounted for only 4% of confirmed covid-19 cases in australia. 24 unfortunately, in the cdc report, clinical data were only available in a small proportion of patients (n=291; 11%). in concordance with our observations, fever and cough were the predominant clinical features at presentation (present in 56% and 54% of individuals, respectively), with similar rates observed in a study from italy. 25 in our cohort almost a quarter of patients had gastrointestinal symptoms, some of whom had no respiratory symptoms, and a substantial proportion of children were entirely asymptomatic. the cdc report also mentions three deaths, 14 but it is unclear how many patients were still hospitalised by the time of publication, so it is difficult to come to firm conclusions regarding the cfr in us children. our data indicate that the cfr in children and adolescents across europe is less than 1%. considering that many children with mild disease will never have been brought to medical attention, and therefore not diagnosed, it is highly probable that the true cfr is substantially lower than the figure of 0·69% observed in our cohort. this hypothesis is further supported by an epidemiological study from china, in which the cfr in individuals aged 19 years or younger was only 0·1% (one death in 965 confirmed cases). 6 furthermore, our data indicate that sequelae related to covid-19 are likely to be rare in children and adolescents. however, after the closure of our study, reports of a hyperinflammatory syndrome affecting children that is temporally, and potentially causally, associated with sars-cov-2 infection have emerged, which has sub sequently been named paediatric inflammat ory multisystem syndrome temporally associ ated with sars-cov-2 (pims-ts; sometimes known as mic-s). 26, 27 further research will be required to characterise this emerging disease entity in detail, and determine the longterm outcome of affected children. importantly, our data show that severe covid-19 can occur both in young children and in adolescents, and that a significant proportion of those patients require icu support, frequently including mechanical ventilation. a small study from madrid also found that four (10%) of 41 children with sars-cov-2 infection required admission to icu. 28 in our cohort, being younger than 1 month, male sex, presence of lower respiratory tract infection signs or symptoms at presentation, and presence of a pre-existing medical condition were associated with increased likelihood of requiring icu admission. our results also show that the majority of children who are intubated due to respiratory failure require prolonged ventilation, often for 1 week or more. this contrasts with observations in children with rsv infection who, on average, only require mechanical ventilation for 5-7 days, 29 but is not dissimilar to observations in children with influenza. 30 this has important implications for service planning, as although the overall demand for icu support might be lower in children than in adults, each patient is likely to occupy icu space for an extended period of time. at this time of intense strain on health-care services worldwide, it is vital that adequate resources are allocated to paediatric services to sustain the provision of high-quality care for children. the observation that, in our study, individuals with viral co-infection (ie, infected with sars-cov-2 and one or more other viral agents) were more likely to require icu support than those in whom sars-cov-2 was the only viral agent identified might have implications for the winter period 2020-21, when the incidence of other viral respiratory tract infections, including rsv and influenza virus infections, is bound to increase. this could result in a greater proportion of paediatric patients with covid-19 requiring icu support than in the cohort described here, as the influenza season 2019-20 was already over in europe before the study commenced. our data also reflect the uncertainties regarding drug treatment options for covid-19. in some countries, including spain and italy, national guidelines were encouraging the use of hydroxychloroquine for selected cases, as reflected in our data, while in other countries, recommendations were more guarded regarding the use of antiviral agents in the absence of robust human data. an expert consensus statement from the usa has emphasised that antiviral treatment should be reserved for patients at the severe end of the disease spectrum, ideally within a clinical trial. 31 overall, the expert panel appeared to favour the use of remdesivir over other agents, based on the currently available data from invitro and animal studies, including in non-human primates, and recent data from compassionate use in humans. 32, 33 the panel members' opinion was split regarding the use of lopinavir-ritonavir, given the disappointing results of a recently published randomised controlled trial. 34 the main limitation of this study relates to the number of variables for which data were collected. in the context of the ongoing covid-19 pandemic, to ensure high levels of participation and avoid diverting substantial time away from clinical front-line duties, a decision was made not to collect detailed data on laboratory parameters or icu interventions. a further limitation was that a variety of inhouse and commercial pcr assays were used across different participating centres, precluding an assessment of diagnostic test performance. also, the number of children receiving antiviral or immunomodulatory treatment was too small to draw meaningful conclusions regarding their effectiveness, which will be addressed by the aforementioned randomised trials. a further limitation is that different countries were using different thresholds to screen for sars-cov-2 at the time the study was done, with some recommending screening of all children admitted to hospital or conducting community screening, whereas others were using more selective testing strategies. despite those limitations, to our knowledge, this study provides the most comprehensive overview on covid-19 in children and adolescents to date. in conclusion, our data, originating from a large number of specialist centres across europe, show that covid-19 is usually a mild disease in children, including infants. nevertheless, a small proportion of children and adolescents develop severe disease and require icu support, frequently needing prolonged ventilatory support. however, fatal outcome is rare overall. our data also reflect the current uncertainties regarding specific treatment options, highlighting that more robust data on antiviral and immunomodulatory drugs are urgently needed. mt conceived of the study. fg, bs-g, sbw, mb, fb, and mt designed the study. fg, bs-g, and mt cleaned and analysed the data, constructed the figures, and wrote the first draft of the manuscript. all authors contributed data to the study, contributed to the data interpretation, critically reviewed the manuscript, and approved the final manuscript for submission. fg has received funding from gilead for research related to hepatitis e. bs-g and mt have received assays free of charge from cepheid for tuberculosis diagnostics projects. mt has received assays at reduced pricing or free of charge from cellestis/qiagen for tuberculosis diagnostics projects, has received support for conference attendance from cepheid, and is currently receiving funding from biomérieux as an investigator of an ongoing tuberculosis diagnostics study. uh reports personal fees from cepi for being a member of the speac-cepi meta-data safety monitoring board for covid-19 vaccine trials, outside of the submitted work. the other authors declare no competing interests. michael buettcher (lucerne children's hospital, lucerne cantonal hospital references 1 who. novel coronavirus (2019-ncov) situation report 5 coronaviridae study group of the international committee on taxonomy of viruses. the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2 who. novel coronavirus (2019-ncov) situation report 148 severe and fatal covid-19 occurs in young children characteristics of pediatric sars-cov-2 infection and potential evidence for persistent fecal viral shedding novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china clinical characteristics and intrauterine vertical transmission potential of covid-19 infection in nine pregnant women: a retrospective review of medical records clinical characteristics of a case series of children with coronavirus disease 2019 severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection in children and adolescents: a systematic review sars-cov-2 infection in children epidemiology of covid-19 among children in china detection of covid-19 in children in early spread of sars-cov-2 in the icelandic population cdc covid-19 response team. coronavirus disease 2019 in children-united states performance of immune-based and microbiological tests in children with tb meningitis in europe-a multi-center paediatric tuberculosis network european trials group (ptbnet) study tuberculosis disease in children and adolescents on therapy with anti-tumor necrosis factor-alpha agents: a collaborative, multi-centre ptbnet study use of xpert mtb/rif ultra assays among paediatric tuberculosis experts in europe availability and use of molecular microbiological and immunological tests for the diagnosis of tuberculosis in europe european shortage of purified protein derivative and its impact on tuberculosis screening practices paediatric tuberculosis network european trials group. shortage of purified protein derivative for tuberculosis testing immunosenescence: a review protecting the newborn and young infant from infectious diseases: lessons from immune ontogeny neonatal innate tlr-mediated responses are distinct from those of adults covid-19 national incident room surveillance team. covid-19 children with covid-19 in pediatric emergency departments in italy hyperinflammatory shock in children during covid-19 pandemic rapid risk assessment: paediatric inflammatory multisystem syndrome and sars-cov-2 infection in children screening and severity of coronavirus disease 2019 (covid-19) in children in high flow nasal cannulae therapy in infants with bronchiolitis characteristics and outcomes of a cohort hospitalized for pandemic and seasonal influenza in germany based on nationwide inpatient data multicenter initial guidance on use of antivirals for children with covid-19/ sars-cov-2 compassionate use of remdesivir for patients with severe covid-19 therapeutic options for the 2019 novel coronavirus (2019-ncov) a trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 we express our gratitude to all colleagues and research personnel involved in the data collection for this study, as well as the members of the human research ethics committees and institutional review boards that have kindly fast-tracked this study. we are also grateful for the kind support of the clinical microbiology & infectious diseases department and the covid-19 group at hospital general universitario gregorio marañón, madrid, spain. this project did not receive specific funding. ptbnet is supported by the deutsche gesellschaft für internationale zusammenarbeit. bs-g is funded by the spanish ministry of health-instituto de salud carlos iii and co-funded by the european union (feder; contrato juan rodés, grant jr16/00036). an-j was supported by "subvencions per a la intensificacio de facultatius especialistes"-departament de salut de la generalitat de catalunya, programa peris 2016-2020 (slt008/18/00193).editorial note: the lancet group takes a neutral position with respect to territorial claims in published maps and institutional affiliations. key: cord-318916-5lzun9bv authors: bruining, hilgo; bartels, meike; polderman, tinca j. c.; popma, arne title: covid-19 and child and adolescent psychiatry: an unexpected blessing for part of our population? date: 2020-07-04 journal: eur child adolesc psychiatry doi: 10.1007/s00787-020-01578-5 sha: doc_id: 318916 cord_uid: 5lzun9bv nan the covid-19 pandemic has left children and adolescents largely unaffected in terms of infectious morbidity and mortality [1] . a greater challenge for this age group is expected in dealing with lockdown and quarantine measures that may push children into crises and destabilize families [2, 3] . especially, when quarantine measures are strict and in the presence of preexisting psychological or psychiatric vulnerabilities [4] [5] [6] , a variety of negative outcomes are to be expected [7] . the covid-19 outbreak has brought new challenges for child psychiatry and mental health services that must be addressed, including national guidelines covering interventions for major public health crises affecting children [8] . these threats and challenges have been rightfully addressed in several commentaries and are currently being studied across the globe [2] . notwithstanding the importance of stressing the need for harm reduction in vulnerable children these days, here, we would like to draw attention to the flipside of the same coin. clinical experience over the last weeks, as well as popular press coverage, shows that the sudden lockdown-induced changes for some children and families reduce daily stress, and sensory exposures and changes family routines. these changes seem to actually reduce child and adolescent mental illness symptoms and even improve well-being. some kids seem to experience alleviation of social and sensory pressure and enjoy the more intensive family life. in this context, the crisis may provide a unique window of opportunity to test long-standing hypotheses on modern life stressors and mental health problems or psychiatric pathogenesis and well-being in developing children and adolescents [9, 10] . at no point in recent history, we have been given a similar chance to evaluate the effects of such a drastic environmental change; not only for the worse, but also for some for the good. for instance, in the netherlands and many other european countries, schools, companies, offices, social and sports clubs were all closed at once, but walks in the park and other outdoor activities were allowed under certain restriction. nuclear family life was forcefully reinvented in many homes in sharp paradox with their usual busy normal routines of balancing work and family. many parents became homebound schoolteachers whilst trying to keep their own professional lives going through online interactions. in the clinic, this led to mixed reports of being tied up in their houses whilst also being able to pay unprecedented amount of time and attention to each other. indeed, another frequent noted observation was that certain patients and families seemed to thrive on the novel situation and context. therefore, we argue that the research agendas currently laid out to register and understand the negative effects of covid-19 on child and adolescent (mental) health should also include the perspective of children and families who are benefitting from the societal changes. taking these heterogenous experiences in mind, we advocate an open scientific mind to covid-19 studies by including 'positive' hypotheses and questions in addition to those testing negative expectations. we suggest that a diverse range of potential effects of the crisis, such as reduction of stress, improved sleep and relaxation, loss of social pressure, more time to think and improved affect. we caution against recruitment bias strategies when merely focusing on increased morbidity and problems. a wider approach will open up opportunities to go beyond studies on mental illness and mental health, by also including mental wellbeing. we should not only aim to help those who suffer, but also support well-being, which is a prerequisite for optimal psychological, social, and physical development. research designs should, therefore, incorporate dimensional symptom evaluations and include multi-directional screenings of potential negative, but also positive influences. hypotheses on both positive and negative responses of children and families to this crisis should be developed to understand the full breadth of impact on modern daily life routines and environments in future post covid-19 times. in all, the covid-19 crisis confronts us with many novel realities and changes and has many insightful messages. for the field of child and adolescent psychiatry, and child development in general, these may be also related to learning how our social and economic environment interacts with child mental health and well-being. comprehensive analysis of psychiatric morbidity in children and adolescents between the pre and post crisis times, in combination with carefully matched population-based control samples, offers an unprecedented window of opportunity to gauge how our current day society impacts well-being; for bad and for good. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. china national clinical research center for respiratory d, national center for children's health bc, group of respirology cpscma, chinese medical doctor association committee on respirology p, china medicine education association committee on p, chinese research hospital association committee on p, china non-government medical institutions association committee on p, china association of traditional chinese medicine cocsh, medicine r, china news of drug information association cocssm the mental health consequences of covid-19 and physical distancing: the need for prevention and early intervention risks to children and young people during covid-19 pandemic lancet institutional care reform commission g (2020) the implications of covid-19 for the care of children living in residential institutions mental health effects of school closures during covid-19 mental health considerations for children quarantined because of covid-19 posttraumatic stress disorder in parents and youth after health-related disasters chinese society of c, adolescent p (2020) mental health services for children in china during the covid-19 pandemic: results of an expert-based national survey among child and adolescent psychiatric hospitals are child and adolescent mental health problems increasing in the 21st century? a systematic review sensory processing sensitivity in the context of environmental sensitivity: a critical review and development of research agenda key: cord-313981-yuh5rwkt authors: burgner, david; richmond, peter title: the burden of pneumonia in children: an australian perspective date: 2005-05-21 journal: paediatr respir rev doi: 10.1016/j.prrv.2005.03.004 sha: doc_id: 313981 cord_uid: yuh5rwkt the burden of pneumonia in australian children is significant with an incidence of 5–8 per 1000 person-years. pneumonia is a major cause of hospital admission in children less than 5 years of age. indigenous children are at particular risk with a 10–20-fold higher risk of hospitalisation compared to non-indigenous children. they also have longer admissions and are more likely to have multiple admissions with pneumonia. there are limited data on pathogen-specific causes of pneumonia, however streptococcus pneumonia is the most common bacterial cause in children under 5 years of age and respiratory syncytial virus (rsv) and influenza are the predominant viral causes in young children. pneumonia due to haemophilus influenza type b (hib) has been virtually eliminated by the introduction of universal hib immunisation. further studies are needed to accurately define the epidemiology of pneumonia due to specific pathogens to help target treatment and immunisation strategies. the burden of respiratory and other infections in australian children reflects the demography of the population, the variations in climate, patterns of migration and the proximity of countries from which less common pathogens may be imported. australia is relatively unique amongst developed industrialised nations: it is comparatively sparsely populated, with the majority of the population concentrated around the southern and eastern seaboard. the total australian population is approximately 20.2 million, 1 predominantly urban and the majority descended from the european migration in the last 200 years. indigenous australians (aboriginal australians and torres strait islanders) have inhabited the continent for at least 4000 years and comprise 2.5% of the total population. 1 the majority of indigenous australians live in deprived socio-economic circumstances, often in remote rural locations. indigenous australians have some of the worst health indicators in the industrialised world. 2 they bear a disproportionate burden of infectious diseases in childhood -and pneumonia is no exception. australia has a large migrant population with over 4.5 million individuals born overseas, equivalent to almost one quarter of the population. 1 the majority of migrants are from other industrialised nations and the epidemiology of infectious diseases in these migrants is likely to be similar to that in non-indigenous australians. in addition, australia currently accepts 12000 refugees under a humanitarian program and many more from refugee-like backgrounds under family reunification programs. 3 the epidemiology of respiratory infections in this population is related to the country of origin or transit, paediatric respiratory reviews (2005) summary the burden of pneumonia in australian children is significant with an incidence of 5-8 per 1000 person-years. pneumonia is a major cause of hospital admission in children less than 5 years of age. indigenous children are at particular risk with a 10-20-fold higher risk of hospitalisation compared to non-indigenous children. they also have longer admissions and are more likely to have multiple admissions with pneumonia. there are limited data on pathogen-specific causes of pneumonia, however streptococcus pneumonia is the most common bacterial cause in children under 5 years of age and respiratory syncytial virus (rsv) and influenza are the predominant viral causes in young children. pneumonia due to haemophilus influenza type b (hib) has been virtually eliminated by the introduction of universal hib immunisation. further studies are needed to accurately define the epidemiology of pneumonia due to specific pathogens to help target treatment and immunisation strategies. ß 2005 elsevier ltd. all rights reserved. previous limited access to adequate health care and the potentially poor vaccination coverage in refugee children. 4 the climate of australia ranges from temperate in the south to large areas of desert in the interior and tropical conditions in the north. the epidemiology of childhood respiratory infections partly reflects these differences, with familiar pathogens occurring frequently throughout the country, but with high incidences of bacterial pneumonia amongst indigenous australians and less familiar pathogens, such as meliodosis, occurring in the northern territory. the close proximity to south-east asia has led to concern (to date largely unfulfilled) of the potential spread to australia of 'new' respiratory diseases, such as avian influenza and severe acute respiratory syndrome (sars). 5 as in other industrialised nations, there has been a substantial decline in infectious disease mortality in australia throughout the twentieth century. in 1907 the mortality rate across all ages from all infectious diseases was 258.9 per 100000 population; 90 years later it was 7.2 per 100000. 6 similar trends are evident in children and are attributed to improvements in sanitation, vaccination and the introduction of antibiotics. in 1996 communicable diseases accounted for 3% of the total disease burden in australia. 6 however, in children infections contribute significantly more to the burden of childhood diseases, although there are no national data. respiratory infections have also declined substantially over the same time period. 6 australia (particularly in western australia) has an impressive resource of linked health-related databases, which provide detailed data on the overall epidemiology of children hospitalised with pneumonia. clearly any data relating to the aetiology of pneumonia should be interpreted with a certain degree of caution, as the discharge diagnosis of pneumonia is usually made on clinical and/or radiological grounds, without microbiological confirmation of the aetiology. 7 much of the australian epidemiological data spans a period where rapid diagnosis of respiratory viral pathogens was not available and diagnostic labels such as 'bronchitis' were more commonly applied than they are currently. however these studies provide useful insights into the overall burden of pneumonia in australian children. in a study of all western australian live births in 1986, 5% of non-indigenous and 17% of indigenous children were admitted to hospital with a diagnosis of pneumonia in the first two years of life. 8 of the indigenous children, 11% had repeated admissions with pneumonia. for all children, low or high birth weight, male sex and measures of social disadvantage (young or unmarried mothers or rural location) were significant risk factors for admission. 8 between 1988 and 1993 in western australia, there were 53311 admissions to hospital with respiratory diseases in children aged up to 14 years, of which 4293 (8.1%) were for pneumonia (table 1 ). 9 pneumonia was second only to asthma as the most frequent admission diagnosis in children beyond one year of age. in indigenous children, the rate of pneumonia was 10-20 times higher than non-indigenous children (table 1) . 9 more recent and partially overlapping data from western australia have examined the burden of childhood pneumonia in the first two years of life in all children born between 1990 and 2000 (k. carville, d. lehmann, r. richmond, n. de klerk and d. burgner, unpublished results). in this cohort of 270068 singleton live births (17366 indigenous births, 252702 non-indigenous births), pneumonia accounted for 4518 hospital admissions, equivalent to 5.8% of all admissions with an infectious diagnosis. almost half of admissions with pneumonia in the first two years of life were in indigenous children, in whom pneumonia accounted for 12.2% of all infectious diagnoses. not only was pneumonia far more common in indigenous children ( fig. 1 ), these children were three times more likely than non-indigenous children to have multiple admissions with this diagnosis. indigenous children with pneumonia also had a longer hospital stay than non-indigenous children, possibly reflecting more severe disease and logistic difficulties with returning families to their remote locations. a retrospective study from suburban sydney assessed the incidence and risk factors for all-cause pneumonia in in this predominantly non-indigenous population the estimated incidence of pneumonia was 7.6 per 1000 personyears. this is comparable to the rate of 5.2 per 1000 person-years reported in non-indigenous children of the same age in western australia. in the former study over 90% of children received antibiotic therapy and 41% were hospitalised. there appeared to be an association with a preceding diagnosis of asthma and increased risk of pneumonia. with some notable exceptions, there is a lack of data on the epidemiology of pneumonia due to specific pathogens in australian children. however, given the ethnic make-up of the australian population, the climate and clinical experience, cautious generalisation of data from other countries is possible. there is increasing awareness that mixed infections, with more than one pathogen, may be important in the aetiology of childhood pneumonia, 10 although this has not been investigated in australia. as in other industrialised countries, group b streptococcus (gbs) is the leading cause of early-onset neonatal infection. 11 pneumonia is the principal clinical manifestation, in contrast to late-onset gbs infection, when meningitis predominates. 12 the incidence of early-onset gbs infection has fallen from 2 per 1000 live births in non-indigenous australians in 1991-1993, to 0.5 per 1000 in 1995-1997. 11 the burden of early-onset gbs disease in indigenous neonates was 2-3 times higher and also showed a similar decline. 11 the fall in the incidence of gbs is due to the increasing introduction of universal screening late in the third trimester and widespread antibiotic prophylaxis, in accordance with international guidelines. 13 interestingly, although only 40% of neonatal gbs occurs in preterm infants, they carry about 80% of the mortality 14 and will not benefit from the screening that occurs in the last few weeks of the third trimester. the pneumococcus is recognised as the most common bacterial cause of community-acquired pneumonia in children, responsible for approximately one third of cases. 15, 16 exact estimates of the burden of disease are hampered by lack of sensitive and specific diagnostic methods in children who have negative blood cultures. 17 the highest incidence of pneumococcal pneumonia is common in children under 5 years of age although a significant proportion of cases occur in older children. in australia, the majority of data relates to pneumococcal pneumonia with bacteraemia in children from the national enhanced invasive pneumococcal disease (ipd) surveillance program. 18 introduction of pneumococcal conjugate vaccine (pcv) was 17.4 per 100000 population, representing 37% of cases of ipd in this age group. 18 the proportion of ipd associated with pneumonia in indigenous children was much higher (72%) compared to non-indigenous children (31%). the overall incidence of bpp in indigenous children was approximately 15-fold higher than in non-indigenous children under 5 years of age. the serotypes responsible for ipd were more varied in indigenous children, with approximately 55% being due to the seven serotypes in the licensed pneumococcal conjugate vaccine (prevnar tm ) compared to 86% in non-indigenous children under 2 years of age. bpp figures clearly underestimate the true burden of pneumococcal pneumonia. in undertaking a cost-effectiveness analysis of pcv in australian children, butler and colleagues estimated the incidence of moderate or severe pneumococcal pneumonia to be 100 per 100000 persons in children under 5 years. 19 vaccine efficacy studies also provide an estimate of the burden of disease. in the pcv efficacy study in northern california, the incidence of chest x-ray proven pneumonia was reduced by 17.7% (95% confidence interval (ci) = 4.8-28.9%) in the intention to treat analysis 20 and a similar level of efficacy was seen in a study of 9-valent pcv in south africa (25% in hiv negative children). 21 the impact of universal pcv in both indigenous and non-indigenous australian children is awaited with interest. the burden of pneumonia due to haemophilus influenzae in australia has not been well defined. the majority of data relates to bacteraemic pneumonia due to haemophilus influenzae type b (hib) in the prevaccination era. hib pneumonia represented 4-8% of invasive hib disease in non-indigenous children in southeastern australia 22,23 but up to 40% of invasive hib disease in indigenous children from the northern territory. 24 the age of onset of bacteraemic pneumonia was much earlier in indigenous children (majority <12 months of age). the epidemiology of bacteraemic hib pneumonia in indigenous children is similar to that in developing countries 25 suggesting that hib was responsible for approximately 20% of severe pneumonia in indigenous children prior to hib vaccination. following the introduction of conjugate hib vaccines, the incidence of bacteraemic hib pneumonia has dramatically decreased in both populations. 26 there are few specific australian data relating to the burden of m. pneumoniae respiratory infection in children. studies from european countries indicate that this pathogen may be responsible for almost one-third of childhood admissions with pneumonia in finland 27 but is much less commonly identified in the uk 28 and the usa. 16 anecdotally m. pneumoniae is thought to be one of the commonest causes of pneumonia in school-age australian children and empiric macrolide antibiotics are widely used in this setting, but this is not evidence-based. interestingly, an australian study suggested that asymptomatic carriage of m. pneumoniae is widespread in children admitted to hospital with non-pneumonic diagnoses, 29 although whether there is significant nosocomial transmission is unknown. similarly, there are no specific studies of c. pneumoniae in australian children. european data suggest this pathogen may be an important cause of pneumonia, especially in children >10 years. 30 a small study of pneumonia in both adults and children from northern australia failed to identify c. pneumoniae. 31 it is likely that this pathogen is underestimated as a cause of pneumonia in australian children. this is an important cause of severe pneumonia, particularly in indigenous children. in one study, from western australia, 69 cases were admitted over a 20 year period, with a decreasing but significant mortality over the study period. 32 there is an increasing prevalence of methicillin-resistant s. aureus (mrsa: both 'local' strains and 'imported' multiresistant strains), particularly in indigenous children, 33, 34 which has clear implications for antibiotic therapy for this pathogen. although tuberculosis (tb) is the world's most prevalent infectious disease, australia has continued to have one of the world's lowest rates. 35 the majority of tb disease occurs in migrants and less commonly in indigenous australians and is predominantly a disease of the aged. 36 tb is reported in few australian children but this is likely to represent a gross under-estimate, given the extreme difficulties in confirming the diagnosis microbiologically in paediatric patients. 37 the prevalence of latent tb, as measured by positive mantoux reactivity, is high, especially in migrants from countries where tb is endemic. in a study of 12-14 year-old sydney children, 2% of the australianborn and 27% of the overseas-born children had a positive mantoux test. 38 the risk of developing tb disease following latent infection may be extremely high in early childhood 39 and remains significant through later childhood and adulthood. 40 active identification of latent tb in recent migrants to australia, especially in children, although not universally performed, would seem prudent. 39, 41 other bacterial pathogens this is a prevalent pathogen in indigenous children from northern australia, who have some of the highest rates of rheumatic fever in the world. 42, 43 streptococcus pyogenes may, therefore, represent a more common cause of pneu-monia in this population than appreciated, although there are no epidemiological studies of its role in pneumonia. melioidosis is an important pathogen in south-east asia and northern australia. 44 in the northern territory the incidence is 5.8 per 100000 population, increasing to 25.5 per 100000 in indigenous australians. 45 it causes pneumonia and septicaemia, together with abscesses in a variety of organs, including the lungs. 44 most infections occur in those with predisposing risk factors, such as diabetes, 44 but it is reported in children from tropical northern australia. 46 the epidemiology of the major paediatric respiratory viruses is generally similar in australian children to that observed in europe and the usa. in industrialised nations, respiratory syncytial virus (rsv) is the predominant cause of viral lower respiratory tract infection in infancy. 47 studies 48, 49 and clinical experience suggest that the same is true in australia. the primary pathology is bronchiolitis, rather than pneumonia. rsv infection is associated with considerable morbidity and mortality, especially in high-risk groups. 47 the epidemiology of rsv appears to be related to meteorological conditions in australia 49 and in neighbouring south-east asian countries. 50 influenza is an important cause of lower respiratory tract infection in australian children, although precise data regarding the size of the problem are lacking. retrospective data suggest that the pattern of epidemics do not necessarily correlate closely with european and usa epidemiology. 51 australia is part of the who global influenza surveillance network (flunet: http://rhone.b3e.jussieu.fr/ flunet/www/), which tracks influenza activity from active reporting from sentinel general practices and publishes regular local and national updates. 52,53 a recent london study indicated that influenza a caused one-third of viral community-acquired pneumonia and 16% of all community-acquired pneumonia. 54 an australian paediatric study suggested that influenza is also an important cause of hospital admission and morbidity and that influenza a affected younger children, whereas influenza b tended to affect those with underlying medical problems. 55 'new' viral infections -severe acute respiratory syndrome (sars) and avian influenza the proximity of australia to the epicentres of newly recognised viral infections (severe acute respiratory syn-drome (sars) and avian influenza), has created considerable concern that these infections may become major public health issues in australia. sars is a newly described coronavirus infection, with a high mortality rate. 56 active sars surveillance has been undertaken in australia since 2003. of the 138 individuals in australia investigated during this period, 111 had 'suspect' and 27 'probable' infection; five of the latter group were reported to the who as likely cases, after other diagnoses were excluded. 5 none of these were children, but given the significant paediatric morbidity reported from neighbouring countries, 57 there is the potential for sars becoming a significant paediatric infection in australia. avian influenza, a viral infection spread from infected birds and poultry, has caused significant morbidity and mortality in asian countries. 58 to date no human cases have been reported in australia but there is considerable potential risk through migration and, to a lesser extent, through adoption of children from overseas. 59 pneumonia is a common disease in australian children and a frequent cause of admission to hospital. whilst australian children suffer from a range of pathogens similar to those experienced by children in industrialised countries in the northern hemisphere, there are several important caveats. in tropical australia, unusual pathogens are encountered and there is the additional risk posed by imported respiratory infections from neighbouring countries. indigenous australians bear a hugely disproportionate burden of many diseases and have a much higher incidence of pneumonia compared to non-indigenous children. the introduction of conjugate hib vaccines decreased the burden of hib pneumonia in both indigenous and non-indigenous children highlighting the importance of vaccination in reducing the burden of pneumonia. the important issues in reducing the burden of pneumonia in australia relate to (1) the impact of newly introduced vaccines, such as the conjugate pneumococcal vaccine, (2) the development of novel vaccines and therapies, especially against common viral pathogens and (3) understanding the causal pathways (and in particular the gene -environment interactions) that underlie the differential severity of essentially ubiquitous pathogens. australia has an impressive epidemiological infrastructure and surveillance networks that will be crucial in addressing these key questions. australian aboriginal child health an issue of access: delivering equitable health care for newly arrived refugee 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type b disease in australia incidence of communityacquired pneumonia in children caused by mycoplasma pneumoniae: serological results of a prospective, population-based study in primary health care community acquired pneumonia--a prospective uk study a survey of nosocomial respiratory viral infections in a children's hospital: occult respiratory infection in patients admitted during an epidemic season chlamydia pneumoniae is an important cause of communityacquired pneumonia in school-aged children: serological results of a prospective, population-based study community acquired pneumonia in north eastern australia--a hospital based study of aboriginal and non-aboriginal patients primary staphylococcal pneumonia in childhood: a review of 69 cases the continuing evolution of methicillin-resistant staphylococcus aureus in western australia emergence of community-acquired methicillin-resistant staphylococcus aureus (mrsa) infection in queensland tuberculosis in australia: bacteriologically confirmed cases and drug resistance tuberculosis notifications in australia diagnosis and treatment of tuberculosis in children the prevalence of tuberculosis infection among year 8 schoolchildren in inner sydney in inconspicuous consumption: disseminated tuberculosis following untreated latent infection incidence of tuberculosis among a cohort of tuberculin-positive refugees in australia: reappraising the estimates of risk missed opportunities for prevention of tuberculosis in victoria multiple strains of streptococcus pyogenes in skin sores of aboriginal australians clinical and epidemiological features of group a streptococcal bacteraemia in a region with hyperendemic superficial streptococcal infection melioidosis in northern australia childhood infections in the tropical north of australia respiratory syncytial virus: a continuing culprit and conundrum clinical severity of respiratory syncytial virus group a and b infection in sydney respiratory syncytial virus: a report of a 5-year study at a children's hospital seasonal trends of viral respiratory tract infections in the tropics influenza epidemics in the united states, france, and australia, 1972-1997 the influenza surveillance program in western australia annual report of the national influenza surveillance scheme influenza a community-acquired pneumonia in east london infants and young children comparison of influenza a and influenza b virus infection in hospitalized children molecular epidemiology of the novel coronavirus that causes severe acute respiratory syndrome severe acute respiratory syndrome among children confronting the avian influenza threat: vaccine development for a potential pandemic emerging infectious disease issues in international adoptions: severe acute respiratory syndrome (sars), avian influenza and measles key: cord-298708-lvahzj59 authors: sahin, ecem; dagli, tolga e.; acarturk, ceren; sahin dagli, figen title: vulnerabilities of syrian refugee children in turkey and actions taken for prevention and management in terms of health and wellbeing date: 2020-07-29 journal: child abuse negl doi: 10.1016/j.chiabu.2020.104628 sha: doc_id: 298708 cord_uid: lvahzj59 background: the syrian crisis, which started in march 2011, has resulted in the displacement of 6.3 million refugees predominantly to neighboring countries in addition to the internal displacement of 6.2 million people. turkey is the country hosting the largest number of refugees in the world with 3.6 million syrian refugees 46 % of which are under 18 years old. objective: the purpose of this article is to conduct a narrative review and analyze the vulnerabilities of refugee children in turkey from the lens of the sustainable development goals (sdg), more specifically sdg goal 3: good health and wellbeing, with a specific focus on syrian refugee children. moreover, this article explores the actions taken to prevent and mitigate issues that arise from these vulnerabilities. method: this narrative review article collected data from various primary and secondary sources on the turkish refugee framework including national and international legislation, governmental and non-governmental data and reports, and scientific papers. results: syrian refugee children in turkey are facing a variety of risks in terms of their health and wellbeing including communicable and non-communicable diseases, post-traumatic stress disorder, depression, family violence, child labor, and child marriage. the measures taken for prevention and response by governmental and non-governmental entities are multilateral and aim to address issues from multiple perspectives including medical, psychosocial, child protection, and legal. conclusions: the interventions and restructuring of the health system in turkey contribute to the sdg number 3 for refugee children. the existence of a legal system which enables refugee access to health, protection, and other social services is key to achieve this goal. however, the existing system could be improved especially through solidifying the legal basis and centralizing the implementation for child and refugee protection. the engagement of all stakeholders to improve the health and wellbeing of refugee children remains vital. on the 30th anniversary of the signature of the convention on the rights of the child (crc), much has been achieved in terms of child rights whereas much is yet to be done, especially for refugee children. there are 25.4 million refugees worldwide, over half of whom are below the age of 18 (unhcr, 2018) . protection, education, health, and access to social services remain crucial issues for displaced children in many parts of the world. within the scope of displacement, the basic rights of children highlighted in the crc such as right to life and development (ohchr, 1989 , article 6), protection from physical or mental violence, injury or abuse, neglect or negligent treatment, maltreatment or exploitation, including sexual abuse (ohchr, 1989, article 19) are often endangered while on the move, in a transit location, and in the target country. since the signing of the crc by 196 countries in 1989, other international efforts which support a more equitable global society with a specific focus on children have emerged. the most recent and prominent one is the sustainable development goals (sdgs), which were launched in 2016. the sdgs are a collection of 17 global goals set as a universal call to action to end poverty, protect the planet and ensure that all people enjoy peace and prosperity (undp, 2019) . although the sdgs are characteristically more encompassing as a development plan rather than a child focused initiative, they specifically target issues which are primarily concerning child rights and wellbeing. indeed, there are 44 child-related indicators integrated across the following sdgs: no poverty (sdg 1), zero hunger (sdg 2), good health and wellbeing (sdg 3), quality education (sdg 4), gender equality (sdg 5), clean water and sanitation (sdg 6), affordable and clean energy (sdg 7), decent work and economic growth (sdg 8), climate action (sdg 13), and peace, justice, and strong institutions (sdg 17) (unicef, 2019) . it is important to note that the indicators developed to measure the progress of sdgs do not specifically mention displacement and refugees (irc, international rescue committee, 2019) except a recent inclusion of an indicator on refugees in the indicator framework: the number of refugees by country of origin as a proportion of the national population of that country of origin (nahmias & baal, 2019) . nevertheless, the sdgs framework gains an additional importance in terms of conflict and forced migration as the sustainability and stability of decent life standards are more likely to be interrupted compared to the situations where these variables are absent. indeed, refugees show significantly lower progress on sdg targets while their disproportionate vulnerabilities remain invisible (irc, international rescue committee, 2019, p.1). the syrian civil war is an example of this gap where the application of sdg principles in governmental and non-governmental levels in syria as well as refugee destination countries remains insufficient. the syrian crisis, which started in march 2011, has resulted in the displacement of 6.3 million refugees to neighboring and developed countries (unhcr, 2018) in addition to the internal displacement of 6.2 million people (unhcr, 2019, p.1). turkey is the country hosting the largest number of refugees in the world with approximately 3.9 million refugees of whom 3.6 1 million of syrian origin (directorate general of migration management (dgmm), m. of i., turkey, 2020) and 46 % of the syrian refugees in turkey are between the ages of 0 and 18 (directorate general of migration management (dgmm), m. of i., turkey, 2020). according to the latest figures announced by the turkish ministry of interior, 405,521 children of syrian origin were born in turkey since 2011 (özdemir, 2019) . the aim of this article will be to conduct a narrative review and analyze the vulnerabilities of syrian refugee 2 children in turkey from the lens of the sdgs, more specifically sdg goal 3: good health and wellbeing, with a specific focus on syrian refugee children. moreover, this article will explore the actions taken to prevent and mitigate issues that arise from these vulnerabilities. in terms of health and wellbeing, several health risks and other vulnerabilities have been observed to affect syrian refugee children significantly in the turkish context since 2011. these vulnerabilities were analyzed in the two groups: (1) health problems, (2) psychosocial wellbeing risks. refugees may face major challenges in sustaining their health due to a variety of reasons including unsuitable living conditions during or after migration, insufficient sanitation conditions, and accessing quality food and potable water (teague, johnston, & graham, 2014; cronin et al., 2008; toole & waldman, 1993; yavuz, 2015; bilukha et al., 2014 kirişçi, 1996) . access to nutritious food, quality housing, and number of people living in the same household. thus, children are faced with the threat of inadequate physical development including wasting and stunting. wasting, assessed via weight for height, indicates a severe weight loss associated with an acute situation such as lack of food or a severe disease. stunting which means low height for age, on the other hand, indicates prolonged and chronic malnutrition (pernitez-agan et al., 2019) . according to syrian family health survey of 2009, overall nutritional situation in syria was poor even before the crisis has started in 2011. in this report, the prevalence of wasting was 9.3 % and stunting was estimated as 23 % (kingori, nasser, abdullahi, & al-asaad, 2015) . to evaluate the nutritional status of syrian refugee children, a study performed in 6 different countries retrospectively reviewed data of the years 2015 and 2016 of routine health assessments of refugee children aged 6-59 months. wasting and stunting prevalences significantly differed among the six countries. the overall prevalence of wasting and stunting were 3.7 % and 9.1 % respectively. in this study, these prevalence rates for the refugee children settled in turkey was 5.1 % and 14.8 % respectively. (pernitez-agan et al., 2019) according to the 2018 report of demographic and health survey -syrian migrant sample conducted by hacettepe university institute of population studies, 17 % of syrian refugee children under 5 years old, in turkey were stunted and 2% were wasted (hips, 2019a) . another study conducted by the same institute in 2018 found that only 6% of turkish children under the age of 5 are stunted. the trend in stunting shows that there is a decrease in stunting of turkish children under 5 years of age, from 12 % in 2008 to 10 % in 2013 10 % in and 6% in 2018 10 % in (hips, 2019b . the comparison of hospital admission studies from different provinces in turkey also facilitates the visualization of the nutritional problems in refugee child health in turkey. in a study which examines the hospital admissions in a tertiary hospital in adiyaman, a northeastern province in turkey with relatively high refugee population (24,766 syrians comprising of 3.97 % of the total population as of june 2019 (directorate general of migration management (dgmm), m. of i., turkey, 2020), 104 babies who were treated in 2015 were examined. the study found that the weight of 19.2 %, of the patients were below third percentile, which is the lower end of the acceptable range in terms of growth. (bucak, almis, benli, & turgut, 2017) . in another study which was conducted between the years 2012 and 2017 in one of the cities with the highest refugee population in the country, gaziantep (437,844 syrians comprising of 21.58 % of the total population as of june 2019 (directorate general of migration management (dgmm), m. of i., turkey, 2020), prevalence of underweight in the patients with a mean age of 4.6 ± 4.15 years was found as 29.1 % (user & ozokutan, 2019) . while the studies differ in their estimations in prevalence of malnutrition in syrian refugee children in turkey, the results indicate that malnutrition is a key issue for syrian refugee children and it is more prevalent in syrian refugee children compared to turkish children. considering the conditions of migration and post-migration, infectious diseases are one of the most prevailing health risks for refugee children. especially children who have not completed their vaccinations and who have not received preventive healthcare services in the host country after migrating may present substantial health risks to both themselves and to the non-vaccinated population in the host country (mipatrini, stefanelli, severoni, & rezza, 2017) . the extended immunization program, which has been in practice throughout turkey since 1981 and provides free of charge vaccination to all children, has achieved a success rate of 96 % vaccine coverage throughout the country (hips, 2019b). meanwhile in syria, the vaccine coverage, which was close to 100 % prior to 2011, has decreased to 66 % in 2018 (who -syria, 2019). the shortcomings of vaccination in the context of conflict and war might become an important health problem leading to increased prevalence of infectious diseases. country-wide data suggests that among syrian refugees living in camps in turkey, 25 % and 33 % were not vaccinated for polio and measles respectively. the percentage of unvaccinated refugees living outside the camps were even higher for these viruses (45 % for polio and 41 % for measles). this poses a public health threat for the population where refugees reside (tayfur et al., 2019) . in addition to problems in decreased coverage for individual vaccines, not completing all age appropriate vaccines is another threat. according to the 2018 demographic and health survey, the rate of children aged between 12-23 months who have completed all age appropriate vaccinations in refugee and non-refugee children were 60 % and 67 % respectively (hips, 2019a). there have not been any reported outbreaks of infectious diseases associated with the lack of vaccination of syrian refugees and the extended immunization program is working towards the immunization of syrian refugee children as well as turkish children. however, the decrease in vaccination rate of children in syria since the start of the conflict and recent low rates of vaccination among refugee children pose a public health risk. 2.1.3. vaccine-preventable diseases 2.1.3.1. poliomyelitis. polio, which was one of the most feared diseases in the early 20th century, was taken under control with discovery of two effective vaccines in 1950s. with global polio eradication initiative, which started in 1988, global incidence of polio cases has decreased by 99 % (polio global eradication initiative, 2019). in 2012, only 223 confirmed cases of polio were reported globally (hamborsky et al., 2015) . turkish health system has worked very hard with vaccination campaigns for polio eradication. last reported case in turkey was in 1998 and no new cases have been reported since then (who -turkey, 2019). eradication program was also effective in syria as vaccination coverage was very high and no cases were present until 2017 when 74 new cases were reported (who -syria, 2019). fortunately, no disease with polio virus has been reported after refugee influx in turkey although as stated above vaccination might have been missed during migration and entering the host country. in the context of conflict and migration, it requires utmost attention to avoid the reemergence of an eradicated disease. 2.1.3.2. measles. measles is a highly communicable disease with complications in approximately 30 % of cases. the complications of measles are most common among children younger than 5 years of age (hamborsky et al., 2015) . the measles vaccine has been in use since the 1960s and vaccination has drastically reduced global measles deaths. although a 73 % drop was observed between 2000-2018 worldwide, measles is still common in many developing countries. the overwhelming majority (more than 95 %) of measles deaths occur in countries with low per capita incomes and weak health infrastructures (who, 2020) . in turkey, measles was a common disease in 2000, with 16,244 cases reported. with successful elimination program, incidence of cases decreased to less than 10 cases/year between 2007 -2010. parallel to increased incidence in european countries after 2012, measles cases started to increase in turkey too. in 2013, 7,405 cases of measles were detected (who turkey statistics, 2019). as a response, catch-up and mop-up measles vaccination campaigns were conducted for turkish citizens and syrian refugees in cities with high refugee population and consequently the number of measles cases decreased to 565 in 2014 (ergönül et al., 2020) . according to turkish ministry of health, intensive immunization efforts have successfully controlled the disease, but virus is known to circulate in the country. (ministry of health, 2019) . in turkey, only 9 cases were reported in 2016 and 84 cases were reported in 2017 (who -turkey, 2019). measles can be controlled through vaccination. as immunization protects 95 % of vaccinated individuals and prevents disease transmission if vaccination coverage is over 83-94 % (doherty, buchy, standaert, giaquinto, & prado-cohrs, 2016) . when coverage is reduced as it was in turkey in 2011, number of cases sharply increased. while the sudden increase in the number of cases in 2013 was not related to syrian refugees, it is likely that the vaccination was not conducted in syria properly. that is why it is important to vaccinate newly arrived refugees to turkey since a susceptible population increases the likelihood for the spread of infection both for immunized individuals as vaccine protection is not 100 % but especially for unvaccinated citizens in the country. hepatitis a is an infection acquired through contaminated food or water and in areas with low socioeconomic levels disease is highly endemic. with increasing hygienic conditions disease prevalence rates show an age shift towards older ages. in turkey, hepatitis a vaccine (hav) was added to childhood vaccination scheme by the end of 2012 with two doses of vaccine performed at 18th and 24th months. incidence rates of hepatitis a in turkey have declined over the past 15 years, due to socioeconomic development and introduction of vaccine (demiray et al., 2016) . in syria, hav vaccination was not included in the national immunization program prior to the start of the conflict. in 2012 and 2013, at the beginning of the conflict, high numbers of hepatitis a cases were reported. a study performed in izmir with syrian refugees admitted to outpatient clinic of a hospital revealed that more than half of the children did not have protective level of antibodies against hepatitis a (köse et al., 2017) . in temporary shelters in turkey, 1,354 hepatitis a cases were diagnosed between 2012 and 2016 and most of the cases were children (ergönül et al., 2020) . hepatitis a outbreak is likely in situations with poor hygiene conditions. since syrian refugee children are not vaccinated against hepatitis a, their protective antibody levels are low. while the incidence in turkish children is low, it is important to vaccinate syrian children to prevent potential outbreaks. . tb is a communicable disease affecting mainly lungs but other organs as well. only a small percentage of people who are infected with mycobacterium tuberculosis develop the disease and for most of the infected people, the infection remains dormant. even so, tuberculosis is still one of the top 10 causes of death (who, 2019). incidence of disease is higher among children with risk factors such as undernutrition. bacille-calmette-guérin (bcg) vaccine which was developed almost 100 years ago, is still the only vaccine against this disease. tuberculin skin testing with purified protein derivates (ppd) is used for diagnosis and it determines exposure to tb bacilli and infection in a person. in turkey, children are vaccinated with bcg vaccine for prevention of tuberculosis with 96 % coverage rate and incidence of disease is 18 per 100,000 population (who turkey statistics, 2019). in syria tb incidence is 20 per 100,000 population. bcg vaccination is available but coverage rates decreased to 81 % from 100 % from 2010 to 2018 (who syria statistics, 2019). refugee children might have a higher risk for tb infection due to this decrease in coverage of bcg vaccine in their countries and they may have disease especially if they have nutritional problems as discussed previously. in a study to evaluate results of ppd test applied at the tuberculosis dispensary between 2012-2015, performed in hatay, one of the border provinces (427,500 syrians comprising of 26.56 % of the refugee population as of june 2019 (directorate general of migration management (dgmm), m. of i., turkey, 2020)), positive ppd reactions and annual risk of tuberculosis infection were found to be more common among syrian refugees compared to local population, more specifically in the 6-18 age group (savaş, barutcu, & yeniçeri, 2018) . another study revealed that in temporary shelters for refugees in turkey, 108 active tuberculosis cases were detected and treated (ergönül et al., 2020) . the presence of active tb cases related to syrian refugees indicate that preventive strategies for tb should be emphasized. refugees are susceptible to other infectious diseases that are not vaccine preventable. between 2012 and 2016, high numbers of incidences were reported in syrian refugees residing in temporary shelters in turkey such as respiratory tract infection (1,299,209 cases), diarrhea (158,058 cases), and bloody diarrhea (59 cases) (ergönül et al., 2020) . a study conducted between 2016 and 2017 examined the hospital admissions of 623 syrian patients in a tertiary pediatric hospital in turkey's capital city ankara (92,073 syrians comprising of 1.67 % of the total population as of june 2019 (directorate general of migration management (dgmm), m. of i., turkey, 2020)). the most common admission reasons were found to be respiratory tract diseases and diarrhea (güngör et al., 2018) . these diseases are likely to have serious consequences in children as they are still among the most common causes of infant mortality (who, 2017). cutaneous leishmaniasis (cl): cl is a disease caused by a protozoan parasite transmitted from human to human by sandfly bites and characterized by chronic skin lesions, leaving permanent scars with deformation of the infected area. outbreaks of cl have been reported in different areas in turkey in the past 3 years, correlated with the influx of syrian refugees. in an analytical cross-sectional epidemiological study of cl cases diagnosed in the gaziantep leishmaniasis diagnosis and treatment center, out of 900 cl patients, 93.8 % (845/900) were syrian citizens and 6.2 % (55/900) were turkish citizens. the disease was more frequent in women with 53.5 % (482/900) and in the age group between 0-20 years with 68.3 % (615/900). the increase in cl frequency is alarming and requires control and prevention measures in highly infected areas (eroglu & ozgoztasi, 2019; zencir & davas, 2014) . early recognition, treatment of cases and vector control measures are essential for prevention. covid-19: during the preparation of this manuscript, a new highly infectious disease "2019 novel coronavirus (covid-19)" has emerged. the "covid-19" outbreak was first identified in december 2019 in wuhan, china and was recognized as a pandemic by the world health organization (who) on 11 march 2020. the government of turkey has reported its first case on the same day and as of june 2020, almost 200,000 confirmed cases were reported. since the specifics of the cases have not been shared publicly and prevalence studies have not been completed at the time of writing this article, it is not clear how many of the reported cases correspond to refugees. however, refugee populations are potentially more susceptible to contracting infectious diseases such as covid-19 as they are more likely to live in overcrowded shelters and substandard conditions (kluge, jakab, bartovic, d'anna, & severoni, 2020) . while the morbidity and mortality of covid-19 cases in children are significantly lower compared to other age groups, the social effects of the outbreak has had negative impacts on the living conditions of syrian families in turkey. although the literature on the impacts of covid-19 on syrian families in turkey is limited at the moment, studies conducted by ngos thus far confirm that syrian refugee families are facing significant challenges including someone in the household losing their job, issues with accessing health services, and having unmet urgent needs (relief international, 2020) . vulnerable groups such as large families or people with disabilities are likely to be disproportionately affected from the disease (danish refugee council, 2020). moreover, unregistered refugees reported fear of arrest or deportation should they approach a hospital (danish refugee council, 2020). as such, covid-19 outbreak presents lower risk for syrian refugee children in terms of direct impact from the disease. however, the general decline in the quality of life due to the outbreak remains to be a significant risk. refugee children and adolescents are exposed to a number of traumatic experiences during war and flight (levy & sidel, 2009 ). related to exposure to traumatic events and post-migration living difficulties refugee children are at higher risk to develop mental health disorders (fazel, reed, panter-brick, & stein, 2012) . while examining the mental health of refugees, risk factors during preflight, flight and post-flight periods have been shown to be related to mainly post-traumatic stress disorder (ptsd), depression, and anxiety disorders. loss of a parent appeared as a risk factor both for ptsd and depression (hasanović, sinanović, selimbašić, pajević, & avdibegović, 2006) . moreover, among the refugee children, the risk for mental health problems is found to be highest for the unaccompanied minors (hodes, jagdev, chandra, & cunniff, 2008) . there is also a dose-response relationship with increasing number of adverse events, the risk for mental health problems is increasing (montgomery, 2008) . moreover, parental psychopathology, such as depression is related to emotional problems among refugee children (kovess-masfety et al., 2016) . the risks related to traumatic events, flight, and post-flight appear quite prominent for the case of syrian refugee children. a study conducted by unhcr in 2015 found that the highest risk for syrian refugee children was psychological concern (51 %) followed by children dropped out of school (25 %) and child labor (11 %) (unhcr, 2015. p. 19) . it is also important to mention that the risks identified in this study, including child labour (habib et al., 2019) , child marriages (el arab & sagbakken, 2019; wringe et al., 2019) and domestic violence (falb, blackwell, stennes, hussein, & annan, 2019; usta, masterson, & farver, 2019) in addition to the aforementioned higher risks, are factors which are likely to influence psychological wellbeing negatively. a study on mental health problems and related risk factors in turkey reported that syrian refugee children have been exposed to a number of traumatic events during war in syria prior to arrival to turkey such as witnessing explosions or gun battles (70 %), to lose someone important to them (56 %), to see dead or wounded people (55 %), or witnessing people being tortured (43 %) (gormez et al., 2018) . consistent with these findings, studies suggest that the prevalence of ptsd symptoms ranges from 18.3 % (gormez et al., 2018) to 50 % (eruyar, maltby, & vostanis, 2018) , and of depression from 19.7 % (ceri, nasiroglu, ceri, & cetin, 2018) to 48 % (kandemir et al., 2018) amongst syrian refugee children in turkey. post-traumatic stress disorder among refugee parents was found to be related to harsh parenting and higher psychological problems among refugee children (bryant et al., 2018) . considering the high estimates of ptsd (alpak et al., 2015; acarturk et al., 2018) , depression (fuhr et al., 2020) , anxiety (fuhr et al., 2020) and somatic distress among syrian refugee adults, and its possible impact on refugee children's mental health, provision of psychosocial interventions to adult refugees becomes an important way to contribute to wellbeing of refugee children. studies also examine the relationship between parenting styles, attachment styles and mental health of refugee children. a previous study with syrian refugee children aged 8-17 living in istanbul showed that perceived secure attachment was positively associated with warmth parenting while negatively associated with rejection parenting. moreover, parental emotional warmth, lower overprotecting and rejecting behaviors were found to be associated with lower levels of emotional and behavioral problems among syrian children (eruyar, maltby, & vostanis, 2020) . associated with the trauma experienced by syrian refugee children due to experiences with conflict and flight as well as parental experiences with trauma, syrian refugee children are at higher risk of mental health problems. in addition to post-war trauma, child labor is also a significant risk factor for refugee children's psychosocial wellbeing (sirin & rogers-sirin, 2015, p.6) . child workers are preferred by employers as cheap workforce (harunoğulları, 2016) . children also learn foreign languages faster than adults which often makes it easier for children to find jobs compared to their parents (hilado & lundy, 2017 ). in turn, child workers are unable to attend school and play as well as often being subjected to physical, emotional, sexual, or economic abuse (ozdemir & budak, 2017, p.216; harunoğulları, 2016) . a study on refugee child labor interviewed 62 refugee children living in one of the border cities with high density of refugee population, kilis (111,608 syrians comprising of 78.3 % of the total population as of april 2020 (directorate general of migration management (dgmm), m. of i., turkey, 2020)). the results of the study suggest that child labor is an important indicator for psychosocial problems in refugee children along with physical and social problems. several factors such as high number of siblings in the household, difficulties in affording rent, and issues with affording basic food needs increase psychological pressure in refugee child workers (harunoğulları, 2016) . 2.2.2.2. domestic violence. refugee children and women are at higher risk for domestic violence which in turn have an effect on their psychosocial wellbeing (rees and pease, 2006) . in a recent systematic review of domestic violence in the refugee families, the ecological model of bronfenbrenner (1977) was used to examine the risk factors for family violence in individual, family, societal and cultural level (timshel, montgomery, & dalgaard, 2017) . parental trauma and mental illness such as ptsd and depression appeared to be significantly related to family violence in the individual level. family level risk factors included interaction between the parent and child, family structure and family acculturation stress (timshel et al., 2017) . the main societal level factor was low socioeconomic level of the household. finally, at the cultural level, patriarchal beliefs were identified as risk factors for family violence in refugee families (timshel et al., 2017) . in a recent study with syrian women in northern syria, emotional, physical, and sexual intimate partner violence were found as predictors of depressive symptoms among women (falb et al., 2019) . moreover, intimate partner violence in syrian families found to be increasing the violence towards children by their mothers (usta et al., 2019) . child marriage stands out as another risk factor for syrian refugee children's mental and physical wellbeing. even though child marriage has been prevalent in syria before the war (save the children, 2014), the occurrence has increased from 13 % to 35 % since the start of the war (unfpa, 2017). child marriage is an issue primarily for girls in both syria and turkey. however, the statistics show that syrian refugee girls are more likely to be married before the age of 18 compared to turkish girls. in a representative study of turkish women aged between 25-49, it was found that 21 % of women were married before the age of 18 and 4% were married before the age of 15 (hips, 2019b). for syrian refugee women, 38 % of the interviewed women were married before the age of 18 and 12 % before the age of 15 (hips, 2019a). since marriage prior to the age of 18 is illegal in turkey, it is difficult to reach accurate statistics of child marriage in turkey. however, academic studies and media forums have consistently flagged child marriage of syrian refugees as a serious issue. in the emergency context, refugee child marriage in turkey is often used as an economic survival mechanism for low-income families by receiving bride wealth in exchange for marrying young girls of the household but also with the perception of providing a better life for their daughters with higher economic prospects (suleymanov, sonmez, unver, & akbaba, 2017, p.243; cetin, 2016, p.209) . child marriage is a multilateral risk factor for wellbeing such as interruption of personal development stemming from leaving school, psychosocial effects of early parenthood, forced sexuality, and premature pregnancies which often lead to unfavorable circumstances including tendency to violence, escaping home, and suicide (suleymanov et al., 2017, pp.237, 243) . about the main reasons of child marriages, a study with syrian refugees in lebanon indicated gender differences. while according to men the main reason was poverty, syrian women accept it as a protection mechanism against sexual violence and harassment (bartels et al., 2018) . same motives for early marriages in syrian refugees were also reported in studies from turkey and jordan (el arab & sagbakken, 2019; wringe et al., 2019). the vulnerabilities of syrian refugee children detailed in the previous sections are closely related to the targets set under sdg 3: good health and wellbeing. namely, provision of universal healthcare, reduction of premature mortality from communicable and non-communicable diseases, and promotion of mental health and well-being are included in the official list of sdg indicators (un statistical commission, 2016) . this section will focus on the actions and measures taken by governmental and non-governmental actors in turkey to improve the health and wellbeing of refugee children on these indicators while also highlighting the challenges and barriers that refugees face. the provision of organized healthcare services specifically for syrian refugees started on april 29, 2011 in yayladagi, hatay which was the first entry point of refugees at the time (tayfur, günaydin, & suner, 2019) . the provision of healthcare services was reported to be accessible in camp settings as the camp residents had direct access to health centers from the earlier years of the crisis whereas urban refugees experienced difficulties in access especially prior to 2014 (zencir & davas, 2014) . the legal basis for the provision of healthcare services to refugees was established with the 2014 regulation on temporary protection and the subsequent 2015 directive on the guidelines for the healthcare service provided to individuals under temporary protection. the prior established the essentials of provision of healthcare services to individuals under temporary protection whereas the latter described the specifics of healthcare provision for individuals under temporary protection including who is eligible to receive and provide healthcare services, remuneration of services, and principles of service provision. healthcare services are highly accessible for refugees and refugee children since the ministry of health ensures their provision to all syrians who are registered with the turkish authorities. the provision of services does not extend to syrians who are not registered. however, emergency care and essential public services are provided in urgent cases and the beneficiaries are referred for registration after their treatment (3rp, 2019, p.60) . the public hospitals have been experiencing issues of capacity due to the high volume of consults from refugees, especially in border cities with a large refugee population, and this issue is causing negative perceptions and reactions from the host community (demir, ergin, kurt, & etiler, 2016, p.91) . to ease the burden on public hospitals, the ministry of health, supported by humanitarian actors, has established migrant health centers (mhc) throughout the country to reach the increased demand. this initiative established a network of mhcs throughout turkey where syrian doctors and nurses offer linguistic-and culturally-sensitive primary healthcare services for the syrian population (3rp, 2018, p.5 ). in 2018, over 580,000 primary health care consultations were provided in the seven refugee health training centers, relating to immunization, maternal care and child health care. 234 syrian doctors, 308 syrian nurses and 629 translators/patient guides were trained and 1,357 syrian health professionals have been employed by ministry of health and serving in migration health centers across the country (3rp, 2018, p.5) . the extended immunization program (detailed under section 2.1) has been expanded to syrian refugee children as well as refugee children of other nationalities since 2017 with the collaboration of ministry of health and unicef (gultac & balcik, 2018; unicef, 2017, p.194) . the immunization campaigns aim to protect children against a variety of communicable diseases such as polio, heamophilus influenza, diphtheria, pertussis, tetanus, measles, mumps and rubella (mmr) and hepatitis b (unicef, 2017). children are screened and registered to the health information system in all provinces, with a focus on the most refugee populated provinces (unicef, 2017) . the immunization campaign has thus far proven successful as there have not been any reported outbreaks of communicable diseases in turkey in connection with lack of immunization of refugee children. while legislation and a formal system for refugee access to healthcare services has been present since 2014, similar efforts have been present for psychosocial services and child protection. the social services under the ministry of family, labor, and social services is the main responsible institution to ensure child protection in turkey. however, since their scope of responsibility is quite wide, there have been more specific initiatives of public-private partnerships for improving the child protection services for the host community as well as the refugee population. even though there is no refugee-specific law on child protection in turkey, syrian refugee children are under the jurisdiction of the child protection law, which aims to regulate the provisions on protection and rights of children with protection needs or children in conflict with the law (republic of turkey, 2005). the child protection law puts forth a series of measures to be taken for children who are in need of protection on counselling, education, childcare, health, and shelter (article 5). in terms of implementation, child advocacy centers (cacs) are established under the ministry of health in turkey. the cacs aim to effectively respond to child sexual abuse cases and minimize the re-traumatization of sexually abused children by completing the judiciary and medical interventions of them in one round and location by trained professionals (bayun & dincer, 2013; republic of turkey, 2012) . the first cac was established in ankara in 2010 as a pilot project and has spread to 42 out of 81 provinces as of april 2020 (ministry of health, 2020) . the turkish prime ministry issued a circular letter in 2012 on the implementation and strengthening of cacs in order to protect vulnerable children with effective implementation of cacs. while cacs are not a refugee-specific project, the number of refugee applications has increased in the last few years. another important child protection project is the establishment of university based child protection centers (ubcpcs). the ubcpc project was kick-started in 2008 by a project technically supported by unicef and since then, 12 ubcpcs were established in universities in different provinces of turkey. the ubcpcs are entities established under public universities in turkey and they consist of an environment to provide education, implementation, and research on diagnosis, treatment, protection, and monitoring of children in need of protection. similar to the cacs, the ubcpcs are also a non-centralized initiative and they are not refugee-specific (akco et al., 2013) . another project on child protection implemented with the contributions of governmental and non-governmental actors is tackling the issues in the court processing of children who have been the subject of violence'. in order to avoid further victimization of children against whom a crime was committed or who witnessed a crime, judiciary interview rooms (jirs) were established in 56 courthouses in 49 provinces in turkey since 2017 in partnership with ministry of justice, unicef, and child protection centers support society (cokmed). the jirs provide a safe environment for interrogating the children to give testimony in a criminal court. the interviews are conducted by an expert (with the presence of a translator if needed) in one room while the judges and public prosecutors in charge of the case follow the interview from a separate room. the judges and public prosecutors provide their inputs and questions via an ear microphone to the expert who in turn asks the question to the child in a trauma-sensitive manner. to this end, in addition to the establishment of the jirs, trainings and supplementary materials are provided to all professionals included in the process to ensure effective child-sensitive implementation (dagli, 2018) . complementary to the above explained jirs project, another project was implemented in 2019 on training arabic-turkish translators on child-sensitive translation in jirs by ministry of justice, unicef, and child protection centers support society (cokmed). the "child-friendly translation project in judicial processes" trained 142 arabic-turkish translators, who are working with refugee children in jirs, in increasing their capacity in terms of their professional roles, responsibilities and limitations about interviewing techniques, special situations, as well as in terms of child friendly terminology and child sensitive approach (dagli & sahin dagli, 2019) . in addition to the projects detailed above, un agencies and other non-governmental organizations support the turkish government in the implementation of healthcare service provision as well as covering the gap for child protection and psychosocial services. the regional refugee and resilience plan (3rp) is the strategic, coordination, planning, advocacy, and programming platform for humanitarian and development agencies to respond to the syria crisis at the regional level and in host countries, namely turkey, jordan, iraq, egypt, and lebanon (3rp, 2020) . in 2018, health and protection actors in 3rp sectors reported their achievements related to child health and protection, as detailed below: the non-governmental health sector actors reported in the 3rp health sector quarterly report 4 for 2018 that as of end of december 2018, the number of refugee children under five years reached through the vaccination programs is around 103,040 (3rp health sector, 2019) . furthermore, more than 72,065 doses of dpt3 vaccines have been administered to refugee children under-oneyear (which amounts to 75 % immunization coverage) and 83,733 doses to the age group of under-five-years (3rp health sector, 2019) . the services provided to refugees by non-governmental organizations include basic health counseling, sexual and reproductive health services, psychiatrist referrals, psychosocial support services, training of medical personnel, and organizing awareness raising activities about hygiene, healthy nutrition, basic health rights, and sexually transmitted illnesses (3rp health sector, 2019) . the non-governmental protection sector actors reported in the 3rp protection sector quarterly report 4 for 2018 that protection services were provided in 56 out of 81 provinces of turkey (3rp protection sector, 2019) . specifically in child protection, 88,387 3 children with protection needs were identified and referred to child protection services, 53,657 4 children were referred to specialized services, and 120,653 5 children participated in structured, sustained child protection or psychosocial support programs (3rp protection sector, 2019) . moreover, non-governmental actors focused on strengthening national systems with the aim to increase refugees' access to protection services by facilitating capacity development activities for staff and establishing social protection desks in peripheral areas (3rp protection sector, 2019) . as an example of public-ngo partnership, a project called 'trauma informed schools' was implemented in 20 schools in two cities of turkey (istanbul and sanlıurfa) by maya foundation in collaboration with the ministry of health. the aim of this project was to increase the knowledge of teachers on psychological trauma related to refugees and its impact on syrian children's mental health (maya foundation, 2019) . furthermore, as part of the same project, refugee children with mental health problems were identified and provided psychosocial intervention. another important example of public-ngo partnership is the conditional cash transfer for education program under the partnership of the ministry of family, labor and social services, the ministry of national education, turkish red crescent and unicef. this project, which was implemented in turkey since 2003, was expanded to syrian refugees in 2017 (unicef, 2020). while this is an education project, it contributes directly to avoid social risks faced by syrian refugee children including child labor and child marriage. the presence of an established system for syrian refugees' access to health and wellbeing and efforts from non-governmental organizations to increase access to these services were detailed in this section. however, it is also important to question to which extent the provided services are inclusive of syrian refugees. syrian refugees reportedly continue to experience difficulties in accessing the healthcare and psychosocial services. one of the main challenges cited by authors is the arabic-turkish language barrier. to tackle the language barrier between arabic-speaker refugees and turkish-speaker host communities, translators are employed in many public hospitals. however, the number of translators remain insufficient in most places (assi, özger-i̇lhan, & i̇lhan, 2019; ekmekci, 2017) . the lack of legal registration of refugees in turkey or registration in a province different than the province of residence is also a prominent issue. as mentioned, syrians are only entitled to healthcare services in the provinces they are registered in. thus, refugees who reside in a different province or has not been able to register with the authorities cannot access healthcare services (assi et al., 2019; ekmekci, 2017) . furthermore, even though the healthcare services are legally free of charge for refugees, syrian refugees living in outside of the camps stated that in practice, not all services are always covered and they may need to pay for prescribed medications and other healthcare related costs (kargin, 2018) . finally, the stigma against syrian refugees by local communities, including healthcare workers, is negatively impacting the syrian refugees' access to healthcare. refugees stated that they were exposed to negative attitudes of healthcare staff and even received poor treatment due to the stigma associated with being a refugee (kargin, 2018) . this article aimed to look into the health and wellbeing of syrian refugee children from the perspective of sdg goal 3 good health and wellbeing. the main commonality of the studies reviewed for this article is that syrian refugee children in turkey are faced with higher risks in terms of a variety of health and wellbeing indicators despite the efforts by governmental and non-governmental entities. the studies from pre-conflict syria confirm that the overall child nutrition situation in syria before the start of the war in 2011 was already poor (kingori et al., 2015) . in the current situation, syrian children are more vulnerable to nutritional problems than turkish children (hips, 2019a (hips, , 2019b . this discrepancy may stem from a variety of factors including lack of income, access to nutritious food, quality housing, and number of people living in the same household. increasing the general life quality of syrian refugees, ideally to the level of turkish nationals, is the way to tackle this issue. the improvement of living conditions is also crucial to the reduction of non-vaccine preventable diseases such as respiratory tract infection and diarrhea, which can become deadly for malnourished children (ergönül et al., 2020) . establishing decent living conditions with adequate shelter and sufficient income to alleviate basic food and hygiene requirements should be the main goal to protect the health status of syrian refugee children in turkey. immunization coverage of syrian refugee children and their susceptibility to vaccine-preventable diseases is a particular situation. vaccination rates in syria prior to the war were high whereas the rates have fallen significantly in syria since then (hips, 2019a; who -syria, 2019) . when syrian children arrived to turkey, their vaccinations were mostly incomplete due to disruptions of the vaccinations during the war. vaccination rates have also been high in turkey in this period and turkey includes syrian refugee children in its vaccination program (hips, 2019b) . in the last years, the vaccination rates of syrian children approach those of turkish children. while some vaccine-preventable diseases have seen an increase in numbers with the arrival of syrian refugees in turkey due to the delays in vaccination in syria since the start of the war, it is also important to note that none of them has reached the level of a serious outbreak thus far (who -turkey, 2019; ergönül et al., 2020) . regardless, it is important to pay close attention to the vaccination of syrian refugee children to avoid potential outbreaks. in light of the aforementioned vulnerabilities, the integration of refugees in the national health system is extremely important for individual and public safety. the turkish national health system is largely extended to syrian refugees free of charge and additional measures have been taken to mitigate issues of overcrowding in the public healthcare services (demir et al., 2016) . the extension of the national immunization campaigns to refugee children is a crucial step towards public health. in this sense, the registration of syrian children with turkish authorities should be the first priority to ensure full vaccination in order to prevent outbreaks. most importantly, the access of refugees to public healthcare services was ensured by its incorporation into legislation, which provides a sound legal basis for the provided services with the 2014 regulation on temporary protection and the subsequent 2015 directive on the guidelines for the healthcare service provided to individuals under temporary protection. syrian refugee children are exposed to various traumatic events such as loss of a loved one, witnessing combat or life threat during war and flight (gormez et al., 2018) . other social risk factors during post-migration period such as child labor, family violence, and child marriage also negatively affect the psychosocial wellbeing of syrian refugee children in turkey (el arab & sagbakken, 2019; falb et al., 2019; habib et al., 2019; usta et al., 2019; wringe et al., 2019) . associated with these risk factors, studies indicate higher estimates of ptsd, depression, and anxiety among syrian refugee children compared to turkish children. however, due to language barrier, lack of mental health professionals and stigma on mental health issues, mental health service utilization is low among syrians (fuhr et al., 2020) . most of the psychosocial interventions are directed to school age syrian children due to feasibility reasons such as accessibility (yaylaci, 2018) . a study of school-based, teacher delivered psychosocial intervention indicated reduction in symptoms of anxiety and ptsd among syrian refugee children (gormez et al., 2017) . however, there is also a need to develop and deliver psychosocial interventions to younger children and those children who are not going to school especially due to child labor or child marriage. social factors such as child labor, domestic violence and child marriage are also risks for refugee children's wellbeing. child labor and child marriage are commonly used as coping mechanisms for the household's economic survival (ozdemir & budak, 2017, p.216; harunoğulları, 2016; suleymanov et al., 2017, p.243; cetin, 2016, p.209) . domestic violence is an increased risk for refugee children due to traumatic experiences affecting parental psychopathology (timshel et al., 2017) . this shows that wellbeing is not a one-way street and mental health support to parents as well as children is necessary for child wellbeing and economic sufficiency might have secondary serious effects on refugee children's wellbeing. while the national and local governmental and non-governmental entities have taken steps in addressing these issues, the legal basis for addressing them are not as established in comparison to the access to healthcare services. as a direct consequence of the presence or non-presence of national legislation on the mentioned issues, the provision of services differs in terms of modality. the provision of healthcare services is highly centralized, led by the ministry of health, which facilitates the harmonization of services throughout the country. however, the issues with registration with the authorities (in a different province or lack of registration) is a significant barrier for syrian refugees' access to the services provided (assi et al., 2019; ekmekci, 2017; kargin, 2018) . moreover, the lack of refugee-specific legislation and the narrow scope of national legislation on child protection have steered the actors to organize in a non-centralized manner. in addition to the governmental policies, the role of the civil society and its cooperation with governmental entities also presents an added value for the improvement of syrian refugee children's wellbeing. the child protection efforts are joint efforts of the turkish government and non-governmental actors in effectively addressing child protection issues (3rp health sector, 2019; 3rp protection sector, 2019; unicef, 2020; maya foundation, 2019) . however, at this stage, these activities are not widespread throughout the country and refugee integration is not optimal due to arabic-turkish language barrier. the expansion of the services countrywide and the integration of refugees into these systems by solidifying the capacities of arabic-turkish translators remain vital for enhancing the health and wellbeing of refugee children. the goals established in the 2030 agenda for sustainable development under paragraph 26 include promoting physical and mental health and wellbeing, extending life expectancy, achieving universal health coverage, reducing newborn and maternal mortality, ending preventable diseases, fighting communicable diseases, and preventing and treating non-communicable diseases (united nations, 2015) . it is clear that the interventions and restructuring of the health system as discussed in this article are very much in line with the cited goals and contribute to the sdg number 3: good health and wellbeing for refugee children in the context of turkey. the provision of universal healthcare rights for syrian refugees is the main parallel with the sdg targets, which also contributes to other sdg targets including reduction of mortality from communicable and non-communicable diseases. un agencies and other non-governmental entities have also been active in the refugee response since the beginning of the crisis and have filled gaps in access to services where possible including but not limited to protection services and referrals, psychosocial services, and nutrition and food security assistance. on the other hand, significant gaps remain in terms of access to social services and the legal system. the existence of a legal system which enables refugee access to health, protection, and other social services is key to achieve this goal. however, the results of this narrative review confirm that the existing system could be improved especially through solidifying the legal basis and centralizing the implementation of child and refugee protection. considering the high number of refugee children and the demand on the health systems of turkey, engagement and capacity building of all stakeholders is essential to provide effective services to improve the health and wellbeing of refugee children. evaluation of these services in terms of impact and costeffectiveness is also important. after evaluation, evidence based services should be scaled up. to increase the delivery and reuptake of health services, barriers such as lack of awareness about available services, lack of translators, and issues with registration of syrian refugees in their provinces of residence should also be addressed. turkey is amongst the 17 countries to distinguish the particular needs of refugees as part of its sdg voluntary national review (out of the 45 countries, each country hosting over 20,000 refugees) (vnr, 2019; irc, international rescue committee, 2019, pp. 4-5) . while the sdg framework aims to "leave no one behind", it is important to remember that syrian refugee children remain more vulnerable to health and wellbeing risks. the sdgs as a national response plan should not leave marginalized groups behind and particular needs of syrian refugee children should be effectively incorporated into the sdg framework. considering that turkey is currently hosting the largest syrian refugee population in the world, we can say that the steps taken in the integration of refugees in turkey in terms of sdg 3 goals of health and wellbeing are significant. the good practices examined in this review article are as follows: -extension of universal healthcare to syrian refugees -extension of universal immunization to syrian refugee children -establishing migrant health centers to ease burden on public hospitals due to the sharp increase in demand -public, civil society, and joint initiatives for the provision of healthcare and child protection services for syrian refugee children however, parallel to the magnitude of the refugee population, there are remaining gaps to be filled and potential improvements to consider as identified in this review article: -poor living conditions (i.e. hygiene, shelter, nutrition) -issues with the registration of syrian refugees in turkey presenting challenges with access to healthcare services -shortcomings in addressing the arabic-turkish language barrier to access to services (e.g.: lack of translators in health facilities) -lack of refugee-specific legislation on child protection -narrow scope of national legislation on child protection -efforts to address the stigma experienced by syrian refugees from the local population in general including healthcare and wellbeing related service providers -limited accessibility for mental health support for syrian refugee children and their parents as such, turkey can significantly improve the current health and wellbeing situation of syrian refugee children and minimize the associated risks by addressing these points. a final point to be made while concluding this article is that in the areas which the national systems are already strong, the system is better able to absorb newly emerging urgent and heightened needs. some examples of this in the context of turkey are immunization coverage extension to syrian children or the extension of universal healthcare to syrian refugees. on the other hand, where national systems are not well established, additional shocks bring extra burden and the vulnerabilities may become intensified. within the context of turkey, this can be observed in addressing social issues such as child marriage, child labor, and domestic violence. in the case of turkey, ngos are working to cover the gaps in these areas. however, a unified response with deeper involvement from the government side is needed in the current context to better address these issues. as such, countries that provide healthcare and protection services widely to its citizens would be better able to cope with such migration crises that require the extension of services to non-citizens. prevalence and predictors of posttraumatic stress and depression symptoms among syrian refugees in a refugee camp child abuse and neglect in turkey: professional, governmental and non-governmental achievements in improving the national 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by-nc-sa 3.0 igo)world health organisationhttps immunization, vaccines and biologicals-measles who | immunization country profile i syria who | immunization country profile i turkey g who vaccine-preventable diseases: monitoring system. 2019 global summary global health observatory country views-turkey statistics summary altered social trajectories and risks of violence among young syrian women seeking refuge in turkey: a qualitative study the legal and ethical foundations of health assistances to syrian refugees in turkey trauma and resilient functioning among syrian refugee children suriyeli sığınmacılar ve sağlık hizmetleri raporu. retrieved from key: cord-331825-dwi350c0 authors: teherani, mehgan f; kao, carol m; camacho-gonzalez, andres; banskota, samridhi; shane, andi l; linam, william m; jaggi, preeti title: burden of illness in households with sars-cov-2 infected children date: 2020-08-11 journal: j pediatric infect dis soc doi: 10.1093/jpids/piaa097 sha: doc_id: 331825 cord_uid: dwi350c0 we investigated the dynamics of illness among household members of sars-cov-2 infected children that received medical care (n=32). we identified 144 household contacts (hcs): 58 children and 86 adults. forty-six percent of hcs developed symptoms consistent with covid-19 disease. child-to-adult transmission was suspected in 7 cases. m a n u s c r i p t 3 background children comprise of a small proportion of overall covid-19 cases at 5.2% of laboratoryconfirmed infections in the us 1 . however, these data are likely an under-representation of the true pediatric infection burden as initial reports occurred in the setting of school closures and shelter-in-place orders. as the us economy reopens, a dramatic increase of cases has occurred in several states. recent studies have shown that children may be both as likely to become infected as adults and to infect others, but are less likely to have symptoms, suggesting that they have the potential to be silent facilitators 2,3. a better understanding of the role children play in the chain of viral transmission is urgently needed. studies investigating household transmission have shown children are often secondarily infected by an adult, however, there is a paucity of pediatric-focused studies [4] [5] [6] [7] . to address this knowledge gap, we utilized a prospective registry of laboratory-confirmed pediatric covid-19 cases and conducted contact tracing of household members to characterize the presumed transmission before and after the child's diagnosis. we identified children (<18 years old) with laboratory-confirmed sars-cov-2 between march 16 and june 14, 2020 who were seen by a healthcare provider at a children's healthcare of atlanta (choa) facility. we utilized a prospective registry of patients with a positive nasopharyngeal (np) swab for sars-cov-2 by pcr performed at a choa healthcare facility or from an outside healthcare facility prior to transfer to choa. demographic and clinical data were obtained through manual chart abstraction of the electronic medical record. only children who presented with symptoms concerning for table i ). household contacts (hcs) were defined as an adult ( 18 years) or a child (<18 years) who resided in the home with the sic at the time of diagnosis. we defined symptoms consistent with covid-19 as fever plus 1 of the following: cough, shortness of breath (sob), myalgias, loss of taste or smell or 2 of the following symptoms: cough, myalgias, sob, and/or loss of taste or smell. the survey also addressed occupational risk factors among adults in the household, smoke exposure in the household, and acceptability of a potential sars-cov-2 vaccine. answers were recorded in a hipaa secure database. we defined the suspected index case as the first person (child or adult) to report symptoms or test positive for sars-cov-2 in the household, documented 14 days prior to, during, or after symptoms of other family members. descriptive statistics were reported as total numbers, percentages, medians and interquartile ranges as appropriate. this study was approved by the choa institutional review board. we identified 138 sics at choa during the study period and called 58 (42%) families at random order. we were unable to contact 21 subjects due to inability to reach parent/lar a c c e p t e d m a n u s c r i p t 5 (n=17) and lar not able or declined consent for research (n=4). thirty-eight follow-up parental interviews were conducted (12 in spanish, 25 in english) and 32 interviews were included in our final analysis. median contact time from positive test was 37.5 days (iqr 26-43.5). six interviews were excluded due to asymptomatic patients diagnosed pre-operatively (n=2), age >18 years old (n=2), and interviews with a child in the same family (n=2). baseline characteristics are summarized in table i we identified 7 sics that were the first to develop symptoms in the household, making them the suspected index case (table ii) . three sics were in school or daycare within 14 days of symptoms onset. sic 1 was febrile for 18 days after initial symptoms and ahc exposure may have occurred beyond 14 days of the sic's symptom onset. the mother of sic 4 developed symptoms during patient's hospitalization but was unable to recall how many days after. for sic 5, the sibling was identified as the first symptomatic household case, followed by 2 siblings and the patient, and then lastly, the mother. sic 6 was admitted to the hospital for 3 days and parents developed symptoms after patient's discharge. in addition, three sics did not have other ill household contacts, but did have a known covid-19 positive or a symptomatic close contact (grandmother, aunt, friend). because pediatric patients are more likely to be asymptomatic or show mild symptoms, it has been challenging to define their role in sars-cov-2 household transmission, which this study aimed to address. although the majority of cases originated in an adult household member, 7 cases (22%) of presumed child-to-adult transmission were identified in this cohort. in contrast, a recently published study from switzerland found only 8% of household cases resulted from child-to-adult transmission 8 , which may be due to differences in community virus circulation during the study period and strictness in social distancing recommendations. in our study of child-to-adult transmission cases, children were symptomatic for at least 4 days prior to seeking care, the time period when they were most likely to be infectious to other household members 5,9 . there has been varied rates of household transmission reported in other countries. we found that 46.5% of household members of a sic developed symptoms or had laboratoryconfirmed covid-19 infection. studies of secondary transmission from china have shown a c c e p t e d m a n u s c r i p t 7 secondary attack rates between 4.6% to 32.4% among household and close contacts 2, 5, 10 . differences in these rates are likely due to multiple factors such as differences in method for identification of secondary cases, household composition, and stringency of isolation measures such as mandatory quarantining of household contacts. one important difference in this cohort was that we presumed secondary cases based mainly on clinical symptoms. differences in child and adult transmission rates are likely affected by differences in their social isolation practices. for a majority of our study period, children were not attending school or daycare. the 3 cases of child-to-adult transmission where the child was still enrolled in daycare or school occurred early during the pandemic prior to school closures, stay-at-home orders, and implementation of widespread face mask procedures. in contrast, over half of the households had adults who were essential workers and continued to work during the pandemic, increasing their own risk of exposure and secondary transmission. as circumstances continue to change, child-to-adult transmission rates will need to be closely monitored. there were several limitations to this study. we had a small cohort of patients at a single hospital system, which were ill enough to seek medical care. in addition, we relied on parental report of symptoms in their child and household members, which may expose our study to recall bias and may miss asymptomatic or minimally symptomatic cases. in the 7 cases of potential child-to-adult transmission, it is possible that the adult and child had the same exposure but a different incubation period or had different exposures. we assumed ill family members also had sars-cov-2 infection based on symptoms instead of pcr confirmation. this study occurred during school closures and for 1 month during statewide shelter-in-place orders, which may not reflect transmission in close-contact settings such as in-person school. a c c e p t e d m a n u s c r i p t 8 we found a higher rate of child-to-adult transmission than previously described. further ongoing surveillance will be needed to understand child-to-child and child-to-adult transmission if or when schools reopen. the authors received no financial support for the research, authorship, or publication of this article. all authors have no significant disclosures related to this publication. coronavirus disease 2019 case surveillance -united states epidemiology and transmission of covid-19 in 391 cases and 1286 of their close contacts in shenzhen, china: a retrospective cohort study contact tracing during coronavirus disease outbreak, south korea, 2020. emerg infect dis transmission potential of asymptomatic and paucisymptomatic sars-cov-2 infections: a three-family cluster study in china transmission dynamics in taiwan and risk at different exposure periods before and after symptom onset multicentre italian study of sars-cov-2 infection in children and adolescents, preliminary data as at 10 the characteristics of household transmission of covid-19 covid-19 in children and the dynamics of infection in families presymptomatic transmission of sars-cov-2 -singapore household transmission of sars-cov-2 a c c e p t e d m a n u s c r i p t 9 1 a 0. a patient was febrile for 18 days following first day of symptoms. b parent developed symptoms while staying in the room with patient but unknown how many days after patient's symptoms onset. c parents did not develop symptoms until after patient was discharged, but days after was not reported. sic: sars-cov-2 positive child who sought care at our hospital, hc: household contact, +: days after sics first symptom % hcs with sxs: 45.7% key: cord-329123-ytezkugu authors: santi, aura daniella; aquino, paolo; dorfman, molly title: atrial fibrillation in a child with covid-19 infection date: 2020-10-19 journal: cardiology in the young doi: 10.1017/s1047951120003893 sha: doc_id: 329123 cord_uid: ytezkugu the sars-cov-2 (covid-19) pandemic has challenged our initial predictions of its ramifications, both short and long term. cardiovascular manifestations of covid-19 in children remain a topic of investigation as literature is lacking. we describe new onset atrial fibrillation in a child with a history of covid-19 infection. understanding of cardiogenic effects of covid-19 can help minimise the delay in diagnosis. cardiovascular manifestations of sars-cov-2 in children remain a topic of novel investigation as literature in this population is lacking. the adult population has been the primary focus for complications of this virus, and data are limited regarding cardiovascular manifestations in the paediatric population. a multi-system inflammatory syndrome in children has been described in association with covid-19 infection, with 80% involving cardiovascular sequelae. 1 immunologic response appears to play a role in hyper-inflammation and cardiac injury. 2 the mechanisms for cardiac injury have been proposed to be secondary to stress, with inflammatory responses leading to cardiac injury, and possibly cardiac muscle ischaemia. 3 cardiac manifestations of covid-19 in adults to date include myocardial infarction, myocarditis, and cardiac arrhythmias. 3 new onset arrhythmias are a poorly described complication in previously healthy children with covid-19. 4 case a previously healthy, 17-year-old 86.3 kg male presented due to refractory hypotension requiring vasopressor support. initially, the patient reported loss of smell and taste about 4 weeks prior to presentation. two weeks prior to admission, the patient was noted to be covid-19 positive, with intermittent fevers, progressively worsening cough, and shortness of breath, as well as an evanescent rash. following a two-week quarantine, symptoms resolved until presentation, when the patient developed neck tenderness, vomiting, diarrhoea, and syncope. the patient was seen at an emergency department on multiple occasions for symptoms and discharged home with the diagnosis of covid-19 and given azithromycin for an unclear diagnosis, without resolution of symptoms. during the 24 hours prior to admission, the patient endorsed blurry vision, eye redness, chest pain, nausea, and vomiting. en route to the hospital, the patient complained of dizziness and reported syncope. on arrival, the patient was hypotensive to the 80s/40s. on initial physical exam, the patient was ill-appearing, with no significant respiratory impairment, pale and diaphoretic, tachycardic to 120s with sinus rhythm, and had a hyper-dynamic precordium. mild hepatomegaly was noted. the conjunctiva was injected and tongue erythematous, and a blanching rash was noted on palms and wrists. criteria were met for severe multi-system inflammatory syndrome in children given the cardiovascular, renal, gastrointestinal, mucocutaneous, and pulmonary involvement with history of covid-19 infection. he received a 3 l normal saline bolus, but continued to be hypotensive despite norepinephrine, before quickly changed to epinephrine for concerns of cardiogenic shock. electrocardiogram at presentation showed sinus tachycardia. a blood gas was notable for respiratory acidosis with mild metabolic compensation and lactic acidosis, troponin and brain natriuretic peptide were elevated; he had evidence of acute kidney injury, and inflammatory markers were elevated (table 1) . cardiology, infectious disease, and rheumatology were consulted. given the severity of symptoms and refractory shock, the patient was admitted to the paediatric icu. he was started on pulse solumedrol 30 mg/kg/day for 3 days per rheumatology recommendations, followed by tapered doses. the patient received recommended intravenous immunoglobulin treatment for multi-system inflammatory syndrome in children (100 g, weight-based maximum). milrinone 0.5 mcg/kg/min and aspirin 81 mg were started. serial troponin continued to be elevated, however, down trending throughout admission. multiple echocardiograms were obtained and significant for small pericardial effusion, but normal cardiac function, ejection fraction, and no sign of pulmonary hypertension. no coronary abnormalities were noted. on hospital day 1, the patient complained of acute chest pain without hypoxia that improved with morphine. ct chest was done and did not show evidence of pulmonary embolus. no evidence of strain on telemetry. he remained persistently hypotensive. on day 2, the patient was started on a 5-day course of biologic therapy with recombinant il-1 antagonist anakinra, 100 mg twice per day given the severity of presentation with elevated inflammatory markers suggesting cytokine storm. on day 3, premature atrial contractions were noted on telemetry with subsequent atrial fibrillation requiring cardioversion with 100 j and 150 j (fig 1a) . he remained stable until day 4 with new episode of atrial fibrillation requiring cardioversion with 150 j (fig 1b) and a bolus dose of amiodarone. lowdose epinephrine 0.02-0.05 was necessary even with sinus rhythm for refractory hypotension with orthostatic hypotension out of proportion to his clinical picture. the patient remained on sinus rhythm, but noted to have a 5 beat run of wide complex tachycardia on day 11. repeat labs showed improvement, with down trending inflammatory markers, troponin, and brain natriuretic peptide. the patient was transitioned to acute care floor on day 14 with the resolution of cardiac arrhythmias. he continued to have dysautonomia with orthostatic hypotension, and fludrocortisone and midodrine were started with improvement in blood pressure. rehabilitation medicine was consulted for therapy given severe de-conditioning. he was discharged on day 16 with follow-up in cardiology, rheumatology and physical/ occupational therapy. multi-system inflammatory syndrome in children is a multiinflammatory condition documented in children and adults that follows infection with covid-19 meeting criteria with fever >38c, elevated inflammatory markers, and involvement of >2 organ systems. 5 cases are classified as mild if the patient does not require vasoactive support, presents with minimal organ injury, and requires minimal to no respiratory support; severe cases present with mild to severe organ injury and require significant respiratory support warranting icu admission. 5 antibody-mediated hyper-inflammatory response has been described, supported by the positive response seen in patients treated with intravenous immunoglobulin. 2 similarly, macrophage activation, cardiac fibroblast, and cardiomyocyte stretching have been proposed to cause elevated interleukin-6 triggering an immunological cascade. 6 current guidelines for multi-system inflammatory syndrome in children treatment include starting low-dose aspirin, steroids, and intravenous immunoglobulin for all patients (dose dependent on severity) and biologic treatment with tocilizumab, anakinra, or infliximab for severe cases. 5 in the case presented, the elevated troponin levels were likely due to cardiac muscle stress from inflammation given no evidence of coronary insufficiency or st-segment changes on echocardiogram and electrocardiogram, respectively. similarly, inflammatory stress and metabolic alterations may have led to the development of cardiac arrhythmia in this patient. 7 monitoring for cardiovascular complications via serial troponin with early intervention is essential for multi-system inflammatory syndrome in children patients. cardiovascular manifestations of covid-19 in children remain a topic of novel investigation as literature in this population is lacking. emphasis has been frequently placed on the respiratory manifestations of the virus, and paediatric cardiovascular complications and treatment are not well understood. this case illustrates the potential for cardiac arrhythmias in children affected by the novel virus and prompts for further investigations and need for research regarding the rates of cardiac dysrhythmias in multi-system inflammatory syndrome in children. the case highlights the importance of developing management strategies in patients with multi-system inflammatory syndrome in children in the setting of viral infection with covid-19. it is important that children with covid-19 infection be screened for cardiac complications through cardiac troponin and brain natriuretic peptide levels to minimise the delay in diagnosis and treatment. 8 cardiology in the young 3 multisystem inflammatory syndrome in u.s. children and adolescents the immunology of multisystem inflammatory syndrome in children with covid-19 coronavirus disease 2019 (covid-19) pandemic implications in pediatric and adult congenital heart disease cardiovascular considerations for patients, health care workers, and health systems chkd treatment guideline for covid-19 in children acute heart failure in multisystem inflammatory syndrome in children in the context of global sars-cov-2 pandemic evaluation and follow-up of pediatric covid-19 in terms of cardiac involvement: a scientific statement from the association of turkish pediatric cardiology & pediatric cardiac surgery rethinking covid-19 in children: lessons learned from pediatric viral and inflammatory cardiovascular diseases acknowledgements. the authors would like to express their gratitude to the medical staff of valley children's hospital.financial support. no specific grant from any funding agency, commercial, or not-for-profit sectors. ethical standards. the manuscript is an original work of all authors. all authors made significant contribution and have read and approved the final version of the manuscript. key: cord-314124-yk4y0kea authors: tsou, ian y.; loh, lik eng; kaw, gregory j.; chan, irene; chee, thomas s. title: severe acute respiratory syndrome (sars) in a paediatric cluster in singapore date: 2003-08-20 journal: pediatr radiol doi: 10.1007/s00247-003-1042-2 sha: doc_id: 314124 cord_uid: yk4y0kea background: severe acute respiratory syndrome (sars) is a major infectious disease pandemic that occurred in early 2003, and one of the diagnostic criteria is the presence of chest radiographic findings. objective: to describe the radiographic features of sars in a cluster of affected children. materials and methods: the chest radiographs of four related children ranging in age from 18 months to 9 years diagnosed as having sars were reviewed for the presence of air-space shadowing, air bronchograms, peribronchial thickening, interstitial disease, pleural effusion, pneumothorax, hilar lymphadenopathy and mediastinal widening. results: ill-defined air-space shadowing was the common finding in all the children. the distribution was unifocal or multifocal. no other findings were seen on the radiographs. none of the children developed radiographic findings consistent with acute respiratory distress syndrome. all four children showed significant resolution of the radiographic findings 4–6 days after the initial radiograph. conclusions: early recognition of these features is important in implementing isolation and containment measures to prevent the spread of infection. sars in children appears to manifest as a milder form of the disease as compared to adults. severe acute respiratory syndrome (sars) is a new form of atypical pneumonia, and is an infectious disease which has caused a pandemic with significant public health concerns. singapore was one of the earliest areas to be affected, with the index case admitted to a local hospital on 1 march 2003 [1] . since then, there have been more than 7700 cases worldwide and 205 cases in singapore, both as of 16 may 2003 [2] . one of the factors which contributes to the large number of cases is that the disease is easily transmissible via droplet infection from close contact. this situation is seen in the household setting, where family members are at risk of contracting the disease from an infected person. the number of children infected appears to be relatively small. we report a cluster of four children affected with sars in this way, with emphasis on the contact history and radiological features. three female siblings, patients a, b and c, aged 4, 8 and 9 years, respectively, were referred by a family physician to tan tock seng hospital, the hospital in singapore designated for the treatment of sars. they all presented with a 4-to 5-day history of pyrexia of ian y. tsou lik eng loh gregory j. kaw irene chan thomas s. chee severe acute respiratory syndrome (sars) in a paediatric cluster in singapore abstract background: severe acute respiratory syndrome (sars) is a major infectious disease pandemic that occurred in early 2003, and one of the diagnostic criteria is the presence of chest radiographic findings. objective: to describe the radiographic features of sars in a cluster of affected children. materials and methods: the chest radiographs of four related children ranging in age from 18 months to 9 years diagnosed as having sars were reviewed for the presence of air-space shadowing, air bronchograms, peribronchial thickening, interstitial disease, pleural effusion, pneumothorax, hilar lymphadenopathy and mediastinal widening. results: ill-defined air-space shadowing was the common finding in all the children. the distribution was unifocal or multifocal. no other findings were seen on the radiographs. none of the children developed radiographic findings consistent with acute respiratory distress syndrome. all four children showed significant resolution of the radiographic findings 4-6 days after the initial radiograph. conclusions: early recognition of these features is important in implementing isolation and containment measures to prevent the spread of infection. sars in children appears to manifest as a milder form of the disease as compared to adults. keywords thorax ae lung ae infection ae pneumonia ae severe acute respiratory syndrome (sars) ae radiography ae child more than 38.5°c, headache and myalgia. none of three children had respiratory symptoms of cough or dyspnoea, and there was no recent travel history. they had been previously well with no significant past medical history. clinical examination of the children showed them to be febrile but not toxic. five other close family members, including their mother and grandfather, were also referred on the same day with a 1-day history of high fever of more that 38.5°c, myalgia and cough. in view of the large number of ill family members with symptoms, there was a high index of suspicion for sars. as such, the children and other affected family members were admitted for further assessment and investigation. their 18-month-old cousin, patient d, was admitted 2 days later with a 5-day history of fever and dry cough. of note, their grandmother, who was the primary caregiver of all four children, had recently fallen ill, 1 week prior to their admission. she presented initially with severe headache followed by a high fever and cough. she then rapidly deteriorated, collapsed suddenly, and passed away at home within 3 days of falling ill. she had been healthy prior to this episode of illness and had no past medical history of note. the postmortem examination performed did not find a cause for her sudden demise, but no investigations for sars were done at the time in view of the lack of travel history and the apparent lack of contact history. this was later done and polymerase chain reaction (pcr) for coronavirus was positive. the link in the contact history only emerged later, when it was discovered that the grandfather of the children worked in a local wholesale vegetable market where there had been a recent community outbreak of sars. he subsequently also passed away from a sars-related cause. despite the lack of respiratory symptoms, the initial chest radiographs in all four patients were all abnormal. each patient showed either one or two areas of air-space shadowing, which were zonal in distribution. the typical appearance and pattern of progression is illustrated with patient b. the radiograph at presentation showed a single rounded area of ill-defined air-space consolidation in the lateral aspect of the left lower zone (fig. 1a) . the size and appearance of the consolidation was essentially unchanged on the second radiograph 2 days later, and partial resolution was seen on the third radiograph taken 4 days after the first (fig. 1b) . the last radiograph on the day of discharge showed almost complete resolution (fig. 1c) . in all four patients, no other areas of consolidation developed apart from that already present in the initial radiograph. no pleural effusions or pneumothoraces were noted throughout the course of the disease. bilateral involvement was seen in patient a (fig. 2) , and unilateral multifocal consolidation in patient c (fig. 3) . patient d had a single area of consolidation in the left upper zone (fig. 4) . the distribution of the radiographic abnormalities is detailed in table 1 . all four children showed significant resolution of the radiographic appearances by 4-6 days after the initial radiograph, similar to that demonstrated in patient b. all four children were initially treated on admission with a combination therapy of ampicillin with a beta-lactamase inhibitor and a macrolide to cover community-acquired pneumonia. initial and subsequent full blood counts showed leucopenia (range 2.2-3.8·10 9 /l) but no lymphopenia, and mild thrombocytopenia (149-164x10 9 /l). the lactate dehydrogenase (ldh) levels were also raised (600-929 u/l) in all four children. blood cultures did not yield any bacterial growth. nasal aspirates for other respiratory viruses were negative in all. oral ribavarin was started for patients a, b and c when they remained febrile and their chest radiographs showed continued progression of pneumonia after 72 h of antibiotic therapy. their fever finally settled 7 days after admission. patient d's fever settled 48 h after admission and as her pneumonia did not show any evidence of progression, she was not treated with ribavarin. though diagnostic tests have not been validated, the pcr for coronavirus was positive in patients a, c and d but negative in patient b. none of the children required intensive care; they also did not require any form of ventilatory support or supplemental oxygen therapy. regarding their outcomes, patients a, b and c were discharged from hospital 8 days after admission and patient d, 6 days after admission. the discharge criteria were based on resolution of fever for more than 72 h, with improvement in chest radiographic findings. the diagnosis of sars at present is based on case definitions issued by the world health organisation (who) [3] . the initial case definitions for surveillance of sars were revised on 1 may 2003 to include classification of probable cases based on positive assays of the sars coronavirus, which has been identified as the causative organism [4] . however, these pcr tests need to be further validated, as there appears to be poor sensitivity with high false-negative results. also, when community outbreaks occur, a contact source may not always be found immediately. as such, a high index of suspicion is needed in the assessment and evaluation of sars patients. stringent infection control measures have been implemented in singapore, with isolation procedures, quarantine enforcement and notification of cases being the mainstays of prevention [5] . sars in children appears to manifest as a milder form of the disease as compared to that in adults. the initial reports from both canada and hong kong did not have any patients below the age of 20 years [6, 7] . a more recent report from hong kong of ten patients in the paediatric age group had only five below the age of 12 years [8] . their preliminary findings showed that younger children develop a milder form of the disease with a less-aggressive clinical course, as compared to teenagers and adults. however, no discernible difference in the pattern of radiographic involvement was noted. other common viral organisms causing pneumonia in children include adenovirus, respiratory syncytial virus and parainfluenza viruses. in general, the radiographic features do not allow identification of a specific causative virus, and sars does not appear to be any different. the basic findings of viral pneumonia are wide-ranging, and include interstitial infiltrates to areas of diffuse consolidation which may coalesce over time. respiratory syncytial virus pneumonia has also been described with peribronchial infiltrates and hyperinflation [9] , and adenovirus infection manifesting as patchy or confluent widespread consolidations [10] . in summary, young children appear to show a much milder response to sars as compared to older children and adults. this is seen in both the clinical and radiographic features, where none of our patients went into respiratory distress requiring mechanical ventilation or intensive care, and the changes on the chest radiographs did not worsen after initial presentation. the difference is interesting, and could possibly be related to a difference in immune response in the different age groups. further studies with a larger pool of patients are warranted, and this may assist in further identifying the behaviour of the implicated coronavirus. chest radiographic findings of a case of severe acute respiratory syndrome (sars) in singapore cumulative number of reported probable cases of severe acute respiratory syndrome (sars) case definitions for surveillance of severe acute respiratory syndrome (sars) coronavirus as a possible cause of severe acute respiratory syndrome severe acute respiratory syndrome-singapore identification of severe acute respiratory syndrome in canada a cluster of cases of severe acute respiratory syndrome in hong kong clinical presentations and outcome of severe acute respiratory syndrome in children the radiological findings in respiratory syncytial virus infection in children radiology of epidemic adenovirus 21 infection of the lower respiratory tract in infants and young children key: cord-333061-d1mdacx3 authors: zhang, xiu-hang; cui, chang-lei; lee, kai-ki; chen, xin-xin; yu, jia-ao; wu, wei-wei title: a specially designed medical screen for children suffering from burns: a randomized trial of a distraction-type therapy date: 2020-05-30 journal: burns doi: 10.1016/j.burns.2020.05.018 sha: doc_id: 333061 cord_uid: d1mdacx3 abstract objective to evaluate the impact of the specially designed medical dressing screen during wound dressing changes of children who suffered burns to their hand or foot. design randomized controlled trial. setting burns and plastic reconstruction unit. participants children (n=120) with burns on up to 1%-5% of the total body surface area. interventions the patients were selected and randomly allocated to 3 equal-sized groups as follows:control group (n=40): the children received only regular dressing changes; computer group (n=40): a touch-screen computer was used for children during dressing changes; medical screen group (n=40): a medical screen combined with the touch-screen computer were used for children during dressing changes. all patients underwent a dressing change once per day for four days. data were distributed four times: immediately after the initial dressing change (t1); and immediately after each times at next three consecutive days (t2-t4). main outcome measures the pain level of the children evaluated by medical staffs was the primary outcome, the pain level of the children evaluated by children's parents and the satisfaction of wound therapist were used as second outcomes. results the mean scores related to pain level at the medical screen group displayed significantly better results than those of control group and those of the computer group. additionally, the results of the pain evaluated by parents and satisfaction score of the wound therapist at the medical screen group was also better than other groups. conclusions this study demonstrated “that the” application of the medical screen for burns can relieve the pain of 1-3 years old children suffering from a burns during dressing changes. additionally, the application of the medical screen also increased the satisfaction of the parents and the wound therapist performing the dressing changes. in developing countries, children under the age of 5 can account for 50-80 % of all children patients, 1 while the 52 morbidity rate of children 3 years old or younger with burn injuries is the highest in china. [2] [3] [4] studies show that burns 53 rank 5th among non-vulnerability injuries for children with resultant irreversible complications such as pain, anxiety 54 and depression. 5 of these complications, pain is considered to be among the most debilitating sequelae of the burn 55 injury. 6-7 56 57 burn pain is a special kind of pain with the fiercest intensity of all types. specifically, pain during wound dressings can 58 be excruciatingly painful and has been considered to be the most painful among all non-surgical procedures. [8] [9] during 59 wound dressing, children can express panic, crying, resistance, etc. due to dressing pain and fear of dressing because 60 their psychological development is immature and lack the ability for autonomous cooperation, which resulted in great 61 inconvenience for clinical work. 10 62 63 pharmacological treatment is the primary approach for relieving pain related to burns, and several categories of drugs 64 have been used to manage burn pain and psychological symptoms caused by pain. however, due to the variability of 65 the intensity of pain in children, the symptoms remain under-treated. 10 recently, much attention has been paid to pain 66 management approaches with non-pharmacological therapies. distraction is a common non-pharmacological pain 67 treatment method that is commonly used in children. currently, there are different types of distraction 68 including music video, visual image, electronic games , etc., which can intervene with the pain when dressing changes 69 are performed for children with burns, and the effect is relatively good. [11] [12] [13] research studies have indicated that 70 distraction can transfer the attention of children to something more attractive to relieve pain, what's more, it has an 71 apparent effect in relieving pain for children with burns. 11 j o u r n a l p r e -p r o o f a function of a screen with a touch-screen computer to design and build a medical dressing screen for children aged 1-3 77 years who are suffering from a burns on their hand or foot and require dressing changes, aimed to provide 78 recommendations for future research and clinical practice. 79 the single-center randomized controlled trial was conducted in our hospital from january 2019 to september 2019. 83 the study was designed to compare the effect of a specially designed medical dressing screen's intervention with usual 84 care or a touch-screen computer alone during wound dressing changes for children aged 1-3 years who suffering from 85 burns on their hands or feet. 86 87 the sample size was estimated to be 40 subjects for each group with 80% power, an alpha value of 0.05, and an 89 attrition rate of 10% and cohen's d = 0.59 (medium effect size). 14 following the children parents' agreement to 90 participate, they were thoroughly screened for eligibility by the main researcher. children between 1 and 3 years old 91 with burns on their hands or feet who came to our department for treatment were selected for tiral. burns were 92 limited to a single hand or foot, with the burnt area <5 % total body surface area (tbsa) and a burned depth of second-93 or third-degree. children were excluded if (1) had a confirmed past of cognition or psychological disorders, (2) had an 94 abnormal neurogenesis or abnormal cutaneous sensation, (3) previous burn injuries. a flow diagram of the study is 95 shown in figure 2 . 96 j o u r n a l p r e -p r o o f a 6 the purpose and method of the study, children's parents were informed about the right to withdraw from the study at 103 any time with no penalties or sanctions. all data collection and management procedures took into account the 104 participants' right to privacy and confidentiality. the authors confirm that all ongoing and related trials for this 105 intervention are registered. 106 107 a total of 137 children were initial included in this study, as 5 children who did not meet the inclusion criteria and 12 109 parents refused to participate in the clinical experiment, 120 children were finally included in this study. written 110 informed consent was obtained from each parent after providing a detailed introduction of the study, but we did not 111 provide a detailed explanation of the differences in intervention among groups. after obtaining informed consent, the 112 children were randomly divided into 3 equal-sized groups according to the use of our permutation block design, which 113 was created by a computer random number generator with a balanced randomized of 1:1:1, and the sample size of 114 each group was 40. 115 116 interventions 118 for all groups,information was gathered from the parents about their child's daily interests and hobbies, including 119 types and names of music, animation, videos, situational dialogues or electronic games. additionally, the demographic 120 and clinical characteristics of children were also recorded via a brief interview. the nurse also introduced actions of j o u r n a l p r e -p r o o f a on the initial day, a routine dressing change (t1) was performed (including all children were treated with the same 128 oral narcotics (tramadol) based on weight (kg), and all the periods were administered by the same anesthesiologist. 129 however, different methods were used at t2-t4 as follows. for the computer group (n=40), in addition routine dressing changes as usual, a touch-screen computer was used 134 during dressing changes (parents guided the child to watch the programme content on the touch-screen computer 135 according to child's daily interests and hobbies which were prepared in advance.). 136 137 for the medical screen group (n=40), in addition routine dressing changes, the medical screen combined with the 138 touch-screen computer was used for children during the dressing changes. before dressing changes, the medical 139 dressing screen for burns was moved to the location of the dressing treatment. the universal wheel on the lower part 140 of the screen was locked to firmly fix the screen so that its location could completely cover the wound therapist. the 141 touch-screen computer was installed and powered on to play the content that was prepared for children in advance. 142 the wound therapist entered the dressing room ahead of time to prepare. then, the nurse informed the parents to 143 take their child into the dressing room (only the parents and the child were allowed to enter the dressing area and to 144 seat on the adjustable seat.). then, the parents guided the child to watch the programme content on the touch-screen 145 computer according to child's daily interests and hobbies which were prepared in advance. when the child's attention locking capability are at the bottom of the screen, and the screen appearance is designed with an animation pattern. 159 the screen is equipped with a height adjustable seat. additionally, in order to facilitate wound dressing, the screen is 160 also equipped with 3 windowsfor the right upper limb, the left upper limb and the lower limbs so that wounds can be 161 conveniently exposed for dressing. 162 the conditions of all groups should be matched as closely as possible to control for confounding variables and 164 minimal-to-no interruptions occurred. to reduce rater bias, dressing changes were performed by the same skilled 165 wound therapist according to the specific wound type in the same treatment room. in addition, the medical screen for 166 burns was disinfected after each dressing change. any complications and adverse effects related to intervention were 167 also recorded. in addition, wound therapist's satisfaction score (pain levels) was also evaluated by the vns, from 0-11 scores, the 187 higher the satisfaction, the higher the score. 188 the evaluation of mbps during dressing changes was performed by 2 nurses with more than 10 years of experience 190 and 1 doctor with more than 10 years of experience by examining the children's performance in the video during the 191 dressing change (we did not provide a detailed explanation of the differences in intervention among groups). the pain 192 evaluated by parents was evaluated by the accompanying parents after each dressing change immedicately (t1-t4). 193 the wound therapist's satisfaction score was evaluated by the wound therapist after t1-t2 dressing changes. table 4 shows the overall satisfaction of the wound therapist, there were significant differences between medical 234 screen group and computer groupby intra-group comparison at t1 and t2 (all p<0.001), but no difference at control 235 group (p=0.564). in addition, there was significant differences at the wound therapist score at t2 by inter-group 236 comparison (p <0.001), but no difference at t1 (p=0.13). 237 238 table 4 . assessment of the wound therapist score in three groups at t1 and t2. year). as shown in table 2 , although the conventional analgesics were injected, the pain experience during the 249 dressing change in both groups was very strong. duo to physicians often prescribe inadequately potent analgesics or 250 inadequate doses of analgesics. the reasons for this are multi-factorial, with the primary concern that the use of drugs 251 may harm children, as a result, the limited control of pain. [17] [18] in addition to being intrinsically very painful, repeated 252 dressing changes can promote anxiety, making subsequent changes even more distressing. 11-12, 18 253 254 additionally, psychological expressions, such as panic, crying and screaming result from a lack of a sense of safety due 255 to the memory of pain from past treatment when face medical workers. 19 thus, if patients do not receive effective pain 256 relief, physiological problems may result and negatively affect their perseverance in treatment. 20 therefore, to reduce 257 children's crying during the procedure, an intervention should be performed to reduce children's memory of pain 258 resulting from the medical staff. 259 as the table 2 shown, there were significant differences in the scores of pain at t2, t3 and t4 by inter-group 261 comparison (all p <0.001), but no difference at t1 (p=0.499). the findings indicate that with respect to phenomena 262 related to burn dressing changes, the medical screen have a significant influence in comparison with other groups as 263 the table 2 shown. 264 in addition, it could be observed from the videos that most of the children in the control or computer group started to 266 have expressions including frowning, closing their eyes, limb tensions, crying, screaming and other escaping resistance 267 actions when they entered the dressing room even before the dressing change was performed. on the contrary, most 268 of the children in the medical screen group were immediately guided to watch the programme content played on the 269 computer screen after they entered dressing room thereby the expressions above were reduced. interestingly, it could 270 be seen that most of children's crying could be reduced in the medical screen group after the parents played many kinds of programmes on the screen for pain intervention when the dressing was uncovered and bound up, except for 272 when the wound was disinfected. in each group at each time point in figure 3 and the inter-group and intra-group comparisons in table 2 in our view, the working pressure for medical workers in the burn department is higher than that in other 293 specialties, 23 and the mental stress is mainly from children's degree of cooperation during dressing and the degree of 294 recognition from parents. 24 the application of the medical screen for burn children in this study not only reduced such this study has shown that this method is effective and user-friendly, however, the study results should be interpreted 301 in light of its limitations. in this small sample clinical trial study, the use of a single site may be considered study 302 limitations. second, as patients are likely to be lost to continued monitoring, this study only assessed the effect of a 303 3-day intervention. therefore, it is essential that future research for longer periods of time. third, the lack of blinded 304 assessments by the clinicians should be a limitation (although complete blinding may not be possible). additionally, 305 perhaps there were differences in pain levels to begin with (as the cause of burn differed slightly, though not 306 significantly), this should be another limitation. last but not the least, in the early stage of this study, all ages of 307 children were included, and it was found that children aged 1-3 were the most affected, so the age was set at 1-3 years 308 old. in this regard, a large number of studies still need to be further explored. 309 according to the result of the present study, this paper strengthens relevant research, which might open the door to 312 the development of methods that can treat children burn patients in the future and so it stands to reason that the 313 special designed medical screen could have longer term efficacy. despite the limited number of previous studies 314 investigating this topic 11 , the current results provide further evidence that the special designed medical screen is more 315 effective than touch computer or usual care, suggesting that this will be a powerful and effective complement 316 treatment method for minimizing pain in children burn patients related to dressing changes. based on the findings of 317 the current study, we recommend the special medical screen can be used as a method of complement due to its pediatric burns mortality risk factors in a developing country's 323 tertiary burns intensive care unit an epidemiological analysis of paediatric 326 burns in urban and rural areas in south central china epidemiology of bedside stove burns in a 330 retrospective cohort of 5089 pediatric patients pediatric burns in military hospitals of china 334 from 2001 to 2007: a retrospective study the global burden of 337 injury: incidence, mortality, disability-adjusted life years and time trends from the global burden of disease 338 study assessing and addressing the problem of 341 pain and distress during wound care procedures in paediatric patients with burns the role of psychological management of pain, anxiety, agitation and delirium in burn 349 patients: a survey of clinical practice and a review of the current literature improvement of burn pain management 353 through routine pain monitoring and pain management protocol analgesia and sedation for children undergoing burn wound care a randomized trial of a distraction-type intervention to 360 assist in managing dressing changes for children experienced burns the effect of virtual reality distraction on pain relief during 364 children with chronic wounds on lower limbs power 3: a flexible statistical power analysis program for the 372 social, behavioral, and biomedical sciences a systematic review of the psychometric properties of the 376 modified behavioral pain scale(mbps) maternal satisfaction from simpar to cimparc: the evolution of international pain 383 research and management sedation and analgesia 386 for dressing change: a survey of american burn association burn centers md:mean difference;ci:confidence interval; ‡kruskal-wallis test key: cord-314810-ny4mnzqc authors: provenzi, livio; baroffio, elisa; ligabue, susanna; borgatti, renato title: the little professor and the virus: scaffolding children’s meaning making during the covid-19 emergency date: 2020-08-13 journal: front psychiatry doi: 10.3389/fpsyt.2020.00817 sha: doc_id: 314810 cord_uid: ny4mnzqc nan this uncertainty-together with the lack of a specific and effective treatment for the covid-19-can further feed the fears and the sense of vulnerability of citizens-both adults and children. in this context, whereas the healthcare policies adopted by different countries could help to contain and mitigate the infection spread, for most families they also represent severe restrictions to social relationships and habits (8) . previous research on the well-being of parents and children during and after healthcare emergencies suggest that both can develop post-traumatic stress symptoms (9) . increased prevalence of post-traumatic stress symptoms was reported in survivals of the sars epidemic (10) and preliminary evidence of similar psychological effects are also emerging for the covid-19 emergency (11) . notably, the stress perceived by parents may widely affect parenting behaviors (12) and the quality of parent-child interaction (13, 14) . neuroscientific (15) and epigenetic (16) evidence suggests that these stress-related parenting effects may have profound intergenerational consequences for children's emotional and cognitive development (17) (18) (19) . thus, it is not surprising that the psychological consequences of covid-19 emergency have been identified as the "second tsunami" of this unprecedented pandemic (20) . in sum, scaffolding children's meaning-making process during the present pandemic is crucial to help them cope with the emergency situation and to avoid the overwhelming and traumatic effects of misleading or partial cognitive appraisal and emotional over-reactions. it is possible to identify different ways in order to create a safe environment in which parents and other adult caregivers (e.g., teachers, educators) can help young children to deal with the covid-19 emergency. in this article, we would like to highlight four ways through which adults can guide their children through the meaning-making process: selfregulation, careful listening, simple talking, and playing and practicing together ( figure 1 ). first, parents should be in touch with their emotions and they are warranted to recognize, express, and regulate them in an adaptive way. despite school-aged children may have a greater understanding of the verbal content of adults' communications, infants are already sensitive to non-verbal cues such as looking, pointing, vocal tone, and other adults' emotional and social expressions (21, 22) . even during preschool age, children could perceive the adults' emotional state and they could respond consistently (23) . nonetheless, as especially young infants during the first two years of life may have only a partial access to the meaning of adults' communications, their "little professor"-who is constantly in search of coherent meanings-may be especially vulnerable to misinterpretations and pragmatic errors (24) . in this context, infants may use the emotional expression of the caregivers to interpret the safety of ambiguous conditions (i.e., meaning-making) and to adopt consequent problem solving actions (e.g., coping strategies). the social referencing literature has largely provided examples of this by means of the so-called visual cliff experiment. in the visual cliff, infants move on a glass-covered table divided into a shallow side under which a checkered pattern is placed right beneath the glass and a deep side under which a similar pattern is placed some distance below the glass, creating an apparent drop (25, 26) . when mothers posed a happy expression, almost all infants crossed the cliff, whereas none of the infants who observed mothers' fearful expression crossed, suggesting that at least from 12-month age infants resolve ambiguous conditions by integrating the parents' emotional expressions in their implicit meaning-making (27) . for this reason, caregivers should validate their own feelings of anxiety, fear, and worries and they should not neglect them dismissively. after all, it is in the reciprocal and mutual exchange of affective states that happen within the parent-child relationship, that children can develop appropriate and successful emotional regulation strategies and resilience to stress (28) . parents who are able to be in deep touch with their affective inner world, validating not only their positive emotional states but even depressive and anxious ones, can provide regulatory support and help their children deal with similar feelings, co-constructing with them instruments capable of adaptive emotional regulation (5) . in other words, parents who let themselves express their real emotions will also grant the same permission to their young children. reassuring children about the perceived alarm and risk for health can be successful only if it second, adults that do not neglect their own emotions can also promote a careful listening of children's affective messages and communications. by supporting their child's spontaneous emotional expression, adults can detect how the "little professor" in their child is trying to develop a coherent meaning of the situation. indeed, previous research suggests that family-based narrative approaches provide a structured opportunity to elicit parents' and children's meaning-making, assemble divergent storylines into a shared family narrative, and thereby enhance members' skills to cope with stressful and traumatic events developing hope and trust in family support (29) . careful and open listening by parents can allow children to freely express their feelings of fear and worries about the emergency within a relationship in which they may feel safe and protected (30) . it should be highlighted that this personal creative and intuitive way of meaning making which is typical of the "little professor" is often limited in options (31). it provides emotional containment and protective survival strategies that require further scaffolding and permissions from parents to allow the emergence of more functional and adaptive coping strategies to face challenging life conditions. additionally, far from hinder this intuitive thinking, adults can engage in a careful listening of children emotional world and they can understand which are the elements contributing to the emergent meaning-making process that they are developing (32) . this is a crucial step for parents to provide further explanations to children and to promote a positive dialogue about the affective states and the cognitive representations arising from the lived experience of the covid-19 emergency. moreover, it should be important to note that this particular attitude to careful listening is warranted to continue across time as new information and knowledge can arrive to the children in different moments, thus requiring continuous interactive rearrangement and mutual refinement of the meaningmaking process. third, when adults' self-regulation is in place and careful listening is available for children, caregivers can now provide active contributions to the meaning-making process by using simple language. avoiding complex concepts and explaining the emergency-related issues with age-appropriate words is crucial to clean up the messy ensemble of information to which the children are exposed (33) . for example, receiving communications expressed in simple language can help the children to understand the covid-19 symptoms, the risk factors and the appropriate behaviors needed to deal with the emergency. as the "little professor" use intuitive and analogic forms of representations, the use of metaphors, drawings and "as if" language can facilitate the integration of information by the child, stimulate curiosity and avoid the emergence of "monsters" or the persistence of scaring images in the meaning mindset of the child. moreover, mother and fathers are encouraged to talk with their child together, as a way to communicate that the family as a system is coherent and to reinforce the strength of the messages. from this perspective, observing children's spontaneous and subjective creations may allow the adults to monitor the meaning-making process that is unwinding within their inner world. fourth, the active engagement of parents during recreative activities can further scaffold children's meaning-making during the covid-19 emergency. indeed, recreational activities represent the best secure setting in which parents and their children can share meanings about the actual emergency (34) . during these moments, caregivers can enhance children's intuitive and creative thinking, offering them coherent explanations about what is happening and directly co-constructing meanings and representations. as previously mentioned, the precocious experiences of parental holding and emotional regulation are key to make meanings about the physical, social, and psychological world the child is living in. for example, drawing and playing together allow parents and children to co-create a shared symbolic and analogic language through which a sensitive emotional education process is warranted to enhance children's capacity to perceive, label, and differentiate among their own emotional feelings and affective states (35) . by playing and practicing together, parents and children develop a shared grammar of meanings that will contribute to create a safe environment for psychological, emotional, and cognitive explorations later in life (36) . in this crucial process, caregivers act like a mirror that may reflect and disentangle their child's affective states. the current italian context provides a clear example of this co-creation, which is the shared drawing of rainbows with the claim "everything will be all right". this symbolic creation highlights the importance to develop a common symbolism within the family that can also be shared on-line with peers, contributing to support hope and resilience for the future (37, 38) . in sum, in times of such an unprecedented global healthcare emergency, adults have the responsibility to take care and partner with children in producing integrated, coherent, and adequate meaning-making on the pandemic (39) . in fact, young children create internal representations of their experiences of "being-with" the adult caregivers who support them to make sense about the surrounding environment (40) . the cognitive and emotional appraisal of subjective experiences by the "little professor" allow the development of adaptive reactions to the situation and peculiar and subjective survival strategies. for this reason, by helping the present generation of children in dealing with the covid-19 emergency, we hope adults can successfully contribute in nurturing a new generation of human beings that will share enhanced resiliency when faced with future unexpected and stressful events. what do you say after you say hello! the psychology of human destiny a comprehensive textbook on transactional analysis the little professor: reflection on the structure development and evolution of the adult in the child acoustic markers of prominence influence infants' and adults' segmentation of speech sequences the power of disconnection during the covid-19 emergency: from isolation to reparation unpacking the black box: how to promote citizen engagement through government social media during the covid-19 crisis covid-19 and italy: what next? measuring italian citizens′ engagement in the first wave of the covid-19 pandemic containment measures a cross-sectional study the role of parents parenting and the family environment in children's post-disaster mental health risk factors for chronic post-traumatic stress disorder (ptsd) in sars survivors psychological status of parents of hospitalized children during the covid-19 epidemic in china maternal stress and sensitivity: moderating effect of positive affect emotional stress during pregnancy-associations with maternal anxiety disorders infant cortisol reactivity and mother-child interaction at pre-school age maternal caregiving and dna methylation in human infants and children: systematic review mother-infant attachment and the intergenerational transmission of posttraumatic stress disorder intergenerational transmission of trauma effects: putative role of epigenetic mechanisms parental advisory: maternal and paternal stress can impact offspring neurodevelopment intergenerational effects of maternal ptsd: roles of parenting stress and child sex systematic review of pediatric health outcomes associated with childhood adversity ptsd as the second tsunami of the sars-cov-2 pandemic infants' understanding of the link between visual perception and emotion social cognition in the first year child and adolescent emotion regulation: the role of parental emotion regulation and expression infants' perseverative search errors are induced by pragmatic misinterpretation fathers' versus mothers' social referencing signals in relation to infant anxiety and avoidance: a visual cliff experiment maternal emotional signaling: its effects on the visual cliff behavior of 1-year-olds social referencing in infancy: important findings and future directions in the everyday stress resilience hypothesis: a reparatory sensitivity and the development of coping and resilience enhancing family resilience through family narrative co-construction parental experiences of supporting children with clinically significant post-traumatic distress: a qualitative study of families accessing psychological services mutual regulation and unique forms of implicit relational knowing healing chronically traumatised children through their families/whanau working and playing together: prediction of preschool social-emotional competence from mother-child interaction what mothers do: everyday routines and rituals and their impact upon young children's use of drawing for meaning making the foundational level of psychodynamic meaning: implicit process in relation to conflict defense and the dynamic unconscious resilience theory and research on children and families: past present and promise infants' meaning-making and the development of mental health problems protecting the psychological health of children through effective communication about covid-19 disentangling the dyadic dance: theoretical methdological and outcomes systematic review of mother-infant dyadic processes key: cord-309860-otx45b8x authors: conway, nicholas t.; wake, zoe v.; richmond, peter c.; smith, david w.; keil, anthony d.; williams, simon; kelly, heath; carcione, dale; effler, paul v.; blyth, christopher c. title: clinical predictors of influenza in young children: the limitations of “influenza-like illness” date: 2012-09-03 journal: j pediatric infect dis soc doi: 10.1093/jpids/pis081 sha: doc_id: 309860 cord_uid: otx45b8x background: influenza-like illness (ili) definitions have been infrequently studied in young children. despite this, clinical definitions of ili play an important role in influenza surveillance. this study aims to identify clinical predictors of influenza infection in children ≤5 years old from which age-specific ili definitions are then constructed. methods: children aged 6–59 months with a history of fever and acute respiratory symptoms were recruited in the western australia influenza vaccine effectiveness (waive) study. clinical data and per-nasal specimens were obtained from all children. logistic regression identified significant predictors of influenza infection. different ili definitions were compared for diagnostic accuracy. results: children were recruited from 2 winter influenza seasons (2008–2009; n = 944). of 919 eligible children, 179 (19.5%) had laboratory-confirmed influenza infection. predictors of infection included increasing age, lack of influenza vaccination, lower birth weight, fever, cough, and absence of wheeze. an ili definition comprising fever ≥38°c, cough, and no wheeze had 58% sensitivity (95% confidence interval [ci], 50–66), 60% specificity (95% ci, 56–64), 26% positive predictive value (95% ci, 21–31), and 86% negative predictive value (95% ci, 82–89). the addition of other symptoms or higher fever thresholds to ili definition had little impact. the centers for disease control and prevention definition of ili (presence of fever [≥37.8°c] and cough and/or sore throat) was sensitive (92%; 95% ci, 86–95), yet lacked specificity (10%; 95% ci, 8–13) in this population. conclusions: influenza-like illness is a poor predictor of laboratory-confirmed influenza infection in young children but can be improved using age-specific data. incorporating age-specific ili definitions and/or diagnostic testing into influenza surveillance systems will improve the accuracy of epidemiological data. population surveillance is used to guide preventative strategies for influenza such as choosing strains for seasonal influenza vaccine constitution and early identification of pandemic or epidemic antigenic drift variants [1] . early diagnosis of influenza disease also influences clinical decision making, especially when managing those at higher risk of severe disease [2] . influenza disease surveillance usually includes a combination of community-and hospital-based syndromic surveillance and routinely collected data concerning morbidity and mortality, with only some including laboratory confirmation of influenza infection. consistent with other countries, australian children <5 years old experience the highest laboratoryconfirmed influenza notification rate (3.4 times the rest of the population in 2008), the highest rate of general practice consultations with influenza-like illness (ili) ( 50 000/100 000 population in 2008), and the greatest morbidity [3] . in the united states, children <5 years comprised 28% of ili presentations in the centers for disease control and prevention (cdc) national network during the 2007-2008 influenza season [4] . the value of these data using ili surveillance depends on a reliable and robust definition of ili as well as a clear understanding of how ili activity relates to influenza. the definition of ili varies between countries and surveillance systems, but it usually includes the presence of fever and symptoms of acute respiratory tract infection [5] [6] [7] . influenza-like illness is a poor predictor of actual influenza infection in adults, despite attempts to improve the accuracy of the definition [8] , but there is limited data on the reliability of ili in predicting influenza infection in children [9] [10] [11] [12] . in this study, we have used data collected from young children recruited as part of a community and hospital influenza surveillance program to assess the clinical predictors of influenza infection in children 5 years old. we developed age-specific ili definitions and tested their diagnostic accuracy against existing definitions and parental opinion. the western australia influenza vaccine effectiveness (waive) study is an observational study designed to measure influenza vaccine effectiveness in children. the study design has been described elsewhere [13, 14] . in brief, children 6-59 months of age were eligible for participation if they presented with symptoms suggestive of an acute respiratory infection to selected general practices (2008 only), emergency departments (eds; 2008 and 2009), and pediatric inpatient facilities (2008 and 2009 ). the recruitment period was for the duration of the winter influenza season as determined by local population surveillance. children were eligible for enrollment in 2008 whether they had a history of fever (by parental report) or a measured temperature >37.8°c on presentation in addition to any acute respiratory symptoms within 72 hours before recruitment. to enhance recruitment in 2009, children were enrolled whether they had a history of fever or a measured temperature of >37.5°c on presentation plus the presence of any acute respiratory symptoms within 96 hours of recruitment. the study received approval from the relevant local human research ethics committees. on enrollment by trained research staff, parents were asked to complete a questionnaire detailing demographics, medical history, and presenting symptoms. temperature measured at enrollment was recorded by research staff. per-nasal swabs (copan diagnostics inc., murrieta, ca) placed in viral transport medium or per-nasal aspirates were collected. influenza testing on nasal swabs was performed by polymerase chain reaction (pcr) directed at hemagglutinin and matrix gene targets in multiplex real-time assay [14, 15] , and by conventional cell cultures [14] . in addition, samples underwent pcr directed at other common respiratory viruses including respiratory syncytial virus (rsv), parainfluenza viruses 1-3, human metapneumovirus, rhinoviruses, adenoviruses, coronaviruses (other than severe acute respiratory syndrome coronavirus), and bocavirus [14] . presence of influenza a or b detected by pcr or culture was collapsed into 1 dichotomous dependent outcome: influenza present or absent. the predictor variables of interest fell into 2 groups: (1) demographic factors (age, sex, race [indigenous or other], deprivation quintile, influenza vaccination status, prematurity [<37 completed weeks gestation], birth weight, past medical history, child care usage, household composition, and household smokers); and (2) symptomatology (recorded temperature and presence or absence of parentally reported: cough, coryza, wheeze, breathing difficulties, earache, sinusitis, sore throat, irritability, rash, diarrhoea, vomiting, lethargy, poor feeding, sleep disturbance, fever, and pallor). vaccination status was verified via the australian childhood immunisation register (acir) [16] . where acir conflicted with parental report, the family doctor was contacted to establish the number of trivalent influenza vaccine (tiv) doses given previously. because they are not normally distributed, categorical variables were created for age, household composition, and duration of fever and respiratory symptoms. postal addresses were geo-coded before conversion to deprivation quintiles using data produced by the australian bureau of statistics [17] . statistical analysis was performed using spss 16.0.0 (spss inc., chicago, il). after initial univariate analysis, variables were analyzed simultaneously within both groups (demographic factors and symptoms) by forced entry into a multivariable logistical regression model. factors found to be significant (p < .05) at the group stage were then entered into a model encompassing both groups. various definitions of ili were then constructed based on the significant predictors of influenza infection. sensitivity, specificity, and positive predictive value (ppv) and negative predictive value (npv) and their respective binomial 95% confidence intervals (cis) were then calculated. in addition, positive and negative likelihood ratios (lr+ and lr-) were also calculated. ninety-five percent cis for likelihood ratios were calculated in the manner described by simel et al [18] . new ili definitions were compared with definitions used by the cdc ( presence of fever (100 o f [37.8°c ]) and a cough and/or sore throat in the absence of a known cause other than influenza [5] ) and parents' response to the questionnaire question: "do you think your child has influenza ('flu')?" nine hundred and forty-four subjects were recruited (315 subjects in 2008 and 629 subjects in 2009). the majority were recruited within the hospital setting (general practice, 153 subjects; eds, 619 subjects; inpatient wards, 172 subjects). twenty-five subjects were withdrawn (specimens not processed, 8; invalid consent, 8; incorrect age, 3; other, 6), resulting in a total sample population of 919. altering the eligibility criteria in 2009 did not result in any additional recruits that were ineligible by 2008 criteria: 17 subjects had a temperature recorded >37.5°c yet <37.8°c; however, all of these subjects also had a history of fever within the previous 72 hours. respiratory viruses were identified in 711 subjects (77.4%). rhinovirus (n = 239), rsv (n = 210), and influenza virus (n = 179) were most frequently detected. of those in whom influenza was detected, 131 had influenza a (including 97 subtyped as influenza a/h1n1 2009) and 48 had influenza b. cultures proved positive for 59% (77 of 131) of those with influenza a and 58% (28 of 48) of those with influenza b. influenza was detected in 23.5% (74 of 315) of recruits in 2008, compared with 17.4% (105 of 604) of eligible recruits in 2009 (p = .03). the median age was 22 months and 526 of 919 (57%) were male. chronic comorbidities were uncommon: 140 children (15%) had a comorbid condition, of which asthma was the most common (89 of 919, 10%). premature births (<37 weeks gestation) accounted for 122 of 919 (13%) subjects. nearly one-half of all children enrolled (430 of 919, 47%) had received the recommended schedule for seasonal influenza vaccination (ie, 2 doses of tiv in the first year of vaccination followed by 1 dose in subsequent years [19] ) with a further 126 of 919 (14%) having received 1 dose in total ( table 1) . the most common symptoms reported by parents were cough (794 of 919, 86%), coryza (801 of 919, 87%), poor feeding (686 of 919, 75%), sleep disturbance (657 of 919, 71%), and irritability (607 of 919, 66%), although wheeze and respiratory distress were less prevalent (410 of 919, 45% and 413 of 919, 45%, respectively) ( table 2 ). for those that tested positive for influenza, the average temperature at enrollment was 39.5°c (range, 37-43.0; standard deviation . five hundred and ninety-eight parents recorded a response to the question, "do you think your child has influenza ('flu')?" seventy-eight of the 333 (23%) answering "yes" proved positive for influenza, whereas 24 of the 265 (9%) answering "no" were positive for influenza (p < .001). age >2 years, lack of tiv, lower birth weight, sharing a home with 2 or more other children, and being cared for by a single adult were significant demographic predictors of influenza infection on univariate analysis (table 3) . with the exception of the number of adult household members, all of these variables were significant when entered simultaneously within this group, and so they were entered into the final model. the symptoms that were significant univariate predictors of influenza infection were as follows: raised temperature, fever for >3 days, presence of cough, absence of wheeze, respiratory distress, and rash. fever, presence of cough, and absence of wheeze remained significant when entered simultaneously within the symptom group, and so they were retained for the final model. with the exception of number of children in the house, all variables entered into the final model remained significant (see table 3 ). based on the results of the regression equation, ili was defined in this population using various combinations of the following criteria: presence of cough, absence of wheeze, and incremental thresholds of fever (see figure 1 and table 4 ). a complete data set for each of these variables was available for 798 cases, which were used for subsequent calculations of the performance of ili definition. the presence of cough alone was highly sensitive (93%; 95% ci, 84-96) yet lacked specificity in diagnosing influenza infection (14%; 95% ci, [12] [13] [14] [15] [16] [17] . if the definition of ili comprised cough and the absence of wheeze, sensitivity was reduced (60%; 95% ci, 52-68) but specificity improved (59%; 95% ci, 55-63). the addition of fever 38°c to this definition resulted in a small the above analyses were repeated with data stratified according to vaccination status (no tiv vs any tiv) and age group (2 years vs >2 years) (see supplementary digital content). the observed ppvs in the unvaccinated group were significantly greater than the vaccinated group. subgroup analysis of each vaccination group stratum by year of illness was undertaken with no appreciable difference noted (data not shown). for those 2 years, an ili definition that included fever 38°c, cough, and the absence of wheeze had a significantly lower sensitivity and ppv and a higher specificity compared with those >2 years. the reliability of parental opinion was unaffected by vaccination status or age group of child. young children and infants with seasonal influenza can present with a wide variety of symptoms and may not yet be developmentally capable of verbalizing symptoms to their caregivers [20] . current definitions of ili are largely derived from adult studies and lack validation within the pediatric setting [5] [6] [7] . fever is a common presenting symptom for young children with influenza. when all children with acute respiratory illness (irrespective of presence or absence of fever) are tested, 95% of those who test positive for influenza had a history of fever [21, 22] . systematic review of the literature has failed to find any particular combination of additional symptoms that can reliably predict influenza infection [8] . only 2 studies in this systematic review enrolled preschool children: in 1 study, 18 of 610 cases with fever and respiratory illness were <5 years old [9] , whereas the other did not stratify by age [10] . later, ohmit and monto [11] reported a ppv of 64% in a subset of 221 children <5 years old presenting with cough and fever (>38.2°c). the generalizability of these figures is limited, however, because the study design excluded children with rsv infection, which would have falsely elevated the incidence of influenza infection in the study population [11] . a further prospective pediatric study assessing the predictive nature of an ili diagnosis in children with fever and symptoms suggestive of respiratory infection (n = 128; age <17 years) did not stratify results by age, making it less generalizable to younger children [12] . this study recruited young children presenting with acute respiratory symptoms during 2 successive winter influenza seasons, which included the first wave of pandemic influenza a/h1n1 2009. in this population, we have found that an existing ili definition in common usage (cdc definition) proved highly sensitive yet lacked specificity in identifying those with influenza infection. a surveillance system that uses this ili definition in isolation would therefore grossly overestimate influenza prevalence by virtue of the large number of false positives generated. in contrast, we found that an ili definition comprising fever 38°c, cough, and absence of wheeze achieved a greater balance between sensitivity and specificity in the study population. however, ili was a poor predictor of influenza infection regardless of which definition was tested. children with ili had a 20%-30% probability of actually having influenza infection, whereas those without ili (regardless of definition tested) had a 10%-15% probability of testing positive for influenza. each definition tested had positive and negative likelihood ratios approaching 1, indicative of little appreciable change in the odds of an individual having disease if they met ili definition criteria or not. furthermore, parental prediction of influenza infection in their children compared favorably with use of an ili definition, underlining the poor diagnostic accuracy of ili overall. decisions regarding the investigation and management of children suspected of having influenza take into account a number of factors, including the known incidence of influenza at that time, the likelihood of severe disease, and the availability of antiviral medication [2] . however our findings would suggest that, due to the inaccuracy of syndromic definitions, clinicians should maintain a low threshold for influenza testing in children with possible influenza. this is especially important for children with moderate to severe illness and/or those requiring hospitalization. similarly, diagnostic testing is required to obtain accurate influenza surveillance in young children. ideally, this should include testing by highly sensitive and specific methods such as pcr, although immunofluorescent antigen detection tests are sufficiently sensitive for use on nasopharyngeal aspirates. the rapid antigen tests have been used in some studies [23, 24] , but they are less sensitive than laboratorybased tests (especially for influenza a/h1n1 2009); their performance is influenced by specimen type, test brand used, and the virus type and subtype; and they do not identify influenza a subtypes. these tests have been successfully incorporated into public health influenza surveillance systems in the past [25] ; however, they need to be reassessed now that influenza a/h1n1 2009 is circulating. the eligibility criteria for our study included a history of fever. this methodology is similar to a number of previous studies [9] [10] [11] [12] and highlights the need for external validation of any clinical predictor tool that is intended to be used in unselected populations. however, our findings remain relevant to the general pediatric population given that the vast majority of children with influenza present with fever [21, 22] . the diagnostic accuracy of ili differed between those vaccinated and those unvaccinated (reflecting the lower prevalence of influenza in those who were vaccinated). the pediatric population studied had high vaccination rates with tiv as a result of a state-wide campaign introduced in 2008 that provides free seasonal influenza vaccination to this age group. the high prevalence of influenza vaccination in our study population contributes to the generalizability of our findings to other countries where influenza vaccination is readily available to children <5 years of age. the reliability of ili as defined by fever (38°c), cough, and absence of wheeze was age dependent, with less sensitivity and greater specificity in those 2 years of age or younger. this is a reflection of proportionally higher numbers of children 2 years old with wheeze irrespective of influenza status (data not shown), presumably as a result of a bronchiolitic-type illness. this age-dependent manifestation of influenza infection further highlights the problems inherent in applying adult-derived ili definitions to the pediatric population. because the presence of wheeze was determined by the parents, the calculated prevalence is likely to be different from one based on a clinical definition [26] . however, because this bias is constant between those who tested positive for influenza and those who were negative, it is not expected to have affected the results. also, in practice, assessing children with an ili usually relies on parental history as well as clinical findings, making our findings relevant to real-life circumstances. to our knowledge, this is the first study attempting to construct a definition of ili for children aged 5 years and under using prospectively gathered data from a general pediatric population presenting with symptoms suggestive of acute respiratory tract infection. we have demonstrated that when predicting influenza infection in younger children, an ili definition constructed using age-specific data and comprising presence of fever (38°c), cough, and absence of wheeze results in a greater balance between sensitivity and specificity compared with a definition of ili used by current surveillance systems. the diagnostic accuracy of influenza virus surveillance systems would be enhanced by developing age-specific ili definitions aimed at the pediatric age group and/or by incorporating diagnostic testing into the system. author contributions. n. t. c. and z. v. w. analyzed the data and revised the manuscript. p. c. r., d. w. s., a. d. k., s. w., h. k., d. c., and p. v. e. devised the waive study and revised the manuscript. c. c. b. supervised the present study, analyzed the data, and revised the manuscript. financial support. the waive study is funded by the western australia department of health. potential conflicts of interest. n. t. c., p. c. r., and c. c. b. are members of the vaccine trials group, telethon institute for child health research. the vaccine trials group has received funding from vaccine manufacturers for conducting clinical trials, although not in relation to this study. p. c. r. has served on a scientific advisory board regarding influenza vaccines for csl ltd., has received travel support from baxter and glaxosmithkline to present at scientific meetings, and received institutional funding for investigator-led who global influenza surveillance network 2010-11 influenza antiviral medications: summary for clinicians annual report of the national influenza surveillance scheme -8 influenza season overview of influenza surveillance in the united states heterogeneous case definitions used for the surveillance of influenza in europe working towards a simple case definition for influenza surveillance does this patient have influenza? evaluation of clinical case definitions of influenza: detailed investigation of patients during the 1995-1996 epidemic in france diagnosing influenza: the value of clinical clues and laboratory tests symptomatic predictors of influenza virus positivity in children during the influenza season clinical predictors of influenza in children lessons from the first year of the waive study investigating the protective effect of influenza vaccine against laboratoryconfirmed influenza in hospitalised children aged 6-59 months vaccine effectiveness against laboratory-confirmed influenza in healthy young children. a case-control study duplex real-time reverse transcriptase pcr assays for rapid detection identification of pandemic (h1n1) 2009 and seasonal influenza a/h1, a/h3, and b viruses australian childhood immunisation register seifa: socio-economic indexes for areas likelihood ratios with confidence: sample size estimation for diagnostic test studies the australian immunisation handbook 9th edition clinical presentation of influenza in unselected children treated as outpatients the underrecognized burden of influenza in young children performance of six influenza rapid tests in detecting human influenza in clinical specimens accuracy and interpretation of rapid influenza tests in children enhancing public health surveillance for influenza virus by incorporating newly available rapid diagnostic tests what do parents of wheezy children understand by "wheeze"? [see comment epidemiological research from glaxosmithkline and csl ltd. d. w. s. is a director of 2 not-for-profit organizations (the influenza specialist group and the asia-pacific alliance for the control of influenza) that receive funding from vaccine manufacturers. all other authors report no potential conflicts.all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord-023239-06a03o14 authors: nan title: ii. topic sessions date: 2016-06-10 journal: pediatr pulmonol doi: 10.1002/ppul.23455 sha: doc_id: 23239 cord_uid: 06a03o14 nan although the majority of children with asthma achieve symptom control on low or moderate doses of maintenance inhaled steroids, there is a small proportion that remain uncontrolled despite high doses of prescribed maintenance therapy. these children are prescribed treatments equivalent to stage 4/5 of the british thoracic society (bts) guidelines for asthma management, and either need at least this amount of therapy to achieve control, or have persistent symptoms and frequent exacerbations despite maximal treatment. children with poor control despite maximal prescribed therapy have problematic severe asthma 1 . however, the reasons for poor control may be very varied and can broadly be divided into two sub-categories. the first, "difficult asthma" is the term used to describe patients whose asthma is difficult to control because of a failure to address the basics of asthma management, an incorrect diagnosis has been made, or there has been a failure to address associated comorbidities. underlying reversible and modifiable factors that can result in poor control include poor adherence, unfavourable environmental exposures such as tobacco smoke and aero-allergens to which the patient is sensitised, poor inhaler technique and psychosocial issues 2 . if modifiable factors are successfully identified and addressed, then control can be achieved in children with difficult asthma without the need for escalating therapy or additional invasive investigations. a multidisciplinary team (mdt) is critical to enable modifiable factors to be identified and addressed in children with difficult asthma. the team must include specialist respiratory nurses, a psychologist, pharmacist, physiotherapist and medical staff. significant resources are therefore required to manage paediatric difficult asthma optimally and only specialist centres should be tasked with the assessment of these patients. although this may have an impact on healthcare resources, long term benefits for lung health are significant. the second sub-category of children that have poor asthma control despite maximal therapy are those with true severe asthma. these patients remain with persistent symptoms, or can only be controlled on maximal doses of maintenance therapy, often including oral steroids, after underlying reversible or modifiable factors have been identified and addressed 3 . importantly, more than half of all children with problematic severe asthma have difficult asthma because of underlying modifiable or reversible factors preventing asthma control 4 . therefore, the overall approach to managing a child with problematic severe asthma includes an initial step to identify and treat difficult asthma, and if symptoms persist after this, true severe asthma can be confirmed, which requires additional investigation and management 5 . very clear criteria and definitions that allow distinctions between difficult and severe asthma have been specified for both adults and children aged six years and above by the european respiratory society and american thoracic society 3 . an important point to consider when faced with a child that has poor asthma control despite maximal doses of prescribed maintenance therapy is that once above a threshold of treatment (>800mcg/day or equivalent of budesonide), the child should be referred to a specialist for further management. the national review of asthma deaths in the uk identified 20% of asthma deaths occurred in patients who should have been referred to a specialist for management of problematic asthma 6 . the modifiable factors that result in a child having difficult asthma may be identified extremely efficiently if the mdt approach described is adopted. however, what remains equally important is the continuing assessment and follow-up of patients with difficult asthma in order to ensure: 1. maintenance therapy is reduced to the minimal amount needed to achieve control 2. symptoms do improve after all modifiable factors have been addressed, and there is no progression to true severe asthma à either after short term follow-up or in the longer term 3. the basics of inhaler technique / device / adherence / allergen exposure are all being maintained a retrospective analysis of follow-up of children with difficult asthma for up to six years revealed that those in whom underlying modifiable factors were identified and addressed had an improvement in lung function and reduction in exacerbations over time, while being able to reduce maintenance dose of inhaled steroids such that the majority fell below the threshold for problematic severe asthma 4 . however, there was a large drop out in the number of patients that could be traced for the full six years, highlighting the need for better prospective longitudinal data of outcomes for children with difficult asthma. these missing data are essential in light of recent cohort studies that have followed children with severe asthma to adulthood and shown the irreversible reduction in lung function and prevalence of copd 7 . asthma is one of the most common chronic diseases in children, with a high prevalence in many developed and developing countries. worldwide prevalence of asthma in children varies from 1.6-36.8% according to the international study of asthma and allergies in childhood (issac) study. (1) despite its high prevalence, information about the prevalence of severe asthma in children is unknown, particularly in countries in transition. some estimates come from different studies that have shown that the prevalence of severe asthma in a general population is approximately 0.5-5% among children with asthma, however its true prevalence in a low-income country is unknown. (2) (3) (4) according to issac phase iii, the centers with the highest prevalence of severe asthma symptoms were mostly from english language countries, latin america, africa, the indian subcontinent and the eastern mediterranean. (5) lack of control of the disease has been attributed to various factors such as low accessibility to basic medications, weak healthcare services, poor compliance with prescribed therapy, lack of asthma education, and social and cultural factors. in general, asthma in both children and adults represents a significant problem in public health given the reduced quality of life, school or work absenteeism and increased healthcare costs, especially in countries in transition. in addition, asthma severity and control in childhood are of particular importance as they have been shown to translate into asthma morbidity in adulthood. (6) practical guidelines addressing the management of severe asthma in children have pointed out various aspects important in the development of this condition: medication issues, the environment, asthma education, comorbidity, and psychological problems. worldwide, but particularly in countries in transition, both intrinsic (race, ethnicity, weight) and extrinsic (exposure to allergens, indoor or outdoor pollutants) factors may overlap in a single child to enhance or diminish asthma control and severity. different to many developing countries from other continents, asthma is highly prevalent in latin america. moreover, issac phase iii showed that asthma prevalence in this region is still on the rise. furthermore, evidence suggests that poorly controlled asthma in some areas of latin america leads to significant economic costs attributed to emergency and unscheduled visits, and high mortality rates from asthma. (7) similar to other regions, asthma control is not obtained in most patients, despite available management guidelines and evidence of ics as controllers. several surveys have shown that close to 2.4% of all patients met all the gina criteria for total asthma control, proposing under-recognition of uncontrolled asthma, underuse of appropriate controller treatment, inadequate patient education, and patient denial as possible explanations. (8) also, several risk factors such as poverty, environmental factors, diet, genetics, vitamin d deficiency and tobacco smoking have detrimental effects on asthma control. cross-sectional data from 616 children with asthma in costa rica suggested that low serum vitamin d detected in children with mild to moderate asthma is associated with asthma severity. (9) since the development of worldwide guidelines on the diagnosis and management of asthma, special attention on achieving and maintaining asthma control as the key goal in asthma treatment has been a priority. in clinical studies of children with asthma, satisfactory asthma control can be achieved and maintained in most patients by regular treatment with ics. nevertheless, large population-based surveys consistently show that poor asthma control is common in many children with asthma, despite ics treatment. (10) other several studies have shown a reduction in the number of hospitalizations caused by asthma in various countries in transition when effective preventive and controller measures are implemented, (11) mainly avoidance of risk factors, importance on the use of basic medications and patient education. patients should be educated about the cause of asthma, what triggers the condition, how it should be monitored and managed and, importantly, the outcomes that can be expected and when to recognize lack of asthma control. moreover, health professionals should also be educated regarding under-recognition and under-treatment of asthma, as patients or parents tend to deny the severity of symptoms. in a recent study performed in costa rica (12) , we aimed to examine trends in hospitalization and mortality due to asthma over a 15-year period (1997-2011) , in particular following a national asthma plan (nap). this nap consisted of education meetings at all major public health care centers, emphasizing early diagnosis, early treatment using ics as first-line therapy for asthma control, early use of reliever medication to treat exacerbations, appropriate referral to specialists for asthma care, and avoidance of common allergen sources (e.g. dust-mite and cockroaches) or tobacco smoke. concurrent with this program, general practitioners, pediatricians and internists were first allowed to prescribe ics for asthma (only pulmonologists or allergists could prescribe ics before 2003). as a result of the implementation of the nap, the total number of asthma hospitalizations in costa rica in both children and adults decreased by approximately 53% over this period. in children younger than 10 years, hospitalizations for asthma were reduced by 57% in boys and 54% in girls between 1997 and 2011. in addition, the number of deaths due to asthma decreased by 80% over the 12-year period, with a more marked reduction occurring after implementation of the nap. in parallel with the decrement in asthma hospitalization and mortality, the number of prescriptions for ics (beclomethasone) increased by 129%. in summary, asthma prevalence in deprived regions is high and shows increased severity. reasons for inadequate asthma control in poor populations include low accessibility to effective controller medications, weak infrastructure of health services for the management of chronic disease, poor adherence to therapy, lack of educational approaches, and social, cultural and language barriers. however, recent studies have shown several alternatives to control its burden and improve outcomes. there is urgent need for more research into severe asthma, in particular in children in countries in transition. it has now become a much used adage that asthma is not a single disease but rather multiple diseases which present with common symptoms [1, 2] . this paradigm has been fundamental in shaping the way we think about asthma and possible approaches to treatment and management strategies. if one is not treating a single disease when we talk about what is commonly known as the syndrome of asthma, then we need a more personalised medication strategy to treat these different syndromes. alongside this acknowledgment of moving medicine towards more personalised treatment and management strategies, statistics and machine learning have been instrumental in helping us to shape the face of medicine by fostering engagement between clinicians, basic scientists, statisticians and mathematical modellers in order to attain a more unbiased approach to classifying different subgroups of patients using probabilistic models. the proliferation of genetic, molecular, clinical and biological data has made it necessary to use a cross-disciplinary approach to understanding the underlying mechanisms which precipitate distinct profiles of asthma and allergic disease during childhood. statistical analysis to understand subtypes of childhood wheezing the seminal paper by martinez et al. [3] was the first to propose the existence of different subgroups of childhood wheezing. based on visual assessment of patterns of wheeze during childhood using data from the tuscan children's respiratory study, they identified four groups of wheezers: "no wheeze", "transient early wheeze", "late-onset wheeze" and "persistent wheeze". this classification has been used as a classical basis for subsequent definitions of distinct subgroups of wheeze and has provided the building block for statistical pattern recognition-based methods to identify heterogeneous groups of children based on probabilistic modelling of the longitudinal profiles of asthma and wheeze over time. one such statistical technique is latent class analysis. latent class analysis assumes that the longitudinal fluctuation observed in data is measured with uncertainty. some of this uncertainty is due to random error, but another element of this uncertainty may be due to the existence of a subgroup or latent class which explains some of the heterogeneity in clinical measures which is not directly observed. henderson et al. were the first to apply such models using a data-driven approach based on wheeze observations from the avon longitudinal study of parents and children [4] . using latent class analysis based on parental reporting of wheeze, this group identified two additional phenotypes to those identified by martinez et al.: "prolonged early" and "intermediateonset" wheeze. this classification has been replicated in other studies. [5] one of the caveats of basing these modelling strategies on parental reporting of wheeze is that parents may not be able to correctly ascertain a clinical diagnosis of wheeze [6] . in light of this, belgrave et al. extended these methods by jointly modelling data from both parental questionnaires and general practitioner records which provided complementary data to give a more accurate measure of wheeze [7] . this model identified two classes of persistent wheeze: a "persistent controlled wheeze" group and a "persistent troublesome wheeze" group who had poorer lung function and more reactive airways compared to the other wheeze groups, including the "persistent controlled wheeze" group. where machine learning begins and statistical modelling ends identifying consistently defined and optimal numbers of subgroups of wheeze across different cohorts is challenging. within the era of "big data" rather than focusing on traditional statistical methodology, the medical field is looking towards data science as a means to extract knowledge and meaning from the vast quantity of information provided by clinical data. to achieve this, both traditional statistical inference methods based on robust assumptions and machine learning models which are more amenable to data complexity, breadth and depth. although there is overlap between the functionality of machine learning and statistics, the flexibility of machine learning is driven towards learning from data and integrating new information in order to update models and create more accurate models with better model performance. the programmatic focus of machine learning which incorporates vast amounts of computational power provides an excellent framework where tools traditionally used for statistical modelling would be unable to accommodate large, multi-scale datasets. in the near future, the capability of machine learning to be able to learn from data interactively may facilitate computer-assisted reasoning in identifying subgroups of patients. identifying such subgroups may be crucial in proposing effective personalised treatment strategies. such an approach will also allow us to capitalise on the existent data. as data-transparency and data-sharing become more widespread in the global community, we will have a better understanding of the evolution of asthma and allergic diseases. research into identifying heterogeneous subgroups of asthma and allergic disease has reached crucial milestones. we have moved from a subjective approach to classifying subgroups of wheezers, whereby the clinician gives a clinical assessment or diagnosis of the most likely subgroup based on observed clinical history, and we are moving towards computer-assisted reasoning, whereby we can use new information to predict the most likely class assignment based on models derived from prospective data. such reasoning would also allow us to model the evolution of asthma and allergic diseases in the future. populations of microbes (such as bacteria and yeasts) inhabit the skin and all mucosal surfaces. healthy individuals host thousands of different types of bacteria and different body sites have their own distinctive communities, with estimates suggesting that 50%-90% of all the cells in the human body are microbes. the highest density and greatest diversity of bacteria is found within the gastrointestinal tract. research suggests that the relationship between the microbiome and humans is not only commensal (a non-harmful coexistence), but is a mutualistic, symbiotic relationship with benefits for both (1) . even though we live in such a "dirty" bacterial world, infections due to bacteria are relatively very rare in individuals with a competent immune system. the microorganisms that make up a microbiome perform a wide range of useful functions, such as fermenting unused energy substrates, educating the immune system, preventing growth of pathogens, regulating the development of organs such as the gut, producing vitamins for the host and producing hormones to influence host metabolism such as directing the host to store fats. in particular, specific microbe-host interactions are thought to be critical for inducing mucosal tolerance and immune regulatory cells such as tregs. why do we develop "tolerance" to the microbes living in us and on us? perhaps we should consider tolerance as an alternative defense strategy. the continuous effort involved in destroying the microbes that surround us would impair organ function and require vast amounts of energy, which is not compatible with life. for this reason, it makes much more sense to have robust tolerance mechanisms that work in tune with potent effector responses, to ensure optimal host fitness. an intriguing question is that posed by the concept of the hygiene hypothesis in that altered exposure to microbes may influence the induction of tolerogenic immune responses, thereby making individuals more susceptible to react aggressively to nondangerous encounters with antigens such as allergens. the balance between immune tolerance and inflammation is regulated through the crosstalk between epithelial and immune cells with the microbiome involving many signaling pathways and molecules. direct contact with bacterial-associated structures can activate receptors (e.g. tlrs) on host cells, which induce signaling cascades resulting in both innate and adaptive polarized immune responses. the microbiome is also metabolically active and microbial metabolites have been shown to exert significant effects on host immune signaling networks (e.g. scfas and biogenic amines). the biogenic amine histamine can promote either pro-or anti-inflammatory effects depending on which of its four receptors are activated (2) . some, but not all, commensal bacteria express histidine decarboxylase (the enzyme needed to convert histidine to histamine). lactobacillus saerimneri 30a produces high levels of biologically active histamine and feeding this strain to mice resulted in a deterioration in health, particularly in histamine receptor 2 knock-out mice (3). significant efforts are underway to determine the positive and negative health effects associated with production of histamine by the microbiota (4). abnormalities in microbiome composition and/or metabolic activity have been shown in a wide range of disease states including type-2 diabetes, obesity, inflammatory bowel disease, colorectal cancer and allergies. efforts to use microbiome-associated therapeutics (e.g. probiotics) have clearly shown beneficial effects in animal models, with inconsistent findings in humans probably due to differences in the bacterial strains used. one probiotic bacterium that has shown consistent immunoregulatory effects in murine models and humans is b. longum subsp. longum 35624. murine models have demonstrated that oral consumption of this strain results in the induction of treg cells and these treg cells dampen nfkb activation, preventing excessive inflammation induced by salmonella infection (5, 6) . similarly, in humans, oral consumption induces treg cells, which is associated with increased secretion of il-10 by peripheral blood cells (7) . interestingly, this strain reduces systemic pro-inflammatory biomarkers in patients with psoriasis, ibs patients with chronic fatigue syndrome and patients with ulcerative colitis (8) . the mechanism involved includes the recognition of this bacterium via tlr-2/6 and dc-sign by myeloid dendritic cells and tlr-9 by plasmacytoid dendritic cells, resulting in changes in dendritic cell cytokine secretion and the production of metabolites such as retinoic acid (9) . however, these effects and mechanisms are not seen even with closely related bacterial strains, suggesting that the careful selection of microbes is essential for the future clinical development of immunotherapeutic microbes for allergy and asthma. overall, it can be concluded that the vast majority of microbes, which interact continuously with the host, are not bad. certain specific microbes can positively influence the host, while there is a minority that can have negative effects on the host. gwas findings are based upon association p-values below 5 ã 10 à8 , socalled "genome-wide significance", as well as replication in independent populations. this generally requires very large sample sizes and in order to obtain these, a 'team science' approach has been used where several studies have combined their data in meta-gwas. the largest gwas on asthma to date combined data from 23 different studies involving more than 26,000 individuals from the gabriel consortium and identified 6 genome-wide significant asthma loci.(1) similar meta-gwas have been conducted, for example by the eagle consortium, revealing a number of susceptibility loci for asthma-related traits, including feno,(2) eczema,(3) and allergic sensitization.(4) it could be expected that the large heterogeneity in disease phenotypes introduced by combining many different studies in meta-gwas would preclude valid discoveries. nevertheless, gwas on asthma and the related traits have resulted in identification of relatively few, but robust, loci with more consistency between studies compared to previous candidate gene studies. one example of this is the first large-scale gwas on allergic sensitization.(4) by meta-analysis of data from 16 different studies, it included a discovery phase of approximately 5,800 cases and 10,000 controls and a similar-sized replication phase. allergic sensitization was assessed objectively and defined by elevated levels of allergen-specific ige and/or a positive skin prick test. this study identified 10 loci associated with allergic sensitization at the genome-wide significant level and with robust replication. simultaneously, another large gwas was performed on allergic symptoms including approximately 54,000 individuals. (5) in spite of the large phenotype differences between the two studies, there was a high agreement in results with all of the 10 genome-wide significant loci from the sensitization study also showing strong association in the study on allergic symptoms, and previous gwas findings were confirmed. there has been some disappointment with the results from gwas. the identified loci only explain a minor part of the heritability, and the susceptibility variants identified in gwas are mainly common variants with relatively small effect sizes (often with odds ratios around 1.1 per risk allele) with no clinical relevance on the individual level. (1, 4) on the other hand, gwas have identified novel and robust susceptibility loci, with the potential to provide important understanding of disease mechanisms. also, comparison of results from gwas on different diseases and traits have increased the understanding of the mechanistic relationship between these, for example the relationship between allergic sensitization and asthma,(4) between allergen-specific ige and total ige levels, (4) and between atopy and autoimmunity. (3) (4) (5) larger, consortium-based studies on asthma and the related phenotypes are ongoing and are expected to identify many novel susceptibility loci. novel loci discovered from these larger studies are likely to have even smaller effect sizes than the ones previously found but, from the perspective of understanding disease pathology, each novel locus may potentially pinpoint a novel mechanism and a potential treatment target. furthermore, the era of genome-wide nucleotide sequencing applied on gene expression-and epigenome-profiling has brought new possibilities of combining gwas data with data from large public 'omics repositories. these data will increase the usefulness of gwas data by providing understanding of functional effects related to susceptibility loci, and future gwas on asthma and related diseases will be a part of integrated approaches to discover how different molecular layers modulate the genetic effect on disease, and will thereby be a central component in the attempt to tailor and improve medical treatment. asthma is a highly heterogeneous disease probably consisting of several subtypes of disease associated with different functional mechanisms. genetic loci may be involved in specific disease mechanisms and thereby help understanding this heterogeneity. for example, the strongest asthma locus identified in gwas, the 17q12-21 locus, seems strongly associated with an asthma phenotype characterized by onset in early childhood (1) and recurrent, severe exacerbations (6) and was stronger associated with asthma than allergic rhinitis. (5) in contrast, another locus at chromosome 11q13 has been associated with multiple allergy-related phenotypes, including allergic sensitization,(4) allergic symptoms,(5) eczema,(3) and asthma, suggesting a different, allergy-related, disease mechanism. the heterogeneous nature of asthma suggests that an alternative to increasing sample size in genetic studies is to focus on more specific phenotypes. such phenotypes are likely closer associated to specific mechanisms and the genetic substrate and might therefore increase study power. this was demonstrated by a gwas focusing on a specific asthma phenotype characterized by onset in early childhood and recurrent, severe exacerbations. (6) in spite of the relatively small sample size, this study resulted in association results of the same magnitude as previous much larger gwas (1) and with much larger effect sizes, particularly for the children with the highest number of exacerbations. one novel asthma gene, cdhr3, was identified, and it was confirmed, in a collaborative effort involving several birth cohort studies, that the cdhr3 locus was strongly associated with asthma exacerbations in the first years of life, both in individuals of european and non-european ancestry. these results highlight the potential of future genetic studies focusing on more homogenous phenotypes. one important future step is the translation of genetic associations to disease mechanisms. a major limitation of gwas is that they often merely identify a susceptibility locus without any clear relationship to a specific gene or biological function. two examples of this are the 17q12-21 and 11q13 loci mentioned above, where the underlying mechanisms are still poorly understood several years after their discovery, even though these loci are strong and probably central to the pathogenesis of asthma and allergy. one example of a gwas discovery where the functional mechanism might have been identified is cdhr3. in the discovery study (6) , it was suggested that the association to asthma was caused by a specific functional variant affecting surface expression of cdhr3. a later study reported that cdhr3 functions as a rhinovirus c receptor and showed that the functional variant associated with asthma exacerbations increases rhinovirus c binding and replication. (7) this potentially explains the underlying mechanism of this locus and identifies a target for future asthma and virology research. another major future challenge is to understand how genetic susceptibility interacts with environmental factors. gene-environment interactions are not accounted for in normal gwas and that might be one reason for the large heritability not explained by gwas findings. one important environmental risk factor for childhood asthma and other wheezing disorders is viral infections, and focusing on this environmental factor might be a tool to understanding mechanisms of asthma genes. (8) as an example, children with 17q12-21 risk variants seem more susceptible to rhinovirus infections, (9) and the finding that cdhr3 seems to be a rhinovirus c receptor (7) indicates that children carrying cdhr3 risk variants will have a specific susceptibility to rhinovirus c infections, a hypothesis that is currently being tested. only a few genome-wide gene-environment interaction studies have been performed, and the results of these have generally been disappointing without convincing findings. there are many inherent challenges in such studies. first, they might require even larger sample sizes than normal gwas, and exact information on environmental exposures is difficult to obtain in such large-scale studies. furthermore, the effect of a specific environmental exposure can be difficult to disentangle from that of other related environmental factors. an alternative approach is to perform cell or animal models where specific exposures can be controlled.(8) a recent study investigated the potentially protective effect of endotoxin and farm dust exposure in a mouse model of house dust mite-sensitized asthma.(10) it was found that a20 was an important mediator of the protective effects of endotoxin exposure, and this was validated in human bronchial epithelial cells. furthermore, a potential modifying effect of a20 was supported by 'look up' of snps located near the human tnfaip3 gene using data from an earlier genome-wide interaction study. this potential gene-environment interaction needs to be replicated, but this study exemplifies how mechanistic studies targeting specific environmental exposures and the use of experimental models can facilitate identification of genes involved in gene-environment interactions. in conclusion, improved understanding of the genetic architecture of asthma and other childhood wheezing disorders will require a combination of gwas focusing on more homogeneous subtypes of disease, geneenvironment interaction studies in birth cohorts and in cell models, and integration with other types of omics data. this challenge can only be overcome by a 'team science' approach bringing together many studies to provide sufficient statistical power and bringing together researchers from many disciplines to translate clinical associations to mechanistic understanding. such studies present great challenges but also the opportunity to understand asthma pathogenesis and heterogeneity, and ultimately to improve prevention and treatment of disease. recently, who definitions have changed to classify children with lower chest indrawing as having pneumonia rather than severe pneumonia and recommending treatment with oral antibiotics as ambulatory cases. [1] however, a recent meta-analysis reported that no single clinical feature is sufficient to accurately diagnose radiological pneumonia and that the who recommended diagnostic signs alone lack sufficient sensitivity or specificity, particularly for identifying children who need antibiotics. [2] radiological diagnosis of pneumonia has relied largely on changes on chest x-ray, principally consolidation or interstitial infiltrates. [3] however, chest x-rays are subject to variable interpretation, expose a child to ionizing radiation and require infrastructure and skill to do. recently, chest ultrasound has been suggested as a feasible imaging modality for diagnosis of childhood pneumonia. ultrasound has several advantages including that it can be used as a point-of-care test, can be taught to non-radiologists, is quick to perform and does not involve exposure to radiation. initial studies suggest that it has high sensitivity and specificity for pneumonia compared to chest x-rays. [4, 5] diagnosis of the etiology of pneumonia remains challenging as bacteremia is rare, distinguishing colonizing from pathogenic organisms may not be possible on respiratory specimens and co-infections are common. improvements in specimen collection and improved molecular techniques for detection of organisms have enabled more accurate detection of organisms, however ascribing etiology may be difficult unless the organism is invariably pathogenic. advances in specimen collection include the use of induced sputum in infants and young children, which provides a better specimen for detection of specific pathogens such as b. pertussis or m. tuberculosis. [6] urine antigen detection has not proven to be useful for pneumococcal pneumonia or for pulmonary tuberculosis in children. [7, 8] for induced sputum, testing of sequential, repeat specimens provides a higher yield for pathogens such as m. tuberculosis. [9] careful attention to specimen collection methods and use of different specimens may maximize the yield especially in the context of new sensitive molecular detection techniques. [10] with the availability of improved tools for etiological diagnosis, and with better vaccine coverage for conjugate vaccines, including pneumococcal conjugate vaccine, viral pathogens especially rsv and other bacteria, such as s. aureus or pertussis, are emerging as prominent causes of childhood pneumonia. [11] [12] [13] in areas of high tb prevalence, m. tuberculosis has been reported to be associated with acute pneumonia in children, with culture confirmed disease occurring in approximately 8% of cases. [14] however, better tools for detection of potential pathogens have also provided data on the complexity of etiology, with several potentially pathogenic organisms frequently identified in a single pneumonia episode. further delineation of the interactions between different organisms and pneumonia pathogenesis is needed. asthma affects as many as 334 million people of all ages in all parts of the world and is the commonest long-term respiratory condition affecting children in developed countries, the prevalence and morbidity varying by ethnic group 1 . accurate diagnosis and effective management of respiratory diseases such as asthma requires objective measures of lung function, but reliable use of such measures is only possible if appropriate normative ranges are available to distinguish the effects of disease and treatment from those of growth and development. evidence for ethnic differences in lung function ethnic differences in lung function have been well documented 2 . in the past, attempts to interpret observed ethnic differences in lung function were often confounded by selection bias related to use of small population samples that were not necessarily representative or generalizable, use of different methods, equipment and quality control (qc) criteria, failure to adjust for other important determinants of lung function, including socio-economic circumstances and/or inappropriate statistical analyses. in recent years, many of these problems have been addressed by applying standard methodology, inclusion criteria and qc to large, ethnically homogenous groups. current research shows that after adjusting for age, sex and standing height, forced expired volume in 1 sec (fev 1 : a measure of airway calibre) and forced vital capacity (fvc: a measure of lung size) are both reduced by approximately 14% in individuals of african ancestry (black) across the entire life span when compared with those of european ancestry (white) [3] [4] [5] [6] . similar though smaller reductions have been observed among south asian (from indian subcontinent) [7] [8] [9] and south-east asian (e.g. china, thailand, malaysia, etc) 6 subjects. since these "ethnic" reductions in fev 1 and fvc are generally proportional, the fev 1 /fvc ratio, which is the most commonly used outcome to assess airways obstruction, is usually independent of ethnic background [5] [6] [7] , suggesting that there are no structural or functional ethnic differences in lung design. thus the observed ethnic differences in lung function appear to be primarily limited to lung size rather than airway or dynamic respiratory characteristics. however, the same adjustment factor cannot be used for all lung volume outcomes. for example, there is evidence that the lower fvc found among black children can be attributed at least in part to a relatively high residual volume, suggesting that factors such as anatomic differences in diaphragmatic position or respiratory muscle strength might contribute to some of the observed differences 5 . furthermore, lung function indices that are internally adjusted for the size of the individual's resting lung volume, such as the lung clearance index (lci: a measure of gas mixing efficiency) 10, 11 or specific airways resistance (sraw: a measure of airway calibre adjusted for lung volume) 11 , do not appear to be influenced by ethnic background. nevertheless, since larger sample sizes will be required to confirm these findings, data interpretation of lci and sraw from non-white subjects should currently be undertaken with caution. recently, the global lung function initiative (gli) collated results from >74,000 healthy non-smokers aged 3-95 years to create the first allage, multi-ethnic reference equations for spirometry with appropriate age dependent lower limits of normal 6 . prediction equations were derived using the lms method, which allows simultaneous modelling of the mean (mu), the coefficient of variation (sigma) and skewness (lambda) of the distribution, and reference equations were derived for caucasians (white); african-americans (black), north-and south-east asians. these equations enable assessments to be evaluated over the entire age range using a single reference data set, thereby avoiding the errors that can occur when switching between equations, particularly during the transition between paediatric and adult care 12 . defining ethnicity ethnicity is extremely difficult to define. self-assigned ethnicity may differ from observer-assigned ethnicity and in certain countries it is against the law to record ethnic origin for any purpose. furthermore, in recent censuses in both the uk (2011) and us (2010), mixed-race populations have been shown to be the fastest-growing ethnic group. thus, classifying ethnicity may become an increasingly complex task! could differences in body proportions explain the ethnic differences in lung function? standing height is a major determinant of lung volumes, reflecting the fact that lung size is adapted to our metabolic needs. however this is not ideal since the size of the lungs is more closely related to thoracic size than leg length and differences in body proportions may underpin much of the observed ethnic variation in lung function. the size and lung function in children (slic) study was designed to improve normative reference ranges for lung function by taking differences in body physique into account to facilitate early diagnosis and treatment of lung disease in all children, irrespective of ethnic background 7 . however, of the numerous additional anthropometric measurements undertaken to quantify body physique, only sitting height and chest width significantly contributed to the prediction of spirometric lung function. chest dimensions and lean mass also significantly predicted fev 1 and fvc within each ethnic group, but did not affect differences between groups. the persistence of ethnic differences after adjustment for sitting height, chest dimensions, body composition and socio-economic factors may reflect the fact that some factors affecting chest size such as diaphragmatic position or muscle strength cannot be assessed by anthropometry, and emphasises the importance of taking ethnicity into account when interpreting spirometry data 7 . while some studies have shown an association between socio-economic conditions (sec) 13, 14 and lung function and suggested that this is a key factor in explaining ethnic differences in lung function 15 , there is increasing evidence that the contribution of sec to variability of lung function is very small except under the most adverse of conditions 7, 14, 16 . a recent study in india 8 , using identical equipment and techniques as those used in the slic study found that while average fev 1 and fvc in urban indian children were similar to those in indian children residing in the uk, they were significantly higher than in semiurban and rural indian children (by $6% and 11% respectively). these results probably reflect the marked differences in the degree of social deprivation between the uk and india 7,8 and suggest that there may be a threshold effect of poverty on lung function. adjusting for sitting height has been shown to reduce the contribution of sec to ethnic variability 7, 14 . the use of inappropriate reference equations and misinterpretation can lead to serious errors with respect to both under-and over-diagnosis. in the past, attempts to correct for ethnic differences, if made at all, tended to apply the same fixed adjustment factor across all ages 2 , all ethnic groups, both sexes and all spirometric outcome measures, an approach now shown to be oversimplistic 14, 17 . in addition to errors relating to ethnic differences in lung function, misdiagnosis may also occur when fixed cut-offs, such as 80% predicted fev 1 or 0.7 fev 1 /fvc are used; particularly in young children and elderly adults. while %predicted has historically been used to interpret lung function results, z-scores are more appropriate as they take into account the between-subject variability of measurements for any given outcome at any given age, as well as the predicted value 17 . similarly, use of <0.7 as a fixed threshold for abnormal fev 1 /fvc can lead to gross under-diagnosis of airway obstruction in the young and over-estimation in the elderly 17 . with exception of extreme deprivation, ethnic differences in lung function cannot be explained by socio-economic factors. after adjusting for confounders, genetic factors do contribute to ethnic differences in body physique and lung function. given the marked ethnic differences in lung function, the magnitude of which are similar across the entire life span, it is essential that lung function results in children are interpreted using ethnic specific equations whether in clinical practice or epidemiological research. although gli-2012 do not and never will cover all ethnic groups, appropriate use of age, height and sex adjusted values of fev 1 /fvc ratio derived from these equations (which is consistent across all ethnic groups) will facilitate better identification of airway obstruction in children irrespective of ethnic background. failure to adjust lung function for ethnic differences will result in overestimation of both the severity of airway obstruction and the severity and prevalence of restrictive lung disease. it is now recognised that asthma is a complex, heterogeneous disease. therefore, we need to move away from offering a single approach to management for all children and consider the identification of individual phenotypes for each child to enable optimal treatment and control. the specific facets of the disease that need to be considered and defined in each child include: i. an accurate description of symptom pattern (exacerbations alone, or persistent symptoms with and without exacerbations), ii. the nature of airway inflammation (eosinophilic, neutrophilic or non-inflamed), iii. the type and degree of structural airway changes (remodelling). although asthma control can be achieved in most children with low-moderate doses of inhaled steroids, we remain unclear about the choice of optimal maintenance therapy for each child. how should a decision between regular inhaled steroids, or leukotriene receptor antagonists be made? when additional therapies are required to achieve control, a scientific rationale for add-on therapies also is unavailable. the majority of decisions about therapies are made using a "trial of treatment" approach 1 . if one approach is not successful, then another is adopted without a clear thought process dictating choice of treatments. it is apparent that we need to change our current one size fits all approach to the management of asthma in children. although perhaps less important for children with mild or moderate disease, this becomes extremely important when we consider those with more severe disease. personalised medicine for severe asthma although atopy, airway hyperresponsiveness, eosinophilic inflammation and remodelling are the cardinal pathophysiological features of paediatric asthma, we now know that each of these features can be present to very different degrees in the individual child 2-4 . pathology has been most studied in children with severe disease, and although features such as eosinophilic inflammation and increased airway smooth muscle represent the patients as a group, there is huge overlap between children with and without asthma, and a huge spread of severity of these features within the group of children with severe asthma 2 . this within-group variability means assessments need to be made in the individual before deciding on the most appropriate add-on therapy. a proposed approach to identifying the "individual phenotype" in children with severe asthma is to split response to steroids into different domains (bossley c et al. j allergy clin immunol 2016, in press). not all children with asthma have abnormal lung function, not all have inflammation or remodelling, the response to a trial of systemic steroids can therefore be split into the following: i. lung function response, ii. inflammation response (exhaled nitric oxide and sputum eosinophils) and iii. symptom response. we have analysed this approach in 54 patients with severe therapy resistant asthma and shown a similar proportion of children (approx. 40%) responded to systemic corticosteroids in each domain, but there were no reliable predictors of a response pattern. furthermore, only 13% were complete responders (response in all domains), 15% were nonresponders (no response in any domain) and the majority (72%) were partial responders (response in >1 domain). these data highlight that childhood severe asthma is heterogeneous and a complete response in symptoms, inflammatory and physiological parameters is rare (bossley c et al. j allergy clin immunol 2016, in press). individual response patterns to systemic steroids need to be applied in the future to guide the choice of addon therapies in each child as a step towards achieving personalised medicine. subsequently, this multi-domain approach was applied clinically to identify characteristics of responders to the add-on therapy omalizumab. it became apparent that only those with a positive response in the inflammation domain (a significant reduction in exhaled nitric oxide after a trail of systemic steroids) had a beneficial response from omalizumab 5 . as increasing numbers of add-on therapies become available for use, specifically in the context of severe asthma, we need to better define pathophysiological phenotypes in individual patients and we need to understand the mechanisms mediating disease in children. in addition, we now need to incorporate individual genotypes into our definition of phentoypes to more accurately define treatment responses 6 , as has been successfully done for response to montelukast in preschool wheeze 7 . not only will this individualised approach allow us to discover novel molecular targets that will be effective specifically in the paediatric population, but it will also enable us to objectively choose the best therapy tailored to the individual child. europe consistently report that 20-40% of children with a recognized asthma diagnosis require acute medical care yearly. this is a reflection of the inadequacy of the available treatment options for prevention and treatment of exacerbations, suggesting that asthma with severe exacerbations may represent a distinct subtype of disease and demonstrating a need for improved understanding of its pathogenesis. asthma heritability is estimated at 50-80%. a number of genes have been verified in genome-wide association studies (gwas), but still the genetic background of asthma remains poorly understood. larger gwas may reveal new susceptibility loci with smaller effects, but due to the large heterogeneity of asthma (1), an alternative strategy may be to increase phenotype specificity. a specific phenotype is likely to be closer related to a specific pathogenetic mechanism and may therefore markedly increase the power of genetic studies. this was the background for a gwas focusing on a particular asthma phenotype defined by repeated, severe exacerbations in early childhood. (2) a sufficient number of cases were obtained by identification of children with recurrent acute hospitalizations for asthma between 2 and 6 years of age in the danish national patient register, and extraction of dna from dried blood spots from the danish newborn screening biobank. the case phenotype was rare with only 1/1000 of children born in denmark between 1982 and 1995 fulfilling the inclusion criteria. the final study comprised 1,173 children with repeated hospitalization and 2,511 healthy controls. five loci were identified with genome-wide significant association (pvalue < 5 ã 10-8): gsdmb, il33, rad50, il1rl1 and cdhr3. even though the sample size of this gwas was less than one fifth of the largest published gwas on asthma from the gabriel consortium,(3), it identified a similar number of genome-wide significant loci with similar statistical significance. the effect estimates were remarkably high with odds ratios between 1.4 and 2.3 per risk allele, compared to the odds ratios around 1.1-1.2 usually found in gwas on complex traits. further increasing phenotype specificity by stratified analysis in the 358 children with the highest number of exacerbations resulted in a further increase in effect estimates, with odds ratios between 1.6 and 2.7 per risk allele, and strong statistical significance. these strong results demonstrate the value of focusing on a more specific phenotype in asthma genetics. furthermore, it indicates that studies on this severe and early-onset phenotype is a "cost effective" approach whereby methodologies requiring large resources and/or strong statistical power can be applied in a limited number of individuals and still provide powerful results. the top-locus in this study, at chromosome 17q12-21 near gsdmb/ ormdl3, has consistently been associated with childhood onset asthma. (3) (4) (5) the effect size in the present study was remarkable with an or of 2.3 (p-value ¼ 1.3 ã 10 à48 ) and increasing to 2.7 for the children with highest number of exacerbations. this suggests an important role for this locus in severe exacerbations in early childhood in line with a previous report from the copsac 2000 birth cohort study.(5) cdhr3 had not previously been associated with asthma or any other disease. the association with asthma was replicated in the publically available gabriel results (3) protein structure modeling showed that the risk-associated variant is located at the interface between two domains where it could be involved in disulfide rearrangement and interfere with inter-domain stabilization, overall protein stability or conformation, in agreement with the observation in experimental studies of altered cell surface expression. (2) the biological function of cdhr3 is unknown but it seems to be a highly plausible asthma gene. it belongs to the cadherin gene family of transmembrane proteins involved in several cellular processes including epithelial polarity, cell-cell interaction, and differentiation (6) and is highly expressed in the lungs. also, other members of the cadherin family have been associated with asthma and related traits, including e-cadherin. (7) recently, it was reported that cdhr3 functions as a receptor for rhinovirus c. (8) cdhr3 was differentially expressed in epithelial cells susceptible to rhinovirus c infection compared to unsusceptible cells, and its expression on epithelial cells enabled rhinovirus c binding and replication. importantly, introduction of the risk variant at rs6967330 by transfection resulted in 10-fold increased rv-c binding and progeny yield compared to the non-risk variant. these data provide strong evidence that cdhr3 is a rhinovirus c receptor and that the association signal in the cdhr3 gene might result from increased susceptibility to rv-c infections. this finding is in line with the exacerbationrelated phenotype from the discovery gwas, since rhinovirus c has been reported to be the most common viral trigger of severe asthma exacerbations in children and associated with more severe disease and higher rates of hospital readmissions compared to other respiratory viral infections.(9,10) if correct, this would indicate that children with the cdhr3 risk variants are specifically susceptible to rhinovirus c infections compared to illnesses triggered by other viruses, a hypothesis that is currently being tested. in conclusion, the strong results found in this gwas on childhood asthma with severe exacerbations demonstrate the value of specific phenotyping in the search for asthma genes. focusing on this extreme subtype of disease might reveal mechanisms that would not be revealed in studies of milder disease, but might also increase the understanding of general asthma mechanisms. identification of cdhr3 as a risk gene might be one of the first examples where the underlying mechanism of an asthma gwas finding is understood. future studies of this gene may improve understanding and treatment of asthma exacerbations in childhood. the timing of bacterial colonization early in life is thought to be important for appropriate immune education and the transmission from mother to the fetus during pregnancy and birth is being better described. cultures of meconium have shown diverse groups of gram-positive and gram-negative bacteria, possibly not all derived post-delivery. the development of the gut microbiome is a dynamic process and early colonization with bacteroides and bifidobacterium species might play a crucial role in the development of immune regulation (1) . factors that can influence early life colonization include antibiotic treatment, method of delivery, maternal and infant diet and biodiversity in the home, surrounding environment and in family members. the gut microbiome increases in diversity during the first years of life. germ-free mice, which are not exposed to live bacteria, display exaggerated th2 and ige responses, associated with diminished polarization of treg cells. monocolonization of the mice with specific microbes, but not all microbes, suppresses the ige response and promotes treg differentiation (2) . however, certain immunological changes, such as increased inkt numbers in the mucosa, cannot be reversed following colonization of mice later in life (3). interestingly, more severe allergic responses and anaphylaxis were observed in mice who received a microbiome transplant from allergic animals, suggesting that certain microbial species can actually promote allergic responses (4). the immune system at birth is dominated by th2 cells. however, the human fetus has a functional immune system at a relative early status of development comprising cd4þ and cd8þ t cells but also foxp3þ treg cells. one concept gaining support is that the developing fetus may become educated by whole bacteria or their genetic material that is provided via maternal serum. dna from bifidobacteria and lactobacilli, two genera typically used as probiotics, are found in human placenta. in contrast, in utero exposure to potentially pathogenic bacteria such as ureaplasma species leads to immune dysregulation commonly ending in fatal complications. maternal consumption of probiotic-containing food components may reduce the risk for childhood allergic diseases and mouse models demonstrate a reduced risk of inflammatory bowel diseases. epigenetic mechanisms may be critical since application of acinetobacter lwoffii to pregnant mice reduced the airway hypersensitivity response of the offspring. the promoter region of ifn-g in cd4þ t cells of the offspring had high levels of histone-4 acetylation, associated with enhanced transcription, while the il-4 promoter region had lower levels of histone-4 acetylation (5). moreover, exposure of pregnant mothers to the farm environment, which have high levels of acinetobacter lwoffii, was associated with dna demethylation of the foxp3 locus and methylation of the th2-associated genes rad50 and il-13. since gut microbiota composition during the first months of life seems to be important for development of appropriate immune regulatory networks and thereby influence later life disease risk, intervention with probiotics, prebiotics or synbiotics might be most effective at this age or even during pregnancy. probiotics can be defined as live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host. notably, the definition of a probiotic does not differentiate between the wide range of potential health benefits and it is clear that not all probiotics will influence the immune system in the same way. findings observed with one probiotic strain cannot be extrapolated to other probiotic strains. current evidence does not indicate that the probiotics clinically tested to date reduce the risk of children developing allergy but there are significant differences between studies such as the use of different probiotic strains, different age groups and different endpoints (6) . despite very poor quality of evidence, it has been suggested that there may be benefits in specific high risk groups, such as pregnant women at high risk of having an allergic child, in women who breastfeed infants at high risk of allergy and in infants at high risk of developing allergy. in general, probiotic-supplemented formula was found to be well tolerated and safe for infants. in conclusion, a better description of the bacterial strains and metabolites, which influence immune function, is required in order to allow for the improved design and selection of future probiotic strains for prevention and treatment of allergic disorders (7). people with cystic fibrosis (cf) are living longer lives than ever in the past. the median predicted survival in developed countries is now above 40 years of age and adults with cf are outnumbering pediatric patients in several regions. various reasons may explain such improvement in life expectancy, including the establishment of cf-dedicated and multidisciplinary centers; greater attention to nutritional issues and use of pancreatic enzymes replacement therapy; airway clearance techniques tailored to individual needs and attitudes; infection control measures; use of antibiotics both chronically by inhalation and aggressively to treat pulmonary exacerbations; mucolytic and airway hydration therapies; and liver and lung transplantation (1, 2). on account of the overwhelming evidence that organ impairment begins very early, even in asymptomatic cf infants, there is now general consensus that at least some of these strategies of care should be implemented as soon as possible in order to prevent or delay irreversible structural lung damage. indeed, this has possibly been the main argument in favor of cf nbs (3). the strength of such argument has been tested by several studies and considering different approaches. randomized studies à only two randomized trials on newborn screening for cf have been completed (5, 6, 7). these evaluations need many years of follow-up and, given the high degree of evidence in favor of cf newborn screening presently available, further implementation of similar studies seems improbable and possibly non ethical. observational studies à although most of these studies confirm clinical benefits from early diagnosis of cf, their results are hampered by several biases inherent to the methodological approach. the constant improvement in treatment and the consequent longer survival has an influence on the comparison of screened individuals and unscreened historical controls. on the other hand, examining the clinical evolution of screened infants and unscreened controls from different geographical areas but born in the same years may be affected by different care practices. finally, ascertainment biases may also have an impact on the assessment of outcomes, as patients presenting clinically are likely to have more severe cf than those identified through screening or unscreened patients with very critical disease may have died before being diagnosed. health economics studies à these studies use surrogate end-points, such as the quantity of treatment needed to remain healthy, and are based on the assumption that the optimal management offered to cf patients makes it harder to detect evidence of better clinical outcome in those diagnosed by screening. late-diagnosed patients may show clinical pictures similar to those diagnosed early, but at the expense of a considerably heavier burden of care (8) . most of these studies have focused on respiratory and nutritional outcomes and on hta assessments. their overall results clearly point in the direction of a positive effect on height and weight, of longer survival and of health service savings in populations screened at birth for cf. positive effects may also be obtained in several other domains, namely: -the prevention of salt loss syndrome thanks to early beginning of salt supplementation the opportunity of surveying from birth the natural history of cf -a better understanding of the early stages of cf. the possibility of testing presymptomatic therapeutic strategies, both conventional and patient targeted. cystic fibrosis (cf) is associated with the presence of two cf-causing mutations, one in each parental cftr gene, resulting in the absence or abnormality of the cftr protein and defect in electrolyte transport across epithelial membranes, the most well known being sweat chloride >60 mmol/l. even in 2016, cf remains by essence a clinical diagnosis. the wide range and severity of symptoms/ organs involved between and within individuals makes it a clinical decision as to whether or not a person should be managed as a cf patient. this is especially the case in a small number of ambiguous or atypical cases. in 1998, a first diagnosis consensus listed criteria for cf diagnosis: (i) one or more of the phenotypic features of the disease or (ii) cf in a sibling or (iii) a positive immunoreactive trypsin (irt), in association with at least one other feature, including a positive sweat test result on two occasions, a cf-causing mutation in each cftr gene or an abnormal nasal potential difference (npd) (1). this consensus statement of the us cystic fibrosis foundation was later modified in europe based on the concept of cftr dysfunction included in the diagnosis algorithm (2) . most atypical cf patients are diagnosed based on sweat tests and/or genetic analysis. these "mild cf" individuals usually present later in their lives with pancreatic sufficiency and milder respiratory disease. they frequently carry wide clinical spectrum mutations. the difficulty occurs when patients present with clinical symptoms suggestive of cf and a sweat chloride value in the intermediate range (30-59 mmol/l). among these subjects, those with abnormalities in npd measurement or 2 identified cftr mutations have, on average, more severe lung disease than the remaining subjects, although their disease symptoms are milder than those in subjects with a sweat chloride concentration above 60 mmol/l. therefore, from a physician's and also from a patient's perspective, these individuals must be differentiated from subjects with the classical life-shortening form of cf. the remaining cases, termed "possible" or "borderline", are difficult to classify because there is poor agreement between sweat test results and prognosis on the one hand and the frequent presence of at least one cftr mutation of uncertain clinical relevance on the other. the term "cftr-related disorders" (cftr-rds) designates these varied conditions, which include multi-system disease and monosymptomatic disorders associated with cftr dysfunction but which do not fulfill the diagnostic criteria for cf (3). this encompasses 3 main clinical entities with cftr dysfunction: cbavd (congenital bilateral absence of the vas deferens), acute recurrent or chronic pancreatitis and disseminated bronchiectasis. diagnosis of cbavd is based on impalpable vas deferens on scrotal examination. even if in a proportion of men scrotal palpable vas deferens are present, surgical exploration reveals a fibrous cord or a non-permeable duct. cbavd males have either a severe and a mild/variable (88%) or two mild/ variable (12%) cftr mutations (4) . approximately 34% of men with cbavd have a cftr mutation in one gene and the splicing variant ivs8-5t on the other allele, often in association with a longer polymorphic dinucleotide repeat, a combination that does not result in cf, but reduces levels of functional cftr protein in wolffian tissues, which constitutively produce less full-length cftr mrnas than other tissues (5) . about 30% of patients with idiopathic chronic pancreatitis or recurrent acute pancreatitis are found to carry cftr mutations. no specific cftr mutations have been reported, but rare class 4 or class 5 mutations are often found (6) . an increased incidence of cftr gene mutations has been found in bronchiectasis. according to the studies, at least 1 cftr mutation is found in 10-50%, and 2 mutations in 5-20% of cases. mutations found are mostly uncommon and likely to result in residual cftr function (7) . no specific cftr mutation is associated directly with bronchiectasis. (2) . these patients must be monitored carefully for development of any complications and appropriate therapy implementation. it should be pointed out, however, that labeling patients with mild or unclear manifestations with a cf diagnosis may have negative implications such as psychological, reproductive, social, employment, and insurance issues. therefore the explanation of the diagnostic challenge, including also prognosis, must be fully and honestly explained to the patient and or his family. department of pediatrics, cf and pcd center, hadassah hebrew-university medical center, mount scopus, jerusalem, <eitank@hadassah.org.il> effective mucociliary clearance (mcc) in the respiratory system requires proper mucus production and functioning airway surface fluid layer as well as competent and coordinated ciliary beating. the vital role of these systems is best demonstrated in patients with genetic defects such as primary ciliary dyskinesia (pcd) and cystic fibrosis (cf), both of which are characterized by impaired mcc leading to acute and chronic sino-pulmonary infections. pcd is caused by defects in genes that encode the structure or regulate the movement or function of the respiratory cilia. cf is caused by mutations in the cftr gene causing abnormality in the airway surface fluid layer, with production of thickened and viscous mucus leading to impaired mcc. in both diseases, recurrent and chronic respiratory infections and persistent inflammation cause progressive lung damage. most patients with cf suffer from pancreatic insufficiency (cf-pi); however, approximately 15% have sufficient pancreatic enzyme production to maintain normal fat absorption (cf-ps). patients with pcd are similar to patients with cf-ps in that they have normal pancreatic function, and are usually without the nutritional deficiencies that are typically associated with more severe pulmonary disease in cf. in addition, pcd and cf-ps are often diagnosed at a later age and have better survival compared to cf-pi (1,2). therefore when comparing cf and pcd, one should differentiate between patients with cf-pi and cf-ps. santamaria et al. compared chest hrct scan scores for patients with pcd and a group of age-and gender-matched cf patients and showed that patients with pcd had significantly less structural damage than cf patients (3) . a recent study comparing between pcd and cf-ps and cf-pi revealed that patients with pcd had disease severity in terms of pulmonary function and structural abnormality similar to patients with cf-ps, which was significantly less severe when compared to patients with cf-pi (4). furthermore, when comparing structural abnormalities by hrct, there was a significant disparity in the distribution of the structural changes in the lungs between the three groups of patients: in pcd, the upper lung zones were relatively preserved and most changes were localized to the middle and lower lobes, whereas in cf-pi, the upper lobes were remarkably involved. in cf-ps, there was no characteristic distribution of the structural damage (4) . other studies showed that in pcd, contrary to cf groups, there was no correlation between fev 1 and ct score and between fev 1 and age (3) (4) (5) (6) (7) (8) , which provides further support to the understanding that, in pcd, lung function is not a strong indicator of severity of lung disease and therefore, follow-up by low radiation chest hrct scans should be considered. it is important to note that, in general, patients with pcd receive less intensive therapy (9) . they are not always followed regularly in specialized centers, and many are not adherent to routine treatments. the most common bacterial infection in pcd patients is h. influenzae, which is significantly less common in older cf patients (4, 10) . in cf, chronic infection with p. aeruginosa is associated with a more severe lung disease (11) . however, among patients with pcd, there was no correlation between p. aeruginosa infection and pulmonary function or hrct severity score, suggesting a different role for this microorganism in the pathogenesis of pulmonary disease in pcd (4). bush et al. compared the mucous properties in both diseases and demonstrated that inflammation, measured by il-8 concentration, was greater in pcd sputa, and that there were no significant differences in biophysical or transport properties of sputum between the two groups; however, survival in patients with pcd was generally better (12). ratjen et al. (13) assessed the inflammatory response in the airways of cf and pcd patients during pulmonary exacerbation. in stable pcd patients, no significant differences were found in sputum inflammatory markers between individuals colonized with different bacterial pathogens. however, higher bacterial density for s. aureus and h. influenzae was found in patients with cf versus pcd, and the absolute neutrophil counts were higher in pcd patients. while sputum elastase activity was similar in pcd and cf at the time of exacerbation, it decreased with antibiotic therapy in pcd but not cf patients. thus, pcd patients differ from those with cf in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the cf airways at the end of treatment. joenesen et al. (14) measured the difference in breath profiles of patients with pcd and cf, with and without distinct chronic lung infections, using an electronic nose. no significant difference was found between the breath profiles of pcd patients with a chronic pa infection and pcd patients without a chronic infection. however, there was a significant difference between the breath profiles of cf patients with a chronic pa infection and cf patients without a chronic pa infection, suggesting a different response to infection between pcd and cf. in conclusion, although pcd and cf are both characterized by impaired mcc and respiratory infections, patients with pcd have a different lung disease expression compared to patients with cf-ps and with cf-pi, as assessed by fev 1 , hrct, nutritional status and bacterial infection on sputum cultures. in pcd, normal fev 1 can be maintained over time in spite of severe structural damage. this suggests a greater involvement of the large airways in pcd and the small airways in cf. furthermore, p. aeruginosa infection is less common in pcd than in cf. bronchopulmonary dysplasia (bpd) is the most important complication following mechanical ventilation in preterm infants and no definite therapy can eliminate this complication. although the mechanism is not completely clear, pulmonary inflammation is believed to play a central role in the pathogenesis. glucocorticoid is one of the most effective therapies to treat or prevent bpd. however, systemic glucocorticoid therapy is not generally recommended because of long-term adverse events (1,2). our previous pilot study in neonates and studies in animals indicated that surfactant can be used as a vehicle to deliver a topical glucocorticoid, budesonide, to the lung periphery and effectively suppress lung inflammation and lung injury (3.4.5). the mechanism for the effective delivery of budesonide using surfactant as vehicle is based on a physical phenomenon, the "marangoni effect": in the interface between high and low surface tension, a convection force is generated and this force can be used as a vehicle to facilitate the delivery of medication (6) . this is an important delivery method because inhaled glucocorticoid is technically difficult and the effect has been shown to be limited (7, 8 there was no significant difference between the groups during the study in serum electrolytes, glucose, bun and in blood pressure, and in physical growth. there was no significant difference between the groups in neuromotor function, and in mdi, pdi and in neurodevelopmental impairment (ndi) score when examined at 2-3 years of corrected age. we concluded that in very low birth weight infants with severe respiratory distress syndrome, intra-tracheal administration of surfactant/budesonide compared with surfactant alone significantly decreased the incidence of bpd or death without apparent short term or long term adverse effect. further large-sample, double-blind trials are warranted. measuring lung function in "non-collaborating" children has always been one of most difficult tasks for pediatric pulmonologists. this is because young children are not able to perform the voluntary forced expiratory maneuvers generally used in adults and schoolchildren. in infants and children up to 2 years, this problem has been generally overcome by the use of sedation, although this contributes to make lung function measurements less suitable for routine clinical use in this age group. preschool children (2-5 years) are too old to be sedated and yet too young to properly perform the forced expiratory maneuvers required for spirometry. for this age group, several techniques that just require tidal breathing have been implemented during the past decades. the american thoracic society/european respiratory society (ats/ers) working group on lung function in young children has published technical recommendations for most infant (1,2) and preschool techniques (3) and their clinical applications have also been recently summarized (4) . this lecture will focus on the most used pulmonary function tests (pfts) in infants and preschool children. chloral hydrate (80-100 mg/kg, maximum 1 g) is commonly used to sedate infants and young children up to 2 years for performing lung function testing. however, chloral hydrate is no longer available in the u.s.a. and the use of other sedatives might lead to different results (4). the most commonly used pfts in infants are the raised volume rapid thoracoabdominal compression and infant plethysmography. other pfts that are performed during tidal breathing (e.g.: tidal breathing measurements, multiple breath washout, forced oscillation technique) are more suitable to be used without sedation, especially in younger infants. the raised volume rapid thoracoabdominal compression (rvrtc) allows for the measurement of forced expiratory flow and volume in sedated infants (2) . repeated inflations using a pressure of 30 cmh 2 o are applied through a facemask and an inflatable jacket is then activated to rapidly compress the infant's chest and abdomen to obtain forced vital capacity (fvc), forced expiratory volume in 0.5 seconds (fev 0.5 ) and forced expiratory flow (fef) at defined proportions of fvc. to ensure that flow limitation has been reached, the inflation pressure of the jacket is increased at each maneuver until no further increase in flow is noticed. recently published reference equations using a current commercially available device (5) will improve the interpretation of the results. rvrtc has been successfully used in children with all kinds of respiratory diseases, including children with cystic fibrosis (cf), children born prematurely, and those with recurrent wheezing (4), showing its capability to distinguish disease populations from healthy control subjects and to detect lung function changes in clinical intervention trials. however, its long-term clinical utility still remains to be established. moreover, the need for sedation along with the time and resource intensity required are other important limitations for its use in routine clinical practice (4) . infant plethysmography is used to measure functional residual capacity (frcpleth) in sedated infants (1) . specific airway resistance (sraw) can also be measured, provided that a proper electronic thermal compensation is applied to the system to account for thermal artifacts. this technique is based on the same principle (boyle's law) as plethysmography for older subjects and uses an infant whole body plethysmograph where the infant lies supine breathing through a facemask sealed with silicon putty (1). infant plethysmography has been successfully applied to children with lung disease, especially cf and bronchopulmonary dysplasia (bpd) (4). however, as for rvrtc, its long-term clinical utility remains to be ascertained and its role in routine clinical practice is hence very limited. preschool children (2-5 years) are too old to be sedated, but also too young to properly perform the forced expiratory maneuvers required for spirometry. for this age group, several techniques that just require tidal breathing have been implemented during the past decades, allowing for lung function to be measured in awake children (3) . also, modified acceptability criteria for spirometry have been proposed for the use in preschool children (3) . it is important to highlight that the feasibility of any lung function technique in preschool children strongly depends on the capability of the operator of keeping the child quiet and focused (3). spirometry has been proposed for preschool children using modified acceptability criteria (3). since the forced expiratory volume in 1 second (fev 1 ) often cannot be obtained in preschoolers due to their different lung physiology, the use of fev in 0.5 (fev 0.5 ) or 0.75 seconds (fev 0.75 ) is recommended in this age group. also, fvc should not be reported if flow stops at more than 10% of peak flow (early termination), but fev may still be reported. less stringent repeatability criteria have also been proposed in preschool children: at least two acceptable maneuvers should be obtained with the two fvc and fev within 100 ml or 10%, but in case of a single acceptable maneuver, this should be recorded nevertheless (3) . spirometry is reported to be feasible in 55-85% of 4-5 year old children, but its feasibility tends to be much lower in younger children (4) . global multiethnic reference equations including preschool children have recently be published (6) . spirometry has been reported to discriminate healthy controls from preschool children with cf and with recurrent wheezing, although substantial overlap between groups may occur and bronchodilator response appears to be more sensitive than baseline values (4). however, a careful and rigorous approach to the use of spirometry must be taken in preschool children and several gaps in our knowledge still limit the application of this technique to clinical practice in this age group (4). the interrupter technique is based on the principle that a sudden flow interruption at the mouth during tidal breathing would make alveolar pressure rapidly equilibrate with mouth pressure, thus allowing an estimation of alveolar pressure by measuring mouth pressure. the interrupter resistance (r int ) is then calculated dividing the change in mouth pressure by the flow measured immediately before the interruption ("classical" technique) or immediately after the interruption ("opening" technique). measuring r int has been proved to be particularly suitable for preschool children, its feasibility being generally higher than 80% in this age group (4). proper reference values have been published (7) and cut-off values for the bronchodilator response have also been reported. r int is able to detect changes in the airway caliber and has been successfully used in preschool children with recurrent wheezing (4). however, its utility in clinical care remains to be established, especially by longitudinal studies (4) . the forced oscillation technique (fot) is used to measure the impedance of the respiratory system (z rs ) during tidal breathing by applying, through a mouthpiece and a filter, low-frequency pressure oscillations generated by a loudspeaker (usually 4-48 hz) (3) . changes in flow and pressure measured at the mouth are used to calculate z rs and its two components, resistance (r rs , reflecting frictional losses) and reactance (x rs , reflecting elastic properties at low frequencies and inertial forces at higher frequencies). forcing signals based on sinusoidal waves or impulses have been used, both as single-frequency or composite signals. frequencies between 5 and 10 hz are considered to reflect the mechanical properties of the total airways. fot has a good feasibility in preschool children (>80%) and several reference equations have been published (8) . fot has been used in many studies on children with recurrent wheezing, showing a good capability in discriminating health from disease, especially when bronchodilator response is used (4). however, for this technique as well, longitudinal studies on its clinical utility in young children are still needed (4). the multiple breath washout (mbw) is based on the washout of an inert gas (typically n 2 washout using 100% o 2 ) to measure ventilation inhomogeneity and frc during tidal breathing (3). non-resident inert gases have also been used. the lung clearance index (lci, the number of lung volumes expressed as frcs required to washout the inert gas) is the most commonly used mbw index. the general standard operating procedure for this technique has been recently reported (9) . lci has a good feasibility in preschool children (nearly 80%). lci has been successfully used in preschool children with cf (4), proving to be more sensitive than spirometry and plethysmography in detecting abnormal lung function. however, longitudinal studies on the clinical utility of mbw in preschool children are lacking (4) and more data are needed before lci or other mbw indices can be recommended in the routine clinical management of patients with cf (10). specific airway resistance (sraw) can be measured at tidal breathing in preschool children using a whole body plethysmograph. since sraw is the product of airway resistance by the thoracic gas volume, it can be calculated without the need to breathe against a closed valve (11), provided that a proper electronic thermal compensation is applied to obviate the need for the panting maneuver. the measurement of sraw has a good feasibility in young children and reference values are also available (11) . however, the lack of consensus on measurement methods and outcome measures makes it difficult to compare results among centers and methodological techniques are urgently needed for this technique. an accurate assessment of pulmonary function is now possible in infants and preschool children using a number of techniques. although these techniques have proven to be powerful research tools, further studies are needed to ascertain their utility in the clinical care of infants and young children with lung disease. . past studies have shown that persistent echocardiographic evidence of ph beyond the first few months of life is associated with up to 40% mortality in infants with bpd. the association of ph with poor survival in bpd has continued into the recent era of the "new bpd," especially in infants with severe disease who require prolonged support with mechanical ventilation. thus, developing insights into the pathogenesis and pathobiology of ph and related pulmonary vascular disease (pvd) in bpd continue as an important challenge and may help to improve early and late cardiopulmonary outcomes after preterm birth. mechanisms that coordinate normal vascular growth and alveolarization during development or cause abnormal lung growth in bpd are poorly understood. disruption of key signals between airway epithelium and endothelial cells can alter vascular and alveolar growth, resulting in decreased arterial and airspace structure. for example, hyperoxic lung injury in newborn animals decreases expression of the critical proangiogenic and endothelial cell survival factor, vascular endothelial growth factor (vegf). early impairment of vegf production inhibits vascular growth and impairs endothelial function, which leads to ph. in addition, disruption of angiogenesis due to adverse antenatal factors, such as chorioamnionitis, preeclampsia or maternal smoking, and postnatal events after premature birth, can cause vascular injury that not only lead to ph but can also impair distal lung growth. ongoing laboratory studies suggest that the developing endothelial cell plays a key role in the regulation and coordination of epithelial growth and distal airspace structure through the production of critical "angiocrines," such as nitric oxide (no), hepatocyte growth factor, vitamin a, insulin growth factor-1 and others. thus, since angiogenesis is necessary for normal alveolarization, it has been suggested that protecting the developing pulmonary vasculature from early injury may not only lower pvr and improve gas exchange, but may enhance distal lung growth and improve long term outcomes. abnormalities of the pulmonary circulation in severe bpd include altered tone and reactivity, structure and growth, which can cause right heart failure, impaired gas exchange, pulmonary edema, decreased exercise capacity and other clinical problems. physiologic abnormalities of the pulmonary circulation in bpd include elevated pulmonary vascular resistance (pvr) and abnormal vasoreactivity, as evidenced by the marked vasoconstrictor response to acute hypoxia and by impaired gas exchange due to abnormal distribution of lung blood flow. abnormal pulmonary vascular structure also contributes to high pvr due to increased smooth muscle cell hyperplasia and altered vascular compliance caused by increased production of an abnormal extracellular matrix. growth of the distal lung circulation is abnormal in infants with severe bpd, and decreased arterial growth (angiogenesis) reduces vascular surface area that further impairs gas exchange and increases the risk for the development of ph and impaired exercise capacity in older children. prominent bronchial or other systemic-to-pulmonary collateral vessels were noted in early morphometric studies of infants with bpd, and can be readily identified in many infants during cardiac catheterization. although these collateral vessels are generally small, large collaterals may contribute to significant shunting of blood flow to the lung, causing edema and need for higher fio 2 . in addition, recent autopsy studies suggest the presence of striking intrapulmonary anastomotic, or "shunt," vessels that link the distal pulmonary and bronchial vessels, and may contribute to poor oxygenation. past clinical studies have further shown that metabolic function of the pulmonary vasculature is impaired in bpd, as reflected by the lack of pulmonary clearance of circulating norepinephrine during passage through the lung, which may contribute to left ventricular dysfunction and systemic hypertension. clinical studies have recently shown that early echocardiographic findings of pvd after preterm birth are strongly associated with the development and severity of bpd and ph at 36 weeks corrected age. interestingly, these findings were not only associated with a worse respiratory course during the initial hospitalization, but also late respiratory outcomes, including respiratory exacerbations, hospitalizations and the need for asthma medications. ongoing studies are exploring the impact of ph-specific drug therapies, such as sildenafil and other agents, on ph and related complications. thus, pvd in preterm infants with bpd is characterized by altered lung vascular development, growth, structure, and function, which precede the onset of measureable ph. pvd due to disruption of normal pulmonary vascular development in association with preterm birth is an important determinant of the pathobiology of bpd and contributes significantly to morbidity and mortality. exposure to adverse stimuli during the antenatal and/ or early postnatal periods impairs normal pulmonary vascular development and creates an imbalance between risk and resiliency factors. recent studies have revealed the magnitude of ph in preterm infants, but many aspects of pvd remain understudied, and ongoing investigations continue to explore risk factors, mechanisms of disease, and long-term outcomes. prospective studies are needed to definitively establish standardized clinical criteria for pvd and ph in bpd, and to determine the best methods for early diagnosis, risk stratification and disease monitoring. larger collaborative studies and improved clinical infrastructure to conduct these important investigations will provide answers to these critical questions. recent evidence suggests that cftr does not act as a pure ion channel but as a platform for multiple cellular signaling pathways. importantly, the protein interactomes of wt-and f508del-cftr are rather different, and there is growing consensus that indirect measures that avoid the enhanced degradation of f508del-cftr may restore its function. recently, we discovered that cftr orchestrates a proteostatic network that influences multiple cellular functions by acting as a hub protein. this hub-dysfunction model proposes that the proteostasis network is widely deranged, both in transgenic cf mice and in primary nasal epithelial cells freshly collected from cf patients bearing f508del-cftr either in homozygous or compound heterozygous form, at two levels. firstly, autophagy, the major mechanism determining cytoplasmic protein turnover, is blocked due to tissue transglutaminase (tg2)-mediated depletion of the essential autophagy-related protein beclin 1 (becn1), leading to secondary accumulation of the autophagic substrate sqstm1/p62. secondly, peptide fragments released from proteolytically-cleaved f508del-cftr provoke an over-activation of a pleiotropic protein kinase (protein kinase ck2), which in turn contributes to f508del-cftr degradation. combined inhibition of tg2 by cysteamine, which is fda-approved for the treatment of cystinosis, and over-active ck2 by the over-the-counter greentea flavonoid epigallocatechin-gallate (egcg) respectively rescue and stabilize a functional f508del-cftr protein at the pm, both in mice and in primary nasal cells from cf patients bearing f508del-cftr or other class ii-cftr mutations. pre-clinical evidence on transgenic mice has provided the mechanistic proof-of-concept for using this combination of proteostasis regulators as an alternative cftr-repairing therapy. moreover the combination treatment reduces lung inflammation and this beneficial effect persists up to 2 weeks following cysteamine withdrawal provided that egcg was administered during washout. this prompted an open-label phase-2 trial to assess the individual response to the synergistic combination of cysteamine and egcg in cf patients bearing different cftr mutations. the combination treatment was well tolerated and decreased sweat chloride from baseline while increasing the abundance and function of cftr protein and restored autophagy in nasal cells. notably, the treatment decreased cxcl8 and tnf-a in the sputum and improved respiratory function. these positive effects were particularly strong in patients carrying f508del-cftr (or other class ii) mutations in homozygosity or heterozygosity, whereas patients with class i cftr mutation failed to respond to therapy. altogether, these results suggest that the combination treatment acts "on target", according to the hypothesis underpinning our drug design. discordance in therapeutic response rate complicates mutation-specific approaches, thus entailing the need of patient-centered (personalized) approaches to assess drug efficacy. testing the putative individual responsiveness to treatment by appropriate biomarkers before in vivo therapy should support the decision to treat. we show that restoring cftr function in vitro in nasal cells in response to cysteamine plus egcg, is highly predictive of whether the combination treatment will restore cftr function in vivo. hence, this in-vitro assay may constitute a tool to guide the clinical development of cf treatments, allowing to select patients for new therapeutic options. general frame for care infants with cf must receive care in an accredited cf care center. they must be reviewed in clinic frequently after diagnosis, for example once a month during the first 6 months of age, every 2 months until 1 year of age, and every 3 months thereafter (3). after initial diagnosis, the cf center should contact the primary care professionals for regular ambulatory follow-up to implement therapeutic strategy. parents of infants with cf should be offered access to genetic advice and counseling. the standard childhood immunization schedule must be applied in accordance with national guidelines. anti-influenza vaccination is recommended for the infant from the 6 th month of life and for all household members and healthcare providers. according to french guidelines, vaccination against chicken pox could be recommended. growth targets should reflect genetic potential, sibling height and local population demographics (1) . french guidelines recommend to catch-up birth weight percentile at 6 months (3). at 2 years, weight-for-height should be at the 50 th percentile and height at the target height percentile (target height: average of the height of the 2 parents plus 6.5 cm for boys and minus 6.5 cm for girls) (3). energy intake evaluation should be performed by a dietician on a regular basis and adapted to achieve the objectives of weight-for-height growth. energy intake could be as much as 150% of the daily recommended calorie intake for the same age in the general population (4). breast feeding is encouraged, all the more that recent data acknowledge its protective effect against pseudomonas aeruginosa infection (4, 5). formula with hydrolyzed cow's milk protein is recommended in infants with risks of malabsorption, or severe undernourishment. sodium chloride supplementation is systematic, particularly in the case of breast feeding and should be adapted to natriuresis (6) . it should be increased during periods of hot weather and all other causes of high salt loss (diarrhea, fever, ileostomy, etc.). at initial diagnosis, infants must have pancreatic function assessed by stool fecal elastase. if elastase is normal, repeat assessment is recommended. pancreatic enzyme replacement therapy should be started at diagnosis in case of clinical symptoms of exocrine pancreatic insufficiency even before obtaining the results of the elastase assay. the starting dose could be 2.000 iu lipase per 100 ml of milk. in case of persistence of symptoms of pancreatic insufficiency despite a maximum dose of 10.000 ui/kg/day of lipase, it may be necessary to evaluate the patient's compliance and the methods of conservation and administration of the pancreatic extracts. in case of poor weight-for-height growth despite an adapted substitutive pancreatic opotherapy, an evaluation is necessary including a dietetic review, a search for sodium insufficiency and other etiologies of malabsorption. in case of persistence of symptoms of exocrine pancreatic insufficiency despite a maximum dose of 10.000 ui/kg/day of lipase and in the absence of other etiologies, the administration of gastric secretion inhibitors may be envisaged. bacterial cultures of bronchial flora should be performed at each session of physiotherapy or, in case of abnormal clinical status, ideally on bronchial secretions expectorated or obtained by sputum induction (7). a chest x-ray should be performed at baseline and annual assessment, and, in case of clinical abnormality. high resolution computed tomography should complete the assessment in case of clinical or radiological abnormality and/or at initial assessment according to local practice to detect early bronchiectasis (8) . systematic respiratory physiotherapy is recommended from the time of diagnosis. the frequency of sessions of physiotherapy depends on the clinical status of the infant. regular therapy might be recommended even in the asymptomatic infant (3). any evidence of respiratory infection justifies performing a respiratory culture and adapted antibiotic treatment of the isolated pathogens. infection by staphylococcus aureus sensitive to meticillin should be treated by adapted antibiotherapy. in case of isolation of s. aureus resistant to meticillin, a treatment aiming eradication is recommended. evidence of p. aeruginosa justifies systematic antibiotic treatment, even in the asymptomatic infant. although there is still no consensus, treatment might begin with an inhaled antibiotic, eventually associated with oral ciprofloxacin. in case of persistence of p. aeruginosa after initial therapy, or if the infant presents with severe clinical signs, intravenous antibiotics should be considered (1, 2, 3) . for other pathogens, there is less clear agreement and treatment should be guided by local policies. in the absence of clinical improvement despite an adapted antibiotherapy, bronchial sampling by bronchoalveolar lavage should be considered and non-infectious causes should be searched for, including gastroesophageal reflux, asthma and an ent cause. respiratory syncytial virus (rsv) may have adverse effects on respiratory status in patients with cf (9) . there is insufficient evidence to support systematic recommendation of palivizumab in the cf infant even if some small studies suggest that there could be benefit from the use of rsv prophylaxis in infants with cf (10). us and french guidelines state that palivizumab could be discussed, namely for the infant of less than 6 months of age during an epidemic period (2,3). finally, dornase alfa, 7% hypertonic saline might be used in symptomatic infants (2) . with increasing numbers of infants with cf being diagnosed by newborn screening across most of europe and in north america, we will have the opportunity for large cohort follow-up and randomized controlled trials. this will help to establish still lacking best available evidence to harmonize therapeutic strategy in infants newly diagnosed with the final aim of improving clinical status at later ages. department of pediatrics, cf and pcd center, hadassah hebrew-university medical center, mount scopus, jerusalem, israel <eitank@hadassah.org.il> bronchiectasis is the distraction of the normal anatomy of conducting airways that results in impaired mucociliary clearance leading to chronic cough, sputum production, and recurrent infections and inflammation that cause further damage to the bronchial and bronchiolar walls leading to a vicious cycle of airway injury. the prevalence of non-cf bronchiectasis (ncfb) in children differs between developed and poor countries. in the developed world, the most common cause of bronchiectasis in children is cystic fibrosis (cf), followed by primary ciliary dyskinesia and immune deficiencies. however, up to half of cases remain without a known etiology. in developing countries, a systematic review of 989 children (1) demonstrated that an etiology was identified in 63% of children, with a previous severe pneumonia of bacterial or viral etiology and b-cell defects as the most common identified disorders. bronchiectasis should be suspected in patients who present with chronic productive cough of mucopurulent sputum. physical findings in bronchiectasis patients are nonspecific but may include crackles and wheezes on lung examination and clubbing of the digits. pulmonary function testing results generally show airflow obstruction. the diagnosis of bronchiectasis is confirmed by hrct scan which is now the gold standard for diagnosis. these include bronchial dilatation (an internal bronchial diameter greater than the diameter of the accompanying bronchial artery [i.e., the "signet ring" formation]) and a lack of bronchial tapering on sequential slices (2) . patients in whom bronchiectasis has been diagnosed should be evaluated for potential underlying causes. they need to undergo chest ct scan to define the extent of their disease. patients with focal disease require bronchoscopy to evaluate for a localized airway obstruction as the cause of the bronchiectasis. patients with diffuse bronchiectasis should be assessed for underlying systemic abnormalities including congenital disorders, chronic aspiration, impaired mucociliary clearance and systemic or local innate immune dysfunction. all patients with bronchiectasis should have a regular routine microbiological examination of their sputum for routine bacterial and ntm organisms. pulmonary exacerbations of ncfb are known to be associated with poor outcomes, and infections are common causes. gram-negative bacteria are isolated more frequently in patients with ncfb, with h. influenzae and p. aeruginosa representing the majority of identified species. however, up to 40% of sputum samples fail to grow any pathogenic bacteria (3). patients with sputum samples dominated by p. aeruginosa (pa) had a higher frequency of exacerbation and poorer lung function compared to patients whose samples were dominated by other organisms (4). nontuberculous mycobacteria (ntm) are opportunistic pathogens that afflict patients with preexisting lung disease; in particular those with ncfb, shown in a meta-analysis by chu et al. to be prevalent in nearly 10% of the patients (5). respiratory viruses were found in nearly 50% of exacerbations. the goals of bronchiectasis treatment are to reduce the number of exacerbations and to improve quality of life. if an underlying systemic etiology such as immune deficiency is identified, it should be addressed. pharmacologic agents and the mechanical mobilization of secretions have been evaluated to a limited degree in patients with non-cf bronchiectasis. short-acting or long-acting bronchodilator adrenergic and anticholinergic agents are commonly prescribed, but there have been no randomized controlled trials to support their use. pulmozyme had adverse effects when studied in patients with non-cf bronchiectasis. inhaled mannitol showed improved time to first exacerbation and quality of life. nebulized hypertonic saline solution (7%) have shown promise in the treatment of patients with both cf and non-cf bronchiectasis, but long-term prospective trials are needed. the role of the use of maintenance antibiotic therapy is uncertain in patients with non-cf bronchiectasis. rotating oral antibiotic strategies have been commonly used. for exacerbations, antibiotic therapy should be tailored to their sputum microbiology results. severe exacerbations, particularly in patients who are infected with organisms that are resistant to therapy with oral quinolones, require iv antibiotic therapy. azithromycin has been shown to attenuate muc5ac and muc2 gene expression, thereby suppressing the synthesis of mucin on human airway epithelial cells. clinically, this was demonstrated in a study that found that mean 24-hour sputum volume and qol were significantly lower in patients with bronchiectasis after 12 weeks of azithromycin compared with control subjects (6) . a recent randomized, double-blind, placebo-controlled trial in adults assigning patients to receive 500 mg azithromycin or placebo three times a week for 6 months, showed that azithromycin significantly reduced the exacerbation rate with no significant effect on fev1 (7) . based on the above and other studies, it is recommended that all patients with ncfb be treated with azithromycin. long-term inhaled antibiotics are used for patients with uncontrolled ncfb, but until more recently, data on their efficacy have been lacking. the use of mechanical aids, including chest physical therapy with postural drainage, active cycle of breathing, oscillatory positive expiratory pressure devices, and high frequency assisted airway clearance, also constitute potential adjunct therapies for patients with bronchiectasis. though these modalities are considered to be standard therapy for patients with cf bronchiectasis, their utility is less well proven in patients with non-cf bronchiectasis. it was shown that comprehensive medical care in children with ncfb was associated with a decrease in exacerbation rates (8) . these findings further exemplify the importance not only of identifying ncfb in pediatric patients, but also of ensuring that they receive close surveillance. treatment burden with lack of immediate apparent outcomes cause patients to avoid daily therapy and seek therapy only for exacerbations. resectional surgery and lung transplantation are rarely required. surgical treatment has classically been an option for patients who have localized bronchiectasis with persistent symptoms despite maximal therapy, or recurrent infections with resistant pathogens (9). the prognosis for patients with bronchiectasis is variable given the heterogeneous nature of the disease. because there are so few randomized controlled trials of therapies for non-cf bronchiectasis, patients must be evaluated and treated on an individual basis in a tailored, patient-focused approach in a specialized center to optimally evaluate and treat individuals with bronchiectasis. in humans, the dominant innervation to the airways is provided by the parasympathetic vagus nerve, whose activation induces the release of acetylcholine [1] . acetylcholine, the primary parasympathetic neurotransmitter in the airways, interacts predominantly with nicotinic receptors and the five muscarinic receptor subtypes. in addition to its well-known functions, i.e. bronchoconstriction and mucus secretion regulation, there is evidence that acetylcholine might also modulate inflammatory cell chemotaxis and activation and participate in signaling events that lead to airway wall remodeling [2] . these findings can have significant implications for anticholinergic therapy of diseases characterized by airway inflammation, bronchial obstruction and mucus hypersecretion, since a variety of data indicate that the function of muscarinic receptors is altered in these patients. nicotinic acetylcholine receptors (nachrs) are ligand-gated ion channels, formed by five homologous or identical subunits, arranged to form a central ion channel [3, 4] . depending on the subunit composition, nachrs show different kinetics and pharmacological properties. in lung tissues, the "muscle" nachrs are localized at the neuromuscular junctions of the smooth muscle cells, whilst the "neuronal" nachrs are expressed by autonomic ganglia, but also by almost every cell type, including bronchial and alveolar epithelial cells, endothelial cells, pulmonary neuroendocrine cells, submucosal glands, airway and vascular smooth muscles, fibroblasts and alveolar macrophages [4] . although nachrs are classically linked to the depolarization of the plasma membrane required for neurotransmission, non-neuronal nachrs in the lung act most frequently as calcium channels and have been linked to regulatory proteins controlling cell proliferation [2] [3] [4] . the functional role of nachrs is particularly complex and depends on subunit composition, dose response, and duration of ligand stimulation. although nachr activation often leads to a positive feedback loop that induces receptor expression, chronic stimulation of nachrs can produce channel desensitization and decreased activity. the majority of studies of nachr function in the lung are related to the effects of nicotine, i.e. to tobacco-induced mutagenesis and lung carcinogenesis, whilst little is known on the physiological functions in regulating lung growth and repair, airway epithelial cell proliferation and differentiation and electrolyte transport [3] . muscarinic receptors belong to the large family of g protein-coupled receptors, characterized by seven transmembrane domains. out of the five subtypes identified, only m1, m2 and m3 receptors have been detected in the airway and lung tissues of most mammals, including humans. almost all airway and lung cell types express muscarinic receptors. m1 receptors are present mainly in the peripheral lung tissue and in the alveolar walls: they are expressed by airway epithelial cells, where they modulate electrolyte and water secretion, by goblet cells, where they regulate mucus production, and by the ganglia, where they facilitate parasympathetic neurotransmission. m2 and m3 receptors represent the major populations in the large airways. m2 receptors are expressed by neurons, where they function as autoreceptors inhibiting the release of acetylcholine from both preganglionic nerves and from parasympathetic nerve terminals. in airway smooth muscles, they modulate different ion channels involved in cell contraction, effects that require concomitant m3 receptor-mediated release of calcium from intracellular stores. in fibroblasts and smooth muscles, m2 receptors stimulate cell proliferation and modulate cellular responses associated with airway remodeling [2, 4] . m3 receptors are the dominant receptor subtype in the regulation of airway smooth muscle contraction and of mucus secretion from submucosal glands and goblet cells [3] . m3 receptors can also favor airway smooth muscle proliferation, increasing the responses to epidermal growth factor and platelet-derived growth factor [3] . acetylcholine, in addition to the parasympathetic nerve, is also synthesized and released by a large number of non-neuronal cells, including neuroendocrine, ciliated, basal and secretory epithelial cells where it can act as an autocrine or paracrine signaling molecule. secretory and ciliated cells release acetylcholine into the luminal periciliary fluid, whereas endocrine and basal cells secrete acetylcholine basally [3] . current knowledge suggests that the local auto/paracrine production of acetylcholine by epithelial cells may play a role in regulating various aspects on the innate mucosal defense mechanisms, including mucociliary clearance. acetylcholine is known to increase ciliary beat frequency in the airways and to modulate the release of inflammatory mediators by these cells through m3 receptors and to affect inflammatory cells involved in the pathogenesis of obstructive airway diseases [3] . expression of muscarinic receptors has also been shown by most inflammatory cells, including macrophages (m1-m3) , t-and b-lymphocytes (m1-m5), mast cells (m1), neutrophils (m1-m3) and eosinophils (m1). in these cells, muscarinic receptors appear to be involved in cell proliferation and release of pro-inflammatory mediators [2, 3] . arteries, veins and bronchopulmonary anastomoses also express muscarinic receptors (m3) and dilate in response to acetylcholine released by vagal nerve stimulation. the postganglionic nerve fibers do not form defined synapses to their target cells but a terminal meshwork called 'autonomic plexus' with numerous varicosities, called sites of transmitter release, in variable and only rarely close contact to cells, such as airway smooth muscle [4] . release of acetylcholine from the parasympathetic nerve terminals in the airways appears to be under complex prejunctional regulatory mechanisms. the available data indicate that acetylcholine release can be enhanced by a variety of pro-inflammatory mediators (histamine, bradykinin, neuropeptides) and by b 2 -adrenergic agents, whist it is under the inhibitory control of muscarinic autoreceptors and downregulated by eicosanoids, such as pge 2 , opioids, nitric oxide and a 2 -adrenergic agents [5] . the activity of m3 receptors in smooth muscle appears to be spared or even increased in asthmatics, possibly because of a greater affinity of the acetylcholine binding site. there is also no evidence that muscarinic receptors are overexpressed or upregulated in airway smooth muscle in disorders characterized by bronchial obstruction or hyperresponsiveness although an acquired loss or impairment of neuronal m2 receptor function may be involved in their pathogenesis [15] . these functional changes occur after exposure to allergens, infectious agents (viruses) or pollutants (ozone) and result in increased acetylcholine release from parasympathetic nerves [6] . m2 autoreceptors dysfunction in allergic asthma is caused by the eosinophil basic protein released by activated eosinophils that, upon binding to m2 autoreceptor sialic acids, acts as an allosteric antagonist [3] . with the same mechanism, an early recruitment and activation of eosinophils is thought to cause the airway hyperreactivity that follows environmental ozone exposure [3] . in contrast, viral respiratory infections are purported to induce bronchial hyperresponsiveness through different mechanisms, including: a) the inhibition of m2 receptor synthesis, mediated by the release of interferon-g by activated cd8þ t-lymphocytes; b) the production of neuraminidase, that determines functional impairment of m2 receptor activity by cleaving their sialic acid; c) m2 receptor dysfunction, caused by the activation of the substance p (nk1) receptor overexpressed by influenza, parainfluenza and respiratory syncytial virus [3] . interestingly, increased substance p production has been reported in patients with asthma and gastroesophageal reflux, a disorder that recognizes vagus-mediated oesophageal-tracheobronchial reflexes in its pathogenesis. experiments performed in humans have corroborated the relevance of pathogenesis of m2 autoreceptors in generating airflow limitation showing that m2 receptor selective agonists inhibit cholinergic-induced bronchoconstriction in normal individuals but not in asthmatic patients [3] . defects in m2 autoreceptor activity may also explain bronchoconstriction induced by b-blockers in asthma. these drugs can increase cholinergic tone downregulating the action of endogenous catecholamines on b 2 -adrenoceptors present on cholinergic nerves [3] . thus, in extreme synthesis, the three muscarinic receptor subtypes expressed in the airways have different, somehow conflicting functions: m1 and m3 receptors facilitate cholinergic-induced events, including bronchoconstriction and mucus glands secretory activities, whilst m2 receptors have a feedback inhibitory function, regulating the release of acetylcholine from cholinergic nerve endings. this information is of great importance to understand the activity of the three anti-cholinergic agents that can be used to treat patients with reversible airway obstruction. two of these, ipratropium and oxitropium bromide, are short-acting and non-selective muscarinic antagonists. because of the lack in selectivity, they also block m2 receptors, increasing acetylcholine release, and therefore reducing the degree of their "useful" action on m1 and m3 receptors [3] . in contrast, the more recent longacting anticholinergic drug tiotropium bromide is characterized by a kinetic selectivity for m1 and m3 receptors over m2 receptors: it dissociates rapidly from m2 receptors and very slowly from m1 and m3 receptors [3, 7] . to date, the anti-cholinergic agents most commonly used to treat respiratory disorder in childhood is the "non-selective" ipratropium bromide which, alone or associated with inhaled b 2 -adrenoceptors agonists, has been demonstrated to significantly improve pulmonary function and clinical outcomes in acute asthma, in preschool wheezing, although no long-term assessments have been included [3, 8] . interestingly, preliminary data show that inhaled tiotropium bromide, once daily, is well tolerated and also improves lung function in pediatric patients with cystic fibrosis [9] and in asthmatic adolescents, symptomatic despite inhaled corticosteroids [10] . evidence from experimental models also suggest that tiotropium bromide may also modulate the acetylcholine-induced inflammatory and remodeling changes induced in the airways by a variety of stimuli, leading to hopes of having favorable clinical responses in other respiratory disorders. a relevant role in the pathogenesis of obstructive airway disorders is thought to be played by an increased acetylcholine release, at least in part due to m2 receptor dysfunction. the most commonly prescribed short-acting anticholinergic drug, ipratropium bromide, is not selective for muscarinic receptor subtypes. despite some efficacy in the most common pediatric airway diseases such as asthma and pre-school wheeze and cystic fibrosis, ipratropium bromide is not commonly prescribed as a standalone medication. the more recently introduced anticholinergic drug, tiotropium bromide, has advanced pharmacologic properties such as long duration of action and a functional selectivity for m1 and m3 receptors over m2 receptors, and has shown a good efficacy and safety profile in adult respiratory disorders, such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. ongoing studies are now under way to define its therapeutic role for pediatric airway diseases. inhalation of smoke from datura strammonium, a member of the deadly nightshade family, was recommended for the treatment of asthma in 17th century ayuverdic literature. general gent, himself an asthmatic, on return from india in the early 19th century, was reported to have brought this therapy to england. strammonium and belladonna cigarettes were widely used to treat respiratory disease until the middle of the 20 th century. however there were frequent side effects, including tachycardia, hallucinations, and even addiction. with the introduction of synthetic atropine derivatives with fewer side effects, there has been a renewed interest in anticholinergic therapy for asthma. bronchial smooth muscle tone is predominantly set by cholinergic activation. patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, likely as a result of cholinergic activity. anticholinergic medications can relax smooth muscle in children with acute asthma, these drugs also appear to have anti-inflammatory properties, and may reduce goblet cell hyperplasia driven by neutrophil elastase à a feature of severe asthma known to be resistant to steroid therapy. the short-acting anticholinergic agents, ipratropium bromide and oxitropium bromide, have been used in asthma for many years, primarily for acute asthma in the emergency department. paradoxically, although the addition of an anticholinergic medication to a beta agonist can decrease acute asthma severity and hospital admission, studies suggest that continuing the anticholinergic while the patient is in hospital does not hasten recovery or decrease length of hospital stay. however these studies have been small and potentially underpowered. until the past decade, these results have dampened enthusiasm for studying anticholinergic medications as maintenance asthma therapy. this has changed with long-acting anticholinergic (lama) bronchodilators under investigation or are available for treating lung disease: these include tiotropium, aclidinium, glycopyrronium, glycopyrrolate and umeclidinium. the once-daily lama, tiotropium bromide, is demonstrated to improve lung function and decrease the risk of exacerbation in adolescents and adults with moderate to severe asthma, despite the use of inhaled corticosteroids (ics) and long-acting b 2 -agonists (labas). in september 2015, the fda in the united states approved tiotropium for the long-term, maintenance treatment of asthma in patients 12 years of age and older. tiotropium by respimat soft-mist inhaler is now included in the global initiative for asthma report (gina) 2015 global strategy for asthma management and prevention. in phase 3 studies, tiotropium improved asthma symptoms in 68% of enrolled subjects and decreased exacerbations by 21% whilst having a safety profile similar to that of placebo. studies also show that tiotropium was effective in improving pulmonary function (fev1) and decreasing asthma attacks in children age 6-11 with poor asthma control despite use of a medium dose of ics with or without a leukotriene modifier. there was no difference in effectiveness when comparing the fda-approved dose or 2.5 mcg (2 â 1.25 mcg) once daily tiotropium to a higher dose of 5 mcg. initial studies in children younger than 6 years do not appear to show benefit. with increasing knowledge about the diverse actions of the cholinergic system in asthma and the role of muscarinic receptors in the airway, we are gaining an increased appreciation of how anticholinergic medication can play an important role in treating children and adults with chronic and poorly-controlled asthma. the 2008 ers task force opted to not use the term asthma to describe preschool wheezing illness since there was insufficient evidence showing that the pathophysiology of preschool wheezing illness is similar to that of asthma in older ages. the task force referred to pre school wheezing and described episodic (viral wheeze) for children who wheeze intermittently and are well between episodes versus multiple-trigger wheeze for children who wheeze both during and outside discrete episodes.(2) we will therefore in our current discussion refer to this young age morbidity as an entity that should be discussed separately from asthma, acknowledging that much has yet to be learned on the nature of this entity. amongst the many mechanism of virus-induced airway hyperreactivity; a common phenomenon in pediatric practice related to this young age group, studies have shown that cholinergic overactivity such as through the modulation of substance p may mediate virus-induced airway hyperreactivity. virus-specific cd8þ t lymphocytes may induce cholinergic activation through m2 receptor dysfunction.(3) hence anticholinergic medications may have a role in viral-induced wheeze with compounds that display selectivity for m1 and m3 muscarinic receptors over m2 receptors having advantages over nonselective compounds. a number of small studies addressed the role of anticholinergics in acute bronchiolitis but failed to show a role for this acute intervention. a study on 69 infants who were randomly assigned to receive nebulized salbutamol, ipratropium bromide or placebo resulted in faster improved clinical scores and oxygen saturation levels in the bronchodilator groups than in the placebo, but no effect to change the natural course of the disease. (4) in studies on this topic from 1981, inhaled ipratropium bromide administered to wheezy children (3 -32 months of age) improved lung function when measured by total body plethysmography and forced oscillation technique. (5) the authors were unable to differentiate between responders and nonresponders by clinical or by physiological parameters, but submitted that the differential distribution of obstruction between small and large airways may underlie response or lack thereof; and that subjects with a predominance of large airways obstruction were the responders to inhaled ipratropium. a logical if unproven additional speculation was that anticholinergics decrease airway secretions and with it reduce large airway resistance. a cochrane review examining the effect of adding ipratropium bromide to b 2 -agonists in wheezy infants (6) suggested that the combined therapy improved symptom scores after 24 hours compared to the use of jb 2 -agonist alone. the ers task force cited above(2) offered evidence-based recommendations on the definition, assessment and treatment of wheezing disorders in preschool children. addition of ipratropium bromide to short acting b 2 -agonists was suggested for patients with severe wheeze. in the 2014 review of the task force recommendations no reference was made to the use of anticholinergic medications. (7) tracheobronchomalacia it is widely believed amongst pediatric pulmonologists that administration of b 2 -agonists in infants with airway structural instability, predominantly tracheobronchomalacia is detrimental, while the use of anticholinergics for bronchodilatation is safe. this notion derives from a study of only 3 infants with intrathoracic tracheomalacia, using infant pulmonary function testing and demonstrating that flows improved significantly after administration of metacholine but worsened after administration of albuterol.(8) these results suggest that in patients with abnormally collapsible tracheas or large bronchi, stimulation of the smooth muscle can improve airway stability, thereby increasing forced expiratory flows, while relaxation of airway smooth muscle by bronchodilators can exacerbate obstruction. the sole support for this observation comes from a review of a series of patients with tracheobronchomalacia from chile, in whom beta-agonist medications were discontinued while the anticholinergics were not. (9) the effect of anticholinergic medication has not been assessed directly in any study, and thus whether this class of medications may have a different effect compared to beta 2 -agonists in such pathology has not been established. further studies on the effect of the various bronchodilators for such pathologies using newer technologies to assess airway resistance (e.g., forced oscillation) should be undertaken. while more invasive and challenging, a technique of direct quantitative assessment of tracheal collapsibility in infants with tracheomalacia has been described, and may be the most adequate technique to answer this important clinical question. (10) tiotropium bromide in pediatric use -asthma and the asthma-copd overlap syndrome ipratropium bromide has a limited role in childhood asthma, largely due to lack of selectivity. the more recently introduced long-acting muscarinic antagonists/anticholinergic (lama), tiotropium bromide, presents advanced pharmacologic properties such as selectivity for m3 muscarinic receptors over m2 receptors and long duration of action. a high safety profile and increasing evidence of efficacy have rendered it a mainstay medication for copd with an emerging role in adult asthma. few studies have emerged on its role in the treatment of childhood asthma and defining its therapeutic niche for pediatric airway diseases. in a recent 1-year randomized controlled trial, tiotropium add-on therapy in adolescents with moderate asthma, (11) significantly improved lung function and was safe and well tolerated when added to at least ics maintenance therapy. a study of 71 pediatric patients with asthma and chronic cough from an asthma center (12) concluded that tiotropium can be beneficial in 3 distinct patient populations: add-on therapy to asthmatics on maximal maintenance medication, an alternative to highdose inhaled steroids in patients who are experiencing significant side effects, and patients with bronchorrhea as their predominant symptom manifested by a chronic productive cough, the latter population is most likely explained by its drying effect on airway secretions. a recent editorial (13) states "approximately 1 in 12 people worldwide are affected by asthma or chronic obstructive pulmonary disease (copd); once regarded as two distinct disease entities, these two conditions are now recognized as heterogeneous and often overlapping conditions. the term "asthma-copd overlap syndrome" (acos) has been applied to the condition in which a person has clinical features of both asthma and copd". in recent years multiple reports describing this interface between asthma and copd have been published recognizing that the demarcation line between these two entities is difficult to define. while the precise definition in various populations is still being worked out, and it is obvious that the majority of such patients are adults, there is early recognition that some pediatric populations, who are viewed as asthmatic, yet have no airway reversibility, may constitute an early presentation of the overlap syndrome. the mainstay therapies for copd are long-acting inhaled bronchodilators, including longacting b2-agonists (labas) and lamas, with its characteristic member being tiotropium bromide. in patients with copd they are recognized as being equally effective because they reduce air trapping by relaxing airway smooth muscle as a result of reducing the effects of intrinsic cholinergic tone. it is therefore intriguing to speculate that once a better definition of the overlap syndrome emerges in pediatrics, an important role for tiotropium is likely to emerge particularly as a potential steroid sparing medication. peter d sly, ao mbbs, md, dsc, fracp, fers, f thor soc, fapsr, fahms p.sly@uq.edu.au the measurement of lung function is of major importance in clinical practice or respiratory medicine and in respiratory research. much has been learned about the risk factors underlying respiratory disease by measuring lung function in patients and comparing it with that in healthy controls. however, for managing an individual patient or assessing risk of disease onset or progression, it is necessary to know whether an individual's lung function is "normal" or "abnormal". over the years, a number of sets of normative equations have been produced by individual research groups in different parts of the world. these have been incorporated into commercially-available spirometers and used in populations other than those in which the data were collected. this situation was far from ideal, especially as some of the normative equations were many decades old. what is the gli? data were obtained from 73 centers in 33 countries (n ¼ 160,330) ; however not all could be used due to lack of data on ethnicity (which is illegal in france!), small numbers, missing data, lack of quality control and other factors. data were also pooled by region with data from europe, israel, while fev 1 and fvc varied between ethnic groups, they did so proportionally, meaning that fev 1 /fvc was independent of ethnicity. the lower limit of normality for fev 1 and fvc showed age dependence that differed between males and females, reaching 80% by mid-childhood and falling progressively below 80% from approximately 40 years of age. the rate of fall in the lower limit of normal for fev 1 and fvc was identical for women but fvc declined more slowly in males. a ratio of fev 1 / fvc >0.7 is taken to indicate pathological airflow limitation; however, the proportion of the healthy non-smoking population with fev 1 /fvc >0.7 rises steadily to 20-25% at 80 years of age. how well do the gli reference equations predict lung function in people in individual countries? given that the gli reference equations were compiled by pooling data from a variety of sources, one might expect that the equations would provide good estimates of lung function for populations that were well represented in the pooled data whereas they may not for populations either not included or underrepresented in the pooled data. indeed this appears to be the case, with the gli equations adequately representing lung function in australasian caucasians 2 , but not performing as well for adults in brazil 3 , north africa 4 , madagasca 5 , and children in poland 6 and peri-urban and rural india 7 . further study is required to ascertain how widely the gli reference equations can and should be applied. what constitutes "normal" data? an important consideration when creating reference equations is what characterizes a "normal" population and who should be excluded? the dataset used to construct the gli reference equations excluded ever smokers, but is this reasonable? if 20-30% of an adult population smoke, should they be excluded from equations designed to the lung function of that population? maternal smoking during pregnancy results in long-term reduction in lung function 8 but is not generally taken into consideration when defining a healthy population. "healthy" children are often defined as those with no prior asthma or hospitalization for respiratory problems, born full term with birth weight ! 2.5 kg and asymptomatic at the time of testing 9 . however, lum et al. 9 recently demonstrated that with the exception of clear-cut factors such as current and chronic respiratory disease, including children born prematurely or with low birth weight, prior asthma and mildly symptomatic made little difference to the reference equations but increased the generalizability to the target population. this debate continues! the implications of switching to the gli equations will depend on how well the gli equations represent lung function of the local population. in poland, a switch from the 1998 polish reference values to the 2012 gli would see an increase in diagnosis of obstructive lung disease from 17.5% to 20.3% and an increase in diagnosis of restrictive lung disease from 3.8% to 7.6%. whether this represents an over-diagnosis with gli or an under-diagnosis with the old equations is a matter of clinical judgment. the impact on parents and children with cystic fibrosis is likely to be substantial as families tend to focus on lung function, especially fev 1 expressed as a percent of predicted as evidence of the state of the child's lung disease. a change in number for a technical reason must be balanced against the likelihood of creating anxiety in the clinic population. respiratory symptoms are very frequent in infants and young children. special emphasis has been put on symptoms signaling bronchial obstruction and bronchial hyperresponsiveness as these may be associated with early onset of asthma. since the early 1980 0 s, several research groups have been focusing on early events in the development of asthma, especially seeking potential risk factors for predicting persistent symptoms. structural changes in the bronchial mucosa and lung function impairment in children with early obstructive symptoms have also been studied. it was documented that eosinophilic inflammation and remodeling (particularly epithelial basement membrane thickening and increased airway smooth muscle mass) are consistently present in patients with persistent asthma. interestingly, some markers of inflammation and even those of initial remodeling have already been described in children before the clinical diagnosis of asthma could be confirmed 1 . this finding supports the hypothesis of remodeling not being a late consequence of a long lasting eosinophilic inflammation but that it may run in parallel with the development of asthma, if not even precede or initiate inflammation in the bronchial mucosa. this hypothesis was later supported by further research based on bronchial biopsies in infants. eosinophilic inflammation and some markers of remodeling have been documented in the bronchial mucosa of symptomatic children as early as in the second year of life 2 . in a recent study, we were able to show that basement membrane thickening could be found even in young children at risk of developing asthma even without a history of recurrent wheeze 3 . however, the significance of these findings in terms of long term prognosis still remains less documented. it is known that airway hyperresponsiveness in infancy is associated with persistent symptoms later in childhood 4 . also, reduced airway patency at birth was shown to be linked to an increased risk of developing asthma and severe bronchial hyperresponsiveness by the age of 10 years 5 . long-term follow up of children investigated in infancy and reassessed in later childhood have so far showed that reduced baseline lung function in symptomatic infants was significantly associated with subsequent respiratory morbidity as well as with the need of anti-asthma medication at the age of 3 years. in addition, the usage of inhaled corticosteroids at the age of 3 years also seems to be in positive correlation with basement membrane thickening and increased number of mast cells in bronchial mucosa in bioptic samples taken earlier in infancy 6 . this study has thus suggested that early morphological changes in the airway wall might indeed play a role in determining subsequent respiratory morbidity. on the other hand, at the next follow-up of these children at the age of eight years, the positive correlation between current respiratory symptoms and markers of inflammation and remodeling described in infancy was no longer found 7 . this finding is consistent with the results of the follow-up of our group of children where we did not find a significant correlation between lung function (both fev 1 and fvc) measured in preschool age and basement membrane thickness measured earlier in infancy and toddler's age both in the risk group and control group of children (unpublished data). more recently, airway smooth muscle mass has come into the center of interest of many researchers in respiratory medicine. smooth muscle hyperplasia and hypertrophy in the bronchial wall of patients with asthma are considered to be a consistent feature of bronchial remodeling. it is notably a possible dysfunction of newly formed smooth muscle bundles that deserves attention and more studies in this area are urgently required. the first works in children have shown that the increase in the airway smooth muscle mass in the bronchial wall might be associated with school age asthma 8 . lately, another study has described a negative correlation between the airway responsiveness at the age of 8 years and airway smooth muscle mass in infancy 7 . however, this area of airway remodeling still remains poorly understood, especially with regard to its role in childhood asthma. based on currently available data, reduced lung function at birth or in early childhood is apparently associated with the persistence of symptoms and the decrease in lung function in later life. however, it still has not been reliably confirmed whether this low lung function has any correlation with early signs of airway remodeling. more long-term follow-up studies are needed in pediatric patients comprising both tissue biopsies taken in early age followed by longitudinal long-term lung function monitoring. nasal and sinus disease is universal in cystic fibrosis (cf). because nasal and sinus disease usually coexist, we will refer to this as "sinonasal disease". since the mucosa of the sinuses and upper respiratory tract and the mucosa of the lower respiratory tract are similar, disease may be similar in both locations and sinonasal disease could influence the severity of pulmonary disease. this view of the "universal airway" has been demonstrated in patients with pulmonary conditions, such as asthma and copd. in these diseases, an improvement in sinus health is reflected by an improvement in the lower airway disease. this has not been well studied in cf but the implications of this relationship combined with increasing life span makes an understanding of sinonasal disease important to the care of these patients. mutations in the cystic fibrosis transmembrane conductance regulator (cftr) gene in cf carriers appear to be independently associated with a higher prevalence of sinonasal disease; 36% of carriers reported chronic rhinosinusitis compared to the 13-14% in the general population. the bacterial flora of the sinuses changes with patient age, can include anaerobes and fungi, and often mirrors the organisms present in the lower respiratory tract. a link between sinus infection and lower respiratory tract infection may contribute to morbidity following lung transplantation and immunosuppression. somewhat surprisingly, the prevalence of otitis media in cf appears to be no greater than in an age-matched general population. endoscopy and computerized tomography have broadened our understanding of how cf affects the sinuses. endoscopic sinus exams are almost always abnormal and give a better indication of the presence of nasal polyposis than physical examination of the nose alone. nasal polyps become more common with age and may represent a proliferative airway repair mechanism. sinus ct has demonstrated several anomalies characteristic of sinonasal disease in cf such as bulging or displacement of the lateral nasal wall, demineralization of the uncinate process, and hypoplasia or aplasia of the paranasal sinuses. serious complications of sinonasal disease in cf are rare and include mucoceles and periorbital abscesses. these usually require surgery. there are few randomized, controlled trials evaluating medical or surgical treatments of cf sinus disease. sinus surgery may provide some benefit, though there are no established selection criteria for appropriate candidates. the trend today in neonatal intensive care units (nicus) is to be as gentle and less invasive as possible in the care of neonates. this attitude takes place in every field of neonatology, and will discuss its implementation specifically in the respiratory care administered to premature infants with respiratory distress syndrome (rds). 1, 2 prenatal corticosteroid therapy is recommended in all pregnancies with threatened preterm labor below 34 weeks' gestation. recently, it was shown that such therapy could also be beneficial in late preterm infants as it significantly reduced the rate of a neonatal composite of respiratory treatments in the first 72 hours or stillbirth or neonatal death within 72 hours after delivery. 3 at delivery, the term stabilization and not resuscitation is preferred for the vast majority of very preterm infants. only a minority of babies should require delivery room intubation. neopuff can be helpful in the delivery room and the transport to the nicu, and enables the administration of continuous positive airway pressure (cpap) and intermittent positive pressure ventilation under controlled conditions. recent large trials that reflect current practice (including greater utilization of maternal steroids and routine post delivery stabilization on ncpap) demonstrated less risk of bronchopulmonary dysplasia (bpd) or death when using early stabilization on ncpap with selective surfactant administration to infants requiring intubation. the comprehensive strategy to prevent bpd in the nicu is based on ventilatory and non-ventilatory measures. 4 the ventilatory route allows an individualized endotracheal intubation approach. recent studies concluded that early nasal cpap (ncpap) is a safe alternative to immediate intubation even in extremely low birth weight (elbw) infants. 1, 2, 4 endotracheal intubation and ventilation can result in significant damage to premature lungs and are independently associated with cerebral palsy. furthermore, despite new modes of ventilation and surfactant, bpd remains a significant morbidity and its incidence was correlated with the use and length of endotracheal mechanical ventilation. bpd in itself is associated with adverse neurodevelopmental outcome. thus, we need to avoid endotracheal ventilation, if possible. when the infant requires nasal respiratory support (nrs), we should aim for adequate oxygenation (spo 2 of 90-95%), 1 permissive hypercapnia (paco 2 of 45-55 mm hg, ph >7.22) and gentle ventilation, similarly as in endotracheal ventilation. 1, 4 ncpap is recommended as the early primary treatment of active respiratory distress syndrome (rds) (to avoid intubation or as part of the insure [intubation surfactant extubation] approach), or later, post extubation at rds resolution, in order to allow shortening of the duration of endotracheal ventilation and to treat apnea of prematurity. 1, 2 recent studies 1, 4 report comparable rates of bpd in elbw infants treated initially with ncpap as compared to endotracheal ventilation with surfactant administration. can we enhance ncpap and get better outcome for nrs by using nasal intermittent positive pressure ventilation (nippv)? nippv was defined as a method of augmenting ncpap by delivering ventilator breaths via nasal prongs. the rationale behind the use of nippv is the administration of "sigh" to the infant, thus opening microatelectasis and recruiting more ventilation units. it was shown that synchronized nippv (snippv) compared with ncpap may improve the patency of the upper airway, could activate the respiratory drive, improves thoraco-abdominal synchrony, stabilizes the chest wall, improves lung mechanics and decreases the work of breathing in premature infants. when nippv was compared to ncpap for the different indications of nrs, it was shown to enhance the potential of nrs. 4 a recent meta-analysis demonstrated a relative risk reduction for intubation in the first 72 hours in the nippv group compared with ncpap (rr 0.60, 95% ci 0.43, 0.83). 5 the nippv trial 6 was a large international multicenter randomized trial powered to study the important outcome of bpd, recruiting 1,009 extremely low birth weight babies, and it showed no difference between babies randomized to nippv compared with cpap. snippv vs. ncpap for later use, post extubation at rds resolution, as a "bridge" to spontaneous unsupported breathing, was shown to be more effective than ncpap. a pooled meta-analysis showed that snippv was more effective than ncpap in preventing failure of extubation [rr 0.21 (0.10, 0.45)] and the number needed to treat was only 3 infants to prevent one extubation failure. 7 snippv vs. ncpap, post extubation, also tended to decrease the rate of bpd. snippv may also be more effective than ncpap for apnea of prematurity. 4 a meta-analysis regarding apnea of prematurity suggests that snippv is more efficacious with apnea that is frequent or severe. however, the studies performed addressed short-term outcomes and as such could not properly address the incidence of requirement for reintubation. thus, more studies are needed before recommending snippv as standard of care for apnea of prematurity. while non-invasive ventilation is probably safe, its success depends on gestational age. the data indicate that surfactant may still have a significant role in the treatment of rds, especially in elbw infants. recent studies reported on an intubation rate of $50% in their ncpap group in elbw infants. 1, 2, 4 this leads us to the insure approach. this approach may allow the infant to benefit from both surfactant and nrs. a cochrane review 8 concluded that the insure approach with ncpap compared with later selective surfactant administration, continued mechanical ventilation, and extubation from low respiratory support was associated with less need for mechanical ventilation, lower incidence of bpd and fewer air leak syndromes. another option for surfactant application to the trachea without endotracheal intubation was described by using a thin catheter in spontaneously breathing preterm infants receiving ncpap. this technique was reported to reduce the need for mechanical ventilation. 9 there are ongoing trials with inhaled surfactant. to summarize, ncpap is still the most common mode of non invasive respiratory support worldwide. 1, 2 the available evidence supports the preference of early or later use of nippv/snippv compared to ncpap because of minimizing the use and the length of endotracheal ventilation. 4 there are data to suggest that this approach may also reduce the rate of bpd, however this has yet to be shown. 4 the results of a large international rct comparing both primary and post-extubation use of nippv with ncpap, with a composite primary outcome of death or bpd at 36 weeks' corrected age, indicate no additional benefit, or risk, conferred by nippv in comparison to ncpap. 6 whether nippv/snippv is more beneficial than ncpap within the insure approach needs to be shown. recently, heated, humidified high-flow nasal cannula (hhhfnc) is frequently used as a mode of nrs. high flows result in washout of anatomical and physiological dead space and contribute to improved fractions of alveolar gases with respect to carbon dioxide as well as oxygen and decrease the work of breathing and the energy cost of gas conditioning. hhhfnc probably creates positive end expiratory pressure (peep) that may contribute to its beneficial effect. however, the peep that is not monitored had raised concerns regarding the safety of hhhfnc in terms of air leak. recent prospective studies support the notion that hhhfnc is as effective as ncpap for early stages of rds, post extubation 10 and for apnea of prematurity. yet, more studies, especially in the initial treatment of rds and in elbw infants, are needed before adopting hhhfnc as an alternative mode of nrs in these conditions. new modes of nrs such as neurally adjusted ventilator assist (nava), and nasal high frequency ventilation, need to be further studied before concluding on benefits for the short and long term outcomes in premature infants. non-ventilatory measures in the treatment of rds, such as caffeine, nutrition, fluid and pda management and postnatal steroids in certain conditions should be included in the care of premature infants with rds in order to minimize the rate of bpd. 1, 4 the noninvasive ventilator strategy needs to be confirmed by large prospective randomized controlled trials (with long-term follow up) in order to assure it is applicable to most elbw infants. furthermore, the strategy needs to be tailored to individualized infants according to the infant's maturation; antenatal steroid treatment and severity of rds; general condition; and to certain practical nicu conditions such as experience, personnel and timing during the day. for many years, it has been generally accepted that the pathophysiology of rsv bronchiolitis is driven by the inflammatory response evoked by horizontal (i.e., interpersonal) transmission of the virus in the first few months after birth (1). however, a recently published study has brought to the forefront a striking new idea: rsv may be transmitted vertically from the respiratory tract of the mother to the lungs of the fetus (2) . until now, we believed that when a pregnant woman got a cold, the developing fetus was protected by the placenta from rsv and other respiratory viruses. in this study, pregnant rats were inoculated with a recombinant rsv strain that could be tracked through expression of a red fluorescent protein (rrrsv). the same virus was subsequently found in 30 percent of fetuses exposed in utero, as well as in the lungs of 40 percent of newborn rats and 25 percent of rats born to inoculated mothers when tested in adulthood. these data provide proof of concept for the transplacental transmission of rsv from mother to offspring and the persistence of vertically transmitted virus in lungs after birth. notably, the intrauterine rsv infection changed expression and function of critical neurotrophic pathways that control the development of cholinergic nerves in the budding airways and lung tissues (3). these changes in cholinergic innervation of the fetal respiratory tract resulted in the development of postnatal airway hyperreactivity upon reinfection with the same virus (2) . the airway smooth muscle tone was normal in the absence of stimulation and its contraction was normal in the absence of either maternal or neonatal infection. but in pups reinfected with rsv after prenatal exposure to the virus, markedly potentiated contractile responses were measured after either electrical nerve stimulation or methacholine inhalation, suggesting the involvement of both pre-and postjunctional mechanisms. these findings are consistent and provide a plausible mechanism to the epidemiologic evidence that early-life rsv infection -or possibly reinfection -predisposes a subpopulation of children to recurrent wheezing and asthma that typically spans through the first decade of life even in the absence of atopic phenotype (4). to our knowledge this is the first report of vertical transmission of rsv, or for that matter any common respiratory virus. a number of infectious agents, including herpesviruses and retroviruses, have been shown to cross the placenta and establish persistent infection in offspring. the new evidence extends this possibility to other infections, such as rsv, once regarded as temporary and localized and that instead may be longer lasting and more pervasive than we thought. also, as shown for other viral pathogens, if rsv seeds the fetus before full t-cell maturation, this could lead to induction of prenatal tolerance and justify the limited synthesis of interferon and other inflammatory cytokines that have been noted when newborns develop severe infections (5) . vertical rsv and asthma -the general concept that we have been working under for decades is that nothing bad happens in the lungs until the baby is born -even with serious conditions such as cystic fibrosis -and that the lungs are "clean" of pathogens at birth. but if human studies replicate the findings from animal models outlined above, our understanding of the pathogenesis of rsv infections would be completely changed. it would turn back the clock of respiratory developmental diseases by months and mean that we would need to start thinking about lung development and pathology during pregnancy rather than at birth. this could create a paradigm shift by extending our focus on prevention from the first few years after birth to also include the last few months before birth. this new paradigm is in line with the emerging evidence that many (or most) chronic inflammatory, degenerative, and even neoplastic diseases plaguing adults have their origins from often-subtle events occurring during fetal life. the "foetal programing hypothesis" was originally formulated by dr. david barker more than two decades ago to explain the extensively reproduced and confirmed epidemiologic evidence that low birth weight predisposes to cardiovascular disease in late adulthood (6) . dr. barker died aged 75 in september 2013, leaving the legacy of this initially controversial, but now widely accepted, idea that common chronic illnesses such as cancer, cardiovascular disease and diabetes result not always from bad genes and an unhealthy adult lifestyle, but from poor intrauterine and early postnatal health. in one of his last public speeches, he argued: "the next generation does not have to suffer from heart disease or osteoporosis. these diseases are not mandated by the human genome. they barely existed 100 years ago. they are unnecessary diseases. we could prevent them had we the will to do so." we believe the same concepts can be extended to chronic obstructive airway diseases like asthma and copd. asthma is the final product of complex interactions between genetic and environmental variables. prenatal events like the intrauterine exposure to viruses with specific tropism for the developing respiratory epithelium (7) or imbalanced maternal diet (8) will cause a shift in the trajectory of structural and functional airway development towards a hyperreactive phenotype. the same intrauterine exposures can affect gene expression via epigenetic modifications like dna methylation, histone acetylation, and by altering the relative expression of regulatory micro-rnas (9) . the resulting neonatal phenotype will predispose the child to aberrant responses to common respiratory infections and airborne irritants, thereby increasing the risk of obstructive lung disease later in life. postnatal events, such as exposure to indoor and outdoor pollutants and allergens, can further shift the equilibrium of the adult phenotype by exacerbating airway inflammation and hyperreactivity (10) . the continuous range of possible developmental trajectories and multiple sequential events acting during development will define the severity and duration of disease. the incidence, severity and mortality from childhood pneumonia has declined substantially in the last decade due to improved socioeconomic conditions, better access to care, wider implementation of effective management and preventative strategies and development and availability of improved vaccines, particularly the pneumococcal (pcv) and h influenzae type b (hib) conjugate vaccines. [1] however, pneumonia remains the leading cause of childhood mortality globally outside the neonatal period and a major cause of morbidity and hospitalization despite good immunization coverage. [2, 3] further, early childhood pneumonia has increasingly been associated with the development of chronic noncommunicable respiratory diseases into childhood and adulthood, such as asthma or chronic obstructive airways disease (copd). [4, 5] with improved global coverage of the newer conjugate vaccines, it is likely that viral causes of pneumonia may be responsible for an increasing proportion of pneumonia cases. [6] however, defining the etiology of pneumonia may be challenging as it can be difficult to distinguish colonizing from pathogenic organisms in respiratory specimens, blood culture rarely is positive and pneumonia, especially severe disease, may frequently be due to multiple co-pathogens. the development of better methods for specimen collection and of molecular diagnostics have provided more sensitive techniques to define potential etiologic agents but further compound the difficulty of ascribing pathogenicity. [7, 8] despite these limitations, studies in the post-pcv era have reported an increasing predominance of viruses in childhood pneumonia cases, with a virus identified in 70-90% of cases. [9, 10] in children vaccinated with 13valent pcv (pcv13), rsv has been reported to be the predominant pathogen in case control analyses from both high income countries and lowmiddle country settings. however, there is frequent co-occurrence of other potential pathogens with rsv, including bacteria and other viruses. [9] children under 6 months of age are at highest risk of rsv disease. [11] to adequately interpret data on viruses in the context of childhood pneumonia, the prevalence of these in healthy control children must be considered. using case control designs, viruses identified in association with pneumonia have been rsv, influenza virus and human metapneumovirus (hmpv); adenovirus, parainfluenza virus and coronavirus have been variably associated with pneumonia while the prevalence of rhinovirus has consistently been similar in cases and controls. [9, 10, 12, 13] the use of quantitative measurements of viral load has not shown to be useful in distinguishing cases from controls except for rsv and for hmpv, but the presence of these alone is sufficient to ascribe etiology. these studies indicate that rsv is a major cause of pneumonia in the era of conjugate vaccines for bacterial pathogens, particularly in young infants. however they also highlight the limitations of current diagnostic strategies, particularly the poor sensitivity of current tests for bacterial etiology and the potential for incorrectly assigning etiology based on molecular diagnostics. they also provide further data on the complexity of ascribing pneumonia etiology, showing interactions between multiple potential pathogens. despite these limitations, the emerging data indicate that a key strategy for reducing the burden of childhood pneumonia lies in prevention of rsv disease in young children. identifying the etiology of pneumonia is key for initiating appropriate management strategies particularly use of antibiotics and to guide development of new vaccines. the reduction in bacterial pneumonia through conjugate vaccines underscores the need to reconsider the empiric treatment of pneumonia in settings where there are strong immunization programs. case management with antibiotics for pneumonia or severe pneumonia in the world health organization integrated management of childhood illness (imci) program has been a highly effective strategy for reducing mortality prior to widespread conjugate vaccine availability [14] , but defining the residual burden and identifying clinical or laboratory features that distinguish bacterial from viral pathogens will be important before any change in pneumonia strategy can be recommended globally. late preterm (lp) newborns (born at 34-0/7 to 36-6/7 weeks gestational age) comprise the fastest growing subset of neonates, accounting for approximately 74% of all preterm births and about 8-9% of total births in the us [1] . "late preterm" infants are born near term, but are "immature". the late premature birth interrupts normal in utero fetal development during the last 6 weeks of gestation that are probably a "critical period" of growth and development of the fetal lungs [2] . three factors play a role in the respiratory vulnerability of lp infants [2] : 1. prematurity with its developmental and consequently physiologic components; 2. heightened rate of respiratory morbidity in the neonatal period; 3. short-term pulmonary outcome respiratory complications are the prime morbidities of lp infants [2] . a large retrospective study [3] found that the odds of respiratory morbidity (respiratory distress syndrome [rds] , transient tachypnea of the newborn [ttn], pneumonia, respiratory failure, surfactant administration, and mechanical ventilation) decreased significantly with each advancing week of gestation up to 38 weeks compared with 39 to 40 weeks. despite a relatively low absolute risk for rds or ttn at 34 weeks compared with more premature infants, this rate poses an increased risk for lp infants when compared with term infants [2] . acknowledgement of these morbidities led to studies aiming to decrease this burden. a recent large randomized controlled study [4] showed that administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of a neonatal composite of respiratory treatments in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hoursr, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. of note, neonatal hypoglycemia was more common in the betamethasone group than in the placebo group. late prematurity may affect the respiratory system in the long term [2] . several studies reported an association of preterm birth (30-36 weeks' ga) without clinical lung disease with altered lung development and function [2] . friedrich et al. [5] in a longitudinal study found that despite normal lung volume, healthy preterm infants had persistently reduced airflow through the age of 16 months and concluded that preterm birth in itself was associated with altered lung development. a single study [6] showed a potential improvement, especially for large airway function, with advancing age. a recent large prospective cohort study showed that the number of hospitalizations caused by respiratory problems during the first year of life was doubled in moderately/late preterm (32-36 weeks' ga) compared with term infants [7] . at preschool age, moderately preterm infants revealed more nocturnal cough or wheeze during or without a cold and increased use of inhaled steroids. at the age of 5 years, rates of respiratory symptoms between moderate and early preterm born (<32 weeks' ga) children were similar; both were higher than in term born children. whether lp birth is associated with airway disease such as asthma in early childhood remains controversial [2] . different findings in published studies could result from the different methods of asthma diagnosis, age groups at diagnosis, and from the difficulties in diagnosing asthma in early childhood. a recent study [8] found that late preterm birth history is not independently associated with childhood asthma until 7 years of age. lp infants are more vulnerable to viral respiratory infections, particularly rsv, which are more severe in these infants vs. term infants. the pernicious combination of rsv bronchiolitis affecting an a priori compromised lung/ airways of lp infants may have a lasting effect on respiratory function and consequent long-term morbidity [2] . long-term persistence of an early decrease in pulmonary function tests (pft) was demonstrated by a longitudinal follow-up into early adulthood for an unselected random population in the tucson children's respiratory study [9] . these observations suggest that the notion of a "critical developmental period" for the respiratory system does exist. deficits in lung function during early life, especially if associated with lower respiratory illnesses (especially rsv), increase the risk for chronic obstructive pulmonary disease later in adult life [10] . summary lp infants are born during a "critical developmental time period" for the lungs. this may result in short and long-term pulmonary consequences. in addition, to screen the population at high-risk for disease. therefore, the effectiveness of early case finding should be a priority, but it depends on several factors such as health care system, contact tracing, and laboratory diagnosis. the diagnosis of tb in children is a common clinical challenge, and relies on a careful assessment of history of exposure, clinical examination, and relevant investigations. the most recommended approach to the diagnosis of tb in both children and adults is based on the who guidelines recommendations from 2010 and 2014 (table 1) . (2, 3) important factors to consider in all children with suspected tb is the endemic setting as well as the age and immune status of the child. in countries with a low incidence of tb, a positive contact with a case in combination with suggestive symptoms makes diagnosis more straightforward. in high tb endemic areas, a history of tb contact remains important, but is much less sensitive, given that transmission often occurs through unknown source cases. (5) laboratory tests for the diagnosis of infections can be grouped into two groups: detection of microbes (or components) and detection of components of the immune response to the microbe. the sensitivity of the first group will depend on the quality of the specimen and the concentration of microorganisms. this group includes microscopy, culture, elisa, and nucleic acid detection (pcr). the second group measures the activity of the immune system against microbe-specific antigens in the possibly infected host. this category includes antibody detection and activated t cells. the gold standard for the diagnosis of tb is bacillary detection by smear or culture. in adults, microscopy can detect up to 60% à 70% of culture-positive samples. in children, this does not work as well due to limited access to appropriate body specimens, and also because children usually have paucibacillary disease, since cavitating disease is rare in children. studies have shown that under best circumstances, acid-fast bacilli sputum smear is positive in only about 10-15% of children with tb while culture gives a better yield of 30-40%. until recently, the diagnosis of ltbi has been based exclusively on the tst, which has relatively poor sensitivity and specificity. despite these limitations, it remains the standard of care for diagnosis of ltbi worldwide, particularly in low-income countries. interferon gamma release assays (igras) measure the in vitro response to specific m. tuberculosis antigens. although they offer several advantages over tst such as better specificity, single visit, little inter-observer variability, and no booting effect; they have not been found better than tst, and are not able to predict the risk of infected individuals developing active tb disease. given their increased cost, replacing tst by igras as a public health intervention in resourceconstrained setting is not recommended. novel approaches to confirmation of tb have been developed. these include methods based on rapid culture techniques and genotypic techniques that improve detection of m. tuberculosis. an example is the xpert mtb/rif assay, which is a fully automated realtime dna based test that can detect both tb and rifampicin resistance in less than two hours. (3, 6, 7) as expected, it should be used rather than conventional microscopy and culture in children suspected of having mdr-tb. the clinical diagnosis of primary tb in children remains challenging because of non-specific signs and symptoms and difficulty with acquiring diagnostic specimens. because of this, the diagnosis of primary tb in practice, relies on a combination of clinical features and chest x-ray (cxr) findings. the detection of lymphadenopathy in the hilar and para-tracheal regions on the frontal cxr, supported by identification of subcarinal lymphadenopathy on the lateral cxr, represent a useful surrogate marker of tb at relatively low cost. however, sensitivity and specificity for identifying lymphadenopathy on cxr in children is relatively poor with significant inter-observer variation in the interpretation of radiographs, complicated further by poor quality of radiographs. affecting both accuracy and observer agreement is the lack of standardized imaging criteria and lymph nodes sizecriteria for a positive diagnosis of primary tb. attempts are therefore being made to establish 'objective' chest radiograph signs backed up by a standard set of images as a guide. ultrasound is an especially attractive imaging alternative to cxr as it does not involve radiation or require sedation and because it is relatively cheap and mobile. ultrasound of the mediastinum has been used to detect mediastinal lymphadenopathy and can also be used to detect extrapulmonary tb through abdominal imaging, at the same sitting. it is particularly useful in rural settings where no other imaging is available. the ability to store digital ultrasound images and cine-loops also enables teleradiology support by expert interpretation and opinion, from a distance. computed tomography (ct) and magnetic resonance imaging (mri) are obvious diagnostic imaging considerations that will improve diagnostic accuracy of primary tb, but the radiation dose in ct, the need for anesthesia in mri, the limited availability and high cost are real barriers to their clinical utility. mri is preferred to ct because it does not involve ionizing radiation. however, the disadvantages of mri for lung imaging (poor signal generated from the air in the lungs and movement artefacts from breathing), the cost and the requirement for the child to keep still for a prolonged period (requiring anesthesia) have slowed its use in thoracic infections. yet, whole body mri, including thoracic imaging is mainstream for detecting lymphadenopathy in childhood lymphoma. the preferred imaging technique varies with the suspected pathology and available equipment. dynamic imaging techniques such as inspiratory/ expiratory cxr, fluoroscopy, and inspiratory/expiratory or cine ct permit the lungs and airways to be imaged at different phases of the respiratory cycle. inspiratory/expiratory cxr and inspiratory/expiratory chest ct have long been the preferred initial imaging methods for detecting foreign body aspiration or bronchiolitis obliterans, respectively, on the basis of air trapping rather than direct visualization of the airway obstruction. fluoroscopy has historically been the preferred noninvasive method for diagnosing tracheobronchomalacia due to its ease of performance, even in uncooperative patients, and its high specificity, but it is limited by its subjective interpretation, low sensitivity, poor depiction of the paratracheal structures, and inability to simultaneously display the anteroposterior and lateral walls of the airway and quantify luminal cross-sectional area 1 . in infants and children too young to comply with breath-hold instructions, inspiratory/expiratory phases can be simulated by imaging during right/left lateral decubitus or prone/supine positioning. controlled-ventilation ct under sedation or anesthesia also permits inspiratory/expiratory imaging of the lungs and airways in uncooperative patients. dynamic cine ct technique allows the airways to be imaged sequentially during successive phases of the respiratory cycle, but coverage was initially limited to short (4 cm or less) segments of the airway, resulting in sampling misregistration and preventing synchronous evaluation of the true extent and severity of airway collapse during the same phase of the respiratory cycle 1 . made possible by recent technologic advances including more rapid gantry rotation and wider detector arrays (up to 16 cm craniocaudal coverage), dynamic volumetric cine ct now allows all or nearly all of the lungs and central airways to be imaged rapidly and sequentially throughout the respiratory cycle without the need for sedation or intubation. this technique is capable of providing multiplanar, 3d and 4d information about the airways during normal tidal breathing or forced expiratory maneuvers, as well as depicting the relationship of the airways to the adjacent vasculature if intravenous contrast is administered 2 . with dynamic volumetric cine ct, intrinsic and extrinsic causes of airway narrowing can be distinguished and fixed airway stenosis can be differentiated from expiratory central airway collapse due to tracheobronchomalacia (softening of tracheobronchial cartilage) or excessive dynamic airway collapse (inward bulging of the posterior membrane) 3 . tracheobronchomalacia is primary (congenital) in approximately 1/2100 children and often resolves in isolated mild to moderate cases by 2 years of age as the cartilage geometry and composition matures and posterior membrane tone develops. tracheobronchomalacia is often accompanied by gastroesophageal reflux disease and is associated with other foregut anomalies, especially esophageal atresia and tracheoesophageal fistula. tracheobronchomalacia can be secondary to extrinsic compression, chronic airway inflammation, intubation, or positive pressure ventilation and is identified in about onefourth of children with chronic respiratory symptoms or signs such as wheezing, barking cough, recurrent respiratory tract infection, apnea, cyanotic spells, or difficulty weaning from respiratory support 4 . tracheobronchomalacia was originally defined as >50% reduction in airway cross-sectional diameter during coughing, but false positives are very common with this definition, especially for the bronchi in which physiologic expiratory airway narrowing is more pronounced than for the trachea. the shape and cross-sectional area of the airway lumen can be precisely determined by ct, but there is no current consensus on the optimal threshold degree of expiratory airway collapse for a diagnosis of tracheobronchomalacia among children of varying ages with or without coexisting lung disease during either tidal breathing or forced expiration. expiratory collapse of normal airways can occur in the setting of obstructive lung disease such as asthma or bronchopulmonary dysplasia due to increased pleural pressure and increased peripheral airways resistance that reduces airway transmural pressure 4 . dynamic volumetric cine ct provides objective information to classify expiratory central airway collapse according to the femos (functional status, extent, morphology, origin, severity) system 5 , but it should be noted that the degree of luminal narrowing is only one factor in airflow limitation. evidence of airway compression or expiratory collapse on imaging does not necessarily indicate a condition requiring therapeutic intervention, and correlation with the clinical symptoms, signs, risk factors, and pulmonary function tests is necessary to determine the functional significance 1, 4 . in addition to the noninvasive nature, the advantages of dynamic volumetric cine ct over bronchoscopy include the ability to directly evaluate for vascular structures or soft tissue masses that impinge on the airway, depict the airways distal to a narrowing impassable by bronchoscope, and assess the lung parenchyma for conditions such as air trapping that may be associated with dynamic central airway collapse 2 . a disadvantage of ct is the exposure to ionizing radiation. for perspective, dynamic airway ct incurs a radiation dose similar or less to than that from a year of natural background radiation exposure 6 . dynamic cine magnetic resonance imaging (mri) avoids exposure to ionizing radiation and is capable of imaging the central airways and vasculature 7 , but is limited by a longer scan time, more frequent need for sedation/anesthesia and less detailed depiction of the lung parenchyma compared to ct. additional studies in children are needed to determine how the anatomic and functional information provided by dynamic ct is best applied to the diagnosis, treatment planning, and post-therapeutic monitoring of pediatric airway disorders. the main driving force to develop sophisticated mri sequences for pediatric chest imaging is that mri is a radiation-free technique. this is especially important for children who are more sensitive to ionizing radiation than adults [8] . this justifies the use of chest mri for short-and long-term follow-up of chronic lung diseases such as cystic fibrosis (cf), so as to reduce the lifelong cumulative radiation dose [1] . chest mri is challenging because of the magnetic heterogeneous environment in the chest region [2] . lung parenchyma is a low proton density structure and hence has a reduced signal-to-noise ratio [3] . in addition, the numerous airtissue interfaces within a voxel induce strong localized microscopic magnetic field gradients, which produce extensive mri signal dephasing leading to extremely short t2 star (t2 ã ) and geometric distortions. these effects become stronger at higher magnetic field strengths (i.e. 3 t), which are increasingly used in clinical settings for enhanced signal-to-noise ratio [1] . however, signalto-noise ratio in cases of lung pathology, such as pneumonia, edema, tumors and atelectasis, is increased by higher fluid content and amount of tissue. these conditions result in higher proton density and improved visualization [4] . moreover, mri has the advantage of integrating anatomical and functional information in a single examination, a possibility not as readily available with other imaging modalities. mri can provide functional information regarding lung perfusion using gadolinium contrast [5] , lung mechanics using dynamic acquisitions [6] , and ventilation using inhaled hyperpolarized gases [7] , oxygen enhancement or dynamic motion-based methods [8] . moreover, dwi is able to give new insight in the management of pneumonia, especially in cf patients [9] . chest mri has reached the point where it can be used in routine clinical practice. although mri cannot yet be compared to ct for anatomical detail, new sequences allow acquisition of lung images with high diagnostic quality in less than 15 s, which makes mri feasible in a clinical setting. mri can be considered an alternative to ct for the diagnosis of lung diseases and for monitoring response to treatment in pediatric lung disease. moreover, in some diseases that require long-term follow-up, such as cystic fibrosis, mri can play an important role in reducing lifelong radiation exposure related to repeated ct scans. furthermore, mri has the ability to offer functional information: information regarding lung mechanics, perfusion and ventilation can provide new insight in different pediatric lung diseases. this functional information can not only improve our understanding with regard to the pathophysiology of pediatric lung diseases, it can also open new diagnostic and therapeutic options. obstructive sleep apnea syndrome (osas) is characterized by prolonged partial airway obstruction and/or intermittent complete obstruction (obstructive apnea) during sleep, affecting about 2% to 3% of children [1] . osas is a complex syndrome with multiple etiologic factors: the main causative factor is adenotonsillar hypertrophy while other conditions, such as craniofacial dysmorphism, obesity, hypotonic neuromuscular diseases, despite inducing reduction of the caliber of the upper airways, are commonly mistreated [2] . adenotonsillectomy has been considered for many years the only treatment in children with osas although its efficacy remains uncertain, depending on the severity and on the presence of other co-morbidities, [3] . since a residual osa is reported in a large proportion of children after adenotonsillectomy [3] , and children with osa display a complex phenotype (mild or major craniofacial anomalies, and/or comorbid obesity, and/or adenotonsillar enlargement), a multi-therapeutic approach to pediatric osas and a defined timing of therapy are required [3, 4] . a narrow upper airway accompanied by maxillary constriction and mandibular retrusion is commonly reported in children with osas [5] . the skeletal conformation showing hyperdivergent skeletal growth pattern associated with posterior displacement of the tongue base, increases the upper airway narrowing and craniomandibular, intermaxillary, goniac and mandibular angles leading to a high-arched (ogival) palate [6] . rapid maxillary expansion (rme) is the most common dento-facial orthopedic procedure used in young patients to treat maxillary transverse deficiencies, starting up to 4 years of age. recently, it has been demonstrated to be efficacious to treat osas in children with a narrow palate and malocclusion: a significant reduction in the apnea-hypopnea index and in diurnal symptoms after six months of therapy with rme [7] , and positive long-term effects in children with osa and malocclusions treated with rme have been reported [8] . similar results were obtained after one year of treatment with rme in 16 preschool and school-aged non obese children with osas and dental malocclusions with a significant drop in clinical symptoms as well as apnea-hypopnea index [8] . this study also demonstrated that starting treatment early when the bone is still extremely plastic and its growth rate is maximum increases the percentage of success of rme treatment. a two-year follow up after the end of the rme application was performed in the same population of children confirming a stable decrease in apnea-hypopnea index, an increase of mean overnight oxygen saturation and a persistent improvement in clinical symptoms [9] . finally, a recent randomized study showed preliminary results regarding the effect of rme applied before adenotonsillectomy compared to the effect of rme applied after surgery, in children with osa. no significant differences between the two different approaches were described [10] . in conclusion, orthodontic treatment is a valid treatment for osa, improving clinical symptoms, respiratory parameters measured during psg with long lasting effect. the widening of the maxilla, the corrections of dental malocclusions and the correct relationships between maxillary and mandibular arches with respect to the anterior cranial base, are the main craniofacial changes induced by rme that may explain the efficacy of orthodontic therapy. orthodontic therapy should be encouraged in pediatric osas, and an early approach may permanently modify nasal breathing and respiration, thereby preventing obstruction of the upper airway. towards the turn of the century, david gozal's group published a series of papers that raised important questions. in a sample of 297 1 st grade pupils whose school performance was in the lowest decile of their class ranking, they found that 18% had sleep-associated intermittent hypoxia and/or hypercapnia; school performance improved in those whose parents had opted for adenotonsillectomy (1) . they then showed that 13% of 14-15 year olds with poor school performance had parent-reported snoring at age 4-5, compared to only 5% among those with good school performance (2). finally, a group of first graders with snoring, but no obstructive sleep apnea, i.e. an obstructive apnea index <1, performed worse on measures related to attention, social problems and visuospatial function than non-snorers, suggesting that simple snoring may not be as benign as hitherto widely believed (3) . against this background, we set out to perform the hannover study on sleep apnea in childhood (hassac), a community-based cross-sectional study on several aspects of sleep-disordered breathing (sdb) in 1144 primary school children incorporating a two-phase sequential screening procedure: participants were screened for symptoms and signs of sdb using an sdbquestionnaire and home pulse oximetry (hpo), those with outlying results on either screening method subsequently underwent an abbreviated home polysomnography (hpsg) for a final diagnosis of obstructive sleep apnea syndrome (osas). overall, participants were representative of the underlying population of third-graders in the study region. we found that 10.1% of this cohort were habitual snorers, while the population prevalence for osas was 2.8% (4, 5) . we then wanted to know how these symptoms affected behavior and academic achievements. for this, we used parental questionnaires and collected teachers' ratings, and defined poor school performance as grade 4 or worse in the last school report form, or requirement for special assistance, with this classification roughly corresponding to the lowest quintile of a class. we found that children with habitual snoring, compared to those who never snored, had 3-10 times the odds for daytime symptoms such as hyperactivity, difficulty concentrating, falling asleep while watching tv or at school or having peer problems, and 2-3 times the odds for poor school performance in mathematics, science and spelling (4, 6) . there was a clear dose-effect gradient, i.e. the proportion of children with poor school performance increased with increasing frequency of parent-reported snoring. considering its high prevalence, and assuming a causal link to disturbed behavior, habitual snoring appeared to be a substantial public health problem in primary school children. given this association, we wanted to know how this is mediated, i.e. whether this is mainly through detrimental effects of intermittent hypoxemia or more likely due to recurrent arousal. contrary to our hypothesis, the increased odds for poor school performance or daytime symptoms associated with habitual snoring stayed the same once children exhibiting intermittent desaturation in their overnight pulse oximetry recording had been excluded, suggesting that even so-called benign snoring, i.e. snoring without hypoxemia, may in fact not be benign. if not via intermittent desaturation, could the relationship with poor school performance be mediated via frequent arousals elicited by recurrent obstructive apnea? to address this question, we took advantage of the fact that children with an abnormal questionnaire score in our hassac study also underwent hpsg. thus, we re-analyzed our data on the relationship of snoring with daytime symptoms and poor school performance after excluding all children with a mixed-obstructive apnea/hypopnea index (maohi) !0.5, but again, the risk for poor school performance was not reduced among snorers after excluding those with recurrent apneas. given that simple snoring has such a strong association with daytime symptoms à are these reversible? in our hassac study, we could collect 1year follow-up data in 82 snorers and 80 controls. among these, 42 snorers (51%) had stopped snoring. while their scores for emotional problems, hyperactivity and problems with peers improved, their school performance did not (6) . this is in line with other data suggesting that reduced scores in executive functioning and iq seen in children prior to adenotonsillectomy may not improve following this operation (7) . similarly, in the avon longitudinal study on parents and children (alspac), even those whose sdb symptoms peaked at age 30 months and abated thereafter still had almost twice the odds for hyperactivity and 60% higher odds for behavioral problems at age 7 years (8). taken together, there is now a growing body of evidence that frequent snoring in children may not be as benign as previously thought, but may instead be associated with impaired behavior and poor academic achievements. these problems may even persist after snoring ceases, which à if these statistical associations were confirmed as causal à would argue for their early recognition and treatment. here, it is encouraging to see that in another longitudinal study on snoring and daytime symptoms, the proportion of children who did not snore at age 2 and 3 years was 42% in those who were breastfed for less than 1 month, but 83% in those who were breastfed for 12 months or longer (9) , suggesting that breastfeeding may reduce the risk of snoring during early childhood. in addition, given the limited availability of sleep labs, we urgently need better and easier-toperform screening methods to identify those who may need treatment for their snoring, e.g. in whom poor school performance can be predicted from a screening test (10) . also, interventions such as nasal steroids, montelukast or orthodontic treatment may deserve further study. diagnosis of osas using home respiratory polygraphy (hrp). alonso-alvarez et al. 3 prospectively assessed the diagnostic reliability of hrp in children aged 2 to 14 years with a clinical suspicion of osas. they found a sensitivity of 91% and a specificity of 94% and concluded that hrp emerges as a potentially useful and reliable approach for the diagnosis of moderate/ severe osas in children. drug-induced sedation endoscopy (dise) aims to reproduce upper airway obstruction during sleep and is gaining increasing popularity, with the hope of guiding efficient surgery and cure osdb children. in a meta-analysis, galluzi et al. 4 concluded that dise may benefit a minority of children with osas, and should only be used in children with unremarkable clinical evaluation or upon persistent osas after at. obstructive sleep-disordered breathing and obesity pathogenesis of osas in obese adolescents. literature on the pathogenesis of osas in adolescents is very limited. schwab et al. 5 prospectively compared upper airway magnetic resonance imaging in 137 adolescents aged 12 to 16 years. results indicated that lymphoid tissue, rather than other soft tissue components (tongue, lateral pharyngeal walls, parapharyngeal fat pads), are the primary upper airway anatomical risk factors for osas. while the pathogenesis of osas is clearly multifactorial (e.g., decreased upper airway reflexes in osas obese adolescents) and often require additional treatment, the results are clinically important since they suggest that at should still be considered as the first-line treatment in adolescents with osas. osdb and metabolic syndrome. in a systematic assessment of the literature on the interactions between sleep, osdb, obesity and disruptions of metabolic homeostasis in children and adolescents, hakim et al. concluded that obesity and osdb appear to contribute to the initiation and progression of each other, and that both are linked to the metabolic phenotype 6 . one intriguing mechanism postulates that osdb/ disrupted sleep as well as other factors favoring obesity, such as high-fat/ fructose diet, disrupt the gut microbiome and lead to increased systemic levels of lipopolysaccharides, in turn promoting inflammation and metabolic dysfunction. treatment of sleep-disordered breathing in children watchful waiting. chervin et al. 7 followed 192 children aged 5 to 9 years with mild/moderate osas after seven months of watchful waiting only. they found resolution of osas in 42% of the children. independent predictors of resolution were lower ahi and normal waist circumference. the authors concluded that, in practice, a baseline low ahi and normal waist circumference, or low pediatric sleep questionnaire and snoring score, may help identify an opportunity to avoid at. myofunctional therapy (mt). camacho et al. 8 performed a meta-analysis of the use of mt as a treatment for osas in adults and children. although the total number of patients (especially children, n ¼ 25) was low, the effects were highly significant. overall, mt decreased ahi by 50-60% in pediatric and adult patients. in children, a positive effect was reported when used as the only treatment in mild osas as well as to consolidate osas cure after at þ rapid maxillary expansion. the authors concluded that mt could be an adjunct to other osas treatments in patients of all ages. evolution of obstructive sleep-disordered breathing in children evolution in preschool children with osdb. walter et al. 9 investigated the long-term evolution of osdb in preschool-aged children with normal weight. half of the preschoolers with osdb were treated, most often by adenoidectomy and/or tonsillectomy. overall, osdb resolved in half of the children, either spontaneously (35%) or with treatment (57%). however, 40% still had osas, similarly to observations in school-aged children. intriguingly, complete resolution of osdb at three years post-treatment was more likely in preschoolers with moderate/severe osas compared to those with mild osas or primary snoring. long-term evolution of osas. spilsbury et al. 10 reported results on both remission and incidence of osas in 490 participants who underwent psg at 8-11 and 16-19 years of age. the authors first observed that osas in middle childhood usually remitted by adolescence. secondly, while habitual snoring and obesity predicted osas at each time point, distinct additional risk factors for osas were found in middle childhood vs. adolescence. hence, prematurity, a disadvantaged neighborhood or african-american origin also predicted osas in middle childhood, while risk factors in adolescents included male sex and previous at. finally, obesity, but not habitual snoring, in middle childhood predicted adolescent osas. these results confirm that prevention and 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than children born full term risk of asthma in late preterm infants: a propensity score approach poor airway function in early infancy and lung function by age 22 years: a non-selective longitudinal cohort study overview of issues in the longitudinal analysis of respiratory data assistant professor, department of pediatrics, school of medicine, university of costa rica. <quiquesoto@gmail.com> bibliography 1. global tuberculosis report 2013. geneva. world health organization. 2013. 2. world health organization who world health organization who. guidance for national tuberculosis programmes on the management of tuberculosis in children a refined symptom-based approach to diagnose pulmonary tuberculosis in children proportion of tuberculosis transmission that takes place in households in a high-incidence area assessment of the xpert mtb/rif assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-saharan africa: a prospective descriptive study evaluation of the 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airway general hospital ca' foncello, treviso (italy) à <gmorana61@gmail.com> 2 department of radiology, sophia children's hospital mri of the lung (2/3). why ... when ... how? mr imaging of pulmonary parenchyma impact of lung volume on mr signal intensity changes of the lung parenchyma /3): methods contrast-enhanced 3d mri of lung perfusion in children with cystic fibrosis-initial results spirometer-controlled cine magnetic resonance imaging used to diagnose tracheobronchomalacia in paediatric patients imaging of lung function using hyperpolarized helium-3 magnetic resonance imag-ing: review of current and emerging translational methods and ap-plications epidemiology of pediatric obstructive sleep apnea upper airway collapsibility in children with obstructive sleep apnea syndrome adenotonsillectomy outcomes in treatment of obstructive sleep apnea in children: a multicenter retrospective study pediatric obstructive sleep apnea: complications, management, and long-term outcomes craniofacial morphology in preschool children with sleep-related breathing disorder and hypertrophy of tonsils craniofacial modifications in children with habitual snoring and obstructive sleep apnoea: a case-control study randomized controlled study of an oral jaw-positioning appliance for the treatment of obstructive sleep apnea in children with malocclusion rapid maxillary expansion in children with obstructive sleep apnea syndrome: 12 months follow-up efficacy of rapid maxillary expansion in children with obstructive sleep apnea syndrome: 36 months of follow-up adeno-tonsillectomy and rapid maxillary distraction in pre-pubertal children, a pilot study germany <christian-f.poets@med.uni-tuebingen.de> references 1. gozal d. sleep-disordered breathing and school performance in children snoring during early childhood and academic performance at ages thriteen to fourteen years neurobehavioral implications of habitual snoring in children snoring, intermittent hypoxia and academic performance in primary school children population prevalence of obstructive sleep apnoea in a community of german third graders. the european respiratory journal: official journal of the european society for habitual snoring, intermittent hypoxia, and impaired behavior in primary school children adenotonsillectomy and neurocognitive deficits in children with sleep disordered breathing sleep-disordered breathing in a population-based cohort: behavioral outcomes at 4 and 7 years persistent snoring in preschool children: predictors and behavioral and developmental correlates predicting poor school performance in children suspected for sleep-disordered breathing utility of symptoms to predict treatment outcomes in obstructive sleep apnea syndrome pediatric osas: oximetry can provide answers when polysomnography is not available reliability of home respiratory polygraphy for the diagnosis of sleep apnea in children drug induced sleep endoscopy in the decision-making process of children with obstructive sleep apnea understanding the anatomic basis for obstructive sleep apnea syndrome in adolescents obesity and altered sleep: a pathway to metabolic derangements in children? childhood adenotonsillectomy trial. prognosis for spontaneous resolution of osa in children myofunctional therapy to treat obstructive sleep apnea: a systematic review and meta-analysis long-term improvements in sleep and respiratory parameters in preschool children following treatment of sleep disordered breathing remission and incidence of obstructive sleep apnea from middle childhood to late adolescence polysomnographic findings after adenotonsillectomy for obstructive sleep apnea in obese and non-obese children: a systemic review and meta-analysis this last year has seen a number of significant advances in the field of pediatric sleep-disordered breathing. the following is a personal selection of a few publications. overnight polysomnography (psg) is considered necessary to diagnose children suspected of sleep-disordered breathing (sdb). in practice, however, most children do not have access to overnight psg, due to the lack of sleep laboratories worldwide. the quest for a simpler means to diagnose sdb, or at least to prioritize children for referral to a sleep laboratory, remains a high priority. questionnaire. in a prospective study in children aged 5 to 9 years with obstructive sleep apnea syndrome (osas), rosen et al. 1 found that, conversely to psg, the pediatric sleep questionnaire results reflect osasrelated impairment in behavior, quality of life and sleepiness as well as predict their improvement post-adenotonsillectomy (at). the authors concluded that while psg is needed to diagnose osas, results from a careful clinical assessment provide important adjunctive information on comorbidities and their improvement after surgery. overnight oximetry in osdb children. kaditis et al. 2 performed a systematic analysis of the literature on the use of nocturnal oximetry in children with obstructive sdb (osdb ¼ from primary snoring to osas). their conclusion confirmed that overnight oximetry (spo 2 ) is useful for diagnosing osdb and for predicting post-at complications in a child with a history suggestive of osdb. overall, a desaturation index (!4%) higher than 2 episodes/hour can predict both mild and moderate-to-severe osdb, while criteria based on clusters of desaturation such as the mcgill oximetry score can predict moderate-to-severe osdb. key: cord-335055-gzuug3p5 authors: kwiyolecha, elizabeth; groendahl, britta; okamo, bernard; kayange, neema; manyama, festo; kidenya, benson r.; mahamba, dina c.; msanga, delfina r.; gehring, stephan; majigo, mtebe; mshana, stephen e.; mirambo, mariam m. title: patterns of viral pathogens causing upper respiratory tract infections among symptomatic children in mwanza, tanzania date: 2020-10-28 journal: sci rep doi: 10.1038/s41598-020-74555-2 sha: doc_id: 335055 cord_uid: gzuug3p5 upper-respiratory tract infections (urti) are the leading causes of childhood morbidities. this study investigated etiologies and patterns of urti among children in mwanza, tanzania. a cross-sectional study involving 339 children was conducted between october-2017 and february-2018. children with features suggestive of urti such as nasal congestion, dry cough, painful swallowing and nasal discharge with/without fever were enrolled. pathogens were detected from nasopharyngeal and ear-swabs by multiplex-pcr and culture respectively. full blood count and c-reactive protein analysis were also done. the median age was 16 (iqr: 8–34) months. majority (82.3%) had fever and nasal-congestion (65.5%). rhinitis (55.9%) was the commonest diagnosis followed by pharyngitis (19.5%). viruses were isolated in 46% of children, the commonest being rhinoviruses (23.9%). nineteen percent of children had more than 2 viruses; rhinovirus and enterovirus being the commonest combination. the commonest bacteria isolated from ears were staphylococcus aureus and pseudomonas aeruginosa. children with viral pathogens had significantly right shift of lymphocytes (73%—sensitivity). majority (257/339) of children were symptoms free on eighth day. viruses are the commonest cause of urti with rhinitis being the common diagnosis. rapid diagnostic assays for urti pathogens are urgently needed in low-income countries to reduce unnecessary antibiotic prescriptions which is associated with antibiotic resistance. | (2020) 10:18490 | https://doi.org/10.1038/s41598-020-74555-2 www.nature.com/scientificreports/ in many low-and middle-income countries. in tanzania, there is only one study that has documented the viral etiologies of rti 3 . therefore, there is a paramount need to establish information on the common etiologies of rtis in tanzania, the information that can stimulate further studies and possible control interventions including introduction of cheap and reliable methods to detect these pathogens in clinical settings. in addition due to increased use of antibiotic without a support of a diagnostic test in the treatment of urti as observed in number of previous studies [11] [12] [13] , make the availability of epidemiological data on the patterns of etiology of urti of paramount important. overuse of antibiotics without prescriptions for urti is widespread in developing countries 14 , this is partially contributed by lacking of data on the etiologies of urtis. therefore, these data are relevant to clinicians in developing countries and policy makers in order to invest on the improved diagnostic facilities and reduce antibiotic prescriptions for urtis. study area, design and study population. a cross sectional hospital based study involving 339 children aged 1-59 months presenting with rti symptoms was conducted from october 2017 to february 2018 in the city of mwanza, tanzania. the study was conducted in two health facilities namely: buzuruga health center (bhc), and nyamagana district hospital (ndh). these are public health facilities providing free services to children below 5 years of age. the study included all children presented with nasal congestion or runny nose, hoarseness of voice with dry cough, painful swallowing with tender cervical lymph nodes and enlarged tonsils on examination, ear pain or ear discharge, nasal discharge with or without fever (axilla body temp of 37.5 °c and above). in this study we defined: pharyngitis as painful swallowing dry cough, plus or minus hoarseness of the voice (sore throat), tonsillitis as painful swallowing with tender cervical lymph nodes and enlarged tonsils(primarily tonsillar inflammation) and rhinitis as presence of one or more symptoms including sneezing, itching, nasal congestion, and rhinorrhea. sample size estimation and sampling procedures. sample size was calculated using yamane taro (1967) with precision level of 5%. the minimum sample size estimated was 270 children. however, a total of 339 children were enrolled. all children who met the inclusion criteria were serially enrolled until the desired sample size was attained. data collection and sample collection. sociodemographic and clinical information were collected using pretested structured data collection tool. nasopharyngeal swabs (copan diagnostics inc. usa, canada) were obtained as previously described 15 by inserting the swab into one nostril straight back along the floor of the nasal passage until reaching the nasopharynx. the swabs were rotated gently for 5-10 s to loosen the epithelial cells and collect the sample. the swabs were then inserted into viral transport medium and stored at − 80 °c until processing. in children presenting with ear discharge; ear swabs were collected using flexible shaft swab via an auditory speculum in case of inner ear while a sample from outer ear was obtained by firmly rotating swab in outer canal. swabs were immediately taken to the laboratory for bacterial culture and sensitivity. for each consenting participant, about 4 mls of blood was also collected for blood cell counts and quantitative c reactive protein analysis. a thorough general and physical examination was performed to all enrolled children to establish clinical features. all children were managed as per local hospitals protocol. patients were followed two times; the first follow up was on the 4th day, where these patients were fully examined and their full blood count, crp and ear swab culture results were revealed. in case of positive ear swab culture treatment was changed based on susceptibility patterns. the second follow up was done on the 8th day as clinical review to evaluate for disease progression. laboratory procedures. ear swab specimens were inoculated onto chocolate agar, blood agar (ba) and macconkey agar (mca) plates and incubated aerobically at 37 °c for 24-48 h. in-house biochemical identification tests were used to identify isolated bacteria to their species level 16 . the identified isolates were tested for antimicrobial susceptibility following clsi guidelines, the tested antibiotic discs included: amikacin (30 µg), gentamicin (10 µg), erythromycin (15 µg), vancomycin (30 µg), clindamycin (2 µg), ciprofloxacin (5 µg) which were used for gram positive bacteria and ampicillin (10 µg), ceftazidime (30 µg), meropenem (10 µg), amikacin (30 µg), piperacillin-tazobactam (100/10 µg) and ciprofloxacin (5 µg) for gram negative bacteria 17 . bacterial isolates obtained were inoculated into brain heart infusion broth with 20% glycerine and stored at -80 °c freezer. e. coli atcc 25992 and staphylococcus aureus atcc 25923 were used as control strains. nasopharyngeal swabs were transported to mainz university germany and were tested to detect enterovirus (ev), influenza virus type a (iva), influenza virus type b (ivb), respiratory syncytial virus (rsv), parainfluenza virus type 1 (piv1), parainfluenza virus type2 (piv2), parainfluenza virus type 3 (piv3), parainfluenza virus type 4 (piv4), adenovirus (av), rhinovirus (rv), human metapneumovirus (mpv), coronavirus (cv), bocavirus, mycoplasma pneumoniae (mpn), chlamydophila pneumoniae (cpn), bordetella pertussis (bp), bordetella parapertussis (bpp) and legionella pneumophila (lpn) using multiplex pcr as previously described 18 . blood samples were quantitatively tested for c-reactive protein following manufacturer instructions (medical instruments co., ltd, shanghai, china). blood in edta container (bd vacutainer, nairobi, kenya) was used to estimate complete blood count (fbc) using hematological analyzer (beckman coulter (uk) ltd) 19 . www.nature.com/scientificreports/ statistical data analysis. data entry was done using microsoft excel then exported to stata version 13 for analysis. continuous variables (age and temperature) were summarized using median with interquartile ranges. categorical variables (sex and level of education) were summarized using frequency and proportions. to determine the utility of fbc, and crp in the determination of causative agents among children below 5 years of age, a 2 by 2 table and receiver operating curve (roc) characteristic analysis were used to determine the sensitivity, specificity, positive and negative predictive values. children presenting with symptoms for more than 7 days were classified as having chronic illness. a child who had no any symptom on day eight of follow was declared cure. ethical approval and consent to participate. the approval for conducting the research was sought from the joint cuhas/bmc research ethics and review with ethical clearance number: crec/255/2017. permission to conduct the study was also sought from the pediatrics departments at bhc and ndh. the aim and importance of the study was explained to parents/caretakers before enrollment of children to the study, followed by a signed informed consent by the parent/caretaker. all information regarding the patient remained confidential. patient's records were kept such that the identity of the patient was not disclosed. for those who refused to participate, were provided with services similar to the participants and had equal chance to treatment regardless of their inclusion status. all methods were carried out in accordance with relevant guidelines and regulations. socio-demographic characteristics of study participants. the www.nature.com/scientificreports/ ing from 1 to 7 days and were classified as acute illness in this study ( table 2 ). the slightly majority 184 (55.9%) of children presented with rhinitis ( fig. 1) . lymphocytes, neutrophils and crp were used to predict the possible causative agents. children with viral pathogens had significantly elevated lymphocytes, with normal or elevated crp. the sensitivity of elevated lymphocytes in detecting viral pathogens was 73.4% (fig. 3a,b ). etiologies of urti among under five children in mwanza city. this is the first study to establish etiologies of rtis in the lake victoria zone tanzania. findings from this study shows that, number of viruses are responsible for rtis among children below 5 years of age attending outpatient clinics in the city of mwanza. the prevalence of 46.9% reported in the current study is low compared to a previous study conducted in ifakara and dar es salaam, which reported prevalence of 70.5% 3 . the possible explanation for these differences could be criteria used in the enrollment of the study participants. in the previous study fever was the main inclusion criterion which was not the case in the current study. in addition, this study was conducted in different season of the year (october 2017 through february 2018) compared to the previous which was conducted from april to august and from june to december at two different sites, respectively. viral infections have been found to be influenced by season variations [20] [21] [22] [23] [24] . further studies to establish seasonality of these viruses are warranted in developing countries. the findings in this study are comparable to the previous study in kenya among children below 5 years of age, whereby viruses were isolated in 45% of children with rtis 25 . in comparison to a previous study in refugee www.nature.com/scientificreports/ camp in kenya the prevalence of viral infection reported in this study is low (46% vs. 66.6%) 26 . the possible explanation could be overcrowding conditions in refugee camp which has been found to facilitate transmission of rtis viruses 27, 28 . regarding distribution of viruses; rhinovirus, adenovirus and parainfluenza 3 were the commonest viral pathogens in the current study which is contrary to a previous study in kenya 26 whereby influenza a virus, respiratory syncytial virus and influenza b were the commonest. the predominance of rhinovirus, influenza viruses was also reported in a previous study in tanzania 3 . the distribution of respiratory viruses is associated with climatic changes; the peak of infection usually occurs in winter period in temperate regions which is equivalent to wet season in hot climates like tanzania 29, 30 . as documented earlier, a significant proportion of children who had viral infection presented with acute illness 27 . however, it should be noted that some studies have shown that some viral diseases may last for several weeks 27, 28 which may account for the few children in the present study who presented with chronicity. regarding ear bacterial infections, staphylococcus aureus, pseudomonas aeruginosa, serratia marcescens, klebsiella pneumoniae, providencia spp. and streptococcus spp. were isolated. this is contrary to the previous study whereby streptococcus pneumoniae was the commonest isolate 3 . the possible explanation could be wide coverage of pneumococcal vaccines. decrease in streptococcus pneumoniae infections has been observed after introduction of the vaccine. a previous study by mushi et al. 31 in similar settings established that staphylococcus aureus and pseudomonas aeruginosa were the commonest pathogens causing csom among adult patients. in the current study, only one nasopharyngeal specimens yielded bacterial isolate (bordetella parapertussis) which is contrary to a previous observation by ndossa et al. 32 that detected streptococcus pneumoniae to be colonizing the nasopharynx of children in the city of mwanza. moreover, the bacterial isolates in the current study were highly resistant to the readily available and the over counter antibiotics like amoxicillin, trimethoprim/ sulphamethoxazole and ampicillin with majority being susceptible to ciprofloxacin ear drops. this could be explained by the fact that, ciprofloxacin is not readily used in children below 12 years of age. in the current study, rhinitis was the commonest presenting disease, followed by pharyngitis and pneumonia. this is further supported by findings in the current study which reported rhinovirus to be the commonest pathogen. a previous study 33 , documented rhinovirus to cause up to 25-85% of the upper respiratory tract infections. systemic responses of th1 for rhinovirus results into stimulation of specific clones of cd4 t cells and secretions of large amount of granulocytes macrophage colony stimulating factor (gm-csf) which are also responsible for the urti symptoms 34 . moreover, rhinovirus infection has also been associated with lower respiratory tract disease, asthma exacerbations and fatal pneumonia [33] [34] [35] . on the other hand, the spectrum of diseases in this study could be also explained by the commonly isolated viruses; influenza viruses, rsv, parainfluenza viruses and adenoviruses which are the common viruses responsible for most of the upper respiratory diseases as previously reported 36, 37 . in the current study, children with viral pathogens had a right shift of lymphocytes with an increased sensitivity of 78.0%, with left deviation of the neutrophils or slightly raised crp (not more than 10 mg/dl). these findings are important and could be used to predict these infections in resource limited setting and assist in decision making on the management of the patients which eventually might reduce unnecessary prescriptions of antibiotics. the observation is further supported by the fact that the majority of children were free from the initial symptoms on day eighth, underscoring that viral caused urti have mild symptoms which tend to disappear with time 38,39 . study limitations. diagnosis of patterns of urti was done clinically with no imaging to support the diagnosis, this might have caused misclassification. however, efforts were made to minimize this by consulting senior pediatricians whenever overlap of symptoms occurred. another potential limitation was failure to perform multiplex pcr for all ear swabs therefore viral pathogens might have been missed in these samples. urti are common in children below 5 years of age and are predominantly caused by viruses. elevated lymphocytes, normal neutrophils with elevation or normal crp levels can predict viral causes of urti while the raise in neutrophils and crp are more likely to predict bacterial infections. clinicians should suspect urti caused by viral infections whenever the children present with runny nose with congestion, fever and dry cough. the use of antibiotics should be minimized in children with urti symptoms since most of the symptoms disappears within a week. further studies to determine etiologies of lower respiratory tract infections are warranted in this setting. all data are included in the manuscript. raw data is available upon request and the request should be made to the director of research and innovation, catholic university of health and allied sciences. scientific reports | (2020) 10:18490 | https://doi.org/10.1038/s41598-020-74555-2 www.nature.com/scientificreports/ human bocavirus symptomatic treatment of upper respiratory tract symptoms in children beyond malaria-causes of fever in outpatient tanzanian children estimates of world-wide distribution of child deaths from acute respiratory infections antibiotic use in acute upper respiratory tract infections pneumonia case management trials group: effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials global estimate of the incidence of clinical pneumonia among children under five years of age disease control priorities in developing countries the clinical impact of human respiratory virus infections disease control priorities in developing countries physicians' antibiotic prescribing habits for upper respiratory tract infections in turkey trends in antimicrobial prescribing for bronchitis and upper respiratory infections among adults and children assessing the overuse of antibiotics in children with urtis in saudi arabia: development of the parental perception on antibiotics scale (papa scale) prescription and non-prescription antibiotic dispensing practices in part i and part ii pharmacies in moshi municipality, kilimanjaro region in tanzania: a simulated clients approach comparison of nasopharyngeal and oropharyngeal swabs for the diagnosis of eight respiratory viruses by real-time reverse transcription-pcr assays evaluation of the bruker maldi biotyper for identification of gram-positive rods-development of a diagnostic algorithm for the clinical laboratory performance standards for antimicrobial susceptibility testing validation of a multiplex reverse transcriptase pcr elisa for the detection of 19 respiratory tract pathogens evaluation of a multiplex reverse transcriptase pcr elisa for the detection of nine respiratory tract pathogens viral infections in relation to age, atopy, and season of admission among children hospitalized for wheezing seasonality of viral infections: mechanisms and unknowns an explanation for the seasonality of acute upper respiratory tract viral infections the seasonality of rhinovirus infections and its implications for clinical recognition epidemiology and seasonality of respiratory viral infections in hospitalized children in kuala lumpur, malaysia: a retrospective study of 27 years aetiology of acute respiratory infections in children under five years in nakuru, kenya improved detection of respiratory viruses in pediatric outpatients with acute respiratory illness by real-time pcr using nasopharyngeal flocked swabs risk factors for acute respiratory tract infections in under-five children in enugu southeast nigeria respiratory tract infections in the tropics seasonal variations of respiratory viruses detected from children with respiratory tract infections in riyadh, saudi arabia epidemiology and seasonality of respiratory tract virus infections in the tropics predictors of disease complications and treatment outcome among patients with chronic suppurative otitis media attending a tertiary hospital factors associated with colonization of streptococcus pneumoniae among under-fives attending clinic in mwanza city rhinovirus: more than just a common cold virus rhinovirus infections in the upper airway an update on the pathophysiology of rhinovirus upper respiratory tract infections adenoviral infections in children: the impact of rapid diagnosis epidemiological analysis of respiratory viral etiology for influenza-like illness during 2010 in zhuhai incubation periods of acute respiratory viral infections: a systematic review estimating incubation period distributions with coarse data the authors acknowledge the assistance provided by department of pediatrics mainz university, the department of microbiology and immunology-cuhas-bugando, and the department of pediatrics and child health-cuhas-bugando. this study was supported by the departments of pediatrics-university medical center of the johannes gutenberg university mainz, mainz, germany, department of microbiology and immunology cuhas-bugando and the department of pediatrics and child health of the cuas-bugando. the authors declare no competing interests. correspondence and requests for materials should be addressed to m.m.m.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. key: cord-324181-nyrpg3ud authors: baker, jeffrey; block, stanley l.; matharu, balpreet; burleigh macutkiewicz, laura; wildum, steffen; dimonaco, sophie; collinson, neil; clinch, barry; piedra, pedro a. title: baloxavir marboxil single-dose treatment in influenza-infected children: a randomized, double-blind, active controlled phase 3 safety and efficacy trial (ministone-2) date: 2020-05-19 journal: pediatr infect dis j doi: 10.1097/inf.0000000000002747 sha: doc_id: 324181 cord_uid: nyrpg3ud baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. we assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza. methods: ministone-2 (clinicaltrials.gov: nct03629184) was a double-blind, randomized, active controlled trial enrolling children 1–<12 years old with a clinical diagnosis of influenza. children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. the primary endpoint was incidence, severity and timing of adverse events (aes); efficacy was a secondary endpoint. results: in total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. characteristics of participants were similar between treatment groups. overall, 122 aes were reported in 84 (48.6%) children. incidence of aes was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). the most common aes were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. no deaths, serious aes or hospitalizations were reported. median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6–163.2) hours with baloxavir versus 150.0 (115.0–165.7) hours with oseltamivir. conclusions: oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. baloxavir provides a new therapeutic option with a simple oral dosing regimen. a nnual influenza epidemics are estimated to cause 3-5 million cases of severe illness and up to 650,000 deaths globally among all ages. 1 influenza infects all childhood age subsets and is associated with substantial morbidity, 2 with the youngest at particular risk of viral injury, secondary bacterial infections and complications. 3, 4 mortality in children varies across seasons and depends on viral subtype, preexisting immunity and presence of underlying disease. 5, 6 recent estimates for children from 92 countries, the majority of whom were <5 years old, are 9000-106,000 (median: 44,888) influenza-associated deaths annually. 7 in addition, children play a central role in influenza dissemination in the community because of their relative susceptibility to infection, high illness attack rates, prolonged viral shedding, and high contact rates between others in the household and community. 2, 8 annual vaccination is the most effective control measure for prevention of seasonal influenza and related complications. 9, 10 vaccination is recommended in the united states for individuals ≥6 months of age, who have no contraindications. 11 however, the need for vaccine reformulations each year, difficulties in producing these within short timeframes, and variable uptake and efficacy across countries mean that this strategy has limitations, 12, 13 and needs to be complemented by the availability of effective antiviral treatments. in many countries, there are currently only 2 classes of antivirals approved for the treatment of influenza in children: m2 blockers and neuraminidase inhibitors. 3 widespread, stable and transmissible resistance has rendered m2 blockers essentially ineffective. 14, 15 although neuraminidase inhibitors are effective in the treatment of influenza in children, there are restrictions for some of these based on age and mode of administration. a simplified dosing regimen (ie, single oral dosing), with better overall antiviral activity and favorable safety and tolerability, is considered desirable for the treatment of influenza in children. baloxavir marboxil (baloxavir) is a novel, first-in-class, capdependent endonuclease inhibitor. [16] [17] [18] baloxavir was first approved in japan in february 2018, followed by the united states in october 2018. in the united states, the initial indication included singledose, oral treatment of acute uncomplicated influenza in patients ≥12 years old, who have been symptomatic for ≤48 hours, which was expanded in october 2019 to include those at high risk of developing influenza-related complications. 17 these approvals were based on the clinical efficacy and safety of baloxavir versus placebo and oseltamivir in 2 pivotal phase iii trials (capstone 1 and capstone 2, respectively). 19, 20 in these studies, baloxavir showed significant improvements in time to alleviation of influenza symptoms (capstone 1) and time to improvement of influenza symptoms (capstone 2) compared with placebo, and faster reduction in infectious viral titers compared with placebo and oseltamivir in adults and adolescents. 19, 20 we report the safety and efficacy results of single oral dose baloxavir treatment in otherwise healthy children 1-<12 years old with acute influenza from ministone-2 (clinicaltrials.gov identifier: nct03629184), a phase iii, randomized, active controlled trial. this was a global, multicenter, double-blind, randomized, active controlled trial of the safety, pharmacokinetics and efficacy of a single oral dose of baloxavir versus twice-daily (for 5 days) oral oseltamivir, in otherwise healthy children with influenza. the trial enrolled children 1-<12 years of age with influenza (who were otherwise healthy) during the 2018/2019 northern hemisphere influenza season, including sites in the united states, south america and europe. enrolled children had a clinical diagnosis of influenza infection consisting of fever (tympanic temperature of ≥38°c) at screening and at least one respiratory symptom (either cough or nasal congestion). the time interval allowed between the onset of symptoms and screening was ≤48 hours. the trial excluded children with severe influenza symptoms requiring inpatient treatment and those with concurrent infections requiring systemic antiviral therapy at screening. acetaminophen was permitted for severe symptoms. children were considered "otherwise healthy" if they met none of the following exclusion criteria: any immunosuppressive disorder (including human immunodeficiency virus infection), uncontrolled renal, vascular, neurologic, or metabolic disease, hepatitis, cirrhosis, or pulmonary disease, known chronic renal failure, active cancer at any site, or a history of organ transplantation. children were enrolled in parallel to 2 cohorts: 1-<5 years old (minimum of 20 children) and 5-<12 years old (minimum of 40 children). using a permuted block randomization method, children were assigned in a 2:1 ratio to receive a single dose of oral baloxavir on day 1 (2 mg/kg for those weighing <20 kg and a single dose of 40 mg for those weighing ≥20 kg), or oral oseltamivir twice daily according to prescribing information (30 mg for patients weighing ≤15 kg, 45 mg for >15-≤23 kg, 60 mg for >23-≤40 kg, and 75 mg for >40 kg) on days 1-5. 21 doses of baloxavir in this study were chosen based on population pharmacokinetic analyses performed using data from a phase 3 study of children in japan (japiccti-173811), and evaluated with respect to their ability to match adult drug exposure. children in both groups received a 5-day regimen (baloxavir and a matching oseltamivir placebo or oseltamivir and matching baloxavir placebo). following randomization, the first dose of the trial regimen was administered under direct observation, and participants were followed until day 29. the primary endpoint was safety, defined as the incidence, severity and timing of adverse events (aes) during the 5-day treatment period and a 24-day follow-up period. vital signs (blood pressure, respiratory rate, heart rate and tympanic temperature) were measured at scheduled visits [days 1, 2, 4, 6, 10, 15 and 29 (if there were abnormal findings or aes since the previous measurement)]. blood was collected for hematology and chemistry assessment on day 1 and day 6, and nasopharyngeal swabs were performed for viral quantification (using infectious titer) on days 1, 2, 4, 6, 10, as well as days 15 and 29 if considered appropriate by the treating physician. parents completed the canadian acute respiratory illness and flu scale (carifs) 22 questionnaire at scheduled visits (day [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] , and responses were used to measure secondary efficacy endpoints including time to alleviation of signs and symptoms (ttass) of influenza [defined as when a score of 0 (no problem) or 1 (minor problem) was reported for cough and nasal symptoms on the carifs questionnaire, return to normal health and activity, and return to afebrile state (tympanic temperature ≤37.2°c), remaining for at least 21.5 hours]. subgroup analyses of ttass based on virus subtype were also performed. other secondary efficacy endpoints were duration of fever [defined as time to return to afebrile state (≤37.2°c)], duration of all symptoms, time to return to normal health and activity, frequency of influenza-related complications (all of which were predefined and required investigator confirmation: death, hospitalization, pneumonia, bronchitis, sinusitis, otitis media, encephalitis/ encephalopathy, febrile seizures or myositis) and proportion of children requiring antibiotics. secondary virologic endpoints included time to cessation of viral shedding by virus titer and change from baseline in influenza virus titer. 23 exploratory virologic endpoints included frequency of treatment-emergent amino acid substitutions (using sanger sequencing). 24 baseline samples from both treatment groups were also tested for coinfections (viral and bacterial pathogens), using the biofire filmarray respiratory panel 2 assay. 25 a sample size of 80 children in the baloxavir arm (120 in total) provided a probability of ≥90% that ≥1 child would experience an ae with a background incidence rate of 3%. a sample size of 120 children provided a probability of 80.1% that ≥1 child would experience an ae with an incidence rate of 2%. because the study was not powered for a statistical comparison between treatments, results are descriptive. the safety population comprised children who received any portion of a single dose. the intent-to-treat influenza-infected (itti) population was used for all efficacy analyses and comprised children who had a laboratory reverse transcriptase-polymerase chain reaction confirmation of influenza infection from any swab sample collected at baseline or during the study. the number of children in the itti population was continuously monitored to ensure an adequate number of influenza-infected children were recruited. data were summarized using descriptive statistics and kaplan-meier plots where applicable (sas version 9.4). this study was conducted in accordance with the declaration of helsinki and good clinical practice (ich e6) guidelines, and was approved by all relevant institutional review boards and/ or ethic committees at each center. all parents/caregivers of participants gave written informed consent and child consent was obtained where applicable. this study was performed between november 20, 2018 and august 27, 2019 at 36 sites across 6 countries (usa, poland, spain, costa rica, mexico and russia). of the 176 children enrolled, 117 (66.5%) and 59 (33.5%) patients were randomized into the baloxavir and oseltamivir groups, respectively. in total, 169 children (96%) completed the trial (fig. 1) . the predominant influenza a subtype at baseline assessed by reverse transcriptase-polymerase chain reaction was h3n2 for both groups, followed by h1n1pdm09. numbers were low for influenza b in both groups (n = 5 for baloxavir and n = 2 for oseltamivir). in the safety population, 49.1% of children were vaccinated against flu, with similar proportions vaccinated in each treatment group. demographics and baseline characteristics were similar between treatment groups (table 1 ). there were no notable differences between the treatment groups in the use of concomitant medications during the study; the most frequently reported class in both was analgesics, most commonly acetaminophen. other concomitant medications were predominantly symptomatic treatments, and were reported in very few children. a total of 122 aes was reported in 84 children (48.6%) during the study (between day 1 and 29) and most aes resolved or were resolving by study end (95.1%). the overall incidence of aes was similar between the baloxavir group (46.1%) and the oseltamivir group (53.4%; table 2 ). the incidence of aes considered related to study drug was low in both groups, 2.6% (3/115) for baloxavir compared with 8.6% (5/58) for oseltamivir. the most common aes in both groups were gastrointestinal disorders (vomiting or diarrhea), experienced by 12 children (10.4%) for baloxavir and 10 (17.2%) for oseltamivir. no deaths, serious aes or hospitalizations were reported during the study. two children experienced aes which led to withdrawal from treatment in the baloxavir group, including accidental overdose of oseltamivir placebo and grade 2 rash occurring on day 4 that resolved after 24 hours without treatment in a child who received an accidental under-dose of baloxavir (4 mg instead of 40 mg). no aes led to withdrawal in the oseltamivir group. all aes observed in the study were grade 1 or 2, except for 3 grade 3 aes. these were abdominal pain on day 8 in the baloxavir group, and severe vitamin d deficiency at baseline (undiagnosed preexisting conditions, determined by raised alkaline phosphatase levels on day 1) in 2 children in the oseltamivir group. there were no clinically meaningful changes from baseline in any laboratory parameters or vital signs. the ttass based on the carifs questionnaire was similar between treatment groups, with a median of 138.1 [95% confidence interval (ci): 116.6-163.2] hours for baloxavir and 150.0 (95% ci: 115.0-165.7) hours for oseltamivir ( fig. 2 and table 3 ). for children infected with h3n2, median ttass was similar between the baloxavir and oseltamivir groups, while for those infected with h1n1pdm09, ttass was numerically lower for baloxavir than oseltamivir; table 3 ). the number of children with influenza b was too low to allow meaningful interpretation of the data. the median duration of fever was similar between the baloxavir and oseltamivir groups: 41.2 (95% ci: 24.5-45.7) versus 46.8 (30.0-53.5) hours, respectively (table 3) the overall incidence of influenza-related complications meeting predefined diagnostic criteria was low overall: 6 (7.4%) children in the baloxavir group and 3 (7.0%) in the oseltamivir group. the most frequent complication was otitis media in both groups [3 (2.6%) for baloxavir, 4 (6.9%) for oseltamivir], with single cases of bronchitis, pneumonia and sinusitis (baloxavir) and febrile seizure (oseltamivir). the proportion of children requiring antibiotics was low in both groups: 2 children in each group received antibiotics for otitis media and 2 children in the baloxavir group received antibiotics for pneumonia and sinusitis. as previously observed in phase ii and phase iii studies, 19, 20 baloxavir was associated with a more rapid decline in infectious viral titer compared with oseltamivir. the mean reduction from baseline in influenza virus titer on day 2 (24 hours posttreatment) was considerably greater for baloxavir than oseltamivir [−3.59 (standard deviation = 1.34) vs. −1.79 (1.54) log 10 median tissue culture infectious dose/ml, respectively]. thereafter, the mean change from baseline was similar in the 2 treatment groups, plateauing on day 2 for baloxavir and from day 4 for oseltamivir. the median time to cessation of viral shedding by virus titer was shorter for baloxavir than oseltamivir by 51.6 hours [24.2 hours (95% ci: 23.5-24.6) vs. 75.8 hours (68.9-97.8); table 3 ]. in total, 32 (25.8%) children in the itti population had a coinfection with another infectious pathogen at baseline [25/81 (30.9%) in the baloxavir group and 7/43 (16.3%) in the oseltamivir group; table 1 ]. for baloxavir, most children with a coinfection had a subtype of coronavirus, followed by rhinovirus/enterovirus and respiratory syncytial virus. for oseltamivir, most children had rhinovirus/enterovirus. no results for coinfections after baseline are available. in an exploratory genotyping analysis of the polymerase acidic (pa) gene using sanger sequencing in the 81 influenza-positive children (itti) treated with baloxavir, none of the children had preexisting pa/i38x mutations in baseline samples; pa/i38x mutations have previously been shown to be the most common determinant of reduced susceptibility to baloxavir. 26 in 57 of the 81 children, sequencing was possible for both baseline and posttreatment samples, whereas 24 children had no detectable virus after treatment, or such low levels that sequencing was not possible. treatment-emergent pa/i38x substitutions were detected in 11 of 57 children (19.3%); 9 had influenza a subtype h3n2 and 2 had subtype h1n1pdm09. however, when the 24 children with no detectable virus or such low levels that sequencing was not possible (suggesting no pa/i38x substitutions) are also included in this calculation, the rate of pa/i38x substitutions is 13.5% (11/81 baloxavir has a novel mechanism of action, preventing the formation of new virions by blocking replication early in the influenza life cycle. 16, 17 two previous japanese studies evaluating the use of baloxavir in children <12 years old have been completed; however, both were small, open-label studies (japiccti-163417 24 and japiccti-173811). ministone-2 is the first global, phase iii, randomized active controlled study designed to investigate the safety and efficacy of a single dose of baloxavir in children. baloxavir safety was the primary objective of this study, and the overall findings were unremarkable, with no new safety signals identified, confirming that baloxavir is well tolerated in children. rates of aes were generally similar between groups and there were no serious aes or deaths reported. the most common aes in both groups were gastrointestinal related (diarrhea/vomiting). the safety population comprised children who received any portion of a single dose of treatment. the safety population comprised children who received any portion of a single dose of treatment. *including american indian or alaska native (n = 1 for baloxavir), asian (n = 1 for baloxavir), native hawaiian or other pacific islander (n = 1 for oseltamivir), multiple (n = 4 for baloxavir) and unknown (n = 5 for baloxavir, n = 1 for oseltamivir). †taken from the itti population. ‡one child had influenza a/h1n1pdm09 and influenza b coinfection. §in the baloxavir marboxil group, 23 children with influenza a had viral coinfections: coronavirus (11), rhinovirus/enterovirus (8) and respiratory syncytial virus (4). in the oseltamivir group, 5 children with influenza a had viral coinfections: rhinovirus/ enterovirus (3) and coronavirus (2) . in the baloxavir marboxil group, 2 children with influenza b had viral coinfections: rhino/enterovirus (1), and both adenovirus and rhinovirus/enterovirus (1). in the oseltamivir group, 1 child with influenza b had a coinfection: rhinovirus/enterovirus. no results for coinfections after baseline are available. treatment-related aes were less frequent in the baloxavir group than the oseltamivir group. most aes were considered by investigators to be related to influenza infection. in both treatment groups, most aes were either mild or moderate in severity and most resolved or were resolving by the end of the study. the data showed that ttass, a key efficacy endpoint for the study, were similar between the baloxavir and oseltamivir treatment groups. all other secondary efficacy endpoints were similar between treatment groups, and there were no differences in the incidence of influenza-related complications or the use of antibiotics. as in previous studies, 19, 20 the antiviral activity of baloxavir was shown to be favorable compared with oseltamivir. the rapid decline of infectious virus titer after 24 hours and reduced time to viral shedding are consistent with those seen previously in completed phase ii and phase iii studies, confirming the marked virologic effects achieved with a single dose of baloxavir. 19, 20 the further potential clinical value of an antiviral with such favorable virologic properties has been recently demonstrated in a postexposure prophylaxis study. 27 moreover, further studies are being conducted to determine whether transmission from infected individuals is reduced by baloxavir, 28 and whether, in combination with a neuraminidase inhibitor, baloxavir can offer benefit in patients hospitalized with severe influenza (clinicaltrial.gov identifier: nct03684044). multiple viral infections are frequent in hospitalized children with respiratory tract disease, and may be linked to greater severity in symptoms and longer lengths of hospital stays. 29, 30 in contrast, although respiratory tract infections are commonly diagnosed and treated in the community, few studies report on the frequency of coinfection in this setting. a quarter of the itti population had a coinfection with another respiratory viral pathogen at baseline. given that no data are available after baseline, there is a possibility that both baseline coinfections and later-onset coinfections contributed to a longer ttass than may have been observed in the absence of coinfections. in this study, there were no bacterial coinfections at baseline, and only 3 cases of otitis media (2 requiring antibiotics) observed in the baloxavir arm following treatment; therefore, these results may potentially indicate a reduction in acute otitis media complications following baloxavir treatment, compared with the 1 in 4 children in whom this usually develops without antiviral treatment. 31 this could contribute to a reduction of the overuse of antibiotics for prevention of this complication, 32 particularly in younger children, similar to the effect observed with oseltamivir. 33 however, these speculative results should be interpreted with caution in the absence of a specific analysis of the reduction in acute otitis media complications following baloxavir treatment. all influenza antivirals can lead to the emergence of resistant variants with reduced susceptibility; 34 however, in acute infections such as influenza, these variants are usually transient. an amino acid substitution at position 38 in the rna polymerase (pa/i38x) has been shown to be the most common determinant of reduced susceptibility to baloxavir. 35 the rate of pa/i38x viral variants in this study was consistent with that observed in 2 previous the itti population comprised children who had a laboratory reverse transcriptase-polymerase chain reaction confirmation of influenza infection from any swab sample collected at baseline or during the study. *the number of children with influenza b was too low to allow meaningful interpretation of the data. †children with a positive virus titer on day 1 were included in this analysis. ‡children whose virus titers did not reach the limit by the last observation time point were censored. completed japanese studies in children (japiccti-163417 24 and japiccti-173811) including higher prevalence rates in children <5 years old, which has also been documented for oseltamivir. 35 in this study, clinical benefit was observed regardless of i38x variants. however, the approach taken to calculate resistance rates is conservative, generally including patients in whom virus is detectable after a certain time (usually days 3-5), but excluding those who have cleared the virus before sampling. potent antivirals would be expected to clear the virus more rapidly, leaving fewer patients with samples for resistance analysis. this can potentially lead to an overestimation of resistance rates. in conclusion, this study showed that a single oral dose of baloxavir is well-tolerated, effective at alleviating influenza signs and symptoms, and results in rapid elimination of the virus in children with uncomplicated, acute influenza. importantly, it presents a new therapeutic option with a simplified and convenient singledose oral regimen, of particular value for children. influenza (seasonal) fact sheet influenza: a global perspective secondary bacterial infections associated with influenza pandemics factors affecting immune responses to the influenza vaccine the burden of seasonal and pandemic influenza in infants and children global seasonal influenzaassociated mortality collaborator network. estimates of global seasonal influenza-associated respiratory mortality: a modelling study risk factors of influenza transmission in households vaccines for seasonal and pandemic influenza strategies to achieve the healthy people 2020 annual influenza vaccine coverage goal for health-care personnel: recommendations from the national vaccine advisory committee influenza vaccines: challenges and solutions new vaccines against influenza virus the evolving history of influenza viruses and influenza vaccines incidence of adamantane resistance among influenza a (h3n2) viruses isolated worldwide from 1994 to 2005: a cause for concern the origin and global emergence of adamantane resistant a/h3n2 influenza viruses baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models xofluza (baloxavir marboxil) prescribing information in vitro characterization of baloxavir acid, a first-in-class cap-dependent endonuclease inhibitor of the influenza virus polymerase pa subunit baloxavir marboxil for uncomplicated influenza in adults and adolescents phase 3 trial of baloxavir marboxil in high-risk influenza patients (capstone-2 study) tamiflu (oseltamivir) prescribing information canadian acute respiratory illness and flu scale (carifs): development of a valid measure for childhood respiratory infections detection of nonhemagglutinating influenza a(h3) viruses by enzyme-linked immunosorbent assay in quantitative influenza virus culture baloxavir marboxil in japanese pediatric patients with influenza: safety and clinical and virologic outcomes multicenter evaluation of biofire filmarray respiratory panel 2 for detection of viruses and bacteria in nasopharyngeal swab samples characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil presented at options x for the control of influenza presented at options x for the control of influenza does respiratory virus coinfection increases the clinical severity of acute respiratory infection among children infected with respiratory syncytial virus? multiple simultaneous viral infections in infants with acute respiratory tract infections in spain influenza in children reducing antibiotic use in influenza: challenges and rewards impact of oseltamivir treatment on the incidence and course of acute otitis media in children with influenza emerging influenza antiviral resistance threats five years of monitoring for the emergence of oseltamivir resistance in patients with influenza a infections in the influenza resistance information study. influenza other respir viruses the authors thank all study participants and investigators who participated in the study, wenyi liu and alan j. mueller-breckenridge for outstanding support with statistical/scientific analyses, and viroclinics biosciences bv for analyses of swab samples. qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). further details on roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). for further details on roche's global policy on the sharing of clinical information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commit-ment_to_data_sharing.htm). key: cord-312266-hnbgaxft authors: krishnamurthy, a.; palombo, e. title: current therapeutics and prophylactic approaches to treat pneumonia date: 2016-08-05 journal: the microbiology of respiratory system infections doi: 10.1016/b978-0-12-804543-5.00017-8 sha: doc_id: 312266 cord_uid: hnbgaxft bacterial pneumonia caused by streptococcus pneumoniae, haemophilus influenzae, staphylococcus aureus, mycoplasma pneumoniae, and klebsiella pneumoniae represents a frequent cause of mortality worldwide. the increased incidence of pneumococcal diseases in both developed and developing countries is alarmingly high, affecting infants and aged adult populations. the growing rate of antibiotic resistance and biofilm formation on medical device surfaces poses a greater challenge for treating respiratory infections. over recent years, a better understanding of bacterial growth, metabolism, and virulence has offered several potential targets for developing therapeutics against bacterial pneumonia. this chapter will discuss the current and developing trends in treating bacterial pneumonia. the mucosal epithelium of the nasopharynx is a well-recognized primary site of bacterial colonisation including the opaque and transparent phenotypes of the pneumococcus. 14 the pneumococcus can traverse down to the lung upon aspiration and start adhering to the alveolar type ii cells to initiate bacterial infection. 15 the progress to pneumonia can occur more rapidly if there is a preexisting respiratory viral infection or increased bacterial adherence facilitated by viruses or cytokines. 16 the different stages of pneumococcal pneumonia are well known. the first stage is characterized by a bulge or engorgement due to the bacterial presence and serous exudate in the alveoli which provides nutrients to the bacteria and facilitates further infection in the lung. 17 the next stage is the intense inflammatory reaction involving leakage of erythrocytes into the alveoli (red hepatisation), followed by the migration of leukocytes into the consolidated area (gray hepatisation), and surface phagocytosis by the leukocytes. 18 due to the intact immune system of the host, normally the type-specific antibodies and the polymorphonuclear leukocytes phagocytise the pneumococci and the lung returns to its normal state. however, in patients with a compromised immune system having certain complement deficiencies or hypogammaglobulinemia (absence of type-specific antibodies), bacteremia can occur and the pneumococcus with its virulence factors (mostly cell wall components such as peptidoglycan, techoic acid, and proteins such as pneumolysin) induce inflammation causing subsequent tissue damage. 19 since the early 1980s, the lrti caused by s. pneumoniae in certain developing countries, such as ghana and south africa, have been reported at >60-90% of all cases in children less than 5 years of age, and 100 per 1000 population of adults per year, and has remained at equivalent rates even a decade later. [20] [21] [22] the incidence of pneumonia in children less than 5 years of age was higher in regions such as south-east asia, africa and western pacific countries in comparison with those in the developed countries like the americas and europe. 22 more recently, the incidence of childhood pneumonia has been estimated to be >120 million globally, of which ∼12% progressed to severe disease with 1% 4 vaccination mortality in children <2 years of age. 23 the risk factors for childhood pneumonia, especially in the developing countries, include nutrition deficiencies, lack of breastfeeding, indoor air pollution due to passive smoking, hiv infection, and substandard housing and living conditions. 24 the etiological agents causing pneumonia include both bacteria and respiratory viruses. certain vaccine studies have indicated the predominant bacterial agent causing pneumonia to be s. pneumoniae resulting in almost 18-25% severe cases and 30-35% mortality, followed by h. influenzae accounting for 4% of severe cases and 16% of deaths. influenza virus remains the dominant viral etiological agent responsible for 7% of the severe cases and 11% of deaths. 23, 25 s. pneumoniae is also well-recognized to cause community-acquired pneumonia (cap) in children with lower fatality rates of 1.5%. 26 in addition to these etiological agents, bacteria such as staphylococcus aureus, klebsiella pneumoniae, and respiratory viruses such as rsv, rhinovirus, human metapneumovirus, human bocavirus and parainfluenza viruses are the other commonly identified agents that contribute to the burden of childhood pneumonia. 25, 27 community-acquired pneumonia (cap) is an increasing health problem and the third most common reason for hospitalization for adults, especially the elderly aged >65 years. the prevalence of cap has been reported as 18-20 cases per 1000 population with an increase from 9% in 65-74 year olds to 17% in 75-84 year olds, and 30% in >85 year olds. 28, 29 several predisposing factors such as impaired immunity and lung function, dysfunctional nasal mucociliary clearance, lung and heart diseases, smoking have been identified as independent predictors for cap in adults and the elderly. 24 certain studies have reported s. pneumoniae, legionella species, h. influenzae, moraxella catarrhalis, and s. aureus as the predominant pathogens in cap. 30 although the role of respiratory viruses has been well-recognized in cap in children and infants, it is not well understood in adults and the elderly. it is still unclear whether a virus by itself can cause pneumonia or whether the virus can act in conjunction with other respiratory pathogens. one study has reported that respiratory viruses such as influenza virus, rsv, adenovirus, and rhinovirus were commonly isolated as part of a co-infection, especially with s. pneumoniae. 31 thus, viral agents in adults with cap most often seem to be part of a mixed infection, usually with s. pneumoniae as the co-pathogen. the world health organisation (who) recommends routine childhood immunization programs that include vaccines that offer protection from various respiratory disease such as pneumonia, influenza (flu), measles, and pertrussis. the haemophilus influenzae type b (hib) vaccine and the pneumococcal conjugate vaccines are increasingly available in both developed as well as developing countries, especially the 7-and 13-valent pneumococcal conjugate vaccines which have shown effectiveness in reducing the incidence and severity of pneumonia and other lower respiratory infections in children. currently, there are three vaccines in the childhood routine immunization schedule; measles, hib, and the pneumococcal conjugate vaccine that is well-recognized to reduce childhood mortality from and related to pneumonia. vaccination remains the primary preventative strategy for pneumonia, including cap in the elderly. the hib vaccine has a proven efficiency of >90% against invasive meningitis and bacteremia and noninvasive pneumonia caused by h. influenzae type b. 32, 33 this impressive efficiency has resulted in the introduction and addition of the hib vaccine worldwide into national immunization programs, and has resulted in a significant reduction in the vaccination gap between developed and developing countries. 34 a recent review from several randomized controlled trials (from 1970s to 2008) from different developing countries indicated a significant reduction of severe pneumonia by 6%, pneumonia-associated mortality by 7%, and reduction of radiological confirmed cases of pneumonia by 18%. 35 based on the preventative approach of pneumonia and pneumonia-related mortality with effective vaccination, a certain modeling-based study has estimated that if implemented at present annual rates of increase in developing countries, the vaccine could save up to 51% of pneumonia deaths by 2025 at a cost saving of us$3.8 billion. 36 high coverage of the hib vaccine immunization in children less than 5 years of age could reduce childhood pneumonia resulting in decreased incidence of severe pneumonia. the 23-valent polysaccharide vaccine (ppv23) and the 13-valent protein-conjugated polysaccharide vaccine (pcv13) are the two vaccines that offer protection against pneumococcal disease, and have replaced the 7-valent conjugate vaccine (pcv7). as the polysaccharide vaccine (ppv) is t-cell independent, it does not boost immunological memory and the immunity offered may not last for a long time. for this reason, this vaccine is not offered to infants aged <2 years of age, but is provided to children aged >2 years and to elderly people who are at risk (>50 years of age) for developing pneumonia. in contrast, the conjugate vaccines stimulate a t-cell dependent response and are more effective in infants and children <2 years of age. 37 the different pneumococcal vaccines, serotypes covered, and the conjugate protein used are mentioned in table 17 .1 pcv7 and pcv10 are offered for children aged from 6 weeks to 5 years of age, whereas pcv13 is given to children aged between 6 weeks and 17 years, and to adults aged >50 years of age. since the introduction of the pcv7 vaccine in 2000, its efficacy against invasive meningitis, pneumonia, and otitis media is well documented. [38] [39] [40] the subsequent vaccines, pcv10 and pcv13, have also demonstrated comparable immunogenicity to pcv7 in several clinical trials. [41] [42] [43] although ppv23 covers 23 serotypes of s. pneumoniae, and is recommended for adults aged >65 years of age, its effectiveness in reducing invasive pneumococcal disease remains uncertain. 44, 45 as pcv13 has equal or greater immunogenicity than ppv23, and has greater immunological memory, the use of pcv13 is now recommended for adults in addition to ppv23, particularly the elderly and high risk individuals. in addition to this, newer pcv's have been shown to reduce the number of healthy carriers of the pathogen in the community because of "herd immunity" where unvaccinated people are protected from the pathogen. since the introduction of pcv's as a part of "herd immunity", the incidence of invasive pneumococcal diseases was shown to decline by almost 70% among vaccinated children <2 years of age, and by 32% in adults aged 20-39 years, and by 18% in the elderly aged >65 years of age, who were not previously vaccinated. 46 the classification of antibiotics is based on the cellular component that they affect, as well as on whether they can induce cell death (bactericidal) or inhibit cell growth (bacteriostatic). antibiotic-mediated cell death is a complex process involving physical interaction between a drug molecule and its bacterial-specific target, and/or modulation of the affected bacterium at the biochemical, molecular, and ultrastructural levels. 47 fig. 17 .1 summarizes the different drug targets and mechanism of actions of various antimicrobials such as; inhibition of cell wall synthesis, inhibition of protein synthesis, injury to cytoplasmic membrane, and inhibition of nucleic acid synthesis and replication. dna synthesis and cell division are well-recognized processes that involve modulation of chromosomal supercoiling through topoisomerase-catalyzed strand breakage and rejoining reactions. antimicrobials such as quinolone target enzymes like dna gyrase (topoisomerase ii) and topoisomerase iv (topoiv) that are required for bacterial dna synthesis and replication, and prevent dna strand rejoining. 48 peptidoglycan, a covalently cross-linked polymer matrix composed of peptide-linked β-(1-4)-n-acetyl hexosamine, is the main component of bacterial cell walls that contributes towards the structural integrity of the bacterial cell. the peptidoglycan layer is maintained through the activity of transglycosylase and transpeptidase enzymes, which add disaccharide pentapeptides to extend the glycan strands of existing peptidoglycan molecules and cross-link adjacent peptide strands of immature peptidoglycan units, respectively. 49 βlactams and glycopeptides are among the classes of antibiotics that interfere with cell wall biosynthesis resulting in changes to bacterial cell shape and size and induction of cellular stress responses that leads to bacterial cell lysis. 50 the process of protein synthesis via mrna translation involves the ribosome that is composed of two major components, the 50s and 30s subunits. drugs that inhibit protein synthesis are divided into two subclasses: the 50s inhibitors and 30s inhibitors. the 50s ribosome inhibitors include the macrolide, lincosamide, streptogramin, amphenicol, and oxazolidinone classes of antibiotics. 51 the 30s inhibitors include the tetracycline and aminocyclitol families of antibiotics. 52 the mortality caused due to pneumonia can be avoided through cost-effective and life-saving treatment from antibiotics for bacterial pneumonia, thereby significantly increasing the patient's chances of survival. the pneumonia management strategy with the use of appropriate antibiotics and supportive care including oxygen systems remains an effective cornerstone in the treatment and management of children suffering from pneumonia. the who integrated management of childhood illness program has consistently reported a reduction of childhood mortality rates by approximately 20%, while certain community based management strategies have reported a decrease in 70% mortality due to the usage of oral antibiotics such as amoxicillin. [53] [54] [55] the four types of antibiotics recommended for children <5 years of age for the treatment of pneumonia are; cotrimoxazole, amoxicillin, cephalosporins, and macrolides, with oral amoxicillin (40 mg/kg/dose) used for 3 days (nonsevere pneumonia) and 5 days for children with severe pneumonia. 56 during severe pneumonia, the first line of treatment is often parenteral ampicillin (penicillin) and gentamicin, followed by ceftriaxone if the first line of treatment is not effective. 56 various randomized controlled studies from the cochrane database of systemic reviews have shown a multitude of available treatments for pneumonia in children with (1) cefpodoxime proving to be more effective than amoxicillin, (2) amoxicillin more effective than chloramphenicol, (3) amoxicillin being an effective alternative to cotrimoxazole for cap patients, (4) coamoxyclavulanic acid and cefpodoxime as alternative second-line drugs of choice, and (5) penicillin/ampicillin plus gentamicin more effective than chloramphenicol for children hospitalized with severe cap. 57 a 3-year pediatric study of the susceptibility of 208 s. pneumoniae isolates, including serotype 19a, using antibiotics such as second-and third-generation cephalosporins showed significant efficacy against 60-70% of the isolates, with clindamycin susceptibility of 60-85%, levofloxacin 95%, and ceftriaxone >95%. 58 the american thoracic society and the european respiratory society recommend that hospitalized patients with cap are preferably treated with a respiratory fluoroquinolone or combination therapy with a β-lactam and a macrolide. 59 the success rates of incorporating the fluoroquninolone or combination with a macrolide based on the clinical, bacteriological, or radiological examinations ranged from 87-96%. 60 vancomycin or clindamycin (based on local susceptibility data) should also be provided in addition to β-lactam therapy if clinical, laboratory, or radiological characteristics are consistent with infection caused by s. aureus. 61 although nonsevere and severe cap have been managed by many antimicrobials as a result of various studies from developing countries that compared different types of antibiotics, there is need for more studies and larger clinical trials for better management of pneumonia in developed countries. another major health concern is the continual rise in antibiotic resistance with approximately 30% of the isolates being resistant to macrolides including erythromycin, azithromycin, and clarithromycin. 62 the introduction and inclusion of the hib vaccine over the past 25 years has resulted in almost complete elimination of h. influenzae in children, therefore it is not considered as a pathogen in cap. nontypeable h. influenzae is also not considered as a pathogen in pediatric pneumonia unless detected in lung disease or copd. when detected as a true pathogen in cap, oral amoxicillin is considered effective against β-lactamase negative strains, and for β-lactamase producing strains, amoxicillinclavulanate, cefuroxime, cefdinir, cefixime, cefpodoxime are all considered effective therapies, while children allergic to oral β-lactam agents are only given fluoroquinolones. 61 although an infrequent cause of cap, group a streptococcus may cause severe necrotizing pneumonia. penicillin g at the dosage of 100,000-200,000 u/kg/day in 4-5 divided doses is used to treat patients suffering from cap due to group a streptococcus. as macrolide resistance is greater in streptococcal infections, along with lower tolerability by tissues, erythromycin and other macrolides are not administered. 63 s. aureus capable of causing pneumonia are usually methicillin-sensitive and are treated with either a β-lactamase stable penicillin (oxacillin or nafcillin) or a first-generation cephalosporin, like cefazolin. community-associated methicillin-resistant s. aureus (mrsa) represents >50-70% of the clinical isolates in some region of the united states, 64 but are shown to be susceptible to vancomycin, clindamycin, and linezolid. however, children intolerant to vancomycin and clindamycin could be treated with linezolid. however, severe adverse effects, including suppression of platelets and neutrophils, nerve injury, mean that this drug should be used with caution. in situations where mycoplasma pneumoniae and chlamydophila pneumoniae are of significant consideration upon diagnostic evaluation, empiric combination therapy with a macrolide and a β-lactam antibiotic is considered. children with moderate to severe cap consistent with influenza virus infection during widespread local circulation of influenza viruses should be administered with influenza antiviral therapy. the susceptible strains of influenza a virus are commonly treated with adamantanes and neuraminidase inhibitors. as the occurrence of genetic variations is highly substantial among influenza strains, resistance to either class of antiviral agents may develop quickly. however, the dosages of antiviral agents currently recommended for seasonal influenza are developed for fully susceptible strains and evaluated in clinical trials mandating the requirement of treatment within 3 days of the onset of symptoms. 65 early antiviral treatment has been shown to provide maximal benefit, and treatment should not be delayed until confirmation of positive influenza test results. negative results of influenza diagnostic tests, especially the rapid antigen tests, do not conclusively exclude influenza disease. therefore, treatment after 48 h of symptomatic infection may still provide some clinical benefit to those with more severe disease. 61 the efficacy of ribavirin for the treatment of rsv cap in infants is debatable, as certain in vitro studies have shown activity of ribavirin against rsv, but its usage for rsv infection is not routinely recommended in the management of lower respiratory tract disease because of the high cost, aerosol administration, and possible toxic effects among healthcare providers. palivizumab (synagis), a humanised murine monoclonal antibody is another effective prophylaxis for rsv infection that is administered intramuscularly. 66 although parainfluenza virus, adenovirus, metapneumovirus, rhinovirus, coronavirus, and bocavirus are associated with pediatric cap, there are no prospective, controlled studies for antiviral therapy against these viruses. since the introduction of penicillin in 1950s, it has been the first choice for treating pneumococcal pneumonia. during the early 1970s, infants and children were successfully treated with amoxicillin (40-45 mg/kg/day divided into 3 equal doses) because of the susceptible nature of the strains at that time. resistance to the commonly used antibiotics poses a major problem and concern for health practitioners while choosing an empirical therapy against bacterial pneumonia, and there are large geographical variations indicating different resistance patterns. in the 1990s with the widespread pneumococcal resistance to penicillin, the dosage was increased to ∼90 mg/kg/day given twice daily for treating children with acute otitis media. 67 a recent review has highlighted advances in the understanding of the various mechanisms by which bacteria acquire resistance to antibiotics, how they prevent access to different drug targets, and modulate or inactivate antibiotics. 68 the introduction of pneumococcal conjugate vaccine and the changes in antimicrobial usage have both significantly altered the resistance patterns of s. pneumoniae. the decreased degree of penicillin resistance further prompted a decrease in amoxicillin dosage compared to that administered in the prevaccine era. 69 over the last decade, a certain multicentre clinical trial study has reported a significant decrease in the susceptibility rates of the commonly used antibiotics such as amoxicillin/clavulante, penicillin, and ceftriaxone from 93.8% to 82.7%, 94.7% to 84.1%, and 97.4% to 87.5%, respectively. 70 the susceptibility rates of macrolides such as erythromycin and clindamycin were also reported to be decreased from 82.2% to 60.8% and from 96.2% to 79.1%, respectively. recently, increasing resistance against macrolides has been reported in several european countries, including the united kingdom. a 3-year surveillance study involving 1545 clinical isolates reported around 26% and 20% increase in the rates of ampicillin and trimethoprim/sulfamethoxazole resistance against h. influenzae, respectively, while antibiotics such as ceftaroline, ceftriaxone, amoxicillin/clavulante, and levofloxacin showed 99-100% susceptibility. 71 this study also showed increasing resistance of penicillin (96.4%) towards m. catarrhalis, because of the prevalence of β-lactamase that is known to reduce the susceptibility to penicillins. the resistance to macrolides against m. pneumoniae in children and adults with cap has been increasingly emerging in countries like japan, france, denmark, united states, and china, with rates as high as 40% in japan, 85% in china, and 3-10% in the europe and the united states. 72, 73 community-acquired mrsa, although primarily associated with skin and soft tissue infections, are now being recognized to cause invasive infections including cap, with almost 50% mortality rates reported in the united states and europe. 74, 75 there are certain ways by which resistance to antimicrobials can be minimized, such as: limiting the exposure to any antibiotic, whenever possible; limiting the spectrum of usage of antimicrobials to that specifically required to treat the identified pathogen; using the proper dosage of antimicrobial to achieve a minimal effective concentration at the site of infection; treatment for the shortest effective duration that will minimize the exposure of both pathogens and normal microbiota to antimicrobials and further minimize the selection for resistance. 61 the increasing incidence of antimicrobial resistance remains one of greatest challenges against emerging bacterial infections and has resulted in some bacteria being essentially untreatable with the current available treatment options. as a result, newer antimicrobials with novel modes of action against multidrug resistant strains are being developed. a recent review has highlighted how combinations of drugs can offer synergistic and antagonistic drug interactions, and how these drug interactions can provide opportunities for discovery of newer drugs. 76 in recent years, the availability of new antimicrobials for human consumption has been lower than in the recent past, with no new classes of antimicrobials developed since the introduction of nalidixic acid (1962) and linezolid (2000) . the availability of antimicrobials in recent years has mostly been the result of modification of existing molecules. one of the reasons for this is that the development of any new antimicrobial agent is very expensive and time consuming, with research and development of infective drugs taking around 15-20 years, and costing around us$1000 million, with further additional costs for bringing the new drug into the market. 77 there is a strong need for newer unexploited targets and strategies for the next generation of antimicrobial drugs against drug resistant and emerging pathogens. some of the new antimicrobial agents that are in the clinical development stage are listed in table 17 .2. some of the new antibiotics that have shown promising results in the treatment of pneumonia and cap are as follows: ceftaroline: a fifth generation cephalosporin known to bind to penicillin-binding proteins and preventing synthesis of bacterial cell walls. it is a novel broad-spectrum antibiotic effective against mrsa, penicillin and cephalosporin resistant s. pneumoniae, vancomycin-intermediate s. aureus (visa), and vancomycin-resistant s. aureus (vrsa). 78 it is also active against many gram-negative pathogens but inactive against extended-spectrum β-lactamase (esbl) producing bacteria. it has been approved for the treatment of cap. different randomized, double-blind, multicentre trials have demonstrated the efficacy (>82% clinical cure) and safety of ceftaroline (intravenous, 600 mg twice daily) for the treatment of cap. 79 ceftobiprole: another newer cephalosporin that has a broad-spectrum activity against mrsa, penicillin-resistant s. pneumoniae, p. aeruginosa and enterococci. 80 a randomized trial consisting of 706 hospitalized adults with severe cap who were administered ceftobiprole (intravenous, 500 mg over 120 min every 8 h) showed no significant differences between the treatment groups but found adverse events including nausea and vomiting in 36% of the patients. 81 telavancin: a semi-synthetic lipoglycopeptide derivative of vancomycin known to disrupt peptidoglycan synthesis and alter cell membrane function. it has been in use for treating complicated skin infections caused by s. aureus, and hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia caused by susceptible isolates of s. aureus. 82 telithromycin: the first ketolide to enter clinical use for the treatment of cap, chronic bronchitis and acute sinusitis. telithromycin is a protein synthesis inhibitor blocking the progression of the growing polypeptide chain by binding to the 50s subunit of the bacterial ribosome. it exhibits 10 times higher affinity to the subunit 50s subunit than erythromycin. in addition, telithromycin strongly binds simultaneously to two domains of 23s subunit of the 50s ribosomal subunit; older macrolides bind to only to one domain and weakly to the second domain. an in vitro study showed activity of telithromycin against s. pneumoniae and, compared with clarithromycin and azithromycin, was found to maintain its activity against macrolide-resistant strains of s. pneumoniae and s. pyogenes. 83 it is formulated as 400 mg tablet for oral administration with good absorption and bioavailability. 84 however, the fda withdrew its approval in the treatment of cap in 2007 due to its safety concerns involving hepatotoxicity, myasthenia gravis exacerbation, and visual disturbances. cethromycin: a 3-keto,11,12carbamate derivative of erythromycin a with an o-6 linked aromatic ring. it binds strongly to the 50s ribosomal subunit and inhibits bacterial protein synthesis. 85 cethromycin displays in vitro activity against streptococci, including strains of s. pneumoniae that are resistant to penicillins and macrolides. 86 its activity was greater than telithromycin against macrolide-resistant streptococci and is more potent than macrolides and fluoroquinolones against penicillin-resistant streptococci. it also displays comparable in vitro activity to azithromycin against respiratory gram-negative organisms including β-lactamase-producing h. influenzae and m. catarrhalis. it was shown to be more potent than erythromycin and clarithromycin but less potent than fluoroquinolones against β-lactamase-producing h. influenzae. 86, 87 it showed similar potency against β-lactamase-producing m. catarrhalis. solithromycin: a new macrolide, and the first fluoroketolide in clinical development, with proven activity against macrolide-resistant bacteria. solithromycin is being developed in both intravenous and oral formulations for the treatment of cap, which should allow both oral therapy and i.v.-to-oral stepdown therapy in appropriate patients. a recent multicentre, double-blind, randomized phase ii study consisting of 132 patients with moderate to severe cap administered with oral solithromycin (800-mg loading dose and 400 mg maintenance dose/5 days) showed efficacy comparable to that of levofloxacin in the treatment of cap, with a favorable safety and tolerability profile. 88 nemonoxacin: a novel nonfluorinated quinolone with proven in vitro and in vivo activity against cap pathogens including multidrug resistant s. pneumoniae. a randomized multicentre trial consisting of 265 cap patients treated with an oral administration of nemonoxacin (750 and 500 mg/7 days) showed a remarkable 80-85% clinical and bacteriological success rate, which was comparable tolevofloxacin therapy. 89 a recent comprehensive review has well documented all the data available on the pharmacodynamics, the pharmacokinetics, and the clinical treatment studies of this antimicrobial agent. 90 zabofloxacin: is being developed as a new fluoroquinolone antibiotic that is a potent and selective inhibitor of the essential bacterial type ii topoisomerases and topoisomerase iv and is indicated for community-acquired respiratory infections due to gram-positive bacteria. two dosing regimens of zabofloxacin (zabofloxacin hydrochloride 400 mg capsule andzabofloxacin aspartate 488 mg tablet) were well-tolerated with no adverse effects. 91 jnj-q2 and kpi-10: two novel fluoroquinolones that are being developed for the treatment of bacterial pathogens responsible for respiratory infections including cap, and other skin infections. both agents have demonstrated increased potency when compared with the marketed fluoroquinolones, thus encouraging further clinical development. 92, 93 bc-3781: a recent semisynthetic pleuromutilin antibiotic with excellent antibacterial activity against skin pathogens such as s. aureus, β-haemolytic streptococci, viridans streptococci, and enterococcus faecium as well as against respiratory pathogens. its activity against respiratory pathogens has also been confirmed in various murine models of infection using s. pneumoniae, h. influenzae, s. aureus, and mrsa (nosocomial and community-associated), with better drug penetration, strongly supporting its potential use in the treatment of bacterial respiratory tract infections. 94 although there are a wide variety of clinically efficacious antibiotics in use today, the development of bacterial resistance has rendered them less effective, with most being bacteriostatic, and acting by either protein or cell wall synthesis inhibition. further research is needed in the design of novel antibacterial agents with new targets. one approach could be to design antibiotics that can be used against novel drug targets such as the bacterial enzymes β-ketoacyl-acyl-carrier-protein synthase i/ii which are required for fatty acid biosynthesis. platensimycin is one such drug undergoing preclinical trials and is known to block these enzymes that are involved in the biosynthesis of essential fatty acids by gram-positive bacteria. 95 it has potent antibacterial activity against gram-positive bacteria including multidrug resistant staphylococci and enterococci. another approach worth investigating could be to combine β-lactam antibiotics with naturally occurring β-lactamase enzymes in the gastrointestinal microbiota. these enzymes are shown to hydrolyse various antibiotics including penicillin, ampicillin, and piperacillin. p1a protein (29 kda) is one such example of having both structural and functional similarities to the β-lactamase enzyme. the emergence of resistant microbes can be significantly reduced by taking advantage of combining this naturally occurring hydrolysis of the antibacterial drug with currently available β-lactam drugs. a phase ii trial for the treatment of serious respiratory infections which incorporated treatment with p1a (β-lactamase product) and ampicillin showed only a 20% change in gut microbiota compared to 50% change in patients treated with ampicillin alone. 96 apart from antimicrobials, strategies involving immunomodulation of inflammatory responses (targeting pattern recognition receptor signaling, corticosteroids, complement inhibitors etc.), improving pulmonary barrier function (using adrenomedullin, angiopoietin etc.) during pneumonia and its associated complications could add a new dimension in providing better therapeutics for patients. 97 despite great advances in management and preventative approaches, pneumonia still remains a major burden of mortality and morbidity in young children and the elderly, especially in the developing and under-developed countries. prevention by means of vaccination is critical for reducing pneumonia mortality in children <5 years of age, and an effective antibiotic therapy is important for the elderly. the widespread emergence of antimicrobial resistance is a well-recognized cause of the ineffectiveness of the large number of the currently used antimicrobials. although numerous efforts have been made to combat this, newer targets need to be identified for the generation of the next level of effective antimicrobials. in addition, a complete understanding of the various aspects of drug resistance in microbes is essential to assist us in designing better targets and help us discover new antibacterial drugs. in the near future, the next challenge will be to identify newer agents for the treatment of multidrug resistant pathogens which are emerging at a rapid rate. the constant and unpredictable 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treatment of patients with community-acquired pneumonia requiring hospitalization telavancin: mechanisms of action, in vitro activity, and mechanisms of resistance macrolides and ketolides: azithromycin, clarithromycin, telithromycin pharmacokinetics of the new ketolide telithromycin (hmr 3647) administered in ascending single and multiple doses the ketolide antibiotic abt-773 is a specific inhibitor of translation and 50s ribosomal subunit formation in streptococcus pneumoniae cells in vitro activity of abt-773, a new ketolide, against recent clinical isolates of streptococcus pneumoniae, haemophilus influenzae, and moraxella catarrhalis in vitro activity of abt-773 versus macrolides and quinolones against resistant respiratory tract pathogens randomized, double-blind, multicentre phase 2 study comparing the efficacy and safety of oral solithromycin (cem-101) to those of oral levofloxacin in the treatment of patients with community-acquired bacterial pneumonia efficacy and safety of nemonoxacin versus levofloxacin for community-acquired pneumonia review of nemonoxacin with special focus on clinical development comparison of pharmacokinetics between new quinolone antibiotics: the zabofloxacin hydrochloride capsule and the zabofloxacin aspartate tablet activity of jnj-q2, a new fluoroquinolone, tested against contemporary pathogens isolated from patients with community-acquired bacterial pneumonia advances in antibiotic therapy for community-acquired pneumonia antimicrobial activity of the novel pleuromutilin antibiotic bc-3781 against organisms responsible for community-acquired respiratory tract infections (cartis) platensimycin, a new antibiotic and "superbug challenger" from nature p1a recombinant beta-lactamase prevents emergence of antimicrobial resistance in gut microflora of healthy subjects during intravenous administration of ampicillin therapeutic strategies in pneumonia: going beyond antibiotics key: cord-327976-pwe95zoi authors: singh, dr shweta; roy, assistant professor.miss deblina; sinha, clinical psychology trainee miss krittika; parveen, clinical psychology trainee miss sheeba; sharma, clinical psychology trainee. ginni; joshi, clinical psychology trainee. gunjan title: impact of covid-19 and lockdown on mental health of children and adolescents: a narrative review with recommendations. date: 2020-08-24 journal: psychiatry res doi: 10.1016/j.psychres.2020.113429 sha: doc_id: 327976 cord_uid: pwe95zoi background: covid-19 pandemic and lockdown has brought about a sense of fear and anxiety around the globe. this phenomenon has led to short term as well as long term psychosocial and mental health implications for children and adolescents. the quality and magnitude of impact on minors is determined by many vulnerability factors like developmental age, educational status, pre-existing mental health condition, being economically underprivileged or being quarantined due to infection or fear of infection. aims: this paper is aimed at narratively reviewing various articles related to mental-health aspects of children and adolescents impacted by covid-19 pandemic and enforcement of nationwide or regional lockdowns to prevent further spread of infection. methodology: we conducted a review and collected articles and advisories on mental health aspects of children and adolescents during the covid-19 pandemic. we selected articles and thematically organized them. we put up their major findings under the thematic areas of impact on young children, school and college going students, children and adolescents with mental health challenges, economically underprivileged children, impact due to quarantine and separation from parents and the advisories of international organizations. we have also provided recommendations to the above. conclusion: there is a pressing need for planning longitudinal and developmental studies, and implementing evidence based elaborative plan of action to cater to the psycho social and mental health needs of the vulnerable children and adolescents during pandemic as well as post pandemic. there is a need to ameliorate children and adolescents’ access to mental health support services geared towards providing measures for developing healthy coping mechanisms during the current crisis. for this innovative child and adolescent mental health policies policies with direct and digital collaborative networks of psychiatrists, psychologists, paediatricians, and community volunteers are deemed necessary. this paper is aimed at reviewing articles related to mental-health aspects of children and adolescents impacted by covid-19 pandemic and lockdowns. there is a need to carry out longitudinal and developmental studies and plan strategies to enhance children's and adolescent's access to mental health services during and after the current crisis. for this direct and digital collaborative network of psychiatrists, psychologists, pediatricians, and community volunteers are of vital importance. background: covid-19 pandemic and lockdown has brought about a sense of fear and anxiety around the globe. this phenomenon has led to short term as well as long term psychosocial and mental health implications for children and adolescents. the quality and magnitude of impact on minors is determined by many vulnerability factors like developmental age, educational status, pre-existing mental health condition, being economically underprivileged or being quarantined due to infection or fear of infection. aims: this paper is aimed at narratively reviewing various articles related to mental-health aspects of children and adolescents impacted by covid-19 pandemic and enforcement of nationwide or regional lockdowns to prevent further spread of infection. methodology: we conducted a review and collected articles and advisories on mental health aspects of children and adolescents during the covid-19 pandemic. we selected articles and thematically organized them. we put up their major findings under the thematic areas of impact on young children, school and college going students, children and adolescents with mental health challenges, economically underprivileged children, impact due to quarantine and separation from parents and the advisories of international organizations. we have also provided recommendations to the above. conclusion: there is a pressing need for planning longitudinal and developmental studies, and implementing evidence based elaborative plan of action to cater to the psycho social and mental health needs of the vulnerable children and adolescents during pandemic as well as post pandemic. there is a need to ameliorate children and adolescents' access to mental health support services geared towards providing measures for developing healthy coping mechanisms during the current crisis. for this innovative child and adolescent mental health policies policies with direct and digital collaborative networks of psychiatrists, psychologists, paediatricians, and community volunteers are deemed necessary. key words: covid-19; lockdown; mental health; children; adolescents there are more than 2.2 billion children in the world who constitute approximately 28% of the world's population. those aged between 10 to 19 years make up 16 % of the world's population (unicef, 2019) . covid-19 has impacted the lives of people around the world including children and adolescents in an unprecedented manner. throughout the world, an essential modus of prevention from covid-19 infection has been isolation and social distancing strategies to protect from the risk of infection (shen et al., 2020) . on these grounds, since january, 2020, various countries started implementing regional and national containment measures or lockdowns. in this backdrop one of the principal measures taken during lockdown has been closure of schools, educational institutes and activity areas. these inexorable circumstances which are beyond normal experience, lead to stress, anxiety and a feeling of helplessness in all. it has been indicated that compared to adults, this pandemic may continue to have increased long term adverse consequences on children and adolescents (shen et al., 2020) . the nature and extent of impact on this age group depend on many vulnerability factors such as the developmental age, current educational status, having special needs, pre-existing mental health condition, being economically under privileged and child/ parent being quarantined due to infection or fear of infection. the following sections discuss about findings of studies on mental-health aspects of children and adolescents impacted by covid-19 pandemic and lockdowns being implemented at national or regional levels to prevent further spread of infection. we searched the electronic data bases of medline through pubmed, cochrane library, science-direct and google scholar databases, from january,2020 till june,2020. we carried out the search with the following methods like, mesh or free text terms and boolean were done by five independent reviewers. a manual search was also conducted of the references of the related articles to gather information about the relevant studies. initial pubmed search with the term with " covid-19 in children" showed only 12 results. among these, only four articles were related to "psychological effects of covid in children". therefore in order to make the review more comprehensive and informative, we also included studies that reported the effect on older children and impact of covid1-19 on their lives. this was done keeping in mind the varied terminologies used to describe the phenomenon of 'children and covid-19". after using the above strategy, our search showed 112 results. only articles in english language peer reviewed journals were included. grey literature such as conference proceedings were not included due to possibility of insufficient information. we included case studies and review articles and advisories by the who (world health organization), apa (american psychiatric association) and nhs ( national health services) and government of india ministry of health. based on these inclusion criteria we included 22 articles. three independent authors participated in study selection and all authors reached a consensus on the studies to be included. being a narrative review, we did not attempt computation of effect sizes or do a risk of bias assessment for included papers. the studies included were categorized under eight headings divided in various thematic sections and discussed with studies and reports found. the data is qualitatively analysed and reported in the paper. a summary of the papers included in this narrative review is presented in table 1. [ table 1 is uploaded seperately] impact on young children: stress starts showing its adverse effect on a child even before he or she is born. during stress, parents particularly pregnant mothers are in a psychologically vulnerable state to experience anxiety and depression which is biologically linked to the wellbeing of the foetus (biaggi et a 2016; kinsella and monk, 2009 ). in young children and adolescents the pandemic and lockdown have a greater impact on emotional and social development compared to that in the grown-ups. in one of the preliminary studies during the on-going pandemic, it was found younger children (3-6years old) were more likely to manifest symptoms of clinginess and the fear of family members being infected than older children (6-18 years old). whereas, the older children were more likely to experience inattention and were persistently inquiring regarding covid-19. although, severe psychological conditions of increased irritability, inattention and clinging behaviour were revealed by all children irrespective of their age groups (viner et al., 2020a) . based on the questionnaires completed by the parents, findings reveal that children felt uncertain, fearful and isolated during current times. it was also shown that children experienced disturbed sleep, nightmares, poor appetite, agitation, inattention and separation related anxiety (jiao et al., 2020) . globally, the pre-lockdown learning of children and adolescents predominantly involved one-to-one interaction with their mentors and peer groups. unfortunately, the nationwide closures of schools and colleges have negatively impacted over 91% of the world's student population (lee, 2020). the home confinement of children and adolescents is associated with uncertainty and anxiety which is attributable to disruption in their education, physical activities and opportunities for socialization (jiao et al., 2020) . absence of structured setting of the school for a long duration result in disruption in routine, boredom and lack of innovative ideas for engaging in various academic and extracurricular activities. some children have expressed lower levels of affect for not being able to play outdoors, not meeting friends and not engaging in the in-person school activities (lee, 2020; liu et al., 2020; zhai & du, 2020) . these children have become more clingy, attention seeking and more dependent on their parents due to the long term shift in their routine. it is presumed that children might resist going to school after the lockdown gets over and may face difficulty in establishing rapport with their mentors after the schools reopen. consequently, the constraint of movement imposed on them can have a long term negative effect on their overall psychological wellbeing (lee, 2020). a study found that older adolescents and youth are anxious regarding cancellation of examinations, exchange programs and academic events (lee, 2020) . current studies related to covid-19 demonstrate that school shut downs in isolation prevent about 2-4% additional deaths which is quite less if compared to usage of other measures of social distancing. moreover, they suggest to the policy makers that other less disrupting social distancing strategies should be followed by schools if social distancing is recommended for a long duration (lee, 2020; sahu, 2020; viner et al., 2020a) . however, in current circumstances, it is controversial whether complete closure of school and colleges is warranted for a prolonged period. it has been reported that panic buying in times of distress indicate an instinctual survival behaviour (arafat et al., 2020) . in present pandemic era there has been a rise in the hoarding behaviour among the teenagers (oosterhoff et al., 2020a) . it is also found that among youth social distancing is viewed primarily as a social responsibility and it is followed more sincerely if motivated by prosocial reasons to prevent others from getting sick (oosterhoff et al., 2020a) . further, due to prolonged confinement at home children's increased use of internet and social media predisposes them to use internet compulsively, access objectionable content and also increases their vulnerability for getting bullied or abused (cooper, 2020; unicef, 2020b) . worst of all, during lockdown when schools, when legal and preventative services do not functioning fully, children are rarely in a position to report violence, abuse and harm if they themselves have abusive homes. there are about 1 in every 6 children within the age group of 2-8 years who have some or the other neurodevelopmental, behavioural or emotional difficulty (cdc, 2019). these children with special needs [autism, attention deficit hyperactivity disorder, cerebral palsy, learning disability, developmental delays and other behavioural and emotional difficulties] encounter challenges during the current pandemic and lockdown (cdc, 2019). they have intolerance for uncertainty and there is an aggravation in the symptoms due to the enforced restrictions and unfriendly environment which does not correspond with their regular routine. also, they face difficulties in following instructions, understanding the complexity of the pandemic situation and doing their own work independently. with the closure of special schools and day care centres these children lack access to resource material, peer group interactions and opportunities of learning and developing important social and behavioural skills in due time may lead to regression to the past behavior as they lose anchor in life, as a result of this their symptoms could relapse (lee, 2020). these conditions also trigger outburst of temper tantrums, and conflict between parents and adolescents. although prior to the pandemic, these children had been facing difficulties even while attending special schools, but in due course they had learnt to develop a schedule to adhere to for most of the time of the day (apa, 2020; cortese et al., 2020; unicef, 2020a). to cater to these challenges, it is difficult for parents to handle the challenged children and adolescents on their own, as they lack professional expertise and they mostly relied on schools and therapists to help them out (dalton et al., 2020). since every disorder is different, every child has different needs to be met. the children with autism find it very difficult to adapt to the changing environment. they become agitated and exasperated when anything is rearranged or shifted from its existing setup. they might show an increase in their behavioral problems and acts of self-harm. it is a huge challenge for parents to handle autistic children due to lockdown. the suspension of speech therapy and occupational therapy sessions could have a negative impact on their skill development and the achievement of the next milestone, as it is difficult for them to learn through online sessions (unicef, 2020a). the children with attention deficit hyperactivity disorder (adhd), struggle to make meaning of what is going around them from the cues they get from their caregivers. it is difficult for them to remain confined to a place and not to touch things, which might infect them. due to being confined to one place the chances of their hyperactivity increases along with heightened impulses and it becomes difficult for the caregivers to engage these children in meaningful activities (cortese et al., 2020). obsessive compulsive disorder (ocd) among the children and adolescents is estimated to be of 0.25%-4% among children and adolescents (cdc, 2019). children with ocd are suspected to be one of the most affected ones by this pandemic. due to obsessions and compulsions related to contamination, hoarding, and somatic preoccupation, they are expected to experience heightened distress. cleanliness is one key protective measure against the spread of covid-19. according to united nations' policy guidelines to fight the infection one has to be careful about washing their hands six times a day, and whenever they touch anything (apa, 2020; united nations, 2020). the lockdown, which has made the healthy population distressed about possessing enough food and prevention related resources like masks and sanitizers, has made it worse for people with hoarding disorder (apa, 2020; mukherjee et al., 2020) social inequality has been associated with the risk of developing mental health challenges. the pandemic and lockdown world has experienced global economic turn-down which has directly worsened the pre-existing social inequality. in developing countries, with the in order to cover up the loss of education during lockdown, many schools have offered distance learning or online courses to students. however, this opportunity is not available to underprivileged children as a result of which they face a lack of stimulation and have no access to online resource material to study. a study pointed out that in underprivileged families, in comparison to boys, girls have decreased access to gadgets, this may diminish their involvement in digital platforms of education (mcquillan & neill, 2009 ). due to this gender inequality, increasing number of girls are prone to bear the consequences of school dropouts once the lockdown is lifted (cooper, 2020; pti, 2020). covid with the objective of universal prevention and mental health promotion, the international it is imperative to plan strategies to enhance children and adolescent's access to mental health services during and after the current crisis. for this direct and digital collaborative network of various stakeholders is required. recommendations for ensuring mental well-being of children and adolescents during the covid-19 pandemic and lockdown and the role of parents, teachers, pediatricians, community volunteers, the health system and policy makers are being discussed. in addition a brief summary of the roles is given in table 2 . [ table 2 is uploaded seperately] in the times of paramount stress and uncertainty, a secure family environment which the parents can provide is a strong protective factor (schofield et al., 2013) . there is evidence to 5. efforts should be made so that a consistent routine is followed by the child, with enough opportunities to play, read, rest and engage in physical activity. it is recommended that family plays board games and engages in indoor sports activities with the child to avoid longer durations of video games. parents should ensure that particularly the bedtime of a child is consistent. it is possible that before the bed time children may need some more time and attention. 6. focus should be on the 'good behaviour' more than 'bad behaviour' of a child. parents must tell more about options regarding what to do rather than what not to do. provide more praise and social reinforcements to children compared to material reinforcements. 7. it is quite possible that parents observe some amount of change in the behavior in children during the times of a pandemic. if the behavior problems are minor and not harmful for children and others, parents should consider ignoring and stop paying attention to them, this may lead to decrease in the recurrence in behavior and would also help in giving space to each other. apart from areas discussed above, certain areas which need especial focus in the phase of adolescence, are being described below: 3. this is an opportunity for older children to learn responsibility, accountability, involvement, and collaboration. by taking some responsibilities at home on an everyday basis, for instance maintenance of their belongings and utility items. they can learn some of the skills including cooking, managing money matters, learning first aid, organizing their room, contributing to managing chores like laundry, cleaning and cooking. 4. excessive internet use e.g. internet surfing related to covid-19 should be avoided as it results in anxiety. similarly, excessive and irresponsible use of social media or internet gaming should be cautioned against. negotiations with adolescents to limit their time and internet-based activities are recommended. more non-gadget related in door activities and games are to be encouraged. 5. in such conditions taking up creative pursuits like art, music, dance and others can help to manage mental health and well-being for everyone. inculcating self-driven reading by making them select books of their choice and discussing about them helps in adolescent development. 6. adolescence is a phase of enthusiasm and risk-taking, hence some may feel invincible and try not to follow guidelines related to distancing and personal hygiene. this has to be addressed with adolescents assertively. 7. it is crucial to value the peer support system of the adolescents. parents should encourage adolescents who are introverts to keep in touch with their peers and communicate with them about their feelings and common problems they face. this may also lead a way for appropriate problem-solving. 8. it is advised to parents to take care of their own mental health needs and try to cope with stress adaptively. in the present times when most schools and colleges are organizing online academic activities, teachers are in regular touch with students, and therefore are in a position to play a critical role in the promotion of psychological well being among youngsters. their role during covid-19 pandemic and lockdown are as follows: 1. teachers can devote some time related to educating about covid-19 and preventive health behavior by using the guidelines of the international organizations, according to the maturity level of the students. they can explain to the students about the need to act with responsibility during the current pandemic. they can model and enact through their behavior the preventive measures. 3. they can conduct creative online academic and non-academic sessions by making their classes more interactive, engaging students in the form of quizzes, puzzles, small competitions, and giving more creative home assignments to break the monotony of the online classes. standard educational material can be used. for instance, unesco has offered many online educational sources (unesco, 2020) they can discuss what is wellbeing and how it is important for students. they can assist in teaching simple exercises, including deep breathing, muscle relaxation, distraction, and positive self -talk. virtual workshops can be conducted in which 'life skills' related to coping in stress can be in focus by using more practical examples. 5. teachers can make children understand the importance of prosocial behavior and the importance of human virtues like empathy and patience among others. this can help them to understand their role in the society and understand how social distancing is not equivalent to emotional distancing. 6. the teachers need to interact with parents online or through phone regarding feedback about students and their mental health. because of the digital divide they can call parents, make their contact available to parents and devote a time slot when they can be available to parents to communicate. 7. they can serve as a doorway for identification and referral to specialty mental health providers. they have a role act as a catalyst between the parent based on their interaction with students and findings of screening tools. if they observe any problem in the child, they can talk to parents and refer children and adolescents to mental health professionals. 8. with the support of school authorities, teachers need to make arrangements to ensure that the reading material related academics and life skills is made available to the underprivileged children who do not have access to the internet. if possible arrangements can be made for them to use internet. during a child's formative years when their personalities are shaped, parents are in regular touch with pediatricians, as parents reach out to their local pediatricians whenever they encounter health/ behavioral complaints associated with their children. parents expect answers from them as they trust them. hence a pediatrician's role is paramount in promoting ptsd, depression, substance abuse in adolescents should also be addressed on similar lines. there is a requirement for creative solutions, often on a case-by-case basis. 9. psychiatrists need to carefully weigh the risks and benefits of psychotropic medications for children and adolescents e.g. anti-depressants, anxiolytics, anticonvulsants, etc., and if possible, arranging medicines for those who cannot arrange. 10. there is a need for mental health care workers carry out longitudinal and developmental studies on short term and long term mental health impact of the covid 19 pandemic and lock down on children and adolescents. it has been recognized by the world that the traditional pre-covid-19 models and policies for children and adolescents' mental health are no longer applicable during covid 19 era. hence, the need is felt for the transformation of policies that can take into account not only lock down duration but also times following the lockdown. the following recommendations may be useful for guiding the functioning of the health system and policy making related to mental health care of children and adolescents : 1. the focus of the health care system should be prevention, promotion, and treatment according to the public mental health system to meet population-mental health needs of the general population at large. no single umbrella policy would be able to take into account various mental health aspects of children and adolescents dwelling in different environments. hence the health system and policies should be based on contextual parameters that are different for each country or region depending on the degree of infection and the phase of infection they are in. 3. since there is a dearth of mental health care workers in most developing countries. there is a need for inclusive approaches in which health care workers e.g. pediatricians, general physicians, schools, non-governmental organizations sectors are involved. moreover, brief basic mental health care training for these arms should be planned. 4. separate rules for the rural, suburban, and concrete domiciles in growing countries spotting the variance among college districts, which includes city, suburban, and rural districts. the studies included in the review were collected after setting criteria to have a comprehensive view of the global vision in managing the crisis of children in the covid-19 pandemic. the majority of the studies included in the review were based on online selfreports (bhat et al., 2020; jiao et al., 2020; oosterhoff et al., 2020b) . the adults and older children were the respondents of the study (lee, 2020; liu et al., 2020; viner et al., 2020b; wang et al., 2020 (wade et al., 2020) . the review articles for this review have been selected during the time of global lockdown, where the issues and challenges were new and the global crisis was at peak times. in our review, we were unable to track the measures of management targeted towards the children. the strategies reported in the studies were isolated to geopolitical conditions. the recommendations provided in this review can be modified to suit the needs of the places according to their local resources and geopolitical scenarios. due to strict selection criteria and the short period of data collection and the only use of electronic databases for our research, there is a possibility of missing studies relevant to the care of children and adolescents. although the rate of covid-19 infection among young children and adolescents is low the children who receive training, therapy, and other treatments are at high risk of being derailed from therapy and special educations. economically underprivileged children are particularly prone to exploitation and abuse. children quarantined are at high risk for developing higher risk for mental health-related challenges. there is a need to ameliorate children and adolescent's access to mental health services by using both face to face as well as digital platforms. for this collaborative network of parents, psychiatrists, psychologists, pediatricians, community volunteers, and ngos are required. there is a need for 'tele mental health compatibility' and be accessible to the public at large. this would be crucial to prevent during and post-pandemic mental challenges in the most vulnerable and underprivileged section of the society. the focal point of the health care system and policymaking should be prevention, promotion, and interventions corresponding to the public mental health system to meet the mental health needs of the population at large by taking the regional contextual parameters into account. disclosure of prior presentation of study data: this paper has not been submitted in full or part in any conference and is not being considered for publication elsewhere. creating material for community volunteers and ngos for identifying high risk children e.g. underprivileged children, children of migrants, provide psychological first aid, coordinating with care givers and mental health care professionals. quarantined parents/children parents if child is separated to keeping contact as much as possible, being supportive and reassuring coordinating with care givers, referring to mental health care professionals foster care givers being supportive, reassuring and educating constructing and administring online questionnaires in order to detect psychological distress and other symptoms for children if they or their parents are quarantined, providing extra support to them and developing ad hoc supportive interventions. impacts of covid-19 on vulnerable children in temporary accommodation in the uk. the lancet public health closure of universities due to coronavirus disease 2019 (covid-19): impact on education and mental health of students and academic staff professional foster carer and committed parent: role conflict and role enrichment at the interface between work and family in long-term foster care diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement children's mental health in times of economic recession: replication and extension of the family economic stress model in finland global population of children 2100 children with autism and covid-19 policy brief: the impact of covid-19 on children school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review. the lancet child & adolescent health school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review. the lancet child & adolescent health why we need longitudinal mental health research with children and youth during (and after) the covid-19 pandemic detection of sars-cov-2 in different types of clinical specimens healthy parenting who | covid-19: resources for adolescents and youth world health organization mental health care for international chinese students affected by the covid-19 outbreak the authors whose names are listed below certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants, participation in spakers' bureaus arrangements, consultancies, memberships, stock ownerships, or other equity interest, or expert testimony and patent licencing arangements) or non financial interests such as ( personal or professional relationships, affiliations, knowledge or beliefs)in the subject matter or materials discussed in this manuscript. all the authors confirm that, all of them has contributed in the conception of design; analysis, interpretation of data; drafting the article; critically revisiting the article for important intellectual inputs; and approval of the final version. this paper has not been submitted elsewhere or is under review at another journal or publishing venue. the authors have no affiliation with any organization, with a direct or indirect financial interest in the subject matter discussed in the manuscript. authorities to be more transparent in their negotiations and to allow candidates sufficient notice to prepare emotionally as well. students to be timely provided counselling. key: cord-333479-d0mgma42 authors: duan, li; shao, xiaojun; wang, yuan; huang, yinglin; miao, junxiao; yang, xueping; zhu, gang title: an investigation of mental health status of children and adolescents in china during the outbreak of covid-19 date: 2020-07-02 journal: j affect disord doi: 10.1016/j.jad.2020.06.029 sha: doc_id: 333479 cord_uid: d0mgma42 objective: : the sudden outbreak of coronavirus disease 2019 (covid-19) has had a dramatic effect on the mental health of the public. in the present study, we demonstrated the psychological effects on children and adolescents associated with the epidemic . methods: : by using convenience sampling method, questionnaires, such as spence child anxiety scale, child depression inventory and coping style scale, were distributed to participating 359 children and 3254 adolescents online. results: : the anxiety levels of children and adolescents were (23.87±15.79) and (29.27±19.79), respectively. 22.28% respondents were suffering from depressive symptoms. seven significant factors associated with increased levels of anxiety, including female, resident in urban regions, emotion-focused coping style. nine factors associated with increased levels of depression, such as smartphone addiction (or 1.411, 95% ci 1.099–1.180), internet addiction (or 1.844, 95% ci 1.209–2.811), and resident in hubei province (or 3.107, 95% ci 1.252–7.708). two additional factors associated with decreased levels of depressive symptoms: hours spend on internet per day before the epidemic (or 0.652, 95% ci 0.609–0.697) and tendency to apply problem-focused coping style (or 0.937, 95% ci 0.923–0.951). conclusion: : our findings indicate that the covid-19 outbreak has had a significant psychosocial impact on children and adolescents. findings of current levels of anxiety and depression not only highlight the need to address emotional distress for children and adolescents during the epidemic but also provide researchers with scientific fundamentals to formulate targeted interventions based on the significant influencing factors. since the outbreak of the covid-19 at the end of 2019, a series of effective epidemic preventive and control strategies have been developed and conducted by the chinese government to curb the spread of the virus. the general public, especially the high-risk group (e.g., elderly people with chronic underlying diseases, children, and others with lower immunologic function), are suggested to stay indoors in quarantine at home, which is recognized as the best way to eliminate chances of being infected. however, due to the long period of separation from the outside world, the impact of multi-channel negative information, excessive fears of being infected, and even the shame and guilt for the infection, many people across china, particularly residents at the epicenter of the outbreak in wuhan, are experiencing fear, loneliness, panic, anxiety and depression amid the coronavirus outbreak (duan and zhu, 2020; xiang et al., 2020) . these negative physical and psychological costs have also been reported in previous studies, such as suicide, substantial anger and sleep disorders (barbisch et al., 2015; rubin and wessely, 2020; wang et al., 2019) . for children and adolescents, due to the lower incidence of infection and mortality than adults, professionals were less focusing on the unique clinical features of covid-19 and mental health status in children (ma et al., 2020) . furthermore, evidence has shown that children and adolescents who experienced disasters might suffer from greater stress and trauma because of the lack of development of proper emotional reactions and coping techniques (lazarus pj, 2003; roussos et al., 2005) . when emotional support and spiritual guidance from family members, teachers, as well as other significant peers and adults in their lives could not be met due to home confinement, deferred back-to-school and lifestyle changes, it adversely affected the mental health of children and adolescents (sprang and silman, 2013) . additionally, according to the latest data from the china's national health of commission, the overall situation in the chinese mainland is somewhat coming to a plateau ( national health commission of china, 2020) . the number of new confirmed cases has dropped dramatically, but authorities are warning that strict prevention measures should stay in place to prepare for a potential comeback of the virus. therefore, in order to effectively cooperate with the government's epidemic prevention work, more than 220 million children and adolescents were confined at home and informed to postpone the start of the spring semester until further notice (wang et al., 2020) . meanwhile, online studying courses which was delivered by tv broadcasts and the internet have been opened gradually to students to guarantee their needs of learning, according to a guideline released by the china's ministry of education (ministry of education of china, 2020) . however, due to lack of monitoring and evaluation of students participating in online courses, the inefficiency of the experience of these courses, unstable network signals, and often no networks in remote rural areas, many parents, students, and teachers have complained of the poor effectiveness of online learning. these effects can be compacted by adverse consequences of reduced vision, as well as unconscious smartphone/internet addiction, and may further contribute to mental distress in children and adolescents. here, we assessed the current status of mental health issues among children and adolescents affected by the epidemic and analyzed its influencing factors to provide scientific guidance to psychological professionals and the government in formulating targeted policies. this study was designed as a cross-sectional online questionnaire survey that was administered during the spread of covid-19 in china. we developed the online questionnaires on the official website of "questionnaire star," which is recognized as a professional online questionnaire survey, evaluation, and voting platform. a set of self-rating questionnaires were distributed to children and adolescents who ranged from grade one in primary school to grade three in high school (aged from 7 to 18 years) in mainland china by employing convenient sampling method. with the help of directors in education bureau, we distribute e-questionnaires to teachers and told them the purpose, significance and announcements of this survey in details. then, they assigned it to school-students and their guardians. before completing questionnaires, all participants and their guardians were debriefed on the study purpose and contents. once consented, participants began filling out the set of questionnaires online. we also included our email addresses and phone number to the first page of questionnaires so that participants could consult and interact with us at any time. the set of questionnaires involved in this study were mainly composed of seven sections. -sociodemographic characteristics were self-designed and included questions regarding sex, age, place of residence, number of siblings, region, family status, education level, and number of electronics owned. -covid-related questions were developed by our research team and assessed the current situation of the respondents' family members involved in anti-epidemic work, the degree of concerns about the epidemic, the implementation of the precaution and control measures, the impact of the epidemic on their course of study and graduation, as well as the electronic products/internet use patterns before and during the epidemic. -the chinese version of spence child anxiety scale (scas) is a 44-item self-report likert's scale that measures anxiety in children and adolescents (zhao et al., 2012) . spence (spence, 1997) first developed it by using community samples, and it has since been used widely in other countries (essau et al., 2011) . this study evaluated the anxiety status of participants affected by the epidemic on a 6-factor scale, including items such as separation anxiety, physical injury fear, social phobia, panic disorder, obsessive disorder, and generalized anxiety. -the child depression inventory (cdi) is a 27-item self-report measure designed to evaluate the severity of depressive symptoms in children and adolescents (kovacs & beck, 1977) and has demonstrated satisfactory levels of reliability and validity in the chinese population (wang et al., 2015) . in general, the total score of cdi is 19 or higher can be identified as possessing clinical depressive symptoms, while scores of 12-18 indicate subclinical depression, and scores of 12 or lower are considered normal (stewart and sun, 2007) . in this study, we classified respondents with clinical depressive symptoms with scores 19 or higher. -the short version of smartphone addiction scale (sv-sas) is a 10-item self-rated developed by kwon et al. 2013 (kwon et al., 2013 and is recognized as a valid screening tool for the prevalence of smartphone addiction. it uses cut-off points by sex, where 31 and 33 classify "excessive smartphone uses in male and female users," respectively. -the internet addiction scale (ias) consists of 20 items derived from the dsm-iv-tr (cooper, 2001) [diagnostic and statistical manual of mental disorders (4th edition, text revised)] in order to identify diagnostic criteria of pathological gambling and the degree of preoccupation and compulsiveness to go online. according to young (young, 1998) , three types of internet-user groups were identified as internet addicts (scores of 70 or higher), possible internet addicts (scores 40-69), and non-addict (39 or lower). in this study, we defined participants with internet addiction with scores 70 or higher. -the coping style scale (css) was developed by chen et al. in 2000 based on the theory of social interaction and self-regulation and measures middle school students' competence in coping with stress (chen sl et al., 2000; folkman et al., 1986 ). this 36-item self-rate scale can be divided into two subscales of problem-focused coping and emotion-focused coping. the former consists of three dimensions, including solving problems, seeking social support, and positive rationalizations, while the later contains four dimensions, including endurance, avoidance, expressing emotions, and fantasy/denial. all data were analyzed using spss (version 18.0, spss inc., chicago). apart from descriptive statistics and frequency analysis of demographic characteristics and covid-related information, t test and analysis of variance (anova) were used to analyze the difference in levels of respondents' anxiety. moreover, multiple linear regression and bivariate logistic regression analyses were used to assess the association between outcome variables (the reported level of anxiety and clinical depressive symptom) and potential predictors (e.g. concerns related to the epidemic, smartphone/internet addiction, and coping style) while adjusting for other identified explanatory variables. in the process of running models, the forward stepwise selection algorithm was used, and variables in the model were screened based on significance levels of the wald inclusion test statistic being less than 0.05. moreover, pearson's correlation analysis was performed to analyze the associations among scas, cdi, smartphone/internet addiction, and coping style, and the statistical significance level was set at 0.05. the sample size of our survey recruited online included 3,613 chinese students. as table 1 shows, the study participants comprised 1,812 males (50.15%) and 1,801 females (49.85%) collected from 20 provinces in mainland china. however, considering that hubei is the hardest-hit place of this epidemic, we classified the sample sources by residential areas, namely 27 (0.75%) in hubei province and 3,586 (99.25%) from other regions. respondents were mainly from nuclear families (68.56%), extended families (24.08%), and single-parent families (5.45%). the sample comprised children aged 7-12 years (9.94%) and adolescents aged 13-18 years (90.06%) and who were in primary school (6.03%), secondary school (55.43%), or high school (38.54%). among them, 54 (1.49%) and 18 (0.51%) who failed the high school/college entrance examination and had to return to secondary/high school again for resuming their study, respectively. additionally, there were 128 (4.01%) respondents who already had electronics before 7-year-old. furthermore, an in-depth analysis of 3,183 respondents who possessed electronic devices showed that the average age at which they started owning electronic devices was 12.14±2.66 years, and the highest rate of smartphone penetration was 90.76% (2889/3183), followed by computer 30.19% (961/3,183) and tablets 26.99% (859/3,183). after analyzing the information related to the epidemic (table 2) , 173 (4.71%) respondents reported that their family members were involved in the anti-epidemic work, and 49 (28.32%) of them were health care professionals (e.g., frontline doctors and nurses). a total of 20 (0.55%) of the participants stated that their family members, friends, or other acquaintances had been infected with coronavirus. in all, 91.06% of respondents clearly reported concerns about this epidemic, and almost the same proportion (93.86%) reported that they have strictly implemented protective measures (e.g., wear mask, wash hands, or avoid public places and crowds). moreover, 1,976 (54.69%) and 1,288 (35.65%) participants reported that the epidemic has affected their learning and graduation, respectively. average time per day spent on internet during the epidemic was also much longer than before, whereas study, as the main reason for internet use, became more significant during the epidemic. after conducting surveys on the willingness to engage in medicine in the future, we found that more people (18.74%) were determined to work in healthcare than those (7.67%) who were a little uncertain after the outbreak. among all respondents, 805 (22.28%) and 218 (6.03%) of them had scores above the threshold for clinical depressive symptoms (19 or higher) and internet addiction (70 or higher). as for sas, due to the gender differences in cutoff values for smartphone addiction, it was found that the prevalence rates of smartphone addiction in male and female respondents were 10.30% and 13.06%, respectively (table 2) . additionally, as shown in table 4 , we analyzed the current situation of the respondents' anxiety level and coping style by variables of gender and age, and the results showed that the anxiety levels of adolescents were significantly higher than those of children (f=62.07, p<0.01), and the total scores of scas for females were significantly higher than those of males (f=10.59, p<0.01). the anxiety levels of males and females in each group of children and adolescents are listed in table 3 . in table 4 , results of anova and t test analyses showed that there were 18 variables had significant difference in scas scores (levels of anxiety) (p<0.05). additionally, in order to further analyze the significant factors associated with the level of respondent' anxiety, we conducted multiple linear regression analysis and obtained the following factors to construct a multiple linear regression model of anxiety: clinical depression levels, implementation of the precaution and control measures, sex, family member or friend was infected with coronavirus, occupation of the mother involved in the epidemic, region (e.g., rural, urban), and emotion-focused coping style, which accounted for 31.0% of the total variance ( table 5) . (table 7) . anxiety symptoms are the most common clinical diagnoses in children and adolescents and can act as a significant risk factor for contributing to other psychiatric disorders in adulthood. moreover, it may worsen by facing the increasingly complex social milieu, and being a cause of impairments in various life domains and can increase societal costs for families (bodden et al., 2008; essau et al., 2008) . similarly, clinical depressive symptoms in children and adolescents are common and recurrent diseases associated with memory impairments (günther et al., 2004) , poor interpersonal relationships (lam et al., 2003) , and even high-risk suicidal behaviors (yorbik et al., 2015) . with the sudden outbreak and rapid spread of covid-19 at the end of 2019, the mental health of children and adolescents in china has been put at risk. according to the results of our investigation, we found that levels of anxiety in children and adolescents during the epidemic were much higher than before (zhao et al., 2012) . as shown in table 3 , the overall scores of five dimensions (including separation anxiety, physical injury fear, social phobia, panic disorder, and generalized anxiety) were higher than before the outbreak, especially the fears of physical injury in children and social phobia in adolescents. this finding may be due to the fact that at the initial stage of the outbreak, protective and therapeutic responses were not yet in place, and the surge in the number of confirmed cases and deaths led children to become excessively concerned about physical damage to themselves and their family caused by exposure to coronavirus. in addition, dong et al. (dong et al., 1994) reported that chinese adolescents demonstrated higher levels of social-evaluative fears than adolescents in western countries. moreover, negative reports on domestic and foreign social media regarding covid-related discrimination and unfair treatment of chinese people, as well as rumors and misinformation around origins of the infectious disease may be an important reason for worsening their social phobia and other mental disorders (calisher et al., 2020) .. the findings were in line with previous research indicating that anxiety, depression, and feelings of helplessness can be worsened by sars-related social discrimination in public places (zheng et al., 2005) . having a family member or friend infected with coronavirus was also significantly associated with increases in anxiety levels. this may be due to the fact that respondents are concerned about the health of the infected and simultaneously afraid of being a suspected or confirmed case, given their level of direct contact. we suggest that the increased awareness of infection control in respondents is consistent with their psychological state of anxiety, thereby reducing the risk of infection. in traditional chinese culture, fathers often assume the role of breadwinners, while mothers tend to perform the bulk of housework and childcare and have more emotional interaction with their children (lee, 2002) . this appeared to be an important factor affecting the anxiety level of the respondents, who believed that if their mother was not medical staff, this exposed them to insufficient and non-standardized protections, as well as a weaker social support network within their mothers' work environment. given that the outbreak originated in a highly dense urban area, and there have been subsequently many more deaths in this area, it could be the case that anxiety levels of urban residents are higher than those of rural areas. significant sex differences in anxiety levels have been reported in many studies (essau et al., 2008; li et al., 2008) , potentially resulting in women being more sensitive to the stressful events of covid-19 and correspondingly expressing stronger concerns and fears. this study also revealed that the prevalence of clinical depression symptoms in children and adolescents was 22.28% during the covid-19 outbreak, which was much higher than the generally estimated 13.2% (stewart and sun, 2007) in china and 2%-6% (phillips et al., 1999) in western countries. results of regression analysis (table 6 ) and pearson's correlation analysis (table 7) showed that levels of clinical depression symptoms were significantly associated with anxiety. evidence has shown that anxiety disorders and depression demonstrate higher overlap in symptomatology, clinical instability, and treatment (lonigan et al., 1994) . it has been estimated that roughly 25%-50% of depressed youth display comorbid anxiety disorders and about 10%-15% of anxious youth have depression (axelson & birmaher, 2001) . this suggests that attention should be paid to the proper medication and psychological interventions. due to the significant number of confirmed patients, as well as the relative shortage of medical resources and first-line medical staff, the rate of mortality in hubei province is higher (4.9%) than the national mortality rate (2.1%) (national health commission of china, 2020). moreover, a series of effective prevention and control measures (e.g., cities on lockdown, traffic controls, postponed semesters) in wuhan (the capital of hubei province) were implemented more strictly and lasted longer than other regions, leading to the interviewed children and adolescents experiencing greater isolation and for a longer period of time. these factors may explain why living in residential areas was a significant factor affecting depression levels of the respondents. moreover, we also found that students' graduation being affected by the epidemic was significantly associated with increases in depression. chinese students may be particularly academically motivated, particularly in successfully completing entrance examinations (essau et al., 2008 ) that will determine the quality of higher education and job prospects. given the current state of the epidemic however, students are taking classes online at home, which may have controversial results due to poor efficiency in managing online courses, visual impairment in students, and instability in internet signals. during the epidemic, 29.58% respondents reported that they spent more than five hours per day online, which could be a potential risk factor for addiction to the internet or smartphones. studies have shown that smartphone/internet overuse may lead to mental or behavioral problems, causing poor performance in study, decreased real-life social interaction, neglecting personal life, relationship disorders, and mood dysfunction (kahraman and demirci, 2018; soni et al., 2017) . psychopathological screening studies on internet addicts have shown that anxiety disorders are the most common diagnoses in this group (liu et al., 2011) , and adverse consequences in sleep disturbances/decreased sleep quality caused by electronic media use at night have been shown to be significantly associated with depressive symptoms (lemola et al., 2015) . in contrast, we observed that respondents spend much less time online pre-outbreak than they did during the outbreak (table 2) , which can also explain the significant correlation between the average time per day spend on internet before the epidemic was significantly associated with the decrease of levels of depressive symptoms. review of the literature has revealed that stress-coping theory posits a broad framework of problem-focused and emotion-focused coping strategies (herman and tetrick, 2009 ). problem-focused strategies tend to concentrate efforts towards fixing a stressful problem, while emotion-focused strategies concentrate on minimizing the emotional outcomes of the problem using strategies such as endurance, avoidance, or venting to someone else. it has been reported that greater degrees of ruminative coping instead of actively seeking for solutions were related to high levels of depressive symptoms, while problem-focused and distractive coping style was negatively associated with depression (li et al., 2006) . we also observed that a problem-focused coping style was closely related to decrease in clinical depression, while an emotion-focused coping style was negatively associated with the increase in depression. this study investigated the mental health status of children and adolescents in mainland china during the epidemic of covid-19. specifically, we examined anxiety and depression and investigated the related influencing factors. the findings of this study not only remind researchers and government officials should be more concerned about the mental health of children and adolescents who are often neglected in the wake of the outbreak due to their comparatively lower mortality than elderly adults, but also provide a scientific basis for the formulation of targeted psychological interventions. this study also has several limitations. first, data collection was completed by distributing questionnaires to children and adolescents online. the results and conclusions may be influenced by the degree of understanding and cooperation of the respondents, especially the younger children who need help of their guardians. second, the stylized answer forms of those questionnaires are convenience for statistics, but it limits the response of subjects and let them fail to express their subjective views on relevant issues. third, due to the fact that the epidemic situation in hubei was not fully controlled during the investigation period, it was difficult to collect data and the sample size was relatively small in this region, which limited the applicability and generalization of the results. therefore, in follow-up studies, we plan to increase the sample size (especially in hubei and other hard-hit regions), employ face-to-face surveys, qualitative interview methods, follow-up studies, and collect responses from primary guardians so as to further improve the study design and the scientific nature of the results. the authors have no conflicts of interest to disclose. no conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. i would like to declare on behalf of my co-authors that the work described was original research that has not been published previously. 'repeated' represents students failed the high school/college entrance examination and had to return to secondary/high school again for resuming their study, while 'fresh' means students have not yet taken the above-mentioned examinations. stepwise selection procedure was employed to select the model from levels of depression, smartphone/internet addiction and subscales of coping style scale, as well as variables listed in table 4 which had statistical difference in levels of anxiety (total scores of scas). table 2 (contents of the covid-related information), as well as levels of anxiety and its six dimensions, smartphone/internet addiction, and subscales of coping style scale. abbreviation: na, not applicable. relation between anxiety and depressive disorders in childhood and adolescence is there a case for quarantine? perspectives from sars to ebola societal burden of clinically anxious youth referred for treatment: a cost-of-illness study the psychological impact of quarantine and 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outbreak on chinese students living in japan key: cord-310677-begnpodw authors: yeasmin, sabina; banik, rajon; hossain, sorif; hossain, md. nazmul; mahumud, raju; salma, nahid; hossain, md. moyazzem title: impact of covid-19 pandemic on the mental health of children in bangladesh: a cross-sectional study date: 2020-07-29 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105277 sha: doc_id: 310677 cord_uid: begnpodw covid-19 pandemic poses a significant mental health threat among children in bangladesh. this study aims to explore the impact of covid-19 on the mental health of children aged<15 years during the lockdown in bangladesh. an online cross-sectional study was conducted from 25th april to 9th may 2020 among 384 parents having at least one child aged less than 15 years using non-probability sampling. k-means clustering used to group children according to mental health score and confirmatory factor analysis (cfa) performed to identify the relationship among the parental behavior and child mental health, and also these associations were assessed through chi-square test. children were classified into four groups where 43% of child had subthreshold mental disturbances (mean major depressive disorder (mdd)-10; 2.8), 30.5% had mild (mean mdd-10; 8.9), 19.3% suffered moderately (mean mdd-10; 15.9), and 7.2% of child suffered from severe disturbances (mean mdd-10; 25.2). the higher percentage of mental health disturbances of children with the higher education level of parents, relative infected by covid-19 (yes), parents still need to go the workplace (yes), and parent’s abnormal behavior but lower to their counterparts. this paper demonstrates large proportions of children are suffering from mental health disturbances in bangladesh during the period of lockdown. implementation of psychological intervention strategies and improvement in house-hold financial conditions, literacy of parents, taking care of children, and job security may help in improving the psychological/mental status of children and the authors believe that the findings will be beneficial to accelerate the rate of achieving the sustainable development goal (sdg) linked to health status in bangladesh. the outbreak of novel coronavirus disease 2019 has emerged in china, which rapidly spread the oddment of the world, and who declared it as a pandemic . the pandemic has been escalating and threatening the welfare of human beings globally and already transmitted to more than 14 million people around the globe with at least 5,97583 deaths as of july 19, 2020 (world health organization, 2020a . to halt the covid-19 transmission and cease the burden on health systems all most all of the countries have brought unprecedented efforts to institute the practice of "social distancing", as a result, many schools have been closed (lancker & parolin, 2020) and classes are shifted to home-based distance-learning models (golberstein et al., 2020) . children are not beyond the grasp of this pandemic, and also the most vulnerable to the drastic effects of it, as they are forced to stay home for extended periods due to lockdown and school closure, resulting in minimal interaction with peers and decreased the opportunities for exploration and physical activities (jiao et al., 2020) . all of these adversely impact children's mental health and welfare, leading to a wide variety of mental health issues, such as anxiety, stress, depression, and sleeping difficulties (dunleavy, 2020; galvin, 2020; rawstrone, 2020) . to prevent the outbreak of covid-19, bangladesh have been closed the academic institutions, therefore, about 3.7 million students and more than a million teachers are staying at home . although the scientific controversy is unremitting concerning the effectiveness of school closures on virus transmission (lancker & parolin, 2020) . schools play an emergent role, not just in supplying educational resources to children, but also in offering students an opportunity to communicate with teachers and receive psychological counseling (brazendale et al., 2017) . moreover, evidence shows that whenever children are beyond schooling (e.g. weekends and summer payday's), they become physically less active, have much-prolonged screen time, irregular sleep schedules and less healthy diets, resulted in excess weight and lack of cardiorespiratory performance (brazendale et al., 2017) . furthermore, pandemic stressors such as terror of infection, dissatisfaction and boredom, lack of knowledge, lack of personal space at home, and family's financial loss may have even more troublesome and enduring impacts on children mental health (brooks et al., 2020) . to assess the impact of home quarantine on children's mental health, a study was performed among 1,800 chinese children and identified that one in five children (20 percent) in china was either suffering from depression or anxiety, or both (dunleavy, 2020) . also, mental health issues remain fairly elevated among u.s. children due to the covid-19 pandemic. according to the centers for disease control and prevention, 4.4 million children between the ages of 3 to 17 years have been diagnosed with anxiety and 1.9 million have been identified with depression because of home quarantine due to . moreover, about three in four children having depression along with anxiety (galvin, 2020) . the effect of the covid-19 pandemic on children's mental well-being is worrying 60% of parents, according to a survey by parents with primary-aged children and 87% reported that their children were missing school and less than half stated that their children were feeling lonely, which altogether affects their children's mental health and wellbeing (rawstrone, 2020) . in bangladesh, as the number of covid-19 cases continues to rise thus an immediate public health response is urgently needed (banik et al., 2020) . consequently, the government of bangladesh enforced full lockdown and all schools were closed from may 17, 2020 (kamruzzaman & sakib, 2020) , which negatively impact children's wellbeing through interruption of their health care, nutrition, security, education, and overall mental health (joining force bangladesh, 2020). yet, there is no literature available in bangladesh on the long-term impact of covid-19 pandemic on children's mental health. thus, it becomes important to determine how extended school closures, stringent social distancing steps and the pandemic itself have impacts on the mental health status of children. therefore, this study aimed to investigate the impact of the covid-19 pandemic on mental health and determining the associated factors among children of bangladesh. this study was conducted among parents having children in bangladesh through an online survey between 25 th april to 9 th may, 2020 after completing 30 days of home-quarantine following lockdown declaration on 26th march 2020 by the government of bangladesh (world health organization, 2020b). here, non-probability sampling (purposive sampling) techniques were used to collect the primary data from participants. firstly, parents who had at least one child aged between 5-15 years, known to the researchers by their facebook friends were invited to complete the survey by filling the questionnaire. we have calculated the sample size using the following where, we considered z = 1.96 and d = 0.05 confidence interval as 0.05. the sample proportion was assumed as 0.5 since this value provide the maximum sample size. hence, the required sample size was 384. however, a total of 387 respondents completed the survey and after cleaning the incomplete responses 384 participants were taken for final analysis. the primary data was collected via an online questionnaire as the face-to-face interview had to be avoided due to ongoing lockdown. the questionnaire was pilot-tested in a sample of 40 subjects before the final study initiation. we sent the link of designed google form to the parents randomly and the inclusion criteria were having at least one child aged between 5-15 years. the questionnaire consisting of several parts such as (i) socio-demographic information (age, sex, educational level, place of living, number of earning members in the family, average monthly family income, knowledge about covid-19, and any family member/relatives/neighbor of the respondent was corona positive or not), (ii) financial and lifestyle information of parents, (iii) information related to child's activity and attitude of parents toward child and (iv) mental health related information of child. participants were given no economic motivation, and anonymity was maintained to make sure data confidentiality. first of all, asking the consent of participating in the survey and it was also notified that at any time, participants could revoke from the survey without giving any justification. this study was carried out online in full conformity with the provisions of the helsinki declaration on human participant research. the 47-item revised child anxiety and depression scale (rcads) (chorpita et al., 2000) includes the 10-item depression total scale in order to measure children's major depressive disorder (i.e., the child feels sad or empty, nothing is much fun, trouble in sleeping, problems with appetite, no energy for things, tired a lot, cannot think, feels worthless, doesn't want to move, & feels restless). children's anxiety was assessed by the generalized anxiety disorder (gad) scale with the help of spence child anxiety scale for parents (scas-p) (nauta et al., 2004) . also, gad6 is a 6-item questionnaire (e.g. my child worries about things, complains of having a funny feeling in his/her stomach, complains of feeling afraid, heart beating fast, child worries that something bad will happen, & feels shaky). parent-reported child behavior checklist (cbcl) (achenbach & edelbrock, 1983) , a questionnaire to assess children's behavior/emotional problems at ages of 5-15 years. a "sleep problem scale" was ascertained by six items from the cbcl ("experiences nightmares," "sleeps less than most children," "sleeps more than most children," "talks or walks in sleep," "trouble sleeping," and "overtired"). the mdd-10 and gad-6 scales are evaluated at 4-points (0=never, 1= once in a week, 2= 2-4 times in a week, & 3= everyday) which gives a total score of 0 to 30 and 0 to 18 respectively. moreover, sds-6 used a 3-point scale (0=not true; 1=sometimes true; 2=very true/often true) which gives a total score of 0 to 12. the higher scores indicate higher level of depression, anxiety, and sleeping disorder. the acceptable reliability test was performed and the value of cronbach alpha was 0.814 which is more than the acceptable value of 0.70. firstly, descriptive statistics were performed to describe the basic demographic characteristics of the respondents. secondly, k-means clustering analysis was applied to cluster depression, anxiety, and sleeping disorder scores (kang et al., 2020 ) of a child. the chi-square test was used to measure the association of socio-demographic variables, parental behavior towards children, and child mental health scores among the cluster. thirdly, a confirmatory factor analysis (cfa) was constructed to explore the components associated with child mental health. finally, a structural model was developed using the identified components of child mental health (hu & bentler, 1998) . the significance level is set at a p-value<0.05 here. data analysis is performed using ibm spss among the participants, there are 157 (40.9%) female and 227 (59.1%) male respondents. the majority of the participants tended to be aged 36-45 years (46.6%), had an educational level of post-graduation (35.4%), and lived in the urban areas (63.3%). a total of 56.3% of the respondents were involved in a job during the lockdown, where 25.3% of participants needed to go to the table 1 ]. [ table 1 here] the depression, anxiety, and sleeping disorder scores of children were classified into 4 groups (sub-threshold, mild, moderate, and severe disturbance) using k-means clustering. results depict that 43% of child had subthreshold mental health disturbances (mean depression: 2.8, anxiety: 2, and sleeping disorder: 1), 30.5% had mild disturbances (mean depression: 8.9, anxiety: 4.9, and sleeping disorder: 3), 19.3% suffered from moderate disturbances (mean depression:15.9, anxiety: 9.2, and sleeping: 6), and 7.2% suffered from severe disturbances (mean depression: 25.2, anxiety: 13.4, and sleeping disorder: 8). significant differences found in the depression, anxiety, and sleeping disorder scores of the child among the four groups using the chi-square test, as shown in table 2 . [ table 2 here] the chi-square test was used to find significant differences in several characteristics among the four groups. results reported that there were no significant differences in sex and age of the parents among the four groups. but significant differences found in the educational level of parents, place of living, any relative/neighbor of child having status positive or not by corona virus among the four groups. in the severe disturbance group, most of the child's parents were graduated 8 family lived in the urban areas (63.3%). the child had higher mental health disturbance scores who had higher corona positive relative/ neighbor [ table 3 ]. [ table 3 here] the result also showed that there was a significant difference in parents needed to go to the workplace or not, any chance of losing the job, and did smoke or not among the four groups. higher the number of parents of the child needed to go to the workplace (25%), had a smoking habit (35.7%) and had the chance of losing their job (28.6%) higher the score of depression, anxiety, and sleeping disorder of child. the score was also found higher for the child who fights frequently with each other, child who watched the cartoon and played the game 2-4 hours using a smartphone or other electronic device in a day, child whose parents didn't take any action to keep them busy, child who complained their parents remained busy, child whose parents called them by name that they (children) didn't like, child whose parents threatened them to be punished, child whose parents screamed and hit them (child) during the home-quarantine period [ table 3 ]. the average score of depression, anxiety and sleeping disorder by different groups are presented in figure 1 and it can be seen that the average score of depression, anxiety, and sleeping disorder of child is increased gradually from subthreshold disturbance group to sever disturbance group [ figure coefficients may also be interpreted. [ figure 1 here] the chi-square test of the model fit yielded a value of 151.890, with degrees of freedom=84, p-value< . the results of chi-square test, rmsea = 0.046, cfi = 0.954, and tli= 0.942 0.001 signaling that the model is well-fitted to data and hence, it is concluded that the assumed model is correct. the results disclosed that the child mental health is affected by the parental mental health as well as parents' attitudes towards child. the results are presented in figure 2 and table 4 . [ table 4 here] [ figure 2 here] mental health is an essential part of any country and ignored particularly in low and middle-income countries (patel, 2007) . bangladesh is a relatively small country according to area however having huge population with inadequate mental health care facilities for children and most hospitals use outpatient services. the largest part of the respondents was aged between 26 to 45 years and most of them were living in the urban areas and majorities are males ( table 1 ). in this study, children's mental health (depression, anxiety, and sleeping disorder) scores were classified into four groups: sub-threshold, mild, moderate, and severe disturbance. the highest percentage of children are suffering from sub-threshold disturbance (43%), and 30.5% had mild disturbances, 19.3% had moderate disturbances, and 7.2% had severe disturbances ( table 2 ). the education level of parents of children, place of living, relatives/neighbors infected with covid-19, still need to go to the workplace of parents, the chance of losing jobs of parents, the smoking habit of parents, hours watching the cartoon by children, children playing games, child fight, keeping busy with other works, acting of the child, children complain about parent's busyness, parent's abnormal behavior to children (call dumb, threat, scream, hit the child), and parent's knowledge about child abuse were significantly associated with children mental status ( table 3) . children who live in urban areas with their parents were more prone to suffer mental healthrelated problems as compared to the rural area's child. perhaps the reason behind this scenario is that the lockdown was perfectly maintained in urban areas and children were forced to stay home anyway (the business standard, 2020). on the contrary, children in rural areas are free to move and can play with their relatives/friends (ranscombe, 2020) . children brought up in a rural environment, encompassed by animals and bacteria, grow stronger immune systems and might be at minor risk of mental illness than without pet-city inhabitants, as indicated in a study (hindustan times, 2020). usually, educated parents remain busy with their jobs as compared to uneducated ones even during this lockdown period in bangladesh, especially the government officials . as a result, they cannot manage time to communicate with their children as they demand. a bunch of social and personal adjustments is necessary to cope with this situation (poduval & poduval, 2009 ). if the work time of mother is longer, then the risks of children who are matured from one to five tended to increase child risks of experiencing psychological distress tended to increase the child risks of experiencing psychological distress as a young adult. the findings of this paper are also congruent with a previous study (poduval & poduval, 2009 ). parents who want to income more or who have higher family income need to give more time to their jobs or company even if they feel pressure to manage the company's activities like workers' activity, managerial team activity, and so on (mendez et al., 2004) . a longer period of part-time job mothers reduced the children's educational attainment and increase their child's mental distress but this effect was lower as compared to full-time employment mothers (saha et al., 2019) . in our study, it is also found that the children of higher-income parents are more likely to have mental disorders than others. parents who still need to go to the workplace and have a chance of losing jobs tended to increase the level of mental disorders of their children whereas it decreases for their counterparts. besides, parents whose feelings bored were tended to be more mental disturbances of their children as compared to their counterparts ( table 3 ). the pressure that guardians bring home from their occupations can diminish their child-rearing abilities, sabotage the climate in the home, and in this way bring worry into kids' lives. moreover, children also feel pressure from their parents and becoming mentally sick (heinrich, 2014) . unfortunately, low-income parents are most apparent to work in stressful, lowquality jobs that prominence low pay, little autonomy, inflexible hours, and few or no benefits (heinrich, 2014) . it is well known that there is a strong association between a parent's smoking habits and child development behavior. since cigarette smoking is additionally connected with sadness, there are numerous unanswered inquiries regarding the interrelationship of these mental issues of children (shimomura et al., 2020) . the findings of this study also showed that parental depression and smoking behavior also linked to child mental disorder ( table 3) . the children's mental depression was relatively low who was busy with some works as compared to who was not ( table 3) , which is very usual. engaging with some works or encouraging daily exercise will help children to reduce depression (hurley, 2020) . children, who fight with others and get threats, scream and hit from their parents were much mentally disordered and increased severe mental disturbances as compared to their counterparts. because paternal and maternal behavior have an adjustment to children's mental health (elgar et al., 2007) . parents who threats, scream, or hit to their children are depressive and these depressive symptoms of parents and emotional behavior affect the child's mental health (gutierrez-galve et al., 2015) . again, children who act normal were in less mental disturbances as compared to others where the percentage increased gradually from less mental disturbances to severe mental disturbances. because if the children's sadness becomes interferes with social activities or regular life, it indicates that he or she has a depressive illness (lima et al., 2013) . this research has some limitations. firstly, considering health threats, a face-to-face interview was avoided whereas compared to face-to-face interviews, self-reporting has certain limitations. secondly, this study did not track the efficacy of psychological services as a cross-sectional study. finally, it would be better to have a larger sample size to validate the results but due to the current situation, it was not possible to collect samples on a large scale. the results demonstrate that large proportions of children are suffering from mental health disturbances in bangladesh during the lockdown period. mothers', as well as fathers' ability to forestall their emotional pain or manifestation of depression from influencing their role as a parent, might be a significant source of resilience for their children. the vulnerable cohorts for this study are children with the urban areas, higher educated parents, both higher and lower family income, smoking status (yes), parental depressive symptoms (threat, scream, hit, etc.), and the abnormal acting of the child. implementation of proper psychological intervention strategies and improvement in house-hold financial conditions, literacy of parents, taking proper care of children, and increasing job security and flexibility of parents may help in improving the psychological/mental status of children in bangladesh and the authors believe that the findings will be beneficial to accelerate the rate of achieving the sustainable development goals (sdgs) linked to public health in bangladesh. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. authors are grateful to all the participants who voluntarily offered their time, conscientiously provided honest and thoughtful responses and the personnel who supported data collection of this study. this study is considered a primary data set and the participants were given no economic motivation, and anonymity was maintained to make sure data confidentiality and reliability. it was also notified that at any time, participants could withdraw 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depression in children: a revised child anxiety and depression scale countries test tactics in 'war' against covid-19 mental health considerations for children quarantined because of covid-19 20% of children on lockdown in china suffer depression, anxiety, study finds maternal and paternal depressive symptoms and child maladjustment: the mediating role of parental behavior the effect of parents' employment on children's educational attainment. iza discussion paper with schools closed, chinese primary school students show signs of depression coronavirus disease 2019 ( covid-19 ) and mental health for children and adolescents paternal depression in the postnatal period and child development: mediators and moderators here's what the city life is doing to your child's mental health fit indices in covariance structure modeling: sensitivity to underparameterized model misspecification my child was diagnosed with depression…now what? psycom temperament as a moderator of the effects of parental depressive symptoms on child behavior problems joint appeal for effective response and mitigation of impact of covid-19 on the children in bangladesh bangladesh imposes total lockdown over covid-19 impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the 2019 novel coronavirus disease outbreak: a cross-sectional study comment covid-19 , school closures , and child poverty : a social crisis in the making. the lancet public health prevalence and predictors of ptss during covid-19 outbreak in china hardest-hit areas : gender di ff erences matter higher income is more strongly associated with obesity than with obesity-related metabolic disorders in jamaican adults a parent-report measure of children's anxiety: psychometric properties and comparison with child-report in a clinic and normal sample mental health in low-and middle-income countries the relationships among parental anxiety, parenting, and children's anxiety: the mediating effects of children's cognitive vulnerabilities working mothers: how much working, how much mothers, and where is the womanhood? covid-19: we can ward off some of the negative impacts on children rural areas at risk during covid-19 pandemic. the lancet infectious diseases survey reveals impact of lockdown on children status of mental health among left behind wives of migrant workers in north-east part of bangladesh association between problematic behaviors and individual/environmental factors in difficult children areas in dhaka under partial or complete lockdown fragile families and child wellbeing ten-year secular trends in sleep/wake patterns in shanghai and hong kong school-aged children: a tale of two cities mitigate the effects of home confinement on children during the covid-19 outbreak coronavirus disease (covid-19) covid-19 key: cord-337561-m0z14iyu authors: gerber, nicole; farkas, jonathan s.; ratner, adam j. title: winter is coming: care of the febrile children in the time of covid-19 date: 2020-11-11 journal: world j pediatr doi: 10.1007/s12519-020-00396-8 sha: doc_id: 337561 cord_uid: m0z14iyu nan in the pediatric emergency department (ped), winter seems to arrive earlier each year. after the broken bones and lacerations of the summer, the winter season brings fevers and respiratory illnesses. fever is our bread and butter-it is the most common reason for ped visits [1] . fever phobia is ingrained in our society [2] . in the pre-vaccine era, a febrile child was cause for concern; those who were ill-appearing had high rates of bacterial meningitis, and even well-appearing children could not be rapidly discharged. occult bacteremia was a common condition in well-appearing young febrile children and frequently required laboratory evaluation and treatment with empiric antibiotics [3] . with the introduction of the protein-polysaccharide conjugate haemophilus influenzae type b vaccine in 1987, and the pneumococcal vaccine based on similar technology in 2000 (expanded in 2010), the evaluation of febrile children became a little easier for pediatricians. rates of invasive bacterial disease declined rapidly, and while we remain vigilant in our evaluation of febrile children, most could be confidently discharged without an extensive workup, with a likely diagnosis of a viral syndrome. these ped visits for well-appearing febrile children were a constant for us. after a thorough history and physical exam, we knew how to counsel parents on the care of their child. make sure to get plenty of rest. encourage oral fluids. use antipyretics for comfort. make sure everyone at home is washing their hands well. return to school when 24-hour fever-free. these visits were enjoyable in a way. we reassured worried parents and briefly counseled them on the difference between viral and bacterial illnesses. we comforted parents that their children would likely recover soon, that the best medicine was the tincture of time. we counseled them on reasons to return and advised close follow-up with their pediatricians if not improving. as pediatricians, we knew what to be worried about. this year, winter ushers in a season of uncertainty. the first case of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection changed the world. the disease (covid-19) continues to spread globally as the world struggles with viral containment. quarantine, isolation, and social distancing have become part of our daily vernacular. much of the world went into lockdown and is only now just starting to emerge. pediatricians braced for the pandemic, but we ultimately found our units quiet. as adult emergency departments, inpatient wards, and intensive care units bulged to care for patients, children were relatively spared with children accounting for only 1-5% of infections, and generally having more mild disease with lower rates of hospitalizations and death [4] . with schools shut down and testing in short supply, febrile children in high prevalence areas like new york city were treated with the recommendation to "assume you have it and stay isolated". as we flattened the curve, the ped saw a resurgence of common viral illnesses. we continued to reassure. then in april, things changed again, when reports of a pediatric multi-system inflammatory syndrome began to surface. we were suddenly faced with a new pediatric disease that we knew little about. initial reports described children with fevers, abdominal pain, and stigmata of kawasaki disease. laboratory evaluation was necessary and consistently showed an elevation of inflammatory markers, often coupled with abnormalities of cardiac markers. although most children did well with available treatments, some presented in shock requiring aggressive therapy and some even had fatal outcomes [5] . suddenly, a fever was no longer just a fever. similar to the age of occult bacteremia, hospitals and health organizations rushed to develop guidelines outlining the screening labs for febrile children. spurred by the media and frightened by this new mysterious disease, worried parents rushed their children to medical care. in the direct aftermath of the peak of cases, we realized that this new disease, now renamed multi-system inflammatory syndrome in children (mis-c), also called pediatric inflammatory multi-system syndrome temporally associated with sars-cov-2 infection, is rare, but with children's lives at stake, we feel compelled to act. we assess febrile children for this disease and many undergo laboratory evaluation and subspecialty consultation. as directed, we report each potential case to local and regional departments of health. unlike the evaluation of patients for invasive bacterial disease, mis-c has no "culture" that will give us the definitive diagnosis. instead, we are left to interpret an array of blood tests and clinical signs. what will we do this winter? as covid-19 cases hopefully remain low, children return to school, and our usual viral culprits such as influenza and respiratory syncytial virus return, how will we evaluate and counsel the families of our febrile children? as we worry about a second peak of covid-19 infections, how will we test for covid-19? will every fever be evaluated with a nasopharyngeal swab and are the results of those swabs trustworthy enough to allow children to return to school? will we recommend 10 days of isolation for every febrile illness and 14 days of quarantine after every exposure? will parents ever be able to return to work? if so, who will take care of their children? what will be the disease course for children with co-infections with covid-19 and another viral illness? as we look for mis-c, the needle in the haystack, how will we decide whom to screen with laboratory tests? in those we test, how should the results even be interpreted? there are no reference values for children with viral illnesses, as these are not children we would normally evaluate with laboratory testing. does an elevated d-dimer, erythrocyte sedimentation rate, c-reactive protein, or ferritin require repeat testing or admission for monitoring? as pediatricians, we adhere to our institutional guidelines, rely on our clinical judgement, and depend on our subspecialists' input. we expectantly wait for evidence-based practical guidance from our professional societies to help inform our management on the front-line. winter is coming. what will we do with our febrile children? author contributions gn, fjs and raj worked together to conceptualize, draft, and revise the manuscript. all the authors have approved the final manuscript as submitted and agree to be accountable for all aspects of the work. funding no funding was obtained. ethical approval not required for this personal viewpoint. national hospital ambulatory medical care survey: 2017 emergency department summary tables fever phobia: misconceptions of parents about fevers occult bacteremia in young febrile children. pediatr clin north am systematic review of covid-19 in children shows milder cases and a better prognosis than adults hyperinflammatory shock in children during covid-19 pandemic conflict of interest raj has served as a consultant to pfizer, outside the scope of this work. all the other authors have no financial relationships to disclose. key: cord-317283-0zzs5cy8 authors: nicoletti, angela; talarico, valentina; sabetta, lucilla; minchella, pasquale; colosimo, manuela; fortugno, carmelo; galati, maria concetta; raiola, giuseppe title: screening of covid-19 in children admitted to the hospital for acute problems: preliminary data date: 2020-05-11 journal: acta biomed doi: 10.23750/abm.v91i2.9607 sha: doc_id: 317283 cord_uid: 0zzs5cy8 background: the new coronavirus identified in whuan at the end of 2019 (sars-cov-2) belongs to the beta coronavirus genus and is responsible for the new coronavirus 2019 pandemia (covid-19). infected children may be asymptomatic or present fever, dry cough, fatigue or gastrointestinal symptoms. the cdc recommends that clinicians should decide to test patients based on the presence of signs and symptoms compatible with covid-19. material and methods: 42 children (the majority < 5 years of age) were referred, to our pediatric department, as possible cases of covid-19 infection. blood analysis, chest x-ray, and naso-oropharyngeal swab specimens for viral identification of covid-19 were requested. results: none of the screened children resulted positive for covid-19 infection. at first presentation, the most frequent signs and symptoms were: fever (71.4%), fatigue (35.7%) and cough (30.9%). an high c-reactive protein value and abnormalities of chest x-ray (bronchial wall thickening) were detected in 26.2% and 19% of patients, respectively. almost half of patients (45.2%) required hospitalization in our pediatric unit and one patient in intensive care unit. conclusions: testing people who meet the covid-19 suspected case definition criteria is essential for clinical management and outbreak control. children of all ages can get covid-19, although they appear to be affected less frequently than adults, as reported in our preliminary survey. further studies are needed to confirm our observations. (www.actabiomedica.it) on 9 january 2020, a novel coronavirus, 2019-ncov, was officially identified as the cause of an outbreak of diffuse pneumonitis in the city of wuhan in hubei province, china. the epidemic has progressed very quickly in the following weeks, and an increasing number of cases have occurred daily in many countries (1) . the highest infection rate occurs in adults; however, neonates, children, and adolescents can also be infected (3) . people of all ages are susceptible to sars-cov-2 2019-ncov infection (3) . the 95% confidence interval of 2019-ncov infections period varies from 1 to 14 days (on average from 3 to 7 days). the majority of covid-19 positive children had a close contact with an infected case or were family cluster cases and their age, at onset of disease, ranged from 1.5 months to 17 years (4) . approximately 90% of cases are associated with household or community exposure, and 10 % are associated with travel. the clinical features are variable. patients display no obvious clinical symptoms at diagnosis and are found by screening, because of close contacts with confirmed patients, or gradually present fever, fatigue, dry cough, accompanied by other upper respiratory symp-toms including nasal congestion, runny nose, and/or gastrointestinal symptoms, such as nausea, vomiting and diarrhoea (3) (4) (5) . from a systematic rieview of the literature, ludvigsson (6) identified 45 relevant scientific papers and letters related to covid-19 in children. the data showed a prevalence from 1 to 5%. the majority of them had a milder infection than in adults, although severe cases have been reported. laboratory findings in children with confirmed infection are variable. approximately one-quarter had white blood cell count <5.5 x 10 9 /l and 3.5 percent had lymphocyte count <1.2 x 10 9 /l (7). procalcitonin was elevated ( >46 pg/ml) in 64 % and c-reactive protein was elevated (>10 mg/l) in 20 % of children. chest radiographs may be unremarkable or demonstrate bilateral consolidation. in order to gain more insights into the outbreak of covid-19, in our population of children and adolescents, we analyzed the clinical presentations, laboratory data and radiologic findings of patients who came to the emergency pediatric department of catanzaro (italy), for an acute disease. the study was performed from 1 march 2020 to 13 april 2020. a total of 127 patients were enrolled in our survey. demographic, clinical, and laboratory data of patients (age, sex, location, date at symptom onset, , travel history and information on relatives) were collected using a standardized electronic medical record. according to the international protocol, nasooropharyngeal swab specimens for the detection of 2019-ncov were requested. a duplex one-step realtime reverse transcription polymeras chain reaction (rt-pcr), using specific target genes (e, rdrp, n), was used to confirm the 2019-ncov positivity (https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance). influenza virus a and b were routinely tested on respiratory swabs. informed consent was obtained from the parents or guardians of children for the publication of clinical and laboratory data. the following variables: age, sex, clinical features, onset of symptoms, laboratory indices and imaging, were collected and reported as number, frequency (%), and median (interquartile range). laboratory indices and chest x-ray descriptions, in our patients and in children and adolescents with covid-19 infections reported in the literature, are also presented. of the 127 children and adolescents admitted to the pediatric emergency room, 42 patients (20 males and 22 females) were suspected to have a covid-19. demographic data and clinical features of these patients are summarized in table 1 . the median age was 6.2 years (1 months-17.8 yrs) and half of them (52.3%) were between 1 mo. to 5 yrs of age. a high personal risk history for suspected covid-19 was present in five patients (11.9%). in three children a personal history of prematurity, bronchodysplasia or sickle cell anemia was reported. the average time of symptoms onset was 2.7 days. fever was present in 71.4%, cough in 30.9%, and fatigue in 35.7% of our children and adolescents. laboratory investigations and the reported radiologic findings are summarized in table 2. the most common abnormalities on chest x-ray were bronchial wall thickening in 8 patients (19%) and nodular or reticulonodular opacities in 2 patients (4.7%). 45.2% required hospitalization in our pediatric unit and 1 patient required intensive care support. none of our patients resulted positive for sars-cov-2 infection. the centers for disease control and prevention (cdc) and several other government health agencies emphasize that fever and respiratory symptoms are the criteria for suspecting a cases of 2019-ncov infection. based on the current who criteria (8) , patients are suspected to have an infection in pres-ence of the following epidemiological and clinical characteristics: a. epidemiological history: 1) children with a travel or residence history in an areas with persistent local transmission within 14 days prior to disease onset; 2) children with a history of contacting patients with fever or respiratory symptoms who had a travel or residence history in an areas with persistent local transmission within 14 days prior to disease onset; 3) children with a history of contacting confirmed or suspected cases infected with 2019-ncov within 14 days prior to disease onset; 4) newborns delivered by suspected or confirmed 2019-ncov-infected mothers. b. clinical presentations: 1) fever or respiratory symptoms (e.g.,cough, dypsnea, pharyngitis, flu-like symptoms) or digestive symptoms (e.g., vomiting, nausea and diarrhea) or fatigue. in italy, the national institute of health (iss; updated to 9 april 2020) reported 136,110 cases of covid-19. the higher positive numbers were registered in the north of italy (2). in calabria region 785 case of covid-19 were registered, with an incidence rate of 40,32 per 100,000 of inhabitants (2) . children represent the 2% of covid-19 diagnosed cases in china (9), 1.2% of cases in italy (10), and 5% of covid-19 in the usa (11) . none of our tested children and adolescents for sars-cov-2 resulted positive. these results could be attributed to several factors: the low incidence of positive cases among children living in our region (about 1.2% of the total registered in italy); the early activation. in our region, of procedures and recommendations for reducing the viral transmission (e.g. schools closure, social distancing); to the different response of immune system in children (12) ; to the different environmental factors (13, 14) , and the absence of additional risk factors (such as: associated chronic diseases, smoking, air pollution exposure). children often experience respiratory infections in winter, and may have higher levels of antibody against virus than adults. furthermore, children's immune system is still developing, and may respond to pathogens differently to adults (11) . it has been also speculated that children are less sensitive to 2019-ncov because the maturity and function (e.g., binding ability) of angiotensin converting enzyme ii (ace2) may be lower than that in adults (15) . ace2 receptors are involved in the protective mechanisms of the lung to sars-cov infection, as indicated by recent evidence (16, 17) . environmental factors, such as temperature, humidity, chemical and biological contaminants can play an important role in progression and spread of sars-cov infection (17, 18) . higher temperatures and higher relative humidity (38°c, and >95% rh) have been found to reduce virus viability (18) . in addition, oxygen saturation <94% -n. (%) 4 (9.5%) chemical and biological contaminants can promote the permanence and the spread of the virus, even over long distances (19) . in conclusion, testing people who meet the cov-id-19 suspected case definition is essential for clinical management and outbreak control. the cdc recommends that clinicians should decide to test patients based on the presence of signs and symptoms compatible with covid-19. an universal testing during the covid-19 outbreak should be taken into consideration because is very important to understand the children's role in spreading the virus in their communities, to determine hospital isolation practices and bed assignments, to inform pediatric emergency care, and to guide the use of personal protective equipment. china novel coronavirus investigating and research team task force covid-19 del dipartimento malattie infettive e servizio di informatica a case series of children with 2019 novel coronavirus infection: clinical and epidemiological features suggestions on the diagnosis and treatment of novel coronavirus infection in children in hubei province clinical features of patients infected with 2019 novel coronavirus in wuhan systematic review of covid-19 in children show milder cases and a better prognosis than adults sars-cov-2 infection in children global surveillance for cov-id-19 caused by human infection with covid-19 virus the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china, 2020 coronavirus disease 2019 (cov-id-19) in italy severe outcomes among patients with coronavirus disease 2019 (covid-19) -united states epidemiological characteristics of 2143 pediatric patients with 2019 coronavirus disease in china covid-19: a relationship to climate and environmental conditions? primary biological aerosol particles in the atmosphere: a review facing the pandemic of 2019 novel coronavirus infections: the pediatric perspectives angiotensin-convertingenzyme 2 is a functional receptor for the sars coronavirus a pneumonia outbreak associated with a new coronavirus of probable bat origin covid-19: a relationship to climate and environmental conditions? primary biological aerosol particles in the atmosphere: a review each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article key: cord-323941-6rdveab3 authors: levine, diane thembekile; morton, julie; o’reilly, michelle title: child safety, protection, and safeguarding in the time of covid-19 in great britain: proposing a conceptual framework date: 2020-08-13 journal: child abuse & neglect doi: 10.1016/j.chiabu.2020.104668 sha: doc_id: 323941 cord_uid: 6rdveab3 abstract background great britain has the highest coronavirus death rate in europe. while the pandemic clearly poses a risk to the lives and wellbeing of vulnerable groups, necessary public health measures taken to delay or limit the spread of the virus have led to distinctive challenges for prevention, family support, court processes, placement and alternative care. the pandemic has also come about at a time when statutory changes to partnerships have led to a reduction in the importance of educational professional representation in the new formulation in england and wales. objectives in this discussion paper, we propose a novel and pragmatic conceptual framework during this challenging time. participants we consulted with 8 education professionals and 4 field-based student social workers. setting bodies responsible for safeguarding have been working quickly to develop new approaches to fulfilling their responsibilities, for example through online home visits and case conferences. however, some communities have been highlighted as experiencing particular challenges because of the pandemic and its impacts. protection of vulnerable children is increasingly dependent on individualised and often pathologising practice with a lack of emphasis on the importance of the social. holistic consideration of the child is side-lined. results our framework comprises two phases: pandemic and aspirational. conclusion the framework illuminates the importance of interconnected sectors and multi-agency working, the need for resilient and adaptable support systems, and the need to promote the importance of children’s rights and voices to be heard above the noise of the pandemic. home was banned, schools, businesses, places of worship and shops were closed, and those deemed 'vulnerable' to the effects of the virus were told to self-isolate or shield themselves. the coronavirus act 2020 gave the government powers that had not been deployed in 75 years. since then, the government has come under significant criticism for its approach, both from within the scientific community (prof sir david king, 2020) and the media (e.g. wolf, 2020) , with considerable concerns being raised about the impact on the most vulnerable and disadvantaged sectors of society (e.g. power et al., 2020; paton et al., 2020 ). an early survey conducted on the public's attitudes to the measures introduced in lockdown showed a willingness to comply but an inability to do so for some groups. those with the lowest household incomes were the least likely to be able to work from home due to the lack of flexibility in job roles and the ability to self-isolate was lower in such households as well as in minority and ethnic groups (atchison et al., 2020) . in the uk, the policy response to the global financial crash of 2008 was widespread cuts to welfare and public expenditure which have been devastating for the most vulnerable in society (featherstone et al., 2018) , and children and young people have been especially impacted. the consequences for the physical and mental health of children in the longer term are therefore of great concern, particularly as the pandemic seems likely to compound and extend the range of difficulties already faced by 'vulnerable' children. socially and politically, children and young people have been constructed as belonging to a vulnerable group, not least because society is positioned as having to taking care of them and protecting their interests as they are unable to do so in a fully competent way. often, the very notion of 'vulnerability' is taken-for-granted and groups falling within the category are typically treated as homogenous. definitions of the concept of vulnerability are however contentious and challenging to create, with little consensus of what constitutes a vulnerable j o u r n a l p r e -p r o o f group (ruof, 2004) , largely because the concept of vulnerability is not static, but contextual (nordenoft & kappel, 2011) . unsurprisingly then, we have seen shifts over time as to how children's vulnerability is constructed, discussed and shaped by influential voices and sociopolitical structures. prior to the pandemic, children's vulnerability was largely classified by policy and practice drawing on the definitions provided by the children's commissioner technical paper 2 (children's commissioner, 2019). these defined groups of children as belonging to a range of vulnerable categories; the commissioner's 2019 vulnerability report published just nine months before the covid-19 outbreak, estimated that 2.3 million children were living in vulnerable family backgrounds in the uk, with 829,000 'invisible to the system', and an additional 761,000 known to the system but with 'unclear' support (children's commissioner, 2019) . since the pandemic the uk government has formalised its definition of vulnerable children and young peoplearguably too narrowly -as those who: -have a formal protection or in need plan, or are who are looked-after -have an education, health and care plan (ehcp) that cannot be safely addressed at home -have been assessed as vulnerable by local authorities or educational providers (department for education, 2020) notably, the following caveat is added, which in effect ensures responsibility is devolved from central government authorities where possible: "this might include children on the edge of receiving support from children's social care services, adopted children, or those who are young carers, and others at the provider and local authority discretion". (dept for education, organisations from different sectors have called on the government to take proactive steps to ensure that these groups of children have their educational and health needs met and are provided with the necessary levels of protection from harm. consequently, this has led to changes in practice, particularly within and across social services, who are the leading organisation for child protection in england and wales. such changes (in legislation and practice) have led to inevitable dilemmas for social workers who have been working in emergency situations where choices and decisions have gone beyond usual ethics and included the rationing of support and resources and more stringent prioritisation of cases. (british association of social workers, 2020). ethical dilemmas and practice challenges have been a significant feature of professionals' everyday work during the covid-19 crisis. the uk government's efforts to address child vulnerability and provide protection and support for those children and young people who fall within its narrow definition have greatly impacted the way in which social services have delivered routine practice. while there have certainly been challenges (the full consequences as yet unknown), there have been some areas of social work practice that have seen positive impacts as a result of the pandemic. these positive examples suggest that there is a potentially an opportunity to re-evaluate current services which focus on 'risky' individuals rather than orienting intervention to alleviate the precarious and fragile conditions some families live with and which create the conditions for risks to children. optimistic accounts were provided by practitioners who informed us that some families were coping well despite the reduction in face-to-face contact prompting them to review existing thresholds of risk and have conversations about the reasons for their involvement in some cases. social workers we consulted spoke of being more proactive in j o u r n a l p r e -p r o o f asking families if they had (for example) food, whereas in the past families would have had to request servicesthis appeared to be appreciated by the families. the covid-19 pandemic period has established the importance of digital means of communication with children and young people and has required professionals to overcome their trepidation about using technology. fears have been expressed to us by practitionersand affirmed by the association of directors of children's services (adcs) -that due to the isolation of children during lockdown there is likely to be a future surge in demand for children's services, resulting in more children coming into care and greater demand for child and adolescent mental health services (camhs). service responses to challenges in the recovery period will need to include creative and innovative use of digital technologies. despite considerable advances in digital technology, and digitally mediated service provision, professionals working with children and young people have historically been resistant to engaging them through these mechanisms (topocco, et al., 2017) . this is arguably counter-intuitive as evidence shows that the key attraction for some young clients to receive services through digital means is factors such as a sense of privacy, feeling less emotionally vulnerable, and feeling less personally exposed (gray et al., 2005; young, 2005) . given that social services work with groups that are often disempowered and disadvantaged, and typically can be challenging to engage, digital interaction has a great deal of potential (e.g. gillingham, 2016; gallagher, 2016) . this potential has been realised and become necessary because of the service parameters created by covid-19, and it has become clear to many professionals that some young people have found it more comfortable to talk to professionals virtually rather than face-to-face. this has in some cases supported relationship-building and trust. despite the positive advancements and possible new ways of working that could be promoted in the future, the covid-19 crisis has spotlighted and exacerbated existing j o u r n a l p r e -p r o o f problems in the system. children's services across health, education and social services sectors have been characterised by a preoccupation with risk and an increasingly bureaucratic and 'technical' approach to assessment. this was evident in the service response at the start of the crisis with initially risk averse and audit driven responses. professionals talked to us about being asked to contact families with vulnerable children and young people with an education and health care plan (ehcp) in order to conduct a superficial telephone risk assessment using a checklist. calls to child protection duty teamsthe teams who deal with initial contacts from those with a child protection concern -are lower in number. child protection professionals have found their caseloads falling with children's services directors reporting a 50% drop in some areas (guardian, april 2020) . this is probably due to the absence of the linked systems and professionals who have regular contact with children (schools and teachers) as well as diminished contact with health professionals (gps, routine hospital appointments and accident & emergency departments). the pandemic has also come about at a time when statutory changes to partnerships have led to a reduction in the importance of educational professional representation in the new formulation in england and wales. the children and social work act (2017) abolished local safeguarding boards and moved to 'local safeguarding' partners. the latter included the local authority chief executive, the accountable officer of a clinical commissioning group (representing the national health service), and the chief officer of police. while these 'partnerships' are still able to join with relevant agencies (including schools) the newer formulationrequired to be implemented by 2019did not place education at the heart of the safeguarding process. finally, while the pandemic clearly poses a risk to the lives and wellbeing of vulnerable groups, necessary public health measures taken to delay or limit the spread of the j o u r n a l p r e -p r o o f virus have led to distinctive challenges for prevention, family support, court processes, placement and alternative care. compounding the multi-layered challenge, just as the 'pandemic paradox' (bradbury-jones & isham, 2020) has impacted heavily on service delivery, the 'stay home, protect the national health service, save lives' narrative that circulated during the lockdown period proved challenging both for those relying on face-toface interactions, and crucially for those trapped living in abusive contexts in the uk. as well as difficulties presented by altered service responses in the crisis it has also become clear that existing social inequalities have been exacerbated. vulnerable socio-economic groups have experienced more financial pressures, greater health risks and worse housing conditions (bergamini, 2020). furthermore, the economic impact of the virus has increased unemployment rates and posed a likelihood of recession (altig et al., 2020) . service responses have been mostly dependent upon technology yet digital poverty and exclusion persists in the uk (holmes & burgess, 2020) meaning that some children and young people will have felt isolated from their peers and education. while for many, maintaining contact with peers through social media, connecting with educational tasks via the internet, and reaching out to supporting organisations through smartphone apps will have provided some protection against this isolation, for those with limited or no technological access, it can exacerbate social comfparison and worsen their current situation (e.g. armitage & nellums, 2020) . our preliminary discussions with social workers and teachers, as well as evidence from media reports, demonstrate that these professionals are fearful of problems that are likely to be compounded or created through such isolation in lockdown (blind, in press). for children who are already negatively affected by poor living conditions, poverty and other factors which increase marginalisation and life-chances, the pandemic can be conceived as 'an additional systemic shock…'(sinha, 2020) with concerns in the uk and globally regarding the effects of children's health and social care being side-lined as these services have been oriented to adults. in addition, black and asian minority ethnic communities have been disproportionately affected by covid-19. multiple and probably intersecting factors such as socio-economic status, pre-existing health conditions and living conditions are implicated but the structural and institutional racism which creates and maintains disparities also needs to be examined (patel et al., 2020) . evidently, covid-19 is impacting certain groups of children who were already in need before the crisis. it is essential to consider the consequences for all children who have experienced trauma and loss through the crisis, while being additionally mindful that this may have been a more frequently occurring experience for children of minority ethnicities. of particular consequence for these vulnerable groups of children and young people is the impact to their mental health and wellbeing. prior to the covid-19 crisis, it was wellknown that the prevalence rates of mental health conditions, especially emotional health conditions like anxiety and depression were rising (nhs digital, 2018) . there is no doubt that the aftermath of covid-19 is going to see a greater demand for camhs (blumenstyk, 2020) , a service that is already stretched, with long waiting lists and limited resource. it is expected, then, that the mental health consequences will be far-reaching and long-lasting as services struggle to meet demand . vulnerable groups of children and young people are likely to be the worst hit in terms of the impact on their mental health, not least because of the multifactorial aetiology of any condition, but because issues like poverty, adverse childhood experiences, parental mental health, stress, poor sleep, and substance/alcohol misuse will influence the trajectory, and are also associated with covid-19. for some of these young people they have lost their social support system, some will be bereaved due to the virus, they have lost their educational routine, their freedoms and may have family challenges, which will have a huge j o u r n a l p r e -p r o o f impact on their mental health, especially for those with pre-existing mental health need . fears have also been expressed that there is a potential to see an increase in suicide rates, and while not inevitable, the risk factors for self-harm, suicidal ideation and suicidal behaviour have also been increased by in press ). this brief snapshot of current child protection practices and challenges presented by social, ethnic and health disparities in the pandemic period has prompted us to probe further into pre-existing tensions in the systems set up to protect and support children. in the united kingdom the children act 1989 distinguishes children identified to be 'in need' (section 17) and children where there is 'reasonable cause' to suspect a child is suffering from or at risk of significant harm (section 47). however, the current child protection paradigm asserts child protection over welfare. there is an emphasis on assessing risk rather than promoting a central feature of current child protection practice is that interventions focus on parents (predominantly mothers) and their (in)ability to protect their children -a simple reification of the 'mother-blaming' discourse that has been entrenched in social consciousness for decades. from our own experience teaching social workers, we know that many feel distressed and conflicted because of the timeframes they are compelled to work within and the outcome driven ways in which they are expected to assess parenting. a further consequence of this current focus on assessment of parenting capability is that children finally, though, there have been some positive steps taken to a more holistic perspective when intervening to help children, (for example the 'team around the child' and strengths-based approaches) change has often been as a response to inquiries into child deaths where inter-professional collaboration was seen to be a significant contributing factor to failures in the systems designed to protect children (laming, 2003; munro, 2013) . current approaches are in practice focused on assessment of parenting capability with limited attention to wider influencing factors. systems to protect children need to develop further to be congruent with contexts and make sense to communities using them (education j o u r n a l p r e -p r o o f development trust, 2018), adapting to socio-political and cultural shifts. families involved in child protection proceedings frequently misunderstand what is happening to them, feeling a sense of injustice (smeeton & boxall, 2011) at how decisions are made and feeling dehumanised in processes (smithson & gibson, 2016) . some of the reported feelings of parents being tricked and under surveillance are echoed by social workers we teach who experience considerable moral distress when compelled to simultaneously follow the rhetoric of working with families whilst collecting evidence which may result in the removal of a child. in addition, the wishes of children are not prominent in decision-making. to empower practitioners who work with children and young people to listen to them and account for their rights in a child-centred way, it is crucial that practitioner voices, experiences, practices, feelings and knowledge are fore-fronted in research and policy. frontline professionals have a wealth of experience and knowledge, and unique insights into the systems within which they operationalise organisational and policy strategic objectives. listening to the voices of student social workers and practising teachers, we propose a novel framework for research during this challenging time. the framework is intended to illuminate the importance of: -interconnected sectors, -robust and well-resourced data-flows, -multi-agency working, mediated through the ethical and excellent use of technologies, -resilient and adaptable support systems, and -the promotion of children's rights and voices to be heard above the noise of the pandemic. the framework accounts for two phases of interrogation. figure 1 below outlines the potential conceptual framework for understanding safeguarding in the uk during the first j o u r n a l p r e -p r o o f months of the pandemic. figure 2 , also below, outlines the potential conceptual framework for understanding safeguarding in a post-pandemic uk society. both phases have some common dimensions: -sequential, rather than cyclical development, reflecting the reality of the safeguarding system in the uk and the enormous challenge we face in potentially moving to a system that truly places the child at its heart in the future. -a/the child. we do not limit our inclusion to the definition provided by the uk government, but rather recognise the tensions in constructing and identifying vulnerability and risk. we argue that practitioners need to take a more holistic perspective of the vulnerable family and the vulnerability of the child, to account for their physical and mental health needs, and their safeguarding concerns. we perceive vulnerability as contextually and temporally fluid. 'fixing' children's vulnerability is unhelpful. instead, vulnerability needs to be understood as distinctive for each child and viewed in relation to other factors. employing figure 2 to understand vulnerability, both personal resources available to the child and their unique relationship to socio-political and cultural contexts would be taken into accounted for and might be assessed as risk or protective factors. -agency, biopsychosocial development, and voice of the child. while acknowledging that realistically, we are not yet in a place where the child is at the heart of our safeguarding systems practice (see sequential point above), our phase 2 aspirational framework places data flows (both face-to-face and digitally-mediated) as emanating from the interdisciplinary intersection between the child's voice, agency, and biopsychosocial development. thus, we recognise the importance of empowering children's voices and placing their views at the centre of decision making. while it is necessary to recognise the various dimensions of development in doing so, traditional stage-based j o u r n a l p r e -p r o o f developmental ideologies are outdated, and now replaced with an acknowledgement of the complex intersection of reciprocal biopsychosocial influences that can enhance or negatively impact a young person's mental wellbeing (drabick & kendall, 2010) . no matter what the developmental ability of the child or chronological age, it is necessary to value what they have to say. -welfare and justice systems including local authorities' statutory responsibilities for 'safeguarding' and promoting children, with the children act 2004 placing a duty to cooperate on all bodies working with children. there are also responsibilities to children who are 'looked after', which means that they are in the care of the local authority. this might include living with foster parents, living in a residential children's home, school or secure setting. -safeguarding policies are present in most uk public and private institutions that intersect with children and young people. these have not proved the comprehensive safety net for the most at-risk that we might wish them to be (e.g. hek et al., 2012) . as with adult safeguarding, policies tend to be shaped by inquiries following serious incidents and focus on micro-systems (practitioners, inter-agency working) rather than the wider systems which influence practitioners' work so that recommendations have lacked analysis of the wider influences on practitioners' work (preston-shoot, 2017). nevertheless, our conceptual framework for both the pandemic and post-pandemic contexts demonstrate the importance of policy as a protective factor in the safeguarding context. -health system, comprising gateway systems such as paediatric accident and emergency staff, general practitioners, community nurses and carers. -education system, comprising school staff (teachers, safeguarding leads, school leaders, teaching assistants and special/additional needs co-ordinators) -community, notoriously difficult to define for vulnerable and at-risk childrenand particularly those in care (jack & gill, 2010) , but potentially comprising faith institutions, charities and child/youth representation and membership organisations, neighbours and hubs. -family, again a contested term (e.g. hantrais, 2004) and inviting debate surrounding who is in need of, and who provides, support in contexts of family complexity (morris et al., 2008) . the ways in which teachers, community representatives, social and health workers understand ideas and implementations of family impact on the ways in which they deliver support in 'normal' circumstances (walsh et al., 2018) , and our conceptual framework suggests that this is even more important in a pandemic context. strategically, the framework highlights three noteworthy points. first, is its sequential nature; the pandemic has highlighted that, despite significant attempts over the past 20 years to place the child at the heart of the safeguarding process, children still remain at one end, with societal contexts at the other, and a range of mediating factors intervening both spatially and temporally. the progression towards our understanding of 'digitally-mediated safeguarding' offers us practical ways in which we can bring children to the heart of the safeguarding process, both in who we listen to when we gather data, how we share it and with whom, and how those data are used to actively empower children to operate the welfare system as a force for positive change in their own lives, for example through serious games (watkins et al., 2018) . second and related, the data/information/reporting flows indicated by the blue arrows are focused on systemic structures and flows; we have not yet been able to take full account of cognitive, affective, and psychosocial development of the child in our systems. this is arguably a function of both microsystems (education, physical health, social work etc) and the macrosystem as a whole in the uk, and presents an extraordinary opportunity for the research community to work in original and interdisciplinary ways to improve system-level, child-led data flows that enable them to reflect on their own development and resilience pathways in vulnerable or at risk circumstances. practically, this means embedding culturally-sensitive tools (which could be as wide-ranging as digital, arts-based, or test-based) in schools and communities that give children the language to describe their personal changes and the risk and protective factors that surround them, and then make use of their insights to manage and plan for their lives despite the precarity in which they may find themselves. third, the location of safeguarding policies and digital mediation of both intelligencesharing and intervention as intermediary factors, and the continuing importance of even limited face-to-face interaction (even in the face of the pandemic). in contrast, the aspirational conceptual framework re-frames the flow of information in a way that enables: a) a more holistic and child-led flow of information/data across the micro and macrosystems; b) places child development and their articulation of that development in a crucial, intersectional position in the data flow; c) suggests a single data flow through the interconnected systems intended to act as protective factors for vulnerable/at risk children and young people, and; d) recognises the importance of effective digital mediation of services for those who need it most. we consulted with eight practising teachers and four student social workers (who were on placement during the crisis) to ensure that the conceptual framework as it arose from the literature and situational analysis resonated with their daily practice during the pandemic, and their hopes for future systemic improvements in a post-pandemic era. almost all the people we spoke with found the proposed framework resonated well with their settings. it should be noted that one education professional felt that the proposed framework was too overcomplicated and insufficiently flexible, and we acknowledge that this may indeed be limitations of the framework that require robust investigation. our framework is propositional it requires further research to clarify and simplify with accuracy and in ways that are resonant with practitioners and service-users, particularly during a time of such dramatically rapid change as the covid-19 pandemic. beyond this caveat, our teachers/student social workers' reflections fall into five categories. teachers in particular were at pains to clarify that in almost all uk settings, vulnerable children have been offered places in school during lockdown. department for education figures showed that the take up of these places has been highly variable during lockdown; in mid-may 79,000 children (15% of those classified as 'in need' or in receipt of a care plan) were in school, where as in late march that figure was closer to 61,000, and during the twoweek spring break was at its lowest (11,000) (department for education, 2020). our consultees' reflections encouraged us to ensure the framework was sufficiently broad to encompass the full range, while still inviting closer and more data-driven collaboration between sectors. face-to-face information-sharing has still occurred j o u r n a l p r e -p r o o f for a small number of cases, face-to-face safeguarding information-sharing has been deemed important even during lockdown, accompanied by suitable protection such as social distancing, hand sanitising, and the use of personal protective equipment. for this reason, this type of interaction is still present in both the mid-pandemic and post-pandemic phases of the conceptual framework. the strains for isolated families in the pandemic have inevitably raised concerns about domestic violence. student social workers we consulted expressed concern about working directly with parents where childcare concerns were apparent, in particular whether both children and adults were being coerced into minimising the risks of their context, or even saying nothing at all about violence, because of fears regarding the consequences during covid-19. emerging literature suggests their fears are not unwarrantedthere has been an increase in domestic homicides in the uk (ingala smith, 2020), with some authors suggesting that domestic abuse behaves much like an infection in ideal conditions during the pandemic (taub, 2020) . globally it has emerged that covid-19 has been used to exert control using mechanisms of abuse such as containment, fear and contagion (usher et al., 2020) . in the uk, even early on in lockdown, calls to the national domestic helpline were up by 25% (kelly & morgan, 2020) , the usual means of escape from abusive situations being unavailable. in light of this, it was not surprising that the british association of social workers (basw) issued a practice guide on working with families where violence and abuse was a concern (basw, 2020). student social workers expressed concern about working directly with parents where childcare concerns were apparent, in particular whether both children and adults were being coerced into minimising the risks of their context, or even j o u r n a l p r e -p r o o f saying nothing at all about violence, because of fears regarding the consequences during covid-19. social workers were concerned that the need to digitise, minimise bureaucracy and streamline systems, for example for adoption, led to much faster processes than would have been the case in a face-to-face context. their concerns surrounded superficiality -the potential of technology use to facilitate productive time can in practice lead to lack of depth. the converse was also true; it has been difficult to maintain contact with those reluctant to use technology or set up new referrals or follow up to assessment/diagnoses in a virtual contact. the fundamental role digital technologies have played during lockdown were raised over and over by both the teachers and student social workers with whom we consulted, for example in reporting concerns, and offering mentoring/therapy services from outside agencies. children and young people benefiting from mental health services appear to have found digital communication productive, and in cases where there were established relationships, virtual meetings with parents were easier to arrange and less fraught. however, as with many aspects of digitally-mediated life, technology-mediation presented challenges as well as opportunities. for example, it has been particularly challenging to raise matters of self-harm with young people, a risk assessment area that practitioners traditionally find difficult to ask children about (blind). in a face-to-face encounter a service user's arm could be observed with discretion, but virtually, social workers have had to ask to see the arm. the apparent digitally-oriented changes brought about during covid-19, and the risks and opportunities they potentiate, could potentially herald a new era of what we have j o u r n a l p r e -p r o o f termed "digitally-mediated safeguarding". the term offers three conceptual and pragmatic advantages for the post-pandemic context. it:  builds on established frameworks relating to power dynamics in digitally-mediated communication (e.g. mansell, 2017) , facilitating a deeper, richer, and more nuanced dialogue than a simple binary dichotomy of technology as effective vs non-effective or even damaging.  invites discourse and debate for practitioners and researchers alike surrounding the potential for new technological advances such as artificial intelligence, machine learning, and virtual/augmented reality, to disrupt problematic practice and address systemic gaps, but also to dramatically increase and magnify system-level inequalities and surface ethical tensions we have only just begun to consider (e.g. leslie et al., 2020) .  invites policy makers at local and national levels to deliver technology-mediated services that are understood as multi-systemic and complex. technology systems require consideration of the whole as well as the partsthe covid-19 experience has shown that partitioned thinking is acting as a barrier to us placing a/the child truly at the heart of the safeguarding process. we began this article by reflecting on the terrifying impact covid-19 has had on child and adolescent welfare in great britain, and the considerable challenges that have arisen from the social care context in which we find ourselves. we have proposed two phases of conceptual framework for future research. the first provides a space within which we can begin to understand the mid-pandemic context. the second invites us to reflect realistically on what a post-pandemic context might look like, appreciating that incremental rather than dramatic system change is most likely. we have noted that despite the rhetoric of placing children and j o u r n a l p r e -p r o o f young people at the centre of support systems, they continue to be obscured or invisible in much research, policy and the processes which intend to safeguard them. what is most notable about our framework is the centrality of the child or young person, their perspectives and their rights, as well as the value of practitioners who deliver services and work with those groups. further, we have critically questioned the uk government's narrow definition of 'vulnerability' and have argued instead that constructions of vulnerability need to be contextdependent, situational, and iterative, accounting for each child's personal resources and their unique relationship to the external world. finally, the social competencies and rights of children and young people must be balanced against protecting them and safeguarding their interests. practitioners are wellplaced to listen, intervene and support. ultimately, this will be achieved more holistically through open dialogue, consultation and respecting young people's autonomy and views. perceptions and behavioural responses of the general public during the covid-19 pandemic: a cross-sectional survey of uk adults. medrxiv. pre-print economic uncertainty before and during the covid-19 pandemic (no. w27418) considering inequalities in the school closure response to covid-19. the lancet global health why coronavirus looks like a 'black swan' moment for higher education. the chronicle covid-19 pandemic: ethical guidance for social workers. basw website domestic abuse and child welfare practice guide. basw website vulnerable groups and latest data supporting vulnerable children and young people during the coronavirus (covid-19) outbreak -actions for educational providers and other partners attendance in education and early years settings during the coronavirus outbreak: 23 march to 11 developmental psychopathology and the diagnosis of mental health problems among youth let's stop feeding the risk monster: towards a social model of 'child protection'. families role of digital technology in child protection: still helping and harming? child abuse review predictive risk modelling to prevent child maltreatment and other adverse outcomes for service users: inside the 'black box' of machine learning family policy matters: responding to family change in europe safeguarding the needs of children and young people seeking asylum in the uk: addressing past failings and meeting future challenges coronavirus has highlighted the uk's digital divide: a short paper counting dead women (undated blog post child abuse review: journal of the british association for the study and prevention of child abuse and neglect coronavirus: domestic abuse calls up 25% since lockdown, charity says. bbc news. retrieved on 17th lbc radio interview the victoria climbié report. london. the stationery office ethics review of machine learning in children's social care: executive summary inequality and digitally mediated communication: divides, contradictions and consequences think family: a literature review of whole family approaches. london: cabinet office the munro review of child protection: final report, a child-centred system mental health of children and young people in england, 2017: summary of key findings vulnerable participants in health research: methodological and ethical challenges submission of evidence on the disproportionate impact of covid 19, and the uk government response, on ethnic minorities and women in the uk on self-neglect and safeguarding adult reviews: diminishing returns or adding value? how covid-19 has exposed inequalities in the uk food system: the case of uk food and poverty vulnerability, vulnerable populations, and policy birth parents' perceptions of professional practice in child care and adoption proceedings: implications for practice less than human: a qualitative study into the experience of parents involved in the child protection system: parental experiences of child protection a new covid-19 crisis: domestic abuse rises worldwide attitudes toward digital treatment for depression: a family violence and covid-19: increased vulnerability and reduced options for support how do you solve a problem like maria? family complexity and institutional complications in uk social work exploring children's understanding of law in their everyday lives fears for child welfare as protection referrals plummet in england the risks of lifting lockdowns prematurely are very large the authors would like to thank the student social workers and practising teachers/educational professionals in england and scotland who were open to reviewing our proposed framework and offering us their thoughts during this very busy time.j o u r n a l p r e -p r o o f key: cord-326963-34hw4oeg authors: panthi, bindu; khanal, pratik; dahal, minakshi; maharjan, sajana; nepal, sushil title: an urgent call to address the nutritional status of women and children in nepal during covid-19 crises date: 2020-06-05 journal: int j equity health doi: 10.1186/s12939-020-01210-7 sha: doc_id: 326963 cord_uid: 34hw4oeg due to the ongoing nationwide lockdown in nepal, women and children face a greater risk of malnutrition and eventually leading to mortality and morbidity. to harness the progress made so far in improving the nutritional status of women and children, a focus on nutrition should be a part of the covid-19 response plan. the impact of the covid-19 on nutrition outcomes has not been acknowledged at this point in nepal but studies have shown that large scale emergencies have increased morbidity and often mortality in infants and young children [3] [4] [5] . these adverse outcomes are usually the result of low immunity, gastrointestinal or respiratory tract infections, and associated with malnutrition or dehydration [6] . malnutrition and its human and economic cost are enormously falling hardest on poor women and children and lasting to generations. according to the nepal's demographic health survey 2016, wasting rate among under 5-year children in nepal is 9.7% [7] , and as per nepal micronutrient survey 2016, the prevalence of reported night-blindness among women aged 15-49 years during last pregnancy is 8.5%, and the prevalence of vitamin a deficiency among children aged 6-59 months is 4% [8] . similarly, 53% of children under five and 69% of children aged 6-23 months and 41% of women of reproductive age group suffer from anemia [7] which is a public health concern according to the who [9] . communities and vulnerable groups like women and children dealing with malnutrition are doubly susceptible to compromised health due to covid-19 pandemic. that is because, malnutrition can weaken the immune system and they may be more vulnerable to acquiring covid-19. in addition, the lockdown has resulted in a decrease in household incomes leading to less availability and reduced access to food, and restriction in receiving essential health care services. nutrition services like vitamin a and deworming campaign, supplementation of micronutrient powders, treatment of malnourished children through the outpatient therapeutic center, and nutrition rehabilitation homes have also been affected as a result of the priority shift of health sector towards covid-19. alternatively, the pandemic could force people to take on behaviors like consumption of unhealthy food, inadequate intake of nutritious food, and poor hygiene and sanitation practice. insufficient breastfeeding practices, due to fear and anxiety of transmission of covid 19 from breastfeeding mothers, result in decreased feeding and caring practices for children. the predictable outcomes of such situations might decrease the immune function, increase the susceptibility to severe diseases, and lead to a high incidence of wasting and stunting among children. food insecurity and hunger is one of the top issues of malnutrition in nepal. covid-19 could further induce malnutrition due to people losing their jobs mainly informal sector and those in foreign employment. similarly, it might also affect the agricultural production due to shortage of seeds, fertilizers and manpower, further plunging the population into poverty and malnutrition. according to global hunger index 2019, nepal experiences a serious threat of hunger, with a score of 20.8 standing at rank of 73 among 117 countries [10] , there is thus likelihood for women and children to suffer from more hunger in the wake of the lockdown. nepal's poor scoring in the global hunger index is reflective of the low minimum acceptable diet of 36% in children 6 to 23 months [7] . this is linked to a high rate of stunting and the intergenerational cycle of malnutrition. furthermore, we can expect an increase in infants with low birth weight (lbw) due to inadequate intake of nutrients during pregnancy resulting in poor pregnant weight gain and reduced fetal nutrition. the lbw will increase morbidity and mortality among children and on survival, produce another generation of adults with lesser physical and cognitive potential. to harness the progress made so far in improving the nutritional status of women and children, it is a crucial time to prepare and put in place steps to prevent an outpouring in malnutrition, micronutrient deficiencies, and lbw babies in the near future and its repercussions on the health system and human capital. also to mention, lockdown can be a risk factor for increased overweight in children which needs equal attention. this can be anticipated in urban areas as there is a high chance of consumption of junk foods and ultra-processed calorie-dense food leading to over nutrition and lack of physical activities during this period. the possible ways to ensure better nutrition among women and children in resource-constrained settings like nepal could be a combination of different measures. this includes developing and implementing mitigation strategies to reach out to those most affected by the crisis and activation and functionality of nutrition clusters at the sub-national level to ensure predictable, timely, and effective nutrition response. similarly, program and service to protect, promote and support optimal breastfeeding and age appropriate and safe complementary feeding and feeding practices should remain a critical component of the response for women and children in the context of covid-19. continuity of safe motherhood services along with maternal and child nutrition interventions are required including vitamin a and deworming tablets supplementation, screening and treatment of children with acute malnutrition, distributing fortified flour to pregnant women and children above 6 months, supplying micronutrient powder, and ensuring proper counseling on infant and young child feeding practices. similarly, mass awareness campaigns on the importance of breastfeeding, complementary feeding, and feeding during pregnancy and breastfeeding children should be done through various sources of media including mobile text messages. counseling and psychological support to mothers and caregivers of under 5year children is also required to promote nutrition, health, and wellbeing. continuation of services through outpatient therapeutic centers to treat malnourished children by applying the simplified treatment approach like reducing the number of visits and by increasing the ratio of ready to use therapeutic food to be taken to the home is required to minimize the risk of contamination. equally important is ensuring nutrition commodities are available and accessible, market supply should not be disrupted and promotion of the locally available nutritious foods should be done. in food-insecure areas where communities have limited access to adequate food, strategies such as the distribution of specialized nutritious food (e.g. supply of fortified flour) can be done. being an issue of serious concern, it would be appropriate for nepal and other similar resource constrained settings to focus its efforts on addressing the nutrition of women and children for building healthier societies. focusing only on covid-19 might bring forward other health consequences which could strain the capacity of the health system and country's socio-economic potential. nutrition should thus be a core component of the covid-19 response plan, integrated into each aspect of prevention, treatment, and recovery. nepal extends lockdown until june 14, flight suspension until ministry of health and population. covid-19 situatiion update status of women and infants in complex humanitarian emergencies complex humanitarian emergencies: a major global health challenge understanding mortality patterns in complex humanitarian emergencies. washington: forced migration and mortality national academies press emergency preparedness for infant and young child feeding in emergencies (iycf-e): an australian audit of emergency plans and guidance ministry of health nneai. nepal demographic health survey kathmandu: ministry of health and population world health organization. vitamin and mineral nutrition information system (vmnis) nepal: concern worldwide and welthungerhilfe publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations the authors acknowledge the efforts of government of nepal in its response towards prevention and management of covid-19. authors' contributions bp conceived the study and wrote the first draft of the manuscript. all others authors critically reviewed and provided their inputs. all authors read and finalized the manuscript. the author(s) read and approved the final manuscript. the authors received no specific funding for this work.availability of data and materials not applicable.ethics approval and consent to participate not applicable. not applicable. the authors declare that they have no competing interests. the views are those of the authors alone and do not necessarily reflect the positions of their employing organizations. key: cord-335582-30rws724 authors: bonal, xavier; gonzález, sheila title: the impact of lockdown on the learning gap: family and school divisions in times of crisis date: 2020-09-15 journal: int rev educ doi: 10.1007/s11159-020-09860-z sha: doc_id: 335582 cord_uid: 30rws724 the lockdown of schools in spain to confront the effects of covid-19 caused an enormous impact at both societal and educational levels. schools and families had to react rapidly to a new teaching and learning scenario without the benefit of previous planning or government guidelines. in this context, some schools were better able to adapt to the new circumstances than others. likewise, the structure and size of families’ economic, social and cultural capital produced significant differences in the learning opportunities for children from different backgrounds. this article assesses the impact of the school lockdown on the learning gap between children from different social backgrounds in catalonia. based on 35,419 responses to an online survey administered between 26 and 30 march 2020 to families with children aged between 3 and 18, the authors’ analysis shows that learning opportunities varied significantly. middle-class families were able to maintain higher standards of education quality in a critical context, while children from socially disadvantaged families had few learning opportunities both in terms of time and learning experiences (schoolwork and maintenance of after-school activities). results differed by type of school (public/private) where students were enrolled, family economic, social and cultural capital, and family living conditions. in the final part of the article, the authors highlight the importance of the role of the school in ensuring learning opportunities for children from low socioeconomic backgrounds, and they discuss some policy implications of their findings. l'impact du confinement sur les écarts en matière d'apprentissage : disparités familiales et scolaires en période de crise -la fermeture des écoles en espagne durant le confinement pour faire face aux effets de la covid-19 a eu d'immenses répercussions sur les plans sociétal et éducatif. les écoles et les familles ont rapidement réagi au nouveau scénario de l'enseignement et de l'apprentissage sans pouvoir s'appuyer sur une planification préalable ou des directives gouvernementales. dans ce contexte, certaines écoles ont réussi mieux que d'autres à s'adapter à ces nouvelles circonstances. de même, la structure et la taille du capital économique, social et culturel des familles a montré qu'en fonction de leur milieu, les enfants avaient des possibilités d'apprendre très inégales. cet article évalue l'impact de la fermeture des écoles en espagne durant le confinement sur les écarts en matière d'apprentissage chez des enfants de différents milieux sociaux en catalogne. s'appuyant sur 35 419 réponses à une enquête en ligne menée entre le 26 et le 30 mars 2020 auprès de familles avec des enfants âgés de trois à dix-huit ans, l'analyse des auteurs révèle de considérables disparités concernant les possibilités d'apprendre. les familles de la classe moyenne ont réussi à maintenir un niveau d'éducation élevé dans cette situation critique, tandis que dans les familles défavorisées sur le plan social, les possibilités des enfants étaient restreintes, tant en termes de temps que d'expériences éducatives (devoirs et maintien d'activités extrascolaires). les résultats étaient différents en fonction du type d'établissement (public/privé) où les élèves étaient inscrits, de la situation économique de la famille, du capital social et culturel de cette dernière et de ses conditions de vie. dans la dernière partie de l'article, les auteurs soulignent l'importance du rôle de l'école pour garantir la possibilité d'apprendre aux enfants de milieux socioéconomiquement faibles. ils abordent en outre un certain nombre de conséquences qu'entraînent leurs constatations pour les politiques en matière d'éducation. el impacto del cierre escolar en la brecha de aprendizaje: divisiones familiares y escolares en tiempos de crisis -el cierre de escuelas en españa para hacer frente a los efectos de la covid-19 causó un enorme impacto tanto a nivel social como educativo. escuelas y familias tuvieron que reaccionar rápidamente a un nuevo escenario de enseñanza y aprendizaje sin contar con planificación previa o con directrices gubernamentales. en este contexto, algunas escuelas fueron capaces de adaptarse mejor a las nuevas circunstancias que otras. asimismo, la estructura y el tamaño del capital económico, social y cultural de las familias produjeron diferencias significativas en las oportunidades de aprendizaje de los niños y niñas de diferentes orígenes. este artículo evalúa el impacto del cierre de las escuelas en la brecha de aprendizaje entre el alumnado de diferentes orígenes sociales en cataluña. sobre la base de 35.419 respuestas a una encuesta en línea realizada entre el 26 y el 30 de marzo de 2020 a familias con hijos e hijas de entre 3 y 18 años, el análisis muestra que las oportunidades de aprendizaje varían significativamente. las familias de clase media pudieron mantener niveles más altos de calidad educativa en un contexto crítico, mientras que los niños de familias socialmente desfavorecidas tuvieron pocas oportunidades de aprendizaje, tanto en términos de tiempo como de experiencias de aprendizaje (tareas reducing physical contact has been the most common strategy adopted by governments to reduce the spread of covid-19. it has led most countries around the world to close their schools for periods of time. the lockdown of schools in spain, one day before the declaration of a state of alarm 1 on 14 march 2020, has had an enormous impact at both societal and educational levels. schools and families had to rapidly adjust to a new teaching and learning scenario without the benefit of previous planning or guidelines from the spanish ministry of education or regional departments of education. in this context, some schools were better able to adapt to the new circumstances than others. likewise, the structure and size of families' economic, social and cultural capital 2 (resources) produced significant differences in the learning opportunities for children from different socioeconomic backgrounds. while the covid-19 pandemic has no precedent in terms of effects on the economy and social life, schools have previously experienced periods of closure. for example, large-scale outbreaks other diseases (such as ebola and influenza), teacher strikes, natural disasters and violent conflicts have already forced schools to stop their activity in the past. researchers and international organisations have studied the effects of school closures on students' learning and found a measurable loss in the acquisition of basic skills, particularly for the most disadvantaged children (quinn et al. 2016; cattaneo et al. 2017) . it is highly likely that the current pandemic will have a dramatic long-term impact on students' competencies and increase existing education inequalities. in this article we reflect on how school closure produces unequal learning opportunities in terms of both formal and non-formal education 3 for children and youth from different socioeconomic backgrounds attending different types of schools in catalonia. during the covid-19 catalan lockdown, the instructional time received by students from different social backgrounds has been unequal, as has the educational value of the activities developed at home in non-school time. we investigated what learning opportunities were available to students from different backgrounds by administering an online survey during the second week of the state of alarm (i.e. between 26 and 30 march 2020). hypothesising that exposure to learning (both formal and non-formal) among children from lower-income households was likely to be lower than for their peers from higher-income families, we expected this to irremediably increase the existing learning gap between them. based on the results of our survey, this article reflects on how students' social background and conditions of confinement were associated with their learning opportunities. these unequal opportunities, in turn, are likely to exacerbate existing inequalities in skills acquisition and academic performance. we begin our article with a review of existing evidence on learning losses and their unequal impact on different groups of students due to past periods of school shutdown. the next section provides information on the context in which we conducted our own survey and the methodology we used to analyse the data. we then present our key findings regarding inequalities in formal and non-formal education, while the final section draws conclusions and discusses some policy implications of our findings. although it has only been a few months since schools in many countries around the world closed due to the covid-19 pandemic, research on the educational effects from that closure has already been notably rich. obviously, most of these studies have measured the short-term effects of the lockdown. it is certainly too early to know whether these effects can be considered a learning loss or just a temporary effect as a result of disuse that can be easily regained with practice (coe et al. 2020) . beyond this recent evidence, several previous studies based on student absenteeeism and past school closures have focused on the impacts of being out of school on learning outcomes (abadzi 2009; eef 2018) . these research studies can help us understand the potential effects of current school closures on learning and the mechanisms by which educational inequalities occur. some of the reasons causing schools to reduce or even stop their activity in the past range from summer school holidays, student or teacher absenteeism and teacher strikes to violent conflicts. extant research evidence based on these experiences identifies the existence of a general loss of learning connected to school absence, which can be more or less severe depending on students' previous performance, family characteristics, age, and education pathway, among other factors. school closure, even when distance (remote) learning is offered, usually implies a reduction in instructional time 4 and, by consequence, also a decline in learning time. 5 past studies have consistently identified a positive relationship between learning time and student achievement -along with other educational outcomes (abadzi 2009; hanushek 2015; scheerens 2014) . therefore, some studies have used instructional time as a proxy for "opportunities to learn". variables that measure exposure to curriculum seem to show a greater effect on learning than variables related to teacher behaviour or school climate. students' prolonged and repeated exposure to stimuli and feedback has been identified as a key educational resource. even though evidence is not always conclusive (cattaneo et al. 2017) , most research suggests that students with a migrant background, and those who are socioeconomically disadvantaged, will be slower learners. thus, these students are likely to benefit more from an increase in learning time than their peers (dahmann 2015; gromada and shewbridge 2016; huebener et al. 2017 ). consequently, not going to school reduces learning opportunities for all, but particularly for students from low-income backgrounds and less-skilled children. student (or teacher) absenteeism can also be understood as a lack of instructional time. student absenteeism results in poorer academic achievement, gaps in skills development, abilities and behaviours necessary for educational success, and an increased likelihood of school dropout. effects go beyond the school environment: absence has also been connected to risky behaviours such as smoking, juvenile delinquency, alcoholism, drug use, risky sexual behaviours or unwanted pregnancies, as well as other effects in adulthood (e.g. unemployment, alcoholism) which diminish life opportunities for young absentees (abadzi 2009; coe et al. 2020; gonzález motos 2020) . in spain, as in other european countries, the school lockdown between march and june 2020 seamlessly merged with the beginning of the summer holidays, resulting in students' absence from school lasting six months. past studies comparing students' learning progress during the school year with the summer break have consistently shown that achievement tends to slow or decline over the summer holidays. although there is no agreement on the magnitude of the learning loss during holidays (von hippel 2019), it is clear that it is steeper for mathematics than reading, and it is especially acute for upper-grade students . moreover, research points out that this loss does not affect all students equally; during the summer period, educational inequalities between socially advantaged and disadvantaged children increase (alegre 2016) . beyond the evidence related to breaks in the ordinary school year (e.g. absenteeism, summer break, instructional time), other research studies have analysed the effects on students' learning caused by external factors. for example, the literature on weather-related school closures (e.g. as a result of heavy snowfall or hurricanes) also contributes to a better understanding of the potential unexpected consequences of disruptive closures. most of the evidence is based on small samples, is geographically specific and refers to short break periods. however, in all cases, studies have found a clear effect of each day of school cancellation on achievement, especially among students attending less-resourced schools or coming from low-income families (goodman 2014; marcotte and hemelt 2008) . teacher strikes have also forced a sudden cancellation of classes. strikes affect student learning outcomes (mainly in terms of achievement and grade repetition) by reducing the time that children attend school, but they also affect the quality of schooling and increase the likelihood that students may engage in risky behaviour (jaume and willén 2019). in addition, research has found heterogeneous (uneven) effects, with children from vulnerable families being most affected by school disruptions (jaume and willén 2019; belot and webbink 2010). the main difference between school closures examined by previous studies and the current lockdown is that this time schools have managed to maintain some contact with students, mostly through online instruction. however, despite the efforts to support remote learning, many students have not had access to it. existing data about the digital gap and surveys conducted during the lockdown indicate that teachers have been unable to contact a significant number of students, mainly because of lack of an internet connection or adequate devices to engage in distance learning ; van lancker and parolin 2020). even when students have been able to connect, remote learning during school closures seems to have widened the existing attainment gap between students from different socioeconomic backgrounds (coe et al. 2020) . for instance, a recent study undertaken by researchers from brown and harvard universities into the use of an online mathematics programme (zearn) before and during lockdown in the united states (chetty et al. 2020 ) shows a sharp decline of student progress in mathematics in classrooms located in low-income zip (postal) code areas, while in high-income zip code areass no changes were observed (goldstein 2020) . before the covid-19 pandemic, in-school learning had already been proven to be more effective than distance learning. furthermore, student outcomes resulting from online learning have been shown to be poorer, on average, than outcomes resulting from face-to-face instruction (heppen et al. 2017) . conditions for effective remote learning (good internet connection, and clear explanations, scaffolding and feedback from teachers) are not easy to accomplish. the combination of a digital gap with teacher inexperience in providing high-quality distance learning makes it difficult to improve students' learning opportunities . moreover, there is now a significant risk that vulnerable students have less access to quality teaching than their peers, widening the attainment gap due to the school lockdown (coe et al. 2020; kay et al. 2020) . if it has already been proven that students from low-income families experience more interruptions and disruptions of their instructional time under normal school conditions (abadzi 2009; alegre and benito 2012) , then poor distance learning can be understood as a new obstacle to effective learning. apart from school organisation or distance learning strategies developed by teachers, parental engagement in children's learning, practised in some families alongside school attendance, becomes more important when school is replaced by at-home instruction. educational studies have demonstrated that parental involvement and the quality of learning at home improve academic outcomes. research in this field has consistently observed greater academic achievement among students whose parents are actively involved in the educational process. it has also found a clear relationship between engagement in the learning process and parental background in terms of social class and ethnicity (oreopoulos et al. 2006) . unequal parental capacities to help children with their homework and different uses of family time have been extensively documented (meyer et al. 2017; mora and escardíbul 2018) . therefore, family reactions to school lockdown are likely to produce significant differences in the learning opportunities for children from different types of social background (burgess and sievertsen 2020) . regardless of their causes and mechanisms, previous crises have had a more intense and negative effect on student learning outcomes in contexts with higher proportions of disadvantaged families (borse et al. 2011; chen et al. 2011; iqbal et al. 2020; sadique et al. 2008; shores and steinberg 2018) . previous research also suggests that the learning loss can not only have a limited short-term effect, but may in fact result in cumulative losses (abadzi 2009 ). likewise, other researchers suggest that the current school lockdowns will widen the learning gap between vulnerable children and their peers, possibly even reversing the progress made during the last decade to narrow this gap (coe et al. 2020 ; van lancker and parolin 2020). on 13 march 2020, the catalan government ordered the closure of all schools and colleges (universities) due to the covid-19 pandemic. more than one million students in compulsory education 6 were asked to stay at home. during the first two weeks of confinement, the catalan department of education advised schools not to provide new curriculum content, in an attempt to contain the adverse effects of the technological gap on educational inequalities. despite the department of education's order, some schools reacted rapidly to the new circumstances and switched to remote learning strategies. other schools stopped their activities entirely. between these two extremes, there were a range of reactions and responses. between 26 and 30 march, after two weeks of school closure and before the spanish government ordered a more restricted lockdown, we (the authors of this article) conducted an online survey with families whose children were aged between 3 and 18. the survey was addressed to families with children enrolled in preschool (3-5 years old), primary school (6-12 years old), lower secondary education (12-16 years old) and post-secondary academic or vocational education (16-18 years old). 7 organised into two main sets of questions, our survey included 78 items, with a variable number of subquestions that branched out to adapt to respondents' particular contexts. the first group of items characterised the different social, spatial and technological conditions in which families had to respond to the school lockdown (such as the size of their home, the availability of outdoor spaces, access to the internet and to digital devices). the second set of questions was designed to assess children's learning opportunities in (a) formal education (contact with school teachers, frequency and types of school tasks, feedback provided by schools), (b) informal education (uses of time, family activities, support to carry out school tasks) and (c) non-formal education practices from home (participation in after-school activities, types of activities and forms of participation). in addition, our survey included variables to characterise respondents' social and economic conditions, such as family structure, parental education attainment, income, ethnic origin, gender and work status. to test the survey, we conducted a brief pilot. due to the exceptional circumstances, the pilot was implemented using an informal strategy: we asked 10 families with children of different ages and on different school pathways to complete the survey. after the pilot was completed, we distributed the final version of the survey through various online communication channels (twitter, facebook and whats app). this strategy helped us to improve the survey's visibility among different social groups as well as reducing sampling bias linked to the use of social networks (blank 2017) . we also mobilised strategic contacts in the most deprived areas of catalonia to reach those families less likely to answer online surveys. in total, 79,668 people clicked the link to the survey, approximately 58,000 started to answer it and more than 40,000 families completed it. after excluding some respondents for reasons like incomplete answers, children's ages outside our survey's scope, families not living in catalonia, the final sample included information from 35,419 families (with a total of 59,167 children aged between 3 and 18). as expected, high-income and highly educated parents were over-represented. due to the lockdown and the urgent need for data collection, we were unable to complement our online survey with other strategies such as telephone calls or face-toface interviews. we opted instead to use non-response weighting to bring the sample closer to the population distribution. to do this, we weighted the sample by the level of parental education attainment, as a key variable of social and cultural differentiation, and as a reliable and accurate source of census data. table 1 shows both the weighted and unweighted samples. of our survey respondents, 86% were female, 89.3% lived in heterosexual biparental households, 9.6% lived in single-parent households and 1.1% were part of a same-sex couple. more than half of the households (53%) were composed of four members, three-member households represented 27% of the sample, and 16% of the households had five or more members. sample distribution according to school variables accurately reflects the distribution between the public and private school sectors. 8 in catalonia, the proportion of children in compulsory schooling who attend public schools is 68% (this was 69.9% in our sample), while 29% of students attend private subsidised schools (27.5% in our sample), and only 2% are enrolled in private independent schools (2.6% in our sample). our sample was also well balanced regarding children's ages, with a slight over-representation of younger students. 9 for our data analysis, we split information across three databases according to different units of analysis. first, a "household database" included information about family members living together during the confinement. second, a "student database" collected information about the learning activities of children aged between 3 and 18. third, the "after-school activities database" contained information about the extracurricular activities children were involved in before and after the lockdown. we also constructed some subsamples to carry out specific analyses. in this article, we present some data based on subsamples by children's age or educational level. in this section, we present and discuss the data from our survey regarding social differences in the learning conditions of catalan children and the impact of these conditions on learning opportunities during lockdown. inequalities in families' economic, social and cultural capital impacted on student learning opportunities by different means, including school responses to the lockdown, access to digital facilities and the level of parental learning support. this section reviews how these factors are drivers of inequalities in the three domains of learning: formal, non-formal and informal. learning conditions at home differ on the basis of a number of variables. for example, the amount of physical space and access to technological devices both have an impact on the learning conditions of children. our survey included questions about the size of the household and the outdoor spaces available, to serve as indicators of the physical conditions of confinement. the responses showed that most homes of confined families had a balcony or other outdoor space/s. however, there were significant differences among residents depending on the size of the municipality (families living in cities had less access to outdoor spaces) and other social indicators, such as parental education attainment. for instance, 13% of families with an adult who had completed compulsory education did not have outdoor spaces, while this was only the case for 4% of households in which at least one adult held a university degree. likewise, 45% of households in the poorest income quintile (q1) 10 had less than 80 square metres of space, reducing to 14% in the case of the richest income quintile (q5). students also had different internet connectivity conditions and unequal opportunities to access technological devices to carry out their schoolwork. since we could only implement an online survey, we were unable to grasp the full extent of the actual digital divide. data from the catalan department of education estimate that there are currently approximately 55,000 school children without access to an internet connection (vallespín 2020) , which would situate the digital gap at between 10% and 15% of all children in the catalan education system. our survey revealed that 3.5% of our sample had only a mobile phone internet connection or no connection at all. most families in our survey had access to a high-speed internet connection. however, there were important differences regarding the "possibilities of use" of technology. for example, 15.3% of respondents declared that they had access to a single device at home or only had access to a mobile phone. we calculated the number of devices per person and found that in 56% of cases there was less than one device per person. the digital divide can also be expressed in terms of access to devices based on the composition of the household. in our survey, 12% of households with two children had only one device available; 32% of households with three children had two or fewer devices available; and 48% of households with three children had three or fewer devices available. access to technology depends on the level of family income. while 25% of surveyed families in q1 (the lowest income quintile) had access to only one digital device, for families in q5 (the highest quintile), the corresponding figure was only 4%. furthermore, while 20% of families in q1 had access to four or more devices, this applied to 54% of families in q5. taking into account the size of the household, 71% of families in q1 did not have access to one device per person. among families in q5, the number of households with less than one device per person reduced to 37%. figure 1 shows the proportion of households for each income quintile that had access to one or more device per person. differences are sorted by income, with an inequality factor of 2.5 between q5 and q1. in addition, the unequal impact of the crisis on parents' working situation also altered the social and psychological conditions that ensured an adequate learning process. our survey revealed that before lockdown, 13% of adults were unemployed, while 80% were working full-time. when we asked about the impact of the covid-19 crisis on their working situation, these figures changed dramatically: 23% of respondents indicated that they had lost their job. of those who were still working, only 21.5% were able to go to work "normally". the rest (39%) were working from home, either with the same schedule or with a more flexible schedule. of those still working, 17% considered it likely that they would lose their job. of those who were already or became unemployed, 50% knew that they were entitled to unemployment benefits, while the other 50% either knew that they were not entitled or did not know. our survey included questions regarding how much time children invested in schoolwork every day since the beginning of the school lockdown, how frequent the contact was with their school and teacher/s, how often they received online teaching lessons, whether they had to complete specific homework tasks, and how often these tasks were reviewed and returned to children. taking into account the intensity of all these tasks, we composed an index of opportunities to learn (otl). to compose the index, which ranged from 0 to 100 points, we normalised indicators and aggregated (combined) frequencies. we only used this index for a subsample of the older children aged between 10 and 18, since assigned school tasks or online teaching were more unlikely for younger age groups. in terms of the index, 28.3% of students had an otl equal to 0, meaning that they dedicated less than one hour a day to school tasks, had almost no communication with teachers and did not have homework to do or to be reviewed. at the other end of the index, 7.7% of students had a maximum otl of 100, meaning that they dedicated more than four hours per day to schoolwork, had frequent contact with their teachers and received regular feedback for school assignments. the majority (80.2%) of all surveyed students in this subsample had an otl score below 60 points. interestingly, we found the otl score to be positively related to a number of variables. having greater access to digital devices, being enrolled in more advanced courses (older students had a higher otl), being native to spain or living in a higher-income household were all factors associated with higher otl scores. students enrolled in private schools, both independent and private subsidised ones, had significantly higher otl scores than those enrolled in public schools. there are explanations for this difference. for example, the catalan department of education announced that the first two weeks after the approval of the state of alarm would be a non-school period. therefore, a significant number figure 2 opportunities to learn (otl) index, by school sector and educational level note: baccalaureate refers to two years of optional upper secondary education preparing students for tertiary level of public schools did not develop school tasks during these two weeks, waiting for new instructions from the department. despite this announcement, private subsidised and independent schools did not stop their teaching activity. one of the plausible explanations for this difference lies in the economic dependency of private schools on fees. they needed to keep providing a service to users despite the exceptional circumstances. figure 2 shows the distribution of the otl index across school sectors for different educational levels. the bar chart reveals strong differences by school sector for students enrolled in the last years of primary education and for those in lower secondary education. the chart also shows how students in vocational education and training (vet) had the lowest otl of post-compulsory education. we also found the otl index to be clearly related to the level of parental education attainment and to family income. for instance, 49% of children in families from the richest quintile (q5) had an otl score of 80 points or higher. this reduced to 33% in the case of the poorest quintile (q1). the absence of schooling increases the importance of families as teacher substitutes in the learning process. our survey included questions regarding whether adults in the family helped students in their school tasks during the relevant lockdown period. an initial remarkable result appeared in terms of gender: while 79% of female adults stated that they supported their children to do schoolwork, only 43% of male adults did. as expected, gender differences were clearly observed, and family support was higher in the case of younger children. figure 3 shows that for children undertaking primary education, the support of mothers who had completed compulsory figure 3 adult support for school tasks, by gender and highest parental education attainment education was comparable to that of mothers with higher educational (in bourdieu's terms) cultural capital. however, for students enrolled in lower secondary education, the differences increased dramatically: only 35% of mothers who had completed compulsory education helped with homework, while 48% of the most educated mothers did. providing support for school tasks to students in post-compulsory education declined to close to 20% for all groups. there are several reasons why support for schoolwork may not have been provided by adults in a student's household. these reasons are remarkably different depending on the level of parental education attainment. in those households in our survey with children enrolled in lower secondary education, 92% of the families with an adult who had a university degree and who did not provide support for schoolwork argued that the child did not need it. this reason was only argued by 69% of respondents from those households with adults who had completed only compulsory education. in this case, a lack of knowledge was proffered as a significant reason for not giving support (by 28% of respondents), which reduced to 2% for those parents with a university degree. differences in cultural capital are therefore reflected in the capacity and possibilities of families to help children with their school tasks. in addition, (and not just in times of school closure) families' cultural capital and everyday informal practices have effects on children's learning experiences and opportunities. interestingly, confinement, which maximises the interactive time between family members, provides ideal research conditions for assessing informal learning activities. figure 4 reveals that in those households with children aged between 3 and 8, there were three activities in which social differences were especially acute. first, accompanying children in reading was more frequent by far in families with high cultural capital: 59% of families with an adult who had completed university studies responded that their children aged between 3 and 8 read with an adult every day. this reduced to only 37% in the case of families with an adult who had completed compulsory education. second, differences were also visible in foreign language informal practices: 44% of families with an adult who had completed university studies responded that foreign language practice was done daily or several days a week, while this practice was carried out by only 36% of families with an adult who had completed compulsory education. third, sporting activities were practised several times a week by 81% of families with university degrees and only by 66% of families with compulsory education. by contrast, other activities were more frequent among families with lower cultural capital. the most relevant was playing video games: 37% of families with an adult who had completed compulsory education reported that their children of preschool age played video games every day or several times a week. this applied to only 21.5% of families with parents who had completed university studies. the differences were also significant in the frequency of watching educational television programmes (52% of households with parents who had completed compulsory education and who had children enrolled in preschool education reported that their children did so every day, versus 30% of parents with a university degree), and in following and carrying out educational activities available via social media. in such an extreme situation of school absence, it appears that families with less cultural capital made more use of external resources to support their children's learning activities, while families with more cultural capital were more confident in their own abilities to respond to their children's learning needs. in the case of older children, the same differences were observed, although the gap increased in musical and other artistic activities and was less pronounced in playing video games. participation in after-school activities is a source of differential learning opportunities for children from different socioeconomic backgrounds (bradley and conway 2016; gonzález motos 2016; lauer et al. 2003; potter and morris 2017) . our survey compared whether children participated in one or more after-school activities before and after the beginning of the lockdown. we found that the effects of covid-19 on these kinds of activities have also increased the gap between socially advantaged and disadvantaged children. before lockdown, after-school activities were more frequent for students enrolled in primary education. this was particularly the case for children whose parent/s had completed a university degree (66%), compared to children from households with parent/s who had completed compulsory education (43%). this polarisation increased particularly for children enrolled in lower secondary education with at least one unversity-educated parent (81%) versus those whose parent/s had completed compulsory education (45%). we also found families' economic, social and cultural capital to be associated with the number of after-school activities in which children participated. for example, for families with two children in lower secondary education, the average number of after-school activities for highly educated households was 3.3, compared to 1.5 for households with lower educational levels. sports, foreign languages and artistic practices were the most frequently reported after-school activities. by income level, students in families in the lowest quintile (q1) were more represented in sports and compensatory education activities, 11 while children from the richest quintiles were over-represented in foreign language and musical after-school activities. as expected, we found that most after-school activities (70%) were interrupted during lockdown. however, economic and cultural inequalities were also visible in the probability of maintaining after-school activities despite the confinement. figure 5 shows that children whose parent/s had lower educational levels already had lower participation in after-school activities before lockdown and were more likely to be unable to continue them after schools closed than children from families with higher educational levels. there are two main reasons for this difference in after-school activities after the closure of schools. first, families with higher economic, social and cultural capital participated in activities that were more likely to continue online (e.g artistic activities, foreign languages), compared to the activities more commonly practised by families with lower capital (e.g. sports). second, voluntary interruption of afterschool activities was also higher among families with lower ecoomic, social and cultural capital, due to difficulties in coping with the costs during times of crisis. for instance, compensatory education activities -which could be undertaken online -were voluntarily interrupted by 25% of families who had previously engaged in figure 5 after-school activities before and after lockdown, by parental education attainment 11 compensatory education, in this context, refers to those after-school classes that some students attend to reinforce their learning competencies. these classes are usually offered to students with marked learning difficulties. them. this voluntary interruption was particularly high among children whose parent/s attained compulsory education (80%), compared to those whose parent/s had a university degree (62%). despite schools' efforts to maintain learning activities during lockdown, our analysis reflects significant inequalities in exposure to school learning depending on family characteristics (income, level of educational attainment) and school characteristics (educational level, school sector). the absence of schooling neutralises the benefits of socialisation provided by early childhood education for the most vulnerable children. it also disrupts those processes of guidance and accompaniment which are especially important for adolescent students in their study, work and life transitions. in addition, the digital divide and visible differences in access to technological devices among students have left some children and young people without options to connect to learning for at least three months or, more probably, for six months. inequalities in being able to maintain school-based learning are not the only existing ones. our analysis shows that families with a lower level of parental education attainment have fewer resources and less knowledge to help their children with school tasks. these limitations become more acute when support from the school has been reduced and demands for autonomous work by students increase. likewise, family economic, social and cultural capital also influences the adoption of everyday informal learning practices that are more or less aligned with school logic, which readily increases differences in learning opportunities and familiarity with what is considered valid knowledge. after-school activities are also more likely to be maintained among children from wealthier families, which also increases the existing inequalities in this area. in sum, if the pre-covid-19 school system already had significant limitations in its ability to eliminate existing social inequalities, the closure of schools during this period of lockdown poses enormous challenges for developing effective policies to compensate for learning losses and learning inequalities. school lockdown has not affected all children in the same way, and significant material and human resources will be necessary to ensure that the most vulnerable children can catch up. an educational emergency plan with social and educational objectives will be needed to restore children's socio-emotional and cognitive skills. the individual and social costs of not intervening are just too high, unfair and unequal. it is the responsibility of states and countries to ensure the right to education in these difficult times. instructional time loss in developing countries: concepts, measurement, and implications are summer programs effective in improving learning and educational outcomes in students? barcelona: ivàlua-fundació jaume bofill climas y (sobre todo) culturas escolares: cómo se explican y qué permiten explicar familia y relaciones intergeneracionales: un espacio de oportunidades para la educación de los hijos e hijas [family and intergenerational relations: a space of opportunity for the education of children do teacher strikes harm educational attainment of students? the digital divide among twitter users and its implications for social research closing schools in response to the 2009 pandemic influenza a h1n1 virus in new york city: economic impact on households the forms of capital a dual step transfer model: sport and non-sport extracurricular activities and the enhancement of academic achievement schools, skills, and learning: the impact of covid-19 on education. vox, cepr policy portal the more, the better? the impact of instructional time on student performance social and economic impact of school closure resulting from pandemic influenza a/h1n1 how did covid-19 and stabilization policies ffect spending and employment? a new real-time economic tracker based on private sector data impact of school closures on the attainment gap: rapid evidence assessment. london: education endowment foundation (eef) how does education improve cognitive skills? instructional time versus timing of instruction. german socio-economic panel study (soep)paper series the attainment gap // 2017. london: education endowment foundation research shows students falling months behind during virus disruptions. the new york times what impact do after-school activities have on children's and youngsters' learning? what works in education? series are programmes to combat school absenteeism effective? what works in education? series flaking out: student absences and snow days as disruptions of instruction time. nber working paper series constitución española [spanish constitution student learning time: a literature review time in education: introduction the struggle to pass algebra: online vs. face-to-face credit recovery for at-risk urban students increased instruction hours and the widening gap in student performance scientific and cultural organization) (n.d.-a). instructional time. ibe-unesco glossary of curriculum terminology learning time. ibe-unesco glossary of curriculum terminology population figures [online resource we should avoid flattening the curve in education: possible scenarios for learning loss during the school lockdowns. education for global development the long-run effects of teacher strikes: evidence from argentina remote learning: rapid evidence assessment. london/cambridge: education endowment foundation (eef)/edtechhub. retrieved projecting the potential impacts of covid-19 school closures on academic achievement the covid-19 slide: what summer learning loss can tell us about the potential impact of school closures on student academic achievement the effectiveness of out-of-school-time strategies in assisting low-achieving students in reading and mathematics: a research synthesis unscheduled school closings and student performance patterns of literacy learning in german primary schools over the summer and the influence of home literacy practices home environment and parental involvement in homework during adolescence in catalonia (spain) the intergenerational effects of compulsory schooling family and schooling experiences in racial/ethnic academic achievement gaps: a cumulative perspective seasonal dynamics of academic achievement inequality by socioeconomic status and race/ethnicity: updating and extending past research with new national data estimating the costs of school closure for mitigating an influenza pandemic effectiveness of time investments in education. springerbriefs in education series the impact of the great recession on student achievement: evidence from population data educació detecta 55.000 famílies sense ordinador o sense connexió per poder seguir les classes a distància covid-19, school closures, and child poverty: a social crisis in the making is summer learning loss real? education next publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations he has been a member of the eu network of experts in social sciences and education (nesse) and is an editorial board member of several international journals on education policies and educational development. xavier has widely published in national and international journals and is the author of several books on the sociology of education, education policy and globalisation, and education and development. he has worked as a consultant for international organisations such as unesco, unicef, the european commission, and the council of europe she is a member of the institute of government and public policy (igop) and the globalisation, education and social policies (geps) research centre. her research interests include public policy analysis and social inequalities, with a special focus on education and migration. sheila has conducted several research projects in this field, and she has experience in policy analysis and policy evaluation the data that support the findings of this study are available from the corresponding author, upon reasonable request. authors' contributions: all authors contributed to the study conception and design. material preparation, data collection and analysis were performed by xavier bonal and sheila gonzález. all authors read and approved the final manuscript. key: cord-343910-jib877fo authors: guidotti, m.; gateau, a.; malvy, j.; bonnet-brilhault, f. title: does autism protect against covid quarantine effects? date: 2020-10-14 journal: nan doi: 10.1101/2020.10.13.20212118 sha: doc_id: 343910 cord_uid: jib877fo introduction: covid-19 outbreak has imposed an eight-week confinement in france. during this period, children and their families were exposed to a full-time home life. the aim of this study was to assess the emotional experience and tolerance of children with autism spectrum disorder (asd) in this particular context. method: a clinical survey was proposed to parents and rated by professionals once a week during the quarantine period in france. 95 autistic children followed by the child and adolescent psychiatry department of tours university hospital were assessed from the 18th of march to the 8th of may. the following clinical points were investigated: child anxiety, family anxiety, behavior problems, impact on sleep, impact on appetite, impact on school work, family tension, confinement intolerance, difficulties to follow a schedule, isolation behavior. results: despite minor changes in family anxiety and school work, no difference was highlighted between clinical scores collected at the beginning and at the end of this period. asd children with or without intellectual disability had non-significant clinical changes during quarantine. this evolution was also independent of the accommodation type (house or apartment) and the parental status (relationship, separated or isolated). conclusion: the sameness dimension in autism and parents adaptation may be involved in this clinical stability during covid confinement. moreover, specialized tools and support provided by professionals could have participated to these outcomes and must be regularly promoted in order to help families in this still difficult period. covid-19 outbreak began in china at the end of 2019 and quickly spread to europe. in france, the confinement of the population began on the 17 th of march and schools closed the day before. this new situation, which lasted officially until the 11 th of may, exposed children and parents to a full-time home life. we know that this lifestyle can be difficult for families, especially for children suffering from mental diseases [1] . the psychological impact of quarantine is heterogeneous and can be long lasting, including anxiety, depression symptoms and feelings of anger and fear. to limit these consequences, it is recommended to reduce boredom and improve communication [2] . in order to help parents at home, some advice was published to manage children suffering from autism spectrum disorder (asd) [3] . furthermore, health professionals regularly contacted families to get news and to provide some personal advice. considering these clinical resources, we investigated how well the covid-19 quarantine was tolerated by autistic children who benefit from regular rehab programs in the child and adolescent psychiatry department of tours university hospital. a telephone survey was proposed to families, once a week, during french lockdown. the following clinical points were investigated by health professionals (doctors, nurses and psychologists): child anxiety, family anxiety, behavior problems, impact on sleep, impact on appetite, impact on school work, family tension, confinement intolerance, difficulties to follow a schedule, isolation behavior. each of these ten clinical items was rated on a 5-point scale in reference to the basal clinical state of the child: 1/not at all, 2/a little, 3/moderately, 4/a lot or 5/enormously. the mean of the completed clinical items, labelled emotional score, was computed. two time points were considered: the 3 first weeks (t1) and the 3 last weeks is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october 14, 2020. . https://doi.org/10.1101/2020.10.13.20212118 doi: medrxiv preprint of the recruitment period (t2). furthermore, the accommodation type (apartment or house) and the parental status were also collected. additionally, parents were regularly contacted by professionals and many supporting materials were sent to families (sensorimotor activities, timetables, simplified covid explanations) during this period. sphinxonline v 4.16 was used for data collection. student t-test and linear mixed-effect models with repeated measures (patients as random effect; time and id, accommodation type or parental status as fixed effects) were carried out to study the effect of the quarantine between t1 and t2 time points. approval of tours hospital ethical committee has been granted to conduct this project. results 95 children with asd, aged from 2 to 16 years old, were recruited from the 18 th of march to the 8 th of may in the child and adolescent psychiatry department of tours university hospital (table 1) . is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october 14, 2020. . https://doi.org/10.1101/2020.10.13.20212118 doi: medrxiv preprint eight clinical items (child anxiety, behavior problems, impact on sleep, impact on appetite, family tension, confinement intolerance, difficulties to follow a schedule, isolation behavior) had an average score of less than 2 and two items (family anxiety and impact on school work) were greater than 2 at both t1 and t2 time points (fig.1) . the emotional score (n=95) was 1.82 (sd: 0.59) at t1 and 1.78 (sd: 0.59) at t2, no statistical difference was observed (t(188)=0.44, p=0.66)). moreover there was no di effect (di effect: p=0.54, interaction di * time: p=0.83), no accommodation type effect (accommodation type effect: p=0.12, interaction accommodation type * time: p=0.61), and no parental status effect (parental status effect: p=0.88, interaction parental status * time: p=0.93). no difference was highlighted between clinical scores collected at the beginning and at the end of french covid confinement in our sample. despite minor changes in family anxiety and impact on school work, the emotional score was unchanged. this evolution was not found by colizzi et al. (2020) , who highlight more frequent and intense behavior problems during confinement [4] . however, unlike colizzi's study, our investigation was a prospective survey and included children followed by professionals. the latter regularly contacted families and offered adapted and personalized tools during quarantine. indeed, we argue that the materials sent and regular support provided by professionals prevented an increase of anxiety and behavioral disturbances. our outcomes may also be linked to autism's sameness dimension [5] , associated to the tendency to seek immutability and to be afraid of changes [6] . furthermore, the decrease of social interactions and sensory exterior inputs during the confinement could have helped to maintain environmental stability. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october 14, 2020. . https://doi.org/10.1101/2020.10.13.20212118 doi: medrxiv preprint another result of our survey was the minor changes in family anxiety and school work. during quarantine, parents had to ensure their children's schooling in addition to their work. this double task was complicated, especially since the education of autistic children presents several particularities and needs specific materials [7] . moreover, lei et al. (2020) described an increased prevalence of anxiety and depression in adults affected by quarantine [8] , which could have participated to our parents' distress. furthermore, we found that the accommodation type and parental status did not influence the emotional experience and tolerance of children to quarantine. these independent factors can highlight the significance of routine and environmental stability. on the other hand, autistic children were allowed to go out longer (> 1 hour per day) than other children from the 2 nd of april (from the mid-time of quarantine); this political decision could have impacted the effect of these variables. finally, our survey has some limits. firstly, clinical points were evaluated by parents and rated by professionals who know the children: this method does not ensure the uniformity of measurements. secondly, our study was based on children followed by a single center with specific procedures which limits generalization to other situations. this prospective study underlines the unchanged emotional experience and behavior in asd children during quarantine in france. asd particularities and parents' adjustments to the situation probably contributed to this clinical stability; moreover, professionals' support and specialized tools likely participated to these results as well and must be promoted in order to help families in this still difficult period. finally, going back to school and the resumption of is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted october 14, 2020. . https://doi.org/10.1101/2020.10.13.20212118 doi: medrxiv preprint activities with covid restrictions will be fragile moments in asd children's lives, and would deserve a specific assessment. how is covid-19 affecting the mental health of children with special educational needs and disabilities and their families? the psychological impact of quarantine and how to reduce it: rapid review of the evidence. the lancet parenting in a time of covid-19 psychosocial and behavioral impact of covid-19 in autism spectrum disorder: an online parent survey investigating the structure of the restricted, repetitive behaviours and interests domain of autism diagnostic and statistical manual of mental disorders: dsm-5 tm transition to school for children with autism spectrum disorder: a systematic review comparison of prevalence and associated factors of anxiety and depression among people affected by versus people unaffected by quarantine during the covid-19 epidemic in southwestern china the authors declare that they have no conflict of interest. key: cord-335051-31imf6bv authors: tsabouri, sophia; makis, alexandros; kosmeri, chrysoula; siomou, ekaterini title: special article: risk factors for severity in children with coronavirus-19 disease (covid-19): a comprehensive literature review date: 2020-07-30 journal: pediatr clin north am doi: 10.1016/j.pcl.2020.07.014 sha: doc_id: 335051 cord_uid: 31imf6bv the ongoing coronavirus disease 2019 (covid-19) pandemic has affected hundreds of thousands of people, including infants and children. we carried out a comprehensive literature review to identify the underlying mechanisms and risk factors for severe covid-19 in children, in comparison with the other two coronavirus outbreaks in the past, sars and mers. search in the pubmed and scopus databases to identify publications between february 26, 2020 and june 10, 2020 identified 23 relevant papers in english. children have so far accounted for 1.7-2% of the diagnosed cases of covid-19. they often have milder disease than adults, and child deaths have been rare. the documented risk factors for severe disease in children are young age and underlying comorbidities, although the potentially fatal multisystem inflammatory syndrome (mis) occurs in older children. it is unclear whether male gender and certain laboratory and imaging findings can also be considered as risk factors, due to current insufficiency of evidence. reports on other potential factors, such as vitamin d level, responsiveness of the immune system, co-infections and genetic polymorphisms have not yet been published. • the ongoing coronavirus disease 2019 pandemic has affected hundreds of 49 thousands of people. • children have so far accounted for 1.7-2% of diagnosed cases of • children often have milder disease than adults, and child deaths have been rare. • risk factors for severe disease from covid-19 in children are reported to be young age 53 and underlying comorbidities, although not confirmed in all studies. • it is unclear whether male gender, and certain laboratory and imaging findings can also 55 be considered as risk factors, due to insufficient data. 1% of the cases were in children younger than 10 years and 1% of the cases were in children 103 aged 10 to 19 years. 8 in the usa, among 149,082 reported cases of covid-19, 1.7% were in 104 children aged under 18 years. 9 from the currently available data it appears that children tend to 105 have asymptomatic or mild disease more commonly than adults, 8,10 but severe cases and even 106 deaths have been reported worldwide in patients younger than 18 years. in a cohort study of 107 32,583 confirmed cases of covid-19 from wuhan, china, 4.1% of severe and critical cases 108 were in patients aged < 20 years. 11 according to a large retrospective study conducted in china, 4 hcovs, 110 hcov-229e, hcov-nl63 and hcov-hku1, were more common in children, , as their 111 prevalence was 4.3%, and the highest prevalence was among infants aged 7-12 months. 12 infection by these 4 strains usually causes acute respiratory disease, with severe manifestations 113 in some children. 13 regarding sars-cov, only 6 case series have been reported, including a 114 total of 135 pediatric cases, from canada, hong kong, taiwan and singapore. 14 a milder form 115 of the disease was observed in children compared with adults, and no child death was 116 recorded. 15 in the mers-cov epidemic, pediatric cases were even fewer, as only two small 117 case series of children were reported, both originating from saudi arabia, one of 31 children 118 with a mean age of 10 years 16 and one of 7 children with a mean age of 8 years. 17 in both 119 studies, 42% of the infected children were asymptomatic, 16,17 and in one, 2 of the 7 had severe 120 disease 17 , while in the other, 2 of the 31 children died (6% can predispose to severe disease. in contrast to adults, in whom older age is an independent 387 risk factor for severity and mortality, very young age is considered a risk factor for severity 388 in children, although this has recently been questioned, and mis occurs in older children. although a distinct pattern of laboratory findings has not emerged as being associated with 390 severity of the disease in pediatric cases of covid-19, lymphopenia appears seems to be a recovery in tracheal organ cultures 416 of novel viruses from patients with respiratory disease. proceedings of the national academy 417 of sciences of the united states of america characterization and complete genome sequence of a novel 419 coronavirus, coronavirus hku1, from patients with pneumonia identification of a novel coronavirus in patients with 422 severe acute respiratory syndrome. the new england journal of medicine molecular epidemiology, evolution and phylogeny of 425 sars coronavirus. infection, genetics and evolution : journal of molecular epidemiology and 426 evolutionary genetics in infectious diseases middle east respiratory syndrome coronavirus: 428 quantification of the extent of the epidemic, surveillance biases, and transmissibility. the 429 lancet. infectious diseases middle east respiratory syndrome coronavirus cov): announcement of the coronavirus study group coronavirus infections-more than just the common cold characteristics of and important lessons from the coronavirus disease 436 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese 437 center for disease control and prevention coronavirus disease 2019 in children -united states epidemiology of covid-19 among children in china. pediatrics association of public health interventions with the epidemiology of 443 the covid-19 outbreak in wuhan, china epidemiology and clinical characteristics of human 445 coronaviruses oc43, 229e, nl63, and hku1: a study of hospitalized children with acute 446 respiratory tract infection in guangzhou, china. european journal of clinical microbiology & 447 infectious diseases : official publication of the european society of clinical microbiology hosts and sources of endemic human 450 coronaviruses severe acute respiratory syndrome in children the pediatric infectious disease journal severe acute respiratory syndrome among children. 454 pediatrics middle east respiratory syndrome coronavirus disease is 456 rare in children: an update from saudi arabia. world journal of clinical pediatrics middle east respiratory syndrome 459 coronavirus in pediatrics: a report of seven cases from saudi arabia. frontiers of medicine a 55-day-old female infant infected with covid 19: presenting 462 with pneumonia, liver injury, and heart damage. the journal of infectious diseases detection of covid-19 in children in early the first infant case of covid-19 acquired from a secondary 467 transmission in vietnam. the lancet. child & adolescent health novel coronavirus infection in hospitalized infants 469 under 1 year of age in china severe covid-19 in children and young adults in the 471 metropolitan region. the journal of pediatrics african american children are at higher risk for covid-19 473 infection. pediatric allergy and immunology : official publication of the european society of 474 pediatric allergy and immunology clinical characteristics of 58 children with a pediatric 476 inflammatory multisystem syndrome temporally associated with sars-cov-2 journal of the pediatric infectious diseases society outcomes and prognostic factors in 267 patients with severe 481 acute respiratory syndrome in hong kong. annals of internal medicine predictors of mortality in middle east respiratory syndrome 484 (mers) case-fatality rate and characteristics of patients dying in 486 relation to covid-19 in italy covid-19) infection admitted to us and canadian pediatric 489 intensive care units. jama pediatrics sars-cov-2 infection in children corona virus disease 2019, a growing threat to children? the 492 journal of infection children with covid-19 in pediatric emergency departments in italy clinical characteristics of children with coronavirus disease 496 2019 in hubei, china. current medical science clinical features of severe pediatric patients with coronavirus disease 498 2019 in wuhan: a single center's observational study. world journal of pediatrics : wjp covid-19) in children in madrid, spain. jama pediatrics severe and fatal forms of covid-19 in children archives de pediatrie : organe officiel de la societe francaise de pediatrie clinical course and risk factors for mortality of adult inpatients with 505 covid-19 in wuhan, china: a retrospective cohort study characteristics and 508 outcomes of coronavirus infection in children: the role of viral factors and an 509 journal of the pediatric infectious diseases society middle east respiratory syndrome coronavirus disease 512 in children. the pediatric infectious disease journal middle east respiratory syndrome 514 coronavirus in children. saudi medical journal epigenetic dysregulation of ace2 and interferon-regulated 565 genes might suggest increased covid-19 susceptibility and severity in lupus patients tissue distribution of ace2 568 protein, the functional receptor for sars coronavirus. a first step in understanding sars 569 pathogenesis. the journal of pathology structural and functional basis of sars-cov-2 entry by using 571 human ace2. cell evolution of the novel coronavirus from the ongoing wuhan 573 outbreak and modeling of its spike protein for risk of human transmission. science china. life 574 sciences age-and gender-related difference of ace2 expression in 579 rat lung. life sciences angiotensin-converting enzyme 2 inhibits lung injury induced by 581 respiratory syncytial virus. scientific reports the host's angiotensin-converting enzyme 583 polymorphism may explain epidemiological findings in covid-19 infections. clinica chimica 584 acta; international journal of clinical chemistry virus-virus interactions impact the population dynamics of 586 influenza and the common cold viral dynamics in mild and severe cases of covid-19. the lancet. 588 infectious diseases evolution of the immune system in humans from 590 infancy to old age clinical characteristics of coronavirus disease 2019 in china. the 592 new england journal of medicine reference ranges for 594 lymphocyte subsets in pediatric patients expression of elevated levels of pro-inflammatory cytokines in 597 sars-cov-infected ace2+ cells in sars patients: relation to the acute lung injury and 598 pathogenesis of sars. the journal of pathology in the eye of the covid-19 cytokine storm long-lasting effects of bcg vaccination on both 602 heterologous th1/th17 responses and innate trained immunity innate and adaptive immune 605 memory: an evolutionary continuum in the host's response to pathogens the association between vitamin d status and infectious diseases of 608 the respiratory system in infancy and childhood preventive effects of vitamin d on seasonal 610 influenza a in infants: a multicenter, randomized, open, controlled clinical trial. the pediatric 611 infectious disease journal key: cord-316260-1t3ifsfi authors: nogueira-de-almeida, carlos alberto; ciampo, luiz a. del; ferraz, ivan s.; ciampo, ieda r.l. del; contini, andrea a.; ued, fábio da v. title: covid-19 and obesity in childhood and adolescence: a clinical review()() date: 2020-08-04 journal: j pediatr (rio j) doi: 10.1016/j.jped.2020.07.001 sha: doc_id: 316260 cord_uid: 1t3ifsfi objective: to identify factors that contribute to the increased susceptibility and severity of covid-19 in obese children and adolescents, and its health consequences. sources: studies published between 2000 and 2020 in the pubmed, medline, scopus, scielo, and cochrane databases. summary of findings: obesity is a highly prevalent comorbidity in severe cases of covid-19 in children and adolescents; social isolation may lead to increase fat accumulation. excessive adipose tissue, deficit in lean mass, insulin resistance, dyslipidemia, hypertension, high levels of proinflammatory cytokines, and low intake of essential nutrients are factors that compromise the functioning of organs and systems in obese individuals. these factors are associated with damage to immune, cardiovascular, respiratory, and urinary systems, along with modification of the intestinal microbiota (dysbiosis). in severe acute respiratory syndrome coronavirus 2 infection, these organic changes from obesity may increase the need for ventilatory assistance, risk of thromboembolism, reduced glomerular filtration rate, changes in the innate and adaptive immune response, and perpetuation of the chronic inflammatory response. conclusions: the need for social isolation can have the effect of causing or worsening obesity and its comorbidities, and pediatricians need to be aware of this issue. facing children with suspected or confirmed covid-19, health professionals should 1) diagnose excess weight; 2) advise on health care in times of isolation; 3) screen for comorbidities, ensuring that treatment is not interrupted; 4) measure levels of immunonutrients; 5) guide the family in understanding the specifics of the situation; and 6) refer to units qualified to care for obese children and adolescents when necessary. since december 2019, the world has been surprised by the appearance, in china, of a severe pneumonia caused by a new type of coronavirus, an infection that spread rapidly throughout countries, being considered a pandemic three months later; the disease received the name coronavirus disease 2019 (covid-19). 1, 2 as in adults, but less frequently, children with comorbidities ---chronic kidney and lung diseases, malignancies, diabetes, obesity, sickle cell anemia, immune disorders, chromosomal abnormalities, heart disease, and congenital malformations ---are more likely to develop severe conditions from covid-19. 3--6 the present review aims to identify the factors that contribute to the increase in the susceptibility and severity of covid-19 in obese children and adolescents, and its health consequences, to collaborate for better clinical care of these patients. although less frequently, covid-19 affects the pediatric age group. some studies indicate that incidence of covid-19 among children and adolescents can reach 5% of confirmed cases, 7 being slightly higher in males. 3, 8 in addition, it presents with less severity when compared to adults. in the united states, in march 2020, hospitalization rates among individuals under the age of 17 ranged between 0.1 and 0.3/100,000 inhabitants. 9 likewise, mortality among children and adolescents has been shown to be low. an epidemiological study in china with 2135 individuals under 18 years of age described only one death; infants presented, proportionally, a greater number of severe and critical cases. 8 in a systematic review 10 involving 2228 patients under 16 years of age, two deaths were found, one of which was the same reported in the chinese study. 8 jped 903 1---13 +model covid-19 and obesity in childhood and adolescence: a clinical review 3 children and adolescents seem to acquire sars-cov-2 mainly through contact with infected family members. 4,11---13 however, the role of children and adolescents in transmission remains unclear; 12 the presence of sars-cov-2 in the oropharynx and stools of asymptomatic and symptomatic individuals has been described 14---16 and viral load does not differ from that of adults. 17 vertical transmission seems to be rare, with few cases described. 18---20 to date, no viable viral particles have been identified in breast milk, although sars-cov-2 rna has been detected in three samples. 21 one study reported the presence of anti-sars-cov-2 iga in breast milk of women who recovered from covid-19. 22 tests to identify the virus in the umbilical cord, placenta, and amniotic fluid have also been negative. 23---26 the incubation period observed in a series of 11 studies involving individuals under the age of 16 was two to 25 days (mean = 7). 13 most children and adolescents affected by covid-19 have mild to moderate symptoms, with a significant percentage of asymptomatic patients; 13, 27 among those with severe symptoms, a small percentage will require intensive care 13 and the highest proportion appears to be concentrated in children under 1 year of age. 28 a systematic review found that, in 13 newborns infected with sars-cov-2 during perinatal period, most remained asymptomatic or had mild symptoms. 29 the most common symptoms of sars-cov-2 infection among children and adolescents are cough and fever; sore throat, sneezing, myalgia, wheezing, fatigue, rhinorrhea, nasal obstruction, diarrhea, and vomiting; hypoxia and dyspnea are uncommon findings; 10, 11, 13, 27, 30 in a chinese study with people under 16 years of age with sars-cov-2 infection, 28.7% presented with tachypnea. 4 discrete changes ---such as leukocytosis, leukopenia, lymphopenia, and small elevation of acute phase proteins ---were the most common laboratory alterations. 4, 13, 30, 31 radiographic changes are generally less pronounced than in adults, with unilateral or bilateral irregular opacification standing out in some case series. 3, 4, 13, 31 in a systematic review that analyzed chest computed tomography of under 18 age patients, 'ground glass' opacification was observed in 37.8% of examinations, most commonly unilateral in lower lobes, and was considered mild. 32 the reasons for the lower severity of covid-19 in pediatric age group remain unanswered. some hypotheses have been raised: less exposure to sars-cov-2 due to social isolation and closure of schools; lower frequency of comorbidities and exposure to smoking when compared to adults; and greater capacity for pulmonary regeneration. 33, 34 children have less angiotensin-converting enzyme 2 (ace-2) expression than adults, making the process of internalizing the virus less efficient 35 and may have more effective trained innate immunity, which is an innate memory response of medium duration, due to increased exposure to viruses and vaccines. 33, 34, 36 this phenomenon has been used to explain the lower death rates by covid-19 in countries that carry out universal bcg vaccination, compared to those that do not adopt such strategy. 33, 34, 37 furthermore, children and adolescents do not have the immunosenescence observed in older individuals, a phenomenon characterized by, among other features, a chronic inflammatory state. 33, 34, 38 finally, particularities of the expression of ace-2 in younger individuals, as observed in animal models, 39 could limit consequences of the decreased expression of that enzyme caused by the invasion of pneumocytes by sars-cov-2, 34 especially those related to the elevation of angiotensin-ii. 40 the relationship between obesity and viral diseases has been studied for several years. during the h1n1 epidemic, this area gained particular interest, as it was observed that obese patients had a higher risk of developing the disease, longer intensive care unit (icu) stay, and higher mortality. 41 this fact was demonstrated even for children, with impairment in immune response, especially cellular, to influenza virus, and also inadequate vaccine response when they were obese. 42 recently, during the covid-19 epidemic in canada, obesity was the third most prevalent demographic factor among children admitted to the icu, behind only those with serious associated diseases, immunosuppression, and cancer. 6 in new york, obesity was the most prevalent comorbidity among 50 severe cases of covid-19 affecting children and adolescents. 43 regarding covid-19, observations at the beginning of the pandemic demonstrated the existence of risk factors, such as arterial hypertension, cardiovascular diseases, diabetes, chronic respiratory conditions, and cancer; 44 however, obesity was later included in this list. 45 in march 2020, wu et al., 46 describing the characteristics of 280 chinese patients, found a statistically significant difference between the bmi of patients with mild and moderate conditions (23.6 kg/m 2 ) and severe ones (25.8 kg/m 2 ), but this fact did not attract the attention of these researchers, because they were unable to demonstrate the independence of bmi as a risk factor. simonet et al., 47 in april 2020, showed a high prevalence of obesity among patients with covid-19 exposed to mechanical ventilation. in addition, the proportion of people who needed this intervention increased according to bmi, reaching 85.7% when bmi was over 35 kg/m 2 . 47 finally, they found that obesity was a risk factor regardless of age, gender, or presence of diabetes or hypertension, and the risk of requiring invasive mechanical ventilation was 7.36 times higher when patients with a bmi greater than 35 kg/m 2 were compared to those with bmi less than 25 kg/m 2 . 47 other studies confirmed these findings: bhatraju et al., 44 reporting the first cases in the seattle region (united states), found a mean bmi of 33.2 among 24 critically ill patients admitted to the icu. among italians hospitalized for covid-19, busetto et al. 48 found that those with overweight and obesity, even if younger, needed assisted ventilation and intensive care more frequently than patients with normal weight. data from new york, regarding 770 patients, showed that obese people were more likely to have fever, cough, and dyspnea, in addition to significantly higher rates of icu admission or death. 49 more recently, with accumulated data from three different populations, a systematic review confirmed obesity as an independent risk factor for greater severity of covid-19, including admission to the icu. finally, a very relevant finding was the demon-jped 903 1---13 +model stration, by yates et al., 50 that the risk of acquiring the disease is greater among obese people. it is still not possible to explain why the number of children affected and their manifestations vary among different regions. 51 the effects of pediatric obesity on covid19 are not yet adequately studied and some data are inferences due to the lack of considerable number of studies published on this subject in this age group. the three main risk factors that link obesity to covid-19 demonstrated for adults 52 are also present among children and adolescents: chronic subclinical inflammation, impaired immune response, and underlying cardiorespiratory diseases. virtually all comorbidities found in adults can be observed during childhood and adolescence, 53 and obese children have inadequate immune responses to other infections, such as bacterial pneumonia, 54 a common severe complications of covid-19. studies in animal models show that rats fed a high-fat diet have increased expression of ace-2 in lungs, which may help explain the greater severity of the disease among obese individuals. 55 zhang et al. showed that obesity predisposes to high mortality due to covid-19 even in young patients, aged 14 years and older 56 and it is considered that it is precisely the high prevalence of obesity among young people that can shift the age curve of mortality in countries where the prevalence of overweight is higher in this group. 57 the mechanisms involved include numerous aspects related to obesity itself and also to its comorbidities, 6 and it should be emphasized that the risks may be present even in mildest cases of obesity. 58 below, each will be covered in detail. in childhood and adolescence, even in the presence of obesity, type 2 diabetes mellitus is relatively uncommon. 59 the high pancreatic capacity of insulin production, characteristic of younger individuals, allows compensation to occur as a result of hyperinsulinism, which has a high prevalence associated with obesity. 60 although glycemia frequently remains at normal levels, the entire pathophysiological process is present, leading to several health repercussions, such as dyslipidemia, arterial hypertension, non-alcoholic steatohepatitis, micronutrients deficiencies, increased oxidative stress, and hyperuricemia. in situations of intense metabolic activity, such as during immune response to coronavirus infection, beta cells are required to produce a high amount of insulin, which may not be achieved when they are already working at their limit; 61 sars-cov-2 can also lead to rupture of beta cells, through interaction with ace-2, further aggravating this process. 61 in addition, insulin resistance leads to a reduction in phosphoinositidyl 3-kinase, impairing the vasoprotective and anti-inflammatory effects of nitric oxide. 62 dyslipidemias are highly prevalent among obese children and adolescents, 60 and low concentrations of hdlcholesterol and increased ldl-cholesterol are proven risk factors for progression of endothelial dysfunction and atherosclerosis. 63 in new york, obesity was the most important risk factor for necessity of respiratory support among 50 pediatric cases of covid-19. 43 normal respiratory physiology is usually impaired in obese patients, including children and adolescents. 64 as the lung is one of the main targets and leads to greater risks for patients with covid-19, this aspect must always be considered. in fact, hematosis is impaired in obesity, which becomes even more relevant when the exchange areas are reduced due to coronavirus action. 65 the pressure exerted by abdominal adiposity on the lungs, through the diaphragm, also acts to limit the movement of respiratory muscles, with less oxygen saturation 66 and worsening clinical presentation due to the lower lung volume of obese patients. 67 in addition, some comorbidities linked to obesity may contribute to a higher risk of pulmonary infections, such as the presence of asthma, which is highly prevalent among obese children, 68 and obstructive sleep apnea. 69 regarding asthma, the same inflammatory mechanisms linked to leptin and il-2, which explain the high prevalence and severity of this disease in obese children, 70 are also involved in the severity of covid-19. finally, in addition to aspects related to impaired lung function, obese children have low exercise tolerance, which closes a vicious circle. 71 cardiac anatomy changes linked to obesity is recognized even in very young children, in whom hypertrophy of left ventricle is observed, related to the degree of obesity and blood pressure, among other structural changes. 72 obese children and adolescents have higher blood pressure, which increases potential endothelial injury, one of the bases of covid-19 pathophysiology. 72 children, especially obese ones, treated with antihypertensive drugs that inhibit angiotensin-converting enzyme or block angiotensin receptors, have increased expression of ace-2, increasing their susceptibility to coronavirus. 73 childhood obesity increases risk of cardiovascular disease later in adulthood, and the explanation for this phenomenon lies in the fact that endothelial dysfunctions, in association with insulin resistance, effectively start during childhood. 74 the intima layer of arteries is thickened in obese children, foreshadowing the onset of atherosclerosis, which occurs very early. 75 endothelial dysfunction occurs even in the mildest cases of obesity. 76 hardening of the arteries, associated with impaired nitrogen performance and chronic oxidative stress, has been implicated in changes linked to the severity of covid-19, such as inflammation of endothelium, myocarditis, multiple organ failure, severe acute respiratory syndrome, and venous thromboembolism. 62 recent data from post mortem anatomopathological studies shows inclusion of coronavirus structures in endothelial cells, possibly through the use of ace-2 receptors in the endothelium by the virus; in these cases, accumulation of inflammatory cells, venous congestion in small pulmonary veins, and inflammation of the endothelium in the intestinal circulation have been found. 77 leptin, which is usually elevated among obese people, damages endothelium leading to less nitric oxide production and increased expression of monocyte chemoattractant protein-1, contributing to the inflammatory infiltrate in vascular cells. 62 perivascular adipose tissue contributes to vasoconstriction and endothelial dysfunction through the production of inflammatory mediators, oxidative stress, and reduction in nitric oxide production. 62 one of the most relevant aspects for understanding the severity of covid-19 among obese patients is related to inflammatory issues. 78 after coronavirus contamination, most patients develop immune defense mechanisms, which include processes related to inflammation, and this happens in a modulated way, so that the host organism is not harmed. however, some patients trigger an uncontrolled process, known as a cytokine storm, which causes tissue damage and intense homeostatic dysregulation, leading to damage of several organic functions, especially regarding the respiratory area.79 obese patients are known to have chronic subclinical inflammation, characterized by a permanent inflammatory state, albeit of mild intensity. 80 high serum concentrations of c-reactive protein and il-6 prove this process 61 which can start early. it is believed that, at least in part, this process is due to cytokines, particularly adipokines with inflammatory properties, produced by adipose tissue 61 and also the drop in adiponectin, which has anti-inflammatory properties. 81 obese people, including children and adolescents, with covid-19 are at increased risk of developing coagulopathy associated with poor clinical outcomes. chronic inflammation leads to negative regulation of anticoagulant proteins (tissue factor pathway inhibitor, antithrombin, and the protein c anticoagulation system). however, it leads to positive regulation of procoagulant factors (tissue factor pathway inhibitor) and adhesion molecules (p-selectin), in addition to increases in thrombin generation and enhanced platelet activation, increasing the risk of thrombosis. 62 in severe sars-cov-2 infections, risk of venous thromboembolism is important, as a significant percentage of patients show elevated levels of d-dimers, while others meet clinical criteria for disseminated intravascular coagulation (dic). 62 severe infections and sepsis are a leading cause of dic, and proinflammatory and immune activation observed in severe covid-19 is likely sufficient to trigger dic. 82 obesity causes several structural, metabolic, and hemodynamic changes in the kidneys, leading to a lesser functional reserve of this organ. 83 ectopic deposition of fat in renal sinus is responsible for increasing its weight and volume. hemodynamic changes lead to increased renal plasma flow and glomerular filtration rate, greater absorption of water and sodium by proximal tubules, glomerular stress, tubular hypertrophy, and glomerulomegaly, which in turn cause proteinuria and secondary glomerular sclerosis, cul-minating in chronic kidney disease. 84 the increase in body weight and consequent reduction in urinary ph predispose to urinary lithiasis due to increased excretion of urinary oxalate, sodium, phosphate, and uric acid; obesity can also favor the appearance of some types of neoplasia in renal tissue. 85 the dysregulation of lipid metabolism and hormonal responses also play a role in deterioration of renal function. oxidative stress caused by increased fat deposition promotes inflammation, cellular hypertrophy, increased mesangial matrix, apoptosis, endothelial dysfunction, and renal fibrosis. 86 fatty acids released by adipocytes stimulate secretion of tumor necrosis factor (tnf)-alpha by macrophages, resulting in increased secretion of il-6 in adipocytes, amplifying inflammation in renal tissue. while tnf-alpha plays a fundamental role in progression of renal fibrosis, the increase in intracellular lipids has a nephrotoxic effect (culminating in glomerulosclerosis), compromising the structure and functioning of mitochondria, which contributes to progression of kidney disease. 87 increased insulin production and insulin resistance contribute to mesangial expansion and renal fibrosis, and the observed activation of the renin-angiotensin-aldosterone system, since the vasoconstrictor effect of angiotensin ii on renal arterioles leads to increased production of endothelin-1, stimulating proliferation of mesangial matrix, sodium retention, and vasoconstriction of renal arterioles. 88 coronavirus can cause acute kidney damage in up to 15% of cases, which contributes to mortality. aggression is due to direct cytotropic effect induced by the virus through ace-2, which is highly expressed in the kidney, 89 and inflammatory response caused by cytokines due to activation of the renin-angiotensinaldosterone system. 90, 91 in addition, acute tubular necrosis and thrombotic effects secondary to endothelial dysfunction are also observed in covid-19. 92 intestinal microbiota is a complex ecosystem with thousands of bacterial phyla and several species distributed throughout digestive tract. it is mostly composed of anaerobic microorganisms and about 90% of fecal bacteria belong to two phylogenetic lineages: firmicutes and bacteroidetes. 93 colonization occurs from birth and is individually different, changes over time, and can be influenced by eating habits or diseases, such as obesity and metabolic syndrome. several studies have demonstrated a correlation between firmicutes/bacteroidetes ratio in both obese children and adults, suggesting intestinal dysbiosis. 94 regarding patients with covid-19, there are reports of intestinal dysbiosis and a decrease in intestinal lactobacillus and bifidobacterium populations, and some hospitalized patients were treated with probiotics in order to regulate microbiota balance and reduce risk of infection secondary to bacterial translocation. 95 obesity in childhood and adolescence alters entire immune system, changing concentrations of cytokines and proteins and the number and function of immune cells. this imbalance leads to a pro-inflammatory state, resulting in the onset or exacerbation of several diseases such as asthma, allergy, atopic dermatitis, and sleep apnea. 96 in relation to covid-19, whose severe conditions evolve with an intense and severe systemic inflammatory reaction (cytokine storms), the imbalance of immune system observed in obesity may contribute to a worse clinical outcome. 79 adipocytokines, especially leptin, play an important role in this process, as they influence number and function of immune cells through directly effects on cell metabolism. in this context, there may be an increase in cytotoxic and effector t-cells (th1 and th7) and m1 macrophages and, in parallel, a reduction in treg cells and m2 macrophages. however, other molecules that are influenced by nutritional status also act on immunity, which may be increased (il-1␤, il-6, il-8, il-10, il-1ra, resistin, visfatin, tnf-␣, mcp-1, mif, mip1 alpha and beta) or reduced (adiponectin, il-33) in obese patients. 62 in addition, imbalance between actions of lymphocytes treg and cd17+ also contributes to the proinflammatory state observed in obesity. 97 furthermore, in obesity, macrophages cells constitute about 40% to 60% of cells of immune system derived from visceral adipose tissue; these macrophages are mostly activated (m1) and secrete high amounts of tnf-alpha, il-6, il-12, il-1b, mcp-1, and nitric oxide. 97 nutrition plays an important role in immune and inflammatory response, since some nutrients modulate cellular and humoral defense systems, either by modifying formation of inflammatory mediators or interfering with cellular signal transduction pathways. nutrients have an immunomodulatory action by stimulating the cell-mediated response, modifying the balance between pro-inflammatory and antiinflammatory cytokines, and attenuating depletion of tissue nutrients. 98 immune response depends on the sufficient supply of nutrients and adequate nutritional status has been considered an important element for coronavirus capacity response. zhang & liu, 99 in a systematic review, showed that some nutrients are fundamental for adequate response to coronavirus: vitamins a, c, d, and e; omega 3 fatty acids; and the minerals zinc and iron. a suitable qualitative and quantitative supply allows to maintain and repair defense systems, which require adequate energy and structural support. 100 obesity has peculiarities that may impair immune response, because diet often has characteristics that can lead to ''hidden hunger.'' this is because, despite eating above energy needs, quality is not adequate; numerous studies point to vitamin and mineral deficiencies in those with excess weight. 101 among the most common nutritional deficiencies, hypovitaminosis d stands out, not only linked to insufficient intake, but also, and mainly, to the displacement of part of the organic pool to adipose tissue due to the lipid affinity of this vitamin. 102 additionally, it is known that a sedentary lifestyle is characteristic of obese children, causing the practice of physical activities outdoors ---which would increase exposure to sun and skin formation of vitamin d ---to be reduced in this group. 102 several studies have linked hypovitaminosis d to an increased risk of severe covid-19, 78 which makes this issue particularly relevant in the pediatric obese popu-lation, where the prevalence of this deficiency is high. 103 vitamin d (vd) has immunomodulatory effects, and activated t-lymphocytes and antigen presenting cells, such as macrophages and dendritic cells, express vd receptor in their membranes, leading to anti-proliferative and immunosuppressive effects on immune system cells. it inhibits secretion of il-12 by macrophages, a fundamental cytokine in differentiation of cd4+ t-lymphocytes in th1 cells. 104 by decreasing activation of th1 response and production of pro-inflammatory cytokines (il-2, interferon-␥, tnf-␣), vd contributes to the targeting and activation of th2 response, favoring greater secretion of anti-inflammatory cytokines, such as il-4. 104 this immunosuppression mechanism is important to minimize deleterious effects in transplants, and in autoimmune and inflammatory diseases. although vd induces th2 response, it also induces expression of antimicrobial peptides in neutrophils and monocytes, as well as promotes an increase in phagocytic capacity and rapid release of reactive oxygen species. 104 induction of cathelicidins and defensins, caused by vd, reduces viral replication and concentration of proinflammatory cytokines that have potential for lung injury in cases of covid-19. 105 additionally, hypovitaminosis d has repercussions for disorders with potential impact on covid-19, such as arterial hypertension, hepatic steatosis, and hyperuricemia. 106 omega-3 fatty acids are considered essential lipids for humans. eicosapentaenoic (epa) and docosahexaenoic (dha) fatty acids are biologically more potent immunomodulators than alpha-linolenic acid. epa and dha decrease activity of nuclear transcription factors that promote transcription of genes that encode proteins with pro-inflammatory action, such as tnf-␣ and il-1␤. 107 in addition, epa and dha compete with arachidonic acid (omega-6) in the constitution of plasma membrane phospholipids and, consequently, for the metabolism of cyclooxygenase in cell membrane, modulating the production of prostaglandins and leukotrienes. 108 higher concentrations of epa and dha favor synthesis of series-3 prostaglandins and series-5 leukotrienes, which attenuate inflammatory response; and inhibit production of series-2 prostaglandins and series-4 leukotrienes, which depress thecytotoxic activity of macrophages, lymphocytes, and natural killer cells, 109 with a consequent reduction in synthesis of pro-inflammatory cytokines such as il-1, il-6, and tnf-␣. 107 immunomodulation exerted is dependent on omega-3/omega-6 ratio: a 1:5 ratio does not impair immune response; however, western diets provide a ratio of 1:15 to 1:50, with pro-inflammatory effects. 110 consumption of omega-3 fatty acids, especially dha, is low in most countries in the world, including brazil. 111 although omega-3 precursors are present in vegetable oils, their conversion into dha is low and the very excess of omega-6 intake diverts the converting enzymes, further impairing the formation of dha and contributing to a high deficiency prevalence. inadequate proportion of omega-3/omega-6, common in obese children, 112 leads to loss of modulation of immune response, which may contribute to exacerbation of inflammatory reactions, in addition to aggravating cardiometabolic risks. 113 vitamins a, e, and c are fundamentally found in fruits and vegetables, usually little consumed by children and adolescents, including obese ones. 114 impaired nutritional status of these vitamins may impact immune response. 115 immune cells are at constant risk of oxidative damage by jped 903 1---13 +model covid-19 and obesity in childhood and adolescence: a clinical review 7 free radicals, which can permanently impair their ability to respond to pathogens. increased amounts of free radicals in activated macrophages are part of normal response. vitamin e (ve) acts as an antioxidant and protects the cell membrane against reactive oxygen species. 114 animal studies have shown that ve supplementation increases resistance to infections, including influenza viruses. 116 vitamin a (va) guarantees the regeneration of the mucosal barriers damaged by infection and supports protective function of macrophages, neutrophils, and natural killer cells. 117 it is also necessary for adaptive immunity and plays a role in development of t-and b-cells. like vd, va can prevent production of il-12 cytokines by macrophages, decreasing activation of the th1 response and increasing th2. 117 va deficiency impairs th2 response, which culminates in a lack of il-4 and fails to induce iga, impairing salivary iga response to influenza virus infection, and intestinal response to cholera toxin. 117 vitamin c (vc) contributes to the integrity of the epithelial barrier and accumulates in phagocytic cells, such as neutrophils, which improves chemotaxis; phagocytosis; production of reactive oxygen species; and induces microbial death. 118 it also contributes to apoptosis and removal of neutrophils, which have suffered cell death, from infection sites, reducing necrosis and possible tissue damage. 118 vc seems to promote differentiation and proliferation of b-and t-cells, probably due to its genetic regulatory effect. 118, 119 deficiency also impairs cytotoxic capacity of neutrophils and t-lymphocytes. 114 vc supplementation appears to be able to prevent and treat respiratory and systemic infections, 118, 119 and a recent review highlights vc, as well as zinc and vd, as micronutrients with stronger evidence regarding their role in immunity. 120 in relation to iron, obese children are at risk for iron deficiency anemia 121 due to the low nutritional quality and low iron bioavailability of the diet 122 and anemia has been widely demonstrated in this group. 123 in addition to inadequate intake, hepcidin, the main controller of iron absorption, has increased expression in obese individuals, contributing to the condition by reducing absorption of iron by enterocytes and their export by macrophages and hepatocytes, increasing splenic and hepatic sequestrations. 124 due to the fact that they have similar nutritional sources, zinc deficiency is also believed to be present among obese children in the same way as iron deficiency, and this has been demonstrated in studies in pediatric age group. 125 it should be noted that, in addition to its immunological role, zinc also participates in insulin and leptin metabolism, which can aggravate metabolic dysregulations in obese children, contributing to inadequate inflammatory response. 126 zinc acts as a cofactor for the enzyme superoxide dismutase, which reduces cellular oxidative stress and decreases activation of signaling pathways that promote inflammatory response. 127 it induces monocytes to produce il-1 and il-6, and to inhibit the production of tnf-␣, and is also involved in regulation of peroxisome proliferator-activated receptors (ppars), whose activation is positively correlated with decrease in inflammatory response. the direct influence of zinc on immune system is due to its ability to stimulate activity of enzymes involved in mitosis. 128 zinc deficiency is related to decreased production of cytokines and interferon-␣ by leukocytes, atrophy of the thymus and other lymphoid organs, and changes in the proportion of lymphocytes. 128 if, on the one hand, obese patients exhibit covid-19 with particular characteristics, on the other hand, the pandemic has also led to socioeconomic changes that may impact childhood obesity, 129 especially among the poorest. 130 in this sense, an important study projected the impact of covid-19 pandemic on the prevalence of childhood obesity in united states, according to different scenarios: 131 closing schools for two months; school closures for two months associated with a 10% drop in physical activity in two subsequent months of summer; adding two more subsequent months of closed schools; adding two more subsequent months of school closures. the increase in prevalence of obesity would be 0.640, 0.972, 1.676, and 2.373 percentage points, respectively. in italy, pietrobelli et al. 132 followed 41 obese children and adolescents during three weeks of lockdown in verona and found no changes in vegetables consumption, but observed increased consumption of fruits, chips, red meat, and sugary drinks; the time spent in sports activities was reduced by two and a half hours per week and, in contrast, sleep period increased by 0.65 h/day; and the most impactful data refers to screen time, which increased by 4.85 h/day. an interesting aspect is the idea often disseminated in lay texts that physical activity should be avoided to protect immunity and supposedly that exercise could reduce body's defenses, a fact that has not been scientifically demonstrated, even among athletes. 133 on the contrary, physical activity is important for the proper formation of vd when performed outdoors. 102 in fact, with regard to situations related to sedentary lifestyle, such as watching tv or playing video games, changes occur that are related to higher risk of obesity, such as high consumption of fast food and sugar-sweetened beverages, 134 in addition to sleep disorders. 135 in relation to this last aspect, the covid-19 pandemic brings high risks for health, as several factors can contribute to quality and duration of sleep being unsatisfactory, such as stress in face of illness, interruption of activities in the morning, time available for screen use, etc. 132 in this sense, in addition to predisposing to weight gain and abdominal adiposity, sleep disorders have other health repercussions, such as insulin resistance, deterioration in food quality, poor school performance, and sedentary lifestyle. 136 living with stress during covid-19 pandemic, in addition to bringing risks of deterioration of immunity, 137 may have consequences for pediatric health, in particular for nutritional and emotional areas. 138 one such consequence refers to the worsening of sleep quality, discussed above. additionally, stress increases food consumption, activates brain reward centers that raise interest in highly palatable foods (sugar, salt, and lipids), increases emotional instability, and worsens quality of life. 138 due to the prolonged time of social isolation, another aspect demonstrated in the united states was a drop in adherence to immunization programs, due to the fear of taking children to vaccinate. 139 finally, a brazilian study showed a high incidence of peri-obstetric mortality due to covid-19 140 and this fact, in cases where delivery is feasible, may lead to a large number of infants being deprived of breastfeeding, known as a protective factor against obesity. 141 the present review has two important limitations. the first is that it is not possible, currently, to carry out a systematic review of the literature with the expected rigor in study classification, since most of published data is based on observations made less than a year ago and, generally, refer to observational and cross-sectional studies. the second is that there are few publications referring to the pediatric age group, which means that some information is, in fact, inferences about the approach to the disease in children and adolescents, based on what is observed in adults. when the patient presents with mild covid-19 symptoms, the treatment is only symptomatic and recovery is usually complete, 142 ranging from supportive measures for mild cases (isolation, hygiene, rest, hydration, and attention to food intake) to invasive hospital procedures, such as mechanical ventilation. the convalescence period may range from one to three weeks in mild case, or up to six weeks for the most severe. 143 non-obese children are usually asymptomatic and even less susceptible to the infection. 144 in these cases, telemedicine alternatives have been proposed in order to help families receive adequate guidance without the need to travel. 129 however, for those who develop the most severe forms, the coexistence of obesity can hinder therapy and worsen prognosis, since the inflammatory condition is as severe as in adults. 145 also, extensive involvement of the cardiopulmonary system is frequent 146 and respiratory disorders such as pickwick syndrome, obstructive apnea, and surfactant dysfunctions may be present. 147 there are also technical issues, such as the fact that many pieces of equipment may not adequately adapt to the obese patient 148 and the greater difficulty of intubation of obese patients, which may lead to the occurrence of lesions and longer periods of hypoxia while the procedure is being completed. 148 nursing care is always more difficult: the possibility of more precarious hygiene and secondary contamination, as well as harder venipuncture and more likelihood to cause injury; control procedures such as blood pressure measurement and cardiac auscultation are more difficult and more error-prone; and the risk of bedsores during intensive care unit stay is always higher the higher the patient's weight. 149 for families, supportive measures that provide high quality information and guidance to help them make decisions on medications, the need to go to the emergency room, and how to conduct emergency care are essential. 129 for adolescents, adequate information can often aid to minimize extreme behaviors, both in the aspect of excessive fear, for some, and in the sense of invulnerability, for others. 150 fig . 1 shows a brief synopsis regarding the relationships between obesity and covid-19. in conclusion, obesity in childhood and adolescence can be considered a risk factor for greater susceptibility and severity of covid-19 and is associated with nutritional, cardiac, respiratory, renal, and immunological alterations, which may potentiate the complications of sars-cov-2 infection. the need for social isolation can have 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the importance of the ratio of omega-6/omega-3 essential fatty acids clinical significance of perioperative immunonutrition for patients with esophageal cancer an increase in the omega-6/omega-3 fatty acid ratio increases the risk for obesity fatty acids consumption: the role metabolic aspects involved in obesity and its associated disorders nutrition and immune system in children with simple obesity diometabolic markers in healthy 8-to 9-y-old children: the fisk junior randomized trial food types in the diet and the nutrient intake of obese and non-obese children nutritional modulation of immune function: analysis of evidence, mechanisms, and clinical relevance the role of vitamin e in human health and some diseases role of vitamin a in the immune system vitamin c and immune function technical advance: ascorbic acid induces development of double-positive t cells from human hematopoietic stem cells in the absence of stromal cells a review of micronutrients and the immune system-working in harmony to reduce the risk of infection overweight children and adolescents: a risk group for iron deficiency iron deficiency anemia: a comprehensive review on iron absorption, bioavailability and emerging food fortification approaches higher body mass index is associated with iron deficiency in children 1 to 3 years of age relationship between obesity and iron deficiency anemia: is there a role of hepcidin? zinc nutritional status and its relationships with hyperinsulinemia in obese children and adolescents leptin: metabolic control and regulation the antioxidant properties of zinc efeitos da suplementação com zinco sobre o crescimento, sistema imunológico e diabetes zooming towards a telehealth solution for vulnerable children with obesity during covid-19 low-income children and coronavirus disease 2019 (covid-19) in the us projecting the impact of the coronavirus disease-19 pandemic on childhood obesity in the united states: a microsimulation model effects of covid-19 lockdown on lifestyle behaviors in children with obesity living in verona, italy: a longitudinal study can exercise affect immune function to increase susceptibility to infection? a model linking video gaming, sleep quality, sweet drinks consumption and obesity among children and youth united states adolescents' television, computer, videogame, smartphone, and tablet use: associations with sugary drinks, sleep, physical activity, and obesity relationship between sleep duration and childhood obesity: systematic review including the potential underlying mechanisms the immunopathobiology of t cells in stress condition: a review the mutual effects of covid-19 and obesity effects of the covid-19 pandemic on routine pediatric vaccine ordering and administration ---united states the tragedy of covid-19 in brazil: 124 maternal deaths and counting every month matters: longitudinal associations between exclusive breastfeeding duration, child growth and obesity among wic-participating children coronavirus disease 2019 and children: what pediatric health care clinicians need to know the immune system and covid-19: friend or foe? kaushal r, editors. reopening us schools in the era of covid-19: practical guidance from other nations hyperinflammatory shock in children during covid-19 pandemic clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 obesity as a risk factor for complications during acute respiratory infections in children the obese child in the intensive care unit what evidence informs the nursing care of people with class iii obesity in an acute care setting? a scoping review attitudes and psychological factors associated with news monitoring, social distancing, disinfecting, and hoarding behaviors among us adolescents during the coronavirus disease 2019 pandemic the authors declare no conflicts of interest. key: cord-317092-5qba9jiq authors: singh, tulika; heston, sarah m; langel, stephanie n; blasi, maria; hurst, jillian h; fouda, genevieve g; kelly, matthew s; permar, sallie r title: lessons from covid-19 in children: key hypotheses to guide preventative and therapeutic strategies date: 2020-05-08 journal: clin infect dis doi: 10.1093/cid/ciaa547 sha: doc_id: 317092 cord_uid: 5qba9jiq the current pandemic of severe acute respiratory syndrome coronavirus 2 (sars-cov-2), the causative agent of coronavirus disease 2019 (covid-19), reveals a peculiar trend of milder disease and lower case fatality in children compared to adults. consistent epidemiologic evidence of reduced severity of infection in children across different populations and countries suggests there are underlying biologic differences between children and adults that mediate differential disease pathogenesis. this presents a unique opportunity to learn about disease modifying host factors from pediatric populations. our review summarizes the current knowledge of pediatric clinical disease, role in transmission, risks for severe disease, protective immunity, as well as novel therapies and vaccine trials for children. we then define key hypotheses and areas for future research that can use the pediatric model of disease, transmission, and immunity to develop preventive and therapeutic strategies for people of all age groups. severe acute respiratory syndrome coronavirus-2 (sars-cov-2) originated in wuhan, china in december 2019, and was deemed a public health emergency of international concern by the world health organization. 1 sars-cov-2 is the etiological agent of the disease known as coronavirus disease 2019 (covid19) , which is characterized by fever, cough, dyspnea, and progression to acute respiratory distress syndrome (ards). in the four months since its identification, sars-cov-2 has led to more than 3 million cases and 228,000 deaths globally. 2 sustained community-based spread is constraining healthcare resources, shutting down economies, and leading to unprecedented governmental recommendations for quarantining and social distancing to limit transmission. while these measures are necessary to slow the rate of new infections, they have been highly disruptive to society and other preventative and therapeutic approaches are urgently needed. surprisingly, epidemiological evidence across countries consistently reveals that children experience less severe disease and lower case fatality from covid-19 than adults. 1, 3, 4 this trend suggests that there are underlying biological differences between children and adults that could inform the development of therapeutics, and preventative measures. recent cohort studies indicate that only up to 6% of infected children experience severe disease, whereas up to 26% of adult cases progress to severe illness requiring icu admission. 5, 6 notably, a similar trend of mild disease and low mortality rate in children was observed during the severe acute respiratory syndrome (sars-cov-1) outbreak in 2003 and middle east respiratory syndrome (mers)-cov outbreak in 2012, indicating that this pattern is driven by common virologic features across coronaviruses (cov). 7, 8 also, varicella disease is similarly known to be milder in young children compared to infants and adults. 9 in contrast, most other respiratory viruses, such as influenza and respiratory syncytial virus, cause more severe disease in young children compared to middle-aged adults 10 . this presents a unique opportunity to learn about disease-a c c e p t e d m a n u s c r i p t 4 modifying host factors to inform our understanding of cov pathogenesis across age groups. understanding differences in children's immunity, host cellular factors required for virus replication, and physiology can provide insights into the correlates of protection from sars-cov-2 and other covs. in this review, we summarize current pediatric-specific knowledge on clinical disease, transmission, risks for severe disease, protective immunity, and novel therapies and vaccines in trial. importantly, we identify key unanswered questions in translating this evidence towards the development of preventive and therapeutic interventions for all ages (table 1) . currently available clinical descriptions of covid-19 consistently describe milder symptoms in children than that of adults. while children constitute 22% of the united states population, they only represent 1.7% of sars-cov-2 infections identified to date, consistent with estimates from china. 11 yet, as more pediatric studies have become available, it is clear that children from birth to 18 years can be infected with sars-cov-2. 6, 12 infected children appear to be less symptomatic, and thus less likely to be tested for the virus in the setting of limited diagnostic capacity. while definitions of clinical severity vary among studies, there are consistently fewer severe or critical cases among children than adults. in a retrospective review of over 2,000 pediatric cases in china, only 6% of cases were severe (112 cases) or critical (13 cases). 6 moreover, in a case series of 36 children in china from whom sars-cov-2 was detected, 28% were asymptomatic. 13 in contrast, severe and critical cases represent up to 19% and 26% of adult cases reported in china and italy, respectively, and occur mostly in people >60 years of age. 1, 4 a c c e p t e d m a n u s c r i p t 5 the most common symptoms of covid-19 include fever and cough, with fewer patients experiencing shortness of breath, upper respiratory symptoms, vomiting, diarrhea, myalgias, and fatigue. 11, 12 interestingly, only 56% of symptomatic children had fever and 54% had cough, while fever and cough were identified in 71% and 80% of adults, respectively. 11 laboratory and radiographic abnormalities are also less common in children. while lymphopenia, elevated creactive protein (crp), and abnormal coagulation tests are common in adults and correlate with disease severity, there are no consistent laboratory abnormalities across pediatric studies. 14 however, laboratory abnormalities that more closely reflect those of adults have been reported in children >5 years of age and adolescents. 13, 15 in both adults and children, ground glass opacities and "patchy shadows" were the most common abnormalities on chest computed tomography. 16 altogether, the differences in symptoms and disease severity between children and adults with covid-19 imply that there are potential immunological or host factors that modulate disease in children. children less than 15 years of age are primarily exposed to sars-cov-2 through close contact with a sick family or household member, although exposure may also occur with travel to an endemic area or contact with other infected individuals. 11 while transmission primarily occurs through aerosolized droplets and fomite contact, there is concern that fecal-oral transmission may also occur, particularly in children. in epidemiological investigations, viral rna was detected in the stool of 8 of 10 children who tested positive for the virus via nasopharyngeal swab. 17 moreover, virus was detected in stool up to 27 days after admission, compared with up to 15 days via nasopharyngeal swab and at higher magnitude of viral rna detected in stool as compared to nasopharyngeal samples, however more studies are needed to determine if detection of viral rna correlates to infectious virus in stool. 17 notably, recent reports identified viable virus in fecal samples from adult patients. 18 given the large proportions of asymptomatic a c c e p t e d m a n u s c r i p t 6 pediatric infections, lower severity of disease, and potential risk of fecal-oral transmission, it is highly likely that children have a distinct role in population transmission. development of reliable and specific serological tests for sars-cov-2, such as those based on binding of serum antibodies to the viral spike protein, are important for accurate detection of rates of infection in children 19 . the possibility of vertical transmission remains of concern for maternal and neonatal health. in a case series of 33 neonates born to mothers with covid-19 pneumonia, 3 presented with early onset of neonatal infection identified by detection of the virus by pcr in nasopharyngeal samples, and are suspected cases of perinatal transmission. 20 also, amongst other cohorts, 17 infants born to sars-cov-2 positive mothers did not demonstrate evidence for vertical transmission 21, 22 . however, elevated sars-cov-2 igm antibodies detected in serum taken within two hours of birth from three newborns, despite negative testing of nasopharyngeal samples by pcr 21,23,24 is also suggestive of in utero sars-cov-2 exposure. 21, 23, 24 nevertheless, these cases could represent false-positive igm testing, as has been reported frequently with serological testing for other viruses. 25 thus far, there is no report of detection of sars-cov-2 in amniotic fluid or breast milk, and it is unclear if vertical transmission occurs when pregnant women become infected during the first or second trimester of gestation. 21 maternal infection can also lead to severe symptoms in the mother, which can result in birth asphyxia or premature birth. 21 in sars-cov-1, there was a higher case fatality among pregnant women and reported cases of miscarriage, spontaneous abortion, preterm birth and intrauterine growth restriction. 26 further research is needed to understand the impact of sars-cov-2 infection on maternal and fetal health. while children represent a minority of severe covid-19 cases, a third of the reported severe cases and more than half of the critical cases were among children less than one year of a c c e p t e d m a n u s c r i p t 7 age. 6 children less than 1 year old also had the lowest percentage of asymptomatic cases as compared to older children. 6 an interesting observation in adults is that slightly higher rates of severe disease have been reported in men than women. 27 similarly, of the >4000 pediatric cases reported in the us and china, 57% were male; however, there are currently no reports of sex differences related to disease severity in children 6, 11 further analysis is required to determine whether a sex bias exists in severe pediatric sars-cov-2 infections. future studies will need to continue examining sex and age-related differences in covid-19 severity as this might provide insights into host factors that mitigate severe disease outcomes. moreover, studies should consider whether physiologic changes during puberty underlie age-dependent disease modifying factors in children 28 . the presence of medical comorbidities, such as hypertension, diabetes, chronic pulmonary disease, and cardiovascular disease is another risk factor for severe disease in adults 29 , and the relative lack of comorbidities in children may contribute to the disparate covid-19 severity between the age groups. of the few reports of severe covid-19 disease in children, all three critical cases had a significant underlying or concurrent medical condition, including acute lymphoblastic leukemia (all), hydronephrosis, and intussusception. 30 however, it should be noted that none of the five severe cases had significant comorbidities. 30 given the low prevalence of severe and critical disease in children, it is difficult to determine the contribution of pre-existing comorbidities to covid-19 severity. specifically, underlying medical issues such as prematurity, chronic lung disease, congenital heart disease, asthma, and even lung injury from vaping and smoking, may result in an increase in the risk for severe covid-19 disease. intriguingly, there are few reports of severe disease in immunocompromised patients with covid-19 despite receipt of immunosuppressive agents and chemotherapies. while data are limited to small cohort studies, adult renal transplant recipients tended to have a typical a c c e p t e d m a n u s c r i p t 8 covid-19 course, while adults with malignancy had more severe disease if they had recently received chemotherapy or underwent surgery. 31, 32 of immunocompromised sars-cov-2 infected children, the aforementioned child with all developed critical disease, but only mild to moderate disease has been observed in pediatric liver transplant recipients. 30, 33 the surprisingly mild course of covid-19 in immunocompromised patients could allude to the substantial role that the host immune system plays in the development of severe disease. protection from severe disease in children may be related to lower expression of host factors required for viral replication, and to differences in the magnitude and timing of innate or adaptive immune responses. host factors: sars-cov-2 uses the angiotensin-converting enzyme 2 (ace2) as a cell entry receptor and the cellular transmembrane protease serine 2 (tmprss2) to activate the spike (s) viral protein for membrane fusion. 34 ace2 modulates vasoconstriction to maintain homeostasis and is expressed in the oral mucosa, respiratory tract, and intestine. 35,36 lower ace2 expression in the lungs of children as compared to adults could contribute to the observed differences in disease pathogenesis across these groups. 37 however, given the large variability in human ace2 expression profiles, further studies are required to confirm differences across age groups. 37 there are also age-dependent differences as lungs develop throughout childhood 38 . in particular, processes that impact the course of lung pathology and respiratory distress such as inflammation, apoptotic activation, surfactant secretion, alveolar fluid clearance, and tissue repair mechanisms differ in children compared to adults. 38 for example, a regulator of lung morphogenesis that is lower in childhood, nuclear factor kappa-light-chainenhancer of activated b cells (nf-b), plays a pathologic role in inflammatory diseases and should be evaluated as a protective host factor in pediatric versus adult sars-cov-2 infections. 38, 39 indeed, even outside the context of sars-cov-2 infections, rates of ards are a c c e p t e d m a n u s c r i p t 9 lowest in children and increase with age, suggesting a role for protective host factors in the lungs of children. 40, 41 innate and adaptive immunity: th1 responses are thought to be important for immune protection against sars-cov-1 since increased th2 cytokines were identified in patients with fatal disease. 42 however, excess th1 pro-inflammatory cytokine responses and circulating neutrophil levels are also associated with increased disease severity and delays in regulatory and repair responses. 43, 44 in fact, over expression of serum il-6 is associated with severe disease and mortality due to sars-cov-2 infection suggesting that aging-related inflammation may contribute to disease severity in elderly. 45 whereas, children who recovered from sars-cov-1 infection demonstrated elevated plasma il-1β but not tnf-α or il-6 early in infection, suggesting a less destructive disease pathology. 46 descriptions of lung pathology from sars-cov-1 and sars-cov-2 fatalities reveal that macrophages are the predominant leukocyte infiltrate in the alveoli 43, 47 . higher prevalence of macrophages in the alveoli may be due to prolonged il-6 inflammation, in combination with monocyte chemoattractant protein-1 (mcp-1) expression, which induces a transition from neutrophil activation in early inflammation to monocyte accumulation in late inflammation 48 . interestingly, lower levels of il-6 and mcp-1 are observed in the lungs of children who survive ards compared to adults. 37 although neutrophils are associated with lung pathology during ards, the role for lung neutrophils in covid-19 severity remains unclear. 49 neutrophil depletion in rodent models of respiratory viral infections such as sars-cov-1, influenza, and respiratory syncytial virus leads to worse clinical outcomes and higher levels of viral replication, suggesting that neutrophils may serve a protective function during these infections 38, [50] [51] [52] [53] . thus, the role for neutrophils and macrophages in sars-cov-2 infections needs to be evaluated further and compared between children and adults. effective immune responses to cov require regulated th1 immunity for viral control and infected cell killing, followed by regulatory signaling that mediate tissue repair 54 . intriguingly, children a c c e p t e d m a n u s c r i p t 10 experience less leukopenia during sars-cov-2 infection than adults and have a relatively higher level of circulating lymphocytes compared to neutrophils, which may contribute to better viral control during acute infection. 5, 12, 55 thus, milder sars-cov-2 infection in children may be driven by intrinsically lower levels of inflammation, higher lymphocyte to neutrophil ratio in blood, and less predominantly monocytic infiltration than adults. recent reports have demonstrated that neonates less than 1 year of age (<1 year) are more susceptible to severe covid-19 disease compared to older children (1-18 years). 6 dynamics of t cell-mediated immunity may contribute to the increased covid-19 severity in adults and neonates (<1 year) compared to the milder disease observed in children (<18 years). for example, virus-specific cd8+ t cells play an important role in viral clearance by directly killing infected cells, but excess cytolytic activity can also mediate lung pathology 56 . the observed increase in lung pathology in both infants <1 year and older adults may be due to inappropriate levels of t cell activity. indeed, in infants <1 year t cell activation is decreased and effector responses are characterized by th2 cytokine secretion as infants transition from tolerogenic fetal immunity 57 . in contrast, higher inflammation associated with aging can lead to t cell exhaustion, which is linked with severe covid-19 disease. 58 in comparison, children between 1-18 years may experience an intermediate level of t cell activation, leading to milder sars-cov-2 disease. 59 also, an age-dependent increase in lung prostaglandin production may play a role in sars-cov-2 pathogenesis. for example, in mice lung prostaglandin concentrations correlated with decreased dendritic cell migration and t cell responses and greater sars-cov-1 induced lung pathology with age. 60 further examination of children t cell immunity during sars-cov-2 infection compared to adult responses is required. our understanding of protective humoral responses to cov infections comes from prior studies of sars-cov-1, and ongoing studies on the current sars-cov-2 pandemic. typically, neutralizing antibody responses against the immunodominant s viral protein are elicited after a c c e p t e d m a n u s c r i p t 11 two weeks of infection and can protect from challenge in animal models. 61 yet, high magnitude and early (< 2 week) peak neutralizing antibody responses were associated with more severe disease in sars-cov-1 infection, indicating antibody responses may also be related to disease pathology. 62 moreover, the sars-cov-2 s protein contains neutralizing and non-neutralizing epitopes and is 76% identical to sars-cov-1 s at the amino acid level. 63 heterologous strains, has led to eosinophilic lung immunopathology. 76, 77 intriguingly, young mice showed less immunopathology as compared to aged mice, indicating that age of vaccination may impact safety profile. though it is unclear whether lung immunopathology reflects enhanced disease in humans, whole virus vaccine platforms must be carefully evaluated for safety. lack of vaccine candidates with a proven safety and/or immunogenicity profile represents a gap in translating these technologies to pediatric populations during a pandemic. while rapidly testing candidates, it will be crucial to consider the earliest possible stage for inclusion of children in vaccine trials. a key question for vaccine development in the current pandemic is the possibility of reinfection with sars-cov-2. prior studies indicate that reinfection may be possible after several years, since sars-cov-1 neutralizing antibody titers reduced substantially 3 years after exposure and virus-specific memory b cells were undetectable 6 years after infection. 78, 79 further, virus-specific memory t cells were undetectable by 6 years post infection in 40% patients who recovered from sars-cov-1 infection. 79 therefore, it will be important to assess if a c c e p t e d m a n u s c r i p t 13 sars-cov-2 immunity in children lasts longer than that of adults, which would indicate that childhood represents an opportune period for vaccination to elicit life-long protection. also, differential waning of vaccine immunity in adults and children should be evaluated to optimize age of vaccination and develop boosting strategies to provide long term protective immune responses. two leading antivirals are currently being tested in patients with covid19. remdesivir is an intravenously delivered investigational antiviral that that is being tested in several randomized controlled clinical trials globally, largely in adults with moderate or severe covid-19. 80 remdesivir is a nucleoside analog that inhibits cov replication by terminating the rna genome transcription. 81 assessments in children are underway to determine optimal pediatric dosing. another option being tested is hydroxychloroquine, an approved oral antimalarial drug that is also used for rheumatoid arthritis and systemic lupus. while hydroxychloroquine demonstrates high antiviral activity in-vitro, underpowered clinical trials have indicated virologic control but no significant effect on clinical outcomes in patients with severe disease. 82 in addition to antivirals, passive immunization strategies using convalescent plasma and purified immunoglobulins to limit virus replication and abrogate disease progression are under investigation. reports of successfully treating critically ill covid-19 patients with convalescent plasma from recovered individuals has enabled approval for emergency use in the us for cases of serious and life threatening covid-19. 83 meta-analysis of this therapy for sars-cov-1 suggests that this intervention appears safe and reduces mortality. 84 however, since antiviral potency of plasma may vary by donor, it is important to determine the characteristics of plasma that support efficacy and optimal prognosis. for example, poor treatment outcomes for sars-cov-1 patients were observed when convalescent plasma intervention was administered during pcr-positivity and before the 14 th day of illness. 85 these observations allude to the relationship a c c e p t e d m a n u s c r i p t 14 between viral dynamics and igg-mediated pathology that may differ between adults and children. the current covid-19 pandemic has resulted in more than 3 million cases worldwide, and the lack of protective vaccines and specific antiviral therapies to prevent severe disease has resulted in more than 228,000 deaths 2 . a pattern of milder covid-19 in children in compared to adults offers a unique opportunity to identify protective host and immunologic factors within pediatric populations and apply findings to the design of interventions for all ages. in this review, we evaluated recent reports on the pathology and immunity to sars-cov-2 infection and offered several hypotheses for how these features may differ in children versus adults, and how they may differentially modulate disease in these populations. further understanding of the pathogenesis of sars-cov-2 infection in children may provide important insights and guide development of therapeutic strategies and vaccines as we collectively strive to generate approaches to reduce the public health burden of sars-cov-2 pandemic. a c c e p t e d m a n u s c r i p t 15 characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese 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mother to her newborn immunoglobulin m for acute infection: true or false? pregnancy and perinatal outcomes of women with severe acute respiratory syndrome clinical progression of patients with covid-19 in shanghai sex differences in pediatric infectious diseases prevalence of comorbidities in the novel wuhan coronavirus (covid-19) infection: a systematic review and meta-analysis clinical features of severe pediatric patients with coronavirus disease 2019 in wuhan: a single center's observational study cancer patients in sars-cov-2 infection: a nationwide analysis in china covid-19 in kidney transplant recipients the facts during the third epidemic -d'antiga --liver transplantation -wiley online library sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor high expression of ace2 receptor of 2019-ncov on the epithelial cells of oral mucosa tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step 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detecting antibodies against sars-cov-2. medrxiv differences between pediatric and adult t cell responses to in vitro staphylococcal enterotoxin b stimulation age-related increases in pgd 2 expression impair respiratory dc migration, resulting in diminished t cell responses upon respiratory virus infection in mice serological responses in patients with severe acute respiratory syndrome coronavirus infection and cross-reactivity with human coronaviruses 229e, oc43, and nl63 neutralizing antibody response and sars severity immunodominant sars coronavirus epitopes in humans elicited both enhancing and neutralizing effects on infection in non-human primates characterization of spike glycoprotein of sars-cov-2 on virus entry and its immune cross-reactivity with sars-cov hepatitis b immunisation induces higher antibody and memory th2 responses in new-borns than in adults impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine early development of broadly neutralizing antibodies in hiv-1-infected infants infant hiv type 1 gp120 vaccination elicits robust and durable anti-v1v2 immunoglobulin g responses and only rare envelope-specific immunoglobulin a responses hiv exposed infants vaccinated with a mf59/rgp120 vaccine have higher magnitude anti-v1v2 igg responses than adults immunized with the same vaccine with record-setting speed, vaccinemakers take their first shots at the new coronavirus. science (80-) rapid development of an inactivated vaccine for sars-cov-2 rapid development of a synthetic dna vaccine for covid-19 under rev the covid-19 vaccine development landscape sars-cov-2 vaccines: status report a double-inactivated severe acute respiratory syndrome coronavirus vaccine provides incomplete protection in mice and induces increased eosinophilic proinflammatory pulmonary response upon challenge immunization with sars coronavirus vaccines leads to pulmonary immunopathology on challenge with the sars virus. poehlmann s duration of antibody responses after severe acute respiratory syndrome lack of peripheral memory b cell responses in recovered patients with severe acute respiratory syndrome: a six-year follow-up study comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against mers-cov hydroxychloroquine and azithromycin as a treatment of covid-19: results of an open-label non-randomized clinical trial treatment of 5 critically ill patients with covid-19 with convalescent plasma the effectiveness of convalescent plasma and hyperimmune immunoglobulin for the treatment of severe acute respiratory infections of viral etiology: a systematic review and exploratory meta-analysis use of convalescent plasma therapy in sars patients in hong kong none. a c c e p t e d m a n u s c r i p t 21 m a n u s c r i p t 24  will antivirals suppress viral load in vivo as well as lower clinical pathology?  in which target population will the vaccine be most effective and durable?  what will be the effect of pre-existing immunity and maternal antibody on the vaccine?  can children respond most effectively to this vaccine, and will infancy be the optimal timing to achieve lifelong protection?  how soon can we include vulnerable populations including pregnant women, neonates, and children in the vaccine development process to optimally tailor vaccine design to these populations?  can we leverage understanding of protective pediatric immunity and pathophysiology to guide design of therapeutic targets and vaccines? key: cord-320002-25ivll3q authors: mathew, joseph l.; singhi, sunit; ray, pallab; hagel, eva; saghafian–hedengren, shanie; bansal, arun; ygberg, sofia; sodhi, kushaljit singh; kumar, b v ravi; nilsson, anna title: etiology of community acquired pneumonia among children in india: prospective, cohort study date: 2015-10-21 journal: journal of global health doi: 10.7189/jogh.05.020418 sha: doc_id: 320002 cord_uid: 25ivll3q background: childhood community acquired pneumonia (cap) is a significant problem in developing countries, and confirmation of microbial etiology is important for individual, as well as public health. however, there is paucity of data from a large cohort, examining multiple biological specimens for diverse pathogens (bacteria and viruses). the community acquired pneumonia etiology study (capes) was designed to address this knowledge gap. methods: we enrolled children with cap (based on who imci criteria of tachypnea with cough or breathing difficulty) over 24 consecutive months, and recorded presenting symptoms, risk factors, clinical signs, and chest radiography. we performed blood and nasopharyngeal aspirate (npa) bacterial cultures, and serology (mycoplasma pneumoniae, chlamydophila pneumoniae). we also performed multiplex pcr for 25 bacterial/viral species in a subgroup representing 20% of the cohort. children requiring endotracheal intubation underwent culture and pcr of bronchoalveolar lavage (bal) specimens. findings: we enrolled 2345 children. npa and blood cultures yielded bacteria in only 322 (13.7%) and 49 (2.1%) children respectively. in npa, streptococcus pneumoniae (79.1%) predominated, followed by haemophilus influenzae (9.6%) and staphylococcus aureus (6.8%). in blood, s. aureus (30.6%) dominated, followed by s. pneumoniae (20.4%) and klebsiella pneumoniae (12.2%). m. pneumoniae and c. pneumoniae serology were positive in 4.3% and 1.1% respectively. multiplex pcr in 428 npa specimens identified organisms in 422 (98.6%); of these 352 (82.2%) had multiple organisms and only 70 (16.4%) had a single organism viz. s. pneumoniae: 35 (50%), cytomegalovirus (cmv): 13 (18.6%), respiratory syncytial virus (rsv): 9 (12.9%), other viruses: 6 (8.7%), s. aureus: 5 (7.1%), and h. influenzae: 2 (2.9%). bal pcr (n = 30) identified single pathogens in 10 (s. pneumoniae–3, cmv–3, s. aureus–2, h. influenzae–2) and multiple pathogens in 18 children. there were 108 (4.6%) deaths. the pattern of pathogens identified did not correlate with pneumonia severity or mortality. conclusions: the majority of children with cap have multiple pathogens (bacteria and viruses). s. pneumoniae and s. aureus predominate in npa and blood respectively. cmv and rsv were the dominant respiratory viruses in npa and bal. the presence of multiple pathogens, especially organisms associated with nasopharyngeal carriage, precludes confirmation of a causal relationship in most cases. pneumonia is a leading cause of childhood morbidity and mortality globally. it is estimated that there were over 120 million episodes of pneumonia among children younger than five years during 2010-11; of which over 10% were severe episodes [1] . a recent systematic review estimated 0.22 pneumonia episodes per child-year in developing countries alone [2] , with nearly one in eight cases progressing to severe disease. yet another systematic review estimated nearly 12 million hospitalizations in 2010 due to severe pneumonia and 3 million due to very severe disease [3] . pneumonia is also estimated to be responsible for almost 1 million deaths among children under 5 years old [4] , with maximum burden in africa and south asia [3] . india has a high burden of childhood pneumonia and the disease accounts for about a quarter of the under-five mortality in the country [5] . recognizing this burden, the world health organization (who) developed and disseminated a simple case definition for identification and treatment of pneumonia, which could be used by field-workers in resourcepoor settings [6] [7] [8] [9] . it relies on the physiological principle that parenchymal lung disease results in compensatory tachypnea; therefore any tachypnea indirectly indicates parenchymal disease including pneumonia. this case definition is highly sensitive, and does not require chest radiography. traditional teaching attributes most cases of childhood community acquired pneumonia (cap) to a few micro-organisms, mostly bacteria [8] . in recent decades, developed countries have witnessed a shift from bacterial to viral predominance on account of hygiene, sanitation, infection control, and vaccination policies. recent systematic reviews of childhood pneumonia etiology suggest that in developing countries, a few bacteria (s. pneumoniae and h. influenzae) and viruses (respiratory syncytial virus, influenza virus) are associated with majority of childhood cap [3, 5, [10] [11] [12] . a systematic review from india suggested that about 15-24% of bacterial pneumonia in south asian countries can be attributed to s. pneumoniae [13] . similarly data from the invasive bacterial infection surveillance (ibis) network in india suggests that invasive pneumococcal disease could be a significant public health problem in the country, contributing to significant morbidity and mortality [14] . however these data were not based on studies designed to determine pneumonia etiology. the pneumonia research for child health (perch) project [15] is a 7-site case-control study to identify the cause of pneumonia among children in developing countries. however, none of the sites is located in india. pilot data from perch reported 152 potentially pathogenic isolates among 108 hospitalized cases, using multiple microbiologic techniques on various body fluids. viruses represented over 80% of the pathogens detected [16] . conventional methods for determining etiology, such as bacterial culture of blood or nasopharyngeal swabs, and/or selective application of serological tests for a few organisms, are limited by poor sensitivity, or low specificity, or both. on the other hand, diagnostic techniques with greater specificity are limited by technical difficulty, invasive procedures, and high cost. accurate, reliable and rapid determination of etiology in childhood cap is important because it would influence individual treatment decisions, antibiotic policy in the community, and also rational immunization policy at a national level. currently, there is no study from india reporting etiology of cap in a large cohort of children, using multiple biological samples, and various sensitive as well as specific microbiologic methods. we initiated the community acquired pneumonia etiology study (capes) to address this knowledge gap by determining the microbiologic etiology of cap in a cohort of indian children using multiple biological specimens (blood, nasopharyngeal aspirates, bronchoalveolar lavage) and the relationship between etiology and pneumonia severity. this prospective study was carried out in the union territory of chandigarh (located in north india with a population of 1.05 million residing in urban, rural and urban-slum areas, of whom 11.3% are children), over 24 consecutive months from 1 april 2011 to 31 march 2013. the study was coordinated from the advanced pediatrics centre (apc) at pgimer chandigarh, a tertiary care centre with nearly 20 000 annual in-patient admissions and 100 000 out-patient visits. enrolment of children aged 1 month to 12 years, fulfilling the who imci case definition of cap designed for children <5 years [6] [7] [8] , was carried out through active and passive surveillance (figure 1) . tachypnea was defined as respiratory rate >60/min for infants <2 months; >50/min for infants 2-12 months; >40/min for children >12-60 months; and >30/min for children >60-144 months. active surveillance was conducted in 30 anganwadi clusters, selected to represent the population of chandigarh, where trained research team members visited households daily, inquiring for clinical symptoms of pneumonia. passive surveillance was carried out by research staff stationed in the out patient and emergency departments of the apc, by evaluating clinical signs of cap in children presenting to these departments. if symptoms were reported and tachypnea confirmed, the child was presented to a medical officer for confirmation and inclusion. children with duration of illness >7 days; those who had received antibiotics for >24 hours at presentation or those with previous hospitalization within the preceding 30 days, were excluded. children with wheeze received a single dose of bronchodilator (salbutamol 0.15mg/ kg by nebulization), and those whose symptoms disappeared were excluded. all children received standard treatment including antibiotics, other medications as required and supportive care as per institution guidelines. confirmation of the diagnosis by a medical officer was required. children whose symptoms of cap disappeared with a single dose of bronchodilator were excluded. after obtaining written parental consent to participate, a total of 2345 children were enrolled in the study and included in analysis. each child underwent a detailed history for demographic data, presence of risk factors for pneumonia, and immunization status. after physical examination, pneumonia severity was categorized based on the who classification [6] [7] [8] . in addition, all children underwent chest radiography. the radiographs were subsequently independently read by two trained investigators and scored as per the who criteria [17] . discordant results were resolved through mutual discussion. in addition, children who required endotracheal intubation were also offered fiber-optic bronchoscopy and bronchoalveolar lavage (bal), based on clinical need. a blood sample was drawn by venepuncture for routine investigations (hemogram, blood biochemistry). one to three ml blood was processed for bacterial culture using bactec 9240 (becton dickinson, haryana, india) in peds plus/f culture media (becton dickinson) [18] . the bottles were incubated at 37 °c for seven days and isolates were identified to species level by conventional biochemical and serological tests. a nasopharyngeal aspirate (npa) specimen was obtained from all children using a sterile, disposable suction catheter [19] . one aliquot was processed for bacterial culture and one aliquot was mixed with 3 ml saline and frozen at -80 °c for subsequent pcr analysis. bal samples were similarly processed for bacterial culture and pcr. the department of medical microbiology at pgimer is accredited by the government of india' s national accreditation board for testing and calibration laboratories (nabl). serum was stored at -80 °c for m. pneumoniae and c. pneumoniae igm serology performed using commercially available kits (calbiotech inc usa) according to the manufacturer' s instructions [20, 21] and analyzed with an automated elisa reader (spectrostar nano, bmg labtech, germany) [22] . serological tests were run in duplicate and only concordant results were labeled as positive or negative. multiplex pcr was performed on a subset of samples representing 20% of the cohort, selected through a randomization procedure stratifying by age, pneumonia severity and season. pcr was performed for detecting a panel of respiratory bacteria and viruses (table s1 in online supplementary document) at xcyton diagnostics pvt ltd, bangalore, also nabl accredited, using the syndrome evaluation system (ses) for pneumonia. the ses was standardized to attain 100% sensitivity and specificity using quantified virus panels available from quality control for molecular diagnostics (qcmd), uk [23] . (table s2 in online supplementary document). limit of detection for all dna viruses was 250 virions/ml and 100 virions/ml for cmv and adenoviruses. for rna viruses, qcmd proficiency panels of 2011 were used. samples were thawed, centrifuged (3000 rpm×10 min) and re-suspended in 1 ml sample supernatant. nucleic acids were extracted using commercially available qiagen kits and cdna was prepared using a commercial cdna archive kit (abi, usa) [24] , both according to the manufacturer' s instruction with the addition of pathogen specific primers. amplification was carried out in bio-rad ptc200 thermal cycler and the detection of amplified products was facilitated using biotin labeled primers. samples were categorized as negative or positive for any pathogen with internal controls (human housekeeping genes β2-microglobulin and β-actin) included in each run as control for dna and rna extraction respectively. descriptive statistics of cohort characteristics and duration of various symptoms are presented with proportional distribution and median (iqr) respectively. ordinal categorical data and mortality status was analyzed using test of linear association. data analysis was conducted in ibm spss statistics 22.0 [25] . the funding agency had no role in study design, data collection, data analysis, data interpretation, writing of the manuscript or decision to submit for publication. all authors had access to the data in the study and approved the decision to submit for publication. a total of 36 676 children underwent active or passive surveillance for cap. figure 1 shows the step-wise process used to enrol children. a total of 2345 children were enrolled and comprised the cohort included in the analysis. similarly, absent or deficient breastfeeding (defined as duration of breastfeeding <6 months for infants older than six months, or less than infant' s age in those <6 months old) was more common in those enrolled through passive surveillance. these children were also more likely to be exposed to solid fuels as well as tobacco smoke in their homes. there were no major differences in gender, history of wheeze, previous history of infections, or family history of tuberculosis in children enrolled through active or passive surveillance. table 2 presents symptoms reported by parents, clinical findings and radiography. almost all children presented with cough, fever and fast breathing with median duration of symptoms being similar in those enrolled through active or passive surveillance. parents reported wheezing during the current episode in approximately one-third of the children. symptoms/signs suggesting greater severity of pneumonia were more frequently identified in those enrolled through passive surveillance. a larger proportion of these children also had who class i and class ii chest x-rays. there were 108 (4.6%) deaths; of these 107 occurred among those enrolled through passive surveillance (mortality rate 9.2%) and one among those enrolled through active surveillance (0.1%). based on disease severity, the mortality rate was 1.2% for pneumonia, 4.7% for severe pneumonia and 15.8% for very severe pneumonia. a comparison between fatal and non-fatal cases suggested that age <12 months, oxygen saturation <95% and radiographic finding of consolidation (who class i) were associated with mortality. figure 2 ). a single bacterium or a single virus was found in only 42 (9.8%) and 28 (6.5%) children respectively. s. pneumoniae dominated (n = 35) followed by s. aureus (n = 5) and h. influ-enzae (n = 2). the single viruses identified were cmv (n = 13) and rsv (n = 9) followed by rhinovirus (n = 2), and one each of influenza, parainfluenza, enterovirus and hmpv. s. pneumoniae was the dominant organism identified in npa culture as well. a comparison of the bacterial yield from npa by pcr and culture is shown in panel b in figure 2 . among the 428 children with npa pcr results, 25 died and pcr showed diverse organisms distributed in a pattern similar to the 428 children (panel c in figure 2) . among intubated children undergoing bronchoscopy as part of clinical care (n = 30), only 2 samples were negative on pcr and the remainder showed organisms in a similar pattern to npa pcr (panel d in figure 2 ). since most npa pcr samples yielded multiple pathogens, the data were analyzed with respect to etiology patterns rather than individual pathogens. these included combinations of two bacteria, two viruses, one bacterium plus one virus, or mixed i.e more than one bacteria and/or virus (panel e in figure 2) . the most common combination of pathogens in individual samples was s. pneumoniae and cmv (n = 100) followed by 2 bacteria or 2 viruses. in bal samples, the single pathogens identified were s. pneumoniae (n = 3), s. aureus (n = 2), h. influenzae (n = 2) and cmv (n = 3); the majority of samples (n = 18) showed multiple organisms (panel f in figure 2 ) that were distributed in a pattern almost similar to npa samples. the complex microbial patterns on pcr were further analyzed with respect to disease severity (defined according to who criteria) but there were no apparent differences (figure 3) . to our knowledge, this is one of the largest single-centre studies of cap etiology in children from a resource-limited setting. our data suggest that cap is associated with a number of pathogens or combinations of viral and bacterial pathogens. further, no single pathogen or combination could be related to disease severity. our findings also confirm that infants <12 months old are particularly vulnerable in terms of disease severity and outcome. as expected, s. pneumoniae was the predominant isolate in npa by culture as well as pcr, although mere detection does not establish a causal role. we could not do serotyping due to resource constraints. it can be argued that the isolation rate by culture in our cohort is lower than expected [26, 27] , especially as pcr identified s. pneumoniae much more frequently. it is possible that clinical pneumonia due to other pathogens masks the presence of s. pneumoniae on routine culture. the major difficulty in attributing etiology to s. pneumoniae is its frequent presence in asymptomatic children also, although a similar argument could be raised for s. aureus too [28, 29] . detection of multiple pathogens in npa by pcr makes it difficult to ascribe a causal role to any one organism. our culture and pcr data also suggest that nasopharyngeal specimens may perhaps be inappropriate for confirming microbial etiology in cap. indeed, this is in concordance with several recent studies showing the presence of various viruses in asymptomatic children as well as those with upper respiratory tract symptoms [19, 30, 31] . it appears that even m. pneumoniae can be identified in the nasopharynx of healthy children [32] . somewhat surprisingly, cmv was the most common virus in our cohort, where none had immune-suppressive therapy, known primary immune-deficiency and where the hiv prevalence during the study period is reported to be <0.25% in the community [33] . while cmv is well-recognized as a pathogen in these latter settings, its frequent occurrence in cap raises the possibility that it may contribute to pneumonia pathogenesis singly or with other pathogens [34] . this novel finding also emphasizes that although pcr is highly sensitive, it can detect only those organisms that are looked for-a limitation that is being overcome by next generation sequencing. after cmv, rsv was most frequently identified as previously reported also [2] while influenza a and b were less frequent. unfortunately, even bal samples in a limited number of children could not ascertain etiology as most children had multiple organisms. further the time-lag between presentation and obtaining bal samples in the majority of children raises the possibility that some of the organisms could represent secondary infection. how to interpret the detection of multiple organisms in respiratory tract samples from a given child? it is possible that infection by one (potential) pathogen facilitates other pathogens, or that mild infection with one organism becomes more severe in the presence of additional organisms. this is well documented with influenza infection [35, 36] and suggested for other organisms also [2] . however, the pattern of pcr findings did not differ with disease severity which is in concordance with initial data from the perch project also [16] . in our cohort, a single organism (bacteria or virus) was identified by npa pcr in only a minority of children. further npa data may be skewed on account of nasopharyngeal carriage. the limited bal data suggests that s. pneumoniae, cmv, s. aureus and h. influenzae may be the dominant pathogens in severe cases of cap. in children with fatal outcome, the same pathogens were identified along with rsv. in the small number of positive blood cultures, s. aureus predominated, rather than s. pneumoniae or h. influenzae, expected in a vaccine-naïve pediatric population such as our cohort. clinical experience suggests that s. aureus is frequently re-sponsible for community acquired infections in india, although it has not previously been documented as the most frequent cause of bacteraemia in childhood pneumonia. in contrast, it is the most frequently recovered pathogen in parapneumonic effusions/empyema complicating pneumonia [37] [38] [39] and also commonly isolated in blood cultures from infants with bacteraemia [40] . therefore it is reasonable to conclude that s. aureus may be an important pathogen in childhood pneumonia as well. however, international and national antibiotic treatment protocols for childhood cap do not use specific antibiotics against this organism. the data presented in this study raise some important points for further research on childhood cap. first, the mere identification of organisms by highly sensitive techniques may not confirm etiology. even comparing the yield among cases vs controls, as planned in the perch project [41] can at best suggest an association, but not causation. in an individual child, even the presence of organisms commonly associated with pneumonia may be of limited value for predicting pneumonia severity/ outcome. the presence of potential pathogens in the respiratory secretions of apparently healthy children also raises the possibility that microbes may not be solely responsible for disease. it is likely that combinations of host immune status and/ or response to infection/inflammation tip the balance from asymptomatic colonization to disease in a given child. although this study had several methodological strengths limiting the risk of bias, it also had limitations. the dispropor-tionately large number of severe and very severe pneumonia cases attest to greater enrolment through passive surveillance. lack of controls is a limitation since it would have provided data on nasopharyngeal carriage of pathogens in asymptomatic/ healthy children in this population. further, research team members could not be stationed in a given anganwadi throughout the study period, hence pneumonia incidence could not be calculated. we could perform only qualitative pcr, and that too in a small proportion (20%) of the cohort. this large cohort study (capes) identified multiple pathogens in various biological samples of children with cap. our data suggest that it is difficult to attribute etiology to a single pathogen in the majority of cases as co-infection is common and independent of disease severity. multiplex pcr proved to be highly sensitive in identifying potential pathogens from respiratory samples; but lacked specificity for establishing a causal relationship. a novel finding of cmv carriage/infection in nasopharyngeal secretions was observed. our findings suggest that clinical practice guidelines for management of suspected bacterial pneumonia in developing countries should additionally consider anti-staphylococcal therapy. rational vaccination policies against s. pneumoniae, h. influenzae and (in the future) rsv could decrease overall burden of childhood pneumonia morbidity and mortality. global burden of childhood pneumonia and diarrhoea epidemiology and etiology of childhood pneumonia in 2010: estimates of incidence, severe morbidity, mortality, underlying risk factors and causative pathogens for 192 countries global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis acute respiratory infection and pneumonia in india: a systematic review of literature for advocacy and action: unicef-phfi series on newborn and child health world health organization. technical bases for the who recommendations on the management of pneumonia in children at first-level health facilities integrated management of childhood illness (imci) technical seminar -acute respiratory infections world health organization. handbook imci. integrated management of childhood illness. geneva, switzerland: world health organization the definition of pneumonia, the assessment of severity, and clinical standardization in the pneumonia etiology research for child health study a literature review and survey of childhood pneumonia etiology studies epidemiology, aetiology and management of childhood acute community-acquired pneumonia in developing countries-a review community-acquired pneumonia in children: what's old? what's new? burden of invasive pneumococcal disease in children aged 1 month to 12 years living in south asia: a systematic review invasive pneumococcal disease associated with high case fatality in india lower respiratory infections among hospitalized children in new caledonia: a pilot study for the pneumonia etiology research for child health project standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies automated blood culture bactec. #9240/9120/9050 clinical utility of pcr for common viruses in acute respiratory illness available ibm spss statistics 22.0. available nasopharyngeal carriage, antibiogram & serotype distribution of streptococcus pneumoniae among healthy under five children epidemiology of nasopharyngeal colonization by s. pneumoniae in indian infants in the first 2 years of life clinical characteristics of children with lower respiratory tract infections are dependent on the carriage of specific pathogens in the nasopharynx community epidemiology of human metapneumovirus, human coronavirus nl63, and other respiratory viruses in healthy preschool-aged children using parent-collected specimens human bocavirus detection in nasopharyngeal aspirates of children without clinical symptoms of respiratory infection carriage of mycoplasma pneumoniae in the upper respiratory tract of symptomatic and asymptomatic children: an observational study department of aids control, ministry of health and family welfare, government of india. state hiv epidemic fact sheets prevalence of herpes and respiratory viruses in induced sputum among hospitalized children with non typical bacterial community-acquired pneumonia predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness insights into the interaction between influenza virus and pneumococcus empyema thoracis in children: a short term outcome study clinico-bacteriological profile and outcome of empyema empyema thoracis in children: still a challenge in developing countries etiology of bacteremia in young infants in six countries the pneumonia etiology research for child health project: a 21st century childhood pneumonia etiology study the investigators are grateful to ms kerstin thurdin (chair of the astrid lindgren children' s founkey: cord-327493-v2iatbol authors: kwon, hyo jin; rhie, young jun; seo, won hee; jang, gi‐young; choi, byung min; lee, jung hwa; lee, chang‐kyu; kim, yun kyung title: clinical manifestations of respiratory adenoviral infection among hospitalized children in korea date: 2013-08-05 journal: pediatr int doi: 10.1111/ped.12108 sha: doc_id: 327493 cord_uid: v2iatbol background: the objective of our study was to understand the epidemiological and clinical features of respiratory adenoviral infections among children at a single institution over the course of several years. methods: from january 2005 to april 2009, 1836 children (≤15 years old) who had been admitted to korea university ansan hospital were tested for acute respiratory infection. the patients who were positive for an adenovirus infection were enrolled in this study, and their medical records were retrospectively reviewed. results: adenoviruses were isolated from 310 patients. the male to female ratio was 1.6:1 and mean age was 32 ± 24 months. children under 5 years of age had the highest prevalence. in 2007, adenovirus infections occurred endemically throughout the year. the clinical diagnoses were primarily upper respiratory tract infections (45.4%), lower respiratory tract infections (48.1%), and neurologic disease (5.2%). associated symptoms, signs and laboratory findings included fever (91.9%), cough (83.9%), pharyngeal injection (62.3%), rale (32.6%) and elevated c‐reactive protein (93.9%). the most common radiologic findings were perihilar and peribronchial infiltrates (42.6%). co‐infections were observed in 29 cases. the mean durations of hospitalization and fever were 6.2 ± 6.5 and 4.8 ± 3.1 days, respectively. the lengths of hospitalization were similar for patients admitted for upper respiratory tract infections with severe morbidity and those admitted for lower respiratory tract infections. no children in the study died. conclusion: our study demonstrates that respiratory adenovirus infections are an important cause of hospitalization in young children, and contribute to a significant morbidity. adenovirus is a major cause of acute respiratory illness in children worldwide. 1, 2 adenovirus-related deaths in children are rare, but adenovirus-attributable hospitalizations in young children and high-risk populations are quite high. 3, 4 a previous study found a high burden of hospital admission among children with adenoviral infection. 5 the spectrum of adenoviral infection in children ranges from subclinical illness to complicated disease involving multiple organs, with pneumonia being one of the most common presentations. although most infections are selflimited, adenovirus can be associated with severe conditions in both immunocompromised and immunocompetent individuals. 6, 7 sporadic serotype analysis and some case reports have been performed in korea since 1995. 8, 9 however, little information on the epidemiology and clinical characteristics of respiratory adenoviral infection, especially in hospitalized children, has been published. the study was performed to more fully characterize the epidemiological pattern, clinical features and complications associated with hospitalization for adenoviral infection in korean children. nasal aspirate specimens were collected from patients presenting with acute respiratory symptoms at ansan hospital, which is affiliated with korea university and serves the communities of ansan city, a city neighboring seoul. nasal aspirates were routinely tested to identify adenovirus, parainfluenza, respiratory syncytial virus (rsv) and influenza a/b by viral culture using three standard cell lines (hep-2, mdck and llc-mk2). we retrospectively analyzed data from hospitalized children 15 years of age or younger who had a laboratory-confirmed adenovirus infection between january 2005 and april 2009. study approvals were obtained from the institutional review boards of korea university ansan hospital. clinical, laboratory and radiological data were extracted from electronic medical records. clinical information regarding diagnosis, management during hospitalization, intensive care unit (icu) stay, the need for mechanical ventilator assistance and any underlying conditions were obtained from the hospital records. the statistical analysis was performed using spss version 12.0 (spss, chicago, il, usa). data were presented as numbers (percentage), mean ϯ sd or median (range) as appropriate. comparisons between groups were carried out using the mann-whitney u-test. a p-value of < 0.05 was considered to be significant in the analysis. from january 2005 to april 2009, a total of 1836 specimens were collected from patients admitted with respiratory viral infection. of these samples, 310 episodes were confirmed as adenoviral infections, an overall proportion of 16.9% (310/1836). ages ranged from 1 month to 11.3 years, and the mean age was 32 ϯ 24 months. the patients in this study were grouped by age as 0-<1, 1-<2, 2-<3, 3-<4, 4-<5, and ն5 years. about 90% of all the adenovirus-related cases occurred primarily in children aged less than 5 years, and the peak incidence was in the 1-<2year group (23.5%) (fig. 1 ). when the <1-year-old group was divided into two subgroups, the subgroup younger than 6 months represented only 8.4% of the total cases, while the 6-<12 month subgroup was 14.2%. the ratio of boys to girls was 1.6:1. twenty-six patients (8.4%) had one or more underlying conditions, including asthma, chronic neurologic disease and/or prematurity. the annual detection (detection rate, numbers of positive/ numbers of specimen) of adenovirus was as follows: 68 cases diagnoses at admission were based on clinical, laboratory, and radiographic information. adenovirus was associated with a wide variety of diagnoses, ranging from upper respiratory tract infections (urti) to severe pneumonia and encephalitis ( table 1 ). the most frequent presentation was lower respiratory tract infections (lrti) (149/310, 48.1%), followed by urti (141/310, 45.4%). among the lrti, the admitting diagnosis was pneumonia for 107 patients (107/310, 34.5%), acute bronchiolitis in 20 (20/310, 6.5%), and acute bronchitis in 22 (22/310, 6.1%). urti included pharyngitis (92/310, 29.6%), otitis media (26/310, 8.4%), sinusitis (13/310, 4.2%) and croup (10/310, 3.2%). twenty patients (6.5%) presented with other diagnoses, including febrile convulsions, neonatal sepsis, gastroenteritis and encephalitis. over 90% of adenoviral infections were accompanied by fever, which was the most frequent clinical finding. the mean duration of fever was 4.8 ϯ 3.1 days (range 0-15 days). a high fever (ն39°c) was described in one-third of all patients, and prolonged fever (ն10 days) was reported in 6.8% of cases. other common features were cough (83.9%), rhinorrhea (63.2%) and sputum (61.3%). respiratory distress was seen in 19 cases (6.1%). gastrointestinal symptoms were also commonly found. sixty-five (21%) patients presented with diarrhea, anorexia was seen in 63 (20.3%), and vomiting was found in 10 cases (3.2%). other clinical symptoms included seizure (8.4%), headache (4.5%) and skin rash (2%). crackles on auscultation were heard in 32.6% (101/310) of patients. wheezing was noted in 37 (12%) patients, and retraction of the chest wall was seen in 14 (4.5%). other abnormal findings on physical examination were pharyngeal injection (62.3%), redness of the tympanic membrane (12.6%) and conjunctival injection (8.7%). in addition, cervical lymphadenopathy was detected in eight (2.6%) patients, and hepatosplenomegaly was found in two (0.6%). leukocytosis was detected in 69 (22.3%) patients, and leukopenia was seen in four (1.3%) ( table 2) . 10 elevated c-reactive protein (crp) and erythrocyte sedimentation rate (esr) were the most common laboratory findings (93.9%). liver enzyme, aspartate aminotransferase (ast) and alanine aminotransferase (alt) levels were elevated in about 10% of the patients. co-infections with other pathogens were identified in 29 cases. the most common cause was mycoplasma pneumoniae (m. pneumoniae) (12/29). influenza a (2/29) and b (4/29), parainfluenza virus (2/29), rsv (2/29) and rotavirus (7/29) were also concomitantly identified with adenovirus infection. five cases of rotavirus infection were identified as hospital-acquired infection, while other bacterial isolates were not detected at the time of admission. chest radiography was performed in all patients at admission, and abnormal findings were found in 42.6% (132/310); 104 (35.5%) had perihilar or peribronchial infiltrates, 23 (7.4%) had lobar infiltration or consolidation, three (1%) had hyperinflation and two (0.6%) had pleural effusion. the mean duration of hospital stay was 6.2 ϯ 6.5 days (range 3-98 days). the majority of patients (93.9%, 291/310) received antibiotics. two or more antimicrobial agents were used in 34.2% of patients. the most commonly used agents were ampicillin/ sulbactam (80.8%), third-generation cephalosporin (24.7%), aminoglycoside (16.2%) and macrolide (8.6%). oxygen supplementation was provided to 11 patients (3.6%). five patients (1.6%) were admitted or transferred to the icu, and three of them received mechanical ventilation. the characteristics of icu patients are detailed in table 3 . two of the icu patients were admitted in 2005, while the remaining three patients were admitted in 2007. all were male, and had no underlying conditions, except one who was born prematurely. the first case was diagnosed with severe pneumonia, which progressed to ischemic-hypoxic encephalopathy. the second case was pneumonia complicated with bronchiolitis obliterans. the third case was a 23-month-old premature infant with bronchopulmonary dysplasia who required ventilator care for 24 days. the fourth case was pneumonia with a long-lasting fever (15 days) that was improved without complication. the fifth case was admitted for fever and seizure, and adenovirus from csf was identified. no deaths were reported. duration of hospital stay and fever were used as parameters for determining disease severity. duration of hospital stay was significantly longer in children with lrti (p < 0.001) and co-infection (p = 0.001). however, the length of hospitalization was not related to age, sex or pre-existing condition. on the other hand, prolonged fever was associated with underlying disease (p = 0.026) and asthma (p = 0.016). age, sex, diagnosis and co-infection, including m. pneumoniae, were not related to the duration of fever. this study revealed that adenoviral infection accounted for a relatively high proportion (16.9%) of all respiratory virus infections in hospitalized children compared to the results of previous reports. 11, 12 other pathogens included rsv (48%), influenza (19%), and parainfluenza (16.1%). in our study, 81.3% of the adenoviral infections occurred in young children between 6 months and 5 years of age. similar demographic features have been reported in other studies. 13, 14 according to pereira's report, children aged 5 years had higher antibody positivity against adenovirus, and most infections happened in children younger than 5 years. 15 infants less than 6 months of age are known to have a neutralizing antibody by maternal transmission, which appears to be protective during the first 6 months of life. the frequency of infection was low in infants under 6 months of age; however, a severe case, such as encephalitis, as reported in this study, may occur. the male to female ratio was 1.6:1. the tendency for male predominance has been described in the literature concerning adenovirus infection, as well as in studies of other respiratory viruses. [16] [17] [18] we observed that more cases of adenoviral infectious disease occurred in 2007. adenovirus was the most common in the spring and summer of 2007, but occurred throughout the year in other years examined in this study. it seems that adenovirus shows a seasonal variation, with sporadic epidemics. in korea, small outbreaks of adenovirus infection were reported in the summer of 1995 and in the spring of 1996. 19 in a temperate climate, such as korea, adenovirus infections are known to occur in the spring, early summer and winter. 20 our data showed similar findings, illustrating a slight tendency toward variations in the seasons in which adenovirus was detected more frequently. in one study, 21 adenoviral diseases in children were characteristically accompanied by a high and persistent (mean 5.4 days) fever. over one-third of the children in our study showed a high fever despite the supportive treatment, and a prolonged fever (ն10 days) was found in 6.8% of cases. larrañaga et al. 22 reported that 70% of hospitalized children with adenoviral infection had pneumonia, while our results revealed a significant proportion of patients (45.4%) with urti. the prolonged fever associated with adenovirus infection highlights the primary cause for hospital treatment in patients with urti. also, many patients appeared to have gastrointestinal symptoms with hepatic involvement, as determined by a mild to high elevation of liver enzymes. adenovirus was detected in the csf of one infant who was diagnosed with encephalitis. according to our study, the clinical manifestation of adenovirus infection varied, with multiple organ involvement. several studies have demonstrated that adenovirus is unique among the common respiratory viruses in that it can involve other organs, resulting in conjunctivitis, gastroenteritis, acute hemorrhagic cystitis and meningoencephalitis. 23, 24 although the white blood cell count was within the normal range in most patients (76.4%), elevated crp and esr levels were shown in 93.9% of all the patients. elevated crp and esr levels are also generally thought to be related to bacterial infection, as they are inflammatory markers. others have reported that adenoviral infection typically results in elevated esr and crp levels, unlike what is seen in other viral diseases. 25, 26 therefore, it is not surprising that many patients were initially treated with antibiotics. the clinical use of antigen detection tests is expected to make earlier diagnosis of adenoviral infection, and to reduce unnecessary treatment of antibiotics. the relation to co-infections has been reported by some authors. korppi et al. reported that mixed infection was common (55%) in children with adenovirus infection, and bacterial co-infection was demonstrated in 45% of patients. 27 another study noted that co-infection with measles was a risk factor for mortality in the acute stage of adenovirus respiratory infections. 28 in our study, the most common cause of co-infection was m. pneumoniae. we found no significant difference in disease severity between adenovirus-infected patients with co-infection and those without. when more than one pathogen is identified with adenovirus, it is difficult to determine whether it is true co-infection because adenovirus can persist in the respiratory or gastrointestinal tract after active infection. further study will be necessary to determine whether co-infection can affect the disease course and prognosis. there were several limitations to our study. first, the serotypes of adenovirus were not determined. therefore, we were unable to make more refined observations regarding differences in age distributions, clinical characteristics and determinants of severity based on the serotypes. second, nearly all the children received antibiotic treatment, and the judicious use of antibiotics and resistant development is becoming increasingly important in korea. finally, we did not test for human bocavirus, coronavirus, metapneumovirus, or aerobic bacteria; therefore, some co-infections may have been overlooked. in conclusion, our study contributes to critical epidemiological baseline on respiratory adenoviral infection in korean children, and highlights the importance of adenovirus as a major cause of hospitalization. adenovirus was more frequently detected in young children and was associated with significant morbidity. prolonged fever was associated with urti and necessity of hospitalization, as well as lrti. large-scale investigation through a multicenter approach is required to determine the optimal monitoring and treatment strategies and to achieve a better understanding of the clinical course of adenoviral infection in children. multicentered study of viral acute lower respiratory infections in children from four cities of argentina, 1993-1994 genetic heterogeneity of the hexon gene of adenovirus type 3 over a 9-year period in korea adenovirus bronchiolitis in manitoba: epidemiologic, clinical, and radiologic features severe diffuse adenovirus 7a pneumonia in a child with combined immunodeficiency: possible therapeutic effect of human immune serum globulin containing specific neutralizing antibody burden of viral respiratory disease hospitalizations among children in a community of seoul severe adenovirus bronchiolitis in children adenovirus: an increasingly important pathogen in paediatric bone marrow transplant patients ten cases of severe adenoviral pneumonia in the spring 1995 comprehensive serotyping and epidemiology of human adenovirus isolated from the respiratory tract of korean children over 17 consecutive years (1991-2007) nathan and oski's hematology of infancy and childhood, 7th edn the association of newly identified respiratory viruses with lower respiratory tract infections in korean children clinical picture and epidemiology of adenovirus infections (a review) adenovirus infection in hospitalized immunocompetent children adenovirus infections in hospitalized patients in israel: epidemiology and molecular characterization adenovirus infections genotype prevalence and risk factors for severe clinical adenovirus infection, united states risk factors associated with severe influenza infections in childhood: implication for vaccine strategy interleukin-9 polymorphism in infants with respiratory syncytial virus infection: an opposite effect in boys and girls clinical characteristics of acute viral lower respiratory tract infections in hospitalized children in seoul, 1996-1998 adenoviral diseases in children: a study of 105 hospital cases adenovirus surveillance on children hospitalized for acute lower respiratory infections in chile (1988-1996) lower respiratory tract infections due to adenovirus in hospitalized korean children: epidemiology, clinical features, and prognosis disseminated adenovirus disease in immunocompromised and immunocompetent children the differentiation of classic kawasaki disease, atypical kawasaki disease, and acute adenoviral infection: use of clinical features and a rapid direct fluorescent antigen test serum c-reactive protein in children with adenovirus infection mixed infection is common in children with respiratory adenovirus infection lower respiratory infections by adenovirus in children. clinical features and risk factors for bronchiolitis obliterans and mortality we thank the doctors and laboratory staff of korea university ansan hospital for their participation in the retrospective adenoviral infection study. we also thank our collaborators at myung moon pediatrics for their support. key: cord-341331-l24oe2pd authors: zheng, baojia; wang, hui; yu, cuixiang title: an increasing public health burden arising from children infected with sars‐cov2: a systematic review and meta‐analysis date: 2020-08-05 journal: pediatr pulmonol doi: 10.1002/ppul.25008 sha: doc_id: 341331 cord_uid: l24oe2pd background: severe acute respiratory syndrome coronavirus 2 (sars‐cov2) is spreading all over the world and poses a great threat to humans. this study aimed to systematically review the current situation and public health burden associated with children infected with sars‐cov2. methods: we searched 4 electronic databases without language limitations. the pooled proportion or odds ratio (or) and 95% ci confidence interval (ci) were calculated for each analysis to explore the prevalence of asymptomatic infection and coinfection, as well as to assess the sex of sars‐cov‐2‐infected children. results: we obtained data from 14 eligible studies with 410 patients for the meta‐analysis. the pooled proportion of asymptomatic infection was 40.45% (95%ci: 24.04‐56.85), while coinfection was 10.14% (95%ci: 3.97‐16.30), of which mycoplasma pneumonia (50%, 95%ci: 28.24‐71.76) and influenza virus or parainfluenza virus (22.76%, 95%ci: 4.76‐40.77) were the most common pathogens. both male and female children were susceptible to sars‐cov2 infection. and the pooled proportion of family clustering infection was 83.63% (95%ci: 77.54‐89.72). conclusion: a high proportion of asymptomatic infections occurs in children infected with sars‐cov2, who are also susceptible to coinfection regardless of sex. these data affirm the increasing public health burden arising from infected children regarding the causation of asymptomatic infection or misdiagnosis and as a significant contributor to virus spread. the public should pay more attention to children during epidemics and conduct multimethod detection to further effectively identify infected children and control the source of infection. this article is protected by copyright. all rights reserved. the city of wuhan in china became the focus of global attention due to an outbreak of pneumonia of unknown etiology in late december 2019 that was epidemiologically linked to a seafood wholesale market, where the sale of live animals also occurred. the pathogen was promptly identified as a novel coronavirus, which is currently designated the 2019 novel coronavirus then officially named sars-cov2. 1, 2 although the estimated mortality rate of sars-cov2 is approximately 6%, 3 which is lower than that of severe acute respiratory syndrome (sars) (9.6%), its transmission rate is similar to that of sars (3%), leading to an increase in mortality. at present, there are no effective medicines, and vaccines against sars-cov2 are still in the trial stage. as a result of humanto-human transmission, sars-cov2 spread very fast and caused a formidable outbreak in many cities in china and globally. as of april 13th 2020, a total of this article is protected by copyright. all rights reserved. 1,773,084 cases were confirmed, with 111,562 deaths. 4 the primary reported cases were mainly middle-aged and elderly patients, with fewer cases among children. however, both adults and children are susceptible to infection with this virus. the first confirmed pediatric case of sars-cov2 infection was reported in shenzhen, china on january 20. 5 this first pediatric case was a ten-year-old asymptomatic child who had a ct scan to determine ground-glassopacity in the lungs after contact with confirmed cases in the family. according to published statistics, there were 44,672 laboratory confirmed cases throughout china as of february 11 , of which only 965 (2%) were younger than 19 years. 6 however, the number of infected children is increasing significantly with the peak of the epidemic, and more tests for pathogens are being carried out in communities. additionally, some children have asymptomatic infections, facilitating virus evasion and diffusion, and this has gradually attracted more public attention. the outbreak of sars-cov2 is catastrophic. there have been many studies on sars-cov2 infection in adults, bringing surveillance precautions into much public awareness, whereas studies on infected children are still relatively scarce due to fewer cases or difficulty in conducting full-scale detection. therefore, it is valuable to perform a comprehensive analysis of the different published sars-cov2 pediatric cases recording clinical and epidemiological features, merging and this article is protected by copyright. all rights reserved. contrasting results across multiple studies and identifying the current status and public health burden of childhood infection through pooled estimates. thus, the present study was undertaken to evaluate the current status of sars-cov2 infection in children by performing a meta-analysis to raise awareness and concern about the growing health burden on the public arising from infected children. the findings provide some helpful information for clinicians and the public health sector for developing tracking policies and for preparing intensive strategies against sars-cov2 threats. the present review adhered to the systematic review and meta-analysis's preferred reporting project (prisma) statement. 7 in the second week of april 2020, a search was conducted in 4 electronic databases, including pubmed, embase, web of science and the chinese databases china national knowledge infrastructure (cnki),without language limitations. the following search terms (mesh) were used in "all fields" to identify relevant published articles: 1. "sars-cov-2" or "sars2" or "covid19" or "covid-19 pandemic" or "covid-19 virus infection" or "coronavirus disease-19" or "2019 novel coronavirus infection" or "2019-ncov infection" or "coronavirus accepted article disease 2019" or "2019-ncov disease" or "covid-19 virus disease" or "2019-ncov" or "2019 novel coronavirus disease" 2. "child" or "children" or "infant" or "infants" the published studies were retrieved with no restrictions of language. the included studies were required to meet the following eligibility criteria: (1) studies focused on pediatric patients infected with sars-cov2 whose nucleic acid test or ct scan were positive; (2) retrospective observational studies, case reports or research articles describing the epidemiological, demographic, and clinical features of confirmed cases, which allowed stratification; and (3) a minimum size of patients (n>3) to conduct a meta-analysis. reports published as review articles, editorials, press, managements or guidance were excluded. we also excluded repetitive cases by searching the hospitals where the data were collected because they contained the same information. all titles were independently screened by two authors in accordance with the search strategy mentioned above (bj and hw). a total of 747 records were acquired from the 4 electronic databases. after removing duplicate records, two authors independently performed an abstract review of potentially relevant records to assess their eligibility based on the this article is protected by copyright. all rights reserved. inclusion/exclusion criteria. differences were resolved through discussion until a consensus was reached. then, a full text search of the remaining 27 records was conducted, and 13 records were eliminated due to case repetition and difficulty in stratifying ( fig. 1) . we stratified the information to evaluate the current status of pediatric infection by asymptomatic infection, sex, coinfection and family clustering. meta-analysis of proportions was also calculated for asymptomatic infection, coinfection and family clustering in children. pooled proportions were calculated by single-arm meta-analysis. as sex was considered a dichotomous variable, we used the binomial distribution to calculate odds ratio (or) and 95% confidence interval (ci) for the included studies. a pooled or not equal to 1 indicated a difference between subjects. heterogeneity was assessed with the i 2 statistics for each analysis, with the significance level set at p<0.05. 8 if significant heterogeneity between studies was detected, a random effects model was used to combine or estimates, or the studies were divided into specific subgroups based on different factors. 9 subgroup analysis was performed based on clinical symptoms and coinfecting pathogens. a forest plot was used to illustrate the distribution of the outcome and effect size obtained from each published study. all statistical analyses were conducted using stata 12.0 (stata corp, college station, tx). the flow diagram of the search and study selection process was shown in fig. 1 . a total of 14 eligible studies 10-23 with 410 patients (table 1) were included. of the 14 selected studies, 1 was from spain and 13 from china, two of which were from the same hospital (wuhan children's hospital); however, they were included because the cases were collected at different times. there were 7 retrospective studies, 6 case reports and 1 research study. all the included studies were published from january to april 2020, after the initial outbreak of sars-cov2 occurred at the end of december 2019. the numbers of cases in the included studies ranged from 5 to 115 cases, with 232 males and 178 females. the overall average age (±standard error (se)) of the pediatric patients was 5.27±2.4 years ( table 1) . after infection, the children might appear to be asymptomatic, though with a positive result using nucleic acid diagnosis with a nasopharyngeal or rectal swab. this article is protected by copyright. all rights reserved. as reported, in adults the routes of infection were diverse, however, the presentation of symptoms in most of the infected children started after a confirmed diagnosis in family members. as shown in fig. 5 , the proportion of family clustering in children highly ranged from 64% to 91.30%, with a pooled estimated of 83.63% (95%ci: 77.54-89.72, fig. 5 ). sars-cov2 is a newly discovered coronavirus with a genetic structure that is 82% similar to sars-cov. 24 this origin of this new coronavirus is wild animals, and it can be transmitted through droplets or contact or through the fecal-oral route, with high incidence and rapid spread, posing a huge threat to global public health. 25 children are also susceptible to viral infection because of their immature immune system. although the number of infected cases in children is comparably fewer than that in adults, there is no doubt that the number of confirmed pediatric cases is showing a tendency to increase significantly as the epidemic continues. however, the current status and characteristics of pediatric infections have not been fully described due to the small number of scattered cases. hence, we collected qualified reported cases of children for systematic review and meta-this article is protected by copyright. all rights reserved. analysis, aiming to evaluate the features and situation of the children infected with sars-cov2 and their possibly increasing health burden on the public. this review included 14 studies encompassing 410 pediatric cases. in all the included articles, there is no record of the prognosis of pediatric patients, but according to the statistics, the prevalence of infected children ranged from 1.2% to 5% in different countries, and children constituted less than 1% of all us hospitalisations. additionally, the prevalence of severe and critical disease was 10.6% in children aged <1 at diagnosis, 1-5 years (7.3%), 6-10 years (4.2%), 11-15 years (4.1%) and 16-17 years (3.0%), indicating that children under one year old have a high incidence of severe illness. 26 we conducted a single-arm metaanalysis to analyze the prevalence of clinical symptoms in infected children. however, we found that the clinical manifestations of the infected children were not as typical as those of adults, which might include asymptomatic, fever and dry cough, or upper respiratory tract symptoms such as stuffy nose, runny nose and sore throat. gastrointestinal symptoms such as abdominal discomfort, nausea, vomiting, abdominal pain, and diarrhea might also occur. furthermore, gastrointestinal symptoms are the first manifestation in neonates. 27 these symptoms of sars-cov2 are similar to sars with the predominant and most consistent symptom is fever. other symptoms include rhinitis, cough and diarrhea 28 this article is protected by copyright. all rights reserved. coronavirus (mers-cov) with more typical symptoms, ranging from asymptomatic infection to severe respiratory distress leading to death. 29 in our study, most cases were of preschool age, and the prevalence of asymptomatic cases highly reached 40%. additionally, the most common clinical symptoms of children with manifestations were fever and dry cough, followed by sore throat and diarrhea or vomiting, but few children experienced symptoms of dyspnea and chest tightness, as adults do. compared with adult cases, the condition of pediatric cases was mostly mild, which maybe related to the underdeveloped respiratory system. one study showed that sars-cov2 can utilize multiple homologous isoforms of angiotensin-converting enzyme ii (ace2) to effectively enter human respiratory tract cells. 30 the weak function of ace2 receptors or their low expression in the underdeveloped respiratory system can limit viral invasion to some extent. nonetheless, a concern is that many infected children were asymptomatic but positive for viral nucleic acid, and they might become the most dangerous group of virus transmission in the public. du et al. 31 estimated that the basic reproduction number (r0) of sars-cov2 was 2.56. adam kucharski et al. 32 believed that r0 fluctuated between 1.5 and 4, suggesting that sars-cov2 has a strong ability to spread. furthermore, the viral load of the upper respiratory tract in asymptomatic patients is roughly equivalent to that in patients with obvious pneumonia. 33 collectively, as found from our this article is protected by copyright. all rights reserved. study, the proportion of asymptomatic children was surprisingly large, suggesting that infected children are an important source of virus spread leading to outbreaks and difficulty in control, as children are easily overlooked by the public due to their social status and stereotype. based on our findings, sex was not a risk factor associated with these sars-cov2-infected children because the pooled or of males compared to females was close to 1 and crossed the invalid line, indicating that boys are not more susceptible than girls. as shown in fig. 4 , approximately 10% of confirmed pediatric cases had coinfections, and the most common coinfecting pathogens it is worth noting that one of the included studies revealed real-time rt-pcr positivity using rectal swabs for eight of ten pediatric patients, which remained detectable well after nasopharyngeal swabs became negative, 22 suggesting that the gastrointestinal tract may shed virus and that fecal-oral transmission between children and adults is possible. positive results of rectal swabs lasting for 13 days in one of the eight patients, a 12-year-old girl, suggests that the discharge standard of infected children cannot rely only on nasopharyngeal swabs; it needs to be combined with rectal swab detection and prolonged detection time. family cluster is one of the epidemic characteristics of sars-cov2. in our analysis, up to 80% of infected children come from family clustering infections, indicating close contact with the confirmed members in family is the key to a cluster of outbreaks. as reported, most cases of mortality involved children under 1 year old or newborns. 10 interestingly, sars-cov2 was not detected in serum or throat swab by rt-pcr in any of the newborns of 6 mothers with confirmed sars-cov2. however, virus-specific antibodies were detected in neonatal blood sera samples. 34 one of the possible explanations is antibody-dependent this article is protected by copyright. all rights reserved. accepted article enhancement (ade) of sars-cov2 because ade can induce the immune response and elicit sustained inflammation, lymphopenia, and/or cytokine storms, one or all of which have been documented in severe cases and deaths. it has been also reported in the literature that the cytokine storm may be related to the severity of covid19. 36 our study had some limitations. we did not analyze the incubation period of children because it was difficult to stratify for meta-analysis due to different descriptions in some different studies. as of february 11, 2020, after analyzing 44,672 laboratory confirmed cases, a study reported that 965 cases were younger than 19. however, only 410 pediatric cases were enrolled in our study because we deleted some duplicate cases, which also resulted in a reduction in case number. only four articles were selected for analyzing coinfection because it was not assessed or reported in the remaining studies. most clinicians directly detected coronavirus and ignored other coinfections if they found suspicious symptoms early in the outbreak. it was estimated that the proportion of coinfection in children maybe increase once the implementation of multiple detection technologies. even thought the number of published articles was limited, we would like to alert the public to coinfection in children based on our findings. whether the coinfected virus will cause increased coronavirus virus virulence or facilitate mutation or severe unknown complications is still unclear. this article is protected by copyright. all rights reserved. in our study, we found that the proportion of asymptomatic infections in children was high; both males and females were susceptible to sars-cov2. children may have coinfection, and the pathogens of coinfection were diverse; of which m. pneumoniae and influenza virus or parainfluenza virus were the main coinfecting pathogens, implying that early misdiagnosis or a single detection method would overlook the virus and facilitate rapid spread in the public. overall, an increasing public health burden indeed arises from the infected children, and we cannot ignore this. nucleic acid detection of both nasopharyngeal swabs and rectal swabs along with lung ct examination should be actively conducted for children with unknown contact history or in families with diagnosed cases. in addition, misdiagnosis at the early stage should be avoided, which is of great significance for controlling the epidemic. the 2019-ncov outbreak joint field epidemiology investigation team, li q. notes from the field: an outbreak of ncip (2019-ncov) infection in china-wuhan a novel coronavirus genome identified in a cluster of pneumonia cases-wuhan covid-19 coronavirus outbreak novel coronavirus(2019-ncov): situation report-84 a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention preferred reporting items for systematic reviews and meta-analyses: the prisma statement measuring inconsistency in metaanalyses applied statistics in the pharmaceutical industry: with case studies using s-plus clinical and epidemiological characteristics of 91 children conformed with covid-19 clinical features of children with sars-co v-2 infection: an analysis of 115 cases 91 epidemiological and clinical characteristic of 10 children with coronavirus disease (covid-19) in jinan a comparative-descriptive analysis of clinical characteristics in 2019-coronavirus-infected children and adults a case series of children with 2019 novel coronavirus infection: clinical and epidemiological features analysis of ct features of 15 children with 2019 novel coronavirus infection chest computed tomography in children with covid-19 respiratory infection high-resolution computed tomography manifestations of 5 pediatric patients with 2019 novel coronavirus clinical analysis of 31 cases of 2019 novel coronavirus infection in children from six provinces (autonomous region) of northern china. zhonghua er ke za zhi= clinical and epidemiological features of 36 children china: an observational cohort study novel coronavirus infection in children outside of wuhan, china screening and severity of coronavirus disease 2019 (covid-19) in children in characteristics of pediatric sars-cov-2 infection and potential evidence for persistent fecal viral shedding clinical characteristics of children with coronavirus disease emerging coronaviruses: genome structure, replication, and pathogenesis a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person to person transmission: a study of a family cluster systematic review of covid in children shows milder cases and a better prognosis than adults sars-cov-2 infection with gastrointestinal symptoms as the first manifestation in a neonate. zhongguo dang dai er ke za zhi= severe acute respiratory syndrome (sars) in neonates and children middle east respiratory syndrome coronavirus and children: what pediatric health care professionals need to know tmprss2 and adam17 cleave ace2 differentially and only proteolysis by tmprss2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein risk of 2019 novel coronavirus importations throughout china prior to the wuhan quarantine preliminary analysis of transmission and control of new coronavirus the london school of hygiene & tropical medicine(lshtm)lshtm 2020 /newsevents/news/2020/preliminary•analysis•transmission•and•control• new•coronavirus sars-cov-2 viral load in upper respiratory specimens of infected patients antibodies in infants born to mothers with covid-19 pneumonia is covid-19 receiving ade from other coronaviruses? liu et al., 12 china, shandong 2020/3 10 key: cord-353482-dz343h7t authors: ellis, matthew; pant, puspa raj title: global community child health date: 2020-05-11 journal: int j environ res public health doi: 10.3390/ijerph17093331 sha: doc_id: 353482 cord_uid: dz343h7t this special issue of ijerph has published a range of studies in this developing field of global community child health research. a number of manuscripts submitted in response to our invitation describing ‘community-based interventions which impact on child health and wellbeing around the globe. in addition to rural community-based initiatives given that most children now live in cities we are also interested to hear about urban initiatives….’ we hope this issue will of great interest to the researchers and practitioners as well as academia from the fields of global health as well as global child health because it comprised of 14 articles representing all five continents. physical activity appears a key component of the scientific community’s current conception of child well-being judging from the four papers published addressing this area. this issue also has papers on childhood obesity to rubella vaccination. despite of the journal’s strive for reaching out to a wider global child health community, this issue missed contributions relating to child safeguarding and social determinants of urban health. global community child health focusses on the health and development of children in a community context across the globe. whilst some threats to the well-being of children may be globally determined (e.g., climate change) many others are more local (e.g., a busy trunk road). whatever the level of the threat it is the mobilisation of community and household level interventions to protect and enable children which lies at the heart of global community child health [1] . community health workers facilitate these interventions working with parents and carers [2] whilst schools, children's centres, nurseries and creches provide enabling environments for interventions to reach children directly. although we know that investment in early child development remains a top priority for all communities [3] , it is becoming clearer that exclusive attention to the early years misses important opportunities both in middle childhood and the adolescent period [4] . this edition of ijerph was conceived of as an opportunity to sample a range of studies in this developing field of research. we invited studies describing community-based interventions which impact on child health and wellbeing around the globe. in addition to rural community-based initiatives, given that most children now live in cities we are also interested to hear about urban initiatives. although sustainable development goal (sdg) three was our primary focus, we were keen to hear about multi-sectoral interventions with synergistic impact across the sdgs. the 14 accepted articles are global in their reach, with papers from all five inhabited continents. physical activity appears to be a key component of the scientific community's current conception of child well-being judging from the four papers published addressing this area [5] [6] [7] [8] . of course, given the global obesity epidemic, this will remain an important issue for community child health, though given the obesogenic environment we all face following societal nutrition transition we suspect the answers to this lie further upstream in the food industry's regulatory framework [9] . infectious disease, despite the epidemiological transition, remains a major threat in childhood everywhere and several aspects come up in this special issue-not least the awareness of a disease (rubella) amongst health care workers in tanzania for which there is an available vaccine [10] . this reminds us that for vaccination, its understanding and promotion are key tasks for community health workers around the globe, even more so in this age of vaccine hesitancy. if there may be one benevolent side effect of covid-19 going forward it may be the greater appreciation of the value of vaccines! we also publish a paper presenting evidence in support of a role for a bacterial lysate to stimulate immunity in childhood [11] and an interesting exploration of traditional healers' knowledge of noma [12] , the disfiguring facial erosion encountered in children in africa, which almost certainly relates to the continuing wide spectrum of infectious disease in childhood. this paper reminds us that community health workers take many forms and a functional health system finds ways of connecting all members of the health care community. community mobilisation through groups is an important vehicle for community child health initiatives and where some of the best evidence of impact lies [13] . in this edition fathers' roles in parent groups supporting families affected by zika virus [14] links well with our review of early intervention for infants at high risk of developmental disability [15] . a team working in fiji also make use of group-based interventions in their description of what a community child health initiative looks like in an island community [16] . the social determinants of health are central to the concept of community child health [17] . these determinants operate at household, local population ("community"), national and supranational levels. we were sorry not to see any contributions relating to child safeguarding-always a sensitive and difficult research area-but one which therefore needs to be illuminated by an especially powerful light! this would be especially timely as we move globally towards legislation outlawing the corporal punishment of children (https://endcorporalpunishment.org/countdown). of course, the physical environment in which children play, go to school and all too often work also has a major impact on their health. given that environmental health is a primary concern of this journal it was good to be able to accept two papers focussing on children, the first investigating the role of toys in the transmission of diarrhoeal disease at children's centres in south africa [18] and the second an exploratory study assessing pesticide levels in children's urine in mexico [19] . strikingly, we did not receive a community-based study from an urban slum where far too many of the world's children are growing up. if we are to promote "health for all" at all ages then we must ensure that, as "a future for the world's children" [20] puts it, "children grow up in safe and healthy environments, with clean water and air and safe spaces to play". research assessing the impact of community led initiatives into road traffic injury reduction, child safeguarding and the social determinants of health in urban slums should be a focus of community child health researchers going forward. community participation: lessons for maternal, newborn, and child health integrated management of childhood illness global survey report; world health organisation early child development-a winning combination disease control priorities, c.; adolescent, h.; development authors, g. investment in child and adolescent health and development: key messages from disease control priorities international comparison of the levels and potential correlates of objectively measured sedentary time and physical activity among three-to-four-year-old children physical activity and quality of life of healthy children and patients with hematological cancers effect of a multidimensional physical activity intervention on body mass index, skinfolds and fitness in south african children: results from a cluster-randomised controlled trial goal-framing and temporal-framing: effects on the acceptance of childhood simple obesity prevention messages among preschool children's caregivers in china beyond food promotion: a systematic review on the influence of the food industry on obesity-related dietary behaviour among children stray-pedersen, a. awareness and factors associated with health care worker's knowledge on rubella infection: a study after the introduction of rubella vaccine in tanzania impact of om-85 given during two consecutive years to children with a history of recurrent respiratory tract infections: a retrospective study sociodemographic characteristics of traditional healers and their knowledge of noma: a descriptive survey in three regions of mali women's groups practising participatory learning and action to improve maternal and newborn health in low-resource settings: a systematic review and meta-analysis engagement of fathers in parent group interventions for children with congenital zika syndrome: a qualitative study early intervention for children at high risk of developmental disability in low-and middle-income countries: a narrative review tuibeqa, i. strengthening health systems to support children with neurodevelopmental disabilities in fiji-a commentary commission on social determinants of, h. achieving health equity: from root causes to fair outcomes bacterial contamination of children's toys in rural day care centres and households in south africa urinary pesticide levels in children and adolescents residing in two agricultural communities in mexico a future for the world's children? a who-unicef-lancet commission key: cord-315825-ckg8mf8t authors: b, liu; qf, han; wp, liang; xy, shi; jj, wei title: decrease of respiratory diseases in one social children welfare institute in shanxi province during covid-19 date: 2020-09-02 journal: j public health (oxf) doi: 10.1093/pubmed/fdaa150 sha: doc_id: 315825 cord_uid: ckg8mf8t background: to assess the impact of disinfection measures on the incidence of common diseases in children welfare institute during the epidemic of corona virus disease 2019 (covid-19), and provide a basis for the daily disinfection management of children welfare institute. methods: this study surveyed and analyzed common diseases among children under the age of 14 in one social children welfare institute in shanxi province from january to may in 2018–2020 by the year-on-year method. results: the prevalence rate of respiratory diseases in 2020 was a significantly negative growth compared with 2018 and 2019. there was no obvious pattern of changes in digestive diseases group. conclusion: in view of the above anti-epidemic measures, it indicates that the children gathering institutions should strengthen effective personal protection and public health management to reduce infectious disease among children. in the middle of december 2019, the corona virus disease 2019 as the third zoonotic human coronavirus (co v) of the century was reported from wuhan, hubei, china, and spread rapidly worldwide within a short time, which was declared finally as the controllable pandemic disease by world health organization. 1, 2 in 20 january 2020, the national health commission of the people's republic of china classified o cially covid-19 as the class b infectious diseases according to 'the law of the people's republic of china on the prevention and control of infectious diseases,' and took powerful measures to prevent and control as class a infectious diseases. 3 notwithstanding epidemic situation is relatively mild in shanxi, the local government initiated firstlevel response to major public health emergencies at the first time, 4 and formulated a series of measures including quarantine home, closing the educational institutions and entertainment venues to contain the contagion of the epidemic and protect public health. 5 children in the welfare institute as one of the social vulnerable groups is the key object to protect, 6 however, no detailed study on them facing the epidemic has been conducted to date. we selected an o cial and comprehensive social children welfare institute in shanxi province as subject to complete this survey. up to now, nearly 800 people have been adopted including more than 600 minors and less than 200 adults. besides, there are about 100 permanent employees and more than 350 hired employees. in order to resist the epidemic of covid-19 outbreak, this welfare institute actively responded to government exhortation and carefully planned many urgent measures according to 'guidelines on the prevention and control of pneumonia epidemic in new corona virus infections in service organizations of children's welfare (first edition)' released by the o ce of the ministry of civil a airs, 7 for examples, disinfection and sterilization, isolation and age-based partitioned management, as well as monitoring body temperature. so far, there has been no case of infection in this welfare institute. at the same time, we find that the prevalence rate of respiratory diseases for children significantly reduced compared with the same period of previous years. this will highly remind us that whether we can strengthen the daily prevention and control for diseases to reduce the incidence of respiratory diseases for children. this study collected the number of patients under the age of 14 in one social children welfare institute in shanxi province during the epidemic of covid-19 and compared with the same period of 2018 and 2019 by the year-on-year method. all data of this study have been reviewed and approved by the ethics review committee of shanxi medical university. the patients were divided into respiratory diseases group, digestive diseases group and other groups. respiratory diseases group includes upper respiratory tract infections, colds, pneumonia, flu, etc. digestive system diseases group includes diarrhea, gastroenteritis, etc. other groups include congenital diseases, surgical diseases, etc. all groups include the number of inpatients and outpatients. we mainly analyzed the number of patients by investigating the original records from the a liated hospital of this welfare institute. table 1 and figure 1 show that the number of patients will show a peak in january and gradually decrease from february to may each year. in 2020 from march to may, the number of patients with respiratory diseases decreased significantly. the year-on-year growth rate of respiratory diseases group in 2020 was lower than that in 2019, which was a significantly negative growth, and there was no obvious pattern of changes in digestive diseases group. according to the data analysis of the same time period from 2018 to 2020, the anti-epidemic measures lead to that the prevalence rate of respiratory diseases reduced significantly among children of the social children welfare institute in 2020 compared with 2018 and 2019. however, the prevalence rate of digestive diseases did not change. respiratory diseases are the most common diseases among children, especially those children living in groups who are more likely to su er from epidemic infective diseases. the decrease in the incidence of respiratory diseases suggests that the level of disease prevention and control in this social children welfare institute has increased significantly. compared with other institutions, the children welfare institute has the following features: (i) the children living in the welfare institute, a relatively closed environment, belong to a fixed population. most children will live in welfare institutions for a long time. (ii) the impact on children's sports here during the epidemic period is negligible because most of these children su er from basic diseases or disabilities which make them carry out fewer outdoor activities than ordinary children. during the epidemic of covid-19, the diet and the sport areas of the children has not changed. (iii) the welfare institute is equipped with an a liated hospital for sick children. all diseases will be diagnosed and treated by the a liated hospital. (iv) during the epidemic of covid-19, the welfare institute has taken some measures such as personal protective measures, public environmental measures, reducing social visits and age-based partitioned management. compared with adults, children are more likely to su er from respiratory or digestive diseases because of their weaker immunity, especially children in the welfare institutes. although these two types of infectious diseases are selflimiting, they can spread rapidly in semi-closed environments such as schools and the welfare institutes, which can a ect seriously the health of children. 8 based on the survey analysis, we can clearly conclude that the actions taken during the epidemic of covid-19 have strikingly resulted in the prevalence rate transform of respiratory diseases for the children, which suggests that the disinfection and management in welfare institutions administration should be strengthened daily. the following are the experiences during the epidemic of covid-19. face masks on the one hand, the use of masks can protect us from transmission by preventing the inhalation of respiratory pathogens and reducing the hand-to-face contact, 9 on the other hand, mask-wearing when sick may reduce the transmission of influenza virus to protect others. 10, 11 the caregivers and medical sta s should wear the mask to protect themselves and reduce the possibility of diseases transmission by a mobile person. it is favorable for the children with a poor physical condition. hand hygiene some studies have shown that contaminated hands are the main mode of transmission of infectious diseases. 12 hand hygiene is important for reducing the transmission of some gastrointestinal diseases and respiratory diseases. 13, 14 simplified three-step hand-washing in 10 s can e ectively remove the hand bacteria and meet the requirements of sanitary hand disinfection, 15 considering children have limited attention. children can use soap and water, or some waterless hand disinfectants to clean their hands before meals, after using the washroom and after playing outside. 16 some studies have proved that exposures of alcohol hand sanitizer may lead to harmful health e ects including ocular irritation, vomiting and so on, by swallowing it deliberately or unintentionally. therefore, alcohol hand sanitizer should be used under adult supervision, and make sure it is placed out of reach for children in daily life. 17 cough etiquette children should be taught cough etiquette like covering the nose and mouth with a tissue or a mask when coughing or sneezing to prevent the spread of bacteria, if tissues are unavailable, using the upper sleeves or elbow, not hands, is also useful. 11, 18, 19, 20 therefore, we recommend highly that managers should take cough etiquette information as a part of regular science and health courses in order to make children understand the healthy benefits of cough etiquette. at the moment, we suggest encourage and monitor children to develop favorable habits by singing motivational songs, posting pictorial flipcharts and painting cue cards in daily life. 21 surface disinfection baths, washbowls, toilets, seats, handles and such 'high-touch' surfaces are highly recommended to use 84 disinfectant or 75% medical alcohol to wipe. 22 when using 84 disinfectant, the sta must realize that it is corrosive so be sure to wipe with clean water after 30 minutes of action. besides, all biocides have some toxicological risks to human health and/or the environment. 23, 24 for children, passive exposure to cleaning bleach may have adverse e ects in increasing the risk of respiratory and other infections. 25 therefore, the sta members should make sense of the potential toxicological hazards before using disinfection procedures. toys disinfection the bigger toys used by all children and the smaller toys used by a certain circle make the virus spread faster. one randomized controlled trial (rct) demonstrated that toys disinfection biweekly can decrease the detection of multiple viruses, including adenovirus, rhinovirus and respiratory syncytial virus in the environment, 26 so tools disinfection is essential in the welfare institute. natural ventilation we should use natural ventilation such as opening doors and windows as much as possible. 27 the air conditioning system should have su cient fresh air input under the safe working situation. when not using air conditioner, the air channel should be closed. due to banning the visit from a social person is unachievable, the children welfare institute should set up a special area for an external person to prevent children from being completely exposed to the infection source. 6 previous and newly enrolled children live in di erent areas according to age and gender. once infectious diseases breaking out, it can limit the scope to children in the same group and area as soon as possible to prevent the spread of diseases. likewise, air pollution plays a role in respiratory diseases. 28, 29 factory closed led to the air quality better during the epidemic of covid-19. according to the related report, air pollution index evidently improves. 30 this suggests us to reduce the outdoor activities during the period of severe air pollution. regrettably, we cannot guarantee that there is no flow of personnel within 3 years, which leads respondents are unfixed. besides, our study is limited to only one child welfare institute in china, so the sample size is relatively small and poorly representative. by analyzing the data, it is found that the prevalence rate of respiratory diseases was decreased significantly for the children in the social children welfare institute during the epidemic of covid-19. it demonstrated that normalized prevention and management are the preferential measures to reduce prevalence rate of infectious diseases. so, we make the following suggestions. first, in the view of the children welfare institutes, they should establish and improve the prevention and control system of infectious diseases, which covers tertiary prevention and specific details of daily work including disinfection methods, disinfection frequency, disinfection ranges and so on. in addition to countermeasures of severe epidemics, the children welfare institutes must also pay more attention to implement the normalized prevention and management of common diseases among children. second, stand on the government's point to consider, it should enhance fund endorsement and policy priority for the children welfare institutes to make sure that they are able to safeguard and raise the life quality of children. the children welfare institutes can replace life facilities, recommend the advanced disinfection equipment, enrich dietary diversity, etc., under the support of the government. at the same time, in order to protect rights of children further, related laws and regulation are also replenished sooner rather than later. third, start from the view of the society, the most people lack the understanding and knowledge of the children welfare institutes, thus, relational society institutes like non-profit organizations should strengthen propaganda of children welfare to improve the social awareness of the charity. for example, conducting lectures, organize charity activities, release information about the children welfare institutes on the internet and so on. most of children in welfare institute are orphan or the disabled, so the society and government should take care of them as much as possible to guarantee a favorable living and educational environment. their healthy growth still demands our joint e orts further in the future. the authors received no financial support for the research, authorship and/or publication of this article. the authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. the data underlying this article were provided by this social children welfare institute by permission. data will be shared on request to the corresponding author with permission of the social children welfare institute. a comprehensive review of animal models for coronaviruses: sars-cov-2, sars-cov, and mers-cov pathological findings of covid-19 associated with acute respiratory distress syndrome national health commission of the people's republic of china. notice of the national health council of the people's republic of china shanxi province initiated first-level response to major public health emergencies isolation, quarantine, social distancing and community containment: pivotal role for old-style public health measures in the novel coronavirus (2019-ncov) outbreak the implications of covid-19 for the care of children living in residential institutions republic of china. the ministry of civil a airs issued an emergency notice novel coronavirus pneumonia epidemic prevention and control work of a service organization in the field of children welfare institute should be done with all e orts e ectiveness of hand hygiene interventions in reducing illness absence among children in educational settings: a systematic review and meta-analysis face mask use and control of respiratory virus transmission in households face masks to prevent transmission of influenza virus: a systematic review visualizing the e ectiveness of face masks in obstructing respiratory jets infection prevention and control in pediatric ambulatory settings hand hygiene and risk of influenza virus infections in the community: a systematic review and metaanalysis e ect of hand hygiene on infectious disease risk in the community setting: a meta-analysis simplifying the world health organization protocol: 3 steps versus 6 steps for performance of hand hygiene in a cluster-randomized trial nonpharmaceutical measures for pandemic influenza in nonhealthcare settings-personal protective and environmental measures reported adverse health e ects in children from ingestion of alcohol-based hand sanitizers-united states influenza in children respiratory hygiene/cough etiquette in healthcare settings e ectiveness of personal protective measures in reducing pandemic influenza transmission: a systematic review and meta-analysis pilot of an elementary school cough etiquette intervention: acceptability, feasibility, and potential for sustainability national health commission of people's republic of china. guidelines for public protection against novel coronavirus infection does disinfection of environmental surfaces influence nosocomial infection rates? a systematic review disinfection and the prevention of infectious disease: no adverse e ects? domestic use of bleach and infections in children: a multicentre cross-sectional study e ect of cleaning and disinfection of toys on infectious diseases and micro-organisms in daycare nurseries roles of sunlight and natural ventilation for controlling infection: historical and current perspectives the influence of particulate matter on respiratory morbidity and mortality in children and infants impact of air pollution on the burden of chronic respiratory diseases in china: time for urgent action environmental perspective of covid-19 key: cord-344823-jl5ph260 authors: jacob, hannah title: safeguarding children in a pandemic: pandemonium with possibility? date: 2020-09-30 journal: child abuse rev doi: 10.1002/car.2654 sha: doc_id: 344823 cord_uid: jl5ph260 nan working as a paediatrician over the last few months has been unlike any other time in my career. the restrictions and changes for children, young people and their families have been enormous. my colleagues and i have felt anxious about the risk to children and young people while schools are closed, services are reconfigured and families are 'locked down' at home. as a paediatrician with a special interest in safeguarding, this has posed a range of challenges and offered a few unexpected opportunities. our task, as we begin to restore our services, is to build on the handful of positive outcomes that have arisen from this pandemic and work together to address the immense safeguarding challenges emerging over the coming months and years. this paper explores some of the clinical situations in which safeguarding challenges have presented themselves during the pandemic. it then explores some of the opportunities that the reconfiguration of services has presented for those working in child health. one of the biggest worries for those of us working in child health has been delayed presentations to health services. parents and carers have felt understandably anxious, particularly about attending emergency departments, and have often waited until their child is very unwell before going to hospital. i have seen children presenting with injuries, sepsis or a deterioration in a long-term condition like diabetes who have been more unwell at presentation because of a delay in coming to hospital. it has been challenging to convey the seriousness of delaying while recognising that, in most cases, this was in response to public health messaging to stay away. another noticeable change is an increase in infants presenting with feeding problems and crying. new mothers have not been allowed visitors in most maternity units and this, combined with worry about exposure to coronavirus in hospital, has meant people leaving with their newborns very quickly after birth. most areas were not running face-to-face consultations with health visitors, and home visits from midwives in those early post-natal days have been limited. as a result, new parents have been left with a fraction of the hannah jacob* great ormond street hospital, london, uk 'one of the biggest worries for those of us working in child health has been delayed presentations to health services' breast feeding, immunisation, crying and sleep advice that they usually receive in the early weeks. this has inevitably endangered perinatal mental health with parents and carers having fewer health encounters during which to express worry or for health professionals to flag concerns. it may be some time before the full impact of this on breast feeding and immunisation rates comes to light. in the meantime, we have seen an increase in very young children brought to hospital with injuries typical of abuse (unicef, 2020) . in a letter to the archives of disease in childhood, sidpra et al. (2020) reported an increase in admissions to their hospital with abusive head trauma in the month following lockdown. however, this report was based on ten cases over one month in a single institution; whether or not this represents a wider shift in incidence remains to be seen. a combination of reduced community services, fewer opportunities to socialise and access wider family support, as well as exposure to more domestic abuse could contribute to the potential for an increase in child abuse. nor is the problem confined to younger children. we have seen a surge in acute presentations of young people following deliberate self-harm or with thoughts of killing themselves (young minds, 2020) . the effect of an overnight severing of their face-to-face interactions with peers, loss of the stability school affords them and the extra pressure of being forced to spend more time with their families at home have all contributed. it has been particularly tricky to plan a safe discharge from hospital with adequate community follow up, especially given the uncertainty about how long it will take for services to be fully restored. we have also completely changed how we see children and young people in the outpatient department. almost overnight our clinics were converted to virtual appointments, most commonly conducted by phone and sometimes via video. before the pandemic, i could count on one hand the number of virtual clinics i had done; in a matter of weeks, it has become the norm. learning to build rapport in a room you are not really in and wondering who is listening when you talk to a young person has been hard. i have been very conscious of what is not being said and missing all the opportunities a face-to-face meeting provides to observe, react and 'read the room'. it has been especially challenging for families who do not have english as their first language and those with limited access to devices or wi-fi. i am getting better at eliciting the voice of the child, but it is certainly harder to configure an electronic room in a way which best allows them to be heard. across the uk there has been a reduction in the number of referrals for child protection medicals (local government association, 2020), despite increases in calls to childline from children worried about the impact of coronavirus (national society for the prevention of cruelty to children, 2020). the closure of schools for most children has removed teachers as important 'eyes and ears' for early signs of abuse. around 20 per cent of referrals for child protection investigations come from schools and, while they are closed, i feel rising anxiety about those children below the radar (department for education, 2019). the most vulnerable children are not attending school though they have been 'i have been very conscious of… missing all the opportunities a faceto-face meeting provides to observe, react and ′read the room′' encouraged to (department for education, 2020). so, there are two issues: those we were already worried about not being at school to access support and all those we do not yet know about. we are all worried about when and how this abuse will be detected but also what the impact on services might be when it is. there can be little doubt that we have paid a child safeguarding debt forward with potentially devasting consequences. the final big challenge for me has been around the working relationships that i cherish and which are such an important part of providing good care for children and young people. we have moved our peer review online which allows us to discuss complex cases and reflect more generally on how we are feeling. but it does feel somehow inferior to a catch up over a cup of tea and a chance to talk through an issue. i am conscious too that my more introverted colleagues perhaps do not find the virtual environment easy and rely more on quiet conversations with individuals. our work can be harrowing and providing space for colleagues to support each other and take stock is vital. it is not all doom and gloom for children's services and safeguarding. the move to virtual platforms has allowed staff to access teaching that they would not otherwise have been able to, across sites and shift patterns. this is an exciting prospect for upskilling the children's healthcare workforce, particularly those working in small units and for those working part-time. it has been invaluable for peer review too as busy clinicians are able to support colleagues across the region from their desks. nevertheless, part of the success of these virtual meetings is that they build on years of face-to-face encounters and well-established relationships. it remains to be seen whether continuing to work in the virtual space is as productive in the future. attendance at multi-professional safeguarding meetings has never been better. almost for the first time, we have had senior nurses, social workers, general paediatricians, subspecialty paediatricians and named safeguarding professionals all together in a virtual room to discuss complex cases. this has sped up decision-making and undoubtedly improved the quality of the conversations possible, where before we may have had to rely on a proxy less familiar with the child or written notes. again, only time will tell if this is sustainable. having meetings held virtually has certainly encouraged attendance as busy professionals can move from one meeting to another without travel time. however, these meetings were being held at a time when professionals could not take annual leave and were restricted from doing much besides working. finally, the disruption brought by health appointments may be much less as we move to virtual consultations. children and young people need not miss school and carers will need less time off work to attend appointments previously conducted at healthcare facilities often hours away. young people are used to interactions occurring online and are undoubtedly more adept than 'attendance at multi-professional safeguarding meetings has never been better' their paediatricians at using these platforms so there is much scope for them to educate us about how they want them to be conducted. the disruption caused to children and young people by this pandemic cannot be understated. from a health perspective, we have already seen changes in emergency presentations to hospitals and considerable changes to the way we conduct our consultations. children and young peoples' health and wellbeing have been impacted in ways which we do not yet fully understand. going forward we will need to be more vigilant than ever about those who are most vulnerable and be ready to advocate continually for them. we must endeavour to take the learning and shreds of hope gleaned over the last few months with us as we rebuild our services, to make them even better for the children and young people who will need them so desperately over the coming years. 'we must endeavour to take the learning and shreds of hope gleaned over the last few months with us as we rebuild our services' characteristics of children in need attendance in education and early years settings during the coronavirus outbreak local government association. 2020. coronavirus: lga responds to children's commissioner report on vulnerable children national society for the prevention of cruelty to children (nspcc). 2020. almost 7000 childline counselling sessions with children about the impact of coronavirus (covid-19) outbreak rise in the incidence of abusive head trauma during the covid-19 panedemic. archives of disease in childhood children in lockdown: what coronavirus means for uk children coronavirus: impact on young people with mental health needs key: cord-337637-wehstffa authors: ferreira, flavia de a; filho, luiz vicente f silva; rodrigues, joaquim carlos; bush, andrew; haslam, patricia l title: comparison of atopic and nonatopic children with chronic cough: bronchoalveolar lavage cell profile date: 2007-08-28 journal: pediatr pulmonol doi: 10.1002/ppul.20648 sha: doc_id: 337637 cord_uid: wehstffa chronic cough is a common complaint in children and its relationship with asthma is controversial. the aim of the present study was to determine the pattern of airway inflammation in atopic and nonatopic children with chronic cough, and to investigate whether atopy is a predictive factor for eosinophilic inflammation in cough. bronchoalveolar lavage (bal; three aliquots of 1 ml/kg saline) was performed in the right middle lobe of 24 (11 atopic and 13 nonatopic) children with persistent cough (8 females, 16 males), mean age 4.7 years (range: 1–11). atopy was defined as an elevated total serum ige or a positive rast test. both atopic and nonatopic children with persistent cough had an increase in total cells/ml in bal (atopic: median 39 × 10(4), range: 20–123; nonatopic: median 22 × 10(4), range: 17–132) compared to nonatopic controls (median 11 × 10(4), range 9–30). the increases were mainly in neutrophils (atopic: median 17%, range 2.5–88.5%; nonatopic: median 6%, range 1.0–55.0%) compared to controls (median 1.55%, range 0.5–7.0%; atopics vs. controls, p < 0.005). there were no significant increases in eosinophils, lymphocytes, epithelial cells, or mast cells. eosinophils were elevated in only 5/11 atopic and none of the nonatopic children. the increased percentage of neutrophils in the bal fluid of atopic and nonatopic children with persistent cough could be due to an underlying inflammatory process driving the cough, or even conceivably, due to the effect of coughing itself. in this highly selected series, the absence of eosinophilic inflammation in the majority suggests that most would be predicted not to respond to inhaled corticosteroid therapy. this study underscores the need to be cautious about treating coughing children with inhaled corticosteroids, even in the context of a tertiary referral practice. pediatr pulmonol. 2007;42:857–863. © 2007 wiley‐liss, inc. cough is a primary defense mechanism that functions to protect the airways, clearing irritants and mucus. cough can be classified into acute and chronic. chronic cough can be defined as a cough persisting for at least 6 weeks 1 however this definition is arguable and others have regarded duration more than 4 weeks as chronic cough. chronic cough is a common complaint in children, with a wide differential diagnosis. in a community setting, most children with chronic cough do not have asthma, although recent diagnostic fashion has been to assume that all chronic cough is due to asthma, and treat it with inhaled corticosteroids. thus this common condition may frequently be overdiagnosed as asthma, 2,3 and harmful medication may be continued for a long period of time without benefit for these children. the relationship between chronic cough and asthma is controversial. although cough variant asthma is recognized as a precursor of bronchial asthma, 4 it is not known whether chronic cough is also a precursor of asthma. 1 atopic patients with chronic cough due to cough variant asthma are thought to have airway inflammation similar to atopic patients with asthma, whose bronchoalveolar lavage (bal) fluid contains eosinophils and mast cells. 5 in adults, eosinophils are believed to be a key effector cell in asthma. some studies 6, 7 have provided evidence of eosinophilic inflammation in the bal of children with asthma. marguet et al. 8 demonstrated that the bal profile in asthma is clearly characterized by a high proportion of eosinophils, which is independent of the severity of the disease and treatment with inhaled steroids. most previous studies have studied milder forms of cough, and there is a paucity of data in a tertiary context, where one might expect there to be a greater likelihood of finding pathology. 9, 10 the aim of the present study was therefore to determine the pattern of inflammation in atopic and nonatopic children with chronic cough, and to investigate whether atopy is a predictive factor for eosinophilic inflammation in this context. we studied 24 (11 atopic and 13 nonatopic) children (8 females and 16 males) with a mean age of 4.7 years (range 1-11 years) seen at the pediatric outpatient clinic of the royal brompton hospital with a history of chronic cough (table 1) . all had coughed for at least 2 months. fifteen had used inhaled corticosteroids, with no evidence of benefit. fifty percent of these children had cough for periods longer than 1 year, and 21/24 (88%) have nonproductive (dry) cough. inclusion criteria were chronic cough (cough for more than 6 weeks), absence of respiratory tract infection in the preceding 30 days, absence of alternative diagnosis such as cystic fibrosis, immunodeficiency, sinusitis and ciliary dyskinesia and agreement of parents after informed consent signature. routine tests performed in these children included chest x-ray and high resolution ct scan, full blood count, serum immunoglobulins, sweat test, nasal brushing for ciliary motility and structure studies, 24-hr ph study. spirometry and exhaled nitric oxide were performed in those older than 7 years old, and evaluation by an otorynolaryngologist performed when indicated. six children (three atopic and three nonatopic) were receiving inhaled steroids. atopy was defined as a positive radioallergosorbent (rast) test (eight children) or elevated total serum ige (compared to age appropriate ige ranges, three children). all children with chronic cough underwent bronchoscopy for clinical purposes. bal was also performed on five children without chronic cough (control group) who underwent bronchoscopy for other clinical reasons, (three children underwent bronchoscopy for investigation of vascular and structural malformation and two for stridor). all were nonatopic and had no history of asthma. none of the patients had a clinical history of respiratory infection in the 4 weeks prior to bronchoscopy, albeit 2/24 patients reported use of antibiotics for other reasons in this period (one received azythromycin and the other amoxicillin-clavulanate). alternative diagnoses such as sinusitis, immunodeficiency, cystic fibrosis, tuberculosis, and primary ciliary dyskinesia were excluded in all patients by conventional tests. chest radiographs showed opacities suggestive of atelectasis in only 4/24 children, but none of them had evidence of bronchiectasis on ct scanning. eighteen of the patients with chronic cough had also undergone a 24-hr esophageal ph test for gastroesophageal reflux (ger) as part of a separate study. 11 the test was defined as positive if the ph was less than 4 for greater than 4% of the 24-hr study period. the study was approved by the ethics committee of the royal brompton hospital, and written informed consent was obtained from the parents of the subjects, and age-appropriate assent from the children. the same bal protocol was used in all patients. the bronchoscopy was performed under general anesthesia using a laryngeal mask airway, or via a facemask with careful attention not to use suction until the bronchoscope had passed the vocal cords; the protected brush method was not utilized. bal was performed in the right middle lobe in all patients and controls using three aliquots of 1 ml/kg saline ( table 2) . bal fluid was centrifuged at 1,500 rpm (300g) for 10 min at 48c. the supernatant was removed and the cell pellet was resuspended in 2 ml of minimal essential medium (mem) containing hepes buffer (invitrogen, london, uk). total bal cell counts were obtained using an improved neubauer counting chamber and the results are expressed as number of cells per ml. cytocentrifuge preparations were made using 100 ml aliquots of a 0.5 â 10 6 cells/ml suspension. after air-drying, the preparations were stained with may-grünwald giemsa to make differential cell counts. the percentages of each cell type were determined by counting 500 cells. a bal sample was sent for microbiological analysis. quantitative cultures were performed in selective media in the routine microbiological laboratory, and a bacterial count !10 5 cfu/ml was considered positive. additionally, direct immunofluorescence was performed in bal samples using specific monoclonal antibodies against respiratory syncytial virus, influenza a and b, parainfluenza 1, 2, and 3, and adenovirus. the data were analyzed using nonparametric tests. the mann-whitney test was used to test differences between unpaired groups of quantitative data and differences were considered to be significant when p 0.05. bal results are summarized in table 2 . recovery of bal fluid was similar in atopic (median: 50%, range: 33-91%) and nonatopic (median: 50%, range: 22-74%) patients, but lower than in the control group (median: 70%, range: 50-76%), albeit the difference was not statistically significant. a nonsignificant increase in the number of total cells per ml of bal fluid was observed in both atopic (median: 39 â 10 4 , range: 20-123 â 10 4 ) and nonatopic (median: 22 â 10 4 , range: 17-132 â 10 4 ) children with chronic cough when compared to controls (median: 11 â 10 4 , range: 9-30 â 10 4 ). the increases in total cells were mainly due to increases in neutrophils in both the atopic (median: 17%, range: 2.5-88.5%) and nonatopic (median: 6%, range: 1-55%) children with chronic cough compared to controls (median: 1.5%, range: 0.5-7.0%). in total, 6 of the 13 nonatopic and 9 of the 11 atopic children with chronic cough had neutrophil percentage counts above the upper limit of 7% for the controls. however, the percentage of neutrophils was significantly higher only in the atopic children compared to controls, p ¼ 0.005 (table 2 and fig. 1 ). microbiological analysis of the bal samples was negative for bacteria and viruses in all cases. there were no significant differences in the number or percentages of lymphocytes, epithelial cells or mast cells. the percentage of bal eosinophils was elevated (>3%) in five of the 11 atopic children, although there was no increase in eosinophils in the nonatopic group (fig. 2) . however, the slightly higher percentages of eosinophils in the atopic group did not reach significance compared with the other two groups (fig. 2) . of the 18 children with chronic cough who underwent 24-hr ph testing for ger, nine were positive (four atopic and five nonatopic). median bal neutrophil percentages were higher in the nine patients with a positive ger (median: 41%, range: 1.5-88.5%) compared to the nine with a negative ger (median: 15.5%, range: 1-47%), but the difference was not statistically significant (p ¼ 0.25, fig. 3 ). seven children with ger showed more than 10% of neutrophils in the bal, although this finding was present in five children without ger. lipid laden macrophages were measured in 23 of 24 children. of the nine with a positive ph study, only three had an index greater than 100. chronic cough, defined as a cough persisting for at least 6 weeks, is a common symptom in childhood. 1 there is little information about the pathophysiology and the airway cellularity in children with chronic cough. [12] [13] [14] we analyzed the inflammatory cell profile of bal fluid from atopic, nonatopic and normal children with chronic cough. the population of coughing children is highly selected, having been deemed sufficiently severe to warrant referral and investigation in a tertiary center; none had a diagnosis of a specific chronic chest disease such as bronchiectasis prior to diagnosis. the control children were matched for age as far as possible, but since ethically we could only perform a bronchoscopy in a child in whom it was clinically indicated, this group is necessarily limited. nonetheless, our control data are similar to those of others who were able to study larger groups. 15 in the present study, the majority of the atopic children and nearly half of the atopic children with chronic cough had an increase in the percentage of bal neutrophils when compared to controls; but even in this selected group, eosinophilia was absent in the nonatopic coughers, and present in less than 50% even of atopic children with cough. an important issue is the upper limit of normal of airway neutrophilia in children. because healthy children cannot be studied for ethical reasons, pediatric bal reference values are difficult to obtain. it is probable that the differential cytology in children is similar to that observed in healthy adults. 16 although bal neutrophil of 17% is the upper limit of normal reported by middula et al. 17 (range 0-17%) and ratjen et al. 18 (0-17%) in five other studies the median normal value for neutrophils is given as 3.5% [17] [18] [19] [20] [21] hence in our study, the median value of bal neutrophils (17%) and the values in both the non atopic group (3.5-88.5%) and atopic group (1.5-55%) were appreciably higher than the values reported in normal children. 15 the mechanism of the neutrophilia is unclear. one of the most common causes of chronic cough in children is recurrent viral infection, 22 with some viral infections causing prolonged periods of cough. an increased percentage of bal neutrophils may be due to an underlying inflammatory process such as occult persistent infections, caused by bacteria or viruses. 13, [23] [24] [25] in a recent cohort study published by marchant et al., 13 a standardized pathway of investigation of chronic cough in children revealed that protracted bacterial bronchitis diagnosed by bal was the most common diagnosis among 108 children, with significant higher neutrophil levels on bal samples. none of our patients had clinical evidence of a respiratory infection in the 4 weeks prior to bronchoscopy, and microbiological analysis of the bal samples was negative for bacteria and viruses. however, we cannot rule out the possibility of a viral infection in these children, because molecular biology methods were not utilized and may improve viral detection, while represent the main tool for detection of some significant respiratory viruses such as rhinovirus, coronavirus, and human metapneumovirus. pertussis, another potential pathogen quoted as a substantial cause of prolonged cough in school age children 26 would be an unlikely etiology once 50% of our children had cough for periods longer than 1 year (range 1-10 years). however, we cannot exclude the possibility of a pertussis infection, because we did not do serology, and children who have been partial vaccinated may have prolonged dry cough without the other classical features of whooping cough. 27 it is also possible that we have underdiagnosed other infections in this group. we defined a positive culture a !10 5 colony forming units per milliliter of balf because the bronchoscopy was performed using a laryngeal mask airway, or via a facemask with careful attention not to use suction until the bronchoscope had passed the vocal cords; the protected brush method was not utilized. the ers task force defined this cut off for non protected bal specimens. 15 baker et al. 28 also recommended that the cut off level of 10 4 cfu/ml for bal is appropriate when pneumonia is suspected and a cut off level of 10 5 cfu/ml for bal is appropriate if the probability of disease is low. lower cut off levels have indeed been used by some investigators 29 when a protected brush is employed (>10 3 cfu/ml) or with suspected ventilator-associated pneumonia (>10 4 cfu/ml). we acknowledge the difficulty of establishing a diagnostic threshold for quantitative culture on bal for bronchitis in children 30 (as opposed to pneumonia). the second potential source of underdiagnosis is sampling error; although there are data on differences between bal in the context of cf 31 we know of no such data on the chances of missing positive cultures in the context of bacterial bronchitis. another potential cause of chronic cough is ger. irwin et al. 32 demonstrated that chronic cough can be the sole manifestation of ger in adults. controversy exists regarding the presence of inflammatory markers in the bal fluid of children with ger, 33 but some studies have shown that ger may increase the percentage of bal neutrophils. 34 in the present study, 9 of 18 children (4 atopic and 5 nonatopic) had a positive 24-hr ph test (>4% of the study period with ph < 4). seven children (four atopic and three nonatopic) who had a positive ph test also had an increased percentage of bal neutrophils. whether or not ger is associated with or is the cause of airway inflammation in children with chronic cough cannot be determined from these cross-sectional data (fig. 3) . a higher percentage of bal neutrophils in patients with chronic cough may also be explained by exposure to environmental tobacco. 35 unfortunately, in the present study we did not actively investigate exposure of the children to tobacco smoke using urine or salivary cotinine. conceivably, the mechanical effect of coughing could itself cause airway neutrophilia; to our knowledge, this has never been tested, and it is difficult to believe that such profound neutrophilia as reported here could be caused by the mechanical effects of cough alone. asthma is usually characterized by wheeze and dyspnoea, and there is controversy as to whether pure cough variant asthma exists. [36] [37] [38] [39] [40] cough variant asthma is usually diagnosed in a child with persistent cough who has airway hyperresponsiveness and a good response to antiasthma medication, with relapse of symptoms when the medication is stopped. 4 atopic children with chronic cough due to cough variant asthma would be predicted to show airway inflammation similar to atopic children with asthma, whose bal fluid contains eosinophils and mast cells. 5, 41 our results are consistent with the findings of other investigators, who found that chronic cough was rarely associated with eosinophilia in bal or induced sputum. 8, 13, 42, 43 furthermore, data from the tucson cohort study 44 have shown that cough without wheezing had a more favorable prognosis than cough with recurrent wheezing, suggesting that chronic cough differs from asthma in several aspects and may have a different pathophysiology. in the present study, atopy did not predict eosinophilic airway inflammation, suggesting that only a minority of these children have eosinophilic asthmatic-type airway inflammation. a review 45 of the use of medications in children with persistent cough has demonstrated an overdiagnosis of asthma and overuse of asthma treatments, with a potential risk of side effects in children with chronic cough. 46, 47 one australian study 48 concluded that, although children with chronic cough were similar to asymptomatic children in terms of atopic status, family history and respiratory morbidity, the rates of asthma diagnosis and use of asthma medication was higher in these children. in the present study, 6 (3 atopic and 3 nonatopic) of the 24 children were using inhaled steroids. we accept that it would have been more rigorous to stop this medication prior to bronchoscopy, but this was not thought to be ethical. one child had an increase in bal eosinophils, despite being prescribed inhaled steroids, although no increase in bal eosinophils was observed in the others. it is possible that in these children inhaled corticosteroids might have suppressed bal eosinophils. none of the patients reported any improvement in symptoms related to inhaled steroid therapy, and indeed, all were still symptomatic at the time of bronchoscopy despite this treatment. we do not have any information on adherence to therapy. however, as a group, children with chronic cough did not exhibit asthmatic-type airway inflammation, underscoring the need for caution in the diagnosis of cough variant asthma, even in patients with severe symptoms investigated in a tertiary center. in conclusion, the evaluation of 24 children with persistent cough demonstrated that atopic and nonatopic children with chronic cough frequently have an increased percentage of bal neutrophils, the cause of which is not known, but which may be due to an underlying inflammatory process. further studies are needed to determine the mechanism of neutrophilia in children with chronic cough. atopy did not predict eosinophilic airway inflammation in children with chronic cough. few of the atopic children, and none of the nonatopics with persistent cough had asthmatic-type eosinophilic airway inflammation, and thus would be predicted not to respond to inhaled corticosteroid therapy. chronic cough in children all that cough is not asthma state of art: cough, cough receptors and asthma in children comparison of atopic cough with cough variant asthma: is atopy cough a precursor of asthma? eosinophilic tracheobronchitis and airway hypersensitivity in chronic nonproductive cough correlation of bronchial eosinophils and mast cell activation with bronchial hyperresponsiveness in children with asthma inflammatory mediators in bronchoalveolar lavage samples for children with and without asthma bronchoalveolar lavage cell profiles in children with asthma, infantile wheeze, chronic cough or cystic fibrosis evaluation and outcome of young children with chronic cough cough quality in children: a comparison of subjects�s bronchoscopic findings gastroesophageal reflux and inflammation in bronchoalveolar lavage in children (abstract) airway inflammation in nonasthmatic subjects with chronic cough evaluation and outcome of young children with chronic cough cough and reflux esophagitis in children: their co existence and airway cellularity bronchoalveolar lavage in children. ers task force on bronchoalveolar lavage in children bronchoalveolar lavage cellularity bronchoalveolar lavage studies in children without parechymal lung disease: cellular constituents and protein levels lymphocytes subsets in bronchoalveolar lavage fluid of children without bronchopulmonary disease investigating paediatric airways by non lavage: normal cellular data bronchoalveolar lavage cellularity in healthy children a controlled study of differential cytology and cytokine expression profiles by alveolar cells in paediatric sarcoidosis analysis of cells obtained by bronchial lavage of infants with respiratory syncytial virus infection rhinovirus16 colds in healthy and asthmatic subjects: similar changes in upper and lower airways persistent and latent viral infections in the pathology of asthma chronic cough in children: bronchoalveolar lavage findings recent developments in pertussis belohradsky bh and the munich vaccine study group. clinical and epidemiological picture of b pertussis and b parapertussis infection after introduction of accelular vaccine discussion making in nosocomial pneumonia. an analytic approach to the interpretation of quantitative bronchoscopic cultures blind protected specimen brush and bronchoalveolar lavage in ventilated children a bronchoscopic scoring system for airway secretions-airway cellularity and microbiological validation interlobar differences in bronchoalveolar lavage fluid from children with cystic fibrosis chronic cough as the sole presenting manifestation of gastroesophageal reflux lipid laden macrophage index and inflammation in bronchoalveolar lavage fluids in children bronchoalveolar lavage and esophageal ph monitoring data in children with difficult to treat respiratory symptoms increased neutrophils and cytokines, tnf and il8 in induced sputum of non-asthmatic patients with chronic dry cough chronic cough as the sole presenting manifestation of asthma cough variant asthma: a review of the clinical literature cough-but is it asthma? isolated cough-probably not asthma clinical significance of cough and wheeze in the diagnose of asthma bronchoalveolar lavage findings suggest two different forms of childhood asthma airway eosinophilia is associated with wheeze but is uncommon in children with persistent cough and frequent chest colds induced sputum: comparison of postinfections cough with allergic asthma in children recurrent cough in childhood and its relation with asthma persistent cough in children and the overuse of medication cough in children clinical significance of cough and wheeze in the diagnosis of asthma persistent cough: is it asthma? the authors thank dr. claudio leone for the technical assistance. this study was supported by royal brompton hospital charitable fund (no. b0437; to plh). key: cord-329499-jh4pbqxu authors: leulseged, t. w.; hassen, i. s.; maru, e. h.; zewde, w. c.; chamiso, n. w.; edo, m. g.; abebe, d. s.; aliy, m. a. title: covid-19 in hospitalized ethiopian children: characteristics and outcome profile date: 2020-11-04 journal: nan doi: 10.1101/2020.10.30.20223115 sha: doc_id: 329499 cord_uid: jh4pbqxu background: considering the number of people affected and the burden to the health care system due to the coronavirus pandemic, there is still a gap in understanding the disease better leaving a space for new evidence to be filled by researchers. this scarcity of evidence is observed especially among children with the virus. understanding the disease pattern and its effect among children is vital in providing timely and targeted intervention. aim: to assess the characteristics and outcome profile of 115 rt-pcr confirmed children with covid-19, and to determine the presence of significant difference in disease severity and survival distribution between groups among children admitted to millennium covid-19 care center in ethiopia. methods: a prospective cohort study was conducted among 90 consecutively admitted eligible rt-pcr confirmed covid-19 children from end of june to mid september, 2020. frequency tables, km plots, median survival times and log-rank test were used to describe the data and compare survival distribution between groups. a chi-square test/ fischer exact test were used to determine the presence of a significant difference between the independent variables and disease severity. a statistically significant difference was detected for variables with a p-value of [≤] 0.05. survival experience of different groups was compared using km survival curves. log-rank test was used to assess the presence of significant difference among survival distributions of groups for equality where a statistically significant difference in survival distribution between groups was detected for variables with a p-value of [≤] 0.05. results: from the 90 children, 67 (74.4%) achieved clinical improvement and 23 (25.6%) were censored. there was no death. the median time to clinical improvement was 14 days. the median age of the participants was 15 years and 63.3% of the participants were females. the commonest reported route of disease transmission was through close contact with a diagnosed person (45.6%). only three (3.3%) had a history of pre-existing comorbid illness. more than a quarter (26.7%) had one or more symptoms at admission, the commonest being cough (22.2%). seventy three (81.1%) of the patients had mild covid-19 at admission and the rest (18.9%) had moderate disease. on the chi-square and fischers exact test, children with one or more symptom at presentation (73.3% vs 36.7%, p-value= 0.0001), fever (40.0 % vs 60.0%, p-value=0.045), cough (20.0 % vs 80.0%, p-value=0.0001), sore throat (44.4 % vs 55.6%, p-value=0.011), and headache (44.4 % vs 55.6%, p-value=0.011) were more likely to develop moderate covid-19. on the log rank test, a significant difference in survival between groups was observed only for sex. a significantly longer time was needed for female patients to achieve clinical improvement compared to male patients (15 days vs 14 days, p-value= 0.042). conclusions: the average duration of time to clinical improvement was 14 days and 74.4% achieved clinical improvement. there was no death during the observation period. the pediatric patients seemed to have a milder disease presentation and a favorable outcome compared to other countries report and also the adult pattern observed in our country. having particular symptom groups is associated with the development of moderate covid-19. being female seemed to delay the time to clinical improvement. further multicenter study with a large sample size is recommended to reach at a better conclusion. the corona virus pandemic which affected more than 43, 341, 451 individuals and resulted in 93,707 deaths worldwide, as of october 27 2020, is reported to affect all age groups 1 . age classified report of the disease in terms of incidence, severity and outcome showed that younger age groups have far less probability of acquiring the disease and with milder disease course and favorable outcome if they do get infected 2 . studies conducted till now have focused mainly on adult patients, resulting in less understating of the disease presentation and outcome among children especially in the african set up. to date there is no study conducted in africa. according to studies conducted till today, the disease seemed to be common among males just like the report from adults 3, 4 . the commonly affected age groups are in the two extremes, infants and adolescent 3, 5 . the majority of kids are reported to acquire the disease through household contact with adults 6, 7 . both symptomatic and asymptomatic cases are reported, with a number of studies showing that a higher proportion of children had one or more symptom at presentation. the commonly reported symptoms are fever and cough, with fever being the predominant symptom in many countries. non specific symptoms like fatigue and myalgia are also reported [6] [7] [8] [9] . this is unlike the adult reports where respiratory symptoms were recorded to be the commonest [10] [11] [12] [13] [14] [15] [16] . mild and moderate diseases are commonly reported with severe and critical cases observed in relatively few cases 6, 8, 9 . admission to critical care was determined by age and race 3 . underlying comorbid illness was found in a considerable proportion of hospitalized patients ranging from 42% in one study to 83% in another study 3, 4 . laboratory derangements including lymphopenia, leucopenia, increased d-dimer and increased creatinine are reported as common findings. chest x-ray reports of children with pneumonia showed that more than half had a ground glass opacity pattern 8,9 . possible outcomes reported range from a complete uneventful recovery to complications like multiple organ failure and multiple inflammatory syndrome up to death. a more favorable disease outcome is observed among children compared to adults with few reports of complications and mortality rate of 1-4% 3-6 . due to lack of study among children with covid-19 in africa, understanding the disease pattern and its outcome is mandatory to guide decision making. therefore, in this study we aimed to assess the characteristics and outcome profile of 115 rt-pcr confirmed children with covid-19, and to determine the presence of significant difference in disease severity and survival distribution between groups among children admitted to millennium covid-19 care center in ethiopia. an institution based prospective cohort study design was conducted at millennium covid-19 care center (mccc), a makeshift hospital in addis ababa, ethiopia. the follow up was made from end of june to mid september, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint the source population was all consecutively admitted children with covid-19 admitted to mccc with a confirmed diagnosis of covid-19 using rt-pcr, as reported by a laboratory given mandate to test such patients by the ethiopian federal ministry of health and who were on follow up from end of june to mid september, 2020 17 . all consecutively admitted children with covid-19 during the three months follow up period were included in the study. during this interval a total of 115 covid-19 patients were admitted to the center. all children with covid-19 who were on treatment and follow up at the center from end of june to mid september, 2020 and with complete follow up data were included o hypoxia: spo2 ≤ 93% on atmospheric air or pao2:fio2 < 300mmhg (sf ratio < 315) o tachypnea: in respiratory distress or rr>30 breaths/minutes o more than 50% involvement seen on chest imaging event: achieving clinical improvement from covid-19. censoring: represents patients lost to follow-up, transferred out, died or completed the followup period before achieving clinical improvement. time to event or censoring: time between admission to the center up to clinical improvement/ censoring (in days). a pre-tested interviewer administered questionnaire was used to collect data from patients and their medical charts. the data was collected by trained data collectors and all the necessary . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020. 10.30.20223115 doi: medrxiv preprint precautions in order to prevent the acquisition and disseminate the virus were taken during the data collection process. before coding and analysis the data, data consistency and completeness was checked and necessary measures were taken. the collected data was coded and entered into epi-info version 7.2.1.0, cleaned and stored and exported into spss version 23 for analysis. data was summarized using frequency tables, kaplan meier (km) plots and median survival times. a chi-square test (or fischer's exact test for those variables which do not meet the chi-square assumptions) were used to determine the presence of a significant difference between the underlying characteristics of the children and covid-19 disease severity. a statistically significant difference was detected for variables with a p-value of ≤ 0.05. survival experience of different groups was compared using km survival curves. log-rank test was used to assess the presence of significant difference among survival distributions of groups for equality. a statistically significant difference in survival distribution between groups was detected for variables with a p-value of ≤ 0.05. from the 115 children admitted during the study period, information was collected from 90 children with complete medical recording. among the 90 patients, 67 (74.4%) achieved clinical improvement and 23 (25.6%) were censored. all of the censored observations happened because of transfer to another hospital. the median time to clinical improvement was 14 days. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint the median age of the participants weas 15 years and it ranges from 6 month up to 18 years. the majority (36.7%) of the participants were 15 to 18 years. almost two third (63.3%) of the participants were females. the majority (88.9%) were from addis ababa, the capital city of ethiopia. the commonest reported route of disease transmission was through close contact with a diagnosed person (45.6%). only three (3.3%) had a history of pre-existing comorbid illness, two had bronchial asthma and one had a history of valvular heart disease. more than a quarter (26.7%) of the patients had one or more symptom at admission. the commonest symptom was cough (22.2%), followed by sore throat and headache (each constitutes 10%), fever, runny nose, chest pain and fatigue (each constitutes 5.6%) and then nausea and vomiting (4.4%). seventy three (81.1%) of the patients had mild covid-19 at admission and the rest (18.9%) had moderate disease. based on the chi-square/ fischer's exact test result, a significant difference in covid-19 disease severity was observed among the groups classified by the presence of symptom, fever, cough, sore throat, chest pain and headache. accordingly, children with moderate covid-19 were more . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint the mean (± standard deviation) vital sign values of the studied population was as follows; heart rate of 94.7 beats/ min (± 15.7), respiratory rate of 19.8 breath/min (± 2.9), systolic blood pressure of 126.0 mmhg (± 14.4), diastolic blood pressure of 74.4 mmhg (± 8.8), temperature of 36.4 o c (± 0.81) and oxygen saturation of 96.1% (± 1.7). based on the results of the independent t-test, a significant difference in baseline vital sign values between mid and moderate cases was observed only in the respiratory rate value ( the complete blood count result of the 17 moderate covid-19 patients showed that the mean hemoglobin, hematocrit, white blood cell and platelet counts were 14.96 mg/dl (± 1.82), 41.65 % (± 9.92), 6.87 x10 3 /l (± 2.33) and 282.0 x10 3 /l (± 82.37) respectively. the renal function test showed that; the mean (± sd) value of urea and creatinine were 27.82 mg/dl (± 9.88) and 0.65 mg/dl (± 0.25). the liver function laboratory report revealed that the mean (± sd) values of alt, ast and alp were 20.67 iu/l (± 0.99), 21.82 iu/l (± 8.61) and 109.69 iu/l (± 68.07) respectively. ( table 3 ) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. similarly, the km survival function graph showed that males have a favorable survival experience (time to clinical improvement) compared to females. the km hazard function also showed that the instantaneous chance of achieving recovery increases for both sexes as the duration of illness increases, with a more favorable pattern seen for males. (figure 2) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint to date there is no research on covid-19 infected children in africa. therefore, in this study we have assessed the characteristics and outcome profile of 90 rt-pcr confirmed children with covid-19 who were admitted to millennium covid-19 care center in ethiopia from end of june to mid september, 2020. understanding this will guide the existing practice. among the study population 74.4% achieved clinical improvement and the median time to clinical improvement was 14 days. similarly, a study conducted in china among pediatric patients showed that the median time to cure was 16 days 6 . the median time to recovery among adults was also the same in the study area 18 . in the current study, there was no death among the study population. this is in contrast to a study conducted in united kingdom and north america where mortality rate of 1% and 4% were reported, respectively 4 . this also shows that the disease might have a different pattern compared to adults as a study conducted at our center among adults reported a mortality rate of 5.3% 18 . this difference could be attributed to the small sample size in our study. the median age of the participants was 15 years and it ranges from 6 month up to 18 years. a similar finding was observed in the north american study 4 . two third of the participants were 11 to 18 years of age. this age group was also reported to have a higher disease incidence than the younger groups in a pattern that is recorded in the united states 5 . almost two third (63.3%) of the participants were females unlike the pediatric studies conducted in other countries where the majority of infected children are males 3, 4 . in addition, researches . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint conducted among adults in our center also showed a contrasting pattern where the majority of infected are males [18] [19] [20] [21] [22] [23] . close contact with a diagnosed person constituted the major (45.6%) route of disease transmission. this was found to be the case in other studies as well where 66% up to 95.6% of admitted children were reported to acquired the disease through household contact with adults 6, 7 . this shows that there is a potential for an increase in the number of new infection among children since both globally and nationally the number of new cases among adults is increasing at an alarming rate from day to day implying the need for taking effective precautions among adults in order to protect the children. only three (3.3%) had a history of pre-existing comorbid illness, two had bronchial asthma and one had a history of valvular heart disease. this seems to be in contrast to other studies where 42% up to 83% of admitted children had a history of one or more pre-existing co-morbid illness 3, 4 . the majority (73.3%) of the participants were asymptomatic at presentation. on the other hand, other studies reported 73% up to 94.1 % of children presenting with one or more symptom 4, 6, 8 . the commonest symptom was cough (22.2%), followed by sore throat and headache (each constitute 10%), fever, runny nose, chest pain and fatigue (each constitute 5.6%) and then nausea and vomiting (4.4%). cough was also reported to be the major presentation in another study in china 7 but fever was found to be the commonest presenting symptom in a number of studies including systematic review and meta-analysis studies that included more than 120 articles 6,8,9 . seventy three (81.1%) of the patients had mild covid-19 at admission and the rest (18.9%) had moderate disease. there was no severe or critical case. on the contrary, studies from other countries revealed that a considerable proportion of children was diagnosed with severe and critical illness with a need of intensive care unit admission and invasive ventilation [3] [4] [5] [6] 8 . based on the chi-square/ fischer's exact test result, the chance of developing moderate disease increases for those with one or more symptom at presentation, particularly those with fever, cough, sore throat, and headache. this indicates that in addition to the symptom categories listed as diagnostic criteria for moderate disease, the symptoms listed here might have a more predictive value in disease classification towards a more severe category than what is thought till now. according to the log rank test and km survival and hazard graphs, a significant difference in survival between groups was observed only for sex. a significantly longer time was needed for female patients to achieve clinical improvement compared to male patients. otherwise, the time to clinical improvement didn't show significant difference among the groups classified by age group, symptoms and disease severity. this is an opposing pattern compared to adult findings in . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted november 4, 2020. ; https://doi.org/10.1101/2020.10.30.20223115 doi: medrxiv preprint the center where survival distribution showed a significant difference between groups classified by age, symptom and disease severity but didn't show a difference between the two sexes 18 . the average duration of time to clinical improvement was 14 days and 74.4% achieved clinical improvement. there was no death during the observation period. the pediatric patients seemed to have a milder disease presentation and favorable outcome compared to other countries report and also the adult pattern observed in our country. having one or symptom particularly fever, cough, sore throat, and headache are associated with development of moderate covid-19. a less favorable survival experience (delayed time to clinical improvement) was observed for females compared with males. further multicenter study with a large sample size is recommended to reach at a better conclusion. the study was conducted after obtaining ethical clearance from st. paul's hospital millennium medical college institutional review board. written informed consent was obtained from the participants and/or their care givers. the study had no risk/negative consequence on those who participated in the study. medical record numbers were used for data collection and personal identifiers were not used in the research report. access to the collected information was limited to the principal investigator and confidentiality was maintained throughout the project. world health organization. weekly covid-19 epidemiological update clinical characteristics of children and young people admitted to hospital with covid-19 in united kingdom: prospective multicentre observational cohort study international covid-19 picu collaborative. characteristics and outcomes of children with coronavirus disease 2019 (covid-19) infection admitted to us and canadian pediatric intensive care units covid-19 trends among school-aged children -united states epidemiological and clinical features of pediatric covid-19 coinfection and other clinical characteristics of covid-19 in children. pediatrics clinical characteristics of children with covid-19: a meta-analysis. frontiers in pediatrics clinical characteristics of covid-19 in children: a systematic review covid-19 presenting as stroke. b r ain b e h a v i novel coronavirus disease (covid-19) in patients with inflammatory bowel diseases clinical features, laboratory characteristics, and outcomes of patients hospitalized with coronavirus disease 2019 (covid-19): early report from the united states. dia g n o sis ( b e rl) prevalence and severity of corona virus disease 2019 (covid-19): a systematic review and meta-analysis clinical characteristics of asymptomatic and symptomatic patients with mild covid-19. clin mic r o biol european patients with mild-to-moderate coronavirus disease epidemiological and clinical features of asymptomatic patients with sars-cov-2 infection ethiopian federal ministry of health. covid19 management handbook characteristics and outcome profile of hospitalized african covid-19 patients: the ethiopian context. medrxiv determinants of developing symptomatic disease in ethiopian covid-19 disease severity and determinants among ethiopian patients: a study of the millennium covid-19 care center duration of oxygen requirement and predictors in severe covid-19 patients in ethiopia: a survival analysis. medrxiv determinants of time to convalescence among covid-19 patients at millennium covid-19 care center in ethiopia: a prospective cohort study. medrxiv predictors of death in severe covid-19 patients at millennium covid-19 care center in ethiopia: a case-control study. medrxiv the authors would like to thank st. paul's hospital millennium medical college for facilitating the research work. the authors declare that they have no known competing interests funding source: this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.authors contribution: twl conceived and designed the study, revised data extraction sheet, performed statistical analysis, and drafted the initial manuscript. all authors contributed to the conception of the study and obtained patient data. all authors undertook review and interpretation of the data. all authors revised the manuscript and approved the final version. key: cord-338007-fa4i981h authors: coyne, lisa w.; gould, evelyn r.; grimaldi, mikala; wilson, kelly g.; baffuto, gabriel; biglan, anthony title: first things first: parent psychological flexibility and self-compassion during covid-19 date: 2020-05-06 journal: behav anal pract doi: 10.1007/s40617-020-00435-w sha: doc_id: 338007 cord_uid: fa4i981h the covid-19 pandemic has brought about significant stress and anxiety for many parents around the world. psychological flexibility and self-care are fundamental aspects of psychological health. for parents, shaping these processes may help promote family nurturance, support children’s prosocial behavior, and provide effective and consistent use of evidence-based parenting “kernels.” the goal of this article is to provide practitioners with evidence-based tools that will support psychological flexibility, self-care, and positive parenting behaviors in caregivers during covid-19 and beyond. placed under conditions such that they are more vulnerable to becoming sick (valentino-devries, lu, & dance, 2020) . in addition, whereas 9 out of 10 americans are under a shelterin-place order, many first-line health care workers are unable to stay home. consider that these parents may be returning home at the end of the day, unable to hug their children due to contamination fears, burdened by working with the very ill without adequate medical supplies, and perhaps traumatized by the necessity to make difficult treatment decisions. the covid-19 pandemic has confronted many parents with difficult choices. parents may be dealing with the stress of going back and forth to work and the potential contamination of their homes. some may be dealing with increased demands of homeschooling their children while still trying to meet their own employment requirements. some may have elderly parents whom they need to care for and ensure the safety of. for parents of children with developmental delays, chronic emotional or behavioral difficulties, or other health challenges, the demands are further increased. as demands and parent stress increase and resources dwindle, children may also be placed in increased proximity of domestic abuse (tolan, 2020) . in sum, parents in the united states and beyond are experiencing a collision of roles-parent, partner, employee, business owner, employer, sibling, caretaker, friend, child, teacher, and so on. they may be faced with fear and uncertainty about the future and how to keep their families safe, while managing this collision of roles, responsibilities, and expectations. many families are distancing not only from other people but also from everything that is familiar. as practitioners, how do we continue to provide meaningful and effective services when we and the families we serve are faced with intractable, chronic stress and uncertainty that is beyond our control? this can feel like an overwhelming and even impossible task. behavior analysts are generally well equipped with evidence-based behavioral intervention strategies for supporting parents; however, it may also be important to consider the broader context of parent behavior, such as the role of private events (including "psychological distress") and the family's cultural, socioeconomic, and historical context. families may need assistance to ensure that their basic needs are met, including food, shelter, clothing, safety, health care, and financial support, before behavior analysts provide other kinds of support. practitioners will need more than their standard toolbox of behavioral parenting strategies: technical skills must be balanced with fluency in collaboration, compassionate care, therapeutic alliance, and self-care skills (leblanc, taylor, & marchese, 2019; taylor, leblanc, & nosik, 2019) . on an airplane, when there is an emergency, parents are told to put on their own oxygen masks first so that they can effectively support their children and keep them safe. in the time of this pandemic, practitioners must thus teach parents how to care for themselves if they are to expand their ability to nurture their children through adversity. similarly, if practitioners are to effectively support other families, they will also need tools for managing their own distress and buffer against the effects of burnout. the goal of this article is thus to provide immediate tools that strengthen both parent and practitioner resiliency and flexibility in the context of covid-19. such tools may also support families beyond present challenges by creating longer term resilience. specifically, we will describe how to support parents' psychological flexibility and self-care. psychological flexibility refers to the ability to recognize and adapt to situational demands, to remain aware and open to the present moment such that one can recognize and shift behavior strategies as required by situational demands, and to engage in actions that are congruent with one's deeply held values (hayes, strosahl, & wilson, 2012; kashdan & rottenberg, 2010) . self-care, as defined by the world health organization, refers to the practice of taking action to preserve or improve one's own health, especially during periods of stress, or "the ability of individuals, families and communities to promote health, prevent disease, maintain health, and to cope with illness and disability with or without the support of a healthcare provider" (world health organization, regional office for south-east asia, 2014: p. 15). it is our contention that supporting psychological flexibility (burke & moore, 2015; da paz & wallander, 2017; hartley, dorstyn, & due, 2019; irwin, jesmont, & basu, 2019; moyer et al., 2018; williams, ciarrochi, & heaven, 2012) and self-compassion (gouveia, carona, canavarro, & moreira, 2016; neff & faso, 2014) in parents is foundational to bolstering and maintaining psychological well-being in families and that providing parents with tools in these domains is to empower them to better cope with conditions of stress and uncertainty. the tools outlined in what follows are components of acceptance and commitment therapy (act; hayes et al., 1999 hayes et al., , 2012 and can be grouped into three domains: (a) mindfulness and acceptance, (b) committed and valued action, and (c) self-compassion. in behavioral terms, mindfulness and acceptance processes involve paying purposeful attention to the present moment, allowing or making space for unwanted thoughts and emotions, and relinquishing attachment to thoughts as literal truths, where that is helpful. commitment and valued action involve making a promise to oneself about something that really matters and following through with that commitment. self-compassion involves self-kindness, awareness of our common humanity, and willingness to acknowledge difficult thoughts and emotions, without attachment (neff, 2012) . given the urgent need to equip behavioral practitioners with resources for parents, we have avoided more academic language in favor of a more practical approach: we have attempted to describe these tools in such a way that is widely accessible and that may be put into practice immediately. for example, we intentionally use lay language such as "thoughts and feelings" instead of "private events," "taking our minds literally" instead of "excessively rigid rule following with respect to private verbal stimuli," and "coercion" instead of "excessive reliance on negative reinforcement and punishment." the principles behind these strategies are evidence based; however, many of their particulars have not been investigated within the context of a pandemic. nonetheless, they are firmly grounded in behavioral principles. we have intentionally left the fine-grained behavioral interpretations of act procedures out of this article, but we refer the reader to chapter 20 of cooper, heron, and heward (2020) for behavioral conceptual analyses of act. furthermore, the strategies in this article are not offered as alternatives to more mainstream applied behavior-analytic procedures but as supplements to them. overall, the approaches in this article seek to increase access to positive reinforcement and reduce levels of aversive control in the lives of parents and children. we do not need more evidence that an abundance of positive reinforcement and reductions in aversive control are beneficial to those we work with (and all of humanity, for that matter). before behavior analysts provide parents with strategies to support their psychological flexibility, it is worth articulating some "travel guidelines" in preparation for their journey. these are not the "what to do" of self-care but rather "in what way" self-care should be approached. context matters, and as such, these pointers that follow may serve as reminders that can guide continued practice and generalization. we have included them as hashtags to underscore that broad dissemination via social media is possible, and may be an effective way to encourage the use of these practices through social networking. #smallthingsmatter "small things matter" is an important principle for action and informs the study of "kernels," or fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families (embry & biglan, 2008) . larger long-term goals such as "getting in shape," "eating a healthy diet," and "being a better parent" can be daunting. taking the stairs instead of the elevator, eating the apple instead of the cookie, and stopping to kiss a child on the head are smaller steps that may be more attainable. there are lots of data that show big impacts from small changes, such as tiny amounts of running, small reductions in sugar intake, small nurturing social interactions, and just a little more sleep. oftentimes, people may attempt to control things that are beyond their control. thus, it is important to help parents focus their efforts on things that they can influence within the system of the family. with the understanding that everything interacts, this focus should aim toward those areas that may have the most impact. for example, sleep deprivation can have a troubling impact on appetite, social interactions, emotional responses, and immune function (furman et al., 2019) . a little bit of improvement in a single thing like sleep can also make a positive impact on these same areas. parents do not have to lift it all at once. #patternsmatter one of the obstacles to behavior change is that people become too focused on perfection when most often it is the pattern that matters. a doughnut on occasion has little health impact. doughnuts all day, every day, on the other hand, may be problematic. it is possible that parents may be insensitive to the long-term effects of unhelpful patterns due to more immediate contingencies dominating their behavior: consider gerald patterson's work on coercion (patterson, 1982) . patterson illustrated how parents quickly get pulled into coercive cycles with their children, due to the powerful (immediate) effects of punishment and negative reinforcement on parent and child behavior, despite long-term negative effects on both parents and children. mindful awareness of triggers to unhelpful patterns opens a space in which parents can choose to do something different, and potentially more helpful, for themselves and their children. we may encourage parents to become aware of their behavioral patterns and to notice how those patterns are working for them, both in the short and long term. parents may then have the space to create new patterns of flexible, workable parenting behaviors over time. #meaningmatters entire psychologies have been constructed around meaning making (e.g., frankl, 1985) . part of the reason small things matter lies not in the thing itself, but rather in the meaning of the thing. when you take a moment with a child, and that moment becomes a pattern of such moments, it says something to the child. it says, "you are worth pausing over. you are interesting. time with you is valuable. you matter." even if you are wildly busy with work or keeping house and home together, these small pauses and small hesitations speak volumes. the moments of our lives go by in an instant, but what lasts is the stories we tell: "even when things got scary, i knew i was loved." #wearestrongertogether human beings survived and multiplied on the planet because we are super-cooperators (or "eusocial"; wilson & wilson, 2007) . this sensibility is in every cultural tradition, though modern times have deemphasized it with the idea that we should be able to do things "on our own." we encourage parents (and practitioners) to seek and to offer help. two are stronger than one. we encourage parents to care for themselves in their "out-loud voice" and to team up with a friend, even online. this breaks some cultural taboos against seeking help, but if parents adopt it, they give tacit permission for help seeking and partnership in their social network. join groups, make groups, and foster, enrich, and appreciate the connections you already have. as an incredible bonus, our children learn an enormous amount from observing us. when we take time to care for ourselves, our children see that and learn. #selfcareaslove it may be unhelpful to frame parent self-care as an addition to their to-do lists. that list is already too long, and parents are already challenged and accountable in a thousand ways. instead, it may be important to consider self-care as a quality of action: it can be an act of love and kindness. to help parents see this, we suggest encouraging perspective-taking. it may be useful to encourage parents to reflect on an act of love toward them by others. encourage them to pause and recall those times, that person, and their demeanor. essentially, encourage them to look at themselves through the eyes of a loved one. that is the quality of action we are seeking in self-care. small practices to support patterns of psychological flexibility and self-care with the aforementioned qualities in mind, we describe specific tools in the following sections that can equally be adopted by practitioners to support their own well-being and resilience as they strive to respond compassionately and effectively to families in distress. indeed, we invite practitioners to "put on their own oxygen masks first" alongside the parents they are working with. we present these small, actionable steps nestled under the three broad domains mentioned previously: mindfulness and acceptance practices, committed and valued action, and self-compassion practices to support selfcare. step 1: mindfulness and acceptance present-moment awareness enlist parents in a practice of gentle, curious, and open attention on purpose several times during the day, just for a few moments at a time, such that they strengthen this skill. start small and make it doable. embed this practice in activities of daily living-activities that parents are already doing, such as making breakfast, taking a shower, walking, chopping vegetables, folding laundry, and so on-so that it constitutes no extra effort. to introduce the practice, you may ask parents this question: over the course of your day, what percentage of the time are you right here, right now, versus "time traveling"? that is, worrying about the future and what might happen or ruminating about the past-about things you should have done or didn't do? most people notice that they are actually in the present moment for just a modicum of time, and it is an interesting experience to notice that "the lights are on, and no one is home" for much of the day, so to speak. encourage parents to pay attention on purpose briefly, at various points of the day, while engaged in daily activities. it is helpful to simply bring your awareness gently to the present by slowing down-and either noticing what you are experiencing with your five senses, or, alternately, pausingand hold a space in which you can check in with yourself with these simple questions: how am i doing? what is it that i most need right now? it is also helpful to encourage parents to pay purposeful attention to even small things that are meaningful, and to practice bringing awareness to things that they are grateful for-for example, drinking a cup of coffee, feeling the softness and warmth of the bed in the morning, kissing their child's forehead at bedtime, or a quiet moment before sleep. acceptance a necessary corollary to practicing presentmoment awareness is acceptance, which does not mean tolerance, endurance, or "getting used to" stressors. it refers to an awareness of, and openness to, the inevitable sadness and stress that are part of life, and the flip side of joy, without struggle. one context in which nonacceptance can show up for parents is when they feel they have made mistakes, or failed, in child-rearing duties. this tends to engage their critical minds and evokes thoughts like "you are not enough. you are a terrible parent. you are a hot mess compared to other parents." it also evokes a struggle to "feel better," which can compound and intensify the situation, thus occupying so much of parents' mental bandwidth that they have none left to be truly present and connected with their children. in your meetings with parents, take some time to make a space for them to voice these thoughts, and normalize them. resist the urge to immediately jump in to "fix" it or problem-solve it away. instead, we might nonjudgmentally let a parent know that it is okay not to be okay: this is a struggle for all of ussometimes, me too. see if you can make a space to notice those thoughts and feelings; see if you can soften yourself around them, breathe into them. simply allowing parents to be vulnerable-and perhaps sharing a tiny glimpse of your own vulnerability-may help them carry these difficult experiences more gently and with less effort. defusing from painful thoughts evolution has conferred to humans the remarkable ability to learn indirectly, without training, through language. for example, we can avoid danger when someone gives us the rule "don't touch that; it's hot" or thoughts such as "if you don't organize your child's homeschooling properly, you will ruin them!" our ability to treat our thoughts as real things, called fusion, has given us marvelous flexibility in adapting to our changing environment; however, it can also evoke rigid and inflexible patterns of behavior if we always treat thoughts as literal truths. this can create challenges when parents experience triggering thoughts about current stressors. thus, a simple practice that you can teach parents is to notice thoughts for what they areimpermanent mental phenomena that are sometimes useful and sometimes not. encourage parents to do the following: if you are feeling stressed, take a few moments to slow yourself down and notice the process of your thinking. you may notice your mind is pulling you this way and that or going a hundred miles an hour. see if you can bring your curiosity to your thoughts-slow down each one, imagine stretching it out like taffy, and add to it the stem "i'm noticing the thought . . ." or "my mind is giving me the thought . . ." take a few moments to do this "thought spotting" exercise, and as one thought passes, be curious about what the next thought is that might arise. practice this a few times throughout the day, when you think of it, and notice anything about this experience that surprises you or that you didn't expect. in essence, this practice supports mindful awareness of, and detachment from, one's thoughts such that parents are better able to notice and be influenced by the relevant cues in their environments. perspective-taking humans often have a difficult time observing their own behavior, especially in real time. we are so often in our heads that it may be a challenge to track or notice the effects of our behavior on others. it is this insensitivity that factors into the intransigence of our rigid and unhelpful patterns of behavior, such as coercion. thus, practitioners may encourage parents, during calm moments, to reflect back-for example, on interactions with their children-as follows: when you have a few moments to yourself, pause and see if you can imagine yourself as you were earlier today, when you felt like you were struggling. slow down and notice yourself in action, as though you were watching yourself on a movie screen. notice your face, your tone of voice; notice whatever thoughts and feelings show up in the moment. notice what is happening between you and your child-see if you can notice their face, how they are looking at you. what might their experience be? what patterns do you see? in doing so, you may evoke parents' mindful awareness of potentially unhelpful patterns-such as denial of self-care, autopilot, or avoidance. you may also help them notice and reinforce their "wins," of which they may be unaware. step 2: valued and committed action valued action in difficult times, when we are really struggling, the presence of potent long-term reinforcers can help us move forward in an adaptive way. values have the potential to fundamentally alter our relationship with adversity. adversity in the context of what is most important to us can help us be more willing and able to rise to the challenges we are faced with in meaningful ways. practitioners might spend some time with parents and suggest that they consider approaching their current context in a different way: see if you can step back for a moment and imagine that you could choose to make your time during this crisis about the things that are truly important and meaningful to you. if that were so, ask yourself, "who do i want to be during this crisis? what do i want this to be about? what would it look like if i acted toward my values?" practitioners may remind parents that every moment offers a choice and that in every moment parents can choose how best to use this time. this moment can be all about crisis parenting, or it could be about something more meaningful or valued. by connecting with values, we can transform struggle and uncertainty into an opportunity to connect with what matters to us most. committed action when we are on autopilot, stuck in patterns of behavior that are so ingrained we barely notice them, the ability to choose our next steps disappears. thus, you may engage parents in the simple practice of "pause, notice, choose." practitioners might ask, can you notice when you are connected to and acting accordingly with what you care about most, and notice when you are not, and gently bring yourself back to your intention whenever you notice you are off track? in addition, practitioners may encourage parents to make a promise to themselves about something that really matters and start small: "do the hard stuff in whatever order you like" and keep going. "practice everywhere, everywhen, everyhow, everymood, with everyone. don't stop" (sedley & coyne, 2020: p. 71 ). in doing so, practitioners may create a space for this crisis to be incredibly scary and difficult, but also meaningful and important. we may contribute to the creation of more helpful patterns of behavior that support engagement in values-based behavioral activation, or the regular practice of acting with intention in meaningful ways. step 3: self-compassion most of us struggle to offer ourselves the same kindness we offer to others, particularly in times of great stress. this situation is hard. this will be hard. self-compassion can be shaped and strengthened, even while we are struggling, and involves relating to ourselves with kindness and compassion, appreciating our common humanity and staying present and open to our pain and struggle (neff, 2012) . self-compassion builds resilience (e.g., beaumont, durkin, hollins martin, & carson, 2016; shapiro, astin, bishop, & cordova, 2005) and is a strong positive predictor of quality of life and overall psychological health (e.g., baer, lykins, & peters, 2012; van dam, sheppard, forsyth, & earleywine, 2011) . it is also an important "oxygen mask" for practitioners: "if a behavior analyst does not engage in self-compassion, they will likely have difficulties extending reciprocal compassion to others" (taylor et al., 2019, p. 660) . families may be faced with difficult decisions and situations where their values may conflict with what they are being asked to deal with. getting through this will require the willingness to stay with discomfort, rather than trying to fix it. self-kindness when everything around us feels chaotic and we are experiencing distress, our go-to response is likely to be one of "fight or flight." self-kindness has the potential to transform that fight-or-flight response into a caregiving or nurturance response, providing us with a sense of safety and resources. practitioners might begin to invite parents to treat themselves more kindly in session by asking, how are you doing? . . . perhaps take a moment and check in with your body, and ask it if it needs anything. is there something you could do right now to feel just 10% more comfortable? we might then invite parents to find just one moment, every day, to put down whatever they are doing and do something kind for themselves, even if that is simply allowing themselves to think about and focus on something other than all of this, just for a moment. self-kindness could even be shaped within session, perhaps starting with just pausing the session and encouraging parents to breathe into whatever they are experiencing, with kindness, before carrying on. self-kindness also creates a safe space for imperfection and mistakes, which will inevitably happen as we navigate through challenging situations. it creates a space where we can try, even when things might feel impossible, and reduces our tendency to be judgmental, self-critical, and harsh with ourselves and others. if parents are having a hard time offering kindness to themselves, practitioners might invite them to think about what they would offer a friend or their child at the end of a hard day and invite them to give that to themselves. if parents are struggling with making a mistake, guilt, or self-blame that won't let them go, practitioners could invite them to speak to themselves kindly: breathe into and soften around that self-critical part of yourself. create some space around it, and then tell it with kindness, "i know you criticize me because you are suffering. i see you suffering, and i am here, offering kindness and love for you." part of treating oneself kindly is prioritizing and creating space for small acts of self-care. invite parents when possible to share the work at home and encourage them to schedule breaks and do things to promote well-being. start building small patterns of well-being such as movement, social connection, or meditation practices. start small and make it doable. common humanity versus isolation in any moment, there are infinite reasons to be afraid and in pain, and there are infinite reasons to wonder and be grateful. we are all human. different people cope in different ways. self-compassion allows us to recognize that our experiences are common to humanity and we are not alone in our pain or suffering. practitioners can help parents recognize and remember this: we are all capable of amazing, heroic things, and we all make mistakes and struggle-we are all vulnerable and imperfect. mindfulness we cannot be compassionate toward our own and others' suffering while also ignoring, suppressing, and avoiding it. self-compassion involves staying open, present, and curious with respect to our own suffering and that of others. it is a nonjudgmental, gentle way of being with ourselves (our thoughts and emotions). practitioners can support parents in "learning to surf" the uncertainty and distress they are experiencing, rather than being swallowed up by it. they can invite parents to practice mindful attention to whatever they are feeling and carrying with them and to create space for whatever they are experiencing instead of struggling against it. in doing this, parents may be more able to stay fully present in what is happening, listening and responding where it is needed most, without being buried under or paralyzed by stressors. the covid-19 pandemic has resulted in a complete change in context. there are suddenly many things that we simply cannot do or cannot do in the same way that we previously did; it is easy to become overwhelmed. this situation reflects what evolutionary psychologists call "evolutionary mismatch," in which the environmental conditions change so swiftly, and so dramatically, that we find that our old patterns of behavior no longer work (li, van vugt, & colarelli, 2017) . this is a rude awakening, not just for families, but also for practitioners scrambling to adapt their family interventions. when working with families, we must stay sensitive to this huge context shift and be careful not to add yet another item to their already long list of things they "should" do or "have to be" doing, while also encouraging them with potentially meaningful suggestions. although structure and predictability may be helpful, suddenly implementing a high level of structure in a context that is not normally so structured (e.g., home) is likely to be experienced as adding to the stress of the situation and will be resisted and avoided by many. we must deliver self-care support in small, doable doses. even when the dose is so small that it does not appear to make a noticeable physical difference, it can still make an extraordinarily meaningful difference. there is no act of self-care that does not contribute to well-being. editor's note this manuscript is being published on a highly expedited basis, as part of a series of emergency publications designed to help practitioners of applied behavior analysis take immediate action to adjust to and mitigate the covid-19 crisis. this article was submitted on 4/10/20 and received final acceptance on 04/12/20. the journal would like to especially thank dr. amanda kelly for her expeditious review of the manuscript. the views and strategies suggested by the articles in this series do not represent the positions of the association for behavior analysis, international or springer nature. mindfulness and selfcompassion as predictors of psychological wellbeing in long-term meditators and matched nonmeditators measuring relationships between self-compassion, compassion fatigue, burnout and well-being in student counsellors and student cognitive behavioural psychotherapists: a quantitative survey development of the parental psychological flexibility questionnaire applied behavior analysis interventions that target improvements in mental health for parents of children with autism spectrum 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evolutionary mismatch hypothesis: implications for psychological science the impact of acceptance and commitment therapy on positive parenting strategies among parents who have experienced relationship violence the science of self-compassion self-compassion and well-being in parents of children with autism black americans face alarming rates of coronavirus infection in some states. the new york times coercive family process stuff that's loud: a teen's guide to unspiraling when ocd gets noisy mindfulness-based stress reduction for health care professionals: results from a randomized trial compassionate care in behavior analytic treatment: can outcomes be enhanced by attending to relationships with caregivers? behavior some cities see jumps in domestic violence during the pandemic self-compassion is a better predictor than mindfulness of symptom severity and quality of life in mixed anxiety and depression inflexible parents, inflexible kids: a 6-year longitudinal study of parenting style and the development of psychological flexibility in adolescents rethinking the theoretical foundation of sociobiology self care for health publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations ethical approval not applicable.informed consent not applicable. key: cord-330777-xcwppaux authors: esposito, susanna; molteni, claudio g; daleno, cristina; valzano, antonia; tagliabue, claudia; galeone, carlotta; milani, gregorio; fossali, emilio; marchisio, paola; principi, nicola title: collection by trained pediatricians or parents of mid-turbinate nasal flocked swabs for the detection of influenza viruses in childhood date: 2010-04-30 journal: virol j doi: 10.1186/1743-422x-7-85 sha: doc_id: 330777 cord_uid: xcwppaux this study evaluated the efficiency of pediatric mid-turbinate nasal flocked swabs used by parents in 203 children aged 6 months to 5 years with signs and symptoms of respiratory disease. two nasal samples were collected from each child in a randomised sequence: one by a trained pediatrician and one by a parent. the real-time polymerase chain reaction influenza virus detection rates were similar in the samples collected using the two methods (cohen's kappa = 0.86), as were the cycle threshold values. in comparison with the pediatrician-collected samples, the sensitivity and specificity of the parental collections were respectively 89.3% (95% confidence interval [ci]: 77.8-100%) and 97.7% (95% ci: 95.5-100%), and the positive and negative predictive values were respectively 86.2% (95% ci: 73.7-95.1%) and 98.2% (95% ci: 96.4-100%). the children were significantly more satisfied with the parental collections (median values ± standard deviation, 1.59 ± 0.55 vs 3.51 ± 0.36; p < 0.0001). these findings show that mid-turbinate nasal flocked swabs specifically designed for infants and children can be used by parents without reducing the influenza virus detection rate. moreover, the direct involvement of parents significantly increases patient acceptance, thus simplifying collection and suggesting that this novel swab design should be considered for epidemiological surveys and vaccine efficacy studies. in order to monitor the circulation of infectious agents and evaluate the efficacy of specific vaccines, it is essential to be able to identify the viruses that cause respiratory diseases in infants and children [1] [2] [3] [4] [5] [6] , and the adequate collection of respiratory specimens is the first crucial step in obtaining reliable information [7] [8] [9] . such specimens are usually collected in hospital by certified nurses, pediatricians or other medical doctors, but parents may find it troublesome having to go to a hospital every time a specimen needs to be taken from a child with respiratory infection as such diseases occur several times a year. collecting respiratory secretions at home could overcome this, but traditional collection techniques (mainly nasopharyngeal aspiration and nasopharyngeal washing) are too complex, invasive and time-consuming to be used by untrained people [10] [11] [12] . it has been found that recently developed mid-turbinate nasal flocked swabs are as effective as these traditional methods [13] [14] [15] , and simple enough to be used by adult patients themselves and the parents of children [13, 16] . however, as experience with the parental collection of samples is very limited, we evaluated the efficiency of pediatric mid-turbinate nasal flocked swabs when used by parents. the study involved all of the children aged between six months and five years who attended the emergency department of the university of milan's department of maternal and pediatric sciences because of signs and symptoms of respiratory disease between 1 january 2008 and 28 february 2008. only the children with known craniofacial abnormalities were excluded. the protocol was approved by the ethics committee of the fondazione irccs ca' granda ospedale maggiore policlinico, and two nasal samples were collected in a randomised sequence from each child: one by a trained pediatrician (ct) and one by a parent. the pediatric mid-turbinated nasal flocked swabs (copan, brescia, italy, code 56750cs01, suitable for children aged up to two years) and those for older children (code 56380cs01) have a collar respectively 2.5 and 5.5 centimeters along the swab shaft ( figure 1 ) that is large enough to prevent further insertion when it reaches the nostril. the pediatrician and a parent (who was first asked to read a very simply written and illustrated description of the procedure) each inserted a swab gently up to its collar and rotated it three times before placing it in viral transport medium to be delivered to the laboratory within three hours. the parents were then asked to describe their child's satisfaction with the two procedures using a a five-point scale (from 5 for "very satisfied" to 1 for "very unsatisfied"); an independent observer (pm) confirmed that the child's satisfaction was as reported by the parents. there was no refusal to participate, all of the children had two swabs taken (one by the pediatrician and one by a parent), and a satisfaction scale was completed for each. as soon as they were delivered to the laboratory, each patient's paired samples were processed in parallel. viral rna was extracted from both swabs by means of a nuclisens easymag automated extraction system (biomeriéux, craponne, france), using phocine distemper virus (pdv) as an extraction control as previously described [6, 9] . all of the real-time polymerase chain reactions (pcrs) were set up as singleplex pcrs in a total volume of 25 μl, using the taqman universal master mix (applied biosystems, foster city, ca, usa), 200-800 nm of primers, 100 nm of taqman probe and 10 μl of cdna template, and the products were amplified using the abi 7900ht fast real-time pcr system (applied biosystems) and standard cycling parameters. the primerprobe sets were: influenza a, sense aagaccaatcct-gtcacctctga, antisense caaagcgtctacgctg-cagtcc, probe fam-tttgtgttcacgctc acc gtgcc-bhq1; influenza b, sense gagacacaattgc-ctacctgctt, antisense ttctttcccaccga accaac, probe tet-agaagatggagaagg caaag cagaactagc-eclipse; pdv, sense cgggtgccttt-tacaagaac, antisense ttctttcctca acctcg tcc, probe vic-atgcaagggccaattcttccaag tt-bhq1. influenza a and b rna were quantified relatively; the criterion for a positive reaction was a cycle threshold (ct) of <40 cycles. the findings relating to the specimens collected by the parents and pediatricians were compared using sas verthe categorical data were compared between groups using the χ 2 test or fisher's test; the other between-group comparisons were made using wilcoxon's signed-rank test, a non-parametric test for paired samples. p values of 0.05 or less were considered statistically significant. the mean age ± standard deviation (sd) of the 203 recruited children was 1.99 ± 2.96 years: 103 (50.7%) were younger than two years, and the specimens were taken using the smaller swabs. table 1 shows the detected influenza viruses. thirty-two children (15.8%) were positive for influenza: the paired samples were both positive in 25 cases (12.3%), only the samples collected by the pediatrician were positive in three cases (1.5%), and only the samples collected by a parent were positive in four cases (2.0%). the influenza virus detection rates were similar in the samples collected using the two methods (cohen's kappa = 0.86): in comparison with the pediatricians, the sensitivity and specificity of the parental collections were respectively 89.3% (95% confidence interval [ci]: 77.8-100%) and 97.7% (95% ci: 95.5-100%), and the positive and negative predictive values were respectively 86.2% (95% ci: 73.7-95.1%) and 98.2% (95% ci: 96.4-100%). table 2 summarises the ct values in the paired positive samples, which show that similar amounts of viruses were detected in the samples collected using the two methods. however, the children were significantly more satisfied with the parental collections (mean values ± sd, 1.59 ± 0.55 vs 3.51 ± 0.36; p < 0.0001). the detection and satisfaction rates were similar regardless of the patients' age. our findings demonstrate that mid-turbinate nasal flocked swabs specifically designed for infants and children can be used by parents without reducing influenza virus detection rates. the number of influenza-positive nasal swabs and the ct values were similar in the samples collected by the pediatrician and parents. furthermore, the direct involvement of parents significantly increased the patient's acceptance of the procedure and thus simplified collection. these results suggest that, when an early evaluation of the viral etiology of a respiratory tract infection is needed, parents can collect respiratory secretions at home using pediatric mid-turbinate nasal flocked swabs. this has a number of advantages. first of all, if the child is included in an epidemiological survey or vaccine efficacy study, parental collection reduces the risk of losing the sample when respiratory episodes occur. secondly, the samples can be obtained immediately after the onset of the first signs and symptoms, thus favouring the identification of the infectious agent and aiding treatment decision making after a pediatrician's visit. thirdly, it reduces family organisational problems and the children's emotional involvement. however, in order to make the most of such advantages, appropriate swabs specifically designed for infants and young children need to be used because the shafts of adult swabs are too long, and their tips are too big. specifically prepared mid-turbinate nasal flocked swabs with a collar that prevents them from being inserted so deeply that they come into possibly painful contact with inflamed structures are safe and well tolerated, and can therefore be recommended in routine practice. we do not know why the paired samples of seven children were not both positive, but only those taken by the pediatrician in three cases, and only those taken by a parent in four. there were no differences in ct values suggesting less virus and lower sensitivity, and no differences in the timing of the collections or in the age or weight of the children. in any case, the detection rates of the two collection methods were similar, and the sensitivity, specificity and positive and negative predictive values were high. one limitation of this study is that, although the parents collected the respiratory secretions without any particular assistance, they were in our hospital and probably felt more confident knowing that professional help was on hand if needed; it is possible that they may have found it more difficult at home or that the sampling would have been less precise. to reduce these risks, it seems reasonable to suggest that they should be instructed by their child's pediatrician and that an illustrated explanation with details concerning specimen storage and transportation should be included in the package insert. moreover, the study population was small and only influenza viruses were evaluated. however, although further studies of larger populations designed to detect other respiratory viruses would strengthen our conclusions, we suggest that this novel swab design would be useful for epidemiological surveys or vaccine efficacy studies. list of abbreviations ct: cycle threshold; ci: confidence interval; pdv: phocine distemper virus; pcr: polymerase chain reaction; sd: standard deviation. the effect of rapid respiratory viral diagnostic testing on antibiotic use in a children's hospital rapid assays for the diagnosis of influenza a and b viruses in patients evaluated at a large tertiary care children's hospital during two consecutive winter seasons effect of a rapid influenza diagnosis impact of human coronavirus infections in otherwise healthy children who attended an emergency department the global state of influenza in children impact of human bocavirus on children and their families influenza diagnosis and treatment in children: a review of studies on clinically useful tests and antiviral treatment for influenza antigen-based assays for the identification of influenza virus and respiratory syncytial virus: why and how to use them in pediatrics comparison of nasopharyngeal nylon flocked swabs with universal transport medium and rayon bud swabs with a sponge reservoir of viral transport medium in the diagnosis of paediatric influenza nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses comparison of nasopharyngeal flocked swabs and aspirates for rapid diagnosis of respiratory viruses in children comparison of four nasal sampling methods for detection of viral pathogens by rt-pcr-a ga(2) len project comparison of flocked and rayon swabs for collection of respiratory epithelial cells from uninfected volunteers and symptomatic patients comparison between pernasal flocked swabs and nasopharyngeal aspirates for detection of common respiratory viruses in samples from children dry cotton or flocked respiratory swabs as a simple collection technique for the molecular detection of respiratory viruses using real-time nasba comparing nose-throat swabs and nasopharyngeal aspirates collected from children with symptoms for respiratory virus identification using real-time polymerase chain reaction collection by trained pediatricians or parents of mid-turbinate nasal flocked swabs for the detection of influenza viruses in childhood this study was supported in part by a grant from the italian ministry of health (bando giovani ricercatori 2007). the authors declare that they have no competing interests. se and np designed the study and co-wrote the manuscript. cgm, cd and av carried out the real-time pcr. ct collected the swabs. cg performed the statistical analysis. gm, ef and pm examined the patients. all authors read and approved the final manuscript. key: cord-328709-bqf3d6r3 authors: khan, mariam s. title: paid family leave and children health outcomes in oecd countries date: 2020-07-18 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105259 sha: doc_id: 328709 cord_uid: bqf3d6r3 during the past four decades, most oecd (organisation for economic co-operation and development) countries have adopted or expanded paid family leave, which offers leave to workers following the birth or adoption of a child as well as care for ill family members. while the effects of paid maternity leave on child health have been the subject of a large body of research, little is known about fathers’ leave-taking and the effects of paid paternity leave. this is a limitation, since most of the recent expansion in paid family leave in oecd countries has been to expand leave benefits to fathers. mothers’ and fathers’ leave-taking may improve child health by decreasing postpartum depression among mothers, improving maternal mental health, increasing the time spent with a child, and increasing the likelihood of child medical checkup. the purpose of this paper is to examine the effects of paid family leave on the wellbeing of children, extending what we know about the effects of maternity leave and establishing new evidence on paternity leave. the paper examines the effects of paid family leave expansions on country-level neonatal mortality rates, infant mortality rates, under-five mortality rates, and the measles immunization rates in 35 oecd countries, during the time period of 1990 to 2016. using an event study design, an approximately 1.9 to 5.2 percent decrease in the infant, neonatal, and under-five mortality rates has been found following the adoption of paid maternity leave. however, the beneficial impact is not as visible for extension of paid leave to fathers. the implications and potential reasons behind the larger protective effects of maternity leave over paternity leave on child health outcomes are discussed. many oecd countries, except for the united states, have adopted paid family leave and a large body of literature has examined the effect of these leave policies on health outcomes for children. there is consensus that when workers do not have access to such leave they are less likely to accommodate the health needs of children, especially newborns (clemans-cope et al., 2008) . neuroscience and developmental research consistently show that the first two years of life are critical periods during which stable, responsive, warm caregiving is key to children's social, emotional, and intellectual development; a lack of these relationships contributes to stress and has life-long implications for health and development (shonkoff and phillips, 2000) . while the important role of caregivers during the neonatal period is clear, most research has examined the impact of employment leave after birth for mothers-with little to no work focusing on the impact of paid paternity leave on health outcomes of children. the impact of paid paternity leave is not nearly as discussed as the impact of paid maternity leave. this may be attributed to the recency of the availability of paid paternity leave in several countries. to address this gap, this study examines the separate effects of paid maternity and paternity leave policies on the health outcomes of children in oecd countries during the period of 1990 to 2016. since paid paternity leave has been adopted following the implementation of paid maternity leave, there are no countries with only paternity leave. thus, when this study examines paid paternity leave, it is examining extensions to paid maternity leave. the health outcome measures that the study examines include: the neonatal mortality rate, infant mortality rate, under-five mortality rate, and the percentage of children receiving measles vaccination. the neonatal mortality rate is particularly important considering that 2.5 million newborns died within the first month of life in 2018, according to the world health organization (2019). this accounts for 47 percent of all children deaths under the age of five, which is an increase of 40 percent from 1990. paid family leave allows workers to take time off from work with full or partial wage replacement to engage in family caregiving (lester, 2005) . for workers who are unable to take time off for financial reasons, paid family leave makes it affordable to do so. more importantly, paid leave helps retain female workers in the workforce, which is another purpose of paid family leave. according to economic theory, when women are guaranteed pay during the time they take leave and job protection, meaning when employees are guaranteed to return to their same job, it increases the likelihood that they will be in the labor force prior to having children. also, it provides women the ability to plan for their future (gupta, smith, and verner, 2008; summers, 1989; sundström and stafford, 1991) . currently, 34 oecd countries offer paid family leave to parents. a detailed summary of the paid family leave programs in the oecd countries is shown in table 1 . among these countries, 29 guarantee at least 14 weeks of paid family leave to mothers of infants. coincidentally, 14 weeks of maternity benefits has also been recommended by the 2000 international labor organization's maternity protection convention. the first 14 weeks is considered to be important because during this time period, infants begin to form neural connections and recognize the voice, smell, and face of their caregiver (schulte et al., 2017) . for example, in australia, all workers, including full-time and part-time workers, have a guaranteed 18 weeks of paid parental leave at the federal minimum wage (hewitt, strazdins, and martin, 2017) . it should be noted that the united states offers 12 weeks of job-protected leave, but on an unpaid basis, for specified medical and family reasons through the family medical and leave act of 1993 (fmla). employees can use leave during the birth, adoption, or fostering of a child. it can also be used for serious health conditions that make an employee unable to perform their job and, similarly, it can be used to care for an employee's spouse, child, or parent who has a serious health condition. the type of maternity leave coverage provided is correlated to the amount of time that a new mother takes off from work (berger, hill, and waldfogel, 2005) . when new mothers have access to paid leave, they are more likely to spend time at home with their newborns after giving birth (rossin-slater, ruhm, and waldfogel, 2013) . for example, baker, gruber and milligan (2008) analyzed maternity leave mandates in canada, finding that mandatory leave entitlements increased the time that new mothers spent away from work by more than three months. likewise, baum and ruhm (2016) used data from the 1997 cohort of the national longitudinal youth survey to examine california's paid leave, finding that the usage of paid leave by mothers increased by three weeks following the birth of a child. the literature also provides insights into the mechanisms through which additional time mothers spend with newborns yields health benefits. paid leave may improve child health via an increased likelihood of breastfeeding. research has found breastfeeding to be associated with improved child and maternal health (hamdan and tamim, 2012; ip et al., 2007; lichtman-sadot and bell, 2017; pac et al., 2019) . lichtman-sadot and bell (2017) (ip et al., 2007) . similarly, breastfeeding mothers, compared to non-breastfeeding mothers, are less prone to postpartum depression (hamdan and tamim, 2012) . paid family leave is also associated with regular medical checkups at infancy, reduced prenatal stress, and reduced non-parental care during infancy. lichtman-sadot and bell (2017), in particular, found the improvement in health outcomes are driven by children from low socioeconomic households, suggesting that the paid family leave program had the greatest effect on mothers who could not afford to take unpaid leave. conversely, when mothers are pressured to return to work early, it can decrease the likelihood that newborns receive the needed care. berger and waldfogel (2004) found that children whose mothers returned to work within 12 weeks were 7.5 percentage points less likely to be breastfeed, 2.4 percentage points less likely to receive babycare, and 3.4 percentage points less likely to receive all of the required immunizations. paid maternity leave may also improve child health via an improvement in mental health of mothers, since paid maternity leave improves the quality of mothers' sleep, increases the frequency of children's medical checkups, and increases household income (chatterji and markowitz, 2012; heymann et al., 2017; stanczyk, 2019) . chatterji and markowtiz (2012) found that increasing the length of leave to over 12 weeks will reduce the maternal depressive symptoms on the csed (center for epidemiologic depression) scale by 15 percent and the probability of being classified as severely depressed by 2 percent. likewise, as mandal (2018) found, the negative psychological effects of returning to work early after giving birth was alleviated when women received paid maternity leave. specifically, among women who returned to work within 12 weeks of childbirth, those who had received some paid family leave had a lower csed score, compared to those who did not receive any paid family leave. while we know a good bit about maternity leave, we know less about paternity leave. we do know that fathers are somewhat less likely to take leave from their jobs but are more likely to do so when the leave is paid. for example, cools, fiva, and kirkebøen (2015) analyzed the adoption of paid paternity leave in norway in 1993 and found that the share of men taking paternity leave increased significantly, compared to the time period before adoption of the mandate. in fact, in 1993, the share of men taking paternity leave was 24.6 percent and by 2006, it was 60 percent (cools et al., 2015) . similarly, marshall (2008) found that after canada extended the parental benefits program from 10 to 35 weeks in 2001, the proportion of fathers filing for parental leave benefits increased by approximately 10 percent. some evidence from the literature is suggestive of mechanisms, as well. paid parental leave appears to increase the likelihood fathers are involved with the care of their children. tanaka and waldfogel (2007) , who examined paid parental leave in the united kingdom, found that fathers who took paid parental leave were 19 percent more likely to feed their child as well as 19 percent more likely to attend their newborn at night. when looking at sweden's paternity leave program, haas and hwang (2008) also found a positive correlation between paternity leave and the participation of fathers in child care. fathers who took more days of leave were more likely to spend time with their child and participate in child care tasks (haas and hwang, 2008) . the lengthened interaction that fathers have with their children has demonstrated to be beneficial. such strong interactions can have positive effect on the cognitive and physical development of children (allen and daly, 2007) . the infants of highly involved fathers, on average, are more cognitively developed at six months of age (pedersen, rubenstein, and yarrow, 1979) . like paid maternity leave, paid paternity leave may also improve the health of children via an improvement in the health of mothers. persson and rossin-slater (2019) , who examined swedish households, found that increased paternity leave improves maternal mental health. specifically, the study found that in the first six months after birth, paid paternity leave is correlated with a 14 percent decrease in the likelihood of a mother having an inpatient or specialist outpatient visit for child-birth related complications, a 26 percent decrease in the likelihood of a mother having anti-anxiety medication, and an 11 percent reduction in the likelihood of a mother having an antibiotic prescription drug. bratberg and naz (2009) found that norway's paid paternity leave program reduced the sick absence rate of mothers who had recently given birth. tikotzky et al. (2015) also found that greater paternal involvement, which may be encouraged by paternity leave, is associated with greater maternal sleep at six months after birth. overall, there is good evidence that the increased time that both mothers and fathers have been afforded by paid parental leave has improved the health outcomes of children. one important indicator is the immunization rate of children. there is a general consensus that paid parental leave increases the likelihood of vaccination, since parents have more time to take their children to the doctor. a study of 185 countries found that a 10 percent increase in the number of weeks of paid maternity leave is associated with a 25.2 and 22.2 percent increase in measles and polio vaccinations, respectively (daku, raub, and heymann, 2012) . studies also indicate that paid parental leave reduces the mortality of infants, which may partially be a result of immunizations. for instance, winegarden and bracy (1995) found that each week of paid maternity leave was associated with a decrease of approximately 0.5 deaths per 1,000 live births in 16 oecd countries (winegarden and bracy, 1995) . similarly, ruhm (2000) , using annual aggregate data for 16 european countries from 1969 to 1994, found that paid parental leave decreased the mortality of infants and young children. more specifically, a 10-week increase in parental paid leave was correlated with a 3.3 to 3.5 percent reduction in child mortality and a 2.5 to 3.4 percent reduction in infant mortality (ruhm, 2000) . tanaka (2005) estimated that a 10-week increase in paid parental leave would also reduce infant mortality by 2.6 percent. the previous literature on paid family leave provides evidence of benefits for child health, but much remains unclear. first, it is unclear whether the effect of paid maternity leave policies on child health outcomes provide reasonable approximation of the effects of paternity leave policies, as well. second, much of the work on maternity leave examined reforms implemented in the 1980s. it is unclear whether the conclusions would change when taking into account more recent years, specifically from 1990 to 2016. this time period is particularly important, since this is the period when many oecd countries extended or expanded paid leave to fathers, as demonstrated by fig. 1 . this reflects changing gender attitudes in that many countries began to understand the importance of the role fathers play in the development of a child. as in fig. 2 , most countries had adopted paid maternity leave prior to 1990. finally, studies such as cools et al. (2015) and marshall (2008) primarily analyzed the effect of paid family leave for a specific country. the results from one country may not be applicable to another country given differing economic and political structures. by conducting a cross-country analysis with the use of recent data, which takes paid paternity leave into consideration, this study would fill in a gap in the literature. when paid family leave is available, it is expected that access to such leave has an impact on the health of children, considering paid family leave has been demonstrated to decrease postpartum depression among mothers, improve maternal mental health, and increase the rate of breastfeeding (chatterji and markowtiz, 2012; hamdan and tamim, 2012; lichtman-sadot and bell, 2017; pac et al., 2019; persson and rossin-slater, 2019) . in particular, it is hypothesized that paid family leave decreases the neonatal and infant mortality, since research has found that the time that parents spend with their child during that period of a child's life is important for a child's cognitive, social, and emotional development (bernal, 2008; kavanaugh et al., 1997; schulte et al., 2017) . paid family leave can be argued to be lifesaving during infancy, since about 3,500 infants die in their sleep every year from accidental suffocation or unknown causes, known as sudden infant deaths or sids (sole-smith, 2016). research appears to suggest that infants are better off when they are taken care of by a parent rather than by a child care provider, since there is a correlation between infants placed in child care and sids (moon, patel, and mcdermott-shaefer, 2000; patel, 2005, 2005; sole-smith, 2016) . approximately one-third of sidsrelated deaths occur in the first week that an infant spends time in child care, with half of the deaths occurring on the first day (sole-smith, 2016). among infants who died of sids in child care, 17.7 percent were cared by a licensed day care center, 21.3 percent were cared by a relative, and 54.4 percent were cared by a babysitter or homecare provider patel, 2005, 2005) . the problem with babysitters or homecare providers is that many of these service providers are unlicensed and have not received education or training in handling infants. for example, day care providers are more likely to put babies on their stomach, since it can help them to go to asleep faster patel, 2005, 2005) . however, this is a dangerous practice, considering it can increase the risk of sids. according to alison jacobson, the ceo of first candle, which is a nonprofit organization that raises awareness of sids, "the longer that a mom or dad can stay home with a baby, the better." thus, paid family leave can prevent infancy death, since it allows parents to care for their newborns with an extensive amount of care, affection, and precision. additionally, it is expected that paid family leave decreases the under-five mortality rate, since research has shown that parents who have paid family leave are more likely to take their child for a medical checkup, spend additional time with their child, and are more likely to have more household resources that can be spent on the needs of the child (heymann et al., 2017; rossin-slater et al., 2013; stanczyk, 2019; tanaka and waldfogel, 2007) . when a child receives a medical checkup, they are more likely to receive their scheduled vaccination. it is estimated that that 42,000 deaths are prevented every year among children who receive their recommended childhood vaccinations, according to the national prevention council (2011). the hypotheses discussed above are summarized as follows: paid family leave decreases the neonatal and infant mortality. h 2 paid family leave decreases child (under-five) mortality. the theoretical framework for this study is shown in fig. 3 . the primary independent variables of interest in this study are dummy variables measuring paid family leave. paid maternity leave and paternity leave are distinguished, and have separate treatment indicators for country-years. countries that never had paid maternity/paternity leave during this time period are coded as zero, whereas countries that always had paid maternity or paternity leave or later adopted such leave are coded as one. to measure the health outcomes of children, the neonatal mortality rate, infant mortality rate, under-five mortality rate, and the measles immunization rate are used as dependent variables in this study. these health outcomes are consistent with other studies (daku et al., 2012; winegarden and bracy, 1995) . the neonatal mortality rate is particularly important considering more than one third of all child deaths occur within the first month of life, according to the world health organization. the mortality rate and the measles immunization rate are logged because they have a positively skewed distribution, as shown in figure 4 . several annual country-level controls are included to account for country-level differences, which are found to impact the health of children. specifically, the analysis controls for other health, socioeconomic, environmental, and infrastructure factors, including the prevalence of anemia among women and the labor force participation rate of women. each of these factors are arguably justified to be included in the analysis. first, expenditure factors, such as health expenditure of countries (percent of gdp), the public spending on family benefits (percent of gdp), and the gross national income (current u.s. dollars) is controlled for in the analysis, since they are found to be positively associated with the health outcomes of children (ruhm, 2000) . when countries invest more in the overall health of their citizens, there is an improvement in their health. second, the prevalence of anemia among pregnant women has been controlled, since women who are in poor health conditions are more likely to have birth-related problems. third, environmental factors such as the amount of carbon dioxide (co 2 ) emissions and renewable electricity output were included in the analysis, since 1.7 million deaths in children under-five were attributable to the environment, according to the world health organization. pollution has been cited to be a major contributor to childhood deaths, and thus, it is important to control for co 2 emissions (glinianaia et al., 2004) . finally, infrastructure factors, such as the, telephone subscription and the percent of individuals using internet, were also included since these can be considered critical modes of access to information relating to children's health (martínez-fernández et al., 2015) . finally, population size is also controlled in the analysis. table 2 includes the summary statistics of the variables. to estimate the impact of paid family leave on child health outcomes, a two-way fixed effects model has been used. as goodman-bacon (2018) demonstrates, the coefficient of a twoway fixed effects model is equal to the "weighted average of all possible simple difference-indifference that compares one group that changes treatment status to another group that does not." the following two-way fixed effects model was estimated. the indices, c and t are, respectively, country and year, and refer to the dummy variable, indicating whether country c has paid maternity leave or paid paternity leave in year t. the two lead variables, , respectively refer to two years and one year , -2 + , -1 before the adoption of paid family leave in country c in year t. the two lagged variables, , respectively, refer to one year and two years after the , + 1 + , + 2 adoption of paid family leave in country c in year t. furthermore, is a set of control variables, χ such as health expenditure of countries (percent of gdp), public spending on family benefits (percent of gdp), gross national income (current u.s. dollars), life expectancy, prevalence of anemia among pregnant women, labor force participation rate of women (percent of female population, ages above 15), co 2 emissions (kt), fixed telephone subscription (per 100 people), the percent of individuals using internet (percent of population), and population size. furthermore, are country-fixed effects and country-specific time trends, , respectively. the benefit of controlling for country fixed effect is that it accounts for country-level characteristics that do not vary over time. however, the disadvantage of controlling for countryfixed effects is it only identifies countries that change over time. country-fixed effects exploit within-country variation, meaning the results are only applicable to countries that have changed their status over time in terms of their paid parental leave policies. in this study, there is withincountry variation since there are countries that initially did not have any paid parental leave policy, but later adopted maternity and/or paternity leave. specifically, 17 oecd countries adopted paid paternity leave during this period, as demonstrated in fig. 1 , and 7 oecd countries adopted maternity leave during this period, as demonstrated in fig. 2 . the benefit of controlling for country-specific time trends is that it controls for changes within a country over time that may be associated with the implementation of parental leave policies. for example, it may be that countries with atypical growth rates in child health trends are more or less likely to implement paid parental leave policies. country-specific time trends limit the threats to validity that are due to underlying health trends which may be contemporaneous with changes in leave policies. in contrast, common year trend assumes that all countries experience a common trend in a given year. the regressions with the common year trend can be found in appendix a and appendix b. however, it does not account for other changes within a country that may be driving the estimates downward or upward, which could potentially bias the estimates. furthermore, is an error term, assumed to be independent and identically distributed ℰ , (i.i.d.). observations are unweighted. a breusch-pagan test finds no evidence of heteroscedasticity (solon, haider, and wooldridge; . since there is no evidence of heteroscedasticity, the standard errors are not clustered by country in this analysis. further, a country-level panel data has been used with no attempt to draw inference for a super population. estimates are weighted when the impact of treatment is heterogeneous. it is reasonable to expect that weighting would ensure that certain segments of the population are represented. yet, as solon et al. (2013) demonstrate, simply weighting the estimates by the population share of a particular attribute or characteristic will not yield the population averaged treatment effect. instead of weighting, solon et al. (2013) suggest that a regression model should include dummies for each characteristic and a set of interaction terms with treatment. thus, in this study, rather than weighting by population size, it is controlled for in the model. finally, the results have been clustered by country to minimize standard errors. in an additional layer of analysis, this study also examines the effect of the length of paid maternity and paternity leave on child health outcomes. this is important to examine, since there is substantial variation in the length of leave across countries and over time. it is possible that longer leave is associated with better health outcomes. the results indicate that after two years of the adoption of paid maternity leave, there is a statistically significant decrease in neonatal mortality, infant mortality, and under-five mortality (table 3) . paid maternity leave is associated with a 5.2 percent decrease in the neonatal mortality rate, a 2.4 percent decrease in the infant mortality rate, and 1.9 percent decrease in the under-five mortality rate after two years of adoption, when accounting for country-specific time trends. such effects are relatively large, when considering the size of the population being affected. for example, a 2.4 percent decrease in the infant mortality rate means the number of infants dying would drop from 10 to 9.76 per thousand live births. these results are relatively similar to those found by ruhm (2000) and tanaka (2005) . ruhm (2000) finds that a 10-week extension in paid family leave reduces infant mortality by 2.5 percent. tanaka (2005) also finds that a 10-week extension in job-protected paid leave decreases infant mortality by 2.6 percent. in this analysis, a similar trend does not appear to hold true following the adoption of paid paternity leave, meaning that there is a not a statistically significant decrease in the child health outcomes (table 4) . when examining the effect of the length of leave, the study finds that a one-week increase in paternity leave reduces the infant and under-five mortality (table 6 ). however, longer length of paid maternity leave does not have a significant impact on child health outcomes (table 5 ). the variables controlled in this study also provide insight into the results. in all of the analyses (table 3, table 4, table 5 and table 6 ), it was found that an increase in health expenditure is associated with a decrease in neonatal mortality, infant mortality, and under-five mortality. it was also found that an increase in the prevalence of anemia among pregnant women is associated with an increase in these three child health outcomes (table 3, table 4, table 5 , and table 6 ). as the results suggest, paid maternity leave is correlated with a significant decrease in the neonatal, infant, and under-five mortality rate, which was expected. this supports the first hypothesis and partially supports the second hypothesis of the study. however, the impacts of paid maternity leave on the mortality rates are not immediate. the effects are not seen until two years after the adoption of the leave policy. this may be as a result of roll-out delays or compliance lags. governments need to increase the awareness of such leave to individuals who are eligible for the program. schuster et al. (2008) , who examined the implementation of california's paid family leave program, corroborates the lack of awareness among individuals. this study found that within one year of the implementation of california's paid family leave program, parents with children of special health care needs who were receiving care at california hospitals were generally unaware of the program and rarely utilized it. appelbaum and milkman (2011) also found that there was a general lack of awareness of california's paid family leave program. based on the survey utilized in the study, low-wage workers, immigrants, and latinos were the least likely to be aware of the program (appelbaum and milkman, 2011). in general, the impact of paid paternity leave was not as visible as that of paid maternity leave. it is possible that it takes some years to observe a measurable impact of any policy, which is apparent here in the case of paid family leave. paid maternity leave has been in place in many countries for many years, but paid paternity leave is relatively new even in those countries that had paid maternity leave for many years. paid maternity leave was available in 27 of the 35 oecd countries even before 1990, which rose to 32 countries in 2004 and then to 34 countries by 2016 (fig. 2) . in contrast, paid paternity leave was available only in nine oecd countries before 1990 and incrementally rose to 22 in 2016. during the time period of 2004 to 2016, countries with paid paternity leave increased from 15 to 22 (fig. 1) . thus, it is clear that it has taken quite some time for paid paternity leave to be accepted and adopted and even after so many years its acceptance and adoption is not as much as of paid maternity leave. the magnitude of the benefit available also has an impact on the beneficial outcomes. as table 6 demonstrates, a one-week increase in the length of paid paternity leave reduces the infant and under-five mortality. the reason that length of paid paternity leave has a significant effect is that the length of paid paternity leave offered is much smaller than of paid maternity leave. the average paid paternity leave available in the oecd countries is about 0.6 weeks compared to about 15 weeks of paid maternity leave (table 1) . thus, increasing paid paternity leave from one to two weeks may have a larger impact, compared to increasing paid maternity leave from 12 to 13 weeks. it is possible that there is an optimum level of paid maternity leave beyond which the gains in health outcomes of children are minimal. the findings of this study suggest that governments should also provide businesses the time to adjust and comply with the regulation. according to a survey conducted by the bipartisan policy center of businesses with 50 or fewer employees, about half of small business executives stated that it is somewhat or very difficult for their business when employees take leave. they stated that they need some support in providing paid family leave (shaw, 2019) . at the same time, governments should also ensure that there is not a lack of compliance of the regulation. according to armenia, gerstel, and wing (2013), it was estimated that at least 54.3 percent of the firms with 50 or more employees in the u.s. private sector are compliant with the fmla. thus, it is likely that more people utilize leave after a couple of years it goes into effect and the government strictly enforces the regulation. the delay may also be attributed to the country culture. there may be a social stigma attached to taking time off, particularly for men. as studies have found, the take-up rate is not very high among fathers (bartel et al., 2018) . in iceland, portugal, and sweden, the takeup rate is approximately 45 percent (oecd, 2019). in some countries, such as denmark and finland, the take-up rate is as low as about 10 percent (oecd, 2019). this is despite many advocating that paid family leave is not only beneficial for the health of children, it is also beneficial for the health of parents. when paid family leave is not available, it can contribute to the social and economic costs to the family as well as the society. when mothers return to work less than 12 weeks after giving birth, they are more likely to report stress and depression (dagher, mcgovern, and dowd, 2014) . they experience difficulty in handling the demands of work and family life, and, as a result, many choose to leave their job. this can have a negative impact on the productivity and turnover of the firm (gault et al., 2014) . when employers have to replace employees, it can be costly and time consuming. it is estimated that the average cost to replace an employee is approximately 21 percent of that employee's salary (boushey, o'leary, and glynn, 2013) . additionally, when parents do not have access to paid family leave, it may exacerbate their physical health conditions (jou et al., 2018; peipins, berkowitz, and white, 2012) . furthermore, co-workers are exposed to infectious diseases, causing them to take time off from work. similarly, sick children may expose other children to infectious diseases at schools and day care centers. employees with paid leave are more likely to receive preventive care, which can help reduce health care costs in the long term (bartick et al., 2017) . according to bartick et al. (2017) , the united states could be saving $17.2 billions in costs associated with medical expenditures and premature births if mothers were able to exclusively breastfeed for six months. in general, when countries invest more in the health of individuals, it leads to a healthier workforce, which improves the productivity (martin, grant, and d'agostino, 2012) . this study has some limitations. the data does not have information on the number or rate of people that utilize paid maternity leave and paid paternity leave in each country, rather it provides information on the availability of such leave. in other words, it estimates the intent-totreat effect. it is possible that the treatment-on-the-treated effect is stronger compared to the intentto-treat effect. this is important, considering access to leave does not necessarily equate to the uptake of leave. for example, in sweden, about 80 percent of fathers and almost all mothers use parental leave (marynissen et al., 2019) in contrast, in belgium, marynissen et al. (2019) found that only 5.8 percent of belgian fathers used parental leave in the first two years following the birth of their first child between 2001 and 2010. the findings of this study are beneficial in understanding the lagged impact of paid family leave, including maternity and paternity leave, on the health outcomes of children. compared to other studies, the timing of the effect of such leave is of particular significance. this study shows that it takes at least two years for paid family leave to have an effect on the health outcomes of children, indicating that there is a delayed impact after the enactment of paid family leave legislation. the impact of paid family leave on the outcome of the health of children in 35 oecd countries has been examined. the study includes both maternity leave, which has been in place for many years, and paternity leave, which is a relatively new extension of paid family leave. the health outcomes of children included in the study are neonatal mortality rates, infant mortality rates, under-five mortality rates, and the measles immunization rates. data during the time period of 1990 to 2016 was analyzed using a two-way fixed effects model. a significant decrease in the infant, neonatal, and under-five mortality rates was found. paid maternity leave was associated with a 5.2 percent decrease in the neonatal mortality rate, a 2.4 percent decrease in the infant mortality rate, and 1.9 percent decrease in the under-five mortality rate after two years of its adoption. however, the impact of paid paternity leave was not as visible as that of paid maternity leave, which may be attributed to its recency and amount that is much smaller than that of the more common maternity leave. this study provides justification for a national paid family leave law in the united states, at the federal level, particularly in the light of the on-going coronavirus (covid-19) pandemic. in december 2019, federal employee paid leave act was enacted, which covers federal employees. in march 2020, families first coronavirus response act was enacted, which covers those affected by covid-19. these laws cover certain groups and certain situations, and now the need is for a law that can serve the entire workforce. the author(s) does/do not have any conflict of interest related to the submission and publication of this article. this research was not funded by any external funding agency. appendix a. paid maternity leave -common year trend. (1) does paternity leave affect mothers' sickness absence? working papers in economics 06/09 paid family leave, fathers' leave-taking, and leave-sharing in dual-earner households suboptimal breastfeeding in the united states: maternal and pediatric health outcomes and costs the effects of paid family leave in california on labor market outcomes maternity leave and the employment of new mothers in the united states maternity leave, early maternal employment and child health and development in the us the effect of maternal employment and child care on children's cognitive development our working nation in 2013: an updated national agenda for work and family policies family leave after childbirth and the mental health of new mothers breastfeeding and maternal and infant health outcomes in developed countries access to and use of paid sick leave among low-income families with children causal effects of paternity leave on children and parents maternal leave policies and vaccination coverage: a global analysis maternity leave duration and postpartum mental and physical health: implications for leave policies international perspectives on work-family policies: lessons from the world's most competitive economies paid parental leave in the united states: what the data tell us about access, usage, and economic and health benefits. institute for women's policy research does particulate air pollution contribute to infant death? a systematic review difference-in-differences with variation in treatment timing child care and parental leave in the nordic countries: a model to aspire to? the impact of taking parental leave on fathers' participation in childcare and relationships with children: lessons from sweden the relationship between postpartum depression and breastfeeding paid parental leave and family wellbeing in the sustainable development era the benefits of paid maternity leave for mothers' post-partum health and wellbeing: evidence from an australian evaluation paid maternity leave in the united states: associations with maternal and infant health the rewards outweigh the efforts: breastfeeding outcomes for mothers of preterm infants a defense of paid family leave child health in elementary school following california's paid family leave program the effect of paid leave on maternal mental health fathers' use of paid parental leave global health funding and economic development tulasalud: an m-health system for maternal and infant mortality reduction in guatemala fathers' parental leave uptake in belgium and sweden: self-evident or subject to employment characteristics? sudden infant death syndrome in child care settings stable prevalence but changing risk factors for sudden infant death syndrome in child care settings in 2001 national prevention strategy. national prevention council, u.s. department of health and human services infant development in father-absent families the lack of paid sick leave as a barrier to cancer screening and medical care-seeking: results from the national health interview survey when dad can stay home: fathers' workplace flexibility and maternal health. discussion paper no. 12386 from neurons to neighborhoods: the science of early childhood development the effects of california's paid family leave program on mothers' leave-taking and subsequent labor market outcomes parental leave and child health paid family leave: how much time is enough awareness and use of california's paid family leave insurance among parents of chronically ill children key takeaways from bpc's survey of small business views on paid family leave one unassailable reason we need paid family leave: it saves babies' lives. slate magazine what are we weighting for does paid family leave improve household economic security following a birth? evidence from california some simple economics of mandated benefits female labour force participation, fertility and public policy in sweden parental leave and child health across oecd countries effects of parental leave and work hours on fathers' involvement with their babies: evidence from the millennium cohort study vii. infant sleep development from 3 to 6 months postpartum: links with maternal sleep and paternal involvement demographic consequences of maternal-leave programs in industrial countries: evidence from fixed-effects models newborns: reducing mortality. world health organization note: estonia temporarily suspended paid paternity leave from adoption of paid paternity leave key: cord-336562-5qmzne98 authors: auten, richard; ren, clement; yilmaz, ozge; noah, terry l. title: pediatric pulmonology year in review 2016: part 2 date: 2017-04-25 journal: pediatr pulmonol doi: 10.1002/ppul.23719 sha: doc_id: 336562 cord_uid: 5qmzne98 pediatric pulmonology continues to publish research and clinical topics related to the entire range of children's respiratory disorders. as we have done annually in recent years, we here summarize some of the past year's publications in our major topic areas, as well as selected literature in these areas from other core journals relevant to our discipline. this review (part 2) covers selected articles on neonatology, asthma, physiology and lung function testing, and infectious diseases. pediatric pulmonology continues to publish research and clinical topics related to the entire range of children's respiratory disorders. as we have done annually in recent years, we here summarize some of the past year's publications in our major topic areas, as well as selected literature in these areas from other core journals relevant to our discipline. this review (part 2) covers selected articles on neonatology, asthma, physiology and lung function testing, and infectious diseases. since mechanical ventilation inevitably exposes the developing respiratory system to unpredictable mechanical strains and stresses, clinicians have long sought safer and less invasive approaches to respiratory support, and better tools with which to monitor respiratory function during intensive care. there has been a trend to substitute high flow nasal cannulae which are able to deliver positive pressure, but this pressure is typically not regulated or monitored. in an effort to define the limitations of this approach, gerdes et al 1 identified factors affecting delivered mean airway pressure during nasal cpap delivery with the ram™ cannula, an increasingly widely used device favored by some because of its apparent toleration compared with other devices that require more complex fixation systems. using a polymer model of the upper airway and lip, ram cannulae, and corresponding standard ncpap prongs were affixed and delivered pressures measured using a pneumotachograph. as expected, complete occlusion of the nasal passage with either the ram cannula or "standard" nasal prongs delivered comparable pressures that approximated the set pressure, providing that the ram cannula was fully inserted. however, the authors point out a critical limitation to using the ram cannula, namely that nasal expiratory resistance will be quite high if the nares are occluded. for babies that must be managed with mechanical ventilation, efforts are underway to improve both delivery and accurate monitoring of therapy. the safe use of high-frequency ventilation in newborns limits the ability of the clinician to assess ventilation in realtime. minute ventilation and tidal volume cannot be measured, and capnography has been limited to transcutaneous co 2 measurements, which have been problematic in very premature newborns that may not tolerate the skin temperatures that until very recently have been required for accurate measurement. kugelman et al 2 evaluated capnography using a 2-lumen endotracheal tube and microstream capnography correlated with arterial blood gas measurements obtained from an indwelling line. although accuracy was not acceptable, capnography was able to predict very low p a co 2 < 30 torr and very high p a co 2 above 60 torr. respiratory volumes can also be assessed non-invasively using electrical impedance. van findings with their earlier reports of increased methacholine induced respiratory system resistance. 11 the evidence for human susceptibility to neonatal and early childhood pulmonary insults that affect lung function in adulthood continues to mount, as reviewed by goldizen et al. 12 impairments of small airway function were reported by verheggen et al, 13 reporting a case-control comparison of pulmonary function testing in 4-to 8-year old subjects born before 32 weeks with or without bpd. they used forced oscillometry or spirometry. they reported that pulmonary reactance, an oscillometric method used to assess small airway function, was worse in bpd subjects. although this finding is not surprising, it should be tempered by the relatively low recruitment rate they experienced from their original qualifying cohort. factors associated with bpd risk like duration of oxygen exposure and male sex were also associated with increased pulmonary reactance. the genetic basis of asthma has been investigated in many studies recently. hua et al 14 investigated the gene-gene interactions among variants of the il13, il4, il4ra, fcer1b, and adrb2 genes, which have been associated with asthma in children, and demonstrated that single nucleotide polymorphisms il13 rs20541, il4 rs2243250, adrb2 rs1042713n, and fcer1b rs569108 were associated with asthma. moreover, risk of asthma was increased more than 10 times in carriers of all four risk homozygotes (il13 rs20541 gg, il4 rs2243250 tt, adrb2 rs1042713 aa, and fcer1b rs569108 gg). these results add to the evidence for a role for epigenetic mechanisms in the relationship between environmental smoke exposure during pregnancy and pediatric asthma. gene-environment interaction is also important in the development of pediatric asthma. research done in rural and urban parts of china on 854 children revealed that physician diagnosed asthma was significantly lower in children living in rural areas. personal and family history of atopy, high consumption of milk products, and hospitalization younger than three years of age were significantly associated with asthma. similarly, being a member of a crop-farming family and dust endoxtoxin levels were negatively associated with asthma in the child. 16 lautenbacher et al 17 investigated the effects of vitamin d on pulmonary function and compared obese and non-obese asthmatic children. although the frequency of vitamin d deficiency was not different between groups, fev1 and frc were significantly worse in vitamin d deficient obese children than in normal-weight children. moreover, tnf and il-8 were higher in obese asthmatics, while the th2 cytokine il13 was higher in normal-weight asthmatics. however, these inflammatory measures were not related to the association of vitamin d deficiency with poor lung function; thus implying an independent effect of vitamin d deficiency. coexistence of obesity and poor asthma control is well known, but body mass index (bmi) may not reflect regional differences in adiposity. as part of the asthmap-2 project that is an observational study of pediatric asthma, association of neck circumference and asthma control was assessed. 18 it was demonstrated that, in boys, neck circumference combined with bmi explained the variability of asthma control test better than bmi alone. air pollution has a significant influence on respiratory health. rice et al 19 although inflammatory markers did not correlate with ahr, the degree of ahr was less in those study subjects who were receiving hyroxyurea. their results demonstrate that there is a high prevalence of ahr in scd patients and hydroxyurea may be helpful in decreasing ahr in scd. lunt et al 38 impulse oscillometry (ios) uses the forced oscillation technique to assess airway function and does not require the maximal forced expiratory maneuver needed for spirometry. 39 ios measures total respiratory impedance (z) which is a complex number that incorporates both the in and out phase elements of resistance; the former is resistance (r), and the latter is termed the reactance (x). r reflects the airway resistive properties of the respiratory system, while x reflects the visco-elastic and inertive elements of the respiratory system. potential limitations of this method include a limit on the size of the patients studied due to limitations on the volume of the washout collection bag and an inability of detect leak since there is no pnt. this system will require further study in human subjects before determining its utility in clinical research and patient care. tidal breathing analysis is a method to assess respiratory function that does not require sedation or manipulation of the infant's respiratory system. 45 respiratory inductance plethysmography has been used to obtain tidal breathing data, but it only measures chest and abdominal excursion at two points, which does not accurately reflect the true mechanics of the respiratory system. reinaux et al 46 used opto-electronic plethysmography (oep) to measure motion at 52 sites placed in the thorax and abdomen of healthy infants and compared the results obtained using this system to those obtained using a mask with pnt. they found that measurement of tidal volume using oep was in good agreement with that obtained using a pnt with a mean difference of only 0.02 ml. the ability to obtain tidal breathing measurements may lead to new insights into changes in chest and abdominal motion in pediatric respiratory disease. bronchopulmonary dysplasia (bpd) is the most common respiratory complication of preterm birth. despite advances in neonatal medicine, bpd still occurs in 30-50% of infants born before a gestational age (ga) of 29 weeks. 47 acute viral bronchiolitis, due to rsv and other pathogens, continues to have a major impact worldwide on childhood mortality and hospital admissions, 51 is associated with subsequent asthma and allergy risk, 52 and could be increasing in incidence. 53 cangiano et al 54 noted a higher incidence of acute bronchiolitis every 4 years among previously health term infants, largely due to rsv; rhinovirus was a less common cause and had less tendency to occur in seasonal clusters than rsv. while a commonly used standard definition for bronchiolitis is initial episode of wheezing in a child <12 months old, variability in how clinicians actually define bronchiolitis was highlighted in a report from fernandes et al. 55 beamer et al 56 treatment for acute bronchiolitis remains largely supportive and progress has been made in reducing widespread use of corticosteroids and bronchodilators, which have previously been shown to be ineffective. 57 flores et al 58 conducted a randomized clinical trial comparing 3% hypertonic saline to normal saline in previously healthy infants hospitalized with mild-to-moderate acute viral bronchiolitis. the median length of hospital stay, severity score, and need for supplemental oxygen did not differ significantly between groups. patients receiving hypertonic saline had significantly more cough (46% vs 20%, p = 0.025). thus, the study does not support the use of nebulized hypertonic saline over normal saline in therapy of hospitalized children with mild-to-moderate acute viral bronchiolitis. in another study with practical implications, heikkila et al 59 factors influencing delivered mean airway pressure during nasal cpap with the ram cannula diagnostic accuracy of capnography during high-frequency ventilation in neonatal intensive care units the effect of prolonged lateral positioning during routine care on regional lung volume changes in preterm infants role of electrical impedance tomography in clinical practice in pediatric respiratory medicine fgr in the setting of preterm sterile intra-uterine milieu is associated with a decrease in rds association of bnp, ntprobnp, and early postnatal 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study infection and inflammation in induced sputum from preschool children with chronic airways diseases association between exhaled inflammatory markers and asthma control in children concordance between bronchial hyperresponsiveness, fractional exhaled nitric oxide, and asthma control in children patterns of growth and decline in lung function in persistent childhood asthma differences in pulmonary functions in various racial groups multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations pulmonary diffusing capacity in healthy african-american and caucasian children spirometric reference values for hopi native american children ages 4-13 years pulmonary complications of sickle cell disease airway hyperreactivity is frequent in non-asthmatic children with sickle cell disease longitudinal assessment of lung function in children with sickle cell disease clinical application of forced oscillation respiratory impedance in patients 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diseases and injuries among children and adolescents between 1990 and 2013: findings from the global burden of disease viral bronchiolitis in children predictors of asthma following severe respiratory syncytial virus (rsv) bronchiolitis in early childhood admission to hospital for bronchiolitis in england: trends over five decades, geographical variation and association with perinatal characteristics and subsequent asthma bronchiolitis: analysis of 10 consecutive epidemic seasons acute viral bronchiolitis: physician perspectives on definition and clinically important outcomes spatial clusters of child lower respiratory illnesses associated with community-level risk factors value in inpatient pediatrics network quality collaborative for improving hospital compliance with aap bronchiolitis guideline (bqip). a multicenter collaborative to reduce unnecessary care in inpatient bronchiolitis a randomized trial of nebulized 3% hypertonic saline with salbutamol in the treatment of acute bronchiolitis in hospitalized infants high-flow oxygen therapy is more costeffective for bronchiolitis than standard treatment-a decision-tree analysis respiratory viral detection in children and adults: comparing asymptomatic controls and patients with community-acquired pneumonia beta-lactam versus betalactam/macrolide therapy in pediatric outpatient pneumonia paradoxical tuberculosisassociated immune reconstitution inflammatory syndrome in children protracted bacterial bronchitis: the last decade and the road ahead pediatric bronchiectasis: no longer an orphan disease coccidioidomycosis in infants: a retrospective case series interaction between 25-hydroxyvitamin d and variants at 17q12-21 on respiratory infections how to cite this article pediatric pulmonology year in review 2016: part 2 key: cord-324752-t50bg7pq authors: lavery, michael joseph; bouvier, charles alexis; thompson, ben title: cutaneous manifestations of covid-19 in children (and adults): a virus that does not discriminate date: 2020-11-01 journal: clin dermatol doi: 10.1016/j.clindermatol.2020.10.020 sha: doc_id: 324752 cord_uid: t50bg7pq covid-19 is caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2), a beta coronavirus with a characteristic s-glycoprotein ‘spike’ on the cell surface.(1) initial reports did not include cutaneous manifestations as a feature of covid-19; however, there is a growing repertoire of reports demonstrating an array of dermatologic manifestations on the skin in children and adults. dermatologic afflictions have been summarized into different categories several times, with the most recent analysis identifying six clinical patterns: urticaria, maculopapular-morbilliform eruption, papulovesicular exanthem, chilblain-like acral pattern, livedo reticularis-livedo racemose pattern, and purpuric ‘vasculitic’ pattern.(2) in children, the dermatologic features appear to occur before or concomitantly with other covid-19 manifestations. dermatologists play a key role in diagnosing patients with covid-19 who may present for the first time unwittingly exhibiting early signs of covid-19. we have reviewed the current evidence on the dermatologic impact of covid-19 in both the adult and pediatric population. manifestations. dermatologists play a key role in diagnosing patients with covid-19 who may present for the first time unwittingly exhibiting early signs of covid-19. we have reviewed the current evidence on the dermatologic impact of covid-19 in both the adult and pediatric population. the sars-cov-2 (severe acute respiratory syndrome coronavirus 2) virus, a beta-coronavirus of the coronaviridae family, is considered to have originated from bats at a food market in wuhan, china; however, its main transmission since has been human to human. 3, 4 transmission is via respiratory droplets (and possibly aerosols), although there is recent evidence of fecal-oral transmission in children. 5, 6 sars-cov-2 enters cells by attaching to angiotensin-converting enzyme-2 (ace-2) receptors. 4, 7, 8 this receptor is found on numerous mucosal sites, 9, 10 including the endothelium of dermal blood vessels and epithelial cells in eccrine glands, which may account for the cutaneous manifestations of covid-19. 11, 12 current evidence suggests that children are less likely to succumb to infection, accounting for 1-8% of all covid-19 cases. 9, 13, 14 there is, however, an increased morbidity in infants and young children, when compared to older children, as well as in children with a complex medical background. 13 while neonatal cases have been reported, there is no sign of breast milk transmission, 4 but there are reports of possible vertical transmission. 13 there is also an increased risk amongst children of the black, asian, and minority ethnic (bame) community in the united kingdom of both covid-19 and the multisystem inflammatory syndrome. [15] [16] [17] the latter has been called the pediatric inflammatory multisystem syndrome temporally associated with covid-19 (pims-ts), 18 or multisystem inflammatory syndrome in children (mis-c). 9 initial reports did not include cutaneous manifestations as a feature of covid-19. 19 subsequent publications revealed that an eruption was present, albeit in very small numbers. a retrospective review of over 1000 patients throughout china revealed that two patients had developed an eruption (0.18%). 20 a growing body of evidence has since emerged showing an array of cutaneous afflictions in adults. (table 1) in thailand, a patient presenting with a petechial eruption and thrombocytopenia was mistakenly diagnosed as having dengue fever, with a subsequent viral swab detecting sars-cov-2. 21 a later report revealed a purpuric eruption in the axillae and flank bilaterally in a patient with a positive polymerase chain reaction (pcr) to sars-cov-2. while the patient had been given hydroxychloroquine and lopinavir/ritonavir, a viral exanthem was felt more likely, given the rarity of drug eruptions to these medications. 22 the first report to demonstrate cutaneous manifestations on a larger scale was in a cohort of patients in the lombardy region of northern italy. skin afflictions were noted in 20% of inpatients and described as an erythematous eruption, urticaria or chickenpox-like vesicles, all predominantly affecting the trunk. 23 the spanish academy of dermatology and venereology published a review of 375 patients with suspected or confirmed sars-cov-2 who developed cutaneous eruptions. these cutaneous manifestations were divided into five presenting categories: pseudo-chilblain, other vesicular eruptions, urticarial lesions, maculopapular eruptions, and livedo or necrosis. further analysis noted 'other vesicular eruptions' as an early cutaneous sign and 'pseudo-chilblains' as a late sign although the latter was associated with decreased disease severity. livedo or necrosis was associated with increased disease severity. 24 recently, nail changes have been identified in patients with covid-19 manifesting as a convex half-moon shaped erythematous band at the distal margin of the lunula and coined 'the red half-moon nail sign.' 25, 26 in the united kingdom (uk), researchers analyzed data from users of the covid symptom study application and noted 8.8% of 336,847 users, with a positive sars-cov-2 viral swab, reported a skin eruption. similar results were noted in patients with no viral swab but one or more uk government listed covid-19 findings. (8.2%) 27 a subsequent online survey, by the same researchers, of 11,546 sars-cov2 positive participants who reported having an eruption, revealed that 17% had a skin eruption as the first clinical feature, with 21% of respondents who had such an eruption were without other symptoms. the cutaneous signs were divided into three main categories: papular (erythemato-papular or erythemato-vesicular), urticaria and acral lesions (chilblains). 27 some authors have speculated that the pseudo-chilblains may be attributable to novel lifestyle changes due to covid-19, such as decreased activity or walking barefoot in an unheated environment. 28, 29 despite these ideas, the constellation of papers reporting cutaneous manifestations of covid-19 has led to calls of a skin eruption to be included in the list of clinical features suspicious of covid-19 infection. 27 for reasons currently unknown, sars-cov-2 does not have as big an impact on children when compared to adults. this appears counter-intuitive, given the increased prevalence of other viral diseases in this patient population. children with covid-19 present in a similar fashion to adults, with pyrexia and cough the most common presenting features. 30 gastrointestinal symptoms and pharyngeal erythema may also be present. cutaneous manifestations are similar to what is witnessed with other viral exanthems including macular, papular and vesicular eruptions. a varicella-like eruption has been reported in an 8-year old girl who presented to the clinic with a papulovesicular eruption on the trunk sparing other sites, along with a 6-day history of a cough. pcr testing was positive. inflammatory markers were normal with only a mild thrombocytopenia noted on a routine blood panel. 31 acral lesions have also been described in children. in the uk, a teenage boy with a positive pcr swab, presented with a skin eruption accompanied by headache and myalgia with no cough or dyspnea. while the parents reported a subjective fever, vital signs were normal. on examination there were tender plantar papules, macules and petechiae on the legs and an annular patch developing a few days later. papules were also noted in the axillae. 32 an erythema multiforme-like eruption has also been reported in a 12-month old infant in iran who presented with targetoid lesions on the trunk and extremities, along with acral erythema and pyrexia. sars-cov-2 pcr was positive. subsequent clinical deterioration led to admission to the intensive care unit and improvement five days later. 33 a case series from spain has revealed four pediatric patients (11-17 years old) presenting with an erythema multiforme-like eruption on the arms, legs, and ears, along with evidence of chilblain. mild respiratory or gastrointestinal symptoms were also reported with one patient otherwise asymptomatic. all another reported manifestation of covid-19 in children is the development of the pediatric inflammatory multisystem syndrome temporally associated with covid-19 (pims-ts), also termed multisystem inflammatory syndrome in children (mis-c). this syndrome has similarities to kawasaki disease. kawasaki disease (kd), first described by tomisaku kawasaki (1925 kawasaki ( -2020 in 1967, 36 is an acute vasculitis with a global incidence ranging between 8-67 cases per 100,000. 37 kd commonly affects children under 5-years-old with a 1.5:1 male to female ratio. 38 the underlying pathophysiology is complex but postulated to be secondary to an overactive innate and adaptive immune system in genetically predisposed individuals. 9, 16 the diagnosis of kd requires the presence of fever for ≥5 days, and ≥4 'other features' ( table 2 ). the diagnosis of kd may also be confirmed with only 3 'other features' when there is evidence of cardiac involvement (e.g. coronary aneurysm, myo/pericarditis, pericardial effusion). 39 dermatologic features are common in kd and represent the majority of these 'other features. manifestations include acral erythema, edema and desquamation, along with oral mucosal pathology that includes a 'strawberry tongue'. a diffuse polymorphic eruption may be noted including macules, papules, micro pustules and an erythema-multiforme like eruption, distributed on the trunk, groin and perineal sites. 40 a pustular eruption in febrile children can be mistaken for other pathologies, such as acute generalized exanthematous pustulosis or pustular psoriasis. 41 the eruption appears early in the illness and may last days to weeks. nail changes, reported in patients with covid-19, include transverse erythematous bands and beau's lines. 42 in addition, transverse red bands have been reported in kd occurring on the mid-distal portion of the nail plate during the active inflammatory phase of the disease. 42 while the pathogenesis of these red lines is unclear, nail bed hyperemia or localized vasculitis has been hypothesized. it is plausible that the transverse erythronychia at the mid-distal nail plate may be observed in children presenting with kd in the context of covid-19. the pathophysiologic process may be similar to the observed half-moon sign, and it is plausible that these two nail findings could occur in tandem. while the features of mis-c are similar to those observed in kd, the two conditions are considered two distinct entities, with less than 25% of patients with mis-c fulfilling the diagnostic criteria for kd. 43 although cutaneous manifestations are an important diagnostic criteria for kd, just over half of patients report an eruption as part of their clinical presentation in mis-c. 43 multi-organ involvement can occur in pediatric patients with covid-19 ( table 3 ). the pulmonary system is the most commonly affected organ in covid-19. children may suffer from pneumonia, which can progress to acute respiratory distress syndrome (ards). 7 other organ systems involved include cardiac, renal, hematologic, neurologic, ophthalmologic, and the gastrointestinal tract. case definition includes all of the above organ involvements. 45 despite these disparities, the who, cdc, and rcpch case definition for mis-c all include children with features suggestive of kawasaki disease, with which it bears similarities. patients presenting with symptoms of covid-19 undergo investigation with a routine blood panel along with a nasopharyngeal and oropharyngeal swab for pcr testing to sars-cov-2. serum antibody testing to sars-cov-2 immunoglobulin g (igg) is performed several weeks after symptom presentation. false negatives have been reported due to low-test sensitivity, and novel investigational methods have been sought. 46 this was exemplified in an 81-year-old woman in switzerland who presented with fever and an acral eruption, along with a generalized macular and vasculitic-like eruption. while covid-19 was clinically suspected, the sars-cov-2 pcr swab was negative. a skin biopsy was performed revealing a lichenoid interface dermatitis along with a scant perivascular lymphohistiocytic infiltrate. pcr testing of the skin tissue detected sars-cov-2, albeit at low levels. a serology antibody test, performed six weeks later, was negative. 47 the histopathologic, immunohistochemical, (ihc) and electron microscopic analysis have been performed in a cohort of seven pediatric patients presenting with features of chilblain and covid-19 symptoms and having negative sars-cov-2 pcr nasopharyngeal and oropharyngeal swabs. 48 the covid-19 pandemic has placed unprecedented burdens on the economy and healthcare services. it has also had a detrimental effect increasing morbidity and mortality through systemic organ involvement. while the cutaneous manifestations were not initially reported, a dearth of data has shown that the largest organ in the body may yield clues for the diagnosis as world health organization. naming the coronavirus disease (covid-19) and the virus that causes it -2019)-andthe-virus-that-causes-it cutaneous manifestations in patients with covid-19: a preliminary review of an emerging issue clinical features of patients infected with 2019 novel coronavirus in wuhan characterisation of covid-19 pandemic in paediatric age group: a systematic review and meta-analysis infectious sars-cov-2 in feces of patient with severe covid-19 pathogenesis of covid-19 from the perspective of the damage-response framework covid-19 -clinical management of children admitted to hospital with suspected covid-19. royal college of paediatrics and child health web site neurologic and radiographic findings associated with covid-19 infection in children covid-19 and multisystem inflammatory syndrome in children and adolescents pathophysiology of covid-19: why children fare better than adults? tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis exploring the pathogenesis of severe acute respiratory syndrome (sars): the tissue distribution of the coronavirus (sars-cov) and its putative receptor, angiotensisn-converting enzyme 2 (ace2) an evidence summary of paediatric covid-19 literature. don't forget the bubbles covid-19 and kawasaki disease: novel virus and novel case hyperinflammatory shock in children during covid-19 pandemic sars-cov-2-related inflammatory multisystem syndrome in children: different or shared etiology and pathophysiology as kawasaki disease? autoimmune and inflammatory diseases following covid-19 guidance -paediatric multisystem inflammatory syndrome temporally associated with covid-19 (pims). royal college of paediatrics and child health web site clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of coronavirus disease 2019 in china covid-19 can present with a rash and be mistaken for dengue reply to "covid-19 can present with a rash and be mistaken for dengue": petechial rash in a patient with covid-19 infection cutaneous manifestations in covid-19: a first perspective classification of the cutaneous manifestations of covid-19: a rapid prospective nationwide consensus study in spain with 375 cases the red half-moon nail sign: a novel manifestation of coronavirus infection covid-19 and nail manifestation: be on the lookout for the red half-moon nail sign diagnostic value of skin manifestation of sars-cov-2 infection. medrxiv evaluation of chilblains as a manifestation of the covid-19 pandemic assessment of acute acral lesions in a case series of children and adolescents during the covid-19 pandemic sars-cov-2 infection in children varicella-like exanthem associated with covid-19 in an 8-year-old girl: a diagnostic clue? rash as a presenting complaint in a child with covid-19 fever with rash is one of the first presentations of covid-19 in children: a case report erythema multiforme-like lesions in children and covid-19 urticarial eruption in covid-19 infection acute febrile mucocutaneous syndrome with lymphoid involvement with specific desquamation of the fingers and toes in children echocardiography in pediatric and congenital heart disease: from fetus to adult diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association pustular eruption in kawasaki disease nail-bed lines in kawasaki disease clinical characteristics of 58 children with a pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 multisystem inflammatory syndrome in children and adolescents temporally related to covid-19. world health organization web site multisystem inflammatory syndrome in children (mis-c) associated with coronavirus disease 2019 (covid-19) screening and severity of coronavirus disease 2019 (covid-19) in children in madrid sars-cov-2 pcr testing of skin for covid-19 diagnostics: a case report sars-cov-2 endothelial infection causes covid-19 chilblains: histopathological, immunohistochemical and ultrastructural study of seven paediatric cases covid-19 pandemic and the skin: what should dermatologists know? table 1: cutaneous manifestations of coronavirus disease 2019 in both the adult and pediatric population key: cord-355047-ri43d5wk authors: sarangi, bhakti; reddy, venkat sandeep; oswal, jitendra s.; malshe, nandini; patil, ajinkya; chakraborty, manojit; lalwani, sanjay title: epidemiological and clinical characteristics of covid-19 in indian children in the initial phase of the pandemic date: 2020-07-28 journal: indian pediatr doi: 10.1007/s13312-020-1994-4 sha: doc_id: 355047 cord_uid: ri43d5wk objective: to assess the epidemiological and clinical characteristics of pediatric inpatients with covid-19, early in the pandemic. methods: clinical and laboratory profile and outcomes were studied for children (aged 1 month — 18 years) presenting between 1 april, 2020 and 20 may, 2020 with positive nasopharyngeal swab for sars-cov-2 by rt-pcr. results: 50 children (56% male) with median (iqr) age of 6 (2–12) years were included. majority (56%) were from families belonging to kuppuswamy upper lower socioeconomic class. 45 (90%) had positive household contact, and 33 (66%) had overcrowding at home. 29 (58%) children were asymptomatic while 20 (40%) had mild symptoms. fever, cough, and sore throat were the most common symptoms. high c-reactive protein levels were seen in 15 (30%) children. there was no mortality. conclusion: the disease burden appears high in lower socio-economic group with majority having a positive household contact. milder disease pattern in the pediatric age group is reiterated. c oronavirus disease 2019 (covid-19), caused by severe acute respiratory syndrome coronavirus 2 (sars-cov-2), has been in circulation for more than six months now [1] . though there have been a growing number of studies focused on covid-19, limited data is available on epidemiological features, clinical manifestations, and transmission patterns in children with covid-19, more so from india. early observations in a pandemic are pivotal in improving the understanding of the physiological patterns and varied clinical profiles, so as to improve early recognition and appropriate management. we, therefore, describe the clinical and epidemiological features of pediatric patients seen at a single tertiary-care institution. this was a cross-sectional study conducted in a dedicated pediatric covid-19 center in pune, maharashtra between 1 april, 2020 and 20 may, 2020. prior approval was taken from the institutional ethics committee. all children between one month and 18 years of age who tested positive by the rt-pcr technique for nasopharyngeal swab were included in the study -these also included asymptomatic children as per the management guidelines in force. written informed consent was taken from the parents of all children and assent was taken from children who were greater than 9 years of age. detailed information including demographic data, travel and contact history, living conditions and overcrowding, symptoms, and presence of co-morbid conditions were taken. the children were examined and categorized as per degree of severity based on standard criteria [2] . baseline laboratory parameters (complete hemogram and c-reactive protein) were evaluated and repeated as required. chest radiograph was done in all symptomatic children. on chest x-ray each lung was divided into three zones. each zone was given a score of 1 if there was any opacity and 0 if there were none. total score of 3 was considered as 50% involvement [3] . all children admitted were managed as per the hospital protocol. the children were monitored daily for changes in disease severity. discharge from hospital was as per prescribed world health organization (who) guidelines which stated that asymptomatic children who tested negative for two nasopharyngeal swabs taken 24 hours apart after day 14 of illness were fit for discharge [4] . overcrowding was defined based on persons per room criteria [5] . statistical analyses: the data were analyzed using the statistical package for social sciences (spss) software version 25.0. spearman's rho correlation coefficient was used to determine the correlation with disease severity. a p value <0.05 was considered significant. published online: july 28, 2020; pii: s097475591600218 volume 57 __ october 15, 2020 sarangi, et al. a total of 178 children presented to us with suggestive features during the study duration, of which, 153 were negative and 25 were positive for sars-cov-2 by rt-pcr. another 25 children with a positive rt-pcr were referred from other hospitals. thus, a total of 50 children (56% males) with median (iqr) age of 6 (2-12) years were included. majority (82%) of the cases hailed from containment zones in pune. there was history of positive household contact in 45 (90%) children; with 42 having family members with mild illness and three with severe illness. travel history to affected area was documented in only one child ( table i) . more than half (58%) of the children were asymptomatic while 20 (40%) had mild symptoms. in symptomatic children, fever was the chief complaint in 17 (34%). none of the children had hypoxemia measured by pulse oximetry. only two children had co-morbidities; one child had history of simple febrile seizures, and another had underlying type i diabetes mellitus and had presented with diabetic ketoacidosis. immunization was complete in 32 (64%) of the children as per universal immunization program, and 49 (98%) children had a bcg scar. the mean (sd) leucocyte count was 8864 (3727.2) x10 9 /l (range, 3300-19300 x10 9 /l). leucopenia was seen in 3 (6%) children while leukocytosis was seen in 13 (26%) children. lymphopenia, eosinopenia and thrombocytopenia were not seen in any child. neutrophillymphocyte-ratio (nlr) (r=0.35, p=0.01) and lymphocytemonocyte-ratio (lmr) (r=-0.31, p=0.03) showed a significant correlation with the severity of the illness, while platelet-lymphocyte ratio (plr) (r=0.28, p=0.06) and crp (r=0.05, p=0.73) did not show any correlation with severity of the disease. chest radiograph was done in 20 (95.2%) of 21 symptomatic children. it was found to be normal in 18 (85.7%), while two showed bilateral lower zone haziness (<50%). the disease category for all patients remained same all through the hospital stay and no mortality was seen. majority of children in our study were detected in the identified containment zones, most of them reporting exposure to a positive household contact. majority of the children were either asymptomatic or had mild disease. most children were from lower socio-economic groups, a pattern also witnessed in other countries [6] . though the disease was seen in all age groups, children less than five years of age accounted for nearly half the cases. this can be attributed to the inability of this age group to comprehend and follow social distancing norms and their frequent close contact with parents. pediatric observational studies published early in the spread across china reported similar clinical findings with fever being the most common symptom followed by cough and sore throat [7] . a recent meta-analysis has also shown that most of the patients have mild to moderate disease (96%) with only 1% of all the symptomatic pediatric cases being critically sick [8] . the reported mortality rate of covid-19 in children is less than 1% [9] . various hypotheses have been proposed for the lesser disease severity in children [10] , though a definite answer is still awaited. malnutrition has been deemed a risk factor in adult covid-19 [11] . in children, malnutrition is known to foster infections; however, in this study, majority of the children were well-nourished as per weight-for-age criteria. the hematological profile of adults with covid-19 has demonstrated leucopenia with associated neutrophilia, lymphopenia; eosinopenia and thrombocytopenia. also, higher nlr, lmr and plr have been associated with severe disease and used for prognostication [12] . leucopenia, however, was seen in only 6% of our children and there was no evidence of lymphopenia, thrombocytopenia or eosinopenia. increasing nlr in our study showed a moderate positive correlation coefficient while lmr showed a negative correlation. high crp values have now become synonymous with severe covid-19 infection among adults as seen in majority of the studies [13] . the value of crp did not correlate with disease severity in our study. these discordant results may be due to the majority of our patients being asymptomatic or mildly symptomatic, or due to a different history of antigen exposure and immune response. repeat rt-pcr of nasopharyngeal swab was done on day 14 and 15 to check for infectivity status. all the children except one tested negative by rt-pcr on both the days. for the child who tested positive for one swab, a repeat swab was negative after three days, thus indicating that clearance of viral load may vary in different individuals. the degree of infectivity of these individuals after 14 days remains questionable as rt-pcr detects genetic fragments of the virus and cannot distinguish between dead or live virus [14] . in such scenarios, doing a viral culture may be the plausible method of detecting live virus and demonstrating continued infectivity. as performing a viral culture is difficult and requires advanced laboratory facilities, using genexpert platform with (cycle threshold) ct values ≥ 24 may also be beneficial for predicting lack of infectivity [15] . the findings of our study are limited by the size of the cohort and may require further validation by a study with a larger sample size. being a study in the initial phase of the pandemic with lockdown in place, it may not cover the entire spectrum of clinical presentations, severity and magnitude of sars-cov-2 in children from different geographical areas. we could also not collect data for calculation of body mass index (bmi) and z-scores. in conclusion, our study shows that there is a higher disease burden in lower-socioeconomic groups with majority of children having a positive household contact. a milder disease pattern is seen in majority of children with covid-19. pattern of early human-to-human transmission of wuhan guidelines on clinical management of covid-19. government of india ministry of health & family welfare directorate general of health services (emr division) clinical and chest radiography features determine patient outcomes in young and middle age adults with covid-19 global surveillance for human infection with novel coronavirus(2019-ncov) what this study adds? • majority of indian children with sars-cov-2 infection had a mild course of disease during the initial stages of the pandemic covid-19 in indian children www.who.int/publications-detail/global-surveillance-forhuman-infection-with-novel-coronavirus park's textbook of preventive and social medicine centers for disease control and prevention clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study clinical features and outcome of sars-cov-2 infection in children: a systematic review and meta-analysis covid-19: data summary -nyc health sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor prevalence of malnutrition and analysis of related factors in elderly patients with covid-19 in wuhan, china neutrophil-to-lymphocyte ratio and lymphocyte-to-c-reactive protein ratio in patients with severe coronavirus disease 2019 (covid-19): a metaanalysis c-reactive protein levels in the early stage of covid-19 potentials and limitations of molecular diagnostic methods in food safety predicting infectious sars-cov-2 from diagnostic samples key: cord-261938-ls363vud authors: khan, farah; eskander, noha; limbana, therese; salman, zainab; siddiqui, parveez a; hussaini, syed title: refugee and migrant children’s mental healthcare: serving the voiceless, invisible, and the vulnerable global citizens date: 2020-08-22 journal: cureus doi: 10.7759/cureus.9944 sha: doc_id: 261938 cord_uid: ls363vud millions of children are on the run worldwide, with many unaccompanied children and adolescents undertaking risky journeys to flee war, adverse circumstances, and political persecution. the grueling journey and multiple stressors faced by the refugee children, both accompanied and unaccompanied during the pre-migration, migration, and in the country of destination, increase their risk for psychiatric disorders and other medical conditions. unaccompanied refugee migrant children have higher prevalence of mental health disorders than accompanied refugee peers. long after reaching the host country, the refugee, migrant, and asylum-seeking juveniles continue to face adversities in the form of acculturation. in assessing medical fitness and healthcare mediations for refugees and migrant children, special consideration should be given to certain areas such as their distinct history, whether they are with their family or separated or unaccompanied, and whether they have been peddled or have been left behind. an alarming number of children travel with family or alone without proper care to flee organized violence, war, and persecution in their native country. some cross their national borders to become refugees and seek asylum in other countries, a legal process recognized by the united nations. without a family or an adult, these children are often at risk of being exploited and abused. most of the refugee children live in nearby countries close to their own native place of origin that happen to be low-or middle-income countries [1]. in 2016, in italy about 92% of children arriving by sea were separated and unaccompanied [2] . in 2017, the high-income countries resettled 102,800 refugees [3] . in 2018, juveniles under 18 years of age incorporated about half of the refugee population [4] . in 2018, uganda recorded 41,200 child refugees, the largest number of unaccompanied and separated child refugees with the overwhelming majority aged under 15 and a couple thousand aged under 5. from 2012-2018, turkey has been hosting 3.7 million refugees, the largest refugee population [4] . in 2019, the most common country of origin among child asylum seekers happens to be syrian arab republic. in 2019, germany registered 35% of all child asylum applications lodged in europe (71,420 children), while the highest number of first-time applicants with regard to its population was greece [5] . the grueling journey faced by the refugee children, both accompanied and unaccompanied during the pre-migration, migration, and in the country of destination, is associated with multiple stressors resulting in elevated risks for psychiatric disorders and other medical conditions [6] . the clinicians should be aware that exposure to war, a long arduous journey with minimum or no care, and ongoing stressors that refugee kids have experienced are associated with physical, developmental, and mental health problems. this migration is in itself dangerous, and apart from mental and other health costs to it there is also an increased risk of disabilities, and vulnerabilities to acute and chronic ailments. this article discusses some of the commonly seen mental health conditions and other medical conditions in refugee and migrant children from the reviewed articles. it also provides an insight into the refugee mental health struggles during the coronavirus (covid-19) pandemic and the migrant detention facilities. studies were selected and reviewed after applying the inclusion/exclusion criteria on pubmed. the following were the inclusion criteria: (1) age 18 years and younger, (2) both female and male, (3) articles in english, and (4) studies published within the last one year. exclusion criteria were age above 18 years and non-english articles. the articles selected from pubmed were broken down as seen in table 2 . after applying inclusion/exclusion criteria and using regular keywords, the total number of articles selected after review and refined search were 35 as they fit the selection criteria. the articles removed were not included for lack of relevant data. the flowchart seen in figure 1 shows the starting keywords used, and the number of articles obtained on pubmed for literature search with the applied filters. finally, the total number of used articles is displayed alongside those which were not selected. barriers, economic opportunities, lack of understanding of the healthcare system, knowledge about available resources, issues pertaining to accessing health and other services, trust factor, financial problems, transportation issues, and the larger policy and political context of local authorities [7, 8] . primary care physicians, pediatricians, and mental health providers can build trust through culturally competent and trauma-informed care, assess for healthcare needs, provide vaccination update and preventative care, and screen for mental health, communicable diseases, disabilities, and other medical health conditions thereby attending to the holistic needs of the vulnerable child and adolescent refugees. refugee children are less likely to avail pertinent health and social care than non-refugee children peers [9] . most host countries offer some kind of health screening for refugees, both child and adult, upon entering the country of destination [3] . in assessing medical fitness and healthcare mediations for refugees and migrant children, special consideration should be given to certain areas such as their distinct history, whether they have migrated along with their family or have been separated from family, are unaccompanied, whether they have been peddled, or have been left behind [7] . children's right to medical care is guaranteed by all the world leaders and member states of the who european region and is compiled in the convention on the rights of the child (crc), a convention guaranteeing the highest attainable standard of healthcare and treatment of illness and rehabilitation of the refugee, migrant, and asylum-seeking children similar to the children native to the host country [3] . the most vulnerable children include the asylum seekers and the undocumented or unregistered migrants. asylum seekers have usually been tested with war and/or political oppression in their native country and live in uncertainty and temporary circumstances regarding their future. the undocumented children often live in dangerous environments with little or no availability of basic societal rights, in abuse, poverty, brutality, and social boycott, and among threats of deportation [10] . migrants face a myriad of issues during various aspects of their journey between countries. during the pre-migration phase of this process, there is a lack of access to health/dental care, scarcity of food, and exposure to diseases. during the journey, lack of access to health/dental care and food scarcity continue to be problems. additionally, human trafficking, violence, and injuries during the trip are also present. finally, in the country of destination, difficulty in finding resources presents itself as the largest barrier. these resources include health/dental care, education, therapy, and other basic amenities. this process repeats itself and becomes a cycle if migrants are deported back to their country of origin and seek to migrate once again [7] . refugees and migrants arriving in the host country, many of which have different cultures and languages from their native country, go through a course of learning and acclimatization to the new civilization. this stressful process of acculturation compounds the migration strain thereby amplifying the psychological distress. children and adolescents, who are enrolled in school, generally learn the new host country language faster and conform to the new culture faster than parents, who may be secluded giving rise to new challenging family issues. family tensions can cause disharmony, separation, and even assault, with associated adverse effects on a child's mental health [11] . some of the needs of the refugees and migrants include access to mental health services; the youths have a need for civil activities and community acceptance while the parental urgency is to feel culturally protected. competency in a local language of the host country, and support from local community, school, and local authorities make their transitions easier and decrease the acculturation stress. figure 2 shows some of the mental and other health challenges of the refugee and migrant children. communicable diseases: cramped and overpopulated settlement and lack of cleanliness and sanitation in facilities housing refugee and migrant children put them at increased risk for diarrhea and skin infections [3] . the third-world countries show a higher prevalence of tuberculosis, malaria, intestinal parasites, and hepatitis b and c, than the developed nations. these chronic infections are present in increased prevalence in refugee and migrant juveniles [12, 13] . a study reports of unaccompanied refugee and migrant children who were arriving in germany with multidrug-resistant bacteria colonization at higher rates, and other records of a surge of measles, which is vaccine-preventable, have also been seen in asylum-seeking juveniles [14, 15] . clinicians should have a low threshold to screen for sexually transmitted infections (stis) in adolescent refugees as they have the highest rate of curable stis worldwide [16] . some of the commonly seen non-communicable diseases include obesity and psychological problems in migrant children [17] . obesity could be due to stress or change in dietary habits. vitamin d deficiency is often caused by lack of exposure to sunshine in winter [18, 19] . other conditions like malnutrition and multivitamin deficiencies are most likely to be prevalent too due to lack of access to food and health care in the migration journey. as per unhcr data, about 138,600 of refugee children in 2018 were unaccompanied minors [4] . segregation from parents can be harmful to a child's health and prosperity, mostly mental health, as parents lay the foundation for the societal and environmental base for children [20] . unaccompanied refugee minors have a higher prevalence of psychiatric disorders than accompanied refugee peers [21] . when accompanied by families, and after having experienced the migration trauma, children are often "hidden from sight" with no regard to their own personal wishes. mental health must be seen as a complex primary healthcare need and should be served in a holistic and family-oriented manner whenever possible. research studies have shown that freshly arrived migrant and refugee juveniles are at a high risk of psychosocial and mental issues due to exposure to organized crime and migration stress [22] . these are most commonly internalizing disorders -anxiety, depression, and post-traumatic stress disorder (ptsd) [23, 24] . a study of asylum seekers with serious mental health problems, in the netherlands, found that parental symptoms of ptsd were associated to infants' troubled attachment and that parental apathy was related to parental ptsd [25] . a cohort study found that caregivers' ordeal history and postmigration adversities were correlated with greater ptsd, rigid parenting, and an increase in child conduct problems [26] . expressive symptoms, however, were found to be equal to that in children of the host country [24] . longitudinal studies have shown that the high rate of internalizing symptoms tended to wear off slowly over a period of time, with expressions of ptsd fading away in about seven years after arrival to the host country [27] . some frequently reported emotional and behavioral mental health problems among bhutanese refugee youth include fighting, loneliness, depression, and being scared. other symptoms of oppositional defiant disorder, intermittent explosive disorder, conduct disorder, generalized anxiety disorder, major depressive disorder, and disruptive mood dysregulation disorder were also seen among them [28] . migrant and refugee juveniles frequently have to compromise more when parents are suffering from psychiatric disorders after dreadful experiences and migration strain. parents with mental health challenges battle to give their children a feeling of support and stability [29] . migration stress with socioeconomic deprivation takes a toll on the parents and increases the risk for child abuse [30] . early and adequate cognitive, mental, and emotional support for parents suffering from behavioral disorders is thus a vital support for children. refugees may hesitate to seek mental health help due to a culturally based stigma around mental health issues [9] . family separation and parental death drives adolescents to take on parental roles for younger siblings. recognition of these roles will enable physicians to provide suitable emotional and social support. risk factors in the host country, such as financial hardships, parental separation, and aggression/bullying, were analyzed as vital determinants of mental health at follow-up [27] . in recent years, cognitive behavioral psychotherapy, eye movement desensitization and reprocessing (emdr), and narrative exposure therapy for migrant and refugee children who have experienced war and displacement have been established for the evaluation and treatment of ptsd and depression [11] . strengths of refugee children include personal resilience, parental support, close-knit family structure, and lasting association with their religious and cultural identity from the country of origin [31] . the staggering majority, 84%, of the global refugee population is accepted in developing regions with limited access to quality mental health even before the pandemic [32]. now, they are overwhelmed with mental health crisis, as warned by the unhcr. while many refugees and internally displaced people are exceptionally resilient, their abilities to cope are now being stretched to the limit. the loss of daily wages and livelihoods is taking a toll on their mental health and causing psychosocial hardships. social distancing measures and limited mobility are compounding emotional distress with reports of self-harm increasing among the refugees. the covid-19 precautions and reduced staffing levels during this pandemic are also impacting the availability of aid and mental health support as refugees are often unable to travel, and many face-to-face activities have been cancelled. the unhcr is stepping up efforts to ensure the continuity of care by providing mental health services remotely through multi-lingual telephone hotlines and over the internet through online sessions. in addition, they are ensuring that people who need medication can continue treatment during lockdown [33] . the teaching recovery techniques approach is used to decrease children's discomfort and post-traumatic symptoms and to improve peer and kinfolk relations [34] . this psychosocial intervention is meant for juveniles who have experienced dreadful circumstances. children are assembled in organized groups focused at augmenting emotional management, survival competency, and conflict resolution skills. these techniques also help the children to express themselves. there is also a parent component session to educate about intervention and on skills to reinforce care of their children. ladnaan intervention is a culturally adapted parenting guidance program combined with local civic orientation for somali-born parents living in sweden. a trained community educator of somali origin facilitates the program. parents report higher success and satisfaction after completing the course and convincing improvement in behavioral problems in their children. in this 12-week session, parents are educated on local community information, receive lectures and take part in workshops, and exchange views on the parent-child liaison, attachment, child growth, and development of interpersonal skills [35] . mind-spring is a mental health disorder prohibition plan in belgium, denmark, and the netherlands. it provides psycho-education, and psychosocial and parenting skills for refugee and asylum-seeking parents in a culturally conscious manner in their own native language [3] . it deals with topics on mental health such as stress, ordeal, depression, personality, acculturation, and mental health fitness. the program promotes exchanging thoughts on experiences and provides parents with information about mental health expertise to recognize signs of suffering and mental ailment in themselves. it also educates the parents about obtaining help if and when needed. parents also obtain the required skills and support in the parenting process and how to ploy collateral parenting issues. studies have shown that educational institutions play a vital role in conserving and promoting the health and well-being of refugee and migrant children. successful school-based mental health prevention requires experts trained in cultural proficiency, who can interpret the mental health requirements and risks of refugee and migrant children, and who can conform the learning program to the needs of the individual child and family [34, 36] . hearing all voices was a pilot project undertaken by child to child in london aimed at promoting social inclusion, commitment in education, and local community involvement among vulnerable youth, with a prime focus on refugee, migrant, and asylum-seeking youth [37] . the pharos school prevention program conducts classroom-based program in the netherlands with the aim of developing social involvement among migrant children with local host community children and adults while simultaneously attending to individualized requirements of each child [38] . health assessments are performed for refugee and migrant children in a school setting in malmo city, sweden. here, the school nurse meets the juveniles and their caregivers for a health assessment to define and address each child's healthcare requirements. an analytical interview is followed by a broad general examination of the body, including dentition, eyesight, and hearing. mental health is briefly assessed and vaccination history is analyzed. referrals are made based on the necessity of specialized services. national governments have a significant role in establishing living circumstances for refugee and migrant children as most freshly settled refugee families rely on national and local authorities' support for habitation and existential expenses. governments determine the rights of children to access health care maintenance and educational benefits in their country. policies that exemplify humanity should be planned and implemented for the refugees/migrants and asylum seekers. a detailed individualized health evaluation by a healthcare professional on arrival to the host country should determine the healthcare needs and screen for communicable diseases; disability should be assessed and vaccinations should be updated. this response will help detect infections early on, allow timely treatment to be given, and will be most cost effective in the long run. the availability of medical translators and native cultural arbitrators is important to ensure the best healthcare outcome for refugee and migrant children. blueprints to improve welfare, and access to education and health in refugee and migrant children should have a comprehensive framework that targets risk factors on individual, family, and community levels. culturally sensitive, parent and other caregiver support curriculum and interventions in the school and local community centers should be promoted. transferring children between multiple locations should be minimized as it disrupts the peer networks and educational flow; this also holds good for unaccompanied children with substitute caregivers. in order to build good relations with substitute caregivers, unaccompanied children need consistent long-term, definitive housing with the same guardians. the most vital physical, social, and psychological support for children are their parents; therefore, family reunions should be expedited [7] . the united states of america has built the largest immigration detention system in the world. in 2019, a staggering 62,550 migrant children including infants, toddlers, kids, and teens were held in custody in facilities across usa. these facilities lack enough clinicians or specialized care for the detained children [39] . immigration detention has adverse and detrimental consequences for the well-being of those detained, but studies have found that it is most inimical to children [40] . the negative impacts of detention on mental health are more brutal for children than for adults; therefore, detention should not be weaponized for deportation of migrant children. if this is inevitable, then the facilities harboring children should have childfriendly areas, and avenues for healthcare and education should be provided. children on the move also suffer brutality, injustice, and misconduct from law enforcement officials -local police, border guards, and detention officers. such events cause children to quickly learn to mistrust authorities. these adverse psychological effects may last years after release from detention [41] . children are global citizens and their rights move with them; therefore, their healthcare needs should not be defined by geographic borders. mounting evidence suggests welcoming and supportive policies for refugee, migrant, and asylum-seeking children can prevent psychological distress and mental health disorders in these vulnerable children. all-inclusive policies that aim at protecting the rights of every child should be enforced globally. children should not be held in detention centers indefinitely in subhuman conditions away from their parents/primary caregivers. reuniting children with their families should be prioritized and expedited. it is imperative to enforce preventative mental health policies and refrain from practices that abuse human rights. healthcare providers should consider volunteering in refugee and migrant camps, and also in local community free clinics that are accessed by refugee and migrant children. this will ensure adequate staffing in detention facilities specially during the pandemic where the invisible, voiceless, and vulnerable refugee and migrant children along with the adult refugees and migrants can get timely medical attention and treatment for their healthcare needs. research is needed on improving resilience building and for appraising the impact of precise interventions that could improve outcomes. more longitudinal studies are needed to assess interventions that increase better mental health mediterranean situation health of refugee and migrant children: technical guidance . who regional office for global trends -forced displacement latest statistics and graphics on refugee and migrant children health considerations for immigrant and refugee children migrant children in europe: entitlements to health care. models of child health appraised barriers to access to health care for newly resettled sub-saharan refugees in australia structural and socio-cultural barriers to accessing mental healthcare among syrian refugees and asylum seekers in switzerland rights of accompanied children in an irregular situation a systematic review of risk and protective factors associated with family related violence in refugee families assessing the burden of key infectious diseases affecting migrant populations in the eu/eea infectious diseases of specific relevance to newly-arrived migrants in the eu/eea multidrug-resistant bacteria in unaccompanied refugee minors arriving in frankfurt am main measles among migrants in the european union and the european economic area toward global prevention of stis): the need for sti vaccines the health of migrant children in switzerland serum levels of 25-hydroxyvitamin d in mothers of swedish and of somali origin who have children with and without autism high prevalence of somali population in children presenting with vitamin d deficiency in the uk. arch dis child risk of mental health and nutritional problems for left-behind children of international labor migrants incidence of psychiatric disorders among accompanied and unaccompanied asylum-seeking children in denmark: a nation-wide register-based cohort study mental health problems of syrian refugee children: the role of parental factors mental health in syrian refugee children resettling in the united states: war trauma, migration, and the role of parental stress the effect of post-traumatic stress disorder on refugees' parenting and their children's mental health: a cohort study prevalence of serious mental disorder in 7000 refugees resettled in western countries: a systematic review attachment representation and sensitivity: the moderating role of posttraumatic stress disorder in a refugee sample we left one war and came to another: resource loss, acculturative stress, and caregiver-child relationships in somali refugee families exile and mental health in young refugees the transmission of trauma in refugee families: associations between intra-family trauma communication style, children's attachment security and psychosocial adjustment psychological interventions for post-traumatic stress disorder and depression in young survivors of mass violence in low-and middle-income countries: meta-analysis unhcr urges prioritization of mental health support in coronavirus response interventions for children affected by armed conflict: a systematic review of mental health and psychosocial support in low-and middle-income countries klingberg-allvin m: a support program for somali-born parents on children's behavioral problems school and community-based interventions for refugee and asylum seeking children: a systematic review hearing all voices in london us held record number of migrant children in custody in 2019 global protection and the health impact of migration interception mental health of unaccompanied asylum-seeking adolescents previously held in british detention centres key: cord-346338-kdjgu93q authors: spinelli, maria; lionetti, francesca; pastore, massimiliano; fasolo, mirco title: parents' stress and children's psychological problems in families facing the covid-19 outbreak in italy date: 2020-07-03 journal: front psychol doi: 10.3389/fpsyg.2020.01713 sha: doc_id: 346338 cord_uid: kdjgu93q objectives: the present study aimed to explore the effect of risk factors associated with the covid-19 outbreak experience on parents' and children's well-being. methods: parents of children aged between 2and 14-years-old completed an online survey reporting their home environment conditions, any relation they had to the pandemic consequences, their difficulties experienced due to the quarantine, their perception of individual and parent-child dyadic stress, and their children's emotional and behavioral problems. results: results showed that the perception of the difficulty of quarantine is a crucial factor that undermines both parents' and children's well-being. quarantine's impact on children's behavioral and emotional problems is mediated by parent's individual and dyadic stress, with a stronger effect from the latter. parents who reported more difficulties in dealing with quarantine show more stress. this, in turn, increases the children's problems. living in a more at-risk area, the quality of the home environment, or the relation they have with the pandemic consequences, do not have an effect on families' well-being. conclusions: dealing with quarantine is a particularly stressful experience for parents who must balance personal life, work, and raising children, being left alone without other resources. this situation puts parents at a higher risk of experiencing distress, potentially impairing their ability to be supportive caregivers. the lack of support these children receive in such a difficult moment may be the reason for their more pronounced psychological symptoms. policies should take into consideration the implications of the lockdown for families' mental health, and supportive interventions for the immediate and for the future should be promoted. on 30th of january 2020, who declared a public health emergency of international concern after the first clusters of people infected by covid-19 were diagnosed in china (who, 2020) . the day after, the italian government started to define the first containment measures, such as checking people entering the country from china, in order to prevent the expansion of the contagion in the country (government, 2020) . however, from the second half of february the number of italian cases increased, especially in northern italy. this led the government to announce on february 21st the first restrictive measures in what was defined as the first red zone, including defined territories in the regions of lombardia and veneto, the areas most affected by the infection. since the pandemic kept spreading around the country, the prime minister issued on march 9th a decree which extended to the entire national territory the restrictions already in force locally. the rules were supposed to last until april 3rd, but were extended by two more decrees firstly until april 13th and, later, until may 3rd (government, 2020) . at the time of writing (april 26th, 2020), there were in italy 199,000 confirmed cases and 26,977 deaths, more than half of which occurred only in lombardia and veneto. when the data of the present study were collected (between the 2nd and the 7th of april), those numbers were still increasing, showing that the end of the pandemic is still a long way off. the measures, known as #iamstayingathome (#iorestoacasa), include the closure of shops, except those selling crucial necessities, the cancellation of all sports events, and the shutdown of schools and universities across the country (government, 2020) . with schools, all the educative supporting services directed to children of all ages were closed, with teachers from primary grade onwards providing online lectures. quarantine began for the entire population; everyone was banned from leaving home except for non-deferrable and proven work or health reasons, or other urgent matters. smart working has been incentivized, but since most activities are closed many people lost their job or went through a severe reduction of their income. the life condition of families suddenly and deeply changed. in the home environment, the educational role of parents for children has become even much crucial than before. children have only their parents around them, to provide support with homework when necessary and promote a positive development and new learning experiences for toddlers and preschoolers . parents have been left alone not only in taking care of home-schooling their children, but also in general in the management of their children and of the home environment. all other educational services are closed, babysitters and grandparents are not available, and contact with peers is not allowed. many parents also must do smart-working, and handling time and spaces to work with children around may be very problematic. though quarantine means that time that can be shared with loved ones has increased, it also poses a major burden on parents' shoulders, as they are called to take an educational role while also trying to live their own lives and get on with their everyday job commitments. this situation has significantly increased the risk of experiencing stress and negative emotions in parents, with a potentially cascading effect on children's wellbeing (sprang and silman, 2013) . hence, despite its positive effect in reducing the number of new infected cases, the mobility restriction and social isolation abbreviations: sdq, strengths and difficulties questionnaire; psi, parenting stress index short form. associated with quarantine are major concerns for families' psychological wellbeing. related to this, the health care situation of the country is fragile, calling for attention. hospitals are overcrowded, and the number of deaths is still increasing, as well as the number of infected people and those recovering in hospitals (government, 2020) . it is becoming very common to know at least one person who tested positive to covid-19 or was hospitalized, and, most regretfully, to have experienced the loss of a person due to covid-19. this might generate fear and preoccupation in parents and children, even for families who do not have to face health problems . literature concerning previous experiences all over the world that may have some aspects in common with the covid-19 situation reported a high presence of psychological distress such as depression, stress, irritability, and post-traumatic stress symptoms associated with quarantine (hawryluck et al., 2004; brooks et al., 2020) with long-lasting effects continuing for years after the event (liu et al., 2012) . the majority of studies conducted during previous pandemics and from the beginning of the covid-19 outbreak examined psychological consequences on the general population, leaving the study of effects on parents and children mainly unexplored, with few exceptions (brooks et al., 2020) . one study found that levels of post-traumatic stress were four times higher in children who had been quarantined than in those who were not (sprang and silman, 2013) . a preliminary study conducted in china reported the presence of psychological difficulties in children during the covid-19 pandemic, with fear, clinging, inattention, and irritability as the most severe symptoms for younger children (jiao et al., 2020) . still, mechanisms that might explain what specific covid-19 related risk factors put children more at risk of negative outcomes, and what is the interplay between covid-19 lockdown and parents' wellbeing on children's adjustment, have not been investigated yet. a deeper understanding of family processes, protective factors, and risk factors in the home environment might be important if the wellbeing of children is to be promoted in these difficult times . the present study wants to shed light on families' well-being during the covid-19 outbreak in italy, by exploring parents' and children's individual and dyadic adjustment after one month of quarantine. understanding parents' and children's reactions and emotions, and identifying risk and protective factors, is essential to properly address their needs to tailor present and future intervention programs (sprang and silman, 2013) . in general, little is known about which factors may be associated with protection against child behavioral and emotional problems during a health emergency. in order to fill this gap, the main aim of the present study was to explore how pandemicrelated variables, structural aspects of the home and family environment, and parental subjective experience of stress and adjustment to the quarantine, affect the wellbeing of parents and children, and how in turn the well-being of parents and children are associated. specifically, we explored both individual parent stress and dyadic perception of stress since it is well-know that both levels of stress may impair children's well-being (belsky, 1984; abidin, 1992; madigan et al., 2018; martin et al., 2019) . we expected that implications of the covid-19 outbreak might increase parents' psychological difficulties, particularly stress both at the individual and the dyadic level, with a consequent negative impact on children's emotional and behavioral wellbeing (dalton et al., 2020) . parents filled out an anonymous online survey, after reading the written consent form and explicitly agreeing to take part in the study. the survey was shared via social media for a limited time (from april 2nd to 7th, 2020), targeting parents of children aged 2-to 14-years-old. in the case of multiple children, the parent was asked to report on one child only. all the questionnaires, both parent-and child-related, were completed by the parent. there was no monetary compensation for participating. the final sample providing information on all study variables consisted of 854 parents living in italy, of which 797 were mothers (mage = 38.96(6.02) (49% of whom had a high school degree or less, 37% a bachelor's or master degree, and 21% a higher education degree) and 57 were fathers (mage = 41.9(6.75) (41% of whom had a high school degree or less, 33% a bachelor's or master degree, and 26% a higher education degree). children's mean age was 7.14 (3.38); 427 were boys. a total of 271 parents were resident in the north of italy where most covid-19 cases, were registered i.e., lombardia and veneto (from now on defined as the red area). data reported in this study are part of a wider longitudinal research project designed with multiple purposes related to the investigation of the psychological impact of the covid-19 outbreak in italian parents and children. the study was approved by the ethical commitment of the department and was conducted according to the american psychological association guidelines in accordance with the 1964 helsinki declaration. an ad-hoc index was computed to evaluate the amount of contact the parent had with people directly affected by the virus, following the assumption that the greater the number of contacts, and the closer the people affected by covid-19 that the parent knows are to the parent, the greater the impact on psychological wellbeing would be. one point was given for each of the following if present: the parents tested positive for the virus, a familiar or close friend tested positive, a familiar/close friend was hospitalized, a familiar/close friend died. a half=point each was given if the parent knew a person (not familiar or close friend) who tested positive, was hospitalized, or died. an ad-hoc risk index was computed to evaluate the house and family situation, including factors supposed to be related to the quality of life condition. one point was given for each of the following: loss of job due to the pandemic, absence of external spaces (balcony or garden), total family income less than 1250 e per month, only one adult in the house in charge of the child, no wi-fi, no pets. to compute the index, this score was summed with the number of rooms/number of people ratio in the house. difficulties experienced by parents during the quarantine were investigated with a newly developed pool of 13 items. parents were asked to indicate, using a 7-point likert scale, how difficult they were perceiving, during the last week, dealing with several aspects related to the quarantine such as finding a relaxing space alone to unplug, time for the partner and for kids, and to do activities such as sport, reading, cooking, etc. (see appendix 1 for the full list of items). cronbach's alpha was 0.84, with 95% cis [0.83-0.84]. perception of parent's stress in the parent-child interaction was investigated using the 15 items parent/child dysfunctional interaction domain of the parenting-stress index short form (psi) (abidin, 1995) . the scale investigates with a 5-point rating scale the extent of parents' agreement or disagreement with statements describing the parent-child relationship as difficult to manage. cronbach's alpha in the current study was 0.86, 95% cis [0.86-0.86]. parent's individual perception of stress was investigated using the 7 items from the stress subscale of the depression anxiety stress scale-short form (dass) (lovibond and lovibond, 1995) . the scale provides on a 5-point rating scale a measure of individual symptoms indicating stress i.e., irritation and agitation. to obtain the total score, items are summed. cronbach's alpha in the current study was 0.88, 90% cis [0.88-0.89]. behavioral and psychological problems in children were investigated using the parent-report form of the strengths and difficulties questionnaire (sdq) (goodman, 2001) . the current study focuses specifically on the following subscales: emotional symptoms, hyperactivity-inattention, and conduct problems. each subscale is measured by 5 items, rated on a 3-point scale. to obtain the total scores, items are summed. cronbach's alpha in the current study were as follow: 0. first, descriptive statistics and bivariate correlations among study variables were presented. afterwards, two multivariate mediation models were tested, including as a predictor relevant quarantinerelated risk factors (derived from the correlational analysis), as a mediator parents' stress (in one model dyadic parenting stress was explored as the candidate mediator, in the other model it was individual stress) and as outcomes children's psychological problems at the sdq. mediation models were compared with a with a null model and a main effect model, including only quarantine-related risk factors as the predictor. akaike weights, providing the probability of a model to support new data conditional on the set of models considered, were used for model comparison (wagenmakers and farrell, 2004) . parameters were investigated for the best fitting model. finally, as a followup analysis, we explored whether results were comparable distinguishing between parents' living in the red area (including lombardia and veneto regions) with the rest of the sample. to this aim, we performed a multi-group analysis. analyses were run using the statistical software r (team, 2018) , lavaan package (rosseel, 2012) . plots were depicted using package ggplot2. means, sds, and correlation values among variables of interest are reported in table 1 . due to the large sample size, correlation values above 0.06 (i.e., trivial in effect size) were significant at p < 0.05; thus, for interpreting effects, we considered the strength of the association (namely pearson's r) as an effect size. results showed that overall there were no relevant associations of covid-contact risk index and home environment risk index with dyadic parenting stress (psi), parent's individual stress (dass), and children's psychological problems (sdq). because the only risk factor associated with parent's individual and dyadic stress and children's psychological problems was the quarantine parent risk index, we did not include in the model the home and covid risk indices. thus, models tested had as a predictor the quarantine parent risk index, as the candidate mediator parent stress (dyadic and individual), and as outcomes children's emotional and behavioral problems. for both the model including dyadic parenting stress as a mediator and individual stress as a mediator, the mediation model outperformed the null and main-effect regression model. specifically, for the model including dyadic parenting stress as a mediator, akaike weights were lower than 0.001 for both the null and the main effect model, and very close to 1.00 for the mediation model. the same weights were obtained for the comparison with the mediation model including individual stress. standardized estimates of the two mediation models are reported in figures 1, 2 . parameters for indirect effects and proportion of variance explained for each outcome variable for the investigated models are reported in table 2 . because of the significant association between study variables and age, we ran the analyses again, including the effect of the child's age on the mediator and outcome variables. results remained stable overall. with a multi-group analysis, we finally explored whether results were comparable for residents in the red area (lombardia and veneto) vs. other regions. no relevant differences were identified. results are available upon request to the corresponding author. the covid-19 outbreak is a completely new and unexpected situation currently affecting many countries. italy was, after china, the second most highly affected country at the time, with the pandemic spreading very fast. in just a few weeks, the population found itself from thinking that the pandemic was happening far away, to being directly involved (government, 2020) . the closure of schools and the decision to keep children locked at home was obvious, but the consequences of all this for families' well-being were barely considered. our study is the first to examine the impact of the covid-19 outbreak on parents' and children's wellbeing. we explored bivariate associations among the environment, family, and covid-19 outbreak-related factors on parents' stress and children's psychological problems, and the interplay among these variables. results showed that factors such as living in a more at-risk contagion zone or being in closer contact with the virus' effects do not relevantly affect parents' and children's well-being. this confirms findings from a preliminary study in china, where the difference in children's symptoms between areas identified by different levels of epidemic risk was not statistically significant (jiao et al., 2020) . similarly, the quality of the environment, such as the physical characteristics of the living space, is not associated with parents' and children's psychological symptoms. yet, it is the parents' individual perception of the situation, and more specifically how difficult they find it dealing with the many stresses the quarantine imposes, that is significantly associated with parent's stress and children's psychological problems, and that indirectly impacts on children's behavioral and emotional problems through the mediating role of parent's stress. parents who report finding taking care of their children's learning, finding space and time for themselves, the partner, the children, and for the activities they used to do before the lockdown more difficult, are more stressed. this confirms studies that found an effect of the limitations associated with quarantine on the well-being of adults (brooks et al., 2020) . we further add to the literature that this stress is experienced both at the individual (e.g., being over-reactive, feeling nervous and irritated) and at the dyadic level (e.g., finding it difficult to enjoy interactions with the child, and child behavioral and emotional expressions). in addition, we pointed out that it is this stress that significantly impacts on children's well-being. hence, it is mainly when the strains of quarantine affect the ability of the parent to enjoy and appreciate the parent-child relational experience that the consequential negative impact on the child's well-being is stronger, a result with important implications for informing intervention programs that target the family and the child. moreover, this impact is present at every age, even though our age range is quite wide. this underlines that the impact of the lockdown on parents and children is present with similar mechanisms for families with children younger than 14 years. the effect we identified in our study may be explained in many ways. more stressed parents find it more difficult to understand their child's needs and to respond in a sensitive way (abidin, 1992; scaramella et al., 2008) . stress is often associated with rude behaviors and difficulties in explaining limits and discipline. thus, children in these families may feel less understood by their parents and may react in more negative and aggressive ways (pinquart, 2017) . moreover, we know that children have lower personal resources to deal with the many changes the pandemic is imposing on their life and guidelines suggest parents should discuss and explain the situation with them, since correct information about what is happening and the reasons for the restrictions children have to face is crucial to prevent negative psychological consequences (dalton et al., 2020) . however, how and when to do that is completely left up to the parents' choice. we can speculate that more stressed parents may be too overwhelmed by the situation to find appropriate ways to be a supportive figure for their children and to find the best ways to address children's questions and fears (digiovanni et al., 2004) . when children do not find responsive answers to their preoccupations from adults, they may show more distress, evidenced by more emotional and behavioral problems as well as inattention and difficulties in concentrating. these results suggest many interesting implications that should be addressed in the present and in the future in italy, and in all countries involved in the pandemic, if we want to promote children's wellbeing, and prevent the onset of more severe behavioral and emotional problems. the pandemic and the quarantine associated with it require using personal resources to deal with everyday life and fears and worries. correct information and guidelines have to be given to adults about how this stressful situation may affect their personal and children's wellbeing. public health should provide parents with knowledge about, for instance, how children at different ages express distress and the importance of sharing and talking about fears and negative emotions (dalton et al., 2020) . in this way even less resilient and more stressed parents may be helped in finding ways to understand and support their children (belsky, 1984) . the closure of schools may have also contributed to this phenomenon. firstly, because parents are left alone dealing with their children's education and learning, this may be a very challenging duty. moreover, teachers have a role not only in delivering educational materials but also in offering an opportunity for children to interact, and to receive from them support and explanations. organizing online courses in a way to also improve the possibility for children to interact with their teacher about things outside of the learning context should be a priority especially if school closures are to be prolonged. moreover, the government should take into consideration the impact of school closures on parents by finding ways to help them deal with the learning experience of children and with having children at home 24/7, while parents also have to manage homeworking and childcare. this is going to be even more relevant if, during the second phase of the emergency, job activities will re-open, and parents will be asked to go back to work, but schools will be kept closed. how are parents supposed to deal with this? some limitations of the present study should be addressed. firstly, this is a correlational study; a longitudinal exploration of the effects of quarantine on parents and the cascading effects on children over time would help in better understanding the phenomenon. moreover, we have collected children's psychological symptoms from parent reports; although this data collection method is widely used it may be less informant than child reports or direct evaluation of children's well-being made by experts. lastly, we may expect that quarantine risk is higher for more at-risk families i.e., families of separated parents, families with children with disabilities, very poor families, etc. the exploration of the phenomenon with those in at-risk situations would help in developing more tailored interventions. if properly supported by healthcare professionals and other social connections, including the school environment, parents and children can appropriately overcome this critical period of distress and avoid severe long-term consequences. quarantine and social distancing are efficient ways to deal with the pandemic, but these experiences may have consequences on people's wellbeing. however, the media and public institutions concentrate primarily on physical health to recommend steps for the prevention and containment of the disease, leaving the impact on mental health undiscussed. indeed, stable mental health is one of the keys to fight this ongoing pandemic and to restore a post-pandemic society; the well-being of parents and children must be under surveillance since problems on this side may have long-lasting implications. as bowlby suggested 30 years ago, "man and woman power devoted to the production of material goods counts a plus in all our economic indices. man and woman power devoted to the production of happy, healthy, and self-reliant children in their own homes does not count at all. we have created a topsy-turvy world" (bowlby, 1988) . the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by department of neuroscience, imaging and clinical sciences. the patients/participants provided their written informed consent to participate in this study. ms, fl, and mf conceptualized the study and organized the data collection. ms and fl wrote the first draft of the manuscript. fl and mp run the analyses and wrote the results section. all authors contributed to revision of the final version of the manuscript. the determinants of parenting behavior the parenting stress index professional manual the determinants of parenting: a process model a secure base: parent-child attachment and healty human development the psychological impact of quarantine and how to reduce it: rapid review of the evidence protecting the psychological health of children through effective communication about covid-19 factors influencing compliance with quarantine in toronto during the 2003 sars outbreak psychometric properties of the strengths and difficulties questionnaire italian government: measures to face the coronavirus covid-19 sars control and psychological effects of quarantine behavioral and emotional disorders in children during the covid-19 epidemic mental health considerations for children quarantined because of covid-19 depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic manual for the depression anxiety stress scales (2nd a meta-analysis of maternal prenatal depression and anxiety on child socioemotional development associations between child sleep problems and maternal mental health in children with adhd associations of parenting dimensions and styles with externalizing problems of children and adolescents: an updated meta-analysis lavaan: an r package for structural equation modeling and more. version 0.5-12 (beta) a test of the family stress model on toddler-aged children's adjustment among hurricane katrina impacted and nonimpacted low-income families posttraumatic stress disorder in parents and youth after health-related disasters package: splines, r: a language and environment for statistical computing. r foundation for statistical computing the strengths and difficulties questionnaire-parents for italian school-aged children: psychometric properties and norms aic model selection using akaike weights mitigate the effects of home confinement on children during the covid-19 outbreak key: cord-339638-yrxoj1hl authors: goldman, ran d.; mcgregor, sophie; marneni, shashidhar r.; katsuta, tomohiro; griffiths, mark a.; hall, jeanine e.; seiler, michelle; klein, eileen j.; cotanda, cristina parra; gelernter, renana; hoeffe, julia; davis, adrienne l.; gualco, gianluca; mater, ahmed; manzano, sergio; thompson, graham c.; ahmed, sara; ali, samina; brown, julie c. title: willingness to vaccinate children against influenza after the covid-19 pandemic date: 2020-08-07 journal: j pediatr doi: 10.1016/j.jpeds.2020.08.005 sha: doc_id: 339638 cord_uid: yrxoj1hl objectives: to determine factors associated with parents who plan to vaccinate their children against influenza next year, especially those who did not vaccinate against influenza last year using a global survey. study design: a survey of caregivers accompanying their children 1-19 years-old in 17 pediatric emergency departments (ed) in six countries at the peak of the covid-19 pandemic. anonymous online survey included caregiver and child demographic information, vaccination history and future intentions, and concern about the child and caregiver having covid-19 at the time of ed visit. results: of 2422 surveys, 1314 (54.2%) caregivers stated they plan to vaccinate their child against influenza next year, an increase of 15.8% from the prior year. of 1459 caregivers who did not vaccinate their children last year, 418 (28.6%) plan to do so next year. factors predicting willingness to change and vaccinate included child’s up-to-date vaccination status (adjusted odds ratio (aor)=2.03, 95% confidence interval (ci) 1.29 – 3.32 p = .003); caregivers’ influenza vaccine history (aor=3.26, 95% ci 2.41 – 4.40 , p< 0.010), and level of concern their child had covid-19 (aor=1.09, 95% ci 1.01 – 1.17, p=0.022). conclusions: changes in risk perception due to covid-19, and prior vaccination, may serve to influence decision-making among caregivers regarding influenza vaccination in the coming season. in order to promote influenza vaccination among children, public health programs can leverage this information. to determine factors associated with parents who plan to vaccinate their children against influenza next year, especially those who did not vaccinate against influenza last year using a global survey. pediatric emergency departments (ed) in six countries at the peak of the covid-19 pandemic. anonymous online survey included caregiver and child demographic information, vaccination history and future intentions, and concern about the child and caregiver having covid-19 at the time of ed visit. of 2422 surveys, 1314 (54.2%) caregivers stated they plan to vaccinate their child against influenza next year, an increase of 15.8% from the prior year. of 1459 caregivers who did not vaccinate their children last year, 418 (28.6%) plan to do so next year. factors predicting willingness to change and vaccinate included child's up-to-date vaccination status (adjusted odds ratio (aor)=2.03, 95% confidence interval (ci) 1.29 -3.32 p = .003); caregivers' influenza vaccine history (aor=3.26, 95% ci 2.41 -4.40 , p< 0.010), and level of concern their child had covid-19 (aor=1.09, 95% ci 1.01 -1.17, p=0.022). changes in risk perception due to covid-19, and prior vaccination, may serve to influence decision-making among caregivers regarding influenza vaccination in the coming season. in order to promote influenza vaccination among children, public health programs can leverage this information. year, including children (1) . despite the wide availability of seasonal influenza vaccines and clear guidelines for who should be immunized, vaccine uptake remains low in most countries (2) . with the unprecedented coronavirus sars-cov-2 illness, now called the coronavirus disease 2019 (covid19) , which currently lacks a publicly available vaccine, public health authorities worldwide recommended numerous strategies to reduce spread, including reducing physical encounters and wearing masks. these measures have had variable success in curtailing the spread of the virus around the world. vaccines are likely to provide the best protection from contracting the illness and there are currently more than 100 projects centered on the development of a vaccine and many have entered clinical trials (3). there is a high likelihood that community transmission of covid-19 will continue into the next influenza epidemic (4), complicating diagnoses and further increasing the burden on health care systems (5) . to mitigate these issues, vaccinating large parts of the population against influenza in late 2020 is a key goal of public health officials. the objective of this timely survey study was to determine, during the covid-19 peak pandemic, caregiver intentions towards influenza vaccination of their children, as well as themselves. in order to better understand how covid-19 has influenced attitudes towards j o u r n a l p r e -p r o o f influenza vaccination, we specifically aimed to describe characteristics of caregivers who intend to immunize their children in 2020-2021 despite the child not receiving influenza immunization in the prior year. understanding caregivers' attitudes can help public health officials plan targeted messaging to parents in order to promote influenza vaccination in the upcoming season. this study is part of a larger covid-19 parental attitude study (covipas) study, surveying caregivers of children presenting for emergency care, in the era of covid-19. caregivers who arrived to 17 pediatric emergency departments (ed) in the usa (seattle, tacoma, los angeles, dallas, atlanta), canada (vancouver, toronto, saskatoon, edmonton, calgary), israel (shamir), japan (tokyo), spain (barcelona), and switzerland (zurich, bern, geneva, bellinzona) were asked to participate, using posters in waiting areas and patient rooms. for infectious control purposes, respondents used their own smartphones to complete the survey by logging into a secured online platform based on redcap metadata-driven software (vanderbilt university). several irbs (in switzerland and spain) provided a waiver of consent such that responding to the survey was considered consent to participate. languages available to complete the study were english, french, german, italian, spanish, hebrew, and japanese. although sites joined recruitment in a staggered fashion, surveys were obtained between march 27 and june 30, 2020. only one caregiver per family was asked to complete the survey. vaccination against influenza is available for children over 6 months in all countries that this survey took place. the study-specific questionnaire was developed to include questions regarding demographic characteristics, information about the ed visit, and attitudes around covid-19. respondents were also asked about their child's vaccination history excluding influenza. children were presented in this report, were evaluated a priori by 10 individuals representing the target group and 10 healthcare providers working in the ed environment. the final version of the survey is based on the feedback and test clarity generated from these 2 groups. basic descriptive statistics and frequencies were used to describe all variables. we compared survey data from caregivers who stated whether they plan to immunize or not immunize their children against influenza in the coming year. we then compared caregivers that did not immunize for influenza their children last year and compared those that said they do or do not plan to immunize their children for influenza next year. to determine which factors were significantly associated with caregiver decision-making to vaccinate next year despite not doing so last year, we used bivariate analyses: mann-whitney test was used for comparing nonnormal continuous variables, independent t-tests were used for comparing normallydistributed continuous variables, and chi-squared or fisher exact tests were used for categorical variables. multivariable logistic regression was used to estimate the adjusted odds ratio of agreeing to immunize against influenza in the coming year using all the variables that showed a level of p<0.100 in the bivariate analyses. all analyses were conducted with r version 3.5.1. a p-value less than 0.05 in the multivariate analysis was considered statistically significant. results a total of 2785 surveys were completed online. seven (0.3%) were excluded because the surveys were incomplete, seven (0.3%) were completed by the patient, 343 (12.3%) were for a patient less than one year of age, three (0.1%) for patients over 19 years old, and three (0.1%) with an unspecified patient age ( figure 1 ). some participants abstained from answering certain questions, accounting for a small number of unknown responses to each question. the final study sample included 2422 respondents: 2350 parents (97.0%), 67 other caregivers, and 5 respondents who did not specify their relationship to the child. median age of caregivers was 40.0 (standard deviation (sd) = 7.6) years and median age of the child was 8.3 (sd = 4.6) years. a total of 1314 (54.3%) respondents stated they intend to vaccinate their children against influenza in the coming 12 months, an increase of 15.9% compared with those that reported an influenza vaccine for their child in the past 12 months ( figure 1 ). as many as 42/2422 (1.7%) respondents did not specify their intention to vaccinate their child and 1394/2393 (58.3%) respondents stated they planned to obtain the vaccine for themselves next influenza season, compared with 974 (40.6%) in the past year (table i) . table 1 provides demographic information including a comparison between caregivers who plan to vaccinate for influenza in the coming season and those who do not. the highest likelihood of planning to vaccinate the child next year was if the caregiver planned to vaccinate themselves in the upcoming year (1213/2422; 50.1% of children). caregivers were more likely to suggest they will immunize next year if they had education beyond high school, if the child had a chronic illness or took medications regularly, if the child was up-to-date on their vaccines j o u r n a l p r e -p r o o f other than influenza according to their country-specific vaccination schedule, or if the child or caregiver received influenza vaccine the prior year. of 1459 caregivers who did not vaccinate their children against influenza in the last year, 418 (28.6%) indicated they plan to vaccinate next season, 1025 (70.3%) did not vaccinate last year and will not vaccinate this year, and 16 (1.1%) abstained from answering. only 38/2422 (1.6%) vaccinated their child last year but do not plan to do so next year. most caregivers were not concerned about their child having covid-19 when coming to the eds in the six countries where this survey took place, and we found a significant correlation between level of concern and plan to vaccinate against influenza (p-value= 0.037; figure 2 [available at www.jpeds.com]). table 2 describes characteristics of caregivers who did not vaccinate the child last year, but plan to vaccinate their child against influenza in the coming year. caregivers were more likely to change from non-vaccination last year to vaccination in the coming year when they had education more than high-school, they took the vaccine themselves or planning to get vaccinated themselves next year, had a child with an up-to-date vaccination schedule excluding influenza vaccines or were worried their child may have covid-19 or influenza during the visit in the ed. in the multivariate logistic regression analysis (table 3) behavioral changes related to covid-19, including social distancing, hand washing, and wearing a mask, will impact influenza spread in the coming year (3) and it is unclear how relaxation of social distancing measures will influence the spread of influenza. co-infection of covid-19 and other respiratory pathogens, including influenza, occurred in a significant subset of covid-19 patients (8, 9) and a case report from china describing co-infection with covid-19 and influenza a virus represent the difficulty in differentiating other causes of respiratory illness from covid-19 (10) . the director of the us center for disease control predicted that "we're going to have a flu epidemic and coronavirus epidemic at the same time" and that the combination of the two will be "more difficult and potentially complicated" (4). combined influenza and covid-19 pandemics could result in considerable morbidity and mortality, stressing the health system j o u r n a l p r e -p r o o f (3, 7) and a global interest (as seen through google trends) in pneumococcal and influenza vaccines during february-march, 2020 of the covid-19 pandemic ( has been reported (11) . in our global survey of primarily parents attending pediatric eds, a significant shift in parents' plan to vaccinate against influenza in the season following covid-19 pandemic was noted. a total of 54.3% survey respondents plan to vaccinate for influenza and 29.0% (418/1443) of caregivers that did not vaccinate last year report a change in plan to do so next year, adding to the protection of their children and reducing the chance of transmission to others. we report that caregivers who plan to vaccinate themselves are very likely to vaccinate their children and predictors for caregivers to plan to vaccinate after not doing so last year include children that have up-to-date vaccinations other than influenza, if the caregiver received influenza vaccine last year, and if they were worried their child had covid-19. seasonal influenza epidemics result in tens of millions of cases, and we have recently reported that caregivers in 14 eds are likely to provide their children with a covid-19 vaccine if it becomes available (12) . ensuring influenza vaccine acceptance and uptake in children may also serve public health in promoting covid-19 vaccines, when those become available (7). more than 70 independent barriers are associated with vaccine hesitancy and include psychological barriers (such as perceived risk, utility, and social benefit); contextual barriers (such as access to health care services); and lifestyle barriers (such as smoking, drinking, and physical activity) (13) . trust in healthcare providers' advice and mainstream medicine, influence of social network and social norms, knowledge sources about vaccines, and general views toward health are key factors in parental vaccine decision-making (14) . vaccine risk-perception j o u r n a l p r e -p r o o f of parents is often complicated by cognitive bias and personal experience (15) and in our cohort, caregivers were most likely to report plans to vaccinate their children against influenza next year if they plan to vaccinate themselves, meaning they trust the medical system and more specifically put faith in vaccines. of interest, caregivers put more value and enhance the perceived risks associated with taking action, such as a child having a severe reaction to a vaccine, than the risk of an omitted action, like the chance of contracting a disease (16) . it is important for primary care providers to highlight the safety and efficacy of the flu vaccines to parents. past behavior is a strong factor in vaccinating children and those having been vaccinated in the past against seasonal influenza being more likely to be vaccinated against pandemic influenza (17) . in our study, the influenza vaccination status of a child last year was strongly associated with a caregiver's plan to vaccinate next year (p <0.001). similarly, in a study from england, among 1001 parents with half their children vaccinated to influenza, vaccine uptake was associated with the child having previously vaccinated against influenza (18) . understanding factors that influence a change in influenza vaccine behaviour from year-to-year may guide public health efforts to increase uptake. fogel and hicks recently coined the term "flu-floppers," describing patients who received the influenza vaccine in some years but not others. they suggested that many appear to randomly alternate vaccination status from year to year (19) . in a year of covid-19 pandemic it is likely that public health worries influence parents to plan on vaccinating their children and only 4% of children vaccinated last year are likely not to be vaccinated next year (38/930 families) compared w 28.6% (417/1460) "flipping" towards vaccinating. those who stop yearly influenza vaccinations for their children most commonly cited a perceived lack of effectiveness of the vaccine (29%, n=41) (19) . public health officials will need to ensure clear messaging on the safety of influenza vaccines next year, especially in face of covid-19, to influence parental decision making to convert into vaccinating children. in a web-based survey of 500 parents from an online panel representative of the us population, the main drivers of parents' decision to vaccinate their child against influenza were prevention of influenza, reduction of influenza symptoms, and doctor recommendation; barriers to vaccination included the risk of adverse effects and the perceived low risk of influenza (20) . similarly, a review of 64 studies reported an association between vaccination uptake and perceived vaccine safety, general positive attitudes towards vaccination, positive vaccine recommendations, social influences and trust in the healthcare profession, and perceiving fewer practical difficulties with vaccination (21) . we similarly found that caregivers vaccinating their children according to the schedule, and thus likely have trust in the idea of vaccination, are likely to accept the influenza vaccination for their child next year. level of caregiver concern that the child had covid-19 was associated with the change in action towards planning to vaccinate children against influenza. in a systematic review of 37 studies involving the 2009 h1n1 pandemic influenza outbreak, the degree of threat experienced and perceptions of vaccination as an effective coping strategy was associated with stronger intentions and higher uptake of vaccination and concern about the disease as well as believing oneself to be at risk to h1n1 influenza were important factors (17) . fear of the child j o u r n a l p r e -p r o o f being sick with covid-19 is a significant predictor of caregivers changing their mind to start vaccinating next year, which is supported by the fact that correlations were found between online searches for influenza vaccines and covid-19, especially in "hotspots" of covid-19, and increased interest in influenza vaccine compared with similar time periods in non-pandemic years (11) . although caregivers with higher than high school education are more likely to vaccinate their children against influenza (79% vs 71.4%, p<0.01), including those not vaccinating last year (78.5% vs 71.4%, p=0.005), when other factors were assessed in the multivariate analysis, higher education was associated with lower likelihood of families changing their mind to start vaccinating (or 0.71, 95% ci 0.52-0.96), p=0.028). level of parental education is associated with both high and low uptake of vaccines (22) , likely due to education serving as a surrogate marker for other factors impacting adherence. our study has a number of limitations. first, the population of caregivers responding to the survey does not represent all parents in the sites where the study was conducted, as we administered the survey in a pediatric ed setting and only a subset of families (likely <5% of visitors to 17 the pediatric eds) filled out the survey. we also relied on caregiver possession of a smartphone/tablet/computer to complete the survey online, which may have limited a small percentage of caregivers from responding. secondly, we relied on the accuracy of caregiver responses to the status of both influenza and non-influenza vaccinations, because no patient records were checked for confirmation. finally, as in any survey, caregivers may share their j o u r n a l p r e -p r o o f opinions about vaccinations, but act differently once cities are back to a more normal activity, which highlights the importance of public health measures to encourage and ensure adequate vaccination uptake. in summary, we report propensity of caregivers to vaccinate their children against influenza at a higher rate in the next influenza season, with 29% of those that did not vaccinate last year reporting a plan to do so next year. caregivers who plan to vaccinate themselves, who received influenza vaccine last year, who were worried their child had covid-19, and whose children j o u r n a l p r e -p r o o f centre for disease control and prevention. estimated influenza illnesses, medical visits, hospitalizations, and deaths in the united states-2018-2019 influenza season us department of health & human services centre for disease control and prevention. flu vaccine coverage, united states 2018-19 influenza season us department of health & human services covid-19 and the next influenza season the covid-19 vaccine development landscape a looming double threat parental hesitancy about routine childhood and influenza vaccinations: a national survey the dual epidemics of covid-19 and influenza: vaccine acceptance, coverage, and mandates co-infection in sars-cov-2 infected patients: where are influenza virus and rhinovirus/ enterovirus? rates of co-infection between sars-cov-2 and other respiratory pathogens co-infection with sars-cov-2 and influenza a virus in patient with pneumonia silver lining of covid-19: heightened global interest in pneumococcal and influenza vaccines, an infodemiology study paper 2 -covid vaccine -not yet published barriers of influenza vaccination intention and behavior -a systematic review of influenza vaccine hesitancy underlying factors impacting vaccine hesitancy in high income countries: a review of qualitative studies parental decision-making on childhood vaccination refinement of outcome bias measurement in the parental decision-making context factors associated with uptake of vaccination against pandemic influenza: a systematic review: vaccine psychological factors associated with uptake of the childhood influenza vaccine and perception of postvaccination side-effects: a cross-sectional survey in england flu-floppers": factors influencing families' fickle flu vaccination patterns parents' decision-making regarding vaccinating their children against influenza: a web-based survey a systematic review of factors affecting vaccine uptake in young children understanding vaccine hesitancy around vaccines and vaccination from a global perspective: a systematic review of published literature key: cord-347488-th07jo7u authors: akseer, nadia; kandru, goutham; keats, emily c; bhutta, zulfiqar a title: covid-19 pandemic and mitigation strategies: implications for maternal and child health and nutrition date: 2020-06-19 journal: am j clin nutr doi: 10.1093/ajcn/nqaa171 sha: doc_id: 347488 cord_uid: th07jo7u coronavirus disease 2019 (covid-19) continues to ravage health and economic metrics globally, including progress in maternal and child nutrition. although there has been focus on rising rates of childhood wasting in the short term, maternal and child undernutrition rates are also likely to increase as a consequence of covid-19 and its impacts on poverty, coverage of essential interventions, and access to appropriate nutritious foods. key sectors at particular risk of collapse or reduced efficiency in the wake of covid-19 include food systems, incomes, and social protection, health care services for women and children, and services and access to clean water and sanitation. this review highlights key areas of concern for maternal and child nutrition during and in the aftermath of covid-19 while providing strategic guidance for countries in their efforts to reduce maternal and child undernutrition. rooted in learnings from the exemplars in global health's stunting reduction exemplars project, we provide a set of recommendations that span investments in sectors that have sustained direct and indirect impact on nutrition. these include interventions to strengthen the food-supply chain and reducing food insecurity to assist those at immediate risk of food shortages. other strategies could include targeted social safety net programs, payment deferrals, or tax breaks as well as suitable cash-support programs for the most vulnerable. targeting the most marginalized households in rural populations and urban slums could be achieved through deploying community health workers and supporting women and community members. community-led sanitation programs could be key to ensuring healthy household environments and reducing undernutrition. additionally, several covid-19 response measures such as contact tracing and self-isolation could also be exploited for nutrition protection. global health and improvements in undernutrition will require governments, donors, and development partners to restrategize and reprioritize investments for the covid-19 era, and will necessitate data-driven decision making, political will and commitment, and international unity. as a highly communicable disease, coronavirus disease 2019 continues to ravage the state of the world's health and economy (1) . its impact also underscores the limited progress we have made against noncommunicable diseases (ncds). children and adults with underlying comorbidities, particularly ncds such as diabetes, hypertension, undernutrition, and overweight/obesity, are strikingly vulnerable to serious illness and death from covid-19 (2) . yet, covid-19 response measures such as self-isolation, social distancing, and lockdowns of communities can lead to poor management of key risk factors such as unhealthy diets and physical activity (2) , and limited access to preventive care in primary care settings. additionally, insecure economic conditions, restricted travel and access to health care services, delayed vaccination schedules, and shuttering of educational facilities further compound poor health conditions for young children, especially in low-and middleincome countries (lmics) (3) . there is significant concern that covid-19 responses have had a negative impact on the nutritional status of women and children, and that these could worsen over time. a recent modelling exercise of various estimates of the potential impact of covid-19-related economic deterioration, food insecurity, and interruption of programs of community-based detection and management of malnutrition suggests that the prevalence of wasting could increase by 10-50% with an excess of ∼40,000-2,000,000 child deaths (4) . we believe that these projected nutrition effects of the global pandemic could well be underestimates, as they fail to take into account the potential effect on maternal nutrition, micronutrient deficiencies, and intrauterine growth as well as downstream impacts on maternal and child health programs that can impact linear growth and childhood stunting. this is unfortunate since the world has made some, albeit slow, progress in reducing childhood stunting over the last decade. current estimates indicate that 149 million children under 5 y are stunted, a reduction from 166 million in 2012 but still far from the required global targets for progress (5) . covid-19 now threatens to halt or reverse gains even further. if unaddressed, the effects on linear growth in children and consequent stunting could be much more consequential than short-term effects of undernutrition. sectors critical to reducing childhood undernutrition at particular risk of collapse or reduced efficiency due to widespread impact of covid-19 are summarized below and in figure 1 . • food insecurity and poor-quality diets • building resilient food systems during covid-19 requires innovative context-specific demand and supply-side initiatives. food supply chains (fscs) are of particular interest, since 80% of all foods consumed in africa and asia are now dependent on these markets (6) . despite being nominally "exempt" from lockdowns, covid can have direct and indirect impacts on fsc function in lmics, especially the informal sectors. while direct impacts, through closures of restaurants and restrictions on vendors, represent a small share of the total food economy in urban settings, the impact on rural markets could be much greater additionally, indirect impacts due to unemployment and falling incomes of daily wage laborers and industry workers have taken a heavy toll on people in lmic settings (7) . further compounding this is the issue of food pricing. restrictions on mechanisms for production and delivery may drive up cost, while fear of shortages could drive speculative hoarding (8) . loss of household income exposes vulnerable families to price spikes and food shortages, while low agricultural productivity and breaks in the food import-export system disrupt local food markets and small businesses (9). • additionally, given limited access to fresh produce, children and families may be more likely to resort to cheaper and more accessible processed and prepackaged, highsodium, and less-nutritious foods (10), with deleterious health consequences. • reduced income and limited financial resources • covid-19 has pushed millions of households into economic despair and has been described as more lethal than the 2008 global financial crisis (11) . oxfam predicts that half a billion people could be pushed into poverty (12) , while the world bank contends that an additional 40-60 million people could be pushed into extreme poverty (13) . the interruption of existing social safety nets, especially for women, is a challenge in many lmics struggling with covid-19 as funds are diverted to immediate needs compounded by limited mobility and access to services. • limited care and restricted health services • given overburdened health systems, restricted travel, and changing priorities at the primary care level, access to routine health services for women and children has suffered tremendously. while quality of care was an ongoing challenge prior to covid-19 (14) , in its current state and onward for years targeted efforts for highquality health care for those in the most need will likely take a backseat. consequently, the health and risk of undernutrition in mothers and their children may increase dramatically, especially if current conditions persist long term. in pakistan, available data from district health systems indicate a dramatic drop in access for and provision of antenatal care services (za bhutta, personal communication, 2020), and others have highlighted the importance of the unmet need for mental health services and interventions (15) . as has been indicated by united nations population fund (unfpa) (15) , reduced access to family-planning services and enforced confinement of families is projected to lead to 7 million unintended births in some of the poorest countries of the world. persistent disruptions to routine and requisite maternal care and nutrition could lead to adverse fetal outcomes including preterm birth, low birth weight, and small-for-gestationalage newborns. • interrupted education for children and adults • educational facilities, including primary, secondary, postsecondary, and specialized training institutions, have been shuttered almost completely worldwide in the wake of covid-19 (16, 17) . one of the major effects of covid-19 has been on exacerbating inequities in education. much has been made of alternative forms of learning, such as online classrooms, web-based courses, and homeschooling, but these are inaccessible to most children in lmics. women and girls, who often experience the highest rates of illiteracy and school drop-outs in lmics, are yet further debilitated and disadvantaged. the benefits of general and specialized health and nutrition education to improve maternal nutrition and reducing intergenerational childhood stunting are indisputable, having been shown consistently in stunting case studies (18) (19) (20) . an additional setback has been the interruption of school nutrition programs, the mainstay of addressing food insecurity in some of the poorest sections of the population. • unhealthy household environment • given diverted funds and priorities, building safe and healthy household and community environments, particularly as related to clean water, appropriate sanitation, and hygiene (wash), may fall behind on country agendas. yet now more than ever, wash interventions are essential to protecting human health and preventing undernutrition (21) . for instance, in urban slums (some of the most vulnerable communities), lockdowns and limited mobility have impacted access to clean water and safe sanitation services. given the nature of covid-19 transmission, this could result in lethal outbreaks of infectious diseases. • limited access / proximity to available services (e.g., clean water, safe sanitation) we believe that countries can address these extraordinary nutrition risks across the continuum of mothers, newborns, children, and adolescents by addressing determinants and implementing evidence-informed strategies for action. this narrative is aimed at reviewing key areas of concern for supporting maternal and child nutrition progress during and in the aftermath of covid-19, while providing strategic guidance for countries to continue making headway in reducing maternal and child undernutrition while battling covid-19. as our research into stunting reduction exemplars has demonstrated, stunting progress in lmics has been driven by a multifactorial set of investments in sectors that have direct and indirect impacts on nutrition (figure 2) , most of which are extremely relevant in the current covid-19 crisis and must be continued. our exemplars underscore multiple examples of high-impact strategies both within and outside a country's traditional health system. these examples were data-driven and enabled by strong, focused country leadership, efficient financing, and effective partnerships (22) . we believe that the same approach is needed within lmics to address the nutritional consequences of covid-19 mitigation strategies. the state of the world and our collective response to covid-19 is continually evolving as new information is received. nevertheless, initial observations across different countries and contexts, along with key lessons from countries managing through other crises in the past, suggest that we prioritize the following approaches to address and prevent exacerbating maternal and child undernutrition: • food insecurity interventions • given the diversity of food environment and security challenges experienced by lmics during covid-19, solutions must be context specific. lessons from many stunting-reduction exemplar countries could be useful. in the kyrgyz republic, for instance, the unprecedented economic collapse after the dissolution of the soviet union created new opportunities for mobilizing the agricultural sector to drive economic recovery. a range of radical agrarian reforms focused on revitalizing institutions for land, livestock, capital, and labor, while concurrently, shifting land ownership from the state to private households was considered among the most pivotal driving factors of stunting reduction in kyrgyz republic between 1990 and 2014 (23) . while agrarian land reforms focused on shifting land ownership and adopting innovative/efficient agricultural practices may yield dividends on undernutrition in the long term, immediate solutions also have value. one of ethiopia's solutions to food insecurity (i.e., the productive safety net program) was aimed at providing emergency food aid to 15 million individuals vulnerable to food insecurity and was considered important to the country's stuntingreduction narrative (18) . such long-and short-term solutions addressing both supply and demand-side challenges could be considered for nutrition protection in covid-19-affected countries. • social protection programs • the prioritization of efforts to provide economic security by governments to their at-risk populations (e.g., through innovative and targeted social safety net programs, payment deferrals, or tax breaks) is essential to preventing financial collapse of vulnerable households. socialprotection programs are increasingly taking center stage in policy dialogues for tackling poverty, vulnerability, and social exclusion. several exemplar countries, notably peru (20) and the kyrgyz republic (23), employed successful financial-incentive based models as a means for providing social safety nets for reaching marginalized and vulnerable populations. in peru, for instance, the juntos conditional cash transfer program provided households with a fixed monthly cash transfer (∼$30 usd) to comply with basic education, health, and nutrition services for children. this was paired with strong data-management systems that allowed for identification of vulnerable populations and effective targeting to ensure that resources were disbursed effectively. the kyrgyz republic's monthly benefit for poor families with children program is an analogous essential social-protection scheme that was found to be notably important to stunting reduction in the country. in today's covid-19 environment, such systems in peru, kyrgyz republic, and many other countries can be leveraged to build on and enhance social and economic protection for vulnerable families, and consequently prevent ill health and chronic undernutrition in children. • access to health care • as has been shown in several stunting-reduction exemplar countries, access to health care for even the most remote and hard-to-reach populations can happen with an effective community health extension system. ethiopia's health extension workers (hews) (18) and nepal's female community health volunteers (fchvs) (19) showcase successful models of mobilizing community health workers (chws; who receive basic training and commodities) to deliver vaccines, nutritional supplements, health and nutrition education, and even reproductive, maternal, and newborn care. the current recommendations are to remunerate such chws rather than rely on pure volunteerism. amidst the covid-19 crises, while the primary health care system may not be fully functional and supplies short, governments could consider calling on existing chw cadres to reprioritize their tasks and cater to emerging maternal, child health, and nutrition screening in communities. these chws are also key to reestablishing programs for community-based management of malnutrition. governments could also invest in deploying additional health workers and incentivizing current workers to continue delivering high-quality essential interventions to families (e.g., vaccines, antenatal care, referrals) and provide essential communication related to covid-19 preparedness and triage. where community health extension programs currently do not exist, countries may want to consider piloting or adopting such a program to supplement primary health care, as a short-or long-term solution. • educational programs • in the wake of closed formal education systems, countries could mobilize informal institutions such as chws and women's and community support groups to deliver health and general education. these systems are already in place in many lmics and could be revitalized and repurposed for continuing education. several stunting-reduction exemplar countries have shown the potential utility and impact of these mechanisms on stunting reduction. having learned from their experience with ebola, senegal's chw program (24) has proven to be an effective mechanism for communicating health best practices to the community. nepal's fchv (19) and ethiopia's hew (18) programs have also had highly successful health and nutrition counseling components. the kyrgyz republic used women's support groups in communities as a means to keep updated on the evolving health situation and share knowledge (23), a model that could continue to be expanded upon. • safe and healthy household/community environments • ensuring safe water access and appropriate sanitation and hygiene practices is critical to the covid-19 containment agenda and health outcomes beyond. while providing infrastructural support to households and communities (e.g., through building wells, community pipes, latrines) is critical, it may fall off short-term agendas as handwashing and hygiene campaigns take precedence. lessons from exemplar countries suggest that high-impact, low-cost community mobilization efforts could play a pivotal role in creating a healthy environment by reducing open defecation and encouraging hygienic practices and have been linked to stunting reduction. the community led total sanitation (clts) programs in nepal (19), ethiopia (18) , and senegal (24) focus on behavioral change to create open-defecation-free villages. the programs trigger the community's desire for collective change through encouraging innovation and context-specific solutions while fostering a sense of community ownership. the clts programs in exemplar countries such as nepal have had a notable impact on childhood stunting reduction. beyond interventions targeting specific challenges for childhood stunting, many ongoing covid-19 response measures could double as opportunities to address other health and wellbeing priorities such as malnutrition prevention and management in lmics. governments, donors, and development partners during covid-19 response policy and funding dialogues should strategize on cost and system efficiencies for targeting broader health and nutrition goals within their covid-19 response plans. the covid-19 pandemic has thrown the world into an unprecedented crisis, fighting a pathogen that could well be with us for a long time to come. as countries lurch from the shock of large-scale lockdowns to a gradual return to normalcy, the transition will be slow and the new normal very different from the past. safeguarding the health and nutrition of vulnerable women and children is a key policy response and must be based on the best evidence of what works, so that gains in survival and women's and children's health and nutrition are not reversed. governments, donors, and development partners will together need to restrategize and reprioritize investments for the covid-19 era using data-driven decision making. effective execution of strategies will require money, political will, and commitment, and international unity; these will be pivotal drivers, securing not only covid-19-specific gains but also overall protection of global health and improvements in undernutrition. estimates of the severity of coronavirus disease 2019: a model-based analysis comment: prevention and control of noncommunicable diseases in the covid-19 response don't let children be the hidden victims of covid-19 pandemic: statement by unicef executive director henrietta fore early estimates of the indirect effects of the covid-19 pandemic on maternal and child mortality in lowincome and middle-income countries: a modelling study rapid transformation of food systems in developing regions: highlighting the role of agricultural research & innovations covid-19 lockdowns are imposing substantial economic costs on countries in africa how covid-19 may disrupt food supply chains in developing countries food security and covid-19 what does junk food have to do with covid-19 deaths? environmental health news coronavirus crisis could plunge half a billion people into poverty: oxfam [internet]. world economic forum 2020 /04/coronavirus-crisis-could-plunge-half-a-billion-people-into-pove rty-oxfam dignity not destitution: an 'economic rescue plan for all' to tackle the coronavirus crisis and rebuild a more equal world the impact of covid-19 (coronavirus) on global poverty: why sub-saharan africa might be the region hardest hit world bank blogs 2020 high quality health systems in the sdg era: countryspecific priorities for improving quality of care impact of the covid-19 pandemic on family planning and ending gender-based violence, female genital mutilation and child marriage 290 million students out of school due to covid-19: unesco releases first global numbers and mobilizes response covid-19 and children, in the north and in the south drivers of stunting reduction in ethiopia: a country case study drivers of stunting reduction in nepal: a country case study drivers of stunting reduction in peru: a country case study unicef wash programme contribution to covid-19 prevention and response how can countries reduce child stunting at scale: lessons from exemplar countries drivers of stunting reduction in kyrgyz republic: a country case study drivers of stunting reduction in senegal: a country case study the authors reported no funding received for this study. data described in the manuscript, code book, and analytic code will not be made available because this is a review article and did not have primary data analysis.we thank drs. oliver rothschild and niranjan bose from gates ventures for funding support and overall technical/research support this perspective.the authors' responsibilities were as follows-na, gk, and zab: conceived the perspective outline; na and gk: conducted research and prepared the first draft of the manuscript; zab and eck: provided critical review and feedback; zab: is overall guarantor of the content; and all authors: read and approved the final manuscript. the authors report no conflicts of interest. key: cord-310944-tfn0ltrz authors: peck, jessica l. title: covid 19: impacts and implications for pediatric practice date: 2020-07-09 journal: j pediatr health care doi: 10.1016/j.pedhc.2020.07.004 sha: doc_id: 310944 cord_uid: tfn0ltrz since the rapid emergence of the novel coronavirus in december of 2019 and subsequent development of a global pandemic, clinicians around the world have struggled to understand and respond effectively and efficiently. with global response encompassing social, political, organizational, and economic realms, world leaders are struggling to keep pace with the rapid changes. challenges within global healthcare system and the healthcare profession itself include rationing supplies and services within health care systems, many of which were stretched to the brink before this latest viral outbreak (american hospital association, 2020). leaders are making policy decisions while balancing the slow and precise nature of science with the rapid and pressing need for life-saving information (altmann, douek, & boyton, 2020). shortcuts on research are occurring, including publishing papers with lack of peer review. social media and lurid reporting bolster feelings of mistrust and panic-buying while burgeoning conspiracy theories commandeer national dialogue. this is a time in history to prioritize global health and thoughtful pandemic preparedness (lancet, 2020). pediatric nurse practitioners (pnps) are ideally situated to be a trusted source of accurate health information for children. this continuing education article summarizes the latest evidence-based information on the rapidly developing coronavirus pandemic; equipping pnps for clinical preparation and response. 1.. distinguish risk factors for covid-19-related morbidity and mortality and identify modes of transmission. 2.. appraise appropriate covid-19 testing parameters and procedures for children. 3.. compare pediatric clinical presentation to adults with covid-19 infection and recommend appropriate treatment measures. 4.. state appropriate infection-control measures to reduce transmission. 5.. describe measures to reduce the risk of infection spread, mitigate adverse health effects in high-risk children, and to promote general health through preventive care. media and lurid reporting bolster feelings of mistrust and panic-buying while burgeoning conspiracy theories commandeer national dialogue. this is a time in history to prioritize global health and thoughtful pandemic preparedness (lancet, 2020) . pediatric nurse practitioners (pnps) are ideally situated to be a trusted source of accurate health information for children. this continuing education article summarizes the latest evidence-based information on the rapidly developing coronavirus pandemic; equipping pnps for clinical preparation and response. severe acute respiratory syndrome (sars) family and is also referred to as sars-cov-2. covid-19 is a zoonotic, enveloped, single-stranded ribonucleic acid (rna) virus that can quickly mutate and recombine, creating novel virus strains that spread from animals to human. there are currently four strains of coronavirus circulating in humans, all thought to originate in bats. covid-19 was first reported in wuhan, china; with controversial and unsubstantiated reports on the nature of its origin. coronaviruses are known for causing severe respiratory distress and respiratory failure along with coagulopathies, multi-system organ failure, and death (zimmerman & curtis, 2020) . the timeline (see figure 1 ) of the covid-19 outbreak is astonishing, as china first reported a cluster of cases of pneumonia in wuhan on december 31, 2019. just a month later the world health organization (who) declared a public health emergency of international concern and by march 11 th , assessed the crisis as a global pandemic (who, 2020) . response in the united states (us) evolved rapidly as president trump declared a state of national emergency under the stafford act on march 13 th . six days later, california became the first state to issue a statewide stay-at-home order. the following week, the u.s. national guard was activated in all fifty states. by the end of march, new york city emerged as the epicenter in the us and by the end of april, the us reported more than one million cases, the highest number in the world (kantis, kiernan, & bardi, 2020) . declaration of a public health emergency has directed the entire healthcare system to initiate population-based triage, the management of massive numbers of individuals seeking care. tasks in this strategy include providing crisis leadership, sustaining organizational response, and achieving disease containment. triage-based categories include addressing susceptible, exposed, infectious, removed, and/or vaccinated populations, usually through an incident command system. goals are divided into two phases (see table 1 ). phase one addresses broad generic interventions based on best public health practices, while phase two management decisions are surge-dependent and specific to the five aforementioned triage categories (burkle, 2008) . children are a population who have been spared significant burden of severe illness. to date, two studies (n= 2,143 and n= 171) have described similar covid-19 findings in pediatric patients. boys are more commonly affected than girls and most children were either asymptomatic or mildly symptomatic. children younger than three years of age and those with congenital heart disease seem to be disproportionately impacted (yagnik et al., 2020) . social determinants of health are emerging as a predictor of health disparity in covid-19, many of which impact pediatric populations. essential workers are less likely to be able to work from home and financially tolerate furlough. persons with crowded housing, inconsistent access to care, chronic conditions, and high stress levels impacting immune function are more susceptible to adverse outcomes as are those who experience racial or ethnic prejudice and/or discrimination (golden, 2020) . people of color, particularly african americans, experience more serious covid-19-related morbidity and mortality. while african americans make up 13% of the us population, they account for approximately 30% of deaths, and up to 75% of covid-19related deaths in chicago. asian americans show similar disparity at 18% of the us population and 23% of covid-19 deaths (golden, 2020) . other populations at significant risk include older adults (> 65 years of age), persons with underlying medical conditions (e.g., asthma, cardiovascular disease, kidney disease), persons with immunocompromise, persons with severe obesity (body mass index >40), persons with diabetes, persons undergoing dialysis, and persons residing in long-term care or nursing homes (cdc, 2020c) . care must be taken to ensure equitable, transparent provision of services during this pandemic. covid-19 is thought to spread mainly from person-to-person, primarily through close contact and droplet exposure from distances of six feet or less (zimmerman & curtis, 2020). children carry the covid-19 virus in the upper respiratory tract, making it easier to spread in childcare centers, schools, and homes; where pediatric respiratory hygiene is inconsistent and problematic (zimmerman & curtis, 2020). r 0 (pronounced r-naught) is the average number of secondary cases attributable to an index case. in other words, it is the average number of persons someone with covid-19 is predicted to infect. r 0 estimates for covid-19 range from 2.0-5.7. experts project 82% of the population needs immunity (antibody induced or vaccine acquired) to stop transmission and achieve herd immunity (ramirez, 2020) . early analysis suggests active public health surveillance, contact tracing, quarantine implementation, and coordinated social distancing efforts are critical in stopping the spread of covid-19 (sanche et al., 2020) . as of june 25, 2020, there were no confirmed cases of covid-19 intrauterine transmission, although there were concerns over possible correlation to miscarriage, intrauterine growth restriction and preterm delivery (zimmerman & curtis, 2020) . in the weeks following this report, however; there is growing evidence maternal-fetal transmission is occurring (alzamora et al., 2020) . unlike earlier outbreaks of sars, covid-19 yields fewer maternal mortalities (schwartz, 2020) . covid-19 outcomes of pregnant women are similar to women who are not pregnant, including the need for intensive care. as of may 1, seven maternal deaths have been reported (d'ambrosio, 2020). there is currently no evidence to suggest covid-19 transmission is foodborne, although early reports indicate the virus can live up to 24 hours on cardboard and paper (i.e. food packaging containers) and up to three days on harder surfaces (cdc, 2020h) . current advice to reduce transmission associated with grocery shopping or take-out food includes handwashing before and after handling food packaging, removing packaging prior to eating, limiting trips to the grocery store, and ensuring food preparers (including grocers and restaurants) are complying with health guidance such as wearing masks and screening workers for illness (cdc, 2020h) . there are currently no reports of domestic pets as vectors, although one tiger at a new york city zoo tested positive (cdc, 2020e). if persons are ill with known or suspected covid-19, it is wise to self-isolate from pets if possible. to lower risk of transmission, dogs should be walked on a leash, keeping a six-foot distance from other people and animals. crowds should be avoided, and pet-owners should not allow strangers to pet their animals. if a pet shows signs of illness, the veterinarian should be called for further instruction as opposed to arriving unannounced at an animal clinic (cdc, 2020e). pediatric healthcare providers have always demonstrated expertise in promoting general holistic health, and now that task is more critical than ever as persons with pre-existing medical conditions are disproportionately affected by adverse outcomes from covid-19. table 2 offers strategies for targeted health interventions to optimize health and mitigate potential serious and life-threatening outcomes associated with covid-19 infections. non-pharmaceutical interventions (npis) are actions, apart from immunization and medication administration, people and communities can take to help slow the spread of illness. the goals of npis are to prevent and/or minimize morbidity and mortality while minimizing social disruption and economic effects. timing is crucial to ensure npis are applied with the least restrictive measures which provide the greatest public health benefit (banholzer et al., 2020) . the challenge of npis is that evidence of efficacy is always retrospective. evidence concerning npis implemented to mitigate the spread of covid-19 in the us is to date, inconclusive, although early analysis conducted by banholzer et al., (2020) is promising (table 3 ). social distancing (e.g. maintaining a physical distance in public at a minimum of six feet from persons not living together in the same household) has emerged as a critical npi to slow the spread of covid-19 (messonier, lipsitch, stripling, & markel, 2020) . families can be equipped by healthcare providers who emphasize the importance of promoting adherence. role modeling from parents and other adults in the home is an effective way to encourage children to adhere to public health guidelines. parents should emphasize personal responsibility, especially with adolescents, by establishing clear expectations and firm guidelines with instruction including ways in which lack of personal responsibility can adversely impact the lives of others. families should also consider postponing visits to see older family members or grandparents and consider use of technology to maintain emotional and relational connections (inouye, schuchat, aiello, galea, & nuzzo, 2020). on april 3, 2020, the cdc made a departure from previously issued guidance with a broad recommendation for anyone over two years of age to wear face masks or coverings while in public. this does not replace recommendations for social distancing or personal hygiene measures to control the spread of covid-19 (cdc, 2020b). persons excluded from mask usage include babies less than two years of age, and persons who have trouble breathing, are incapacitated or are unable to remove a mask without assistance. mask use is more effective in protecting others from spread of viral pathogens than protecting the wearer from infection. ideal fabrics for do-it-yourself masks include denim, canvas, and paper towels, with scarves as a last resort. layering adds potential protection, but also can decrease ability to breathe easily (cdc 2020b). in general, surgical masks and n-95 respirators should be reserved for healthcare workers and other first responders. in healthcare settings, n-95 masks should be reserved for high-risk aerosolizing procedures such as intubation and endotracheal suction and high-risk healthcare workers including those with a history of asthma. the use of expired n-95 masks may be acceptable in some circumstances. fit-testing and seal-check is recommended for all n-95 mask use, expired or not (mcmillan & rebman, 2020) . the straps and bridge of the nose are usually the first areas to break down and should be visually inspected before use. to preserve masks and maximize usage, longer usage is preferred over re-usage. a face shield used over a mask is preferred and may help extend the life of the mask (mcmillan & rebman, 2020). lack of adequate personal protective equipment (ppe) has been a widely publicized and broadly discussed concern of healthcare providers, first responders, and essential workers. ideal ppe when caring for a patient with known or suspected covid-19 infection includes: a new n-95 mask, gown, medical grade gloves, and eye covers and/or a face shield (cdc, 2020b). proper donning and doffing of ppe are essential to prevent viral spread. institutions should take care to implement protocols and training to adequately equip personnel. hand hygiene should be performed before and after removal and masks should be removed by the straps and handled with gloves. if there is limited or no ppe in a health care setting, usage should be reserved for high-risk persons (e.g. persons > 60 years of age, with chronic medical conditions, or pregnant) or those performing high-risk aerosolizing procedures such as intubation, endotracheal suction, or cardiopulmonary resuscitation. limiting visitors in the healthcare setting can be a measure to reduce ppe usage (mcmillan et al., 2020) . the cdc has issued guidelines for reuse of surgical gloves, masks, and other ppe should new items not be available. homemade ppe should be used a last resort. the cdc has a ppe burn rate calculator tool available online to help estimate usage and ordering needs for healthcare settings (cdc, 2020b). frontline personnel and essential workers are concerned about covid-19 transmission to family members and household contacts. self-quarantine should be considered, particularly if there are persons in the home at high-risk for adverse outcomes from covid-19 (little et al., 2020) . several hotel chains are offering free lodging to frontline personnel, and many other community efforts include donation of vacation homes or recreational vehicle use. if selfisolation is not possible, a separate room and bathroom is ideal if available for symptomatic persons, with delivery of meals using disposable plates and utensils. frontline workers should remove all clothing and shower at their place of employment if possible. alternatively, stripping clothing in the garage or designated entry spot of the home while placing soiled clothing in a garbage bag for laundering is preferred. shoes should be removed and placed in a plastic bin at the home entrance. cleaning soles of shoes with bleach is not recommended, as it may increase risk of exposure. frontline workers should regularly self-monitor for symptoms including temperature and promptly report any potential signs of illness (charbonneau, 2020). evidence is still emerging on efficacy of these efforts, but early results point to handwashing, disinfecting carefully, avoiding sharing rooms and surfaces, managing home deliveries with caution, and ensuring adequate ventilation as most efficacious. healthcare providers can help families plan for modifications of behavior and factors in the home environment with assistance in problem solving to overcome barriers (little et al., 2020) . in addition to consideration in the home setting, careful attention should be given to measures within the healthcare setting to minimize the risk of nosocomial infection (table 4) . the gold standard of diagnosis for covid-19 remains the reverse transcriptasepolymerase chain reaction (rt-pcr) using a nasopharyngeal swab, which demonstrates greater reliability over salivary or oropharyngeal specimen analysis (sethuraman, jeremiah, & ryo, 2020) . rt-pcr positivity is estimated to persist approximately three weeks beyond the onset of illness, indicating only the detection of viral rna and not necessarily viable transmittable virus (sethuraman, jeremiah, & ryo, 2020) . at the end of may 2020, the us is performing approximately 150,000 tests per day with a daily goal of 500,000. nationally, the positive rate is around 20% while germany is reporting 6% and south korea 3%. positive rates of more than 10% indicate less than ideal conditions and inadequate testing (relman, taylor, & benjamin, 2020) . currently there are approximately 70 assays commercially available with wide variability in length of testing and significant supply chain issues affecting availability of cotton swabs, reagents, and other items necessary to complete testing. as rapid point-of-care tests emerge on the market (currently there are three), they arrive with a disadvantage of threats of inconsistency in reporting, creating more challenges with contact tracing. sensitivity and specificity currently vary widely and need further investigation (relman et al., 2020) . in clinical cases with a high index of suspicion and an initial negative nasopharyngeal rt-pcr, repeat testing should be pursued (zimmerman & curtis, 2020). testing of children is variable by region related to state and county guidelines, testing availability and accessibility, and community prevalence. time estimations of rt-pcr positivity and seroconversion are still unknown in children because largely adult populations have been studied to date. some concern has emerged after reports of persistent pcr in stool specimens, suggesting possible implications for high-risk caregivers of children who need assistance with elimination needs (sethuraman et al., 2020) . serology testing for covid-19 antibodies is rapidly emerging to explore individual immunity as well as the use of convalescent plasma in therapy for persons with active infection. the food and drug administration (fda) issued rapidly changing guidance on antibody testing, initially waiving the need to apply for an emergency use authorization (eua) but later requiring application within ten days of appearance on the commercial market. if the test does not meet fda standards, testing must be suspended (shah & shuren, 2020) . experts advocate for a thoughtful, deliberate approach to ensure the utmost standards of scientific rigor and safety to guide high-stakes policy decisions (altmann, douek, & boyton, 2020) . barriers to testing are influenced by social determinants of health. although the federal government passed legislation to cover cost of covid-19 testing, cost of care associated with the diagnostic test may not be covered. locations of testing centers should be accessible to the community and drive-through testing centers should make accommodations for those who do not have a car (relman et al., 2020) . testing times should provide flexibility in consideration of employment hours of essential workers. efforts should be made to eliminate racial or ethnic discrimination while providing reassurance and anticipatory guidance to counter fear of stigma resulting from a positive test. many primary care systems are severely impaired, and many overwhelmed emergency centers may turn patients away. there is much work to be done to ensure equitable access for all to covid-19 related care (relman et al., 2020) . it appears children present with similar symptoms described in adults with active covid-19 infection, although most are either asymptomatic or mildly symptomatic. in late april 2020, the cdc added six symptoms now believed to be associated with covid-19 including: chills, shivering, muscle aches, headache, sore throat, and a loss of taste and/or smell (neuman, 2020). these were added to previously identified symptoms of fever (91-100%), cough (43-80%) and rhinitis (33-60%); 50-80% of reported cases reported an ill family contact and 30% reported nosocomial contact (zimmerman & curtis, 2020). although much has been discussed in the media concerning gastrointestinal symptoms as a pediatric presentation, the reported study referenced had five subjects, leaving much to be discovered (feder, 2020) . emerging characteristics of serology and radiologic findings are listed in table 5 . recent developments include concern of what is being called "covid-toes." initially, dermatologists had concern for children with pre-existing skin conditions, particularly those taking biologics or immunomodulators, who might be at increased risk for covid-19-associated morbidity and mortality. anecdotal reports were channeled to a registry development with the global rheumatology alliance where more organized reports of pernio-like lesions on the toes began to coalesce. these lesions are characteristic of chilblains, but without any cold exposure. children report a burning sensation, pain, and/or tenderness lasting approximately two weeks. there is no correlation currently between dermatologic manifestation and severity of illness (forand, 2020) . as skin eruptions are common with viral illnesses of childhood, it is important to reassure parents covid-toes seem to be an uncommon occurrence and to seek care with any health concerns (cleveland clinic, 2020). concerned providers may report possible cases to www.aad.org/covidregistry. also, of concern are reports of a kawasaki-like syndrome (referred to by the cdc as multisystem inflammatory syndrome in children (mis-c) in fifteen children aged 2-15 years hospitalized in new york city (hester, 2020) . while none of these children have died related to mis-c, five have required ventilator support and six have died from other covid-19 complications. reports of misc-c in europe include 20 cases in italy, 20 in paris, and 12 in britain (goldstein, 2020) . some children appear to have signs of initial recovery followed by a secondary inflammatory response. clinical implications include increased vigilance of potential manifestations of systemic vasculitis with appropriate clinical assessment and public health reporting for covid-19 (hester, 2020) . parents can be reassured mis-c still appears quite rare as a complication and in and of itself is not contagious (steenhuysen, 2020) . other vascular complications include higher than previously indicated coagulopathies, possibly initiated by a cytokine storm. retrospective autopsy findings suggest mortality related to undiagnosed deep vein thrombosis. further exploration is needed to investigate the molecular mechanism, incidence, and clinical implications of these findings (bandyopadhyay et al., 2020). the national institute for health (nih) published the first covid-19 treatment guidelines in may of 2020. there are some special considerations for pediatric populations, but the majority of guidance includes statements iterating insufficient data exists for or against use of pharmacologic therapies to treat covid-19 infections in children (nih, 2020). treatment mainly consists of supportive care with provision of sufficient fluid and calorie intake along with oxygen supplementation and airway support. most cases appear to be mild and can be treated at home following clinician determination of minor illness with appropriate anticipatory guidance and evaluation of available resources. vitamin d supplementation may play a role in reducing the risk of covid-19 infections, but there is insufficient evidence to support universal recommendation for children (grant et al, 2020) . children who are ill enough to require hospitalization need observation for progression of respiratory distress, multi-system organ failure, and development of secondary nosocomial infections (zimmerman & curtis, 2020). other covid-19 pharmacologic treatment explorations include monoclonal antibodies, protease inhibitors, and rna synthesis inhibitors (zimmerman & curtis, 2020). chloroquine in particular has been widely publicized and publicly debated. emerging recommendations include prioritizing available supply for rigorous, scientific clinical trials, preventing treatment interruptions for those on chloroquine for chronic rheumatic diseases, and provision of clear messages with transparent and accurate interpretation of available data concerning covid-19 treatment (yazdany & kim, 2020) . if a child has a laboratory confirmed or clinically suspected case of covid-19, isolation should be initiated. discontinuing isolation can be test-based with two or more negative tests (with eua approval from the fda) more than 24 hours apart and meeting requirements for symptom-based strategy. if testing is not available, isolation may be discontinued solely with a symptom-based strategy after a minimum of ten days from the onset of symptoms and more than three days from recovery (defined as a minimum of 72 hours afebrile without antipyretics and improvement in respiratory symptoms cdc, 2020f). the world is waiting with bated breath for a covid-19 vaccine. with more than 100 potential vaccines in development, safety and scientific rigor in the process will need to take highest priority (altmann et al., 2020) . many approaches are being studied including liveattenuated, inactivated, subunit, recombinant, viral vector, and dna vaccines (zimmerman & curtis, 2020) . vaccine development is a process which customarily takes 20+ years, but in the case of covid-19, is being attempted in 12-18 months. comparatively, other vaccines for children have gone through rigorous clinical trials with more than 70,000 subjects studied over four years or more, a difficult bar to clear in these conditions. in biologics, the process is the product, and it is essential the process is the same for every dose (offit, 2020). on may 4, 2020, the national institute of allergy and infectious disease announced the human epidemiology and response to sars-cov2 (heros) study. more than 6,000 children in 2,000 families currently enrolled in nih-funded pediatric research in 11 cities will participate in the effort to provide answers as to why most children with acute covid-19 infection are not seriously ill. families will be studied remotely with caregiver collection of specimens. questions to be addressed include: 1) do infection rates differ in children with asthma? 2) how many children infected with covid-19 develop symptoms? and 3) are children resistant to covid-19 infection? (nih, 2020). primary care access has been severely disrupted by restrictions implemented to prevent covid-19 transmission. challenges include limited ppe, limited availability of covid-19 tests, patient workflow disruptions with closed waiting rooms and drive-through services, dramatic patient census drops and revenue shortfalls, and parental fears resulting in hesitance to present for care. in addition, rapid changes in telehealth in the last two months have exceeded changes made in the last two decades, with many practices quickly adapting from little-to-no telehealth to a majority of services being delivered remotely (mostashari, 2020) . long-term health impacts and outcomes remain to be seen. many pnps have been called upon to care for young adults, converting inpatient critical care units to house persons aged into their 30s (philips et al., 2020; renke et al., 2020) . in times of emergency, this may be necessary. the national association of pediatric nurse practitioners (napnap) asserted this is appropriate in certain circumstances but clarified certain conditions for consideration including: 1) individual state nurse practice acts should be consulted and followed, 2) the pnp has education and training to give appropriate care to the assigned patient, 3) safe harbor protections are in place to protect the pnp from being forced to accept unsafe assignment, and 4) care will transition to an adult provider as soon as possible (napnap, 2020a). early estimates suggest measles vaccination rates have fallen up to 60% since onset of the covid-19 pandemic (dunleavy, 2020) . pnps play an important role in promoting vaccination by encouraging and equipping families to stay on schedule to avoid vaccinepreventable illness (goza, 2020) . napnap recommends innovative solutions to provide safe opportunities to keep vaccination schedules on time including: 1) separating well and sick visit hours, 2) staggering appointment times, 3) closing waiting rooms, 4) reminding families about upcoming vaccines, 5) using every patient encounter as an opportunity to administer vaccines, and 6) administering as many simultaneous vaccines as possible (napnap, 2020b) . the world has changed on a 9/11 type of scale in the weeks following rapid spread of covid-19. this is likely to change society in several ways with long-term implications still largely unknown. professional experts in science, medicine, nursing, economics, business, journalism, and others are offering professional opinions of their expectations of world changes and paradigm shifts (politico, 2020). schools are struggling to adapt rapidly, making high-stakes decisions with little information available. the american academy of pediatrics issued guidance regarding return to school to shape conversations around holistic health and equity (hester, 2020) . napnap (2020c) issued a position statement concerning child health and wellness during covid-19. recommendations for families include: 1) supporting children as they ask questions about the pandemic, 2) close monitoring of child health and well-being with prompt contact of primary healthcare providers if changes are noticed, and 3) continuing to seek care in-person or using telehealth to maintain well visits and immunization schedules while receiving anticipatory guidance and necessary screenings. recommendations for providers include: 1) increasing utilization of telehealth and telemedicine, 2) designing office experiences to support social distancing in a developmentally appropriate way, 3) increasing access to hand sanitation, 4) providing masks as indicated, 5) ensuring ppe is available for all staff, 6) advocating for mental health awareness and connection to resources, 6) referring families to credible sources of health information, 7) reminding families to present for well care, and 8) considering participation in research efforts. pnps will need to continue to be active learners, adaptive and flexible while serving as trusted sources of information for families with children who concerned about immediate and long-term impacts and implications of covid-19. 1. which statement is most accurate concerning covid-19 morbidity and mortality in the pediatric population? a. children have been disproportionately affected, with high rates of morbidity and mortality b. children have lower rates of infection, but higher rates of death than adult populations c. children with covid-19 infection are mostly asymptomatic or mildly symptomatic d. children are at much higher risk for acquiring covid-19 than adult populations 2. which of the following statements are true about non-pharmaceutical interventions (npis)? select all that apply. a. the goal of npis is to eliminate all mortality associated with covid-19 b. timing is critical to ensure least restrictive measures with greatest public health benefit c. social distancing is the least effective measure to prevent the spread of covid-19 d. healthcare providers should emphasize personal accountability by establishing clear expectations and firm guidelines e. school closures are one of the most effective npis in helping slow the spread of covid-19 3. which of the following represents most appropriate mask usage according to cdc guidelines? a. cloth face coverings for infants less than two years of age b. surgical grade masks for school-aged children when in public c. do-it-yourself masks with scarves and coffee filters for primary care providers d. n-95 mask use for a pediatric nurse practitioner with a personal history of asthma 4. what actions should be taken to preserve ppe supplies for healthcare workers? select all that apply. a. use expired 3m n-95 masks for low-risk exposures* b. removal, disinfection, and reuse of ppe is preferred over extended single periods of use c. ideal ppe for covid-19 care includes a new n-95 mask, gown, medical grade surgical gloves, and eye covers and/or a face shield* d. visitors to the healthcare setting should be limited* e. mask removal should be preceded and followed by strict hand hygiene* 5. what should healthcare or essential workers do to help prevent transmission of covid-19 to household contacts? a. all essential or frontline workers should remain in self-quarantine for 30 days after providing care b. soles of shoes worn in healthcare setting should be cleaned with bleach after removing c. self-isolation at home should ideally occur in a separate room with private bathroom* d. n-95 masks and ppe gowns should be worn at home 6. if a child presents to the clinical setting with symptoms of covid-19 compatible illness, what test should the pediatric provider order? a. rt-pcr nasopharyngeal swab b. serology for covid-19 antibodies c. chest ct without contrast d. home-testing kit with saliva collection 7. which of the following clinical presentation scenarios is most concerning for possible covid-19? a. 6-year-old with one episode of diarrhea, two episodes non-bilious emesis, and no ill contacts b. 18-year-old with a bmi >40 and prior history of type ii diabetes mellitus who presents with cough, chills, fever, and loss of smell* c. 12-year-old with sore throat, lymphadenopathy, and nausea d. 1-year-old with maculopapular rash to the hands, feet, and buccal mucosa 8. what is the most appropriate response to parental concerns over multisystem inflammatory syndrome in children (mis-c)? a. this is a life-threatening illness becoming common in children b. this is a rare and usually treatable complication from a viral illness c. this is a contagious illness that can easily spread from child-to-child d. kantis, c., kiernan, s., and bardi, j.s., 2020, think global health (https://www.thinkglobalhealth.org/article/updatedtimeline-coronavirus) . "who timeline covid-19, by the world health organization, 2020 (https://www.who.int/news-room/detail/27-04-2020-who-timeline---covid-19). what policy makers need to know about covid-19 protective immunity. the lancet. advance online publication severe covid-19 during pregnancy and possible vertical transmission hospitals and health systems face unprecedented financial pressures due to covid-19 covid-19 pandemic: cardiovascular complications and future implications impact of non-pharmaceutical interventions on documented cases of covid-19. medrxiv. advance online publication autopsies of covid-19 patients reveal clotting concerns population-based triage management in response to surge-capacity requirements during a large-scale bioevent disaster strategies for optimizing the supply of facemasks discontinuation of transmission-based precautions and disposition of patient with covid-19 in healthcare settings are covid toes and rashes common symptoms of the coronavirus? why are we hearing so much about them these days? cleveland clinic miscarriage and maternal mortality in pregnant patients measles vaccinations in u.s. children fall up to 60 percent since pandemic, cdc says digestive issues were an early symptom of coronavirus for 5 children who needed hospital treatment, a study says dermatology expert weighs in on 'covid toes,' tracking dermatologic symptoms of covid-19 evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths coronavirus in african americans and other people of color 15 children are hospitalized with mysterious illness possibly tied to covid-19. the new york times aap statement on new data showing declines in childhood immunizations promoting healthy movement behaviours among children during the covid-19 pandemic. the lancet child & adolescent health aap offers guidance for reopening schools the science of social distancing updated: timeline of the coronavirus. a frequently updated tracker of emerging developments from the beginning of the novel coronavirus outbreak reducing risks from coronavirus transmission in the home-the role of the viral load be confident protecting yourself and providing the best care to your patients during this covid-19 pandemic american nurses association the science of social distancing collapse national association of pediatric nurse practitioners [napnap]. (2020a, april) study to determine incidence of novel coronavirus infection in u.s. children begins covid-19 vaccine update: will we have the vaccine any time soon? is the immune system induced by the vaccine really protective? rapid implementation of an adult covid-19 unit in a children's hospital. the journal of pediatrics coronavirus will change the world permanently. here's how what is r 0 ? gauging contagious infections. healthline covid-19 testing: possibilities, challenges, and ensuring equity utilization of pediatric nurse practitioners as adult critical care providers during the covid-19 pandemic: a novel approach high contagiousness and rapid spread of severe acute respiratory syndrome coronavirus 2 an analysis of 38 pregnant women with covid-19, their newborn infants, and maternal-fetal transmission of sars-cov-2: maternal coronavirus infections and pregnancy outcomes. archives of pathology and laboratory medicine interpreting diagnostic tests for sars-cov-2 insight into fda's revised policy on antibody tests: prioritizing access and accuracy three u.s. children with covid-18 have rare inflammatory syndrome who timeline-covid-19 pediatric characteristics of 2019 novel coronavirus: review of available use of hydroxychloroquine and chloroquine during the covid-19 pandemic: what every clinician should know. annals of internal medicine coronavirus infection in children including covid-19: an overview of the epidemiology, clinical features, diagnosis, treatment and prevention options in children key: cord-329905-dwfwwdbn authors: staat, dana d.; klepser, michael e. title: international adoption: issues in infectious diseases date: 2012-01-06 journal: pharmacotherapy doi: 10.1592/phco.26.9.1207 sha: doc_id: 329905 cord_uid: dwfwwdbn international adoptions have become increasingly common in the united states. children awaiting international adoption and families traveling to adopt these children can be exposed to a variety of infectious diseases. compared with the united states, foreign countries often have different immunization practices and methods of diagnosing, treating, and monitoring disease. reporting of medical conditions can also differ from that of the united states. the prevalence of infectious diseases varies from country to country and may or may not be common among adopted children. the transmission of tuberculosis, hepatitis b, and measles from adopted children to family members has been documented. furthermore, infectious organisms (e.g., intestinal parasites), bacterial pathogens (e.g., bordetella pertussis and treponema pallidum), and viruses (e.g., human immunodeficiency virus and hepatitis viruses) may cause clinically significant morbidity and mortality among infected children. diseases such as severe acute respiratory syndrome or avian influenza have not been reported among international adoptees, but transmission is possible if infection is present. family members may be infected by others during travel or by their adopted child after returning home. families preparing to adopt a child from abroad should pay special attention to the infectious diseases they may encounter and to the precautions they should take on returning home. states citizens. if this number does not seem impressive, families in the united states adopted more than 210,000 children of foreign origin since 1989. also striking is that, since 1990, the number of international adoptions in the united states has increased by more than 320% (figure 1 ). 1 internationally adopted children originate from countries that unfortunately are often poor, developing, or war torn. their governments are often poorly equipped to manage the number of orphaned or abandoned children. as a result, they allow individuals from foreign countries to adopt these children. owing to changing economic, political, and social climates around the world, policies pertaining to foreign adoption in these countries are constantly changing. as a result, a country may have a liberal foreign adoption policy or high quota one year, but it may close its doors to adoption the next. figure 2 highlights the effect of these changes on the origins of adopted children who were brought into the united states over the past decade. at present, more than 70% of internationally adopted children brought to the united states are from china, russia, and guatemala. 1 the emergence of a disease or a medical condition sometimes overshadows the joy of bringing a new child into a family. family members traveling to a foreign country to complete an adoption are at risk for acquiring infectious diseases in that country. all too often, travelers, nontraveling family members, and other contacts are at risk for acquiring an infectious process because appropriate safeguards are not followed or considered. two published reports highlight the potential health risks associated with international adoption. 2, 3 because of the devastation these diseases can cause and because of the ease with which many can be spread, health care practitioners must be familiar with medical obstacles associated with international adoptions. in addition, since many of these diseases can easily be prevented with vaccination, prophylaxis, and/or education, the pharmacist can play an integral part in minimizing the health risks of the families involved in these adoptions. internationally adopted children often enter the united states without a caregiver who is familiar with their medical history, vaccination status, or social experiences. this situation is in stark contrast to immigrant or refugee children, who often arrive with parents or other guardians. the absence of a parent or guardian is one reason why medical records of international adoptees are often incomplete. information regarding their family history, prenatal health, and birthing conditions are generally not available. even their exact date of birth is often unknown. adding to the confusion for adopting families is that medical terminology and medical practices vary widely depending on the country of origin. 4 for example, a case-series review of preadoptive medical records showed that more than 90% of 56 children from the former soviet union and eastern europe had several diagnoses suggestive of severe neurologic impairment. 5 of interest, postadoptive evaluation in the united states failed to confirm the diagnoses in any of the children. in contrast, documentation of medical records is excellent for children from korea because of government-controlled adoption agencies. 6 documentation from other countries, such as china or russia, is highly variable. 6 in addition to confusion and uncertainty pertaining to diagnostic and medical terminology, adoptive parents and their medical consultants must be vigilant for errors in medical diagnoses and vaccination schedules in the medical records. examples of such errors are vaccinations that were apparently administered before the birth date of the adopted child. records that appear perfect, such as vaccinations given exactly 1-2 months apart, are often modified to align with current immunization schedules in the united states. 6 in addition, descriptions of child development should be accepted cautiously. under close scrutiny, developmental milestones are often found not to match the child' s estimated age, or they are found to be virtually identical to those of other children from the same orphanage. the old adage applies: if it seems too good to be true, it probably is. immunization records for internationally adopted children are often unclear, incomplete, or even missing altogether. a retrospective analysis of 504 internationally adopted children showed that 65% had no written records of immunizations given before their adoption. 7 adopted children may have received vaccines of differing potencies or at different ages, or they may have been given a number of doses other than what is recommended in the united states. furthermore, in some countries, various vaccinations may be given at minimum intervals of 4 weeks, as opposed to the 6 weeks required in the united states. 8, 9 as a result of these discrepancies in administration schedules, u.s. immigration officials may not accept documentation of previous vaccinations. another concern is that children adopted from orphanages or other large institutions are frequently severely malnourished or chronically ill. under these conditions, even if vaccines are administered appropriately, adequate immunity may not be observed owing to the child' s inability to mount an immune response. 6, 8 for children who arrive in the united states with an unclear or questionable immunization status, serologic titers may need to be drawn to test their immunity. serologic titers were drawn in 98 children adopted from china who had documented immunizations against tetanus, diphtheria, and poliomyelitis. 10 the titers revealed that only 60% of the children were fully protected against each disease. although titers for diseases such as diphtheria or type-specific polio can be drawn, they are not routinely obtained. the infrequency with which these tests are performed may cause substantial expense and a delay in obtaining results. even if a child is reported to have had a specific primary disease that generally affords immunity, vaccinating the child may still be prudent because he or she might not have mounted an immune response or because the disease might have been misdiagnosed. furthermore, if no written documentation of vaccinations is available, appropriate vaccination series should be begun as soon as possible. 11 also, vaccination should be considered missing if the documentation is only partial. examples are if names of the vaccine or if the vaccination dates are missing, if the vaccination record appears too good to be true, if the vaccinations are self-reported, or if the records appear questionable in any way. finally, vaccinations given at intervals of less than 6 weeks should not be counted because this schedule may elicit suboptimal immune responses. 9 in most instances, administering or readministering the vaccine series is easier than attempting to assess the child' s immune status. because other countries may focus on required vaccinations for diseases endemic to their region, clinicians should ensure that all vaccinations that the centers for disease control and prevention (cdc) and the advisory committee on immunization practices recommend are given to newly adopted children. vaccines most commonly omitted from foreign vaccination programs include those for haemophilus influenzae type b, hepatitis b, varicella, and measles, mumps, and rubella. catch-up or initial vaccination series should be given as soon as possible, unless the adopted child is acutely ill and has a high temperature. 9 figures 3 and 4 show the cdc primary immunization schedule for 2006 and the catch-up schedule, respectively. 12, 13 a good general rule is to revaccinate when in doubt. the risk of not vaccinating is generally greater than the risk of revaccinating. table 1 illustrates the approach of the advisory committee on immunization practices and the american academy of family physicians to the evaluation and revaccination of internationally adopted children. 14 in the united states, the occurrence of tuber-culosis has been steadily declining; however, this is not the case in many developing countries, 15 where tuberculosis continues to be among the leading causes of death. 16 many countries from which children are adopted, such as china, russia, korea, and vietnam, have a high rate of tuberculosis. 17 as a region, southeast asia has the second highest incidence of tuberculosis in the world after africa. the incidence in africa is 345 cases of tuberculosis/100,000 people, whereas in southeast asia it is 190 cases/100,000. in contrast, the incidence of tuberculosis in the americas is approximately 43 cases/100,000 people. 18 another consideration is that the worldwide occurrence of drug-resistant tuberculosis is increasing. according to the world health organization, more than 300,000 cases of multidrug-resistant tuberculosis have been reported. 19 between 1994 and 2000, almost every country the world health organization surveyed had documented cases. 20 of all cases of tuberculosis in the united states, multidrug-resistant mycobacterium tuberculosis caused 1.2%. multidrugresistant tuberculosis is most problematic in china, eastern europe, and russia. rates of resistance in russia and eastern europe are 6.5-14%, whereas rates in china range from 1.4% in hong kong to 10.8% in the henan province. 21 in 1999, a report described a 9-year-old child adopted from the marshall islands who had a diagnosis of extensive, bilateral, cavitary pulmonary tuberculosis. 22 this child was not screened for tuberculosis before entering the united states. as a result, he transmitted m. tuberculosis to 20% of his direct contacts in rural north dakota. although active tuberculosis is infrequently reported among immigrant children, internationally adopted children are more likely than domestically adopted children to have active tuberculosis. the rate of tuberculosis among internationally adopted children is 50-150 times that among the general population of the united states. 6 latent tuberculosis is more common among internationally adopted children than active tuberculosis. tuberculosis skin tests were positive in approximately 0.6-5% of internationally adopted children. 17, 23 children who resided in orphanages had rates of latent tuberculosis higher than those of children who were raised in foster homes. 23 a study of 404 international adoptees revealed that 75 (19%) who were screened with tuberculin skin testing were given a diagnosis of latent tuberculosis. 24 of note, the high rate of positive results among internationally adopted children may be due to not only exposure to active cases of tuberculosis in their countries of origin but also vaccination with the bacillus calmette-guérin (bcg) vaccine, which is more common in developing countries than in the united states. routine screening for tuberculosis in internationally adopted children should include a tuberculin skin test administered by using the mantoux method. 6, 9, 22, 25 testing should be performed regardless of the child's history of receiving the bcg vaccine. 22 although the reaction to a tuberculin skin test due to the bcg vaccine cannot be distinguished from the reaction due to latent tuberculosis, immunity secondary to the bcg vaccine wanes over time. a health care professional should review the results 48-72 hours after the tuberculin skin test is performed. indurations of at least 10 mm should be considered positive in a healthy child. in a child infected with human immunodeficiency virus (hiv), indurations of 5 mm or larger require further evaluation. 6 skin testing should be repeated after 6 months in children in whom an induration of smaller than 10 mm is elicited. this recommendation is based on the fact that children may not respond to the test because of other illness, malnutrition, or recent infection with tuberculosis without time to mount an adequate immune response. 9, 26 in children with a positive tuberculin skin-test result, chest radiography and full physical examination should be performed to determine if they have active tuberculosis. also, in newborns with a recent history of bcg immunization, chest radiography and a tuberculin skin test should be done 1 year after vaccination. 6, 9 for the treatment of a child with active tuberculosis, physicians should select an antituberculosis regimen based on resistance patterns from the adopted child's country of origin. recommended treatment for active tuberculosis includes 6 months of therapy: isoniazid, rifampin, and pyrazinamide given for 2 months, then isoniazid and rifampin given for the last 4 months. table 2 shows common drugs and dosages used to treat tuberculosis. 25 in the case of latent tuberculosis, children should be treated with a 9-month course of isoniazid 10-15 mg/kg/day (table 3 ). if a patient cannot tolerate isoniazid or if he or she was exposed to a documented isoniazid-resistant strain of m. tuberculosis, rifampin 10-20 mg/kg/ day for 6 months is an acceptable alternative (table 3) . 23, 25 close contacts and family members of internationally adopted children who have active tuberculosis should also undergo tuberculin skin testing performed with the mantoux method. hepatitis b is the most common chronic viral illness worldwide. 27 although some patients infected with hepatitis b may never have symptoms, as many as 25% of children who acquire chronic hepatitis b eventually develop hepatocellular carcinoma or cirrhosis. 28 children adopted from impoverished orphanages are at high risk of being infected with hepatitis b. 27 hepatitis b is endemic in china and southeast asia, as well as in eastern europe (especially romania), most of the middle east, africa, and the amazon basin, among other regions. 28 more than 50% of children adopted from romania have serologic evidence of past or present hepatitis b infection. 29 institutionalized children usually acquire hepatitis b from vertical transmission (transmission at birth) or from the transmission of body fluids when living in close quarters with other infected individuals. overall, about 5% of international adoptees to the united states have a table 4 provides information to guide the interpretation of serologic results. 30 hepatitis b virus may incubate for as long as 180 days; therefore, internationally adopted children should have their initial hepatitis b panel repeated approximately 6 months after arriving in the united states. this testing may be deferred in children who are clearly immune or clearly infected. when the history of hepatitis vaccination is questionable or missing, children should receive the three-dose hepatitis b vaccination series. immunization does not harm a child with an active hepatitis b infection and may help a child with incubating disease avoid chronic disease. 9 the risk of transmitting hepatitis b to household members is well documented, albeit low. 17, [31] [32] [33] families of children adopted from asia with documented hepatitis b infection had a 9% occurrence of subsequent hepatitis b infection compared with a 2% risk in a control population. 31 household members of any child with a positive hbsag result should be vaccinated if they have not completed the vaccination series. 9 specific recommendations to guide therapy for children with acute hepatitis b infection are not readily available. 28 lamivudine decreased serum dna levels of hepatitis b virus to below the limit of the research assay at the end of a 52-week trial (23% vs 13% with placebo) in children with chronic hepatitis b. 34 interferon-alfa was relatively ineffective for chronic infections acquired during childhood. adefovir dipivoxil has yet to be studied in children. other promising treatments for hepatitis b, such as entecavir, tenofovir, clevudine, telbivudine, and pegylated interferon alfa-2a, are in various stages of development and approval by the u.s. food and drug administration. efficacy and safety data for new agents to treat chronic hepatitis b infection in children have yet to be published, but these agents may be alternative treatments for hepatitis b in the future. as with hepatitis b, hepatitis a is endemic in many areas, such as southeast asia, china, and latin america. 35 because hepatitis a is transmitted by means of the fecal-oral route, hepatitis a is commonly associated with areas that have poor sanitation and/or crowded living conditions. infection with hepatitis a is worrisome and may lead to fulminant hepatitis and death. hepatitis a is observed relatively infrequently among adopted children. owing to the low occurrence of infection, internationally adopted children generally do not have serology for hepatitis a tested unless they have symptoms suggestive of hepatitis. symptoms of hepatitis a, if manifested, may include jaundice and/or fever. no treatment for hepatitis a is available, and only supportive care is recommended. however, all individuals traveling to areas with high rates of hepatitis a should be given the hepatitis a vaccine, which consists of an inactivated virus. two doses of the vaccine should be administered at least 6 months apart. one month after receiving the first dose of the vaccine, 94-100% of adults develop protective antibodies. if an unvaccinated individual is exposed to hepatitis a, postexposure prophylaxis with immunoglobulin may be warranted. immunoglobulin should be given no more than 2 weeks after exposure. 36 hepatitis c among the general population, hepatitis c has a worldwide prevalence comparable to that of hepatitis b. however, among internationally adopted children, the prevalence of hepatitis c infection is not well documented but believed to be considerably lower than that of hepatitis b. according to limited serologic data, hepatitis c infection appears to be present in less than 1% of internationally adopted children. 24, 37 therefore, routine screening of asymptomatic children for hepatitis c is usually not warranted. however, screening may be appropriate for children who have symptoms consistent with hepatitis, those whose mothers have a history of drug abuse, and those who come from areas with high frequency of hepatitis c. according to the world health organization, areas with the highest prevalence of hepatitis c are africa (rate of 5.3%), the eastern mediterranean (4.6%), and the western pacific (3.9%). 38 pertussis pertussis, or whooping cough, is a disease that clinicians in developed countries tend to overlook. pertussis appears to be mounting a comeback in both developed and developing countries. although the disease commonly occurs in unvaccinated individuals, its occurrence is also described among those who received the vaccine while they were malnourished or immunocompromised. in addition, data suggest that even those who were appropriately vaccinated may be at risk for acquiring infection with bordetella pertussis secondary to waning of their protective immunity. 39, 40 in the united states, children receive a fourdose pertussis vaccination series as part of combined vaccination that includes diphtheria and tetanus. in contrast, foreign-born children may not receive vaccination against pertussis. in the absence of appropriate vaccination, these children are at increased risk for developing active disease. a 10-month-old infant adopted from russia had no record of being vaccinated against the disease. 41 as a result, close contacts during travel and family members were all exposed to the disease. the cdc recommends that antimicrobial prophylaxis with erythromycin be given to any person who was exposed to an active case of pertussis, regardless of their immunization status. 42 if an individual is thought to have pertussis and if the cough has lasted less than 3 weeks, antimicrobial therapy is indicated. the drug of choice for pertussis is erythromycin. however, most data pertaining to the treatment of pertussis are decades old; therefore, most agents newer and better tolerated than erythromycin have not been thoroughly evaluated for this indication. despite the completion of only a few well-controlled clinical studies, azithromycin, clarithromycin, and trimethoprim-sulfamethoxazole appear to be appropriate treatment alternatives. 43, 44 clinical data about fluoroquinolones and ketolides are lacking. although uncommon in the united states, the measles virus is common in countries from which children are adopted. in april 2004, adoptions from an orphanage in china were temporarily suspended because of an outbreak of measles among adoptees from the hunan province. 3 in 2001, 14 cases of measles were identified in children recently adopted from china and in their close contacts. 2 measles was diagnosed in 10 adopted children, along with two adoptive mothers who were born in the united states, a caregiver who lived with the adoptive family for 1 week, and a sibling of a child adopted from china who never contracted the disease. based on the dates of infection, the measles exposure was determined to occur in china. this exposure was most likely from the orphanage, but it could have occurred during the screening period or during travel. the cdc launched a measles vaccination campaign at the infected orphanage, and adoptions resumed 3 weeks after the last case of measles was reported. because measles is a major medical concern, children in the united states are routinely vaccinated against the disease, generally along with mumps and rubella in a combination vaccine. however, combination vaccines are not universally used. many countries immunize children with vaccines for only measles or for a combination of measles and rubella. 17 as a result, adopted children may lack coverage against mumps, rubella, or both. therefore, information regarding the types and content of vaccines administered to the child should be obtained. also, because the child may lack immunoprotection and have active disease, family members of an internationally adopted child must have up-to-date immunization against measles, mumps, and rubella. the cdc recommends that adults born after 1957 receive at least one dose of the measles, mumps, and rubella vaccine unless they had a documented case of the measles. because of their high risk of acquiring measles, college students, international travelers, and health care workers should receive two doses of the vaccine given at least 1 month apart. of note, pregnant women should not receive the measles, mumps, and rubella vaccine, and women should avoid pregnancy for 3 months after receiving the vaccine. 45 human immunodeficiency virus although the rate of infection with hiv in many developing countries is rising, hiv infection is infrequently noted among international adoptees. investigators reported that two (0.4%) of 490 internationally adopted children screened had hiv antibodies. 24 of interest, both children subsequently had negative results for hiv with a polymerase chain reaction test. other investigators did not identify any internationally adopted children infected with hiv. 5, 29, 37 one potential reason for the lack of hiv infections among adoptees is that preadoption screening has become widespread in eastern europe and in countries such as china. 46 as a result, hivinfected children may be removed from the pool of children available for adoption. regardless of the results of preadoption screening, all children should be tested for hiv on their arrival to the united states, and they should be retested 6 months later to determine if seroconversion occurred secondary to a recent hiv infection. syphilis, which is caused by the spirochete treponema pallidum, can be transmitted to children by means of sexual abuse or maternal transmission. eastern european nations have documented increases in the occurrence of congenital syphilis. in russia alone, the occurrence of congenital syphilis has doubled every year from 1992-1997 and reached a total of 714 cases in 1997. 47 in contrast, less than 1.7% of international adoptees test positive for syphilis. 24, 29, 37 syphilis serology is required in the medical examination for united states visas, but regardless of the test results, internationally adopted children should be retested for syphilis on their arrival to the united states. 48 treatment of syphilis may often be accomplished with one dose of benzathine penicillin. experts in the field of adoption medicine listed parasites second only to hepatitis b virus for their propensity to cause long-term problems in children. 6 parasites may cause severe diarrhea, dehydration, and malnutrition in addition to chronic starvation. protozoa may be present in drinking water in undeveloped countries. institutions such as orphanages promote the transmission of parasites because of close contact, diminished immunity secondary to malnutrition, and inadequate treatment. although transmission of intestinal parasites from adopted children to families and other contacts is not reported, it is possible. in addition, appropriate diagnosis is essential for the well-being of the child. intestinal parasites can be found in 9-51% of internationally adopted children. 17, 37 the risk of being infected with intestinal parasites is higher in older children and children from eastern europe than in younger children and children from other areas of the world, such as china, korea, or guatemala. 24, 26, 29 according to one group of investigators, 58% of romanian children older than 18 months who were screened for intestinal parasites had evidence of infection. 29 this rate was in contrast to 0% of infants aged 17 months or younger. giardia lamblia is the intestinal parasite most frequently encountered among internationally adopted children; however, it is not uncommon for infected children to have more than five organisms. 24, 29 symptoms are not reliable indicators of parasitic infection. other diseases, such as lactose intolerance or refeeding syndrome after starvation, may mimic infection with intestinal parasites. in all children, at least three fresh fecal specimens should be examined for parasites at intervals of no less than 1 week. 8, 11, 26, 46 rates of detection increase with the use of several specimens. if parasites are detected and treatment started, stools should be reexamined after each course of therapy because of the high prevalence of several infecting parasites. 8, 11 scabies and lice scabies (sarcoptes scabiei) and lice (pediculus species) are common among internationally adopted children. a major risk factor for scabies and lice infestations is residence in an orphanage. investigators reported a greater than 10% rate of scabies or lice in adopted children, but documentation is limited. 46 scabies is often difficult to identify among internationally adopted children, especially if they were partially treated or if they have numerous insect bites. 44 some experts recommend treating any rash as if it were a scabies infection. general treatment with topical permethrin cream or shampoo is appropriate. 9 severe acute respiratory syndrome an unusual pneumonia was first reported in the guangdong province of china in november 2002 and has since been referred to as severe acute respiratory syndrome (sars). the sars virus spread to more than 8000 people in 29 countries and killed 774. 49 the cause of the disease was determined to be a novel coronavirus similar to a virus seen in some animals consumed in china. the only other known coronaviruses cause the common cold. 49 aggressive health measures have limited the occurrence of sars. 46 since july 2003, the end of the pandemic, 21 additional cases of sars have been reported. 50 although person-to-person transmission is possible, other sources of infection have been identified. transmission of the sars virus from an internationally adopted child to a prospective parent or other family member is possible; however, such a case has not been reported. children with sars typically have a minor respiratory illness compared with infected adults. during the initial sars outbreak, children accounted for a small number of reported cases. 51 for prevention, the cdc recommends that travelers avoid areas where transmission is most likely to occur. these areas include hospitals treating patients with sars and live animal markets. frequent hand washing is also recommended. avian influenza involves a large number of influenza viruses that primarily affect birds and not humans. avian influenza type a/h5n1 is a virulent form that can cause disease in humans. avian h5n1 is believed to be primarily transmitted from direct bird-to-human contact and not from human-to-human contact. the concern is that the strain will mutate to a virulent strain that is easily transmitted from human to human. according to the world health organization, 130 confirmed cases of avian influenza in humans have been documented from 1997-november 2005. 52 countries that have had confirmed cases are vietnam (92 cases, 42 deaths), thailand (21 cases, 13 deaths), indonesia (11 cases, seven deaths), cambodia (four cases, four deaths), and china (two cases, one death). 52 to our knowledge, no internationally adopted children have yet to contract the virus. symptoms range from typical flu symptoms of fever, cough, sore throat, and muscle aches to eye infections, pneumonia, and respiratory distress. the antiviral drugs oseltamivir and zanamivir are expected to be used to treat avian influenza a, but their effectiveness is unclear. analysis of some strains of h5n1 in 2004 revealed resistance to rimantadine and amantadine. 53 a vaccine to prevent this virus is not yet available, but clinical trials to test a newly developed vaccine began in april 2005. although requirements vary from country to country, most individuals considering an international adoption can plan to stay in their child's home country for several days to weeks. during this time, travelers may be exposed to a number of potential pathogens from a variety of sources, including water, food, children, and the environment. all people who plan to travel for the adoption should seek medical advice regarding immunizations and preventive therapy at least 4-6 weeks before traveling. in addition to consulting a travel medicine specialist, they may also seek advice from a physician specializing in adoption. many institutions now have an adoption medicine physician or clinic that is familiar with issues encountered when an international child is adopted. during the trip, travelers must follow general travel guidelines. for example, they should avoid ingesting tap water directly by drinking it or indirectly by eating uncooked foods that may have been cleaned with tap water or drinking beverages with ice. in addition, food parasites and bacteria may contaminate a variety of foods. therefore, it is prudent for them to avoid foods that were not properly cooked. the cdc recommends avoiding uncooked meat, fruits and vegetables, and milk products. 54 mosquitoes and ticks may carry infectious diseases, such as malaria, yellow fever, and japanese encephalitis. 11, 55 travelers to central america, south america, eastern europe, asia, and other areas of the world are at risk for contracting malaria. 56 protective clothing (long pants, longsleeved shirts) should be worn, and topical insect repellents containing diethyltoluamide, or deet, should be used. prescription drugs may also be used to prevent malaria. most drugs should be started before the person travels and be continued after he or she returns to the united states. table 5 presents malaria prevention options. because of concerns related to resistance, specific antimalarial treatment should be based on the country being visited. travelers should be familiar with the signs and symptoms of malaria, which may include chills, headache, fatigue, and muscle aches. immediate treatment should be sought at onset of these symptoms and continued for as long as 1 year after travel to an endemic area. 56 questions about malaria can be directed to the cdc web site (available from http://www. cdc.gov) or the cdc malaria hotline (telephone number 1-770-488-7788). routine vaccinations and boosters should be current for all travelers and nontraveling family members. the recommended adult immunization schedule can be accessed through the cdc web site. vaccines usually administered in the united states, often in childhood, are directed against tetanus, diphtheria, pertussis, varicella, polio, hepatitis b, h. influenzae type b, pneumococcal disease, and measles, mumps, and rubella. a tetanus-diphtheria booster is recommended every 10 years. 57 table 6 shows recommendations for specific vaccinations. suggestions for vaccination vary depending on the destination country. at this point, the only required vaccination is the yellow fever vaccination for travel to certain countries in sub-saharan africa and tropical south america. the u.s. government requires internationally adopted children to undergo physical examination before entering the country. this examination is not intended to ensure that the adopted child is completely healthy; rather, it is designed to ensure that the child will not harm residents of the united states. therefore, clinicians usually do not test for infectious diseases that are common in the united states or that are not transmitted by casual contact. table 7 lists the components of the medical examination. 58 parents should not rely on the medical examination to reveal all potential infections, and they should still seek medical care for their adopted child after they enter the united states. a physician should immediately examine acutely ill children or children who have serious chronic diseases on their arrival to the united states. children who appear healthy should see their physician within 2-4 weeks of their arrival for a comprehensive medical examination. 9, 48 for screening, the american academy of pediatrics recommends hepatitis b serology, syphilis serology, hiv serology, mantoux intradermal skin testing for tuberculosis, stool examination for ova and parasites, and a complete blood cell count with red blood cell indexes. other ageappropriate tests may be indicated, depending on the country of origin and on the specific medical concerns associated with a particular child. the adoption of a child should be a joyous occasion. however, the detection of an illness in the adopted child or the acquisition of an for the safety and well-being of all those involved, the adoptive parents should be well informed about the potential infectious complications associated with international adoption. many infections can be avoided altogether, or the effect of disease can be minimized with proper travel planning and follow-up. despite the travel advice that adoptive parents receive from adoption agencies, simple measures, such as reviewing the child's vaccination status, are often overlooked. in addition, adoption agencies may not be helpful in interpreting preadoption medical reports. as health care providers, we can help these families prepare for their travel and homecoming by providing counseling and information about potential infectious diseases that they may encounter. children and adolescents younger than 15 years are not required to undergo blood testing for syphilis and human immunodeficiency virus infection or chest radiography for tuberculosis unless the examining physician believes that they are likely to have been exposed. immigrant visas issued to orphans coming to the u measles outbreak among internationally adopted children arriving in the united states update: measles among adoptees from china-april 14 preparing families for international adoption health of children adopted from the former soviet union and eastern europe: comparison with preadoptive medical records infectious disease and the internationally adopted child evaluating acceptability and completeness of overseas immunization records of internationally adopted children the immigrant, refugee, or internationally adopted child health care of the internationally adopted child part 1. before and at arrival into the adoptive home immunisation status of children adopted from china preparing to meet foreign bugs. travel, immigration, and international adoptions require special precautions recommended childhood and adolescent immunization schedule-united states recommended immunization schedule for children and adolescents who start late or who are more than 1 month behind-united states general recommendations on immunization. recommendations of the advisory committee on immunization practices (acip) and the american academy of family physicians (aafp) table 1. tuberculosis cases, case rates per 100,000 population, deaths, and death rates per 100,000 population, and percent change: united states world health organization. the world health report preventing infectious diseases during and after international adoption world health organization. drug resistance: tuberculosis a prioritised research agenda for dots-plus for multidrug-resistant tuberculosis (mdr-tb) global trends in resistance to antituberculosis drugs. world health organization-international union against tuberculosis and lung disease working group on anti-tuberculosis drug resistance surveillance extensive transmission of mycobacterium tuberculosis from a child pediatric tuberculosis collaborative group. targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents prevalence of infectious diseases among internationally adopted children mycobacterium tuberculosis infectious disease issues in internationally adopted children hepatitis b: no guarantee [families with children from china web site red book: report of the committee on infectious diseases the health of children adopted from romania basic skill in interpreting lab data transmission of hepatitis b virus from adopted asian children to their american families hepatitis a and b in the family unit: nonparenteral transmission by asymptomatic children adoption of children from countries with endemic hepatitis b: transmission risks and medical issues epivir-hbv (lamivudine) package insert world health organization, department of communicable disease surveillance and response prevention of hepatitis a through active or passive immunization: recommendations of the advisory committee on immunization practices (acip) health of children adopted from china changing epidemiology of pertussis in the united states: increasing reported incidence among adolescents and adults summary of notifiable diseases-united states pertussis in an infant adopted from russia guidelines for the control of pertussis outbreaks efficacy of short-term treatment of pertussis with clarithromycin and azithromycin azithromycin is as effective as and better tolerated than erythromycin estolate for the treatment of pertussis centers for disease control and prevention. measles: recommendations for prevention epidemiology and management of infectious diseases in international adoptees recent declines in reported syphilis rates in eastern europe and central asia: are the epidemics over? international adoptions. travelers' health: yellow book the severe acute respiratory syndrome severe acute respiratory syndrome. travelers' health: yellow book severe acute respiratory syndrome among children world health organization. cumulative number of confirmed human cases of avian influenza a/(h5n1) reported to who avian influenza infection in humans centers for disease control and prevention. protection against mosquitoes and other arthropods. travelers' health: yellow book centers for disease control and prevention. malaria and travelers general recommendations for vaccination and immunoprophylaxis. travelers' health: yellow book the visa medical examination: the facts [families with children from china web site key: cord-329399-d0w8fof0 authors: nobakht, z.; rassafiani, m.; hosseini, s.a.; hosseinzadeh, s. title: a web-based daily care training to improve the quality of life of mothers of children with cerebral palsy: a randomized controlled trial date: 2020-07-10 journal: res dev disabil doi: 10.1016/j.ridd.2020.103731 sha: doc_id: 329399 cord_uid: d0w8fof0 background: mothers of moderately to severely affected children with cerebral palsy (cp) have to spend a long time to take care of their children. this time-consuming responsibility affects their physical and psychosocial health. therefore, mothers as caregivers are required to receive special training to take care of their children. aims: the aim of this study was to evaluate the effectiveness of a developed web-based intervention for daily care training of children with cp on their mothers’ quality of life (qol), anxiety, depression, stress, and their musculoskeletal pain. methods and procedures: this study was a single blind randomized controlled trial. 91 mothers of children with cp with gross motor function classification system (gmfcs) levels iii, iѵ, and ѵ, who aged from 4 to 12 years were assigned to the intervention and control groups using block randomization. mothers in the control group received their routine face to face occupational therapy intervention and mothers in the intervention group received 12 weeks web-based intervention. qol, depression, anxiety, stress, and pain were measured before and after the intervention in both groups. outcomes and results: the results of analysis of covariance showed that after controlling the mean score of pretest of pain, the mean score of post-tests in the intervention and control groups was significantly different (p < 0.05). the mean scores of physical health and total qol scores of post-tests in the intervention group were significantly higher than the control group with controlling pretest scores. conclusions and implications: designed web-based intervention affects the caregivers’ qol and pain significantly. this intervention can be used to provide daily care training for mothers of children with cp. cerebral palsy (cp) describes a group of permanent and non-progressive disorders of the movement and posture, causing activity limitation, in the developing fetal or infant brain (rosenbaum et al., 2007) . moderately to severely affected children with cp are more dependent to their mothers as main caregivers in performing their activities of daily living for their whole life (razavi, rassafiani, sarfaraz, malekpour, & salehi, 2013) . as a result, mothers have to spend a long time for taking care (e.g., to feed, bathe, and clothe) of these children (rassafiani & sahaf, 2011; stillerova, liddle, gustafsson, lamont, & silburn, 2016) . taking care of these children is time-consuming and is a source of stress for their mothers (rassafiani, kahjoogh, hosseini, & sahaf, 2012) . in addition, it affects physical and social welfare, freedom and independence, comfort, and financial stability of the whole family (davis et al., 2010; jalili, godarzi et al., 2013) . it has been well established that 24 -h care of a child with cp who has special needs for transportation, eating, bathing, dressing, sleeping, and toileting have a significant negative impact on the physical and mental health of his/her mother (al-gamal & long, 2012; altindag et al., 2007; brehaut et al., 2004; mobarak, khan, munir, zaman, & mcconachie, 2000; yilmaz, erkin, & nalbant, 2013) . mothers of children with cp require special training to either reduce or prevent this negative impact (razavi et al., 2013) . there are several methods to train such mothers including face to face, workshops, booklets, and videos . basically, child handling interventions focusing on physical aspects of caring. the subjects provided in handling interventions consisted of feeding, bathing, toileting, carrying, dressing, movement principle and sleep. the effectiveness of mothers' training through these methods have been well investigated and their results demonstrated positive influences on mothers' knowledge, as well as reducing their stress, and improving their quality of life (qol) (allah, el awady, & hameed, 2012; ghorbanpoor et al., 2014; hettiarachchi & kitnasamy, 2013; nobakht & rassafiani, 2016) . however, there is little evidence about the effectiveness of telehealth model, which uses electronic information and telecommunication technologies, to provide health-related services for mothers of children with cp (cason, 2012; nobakht, rassafiani, hosseini, & ahmadi, 2017) . chi and demiris (2015) , in a systematic review conducted on telehealth services for caregivers in general (mothers were considered as caregivers), found out that caregivers had significant improvements in the outcomes of interventions such as anxiety, depression, stress, and qol (chi & demiris, 2015) . one of the common forms of providing services in telehealth model is web-based intervention ((aota), american occupational therapy association (2013)). chiu and eysenbach (2011) in a study conducted on caregivers theorized three main factors influencing the use of internet-based health service: a) caregiver needs (personal capacity, available social support, and care giving belief); b) information communication technology factors (accessibility barriers and perceived efforts to use the technology); and c) the style of using the technology (preference for using email or the customized website). they showed that new caregivers employed interactive intervention such as using email while more experienced caregivers used more reflective learning such as information on website (chiu & eysenbach, 2011) . therefore, it appears that a web-based intervention for experienced caregivers compared with less experienced caregivers of children with cp is more appropriate. rehabilitation is a long-term and continuous process, which sometimes leads to the disruption of a mother's job, daily routines, and the role of the family members. it appears that limited numbers of experts in remote areas reduce training accessibilities. then web-based interventions provide more accessibility to services for children who live in remote areas. also in some special circumstances such as widespread of covid-19, web-based intervention is one of the possible way to support these children and their families. it seems that clients' satisfaction of telerehabilitation is high in various areas such as saving their time and low cost of services (cason, 2014; kairy, lehoux, vincent, & visintin, 2009) . however, there is no evidence to show whether this type of training can be effective if it is used for training of mothers of children with cp. furthermore, if it is effective, which aspects of their health and how are they affected? therefore, the primary purpose of this study was to evaluate firstly the efficacy of a developed and evaluated web-based intervention for daily care training of children with cp on the mother's quality of life (qol). the secondary purposes of this study were to evaluate the efficacy of the intervention on mother's anxiety, depression, stress, and their musculoskeletal pain. in order to achieve the aim of this study, a randomized controlled trail was designed. a single blind randomized controlled trial was designed and conducted. mothers of children with cp were included in this study if their children had gross motor function classification system (gmfcs) levels iii, iѵ, and ѵ, and aged between 4 to 12 years. if the participants had two or more children with disabilities, or previously received face to face caring training they were excluded from this study. to determine a difference of at least 10 score in the mean of qol between the intervention and control groups with a power of 0.80 and a significance level of p < 0.05, 45 participants in each study group were needed . participants were recruited from 14 occupational therapy clinics in tehran, karaj, and shiraz, (three main cities of iran). first, mothers of children with cp received some information about the study from the assessor. informed consent was obtained from mothers who were eligible to be included. then they were requested to complete a demographic questionnaire, and perform qol, depression, anxiety and stress, and pain measurements. then, they were assigned to the groups using block randomization that was prepared by an expert in this field. obtained sequentially block randomization was written on envelops and mothers picked up one by chance, by which they were assigned to the intervention or control group accordingly. both the outcome assessors and data analyzer were blind in this study. after that, mothers in the intervention group received the study website address and a sitemap. they were requested to visit the page and register to the website. after registering to the website and the confirmation by the site admin, the mothers entered to their own page and determined their educational priorities. then, they received nine educational topics weekly. also, they received an sms reminder weekly to download their educational priorities. during 12-week intervention, they had access to an expert to ask any question. mothers in the control group received their routine face to face occupational therapy intervention. approval was obtained from the ethics committee of the university of social welfare and rehabilitation sciences ir.uswr.rec.1394.111. the protocol of the study was registered at the iranian registry of clinical trials (id: nct02545179). both groups continued each treatment they received and additionally the intervention group received web-based intervention. recruitment of the participants started between october and december 2016; and follow-up was between january 2016 to march 2017. the web-based intervention was developed and evaluated by applying the steps of the cehres road map (van gemert-pijnen et al., 2011) with some modification. as typical web-based interventions, our web-based intervention was developed to be used by caregivers once a week, lasts for 12 weeks and includes interaction with the system, an occupational therapist, and peers on the web. to help all participants with different level of experience, we provided interaction through email with an expert occupational therapist. then, our web-based intervention for caregiver training included nine general topics that were received by caregivers weekly for the first 9 weeks. these topics consisted of feeding, bathing, toileting, carrying, dressing, movement principle, sleep, and play, as well as, caregiver self-care. the participants had three further weeks to interact with an expert who was a phd holder in occupational therapy with more than 25 years working experience in the field of children with cp regarding any questions arise. when they accomplished the final priorities and submit questions on their own web-page then they received responses by the expert. the web-based intervention had the possibility that the caregivers could determine their educational priorities. also, the users could share their experiences with other users and could ask questions from an expert (http://www.cpcare.ir). the website has various capabilities including registering caregivers of children with cp and to confirm registration with an sms (nobakht, rassafiani, & hosseini, 2018) . three outcome measures were employed for this study including sf-36, depression anxiety and stress scales (dass-21), and visual analog scale (vas). sf-36 is a general qol instrument, translated to different languages with high validity and reliability (bullinger, 1995; razavi & gandek, 1998) . it measures eight concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and perceived mental health. each concept is directly transformed into a 0-100 scale. lower score indicates less qol and higher score indicates higher qol (ware & sherbourne, 1992) . the persian version of sf-36 has acceptable validity and reliability. reliability of the persian version of sf-36 was estimated using the internal consistency that showed all eight scales met the minimum reliability standard. the cronbach's α coefficients was from 0.77 to 0.90. convergent validity showed correlations ranging from 0.58 to 0.95 (montazeri, goshtasebi, vahdaninia, & gandek, 2005) . dass-21 is a set of three self-report scales designed to measure the negative emotional states of depression, anxiety, and stress. evidence supports the validity of dass-21 as a routine clinical outcome measure and it was translated to variety of languages (ng et al., 2007) . validity of the persian version of dass-21 was measured using factor analysis and criterion validity. the reliability of that scale was assessed through its internal consistency. in general, the validity and reliability coefficients were very satisfactory and were significant at p < 0.001. correlation between depression subscale and the beck depression inventory scale was 0.77, anxiety subscale with zunq anxiety inventory was 0.67, and the stress subscale and perceived stress inventory was 0.49 (sahebi, asghari, & salari, 2005) . visual analog scale (vas) is a simple method for evaluating variations in pain intensity. it is often used in various studies. participants were encouraged to indicate the intensity of the pain by marking a 100-mm line for each body part in whole body including head and neck, trunk, and upper and lower extremities according to the deloach, higgins, caplan, and stiff (1998). the data were checked for normality using kolmogorov-smirnov test (k-s test). analysis of covariance (ancova) was used to evaluate between-group differences in each at post-test controlling for pre-test scores. all analyses were performed using spss software version 20. 97 participants were randomly assigned to the intervention and control groups. of them, 42 were in intervention group, 49 were in the control group, and six did not receive allocated intervention due to family problem (1) and unknown reasons (5). eight participants lost to follow up (4 in each group). therefore, an intention-to-treat analysis was used by imputing their pretest outcome scores for their post-test outcome score (fig. 1) . caregivers had a mean age of 33.62 years (sd = 5.76). 35.2 % had university education, and 91.2 % were housewives. their children had a mean age of 82.65 months (sd = 29.87) and 62.6 % of them were male (table 1) . no statistically significant differences were found in caregivers' age and educational level between the intervention and control groups. also, there were no significant differences in the age, sex, and gmfcs level of the children under their care between the two groups (p > 0.05) ( table 1) . the results of ancova showed that the mean score of pretest of physical health and total score of qol and pain had significant effect on mean score of post-tests. the mean scores of physical health and total qol scores of post-tests in the intervention group were significantly higher than the control group with controlling pretest scores. after controlling the mean score of pretest of physical health and total score of qol and pain, the mean score of post-tests in the intervention and control groups was significantly different (p < 0.05) ( table 2) . to further understand pain in which body parts was influenced by the intervention, two further analysis were used. an exploratory factor analysis was initially carried out to identify related components. to conduct this, a principle component analysis was done using spss (kmo = 0.715, p value for bartlett's test = 0.000). at this point three factors (components) were discovered. questions related to the severity of pain in the area of neck and shoulder were placed in factor 1, elbow, wrists and fingers, low back, and knee were placed in factor 2, and upper part of the spine, pelvis and thigh, and ankle and toes were placed in factor 3. also, a reliability test was run on each new factor. cronbach's alpha for factors 1, 2, and 3 were 0.590, 0.742, and 0.701, respectively. then, ancova was performed to evaluate between-group differences in each factor. the results demonstrated that there are significant differences between two groups in these three factors and pain in intervention group was reduced (table 3) . since late 20th century, there is evidence demonstrating the influence of daily care training for mothers of children with cp on their qol and health. in this era, also, the provision of clinic-based services was changed into family-based services .with the advances in communication technology, health-related services were possible while the client was at a point away from the therapist. these kinds of services and interventions are still under development and evaluation. there is lack of evidence in providing remote services to increase the capacity of mothers of children with cp. therefore, according to the best of our knowledge it appears that this study is the first study to examine the effectiveness of web-based training for mothers of children with cp. the effectiveness of web-based training on qol, depression, anxiety, stress, and pain of mothers of children with cp were analysis of covariance with post-tests scores as the dependent variable, group as the independent variable, and pretest scores as covariates. z. nobakht, et al. research in developmental disabilities 105 (2020) 103731 investigated in this study. mean scores of qol in the intervention and control groups were compared using covariance analysis. the mean scores of physical health and total qol scores of post-tests in the intervention group were significantly higher than the control group with controlling pretest scores. chi and demiris (2015) systematically reviewed the provision of remote health care to support caregivers in their study. only 12 % of the studies with entry criteria examined the effects of these kinds of interventions on the qol of the caregiver. in this review, about 50 % of the studies with entry criteria were in the field of caregivers of children. although there was no specific evidence of effectiveness of service provision for caregivers of children with cp and the number of studies was limited, they reported significant differences in intervention group compared with control group, which is in agreement with our study. in our study, there were no significant differences in the mean score of post-test of depression, anxiety, and stress in the intervention group in comparison with the control group by covariance analysis with controlling pretest scores. there is no similar research on mothers of children with cp. however, the effectiveness of web-based interventions on other groups and conditions showed mixed results. for example, hadjiconstantinou et al. (2016) , in a systematic review with meta-analysis examined the emotional effects of web-based interventions for people with type 2 diabetes and reported that although a number of studies had shown significant effects on participants' depression and distress, this was not approved by the results of meta-analysis (hadjiconstantinou et al., 2016) . davies and their colleagues, in a systematic review with meta-analysis assessed the effects of webbased interventions on the improvement of depression, anxiety, and stress in postgraduate students reported that there was significant improvement in intervention group compared with the control group that received no intervention. while there was no significant improvement in intervention group compared with the control group receiving placebo or other interventions (davies, morriss, & glazebrook, 2014) . in the review of chi and demiris, about 50 % of the studies with entry criteria examined the effects of these kinds of interventions on reducing depression, anxiety, and stress. in most of these studies, depression, anxiety, and stress were significantly decreased (chi & demiris, 2015) . there was no specific evidence of effectiveness of service provision for mothers or caregivers of children with cp in the study of chi and demiris. the present study is the first study on mothers of children. as mentioned before, significant effects have been reported in some studies. this might be due to using video conference along with web-based intervention. therefore, adding video conference may increase the effectiveness of these types of interventions on mothers' mental health. the results of this study also demonstrated that the mean scores of musculoskeletal pain of post-tests in the control group were significantly higher than the intervention group with controlling pretest scores. after performing factor analysis and finding new components, correlation between knees, low back and upper limbs, and neck and shoulder were discovered. after controlling the mean score of pretest of these three factors, the mean score of post-tests in the intervention and control groups was significantly different and the most effect was on the pain of the lower back, knee, elbow, wrists, and fingers. there was promising evidence in terms of pain reduction by web-based interventions. however, more well designed studies are needed to strengthen the evidence concerning the impact of web-based interventions on mothers' pain (johari, rassafiani, dalvand, ahmadi kahjoogh, & daemi, 2016) . in the present study, it was not possible to take into account the level of caregivers' experiences. therefore, it is suggested to pay attention to the duration of mothers' experiences in future studies. chiu and eysenbach in a qualitative study identified effective factors in the use of internet-based services. these factors included mothers' needs, factors relating to communication technology, and information use style. this study noted that the experience of mothers affected the style of using that information (chiu & eysenbach, 2011) . another limitation to this study was to consider the iranian culture within which, most of caregivers of children with cp were mothers. therefore, training was provided to mothers as the main caregiver. so, it is suggested that future studies be designed for fathers and other family members of children with cp who are responsible for caring these children. also, in the present study, it was not possible to record the amount of time mothers spent on the website. in other words, downloading information could have taken more time and did not give us accurate information. therefore, we suggested providing this possibility in the future studies to determine the frequency of using the website. analysis of covariance with post-tests scores as the dependent variable, group as the independent variable, and pretest scores as covariates. z. nobakht, et al. research in developmental disabilities 105 (2020) designed web-based intervention can be used to provide daily care training for mothers of children with cp. given that the intervention provided was entirely web-based and that there was no need for travel, pay, spending time, and continuing communication between the website's supervisor and the mothers, such interventions would be cost-effective. psychological distress and perceived support among jordanian parents living with a child with cerebral palsy: a cross-sectional study improving the care provided to hemiplegics cerebral palsy children by their family caregivers: an intervention study anxiety and depression levels in mothers of children with cerebral palsy the health of primary caregivers of children with cerebral palsy: how does it compare with that of other canadian caregivers? german translation and psychometric testing of the sf-36 health survey: preliminary results from the iqola project telehealth opportunities in occupational therapy through the affordable care act telehealth: a rapidly developing service delivery model for occupational therapy a systematic review of telehealth tools and interventions to support family caregivers theorizing the health service usage behavior of family caregivers: a qualitative study of an internet-based intervention computer-delivered and web-based interventions to improve depression, anxiety, and psychological well-being of university students: a systematic review and meta-analysis the impact of caring for a child with cerebral palsy: quality of life for mothers and fathers the visual analog scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale the effect of "handling training" for caregivers at home and home adaptation on gross motor function of 15-72 months old cerebral palsy children do web-based interventions improve well-being in type 2 diabetes? a systematic review and meta-analysis effect of an experiential dysphagia workshop on caregivers' knowledge, confidence, anxiety and behaviour during mealtimes the influenced factors on quality of life of mothers of children with severe cerebral palsy: a survey study the effectiveness of handling training on stress and quality of life among mothers of children with cerebral palsy aged 4-12 years old effects of maternal handling training at home, on development of fine motor skills in the children with cerebral palsy: a randomized clinical trial a systematic review of clinical outcomes, clinical process, healthcare utilization and costs associated with telerehabilitation a randomized controlled trial of alternative modes of service provision to young children with cerebral palsy in bangladesh predictors of stress in mothers of children with cerebral palsy in bangladesh the short form health survey (sf-36): translation and validation study of the iranian version the validity of the 21-item version of the depression anxiety stress scales as a routine clinical outcome measure review of caring training for caregivers of children with cerebral palsy a web-based caring training for caregivers of children with cerebral palsy: development and evaluation telehealth in occupational therapy: a scoping review hypertonicity in children with cerebral palsy: a new perspective time use in mothers of children with cerebral palsy: a comparison study testing dutch and french translations of the sf-36 health survey among belgian angina patients a survey on caregivers' knowledge about special caring for 1-to-5 year-old children with cerebral palsy and their compliance with these practices a report: the definition and classification of cerebral palsy validation of depression anxiety and stress scale (dass-21) for an iranian population could everyday technology improve access to assessments? a pilot study on the feasibility of screening cognition in people with parkinson's disease using the montreal cognitive assessment via internet videoconferencing a holistic framework to improve the uptake and impact of ehealth technologies the mos 36-item short-form health survey (sf-36): i. conceptual framework and item selection depression and anxiety levels in mothers of children with cerebral palsy: a controlled study we gratefully acknowledge the valuable contribution of ms elahe nemati, ms narges mortazavi, ms neda gasemi, and mr ohadizade, and gameno occupational therapy center. we acknowledge mothers of children with cerebral palsy who participated in this study. key: cord-343818-pj1oludh authors: liu, chan; he, yu; liu, lian; li, fang; shi, yuan title: children with covid-19 behaving milder may challenge the public policies: a systematic review and meta-analysis date: 2020-09-01 journal: bmc pediatr doi: 10.1186/s12887-020-02316-1 sha: doc_id: 343818 cord_uid: pj1oludh background: the emerging virus is rampaging globally. a growing number of pediatric infected cases have been reported. great efforts are needed to cut down the transmission. methods: a single-arm meta-analysis was conducted. we searched pubmed, google scholar, web of science, and several chinese databases for studies presenting characteristics of children confirmed with coronavirus disease 2019 (covid-19) from december 12, 2019 to may 10, 2020. quality appraisal of case series studies checklist was used to assess quality and publication bias was analyzed by egger’s test. random-effect model was used to calculate the pooled incidence rate (ir) or mean difference (md) with 95% confidence intervals (ci), or a fixed model instead when i(2) < 50%. we conducted subgroup analysis according to geographic region. additionally, we searched united nations educational scientific and cultural organization to see how different countries act to the education disruption in covid-19. results: 29 studies with 4300 pediatric patients were included. the mean age was 7.04 (95% ci: 5.06–9.08) years old. 18.9% of children were asymptomatic (95% ci: 0.121–0.266), 37.4% (95% ci: 0.280–0.474) had no radiographic abnormalities. besides, a proportion of 0.1% patients were admitted to intensive care units (0, 95% ci: 0.000–0.013) and four deaths were reported (0, 95% ci: 0.000–0.000). up to 159 countries have implemented nationwide school closures, affecting over 70% of the world’s students. conclusion: children were also susceptible to sars-cov-2, while critical cases or deaths were rare. characterized by mild presentation, the dilemma that children may become a potential spreader in the pandemic, while strict managements like prolonged school closures, may undermine their well-beings. thus, the public policies are facing challenge. in december 2019, dozens of pneumonia cases with unknown etiology were reported in wuhan, hubei province of china. further sequencing analysis on samples of bronchoalveolar lavage fluid from pneumonia patients indicated that a new type of coronavirus, 2019 novel coronavirus (2019-ncov), later renamed as severe acute respiratory syndrome coronavirus 2 (sars-cov-2), was to blame for this outbreak [1, 2] . the emerging disease caused by this pathogen, was then named coronavirus disease 2019 officially by the world health organization (who). human-to-human transmission has been recognized early onset of the spread of covid-19 [3] , and the numbers of confirmed cases keeps surging over the past few months. on 11 mar 2020, the outbreak of covid-19 was formally classified as a worldwide pandemic. as of 17 may, altogether 4,525,497 confirmed cases and 307,395 deaths across 215 countries were reported by who [4] . though the sars-cov-2 is, based on current updated knowledge, phylogenetically, different from severe acute respiratory syndrome coronavirus (sars-cov) and middle east respiratory syndrome-coronavirus (mers cov), which were identified as the cause of the two previous epidemics occurred in china and saudi arabia, they do share certain similarities. sars-cov-2 shares 79% genome sequence similarity to sars-cov and 50% genome sequence homology to mers-cov [5] . all the three viruses belong to beta coronavirus and are enveloped positive-strand rna viruses, patients got infected mainly manifested with respiratory symptoms (e.g. fever and cough) and poor clinical outcomes often associated with older age and underlying diseases [5, 6] . children with sars or mers appeared to develop a milder clinical course, thus resulted in a significant low mortality in the two previous outbreaks [7, 8] . an earlier study on 2143 pediatric patients by dong [9] and colleagues found that 3% of laboratory-confirmed cases were severe/critical, while 7.4% in suspected cases. so far, sars-cov-2 infection has aroused grave concern globally, however, it seems that children got less focused due to a milder presentation. evidence-based data is in an urgent need to make up the gap in understanding clinical spectrum of covid-19 in children. therefore, we are going to synthesize and summarize the clinical characteristics and epidemiology of children with covd-19 based on the latest literatures to provide a systematic view towards pediatric patients. the protocol of this review followed recommendations established by preferred reporting items for systematic reviews and meta-analyses (prisma) guidelines [10] and was registered in the international prospective register of systematic reviews (prospero) database (id: crd42020173233). a systematic search was conducted in the following electronic databases: pubmed/medline, google scholar, web of science, china national knowledge infrastructure (cnki), wanfang and several chinese medical journals from december 1, 2019 to may 10,2020, incorporating the terms "covid-19", "sars-cov-2", "children", "pediatric" etc. no language limitations were applied. the detailed search strategy can be found in additional file 1. additionally, we searched united nations educational scientific and cultural organization (unesco, https:// zh.unesco.org/) to find out how different countries act to the education disruption in covid-19. the studies included in this meta-analysis should meet the following criteria: (1) all types of studies either retrospective or prospective (e.g. cohort, cross-sectional study, case report, case series); (2) studies reporting information regarding covid-19; (3) studies describing clinical characteristics of pediatric patients (0-19 years) diagnosed by rt-pcr; (4) clinical data of more than five cases can be drawn from the articles. duplicate studies were removed. studies that select cases from the same hospital during the same period were excluded to avoid regional bias and potential redundant report, then articles with maximum cases were retained. we also excluded studies that reported data on both adults and children, where we failed to extract pediatric data. data were extracted from included studies by two reviewers (cl and ll) using microsoft excel 2019 independently, any disagreements were resolved by discussion with a third investigator (yh). we extracted study characteristics including study design, time of enrollment, institutions, sample size, study subject features age, gender, epidemiology, symptoms and signs(e.g., fever, cough, lack of symptom), laboratory findings (e.g. white blood cell counts [wbc], lymphocyte counts [l],et.), radiographic images, treatments and outcomes(e.g. discharged, death). primary presentation described in each study were extracted with no assumptions. quality assessment of eligible studies was performed by the quality appraisal of case series studies checklist of the institute of health economics (ihe) [11] , which is comprised of 20 items. each item would be scored '0' if it was answered 'no' or 'unclear', if the answer was 'yes', the item scored '1'. a study with 14 or more scores (≥ 70%) was considered to be of acceptable quality. the statistical software r 3.6.3 (r foundation) was used to carry out the single-arm meta-analysis. original data extracted from the literature will be transformed by the double arcsine method if the data is not normally distributed. pooled incidence rates (ir) and 95% confidence intervals (95% ci) were calculated or dichotomous data and mean difference (md) with 95% ci were used to report continuous data. the χ 2 test and the i 2 statistic were used to assess heterogeneity among studies with the random-effect model and dersimonian and laird method, or a fixed model instead when i 2 < 50% (i 2 > 50% indicated that heterogeneity was statistically significant). we also conducted a subgroup analysis according to geographic region (wuhan and outside wuhan) to explore reasons for heterogeneity. in addition, a sensitivity analysis was followed by. publication bias was assessed using funnel plots and egger's regression asymmetry test for meta-analysis that included at least 10 studies. p-value of < 0.05 indicated the existence of publication bias. a total of 1375 relevant papers were identified after a systematic search. (see fig. 1 ). for those which were accessible to pediatric data, we conducted a comprehensive screening and comparison according to time of enrollment, institutions and demographic characteristics of subjects, 24 articles were under suspicion of an overlapped data were removed. of 29 studies incorporating 4300 children included in this meta-analysis, 20 were case series, 4 cross-sectional, 3 prospective cohorts and 2 retrospective cohort, none compared cases with controls. study size ranged from 5 to 2572 participants from six countries (china, italy, united states, canada, spain, rome). the detailed characteristics can be found in supplementary table 1 (see additional file 2). as of 17 may 2020, 159 countries were reported to have implemented nationwide school closures to mitigate the impact of covid-19 on children, affecting over 70% of the world's student population. the mean age of pediatric patients enrolled in the 29 studies was 7.04 years old (95% ci: 5.06-9.08), range from 1 day to 19 years old. particularly, 12% (95% ci: 0.063-0.188) of children were less than 1 year old, 14.9% (95% ci:0.105-0.196) were 1 to 4 years old, 23.2% were 5 to 9 years, 23.1% were 10 to 14 years and 5.8% were more than 15 years old. among them boys accounted for 53.6% (95% ci: 0.494-0.577). comorbidities were reported in six studies with a proportion of 9.9% (95% ci: 0.002-0.215). a large number of cases were identified as part of family clusters with covid-19, the pooled incidence rate was up to 81.5% (95% ci:0.710-0.903). besides, the pooled prevalence of cases associated with original epidemic area was 39.8% (95% ci:0.180-0.635). fourteen studies described the severity of covid-19 in pediatric group with 1 patient diagnosed as critical type (0, 95% ci:0.000-0.006) and 2 as severe type (0, 95% ci: 0.000-0.006). after a systematic review, we found 26 symptoms and signs reported in children infected with sars-cov-2. for the features of "sneezing", "swollen tonsils", "headache", "wheeze", "chill/rigor", "chest pain/distress", "abdominal pain", "seizure/convulsion", "rash", "constipation", "anosmia", "arthralgia", "conjunctivitis", "cyonosis" and "tachycardia", meta-analysis was thought to be unnecessary since few researches have presented. as is shown in table 1 , fever (52.7, 95% ci: 0.443-0.610) and cough (41.9, 95% ci:0.357-0.481) were the most prevalent and mild or moderate fever was more frequent than high fever. lack of symptoms was also relatively common in these included cases, which turned out a proportion of 18.9% (95% ci: 0.121-0.266). conversely, other symptoms or signs didn't have such a frequent presentation (summarized in table 1 ). the frequency of decreased wbc was similar to increased wbc in reported cases, the pooled incidence rate was 10.6% (95% ci: 0.054-0.168) and 10.3% (95% ci: 0.066-0.146). compared to lymphopenia (10.8, 95% ci: 0.039-0.197), the incidence of lymphocytosis (15.4, 95% ci: 0.098-0.217) was slightly higher in pediatric patients. increased c-reactive protein (crp) was in 12.3% (95% ci: 0.054-0.210) of subjects. the pooled incidence rate of an elevated level of aspartate aminotransferase (ast), alanine aminotransferase (alt) and lactate dehydrogenase (ldh) were 10.9% (95% ci:0.050-0.182), 6.5% (95% ci:0.038-0.096), 23.0% (95% ci:0.088-0.383) respectively. normal radiologic presentation was reported in 37.4% (95% ci: 0.280-0.474) of cases. apart from that, the most common manifestation was ground-glass opacity (ggo) (35.7, 95% ci:0.310-0.405), unilateral compromised lesions were more frequently presented than bilateral (28.2, 95% ci:0.194-0.378 vs 21.9,95% ci: 0.104-0.355). additionally, 10 .5% of subjects (95% ci:0.016-0.236) were reported with consolidation on computed tomography (ct) imaging. approximate 63.0% (95% ci: 0.255-0.939) sars-cov-2 infected children were treated with interferon and lopinavir-ritonavir (26, 95% ci: 0.255-0.939) was more frequently applied compared with other antiviral agents including ribavirin, oseltamivir and arbidor. few cases received administration of corticosteroid, immunoglobin therapy and mechanic ventilation, the pooled incidence rate was 0.0% (95% ci: 0.0000-0.004), 0.0% (95% ci: 0.000-0.003) and 0.0%(95% ci:0.000-0.002), respectively. the majority of patients (84.1%,95% ci: 0.696-0.951) got discharged from hospital and 0.1% (95% ci: 0.000-0.013) were transferred to intensive care units. unfortunately, 4 deaths (0,95% ci: 0.000-0.000) were ultimately confirmed. the results of heterogeneity assessment and publication bias are shown in table 1 . subgroup analysis indicated that geographic region may account for the heterogeneity of "fever (mild)" and "unilateral compromised". (table 2) . a further exploration for between-study heterogeneity by sensitivity analysis showed that none of these studies should be excluded. the unpredictable emergency of sars-cov-2 has posed a substantial threat to public health. implementing efforts on aggregating the existing data about epidemiology, clinical, laboratory, and imaging characteristics to have a better understanding of the virus, its patterns of spread and the spectrum of illness is of critical significance. through a comprehensive searching, a total of 29 articles with 4300 cases were included. the proportion of male to female of this analysis (53.6% vs 46.4%) is similar to the gender distribution in an initial investigation [9] (57.5% vs 42.5% in 731 confirmed cases) and general population [41] (55.9% vs 44.1%) ( table 3 ). all the results seem to show that male have a slightly higher incidence than female in covid-19. according to our results, children got infected with sars-cov-2 mainly through family clustering, quite the same as sars-cov [7] and mers-cov [8] .while compared to adults, children are more likely to be asymptomatic or present with milder symptoms, this reminds us that, whenever there's a family member caught with this virus, it is necessary to conduct a virologic screening test on the child as soon as possible. otherwise, the infected child may become a threat to other vulnerable populations (e.g. elderly people or people with severe underlying disease), resulting in further extension of ongoing pandemic, as was seen during influenza outbreak [44] . fever and cough are the most common symptoms in covid-19 children, in our study, the pooled incidence of fever is 52.7%, which is lower than that in adults [41] , sars [7, 42] and influenza [43] . clearly, children with covid-19 rarely had obvious signs and symptoms of upper respiratory tract (pharyngeal congestion, rhinorrhea, sore throat, stuffy nose). through a comprehensive review, it's easy to draw the conclusion that sars-cov-2 leads to a less aggressive clinical course in children with more asymptomatic and fewer symptoms, compared to that in adults and the other two pathogens. (table 3 ). in terms of laboratory abnormalities, only 10.8% of infected children presented with lymphopenia, which is quite different from findings in covid-19 adults [41] and sars [7] .besides, leucopenia was found in 10.6% of patients, nevertheless, a research including 80 virologicconfirmed children cited by henry [45] reported 46% of lymphopenia. theoretically, virus particles primarily spread through the respiratory mucosa, initially using note: the results of characteristics of covid-19 in children and general population were presented with pooled incidence and 95% ci, characteristics of "comorbidities" in children with covid-19 were presented with incidence(n/n) due to insufficient data no meta-analysis results of characteristics of children with sars and h1n1 influenza were found, incidence(n/n) was presented as a substitute "-": not available the angiotensin-converting enzyme 2(ace2) receptor (the cell-entry receptor for sars-cov-2) at ciliated bronchial epithelial cells and infect other cells, induce a cytokine storm in the body, generate a series of immune responses, and cause changes in peripheral white blood cells and immune cells such as lymphocytes [46, 47] . presumptions have been made that children may be protected against sars-cov-2 because this enzyme is less mature at a younger age, since the immune system undergoes substantial changes from birth to adulthood. in general, wbc and lymphocyte remained normal in the majority of pediatric patients, suggesting that the newly emerging virus, sars-cov-2, may have a marginal influence on the immune function of children. as for radiologic aspects, our research found that a proportion of 37.4% of 501 virologic positive cases were in absence of ct abnormalities, and ground glass opacity, also typical signs of severe acute respiratory syndrome (sars) [7] , was shown in 35.7% of pediatric patients. this kind of low sensitivity hints us that routinely radiologic scans should not be overemphasized for screening or early identification of covid-19 in children in consideration of substantial radiation exposure, especially when the child is lack of symptoms or running a mild clinical course. therefore, more strict strategies and screening practices are required for the better management of pediatric cases. compared to adults [41] , the spread of sars-cov-2 yield a much better prognosis in pediatric patients, similar to sars [7] and middle east respiratory syndrome (mers) [8] . 84.1% of cases were discharged, the discharge rate ought to be higher actually since many children were still in hospital before the submission of the papers. the reasons why children experience a milder covid-19 disease remain elusive. one possible explanation is that the response of children to sars-cov-2 is fundamentally different from that of adults, as demonstrated in earlier reports [48] , the frequency of lymphopenia found in adults suggests that sars-cov-2 might act on lymphocytes, which is rare in children. prior exposure to other respiratory virus may exert an influence, making children's immune systems more resilient [7] . besides, some researchers proposed that the mild disease in children may be associated with trained immunity, which refers to the use of certain vaccines such as bacille de calmette guerin (bcg). bcg has been proved to provide nonspecific protection of mice against influenza virus infection probably by the induction of trained immunity [44] . in addition, the virulence and pathogenicity of the virus may decrease in pediatric patients who are usually belong to the second or third generation infection. accordingly, further studies in fields of immunology, anatomy and virology are required to ravel out this puzzle. with massive public health interventions implemented actively and effectively, the spread of sars-cov-2 seems to have been under control in several countries. on 17 may 2020, there were only 7 newly confirmed cases across mainland china and 4 were imported [49] . at present, while some countries are considering enhancing control measures, china is planning to lift restrictions, work resumes and school starts are on agenda. nevertheless, concerns have been proposed that a second wave of cases might occur in light of the absence of herd immunity against covid-19, escalating case importation or residual infected seeds and resumption of economic activities [50, 51] . it's plausible to suggest whether children have to get away from school again to mitigate the revival transmission. school closures can affect the spread of virus during a pandemic through reducing transmission and new cases, while long periods of social distancing interventions in school may put students in a disadvantaged situation. recently, some scholars are questioning the benefits brought by closing schools. on the one hand, school closures are based on empirical evidence and assumptions from influenza outbreaks, it's hard to say such measures are also effective in coronavirus outbreaks like sars, mers and especially covid-19, for which transmission dynamics appear to be different [52] . a systemic review [52] concluded that school closures in sars did not contribute to the control of the epidemic and its effectiveness in covid-19 would be less than other social distancing interventions, with only 2-4% of death prevention. meanwhile, less comprehensive and deliberate plan can result in a completely converse consequence. jude bayham and eli p fenichel [53] estimated that school closures could lead to mortality rate increased by 0.35% and a greater number of deaths than they prevent when the health-care workforce declines by 15.0% due to unintended childcare obligations. (table 4 shows alternative closure strategies in five countries). on the other hand, prolonged school dismissals can be detrimental to children's physical and mental health [59, 60] . out of school means a totally altered lifestyle-for example, fewer physical activities, less interaction with peer groups and longer screen time. besides, many schools are offering online courses, but this is not available to all, especially to children from low socioeconomic households, and they may be further disadvantaged by nutrition shortfalls. moreover, with home confinement, communities lockdown and economic recession deepens, family conflicts are rising, children are more likely to be exposed to domestic violence and abuse. consequently, it is imperative for the policy makers to weigh the benefits of school closure against its costs carefully and deliberately and provide alternative strategies to minimize the adverse impacts of the covid-19 on children's well-being. there are several limitations need to be acknowledged. firstly, most of articles included in this meta-analysis are descriptive and retrospective with wide range of sample size, which highlighted different aspects of the illness, consequently, high heterogeneity was inevitable. secondly, reports derived from china dominated the largest part, data from other countries are still in short. in addition, we have intended to conduct a subgroup analysis based on age stratification and severity of the disease, while enough information was unavailable. therefore, the findings of this meta-analysis still need to be updated by more relevant studies with more strict design and larger sample size. in conclusion, our study highlights the epidemiology, clinical characteristics of covid-19 in pediatric patients. this quantitative analysis provides evidence-based knowledge for the diagnosis and management in pediatric patients in the ongoing pandemic. children were also susceptible to sars-cov-2. compared to adults, children experienced a milder clinical course. the most frequent symptoms were fever and cough, asymptomatic were also quite common. children with no or mild symptoms should be virologic-screened and isolated from immunocompromised populations at once when a family member is diagnosed with covid-19 to prevent child-driven transmission. a group of children were absent from ct abnormalities, ct scans should not be overemphasized to avoid excessive radiation exposure. public health officials should attach importance to additional childcare programs to protect the wellbeing of children in this pandemic context. supplementary information accompanies this paper at https://doi.org/10. 1186/s12887-020-02316-1. additional file 1. search strategy: this file describes the search strategy of this meta-analysis additional file 2: table s1 . characteristics of the included studies table 4 school strategies in different countries in response to covid-19 uk [54] localized closures have been implemented since 28 feb. all educational settings are closed to everyone except the children of critical workers and vulnerable children a since 20 march and will stay closed until further notice. us [55] school-based strategies (e.g., short-term or extended dismissals, event cancellations, social distancing measures) are adopted locally in collaboration with local health officials based on level of community transmission of covid-19 and presence of covid-19 cases within the school, combined with open child care programs b like private child care centers for essential service providers. the majority of states have mandated school closures since 10 april, including until the end of the academic year in june. some states, however, have recommended but not mandated the school closures. italy [56] some schools in the heaviest hit area have been shut down since 24 feb. mandatory closure of all schools and universities across the country were implemented from 10 march and will remain shut until 3 may. france [57] all nurseries, schools, colleges, high schools and universities are closed from 16 march and will gradually reopen from 11 may with the exception of universities, which will not reopen until the summer. childcare services are established for staff who are essential to the management of the health crisis. german [58] temporarily closing kindergartens and schools and postponing restart of colleges were implemented in state levels since mid-march are to be extended until 3 may 2020. schools remain open for those who are willing to continue classes in some states. daycare centres are available and will continue and will be extended to other occupational and needed groups. note: a vulnerable children include children who are supported by social care, those with safeguarding and welfare needs, including child in need plans, on child protection plans, 'looked after' children, young carers, disabled children and those with education, health and care (ehc) plans b other open child care 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closure-of-educational-settings-information-forparents-and-carers/closure-of-educational-settings-information-for-parentsand-carers#closures-of-schools-childcare-and-other-educational-settings interim guidance for administrators of us k-12 schools and child care programs to plan, prepare, and respond to coronavirus disease coronavirus, the measures taken by the government the lancet child adolescent, h. pandemic school closures: risks and opportunities. lancet child adolesc health mitigate the effects of home confinement on children during the covid-19 outbreak publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable. authors' contributions ys generated the idea, designed the study and participated in the whole process of research. cl and ll conducted literature screening and data extraction, yh was responsible for data analysis and interpretation. cl, yh and ll wrote this manuscript collaboratively, fl and ys contributed to the final revision of the paper. all authors have read and approved the final manuscript. none. data sharing is not applicable to this article as no datasets were generated or analysed during the current study.ethics approval and consent to participate not applicable. not applicable. yuan shi is an associate editor in this journal. key: cord-322348-8opy5z9h authors: morelli, mara; cattelino, elena; baiocco, roberto; trumello, carmen; babore, alessandra; candelori, carla; chirumbolo, antonio title: parents and children during the covid-19 lockdown: the influence of parenting distress and parenting self-efficacy on children’s emotional well-being date: 2020-10-06 journal: front psychol doi: 10.3389/fpsyg.2020.584645 sha: doc_id: 322348 cord_uid: 8opy5z9h on march 10, 2020, italy went into lockdown due to the coronavirus disease-19 (covid-19) pandemic. the world health organization highlighted how the lockdown had negative consequences on psychological well-being, especially for children. the present study aimed to investigate parental correlates of children’s emotion regulation during the covid-19 lockdown. within the social cognitive theory framework, a path model in which parenting self-efficacy and parental regulatory emotional self-efficacy mediated the relationship between parents’ psychological distress and both children’s emotional regulation, and children’s lability/negativity, was investigated. a total of 277 parents of children aged from 6 to 13 years completed an online survey that assessed their psychological distress, regulatory emotional self-efficacy, and parenting self-efficacy. parents reported also children’s emotional regulation and lability/negativity. a structural equation model (sem) using mplus 8.3 was tested. results showed that the hypothesized model exhibited excellent fit, chi-square (83) = 140.40, p < 0.01, rmsea = 0.05, cfi = 0.97, tli = 0.96, srmr = 0.04. the influences of parents’ psychological distress and parents’ regulatory emotional self-efficacy on children’s emotional regulation and lability/negativity were mediated by parenting self-efficacy. the mediation model was invariant across children’s biological sex and age, and geographical residence area (high risk vs. low risk for covid-19). results suggested how parents’ beliefs to be competent in managing parental tasks might be a protective factor for their children’s emotional well-being. implications for intervention programs are discussed. the spread of the pandemic covid-19 in italy from february 2020 and the subsequent health emergency led to several restrictive measures. schools and universities have been closed at the end of february, and starting from march 9th, 2020, a quarantine measure became necessary leading to a general closure of almost all public businesses and work activities. children and families have been deprived of their educational, work, and sport activities, but also from all their friendship and relational contacts. suddenly parents had to manage their children at home from school 24 h a day and, at the same time, most of them had to start smart-working from home, still carrying out their children's school commitments. many parents also had to manage difficulties and pain related to having sick or dead relatives, having had wages reductions, or in some cases, having lost their work. it is easy to understand how italian families have been exposed to a very strong emotional and psychological stress. this situation had relevant repercussions on daily life of families, especially of children that have been deprived of their socialization and play spaces. the parents suddenly became the only point of reference for their children since the other references and educational figures were no longer available. as enlightened by the world health organization (who, 2020a,b) , this situation could have long-term negative consequences on psychological well-being and there is a need to invest in mental health services and other services. a recent review stressed how people all over the world can show many different psychological disorder symptoms related to the pandemic (shahyad and mohammadi, 2020) . the who (2020a) highlighted that children were also showing signs of mental illness. in fact, both international and domestic studies showed that, during the lockdown, children exhibited several problems, such as anxiety and emotional and behavioral disorders (jiao et al., 2020; spinelli et al., 2020; xie et al., 2020) . the european pediatric association-union of national european pediatric societies and associations (epaunepsa; jiao et al., 2020) has stressed the importance to address children's psychological needs during the pandemic due to the negative repercussions on their psychological well-being, highlighting the relevant protective role of parents in decreasing their fear and stress. research on psychological consequences of traumatic events, such as the terroristic attack of september 11, 2001, showed how children can also experience long-term effects on psychological well-being, reporting mental disorders after 6 months (hoven et al., 2005) . all these data highlight the importance of not underestimating the psychological risks that children and their families could face. in a report on may 13th, 2020, the united nations also underlined how, during the covid-19 pandemic, the emotional problems of children and adolescents were exacerbated by family stress, social isolation, interruption of school and educational activity, and uncertainty for the future which occurred in critical moments of their emotional development (united nations, 2020) . understanding how to strengthen parents and families in this situation, with the aim to protect children, represents an important goal that researchers should have in this period because it is possible that other future pandemics will affect humanity (cluver et al., 2020) . the limited research conducted to date on the effects of the covid-19 pandemic on well-being of parents and their children both in china and in italy showed that covid-19 related risks, such as (a) living in a red zone (i.e., a high-risk zone like lombardia and veneto for italy), (b) being a parent positive to sars-cov-2, (c) having relatives or friends positive to the sars-cov-2 or who died from the sars-cov-2, and (d) living in a high-risk environment (i.e., not having an open space in the home during the lockdown, losing a job during the pandemic, having a low income, not having internet connection), did not have strong negative direct effects on families' well-being (spinelli et al., 2020) or on children's symptoms and problematic behaviors per se (jiao et al., 2020) . actually, the research conducted by spinelli et al. (2020) in italy showed that it was the parenting stress related to the health emergency, the pandemic, and the lockdown that increased children's psychological, emotional, and behavioral problems. in line with these findings, wang et al. (2020) suggested the need to deeply understand the family functioning and processes that can promote children's psychological wellbeing during the pandemic. for this reason, this study focused on identifying which parental psychological variables can mediate the relationship between parents' psychological distress during the pandemic and the lockdown and their children's emotional regulation, in order to understand which possible intervention should be implemented to ameliorate families' well-being. two recent meta-analyses highlighted the relevant role that the parent-child relationship can have in promoting children's effortful self-regulation (pallini et al., 2018) and in decreasing children's behavioral problems, specifically attention problems (pallini et al., 2019) . the stress of quarantine can affect psychological well-being of adults, as confirmed in a recent review (brooks et al., 2020) , and might also have long-term effects (liu et al., 2012) . a study conducted on parents and children quarantined in 2009 during the h1n1 influenza showed that the high-stressful isolation increased parents' psychological distress that in turn had an impact on their children's well-being (sprang and silman, 2013) . children who have parents with high levels of stress showed more externalizing problems and developed less emotion regulation (deater-deckard and panneton, 2017) . as reported by leary and hoyle (2009) , psychological distress upsets the ability to self-regulate (tillema et al., 2001; scott and cervone, 2002) but regulatory emotional self-efficacy is crucial in the self-regulation of relationships and behavior (bandura et al., 2003) . according to bandura (1997) , psychological distress, such as lack of social support or parental depression, can affect parenting self-efficacy, which is the belief that parents have to be able to manage their parental tasks successfully and that it is, in turn, related to children's adjustment (jones and prinz, 2005) . some previous studies showed that the relationship between parental mental health and children's emotional and behavioral well-being is mediated by positive parenting strategies (giallo et al., 2014) . according to eisenèberg et al. (2005) , parents' positivity and warmth can promote effortful control in children, reducing their externalizing behaviors. likewise, self-efficacy, specifically parenting self-efficacy, can function as a mediator between environmental variables or psychological conditions related to an external situation (e.g., the stress related to the pandemic) and parenting competence. in fact, environmental aspects might also indirectly affect parents' belief to be competent in managing parental tasks, and this could lead to less psychological well-being of the children (jones and prinz, 2005) . for this reason, it is important that parents have a good parenting self-efficacy in order to display positive parenting strategies that can foster adaptive functioning and emotion regulation in children (stack et al., 2010) . within the theoretical framework of social cognitive theory (bandura, 1997) , the present study aimed to investigate a path model in which parenting self-efficacy and parents' regulatory emotional self-efficacy (related to covid-19 lockdown) mediated the relationship between parents' psychological distress and both children's emotional regulation, and children's lability/negativity, in line with a previous study that stressed how parenting self-efficacy can mediate the relationship between parents' psychological distress and children's adjustment (giallo et al., 2014) . additionally, in our model parents' psychological distress was also predicted by being exposed to several risks related to covid-19 quarantine and the pandemic. moreover, the second aim was to assess whether children's biological sex, children's age, and geographical area (northern italy, which is the most at-risk area for the spread of the pandemic and for the risk of contagion, vs. the rest of italy) moderated the structural paths of the model. there is evidence that children's biological sex can affect parents' way to respond to children (sanders and morawska, 2018) and that parenting selfefficacy can change over time (deater-deckard and panneton, 2017) , growing during early childhood (weaver et al., 2008) , and decreasing when children become adolescents (glatz and buchanan, 2015) . conversely, we did not expect to find any differences regarding living (or not living) in a high at-risk zone for the covid-19 (i.e., northern italy), as found by recent italian and chinese studies (jiao et al., 2020; spinelli et al., 2020) . the present study was conducted in italy, via an online survey, during april 2020 when there was a lockdown related to the health emergency due to the covid-19 pandemic. specifically, italian parents with a child aged between 6 and 13 years were recruited through a snowball sampling procedure to complete the online survey. at the time of data collection, italy had been in quarantine for more than 1 month. a link to the survey was shared among parents using different social networks (e.g., facebook, whatsapp), also asking parents to share the link among their contacts. overall, 417 parents have had access to the survey, and a total of 277 valid questionnaires were used in the present investigation, yielding a response rate of 66.4%. parents' age ranged from 30 to 58 years old (m age = 43.36, sd age = 4.76) and the recruited sample mostly consisted of mothers (n = 248; 89.5%). as abovementioned, children were aged between 6 and 13 years (m age = 9.66, sd age = 2.29) and were almost equally distributed for biological sex (48% were boys and 52% were girls). parents' socioeconomic status (ses) was predominantly medium-high (92.1%; n = 255). 14.1% (n = 39) lived alone at home with children during the quarantine. 62% (n = 171) of parents were from northern italy, the italian area most affected by the pandemic, and 37.9% (n = 105) were from central and southern italy which were areas less affected by the pandemic (although they were also put in lockdown). regarding their work situation, 195 parents (70.4%) continued to work and earn as before the quarantine, while 82 parents (29.6%) lost their works or have had wage reductions or layoffs. 7.9% (n = 22) were health workers and 5.8% (n = 16) were health workers in a hospital department that treated sars-cov-2-positive patients. 91.7% of parents (n = 254) did not have any relative tested positive for the sars-cov-2, and 8.3% (n = 23) had at least one relative that tested positive for the sars-cov-2. 96.8% (n = 268) have not-hospitalized relatives due to sars-cov-2, and 3.2% (n = 9) have at least one hospitalized relative. finally, 32.5% of parents (n = 90) did not have any acquaintance or a loved one that tested positive to sars-cov-2, and 67.5% (n = 187) had at least one acquaintance or a loved one that tested positive for sars-cov-2. each parent gave his/her consent by clicking "yes, i accept to participate in the study" on the first page of the survey. this study was approved by the ethics committee of sapienza university of rome, department of developmental and social psychology, protocol number: 427, april 16, 2020. two power analyses were conducted to determine the recommended minimum sample size: (1) for detecting a significant bivariate effect and (2) for conducting a structural equation model (sem; cohen, 1988) . a moderate effect size of 0.25 was anticipated with a power level set at 0.80 and a significant alpha level set at 0.05. the minimum sample size necessary to detect a significant bivariate effect was n = 124. regarding the sem, with five latent and fifteen observed variables, using the software developed by soper (2020) , results indicated that the required minimum sample size to run a sem and detect a significant effect was n = 229. using a similar procedure as used by spinelli et al. (2020) , we created an ad hoc index that assessed risks related to the covid-19 pandemic. specifically, a composite index was created given one point for each of the following risk factors, if present: (a) relatives that tested positive for sars-cov-2, (b) friends or acquaintances that tested positive for sars-cov-2, (c) hospitalized relatives due to sars-cov-2, (d) living in northern italy, which was the most at-risk area for the spread of the pandemic and for the risk of contagion, (e) being a health worker, and (f) being a health worker in hospital departments that treated sars-cov-2 positive patients. again, using a similar procedure as used by spinelli et al. (2020) , we created an ad hoc index that assessed risks related to family situation during the quarantine and the pandemic. specifically, a composite index was created given one point for each of the following risk factors if present: (a) a lower ses, (b) a worsened working situation during the quarantine, and (c) being a single or divorced parent who had to manage her/his own children at home alone during the quarantine. both the family risk index and the covid risk index are intended as summative rating scales that were created ad hoc for this research. parents' psychological distress during the lockdown was evaluated using the perceived stress scale (cohen et al., 1983; italian validation by mondo et al., 2019) . parents were asked to think about the last month. the scale is composed of 10 items that parents rated on 5 point-likert scales from 1 (never) to 5 (very often). an example item is "during last month how do you usually feel nervous and stressed?" the scale showed a good reliability and validity also in the italian validation (mondo et al., 2019) . in the present sample, the measure showed a good reliability, cronbach's alpha of 0.84. the regulatory emotional self-efficacy scale (caprara et al., 2013b ) is a 13-item scale that evaluates the belief of parents to be able to manage with their negative emotions (i.e., anger, sadness, fear, and guilt) during the covid-19 lockdown on a 5 point-likert scale from 1 (not able) to 5 (able). the scale was modified asking parents to think about the quarantine period related to covid-19 health emergency, and the following item was added to the scale "how do you feel able to manage the anxiety caused by hearing the news about coronavirus that is given on tv or that you read on the internet?" the scale showed good validity and reliability (caprara et al., 2013a,b) . in the present sample, the scale showed a good reliability: cronbach's alpha of 0.87. parents completed the parenting self-agency measures (dumka et al., 1996; baiocco et al., 2017) which is an 8-item scale that evaluates the belief of parents to be able to manage with daily parental demands (i.e., feeling to be a good parent, working to face and solve difficulties with their children) during the month of lockdown on 7-point likert scales from 1 (seldom) to 7 (always). the scale was modified, asking parents to think about the quarantine period related to covid-19 health emergency, and three items were added to the original scale. these three items asked parents how they feel able to reassure their children about the health emergency, to organize their children's daily life during the quarantine, and to explain to their children what is happening. the scale showed good validity and reliability (baiocco et al., 2017 . in the present sample, the scale showed a good reliability: cronbach's alpha of 0.87. parents were asked to think about their child during the quarantine and to complete a short version of the emotion regulation checklist (molina et al., 2014) . this is a 10-item scale that evaluates two sub-dimensions, namely, emotional regulation (i.e., positive emotions, being able to give voice to his/her negative emotions) and lability/negativity (i.e., anger, disruptive behaviors, excessive exuberance) of children during the covid-19 lockdown on a 4 point-likert scale from 1 (almost never) to 4 (almost always). the scale showed good validity and reliability (molina et al., 2014; di maggio et al., 2016) . in the present sample, both emotional regulation and lability/negativity scores showed acceptable reliability, respectively cronbach's alpha of 0.65 and 0.78. firstly, bivariate correlations among variables were calculated along with descriptives. afterward, a mediation analysis with latent variables was performed via sem, employing a parceling strategy (e.g., bagozzi and heatherton, 1994; little et al., 2002) . a parcel represents an aggregate of different items measuring a specific construct (little et al., 2002; coffman and maccallum, 2005) . two or three parcels were constructed for each of the latent variables using the "item-to-construct" balance approach (little et al., 2002) , which means building each parcel by examining the item-construct relationships as represented by factor loadings in the item-level factor analyses (for a detailed description of this procedure, see little et al., 2002) . in such a way, parcels typically contained a balanced number of items and had comparable reliabilities. therefore, our model comprised three latent variables with three parcels each and two latent variables with two parcels each. summative indexes (such as the cri and fri) were treated as manifest variables. model fit was evaluated with the following indices: (a) the comparative fit index (cfi); (b) the tucker-lewis index (tli); (c) the root mean squared error of approximation (rmsea); (d) and the standardized root mean square residual (srmr). in general, for tli and cfi, values between 0.90 and 0.95 are considered acceptable (e.g., bollen, 1989; byrne, 1994; marsh et al., 2004) and values above 0.95 are deemed to be very good (hu and bentler, 1999) . on the other hand, rmsea and srmr values smaller than (or equal to) 0.08 indicate a good fit (e.g., bollen, 1989; browne and cudeck, 1993; hu and bentler, 1999; marsh et al., 2004) . in order to evaluate the statistical significance of indirect effects, which represented the "mediated" effects, the bootstrapping procedure was used employing 5000 samples with replacement from the full sample to construct biascorrected 95 percent confidence intervals (ci) (preacher and hayes, 2008; hayes, 2009) . mediation typically occurs if the indirect effect is significant, that is, the zero value is not included in the ci (preacher and hayes, 2008; hayes, 2009 ). finally, to test possible moderation effects of children's biological sex and age, and living in a geographical area with high covid-19 risk, a multigroup approach within sem was employed as suggested by baron and kenny (1986) . in this procedure, the invariance of the structural parameters of the proposed model was tested separately for (a) boys and girls; (b) different levels of children's age; (c) geographical residential area, that is, living (vs. not living) in northern italy. a detailed description of the procedure will be given in the "results" section (see also sauer and dick, 1993; cattelino et al., 2019) . all analyses were run with statistical software spss 25 and mplus 8.3. the family risk index was positively related with parents' psychological distress and positively with lability/negativity. parents' psychological distress was negatively related with parenting self-efficacy, parents' regulatory emotion self-efficacy, and children's emotion regulation and was positively related with children's lability/negativity. parenting self-efficacy was positively related with parents' regulatory emotion self-efficacy, and children's emotion regulation, and was negatively related with children's lability/negativity. parents' regulatory emotion selfefficacy was positively related with children's emotion regulation and negatively related with children's lability/negativity. finally, children's emotion regulation was negatively related with children's lability/negativity. correlations, means, and standard deviations are reported in table 1 . a sem was employed to test the hypothesized mediation model in which parenting self-efficacy and parents' regulatory emotional self-efficacy (related to the covid-19 lockdown) mediated the relationship between parents' psychological distress and both children's emotional regulation and children's lability/negativity. moreover, parenting self-efficacy mediated the relationship between parents' regulatory emotional self-efficacy and both children's emotional regulation and children's lability/negativity. in the present paper, the mediation analysis strategy recommended by james et al. (2006) was followed. in the first step, the mediation model was tested (i.e., model without the direct effects, indicated with m med ). in the second step, a full model, including all the direct effects, was tested (indicated with m full ). the two nested models were compared via the chi-square difference test, contrasting m med with m full ( χ 2 , satorra and bentler, 2001) . a non-significant χ 2 would reveal that the full model does not significantly increase the fit and therefore the mediation model is to be preferred since it is more parsimonious. the mediation model (m med ) showed an overall good fit, chisquare (83) = 140.40, p < 0.01, rmsea = 0.05, cfi = 0.97, tli = 0.96, srmr = 0.04. the full model including direct effects (m full ) did not apparently improve the model fit, chisquare (79) = 134.52, p < 0.001, rmsea = 0.05, cfi = 0.97, tli = 0.96, srmr = 0.04. in fact, the two models were contrasted, and the chi-square difference test was not significant, χ 2 (4) = 5.88, p = 0.20. therefore, the mediation model (m med ) should be preferred due to being more parsimonious compared to the full model. in figure 1 , all measurement and structural parameters of the mediated model (m med ) are reported. parents' psychological distress (ppd) was significantly, although modestly, affected by both covid and family risk indexes. in turn, parents' psychological distress significantly and negatively affected both parents' regulatory emotional self-efficacy (pser) and parenting self-efficacy (pse). parents' regulatory emotional self-efficacy significantly and positively affected parenting self-efficacy. finally, parenting self-efficacy positively and significantly influenced children's emotional regulation (er_c) and negatively children's lability/negativity (ln_c). more importantly, parenting self-efficacy mediated the effect of parents' psychological distress and parents' regulatory emotional self-efficacy on both children's emotional regulation and children's lability/negativity. with the exception of those involving the covid and family risk indexes, all other indirect effects were statistically significant, supporting the mediated model (see table 2 ). in table 2 , a full decomposition of total and specific indirect of the mediated model (m med ) are reported. the covid and family risk indexes displayed no significant effects on the other variables except for the aforementioned influence on parents' psychological distress. moreover, referring to the full model (m full ), we also decomposed total, direct and indirect effects (see table 3 ) with the aim to report the ratio of indirect to the direct effect and the proportion of mediated effect (mackinnon et al., 1995) . in regard to the relationship between ppd and er_c, the ratio of indirect to the direct effect was 1.06 (−0.18/−0.17 = 1.06), while with respect to the relationship between ppd and ln_c the ratio was 0.64 (0.09/0.14 = 0.64). in regard to the relationship between ppd and er_c, about the 51.42% of the effect was mediated (−0.18/−0.35 = 0.5142), while with respect to the relationship between ppd and ln_c about the 39.13% of the effect was mediated (0.09/0.23 = 0.3913). in regard to the relationship between pser and er_c, the ratio of indirect to the direct effect was −1.11 (0.20/−0.18 = −1.11), while with respect to the relationship between pser and ln_c the ratio was −3.5 (−0.07/0.02 = −3.5). more problematic was to estimate, in the same fashion, the amount of mediated effect regarding the relationship between pser with both er_c and ln_c since in those cases the indirect and the direct effects have opposite signs (as can be seen in table 3) , and therefore, they tend to suppress each other, resulting in a reduced non-significant total effect (pser er_c:0.02 = −0.18 + 0.20; pser ln_c: −0.05 = −0.07 + 0.02). with respect to non-significant total effect, scholars have pointed out that mediation can occur also in the absence of a detectable total effect if the indirect effect is significant (e.g., mackinnon, 2008; all effects are standardized coefficients. if the zero value is not included in the bootstrap 95% ci, the effect is significant at p < 0.05. ppd, parents' psychological distress; pser, parents' regulatory emotional self-efficacy; pse, parenting selfefficacy; er_c, emotion regulation of children; ln_c, lability/negativity of children. hayes, 2009) . this is apparently the case. in this perspective, although it cannot be absolutely claimed that effects were totally mediated and despite the presence of null total effects, it is worth to note that indirect effects were significant and that mediation has occurred. overall, we can conclude that the hypothesized mediation model (m med ), reported in figure 1 , is consistent with the data. all effects are standardized coefficients. if the zero value is not included in the bootstrap 95% ci, the effect is significant at p < 0.05. ppd, parents' psychological distress; pser, parents' regulatory emotional self-efficacy; er_c, emotion regulation of children; ln_c, lability/negativity of children. moreover, the mediation did not fit significantly worse than the full model (m full ) and therefore it was retained since it is more parsimonious (james et al., 2006) . additionally, all indirect effects of the mediated model (m med ) were significant, indicating that mediation has occurred (e.g., preacher and hayes, 2008; hayes, 2009 ). within sem, the test for a moderator effect can be performed using a multigroup analysis of the model in which the structural parameters are constrained equal across groups. firstly, the structural parameters are freely estimated across groups to test for the baseline model. secondly, the structural parameters are constrained to be equal across groups to test for the invariant model. in order to compare the fit of the two models, the chi-square difference test was used (satorra and bentler, 2001) . a non-significant chi-square indicates that the parameters cannot be ruled out to be equal, then the invariant model should be retained and no moderation occurs. instead, if the chi-square difference between the invariant and the baseline models is significant, which would mean that the invariant model fits significantly worse. therefore, parameters are not equal across the groups and there is a moderation effect. results of chi-square difference tests of multigroup analyses with sem are reported in table 4 . regarding children's biological sex, the fit of the baseline model was chi-square (134) = 185.88, p < 0.01, rmsea = 0.05, cfi = 0.97, tli = 0.97, srmr = 0.07, whereas the fit of the invariant model was chi-square (139) = 187.98, p < 0.01, rmsea = 0.05, cfi = 0.98, tli = 0.97, srmr = 0.08. the chi-square difference test was not significant showing that the invariant model could not be rejected (table 4 ). this finding suggests that biological sex of the children was not a moderator variable. in regard to children's age (6-10 y.o. vs. 11-13 y.o.) , the fit of the baseline model was chi-square (134) = 169.55, p < 0.01, rmsea = 0.04, cfi = 0.98, tli = 0.98, srmr = 0.06; conversely, the fit of the invariant model was chi-square (139) = 179.32, p < 0.01, rmsea = 0.05, cfi = 0.98, tli = 0.98, srmr = 0.07. the chi-square difference test was not significant showing that the invariant model could not be rejected (table 4) . therefore, children's age did not appear to moderate the mediational effects tested in our model. finally, turning to geographical area (northern italy vs. rest of italy), the fit of the baseline model was chi-square (134) = 172.56, p < 0.01, rmsea = 0.05, cfi = 0.98, tli = 0.98, srmr = 0.06. instead, the fit of the invariant model was chisquare (139) = 182.53, p < 0.01, rmsea = 0.05, cfi = 0.98, tli = 0.98, srmr = 0.09. the chi-square difference test was not significant, showing that the invariant model did not fit significantly worse and therefore could not be rejected (table 4 ). this result suggested that living in a high at-risk area for covid-19, as it was northern italy at the time of data collection, did not significantly affect the structural parameter of our hypothesized model. the health emergency related to the covid-19 pandemic and the consequent restrictive measures of quarantine have upset our lifestyles and our daily life. in particular, families with children had to face an unprecedented and completely new situation in which parents suddenly remained the only reference point for their children. results of the present study, indeed, showed that the covid risk index and the family risk index partially contributed to the psychological distress of parents, although their impact was modest in terms of accounted variance. specifically, parents with higher levels of psychological distress tendentially had a lower ses, had seen their working situation worsened during the quarantine, and were single or divorced parents who had to manage their children at home alone during the quarantine. furthermore, regarding the covid-19 risk index, parents with more psychological distress more likely had relatives, friends, or acquaintances tested positive for the sars-cov-2, had hospitalized relatives because of the sars-cov-2, lived in northern italy which was the most at-risk area for the spread of the pandemic and for the risk of contagion, were health workers, and worked in hospital departments that treated sars-cov-2-positive patients. however, our sem showed that parents' psychological distress impacted on the emotional regulation and lability/negativity of their children passing through the mediators' effect of parenting self-efficacy and parents' regulatory emotion self-efficacy. these findings suggested that what could have a positive effect on children's well-being and positive emotional regulation was not just being exposed to low level of parents' psychological stress, but it was the fact that parents felt able to manage and carry out their parental role and the related tasks. our results suggest that self-confident parents can successfully activate many personal resources that in turn seem to prevent their children's emotional dysregulation, even in emergency situations such as the pandemic that increased their levels of psychological distress. furthermore, three multigroup analyses were performed to test the possible moderation effects of children's biological sex and age and of geographical area (i.e., living or not living in northern italy, which is the most at-risk area for the spread of the pandemic and for the risk of contagion). the multigroup analyses showed that the hypothesized model was robust and invariant across children's biological sex, and age, and living (or not living) in northern italy. thus, in line with spinelli et al. (2020) , parents' and children's psychological distress was not affected by living in the high at-risk zone for covid-19 (vs. not living in the high at-risk zone). we can speculate that, regardless of living in a more risky area, relationships among variables remained stable because this unprecedented situation characterized by the isolation and quarantine measures was perceived in the same way throughout italy. alternatively, it is also possible that our study did not have enough power to detect differences in parameters between groups. parents should be supported to improve their strengths and to feel able to manage their parental role and their emotions. during the quarantine, parents were the unique reference point for their children aged between 6 and 13 years who rely much on their parents in this life stage. it is important that parents know that they can protect their children, preventing their emotional dysregulation, using their strengths and self-confidence, even if they are experiencing fear and severe stress for the health emergency. moreover, even if parents are exposed to high levels of stress, they can still promote a positive emotional functioning in their children if they feel able to reassure their children about the health emergency, to organize their children's daily life during the quarantine, and to explain them what is happening. despite these important findings, this study had some limitations. we collected a convenience sample that was not representative of the italian population. moreover, emotion regulation and lability/negativity of children were reported by parents and this could be less informative. however, many other scholars have used this type of data collection which is very common in this kind of studies (e.g., trumello et al., 2018; spinelli et al., 2020) . moreover, our data are correlational and it is also conceivable that parental distress and self-efficacy could be affected by children's lack of emotion regulation and lability/negativity. furthermore, we assessed the parent's own judgment of their children's well-being and it is possible that parents who experience (according to themselves) a lot of distress also tend to judge their children's well-being more negatively irrespective of the children's actual well-being. finally, it is not possible to infer causal relationships among variables because of the correlational nature of data. future longitudinal study can be conducted in order to deeply test the possible long-term effects of parents' psychological distress related to the health emergency on their children's psychological well-being and the possible reverse causation effect. however, despite these limitations, the present study presents many implications for prevention and intervention programs. in order to prevent children's distress, intervention programs should start from family and parents. this programs should be aimed at increasing parents' regulatory emotional self-efficacy and parenting self-efficacy, by activating their adaptive strategies and resources to deal with daily tasks and reinforcing their strengths. these parents' skills could be taught and learned, representing an important resource even in emergency situations such as a pandemic, in which parents remain the only points of reference and education for their children. these prevention programs should be primarily addressed at (but not limited to) parents who are health workers, who lived alone with children during the quarantine, who have sick relatives, and who have a low ses and a worsened work situation, in order to prevent the impact of their psychological distress on their children, reinforcing their belief to be able to face this difficult situation and to manage both their parents tasks and their unavoidable negative emotions. these findings suggest how clinicians should give psychological support to parents remotely during a lockdown, reinforcing their personal strengths and working on effective parenting and regulatory efficacy strategies. indeed, parents with beliefs of self-efficacy in parenting behaviors and emotional regulation have children more emotionally regulated and psychologically healthy. likewise, the present results can be used to implement psychological and educational intervention for parents in order to prevent their children's psychological distress. these results can also give pediatricians and psychologists important indications on how to specifically support families during the quarantine due to a global pandemic, providing advice to parents who in this period turn to pediatricians or psychologists to understand what to do to improve the well-being of their children. telling parents that, even if they experience negative emotions, they can do a lot to help their children could empower parents, activating their skills and strategies. intervention programs should be aimed to explain parents how to communicate to their children what is happening in the world around them. using the correct words is more probable when parents have high levels of parental self-efficacy and emotional regulation self-efficacy (jones and prinz, 2005) , and this could be very useful for parents' and children's well-being. talking about the fear and the negative emotions related to the pandemic and the isolation would represent an important protective factor for families' well-being. if parents understand which is the right way to communicate about the pandemic with their children, they can probably feel more self-confident in managing their parental tasks and their children's emotion, and this aspect can have in turn positive effects on their children's positive adjustment. a general approach to representing multifaceted personality constructs: application to state self-esteem same-sex and different-sex parent families in italy: is parents' sexual orientation associated with child health outcomes and parental dimensions? same-sex and different-sex 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in adolescents'. internet addiction policy brief: covid-19 and the need for action on mental health mitigate the effects of home confinement on children during the covid-19 outbreak parenting self-efficacy and problem behavior in children at high risk for early conduct problems: the mediating role of maternal depression mental health and psychosocial considerations during the covid-19 outbreak substantial investment needed to avert mental health crisis mental health status among children in home confinement during the coronavirus disease 2019 outbreak in hubei province the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. the studies involving human participants were reviewed and approved by the ethics committee of the department of developmental and social psychology, sapienza university of rome. written informed consent was not provided because data were collected via an online survey and participants were recruited via a snowball sampling. thus, participants gave their informed consent by clicking "yes, i accept to participate to this study" on the first page of the online survey. mm, ac, ec, and rb conceptualized the study and organized the data collection. mm, ac, ec, rb, ct, ab, and cc collected the data. ac and mm run the analyses and wrote the methodological and results section. mm wrote the first draft of the manuscript. ec, ct, ab, and cc contributed to revision of the final version of the manuscript. all authors contributed to the article and approved the submitted version. key: cord-005646-xhx9pzhj authors: nan title: 2nd world congress on pediatric intensive care 1996 rotterdam, the netherlands, 23–26 june 1996 abstracts of oral presentations, posters and nursing programme date: 1996 journal: intensive care med doi: 10.1007/bf02316512 sha: doc_id: 5646 cord_uid: xhx9pzhj nan we present the results of a prospective population-based audit of paediatric intensive care activity in two comparable communities with markedly different delivery systems. in the trent region of the uk (4.2 million people), children receive intensive care largely without the supervision of a paediatric intensivist in a variety of hospitals, few of which have designated paediatric intensive care units (picus). critically ill children otherwise receive intensive care in children's wards, special care baby units (scbus) or adult intensive care units. in the australian state of victoria (4.5 million people), children receive intensive care almost exclusively in one centre -a picu staffed by full time paediatric intensivists. the two regions are otherwise demographically comparable. in both groups, data were collected on all children admitted to an intensive care unit between 1/4/94 and 31/3/95 and children who received intensive care (defined by levels of intervention and nurse dependency) in other sites during the same period. values of each variable at first contact with the icu, and the highest and lowest values over the first 24 hours were recorded. the principal outcome was survival to discharge from the intensive care unit. severity of illness was assessed using pim (paediatric index of mortality) and prism. risk-adjusted mortality was compared using flora's z test and logistic regression. the rate of utilisation of intensive care (>1000 admissions in each region) were similar. there was some variation in case mix between the two groups, but crude mortality rates were similar (7.4% in trent and 6.6% in victoria). however severity corrected data and other measures of picu performance were dramatically better in' the centralised delivery system. the substantial excess mortality in the trent region provides strong evidence for the benefits of centralisation of paediatric intensive care services. there are considerable difficulties in evaluating the efficiency and effectiveness oflcare in children presenting with respiratory failure during acute medical illness. optimal outcomes for such episodes include survival and the shortest length of stay (los) in intensive care with negligible risk of readmission. we have tried to determine whether or not the time course of acute severe medical illness with respiratory failure is predictable. study i (n=1000): a retrospective study of intubated and mechanically ventilated children (>28 days, <17 years) with acute severe medical illness. measures: diagnosis, intensive care los in calender days, and survival. results: the underlying diagnosis fell within one of three broad categories: respiratory disease (n=521, mortality 19.2%), central nervous system (cns) disease (n=342, mortality 38.7%), and systemic inflammation or multisystem (sims) disease (n=137, mortality 47.5%. the los in survivors was: respiratory -median (interquartile range) 8(4-16) days, cns 4(3-8) days, £p,4£ 5(7-g) days. 5:i'~'-+cen diag~,~is-rc!ated-grnnp~ (drgs) were identified (8 respiratory, 5 cns, 3 sims disease) and each have been characterised by mortality and los. study ii (n=300): a prospective study of patients supported by the hypothesis that los for the above drgs was predictable (compared with study i data). in certain instances attributable causes for variances in los were identified: e.g. disease severity, timing ofdrug therapy, and associated disease. with daily paediatric risk of morality scoring within each drg, four profiles of instability were identified. discussion: the time course of acute severe medical illness with respiratory failure is predictable and variance may be attributable to specific care or diagnostic factors. we are now developing a means of linking drg-specific clinical care pathways with an integrated computerised decision support and education facility at the bedside. the objective of this open, prospective study was to assess the relation between basic patient characteristics as well as effectiveness of treatment on the one hand and resource utilization in pediatric intensive care on the other. as universal, non-monetary indicators of resource utilization we used the therapeutic intervention score system (tiss) and length-ofstay (los), from which indicators for total resource utilization per admission (tisstot) and average daily resource utilization (tiss-mean = tisstot/los) were obtained. overall 593 admissions, totalling 3130 days, were included. mortality was 8.4%; non-survivors accounted for 14.1% of overall resource utilization. in non-survivors, both total resource utilization per admission and average daily resource utilization were higher, whereas los was not different from survivors'. severity of illness, surgical status, the presence of substantial chronic comorbidity, emergency admission and transfer from another hospital constituted the major predictive determinants of tisstot (r:=0.19) and tissmean (ra=0.45) in multiple regression analysis (p<0.0001). hence these indicators are appropriate non-monetary measures of resource utilization, a considerable proportion of which are determined by a concise set of basic clinical characteristics. subsequently we analysed the relation between effectiveness of care and resource utilization by assessing severity of illness corrected mortality in low, medium and high resource users, respectively. these 3 categories were delineated by percer/tiles of resource utilization (< p20, p20-ps0, > ps0). despite on average long los and high resource utilization in the high risk group, a relatively low standardized mortality was found, probably warranting prolonged intensive treatment in this patient category. summary: objective:the primary purposes of intensive care are to provide treatments to patients with life-threatening physiological dysfunction or to monitor and observe patients perceived to be at significant risk of dying. this collaborative study was performed to describe our patients and their outcome. in order to improve our results we tried to identit~ high risk groups, patients and methods: 13 picus entered the study, the data included all the admissions with >12 hs. during a 60 days period between the l°june and the 30th september 1993. the records included: age, sex, weight, mechanical ventilation (mv), post-operative condition (p.op), malnutrition, diagnosis, length of stay, prism score and outcome. student test, mann-whitney or wileoxon were performed for univariate analysis. fisher exact test or chi square for dicotomic variables. risk group analysis was performed by logistic regression, odds ratio and 95% confidence interval. results: 650 patients entered the study. mean age was 47.6 months (ds hh¢# 60) and median 18 months. we found significant statistical differences in calculated ,is observed mortality rate comparing malnourished with euthrofic patients; mechanical ventilated (mv) with non mv patients. no differences in ter ~,h of stay or di~ noses were found. effect of the un sanctions on the morbidity rate araong the iraqi small children ( below 3 years old of age ) in bagdad. abdulsamad a.abood / institute of medical technology, bagdad. meningitis is essentially a childhood disease (i). the risk of infection are increased by powerty and overcrowding (7). the impah'ed immunity may be an important pathogenic factor underlying the susceptibility to infections in undernourished subjects (5). in general, malnutrition is a man made disease and it begins quite in the womb and ends in the grave (i). 1918 small children, below 3 years of age were admitted to the pediatric hospital in washash with meningitis over 4 cold months in i994, in contrast to only 176 child admitted with meningitis over the same period in1989. all of the children who admitted in 1994 were frankly undernourished, 45% of them were infected with enterobacteriae, because they were exposed to faulty hygiene and lack of asepsis. these facts showed precisely that our small children had suffered at most from the un_ sanctions against iraq, because of food, milk and drug shortage, since 4 years which had resulted a severe undernutrition among them, which impaired their immune status. m wells, of riera-fanego, j lipman. baragwanath intensive care unit, university of the witwatersrand, south africa. background the use of prism or other scoring systems in the icu is of great importance for evaluating the efficacy and efficiency of a particular icu, the prism score was developed and validated in the usa and europe but has recently been shown to be inaccurate in a south american population, a south african population as well as several european studies. part of the poor performance of the prism score is as a result of differences in the case mix between the reference population and other paediatric icus. since scoring systems should generally be used only in populations similar to the reference population from which the prediction model was developed, a modification of the prism score is necessary to improve its discriminatory ability in a wide range of patient groups, aim to improve the predictive power of the prism score in a south african paediatdc icu population. patients & methods we analysed prism, demographic and clinical data collected prospectively from 1528 consecutive paediatrie icu admissions. the prediction of actual mortality by prism was evaluated by standard statistical methodology (goodness-of-fit test and receiver operating characteristic (roc) analysis), the components of the prism logistic regression equation (prism score, operative status and age) and the 14 physiological variables making up the prism score in addition 10 new variables analysed (nutritional index, the need for inotropes and institution of mechanical ventilation) were subjected to discriminant analysis to determine their association with outcome. results the goodness-of-fit test showed a significant failure of prism to accurately predict mortality over a wide range of expected mortality (chi2[8] = 195, p = 0). prism underpredicted mortality at lower prism scores, but overpredicted mortality in patients with high prisms. similarly roc annysis indicated apoor predic~jve power (az = 0.73 ± 0.01), with an area under the curve significantly less than that for the prism reference population (p = 0), prism showed equally poor discriminatory function at all age groups and diagnosfic categories. '~mth the addition of an index of nutrifional status (proportional weight-far-age), and indicators of early respiratory and cardiovascular failure to the logistic regression formula, and a recalibration of the acute physiological score component, the roc can be improved to 0.83 ± 0.02, with a good fit described by the goodness-of-fit test (cn218] = 3, p = 0.89). discussion the prism score is not accurate in our patient population has been recalibrated in view of the poor discriminatory function that we have shown. part of the inaccuracy derives from the different demographic characteristics of our icu population and a different pattern of diseases. in addition to assessments of acute physiological aberrations, an assessment of nutritional status and early respiratory and cardiovascular failure significantly improve the discriminatory ability of the prism score, these parameters have been devised with a view to improving the accuracy of prism in our population, while not decreasing its accuracy in icus similar to the reference population. in interviewing parents regarding how physicians have communicated bad news, the response i have received is that it has not infrequently been done without appropriate care, understanding and compassion. personal experience and the lessons learned from parents, chaplains and others who deal extensively with these situations have provided me with an approach that has been supportive, compassionate, and caring. an especially difficult communication situation for the intensivist occurs when the parents have to be informed of the death of their child. for the parent, death is the hardest loss of all -the ultimate unalterable loss. circumstances surrounding the death are an important consideration (e.g., a fatal crash caused by a drunken driver, a prolonged illness, a suicide, aids). each produces a different grief reaction. the physician needs to inform parents of their child's death sympathetically coming right out with the news and leaving details until later. allow pauses and time for the paren~ to express sorrow and grief, the best communication may be thoughtful silence and a tender touch. there is disbelief that this happened. it is necessary to repeat oneself. acknowledgment of the parent's "feeling terrible" and the physician's acknowledgment of how terrible he/she feels that the life of the child could not be saved is an important first step in the parent's dealing with this tragic loss. with prolonged resuscitation, it is helpful to have a member of the icu team talk to the parents while the resuscitative efforts are ongoing so that the parents are not left unsupported at this time. a progress report should be delivered in a caring, lucid, and sensitive.manner, indicating that every effort is being made to save the life of their desperately injured child. after a child has died, it is helpful to the family if the physician maintains some contact with them. this should take the form of follow-up telephone calls at approximately 6, 12, and 24 months. this can help to screen for depression in the parents. in giving bad news to the family and making every effort to support them through this tragic time, it is necessary to remind oneself that the intensivist has personal needs for dealing with grief and will also require support to pass through this stage. direct evidence that child mortality is lower in specialist pediatric icus comes from 3 studies. a study in oregon (ccm 1981; 19:150-9) found that mortality adjusted for severity of illness was 102% of expected in 3 pediatric units and 139% of expected in 71 general units (p<0.05). a study in holland (ccm 1995; 23:238-45) found that mortality in high risk patients was 85% of expected in 6 tertiary pediatric units, and 143% of expected in 4 nontertiary units (p<0.05). a third unpublished study, has found that children in victoria (who almost all receive intensive care in a pediatric icu) have a much lower standardised mortality rate than children in the trent region of the uk (where many children receive intensive care in adult icus). there is indirect evidence that icus looking after many children are likely, on average, to perform better than icus looking after few children: numerous studies in many specialities have found that units looking after many cases of a particular disease have better results than units with few cases. see luft hs, "hospital volume, physician volume, and patient outcomes", happ, 1990; and farley d, medical care 1992; 30:77-94. compared to general icus, medical and nursing staff in pediatric icus are likely to be better at looking ~fter children, and plcu rmos have greater skills in pediatric intubation, ventilation, iv drip insertion and drug doses. picus are more likely to have appropriate equipment to manage children -especially for uncommon but life-threatening situations. icus in pediatric hospitals are more likely to have physicians and surgeons with pediatric expertise available for consultation at all times. the american academy of pediatrics, the society of critical care medicine, the british paediatric association and the australian nh&mrc have all said that children should receive intensive care in'specialist pediatric units. the weight of authoritative opinion, and direct and indirect evidence is strongly in favour of looking after children in dedicated pediatric icus. neurological deficit showed higher cbf values (125.7/115.2 ml/100g/ rain.) than the 11 patients with good outcome (mean cbf 1 17.5 sd +8.1; cbf 2 19.9 sd _+9.1 ml/100g/rain}. discussion: in asphyxia decrease of ph is due to reduced tissue oxygenation and indicates the severity of metabolic derangements. co2reactivity in newborns with perinatal asphyxia correlates with the lowest ph and therefore may reflect severity of asphyxia. continuous monitoring of cerebral activity is carried out in our unit on all admissions at risk of cerebral dysfunction, a number of monitors are commercially available and we report our experience with the cfam2 which provides in addition to amplitude integrated eeg analysis, continuous raw eeg display and frequency distribution. bilateral recordings are commenced as soon as possible and continued while clinically indicated. forty one children ranging in ages from 4 weeks to 16 years were monitored for periods from 3 hours to i0 days, diagnoses included traumatic brain injury (11), sepsis/meningitis/encephalitis (1 t), status epilepticus (8) and miscellanous others (11). results are tabulated below. patients 13 12 16 status epilepticus 10 4 1 * beta activity 1 8 15 * background voltage 10 3 1 * < i o/zv 2 or more of above 12 2 1 * (*z2 p < 0,001) asymmetry developed in 4 children, all of whom died. positive predictors of good outcome included a mean background activity of >10zzv, the presence of faster frequencies (usually 13) in response to sedative drugs and the absence of seizures. all monitoring is performed by the picu staff and increasing expertise in interpretation has resulted in earlier therapeutic and diagnostic interventions. regional it was previously found that histamine, a vasoactive mediator, accumulated in brain compartments (kov~ics et al 1995 neurosci lett 195:25) , and antihistamines prevented brain edema formation (dux et al. 1987 neuroscience 22:317) in asphyxiated newborn pigs. in the present study we investigated the effect of intracarotid histamine injection on the blood-brain barrier (bbb) permeability, left internal carotid artery of 30 newborn pigs (4-8 h; 1,180-1,530g; ketamine anesthesia, 10 mg x kg 4) was catheterized through the external branch and different doses of histamine (0, 10 -6, 5xi0 -6, 10 -5, 5x104, 104 m, respectively, in 6 groups of animals; n=5 in each) diluted in 1.0 ml isotonic saline was injected into the vessel through 1 rain. bbb permeability was determined for a small (sodium fluorescein, sf, 376 da) and a large (evans blue/albumin, eba, 67 kda) tracer (2%, 5 mlxkg 4, 30 rain circulation time for both dyes) concomitantly in frontal, parietal and occipital cortex, hippocampus, and periventrieular white matter both on left and right sides 1 h after the challenge. then, intravascular dyes were removed by perfusion and bbb permeability for both tracers was quantified by fluorescence spectrophotometry (wavelengths for excitation and emission were 440 nm and 525 nm for sf; and 620 nm and 680 nm for eba, respectively). histamine injection, in doses higher than 10 .6 m, significantly (p<0.05; kruskal-wallis one way anova on ranks followed by dunn's test) increased bbb permeability for both tracers in each brain region. changes in left hemisphere were more intense (p<0.05) than those in right one after the doses of 5xi0 -6 and 10 -5 m in each region, i0 4 m histamine administration induced similar edema in both sides. increased intracarotid histamine levels resulted in a dose-dependent vasogenic brain edema formation. histamine might have a pathogenetic role in neonatal hypoxicischemic cerebral injuries. supported by otka f-12722 and h-u.s,-jfno.392, $162 in coma caused by traumatic brain jnjury, an indication of the likely outcome is provided by the best motor response to pain in the first .$ hours after the insult. in a study in our picu, the proportion of children who died or had a severe disability was 100% in 35 who had no response to pain, 40% in 47 with an extensor response, 14% in 64 with a flexor response, and 1% in 61 who localized in response to pain. the long term outcome of traumatic brain injury appears to be worse in children <4 years old. other risk factors in traumatic brain injury are absent basal cisterns, midline shift or subdural haemorrhage on ct scan (or loss of grey-white differentiation in nontraumatic injury); or an intracranial pressure >30 mmhg despite hyperventilation, mannitol and barbiturate infusion. apart from brain death, there are two findings implying such a poor prognosis that consideration should be given to stopping treatment: first, after traumatic injury, the absence of any motor response to painful stimulus in the cranial nerve distribution (providing drug effects and a post-ictal state have been excluded); and second, in acute brain injury from trauma, infection, hypoxia, or ischaemia, the b{lateral absence of short-latency somatosensory evoked potentials (providing brain stem haemorrhage, subdural and extradural effusions, and decompressive craniectomy have been excluded). in children over 2 months of age, recovery from prolonged coma or a vegetative state is exceedingly rare when more than 12 months have elapsed after traumatic brain injury, and when more than 3 months have elapsed after nontraumatic injury. overproduction of nitric oxide (no) via an inducible isoform of" no synthasc (inos) produces profound vasodilatation in adult septic shock. high nitrate levels have been reported in hypotensive children with sepsis syndrome ]. cardiovascular collapse is a prominent feature of severe meningocoecai disease (mcd). however, systemic vascular resistance (svr) was slightly higher in a group of non-survivors ~ and the rote of no in ivicd remains unclear. children with a presumptive diagnosis of mcd were enrolled. parental consent was obtained. blood was drawn on admission and 12hrly thereafter. plasma was separated immediately and stored at -80°c. the final concentrations reported represent the product of nitrite and nitrate (nox). nox was measured spectrophotometrically using the greiss reaction. 21 children were studied (median age (range); 27m (5-203)). the diagnosis of mcd was confirmed in 18 children, 12 of whom had a glasgow meningococcal score (gms) of" ~8. in this group with severe mcd there were 3 deaths. peak nox was significantly higher (,.54(27-78) vs 96(50-363)nmol/ml, median) and systolic btood pressure was significantly lower in children with severe mcd than mild mcd (p<0.05. wilcoxon rank test). there was a significant correlation between peak nox and gms (spearman's rank correlation r=0.6 (p=0.01)) and prism (r=0.6 (p:0.01)). nox production from adm.ission onwards was also higher in the severe mcd group (p:0.002, kmskal ~wallis). we have demonstrated that plasma nox levels are elevated in children with mcd, correlate directly with the severit 3' of disease and are inversly related to systolic blood presssure. similar to hypotensive septic syndrome, mcd appears to be associated with an up-regulation of the l-arginine-no pathway.. non-survivors with mcd have higher svrs and may be relatively hypovolaemic. in our group of severe mcd there was a significantly lower systolic pressure and increased no formation. excess inos expression at different stages in mcd may contribute to the pathology of the disease. the identification of agents which can boost and/or inhibit no reiease may therefore represent different treatment strategies for mcd. u. merz, th. peschgens, g. kusenbach, m. b6hle, h. h6rnchen in this controlled, prospective study 30 ventilated premature infants with a birth weight < 1250 g were randomized to receive treatment with dexamethasone (dex) either on day 7 of life or on day 14 of life. dex was given over 16 days tapering from 0.5 mg/kg/day to 0.1 mg/kg/day. the infants treated with dex on day 7 of life could be weaned earlier from the ventilator -in median after 14 days (range 10 -34) versus 24 days (range 8 -44) in the [ate treatment group (p = 0.01). the need for supplemental oxygen was shorter in the early treatment group -in median 24 days (range 10 -50) versus 40 days (range 10 -70) (p = 0.2, ns). the incidence of chronic lung disease was lower in the early treatment group -6 of 14 infants (42.9%) versus 10 of 16 patients (62.5%) (ns). to evaluate the long-term efficacy of early dex treatment we performed a respiratory function test in the age of 3 -6 months using an infant whole body-plethysmograph. the intrathoracic gas volume (itgv), the airway resistance (r.w) and the airway conductance (gaw) were measured and no significant differences could be detected between the groups. the frequency of adverse effects due to dex therapy was found to be without significant differences between the early and the late treatment group. we conclude that early dex treatment had short-term improvements in pulmonary outcome in our study population, long-term efficacy however, remained unproven. several factors contribute to the development of chronic lung disease (cld) in premature infants including structural immaturity of the lung, mechanical ventilation, and oxidative stress. reactive oxygen species are formed during normal cellular metabolism but they are generated in higher concentrations during inflammation or inhalation of high oxygen concentrations. to study the relationship between increased oxidative stress, antioxidants and the development of cld we examined 102 ventilated premature infants with birth weights below t500g. 32 infants developed severe chronic lung disease of prematurity (cld), defined by radiological signs of cld and an increased oxygen requirement at a postconceptional age of 36 weeks, and 29 infants had moderate cld with an increased oxygen requirement on day 28 but not at an age of 36 weeks. ventilator settings (fio2, peak inspiratory and mean airway pressure) and the incidence of early-onset-sepsis were significantly higher in the severe cld group than in infants with moderate cld or without cld (n=41) during the first week of life. plasma concentrations of the two antioxidative substances bilirubin and uric acid (ua) were comparable in all groups during the first days of life. however, on day seven bilirubin and ua were significantly decreased in the plasma of infants with severe and moderate cld compared to the non cld group (p<o.001). there was no difference between both cld groups. in serially obtained tracheal aspirate fluids (taf) malondialdehyde (mda) was measured by hplc as an indicator of lipid peroxidation reflecting oxygen injury of the lung. ua was found in higher concentrations in taf than bilirubin. ua has been proven to be a potent antioxidant, capable to react especially with hydroxyl radicals and hydrochlerous acid, which play an important role in the induction of lipid peroxidation. infants with severe cld had significantly higher mdnua ratios in taf from day 5 to 14 compared to the non-cld group (p<o.01). mdnua ratios in taf of infants with moderate cld were significantly higher from day 7 on but still lower than in the severe cld group. in addition, the ratio oxidized / reduced glutathione was significantly increased in taf of infants with cld compared to infants without cld between day 5 and 14. the data support the hypothesis that an imbalance of oxidative stress and antioxidant defense contributs to the onset of cld at the end of the first week of life. introduction. rocuronium bromide (roe), a neuromuscular blocking agent with an onset time dose to that of succinyleholine l'z, has been studied in american society of anesthesiologists' physical status (asa) i or ii pedlatrie patients under non-critical elective conditions. there is a paucity of studies looking at the pharmacodynamics of roc under emergent conditions, involving pediatric patients who are asa iii or iv, without the use of adjuvant inhaled anesthetics ~. methods. with approval of our committee on clinical investigations (irb), roe 1.2 mg/kg was administered to 15 asa iii/iv pediatric intensive care patients (age 40 days to 23 months; m:f=8:7) on intravenous sedation. the time to reach 25% a~d 10% of b~elinc tetanie stimulus response was recorded using a r.elaxogra'ph/qmt-100 nerve stimulator/recorder (datex, helsiaki). depth of clinical relaxation at the 25% level was recorded. results. the time from rapid bolus to 25% was 25.4+12.6 see with a range of 10-50 see; and to 10% was 30.1+17.6 see, with a range of 10-69 see. at the 25% level, excellent clinical relaxation was seen. conduslon. in critically ill children, use of roe at 1.2 mg/kg produces rapid onset of neuromuscular blockade and excellent clinical relaxation, such that roe should be considered for rapid sequence intubation. int anesth clin. 1995;33(1):39-60. anesthesiology. 1994;81 (5) computed tomography of the chest (ct) in mechanically ventilated adults can detect intrathoracic pathology not appreciated on chest radiographs (cxr) and influence intensive care management. no such data exists for ventilated children. aims: 1) to assess if ct provides additional information over cxr regarding extent and nature of intrathoracic disease in ventilated children. 2) to determine whether such information alters clinical management, inclusion criteria :10 ventilated children with cxr changes inconsistent with their respiratory status underwent ct if either a) pao2:fio2 ratio <30 and/or mean paw>15 cm h20 or b) there was an unexplained increase in ventilatory requirement. methods : high resolution ct was performed in 3 patients and spiral ct in 7 patierits, to ensure minimal transport related morbidity, patients were transferred to the ct scanner by a specialised mobile intensive care team. results: in 2/10 patients ct demonstrated greater extent of disease than appreciated on cxr but did not significantly alter clinical management. in 7/10 patients ct provided additional information regarding the nature of disease present, in 2/7 children this involved a further diagnosis and in 5/7 children the exclusion of a suspected pathology. new information led to a positive therapeutic intervention in 2 children, prevented inappropriate manoeuvres in 3, and had no significant effect on acute management in 2 children. conclusions: initial data suggests that in a selected group of mechanically ventilated children chest ct can add to the sensitivity and specificity of intrathoracic diagnosis provided by the chest radiograph and directly influence acute management. case selection criteria and choice of the most appropriate protocol requires further study. pressure control ventilation (pcv) utilizes a decelerating flow pattern which may improve gas distribution and lead to alveolar recruitment. in contrast, volume control ventilation (vcv) employs a constant flow. in children, the effects of pcv as compared to vcv are unclear. the purpose of this study was to determine how these two modes compare in terms of dynamic compliance (cdyn). peak iaspiratory pressure (pip), and mean airway pressure (paw) at equivalent minute ventilation. methods: sixteen infants and pediatric patients ranging in age from 1 day to 13 years were studied. diagnoses included ards (6), postoperative cardiac surgery (7), head trauma (1), and resfrictive lung disease (2). patients were randomized to pcv (9) or vcv (7). initial measurements of gas exchange (abg's) and respiratory mechanics (ventrak, novametrix medical systems) were obtained after a 20 minute stabilizadon period. respiratory mechanics included pip, peep, paw, delivered tidal volume, and cdyn (avolume/apressure). the patients were then crossed over to the alternate mode of ventilation holding delivered tidal volume, peep, inspiratory time, minute ventilation, and fio2 constant. data were collected after 20 minutes, in each mode the absence of intrinsic peep was confirmed. to assure that the measurements were not affected by changes in clinical status, the patients were returned to the initial mode of ventilation and measurements repeated (final) . patients were ventilated with a siemens 900c or sv300. reselts: data were analyzed using 2-way analysis of variance with repeated measures. ~ <0.05 vs. vcv) vcv pcv ~ initial ] final ! cdljn 3.5_+0.7 4.3_+0.8 * 3.7_+0.6 3.9_+0.7 i , pip 32+1.0 30l-_t.0 * 31_+1,0 31+-1,0 paw 9.2_+0.6 10.9i-_0.7 * 9.7+0.7 10.0-!-_0.8 pao2 97_+14 92+-10 87_+9 97_+14 discussion: at the same minute ventilation, the decelerating flow pattern of pcv resulted in a 23% increase in cdyn and an 18% increase in paw while decreasing pip by 6%. the lack of a significant change in oxygenation may be a result of the limited time in each ventilator mode as well as the inclusion of patients with both normal and abnormal lungs. there was no significant difference in initial and final measurements indicating patient stability. the beneficial effects of iecre~l~iug cdyn and paw while decreasing pip indicate that pcv may be a preferable mode of ventilation in patients with lung injury. further randomized studies examining the effect of pcv on respiratory outcome measures in pediatrics are indicated. prolonged positive pressure ventilation following repair of cdh is associated with a high prevalence of iatrogenic lung injury, in our unit dudng 1981-1990 314 late deaths after repair of cdh were due to chronic lung disease. since 1990 babies requiring assisted ventilation for more than 7days following surgery were transferred to a cnep chamber to limit lung injury. cnep of -6cm of h20 was combined with positive pressure ventilation via an endotracheal tube dudng the transition phase. immediate reduction of peak inspiratory and positive end pressures were possible and following extubation respiratory support was maintained by cnep v~th appropriate inspired oxygen. overall outcome: [1981] [1982] [1983] [1984] [1985] [1986] [1987] [1988] [1989] [1990] n=68 deaths before surgery (%) 11 ( ecmo during 1990 -1995 /16 who were ventilated for more than 7 days received cnep and there were no deaths and no chronic lung disease in that group. cnep assisted ventilation may be an important management option for babies who require prolonged respiratory support to avoid the adverse effects of chronic positive pressure ventilation, introduction so far 2 modes of liquid ventilation (lv) have been used in experimental animals and, exceptionally, in humans: 1. total liquid ventilation (tlv)-functional residual capacity (frc) is filled by perfluorocarbons (pfc), and slow tidal volume (tv) breathing is performed by pfc. 2. partial liquid ve,0ti,la~ion (page) -only frc is filled by pfc. gas tv is delivered by conventional mechanical ventilation (cmv), high frequency jet ventilation (hfjv) or high frequency oscillation (hfo). the aim of our study is to present our limited experience with page in newborns and infants. page was used in two groups of infants: 1, in 2 infants with brain death before disconnection from cmv, because recipients for organ transplantation were not available. these infants have relatively normal lungs (fio~ less than 0.4). infants stayed on page for 1 hour, during that period no ventdator manipulations were made. after page, infant were switched to cmv for next 6 hours. 2. very critically diseased infants with ards (rds) -2 on ecmo more than 5 days, 1 before cannulation for ecmo, 4 on hfo because of intractable respiratory failure, preoxygenated rm 101 (miteni, italy) was used in the doses up to 40 ml/kg intratrachealy. blood gases and parameters of pulmonary mechanics were followed (dynamic compliance -c dyn, airway resistance -raw, bicore monitor). page was combined with no inhalation (5-80 p.p.m, in 2 infants). in both groups ad hoc an approvement from e local ethical commission and informed parental consent were obtained. in the first qroud with relatively normal lung parameters of oxygenation drops after pfc instilation intratracheally and stayed depressed for 4-6 hours. slight pco2 retention occured in both cases during page. c dyn increased almost double during page period, raw drops transitorily after pfc instilation but in 10 minutes they were identical like in prepage period, parameters of oxygenation (peo2/fio2) after 4-6 hours after page improved and were better than in prepage period. after that time infants were disconnected and died. in the second group no improvement of oxygenation was seen in one ecmo baby, in spite ()f transient improvement of c dyn. in the second ecmo baby, oxygenation improved and flow of pump could be decreased by more than 20%. none of these babies, however, survived, improvement was only transient in spite of repeated dosis of pfc. in these babies serious problems were to maintain the adequate frc by liquid, because of severe air leak, in 5 babies on hfo/hfjv with severe ards/rds the improvement of oxygenation were seen in all the cases immediately after pfc instiletion for the period of 4-5 hours. after that period, pfc dose had to be repeated. two babies of this group survived. conclusion. page is going steadily from tabs to clinical practice. it is simple, could be performed anywhere, cheaper than tlv. however, because liquivent -perflubren (aliance pharmaceutical) is not available in europe, rm 101 of 82 (mitenti, italy) is the only solution, which could be currently used here. before the widespread use of page in clinics, liquid network among most nicus and picus must be built up, the criteria for page must be defined and ethinal-legal problems resolved as well. after resolution of these particular problems page can be life saving procedure for very special part of critically ill newborns end infants. catherine caronia, peter silver, laura nimkoff, cad quinn, jack gorvoy, and mayer san. division of pediartic critical care, medici,, schneider children's hospital, new hyde park, ny 11040, imroduetiun: cystic fibrosis (cf) patients awaiting lung transplantation present a therapeutic dilenuna when severe respir, aory decompemalion occurs, endotracheal intubation and mechanical ventilation is known to have no long term benefits and is associated with high morbidity and mortality. noninvasive respiratory support appears to be a beneficial alternative. methods: we instituted bipap (respironics, inc,, murrayville, pa) in 9 end-stage cf patients who were admitted to the pediatric icu with severe respiratory decompeusation. all patients were awaiting tung transplantation. after a control period, bipap was applied via a tight fitting nasal or facial mask, using the spo~aneous breathing mode, expiratory pressures were set at 4-8 cm hhzo. inspiratory pressures were started at 8 cm ~i o and increased in 2 cm i-i20 increments until the patient's respiratory comfort was achieved and substantiated by non-invasive monitoring. patients were instructed to use bipap during night sleep and whenever subjectively required, data are reported as mean _+ s.d. results: all 9 patiems utilized nocturnal bipap for 6-10 hours/day during a follow-up period of 2-19 months. compared to their pre-bipap status, the patiems' oxygen requirement and respiratory rate both oz~ cundusion: bipap tl~rapy improves the respiratory status of decompeusatir!g end-stage cf paacnts. it is well tolerated for long term use at home, and provides an extended period of respiratory comfort and stability for cf patients awaiting lung transplantation. l. bindl*, g. kiihl**, p. lasch***, appel**, j.m611er**** and the "arbeitsgemeinschaft ards im kindesalter" background acute respiratory distress syndrome (ards) is a therapeutic challenge in pediatric intensive care in view of the high mortality, in 1992 about 50 german paediatlic hospitals founded a working group aiming on collaborative clinical research in this field. aims and methods the aim of both a prospective and retrospective survey conducted in german pediatric intensive care units in 1993 was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ards patients who were treated in the tt~ee year period from 1991 to 1993.all patients had acute bilateral alveolar infiltration of noncardiogenic origin and a po2~io2 ratio < 150mmhg. the influence of sex, underlying disease and single organ failure was analyzed using the fischer's exact test, the influence of additional organ failure on mortality was tested with the cochran-mantel-haenszet statistics. results 112 patients were reported giving an incidence of 7 cases per 1000 admissions to pediatric icus. median age was 24 month. in 43% of the cases, ards was associated with a pulmonary, in 39% with a systemic underlying disease. in 20% immunocompetence was impaired. mortality was 46% and not dependent on age, sex and triggering event. the number of associated organ failures, however, strongly influenced mortalib,. mortafity in immuno-compromised patients was 8 t %. the analysis of treatment modalifies employed in the patients revealed a lack of uniform therapeutic strategies. on the other hand, the patients were exposed to interventions not yet supported by controlled trials. conclusions the observation of the lack of uniform treatment strategies led to the elaboration of recommendations on ventilator therapy and patient monitoring within the working group. the data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modafities in pediatric ards. recurrent apnea and respiratory failnre due to severe lower respiratory tract disorders such as bronchiolitis or pneumonia are the most common reasons for mechanical ventilation during respiratory syncytial virus (rsv) infection. acute respiratory distress syndrome (ards) has been described as a complication of severe rsv infectionj in contrast to the low mortality rates associated with rsv infection (< 5 %), mortality rates in the range of 40-70 % have been reported in pediatric patients with ards. however, studies on ards are usually lumped in respect to causation and the disease course of rsv induced ards has not been previously studied. we examined the lung function abnormalities of 37 infants with rsv induced respiratory failure requiring assisted ventilation, measurements included respiratory mechanics, maximal expiratory flow-volume curves and lung volumes, ards was defined clinically using the criteria which were recently proposed by the american-european consensus conference on ards~: acute disease onset, pao2/fio~ ratio _< 200 mrn hg, bilateral infiltrates on chest radiograph and absence of clinical evidence of left atrial hypertension. we calculated the murray lung injury scores modified for use in pediatric patients 3 from total respiratory system compliance, radiographic findings, ventilator settings and blood gas results. we identified 10 infants with severe restrictive lung disease that fialfilled the clinical criteria fbr classification as ards. all had lung injury scores above 2.5 which is the recommended cut-off for a diagnosis of ards, twenty-seven infants had obstructive disease consistent with a clinical diagnosis of bronchiolitis. the ards patients were significantly younger, had a longer time of assisted ventilation (p <0.05) and a greater proportion of infants with preexisting illnesses (p=0.023, odds ratio =6.67) when compared to the patients with obstructive disease. with the exception of one immunodeficient patient, none of these infants died. given the low mortality despite a clinical picture of severe lung injury, there is evidence that rsv induced respiratory failure may represent a relatively benign cause of ards in pediatric patients, bachmann an audit of patients with severe acute bypoxic respiratory failure (ahrf) receiving highfrequency oscillatory ventilation (hfov) in our unit ( n=32, mortality 75%) revealed that sub-groups with severe underlying disease (n=14, mortality 100%)and those with mu~pie organ failure ( > 2 systems failing, n=7 mortality 100%) accounted for all the deaths beyond the neonatal period. v~ therefore hypothesized that in a modem paedistric intensive care unit (picu): a) children greater than one month of age with ahrf do not die in the absence of severe, pre-existing disease or multi-organ dysfunction syndrome, b) respiratory parameters alone will predict outcome poorly in ahrf. method prospect~/e sty/of all adm~ns to our tertiary picu. data it, citing the respiratory parameters (oxygena~n index [ol] , aiveolar-artedal oxygen tension gradient , pao2/fio2 ratio) were collected hourly from the bedside charts throughout admission. patients were included in the study if ahrf was present at admission either none or in combination with other organ dysfun~on. ahrf was defined as the acute (<48hour) onset of respiratory dysfunctk:~l with a pao2/fio2 ratio.< 200 for six consecutive hours dunng the first 24 hours of admission (with no evidence of left anal hypertension), x-ray review defined a sub-group of patients with acute respiratory distress syndrome (ards) by the presence of bilateral interstitial infiltrates. results to date 59 children (ages 1-168 months, weight 1.2-70 kg) have been admitted in ahrf. 18 of these also had ards. the overall mortality was 23.7% (14/59), and greater in the ards group than the non-ards group (10t18, 55.5% vs, 4141, 9.7%, p< o.01) . it was not possible to predict survivors from non-survivors on the basis of the seventy of the respiratory failure alone, the a-ado2 on the day of admission (best in 24 hours) was not significantly different between survivors and non-survivors: (mean, + sd)(174 mmhg +_108, vs 304 mmhg _+_156). kdl non-survivors were immunodeficient (n=8), previously extmrnsly premature infants (<28140),(n=3) or suffedng fcom chronic metabolic or gastrointestinal disease (n=3). no previously normal child died. conclusion the severity of respiratory failure does not allow predioljon of outcome in our patients. we believe that this reflects that modem picu is so effective at providing respiratory support that pre-existing pathology alone de~ prognosis. this suggests that an abnormally regulated host response or abnormal persistence of a pathogen may be required to induce lung injury of sufficient severity that the resulting respiratory failure cannot be supported in a modem picu. introduction: postural changes (supine to prone) is a therapeutic intervention that could be useful in children with adult respiratory distress syndrome. objective: to determine the effects of postural changes in the oxygenation of young children with ards. method,s: a prospective stud3," was performed in eleven subjects aged 6 to 120 months (mean=33) with the diagnosis of ardsreceiving vendlatory support. (mean peep and fio2 of 9 and 0.75 respectively). postural changes was performed every 8-12 hours, during a period of time ranging from 5 to 16 days. arterial blood gases were determined before and 30-60 n~n after the postural change, no modification in the mechattical ventilation other that changes in the fio2 were performed. the oxygenation was determined by the index pao2/fi02 (p/f). to study the differences between the oxygenation mean, before and after the postural changes the wilcoxon test for paired samples was used, results: 184 changes were performed (104 from supine to prone and 80 from prone to supine). a9% increased p/f ratio was obtained after the change from supine to prune. although, not all the patients receiving postural changes improved their p/f. six of them (group i) showed an improve in the p/f when changed from supine to prone, returning to their base line when positioned from prone to supine. no improvement on the p/f was observed in the remaining 5 subjects (group ii)after postural changes (table 1) . during the maneuver no complications were observed. two patients had a pneumothorax, not related with the postural change. conclusions: postural changes (supine to prone) is an easy way to improve oxygenation in some children with ards. change to prone change to supine introduction: the common noninvasive diagnostic efforts to identify possible obstruction of the intrathorucic airway, are of limited value. invasive procedures such as bronchoscopy and bronchography may also be noncontributory and entail risks. we evaluated the usefulness of 3d-ct in the diagnosis and management of pediatric patients with suspected intrathoracic airway obstruction (itao). methods: we used a diagnostic algorithm (see diagram) in patients with suspected itao resulting in respiratory distress. three-dimensioual imaging of the tracheobronchial tree was reconstructed, following high speed spiral ct scan, by specific computer software (advantage window computer work station, general electric, milwaukee, wisconsin). non-ionic contrast medium was injected, in some patients, to delineate the intrathoracie large vessels.. results: eight patients were studied. in 5 patients the 3d-ct revealed intrathoracic airway abnormalities. these patients underwent further invesive studies which confirmed the following diagnoses: 2 patients had bronchomalacia, 1 had bronchial stennsis due to a dilated pulmonary artery mad 2 patients had subglottie stenosis extending to the thoracic cavity. three patients had no significant disruption in the configuration of the tracheobronchial tree and thus did not require invasive diagnostic procedures. conclusion: computer reconstruction of three dimensional images of the tracheobronehial tree is a safe and reliable diagnostic tool for itao. ards and ecmo; preliminary data from a randomized clinical trial. j fackler, c steinhart, d nichols, d bohn, m heulitt, t green, l martin, k newth, m klein, j ware. many suggest ecmo be considered experimental for ards and undertaken only with careful data collection and reporting. a mtflticenter pediatric rct is in progress to determine whether 1) ecmo and/or 2) permissive hypercapnia, offer significant advantage for the treatment of ards. methods: all patients aged 2 wk to 18 yr (without congenital heart disease) are eligible for study. data collection begins when a patient receives at least 50% oxygen and a peep of 6 cm h20 for 12 hours (stage t). if the predicted mortality reaches 60% within 7 days (stage 2), eligible patients are asked for written consent for randomization. patients are excluded from randomization with significant chronic lung disease, immune compromise, cardiac disease; or profound acute central nervous system damage. the prime outcome variable is survival. at the studies onset, 400 pts were estimated to be required so that 65 pts were randomized per arm. results: 131 patients are enrolled from 9 centers. data are complete on 85. 66 patients never reached stage 2 (i.e. 60% mortality). 47 patients improved and 19 died. of the latter, 13 had randomization exclusion criteria even if stage 2 was reached. 19 patients reached stage 2. 11 had exclusions from randomization and all died. eight patients (4 survivors were eligible for randomization; consent was obtained in no case. two patients received ecmo. overall survival is 60% (51/85). in patients without randomization exclusions, survival is 77% (34/44). morbidity m survivors (discharge -admission popc or pcpc score >_2) was seen in none of the 4 stage 2 surviviors and 15% (7/41) of those who reached only stage !. conclusion: the rct requires completion. the records of hospital in-patients at king faisal specialist hospital and research center who received external cardiac massage as part of their cardiopulmonary resuscitation were reviewed. success of resuscitation was analyzed as (1) short term (restoration of spontaneous circulation), and (2) long term (discharge from hospital). of 234 such patients, 171 (73.1%) survived the initial resuscitation, and 66 (28.2%) were discharged. success of outcome was not related to age, location of patient, time of day, or rhythm at arrest, including asystole. longer resuscitation time was associated with less chance of restoration of spontaneous circulation (p<0.001), but not associated with hospital discharge rate. results for patients with congenital heart disease were similar to those with other medical or surgical conditions. in this series, 36.7% of ward in-patients survived to discharge, compared to two 5"*;'~r ~r;~'9 ,.,.'her,, the r-e~ult~ were 0c/ "'~d ~, ~,°(. overall, 39 7% of patients who survived the initial resuscitation were discharged from hospital. where resuscitation continued for more than 30 minutes, 18.9% of patients had tong term survival. outcome from asystole was no worse than for other cardiac rhythms, we believe that previous reports of poor outcome from asystole in pediatric cardiac arrest should noi influence decisions to stop resuscitation for pediatric in-patients prematurely. successful restoration of spontaneous circulation with long term survival can be achieved after prolonged resuscitation. abdelmoniem~ lindsey jahusou~,mariano fiallos, university of florida, 820 prudential drive, suite 203 jacksonville, florida 32207 usa central acidosis is well recognized as a marker of inadequate tissue perfusiou, and ventilation. however, obtaining central venous blcod is difficult and fraught with complications in the child undergoing cardiopuimonary resuscitation. intraosseous blood may be used instead of central venous blood to judge ph and pcoz during short durations of cardiopulmonary resuscitation and during hemorrhagic shock. the purpose of this study is to compare the ph and pcoz status of intraosseous and central venous during prolonged cardiopulmonary resuscitation after fluid and drug infusion. we hypotbesized that there would be no difference in ph and pco2 values of simultanecusly obtained intraosseous and central venous blood samples. eighteen (18) introduction: cardiopulmonary arrest (cpa) in children is usually preceded by a deterioration of cardiac or respiratory function due to sepsis, dehydration and hypovolemia. early recognition of clinical and laboratory signs followed by immediate intervention are essential for prevention of cpa. the purpose of the present study was to identify factors which contributed to high rates of mortality from cpa in patients admitted to a paediatric intensive care unit (p1cu). methods: a prospective study was done of all non-surgical patients with cpa who were admitted to the picu, hospital baca ortiz, quito ecuador from january to october 1995. clinical and laboratory variables before and after admission to the picu, time from hospital admission to picu admission and the pediatric risk of mortality score (prism) were recorded on a questionnaire designed specifically for this study. results: of the 70 non-surgical patients admitted to the picu, 14 (20%) were admitted after developing cpa on the general pediatric wards. mean age was 16 + 19.1 months, with 13 of 14 patients under 20 months of age. initial diagnoses upon picu admission included meningitis (n=3), respiratory failure (n=2), congenital heart disease (n=2), severe neurological impairment (n=2), end stage neoplastic disease (n=2), hypovolaemic shock (n=l), peritonitis (n=l) and sepsis (n=l). mean time from hospital admission to p1cu admission was 16 _+ 19.2 hours. the mean prism score upon hospital admission was 30+ 13.7 (score > 20 = > 50% mortality). 79% (11/14) of the patients died. one of the three survivors had severe neurologie injury. prior to picu admission, patients experienced tac~,cardia (n=9), hypotension (n=8), neurological deterioration (n=8), respiratory, distress (n=7), oliguria (n=5), bradycardia (n=3), metabolic acidosis (n=7), hyponatremia (n=4), hypokalemia (n=2), hypocalcemia (n=2) and severe hypoglycemia (n=2). there were serious delays from the time of development of clinical and laboratory abnormalities to the time of admission to picu. conclusion: in the critically ill pediatric patient, rapid recognition of clinical and laboratory signs of deterioration, followed by immediate intervention, are required to prevent end stage shock and cpa. we found serious delays in intervention following development of important premonitory clinical and laboratory abnormalities in patients less than 20 months of age on the general pediatric wards, which iikely contributed to the dismal 79% mortality rate. hospitals throughout ecuador should institute immediate improvements in ctinical supervision, and provide training in paediatric advanced life support (pals) to decrease excessively high rates of and mortality from cpa. intraosscous access is recommended by the american heart association and american academy of pediatries as a means of rapid access to the vascular system for childhood emergencies. bone marrow and fat embolism is a concern and has been reported post intraosseous infusion in stable animals but has never been studied in animals subjected to cardiopuimonary resuscitation. we undertook this study to investigate the incidence and magnitude of lat and bone marrow embolism with the use of intraosseous infusion during prolonged cardiopuhaonary resuscitation and after fluid and drug infusion. we hypothesized that there will be no difference in the magnitude of fat embolism between cardiopulmonary resuscitation only and other cxperirnental conditions. thirty-one (31) piglets were anesthetized, mechanically ventilated, and instrumented (carotid artery, pulmonary artery and intraosseous earmulas ). the animals then underwent bypoxic cardiac arrest followed by chest compressions with the mechanical thumper (michigan insmunents) and mechanical ventilation for a minimum of 45 minutes. the animals were divided in groups: a (n=5) which had no intraosseous, ~'oup b (n=6) had intraosscous with no infi~ion, and groups c (n=6), d (n=6), e (n=8) had intraosseous with infusion of adrenaline, normal saline and sodium bicarbonate, at cessation ofcardiopulmonary resuscitation, representative lung samples were collected fi'om upper and lower lobes of each lung, embedded in ocp and firozen immediately. ltmg specimens were stained using oil red-o dye and observed for fat globules and bone marrow elements. the amount of emboli present was rated as a percentage in relationship to iung tissue, by a pathologist blinded to the experimental groups. buffy coat specimens were collected before and at cessation of cardiopuimonary resuscitation, stained with oil red-o dye and observed for fat globules. percentage of fat present were compared using analysis of variance. fat globules were seen in the prebronchial blood vessels and in intravascular areas throughout all lung fields. there was no difference in appearance or distribution of fat globules between groups. quantity varied in the different groups[(a) 45%, (b) 44%, (c) 30% (d) 23%, (e) 25%], but were not statistically significant (p = .097). fat globules in the buffy coat were few and inconsistent with lung findings. fat and bone marrow emboli were present in all experimental conditions, the use of the intraosseous cannula does not increase the magnitude of embolization during cardiopuimonary resuscitation. the decision to use the intraosscous route should not be influenced by the risk of embolization. tzareva iv/,, md*, nedialkova r, md**, *dept. of pathophysiol, *~dept. of child surg. and icu, emergency medical institute pirogov, sofia, among 566 children with blunt abdominal trauma, treated in emi pirogov during the last five years, 79 children had serious disturbances of the basic vital functions, connected with the trauma, and most often with massive haemorrhage, for this reason being an object of reanimation and intensive care. in the group of children who survived -37, predominated the trauma of only one abdominal organ (mainly the spleen, rarely the kidneys, the intestine) and only 15 children had injuries of more than one abdominal organ. in the same group, in 15 children the abdominal trauma was combined with chest or head trauma or bone fractures. in the group of children who died -12, a profound combined trauma was present. the haemodynamic parameters in all children showed a characteristically significant tachycardia along with normal or even high blood pressure, while hypotonia was present in only 64% of the children on the first trauma day. despite the fact that only 13.4% of the children had direct chest injury as well, the gas exchange was considerably disturbed -899'0 of the children were hypoxemic during the first, and 100% during the third trauma day -in 25% significant -below 8.0 kpa (60 mmhg). together with the markable decrease in haemoglobin levels, this determines the pronounced disturbance in oxygen transport. during the first trauma day all the children were acldo~c, and a metabolic alkalosis was present during the following days. twelve of the children with severe combined trauma died within several hours, with the symptoms of irreversible haemorrhagic shock, or in the next 2-3 days, developing multiple organ failure. in conclusion, the intensive therapy of children with severe abdominal and combined trauma, should take in consideration the special haemodynamical trauma answer in children, and requires dynamic monitoring of the most influenced homeostatic parameters -blood gases, acid-base metabolism, haemostasis. introduction: endocrine emergencies, other than diabetic ketoacidosis, are uncommon causes of pediatric intensive care unit (picu) admissions. we report our experience of children diagnosed of adrenal insuficiency (ai) admitted in the picu, during the last four years. subjects: five eases of ai requiring 7 intensive care unit admissions are presented. four females anna 1 male, with ages ranging from 11 days to 7 years, none of them had a previous systemic or endocrine diseases that could suggest al the initial clinical manifestations were: dehydration (5), vomits (3), abdominal pain (2), seizures (2), lethargy (2) and hyperpigmentation in the muco-genitat area in a newborn male and ambigna genitalia in a newborn female. the reason for their admission in the p1cu were: shock in two subjects; three because of hyperkalemia and hyponatremia (k/na: 5.6/123; 9/126; 7,1/134 meq/l); and two with severe hyponatremia (na: 117; 113 meq/l). laboratory findings: severe hyponatremia (5), increased concentration of urinary sodium and chloride (4); metabolic acidosis (4); hyperkalemia (3); increased levels of urea (3) and hypoglycemia (2). in all of them, the electrolytes abnormalities did not normalize with replacement and only normalized after the administration of hydrocortisone. tile ai was due to: autoimmtme disease in two subjects, congenital adrenal hypoplasia, congenital adrenal hyperplasia secondary to 21 alia hydroxylase deficiency and in one no etiology was found, at the present time, comments: aiis an uncommon disease in the pediatric age. anearly diagnosis is crucial, as if the treatment is delayed could lead to patients death. in subjects with arterial hypotension and electrolytes abnormalities refractory to the usual treatment, they should be treated with corticosteroids, if no etiology is found. although, previously samples must be obtained to make the diagnosis, 0: denotes the number of cases. gerbaka b; hakme c; akatcherian c. toxics are frequently involved in domestic accidents during childhood; among non medical products ingestion, carbohydrate poisoning is a serious injury often made possible by inadequate stocking. over 10 years, 43 children aged 10 years and less were examined in the emergency department of hotel-dieu de france hospital for carbohydrate ingestion. 62,8% are boys; age goes from 13 months to 6 years (moan = 2,5years). kerosene is found in 35,8% of cases; all were admitted (mean = 2,8 days). 79,1% were symptomatic on first examination but 93% of all children presented signs of gastric (58%) or respiratory (69,8%) irritation sometime during their history; 37,2% had neurological signs and 41,9% presented some fever. leucocytosis is found in 65% of cases; 25,6% of the children received antibiotics. chest x ray was abnormal in 48,8% of cases: mainly parahilar infiltrates were found, all children survived; 76,7% with a normal course (1,9 days of hospital stay) whereas those who presented complications (severe pneumonia, coma) stayed in the hospital for 6 days (mean) with short course of assisted ventilation for two of them; long term follow up was not possible. we fonnd nick's criteria for hospital admission to be of value: -symptomatic children with normal x ray } 6 to 8 hours monitoring -asymptomatie children with x ray abnormality } -symptomatic children with x ray abnormality: hospital admission -asymptomatic children with normal x ray : no admission. these criteria would have helped to avoid admission in 8 children and would have allowed a short t2 hours stay for 6 more. we found chest x ray to be mandatory in carbohydrate ingestion; other tests were not helpful, aside arterial blood gases measurement in case of respiratory involvement; we now also advocate more restriction in antibiotic use. prevention remains efficient and should be stressed on. severe liver failure [slf] is a rare but severe condition in infants. we report our experience. patients: slf was defined as liver insufficiency with hepatic encephalopathy and a decrease in the level of factor v to below 25 %. between 1984 and 1996, 29 infants (mean : 4 mo) were admitted for slf (neonates excluded). main causes were metabolic disorders (41.3%) (tyrosinemian=5, hemochromatosis n=2, reye's syndrome n=2, other n=3), virus-induced flf (20.6%) and hematologic diseases (13.7%). in 4 cases, the causes remained undetermined. results: olt was contraindicated in 12 cases because of multiple organ failure (n=10), or underlying disease. all of them died within 6 days after admission. 7 patients had no indications for olt, all but one are alive. (1 of them was transplanted later for tyrosinemia and 1 died lately (virus induced-slf). among the t0 infants who underwent emergency olt, 6 are alive and 4 died because of primary non function of the graft. conclusion: slf in infants admitted before their first birthday is a severe condition with an overall mortality rate reaching 60%. inherited metabolic disorders are the first cause of slf at this age. contraindications for olt are frequent because of underlying disease or multiple organ failure. a number of children undergo primary graft failure after liver transplantation. it is unknown if there is any increased morbidity or mortality following retransplantation. this study seeks to explore these issues. methods: a pediatric intensive care/iiver transplant database is in formation. records of all liver transplant patients are reviewed and abstracted. this data is then computerized to allow analysis. this data provides the source for this study. statistical analysis was performed via student's t-test where appropriate. results: of the 350 patients who have thus far received at our center orthotopic liver ransplants, the records of 112 who underwent 140 transplants form the basis for this review. twenty-three patients underwent multiple transplants, 19 required one additional, three required 3 organs, and one patient survived after a fourth organ transplant, there was no significant difference in age at first transplant between those who received multiple organs and those who did not (40 vs, 44 months, p=ns). the anesthesia time for the procedure did not significantly increase tbr subsequent transplants (8.3 vs, 7,3 hours), nor did time in the intensive care unit (t6.6 vs. 22.2 days), nor did time on the ventilator (8.4 vs. 15.3 days) subsequent transplants did not predispose to having more bleeding in the intensive care unit for usage of packed red blood cells or platalets was not significantly altered (299 vs 306 ml and 127 vs 207 ml respectively). patients who required retransplantatior~ did receive mere fresh frozen plasma (ffp)daring their first transplant than in the subsequent ones (275 vs 81 ec, p < 0.05). however ffp use was not significantly different than patients who did not require retransplant. patients who underwent retransplant had a markedly increased mortality (47%) than the overall mortality for liver transplants at our center (20%), conclusion: children who require another liver transplant have a markedly increased mortality. bleeding and prolonged icu stay is not significantly different between the first and subsequent transplants, fulminant hepatic failure and ortothopic liver transplantation.dr.sasb6n,j;centeno,m;entin,e;acarenza,m;ciocca, m:gofii,j;bianco,g;weller, g;imventarza,o. unidad de cuidados intensivos.hospital de pediatria "dr.j.p. garrahan"1245.buenos aires.argentina. introduction:fulminant hepatic failure (fhf) is a clinical syndrome, defined by the development of hepatic encefalopathy within 8 weeks from onset of illness in a previously healthy person.by far,the most comun cause of pediatric fhf in all series, is acute viral hepatitis.we report our experiences with the pediatric fhf and ortothopic liver transplantation (olt) as attemative of treatment. patients:30 childrens with fhf diagnosis were admitted at the picu from 1/1/1993 to 1/12/1995.symptomatic treatment was given to all children and all were put on list for olt,) following the king's college criterion (protrombina time,age,atiologies,bilirrubin,and encefalopathy state). results:etiologic causes corresponded to the 30 childrens were:23, hav (76%); 6, noa nob (20%);1 ,autoinmune (4%).the age was mean:4 years (range:16 month-10 years).seventeen patients were transplanted,13 chidmn were discarded because:no donors:5;withdrow of the list:3,because sepsis in 2 and bleeding of cns 1;and no admission at list:5 because genetic syndrome 1 ,massive intestinal necrosis, 1 ,mitral valvulopathy 1 and sepsis,2. 25 patients (86%) had at least one complication dudng the post operative period.the most frequent was the acute renal insufficiency(ari) and 4 patients requiered continuos hemofiltration.the gtobal mortality rate was 75%.the mortality of patients without olt was 100% and the mortality of patients with olt was 41%,4 patients dayed because sepsis, (2 candidiasis) and the others 3 because mof.the actuarial survival at 1 year is 54% and the follow up of 8 months. conclusions:the fhf is a very severe and frequent disease at picu. supportive treatment only is associated with a very poor prognosis and high mortality rate.the most frequent etiology in our country is the hav. the olt is applicable in this cases and is a valid alternative of treatment (mortality in our series 41%).the ari is the most frequent complication during the post opeative period.in argentina,due the high prevalence of hav,prevention must be considered the main and only way to avoid this catastrophic illness.to assess the efficacy of gastric intramucosal ph (phi) for evaluation of tissular perfusion and prediction of hemodynamic complications m critically ill children. patients and methods: thirty critically ill children (16 boys and 14 girls) whose age ranged from 3 month and 12 years old were studied. a tonometry catheter was placed in the stomach of all patients at their °admission in pediatric icu. intramucosal ph measures were made at the admission and each 6-12 hours during the study: a total of 202 determinations were made. the catheter was removed after extubation and/or checking of hemodyrmmic stability of the patient. the intramucosal ph was derived from application of the henderson-hasselbaeh formula using the pco2 value from the tonometer and the arterial bicarbonate. values of phi between 7.30 and 7.45 were considered normal. the relationship between phi and severity of patient measured through prism, presence of major (cardiorespiratory arrest, shock) and minor (hypotension, hypovolemia or arrhytlmtias) hemodynamic complications, mortality and stay in the picu, was analysed. results: the admission value of phi was 7.48 -t-0.15 (range 7.04-7.68). five patients (16%) had an admission phi < 7.30. no relationship was found between an admission phi < 7.30 and a higher incidence of hemodynamic complications. sixteen patients (53%) showed some values of phi < 730 during their evolution. patients with phi < 7.30 had a higher number of hemodynanuc complications than the rest (p< 0.0001). every cardiorespiratory arrest (cra) and shock cases were related to a phi < 7.30. patients with major complications (cra and shock) had a phi lower (p= 0.03), as well as a higher number of measurements of low phi (p= 0.003) than patients with minor hemodynamie complications. the value of phi lower than 730 presented a 90% of sensibility and 98% of specificity with regard to hemodymanic complications. there was no relationship between phi < 7.30 and prims score and stay in picu. patients with phi < 7.20 presented a prims higher than the rest of patients (p< 0.05). conclusions: the phi value may be an early sign of presence of hem0dyaaimc complications in the critically ill child. we tested the hypothesis that gastric intramural ph (phi) can be used as an early sign of failure m weaning pediatric patients because the blood flow from nonvital areas is diverted to meet the increased demands of respiratory muscles. methods: 24 children (mean age (4.2_+0.3) years + sd) who were thought by their physicians to be weanable from mechanical ventilation (mv.). these patients were ventilated on serve 900c ventilators, receiving ranitidine, and had intestinal tonometer (tonometrics, inc.) 60 minutes before obtaining a sample.. all children were placed on pressure support (ps) at levels judged to overcome the resistance of the endotracheal tube and ventilatory circuit (2 em h.,o). a sample of arterial blood and a sample oftonometer were obtained during vm and weaning (ps). phi, hemodynamic and respiratory data were recorded during vm and weaning we did not interfere with the primary caretaker's decisions regarding extubation. patients were considered to be successfully weaned if they were able to sustain spontaneous ventilation for more than 24 hours after extubation. paired t-test were used to compare the values obtained during mechanical ventilation with those obtained during weaning trials. unpaired ttest were used to compare values from the group that was successfully weaned (a=i5) with those from the group that were not (b=9). results: we did not find statistical differences in any of those variables mesured during mv for patients who were successfully weaned(group a) and those who were not (group b). gastric phi was in group a: 7.35 + 0.03 (vm) and 739 + 0.02 (weaning); in group b: 7.40 _+ 0.04 (vm) and 7.4t _+ 0.02 (weaning). discussion: although we did not find differences in gastric phi during vm, the group a had a lower value than group b because of the number of cardiac patients (70%) and transfusion therapy, in fins group. in group b 75% of patients showed a problem in upper airway (subglottic edema, and enlarged tonsils). we found it after extubation. conclusion: 1) gastric phi is a good predictor of risk in critically ill patients but maybe because of the small size of the sample, in our study is not of practical value as a predictor of failure in weaning pediatric patients from vm. 2) this test is not a predictor of problems in upper airway~ important etiology of failure weaning in children. objectives: i-to determine the prognostic value of the gastric intramueesal phi in mortality and multiple organ dysfunction (sdmo) in critically ill children. 2-to compare this value, with the pediatrics risk index mortality score (prims). methods: aprospective study was performed with 51 critically illcbildren, aged from 1 mouth to 16 years. the athnittiug diagnosis was: 26 post-surgery (13 neurosurgery, 9 spinal fusion and 4 thoracic or abdominal surgery), 7 sepsis, 6 polytraumatism, 5 adult respiratory distress syndrome and 8 with miscellaneous. all the subjects were monitorized on picu admission and treated for their underlying condition. gastric intramucnsal pt{ was measured following the tonometric method, ou admission and every 4-8 hours depending on the patients state. the severity of the clinical condition was evaluated using the the prims, on admission (prims-i) and during the first 24 hours, when the clinical condition deteriorate, the worse score was utilized for the statistical analysis (prims-2). to perform the statistical analysis the subjects were divided in two groups, one with the phi<7.30and the other with phi>7.30.aunivariate analysis (student's tand wilcoxon two tailed test, chi-square) and multivariate analysis were used. results: 12 out of the 51 subjects dyed. of 14 children developing multiorgan failure (mof) 9 expired. 50% of the patients admitted to the picu with sepsis, ards and miscellaneous had a phi < 7.30. in contrast, with 27 % of post-surgical and none of the postqraan~atism. the mortaliry rate, in children with a phi<7.30was 47% (ci 95%:26.16; 69,04) and 11.76% (ci 95%:4,67; 26.62) in children with phi>7.30 (p=0.011). mofwas observed in41,18% of children withphi<7.30v.s, 20.6% with phi >7.30.no relatiouship was observed between the phi and the score of prims-i and 2. perforating an unconditional logistic regression analysis, two independent variables have mortality predictive value: the phi and the prism-2. (table i) following induction of anaesthesia, a laser doppler probe (moorsoft instruments ltd) was inserted 7cm into the patient's rectum, the probe's special design ensuring that the optical prism lay against the mucosa. continuous monitoring of rectal mucosal perfusion ("flux") was continued throughout the operation. after 10 rain cpb at 35°c, "steady state" readings of nasopharyngeal temperature, mean femoral arterial pressure (map) and flux were recorded over a further 5 min before cpbinduced core cooling to 14-24°c. steady state was defined as a 5 rain period with no change in core temperatures or map. other 5 rain steady state recordings were taken immediately prior to low flow, immediately prior to rewarming and after rewarming to 35°c, before initiation of any vasoactive drugs. the cpb flow rate was kept at 100 m l k g -1 min q, the pcv at 25_+3%, the p~co 2 at 5.3+0.5 kpa and the pro2 at 20+5 kpa. results: initial warm and rewarm map (both 46 mmhg) were significantly lower (19=0.008) than during the 2 cold cpb periods (63 & 64 mmhg). the mean cold flux before (152) and after (159) low flow were both significantly lower (p=0.001) than the mean initial warm cpb flux (211). the mean rewarm cpb flux (127) was significantly lower than all other flux values (p=0.001). there were no siglaificant correlations between map and flux except at the first warm cpb period (r=0,33, p=0.04). conclusions: although hypothermia significantly reduces rectal mucosal perfusion, rewarming produces an even greater reduction in gut perfusion which, considering that mucosal oxygen constmaption is highest during this time, may prove crucial in the postoperative development of mof. therapy aimed at improving gut perfusion during cpb should be directed at the rewanning period in particular. abstract this work is aimed at establishing a clinical procedure for the diagnosis of enteritis necroticans (en), even at the communal level, and to define criteria for diagnosis able to distinguish between acute forms. subjects and method : 100 cases admitted at the institute for protection of children's health dpch), having characteristic symptoms, were examined clinically, by roentgenography of the abdominal cavity, with the analysis of the blood (total protein, electrolytes, hematocrite) and cultures of intestinal fluid and faeces. through surgical operations, the pathological lesions were observed and recorded. results: common epidemiological features: the average age is 6-8 years old (3-15) ; male/female : 1.85; in 70% of the cases, the disease occurred after a meal rich in protides. the acute toxic form accounted for 15% : severe shock appearing early, with very severe dehydration associated with profoundly decreased blood protein concentration and lowered natriemia as well. the lesions of the small intestine were expanded, all of them were necrotic. in the surgical form (20%), the predominant feature was an obstruction -peritonitis syndrome, the peritoneal fluid showed a characteristic inflammatory reaction. for the rest of cases 65% were the internal form, the shock syndrome was less severe, the abdominal distention was light and disappears gradually, the inflammatory reaction of the peritoneal fluid was not so characteristic. conclusion (ino) is a selective pulmonary vesodilator that is rapidly inactivated compared to intravenous vasodilators. these qualities make ino an attractive agent for the treatment of pulmonary hypertension (pittn). the efficacy of ino has been studied in persistent fetal circulation, acute respiratory distress syndrome (ards), and congenital heart disease (chd). potential adverse effects oflno include: nitrogen dioxide (no0 toxicity, methemoglobinemia, and platelet dysfimction. our objective was to evaluate the safety of ino in pediatric patients (pts). methods: pediatric pts. with phtn from ards or chd were studied under an established, approved protocol conforming to fda guidelines tbr an investigational new drug. informed consent was obtained for each child prior to treatment. 1no was sequentially titratad from 10 parts per million (ppm) to 20, 40, 60, and 80 ppm at ten minute intervals. parameters monitored before and during therapy included nitric oxide (no) and no~ concentrations (cone.), mean arterial blood pressure (map), and percent methemoglobin (mhg). no and noz levels were continuously monitored using an inline dr~ger electrochemical detection device. ~,litp was continuously measured with an indwelling arterial catheter. mhg was measured by co-oximetry. a mhg level e 5% or no2 cone. ~ 5 ppm were considered adverse effects by study criteria. pretreatment map was compared to map at 40 and 80 ppm ino using paired t-tests. ap value < 0.05 was considered statistically significant. results: thirty-two mechanically ventilated children with phtn (16 with ards, 16 with chd) were studied. five pts. were treated following cardiopulmonary bypass. methemoglobin (met-hb) levels were routinely measured in two prospective clinical studies on no inhalation in 25 pediatric patients with pulmonary hypertension following heart surgery with extracorporeal circulation and in 19 pediatric and neonatal ards patients, the observed differences between the groups prompted in an in vitro study, red blood cells (rbc) of 20 patients sampled before and after surgery with and without extracorporeal circulation (ecc), respectively, were incubated with 32 ppm no for 100 rain, met-hb, atp, and nadht nadph concentrations were compared, during therapeutic exposure no increased met-hb from 0.2 -2-_ 0.1 to 1.2 _+ 0.7 % in cardiac surgery patients and from 0.2 ± 0,1 to 0.5 ± 0.4 % in ards patients (p < 0.01 ). rbc's having undergone ecc were more susceptible to met-hb formation (p< 0,001 ) whereas intracellular coenzymes did not differ neither between the groups (table) nor before and after no exposure. ecc predisposes to increased methemoglobinemia upon exposure to no both in vivo and in vitro. our data suggest a reduced activity of met-hb reducing enzymes rather than diminished availability of energetic substrates, variation of the inhaled nitric oxide concentration with the use of a continuous flow ventilator. anne pmc de jaegere ~, frans im jacobs 2, nico gc laheij 2, john n van den anker t . dept. of paediatrics ~, central instrumentation 2, sophia children's hospital, erasmus university rotterdam, rotterdam, the netherlands. objective: to investigate the homogeneity of nitric oxide (no) concentration in a delivery system with a continuous flow ventilator. design: bench study, setting: biomedical laboratory. interventions: a nitrogen/nitric oxide (njno) gas mixture was injected at three different sites in the patient circuit: just before and just behind the humidifier, and 20 centimetres before the y-connector. ventilator flow (12, 15, 20 l/rain), ventilator rate (40 to 110, increments of 10) and compliance of the testlung (0.36; 0.5; 1.0 ml/cm h20) were changed. carbon dioxide (co2) instead of n2/no was injected at the same points in the circuit. measurements and main results: a) though the flow ratio of the njno and the ventilator gas were kept constant, the no concentration ([no]) raised with increasing ventilator rates. the increase in [no] was up to 40% when the n2/no injection site was close to the y-connector of the ventilator circuit. minimal changes in [no] were noticed when the n~/no was mixed to the ventilator gas before the humidifier. b) analysis of the ventilator flow pattern showed variations at different places in the ventilator circuit. the magnitude cf the p, ow change depended on the meas~:rement site. the closer to the expiratory valve the highest the flow change was. the duration of the flow change was inversely proportional to the adjusted ventilator flow. c) real time measurements of the co 2 concentration ([coz]) showed variations during tile respiratory cycle. these [co2] variations were higher when the co2 gas was blended closer to the yconnector. conclusions: the ventilator flow variations in relation to the fixed side flow of the n2/no gasmixture result in changes of the inhaled [no] during the respiratory cycle. the no concentration during inspiration is always higher then during expiration. this could not be detected with the available monitoring system. to ensure a constant [no] by blending a njno gas balance in a continuous flow ventilator, the site of injection should be as close as possible to the inspiratory outlet. nitric oxide, a potent and selective pulmonary vasodilator, has recently been successfully used to treat pulmonary hypertension of variable etiology in infants and children. side-effects and complications in infants are so far not well known. we describe here two cases in which prolonged (5 and-7 days respectively) high-dose (50 -80 ppm) nitric oxide was used to treat refractor~¢ pulmonary hypertension. one patient was a newborn infant with pulmonary hypertension secondary to a large leftsided diaphragmatic hernia. nitric oxide was begun under conventional ventilation (babylog 8000) at 7 hours of life with a slight initial improvement in oxygenation. he was then placed on oscillation with the same nitric oxide concentration due to worsening respiratory failure. he died on 5th day of life. monitored nitric dioxide concentration never exceeded 4 ppm. the other patient was a 3 months old infant with severe pulmonary hypertension due to a complete atrioventricular septal defect. he required high-dose nitric oxide to come off cardiopulmonary bypass after surgical repair of his heart defect. he slowly improved over the week following surgery but developped suddenly respiratory failure due to massive pulmonary hemorrhage and died. surprisingly, a particular autopsy finding in both infants was a massive acute necrotizing tracheobronchitis. we conclude that nitric oxide is an excellent and sometimes lifesaving treatment of pulmonary hypertension in infants. tracheobronchitis has not yet been reported as a possible complication of nitric oxide administration. we suggest that caution needs to be taken with prolonged high-dose administration and this possible complication to be looked for at autopsy. introduction: permissive hypereapnia (ph) is a beneficial strategy for patients with acute respiratory distress syndrome (ards) to minimize barotrauma by decreasing the peak inspiratory pressure (pip). hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (pa) hypertension, and, thus, an increased afterload to the right ventricle. this increased afterload may result in increased right ventricular (rv) work load and subsequent rv dysfunction. one therapeutic approach is the use of inhaled nitric oxide (inn), a selective pa vasodilator. the objectives of this study were to test the hypothesis that in a swine model of ards with ph, inn would improve rv work load and not change intrinsic rv contractility. methods: in 11 swine (25-35 kg), ards was induced by surfactant depletion. hypercapnia was achieved by decreasing the pip while increasing the peep to maintain a constant mean airway pressure, inn was administered in concentrations of 2, 5, and 10 ppm in a random order. pulmonary blood flow (qpa) was determined by an ultrasonic flow probe. rv total power (tp) and stroke work (sw) were calculated by fourier transformation of the pa pressure (ppa) and qpa data. preload recruitable stroke work (prsw), a preload and afterload independent measure of ventriculur contractility, was determined by a shen-subtraction method and vena caval occlusion. respiratory failure with pulmonary hypertension in piglets gerfried zobel*, bernd urlesberger*, drago dacar**, siegfried rtdl*, fritz reiterer* and ingeborg friehs** depamnents of pediatrics* and cardiac surgery**, university of graz,austria objective: to evaluate gas exchange, pulmonary mechanics and bemodynamic data during partial liquid ventilation (plv) combined with inhaled nitric oxide (no) in acute respiratory failure with pulmonary hypertension. design: prospecfive~ randomized, controlled study. setting: university research laboratory. subjects: twelve piglets weighing 9 to 13 kg. interventions: acute respiratory failure with pulmonary hypertension was induced by repented lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. thereafter the animals were randomly assigned either for plv or conventional mechanical ventilation. initially perfhiorocarbon liquid (30ml/kg) was instilled into the endotracheal tube over 5 min followed by 5-10ml/kg~. all animals were treated with different concentrations of no ( 1-10-20 ppm) inhaled in random order. measurements and results: continuous monitoring included ecg, cvp, mpap, map, san2 and svo2 measurements. during plv pao2/fio2 increased significantly from 62_+3.2 mmhg to 193±44 mmhg (p<0.01) within 10 rain, while pao2]fio2 remained constant at 61 -+3.3mmhg. qs/qt decreased significantly from 48-+4% to 25-+5% (p<0.01) during plv and did not change during conventional mechanical ventilation. static pulmonary compliance (cstat) increased significantly ff~m 0.4r±0.07 to 0.75_+0.03 ml/cmh20/kg (p<0.01) during plv and decreased slightly from 0.58_+0.08 to 0.46e0.04 ml/cmh20/kg during conventional mechanical ventilation. the infusion of the endoperoxane analogue resulted in a sudden decrease of pao2/fio2 from 262_+44 to 106_+8.0 mmhg in the plv group and from 71±7 to 52+_2.0 mmhg in the control group. inhaled no significandy improved oxygenation in both groups (pao2/fio2:344_+38 mmhg during plv and 196+_.56 mmhg during conventional mechanical ventilation). during inhalation of no mpap decreased significantly from 57-+2 m 35±2 mmhg (p<0.01) in both groups. there was no significant change in oxygenation and mpap during inhalation of 1 and 20 ppm no. conclusions : plv significantly improves oxygenation and pulmonary compliance in acute respiratory failure. the additional application of inhaled no further improves oxygenation and pulmonary hemodynamics when acute respiratory failure is associated with severe pulmonary hypertension. inhaled no is very effective in improving oxygenation and pulmonary blood flow even at low doses. the work was supported in part by grants of the austrian nationalbank nr 5545. as in neonates, severe respiratory failure in infants and children can be aggravated by pulmonary hypertension, resulting in further deterioration of oxygenation due to increasing intrapulmonary shunting. we analysed the influence of inhalational nitric oxide (ino) in treatment, course and outcome of severe ards in a pediatric population. since 1993 20 infants and children (age: 1-107 months) with ards and oi > 15 (mean value: 32.5± 11) underwent a trial with ino (concentration: 3, 10, 30, 60 and 100 ppm) to prevent further respiratory failure. 11 patients had a significant improvement of their oxygenation (rise of pa09 > 15 mm hg) for at least 24 hours (responders); mean best ~fficient no dose: 24.6 ppm. the non-responders had only a short-term improvement or ino had no effect. in responders and nonresponders there was no significant difference with regard to age, underlying disease, ards severity, time on mechanical ventilation, blood gases and ventilator settings before notrial, nor was there a different grade of pulmonary hypertension (estimated by echocardiography). the only difference was an higher ol in the group of the non-responders: 40.9 ± 9.i vs. 25.6 ~ 6.7, p < 0.002. in the group of the 11 respenders there was a secondary deterioration of lung function after i -6 days on ino in 5 children (transient responders): in these patients, as well as in the group of the non-responders, alternative modalities of treatment (hfov and/or ecmo) became necessary. 6 children (30 %) died: 2 transient respenders and 4 non-responders. in infants and children with ards due to different underlying diseases ino can acutely lead to a significant improvement of oxygenation in about 50 % of the cases. the right selection of patients for no therapy and the influence of ino on the survival rate of ards in childhood has to be evaluated in further studies. and pediatric cardiology, university of graz, a-8036 graz purpose: after fontan procedure cardiac output is critically dependent on the pulmonary vascular resistance. even minor elevations of the pulmonary vascular resistance may significantly decrease cardiac output. inhaled no is an effective, selective pulmonary vasodilator in experimental and clinical situations of pulmonary hypertension. the aim of this study is to evaluate the effects of inhaled no on oxygenation and pulmonm 3, circulation in children after a bidirectional glenn-anastomosis (n-~) or a fontan-like operation (n=9). material and methods: from june t993 to january 1996 13 children with a mean age of 7.1+~2.1 (sem) yrs and a mean body weight of 24.3-+5.8 (sem) kg were treated with inhaled no after glenn-or fontan-like operations. all but one had complex cardiac malformations with single ventricle. all children were mechanically ventilated with an fin2 >0.75. inhaled (no) was applied using a rrdcrdproeessor based system which additionally allowed measurement of no/nox using the chemihimniscence method. methemogtobin concentrations were determined 3 times a day. the major indication for postoperative inhalation of no was a high (>10mmhg) transpulmonary pressure gradient (tpg--cvp-lap). severe myocardial dysfunction of the single ventricle was excluded by echocardiography. results: the mean duration of mechanical ventilation was 8.1_+2.2 (sem) days the. mean dose of inhaled no was 4.4-+0.8 (sem) ppm, the mean duration of no-inhalation was 106_+19 (sem) hours. the mean methemoglobin concentration was 1.2-+0.2 (sem)%. hemodynamic data and arterial oxygen saturation before inhaling no and 15 minutes later are given in table 1 acute hypoxaemic respiratory failure (ahrf) in children occurs in a heterogenous group of diseases with pulmonary pathophysiological processes ranging from reversible physiological intrapulmonary shunting to fixed structural lung damage. we hypothesized that inhaled nitric oxide (ino), a selective pulmonary vasodilator, might identify those patients with potentially reversible disease, i,e, large response may indicate a greater likelihood ef reversibility and thus survival. a retrospective review of the early response to ino in 30 infants and children (aged 1 month to 13 years, median 7 months) with severe ahrf(18 with ards). the mean p(a-a)o2, pao2 / fio2, oxygenation index (oi) and acute lung injury (all) score prior to the commencement of ino were 568 +_9.3, 56 +_2.3, 41 _+3,8 and 2.8 +_0.1 respectively, the magnitude of response to ino was quantified as the % change in oi occurring within 60 minutes of 20 ppm ino therapy. this response was compared to patient outcome data. results. there was a significant correlation between response to ino and patient outcome, kendall tau b r=0,43, p<0.02 (table) conclusion. in ahrf response to ino appears te define a subgroup of patients with improved outcome compared to nonresponders. we speculate that response to ino may be useful in selecting patients with potentially reversible lung disease for special support therapies such as ecmo. randomised controlled trials are needed to define the role of ino in paediatric ahrf. between may 1994 and december 1995, 22 patients (pts) were treated for mas. treatment groups were: group i only 02:6 pts; group i1 conventional mechanioal ventilation (cmv): 11 pts; group ii1 hfo: 1 pt; group iv hfo+no: 4 pts. therapy was stepwise intensified until oxygenation improved ( i -) ii -) iii --) iv). "high volume strategy" was used with hfo (mawp 18-24 cm h20). the initial no-concentration was 20-30 ppm, with rapid reduction down to 5-10 ppm once oxygenation improved. results: one pt (group it) died of hypoxic-ischemic encephaiopathy (termination of therapy); all other newborn babies survived. in group iv pt 1 and 2 showed barotrauma prior to hfo. pt 1,2 and 4 were treated with additional mgci2 (max. mg serum concentration 2.8 -6.5 mmol/i). following the identification of inhaled nitric oxide 0"no) as a selective pulmonary vasodilator (frostell et al 1992) [ 617 .+6,3 626+6.3 data are compared to baseline values within each group. *=p<0.05, **=p<0.03, ***=p<0.0l among 12 patients who fulfilled ecmo criteria, 6 improved with no and did not required extracorporeal life support. tltree out of 6 ecmo patients eventually survived. conclusions: m our study low-dose of irthaled no showed a variable effect on oxygenation in newborns with acute respiratory failure. an acute response to no appeared to be correlated with a better short-term outcome and the avoidance of extracorporeal support in ecmo candidates. differently, lack of acute and/or sustained response was associated with death or need for ecmo. although the nature and severity of the underlying disease or the degree of prematurity may play an important role in these patients, we believe lack of acute response to no may be an early predictor of bad outcome, prompting toward alternative treatments such as ecmo or liquid ventilation. *picea s., °bartuli a.,°dionisi-vici c., *dello strologo l., §villani a., §bianchi r., ^salvatori g.,*rizzoni g, °sabetta g. *div. of nephrology, °div. of metabolism, §intensive care unit, ^div. of neonatology. "bambino gesfl" children research hospital. rome, italy. successful prevention of handicaps or death in newborns with ~ depends on rapidity and efficiency of treatment. poor response to nutritional and/or pharmacological treatment requires extracorporeal removal of nh4. efficiency and cardiovascular tolerance are often difficult to obtain with peritoneal or hemodialysis in neonates. we report the results of cavhd in 3 newborns with hc. methods: vascular access: femoral vessels. blood flow: 10-35 ml/min, dialysate flow: 200-500 ml/h. filter: amicon minifilter plusrm(polysulfone membrane; 0.08 sq.m.). no ultrafiltrate(uf) production, patients: case 1 with carbamoytphosphate synthetase deficiency (body weight -bw-: 3.2 kg) showed hc at day 4, a relapse of hc occurred at day 14 due to an infectious event. case 2 and 3 (bw: 3.0 and 2.8 kg), both affected by propionic aeidemia, showed hc at day 5 and day 7, respectively. plasma nh4 (~tg/dl) decrease is shown in the complications: transitory ischemia of arterial cannulation limb and transitory thrombocytopenia occurred in case 1; surgical repairing of artery after cavt-id was necessary in case 3; no cardiovascular instability was observed during cavhd . outcome,'all patients recovered from hc in less than 1 day: case 1: alive, mild b)iootonia at 34 mos; case 2: dead after 10 days from cavhd withdrawal for pulmonary hemorrhage; case 3: alive, normal development at 7 mos. conclusions: 1) in newborns with hc, ca~q-id provides good cardiovascular tolerance,high efficiency and quick removal of nh4, even without uf production (i.e. only by diffusion). this allows easier management (no need of fluid and electrolyte balance). 2) arterial complications seem frequent in neonates treated by cavhd. venovenous circulation could overcome this problem. vb nguyen, m jokie, c leeaeheux paediatric intensive case service, hospital university centre, avenue c6te de nacre, 14033 caen cedex, france background, the implication of polymorphonuclear neutrophils (pmns) in the physiopathology of children's haemolytic.uraemie syndrome (hus) becomes more and more evident. the purpose of the present study is to role out their impact among other pronostie elements during the course of the disease. patients and methods. diarrheal prodrome and its duration, patient's age, maximal blood nitrogen level, anuria and dialysis time, extra.renal involvements, white enll and pmn counts and thrombopenia duration have been retrospectively analysed in 18 infants with good outcome and in 8 another children with unfavorable outcome. results. neither diarrhoea or its duration, nor children's age, nor blood nitrogen level, nor anuria or dialysis time had any predictive value for the disease evolution in the acute phase of our patients. adversely, extra-nenal involvements was accompanied by severe and complicated courses of the disease (p<0,02). the elevation of white cells and pmns (heyon 20 x 109/i) and pmns (more than 15 x 109/1) as well as its persistence beyon a week were most frequently observed in complicated forms (p<0,001, p<0,001 and p<0,01, respectively). a transient thrombopenia (less than 5 day@ in patients with elevated counts of white cells may be a filrther obvious sign of an unfavorable course of the disease (13<0,02). conclusion. the elevated count of white cells and pmns, either alone or associated to one rapid regeneration of platelets, seems enabled to predict an unfavorable evolution of the hus in children. msud results from an inherited impairement of catabolic pathway of branch chain amino-acids. high leucine blood levels may induce acute brain dysfunction. this dramatic complication led us to propose leucine removal procedures as continuous hemofiltration. patients and methods three newborns in acute msud onset were treated by hf, hdf and hd. extracorporeal circulation was performed through a 6.5 fr catheter, a circuit with a blood pump (priming volume = 40 ml). patients and procedures characteristics are summarized below in the sucralfate (an aluminium salt of sucrose octa sulfate) is used to prevent and treat upper gastrointestinal bleeding in critically ill patients. with minimal absorption, the potential for side effects is thought to be limited, though aluminium toxicity has been reported in patients with chronic renal failure. these patients may already have had high body stores of aluminium. we report 5 critically ill children with high serum concentrations of aluminium following sucralfate therapy. all 5 had renal impairment. the normal aluminium level is < 0.4 gmol/l and in patients with chronic renal failure < 2.2 ].tmol/l. none of these patients had known preexisting chronic renal disease. cpb was conducted under deep hypothermia (t,°16°c) and cardiocirculatory arrest (cca) or under hypothermia (t,°24°c) and low-flow perfusion. continuous holter-electrocardiograms (h-ecg) were recorded from the ilranediate postoperative (po) period on for 72 hours. h-ecg were also recorded prior to the operation and before discharge. following dr were observed: snpraventricutar (sv) and ventricular (v) extrasystoles (es) (>50/24h), sv and v tachycardia (svt and vt), accelerated junctional rhythm (ajr) and junctional ectopic tachycardja (jet), and 2nd and 3rd degree atrioventricular block (avb2 and avb3). the incidence of po dr was 20% in the pre-op h-ecg, 74% on the 1st, 33% on the 2rid, 34% on the 3rd po day and 21% befbre discharge. compared to the pre-op findings, an increased incidence of sves, ves, svt and avb3 on the 1st po day was observed, whereas vt and a jr or jet were exclusively observed po. all types of dr were observed up to the 3rd po day. ty23e of dr before discharge was similar to pre-op findings and there was no definitive avb3. considering patient groups according to the most frequent isolated op-procedure, the incidence of dr on the first po day was 56% after asd ii-closure (n=23), 74% after stthaortal vsd-closure (n=lg), 75% after correction of a complete avsd (n=8), 80% after correction of a tetralogy of fallot (n=20) and 100% after fontan-operation (n=10). incidence and type of dr were not significantly different between groups. longer cpb-dttration and use of cca were risk factors for po ves and vt (p<0,005 and p<0,05, respectively) whereas use of cca and degree of hypothermia were risk factors for the development of a jr and jet (p<0,02 and p<0,0001, respectively). -our results indicate that po dr after cpb in children m'e frequent but mainly transient. in our series, specific cpb-related parameters are of greater influence than surgical procedure itseif for the development of dr and are discriminant risk factors for particular types of dr. the course of anp, cgmp/anp (as indicator for atrial natriurefic peptide biological activity), and no2 and no3 (as indicator for endogenous nitric oxide (no) synthesis) was investigated in i9 infants (median age 4 months) undergoing cardiopulmonary bypass (cpb). patients were divided into 2 groups according to whether they had (group 1, n=13) or not (group 2, n=6) preoperative heart failure (hf) and pulmonary hypertension (pht). group 1 patients had preoperatively significantly higher levels of anp (p<0.005), cgmp (p<0.02) and no2 and no3 (,p<0.02) but had significantly lower cgmp/anp (i0<0.05) than group 2 patients. during cpb, anp was significantly higher in group 1 patients ~<0.02). as compared with prebypass values, cgmp/anp was reduced in both groups during cpb (p<0.0001). cgmp/anp inversely correlated with duration of cpb and aortic clamping time (p<0.001, respectively). no2 and no3 were significantly higher in group 1 than in group 2 patients (p<0.05) without any intraindividual change during cpb. from the early postoperative period on anp, cgmp/anp and no2 and no3 were similar in both groups. after cpb, anp correlated in both groups with blood pressure (p<0,001) and diuresis (p<0.05). no2 and no3 inversely correlated with pulmonary arterial pressure immediately after cpb (19<0.05 patients after a fontan-type of procedure have elevated central venous pressures (cvp) leading to congestion in the gastrointestinal system and often ascites. purpose of this study was to evaluate whether this causes a different postoperative gastric mucosal ph (phi). methods: we evaluated a series of 35 patients, who underwent cardiac surgery with cardiopulmonary bypass (age: 5 days to 16 years (mean 2,2 yrs), weight: 3.2 to 37kg (mean 10.2 kg). a commercially available tonometer (tonometics®) for sigmoidal use in adults was inserted into the stomach after induction of anesthesia. the phi measurements were done according to manufacturer recommendations we compared three groups of patients: 1) aeyanotic (n=20), among them 9 p with vsd and 5 p with avsd; 2) cyanotic (n=10): tof: 6p, tga: 4p; 3) cyanotic after a fontan-type procedure (n=5). phi were measured at picu arrival and after 6h. fudhermore we compared lactat levels at these time points. differences between the groups were evaluated with one way anova on ranks with pairwaise multiple comparisons (dunn's method). the relationship between cvp and phi was investigated by regression analysis. results: the median phi for groups i, 2 and 3 were 7.28, 7.27 and 7.13 at ardval and 7.30, 7.25 and 7.21 after 6h respectively. at picu arrival group 3 was significantly (p<0.05) different from groups 1 and 2. there was no significant difference between the latter two groups, after 6h group 1 was different from group 3, there were no other significant differences. the median lactate levels for groups t, 2 and 3 were 2.2, 3,2 and 4.1 at ardval and 1.6, 3.1 and 3.3 after 6h respectively. at ptcu arrival group 3 was significantly (p<0.05) different from group 1, after 6h there were no significant differences. there was a weak negative correlation between cvp and phi: r= -0.21; p<0.05. conclusion: patients after a fontan-type of procedure have lower phi than patients after other cardiac surgical procedures, however, this is only in part due to the elevated cvp and venous congestion. eleven children were investigated 32 months (median) after postoperative mof. iviof was defined as the failure of at least two vital organ systems (kidney, liver, lung, central nervous system) in addition to cardiac insufficiency and high fever. underlying surgical procedure was repair of tetralogy of fallot (n=3), fontan-(n=7) or seuning procedure (n=l). all patients fulfilled criteria for mof in the 3 first postoperative (po) days. six patients needed peritoneal or hemodialysis for 31 days (median) during the po period. one patient showed cerebral infarction due to thromboembolism in the territory of the right internal carotid artery immediately after the operation. the follow-up protocol consisted of extensive investigations of heart-, renalliver-, and lung functions as well as complete neurological and psychological examinations. all patients had adequate cardiac examination. lung function was normal in all but 2 patients who had an obstructive syndrome. only 1 patient showed an isolated decreased creatinine clearance. abnormalities of the liver ftmction tests were only noticed in patients after fontan procedure. severe neurological sequels such as paraplegia (n = 1) and diplegia (n-i) were observed in 2 of the 11 patients. the remaining 9 children presented with a delayed graphomotorical and speech development associated with normal intelligence. -in our series the most frequent and severe sequels after postoperative mof were neurological. -abnormal liver fimction tests are more likely to be a consequence of the fontan hemodynamics than a sequel of mof. the optimal dosing schedule of surfactant therapy for the treatment of neonatal respiratory distress syndrome (rds) remains unclear. goal: surfaetant function and the concentration of phospholipids (pl) in tracheal aspirates are compared in a prospective randomized trial involving neonates with rds who received either two or more (3 or 4) doses of survanta. methods; ventilated neonates <35w with rds were treated with survanta 1oo mg/kg if fio 2 >_40% or mean airway pressure _>7,5 cm hzo, after 6h a 2nd dose was given (same criteria), if the support still exceeded the criteria 12h after the 2nd dose, the patient was randomized to no extra dose (two}, or to an extra dose of survanta (morel (and a 4th dose 12h later; same criteria), pl was measured in tracheal aspirates and corrected for dilution with the urea method. "active" large aggregates and "non-active" small aggregates of surfactant were separated by centrifugation and quantified. surface tension of the large aggregate fraction was measured by pulsating bubble surfactometer, results: 13 neonates were randomized, 6x two and 7x more (5x3 and 2x4 doses), gestational age was 31,7±2,4w and birth weight 1582±568g. most patients had severe rds with initial ventilation: rate 63.1_+11,1, peak inspiratory pressure (pip) 24,3-+6.4 cm hzo, fio 2 75.3±21.0%. at randomization: rate 63.5±6.9, pip 20.3-+2.5 cm hzo, fio 2 29.5±15.7%, and 24 h after randomization: rate 45.9±17.1, pip 18.7_+2.2 cm hzo, fio 2 26.8±6.6%, without signif, differences between the groups. there was 1 relapse (again fio2_>60% within 72h) in group two and t bpd in group more. in total, 112 tracheal aspirates were analyzed. pl was not signif, different before randomization (two 27.5 ± 15.7 vs more 24.5 ± 11.4 /jmol/ml), but neither after randomization (two 21.2-+ 11.0 vs more 19.3±7,o /~mol/ml). there was no difference in the % small aggregates (two 4.2±1.9 vs more 6.9±5.5%), the surface tensions (ran/m) were not signif, different (each time two vs more): before randomization 10.0±2,3 vs 14.2-+7.2, in the 24h after randomization 12.6±5.0 vs 11.2-+3,8, or 24-48h after randomization 17.0-+5.5 vs 12.8±9.8, or 48-72h after randomization 15.7_+0.4 vs 13.7-+5.6. conclusion: neonates who received more than two doses of survanta did not have higher pl, nor a better surfactant function than neonates who received only two doses of survanta. continuation of the trial is necessary to evaluate clinical outcome. may not indicate need for treatment p.c. clemens s.j. neumann university of hamburg, department of pediatrics, klinikum schwerin, wismarsche str.. 397, d-19049 schwerin. aim of the study: the finding of elevated tsh and decreased t4 in the newborn usually is classified as "transient hypothyroidism", thus the elevation of tsh is classified as consequence of the lowered t4. but on the other hand several data sets show that tsh elevation as well as low t4, one independently of the other one, are associated with different kinds of perinatal stress. each of these laboratory deviations, if not associated with the other value being abnormal too, is generally accepted not to be an indication for treatment. from this we conclude, that more pefinatal stress, as in intensive care neonates, may produce tsh elevation as well as low t4, but only coincidentially, not the tsh elevation being the consequence of low t4, thus not to be classified as "hypothyroidism", thus not indicating treatment. if this hypothesis is right, we should find an association of increasing pefinatal stress with an increasing number of neonates from tsh and t4 normal via tsh or t4 abnormal to high tsh and low t4. method: in the newborn screening program in germa w we determine primarily tsh, and only in the neonates with elevated tsh, in addition we determine t4. thus in our study we asked whether we find an association of increasing perinatal stress with an increasing number of neonates from tsh normal via tsh abnormal while t4 normal to high tsh and low t4. definitions for this study were: tsh elevation = >20 mu/1 (as usual in the german screening programs), t4 lowered = < 6 p_g/dl perinatal stress score was 0 or 1 or 2 or 3 in dependency of the neonate having stress in none to all of the following three categories: (a) forceps or vacuum extraction or sectio co) birth weight below 2500 g (c) at the 5th day existence of a relevant neonatal disorder (rds, ictems gravis, infection/sepsis, vitium cordis with hemodynamic relevance, severe malformation). results: our data of 1131 neonates show a high significant association (chi2 = 84, p <0.001) of, on one hand, perinatal stress score 0 with normal tsh, versus, on the other hand, perinatal stress score 2 or 3 with high tsh and low t4. discussion: facing the background given above, in the intensive care newborn, the constellation of high tsh and low t4 may be only a coincidential addition of two independent abnormalities. in tbese cases -the high tsh not being the consequence of low t4 -the classification as "hypothyroidism" is not justified, thus a therapy not indicated. on the other hand of course there exist rare cases with high tsh as consequence of low t4 thus with hypothyroidism tlms with indication for therapy. unfortunately we have no criteria, that enable a certain discrimination of these two categories thus in respect to the question of therapy or not. conclusion: further research has to be done to learn how to discriminate the coincidential high tsh and low t4 from the causal constellation of high tsh and low t4. until we have certain discrimination criteria we have to treat both groups of neonates. few studies have focused on fa composition of surfactant pc in preterm infants before and after surfactant therapy. methods: tracheal aspirates were collected in 7 venttlated mfants from birth until extubatlon (27/7_1 /twk ga, 859.+ 155g bw). after lipid extraction, t.l.c,, and methylation, fas of pc were quantified by gaschromatography. intralipid a (53.2 % linoleic acid,18:2•6) was started 48h after birth. results: six infants developed respiratory distress syndrome (rds) and received survanta r i00mg/kg (sr), all doses within 18h after birth (ix s r n=l, 2x s r~ n=3, 3x s r n=2). one child did not develop rds. in alt patients, the patmitate % in pc was ~ 65% (before sr<=natural composition), increased to ~ 85% after s r, and remained >80% for i5h after lx s a, 22.3.+i1.8h after 2x, and 38.5.+3.3h after 3 doses. in 4 patients, intubated long enough, the palmitate % decreased with a half-life of 78.7_+42.8h to a new plateau which was still higher than baseline after 1 week. linoleic acid % was 5.85_+2.3 (with rds), decreased after s r~ and returned to baseline due to the decrease in patmitate %. thereafter the linoleic acid % increased linearly with 0.021% per h, in 1 patient even up to 15.1%. other fas did not increase after return to baseline. in neonatal medicine the current parameters, arterial oxygen saturation and arterial oxygen pressure, are poor indicators for oxygen delivery and oxygen demand. the purpose of this study was to obtain venous blood samples from the inferior vena cava in stable neonates with respiratory failure and to determine a parameter that reflects more adequately the balance between oxygen delivery and oxygen demand. "l~e study included 22 neonates requiring mechanical ventilation tbr severe respiratory insufficiency. an umbilical venous and arterial catheter were inserted in the inferior vena cava and in the aorta respectively. paired blood samples were obtained at the time that the patients were hemodynamically stable. fifty paired arterial and mixed venous blood samples were analyzed. 1jnear regression analysis showed the following correlations: in a neonatal intensive care unit adjacent to a delivery room caring for 4000 mothers per year, (with a referral of 400 mostly for preterm delivery), virtually every neonate <ls00g was seen by the same ophtalmologist, j.o. the incidence of retinopathy of prematurity (rop) was in 1976-80 of ii cases (464 preterms <ls00g with 58% surviving to discharge, and 4% rop in survivors; 8% if less than 30 weeks). in 1987-1993, 57 cases of rop were diagnosed by the same ophtalmologist. 679 were born at less than 30 weeks, of which 452 (66%) survived to discharge, and among those survivors, rop was present in 53 (12%), with rates varying from 58% at 24 weeks to 5% at 29. objective: to compare a method of teicoplanine (teico) infusion using an electrical syringe-pump with a manual injection. methods: infusion of teico was simulated through a standart neonatal i.v. system. the infusion system consisted of an life care 4 infusion pump (abbo'it lab.) with its i.v. set for maintenance intravenous fluid (flow < 6 mi/h) connected to a 3-way stopcock. an 1 meter extension tubing (vygon lab.) was placed between the stopcock and a neonatal catheter, an another 1 meter tubing (injection tubing) was connected to the stopcock. the volume of the injection circuit was 2.6 ml. simulations were realised for 2 weights (1 or 3 kg), with a doses of 8 mg/kg and a injected volume of 0,8 ml to 3 ml. our goal was to perform a complete infusion in 10 minutes. we compare one method of infusion with an electrical syringe-pump with 2 manual methods: a: teico was infused with a syringe-pump pilot c (becton & dickinson lab.) according to a protocol using 1) a priming before connecting the syringe to the tubing (for immediate starting of infusion), 2) a programmed volume injected in 5 minutes (the drug volume was greater than the dose prescribed to avoid loss of teico into the syringe), 3) a 5 ml wash out was performed over 5 minutes with the syringe pump. b: teico was manually injected in a few seconds in the tubing followed by a 5 ml wash out over 10 minutes. c: idem as b but a nu site valve (medex) was connected to the proximal end of injection tubing to avoid leakage between removal of the teico syringe and connection of the wash out syringe. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at 10 minutes was calculated and expressed as a perventage of the total amount of teico prescribed. results are a mean of 5 to 8 rons. a b c 1kg 94.2+17,9% 86,8+9.1% 94,4-+6.4% 3kg 95-+4,9% 72-+13,4% 90.9-+6% conclusion: with a drug volume injected < circuit volume and a valve, a direct i.v. administration of the drug in the circuit followed by a wash out seems an accurate alternative to drug infusion conbroled by a syringe pump and is easier to perform. doxapram hydrochloride is a central and respiratory stimulant which is used in neonatal intensive care units to treat caffeine-resistant apnoes of the newborn. routinely, doxapram is administered intravenously. oral administration would be much easier but data on bioavailability after oral administration are limited (two studies) and show a large variation. we therefore studied the oral bioavailability of doxapram in 8 preterm infants. doxapram treatment was started with an intravenous loading dose of 2,5 mg/kg during 15 minutes, followed by a continuous infusion of 1 mg/kg/h. after 24 h the intravenous administration was changed to continuous oral administration with the same dosage, blood samples were collected 24 h after both the intravenous and oral administration and analyzed by hplc-assay. apnoea rates per 6 hours were listed before and after starting doxapram treatment. the median apnoea rate per 6 hours declined from 9 to 2 after both the intravenous and oral administration. the oral bioavailability of doxapram is between 43 and 65%, indicating that the oral route can be used effectively in these infants 2. there were no differences in the decline of the apnoea rate after intravenous versus oral administration of doxapram, infasurf r has been comnared with exosurf r in two studies: one as drodhvlaxis and the other a rescue trial. similar. althouah non-sianificant benefits were found for the natural surfactant. in 6 trials there was a sianificant reduction in dulmonarv air leaks for 0.53: 95% ci 00.41-0.641 for babies treated with natural comnared to svnthetic surfactants. for 7 trials (3554 babies~ comdarina natural and synthetic surfactants for rds {6 comdarina survanta r and exosurf r. and one infasurf r and exesurfr% neonatal mortalitv was sianificantlv reduced (or 0.80: 95% ci 0.66-0.971 with natural compared to synthetic surfactant treatment. in two further trials different natural surfactant drenarations were compared. reduced oxvaen needs for 24 hours after treatment were found for r r infasurf and curosurf respectively when each was compared to survanta r. andarent lonaer-term benefits from these surfactants were not statisticallv sianificant. further trials will be needed to ascertain differences between various surfactant preparations. introduction bacterial meningitis is a common cause of admission in the paediatric age group, and one which still carries a high morbidity and mortality. these complications are strongly associated with a delay in antibacterial therapy. a significant proportion of these patients require mechanical ventilation; it is in this particular group of patients that survival is greatly diminished. the identification of risk factors for mechanical ventilation associated with bacterial meninges may help improving survival by shortening the delay to icu referral. the paediatdc risk of mortality score (prism) is the most widely used scoring system in the paediatric icu literature; the accuracy of prism on predicting outcome in meningitis has been shown to be poor. aim we aimed to describe our population of patients with bacterial meningitis requiring ventilation, and then to identify predictors of survival. methods this study was conducted at the baragwanath hospital in south africa which is an universityaffiliated institution with end average annual paediathc admission of 4500 patients. baragwanath icu admits 250 non-neonatal paediatdc patients per year. a retrospective chart review from january 1991 to december 1995 of 42 consecutive paedistdc icu admissions with bacterial meningitis was performed. results approximately 150 cases of bacterial meningitis are admitted to the general paediatric wards every year; this constitutes ± 3% of all admissions. the mortality of these patients is + 14%. during this time 42 (23m, 19f) patients (7%) were accepted for icu admission, with a mortality of 42.2%. the median age was 9 months (range 15 days to 17 years). the median delay to hospital admission was 48 hours, and the median delay to icu admission was a further 4 hours. the median duration of tcu stay was 48 hours (40 for non-survivors, 120 for survivors). the main presenting features were convulsions (34%), altered mental state (40%), fever (50%), respiratory symptoms (24%), headache (18%), and diarrhoea and vomiting (32%). the most common indications for icu admission were seizures (55%), coma (36%), shock (26%), respiratory failure (29%) and acidosis (21%). in 29% of patients there was a cardiorespirstory arrest prior to admission. the most common organisms in the csf was pneumococcus (57%), haemophilus influenza (15%) and e coli (12%). the presence of leucopenia (wcc < 5), a low platelat count (<100), acidaemia (ph<7.2), and the need for inotropic support were strongly associated with nonsurvival. tachycardia and hypotension were not significantly essorjsted with poor outcome, as has been previously reported. discussion early diagnosis of meningitis and prompt institution of antibiotic therapy requires a high level of clinical suspicion. paediatric patients with bacterial meningitis that require mechanical ventilation have a poor prognosis. there is little evidence to suggest that nomsurviva[ can be predicted prior to icu admission, but a rapid deterioration requiring ventilation and inotrepic support with evidence of severe sepsis (low platelet count, leucopenia) is nmost invariably associated with a fatal outcome. the long term functional outcome of these patients make this disease even more devastating; the rote of icu in the management of these patients has yet to be fully estanished. objective and study design: a retrospective study was pertbrmed for all patients diagnosed with hemorrhagic shock and encephalopathy syndrome (hse) during 1984 to 1994. soroka medical center is the only medical facility in the southern negev region of israel serving a population of -400,000 residents, consisting primarily of jews and bedouins. results: 20 patients (17 bedouins and 3 jews) were diagnosed with hse. main features on arrival included profound shock and coma with con~alsions. active bleeding and/or disturbing coagulation tests with falling heuroglobin levels and thrombocytopenia was noted in every case. all infants developed diarrhea shortly after arrival. elevated urea, creatinine and liver enzymes was noted in all cases. annual incidence tbr inlhnts <1 year of age was 5:10,000 for bedouins and 0.6:10,000 for jews. patients ranged in age from 6-32 wks and arrived at the hospital late night/early morning (2:00am-ll:00am), during winter/early spring (november-april). all were healthy prior to admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in 10 cases. most infants had markedly elevated body temperature on arrival. a history of overwrapping and/or excessive hearing was obtained in 4 of 20 infants. bacteriological and virological cultures were negative in all infants. one infant died and neurological sequelae were observed in all survivors. the high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive hearing, and the high incidence of rise among a closed, culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that hse results from hyqperpyrexia, originating in most cases from a "physiologic" heat induced trigger which starts and peaks during the night in previously healthy infants with susceptible, predisposing genetic underlie. approximately 10% of hospitalised infants with respiratory syaacytial virus (rsv) infection require mechanical ventilation. our general practice is not to use specific antiviral therapy. we have undertaken studies of rsv-infected mechanically ventilated patients without underlying congenital heart disease or immunodeficiency. study i (n=45): a retrospective review of 45 infants (mean post-conceptual age 48 weeks; median duration of intubation was 8 days (interquartile range 5-11 ). blinded review of chest x-rays during the first three days of mechanical ventilation revealed a spectrmn of lower respiratory tract findings from marked diffiase consolidation in all zones without hyper-inflation (n=10) to gross hyperinfiation without consolidation (n=5), with the remaining patients have an intermediate picture (n=30). death occurred only in patients who were at the poles of this continuum (4/10 consolidation and 1/5 hyperinflation). patients at these poles could be differentiated by gender predominance, birth gestation, alveolar-artarial (a-a) oxygen gradient (p<0.0 l), oxygenation index (p<0.0 l), peak inspiratory pressure (p<0.05), and intubation days (p<0.01). study ii (n=28): prospective audit of infants with the aim of verifying the above differentiation. separating patients based on their early x-rays and a-a gradient we confirmed the above predictable difference in duration of supportive therapy (consolidation v intermediate: 6(4-7) v 14( 12-33 ) p<0.01 ). severe lower respiratory tract rsv-infecrion in young infants results in different distinctive partems of disease with characteristic radiological and clinical features, and each has a predictable timecot~se. conflicting reports on special therapy should be interpreted with respect to these observations before making conclusions about the efficacy of any specific treatment. the clinical data of 186 children wich suffered from a severe mycosis between jan.1990-dac.1994 and wich were treated with amphotericin b in 10 spanish hospitals were collected. mean age was 6+3.9 years; 157 were mate (84%) and 29 female (16%). the most common underlying diseases were leukemimymphoma (31%) and congenital heart defects (20%). the major pathogens isolated were candida albieans (61%), other candida (18%) and aspergillus (17%). and liposomal amphotericin (la) in 68 (37%). in the ca group, the starting dose was 0,3~0,1 mg/kg, reaching a maximal dose of 0.9+0,3 mg/kg after 4.7+3 days. maintenance time was 14+10 days and the cumulative dose: 12~17 rag. in the la group, the starting dose was 1.1±1 mg/kg, reaching a maximal dose of 2.9_+2.4 mg/kg (p<0.01) after 5+5 days. maintenance time was 19~16 days (p<0.05) and the cumulative dose 42_+37 mg (p<0.05). the reasons for la use were: elective in 66% of cases, previous renal failure in 29%, and ca inefficacy in 4%. hepatic or renal function impairment was two times more frequent in la group than in ca group, the antifungal efficacy was 62% for ca and 67% for la. therapeutic failure or toxicity induced withdraw of ca in 7% of cases, vs, 1,5% for la (p<0,01). mortality was not different in both groups (21 vs. 22%), adverse effects were related to ca in 28 events vs, only one in la group (p<0,01). the commonest side effects in ca patients were fever (18%), chilis (10%) and nausea (9%). in ca group, 44 cases (37%) developped analitical anormalities related with amphotericin, vs. 10 cases (15%) in la patients (p<0.001). in the first group, the commonest serum alterations were hypokaliemia (25%), raised creatinine (14%) and bilirrubin (6%). in the second one, hypokaliemia presented in 7% of cases (p<0.01), raised bilirrubin in 6% and creatinine in 3% (p<0,05), the antifungal efficacy of la is at least the same of ca. from the clinical and analitical points of view, la is much less toxic than ca. la can be used at a greater dose than ca and is safe in children with renal failure. laurence desplanques -serge gottot -christian dageville d~artement de sant~ publique -facult~ xavier bichat -16 rue henri huchard 75018 paris -france -the french << reaped ~> network was created to implement a nosecomial infections (ni) quality care program in nicu and picu, the first objective was to describe the annual ni incidence rate in each icu population : all patients stayed more than 48 hours in icu. methods : n] criteria were defined by the reaped group according to cdc criteria. all data were collected by a medical and nursing team. all infection data were validated by an external investigator. results : 4525 patients were admitted over a 14 months period. 68% were newborns. 371 ni were identified among 311 patients. the overall ni incidence rate (ir) was 8.2% and 5.9°/00 person day (from 5.0 to 8.2°/00 according to age, lowest rate for newborns). septicemia (50% of ni) and pneumonia (41% of ni) were the two main ni. according to age, the septicemia ir varied from 6.8 to 10.9°/oo catheter day (lowest rate for newborns) and the pneumonia ir from 3.9 to 7.4°/00 ventilator day (lowest rate for newborns). there were very few other infections (uti : 4%, ir : 7.4°/00 catheter day). gram positive cocci were isolated in 73% of septicemia ( 70% of them were coagulase negative staphylococcal). gram negative bacilli were isolated in 53% of pneumonia (40% of them were pseudomonas). 5% of ni were caused by candida, mostly septicemia. the septicemia and pneumonia ir varied according to unit even after adjustment for age. discussion the aminoglycoside antibiotics are frequently used in newborns for the treatment of severe infection and sepsis due to gram-negative microorganisms. the currently recommended dosage schedule for tobra (2.5 mg/kg q18h) does not take into account differences in gestational or postnatal age during the first 4 weeks of life. we questioned the validity of these recommendations and studied the population kinetics of tobramycin to establish predictive equations that enables the clinician to select the appropriate initial dosing schedule. methods tobra trough (t=0) and peak values (t= 1) were taken on day 2-4 after birth in 460 newborns. tobra was administered as a 30-minute intravenous infusion already in an adapted dosage schedule: 3.5 mg/kg q24h in infants with gas < 28 weeks; 2.5 mg/kg q18h in infants with gas between 28-36 weeks and 2.5 mg/kg q12h in infants with gas > 36 wks, tobra concentrations were analyzed by tdx-assay, a one-compartment model was assumed and non-linear mixed effect modelling (using nonmem) was applied to the data, a trough level < 2 mg/l and a peak level between 6 and 10 mg/l was required, with the present dosage scheme 40% of the trough levels were too high and almost 60% of the peak levels too low. calculations showed that the following dosage schedule should result in optimal levels of tobra. preterm infants gas < 28 wks: 6 mg q48h preterm infants gas 28-36 wks: 4.5 mg q36h preterm infants gas > 36 wks: the currently recommended dosage schedules for toeira result in high trough and low peak levels. prolongation of the dosing interval and increasing the amount of drug per dose according to the above scheme will improve tobra level control. since january 1993 british clinicians have been conducting a randomized controlled trial of neonatal ecmo. mature infants (>-35 weeks gestation and birthweight 2 2 kg) with severe cardiopulmonary failure have been randomized to receive continued care in their referring institution or referral to a designated ecmo centre for further management. we now present the preliminary results which have prompted closure of recruitment to this trial. the final outcome will be assessed as intact survival against death or severe disability at one year of age for all the recruited patients. patients were categorised by diagnosis such as isolated persistent fetal circulation, secondary persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia and by severity of illness at the point of first contact with the clinical coordinators of the trial -judged primarily by the oxygenation index (240 before randomization). 180 patients were randomized (90 in each arm). hospital outcome data are reported for all patients and 1 year outcomes on t18 (65 survivors). at this stage 26 of the babies allocated to ecmo are known to have died compared to 52 of those allocated to conventional management (rr 0.5; 95% ci 0.35-0.72; p=0.0002). fewer deaths have been obsea-ved amongst ecmo allocated babies in all the diagnostic categories used. a 28% incidence of disability and impah~nent has been observed amongst survivors. this rate is similar in both groups and the survival advantage is not offset by an increased rate of disability or impairment following allocation to ecmo. we consider that these data combined with those available from other studies provide conclusive evidence that the survival to discharge from hospital is substantially higher in patients allocated to ecmo than in comparable infants not so allocated. therefore recruitment to this trial has been closed whist awaiting complete one year outcome data. sigston pe, goldman ap. #keating j. crook r. ~e dj~. great ormond street hospital for children nhs trust, and ~biochemistry department, kings college hospital, london, united kingdom. isoflurane is a safe and effective means of long term sedation in both children and adults in the intensive care setting. the use of isoflurane, by adding it to the sweep gas allows the use of this volatile anaesthetic agent in patients on ecmo, enabling rapid control and weaning of sedation. a potential problem with the long term use of isoflurane is fluoride ion accumulation with the possibility of renal toxicity, the purpose of this study was to assess plasma fluoride levels in patients receiving prolonged isoflurane on ecmo. method: fifteen infants and children (aged 1 day -10 years, median 2 weeks) receiving ecmo support for either cardiac or respiratory failure were recruited to this study. the patients were sedated with isoflurane as well as intravenous agents (morphine and midazolam). isoflurane was administered (0% -3%) via a calibrated vaporiser to the sweep gas, adjusting the level to maintain adequate sedation. blood samples were obtained on a daily basis for plasma inorganic fluoride assay. the relationship between plasma fluoride and amount of isoflurane administered, as %-hours (vaporiser setting in % x hours) was calculated by linear regression. results: the duration of ecmo ranged from 42 to 532 (mean 207) hours, during which the amount of isoflurane administered varied from 7 to 418 (mean 168) %-hours. 75 blood samples were anaiysed, demonstrating individual peak plasma fluoride levels of 2.7 to 16.5#mol/1, mean 7,1p.molli (toxic threshold = 50gruel/f). the plasma fluoride positively co;related with the %-hours of isoflurane (r = 0.65, p = < 0.001). conclusion: this study shows that although there is a dose related accumulation of inorganic fluoride ions in patients sedated with isoflurane on ecmq, the peak fluoride levels are well below the suggested toxic threshold. merzel y, lev a, bar yosef g, halbertal m, lorber a ecmo center, picu, emek medical center, israel. the mortality rate of pediatric patients with acute myocarditis is 20-60% according to the severity of myocardial damage. a 15 month old gzrl presented with high fever, respiratory and cardiac failure. diagnosis of acute myocarditis was made and the patient was ventilated with high pressures and fio2 of 1.0. she required high doses of inotropes. echocardiography revealed a dilated la and lv with severe mr. lvedd was 41 mm and lvsf 9%. calculated oxygenation index was 55. she was resuscitated after a cardiac arrest. she was commenced on ecmo (using biomedicus centrifugal pump and avecor 800 oxygenator) at a flow of 100 ml/kg/mm with immediate improvement of hemodynamlcs, oxygenation and pc02. resptratory assistance and vasoactive drugs were reduced. the patient was transported by air, on ecmo, to the ecmo cevter. she developed arf and cvvh-d was performed. cardiac fimction started to improve after 12 days. ecmo was discontinued on day 18. echo revealed lvedd 34 mm and lvsf 24%. ippv was discontinued on day 20. on discharge, a month later, her lvedd was 29 mm and lvsf 28%. she behaves normally for age without neurologic or other medical sequellae. literature search revealed no case of acute myocarditis, as severe, that was treated successfully. survavors of disease this severe usually suffer dilated cardiomyopathy and permanent disability. the use of ecmo allows myocardial rest which prevents long term myocardial damage. introduction ecmo is increasingly used in the care of critically ill newborns. despite the frequent use of betalactam antibiotics in the treatment of these infants there are no data available on the dispbsition of cefotaxime (ctx) and amoxicilfin (am) d0ring ecmo. the purposes of this study were to determine the pharmacokinetics of these two drugs in infants on ecmo and consequently formulate appropriate dosing regimens. we therefore studied the pharmacokinetics of ctx (100 mg/kg ql 2h) and am (50 mg/kg q6h) in 8 term infants on day 3 after birth, blood samples were taken before (t-o) and 0.5,1,2,4,6 (am) and t2 h (ctx) after the intravenous bolus injection and analyzed by hplc-assays. 2. ctx 100 mg/kg q12h results in adequate serum levels of ctx in fullterm infants on ecmo, am 50 mg/kg q6h results in very high serum trough levels. recalculation based on the known volume of distribution and elimination serum half-life of these infants resulted in the following dosage recommendation: 50 mg/kg q12h. persistent pulmonary hypertension of the new-born (pphn) is characterised by rapid fluctuations in pulmonary artery pressure (pap) and a clinical impression of stifflungs. lung mechanics were measured in 35 term infants, mean age 1.5 +_ 0.7 days who were paralysed and ventilated within the first three days of life. fourteen infants had pphn with systemic or suprasystemic pap measured by echocardiography. in these patients, the respiratory system resistance was 29.4% higher (p < 0.001) and compliance 22.4 % lower (p = 0.03) during systemic or suprasystemic pap compared to when the pulmonary hypertension had resolved. in contrast, there were no changes in resistance in the 14 infants with respiratory distress syndrome (rds) and no pulmonary hypertension or in the seven infants with normal lungs, where two readings were taken 24 hours apart. the changes in lung mechanics interfered with mechanical ventilation, resulting in a 12.5 mmhg rise in paco2 (p=0.007) during pulmonary hypertension. inhalation of nitric oxide 10 ppm resulted in a 16% decrease in respiratory system resistance and an improvement in oxygenation. the bronchial and vascular smooth muscle was increased by 120% in postmortem lung samples from eight infants with pphn compared to six age matched post-mortem controls with normal lungs (p<0.001). these findings suggest a co-constriction and co-hypertrophy of bronchial and vascular smooth muscle during pphn. anatomically the pulmonary vasculature and bronchi lie in close proximity to each other. thus mediators such as endothelin-1 released locally may act on both vascular and bronchial smooth muscle to produce the observed vasoconstriction, bronchoconstriction and smooth muscle hypertrophy. prince of wales children's hospital university of new south wales, randwick, n.s.w. australia. introduction an increasing mortality in asthmatic children has been reported. the increased severity of asthmatic illness leads to an increased demand for icu admission, and a corresponding increased need for mechanical ventilation. geographic end environmental factors are thought to be partly responsible for differences in disease sevedty throughout the wodd. for this reason, epidemiological studies from diverse areas are important, risk factors for icu admission, and for the institution of mechanical ventilation should be identified, to optimise icu admission criteria and to avoid unnecessary delays in admitting at-risk patients. aim to document the clinical characteristics of ventilated and non-ventilated asthmatic patients admitted to icu. methods this is a retrospective study of all paediatric asthma icu admissions from january 1990 to december 1995. results there were 65 patients admitted to the icu for acute severe asthma in the study period. the male:female ratio was 33:32, the mean age 76.1 • 57.3 months, the mean prism 8.5 4-11.1%, and the mean duration of admission 135 4. 129 hours. there was no seasonal variation in admissions. only 40% (26/65) patients required mechanical ventilation. in 22% of all patients this was the first presentation with asthma. there were some significant differences between ventilated and non-ventilated patients (see table) . there was a significantly higher incidence of concomitant and nosocomial pneumonias in the ventilated patients (84.0% vs 21.1%) as well as segmental lung collapse (68.0% vs 26.3%). there were no deaths. discussion the need of mechanical ventilation significantly increases the morbidity of and duration of icu stay of asthmatic patients. younger asthmatic paediatdc patients have a significantly higher risk of ventilation. the need for ventilation is predicted principally from a worsening pco2 and respiratory acidaemia, which is often independently interpreted by the clinician as respira4ory exhaustion. this study has shown that icu admission is important in the management of young paediatdc patients with acute severe asthma and respiratgry fa!!ure. intravenous salbutamoi in the emergency, department management of severe asthma in children. g.j.browne,a. perma,x. phung,m.soo westmead hospital, sydney, australia. it is postulate that if an initial intravenous loading dose of salbutamol is given in severe asthma, a more rapid clinical response will occur, reducing requirements for continued high doses of nebulised salbutamoi with fewer side effects. this double blinded study was conducted in the emergency department of westmead hospital a university hospital in sydney, australia. all children with severe asthma had initial nebuliser therapy (5rag of salbutamol with 4ml of saline). if asthma remained severe 20 minutes later, they were given a dose of intravenous hydrocortisone (5mg/kg) and either normal saline or salbutamol 15microgm/kg intravenously. frequent nebulised salbutamoi therapy continued during the initial first hour if clinically indicated. continuous respiratory and haemodynamic monitoring occurred in the first 2 hours. serum potassium and glucose determinations were made at study commencement and 1 hour after intravenous therapy. salbutamol determination was made at study commencement. children remained clinically monitored for the next 22 hours, with their ongoing treatment determined by clinical response. 29 children with severe asthma 12 months to 12 years of age were studied, with 14 given intravenous salbutamol and 15 given intravenous saline. the intravenous satbutamol group (ivsg) showed rapid reduction in asthma severity scale in the first 2 hours, with reduced need for high frequency nebuliser therapy ( _<2 hourly), occurring 8.78 hours.earlier. no clinically significant side-effects were found in either group, although, tremor more frequent in the [vsg. biochemistry and salbutamol concentrations were similar in both groups. the use of intravenous salbutamol (i5 microgm/kg) in the management of severe childhood asthma is a safe and effective therapy with no significant side-effects and the potential to abort severe asthma attacks in the emergency department. intravenous terbutaline in picu piva j., amantra s, rosso a., zambonato s, giugno k, maia t. introduction: the admission to a picu of children with respiratory failure secondary to an acute obstructive lower airway disease is a common event, especially during winter seasons. these diseases have several causes, but most of them (especially asthma and chronic airway disease) have a good response to the administration of b2-adrenergic drugs. objective: to find the dosis of intravenous terbutaline that is safe, efficient and with minimal adverse effects when used in children admitted to a picu with acute obstructive lower airway disease and respiratory failure. material and methods: we study the records of all children that were admitted to our picu during the winter of 1995. only the patients that had respiratory failure and acute lower airway disease and who needed the use of iv terbutaline were selected. the records were divided in two groups: less than 12 months and more than a year old these two groups were compared in the following aspects: the minimal and maximal dosis, and the length of time of use of iv terbutaline, frequency of tachycardia, hypokalemia, and mechanical ventilation. to establish any difference in the two groups we use the t exact test of fisher and x2, with p< 0.05, results: during the period of study were admitted 367 patients to the picu, and 38 (10,3%) of them used of iv terbutaline. the mean age was 14.2 +12.2 month, used iv terbutaline during 7.24 +3.75 days (0.5 to 17 days), the initial rate was 0.55 +0.26p~g/kg/min, and the means of therapeutic dosis was 2.48 +l.181~g/kg/min (ranged from 0.5 to 4.4). twelve (31.5%) patients had tachycardia art obstacle to the increases in the rate of use of iv terbutaline during any time. mechanical ventilation was necessary in 22 patients (57.8%) and 11 (28.9%) patients died. the children under 1 year of age used initial dosis of iv terbutaline lower than the children up of 1 year old (0.45 p.g/ kghnin x 0.57 ~tg &g/rain, p<0.001), but without difference in the length of use, the maximal dosis, the rate of mechanical ventilation and tachycardia. the frequency of hypokalemia was most common in the group of children under year of age. acute respiratory failure during status asthmaticus may require mechanical ventilation. current therapy includes paralysis, pressure control ventilation (pcv) and permissive hypercapnia to limit pulmonary barotranma and its hemodynamic consequences. asthmatic children exert a significant amount of respiratory effort during exhalation. with paralysis, this expiratory effort is lost. unloading the inspiratory work of breathing while maintaining the patient's expiratory eftbrt using pressure support ventilation (psv), may be beneficial. methods: children receiving pcv (peak inspiratory pressure (pip) = 4 kpa. rate 10 breaths/min) and pco2 > 8 kpa were switched to psv. children were initially ventilated with psv 3.7 kpa and peep = 0.3 kpa (servo 900c). all children received beta agonist therapy, ipratropium and anesthesia with ketamine or inhalational anesthesia, and were breathing spontaneously. respiratory parameters and blood gases are shown be~bre psv, within 30 minutes (start) and when the ph had normalized (during). data are presented as median and range, * p < 0.03 compared to before psv. results: children with hypercarbia during pcv responded to psv, normalizing pcos and ph within 6 hours. the mean respiratory rate decreased from a median of 45 (31-46) to 35 (22-35) while the pip was decreased to 3.2 (2.5-4.0) kpa within 6 hours. the i:e ratio also significantly decreased. conclusion: psv permitted patients to active/y exhale while unloading the inspiratory work of breathing. perhaps this strategy shifts the patient's respiratory effort from inspiration to exhalation, thus permitting the child to meet the excess work of breathing caused by bronchoconstriction. maged z. youssef, peter silver, laura nimkoff, and mayer sagv. division of pediatric critical care medicine, schneider children's hospital, new hyde park, ny 11040. introduction: mechanical vemiladon of patients with severe bronchospasm can be difficult, due to poor chest compliance and increased airway resistance. ketarmne is a cormnonly used anesthetic agent that has been shown to have bronchodilator properties. the purpose of this study was to determine ifa continuous infusion of ketamine had an effect on the oxygenation and chest compliance of children with severe lironchospasm who were mechanically ventilated. methods: a retrospective chart review was conducted of pediatric patients in severe bronchospasm who were mechanically ventilated in our picu and treated with a continuous ketamine infusion. all patients were receiving aggressive bronchodilator therapy and adequate sedation prior to keramine. patients were excluded if any new bronchodilator or sedative agents were started within 24 hours of initiation of ketamine treatment. all patients were simultaneously treated with benzodiazepines. for each patient, the pao2/fio ~ ratio and dynamic compliance [tidal volume/(peak imp. pressure -peep)] was determined immediately prior to ketamine, and at 1, 8, and 24 hours post-ketsmine initiation. data are presented as mean ± s.d., and were a~yzed using one way anova and the multiple comparison method of bonferroni. patients (age 6.0 ± 5.7 yrs.) received * p<0.05 ketamine for severe bronchospastu during mechanical ventilation in our picu. both . .xto-* * the pao2/fio2 ratio and dynamic . . -.... . compliance increased significantly following initiation of the ketamine 200infusion (see figure) . the mean ketamine dose was 32 ± 10 mcg/kg/min, and the -, mean infusion duration was 40 ± 31 too-[/ hours. one patient required glycopyrrotate 6 ~' to control excessive airway secretions, and " one patient required an additional dose of o--j i ~-~4 ~/me diazepam to control hallucinations after i 8 cessation of ketamine. all patients were t~n~,mr~ *~am~ successfully weaned off mechanical ~l~s ~,~s~on ventilation and discharged from the picu. conclusion: continuous ketamine infusion to mechanically ventilated pediatric patients with refractory broncliospasm results in a significant improvement in oxygenation and dynamic compliance of the chest. reports of adults with status nsthraaticus document significant morbidity and mortality, whereas studies in children have had more varied results. different centers report mechanical ventilation (mv) in 10 to 33% of admissions, occurrence of pneumothoraces or paeutuomediastinums in 2 to 11%, and mortality in up to 7% of patients ~'t3. we retrospectively reviewed 113 status asthmaticus admissions to the pediatric intensive care unit (picu) between january 1993 and december 1995. seventy-five of these patients were admitted fr~an the emergency department of chla (er admit). the mean length of stay in the picu was 2.1 days and the mean length of stay in the hospital was 4.6 days. based on 95 patients who had arterial blood analyses, 36 patients had hyperoapnia (pco2 > 45). all patients received oxygen, inhaled albuterol (alb), and cortieosteroid therapy. ninety-five percent of patients also received methylxanthine (mx) therapy. of the 113 admissions, 12 patients (11%) required mv. only 4 of these patients were admitted through our emergency department, whereas the remaining 8 patients were intuhated at outside facilities. twenty-three cases required intr:wenous beta-agonist therapy, either isoproterenol osop) or terbutaline (terb). h~ff of the ea.~es re~%wed were complicated with hypokalemia (k+< 3.5). c,', ,~lications ofpoeumothoraces or pneumomediastinums were seen in 10% of ,'r:u~ported patients, but in only 4% of er admit patients. only 2% of these were in mechanic.all, )atients. there were no deaths in the review. respiratory mechanics measurements 'are useful in mechanically ventilated children to optimize ventilator settings. nevertheless, the transducers used to measure flow (f) and pressure (p) remain expensive. objective. to evaluate the performances of piezoelectric p transducers (350 us dollar) in measuring f and p. methods. we used a previously described monitoring system measuring respiratory parameters [ 1] . in this study f was obtained by a differential piezoelectric p transducer (_+ 12.7 cmi-i20, honeywell) whose sensitivity has been reduced to +_ 2 cmh20 by an electronic amplification equipment and p by a piezoelectric p transducer (_+ 7().3 cmhzo, honeywell) connected to a grid pneumotachymeter &nt) ffleisch 0 or 1 ). volume (v) (5 to 400 ml) obtained by numeric integration off (0.125 to 10 l/rnin ) and p (2 to 70 cmh20) were respectively delivered through a calibrated seringe and an electronical manometer (pic 400 premier) and calculated by the computer. bland and altman analysis was used for assessment of results bias. coefficient of repeatability (cr) was estimated by the standard deviation of repeated measurements of the parameters as calculated in a oneway analysis of variance. results. mean difference (mdi 0 between injected v (5 to 50 ml) and measured v using pnt 0 was 0.15 ml, sd = 0.13 ml. difference and mean v were not correlated. sd of repeated v measurements were not correlated to v. cr was 0.4 ml. mdif between injected v (25 to 400 ml) and measured v using pnt 1 was 3 lrd, sd = 6 ml sd of repeated v measurements were not correlated to mean v. cr was 6 ml. mdif between injected p and measured p was 0.3 cmi-i20, sd 0.4 cm h20 sd of repeated p measurements were not correlated to mean p. cr was 0.3 cmh20. conclusion. inexpensive piezoelectrical transducers can be used to measure f and p and evaluate respiratory mechanics in ventilated children. previous studies have already shown the problem of the reproducibility of pft in preterm ventilated babies. were studied 10 preterm ventilated babies {mean weight 1128 gr) in the first week of life in clinically stable condition, measuring flow, airway pressure and esophageal pressure simultaneously. each baby was studied twice with an interval of one hour and each study was done increasing the rate till 60 to inhibit spontaneous breaths. none sedative has been used. only mechanical breaths were analyzed. compliance and resistence were calculated with a computer system using the linear regression method. we expressed quantitatively the intrapatient variability as the percentage of variation of tidal volume, compliance and resistence between the two studies in each baby. then intraclass correlation coefficient test (icc) was applied to confirm qualitatively our results (total agreement =1, good reproducibjtity > 0.75). we h~£ed, an a6eept~ble ~efiabirl¢, ~-~r;= '~ . during mechanical ventilation, an air leak (al) and plateau phase duration (pl) may influence dynamic and static compliance (cdy and cst, respectively). this study evaluated the effect of al and pl on two methods of measuring c.dy and est. methods. 13 intubated, ventilated patients in a pediatric intensive care unit were evaluated after obtaining informed consent. patients were intuhated with a cuffed endotracheal tube and ventilated with a serve 900(2 ventilator. cdy and cst were determined using the serve ands~rmedics 2600. objective: evaluate the repercussion in respiratory mechanics and arterial blood gases and the impact of the ventilator adjustments on the auto-peep magnitude. material and methods: the measurement of the auto-peep was performed using an eletronic-pneumatic controlled device with a oclasion valve installed between endotracheal canutla and the ventilator circuit. the d~'ice was connected to a solenoid to detecte the end of inspiratuo phase and thus, the activation of the oclusion valve. the signs of pressure and flow were monitorized using a diferential transducer and it was processed using a pc computer and tmeumoview® software. the stud3 were divided in 2 phases: phase a. where the ventilator adjustments was performed using the routine of the unit and phase b, where the targets of mechanical ventilation were to minimize the auto-peep. static compliance (crs) was ineasured by the single-breath occlusion technique, using a mean of ten occlusions for analysis. passive respiratory resistance measurements and the tidal breathing flow-volume loops were also obtained., while the ventilatory settings were siguificantly reduced soon atier ecmo was started. before ecmo crs measured in all patienls was 0.23_+t).03 ml/cmh20/kg (mean_+sem). for each patient the ecmo course was divided into four periods, proportional to the duration of the treatment, and the best ~alue of crs in each period was chosen for analysis. as shown on the figure. crs significantly improved (*p<0,05) from the second half of the ecmo course in the group of patient that finally were successfidly weaned from ecmo. no change ill compliance was measured in the group of patients who failed to respond to the extracorporeal hmg support our data suggest that compliance measurements during ecmo can be useful togelher with overall clinical evaluation to predict both outcome and duration of cxtracorporeai support in the neonatal and pediatric population. objectives: brain temperature determines the amount of neuronal damage caused by hypoxic insults. thus measuring brain temperature at standardised conditions is in request. we investigated whether brain temperature of neonates varies with head insulation environmental temperature, body activity and time course. patients and methods: we investigated non-invasive brain temperature analogues in 19 healthy prematures tess than two weeks of age in an incubator (gestational age 31.5 + 2.1 wks; x + sd, weight 1653 + 370 g). we measured nasopharyngeal temperature (tnasoph) by a thermistor placed in the nasopharynx via a feeding tube, zero-heatflux temperature (zht) at the temple by a thermistor and healflux transducer, insulated by two pads, as well as rectal and incubator temperatures. patient activity was documented by video taping. measurements were performed during periods of increased insulation 1) by turning the head with its measuring site on to the mattress ( (5) 3 (5) -2 (6) 4 (5) 0 (6) 4 (3) 2.5 2 4(5) 25(10) 20{12) 8(5) 5(10) -2(7) 5 6 38 (22) 112(34)i70 (48)51(27) 20 (18) 5(15) 7.5 3 38 (19) 125(21) t85(29) 120(30) 70(30) 30(20) 10 4 53 (30) 133(28) 182(33) 157(24) 154(34) 110(45) web 2170 (lmg/kg) 5 at 30 rain 3 3 (5) -4 (6) 5 (6) 4 (3) 5 (4) -3 (6) the vehicle had no effect. paf caused dose dependent rise in ao and pa pressure and reduction in flow to lpa (up to 80% like the vascular endothelium, the endocardial endothelium (ee) has a significant impact on adjacent myocytes, and may critically alter myocardial function.~ we have previously shown that ee cells are capable of sensing and responding to hypoxia by the release of prostacyclin (pgl). 2 potassium channels in other cell types have been reported to be oxygen sensitive. to determine whether potassium channels modulate the ee hypoxic response, we investigated the effects of three potassium channel inhibitors on hypoxia-induced pg] 2 release from ee cells. methods: ovine endothelial cells were harvested and passaged onto 30 ,~ microcarriers. cells were constantly perfused with normoxic and hypoxic kreb's solution, and with three potassium channel blockers: glibenclamide (gb, 3 #g/ml), tetraethyl-antmonium (tea, 10 ram) and 4 aminopyridine (4ap, i0 mm), perfusate was assayed for prostacyclin (ria). data were compared by analysis of variance. * p<.05 compared to 3normoxic control; # p< .05 compared to hypoxic control. adrenaline is extensively used for resuscitation in neonates with rds. however, effects of adrenaline on systemic, pulmonary and cerebral hemodynamics have not been defined in newborns with rds. thirteen anesthetized, and ventilated newborn piglets were subjected to repeated saline lung-lavage series while mean systemic arterial pressure (abp), mean pulmonary arteriat pressure (pap), mean left atrial pressure (lap) and mean central venous pressure (cvp), cardiac output and blood flow in the internal carotid artery (ica) were measured. systemic vascular resistance (s~), pulmonary vascular resistance (pvr) and cardiac index (ci) were calculated. sixty minutes after luug-lavage, the adrenaline group (a) (n=6) received adrenaline as a continuous infusion of 1.2 lag/kg/mi, while the control group (c) (n=7) received saline. none of the varlables were changed by saline. however, significant increases in abp (p<0.0001), pap (p<0.0001), ci (p<0.001) and svr (p<0.01) were observed after administration of adrenaline, whiie pvr and ica were not modified. mean±sd for abp/pap (p/a), fvr/svr (p/s) and ci (ml/mirdkg) were: ratios of pap/abp and pvpjsvr significantly increased following infusion of adrenaline. these data suggest: 1) the cerebral perfusion is preserved during the infusion of adrenaline; 2) effect of the adrenaline infusion on the systemic circulation is more pronounced than its effect on the pulmonary circulation in newborn piglets with surfactant deficiency. s demirak~a, ch knothe, kj hagel, j bauer department of pediatrics, justus-liebig-university giessen, frg inhaled no is a short acting selective pulmonary vasodilator. we studied the effects of 80 ppm no and 100% oxygen during heart catheterization in 16 children (age 1 -6 years, median 9 years) with heart defects and elevated pulmonary vascular resistance index (pvri) in order to asses the value of no as a tool of decision making for corrective cardiac surgery. patients were eligible for testing when they were more than one year old and had a pathologically elevated pvri in a previous heart catheterization. intubation, 'anesthesia and muscle paralysis were performed in all patients during testing of pulmonary reagibility. calculations of pulmonary vascular resistance and flow were based on the fick method. response to no was assumed when pvri declined more than 30%, 9 of the 16 patients were responders to no. effects of no and oxygen on pvri, mean pulmonary arterial pressure (mpap) and pulmonary vascular flow (qp) in all responders are described in the table below. cardiac surgery was offered to all responders, and 5 of them were successfully operated. surgery is planned in another 3 patients and parental consent for surgery was not given in one patient. in ebstein disease, during the first days of life, the ability of right ventricle to propel blood to the pulmonary artery is impaired due to high pulmonary vascular resistances. the flow is mainly directed to left atrium through tricuspid insufficiency, right atrium and foramen ovale. to decrease pulmonary resistances and increase pulmonary blood flow, high frequency oscillations, mechanical ventilation, nitric oxide and prostaglandin are required. after few days, a forward circulation is normally established. we cared two newborns with ebstein disease where this approach was hindered by a large pulmonary valve insufficiency. both of them were diagnosed in utero, showing a large tricuspid insufficiency with a non opened pulmonary valve and a ductal left to right shunt. one fetus was hydropic. at birth, blood stream from the ductus arteriosus was directed to the right ventricle through the pulmonary valve insufficiency then to right atrium, left atrium and ventricle, aorta and ductus arteriosus. a low pulmonary blood flow was demonstrated by low mean velocities (10cm/sec). a high reverse flow was seen in descending aorta with a negative flow in the renal artery. both of these newborns were oliguric because of ductus arteriosus steal. pulmonary blood flow doppler evaluation allowed different strategies of ventilation, switching between hfo and conventional ventilation, modulation of pge1 doses, inhaled pulmonary vasodilators (nitric oxide) and surfactant. the hydropic baby died, the other survived after 3 weeks of intensive care complicated by supraventricular arythmia (wpw). in conclusion, during neonatal period, in ebstein disease, a large pulmonary insufficiency leads to a vicious circle where lungs are excluded, inducing severe asphyxia and high pulmonary resistances. the blood is backward propeled from the aorta through the ductus arteriosus to the right ventricle and atria, then left cavities to aorta. arec must be considered when pulmonary blood flow does not increase despite optimal therapy. guti~rrez-larraya f*, mandoza a*, velasco jm*, zavaneua (3**, gatindo a ~, s&nchez-andrede r, s&nchez jl***, mellon a***, mar f***. pediatric cardiology*, pediatric cardiac surgery**, pediatric intensive care unit***. hospital 12 de octubre. madrid. background: transesophageal pacing (tp) is effective and sate both for diagnosis and treatment of pediatric arrhythmias. material and methods. eleven consecutive patients are included. a tri or quaddpolar 6 or 7f temporal transvenous catheter with an interpolar distance of 13 to 22 mm was advanced through the nares and positioned to the point with the largest amplitude of atrial deflection, surface ecg and a bi or monopolar electregram were recorded simultaneously, selecting filters when needed (5 to 100 mhz). pacing was performed with a programmable stimulator (medtronic 5328) beginning with 2 ms and increasing ma to 10 and then increasing up to 9.9 ms. narula method was selected to diagnose sinusal node disfunction (snd) and overdrive pacing to treat tachyarrhythmias. results. tp was useful in all the 11 patients and no complications were observed: in 3 patients a snd was diagnosed (one needing a definitive pacemaker), in two patients with atrial ratter (ripe 1) sinus rhythm was recovered, in one patient with a postoperative junctional ectopic tachycadia we were able to get atrial synchrony with marked bemodinamic improvement, and 5 patients with paroxysmal supraventricular tachycardia sinus rhythm was easily and quickly restored (2 of them recquirad repited episodes of tp until pharmacelogycal levels of antiarrhythmic drugs were raised). mean age and weight were 31 months and 12.7 kg (one patient had 2.1 kg). there was a close relation between height and depht insertion (r= 0.98). mean stimulation parameters were 9,1 ms and 13.5 ma. discussion. in experiencied hands tp is an effective and safe way to treat and diagnose cardiac arrhythmias even in newborns. it should be tried before endovenous pacing is stablished and it is faster than pharmacologycal treatment. bailing g., eicken a., sebening w., vogt m., schumacher g., bl~hlmeyer k.; kinderkardiologie, deutsches herzzentrum m0nchen, germany to assess the outcome of balloon valvuloplasty in infants with cardiac failure caused by critical aortic stenosis a retrospective study was performed. between 1986 and 1995 33 neonates, aged 1 -28 days (median 9 d), weight 2.t -4,1 kg (median 3,3 kg) with critical valvar aortic stenosis were dilated by balloon (aovp) as the first line treatment. 21 patients received prostaglandin el, 18 needed inotropic drugs and 16 mechanical ventilation. associated cardiac lesions : persistent ductus arteriosus (pda) in 27 patients (restrictive pda in 8 cases), a mitral regurgitation (mivr) in 27 cases (15 severe and 12 moderate or mild mivr), angiographic findings of endocardial fibroelastosis (efe) in 12 patients, mitral stenosis (mivs) in 8, coarctation of the aorta (coa) in 2, and finally a small musculary ventricular septum defect (vsd) in i patient. vascular approach for ballooning : a. axitfaris in 20 cases (61%) a. femoralis in t 0 (30%) and v. femoralis in 3 cases (9%). the median ratio between inflated balloon and aortic valve diameter was 0,99. dilatation was achieved in all 33 cases. the peak systolic gradient across the aortic valve (pre aovp) ranged from 0 to 137 mmhg (median 50 mmhg) and was reduced to 0 to 55 mmhg (median 15; gradient reduction is significant (p < 0,01)). aortic regurgitation (aovr) was absent or mild in 30, moderate in 2 and severe in 1 patient after aovp. 23 children survived (actual suwival rate: 70%; early mortalffy: n = 3; late mortality: n = 7). mid term follow up (0-8,8 years; mean 2,7 years) showed an increase of the systolic peak doppler gradient across the aortic valve (median 41 mmhg) but no increase of aovr. 10 re-interventions (re-aovp: n = 3, commissurotomy: n = 2, mitral valve replacement n = 2, resection of subaortic stenosis: n = 1, resection of coarctation: n = 2,vsd-closura: n = 1 ) were performed in 6 patients. rv contractility and pulmonary vascular mechanics(pvm) in immature animal models are poorly underslood. we developed an acute rv injury model to measure rv contractility and pvm in response to commonly used cateehalamines. ten anesthetized piglets (9-12kg) were instrumented with micromanometers in the lv, rv, pa, and la. a pulmonary artery flow probe was placed to measure cardiac output(qpa). ultrasonic dimension crystals were sutured to the myocardium and dynamic chamber volumes estimated using shell subtraction methodology. rv injury was induced with 3-7 cryoprobe injuries at -50 to -70°c for 3-4 minmes each. da at 10mg/kg/min, db at 10mg/kg/min, and ep at 0.1 mg/kg/min were infused in random order. rv contractility was evaluated by calculating a load independent measure of contractility, the preload recmitable stroke work(prsw), during vena caval occlusions. to describe pvm, input resistances), characteristic impedance(z0), total pewer(tp), and efficieacy 03f=qimo"p) were measured. measurements were made pre-and post-injury, during infusions, and between infusions. clyoablation decreased prsw (22.8_+7.8 to 13.8+4.1, p<0.001). at the end of the experiment, prsw remained depressed to this level indicating stability of the model. one factor contributing to organ dysfunction for infants undergoing repair of congenital heart defects (chd) is their "inflammatory response" to cardiopulmonary bypass (cpb). this response is characterized by an increase in cytokine release, complement activation and endothelial injury. modified ultrafiltration (muf) is a method for removing tissue water and inflammatory mediators by rapid ultrafiltration followin~ cpb, muf may acutely improve post-operative end organ function. in this study, we evaluated the effects of muf on the pulmonary and cerebral function of infants undergoing cpb for repair of chd. we prosnecrivety randomized 30 infants (.~ 5 mos) to either muf (n=16) or no muf (n=14)(control) following correction for chd. the study intervals were 1) before cpb, 2) immediately after cpb, and 3) 20minutes after cpb. pulmonary function was evaluated by measuring dynamic compliance (cdyn) and airway resistance (raw). for 13 pts (mue=6 pts; control=7 pts) exposed to a period of deep hypothermie circulatory arrest (dhca), cerebral metabolism (cmro2) was calculated at each interval using the xe 133 clearance technique for cerebral blood flow measurements and arterial and jugular bulb saturation measurements to calculate cmro2. a reduction in cmro2 has been consistently demonstrated after dhca. the effects of muf on cdyn and on cmro2 are shown below: p<0.05 vs pre-cpb; # p<0.05 vs post-cpb • p--o.06 vs. post-cpb this study demonstrates that immediately following exposure to cpb, muf will improve pulmonary compliance. raw was not different between groups. there was no significant difference in hours of post-op ventilation for either group. in those pts exposed to dhca a trend towards better cerebral metabolic recovery compared to control was demonstrated. this is the first technique applied to infants undergoing dhca where cmro2 after cpb was greater than precpb measm~s. although this may be beneficial to postoperative hemodynamics, ventilatory management and long-term neurologic recovery, more patients and longer follow up will be necessary to verify such an effect. the effects of conventional mechanical ventilation (cmv) on left ventricular (lv). diastolic filling in neonates are not well established. one approach to improve lv filling is the use of cmv to provide a phasic increase in airway pressure {thoracic augmentation). this phasic increase in airway pressure may result in an increase in lv filling similar to that which occurs with cpr. thoracic augmentation has not been evaluated in neonates with ventricular dysfunction who frequently demonstrate increased heart rates. attempts to maintain low peak airway pressures during cmv may result in a prolonged inspiratory time that occurs over multiple cardiac cycles. this may alter lv filling in the later cardiac cycles. to determine the effects of inspiratory time on lv diastolic filling, 10 infants were examined with doppler echocardiography less than 24 hrs after surgery for the arterial switch procedtme. pulsed doppler recordings of the millal valve (mv) were obtained with the inspiratory time adjusted to occur over 3 cardiac cycles (21 sec.). a pressure transducer was placed in line with the ventilator, and the respiratory cycle was recorded superimposed on the doppler tracing to provide accurate determination of inspiration and expiration. doppler recordings were obtained from the apical 4-chamber view and the following measurements were made: peak e and peak a velocities, eia ratio, and deceleration time. compared to the expiratory phase of cmv, the initial beat during the iuspiratory phase of cmv resulted in an increase in mv peak e (.53 +-.06 vs .65 -+ .08 m/s, p<0.05) and peak a (.47 + .07 vs .63 -+ .09 m/s, p<0.05) velocities with no change in mv deceleration times (p<.01). compared to the initial beat during tile inspiratory phase, the third beat during the inspiratory phase resulted in decreased peak e (.65 + .08 vs .40 + .05 m/s, p<0.05) and peak a (.63 + .09 vs .40 + .05 m/s, p<0.05) velocities with no difference in deceleration times. thus, cmv augments lv filling during the initial phase of inspiration. however, as the increase in airway pressure is distributed over multiple cardiac cycles, lv filling falls below baseline levels. these observations indicate that while thoracic augmentation may be beneficial, to optimize lv filling the inspiratory time of cmv must be < 3 cardiac cycles. energy expenditure in pediatric orthotopic liver tranaplantat~on, to determine the actual calorie requirements of critically ill children and evniuate the correlations between measured, stress-p~lictod and repleted energy exponditttm and the severity of illness. des/gn: a prospective, dinlcal study. se~ng: tertiary care pediatric icu in a university hospital. patients: ten patients aged 6 to 210 months with disorders prompting picu admission, including sepsis, respiratory failure, solid organ transplantation, and cardiovascular surgery. inta~entions: all patients were studied within 24 hrs of major surgery or transplantation, or following acute illness. all patienls were severely stressed clinically and all but two were intubated by cuffed tubes, in three of them, still in a stress state, the study repeated on the third day of the disease, energy expenditure mensurements (mee), as well as illness seventy scoring systems, mtfltisystern organ failure scores and various anthropemetric and clinical indices of nutritional status, the stress-predicted energy expenditure (s-pee), the basal metabufie rote (pbmr), the repleted energy (re) and the recommended dietary allowances (rda) were measured or calculated in each patient. multiple regression analysis was used to analyze the data. measurements and main results: although the mean mee was significantly lower than the mean s-pee (37.6+11 kcal/kg/day vs. 50.35:16 kcal/kg/day, p<.002), it did not differ significantly from the pbmr (mean difference -2.62 kcal/kg/day, range -10.07 to +9.06 kcal/kg/day). the s-pee/mee ratio ranged from 1.04 to 2.07, while the re/rda ratio (21.25:4 kcal/kg/day)/(75.85:7 kcal/kg/dny) ranged from only .1 to .5. the prism/tiss ratio was not correlated better with mee than the diagnostic category (r~=.36 vs..38, respectively). the re was positively correlated withthe mee (rz=.65, i)=.07) while negative oarrelatian has been found between mee and age, mid-arm circumference, triceps skinfotd and the use of vaseactive agents (r~.81, -88, -.67, p<.005 and -.71 resp~lively). concl.m~: if s-pee is used for caloric repletion in the stressed oritic~ly fll el~d, these patients will be substantially overfed by as much as 100%. although pbmr appears to approximate the mee by ±10%, other clinical and nutritional indices should also be ennsidered. objective: to deter .mine..t.he metabpli.c and.nutritional state of mechanically ventilated intants and children m relatmn wlm severity or msease. patients and methods: 37 mechanically ventilated infants and children, median age 7 months (range 3 days to 13years), were studied. severity of illness was assessed using prism, prism-ii~ and fiss-scores. oxygen consumption (vo2), energy expenditure (mee) and respiratory quotient (rq) were determmed by mdirect calorimetry. total urinary nitroger(tun) and creatinine excretion, levels of albumin and crp were aetermmed in 16 patients. in these patients daily caloric intake and substrate utilization were assessed. they were categorized in subgroups: a partial feeding (recent admission to p1cu); b complete feeding. results: mee of the total group (n=37) 0a) i=intake g/kg/day (% total intake); u=utilization g/kg/day (% total production). nitrogenba]ance was negative in all patients in group a (mean -227.7 --176:4 mffkg/day) and positive in all but one patient in group b (.mean 84.9±109.d n~g/..kg/day;p=0.001). no significant correlations were round between creatinine height index, crp, albumine, jun vs v u2/kg conclusions: the mean measured energy expenditure does not exceed predicted resting energy expenditure, but ~ere is a wide range. in a majority ot patients with complete feeding h.igh carbohydrate intake resulted, in high kq and lipogenesis. in patients witla partial teeding the highly negatwe nitrogen'balance suggests that in the early phase of diseasean higher protein intake should be provided. severity of illness scores ann oiocnemicm markers of physiologic stress correlatedpoorly with oxygen consumption. leite,hp; iglesias, s; faria, c; ikeda, a; albuquerque, mp; carvalho, wb pediatric icu -s~o paulo federal university -s~o paulo, brazil objectives: 1 ) to evaluate patterns of use and monitoring of nutritional support in critically ill children; 2) to evaluate an education program in nutrition support given throughout the resident physician training in the pediatric icu. patients and methods: records of 37 patients receiving nutritional support during 1993 were reviewed. aider this first phase, knowledge and understanding of the role of nutrition support was conveyed to the residents through didactic lectures. in a second phase thedata were reevaluated in 35 children who were given nutrition support in 1995. results: from a total of 425 days ofthempy, the single parenteral route was utilized in 80,5%, the digestive route (tube feeding or oral route) in 19,5%. of this time. a previous nutr~ional assessment was performed in 3 children; no patient had the nutr~on goals set. the nitrogen to nonprotein calories ratio ranged among 1:80 and 1:250. only 29,7% of the patients had their estimated caloric needs supplied and this goal was achieved only in those patients who were on enteral tube feeding. patients did not achieved their goals for vitamins. the supply ofoligonleme~s was adequate except the zinc. nutritional monitoring parameters including weight, serum albumin and serum triglycerides were performed in almost all the patients but without uniformity. the reevaluation ofthase parameters showed adequacy of protein and micronutrients supply; however deficiency in nutritional monitoring and infrequent enteral feeding were still detected. conclusion: there were lacks in the implementation of nutritional support, which were partially corrected in the 2rid phase of the study, although the training of residents may have contributed to give them cognitive skills, it didn't changed policies and procedures as desired. we recommend reinforcement of the education program concerning basic nutritional aspects, and the organization ofa multidisciplinary team in charge of coordinating the providing of nutritional support. plasme free fatty acids (ffa) are the meier energy source for mast tissues. during fasting ffa are released from the breakdown af triglycefides in edipose lissue (at). lipalysis, le. the rote of release o/ ffa, has been megsured in humans by means of stable isotope techniques using labeled pa or glyeerd as traces. no information is avoilob!e io dale on the ro of la. we infused albumin hound u13c-pa and u13c-la in 7 critically ill infants, receiving 20 kcel/kg/doy of iv glucose end na oral feeding (weight 3.6,i.,3 kg;, range 1.9-5.8; ego 57:64 days, range 1 149) and measured simultaneously the ra of pa and la from (he isotopic enrichment of plasma fea by gas chromatography-mass speclrome|ry ai 1:50, 2:00 and 2:10 hours from tile shod of the infusion. a subcutaneous gluted at biopsy was obtained far fatty acid (fa) composition. we intended to (1) in fie infants sbjdied atipa ~'os hi9her than attla (~p<o.o01)' and ihe ra of pa was higher then thai of la (~p=0.00 §). however the ratio el the re's to the respeclive fa in at was higher for la than far pa (*p=0.02). in conclusion the ra af la was higher then expected from ~he fa composition of at. we speculate [hat la is preferentially released during tipolysis and its contributuion to the energy metnbolism of the sick infonl could io !orger than what: is normai!y assumed from ihe fa composilion of at and of plasma fea. preoperative starvation can be prevented in infants undergoing non gi surgery by continuing feeds till as long as it is safe to do so. some gi disorders require withholding of feeds for a long period. for these and for infants already suffering from pem~ parenteral feeds are given preoperatively. peroperatively nutrition is maintained by ensuring adequate glucose supply in the infusion fluid and its smooth metabolism. proper placement of feeding tubes are also carried out peroperatively. postoperative early resumption of oral feeds is ensured by new techniques of anaesthesia and pain relief and methods to ensure early return of peristalsis. enteral feeds of pre digested substances and feeds through transanastomotic tubes and through gastrostomies and jejunostomies can prevent starvation in many situations. parenteral feeding is carried out only when enteral feeding is not possible, for example in necrotising enterocolitis~ gastroschisis, short gut syndrome, high enteric fistula and acute pancreatltls. the artedal ketone body ratio (akbr) is established as a valuable tool in the management of adult patients undergoing surgery for severe liver disease.the redox theory emphasises the central role of the liver in preserving homeostasis and the importance of the hepatic mitochonddal redox potential (nad+/nadh) in monitoring liver function and integrity.the akbr (plasma acetoacetate/3hydroxybutyrate) is a measure of hepatic mitochonddal redox status, reduced ratios associated with poorer outcome. the venous ketone body ratio (vkbr) is influenced by peripheral ketone utilisation and therefore thought unreliable in assessing hepatic redox its use has been dismissed as no correlation with the ratio in hepatic venous blood was found. inspite of this. vkbr is used in the diagnosis of lactic acidoses and respiratory chain defects. the objective of this study was to determine the relationship between the akbr and vkbr in a paediatnc intensive care population. 31 children admitted to the paediatdc intensive care unit, with indwelling arterial and central venous lines as part of their routine care, were recruited for the study. the median (range) age was 2.0 years (0-16.6 years) with prism score 10 (0-36), simultaneous akbr and vkbr were measured. suppression of ketogenesis was confirmed using a rapid 3-hydroxybutyrate strip test (ketofilm, genzyme diagnostics) pdor to sampling. the median vkbr 0.50 (range 0.13-1.46) was lower than median akbr 0.56 (range 0.11-1,33), there was good agreement between artedal and venous ratios, bland-altman analysis giving a 95% confidence interval for relative bias of -0.13 to -0.03. there was a significant correlation between vkbr and akbr r 2 0,8271, p,0.001 (intercept 0.02, slope 0,85) conclusions; values for akbr tend to be higher than vkbr, however there is a consistent relationship in critically ill children. in paediatdc patients in whom ketogenesis is suppressed, vkbr may be considered equivalent to akbr. this simple test may prove to be a useful adjunct in predicting mortality in cdt{cally ill children. to understand the present status of pediatric intensive care in china, we conducted a survey between october and december, 1993, involving 20 hospitals in 14 provinces and municipalities. the results showed that there were totally 41 icus for pediatric patients, including 19 pediatric icus (picu), 18 neonatal icus (nicu) and 4 pediatric surgical icus (sicu), with total of 403 beds. the physicians to bed and nurses to bed ratios were 1:1.5 and 1:0.91 respectively. the average number of equipment per bed was 0.47 ventilator, 0.34 multi-fnnction monitor and 0.47 infusion pump. very few of the icus had portable x-ray machine, biochemical and blood gas analyzers, and hemodialysis machines. the most frequently treated diseases/conditions were pneumonia, intracraniat infections, post-operation and sepsis in picus, and neonatal pneumonia, hypoxic ischemic encephalopathy and sclerema in nicus. pneumonia and respiratory failure accounted for 33.29% and 26.50% of all the diseases/conditions treated in the icus and the mean case fatality rate of respiratory failure was 24.50%. the results of the survey suggest that there is shortage of tcu beds and modern equipment, and treatment is often delayed due to excessively strict criteria for mechanical ventilation. a set of simple, and nationally acceptable criteria for evaluation of severity and cure of the diseases/conditions is urgently required. the medical reports of 286 children were reviewed and each admission was analysed in terms of age, sex, diagnosis, management within the hosp~al, length of hospital stay and type of poisoning. the youngest age was 23 days and the oldest was 16 years. hundred and twelve (39.5%) of the children were girls and 174 (60.5%) were boys. the most common (26.5%) reason of admission was intoxication among all of the cases and the greatest group (73.7%) of the poisoned children had ingested medication which was followed by another group of patients (9.2%) who had eaten mushrooms. the peak incidence of drug ingestion was salicylate intoxication (20%). forty drug poisoninigs were accidental while 16 was intentional. the majority (82.4%) of the cases that committed suicide was between 12 and t7 years old, and the main cause of suicide was being unsuccessful at school. we conclude that poisoning -especially salicylate intoxication -is still a major problem in turkey and we believe that emphasis on the need to stere all kinds of drugs in a secure place and re-examination of a chin resistant packaging should help to reduce childhood poisoning significantly which is a preventable condition. included were all patients who died in the hospital, except those treated in the neonatal icu (predominantly premature and sga newborns) and those who died in the emergency room. among a total of 7179 hospital admissions (excluding the neonatal icu and emergency room), 99 patients died (1.4%). of these 99 patients 73 (74%) died in the pediatric icu, 18 (18%) in the ward and 8 (8%) in the operating room. a chronic underlying disease was present in 66 (67%). withholding or withdrawal of therapy was implemented in 48 (48%) children, 27 (27%) died due to failed cpr, 20 (20%) were brain dead and 4 (4%) died following a dnr order. justification for therapeutic restrictions in the 52 patients of the dnr and w/w groups was imminent death in 32 (62%), lack of future relational potential in 12 (23%) and excessive health burden in 8 (15%). withdrawal or withholding of therapy was carried out by extubation in 46%, vasoactive drugs were stopped in 25 %, and mechanical ventilation was withdrawn in 21%, analgetics and sedatives were frequently used (in 73% and 79%, respectively). hence decisions concerning restrictions of treatment are common in pediatric practice, mostly due to imminent death. patients in which treatment was restricted were characterised by a longer hospital stay, a worse prognosis, a higher frequency of chronic underlying diseases and a lower acute mortality risk. despite restrictions of intensive therapy, most patients were allowed to die in the pediatric icu. background microalbuminuria (mca), a subclinical increase in urinary albumin, reflects glomerular and overall vascular permeability 1"2. an increase in urinary excretion of albumin occurs after burns and trauma. transcanillary albumin escape rate is also increased in response to elective surgery 3 and in critically ill adult patients 4. we investigated a possible relationship between urinary albumin levels and clinical instability, as measured by pediatric risk of mortality (prism) scores. method we studied 26 consecutive patients (median age of 13 months, range 2-100). patients whith nephropathies or any abnormality of urine analysis were excluded from the analysis. prism scores, mca (mg.1-1) (immunonepbelometric) and urinary creatinine (cu) (mmol.l -!) (jaffb) (48 hour collection sample) were determined within 48 hours from admission to the picu. the mca/cu ratio (mg.mmol.1 "l) was used to correct for urine output variability. diagnoses included respiratory failure (6), postoperative (5), neurologic (5), sepsis (4), trauma (3) and miscellaneous cases (3). pearson's correlation was performed to correlate data. results and conclusions. mean prism score and mca/cu were 16.9 ± 5.9 sd and 1004-39 sd, respectively. a significant correlation was found between mca/cu and prism scores (r=0.80, p<0.001). our observations show that, independently of the initial insult, the paediatric unstable patient may have increased capillary permeability, which is correlated with the degree of physiological derangement, as measured by prism scores. microalbuminuria can be rapidly determined since it is routinely used in the management of diabetic patients, it is inexpensive, simple to measure and blood-spearing. therefore, it might have a role in the clinical assessment of capillary permeability and transcapillary albumin escape worldwide the demand for paediatric intensive care services exceeds the supply. in developing countries sporadic access to such services alters expectation of care and can lead to children being either mechanically or handventilated in general paediatric wards. the outcome of children requiring ventilation in a major teaching hospital in india was reviewed.children were ventilated on an adult intensive care unit (aicu) if a bed was available, otherwise in the general paediatric wards. over a 4 year period 109 children were ventilated on aicu with 54 deaths. yearly mortality rates varied between 43-58%. over a 3 month period 37 patients were ventilated on the paediatric wards. of the 15 p~tients over 4 weeks of age 11 died (chi squared 0.t >p>0.05) reasons for the higher mortality rate on the paediatric ward likely include the higher patient:nurse ratio, and more limited resources. a predictor of mortality based on simple physiological observations without the need for expensive blood tests and including chronic health status would be a useful tool. the establishment of a paediatric intensive care unit is proposed to redress the balance of care. to assess the performance of the pediatric intensive care unit of hospital dona estef~nia by an international standard score, the authors did a prospective study of 1149 consecutive admissions to the unit during a period of 29 months. mean age was 50.63 _+ 54.07 months; mean lengh of stay was 3.16 + 5.59 days. the effectiveness and efficiency were determined by the admission prism. admission efficiency was defined by two criteria: a) mortality risk > 1% or b) the administration of at least one intensive care unit-dependent therapy. the cumulative observed mortality was 5.57% and the expected mortality was 5.97%, with a standardized mortality ratio (smr) = 0.933. the overall performance of the prism score-based predictive model was found to be good (goodness-of-fit test x2 [5] = 6.387;p=0.271). of 1149 patients admitted, combining the two criteria (icudependent therapy and mortality risk) an admission efficiency of 825 (71.8%) was found, equating to 3263 (89.94%) of 3628 1cu days. conclusion: in our study the assessment of the admission efficiency and of the effectiveness of the unit was possible by using the prism score of admission. there was no significant difference between mean values for otiss and ntiss)in level l patients (p=0.12 paired t-test).for level 2 and 3 patients mean value of ntiss was greater than otiss (p<0.0001). there was a significant correlation between levels using either ntiss or otiss (mean difference level 1 and 2, level 2 and 3, ( p < o.oool). conclusions: a new tiss has been developed and used in a picu. nurses were able to accurately score the interventions on their shift. the assignment of patients to intensive care levels correlates with tiss values allowing a quantitative measure of severity. objective : to compare the rate of cerebral palsy (cp) between monochorionic-twins, dichorionic-twins and singletons born at 25 to 32 weeks' gestation. design : two-year prospective cohort study. setting : geographically defined study (region of franche-comt~., france). main outcome measures : type of plasentation was obtained by anatomopathological, or macroscopic examination of placenta and comparison of 6 twins' blood-groups. neurological assessment was performed at two years of age (uncorrected for gestational age) by family doctor (pediatrician or physician), or neonatologist of the icu at tertiary center. sample : 167 of 17i survivors aged of two years (98% follow-up rate), born between 09/30/90 and 10/01192. triplets and chromosomic malformation were non included. results : thirteen (11%) of the 119 singletons had cp.vs 3/29 (10%) of dichorionic twins and 6/19 (32%) of monochorionic twins (p=0.04). four of the 19 monochorionic twins (21%), 2/29 dichorionic twins (10%) and 4/119 (3%) nngletons suffer from quadriplegia (p<0.01).in a multivariate approach, monochorionic twin placentation was the strongest risk-factor of cerebral palsy (or=9.7, ic 95% = 2a-39, p<6.01). others risk-factors of cp were : lack of father's profession (or 11, p<0 .03), maternal antecedent of abortion (or 3.2, 1-10, p<0.04), vaginal delivery (or 3.4, 1-11, p<0.03), hyaline membrane disease (or 3.4, 1.2-t0, ~0.02). discussion : this is the first population-based study to uplight the role of monochorial twin-placentation as a strong risk factor of cp for premature infants. cp is more severe in monochodonic twins than in other infants. mecanism of cerebrat deficiency is not clear since none of our infants with cp was survivor of an in utero cotwin's death, and none of these infants was exposed to twin to twin transfusion syndrome. were these monochorionic-twins affected by an undiagnosed neurological structural defect that could lead both to prematurity and handicap remains an open question, a vital role of the intensivist is to ensure that knowledge and practice are imparted to trainees in the icu so that patients receive optimal care. teaching effectiveness varies widely leaving gaps in knowledge and practice in the trainee. being an effective teacher should not be a "gift" of a privileged few. the icu provides a fertile ground for using a variety of methods for teaching, e.g. didactic, at the bedside, emergencies, and in the performance ofproeeaures. in this environment, much can be learned. we have embarked upon a program to facilitate this learning process. i) teaching needs to be recognized as the foundation of good clinical care, i.e., patient related, and in its ability to generate discussion and research investigation. 2) teaching structurally has many components including the speaker, audience, varying situations, and the message delivered. 3) establishment of a program using these components to enhance teaching abilities at all levels, a) evaluate base-line teaching skills initially, b) individualize interventions to improve teaching skills, e) demonstration of learned skills with re-evaluation. this process is analogous to the analysis of a clinical disorder in a patient which, once recognized, interventions are then instituted and then re-evaluated. 4) instill the desire to use these attained skills to teach and interest others to teach. teaching excellence should be recognized through awards, honors, and academic advancement. a major emphasis of this program is to provide participants with skills necessary to teach thought processes, decision-making skills (what to do, what to avoid) and implementing appropriate management during stressful emergency situations common to the picu. introduction: many" e-mail based discussion groups exist on the internet to provide medical professionals with a rapidly responsive medium for the international exchange of ideas relating to patient care. several such lists each serve more than a thousand professionals in more than 30 countries, each distributing a dozen or more messages each day to every subscriber. there is very little known about the time being spent by professionals interacting with these lists, and very little known about the impact of the discussions on patient care. we wished to test the hypothesis that these discussion groups provide infortuation which is being used to change the care of individual patients and the general approach to patient problems. methods: in early january 1996 a pilot electronic survey was sent to a small fraction (n=63) of the memberships of 2 e-mail discussion groups, picu@its.mew.edu, and nicu-net@u.washington.edu (the full memberships of both. groups (n=t439 for nicu-net, n=1045 for picu) will be surveyed in early february of 1996). participants were asked for demographic information, experience and skill level relating to e-mail, time spent with the discussion groups, perceived usefulness of different types of discussions, and the ways in which the discussions were used clinically. the pilot study was analyzed for construct validity by correlating an overall assessment question with a summary of the specific questions. scale reliability was measured by cronbach's alpha statistic. results: the pilot survey response rate was 30163 (48%). the majority of respondents were male physicians, with an average age of 39+_5 years, who had completed subspecialty training in intensive care, and were working at a university-affiliated hospital. most had been using e-malt for more than 6 months, and considered themselves moderately adept in that use. 63% felt that the list helped weekly to keep them informed about current issues and practices in their field(s), and 57% felt that, at least monthly, they used information from the list(s) that was not readily available in medical journals. overall, 75% agreed that the list improved their professional competency. when asked to compare the value of 6 months of membership on an e-mail discussion group with more traditional educational media, 34% compared it with attending a national conference, and 26% compared it to a journal subscription. cronbach's alpha was .76, construct validity testing yielded coeff=.50, p <.05. conclusior~: internet-based e-mail discussion groups for health care professionals can be an important part of a strategy for maintaining professional competency. despite the very low cost of this medium for most, the value is felt to be comparable to that of t~r more expensive forums for education. further study will include distribution of the full survey in early february of 1996. fronk shann, tony slater, gale pearson and the pim study group we have developed a new score for predicting the risk of mortality in children admitted to intensive care. the score is calculated from only seven variables collected at the time of admission to icu: mechanical ventilation (yes/no), booked admission after elective surgery (yes/no), the presence of any one of 14 specified underlying conditions, both pupils fixed to light (yes/no), the base excess, the pao 2 divided by the fio2, and the systolic blood pressure. most scores used to predict outcome in intensive care require the collection of a large number of variables (so many icus do not calculate them routinely), and they use the worst value of each variable in the first 24 hours in intensive care. this means they appear to be more accurate than they really are (about 40% of child deaths in icu occur in the first 24 hours -so they are diagnosing these deaths rather than predicting them), and they blurr the differences between traits (a child admitted to a good unit who recovers will have a low score; but the same child who is mismanaged in a bad unit will have a high score -the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients). pim was developed in the picu at the royal children's hospital in melbourne, and has been tested in six other picus in australia and one in the uk. objectives: to study the characteristics of the muhiorgan dysfunction syndrome (mds) in children. methods: a retrospective study with all the children with mds diagnosed from january 1990 to june 1995 is presented. 173 children fulfilled the wilkinson criteria (i). in all of them the number of organs affected and the prims score were determined during the first 24 hours. several groups were performed according to the clinical diagnosis, the hospital of origin and the order of organs affected. results: the 173 subjects studied were an 8% of the pediatric intensive care unit admissions. 100 of them expired (58%). no differences in age, sex and weight were observed between the children dying and the survivals. the most common causes of mds were sepsis, both nosocomial (25%) and medingococcal (i4%) and acute respiratory failure. sixty-fivepercent of the patients were from the hospital wards and the remaining were directly admitted to the pigu from the emergency room. the systems affected were: respiratory (93%), cardiovascular (92%), hematologic (61%), central nervous system (52%), renal (43%) and (hepatic) liver (28%). the organs initially failing were: heart (39%), tung (28%) and central nervous system (18%). the children dying had a larger number of organs with failure than the survivors (3.89 v,s. 3.34, p<0.001).the prmis score was higher in the children expiring than in the survivors (22.4 v.s. 17, p <0.001). s.mmary: the mds is a common pathology in picu, with a high mortality, the mortality is higher in children with a larger number of organs affected and a higher prism score. sepsis is the most common etiulogy. methods : from june ist to july 15th 1995, all patients admitted to the pediatric icu were included. the score was measured at day 1 (d1) and day 3 (d3) and we used 10 variables. for each organ system, we defined 2 categories : dysfunction or failure, which we respectively confered 1 or 4 points. results : 56 patients were admitted : 22 newborns, 34 children. 23 were medical and 33 were surgical patients. 36 (64 %) patients had two or more organ failure at the admission, 12 (21,4 %) patients died, which 6 (50 %) in the first 48 hours. the mortality rate was the same for children with two or more organ faiiure at d1 and d3 : 6/36 (16,6 %) at d1, 4/22 (18,2 %) at d3. the mean score is different for children who survived or who died : 8,6 versus 17,9 at d1 ; 10,6 versus 18,2 at 133. when the score is > 15, the mortality rate is significant. conclusion : in this study, there is a good correlation between the score of severity and the mortality rate but we have few included patients. we need a prospective multicentric study to assess these results and we must compare this score to other scores of severity used in picu. back.qround: injury to the central nervous system is the cause of death in the majority of pediatric trauma victims, studies have identified a wide range of factors associated with poor outcome from brain injury. however, when single features are analyzed, they are not sufficiently accurate predictors. few studies have used a multivariate analysis of these factors and pediatric outcome, methods: clinical and radiographic features of 164 comatose children after traumatic brain injury were analyzed, clinical parameters, the initial cranial ct scan, and demographic characteristics were analyzed for an association with death or vegetative survival at 6 months. a tree diagram in which risk factors may differ within the study subpopulations was constructed using recursive partitioning. results: chitdren with a motor score _<2 had an 11-fold increased risk of poor outcome compared to those with motor scores >2. among patients with scores of _<2, those with abnormal pupillary reflexes experienced a 13-fold increased risk of death compared to those with normal pupillary reflexes. among patients with a motor score >2, an intracranial diagnosis code (no pathology, mild shift _<5 mm, swelling, shift >5 mm, surgical mass lesions, or non-operative mass lesions) was highly predicative of poor outcome at 6 months. children with ct findings other than normal or mild swelling had a 4-fold increased risk of poor outcome. of children with swelling, shift or mass lesions, the pupillary light reflex was associated with outcome. children with abnormal pupils had a 6-fold increased risk of poor outcome. discussion: a few clinical and radiographic features stratified comatose children into fairly distinct risk groups. information available early after traumatic brain injury in comatose children provides useful prognostic information on the likelihood of death or devastating injury. a retrospective study of 70 children with the diagnosis of epidural hematoma was made during 1990-1995 period. ages ranged between 7 days and 17 years (18% less than 1 year, 40% between 1 and 10 years, and 42% older than 10 years), 82% of them were admitted at the picu. 51% of the cases were due to falls, 35% to road traffic accident and 14% to other causes. on admission gcs was less than 8 in 19% of the cases and more than 14 in 53%. diagnosis was made during first 4 hours in 63% of patients and delayed more than 12 hours in 28% of them. neurologic impairment was present at admission in 33% of patients, and delayed in 30%. even so,27% remained without impairment. radiological findings at first ct were skull fracture (68%); epidural hematoma localization was: in the right side (63%), frontal area (24%), temporoparietal (66%) and occipital (t0%). associated lesions were: several (13%) or unilateral (51%) cerebral contusions, diffuse brain oedema (10%), unilateral hemispheric oedema (14%) and 38% showed shifted middle line. four patients died, half of them during the first 24 hours. 41 fully recovered (58.6%) and 25 have sequelae of different nature :7 were left with severe motor disability (10%); at the follow-up t3 have some degree of neurodisability. next datas keep correlation with death or neurosurgical impairment: only were significative multiple cerebral contusion (p=0.002) and brain oedema (p=0.05), gcs less than 8 at the admission (p--0.002), shock (p=0.003) and remaining cerebral contusion in control ct correlated with death or diasability at discharge. on the other hand, neither surgical drainage volume nor first or highest levels of icp (12 cases),nor pupillary abnormalities (10 cases) correlated with worse prognosis. conclusion: gcs equal or less than 8 an shock are main factors related to worse prognosis, also multiple cerebral contusions in ct and diffuse brain oedema. the results of a modified gcs were compared to outcome and intensive therapy in 78 children (mean age 8,5t4,7 years) with head and associated injuries (53,6% of all cases) of different causes (traffic accidents, falls). the gcs was regularly used inn the course of intensive therapy. according to our own and other experiences the gcs was divided in 3 stages: stage 1 (4-8 points), stage 2 (9-12 points) und stage 3 (13-19 points) palhuiugy wile sp, tdhlg c~'lcb1al blood ~0w. sabgcqucntl}. rhc slat,: rerltncd to t1011tl,91 iiltlils. the p0st,~pem~v~ b}i~g wij!!,:q1! ,:_a!~p!ica!j0n~:. 4 ri~;¢ ill the level of sensibflizatjou lo tile cerebn~ anhgrns up to 1t.4-o7 was flofcd iu 9 i,alicnts. there wa.~ al~ iuclt~a~e ill cerebral vdociij,. ~m d~;'ati0a il~ p¢fiphc~ai re~ista/isc of the large ce~'bral ve~ds. neur0h;~c ~:yn'.pt,m~at0!a~, (s::mno!en~', _r_uscu!~r l~:pot0ni& !ryper*'flema) was nbserwed tu lt~ese pal~enls o. cbruc~l ~0nnds. rile ple~c.ut abse~vafion~ suggesl ihal die ~tttdy at" ihe stale ~f hematocr~chcplm/itic bm~ic~ in ckil&en with 31110on emergensy is of abviou.~ !?ece~sib; in co~.te ctin g severe pa~0lo2~-i~mnediately f0u0wing ne ,:~per,'~fion. background: reconstruction of the heart by three-dimensional (3d) echocardiography provided new information on anatomy of complex congenital heart defects, we assessed the utility of 3d ultrasound in detecting morphological changes in cerebral anatomy in newborns before and after cardiac surgery. methods: transfontanel cross-sectional ultrasound, scans were obtained in standardized coronal and median sagittal planes. subsequently, rotational scanning was used to acquire the multiple sequential crosssections of the brain. for rotational scanning, a conventional 5 mhz transducer was rotated 180 degrees.scanning took less than one minute and required no sedation, data was stored in the image processing computer which allowed for off-line three dimensional reconstruction of different brain regions.twelve infants aged 3 -21 (median 7) days were assessed before and after cardiac surgery, results: cavity of lateral ventricle, choroid plexus and the periventricular brain parenchyma could be reconstructed in all. accurate estimation of size and volume of lateral ventricle, aqueduct, and other ultrasonographic visible pathological brain lesions could be performed. reconstruction of various brain areas was accomplished in 3-10 minutes. the localisation and extension of severe periventricular hemorrhage which was detected preoperatively in one infants was better visualized than in conventional ultrasonography. epicortical and subarachnoidal space could be reconstructed in all and allowed detection of hemorrhage in one case which was not detected by conventional ultrasound. conclusion: 3d reconstruction of different areas of the brain may provide additional quantitative information on size and volume of the internal ventricle and choroid plexus, and better understanding of the topographical aspects and the extension of intra-and periventricular hemorrhage than conventional cross-sectional ultrasound. introduction: intracranial cerebral blood has been estimated to be 70% venous, the invasive measurment of venous blood saturation in the jugular bulb provides quantitative information on cerebral oxygen supply and consumption. however, routine oxymetric measurement of blood saturation in the jugular bulb by insertion of a catheter line into the internal jugtdar vein is an invasive procedure which has limited use especially in infants and young children. thus the aim of this study was to investigate the correlation between the non-invasive spectroscopic measurement of rso2 and the oxymetric determination of the blood saturation in the jugular bulb in infants and children undergoing routine cardiac catheterization.. methods: during routine cardiac catheterization 30 infants and children (age 5 day-16 year, median 4,5 year) the rso2 was measured continuously using a two chanel cerebral oxymeter (invos 3100a). the sensor was placed in standardized location at the left temporal head side. after the routine oxymetric blood sampling in the superior vena cava the oxymetric catheter was manupilated into the left jugular bulb. after control of the catheter position simultenuous values of the rso2 were documented. results: over a range of (33-87%) sjo2, a significant linear correlation was found between the spectroscopic measurement of rso2 and the oxymetric determination of venous blood saturation in the jugular bulb (r=0,83, p<0,001) and the superior vena cava (r=0,65, p<0,05). no significant correlation was found between rso2 and the arterial blood saturation in the descending aorta and as well as to the standared hemodynamic parameters. conclusion: meusurement of rso2 by mrs may provide continuous non-invasive information on cerebral venous blood saturation and thereby possibly on cerebral oxygen supply and consumption in infants and children. these may be of clinical value particulary during and immediately after heart surgery by means of non-pulsatile cardiopulmonary bypass. information on refractory status epilepticus (rse) from developing countries is scarce. we analysed 43 cases of rse admitted over last 2 yrs. the objective was to study etiology end evaluate efficacy of diezepam infusion. median age of the patients was 1.25 years irange 1.5 months to t 1.5 yrs); 70% were boys. onset of seizures was 1-t44 hours (median 24 hours) prior to hespitalisation. the glasgow coma scale score ranged from 3.11 (mean+sd 5 + 2). the commonest underlying causes were acute cns infections (26/43, 60%; bacterial meningitis, 16, encephalitis, 10) and epilepsy (8/43, 10%). oiazepam infusion in incremental dose (range 0.01-0.025 mg/kg/min) was used in 38 patients over 3.4_+2.1 days. seizures were controlled n 31 (82%), mechanical ventilation was required in 10 (26%)only, while none had hypotension; 84% patients survived. thiopental infusion (holus 5 mg/kg followed by 0.2 mglkg/min, and increments of 0.1 mg/kg/min till seizure control) was used in 8 patients over 1.7_+0.7 days; seizure were controlled in all, but five patients needed mechanical ventilation, six developed hypotension needing infusion of vasopressoi drugs, 3 out of 8 (38%) died, overall mortality was 26%, mainly due to acute cns infections (n-6) and prolonged se. the patient was a 2-year-old gift di~aosed of dov,~'s s~drom¢, tetralogy of fallot. (t.f.) before admission a vasovagal crisis after coughing and vomiting was seen, and she was taken to the emergency room. mother said she had eyanosis in the mucous membranes of the mouth with exercise.on physical examination, she ~as afebrile, normal fundi and neurologic examination was normal. a harsh systolic murmur was hear~ with decrased intensity during bradycardia. chest rx disclosed a decreased pulmonary vascular markings. ecg: synus rhythm, with bradycardia and nodal escape rhyflmas. she was transferred to our picu because of severe h3,pertomc seizure, lost conciousness, and deeembrate poslamng~ ~t cyancx~is. the episode lasted for ~weral seconds, and ceased v~th diazepam. on admission she was lethargy, and neurologlc exammation showed weakness of left leg without babinski, and normal funduscopic. the patient had two episodes of bradycardia and isoproterenol was begun. during those episodes the patient was cyanotic, and the murmur was heard with the same intensity. act scan disclosed a tight parieto-temporai abscess with midline shift, lnmediately after the diagnostic ct, we administered antibiotics, antiedema treatment and it was drained. the abscess culture was negative. a ct control disclosed air and midlme shift. ~ the next two days she had three episodes of h39oxia and c'yauosis ceased with o@gen, morphine and propanolol the patient died during a fourth episode. discussion: arrhytmias are uncommon in patients with tetralogy of fallot before surgery. in our case the first diagnosis was sick sinus syndrome vs bradycardia secondary to cyanotic episodes. the incidence of cerebral abscess in children with congenital heart disease (chd) is approximately 5%. tetralogy of fallot is the most common associated lesion, and is unusual in children under 2 years of age. conclusion: 1) brain abscess is a rare complication of patients with cyanotic chd, but should be suggested in patients with °'apparent" sick sinus syndrome. in patients with down's syndrome, t.f.,with cyanotic episodes, and difficult neurologic exploration, a brain ct scan is recommended. guillain-ba~re syndrome (gbs) is an acute autoimmune reaction, directed primarily toward the myelin encasing the peripheral motor nerves= this reaction causes a delay or block in nerve conduction. the presentation often can be very subtle but is followed by rapid loss of neuromuscular power, leading to acute respiratory distress, resulting from weakness of muscles and aspiration pneumonia. there were 3 boys -4, 8, and i i years old with gbs, treated in our icu. two of them due to the respiratory distress were intubated nasotracheally and ventilated mechanically with servo-9ooc (siemens-elema, sweden) ventilator. duration of ventilation was i i and 34 days, respectively. plasma exchange was performed in all cases. the numbers of plasma exchange sessions were 2-4 in each case. mean amount of plasma exchanged per session was 28,24 ml/kg. plasma was substituted with albumin, plasma or saline. the most important aspect of the management of patients with gbs in the icu involves the airway care, prevention and treatment of aspiration pneumonia and the mechanical ventilation if respiratory distress presents. endotracheal intubation should be performed whenever there is evidence of retention of pulmonary secretions, refractory to chest physical therapy, weakness of protective reflexes of the airway, leading to aspiration pneumonia and (or) atelecr~sis. cardiac arrhithmias too, is a main threat to the circulatory stability in gbs. therapeutic plasmapharesis has been shown to be beneficial, reducing the time for weaning from the ventilator and for achieving independent ambulation. however, plasma exchange is expensive and not without significant risks for the patient. some authors find that plasmapheresis is not effective for patients with fulminant course of gbs and blocking of nerve conduction. recent studies have demonstrated that intravenous high-dose immunoglobulin can be equally effective. there were no significant complications associated with plasma exchange. all presented patients survived without residual disability. tetraparesis associated with long-term paneuronium use in an infant. paneuronium is a muscle relaxant used in ventilatory management of patients with respiratory distress in intensive care unit. after the end of sedation some patients were found to have severe tetraparesis. paresis was accompanied by complete areflexia and diffuse atrophy of alt extremity muscles. this neuromuscular complication is caused by prolonged high-dosage pancuronium treatment. in the last 5 years, numerous reports have linked the use of pancuronium bromide with prolonged paralysis, disuse atrophy and areflexia. this side-effect is well known in adults patients but rare in a pediatric intensive care unit. we describe one pediatric observation of tetraparesis after prolonged pancuronium treatment in a 9-month-old girl, this female infant developed respiratory distress syndrome and was intubated and mechanically ventilated. to decrease chest wall rigidity pancuronium bromide was administered during 11 days. (she received approximately 120 mg of pancuronium bromide). on day 12 the drug was discontinued and the patient had severe tetraplegia and areflexia with normal head movements. electromyograpliy showed absence of any disorder of neuromuscular transmission. this infant showed a recovely of muscles after 3 months. the other causes of peripheral neuropathies were eliminated. electroencephalograms and head scans were normal. the recovery pattern observed in our patient correspond to the process of regeneration after axonal degeneration. it is suggested that these neuromuscular complications were caused by prolonged high-dosage pancuronium treatment (associated with cortieoid and aminoglucosides). polyneuropathy syndrome in adult lc.u. appeared in literature in 1984 and is extremely common in long stay cases. the etiology of these disorders remains elusive. it is tempting to ascribe them to administration of drugs (muscle relaxants, steroids, aminoglycosidea), plolonged immobility, malutrition, sepsis and ischemia associated with reperfusion injury. to our knowledge there is only one case report of similar condition in a children i.c.u. (pascucci 1990) we present a serie of 16 previously healthy children, aged 9 months to 13 years, who admitted in i.c.u with respiratory failure and who following weaning from m.v, remained in profound diffuse hypotonia with proximal and distal muscle weakness for various length of time, recovery of muscle strength occured in a week or months {the longest i0 months), all children, except one, 3-4 days before admission developed symptoms of either respiratory or upper airway infection with fever. on admission viral and bacterial cultures were positive in 2 cases (haemophilus influenze, herpes virus). during treatment 9 patients became septic. muscle histological and neurophusiological investigations have not been done. considering the multifactorial nature of the aquired nmd in adult critically ill pts, is impossible to attribute the muscle weakness of our pts to any specific cause, in conclusion, our findings suggest the need for further investigation of nmd in critically ill children treated in i.c.u. a van esch, ha van steen~l-m011, ir ramtal, g derksen-lubsen, idf habbema. febrile status epilepticus (fse) is a prolonged and serious febrile seizure. little is known about the outcome of fse in neurologically normal children. this survey involved patients between 6 months and 6 years of age who had visited due to their first fse, the sophia children's hospital during the period of january 1981 till december 1991. patients with a history of neurologic disorders were excluded. 57 patients were identified, 65% were male. the cause of the fever remained unknown in 51% of the cases. in all case the fse was generalized and it most frequently occurred at night (47%). the mean age at fse was t.6 years (0.5-4.7), the mean temperature 39.6°c (38.5-40°c). the mean follow up time was 1.7 year. twelve children (21%) had neurologic sequelea. the neurologic sequelae varied from speech deficit (4 case mild, v2 -1 year delayed; 4 case moderate > 1 year delayed) to severe retardation and epilepsy (4 cases). speech deficit was detected after a mean period of 6 months (range 0-18), age, gender, temperature, family history and time of onset were no significant risk factors for neurologic sequelae. duration of seizure [rr 3.0 (0.8-11.3)] and more than two drugs to treat fse (rr 5.2 (t.5-18.1) were related to neurologic sequelae. we recommend that fse children should be followed for at least a year to detect possible speech disorders properly and start early intervention. unusual presentation of myasthenlg gra%qs ibtza e. modesto ,v~ abe~gochea a, sanch]s 1l all, go l varas k folgado s, garcia e. p.1.c.u. la fe, valencia. spain case report: the patient was a 2-year-o!d gift transferred to our pic because of severe respiratory failure. the patient, convaleseem of ehiekenpox, came into contact with horse manure previous afternoon. in the morning, she was lethargy, and irritability, with poor finding, and ~ an episode of coughing, cyanosis and acute respiratory failure after mucous vomiting when she was drinking milk. on admission she had severe respiratory distress, respiratory acidosis, and the sat 02 was 86%. she was mtubated without difficulty, and was transferred to our p.i.c.u. physical examination reveals stable hemodynamies, pupils equal, round, reactive to light, normal fandi, and muscle relaxation. crusted vesicles diseminats~d. rhonehi over both lungs. hepatomegaly (+) and splenomegaly (+). ~lhe urine, hematologic, and c.s.f. laboratory findings were normal. c.t. scan of the brain, e.e.g., and ekg. revealed no'abnormalities. rx chest disclosed a retrocardiac atelectasis. speci~ts of stool and blood were obtained for cultures and study of c. botul#num toxins. pending receipt of these results, a broad-speotmm antibiotic and acyctovir was begun. the initial differennal diagnosis consisted of laryngospasm associated with aspiraqlon, botulism, and postmfecfious varicella encephalitis. after 15 hours, weatm~ was begun. the neurologic examination showed a low modified glasgow coma ~ale (mgcs), generalized hypotouia and muscle weakness. these data suggested three diagnoses, posfnfecfious encephalitis, residual neuroumsoaar blockade, and excessive doses of sedative and analgesic drugs. after 20 hours she regained skeletal muscle poxver and ufltlcient respiratory effort, the mcgs was acceptable, and blood gases were normal. she was given n~-tigmine and atropine, and her tr~ma was extubated. an acute respiratory failure ocurrs 120 ram. after. chest radioga'aph disclosed a left inferior lobe atelectasis. after 20 hours weaning begun~and the same episode w~as seen. at this point her mother stated that the girl showed weakness of the eyelids or extraneular muscles. it suggested myasthenic syndrome vs ~-barr6 syndrome. c. botul#num toxins were negative, chotinesterase level ~as normal. edrofoinum test ~as positive. anti-acetyleholine receptor antibodies were negatives. e.m.g. confirmed myasthenia gravis (congenital vs juvenile serenegative). pyridostigmine was begun and the trachea was extubated without complications. conclusion: din the differential diagnosis of weamng failure we must consider ~c gravis~ 2)myasthenia gravis could resemble encephalitis, because of low ocs, overall if is triggered by viral infection. 3)in some diseases (this case) gcs could not he an aemuate index of mental state. a burguet*, a menget*, e monnet**, a gasca-avanzi*, c fromentin*, h allemand**, jy pauchard*, ml dalphin*. * r4animation infantile potyvaiente chu st jacques 25030 besancon cedex. ** d~padement de sant6 publique 25030 besancon cedex, france, objective : to point out that strabism is) of one-year-old premature is a good predictor of a poor neurological outcome at two years of age. design and setting : two-year prospective cohort study and geographically defined study (region of franche-comte, france). main outcome measures : neurological assessment was performed at one and two years of age (uncorrected for gestationnal age). a mailing questionnaire was sent to the famity and fuu-filled by thefamily doctor (pediatrician or physician), or neonatologist of the icu at tertiary center, s was diagnosed at one year of age by the examinator but s was not used to diagnose cerebral palsy (cp). sample : 161 of 171 survivors (94%) evaluated at one and two years of age. results : correlation of one and two years neurological evaluation is weak (kappa=0.5). correlation of s at one year and cp at two year is fair (kappa=0,72). the goal of this paper is to review evidence related to hypothesis that the "waiting" axons and cells of the transient subplate zone may participate in the structural plasticity of the human cerebral cortex after perinatai brain damage (kostovic et al, metabot brain res4:17, t989) and to correlate this phenomenon with different forms and mechanisms of structural plasticity. it is our basic assumption that all lesions occuring during cortical histogenesis will lead to more or less pronounced structural reorganization. here we show that various components of the subplate zone participate in several forms of the structural "plastic" responses in the human cortex: modification of convolutional pattern, changes in size of cytoarchitecturat areas~ columnar reorganization, dendritic and synaptic plasticity. the etiological factors which induce lesions and subsequent plastic changes act via the following pathogenetic mechanisms: * disturbances of radial unit formation (rakic); * changes in ingrowth of afferent fibres; * changes in the rate of normally occuring reorganisational events, depending on the critical period for a given histogenetic event. in the present study developmental lesions (localized perlventricular leukomalacia and haemorrhages) were demonstrated by ultrasound in live-born infants ranging between 26 to 40 weeks of gestation. in younger infants (24-34 w) who died shortly after birth, examination revealed lesions of the white matter with the preservation of the subplate zone. in infants who died one week of more after the lesion, we have observed localized micropolygyria, cavities, condensed layer vi -subplate zone, and columnations of the cortical plate. these changes are less prominent if the lesion occurs after diminishment of the subplate zone (after 34 w). since in the fetal cortex the subplate zone serves as predominant source of growing fibers, transient neurons, trophic factors and contains cellular substrata for migration, this zone is the most likely candidate for major types of structural plasticity. in conclusion, cerebral cortex of the low -birthweight infants is more susceptible to the various lesions but shows vigorous structural plasticity and conspicuous functional recovery due to the growing, transiently located neuron at elements. the mortality due to meningoccocal sepsis is high in spite of important progress in emergency and intensive care medicine. during the last decade multiple scoring-systems have been developed in order to establish a therapeutic approach and to evaluate the final outcome of a meningococcal infection. different clinical and biological data (shock, ecchymosis, peripheral wbc and platelet count, coagulopathy, acidosis, meningism, etc) are taken into consideration and the importance given to these data depends on the scoring-system used. a review of the different scoring-systems is given and a clinical case is presented. we report the case of a 4 year old male, who was transfered to our icu 12 hours after onset of temperature and skin rash. the parents described a fast deterioration of his condition. the boy presented wide spread ecchymosis, high temperature, no signs of meningism, circulatory insufficiency and shock, coagulopathy and low peripheral wbc and platetet count. disseminated intravascular coagulopathy developed promptly. the glasgow meningococcal septicemia prognostic score (gmss) was used and the obtained score reached the highest level (15/15). this corresponds to a 100% mortality. the patient required mechanical ventilation for 5 days. at admission he received human albumine, fresh frozen plasma, dexamethason, dopamine, dobutamine and a continuous infusion of adrenaline. antibiotical treatment consisted of ceftdaxone. the evolution was favorable and the infant fully recovered. retrospectively the gmss was compared to other meningococcal scoring scales which gave the same mortality (100%). we conclude that the scoring-systems are important to evaluate the seriousness and to assess the therapeutic approach, but they should be used cautiously even when 100% mortality is predicted by several risk evaluations scoring-systems. the aim of this study was to assess the haemodynamic status on admission and the critical care management of children presenting with meningococcat infection. this was a retrospective study of the charts of 46 consecutive admissions. mean age was 3.43 years (+/-3.46). the average duration of symptoms prior to admission was 20.4 hours (+/-14.09). on admission 17.4% were hypotensive, 45.6% had clinical signs of haemodynamic instability and 54.8% of cases that had a blood gas analysis on admission had a metabolic acidosis (bases excess < -5.q): the mortality rate was 10.9%. 80% of patients that died were hypotensive on admission and all had a metabolic acidosis. of the 41 survivors 9.7% were hypotensive on admission, 39% had clinical signs of haemodynamic instability, 25% required invasive pressure monitoring and 7.3% were ventilated and received inotropic support. this study demonstrates that at the time of presentation with meningococcal infection children had a high incidence of established haemodynamic instability. successful management of this infection is dependent on early presentation and initiation of therapy and on aggressive support of the cardiovascular and vital organ systems. dept. of intensive care medicine and dept of infectious diseases, our lady's hospital for sick children, crumlin, dublinl2, ireland. jude. pediatric intensive care unit, ch&u, 59037 lille-france. more than 10% of children surviving sip (defined as purpura with shock) have snli. objective. to search for a specific hemostatic profile in children with snli. patients and methods. between may 1989 and march 1995, 34 children with sip were admitted to our picu : 6 (17.6%) died and 28 (82.4%) ranged in age from 1 to 185 months (mean : 29) survived, 5 of them (17.8%) with snli (defined as the need of a surgical procedure). in survivors, two hemostasis studies (between h0 and h12, and 24 h later) included the determination of coagulation factors (routine tests), protein c (pc : amidolytic activity, biogenic), total protein s (ps : elisa, stago), c4b binding protein (c4bbp : laurell's technique, stago), antithrombin3 (at3 : chomogenic test, stago), and plasminogen activator inhibitorl (pail : chromogenic test, biopool). three severity scores were determined at admission : french group of pediatric intensive care, gedde-dahl, and crp. statistical analysis used the wilcoxon's test. results. at admission (lst sample) severity scores and at3, pc, ps, c4bbp levels were not different between the group with snli and the group without snli ; quick time (22 4-5% vs 35 ± 14% ; p = .025), vti+x (20 4. 3% vs 30 4-10% ; p = .04i) and pall (105 4-157 ui/m! vs 580 4. 570 ui/ml ; p = .028) were lower in the group with snli. on the 2nd sample there was no difference between the two groups. kinetics of hemostatic abnormalities was not different between the two groups. conclusion. in the literature, intravascular coagulation (dic), low fibronectin and at3 were identified as predictors of snli, and a negative correlation was found between the mean size of the skin lesions and pc activity, at3, and total ps. in this series, apart from dic, there were no specific hemostatic abnormalities that support the use of treatments such as pc, at3, and pail antibodies administration to prevent snli. further studies including more children are needed. the aim of study was to investigate the efficacy of intravenous immunglobulin with enriched igm content pentaglob/n /biotest/. in our pediatric intensive care unit ten septic children /group i/-their average age 2,6 years /sd:o,6/, 7 of them with gramm negative and one with gramm positive blood cultures, and two with unindentified bacteria-were treated with basis sepsis therapy and pentaglobin. the application of pentaglobin was as follows: 1,5 ml/kg loading dose for one hour, followed by a continuous intravenous infusion 0,1-0,4 ml/kg/hour depending on body temperatura /lanser scheme/ for 72-96 hours. another ten septic patients /control-group ii/the mean age 2,5 years/sd:o,65/, their blood cultures were gramm negative bacteria 6, positive 2, and the bacteria was not indentified in two cases -were treated with only the basis therapy. results: the duration of intensive treatment decreased from an average 22,7 days /sd:8, min 12-max 38 days/ to 19,5 days /sd:5,2 min 9-max 25 days/ in the group treated wit pentaglobin. the difference was significant /x 2 p<0,01/. in the group i nobody died, but three in the group ii. conclusion: the pentaglobin therapy can improve the efficacy of the basis therapy of sepsis. sinus bradycardia after an episode of sepsis is a rare symptom complex decribed in children with hematologic malignancies. we present a case of postsepsis bradycardia following severe typhlitis and septic shock in a 12 year old boy with relapse common all. blood and ascitic fluid specimen grew clostridium species and pseudomonas aeruginosa. at surgery there was a necrotic gangrenous terminal ileum and cecum, requiring ileocecal bowel resection with ileostoma. while clinically recovering from sepsis he developed bradycardia for 120 hours. extensive diagnositic procedures was given and the heart rate slowly increased to normal range of age. postsepsis bradycardia in children with hematologic malignancies after an episode of sepsis is self-limiting and after careful differential diagnostics warrants an expectative attitude. nitrate level is known to be enhanced during sepsis. serum nitrate is the stable metabolic end-product of endogenous nitric oxide generation. nitric oxide has demonstrated to be a powerful anti microbial final mediator and also a key molecule driving to the lethality of one of the most common complication of sepsis; the endotoxic shock. such facts prompted us to investigate the possible diagnostic and/or prognostic value of monitoring serum level in high risk, presumptive and confirmed sepsis patients. additionally we have explored the usefulness of this mediator as index of therapeutic response. in our study it is demonstrated that there is an important relationship between nitrate level and the occurrence of neonatal sepsis. septic newborn group showed 6 fold higher nitrate level than that of healthy control group. in addition, the group of patients with high risk of sepsis which finally became septics, exhibited 3 fold higher nitrate level at 24-72 hours before the first symptoms appeared, when compare with those who did not develop sepsis. however in the presumptive sepsis group, there was no difference between the patients which finaliy ,&'ere considered septics and those which not. in all septic cases, after 7 days of a successful therapy with antibiotics, the level of nitrate diminish 3 fold. our results suggest the utility of monitoring nitrate as index for the diagnosis of neonatal sepsis. the potential benefits of exchange transfusion, plasma exchange, and haemofiltration have all been described in children with overwhelming sepsis. however, little hard evidence exists to prove the benefits of any of these techniques. i have treated five patients with plasma exchange (pe), having been asked to see all these patients at a point when it was felt death was inevitable. two of the patients had staphylococcal, two meningococcal and one enterococcal septicaemia. all patients showed a dramatic haemodynamic improvement following pe with improvement in blood pressure, reduction in inotrope requirement and improvement in tissue perfusion. three patients survived. one of the patients with staphylococcal sepsis and both of the patients with meningococeal sepsis had developing gangrene of the limbs which showed remarkable reperfusion with pe. in two of the patients measurements of cardiac output (co) and systemic vascular resistance (svr) showed ~a reduction in co and a rise in svr over the course of a pe despite the reduction or cessation of vasoconstricting inotropes. many believe haemofiltration is of value in septic shock. a trial with a no treatment limb is difficult to achieve. i believe we now have enough evidence to justify a controlled trial of haemofiltration versus plasma exchange in patients with septic shock and unstable haemodynamic status whilst on inotropic support. during the next several days, cough and chest pain suggested pulmonary embolism confirmed by radiologic evaluation. echocardiographic examination showed multiple thrombosis of the superior vena cava, right atrium and ventricle and pulmonary artery. estimated protein c level was 50.7 % (normal range 70-140%); identical deficiency was found in patient's mother and elder sister. cvc was removed, and alter 2-month heparin therapy and supstitution of protein c with fresh frozen plasma, there was almost complete thrombolysis of the great vessels and cardiac chambers. we conclude that invasive diagnostic and therapeutic procedures in such patients may result in higher risk for severe thrombosis at unusual sites, and numeuos further complications bronchopulmonary dysptasia (bdp) is a chronic pulmonary disease of preterm and term babies treated with mechanical ventilation for respiratory problems of different origin and requiring oxygen therapy 28 days after birth. bpd is a disease affecting the growth and development of pulmonary tissue. such pulmonary }esions heal by squamous metaplasia leading to scar formation and fibrous tkssue r~growth, the pediatric intensive care unit makes the survival of babies w~h very low birth weight (500 -999 g) possible. with the increase in their aulyival, the number of complications in low birth weight babies increases as well. bdp is a very serious complication. therefore the importance of early diagnosis and treatment of bdp must be stressed in order to reduce the consequences. babies with bdp must be under medical suveillance for at least 3 years as the disease needs at least that long for complete resolution. tn the icu of pediatric department at madbor teaching hospital: during the past two years (1994-95) 154 newborns were treated with mechanical ventilation. the neonatal and postnatal death rate of all newborns admitted to our icu was 7,1%o.ln the two years from 1994 to 1995, 16 newborns were admitted to our icu (2 %~ of all newborn babies at maribor teaching hospital), with birth weight 500-999 g. in the icu, the survival of these babies and parallel to it the number of complications is increasing. during the mentioned 2-year period, 8 babies with very low birth weight (500-999 g) survived: 5 in 1994 and 3 in t995. in 45-50 %, first or second stage bdp was treated,there was no case of third of fourth stage bdp. the treatment consisted of eary removal from mechanical ventilation, oxygen therapy~ intensive treatment of infection, volume and caloric intake contro}, corticosteroid treatment throught 6 weeks with decreasing doses, diuretic end antioxydant therapy. the children are to be reevaluated at the age of 3 and 6 months and again at i and 3 years. oeure j van der, markhorst do, haasnoot k department of pediatrics, pediatric intensive care unit, free university hospital, amsterdam, the netherlands. case summary a 4%-month 6.5 kg girl of african origin was admitted to the pedfatric irtensive care unit with pneumonia and progressive respiratory irlsuffjderey. she was intubated and ventilated by pressure regulated volume controijed ventilation (servo 300c, siemens, soma, sweden). maximum conditions were inspiratory minute volume 3.2 l, peep 10 cm h~o ahd 100% 0~. chest x-ray showed bilateral interstitial consolidation. material obtained by broncho-alveolar lavage showed preumocystis car}nil htv-serology (elisa and westerll blott) and p24-antigerl were positive, confirming the diagnosis of pediatric aids. she was then treated with high dose co-tllmoxazoie, penthamldine, z{(~ovudire and steroids iv. because of thee x-ray features, high need for o 2 (100%, pad 2 56 mm hg), not responding to elevatiofi of peep (max 10 cm h=o) and pao2/fio = <200 (s6). m acute respiratory distress syhdrome (ards) was diagnosed. because conventional ventilation (cv) failure, hfo-v (31ooa, serisor medics,yorba linda, ca) was initiated. starting mean airway pressure (map) of 19 cm h~o was based or map of the cv, oscillatory pressure amplitude (dp) of 47 was, at ii~itial frequency of 7.5 hz, adjusted ur~til chest wall vibrations were visible, it was required to raise map to 26 cm h20 and dp to 66 before optimal lung volume and ventilation were achieved and need for o 2 reduced within hours, this was monitored by frequent blood-gas analysis and chest x-rays. map and dp could slowly be reduced, after a good response the first day, gradually 02demand reduced and the patient could be weaned from the ventilation. map, dp, fi02 and oxygenation index (map x pa0~jfio 2) are shown in table i. chest x-ray follow-up showed gradually improving lung features, with marked improvement of aereation. after 10 days hf0-v she could be succesfully detubated when a map of 10 cm h20 was acmeved. results : sianificant increase in ventilato~ rate and mean airway pressure was noticed after the change to savi. no differences in oxygenation, co 2 partial pressure and systolic, diastolic or mean blood pressure between imv and savi periods were noted. in 6 infants however an improvement in pao2/p43.ol/ and decrease in paco 2 was observed after the switch to savi. these babies had a lower initial a/a oxygen tension ratio and required higher initial ventilator rate /p<o.05/ in comparison to the rest of the studied patients. conclusion:infants with low a/a po2ratio who need high initial ventilator rate are likely to obtain benefit from savi.. fumimare hatori, haruo uchida, masao katayama, and rika muto department of anesthesia and critical care medicine chiba children's hospital, chiba city, japan. purpose: this study was made to find out whether the heat and moisture exchangers (hme) was effective enough to humidify in the respiratory management for children. patients: the study population consisted of 21 patients who were provided with artificial airway. they were divided into the two groups: ii with heated humidifier (a) and i0 with hme (b). methods: hme could be used for those without pulmonary complication and with less leakage around the endotracheal tube. in both a and b groups, (i) we have measured relative humidity, temperature, and absolute humidity at the endotracheal tube connector. for these measurements, humidity sensor system was utilized. (2) any troubles and complications caused by the artificial airway were investigated. results: (i) in group a, we confirmed the mean values as the relative humidity of 96.5%, the temperature of 32.8~c, and the absolute humidity of 34.0mg/l. in group b, they were 92.7%, 29.5°c, and 28.7mg/l respectively. no difference was noted between the two groups as to the relative humidity, but the temperature and absolute humidity were lower in group b with a significant difference (p<0.0001). (2) in neither of the groups, any respiratory complications such as obstruction or stenosis of the artificial airway were noted. in pediatric icu, hme can be used without any problems under given conditions. titei: objective: evaluate the precision, reproductibility and aplicability of a new device to measure auto-peep in pediatric patients during mechanical ventilation. material and methods: it's an electromc-pneumatic eontolled device with an oclusion valve and a pressure monitor installed between endotracheal canulla and the ventilator circuit. the measurements were performed with a sollenoid conected with to the ventilator to detect the end of inspiration phase and the actwation of the oclusion valve. the signs of pressure and flow were moniturized using a difere~rtial transducer and it was processed using a pc computer and a pneumoviaw® software. the auto-peep also displayed in the ventilator pressure monitor. results: we submitted 17 children with neuromuscular disease or respiratory distress in this study. the incidence of auto-peep was 76%, with variability between 1,5 to 13 cmh20. all the measurements were performed 3 times to verify the precision and the reproduetibility and evaluation of the pressure and flow curves. conclusion: the device is low cost, easy to use and can be used without the pneumotacograph. the auto-peep measurement can be done during mechanical ventilation with time cycled, pressure limited and continuous flow, the most commom ventilator used in pediatric patient. resistance was modeled by 3 endotracheal tube (ett) sizes (2.5, 3, 3,5), and compliance by 2 test lungs (1 and 5 ml/crnh20), for each resistance -compliance arrangement, we measured tidal volume (vt) at various frequencies, peak to peak (p-p) and mean airway pressures. results vt increased when ett size increased with all 3 ventilators in accordance with fredberg results (jap, 1987; 62: 2485-90) . the maximum vt delivered was smaller with the hfv-babyiog 8000 than with the ohf 1 or the sm 3100a at a given frequency (figure on the left). increasing p-p resulted in a linear increase in vt delivery in the 0-30% range of maximum p-p (figure on the right). hfv-babylog 8000 didn't provide significant vt increase when p-p was set above 50% and vt deliven/decreased when mean airway pressure decreased. --i 5~ sm 3100a a number of ventilatory parameters had been analyzed with russia-produced monitor humitemp htm 902 (servisinstrument j,-s. co) in 24 newborn infants with rdsn of t-iv stages on cmv, cppv, imv, and cpap steps using respirators of various kinds (stephan-staxel, bear-2001, newport 8rezee, sechrist). parameters investigated were: temperature of inspired mixture (t), relative and absolute humidity (rh and ah, respectively), static compliance (c), expired tidital volume (vte), expired minute volume of ventilation (mve). the monitor read these parameters in following ranges; rh-from 10 to 100%; ah-up to 55mg/i; mve-up to 3.0 i/mini vte-from 3 to 130 ml; t-accurate to 3%; c-from 0.1 to t0 ml/cm h20. continuous monitoring time ranged from 2 to 96 hours, it was noted, that during this time the monitor and transducers had no malfunctions, and it's using didn't require additional calibration, it was found, that humidifiers mr 498 and mr 410 (fisher, paykel) couldn't maintain parameters t and ah continuously (these values varied from 34,3 to 38.2 c and from 37,5 to 47.1 mg/i, respectively, when heating regulator position was unchanged). changes of parameters c depended clearly on cppv conditions and rdsn severity (with rdsn of stages i-ii c value ranged from 2.4 to 1.2 ml/cm h20; and with stages iit-tv-from 0.3 to 1.1). tn 6 newborn suffering from rdsn of stages ii-ltl and ill-lv with pip>25 mbar, fi02>0,7, peep=4-7 mber, c-from 0.3 to 1.2 ml/cm h20, effectivity of exosurf therapy was studied. in 4 newborns in 4-12 hours of therapy pip decreased to 0.3-0.4, and c increased to 1,7-2.4 ml/cm h20. in 2 newborn infants with aad02>500 mmhg and c from 0,3 to 0.8 mltcm h20 positive effects of exosurf on lung compliance were not observed. in 3 newborns the monitor had revealed decreased of c (from 3.4-2.9 to 1,8-1.3 ml/cm h20), manifested clinically by pneumothorax. in general, monitor htm 902 made possible; 1), to estimate the adequacy of cmv-parameters and regimes in newborn infants; 2). to select optimal t and ah values in the respiratory outline in dependence on lung damage severity and infused volume; 3). to reveal rdsn severity; 4), to optimize indications and adequacy of surfactaot therapy; 5). to diagnostieate the air leakage syndrome; 6). to effects to some agents (broncholytics, spasmolytics); 7). to obtain objective indications for imv/simv and cpap regimes. albano communication is an important aspect of human development and existence, and an inability to vocalise can be a problem in ventilatordependent patients. we present our experience with speaking aids as a means of enhancing verbal communication in four ventilatordependent children in our paediatric intensive care unit. the age of the children ranged from 7 months to 5 years, and the period of ventilation ranged from 3 months to 21 months via a tracheostnmy. they require continuous flow generated pressure limited or control ventilation at rates of 13-20 bpm. the reasons for ventilation include tetraptegia following a shrapnel injury; tetraplegia following congenital cervical spine damage; tetraplegia following atlanto-axial subluxation; and critical illness polyneuropathy following adult respiratory distress syndrome from prolonged ventilation for a severe head injury. the first three patients have passy-mnir one-way speaking valves and the final patient has a bivona foam cuffed tmcheostomy tube with a talk attachment in view of recurrent aspiration. an improvement in quaiity of speech has been shown by independent assessment. we will review the present literature on this subject and discuss the advantages and disadvantages of these two types of speaking aids in the light of our experience. the prognosis of antenatally diagnosed cdh is closely related to the degree of ph. there have been attempts to correlate antenatal or postnatal criteria to mortality: none have been demonstrated to be predictive of lethal ph. the aim of this retrospective study was to determine whether antenatal or early postnatal data could correlate with the findings of post-mortem examinations. patients and methods: between july 1990 and july 1994, 32 cdh patients have been antenatally and postnatally managed at our institution. twentythree infants underwent a post-mortem examination. ph was assessed by using the lung weight to body weight ratio (lw/bw) and the radial alveolar count (rac). antenatal results: cdh diagnosis was made at 24 weeks of gestation (wg) (15-37). twenty-eight patients had a left sided cdh, 3 had a right sided cdh, and one had a bilateral cdh. herniated organs were stomach none (n=21), or liver alone (n=4), or both stomach and liver (n=5 the patient was a 3-yenr-old girl with chronic renal insufficiency see~ to renal dysptasm, two months before admission a kidney trar~ptant was performed. one morah later she showed acute graft rejection with serum ereafinine (cr) level of 0.7 mg%. the rejection was unreslxmsive to an increased steroid dosage, and okt3 was begun with resolution of the rejection. one week arer, new rejection episode was seen marestxmsive to an increased steroid dosage, and transp~ ~s performed five days before admission to our ptc. hemedialysis and peritoneal dialysis (p.d.) each other day, was indicated (g.r.f.< 10 ml/rnin). four days before admission t ~ rose to 38°c. "lhe diagnosis of opporttmistic pneumoma was made on the basis of tach3,pr',e~ hypoxi~ and diffuse interstitial infiltrates. senma ~ was positive for cytomegaloviras (cmv), and stool culture for c albicans. pentamidine, ganciclovir (dhpg), arai-cmv gamma globulin, eritromicine and amphotericin b was administered. on admission in our picu, trachea was mmbated, (a-a) o2 gradient was 600, paofffio~: 65, lung injury score > 3 with peep level of 8 cm hzo. she had normal fiver function. during te next days she had fever and developed ards. bal was negative. p.d. was of little efficiency. we adjusted pentanfdine, and dhpg doses for severe renal failure, with supplements after hero, sis, and at~rp.d.. during ~ next days she was afebrile, and the chest became radiologlcally normal. after ten days on menhani~al ventilation (mv.), the patient was extubated. cr. level was 3.2 rag%, (a-a) oz gradient was 20, and paoyfioz was 375, the patiem was discharged with chronic ambulatory p.d. discussion: opportunistic pneumonia is a major complicalaou in imm~romised children, specially after kidney tvansplaraafion. c m.v. infection can result at~r okt3 administration. in the treatment dhik} dose must be adapted to the degree of renal insu~cieney, with supplements after hemedialysis, and after pd. pneu~y~tis cann# tmeumov~ is ehemeterized by ventilafion-perfusion mistmaeh, decreased pulmonary compliance, hypoxia arld elevated (a-a) oz gradient, with diffuse interstitial infiltrates. in our ease bal was negative. although we did not find the etiology the prevoclons eombh~ation of arairmcrobiat therapy, along with m.v., and supportive measures were the most effective trealme~. conclusion: 1) in patients with severe renal failure and life-threatening infections, we must co~ider drug adjuslments. 2) in our patient we gave dhpg supplements at~r pd. with excett~at results, although p.d. was of little effiele~. introduction: endotracheal intubation and mechanical ventilation have become an important treatmem for many diseases accompanied by respiratory failure. with the frequent use of this treatment modality, an increasing number of complications associated with endotracheal intubation have gained clinical significance. material and methods: a transversal study was realized to find the prevalence of pulmonary aspiration with endotracheat tubes in 36 infants and children. aspiration was assessed by applying two dyes (evans blue, er)¢rosine sodic) on the tongue and searching for the dye during suctioning in the endotracheal aspirate. the factors, that potentially have influenced the aspiration, including weight, age, sex, cause of respiratory failure, main pressure airway (map), level of consciousness, presence of swallowing and body position were evaluated. all the variables studied had their association with aspiration tested by chi-square method with relative risk considering a confidence interval of 95%. the results were adjusted by multivariate analysis. results: the overall prevalence of aspiration was 36.1%. among all children who aspirated, compared to those who did not, there was a statistically significant difference in the presence of swallowing (p=0.005). the odds ratio to aspiration in the presence of swallowing was 38.4 (t.75 -100 c.i.95%) and the relative risk 55.5. aspiration was not significantly affected by sex, weight, age, cause of respiratory failure, map, level of consciousness and position of the body during the ventilation. conclusion: the endotracheal intubated children frequently aspirate as intubated adults and that preventive measures are ineffective. the presence of swallowing movements is the main risk factor to aspiration of oropharingeal content in intubated patients. clinical features and shortterm outcome skling, rp gie pneumonia is the second most important cause of death in young south african children. the clinical features, intensive care course and outcome of children being ventilated for pneumonia in the developing world is unreported. aim: to describe the clinical findings, aetiology and shortterm outcome of children younger than 6 months with pneumonia requiring ventilation. the data of all babies under the age of six months with a lower respiratory tract infection admitted to the paediatric icu for ventilation were prospectively collected over a period of 14 months. tracheal aspirates and blood specimens were submitted for viral and bacterial cultures. results: forty-seven babies aged 14 to 174 days were ventilated for pneumonia. twenty-six infants had been born prematurely; t2 had been ventilated during the neonatal period and 4 had bpd. the median duration of symptoms was 1 day, the most common being cough, tachypnoea, apnoea and cyanosis. five babies (10%) died. the mean duration of ventilation was 8 days (range 1-85 days) and of ward stay after icu discharge 19 days (range 1-161 days), blood euttures were positive in 7 children (15%). viruses were cultured in 14 children (30%). conclusion: 1) fifty-five percent of children below 6 months requiring ventilation for pneumonia were premature infants, of whom 46% had been ventilated during the neonatal period. 2) the median duration of symptoms prior to admission was 1 day. 3) ninety percent of the children survived and were discharged from hospital. 4) viral pneumonia was responsible for 30% of the admissions. mechanical ventilation and atrial natriuretic factor release ulloa santamarfa, e, p6rez navero jl, ibarra de la rosa i, espino hernladez m, velasco jabalquinto mj, frfas p6rez m. picu. reina sofia children's llospital. c6rdoba. spain. mechanical ventilation effects on renal function decreased diuresis and natriuresis due several factors including anf. several studies have demostrated anf released due increaasing pressure in right atrium. on the other hand, mechanical ventilation, overall peep modality, inhibits peptide release althougt cvp increased is found. this study was designed to demostrate anf stimulation is due rigth atrium stretch which be higher during mechanical ventilation instead of atrium pressure. we desing a prospective study including 14 patients, age range 16 months-13 years with congenital heart disease. all of them were admitted at pediatric intensive care unit after extracorporeal surgery and were assisted by mechanical ventilation. hemodinamic state was stabilized in all patients and nor renal neither neurological diseases were found. after 24 hours with mechanical ventilation, plasmatic levels of anf were measurement, pvc, pericardical pressure were assessment; all patient were sedated with midazolan and paralized with neuromuscular blocking agent; mechanical ventilation technique was as follow: imv between 20 and 30, tidal volume and fi o2 enough to mantain respiratory parameters in normal range. afterwards, at least twentyfour hours in spontaneous breathing, the study was made again in each patient. atrial stretch was assesssment according to following equation: transmural pressure= cvp -pericardial pressure. cvp were significantly higher with mechanical ventilation than when the patient was breathing by himself. (5.4+__ 2.2 vs 3.8 + 1.8 mm hg; p<0.01). however, transmural pressure during mechanical ventilation were lower than during spontaneous breathing (8.92 +__ 3.86 vs 11.76 +__ 3.32 mm hg; p < 0.01) equal, plasmatic anf levels were lower during mechanical ventilation ( 87.77 + 46.55 vs 108.92 + 49.06 pg/rnl; p<0.01). in conclusion, anf secretion decreases during mechanical ventilation, even with cvp higher. anf release would depend on atrial stretch meassured by transmural pressure, lower in patients with mechanical ventilation and it would not depend on atrial pressure. the paediatric intensive care unit shaikh zayed hospital, lahore is an acute care area devoted to the care of critically sick children upto the age of 13 years. in a 6 bedded unit with limited equipment, constant care is ensured by the presence of at least one nurse aed one doctor round the clock. in this setup we have the facility to ventilate 2-3 children at one time, between sep. 93 and dec. 95, out of 885 patients admitted to icu, 171 (19.32%) were below 1 yr of age, while 48 (28%) were below 1 month of age. life support was discontinued in 17 (9.9%). total mortality was 56 (32.7%), major mortality was in 0-1 month age group 22 (12.8%), and 1 month to 6 month 15 (8.7%). majority of the patients were of sepsis (36.2%), cns disorder (22,2%) followed by respiratory problems (14.6%). it seems therefore that the major indicatiou for ventilation was overwhelming septicemia leading to multiple organ failure, rather than purely respiratory problems. high frequency oscillation (hfo) in the therapy for ards in pediatric patients requiring aggressive conventional mechanical ventilation (cmv) -routine or experimental mode ef pre ecmo therapy. fedora m., nekvasi~ r, vobruba v., srnsky p,, zapadlo m. dpt. critical care medicine, nicu and ecmo center, university children's hospita! brne, nicu of university hospital prague, czech republic. introduction: 9 pediatric patients (8 males, 1 female, average age 4.7 months, average body weight 5,8 kg) with severe ards ventilated with aggressive regimen of pcv or prvc were connected to hfo (sensormedics 3100) as the last "rescue" therapy due to uncontrollable respiratory failure before intended ecmo. in the course of hfo 2 of them were given no in the concentrations of 5-80 p.p.m., 3 were subjected repeatedly to surfactant replacement therapy (alveofact). results: ecmo was needed in no patient, 8 patients survived, 1 patient was disconnected from the ventilator because of brain death in spite of conspicuous improvement of oxygenation and other parameters, some relevant parameters 48 hours before and 48 hours after starting hfo are given in table 1~ in all the cases, the disconnection from hfo was carried out through the simv regimen, never directly to cpap. table 1 : the levels of blood gases, oxygenation index (oi), aado2,map,fio2 and pao2/fio2 ratio 48 hours before and 48 hours after starting hfo. conclusion: although none of the patient had to be subjected to pediatric ecmo, hfo should be carried out only in workplaces having the immediate possibility of using this method in the case of hfo failure. speculation: should not hfo be used ir pediatric patients with ards earlier than aggressive cmv? can hfo ce considered standard, not experimental method of therapy? refractory hypoxemia in premature patients is characterized in a persistent elevation of pulmonary vascular resistance, with right to left shunt through the ductus arteriosus and or foramen oval. we report the case of a vlbw patient (ga 27w, bw 1010g) who present a severe hypoxemia related to hyaline membrane disease and a pulmonary and systemic infection to group b streptococcus, refractory to conventional ventilatory support and surfactant therapy, associated to hemodynamic failure falling in ecmo criteria used for term infants. a rescue therapy with hfov (sensor medics 3100a) is decided at 5 h of live, the table resume the patient's evolution before and after hfov. at 36w of postgestational age the patient present a fio2 of 0.23 with a chest x ray compatible with a cld type l at discharge no oxygen requirements was needed and actually he's doing well. conclusion: hfov, using an adequate alveolar recruitment strategy, was effective in the rescue of a severe hypoxemic respiratory failure with a rapid off of ecmo criteria entry in our vlbw premature patient, during the united nmioffs embargo ~nst yugoslavia the prevalence of the ast}nnafic ~acks in c~dldren aratsed. the mo~t common causes have beem dramm~e worsening of life standard, ecom~c disaster in global community, gr~ number of refugees from the other parts of former yugodavia. it wm obviom that mcio-ecoumnical conditions took a part in the exacerbations of previously known cldldhood asthra~, ~av~ of micro-and m~mclimaflc changes, psychosocis] and emotional cryses, lack of medics-m~nts for p~ve~on and tl~rspy of acute asflanatic attacks. about 10% of d-dldv~ tmslod in our picu for these year~ exp~dvncod ~vcr~ attack for the flint time iu ~jzeir lifts. it has been cu~ 1~%~ children in mspir~ry picu of our hos~mt. the scut~ revere attack (more ~asn ~/o of hight clinical score) was detected in 62% of all children admitted with respirak~ problems. from tl~ mmlysss we exclu&d: bmncldolifis, ~i anomalies, ~eve~ i~ccqions. concerning our drug supplies (which wc~e reduced), we started our therapy by administration of oxygen, ~ta2-ago~dst inhalations (but sometimes we had the solution for jet nebulizcm only for o~e inhalation per p~cnt), mwinophyllin and mefl~ylpr~ini~done in/ravenously. 48% of ih~ asthmatics needed repea~ doses of muinophyl~n pinch.ally, tnch.,ding the fluids. the bronchodilak)r msponm was poor ~r~cl slow, hospital stay in picu was for 4 days and for 14 days in other units sl~rwsvds. tim ~ of their stable condifio~ was hard at borne (or refugees camps), without p~ventkm, so they came bsvk to hospital for morn than 3 times in 27% of cases, dtrdng ~e4je last motlfl~s file dtustion improved, concerning tim drugs supply for prevention, and we hope that these lifc~restening conditions wouldd~ introduction: the incidence of ards is increasing as survival of critically ill patients is higher. the application of new therapeutic modalities have increased the survival rates in (ards) adult patients. objective: to study the therapeutic efficacy of new tleamlents in children with ards material and methods: a retros~ctive study was conducted from 1990 to 1995. 17 children with severe ards, (lung severity score > 2,5) (r), aged 15 days to 16 years, were included. the diagnosis were as follows: 9 interstitial pneumonitis, 5 non interstitial lung infection, 2 with lung aspiration and 1 with clinical sepsis. 5 patients had different tipes of cancer and 4 to suffer inmunodeficiency disease, the first 8 subjects (group t) were treated with conventional measures. from october of 1994new therapeutic modalities were introduced, including: less agressive ventilatory support, postural changes (prone to supine) in 9 subjects, administration of corticosteroids in 8 patients, rfitric oxide in 3, pe~ssive hypercapnia and administration of exogeans sarfactant in one, pao2/fio2, d(a-a)o2, oxigenation index (oi) and the score of respirator), severity disease were similar in both groups. the two groups evolntiou was compared. results: -ten patients died, 6 from group i and 4 from group ii (75% v.s.44:4%,ns). -the evolution time, either to exitus or weaning from ventilatory support was higher in group ii (22.9 v.s. 13.6days in group i, ns), -the incidence of barotrauma was observed in 12 subjects (70.6%), 6 from group i and 6 from ii. of these patients 75% expired. -during the course of the disease, 15 (88%) patients had more than one damaged organ. only in one subjet mof was considered to be the main cause of death. the majority of the patients expired because of their respiratory disease, although, 80% of them met criteria of mof. -fifty percent of the subjects were infected at the time of death. stmmry: a trend toward a higher survival rate is observed in the subjects receiving the new modalifies therapeutic intervention (corticosteroides, postural changes and permissive hypercapnia). our results are not significative,probably because of the small number of subjects studied. a new doubleaurae~t two-stage et-tube (dl-ett) was desig~aed and tested in the rabbits with acute king injury under conventional mechanical ~entilation_ ventilation efficiency of dl-ett was emrrpared with that of canveniionally t~sed single lumen et-tube (sl-ett). meth~s: dl-ett was specially made out of two sl-ett. vertical crosssections at the distal end of two et-tube (td 3_0 rmn portax) were adhered with each other to form a tracheal stage lumen wifu id 3.0mm the two remained uncut parts of the tubes corlntithted the oval s~ge with two separate imnens. dl-ett and sl-ett were randomly applied to five adult paralyzed rabbits with acute lung injury (by 0.1 nffkg oleic acid. iv). a bird inter 3 vetffttator (bird products corporation) was used for time-cycled pressure-limited ventilation at 40/min of respiratory rate, 10 ern h20 of peak i_~piratory pressure, l: 1 of ire ratio, 6 ljmin. of flow rate and 0.21 of fich. peak inspirntory pressure, mean mrway pressure, posi6ve end-expiratory pressure at tip of et-mbe and bemodynamics were measured and recorded continuously. arterial blood and expired gas were measured ~by avl 993 blood gas analyzer) after each stabilization t.~iod of 30 minntes. _analysis w~as by prated t test. result: dl-ett acaltety improve cos removal at all amman. pa(?oz was decreased by t0.6+_t.5 (p<0.0l) and physiologic dead space fraction (v~zvt) reduced by 22% +-1.8% (p<0.0t), compared with dl-ett. there were no significant change in arterial oxygenation. conelus|on: the double-lumen two-stage et-tabe significantly increases ventilation effmiency with simple operation in rabbits v, ith acute hmg injury, lts availability may influence future clinical management of ~ennated patient~. this ~muly was fimded by the science and technology. commiuee of beijing municipality. analis of hemostasis alterations on different coagulation cascades in 46 children with septic shock has shown that coagulation disorder character is dependent on lung affection rate. the initial manifestation of the respiratory distress-syndrome (rds) are characterized by the obvious activation of blood thrombin potential, moderate coagulopathy and not sharply marked endoteliosis, the witlebrand's factor (wf) increase tot 140-220%. progress in the clinical picture of "shock lung" leads to chronometric and structural hypocoagulation with potential hypercoagulation in "mix-test", high level of firbin derivative, thrombocytopenia with thrombocytopaty and the wf increase to 210~315%, terminal stages of the rds, as a rule, are characterized by potential hypercoaguletion absense, depletion of at-lit and plasminogen, prevalence of antithrombin and antiaggregating activity, obvious endoteliosis (the wf to increase250-540%). the arteriowenous difference according to index of the thromboelastography (teg) in the rds ill-iv rates was 69,8% less than in the 1-11 rates, disorder of lung filtering ability in severe rds is confimed also by minimal arterio-venous difference of activated euglobulin lyses (ael) in children with the rds ill-iv rates is only 11,4%, while the patients whit rds i-i1 rates have the ael-activity in arterial blood 2,1 times as much than in venous blood. the use of then allows to determine the potential hypercoagulation rate, the at-ill level and fibrinogen quantity during the anticoagulant therapy and also the character of the x-factor activation and thrombocytic hemostasis. the effective therapy component of septic genesis rds in children is the controled coagulation method with the use of the individual selected heparin doses in according to desagregants, kryoplasma, proteolisis inhibitors and trombolytics. it is necessary to avoid the heparintherapy for children with the rds complicated with producting coagulopaties and termal phases of blood disseminated intravascular coagulation (dic). bronchoseopy has been used for evaluation of the potential problems of the airways and for investigation the bronchial specimens for diagnostic purposes. regent technical advances result in performing this procedure at the bedside manner and in critically ill patients. we have performed 150 hronehoaeopy during last three years on 1362 pediatric patients with respiratory problems, in 90% of cases the opentube hroneh0seopy was performed (for diagnostic as well as for therapeutic reasons) and collected secretions or bioptic material were examined. the indieatiuns were: acute upper respiratory problems, chronic wheezing, inspiratory strider, tracheal or bronchial bleeding, chronic eongh, retractable atelectssis, severe pulmonary infections, lymph node perforation in lung tuberculosis and soquells like bronehiectssis and fibrosis. our results were: anatomical malformations in 10%, mueosal oedema with chronic inflammation and thick secretions in 56%, easuos masses in 11%, granulation tissue and purulent secretions in foreign bodies and bronehieetasis in 16%, and only 7% of eases were normal finding. our exlxdenees pointed that this invasive procedure in carefully selected patients has important role in establishing the diagnosis and in theintroduction: tbg has been a useful investigation in the management of ventilator-dependent infants in our experience. one ml of contrast was hand ventilated into the respiratory tree via their nasotracheal tubes and their anatomy and dynamics demonstrated on radiological screening. case descriptions: three infants who were difficult to ventilate requiring high airway pressures, high peep and a significant oxygen requirement had tbgs. the ages ranged from 3 to 9 months. two cases were complicated by complex cardiac lesions. in all cases there were frequent episodes of desaturation, where hand ventilation proved difficult and various intermittent lobar collapses occurred. microlaryngobronchoscopies (mlb) performed on the infants by experienced paediatric ent surgeons failed to identify the airway problems. more than one mlb was frequently done. concern about introducing contrast into the airways of infants with limited cardiorespiratory reserve combined with an uncertainty about how much extra intbrmafion would be gained often led to a delay in investigation. when performed these fears proved groundless, the anatomy and pathology of the airways were demonstrated in full and the correct therapeutic plan started. in two cases tracheostomy and peep producing patency of bronchomalacic segments allowed weaning to low levels of ventitatory support. in one case tracheal reconstruction was undertaken and in the cardiac cases the respiratory component of the ventilatory dependence was fully assessed. at the age of 4 months, a baby boy with a history of minor respiratory problems, was admitted to hospital with an upper airway infection and severe dyspnoea. shortly after arrival at the icu he had a total airway obstruction. after intubation there were still difficulties to establish a normal gas exchange, and he was tranferred to the regional picu. ct scan and bronchoscopy verified a congenital tracheal stenosis affecting the whole trachea except the upper 15 mm below the vocal cords. the diameter was estimated to less than 2 ram. an unsuccessful attempt was made to dilate the extremely rigid stenosis with a balloon. after the procedure he had a respiratory and circulatory arrest, and he was put on ecmo as a bridge to surgical correction. after 4 stable days on ecmo, surgery was performed during ecmo with a tracheal homograft transplantation. immediately after surgery, ecmo was discontinued. a silastic dumont type stcnt was inserted inside the homogra~, and a nasotracheal tube was placed inside the stent for assisted intermittent mechanical ventilation. repeated bronchoscopies were performed to remove granulation tissue and secretions. at 9 months of age, the stem was removed with an endoscopic procedure. however, the trachea was still soft and collapsable, and another silicon stent was placed inside the trachea for another 4 months period, after removal he had some respiratory problems and he was treated with nebulized salbutamol, mcemic epinephrine and steroids. he was discharged from the hospital at 14 months of age and his condition is now stable. this is the first procedure of its kind in sweden. it was accomplished by international and multidisciplinary collaboration. ecmo may be a bridge to corrective surgery and long time stenting may be necessary in the postoperative period. post mtubation laryngitis ( pil ) is still a frequent complication, occurmg in l -6 % of intubated patients. inhaled racemic epinephrine has for long been used as an accepted therapy, but this drug is not always available. the authors undertook a randomized, double-blind, placebo-controlled trial to determine the efficacy of inhaled l-epinephrine(le) in the treatment of plu in the period between july/93 and may/95, 289 patients were submitted to endotracheal intubation for ventilatory support. atter the extubation procedure patients were considered for enrollement if they met the following criteria: clinical signs of laryngeal estridor and a downes and rafaelly score for upper respiratory obstruction equal to or higher than 4 patients with primary upper respiratory disease were excluded all patients enrolled reeieved either inhaled l-epinephrine 1% or normal saline. dexametasene ( 0,6 mg/kg/day) was given to all patients in both groups. after 2 inhalations, au patients were monitored for a period of 1-20 minutes and monitoring included cardiac and respiratory rate, mean arterial blood pressure, arterial blood gases and the dowries and rafaelly score. statistical analysis included, qui-square with the fisher correction test and the z-test for paired variables. thirty eight patients ( 13,1% ) met the criteria for enrollment, 18 to the le group and 20 to the placebo group.there were no significant differences in both groups in regard to age, sex, initial score ( 5,05 x 5,1 ) and endotracheal tube diameter. the period of ventilatory support and tracheal intubation was significantly higher in the le group (8,06 x 4,54, p = 0,01). the follow-up score showed a significant drop only at 30 minutes after the inhalations (p = 0,03). re-intubation due to laryngitis, occured in 1 patient of the le group and in 4 of the placebo group with no statistical sxgnificance (p = 0,2). no difference was observed on the monitored hemodynamic variables during the 120 minutes, except for the mean arterial pressure at 60 minutes, being heighar on the placebo group (p = 0,05). we concluded that, although the l-epinephrine group showed a trend in better scores post-inhalation and fewer re-intubations due to laryngitis, the results were not statistically significant. we especulate that the period of intubation may have affected our results. similarlly there were no differences in the incidence of adverse effects between both groups. objectives:to evaluate the complications of endotracheal intubation in children with upper airway obstruction due to epiglottitis or croup. methodes: during a 5 year period (1991 -1995) all patients with epiglottifis or croup were reviewed to determine the complications of endotracheal intubation, especially upper airway obstruction due to granulomas. results: 33 patients were reviewed. in 17 children (mean age 2.5 years) with epiglottitis the mean duration of intubation was 4.0 days (3 -5). no complications were seen. in 16 patients (mean age 2.3 years) with croup the mean duration of intubation until the first extubation was 8.1 days (1 -15 days). elective extubation was performed if an airleak was present or after 7 days without airleak but in the absence of fever and obvious secretion. reintubation was not necessary in 10 children (62.5%). in this group the mean duration of intubation was 6.4 days (1 -12). in 6 patients (37.5%) reintubation was necessary because of severe upper airway obstruction due to granulomas. mean duration of intubation until the first extubation was 10.8 days (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) . there seems to be a difference in duration of intubation between these two groups with croup, however it is not significant (p > 0.1). all the patients with granulomas could be successfully extubated after microlaryngeal surgery, with a mean intubation period of 35.3 days (21 -47). revealed no complications, where as endotracheal intubation in children suffering from croup showed a high incidence (37.5%) of granulomas. however1 laryngeal steepsis and other serious complications were not sesn~ 3 patients (42 days averagely] was obviously seen in ~he peak =one of fl, f2 resonance and in the zone of high freq,-~ncy :r, ~;~e composition while 12 cases(3 day~ average;y] :~bowed no abnormality both clinically and isryngoscopica!~y. 7/10 patients with catheter placement for more than 6 week~ end 1126 p~tie,~ts for less than 5 weeks had t;~ryngeal abnormal change in their larynges,abnormal changes of sound spectrogram were all seen in 3 patients with placement for mope than 5 weeks. our data suggest= ca] the complication of endotracheal intubation was increases with increasing length of time of catheter placsm. entjbut aeriuoa complication is rare i (b] the time limit of pernasal endotraoheal catheter placement is 5 weeks within which the procedure is • comparatively safe and effective means for maintaining e tong term artificial airway. in a 6-year period (1986) (1987) (1988) (1989) (1990) (1991) (1992) we diagnosed tbm as an apparent dilatation of the trachea and main bronchi ih four premature infants on continued mv for respiratory distress syndrome (rds). the infants were three boys and one girl with gestational age (ga) 26-33 weeks and body weight (bw) 1100-1965 g. mv was provided by bourns 2001 cub time-cycled and pressure-limited ventilator to attain normal gas tensions. no jet ventilation was used. chest radiographs were reviewed for a complete evaluation, and for the evaluation of the airway. after the intial subjective diagnosis of tbm, the width of the tracheal and main bronchial air column was measured at the lower level of the first and the third thoracic vertebal body it1, t3) and near the carina; the width of the main bronchi below the carina was also measured. in all infants, tbm became apparent close to the 20lh day, that is, after 2-3 weeks of mv. therefore, for the time period from birth to the 20th day the following ventilatory parameters were reviewed and analyzed: (1) the percentage of total ventilation time when more than 40% o2 concentration was required, (2) the peak inspiratory pressure, (3) the positive end-expiratory pressure, and (4) the duration of high frequency ventilation (80-160 breaths per minute). also noted were the apgar scores (1 and 5 min after birth), the duration of hypotension (systolic bp below 40 mmhg) and circulatory instability, the presence of systemic or tracheal conatal or later infection, the duration of mv, and the final clinical outcome. the records were also reviewed for other possible pertinent data. rigid respiratory endoscopy in children fraga j, amant6a s, piva j, nogueira a, palombini b. introduction: the respiratory endoscopy is an important procedure to diagnose and treat many airway's diseases in children. although have had advances in radiologic investigation exams and pulmonary function tests, the direct anatomic visualization of airway is important to the management of many respiratory problems. objective: evaluation the respiratory endoscopies performed with a rigid bronchoscope in a pediatric reference hospital. material and methods: we study the records of all children that were submitted to respiratory endoscopy under general anesthesia from march 1989 to march 1992. age, sex, clinical to indicate the procedure, diagnosis and complications of endoscopy were registered. results: three hundred and fifty six respiratory endoscopies were performed. the most common indications for endoscopy were strider (52%), suspected foreign body (16%), atelectasis (16%) and difficult tracheal extubation (8%). the most frequent diagnosis were laryngomalacia (36%) and subglottic stenosis (6%) in the glottic and subglottic areas, and foreign body (9%) and tracheomalacia (7%) in the tracheobronchial area. normal endoscopy was performed in 54 (21%) of the children. only three slight complications of the endoscopy were observed. two patients presented bradycardia during the exam, and the third need tracheal intubation due to post-endoscopic subglottic edema. conclusion: the rigid endoscopy in children is efficient and has no serious complications. near drowning; indicators of acute and long term prognosis bernardien t.mj. thunnissen t, reinoud j.b.j. gemke 1, loes veenhuizer?, krijn haasnoot 3, a.johannes van vugh0 department of pediatrics, ~wilhelmina children's hospital, utrecht, 2sophia hospital, zwolle, and ~free university hospital, amsterdam, the netherlands. in this retrospective study factors that affect short and long term prognosis after submersion were analysed. all patients that were admitted to a tertiary pediatric icu between january i, 1986 and january i, 1992 were included. of 34 patients, aged 0-13 years, 8 died in the icu, one after hospital discharge. survivors and non-survivors showed significant differences with respect to central temperature, pupillary reactions, arterial ph, pediatric risk of mortality (prism) score and therapeutic intervention scoring system (tiss) upon admission (p < 0.05). non-survivors more frequently required mechanical ventilation, bicarbonate administration and active reheating. ards was seen in 22 patients (65 %), invariably within 6 hours after admission. no patients with cardiac arrest on" admission snrvived without sequelae. hypothermia appeared to have no protective effect on hypoxic damage. survivors with persistent sequelae _> 6 months after discharge had significantly higher prism and t1ss scores (mean 27 and 34, respectively) than those with complete recovery (mean 14 and 23, respectively). long term cognitive problems were present in 7/25 survivors (28%) and emotional disturbances in 5/25 (20%). in conclusion, a concise number of clinical and laboratory parameters, representing acute severity of illness, are important prognostic indicators for survival and health status of children after submersion. there were 59 (91%) bronchoscopies, and 6 (9%) were oesophagoscopies.the average age was 2,8 years for bronchoscopies, and 4 years for oesophagoscopies. the outcome of the patients was good. no complications were observed. extraction is recomended in every symptomatic patient. orphenadrine is an anticholinergic drug mainly used to decrease symptoms of parkinson disease. orphenadrine has a peripheral and central effect and overdose can result in athetoid movements, convulsions, cyanosis, coma, arrhythmias, shock and cardiac arrest. physostigmine is a specific antagonist of the peripheral and central effects and can be a useful antidote. we report the case of a two and a half year old female who was transfered to our icu for general convulsions. the little girl had, three hours before admission, accidently ingested 400rag of orphenadrinehydrochlodde (disipal®), which was her grandmothers anti-parkinson medication. three hours after ingestion she presented neurological signs: confusion, unstable walking, and periods of aggression. generalized tonic-clonic seizures appeared who were rebel to administration of multiple anti epileptica but ceased after iv administration of diazepam and endotracheal intubation and ventilation. an episode of ventdcular tachycardia responded well to the iv administration of tidocaine. the levels of orphenaddne in the serum were high at admission (3550pg/l) and were present in the blood up to 96 hours after ingestion. high serum levels are, in the literature, associated to a high mortality rate. physostigmine was administered three times at a 0.02mg/kg dose in the first 24 hours. we decribe the noted effects of physostigmine on the different symptoms. the patient survived and could leave the icu after one week. in conclusion: orphenadrine poisoning is a very complicated medical problem associated with high mortality. in severe intoxication, the benefit of physostigmine more than counterbalances its side effects. objective: to define the optimal volume of dilution for endotracheal (et) administration of epinephrine (epi) design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine (1.2, 5, and 10 ml of saline) setting large animal research facility ofa universi~ medical center subjects and interventions: epinephrine (0.02 mg/kg) diluted with four different volumes ( 1, 2.5. and i 0 rot) of normal saline was injected into the et tube of five anesthehzed dogs. each dog served as its own control and received all four volumes in different sequences at ieast one week apart. arterial blood samples for plasma epinephrine concentration and blood gases.were collected before and 0.25, 0.5. 0.75_ 1.2.3, 4. 5. 10, 15.20, 25.30 , and 60 minutes after drug administration. heart rate and arterial blood pressure were continuously monitored. measurements and main results: higher volumes of diluent (5 and i0 ml) caused a significant decrease of pao2, from 147:!:8 tort to 106±i0 torr, compared to the tower volumes of diluent (1 and 2 ml), from 136±10 torr tu135+_7 torr (p<0.05). these effects persisted for over 30 minutes. mean plasma epinephrine concentrations significantly increased within 15 seconds following administration for all the volumes of diluent. mean plasma epinephrine concentrations, maximal epinephrine concentration (cmax), and the coefficient of absorption (ka) were higher in the 5 ml and 10 ml groups. the time interval to reach maximal concentration (tmax) was shorter in the 5 ml and 10 ml groups. yet these results were not significantly different. heart rate. systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. conclusions: dilution of endotracheal epinephrine into a 5 ml volume with saline optimizes drug uptake and delivery, without adversely affecting oxygenation and ventilation. the aetiology and outcome of paediatric out-of-hospital cardiac arrest was studied during a 10-year period in southern finland served by physician staffed emergency care units. the files of 100 prehospital patients less than 16 years old without palpable pulse and spontaneous respiration were analysed retrospectively. fifty patients were declared dead on the scene (dos) and resuscitation (cpr) was initiated in 50 patients. the sudden infant death syndrome was the most common cause of arrest (68%) in the dos patients as well as in patients receiving cpr (36%). asystole was the initial cardiac rhythm in 70% of the patients in whom cpr was attempted. eight of the 13 hospitalised patients were discharged, 6 of them with mild or no disability, 1 with moderate disability and one in vegetative state. in multivariate analysis the short duration of cpr (<16 minutes) was the only factor significantly associated with better survival. due to various aetiologies the survival rate from prehospital paediatric cardiac arrest is quite low. on the other hand, hypothermic near-drowning victims seem to have a relatively good prognosis. duration of cpr less than 16 minutes was the best predictor of intact survival, our study supports the previous findings of the importance of early and effective resuscitation efforts for establishing ventilation and perfusion on the scene. in our system well trained physician staffed emergency care units are able to provide immediate and effective als on the scene. on the other hand, these units also appear to be able to refrain from resuscitation when the prognosis is pessimistic. objective: to assess the normal ,gastric intramucosal ph ~hi) by tonometry in healthy children patients and methods: twelve healthy children (6 males and 6 females) with age rmaged from 6 months to 12 years scheduled for minor plastic or urologic surgery. children were previously medicated with midazolam (0.25 mg/kg) and atropine (0.02 mg~) both i.m.. anaesthetic induction was standardized with 02 -n20 (75%) administered via facial mask and increased halotane concentrations (up to 2%). all patients got an endotraeheal tube after iv. administration of femanile (2 mcg:jkg) and vecuronium (0.1 mg/kg) or suxametonio (1 mg/kg), pmaesthesia was maintained with o 2 -n20 (60-75%) and isofluorane (0.5-1%). during surgery, 8 children needed mechanical ventilation and the others maintained spontaneous breathing. ekg, heart rate, blood pressure, and pulse oximetry were moniterized. after anaesthesia, a sigmoid tenometry catheter (tonometrics, inc.) was inserted in the stomach of the patients by direct visualization with laryngoscope and magyll clamps. children were all maintained normoventilated and with normal cardiorespiratery variables. cadet's balloon was £~led with 2.5 ml of saline. thirty minutes after the insertion 1 rrd was extracted and rejected, just afterwards the remanent 1.5 ml was extracted and immediately analyzed. simultaneously an arterial gasometry by puncture was performed. gastric phi was calculated by the henderson-hasselbalch's equation using the pco 2 obtained from the tenometry catheter and the bicarbonate value obtained from the arterial gasometry. results: average gastric phi was 7.34 -i-0.027, range (7.29-7.46). objective: demons~ating intramucesai ph (phi) alterations during transport of patients from operative room to pediatric intensive care unit (picu), material and methods: phi measurements were performed with gastric tonometer catheter in t4 patients undergoing cardiac surgery with cardiopulmona d" bypass (cpb), there was 9 mate and 5 female, the average age = 3yl0ra, average weight = 12,5 kg, average time of cpb = 70 rain. the measurements were made at the end of the surged' and when the patients had arrived in the picu statistical aualysis: average and ~andart deviation and test "t" student. objetive: to asses the efficacy of gastric iatramucosad ptt (phi) and arterial lactate levels to evaluate splacalc tissular perfusion in an experimental model of intestinal ischemia. suneets ~nd methods: twelve piglets weights t3-20 kgs. undergoing orthot~ie liver trasplantation. the intestinal ischemia was induced by aortic damping. tonometry catheter (tonometrics inc.) w~s placed in the stomach after artaesthesia and ot intubation. phi ~s determined 7 times and lactate levels was determined fi times in 3 stages: i) pre-ae~hepatic stage (twice: before surgery and before aortic clamping ); ii) end anhepatic stage (only phi): iii) reperfusion stage (a 30, 90, 120 and 180 minutes). the phi was derived from application of the henderson-hassdbach formula using the pco2 value from the tonometer and the arterial bic~rbonate. all pipets received raaitidiila before sttrgery. values of phi above 7,35 and lactate levels between 6 and 15 mg/dl were considered nortrm. the results were statistically anaj.izated with anova and bonferroni tests. results: the phi was normal on pre anhepatic stage (> 7,35) and lactate levels were slightly increased (21, 5 +_ 8, 9 and 19, 5 ±5, 9mg/dl ns) . in relalion to we-anhepatics values, phi decreased signncatly at the mid of anhevatic stage (7,39_+0,14 vs 6,94_+0,1 p<0,001), phi remain low in stage iii, at 30 rain (6,86+0,12 p< 0,001) and 90 min(g94-+o, 12 p< 0,001). arterial lactate levels increased significatly in relation to levels in stage i, at 30 rain (63,6_+9,7 p<0,o01) arid 90 rain (65,8±9,9 p<0,001) of reperfusion stage. there is a slight improvement on phi and lactate ievels at 120 and t80 rain althought the differences did not reach significance. cnmments: phi and arterial lactate levels propperly reflect hypoperfusion on the experimental model of acute intestinal isdlemia. b~kground : the paediatrie gallbladder diseases generally described are calculous ¢hol~tstitis, cystic duct obstruction, congenital anomaly of the biliary tract, and inflammation. in the neonatal period, noulithogenie gallbladder disease could be also due to erythroblastosis or hyperalimentation. obieetive : we describe an other type of disease affecting the gallbladder in neonates thought to be related to their vascular vulnerability. methods : four patients with abnormal gallbladder ultrasound not related to classical observations were included. we have studied and reviewed the biological and clinical data, the ultrasound findings and their evolutions. results : four patients, 30 to 32 ~.k-old neonates ~ffth a birthweight be~,een 1,3 and 1,9 kg, were intubated and under total parenteral nutrition for 10 to 35 days. none of them were symptomatic on repeated clinical evaluations. one newborn developped hypotensien on umbilical bleeding at 3 hours of life. in two cases, signs of cholestasis were discovered : the total bilirubin level has risen to 5 mg/dl; the direct bilirubin level was 1,5 mg/dl while the urina were dark and the ~o~,ls :mcolour~. the c~mplct~ ~crology as a!! the culvare~ remained negative. the ultrasound explorations were atypical : in the four eases, an initial increasing broad and thickness of the wall of the gallbladder with an hyperecbogenie inside content, which was not sludge, was discovered. in three eases the images resolved in ten to fifteen days. in one ease, an asymptomatie thrombosis of the vena portu which remained patent was discovered. in this case, at one month, the ultrasound showed images encountered in chronic ebolecystitis and, at one year, the gallbladder appeared atrophic. none of them underwent surgery. conelusiou : the gallbladder diseases are multifactorial. besides the prematurity, the infections, the total parenteral nutrition, the premature neonate is exposed to vascular vulnerability affecting also the gallbladder and this may explain our findings. progress in prognosis of pts with b-nhl had followed the use of multimodality chemotherapy (ct). with the prolonged survival, there are comlications due to myetosupression & desease process. the syndrome of neutropenic enterocolitis (ne) is one of the ominous problems because ofpts increased susceptibility to infection & overwhelming sepsis. this material included 25 neutropenic pts (4-14 years) with the stages iil& iv of b-nhl who were treated with the modifired bfm-90 (mtx 1 g/m 2 in 24-h inf.); 22 males, 3 females. seventeen episodes of ne were observed & only after the first 2 courses of ct (13 of 25 after tst, 53%; 4 of 24 after 2nd, 17%). the symptoms existed 3 to 14 days. wbc ranged from 50 to 600 in l~tl (median, 100). the first signs of ne were directly correlated to the beginning of the neutropenia & the recovery of neutrophils led to the disappearance of abdominal recovery of neutrophils led to the disappearance of abdominal pain. the conservative treatment included gastrointestinal tract decompression, broad spectrum antibiotics initially, volume & electrolyte substitution, nutritional support, correction of acid-base balance, symptomatic treatment. sixteen pts were treated nonoperatively, 1 died. on autopsy the transmural bowel necrosis due to thrombosis of branches of a.mes.sup, was found. the bowel perforation occurred in one patient, he was undergone laparotomy & hemicolonectomy & survived. we conclude that ne is a frequent complication in neutropenic pts with the st. lii& iv of b-nhl. it occurs after the induction courses of ct. close observation by surgeons, oncologists & pediatric intensivists is mandatory. conservative treatment is effective & more preferable until leucopenia resolves. operation is necessary only for those.with perforation. near infrared spectroscopy as a tool for evaluation of intestinal perfusionpresentation of an animal model. c. scheibenpflug, p. buxbaum and a.m. rokitansky the recent development of and investigations in the so called near infrared spectroscopy ( nirs --transcutanous emission and simultaneous registration of intensity of spectralcolours depending upon modulations of tissue perfusion ) enable physicians to measure and qualify organ perfusion and nowadays is mainly used to control cerebral as well as skeleton muscular blood flow in trauma patients at intensive care units ( icu ). today intestinal perfusion, hypoperfusion , cell damage caused by reperfusion injury, bacterial and toxin translocation are serious problems in critically ill patients at an icu. paediatric intensive care physicians put major concern on intestinal perfusion, which for. instance gains more and more importance, especially in the neonatal period for example as an etiologic factor for necrotizing enterocolitis. we established an animal model, in which we measured intestinal perfusion by nirs under various invasive and noninvasive conditions. methods and results will be referred. for preliminary conclusion we propose near infrared spectroscopy ( nirs ) also as a potent diagnostic tool to determine early intestinal malperfusion in order to prevent lethal outcome. fm'ther investigations in animals as well in paediatric iritensive care patients should be done to estimate our efforts. introduction: following the acute phase of necrotising enterocolitis (nec) starvation of the gut for a period up to 3 weeks is a generally accepted treatment modality in many centres. objective criteria to refeed these patients are hardly available. recently the double sugar test has become available as a parameter for (ab)normal gut permeability ~'2. aim of the study: to evaluate the changes in permeability of the small bowel in patients with nec and controls before introduction of enteral feeding. methods: a lactulose! rbarrmose (i/r) test was performed in two groups. group 1 was studied 2-3 times within a 5-week period of starvation (n=5, mean gest. age 35, range 31-40 weeks). in group 2 seven different control patients were studied (mean gest.age 33, range 28-38 weeks). the test was performed by giving a patient after at least a 4 hour fast 1 ml/kg bodyweight l/r solution and determination of the 1/r ratio in a 4-hour urine sample by chromatography. results: objective: to evaluate the prognostic factors in the response to nitric oxide (no) in children with acute respirator/ distress syndrome (ards) and/or pulmonary hypertension (pht). patients and methods: 23 critically ill children received no inhaled for ands and/or pht treatment. 14 patient before and after cardiac surgery (2 cardiac transplants), 5 with bronchopneu~onia, 2 multiple trauma, 1 sepsis and 1 cardiorespiratory arrest. 15 patients showed /j~ds and 8 pht, in 4 with associated ards. we analyzed age, sex, diagnosis, pao2, pa02/fi02, oxygenation index, pht, shock, and sepsis as prognostic factors and response factors to n0. results : after no administration oxygenation did not improve in 2 patients (8.6 %) and pht did not diminishe in one children (12 %). 12 patients survived (52 %), 8/15 (53.3 % with /d%ds) and 4 /8 (50 %) with pht. the four patients with isolated pht survived , and the 4 patients with pht and ards dead. patients after cardiac surgery presented less mortality (35.7 %) than the rest of patients (66.6 %). patients with shock presented higher mortality (64.2 %) than the rest of patients (22.2 %). there are no differences in response to no in respect of sex, age, diagnosis, shock, and sepsis. survivors showed higher increase of pao2/fi02 64.3 ± 58.4 to no than non-survivors 48.4 ± 51.1 (n.s). patients with pht showed higher increase in pa02/fi02 to no administration ( 88 ± 47.1) than patients with ards (43.4 ± 50.8), (n.s), but patients with ards showed a higher increase in 0!, 15 ± 6.7, than patients with pht 4.8 ± 4 (p < 0.05). patients with pa02/fi02 < i00 showed less increase in pa02/fi02, 47.8 ± 46.3, than the rest of patients 82.8 ± 65.5 (n.s) conclusions: i. mortality of isolated pht treated with no is less than patients with ap~s. patients with shock and those with pht and ards showed higher mortality. 2. we have not found any clinical or analytical factor to predict clinical response to no administration. 14 patients showed ards, and 9 severe pht after cardiovascular surgery, in 5 with associated ards. we registered respiratory assistance, blood gases, pao2/fi02, the oxygenation index (oil, and mean pulmonary pressure/ mean systemic pressure (pap/sap) before and after no inhalation. we measured continuous concentration of no and no2 by electrochemical method (noxbox, bedfont, airliquide). results: no administration improved oxygenation mean pao2 from 74 ± 17 tm~g to i19 ± 54 ~g (p < 0.01), mean pa02/fi02 fr<xa 83 ~ 30 to 13£± 72 (p < 0.01)and 0i from 28 ± 14 to 20 ± 12 (p < 0.01). 2 patients did not improved with no administration. the oxygenation improved in the first five minutes and the best oxygenation was achieved with 5 -15 ppm. there is no significant change in pac02. pap/sap diminished from 62 ± 17 % to 42 ± 9 % ( p< 0.05), in one patient there is no response. the no administration was maintained between ~5 minutes to 47 days. the effect of no on pulmonary pressure and oxygenation was maintained without change during all the time it was administrated. n02 concentration were always less than 2 ppm y metahemoglobinaemia less than 3.5 %. there are no side effects secondary to no administration. 12 patients survived (52 %). concluaions:l.administration of no improves oxygenation in children with ~/eds and diminishes pht after cardiac surgery. 2.no effect is fast and maintained during the evolution. high frequency oscillatory ventilation in combination with inhaled nitric oxide g~thberg sylvia, md, edberg k e md, phi), dept of paediatric intensive care, children's hospital, s-416 85 g6teborg, sweden background: for man), years severely sick infants with congenital heart malformations or acute lung disorders have died due to pulmonary hypertension, hypoxia and multiple organ failure. today there are several therapeutic facilities coming up for these infants. ecmo progranunes have been introduced in severul centres as well as improved venlllatory techniques, as high frequency oscillatory ventilatior~ (hfov), which provides adequate ventilation with less risk for hmg injury.. in 1987, the endothelium derived relaxing factor was identified as nitric oxide (no), and extensive studies have sho~-a that inhaled no reduces pnimonm3 o vascular resistance and improves oxygenation in hypoxic infants with pulmona~ hypertension. material.. from july 1994 to january 1996, we have treated 13 severely hypoxic children with combined ttfov-no. seven were newborn, 3 with cdh, one with mas, one with irds, one with paediatric ards due to rsv infection and one with poor oxygenation atler open heart surgery. 6 were between 1 month and 9 years and all had ards of differentorigin but one who was hypoxic after open heart surgery. method: hfov was given by means of sensormedics 3100a oscillatory ventilator to 12 patients, and dr~ger babylog 8000 was used in one case. mean airway pwssures varied from 10-34 cm h20. oscillatory pressures varied from 25-85 cm h20 and ventilatory rates from 6-15 hz. fi o2 varied from 0,21 -1,0. no was administered by nomius classic. no and no2 was measured in the inspiratory limb with an electrcchemieal device. noconcentration varied from 2 to 20 ppm and the no2 -concentration between 0-0,2 ppm. methemoglobin was never more than 3,7 % (average 1,7). duration of treatment varied from 1 to 20 days. combined trealment with hfov and inhaled no improved oxygenation and carbon dioxide elimination in 12 out of 13 treated childretl 5 patients died, 3 due to their underlying congenital heart disease, one of asphyxia due to rsv-infection and one of cdh with progressive hypoxia and multiple organ failure. combined treatment with hfov and inhaled no improves oxygenation in severely hypoxic children. treatment should be slarted early to reduce the risk for chronic lung injury following barotranma and high oxygen concentrations. we speculate that the combined hfov-no may reduce the use of ecmo, and that it may improve outcome in ceotres where ecmo programmes are not introduced. apart from its vasodilative properties nitric oxide appears to act also in physiologic immune defense. intracetlular concentrations of no synthesized by macrophages are in the range of 103 above those produced by vascular endothelium. we investigated the bacteriostatic effect of nitric oxide at concentrations used during inhaled therapy for pulmonary vasodilation in neonates. ten different strains of five species were used (staph. anrens, staph. epidermidis, strop. group b [gbs], e. coil and pseudomenas aeruginosa), which are ~e most often tracheally isolated bacteria in mechanically ventilated premature infants and neonates. we compared bacterial growth of cultures applying three different concentrations of nitric oxide (40 ppm. 80 ppm, 120 ppm) m the growth of the same strains in room air for a duration of 24 hours. no bacteriostatic effect was demonstrable at no concentratioes of 40 ppm. e. coil showed decreased bacterial growth at 80 ppm and 120 ppm, however without reaching statistical significance (p=0.058). at nitric oxide concentrations of i20 ppm staph. epidermidis and gbs grew significantly less as compared to colonies of the same strains in room air. no effects were found regarding the growth of staph. aureus and pseudomonas aneruginosa. we conclude that nitric oxide has a selective bacteriostatic effect on some of the most often trachealb, isolated bacteria in premature infants and neonates. this effect appears to be dose-dependant and occurs in the upper range of dosages used with inhaled no therapy. further research is required in order to examine the mechanisms of action as well as specific interactions between different strains of bacteria and nitric oxide. the no,box monitor (bedfont, kent, uk) is used to monitor nitric oxide (no) and nitdc dioxide (no 2) during no administration in ventilated neonates. according to the manufacturers specifications the monitor can be applied in cases where airway pressures range from 5 to 50 mbar. we investigated in-vitro the accuracy of the no monitor in a range of ventilatory conditions. using a dr~ger babylog 8000 we ventilated an artificial lung. no was administered {800 ppm no in 100% nitrogen) with a mass flow controller to the inspiratory tube, at a distance of 20 cm from the y-piece. the no target value was set to 10 ppm. the ventilator was operated in both cpap and ippv modes at different settings. the no sampling tube was placed on two different locations; in the inspiratory tube dose to the y-piece; in the expiratory tube haft way between the y-piece and the ventilator. the no-monitor was ca)ibrated with 84 ppm no at 30 mbar. fig. 1 and 2 show the sensitivity of the no-monitor for respectively static pressure (cpap) and pulsatile pressure (ippv) with the sampling tube located in the inspiratory tube. fig. 3 shows the resur for pulsatile pressure with sampling in the expiratory tube. we conclude that the accuracy of the bedfont no-monitor is dependent upon airway pressure and sampling site, the latter possibly caused by incomplete mixing, pressure and no are linearly related when sampling occured further away from the administration site. based on this study we suggest to place the sampling tube in the expiratory tube. during neonatal care the clinician should be aware of varying inaccuracies depending on the respiratory pressures. hypothesis: availability of therapy with inhaled nitric oxide (ino) decreases ecmo use in patients referred .to a tertiary care hospital for treatment of respiratory, failure unresponsive to conventional therapies. background: at children's hospital of wisconsin (chw) treatment for patients who have failed conventional treatment for respiratory failure, sometimes called "rescue" therapy, has included ecmo since 1986 and high frequency oscillatory ventilation since 1992. ino has been in experimental use at chw since may of i994 and has resulted in the perception of a decreased need for ecmo therapy in those patients referred for rescue therapy. this study was designed to tbst the validity of that perception. study type: retrospective cohort. methods: the medical records of all 105 patients referred to chw from 1/lj93 to 4/1/95 for rescue therapy for severe respiratory failure were included in the chart review. data were collected regarding diagnoses, illness severity, hospital course including interventions and complications, and outcomes. exclusion criteria w~ere the finding of structural heart disease or congenital diaphragmatic hernia as the basis for hypoxemia. qualification for ino treatment included an a-ado2 -600 or oi ~-40 for two hours or -> 25 for twelve hours and echocardiographic demonstration of persistent pulmonary hypertension of the newborn. patients were classified into two groups based on the availability of ino at the time of their hospitalization. results: in the time period of the study, 105 patients were referred for possible ecmo therapy. twelve patients greater than 4 weeks old, 31 with congenital diaphragmatic hernia and 12 with congenital heart disease were excluded from this analysis, leaving 50 patients for study, ino availability reduced ecmo use from 16 of 34 (47%) patients in the ~ino unavailable" group to 2 out of 16 (12.5%) patients in the "ino available" group, p=&026 by fisher's exact test. the fact that the two groups were composed of patients of similar severity of illness is reflected by comparable rates of ecmo and ino rescue therapy (47% vs. 56%). conclusion: by providing an alternative rescue therapy, ino has reduced the need for ecmo in this group of neonates referred for respiratory failure. introduction: true hepatnrenal syndrome (his) is defined an acute renal failure {arf) in the presence of severe liver disease without other known causes of renal failure. hrs is frequently seen in the course of hepatic cirrhosis• in children, cirrhosis is rare; however, arf can be seen in combination with aseites and liver dysfunction• we describe 3 patients with hepatic dysfunction and aseites in combination with ar~ and abnormal sodium-water handling, leading to the diagnosis of hrs. pathophysiology: three factors are considered in the pathogenesis of hr~: i) hepatic dysfunction, 2) deranged hemodynamics, including abnormal blood pressure, reduced effective arterial blood volume and abnormal blood flew distribution, and 3) neuro-humoral dysrsgulatiom, including elevated levels of aldosteron, renin, angiotensin-ll, ade, vasodilatim 9 nitric oxide and vasoconstrictor peptide endothelin-l. the main pathogenetic feature is decreased cortical renal blood flow, decrease of glomerulur filtration rate (gfr), vastly increased sodium retention, uliguria, and azotemia. treatment: therapy is based on counteracting sodium and fluid retention by highdose aldosteron antagonists and loop diuretics, improving renal perfusion by lowdose dopamin, and strict restriction of fluid and sodium. interventions as paracenteals of aacites or n peritoneo-systemic shunt are associated with high morbidity and poor outcome in children. reversal of hem by conservative measures can only be attained at early stages of hrl liver transplantation is the only definitive treatment that can reverse ere at advanced stages. patients: the described patients developed severe ascites with insidious renal dysfunction and abnormal sodium-water handling during admission at picu and fullfilled clinical criteria fur hrs. treated according to the cited principles, all patients showed improvement of gfr, with increased natriuresis and gradual decrease of ascites. eventually, renal function normalised completly. conclusion: ere deserves greater recogmitimn in the picu population; diagnosis can be suspected on clinical criteria. with this increased awareness, therapy tun be instituted at an early phase, with better prospects for recovery. positive outcome of hem depends on early recognition of the clinical picture, understanding of the pathophysiology, and early institution of consistent treatment. mtx is an antimetatxflite widely used as chemotherapeutic agents. high dose ivitx (i to 30~m2) administered as a prolonged intravenous infusion (over 4-42 hours), is often used to treat malignant paediatric diseases. major complications of this treatment are myelosuppression, orointestinal mucositis, dermatitis and impairment of anal function. we report two cases of mtx overd~age occurred in two children (5-year-old. 14 month-old) t~ted for acute lymphoblastic leukaemia. they were treated by cavh and the mtx bhk~d levels rapidly decreasedavoiding multisystemic involvement. establishment of alkaline diuresis and monitoring of plasma mtx levels during treatment is essential to prevent nephrotoxicity. however. leuco',cnn rescue may not prevent the development of potentially lethal toxicities in patients with mtx concentrations persistantl} exceeding t0mm. in theses cases, em'ly treatment of mtx intoxication may pm~cnt myelosuppression and reducerenal damage. the goal is to lower the concentration to below 10 mmoll, at which time rescue agents aleme would be expected to be cllcctive. respective indications of these remo',at mctny.:is are still discussed : hacmt~ialysis t~ eharc(~l haemoperfusion should be prolx',sed for massive and acute intoxication. however, rebound has been reported after combined hcmodialysis and hemoperfusion. exchange transfusion may be proposed as a treatment for prolonged and moderate intoxication. peritoneal dialysis is an incflbedve method for remo~ al of mtx. cavh was used in our icu. cavh is a simple method for blood purification and n':dy iluid control. use of cavh was never be reported in this indication to our knowledge. simplicity, rap~d application and gco.l clinical tolerance are the main advantages of this technique. the technique presents ~peclal advantages in terms of low priming volume of extracorporeal circuit, low blood flow, low rate heparinisation. our results show a decreaseof plasma mtx concentration and a rapid reduction of halfqite of elimination (t5 hours over the period of cavh). moreover, we didn't delec~d rebound after stopping prc,xedure. small size of the i:ratients may present sometime special problems, but these technical problems can be overcome, no severe complication (needing, inlection) were observed during filtration, in summary, aggressive intravenous fluid hydration and alkaliniaation of the urine coupled with careful monitoring of renal function and plasma mtx concentrations during and al'tcr infusion along with lem~overin rescue has reduced the inndcace of life-threatening toxicity after highdose mtx. however, some mtx inu>xication still occurred, leading to se~em toxicity, particularly nephrotoxicity. in these cases, we think that cavh (or cavhd) is a reliable, rapid method without rcix~und increase in plasma mtx concentration or important adverses effects compared to other procedure removal. gouyon jb, germain jf, semama d, pr6vot a, desgres j preliminary limited data suggested that hemofiltration and hemodiafiltration may be valuable in some neonates with decompensation of maple syrup urine disease (msud). venovenous hemofiltration (vvhf) and hemodiafiltration (vvhdf) were performed with a new neonatal hemo(dia)filter (miniflow 10, hospal) on 8 anesthetized rabbits infused with branched-chain amino acids (leucine, isoleucine and valine) and c~-keto-isocaproate. the bcaa and aketo-isocaproate blood levels were close to those previously observed in neonates with msud when extracorporeal blood purification was required. vvhf and vvhdf performances were assessed with two different blood flows (qb = 8.3 and 16.6 ml/min). vvhdf was performed with 4 dialysate flow rates (qd = 0,5, 1.0, 2.0 and 3.0 l/h). thus, each animal was submitted to 10 successive procedures. within each studied period, clearances of the 3 bcaa were strictly similar. bcaa clearances obtained by vvhf were similar to ultrafiltrate rates (respectively, 0.78 4-0.14 and 1.79 4-0.28 ml/min at high and low qb ; p < 0.05). the ~x-keto-isocaproate clearances obtained by vvhf were 0.39 4-0.17 and 0.92 4-0.43 ml/min at low and high qb (not significantly different). whatever qd value, the vvhdf procedures always allowed higher bcaa and c~-keto-isocaproate clearances as compared with the corresponding v'~hf period with similar qb. bcaa clearances obtained by vvhdf with a 0.5 l/h dialysate flow, were 4.1 4-0.5 mljmin and 5.4 4-0.5 ml/min at iow and high qb, respectively. the concurrent a-keto-isocaproate clearances were 2.5 4-,. 0,8 ml/min and 2.9 _+ 1,0 ml/min. at both qb regimens, bcaa clearances provided by vvhdf were markedly higher than values previously obtained with peritoneal dialysis in human neonates with msud. the management of renal failure in the newborn is difficult. when dialysis is instituted peritoneal dialysis (pd) is usually the technique of choice. this is can be problematic and impossible in some patients with pre-existing intra-abdominal pathology. continuous arterio-venous haemofiltration (cavh) has been described in infants but sick preterm infants are not able to support the circuit. i have devised a means of having pumped haemofiltration in small/preterm infants (phis/pi) and describe its use in nine patients ranging in size from 750 to 3000gms for periods of 1 to 7 days. vascular access was achieved through 24 or 22 guage cannulae in either a peripheral artery and a central vein or through two central veins. blood was pumped out using an ivac 572 infusion pump and through a gambro fh22 haemofilter. a second ivac pump was used to remove haemofiltrate from the filter and a third to infuse replacement solution. removal rate was set to give a clearance of 15mls/min/1.73sq.m and blood flow rate set to between 5 and 10 times the removal rate. heparin was infused into the circuit to prevent clotting of the filter. biochemical and fluid balance control was achieved in all infants. guaranteed fluid removal allowed the administration of full nutritional support. four patients died when treatment was withdrawn because of an untreatable underlying problem. one recovered renal function but died some weeks later from unrelated problems, three survived and recovered renal function and one patient is still on treatment. this system allows a secure means of achieving fluid and electrolyte control in the preterm infant. the use of this technique may allow haemofiltration to become as applicable to preterm infants as it is to older children and adults. unibrtunately, children often receive no treatment, or inadequate treatment for pain and painful procedures. this prospective, multicentric study focuses on the efficacy, safety and side effects of novalgin (metamizol sodium) for this indication. patients and method: novalgin was administered to 56 children, aged between 6-16 years, with acute, postoperative or procedural pain. novalgin (10-15 mg/kg) was given 6-8 hourly iv or im respectively, in some cases (15) in combination with opioids (tramadol 10, piritramid 3, butorphanol 2). the pain relief was assessed by six-step verbal rating scale (vrs) from 0 to 5, vital signs were monitored, the side effects, that occured were recorded. results: pain relief was good (vrs less 2) in 53 children -94.6 % of study patients. novalgin was very well tolerated, only one patient had adverse reaction -hyperpyrexia following intravenous application of the drug. discussion: novalgin (metamizol sodium) is safe and effective drug in the management of acute pain in children with low incidence of side effects. obie~qve: a prostx~tive study comparing simultaneous, indepeadent ratings conducted by intensi~4sts using an american (comfort) and an european chartwig) sedation scale for mechanically ventilated pediatric patients. measurements and results: the study comprised 30 observations in 18 mechanically ventilated pediatric patients (aged 16 days to 5 years) in a pediatric intensive care unit (from march 1995 to january 1996 . each patient was sedated by his/her managing physician with opiates, benzodiazepines, barbiturates, used isolated or in combination. each observation consisted of a 3-mid period of oly~ervatien of the patient in his or her pediatric icu bed, after each observation, the comfort (analyses 8 dimensional physiologic and behavioral subscores -range 8 to 40 paints) and hartwig (analyses 4 dimensional behavioral subsenres -range 8 to 25 points) were performed by the intensivist. we established the comfort scores ~ correspanding to adequate (range 17 to 26), excessive (range 8 to 16), and inadequate (range 27 to 40) sedation; and, hartwlg scores z correslxmding to adequate (range 15 to t8), excessive (range 8 to 141, and inadequate (range 19 to 25). statistical mmlysisj: agreement rate (kappa) and p <.01 was considere d s!l~nificant. comfort 18 (60.9%) 2 (6,6%/ 10 (33.4%) hap, twig , 17 (56.6%) 7 (23.4%) 6 (20.0%) to the comfort score, the average for adequately sedated, inadequately sedated, and too sedated was 20.28+-2.78, 2z5_+0.70, and 15a.+_l10, respectively. and to the ha~twig scorn, the average for adequately sedated, inadequately sedated, and too sedated was 16.35:k-'0.77, 20.85-&l57, and 13.0l-0.89, respectively. conclnsion: in our study there were no significantly statistical difference when you apply a more complex scale (conff'ort) or a less complex scale (hartwig) to assess the sedation of mechanically vemilated pediatric patients. the application of local and intravenous morphine infusion after surgery of urinary tract eva nemeth , m.d. semmelweis medical university , first oepartment of paediatrics , budapest , hungary in±roduction:continuous analgesia with morphine may be ~egaroed as a safe and effective method of pain relief during postoperative period. subjects and methods: 24 children /mean age 2.3 years/ underwent elective ureteroneoimplanta±ion were randomly selected to receive either morphin intravenously of lo ug/kg/h /group one/ or bladder morphineinfusion 50 ug/kg/h /group two/ after surgery. all patients were prospectively evaluated during their s±ay in the postanaesthetic care unit. cardiac and respirafory rates,blood pressure,sa 02 ~,degree of alertness,pain perception and complaints of the paticnto ~cr~ recorded hourly. pruritus,nausea and vomiting,voiding difficul-±ies,sedation,dysphoria were systematically sough and quoted. statistical analysis was performed by chi square test. results:postoperative analgesia was the same in the two groups,but side effects were less in the bladder morphine group,because of the lower se morphine concentration.the differentes weren't significant in two groups. conclusions:the administration of bladder morphine infusion is a safe and effective method in children. objetive: compare the evaluations of sedation level made by physicians and nurses with the visual analog scale (vas) and the comfort scale (cs) in pediatrics patients receiving difforents modes of intravenous sedation. material ~ method." file evaluations were made by an attending physician and nurse with the vas and by another physician (always the same) using the cs. the observations were divided following the sedation mode: one drug (fentanyl or midazolan), two continuous drugs, one continuous and one intermi~ent drug and two intermittent drug (fentanyl and midazolan). the groups were compared using the t-student test. the groups also were compared between the percentual of agreement of the evaluations of sedation level made by physicians and nurses with the cs and vas using the x 2 . results: we didnk find any statistical difference between the observations made by physicians and nurses with the vas in the differmts modes of intravenous sedation, the average of the observations using the cs betwom one drug and two drugs modes didnk exhibit also statistical difference. the observations made by physicians mad nurses using the the vas when compared with the cs didn't show statistical difference between the sedation level. we found statistical difference only in percentual of concordance of sedation level between physicians and nurses when compared the one and two drugs modes of sedation. conclusion: we didn't find differences in the observations made by physicians and nurses in the sedation level, only in concordance pereentua/ of observations when compared two modes of sedation. the observations using the cs (more complex) didnk show differences when compared with the vas. effects of age, concurrent administration of other pharmacologic agents, and disease [cardiac(n=31) & pulmonary(n=22)] on the pk & pd of b were evaluated in volume overloaded infants aged 4 days-6 mo (n=53). single doses of 0.005,0.01,0.015,0.02,0.025, 0,03, 0.035,0.05 & 0.10 mg/kg iv were given over 1-2 min after baseline evaluation. age was used as a continuous vadable to determine its effects on the variability in the pk & pd of b. values for pk parameters were compared between patients in cardiac and pulmonary disease groups. hierarchical multiple regression analyses were used to determine the effects of age, disease and other pharmacologic agents on the variability of bumetanide excretion rate (ber) and pd responses, e.g. urine flow rate (ufr) & electrolyte excretion. cit, cir & cinr increased with age (p<0.05) while t,2decreased markedly in the first monthe of life (p<0.05). ber normalized for dose increased with increasing age. patients with pulmonary disease exhibited significantly greater clearance and shorter t~= (p<0.05) than those with cardiac disease whereas vd~ was similar in both groups. the administered dose of b was the primary determinant of ber but increasing age also contributed. penicillin antibiotics decreased ber. dose response curves for ufr and electrolyte excretion were similar between disease groups. more of the variability in ber and pd responses could be accounted for in the pulmonary group than the cardiac group but this was not statistically significant. conclusion: the pk of bumetanide were influenced significantly by age and disease. differences in pk between patients with pulmonary and cardiac disease were primarily due to differences in total clearance. age and the administered dose of b were positive determinants of ber and pd responses while penicillin antibiotics had a negative impact on both, once b reached its site of action, no differences in pd responses were detected between disease groups. the pharmacodynamic effects of bumetanide were evaluated in volume overloaded infants (n=56) aged 4 days-6 months. single doses of 0.005, 0.01,0.015, 0.02, 0,025, 0.03, 0.035, 0.05 & 0.10 mg/kg iv were given over 1-2 rain. bumetanide concentration in blood (n=l 0) & urine (n=6) samples were quantified by hplc. baseline urine samples were collected over 2-4 hours prior to drug administration. determinations of urine volume, electrolytes (na ", k +, ci, ca ++ and mg++), creatinine and osmolality were performed before and at 0-1, 1-2, 2-3, 3-4, 4-6 and 6-12 hours after bumetanide dosing. changes in urine flow rate and electrolyte excretion were plotted as a function of bumetanide excretion rate which was considered the effective dose of the drug. peak bumetanide excretion rate increased linearly with increasing doses of drug and showed no evidence of approaching a maximum. time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. urine flow rate and electrolyte excretion increased lineady up to a bumetanide excretion rate of approximately 7 #g/kg/hr and either plateaued (urine flow rate) or declined at bumetanide excretion rates > 10 #g/kg/hr. bumetanide had no detectable effect on serum electrolyte concentrations, conclusion: maximal diuretic responses occurred at a bumetanide excretion rate of about 7 ;~g/kg/hr. higher bumetanide excretion rates produced no increased diuretic effect. peak bumetanide excretion rate of about 7 #g/kg/hr corresponded to bumetanide doses of 0.035-0.050 mg/kg. neonates using an electrical syringe-pump. authors: tr~luyer j.m., sertin a., bastard v., settegrana, c., bourget p., hubert p. background and objective: many problems can be observed with drug administration by i.v. route, especially in neonates. so we evaluate different protocols of teico delivery using an electrical syringe-pump. methods: we simulate infusion of teico with a syrlnge-pump (pilot c, becton & dickinson lab.) trough d standart neonatal i.v. system. for 2 weights (1 or 3 kg) we used 2 doses of teico (8 mg and 16 mg/kg) and a dose volume _<4.2 ml. our goal was to perform a complete infusion in 10 minutes. the infusion system consisted of an life care 4 infusion pump (abbott lab.) with its lv. set for maintenance intravenous fluid (flow _< 6 ml/h) connected to a 3-way stopcock. an 1 meter extension tubing was placed between the stopcock and a neonatal catheter. an another 1 meter tubing (injection tubing) connected the teicoplanine syringe to the stopc, ock. the volume of the injection circuit (from the syringe to the distal part of the catheter was 2.6 ml 4 methods of injections were assessed: a: injection of the predetermined volume of teico in 10 minutes with no wash out. b: idem as a but the teico was injected in 5 minutes, followed by a wash out (5 ml / 5 minutes). c: twice the required volume was introduced in the syringe and the volume to infuse was programed in 5 minutes, followed by a wash out (5 ml/5 minutes). d: ]dem as c but a priming was performed before connecting theteico syringe to the tubing. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at 10 minutes were calculated. the results are a mean of 2 to 6 runs and expressed as the percentage of the total amount of teico prescribed. a 2,8 % 6,4 % b 47 % 62,3 % c 82a % 86,8 % d 94,2% 95 % conclusiom for accurate and reliable intermittent drug infusion with a syringe pump it is mandatory to use a precise protocol of administration and to take in account 1) a priming (for immediate starting of infusion), 2) a drug volume greater than the dose prescribed and a programmed volume injected, 3) a wash out of the tubing (with a volume ~ 1,5 x volume of tubing injection) caz is an antibiotic with activity against the major pathogens responsible for neonatal bacterial infections. we previously reported the pharmacokinetics of caz in 136 preterm infants on day 3 of life which showed that the clearance of caz increased with increasing gestationat age (ga). mean serum half-life of infants with gas < 32 wks was 8.7 h. we wanted to investigate the effect of postnatal age on caz pharmacokinetics, we therefore studied caz pharmacokinetics on day 19-21 of life in 10 preterm infants with gas < 32 wks. caz (25 mg/kg) was administered as an intravenous bolus injection. blood samples were coilected before (t =0), and 0.5,1,2,4,8 and 12 h after the caz dose and analyzed by hplcassay, the pharmacokinetics of caz followed a one-compartment open model. during 1995 11 newborns with complex congenital heart defects requiering either htx or palliative staged single ventricle repair were admitted to our hospital: hlh n=8, unbalanced cavsd, tga with hypopl. rv and hypoplastic aoa. tga with hypopl. rv, sas and dextrocardia. 8/i 1 children had been admitted with cardiogenic shuck and mukiorgan failure due to intermittend closure ofductus arteriosus; in 3/8 stabilization failed. parents were informed about the known and unknown risks of the always palliative surgery; in 2 cases parents denied further therapy. one pafiem with hlh underwent orthotopic htx at the age of 5 month after the ducms art. had been stunted in the newborn period. 9 month later he is still in favourable condition and without any sign of acute organ rejection. 5/11 underwent first stage of palliative single ventricle repair: norwood -op. ( 3 ) ( n=3 ), damus-kaye-stansel -procedure ( 2 ). the clue to adequate postoperative management was to archieve a balanced distribution of flow to systemic and pulm circulation, that is to protect the single ventricle from volume overload and to guarantee sufficient oxygenation and pulmonary development as well. with the centralvenous sato2 at about 50% provided maintaining the arterial sato2 at about 75_+5% is corresponding with a qp/qs of 1:1. using modified bt-shunts of3.5mm resp. a central anrtopulm, shunt of 4mm in one case l severe puim. hypertension, surgery at 6 weeks of age ) there was no excessive pulm. blood flow and no need to increase pvr with inspired co2. one child ( norwood at 5 weeks, preexisting pnim_ edema ) developed severe pulur hypertension and parenchymal pulm. dysfunction after prolonged bypass and multiple transfusions due to intraoperative bleeding: hypoxemia could be managed successfully by implanting a second shunt of4mm 18hh later and temporarily using prostacyclin and no; at sternum closure 6 dd later the second shtmt was banded to 3ram. follow-up ranges 5-5 month: all 5 children are at home being assigned for second stage operation at about 6 month of age. establishing clinical practice guidelines has become increasingly important in the current health care environment. significant effort has been focused upon development of post-operetive critical care pathways. however, benchmark data upon which such pathways should be based has not been well reported. length of mechanical ventilation (lmv) and length of stay (los) for children following cardiac surgery, for example, is poorly described. we prospectively recorded the lmv and los in 168 patients who underwent cardiothoracic surgery between 9/1/93 to 6/30/95. only patients who belonged in any one of five categories of congenital heart disease (ventricular septal defect _+ other septal defects (vsd), atrioventricular (av) canal, tetralogy of fallot (tof), transposition of great arteries (tga), and single ventricle physiology (fontan)) were included. eight non-survivors were excluded from the analysis. all patients were admitted to an intensive care unit 0cu) post-operatively where mechanical ventilation was managed by 4 pediatric intensivists. lmv was defined as the period from post-operative admission to planned extubation. length of stay (los) was defined to be from le from the icu. cytokine patterns during and after cardiac surgery in young children. especially in children, cardiac surgery with cardiopulmonary bypass (cpb) can cause a systemic inflammatory response. this process is thought to be mainly a result of inflammation induced by surgery and exposure of blood to an artificial surface, and of reperfusion injury during weaning of bypass. complement activation, degranulation of granulocytes, induction of free oxygen radicals, endotoxemia and release of cytokines, are important contributing factors. we studied cytokine patterns before, during and after cpb in young children admitted for complex surgery or for septal defect correction. in the first group, significant amounts of il-6 and il-lra could be detected preoperatively. these findings could reflect the already existing hemodynamic dysregutation. in both groups, cpb procedure upregulated the circulating pro-inflammatory cytokines il-6/8, but not il-1b. at the same time, il-lra became detectable. therefore, we suggest that in these patients the production of the anti-inflammatory cytokine il-ira was not induced by the preceding acnvity ot pro-inflammatory cytoidnes. during cpb, we noticed a sharp decline in the capacity of the leucocytes to secrete il-6/8. the ex-vivo production of il-lra however, was only slightly attenuated. we conclude that there is a differential regulatory pathway for the induction of il-6/8 and il-lra. in addition, we studied the influence of dexamethasone administration on the cytokine pattern. administration delayed the appearance of il-6/8 and il-ira in the plasma, interestingly, it did only interfere with the ex-vivo production of pro-inflammatory cytokines. the latter supports our hypothesis that production of il-6/8 and of il-lra is regulated by two independent pathways, (60%) of 43 pts. 82% ofpts < 12 months of age developed metabolic alkalosis as compared with 38% ofpts > 12 months of age.the infants with metabolic alkalosis received more citrated blood products and furosemide. following cardiac pulmonary bypass the highest ph-values and be-values were observed 24-48 hours and 48-72 hours, respectively. ii. prospective study: metabolic alkalosis was registerd in 2t children (70%), 8 of those <12 month (75%) developed metabolic alkalosis and 67% of those elder than 12 monms.durmg the postoperative course patients younger than 12 months developed the highest ph-and base excess values after 102 and t05 hours, in the subset of the older patients maximum ph and base excess was found after 48 and 81 hours, respectively. in one case the top level ofph-value exceeded 7.6, the base excess +20 mvalb. conclusion: children undergoing cardiac surgery with cardiopulmonary bypass often develop metabolic alkalosis.in contrast to previous reports, we did not observe an association between metabolic alkalosis and mortality, nor greater frequency of cardiac arrythmias or prolonged mechanical ventilation. in context with decreasing serum lactate levels, our data show positive correlation of metabolic alkalosis with postoperative improvement of liver function. respirator, mechanics and weaning outcome in children undergoing cardipvascular surgery. vassallo j., cernadas c., saporiti a., landry l., rivello g., buamsha d., rufach d., magliola r. mechanical ventilation (mv) and acute respiratory failure are common events in children unergolg cardiovascular surgery (cvs), the development of new techniques helped to measure some of the main respiratory mechanics (rm) in a non invasive fashion. our goal was to evaluate the predictive value of these measurements in weaning (w) outcome in these patients, patients and methods: we prospectively evaluated children considered clinically to be ready for w with < 20 kg and > 24 hs mv. patients with diaphragm paralysis and those who failed w because of upper airway obstruction were excluded. before patient extubation the following measurements were recorded during spontaneous ventilation (cpap/t piece) using the cp 100 neonatal pulmonary monitor bicore (lrvine, ca): total respiratory system static compliance (cssr) and resistance (rts), rapid shallow breathing index (rsbi). maximal inspiratory negative pressure (pi max) was measured using an unidirectional expiratory valve. threshold values predicting w success (ws) were: cssr > 0.5 ml/cm h20, rts < 75 cm h20 /l/sec, rsbi 160 and pi max > -30 cm t120. w failures (wf) -patient reintubation within the following 48 hs, these values were compared between w success and failures using fisher exact test. an apriori level of statistical significance was chosen at p < 0.05. 4 considered, an increase in tnf-a levels is observed after cardiac surgery (p<0.001) with a return to previous values after 24 hours (p<0.005). 72 hours after cpb, similar values are observed in groups ii and ill, but there is a further increase in serum tnf-a levels in group i when compared with both other groups (p<0.03). we found no statistically differences in any other moment. there was a significant correlation between serum tnf-o levels determined 72 hours after surgery and cpb duration (p<0,003). conclusions: cpb in childhood provokes a significant increase in serum tnfa levels, in newborns the inflammatory response is maintained 72 hours after surgery. this enhancement of serum tnf-e levels indicates the existence of a relevant inflammatory response in these patients. introduction: cardiac surgery appears to induce a systemic inflammatory response. we have investigated the behaviour of il-1 i~ and il-6 before and after cardiac surgery. patients and methods: we studied serum il-1 6 and il-6 levels from 20 children with congenital heart disease (10 boys and 10 girls), aged from 7 days to 14 years, undergoing open heart surgery, before cpb (d we found no statistically differences in the il-i levels in the different groups and moments. there is a significant increase in il-6 immediately after surgery (p<0,01) with similar levels 24 hours after cpb and a significant decrease (p<0.01) 72 hours after cpb. preoperatory il-6 levels were higher in the groups i and tl than in group i11 (p<0.05). 24 hours after cpb serum il-6 levels in group 1 were significantly higher when compared with group 111 (p<0.05). conclusions: cpb in childhood induces a significant transient increase in serum il-6 levels, strongly relevant in newborns. cpb was not associated to a significant modification in serum il-1 6 levels. thus, cpb in childhood induces a dissociated behaviour in the proinflammatory il-6 and il-1 & pathways. obiective, to evaluate the effects of amg receipt on the clinical condition during the first 12 hours after birth (t2), the morbidity and mortality in immature outborn neonates. methods. we studied 44 outborn neonates with ga 26 to 29 wks, admitted during the years 1993 to 1995. eighteen neonates exposed to amg (ga:27,6+lwks, bw: 1066_+195g) and 26 neonates did not (ga: 27,7_+1wks, bw: 1042_+187g). results. amg-exposed neonates compared to those not exposed had lower incidence of apgar score at 5 min _< 3 (6% vs 35%, p<.05), lower incidence of ph t2 <7.20 (11% vs 48%, p<.05), decrease need of bicarbonate 12 (22% vs 54%, p<.05), lower fio212 (fio212min>40: 17% vs 48%, p<.05 and fio212max >80: 17% vs 52%, p<.05), lower incidence of intubation (67% vs 92%, p<.05), lower requirements of surfactant (50% vs 79%, p<.05) and lower mortality (11% vs 50% p<.01). there were no differences between the two groups for the following parameters: type of delivery, hypothermia hypoglycemia and anemia during admission, hypernatremia, hypotension 12 (map<30mmhg), need of dopamine and or plasma 12, incidences of ptx pda sepsis nec severe rop major ivh (plus pvl) and bpd and duration of intubation. conclusions. the main beneficial effects of amg receipt on the immature outborn neonates were the decrease of mortality and the decrease of surfactant need. there was no effect of amg receipt upon other severe morbidity in this high risk group of neonates. premature babies are very sensitive on homeostatic disturbances, and often develope intracranial haemorrhage (ich). ultrasound scan of the bram shows four grades of ich: -grade i -only periventricular hyperechogenic areas -grade ii -haemorrhage ham the lateral ventricles -grade ili-dilated lateral ventricles -gtrade iv -intracerebral haemorrhage. the purposes of this study were: 1 to show the incidence of ich in premature babies and its correlation with the gestational age, 2. to determine the severity of ich 3. to present the outcome &those babies. in the study were included 393 premature babies successively-born at the department of gynecology and obstetrics before 37 gestational week (g.w.) and grouped in three groups: less than 28 g.w., 28-32 g.w., 33-36 g.w. to all of them was performed ultrasound scan of the brain. results : 1. the incidence of ich hi premature babies is 49 % and there is ingh level of correlation with the gestational age: -babies born before 28 t~ g.w. have 100% incidence of ich and graduated : i grade -5%, ii grade -65%, iii grade -25%, iv grade -5% -babies old between 28-32 g.w. have incidence of 61% : i grade -24%, i[ grade -62%, iii grade -14%. -babies older than 32 g.w. have incidence of 33%: i grade -46%, ii grade 48%, iii grade -6% 2. sixty of 393 premature babies have died and it is 15.2% lethality. in all died ilffant was confirmed the grade of ich diagnosed by ultrasotmd scan of the brain. d. maksimo~5c. z.braiko~ic, n.vunjak. p. ivanovski (5~iversi~, children's hospital. belgrade, yugosla~, ia infantile intracranial hemorrhage is the most frequent and serious manifestation of late hemorrhagic disease of the newborn caused by ,,~tamm k deficiency in earl?,, ti~fancy. in the last two years, we recorded five cases of infantile intracranial hemorrhage due to "dtamin k deficiency, despite routine prophylax~s (intramuscular vitamin k, 1 mg) , with bpieal clinical presentation: age was 18 -65 days (average 40 days): vomiting, poor feeding, lethar~'irritabiljty, palor, bulging t0ntanelle and convatsiones were present in most cases.two patients developed signs of hemorrhagic shock, with hemoglobin level less than 70 g.1. in 3~5 f \qi level was less than 30 % of predicted value. there was no evidence of head trauma or liver disease in none of patients. four inlants were breast fed, while one, who had diarrheal disea.se, was on adapted milk formula. routine therapy wa.s given (including vitamin k and fresh frozen plasma). two patients were discharged with no sequellae, one developed posthemon'hagic hydrocephalus as a complication and two patients died. late hemorrhagic diseo.se of the newborn is sill/ a significant cause of morbidib' and mortality in earl3' infancy, despite different approaches to prophylaxis developed in recent years. background: neonatal hearing screening in at risk newborns can detect 50% of the children with a congenital hearing loss. automated abr hearing screening (algo-1) has been introduced for healthy newborns. the aim of this study is to test the validity of this algo-1 screener in at risk newborns in a neonatal intensive care unit. subjects: 250 at risk newborns (median gest.age: 30.0 wks, median birthweight 1350 g) selected according to the criteria of the american joint committee on infant hearing. interventions: algo-i automated abr-hearing screening at a level of 35 db was performed in the neonatal intensive care unit. when bilaterally referred, further audiologic screening and/or therapeutic intervention took place. when passed uni-or bilaterally, children enrolled in a) a nation wide screening programme (ewlng) at the age of 9 months and b) in a half yearly follow-up programme in which hearing and speech-and language development were observed according to egan an illingworth. results: screening without disturbance from ambient noise or from routine technical equipment was possible in the incubator, even during nasal cpap therapy. 245 (98%) newborns passed algo-1 screening. 5 (2%) did not pass bilaterally. 1 of 5 with a congenital rubella died shortly after screening.in 4 of 5 bilateral congenital hearing loss of ->35 db was confirmed. 235 of the newborns passed were still alive at the age of 1 year. ewing screening was performed in 183 of 235 (77,9%). 161/183 passed, 15 of 183 had passagere conductive hearing loss, in 7/183 no further investigation was performed. all 235 children enrolled in the i/2 yearly follow-up programme had normal speech-and language development. in this study all 4 at risk newborns with bilateral congeni "tai hearing loss were detected with algo-1 screening. screening results showed no false negatives at follow-up. the algo-1 infant hearing screener can be used as an valid automated abr-screener to detect hearing loss in at risk newborns in a neonatal intensive care unit. gancia gp, bruschi l pnlito e, ferrari g, rondini g -divisione di patologia nc~matate e turapia intensiva -irccs policlinico s. mattco -pavia, italy latrogenic esophageal perforations (iep) in preterm and term infants are seldom reported in litteraturc, in association with difficult endotracheal (et) intubation (with or without stylets), insertion of gastric tube, and pharyngeal suctioning with stiff catheters. crieopharyngeal muscle spasm caused by instrumentation may also lead m a narrowing of lumen, with increased risk of local injury. we report 4 iep observed in intubatcd, mechanically ventilated newborn infants (2 male, 2 female, all outborn). a common feature of iep was inability to pass a nasogastric (ng) tube into the stomach, mimicking e~)phageal atresia.~se 1: birth weight (bw) 185(i g, gestational age (ga) 37 wk, sepsis. before admission to n1cu, the baby underwent multiple et inmbations, because of inappropriate securing of et robe. bloody secretions in pharynx were observed. the endoscopy showed a large lesion at the end of proximal third of the esophagus, case 2: bw 1080 g, ga 32 wk, rds. chest x-ray (cxr) showed a retrostcrnal air leak: the ng tube was stopped }~etwcen d8 and d9 and soluble contrast was seen in upper mediastinum.case 3: bw 76(/g, ga 26 wk, rds. the endo~opy showed an esophageal lesion. cxr showed a paravertebral route of ng tube and a right pneumothorax.case 4: bw 102(i g, cz 22 ,.v!:. rd c. ~!,'.::;;: ::':'_'rvt!~'2s l" ~k':.rvrx. cwr, d,,,,vs ~,,mr~e, ~n rhe upper mediastinum and abnormal route of ng tube through a false passage. surgical intervention is needed in case of mediastinitis or mediastinal abscess: conservative management included broad spectrum antibiotics, total parenteral nutrition, antireflux therapy and, if necessary, drainage of air leaks. enteral feeding has been stopped lor 15 days and cautiously resumed after radiographic study. [x~cal sequelae and death are uncommon, but iep occur in newborns with high risk of death due to prematurity and other diseases. in our patients, et intubation has been performed by experienced personnel: therefore the lack of skills in resu~itative procedures is not always the main factor of iep. prevention of iep requires appropriate materials (et tubes, laryngoscope blades, suction catheters), and procedures (positioning of the infant with correct neck estension, firm et placement). sedation and pain control may help to prevent the muscle spasm. aggressive treatment has improved the tong-term outcome of extremely low birth weight neonates (elbw) but it has also increased the chances of iatrogenic lesions. reviewing the charts of our neonates we observed a high number of vascular injuries. from 1987 to 1994, 2898 neonates were admitted to the neonatal intensive care unit (nicu); 335 of them were elbw (11.5%). studying the charts of these elbw we observed 9 cases (4 m -5 f) with vascular lesions (2.6%). mean gestational age of these patients was 28.7 weeks (rain 24-max33). mean weight at birth was 880g . mean weight at diagnosis was 1825g (1230-2700). in the same period 10 patients with vascular injuries were reported in the 2563 neonates over 1500g (0.3%). the injuries observed in elbw group were: 6 arteriovenous fistula (2 bilateral) at femoral,level, 1 carotid lesion and 2 limb ischemic lesions. aetiology was in 7 cases by venipuncture, in one case umbilical catheter and in the case of carotid lesion a wrong surgical maneuver. no general simptoms were observed. the vessels were repaired with microsurgical technique in six cases: the carotid lesion and five arteriovenous fistula; one case was solved with thrombolitic drugs; an amputation at knee level was required in one case after a long period of medical treatment. the last neonate with an arteriovenous fistula was only observed for parent's will. at follow-up (clinical and by ecodoppler) 7 out of 9 neonates presented normal vascular function without sequelae. from our experience elbw neonates have more chances than older neonates to develop iatrogenic vascular lesions. we advocate an aggressive microsurgery and/or medical treatment to obtain good results and prevent late sequelae. a retrospective comparison between 2 natural surfactants l.j.i.zimmermang m.c.m,van oosten. dept. pediatrics, div. neonatofogy, sophia children's hospital/erasmus university, rotterdam, the netherlands. aim: retrospective comparison of alvofact (in 1993) versus survanta (in 1994) as rescue treatment for neonatal respiratory distress syndrome (rds). methods: both surfactants were given at an initial dose of 100 mg/kg (except for alvofact 50 mg/kg for mild rds grade mi). repeat doses were attowed (survanta 100 mg/kg, alvofact 50 mg/kg) up to a maximum of 200 mg/kg, all parameters and outcome criteria were strictly defined beforehand. the initial response (good,mild,no response,relapse) to surfactam therapy was defined on the basis of the decrease in fio 2. results: there were no signif. differences in patient population and initial parameters: ga (29.9+_2.2 vs 29a _+2,6 wks), birth weight (t332_+431 vs 1227-+444 g), severity of rds (grade ill-iv: 78.6% vs 80.3%), apgar scores, cord blood gases, initial ventilatory settings. in '93 however, the initial surfactant dose was administered earlier than in '94 (14.4-+ 17.4 vs 6.5_+7.8 hrs postpartum, p= 0.025). although the average total cumulative dose was equal in '93 and '94 (169.3-+65,8 vs 167.4_+69 .4 mg/kg), more doses of alvofact were given compared to survanta {2.3_+1.1 vs 1.7_+0.6, p=o.o01) and more patients in '93 received more than two doses than in '94 (46% vs 18 % of patients). there was no difference in the incidence of non-putmonarycomplications. aivofact ( there was a better initial response to survanta and a better respiratory outcome in 1994: in the group < 1250g the duration of ventilation was half in 1994, and in the group >~125og the duration of extra o 2 need was half in 1994 as compared to 1993. we speculate that the main reason for this difference is the earlier and initially higher dosing used with survanta compared to that used with alvofact which was given in the same total cumulative dose but over a larger time span. background: e×ogerlous sur&ct~t raplacem~t treatmem has become rou~ne k~ the t~eatme~t of respira~"¢ dim'~ syndrome (i~ds) of pr~e~tur~, wh~eas its effica w th odi~ respiratory diseoses is sdi1 being wader mvesugatio~. objective: "eac~ mt ereat isto report ottr results of prospect/re, non-randomized "re~-o.e" study oe suffact~t replacement in outhom premamae infa~t~ with rds reruirmg me~aical ventilatioa (nfv). p~tien~ and metho0.s: from j-aly 1993 to june 1995, 18/58; (31%) out~ ~¢ infaats, at a mesa age of 22 z 2,7 horn's ( 13 boys, 5 ~rls; ~ gestafioan age 32-+2.8 weeks, mera~ birth weight 1846 _+ 544 g, ~ 7.2 i" 17 at 5 minutes) with rds, requiring mv, received bov~e-suff~amt (survanta, ros~/aboti, laboratotie~ columbus, ohio) eadotracheally, as was recomm~aded by maaufacturer. as the c,~:ttrol group 19 o~bom premature infants (ot~ of 49; 39%, admitted with rds from euiy 1991 to eune 1991) were saelected ~d who did not receive surfaaam, compared with ~hctant ~'oup they were admitted for treatmeat e~'li~" aft~" daliv~:y (at the age 6.4::2.2 hours vs. 11.7+-13 hours), but they did not diff~ in othe~ baseline dam'a~eri~cs at ~ti~ion. entry crkeda for ~¢fa~aut ~hcadou were fractional i~firat o~ oxtgem r~emeats -fio2 > 0.50 -0.60, ratio au-lerlal to alveolar oxygea pre~are~ao2~ao2 < 0,20 ~ad oxyge~at,~ i~.dex -ol > 10. primary o~comes were deter~caned by ~hanges m exs'ge~ab, c~ ~r~d vmtilatic~ ~ the following variable~; (1) fi'aaic~ of i~spired oxtge~ (fio2); (2) mesa nnvay presmzre (map) (3) pag2 ~ao2 ratio, (4) oxyge~ion index (oi). commo~ comphcadces of prem,musty ~d con~ol mechamcal v~ati]al~on (pater dumas merios.s, intracr~nlal haemcrn:hage, air leak, br onchop ulmrmm'y dy~pl~a ~d death) were reg~ded as sec~d,~y outcomes. r~suas: in warfactaat group we observed slg~5.c~t improve~aeat (p<0.05) in oxygea~thia md veaatilation at 24 hours all~ e~try k~to the m~dy in compari~ion to nons~fa~m" group. compa~on of secondao' outcomes in ~ts with p,.ds showes table l we did not observe ~y major acute hfe fl:u-eattming complicatlola,s m sxlrlhct~mt grou~ tr/lmediately after stu'~actsmt rcplacemev_t therapy. the duramm of mechmucal ven~ation ~ad oxygen lreau~ent m survivals of both groups did not dafter 51gmficautl y a-ore ead~ other. condusion: l!a premature mthats with rds treated with surfaaaat replacemeaat therapy we observed decrease m mc~de~ce of tme'~m~o~oraces add de~th (p<0.01 and p<0.05), whe~e~s m othe~ observed variables thee was uo ,igmfi~t d~=ecce infectious complications during the therapy of respiratory insufficiency in neonates with birth weight less than 1500 g in the course of 3 yearsretrospective study. zitek infants on cmv, cppv, and imv were administered exosurf in dose of 50-60 mg/kg twice endotracheally (see table) . in 32 newborns (86.4%) 2 hours after surfactant admin fi02 value decreased by 20.8%, and after 6 hours -by 28.1% compared with initial value; pip and peep values decreased by 3-5 cm h20 and 1-2 cm h20 after 6 hours, and by 4-7 cm h20 and 2-3 cm h20 after 1 day, respectively accompanied by mean decrease of aado2 from 486,2 to 240.2 mmhg, qs/qt decrease from 24.9 to 13.2% (see table) . mean time of cmv, cppv was 7.8 days, imv-14-36 hours, cpap -10-24 hours. respiratory therapy in 5 newborns (13.5%) was complicated by pneumothorax (bilateral -in 2 infants chorioangioma is a rela~ively rare placentai malformation associated with considerable mortality and morbidity. a chorioangioma can be regarded as an arterio-venous shunt in the circulatory system of the fetus. this causes volume loading eventually resulting in cardiomegaly and high output cardiac failure. a female neonate (gest age 40 wk, birth weight 2290 g, -2.6 sd) was born with an apgar score of 4 and 7 after 1 and 5 rain respectively. the placenta showed multiple chorioangioma. ultrasound of the heart showed a hypertrophic cardiomyopathy. she developed severe hypertension (100/70 mm hg), treated with nitroglycerine and nitropruside. finally blood pressure decreased when enalaprillic acid was given (0.15 mg.kg4). we measuered the activity of the renin-angiotensinsystem. an elevation in renin-angiotensin system is shown probably to compensate for the low resistance circulation before birth, hypothesis: the instantaneous cut off of a large arteriovenous shunt did not result in a fast downregulation of the renin-angiotensin system resulting in hypertension. hypertension should be added to the list of complications of chorioangioma of the placenta. the authors studied 75 cases of children's septicemia with blood culture yielding staphylocucetts aurens. the age of patients varied from 2 months to 15 years (51,3% from 3 years downward), 74% of the children caught their disease in the hot season (may to october). the deaths also occured in this season: 87,5% (21/24). following were the anatomo-dinical lesions. -skin 42%, muscle 60,0%, bone 21,3%, joint 9.3%. -viscera : lung 50%, heart 33.3%, cerebrum 22.6%, kidney 60.6%, fiver 17,3%. -simple lesion skin-muscle-bone joint: 12%, no death in this group. the concomitant lesions of the soft tissue,bone-joint and viscera : 34% with one viscera, 26% with two viscera, 18% with three viscera and 9% with four viscera. -bone lesion : mainly on the long bones (50% on the tibia, 25% on the femur, the remainder being the mandible (3) and the humerus), inflammation of' the hip joint was the main one. -i,ung lesion had forms pneumatocele (4 cases), bronchopneumonia (6 cases), pleural effusion (7 cases), multimicroabcess bursting into the pleura (8 cases), most multimicroabcesses were lethal : 20/22 (90,9%), -heart: all thethreelay~rs got le@~r~, 20% had 2 or 3 layers alrected and death ensued. -cerebrum : the meninges had three forms of lesions purulent meningitis (13 cases), obturafing embolns of brain vessels (2 cases) and cerebral abcess (one case). the characteristic clinical sign was paralysis and meningismus, phlebothrombosis of eavcrnous finus (13 cases)was mually ther~sultofalxil vdfi:h burst there were 6 cases of death with lesion of the meninges and 2 cases of obturating embolns of brain vessels. -the main sign of lesion of the kidney was a change in the components of urine: 60% got proteinuria, 75% had leucocytes in their urine, 42% had erythrocytes in their urine, the urea in their blood increased (over 60rag%) in 21.4% of cases.the lesion of the kidney seemingly had little relation to death. seven cases of ictertts due to an increase of direct bilirubinemia and a decrease of blood-albumin. -the biological characteristics of the pathogen staphylococci showed that all the 75 isolated specimens had positive coagulaza ; the specimens from the dead patients were less semiti~e to, mad ~t to mali~ overag death rate was 34.7 % (24/75). the fungal infection to fusariun species in immunocompromissed child have been reported in the literature with a rare, severe and high, mortality rate in spite.of the use of antifungal drugs. we report a case of successful treatment of a severe disseminated fusariun infection in a ll-year-old boy with acute lymphocytic leukemia (lla-l3), after use a chemotherapy followed by absolute granuloeytopenia. the patient developed fever, skin lesions, pneumonia and fungaemia. fusariun species was cultured from the blood, necrotic skin lesions and lung secretion. the child developed multiple organ system disfunctiou in spite of use broad spectrum antibiotcs and antimycotic therapy needing. uci during 18 days. the patient receive suport treatment (mechanical ventilation, inotropie d~.ugs, diuretics, imunestimulants, blood components, a broad spectrum antibiotes and antifungal agents). we absorved a gradual recovery in the white blood cell count and regression on the sites of infection. the association of preeoce diagnostic and the terapentic with increase in the white blood cell count was the most important in a successful treatment. a 5 year old african-american child suffered a severe pulmonary injury in a house fire. initial survey revealed 1% total body surface burns, soot on the face, and bloody endotracheal secretions. initial chest radiograph revealed diffuse, bilateral infiltrates. severe respiratory failure with an oxygenation ratio of 73 rapidly developed. he developed a pneumomediastinum and subcutaneous emphysema. although transient improvement occurred with inverse i:e ventilation and surfactant, he became more hypoxic (sac2 as low as 47%) and acidotic. on day 2 post injury, he was placed on venc~venous extracorporeal life support (ecls). on ecls day 30 he was decannulated. chest radiograph on ecls day 15 showed an opacity in the left chest. ultrasound of the left chest was consistent with atelectasis rather than pleural fluid. flexible bronchoseopy failed to reveal any obstruction in the left lung. a computed tomography (ct) seen of the chest, which was performed after decannulation, revealed a large loculated collection of fluid in the left, anterior chest. under ct guidance, a 14 f cope loop catheter was inserted and 40 cc of thick blood was removed, follow-up ct performed immediately after this procedure revealed minimal change in the size of the fluid cavity. over the next 48 hr, we instilled urokinase 20,000 units over 20 minutes every two hours. a 30 minute dwell time was allowed before draining the fluid. repeat ct scan done at the end of the urokinase infusion showed a marked decrease in the size of the fluid cavity. act scan was not performed prior to decarmulation because the ecls circuit tubing was too short to allow appropriate positioning of the child in the ct scanner. after a ct scan revealed loculated pleural fluid, a simple drainage procedure was diagnostic but inadequate treatment. we were able to successfully dissolve the thrombus after 48 hr of urokinase therapy even though the thrombus was > 14 days old. we suggest that large loculated plenral thrombi which develop as a complication of ecls therapy may be successfully managed with urokinase infusion. introduction: haemorrhages, particularly intracranial, are major complications experienced in 10-35% of neonates treated with extracorporeal circulation. an induced thrombocytopenia and impaired platelet function play a key role in the increased bleeding tendency observed in these patients. the aim of the present study was to establish a dose-respons curve for the effect of a synthetic protease inhibiting agent, nafamostat mesilate (fut-175), on platelet membrane glycoprotein density and platelet activation during experimental perfusion. methods: two identical extracorporeal life support (ecls) circuits were primed with fresh, heparinized human blood and circulated for 24 h. four different concentrations of fut-175 (7.12 mg/l blood/h; 14.25 mg/l/h; 14.25 mg/l/h+25% bolus at the start of the perfusion and 2&5mg/l/h+25% bolus) were used in different perfusion experiments. a total of eight paired experiments were performed. platelet count, plasma betathromboglobulin levels and platelet membrane density of glycoprotein ib and lib/ilia were followed as well as plasma concentration of haemoglobin. results: a protective effect of the agent on platelet count, plasma concentration of btg and platelet membrane gpib could be observed during the first 3 hours of the perfusion when a bolus dose was added. no positive effect could be recorded with the two lower doses used. plasma concentration of haemoglobin was higher in all the fut-circuits compared to the control circuits. conclusion: the addition of a bolus dose of fut-175 at the start of the perfusion seem to induce a protective effect on platelets during the first hours of perfusion. extracorporeal membrane oxygenation (emco) is a form of invasive cardiopulmonary support that can provide imporary physiologic stabilisation in reversible circulatory failure and or respiratory failure. we reviewed our expierence with extra corporeal membrane oxygenetion in 4 children aged 1 day to 4 year between 1991 and 1995. two neonates was succesfully decanulated, but died 1-2 well after decanulation due to septic complictions. one child 4 years old, one neonates died on day 5 and day" 7 respectively while still on emco. complication which were and encountered were heavy bleeding in case 1 (child), 4 (neonate) and raceway rupture in case 2 (neonate). problems which are specific developing countries like indonisia are: high cost (20.000 us for 7 days) difficulty in transportation (transporting intubated baby) from the orgin hospital, lack of knowledge and understanding of the primary physician and nm-ses and difficulty organizing in 24 hours emco team. resnratory mon1tor/ng in picu z,zjvkovic, s. mihailovic, o, tosev respiratory monitoring in pediatric intensive care unit 0picu) provide the importartt informations for understanding of the pathophysiology of the clinical signs, aid with the diagnosis, and assist in therapeutic management and predicting prognosis. pien in children's hospital for ~flmonary diseases and tuberentosis remained for the t~s't two end a half years relatively limited for diagnomic tools and therapeutic regimens, mostly because of the poor fmnaeial suptx~rt. the number of children admitted for aurae asthmatic at.lzek~ severe pneumonias, bronehiolitis, complicated pulmonary tuberculosis, foreign bodies and exacerbations of ehronit'. pulatonary diseases was t362. for all patients the respirator' monitoring system means: physie~d examination, ehe~ x rays, capillary bltxxl gas mmlyses (vevv few ehiktren experienced itwasive arterial blt~.~'i gases), noninvasive oxyntctry, measuring of the vital capacity in coopo-able patients, as~d capnography. later on, after the imtial critical illness, a complete hmg fimction tests was performed, as well ,~s bronehoscopy in selected eases, (~lr experience revealed that abotrt 60% of ehil&en heos suecessthl outcome, without s~lllens , instead they had been tremted in limited conditions. ']'he rest of our patients were previously diagnosed ~s ettronie pulmonary patients, with high risk score system ibr having seqnells 'llae mortality rate were 0,5%. the continuous blood gas monitor, pasatrend 7 (biomedical sensors, ltd., high wycombe, bucks, england) has the capability of measuring ph, pco2, and po2 via an indwelling optical absorption optodelclark electrode sensor that is placed through an intra-arterial catheter. we evaluated the accuracy of the sensor in radial and femoral locations in critically ill pediatric patients. methods: the simultaneous values of ph, pcoz, and po2 recorded from the paratrend 7 monitor were compared to values measured by standard arterial blood gas analyzer (coming 278, ciba-corning diagnostics, medfield, ma). criteria for the elimination of data points included a core vs. sensor temp. gradient, and sensor pulled back beyond accepted insertion distance. mean time of monitoring per sensor was 108 hours (range 0.75-403.7 hrs). mean time of radial monitoring was 35 hrs (range 0.75-160.5hrs) and of femoral monitoring was 137.2 hrs (range 12.8-403.7 hrs.). linear regression and bland-altman analysis for bias and precision for each parameter were calculated. results: a total of 49 patients (age range 2 weeks to 18 years) had paired samples of ph, pens, and poz made by the sensor and blood g&s analyzer. the range of measurements were ph 6.99-7.66, pco, 16.0-i14.2 t(n r, and po2 34-480 torr. the paratrend 7 monitor demonstrated accuracy that is comparable to the accepted standard of blood gas analysis in a group of critically ill pediatric patients manifesting wide variation in ph, pen2, and poz..this technique appears m be very useful especially in the extreme values of the parameters measured. funding provided by biomedical sensors. understanding of pulse oximetry d.semple, l.e.wilson. royal hospital for sick children, edinburgh, eh9 1lf, scotland, uk. pulse oximetry is a useful, non-invasive monitor, routinely used on the itu and increasingly often on the general wards. we used a questionnaire incorporating questions on the theory and clinical uses of the pulse oximeter to assess understanding of pulse oximetry in medical and paramedical staff doctors indicated grade, speciality, pulse oximetry tuition and neonatology experience. 45 doctors, 15 itu nurses, t9 medical students and 4 physiotherapists completed the questionnaire. some confusion existed between the principles of pulse oximetry and transcutaneous oxygen measurement. wide variations in the lowest acceptable saturation in fit children were seen (80-95%), with around 20% of respondents in all groups accepting values of 90% or less. some potentially serious mistakes were made in the evaluation of oxygen saturations in the clinical scenarios. there were widespread variations in correct responses at all grades of medical staffing. nurses scored well on more clinically-orientated questions but relatively poorly on theory. only 15% of doctors (mostly senior grades) had received tuition in putse oximetry. neonatology rotations appeared to confer little additional knowledge on pulse oximetry. few doctors and nurses receive tuition in the use of pulse oximetry a significant proportion of nurses and doctors, of all grades, exhibited a lack o{" understanding of the principles of pulse oximetry. this may result in unsafe use of the equipment and put patients at risk. one can see from the table that blood composition in uv and ua differens in some characteristics, and similar in sgp magnitude. venous-asterlal gradients "gas functiomals" between uv and ua represent the measure of difference in this characteristics. the gradient cari be positive, zero -order or negative and change both in value and in sign but not reach apo2 (positive) and apco2 (negative) in absolute significance.minimization of "gas functionals" deviations atom the zero is achieved due to"mutual replacement acts" between po2 and pco2 in uv and ua blood. we suggest that presented tests can be useful in full evaluation of gas exchange in newborns. (pap) in the context of pulmonary hypertension is oft desired but rarely achieved. inhaled nitric oxide (no) has been shown to produce this desirable effect, but is relatively difficult to administer or monitor. we wondered whether np, chemicaily related to no but more stable in solution, would produce similar physiologic effects when administered in the convenient modality of nebulization. methods: 9 piglets were anesthetized, mechanically ventilated, and surgically instrumented. systemic blood pressure (bp), pap, and cardiac output (co) were monitored continuously. after postoperative stabilization, 0.9% nac} nebulization was begun, and pulmonary hypertensiorr was induced by reducing fio2 from 0.30 to 0.07. the piglets were monitored for 15 minutes during this hypoxic phase, next, without altering fio2 or ventilator settings, np (10 mg/ml, dissolved in 0.9% nacl, flow 4 ipm) was substitued for 0.9% nacl in the nebulizer circuit. np was nebulized for 15 mins. results: during hypoxia, pao2 fell from 159 to 29 mm hg. pap rose during hypoxia from 14 to 31 torr (p< 0.01). ,^fhile bp and co did not change significantly. pap fell during nebulized np in each piglet, (mean apap = 31 to 21 torr; p< 0.01; mean reduction of hypoxia-induced rise in pap = 61%; range: 36 to 78%; p < 0.01). pvr/svr fell by 28% during np nebulization (p< 0.01), while bp and co did not fall significantly (90 to 86 tort; 653 to 636 mllkg-min), the reduction in pap began within 2 minutes of the onset of nebulized np, and appeared to reach a plateau by 15 minutes. no tachyphylaxis to nebulized np was noted. nebulized np did not significantly affect pap, bp, or co under normoxic conditions. conclusions: 1) like no, np selectively reduced hypoxia-induced pulmonary hypertension without altering systemic bp, 2 ) unlike no, np can be administered by nebulizer, a technique familiar to virtually all health-care providers, and potentially adaptable to both intubated and non-intubated patients. 3 } nebulized np may be beneficial in clinical contexts where inhaled no is impractical. dang phuong kiet and nguyen xuan thu examining 6 cases of purulent pericarditis with various clinical forms treated by surgery, the authors drew the following experiences for their diagnosis. t. clinical factors. purulent pericarditis appeared like a cardiac tamponade in a septicemia due to staphylococci with dassieal symptoms: severe dyspnea, tachycardia, faint heartsound, big liver, prominent cervical vein ; rentgenography of the chest showing enlargement of the cardiac silhouette, a diminution of ventricular pulsations, ~i clear lung field. by an emergency operation, 500ml of diluted blood were drained. purulent pericarditis and pleural effusion appeared at the same time but at first tile symptoms of purulent pericarditis were masked by the predominant symptoms of plearal efihsion. after the pleura was drained, its pus was no more, the general state was relatively stabilized but there still were big liver, dyspnea, enlargement of the cardiac silhouette while central venous pressure increased. purulent pericarditis appeared late. in the first stage (about 2 weeks) there was no suspected sign. later on gradually appeared such symptoms as dyspnea (during serum transfusion for instance). central veinous pressure also raised. the heart chest diametre increased at first (up to 60-65%) then decreased (down to below 50% ) but the liver kept on swelling together with the particular changes of electroeaediegramme. now the pericardium had no more pus but get fibrous (up to 3ram) thus constricting the heart and its main arteries 0ike pick syndrome). 2. diagnostic values of electrocardiograms : common signs of ecg related of these purulent pericarditis were: a diminution of voltage, a widespread elevation of the st segment, the tf wave flattened and inverted. however, what should be stressed was : the diagnostic values of an electrocardiogram for purulent pericarditis was mainly in the dynamics of their signs: in the first week, the voltage diminished corresponding to a pericardium containing pus, while the st segment went up then seemed parallel to the fibrosis of the epicardium, the liver swelled, the central velnous pressure increased, the heart/chest dimension ratio decreased, the st segment went down, the t wave became more flat and inverted. between 1986 and 1995 23 neonates, aged 2 -23 days (median 5), weight 2,38 -4kg (median 3,28) with critical valvar pulmonary stenosis were scheduled for balloon dilation (psvp), 19 children (83%) were on pge1 and 13 (57%) needed mechanical ventilation. after stepwise dilation a final balloon : pulmonary valve (pav) ratio of 114% (25-150) was achieved, there was a significant correlation (p<0,01) between an adequately sized balloon and freedom of reintervention. two valves could not be passed, four neonates underwent surgical procedures (brock n = 3, commissurotomy n = 1), two children (10%) died of sepsis. 17/23 patients (73%) were successfully palliated by psvp in the first month of life. the rv : systemic pressure value fell from 132% (75-231) to 58% (40-87), complications included 2 transient dysrhythmias, 1 transient hypoxia, 3 vessel occlusions;-1 right ventricular outflow tract perforation. in 16/17 patients follow up data is available. the residual systolic peak doppler gradient over the pav on the last out patient visit (5-103 months after psvp) was 10-41 mmhg (median 20). four children needed repea.ted psvp 26 to 72 months after the initial intervention. conclusion: psvp of critically ill newborns is possible. the risk of mortality is relatively low. psvp in neonates with an adequately sized balloon is a challenging alternative to surgical treatment. post hypoxic-ischemic (hi) reperfusion induces the formation of non protein bound iron (npbi), leading to production of the reactive hydroxyl radical. it was investigated if the ironchelator deferoxamine (dfo) could reduce free radical production and improve neonatal myocardial performance after hi. severe hi was produced in 13 newborn lambs and changes from pre-hl values were measured at 15, 60 and 120 min post-hi for (mean) aortic pressure (mean pao), cardiac output (co) and stroke work (sw). left ventricular (lv) contractility and co were assessed by measuring lv pressure (tip-manometer) and volume (conductance catheter), using inferior caval vein occlusion to obtain slope (ees) and intercept of the end systolic pv relationship (v10). npbi, reduced and oxidized vitamine c ratio (vcred/ox) and lipid peroxidation (mda) were measured from sinus coronarius blood. 7 lambs received dfo (10 mg/kg i.v.) immediately post-hi, control lambs (cont) received a placebo. results: mean pao was stable, co and sw decreased up to 60 and 40% respectively in cont as compared to pre-hi. in both dfo-groups co and sw remained within the normal range. ees and v10 decreased in all groups post hi, but did not differ between groups. npbi and mda were higher at 15 min post hi (p<o.05), vcred/ox was lower at 15 min post-hi (p<o.o5) in cont as compared to dfo-group, indicating more oxidative stress in cont. conclusions: dfo reduced the oxidative stress of the heart and prevented co and sw to drop, suggesting a positive effect of iron chelation on the myocardium after h{. from 1987 we published reports with analysis of performance of the heart as a whole organ.while analysing the heart performance as a whole, we recognize three block in it located intrapericardially: l."atrial"block -left (la) and rigth (ra) atriums; 2."aorta-pulmonary" block-aorta 'bulb (a) and pulmonary artery(pa); 3.ventricular "three-chambered" block (vb) consisting of: -left (lv) and right (rv) myocardial chambers, both frith blood outflow into "aorta-pulmonary" block vessels, and -spongy (venous) myocardial chamber with the blood outflow through coronary sinus (cs) and thebesiau vein (tv) into "atrial" block. the following conceps are introduced for vb functions assessment "common" systole and "common" diastole of "three-chambered" vb. the process of normal "common" vb systole: -begins with blood ejection from vb spongy chamber into the "atrial" block; -continues with blood outflow from rv and lv into "aorta-pulmonary" block wi~ venous minimums -x-coiiapses -~btmation iu "a~riai" block; -completes with "three-chambered" vb general emptying. at this period the following blood volumes are transferring: -two-from rv and lv(their stroke volumes)into"aor~o-pulmonary"block; -two-from "spongy" chamber .into "atrial" block; -two-from systemic and pulmonary veins into "atrial" block during the process of so called "systolic" membrane suction (at pulling atrio-ventricular valves into rv and lv chambers as blood ejects out of them). it appears to be the regulation of blood inflow to "atrial" block by blond outflow from "three-chambered" vb into "aorto-pulmonary" block. objective: to evaluate the efficacy and complications of transpyloric enteral nutrition(ten) in critically ill children patients and methods~ from june 1994 to january 1996 23 children (i0 boys and 13 girls), aged from 5 days to 11 years (mean l.8 ± 3.4years) were treated with ten. 18 patients were included after cardiac surgery, 3 with acute respiratory failure, and 2 after cerebral surgery. the indication of ten was mechanical ventilation in 22 patients and failure of nasogastric nutrition in 1 patient.19 children (82 %) had previously received parenteral nutrition. 8 and i0 fg enteral tubes was inserted into duodenus through nasogastric intubation en 21 patients and by endoscopy in 2 patients. rx and ph determination were used as methods to control tube situation. 18 children received adapted formula, 7 caseine hidrolisate, and 3 enteral formulas. (in 5 patients the nutrition formula was changed during ten). 22 patients were supported with mechanical ventilation during ten, 17 received midazolamperfussion(range 2 to 15 mcg/kg/min), 15 fentanyl (i -12.5 mcg/kg/h), and 6 vecuronium (0.1 -0.3 mg/kg/h). resulte: ten was used during 3 to 73 days (mean 18.3 ± 19.3 days). mean maximmnvolume ad~iniateredwas 132 ± 47 ml/kg/day (range 34 208) .patients with midazolam, fentanyl and vecuronitml tolerated ten similar than children without sedatives. complications were diarrhoea 1 patient, abdominal distension and/or important gastric fed residuals 2 patients. pulmonary aspiration or respiratory complications were no registered. ten was ended in one patient due to diarrhoea, in 18 due to change to oral or nasogastric nutrition, 3 children continue yet with ten and 1 was discharged of picuwith ten. conolusion: ten is an useful method of nutritional support in critically ill children with mechanical ventilation and/or nasogastric intolerance. introduction: the enteral nutritional support of the critically ill child may reduce the morbidity and mortality by attenuating, the hypermetabolic and catabolic response, decreasing the gut translocation and the septic complications, improving the bowel mucosa integrity and the wound healing. the aim of this study was to show the safety and tolerance of en. methods: we enrolled 36 consecutive patients admitted to our unit from may to december 1995, mean age 3.4 years (range imonth to i7 years). the prism, mechanical ventilation, inotropic use, opiates and other drugs were recorded. the en was delivered by continuous infusion across a polyuretane tube.we kept the patients head elevated 30 °, and we used cisapride routinely. the gap betweeen admission and the en beginning, average time to meet the nutritional objective, en duration, selected formula, patients outcome and complications were recorded. results: prism groups were 0-1=0 patients; 1-5=1; 5-10=13; 10-15=7; 15-30=12. two patients with mof (multiorgan failure) died. 72% needed mechanical ventilation.the average time elapsed from picu admission to initiation of en was 2.1 days (range 1 to 7 ) and the average duration of the en was 7.3 days (range 3 to t4). the average time to meet the nutritional objective was 2 days (range 1 to 3). the selected formula were: lactose free infant formula in 10 patients, elemental diet in 8, pediasure in 16 and jevity in 2. we recorded vomiting in 4 patients, diarrhea in 5 and constipation in 4. none of them forced the en suspension. we didn't recorded any case of ~spiration or pneumonia. we found no relation between drugs, selected formula and complications. we think that en may be a safe and well tolerated procedure at the picu setting. generation of free radicals in iipid emulsions used in parenterai nutrition (pn) has been described recently. this seems to be due to high polyunsaturated fatty acid content. we studied lipoperoxidation status and antioxidant parameters presurgically and through the postoperative period (5 days) in a group of twelve children (ranging from 4 months to 12 years of age), who underwent heart surgery and received nutritional support with pn. malondiaidehyde (mda), an end product of lipid peroxidation was used as a marker of oxidative stress. it was determined by the yagi spectrofluorometric method. antioxidant activity was measured with an assay based on the inhibition of spontaneous autooxidation of a brain homogenate, and vitamin e in serum by the technique of hansen and warick. erythrocyte mda release fonowing incubation in hzo 2 in vitro was used as a functional measure of tissue vitamin e levels. data were compared using one-way variance analysis. there was not significant differences in the plasma mda production among the values obtained before surgery (3 :t: 0.5 nmol/ml), postoperative pre-pn (3.5 +_ 0.6 nmol/ml) and through the course of pn (3.5 5:0.6 nmol/ml). levels of vitamin e previous to surgery were 5,1 5:1.1 #g/ml and decreased to 3.2 _+ 1.4 #g/ml at 24 hours post-surgery before starting pn. while receiving pn, concentrations of vitamin e increased progressively up to 7 + 4. l #g/ml (p = 0.08). pre-surgicai plasma antioxidaut activity values (72 :i: 11%) dimiuished in the first postoperative day (56 _+ 9.5%) and then showed a clear increasing tendency, directly correlated with that observed in vitamin e levels. the measurements of the maximal percentage of mda release of erythrocytes in vitro, showed an inverse relationship with plasma vitamin e levels and with the plasma antioxidant capacity: preoperative 5.8 + 2.4 % and postoperative descending from 20.5 + 14% to 12 _+ 9.5%. our results indicate that during surgery and within 24 hours postsurgery, a decline in antioxidant defenses occurs, in the postoperative period, while patients are on pn and taldng into account our obtained data: the unaltered mda values, the rise of plasma vitamin e levels, the recovery of both functional erythrocyte membrane antioxidant protection and the plasma antioxidant activity, they do reflect that during the intravenous administration of lipid infusions, oxidative damage does not occur, probably due to the addition of vitamin e to pn solutions in order to avoid autooxidation of lipid emulsions. garnitine is one of the essential nutrient in the diet of newborn infants. mother's milk represents the natural eamitine source for the newborn infants. we studied enteral earnitine intake in 71 premature infants 35 eutrophic (eu) and 36 hypotrophic (hy), fed with mothers milk trough 5 consecutive days-from fifth to tenth day of life. mean gestational age was 33 (range 32-36) weeks for eu and 34 (range 32-36) weeks for hy. birth weight was ranged 1430-2450 g for eu and 1250-2300 g for hy (p < 0,05). breast milk carnitine concentration was 78,88 i.tmol/i in mothers milk delivered eutrophic babies, and singnificant higher mean coenetration 113,88 l.tmol/i, of hypotrophic premature infants (p<0,05). breast milk earnitine concentration was ranged between 39,15-163,71 ~moi,'l, and daily carnitine excretion was between 9,7-165,48 p.mol/i, mean 60,6 +-38,7i p.molll. the daily mean carnitine intake was from 1-1,93 mgkg/d, in eutrophic and 1,23-1,93 mg/kg/d, in hypotrophic premature infants, in milk volumene intake from 150-200 mllkgld., the results of this study suggest that premature infants should be fed with own mothers mitk in eady neonatal pedod in attempt to prevent camitine deficiency. keto-acids and parenteral lipid admlnistration. castorina m., antuzzi d., ricci r., rendeli c., polidori g. pediatric intensive care unit -catholic university -roma (italy). some metabolic studies have suggested that the administration of mediumchain tltgticerides (mct) might induce a marked increase in ketone body concentrations; the aim of this study is to evaluate the effective ketogenetic risk of infusing mct emulsions in total parenteral nutrition (tpn). two groups of seriously infected children were examined: a-12 septic infants were given to tpn with a 100 % of long-chain tryglicerides (100 lct). b-10 septic infants, in wich the lipid source in tpn consisted in a 50-50 mixture of lct and mct. the children in the different groups showed similar severity and therapeutic scores (prism, tiss, ~, f~2, f~3); the lipid intake was the same, corresponding to 1-1.5 g, ckg bodyweight/day. in all patients a sample of urine was taken six times a day for the whole time of tpn the urine samples were screened by the diphenylhydrazone test, and the ketoacids excretion was confirmed by a chromatography. the urinary excretion of 13-keto-acids equivalent to p-ohphenyl-pymvate (mcg/ml urine) is summarized in the no significant increases in frequence and/or in severity of acid-base disturbances were found in all studied patients in consequence of the lipid infusion. the patients of b-group showed a lower excretion of 13-ketoacids. the c~-keto-acids excretion was ever unsignificant and seemed to be correlated with the illness severity more than with the lenght of the tryglicerides chain. this observations let us suppose that the mct, at employed doses, can be safely administred also in childen with metabolic acidosis and/or serious illness. reye syndrome cayetano heredia hospital, lima, peru five patients with reye syndrome were studied; included were those diagnosed from january 1991 to march 1994 and treated at cayetano heredia hospital. the age of presentation varied from z.5 to 7 months. the syndrome occurred more frequently in males (4/5); the time of illness at the presentation varied from 2 to lo days, and the following features were found: fever (3/5), akeration in mental status (5/5), seizures (4/5), gastrointestinal illnesses (diarrhea) (4/5), and respiratory insufficiency (1/5) --in this case ventilator)-support was needed, in all cases hepatomegaly, intracranial hypertension, hypokalemia hyponatremia, metabolic acidosis, hyperammonemia and elevation of hepatic enzymes were found. coagulation blood tests were abnormal in three patients. cerebrospinal fluid (csf) showed hypocellularity in all cases (less than 8 cells/ram3). the cultives were negative, and the final diagnosis was confirmed by hepatic biopsy. no deaths were due to reye syndrome. a contribuhon to the study of reye's syndrome the aulhors analysed 38 records of patients meeting all the clinical, biochemical and anatomic criteria put forward by hutrealoch~ and samaha (1975) who were ireated at the emergency and resusdlation depammlt tithe ipch in 10 years. the average age of the children was 3 years (the 3~umgest 11 monks and the driest 7 year~ most of lhon (34/38) came from lhe countryside to lhe lmfia~ willfin 24 hours of file oulbreak. a few days previously the patients w¢~ld have fever (some of ahem wilh diarrhea or cough) ,,rod vomit then rapidly fidl into coma and c~nvuksien. they ~me to the imtia~ with the signs of typical increased inlracranial pressure ( stages 2-4 according to lovejiy for most cases) but the liver was unllkely big. the main biocheafical dmnge of the blood was acute hepatic thilure -the bllod glucose decreased : (ha the aver~ 23,46n~% (26) ~ not measured in five cases (glucose a"aces). -the blood ammonia ino~ased riven 158 to 275 microg/dl fin lhe average 220, n = 3) -the percentage of p~in was low, in the average 44,5% (n--9), 11% at the lowest (a case ofmekaa lasling five days was ctwed with vitamin k). -got and gpt enzymes increased 3 -4 times (n=14) besides, tht~re was decompcmated addt~is with lhe average valnes ph = 7.19; pcoz = 2~6mmhg and eli = -1~6 ~, (n~). the charadaislic dumge in the ¢~'ebrospinal fluid was a low glucose tx~acenwalien h the average of 1k65mg/dl (3 cases of glucose it'aces) ; meanwhile protein decreased in the average of 14mg/dl (4 cases below 10mg/dl). besides ~here was no inflammatory lesion ~tion) : very serious brain oedona and fatty degeneration of live~ scatteredly or parllally.microso~ically (biopsy and necropsy) in file brain appeared bright space around blood arteries and glioma extended v'lrdmw -robin space, with no inflammatory reaction. liver.-the sa~dure was intact there was no " "mtlammal~s3' cell, the kupffer cells did not show hyperplasia but show a heterogenous deg~nerafion~eart: also showed a fatty degencralion in some areas of the myocard eellkidney: the ihtty degenerati~l scattetedly in the tubular cell. pano~as:fatty degeneration scattetedly in file pancreatic cell. two cases of liver biopsy for lhe 2rid lime (check before leaving file inslitute) found that fatty degeneration was r~tta~ nearty ff~pletely. the exact muse remained unknown. objectives: to analyse whether there exists serum and urine electrolyte disorder in children with respiratory failure, methods: we have made prospective study of 48 children in our icu during a 12 month period, electrolyte concentrations were measured in serum and urine collected during 24 hours (sodium-na, potassium k, chloride-ci, calcium-ca, magnesium-mg and phosphorus-p). results: average values in serum were: na 139.28 +/-3,20 (rv:133-146) mmol/i, k 4.22 +/-0.55 (3.3-5.2)mmol/i), cl 95.20 +/-3.98 (93-106) mmol/l, ca 2.t2 +/-0.12 (2.20 2.65)mm01/i), mg 0.82 +/-0.22 (0.77-1.12)mmol/i. average electrolyte levels in 24 hours urine were: na 64.23 ~/~ 44.11 (42-202)mmol/day. k 22.14 +/-10.33 (22-112)mmol/day, ci 56.14 +/-27.22 (100-244)mmol/day, ca 1.17 +/-0.13 (1.68-6.8)mmol/day and p 11.89 +/-7.12 (11.7-32)mmol/day. conclusions: average serum ci and ca levels were decreased in children with respiratory failure. in urine, average k, ci, ca and mg levels were decreased and urine p concentration was increased. we concluded that serum and urine electrolite disbalance may be expected in children with respiratory failure. the nurse is going to kill me! (icu syndrome) anita duvndam ~, sonia v.d,sluis 2 ~dpt. of pediatrics, div. pediatric intensive care, sophia children's hospital, rotterdam 2dpt. of pediatrics, div. pediatric tntensive care, juliana children's hospital, the hague. content description: this presentation will provide the critical nurse with background information concerning the identification, the prevention and management of the critical ill child who has developed the icu syndrome. the results of a questionnaire concerning the occurrence of icu syndrome on a picu will be presented. behavioral objectives: at the end of this session the participant will be able to: 1. describe four clinical symptoms of the tcu syndrome, 2. identify major sources of picu environmental stress, 3. discuss nursing's unique role in helping the child to cope with the icu syndrome, 4. discuss nursing's unique role in preventing icu syndrome. content outline: the icu syndrome is a situation in which the individual is not able to deal with changes in observation and interpretation of both quantity and of patterns of sensory perceptions. in other words the borders between the inner and outer world becomes unclear for the person. the exact incidence of the icu syndrome in the critical care setting is unknown, we have limited knowledge of the occurrence of the icu syndrome in critical ill children. yet critical ill children in our hospitals sometimes show the symptoms of icu syndromes. to be able to identify the occurrence of icu syndrome we developed a questionnaire. the thesis of the questionnaire was: does the icu syndrome occur in critical ill children in the age between three and ten, who have been intubated and/or ventilated in a picu? eighteen questionnaires have been send out to parents of critical ill children in two hospitals. the response was 90 percent. conclusions: 1. most of the children were anxious (n=11), showed regression (n=8) or had sleeping problems (n-lo) during the stay on the picu. 2. children showed the same problems after discharge. 3. there is no relationship between environmental factors and symptoms of the tcu syndrome during the stay. 4. there is no relationship between preexistential behavior and symptoms of the icu syndrome during the stay. because the lack of a scientific definition for the icu syndrome in children and good criteria for diagnosis, we were not able to get an answer to our thesis. more research is needed. continuous veno venous haemofiltration (cvvh) was adopted as a first line renal replacement therapy in our paediatric intensive care unit (picu) some three years ago. ~/he process of introduction and development of cvvh proved to be an exciting challenge for nurses as indeed it was for the whole multidisciplinary team involved. we have successfully used cvvh in the treatment of over 20 infants and children, weighing between 3-85 kg. the range of conditions treated is ever increasing. to date we have not only used cvvh for patients in renal failure and fluid overload, but also to gain biochemical control in tumour lysis syndrome-and metabolic disorders. other distinct patient benefits in comparison with more conventional means of renal replacement therapies are that, it is a continuous controlled treatment being extremely effective in creating 'space' for nutrition, which is especially important in the fluid restricted, catabolic patient. of paramount importance in providing this level of service is the education and training necessary to impart the skills and knowledge for nurses to become expert practitioners in this field. we now have a teem of highly advanced practitioners who have developed their nursing skills to provide even more holistic care for their patients. this group are embracing new challenges and responding positively to the developing service whilst expanding their knowledge base. this paper will discuss the advantages and disadvantages of cvvh as we have experienced, relating i t to the wide variety of patients we have treated. we wish to share how cvvh has become an accepted role of the picu nurse and how the service has been successfully implemented. integrated care pathways (icp's) define the optimum course of events in the care of a patient with a specific condition, within a set timescale. aims and methods: icp's and case management (cm) were introduced to evaluate and improve clinical practice. icp's were developed for patients undergoing surgery for atrial septal defect (asd) ventricular septal defect (vsd) and fallots tetralogy. they were based on the median experiences of the last 31 patients. 108 patients have been managed using icp's. results: analysis of variation from the icp's shows a reduction in the following potentially avoidable causes of variation: delay in extubation has been reduced from 29% to 10%, and 31 patients (29%) were extubated earlier than the median. prolonged stay on the intensive care unit (icu) has decreased from 13% to 0%, and 24 patients (22%) were discharged to the ward a day earlier than the median. the number of patients receiving inadequate post operative analgesia has decreased from 35% to 15%. delayed feeding after operation has been reduced from 52% to 28%. unavoidable delays in extubation and discharge from icu occurred in 22 patients (20%) because of haemodynamic instability" or lung problems. cm utilising individualised pathways for these patients has reduced variation in care which can improve patient outcomes. pathways have been developed for other conditions and it is anticipated that approximately, 80% of patients will be treated using an icp revision of icp's results in continuous evaluation and improvement of the care provided, conclusions: the use of icp's and cm has improved patient care and decreased avoidable delays and variations. the future development of other icp's, combined with a case managed model for selected patients, is seen as a viable method of continuously improving patient care. this paper is a retrospective audit of 24 children who received continuous veno venous haemofiltration (cwh) whilst on the paediatrie intensive care unit (picu), data was collected over a 21 month period from may 1994 to january 1996. the 9 girls and 15 boys were aged from 1 day to 15 ½ years (median 4½ years) and weighed between 2,5 and 85 kg (median 17.75 kg). length of admission to picu was 2 to 47 days (median 9 days). sepsis syndrome was diagnosed in 11 cases: 4 of these had bowel necrosis and 3 meningoceccal disease. eight patients had an underlying haematological, oncolngical or immune disorder. the remaining children had inborn errors of metabolism (2), nephrotic syndrome (2), or cardiac failure (1). cvvh was instituted for a variety of reasons. muttiorgan dysfunction was present in 46% of patients, 29% had acute renal failure, 12.5% tumour lysis syndrome, 8.5% uncontrollable metabolic acidosis with hyperammoneemia and 4% required fluid management. treatment was continued for between 4 hours and 26 days (median 4½ days). haemofiltration was successful in achieving its desired effect in all except one patient. 87.5% of children with haematological, ontological or immune disorders died despite successful haemofiltration. survival was higher in cases of septicaemia (45.5%), nephrotic syndrome (50%) and errors of metabolism (50%). overall mortality was 62.5%. this was attributed to the severity of the underlying disease process rather than the effectiveness of cvvh as a renal replacement therapy. asynchronous defibrillation and synchronized cardioversion deliver direct currents of high amplitude through the chest, to stop ventricular fibrillation or to convert life-threatening arrhythmias. since the human body is partially conductant, it should be possible that after a brief delay of time, a derivation of this monophasic defibrillation pulse is measurable in regions of the defibrillated body, other than the traject between anodal ("sternum") and cathodai ("ape~;") paddles. one could also estimate that health care personnel in the immediate environment of defibrillatoty shocks, are always at risk to possible electric injury. accidents might occur when health care personnel do not stand clear from the patient during firing and create an additional electric path from this patient through their own body. most likely, the nonisolated parts creating a transversal eiectric path, will be the hands of the caretaker. since defibrillation generates touch voltages up to 5000 v and 60-70 a in ved, short delay's (5 to 10 millisec), the total body resistance during skin to skin or skin to paddle contact, is calculated to be as [ow as 750 ohm (percentile tank 50 for the entire population). an experimental protocol was developed to evaluate the conducted currents during defibrillation. mature pigs with a weight of 100 up to 150 kg. were used as animal models. the:,, had barbiturate anaesthesia, inotropic support with dobutamine at l 0 micmgrams/kg bodyweight and all had a sinasat rhythm at the begining of the test-rounds. synchronized defibrillation at 100 j (approx. 0.75 j/kg) and asynchronized -at 360 j (whenever ventricular fibrillation or ventricular tachycardia occurred), were attempted, through latero-lateral placed and firmly pressed defibrillation paddles and/or adhesive multi-function electrodes. gel pads were choosen as contactmedium to cross the skinpaddle barrier. subdermal electro-myography needle electrodes were put at different parts and regions of the pig's body, but not between the paddles. these electrodes were coupled to a resistance device of 800 ohm and a measuring computer. we measured monophasic and low current pulses up to 0,10 a during the defibrillation burst. thus conducted currents are high enough to produce accidental electric shocks when additional electric paths are created by the caretaker. "llaese are usually harmless, but in some "worst case" (wet or transpiring hands, rings,...) or in association with defectuous equipment, peak currents might be harmfull, and can produce pain, bums, apnae or cardiac (transient or persistant) arrhythmias. maria skogbv. karin mellgren, lars-g6ran friberg, g6sta mellgren, hans wadenvik. g6teborg, sweden. bleeding complications in extracorporeal circulation is partly due to perfusion-induced platelet dysfunction. the aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeat system. study: two complete extracorporeal life support systems were perfused with fresh heparinized human blood for 24 hours. piatetet membrane glycoprotein changes, platelet granule release and platelet count were followed. eight paired experiments were performed. one of the circuits was perfused by a roller pump (polystan) and the other by a centrifugal pump (biomecicus), other components were identical. results: a continuous increase in glycoprotein (gp) ib-negative platelets was seen in both circuits. a marked increase of plasma beta-thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. the plasma concentration of glycocalioin increased in parallel with a reduced platelet surface expression of gpib, suggesting that the loss of gpib is caused by proteolysis rather than by a downregulation of this receptor protein. conclusion: 24 hours of ecls perfusion induces pronounced platelet degranutation and causes changes of important membrane receptors. this is in accordance with clinical studies, suggesting that our in vitro model does mirror the platelet exhaustion observed in a clinical reality. no significant difference was observed between the two pumps. the purpose of this study was to examine signs of distress exhibited by several patients following the discontinuation of opioids and benzodiazepines (o & b) in a 7-bed pediatric intensive care unit. the authors compiled a list of all cases of possible withdrawal reactions reported by nurses in the study setting over a one-year period. five cases were selected for study in terms of their wide diversity of relevant circumstances. the 5 cases were examined through a retrospective chart review. data pertaining to analgesic and sedative administration, along with nurses' reports of behavioral distress, were transcribed and coded. a remarkable pattern of behavioral distress was clearly associated with discontinuation of o & b. cessation of benzodiazepines was associated with severe distress. these reactions were characterized by various combinations of crying, irritability, tremors, grimacing, gagging, vomiting, or feeding problems. some of these persisted in spite of large amounts of bolus drug administration. these signs were manifested for 2 to 9 days following cessation of o & b. these findings demonstrate that the rapid weaning of o & b infusions, sometimes following short-term therapy, can cause severe withdrawal reactions. the particular course that a specific patient will follow will likely be modulated by underlying manifestations of "icu psychosis" and unresolved pain and emotional distress. hermana tezano8 mt, pilaf orive j, latorre garcia j, lizarraga azparren ma, lopez bayon j ucip hospital de cruces. bilbao. spain a female child, one year old, was referred to our unit from another hospital because she had ischemic syntomsjn her right forearm wich started three days before. she had ~i downs syndrome and fallot's tetralogy with a systemic-pulmonary by-pass. nine days before the admission in our hospital she was undergone to a cardiac catheterization by arterial and venous femoral punctures with no incidences. on the admission to the picu her forearm was cold and pale with absence of cubital and radial pulses and slow capilary filling. treatment with heparine was started unsucessfully in the firsts 24 hours, so uroquinase was added that later was changed to rtpa plus brachial plexus blockade. by the time me arterial tlux became more and more evident (doppi~) il bccuute aiat) evident a regional aedema witch made necessary a fasciectomy &the wrist. she also developped necrotic delimitted areas that included her first and fifth fingers. she was discharged from the picu after 13 days and a week later she went to the operating room where an amputation of the distal phalange of the fifth finger was made. the etiolgy of this ischemic picture can't be attributed to the catheterization itself, but probably it should be due to some attempts in arterial puncture in its course, attempts that could be guess by the little marks noticed at the elbow flexure when she was admitted. long maintenance of cardiovascular funtion by assisted ventricular device with membrane oxigenator hermana tezanos mt, pilar orive j. latorre garcia j, lizarraga azparren ma lopez bay6n j. ucip. hospital de cruces. bilbao. spain a little girl of three and a half years came to the intensive care unit from the operating room. affected of great vessels transposition with a pulmona~' banding corrected vith rastelli technique, it became impossible to discharge her from the by-pass circulation. it was assumed that this factt was due to a transient myocardial disfunction dfter the surgeon x~ent through the technique and found no wrong step in it. at the picu admission she had an ejection fraction belox~ 20% (echncardiografy), and was manteined on veutricular assistance with a circuit consisting ofa plate's membrane oxigenator, a bio-medicus pump and pvc rubber tubes, with monitoring of pulmonary', right and left atrial pressures. initially she needed a ventncular support of 1.2 l/min with dopamine. dobutamine and adrenaline; gradually the ejection fraction rose to 60% aliowing a decrease in the mechanical and inotropic support. the organic function ,.'.-as preserved but x-ray of the thorax showed images of pulmonary aedema with an increase in the 02 needs until a fi02 of 0.4. even though she was placed in a transplant program, she was remouved when the ejection fraction rose to 50% on the 1 lth da 3 of the evolution. there were no signs of infection (profilactic coverage). on the fifhteen postsurgery day. with a good cardiac sound and an ejection fraction of at least 60%. it was considered the withdrawal of the ventficular support, but unsucessfully despite the increase ofinotropic drugs, so she died. we think that our patient is a good example of the posibiti~ to mantain x~ith ecmo during a prolonged period of time a potential transplant receiver without major complicatios. joan wierema; ma0)an mourik. sophia children's hospital, department of pediatric surger,j, rotterdam, the netherlands. the success of an ecmo program is heavily determined by the organizational structure and the daily availability of both well trained nurses and physicians. until now there is no general guideline to determine the optimal training schedule to set up an ecmo program. objective: to evaluate the set-up of an ecmo program in an area without direct availability of perfusionists of cardiothoracic surgeons. description of the progress: during the preparation of the ecmo program which started november 1991, different phases are identified. first phase, acquisition of experience by training abroad of one physician, staff member of the icu, physician acting as a fellow and one icu nurse with theprimary task to serve as an ecmo coordinator and train the nursing start. in the second phase 12 animal experiments were performed by 2 paediatric surgeons, 2 staff physicians, 2 fellows and 12 nurses. third phase, start of the actual ecmo program, priming by one trained nurse and ecmo fellow, daily care of the patient by 2 nurses, 1 icu nurse taking care of the patient related activities, 1 ecmo trained nurse taking care of the circuit. fourth phase, transition of the tasks for priming the system from the ecmo fellow to the ecmo nurse and changing daily care for the ecmo patient now including the circuit by 1 trained icu nurse with special legislation for ecmo. ongoing training of 6 to 8 nurses working for at least half a year in the icu. during an ecmo run direct contact between the ecmo nurse and one of the staff members; patient data: in a 4 year period 52 neonatal ecmo cases were performed with an overall mortality of 74%, ranging from over 95% in meconium aspiration to 45% in congenital diaphragmatic hernia. in 7 other patients pediatric ecmo (age range 1 month -14 months) mortality was 50%. conclusions: ecmo can be established without perfusionists or cardio surgical back up once a predetermined training schedule is available, resulting in comparable results with the international ecmo registry both for neonatal as well as for pediatric cases. mechanical ventilation at home makes normal development of the child with chronic respiratory failure possible. the parents must be encouraged to accept the treatment at home; therefore, they should be enabled to take care of their children all by themselves and the continuous professional support has to be offered to them. it must be stressed that the nurse is the link between the diseased child and his family introducing them into the process of the medical care at home. all the equipment needed for the mechanical ventilation of the child at home (ventilator, suction device, pulse oxymeter, oxygen tanks) has to be provided before the child is discharged. it is paid by the national insurance company. the maintainance service workers will make the necessary installations available and they will renew oxygen and compressed air weekly. the ventilation assembly must not interfere with the childs activities. the related dispensary and nursing service should be notified of the child's condition and the list of the required material (suction tubes, cannulas, desinfectants etc.) has to be made. our experience is so far -from the nursing and medical point of view -satisfactory, however the social status of the parents needs further regulations, omphalocele. mourik m, sophia children's hospital, department of pediatric surgery, rotterdam, the netherlands. in patients with (giant) omphalocde operative closure is impossible due to the lack of intra-abdominal space and a variable degree of pulmonary hypoplasia. consequently conservative treatment allowing epithelialization is the treatment of choice with a high risk of infection and/or sepsis due to a sometimes very long stay in the icu. this conservative treatment consists of daily application of an antibiotic containing powder on the cele which is covered by sterile gauzes. furthermore the enteral intake is started as soon possible. objective: to evaluate whether this treatment renders a high risk for serious infections. patient characteristics: in a 10 year period 23 patients with a giant omphalocele were admitted; mean birth weight 2800g (1500-3990g) mean gestational age 38.5 (33-42 weeks). overall mortality 6 (19%). 11 patients had to be ventilated for a median duration of t6 days (2,5-164). results: patients were discharged at the mean of 68 days following birth (17-260) following complete epithelialization of the omphalocele. following the initial stabilisation period parents were involved in daily care of all patients even during artificial ventialation. enteral intake was started at a median of 2 days (1-18). colonization of the omphalocele was observed within 2 -4 days in all patients. although infectious periods were observed at regular intervals, sepsis was the primarily cause of death in only 3 of the 6 patients who died, in conclusion: nursing care to prevent sepsis in patients with (giant) omphalocele is feasible for a long period of time and can be performed with simple measures, since june 1994, we have been using nasal cpap in the treatment of respiratory disorders in newborn infants (severe apnea syndrom, tachypnea, hyaline membrane disease). in newborns presenting hyaline membrane disease, we have used cpap and administered surfactant therapy to 25 premature babies out of 70. clinical data were : mean ga : 30.8 + 23 weeks. mean bw : 1686 + 551 g. mean administration time was 11 hours. before administration, mean fio2 was 0.4 + 0.07, mean pao2 6.2 + 1.8 kpa and mean a/ao2 ratio 0.21. all babies were intubated for administration of surfactant (curosurf) and were extubated after half an hour to 3 hours after administration. this treatment failed for seven babies and they were ventilated by oscillation ventilation ; all babies survived. complications : we have observed pneumothorax in 2 cases and 1 cerebral hemorrage. mean duration time of nasal cpap was 71 hours for the 18 babies without assisted ventilation. nurses in charge of babies with nasal cpap should be aware of neonatal care, of the possibility of surfactant administration and of complications during this type of treatment. therefore nurses should know very well the use of nasal cpap, the monitoring during this treatment, the fixation of the system on the baby, nursing of the babies during this treatment and finally should take care of the baby physical and psychological well being. as a conclusion, nurses in intensive care neonatal units should know the possibility of treatment of rds by nasal cpap and should be aware of baby-nursing. emco in the postcardiotomy infan_t : a simplified circuit and reduced management grillet lsabelle, bosson christa, goelz andrea, helmer pascale, icu nurses, tschaut rudy perfusianist aldo castaneda institute, clinique de genolier, suisse to improve postoperative survival of infants with repaired cardiac tessions but severe residual cardiopnlmonary dysfunction, emco was used in 4 infants, ranging in age from l0 days to 9 months and in weight from 2,8 kg to 7,8 kg. diagnosis included tga / intact ventricular septum (2) (both subiected to rapid arterial switch operation because of unsuitable lv function) and tga +vsd (2). "['he emco circuit included a sarns roller 15ump, a medtronic minimax plus hollow fiber oxygenator and tubing (1/4 -1/16 inch) with bioactive surfaces, an arterial canula 10 fr., 2 venous canulas : right atrial 20 fr, left atrial 12 fr., an air oxygen mixer and a sarns heater. the act was kept between 180-200 sec. after the infant was connected to emco by the surgical team and the perfusion technologist, the patients were being cared for and controlled exclusively by the 1cu nurse assigned to the patient and the physician on call for the icu, pump flows of 100-150ml / kg / mln were targeted to insure an adequate urine output, a brisk capillary fill and physiologic left and right atrial pressures. sodium nitroprusside was used to control systemic hypertension while all other inotropic drugs were discontinued. inspired oxygen fraction on the ventilator was reduced to 0,25 at a respiratory rate of 10-15 breaths per minute. body temperature was maintened close to normal. when the heart started to eject again, inspired oxygen was increased to about 0,40. the preparation for weaning from emco was done by the icu nurse: including oxygen fraction and ventilator rate. weaning from emcowas coordinated by the medical / surgical team and the perfusion technologist. the duration of emco in the 4 patients ranged from 2 to 9 days. three patients (75%) were saccessflly weaned from emco. one of the three died within 24 hours from neurologic complications, unrelated to the emco. the other 2 patients ( both with tga + vsd ) are long term survivors and are doing well. neither the survivors nor the patients who died bad hemorrhagic complications, despite the fact that 3 of the 4 were placed on emco because of failure to wean from cardiopulmonary bypass. the simplified emco circuit worked reliably throughout this experience and no complications occurred nor could any shortcoming be ascribed to the use of this reduced, cost effective management team. 10 years of praciical experience wiih exiracorporeal membrane oxygenation (echo) -the viewpoint of the nursing siaef monika schindler in 1985 a training program was started for the introduction of echo in the kinderklinik of mannheim/germsny. 2 years later (1987) the first european echo patient, a 3 days old newborn baby, ~as treated successfully in our institution. with echo, more treatment modalities ~ere available after failure of conventional therapy in eases of severe lung diseases like meeonium aspiration syndrome, congenital diaphragmatic hernia, sepsis/pneumonia, primary persistent pulmonary hypertension of the newborn and -in infants and children -ards (acquired respiratory distress syndrome) due to multiple underlying illnesses. in 1989 the first ards patient, a 5 years old girl, was treated successfully ~ith ecmo in mannheim. until now 137 patients (age: i day -10 years) were treated with echo in our institution; 111 additional patients were transferred to us from other institutions for therapy with echo, but could be treated ~ieh alternative moda]ities of therapy like improved conventional ventilatory support, high frequency oscillatory ventilation (hfov) and inhaled nieric oxide (no), unexpectedly the more ~ide-spread use of hfov and no -also in other ~ntensive care units -did not lead to a reduction of the echo frequency in our hospital. due to this long ecmo practice, which is helpful in many critical situations, a certain routine came up in the nursing staff of our intensive care units; but ecmo continues to be a maximum strain for all co-workers and implies an high personnel and material/financial-expense. but in our opinion the improved survival rates in severe respiratory failure-(70 % in neonates and 50 % in infants and children, estimated survival rates under continued conventional management: < 20 %) by the use of echo justifies this expense, even in times of less financial support for public health. • analyse the differences between each urdt. method : ni criteria were defined by the rt~a ped group according to cdc criteria. all data were collected by a nursing and medical team. data 3vere dealed with epi info software. all u-dections data were validated by an external mvestigatol : 4 525 patients who stay more than 48 hours in an icu were included over a 14 months period. 68 % were newborns, 19 % infants and ,13% children. 371 ni were idenlified among sll patients, the overall ni incidence rates was 8,2 % and 5,9 person day, septicemia was the first cause of ni (50 %). staphylococcus epidermidis were isolated in 60 % of septicemia cases. pneumonia was the other main ni (41%) with gram negatwe bacille isolated m 53 % (40 % of them beei,ng fseudomonas) accordmg to age, the septicemia mcidence rate varied from 6,8 ~., to 10.9 %,, catheter/day and pneumonia incidence rate from 3,9 %, to 7,3 % ventilation/daywith the lowest rate for newborns. : this survey was possible thanks to the collaboration between laboratories, bacteriologist, physicians and nurses, and allowed each concerned unit to work together in~tead of every one in his own field. 'lhe results of this survey bring changes in attlhades and empower the different team work the next step is to analyse the ditferent nurses procedures of indwelling central venous catheter in each unit ar)d implement a ni quatity care. program in all nicu anti picu. v~,~jl~j~'v~y : new born in~ra-v~6nous drugs ~md lheir pr~taration mcounter a lot of risk ~)f utters, due to inadapted conditionn~ng to podia)eric and minimal amount injec~.~d, th~ study t~ed to evaluate degrees of do.~age er~o~ dye tt) dru~ preparaek, n i~ nc,:,~atol~gy and to come out w~th ~ method of dihttion able to reduce risk to minima (errors _< 5 %) at the ~eme t~me, ¢o~,~x-tueaces on cost were studioj methnd~ : amikacine was choosen because this antibiotic is regularly ~,~l in neonatology unit and its dosage is easily used by standardiaud method, 30 amikacine doses (15, 23 mg doses and 15, 12 mg doses) were prepared" by 15 nurse~ form 50 mg for 1 m) vial. each dose w'a~ diluted to obtain 2 mi volume, tallowing usual ward method, for each dilution, amikacine con<entrati('m and it,s volume was measured and used equipment for preparation wa~ regi~tred. 10 "first s01utj(m" were prepared diluting ~t'~ mg amikacine pouder inn 51) ml glucnse solution bag (viaflex baxter bag with transfer cap), from tho~e "first solution" 15 doses at 23 mg and 15 doses of ~2 rng were prepared, amik~cine coc, cenir,)tmn for each preparabon and their volume were measured, ai,~n ntttl~,ber of seringe were tounted. first soiuhon staeiiity was conrroieo aher one week conservation at + 4'>c. amjkacine concentration were measured by fluorescence process (tdx abbott) after sample dilurion. on a 10 mg/l sample, tovhnical reliahility show~ > 9~ % of result mpmductlon and < 5 % of variation due to dilutions. results : when amikacine injection werv pro.pared from araikacme 5/) mg for 1 mt vial > 10 % do~ge, ermr~ were found in 19/40 cases ; ~ 30 % in ,t1,to cases. if preparation is done from amikacine "~it'st soltltion", les.--concenvr~tcd, it i~ more preci,,,e and only one dosage error ~ 5 % (6,3 %} is found in eli 30 studied doses. in add)inn to )hal if 10 doses were wep,m-'d from one "first soiatiol~' bag, the cost economy sl~ouid b~" of 32 fr~, and ii 20 dos~$ were prepared tram the same bag the saving mtmey should be o{ i72 its .cencluslon : .ur survey shows th~t h' ntu)nato|ogy the u~ of a "first sohation which can be kept fi~r one week is enable to reduce dosage erroes and i~ co,~tsavmg, regarding [,v. admimst'rahon method the survey is still on, introduction: so-called vein of galen m~iformations ale rare in~racranial embryologycal anomalies, repl~senti~g tess than 1 of symptomatic intracranied artefiovenoas l~alform~tions. the spontlneous prognosis is ~s~u~lly fatal, because of cardiac frilure due to left-to-right shunt thrq~ugh the fistula. recent developments of new techniques of treatment of the malformation and its cardiac consequence have led to a revolution in the practical approach of children w~th galen malformation. our fukfose is to contribute, with our persoaal series of 7s newborns and infal~ts admitted in our unit after endov~,scular embolization, to a better management of these children. such a management requ!res a rnultidisciplinary approach. intensive care are required prior to embollzation for patients with cardiac failure or cardiogenic shock and after cmbolization in order to insure cardiac and cerebral hemodyna.mic stabilities. this overlooking suppose for the nursing team to understand: prior to embolization : heart failure and cardiogenic shock. after cmbolization : evaluation of neurological and hemodynamic consequences of this proccdure, without forgetting the nursing and psychologic aspects, in concl'iision, this last ten yerrs, these new approaches give to the patients and their famitiy a good reason to hope a total recovew, in our exl)erience, the global mortality is 9 % aad 66 % of children #j-e neurologically normal after embolizafion, ii ii~ i ~ii i ii i i l i iiii~ i ~i iii i background: venous oxygen saturation (svo z) reflects the residuai oxygen after tissue oxygen extraction and represents the relation between tissue oxygen supply and demand. we studied svo 2 and arterial lactate during progressive isovolemic anemia to assess the relation between svo2 and tissue hypoxia. subjects: ten 8-10 day old anesthetized ventilated piglets sao 2 and svq were measured continuously by a fiberoptic catheter (oximetrix, abbott lab.) in the carotid and pulmonary a~epy tissue hypoxia was confirmed by a reduced vo, and an increase in lactate. conclusion: svo 2 reflects better a reduced dp obtained by progressive anemia surfactant replacement improves gas exchange in early-stage adult respiratory syndrome (ards) [1,2], but not in late-stage ards [3] . we report the first case of successfull treatment of ards after repeated instillation of surfactant.a ten year old boy, weighing 32 kg, presented with hemorragic shock. biphasic-positive-airways-pressure ventilation was performed (evita ii, dr~ger, germany). he had recieved nine units of packed red blood cells and underwent surgical exeresis of two bleeding gastric ulcus. post-operatively, a cardiac arrest required cardiopulmonary resuscitation for three minutes. hemodynamic status was subsequently stabilised. the chest-radiograph showed infiltrates of both lungs without signs of cardiac failure. on the third day, the patient became severely hypoxic with a pao2/fio 2 ratio of 30. gas exchange was not improved by high ventilator settings. peak inspiratory pressure (pip) and ventilatory rates were 40 cmh~o and 18 breaths/min respectively. inspiratory:expiratory time was 1:1 and the positive end expiratory pressure (peep) 8 cmh20. after increasing the peep level to 11 cmh20, we instilled over 2 minutes, 80 mg/kg of porcine surfactant (curosurf, serene france), in two equal volumes in both main bronchus,the spo~ rose to 97% within 15 rain, the fie 2 could be reduced to 0.6. twenty four hours later, gas exchange worsened again (pao2/fio2 ratio 90). we increased the peep from 8 to 11 cmh20, and instilled a second dose of surfactant (60 mg/kg). again, fie 2 could be reduced within 15 minutes (spo 2 95; fie 2 0.6.). the patient was weaned from the ventilator and extubated on the tenth day. follow-up at four month showed normal lung function.we demonstrate improvement in oxygenation after repeated exogenous surfactant administrations. we assume that in early-stage ards, surfactant may potentiate shunt-reducing effect of peep as it has been demonstrated in experimental model of ards [4] , and allow decrease in fie2. in case of secondary deterioration, we think that a second dose of surfactant should be administered. 1. weg jg, balk ra, tharratt rs, et al. ,lama 1994 : 272: 1433 -8. 2. spragg rg, gillard n, pdchman p, et al. chest t994: 105: 195-202. 3. haslam pl, hughes da, mcnaughton pd. et al. lancet 1994 343:1009 -11. 4. huang yc, caimulti sp, fawcett ta, et al. jappl physiol 1994 76:991-1001 43% (ref) . the aim of this study was to verify these data: patients/~lethods: all pts admitted to our multidisciplinary nicu/picu in 1995 were included if they were in respiratory failure recruiting conventional mechanical ventilation (cmv) with peep >_ 6 and 'fig2 -:2 50% or high-frequency oscillation ventilation (hfo) with mean airway pressure _> t8cm h20 for 12 or more houm. diagnosis, maximal ventilatory parameters, barotrauma, organ/ system failures, mechanism of death and glasgow oulcome scale (gos) 1 and 6 months after study entry were prospectively collected. results: 685 patients were admitted to the unit, o1 whom 337 required mechanical ventilation for a mean duration of 4.0 days. overall mortality was 5%, 22 patients fulfilled study criteria. 17 survivors had gos 5, 2 pts with preexisting neurological impairment survived with gos 3. neonatal diseases included hyaline membrane disease (7), meconium aspiration syndrome (4) and cardiovascular surgery (1), pediatric diseases included bacterial (1) and viral (5) pneumonia, aspiration (1) and cardiovascular surgery beyond the neonatal period (3). 1990 -1994) . patients and methods: cefotaxim was used as a prophylactic agent in 43 patients in life threatening situations (e.g. multitrauma, neurosurgery atc.). more than 85 % children required cefotaxim for the treatment of severe infections (epiglotitis, meningitis, sepsis, pneumonia mainly in immunodeficient and neutropenic patients) in monotherapy or in the combination with the other antimicrobial agents. results: cefotaxim as a prophylactic drug was successful in all 43 cases (100 %). the effectivity of treatment of infections was 82.8 % (313 patients). the change of antibiotic therapy required 9 patients (2.4 %). 40 patients (10.6 %) died, but only in 12 of them (3.2 %) the obduction confirmed infection. conclusion: we conclude that cefotaxim is very effective and safe antibiotic and represents "golden standard" in the treatment of severe infections in childhood. in order to improve nursing quality, we recently adapted nursing care to the "five nursing functions" (activities of daily living, accompagnment in crisis, treatment, prevention and research) as described by the swiss red cross in accordance to the new educational guidelines of the european community, the aim of this study was to document complications of "treatment nursing function".methods: all treatment complications were prospectively collected by the nursing and medical staff. the nursing staff included patient (pt) name, time of occurence and exact description of complication, proposal for prevention and information of parents. the medical staff reported type of complication together with pt information, diagnosis, medication, treatment and interventions, outcome and referral, all complications were discussed in monthly meetings including nursing and medical staff.results: from january until december 1995, 685 pts were admitted to the picu/nicu for 3233 nursing days (81% of total bed occupancy). 337 pts needed endotracheal intubation for an average of 4.0 days and 47 pts required nasal cpap. 26 complications in 21 pts were noted (1 per 26 pi): inadequate check-up of equipment 11; accidental extubation 4 (1 in 85 intubated pts); bedsores 3; false drug dosing 2; wrong drug 2; umbilical bleeding 2; wrong transfusion setup 1; nasal septal necrosis 1). there was no mortality due to these complications. exact documention of treatment complications and their meticulous discussion within the medical and nursing staff may improve "treatment nursing function". however, documentation and evaluation of nursing within all "five nursing functions" will be nessecary in order to achieve optimal nursing care. cardiac output determination by thermodilution, using iced injectate has been shown to be valid and reliable in pediatric patients. it has been demonstrated in adult patients that there is no difference in cardiac output values when using room temperature injectate as compared to iced temperature injectate. the purpose of this study is to examine the effect of injectate temperature on cardiac output values in pediatric patients. our study consisted of sixteen pediatric patients who had oximetric thermodilution catheters in place after cardiac surgery and who had cardiac output determined using both iced and room temperature injectate. with each patient, cardiac output was measured once on the day of surgery and again the following day. in each case cardiac output was measured using both iced and room temperature injectate. statistical analysis included a two-way, repeated measures analysis of variance for each individual injectate administered and no significant differences were found in cardiac output. no statistically significant differences were found between groups with regard to the order of injectate administration or volume of injectate used (i,e., 3 or 5 cc's). the correlation coefficients between groups for cardiac output measurements at each injectate administration time, and for the average measurements across times, ranged between 0.81 to 0.94 (p < .0005). preliminary data analysis suggests that cardiac output measurements for children are not effected by the temperature of injectate. a lenghty stay at a paediatric intensive care unit will always have sideeffects on a child's well-being and will put a high strain on the parents. in order to minimize the side-effects longterm intensive care unit opened in 1990 at the childrens' hospital. admitted children are all ~ongterm-ill and technically-dependent and the ventilatory support can alter from a tracheostoma to cpap or portable volume ventilator. nutritional support is applied by gastrostomies. a homelike atmosphere surrounds the children, they share a dormitory, a living-room and a dining-room the main purpose is to send the child home with or without technical equipment. this can only be implemented by giving structured education (theory and practice) to all categories involved. the multi-disciplinary team consists of one anaesthesiologist, head nurse, clinical specialist, rn nurses, nurses, one habilitation doctor, one social worker and therapists. twenty-four patients have been admitted to licu during these six years. length of stay was from one day to four years. four are presently staying at the trait. the assessment of pain in children (0-3 yrs) is still difficult, because children of this age have limited language and cognitive skills. to standardize the assessment of postoperative pain and distress in the intensive care unit an observational mstrument was needed that met several criteria. it should be easy to use in daily routine care. be suitable for the i.c. situation, and in children of 0-3 hrs of age. the comfort scale, an observational instrument designed to assess distress in infants in i.c. units, met these criteria. to accommodate the use of the comfort scale in the i.c. units and in research, nurses should be trained to use the scale. an additional requirement was that the inter-rater reliability should be sufficiently high, (cohen's kappa > .60). objectives: 1) to introduce the comfort scale in the i.c.u.; 2) to examine whether this instrument can easily, be incorporated into routine care; 3) to investigate the inter-rater retiabtlity. methods: the comfort scale is an 8-item instrument specifically designed for use in pediatric i,c, units and contains both physiological items (heart rate, blood pressure) and behavioral items (e.g., alertness behavior, calmness/agitation, body movement, facial expression respiratory response, muscle tension). the observation period is 2 minutes. the scale is supplemented with an item on crying tbr children who are not mechanically ventilated. groups of 8 t.c. nurses were trained by means of video's and observations at the wards. after the training, each nurse completed 10 scores with other nurses, after which the cohen's kappa was computed. when the kappa's for the items met or exceeded our .60 criterium, a new group of nurses was trained. results: to date, 30 nurses have been trained. nurses find the comfort scale easy" to administer and a valuable addition to routine care in the i.c. unit. the cohen's kappa's were higher than .60 for all items that the inter-rater reliability was high. the comfort scale is feasible in postoperative care in the i.v. and is considered a valuable instrument to improve and maintain high postoperative quality of care in the i.c. unit. introduction:children with neuro-muscular disease are believed to have a higher resting energy expenditure (ree), because of their increasedwork of breathing.the influence of nocturnal nasal mask ventilation on energy metabolism and nutritional state of these children has not been studied so far.objective:l,ls the ree inereased?2.1s there an influence of nasal mask ventilation on the ree?3.what is the nutritional state?4.what is the estimated total energy expenditure(ete) in relation to the caloric intake? methods:a pilot study of 4 patients(12-16 years) .the following measurements were performed:l.anthropometry.2.bioelectric impedance-3.ree was measured by indirect calorimetry during the day (in bed) with and without nasal mask ventuation,ree was compared with predicted ree according to schofield(pee),4.caloric-intake and activities were recorded during 48 hour before measurement.5.total energy expenditure was calculated as follows:measured ree x estimated activity factor. results:tin all children weight for height was too low, <p3.2.aii children had a low % of fat.3.according to the healthy group, ree is not increased.4,nasal mask ventilation lowered ree in 2 patients, in 1 patient we measured a clear decrease.conclueion:l.anthropometry and indirect calorimetry were helpful in evaluating the nutritional state.2.there is no increased ree,in t patient there is clearly effect of nasal mask ventilation.3.when caloric intake was related to ree and level of activity 2 patients had too low caloric intake.4.the influence of nocturnal nasal mask ventilation and nutritional assessment should be evaluated longitudinally. increasing awareness that the neonate can percept pain and suffer following surgical procedures, has major impact on pain management. in our unit continuous morphine infusion (t0/~g/kg/hr) was introduced from january 1990 as a standard medicatton following surgical procedures. before 1990 morphine was given as a bolus (i.m., i.v., rectal) of 100/~g/kg up till four times a day. repeated gifts of morphine were only gwen following observation by the nurse that the child experienced pain. aim of the study: to evaluate pain management before and tbllowing introduction of a continuous morphine infusion for postoperative pain in our icu. patients and methods: term born babies with isolated oesophageal atresia and tracheo-oesophageal fistula were included in the study. the total amount of morphine (/~£/kg/24 hours); number of days morphine was given; duration of artificial ventilation was evaluated in a case control study. res ults: 1985 -1990 1991 -1994 central venous catheters (cvc) have been increasingly used also at our picu, university medical centre ljubljana. besides advantages, the cvc has brought numerous risks of complications; the catheter sepsis occurs most often and can be fatal for the patient. for example, in 1995 we dealt with 400 children aged 0 -12 years or in other words 1.14 cvp per a child treated at our picu. a specialized unit for preparing parenteral natrition started to function in the university medical centre pharmacy in 1977. after that we equipped a special room for preparing other necessary infusion mixtures and organized a team of nurses -"catheter nurses".their tasks comprise: managing cvcs, replacing and installing infusion systems and mixtures made at pharmacy, preparing drugs and some necessary infusion mixtures in special room, permanent training and co-operation with related disciplines, pharmacy, epidemiology, microbiology, etc. all registered nurses at picu have been trained for this work. the routine is as follows: in the morningafter the doctor's visit, we first check the cvc and change the dressings; according to the nurse's observations, the doctor decides whether there is a need to remove or replace the cvc. if the catheter site is inflamed, swollen, or purulent, a swab is taken for microbiological culture and the area cleaned. in case of systemic infection signs, cvc has to be replaced, blood culture taken and the infection treated with antibiotics. the dressings are always changed by two tmcatheter nurses together. afterwards the infusion mixtures for the next 24 hours are prepared for each child. the infusion mixtures which will not be used immediately are kept on +4°c; before application they are, of course, warmed to at least room temperature. finally the "catheter nurse" supplies the cvc with new infusion mixtures made at our pharmacy. our observations show that such work requires responsibility and is demanding; but our pemanent care lessens the number of complications. thus the described scheme fulfilled our expectations. perl-0perative management of neonates with hypoplastic left heart syndrome muir warren, blondel maryse, foltz rhonda, farine martine, icu nurses, the aldo castaneda institute, clinique de genolier, switzerland both the pre-operative and post-operative physiology of patient with hypoplastic left heart syndrome is critically determined by the puhnonary-tosystemic resistance ratio. a high ratio results in minimum volume work for the right ventricle but is at the expense of important hypoxemia. a low ratio is reflected in minimum hypoxemia but an unfavorable increase in excess ventricular volume work. a resistance ratio of approximately 1 results in an arterial oxygen saturation of 75% -80%, a qp/qs of 1, and ventricular volume work only twice normal. this latter physiology appears best for oxygen delivery and systemic perfusion with tolerable volume work. carbon dioxide (co2) in the inspired gas is known to increase pulmonary vascular resistance without significantly influencing systemic resistance in the range of 1 to 20 tort partial pressure. hyperventilation with no co2 in inspired gas decreases pulmonary vascular resistance. thus, managing co2 may be useful to modulate the pulmonary-to-systemic resistance ratio, in the tast 16 months, 20 patients with hypoplastic left heart syndrome were managed by a norwood procedur e. 10 patients with endotracheal entubation pre-operatively had co2 added to inspired gas to modulate the pulmonary-to-systemic flow ratio. 17 patients had co2 added to inspired gas post-operatively. all but 1 patient had characteristically large pulmonaary-to-systemic flow ratio with oxygen saturation mean 90 % preoperatively, even in those patients receiving co2, co2 was accompanied by elimination of metabolic acidosis pre-operatively. the most comlnon partial pressure of co2 added post-operatively was 14 torr. po2 ranged from 25 mmhg to 40 mmhg. all surviving patients developed a metabolic alkalosis (10 mean) when treated with co2. there were 4 deaths, one from drug toxicity, one from excessive post-operative hemorrhage, two from sepsis or mocardial insufficiency. only one patient benefited from catecholamine support which can increase systemic resistance unfaborably. in this experience co2 was felt to be an important adjunct in some patients pre-operatively and most patients postoperatively to faborably modulate the critically important systemic-topulmonary flow ratio, to maximize oxygen delivery and systemic perfusion, while minimizing excessive right vantricular volume work. key: cord-352222-zq9o66i4 authors: rajatonirina, soatiana; razanajatovo, norosoa harline; ratsima, elisoa hariniana; orelle, arnaud; ratovoson, rila; andrianirina, zo zafitsara; andriatahina, todisoa; ramparany, lovasoa; herindrainy, perlinot; randrianirina, frédérique; heraud, jean-michel; richard, vincent title: outcome risk factors during respiratory infections in a paediatric ward in antananarivo, madagascar 2010–2012 date: 2013-09-12 journal: plos one doi: 10.1371/journal.pone.0072839 sha: doc_id: 352222 cord_uid: zq9o66i4 background: acute respiratory infections are a leading cause of infectious disease-related morbidity, hospitalisation and mortality among children worldwide, and particularly in developing countries. in these low-income countries, most patients with acute respiratory infection (ari), whether it is mild or severe, are still treated empirically. the aim of the study was to evaluate the risk factors associated with the evolution and outcome of respiratory illnesses in patients aged under 5 years old. materials and methods: we conducted a prospective study in a paediatric ward in antananarivo from november 2010 to july 2012 including patients under 5 years old suffering from respiratory infections. we collected demographic, socio-economic, clinical and epidemiological data, and samples for laboratory analysis. deaths, rapid progression to respiratory distress during hospitalisation, and hospitalisation for more than 10 days were considered as severe outcomes. we used multivariate analysis to study the effects of co-infections. results: from november 2010 to july 2012, a total of 290 patients were enrolled. co-infection was found in 192 patients (70%). co-infections were more frequent in children under 36 months, with a significant difference for the 19–24 month-old group (or: 8.0). sixty-nine percent (230/290) of the patients recovered fully and without any severe outcome during hospitalisation; the outcome was scored as severe for 60 children and nine patients (3%) died. risk factors significantly associated with worsening evolution during hospitalisation (severe outcome) were admission at age under 6 months (or = 5.3), comorbidity (or = 4.6) and low household income (or = 4.1). conclusion: co-mordidity, low-income and age under 6 months increase the risk of severe outcome for children infected by numerous respiratory pathogens. these results highlight the need for implementation of targeted public health policy to reduce the contribution of respiratory diseases to childhood morbidity and mortality in low income countries. respiratory infections are a major cause of infectious diseaserelated morbidity, hospitalisation, and mortality among children under 5 years old worldwide, and particularly in developing countries [1] . these diseases are responsible for 4 million deaths worldwide every year [4] : they are thus among the leading causes of death and the most common infectious cause of death [2] . although many episodes of respiratory infection are mild, 7 to 13 percent are severe enough to warrant hospitalisation [3] . these diseases are responsible for at least 6% of the world's disability and death [1] . it is estimate that there are 33.7 million cases of respiratory infection annually among african children and longitudinal studies suggest that the overall mortality rate among children in developing countries is between 6.6% and 14.1% [5] . despite respiratory infections being a public health priority, data on their epidemiology in africa are sparse. diagnostic methods to identify the pathogen rapidly are not available in lowincomes settings, so most patient with respiratory infections are treated empirically with antibiotics based on local epidemiology [6] . administering appropriate therapy at the appropriate time would improve outcomes. these diseases also have an economic impact, as they lead to substantial consumption of antimicrobial agents in both community and hospital settings. furthermore, the high frequency of respiratory infections and the excessive use of antimicrobial agents are major contributors to the development of antibiotic-resistant pathogens. knowing the local epidemiology of respiratory infections is essential if appropriate empiric therapy is to be prescribed. evaluation of mixed infections and the relative importance of each potential pathogen may also contribute to improving the understanding of the pathogenesis of these infections [7, 8] . our study aimed to evaluate the risk factors associated with the evolution and outcome of respiratory illnesses in patients aged under 5 years old hospitalised in one of the four main public hospitals in antananarivo. the study was conducted at the ''centre hospitalier de soavinandriana'' (cenhosoa) in antananarivo, the capital city of madagascar, which is located in the central highlands. antananarivo consists of administrative, commercial, industrial and residential areas, with patches of agricultural land, mostly rice fields. the city is divided into six administrative districts. in madagascar, hib vaccine was introduced in 2008, and pneumococcia vaccine in 2012 cenhosoa is a national referral hospital in the third district of the urban municipality of antananarivo; hospitalization and care at this hospital is paid for by the patients. it is located near the institut pasteur of madagascar (ipm). the paediatric and neonatology ward of cenhosoa has 54 beds, and the annual number of children hospitalized for respiratory infection was estimated to be 150. a prospective, hospital-based, study was conducted at cen-hosoa from november 2010 to july 2012. the case definition and eligibility criteria used during this study are described in figure 1 . demographic, socio-economic, clinical and epidemiological data were recorded in case report forms (crfs). paediatricians completed the crfs which were then validated by a clinical research officer. instruction sheets were provided to clinical research officers to ensure accurate data collection. the data collected was managed by a senior medical epidemiologist. on admission, trained personnel using standard operating procedures had collected nasal and throat swabs, and sputum sample by aspirating airway secretion from the hypopharynx through the nose or tracheal aspirates. nasopharyngeal secretions, tracheal aspirates and sputum were obtained before start of antibiotic therapy. specimens were transported within 30 minutes of sampling to the ipm for tests of respiratory pathogens. hiv serostatus was not determined; the prevalence of hiv in madagascar is low, estimated to be around 1 per 1000 [7] . the study was approved by the national ethics committee of the ministry of health of madagascar. written informed consent was obtained from parents or legal guardians of children enrolled in the study. consenting to be enrolled in the study required consent to provide samples for diagnosis of influenza and other respiratory pathogens and to fill out a case report forms (crfs). refused consent and hospitalization within the two weeks before consultation were reasons for exclusion from the study. virological analyses were performed by national influenza centre (nic). a panel of multiplex real-time rt-pcr was used for the detection of viral pathogens in nasopharyngeal swabs. primers and probes were obtained from the authors of reported studies or were developed at the nic [8] . viral rna and dna were extracted from 140 ml of each specimen using the qiaamp viral rna mini kit and qiaampminelute virus kit (qiagen, courtaboeuf, france) according to the manufacturer's protocols. an abi 7500 fast real-time pcr system (applied biosystems) was used for amplifications. each sample was subjected to five different amplification reactions, each containing primers and probes specific for two or three viruses such that the following 12 respiratory viruses were targeted as previously described: parainfluenza virus 1-3 (piv), human coronaviruses (hcov) -oc43, -229e, -nl63 and hku1, respiratory syncytial virus (rsv), human metapneumovirus (hmpv), human rhinovirus (hrv), adenovirus (adv) and bocavirus (bov). as part of our routine influenza surveillance, screening for influenza viruses is performed by mdck cell inoculation and realtime rt-pcr according to the cdc protocols [9] . bacteriological analyses were performed by the medical analysis laboratory of ipm gram-stained sputum preparations were examined for polynuclear neutrophils (pn) and epithelial cells. the areas of maximal purulence were examined and graded as follows: class 1: more than 25 cells and fewer than 10 pn, class 2: more than 25 cells and 10-25 pn, class 3: more than 25 cells and more than 25 pn, class 4: 10-25 cells and more than 25 pn and class 5: fewer than 10 cells and more than 25 pn. only the classes 4 and 5 present a high positive predictive value. if the laboratory determined that the sample was of oral origin it had been rejected. so, classes 1 to 3 had been considered as rejection criteria. quantitative sputum cultures were performed on each specimen by a previously described method [10] : sputum specimens were homogenized with an equal volume of digest-eurh on a vortex mixer; 10 ml aliquots of the homogenate were serially diluted in saline and 10 ml aliquots of the dilutions were plated with a sterile inoculator on blood columbia agar with nalidixic acid and colistin (anc), chocolate polyvitex (pvx) agar, and drigalski agar. plates were incubated under 5% co 2 at 35uc for 24 to 48 hours. colonies growing on plates inoculated with suitable dilutions were counted to enumerate each bacterial species present. the threshold of significance was set at $10 7 /ml (for one or two species only). isolates were identified by standard laboratory methods. mono-infection was defined as the presence of only one pathogen as determined by viral and bacterial analysis. patients for which more than one pathogen was detected were considered to have co-infections. the outcome was scored as severe if the patient died, or presented a wrong clinical evolution during hospitalisation (complication) or the hospitalization was longer than 10 days (3 rd quartile). analyses were performed with r software [11] . the nonparametric wilcoxon test was used to compare means. qualitative variables were compared with the fisher exact test. statistical differences were considered significant for p-values,0.05. multivariate backward step-by-step logistic regressions were performed to take into account confounders, bias and interactions involving pathogens linked to the dependent variable. all variables with a pvalue,0.20 were included in the initial model. five age groups were defined for the analysis: [0-5] months, [6] [7] [8] [9] [10] [11] [12] months, [13] [14] [15] [16] [17] [18] months, [19] [20] [21] [22] [23] [24] months, [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] months, .36 months. from november 2010 to july 2012, 290 children were recruited from the 301 hospitalized patients eligible. eleven eligible patients refused to participate in the study, and they did not differ from included patients for age, sex or diagnosis on admission. the baseline demographic and clinical characteristics of the patients are shown in table 1 . the sex ratio (male/female) was 1.3. the mean of age was 1.1 years [95% ci: 1.0 to 1.2], the age range was from 1 day to 5 years, and 250 (86%) patients were 2 years old or younger. the diagnoses on admission (table s1 ) were significantly different between the age groups: bronchiolitis was found more frequently among patients under 6 months old (55%, p,0.01); ltri and pneumonia were more frequent among patients aged over 12 months (respectively, 68% and 85%,p,0.01). forty-nine (17%) patients had at least one underlying disease, with asthma being the most frequent (5%). some of the children had underlying conditions, particularly atopy (52; 18%) and passive exposure to tobacco smoke (113; 39%). seventy-one (24%) had been hospitalized during the previous 12 months. patients aged under 18 months had significantly more prior hospitalisations (p = 0.01). the difference between sexes was not statistically significant. around 45% (131/290) of patients had been treated with antibiotics before hospitalisation (table s2 ). significantly more patients under than over 12 months old had received antibiotic treatment before hospitalisation (p,0.01). the difference between sex was not statistically significant. the frequency of bacterial detection was lower in the group with prior antibiotic treatment (49% versus 65%, p = 0.01). no such relationship was found for viral results. accurate information about immunisation was available on vaccination cards for 82 (26%) children. eighty-seven percent of children had completed vaccination against bcg, 77% had received one haemophilus influenzae type b vaccination. no child was vaccinated against streptococcus pneumoniae and only two were vaccinated against influenza. the average of duration of hospitalisation was 7.9 days [95% ci: 7.1 to 8.6], range 1 to 79 days. the median duration of hospitalisation was 7 days, and 61% of patients were hospitalised for more than 7 days. the duration of hospitalisation for living patients was 8.0 [7.2-8.7 ] days, and for fatal cases was 3.9 [1.4-9.2]. there were no significant differences between sex and age groups. discharge information was available for all cases: 79% (230/ 290) of patients fully recovered without any complication during their hospital stay; the condition of 60 children worsened during hospitalisation, and nine patients (3%) died. all deaths were of children under 18 months of age, and six (67%) were of children less than 6 months old. for the patients who died, streptococcus pneumoniae (56%, 5/9) was the pathogen most frequently detected, followed rsv (33%, 3/9) and influenza type a virus (22% 2/9). for multivariate analysis of factors possibly associated with coinfection, sex, age group, number of rooms in the home and antibiotic treatment before hospitalisation were included in the initial model. the multivariate analysis indicated that children under 36 months of age were more often infected by more than one pathogen; the difference was statistically significant for the 19-24 months old group (adjusted or = 8.0) ( table 1) . previous antibiotic treatment before hospitalization was a significantly protective factor against co-infection (or = 0.5). in univariate analysis, influenza a, rhinovirus, streptococcus pneumoniae, and haemophilus influenza type b were significantly associated with co-infections. haemophilus influenzae and s. pneumoniae were most often associated with co-infection (adjusted or = 20.5 and 11.1, respectively) ( table 1) . univariate analysis showed that a severe outcome was significantly more frequent for patients with comorbidity (or = 3.9), including prematurity or congenital disease (such as heart disease or cerebral malformation). also, two of the three patients presenting with malnutrition died. hospitalization during the 12 months prior to admission was also associated with a severe outcome (or = 2.1). a low household income, of less than 455 us$ (less than 182 us$ or = 4.4 and between 182 and 455 us$ or = 3.5) was associated with severe outcomes. for multivariate analysis, age group, monthly household income, admission diagnosis, comorbidities, previous hospitalisation, and infection with influenza virus type a, rsv and rhinovirus were included in the initial model. multivariate analysis (table 3 ) adjusted for these variables showed that age below 6 months (or = 5.3), living in a household with low income (or = 4.1), and the presence of comorbidities (or = 4.6) were significantly aggravating factors. infection with an influenza type a virus was a significantly protective factor against a severe outcome (or = 0.4 [95% ci = 0.2-0.9]). in the paediatric ward of cenhosoa, most children under 36 months, hospitalised for respiratory infections, were co-infected, and the most frequently encountered pathogens were h. influenza, s. pneumonia, influenza a and rhinoviruses. during hospitalisation, the evolution of respiratory infections was worse for the youngest children and for those presenting comorbidities and living in lowincome household. over all, viral infections made a large contribution to the burden of infectious respiratory disease. viral pathogens were found in 85% of the patients and bacterial pathogens in 57%, although for 45% of the patients had been treated with antibiotics before hospitalisation, and this presumably affected the observed prevalence of bacterial infections. our findings for viruses were similar to those of other studies. for example, the detection rate for viral pathogens was 72% in a study in vietnam [12] , 50% in a study in mozambique [13] , both focusing on hospitalised children. these results are consistent with those for the paediatric ward in cenhosoa. our findings are also consistent with another report from madagascar indicating that rsv (30.5%) and by influenza a (22.6%) are the most frequent viral causes of community respiratory infection [8] . few studies in developing countries have addressed the role of bacterial co-infection in severe respiratory illness. most focus on the viral aetiology because molecular diagnosis tools are available for these pathogens allowing to identify the infection in 80%-95% of cases [14, 15] . in developing countries, laboratory methods to identify bacterial pathogens are more difficult to implement, because of the lack of appropriate facilities and material in hospital laboratories and then, long transit times are prejudicial for stability of specimens. in our study the transit time was reduced because of the proximity of the cenhosoa and the ipm. unfortunately, our findings for the rate of bacterial infection may be artificially low due to prior antibiotic use. in our study, streptococcus pneumoniae was the most common bacterial pathogen as in other studies of hospitalised patients with acute respiratory illness, and haemophilus influenzae type b was the next most frequent [16] [17] [18] [19] . primary infection by a respiratory virus increases the risk of secondary bacterial pneumonia, and viral and bacterial coinfection is common in young children with pneumonia in developing countries (about 20-30% of episodes) [20, 21] . evidence of probable mixed viral-bacterial infection has been recorded in up to 45% of cases of community acquired pneumonia in children [22] [23] [24] [25] . a large proportion of our patients had coinfection (70%; 192/273) and the [0-6] months age group had the highest risk. these results are consistent with a study of patients with community respiratory infection in madagascar [8] . viral and bacterial co-infection was found in 57% of our patients; the most frequent combination was streptococcus pneumoniae with one of several respiratory viruses (88%). data from gambia and nigeria indicate that mixed bacterial and viral infections may occur in 8 -40% of cases of childhood pneumonia [26, 27] . recent data from south africa indicate that in at least 31% of cases, viral-associated pneumonia may be due to concurrent infection with streptococcus pneumoniae in the absence of vaccination with pneumococcal conjugate vaccines [28] . appropriate management of respiratory infections can have a significant impact on child mortality and it is important to target priority groups of children most at risk of dying: these groups include very young infants, children infected with hiv and malnourished children [29] . in our study, the outcome was severe for all of the children who presented malnutrition and 67% (2/3) died. chisti et al show that the combination of pneumonia with severe or moderate malnutrition is associated with a high risk of death: the rr ranges from 2.9 to 121.2 for severe malnutrition, and from 2.5 to 15.1 for moderate malnutrition. for moderate malnutrition, rr = 1.2 to 36.5. several other studies also lead to the same results [30] [31] [32] [33] . ballard et al. report that malnutrition and level of parental education both have an impact on the incidence of respiratory infections [34] . pneumonia is the leading causes of childhood mortality, and is responsible for approximately 21% of deaths of african children under five years of age each year. however, little information is available about the causes of childhood pneumonia in developing countries. in our study, only 3% of the patients died; this value is low. note that the study population consists of patients from families with a socioeconomic level that is above the average for the general population in madagascar. the patients who died were more frequently co-infected and under 6 months old. these results are consistent with other studies on this topic in developing countries [35, 36] . however, study design may have an impact on the mortality rate observed: indeed all fees for hospitalisation were paid by the study to allow follow-up to be optimised. the study identified living in a low-income household as a risk factor for severe outcome. this is important for patient management during hospitalisation and also highlights the consequences of financial barriers to access to vaccination against influenza and pneumococci. these vaccinations were not included in the panel of vaccinations in expanded programme of immunisation (epi) during this period in madagascar. they were only available in private centres and were expensive, and therefore inaccessible for much of the population. only two of the patients included in this study had received vaccination against influenza and none had received vaccination against pneumococci according to their vaccination cards. our statistical analysis identified influenza a infection as a protective factor against a fatal outcome; however, it is well-known that influenza a may have an impact on high mortality during major epidemics [37] [38] [39] . the co-circulation of influenza a virus, rsv and the high frequency of streptococcus pneumoniae in co-infections in children aged less than 5 years raised issues about the indirect impact of influenza vaccination on respiratory infections. in particular, the benefits of establishing a system of vaccination against infectious agents for which a vaccine is available should be considered to provide access to a larger proportion of the population. in conclusion, we advocate to further research in developing countries to document in more detail the impact of viral and bacterial co-infections on the prognosis of severe respiratory illness. as numerous infections found in our study could be avoided by immunisation, we recommend that appropriate vaccination must be rapidly available for all the malagasy children. this would reduce mortality among the youngest children, as this age group currently suffers the greatest burden of morbidity and mortality associated with respiratory infections. table s1 diagnosis at admission according with age groups. (docx) estimates of world-wide distribution of child deaths from acute respiratory infections community-acquired pneumonia epidemiology and etiology of childhood pneumonia study of community acquired pneumonia aetiology (scapa) in adults admitted to hospital: implications for management guidelines community-acquired pneumonia in children british thoracic society guidelines for the management of community acquired pneumonia in childhood bayesian mapping of pulmonary tuberculosis in antananarivo viral etiology of influenza-like illnesses in antananarivo who | cdc protocol of realtime rtpcr for influenza a (h1n1) (n.d.). who. available remic référentiel en microbiologie médicale r: a language and environment for statistical computing. r foundation for statistical computing viral etiologies of acute respiratory infections among hospitalized vietnamese children in ho chi minh city viral acute respiratory infections among infants visited in a rural hospital of southern mozambique intranasal fluticasone propionate does not prevent acute otitis media during viral upper respiratory infection in children human bocavirus and acute wheezing in children epidemiology and etiology of childhood pneumonia etiology of community-acquired pneumonia in hospitalized patients in northern israel etiology of severe pneumonia in children in developing countries the bacterial etiology of community-acquired pneumonia in korea: a nationwide prospective multicenter study etiology of acute lower respiratory tract infections in gambian children: ii. acute lower respiratory tract infection in children ages one to nine years presenting at the hospital diagnoses of acute lower respiratory tract infections in children in rawalpindi and islamabad induced sputum in the diagnosis of childhood community-acquired pneumonia etiology of community-acquired pneumonia in 254 hospitalized children etiology of community-acquired pneumonia in hospitalized school-age children: evidence for high prevalence of viral infections malnutrition as an underlying cause of childhood deaths associated with infectious diseases in developing countries etiology of acute lower respiratory tract infections in gambian children: ii. acute lower respiratory tract infection in children ages one to nine years presenting at the hospital the etiology of pneumonia in malnourished and well-nourished gambian children a trial of a 9-valent pneumococcal conjugate vaccine in children with and those without hiv infection challenges to improving case management of childhood pneumonia at health facilities in resource-limited settings multihospital surveillance of pneumonia burden among children aged ,5 years hospitalized for pneumonia in bangladesh bacterial aetiology and outcome in children with severe pneumonia in uganda etiologic agents and outcome determinants of community-acquired pneumonia in urban children: a hospital-based study improvements in nutritional management as a determinant of reduced mortality from community-acquired lower respiratory tract infection in hospitalized children from rural central africa the effects of malnutrition, parental literacy and household crowding on acute lower respiratory infections in young kenyan children bacterial etiology of serious infections in young infants in developing countries: results of a multicenter study. the who young infants study group neonatal pneumonia in developing countries excess mortality associated with the 2009 a(h1n1)v influenza pandemic in antananarivo this study would not have been possible without the excellent support from all the clinicians (dr emma rasoanirina, dr roland randriamirado, dr harimboahangy rakotoarison, dr lucien radozahana, dr rani razafindrakoto and dr domohina rakotovao), and all the nurses of the paediatric ward of the cenhosoa, antananarivo. we are deeply indebted to all staff who contribute, every day, to the hospital surveillance programme. we also acknowledge the tremendous work of all technicians of the virology unit and cbc.disclaimer: the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the ministry of health. conceived and designed the experiments: sr. performed the experiments: sr jmh vr. analyzed the data: sr vr nhr. contributed reagents/ materials/analysis tools: nhr ao ehr lr rr ph fr zza ta. wrote the paper: sr nhr ehr vr. key: cord-353214-qo98m7jx authors: jhaveri, ravi; shapiro, eugene d. title: fever without localizing signs date: 2017-07-18 journal: principles and practice of pediatric infectious diseases doi: 10.1016/b978-0-323-40181-4.00014-1 sha: doc_id: 353214 cord_uid: qo98m7jx nan most young children with fever and no apparent focus of infection have self-limited viral infections that resolve without treatment and are not associated with significant sequelae. however, a small proportion of young children with fever who do not appear to be seriously ill may be seen early in the course of a bacterial infection that could progress to bacteremia or meningitis. despite numerous studies that have attempted to identify the febrile child who appears well but has a serious infection and to assess the effectiveness of potential interventions, no clear answers have emerged. [1] [2] [3] [4] studies show that parents usually are more willing than physicians to assume the small risk of serious adverse outcomes in exchange for avoiding the short-term adverse effects of invasive diagnostic tests and antimicrobial treatment. 5, 6 the best approach to the treatment of the febrile child combines informed estimates of risks, careful clinical evaluation and follow-up of the child, and judicious use of diagnostic tests. 7 the list of microbes that cause fever in children is extensive. relative importance of specific agents varies with age, season, and associated symptoms. the goal of this chapter is to assist in identifying the febrile child with a serious bacterial infection (sbi). table 14 .1 shows the most common causes of sbi in children younger than 3 months. [8] [9] [10] [11] [12] the division at 1 month is not absolute; considerable overlap exists. receipt of vaccines typically administered at 2 months also reduces the risk of sbi. certain viruses, notably herpes simplex, influenza, and enteroviruses, can cause serious infections in neonates, mimicking septicemia and beginning as fever with no apparent focus of infection. less serious viral infections are the most common causes of fever in children of all ages. in children between 3 and 35 months of age, most bacterial infections with no apparent focus are caused by streptococcus pneumoniae (in unimmunized children), neisseria meningitidis, or salmonella spp. infection (which often is associated with symptoms of gastroenteritis). because universal administration of pneumococcal and haemophilus influenzae type b (hib) conjugate vaccines, hib has become rare, and the incidence of infection with s. pneumoniae has fallen substantially. 13, 14 other common causes of invasive bacterial infections in these children, such as staphylococcus aureus, are usually associated with identifiable focal infections. the risk of serious bacterial infection varies with age. although longitudinal studies have shown that only 1% to 2% of children are brought to medical attention for fever during the first 3 months of life, a greater proportion of febrile infants has serious bacterial infections than older children. [15] [16] [17] [18] risk is greatest during the immediate neonatal period and through the first month of life, and risk is heightened for infants born prematurely. in a prospective study conducted by investigators at the university of rochester, factors were identified that indicate a low risk of serious bacterial infection in febrile infants younger than 3 months. 19 among 233 infants who were born at term with no perinatal complications or underlying diseases, who had not received antibiotics, and who were hospitalized for fever and possible septicemia, 144 (62%) were considered unlikely to have a serious bacterial infection and fulfilled all of the following criteria: no clinical evidence of infection of the ear, skin, bones, or joints; white blood cell (wbc) count between 5000 and 15,000/mm 3 ; less than 1500 band cells/mm 3 ; and normal urinalysis results. only 1 (0.7%) of the 144 infants had a serious bacterial infection (i.e., salmonella gastroenteritis), and none had bacteremia. in contrast, among the 89 infants who did not meet these criteria, 22 (25%) had a serious bacterial infection (p < 0.0001) and 9 (10%) had bacteremia (p < 0.0005). sedimentation rate, c-reactive protein, procalcitonin, morphologic changes in peripheral blood neutrophils, and quantitative cultures of blood. 28, [51] [52] [53] [54] [55] [56] [57] [58] clinical scales have been developed to help identify the febrile child with a serious illness. 59 unfortunately, no test has sufficient sensitivity and positive predictive value (ppv) or npv to be clinically useful for an individual patient. in the era before conjugate vaccinations for hib and s. pneumoniae, several studies examined the risk of bacteremia among children with a temperature higher than 40°c and in those with fever and a wbc count of at least 15,000/mm. 3, 41, 51, 60 the ppv of the tests for bacteremia was only about 15%. in the current era of low incidence and unconfirmed predictive value of wbc for remaining pathogens, laboratory testing no longer is justified. 1, 7, 45, 47 making a laboratory-confirmed diagnosis of a viral infection significantly reduces the likelihood that a febrile infant has a concomitant bacterial infection (with the exception of a uti). this currently holds true for influenza, rsv, and enterovirus, and in the future, it will likely be true for many other respiratory viruses (e.g., human metapneumovirus, parainfluenza virus, coronavirus) that are being diagnosed with multiplex polymerase chain reaction (pcr) technology. one study showed that incorporating viral diagnostics into the initial evaluation of febrile infants reduced the length of hospitalization and healthcare costs. 61 although there is no single correct approach to the management of febrile infants without localizing signs who appear well, studies have provided data based on which informed decisions can be made. 7 there is general agreement that febrile children who are very young (i.e., variously considered to be younger than 3, 2, or 1 month of age) should be managed differently from older children. because of the substantially greater risk of serious infections in very young infants with fever and the difficulty in assessing the degree of wellness accurately, pediatricians have approached the management of these cases conservatively. some clinicians adhere to a protocol of treating all young infants with fever and no apparent focus of infection with broad-spectrum antimicrobial agents administered intravenously in the hospital until the results of cultures of the blood, urine, and cerebrospinal fluid (csf) are known. 62 although perceived as the safe approach, it incurs considerable financial cost and risk of iatrogenic complications and of diagnostic misadventures associated with hospitalization. [63] [64] [65] these risks include errors in the type and dosage of drugs, complications of venous cannulation (e.g., phlebitis, sloughing of the skin), and nosocomial infections. hospitalization of a young infant is a major disruption for the family and may potentiate development of the vulnerable child syndrome. 66 investigators have found that selected young infants with fever can be treated expectantly without hospitalization. 4, 7, 19, 21, 27, 67 consequently, many experts think that febrile infants between 4 and 12 weeks of age with no apparent focus of infection who appear well or have a laboratorydocumented viral infection can be treated without additional laboratory tests or hospitalization, provided that careful follow-up is ensured. 7 others prefer to confirm laboratory criteria that predict low risk (sometimes including a normal csf analysis result). some providers observe the patient very closely without giving antimicrobial therapy; others treat all such infants for 2 days with a single daily dose of ceftriaxone (50 mg/ kg) administered parenterally while awaiting the results of blood, urine, and csf cultures. either approach, if careful and vigilant, is defensible. before an antimicrobial agent is administered, cultures of the blood, urine, and csf should be obtained. rapid tests for specific viral pathogens are widely available, can aid decisions about managing patients, and can reduce the duration of hospitalization or eliminate the need. 7, [31] [32] [33] 68 febrile infants at low risk for serious bacterial infection for whom adequate home observation and follow-up cannot be ensured should be hospitalized and can be observed without antimicrobial treatment. if the child appears well, doing so is reasonable and avoids the adverse side effects of antimicrobial agents and intravenous cannulation, shortens the duration of hospitalization, and saves money without placing the child at significant risk for complications. 21, 27, 67 many studies have largely corroborated results of the rochester study. 11, 12, [20] [21] [22] [23] [24] [25] although investigators have used slightly different criteria to define young febrile infants at low risk for serious bacterial infection (and some investigators excluded children younger than 1 month old), all found that the risk of a serious bacterial illness in the group defined as being at low risk is very low. approximately 10% of young febrile infants have urinary tract infections (utis), largely due to escherichia coli, and 10% of this group (1% overall) have concomitant bacteremia or meningitis. 11, 12, 26 in a meta-analysis of studies of febrile children younger than 3 months, the risks of serious bacterial illness, bacteremia, and meningitis were 24.3%, 12.8%, and 3.9%, respectively, for high-risk infants and 2.6%, 1.3%, and 0.6%, respectively, for low-risk infants. 15 the negative predictive value (npv) for serious bacterial illnesses among infants fulfilling low-risk criteria ranged from 95% to 99%, and the npv was 99% for bacteremia and 99.5% for meningitis. 15 although the risk of serious bacterial infection is high among febrile infants younger than 3 months of age with no apparent focus of infection, clinical and laboratory assessment can identify the slightly more than 50% of infants at very low risk. an observational study of more than 3000 infants younger than 3 months of age with fever greater than 38°c treated by practitioners and reported as part of the pediatric research in office settings network found that 64% were not hospitalized. 4, 27 practitioners individualized management and relied on clinical judgment; guidelines were followed in only 42% of episodes. 4, 27, 28 outcomes of the children were excellent. if the guidelines had been followed, outcomes would not have improved, but there would have been substantially more laboratory tests performed and more hospitalizations. 4 risk of serious bacterial illness in young infants has fallen further due to the marked reduction in early-onset group b streptococcal infections because of the effectiveness of peripartum antimicrobial prophylaxis of pregnant women with positive screening test results for colonization with group b streptococcus. 29 in febrile children younger than 3 months of age who have an identified viral infection such as influenza, respiratory syncytial virus (rsv), or enteroviruses, the risk of a serious bacterial infection other than a uti falls to almost zero. 24, [30] [31] [32] [33] in the 1970s and 1980s, there was concern about occult bacteremia in febrile children between 3 months and 24 to 36 months of age. 34 studies performed in that era showed that some children 3 months of age or older with fever who did not appear to be toxic and who had no apparent focus of infection had bacteremia, most often due to s. pneumoniae but occasionally due to hib or n. meningitidis. [34] [35] [36] [37] [38] [39] [40] [41] in some instances, serious focal infections such as meningitis developed in children with occult bacteremia. the concern about progression to focal infections resulted in protocols being developed to identify and intervene for infants at high risk. protocols emphasized routine blood cultures and empiric antibiotic administration for many febrile children in this age group. 28 these practices discounted several facts. first, most children with occult bacteremia have transient infection and recover without antimicrobial therapy and without developing a serious complication (e.g., meningitis, septic shock). 28, 42, 43 second, risk of meningitis complicating occult bacteremia varies with bacterial species (n. meningitidis ≫ hib ≫> s. pneumoniae). 35 third, universal vaccination against hib led to elimination in vaccinated infants of the most concerning occult bacteremia, and subsequent use of conjugate pneumococcal vaccine eliminated almost all other cases of occult bacteremia. [44] [45] [46] [47] [48] [49] the risk of uti in well-appearing febrile children in this age group has not changed significantly over the years. several studies have shown that the rate of uti varies among different populations (e.g., girls vs. boys, uncircumcised vs. circumcised) within this age group and varies with height and duration of fever. uti should be considered as a potential source of sbi in these patients. 44, 50 various diagnostic tests to quantify the risk of bacteremia and its complications have been assessed. they include the wbc count and differential count, microscopic examination of buffy coat of blood, erythrocyte if no focus is found and the child does not appear toxic, no diagnostic tests are indicated routinely. parents should be instructed to look for signs that a more serious problem is developing (e.g., persistent irritability or lethargy, inattentiveness to the environment). serial observations should be planned that permit subsequent clinical and laboratory evaluation and antimicrobial treatment as indicated. if a practitioner encounters a febrile child older than 4 months of age who is unimmunized or partially immunized, a more aggressive plan for evaluation and management may be warranted. this chapter focuses on invasive bacterial infections, particularly bacteremia, as a cause of fever without apparent focus. although other serious illnesses such as autoimmune diseases and inflammatory bowel disease can manifest as fever without a focus of infection, they are rare and come to attention because of persistence or recurrence of fever (see chapter 15) . all references are available online at www.expertconsult.com. most infants with fever who are younger than 1 month should be hospitalized and treated with antimicrobial therapy (with or without acyclovir for herpes simplex virus), although in selected instances, hospitalization without antimicrobial treatment or outpatient management after laboratory evaluations, including csf analysis, may be reasonable. if a decision is made to administer antimicrobial agents intravenously, ampicillin (100 to 200 mg/kg per day every 6 hours) plus gentamicin (7.5 mg/kg per day every 8 hours) or a third-generation cephalosporin (e.g., ceftriaxone, 50 mg/kg per day in one dose; cefotaxime, 150 mg/kg per day every 8 hours) could be chosen. ampicillin and gentamicin is a well-established combination with narrower spectrum of antimicrobial activity than ceftriaxone and excellent effectiveness against group b streptococcus, listeria monocytogenes, and many enteric gram-negative rods. because of the rising incidence of ampicillin-resistant e. coli and the rarity of listeriosis in recent large studies, a regimen with a third-generation cephalosporin without ampicillin offers coverage for the few infants who have bacteremia or meningitis with a uti due to ampicillin-resistant e. coli. 11, 12, 25 no study has directly assessed the relative risks and benefits of either regimen. before initiating antimicrobial treatment with any regimen, cultures of the blood, urine (obtained by urethral catheterization or suprapubic aspiration of the bladder), and csf should be obtained. children 3 months of age and older who appear well and have no apparent focus of infection can be evaluated clinically without laboratory tests or treatment with antimicrobial agents, with the exception of examination of the urine. in the current conjugate vaccine era, blood culture isolates are substantially more likely to be contaminants than to be pathogens. 7 substantial evidence suggests that obtaining blood cultures routinely from these children has little impact on outcome, although false-positive blood culture results lead to substantial unnecessary costs. 69, 70 the following approach seems appropriate. the febrile child should be carefully assessed for a focus of infection, including uti, and if a focus is found, the child should be treated according to likely pathogens. if the child appears toxic, appropriate cultures and diagnostic tests should be performed, and antimicrobial treatment (usually with cefotaxime, 150 mg/kg per day in divided doses every 8 hours, or ceftriaxone, 50 mg/kg once daily) should be initiated; some physicians add vancomycin (40 mg/kg per day in divided doses every 6 to 8 hours). most of these children should be hospitalized. management of the non-toxicappearing acutely febrile child: a 21st century approach changing epidemiology of serious bacterial infections in febrile infants without localizing signs changing epidemiology of bacteremia in infants aged 1 week to 3 months identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections influenza virus infection and the risk of serious bacterial infections in young febrile infants risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections diagnosis and outcomes of enterovirus infections in young infants risk factors for development of bacterial meningitis among children with occult bacteremia urinary tract infections in young febrile children management of febrile children in the age of the conjugate pneumococcal vaccine: a cost-effectiveness analysis should blood cultures be obtained in the evaluation of young febrile children without evident focus of bacterial infection? a decision analysis of diagnostic management strategies strategies for diagnosis and treatment of children at risk for occult bacteremia: clinical effectiveness and cost-effectiveness febrile infants: a 30-year odyssey ends where it started parents' versus physicians' values for clinical outcomes in young febrile children management of the young febrile child: a commentary on recent practice guidelines management of the non-toxicappearing acutely febrile child: a 21st century approach management of the febrile infant three months of age or younger viral and bacterial pathogens of suspected sepsis in young infants serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens changing epidemiology of serious bacterial infections in febrile infants without localizing signs changing epidemiology of bacteremia in infants aged 1 week to 3 months invasive pneumococcal disease in young children before licensure of 13-valent pneumococcal conjugate vaccine-united states progress toward eliminating haemophilus influenzae type b disease among infants and children-united states probability of bacterial infections in febrile infants less than three months of age: a meta-analysis the serious implications of high fever in infants during their first three months. six years' experience at yale-new haven hospital emergency room potential bacteremia in pediatric practice fever in the first eight weeks of life identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis the febrile infant outpatient management without antibiotics of fever in selected infants ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections febrile infants at low risk for serious bacterial infection-an appraisal of the rochester criteria and implications for management. febrile infant collaborative study group serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections epidemiology of bacteremia in febrile infants in the united states the changing epidemiology of serious bacterial infections in young infants management and outcomes of care of fever in early infancy practice guideline for the management of infants and children 0 to 36 months of age with fever without source. agency for health care policy and research trends in perinatal group b streptococcal disease-united states influenza virus infection in infants less than three months of age influenza virus infection and the risk of serious bacterial infections in young febrile infants risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections diagnosis and outcomes of enterovirus infections in young infants bacteremia in febrile children seen in a "walk-in" pediatric clinic risk factors for development of bacterial meningitis among children with occult bacteremia complications of occult pneumococcal bacteremia in children unsuspected meningococcemia unsuspected bacteremia due to haemophilus influenzae: outcome in children not initially admitted to hospital bacteremia in febrile children under 2 years of age: results of cultures of blood of 600 consecutive febrile children seen in a "walk-in" clinic a comparative study of the prevalence, outcome, and prediction of bacteremia in children temperature greater than or equal to 40 c in children less than 24 months of age: a prospective study occult pneumococcal bacteremia: what happens to the child who appears well at reevaluation? reevaluation of outpatients with streptococcus pneumoniae bacteremia outcomes of febrile children without localising signs after pneumococcal conjugate vaccine prevalence of occult bacteremia in children aged 3 to 36 months presenting to the emergency department with fever in the postpneumococcal conjugate vaccine era an analysis of pediatric blood cultures in the postpneumococcal conjugate vaccine era in a community hospital emergency department incidence of occult bacteremia among highly febrile young children in the era of the pneumococcal conjugate vaccine: a study from a children's hospital emergency department and urgent care center occult bacteremia from a pediatric emergency department: current prevalence, time to detection, and outcome serotype prevalence of occult pneumococcal bacteremia urinary tract infections in young febrile children antimicrobial treatment of occult bacteremia: a multicenter cooperative study quantitative blood cultures in childhood bacteremia detection and quantitation of bacteremia in childhood comparison of acute-phase reactants in pediatric patients with fever early diagnosis of bacteremia by buffy-coat examinations relationship between the magnitude of bacteremia in children and the clinical disease temperature and total white blood cell count as indicators of bacteremia procalcitonin and c-reactive protein as diagnostic markers of severe bacterial infections in febrile infants and children in the emergency department history and observation variables in assessing febrile children role of the complete blood count in detecting occult focal bacterial infection in the young febrile child costs and infant outcomes after implementation of a care process model for febrile infants febrile children with no focus of infection: a survey of their management by primary care physicians hospitalization v outpatient treatment of young, febrile infants iatrogenic risks and financial costs of hospitalizing febrile infants management of young, febrile infants vulnerable children: parents' perspectives and the use of medical care the efficacy of routine outpatient management without antibiotics of fever in selected infants impact of rapid viral testing for influenza a and b viruses on management of febrile infants without signs of focal infection impact of a false positive blood culture result on the management of febrile children effects of obtaining a blood culture on subsequent management of young febrile children without an evident focus of infection key: cord-352952-91goqi90 authors: francis, joshua r.; richmond, peter; robins, christine; lindsay, katie; levy, avram; effler, paul v.; borland, meredith; blyth, christopher c. title: an observational study of febrile seizures: the importance of viral infection and immunization date: 2016-12-03 journal: bmc pediatr doi: 10.1186/s12887-016-0740-5 sha: doc_id: 352952 cord_uid: 91goqi90 background: febrile seizures are common in young children. annual peaks in incidence mirror increased respiratory virus activity during winter. limited virological data are available using modern diagnostic techniques for children with febrile seizures. we aimed to determine the frequency of detection of specific viral pathogens in children with febrile seizures, to describe risk factors including recent vaccination and clinical features associated with specific etiologies. methods: an observational study was performed. children aged 6 months to 5 years presenting to the emergency department of a tertiary children’s hospital in western australia with febrile seizures were enrolled between march 2012 and october 2013. demographic, clinical data and vaccination history were collected, and virological testing was performed on per-nasal and per-rectal samples. results: one hundred fifty one patients (72 female; median age 1.7y; range 6 m-4y9m) were enrolled. virological testing was completed for 143/151 (95%). at least one virus was detected in 102/143 patients (71%). the most commonly identified were rhinoviruses (31/143, 22%), adenovirus (30/151, 21%), enteroviruses, (28/143, 20%), influenza (19/143, 13%) and hhv6 (17/143, 12%). more than one virus was found in 48/143 (34%). no significant clinical differences were observed when children with a pathogen identified were compared with those with no pathogen detected. febrile seizures occurred within 14 days of vaccine administration in 16/151 (11%). conclusion: at least one virus was detected in over two thirds of cases tested (commonly picornaviruses, adenovirus and influenza). viral co-infections were frequently identified. febrile seizures occurred infrequently following immunization. febrile seizures are common in children aged 6 months to 5 years, affecting 2-8% of children [1, 2] . complex febrile seizures, featuring any of: focal seizures, prolonged seizure duration (greater than 15 min) or multiple febrile seizures in the course of a febrile illness, comprise 10-35% of all cases [1] . simple febrile seizures are usually self-limiting. neurological sequelae rarely result from either simple or complex febrile seizures [1, 2] . seasonal variation in febrile seizures is observed and follows a similar pattern to that seen with common respiratory pathogens [3] . despite this, there are limited data using modern diagnostic techniques examining the role of viral infections in children who present with febrile seizures [4, 5] . previous studies have suggested a possible role for influenza, adenovirus and human herpesvirus 6 (hhv6) [4] [5] [6] [7] [8] [9] . recent literature has focused on the possible association between febrile seizures and complications of vaccine administration, with particular emphasis on measles-containing vaccines [10] [11] [12] [13] [14] [15] [16] . in australia in 2010 there was an increase of reported incidence of children with febrile adverse events following administration of one brand of trivalent influenza vaccine (biocsl fluvax®). a 2011 report identified febrile seizures in 20% of 190 children presenting with vaccine-related febrile adverse events [17] . the febrile seizures: viruses and their etiologic role (fever) study was established to determine the frequency of detection of specific viral pathogens in children with febrile seizures, to describe risk factors and clinical features associated with specific pathogens, and to examine the role of recent immunizations in children presenting with febrile seizures. the fever study prospectively enrolled children aged 6 months to 5 years presenting to princess margaret hospital emergency department (ed), the sole tertiary children's hospital in western australia (wa). patients were recruited between march 2012 and october 2013. children were recruited on the basis of a history of seizure activity [18] within the context of a febrile illness which was defined as a history of fever in the preceding 96 h or a measured temperature of more than 37.5°c elsius whilst in the ed. a simple febrile seizure was defined as a single seizure of total duration 15 min or less with no focal features and complete neurological recovery. complex febrile seizures featured any of: focal seizure activity, seizures lasting more than 15 min, multiple febrile seizures during the one febrile illness or incomplete neurological recovery. children diagnosed with a central nervous system infection or encephalopathy were excluded from the study, as were those with a history of previous afebrile seizures or an underlying neurological disorder. following written consent from the parent/caregiver, demographics, immunization history and clinical data were collected. results of all investigations carried out in the course of clinical care were recorded. per-nasal samples were collected by trained healthcare staff using nasopharyngeal aspirate (npa) or nasopharyngeal floqswab™ (copan diagnostics inc. murrieta, ca). stool or per-rectal swabs were collected where possible by trained healthcare staff and placed in viral transport media immediately after collection then transferred to the laboratory. nucleic acid was purified from clinical sample using the magmax express-96 platform (applied biosystems) as previously described [19] . respiratory samples underwent tandem multiplex real-time polymerase chain reaction (pcr) testing for respiratory viruses including human adenovirus species b-e; human bocavirus (hbov); human coronaviruses oc43, 229e, hku1 and nl63; influenza viruses a and b; parainfluenzaviruses 1-4; human metapneumovirus (hmpv) and respiratory syncytial virus (rsv) types a and b [20] . additional pcr assays were directed at the 5′utr of enteroviruses [21, 22] . enterovirus species a-e and rhinovirus species a-c were identified by sanger sequencing of the 5′utr product. per-rectal samples were tested using the same enterovirus pcrs as well as a rotavirus pcr [23] . statistical analysis was performed using microsoft excel and graphpad prism 6.0 statistical software (graphpad). continuous variables were compared using the student's t test, and categorical variables were compared using fisher's exact test. a two-tailed p value of less than 0.05 was considered significant. subjects with missing data were excluded from descriptive analyses for individual variables where data were missing. ethical approval for the study was granted by the human research ethics committee at the princess margaret hospital for children in perth, australia (hrec number 1950/ep). during the study period, 683 presentations to the ed were recorded to have had febrile seizures. of these, 259 (38%) were approached for enrollment in the fever study. seventy-three were found to be ineligible due to age, history of afebrile seizures or underlying neurological disorder, diagnosis of acute infection involving the central nervous system. fifteen were eligible but not recruited prior to discharge, and consent was refused for 20. a total of 151 were enrolled in the study (fig. 1 ). children requiring admission were overrepresented in the cohort compared to those not enrolled (32% in the fever cohort vs 18% in all febrile seizures; p < 0.001). median age of enrolled patients was 1.7 years (range 6 months-4 years 9 months); 79/151 (52%) were male. a past history of febrile seizures was identified in 38/151 (25%) and a family of history of either febrile and/or afebrile seizures was identified in 46/151 (30%) and 24/ 151 (16%) respectively. median duration of symptoms prior to presentation was 0.6 days (range 0-14 days). most patients presented with a history of fever (140/151, 93%) and respiratory symptoms (123/151, 82%). gastrointestinal symptoms (64/151, 42%), rash (32/151, 21%) and headache (13/151, 9%) were less frequently reported. the majority of cases (98/151, 65%) presented with a simple febrile seizure, including most of the cohort of children with a past history of febrile seizures (27/38, 71%). seizures were complex in 50/151 (33%) cases: prolonged seizures (lasting 18-60 min) occurred in 17/151 (11%), multiple seizures (2-10 seizures) in 38/151 (25%) and focal seizures in 12/151 (8%), with some overlap between these groups. insufficient information was recorded in 3/151 (2%) to determine whether they had simple or complex febrile seizures. children with complex febrile seizures were younger than those with simple febrile seizures (median 1.4 years vs 1.8 years). anticonvulsant medications, used to terminate seizures in 19/151 (13%), were more often administered to patients with complex compared to those with simple febrile seizures (14/50, 28% vs 5/98, 5%; p < 0.001). for those requiring admission, the median length of stay was 1 day (range 0-8 days). admissions were more common for complex compared to simple febrile seizures (37/50, 74% vs 32/98, 33%; p < 0.001). no patients were admitted to the intensive care unit and all patients were reported to have had a complete neurological recovery. virological testing was successfully carried out on pernasal samples in 143/151 (95%) cases. at least one virus was identified in 102/143 (71%) and viral co-infection in 48/143 (34%). in children with a previous history of febrile seizures, at least one virus was detected in 31/36 (86%). rhinovirus, adenovirus and enterovirus were the most commonly encountered viruses (31/143, 22%; 30/143, 21%; 28/143, 20%; respectively), but were frequently identified in the presence of other viruses (table 1) . influenza was identified in 19/151 (13%) and usually as a single viral infection. the proportion of cases presenting with complex febrile seizures were highest in the cohorts with influenza and hhv-6 (42 and 41% respectively), but differences from other groups did not reach statistical significance. most influenza cases (16/19, 84%) presented during the australian influenza season (may-october). the same seasonal distribution was observed across the whole enrolled cohort (125/151, 83%). per-rectal samples were analysed in 58/151 (38%) but did not reveal any viruses that were not also identified on corresponding pernasal samples. no cases of rotavirus infection were found. no pathogen specific differences in clinical presentation and admission were identified (table 2) . additional requested diagnostic investigations included urine culture (36/151; 24%), blood culture (44/ 151; 29%) and cerebrospinal fluid (csf) analysis (9/151; 6%). urine and csf cultures were negative in every case. of four cases with positive blood cultures, three were considered contaminants; one was positive for streptococcus pneumoniae. this case also had multiple viruses identified on per-nasal sample (adenovirus, hbov, hhv6, hmpv, enterovirus a-16, rhinovirus a). sixteen subjects (11%) presented within 14 days of routine childhood vaccinations, mostly with simple febrile seizures (table 3) . of these, 14/16 (88%) had been administered measles, mumps and rubella (mmr) containing vaccines a median of 9 days prior to their febrile seizure (3 had been administered the measles, mumps, rubella, varicella (mmr-v) vaccine); 9/16 (56%) also had at least one virus identified. one child had a febrile seizure 2 days after administration of routine 6-month immunisations (infanrix-hexa, prevenar-13) and another presented 9 days after varicella zoster virus vaccination; in both cases at least one virus was also identified. none of the children enrolled in the study had received an influenza vaccination. these data demonstrate that, despite increasing interest in vaccination as a cause of febrile seizures in young children, respiratory viral infections are more commonly found in children with febrile seizures than a history of recent vaccination. viruses were frequently detected in the nasopharynx of children with febrile seizures, but rectal sampling did not provide any additional information. respiratory viruses such as influenza, rhinovirus and adenovirus were frequently detected. enterovirus was also commonly detected, although no one strain was predominant. viral coinfection was common and is indicative of the tendency of children aged 6 months to 5 years to acquire repeated viral respiratory tract infections and demonstrate prolonged viral shedding. whether or not coinfection is important in the pathogenesis of fever in children with febrile seizures is not clear from these data. in contrast to other viruses found in this study, the majority of influenza and parainfluenza positive cases had only the one pathogen detected. influenza is known to have an important association with febrile seizures [4, 5, [7] [8] [9] , with a recent study reporting febrile seizures complicating influenza in 4% of children aged less than 5 years, admitted with influenza in the united states [24] . clustering of febrile seizures in the 2 weeks following mmr containing vaccines is an expected finding, given previous studies which demonstrate an association, with the greatest risk occurring between day 5 and day 12 following vaccination [10, [13] [14] [15] [16] . it is not possible to determine causality in this study though, especially given that half of the subjects with febrile seizure following mmr also had at least one virus identified. the lack of detection of febrile seizures following other childhood vaccines is reassuring. current influenza vaccines in use for children aged less than 5 years have demonstrated excellent safety profiles [25] . the australian childhood immunisation register recorded more than 28,000 doses of trivalent influenza vaccine administered to children aged 6 months to 5 years in western australia during the study period; yet no children were enrolled in this study with febrile seizure following influenza vaccine. the study had several limitations. firstly, enrollment was skewed towards children who were admitted as inpatients, due to increased opportunities for study personnel to access children and their caregiver(s) prior to discharge from hospital. the high proportion of admitted children is reflected in higher than expected rates of complex febrile seizures and use of anticonvulsant therapy in acute management. it is possible that this enrollment bias may have impacted on the range of virologic diagnoses, although the fact that viral etiology was similar in simple and complex febrile seizures suggests that the impact of this potential bias was small. the exclusion of children with central nervous system (cns) infections and/or abnormal csf findings enabled the study to describe the findings of true febrile seizures, but it also precluded any comparison of clinical features between children with cns infections and those with febrile seizures where cns infection has not been confirmed or suspected. in addition, the lack of a control group limits the ability to attribute fever (or febrile seizures) to viruses that were detected in the nasopharynx. previous pcr studies have reported high rates of virus detection in the nasopharynxes of healthy, asymptomatic children [26, 27] and it is possible that some children enrolled in this study were colonized rather than infected with detected organisms. respiratory viruses are important in the etiology of fever in children who present with febrile seizures. administration of vaccines in the 2 weeks prior to febrile seizures was infrequently reported in our series. given the large number of vaccines administered to children in wa during the study period, this finding suggests that immunization is not a common cause of seizures in our setting. febrile seizures: risks, evaluation, and prognosis febrile seizures circadian and seasonal variation of first febrile seizures role of viral infections in the etiology of febrile seizures relationship between five common viruses and febrile seizure in children febrile seizures pediatric neurologic complications associated with influenza a h1n1 influenza a infection is an important cause of febrile seizures influenza virus and febrile convulsions the risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and haemophilus influenzae type b timely versus delayed early childhood vaccination and seizures measlesmumps-rubella-varicella combination vaccine and the risk of febrile seizures vaccines for measles, mumps and rubella in children safety of measles-containing vaccines in 1-year-old children febrile seizures following measles and varicella vaccines in young children in australia trivalent influenza vaccine and febrile adverse events in australia, clinical features and potential mechanisms generalized convulsive seizure as an adverse event following immunization: case definition and guidelines for data collection, analysis, and presentation duplex realtime reverse transcriptase pcr assays for rapid detection and identification of pandemic (h1n1) 2009 and seasonal influenza a/h1, a/h3, and b viruses an economical tandem multiplex real-time pcr technique for the detection of a comprehensive range of respiratory pathogens polymerase chain reaction for human picornaviruses improved detection of rhinoviruses in nasal and throat swabs by seminested rt-pcr sensitive detection of group a rotaviruses by immunomagnetic separation and reverse transcription-polymerase chain reaction complications and associated bacterial coinfections among children hospitalized with seasonal or pandemic influenza the safety of seasonal influenza vaccines in australian children in 2013 high detection rates of nucleic acids of a wide range of respiratory viruses in the nasopharynx and the middle ear of children with a history of recurrent acute otitis media viral respiratory infections in hospitalized and community control children in alaska we thank jurissa lang and simone tempone for clinical sample preparation and processing. all components of this study were supported by a grant from the communicable disease control directorate of the health department of western australia, which was also involved in the analysis and interpretation of data through the contribution of co-author pve. the datasets generated and analysed during the current study are not publicly available but may be available from the corresponding author on reasonable request.authors' contributions jrf conceptualized and designed the study, drafted the initial manuscript, and approved the final manuscript as submitted. cr coordinated and supervised data collection, critically reviewed the manuscript, and approved the final manuscript as submitted. kl and al coordinated and supervised laboratory investigations, contributed to data analysis, reviewed the manuscript, and approved the final manuscript as submitted. pr, pve, mb and ccb contributed to the conceptualization and design of the study, reviewed and revised the manuscript, and approved the final manuscript as submitted. the authors declare that they have no competing interests. not applicable.ethics approval and consent to participate ethical approval for the study was granted by the human research ethics committee at the princess margaret hospital for children in perth, australia (hrec number 1950/ep). written informed consent was obtained from parents or caregivers prior to enrolment.• we accept pre-submission inquiries • our selector tool helps you to find the most relevant journal submit your next manuscript to biomed central and we will help you at every step: key: cord-321514-knyw023l authors: bénet, thomas; picot, valentina sanchez; awasthi, shally; pandey, nitin; bavdekar, ashish; kawade, anand; robinson, annick; rakoto-andrianarivelo, mala; sylla, maryam; diallo, souleymane; russomando, graciela; basualdo, wilma; komurian-pradel, florence; endtz, hubert; vanhems, philippe; paranhos-baccalà, gláucia title: severity of pneumonia in under 5-year-old children from developing countries: a multicenter, prospective, observational study date: 2017-07-12 journal: am j trop med hyg doi: 10.4269/ajtmh.16-0733 sha: doc_id: 321514 cord_uid: knyw023l pneumonia is the leading cause of death in children. the objectives were to evaluate the microbiological agents linked with hypoxemia in hospitalized children with pneumonia from developing countries, to identify predictors of hypoxemia, and to characterize factors associated with in-hospital mortality. a multicenter, observational study was conducted in five hospitals, from india (lucknow, vadu), madagascar (antananarivo), mali (bamako), and paraguay (san lorenzo). children aged 2–60 months with radiologically confirmed pneumonia were enrolled prospectively. respiratory and whole blood specimens were collected, identifying viruses and bacteria by real-time multiplex polymerase chain reaction (pcr). microbiological agents linked with hypoxemia at admission (oxygen saturation < 90%) were analyzed by multivariate logistic regression, and factors associated with 14-day in-hospital mortality were assessed by bivariate cox regression. overall, 405 pneumonia cases (3,338 hospitalization days) were analyzed; 13 patients died within 14 days of hospitalization. hypoxemia prevalence was 17.3%. detection of human metapneumovirus (hmpv) and respiratory syncytial virus (rsv) in respiratory samples was independently associated with increased risk of hypoxemia (adjusted odds ratio [aor] = 2.4, 95% confidence interval [95% ci] = 1.0–5.8 and aor = 2.5, 95% ci = 1.1–5.3, respectively). lower chest indrawing and cyanosis were predictive of hypoxemia (positive likelihood ratios = 2.3 and 2.4, respectively). predictors of death were streptococcus pneumoniae detection by blood pcr (crude hazard ratio [chr] = 4.6, 95% ci = 1.5–14.0), procalcitonin ≥ 50 ng/ml (chr = 22.4, 95% ci = 7.3–68.5) and hypoxemia (chr = 4.8, 95% ci = 1.6–14.4). these findings were consistent on bivariate analysis. hmpv and rsv in respiratory samples were linked with hypoxemia, and s. pneumoniae in blood was associated with increased risk of death among hospitalized children with pneumonia in developing countries. despite reduced mortality rates in recent years, pneumonia is the foremost cause of death from infectious diseases in under 5-year-old children worldwide, accounting for 15% of total deaths, mostly in developing countries. 1 hypoxemia, frequently associated with pneumonia and a marker of disease severity, leads to 3-to 4-fold increased risk of death in children with pneumonia. 2 a cochrane review 3 has reported that systematic hypoxemia screening with pulse oximetry and appropriate oxygen supply are effective in preventing death from pneumonia in children. a large simulation study estimated that systematic pulse oximetry may globally prevent almost 150,000 deaths from pneumonia annually. 4 however, the microbiological agents linked with hypoxemic pneumonia are poorly recognized. the identification of such etiological agents would serve to better target preventive (i.e., vaccination) and curative measures (i.e., antibiotics and antiviral drugs), reducing the global burden of hypoxemia and pneumonia. because of its high incidence and related mortality, particular attention must be paid to hypoxemic pneumonia in developing coun-tries. pulse oximetry is still rarely available in health-care settings of developing countries. 5 in the absence of oximeter, hypoxemia can be detected by several clinical signs or symptoms, including cyanosis and increased respiratory rate. however, none is sensitive and specific enough to reliably detect hypoxemia. [6] [7] [8] most studies of hypoxemia in children with pneumonia were performed in one country and rarely investigated the relationship between hypoxemia and microbiological results, so it would be useful to reassess them in a more recent multicontinental investigation. 2 the risk factors of death among children with pneumonia in developing countries have already been identified, 9, 10 but rarely regarding the relationship between microbiological findings and mortality. assessment of clinical, para-clinical, and microbiological predictors of death would be useful to prioritize public health campaigns. identification of microbiological agents associated with death and/or hypoxemia would be useful to better focus therapeutic measures. indeed, hypoxemic pneumonia can be treated with oxygen in conjunction with other measures, whereas non-hypoxemic pneumonia with poor vital prognosis might need other regimens, such as antibiotics/antivirals or intensive care. the objectives of the present study are to assess the microbiological agents linked to hypoxemia in hospitalized children with pneumonia in developing countries, to identify clinical and para-clinical predictors of hypoxemia and to pinpoint factors associated with death within 2 weeks after admission. study sites and design. findings from a prospective, hospital-based, multicenter, longitudinal study, conducted at five sites in four countries located on three continents, were analyzed: lucknow and vadu in india, antananarivo in madagascar, bamako in mali, and san lorenzo in paraguay. the participating sites are members of the gabriel (global approach to biological research, infectious diseases and epidemics in low-income countries) network established by fondation mérieux. 11 the study protocol and sites are described elsewhere. 12 pneumonia cases from the original case-control study were followed up during hospital stay and constituted the analyzed cohort. the study population comprised children aged between 2 and 60 months, complying with protocol definitions and inclusion criteria. eligible patients were identified by study clinicians at each participating site. all consecutive patients hospitalized in pediatric departments, who were eligible for study entry, were enrolled during each season (dry and rainy) for at least a 1-year period. the study aimed at obtaining an equal number of individuals in each season at each study site. incident cases were defined as hospitalized children aged 2-60 months, with clinical features of pneumonia, as described latter, radiological confirmation of pneumonia on chest x-ray as per world health organization (who) guidelines, 13 and informed consent statement signed by the children's parents or legal guardian. wheezing at auscultation was initially an exclusion criterion, but was amended because it slowed the inclusion process. thus, it was finally decided to include children presenting pneumonia with or without "wheezing." the present study selectively comprised sites with better quality data on oxygen saturation (so 2 ) at admission, mortality among pneumonia cases, and documented recording of patient follow-up during hospitalization. main characteristics were compared by site, and multivariate analysis accounted for heterogeneity of sites regarding observed or non-observed potential confounding factors. patients with missing data on follow-up, so 2 measurement, and vital status at discharge were excluded (n = 59). excluded patients did not differ from those analyzed for gender and weight-for-height z score, but were older (p = 0.03). definition of pneumonia. pneumonia cases were defined by the following criteria: data sources and quality control. data quality was monitored and evaluated by each site and by the emerging pathogens laboratory (lyon, france) for pooled data analysis. demographic characteristics, underlying diseases, medical history, clinical examination at enrollment, therapeutics, vaccinations, and outcomes were recorded prospectively for each patient on a standardized paper form. each potential error was discussed with local investigators, and a final ruling was applied. the principal investigator at each site was informed about quality assessments and was involved in their resolution. hypoxemia was defined as so 2 < 90%, according to who recommendations. 15 so 2 was measured at hospital admission, before the administration of oxygen or other therapeutics. vital status was recorded until patient discharge. biological samples. samples were collected in the first 48 hours of patient hospitalization. nasal swabs/aspirates, whole blood, and pleural effusions (in case of pleurisy) were sampled from all patients. urine was collected at patient admission to ascertain history of antibiotic use. biological samples were taken before the in-hospital administration of antibiotics. whole blood allowed complete blood count and culture, with real-time multiplex polymerase chain reaction (rt-pcr) assay for the identification of staphylococcus aureus, streptococcus pneumoniae, and haemophilus influenzae type b. c reactive protein (crp) and procalcitonin (pct) were quantified in serum. respiratory specimens permitted the identification of viruses and bacteria by rt streptococcus pneumoniae-positive specimens were serotyped by multiplex rt-pcr that detects 29 different serotypes. a centralized, blinded pcr respiratory quality control panel was provided to all sites to ensure procedure validation on-site before specimens were processed locally. statistical methods. qualitative variables were described as numbers and percentages with comparison by χ 2 test, if appropriate, or fischer's exact test. quantitative variables were reported as median and interquartile range (iqr) and compared by the mann-whitney u test or kruskal-wallis one-way analysis of variance. positive likelihood (lr+) and negative likelihood (lr _ ) ratios of various clinical signs and symptoms were calculated to detect hypoxemic cases with the following formulae: lr+ = sensitivity/(1 _ specificity) and lr _ = (1 _ sensitivity)/specificity. it has been underlined that lr calculation is useful to improve diagnostic accuracy. 16 lr could thus express the proportion of hypoxemic children who presented a particular sign or symptom divided by the proportion of non-hypoxemic children with the same result. microbiological findings from different sample sites associated with hypoxemia were assessed by logistic regression modeling. multivariate analysis was performed after univariate analysis, with forced adjustment on patient age, time per quarter, and study center. microorganisms with p < 0.15 values on univariate analysis were initially entered in the multivariate model. thus, backward stepwise deletion was applied until all p values were < 0.05. models were compared by wald testing. factors associated with in-hospital mortality were assessed with kaplan-meier curves and compared by log-rank test. follow-up was censored at 14 days after admission or discharge, if duration of hospitalization was less than 14 days. the characteristics of patients deceased within 2 weeks (n = 13) were compared with non-deceased patients (n = 392). univariate and bivariate proportional hazard cox regression analyses were undertaken. no multivariate cox model was fitted owing to the limited number of events. bivariate analyses expressed the effect of one major risk factor from univariate analysis adjusted on one other possible confounder (age category, human immunodeficiency virus [hiv] seropositivity, time per quarter, or weightfor-height z score). all tests were two tailed, and p < 0.05 was considered significant. statistical analysis was conducted with stata version 13.0 (statacorp., college station, tx). ethics. the study protocol, informed consent statement, clinical research form, amendments, and all other study documents were submitted to and approved by the institutional research ethics committee of each site. population description. overall, 405 children with pneumonia, accounting for 3,338 hospitalization days, were included. among them, 235 (58.0%) were male. median age was 14 months (iqr = 8-27 months). ninety-six (23.7%) patients came from lucknow, india, 71 (17.5%) were from vadu, india, 26 (6.4%) were from antananarivo, madagascar, 114 (28.1%) from bamako, mali, and 98 (24.2%) from san lorenzo, paraguay. the study periods at each site were patients differed between sites according to median weight-for-height z score (p = 0.001) and age category (p = 0.007), but did not differ between sites according to hiv seropositivity (p = 0.33) and mortality (p = 0.37). seventy patients were hypoxemic at admission. global prevalence of hypoxemia was 17.3% (95% confidence interval [ci] = 13.9-21.3%). median so 2 was 95% (iqr = 92-97%), without differences between countries (from 95% [iqr = 87-96%] in mali to 96% [iqr = 89-98%] in vadu, india, p = 0.14). table 1 compares the characteristics of hypoxemic and nonhypoxemic patients. hiv prevalence was 1.0% (n = 3). median weight-for-height z score was _ 1.1 (iqr = _ 2.4; +0.1). median length of hospital stay was 7 days (iqr = 4-10 days). median crp level at admission was 24 mg/l (iqr = 6-90 mg/l), median white blood cell count was 12,600 × 10 9 cells/l (iqr = 1,000-25,000 × 10 9 cells/l), and median neutrophil proportion was 47% (iqr = 28-64%). median pct level at admission was 1.9 ng/ml (iqr = 0.3-8.1 ng/ml), with mean of 15.6 ng/ml (minimum: 0.05, maximum: 585.5 ng/ml). overall, 70.5% tested positive for urinary antibiotics at admission. among the 402 (99.3%) patients given antibiotics during hospitalization for a median duration of 7 days (iqr = 5-10 days), 298 (74.5%) received monotherapy, with some also getting multiple antibiotic lines. the main drugs were ceftriaxone (n = 135, 26.0%), amoxicillin (n = 120, 23.1%), ampicillin (n = 51, 9.8%), amoxicillin/sulbactam (n = 36, 6.9%), amoxicillin/clavulanic acid (n = 35, 6.7%), oxacillin (n = 35, 6.7%), and vancomycin (n = 22, 4.2%). microbiological agents associated with hypoxemia in children with pneumonia. hypoxemic (n = 70) and nonhypoxemic (n = 335) pneumonia cases did not differ by median number of bacteria (1 versus 1, respectively, p = 0.85) or viruses detected (1 versus 1, respectively, p = 0.72) in nasal swabs/aspirates. infection types (bacterial/viral/mixed) did not differ in hypoxemic and non-hypoxemic patients (p = 0.96). table 2 reports the microbiological agents linked with hypoxemia. univariate analysis disclosed that hmpv and rsv detection in nasal samples was associated with increased risk of hypoxemia (p = 0.04 and 0.008, respectively). after adjustment on age, center, and calendar time, microorganisms independently associated with heightened risk of hypoxemia were hmpv (adjusted odds ratio [aor] = 2.5, 95% ci = 1.1-5.3) and rsv (aor = 2.4, 95% ci = 1.0-5.8). median so 2 was lower in rsv-and hmpv-positive patients than in -negative patients but not different between rsv-and hmpv-positive patients ( figure 1 ). pneumococcus serotypes 6ab and 10a from respiratory samples were more frequent in hypoxemic than in non-hypoxemic patients (22.9% versus 9.5%, respectively, p = 0.002; 7.1% versus 1.5%, respectively, p = 0.006). the distribution of other serotypes was not significantly different in hypoxemic and non-hypoxemic children (supplemental figure 1) . clinical and para-clinical presentation in children with hypoxemic pneumonia. hypoxemic patients differed from non-hypoxemic patients according to age (p = 0.02), history of common cold/pharyngitis (p < 0.001), receipt of one dose of pentavalent vaccine (p < 0.001), breathing rate (p = 0.009), blood pressure (p < 0.01), chest indrawing (p = 0.02), cyanosis (p = 0.003), conjunctivitis (p = 0.01), rasping (p = 0.03), radiological presentation (p = 0.009), mean white blood cell count (p < 0.001), and pct (p < 0.001) at admission ( table 1) . lr+ of lower chest indrawing was 2.3 (95% ci = 1.1-4.9), and lr-was 0.9 (95% ci = 0.8-0.95). lr+ of cyanosis was 2.4 (95% ci = 1.4-4.1) and lr _ was 0.7 (95% ci = 0.5-0.99). other signs and symptoms were less predictive of hypoxemia (data not shown). hypoxemic patients differed from non-hypoxemic patients in mean white blood cell count (p = 0.001) and pct at admission (p = 0.03) but not regarding crp level. factors associated with death. fourteen (3.5%) patients died during hospital stay. among them, 13 died within 14 days after hospital admission. the mortality rate was 8.6% in hypoxemic and 2.4% in non-hypoxemic patients (p = 0.01). eight deceased patients were not hypoxemic at admission. among them, the causes of death were multiple organ dysfunction syndrome (n = 4), acute respiratory distress syndrome with septic shock (n = 2), severe pneumonia in hiv (n = 1), and cardiac arrest (n = 1). table 3 reports the microbiological, clinical, and paraclinical findings associated with death on univariate cox analysis. streptococcus pneumoniae detection by blood pcr, hypoxemia, and pct ³ 50 ng/ml at admission were associated with increased risk of death (log-rank test: p = 0.003, p = 0.002, and p < 0.0001, respectively, figure 2a -c). other characteristics or microorganisms, including s. pneumoniae in respiratory samples, were not significantly associated with death ( supplemental tables 1 and 2) . no figure 2 ). in addition, s. pneumoniae detection by blood pcr was associated with increased risk of death (aor = 4.0, 95% ci = 1.3-12.4), independently of hypoxemia at admission (aor = 4.3, 95% ci = 1.4-12.8). one of the objectives of this study was to assess microbiological agents and other predictors of hypoxemia and death in under 5-year-old hospitalized children with pneumonia from developing countries. we observed that two viruses, namely rsv and hmpv, detected in respiratory samples by pcr, were independently associated with increased risk of hypoxemia, while no bacterial agent was significantly linked with it. on the other hand, s. pneumoniae detection by blood pcr was associated with a higher rate of in-hospital mortality in the study population independently of hypoxemia at admission. several predictors of hypoxemic pneumonia were identified. however, none had high likelihood ratio. elevated pct concentration and hypoxemia were straightforward predictors of death in children with pneumonia. the contribution of hypoxemia to the risk of death was independent of pneumococcus detection by blood pcr. several studies have investigated factors associated with hypoxemia, particularly clinical predictors. [6] [7] [8] 17 however, few of them have researched the links between microbiological findings and severity in different developing countries, with a standardized protocol. we observed that two viruses were associated with increased risk of hypoxemia. viral pneumonia induced diffuse, bilateral, pulmonary damage, 18 compared with bacterial pneumonia, with more frequent, well-systematized alveolar localization. 19 this is probably the reason why we noted that the two viral etiological agents evoking pneumonia were associated with hypoxemia. rsv is the leading cause of viral pneumonia in children, 20 frequently in association with severe disease. 21 we observed that it might be also a major cause of hypoxemic pneumonia. on the other hand, rsv detection was not related to increased mortality, but it is estimated that 66,000-199,000 children could die of rsv-associated pneumonia worldwide every year. our study's power was probably too limited to demonstrate such associations. however, with prevalence of exposure in non-hypoxemic patients ranging from 10% to 50%, with bilateral tests and α < 0.05, study power was ³ 80% to detect or ³ 2.5. similar results have been reported recently in a study from botswana, 22 where researchers noted that rsv pneumonia in children induced more complications and longer duration of hospitalization, but mortality was lower in comparison to other agents. hmpv is recognized as a frequent etiological agent of pneumonia, causing severe disease. 23 here, we determined that detection of this virus was associated with hypoxemic pneumonia in children. these findings might be related to the fact that these two viruses in respiratory samples might be the etiological agents of pneumonia. another hypothesis is that they might be associated with co-infections. however, we did not discern any relationship between infection type (bacterial, viral, or coinfection) and the risk of hypoxemia. the main clinical predictors of hypoxemic pneumonia were lower chest indrawing and cyanosis with lr+ ratios between 2 and 3. if these signs are present, hypoxemia must be suspected in the absence of pulse oximetry, and oxygen therapy should be initiated promptly. nevertheless, we did not discern that one sign had a high lr+ ratio, confirming that pulse oximetry is important for initial evaluation of pneumonia severity and should be implemented more widely in developing countries. 4 lower chest indrawing has been reported to be predictive of hypoxemia in children from nigeria, 8 while breathing rate ³ 60 cycles/minute has been encountered with hypoxemia in children from papua new guinea. 24 other predictors are less known. the designation and validation of a simple, robust score predicting hypoxemia might be useful in resource-limited settings. streptococcus pneumoniae is recognized as the main etiological agent of severe pneumonia and death from pneumonia in children. 25 the diagnosis of pneumococcus pneumonia is, however, difficult at the individual level, because of the low sensitivity of blood culture, particularly in case of previous exposure to antibiotics. in addition, the clinical meaning of pneumococcus detection in nasal samples by molecular testing is difficult to interpret because of the high prevalence of s. pneumoniae respiratory carriage in asymptomatic children. 26 we did not observe associations between pneumococcus detection in nasal samples and disease severity, although pneumococcus-positive blood pcr was linked with greater mortality. molecular s. pneumoniae detection by blood pcr is thus helpful in identifying bacterial pneumonia cases with the poorest prognosis who might need intensive therapies. interpretation of molecular methods, such as pcr, to identify the etiology of pneumonia in children is, however, challenging. respiratory viruses can be identified in asymptomatic children, and secondary bacterial infections in the lungs can easily be missed by these methods. in addition, identification of s. pneumoniae in blood by highly sensitive pcr may detect children with nasopharyngeal colonization only, which could lead to potential misclassification bias, particularly when using results of nasopharyngeal specimens to determine the etiology of pneumonia in children. we must be cautious with results interpretation. moreover, pct was the major biomarker associated with in-hospital death in our cohort. several studies previously found an association between pct and the risk of death or bacterial disease. [27] [28] [29] [30] however, such linkage has rarely been seen in pneumoniainfected children living in developing countries. the main strength of the present study is the prospective data collection on a standardized form at different sites, with advanced molecular diagnosis in all cases, which reinforces internal validity. its main limitations include paucity of information on exposures before hospital admission (i.e., breastfeeding, food intake, or vitamin supplementation). in addition, microbiological diagnosis of pneumonia is difficult because sensitive and specific tests are not routinely available in practice. thus, based on respiratory samples, we were unable to differentiate colonization from infection, particularly by s. pneumoniae. 31 however, analysis of the relationship between results from different samples and severity was contributive: we did not find associations between nasal colonization by pneumococcus and disease severity, hypoxemia, or death. finally, selection bias might have occurred because of patient recruitment in hospital with inclusion of more severe cases or patients with easier access to care. however, we did not discern significant heterogeneity regarding so 2 of infants at admission and inhospital mortality, which suggests that the results might be generalizable to different settings. we must acknowledge that 41% of the study population was enrolled in two sites from india, which might limit external validity. this proportion is, however, in accordance with estimates of global pneumonia incidence and related mortality: india might have accounted for almost 30% of the total number of severe pneumonia cases in children and 40% of the number of deaths worldwide. 25 in conclusion, rsv and hmpv could be major causes of hypoxemia in children with severe pneumonia in developing countries, while s. pneumoniae detection by blood pcr is predictive of high risk of in-hospital mortality. viral etiology might be considered in hypoxemic patients, whereas in very severe pneumonia, which can lead to death, s. pneumoniae may be implicated as the primary cause, even in the absence of hypoxemia at admission. tachypnea and lower chest indrawing could be useful indicators of possible hypoxemia requiring oxygen therapy. pulse oximetry should be included for better diagnosis in developing countries. given these findings, preventive measures, such as increased vaccination coverage of children in developing countries, oxygen therapy of hypoxemic patients, and intensive cardiovascular support, even in non-hypoxemic patients, would reduce the burden of death by pneumonia in children. this protocol was developed on behalf of gabriel network members: http://gabriel. globe-network.org. we especially thank the following gabriel pneumonia experts: ron dagan from the pediatric infectious disease unit saha from the department of microbiology, bangladesh institute of child health, dhaka shishu hospital, bangladesh; and werner albrich from kantonspital aarau ag, bereich medizin, switzerland. we also thank ovid da silva for doing financial support: this study was funded by fondation mérieux and the gabriel network disclaimer: the corresponding author had full access to the data and has the final responsibility to submit the manuscript for publication e-mails: thomas. benet@chu-lyon.fr and philippe.vanhems@chu-lyon.fr. valentina sanchez picot, florence komurian-pradel, hubert endtz, and gláucia paranhos-baccalà, laboratoire des pathogènes emergents, fondation mérieux global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis the prevalence of hypoxaemia among ill children in developing countries: a systematic review oxygen therapy for lower respiratory tract infections in children between 3 months and 15 years of age evaluating the impact of pulse oximetry on childhood pneumonia mortality in resource-poor settings oxygen and pulse oximetry in childhood pneumonia: a survey of healthcare providers in resource-limited settings hypoxaemia in acute respiratory and non-respiratory illnesses in neonates and children in a developing country hypoxaemia in children with severe pneumonia in papua new guinea hypoxaemia in hospitalised under-five nigerian children with pneumonia who/unicef's child health epidemiology reference group (cherg), 2010. causes of deaths in children younger than 5 years in china clinical risk factors of death from pneumonia in children with severe acute malnutrition in an urban critical care ward of bangladesh enhancing research capacities in infectious diseases: the gabriel network, a joint approach to major local health issues in developing countries multicenter case-control study protocol of pneumonia etiology in children: global approach to biological research, infectious diseases and epidemics in low standardized interpretation of paediatric chest radiographs for the diagnosis of pneumonia in epidemiological studies case management of childhood pneumonia in developing countries guidelines for the management of common childhood illnesses. pocket book of hospital care for children refining clinical diagnosis with likelihood ratios epidemiology of hypoxaemia in children with acute lower respiratory infection viral pneumonia differentiation of bacterial and viral pneumonia in children global burden of acute lower respiratory infections due to respiratory syncytial virus in young pneumonia severity in children from developing countries children: a systematic review and meta-analysis viral etiology of severe pneumonia among kenyan infants and children association of respiratory viruses with outcomes of severe childhood pneumonia in botswana human metapneumovirus: review of an important respiratory pathogen hypoxaemia in children with severe pneumonia in papua new guinea global burden of childhood pneumonia and diarrhoea colonisation by streptococcus pneumoniae and staphylococcus aureus in healthy children procalcitonin is useful in identifying bacteraemia among children with pneumonia markers that predict serious bacterial infection in infants under 3 months of age presenting with fever of unknown origin procalcitonin in children admitted to hospital with community acquired pneumonia the diagnostic and prognostic accuracy of five markers of serious bacterial infection in malawian children with signs of severe infection streptococcus pneumoniae colonisation: the key to pneumococcal disease this is an open-access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. key: cord-335148-2ngwjp3r authors: noda, tatsuya; ojima, toshiyuki; hayasaka, shinya; murata, chiyoe; hagihara, akihito title: gargling for oral hygiene and the development of fever in childhood: a population study in japan date: 2012-01-05 journal: j epidemiol doi: 10.2188/jea.je20100181 sha: doc_id: 335148 cord_uid: 2ngwjp3r background: fever is one of the most common symptoms among children and is usually caused by respiratory infections. although japanese health authorities have long recommended gargling to prevent respiratory infections, its effectiveness among children is not clear. methods: the children in this observational study were enrolled from 145 nursery schools in fukuoka city, japan. children in the exposure group were instructed to gargle at least once a day. the endpoints of this study were incidence of fever during the daytime and incidence of sickness absence. differences among gargling agents for each endpoint were also analyzed. results: a total of 19 595 children aged 2 to 6 years were observed for 20 days (391 900 person-days). in multivariate logistic regression, the overall odds ratio (or) for fever onset in the gargling group was significantly lower (or = 0.68). in age-stratified analysis, ors were significantly lower at age 2 (or = 0.67), 4 (or = 0.46), and 5 (or = 0.41) years. regarding sickness absence, the overall or was 0.92 (not significant) in the gargling group. in age-stratified analysis, ors were significantly lower at age 4 (or = 0.68), 5 (or = 0.59), and 6 (or = 0.63) years. in subgroup analysis, significantly lower ors for fever onset were observed for children who gargled with green tea (or = 0.32), functional water (or = 0.46), or tap water (or = 0.70). however, the ors were not significant for sickness absence. conclusions: gargling might be effective in preventing febrile diseases in children. fever is one of the most common symptoms of disease in childhood and results in psychological and economic burdens for patients and their families. the prevention of febrile diseases therefore plays an important role in child health. the most common cause of fever in childhood is respiratory infection. 1 however, the evidence for putative preventive approaches for such diseases in childhood is not yet conclusive. the custom of gargling as a preventive approach is not widespread in many western countries. in japan, however, health authorities have officially recommended gargling to prevent respiratory infections for more than 90 years, and almost all japanese believe in the preventive effect of gargling. 2, 3 although the effectiveness of gargling had long been unproven, a recent randomized controlled study in japan showed that gargling with tap water inhibited the onset of upper respiratory tract infections among adults. 4 another study suggested that gargling among adults had beneficial economic effects. 5 nevertheless, the effectiveness of gargling among children remains to be clarified. as an initial step in collecting the necessary data, we conducted an observational survey of a large number of children. because it would have been prohibitively expensive to investigate complicated outcomes requiring diagnosis by a doctor, we focused on overall febrile disease as a proxy of respiratory infections among children. our aim in this largescale population survey was to examine whether gargling prevented development of fever and the incidence of sick absence among children. the fukuoka preschool health study was conducted by the joint committee for preschool children's health of the fukuoka city medical association from january through february 2006. the eligible facilities were all 166 mayorauthorized nursery schools in fukuoka city, japan, of which 145 agreed to join this study. we conducted a follow-up study of cohorts identified in the fukuoka preschool health study. the observation period was 20 weekdays between january and february 2006. the inclusion criterion was attendance at any of the participating schools. we excluded children who: were too young to gargle (ie, younger than 2 years), had disabilities that are associated with febrile diseases or hindrance of gargling, withdrew from the study, and did not answer all required questions. first, children younger than 2 years were excluded. then, children who met the other exclusion criteria were excluded. the baseline characteristics and health status information of the children were collected by using a teacher-administered questionnaire, which asked about sex, age, body temperature (if feverish), dates of absence, reasons for absence (if absent), size and location of school, and whether they gargled once or more a day at nursery school. some classrooms in each school had a policy of letting children gargle; others did not. although gargling information was collected by a questionnaire and analyzed on an intention-to-treat basis, a classroom teacher instructed children to gargle at all scheduled times and visually confirmed that they had gargled. gargling was conducted by rinsing the throat (garagara-ugai method) at least once a day with any of the following agents: tap water, saline water, green tea, and functional water (alkali ion water or ozone water). body temperature was measured by the classroom teacher, and fever onset was defined as a body temperature of 37.5°c (99.5°f) or higher. each teacher recorded dates of absence and, when a child was absent, the reason for absence was obtained from the children's parents. one-way analysis of variance was used for group comparisons of numerical variables, and the chi-square test was used for comparisons of categorical data. we then used logistic regression analyses for repeated measurements for correlations between repeated measures of individuals, using generalized estimating equations. 6 the primary study endpoint was incidence of fever during the daytime. we used incidence of sickness absence as a surrogate endpoint because nursery school regulations recommended that children with a high fever at night should not attend school the next day. in addition, the differences among gargling agents for each endpoint was tested using logistic regression for repeated measurement. all statistical analyses were performed with sas (version 9.1). all participating nursery schools provided written informed consent for the acquisition and research use of data. the governing board of the fukuoka city medical association granted ethical approval, and we obtained anonymized datasets before beginning the study analyses. from among 22 692 children recruited at 145 nursery schools, 2528 who were younger than 2 years were excluded, after which an additional 569 children were excluded because they met other exclusion criteria. ultimately, 19 595 children aged 2 to 6 years were observed for 20 days (391 900 person-days). table 1 shows the baseline characteristics of the participants. the size of schools was categorized according to quartiles of the number of children in the school, and school location in fukuoka city was classified by city ward. no significant differences were observed between sexes. there were significant differences between the gargling and nongargling groups in the distribution of age, school size, and school location. the rates for fever onset and sickness absence were significantly lower in the gargling group than in the nongargling group (table 2) . although the proportion of gargling children across the 145 schools ranged from 18.2% to 100% (interquartile range: 70.4%-88.8%), the proportion across the 7 wards ranged from 76.3% to 83.9%. the rates of fever outcomes across each size of school ranged from 0.28% to 0.40% in the gargling group and from 0.85% to 1.31% in the non-gargling group. furthermore, the rates of fever outcomes across 7 wards ranged from 0.21% to 0.49% in the gargling group and from 0.59% to 1.46% in the non-gargling group. we divided all schools into 4 quartiles, based on the proportions of gargling children in attendance, to compare the rates of fever outcomes in nongargling groups among the 4 school groups. there was no trend in the rate of fever in the non-gargling group over the 4 school groups. the results of logistic regression are shown in tables 3 and 4 . each table shows the 4 models used to estimate the odds ratio for gargling. we first conducted the analyses adjusted by age (models 1 and 2). however, considering the strong influence of age on outcomes, analyses stratified by age were added (models 3 and 4). as shown in table 3 , gargling was associated with significantly lower odds ratios for fever onset, except among children aged 3 (in model 4) and 6 years. the odds ratios for sickness absence were significantly lower among gargling children aged 4 or 5 years and among those aged 6 years in model 3 ( table 4 ). the gargling agents were added to the model in subgroup analysis ( table 5) . as compared with the non-gargling group, each agent was associated with significantly lowered odds ratios for the incidence of fever onset, except for saline water in model 2. in particular, gargling with green tea yielded an odds ratio of approximately 0.3. in contrast, no gargling agent had a clear effect on sickness absences. to our knowledge, this is the first study to assess the effectiveness of gargling in preventing febrile diseases and sickness absences among healthy children. we found that gargling once or more a day was associated with lower onset of both febrile diseases during the daytime in children aged 2 to 6 years and sickness absences in children aged 4 to 6. the effect on prevention of febrile diseases differed by gargling agent. in a large proportion of children, fever is caused by viral respiratory infections (eg, rhinovirus, coronavirus, rs virus, influenza virus, and adenovirus), followed by bacterial respiratory infections (eg, streptococci, pneumococci, and moraxella catarrhalis). [7] [8] [9] other febrile diseases (eg, urinary tract infections, otitis media, etc.) account for a small percentage or less than 1% of febrile disease in children. 10 the results of this study and the site of action of gargling suggest that gargling might prevent viral upper respiratory tract infections. however, the incubation times of the viruses mentioned above are less than 12 hours, and the viruses bind to specific cell receptors. [11] [12] [13] thus, it is uncertain whether simple flushing could actually wash out the viruses. in 2 previous studies showing that gargling prevented adult upper respiratory tract infections (mainly induced by viral infections), the authors also could not explain how gargling prevented viral infection. 4, 14 a plausible explanation is that chlorine is added to tap water by law. the concentration of residual chlorine in tap water in fukuoka city was 0.60 mg/l at the time of our study, which would have ensured inactivation of viruses and bacteria. 15, 16 another explanation was suggested by a randomized clinical trial showing that oral rinsing with chlorhexidine gluconate for 30 seconds twice a day reduced the total nosocomial respiratory infection rate among patients in a cardiovascular intensive care unit. 17 the authors of that article noted that reducing oropharyngeal microbial flora by oral rinsing with an antiseptic agent twice a day could have impeded aspiration of organisms that cause respiratory infections. although the above hypotheses are consistent with our findings, more laboratory research is needed to clarify the mechanism by which gargling prevents disease. gargling was associated with a lower incidence of sickness absences in several age groups; however, the odds ratios were close to unity, possibly because some sickness absences were caused by diseases or symptoms other than respiratory diseases, such as enteritis and otitis media. to better understand the effect of nocturnal fever onset, the reasons for absences associated with fever should be selectively extracted and analyzed. however, the reasons reported by parents varied widely and were often too vague to identify a specific disease (eg, "hoarseness," "looking sick," or "not doing well"). therefore, we could not confirm the effect of gargling on sickness absences or determine why the odds ratio for nocturnal fever onset was close to unity in gargling children. regarding gargling agents, we found that gargling with green tea had a greater impact on febrile disease. the results of a prospective cohort study of the effect of gargling with green tea suggested that such gargling lowers the risk of influenza infection, although the effect was not significant in that study. 18 tea catechin is a type of flavonoid in green tea and has antiviral and bacteriocidal effects. [19] [20] [21] [22] in a previous clinical study, gargling with a catechin extract of green tea inhibited influenza infection, and application of green tea extract to the oral or nasal cavities suppressed various pathogenic bacteria. 23, 24 the effect of green tea in our study might thus be related to tea catechin. previous studies of gargling were relatively small. the main advantage of this study is that it was a large-scale study of approximately 20 000 children, which ensured high statistical power. the preventive effect of gargling is affected by the prevalence of the target disease; however, there was no mass outbreak of influenza or other major febrile infection in fukuoka city during the study period, according to the fukuoka city health authorities. there were 2 main limitations in this study. first, because this was an observational study, assignment was not randomized or masked to the subjects. randomization is preferable, as it avoids potential confounding factors. however, randomization of gargling is difficult, as it is believed to be a beneficial behavior. to minimize the effect of potential confounding factors, we conducted analyses stratified by age, which was considered a major confounding factor, and included the location of the school (ward) in some models. since there was some variability among wards in the proportion of fever onset in the gargling group, the location of the school was assumed to be a confounding factor in the effect of gargling. we postulated that differences in socioeconomic status (ses) played a major role in this variability. ses is believed to be associated with susceptibility to respiratory infection, and previous studies suggested that decreases in ses were correlated with lower susceptibility. 25 unfortunately, data on parameters that directly reflect ses were not collected in this study, and we could not acquire information on the ses of each school or child after the survey. the effect of ses, therefore, was not fully adjusted and should be addressed in future surveys. second, we did not collect detailed information on the method of gargling and other practices of infection prevention (especially hand washing). however, it is unlikely that they varied greatly among children in japan because gargling and hand-washing are widely practiced throughout the country, and children receive instructions on gargling and hand-washing technique. in addition, both the child health authority of fukuoka city and fukuoka medical association provided explicit instruction to participating nurseries to encourage children to wash their hands. it is important for preschool children to perform infection control techniques in nursery school because infectious diseases tend to be spread in such environments. gargling is an inexpensive and straightforward hygienic measure for children and can be done anywhere. green tea is a common and safe beverage in japan, and there seem to be few problems in using it as a gargling agent. while gargling is not a popular decontamination method, except in some asian countries, there is no reason to hesitate to use it as a preventive measure against febrile diseases in childhood. this study was supported by a research grant from the society of ambulatory and general pediatrics of japan. we are grateful to the members of the fukuoka preschool health study for their support of the survey. we also greatly appreciate the generous assistance of all the staff of the participating nursery schools. conflicts of interest: none declared. nelson essentials of pediatrics abc's of the history of influenza pandemic. the yomiuri shimbun ministry of health, labour and welfare. guideline for new type of influenza management. tokyo: ministry of health, labour and welfare prevention of upper respiratory tract infections by gargling: a randomized trial cost-effectiveness of gargling for the prevention of upper respiratory tract infections longitudinal data analysis using generalized linear models management of fever without source in infants and children managing fever in infants and toddlers: toward a standard of care evidence based pediatrics and child health practical approach to the febrile child in the emergency department clinical significance and pathogenesis of viral respiratory infections review: rhinoviruses and their icam receptors species-specific receptor recognition by a minor-group human rhinovirus (hrv): hrv serotype 1a distinguishes between the murine and the human low-density lipoprotein receptor can we prevent influenza-like illnesses by gargling effects of chlorine, iodine, and quaternary ammonium compound disinfectants on several exotic disease viruses chlorine inactivation of adenovirus type 40 and feline calicivirus chlorhexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing heart surgery a randomized controlled study on the effects of gargling with tea catechin extracts on the prevention of influenza infection in healthy adults effects of tea catechin inhalation on methicillin-resistant staphylococcus aureus in elderly patients in a hospital ward oral care for elderly persons with oral lesion the effect of tea on various microorganisms the prevention of mrsa infections by tea extracts gargling with tea catechin extracts for the prevention of influenza infection in elderly nursing home residents: a prospective clinical study the potential of gargling with tea social status and susceptibility to respiratory infections key: cord-332404-va3rxy5p authors: landeros, a.; ji, x.; lange, k. l.; stutz, t. c.; xu, j.; sehl, m. e.; sinsheimer, j. s. title: an examination of school reopening strategies during the sars-cov-2 pandemic date: 2020-08-06 journal: medrxiv : the preprint server for health sciences doi: 10.1101/2020.08.05.20169086 sha: doc_id: 332404 cord_uid: va3rxy5p the sars-cov-2 pandemic led to the closure of nearly all k-12 schools in the united states of america in march 2020. although reopening k-12 schools for in-person schooling is desirable for many reasons, officials also understand that risk reduction strategies and detection of cases must be in place to allow children to safely return to school. furthermore, the consequences of reclosing recently reopened schools are substantial and impact teachers, parents, and ultimately the educational experience in children. using a stratified susceptible-exposed-infected-removed model, we explore the influences of reduced class density, transmission mitigation (such as the use of masks, desk shields, frequent surface cleaning, or outdoor instruction), and viral detection on cumulative prevalence. our model predicts that a combination of all three approaches will substantially reduce sars-cov-2 prevalence. the model also shows that reduction of class density and the implementation of rapid viral testing, even with imperfect detection, have greater impact than moderate measures for transmission mitigation. the best way to reopen k-12 schools has justifiably been a topic of intense discussion among government officials, the media, teachers and parents. given transmission of sars-cov-2 occurs through respiratory droplets, any reopening policy must adequately reduce crowded environments at school to protect children, teachers, staff, and ultimately communities. unfortunately, many factors work to the detriment of ostensibly reasonable strategies. for example, splitting a school day into morning and afternoon blocks may extend teachers' working hours or fail to adequately reduce class density in already overcrowded school districts. primary caretakers who work outside the home face additional challenges in dropping off and picking up children from school. finally, there is the issue of the quality of educational experiences to consider. a recent study on the effects of school closure in march in the u.s. suggests that it reduced covid-19 cases in states with low cumulative incidence [2] , yet education researchers worry that teachers will face lagging educational development of children once schools reopen due to the extended period of remote learning [11] . a predictable, regular attendance policy is crucial in balancing social burden with maintaining steady educational progress. having to close schools that have reopened due to an unacceptable risk in covid-19 cases is a serious concern and has prompted the inclusion of stopping rules in guidelines for school reopening [31] . as school systems have proposed different scenarios of reopening to reduce the density of students and the number of student interactions, it is helpful to investigate quantitatively the ramifications of the proposed plans. here we explore a simple and interpretable mathematical model that compares the infection rates in children and adults under various reopening scenarios. our approach stratifies members of a school community into two age groups, school-age children and adults, and assigns children to a single or two or three different cohorts. the two age groups differ in size, but within each group all children or all adults exhibit homogeneous disease behavior. with multiple cohorts, the goal is to limit the density of children in the classroom at a given time. specifically, we compare the consequences of (1) reopening at full capacity, (2) allowing half of all children to return to in-person schooling while the other half continues with remote learning (parallel cohorts) and (3) alternating sessions in which different cohorts of students attend school by the week (rotating cohorts). the latter scenario is designed to reduce classroom density and contacts between children while providing some of the benefits of in-person learning to all children. our goal is to provide insight into the epidemiological implications of these reopening strategies and to quantify their consequences. in particular, we explore implications of the recent guidelines announced by governor gavin newsom for california schools [31] . we find that reopening schools at half capacity, by running either two parallel cohorts of inperson and remote learning or two rotating cohorts of in-person learning, is likely to have a greater impact in controlling virus spread than direct measures that mitigate transmission risk. that is, reducing the number or density of contacts produces a larger effect than diminishing the transmission rate per contact. our models also suggest that the regular administration of rapid surveillance tests, even with imperfect sensitivity, can significantly delay disease outbreaks. it is our hope that our results along with further data and modeling by other experts will guide public health policy decisions. compartmental model. our approach uses a deterministic susceptible-exposed-infected-removed (seir) model stratified by age group and cohort. in full generality, let s(t), e(t), i(t), and r(t) denote the fraction of susceptible, exposed, infected, and removed individuals, respectively, in the overall population at time t. infecteds may or may not present with symptoms. the removed pool accounts for individuals with negligible contribution to the spread of infection, including individuals that have either recovered with full immunity or are no longer part of the population due to disabling morbidity or death. although prospects that infection leads to permanent immunity are unclear, immunity on the time scale of several months or more is plausible [20] , so we make the assumption that individuals do not return to the susceptible pool once they are infected. denote by i il (t) the fraction of infecteds in age group i and cohort l. we propose the following frequency-dependent model for the force of infection on individuals in age group j and cohort k: cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. for pairs of cohorts k = , the choice α kl = 0 reflects complete separation, whereas α kl = 1 corresponds to complete mixing under no mitigating policies. values in between these limits may be interpreted as decreased interaction due to physical or social distancing. we allow for weak cohort interaction (α k = 0.05, k = ) in all our simulations. to capture the variability in exposure to infectious individuals across age groups and different cohorts, the transmission rate β ij (t) is timeinhomogeneous. these choices effectively model the density dependence of coronavirus transmission on cohort isolation and contact patterns between different age groups. we model two age groups, children and adults, and ignore vital dynamics (that is, ordinary births and deaths) altogether. the latter choice is justified by the relatively short time period over which the model acts. the resulting ordinary differential equation (ode) subsystem describing cohort k is given by with the left and right columns corresponding to children and adults, respectively. for simplicity in communicating the key ideas in our model, we limit the scope of simulations to two age groups, children in k-12 education and individuals over the age of 18, and to 1 to 3 child cohorts. we also neglect any inhomogeneity in susceptibility and transmission within each of the two age groups [4, 9] . to our credit, we emphasize the interplay of transmission across and within age classes, that is the ratios β ii /β jj and β ij /β ji . by design, our model makes it easy to explicitly incorporate susceptibility, contact patterns, and, ultimately, finer age stratification. in broad outline, our model is similar to that of zhang et al. [26] . however, these researchers emphasize differences in contact patterns across age groups rather than school reopening policies. cohort structure and transmission rates. previous work suggests that a cyclic attendance strategy tuned to the latent period of sars-cov-2 may curtail secondary infections [10] . to compare with full-time and online-only instruction, we investigate the consequences of reopening at 50% and 33% capacity with rotating cohorts. assuming a latent period within the range of 3-4 days, a weekly rotation schedule synchronizes with peak infectiousness. our simulations therefore model transmission between children using periodic rates that cycle between high and low contact values. namely, we take β 11 (t) = c × β on school days and β 11 (t) = β otherwise, where β is a baseline rate outside of school and c is a multiplier increasing transmission between children. this function is phased between cohorts to reflect school rotation. in summary, children in rotating cohorts attend school for 5 consecutive days and then rotate with the next cohort at the beginning of the following week. with two cohorts children attend school every other week; for three cohorts they attend every third week. as noted previously, this is referred to as the rotating cohort strategy. an emerging national trend in the u.s. is to allow families to opt for remote learning in lieu of in-person instruction during the sars-cov-2 pandemic. specifically, we divide our virtual school community into two cohorts of equal size, one of which attends school and thus has the elevated transmission rate while a second group opts for a remote learning option. this is referred to as the parallel cohort strategy. 3 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august 6, 2020. . choice of model parameters. as of august 3, 2020, the cdc reports 4.6 million covid-19 cases in the united states [32] . california, florida, and texas are each burdened with nearly 0.5 million cases, which corresponds to 1% infection in their respective populations. given that the u.s. has considerable variation in density, we seed all our simulations, which represent school communities rather than states, with 0.1% infected individuals. increasing this value accelerates infections in our model; decreasing it lessens the spread. our simulations therefore represent scenarios far from herd immunity [12, 21] . although children have fewer symptoms, less severe disease, and lower case-fatality rates than adults, they may be just as prone to sars-cov-2 infections as adults [28] . children may present with a variety of symptoms ranging from fever, rhinitis, cough, and gi symptoms, to a kawasakilike disease [22] . however, because children's symptoms are typically less severe and of shorter duration than those of adults, the likelihood of pediatric infection escaping symptom-based monitoring, such as temperature screening, is therefore is higher than that of adults and increases asymptomatic transmission. thus, detecting transmission between children specifically is difficult; quantifying it is all the more challenging. an analysis of contact tracing data from singapore suggests that per contact transmission between children, particularly in educational settings, is low compared to adult-adult transmission [24] . yet the number of contacts between children is expected to be significantly higher compared to other age groups [26] . li et al. provide estimates for transmission rates in wuhan prior to (1.12 per day) and following travel restrictions (0.52 per day) [16] . reconciling estimates of transmission rates across populations, which are necessarily based on different scientific models, is unproductive in proposing policy. instead, we vary each β ij in simulations to underscore the influence of modeling assumptions on epidemiological consequences. in later simulations we opt to model child-to-child transmission with lower rates to reflect evidence suggesting children are rarely index cases [15] and have fewer contacts outside of school. in this setting, transmission is elevated by a factor c in children only on school days, β 11 (t) = c × β, so as to account for increased contacts. a recent study indicates that viral rna in the nasopharynx of young children is elevated compared to adults [8] , partially justifying this modeling choice. in contrast to contact rates, the latent, infectious, and incubation periods for sars-cov-2 are well characterized in the literature. lauer et al. estimate a median incubation period of approximately 5 days [14] . li et al. [16] infer latency and infectious periods of 3.69 and 3.47 days, respectively, in a study aimed at characterizing contributions of undocumented infections to disease spread in china. the review by bar-on draws from these studies and reports median latent and infectious periods of 3 and 4 days, respectively [3] . other studies report serial intervals and incubation periods consistent with these estimates for latency and infectiousness [6, 7] . unfortunately, the literature on similar epidemiological inferences in children is sparse. table 1 summarizes our choices and lists references pertinent to each choice. basic reproductive number. we now characterize the basic reproductive number r 0 indicative of the growth potential of an epidemic. specifically, r 0 quantifies the expected number of secondary infections due to a single infected within a completely susceptible population. the threshold r 0 value of 1 marks the boundary between explosive growth (r 0 > 1) and decline of an epidemic to extinction (r 0 < 1). we characterize r 0 using the next generation method as outlined by diekmann, heesterbeek, and roberts [5] . under the assumption that viral infections have been sufficiently contained in the community prior to reopening, it is reasonable to linearize dynamics by taking s(0) ≈ 1. thus, the transmission and transition operators t and σ are given respectively 4 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . https://doi.org/10.1101/2020.08.05.20169086 doi: medrxiv preprint by the matrices for a single cohort, where 1 denotes children and 2 denotes adults. together, these linear operators define an embedded subsystem that completely characterizes infectious dynamics, namely dx dt = (t + σ)x. the standard theory identifies r 0 as the spectral radius of −t σ −1 , a quantity that can be computed numerically in practice. in the case of multiple cohorts, the structures of t and σ as given are repeated in a tiled fashion, with the appropriate changes in indices for α k and s j . effect of reducing density via cohorts. transmission of sars-cov-2 is thought to occur primarily through respiratory droplets. thus, it is critical to first examine the effect of separating children into several rotating cohorts in our model, which implicitly reduces density via the contact network of a population. figure 1 summarizes the influence of time-homogeneous transmission rates β ij (t) = β ij on the reproductive number r 0 under various scenarios, assuming a population mix of 55% children and 45% adults and strong adherence to mitigation policies (with α k = 0.05 for each k = ) that keep both children and adults isolated from members of other cohorts. splitting a school community into even 2 or 3 rotating cohorts substantially reduces r 0 under a wide range of parameter values and slows viral spread in cases of moderate transmissibility. for example, moving from full capacity to 2 cohorts reduces r 0 by 50% for the range 0 ≤ β 11 , β 22 ≤ 1 (figure 1 , a and 1b). using three cohorts further reduces r 0 for comparable β 11 and β 22 ( figure 1c ). this parameter range is of interest because it corresponds to r 0 ≈ 2 in the full capacity scenario. likewise, two or three rotating cohorts for children also decrease r 0 when transmission rates between children and adults are asymmetric; that is, β 12 > β 21 or β 12 < β 21 (figure 1 , d to f). as demonstrated by the skew present in our contour plots, age structure amplifies the influence of transmission rates. reopening under stopping rules. we now consider the effect of a stopping rule on cumulative prevalence. inspired by california's recent guidelines that urge schools to close down whenever the percent of infecteds within a school reaches 5% over a 2 week period [31] , we use a cumulative prevalence of 5% as a stopping rule. in symbols, the stopping rule is given by the condition which relies on the detection of cases on school days as well as on surveillance reports from outside of school. detection is based on testing at the beginning of a school day, after which infected individuals in the active cohort are immediately isolated and placed in the removed state (i(t) → r(t)). the isolation rule does not apply to the out of school cohort or cohorts. the sensitivity factor in the rule captures imprecision in testing and reporting. because our model does not explicitly account for adult staff at school, we measure only the cumulative prevalence within the child population. this choice is partially justified because students typically well outnumber teachers and ancillary staff. under the assumption of a 20:1 student-staff ratio, a school with 1000 students would need approximately 53 cases in a 14-day period to meet the closure criterion. please note 5 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . that our simulations deviate from california's proposed policy by tracking cumulative cases rather than cases within a sliding 14-day window. figure 2 reports the number of weeks to reach the 5% threshold in our model in various parameter regimes, assuming the monitoring program exactly identifies infections in children as they begin a new day of school. cohort separation tends to dramatically reduce the spread of infection. owing to high child-to-child transmission effects within school (c = 10), our model predicts closures within a month in a full-capacity high transmission scenario with no mitigation (figure 2, a and e) . under the more optimistic assumption of preventive measures, hitting the 5% threshold may take several weeks and may, in fact, never occur in the ideal circumstances of low density and effective risk mitigation (figure 2, b to d and f to h) . notably, under most of the parameter values we chose, 2 parallel cohorts and 2 rotating cohorts show similar time to 5% infecteds, with the parallel cohort strategy having a slight advantage when β 11 and β 22 are large. for example when β 11 = 1 and β 22 = 1, 2 rotating cohorts reach the 5% infected level in 6 to 8 weeks, and 2 parallel cohorts reach it in 8 to 10 weeks (figure 2 , b and c). this behavior is partially driven by the testing protocol, which only detects and isolates cases in the active cohort. unfortunately, the issue of detection is complicated by the availability of testing resources, administration of tests, and specificity of the tests used. in light of this reality, we compare predictions of our model over 6 months when (1) no action is taken (figure 3 , a and b), (2) the monitoring program uses a perfectly sensitive test with no delays in reporting (figure 3 , c and d), and (3) the monitoring program uses a rapid but less sensitive test (figure 3 , e and f). our simulations with a single cohort indicate that a 5% percent threshold policy can shift infections in children from 80% to 55% over a 6 month period when child-to-child transmission rates in school are high ( figure 3c ). compared to this ideal testing scenario, an imperfect test with 50% detection leads to an earlier stopping time, owing to infections spread by undetected cases, and to greater pediatric infections but still far less than the no testing scenario ( figure 3e ). let us emphasize our finding that reopening with a surveillance program in place may provide 10 to 12 weeks of continuous instruction with low infection risk. infections after closing are driven by a lack of interventions outside of school; testing and isolation in this context can curtail this growth. in general, our results support the importance of testing and the failsafe of complete school closure in preventing a major disease outbreak after reopening. next, we explore the ramifications of two parallel cohorts using the simulation study design just considered. specifically, we assume the elevated transmission rate β 11 (t) = c × 0.15 during a regular 5-day school week and and the reduced transmission rate β 11 (t) = 0.15 during the off week. the remaining transmission rates are chosen with r 0 > 1 to capture outbreak conditions. these choices lead to more rapid acting infection and earlier school closure than those chosen in figure 3 under the single cohort policy. figure 4 reports the same indices recorded in our simulation study with the single cohort policy. as our earlier figures illustrate, reducing density through the community's contact network successfully decreases cumulative prevalences, sustained contact between children notwithstanding (figure 4, a to d) . the in-person stopping rule (the entire school goes online when cumulative prevalence reaches 5%) is triggered even when detection is imperfect (figure 4 , e to f). because cohorts reduce contacts, our model predicts a longer period of instruction (18) (19) (20) (21) (22) weeks) with the parallel strategy (figure 4 , c and e) compared to the previous simulation with all students attending at once (10-12 weeks) (figure 3 , c and e). we note that, despite the remote cohort child-to-child transmission rate being 1/10 of the in-person cohort child-to-child rate, the remote cohort has more infections than the in-person cohort in both surveillance scenarios. this result occurs because only the latter cohort is monitored through the school's testing program. one may interpret this as an upper bound on infections for the remote learning cohort as there will likely be some monitoring for this group in practice. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . mitigating transmission between children. transmission mitigation strategies that may work well for adults may be less practical to implement with children. as an example, although face masks have been shown to reduce the spread of sars-cov-2 by 40% [17] , there are valid concerns about the ill effects of mask wearing by elementary school children. these concerns include impaired learning, speech development, social development, and facial recognition [29] . there is also doubt about whether young children can properly keep their masks on. the protection gained from mask wearing needs to be weighed against the disadvantages just enumerated. regardless of their form, we assume that effective strategies will be employed. using reasonable approximations for contact and transmission risks, we explore the impacts of varying degrees of protection conferred by combined risk reduction strategies, including but not limited to mask wearing, desk shields, hand washing, vigilant cleaning of surfaces, improved ventilation, and outdoor instruction. the combined impacts of these risk reduction strategies are modeled as 20%, 40%, 60%, and 80% reductions in the transmission rates β 11 and β 12 relative to reference values. we particularly examine the changes in infection levels under each scenario, taking care in selecting the adult values β 21 and β 22 to account for simultaneous risk reduction strategies among adults. specifically, we take β 11 = 0.1 and β 12 = β 21 = β 22 = 0.5 as natural rates. under a baseline model reducing transmission rates in adults to β 21 = β 22 = 0.2, we achieve an r 0 ≈ 1.8 when schools remain closed. we choose to model increased contact rates β 11 (t) = c × 0.1 by taking c = 10, which corresponds to r 0 ≈ 3.3 under the full capacity reopening scenario. this necessarily represents an extreme that illustrate effects in a poor situation. figure 5 compares prevalence trajectories by interventions directly targeting transmission under a single or two rotating child cohorts. with a single cohort and no mitigation, our choices lead to approximately 2%, 46%, and 65% infected children after 1, 3, and 6 months following reopening, respectively ( figure 5a ). however, with measures that lead to an 80% reduction in transmission, it would take more than 24 weeks to reach a cumulative prevalence of 5% in children ( figure 5a ). achieving an 80% reduction in transmission would be difficult in practice. with a more realistic reduction factor of only 20%, our model predicts that 5% cumulative prevalence in children would be reached in roughly 8 weeks ( figure 5a ). targeting transmission rates in children also reduces infections in adults to a similar degree ( figure 5b ). although policies such as mask use and hand washing have an appreciable effect in reducing infections, our model predicts the intuitive conclusion that stricter adherence to transmission mitigation measures is required to lead to low levels of infection when there is a single cohort than when there are two cohorts. in fact, we show that an 80% reduction in child-to-child transmission is required to lead to 0.5% pediatric infections over 6 months, which is roughly equivalent to the effect of 2 rotating cohorts ( figure 5c , d) without mitigation strategies. a combination of both types of interventions ultimately results in even fewer infections. our models highlight the profound potential impact of reducing cohort size with parallel or rotating cohorts under a range of transmission rates and reproduction numbers. for example, if we take transmission rates β 11 = β 22 = 1, it would take approximately 2 weeks to reach a threshold of 5% children infected, whereas under the same transmission rates splitting the school population into two or three rotating cohorts would lead to a month or more of uninterrupted instruction (figure 2 ). quite apart from cohort strategies, our work also reveals the importance of tracking infections and setting a threshold for reverting to remote learning. in the absence of any intervention to in-person instruction, the cumulative proportion of the school children population can quickly reach 20% within 6 weeks ( figure 3a ). this compares with keeping that cumulative proportion at 5 − 10% 7 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . for at least 3 months under the combination of a rapid testing program, a stopping rule, and just a single cohort ( figure 3c ). finally, our results demonstrate that simultaneous adherence to transmission mitigation measures and multiple separated cohorts can keep cases low, for example under 0.5% ( figure 5c,d) . there are several limitations to our simulations. first, we account only for two separate age classes, children and adults. a finer level of age stratification may be better suited for predicting outcomes in specific communities and is, in principle, straightforward to implement within our modeling framework. for example, our model currently makes no distinction between high school and elementary school children. high school students may be more easily convinced into wearing masks reliably and practicing physical distancing, but they also may have transmission rates closer to those of adults. second, we treat all adults, including teachers, as having the same transmission rates and omit interactions between students and teachers within a classroom. the latter are clearly critical in implementing backup protocols that allow the switch to remote learning. a networkbased model that accounts for households and classrooms in more detail would be better equipped to identify optimal policies. third, our model treats school communities in isolation. schools in urban settings undoubtedly have more diverse commuting patterns and face a greater potential for importing cases from outside adjacent neighborhoods. finally, our models are deterministic and cannot account for the stochastic nature of infections. the caveats outlined here limit the quantitative accuracy of our predictions, but we contend that our qualitative conclusions are correct. as already mentioned, our simulations suggest that measures that reduce class density by rotating cohorts between in-person and online schooling are likely to have the greatest impact in reducing the spread of sars-cov-2 brought on by the resumption of in-person instruction. from the perspective of mathematical epidemiology, this is to be expected as separating a contact graph into disconnected pieces ultimately limits the proliferative potential of an infectious disease. parallel cohorts present an attractive alternative to rotating cohorts because the latter require a great deal of coordination and place a burden on parents to adjust their work schedules to match their children's in-class and at home schedules. although less than ideal from an educational perspective, educating children under either cohort strategy should be a priority in school reopenings. even so, our findings indicate that implementation of specific in-class policies such as mask wearing, hand washing, and physical distancing in the classroom will be helpful in reducing transmission rates. our simulations of a backup plan to switch to remote learning when the number of infections climbs to an unacceptable level emphasize the need for rapid testing and efficacious surveillance programs. these results are consistent with a recent study on the influence of viral kinetics, test sensitivity, test frequency, and sample-to-answer reporting time in surveillance protocols [13] . this study concludes that test efficacy should be a secondary concern in implementing testing given the dangers of the current pandemic. finally, different communities should be treated differently. high-risk communities with large class sizes need to be especially careful in exposing children to unnecessary risks. we are happy to share our software and assist in its improvement. until effective vaccines become available, we are in a battle against time in limiting mortality and morbidity. table 1 : summary of model parameters with ranges, estimates, and references. the range for transmission between adults is informed by [16] . latent and infectious period estimates are based on [3, 16] . 9 . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . figure 2 : number of weeks to reach the 5% stopping threshold in a community with equal proportions of adults and children. we use children as representatives of the entire school subpopulation. the 5% threshold tracks cumulative prevalence over all cohorts, k [i 1,k (t) + r 1,k (t)] ≥ 0.05 × 1 2 , thus accounting for the size of the schoolchildren population (50%) relative to the overall community. in each simulation, children have an elevated transmission rate due to school contacts over the rate they have when they are not in school; for example, β 11 (t) = 1 = c × 0.1 with c = 10. results are based on latent and infectious periods of 3 and 4 days, respectively (σ 1 = σ 2 = 1/3, γ 1 = γ 2 = 1/4), and the additional assumptions that (a-d) transmission between age classes is equal (β 12 = β 21 = 0.5), and (e-h) where adult-to-adult transmission dominates outside of school (β 11 = 0.1 and β 22 = 0.5). deep purple is used to indicate scenarios in which the threshold is hit after 22 weeks or more. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted august 6, 2020. . figure 3 : comparison of outcomes when a school does not track infections (a,b) and when a school reverts to online instruction as a result of a careful screening program (c,d). in both scenarios, the school is assumed to operate at full capacity. simulations are based on parameter values β 12 = β 21 = β 22 = 0.5, σ 1 = σ 2 = 1/3, and γ 1 = γ 2 = 1/4. for child-to-child transmission, we set β 11 (t) = 0.1 outside of school and β 11 (t) = 1 = c × 0.1 during school (c = 10). curves correspond to active infections (blue), removed individuals (orange), and cumulative prevalence (green). the school switches to online instruction when detected cases affect 5% of the school population (vertical line), dramatically reducing spread. (e,f) closures occur earlier and the cumulative prevalence is larger compared to the ideal detection scenario. however, there is not an appreciable increase in long term-infections when the monitoring program has poor detection, and both monitoring scenarios have appreciably less long term infectious than the no intervention scenario. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august 6, 2020. . . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted august 6, 2020. . figure 5 : cumulative prevalence trajectories under risk reduction strategies for children while at school. simulations are based on parameter values β 12 = β 21 = β 22 = 0.2, σ 1 = σ 2 = 1/3, and γ 1 = γ 2 = 1/4, assuming a population with equal numbers of children and adults. for child-child transmission, we set β 11 (t) = 0.1 outside of school and β 11 (t) = (1−r)×c×0.1 during school, where r is a reduction factor due to effective risk reduction strategies and c = 10 accounts for increased contact between children. (a,b) mitigation that reduces transmission between children can lead to a substantial reduction in infections, provided the mitigation effects are large. (c,d) the impact of risk reduction strategies persists when children are separated into 2 rotating cohorts but does not demand as strict adherence to be effective. an 80% reduction in pediatric transmission is nearly equivalent to separating children into 2 rotating cohorts as both strategies result in fewer than 0.5% pediatric infections over 6 months. . cc-by 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. 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key: cord-346388-j6pajd68 authors: song, hwasung; park, chanyul; kim, miseong title: tourism destination management strategy for young children: willingness to pay for child-friendly tourism facilities and services at a heritage site date: 2020-09-28 journal: int j environ res public health doi: 10.3390/ijerph17197100 sha: doc_id: 346388 cord_uid: j6pajd68 the present study seeks to establish tourism destination management centered on young children for accessible tourism from a public perspective. preferences for services and facilities for young children were identified using a choice experiment (ce). the present study was conducted at hwaseong fortress, a unesco world heritage site, located in suwon city, which leads the clean restroom culture. overall, 1870 experiments were conducted with 374 participants to estimate their willingness to pay for child-friendly tourism facilities and services. as a result, willingness to pay was found in the order of specialized courses for young children, rest areas, restrooms, and rides. in conclusion, the importance of health/hygiene and amenities has implications for tourism destination management for young children. this study contributes to a better understanding of families with young children by evaluating preferences for levels of services and facilities for young children. have you ever experienced tourism with young children? in the republic of korea, under article 2 of the child care act, infants and young children refers to preschoolers under the age of six [1] . tourism with a child under 6 years of age brings many restrictions at tourist destinations. during tourism with young children, one faces the constraints of the basic needs for rest, eating, and toileting [2] [3] [4] . thus, it is expected that the contents that can be enjoyed at tourist destinations will change. the impact of children on tourism purchasing power is gradually increasing, and family vacations are expected to become more important for society in the future from the perspective of creating social benefits [5] . parents are gradually spending more money and energy to travel with their children [6] . additionally, travel experiences during one's childhood could affect travel behavior after becoming an adult [7] [8] [9] . therefore, not only is the scale of young children's tourism growing, but its importance in marketing is also increasing [9] . from these perspectives, research on travel time and cost for travel with young children [6] , preferred activities [4, 10, 11] , and facilities and services [2, 3, [12] [13] [14] has been steadily progressing. these studies have contributed to a better understanding of the tourism market for young children, but there is still a lack of answers as to which management strategy is needed from the view of providers. in particular, in terms of safety and hygiene, it is necessary to consider how to differentiate food, sleeping, facilities and services, and experiences. this is a more difficult aspect to deal with in the public domain. however, since tourism is a right that everyone should enjoy, not only an understanding of the economic importance of young children's tourism, but also the development of a tourism destination management strategy for young children's tourism in the public domain is needed. accessible tourism for all means "the ongoing endeavor to ensure tourist destinations, products, and services are accessible to all people, regardless of their physical limitations, disabilities, or age" [15] . young children, who have more restrictions than adults in terms of hygiene, safety, walking, and rest, are also the subject for accessible tourism. that is, the public sector should also improve facilities and services for young children. the tourism industry has been negatively impacted due to the covid-19 pandemic, and long-distance tourism such as overseas tourism has become very difficult [16, 17] . however, tourism and leisure are basic needs of humans [18] , and as covid-19 has become prolonged and new cases have significantly decreased, travel to nearby destinations such as parks is rapidly recovering in korea [19] . however, covid-19 makes tourism activities difficult for young children with weak immune systems. tourists with young children are very concerned about the fatigue of their children, so the younger the children are, the more they prefer short distances and try to reduce travel time as much as possible [4, 10] . in addition, the comfort and safety of the destination is an important determinant of the intention to visit, and the cleanliness of the destination is especially important [12] . this is the reason why covid-19 further reduces tourism activities, especially for tourists with young children. in the republic of korea, childcare facilities have been closed due to covid-19, and children spend most of their time at home. social exchanges and education provided by childcare facilities are on hold, tourism and outdoor activities are reduced, and people are suffering from increases in obesity due to mental stress and lack of exercise [20] . in particular, children belonging to the socially vulnerable class are more alienated, mentally stressed, and worsening in their physical health [21] . accordingly, it is necessary to look at young children's tourism from the perspective of accessible tourism in terms of public interest and to improve the conditions of young children's tourism to help heal the society after the covid-19 pandemic. under these circumstances, the importance of health/sanitation management for young children's tourism is growing [16] . therefore, the present study examines the preferences of tourists in order to establish a tourism destination management strategy for young children as a type of accessible tourism from a public perspective. choice experiments (ces) were used to estimate the willingness to pay (wtp) for facilities and services for young children at a tourist destination, in order to understand preferences. the ce method of estimating economic value based on stated preferences is widely used for estimating the wtp of tourists. the advantage of the ce is that you can check the wtp for the different levels of any attribute. for example, it is possible to check how much the wtp is based on the level of restrooms for young children. suwon hwaseong fortress, the target site of this study, was designated as a unesco cultural heritage site in 1997 and is a popular historical and cultural tourist destination in korea, even among young children, due to its educational aspects [22] . in particular, suwon city, in which hwaseong fortress is located, is the place where the "world restroom culture movement" began and is well known for its clean public restrooms [23] . yet, facilities and services for young children including restrooms at the tourist destination are insufficient. thus, this site was selected as the target site for establishing an optimal tourism destination management strategy for young children's tourism. the purpose of the present study was to establish a tourism destination management strategy centered on facilities and services for young children's tourism before the outbreak of covid-19. however, hygiene and amenities in young children's tourism and providing preferred facilities and services has become even more relevant in the era of covid-19, with implications for the tourism destination management for young children's tourism. young children are an important consumer group in the tourism industry. tourism has become one of the essential consumption elements for families with young children, and parents are spending more and more money and energy on travel with their children [6, 8] . children have a fair amount of influence on the tourism decision-making in the family. therkelsen revealed that the roles of mothers and children are equal in vacation planning [4] , and curtale found that parents are sensitive to their children's best and worst choices, and they make choices tailored to their preferences [9] . in addition, the satisfaction of children affects the satisfaction and behavior intention of parents [7, 9] . in particular, younger children have a greater influence on tourism decision-making [9, 10] . the size of the domestic children's industry in korea was 40 trillion in 2018, surpassing the 27 trillion from 2012, and new words such as vib (very important baby) and yucance (infant + hotel + vacation) were born [24] . in the tourism sector, in particular, various specialized programs are being provided for these vib customers. for example, worldwide resort club med provides various activities and facilities that are adapted to children of different age groups, ranging from 4 months to 17 years [25] . even in korea, midas hotel and resort [26] was designed for vacationing with children and operates premium children's clubs in line with this trend. therefore, in the tourism industry, it is necessary to establish marketing strategies for children in order to attract new customers, and it is important to provide tourism products that satisfy the preferences of children [9] . the private sector focuses on the market value of the children's industry, while the public sector focuses more on creating child-friendly tourism environments from an accessible tourism perspective [24] . since tourism is increasingly being conceived as a necessity, rather than a luxury [27] , accessible tourism is being considered both as a fundamental right as well as a new business opportunity [28] . accessible tourism for all means "the ongoing endeavor to ensure tourist destinations, products, and services are accessible to all people, regardless of their physical limitations, disabilities, or age" [15] . it could also be understood as the set of "facilities and services (including the physical environment, transportation, information, communication) which enable persons with special access needs, either permanent or temporary, to enjoy a holiday and leisure time with no particular barrier or problem" [29] . from this perspective, it has become important to consider the level of accessibility for young children when designing facilities and services of tourist destinations. in order to create child-friendly destinations, it is necessary to understand the characteristics of young children as tourists. first, young children need to have their primary needs for food, nap/bedtime, safety, and sanitary facilities met first [4] . families with young children will give positive reviews on tourism attraction if they are provided convenience facilities and food for their children [3] . nistoreanu and dragolea found that specialized facilities for children such as beds for children or rest areas are needed for providing comfort, and caring staff and hygienic conditions could improve safety [12] . in addition, khoo-lattimore and yang emphasized that a comprehensive approach should be taken when designing facilities and services for young children by considering accessibility, possibility of interaction with other children, safety, hygiene, room size, and staff size for child-friendly programs [14] . secondly, young children are usually satisfied with dynamic activities. nickerson and jurowski revealed that young children prefer dynamic activities such as gold mining more than static activities such as seeing an exhibition [11] . young children need engaging activities including various ecological experiences such as picking fruit, playing with animals, and fishing [12] . in addition, children prefer dramatic play opportunities such as horse riding and superheroes, and functional play opportunities such as swinging and rocking [30] . cosco found that children enjoy riding on wheeled toys on hard, curvy pathways [31] , and babara found that most observed play focused on standing, walking, running, and riding [32] . in sum, children need facilities that are comfortable and safe, and dynamic activities that are fun and entertaining. due to the characteristics of young children as previously discussed, facilities and services at tourist destinations must also be designed for young children. for families with young children, tourist attractions should provide customized facilities and services for children to minimize problems and to maximize their satisfaction during the tour [12, 13] . when comfort and safety are secured, families with young children are willing to visit tourist destinations. parents consider a safe and clean environment as the most important factor for choosing destinations while accompanied by young children [3, 13] . asians, in particular, regard clean restrooms as more important than hispanic or african americans [33] . furthermore, the worldwide pandemic situation due to covid-19 has highlighted cleanliness as the most important aspect which could make relieve visitors of anxiety and instead attract them [34] . as handwashing is recognized as an essential activity in maintaining cleanliness, children's handwashing has increased compared to before the outbreak of covid-19 [35] . therefore, it is necessary to prepare facilities (toilets, sinks) that can meet the needs of maintaining cleanliness including hand washing. restrooms are also an important facility from the perspective of accessible tourism destinations. various guidelines for accessible tourism destinations include the criteria of accessibility to public restrooms [15, 29, 36] . the guidelines of kto state the importance of the installation of convenience facilities such as nursing rooms and diaper changing stations, and designing these with consideration of children's characteristics, such as lowering the height of sinks [36] . regarding the design of restrooms and other convenience facilities, gender parity also needs to be considered. the increase in male participation and co-parenting in early childhood education and care [37] , including diaper-changing duties, helps to improve parent-child bonds and family relationships [38] . in this context, male restrooms should also include childcare facilities. in addition, rest areas such as benches and restroom are important facilities for young children. in order to make children feel safe and comfortable, it is necessary to provide areas for rest and some adequate protection from stressful natural elements such as wind, rain, and sun [12, 39] . even in the view of accessible tourism, having enough accessible rest points such as benches is a basic element [15] . children's vehicles should be an additional consideration as well. various guidelines for accessible tourism destinations regard the secure accessibility of public transportation and accessibility to any tourist spots without difficulties [15, 29, 36] . for example, a necessary consideration is that young children will usually take strollers into tourist destinations. as nyman and others revealed that an accessible setting with a universal design could be the reinforcement factor for choosing tourism destinations especially for families with wheelchair-bound children [40] , accessibility could be an important factor for travel decision-making for families with young children who should be carried in strollers. in addition, numerous tourist destinations, such as the representative theme park disney world, provide stroller rental services for families with young children [41] . for providing convenience, stroller or other vehicle rental services should be considered when designing tourist destinations. providing rides could also add a fun factor to destinations. various studies have revealed that children love to ride vehicles with wheels, so providing them with vehicles such as baby bicycles, strollers, and minicars could be a specialized option for tourist destinations [30] [31] [32] . lastly, specialized programs could strengthen the attractiveness of the destination. as we noted in the previous section, children prefer experiential activities [11, 12, [30] [31] [32] . various tourist destinations provide specialized programs for young children. numerous museums (e.g., guggenheim museum in the united states [42] , remai modern in canada [43]) offer stroller tours for families with young children, and some public parks offer playground associate programs for young children (e.g., 'kids in motion' in new york city parks [44] , 'playground program' in appleton parks [45] ). these specialized programs may have a positive effect especially during a pandemic era. specialized programs could broaden the recreation opportunity spectrum (ros), which is a frequently used management tool for protecting areas [46] . since it could manage the demand of visitors, it may be used to affect the number of visitors during a particular period in a specific area [47] . in this aspect, specialized programs with limits on time and number of participants, could disperse tourists and lower the density of visitors. this is also a good management plan for reducing the risk of infection by reducing exposure density [48] . suwon hwaseong fortress was recognized for its historical meaning and architectural excellence and designated as a unesco cultural heritage site in 1997 [49] . it is the representative historical and cultural legacy of beautiful asian fortresses, not confined to the joseon dynasty in korea. with various attractiveness, as shown in figure 1 , hwaseong fortress is known as one of the child-friendly places. according to the latest tourist survey of suwon in 2017, the rate of visitors in their 30 s and 40 s at suwon hwaseong was 41.7%, much higher than for other age groups. additionally, the primary type of companions of visitors in their 30 s and 40 s was family members (74.7%), so this group is comprised mainly of families with young children [50] . suwon has a large population of young children under the age of 6 [51] , and the city is recognized as a city with a child-friendly environment, as it received a child-friendly city (cfc) recognition from unicef [52] . in particular, suwon city, in which hwaseong fortress is located, is where the "world restroom culture movement" began and is well known for its clean public restrooms [23] . suwon is the only city which has a toilet museum (haewoojae) in korea and the world toilet association is located in suwon as well. as shown in figure 2 , the city is leading the world restroom culture as the birthplace of restroom culture and plays a pivotal role in the development of restroom culture through the operation of a toilet museum. therefore, it is the ideal place to evaluate and find the best options for restrooms, the representative convenience facility for tourists, especially in the era of covid-19 in which hygiene management has become more important. in this study, ce analysis was used for investigating preferences for child-friendly tourism facilities and services. the ce is a stated preference-based methodology to estimate the marginal willingness to pay (mwtp) using a multidimensional approach [53] . since this method can estimate the mwtp for each attribute, such as tourism facilities and services, it has been used in various tourism studies to evaluate the preference of tourists [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] . therefore, ce was selected as the analysis method for understanding tourists' preferences for child-friendly tourism facilities and services and developing a tourism destination management strategy for young children. for the experiments, the attributes and levels of child-friendly tourism facilities and services were employed based on previous studies as presented in section 2 above. the specific attributes of young children's tourism at suwon hwaseong fortress consist of rest areas, restrooms and facilities designed for young children, children's vehicles, and specialized courses, as shown in table 1 . an entrance fee was used as payment for the vehicles. each attribute was divided into three levels. level 1 for each attribute indicated the current state of the attribute or nothing. levels 2 and 3 indicated alternative facilities and services which require more investment. after collecting the choices of respondents, the indirect utility function was estimated by a conditional logit model (cl) designed by mcfadden [53] . using a maximum likelihood estimator for each attribute, mwtp was calculated. as all variables except the price variable (entrance fee) were binary variables, mwtp values for level 2 and level 3 of each attribute indicate additional wtp compared to level 1. the choice set for the experiment was composed of level-specific combinations of attributes from table 1 . since there are too many choice profiles in the full factorial design (3 4 ã� 4 = 324) to evaluate, a fractional factorial orthogonal design was used [60, 61] . in this study, 16 profiles were used as the choice set for the experiment which were derived by an orthogonal design using spss 23.0. for each round, survey respondents could randomly select 3 of these 16 profiles, as shown in table 2 , and choose the most preferred alternative for them, or nothing. the experiment was conducted by all respondents over 5 rounds. the number of valid responses to the questionnaire was 374, and the total number of experiments was 1870. the target population of this study was tourists in suwon hwaseong who were accompanied by young children under the age of 6. in order to increase the objectivity of the survey and to enhance the readability of the questionnaire items, a pretest with 35 responses was conducted in april 2019. after the questionnaire was revised, the main survey was conducted as an in-person 1:1 survey in korean from april to may 2019 (peak season of outdoor recreation) by skilled interviewers. sampling was performed using random sampling. a total of 500 questionnaires were distributed, and for a more accurate evaluation of facilities and services, the first visitor was excluded, and the final 374 samples were included in the analysis. the questionnaire also included items regarding general characteristics of tourism with young children, tourism characteristics of young children in suwon hwaseong, and demographic characteristics of respondents. the time required for the survey was about 20 min. the sample of 374 respondents with children included more women (n = 286, 76.5%) and mothers (n = 221, 59.1%). the average age of participants was 38.78 years (sd = 6.59) with more visitors in their 30 s (n = 237, 63.4%) than those in their 40 s (n = 100, 26.7%). college attendance/graduation was the most common educational level (n = 266, 71.1%) and household income was more than 4000 usd a month (n = 199, 53.2%), which indicated a high proportion of highly educated and high-income visitors. the results of the cl model estimation of the responses of the selection experiments are shown in table 3 . first, the coefficient estimate of the price variable is negative and statistically significant at the 1% significance level. it indicates that rational decision-making-larger payment, lower choice probability-occurred in the experiment. the coefficient estimates for each attribute and level were significantly positive. it means that ceteris paribus, the probability of choosing alternatives (level 2 or 3) was higher against the current state (level 1). table 4 summarizes the mwtp calculation results based on the coefficient estimates of cl for each attribute and level. first, we confirmed the mwtp of an additional entrance fee of about 6000-9000 krw for each attribute and level in general. despite the relatively low mwtp for child-friendly restrooms and children's vehicles, it is still more than 5000 krw (=4.22 usd), which is still more than five times the current admission fee of 1000 krw (=0.84 usd). second, among the suggested attributes, the highest mwtp was seen for a specialized course that young children can actively enjoy (level 1 â�� 3). however, the difference in mwtp for each attribute was not statistically significant. third, in general, the mwtp of the third level was higher than that of the second level, so the more investment in facilities and services is made, the higher the preference. again, there was no statistically significant difference between levels. in the case of the rest areas, it was found that among the attributes belonging to the third level, indoor rest areas had less mwtp than in the second level. the present study seeks to establish a tourism destination management strategy centered on young children for accessible tourism from a public perspective. preferences for facilities and services for young children were identified using ces. the study site was hwaseong fortress, a unesco world heritage site, located in suwon city, a leader in the clean restroom culture. the main implications of the study are as follows. first, the wtp for child-friendly tourism facilities and services was high. according to existing research, the weak immune systems of young children leads to increased concerns about environmental hygiene and health. in addition, young children's physical constraints lead to high demand for convenient mobility and comfortable rest [3, 4] . the results show that the wtp for each attribute and level was about 5-9 usd. considering that the admission fee for hwaseong fortress is about 1 usd, the high preference for facilities and services for young children was confirmed, as seen in previous studies [3, 4, 11, 12] . a small fee is required for rides, but restrooms and rest areas are generally free. nevertheless, the generally high wtp reflects the desire for improved facilities and services for young children. second, an examination of attributes indicated that the wtp was found in the decreasing order of specialized courses for young children, rest areas, restrooms, and vehicles. respondents showed the highest wtp for level 3 of a specialized course for young children, which aims to develop a special zone or course that young children can actively enjoy. a key characteristic of young children's tourism is to emphasize primary needs such as hygiene and safety [4] . in particular, it is necessary to engage young children who have difficulty understanding the historical value of hwaseong fortress in simple play activities and games that utilize amusing characters and colors, in order to stimulate their interests. third, wtp was higher for outdoor rest areas than indoor rest areas. the outdoor-oriented hwaseong fortress has rest areas in the form of unroofed benches that may not be appropriate as resting areas for young children since they do not shield out the sunlight and rain. level 2 is an outdoor rest area that adds shades to existing outdoor benches, and level 3 is an indoor rest area equipped with air conditioning and air purifiers. the results indicate that level 2, the supplementation of existing outdoor rest areas, was most preferred. this preference implies that visitors to the outdoor tourist destination of hwaseong fortress prefer to relax in outdoor areas rather than stay indoors for long periods of time. fourth, with regards to restroom facilities, wtp was high for child-friendly restrooms including hot water, diaper changing stations, and child-friendly toilets and sinks. although suwon is a leader in restroom culture, these results point to insufficiencies in tourism facilities and services for young children. for example, more careful management of the height of sinks as mentioned in kto's guide is needed [36] . interestingly, the preference for installation of young children's facilities and services in both male and female restrooms was higher than for in female restrooms only. the recognition of only mothers as the main caregivers of young children, and the provision of child-friendly facilities and services in female restrooms only, imply the need for improvement in gender parity in young children's care facilities. fifth, whereas mwtp for level 2 (convenience) and 3 (convenience and fun) for children's vehicles was smaller than for other attributes, wtp was still five times that of the current admission fee. nyman and others also cited accessibility as an important factor for travel decision-making for tourists with young children [40] . the difference between level 2 and level 3 was very small, and the preference for providing fun in addition to convenience was not large. the various linked resources within the open spaces of hwaseong fortress create long travel distances. as accompanying young children have limitations in walking long distances, as compared to adults, there is a large preference for rides that enhance convenience. the provision of ride services is particularly important at a destination such as hwaseong fortress, which has long travel distances and limited accessibility for young children. in addition, the hygienic management of these vehicles utilized by young children will be important, particularly in the era of covid-19. the present study has significant practical implications in that the preferences for facilities and services for young children at tourist destinations was estimated using ces, and tourists' priorities were identified from a public perspective. previous studies on young children's tourism focused mainly on the importance of tourism for young children, and key factors in tourist destination choices. in contrast, the present study examined more specifically preferences for levels of facilities and services as a key factor in choosing a tourist destination. this is useful in terms of tourism destination management for young children. due to the covid-19 pandemic, the importance of health/hygiene management strategies is growing. based on the results, the following suggestions for a tourism destination management strategy for young children can be provided. first, child-friendly restrooms have become a necessity, not just a preference, in a covid-19 tourism environment in which cleanliness is most important [35] . in particular, convenience facilities for children should be installed in both men's and women's restrooms, not in women's restrooms only. in addition, not only installation but also continuous cleanliness management is required. second, it is necessary to install rest areas suitable for outdoor tourist attractions. the existing resting space for children was mainly a private indoor space for baby feeding and diaper changing. however, in outdoor spaces, since the distance that children can move around is short and they have to take frequent breaks, the preference for basic rest areas with more benches and awnings was rather high. therefore, maintenance of outdoor rest areas with improved convenience is required. third, the effort to minimize crowding during the covid-19 era is emerging as a top priority at tourist destinations. minimizing contact is particularly relevant for young children with weak immune systems. the present study showed the highest preference for specialized courses for young children. not only can this lead to more attractive tourist destinations for young children, but also be a zoning strategy that separates adult tourists from young child tourists as a response to covid-19. in addition, convenience vehicles such as strollers and wagons can also serve to provide a private space by separating young children from other adults. the present study focused on child-friendly tourism facilities and services including restrooms, children's vehicles, rest areas, and specialized courses. there are other important factors in the dimension of tourism destination management such as programs and information provision that need study. for example, preferences for various levels of information provision can be analyzed. it is possible to consider an information map or app for caregivers of young 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polyomaviruses-associated respiratory infections in hiv-infected and hiv-uninfected children date: 2014-10-28 journal: j clin virol doi: 10.1016/j.jcv.2014.10.013 sha: doc_id: 320156 cord_uid: xs936r6u background: two recently discovered polyomaviruses (pyv), wu and ki, have been identified in respiratory-tract specimens from children with acute respiratory infections, although there are limited data in hiv-infected children. objectives: to determine the prevalence and clinical manifestations of wupyv and kipyv-associated lower respiratory tract infections (lrtis) hospitalization in hiv-infected and -uninfected children; and probe the role of pneumococcal co-infection. study design: nasopharyngeal aspirates were collected from a cohort of 39,836 children randomized to receive 9-valent pneumococcal conjugate vaccine (pcv9) or placebo when hospitalized for lrtis, and were screened by pcr for wupyv, kipyv and other respiratory viruses. results: in placebo-recipients the prevalence of wupyv was 6.3% (18/285) in hiv-infected and 13.9% (66/476) in hiv-uninfected children (p = 0.002). in wupyv-positive lrtis hiv-infected children had lower oxygen saturation at admission and a higher case fatality rate (11.1% vs. 0%; p = 0.04). kipyv was identified in 10.2% (29/285) of hiv-infected and in 7.4% (35/476) of hiv-uninfected placebo-recipients with lrtis (p = 0.13). hiv-infected compared to hiv-uninfected children with kipyv-positive lrtis had lower oxygen saturation, higher respiratory rate and longer duration of hospitalization. co-infections with other respiratory-viruses were detected in 65.5% of wupyv-positive lrtis and in 75.0% of kipyv-positive lrtis. among hiv-uninfected children, there was a lower incidence of hospitalization for clinical pneumonia episodes in which kipyv (80%; 95% ci: 41, 93) and wupyv (49%; 95% ci: 9, 71) were identified among pcv9-recipients compared to placebo-recipients. conclusions: polyomaviruses were commonly identified in hiv-infected and -uninfected children hospitalized for lrtis, frequently in association with other viruses and may contribute to the pathogenesis of pneumococcal pneumonia. lower respiratory tract-infections (lrtis) are a major cause of hospitalizations during childhood [1] . determining pathogen specific causality of lrtis is hampered by lack of sensitive methods for diagnosing bacterial pneumonia, as well as the concurrent identification of multiple respiratory-viral pathogens, particularly when using molecular assays [2] . nevertheless, worldwide studies attribute a large proportion of lrtis to viral infections [3, 4] . largescale molecular screening based technologies have contributed to the discovery of new infectious pathogens, including in 2007 two polyomaviruses (pyv), wu-and ki-polyomavirus [5, 6] . these pyv belong to the polyomaviridae family and have been associated with respiratory disease in humans, although direct evidence of causality is lacking [7] . two other polyomaviruses (bkpyv and jcpyv) have been implicated in disease in immunocompromised patients [8] [9] [10] . there are, however, conflicting data with regard to the role of wupyv and kipyv in immunocompromised individuals [11] [12] [13] . previous studies have used pneumococcal-conjugate-vaccine (pcv) randomized placebo-controlled trials (rct) as a probe to establish the probability of co-infections by streptococcus pneumoniae (pneumococcus) vaccine-serotypes and respiratory-virus in children hospitalized for pneumonia [14, 15] . the rational of this approach is that any biological-plausible difference between pcv-and placebo-recipients in the incidence of any disease which could be associated with vaccine-serotype pneumococcal infection would indicate a role of vaccine-serotypes in the outcome of interest (for review [16] ). for example, we have previously reported that pcv-recipients, had a 45% lower incidence of pneumonia hospitalizations in which influenza-virus was identified, and as such concluded that at least a similar proportion of the influenza-associated pneumonias among placebo-recipients was precipitated by co-infection with pcv-serotypes [14] . the aim of this study was to determine the burden and clinical features of wupyv and kipyv infections in hiv-infected and hiv-uninfected children hospitalized for lrtis. furthermore, as an exploratory analysis we used the design of a rct of a 9-valent pcv (pcv9) to probe whether pneumococcal co-infection may contribute to hospitalization for pyv-associated pneumonia. we analyzed respiratory specimens collected from children who participated in rct in south africa as previously described [14, 17] . briefly, 39,836 children were randomized (1:1) from 1998 to 2000 to receive 3 doses of pcv9 or placebo [17] . hospitalbased surveillance for all-cause hospitalization was undertaken, all hospitalized children underwent hiv testing [17] . nasopharyngeal aspirates (npas) were obtained from children hospitalized with lrtis for identification of selected respiratory-viruses [14] and archived from february 2000 onward. in this study only npas collected from february 2000 to january 2002 from children <2 years old were analyzed. if a child had recurrent lrti hospitalizations, only npas collected >28 days apart were included in the analysis. these samples had been previously investigated for respiratory syncytial virus (rsv), influenza a/b, parainfluenza viruses (piv) and adenovirus using immunofluorescence and for humanmetapneumovirus (hmpv) by nested-pcr, as described [14, 15] . archived npas were tested by real-time reverse transcriptase-pcr (rrt-pcr) using the primers and probes as described [18] . we tested for wu-and ki-polyomavirus, as well as for human-bocavirus (hbov), human-rhinovirus (hrv), and four human-coronaviruses (cov). a comprehensive overview of the identified individual viruses has been reported separately [18] . the current analysis details the epidemiology of wupyv and kipyv-positive lrtis in the study cohort. the clinical definitions used in this study have been described [14] . the analyses on the epidemiology of wupyv and kipyv in children hospitalized for lrtis were restricted to placebo-recipients in the context of the initial trial [17] . proportions were compared by chi-square or fisher's exact tests and continuous variables by student's t-test or mann-whitney test. regression analyses were performed to compare clinical features between hiv-infected and -uninfected children. multiple regressions were controlled for age at hospitalization, detection of a virus previously-tested and year of collection. in an exploratory analysis using the concept of vaccine-probe studies [14, 19] , we explored whether there was any association between pcv9 and the risk of hospitalization for lrtis in which wupyv or kipyv were detected by estimating vaccine efficacy (ve) based on the formula: incidence rate in the unvaccinated − incidence rate in the vaccinated incidence rate in the unvaccinated × 100 children were included in the per-protocol analysis if they received all the study-vaccines as per planned schedule and the lrti event occurred >14 days after the third dose of study-vaccine. only the first episode of viral detection was included in the ve calculation for an individual participant. p-values <0.05 were considered significant. analyses were performed using stata version 12.1 (college station, tx, usa). a total of 1460 npas were analyzed by rrt-pcr, including 699 from pcv9-recipients (48.8%) and 761 (52.1%) from placeborecipients [18] . wupyv was detected less frequently in hiv-infected (6.3%) compared to hiv-uninfected children (13.9%, p = 0.002) ( table 1) . one hiv-infected and three hiv-uninfected children had at least two episodes of wupyv-positive lrtis more than 28 days apart. among hiv-uninfected children, wupyv was generally detected concurrently with other respiratory-viruses (72.7%), which was at a higher frequency compared to hiv-infected children (38.9%, p = 0.005) ( table 1 ). the most common co-detected viruses were hrv (31.8%, n = 21), hbov (16.7%, n = 11), rsv (12.1%, n = 8) and hmpv (10.6%, n = 7) in hiv-uninfected children; and hrv (27.8%, n = 5) and kipyv (16.7%, n = 3) in hiv-infected children. by multivariate analysis of wupyv-associated lrtis, hivinfected compared to hiv-uninfected children were more likely to have oxygen saturation <90%, present clinicallyas pneumonia f other laboratory investigations assessed that were not significantly different between hiv-infected and hiv-uninfected children included: percentage of children presenting with c-reactive protein levels ≥40 mg/l or procalcitonin levels ≥2 ng/ml and mean white cell count. g streptococcus pneumoniae was isolated from one hiv-infected child and in two hiv-uninfected children in whom wupyv was detected. h bacteria isolated from hiv-infected children in whom kipyv was detected included: streptococcus pneumoniae (n = 3), escherichia coli (n = 2) and haemophilus parainfluenzae (n = 1). rather than bronchiolitis. pneumococci were isolated by blood culture in one hiv-infected child and two hiv-uninfected children with wupyv-associated lrti (table 1) . hiv-infected (11.1%) compared to hiv-uninfected children (0%, p = 0.04) had a higher case fatality rate (cfr). the two hiv-infected children who died were 13 and 15 months old, both presented with pneumonia and wupyv was the only respiratory-virus identified, neither had evidence of bacteraemia nor pulmonary tuberculosis and the one child tested for pneumocystis jiroveci (pcp) infection was negative (table 2) . kipyv was detected in 10.2% of the specimens available from hiv-infected and in 7.4% from hiv-uninfected children (p = 0.13) ( table 1) . recurrent kipyv-associated lrti episodes occurred in five hiv-infected children, including three children with two episodes each, one child with 3 episodes and one child with 5 episodes. there was a single hiv-uninfected child with two kipyv-positive lrtis. identification of kipyv was perennial, albeit uncommon during november and december 2001 (fig. 1) . there was a lower prevalence of kipyv detection in 2000 compared to 2001 among hiv-infected (6.6% [13/198] kipyv was frequently detected in combination with other respiratory-viruses in both hiv-infected (75.9%) and hivuninfected children (74.3%) ( table 1 ). in hiv-infected the most common co-detected viruses included hrv (51.7%, n = 15), wupyv and hmpv (10.3%, n = 3 each). in hiv-uninfected the most common viruses associated with kipyv were hrv (31.4%, n = 11), hmpv (14.3%, n = 5) and wupyv (11.4%, n = 4). hiv-infected compared to hiv-uninfected children with kipyvassociated lrtis were more likely to have oxygen saturation <90%, higher respiratory rate, longer duration of hospitalization (median [range]: 5.0 days vs. 1.0 day [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] ; p = 0.008) and were more likely to have alveolar consolidation on chest x-ray (cxr-ac) and concurrent bacteraemia (table 1) . pneumococci were isolated from three hiv-infected children. four hiv-infected (13.8%) and two hiv-uninfected (5.7%) children in whom kipyv was detected died during hospitalization. hiv-uninfected children with kipyv-associated lrti who died compared with those who survived were younger (3 vs. 12 months; p = 0.03). both hiv-uninfected children, aged 3 months, presented with pneumonia, had co-infections with other viruses and one child (who was malnourished) also had pcp infection (table 2) . of the four hiv-infected children who died, kipyv was the only respiratory-virus identified in two of them although at least one was co-infected with pcp. overall, five of the six children who died had indirect markers of bacterial infection, including three hiv-infected with raised c-reactive protein and procalcitonin levels (two of whom also had escherichia coli bacteraemia) and the other two (one hiv-infected and one hiv-uninfected) with cxr-ac ( table 2) . as an exploratory analysis the effect of pcv9-vaccination on the incidence of polyomavirus-associated pneumonia hospitalizations was evaluated. in fully vaccinated hiv-uninfected children, the incidence of wupyv-positive clinical pneumonia hospitalizations was 48.5% (95% ci: 9.1, 70.8) lower in children who received pcv9 compared to placebo-recipients (table 3) . a similar ve pointestimate was observed in cases restricted to episodes in which wupyv was the sole detected virus (45.4%, 95% ci: −47.6, 79.8). there were also reductions in the incidence of hospitalization for kipyv-associated clinical pneumonia in pcv9-recipients compared to placebo-recipients overall (51.3%, 95% ci: 14.5, 72.3) and specific in hiv-uninfected children (80.0%, 95% ci: 41.4, 93.2). similar reductions were observed when kipyv was the only identified virus (table 3) . no differences in incidence were observed between pcv9-and placebo-recipients in hospitalizations for wupyv-or ki-associated clinical pneumonia in hiv-infected children and in hospitalizations for wupyv-or kipyv-associated bronchiolitis. to our knowledge, this is the most detailed report on the prevalence and clinical features of lrtis where polyomaviruses were detected in hiv-infected and -uninfected children. among hospitalized hiv-infected children, wupyv was detected in 6% of the cases and kipyv in 10%. in hiv-uninfected children the prevalence of wupyv was 14% and of kipyv was 7%. in hiv-infected children 11-14% of the cases positive for at least one polyomavirus were fatal and in 67% (4 cases in total) of these wupyv or kipyv were identified as single-detections. our study also established a possible interaction between polyomaviruses and pneumococcus in hiv-uninfected children, although this may have been masked in hiv-infected children in whom pcv9-vaccination was demonstrated to be less efficacious against pneumonia [17] . wupyv was detected in 9% of respiratory samples from children presenting with upper or lrti in germany, 7% in south korea and south africa and 6% in thailand; kipyv has been identified in 1-6% of children presenting with respiratory-tract infections [12, 13, [20] [21] [22] . another study from south africa reported that 57% of 21 children with lrtis with wupyv and 33% of 3 with kipyv were hiv-infected, however, the hiv-status was unknown in 50% of the cases [12] . in that same study, both polyomaviruses were table 3 differences in incidence of wupyv and kipyv-associated lower respiratory tract infections between fully-immunized children who received 9-valent pneumococcal conjugated vaccine and placebo recipients; per-protocol analysis. absent among 50 healthy immunocompetent controls [12] . the role of wu/kipyv as more serious pathogens in immunocompromised individuals is uncertain. higher viral loads of pyv were documented in lymphoid tissues and in the brains of hiv-infected adults compared to those from immunocompetent individuals [23, 24] . similarly higher kipyv viral loads were found in respiratory-tract specimens from haematology/oncology paediatric patients with respiratory infections, however, whether the viral loads correlated with disease severity was not established [13] . these observations suggest that there may be more viral replication and/or that polyomaviruses might reactivate in immunosuppressed individuals, implying that t-cell impairment might be a factor in facilitating polyomavirus replication. norja et al. found that wu/kipyv detection on respiratory samples occurred predominantly in two groups of subjects: immunocompetent <2 years of age with lrtis (7%) in whom there was a high frequency of co-infection (75%), and among older, generally immunocompromised individuals without respiratory illness (11%) or with mild upper respiratory-tract infections (7%) [7] . although our study was not designed to establish whether polyomavirus infections caused more severe disease in hiv-infected children, among hospitalized children in whom polyomaviruses were detected hiv-infected were more likely to present with pneumonia rather than bronchiolitis, had a longer duration of hospitalization and higher cfr compared to hiv-uninfected children. similar observations have been detected between hiv-infected and hiv-uninfected children for other viruses [18] , and consequently may not necessarily infer causality for polyomaviruses precipitate more severe illness in hiv-infected children. the increased morbidity and mortality in hiv-infected children could have been related to other co-morbidities such as bacterial or other non-viral co-infections. in the absence of sensitive tools for diagnosing bacterial pneumonia, as well as lack of investigating for other non-viral causes of pneumonia, our study is unable to conclude the actual role of polyomaviruses to more severe disease in hiv-infected children. nonetheless, the higher cfr, as well as that four fatal cases with polyomavirus as the sole respiratory-virus detected were all hiv-infected children suggest a possible association of polyomavirus causing severe disease in hiv-infected. furthermore, five hiv-infected children had recurrent kipyv-positive lrtis compared to only one hiv-uninfected child. this could have been due to extended viral shedding, viral reactivation or reinfection. a study from germany detected kipyv dna in the respiratory-tract of an immunocompromised child for 7 months and hypothesized that a kipyv infection during childhood could result in latency of the virus in normal individuals, however, an immune impairment could result in viral reactivation [25] . in 2001 the detection rate of kipyv in hiv-infected children was higher than in 2000 this may be because of the older cohort in 2001, hence possibly different risk of infection, or differences in year-to-year epidemics. the concept of a vaccine-probe analysis was initially used in attributing the contribution of haemophilus influenza-type b in the aetiology of radiological-confirmed pneumonia, as well as subsequently in pcv trials [14, 16, 19] . we have used the same approach in probing the likelihood of co-infection by pcv9-serotypes in children hospitalized for pneumonia associated with influenza virus, piv and hmpv [14, 15] ; and we demonstrated that 44-58% of children hospitalized for pneumonia-associated with these viruses were likely to have pneumococcus co-infection [14, 15] . using this type of analysis, our study suggests that co-infections with pcv9serotypes contribute to hospitalizations for clinical pneumonia in which wu/kipyv were identified. the imputed rate of coinfection of pneumococci in children with polyomaviruses-positive pneumonia from our study provides a conservative estimate of this possible interaction as only 9 serotypes were included in the vaccine and ve even against vaccine-serotypes pneumococcal pneumonia was not 100%. the high ve estimate for kipyv-positive disease needs to be contextualized within the wide uncertainty bounds of this estimate. the suggested interaction between polyomaviruses and pneumococcus warrants further study. high co-infection rates with other respiratory-viruses were found for wupyv and kipyv which are similar to previous reports [6, 13, 20] . in the absence of a control group of children without lrtis a definitive causal relationship between polyomavirus detection and disease could not be inferred and this constitutes a limitation of our study. another limitation of our study is that we relied on npas, where identification of an organism does not necessarily imply infection. also in our study the hiv-infected children were not treated with anti-retroviral treatment (art), which may have contributed to their clinical course and may differ to hiv-infected children treated with art. determining the aetiology of pneumonia remains a challenge, especially in children and the pathogenic potential of some of the newly-described respiratory-viruses is difficult to address in the context of multiple infections and without specific symptoms. although polyomaviruses were frequently detected in children hospitalized for lrtis in our study, further studies which include autopsy samples from fatal lrti cases, lung aspirate ant-mortem and also enrolment of healthy controls [26] , are required to clarify the role of polyomaviruses in the pathogenesis of pneumonia. global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis etiology of community-acquired pneumonia in 254 hospitalized children viral infections of the lower respiratory tract: old viruses, new viruses, and the role of diagnosis viral pneumonia identification of a third human polyomavirus identification of a novel polyomavirus from patients with acute respiratory tract infections no evidence for an association between infections with wu and ki polyomaviruses and respiratory disease human polyomavirus (bk) infection and ureteric stenosis in renal allograft recipients renal failure due to bk virus infection in an immunodeficient child cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy polyomaviruses ki and wu in immunocompromised patients with respiratory disease human polyomaviruses: wu and ki in hiv exposed children with acute lower respiratory tract infections in hospitals in south africa wu and ki polyomavirus infections in pediatric hematology/oncology patients with acute respiratory tract illness a role for streptococcus pneumoniae in virus-associated pneumonia pneumococcal coinfection with human metapneumovirus use of vaccines as probes to define disease burden a trial of a 9-valent pneumococcal conjugate vaccine in children with and those without hiv infection clinical epidemiology of bocavirus, rhinovirus, two polyomaviruses and four coronaviruses in hiv-infected and hiv-uninfected south african children randomised trial of haemophilus influenzae type-b tetanus protein conjugate vaccine [corrected] for prevention of pneumonia and meningitis in gambian infants presence of the newly discovered human polyomaviruses ki and wu in australian patients with acute respiratory tract infection wu polyomavirus in children with acute lower respiratory tract infections prevalence and molecular characterization of wu/ki polyomaviruses isolated from pediatric patients with respiratory disease in thailand reactivation and mutation of newly discovered wu: ki, and merkel cell carcinoma polyomaviruses in immunosuppressed individuals wu and ki polyomaviruses in the brains of hiv-positive patients with and without progressive multifocal leukoencephalopathy prolonged ki polyomavirus infection in immunodeficient child pneumonia etiology research for child health. introduction this work is based upon research supported in-part by the south african research chairs initiative of the department of science and technology (dst) and national research foundation (nrf) in vaccine preventable diseases. additional funding support was received from the national health laboratory service research fund and medical research council (respiratory and meningeal pathogens research unit). any opinion, findings and conclusions or recommendations expressed in this material are those of the author(s) and therefore the nrf and dst do not accept any liability with regard thereto. mcn had financial support from the university of the witwatersrand. the authors thank the essential contribution of the members of the vaccine trialist group [17] for their involvement in the original study, all the trial participants and all rmpru staff involved in the study. the authors also thank john w. rossen for technical assistance and biomérieux south africa for providing reagents. the authors have no conflicts of interest to disclose. the main efficacy trial and subsequent retrospective analyses were approved by the human research ethics committee (hrec) of the university of the witwatersrand. signed written informed consent was obtained from the parent/legal guardians as part of the trial. hrec did not require additional consent for this analysis. the main study was not registered under any clinical trial registry as it was undertaken prior to registration being mandatory. key: cord-341208-vlzbri33 authors: narzisi, antonio title: handle the autism spectrum condition during coronavirus (covid-19) stay at home period: ten tips for helping parents and caregivers of young children date: 2020-04-01 journal: brain sci doi: 10.3390/brainsci10040207 sha: doc_id: 341208 cord_uid: vlzbri33 covid-19 has become pandemic [...]. covid-19 has become pandemic [1] and many government decrees have declared restrictive measures in order to prevent its wider spread. for parents and children, staying at home is one of these measures. in this situation the handling of young children with special needs such as autism spectrum condition (asc) could be challenging for families and caregivers. usually these children have interventions for several hours a week at home with special therapists or in dedicated hospitals and institutes. however at the moment, due to contagion containment measures, both the families and the asc children are not physically supported by their therapists and they cannot attend the outside interventions. these measures, necessary for the health of all of us, need to be carefully handled to avoid an increase in parental stress and an exacerbation of children's behavioral problems. asc is a severe multifactorial disorder characterized by an umbrella of specific peculiarities in the areas of the social communication, restricted interests, and repetitive behaviours [2] . the incidence of asc is worldwide and recent epidemiological data estimated it to be higher than 1/100 [3, 4] . the main aim of this editorial is to give some advice, summarized in 10 tips, to help families to handle children with asc during this period. children with asc have a concrete cognitive style and some of them can have serious verbal issues and show difficulties in phenomenological perception [5] . it is important to explain what covid-19 is and why we all have to stay at home. the explanation has to be simple and concrete. for this purpose it is possible to appeal to augmentative alternative communication (aac). it is also possible to ask for help from therapists in preparing a brief pamphlet titled 'what is covid-19?' using individualized aac strategies. for verbal young children the explanation should be supported with concept mapping to make it easier for the child to understand. it is widely reported that children with asc have executive functioning deficits [6] and they could show issues in planning their daily life activities, especially when their routine is broken. for this reason it is important, especially now, to structure daily life activities. the home is the unique setting in which activities take place. it would be useful to subdivide the daily activities, assigning a different room for each one of them. this structure can be useful not only for children with asc who are low and/or middle functioning but also for those who are high functioning. this can be an activity to share with the entire family as a type of game. using a blackboard, each member of the family can have his space to write the planned activities. children with asc enjoy playing, but they can find some types of play difficult because of sensory issues or because they prefer structured or semi-structured activities [7] . during the day it will be important to handle play activities. these can be individual and/or shared. choose activities that your child prefers. for example, lego therapy [8, 9] could be a good solution for children with asc who are low or high functioning. lego-based therapy is an increasingly popular social skills programme for children and young people with social communication problems such as asc. it can be a semi-structured play activity shared with parents or siblings in a home setting [10] . serious games can be useful to improve social cognition and to recognize facial emotions, emotional gestures, and emotional situations in children with asc [11] . serious games can be a fundamental resource for asc children. many serious games are free and can be downloaded as an app for tablet and/or pc from specialized sites. serious games could be an educational alternative to video games or the internet tout-court. video games and the internet are extremely attractive for children with asc but they could become an absorbent interest [12] , especially in this period when children are called to stay at home. it is not possible to avoid children playing with the computer but at the moment, when parents are also at home, it could be useful establish a rule whereby children are expected to share the video games/internet (with parents, siblings, or other caregiver). this could avoid a potential risk of isolation of the child and an internet addiction. special interests can be a characteristic of the people with asc. there is a growing amount of evidence recognizing the potential benefits that special interests can bring [13] . special interests have to be supported from parents and/or caregivers. trains, maps, animals, comic books, geography, electronics, and history can be just a few of potential special interests. in this period in which parents and children stay at home they could plan some activities sharing these special interests. it is well recognized that psychiatric vulnerabilities and/or comorbidities are high in children with asc. among these comorbidities anxiety disorder is one of the most reported [14] . psychiatric comorbidities could contribute to a developmental breakdown especially in adolescence age. the actual state of alert for covid-19 could be an event that is difficult to mentalize for children with asc. for this reason, if the children were engaged in psychotherapy before the covid-19 alert, it is very important that they continue it. since many therapists have stopped their face-to-face therapy, it is strongly advised to continue the psychotherapy in an online video or audio modality with the same weekly appointments. it could reduce the anxiety, check the mood, and offer to the children a private space in which to talk with a specialist. parents of children with autism experience more stress and are more susceptible than parents of children with other disabilities [15] . at the moment, parents are alone in the handling of their children with asd. this can represent a further high risk for their stress levels, which are already severely tried. for this reason it can be very useful to have the opportunity for a weekly online consultation with the therapists of their children. it is valid for parents of both low-and high-functioning children. in the case of low functioning, parents could share a brief home video with the therapists about the behavior of the children during free play or structured sessions at home. in the case of children who are high functioning the consultation could be a dialogical exchange focused on the most appropriate ways to manage this difficult time of covid-19 alert and to update parents about the degree of coping strategies of the children. a growing body of research supports the suggestion that the relationships which children form with their teachers and classmates have an impact on learning [16] . it is very important to dedicate a time slot for the homework. this is a routine that has to be maintained. for the maintenance of social contacts with the school companions it is suggested to have at least a weekly contact with one of the class companions. the modality of this contact should depend from the child's preferences. it could be an online video for those that prefer it. for children with asc who do not prefer to use video for online contacts they could be encouraged to write a letter to one of their school companions or to call them via phone [17] . for both children and parents, it is strongly encouraged to maintain contact with a special teacher online or by phone. children with asc have to be stimulated, as pointed in tips 1-9, but it is also possible be leave them a proper quota of spare time during the day (e.g., take a short walk near the house). in this period children could have an increase in stereotypies. this does not need to be a particular concern. at the moment, when habits are changing, the stress levels can be elevated for children with asc and the increase of stereotypies could be the behavioral result of perceived stress. they will certainly not regress. these suggestions are obviously not exhaustive but they could represent a useful help for parents and/or caregiver of children with asc to handle the severe situation caused covid-19 and to optimize the person-environment fit. covid-19 is questioning the routine of our young children with asc and they are called to respect rules and habits that are not always understandable for them (i.e., disinfect your hands, do not touch your eyes or nose, and cover your mouth. they are also not able to see people they would like to meet and must stay at home). these changing routines could cause them profound suffering. for this reason we all (parents, therapists, and researchers) must be united and quickly establish new and functional routines to allow our young children to be safe and peaceful. as asc experts we have to find different ways to be close to our patients and their families. i wish to conclude this editorial by citing and sharing a sentence from italian colleagues currently engaged in the emergency medical system in milano: "the italian public health authorities has just started to fight a battle that must be won" [18] . the author declare no conflicts of interest. covid-19: time for who to reconsider its stance towards taiwan diagnostic and statistical manual of mental disorders years-autism and developmental disabilities monitoring network, 11 sites, united states prevalence of autism spectrum disorder in a large italian catchment area, a school-based population study within the asdeu project when the world becomes 'too real': a bayesian explanation of autistic perception neuropsychological profile in high functioning autism spectrum disorders sensory processing issues and their association with social difficulties in children with autism spectrum disorders evidence-based support for autistic people across the lifespan: maximising potential, minimising barriers, and optimising the person-environment fit use of lego as a therapeutic medium for improving social competence maternal experience of lego therapy in families with children with autism spectrum conditions: what is the impact on family relationships? interactive technologies for autistic childre: a review cost action network, chamberlain sr. manifesto for a european research network into problematic usage of the internet we can see a bright future": parents' perceptions of the outcomes of participating in a strengths-based program for adolescents with autism spectrum disorder prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis report: stress and perceived social support in parents of children with asd interpersonal behaviors and complementarity in interactions between teachers and kindergartners with a variety of externalizing and internalizing behaviors feasibility of autism-focused public speech training using a simple virtual audience for autism spectrum disorder the response of milan's emergency medical system to the covid-19 outbreak in italy key: cord-343985-0p2j5hzc authors: self-brown, shannon; reuben, katherine; perry, elizabeth w.; bullinger, lindsey r.; osborne, melissa c.; bielecki, joanne; whitaker, daniel title: the impact of covid-19 on the delivery of an evidence-based child maltreatment prevention program: understanding the perspectives of safecare® providers date: 2020-11-05 journal: j fam violence doi: 10.1007/s10896-020-00217-6 sha: doc_id: 343985 cord_uid: 0p2j5hzc child maltreatment (cm) is a global public health problem. evidence-based home visiting programs, such as safecare®, reduce cm risk, and enhance parent-child relationships and other protective factors. as the result of the covid-19 pandemic and resulting restrictions, safecare providers transitioned from home to virtual delivery for the safecare curriculum. the purpose of this study is to 1) examine active safecare providers’ opinions on the feasibility and effectiveness of safecare via remote delivery, and 2) better understand workforce concerns for human service professionals within the context of covid-19 mitigation efforts. data are from a cross-sectional survey of safecare providers (n = 303) in the united states, canada, and australia. the majority of providers reported they were actively delivering safecare virtually and were comfortable with the delivery format. providers indicated that the majority of safecare families are making progress on target skills, and that engagement is high among many families. some service delivery challenges were reported, ranging from family data plan limitations to difficulty with delivery of specific components of the safecare curriculum related to modeling and assessment. the impact of covid-19 on providers’ daily routines, stress level, and work-life balance has been significant. remote, virtual delivery of cm prevention programming offers the opportunity to continue serving vulnerable families in the midst of a pandemic. barriers related to family technology and data access must be addressed to ensure reach and the effective delivery of prevention programming during the pandemic and beyond. reports in the aftermath (curtis et al. 2000; keenan et al. 2004; self-brown et al. 2013) . further, studies have examined the impact of the 2008 great recession and war time on cm perpetration risk and found increases in harsh parenting and spanking (brooks-gunn et al. 2013 ) and lower levels of parental warmth (eltanamly et al. 2019) . with the world health organization's declaration of covid-19 as a global pandemic (perc et al. 2020) , there is much to learn about how the resulting circumstances will impact cm risk. unlike the community togetherness that often emerges in times of community-wide disaster circumstances, the response to covid-19 across the world has been to mandate physical separation with shelter in place and stay at home orders (campbell 2020) . resulting consequences have included unemployment, reduced income, limited resources, alcohol abuse, intimate partner violence, and limited social support, which are all factors found in prior research to increase cm risk (bright et al. 2018; catalá-miñana et al. 2017; lindo et al. 2018; lowell and renk 2017; paxson and waldfogel 2002; schenck-fontaine et al. 2017) . additionally, many parents are now expected to work from home, which can increase the risk for inadequate child supervision and unintentional child injury (e.g., while parents are working; feely et al. 2020 ). due to covid-19 concerns, parents may also be delaying child medical care, which could result in medical neglect for emerging health issues (santoli et al. 2020; wenner moyer 2020) . with the increased parenting burden many families are experiencing, news reports have indicated that there are increases in calls to parenting helplines. for instance, national parent helpline calls in the united states increased 30% in early april, with calls focused on concerns about child care, food, and other virusrelated stressors (hurt et al. 2020) . anecdotal evidence from the united states, china, brazil, and australia indicate increases in violence to children due to isolation and quarantine (campbell 2020; peterman et al. 2020; van gelder et al. 2020) , and preliminary data from hospitals supports increases in severe child abuse and neglect (cbs dallas fort worth 2020). however, child protection service settings have consistently documented significant drops in reports of cm, especially in countries with similar mandated reporting laws like the united states, canada, and australia (matthews and kenny 2008) . for instance, a recent working paper by baron et al. (2020) calculated the number of child maltreatment allegations in florida and found that in march and april 2020, these were 27% lower (212,500 cases) than would be expected (baron et al. 2020 ). further, whaling et al. (2020) documented that the frequency of case openings in new york city in march 2020 was significantly lower than the frequency of case openings during the same month for the prior 7 years (march 2013-2019; whaling et al. 2020 ). these declines do not likely reflect the true incidence rates, but instead are the result of lower child access to mandated reporters who are typically responsible for approximately 67.3% of child welfare allegations (u.s. d e p a r t m e n t o f h e a l t h , a n d h u m a n s e r v i c e s , a d m i n i s t r a t i o n f o r c h i l d r e n a n d f a m i l i e s , administration on children youth and families and children's bureau 2020). clearly, this is a very complicated time, and children may not be getting adequate protections. given the current circumstances and associated risks, our society runs the risk of a substantial number of children at risk for child maltreatment being unidentified, overlooked, and underserved (whaling et al. 2020 ). vulnerable, high-risk families may be engaged in cm prevention programming following involvement with child protective services or via other referral-based systems that connect families to programming through available community prevention efforts. in the united states, state child protection systems have begun to adopt evidence-based interventions, and recent federal child welfare legislationthe families first prevention and services act of 2017will accelerate the adoption of such programs. the california evidence-based clearinghouse for child welfare (cebc n.d.) rates three programs as "supported" in the area of "parent training to address child abuse and neglect;" two of the three are delivered via home visiting. for broader prevention, the home visiting evidence of effectiveness (homvee; u.s. department of health and human services and administration for children and families n.d.) identifies the quality of home visiting models, based on research evidence, used for broad prevention efforts with pregnant women and children from birth to kindergarten entry. similar dissemination efforts are ongoing in australia (australian research alliance for children and youth 2020; parenting research centre 2020) and canada ; national collaborating centre for determinants of health 2009; romano et al. 2020) . the goals of these programs, whether delivered in child protection or prevention service settings, is to promote childhood health, safety, and development and improve parenting skills and responsible parenting among mothers and fathers, which correspond with decreases in maltreatment risk (howard and brooks-gunn 2009; supplee and adirim 2012) . an additional benefit of many of these programs is the resulting positive parent-child relationships, which are documented as a protective factor in helping children recover from large scale trauma events such as the terrorist attack in the u.s. on september 11, 2001 , (lutz et al. 2007 ), war (eltanamly et al. 2019) , and natural disasters (e.g., hurricane katrina; salloum and lewis 2010), and could be a protective factor in the covid-19 pandemic. collectively, evidence-based home visiting programs reach hundreds of thousands of vulnerable families a year in the united states alone (national home visiting resource center 2019). while these services are certainly needed during the covid-19 pandemic to address the increased family risk, the continuation of home visiting services has been difficult due to concerns for worker and family safety (crary 2020; hardison 2020; kelly and hansel 2020) . home visits were suspended in many u.s. states and abroad, and consequently, numerous evidence-based home visiting programs have been exploring the use of virtual session delivery via telephone and/or video communication in lieu of face-toface home visits (health resources and services administration and maternal and child health bureau 2020; national alliance of home visiting models 2020). in recent years, there has been growing evidence for the effectiveness and acceptability of telehealth and video-based counseling and therapy for children typically developed in clinic settings (nelson and sharp 2016) . however, little is known about how well virtual services can work for parenting programs typically delivered via home visits and there are questions regarding both feasibility and effectiveness. a recent published report that summarizes a survey of evidence-based home visiting programs during the pandemic in the united states, conducted by the home visiting applied research collaborative (harc; o'neill et al. 2020), suggest that multiple modalities are being used to replace in home visits, including interactive video conferencing, telephone, and texting. the most noted challenges regarding feasibility are that families (approximately 50%) do not have stable internet access. this is not surprising given the literature noting issues with a digital divide and the social injustice that not all families have access to the internet and internet-enabled devices (farakas and romaniuk 2020; goldschmidt 2020) . other noted issues for families documented by the survey included parent challenges with having the emotional capacity to engage in programs during the current circumstances and constraints related to confidentiality. for providers, challenges included reduced capacity to deliver curricula effectively given their own home environment issues (o'neill et al. 2020) . the goal of this study is to present findings from a recent survey on the feasibility and effectiveness of virtual delivery of safecare® and to better understand workforce concerns. safecare is a home visiting program designed for parents of children aged 0-5 years and targets proximal risk factors for physical abuse and neglect (self-brown et al. 2014 ). this program is typically delivered weekly in the home over 18 sessions by a trained safecare provider, and includes three modules: child health, home safety, and parent-child interaction. the child health module focuses on helping parents identify symptoms of illness and injury and take appropriate action. training in this module includes parental psychoeducation pertaining to common childhood illness and injury and preventative health care, and parental practice of decision-making steps in response to hypothetical child health scenarios. the home safety module focuses on teaching parents to identify and secure home hazards that pose a danger to children, and to supervise children around unsafe environments. parent training in this module focuses on education to help caregivers identify hazards in their home, and then the active removal of hazards to reduce the risk of child unintentional injuries. the parent-child interaction module seeks to build a positive parent-child relationship. parent training includes psychoeducation followed by providers modeling positive parent-child interactions to the caregiver and then the observation of the caregiver practicing these skills as they engage in daily activities and play with their child. families receive all three modules, which can be delivered in any order. each safecare module is planned for six sessions, though the number of sessions can vary depending on progress. recent evaluations have shown safecare to influence important outcomes, such as parenting behaviors and parenting stress , child maltreatment recidivism (chaffin et al. 2012) , and out-of-home placements (beachy-quick et al. 2018) . safecare providers serve more than 6000 families per year, providing parent training and intervention services that reduce and prevent the maltreatment of young children. when the covid-19 pandemic struck, safecare providers quickly adapted to technology-based delivery, and the purveyors of safecare developed best practice guidelines for virtual delivery to allow for the continuation of services in this very vulnerable time. however, the extent to which providers were successfully able to deliver safecare components is not known. additionally, workforce challenges of service delivery during this time are also largely unknown. thus, this study has two research aims: 1) examine active safecare providers' opinions on the feasibility and effectiveness of safecare via virtual delivery, and 2) better understand workforce concerns for human service professionals within the context of covid-19 mitigation efforts. as an exploratory aim, we examined whether key outcomes for aim 1 and 2 differed according to the safecare provider country of residence or safecare provider experience. results from this study will inform us whether delivering the safecare curriculum to families via technology, rather than solely in-person, is a feasible option for safecare delivery during times where home visiting is restricted (or even if preferred by the client). the present study seeks to fill a gap in the literature and will offer a data-based call to action for examining child prevention outreach during pandemics and beyond. participants for the current study were recruited by email between june 3rd and june 16th of 2020 from a list of active safecare providers registered in the national safecare training and research center's training portal. a total of 1039 email invitations were sent. inclusion criteria were: 1) active safecare providers, which included certified safecare home visitor providers who are currently delivering safecare to families, and active safecare coaches and trainers who are currently supporting safecare providers through certification or in the post-certification process, and may also be delivering safecare to families; 2) provider had a working email address with the national safecare training and research center portal. we excluded safecare providers who reside within the european union from this study, as they were not eligible to participate due to general data protection regulation compliance. in total, 390 individuals viewed the consent form; 303 participants completed all survey sections and compose the final analytical sample for this study. this includes 222 (73.5%) who had attained safecare provider certification and 80 (26.5%) who had completed additional training to become a certified safecare trainer or coach. most safecare providers resided in the united states (n = 286, 94.4%), and the remainder (n = 17, 5.6%) resided in another country (australia, canada). the majority provided services in an urban cluster/suburb (n = 144, 47.8%), while 27.2% (n = 82) provided services in urban areas, and 24.9% (n = 75) provide services in rural areas. the experience level for participants was similar across categories, with 24.4% (n = 74) having less than 1 year of experience, 27.7% (n = 84) reporting one to two years of experience, 22.8% (n = 68) reporting two to four years of experience, and 25.1% (n = 75) having five or more years of experience. this study survey did not include questions related to age or gender. however, based on prior research with safecare providers, it is likely that 90% or more of the providers were female (selfbrown et al. 2017; whitaker et al. 2019) , with an average age of midto late-30's. active safecare providers were emailed an invitation to participate in the survey, along with the survey link, to the address listed in the nstrc portal. those who clicked the link were taken to a qualtrics survey that first presented a consent form, approved by the institutional review boards at the two sponsoring institutions, which provided detailed information about the purpose of the survey and the opportunity to receive a $15 amazon gift card for survey completion. providers who consented to the study were allowed to proceed to the main survey that included questions pertaining to how safecare delivery, the safecare workforce, and safecare families were being impacted by the covid-19 pandemic. the main survey was anonymous and collected no identifying information. participants were given the option to request a gift card by following a link at the end of the survey, which collected participants' names and email addresses. responses were not linked between the main and reimbursement surveys. responses were included in the analysis if they were recorded in qualtrics as 99-100% complete (n = 303), indicating that the participant viewed all pages of the survey. this was done in order to minimize the likelihood that duplicate responses were included in the final analytical sample. safecare covid-19 survey for purposes of the current study, three sections of the survey were examined. all survey items were developed by the authors. first, the demographic questions asked about participants' safecare experience and location of service delivery. the second section inquired about virtual delivery of safecare. questions inquired about the technology capabilities of the families served, the strengths and challenges of remote safecare delivery, technical aspects of remote delivery such as keeping families engaged, and factors that would improve the experience of remote delivery for providers. a third section included questions on how covid-19 was impacting providers, trainers, and coaches in their daily, financial, and emotional lives. specifically, questions were asked about how the pandemic impacted the work of participants, how they were coping, and what could be done to support them during the pandemic. a selection of items from the survey is shown in table 1 . descriptive data from the survey were analyzed in ibm spss 25 (ibm corp. 2017). chi-square analyses were completed to examine if safecare provider country of residence (u.s., canada, or australia) and safecare provider experience (less than 1 year of safecare experience or greater than 1 year experience) was significantly associated with key variables for study aim 1 and aim 2. aim 1 outcomes examined include: provider comfort with safecare delivery; family smart device ownership; family data plan access; providers' opinions of family engagement in virtual delivery and progress on safecare skills. aim 2 outcomes of interest for the chi-square analyses were: impact of covid-19 impact on the daily life; and impact of covid-19 on work hours of safecare providers. open ended responses from the survey were examined by four research team members to identify consistent response themes. where relevant, frequencies of the number of times a theme was listed in open response items were computed using the frequency of the word(s) as numerator and the total number of open-ended responses as the denominator. aim 1: examine active safecare providers' opinions on the feasibility and effectiveness of safecare via virtual delivery the majority of safecare providers (n = 263, 87.1%) indicated they thought that maltreatment risk had increased during the pandemic period, suggesting that finding effective options for continuing prevention programming are imperative. more than half of the participants reported that they had transitioned to conducting all safecare sessions remotely (n = 190, 62.7%), while over a quarter of the sample (n = 92, 30.4%) reported conducting both remote and in-person safecare sessions. in total, 87.1% of participants (n = 255) reported that they had completed a remote session, and 83.1% (n = 24) indicated that they were comfortable with this virtual delivery (39.7% somewhat comfortable, 43.4% very comfortable). approximately 76% of providers (n = 230) reported that they had enrolled a new family in virtual delivery of the safecare program. the most commonly used applications for virtual delivery were zoom (50%), facetime (19%), and google duo (15%). providers overwhelmingly reported using their smartphones for session delivery (n = 202, 66%). in terms of family technology access, participants indicated that the majority of the families they serve own a smart device (n = 258, 87.8%) and reported that the parents they served had the skills to use the smart device to engage effectively in a safecare session (n = 231, 89.9%). providers noted that approximately 21% of the families they serve do not have a sufficient data plan to allow them to use the device effectively for safecare sessions. with regard to virtual delivery feedback specific to the safecare modules, the large majority of participants 85.8% (n = 212) reported that the child health module is similar or easier to deliver virtually than in home visitation. this module focuses largely on parental psychoeducation pertaining to common childhood illness and injury and preventative health care, with a practice component that consists of parents responding to written scenarios for how to best respond to illness and injury scenarios (i.e., treat at home, call the doctor, go to emergency room). conversely, for the other two safecare modules (home safety, parent-child interaction) that both include more active skill modeling and practice in the home environment, the majority of providers indicated a greater difficulty in remote delivery (n = 215, 87.4% for home safety; n = 188, 77.4% for parent-child interaction). results were mixed regarding family engagement in virtual delivery, with 54.3% (n = 139) of participants reporting that safecare session engagement for virtual delivery is either about the same (39% respectively) or better than in-person sessions (15.3% respectively); 45.3% (n = 115) endorsed less engagement than during home visit delivery. safecare provider participants noted a variety of tactics they are utilizing to increase virtual session engagement, including holding sessions at alternate times (n = 230, 75.7%), using texts between sessions to maintain connection (70.4%), dividing or chunking sessions into parts (51.3%), and (19.6%) providing tablets or smart devices to families in need. for this item, an "other" option was included, and some providers also reported, through an open response option, dropping off care packages and scheduling "yard visits" to keep some connection with families in person. participants indicated that families were progressing positively on safecare target skills during virtual delivery, with approximately 60% noting that parent target skill improvement is about the same rate or occurs more quickly as compared to traditional home visit sessions. however, a considerable proportion (n = 98, 40.3%) of providers noted that family improvement was either a bit slower or much slower with remote delivery. when asked for open ended feedback on the successes of virtual delivery, participants shared numerous examples of positive family engagement and progress. for instance, one participant stated, "parents are implementing parent-child interaction skills a lot more since children are home all day. parents especially like to use these skills during play time and homework time." several others included open ended comments indicating that "parents have been engaged," "retention seems higher," "parents like that sessions are less intrusive since providers are not required to be in home," and "clients are completing the modules with success and mastery of target skills." in terms of challenges, open ended comments were largely focused on issues with technology and internet connection, difficulties with the provider modeling parenting and home safety skills for parents, and uncertainty about the accurate assessment of home hazards and hazard removal to promote child safety. none of the chi-square analyses examining aim 1 key outcomes with safecare provider experience or country of residence were found to be significant. safecare experience was not associated with provider comfort with remote delivery overall, covid-19 has had a significant impact on the daily life and habits of safecare providers. the majority of participants (n = 255, 85%) reported a moderate to extreme impact on their own day-to-day lives as a result of covid-19. providers reported that the most impacted daily habits included leaving home less often (n = 253, 83.2%), socializing less often (n = 230, 75.7%), and leaving home only for essential needs (n = 208, 68.4%). the majority of participants also reported increases in caretaking responsibilities for children or a sick loved one (n = 140, 78.2%). in terms of employment and financial impact, participants reported that slowed business for someone in their household (n = 77, 25.3%) and paying bills for things they are not currently using (n = 77, 25.3%), such as daycare, had the biggest impact on their financial security. notably, no providers from outside the us (canadian and australian respondents) reported slowed business or paying bills for non-utilized services as a concern. the majority of participants (n = 226, 75.3%) reported that they did not experience a change in work hours, or they worked the same number of hours but on a different schedule. only 15.3% of providers reported working longer hours. when asked about the biggest ways in which the outbreak has impacted their work, many providers noted the impact of delivering sessions virtually from their home environment as a challenge in terms of maintaining confidentiality of clients being served and home-life balance. for instance, in response to the question "in what ways does covid-19 impact your personal ability to fulfill your role as a provider?", one participant noted, "sessions were conducted in my home and it could be difficult to find a space that would keep confidentiality in place. family members would sometimes walk into the room [where] i was conducting sessions without realizing i was on a call. they did not see the client, but it was a distraction for me as a provider to have to tell them to leave and then ensure to the family that their privacy was not breached." another participant stated, "…having to balance taking care of my son and work. i have to have my son do more things independently while i am doing sessions." similarly, another participant indicated, "balancing work and personal life is a major deal for many of us providers." several providers also noted that they really miss having the personal connection with families that in-person sessions allow. another common response highlighted by several participants acknowledged the challenge of being there for others in a time when everyone is experiencing so much anxiety and uncertainty. for instance, one provider stated, "my personal anxiety level has been high. at times it has been difficult to be positive and helpful when families are struggling." similarly, another provider indicated, "it has been difficult mentally for me to lose contact with friends and family and practicing selfcare, while attempting to continue to help consumers at work." nearly three-quarters of participants (n = 218, 72.0%) reported that they are moderately to extremely concerned about becoming infected with covid-19. a smaller majority indicated they were moderately to extremely concerned about contracting covid-19 through work (n = 215, 67.9%). in open ended responses to the question "how is the outbreak affecting your quality of life and mental state?", approximately 40.2% of participants noted feeling overwhelmed or experiencing anxiety, stress, depression, or worry during this time. in terms of self-care, participants described going for walks (n = 219, 72.0%), connecting with loved ones using technology (n = 213, 70.1%), making meals (n = 197, 64.8%), having more in-person family time (n = 150, 49.3%), doing creative activities (n = 127, 41.8%), and spending time on a hobby (n = 126, 41.4%). two chi-square analyses emerged as significant for outcomes related to the impact of covid-19 on the workforce based on country of residence. notably, providers in the united states were more likely than providers from other nations to be very or extremely concerned about contracting covid-19 (χ 2 [4, n = 303], = 15.75, p = .003). 40.2% of us providers (n = 115) were very or extremely concerned compared to only one provider outside of the us (5.9%). slowed business was especially a problem for providers in the united states (χ 2 [1, n = 303], = 4.58, p = .032), affecting 26.9% of us providers (n = 77); no providers from outside the us reported this as a concern. safecare provider experience was associated with work hour changes (χ 2 [3, n = 300], = 21.09, p = .012); providers who had worked for less than 1 year were more likely to have their hours reduced (12.3% compared to 8.4%) and more likely to have their schedule changed (43.8% compared to 31.3%) than all other providers. covid-19 has increased risk factors associated with cm perpetration worldwide, such as unemployment, reduced income, alcohol abuse, intimate partner violence, and limited social support (bright et al. 2018; catalá-miñana et al. 2017; lindo et al. 2018; lowell and renk 2017; paxson and waldfogel 2002; schenck-fontaine et al. 2017) . while there have been some reports that calls to parent helplines have increased during the pandemic (hurt et al. 2020) , child maltreatment allegations are lower than would be expected for countries with similar mandated reporting laws, like the u.s., canada, and australia, likely due to limited child access to mandated reporters (baron et al. 2020) . evidence-based programs that serve families involved with child protection and prevention service settings have an increasingly broad reach and have been found to reduce risk for cm perpetration and recidivism (chaffin et al. 2012; howard and brooks-gunn 2009; supplee and adirim 2012) . due to covid-19, many of these programs, which are delivered in the home setting were suspended in the u.s. and abroad, resulting in a quick shift to virtual session delivery. this exploratory study examined the feasibility and effectiveness of virtual delivery for one evidence-based program, safecare, by surveying active safecare professionals working in the u.s., australia, and canada. additionally, the study examined current workforce concerns and challenges among safecare providers in the midst of the pandemic. notably, a majority of participants indicated they thought that maltreatment risk would increase during the covid-19 pandemic period. the data are also convincing that providers remained committed to the continued delivery of child maltreatment prevention services during this time, with a substantial number of safecare providers reporting active delivery of virtual sessions. reported rates of safecare virtual delivery were commensurate with what was reported in the larger field of evidence-based home visiting in the recent harc survey report (o'neill et al. 2020) . importantly, most families served by safecare providers do own a smart device and can effectively use them for session participation; however, data plan limitations and internet access for safecare families has negatively impacted active and ongoing participation. recent pew data indicate that approximately 71% of low-income individuals (the majority of safecare families live in low socioeconomic households; whitaker et al. 2020) own a smartphone, but a much smaller percentage (59%) have home broadband access (pew research center 2018, 2019). in contrast, 94% of canadians have home internet access (theckedath 2020) , and australia is actively implementing internet plans for low-income households with school aged children as the result of the pandemic (kidman 2020) . it is imperative that we invest in efforts to remove these logistical barriers for all families to ensure equity and avoid exacerbating negative outcomes amongst the most at risk children and families. global strategies to ensure affordable access to technology and broadband are necessary to prevent increases in access gaps for evidence-based programming, healthcare, and education. there were some discrepancies between safecare provider opinions and responses regarding the feasibility of virtual delivery according to safecare modules. provider responses indicated that the safecare module that is the most didactic, child health, was the easiest to deliver virtually, while the two modules with more modeling and active role play, home safety and parent-child interaction, were more challenging. there is a paucity of literature focused on how well telehealth or virtual delivery lends itself to more active teaching practices, such as modeling, role-play, and behavioral practice, that are critical aspects of evidence-based behavioral parenting interventions (serketich and dumas 1996) and a key aspect of improving target behavioral skills related to child maltreatment prevention. as the need for virtual delivery of programming continues, it will be key for purveyors of programs and service providers to become more systematic in their delivery of virtual programs. purveyors may need to create materials (e.g., video clips) that allow families to view skills that are typically modeled, and create interfaces for families to submit rehearsal examples for review. ironically, this may improve practice beyond in-person delivery as more consistency may emerge in how skills are modeled and reviewed. in terms of family engagement and program effectiveness, safecare providers' responses were mostly positive, suggesting that families are actively engaged and making positive progress in target skills. providers reported several considerations and augmentations they were implementing to ensure positive engagement, with flexibility of session delivery time (evening and weekend delivery) and chunking of one session into multiple shorter sessions being two very commonly implemented strategies. while parent target skill mastery is reportedly taking longer to achieve via virtual delivery, providers reported that parents are continuing to achieve skill mastery and success with this delivery format. interestingly, some providers commented on the increased opportunity that parents have to practice and implement the safecare skills they learn in session during the pandemic, and that the increased time with children appears to positively impact parent motivation to use the skills they are learning. additionally, some providers noted that the virtual delivery is perceived as less intrusive by parent program participants, given they can get the benefit of the service without allowing a provider into their home. virtual delivery challenges were also noted, with the unreliability of technology being the most commonly reported. other challenges include providers struggling with target skill modeling and conducting accurate assessments, given the lack of best practice guidelines for how to navigate these skills over technology. with regard to impact on the workforce, it is clear that safecare providers' daily lives and habits are deeply impacted by the pandemic, especially in terms of home restrictions, decreased socializing, and increased caretaking responsibilities. work responsibilities and finances were reportedly significantly impacted for approximately a quarter of the provider participants. of note, based on the survey responses, u.s. safecare providers' employment, especially related to decreased work hours, were significantly more impacted than canadian and australian providers. emerging literature suggests that rates/projection of unemployment are fairly consistent across the u.s., canada, and australia (approximately 10 to 15%; lemieux et al. 2020) ; however, perhaps human services positions are being differentially impacted. this would not be surprising based on the substantial differences that exist for policy and funding for human services across these countries. as would be expected, providers who were newest to the job were also the most likely to experience reduced or changed hours. safecare providers are concerned about being infected with covid-19 through work, with providers living in the u.s. reporting significantly more concern than their canadian and australian counterparts. despite these fears, safecare providers are clearly engaged in their work and committed to continuing serving their caseloads however possible. this commitment has not been without negative consequences, as the providers reported challenges with work-life balance and with managing their own feelings of anxiety, worry, and depression. importantly, safecare providers reported engaging in numerous positive self-care behaviors. prior research has demonstrated that personal self-care activities play a critical role in reducing burnout and secondary trauma among human service professionals (salloum et al. 2019) . thus, it is critical that supervisors and administrators supporting those working in human services, especially in the midst of this pandemic, are encouraging quality self-care to buffer negative outcomes for these critical professionals. this study is the first to examine the impact of the covid-19 pandemic on the delivery of an evidence-based child maltreatment home visiting program that has transitioned to virtual delivery, as well as the impact of covid-19 on the workforce responsible for delivering these programs. however, there were some limitations to the study. the data were collected with a convenience sample, and approximately 29% of those invited completed the survey. thus, there may be some bias or unanticipated motivations for the percent of providers who completed the survey. for instance, perhaps those that responded were more greatly impacted by the pandemic and resulting circumstances, which made them more willing to participate. or perhaps the converse is true, with those individuals not as impacted by covid-19 having more time and energy to participate in such a survey. unfortunately, this study did not allow for the comparison of provider respondents to non-respondents on any variables that could allow us to determine if there are existing significant differences between groups. the survey was self-reported, and all biases related to this form of data collection are relevant. data collection occurred in june 2020 and may not accurately represent the impact of the pandemic during the most extreme restriction periods, or how the impact of the continued rise of cases in the u.s. occurring in july 2020 and beyond might impact ongoing virtual delivery and the workforce. finally, no family-level data collection occurred, so the reports on family engagement and intervention progress are the subjective impressions of providers and does not offer descriptors of families that were perhaps the most negatively impacted by covid-19 with regard to the outcomes explored. given the risks impacting our world's most vulnerable families during the covid-19 pandemic, it is imperative to ensure effective and sustainable delivery of evidence-based programs that can reduce maltreatment risk for young children. much more research is needed to ensure that virtual program delivery will lead to similar positive outcomes as in-person delivery, as well as an explication of the benefits and challenges associated with this delivery approach. additional evidence supporting the successful virtual delivery of evidence-based cm prevention programming could lead to important benefits for the field as a whole, especially with regard to costs and time burden associated with home visiting program delivery. much more research is needed with the parent consumers of these programs, to assess their feedback and preferences. if some parents prefer this mode of delivery given the higher flexibility and lower intrusiveness, as was suggested by safecare providers who completed the current survey, then our field must respond in moving forward with identifying best practices and addressing challenges involved with virtual delivery. for purveyors of evidence-based cm prevention programming, the results of this survey offer some information on how to best support program providers in transitioning to virtual delivery. first, we must reconsider our messaging about program fidelity. many evidence-based programs have strict requirements for both the program curriculum and process of delivery. if we engage in a shift of the delivery process, then we must ensure that the curriculum is flexible enough to shift across delivery modes and maintain the active ingredients that lead to positive outcomes for parents and families. second, purveyors should consider what supports are needed to ensure effective virtual delivery. offering webinars, connecting providers delivering programming in similar settings (e.g., settings where broadband issues may be greater), and treating best practice guidelines as a fluid document to be revised as lessons are learned, are just a few of the many suggestions the current survey feedback offered. third, it is important to consider which curriculum adaptations are needed to advance virtual delivery, especially for assessments and programmatic materials that need to be shared with clients. further, understanding if these program curricula should be augmented with information on covid-19 is a consideration. fourth, efforts encouraging and supporting positive provider self-care to address their own anxiety, household changes, and employment requirements are sorely needed. given the personal impact of the current pandemic on trained safecare providers, and although this study did not address parent-level outcomes, it may be worth noting that purveyors may want to consider the impact of incorporating parent self-care into curriculum adaptations on child maltreatment outcomes. lastly, purveyors must consider what their recommended options for program delivery will be once home visits become safer. will the programs remain flexible and consider hybrid approaches to delivery, or return to the status quo? in conclusion, perhaps the two largest issues the cm prevention field must consider with virtual delivery is family access and child safety. issues related to data plans and internet availability, or lack thereof, could increase disparities and reduce program reach for families who do not have the consistent access and, consequently, capacity for participating in virtual delivery. also, we must better understand how well providers can accurately assess child safety and maltreatment risk virtually. that is, what are program providers able to effectively observe and assess in terms of child safety through technology, and how does this impact mandated reporting. these questions, and the further study of them within the context of randomized, prospective research designs, are imperative to the effective establishment of the next phase of child maltreatment prevention program delivery during the pandemic and beyond. funding this work was supported by the georgia tech office of the executive vice president for research covid-19 rapid response seed grant program. the content is solely the responsibility of the authors and does not necessarily represent the official views of georgia institute of technology. declarations of interest the authors declare that they have no conflict of interest. informed consent informed consent was obtained from all individual participants included in the study. australian research alliance for children and youth. (2020). right@home. aracy suffering in silence: how covid-19 school closures inhibit the reporting of child maltreatment safecare colorado program evaluation report animal cruelty as an indicator of family trauma: using adverse childhood experiences to look beyond child abuse and domestic violence the great recession and the risk for child maltreatment adverse childhood experiences are associated with the risk of lung cancer: a prospective cohort study an increasing risk of family violence during the covid-19 pandemic: strengthening community collaborations to save lives contextual factors related to alcohol abuse among intimate partner violence offenders. substance use and misuse north texas hospital reports spike in severe child abuse cases; believe linked to stress from coronavirus pandemic. cbs dallas fort worth a statewide trial of the safecare home-based services model with parents in child protective services healthrelated quality of life among adults who experienced maltreatment during childhood child welfare systems struggle during coronavirus pandemic changes in reports and incidence of child abuse following natural disasters adverse childhood experiences and self-reported liver disease insights into causal pathways for ischemic heart disease cumulative childhood stress and autoimmune diseases in adults parenting in times of war: a meta-analysis and qualitative synthesis of war exposure, parenting, and child adjustment social work, ethics and vulnerable groups in the time of coronavirus and covid-19 practical steps to prevent child neglect in the covid-19 pandemic investigating the impact of the safecare program on parenting behaviours in child welfare-involved families the covid-19 pandemic: technology use to support the wellbeing of children setting a violence prevention agenda at the centers for disease control and prevention the perfect storm:' how covid-19 has multiplied the risk for children in abusive households. pennsylvania capital star important home visiting information during covid-19 the role of home-visiting programs in preventing child abuse and neglect children more at risk for abuse and neglect amid coronavirus pandemic, experts say. usa today increased incidence of inflicted traumatic brain injury in children after a natural disaster coronavirus: what child welfare systems need to think about. the imprint do i qualify for nbn co's $150 million coronavirus broadband relief package? finder initial impacts of the covid-19 pandemic on the canadian labour market caution! men not at work: gender-specific labor market conditions and child maltreatment predictors of child maltreatment potential in a national sample of mothers of young children children's communication about distressing events: the role of emotional openness and psychological attributes of family members pan-canadian inventory of public health early child home visiting: key facts and glossary. antigonish: ns: author. national home visiting resource center a review of pediatric telemental health covid-19's early impact on home visiting: first report from a national harc-beat survey of local home visiting programs reducing child abuse and neglect in nsw work, welfare and child maltreatment pandemics and violence against women and children demographics of mobile device ownership and adoption in the united states does the safecare parenting program impact caregiver mental health? exploratory study on the role of trauma-informed self-care on child welfare workers' mental health an exploratory study of african american parent-child coping strategies post-hurricane katrina effects of the covid-19 pandemic on routine pediatric vaccine ordering and administration -united states local job losses and child maltreatment: the importance of community context child maltreatment and disaster prevention: qualitative study of community agency perspectives a technology-mediated approach to the implementation of an evidence-based child maltreatment prevention program the effectiveness of behavioral parent training to modify antisocial behavior in children: a metaanalysis evidence-based home visiting to enhance child health and child development and to support families child maltreatment: daunting and universally prevalent the state of broadband internet in canada department of health & human services, administration for children and families covid-19: reducing the risk of infection might increase the risk of intimate partner violence doctors expect a "huge spike" in pediatric injuries at home. the new york times reduced child maltreatment prevention service case openings during covid-19 does adoption of an evidence-based practice lead to job turnover? results from a randomized trial effect of the safecare© intervention on parenting outcomes among parents in child welfare systems: a cluster randomized trial publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-338674-tnnd1s57 authors: yin, j kevin; lahra, monica m; iskander, mary; lambert, stephen b; heron, leon; nissen, michael d; rost, laura; murphy, jennifer; sloots, theo p; booy, robert title: pilot study of influenza vaccine effectiveness in urban australian children attending childcare date: 2011-06-10 journal: j paediatr child health doi: 10.1111/j.1440-1754.2011.02098.x sha: doc_id: 338674 cord_uid: tnnd1s57 background: influenza outbreaks in the childcare setting are a significant cause of excess winter morbidity. this study explored methods of follow up and sample collection for a proposed randomised controlled trial of influenza vaccination in children attending childcare. methods: the study was conducted in four sydney childcare centres during 2007. healthy children aged 6–59 months eligible for vaccination were recruited in two centres, with another two acting as controls. data on influenza‐like illness (ili: ≥37.8°c plus at least one respiratory symptom) occurrence were collected weekly. in those children with an ili, parents were asked to collect nasal swabs and send via surface mail for viral polymerase chain reaction. vaccine efficacy (ve) for ili was estimated overall and for subgroups aged 6–23 and 24–59 months using the formula ve = 1 − relative risk (rr). results: sixty‐three per cent (151/238) of eligible children had parents give consent. sixty‐three children received influenza vaccine and 88 participated as controls. of 26 specimens returned, a virus was detected in 18 (69%); none with influenza. two symptomatic children had positive near‐patient influenza tests in general practice (one a vaccine failure). the rr with 95% confidence interval in all children and those aged 6–23 months were less than one, 0.56 (0.32–1.02) and 0.46 (0.15–1.45), respectively. conclusions: this study demonstrated the feasibility and utility of parent‐collected and mailed respiratory specimens for ve research in the childcare setting. two‐thirds of parent‐collected swabs proved positive for at least one virus. finding ways to reduce reluctance of parents to submit samples could improve the representativeness of samples collected and the power of the study. no evidence was found for influenza ve, but point estimates were in the direction of protection. influenza is a seasonal, vaccine-preventable disease which causes excess morbidity and mortality during winter in temper-ate climates. the health and economic costs associated with childhood influenza are substantial. 1 for example, in australia during 2002-2005, there were reports of 25 433 hospitalisations and four deaths for influenza and pneumonia among children aged under 5 years. 2 the annual cost due to influenza-related diseases in australia is estimated to exceed $115 million. 3 the world health organization recommends annual influenza vaccination as the cornerstone for prevention and control. efficacious influenza vaccines have been available for over 50 years, and yet, routine use in childhood remains the what is already known on this topic 1 children in childcare are more likely to contract influenza and transmit infection to their siblings, parents, extended families and child-care workers. 2 usa, canada and western australia currently have a routine influenza vaccine policy in place that includes children 6 months of age and older. 3 evidence for the effectiveness of influenza vaccine in children aged less than 24 months is limited and high quality, appropriately powered, randomised controlled trials are needed. 1 it is feasible to follow children weekly for 3 months to obtain swabs for influenza-like illness. 2 two-thirds of parent-collected swabs were positive for at least one virus demonstrating the utility of this approach for future studies. reluctance of parents to submit swabs for analysis may be a limitation of this approach. exception in most countries. the effectiveness of influenza vaccine for children in childcare has been demonstrated for children aged ն24 months. [4] [5] [6] [7] [8] although the us advisory committee on immunisation practices has recommended children aged 6-23 months to be vaccinated with influenza vaccine since 2004, 9 there is ongoing debate about vaccine effectiveness in this age group. three recent systematic reviews [10] [11] [12] concluded that either influenza vaccine was not effective in children յ24 months of age or that there were insufficient data to form a conclusion. influenza is transmitted from person to person through contact and respiratory droplets; however, the droplets do not remain suspended in the air for long nor do they travel far. 13 transmission of influenza generally requires close contact with an infected person or contact with a contaminated surface or object. 14, 15 the childcare setting provides enhanced opportunities for transmission of infections including influenza as there is prolonged close interaction between young children and the sharing of toys and other objects. further to this, young children are particularly susceptible to infection as they are immunologically naïve to many viruses. commercial childcare in australia is available in two broad categories: daycare centres (dcc) for children aged 6 weeks until 6 years and pre-school centres (psc) for children aged 3 to 6 years. commercial childcare usage in australia is increasing. the median attendance time for australian children who use childcare is 10 h per week, but 13% attend 35 h a week or more. 16 children in childcare are known to be more likely to contract respiratory illnesses, including influenza, [17] [18] [19] [20] [21] and are considered to be major transmitters of influenza to their siblings, parents, extended families and care workers. 6, 8, 22, 23 the 2007 influenza season in australia ran from late may until october and notifications peaked during august. 24 australia witnessed antigenically drifted influenza virus (a/brisbane/ 59/2007 (h1n1)-like and a/brisbane/10/2007 (h3n2)-like), and it was the most severe influenza season since a national influenza reporting system was established in 2001. 25 with this study, the primary process issues of conducting influenza vaccine research in the childcare environment were evaluated, including recruitment, retention, vaccination and specimen handling. while this pilot study was not powered to assess an efficacy end point, preliminary vaccine efficacy (ve) data were also examined. from july to august 2007, children aged 6-59 months attending four childcare centres in new south wales were recruited for this study: two dcc caring for children aged 0-59 months and two psc caring for children aged 36-59 months. the four dcc were chosen by convenience (proximity to the children's hospital at westmead) with equal number of children between dcc and psc. one dcc and one psc were allocated to influenza vaccination, and one dcc and one psc were allocated to be controls. this study was approved by the royal alexandra hospital for children ethics committee, and informed parental consent for participation was obtained prior to study procedures. the par-ticipating children were evaluated in two age groups based on age at enrolment: 6-23 months and 24-59 months. the influenza vaccine administered was a 2007 southern hemisphere preparation, purified, inactivated, split vaccine (vaxi-grip junior, provided by sanofi pasteur, lyon, france), incorporating: children were administrated the vaccine according to the standard recommended dose and schedule for age. 26 as all children at the centres randomised to receive vaccine were influenza vaccine naïve, each received two doses of vaccine 1 month apart -0.25 ml intramuscular dose for those less than 36 months of age and 0.5 ml intramuscular dose for those aged 36-59 months at the time of their first dose. vaccines were administered between 11 july 2007 and 19 september 2007. we defined influenza-like illness (ili) as an illness with fever >37.8°c and with one or more respiratory symptoms (cough, blocked nose or runny nose) to maximise sensitivity. as a protective level of antibody is usually detectable within 2 weeks of the second dose of vaccine, 13,27 ili surveillance was commenced in vaccinated children at this time point. in control children, ili surveillance was arbitrarily commenced from the week ending 26 august 2007: at this time, just over half (32/62) of the children eventually fully vaccinated had received vaccine, and from that week, the ratio of child-weeks of follow up in vaccinated and unvaccinated children was similar (fig. 2) . parent education for ili surveillance was provided at study entry. households received a weekly email or telephone call from 30 july until 21 october 2007 (12 weeks) to monitor the study children for ili symptoms. parent training for the collection of nasal swabs was conducted by study nurses after the second immunisation. nasal swabs were collected using the virocult collection system (mw950) consisting of a rayon swab on a plastic shaft, with viral transport medium-soaked foam pad in the base of the transport tube (copan italia, brescia, italy), and were returned to the queensland paediatric infectious diseases laboratory using a pre-addressed, postage-paid envelope. returned specimens were tested using previously reported, real-time polymerase chain reaction assays with reverse transcription for rna viruses. a total of 16 viruses were investigated: human rhinoviruses (hrv), 28 influenza a, influenza b, rsv, adenoviruses, hmpv, parainfluenza viruses i, ii and iii, 29 bocavirus 30 hpyv-wu, hpyv-ki, 31 and human coronaviruses: oc43, 229e, nl63 32 and hku1. 33 while it was not part of the study protocol, some children had near-patient influenza tests performed by their general practitioners and these were reported by parents to study staff. ili incidence rates were calculated using child-weeks in the denominator. rate ratios (rr) and 95% confidence intervals were calculated comparing vaccinated and unvaccinated groups. these values were used to estimate ve using the formula ve = (1 -rr) ¥ 100%. comparisons were performed in three age groups, 6-59 months (all children), 6-23 months and 24-59 months. the average ages of the children in the vaccine and control centre were 43.4 (7.7-65.4) and 44.1 (7.9-66.0) months, respectively, while the proportions who were males were 50.8 and 58.0%. data on non-enrolled children were not recorded. there were 239 children in total attending the four childcare centres, and 151 children were enrolled giving a recruitment rate of 63%. complete information was available for analysis in 150 children, with one vaccinated child lost to follow up during the study period (fig. 1 ). there were 481 (62 children) and 792 (88 children) child-weeks of follow up in vaccine and control centres, respectively. a total of 59 ilis were identified in all study children, and weekly ili incidence rates are provided (fig. 2) . of the 26 swabs received during the study period, 18 (69%) had at least one virus identified, with bocavirus being the most common virus found in six swabs (table 1) , followed by hrv in five swabs. one swab contained three viruses (hrv, adenovirus and bocavirus). thirteen of these swabs were from 12 vaccinated children, with the other half from 13 controls. two positive near-patient influenza tests (one a vaccine failure) were reported by parents to the study staff: one was from an unvaccinated child in a control centre; the other child was vaccinated with the test done 14 days post-second vaccination ( table 1) . there were a total of 59 ilis identified with efficacy point estimates in the direction of protection for all age-groups but not significant ( table 2 ). the key findings of this pilot study were that a high recruitment rate could be achieved, that recruited families were tolerant of regular weekly follow up over an extended period (3 months) and that there was no evidence of protective efficacy, but point estimates of ve for the less-specific end point of ili were in the direction of protection. it is inevitable that ili would include non-influenza infections which cause respiratory signs and symptoms, especially as we used a sensitive definition (at the expense of specificity), so it is not surprising that a range of other viral pathogens were identified in our study. a population-based surveillance study showed that less than 10% of hospitalised children aged յ59 months with ili had confirmed influenza infection. 34 our study has some limitations. the childcare centres were not randomised. the commencement midway through an influenza season limited the number of influenza cases identified. less than half the episodes in children of ili (26 out of 59, 44%) had a respiratory sample sent. this reduced sampling is probably due to the added burden on parents of sample collection (and posting) while a child is ill. in addition, as the childcare centres were in the suburbs with relatively lower socio-economic indexes for areas 35 (and also involved larger families), this, too, may have limited parental cooperation. the participants were only followed from the 2nd half of august when the 2007 season was peaking, so some may have thought that sample collection in september or october was too late. given the limited data that were collected on symptomatology and the relatively small number of specimens, it was not possible to do an extensive analysis comparing symptoms by virus type to address if there are differences in symptoms among various viruses. furthermore, the demographic data (e.g. sex, age range) of those who did not participate in the study were not collected; therefore, it was not possible to identify if there was any recruitment bias. greater efforts are required for future studies in (i) improving the proportion of swabs collected and sent by initiating ili follow up before the influenza season starts and findings better ways to overcome parents' reluctance in submitting swabs; (ii) obtaining more detailed data on symptomatology of respiratory infection; and (iii) collecting de-identified demographic data on those who are not enrolled in the study. this study showed no evidence for influenza ve. there was only a suggestion of protection in that all the point estimates were in that direction. trivalent, live, cold-adapted influenza vaccine (caiv-t) may be a better option for young children and has been demonstrated to have significantly higher efficacy than inactivated vaccine among young children during moderate 36, 37 and high attack-rate influenza seasons. 38 caiv-t was also able to provide protection even when the circulating influenza virus was an antigenically distinct strain. 37 there were two children with positive results for influenza a from the near-patient test. this type of test is known to have only moderate sensitivity but high specificity, so a positive test is unlikely to be false. 39 week ending date (2007 older children (24-59 months) are more likely to have developed natural immunity through previous infection and are more likely to have developed better personal hygiene. for these reasons, older children are less susceptible to influenza as well as other non-influenza infections that may cause ili. this pilot study has shown the feasibility and value of parentcollected (and mailed) nasal sample for influenza ve research in childcare. two-third of parent-collected swabs proved positive for at least one virus. means of lessening reluctance of parents to submit respiratory samples from their children need to be found to improve the representativeness of samples collected and the power of the study. no evidence was found for influenza ve, but point estimates were all in the direction of protection. the cost of community-managed viral respiratory illnesses in a cohort of healthy preschool-aged children vaccine preventable diseases and vaccination coverage in australia influenza-related disease: the cost 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influenza and respiratory syncytial virus to community cases ofinfluenza-like illness: an observational study annual report of the national influenza surveillance scheme australian government department of h, ageing c. national health and medical research council. the australian immunisation handbook amplification of rhinovirus specific nucleic acids from clinical samples using the polymerase chain reaction comparing nose-throat swabs and nasopharyngeal aspirates collected from children with symptoms for respiratory virus identification using real-time polymerase chain reaction detection of human bocavirus in respiratory, fecal, and blood samples by real-time pcr development and evaluation of real-time pcr assays for the detection of the newly identified ki and wu polyomaviruses real-time rt-pcr detection of 12 respiratory viral infections in four triplex reactions human coronavirus infections in rural thailand: a comprehensive study using real-time reverse-transcription polymerase chain reaction assays community epidemiology of human metapneumovirus, human coronavirus nl63, and other respiratory viruses in healthy preschool-aged children using parent-collected specimens census of population and housing: socio-economic indexes for areas (seifa), australia live attenuated versus inactivated influenza vaccine in infants and young children various factors associated with the manifestation of influenza-like illness trivalent live attenuated intranasal influenza vaccine administered during the 2003-2004 influenza type a (h3n2) outbreak provided immediate, direct, and indirect protection in children laboratory diagnosis of human seasonal and pandemic influenza virus infection key: cord-322711-u6yr8wqh authors: imran, nazish; aamer, irum; sharif, muhammad imran; bodla, zubair hassan; naveed, sadiq title: psychological burden of quarantine in children and adolescents: a rapid systematic review and proposed solutions date: 2020 journal: pak j med sci doi: 10.12669/pjms.36.5.3088 sha: doc_id: 322711 cord_uid: u6yr8wqh as covid-19 grips the world, many people are quarantined or isolated resulting in adverse consequences for the mental health of youth. this rapid review takes into account the impact of quarantine on mental health of children and adolescents, and proposes measures to improve psychological outcomes of isolation. three electronic databases including pubmed, scopus, and isi web of science were searched. two independent reviewers performed title and abstract screening followed by full-text screening. this review article included 10 studies. the seven studies before onset of covid 19 about psychological impact of quarantine in children have reported isolation, social exclusion stigma and fear among the children. the most common diagnoses were acute stress disorder, adjustment disorder, grief, and post-traumatic stress disorder. three studies during the covid-19 pandemic reported restlessness, irritability, anxiety, clinginess and inattention with increased screen time in children during quarantine. these adverse consequences can be tackled through carefully formulated multilevel interventions. children and adolescents account for 42% of the world's population with 26% being younger than 15 years of age. 1 initial studies suggest that although children and adolescents are less likely to be infected with covid-19 and they stay asymptomatic or have milder symptoms of illness if get infected, but they are not indifferent to the psychological distress of pandemic. 2 children aged 2 years are reported to be aware of the changes around them. 3 uncertainties regarding pandemic itself, strict social distancing measures, widespread and prolonged school closures, parental stressors, and loss of loved ones are likely to affect children and adolescent's wellbeing in addition to specific psychological effects of quarantine and isolation. 4, 5 the word "quarantine" originated from the italian words "quaranta giorni," which mean 40 days. 6 quarantine is a state of enforced isolation of people with exposure to a contagious disease to prevent the spread of illness. 6 quarantine and isolation have been used as disease containment measures in leprosy, plague, severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers), ebola, and more recently in covid-19. [7] [8] [9] citywide quarantine measures are being imposed around the world to prevent the transmission of covid-19 in the communities. furthermore, people with infection including children and adolescents are either being isolated at homes or in state run isolation facilities as per different countries's policies. quarantine and isolation are no doubt an unpleasant and distressing experience for all people who face it. 7,10 uncertainty of disease status, restrictions on mobility and daily activities, separation from loved ones, and boredom may contribute to negative effects of quarantine. 7 literature suggests significant psychological issues in quarantined individuals including anxiety, depression, sleep difficulties, anger and posttraumatic stress disorder in addition to suicide in adult. [11] [12] [13] duration of quarantine, provision of inadequate information, boredom and frustration, fears about being infected, financial losses, and stigma were some of the factors identified with stress in quarantined population. 7 stigma in particular has been a recurrent theme in literature with regard to distress associated with quarantine. [14] [15] [16] [17] there is lack of conclusive evidence of the impact of quarantine and isolation on children and adolescents. routines, social interactions and friendships are among the most important factors responsible for children's normal psychological development. being quarantined or isolated often break their usual routines and can make an already challenging situation far more difficult for all children and adolescents, particularly for those with special needs or preexisting psychiatric difficulties. 5 since the covid-19 outbreak related disease containment measures and school closure has become relevant to all affected countries around the globe, urgent evidence synthesis is needed to help policy makers understand the mental health outcomes of quarantine in children and adolescents. the world health organization recommends rapid reviews in such situations due to urgency of this matter. 18 in view of the scarce information about the mental health implications of quarantine in younger individuals, we undertook a review of evidence to explore quarantine's likely effects on stigma, children and adolescent's mental health and psychological wellbeing, and factors that contribute to or mitigate these effects. this rapid review was conducted according to prisma guidelines. three electronic databases including pubmed, scopus, and isi web of science were searched using following search terms: (stigma or stigmas or stigmatization) and (psych* or mental or anxiety or depression or stress or insomnia or adjustment) and (quarantine* or patient isolation or isolate* or lockdown or lock-down or cordon) and (child* or adolescent or adolescence or youth). two independent reviewers performed the title and abstracts screening, followed by the screening of full texts and discrepancies were resolved through discussion. manual search of included full-text articles was performed. the authors also propose interventions to reduce distress from these disease containment measures. eligibility criteria: our inclusion criteria were: 1. studies including primary research 2. english-only articles 3. studies including data on the prevalence of mental illness or psychological wellbeing or stigma, or on factors associated with mental illness or psychological wellbeing (ie, any predictors of psychological wellbeing during or after quarantine). 4. age<18 years. our exclusion criteria were: 1. studies that were not evaluating for psychological impact and stigma related to quarantine in children and adolescents. 2. unreliable data sets, duplicate, overlapping, or non-peer-reviewed articles. 3. review articles, research articles without available full texts, book chapters, conference papers, theses, case reports and case series, abstract-only articles, and animal studies. data extraction: descriptive statistics regarding study population, country of study, scales used to measure for outcome, summary of results, and limitations were extracted. two independent reviewers extracted the data of included articles and discrepancies were resolved through discussion. the initial literature search revealed 530 unique citations, among which 10 studies were included after the screening process. fig.1 elaborates the screening process in prisma flow diagram and tablei provides a summary of included studies. study designs and scales used: among the included studies, study design was cohort in four studies, cross-sectional in three, and descriptive qualitative in three. outcome measures were assessed by using surveys (n=4), interviews (n=4), focus groups (n=1), review of hospital records (n=1), home visits and observations (n=1), drawing and captions (n=1). these scales have been summarized in tablei. parents or caregivers were reporter of symptoms in eight studies whereas one study used hospital records. 19 and other used drawings and captions by children. 20 nature of disaster: disease or disaster containment measures were adapted due to covid-19 in three studies. [21] [22] [23] other disasters included influenza a virus subtype h1n1 pandemic, severe acute respiratory syndrome (sars), and avian influenza in one study 13 27 summary of included articles: a qualitative study was performed in children requiring mechanical ventilation that highlights the importance of sociological framework in improving our understanding of the medical and social problems. 25 it also describes socialization processes that can help resolve the social exclusion, isolation and social sufferings experienced by disabled children and their families. in most cases, parents were working as a protective capsule for their disabled child by creating their own social norms, alienating themselves from their stigmatizing community, or engaging in passing techniques to manage information and their 'discreditability' among community. 25 a study conducted among the survivors of tsunami in 2004 reported that most of the children and parents suffered from 3-4 traumatic tsunamirelated incidences and about 98% of the parents had a ptsd reaction. in both children and parents, the immediate subjective response to tsunami was correlated to ptsd reaction 6-8 months later. there was a significant association between children's and parents' exposure to the stressor and parents' ptsd with children's levels of post-traumatic stress reactions. 24 sprang and colleagues (2013) reported an increased risk of ptsd in children (30%) and parents (25%) (id 2). this risk was higher in children and young parents. the most common diagnoses were acute stress disorder (16.7%), adjustment disorder (16.7%), and grief (16.7%). only 6.2% of these children were diagnosed with ptsd. however, the mental health service utilization was 33.4% among quarantined families for their children, either during or after the pandemic. 13 in study among children who were evacuated during the world war ii, evacuation was not reported to be a predicator for admission to the psychiatric hospitals. men experienced low rates of psychiatric admission between evacuated and non-evacuated siblings. for women, no association was established between evacuation and admission for a psychiatric disorder, with higher risk of mood disorders among women. 19 a qualitative descriptive study assessed 24 children by using drawing and captions. 26 this study suggested that psychological burden of quarantine in children and adolescents ebola was represented as a highly stigmatized and feared disease through the content of the drawings and captions. moreover, health campaigns initiated to contain the epidemic, such as the 'no touch' policy and quarantine of suspected ebola cases were the most common themes. the stigma and psychological consequences were experienced more often in children orphaned by ebola. 26 elsbernd and colleagues conducted a study among nine cancer survivors that included adolescents and younger adults. the frequent challenges were both systemic and social in nature such as constraints to return to education due to symptoms and late effects, most commonly fatigue and lack of concentration. moreover, these individuals felt that it was difficult for their peers to understand their difficulties and circumstances. in this situation, there were minimal official resources but this lack of support was compensated by family and counselors. 20 muenks and colleagues conducted qualitative interviews in participants who were diagnosed with mrsa skin and soft tissue infection. it was reported that 42% of survey respondents expressed that their child's mrsa diagnosis caused a change in how household contacts interacted with one another. about 40% of caregivers stated that they personally treated their children (with a history of mrsa infection differently than their children) who had not experienced mrsa infection. the majority (91%) of participants shared their child's mrsa diagnosis with people outside of their household. 27 three studies were conducted in children and adolescents in midst of the current covid-19 pandemic. in a study by jiao and colleagues (2020), children aged 3-6 years were more likely than older children to manifest symptoms, such as clinginess and fear that family members could contract the infection. 23 other symptoms were inattention, persistent inquiry, clinging, inattention, and irritability. these distressing symptoms were relieved by using entertainment through social media and physical exercise. 23 in a similar study conducted in italy and spain, the most frequent symptoms were difficulty concentrating (77%), boredom, irritability, restlessness, nervousness, feelings of loneliness, being more uneasy and increased worrying. most parents reported a change in the emotional state and behaviors of their children. about 12% of the italian and spanish parents informed that family coexistence was difficult or very difficult with their children being more restless, angry and irritable. there was also increased use of screen time in both countries (82% italian and 90% spanish children). spanish children stopped being physically active and were sleeping for more hours than italian children. 22 these symptoms were corroborated by study among children in italy. 21 to our knowledge, this is the first systematic review to assess psychological impact of quarantine in children and adolescents. we identified a remarkable dearth of data on the impact of quarantine on children and adolescents during disease outbreaks. it was surprising that majority of studies we found, were for the rapidly emerging covid-19 pandemic rather than previous sars or mers outbreaks. 21, 22 furthermore, none of the identified studies were designed to specifically examine children and adolescents' own experiences or perceptions of quarantine on different aspects of their lives. psychiatric issues: although children are vulnerable to environmental risks but statistics regarding psychological impact of home confinement, quarantine and isolation in children and adolescents are elusive and very few studies address this important aspect. data from the covid -19 studies from italy, spain and china suggests significant emotional and behavior changes during quarantine in children and adolescents. [21] [22] [23] common reactions of children and adolescents to disasters including health related ones depends on child age and developmental levels. 28 while younger children may be clingier or regress in behaviors, older children may become more anxious, angry, restless and withdrawn while in quarantine. 29 literature suggests that children often display their worries in ways that caregivers may interpret as defiant behavior. 29 children subjected to quarantine in pandemic disasters have more likelihood of developing acute stress disorder, adjustment disorder and grief and reported four times higher scores of ptsd compared to those who were not quarantined. 13 the fact that high ptsd prevalence noted in literature was related to short lived infectious outbreaks like sars, there is likelihood of huge segments of young population to experience residual and lasting distress and trauma due to larger scale and prolonged covid-19 outbreak. it is also important to note that travel restrictions, closure or availability of limited outpatient services in many hospitals in different countries, may lead to reduce access to mental health services during the current pandemic. available child and adolescent evidence are consistent with broad range of impact of quarantine in adult population. studies found elevated levels of anxiety, distress, and depression among quarantined individuals. 7, 14, 30 none of the child studies looked at duration of quarantine and its association with psychological impact, but literature suggests higher ptsd symptoms in those quarantined for longer duration specifically for more than ten days. 14 given the prolonged quarantine and isolation in covid-19, likelihood of worse psychological outcomes in vulnerable populations including children and adolescents won't come as a surprise. as there is evidence that significant burden of mental illnesses originate in young age and adult life productivity is also deeply rooted in early years, close attention to mental health of young people in quarantine is warranted to avoid any long-term consequences. 31, 32 stigma: infectious diseases, where quarantine is required, are likely to evoke social processes that stigmatize people affected by it. 33 our study identified only four studies focusing on quarantine related stigma, discrimination and social exclusion felt by families and children due to ebola, mers, cancer and physical disability. stigma related to quarantine and causes of quarantine has been a major theme throughout the literature, however only limited data is available regarding stigma faced by children and adolescents in this context. children affected by hiv and aids were discriminated against, stigmatized and isolated by community members in a study by khewsa et al. 34 similar stigmatization with reduction in social interaction with other children has been noted in relation to ebola. 26 quarantined households continued to be associated with ebola leading to secondary stigma which hampered reintegration of young people in society, long after the end of quarantine. stigma linked with quarantine thus have real implication for children's social relationships at community level and contribute to significant psychological distress. political conflicts, poverty, unfounded fear of transmission of infection have all been identified as factors for perfect storm of fear and stigma. 34 physical health: confinement during disease outbreak is likely to have negative effects on children's physical wellbeing and it has been documented in recent covid-19 pandemic studies as well. 22, 23, 35 parents in italy and spain during covid-19 reported negative impact on physical health with less physical activity, and more screen time than usual among children. 22 this is consistent with past evidence suggesting that children during school days are physically more active, have regular sleep patterns and less screen time, while increase screen time, less physical activities and poor dietary patterns leading to weight gain is reported during summer vacations and weekends. 35, 36 spanish children showed worse behavioral and emotional response to the quarantine and one possible hypothesis proposed was permission by italian government for young children to go for short walk accompanied by parents and more italian homes having gardens. education: there is compelling evidence that school closure as a disease containment measure during outbreaks like influenza can dramatically reduce the spread of disease but there may be high cost of prolonged school closures among children and adolescents. 37 the united nations educational, scientific and cultural organization highlighted that with mass school closures in more than 188 countries during covid-19 pandemic, "the global scale and speed of the current educational disruption is unparalleled". none of the studies in our review looked at impact of quarantine on children academics and schooling. however, a recent paper by joyce lee highlighted the mental health effects of school closures. some previous reviews also emphasized loss of education, nutritional problems and social isolation leading to psychological harm as few of adverse effects of school closures. 38 besides, academics, school routines are important for children and they access many services including mental health support through schools. 38 another area of concern during quarantine is increase rates of child abuse, neglect, and exploitation while children stay at home and it may go unchecked due to social isolation. increase in reports of domestic violence in china during recent covid-19 pandemic is of concern. studies from previous natural disasters, and outbreaks like the ebola outbreak in west africa from 2014-2016, also revealed increased rates of child abuse during disease containment measures like quarantine and isolation. 29, 39 there is urgent need to monitor how prolonged school closures and strict social distancing impact children and adolescent wellbeing in the long run. socialization: social distancing measures like quarantine can worsen feelings of loneliness and isolation. children and adolescents need to stay connected with family and friends, which gets difficult with school closures, limited visits with friends and families etc. inability to activate your social network is noted to be associated with anxiety and distress. 40 one of the studies in our review looked at impact of isolation on socialization of families of children with disability. they reported feeling strangers in their own communities due to rejection they faced because of their children problems. reduction in social interaction with other children has also been reported in ebola and hiv outbreaks. 26, 34 it is important to have support groups for children and families in quarantine so that they may feel connected and empowered and it can reduce psychological distress. parental perceptions: most of the studies in our review had parents as reporter of child symptoms. many parents isolated at home are also under lots of stress. parental perception of quarantine impact on children and adolescents thus have element of subjectivity. parents reporting more child emotional and behavioral difficulties were noted to be one who found family coexistence difficult or very difficult. 22 parental stress has been shown to predict stress reactions in children and therefore parents need to maintain their own calm. although it is considered natural to protect children from unpleasant information, but even very young children react to environmental changes and often assume the worst. by managing their own stress better, parents can help to manage children stress. thus, to summarize, this review shows considerable psychological impact of quarantine and other disease containment measures among children and adolescents. quarantine also has negative impact on their physical health, academics and social network. many of our findings resonate strongly with adult studies calling for greater focus on quarantine related stigma experienced by children and adolescents. psychological distress of children in quarantine need to be considered in planning of response to any disaster including health related emergencies. proposed interventions and components: given the evidence of adverse psychosocial impact, effective measures need to be in place to mitigate the effects of home confinement on children and adolescents. the lancet commission on the future of the world's children urges various stakeholders to ensure that all children's needs are met during these uncertain times as "early investment in children health, education and development have benefits that compound throughout the child's lifetime, and societies as a whole". 41 immediate actions are warranted in various sectors. fig.2 provide a framework for interventions to address psychological burden and stigma among quarantined children and adolescents. education: education is one of the strongest predictors of the health of a nation and thus needs to be addressed on priority basis. with widespread and extended school closures around the globe, educational institutions need to be innovative and provide lessons and other services to students through alternate resources to minimize disruption in education. education and health officials need to work in collaboration with public health officials and provide guidelines for effective online learning and ensuring that contents of courses meet the educational requirements. restricting the duration of school closure to minimum and making plans and guidance documents for safe return of children in schools are also essential to prevent consequences of quarantine. information dissemination from media and other sources: kids tend to worry more, when they are kept in dark about what's happening around them. it is a challenge to increase the sensitivity of media regarding reporting of events to reduce anxiety in the eye of lockdown and pandemics. 42 ensuring that children under quarantine have good, age-appropriate understanding of the illness and reason for quarantine should be a priority. watching news with children, asking about what the child has seen or heard, providing reassurances and monitoring regularly if news is troubling or upsetting the child may help in lessening the negative effects of news during quarantine. it is important to acknowledge and validate children's thoughts, feelings and reactions in order to provide children with emotional scaffolding they need to thrive during quarantine. behavioral activation: behavior activation (ba) is a component of cognitive behavior therapy that aims young people to engage more often in enjoyable activities and improve their problem-solving skills alongside addressing excess of avoidance behaviors. it can be an appropriate culturally sensitive intervention to reduce the psychological impact of quarantine among children and adolescents, complemented with other approaches like lifestyle changes, counselling and family therapy. 43 healthcare system response -telehealth: telehealth including telepsychiatry although an established modality in developed world is yet to gain momentum and popularity in low-and-middle income countries (lmic). it can be used as an effective tool to provide counselling and psychological support to children and adolescents at risk with prevailing higher social media use in youth. 35 however, there needs to be some mechanism to monitor the quality of telehealth services, ensuring that ethical standards are maintained, trained professionals are providing collaborative services and appropriate referral pathways to hospitals is in place should it is required. 44 school-based strategies: schools are increasingly being identified as a context in which apart from traditional subjects, life skills and "social emotional education" need to be imparted to students. 45 this role becomes even more relevant following situations where children and adolescents are confined at home for longer periods. many children also experience severe illness themselves or in family or loss of loved ones during infectious diseases outbreak placing them at even higher risk of psychological distress. schools offer a unique opportunity and a cost-effective way to reach out a large number of students. in some lmic, they could be the only mental health service provision opportunity in rural areas. who's global vision of 'health promoting school' through multifaceted response can be helpful in post quarantine situations to prevent long term adverse consequences. 45 other coping strategies: positive parenting: children pick up and reacts to parental and family's emotions and stress during quarantine. good parental skills are extremely crucial especially, when children are quarantined at home. quarantine can be used as a good opportunity to enhance positive interaction between parents, children and siblings, thus strengthening family bonds. various guidelines by international organizations are available to help parents during quarantine. during this time of change and uncertainty, sticking to routines/ schedule as much as possible helps in reducing the psychological impact of quarantine. social distancing, not social isolation: social distancing measures like quarantine can worsen feelings of loneliness and isolation. social media can play an important role in communication with others. children and adolescents need to stay connected with family and friends virtually by phone, emails, facetime, skype, zoom. playing online games with friends can also be relaxing for children during quarantine seeking professional help: families should be provided information to consult mental health professionals if child is too preoccupied with illness during quarantine or exhibiting signs of severe emotional disturbances. limitations of the study: this rapid review comes with few limitations. first, meta-analysis was not performed due to different study designs, measurements tools, study outcomes, and methodology of rapid review. second, the psychological effects should be carefully interpreted as they can be due to the effect of diasaster, disease or diasaster containment measures, or synergitic effects of both. www.pjms.org.pk 1115 nazish imran et al. overall, this review suggests that quarantine is associated with far reaching and significant negative impact on psychological wellbeing of children and adolescents. of more concern is the finding that this negative psychological effect can still be detected months or years later. stigma has also been rife in children and families who underwent quarantine. as quarantine is essential to contain diseases in many cases, it is important that steps and measures are taken to make this experience less traumatic for vulnerable young people. this can be done by honest and age and developmentally appropriate communication, ensuring routines and minimizing disruption in education, encouraging healthy lifestyle, enhancing positive relationship between families, managing parental stress and incorporation of health promotion activities in school curriculum. these strategies may ensure that the physical and mental health impact of quarantine on children and adolescents are kept minimal. further research to examine long term impact of quarantine and prolonged school closures on children are urgently needed to guide policies. none. coming of age: adolescent health. world health organization national health commission of the people's republic of china. interpretation of notice on strengthening the treatment and management of patients with severe mental disorders during the outbreak of the new coronary pneumonia communication with children and adolescents about the diagnosis of a life-threatening condition in their parent protecting the psychological health of children through effective communication about covid-19 mental health considerations for children quarantined because of covid-19 cambridge dictionary the psychological impact of quarantine and how to reduce it: rapid review of the evidence mental health status of people isolated due to middle east respiratory syndrome ebola and quarantine view of covid-19 and mental health depression after exposure to stressful events: lessons learned from the severe acute respiratory syndrome epidemic is quarantine related to immediate negative psychological consequences during the 2009 h1n1 epidemic? posttraumatic stress disorder in parents and youth after health-related disasters sars control and psychological effects of quarantine ebola and healthcare worker stigma social consequences of ebola containment measures in liberia understanding, compliance and psychological impact of the sars quarantine experience rapid reviews to strengthen health policy and systems: a practical guide. geneva: world health organization long term mental health outcomes of finnish children evacuated to swedish families during the second world war and their non-evacuated siblings: cohort study adolescent and young adult cancer survivors' experience of managing return to secondary or higher education in denmark a qualitative report on exploratory data on the possible emotional/behavioral correlates of covid-19 lockdown in 4-10 years children in italy immediate psychological effects of the covid-19 quarantine in youth from italy and spain behavioral and emotional disorders in children during the covid-19 epidemic children's and parents' posttraumatic stress reactions after the 2004 tsunami revisiting goffman's stigma: the social experience of families with children requiring mechanical ventilation at home. j child heal care in the midst of a 'perfect storm': unpacking the causes and consequences of ebola-related stigma for children orphaned by ebola in sierra leone methicillin-resistant staphylococcus aureus: the effects are more than skin deep helping children cope with emergencies mental health considerations for children & adolescents in covid-19 pandemic geriatric care during public health emergencies: lessons learned from novel corona virus disease (covid-19) pandemic global child and adolescent mental health: the orphan of development assistance for health age of onset of mental disorders: a review of recent literature stigmatization, scapegoating and discrimination in sexually transmitted diseases, overcoming 'them' and 'us exploring hiv and aids stigmatisation: children's perspectives mitigate the effects of home confinement on children during the covid-19 outbreak understanding differences between summer vs. school obesogenic behaviors of children: the structured days hypothesis school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review mental health effects of school closures during covid-19 changes in reports and incidence of child abuse following natural disasters mother nature versus human nature: public compliance with evacuation and quarantine a future for the world's children? a who-unicef-lancet commission psychological interventions during covid-19: challenges for lowand middle-income countries depression: management of depression in primary and secondary care. nice online mental health services in china during the covid-19 outbreak. the lancet psychiatry mental health interventions in schools in low-income and middleincome countries ni & sn: conceived the idea of this review article. sn, ni, ia, mis, zhb: extracted and analyzed data, prepared tables, and wrote the manuscript. ni: was responsible for the supervision of this project. all authors approved the final version of this review article. key: cord-348411-nrhe8aek authors: shah, kaushal; mann, shivraj; singh, romil; bangar, rahul; kulkarni, ritu title: impact of covid-19 on the mental health of children and adolescents date: 2020-08-26 journal: cureus doi: 10.7759/cureus.10051 sha: doc_id: 348411 cord_uid: nrhe8aek the coronavirus disease 2019 (covid-19) outbreak was first reported in wuhan, china, and was later reported to have spread throughout the world to create a global pandemic. as of august 18th, 2020, the coronavirus had spread to more than 216 countries with at least 21,756,357 confirmed cases, resulting in 771,635 deaths globally. several countries declared this pandemic as a national emergency, forcing millions of people to go into lockdown. this unexpected imposed social isolation has caused enormous disruption of daily routines for the global community, especially children. among the measures intended to reduce the spread of the virus, most schools closed, canceled classes, and moved it to home-based or online learning to encourage and adhere to social distancing guidelines. education and learnings of 67.6% of students are impacted globally due to coronavirus in 143 countries. the transition away from physical classes has significantly disrupted the lives of students and their families, posing a potential risk to the mental well-being of children. an abrupt change in the learning environment and limited social interactions and activities posed an unusual situation for children's developing brains. it is essential and obligatory for the scientific community and healthcare workers to assess and analyze the psychological impact caused by the coronavirus pandemic on children and adolescents, as several mental health disorders begin during childhood. countries across the globe, including the united states, are in the dilemma of determining appropriate strategies for children to minimize the psychological impact of coronavirus. the design of this review is to investigate and identify the risk factors to mental health and propose possible solutions to avoid the detrimental consequence of this crisis on the psychology of our future adult generations. since the first reported coronavirus case in wuhan, china, in 2019, the outbreak, now known as covid-19, has spread globally [1] . the world health organization (who) acknowledged this coronavirus epidemic as a pandemic and declared the outbreak as a public health emergency of international concern [2-3]. most regions around the world are affected severely, including the united states, brazil, india, russia, and europe, which have seen an increasing number of cases and deaths than the rest of the world [3 -4] . as of august 18th, 2020, the coronavirus had spread to more than 216 countries and has at least 21,756,357 confirmed cases, resulting in 771,635 confirmed deaths globally. in the united states, between january 20th and august 18th, 2020 , there have been 5,354,013 confirmed cases of covid-19 with 168,999 deaths [5] . the spread of the virus has caused global economic and social disruptions and has brutally overwhelmed the healthcare and educational systems [6] . the unexpected disruption of the social fabric and norms has affected the behavioral and mental health of the public, including children. the mental health of children has been influenced by several ways, as this unprecedented situation changed a way they typically grow, learn, play, behave, interact, and manage emotions. children with pre-existing psychiatric disorders such as attention-deficit/hyperactivity disorder (adhd), anxiety, depression, mood disorders, and behavior disorders could be adversely impacted during this stressful situation [7] . mental disorders are the leading cause of disability worldwide in adolescents and children. about 15% of children and adolescents in the world have mental health disorders or conditions. nearly 50% of mental disorders start to affect the children by the age of 14. if left untreated, a child's mental development has been found to be drastically and detrimentally impacted. it is well established that mental health is one of the essential parts of human development and determines the outcome of a child's educational attainments and the potential to live fulfilling and productive lives [8] . mental illness can affect children at any point during their childhood, but it most significantly affects them during adolescence. among the several mental illnesses that can be prevalent in childhood, depression is one of the major leading causes of mental illness amongst children. in 2016, an estimated 53,000 deaths were due to adolescent suicide, which is the third leading cause of morbidity in this group. this emphasizes that adolescence is a period of vulnerability for the onset of mental health conditions [9] . as of august 18th, 2020, 143 countries have closed schools and educational facilities worldwide due to the covid-19 pandemic, impacting 1,184,126,508 learners, consisting of about 67.6% of students globally. it has forced several countries to implement home-based learning or online training [10] [11] [12] . approximately 1.1 billion students and their families have been affected by school closures due to the pandemic. these students are experiencing further distress due to the unavailability of adequate help and attention from the trained instructors, making education more expensive for them and their families as they need to utilize additional time, support, and resources. due to the closing of schools, students' interaction and communication with school mates, play, exercises, and peer-activities are hindered, which have proven vital for the growth, development, and learning of the young human minds [10] . the children who are at most significant risk are the youngest ones as their brains are still developing and are being exposed to high levels of stress and isolation, which can lead to permanent abnormal development. children exposed to stressors such as separation through isolation from their families and friends, seeing or being aware of critically ill members affected with coronavirus, or the passing of loved ones or even thinking of their own death from the virus can cause them to develop anxiety, panic attacks, depression, and other mental illnesses [11] [12] . the conducted literature search was through medline, pubmed, pubmed central, and embase using the keywords, 'coronavirus,' 'covid-19,' 'mental health,' 'child and adolescent,' 'behavioral impact,' 'psychological conditions,' 'quarantine,' and 'online education.' the indexed search aimed to identify literature and articles relevant to our focused topic. the objectives of this review article are 1. to understand the overall psychological impact of covid-19 on children and adolescents; 2. identifying factors contributing adversely to their mental health; and 3. proposing interventions based on the guidelines and evidence-based practices. the outbreak of covid-19 has disrupted the lives of many people across the world. the pandemic has imposed a sense of uncertainty and anxiety, as the world was unable to predict or prepare for this crisis. it has caused a tremendous stress level among children, adolescents, and all students in general, primarily due to the closure of their schools. this stress may lead to undesirable adverse effects on the learning and psychological health of students [13] . children exposed to these incidents can precipitate the development of anxiety, panic attacks, depression, mood disorders, and other mental illnesses [11] . distressing events such as separation from family and friends, seeing or being aware of critically ill members affected with coronavirus, or the passing of loved ones or even thinking of themselves perhaps dying from the virus would have a detrimental effect on the mental health. additionally, the healthy daily routines of children have been disrupted due to the covid-19, which contributes to the additional stress and sleeping difficulties that many children face. uncertainty of their future ambitions, academics, personal relationships, and inactivity due to the pandemic poses a significant threat to their mental well-being and putting them at risk of drug abuse [14] . covid-19 can seriously leave a negative impact on children's mental health, just like other traumatic experiences humans may face. it can lead to higher rates of depression, anxiety, and post-traumatic stress disorder. this causes fear in children because the virus threatens not just them but also their families and surroundings, especially as they see their parents working from home, leading to fear and shock [15] . previous studies on severe acute respiratory syndrome (sars), middle east respiratory syndrome (mers), and ebola have revealed that the disease causes severe emotional distress during the outbreaks. unfortunately, studies were not adequately conducted on the children and adolescents during the past outbreaks to measure its impact on their mental health, but several parallels can be drawn. the situation of covid-19 is comparable with the mers and sars, as similar claims made about the severity of mers caused fear, worry, and anxiety among the public. a study on the sars survivors with psychiatric disorders revealed that about 25% of the patients showed signs of post-traumatic stress disorder (ptsd), and 15.6% of them had worsening depression [16] . this finding corresponds to the increased suicide deaths among sars survivors, consisting of older adults from hong kong in 2003 and 2004 [17] . among those mers survivors, lower quality of life was also noticed. neuropsychiatric linkage has been established based on the previous outbreaks [18] . during this pandemic, children and their families have been exposed to direct or indirect factors that could pose stress and emotional disturbance. several weeks of homestay has forced parents and/or caregivers to work from home. also, many families lost their financial independence due to job losses [11] . this disease is installing fear in children because children are worried about not only getting infected but also having their parents staying at home and not leaving for work [15] . some families are struggling to feed their children, as many were dependent on school programs or food stamps, and not all families with resources can provide adequate supplies [19] . however, the reach of the pandemic is unequal as numerous families have lost loved ones while others live in regions untouched by the virus. some children have parents who work on the front lines in covid-19 settings, and others have parents who now work from home or have recently been terminated [19] . additionally, international students are impacted by uncontrollable factors such as school closure, campus closure, and travel restrictions. nations across the globe have restricted their borders to internationals to help mitigate the pandemic as many students might not have any other place to reside. this sudden closure of many nations to outsiders has placed a great burden on school administrators to ensure housing, sustenance, and safety of their international students [19] [20] . while transitioning to online classes has helped both international and national students to continue their education, several children and faculty members are experiencing distress because they may not have the technological capability or expertise required to navigate this new mode of interaction. the online teaching method has raised questions for the faculty about their capability to deal with the existing technology [20]. the covid-19 pandemic has caused unprecedented health and humanitarian crisis. it has created an economic downturn due to the necessary measures to contain the spread of the virus. as per the latest global financial stability report, there is likely to be financial instability, which would lead to a devastating recession. the combined economic uncertainty and emotional distress placed on a family will challenge the overall well-being of families as well as their mental health [21] . it is paramount to encourage and adopt healthy behavior to maintain the overall well-being of families. the well being of caregivers or parents can directly impact the mental health of the children. parents are advised to follow and practice the guideline provided by the world health organization (who). the who has urged people to follow social distancing guidelines and avoid close contact with anyone, especially from the person showcasing any respiratory symptoms [22] . the health organization has also emphasized maintaining better hygiene by consistently washing hands and using appropriate protective gear such as facial masks [22] . it has also advised to take breaks from watching, reading, or listening to news stories, including social media, because continually being bombarded by news of the pandemic can be distressing. exercising regularly, practicing yoga or meditation, eating healthy, taking adequate and proper sleeping properly, and avoiding alcohol or drugs is key to maintaining mental health. it is also crucial that parents provide enough support to their children and help them to process the information about the pandemic because these interventions could help minimize their anxiety or fear [22] . schools, parents, and healthcare institutions can also implement psychological first aid (pfa) guidelines to assist children with their mental distress. pfa can provide psychosocial support to any survivors of epidemic or disaster [23] . it is developed to mitigate acute distress and assess the need for more advanced psychiatric care. it is beneficial to implement it during the early stages of crisis to assist survivors in coping with grief and avoiding the long-term impact of stress on mental health. the 'rapid' model of the john hopkins pfa tool includes five steps, (i) r -rapport and reflective listening, implemented throughout the interaction; (ii) a -assessing and evaluating the psychological needs; (iii) p -prioritizing the needs based on severity; (iv) i -intervening to mitigate distressing factors; (v) d -disposition and distribution of intervention to stabilize the survivor [24] [25] . schools should emphasize the mental health of students by supporting and providing updated health organization guidelines through online lectures. also, a licensed counselor should help students manage the covid-19 related stress by providing coping mechanisms and strategies in both group and individual sessions. counseling services should be available to support the mental health and well being of students on time. universities can establish a task force to make a plan to reduce the spread of the virus and for the following centers for disease control and preventions (cdc) guidelines. the committee should include members from diverse professional backgrounds and experiences, such as public health department, physicians, psychiatrists, psychologists, social workers, administrators, health and human services, international services center, human resources, admission offices, enrolment, and billing department, athletic department, and teachers. to reduce the distress experienced by students and faculty related to information technology (it) issues, a technical team should be available continuously, and learning tutorial videos should be shared with the end-users. similarly, teachers and faculty should support students and their parents through clear communication and assigning clear expectations [24] . a licensed counsel should take a comprehensive assessment of students deemed susceptible through risk factors such as psychological issues, including poor mental health before the crisis, bereavement, injury to self or family members, life-threatening circumstances, panic, separation from family, and low household income. minimizing the interruption of psychiatric care for patients with pre-existing conditions via telepsychiatry will be helpful to continue monitoring patients as the pandemic may worsen some patients' conditions and would adversely impact them if they were unable to contact their doctor. psychological assessment will help them to cope with their mental issues and stabilize their condition as they gain more education and discuss the impact of a pandemic. it will provide them support and reassurance to build resilience and encourage them to stay positive and motivated [26] . mental health involves the regulation of our emotions, psychological, and social well-being. per the cdc, mental health affects how we think, feel, and act. it also helps determine how we react to stress, correlate with others, and our decision-making. mental health is significant throughout our lives, from early childhood to adolescence and through adulthood. mental illnesses occur when mental health is affected and leads to conditions that affect the way a person thinks, feels, or behaves, such as depression, anxiety, bipolar disorder, or schizophrenia. mental health can cause conditions that may be acute or chronic and alter the way we live our lives daily by our rationalizations. psychological and physical health are interdependent, both working together to form who we are. mental illness, especially depression, limits rational thinking, and increases the risk for other health problems such as diabetes. the presence of chronic conditions can increase the risk of mental illness. it is vital to strike a healthy balance between students' physical and psychological well-being [26] . protecting and maintaining the mental health of the future adult generation is only possible with the robust schooling and healthcare system. it is necessary to have adequate resources to overcome this crisis. recruiting additional school personnel, clinicians, and mental health counselors are needed to address the strain on the system for supporting students during this pandemic [27] [28] . comprehensive school mental health systems (csmhss) is required to deliver adequate assistance for the students effectively [27] . csmhss is a school-community association developed for all students to provide a variety of services for every type of students, such as mental health services, health promotion and prevention, early identification and interventions of diseases, and treatments for students evidence-based medicine [27] . the csmhss should be enabled to collaborate with counselors, community mental health, and physical healthcare providers to help prevent mental health issues and make necessary referrals through an online interface for the treatment. the recruitment of additional school personnel and mental health counselors will help the students manage their anxiety, depression, and/or stress due to covid-19; and to stabilize any previously diagnosed mental illness or prevent new mental illness from developing [27, 29] . moreover, children with inadequate information about why quarantine measures have been taken are found to have more anxiety. therefore, it is essential to expose children to more information about covid-19 through several sources, such as the evening news [29] [30] . this will make children more aware of the reason behind not only why quarantine measures were put in place, but they will also learn more about what covid-19 is. parents and guardians are encouraged to speak with their children about the information they learned, which may help lessen the negativity associated with covid-19 and quarantine. additionally, communicating with children about how they are processing the information will provide children with the emotional tools they require to do well in quarantine [27] . not only can parents inform children about quarantine, but they can also employ "positive parenting" [31] . children are prone to observe parents' and family members' moods during quarantine, which the children react to. through positive parenting, parents, guardians, and family members can create consistent daily routines to avoid the distress of unstructured days [31] [32] . while parents can provide a deeper understanding of the covid-19 and quarantine, school systems can provide further reassurances and educate children about emotions [33] . school systems have the unique opportunity to provide consistent information to a large student body, who is unable to access other mental health programs in the areas [34] . furthermore, school systems must adapt to the new online learning method and help students adjust and thrive in online classes [34] [35] . additionally, children can be taught coping mechanisms to self-regulate their own emotions without dependence on others. one method that achieves this goal is behavioral activation, which focuses on participating in activities they enjoy and not employing avoidance behaviors [31] [32] . alongside the other interventions mentioned above, behavioral activation can help children improve their problem-solving skills by engaging in healthy behaviors rather than unhealthy ones [27] . due to the isolation indirectly imposed by the pandemic, children would be expected to prosper better in these times when they are taught ways to help themselves [31, 35] . the epidemiology and clinical information about covid-19 covid-19 strategy update children's mental health child and adolescent mental health adolescent mental health empowering students with disabilities during the covid-19 crisis covid-19 is hurting children's mental health coping with stress as coronavirus prompts colleges to close, students grapple with uncertainty long-term psychiatric morbidities among sars survivors a revisit on older adults suicides and severe acute respiratory syndrome (sars) epidemic in hong kong coronavirus: universities are shifting classes online -but it's not as easy as it sounds covid-19 crisis poses threat to financial stability focus on mental health during the coronavirus (covid-19) pandemic: applying learnings from the past outbreaks sustainability of psychological first aid training for the disaster response workforce the johns hopkins model of psychological first aid (rapidpfa): curriculum development and content validation the role of psychological first aid to support public mental health in the covid-19 pandemic guidance to states and school systems on addressing mental health and substance use issues in schools how essential is to focus on physician's health and burnout in coronavirus (covid-19) pandemic? lifetime prevalence of mental disorders in u.s. adolescents: results from the national comorbidity survey replication-adolescent supplement (ncs-a) lifetime prevalence and age-of-onset distributions of mental disorders in the world health organization's world mental health survey initiative. world psychiatry psychological burden of quarantine in children and adolescents: a rapid systematic review and proposed solutions mental health effects of school closures during covid-19 psychological interventions during covid-19: challenges for low and middle income countries mental health interventions in schools in low-income and middle-income countries school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review key: cord-353886-wvxohfum authors: sevilla vallejo, santiago; ceballos marón, natalia andrea title: theoretical and applied study of the psychological and educational effects of lockdown in primary school students in argentina date: 2020-12-31 journal: social sciences & humanities open doi: 10.1016/j.ssaho.2020.100039 sha: doc_id: 353886 cord_uid: wvxohfum abstract emotions are complex states, which have a fundamental role for children’s mental health and learning. the proper self-regulation of emotions allows to tolerate frustrations, improves social skills and healthy bonds with peers and adults in the environment (bisquerra, 2003, p. 12). the lack of regulation causes discomfort that leads to a decrease in academic performance (graziano, reavis, keanes & calkins, 2006) and particularly in reading comprehension, because this competence requires motivation and cognitive processes that will allow to process the linguistic code, interpret it and represent it symbolically (alonso-tapia, 2005, p. 64). in this work, we show the essential relationship between emotional regulation and reading comprehension in primary school students. after that, we study the effect of lockdown on these two processes. the aim is to have preliminary information about the challenges and effects of the current situation. to do this, a semi-structured survey has been conducted of parents and teachers in order to assess the psychological and educational effects of the current health situation. the results of 40 semi-structured telephone surveys are analyzed, 20 of parents of children with learning disorders and 20 of their classroom teachers in traslasierra, córdoba-argentina. the results inform that the students and their parents have difficulties to regulate their emotions and this emotional struggle has a negative impact on comprehension of texts. the problems that previously presented in these two areas have increased due to the lack of adaptation of activities by teachers, the lack of knowledge of their parents to help them and the difficulty in accessing digital technologies. both parents and teachers express that lockdown affects learning processes, although parents are also concerned about the effects on social life. emotions are complex states that have a fundamental role for children's mental health and learning processes. to express emotions is to communicate to others what we are feeling at a certain moment, a task that is often not easy (ramos, 2011, p. 15) . a suitable way of expressing emotions is called self-regulation of emotions. this allows children to tolerate frustrations, improve social skills and healthy bonds with peers and adults in the environment (bisquerra, 2003, p. 12) . in early childhood, emotional regulation starts out precarious and depends entirely on protective adults. around the age of 8, cognitive development makes children achieve self-regulation in a more conscious way, although early experiences and the established attachment to parents will continue to be very important (p aez, fern andez, campos, zubieta and casullo, 2006; garnesfski, rieffe, jellesma, terwogt & kraaij, 2007) . therefore, a good cognitive development will be key in the childhood. campos (2010) expresses that emotional processes give rise to a good brain functioning and executive components, and they will be the ones who promote the ability to regulate, reason, memorize, make decisions in learning processes (p aez, fern andez, campos, zubieta and casullo, 2006) . in this work, we show the relationship of these psychological processes with linguistic performance. according to the results obtained by graziano, reavis, keanes & calkins (2007) and alonso-tapia (2005, p. 64) , the lack of regulation causes discomfort that leads to a decrease in academic performance and particularly in reading comprehension (ceballos-mar on & sevilla-vallejo, 2020). this is because this competence requires motivation and cognitive processes that will allow the linguistic code to be processed, interpreted and represented symbolically. then, we will see how the current situation of lockdown or quarantine and preventive and compulsory social isolation affect both the regulation of emotions and the reading comprehension specifically of primary school students with learning disorders. 1 we are concerned about the importance of dealing with emotions to help students to improve in human and academic terms. this is even more necessary to be considered when we work with students having learning disorders. the aim of this study is to know in which sense emotional regulation and reading comprehension are affected by lockdown. it is essential to have some guidelines to improve the psychological and educational care of students. a comparison will be made between the gaze of the teacher and the student's parents. this study is justified by the collaboration between teachers and families which has become especially important in the current situation. both the former's work and the latter's accompaniment have been transformed into a situation of social isolation. the teachers are in charge of the academic training and students' human development. in the family case, parents play a fundamental role in children's life and development because they can further promote an integral children's growth not only in their affective development but also in their regulation of their emotions. besides, they can accompany academic learning. regarding to learning, children's case with difficulties in academic learning, it is of great importance that parents have confidence that they will be able to achieve it and improve themselves day by day (ramos, 2011, p. 30) . this study will focus on the effects of the health crisis in argentina, because we have access to students, parents and teachers there. this allows us to collect testimonies of emotional regulation and reading comprehension to offer results that allow interventions in the current situation. likewise, a comparative study of the responses to telephone interviews given by parents and teachers will be offered to analyze the effects on emotions and students' reading comprehension. this will allow us to know to what extent parents and teachers are finding ways to collaborate to overcome this crisis. teachers and psychologists must realize the complex relations between emotional regulation and reading comprehension. the former affects wellbeing and learning processes. the latter is an essential skill for any subject and it is important beyond education. we will start showing the relation between the necessary processes to regulate emotions and the necessary processes to read. in the case of children, processes such as motivation, self-esteem, and emotional regulation depend largely on the bond and attachment to the primary figures (p aez, fern andez, campos, zubieta, and casullo, 2006, p. 340) . so, it must be taken into account that the current situation also has an impact on parents who are living, at this particular moment, an atypical situation that affects them emotionally, physically and financially. we consider that at this uncertain moment the consequences for students could be reflected especially in reading comprehension, because the tasks that involve it demand a great deal of concentration. reading is a complex task that requires adequate emotional regulation in order to be carried out satisfactorily. first, reading involves active meaning-building processes such as interpreting, discriminating, classifying, examining, criticizing, contrasting, and constructing representations of the information received (sevilla vallejo, 2018, p. 5) . secondly, the following must be born within the mind: "motivation and processes are the two pillars on which understanding is based 2 " (alonso-tapia, 2005, p. 2). motivation will be given by the interests of the students (sevilla vallejo, 2017, p. 291) . reading can be a source of discovery for them: "our cognitive and emotional engagement with fiction is to a high degree and emotional engagement with fiction is to a high degree dependent on surprise" (nikolajeva, 2016, p. 36) . according to jesús alonso tapia, motivation depends on the beliefs that readers have not only regarding the objective that they should achieve but also regarding what understanding implies. the teaching community is aware of the necessity to promote active reading among students and for this, we must keep in mind that "we always read with a purpose" (alonso-tapia, 2005, p. 14). the student needs to regulate his or her own emotions to maintain reading motivation and to carry out the cognitive processes involved. as panadero and alonso-tapia (2014 p. 454) have pointed out, although this model incorporates emotion to a lesser extent than cognition, it represents the psychological elaboration process necessary to manage complex tasks, such as reading. alonso-tapia (2005) adapts the previous model to the linguistic levels of reading: 1. identification of graphic patterns. graphemes are discriminated and are associated with their respective phonemes to recognize the words. it depends on learning factors, such as the identification of distinctive features of the letters or the practice of identifying them; but it is also related to neurological aspects such as "the necessity for the inhibition of perceptual representation mechanism to be intact, if this inhibition does not occur, the images overlap" (p. 67). 2. recognition of the lexicon. this factor is about the amount of vocabulary, the closeness or familiarity of that vocabulary and the semantic context in which it is used and the use of that context. 3. construction and integration of the meaning of the sentences. the meaning is constructed in cycles that correspond to the phrases. in these, each representation is connected and integrated with the previous one, as well as with prior knowledge. it depends on the recognition of the syntactic structure of the phrase (subject, predicate and hierarchical relations). 4. integration of the cycle. the ideas of each proposition or phrase must be integrated in a coherent way. this would form a last set of ideas that would synthesize all the others that are called macro-propositions. to achieve this integration, one must rely on thematic progression to establish an understandable relationship between ideas. 5. construction of the global meaning of the text. finally, the ideas contained in the text must be integrated and simplified. for this, some strategies can be followed: selection: set aside the sentences that do not provide necessary information or are accessory. generalization: substitute specific phrases for more general ones that include them. construction: substitute one series of sentences for another, which does not appear in the text, but which synthesizes the content of the others. this theory allows us to divide the problems in reading comprehension into the levels of construction of the text (recognition of signs and understanding of words, sentences, ideas and of the text as a set of ideas). up to this moment, there are no scientific studies on the effects of lockdown on reading comprehension; however, we hypothesize that this situation increases previous difficulties at any of these levels. although the concision of this study does not allow us to delve deeper, it is evident that emotional regulation and reading comprehension are two related and educationally relevant aspects that have been influenced by lockdown. nevertheless, we would like to provide some preliminary information about how this situation provokes a particular sense of lack or emotional regulation and increases problems of reading comprehension in specific linguistic levels. as we mentioned before, in the case of argentina, the national government decided to suddenly implement that each student receive at home the same activities that they would have in their classrooms. as a result, teachers have to accompany their students in a virtual way, without in many cases having previous experience in 1 in a previous work, we studied the relation between emotional awareness and reading comprehension: el efecto del aislamiento social por el covid-19 en la conciencia emocional y en la comprensi on lectora. estudio sobre la incidencia en alumnos con trastornos de aprendizaje y menor acceso a las nuevas tecnología. revista internacional de educaci on para la justicia social, 9(3), número extraordinario. 2 all translations are the author's. digital technologies and in didactic procedures to do so. suddenly, our society experienced physical restrictions, which implied compulsory social isolation or lockdown in order to avoid massive contagions. family routines underwent a profound change, among which is that children must take classes at home. teachers send the activities to the families through different virtual means that have been stipulated by the school institutions and the different teachers. as psychiatrists and psychologists who attend to this crisis situation have pointed out, this alteration causes feelings of discomfort at the individual and social level, physical and emotional disorders such as anxiety, anguish, fear, ocd … (diario p agina 12, 2020). specifically, maría de los angeles l opez geist, psychoanalyst, expresses the following: "there are immeasurable loneliness of children and adolescents due to parents overburdened with work or lack thereof." 3 it also states that children have a childish view of their parents, which means that they do not trust that their parents are capable of protecting them and this in turn causes suffering and aggressive reactions from children. it is necessary for parents to manage their emotions and accompany their children in this process in order to avoid negative emotions that affect their personal and school life. our own teaching and psychological experience tells us that the difficulties to acquire the reading comprehension with confidence and quickness are related to the difficulties presented in the regulation of emotional states, because these affect behavior, bonds and social skills and, especially, regulation of the cognitive processes necessary for reading. now, we should ask ourselves what is happening at this special moment with those children who have some type of learning disorder and are at home receiving tasks from teachers. it is worth asking if they learn and they continue a similar process that they would have had at the school in normal circumstances. the international classification of diseases describes in its latest version, icd 11, learning disorder as a significant and persistent disorder in academic skills that include reading, writing and arithmetic. the intellectual performance of the child with this disorder is under what is expected at their chronological level, causing deterioration at the academic level at the present time and possible professional difficulties in the future. this problem usually appears during the first school years and it is not due to intellectual, sensory or neurological causes. ramos (2011) also adds that children with these difficulties have problems in expressing emotions, thoughts and behaviors, as well as in understanding society when the context is changing (p. 16). it is relevant to mention that, in the case of argentina, on april 1, the national disability agency authorized the relaxation of social isolation for boys and girls diagnosed with mental, cognitive and psychosocial disabilities, as well as those with autism. that resolution became void hours later and it is expected that the ministry of health and cabinet will be able to take measures in this regard. on a national broadcast, on april 10, the president commented that this decree is being studied at this moment to achieve its possible implementation, since it will decrease the emotional consequences on the mental health of children (diario p agina 12, reprint april 12, 2020). this is an example of the significant importance of isolation for students with learning disabilities. regarding the use of technologies, it can be specified that the national government of argentina encourages all students to own computers and thus achieve inclusion in a more formal education system, ensuring that everyone achieves general knowledge about the use of computer tools to give a new way of thinking and reflecting. the economic differences that hinder access to new technologies are very important for educational training (finquelievinch, 2000) and are having a decisive influence on the current situation of social isolation. in the province of c ordoba, a platform was announced for teachers to work with students at different levels. it aims to continue school activities from home through the website. 4 this is updated weekly and has essential contents for students (government of c ordoba, 2020). these tools are not only intended to establish the means for the interaction of teachers, students and their families, but also, they transform the identities of students and they also modify their access to texts because it is opened up the possibility of dialogical education: this particular theory of dialogic education implies an ontological vertical dimension of growth in education from a monologic ontology at one extreme and towards a dialogic ontology at the other extreme. a monologic ontology assumes identities with locations and boundaries. a dialogic ontology, on the other hand, asserts that every apparent identity is in dialogue with every other apparent identity (wegerif et al., 2017, p. 2). the current situation presents an educational challenge, but also an opportunity for an approach in which the student investigates and builds knowledge. the digital technologies can allow dialogic learning to be implemented because the forms of interaction are expanded. in this way, it could be possible for students to regulate their own emotions and access to reading. however, we are going to study how the current situation can also hinder the proper use of technologies to achieve these objectives. this study consists of 40 interviews, 20 with parents with children with learning disorders and 20 with their classroom teachers. in addition, students have comorbid disorders: 7 of them also have asd, 6 adhd, 2 epilepsy, 2 behavioral disorders, 2 fragile x disorders, 1 language disorder and 1 childhood psychosis. the sample is form out of the patients attended in traslasierra, c ordoba-argentina. it is not expected that this sample represents the situation of argentina because it would be necessary to have a bigger number of cases and to choose them from different areas. however, we consider that it is more relevant to have some preliminary results during the current crisis rather. this study could help to wider and more rigorous following studies. we will not either differentiate between these comorbid diagnoses. we simply point them out to indicate that these are students who require very careful educational and emotional attention. we developed a semi-structured survey with questions about the effects on emotional regulation and reading comprehension (appendix a). the survey is composed by 13 questions. questions 1 to 3 ask about the general effect of lockdown and the support that students receive from the therapeutic team or special education teacher, the school and parents. questions 4 and 5 are about the emotional effects of lockdown on students and their parents. it was decided because we wanted to know in depth the situation of families. we have the hypothesis that the lockdown is making more difficult the emotional regulation of those people who are living together. primary students are influenced by the emotions of their parents. questions 6 to 12 are related to the educational adaptation to current situation and the lockdown effects on reading comprehension. this section ranges from quite open questions to more precise questions to know parents and teachers' concerns of the general situation and the specific effect on linguistic competence. finally, question 13 is open to other comments to receive other information that we could have missed in the previous questions. the objective is to compare the views from teachers and parents in order to propose ways to improve collaboration. we are going to analyze the results according these sections. the first question of the survey asked for the implications of lockdown. the two most frequent responses of parents are delayed learning 3 "hay soledades inconmensurables de niños y adolescentes por padres sobrecargados de trabajo o por falta del mismo". 4 the domain is the following: https://tuescuelaencasa.isep-cba.edu.ar/. (8 cases) and lack of social bonds (8 cases). in other words, these two problems have an equivalent incidence in the sample taken. to a lesser extent, parents transmit problems regarding routines (2 cases) and see an improvement in assignments performance in the situation (2 cases). in other words, the first ones find it difficult to manage study routines and understand the educational needs of their children. they express the lack of tools to help their children ("i don't understand how to help him" 5 ) and also that they have needed a long period of adaptation until they could contribute to the education of their children ("only now [20 days have passed] i understand how to help them to download the content and to enjoy it" 6 ). however, the second ones have children who find it difficult to adapt to the educational center, and therefore they see a benefit in studying at home. this is, for example, the case of students diagnosed with asd, in which it is found difficulties in admission and permanence in the school. on the other hand, when teachers are asked the same question, they consider that the greatest problem is the delay in learning (13 cases) and, secondly, the social bond. in other words, parents are equally concerned with academics and social issues, while teachers give more importance to the former. in relation to support from teachers, 17 consider that there is accompaniment, and 3 that there is not. on the other hand, 13 of the teachers consider that families are accompanying their children with their homework, 5 comment that only some families do it and 2 do not answer. this indicates that the majority of families perceive school accompaniment and the majority of teachers receive family accompaniment. this is striking in relation to what has been said about the comprehension problems and emotional difficulties mentioned above. regarding the knowledge that teachers have about their students, 12 answered that they do recognize all the students in the classroom, 7 answered that they know some of them and 1 answered that she does not know her students. most of the teachers comment the following: "we only attended 2 weeks of classes and we have been in virtual classes for a month". 7 the teachers who answer that they do know their students express that they were able to internalize the diagnoses of those who have a school integration process and the rest were unable to read the documentation. the teachers indicate the difficulty of the situation due to the short time they had to work with their students. regarding the question of how their children felt, after approximately 20 days of quarantine, from the total parents, 25% answered that their children are "exhausted", "frustrated" and "irritable"; another 25% "distressed" and with feelings of uncertainty, 15% "sad"; 20% "happy" and another 15% "calm" and "bored". 8 in addition, parents who expressed that their children were frustrated or distressed commented that the children presented maladaptive behaviors: "he cries silently", "constantly asks if he and the whole family are going to die", others refuse all the proposals from therapists and teachers: "he doesn't want to do anything", "he is distressed, i don't know what to do" 9 . they also express that they experience other disorders related to emotions: sleep problems ("they fall asleep late", "they sleep until afternoon"), anxiety ("they bite their nails") and eating disorder ("they eat more quantity", "skip meals" 10 ). regarding parents' emotions, 40% of parents answered that they feel sad and/or distressed, 30% they are frustrated, exhausted and feel collapsed, 15% feel good, 10% do not know what is emotionally happening to them and 5% felt bad but it is improving. likewise, 65% of them answered that these emotions affect their children, 20% that it does not affect because "i try not to seem worried" 11 and 15% answered that they do not know. this is coherent with the negative emotions of the students which were discussed previously. most of the parents have emotional regulation problems, since only 3 of them have managed them properly. these difficulties in regulating their emotions have a negative impact on their children. in turn, it coincides with what the teachers have stated: 70% express that they perceive the families stressed and/or exhausted, 5% scared, 5% want to leave, another 5% who are calm and 15% do not know how they feel. that is, negative emotions in parents predominate both according to parents themselves and according to the teachers. regarding the accomplishment of the tasks, the majority of parents (70%) express that their children find it difficult to have to carry them out at home with their help and only 20% consider that their children are able to solve them without difficulty. avoidance behaviors can be observed: the majority answered that their children "are apathetic", "they get angry", 12 they avoid sitting down and doing their homework, they make excuses: "she opens the folder and gets sick because it is difficult. she wants to go to school." 13 these answers don't coincide with the ones given by the teachers, who express to a greater extent that the students have adapted to the new modality partially (40%), completely (25%), while the rest do not know if they adapt (25%) and only 10% consider that the students have not adapted. when asked if the children understand the task that their teachers send, 65% families answer no, 20% of them do understand it and 15% do it but with difficulty. families who answer that their children do not understand the activities to be carried out ask the special education teacher to explain it to them and then transmit it to their children. the problem is that the teachers wrote on the blackboards in capital letters and the students worked on copying and, at the current situation, parents express that they do not have the necessary tools such as blackboards and do not know how to adapt the tasks or how to teach their children. on the contrary, many teachers send activities to a whatsapp group without such adaptation. most of the students are not used to practice dictation with their parents, so they express ideas such as "we don't have a blackboard at home", "they don't know how to read the letters". 14 on the other hand, teachers consider that students do not read with enough attention the tasks that are sent to them. we also asked parents about the actions they take when they don't understand the tasks. 50% answered that they consult with the special education teacher, 30% ask close relatives and neighbors, 15% search the internet and only 5% of them ask their questions to the classroom teacher. therefore, parents ask more frequently to the special education teacher and it is striking that, they ask to lesser extent to classroom teachers. from 100% of parents, 45% answered that children did not read at home before social isolation, 40% of them did read and 15% only on some occasions. during quarantine, this behavior has increased in 65% of cases and it hasn't changed in 35% of cases. before quarantine, reading at home was not very frequent, since 45% cases is almost half of the sample; and, 5 "yo no entiendo c omo ayudarlo". 6 "reci en ahora [pasaron 20 días] me doy cuenta c omo bajar el contenido y lo disfrute". 7 "asistimos s olo 2 semanas de clases y llevamos un mes de clases virtuales". 8 5 respondieron "agotado", "frustrado" e "irritable"; 4 "angustiado" y con sentimientos de incertidumbre, 3 de ellos "triste"; 4 tienen días en que se sienten bien y días mal; 4 "alegres" y 3 "tranquilos" y "aburridos". 9 "llora en silencio", "pregunta constantemente si el y toda la familia nos vamos a morir", otros se niegan a todas las propuestas de los terapeutas y escolares: "no quiere hacer nada", "se angustia, no s e qu e hacer". 10 problemas de sueño ("se duermen tarde", "duermen hasta pasado el mediodía"), ansiedad ("se come las uñas") y trastorno de alimentaci on ("comen m as cantidad", "saltean comidas"). 11 "trato que no me vea mal". 12 "est an sin ganas", "se enojan". 13 "abre la carpeta y se pone mal, porque le cuesta. ella quiere ir a la escuela". 14 "no tenemos pizarr on en casa", "no sabe leer la letra". based on the responses, reading behavior has improved quantitatively. on 18 occasions, parents comment that their children have a hard time reading, on 1 occasion there are minor difficulties and on 1 occasion there are no problems at all. about the main difficulties that children have when they read, in 50% of the cases they answer in vocabulary and text comprehension, 30% in sentences, 15% in vocabulary and 5% in pronunciation. these roughly coincide with the results of the teacher interviews. on 14 occasions they indicate difficulty in understanding and 6 occasions in vocabulary. according to the families, half of the students have a general problem to read a text, which affects all levels of comprehension. secondly, the highest incidence is at the syntactic level. according to the teachers, the main problem is also the understanding as a whole, but the second aspect is the lexicon. most of the teachers value the reading comprehension of texts through auditory or audiovisual means: audio and video on whatsapp (11) and telephone calls (1). there are some teachers that send images of texts (3), who consider that if the students have answered correctly there must have been reading comprehension. the rest don't have a method: 1 of them still does not know how to evaluate reading ability, and 4 did not answer the question. when receiving the teachers' assignments, 8 families respond that their children accept it very well, 6 indicate that they get upset and 6 do not answer. it can be observed that, with high frequency, receiving daily activities provokes emotional conflict in students. teachers not only face the challenge about not knowing their students well but also about having technological difficulties in communicating with them. regarding the ways used to send assignments by most teachers, 17 use whatsapp, 3 virtual platforms, 2 mail and 1 uses both a platform and whatsapp. on this matter, teachers are very often using technological means. instead, it is more debatable whether the use is appropriate. families comment that, at first, the teachers were "inflexible", they use whatsapp broadcast lists. this way of communication did not allow teachers to answer questions. however, after that, teachers opened other spaces to interact. in other words, it was not possible to take advantage of the dialogical character defined by wegerif et al. (2017) from the beginning of the isolation. teachers use these means to send photos of their folders, word files and other activities in pdf. parents were not very happy with these means at the beginning, although the situation has improved. parents point out that it is difficult to interact with the teachers and they do not have the adequate means to follow the teachers' instructions. on the other hand, teachers also have difficulties in communicating with families through technological tools on a continuous basis because many parents cannot receive the homework files and this establishes a significant inequality in their students. the results presented by the carried-out surveys lead us to conclude that both, teachers and families, are making an additional effort due to isolation. it can be seen that both are using digital technologies to overcome the current situation. however, the responses indicate that reading comprehension has worsened and that students and parents have more difficulty to regulate their emotions. it has been observed that, although the number of students who read at home has increased in isolation, the proportion continues being low. this is very relevant in order to solve this situation because reading is essential as a tool for acquiring academic knowledge and for self-knowledge (sevilla vallejo, 2019, p. 243) . in this work, the sample is made up of students with learning disorders, whose requirement to achieve significant learning demands adjustments to access the curriculum. these students had problems with reading comprehension before lockdown, due to the diagnosis presented. likewise, in the psychological work carried out with them, it is observed that not only do they present these difficulties, but they also lack their regulation on an emotional level. in addition, it is verified that the students show negative emotions when they receive their tasks. this may be caused by a lack of understanding of them. the circumstances in which social isolation has occurred have caused teachers not to know the diagnosis of the students and have not had time to prepare for the adaptation of their subjects, because the measure was established just 2 weeks after classes began. although teachers use digital technologies to communicate with students and their families, parents rarely ask them and some teachers have not decided with which methodology to work students' reading comprehension. parents prefer to contact special education teachers or close family members and neighbors first, to help them to solve the activities. in other words, due to the answers given, part of the classroom teaching responsibility has been transferred to the special education teachers. furthermore, it is observed that families are equally concerned about the effects of the situation on sociability and on students' training, while teachers are more concerned about the latter. it can be seen that teachers have more difficulties accompanying students in the aspects most related to emotions. we can conclude that isolation is causing a negative emotional impact on students with learning disorders, since it is currently observed that feelings of exhaustion, frustration, irritability, sadness, anguish and uncertainty prevail. likewise, emotional instability is observed, which also affects academic performance. the lack of regulation of children's emotions is proportionally linked to that of their parents', who have equivalent emotions and have a negative impact on their children. in relation to reading comprehension, it has been observed that a generalized worsening occurs. although students have increased their reading at home quantitatively, the emotional difficulties and the change in the situation in which they receive their training have qualitatively worsened their reading comprehension, which has been impaired in many cases in all linguistic levels that comprise it. the problem of some students' access to digital technologies is also very relevant in order to face the current situation of social isolation. this study shows the necessity to make some changes to reduce the effect of lockdown on emotional regulation and reading comprehension. it is necessary to build a real dialogical education based on a deeper knowledge of the digital technologies and the access to them. students, parents and teachers are not using these tools as effective and they have difficulties to understand their own roles in the current situation. the authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. credit authorship contribution statement santiago sevilla vallejo: writing -original draft. natalia andrea ceballos mar on: writing -original draft. name and surname: child's name: diagnosis of the child: grade and school: 1 does your child have a therapeutic team to accompany him or her at this time? 2 what are the educational consequences at the time of compulsory social isolation? 3 do you think that the teacher and the school are supporting them adequately in the current situation? in what way? 4 how does your child feel right now? 5 how do you feel emotionally right now? do you think it affects your children? 6 how would you evaluate the accomplishment of the school tasks? 7 do you understand the tasks to be carried out? 8 what do you do when you don't understand the activities? do you read generic bibliography, ask the teacher, search the internet, etc.? 9 how often do your children read at home? has this behavior changed? 10 what are the main difficulties that your child has when reading? with the lexicon, with the sentences, with the meaning of the text? 11 is your child having a harder time understanding texts these days? in what sense? 12 how does your child reacts when receiving the teacher's activity? 13 do you want to comment on any other data of interest? name and surname: age: school and grade: 1 do you know all of your students and if any have a school inclusion process? if positive, what is the child's diagnosis? 2 what are the educational implications at this time of compulsory social isolation? 3 are families supporting students appropriately? 4 how do you think your student with a process of school inclusion feels emotionally? and his or her family? 5 how do you accompany them at this time? 6 how would you evaluate your student accomplishment of the school tasks? 7 what is your teaching work method like at the moment? 8 do you think your students are adapting well to the change to remote methodology? 9 how do you value the reading comprehension of the students? have you change the methodology in the current situation? 10 what are the main difficulties that your students have when reading? with the lexicon, with the sentences, with the meaning of the text? 11 these days, do you think students are having a harder time understanding texts? in what sense? 12 how does your students reacts when receiving the teacher's activity? 13 do you want to comment on any other data of interest? claves para la enseñanza de la comprensi on lectora educaci on emocional y competencias b asicas para la vida neuroeducaci on: uniendo las neurociencias y la educaci on en la búsqueda del desarrollo humano el efecto del aislamiento social por el covid-19 en la conciencia emocional y en la comprensi on lectora. estudio sobre la incidencia en alumnos con trastornos de aprendizaje y menor acceso a las nuevas tecnologías [the effect of social isolation by covid-19 on emotional awareness and reading comprehension cuarentena: piden flexibilizar las condiciones para niñez con discapacidad [quarantine: request to make conditions for children with disabilities more flexible educar en argentina de la era digital cognitive emotion regulation strategies and emotional problems in 9-11-years-old children: the development of and instrument gobierno de c ordoba la provincia lanz o la web tu escuela en casa [the province launched the web your high-school at home el papel de la regulaci on de la emoci on en el exito acad emico temprano de niños. revista de psicología escolar navigating fiction: cognitive-affective engagement with place in children's literature apego seguro, vínculos parentales, clima familiar e inteligencia emocional: socializaci on, regulaci on y bienestar ¿c omo autorregulan nuestros alumnos? revisi on del modelo cíclico de zimmerman sobre autorregulaci on del aprendizaje [how do our students self-regulate? review of zimmerman's cyclical model on self-regulation of learning habilidades sociales en niños y niñas con discapacidad intelectual why should teachers tell stories at class? narration for educative and identity purposes la aventura interminable. algunas claves sobre la motivaci on y los procesos de lectura [the neverending adventure la lectura viva. criterios psicol ogicos y did acticos para fomentar el descubrimiento en los textos [living reading. psychological and didactic criteria to exploring the ontological dimension of dialogic education through an evaluation of the impact of internet mediated dialogue across cultural difference key: cord-340512-wjbh1z8y authors: dugas, m.; carnovale, v.; poirier, a.-a.; mailot, b.; skidmore, b.; faust, l.; costello, c.; thomson, d.; majnemer, a.; goldowitz, d.; miller, s.; leblanc, a. title: covid-19 in children with brain-based developmental disabilities: a rapid review date: 2020-05-06 journal: nan doi: 10.1101/2020.05.01.20088021 sha: doc_id: 340512 cord_uid: wjbh1z8y background. the prevalence of symptomatic covid-19 in children remains low to date. in just a few months, covid-19 has affected millions of people worldwide, and as of the date of this publication, the pandemic continues. based on the current available evidence, children do not appear to be at higher risk of contracting covid-19 than adults. however, children with neurological and neuromuscular conditions are vulnerable to the respiratory complications of other viral infections. objectives. to assess whether children with brain-based developmental disabilities were more likely to develop covid-19 and have complications or poorer outcomes following infection. methods. we conducted a two-week rapid review on studies with primary data regarding children aged between zero and 18 years old with brain-based developmental disabilities, or who were at risk of developing such disabilities, with confirmed or suspected covid-19. we performed our literature searches on april 18, 2020. results. our search strategy identified 538 individual records, of which four were included in our review. of the 50 covid-19 pediatric patients reported in the included studies, a total of seven children were at risk of developing brain-based disabilities. symptoms ranged in severity. however, generally, patients were discharged or saw improvements in their symptoms by the end of the study period. no deaths were reported. discussion. our study highlights a knowledge gap regarding the impact of covid-19 in children with brain-based developmental disabilities. according to the world health organization, sars-cov-2 has infected close to three million and caused the death of over 200 000 individuals worldwide, as of april 26th, 2020 (1) . the prevalence of covid-19 in children remains low to date. of the 23,082 cases reported in canada (april 23rd, 2020), 1,055 (4.6%) were in patients aged 19 years old and under (2) . of those, 14 were hospitalized, and two were admitted to intensive care unit, with no deaths being reported. data gathered for the u.s. between february 12th, 2020 and april 2nd, 2020 indicated that of the 149,760 cases, 1.5% (2, 572) were children, of which 13% had underlying conditions, 5 .7% were hospitalized, and included three deaths (3) . as of february 11th 2020, china had reported that of 44,672 confirmed cases in mainland china, 965 (2.1%) were children, with one reported death (4) . as of april 24rd, 2020, a total of 150,383 cases were reported in germany, of which 2,476 (2%) were under 10 years old, and 6,209 (4%) were aged between 10 to 19 years old (5) . numbers of hospitalizations and deaths were not available. finally, as of march 12th, 2020, 7,755 cases were reported in the republic of korea, of which 480 (6.2%) were pediatric, with no deaths being reported (6) . based on the current available evidence, children do not appear to be at higher risk of contracting covid-19 than adults (7) . however, children with comorbidities may be vulnerable to severe covid-19 disease (8) . indeed, children with neurological and neuromuscular conditions had an increased risk of respiratory failure when hospitalized with influenza, another viral infection (9) . symptom manifestation in children appears to be milder than in adults (10, 11) . further, the incidence in individuals under 19 years of age has been quite low (8, 10, 12) and children could even be less susceptible to the covid-19 disease (7) . to the best of our knowledge, no review has searched for the impact of covid-19 on children with brain-based disabilities affected by covid-19. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 6, 2020. this rapid review was commissioned by the strategy for patient-oriented research (spor) funded child-bright network, an innovative pan-canadian network that aims to improve life outcomes for children with brain-based developmental disabilities and their families (https://www.child-bright.ca/). concerned with the potential impact of the novel coronavirus on children with brain-based developmental disabilities, they requested support from the spor evidence alliance to conduct a rapid review within a two-week period, on the topic. thus, this review aimed to answer the following questions: 1) are children with brain-based developmental disabilities more likely to develop covid2) are children with brain-based developmental disabilities more likely to develop complications due to covid-19? 3) are children with brain-based developmental disabilities more likely to have a poorer prognosis once they develop covid-19? we engaged with a panel of knowledge users (patients, caregivers, clinicians, decision makers) and researchers from the child-bright network throughout the review process, from question development, literature search, interpretation and writing of results, and dissemination of findings. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint we conducted the rapid review based on the proposed methodology guide of the cochrane rapid reviews methods group (13) . we report our results based on the preferred reporting items for systematic reviews and meta-analyses (prisma) statement (14) . an experienced medical information specialist developed the search strategies through an iterative process in consultation with the review team and the panel of knowledge users. the we used a combination of controlled vocabulary and keywords (e.g., "coronavirus infections", "coronavirus", "child") for the strategies and adjusted vocabulary and syntax across databases. we initially also included vocabulary and keywords specific to brain-based developmental disabilities but removed them after piloting of that strategy yielded no citations to be included in the review. there were no language restrictions on any of the searches but when possible, animal-only records were removed from the results. we limited results to publication years 2019 to the present. specific details regarding the strategies appear in appendix 1. from the included studies and the reviews identified from our searches, we reviewed reference lists for original studies and cross-referenced them with a list of articles provided by content experts from our knowledge users panel. considering the fast pace at which information becomes available in the context of covid-19, we developed a grey literature search strategy in consultation with our experienced medical information specialist, which consisted of preprint articles from ssrn and medrxiv (last consulted april 23 rd , 2020), ongoing trials from the who international clinical trials registry platform (last consulted april 23 rd , 2020), ongoing reviews . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint from prospero (last consulted april 23 rd , 2020), and government or health organizations' websites and reports (consulted between april 17 th to april 25 th , 2020) (appendix 2). we followed the peco framework in establishing eligibility criteria (16, 17) (table 1) . we considered any study with primary data that included children aged between zero and 18 with a brain-based developmental disability or at risk of developing such disability with confirmed or suspected covid-19 (see appendix 3 for full list). children (18 years and under) with brain-based developmental disabilities (e.g., cerebral palsy, autism, developmental delay, attention deficit hyperactivity disorder, severe impairments) or at risk of developing brain-based disabilities (e.g., premature, congenital heart disease/defect). covid-19 any outcome four reviewers individually performed screening for titles, abstracts and then full text using pilot-tested standardized forms (25 and five citations respectively for each level of screening). we developed a standardized extraction form that included study (e.g., authors, country, study design) and case characteristics (e.g., type of disability, age), complications, and any outcome reported. single reviewers extracted data which was then confirmed by a senior reviewer. we resolved discrepancies through discussion. no risk of bias was performed due to the short turnaround timeline. we report data using a narrative approach which includes tables of study characteristics and detailed reporting of case characteristics, complications, and outcomes. our data synthesis focused on providing a descriptive summary to inform knowledge users. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 6, 2020. our search strategy identified 538 individual records. following the screening of titles and abstracts, we excluded 331 records. after full-text screening of 207 records, we excluded an additional 203 records resulting in a total of four records included in our review (18-21) ( figure 1 ). our grey literature search did not identify any ongoing trials or preprint articles of research regarding children with brain-based developmental disabilities. of the four included studies, one was a case report (18) , one was a cohort study (19) , one was a retrospective cross-sectional analysis (20) , and one was a retrospective study of medical records (21) ( table 2) . three studies took place in wuhan, hubei province, china (19) (20) (21) and one in the . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint u.s. (18) . the four included studies reported on a total of 80 pediatric patients with 50 infected or suspected of being infected. we did not identify any study reporting on children with brain-based developmental disabilities, all included studies reported on children at risk of developing a brain-based developmental disability. two of the studies included preterm infants (18, 19) while the others included children with congenital heart disease or epilepsy (20, 21) . detailed information was only available for three of the four studies (18) (19) (20) (table 3) . symptoms for preterm infants ranged from a single fever to overall mild symptoms (18, 19) , with one infant developing complications (fetal distress, neonatal respiratory distress syndrome, pneumonia, and suspected sepsis) and requiring resuscitation at birth (19) . the preterm infant . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint without complications was discharged in stable condition (18) whereas the infant developing complications saw its condition resolve on day 14 of life (19) . children with congenital heart disease expressed symptoms including cough, dyspnea, fever, and diarrhea and required pediatric intensive care with invasive mechanical ventilation (20) . their symptoms were later partially or significantly alleviated (20) . the fourth study identified one patient with epilepsy (resulting from sequela of previous encephalitis) and two with a history of atrial septal defect surgery but no individual information was available (21) . overall, symptoms were mild, and eighteen of the 20 children were cured and discharged with an average stay of 12.9 days (8-20 days). . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint the prevalence of covid-19 in children has been reported as being low. however, we were unable to find information regarding the prevalence of this coronavirus in children with brainbased developmental disabilities. we did not identify any study investigating the effects of covid-19 in children with brain-based disabilities but did identify four studies discussing the coronavirus disease in children considered at risk for disability (preterm infants or children with some pre-existing medical conditions). although some of the children in the included studies did develop complications, symptoms were reported as being partially or significantly alleviated or resolved, with most patients being discharged from the hospital and no deaths being reported. these results are in accordance with other studies on covid-19 in children which reported that symptoms in the pediatric population appeared milder than in adults with the occurrence of death being very rare (11, 12, 22) . our review highlights the lack of evidence regarding the effects of covid-19 in children with brain-based disabilities and those with at-risk conditions. indeed, it appears as though this specific population has been overlooked. the lack of data could be due to the low occurrence rates as well as the milder symptoms which have previously been reported in children (11, 12, 22) . in addition, it is possible that due to their milder or absent symptoms, these cases simply do not get reported. however, clinical guidelines from the centers for disease control and prevention (cdc) clearly state that individuals of any age with underlying conditions, including congenital heart disease, may be at higher risk of developing moderate to severe symptoms from covid-19 (23) . moreover, unicef warns that children with underlying disabilities may be at greater risk of developing complications (24) . more data, including the presence of brainbased disabilities and other at-risk conditions in children, are required to have a better understanding of the clinical impacts of covid-19 on these potentially more vulnerable populations. with that goal in mind, one ongoing review is currently examining comorbidities in the adult and pediatric populations (25) . our rapid review has limitations. due to our study design, screenings and data extractions were performed by single reviewers. however, we did perform pilot-testing for each review form to optimize consistency between reviewers. further, despite our best efforts to identify all relevant . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 6, 2020. . https://doi.org/10.1101/2020.05.01.20088021 doi: medrxiv preprint studies or relevant documentation, it is possible that some were missed due to the rapid flow at which new information becomes available. our rapid review has identified knowledge gaps in the literature regarding the effects of covid-19 in children with developmental brain-based disabilities, and those at risk of developing such disabilities. without data regarding children and high-risk populations, it is difficult for decisionmakers to determine the best course of action not only for medical treatment, but also the reintegration of children with disabilities to school and the community with regards to the eventually alleviated confinement measures. world health organization. coronavirus disease 2019 (covid-19) daily epidemiology update coronavirus disease 2019 in children -united states the novel coronavirus pneumonia emergency response epidemiology team. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china the first 7,755 cases in the republic of korea are children less susceptible to covid-19 novel coronavirus infections: standard/protocol/guideline recommendations for the diagnosis, prevention and control of the 2019 novel coronavirus infection in children (the second edition) neurological and neuromuscular disease as a risk factor for respiratory failure in children hospitalized with influenza infection characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention clinical and epidemiological features of 36 children with coronavirus disease 2019 (covid-19) in zhejiang, china: an observational cohort study. the lancet infectious diseases why is covid-19 so mild in children? acta paediatrica cochrane rapid reviews. interim guidance from the cochrane rapid reviews methods group preferred reporting items for systematic reviews and meta-analyses: the prisma statement press peer review of electronic search strategies: 2015 guideline statement evaluation of pico as a knowledge representation for clinical questions utilization of the pico framework to improve searching pubmed for clinical questions. bmc medical informatics and decision making sars-cov-2 infection (covid-19) in febrile infants without respiratory distress neonatal early-onset infection with sars-cov-2 in 33 neonates born to mothers with covid-19 in wuhan, china. jama pediatrics clinical characteristics of children with coronavirus disease clinical and ct features in pediatric patients with covid-19 infection: different points from adults. pediatric pulmonology systematic review of covid-19 in children show milder cases and a better prognosis than adults people who are at higher risk for severe illness: center for disease control and prevention covid-19 response: considerations for children and adults with disabilities prevalence of symptoms and comorbid conditions in novel coronavirus (covid-19)-infected adult and paediatric patients: a systematic review and metaanalysis of first three-month data of the outbreak crd42020176341 the authors would like to thank the panel of knowledge users for their support throughout this review. the authors have no conflict of interests to declare. key: cord-326328-9w2p3xla authors: jenkins, ian a.; saunders, michael title: infections of the airway date: 2009-06-25 journal: paediatr anaesth doi: 10.1111/j.1460-9592.2009.02999.x sha: doc_id: 326328 cord_uid: 9w2p3xla infections of the airway in children may present to the anesthetist as an emergency in several locations: the emergency department, the operating department or on intensive care. in all of these locations, relevant and up to date knowledge of presentations, diagnoses, potential complications and clinical management will help the anesthetist and the surgical team, not only with the performance of their interventions, but also in buying time before these are undertaken, avoiding complications and altering the eventual outcome for the child. diseases such as epiglottitis and diphtheria may show diminished incidence but they have not gone away and their clinical features and essential management remain unchanged. paradoxically, perhaps, some conditions such as lemierre’s syndrome appear to be making a comeback. in these instances, clinicians need to be alert to these less common conditions, not only in regard to the disease itself but also to potentially serious complications. this article describes those infections of the airway that are most likely to present to the anesthetist, their attendant complications and recommendations for treatment. given that both viral and bacterial infections may produce disorders of similar presentation and sometimes may do this concurrently, it is more logical to examine these disorders by the site and nature of their condition rather than by their infective origin. in a 6-year series of head and neck infections in children, it was noted that 49% affected the peritonsillar space, 22% the retropharyngeal and 2% para-pharyngeal (1) . tonsillitis, peritonsillar abscess, retro-or parapharyngeal abscesses may compromise the airway and so these will be described in turn, together with rarer but important conditions and their complications. bacterial tonsillitis & peritonsillar abscess (quinsy). bacterial tonsillitis can cause airway compromise without extension into surrounding tissue (figure 1 ), although this is unusual and more likely in mononucleosis (see below). the lingual tonsil has also been implicated in airway compromise (2) . the typical flora associated with tonsillitis comprises aerobes; streptococcus pyogenes, staphylococcus aureus and pneumococci, and anaerobes; fusobacterium spp., prevotella spp., porphyromonas spp. and actinomyces spp. aerobes predominate in the acute primary infection, whereas anaerobes are associated with abscess formation or extension across tissues that form deeper infections through fascial planes (3) . penicillin resistance in beta-lactamase forming organisms is common and third generation cephalosporins or amoxicillin-clavulanate should be used, in part, because they allow growth of 'nonpathogenic interfering bacteria' which compete with the pathogens (3) . where the infection has extended outside of the tonsil itself, antibiotics effective against anaerobes should be used; metronidazole, carbapenems or beta-lactamase resistant penicillins (e.g. amoxicillin-clavulanate, piperacillin-tazobactam). if the patient is toxic, then clindamycin or linezolid should be added for their ability to prevent bacterial exotoxin release (4) . there is some controversy whether surgical removal of tonsils that have caused airway compromise should be undertaken early because of possible excessive bleeding (5) . when pus has formed, surgical drainage is usually indicated to prevent spontaneous rupture and the serious risks of aspiration, extension into the mediastinum or laterally causing erosion of blood vessels (6) . infectious mononucleosis (im) can cause compromise of the airway ( figure 2 ) and this has been reported in as many as 25-60% of children presenting with im (7) (8) (9) . although most authors since the 1960s have advocated the use of glucocorticoids to avert the need for surgical intervention, several series note that, despite steroids, 40-88% of patients with airway obstruction required tonsillectomy (7, 9) . in these reports, no cases of excessive hemorrhage were noted. the use of glucocorticoids does reduce duration of fever, pharyngitis and abnormal hematological findings and does not appear to be associated with a predilection for development of peritonsillar abscess (10). the bacterial organisms involved in these infections are identical to those producing peri-tonsillar abscesses and can be considered together from the point of view of their microbiology and clinical management as 'deep neck infections' (11, 12) . the retropharyngeal space contains loose connective tissue and lymph nodes that drain the nasopharynx, paranasal sinuses, middle ear, teeth and adjacent bones. retropharyngeal abscesses are more common in young children and this may be because lymph tissue in this area involutes and atrophies in older patients (13) . most studies give a male to female ratio of nearly 2 : 1 (11, 14) and a median age of 32.5-36 months (15, 16) . the incidence of this condition appears to be markedly on the rise (15) . in a recent series covering 11 years (1995-2006) and 162 children with retropharyngeal abscesses, page (11) noted a linearly rising incidence over the study period. computed tomography was performed in 94% and had an accuracy of 68%. the principal symptoms were fever, sore throat, torticollis and neck pain. there was obstruction of the airway in only 8%. the commonest clinical signs were lymphadenopathy, local tenderness and limited range of movement. however, more specific findings were somewhat less common, e.g. pharyngeal bulge in 23% (figure 3 ), tonsillar deviation in 12% and drooling in 10%. at drainage, 80% of cases showed cloudy fluid or frank pus. a single organism was grown in 25% and polymicrobial in 79%; organisms include group a b-hemolytic streptococci, streptococci, staph. aureus, of which 30% were methicillin-resistant, moraxella, haemophilus and other mixed oropharyngeal flora. features associated with surgical drainage were symptoms for 2 days or more, prior administration of antibiotics and fluid on computed tomography scan with a cross-sectional area of >2 cm 2 . there was a trend indicating pharyngeal bulge as a factor but not significant (p = 0.051). some authors disagree with the primacy of surgery as the treatment of choice (16, 17) particularly where clindamycin was used in all cases and combined with cefuroxime in most (17) . airway compromise may be more frequent in those below 1-year-old group (18) .the anesthetic management of airways obstructed by such abscesses can be challenging. the airway must be secured without rupturing the abscess and soiling the airway with pus. inflammation may also have extended to adjacent tissues and the glottis may be hard to visualize and even to locate (19) . where there is stridor a cautious inhalational induction with an otolaryngologist present is appropriate, either in the or or in the icu. the use of a cuffed endotracheal tube will be useful to prevent soiling of the lungs from either spontaneous rupture or surgical drainage of the abscess. the use of cuffed tubes, even in young children, has been shown to be safe (20) (21) (22) . administration of glucocorticoids does not feature in the large series quoted here and there is no evidence of benefit (11, 16) . more than two-thirds of deep neck abscess contain beta-lactamase producing organisms and most abscesses contain anaerobes (6) . antibiotic treatment must take these features into account. complications of these abscesses are descending mediastinitis and lemierre's syndrome. mediastinitis following retropharyngeal abscess (see figure 4 ) may be more common in younger patents and those with methicillin-resistant staph. aureus (mrsa) infections (15) . mediastinitis has been associated with a high mortality ranging from 16.5 to 50% and the place of surgery to drain the areas affected a subject of debate ct with contrast -retropharyngeal abscess with descending mediastinitis: a, abscess; b, nasogastric tube. but should probably depend on response to maximal antibiotic therapy and monitoring of both clinical infective markers and radiological appearances (23). this is a relatively rare but possibly increasingly seen complication of pharyngo-tonsillar infections (24, 25) ; 'the forgotten disease' (24) . in 1936, lemierre described a condition of 'anaerobic postanginal septicaemias' associated with 'bacillus funduliformis' -now known as fusobacterium necrophorum -and 'b. symbiophiles' (26). this paper described an evolving condition beginning with suppuration at the local site, followed by thrombophlebitis with septic emboli a later feature. no specificity was attributed to f. necrophorum but rather a recognition that the picture may be caused by normally saprophytic anaerobes, possibly working in synergy (26) , and indeed its growth may be promoted by coexisting aerobes (27) . the septicemic phase typically occurs 4-5 days after the onset of a sore throat or tonsillitis and is characterized by a rise in temperature and rigors, whereas the original pharyngeal ⁄ tonsillar condition may have improved (28) . the infection has local effects, classically causing thrombosis in the ipsilateral internal jugular vein (ijv), and more distant spread with suppuration most commonly affecting the lungs, but also causing septic arthritis and osteomyelitis, meningitis and liver, renal and skin abscesses ('necrobacillosis') (28). lemierre's syndrome is normally associated with previously healthy adolescents and young adults. mortality in the preantibiotic era was 90% and still runs at 4-12% depending on promptness of detection (29) and where fulminant, cavitating suppuration can still be seen (30) . however, the full syndrome has been reported in a 3-year old child (31) . additionally, ijv thrombosis has been reported in a 5-month old with mastoiditis infected with f. necrophorum (32) and in a 3-month-old female infant with a retropharyngeal abscess infected with mrsa (33) . examples of both thrombosis of the ijvs and thrombosis in the pulmonary artery are shown in figures 5 and 6 in a patient presenting with a retropharyngeal abscess complicated by descending mediastinitis (seen above in figure 4) where streptococcus milleri was the organism isolated from blood and abscess. the incidence of this condition is rising. whether this is due to better forms of detecting the anaerobic bacteria involved is doubtful, as this is a condition with a distinct clinical presentation (25, 26, 30) . another theory is that the move away from treating pharyngitis and tonsillitis with antibiotics in primary care has allowed bacterial infections to cause the conditions in which these anaerobic saprophytes can cause opportunistic, but disastrous, infections (25, 27, 28) . additionally, there may be a genetic explanation why some individuals develop a serious infection from a normally harmless saprophyte (34). ct with contrast -retropharyngeal abscess with thrombophlebitis: a, right internal jugular vein with intraluminal thrombosis (also seen on left); b, internal carotid artery; c, trachea with endotracheal tube; d, nasogastric tube; e, descending retropharyngeal abscess; f, replogle tube placed into abscess cavity. ct scan with contrast -thrombus sitting within branch of left pulmonary artery (same patient as figure 5 ). treatment should be intravenous to start with, using high-dose penicillin with metronidazole or monotherapy with clindamycin. in penicillin allergy, clindamycin should be used because f. necrophorum can show resistance to macrolides. a total duration of 2-6 weeks is recommended as viable bacteria can be found in necrotic abscess formations for some weeks (27) . the clinical case for or against anticoagulation is not clear; however, in cases of propagating thrombosis or embolization, heparin administration is advisable (27) . septic presentations in young people, even when these seem to affect distal sites such as the lungs or the liver should be accompanied by examination of the head, neck and throat to exclude a rare but classic disease (27, 30) . initially described in 1836, this is a diffuse infection of the submandibular and sublingual spaces. symptoms of severe pain, fever, malaise and dysphagia occur with swelling that can be large enough to cause airway compromise. normally associated with dental caries, sickle cell disease, immunodeficiency and trauma, it can occur de novo in children (35, 36) . in one series from india, the proportion of children was 24% (35) . it has been described in a 4-month-old infant (37) . bacterial isolates are variable; staphylococci, a-haemolytic streptococci and anaerobes such as bacteroides, peptococci and peptostreptococci (36) . antibiotic treatment covering these organisms should include metronidazole, penicillin, flucloxacillin or penicillin-betalactam inhibitor combinations: ticarcillin-clavulanate, amoxicillin-clavulanate or piperacillin-tazobactam. where penicillin allergy occurs, clindamycin is effective (36) . reduction of edema with glucocorticoids has been proposed (38) but there are no controlled studies to support this. surgical drainage is sometimes indicated where there is accumulation of pus (35) . recurrent respiratory papillomatosis (rrp) is caused by the human papilloma virus (hpv), usually types 6 and 11; the same types seen in more than 90% of genital condylomata and has a prevalence varyingly reported as 3-5 per 100 000 population (39, 40) . it usually affects the larynx and typical lesions are shown in figure 7 . the squamouscolumnar junction is the most frequently affected area (39) but this can extend distally to the larger airways in as much as 29% of patients and intrapulmonary in 7% (41) . the obstruction is of slow onset and the presenting symptom usually hoarseness but if the diagnosis is delayed respiratory obstruction may supervene (39) , especially with concomitant acute respiratory infection (40) . a more aggressive course is seen in the younger the age of first presentation and in those infected with type 11 (40) . possibly, 25% of all childbearing women worldwide harbor hpv in the genital tract. although cesarean section possibly reduces transmission, it is thought that transmission may occur in utero (42) . the papillomata are treated with laser (co 2 or ktp) or endoscopic micro-debridement. surgical access to these lesions is most often achieved using a suspension laryngoscope and anesthesia achieved with either spontaneous ventilation with insufflation of gases into the hypopharynx or by jet ventilation. the latter can be used either supra-or infra-glottically by rigid cannulae fixed to the laryngoscope (43) . in either case, an antisialogogue is administered and topical lidocaine sprayed onto the larynx (max. 6 mgaekg )1 ) (44, 45) . disadvantages of jet ventilation, particularly supra-glottically, are the potential dispersion of papillomatous matter distally and the need for muscle relaxation and, if used sub-glottically, one must ensure adequate escape of gases to prevent barotrauma. however, contamination of the field and the or with vapors are then avoided (46) . advantages of spontaneous ventilation are the preservation of the patient's respiratory drive, a potential safety factor, and the relative containment of debrided material. additionally, total intravenous anesthesia can reduce or supplant the need for vapors (44) (45) (46) . tracheostomy is generally avoided as this is associated with increased distal spread (41) . attention has been increasingly paid to 'adjuvant therapies' such as: interferon -given subcutaneously for 6 months, ribavirin and acyclovir. more recently intra-lesional injections of cidofovir have become the most common adjuvant in resistant cases and it has been given systemically for intrapulmonary lesions with some success. however, there is an association with carcinogenicity in animals and so it needs to be used selectively. recently, a quadrivalent vaccine has been developed against types 6, 11, 16 and 18, the major causes of rrp, and it is hoped that this will reduce the exposure of infants to this vertically transmissible disease (40) . historically, epiglottitis has been associated primarily with haemophilus influenzae infections, typically occurring in children aged 3 months to 5 years, with a peak incidence between 1 and 3 years, and characterized by a rapid onset of fever, drooling and stridor (47) . haemophilus influenzae is a gramnegative coccobacillus that affects only humans. serious infections are usually caused by the capsulated forms, serotypes a to f. however, type b (hib) was responsible for approximately 85% of invasive disease in children prior to immunization against this type (48) and epiglottitis accounted for about 12% of hib infections (49) . for those nations who undertook widespread immunization in the late 1980s and early 1990s, the incidence of hib-related infections dropped dramatically. the adult form seems different; a slower onset of symptoms where dysphagia and sore throat precede stridor (47), a more diffuse anatomic involvement, justifying the term supraglottitis (50) , and half the need for airway intervention (47) . in the uk, there was a resurgence in 2003 with over 260 cases of hib infections, causing a booster program to be launched (51) . the uk vaccine is now thought to be only 57% effective (52) . this may be due to its acellular composition. where whole cell vaccines are utilized, effectiveness rates of 95-100% have been demonstrated in california and the gambia (53) . in the postvaccination era, epiglottis is more likely to be an infection with a 'vaccination breakthrough' type b, or infection with any of the other organisms associated with this condition; h. parainfluenzae, group a streptococci, pneumococci or staphylococci (54) (55) (56) . in immuno-compromised patients, this can also include candida spp., herpes simplex type 1, varicella zoster and parainfluenza. vaccination failure is thought to be due either insufficient antibody level (57, 58) or to a defect in immunological priming and a decrease in avidity of anticapsular antibodies (59) . the child will be pyrexial and possibly toxic, dysphagic, possibly drooling, anxious and will often adopt a characteristic posture, sitting forward with the head extended; the so-called sniffing position (60) . this situation requires skilled airway management with inhalational induction, the presence of an otolaryngologist prepared to undertake emergency tracheostomy (58) and administration of broad spectrum antibiotics (54, 55, 61) . practice varies considerably regarding imaging prior to securing the airway. either computed tomography or lateral neck radiographs (looking for the 'thumb sign') are still frequently undertaken in some centers; 84% of cases in one us series (55) . stridor is a late feature and imaging should not delay securing the airway (45, 50) and consequently is very often not performed at all, where the priority is seen to be clinical diagnosis and the securing of the airway with confirmation of diagnosis at laryngoscopy (58) . the child can be re-intubated nasally and then managed on the pediatric intensive care unit (picu). practice varies between keeping the child sedated and possibly ventilated, or allowing the child to wake and breath spontaneously. if the child is awake, some form of physical restraint is frequently used to prevent accidental extubation and a heat and moisture exchanger attached to the endotracheal tube to prevent drying of secretions. the choice of antibiotics will vary depending on local flora but should always include an agent with beta-lactamase resistance; a third generation cephalosporin or a penicillin-derived drug combined with a beta-lactamase inhibitor (55, 58, 62) . some authors recommend administration of steroids (50,55) but this practice is not universal and does not alter outcomes with respect to intubation, duration of intubation, icu stay or hospitalization (47) . in a more recent series from denmark, the use of steroids was associated with longer hospital stay. this may have been because those receiving steroids were more severely compromised patients but, again, no evidence of benefit was demonstrated (63) . extubation is usually possible after 48 h (45). inhalational anesthesia can be employed so that the airway can be reassessed and extubation then performed under controlled conditions. this is a fairly common childhood disease characterized by a distinctive barky, hoarse cough progressing to stridor. this is initially associated with inspiratory subcostal recession and then, as the condition worsens, sternal recession and expiratory stridor. these symptoms are often preceded by a nonspecific upper respiratory tract infection for 12-48 h. denny et al. carried out an 11-year study showing that croup occurs between 6 months and 3 years of age, with a peak incidence during the second year. the parainfluenza viruses accounted for 74.2% of all isolates with 65% parainfluenza type1 (64) . respiratory syncytial virus (rsv), influenza viruses a and b, and mycoplasma pneumoniae were the only other agents isolated in appreciable numbers. rsv caused croup in children less than 5 years of age whereas the influenza viruses and m. pneumoniae were significant causes of croup only in children more than 5-6 years old (64) . an increasing variety of viruses are now associated with croup, undoubtedly because of improving methods of detection. in 2004, human metapneumovirus was demonstrated 20% of previously virusnegative samples, a fifth of these had presented with croup (65) . coronavirus was first described in german children in 2005 (66) and bocavirus recently in korea, with less predominance of parainfluenza 1 (67) . parainfluenza virus has specific effects on the ion transport of respiratory epithelium, which causes more airway secretions and exacerbates the effects of tissue edema (68) . mortality is relatively rare and an extensive review of the literature estimates overall mortality at 1 in 30 000 cases (60) . although the diagnosis is usually clear, the differential should include foreign body aspiration, epiglottitis, bacterial tracheitis, tonsillitis and peri-tonsillar and retropharyngeal abscesses, tracheobronchiomalacia or vascular rings. mediastinal masses can also present with 'croup' in all age groups (69) . on a worldwide basis, laryngeal diphtheria still occurs and also presents at any age (see below). the presentation is usually with acute onset of a barky, coarse cough, hoarseness and respiratory distress with stridor ( figure 8 ). pyrexia is usually present but the child should not drool nor appear toxic. laboratory and radiologic tests are not needed to confirm the diagnosis. indeed, such unnecessary disturbance may make the situation worse. only where the diagnosis remains uncertain in the absence of clinical features either for or against the diagnosis of croup should imaging take place. simple antero-posterior and lateral neck and chest radiographs may then indicate the presence of one of the differential diagnoses. it is clearly safer for the radiography to be performed in the ed, or or icu, rather than the child travel to the radiology department for such investigations (60) . the management consists of minimal disturbance, making a clinical assessment of the degree of severity and administering glucocorticoids, nebulized epinephrine, antipyretics. the use of humidified gases, although a traditional therapy, has been shown not to have any benefit on outcome (70) . most studies employ the 'westley score' of assessing the severity of the condition (71) but this has not found its way into general clinical practice because of reported inter-observer variance (60) . a meta-analysis of studies showed that treatment with glucocorticoids was associated with nearly a fivefold reduction on the rate of intubation (72) . if intubated, the duration of intubation and the rate of reintubation are reduced (73), although a meta-analysis was repeated in 1999, selecting only for randomized controlled studies, which found that while there was general benefit on administering glucocorticoids, no effect on intubation rates was demonstrated (74) . although the inhaled route is of benefit, the best routes to give glucocorticoids are intramuscular or oral (75) . it appears dexamethasone at 150 lgaekg )1 is superior to prednisolone 1 mgaekg )1 (76) . it has been observed that the duration of the anti-inflammatory effect of one dose of dexamethasone is 2-4 days and the natural history of croup last approximately 72 h, thus making subsequent doses superfluous (60) . regarding the exact dose of dexamethasone required, two recent studies suggest that 150 lgaekg )1 is as effective as 600 lgaekg )1 (77, 78) . should the clinical condition be severe on presentation or deteriorate despite steroids, value of nebulized epinephrine has long been established (71, 79, 80) . these effects have a duration of less than 2 h but there does not appear to be a 'rebound' in deterioration (71) . although the first studies were done using racemic epinephrine, the more commonly available 'l l-epinephrine' is just as effective (81) . a systematic review of dosage concluded that use of 3-5 ml of 'neat' 1 : 1000 l l-epinephrine was safe and effective (82) . paradoxically perhaps, the only report of ventricular tachycardia and a myocardial infarction in an otherwise healthy 11-year old with normal echocardiography and coronary anatomy was associated with the use of diluted racemic epinephrine (83) . should the above measures fail, then consideration can be given to the administration of a heliumoxygen mixture ('heliox'), which is examined in a separate section. otherwise, the child should be intubated in a controlled manner with the most skilled anesthetic practitioner available. the usual provisos apply: a full range of airway instrumentation and the presence of an otolaryngologist prepared to undertake tracheostomy should intubation fail. preservation of spontaneous ventilation till the airway is secured is still recommended, especially when there may be co-existing problems such as underlying tracheal stenosis or compression (69, 84) and best achieved with nonirritant inhalational vapors such as sevoflurane and halothane. typical appearances of the larynx on intubation are shown in figure 9 . endotracheal tubes of at least one whole size smaller than predicted by age should be available and so it is unrealistic to expect a leak round the endotracheal tube once the airway is secured. the croup -diffuse acute laryngotracheitis. child should be cared for in the intensive care unit and the size of the tube may well dictate whether the child should be managed spontaneously ventilating (and possibly awake) or remaining sedated and ventilated. the tube is left in place until there is a clear leak indicating resolution of the edema. if the clinical course extends beyond 48 h further dosing of steroids should be considered (60, 73) . normally this condition resolves within a week. if this does not occur then other diagnoses, mentioned above, should be considered. some clinicians prefer to extubate with the child re-anesthetized but spontaneously ventilating to assess the adequacy of the airway. if there is any suspicion of bacterial secondary infection, then treatment for bacterial tracheitis should be commenced (see appropriate section below). from a world viewpoint, diphtheria is still very much with us. it is caused by cornyebacterium diphtheriae and cornyebacterium ulcerans. it is a condition commencing with a croup-like illness, cough and sore throat, but often progressing to death through sepsis (disseminated intravascular coagulation and renal failure), suffocation by the 'pseudomembranes' of serocellular exudate forming in the respiratory tract, and direct effects of the powerful exotoxin that has affinity for neural endings (paralysis), cardiac muscle (heart block and myocardial failure) and the adrenal glands (hypotension with endocrine failure) (85) . electrocardiogram abnormalities can occur in the first week; the overall incidence of cardiomyopathy is 10-20% and this has a mortality of about 50% (86) . immunization was commenced in the uk in 1942 and the incidence of deaths plummeted, so that by 1952 it was extremely rare (87) . the last child deaths from diphtheria infection in the uk were in 1994, in an immigrant child infected in pakistan, and then in may 2008, in a child that was not immunized and had moved from europe to the uk in late 2007. swabs from family and hospital contacts proved negative (88) . sporadic cases occur in countries with developed immunization programs as a result of immigration (89) . unless there is a high index of suspicion, it is a diagnosis easily missed. even if correct management is instituted early, there is an appreciable mortality of 8-10% (86, 89) . presence of pseudomembranes and 'bull neck' are predictive of development of cardiomyopathy (86) . a breakdown in primary immunization and booster programs led to the major outbreak in former soviet states 1990-1995, where nearly 50 000 cases occurred (90) . in a large series of 154 children in 1 year in vietnam, treatment consisted of specific antitoxin, high-dose penicillin (or erythromycin if allergic) and intravenous hydrocortisone for severe neck edema. if edema or laryngeal pseudomembranes were causing obstruction, tracheotomy was performed (86). it is possible that this condition is becoming relatively more common. over a 10-year period in vermont, usa, of the airway infections causing picu admissions, tracheitis was the most common. whereas only 17% of viral croup admissions were intubated, 83% of those with tracheitis were. only 6% of picu admissions in this period had epiglottitis (91) . immunizations against haemophilus type b and the efficacy of glucocorticoids in viral croup may have changed the spectrum of picu admissions. the clinical presentation often follows a prodrome of viral upper respiratory infection, but with sudden progression of cough, stridor and pyrexia with a toxic element (92) (see figure 8 ). the endoscopic features are erythema, edema and thick purulent secretions (91) -see figure 10 ; sometimes these have the appearance of pseudomembranes (93) . the microbiology is mixed; predominantly staph. aureus -the most frequent according to most authors (91, 93, 94) , streptococcus pneumoniae, lancefield group a streptococci, moraxella catarrhalis and haemophilus spp. (92, 93) . the presence of moraxella was associated with a higher intubation rate (93) . these bacterial infections may occur in the presence of influenza virus a or b (91) but the presence of viruses did not relate to the intubation rate (93) . the therapy consists primarily of antibiotics; these should cover the likely flora and so include third generation cephalosporins with anti-staphylococcal agents, e.g. cefotaxime and flucloxacillin. glucocorticoids are not thought to have any beneficial effect on the course of the disease, which may develop into full blown sepsis with pneumonia and acute respiratory distress syndrome (91, 94) . salamone reported a 10-year series of 94 cases and described a subset of patients that have exudative pseudomembranes that required repeat debridement by bronchoscope and termed this 'exudative tracheitis' (93) . with increasing respiratory distress intubation is necessary. if the diagnosis is in doubt then inhalation induction should be considered and the presence of an otolaryngologist is recommended especially where tenacious secretions may require immediate bronchoscopy and bronchial toilet (93) . respiratory difficulties observed with obstructed airways may not be due simply the proximal obstruction itself. increasing respiratory effort is capable of quite large decreases in intrapleural pressure. this will increase the pressure gradient across the pulmonary capillary and override the starling equilibrium. the resulting transudation of fluid will cause acute pulmonary edema (95) . hypoxia itself will cause failure of the integrity of the alveolar-capillary membrane and exacerbate the transudative leak. the result is decreased pulmonary compliance which then, in turn, exacerbates the child's dyspnea and respiratory compromise (95, 96) . two gas physics equations provide the rationale for substituting helium for the nitrogen in air where there is airway compromise. the poiseuille equation applies to laminar flow: (dp is pressure gradient, r is radius, g is viscosity, l is length of airway). here, helium has nothing to offer; its viscosity (188 micropoises) approximates to those of nitrogen and oxygen (167 and 192, respectively). however, with a narrowed airway segment, as in many of the conditions referred to above, turbulent flow is more likely to occur. to maintain flow across a restricted cross-sectional area, gas velocity must increase. in these circumstances, turbulent flow is associated with a 'reynolds number' greater than 2000 (no units) as given by the following: (q is density and v average velocity). here, helium has a density 0.18 gael )1 , whereas nitrogen and oxygen densities are 1.25 and 1.43, respectively. a helium-oxygen mixture of 79 : 21 has a density of 0.43 gael )1 ; this means that, for a given velocity, the reynolds number will drop by three times and the propensity for turbulent flow drops accordingly (97) . 'heliox' refers to mixtures of helium and oxygen. potentially this could be in any ratio as found in the bespoke mixtures utilized in sub-aqua diving. however, medically, it is commonly provided as 79 : 21%. this can be added to an oxygen blender and the output monitored, thus providing a variable fio 2 as needed (97, 98) . in patients that are already hypoxic, the introduction of heliox should be done incrementally. as the viscosity of the inspired gases drops, any benefit or deterioration in oxgenation should be monitored carefully. when used in croup, heliox has been shown to procure improvements in croup scores similar to nebulized epinephrine (99) . reviews of the available evidence to support the use of heliox in this situation have demonstrated a need for further studies in this area bacterial tracheitis: erythema and mucosal edema with copious purulent secretions. (97, 98, 100) . helium has high thermal conductivity and so care needs to be taken with respect to humidification and avoidance of patient hypothermia (101, 102) and it should not be used in nebulizers as these depend on the generation of turbulence to deliver the drug (102) . acute infectious upper airway obstructions in children infectious mononucleosis complicated by lingual tonsillitis current management of upper respiratory tract and head and neck infections impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant staphylococcus aureus early adenotonsillectomy for relief of acute upper airway obstruction due to acute tonsillitis in children microbiology and management of peritonsillar, retropharyngeal, and parapharyngeal abscesses the management of severe infectious mononucleosis tonsillitis and upper airway obstruction airway obstruction in children with infectious mononucleosis acute tonsillectomy in the 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in newly independent states of the former soviet union changing epidemiology of life-threatening upper airway infections: the reemergence of bacterial tracheitis tracheitis in pediatric patients bacterial tracheitis reexamined: is there a less severe manifestation? systemic complications associated with bacterial tracheitis negative pressure pulmonary edema in children -pathogenesis and clinical management pulmonary edema associated with croup and epiglottitis heliox administration in the pediatric intensive care unit: an evidence-based review use of heliox in children a randomized comparison of helium-oxygen mixture (heliox) and racemic epinephrine for the treatment of moderate to severe croup heliox in croup heliox questions heliox questions the authors would like to acknowledge the help given by dr rob hawkes, paediatric radiologist, royal hospital for children, bristol, regarding the authors have declared no conflicts of interest. none. key: cord-348212-c2iibuqa authors: cavallo, federica; rossi, nadia; chiarelli, francesco title: novel coronavirus infection and children date: 2020-05-11 journal: acta biomed doi: 10.23750/abm.v91i2.9586 sha: doc_id: 348212 cord_uid: c2iibuqa background and aim: coronavirus disease 2019 (covid-19) is caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2). its outbreak in many states of the world, forced the world health organization (who) to declare a pandemic. currently, covid-19 has infected 1 991 562 patients causing 130 885 deaths globally as of 16 april 2020. the aim of this review is to underline the epidemiological, clinical and management characteristics in children affected by covid-19. methods: we searched pubmed, from january to april 2020, for the following search terms: “covid-19”, “children”, “sars-cov2”, “complications”, “epidemiology”, “clinical features”, focusing our attention mostly on epidemiology and symptoms of covid-19 in children. results: usually, infants and children present milder symptoms of the disease with a better outcome than adults. consequently, children may be considered an infection reservoir that may play a role as spreader of the infection in community. (www.actabiomedica.it) in the last few months, some cases of pneumonia of unknown aetiology were identified worldwide. the first cases were detected in wuhan, china. collecting the samples of these patients, scientists have discovered a new coronavirus that is now known as the cause of the disease named severe acute respiratory syndrome coronavirus 2 (sars-cov-2) (1). by 16 april 2020, 1 991 562 cases have been confirmed and 130 885 deaths have been reported globally (2) . transmission takes place through respiratory droplets or contact with symptomatic cases. transmission from asymptomatic cases, especially children, seems to have also an important role (3) . moreover, sars-cov-2 rna has been detected in stool of some patients, so faecal-oral transmission could be possible (4) . the most common symptoms in adults are fever, dry cough, sore-throat, myalgia, fatigue and in severe cases (usually older patients with comorbidities) acute respiratory distress syndrome (ards) with lung failure or severe coagulation dysregulation as a result of an uncontrolled inflammation (5) . according to the experience of wuhan, children usually present milder symptoms. the initial viral replication occurs in mucosal epithelium of upper respiratory tract and later in lower respiratory tract and gastrointestinal mucosa. cov-id-19, like others coronavirus, uses a specific receptor to infect human cells. this receptor is angiotensin-converting enzyme 2 (ace2) and it's a functional receptor that is widely expressed in many organs, especially in lungs, but also in heart, kidney, vascular endothelium and intestine (6) . severe complications of covid-19 infections are ards with consequently lung failure, immune disfunction and coagulation disorders. the rapid viral replication may cause massive epithelial and endothelial cell death, stimulating the production of pro-inflammatory cytokines and chemokines. this 'cytokine storm' with an uncontrolled inflammation is considered a leading cause of fatality (7) . current data show that children with sars-cov2 usually belong to cluster family cases. infected children may appear asymptomatic or present mild symptoms like cough, fever, nasal congestion. in addition, gastrointestinal symptoms such as diarrhea, nausea, vomiting, abdominal discomfort are more frequent in children than in adults. despite mild respiratory symptoms with interstitial pneumonia, radiographycally assessed, only few cases have needed intensive care because of respiratory complications (8) . a recent study analysed 44,672 laboratory-confirmed cases across china and reported that only 416 (0.9%) were less than 10 years of age and 549 (1.2%) between 10 and 20 years of age. according to this study, children usually have a good prognosis and they recover within 1-2 weeks after the onset of the disease (9) . data provided by the centers for disease and control in usa are stackable. only 5.7% of children have been hospitalized because of the appearance of dyspnoea. according to this report, children aged < 1 year and children with comorbidities have presented the highest percentage of complications. the most common underlying conditions have been cardiovascular disease, chronic lung disease especially asthma and immunosuppression. however, compared with the adult cases, the severity of children's covid-19 cases has been milder (10) . at variance, in spain around 60% of children affected by covid-19 have been hospitalized for mild symptoms and 9.7% of these patients have requested intensive care because of the comparison of respiratory complications. only one patient had recurrent wheezing as previous condition. no patients died. the spanish series agrees with those previously published except for the number of admissions. this probably depends on the fact that the percentage of children tested have been higher than in other countries and it could be associated with different hospitalization criteria (11) . children usually are asymptomatic or with few accompanying symptoms. fever and mild cough are common symptoms at onset of the disease. other symptoms at presentation include sore throat, nasal congestion and rhinorrhea, diarrhea. for mild case, fe-ver is brief and resolved rapidly. usually children do not need admission in hospital. only a small percentage of all the patients have been in need of intensive care and usually they have been children with comorbidities or children aged < 1 year (12) . on the basis of these studies and clinical experience, covid-19 vertical transmission hasn't been detected but further studies are needed. the infection of 2019-ncov during pregnancy seems less serious compared to infection of sars-cov and mers-cov with no cases of maternal death, or perinatal death (13) (14) (15) . usually, neonates have evolved favourably. there are no contraindications to breastfeeding if mothers observe proper hygiene rules (16) . in adults, it is usually possible to find a decreased lymphocyte count and increased liver enzymes and muscle enzymes. many patients present elevated c-reactive protein levels and erythrocyte sedimentation rates, and normal procalcitonin levels. with the worsening of the disease, it is possible to find also a high d-dimer level with a dysregulation of the coagulation. unfortunately, there are limited data on children in literature. according to a study published by brandon mh et al., only few infants experienced lymphopenia. usually in children the leukocyte count is normal and cpr and procalcitonin sometimes are elevated. the lack of significant lymphopenia may depend on the relative immaturity of the children's immune system (17, 18) (table 1) . currently, the better method to detect rna the virus through rt-pcr is to collect samples from table 1 . laboratory findings in children. unlike adults, children usually don't present lymphopenia and the leukocyte count is normal. in a small percentage of children, it is possible to find increased crp and ldh 17, 18 . leukocytes count usually normal. lymphopenia is uncommon in children. normal or increased usually normal throat swabs (better using nasopharyngeal swab in children), sputum, or lower respiratory tract secretions. another important technique for covid-19 diagnosis is using imaging technology (ct scan or chest x-ray). in fact, chest images show a characteristic distribution with interstitial changes which are initially in the lung periphery and further deteriorate to small nodular ground glass opacities (19,20) (figure 1 ). in infants and children, it may be also useful to make lung ultrasound to avoid radiation and to obtain images directly at patient bedside. lung ultrasound clearly document signs suggestive for interstitial-al-veolar damage showing bilateral, diffuse pleural line abnormalities, subpleural consolidations, white lung areas and irregular vertical artefacts (21) (figure 2) . on the basis of the chinese experience, the severity of covid-19 disease in children is defined by clinical features, laboratory testing and chest radiograph into 5 groups (22) ( table 2 ). actually, there aren't any drug trials specific for the children and adolescents. according to the chinese management protocol, the recommended treatment is usually supportive. in severe cases, when there is a respiratory involvement characterized by dyspnoea, central cyanosis and an oxygen saturation of less than 92%, they suggest to start oxygen therapy and antibiotics for bacterial superinfections (23). table 2 . severity of covid-19 infection in children. this classification has been formulated on the basis of chinese data and experience to standardize prevention and management of 2019-ncov infections in children 22 . no clinical symptoms and signs, normal chest imaging, with positive 2019-ncov nucleic acid test. symptoms of acute upper respiratory tract infection, including fever, fatigue, myalgia, cough, sore throat, runny nose and sneezing. some cases may have nausea, vomiting, abdominal pain and diarrhoea. pneumonia with fever and cough (mostly dry cough, followed by productive cough) without hypoxemia. some cases may have no clinical signs and symptoms, but chest computed tomography shows typical lung lesions. the disease progresses with dyspnoea and central cyanosis. oxygen saturation is <92%. children and particularly adolescents and young adults can progress to respiratory failure and shock or other organs failure (encephalopathy, acute kidney injury, heart failure, coagulation dysfunction) . the antiviral treatment and gamma globulin treatment are currently disputed (24) . covid-19 infections remain undiagnosed in children because they often present mild symptoms. fortunately, according to literature only a small proportion of children become critically ill. children represented 2% of diagnosed cases in china (25), 1.2% of cases in italy (26) , and 1.7% of covid-19 positive cases in the us (27) . the prognosis seems to be good with a recovery in 12-14 days for the majority of the reported cases worldwide. only a death has been reported in a study of lu x and zhang, because of a secondary intussusception in a 10 month old child (28) . another report has showed that of the 2135 paediatric patients included in the study, only 1 child died (14year-old boy from hubei province) and most cases were mild (12) . children are often exposed to viral infections so it is possible that they have higher levels of antibody against virus than adults. another possible explana-tion is that children may be protected against sars-cov-2 because ace-2 is less expressed at a younger age. moreover, children's immune system is still developing and may respond to pathogens differently from adult immune system. despite all, asymptomatic cases may have a lower transmission rate but remain a great source of infection. the determination of the potential cluster transmission is very important for an epidemiological survey and to develop adequate measures for a better pandemic control. paediatricians are responsible for testing patients on the presence of signs and symptoms compatible with covid-19, in order to protect vulnerable people, such as elderly and people with comorbidities. table 2 . severity of covid-19 infection in children. this classification has been formulated on the basis of chinese data and experience to standardize prevention and management of 2019-ncov infections in children 22 . no clinical symptoms and signs, normal chest imaging, with positive 2019-ncov nucleic acid test. symptoms of acute upper respiratory tract infection, including fever, fatigue, myalgia, cough, sore throat, runny nose and sneezing. some cases may have nausea, vomiting, abdominal pain and diarrhoea. pneumonia with fever and cough (mostly dry cough, followed by productive cough) without hypoxemia. some cases may have no clinical signs and symptoms, but chest computed tomography shows typical lung lesions. the disease progresses with dyspnoea and central cyanosis. oxygen saturation is <92%. children and particularly adolescents and young adults can progress to respiratory failure and shock or other organs failure (encephalopathy, acute kidney injury, heart failure, coagulation dysfunction) . a novel coronavirus from patients with pneumonia in china covid-19): situation report; world health organization the role of children in the transmission of mild sars-cov-2 infection acta paediatr coronavirus disease (covid-19) and the gastrointestinal system in children clinical characteristics of coronavirus disease 2019 (covid-19) in china: a systematic review and meta-analysis a pneumonia outbreak associated with a new coronavirus of probable bat origin epidemiology, pathogenesis, and control of covid-19 detection of covid-19 in children in early sars-cov-2 infection in children: transmission dynamics and clinical characteristics covid-19): cases in united states screening and severity of coronavirus disease 2019 (covid-19) in children in epidemiology of cov-id-19 among children in china clinical characteristics and intrauterine vertical transmission journal pre-proof 6 potential of covid-19 infection in nine pregnant women: a retrospective review of medical records infants born to mothers with a new coronavirus (covid-19). front. pediatr the novel coronavirus (2019-ncov) in pregnancy: what we need to know covid-19 virus and children: what do we know? arch pediatr laboratory abnormalities in children with novel coronavirus disease 2019 clinical characteristics of cov-id-19 in children compared with adults in shandong province chest computed tomography in children with covid-19 respiratory infection clinical and ct imaging features of the covid-19 pneumonia: focus on pregnant woman and children our italian experience using lung ultrasound for identification, grading and serial follow-up of severity of lung involvement for management of patients with covid-19. echocardiography recommendations for the diagnosis, prevention and control of the 2019 novel coronavirus infection in children diagnosis, treatment, and prevention of 2019 novel coronavirus infection in children: experts' consensus statement potential interventions for novel coronavirus in china: a systematic review the epidemiological characteristics of an outbreak of coronavirus disease 2019 (cov-id-19) in italy covid-19): cases in united states sars-cov-2 infection in children each author declares that he or she has no commercial associations (e.g. consultancies, stock ownership, equity interest, patent/licensing arrangement etc.) that might pose a conflict of interest in connection with the submitted article key: cord-327963-dqsg84e5 authors: tang, suqin; xiang, mi; cheung, teris; xiang, yu-tao title: mental health and its correlates among children and adolescents during covid-19 school closure: the importance of parent-child discussion date: 2020-10-12 journal: j affect disord doi: 10.1016/j.jad.2020.10.016 sha: doc_id: 327963 cord_uid: dqsg84e5 background: : school closures due to the covid-19 outbreak have affected 87% of the world's students physically, socially, and psychologically, yet rigorous investigation into their mental health during this period is still lacking. methods: : a cross-sectional online survey of 4,342 primary and secondary school students from shanghai, china was conducted during march 13–23, 2020. besides demographic information, psychological distress (including depression, anxiety, and stress), life satisfaction, perceived impact of home quarantine, and parent-child discussions on covid-19 were assessed. results: : the three most prevalent symptoms were: anxiety (24.9%), depression (19.7%), and stress (15.2%). participants were generally satisfied with life and 21.4% became more satisfied with life during school closures. senior grades were positively correlated with psychological symptoms and negatively associated with life satisfaction, whereas the perceived benefit from home quarantine and parent-child discussions on covid-19 were negatively correlated with psychopathological symptoms and positively correlated with life satisfaction. among participants who perceived no benefit from home quarantine, those who had discussions with their parents about covid-19 experienced less depression, anxiety, and stress. limitations: limitations included the inability to infer the casual relationship, no parental report for mental health of children aged 6 to 9, and the inadequate measurement of parent-child discussion. conclusions: : mental health problems and resilience co-existed in children and adolescents during the covid-19 outbreak. given the important role of parent-child discussions, open communication between parents and children about the pandemic should be encouraged to help children and adolescents cope with mental health problems in public health crisis. the outbreak of the coronavirus disease has brought global affects with over 33 million cases and over 1 million deaths as of september 30, 2020 (world health organization, 2020a . most countries implemented social distancing measures to slow down the spread of the infection, the most universally used methods include home quarantines and national school closures. in shanghai, china, where this study was conducted, there were 339 local cases and 75 imported cases by march 23, 2020, when the data collection ended (state council information office of the people's republic of china, 2020) . shanghai launched its highest-level emergency response against the covid-19 on january 24, 2020, and the level 1 emergency response had been active until march 23, 2020 . during the level 1 emergency response period, shanghai had closed all public venues and canceled all large-scale public events, and required people from infected areas to stay at home or be quarantined in groups for 14 days (cui, 2020) . due to school closures, online learning had been implemented to all 1.435 million primary and secondary students in shanghai (shanghaieye, 2020). as estimated by the united nations educational, scientific and cultural organization (unesco) on march 26, 2020, school closures have affected 87% of the world's students (i.e., more than 1.5 million children and young people in 165 countries) by restricting access to education (united nations educational, scientific and cultural organization, 2020) . besides the potential inequality caused by the digital divide and distance learning practices (united nations educational, scientific and cultural organization, 2020) , school closure may also cause disruptions in the physical activity, social interaction, and mental health of children and adolescents . restrictions on movement can have a substantial psychological impact. a systematic review of 24 studies examined the psychological impact of pandemic-related quarantine on hospital staff, parents, children, and the general population (brooks et al., 2020) . they found that quarantined people had an elevated risk of developing acute and post-traumatic stress symptoms and disorders, and showed a higher prevalence of general psychological symptoms, emotional disturbances, depression, stress, low mood, irritability, and anxiety-induced insomnia. serious concerns about the mental health of children and adolescents during the pandemic-related quarantine and school closures have been raised (golberstein et al., 2020; wang et al., 2020) ; the debate whether the benefits of the mandatory measures outweigh the psychological costs continues viner et al., 2020 ). an earlier study found 30% of isolated or quarantined american children in areas severely impacted by h1n1 met the criteria for posttraumatic stress disorder (ptsd) based on parental reports (sprang and silman, 2013) . current evidence related to covid-19 were all provided by chinese scholars. the prevalence of depressive symptoms were 22.6% in primary school students (xie et al., 2020) and 26.3% in secondary school students (tang and ying, 2020) . the prevalence of anxiety symptoms in china were 18.9%, 22.0%, and 29.8% in primary students from hubei province (xie et al., 2020) , primary and secondary students from shaanxi province (li et al., 2020) , and secondary school students from sichuan province (tang and ying, 2020) , respectively. in addition to capturing children and adolescents' mental health status during the covid-19 pandemic, key risk and protective factors need to be identified to further understand who are in the at-5 risk subgroups and what could be done to protect them against mental health problems and to maintain their mental health status. perceptions on the epidemic and its possible impact matter in predicting mental health status. fear of being infected was another risk factor for depressive symptoms in primary school students (xie et al., 2020) and anxiety symptoms in children and adolescents during the covid-19 pandemic (li et al., 2020) . similarly, it is likely that for children and adolescents who are confined to their homes due to school closure during the covid-19 pandemic, their perception of the impact of home quarantine may play an important role in relation to their mental health. during home confinement, parents are usually the ones who interact the most with children and adolescents. the world health organization (who) advises parents to discuss covid-19 with their children in an honest and age-appropriate way that addresses children's concerns and eases their anxiety (world health organization, 2020b) . in this way, close and open communication between parents and children may serve as a protective factor in children's mental health. previous studies on epidemics and pandemics, however, have not examined either the perceived impact on children and adolescents nor that of parent-child discussion. to address these gaps in the literature, we aimed to estimate the prevalence of depressive, anxiety, and stress symptoms, and levels of life satisfaction, among children and adolescents experiencing home quarantine and school closure in shanghai due to covid-19. we also aimed to identify factors related to their mental health status, with a closer examination of the role of the perceived impact of home quarantine and parent-child discussion relating to mental health status during the covid-19 pandemic. we followed the cherries guideline for online surveys (see supplementary file 1). this crosssectional online survey was conducted among 4,391 students in primary school (grades 1-5), junior 6 secondary school (grades 6-9) and senior secondary school (grades 10-12). cluster sampling was adopted to randomly select one school from each of the six districts in shanghai, china, and all students in the six identified schools were recruited. depression, anxiety, the chinese version of dass-21 (wang et al., 2016) was used to measure psychological distress during home quarantine due to covid-19. the chinese dass-21 is a self-report measure containing seven items in each subscale to measure the constructs of depression, anxiety, and stress. participants responded to each item by rating the frequency and/or severity of symptoms over the previous week using a 4-point likert scale (0 = did not apply to me at all, 4 = applied to me very much or most of the time). to yield equivalent scores to the full 42-item version of dass-21, the total score of each subscale was multiplied by two for scores that range from 0-42. the scale could be used to identify individuals who were at high risk of developing mental health problems with cutoffs, 10 for depression, 8 for anxiety, and 15 for stress (lovibond and lovibond, 1995) . the dass-21 has previously been used to assess children and adolescents aged 11 to 19 in china (mellor et al., 2014; and populations after traumatic events such as the sichuan earthquake (chan et al., 2012; . in the current sample, the cronbach's alphas of depression, anxiety, and stress subscales were .913, .883, and .898, respectively. life satisfaction was assessed using two parameters, namely, current life satisfaction and a change in life satisfaction since the pandemic. the former was assessed using a 11-point likert scale (0 = extremely dissatisfied, 11 = extremely satisfied), and the latter asked the question, how do you see your current life now compared to before? and rated on a 5-point likert scale (-2 = a lot worse, -1 = worse, 0 = pretty much the same, 1 = better, 2 = a lot better). children and adolescents' perceived impact of home quarantine due to covid-19 was measured in terms of positive and negative impact using a self-constructed questionnaire. the positive impact consisted of five possible benefits and negative impact consisted of eight potential problems. participants were asked to rate how well each item applied to them on a 6-point likert scale (0 = did not apply to me at all, 5 = applied to me very much). the average scores of each dimension were calculated to represent the overall positive and negative impact. the differences between the two dimensions were recoded as perceived beneficial (1) if the average score of the positive impact was higher than that of the negative impact, and recoded to perceived not beneficial (0) if the average score of the positive impact equaled to or was lower than that of the negative impact. if participants rated "did not apply to me at all" for all items, their data would be excluded in analyses using this variable. in the current sample, the cronbach's alphas of the positive and negative impact dimensions were .829 and .868, respectively. parent-child discussion on covid-19 was measured by asking participants whether their parents had discussed covid-19 with them or not. if the participants responded yes, they were asked about the frequency of discussion during the past month. answers were recoded as not at all (0), at least once monthly (1), at least once weekly (2), or at least once daily (3). the online survey was conducted during march 13-23, 2020 (after approximately two months of the covid-19 outbreak). the survey was performed by wenjuanxing (wjx.cn). prior to distribution, we piloted the survey within several co-workers, postgraduate students, primary and secondary school students who did not study in the sampled schools and asked them to give feedback on content and functionality. a link to the survey was sent to six teachers in charge of student affairs in six schools. 8 the teachers then forwarded the link to all classes' social network groups and asked parents to have their child completing the self-reported questionnaire. both the students' and parents' consent were obtained. for students, implied consent was adopted. the consent information page including the purpose of the study, voluntariness of participation, confidentiality, length of time of the study, data retention was presented before entering the formal survey. only when the students ticked the box "i understand the information described above and agree to participate in this study", they would enter the formal survey. otherwise, the webpage window would be closed automatically. for parents, as the schools agreed to participate in the study, passive consent was adopted. if they did not wish to give consent, they were requested to make this known to the school. to ensure quality responses, research assistants and teachers were assigned to each of the six schools to be on duty online. if the parents and students were confused about certain questions in the questionnaire, they can ask the research assistant and teachers immediately so that the questions could be explained and clarified on time. other than clearing the confusion, the research assistant and teachers were required not to provide help on answering questions. parents were instructed to assist primary school students. ethical approval was obtained prior to data collection from the ethics committee of shanghai jiaotong university school of medicine (sjupn-201813). the characteristics of the sample were summarized using descriptive statistics. cronbach's alpha coefficients measured the internal reliability of each subscale of dass-21 and the self-constructed questionnaire for the perceived impact of home quarantine; a cut-off of .70 was used to indicate good internal reliability. comparative profiles of demographic and quarantine-related variables between screened and unscreened subgroups of depression, anxiety, and stress were examined using chi-square tests. independent sample t-tests and one-way analyses of variance (anova) were conducted to investigate group differences in symptom levels of depression, anxiety, and stress, and life satisfaction. binary logistic regression analyses and multiple linear regression analyses were conducted to examine the independent associations between demographic and quarantine-related characteristics and depression, anxiety, stress, and life satisfaction. demographic and quarantine-related variables were entered into the regression models as independent variables, and mental health variables were considered dependent variables. multivariate analyses of variance (manova) were used to test the interaction between significant quarantine-related variables in association with the severity of depression, anxiety, and stress, and simple effect tests were conducted following significant interactions. the associations were reported as odd ratios (ors) or unstandardized coefficient b and 95% confidence intervals (cis). p values <.05 were considered statistically significant (two-sided). analyses were performed using ibm spss statistics, version 26. the total of 4,722 students were approached, and 4,391 students completed the survey, with a response rate of 93.0%. among the respondents, 35 students did not fill out their demographic information and 14 students responded in patterned ways. their responses were excluded, resulting in a valid sample of 4,342 students. post-survey interviews with teachers suggested that the two most frequently mentioned reasons for not submitting or not completing the survey were having forget to fill out the questionnaire during the given time frame and the lengthiness and tediousness of the survey. the mean age of the sample was 11.86±2.32 years, ranging from 6-17. boys accounted for 51% of the sample. the proportion of primary, junior secondary, and senior secondary school students were 22.9%, 69.6%, and 7.4% respectively. over half (51.8%) of the students experienced the impact of home quarantine as positive. the majority (84.7%) had discussed the pandemic with their parents. table 1 shows the detailed demographic and quarantine-related information. table 2 provides the percentages that met threshold for depression, anxiety, and stress, as well as means and standard deviations of symptom scores in the total sample and subgroups. among the participants, 24.9% had experienced symptoms of anxiety, followed by 19.7% for depressive symptoms and 15.2% for stress symptoms. five hundred participants (11.5%) met thresholds of depression, anxiety, and stress at the same time. percentages of mild, moderate, severe, and extremely severe levels of these symptoms are listed in supplementary table 1. senior secondary school students yielded the highest prevalence and levels of depressive, anxiety, and stress symptoms, and primary school students the lowest. positive screens and symptom levels for depression, anxiety, and stress were higher among those who were more negative about the impact of home quarantine and who had no discussion about the covid-19 with their parents. boys and girls did not show any difference in the prevalence and symptom levels of all three conditions. table 3 presents the means and standard deviations of overall and subgroups' levels of life satisfaction. participants were generally satisfied with their current status, with the mean score (8.74±2.21) significantly higher than 6 (satisfied) [t(4341) = 81.835, p < .001]. the median was 9 (very satisfied) and the mode was 11 (extremely satisfied), indicating that half of the participants were very satisfied and those who were extremely satisfied were the largest subgroup (29.8%). most participants experienced no change in life satisfaction (59.4%), and 21.4% were more satisfied with their lives during the pandemic. bonferroni post hoc tests showed that senior secondary students were more satisfied with life than primary (p = .011) and junior secondary (p = .005) students. participants who perceived themselves as having benefited from the quarantine reported higher current life satisfaction. in addition, participants who had discussed the pandemic with their parents reported higher levels of current life satisfaction than those who had not. table 4 shows the odds ratio for depression, anxiety, and stress from binary logistic regression analyses and the unstandardized coefficients for the symptom levels from multiple linear regression analyses. the rates of positive screens for depression, anxiety, and stress and the symptom levels varied based on grade, perceived impact of the quarantine, and parent-child discussion about the pandemic. junior secondary school students were at higher risk of developing anxiety and experienced more severe levels of all symptoms than primary school students, while senior secondary students were at higher risk of developing depression, anxiety, and stress than other grades. the presence of perceived benefit and parent-child discussion lowered the risk of meeting the threshold of depressive, anxiety, and stress symptoms. similarly, being senior secondary students and the absence of perceived benefit and parentchild discussion were associated with higher levels of all three types of symptoms. table 5 presents demographic and quarantine-related variables relating to current and changed life satisfaction in two multiple linear regression models. taking all factors into consideration, participants who perceived themselves as having benefited from the home quarantine and had discussion on covid-19 with their parents reported significantly higher levels of current life satisfaction. besides, perceived beneficial was significantly associated with increased life satisfaction during the pandemic. interestingly, senior secondary school students were less satisfied with life than others, but their levels of life satisfaction had increased more dramatically than others during the pandemic. in order to further explore how children and adolescents' intrapersonal perception on the impact of quarantine, interpersonal interaction with parents regarding covid-19, and the interaction effects between perceived beneficial and parent-child discussion in association with the severity of depression, anxiety and stress, as well as levels of life satisfaction, were examined. the 2 (perceived beneficial) × 2 (parent-child discussion) anova analysis indicated significant effect for interactions between perceived beneficial and parent-child discussion for depressive this study examined the mental health status of children and adolescents during school closure due to covid-19 in shanghai, china. primary and secondary schools started online education from march 2, 2020 and continued until schools started to reopen after april 27, 2020. children and adolescents' most prevailing mental health problem was anxiety, with a prevalence rate of 24.9%, which is slightly higher than reported in a study conducted one month earlier (22.0%; li et al., 2020) mostly due to the elevated prevalence for secondary school students. in china, secondary school students face more academic pressure than primary school students as they need to prepare for the zhongkao (entrance examination for senior secondary school) and gaokao (the national higher education entrance examination). since our study was conducted in the first two weeks of online schooling, adjusting to new forms of learning, online classes, and studying alone at home without faceto-face interaction with teachers and classmates may have contributed to secondary school students' more elevated anxiety levels. the second most prevalent mental health problem was depression, with an incident rate of 19.7%. the rate for primary school students (17.3%) was very similar to the pooled prevalence of depressive symptoms in chinese primary school students reported in a recent systematic review (17.2%; 95% ci: 14.3%-20.5%; xu et al., 2020) but lower than reported in primary school students in wuhan and huangshi, in hubei province, who were also surveyed during the same period of time (22.6%; xie et al., 2020) the latter is understandable as hubei was the most seriously affected area in china during the covid-19 pandemic. the prevalence rate of depression for secondary school students (20.5%) was slightly lower than the pooled prevalence rate reported in a systematic review on depression among chinese secondary school students (24.3%; 95% ci: 21.3%-27.6%; tang et al., 2019) and lower than findings during the covid-19 pandemic (tang and ying, 2020) . the lower prevalence of depressive symptoms among secondary school student in our study could be explained by the choice of screening instrument. screening instruments can affect findings among adolescents (tang et al., 2019) but not children (xu et al., 2020) . the study's adapted dass-21 showed a relatively lower prevalence of depression than other measures (tang et al., 2019) . the prevalence of stress symptoms (15.2%) was lower than anxiety and depressive symptoms. acute stress symptoms are usually observed within the first month of a stressful event (american psychiatric association, 2013). since the current data was collected more than one month after the outbreak of covid-19, due to the strict measure implemented by the chinese government, the pandemic was under control by early march, so children and adolescents may have started to experience less stress symptoms. notwithstanding, researchers and clinicians should pay attention to the fact that three out of twenty children and adolescents suffered from stress symptoms and provide timely intervention before they develop ptsd. children and adolescents were generally satisfied with their current life status. over 80% thought their lives were either the same or better since the pandemic. this finding was not surprising, given the co-existence of psychological distress and resilience in children and adolescents when faced with change or adversity. the study conducted in wuhan and huangshi, hubei province, showed that 51.7% of primary school students worried about being infected with covid-19; that said, 40.8% of them were optimistic about the development of the pandemic (xie et al., 2020) , supporting the finding that negative and positive feelings could co-exist during a traumatic event such as the covid-19 pandemic. our study revealed a pattern that depression, anxiety, and stress among children and adolescents increased gradually and substantially from primary and junior secondary to senior secondary school. this is consistent with previous findings in systematic reviews (barker et al., 2019; tang et al., 2019; xu et al., 2020) . the increased psychological distress from early to late adolescence might be due to biological changes (especially hormonal changes during adolescence), increased adverse life events (e.g., academic pressure increasing from primary to secondary school, interpersonal challenges with parents and friends; schubert et al., 2017) . our study also found that as adolescents progress to higher grades, their life satisfaction decreased. this was not surprising given the negative correlation between life satisfaction and psychological distress in the current study (from -.188 to -.161, all ps < .01). benefit finding was identified as one of the important protective factors against depression, anxiety, and stress. our study found that children and adolescents perceived home quarantine as more positive than negative, and this yielded less psychological distress and more life satisfaction. their perceived benefits of home quarantine included increased time available to spend with parents and on personal activities. benefit finding is defined as "the positive effects that result from a traumatic event" (helgeson et al., 2006) and is commonly observed among children and adolescents facing healthrelated threats such as cancer (rosenberg et al., 2019; wicks and mitchell, 2010) and diabetes (helgeson et al., 2009; tran et al., 2011) . a meta-analysis of studies showed that benefit finding in adults was related to less depression and more positive well-being, but was unrelated to anxiety (helgeson et al., 2006) . another meta-analysis of studies conducted on children and adolescents found a significant to marginally significant negative relation between post-traumatic growth (or benefit finding) and depression, anxiety, general symptoms of stress, and emotional distress (meyerson et al., 2011) . our findings also echo other studies conducted during the covid-19 pandemic. for instance, primary students who were not optimistic about the development of the pandemic were at an increased risk of depressive symptoms compared with those who were optimistic (xie et al., 2020) . in short, benefit finding can buffer the possible negative impact brought on by home quarantine and school closures due to pandemic. guiding children and adolescent to perceive the pandemic from a constructive angle and to discover positive aspects in difficult times could be an appropriate way to help them to cope with the pandemic. parent-child discussion on the pandemic was another important protective factor, as children and adolescents who discussed the pandemic with their parents were less likely to present symptoms of depression, anxiety, and stress. even in those who failed to find benefit from their current situation, parent-child discussion still prevented them from developing more severe symptoms of depression, anxiety, and stress. this highlights the crucial role of open communication between parents and children when coming to terms with stress and crisis. among all psychosocial factors associated with depression in chinese adolescents, parent-child communication had the largest effect size (r = .43; tang et al., 2020) in line with previous findings, the duration and frequency of communication alleviated the effects of stressors on depressive symptoms (guang et al., 2017) . our study also found that the frequency of discussion about the ongoing public health crisis mitigated depression, anxiety, and stress, and boosted life satisfaction. it is worth noting that chinese parents tend to use supportive behaviors rather than verbal expression to deliver care and love to their children compared with american parents (zhang and wills, 2016) , so chinese parents especially need to be encouraged to discuss life events more frequently with their children to facilitate their children's mental health during times of public health crisis. several limitations should be considered in interpreting the results. first, the cross-sectional design of this study was unable to illuminate the causal relationship between risk and protective factors, and mental health outcomes. a longitudinal study with follow-up surveys after the schools reopen is needed to clarify these relationships. second, although primary school students completed the survey with the assistance of their parents, self-reporting on dass-21 by primary school students, especially those who aged 6-9 years old, may not be as reliable as other age groups due to possible misinterpretation of some items of the mental health measures. future research should include both self-reporting and parental reports when assessing mental health outcomes among young children to guarantee the data accuracy. third, parent-child discussion was measured merely in terms of frequency. the way how parents communicate with children, the specific content of their discussion on the pandemic, the quality of parent-child relationship, and their role in contributing to children's mental health status, are worth exploring in future studies. finally, some psychosocial factors of children and adolescents' mental health (e.g., academic performance, academic pressure, peer relationship; tang et al., 2020) were not included in this study. yet, this study cannot eliminate the possibility of residual confounding caused by these unmeasured variables. moreover, we did not had the chance to explore the reasons for not participating in the survey from the 7% non-respondents, whom may be from disadvantaged groups such as who had less parents' supervision for online learning, were less adaptive to online learning like reading online materials, or suffered from more psychological distress. despite these limitations, this study recruited a large representative sample of children and adolescents, assessed their mental health status, and identified the risk and protective factors during covid-19related school closures in shanghai, china. anxiety, depression, and stress were common among children and adolescents experiencing home quarantine and school closure due to the outbreak of covid-19. however, students were generally satisfied with their current life status. secondary school students were at greater risk of developing depression, anxiety, and stress, whereas benefit finding and parent-child discussion on the pandemic were two protective factors. policy makers and mental health professionals should ensure that mental health interventions are available and tailored to help children and adolescents cope with public health a participants who rated "not applied to me at all" for all items of perceived impact of home quarantine were excluded in all analyses (n = 235). * p < .05, *** p < .001. correlates diagnostic and statistical manual of mental disorders prevalence and incidence of anxiety and depression among children, adolescents, and young adults with life-limiting conditions: a systematic review and meta-analysis the psychological impact of quarantine and how to reduce it: rapid review of the evidence extending the utility of the depression anxiety stress scale by examining its psychometric properties in chinese settings cities launch emergency response to contain virus coronavirus disease 2019 (covid-19) and mental health for children and adolescents depressive symptoms and negative life events: what psycho-social factors protect or 20 harm left-behind children in china? benefit finding among children and adolescents with diabetes. medical illness and positive life change: can crisis lead to personal transformation? a meta-analytic review of benefit finding and growth investigation on the influencing factors for anxiety related emotioanl disorders of children and adolescents with home quarantine during the prevalence of novel coronavirus pneumonia manual for the depression anxiety stress scales factorial invariance of the dass-21 among adolescents in four countries posttraumatic growth among children and adolescents: a systematic review hope and benefit finding: results from the prism randomized controlled trial the psychological effects of quarantining a city depressive symptom trajectories in late adolescence and early adulthood: a systematic review online classes as schools to stay closed posttraumatic stress disorder in parents and youth after health-related disasters the 58th press on prevention and control of the covid-19 held in shanghai investigation on mental health status and its influencing factors among secondary school students during the covid-19 epidemic benefit finding, affective reactions to diabetes stress, and diabetes management among early adolescents unesco rallies international organizations, civil society and private sector partners in a broad coalition to ensure #learningneverstops school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review. the lancet child & adolescent health 0 mitigate the effects of home confinement on children during the covid-19 outbreak the adolescent cancer experience: loss of control and benefit finding world health organization, 2020a. who coronavirus disease (covid-19) dashboard [www document helping children cope with stress during the 2019-ncov outbreak mental health status among children in home confinement during the coronavirus disease prevalence of depressive symptoms in primary school students in china: a systematic review and meta-analysis application of the short version of depression-anxiety-stress scale to stress assessment on students after earthquake a u.s.-chinese comparison of affectionate communication in parent-child relationships 4339) depression = 15.809; χ 2 (2) anxiety = 45 4339) anxiety = 21.782; χ 2 (2) stress = 28.670 4339) stress = the authors gratefully acknowledge the research members, families, children, and adolescents who took part in this research, without whom it would not have been possible. table 2 means key: cord-344486-iu5flbcl authors: chiotos, kathleen; hayes, molly; kimberlin, david w; jones, sarah b; james, scott h; pinninti, swetha g; yarbrough, april; abzug, mark j; macbrayne, christine e; soma, vijaya l; dulek, daniel e; vora, surabhi b; waghmare, alpana; wolf, joshua; olivero, rosemary; grapentine, steven; wattier, rachel l; bio, laura; cross, shane j; dillman, nicholas o; downes, kevin j; oliveira, carlos r; timberlake, kathryn; young, jennifer; orscheln, rachel c; tamma, pranita d; schwenk, hayden t; zachariah, philip; aldrich, margaret l; goldman, david l; groves, helen e; rajapakse, nipunie s; lamb, gabriella s; tribble, alison c; hersh, adam l; thorell, emily a; denison, mark r; ratner, adam j; newland, jason g; nakamura, mari m title: multicenter interim guidance on use of antivirals for children with covid-19/sars-cov-2 date: 2020-09-12 journal: j pediatric infect dis soc doi: 10.1093/jpids/piaa115 sha: doc_id: 344486 cord_uid: iu5flbcl background: although coronavirus disease 2019 (covid-19) is a mild infection in most children, a small proportion develop severe or critical illness. data evaluating agents with potential antiviral activity continue to expand, such that updated guidance is needed regarding use of these agents in children. methods: a panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse north american institutions was convened. through a series of teleconferences and web-based surveys, a set of guidance statements was developed and refined based on review of the best available evidence and expert opinion. results: given the typically mild course of covid-19 in children, supportive care alone is suggested for most cases. for children with severe illness, defined as a supplemental oxygen requirement without need for non-invasive or invasive mechanical ventilation or extra-corporeal membrane oxygenation (ecmo), remdesivir is suggested, preferably as part of a clinical trial if available. remdesivir should also be considered for critically ill children requiring invasive or non-invasive mechanical ventilation or ecmo. a duration of 5 days is appropriate for most patients. the panel recommends against the use of hydroxychloroquine or lopinavir-ritonavir (or other protease inhibitors) for covid-19 in children. conclusions: antiviral therapy for covid-19 is not necessary for the great majority of pediatric patients. for children with severe or critical disease, this guidance offers an approach for decision-making regarding use of remdesivir. in december 2019, the novel coronavirus severe acute respiratory syndrome coronavirus 2 (sars-cov-2) emerged in wuhan, hubei province, china, as the cause of a severe respiratory disease, coronavirus disease 2019 (covid19) . as of august 22, 2020, over 23 million people worldwide have been infected, including over 5.6 million in the united states (us) alone, with over 800,000 deaths reported globally (1) . in light of this public health crisis, there has been significant interest in identifying potentially efficacious antiviral therapies, including novel and "repurposed" medications. to guide pediatric clinicians in the use of these agents, and leveraging the sharing antimicrobial reports for pediatric stewardship (sharps) collaborative, we developed an initial antiviral guidance document, published in april 2020, based on best available evidence and expert consensus (2, 3) . in the few months since this initial publication, new evidence has emerged demonstrating the efficacy of the antiviral medication remdesivir in shortening time to clinical recovery in adults with covid-19, while several other studies have shown ineffectiveness of hydroxychloroquine and lopinavir-ritonavir (4) (5) (6) (7) (8) . based on these data, the us food and drug administration (fda) issued an emergency use authorization (eua) for remdesivir, and the previously issued eua for hydroxychloroquine was revoked (9, 10) . further, additional observational studies have provided insight into the clinical epidemiology of covid-19 in children, demonstrating that while most young patients experience mild illness, a small proportion develop severe illness associated with adverse clinical outcomes, including need for pediatric intensive care unit (picu) admission and mortality (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) . finally, in april 2020, a newly recognized hyperinflammatory syndrome seemingly associated with covid-19 emerged, referred to by the royal college of paediatrics and child health as pediatric inflammatory multisystem syndrome temporally associated with sars-cov-2 (pims-ts) and by the world health organization and us centers for disease control and prevention as multisystem inflammatory syndrome in children (mis-c) (25) (26) (27) (28) (29) (30) (31) (32) . affected 7 children present with evidence of multisystem inflammation, with variable manifestations that may include fever, cardiovascular shock, gastrointestinal symptoms, or dermatologic or mucocutaneous changes (25) (26) (27) (28) (29) . the syndrome, while fortunately rare with an estimated incidence of 2 in 100,000 persons <21 years of age often necessitates picu admission and has resulted in rare mortalities (33) . considering the rapidly expanding evidence base regarding optimal antiviral therapy for covid-19, yet an ongoing paucity of pediatric-specific data, we reconvened the expert panel to update our initial guidance document. we remind the reader that this document is not a guideline, and we emphasize the ongoing importance of critical review of emerging literature to inform treatment decisions. we additionally refer the reader to guidelines published by the infectious diseases society of america and the national institutes of health (34, 35) . a panel of pediatric infectious diseases physicians and pharmacists from 20 geographically diverse north american institutions developed and refined a set of consensus guidance statements through a series of teleconferences and web-based surveys. the panel considered three major questions: 1) what criteria define the pediatric population in whom remdesivir should be prescribed? 2) does the presence of any underlying medical condition or characteristic warrant different criteria for remdesivir use based on an increased risk of covid-19-related morbidity or mortality? 3) should any other agents with potential antiviral activity be used to treat covid-19? following each consensus statement, we summarize our rationale and the relevant available evidence, prioritizing human studies. given the overall limited nature of pediatric data, a systematic review was 8 not performed, nor was the available evidence formally evaluated using grading of recommendations assessment, development, and evaluation (grade) or other methodology. of note, this panel considered only antiviral use, with use of corticosteroids and other immunomodulatory therapies reviewed elsewhere (36) . this guidance document has been reviewed and endorsed by the pediatric infectious diseases society. a statement of "recommend" reflects the panel's view that the evidence base for or against a therapy is sufficiently strong that departures from these recommendations could be viewed as outside the range of usual practice. a statement of "suggest" reflects the panel's view that there is weighting towards risk or benefit from the therapy. a statement of "consider" reflects the panel's uncertainty about the risk or benefit from the therapy. guidance statement: the panel recommends remdesivir be used only in children with positive sars-cov-2 viral testing. rationale: the clinical presentation of covid-19 in children is heterogeneous and overlaps significantly with other infections. administration of remdesivir without confirmation of sars-cov-2 infection poses a significant risk of exposing patients to unnecessary harms without the possibility of benefit and may deplete scarce remdesivir supplies. a rare exception might be made for critically ill patients with a high 9 suspicion for covid-19 (based on a highly consistent clinical presentation combined with high local prevalence or contact with a confirmed case) for whom a significant delay in sars-cov-2 test results is anticipated. in such a scenario, empiric initiation of remdesivir could be considered while awaiting test results. guidance statement: the panel recommends that clinical criteria, particularly respiratory support requirements, be used to define scenarios in which treatment with remdesivir is considered. rationale: respiratory support requirement has been used to define illness severity categories in the published clinical trials evaluating remdesivir efficacy (table 1) . because the potential benefit of remdesivir across illness severities may differ, we suggest respiratory support requirement be the primary determinant of whether remdesivir is used. the panel additionally recognizes that the spectrum of clinical presentations varies in children, and that rapid deterioration in clinical status and/or cardiovascular compromise may be additional considerations. finally, the panel also considered radiographic criteria, but because radiographic infiltrates are common, even among well-appearing, clinically stable children, respiratory support requirement was favored as the more objective and therefore relevant measure (37) . guidance statement: remdesivir is suggested for children with severe covid-19. rationale: we regard covid-19 cases as "severe" if there is a new requirement for supplemental oxygen (or an increased requirement from baseline) but without the need for new or increased non-invasive or invasive mechanical ventilation or ecmo (table 1) . remdesivir is suggested in this population based on a randomized trial demonstrating a shorter time to clinical recovery in hospitalized adults treated with remdesivir, with the greatest benefit in the subgroup requiring supplemental oxygen without need for mechanical ventilation. however, the clinical course of severe covid-19 may be milder in children, and therefore the benefit of remdesivir is less certain, necessitating continued case-by-case assessments of benefit and risk in children. this assessment should be informed by illness severity, illness trajectory, hypothesized risk factors for poor clinical outcomes as detailed in section ii, and remdesivir availability. when available, patients should be enrolled in clinical trials. guidance statement: remdesivir should be considered for all children with critical covid-19, unless there are contraindications. rationale: we regard covid-19 cases as "critical" if there is a new or increased need for non-invasive or invasive mechanical ventilation, hemodynamic instability requiring vasoactive agents, multisystem organ failure, or a rapidly worsening clinical trajectory ( table 1) . the aforementioned randomized trial demonstrated no difference in time to clinical recovery among the subgroup of adults requiring mechanical ventilation or ecmo. the benefit of remdesivir therapy is therefore uncertain in this population. however, given extreme illness severity and lack of pediatric-specific data evaluating efficacy, remdesivir should be considered on a case-by-case basis in all critically ill children. this assessment should be informed by illness severity, illness trajectory, duration of ventilation (with initiation earlier in the intubation course favored), and remdesivir availability. when available, patients should be enrolled in clinical trials. rationale: based on the duration recommended in the fda eua and no difference in outcomes in a randomized trial comparing 5 versus 10 days of therapy in adults, we suggest a duration of up to 5 days for most children with covid-19 who are treated with remdesivir. for children requiring mechanical ventilation or ecmo, a duration of up to 10 days is recommended in the fda eua and was the duration studied in the placebo-controlled trial establishing remdesivir's efficacy in hospitalized adults. however, given data suggesting no difference in outcomes between 5 versus 10 days of therapy, and uncertainty as to whether remdesivir provides any clinical benefit at all for critically ill patients, we suggest a duration of 5-10 days, with up to 10 days considered on a case-by-case basis for those patients not improving after 5 days of therapy (table 2) . remdesivir is a nucleoside analog prodrug which, when activated, binds to viral rna polymerase, resulting in premature rna chain termination (38, 39) . the fda issued an eua for remdesivir on may 1, 2020 for adults and children with severe or critical covid-19, which was subsequently expanded to include all hospitalized patients on august 28, 2020 (9) . prior to the eua, remdesivir could be obtained through single patient expanded access ("compassionate use") requests through the manufacturer, gilead scientific. in vitro data 13 while other nucleoside analogs (e.g., ribavirin) are ineffective against coronaviruses due to the proofreading capability of a unique 3'-to-5' exoribonuclease and resultant high-fidelity viral replication, remdesivir maintains activity despite the existence of this exoribonuclease (40, 41) . in vitro studies also demonstrate a low likelihood of developing resistance, further supporting use of remdesivir (40) . halfmaximal effective concentration (ec 50 ) for sars-cov-2 was low in vero e6 cells (0.77 m), while cytotoxic concentration was high, suggesting remdesivir specificity for viral rna polymerase and a wide therapeutic index (42) . the results of four randomized trials evaluating the efficacy of remdesivir have been published at the time of this guidance document. the adaptive covid-19 treatment trial (actt) (nct04280705) was a national institutes of health (nih)-funded, multicenter, double-blind, placebo-controlled trial evaluating the efficacy of a 10-day course of remdesivir in hospitalized adults with covid-19. the primary outcome was time to recovery, defined as either hospital discharge or hospitalized without need for ongoing medical care, and was measured on an eight-point ordinal scale. preliminary results demonstrated that patients treated with remdesivir had a median time to recovery of 11 days as compared to 15 days in the placebo group (rate ratio 1.32, 95% confidence interval [ci] 1.12-1.55). in a subgroup analysis stratified by respiratory support requirement, time to recovery was reduced in the group requiring supplemental oxygen only, with no difference in patients not requiring supplemental oxygen (i.e., patients with moderate disease) or in patients requiring mechanical ventilation (invasive or noninvasive) or ecmo (i.e., patients with critical disease). no statistical difference in mortality was detected (7.1% in the remdesivir arm versus 11.9% in the placebo arm). there were no differences in key safety outcomes between treatment groups, including anemia, acute kidney injury, or hepatic transaminase elevations (4) . additional analysis of these data is ongoing. 14 an industry-sponsored trial compared 5 versus 10 days of remdesivir therapy in a cohort of 397 patients aged ≥12 years with severe covid-19, defined as pulmonary infiltrates on imaging and an oxygen saturation <94% on room air or need for supplemental oxygen at randomization (nct04292899). the primary outcome was clinical status on day 14 using a 7-point ordinal scale, similar to the previous study. after adjustment for baseline clinical status, which was more severe in the 10-day group, no differences in the primary outcome were detected in the two treatment arms (43) . a second industrysponsored, open-label, non-placebo-controlled randomized trial compared standard care versus a 5-or up to 10-day course of remdesivir in hospitalized patients with moderate covid-19, defined as pulmonary infiltrates on imaging and an oxygen saturation >94% at randomization (nct04292730). the primary outcome of this study was clinical status score on day 11 following randomization on a 7-point ordinal scale, with differences in the distribution of scores across treatment groups reported as odds of a better clinical status. relative to patients randomized to standard care, patients randomized to 5 days of remdesivir had a greater odds of a higher clinical status (odds ratio 1.65, 95% ci 1.09-2.48) at day 11, whereas no statistical difference in clinical status was detected in the 10-day group. significant limitations to this study include 1) the unblinded nature of the trial and 2) uncertainty as to how to translate the summary odds ratio presented in the primary analysis into a quantifiable and clinically meaningful difference in outcome (44) . finally, a double-blind, placebo-controlled randomized trial compared remdesivir to placebo in hospitalized adults with severe covid-19, defined as radiographically confirmed pneumonia and oxygen saturation of <94% on room air or an arterial partial pressure of oxygen to fractional inspired oxygen of ≤300 mmhg. similar to the previous two trials, an ordinal outcome scale was used, with the primary outcome of time to clinical improvement defined as the first day within 28 days of randomization that 15 patients experienced improvement of ≥2 ordinal levels. this trial was halted prior to target enrollment due to the decline in covid-19 cases in china, but there was no statistical difference in the primary outcome between treatment groups. complicating the interpretation of these results, use of additional therapies, including antivirals, immunomodulators and corticosteroids, was permitted (45) . additional published data describing use of remdesivir for covid-19 include case reports and case series (46) (47) (48) . there are no comparative clinical data evaluating the efficacy or safety of remdesivir for covid-19 in pediatric patients. most covid-19 in children is asymptomatic or of mild or moderate severity (11, 13, 14, (19) (20) (21) (22) (23) . in a large case series of 2,135 confirmed and suspected pediatric covid-19 cases in china, >90% had asymptomatic, mild, or moderate infections (13). data from the us is consistent with these findings, with the majority of children managed as outpatients (11, 22) . children receiving remdesivir have been included in several pediatric case series, though data related to clinical outcomes and adverse events are not specifically reported (12, (14) (15) (16) 21) . a multinational european cohort of 582 children demonstrated that 507 (87%) had mild or moderate disease, with 48 patients requiring picu admission and just four mortalities. remdesivir was used in 17 patients, but the impact on clinical outcomes was not reported (14) . similarly, among a cohort of 576 hospitalized children in the us, 5.8% required icu admission and only one mortality was reported. among the 208 children with data on antiviral medication use, just nine received remdesivir (21) . finally, among 43 children aged <18 years enrolled in a randomized trial evaluating the efficacy of remdesivir for ebola, there were no serious adverse events attributed to remdesivir in children (49). the fda-recommended dosing of remdesivir for children is summarized in table 2 (50) . these recommendations are based on adult physiologically based pharmacokinetic (pbpk) modeling and reflect those used in the aforementioned ebola trial, as well as those recommended for use under the single-patient expanded access ("compassionate use") program. while these doses are expected to provide similar drug exposure to those observed in healthy adults, there are no published pharmacokinetic studies that validate this approach. pediatric providers should be aware that remdesivir is available as an injectable solution and a lyophilized powder, which differ in their concentration of sulfobutylether-β-cyclodextrin sodium salt (sbecd), a renally cleared excipient. the injection solution contains 6 g sbecd per 100 mg vial, whereas the lyophilized powder formulation contains 3 g sbecd per 100 mg vial. for pediatric patients <40 kg, remdesivir lyophilized powder is used to limit cyclodextrin exposure to less than 300 mg/kg (50) . finally, while remdesivir is a substrate for cyp2c8, cyp2d6, and cp3a4 in vitro, it has a low potential for drug-drug interactions as its metabolism is likely mediated by hydrolase activity. that said, providers are nevertheless encouraged to check drug interactions prior to use (51) . the fda has warned of possible antagonism between remdesivir and hydroxychloroquine based on in vitro data, so concomitant use of these drugs is not recommended (52) . several ongoing clinical trials in the us are evaluating the efficacy of remdesivir alone or in combination with various immunomodulatory agents, including baricitinib (nct044015799, nct04373044), tocilizumab (nct04409262), and merimepodib (nct04410354). additionally, remdesivir is being studied in the who-sponsored solidarity trial (nct04330690). finally, an industry-sponsored study evaluating the safety, tolerability, pharmacokinetics, and efficacy of remdesivir from birth to 18 years of age is underway to inform optimal pediatric dosing (nct04431453). evidence summary: the pathogenesis of mis-c remains unknown, but the syndrome is presumed to be post-infectious based on three main observations. first, a region's incidence of mis-c has been reported to peak about 1 month after its peak in acute covid-19 cases (25, 26) . second, some affected children have preceding symptoms consistent with acute covid-19 (25) (26) (27) . finally, a substantial proportion of affected children have positive sars-cov-2 serology but negative rt-pcr assays, suggesting that their hyperinflammatory state may reflect a post-infectious phenomenon with an aberrant immune response (25, 26, 53) . however, the sars-cov-2 testing profile is variable in patients meeting criteria for mis-c, with some patients having positive rt-pcr results, sometimes without sars-cov-2 antibodies (25) (26) (27) . it is unknown whether rt-pcr positivity in mis-c represents replication-competent virus that may act as an ongoing inflammatory trigger. in addition, the overlap of clinical and laboratory features between acute covid-19-associated hyperinflammatory syndrome and mis-c can result in diagnostic uncertainty. until the pathogenesis of mis-c is better understood, we suggest limiting remdesivir use to select patients with mis-c and a positive viral testing, including those with an ambiguous clinical presentation, severe illness, or an rt-pcr cycle threshold result suggestive of a high viral load. another potential consideration for remdesivir use is concurrent use of immunosuppressive therapy -particularly corticosteroids -that may impair virologic control. guidance statement: there are no definitive data to support any specific risk factor for severe in children. rationale: the majority of pediatric data related to covid-19 remains descriptive in nature, including population-level epidemiologic studies and single-and multi-center case series describing primarily hospitalized and/or critically ill patients. the reported prevalence of any comorbidity in these series varies widely, ranging from 25% to 83%. nevertheless, the panel recognizes that pediatric clinicians are likely to consider comorbidities when weighing the risks and benefits of antiviral therapy on a case-bycase basis, and in making these decisions may consider: 1) the available, albeit limited, pediatric covid-19 literature; 2) risk factors associated with severe covid-19 in adults; and 3) pre-existing medical conditions in children associated with worse clinical outcomes for other viral infections. we have therefore summarized relevant data and highlighted hypothesized risk factors ( table 3 ) that clinicians may consider in determining whether to administer remdesivir. evidence summary: although there is no standard definition for children with medical complexity (cmc), this term generally refers to children who have multiple chronic health conditions, may be dependent on medical technology, and may have functional limitations (e.g., due to neurologic impairment, developmental delays, or genetic syndromes) (54) . this group's risk of decompensation with pulmonary infections is likely driven by a combination of factors, including abnormalities in mucociliary clearance, muscle tone, and craniofacial structures, as well as potentially delayed recognition of illness due to impairments in communication (55) . it would therefore not be unexpected if cmc experienced a more severe course following sars-cov-2 infections, though empiric data confirming this assumption are lacking, and interpretation of published studies is confounded by inconsistent definitions of cmc. in a cross-sectional study of 48 children admitted to north american picus, 19 (40%) were classified as medically complex, whereas only an estimated 0.4% of children in the us are cmc (15, 56) . in a large european study of 582 children, both underlying pulmonary disease and neurologic disease were associated with increased risk of picu admission, though whether children in these categories would have met the definition for cmc based on the severity of the underlying condition was not reported (14) . similarly, two smaller us case series highlight a numerically higher prevalence of children with underlying genetic and neurologic conditions among patients requiring picu admission, though these differences did not achieve statistical significance (12, 16) . collectively, these data support the possibility that cmc may be at risk for severe covid-19, and medical complexity therefore could be considered in making antiviral treatment decisions. the pediatric cohort described by dong and colleagues remains the largest to date and included 376 children in the <1-year category (13). of these, 89% had mild to moderate symptoms or were asymptomatic. a more recent case series of 130 children from italy found that infants <6 months old were at increased risk of critical disease compared to older children, though no deaths occurred. in this series, 33% of the children who received icu-level care also had comorbidities, and 3 out of the 6 infants in the icu did not require respiratory support (17) . similarly, a multinational european study including 582 children identified an association between age <1 month and icu admission, as compared to outpatient management or management on the general ward. however, the degree of respiratory or inotropic support was not reported, so illness severity cannot be assessed, and as in the prior report, there were no mortalities in this age group (14) . in the report of covid-19 in us children described above, among 59 infants <1 year of age, 8% required icu-level care, compared with 11% of the 88 children >1 year of age, suggesting that young age is not associated with increased risk of severe disease (11) . likewise, the covid-19-associated hospitalization surveillance network (covid-net) recently reported surveillance of 576 children hospitalized in the us with covid-19, among whom infants <12 months of age accounted for 27.3% (157/576) of the pediatric hospitalizations. further analysis of clinical severity in 208 of these hospitalized patients did not separate out infants <1 year but found that children aged 0-2 years did not have increased rates of icu-level care compared to older children (31.1% vs 34%). no children 0-2 years of age required invasive mechanical ventilation (21) . several additional reports have also described infants experiencing only mild infection who frequently improved without any intervention (57) (58) (59) . this includes a case series of 18 hospitalized infants <90 days, none of whom required supplemental oxygen or intensive care (59) . overall, data are insufficient to suggest that young age alone is a risk factor for severe covid-19. initial reports of covid-19 in the us suggested that adolescents were not at risk of severe disease (11) . however, as the pandemic has unfolded, single-center reports on the us experience among hospitalized children have suggested an increased proportion of severe respiratory disease in adolescents compared with younger children and infants (12, 16, 23) . a large multicenter report of north american picu hospitalizations describes that the majority of picu admissions occurred in the 11-to 21-year-old age group (15) . as risk factors among adolescents similar to those identified in adults (e.g., obesity) could contribute to icu admissions, older age could be considered a risk factor for increased covid-19 severity and therefore could be considered in guiding antiviral treatment decisions. in a cohort of children admitted to picus in new york city with acute covid-19, 17% had hematologic malignancy/immunosuppression listed as a comorbidity (24) . in a separate cohort from the north american picu collaborative study group, 23% of patients had malignancies or were otherwise receiving immunosuppression (15) . outcomes were not stratified by co-morbidity in either study, and it remains unclear whether immunocompromised status is a risk factor for severe disease requiring icu-level care. in a large multinational european study, children with malignancy accounted for 10% of the cohort requiring picu admission (14) . cohorts of pediatric cancer patients from new york, madrid, and italy had both low rates of infection and low morbidity when infected (60) (61) (62) (63) . covid-net reported 5.4% of all hospitalized pediatric patients with underlying disease were immunocompromised (21) . no cohort studies of pediatric solid organ transplant patients with covid-19 have been published, though case reports and anecdotal information suggest that severe covid-19 in this population is rare (64) (65) (66) (67) . finally, in two electronic registries of pediatric covid-19 cases, severe disease or death appeared uncommon in children who were immunocompromised or in those receiving treatment for cancer (68, 69) . these data suggest that children who are mildly to moderately immunocompromised are not at higher risk of severe covid-19; however, the limited number of studies and lack of comparative data preclude an assessment of risk in severely immunocompromised children (table 4) considering the limited available data in sars-cov-2-infected children, and extrapolating from other viruses, children with severe t-cell deficiency or dysfunction may be at risk of more severe disease and may exhibit longer viral shedding than non-immunocompromised children. these factors could be considered in deciding whether to prescribe remdesivir (table 4 ). we remind clinicians to consider the potential for drug toxicity and drug-drug-interactions given the numerous medications that immunocompromised patients receive, particularly for patients receiving other experimental agents. adult data suggest that, in addition to older age, presence of underlying cardiovascular disease, including coronary artery disease, cardiomyopathy, and hypertension, and chronic respiratory disease are associated with covid-19-related morbidity and mortality (80) (81) (82) (83) (84) . however, differing etiologies of cardiopulmonary disease in children make direct application adult data challenging, with congenital heart disease as well as bronchopulmonary dysplasia being additional pediatric considerations (table 4) . patients with congenital heart disease have not consistently been reported in series describing severely or critically ill cohorts, though one large european series reported that 4% of non-picu versus 10% of picu patients had congenital heart disease (14, 85) . limited experience suggests a high prevalence of 23 underlying pulmonary disease among children with severe covid-19, including children with chronic respiratory insufficiency or failure resulting in technology dependence (i.e., chronic invasive or noninvasive mechanical ventilation) (11, 14, 15, 23) . a significant prevalence of asthma among children with sars cov-2 infection has been described in some reports, although data are insufficient to demonstrate an association between underlying asthma and increased risk of severe covid-19 (12, 23) . however, there is evidence to support more severe outcomes from other respiratory viral infections, such as influenza (86, 87) , parainfluenza (88), rsv (89) (90) (91) (92) , and non-covid-19 coronaviruses (73, 93) , in children with chronic cardiac and pulmonary conditions. presence of severe underlying cardiac or pulmonary disease could therefore be considered when weighing risks and benefits of potential antiviral therapy (94) . data from retrospective studies suggest that being overweight (bmi >85 th -95 th percentile for age and sex) or obese (bmi ≥ 95 th percentile for age and sex) is an independent risk factor for hospitalization and severe manifestations of covid-19 in adults (95) (96) (97) (98) (99) (100) . being overweight or obese is common in children (101) , but unlike adults, comorbid cardiovascular disease (e.g., hypertension, diabetes, or renal disease) less often complicates these conditions. initial reports of hospitalized children with covid-19 are mixed with regard to disease severity in obese children. for example, a case series of children hospitalized with covid-19 in new york city indicated that obesity was the most prevalent comorbidity, with a significant association with mechanical ventilation in children ≥2 years of age (16) , whereas other series have not demonstrated this association (12, 23) . recognizing the limitations of these small series reporting unadjusted analyses, and considering the growing body of evidence supporting an association between overweight and obesity and covid-19 severity in younger adults, an elevated bmi could be considered 24 when determining whether to administer remdesivir, particularly when associated with cardiovascular comorbidities (96, 97) . based on observational data, adults with diabetes mellitus appear to be at elevated risk for several complications of covid-19, including progression to severe disease, development of ards, and death (22, 84, (102) (103) (104) . however, diabetes mellitus has not emerged thus far as a clear independent risk factor for complications of covid-19 in children (11, (15) (16) (17) . this may be due in part to limited pediatric data, but may also be due to a higher prevalence of type 1 versus type 2 diabetes in children relative to adults, as well as a higher prevalence of associated comorbidities in adults, including obesity (105) . based on emerging data that support obesity as a risk factor for severe covid-19, obesity may be an important comorbidity modifying risk for complications of covid-19 in children with diabetes mellitus (16, 96) . a related issue is that while use of concomitant medications acting on the renin-angiotensin-aldosterone system has been hypothesized to influence risk for covid-19-associated complications, current evidence does not support a detrimental effect of these medications (106) . when considering remdesivir in a pediatric patient with covid-19, diabetes mellitus and associated comorbidities such as obesity could be considered in the decision-making process, but diabetes mellitus should not be the sole rationale for choosing to administer antiviral therapy. exposure to angiotensin-converting inhibitor or angiotensin receptor blocker therapy should not influence risk assessment in decisions to administer remdesivir. the initial human data that led to enthusiasm surrounding use of hydroxychloroquine, with or without azithromycin, included small observational studies and randomized controlled trials early in the pandemic (109) (110) (111) (112) (113) this study was terminated prior to target enrollment due to waning of the pandemic in china, but no difference in the primary outcome of virologic clearance at 28 days (81% versus 85%) or time to virologic clearance (8 versus 7 days) was detected (6) . finally, a brazilian trial compared the impact of hydroxychloroquine plus azithromycin versus hydroxychloroquine alone versus standard therapy on 15day clinical status using a 7-point ordinal scale in just over 500 hospitalized patients with mild to moderate covid-19. no difference was detected in any treatment arm (7) . also supporting the lack of efficacy of hydroxychloroquine are the results of a randomized trial comparing hydroxychloroquine to placebo for post-exposure prophylaxis following a moderate-or high-risk exposure to sars-cov-2. no difference in sars-cov-2 rt-pcr positivity or sars-cov-2-compatible illness within 14 days was detected (114) . most observational studies have also demonstrated a lack of benefit of hydroxychloroquine. mahavas and colleagues performed a multicenter study evaluating the impact of hydroxychloroquine compared to standard care on icu-free survival at 21 days in a cohort of 173 hospitalized adults with severe covid-19. following inverse probability of treatment weighting (iptw), no difference in icu-free survival was detected (76% versus 75%; hr 0.90, 95% confidence interval 0.40-2.10) (115) . similar findings were demonstrated by geleris and colleagues, who found no difference in a composite outcome of intubation or death with hydroxychloroquine versus standard care following iptw in a single-center cohort of 1376 patients (hr 1.04, 95% confidence interval 0.82-1.32) (116) . three large observational studies additionally considered the combination of hydroxychloroquine and azithromycin. the first was a multicenter study comparing hydroxychloroquine alone (n=97), hydroxychloroquine plus azithromycin (n=113), or no hydroxychloroquine (n=158) in a cohort of men admitted to us veterans affairs hospitals. unadjusted mortality was highest in the hydroxychloroquine group (27.8% versus 22.1% in the combination therapy group versus 11.4% in the untreated group). following propensity score adjustment, hydroxychloroquine therapy remained associated with mortality (hr 2.61, 95% confidence interval 1.10-6.17), while hydroxychloroquine plus azithromycin was not (hr 0.43, 95% confidence interval 0.16-1.12). cause of death was not reported in this study, and given its observational design, it is possible that the association between hydroxychloroquine use and death is the result of residual confounding (117) . a second study utilized data from the new york state department of health to compare in-hospital mortality in a cohort of 1438 patients, including 25 children. no difference in mortality was detected among patients treated with hydroxychloroquine alone (n=271), azithromycin alone (n=211), hydroxychloroquine plus azithromycin (n=735), or neither drug (n=221). cardiac arrest was more common in the group receiving hydroxychloroquine and azithromycin relative to no treatment, but not in patients receiving either drug alone (118) . finally, a retrospective study including 2,541 hospitalized adults suggested reduced in-hospital mortality among patients treated with hydroxychloroquine (hr 0.34; 95% ci 0.25-0.46) or the combination of hydroxychloroquine and azithromycin (hr 0.29; 95% ci 0.22-0.40) relative to neither drug (119). however, a notable limitation was that the hydroxychloroquine-treated patients more often received steroids, a therapy that has been shown to reduce covid-19 related mortality. this raises the possibility that the mortality benefit seen in the hydroxychloroquine-treated groups was, in fact, driven by the receipt of steroids, especially when considered in the context of multiple randomized trials demonstrating no benefit with hydroxychloroquine therapy. in addition to the lack of efficacy, several reports have highlighted the potential for qtc prolongation with concomitant hydroxychloroquine and azithromycin therapy, occurring in up to 30% of treated patients (120, 121) . the high-dose arm of a randomized trial comparing high-dose (600 mg twice daily for 10 days) to low-dose (450 mg twice daily on day 1, followed by 450 mg daily for a total of 5 days) chloroquine was terminated after detection of higher mortality in the high-dose arm (122) . there are no comparative observational studies or randomized trials evaluating safety or efficacy of hydroxychloroquine or chloroquine in children. frequency of hydroxychloroquine use has been reported in several pediatric case series and was as high as 44% in a us cohort of critically ill children (12, (14) (15) (16) 18) . several authors have evaluated dosing strategies for hydroxychloroquine and chloroquine in children using pharmacokinetic modeling; however, detailed discussion of these studies is beyond the scope of this review (123) . lopinavir-ritonavir is a protease inhibitor approved by the fda for treatment of pediatric hiv. the ritonavir component inhibits the cyp3a metabolism of lopinavir, increasing plasma levels of lopinavir. it is a preferred therapy for children 2 weeks to 3 years of age who require antiretroviral therapy and is an alternative antiretroviral agent for children >3 years of age (124) . it is not fda approved or authorized for use in the treatment of sars-cov-2 infection. its hypothesized mechanism of action for sars-cov-2 is inhibition of the viral proteinases papain-like proteinase and 3c-like proteinase, which are key enzymes in coronavirus polyprotein processing. an in vitro study of the antiviral activity of lopinavir in vero e6 cells demonstrated an ec 50 of 26.1 m, which is well above the trough lopinavir serum concentration with dosing used for hiv and doses used in studies of sars-cov-2 (125, 126) . no animal data exist evaluating lopinavir-ritonavir for sars-cov-2. a randomized controlled trial compared lopinavir-ritonavir to usual care in 199 hospitalized adults with severe covid-19. there was no difference between the groups in time to clinical improvement, defined as a two-point improvement on a seven-point clinical severity scale between the groups (16 days versus 16 days), 28-day mortality (19.2% versus 25%), or virologic clearance. the lopinavir-ritonavir group did experience shorter icu length of stay (6 versus 11 days). concerns about the generalizability of these findings include: 1) a relatively small sample size, such that only a large difference in outcome was detectable; 2) lopinavir-ritonavir was started late in the disease course (median of 13 days after symptom onset), perhaps beyond the time of peak viral replication; and 3) a high mortality rate in this cohort, perhaps limiting ability to extrapolate these data to other, less sick patients (8) (127) . two smaller trials have reported consistent findings, with no differences in virologic 31 clearance in hospitalized adults treated with lopinavir-ritonavir or another protease inhibitor, darunavir/cobicistat (128, 129) . published observational studies largely do not support use of lopinavir-ritonavir for treatment of covid-19 and highlight a high prevalence of adverse effects, particularly gastrointestinal effects, as well as potential drug-drug interactions from prolonged cytochrome p4503a inhibition (130) (131) (132) . there are no comparative observational studies or randomized trials evaluating safety or efficacy of lopinavir-ritonavir or other hiv protease inhibitors for treatment of sars-cov-2 infection in children. reports of use are sparse and limited to case series, the largest of which included 14 children treated with lopinavir-ritonavir, all of whom recovered (14, 133) . fund. md has nih-supported collaboration with gilead sciences (u19 ai142759) but does not receive monetary support from gilead. ar is a prior consultant for pfizer outside the scope of this work. there is insufficient evidence to support young age alone as a risk factor for severe covid-19. there is insufficient evidence to definitively support older age (i.e., the adolescent age group) as a risk factor for severe covid-19. however, based on the higher prevalence of adolescents in published pediatric cohorts relative to younger children, older age could be considered in making antiviral treatment decisions. there is insufficient evidence to definitively support severe immunocompromise as a risk factor for severe covid-19 in children. however, given the limited evidence base, and based on adult studies of covid-19 and extrapolation from other viral infections, severe immunocompromise could be considered in making antiviral treatment decisions. evidence to date suggests that mild/moderate immunocompromise should not be considered a risk factor for severe covid-19 in children. there is insufficient evidence to definitively support underlying cardiac disease as a risk factor for severe covid-19 in children. however, based on adult studies of covid-19, extrapolation from other viral infections, and limited data in children with covid-19, presence of underlying cardiac disease could be considered in making antiviral treatment decisions. there is insufficient evidence to definitively support underlying pulmonary disease as a risk factor for severe covid-19 in children. based on adult studies of covid-19, extrapolation from other viral infections, and limited data in children with covid-19, underlying pulmonary disease could be considered in making antiviral treatment decisions. there is insufficient evidence to definitively support isolated overweight or obese as a risk factor for severe covid-19 in the pediatric population. current reports indicate that obesity is prevalent among pediatric covid-19 hospitalizations, 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cord-342133-khrljehj authors: principi, nicola; piralla, antonio; zampiero, alberto; bianchini, sonia; umbrello, giulia; scala, alessia; bosis, samantha; fossali, emilio; baldanti, fausto; esposito, susanna title: bocavirus infection in otherwise healthy children with respiratory disease date: 2015-08-12 journal: plos one doi: 10.1371/journal.pone.0135640 sha: doc_id: 342133 cord_uid: khrljehj to evaluate the role of human bocavirus (hbov) as a causative agent of respiratory disease, the importance of the viral load in respiratory disease type and severity and the pathogenicity of the different hbov species, we studied all hbov-positive nasopharyngeal samples collected from children who attended an emergency room for a respiratory tract infection during three winters (2009–2010, 2011–2012, and 2013–2014). human bocavirus was detected using the respiratory virus panel fast assay and real-time pcr. of the 1,823 nasopharyngeal samples, 104 (5.7%) were positive for hbov; a similar prevalence was observed in all three periods studied. among hbov-infected children, 53.8% were between 1–2 years old, and hbov was detected alone in 57/104 (54.8%) cases. all of the detected hbov strains belonged to genotype 1. the median hbov load was significantly higher in samples containing strains with both the n546h and t590s mutations compared to other samples (p<0.05). children with a single hbov-1 infection more frequently had upper respiratory tract infections (urtis) than those who were co-infected (37.0% vs 17.8%, respectively, p = 0.04). the duration of hospitalization was longer among children with high viral loads than that observed among children with low viral loads (8.0 ±2.2 days vs 5.0 ±1.5 days, respectively, p = 0.03), and the use of aerosol therapy was more frequent among children with high viral loads than among those with low viral loads (77.1% vs 55.7%, respectively, p = 0.04). this study shows that hbov is a relatively uncommon but stable infectious agent in children and that hbov1 seems to be the only strain detected in italy in respiratory samples. from a clinical point of view, hbov1 seems to have in the majority of healthy children relatively low clinical relevance. moreover, the viral load influences only the duration of hospitalization and the use of aerosol therapy without any association with the site of the respiratory disease. human bocavirus (hbov) is a recently identified viral agent that belongs to the family parvoviridae and contains a single linear positive-sense or negative-sense single-stranded deoxyribonucleic acid genome [1] . this virus has been detected mainly in younger children, in nasopharyngeal secretions, in sera and blood samples of patients with upper (urti) and lower (lrti) respiratory tract infections and in faecal specimens of subjects with gastroenteritis [2] . currently, hbovs are classified into species 1 through 4; hbov1 is predominantly found in the respiratory tract, and hbov2, hbov3, and hbov4 are found mainly in stool [3] . despite there are studies suggesting that hbov is able to infect the lower airways causing severe infections in both children and adults, the role of hbov as a causative agent of respiratory disease is frequently questioned due to its common detection with other potential pathogens [4] and the evidence that in some studies co-infections can have a significantly greater clinical and socioeconomic impact on infected children and their households than hbov infection alone [5] . moreover, the importance of the viral load in determining the type and severity of respiratory disease as well as the pathogenicity of the different hbov species [6] are not precisely defined. the main aim of this study was to contribute to resolving these problems. the circulation of hbov during several winter seasons in italy was investigated, and a phylogenetic analysis of detected strains was performed. in addition, correlations between different hbov strains and the severity of disease in cases with infections due to hbov alone or due to co-infections were studied. finally, the role of the viral load was analysed. to evaluate the circulation of the different hbov types and the possible relationships between viral load, virus genetic characteristics, and the severity of infection, nasopharyngeal swabs were collected from otherwise healthy children attending the emergency room of the fondazione irccs ca' granda ospedale maggiore policlinico, university of milan, italy, due to a respiratory tract infection arising between november 1 and march 31 during 3 winters (2009-2010, 2011-2012, and 2013-2014) . the study was approved by the ethics committee of the fondazione irccs ca' granda ospedale maggiore policlinico, milan, italy. written informed consent of a parent or legal guardian was required, and children 8 years of age were asked to give their written assent. patients' demographic characteristics and medical histories were retrieved from hospital charts and were systematically recorded before and after the first visit to the emergency room using standardized written questionnaires [7] . the study patients were classified into disease groups (i.e., acute otitis media, rhinosinusitis, pharyngitis, croup, infectious wheezing, acute bronchitis, pneumonia) on the basis of signs and/or symptoms using well-established criteria and were finally subdivided into two subgroups: upper (urtis) and lower respiratory tract infections (lrtis) [8] . nasopharyngeal secretions were collected from all of the children immediately after admission to the emergency room using a paranasal flocked swab (1 swab per child), which was stored in a tube containing 1 ml of universal transport medium (kit cat. no. 360c, copan italia, brescia, italy). viral nucleic acids were extracted from each swab by means of a nuclisens easymag automated extraction system (biomeriéux, craponne, france), and the extract was tested for respiratory viruses using the respiratory virus panel xtag rvp fast v2 (luminex molecular diagnostics, inc., toronto, canada), which simultaneously detects influenza a virus (subtypes h1 or h3); influenza b virus; respiratory syncytial virus (rsv) types a and b; human parainfluenza virus types 1-4 (hpiv1-4); adenovirus (adv); human metapneumovirus (hmpv); coronaviruses (hcov) 229e, nl63, oc43 and hku1, enterovirus/rhinovirus (ev/hrv); and hbov, in accordance with the manufacturer's instructions [9, 10] . samples that were positive for hbov were stored at -80°c. hbov real-time polymerase chain reaction (pcr) viral nucleic acid extracts previously testing positive for hbov were re-tested for confirmation by two different singleplex real-time pcrs using taqman universal master mix ii (applied biosystems, california, usa). amplification and detection of viral dna were performed with a 7900ht real-time pcr system machine (applied biosystems, california, usa). conserved regions for rt-pcr primers and probes were identified in the hbov ns-1 and np-1 genes from the nucleotide sequence alignments available from genbank (for ns1, dq206700-08, dq000495-96, and dq200648, and for np-1, dq000495-96, ab243566-72, dq296618-35, dq353695-99, dq299885, dq267760-75, dq284856, dq295844, and am109958-66; http:// www.ncbi.nlm.nih.gov/genbank/). each 25 μl singleplex reaction mixture consisted of 0.5 μl of forward primer 5'-tgcagacaacgcytagttgttt-3' and reverse primer 5'-ctgtcccg cccaagataca-3' for the 88 base pair ns-1 target or forward primer 5'-agcatcgctcctacaaaagaaaag-3' and reverse primer 5'-tcttcatcacttggtctga ggtct-3' for the np-1 target, 0.125 μl of probe 5'-ccaggattgggtggaacctgcaaa-3' or 5'-aggctcgggctcatatcatcaggaaca-3', and 2.5 μl of sample viral dna. pcrs were conducted at 50°c for 2 min and then at 95°c for 10 min, followed by 45 cycles at 95°c for 15 sec and at 60°c for 1 min. taqman probes were labelled at the 5' ends with the reporter molecule 6-carboxyfluorescein and at the 3' ends with black hole quencher 1 (biosearch technologies, inc., novato, ca). each run included one synthetic template control and one no-template control for each target. specimen extracts were also tested by real-time pcr for the human rnase-p gene to monitor specimen quality and the presence of pcr inhibitors. a positive test for both the ns1 and np-1 targets or for a single target confirmed from a second extraction from a new sample aliquot was considered definitive evidence of hbov infection. the viral load was obtained using real-time pcr with the ns1 primers and probe previously described and a dna plasmid used as the standard calibrator. the amplified target fragment of the plasmid was verified by sequencing. plasmid dna concentrations were detected with an nd-1000 spectrophotometer (nanodrop products, wilmington, de, usa). each run included plasmid and negative controls. standard precautions were taken throughout the pcr process to avoid cross-contamination. negative controls and serial dilutions of the positive controls were included in every pcr assay. finally, quantitative results were reported as dna copies/ ml of respiratory samples. the viral load was defined as low for values 10 6 log (copies/ml) and as high for values >10 6 log (copies/ml). for genotyping, the viral vp-1/2 gene was amplified using a conventional pcr assay. briefly, 4 sets of forward and reverse primers (5'-cacagacagaagcagacgagat-3' and 5'-ggtg agaagtgacagctgtattg-3'; 5'-ttcagaatggtcacctctaca-3' and 5'-ctgtgc ttccgttttgtctta-3'; 5'-aactttgactgtgaatgggtta-3' and 5'-aaatagtgcc tggaggatgat-3'; 5'-ctatcaccagagaaaatccaatc-3' and 5'-gagacggtaaca ccacta-3') were used in pcr amplification and the quantitect probe master mix (qia-gen, venlo, netherlands) was used as the basis for the reaction mix. viral products were analysed by electrophoresis on a 1.5% agarose gel and purified with the qiaquick gel extraction kit (qiagen, venlo, netherlands). sequencing reactions were set up with purified dna, one of the specific primers used in the pcr and bigdye terminator v3.1 cycle sequencing kit (applied biosystems, california, usa) according to the protocol recommended by the manufacturer. sequencing and sequence analysis were performed on a 3130 genetic analyser (applied biosystems, california, usa). all alignments were performed using clustalx 2.1 and bioedit (version 7.1.3.0) software (ibis biosciences, carlsbad, ca). phylogenetic trees of the vp-1/2 protein gene were generated using the neighbour-joining method and p-distance model of the molecular evolutionary genetics analyses (mega) software, version 5.05 [11] . bootstrap probabilities for 1,000 iterations were calculated to evaluate confidence estimates. the graphs were made using graphpad prism version 5.01 for windows (graphpad software, san diego, ca). all genotyped sequences of the hbov vp-1/2 gene were submitted to genbank (accession numbers kr014412-kr014516). tests for positive selection were conducted on the datamonkey server [12] using the singlelikelihood ancestor (slac), and the fixed-effects likelihood (fel) [13] , the internal branch fixed-effects likelihood (ifel) [14] , the mixed effects model of evolution (meme) [15] , and fast unconstrained bayesian approximation methods (fubar). the dn/ds ratios were calculated using the slac and fel codon-based maximum likelihood approaches. the slac approach counts the number of non-synonymous changes per non-synonymous site (dn) and tests whether it is significantly different from the number of synonymous changes per synonymous site (ds). the fel approach estimates the ratios of non-synonymous to synonymous changes for each site in an alignment. the ifel method is similar to the fel, but tests site-bysite selection along only the internal branches of the phylogeny. in order to avoid an excessive false-positive rate, sites with slac, fel, ifel and meme p-values of <0.1 and a fubar posterior probability of >0.90 were accepted as candidates for selection. descriptive statistics of the responses were generated. continuous variables were presented as mean values and standard deviations (sds) and categorical variables as numbers and percentages. for categorical data, comparisons between groups were performed using a contingency table analysis with the χ 2 or fisher's exact test when appropriate. for ordered categorical data, a cochran-armitage test for trend was used to compare the groups. continuous data were analysed using a two-sided student's t-test after ensuring the data were normally distributed (based on the shapiro-wilk statistic) or using a two-sided wilcoxon's rank-sum test if the data were non-normal. all analyses were two tailed, and p-values of 0.05 or less were considered to be statistically significant. all analyses were conducted using sas version 9.2 (cary, nc, usa). during the three study periods, 1,823 nasopharyngeal samples were collected in the emergency room. of these, 104 (5.7%) tested positive for hbov (table 1) . among hbov infected children, 53.8% were between 1-2 years old, whereas 28.8% and 17.3% were aged <1 and 3 years, respectively. the prevalence of hbov detection was quite similar in the three studied periods; hbov was the only virus detected in 57/ 104 (54.8%) cases and was detected in association with one (89.5%) or more (10.5%) viruses in 47 (45.2%) cases. ev/hrv and rsv were the most common co-infecting viral agents and were found, respectively, in 20 and 18 samples. subjects with co-infection were younger than those without (p = 0.03). considering 10 6 dna copies/ml as a cut-off, the viral load was classified as low in 66 (63.5%) cases and as high in 38 (36.5%) cases. the phylogenetic tree constructed using the vp1/vp2 sequences showed that all of the italian hbov strains detected during the three study periods belonged to hbov genotype 1 (fig 1) . no unusual clustering was observed among the identified strains; hbovs circulating in 2009 were closely related to strains circulating in 2014. the sequence identity matrix of the vp1/vp2 gene showed minimum to maximum identity ranges of 97.8-100% between the italian strains and 98.4-99.7% with respect to hbov st1 reference strains (dq000495). in comparison to the reference strain, 8/105 (7.6%) strains had only one amino acid difference, 32/105 (30.4%) strains had two amino acid differences, and the remaining strains (65/105; 61.9%) had at least three amino acid changes. a total of 61/672 (9.1%) amino acid positions were observed to have at least one change in the vp1/vp2 sequence alignments (fig 2) . of these, 7/61 (11.5%) changes occurred within the vp1 unique (vp1u) region corresponding to the first 129 amino acids at the n-terminus of the vp1 gene. specifically, the following changes were observed: r17k, g28d, e29k, l40s, h43q, d72n, and g126e (fig 2) . the vp1u region includes the conserved phospholipase a 2 (pla 2 ) motif (nt 21-63). the vp1u sequences of all hbov isolates identified in this study revealed conserved yxgxg (nt [16] [17] [18] [19] [20] and hdxxy (nt 41-45) motifs in the catalytic site of secreted pla 2 . in addition, the amino acid residues at positions 21, 41, 42 and 63 have been hypothesized to form the catalytic network for enzymatic activity. in our hbov strains, all the sequences had amino acids associated with efficient enzymatic activity (p21, h41, d42, and d63). of note, two hbov strains (mi-267-jan2014 and mi-272-jan2014) had a peculiar amino acid sequence in the 19-amino acid segment starting at amino acid 411 (kvptrrvqpyirqtnwkhr), which has not been previously reported in hbov strains included in the genbank database (in red, fig 1) . overall, these two strains had 13 and 14 amino acid changes compared to the hbov st1 strain, and almost all these changes were included in the region described below. the origin of this highly divergent region, which occurred in spite of the conservation displayed in the rest of the hbov dna genome, remains to be defined. a global analysis of selective pressure made using the slac model indicated an estimated overall dn/ds ratio of 0.18. overall, the site-specific analyses identified three sites (411, 536, and 546) as under positive selection by at least two methods used (slac, fel, fubar, and meme). the ifel model was used to determine the selection pressure acting on the vp1/vp2 codons along the internal branches of the tree. two positively selected codons (411 and 546) were identified. the selected sites, highlighted with arrows in fig 2, were presumably located in of these strains, 6/13 (46.1%) were also characterized by the n534k, q535p, and q535d mutations. several negatively selected sites were identified by different methods (table 2 ). regarding the viral load, a wide range of hbov dna levels from 3.5x10 2 to 7.5x10 9 copies/ml were found in the clinical samples. in fig 2 (right side) , the viral load of each italian hbov strain is reported near the aligned mutations. in the group of strains (n = 70; 66.6%) harbouring at least 2 mutations in addition to a149t, the values of the hbov load greater than 1x10 8 dna copies/ml are reported in grey. a total of 16 strains had a very high viral load, and 13/16 (81.3%) harboured the t590s mutation. this percentage is nearly significantly different than the overall frequency (42/70; 53.8%) of t590s in the group of strains described below (p = 0.08). seven of the 13 strains with the t590s mutation had an additional mutation in one of the sites under positive selection (reported in fig 2 with an asterisk) . in detail, 4/13 (30.8%) had the n546h change, 2/13 (15.4%) had the a411d change, and 1/13 (7.7%) had the a411t change. based on the observed data, we hypothesize that the double mutation of n546h with t590s may positively affect viral replication and specific immune response. as shown in table 3 , the median hbov load was significantly higher in samples of strains with the n546h and t590s changes than that in samples of wild type t590 strains, strains with only the t590s mutation, and strains with only the n546h mutation (p-values of 0.0078, 0.016 and 0.018, respectively). finally, the two divergent strains (mi-267-jan2014 and mi272-jan2014) with unusual amino acid changes were observed with viral loads lower than 10 6 dna copies/ml. this could suggest that these mutations do not confer a replicative advantage in these virus strains. in table 4 , data regarding demographic, clinical and laboratory characteristics of children infected by hbov-1 alone or co-infected with hbov-1 and one or more other respiratory viruses are reported. because a preliminary evaluation did not find any differences among subjects co-infected with ev/hrv, rsv or other viruses, all co-infections were considered together. as shown, children infected with only hbov-1 had urtis more frequently than those with a co-infection (37.0% vs 17.8%, respectively, p = 0.04). moreover, a similar illness within the family in the 7 days since patient enrolment was significantly more common among co-infected children than among those with a single infection (48.9% vs 26.5%, respectively, p = 0.02). no other significant differences between the groups were observed. table 5 shows the demographic, clinical, and laboratory characteristics of the enrolled subjects according to the hbov load. subjects with low and high viral loads were quite similar. the only significant differences were found in the duration of hospitalization, which was longer among children with a high viral load than among those with a low viral load (8.0 ±2.2 days vs 5.0 ±1.5 days, respectively, p = 0.03), and in the use of aerosol therapy, which was more frequent among children with a high viral load than among those with a low viral load (77.1% vs 55.7%, respectively, p = 0.04). moreover, mutations leading to a high or low viral load were not associated with atypical clinical characteristics. this study shows that in italy during the winter periods 2009-2010, 2011-2012, and 2013-2014, the incidence of hbov infection among children with respiratory disease was relatively low, limited to approximately 5% of cases, and did not significantly vary from year to year. the phylogenetic analysis showed that all of the strains detected in this study belonged to hbov genotype 1 and were closely related to the prototype strain identified by allander et al. [1] . this was expected because this genotype is the most common among hbovs associated with respiratory infections [1] . most of the patients in whom hbov1 was identified were younger than 3 years of age, further highlighting that younger children are the individuals most frequently infected by this viral agent [1] . serological studies have shown evidence that the number of subjects positive for anti-hbov1 antibodies continuously increases with increasing age group from the ages of 6 months to 6 years, and by the age of 2 years approximately 80% of children have been infected with hbov1 [16, 17] . more than 50% of the children infected by hbov1 in this study were coinfected with at least one other respiratory virus. moreover, co-infected patients had lrti more frequently than those infected by hbov alone. these findings are not surprising because simultaneous detection of hbov1 and other viruses in children with respiratory disease and greater severity in co-infected cases have been already reported in studies in which it was also demonstrated that hbov1 can frequently be identified in the respiratory secretions of asymptomatic subjects [18] [19] [20] [21] [22] [23] . recently, it has been reported that hbov1 can be shed for several days or months after a previous infection [24] , which could explain the simultaneous identification of hbov1 and other respiratory viruses, the frequency of asymptomatic infections and the generally greater severity of infections in co-infected individuals compared to those with hbov1 alone. in most of the co-infected cases, detection of hbov in the respiratory secretions with the new sensitive molecular methods able to identify very low viral loads might be a consequence of a previous clinically resolved disease, and a virus other than hbov was therefore the real cause of the disease. however, reports of severe clinical manifestations in patients infected with only hbov have been published [25] , highlighting that the assessment of the real importance of hbov infection in a single patient remains very difficult. studies on children with severe pneumonia, acute wheezing, asthma and/or bronchiolitis suggested that hbov1 is able to infect the lower airways down to the bronchioles [26] [27] [28] [29] [30] [31] [32] . moreover, hbov1 has been found as the only infectious agent in adult lung transplant recipients with severe lrti, whereas it was not detected in respiratory secretions of asymptomatic transplanted subjects [33] . this would indicate that hbov1 is not always a bystander or the cause of mild respiratory problems but rather a real, although relatively rare, causative agent of severe disease in both children and adults, particularly when they are immunocompromised. on the other hand, hbov can cause serious neurological infections [34] and contribute to chronic disease in adult patients mainly because it can persist after childhood infection and reactivate [35] . evaluation of the viral load has been considered a possible method to define when this virus is the real cause of a respiratory disease and when it is only a secondary infection. unfortunately, this approach has had no success because although some studies have shown evidence for a strict correlation between high viral load and severe lrti in children with a single hbov infection [36] [37] [38] , others, including the present study, did not show a clear relationship between these two variables [39] . however, the evolution of virulence appears to involve a variety of mechanisms in different viral systems, including mutations in regulatory regions and viral adaptation for utilization of alternative or expanded repertoires of cellular receptors. an alternative hypothesis to evaluate the importance of hbov1 concerns the correlation between viral load levels and the presence of specific mutations. however, mutations associated with increased or reduced replication are rarely reported for hbov. recently, hao et al. have reported that few nucleotide changes were correlated with a lower viral load [40] . in the present study, a double mutant (n546h and t590s) was observed in samples with a significantly higher viral load. however, further phenotypic validation studies are required to draw major conclusions regarding the impact of these mutations on viral replication. furthermore, as reported by qu et al. [41] , it seems that nucleotide changes in the vp1u region could affect the replication efficiency of hbov. likewise, in our strains all the amino acids of the catalytic site were conserved, and no mutations that affect spla 2 activity were identified. in agreement with others [42] , the phylogenetic analysis of this study confirmed the very low degree of variability in the hbov genomic region encoding proteins that are exposed to the virus surface and are therefore under immunologic pressure. only 9% (62 codons) of amino acids were found to have at least one change in the vp1/vp2 gene, a finding not substantially different from that reported by hao et al. in a different geographic area [40] . in our study, several amino acid changes were observed in strains circulating in almost all the respiratory seasons. this finding provides evidence that the selection of those variants best adapted to each particular environment might select for variants with an evolutionary advantage. seven of these mutations were located in a genomic region (i.e., vp1u) previously reported to be involved in the mechanisms of virus replication. for instance, the vp1u amino acid variations r17k and l40s have been previously reported [43] , whereas the remaining variations have not yet been described. interestingly, two hbov strains identified in respiratory samples collected in january 2014 had unusual amino acid sequences in a somewhat conserved genomic region. the reason for this genetic diversity is still undefined. however, as described for hbov, other parvoviruses [44] , and enteroviruses, a series of α-helices and β-barrels in the vp2 protein were intercalated by an external loop, in which the majority of the genetic variability accumulated. nevertheless, these two divergent strains were found in samples with low viral loads, and we might hypothesize a loss of replication advantage for these strains. in the present study, the dn/ds ratios for all pairwise comparisons were <1, which is in line with previous results showing that positive selection was extremely limited in parvoviruses [45] . in fact, selective pressure analyses have identified 3 codons under positive selection. in a previous paper, a different codon (l40) was identified as being under positive selection [46] . nevertheless, the great majority of codons were under negative or neutral selection, which has also been confirmed by others [47] . this finding suggests that only a few amino acids of the vp1/vp2 proteins present on the surface of the virion are potentially subjected to a strong selective pressure by the host immune response. in conclusion, this study confirms that hbov is less common than other respiratory viruses but that the frequency of its detection in children with respiratory disease is in time stable. it was detected with a prevalence of about 5% in several consecutive seasons and no unusual clustering was observed among identified strains, with strains circulating in 2009 being closely related to those circulating in 2014. moreover, only a minority of virus sites were found to be under positive selective pressure, and all the strains detected in respiratory tract infections of this italian study belonged to genotype 1. from a clinical point of view, this study highlights that in otherwise healthy children, hbov1 seems to have relatively low clinical relevance, because patients infected with hbov alone mainly suffered from an urti. the viral load was not associated with clinical characteristics of the infection, and viral mutations, despite affecting viral replication, did not affect the conditions or severity of the clinical presentation. further studies are needed to clarify the clinical relevance of hbov in children, particularly in those at risk for severe chronic underlying disease, and to evaluate the role of viral modification in conditioning the degree of viral virulence and the specific immune response. conceived and designed the experiments: np se. performed 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vp1 unique region human bocavirus amongst an allages population hospitalised with acute lower respiratory infections in cambodia complete coding sequences and phylogenetic analysis of human bocavirus (hbov) human bocavirus capsid structure: insights into the structural repertoire of the parvoviridae evolutionary relationships among parvoviruses: virus-host coevolution among autonomous primate parvoviruses and links between adeno-associated and avian parvoviruses epidemic and molecular evolution of human bocavirus in hospitalized children with acute respiratory tract infection rapid molecular evolution of human bocavirus revealed by bayesian coalescent inference key: cord-348717-qgny6f6y authors: shumba, constance; maina, rose; mbuthia, gladys; kimani, rachel; mbugua, stella; shah, sweta; abubakar, amina; luchters, stanley; shaibu, sheila; ndirangu, eunice title: reorienting nurturing care for early childhood development during the covid-19 pandemic in kenya: a review date: 2020-09-25 journal: int j environ res public health doi: 10.3390/ijerph17197028 sha: doc_id: 348717 cord_uid: qgny6f6y in kenya, millions of children have limited access to nurturing care. with the coronavirus disease 2019 (covid-19) pandemic, it is anticipated that vulnerable children will bear the biggest brunt of the direct and indirect impacts of the pandemic. this review aimed to deepen understanding of the effects of covid-19 on nurturing care from conception to four years of age, a period where the care of children is often delivered through caregivers or other informal platforms. the review has drawn upon the empirical evidence from previous pandemics and epidemics, and anecdotal and emerging evidence from the ongoing covid-19 crisis. multifactorial impacts fall into five key domains: direct health; health and nutrition systems; economic protection; social and child protection; and child development and early learning. the review proposes program and policy strategies to guide the reorientation of nurturing care, prevent the detrimental effects associated with deteriorating nurturing care environments, and support the optimal development of the youngest and most vulnerable children. these include the provision of cash transfers and essential supplies for vulnerable households and strengthening of community-based platforms for nurturing care. further research on covid-19 and the ability of children’s ecology to provide nurturing care is needed, as is further testing of new ideas. the coronavirus disease 2019 (covid19) pandemic is spreading in unprecedented ways and has a significant impact on nurturing care and early childhood development outcomes. currently, there are over eighteen million covid-19 confirmed cases globally, kenya recording over 20,000 cases as of 3 of 19 therefore, there is a need to mitigate the impact of covid-19 by prioritizing programs and policies that support the continuum of ecd [10] . anecdotal evidence in kenya shows that the covid-19 pandemic is contributing to deteriorating optimal environments that threaten children's early development and has direct health impacts on caregivers and children [11] [12] [13] . strategies are required to prioritize a range of ecd interventions during the covid-19 pandemic to support caregivers so that they can meet the needs of their young children. ecd goes beyond improving child survival to enabling children to reach their full potential through cognitive, socio-emotional and physical development. failure to prioritize ncfecd will lead to a future pandemic where children who are presently most vulnerable, will have significant deficits on their health, wellbeing and productivity. previous pandemics have had long-term negative impacts over multiple generations. the development of children who were exposed to the asian influenza pandemic in 1957, while in utero, was hampered with evidence of poor cognitive development [14] . the 1918 spanish flu was reported to lower educational attainment for those individuals whose mothers had potential in utero exposure [15] . in japan, primary school children born between 1919 to 1929 were shorter than those in surrounding cohorts [16] . the timing of the prenatal exposure to influenza was also reported to have had worse consequences in those who were exposed in early gestational 0 to 8 weeks, as it was associated with delayed psychomotor development at 6 months of age [17] . in fact, it has been established that the spanish flu had negative outcomes in later life for those who were exposed in utero in several countries such as the usa [18] , brazil [19] , switzerland [20] , and taiwan [21] . in a narrative review of infants and children with congenital zika virus, epilepsy and motor abnormalities were noted [22] . wearing masks to prevent the transmission of sars also negatively impacted communication between children and adults, and was also threatening to children who had been sexually abused [23] . the hiv pandemic had a negative impact on child growth and development. globally and in sub-saharan africa including in kenya, young children affected by hiv particularly those who are hiv-infected, have a high risk of mental health problems, neurocognitive deficiencies, developmental delay, and poor nutrition outcomes [24] [25] [26] [27] [28] . the hiv pandemic generated a lot of lessons related to ecd. however, for a very long time, ecd was associated with child survival only, without a strong focus on promoting thriving and transforming [29] . ecd-related outcomes such as cognitive impairment and developmental delays as well as long-term impacts across the life course have not been tracked widely. even where there are attempts to focus on thriving and transforming, during epidemics and pandemics, the focus reverts to child survival. despite the frequency of epidemics, there is a scarcity of research on holistic ecd outcomes in the sub-saharan africa context. where research in sub-saharan africa exists, it has focused on other types of emergencies such as conflict and refugee crises [30] . there are several far-reaching, interlinked direct and indirect impacts of the covid-19 pandemic and associated control measures on nurturing care and related ecd outcomes including children's cognitive, physical, language, motor, and social and emotional development (figure 1 ). these include direct physical and mental health impacts resulting in illness and/or death from covid-19 infection, and severe stress leading to deterioration of mental health and well-being. with deaths increasing, many children are becoming orphaned or experiencing greater adversity. covid-19 has also affected access to health and nutrition systems including routine immunizations. social impacts include increased teenage pregnancies and a rise in gender based violence, all with a bearing on ecd outcomes. they also include lack of social and child protection services to support parents and primary caregivers. furthermore, child development and learning impacts including lack of access to institutional-based childcare services and critical nurturing environments have become more severe during this period, affecting the learning that children need during the most critical period of brain development. finally, the economic impacts have a direct interplay with all other impacts, and have contributed to increased stress among caregivers and children. in some places, it has resulted in food insecurity, thereby also influencing children's physical health. all these impacts have short-term consequences that will translate into long-term changes in children's life trajectories. deaths increasing, many children are becoming orphaned or experiencing greater adversity. covid-19 has also affected access to health and nutrition systems including routine immunizations. social impacts include increased teenage pregnancies and a rise in gender based violence, all with a bearing on ecd outcomes. they also include lack of social and child protection services to support parents and primary caregivers. furthermore, child development and learning impacts including lack of access to institutional-based childcare services and critical nurturing environments have become more severe during this period, affecting the learning that children need during the most critical period of brain development. finally, the economic impacts have a direct interplay with all other impacts, and have contributed to increased stress among caregivers and children. in some places, it has resulted in food insecurity, thereby also influencing children's physical health. all these impacts have short-term consequences that will translate into long-term changes in children's life trajectories. 5.2.1. impacts on children's health covid-19 is an evolving pandemic, and despite the worldwide spread, the effects of covid-19 on pregnancy, childbirth in addition to newborns and toddlers are not well-established, and the evidence is mixed. recent experience suggests there is a low risk of intrauterine infection by vertical transmission in women with covid-19 disease [31] [32] [33] , although the first case of vertical transmission was recorded in july 2020 in india [34] . a systematic review by zimmermann and curtis (2020) [35] on covid-19 in children, pregnancy and neonates reported fetal distress in 30% of pregnancies, with 37% of women having preterm deliveries. neonatal complications including respiratory distress or pneumonia (18%), disseminated intravascular coagulation (3%), asphyxia (2%) and two perinatal deaths were also reported. 5.2.1. impacts on children's health covid-19 is an evolving pandemic, and despite the worldwide spread, the effects of covid-19 on pregnancy, childbirth in addition to newborns and toddlers are not well-established, and the evidence is mixed. recent experience suggests there is a low risk of intrauterine infection by vertical transmission in women with covid-19 disease [31] [32] [33] , although the first case of vertical transmission was recorded in july 2020 in india [34] . a systematic review by zimmermann and curtis (2020) [35] on covid-19 in children, pregnancy and neonates reported fetal distress in 30% of pregnancies, with 37% of women having preterm deliveries. neonatal complications including respiratory distress or pneumonia (18%), disseminated intravascular coagulation (3%), asphyxia (2%) and two perinatal deaths were also reported. the epidemiological and pathophysiology of covid-19 in children remains unclear. evidence from china [36] , italy [37] , netherlands and the uk [38] indicate that children represent less than 5% of diagnosed covid-19 cases. however, children under one year and those with comorbidities such as asthma are more likely to be hospitalized [39] . although covid-19 in children seems to have mild symptoms, there is a high prevalence of pneumonia associated with covid-19 in children at 53% [40] . the majority of children have less severe symptoms, and thus are less likely to be tested, leading to an underestimate of child infections. indeed, studies confirm that severe illness and mortality from covid-19 is rare in children [41] . however, there are emerging concerns of a novel severe kawasaki-like disease in children related to covid-19 that may represent a post-covid infectious syndrome [38] . in a systematic review, children were found less likely to be the main drivers of the pandemic compared to adults who get severe disease [41] . in kenya, the reported cases of young children testing positive for covid-19 are low; 9% of reported cases as of 27th july were children aged 0-9 years with a 2% case fatality rate [42] . although children do not account for the majority of cases, they are likely to face the most substantial impact of the covid-19 pandemic [43] . consequently, a focus on children, and especially the youngest, is vital not only due to the impact that they may face during the current crisis, but also because the negative impact has the potential of persisting across their lives in many years to come. there is also heightened stress and psychosocial difficulties among parents and caregivers that threaten the provision of optimal nurturing care environments which children need to achieve their potential [12] . worry, stress, and being anxious have been reported among 75% of kenyans due to covid-19 [44] . school and daycare closure, job losses, economic uncertainty, inability to afford food and lack of access to essential services have resulted in increased stress and anxiety among caregivers. some level of stress is normal and can even be beneficial when it is positive, but when it is elevated, constant and adds to existing adverse conditions, it can become toxic [45] . toxic stress can have long-term impacts on a person's hormones, thereby affecting a child's brain architecture, physiological and chemical makeup, and overall development over a lifetime that may never be fully reversed [45] . the ministry of health in kenya developed a comprehensive guide for health workers on mental health and psychosocial support during the covid-19 pandemic to cover the needs of the population and people on treatment for covid19 [46] . however, it is not clear if this has been widely disseminated, and the extent to which various population segments are benefitting from the guidance is also unclear. access to material and psychosocial support, caregivers' and families' ability to cope with the pandemic and its consequences may be limited, and they may not be able to provide effective nurturing care [10, 47] . when children experience trauma, experience adversity and lose secure attachment and bonding due to deficiencies in responsive caregiving, they experience stress, which has negative impacts on their health, wellbeing and lifelong learning, including a higher risk for developing a variety of cognitive, behavioral and emotional difficulties later in life [45] . aside from the direct health impacts on the physical and mental health and wellbeing of children, caregivers and families, covid-19 has also affected health systems and disrupted access to routine nurturing care services. covid-19 has placed a strain on the overstretched healthcare systems, a key entry point for nurturing care, and disrupted the delivery of vaccination of children under five years due to supply chain and human resource constraints [48] . the weak health systems in lmics such as kenya are vulnerable to the spread and impact of covid-19, having witnessed service disruptions and lack of preparedness in the face of the crisis. the basic tenets of the right to health are being tested. public health expenditure as a percentage to gdp is deficient in the region, and kenya stands at 5.7%, far below the recommended 15% per the abuja declaration [49] . the country already had a shortage and maldistribution of health workers, but with covid-19, the disparities in access to healthcare between the rich and the poor in urban areas, as well as between the rural and urban divide, are widening. though most nurturing care interventions in kenya begin at birth, maternal preconception health and wellbeing influences child development. intrauterine growth restriction has been linked to adverse outcomes including prematurity, low birth weight, stunting, anemia, neurodevelopmental conditions, stillbirths and child mortality [50, 51] . evidence from lmics shows that reproductive, maternal, newborn and child health interventions including iodine, iron and folate supplementation during preconception have had a significant impact on children's cognitive, physical and socio-emotional wellbeing [52] . the uptake of preconception care in kenya is very low since over 40% of the pregnancies in the country are unintended [53] . notably, the majority of the unintended pregnancies occur in young girls who take time to acknowledge their pregnancies. this leads to delay of the first antenatal visit and, in some instances, non-uptake of antenatal services throughout the pregnancy [54] . in a context where covid-19 has led to an increase in the number of teenage pregnancies as well as a disruption in routine care, the net effect will be delays and low uptake of antenatal services. consequently, there may be an increased risk of infant and maternal morbidity and mortality. the covid-19 pandemic has disrupted maternal and child health and nutrition, including antenatal, skilled delivery and postnatal services, as well as immunizations, health education and promotion, all resulting in a reversal of the previous gains made in reducing maternal and neonatal mortality [55] . the reduced accessibility of essential maternal and child health and nutrition services is worsening ecd outcomes and further exacerbating disparities among vulnerable households such as those living in informal urban settlements. the pandemic threatens the continuity of critical and essential services for expectant women, newborns, and children under five years including those with disabilities and developmental delays. the reluctance of parents to visit clinics due to fear of infection with covid-19 may also interrupt immunization and other child health programs [56] . the social distancing, lockdown and curfew measures have led to decreased utilization of maternal health services. pregnant women experience challenges in accessing health and nutrition services, which has been worsened by the covid-19 crisis. for example, lack of transport during lockdown and curfews, and fear of visiting health facilities due to concerns regarding covid-19 infection have been observed [57] . maternal and child malnutrition, including micronutrient deficiencies and child stunting are expected to increase [58] . mothers and children need access to key essential nutrition actions and services so that they are well-nourished pre-conceptually, intrapartum and during lactation. furthermore, they also need services to diagnose and address micronutrient deficiencies through iron and folic acid (ifa) supplementation to prevent neuro-developmental disabilities in children [59] . however, anecdotal reports confirm reduced utilization of maternal and child health services in kenya, worsened by infection of some health workers leading to the suspension of maternal services [60] . likewise, in sierra leone and liberia, the ebola crisis exacerbated the poor health outcomes within weak health systems [61, 62] . liberia and guinea experienced a sharp decline of more than 25% in the monthly number of children vaccinated against measles in 2014 and 2015 due to the ebola outbreak as compared to the previous years [63] . the indirect effects of ebola on maternal and child health were believed to be greater than the direct consequences [62] . antenatal care, family planning, facility delivery and postnatal care were adversely affected, leading to an increase in maternal neonatal and stillbirth deaths in 2014-2015 [61] . the economic well-being of a family affects a child's ecd outcomes because it affects the child's ability to be in a safe and protective home and access health services and programs and nutritious foods, all of which cost money. children growing up in vulnerable households face even greater challenges to thrive given the pandemic and existing adversities [64] . the directives to reduce transmission through social distancing, hand-washing, self-isolation and self-quarantine for 14 days for those exposed to the virus may be unattainable for informal settlement residents who have space limitations and limited access to water, sanitizers and masks. families who were already vulnerable prior to the pandemic have been pushed to dire circumstances with losses in income and are unable to afford basic necessities, while others juggle work and childcare among other responsibilities. stay at home orders and lockdowns are unlikely to be followed through as quest for food and basic commodities is necessary [65] . the economic impacts of the pandemic are anticipated to have far-reaching consequences on long-term health and wellbeing of the population compared to the direct health impacts [66] . there is a downward trend in the kenyan economy marked by job losses, inconsistent food supply and an increase in stress levels among adults and children [67] . the pandemic has caused a severe unemployment crisis in kenya, with at least one million people having lost their jobs or been placed on indefinite unpaid as of june in both the formal and informal sectors [68] . there was a marked decline in labor force participation from 75% in 2019 to 57% in april 2020, and women are the most affected with a participation rate of 49% compared to men at 65.3% [69] . the government has introduced various fiscal policy and income support measures such as tax waivers, reduction in taxes for all micro, small and medium enterprises, as well as covid-19 emergency funds and earmarked funds for social protection in the form of cash transfers [66] . however, the number of vulnerable families continues to increase as the pandemic persists. families living in informal settlements live in overcrowded areas and lack basic housing, water and sanitation, which make them vulnerable to disease outbreaks despite having the knowledge of covid-19 measures [65, 70] . contact tracing has shown local transmission of covid-19 to rise as community transmission becomes a significant driver, especially with people living in a big families leading to an increase in deaths [71] . this can be related to the respiratory viral transmission of covid-19 through direct contact in the households where space is inadequate and social distancing impossible. families also continue to experience other non-covid-19-related health challenges coupled with movement restrictions, placing caregivers of children at greater risk of morbidity and mortality. as the situation continues to unfold and countries adopt this 'new normal', the potential negative impact of the prevailing situation on unborn and young children cannot be ignored [57] . holistic child development requires a stimulating, safe environment, social interaction, education opportunities and adequate nutrition, all of which have been affected in one way or another [57] . the resultant economic impacts of covid-19 have been felt at household level with a ripple of negative impacts on nurturing care. there has also been increased risk of abuse, neglect and violence against children of all ages [72] and domestic violence in kenya [73, 74] . children with developmental delays and disabilities are very vulnerable and are often subjected to stigma and various forms of neglect and abuse [75] . stress and anxiety among children are also likely due to disrupted routines. routines are critical to enabling children to thrive in supportive environments in the home, childcare and early learning centers. all these circumstances mean that children in lmics such as kenya are at risk of faltering outcomes, as caregivers find it challenging to provide their children with the nurturing care they need during this pandemic. children need a safe, secure and loving environment, yet these stressful experiences in early life increase the risk of developmental delays and non-communicable disease in later life [3, 10] . therefore, to promote safety and security, families and children need to live in safe environments, where children experience supportive discipline and do not experience neglect or violence. responsive caregiving ensures sensitivity to children's cues, thus promoting play and stimulation for early learning through day-to-day activities as well as caregiver-child interactions that are enjoyable [76, 77] . it is plausible that with the lockdown and restrictions on movement, caregivers and families may have limited access to child protection services and programs. where the services are present, they may experience difficulties reaching and providing care to vulnerable children. the closure of "babycares" may have implications for child protection, as the children are not being looked after by caregivers who offer an environment with some level of safety and security. due to the ongoing crisis, children may also be locked up and restricted from exploring their environments or playing with other children due to fear of infection. without access to social protection, caregivers facing heightened vulnerability due to loss of income may lack the safety nets to provide for and protect children. in cases where caregivers succumb to direct covid-19 infection or due to the indirect health impacts of covid-19, children are orphaned. this affects children's access to basic needs and nurturing care [78] . the experience of bereavement itself is a form of adversity, and could lead to emotional and psychological trauma, and induce fear and a sense of helplessness in children without positive coping mechanisms [79] . orphaned and vulnerable children have an increased risk of being neglected, harmed, exploited, and they may experience gender-based violence, including early marriage. they also miss out on opportunities for play, a crucial aspect of child development and early learning. in kenya, there is weak oversight of services to support orphaned and vulnerable children. traditionally children would live with other relatives, and, in general, family-based care is preferred to institutional care where there are reports of abuse, neglect and exploitation [80] . however, with covid-19 putting increasing food insecurity and economic hardships of families, orphaned and vulnerable children may not be supported in these families without the provision of safety nets. high teenage pregnancy is not new in kenya. data from the demographic and health surveys show that almost 2 out of 10 girls between the ages of 15 and 19 are reported to be pregnant or already had a child [81, 82] . this trend has been fairly consistent for more than two decades with little change in prevalence between 1993 and 2014. nevertheless, in light of the covid-19 pandemic, the trend of teenage pregnancy is already showing signs of being more severe as a result of prolonged school closure, sexual violence and the declining economic situation in kenya [83] . this trend is dire, as girls from poor families across the country are engaging in transactional sex to acquire money to buy sanitary pads and food [83, 84] . globally, it is predicted that due to the harsh economic times, the number of girls involved in survival sex will increase [85] . previously, girls were able to access free sanitary towels through their schools; however, this is no longer the case since schools were closed following the covid-19 crisis [86] . teenage pregnancy presents significant health consequences to both mothers and newborns. complications in pregnancy and childbirth are the leading cause of death among girls aged 15-19 years globally [87] . the risks are even higher for girls below the age of 16 years. pregnant adolescents face a higher risk of eclampsia, endometritis and puerperal infections than women aged 20-24 years [88] . in addition, adolescent births are more likely to result in preterm births, low birth weight and newborns with severe congenital conditions. furthermore, teenage pregnancy is a major contributor to a never ending cycle of ill-health and poverty [87] . the impact of teenage pregnancy includes loss of education opportunities, early marriages, and economic disempowerment [83, 89] . studies have shown that most teenage pregnancies occur among teenagers from deprived backgrounds [81, 90] . therefore, all these factors result in the intergenerational transmission of poverty from the teen mothers to their children with poor ecd outcomes. the situation is bound to get worse with the covid-19 pandemic. furthermore, cases of gender-based violence, in particular, child and early marriages are also on the rise [83, 91, 92] . it is well understood that children of teenage mothers tend to have poor ecd outcomes. the children have lower iqs and academic achievement, and are at a greater risk of repeating a grade. they are also at a greater risk of perinatal death and having a fatal accident before turning one year old [93, 94] . the ministry of education announced that all schools within the territory of the republic of kenya shall remain closed until january 2021 [95] . this announcement is worrisome given the increasing cases of teenage pregnancy during the extended period of schools' closure [96] . the closure of daycares and pre-primary classes, which includes children up to four years, has affected children's access to early learning, that is, building their brains in a safe and stimulating environment and developing their social and emotional skills while their parents work. children learn best through play and interaction with peers; with daycares and other early learning centers closed, many children are not able to receive these critical inputs. these centers are also important sites for immunizations, meals and psychosocial support, all of which are being disrupted due to covid-19 [97] . prior to the covid-19 pandemic in kenya, along with the rising urban population and the need for parents to find informal work, there was a growing demand for childcare and early learning services. high unemployment and literacy rates of parents, and the absence of extended family support and public amenities and the prohibitive cost of quality childcare services led families relying on informal childcare centers as they sought employment. there was a proliferation of relatively low-cost, non-regulated and informal privately owned childcare centers for children aged three years and below, commonly referred to as 'babycares' with at least 2700 of them in nairobi [98] . these informal babycares are often home-based or faith-based and lack the minimum standards, expertise and infrastructure required to support children to attain their developmental potentials. some of these have poor lighting, are crowded with children that sleep most of the time, lacking play and stimulation and being served nutrient-poor or deficient foods. this large number is exacerbated by the lack of policy and legal framework to guide the services they provide for children below four years and their families. the 2006 national ecd policy framework of 2006 was not implemented due to operational issues [99] . numerous conversations among stakeholders continue on the state of ecd for children below the age of four. with the nurturing care framework adopted in kenya, the focus on children below four years is taking center stage alongside the prioritization of programs and services to meet their needs. while nascent, at the beginning of covid-19, there had been considerable traction. with the pandemic, these gains are threatened, as policy makers' focus and funds have been diverted to physical health, which includes preventing and treating those with covid-19, rather than considering all aspects of child development. for middle-and upper-class families, they can hire childcare or early learning support, but this is out of reach for poor families. during the covid-19 pandemic and beyond, the kenyan government and other ecd stakeholders interested in ensuring that the youngest of children in the country are able to survive, thrive and continue on a positive life trajectory can reorient nurturing care. this is possible through utilizing the lens of direct health; health and nutrition systems; economic and social protection; and child development and early learning. children's needs are inter-related and holistic and so support must also possess these qualities. kenya has a number of policies and systems in place to bolster nurturing care during the covid-19 pandemic, but as is the case with many countries around the world, they are not fully financed and operational. actions to mitigate the negative impact on maternal, newborn, child and adolescent health need to be addressed by borrowing, developing, and implementing strategies utilized in previous epidemics and pandemics. this will guarantee continuity of care and avoid a rise in maternal and newborn morbidity and mortality. support to caregivers and families would enable them to nurture their young through a multi-sectoral approach that builds on existing programs [100] . it is crucial to examine existing evidence on the direct effects of covid-19 on maternal and newborn care and develop programs that target easy access to maternal and newborn health services, warranting safety for mothers, children and health professionals following the guidelines. this could include increased bottom-up community health education and promotion strategies on the current covid-19 guidelines, utilizing a multi-sectoral approach through establishment of partnerships with community gatekeepers to teach mothers and caregivers. these strategies should be designed to be evidence-based and culturally appropriate, leading to holistic well-being for caregivers. particularly, families and caregivers of children with developmental delays and disabilities require targeted support that meets their needs during the ongoing crisis, enabling them to practice responsive caregiving through ensuring child safety and security [47] . these children and those who are orphaned should be prioritized for social protection interventions implemented by both the government and development agencies. this support could include some or a combination of the following: cash transfers, food packs, mobile health and nutrition services, as well as regular support and monitoring by child protection teams. children with disabilities may experience stress, have underlying health conditions that increase their risk of complications from covid-19, and may also be unable to access therapy during this period. similarly, their caregivers may have heightened stress. therefore, it is important to take care of their physical and mental health by improving access to community and home-based play spaces, therapy, health and psychosocial services, as well as other service navigation support. creatively delivering parenting education focused on enhancing caregiver capacities to become more responsive, promote maternal and child health and wellbeing, as well as adequate nutrition services will be at the core of driving nurturing care, and hence improving ecd outcomes. critical and essential health and nutrition, as well as other social services, can be delivered and sustained during the pandemic period with adherence to adequate infection prevention and control measures. furthermore, health education and promotion in addition to continuous engagement and referrals of caregivers and families through community health structures is crucial. innovative culturally acceptable strategies that transcend the existing pandemic barriers with a strong emphasis on strengthening community-based reproductive, maternal, newborn, child and adolescent health services are required. these services include family planning services; maternal nutrition such as promoting the uptake of iron and folic acid supplements; antenatal care; seeking skilled delivery and post-natal services; as well as essential nutrition services to support infant and young child feeding, routine growth monitoring and counselling through baby-friendly community initiatives. these should be further complemented with adequate transport to a health facility during curfew or lockdown situations. in some settings, health services are being taken to families in remote locations, especially those through mobile vans or clinics, thereby enabling greater and equitable nurturing care support for the youngest of children during the covid-19 crisis [101, 102] . essential new-born care should be an area of sustained focus: early initiation and assessment for exclusive breastfeeding, addressing danger signs for referrals and timely linkages to health services. mothers and caregivers also need timely referrals and access to services for treatment of maternal and child undernutrition. integrated community case management of common childhood diseases, in particular malaria, diarrhea, pneumonia and malnutrition, should not be neglected. mental health, often overlooked, has risen to the consciousness of policy makers and donors. this pandemic provides an opportunity to take the innovations and expand mental health/psycho-social services throughout kenya. all people, young and old, are facing mental and emotional difficulties. caregivers juggling full-time jobs, caring for others such as the elderly and children at home, are feeling especially overwhelmed. development agencies are supporting families' mental health and psycho-social wellbeing where possible by establishing phone helplines to increase access to free professional mental health support. referral systems are also being established through these helplines, and this needs to be expanded and accessible. simple tips and exercises, relevant to both the young and old, are being broadcast on tv, radio, social media (facebook (facebook, inc., san francisco, ca, usa) or whatsapp (whatsapp inc., san francisco, ca, usa)) and through short videos. the design and utilization of mhealth can lead to improved ecd outcomes. in particular, the use of telehealth consultations where possible, with health professionals, can also help to minimize hospital visits. efforts should be made to scale up provision of nurturing care through integration into their health systems by adopting the mnurturingcare app in clinical encounters and at the community level [103] . in addition, partnerships with the local communities are important to increase engagement and dialogue on the measures for supporting nurturing through heightened communication with health professionals who can offer prompt identification of complications and provide appropriate referrals. as covid-19 is negatively affecting the economic situation of many families in kenya, especially those who work in the informal sector and/or were already in precarious economic situations prior to the outbreak, innovative approaches such as cash transfers are necessary. in various emergencies around the world and in kenya, conditional and unconditional cash transfer programs have provided an economic safety net and positively impacted health during difficult periods such as the one we face [104] [105] [106] . although the government has instituted social protection schemes in the form of cash transfers to cushion vulnerable families, the need is greater. more investments are required, particularly programs that support those who were previously working in the informal sector and have lost incomes. this can be achieved through reallocation of funds to social protection to increase the resources available for cash transfers and food supplies in order to mitigate socio-economic impacts, including addressing food insecurity [58, 66] . these measures should be accompanied with the introduction of functional community mechanisms for identifying vulnerable households and children who lack access to basics such as food, water, shelter and healthcare, and provide targeted support. social safety nets for vulnerable families during this pandemic enable them to provide nurturing care to promote resilience among children, despite the stressors surrounding them. it is clear that many social and child protection services targeted at children and adolescents in kenya, such as meals and sanitary pads among others, have largely been delivered through childcare and school platforms; with school closures, this avenue is not viable. there is a need to build and leverage community level programs and policy support, targeting children at risk of abuse and neglect, and adolescents at risk of early pregnancy, to ameliorate the negative effects of the pandemic, such as poor nurturing care environments and transactional sex for food and pads among adolescent girls, all of which subsequently leading to poor child development outcomes. mitigation strategies should focus on safety nets for poor families in addition to identifying and supporting vulnerable children and adolescents within these families. urgent strategies are required to protect young children and girls from the increased gender-based violence during the pandemic period. these strategies include improved access to psychosocial support services through community agents or call-in centers to reduce caregiver stress, expansion of social and child protection services such as family tracing and reunification of separated or orphaned children, and increased delivery of reproductive health services through mobile reproductive health services and telemedicine in remote communities. for orphaned children, evidence indicates that family-based care is better for young children than institutional care [80] . the landmark longitudinal study of romania's orphans led by the bucharest early intervention project showed that brain development can be severely affected when orphaned children are in institutional care without nurturing care [107] . the study indicates that this effect can last over a person's lifetime. key stakeholders therefore should find safe and protective homes for orphaned children with other relatives and ensure they benefit from social and child protection services. this could also include conditional and unconditional cash transfers to help relatives of orphaned children that want to take care of them in supportive family environments. other critical community outreach strategies are also required to address poor nurturing care environments and rising transactional sex in partnership with nurses and community workers. these include expanding community outreach for nurturing care skills among caregivers and increasing access to sexual and reproductive health and rights education, as well as distribution of sanitary pads and contraceptives among adolescent girls. these strategies must be accompanied by facility and community-based youth-friendly reproductive health services. special attention needs to be given to the children of young teen mothers through social protection schemes to ensure that their children can achieve the highest developmental potential during this period. children and their primary caregivers/parents need social and educational support to ensure socio-emotional well-being, safety and security from violence and harm and opportunities to boost young children's brain development. children are separated from peers and extended family members such as grandparents, and are unable to attend early learning centers, daycares, and crowded areas. some children, just by being home, are exposed to domestic violence; early evidence points to an increase in such cases as stress levels of families' increase [72] . concerted efforts including awareness raising are necessary to reduce violence against children. some innovations are being tested in this area by development agencies. for instance, the use of tv, radio, pre-made videos and social media to support early childhood educators, teachers, and family members with simple ways to support young children's learning and development at home has been observed. parents and caregivers are the most important support structure for young children, and their ability to nurture adequately while remaining physically and mentally healthy is critical. parents and caregivers should therefore become a critical target audience for ecd stakeholders in kenya and the region, ensuring that nurturing care becomes a family-centered with a whole-society approach. with the additional burdens being placed on parents and caregivers, they need to prioritize their physical and mental health. the strategies suggested above in the section on health and health systems support can be crucial. additionally, parents and caregivers also need practical tools and guidance to enable them to provide early nurturing care in the home environment, particularly providing opportunities for early learning as well as increasing community-led sanitation and nutrition programs. this includes strategies on how to regularly interact and communicate with children and provide them with age-appropriate play and learning resources at home, using locally available, low-cost or household materials easily found in their surrounding environment. the care for child development package is a useful intervention that can be cascaded widely, leveraging multi-sectoral community counselling platforms to encourage greater parental or caregiver responsiveness through communication and play [108] . this will contribute to the healthy development and growth of children by supporting caregivers to build stronger relationships with their children and solve challenges in providing nurturing care. for those children who may have been attending babycares that have been closed due to the crisis, the caregivers need practical support to provide quality early learning in the home environment. linkages with child and social protection actors should be strengthened to promote nurturing care, as parents have now taken over childcare and schooling in the home while balancing dual roles of work and managing the household. in the critical early years, young children need at least one loving and trusted adult to feel secure, grow and develop holistically. in this period of adversity, children need nurturing relationships with caregivers and families to provide a buffer to counterbalance the hardships [10] . covid-19 is still ravaging kenya and most of the world. there is still a lot to learn about what can work and what cannot. little research is currently published on how to support nurturing care for children under 4 years in the wake of such a pandemic, especially in africa. while the impacts of the pandemic on the lives of young kenyan children and their families have been severe, and evidence around further impacts is coming to light, there are opportunities to learn and "build back better". interventions need to address five critical areas: direct health impacts, health and nutrition systems impacts, economic impacts, social and child protection impacts and child development learning impacts. there is need to leverage technology and use a community-based approach to support continuity of nurturing care services with timely referral and follow-up to a wide range of cross-sectoral services including psychosocial support. kenya has an opportunity to learn from other countries about how to develop practical and feasible guidance to reopen childcare centers and early learning spaces, given the low incidence of covid-19 in younger children. tailored plans are required for children with unique needs, and consideration should be given to provide holistic and inclusive support. the government and development actors need to consider increasing their investments to scale-up nurturing care through the development of policies and coordinated intervention programs during this pandemic period. this paper took stock of what we currently know about the impacts of covid-19 on nurturing care for the youngest kenyans, but this is just the tip of the iceberg. although our review paper has provided useful insights and made an important contribution to the body of knowledge, the key limitation is that it is mainly based on secondary sources including grey literature, and it did not rely on primary data. further primary research and investigation on the youngest children and the ability of children's ecology to provide nurturing care is needed, as is the further testing of new ideas. primary research is required particularly to explore the mental health impacts on caregivers and children; understand how domestic violence has impacted nurturing care; and shed more light on the experiences and support available to teenage mothers and caregivers of children living with disabilities. additional evidence would light the way forward for kenya and similar settings to ensure its youngest citizens can reach their full developmental potential. the authors declare no conflict of interest. first case of coronavirus disease confirmed in kenya; ministry of health the covid 19 global pandemic: impact to the economy and policy options nurturing care for early childhood development: a framework for helping children survive and thrive to transform health and human potential; world health organization the role of nutrition in brain development: the golden opportunity of the "first 1000 days early childhood development coming of age: science through the life course poverty incidence in kenya declined significantly, but unlikely to be eradicated by 2030 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children of teenage mothers: psychological, behavioural and health outcomes from an australian prospective longitudinal study kcse exams as covid-19 bites. daily nation we must mitigate teenage pregnancy crisis amidst covid-19 framework for reopening schools there are at least 2700 informal child daycares in nairobi-tiny totos is working to help them upgrade their services national pre-primary education policy; ministry of education the assessment of satisfaction with care in the perinatal period mobile health clinic model in the covid-19 pandemic: lessons learned and opportunities for policy changes and innovation health educator uses a mobile van to educate communities about covid-19 mthrive: a nurturing care app that supports community health workers. early chilhood matters cash transfer programs have differential effects on health: a review of the literature from low and middle-income countries the cash dividend: the rise of cash transfer programs in sub-saharan africa an emergency cash transfer program promotes weight gain and reduces acute malnutrition risk among children 6-24 months old during a food crisis in niger romania's abandoned children care for child development: an intervention in support of responsive caregiving and early child development. child care health dev key: cord-347033-ha095nwp authors: jethwani, pratap; saboo, b.; jethwani, l.; kesavadev, j.; kalra, s.; sahay, r.; agarwal, s.; hasnani, d. title: management of children and adolescents having type 1 diabetes during covid-19 pandemic in india: challenges and solutions date: 2020-09-15 journal: int j diabetes dev ctries doi: 10.1007/s13410-020-00865-w sha: doc_id: 347033 cord_uid: ha095nwp purpose: type 1 diabetes (t1d) requires a holistic approach and continuous care. the current covid-19 pandemic has made the health care professionals realise its challenges even more ardently than in the normal times. in a country like india with its huge population burden and a significant number of people having t1d, the risk of covid-19 in people having t1dm is considerably high. methods: in this article, we are sharing our practical experiences of problems faced by children and adolescents having t1dm during the past 2 months of lockdown. results: we have classified the challenges into 3 broad categories based on diabetes self-management, healthcare system and psychosocial aspects. we have tried to provide precise, comprehensive and region specific solutions to these challenges. solutions briefly include maintaining the supply chain of essentials like insulin, syringes and glucose meter strips to psychological support, financial aid and support for hospitalization in case of covid-19 itself or diabetes complications including diabetic ketoacidosis. conclusions: children and adolescents having t1dm require special care and attention during this period of covid-19 pandemic because of various challenges as discussed. our proposed solutions may help them overcome these problems and help them in better diabetes management during such emergency situations. as per idf, there are estimated 1.1 million children and adolescents having type 1 diabetes (t1dm) globally [1] . india was home to 95,600 t1dm between 0 and 14 years of age in 2019 and about 15,900 new cases diagnosed every year in the same age group [1] . currently, mankind is facing a global pandemic of covid-19, caused by the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection [2] , with 18,575,326 people infected in more than 200 countries and 7,01,754 people who have died, as per the who as of 6 august 2020 [3] . the indian numbers have now risen to 19,64,536 total reported positive cases and 40,699 deaths [4] . a recent study (currently under peer review) from england demonstrated an independent association between the level of glycemia and covid-19 mortality in people having t1dm or type 2 diabetes [5] . another nhs-funded population cohort study reported 3.5 times more risk of in-hospital deaths with covid-19 in people having t1dm as compared with those without diabetes [6] . the gaps in pediatric diabetes management can be bridged with the use of telemedicine, virtual diabetes clinics, and diabetes technology in the current covid-19 situation [7] . as there is no definitive treatment or preventive vaccine for this viral infection, personal hand hygiene, respiratory etiquette, and social distancing are the most widely used strategies for the control of this highly contagious virus. outbreak control measures to reduce the amount of mixing in the population include work from home, closure of academic organizations, and strict lockdown [8] . for this reason, a nationwide lockdown has been imposed in india from 25 march 2020 up to 30 june 2020 [9] . lockdown, although effective in curbing the community transmission of this virus, has potential impact on people living with diabetes, particularly t1dm. we intend to enumerate the challenges being faced by the children and adolescents having t1dm and some solutions that have been proposed and worked out. these challenges can be broadly divided into 3 categories as shown in table 1 . skills of dsm are essential for children and adolescents having t1dm to improve or maintain glycemic control, to improve quality of life, and to minimize the risk of complications [10, 11] . for people living with t1dm, dsm includes regular insulin injections with proper technique, regular blood glucose monitoring, healthy eating, physical activity, problem-solving, and healthy coping [10] . current situation of lockdown has had an impact on many components of dsm as described below. (i) insulin therapy: it is essential for survival in all people with t1dm. children and adolescents with t1dm require multiple daily insulin injections (1-2 basal insulin injections plus at least 3 regular or rapid acting insulin injections) as per recommendation by the major organizations [12] [13] [14] . many of these children and adolescents are supported by various programs (like changing diabetes in children (cdic) and life for a child program) for regular supply of insulin and glucose meter strips [14] . this is being facilitated by local healthcare teams. because of lockdown, many children residing in remote villages may not get regular insulin supplies because of closure of nodal healthcare facilities and local transport facilities. proposed solutions: children and adolescents having t1dm should be able to reach nodal persons of supporting programs in case of inability to get insulin vials or cartridges. the research society of study of diabetes in india (rssdi) has circulated the contact numbers of nodal persons of insulin manufacturers and supporting programs to people having t1dm and their doctors through email and social media. a dedicated helpline number, supported by diabetes educators and medical specialists, should be available to provide solutions to day-to-day problems. unavailability of any type of insulin may require switching to another type so as to avoid risk of hyperglycemia and consequent dka. one of the approved protocols suggests 20% reduction in insulin dose during switch from rapid acting insulin analogue to regular human insulin or vice versa to avoid hypoglycemia [15] . (ii) glucose monitoring: regular self-monitoring of blood glucose and continuous glucose monitoring at times is an essential component of t1dm management [16] . lockdown may interrupt regular supplies of glucose meter strips to children and adolescents, being supported by programs like cdic, because of closure of local nodal centers and local transport facilities. proposed solutions: rssdi has circulated a list of contact numbers of nodal persons of glucose meter manufacturers and urine ketone strips to people having t1dm and doctors through email and social media. (iii) medical nutrition therapy: because of strict lockdown and suspension of even vegetable supplies in certain areas, children and adolescents may not get regular supply of vegetables and fruits, an important component of their healthy eating plan [17] . there may be reduction in eating outside and consumption of junk foods because of lockdown, and this will probably have an impact on insulin requirements. however, no definite data related to this issue is available. proposed solutions: local support groups like juvenile diabetes foundation (jdf), in collaboration with local health authorities, should arrange for regular supply of milk, vegetables, fruits, and other essentials to these children and adolescents. information booklets and animated videos related to healthy eating and healthy recipes may also be circulated through digital media. (iv) physical activity: because of lockdown and stay at home orders, children and adolescents may not be able to participate in daily sports and playground activities [13] that may worsen their glycemic control. proposed solutions: children and adolescents with t1dm should be encouraged to do indoor exercises by educating them through online tools as well as through social media. because of closure of schools and colleges, they may get more time and should be encouraged for indoor physical activities. use of animated videos featuring cartoon characters may prove useful in motivating children for indoor plays and exercises. local support groups may also provide peer support for the same. (v) sick day management: during periods of stress and acute infections, reduced oral intake and increased release of stress hormones may impact blood glucose levels, thereby increasing the risk of both hyperglycemia and hypoglycemia [13] . therefore, sick day management is particularly useful to avoid glycemic fluctuations and subsequent risk of dka or hypoglycemia [18] . lack of continuous insulin supply with lack of glucose monitoring may also increase the risk of hypo-or hyperglycemia. proposed solutions: every child and adolescent with t1dm should be educated about sick day management rules at frequent intervals during lockdown with the help of information booklets and videos through social and digital media. these should be prepared in english, hindi, and also local languages. dedicated customer care helpline may assist them in better t1dm management during sick days, thereby reducing the risk of dka and subsequent hospitalization. (vi) emergency preparedness: emergency preparedness of t1dm children and adolescents and their families are very much lacking in our country. any emergency situation like the current covid-19 epidemic, resulting in panic, may worsen their glycemic control with consequent dka. proposed solutions: emergency preparedness plans can help children and adolescents having t1dm and their families in managing diabetes better during such emergencies. sample emergency preparedness plan for use during lockdown has been proposed by authors as shown below in table. 2. people having t1dm require continuous access to healthcare services. lockdown may impact the access to healthcare services for their day-to-day management as well for their emergency issues like hypoglycemia, dka, or any infection including covid-19. (i) routine healthcare support for t1dm management: because of lockdown and closure of healthcare services, children and adolescents may find it difficult to get medical support for their day-to-day management of t1dm as well as for management of their complications like diabetic neuropathy, retinopathy, and nephropathy. proposed solutions: telemedicine guidelines, by the ministry of health and family welfare, government of india, may be followed to provide medical support to them for issues related to insulin dose adjustment and management of their complications [19] . this may be further improved by creating virtual diabetes clinics providing support of nutritionist, physiotherapist, diabetes educator, podiatrist, as well as specialist services. similarly, web-based tools may be used to educate them about diabetes self-management including foot care [11] . (ii) emergency issues related to glucose control: emergency issues like hypoglycemia or dka requiring hospitalization may be precipitated by lack of proper dsm, stress, and acute infections in these subjects. during lockdown, there may be difficulties in getting hospitalized mainly in remote areas because of lack of transport facilities and lack of availability of beds in covid-19 affected areas. (iii) emergency issues related to covid-19 or other infections: children and adolescents having t1dm may develop covid-19 or any other infection requiring hospitalization. infections may also result in glycemic fluctuations and may increase the risk of dka or hypoglycemia further increasing the chances of hospitalization [18] . (iv) technical issues: people having t1dm require use of technology in the form of glucose meters, pricking devices, insulin pens, as well as insulin pumps for routine management. during lockdown, they may not get support to resolve their technical issues because of unavailability of transport services and skilled personnel. technology-related problems like pump dysfunction may result in unwanted hyperglycemia with consequent dka. proposed solutions: people having t1dm should be provided with 24/7 technical support either onsite or through telecommunication, for successful use of these devices for insulin therapy as well as for glycemic monitoring. children and adolescents having t1dm are already at risk of psychosocial issues because of the impact of disease on them and their families. this may be further aggravated or precipitated by lockdown. (i) psychological problems: children and adolescents with t1dm because of social stigma and other issues related to t1dm are already prone to psychological problems like anxiety, phobia, etc. [12, 20] . fear of covid-19, closure of schools and colleges, and restrictions imposed by strict lockdown may impact their mental health and further increase the risk of psychological problems in them. proposed solutions: local help groups run by jdf along with educational institutions can provide mental support by engaging children and adolescents in online educational and funfilled activities. yoga and meditation may be taught through online platforms to provide them psychological support. educational institutions may start routine class work through online platforms to keep them busy and engaged in their studies. information booklets to clear myths and doubts about covid-19 may help in reducing fear and anxiety related to this disease. (ii) financial problems: financial problems are the most negative aspect of this extreme lockdown. children and adolescents of lower as well middle socioeconomic status may be hit very hard by financial problems of their parents. this may be due to salary cut, unemployment, and loss of daily wages making it difficult to follow proper t1dm management for them. proposed solutions: these vulnerable families definitely require assistance in the form of free insulin and glucometer strip supplies through programs like cdic. organizations like rssdi and support groups like jdf may employ such parents as educators to provide dsm education to others having t1dm. donors should be sought for to provide financial assistance to such vulnerable families through social media. we can briefly summarize that children and adolescents having t1dm require special care and attention during this period of covid-19 pandemic because of various issues as discussed above. proposed solutions in this article may help them overcome these problems and help them in better diabetes management during such emergency situations with reduction in the risk of complications particularly dka. we need to conduct proper prospective studies to identify the problems faced by children and adolescents with t1dm during lockdown and their impact on glycemic control and complications. this may help us to develop precise solutions to improve t1dm management during such pandemic. international diabetes federation. idf diabetes atlas from containment to mitigation of covid-19 in the us who coronavirus disease dashboard # indiafightscorona covid-19 in india, coronavirus tracker type 1 and type 2 diabetes and covid-19 related mortality in england: a cohort study in people with diabetes type 1 and type 2 diabetes and covid-19 related mortality in england: a whole population study covid-19, type 1 diabetes, and technology: why paediatric patients are leading the way the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study government of india. government of india issues orders prescribing lockdown for containment of covid19 epidemic in the country enablers and barriers to effective diabetes self-management: a multi-national investigation type 1 diabetes self-management: developing a web-based telemedicine application ispad clinical practice consensus guidelines 2018: insulin treatment in children and adolescents with diabetes type 1 diabetes in children and adolescents: a position statement by the american diabetes association type 1 diabetes: awareness, management and challenges: current scenario in india switching between insulin products in disaster response situations. approved by the american diabetes association, the endocrine society ispad clinical practice consensus guidelines 2018: glycemic control targets and glucose monitoring for children, adolescents, and young adults with diabetes ispad clinical practice consensus guidelines 2018: nutritional management in children and adolescents with diabetes clinical practice consensus guidelines 2018: sick day management in children and adolescents with diabetes board of governors in supersession of the medical council of india ispad clinical practice consensus guidelines 2018: psychological care of children and adolescents with type 1 diabetes publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-342853-n3e6yawi authors: naghipour, mohammadreza; cuevas, luis e.; bakhshinejad, tahereh; dove, winifred; hart, c. anthony title: human bocavirus in iranian children with acute respiratory infections date: 2007-03-26 journal: j med virol doi: 10.1002/jmv.20815 sha: doc_id: 342853 cord_uid: n3e6yawi human bocavirus (hbov), a virus discovered in sweden in 2005, has been associated with acute respiratory infections in young children and subsequent reports suggest that hbov may have a worldwide distribution. this report describes the frequency and clinical presentation of hbov in 261 iranian children<5 years old with acute respiratory infections attending two regional hospitals in rasht, iran in the winter of 2003–2004. polymerase chain reaction (pcr) and reverse transcription pcr (rt‐pcr) were used for the detection of hbov and other respiratory pathogens from nasopharyngeal specimens. hbov was detected in 21 (8%) children. fifteen (12%) of these children were identified among 122 children admitted to hospital and 6 (4%) from 139 outpatients (p < 0.05). most children with hbov were less than 2 years (17/21, 81%) and 7 (33%) were less than 1 year old. although hbov was identified in all ages it affected slightly older children than the respiratory syncytial virus (rsv). the frequency of the virus varied from 1 (3%) in 40 patients in november to 7 (12%) of 61 in february, suggesting a seasonal pattern during the autumn and early winter. seven children had co‐infections with rsv, adenovirus or influenza a. the relatively high frequency of hbov suggests that the virus may contribute substantially to acute respiratory infections in children. j. med. virol. 79:539–543, 2007. © 2007 wiley‐liss, inc. acute respiratory infections are among the most important causes of childhood morbidity and mortality and are responsible for one-fifth of all deaths in children under five, resulting mainly from pneumonia and bronchiolitis [bryce et al., 2005] . viruses play a significant role in these infections and the number of viruses associated with severe acute respiratory infections has increased in recent years with the detection of new pathogens such as human metapneumovirus (hmpv) [van den hoogen et al., 2001] and severe acute respiratory syndrome associated with a coronavirus [chan-yeung and yu, 2003] . despite the advances in understanding the aetiology of acute respiratory infections, a significant proportion of episodes remain unclassified and it is likely that more ''new'' viruses will be discovered [snell, 2004] . human bocavirus (hbov) was first described in 2005 [allander et al., 2005] and it was suggested that the virus might be a cause of acute respiratory infections. a case series of 21 patients infected with hbov who presented to two referral hospitals in iran is described. the study was conducted from november 2003 to march 2004 based on 17-shahrivar and rasoul-e-akram hospitals. 17-shahrivar is a paediatric reference university hospital with 200 beds and rasoul-e-akram is a general regional referral hospital in rasht, guilan in northern iran. the original aim of the study was to describe the etiology of acute viral respiratory infections in children in northern iran. these included respiratory syncytial virus (rsv), hmpv, influenza a and b, parainfluenza, and adenovirus, plus chlamydia spp. and mycoplasma pneumoniae. children less than 5 years of age with acute respiratory infections of less than 7 days duration attending the outpatient department or being admitted to hospital from saturday to thursday were enrolled after informed parental consent. acute respiratory infections were defined following the world health organization (who) protocol and were classified into upper and lower tract infections on the basis of the children's respiratory frequency and the presence of subcostal indrawing [pio, 2003] . oxygen saturations (po 2 ) were measured in all patients admitted using a pulse oximeter (nonin medical, inc. mpl, mn, model 8500) before initiation of oxygen therapy. children were classified as having mild/moderate (po 2 !94%) or severe hypoxia (po 2 <94%) and a questionnaire containing socio-demographic, clinical, therapeutic, and outcome data was completed for each patient. ethical approval for the study was obtained from the research ethics committees of the liverpool school of tropical medicine and guilan university of medical sciences and informed consent was obtained from all parents. nasopharyngeal aspirates or swabs (medical wire & equipment co. ltd., corsham, wilts, uk) were collected from all children using sterile mucus extractors for nasopharyngeal aspirates and stored at à808c until processed. samples were processed in the department of medical microbiology, university of liverpool, uk. dna and rna were extracted using qiaamp1 dna and rneasy mini kits (qiagen ltd., crawly, west sussex, uk). extracted rna was processed using reverse transcriptionpolymerase chain reaction (rt-pcr) for detection of rsv and hmpv [greensill et al., 2003] , influenza a & b, and parainfluenza 1-4 viruses [templeton et al., 2004] , using primers and methods described previously. pcr assays were used to amplify the dna of adenovirus, chlamydia spp, and mycoplasma pneumoniae [couroucli et al., 2000] . the hbov np-1 gene was detected by pcr using the primers 188 f (gagctctgtaagtactattac) and 542 r (ctctgtgttgactgaatacag) and the same reactions and thermal cycler programme as described and corrected subsequently by allander et al. [allander et al., 2005] to detect a 345-bp product. one-third of the hbov amplicons were sequenced to confirm the identity of the virus (lark technologies, essex, uk). epi info 2002 (cdc, atlanta) was used for the descriptive analysis of characteristics of the children included means, standard deviations (sd), median, inter quartile range (iqr), and percentages. cross tabulation of the frequency of the virus in hospitalized and ambulatory children and their clinical presentations were compared using parametric tests. p values <0.05 were considered statistically significant. respiratory specimens were collected from 261 children. of these, 139 were ambulatory and 122 were hospitalized. their median (iqr) age was 14 (7-32) months and 167 (64%) were male. hbov dna was detected in 21 (8%) children; 15 (12%) were identified among the 122 hospitalized children and 6 (4%) among the 139 outpatients (p < 0.05). fourteen (67%) cases were male and seven female. five patients were known to have a history of asthma and six had been hospitalized previously with asthma or pneumonia. the age distribution of the children with hbov is shown in figure 1 . most cases (17, 81%) were less than 2 years of age and 7 (33%) were less than 1 year old. the numbers of children enrolled and those with hbov by month are shown in figure 2 . the proportion of children infected with hbov each month ranged from 1 (3%) out of 40 patients in november to 7 (12%) out of 61 in february, suggesting a seasonal pattern (chi square for trend, p ¼ 0.05). in total, 39 (15%) children with rsv, 37 (14%) with adenovirus, 11 (4%) with influenza a, 4 (2%) with chlamydia spp, 2 (1%) with m. pneumoniae, and none with hmpv or parainfluenza were identified. seven children with hbov were co-infected with another respiratory pathogen (1 with inf a and 3 each for rsv and adenovirus). none of the hbov positive children were co-infected with hmpv, parainfluenza viruses, chlamydia spp, or m. pneumoniae [naghipour et al., in press] . the clinical presentation of the patients is described in table i and are compared to children without hbov in table ii . all children had a history of cough (100%) with a mean duration of 4 days (range 1-7), 17 (81%) had fever with a mean duration of 2 days (range 1-5), and 11 (52%) had tachypnoea. the po 2 concentrations <94% were recorded in 3 of the 15 hospitalized children, and one was co-infected with influenza a. the clinical diagnoses on discharge were pneumonia in ten, upper respiratory infections in six, tracheobronchitis in three, and asthma in two cases. fourteen of the children admitted had chest radiography performed and hyperinfiltration was the most frequent finding reported in 11 children (8 infected with hbov alone), in addition to consolidation in 3. the mean (sd) duration of admission in the patients was 5 (2) days with a range from 3 to 9 days. a total of six of the amplicons were subjected to dna sequencing of both strands. of these, four were identical to those of the swedish reference strain. two showed changes, one with a point mutation at codon 47 (r ! k) and the other at codon 78 (s ! n). these are available at www.ddbj.nig.ac.jp with accession numbers of ab257721 and ab257722, respectively. this case series describes the presence of hbov outside industrialized countries. the frequency of hbov in the study was 8%, which is slightly higher than in earlier reports (canada 1.5%, sweden 3.1%, australia 5.6%, and japan 5.7%) [allander et al., 2005; bastien et al., 2006; ma et al., 2006; sloots et al., 2006] , but lower than reported recently from germany (10.3%) [weissbrich et al., 2006] and korea (11.3%) [choi et al., 2006] indicating that more studies are required to assess its relative importance. hbov was observed more frequently in patients admitted to the hospitals, some of whom had severe hypoxia, than in ambulatory children. this higher frequency however could also reflect the sampling technique used, as samples for admitted patients were collected using nasopharyngeal aspirates while ambulatory patients were tested with throat swabs, and further studies would be required to confirm these findings. similar to previous reports, a higher proportion of the cases were male, although this was a reflection of the higher number of male children enrolled in the study. overall, there was no significant difference in the prevalence by sex. most children infected with hbov were also less than 2 years of age, which is similar to the swedish (12 out of 14 cases), japanese (16 out of 18), and australian children. however, as acute respiratory infections in general mostly affect young children [bryce et al., 2005] , it is not surprising that most of the children with hbov had this age distribution. interestingly, different to rsv, which affects mostly children <6 months of age [constantopoulos et al., 2002] , hbov seems to affect slightly older children, as has been observed with hmpv [al-sonboli et al., 2005] . although, the study only enrolled children for 5 months, there seems to be a seasonal pattern during the late autumn and early winter, as reported from earlier studies and larger studies are warranted to confirm these findings. co-infections with other respiratory viruses have been observed in previous studies [allander et al., 2005; bastien et al., 2006; ma et al., 2006; sloots et al., 2006 ] and a relatively high proportion of co-infections is reported in this study (33%). this noticeable proportion of co-infections needs to be further elucidated as it might suggest that hbov is an incidental finding without a significant role in the causation of acute respiratory infections or, as suggested for hmpv [greensill et al., 2003] , it might play a role modifying the clinical presentation of children who have co-infections with other viruses. given the high frequency of hbov in iran, this virus might play a significant role as a cause of acute respiratory infections in children. however, given that up to now all the information is based on small case series, without a negative control group of healthy children to confirm that hbov is indeed responsible for the clinical manifestation observed, the aetiological role of hbov as a cause of acute respiratory infections still needs to be demonstrated conclusively. from the cover: cloning of a human parvovirus by molecular screening of respiratory tract samples respiratory syncytial virus and human metapneumovirus in children with acute respiratory infections in yemen who estimates of the causes of death in children outbreak of severe acute respiratory syndrome in hong kong special administrative region: case report the association of newly identified respiratory viruses with lower respiratory tract infections in korean children burden of respiratory syncytial viral infections on paediatric hospitals: a twoyear prospective epidemiological study detection of microorganisms in the tracheal aspirates of preterm infants by polymerase chain reaction: association of adenovirus infection with bronchopulmonary dysplasia human metapneumovirus in severe respiratory syncytial virus bronchiolitis detection of human bocavirus in japanese children with lower respiratory tract infections contribution of viruses, chlamydia spp. and mycoplasma pneumoniae to acute respiratory infections in iranian children standard case management of pneumonia in children in developing countries: the cornerstone of the acute respiratory infection programme evidence of human coronavirus hku1 and human bocavirus in australian children novel and re-emerging respiratory infections rapid and sensitive method using multiplex realtime pcr for diagnosis of infections by influenza a and influenza b viruses, respiratory syncytial virus, and parainfluenza viruses 1,2,3,and 4 frequent detection of bocavirus dna in german children with respiratory tract infections this study was supported by the iranian ministry of health and medical education through a study scholarship for dr. naghipour. key: cord-332173-m38sr6oc authors: denburg, avram e.; ungar, wendy j.; chen, shiyi; hurley, jeremiah; abelson, julia title: does moral reasoning influence public values for health care priority setting?: a population-based randomized stated preference survey date: 2020-05-13 journal: health policy doi: 10.1016/j.healthpol.2020.04.007 sha: doc_id: 332173 cord_uid: m38sr6oc objective: preferences of members of the public are recognized as important inputs into health care priority-setting, though knowledge of such preferences is scant. we sought to generate evidence of public preferences related to healthcare resource allocation among adults and children. methods: we conducted an experimental stated preference survey in a national sample of canadian adults. preferences were elicited across a range of scenarios and scored on a visual analogue scale. intervention group participants were randomized to a moral reasoning exercise prior to each choice task. the main outcomes were the differences in mean preference scores by group, scenario, and demographics. results: our results demonstrate a consistent preference by participants to allocate scarce health system resources to children. exposure to the moral reasoning exercise weakened but did not eliminate this preference. younger respondent age and parenthood were associated with greater preference for children. the top principles guiding participants’ allocative decisions were treat equally, relieve suffering, and rescue those at risk of dying. conclusions: our study affirms the relevance of age in public preferences for the allocation of scarce health care resources, demonstrating a significant preference by participants to allocate healthcare resources to children. however, this preference diminishes when challenged by exposure to a range of moral principles, revealing a strong public endorsement of equality of access. definitions of value in healthcare based on clinical benefit and cost-effectiveness may exclude moral considerations that the public values, such as equality and humanitarianism, highlighting opportunities to enrich healthcare priority-setting through public engagement. faced with both scarce resources and pressures to keep pace with innovation, health systems in most developed nations emphasize the comparative value of health interventions in payment policies and coverage decisions [1, 2] . such appraisals of value rely on assessments of clinical efficacy, economic efficiency and, increasingly, societal values. growing recognition that democratic commitments warrant more room for public voice in health and social policy decisions particularly when allocating public resourceshas spurred attempts to incorporate citizens' values and preferences in health technology assessment (hta) in an increasing number of developed countries [3] . while approaches to measuring clinical and economic value are wellspecified, the means of identifying and assimilating relevant societal values in hta are not [4, 5] . to bridge this gap, a growing academic literature has sought to address the measurement and interpretation of societal value judgements for health system priority setting. two contrasting approaches to the elicitation of societal values have prevailed: population-based surveys and exercises in deliberative engagement. both admit of strengths and limitations. while survey methods are able to elicit preferences from a large swath of the public, they often preclude in-depth reflection and discussion about the complex ethical issues involved in setting priorities [5, 6] . by contrast, deliberative engagement with patients or publics offers rich opportunities for nuanced and recursive consideration of the values that motivate allocative decisions, but from the bounded perspective of a small and select group of persons [7] . a few attempts have been made to marry deliberative and survey methods, either by bookending deliberative events with survey questions or by embedding opportunities for deliberation within survey designs [8] [9] [10] . we adapt an approach to the latter to investigate societal preferences for allocating health care resources to children as compared to adults. age represents one of the most prominent issues explored in the literature on social values for health system resource allocation [11] [12] [13] [14] [15] [16] . the focus on age stems in part from the utilitarian assumptions that anchor prevailing methods of health economic evaluation [17, 18] . qualityadjusted life years (qalys) have played a dominant role in assessing the value of health interventions, as a universal metric for comparisons of benefit among different technologies that incorporate quantity and quality of life into a unified indicator. closely allied to the use of qalys as an outcome measure in applied health economic evaluation is the assumption of utilitarian qaly maximization as a normative goaland thus decision-criterionwhen selecting the best alternative among competing interventions [19] . the prominence of qaly maximization as a decision-criterion in applied health economic evaluation, including by hta institutions internationally, has prompted theoretical and empirical inquiry into the strength of societal preference for qaly maximization [20] [21] [22] [23] . moral philosophers and social choice theorists have challenged the moral legitimacy of purely consequentialist approaches to health care rationing, including qaly maximization, citing the relevance of ethical concepts ranging from distributive justice, priority to the worst off, and rightsbased entitlements in health resource allocation [24] [25] [26] [27] [28] [29] . empirical studies of public preferences for health care resource allocation often employ recipient age as a proxy for qaly gains. studies of public preferences have yielded considerable evidence favouring priority to younger populations [13] [14] [15] [16] . such studies have often compared adults of various ages; select studies include a childhood age range among their comparators (15, (30) (31) (32) (33) . however, few studies have explored public preferences for health resource allocation decisions related to children as such. underlying societal preferences for health resource allocation: 1) 'health maximization ageism' (constant relative value of life-years, irrespective of age); 2) 'productivity ageism' (higher value of life-years in young adulthood, related to greater social and economic productivity); and 3) 'fair innings ageism' (emphasis on opportunity for equal aggregate lifetime health (or qalys) through priority to those expected to experience less, such as the young or disadvantaged) (16) . each of these approaches is outcome-oriented and concerned with health gains, though calibrated to prioritize different groups based on alternative ethical arguments. 'health maximization ageism', which corresponds to pure qaly maximization, receives its strongest support in age-based stated preference studies that focus on life-saving interventions, or those that result in more aggregate qalys for younger recipients. even so, evidence for societal disavowal of pure qaly maximization exists, with some studies yielding majority preferences for equal allocation in the face of discrepant potential qaly gains across age groups (17, 33) . importantly, studies that test preferences for age-based allocation in terms of qaly maximization alone cannot discern whether distinct moral principles inducing priority to the young (be it children or younger adults) are at play. when controlling for qalys gained, the evidence in support of priority to younger groups is mixed. stated preferences consistent with both 'fair innings ageism' and 'productivity ageism' are evident in select studies examining age-based trade-offs in the context of fixed benefits. when the duration of benefit across age groups is standardizedthereby in effect neutralizing 'health maximization ageism', or pure qaly maximizationconsistent prioritization by age breaks down, with participants alternately preferring allocation to children, people in middle age, or equal allocation across age groups (15) (16) 30, (34) (35) . it is, however, often difficult to disentangle evidence in support of one of these forms of ageism from the other in the extant literature. in addition to studies of age-based priority setting that focus on health outcomes, a number of studies explore the moral bases for allocative decision-making by examining the relevance of causes. anand and wailoo demonstrate weak societal preference for consequentialist rationing rules, including qaly maximization, through experimental rationing decisions that force tradeoffs between hypothetical adult recipients of different ages (17) . notably, they also empirically examine the relevance of deontological considerations in health care rationing, including personal responsibility for one's health state, socioeconomic status, and procedural considerations in priority setting. their work demonstrates a disavowal by participants of pure qaly maximization, and highlights other salient normative considerations for potential incorporation into rationing exercises, including equality of treatment, individual rights and duties, and procedural fairness (17, 36) . relatedly, a limited body of evidence points to the impact of embedded moral reasoning on attenuated public preference for the young, suggesting that deliberation on a range of ethical principles can influence stated preferences for allocating resources based on age (10) . however, this evidence pertains to age variations amongst adults. j o u r n a l p r e -p r o o f despite this focus on age as a morally relevant variable, the extant literature contains little dedicated inquiry into allocative preferences regarding children per se (37) . this lack of evidence has contributed to a vacuum of both theoretical and context-specific knowledge about societal preferences related to the prioritization of health system resources for children. the need for more and better knowledge of public values attached to health care priority-setting affecting children is underscored by inherent challenges associated with the assessment of child health technologies [38] [39] [40] . health system funding decisions for children are often constrained by limited evidence for the clinical efficacy or economic efficiency of child health technologies [41] . childhood diseases are typically rare, the conduct of research in pediatric populations is complex, and standard metrics of clinical and economic assessment fail to incorporate unique dimensions of childhood, such as family context and life-course impacts [1, 42] to better understand societal values for health resource allocation, we conducted a population-based stated preference survey with a nested randomized controlled moral reasoning intervention. our objective was to generate evidence to inform economic evaluation and policymaking on health care priority-setting and payment reform in developed health systems. uniquely, we sought to explicitly assess societal preferences for allocation to children, and to test j o u r n a l p r e -p r o o f the influence of structured deliberationin the form of an individual-level moral reasoning exerciseon allocative preferences. our principal aims were to: (1) understand the direction and strength of public preferences for health resource allocation between children and adults for varied treatment scenarios, (2) assess the impact of a moral reasoning intervention on the expression of such preferences, and (3) identify sociodemographic factors that impact the expression of public preferences on health resource allocation between children and adults. we also sought to test the divergence of participant preferences for children or adults from an assumption of age-neutrality, to understand the treatment scenarios within which significant preferences for either children or adults emerge. finally, we aimed to characterize the principles that most influenced participants' allocative decisions, to gain a deeper understanding of the moral reasoning behind societal preferences for health resource allocation. in keeping with much of the prior literature on age-based resource allocation, we expected that control group participants would display an aggregate mean preference for allocation to children, particularly in scenarios where theoretical qaly gains were largest (i.e. cancer treatment and eating disorders therapy). in scenarios with fixed and equal life-year gains across children and adults (i.e. chronic disease drug, liver transplant), we hypothesized that participant preferences for children would be less pronounced, but persist on average, due to intuitive conceptions of 'fair innings'. we included a palliative care scenario to test the direction and strength of age-based preferences in a context focused on relief of suffering rather than hypothetical qaly gains, anticipating weak or no preference for allocation to children. in terms of participant sociodemographics, we presumed that younger adults and those with children of their own would j o u r n a l p r e -p r o o f preferentially favour allocation to children, due to temporal and emotional proximity to childhood states. in contrast to prior evidence demonstrating diminished preference for younger adults induced through moral deliberation [10] , we hypothesized that a moral reasoning exercise would increase the strength of public preference for allocation to children, as compared to adults. this hypothesis was predicated on insights from foregoing normative analyses of public policies for children, which have identified distinguishing characteristics of childhoodsuch as vulnerability, dependency, rarity, social distinction, and future potentialas drivers for policy development [43] [44] [45] [46] [47] [48] . we postulated that the moral reasoning exercise, which incorporated a number of valuesbased considerations specific to children, would prompt participants to consider their allocative preferences in light of these unique concerns. given the ethical tools to unpack intuitions about what children might deserve relative to adults, we anticipated that participants randomized to the moral reasoning arm would apprehend justifications for preferential allocation to children that may not be immediately apparent. we further hypothesized that participants in the intervention arm would display stronger aggregate preference for children across all the clinical scenarios tested, regardless of the duration of life years gained, as a result of their access to a varied palette of ethical principles by which to justify preferential allocation to children, including vulnerability, dependency, potential, and social distinction. we conducted a population-based stated preference survey of societal views on the prioritization of health resources among children and adults, administered to a non-probability sample of j o u r n a l p r e -p r o o f canadian adults. participants were recruited through letters of invitation emailed to a random sample from a panel of over one million canadians maintained by a survey research firm. a limitation of non-probability sampling is the absence of general statistical theory to predict sample representativeness from survey design assumptions [49] . to minimize sampling bias and maximize the potential for national population representativeness, we employed interlocking quotas for stratified sampling (age, gender and region), balanced against statistics canada norms, and evaluated the composition of our final sample in comparison to the canadian population on a range of sociodemographic characteristics. the survey was web-based and loyalty program rewards were offered to encourage participation. development of the survey instrument drew on prior literature on the ethics of health resource allocation and social values relevant to child health policy. the principles included in our moral reasoning exercise were derived from a systematic review of the literature on social values relevant to child health and social policy, refined through an in-depth qualitative case study of health technology assessment and policymaking for children in canada [47, 48] . iterative refinements to the survey were informed by a pilot phase with experts (n=3) and laypersons (n=2) and field testing with members of the public (n=32). the final survey questionnaire directed respondents to assign numerical preference scores for the allocation of resources in different health care scenarios based on age-related criteria. it presented each participant with the same five hypothetical treatment scenarios (chronic blood disease, liver transplant, cancer therapy, palliative care, and eating disorder); these scenarios were intended to provide variation in disease characteristics such as acuity, morbidity, mortality, potential for cure, and nature of participants chose between funding for treatment among adult (average age 40) and child (average age 10) patients, from the perspective of a citizen advisor to a health system administrator. preferences were captured as continuous variables on a visual analog scale (vas) from -5 (full preference for children) to +5 (full preference for adults), with zero representing neutrality. we employed a vas design to explore changes in the strength of participant preferences for children or adults in order to capture more subtle variation in preference than would have been possible with categorical choices, while still allowing for preference neutrality. demographic data related to age, sex, income, education, employment, health status, and family structure were collected. randomization of participants to either an intervention or control group was achieved via a leastfill approach, employing computational logic to assign respondents to the group with the lowest current quota count, which enabled random assignment with respect to stratification variables (age, gender, region). we subjected participants in the intervention group to a moral reasoning exercise prior to each choice scenario. the exercise presented subjects in the intervention group with a list of twelve ethical principles relevant to allocative decisions ( figure 2 ). we fashioned principles to capture concepts identified as uniquely germane to health resource allocation involving adults and children, including 'fair innings', vulnerability, dependency, future potential, and distinction, as derived from a foregoing systematic review of social values relevant to health and social policy for children [47] . balance was sought between principles that might inherently favour allocation to either children or adults. participants in the intervention arm were j o u r n a l p r e -p r o o f asked to select the three principles that most influenced their choice in each scenario. subjects in the control arm responded to the choice scenarios without exposure to a moral reasoning exercise. to minimize question order bias, we randomly rotated the order by which health care scenarios were presented to participants; in addition, we randomly rotated the order of principles within the moral reasoning exercise for the intervention cohort. participants were prevented from revising their prior responses as they proceeded through the questionnaire. quantitative survey data were imported into sas (version 9.4) for analysis. descriptive statistics were employed to characterize the respondent population and compare groups using the student's t-test for continuous variables (age) and chi-squared for categorical variables. we compared select sociodemographic variables from the overall sample with general canadian population demographics from the 2016 statistics canada census of population using onesample proportion tests [50] . we employed a linear mixed-effects random intercept model, which allows for modelling of correlated continuous data, to analyze the strength of participant preferences for each of the scenarios presented and examine the impact of experimental group, scenario, and sociodemographic variables on mean preferences scores, while accounting for the correlation between repeated measures within the same subject. the model examined: 1) the difference in mean preference scores by group, scenario, and demographic characteristics and 2) the difference in mean preference scores between the intervention and control for each scenario. we analyzed the interaction of group and scenario on preference scores to understand whether group mean preference scores varied by scenario type, controlling for covariates (including age, geographic j o u r n a l p r e -p r o o f region, gender, language, education, employment, income, health, and family structure) (emethods). to further characterize the strength of participant preferences for children or adults, and explore potential choice uncertainty, we analyzed the proportions of respondents displaying any allocative preference beyond the bounds of a 'neutral' construct (zero midpoint), and modelled differences in neutral versus preferential responses as a binary outcome between groups and across scenarios through generalized estimation equation (gee) modelling. odds ratios with 95% confidence limits were computed to indicate the likelihood of a neutral response for each scenario, using chronic disease as the reference scenario. gee was also used to assess the likelihood of a neutral response by experimental group in each scenario, with moral reasoning as the exposure. lastly, we quantified the proportion of respondents selecting each allocation principle overall and by scenario. we tested equality of proportions across scenarios to detect significant differences in the proportions of respondents selecting a given allocative principle. chi-squared analyses were used to compare the proportions of participants selecting each moral reasoning principle in a given scenario, using one scenario (chronic disease) as a referent. mcmaster university. informed consent was obtained online as part of the survey panel opt-in process prior to individual survey initiation. the authors received no funding related to study design; collection, analysis, and interpretation of data; the writing of the report; or the decision to submit for publication. between april 18 and 24, 2017, a total of 12,803 individuals were screened for inclusion: 10,026 were deemed ineligible or declined to participate and 2,777 individuals were randomized. of these, we excluded 1,048 for incomplete surveys. a total of 1,729 (62.3%) respondents completed the survey; 173 were subsequently excluded for poor quality (e.g., racing). our final sample included 1,556 participants, with 773 in the intervention group and 783 in the control group (efigure 1). respondent characteristics were similar across groups (etable 1). as compared with 2016 canadian population census data, our sample evinced an overrepresentation of individuals with higher educational attainment. we present our results in sequence corresponding to the hypotheses listed above. we begin with an exposition of control group results, to ascertain whether a baseline predilection for allocation to children was apparent in our sample, and how it varied across disease-specific scenarios. we then move to analysis of mean preference scores in the intervention group, and observed differences between the intervention and control group, to isolate the impact of the moral reasoning exercise on participant preferences. our analysis of preference divergence from an age-neutral construct (-0.5 to +0.5) follows, to test the strength of allocative preference in either direction. finally, we analyze participant choices about the moral principles guiding their allocative preferences, focusing on the frequency and patterning of principle selection across scenarios. allocative preferences analysis of mean preference scores demonstrated a consistent aggregate preference by control group participants to allocate scarce health system resources to children across all trial scenarios ( figure 3 ; table 1 ). the strongest control group preference for children was observed in the cancer therapy (-1.77, 95% ci -2.06 to -1.48, p<0.0001) and eating disorders treatment (-2.01, 95% ci -2.30 to -1.71, p<0.0001) scenarios, in which the theoretical qaly gains were largest. mean scores were statistically significantly higher (more positive) in the intervention group overall, suggesting a weaker preference for allocation to children in those subjected to the moral reasoning exercise (figure 3 ; table 1 ). in the intervention group, a significant preference for allocation to children was retained in the cancer therapy (-0.83, 95% ci -1.11 to -0.54, p<0.0001) and eating disorder treatment (-1.11, 95% ci -1.39 to -0.82, p<0.0001) scenarios, but there was no age preference in the chronic disease drug, liver transplant and palliative care scenarios ( table 2) . when analyzing the difference in mean preference scores between experimental groups for each scenario, the intervention had the largest absolute impact for the cancer therapy (0.94, 95% ci where the benefits of an intervention were most obvious and different between adults and childrenas they were in respect of life-years gained from cancer and eating disorders therapy -j o u r n a l p r e -p r o o f a choice to prioritize those benefitting most may have seemed easiest, even in the face of exposure to competing moral principles. this explanation is supported by theories of rational decisionmaking from the field of cognitive psychology that posit dual-process thinking, distinguishing intuition from reasoning [51] [52] [53] . the design of our studyincluding the survey format and pacing, question framing, and lay samplemay have induced intuitive responses from some participants, in the face of complex moral problems characterized by inherent uncertainty. in particular, participants may have allowed more obvious differentiators, such as discrepant benefits in length of life, to intuitively shape their preferences, rather than take the time and cognitive effort to work through conflicting moral choices in a rule-bound manner. this is likely particularly true of those unexposed to the moral reasoning intervention, and might explain why preference score differences between the intervention and control groups were largest in respect of cancer therapy and eating disorders treatment. it may also explain why variance in preference scores narrowed consistently across scenarios in the intervention group as compared to the control group: it is possible that this reduction in variance represents a reduction in choice uncertainty, in the context of enhanced participant reliance on analytical reasoning induced by the study intervention. proportions of neutral response (score between -0.5 and +0.5) were consistently higher in the intervention group across all scenarios (etable 4). univariate gee analysis revealed the impact of the moral reasoning intervention on preference neutrality across children and adults, with neutral responses significantly more likely in the intervention group than the control group we made a conscious attempt to incorporate principles related to an array of individual and societal benefits and costs, to induce reflection on the range of moral reasons one might consider germane to health system resource allocation. we also sought balance between principles that might intrinsically engender preference for children or adults. participants exposed to the moral reasoning exercise demonstrated remarkable consistency in their prioritization of principles for allocative decision-making. the top three principles guiding participants' allocative decisions were: 1) treat equally (54.3% -63.9%), 2) relieve suffering (39.6% -66.1%), and 3) rescue those at risk of dying (37% -40.8%). in all cases except palliative care, 'treat equally' ranked number j o u r n a l p r e -p r o o f one, with a proportion uniformly greater than 50%; subjects deemed 'relieve suffering' most important (66.1%) in the context of palliative care, followed closely by 'treat equally' (63.9%). the least endorsed principles (10%) for assigning allocative preference were: priority to rare diseases, priority to special populations, and priority based on societal productivity. despite consistency in ranking of principles, the proportion of participants selecting a given principle to guide allocative decision-making varied significantly across scenarios ( table 3 ). as compared to the chronic disease treatment scenario, the cancer therapy scenario prompted significantly more participants to cleave to principles that, in theory, justify preferential allocation to children: opportunity to live a full life (24.7% vs 19.2%, p<0.0028), duration of benefit (34.5% vs 19.5%, p<0.0001), and concern for special populations (11.9% vs 7.4%, p<0.0026). they also tended to disavow principles favouring allocation to adults, including family responsibilities (14.2% vs 24.7%, p<0.0001) and economic productivity (7.9% vs 16% p<0.0001). a similar pattern was observed for the eating disorder treatment scenario, with the addition of vulnerability (36.1% vs 21.9%, p<0.0001) to the principles endorsed. by contrast, in the palliative care scenario, participants displayed significantly more concern for equality of treatment (63.9% vs 55.2%, p<0.0005) and relief of pain and suffering (66.1% vs 39.6%, p<0.0001), and less concern for 'fair innings' (the entitlement to a full lifespan) or duration of benefit. a principal finding of our study is the consistent preference for allocation to children across health care scenarios in the overall cohort. this finding is in keeping with much of the extant evidence on societal preferences for allocation to the young, but adds depth and specificity in preference in response to changes in the duration of benefit from a given intervention [16] . in the face of life-long benefits (e.g. life-saving interventions), their study participants gave consistent precedence to younger groups when allocating scarce resources. by contrast, when juxtaposed with life-long benefits, fixed benefits induced a preference pattern that privileged young to middle adulthood. our results may indicate similar moral intuitions behind participant choices, though with the notable difference of an equal allocation option. where pure qaly maximization was possiblenamely, in the cancer therapy and eating disorders treatment scenariosparticipants seemed to adjudge the life-long benefits that would accrue to children too large to overlook. conversely, in the scenarios with fixed benefits, preference for allocation to children was weaker in the control group, and a trend toward preference for equal allocation j o u r n a l p r e -p r o o f emerged in the intervention cohort. an alternative explanation could be that participants perceived scenario-specific differences in duration of benefit more readily than other benefits that, though not explicitly mentioned, also retain moral relevance in the context of these and similar scenarios. such benefits could include reduction in inequality of outcomesfor instance, founded on inherent characteristics of the disease (rarity) or population (vulnerability, dependency)or equitable chances to live a full life ('fair innings') [54] [55] [56] [57] [58] [59] . interestingly, our results at once confirm and challenge prior evidence that suggests decision-making from an impersonal vantage point (e.g. a budgetary decision-maker) makes it easier to discriminate in favour of one group as against another. nord et al. elicited allocative preferences from study participants within two different assumed perspectives: a 'veil of ignorance', in which the participants themselves might need the health intervention in question one day; and a health system administrator role, in which they were tasked with decisions about resource allocation to others from a budgetary standpoint [15] . they found that the tendency to privilege younger people in allocative decisions was more evident amongst those who assumed the latter perspective, and argued that the degree of emotional remove induced by the shift in perspective might account for this difference. evidence from our study for the moderating effect of a moral reasoning exercise on participant preferences for allocation to children, from an administrative perspective, suggests the opportunity for ethical reflection mitigated participant willingness to discriminate between groups on the basis of age. this may reflect choice uncertainty and a resultant instinct for preference neutrality, rather than evidence of real, rich moral deliberation. alternatively, this may represent a 'depersonalizing' effect of moral deliberation on allocative decision-making, one sufficient to impact societal preferences for health resource allocationbut in the opposite direction to that observed by nord et al. counter to our hypothesis, exposure to a moral reasoning intervention diminished participant preferences for allocation to children. evidence of a moderating effect of moral reasoning on allocative preference for children suggests the opportunity for ethical reflection mitigated participant willingness to discriminate between groups on the basis of age. this relationship may have been driven by a more varied set of ethical principles with which to draw conclusions. interestingly, this is the same consideration that motivated our hypothesis of increased preference for children through moral reasoning. we presumed that the ethical nuances attached to funding health interventions for childrenincluding distinguishing features such as vulnerability, dependency, neglect, and future potential, that stood out in prior normative analyses of child health and social policywould come through more clearly to participants when exposed to a range of principles touching on them [43] [44] [45] [46] [47] [54] [55] [56] [57] [58] . notably, the strength of preference for equal allocation increased among those randomized to the moral reasoning exercise. one interpretation of this is that the intervention prompted participants to evaluate the relationship between their moral intuitions and their stated preferences, and induced a reasoned judgment about the importance of equality as a guiding principle for resource allocation. an alternative explanation is that, despite the study intervention, it remained cognitively difficult for participants to reason through the uncertainty inherent in weighing competing moral principles. the greater predilection for neutrality in the experimental group may have represented retreat to equality in the face of difficult choices. our study admits of potential limitations. in relation to the survey instrument, the brief statements used to evoke the meaning of each principle may have failed to capture its ethical nuances. different framing of the principles may have led to different patterns of preference among participants; however, randomly varying the sequence of principles mitigated any ordering effect bias [60, 61] . use of a continuous scale overlapping zero to measure the strength of allocative preferences in the context of a binary choice task (fund either intervention a or b) may have led some participants to misinterpret zero as a choice to allocate equal sums of money to each population, rather than agnosticism about which intervention to fund. we sought to mitigate this potential limitation through simple, explicit scenario instructions; however, it is possible that misapprehension of the 'neutrality of preference' state by some participants impacted our results. the study was not designed to measure the time it took to read the principles in the moral reasoning intervention separately from completing the choice tasks. this could have given a proxy sense of whether participants read and engaged with the ethical ideas and choices involved. the assembly and composition of our study sample may have also limited the external validity of our results. values endorsed by the canadian public may not reflect those of other polities. the use of covariate-adaptive randomization to form balanced treatment groups with respect to relevant covariates has both benefits and inherent shortcomings; use of stratified randomization may have permitted some selection bias and only balanced a limited number of potentially relevant covariates [62] . more specifically, the survey firm generated cohorts from an opt-in panel of eligible canadians recruited and incentivized through brand loyalty points programs. some of the inherent selection bias associated with online opt-in panels was evident, privileging those with higher education who are web literate. however, the lack of statistically significant impacts of education and income on preference scores in the multivariate model attenuates theoretical concerns about sociodemographic bias. our study also has important strengths. it is, to our knowledge, the first to experimentally examine the values behind health and social policy decisions about children, their valence in relation to adult needs and priorities, and their stability in the face of moral deliberation. its randomized design and large, heterogeneous population-based sample allowed for robust conclusions about the effect of the intervention on participant preferences. our findings demonstrate a convincing relationship between exposure to a range of relevant moral principles and the priorities set. this affirms the complexity of such decisions and the impact of ethical deliberation on them. these findings challenge reflexive trust in survey-based preference elicitation, and imply the need to complement such modalities with deliberative modes of public engagement on questions of social importance, such as the allocation of scarce public resources. in policy terms, our work both supports and challenges conceptions of value in health care based primarily on qaly maximization. dominant modes of health economic evaluation privilege interventions that maximize aggregate individual and societal utility, typically in the form of the duration and magnitude of benefits reaped and the size of the population reached. our results demonstrate a stronger preference for children in the hypothetical scenarios (cancer and eating disorders) in which the duration of benefit accrued mainly to children; this may represent an underlying motivation by participants to maximize benefits. however, we also observed a strong inclination for equality and humanitarianism amongst study participants, regardless of experimental group. the three principles deemed most salient to priority-setting were equal treatment, relief of suffering, and rule of rescue. none of these prioritizes age as a relevant variable; each starts from a belief in the intrinsic value of all human life, and resists grading that j o u r n a l p r e -p r o o f value by social context or circumstance. our results, therefore, suggest the need to incorporate other values into health care priority-setting, as some value frameworks for funding decisions have begun to do [63] . the salience of these findings to priority-setting efforts in the context of public health emergenciesincluding access to scarce ventilators or drugs in the context of the covid-19 pandemicis readily apparent. they furnish empirical evidence for the adjudication and refinement of ethical frameworks for triage and resource allocation during the pandemic based on public values in canada [64, 65] . efforts to incorporate a broader range of public values and preferences in health and social policy decisions also involve inherent risks. among them is the need to confront and grapple with public attitudes that conflict with the fundamental normative or legal principles that structure most democratic societies, including basic commitments to the protection of individual rights and nondiscrimination [66] . future research to explore this tension and ways to resolve or address it is warranted. allied to this, our study affirms the importance of process in health care priority-setting exercises. the opportunity to explicitly consider varied normative ideas appears crucial to informed allocative decisions based on public values. the observed changes in public preferences in the face of competing moral principles imply the impact, and potential relevance, of structured opportunities for moral reasoning when making such consequential decisions. this includes the potential value of deliberative public engagement to health policymaking, particularly in domains where distinct ideas about the public good may compete. specific to children, few efforts to incorporate public deliberation in research and policy on child health and social policy priorities have prevailed to date. in the face of resource scarcity, evidence-informed child health and social policies will depend on the careful elicitation and integration of public values. this and allied work bear potential relevance in social policy domains beyond health, including public attitudes to j o u r n a l p r e -p r o o f 'deservingness' attached to welfare state distributional policies in domains as diverse as labour markets and education [67] [68] [69] [70] [71] [72] [73] . crucial future areas of inquiry and application include the inclusion of child voices in research and policymaking, and the exploration of social values for priority setting within public policies and programs for children. our study underscores the relevance of age in public preferences for the allocation of scarce health care resources, extending evidence of this calculus to trade-offs involving children. nevertheless, it demonstrates the mutability of such preferences in the face of structured moral deliberation. this finding has three main repercussions. it furnishes a critical lens for the interpretation of stated preference surveys; introduces a note of caution into dominant modes of health care funding allocation decisions premised on utility maximization; and implies the value of deliberative methods as a complement to both. we observed a strong inclination for equality and humanitarianism amongst study participants, regardless of experimental group. these moral impulses prevailed over consequentialist logic, including priority to the young founded on aggregate benefit. the stability of these principles in the face of changing allocative preferences signals their importance as public valuesbut it also hints at the complexity of values-based decision-making. the public seems, at face value, to believe in equality of access and defend a set of shared human entitlements to care. it also seems to assign intuitive priority to children. the challenge of reconciling these convictions demands processes nimble enough to negotiate this paradox. spaces for moral deliberationwhether in large-scale surveys or focused qualitative engagementare essential to arrive at health care priorities that reflect what we collectively hold dear. j o u r n a l p r e -p r o o f contributions: ad conceived and designed the study. sc and ad performed the statistical analysis. ad prepared the first draft of the manuscript. all authors contributed to study design, critically revised the manuscript, and approved the final version. as corresponding author, ad accepts responsibility for the work, had full access to the data, and controlled the decision to publish. ad attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. acknowledgements: during the period of this research, ad was supported by grants from the canadian institutes of health research, pierre elliott trudeau foundation, canadian child health clinician scientist program, and pediatric oncology group of ontario. imagine that two different medicines are available to manage an incurable chronic blood disease: one drug treats the child form of the disease, while a different drug treats the adult form of the disease. without treatment, patients die of the disease within 6 months of diagnosis. with drug treatment, both child and adult patients can be expected to live about 20 years from diagnosis, after which they usually die from progressive complications of the disease. each drug costs the same amount of money and would serve the same number of people. the health system can only afford to fund one of the two drugs at present, and cannot split the money between the two drugs. please slide the bar to any point on the scale from -5 to +5 to show your strength of support for funding one of the drugs. a drug is available for patients with childonset blood disease. a drug is available for patients with adultonset blood disease. patients live about 20 years with the treatment, at which point they usually die of complications from the disease. without the drug, the disease causes death within 6 months. without the drug, the disease causes death within 6 months. fund treatment based on evidence that it works  "fund treatments best proven to be safe and effective."  "since it is harder to study treatments in children, evidence is usually stronger for adult treatments."  "the older patients have had their turn."  "give the younger patients a chance for a full life." treat people who will benefit longer  "giving the treatment to the younger group makes sense, since they will enjoy it longer."  "lifelong potential should be factored into decisions about which health interventions to fund."  "at 40, people may be raising families or have others who rely on them."  "resources should be directed to help those that cannot protect or advocate for themselves."  "children are still developing, so can suffer lifelong consequences from untreated disease." treat people who are productive  "helping people who are in the workforce has benefits for all." treat everyone equally  "all patients deserve equal access to medical care."  "both groups should have the same chance." treat those who are dependent on others  "children are dependent on their parents or caregivers, so their illness has direct impacts on the lives of others." r 2 : the full model with predictors explained 9.7% of within-subjects variance and 4.3% of between-subjects variance, as compared with the null model (without predictors). comparing the full model with a parsimonious model (non-significant predictors removed), the two models were almost identical. the parsimonious model explained 0.05% more of the between-subjects variance; there was no difference in within-subjects variance explained. details omitted for double-blind reviewing making the case for value-based payment reform in children's health care details omitted for double-blind reviewing health technology funding decisionmaking processes around the world: the same, yet different details omitted for double-blind reviewing effect of discussion and deliberation on the public's views of priority setting in health care: focus group study details omitted for double-blind reviewing democracy and deliberation considered opinions: deliberative polling in britain can a moral reasoning exercise improve response quality to surveys of healthcare priorities which of two individuals do you treat when only their ages are different and you can't treat both the utility of health at different stages in life: a quantitative approach is the valuation of a qaly gained independent of age? some empirical evidence an empirical study of the fairness of allocation of health care resources the significance of age and duration of effect in social evaluation of health care measuring people's preferences regarding ageism in health: some methodological issues and some fresh evidence utilities versus rights to publicly provided goods: arguments and evidence from health care rationing ethical and distributive considerations measurement of health state utilities for economic appraisal the social value of a qaly: raising the bar or barring the raise? qalys and ethics: a health economist's perspective qaly maximisation and people's preferences: a methodological review of the literature consequentialism and its critics rights, goals, and fairness development as freedom personal utilities and public judgements: or, what's wrong with welfare economics rational normative economics vs 'social welfare' and 'social choice the social value of health programmes: is age a relevant factor? preferences for lives, injuries, and age: a stated preference survey are some lives more valuable? an ethical preferences approach maximizing health benefits versus egalitarianism: an australian survey of health issues preferences for life saving programs: how the public discounts time and age health priorities and public preferences: the relative importance of past health experience and future health prospects the nature of procedural preferences for health-care rationing decisions should health gains by children be given the same value as health gains by adults in an economic evaluation framework? in: economic evaluation in child health details omitted for double-blind reviewing details omitted for double-blind reviewing details omitted for double-blind reviewing details omitted for double-blind reviewing the generation gap: differences between children and adults pertinent to economic evaluations of health interventions are newborns morally different from older children? social policy for children and families: a risk and resilience perspective life course health development: an integrated framework for developing health, policy, and research towards a sociology of child health details omitted for double-blind reviewing details omitted for double-blind reviewing a review of conceptual approaches and empirical evidence on probability and nonprobability sample survey research a perspective on judgment and choice -mapping bounded rationality individual differences in reasoning: implications for the rationality debate? who is rational? studies of individual differences in reasoning intergenerational equity: an exploration of the 'fair innings' argument an equity framework for health technology assessments voices for children: rhetoric and public policy values and assumptions underpinning policy for children and young people in england an evaluation framework for funding drugs for rare diseases age-related preferences and age weighting health benefits eliciting preferences for prioritizing treatment of rare diseases: the role of opportunity costs and framing effects psychology and economics a better alterative to stratified permuted block design for subject randomization in clinical trials details omitted for double-blind reviewing a framework for rationing ventilators and critical care beds during the covid-19 pandemic fair allocation of scarce medical resources in the time of covid-19 details omitted for double-blind reviewing who should get what, and why? on deservingness criteria and the conditionality of solidarity among the public the deservingness heuristic and the politics of health care the political logic of labour market reforms and popular images of target groups public support for sanctioning older unemployed-a survey experiment in 21 european countries the need for and the societal legitimacy of social investments in children and their families: critical reflections on the dutch case the role of welfare state principles and generosity in social policy programmes for public health: an international comparative study contemporary public policy influencing children and families  "when it comes to relieving suffering, other factors shouldn't count."  "we should always relieve pain when we can."we should rescue those at risk of dying  "everyone deserves the same chance of rescue from life-threatening circumstances."  "saving someone's life is important, regardless of age."treat those society considers special  "children are a distinctly valued social group that deserves privileged treatment."give priority to rare diseases  "rare diseases are often neglected, so should receive special priority."  "childhood disease are often rarer than adult ones, so might be unfairly overlooked in health system planning." key: cord-354993-gdz63spj authors: larcher, victor; brierley, joe title: children of covid-19: pawns, pathfinders or partners? date: 2020-06-05 journal: j med ethics doi: 10.1136/medethics-2020-106465 sha: doc_id: 354993 cord_uid: gdz63spj countries throughout the world are counting the health and socioeconomic costs of the covid-19 pandemic, including the strategies necessary to contain it. profound consequences from social isolation are beginning to emerge, and there is an urgency about charting a path to recovery, albeit to a ‘new normal’ that mitigates them. children have not suffered as much from the direct effects of covid-19 infection as older adults. still, there is mounting evidence that their health and welfare are being adversely affected. closure of schools has been a critical component of social isolation but has a far broader impact than the diminution of educational opportunities, as important as these are. reopening of schools is therefore essential to recovery, with some countries already tentatively implementing it. children’s interests are vital considerations in any recovery plan, but the question remains as to how to address them within the context of how society views children; should they be regarded as pawns, pathfinders or partners in this enterprise? countries throughout the world are counting the health and socioeconomic costs of the covid-19 pandemic, including the strategies necessary to contain it. profound consequences from social isolation are beginning to emerge, and there is an urgency about charting a path to recovery, albeit to a 'new normal' that mitigates them. children have not suffered as much from the direct effects of covid-19 infection as older adults. still, there is mounting evidence that their health and welfare are being adversely affected. closure of schools has been a critical component of social isolation but has a far broader impact than the diminution of educational opportunities, as important as these are. reopening of schools is therefore essential to recovery, with some countries already tentatively implementing it. children's interests are vital considerations in any recovery plan, but the question remains as to how to address them within the context of how society views children; should they be regarded as pawns, pathfinders or partners in this enterprise? as countries emerge from lockdown, the true effects of widespread social isolation can be assessed. despite the overwhelming desire for a return to normality, a new 'normal' is required to both address those effects and to mitigate against them in any second wave. 1 covid-19 infection has been comparatively benign in children, but there is mounting evidence that their health and welfare have been aversely affected by social measures to control the pandemic. 2 the uk response to covid-19 has been guided by science, operating within an ethical framework developed in response to previous pandemic threats. 3 neither has given a great deal of consideration to the recovery process, though presumably similar ethical principles apply to plans to ease current restrictions, as they did to their implementation. there have been little scientific data to guide how children might be involved in the recovery from social isolation. covid-19 seems to have, at least initially, affected children less severely than adults with <2% of infected children needing critical care and mercifully few deaths. 4 5 but the extent to which they may be asymptomatic carriers is unclear, though they do not appear to be super spreaders. in this context, school closures may have a relatively small contribution in preventing the spread of the virus when compared with other social distancing techniques but have profound adverse socioeconomic effects. 6 also, the relationship between past exposure and consequent immune status is currently unknown, but plainly essential information in considering children's potential part in the recovery process. the role of specific host defence factors, genetic factors, ethnicity and socioeconomic deprivation (the latter two parameters seemingly related to covid-19 susceptibility and severity in adults) is also not known-though all are important in other childhood diseases. in the sense that they operate in childhood, they create additional jeopardy to any conferred by the state of childhood per se. ethical guidance so far issued makes no specific provision or concession for children-or indeed any vulnerable group, or those with instrumental value to society, 3 but is founded on the principle of equal concern and respect. application of the underpinning principles of inclusivity, respect, solidarity, proportionality and reciprocity necessarily entail that the interests of children are given as much weight by society as those of adults. for example, the principle of reciprocity requires that those risks others bear on our behalf be accounted for and ameliorated, such as in the provision of adequate personal protective equipment (ppe) for all who need it. it is not clear the extent to which application of this principle to children has occurred. indeed, it may be the case that children effectively continue to be regarded as pawns, insofar as their interests can be sacrificed by others in pursuit of other goals-as they have in the past. 7 traditional moral theories grant children limited moral status, broadly proportionate to their state of moral development; others have ethical and legal authority to make appropriate decisions on their behalf. granting children rights confers some moral agency; the un convention on the rights of the child provides protection, welfare and education rights, irrespective of the child's ability to claim them. 8 this convention would apply to children's involvement in the recovery from lockdown, for example, return to school, even if a consequence was of significant concomitant benefit to adults such as the ability of parents to return to work, improvement of family social circumstances and mental health. it follows that children, even if they had no say in the process, should receive adequate protection, for example, by provision of appropriate public health facilities and social distancing. any harms that might accompany a return to school should be minimised and balanced against those of remaining in lockdown. adequate and appropriate ppe for staff and supporters is an essential requirement for all staged returns to school. nevertheless, contemporary thinking about childhood accords children more active roles and a voice in matters that concern them. current controversy a staged return to the 'new normal' might plausibly cast children in a pathfinder role. in world war 2, pathfinders were elite troops, often volunteers, with advanced technological equipment, who prepared the way for the main forces. in the case of children's return to school, this might mean that older children, whose educational prospects and crucial examinations have been compromised, might lead the process, with appropriate safeguards, and use of technology such as track and trace apps. an additional reason for selecting older children might be that they are more likely to have the capacity to give valid consent for the use of technology and for minimally invasive testing, for example, swabs and blood sampling necessary to safeguard the process. arguably they might be more likely to comply with hand hygiene social distancing and understand the need to do so. if predetermined endpoints could document the efficacy and safety of this approach, it could be useful in extending the return to school more widely. it would also encourage the more active involvement of children in the process, be compatible with participation rights as granted by the united nations convention on the rights of the child (unrc) and give participants a sense of inclusivity and partnership that would be of social utility. it might seem to strain credulity to regard children as partners in the easing of lockdown; after all, they may lack the ability to define and claim the liberty rights that adults have. 9 however, they will inhabit the new normal, with all its attendant socioeconomic changes, just as inevitably as adults will. in support of this concept of partnership and participation, article 12 of the unrc requires children to be informed and consulted over matters that concern them and that their views be given due weight in accordance with their age and maturity. 8 in recent years, children have become actively involved in healthcare, 10 11 research 12 and as activists for prevention of climate change. 13 some children have shown the capacity for self-directed acts of kindness and altruism, in keeping with a level of moral development that some adults may never achieve. 14 in short, their evolving moral agency throughout childhood is unquestionable, and for many of serious weight before adulthood. because of the attendant uncertainties attached to the easing of lockdown, such as the existence of any second wave of infection and its containment, easing can be considered an experimental procedure in which children, in common with other groups, are de facto research subjects. since children are increasingly active participants in the identification of research topics and the design and implementation of trials, it seems logical to include them in this 'project', especially as they will experience the future consequences of the pandemic. indeed, the principles of equal concern and respect, and inclusivity appear to require this. children in common with others need clear explanations of the risks and benefits of leaving lockdown in terms that they can understand. if future societies (including today's children) are to retain trust in governmental strategies, it is essential that governments 'show their working out'; the principles of ethical decision-making require transparency, accountability and reasonableness. society has a clear duty to protect children from the harms that the pandemic and the means to control it can cause. but, necessary as this is, children should be more than passive recipients of our concern, they are after all future citizens with a right to an open future. 15 post covid-19, we need to build a new normal, that is a kinder, more inclusive and equal society, in which today's children are to be active members. we should involve them in the process rather than consider them as mere pawns in a societal game of chess. however, we would do well to remember that '[pawns] are the soul of chess…on their good or bad arrangements depends the gain or loss of the party', 16 -not such an inappropriate metaphor after all? mitigating the wider health effects of covid-19 pandemic response risks to children and young people during covid-19 pandemic bmj 2020 department of health and social care u. guidance. responding to covid-19: the ethical framework for adult social care chinese pediatric novel coronavirus study team.sars-cov-2 infection in children coronavirus disease 2019 in children -united states school closure and management practices during coronavirus outbreaks including covid-19: a rapid systematic review offline: the uk's child health emergency un general assembly, convention on the rights of the child children: rights and childhood. london: routledge a guide to the participationof children and young peoplein health services children as active researchers: a new research paradigm for the 21st century why the world is watching young climate activists. nature media children are not small adults: significance of biological and cognitive development in medical practice the child's right to an open future a guide to chess endings contributors both composed the manuscript. vl wrote the first draft and jb added to it, edited and finalised.funding the authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.competing interests none declared. provenance and peer review not commissioned; internally peer reviewed. this article is made freely available for use in accordance with bmj's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by bmj. you may use, download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained. key: cord-329750-purunxce authors: waldman, amy; o'connor, erin; tennekoon, gihan title: childhood multiple sclerosis: a review date: 2006-06-28 journal: ment retard dev disabil res rev doi: 10.1002/mrdd.20105 sha: doc_id: 329750 cord_uid: purunxce multiple sclerosis (ms) is an autoimmune demyelinating disorder of the central nervous system (cns) that is increasingly recognized as a disease that affects children. similar to adult‐onset ms, children present with visual and sensory complaints, as well as weakness, spasticity, and ataxia. a lumbar puncture can be helpful in diagnosing ms when csf immunoglobulins and oligoclonal bands are present. white matter demyelinating lesions on mri are required for the diagnosis; however, children typically have fewer lesions than adults. many criteria have been proposed to diagnose ms that have been applied to children, mostly above 10 years of age. the recent revisions to the mcdonald criteria allow for earlier diagnosis, such as after a clinically isolated event. however, children are more likely than adults to have monosymptomatic illnesses. none of the approved disease‐modifying therapies used in adult‐onset ms have been approved for pediatrics; however, a few studies have verified their safety and tolerability in children. although children and adults with ms have similar neurological symptoms, laboratory (cerebrospinal fluid) data, and neuroimaging findings, the clinical course, pathogenesis, and treatment of childhood onset ms require further investigation. mrdd research reviews 2006;12:147–156. © 2006 wiley‐liss, inc. m ultiple sclerosis (ms) was first described more than 170 years ago in adults. although rare, ms was recognized in children as early as 1922 [wechsler, 1922] . nevertheless, ms is still thought to be a disease of young adulthood, typically presenting between the ages of 20 and 40 years, and the diagnosis is rarely considered in children. physicians have questioned whether or not childhood ms is the same entity as seen in adults. in 1958, gall et al. published one of the earliest retrospective studies on pediatric-onset ms [gall et al., 1958] . between 1920 and 1952 , 40 children met inclusion criteria for the study. the patients demonstrated neurological signs and symptoms due to scattered lesions within the cns separated by time and space and supported by objective evidence. the study concluded that children and adults with ms have similar clinical profiles, including mode of onset, symptoms, and physical and laboratory (cerebral spinal fluid [csf]) findings. nevertheless, diagnosing ms in children is often difficult and controversial. the estimated prevalence of ms worldwide is 50 per 100,000 with 2.7-5.6% of patients presenting before the age of 15-16 years [ sindern et al., 1992; gadoth, 2003 ]. the calculated frequency of childhood-onset ms is 1.35-2.5 per 100,000 [gadoth, 2003] . ms has been diagnosed during infancy and early childhood (younger than 10 years of age) accounting for 0.2-0.7% of all cases [ruggieri et al., 1999] . there are reports of children presenting before the age of 2 years, even as early as 13 months [cole et al., 1995] . as seen in the adult population, there is a female predominance in childhood ms ranging from 2.1-3:1 [gall et al., 1958; duquette et al., 1987] . the presenting symptoms of ms in children are similar to those reported by adults. in 1987, duquette et al. reviewed 125 pediatric patients with ms who presented most commonly with either pure sensory symptoms or optic neuritis [duquette et al., 1987] . diplopia, pure motor symptoms, abnormal gait including ataxia (cerebellar or vestibular), mixed sensory and motor symptoms, and sphincter disturbances were also reported. in 1992, sindern et al. identified 31 patients with ms using poser's criteria (see diagnosis section) who presented before the age of 16 years and compared them to 72 sex-matched control patients diagnosed with ms between the ages of 20 and 40 years [sindern et al., 1992] . the most common finding at the onset of disease for both children and adults was optic neuritis, accounting for 52% and 40%, respectively. the second most common presenting symptom in children was sensory disturbance, seen in 16% of children and 15% of adults. transverse myelitis was more common in children, whereas motor symptoms were more common in adults (18%) than in children (6%). furthermore, in 71% of children, the initial presentation was rapid, resulting in admission to the hospital within a few hours to days. a longitudinal study by boiko et al. confirmed duquette's and sindern' s findings that sensory symptoms and optic neuritis were the most common initial manifestations in patients with the clinical onset of ms before the age of 16 years [boiko et al., 2002] . in 1995, poser et al. characterized the presentation of ms in adults (table 1) [poser, 1995] , and the diagnosis of ms should be considered in children presenting with similar symptoms. the clinical course of ms is divided into four subtypes: relapsing-remitting (rrms), primary progressive (ppms), secondary progressive (spms), and progressive-relapsing (prms). rrms is the most common subtype in both adults and children. there are no diagnostic tests for ms. however, a lumbar puncture is routinely performed to obtain supportive evidence of cns inflammation. in approximately 60% of patients with childhoodonset ms, the routine analysis (cell count, protein, and glucose) of csf is normal [duquette et al., 1987; dale et al., 2000] . the remainder of patients has a lymphocytic pleocytosis (typically ͻ50 cells/mm 3 ) and/or elevated protein (typically ͻ75 mg/dl) [dale et al., 2000] . intrathecal synthesis of immunoglobulin (ig), predominantly igg, is also seen in patients with ms. approximately 80% of children with ms have increased csf igg synthesis [jones, 2003] . furthermore, oligoclonal bands (ocb), markers of antibody synthesis in the cns, are present in about 85-95% of adult patients with ms [olek and dawson, 2004] . in children, ocb were present in 40 -87% of patients and may appear later during disease convalescence or relapse [sindern et al., 1992; selcen et al., 1996; dale et al., 2000; jones, 2003 ]. ocb are not specific to ms [poser, 1983; olek and dawson, 2004] . they can be found in chronic cns infections, such as subacute sclerosing panencephalitis, viral infections of the cns, autoimmune neuropathies, cervical myelopathies, and cns tumors [ cohen et al., 2000] . magnetic resonance imaging (mri) reveals asymmetric, multifocal white matter lesions on t2-weighted sequences and fluid-attenuated inversion recovery (flair) images [miller et al., 1990] . the lesions are most commonly located in the periventricular and subcortical white matter where they appear ovoid with extensions called dawson fingers [barkhof et al., 1997] . additional lesions can be seen in the cerebellum, spinal cord, basal ganglia, and thalami [dale et al., 2000] . new lesions may enhance with gadolinium administration. there are no longitudinal mri studies in childhood ms to establish whether there is progressive atrophy of the brain or the appearance of "black holes" (chronic inactive lesions). furthermore, unlike in adults, diffusion tensor imaging (dti) and magnetization transfer ratios (mtr) have not been systematically performed. finally, magnetic resonance spectroscopy (mrs) shows similar changes to those reported in adult ms patients with decreases in nacetyl aspartate (naa) reflecting neuronal loss, increases in choline reflecting remyelination, and increases in myoinositol reflecting gliosis [wolinsky and narayana, 2002] . ms remains a clinical diagnosis. in 1983, poser et al. published guidelines incorporating laboratory, neuroimaging, and neurophysiologic data into the diagnostic criteria with four proposed subtypes: clinically definite ms, laboratory-supported definite ms, clinically probable ms, and laboratory-supported probable ms (see table 2 ) . in 2001, the mcdonald criteria were introduced to facilitate and simplify the diagnosis of ms for patients between 10 and 59 years [mcdonald et al., 2001] . the authors further defined mri criteria and included both monosymptomatic disease and ppms in the clinical presentations. caution was suggested in applying these guidelines to children younger than 10 years. in fact, the sensitivity in diagnosing pediatric cases was questioned by a second panel that revised the mc-donald criteria in 2005 (see table 3 ) [polman et al., 2005] . furthermore, hahn et al. reported that many pediatric patients did not meet the mcdonald mri criteria for dissemination in space (see table 4 ) [hahn et al., 2004] . demonstrating dissemination in time (see table 4 ) is also challenging in pediatrics due to the possibility of relapses in a monophasic disease (see differential diagnosis section). nevertheless, a repeat mri performed three months after the initial study is recommended to show dissemination in time. acute disseminated encephalomyelitis (adem), multiphasic disseminated encephalomyelitis (mdem), and ms share similar clinical presentations, laboratory data, and neuroimaging abnormalities. subtle differences between the [dale et al., 2000; hynson et al., 2001; stonehouse et al., 2003 ]. in addition, hepatitis b; measles, mumps, rubella (mmr); bacille calmette-guérin (bcg); meningitis a and c; rabies; influenza; smallpox; and japanese b encephalitis vaccines, given within the six weeks prior to the onset of adem, have been suspected in triggering an autoimmune response [dale et al., 2000] . clinically, adem is more likely to present with ataxia, encephalopathy, bilateral optic neuritis, and seizures [hynson et al., 2001] . children typically have a polysymptomatic presentation with sensory, pyramidal, cerebellar, and bulbar symptoms [dale et al., 2000] . headache, fever, meningismus, and vomiting are more often associated with adem [brass et al., 2003] . unilateral optic neuritis and internuclear ophthalmoplegia are more common in ms [dale et al., 2000] . in adem and ms, the csf can be normal, although many patients have a lymphocytic pleocytosis or elevated protein. in adem, the csf white blood cell (wbc) count can be as high as 270 cells/mm 3 , with a mean around 51 cells/ mm 3 . in ms, the cell count is lower (range, 0 -130 cells/mm 3 ; mean, 18 cells/ mm 3 ) [dale et al., 2000] . the csf protein varies from 0.1 to 3.3 g/dl (mean, 0.69 g/dl) and 0.2 to 0.99 g/dl (mean, 0.38 g/dl) in adem and ms, respectively [dale et al., 2000] . ocb are seen in the csf in more than half of patients with childhood ms but can be seen in adem [dale et al., 2000; brass et al., 2003] . with considerable overlap between clinical and laboratory findings, mri is an important tool in determining the difference between adem and ms. both can affect the periventricular, sub-cortical, and deep white matter; deep gray matter; brainstem; cerebellum; and spinal cord. cortical white matter lesions are typically bilateral but asymmetric. in adem, lesions are less likely to be periventricular. also, adem more com1 yr of disease progression (retrospectively or prospectively determined) and two of the following: a) positive brain mri (9 t2 lesions or 4 or more t2 lesions with positive vep) f b) positive spinal cord mri (two focal t2 lesions) c) positive csf d note: if criteria indicated are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ms; if suspicious, but the criteria are not completely met, the diagnosis is "possible ms," if another diagnosis arises during the evaluation that better explains the entire clinical presentation, then the diagnosis is "not ms." a an attack is defined as an episode of neurological disturbance for which causative lesions are likely to be inflammatory and demyelinating in nature. there should be subjective report (backed up by objective findings) or objective observation that the event lasts for at least 24 hr. b no additional tests are required; however, if tests (mri, csf) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of ms. alternative diagnoses must be considered. there must be no better explanation for the clinical picture and some objective evidence to support a diagnosis of ms. c mri demonstration of space dissemination must fulfill the criteria derived from barkhof et al. [1997] and tintoré et al. [2000] as presented in table 4 . d positive csf determined using ocb detected using established methods (isoelectric focusing) different from any such bands in serum, or using an increased igg index. e mri demonstration of time dissemination must fulfill the criteria in table 4 . f abnormal vep of the type seen in ms. abbreviation: vep, visual-evoked potential. three of the following are required for demonstrating dissemination in space 1. at least one gadolinium-enhancing lesion or nine t2 hyperintense lesions if there is no gadolinium-enhancing lesion 2. at least one infratentorial lesion 3. at least one juxtacortical lesion 4. at least three periventricular lesions there are two ways to show dissemination in time: 1. detection of gadolinium enhancement at least three months after the onset of the initial clinical event, if not at the site corresponding to the initial event 2. detection of a new t2 lesion if it appears at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event note: a spinal cord lesion can be considered equivalent to a brain infratentorial lesion, an enhancing spinal cord lesion is considered to be equivalent to an enhancing brain lesion, and individual spinal cord lesions can contribute together with individual brain lesions to reach the required number of t2 lesions. based on data from barkhof et al. [1997] and tintoré et al. [2000] . monly affects the thalami and basal ganglia, with a greater tendency for symmetry in the latter [dale et al., 2000] . in adem, a repeat mri scan performed more than two months after the onset of symptoms often shows partial or complete resolution of lesions with no new lesions. enhancement after the administration of gadolinium can be seen on the initial scan; however, no lesions enhance on the follow-up mri in adem. in ms, both new and enhancing lesions may be present when the scan is repeated, although the time to develop new lesions is unpredictable. in the absence of clinical symptoms, new findings on mri are useful in differentiating ms from adem. mdem presents a challenging dilemma in diagnosing childhood-onset ms. the clinical presentation, laboratory data, and neuroimaging features of mdem resemble adem, both of which are monophasic illnesses. however, patients with mdem have a clinical relapse after their initial illness or develop new lesions on mri, suggestive of a chronic demyelinating disease or ms. despite the presence of new lesions on mri, suggesting dissemination in time, some investigators believe that mdem and ms are separate entities. a diagnosis of mdem should be reserved for patients whose relapses are caused by the same trigger responsible for the inciting event and occur shortly after presentation or within two months of discontinuing steroids [dale et al., 2000] . ms is a neurodegenerative disease that affects young adults and children, often women. linkage and twin studies demonstrate that individuals carry a genetic susceptibility to this disease [rice, 2004] . a susceptibility locus for ms has been identified on chromosome 6, specifically the major histocompatability complex (mhc) class ii alleles human leukocyte antigens (hla) dr15 and dq6. this association is seen in all populations. in sardinians, there is an additional association with dr4, and, in turks, there is an association with dr2 and dr4. in finns, there is an association of ms with myelin basic protein (chromosome 18); however, neither this association nor an association with any other myelin genes has been noted in non-finnish populations [kenealy et al., 2003] . aside from the mhc locus, other regions of interest identified from the united kingdom study for ms susceptibility are located on chromosomes 1, 5, 6p, 7p, 14q, 17q, 19q, and xp [chataway et al., 1998] . some of the genes in these regions include tumor necrosis factor [tnf]␣, interleukin [il]-1ra, il-4, and cytotoxic t-lymphocyte-associated protein 4 (ctla-4). aside from the genetic predisposition for ms, epidemiological data indicates that an environmental factor also plays a role [compston, 2003] . for some time, an infectious agent has been suspected in triggering an autoimmune response. this theory was supported by apparent epidemics that occurred in the faroe islands and iceland following world war ii [rice, 2004] . additional support for an infectious etiology was provided by further studies that showed elevated antiviral titers (measles, rubella, mumps, varicella/zoster, ebv, influenza/parainfluenza,coronavirus, htlv-1, borna, etc) in the csf of ms patients during an acute exacerbation [ sibley et al., 1985; panitch, 1994] . presumably, the elevated titers represent nonspecific activation of b cells in the nervous system. in addition, the ms literature is replete with the isolation of viruses from the brains of patients with ms including measles, coronavirus, retroviruses, htlv-1, hhv-6, and scrapie agent. current focus on infectious agents includes ebv, hhv-6, endogenous retroviruses such as herv-w, and chlamydia pneumoniae [johnson and major, 2003] . oldstone postulated that an environmental trigger activates the immune system by "molecular mimicry" in which an infectious agent has sequence homology to a myelin protein. following the infection, tolerance is broken and an immune response ensues with the appearance of autoreactive t cells (cd4 and cd8) [oldstone, 1998] . alternatively, the pathogen activates toll receptors that then initiate the cellular immune response with the production of il-12 and il-23 [vasselon and detmers, 2002; frohman et al., 2006] . the earliest pathological change seen in an ms lesion is oligodendrocyte apoptosis with microglial activation but lacking infiltrating lymphocytes [barnett and prineas, 2004; matute and pérez-cerdá, 2005] . older lesions have perivascular infiltration by lymphocytes, plasma cells, and macrophages; loss of myelin and oligodendrocytes; axonal damage; and reactive astrocytes. chronic lesions are sharply demarcated with a hypocellular center and axonal loss, perivascular infiltration by lymphocytes, and increased number of oligodendrocytes. in chronic silent lesions, there is a loss of axons and oligodendrocytes. lucchinetti et al. have grouped the neuropathological lesions into four types, each containing t cells [lucchinetti et al., 1996 [lucchinetti et al., , 1999 [lucchinetti et al., , 2000 . type 1 is characterized by a predominance of macrophages, type ii by the deposition of immune complexes, type iii by oligodendrocyte malfunction, and type iv by oligodendrocyte death. there is insufficient data to describe the pathology of ms in children. ms is an organ-specific autoimmune disease mediated by type 1 helper t cells (t h 1) that recognize components of myelin and induce an inflammatory process by recruiting other inflammatory cells such as macrophages. in patients with ms, myelin-reactive t cells found in the blood stream produce a cytokine profile consistent with t h 1 cells. in demyelinating lesions, t h 1 cytokines, such as interferon ␥, tnf-␣, and il-2, are expressed by these leukocytes. the chemokine profile also suggests a t h 1-mediated inflammatory process. nevertheless, ms is likely to be more than a purely t h 1-mediated disease because it is likely that cd4 cells, macrophages, b cells, and a paucity of regulatory t cells also play a role [merrill, 1992; sorensen et al., 1999; frohman et al., 2006] . therapy in ms targets four different aspects of a child's illness. first, disease-modifying drugs, or immunomodulators (id), are used to alter the biological activity of the disease, thereby preventing neurological disability. second, additional medications help alleviate symptoms such as fatigue, spasticity, bladder dysfunction, and depression. third, neuroprotective agents are being studied to prevent and repair nerve injury. finally, rehabilitation is needed to overcome physical handicaps. disease modifying, symptomatic, and neuroprotective therapies will be described in this review. in evaluating effectiveness of therapies that modify the biological activity of the disease in children, a major challenge is the inability to predict the outcome of the disease and the lack of good outcome measures. the goal of any disease-altering therapy is to prevent longterm disability which evolves over many years [goodin et al., 2002] . the efficacy of the newer therapies has predominantly been studied over a short time period. moreover, the expanded disability status scale (edss) that is used as an outcome measure in adult studies has not been validated for use in children. children with ms may have cognitive dysfunction, which has not been evaluated as an outcome measure, although the ms functional composite (msfc) places some weight on mental functioning. once again, the utility of this scale has not been established in children. currently, most studies use the short-term attack rate as an outcome measure as well as mri data to assess t2 disease burden, cerebral atrophy, and the appearance of t1 black holes. although there are very few trials that have included children, in this article we review therapies that are recommended for adults and, where data is available, highlight the pediatric studies. glucocorticoids, such as intravenous (iv) methylprednisolone, are the mainstay of treatment for acute attacks or relapses in ms [goodin et al., 2002] . they suppress the immune system in many ways, such as altering cytokine profiles, inhibiting the synthesis of matrix metalloproteinases, and reducing csf antibodies to mbp and ocb [kupersmith et al., 1994] . in 1970, a multicenter trial compared adrenocorticotropic hormone (acth) (80 u/day given intramuscularly [im] for four days with a 7-day taper) against placebo in 197 patients with acute ms [rose et al., 1970] . after four weeks, the authors found that acth accelerated clinical improvement, although there was no significant difference in the outcome. in another study, acth (80 u/day for one week followed by a taper) was compared with 1 g of iv methylprednisolone for three days. in this study, there was no significant difference between the two treatment arms [thompson et al., 1989] . subsequently, a number of studies have been published using glucocorticoids for optic neuritis, most notably the optic neuritis treatment trial. this multicenter study compared iv methylprednisolone for three days followed by oral prednisone for 11 days against a 14-day course of oral prednisone and a placebo group. for both primary (visual fields and contrast sensitivity) and secondary (visual acuity and color vision) endpoints, the group that received iv methylprednisolone had an accelerated recovery of visual function compared to the placebo group. the rate of recovery for the group receiving oral prednisone was in between the iv and placebo groups. at six months, there was no difference between the treated and the placebo groups [beck, 1988] . furthermore, the group receiving oral steroids had an increased number of recurrences of optic neuritis. in addition to their use in optic neuritis, high-dose ste-roids are also known to enhance the resolution of gadolinium-positive mri lesions [barkhof et al., 1991; burnham et al., 1991] . finally, abrupt discontinuation of steroids can lead to severe clinical, radiographic, and histopathologic relapses; therefore, an oral taper is recommended. although these studies were performed in young adults with rrms and cis, iv steroids (15-30 mg/kg/day given daily for 3-5 days followed by an oral taper over 14 days) are used in children with acute attacks that impair function. interferons (ifn␤-1a and ifn␤-1b) are recombinant proteins, which inhibit the adhesion and the migration of wbc across the blood-brain barrier, thereby blocking antigen presentation and the synthesis and transport of matrix metalloproteinases [harris and halper, 2004] . in addition, they may cause a shift from a t h 1 to a t h 2 response. in adultonset ms, ifn-␤ has a beneficial effect on the clinical and radiological outcome measures. because the drug is not marketed for the pediatric population, there are no recommendations available for dosing children. for older children and adolescents, adult doses are most often used. interferon ␤-1a (inf␤-1a) is available in a weekly im injection (avonex, 30 g) or a subcutaneous (sc) injection given three times a week (rebif, 22 g or 44 g). interferon ␤-1b (inf␤-1b, betaseron, 8 million international units (miu) or 250 g) is given sc every other day. for smaller teens or children younger than 10 years, the doses are often adjusted to minimize adverse events and increase tolerability, such as starting with a half-dose of avonex or betaseron or using the lower dose for rebif. in 2006, banwell et al. retrospectively studied dosing, safety, and tolerability of ifn␤-1b in 43 children diagnosed with ms who had been treated for an average of 29.2 months [banwell et al., 2006] . treatment was initiated at full dose (8 miu or 250 g) in 15 children, all of whom were older than 10 years of age. younger children were started at 25-50% of the full dose and slowly increased; two children, both under the age of 10 years, were unable to tolerate the dose escalation. none of the children had any serious adverse events. therapy was discontinued in 25 of 43 patients after being treated for a mean duration of 111 weeks for various reasons, such as perceived lack of efficacy, cost of medication, lack of adherence, injection pain, and change in diagnosis. nevertheless, of the 38 patients with confirmed ms, the annualized relapse rate was reduced by a mean of 50%. the side effects of inf␤ in children are similar to those reported by adults. fever is the most common side effect, reported in 50% of the patients [ghezzi et al., 2005] . additional side effects include headache, myalgia, flu-like symptoms, injection site reactions, fatigue, nausea, and asthenia [waubant et al., 2001; banwell et al., 2006] . the majority of these symptoms are transient. to alleviate side effects, children may be pretreated with acetaminophen, ibuprofen, or naproxen. laboratory abnormalities, such as elevations of liver function tests, can also occur. when present, a temporary discontinuation of the medication is recommended. often, the inf␤ can be restarted without a recurrence of the elevated transaminases [banwell et al., 2006] . ga is a random polypeptide composed of four amino acids (l-glutamic acid, l-lysine, l-alanine, and l-tyrosine) resembling myelin basic protein (mbp). this drug has a number of effects on the immune system including inhibition of antigen presentation, competition and displacement of bound mbp, conversion of cd4 t cells from t h 1 to t h 2 type cells, and induction of brain-derived neurotrophic factor (bdnf) expression [teitelbaum et al., 1992; neuhaus et al., 2001; aharoni et al., 2003; azoulay et al., 2005] . it also induces antigen-specific suppressor t cells which release anti-inflammatory cytokines thereby generating tolerance to self-antigens [harris and halper, 2004] . there are no trials similar to those conducted in adults that have primarily focused on the efficacy of this drug in children with ms. there are, however, reports of using this drug in children who were given 20 mg sc daily, the standard dose for an adult. in one child treated with ga, chest pain was reported; however, no other clinical or laboratory abnormalities were identified [ghezzi et al., 2005] . although inf␤ and ga have been used in practice, the long-term tolerability, side effects, and overall efficacy in the pediatric population is not yet known. in a multicenter italian study published in 2005, ghezzi et al. focused on effectiveness and tolerability of interferons and glatiramer acetate in patients treated before the age of 16 [ghezzi et al., 2005] . sixty-five cases were reviewed. the majority was treated with avonex (38), followed by rebif (18), betaseron (16), and copaxone (9). relapses were defined as the occurrence of new symptoms lasting more than 24 hr with objective findings of cns involvement in a previously unaffected patient or the acute worsening of preexisting symptoms lasting more than 24 hr and causing an increase of at least 1 on the edss. all four of the drugs substantially reduced the relapse rate with combined data showing a decrease from 2.8 to 0.5 relapses per year and similar results for the individual medications. the change in edss was not significantly different when comparing the first and last visit in the inf␤ subgroups; however, a statistically significant difference was seen in the ga subgroup (baseline: 1.1 ϯ 0.5, posttreatment: 0.6 ϯ 0.5, p ϭ 0.007). it should be noted that the patients on ga had overall lower disease duration when compared to the other groups and edss at entry was lower than that in the avonex and rebif/betaseron groups. natalizumab is a recombinant monoclonal antibody directed against ␣4-integrin. in experimental autoimmune encephalitis (eae), the animal model for ms, the expression of t-cell surface receptors (integrins) promotes adhesion and transport of these cells through capillary endothelial cells. this antibody against ␣4-integrin blocks the adhesion of activated t lymphocytes to endothelial cells thereby preventing these cells from entering the nervous system. this is the only selective immunomodulating drug for the treatment of ms. the results from the natalizumab safety and efficacy in relapsing remitting multiple sclerosis (affirm) and safety and efficacy of natalizumab in combination with interferon ␤-1a in patients with relapsing remitting multiple sclerosis (sentinel) studies in adult patients indicate that the annualized rate of clinical relapses was reduced by 68%, the number of new and enhancing mri lesions was reduced by 83%, and a decrease occurred in progression and prolongation of the interval before neurological deterioration, demonstrating the usefulness of the drug [polman et al., 2006; rudicket al., 2006] . although natalizumab had significant short-term beneficial effects, unfortunately, three patients who received this drug developed progressive multifocal leukoencephalopathy (pml). the relative risk of developing pml in ms patients on natalizumab is 1 in 1,000 [ropper, 2006 ]. moreover, the use of this drug may have other long-term effects, such as unmasking latent viral infections as well as other diseases that are dampened by immune surveillance. in children who have a malignant course of ms, the use of this drug on a short-term basis may be warranted. campath-1h binds cd52 antigen, which is present on the surface of all b and t lymphocytes, as well as some monocytes. it is a lympholytic antibody that has been shown to prevent relapses and the formation of new mri lesions in ms; however, it does not seem to have any effect on disease progression [paolillo et al., 1999] . furthermore, when campath-1h was initially used in patients with ms, a transient worsening of symptoms occurred due to the release of cytokines and nitric oxide (no) [moreau et al., 1996] . in vitro studies demonstrated that no can cause conduction blocks that could account for the transient worsening of symptoms with treatment initiation. pretreating with steroids can avert the cytokine release. rituximab is a humanized monoclonal antibody directed against cd20 and antigens found on b lymphocytes [valentine et al., 1989 ]. b-cell proliferation, as well as an increase in the mutations of their receptors, has been shown in the csf of ms patients. the b-cell response reflects the presence of a specific antigen in the cns. thus, the b cells have become another therapeutic target in ms. rituximab, a drug that depletes b cells, is currently being investigated in the treatment of ms [reff et al., 1994; frohman et al., 2006] . mitoxanthrone is an anticancer drug that acts by intercalating into dna thereby producing dna strand breaks and interstrand crosslinking. in the immune system, it causes the elimination of lymphocytes and reduction of t h 1 cytokines. the major side effects include cardiac toxicity, presenting as a cardiomyopathy with irreversible congestive heart failure, and increased risk of developing malignant tumors. nevertheless, this drug reduced the attack rate of patients with rrms by 66%, reduced the number of gadolinium-enhancing and new lesions on the mri, and reduced the clinical rate of progression of the disease [millefiorini et al., 1997] . given the toxicity profile, this is not a first-line drug for the treatment of ms in children. cyclophosphamide is a powerful immunosuppressive agent that has been used to treat relapsing-remitting and progressive forms of ms. side effects include alopecia, nausea and vomiting, hemorrhagic cystitis, sterility, and long-term risk of malignancy. the use of iv cytoxan (400 -500 mg/day with wbc counts about 4,000 per microliter) did not show any benefit for patients with progressive ms at 1-and 2-year follow-up after the initiation of therapy [hauser et al., 1983; likosky et al., 1991] . in a canadian study using 1,000 mg of cytoxan with a 3-year follow-up of patients with progressive ms, there was no significant benefit from use of this drug [canadian cooperative ms study group, 1991] . nevertheless, in a study of 256 patients with progressive ms, younger patients derived some benefit from the use of cytoxan [weiner et al., 1993] . methotrexate acts as a folate antagonist, thereby affecting dna synthesis in immune cells. it decreases proinflammatory cytokines and enhances suppressor t-cell function. the major side effects are nausea, headache, diarrhea, liver damage, and the risk of developing non-hodgkin's lymphoma. a small, doubleblinded study of low-dose methotrexate revealed a benefit for patients with rrms but not for patients with the progressive forms of the disease [currier et al., 1993] . however, in another study of 60 patients with chronic progressive ms, low-dose methotrexate was found to be beneficial and showed a reduction in the t2 diseased burden [goodkin et al., 1995] . azathioprine is an analog of 6-mercaptopurine that inhibits purine synthesis, thereby impairing dna and rna synthesis in b cells, t cells, and macrophages. its side effects are anemia, lymphopenia, alopecia, liver dysfunction, pancreatitis, reactivation of latent infections, and the risk of developing malignancies. in a retrospective analysis of seven studies that had enrolled 793 patients, use of imuran reduced the number of relapses; however, the drug did not seem to affect the course of patients with progressive ms or their disability [yudkin et al., 1991] . cyclosporine is a potent immunosuppressive agent that selectively inhibits helper t cells. side effects include hirsutism, headaches, nausea, hypertension, edema, paresthesias, nephrotoxicity, and abdominal pain and discomfort. studies conducted in london and amsterdam showed no benefit on the relapse rate but did show some effect on slowing the progression of the disease [rudge et al., 1989] . given the side effects of this drug, its use in ms is very limited [goodin et al., 2002] . cladribine, an adenosine deaminase-resistant purine nucleoside, is a potent immunosuppressive drug that is selective for lymphocytes. side effects include nausea, diarrhea, fever, fatigue, and leukopenia. although cladribine does not have a significant effect in reducing the relapse rate, it may slow the degree of disability. in addition, it reduces the appearance of gadolinium-enhancing lesions on mri [beutler et al., 1996; rice et al., 2000] . 3-hydroxy-3-methylglutaryl coenzyme a (hmg-coa) reductase inhibitors, also called statins, have been recently studied in a variety of cns disorders, including ms. statins disrupt the activation of proinflammatory t-cells by inhibiting signals from mhc class ii molecules [neuhaus et al., 2002] . they also decrease migration of leukocytes into the cns, expression of inflammatory mediators by t-lymphocytes and in the cns [stüve et al., 2003] . statins, such as simvastatin (zocor) and atorvastatin (lipitor) have been shown to inhibit and reverse chronic and relapsing eae [stüve et al., 2003] . atorvastatin induces stat6 phosphorylation and enhances the secretion of t h 2 cytokines (il-4, -5, and -10 and transforming growth factor [tgf] ␤) while inhibiting stat4 phosphorylation and secretion of t h 1 cytokines (il-2, -12, ifn-␥, and tnf␣) [youssef et al., 2002] . in small, shortterm studies, zocor decreased the number and size of gadolinium-positive lesions on mri scans without effect on progression and disability [vollmer et al., 2004] . the immunomodulatory effects of the statins offer promise in the treatment of ms, and their usefulness is being further investigated [neuhaus et al., 2004] . vaccination therapies are currently being developed that would alter the treatment of ms. vaccinations that promote the development of tolerance have been effective in eae [robinson et al., 2003 ]. in addition, t cell and t cell receptor peptide vaccinations have been studied in humans with ms [correale et al., 2000; bourdette et al., 2005] . none of the vaccines have been studied in children. iv immune globulin (ivig) blocks fc receptors on macrophages, alters the cytokine profile, and has antiidiotypic effects. ivig is typically used as an adjunct for acute relapses; however, its recurrent use has been studied in rrms. in a multicenter, double-blind, placebo-controlled study of 148 rrms patients given ivig (0.125-0.2 g/kg) monthly for two years, a reduction in the clinical attack rate (ϫ49%) with a possible reduction in the degree of disability (not significant) was observed [fazekas et al., 1997] . in a separate study, the number of total and enhancing lesions seen on mri was decreased by more than 60% in patients treated with ivig compared with placebo [sorenson et al., 1998 ]. thus, it appears that ivig may reduce the attack rate in rrms but probably has little effect in slowing the progression of the disease. although it does not alter the long-term course in ms, plasma exchange has been used to treat acute relapses, presumably by removing harmful antibodies. several groups have investigated this particular therapeutic modality for treatment of patients with progressive ms [hauser et al., 1983] . for some patients who had not responded to iv steroids, plasma exchange performed every other day for a total of 14 days provided a greater degree of improvement when compared with a sham-treated group [weinshenker et al., 1999] . some patients receiving plasma exchange improve very rapidly, which is unlikely due to the repair of the injured tissue. instead, the rate of recovery may be due to the rapid shifts in electrolytes that result in improved axonal conduction or the possible removal of an antibody that affects transmission of electrical impulses. although fatigue is a common and debilitating symptom is adults, children rarely complain of this symptom. the mechanism for fatigue is multifactorial and includes depression, excessive effort due to muscle weakness or spasticity, re-lease of cytokines, and sleep disturbance. therapies for fatigue in ms include the use of amantadine, modafanil, and pemoline. all have been shown to have modest beneficial effect in adults. when patients have involvement of the corticospinal tracts, whether it be due to lesions in the spinal cord or higher, treatment should include physical therapy, splints to prevent contractures, and stretching exercises combined with pharmacological treatments, such as diazepam (valium), tizanidine (zanaflex), baclofen (lioreseal), and dantroline (dantrium). less well established is the use of tetrahydocannabinol. for contractures that do not respond to stretching, alternatives include serial casting, botox injections, and tenotomy. in more severe cases, a baclofen pump, or rhizotomy or myelotomy, may be considered. hemiplegia in children is disabling, particularly because of the loss of dexterity. sensory impairment further aggravates movements of the hand. such children do not use the affected hand, which results in learned nonuse of that hand. recent studies indicate that such children benefit from intensive practice and forced use; restraint of the noninvolved arm appears to improve function of the affected hand, probably due to functional reorganization of the nervous system. patients with ms have a variety of paroxysmal symptoms that last seconds to minutes and are not associated with alterations in consciousness or any electroencephalogram correlate for seizure. paroxysmal sensory symptoms and motor symptoms, such as ataxia and lhermitte's sign, respond to low doses of carbamezapine, phenytoin, and acetazolamide. heat-sensitive symptoms can respond to potassium channel blockers with the caveat that these drugs can induce seizures. this is not an uncommon symptom in some children. nonsteroidal antiinflammatory agents are recommended. if they are not sufficient, gabapentin (neurontin), carbamezapine (tegretol), or amitriptyline (elavil) can be beneficial. in ms, axonal injury occurs early in the course of the disease with eventual transection of axons. factors that have been associated with axonal injury are cytokines, no, superoxide radicals, proteases, cd8 t cells, cholesterol breakdown products, abnormal expression of sodium channels and function of the sodium-calcium exchanger, and glutamine excitotoxicity [waxman et al., 2004] . when an axon is demyelinated, there is abnormal expression of voltagegated sodium channels with increased influx of sodium in an attempt to restore conduction. to compensate for this, there is a reversal of the sodium/calcium exchanger with efflux of sodium and an influx of calcium. this could result in calcium-mediated neuronal degeneration. this hypothesis has received some support from work on eae models where sodium channel blockers, such as flecainide and phenytoin, help preserve axons [lo et al., 2003; bechtold et al., 2004] . in patients with ms, mrs has demonstrated increased glutamate concentration, providing the underpinning for considering glutamate excitotoxicity. the increased glutamate could result from a decrease in glutamate transporters in glial cells and elevation of glutaminase, a glutamate-synthesizing enzyme, in microglia [werner et al., 2001] . however, increased glutamate acting through the ␣-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (ampa) and/or nmethyl-d-aspartate (nmda) receptors, which are present on neurons and oligodendrocytes, can result in calcium-mediated cell death. riluzole, a glutamate antagonist that has been used in infants with spinal muscular atrophy, blocks nmda and sodium channels and reduces the number of t1-weighted hypointense lesions on the mri scans of patients with ms [frohman et al., 2006] . because axonal damage is a feature of ms, promoting neurite outgrowth could be beneficial. however, axonal sprouting is inhibited by activation of the nogo receptor by agonists such as nogo, oligodendrocyte-myelin glycoprotein (omgp), and myelin-associated glycoprotein (mag). thus, blocking the nogo receptor could represent a therapy that would be of value in promoting axonal sprouting [wang et al., 2002] . in acute ms plaques, there is clearcut evidence for remyelination; however, this is minimal in chronic lesions. the recruitment of oligodendrocyte precursor cells to areas of demyelination is mediated via chemokine and cytokine receptors, a pathway that appears to be intact. once attracted to areas of damage, these precursor cells recapitulate the differentiation process; however, full differentiation of these cells may be dampened by macromolecules that are negative regulators of this process, such as activation of the notch pathway due to reexpression of the ligand jagged or the nogo receptor interacting protein. in the future, both of these targets may be sites for therapeutic intervention that will aid the process of remyelination. in addition, transplantation of stem cells or oligodendroglial progenitor cells may be a consideration [john et al., 2002; mi et al., 2005; frohman et al., 2006 ]. ms is best recognized for its relapsing and remitting clinical course. in fact, in both children and adults, rrms is the most common form, followed by the secondary and primary progressive forms. however, the prognosis for pediatric ms remains controversial. the edss has been used to quantify the disability associated with ms by assigning a functional score for multiple systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, and cerebral) [kurtzke, 1983] . patients with a score of 0 have a normal neurological exam. scores between 1.0 and 3.5 are fully ambulatory, whereas 4.0 -5.5 are ambulatory for short distances without aid or rest. patients with scores greater than 6 require assistance with ambulation as well as other activities of daily living. in 2002, boiko et al. compared the time to edss of 3.0 (mild disability in at least three domains or moderate disability in one area) and 6.0 (requiring intermittent or constant unilateral assistance to walk 100 meters with or without resting) in adult-and pediatric-onset ms [boiko et al., 2002] . on average, adults had a 50% risk of reaching edss scores of 3.0 and 6.0 in 10 and 18 years, respectively, after onset whereas disability in children was much slower, taking 23 and 28 years, respectively. in addition, 53.1% of children with rrms progressed to spms after an average of 17.7 years (sd 1.17 years). the 50% risk for conversion from rrms to spms was 23 years in children, whereas it was 10 years in adults. although this data suggests a slower disease course in children, the overall morbidity is typically greater when children reach adulthood. children have higher edss scores when compared to adults with ms of the same age [ghezzi et al., 2005] . ms is under-recognized in the pediatric population and presents new challenges in diagnosis and treatment. despite significant advances in neuroimaging, ms remains a clinical diagnosis. new guidelines allow earlier diagnosis, but they have not been reliably established in children, especially those younger than 10 years of age. in addition, these guidelines may not be sufficient to prevent the inclusion of monosymptomatic demyelinating disorders, which do not require long-term treatment. early diagnosis and treatment with immunomodulatory agents are critical to reducing the morbidity and mortality associated with this disease. although these drugs have been used in practice, more data is needed on long-term tolerability, side effects, and overall efficacy in the pediatric population. f glatiramer acetate-specific t cells in the brain express t helper 2/3 cytokines and brainderived neurotrophic factor in situ lower brain-derived neurotrophic factor in serum of relapsing remitting ms: reversal by glatiramer acetate safety and tolerability of interferon ␤-1b in pediatric multiple sclerosis comparison of mri criteria at first presentation to predict conversion to clinically definite multiple sclerosis quantitative mri changes in gadolinium-dtpa enhancement after high-dose intravenous methylprednisolone in multiple 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cell vaccination in secondary progressive multiple sclerosis low dose oral methotrexate treatment of multiple sclerosis: a pilot study acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children multiple sclerosis in childhood: clinical profile in 125 patients randomised placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis multiple sclerosis-the plaque and its pathogenesis multiple sclerosis in children multiple sclerosis in children: a clinical study of 40 cases with onset in childhood disease-modifying drugs in childhood-juvenile multiple sclerosis: results of an italian co-operative study disease modifying therapies in multiple sclerosis: report of the therapeutics and technology assessment subcommittee of the american academy of neurology and the ms council for clinical practice guidelines low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic 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the northeast cooperative multiple sclerosis treatment group a randomized trial of plasma exchange in acute cns inflammatory demyelinating disease multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage magnetic resonance spectroscopy in multiple sclerosis: window into the diseased brain the hmg-coa reductase inhibitor, atorvastatin, promotes a th2 bias and reverses paralysis in cns autoimmune disease overview of azathioprine treatment in multiple sclerosis key: cord-354608-1me3nopu authors: rabinowicz, shira; leshem, eyal; pessach, itai m. title: covid-19 in the pediatric population—review and current evidence date: 2020-09-19 journal: curr infect dis rep doi: 10.1007/s11908-020-00739-6 sha: doc_id: 354608 cord_uid: 1me3nopu purpose of review: coronavirus disease 2019 (covid-19) pandemic has major health and economic impacts. we review disease characteristics in children. recent findings: children comprise 1–2% of the diagnosed cases, and typically suffer mild disease. the median age of infected children is 3.3–11 years, and male/female ratio is 1.15–1.55. common symptoms in children include upper respiratory symptoms (26–54%), cough (44–54%), fever (32–65%), and gastrointestinal (15–30%) symptoms. substantial proportion (4–23%) are asymptomatic. death rates are up to 0.7%. risk factors associated with severe disease are neonatal age group, male gender, lower respiratory tract disease, and pre-existing medical conditions. vertical transmission was reported. multisystem inflammatory syndrome (mis), characterized by fever, multisystem organ involvement, and laboratory markers of inflammation, causes critical illness in > 50% of cases and is increasingly reported from endemic countries. indirect effects of the coronavirus epidemic include higher rates of psychiatric morbidities, education loss, unhealthy lifestyle changes, and increased child neglect. vaccines are in clinical trials and immunogenicity has not yet been shown in children. summary: overall, covid-19 has lower incidence and causes milder disease in children compared with adult patients. mis is a rare severe complication more common in children. more data on the efficacy and safety of antivirals in children are needed. emerging in late 2019, coronavirus disease 2019 (covid -19) has been spreading worldwide, with major health and economic impacts. by mid-august 2020, the world health organization reported over 23 million confirmed cases of infection with sars-cov-2 (severe acute respiratory syndrome coronavirus 2), resulting in more than 710,000 death worldwide [1] . according to current data, children show lower incidence of symptomatic disease and develop a milder course [2] [3] [4] [5] . we review the current evidence of epidemiology, clinical presentation, treatment, and indirect health consequences of sars-cov-2 on children. (pids) for references. the search was restricted to english language publications during january-august 2020. pathophysiology sars-cov-2 is an enveloped, positive sense single-stranded rna virus with a glycoprotein spike (s) on the surface. cell entry requires binding of the s protein to the cellular receptor ace-2 (angiotensin-converting-enzyme-2) and priming of the s glycoprotein by the host cell serine protease tmprss2 [6] . the milder morbidity in children, despite similar or higher viral loads compared with adults [7, 8] , is the focus of multiple studies but has yet to be fully understood. the differences may be partly explained by several characteristics of the pediatric immune system. according to the hypothesis by carsetti et al., the immune system of children is highly prepared to novel pathogens, due to high levels of innate igm antibodies and the ability to rapidly produce natural antibodies with broad reactivity, in addition to the production of the antiinflammatory interleukin (il)-10 by neonatal b cells [9] . additional suggested explanations are alterations in t cell populations in adults due to continuous antigen stimulation and thymic involution, varied levels of ace-2 expression in children, and the simultaneous presence of other viruses in the respiratory mucosa of children, competing with sars-cov-2 [10] . furthermore, children have fewer comorbidities and a stronger pulmonary regenerative potential than adults [11] . disease burden of covid-19 in children is difficult to determine because case definitions for screening, testing, and disease severity in children are not universal and the proportion of asymptomatic infected children is high. in addition, young children attending daycare may contract several febrile and respiratory illnesses in a course of a few months [12] , and it is plausible that sars-cov-2 test is not routinely performed. in reports from countries that were severely affected early in course of the pandemic, children comprise 1-2% the diagnosed covid-19 cases, underrepresented compared with other age groups [3, [13] [14] [15] . the median age of the diagnosed children ranges from 3.3-11 years in different reports, and data shows that children younger than 1 year are disproportionally represented [2, 3, [15] [16] [17] . like in the adult population, there is a male predominance [2, 3, [15] [16] [17] ( table 1) . the contribution of children in spreading the virus through the community is a field of uncertainty, mainly due to the high rates of asymptomatic infection at younger age groups. a recent report found that in only 8% of households of 40 sick children, the child was the suspected index case. in the reminder, the child developed the symptoms following or together with a sick adult [18] . the same finding was seen in a cohort of sick children from china [19] . however, these cohorts may have been evaluated when educational institutes were closed, so children were less likely to contract the disease outside the house. in addition, recent reports show outbreaks in a high school and a summer camp [20, 21] . this is an issue of concern considering recent evidence of equivalent or higher amounts of viral nucleic acid in children < 5 years with mild to moderate disease, compared with older children and adults [8] . as schools worldwide are set to reopen, proposed adjustments of the education system include universal masking, breaking classes into capsules, attendance on alternate days, outdoors classrooms, online lessons, temperature checks, and reconfiguration of ventilation and air conditioning systems [22, 23] . the rate of asymptomatic children, ranging from 4.4-23% of confirmed cases, is higher than reported in adults and most probably represents a significant underestimation as many asymptomatic children are not screened [2, 3, 16, 17] . the clinical presentation in adults ranges from mild illness to severe pneumonia. severe cases may suffer complications including acute respiratory distress syndrome (ards), acute cardiac injury, and thromboembolic complications. patients with severe disease have evidence of hyperimmune response with persistent fevers, elevated inflammatory markers (d-dimer, ferritin), and elevated proinflammatory cytokines [24, 25] . in children, respiratory symptoms are the most common, followed by fever and gastrointestinal symptoms [3, [16] [17] [18] (table 1) . anosmia and ageusia are commonly described in adults [26] but may be more difficult to elicit in young children and thus underreported [27] . the rate of children with critical illness ranges from 0.4-9% of confirmed cases, probably reflecting population bias since some reports include mainly patients diagnosed in hospitals [3, 4, [15] [16] [17] . data from the usa indicates a hospitalization rate of 8 per 100,000 population in children < 18 years, much lower than 164.5 per 100,000 in adults. however, a third of the hospitalized children required admission to the intensive care unit (icu) [28] . the analysis of critical patients may indicate which children are at higher risk. in various reports, half of the children admitted to the icu had an underlying medical condition [15-17, 28, 29] . factors associated with icu admissions were neonatal age group, male gender, lower respiratory tract disease, and pre-existing medical conditions [17] . infants aged < 3 months comprised 19% of the hospitalized children in a recent report from the usa. however, this may have been due to the diagnosis of neonatal fever and not due to disease severity [28] . because these data are driven from potentially biased datasets with over representation of symptomatic children, the association of young age and severity needs to be further investigated. death ensued in 0-0.7% of diagnosed children [2, 3, [14] [15] [16] . in the european cohort of 582 children aged 0-18 years, four children died, all were older than 10 years, two had no pre-existing medical conditions, one had undergone human stem cell transplant (hsct) 15 months earlier, and the other patient's condition was not specified [17] . in a multinational study from north america on children hospitalized in the icu, two patients, aged 12 and 17 years, died; both had unspecified pre-existing comorbidities and 1 had also prior gram-negative sepsis [29] . in a cohort from new york, one patient with metastatic malignancy died [30] . two cohorts from china reported one death each-a 10-month-old baby with intussusception [16] and a 14-year-old boy with no further details [2] . because mortality rates in pediatric cohorts are low, it is difficult to define risk factors and disease course leading to fatal result in pediatric population. a more distinct population among the pediatric population are neonates. early reports showed that infants of mothers infected in the last trimester have normal course and that amniotic fluid, umbilical cord blood, throat swab, and breast milk were negative to the virus [31, 32] . however, more recent reports show clinical infections in neonates and suggest prevention procedures, such as isolation of the infant and physical barriers after the delivery [33] [34] [35] . recently, vertical transmission with high placental viral load and neonatal compromise requiring resuscitation was documented [36] . when screening neonates, a possible contamination of the neonatal swab by maternal sars-cov-2 should be taken into account [37] , in addition to transmission of an undiagnosed maternal infection after birth. in a review of cases in the neonatal period, most of them were asymptomatic (20%) or had mild (48%) and moderate (20%) signs of clinical infection. the rate of severely ill patients was higher compared with older children (12% vs. up to 9% in the general pediatric population aged < 18 years). dyspnea was the most common sign (40%), followed by fever (32%) and feeding intolerance (24%) [4] . since may 2020, several highly endemic countries reported an exceptional high incidence of multisystem inflammatory syndrome (mis) in children [38] [39] [40] [41] [42] [43] . several case definitions were proposed, all include fever, elevated inflammatory markers, and organ dysfunction not attributed to another infectious cause ( table 2) . a minority of patients had been symptomatic prior to onset of mis onset, and the median interval from covid-19 symptom onset to mis onset is 25 days [44] . the higher rate of positive serologic tests compared with nasopharyngeal reverse transcription-polymerase chain reaction (rt-pcr) is suggestive of a late complication of the disease (table 3 ) [38, 39, 41, 44, 45] . according to the centers for disease control and prevention (cdc) report, in 27% of the patients, both were positive. similar to the acute covid-19 [30] , obesity is a risk factor for mis, present in a quarter of the patients in the cdc report [43] . suggested mechanisms for mis include viral mimicry, formation of immune complexes, and host immune cell activation due to viral superantigen sequences [46] . besides fever, the most common presentations of mis are gastrointestinal (diarrhea, vomiting, abdominal pain), cardiovascular, mucocutaneous (rash, mucus membrane changes, conjunctival injection), respiratory (including sore throat), headache, and limb and periorbital edema [39, 43, 44] . associated laboratory findings are elevated inflammation markers (neutrophilia, c-reactive protein, ferritin, erythrocyte sedimentation rate), thrombocytopenia, lymphopenia, elevated troponin and n-terminal pro-b-type natriuretic peptide (nt-probnp), hypertriglyceridemia, and elevated d-dimer and fibrinogen. some patients meet the criteria for macrophage activation syndrome (mas). the disease course is typically severe, with high rates of icu admissions, mechanical ventilation, and death (table 3) . severe course is characterized by shock, and coronary aneurysms [39, 41, 43, 44, 47, 48] . in addition to supportive care, children diagnosed with mis were treated with intravenous immune globulin ± aspirin, glucocorticoids, il-6 receptor antagonist, il-1 receptor antagonist, and tnf-α antagonist [48] . in the larger cohorts, from the usa, 2% of the patients died, one of them reported that half of them had underlying medical conditions [43, 44] . the clinical presentation was compared with that of kawasaki disease. however, children diagnosed with mis were older [38, 39, 44, 47] , showed a greater elevation of inflammatory markers [39] , and more frequent cardiovascular hemodynamic involvement [38, 44, 47] . treatment in children infected with sars-cov-2 consists mainly on supportive care, including oxygen and advanced respiratory support, hydration, and antipyretics [49, 50] . metered dose inhalers are preferred over nebulizers due to the decreased risk of virus dissemination [49, 51] . the inclusion of children in early phase clinical trials of novel agents is usually delayed; hence, trial data regarding efficacy and safety are scarce [52] . antiviral and antiinflammatory drugs may be considered in severely ill children and those at higher risk for severe disease, preferably as part of a clinical trial. severe disease is often associated with hyperinflammation and cytokine storm that may lead to acute respiratory distress syndrome [49, 53] . hence, medications targeted to the immune system were suggested, in addition to antivirals. several medications were used in hospitalized children [28, 29] , but not in the context of a clinical trial, making it difficult to accurately assess their outcome. the antiviral agent remdesivir was suggested as the preferred agent for treating covid-19 in children [50] . this is an adenine nucleoside analogue that interferes with the virus' rna-dependent rna polymerase. remdesivir was used in children suffering ebola infection, but pediatric safety data were not separately reported [54] . studies in adults showed it may have some benefit [55] [56] [57] , and clinical trials including children are ongoing. currently, the nih recommends using remdesivir in adults with severe disease [58] . the drug is available through the us food and drug administration emergency use authorization and compassionate use requests are reviewed by the manufacturer [59] . a clinical trial is currently evaluating the pharmacokinetics in children [58] . dexamethasone was found in the randomized-controlled uk-based recovery trial to reduce mortality in patients who require respiratory support [60] . despite the enrolment of children, it is not clear if the analysis included children, so further data is still needed. the nih guidelines state that dexamethasone may be beneficial in pediatric patients who require mechanical ventilation and suggest treatment according to individual considerations in milder cases [58] . another potential adjunctive therapy for covid-19 is convalescent plasma, with only scarce experience in adults [58, 61, 62] . shekerdemian et al. reported the use of convalescent plasma in a child, but the results were not discussed [29] . currently, there are insufficient data to recommend either for or against the use of convalescent plasma for the treatment of covid-19. clinical trials of covid-19 convalescent plasma in children are ongoing [58] . other drugs were initially suggested for the treatment of covid-19 and their use in infected children was reported [28, 29] . however, current recommendations are against their use due to questionable safety and efficacy [58] . the antiviral lopinavir/ritonavir (kaletra) is a protease inhibitor used for treatment of hiv infection, including young infants. its suggested mechanism of action is inhibition of the sars-cov-2 proteinases papain-like proteinase and 3c-like proteinase, which are key enzymes in polyprotein processing [50] . the nih recommends against its use outside of clinical trials in covid-19 due to lack of proven efficacy and concerns on its pharmacodynamics [63] . hydroxychloroquine was suggested as another potential treatment. it was previously shown to inhibit sars-cov-2 entry into cells and interfere with the glycosylation of the ace-2 receptor (virus' binding site) and inhibit its spread [64, 65] , and has additional host immunomodulatory effects [61] . there is no solid evidence for its efficacy in adults [66] . the drug is available and was previously used to treat children in other indications. due to substantial risk of qt prolongation, it is not recommended combining hydroxychloroquine with azithromycin. patients with known g6pd deficiencies should be monitored for hemolysis [50] . shekerdemian et al. reported its use in almost half of a cohort of children hospitalized in intensive care units in north america, but there is no analysis of the outcome of the specific treatment [24] . the nih recommends against its use except for clinical trials [58] . tocilizumab, an il-6 receptor antagonist, was used in adults with cytokine storm and hyperinflammation due to sars-cov-2 with conflicting results [53, [67] [68] [69] , and in a small number of children admitted to icu, but the outcome was not specified [29] . it is fda approved to treat cytokine release syndrome in children 2 years of age and older, and in the recovery trial used in children > 1 year [52, 70] . screening and monitoring infectious complications especially latent tuberculosis should be performed prior and during therapy [69] . the nih recently recommended against the use of il-6 inhibitors for the treatment of covid-19, except for clinical trials [58] . however, reports suggest its use in children who develop multisystem inflammatory syndrome (discussed later). other potential treatments are currently under evaluation, including antiil-1 (anakinra), interferon-beta, and ivermectin [49, 58, 61] . following the concern regarding the consequences of sars-cov-2 infection in children with chronic diseases, several guidelines were published. a statement endorsed by the us pediatric infectious diseases society has recently proposed that children with severe immunocompromise, severe cardiac, or severe pulmonary diseases may be more likely to experience severe covid-19 disease. obesity and diabetes should be also taken into account, especially with comorbidities [50] . the european academy of allergy and clinical immunology recommends treating children with allergic asthma, allergic rhinitis, or other allergy conditions according to usual guidelines. one exception to this is the advice to withhold biologics (antiil-5rα, il-4rα, and omalizumab) during acute covid-19 disease, since they are directed towards type 2 response, which may counteract the "cytokine storm" seen in severe covid-19 [71, 72] . the global initiative for asthma (gina) recommends continuation of inhaled asthma treatment and treatment with biologic therapies if needed. treatment with oral corticosteroids should be administered in the lowest possible dose in patients at risk of severe attacks [51] . patients with immunodeficiency, either primary, secondary to other diseases or medical treatments, are advised to strictly follow national precaution recommendations and in case of a suspected infection be in touch with their physician [71] . clear data regarding the severity of the disease in immunocompromised children are lacking. previously, immunocompromised children showed increased risk for severe lower respiratory tract disease due to seasonal coronaviruses [73 • ]. on the contrary, a report from bergamo, italy, stated that children who underwent liver transplant did not develop clinical pulmonary disease during the outbreak [74] . in adults, patients with malignancy and solid organ transplant recipients may be at increased risk of severe covid-19 disease and death. evidence regarding other types of immunocompromise is scarce [75] . according to the guidance endorsed by the pediatric infectious diseases experts, patients with mild to moderate immunodeficiency were not proven to be at increased risk, and those severely immunocompromised (e.g., severe combined immunodeficiency, < 100 days post-allogenic-hsct, hiv infection with cd4 count < 15% or < 200/mm 3 , treatment with costimulation inhibitors like belatacept or abatacept, highdose corticosteroids, and more conditions) should be considered for antiviral treatment. the panel suggests reducing t cell immunosuppression in infected children [50] . beyond the physiological manifestation of covid-19, other pediatric health issues during this pandemic bear mention. data show that lockdown, combined with intense fear of covid-19 contagion, led to a dramatic decrease in patients seeking medical care for other emergent issues [76] [77] [78] . in addition, ambulatory and screening services were postponed, including routine immunizations given to infants and children [79] . lower immunization rates may diminish herd immunity for some vaccine preventable diseases and lead to the reemergence of other infectious diseases in children. this trend may wane as the epidemic continues and routine health seeking behaviors resume. masking of the medical staff poses another barrier for the routine medical care of children, making communication with pediatric patients challenging [80] . school closure was a major step of infection control in many countries, affecting over 1.6 billion learners [81] . the consequences to the child's well-being of these steps are numerous: learning loss, (especially for those in low-income settings), lack of access to school-provided social assistance, reduced physical activity, and a significant harm to social life. in low-and middle-income countries, where access to education may be limited, some children may drop out as a result of the indirect impact of the outbreak [81, 82] . following school reopening, frontal teaching is partially replaced by remote online lessons. despite its innovative nature, this mode of studying is impossible to children affected by a lack of resources and requires extreme effort from children dealing with attention deficit hyperactivity disorder (adhd) [83] . a study from china found that children's adhd behaviors significantly worsened during covid-19 outbreak in comparison with their normal state [84] . the european adhd guidance group (eagg) adjusted its protocol, and frontal cardiovascular exam is no longer needed to initiate drug therapy, given normal personal and familial cardiac history and normal blood pressure and heart rate [85] . additional effects of the epidemic on mental health include anxiety and depression [86] [87] [88] . a survey among chinese school-aged children during lockdown revealed higher rates of anxiety and depression than usual [89] . safe, secure, and supportive domestic environment for children requires engaged parenting. however, during these times, parents are challenged by unemployment, remote work, economic instability, home confinement, health worries, and home-learning of their children [90, 91] . thus, children are at higher risk than usual to neglect abuse and domestic violence [91] [92] [93] . despite increased incidence of child abuse and neglect during covid-19 pandemic [93, 94] , the number of official reports to maltreatment lines in a few us states decreased sharply, raising a concern of under-reporting due to decreased contact with the insulted children. spotting signs for abuse and assessing home safety through distance learning should be practiced [93] . the economic impact of the pandemic is likely to deepen unemployment and poverty worldwide. the resultant food insecurity and malnutrition are concerning [95, 96] , particularly in young children who are the most vulnerable to its consequences [97] . on the other hand, in wealthier countries, quarantine, social distancing, and parental difficulties led to unhealthy lifestyle modifications among adolescents with increased consumption of unhealthy foods and reduction in physical activity that may lead to obesity and sleep disorders [98] [99] [100] [101] [102] . suggested steps to encourage physical activity during this period include incorporating physical activity into children's daily routine, using electronic devices for engaging children to physical activity, encouraging family members to join ongoing activities, and avoiding extended sitting [101] . the standard precautions face masks, hand hygiene, and social distancing are extremely difficult to implement in young children. alcohol-based hand sanitizers contain above 60% ethanol, and according to the cdc should be used with adult supervision in children under 6 years of age. the use of masks may be cumbersome in children. the minimal proposed age for mask use is 2 years old. in younger ages, the smaller airways may interfere with breathing and the child may be unable to remove the mask on his own. in older children, size fitted mask and education on appropriate mask removal are needed [103] . over 140 sars-cov-2 vaccine candidates are currently evaluated, including nucleic acid-based, viral vector vaccines, and inactivated or recombinant protein vaccines. most of them focus on immunity against the viral spike (s) glycoprotein [104, 105] . results of three vaccine trials were recently published: a phase 1 trial of an mrna vaccine that encodes the s glycoprotein [105] , a phase 1 trial of a recombinant adenovirus type-5 vectored expressing the s glycoprotein [106] , and a phase 1/2 trial of a chimpanzee adenovirus-vectored vaccine expressing the s glycoprotein (chadox1 ncov-19) [107] . all showed both humoral and cellular immunogenicity to the spike glycoprotein. the most common reported side effects include fatigue, headache, and fever, with higher rates compared with other vaccines [105] [106] [107] . none of the trials included children. in summary, children at any age may be infected with sars-cov-2, with reduced frequency and severity compared with adults, although clear epidemiologic data is still missing. in addition, the recently identified mis may pose an additional threat. data on the outcome of antiviral treatments, the safety and immunogenicity of vaccinations, and better specification of high-risk patients in the pediatric population are still needed. as the pandemic continues to evolve, it is still hard to fully assess or forecast the mid-and long-term effects of the resulting significant changes to society, economics, and human behavior on future child health and well-being. it is important that both medical and social efforts focusing on the pediatric population are undertaken to protect the children of the world allowing them to fulfill their enormous potential. conflict of interest shira rabinowicz, itai m. pessach and eyal leshem declare that they have no conflict of interest. human and animal rights and informed consent this article does not contain any studies with human or animal subjects performed by any of the authors. epidemiology 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play behaviours of canadian children and youth: a national survey promoting healthy movement behaviours among children during the covid-19 pandemic available from reduced physical activity during covid-19 pandemic in children with congenital heart disease to mask or not to mask children to overcome covid-19 draft landscape of covid-19 candidate vaccines an mrna vaccine against sars-cov-2 -preliminary report safety , tolerability , and immunogenicity of a recombinant adenovirus type-5 vectored covid-19 vaccine : lancet articles safety and immunogenicity of the chadox1 ncov-19 vaccine against sars-cov-2 : a preliminary report of a phase 1 / 2 , single-blind publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-017184-1ewi3dka authors: nan title: primary immunodeficiencies date: 2008 journal: pediatric allergy, asthma and immunology doi: 10.1007/978-3-540-33395-1_22 sha: doc_id: 17184 cord_uid: 1ewi3dka primary immunodeficiencies (pids), once considered to be very rare, are now increasingly recognized because of growing knowledge in the immunological field and the availability of more sophisticated diagnostic techniques and therapeutic modalities [161]. however in a database of >120,000 inpatients of a general hospital for conditions suggestive of id 59 patients were tested, and an undiagnosed pid was found in 17 (29%) of the subjects tested [107]. the publication of the first case of agammaglobulinemia by bruton in 1952 [60] demonstrated that the pid diagnosis is first done in the laboratory. however, pids require specialized immunological centers for diagnosis and management [33]. a large body of epidemiological evidence supports the hypothesis of the existence of a close etiopathogenetic relation between pid and atopy [73]. in particular, an elevated frequency of asthma, food allergy (fa), atopic dermatitis and enteric pathologies can be found in various pids. in addition we will discuss another subject that is certainly of interest: the pseudo-immunodepressed child with recurrent respiratory infections (rris), an event that often requires medical intervention and that very often leads to the suspicion that it involves antibody deficiencies [149]. structural genes, and also perhaps on the lack of 2/4 c4 genes [506] . mbl deficiency is due to one of three point mutations in the gene for mbl, each of which reduces levels of the lectin by interfering with the protein oligomerization [351] . in children with this kind of deficiency, the level of mbl is 4.9 mg/l compared to the 143 mg/l in controls [487] . regardless of whether the children are homozygote (hz) or heterozygote (het) in relation to a given mutation, the defect appears to be more consistent in small babies aged 6-18 months [487] , who show an immaturity in providing immune response to capsular bacteria and in whom low levels of opsonin are incapable of compensating for this [506] . the risk of contracting infections is similar in hzs [175] and hets [486] , though it persists throughout life in hzs because of an abnormal allele, while it exhausts itself in the hets, where the frequency of abnormality is similar to that of the general population [175] . anomalies in immunoglobulins (ig) and in opsonization have been observed, respectively in 13%-20% of children suffering from frequent asthma and igg subclass deficiencies. children suffering from cystic fibrosis also present an elevated prevalence of immediate cutaneous reactions to aeroallergens, and although without primary defects of adoptive immunity, they are susceptible to severe rris; therefore it may be possible that they suffer from the mucosal antigenic exclusion [61] . unlike asthmatic children, in whom a relatively high concentration of ige for respiratory viruses was observed [172, 173, 457] , positive skin prick tests (spts) are more common for aspergillus fumigatus [61] . the hypothesis suggested by these observations is that atopy derives from an unbalanced immune response to foreign antigens, with a consequent lack of their early identification or the capacity to neutralize or eliminate them. this hypothesis is based on the evidence that id precedes the development of atopy: in the taylor et al studies, 22 newborn babies, the children and/or siblings of atopic patients, presented a significant reduction in serum concentrations of iga when aged 3 months: this was transient hypogammaglobulinemia (hgg) of infancy (thi). the association of very low iga levels with atopy has been proposed again in the classic prospective study on the association of viral respiratory infections (vri) and the onset of allergic manifestations, which proved serum iga levels at the lowest normal levels in the children studied [173] . this data has been confirmed within primary immunodeficiencies (pids), once considered to be very rare, are now increasingly recognized because of growing knowledge in the immunological field and the availability of more sophisticated diagnostic techniques and therapeutic modalities [161] . however in a database of >120,000 inpatients of a general hospital for conditions suggestive of id 59 patients were tested, and an undiagnosed pid was found in 17 (29%) of the subjects tested [107] . the publication of the first case of agammaglobulinemia by bruton in 1952 [60] demonstrated that the pid diagnosis is first done in the laboratory. however, pids require specialized immunological centers for diagnosis and management [33] . a large body of epidemiological evidence supports the hypothesis of the existence of a close etiopathogenetic relation between pid and atopy [73] . in particular, an elevated frequency of asthma, food allergy (fa), atopic dermatitis and enteric pathologies can be found in various pids. in addition we will discuss another subject that is certainly of interest: the pseudo-immunodepressed child with recurrent respiratory infections (rris), an event that often requires medical intervention and that very often leads to the suspicion that it involves antibody deficiencies [149] . in several pids (table 22 .1) [61, 65, 76, 101, 162, 351, 414, 480, 514, 543] , atopic symptoms are present: gastroenteric and rhinitis in selective iga deficiency (sigad), severe ad in wiskott-aldrich syndrome (was) and hyper-ige syndrome (higes), in which it spreads over the entire body, and to which other allergic manifestations can also be associated such as asthma, rhinitis and angioedema. various acquisitions indicate that pid is also an opsonization deficiency, observed in 5% of the normal population [469] . in this disease, microorganism phagocytosis by polymorphonuclear (pmn) leukocytes appears annulled, and the patient is subject to severe infections supported by capsular bacteria: the deficiency, described in association with severe and recurrent infantile infections [175, 485, 487] , depends on the lack of mannose-binding lectin (mbl) [487] , its primary immunodeficiencies a possible atopy dependence on iga underproduction rather than on ige hyperproduction ( fig. 4.1 ): in children with levels of iga at the minimum normal level, and followed from birth until the age of 18-23 months, a greater severity of atopic manifestations and an increased cumulative incidence of asthma, ad and otitis media with effusion (ome) were observed compared to controls. the close links between id and atopy are confirmed by symptoms similar to ad present in some forms of was (70%), higes (85%), xla (x-linked agammaglobulinemia) or autosomal recessive (ar), ataxia-telang1268 chapter 22 primary immunodeficiencies proposed that in these patients cd4-th2 levels are sufficient for modulating ige synthesis, but cd8 t-cell levels are inadequate for inhibiting ige synthesis, which results in increased ige synthesis. this hypothesis is supported by the observation that omenn syndrome, was and especially higes, with an immunological phenotype characterized by a quantitative and qualitative reduction of cd8 t cells, are accompanied by extremely high levels of serum ige [61, 162, 196] . lymphocytes in subjects with normal levels of ige are incapable of producing them, not even after stimulation with polyclonal activators such as pwm (pokeweed mitogen) or ebv (epstein-barr virus), while patients with high antibody levels spontaneously synthesize in culture sige (specific) levels between 200 and 2,000 pg/ml, also releasing factors capable of increasing ige secretion (ige-pf) [287] . supernatant derivatives from the t cells of patients with higes are in fact capable of inducing in vitro the pre-b cells to increase ige production; furthermore, when the t lymphocytes in these patients are isolated on the basis of receptors for the ige fc fragment, the remaining cells release ige-pf [287] . considering the suppressive activity of human lymphocytes with cd8 phenotype on sige, it has been observed that these lymphocytes are able to suppress sige synthesis in patients with high antibody levels; similarly cd8 + cells from a bone marrow transplant (bmt) can suppress ige production in the hla-compatible recipient [478] . the study of patients with id associated with hyper-ige has supplied useful information concerning ige system biology, although the immune defect essentially responsible for ige increased production and for severe atopic iectasia (ata), thymic alymphoplasia, scid (severe combined id) (48%) [44] and, occasionally, by digeorge syndrome (dgs), id with hyper-igm (higms) now cd154/cd40l deficiency, selective igm deficiency, biotin-dependent carboxylase deficiency, cgd (chronic granulomatous disease), primary neutropenia, and in netherton, nezelof, omenn and shwachman syndromes [434] . other forms, in addition to those discussed, are associated with gastrointestinal symptoms: diarrhea and malabsorption of xla and thi, diarrhea in was and dgs, food-related allergies (43%) in sigad and also an elevated frequency of asthma [36] .among secondary id, only aids is associated with ad (chap. 23). the association between a deficiency of t cells and high levels of ige, observed in patients with higes, nezelof syndrome, ata, was and other diseases, has been known for some time (table 22. 2) [62] . experimental studies on animals indicate that there may be an inverse correlation between serum ige levels and t-cell functions: this could be attributed to a t-lymphocyte deficiency in atopics, genetically determined, which makes them more vulnerable to the camp inhibiting activity, and consequently causing an imbalance between the two subclasses of t cells, which could lead to ige hyperproduction and atopy development; however, in no case is there evidence of a relationship between cd8 deficiency, ige levels and allergic symptoms. it has been 1269 serum ige concentrations 54 7 chronic granulomatous disease 10 6 m-17 y <1-3, 160 88 hyper -ige syndrome 11 3-31 y 3150-40,000 11,305 nezelof syndrome 3 8 m-3 y 5-7,000 55 non-x-linked agammaglobulinemia 15 6-35 y 1-10 3 other variable immunodeficiency normal infants and adults 106 2-55 y 2549 55 data from reference [62] . m months, y years, gm geometric mean. manifestations has not yet been identified. the most interesting syndromes from this point of view are the three syndromes analyzed above, characterized by common clinical indications such as early ad onset, increased susceptibility to all varieties of pathogens, as well as an exceptionally high ige serum level [162, 394] ( table 22. 2). several pids have autoimmune features, including chédiak-higashi syndrome, cgd, complement deficiencies c1q, c1r, c1s, c2, c4, griscelli syndrome, higms (cd154 deficiency), lad (leukocyte adhesion deficiency), hla class i deficiency, hla class ii deficiency, omenn syndrome, was, and xlp (17) , which will be dealt with subsequently. in 25 children with a mean age of 44 months, autoimmunity was chronic and severe requiring prolonged immunosuppression, however with no spontaneous remission of such manifestations [44] . definition pids ( fig. 22 .1) [413] consist of a heterogeneous spectrum of congenital, individual and combined anomalies of the immune system (humoral deficiencies, combined deficiency of b and t cells, the complement, phagocytes, neutrophils, etc.), as well as syndromes and diseases associated with id that are traditionally classified as pids. the updated classification (table 22 .1) has divided ª100 pids into six main groups, also including secondary id with infections (first among them all aids) that cause deficiency and immunosuppression [414] . the classifications of pids is based on characteristic clinical features and specific alterations in immune status. advances in molecular genetics now make it possible to complete the table according to the types of genetically altered molecules involved [63] . to complete this data, see table 22.1 and table 22 .3 [236, 246, 407, 453] showing the behavior of antibodies and circulating b and t cells. pids occur infrequently and are highly heterogeneous in nature, relatively few centers gain extensive experience in the diagnosis, so it is difficult to estimate the prevalence of these disorders from routinely collected health statistics [33] . studies in 13 countries on all continents have included 10,895 patients: tables 22.4 and data concerning incidence has increased considerably thanks to a greater availability of specific tests and more widespread knowledge in the medical profession related to these pids, including ata [94] . however, because 1271 primary immunodeficiencies [236, 453] ; other data from [246] (omenn syndrome) and [408] (jak3). ada adenosine deaminase, id immunodeficiencies, jak janus-family kinase, pnp purine nucleoside phosphorylase, ø decreased, øø markedly decreased, ≠ increased, -absent, + present, n normal. a progressive. b not functional. predominantly t-cell defects 3 the total may not correspond to the sum of the cases because it may include some pid with very low incidences. the figures should be divided into the years that were considered. a incidence × 10 6 live births; the thi figure includes probable cases. thi 14 60 11 selective igg subclass deficiency 10 39 autosomal hyper-igm syndrome 3 34 2 selective antibody deficiency with normal igs 4 20 10 cellular and antibody id syndromes associated with other major defects 20 ata 7 149 12 wasp syndrome 31 34 2 digeorge anomaly 1 18 6 hie 4 63 6 nijmegen anomaly 1 immunodeficiency associated with or secondary granulocyte dysfunctions 9 defects of phagocyte number and function cgd 14 85 3 cyclic neutropenia 1 11 1 kostmann's syndrome 4 14 schwachman syndrome 1 complement deficiency -undefined 1 total pid 166 1, 428 122 time period 15 years 20 years 11/1983-12/1999 latin america includes eight countries. xla x-linked agammaglobulinemia, cvid common variable immune deficiency, thi transient hypogammaglobulinemia of infancy, scid severe combined id, was wiskott-aldrich syndrome, ata ataxia-telangiectasia, cgd chronic granulomatous disease. to be reliable and can also be used for other recessive x-linked pids to identify cell lines with genetic defects, as is the case of was [537] . one must, however, properly consider the phenomenon of mutations, that can render useless the inactivation method, as has been proved in was, in xla and also in scid, in which the mutation is not in the maternal t cells but in the germlines [389] . the main clinical aspects of humoral and cellular pid are schematized in table 22 .6 [80] ; further in numerous pids there is a deficiency of chemotaxis (table 1 .65) as in cgd [416] . in antibody deficiencies, current treatment, while waiting for genetic treatment to become available, complicated in xla by several btk mutations, is based on the prophylactic administration of ivig, combined with quick antibiotic treatment during infectious episodes. the genes responsible for id linked to chromosome x have been recently mapped on the respective chromosome bands (fig. 22. 2): the bands on the short limb are designated "p" and those on the long limb "q" (table 22 .1). this was possible thanks to the refinement of dna recombinant technology (rdna), including dna probes (sequences of radio-marked dna) and restriction fragment length polymorphism (rflp). the closer the gene segregates to rflp, the lower the chance that they might be separated by recombination phenomena when meiosis occurs: the identification of deficient genes allows early diagnosis, even prenatal, and if necessary gene therapy or bmts [76] . furthermore, the observation that numerous pids are transmitted with an x-linked modality allows a relatively simple diagnosis of males with a positive family history (fh); if fh is negative (40%-50% of xla cases) or there are females presenting a clinical pattern of pid, or when sporadic cases are caused by a new mutation, carrier identification is based on the study of immunologically normal female carriers, with two populations of b precursors, using x-chromosome inactivation analysis. this test does not take into account the existence of possible gene mutations and the availability of already affected relatives, and it is also relatively simple and fast [537] . molecular studies follow the hypothesis that, at an early stage during embryogenesis, one of the two x chromosomes is randomly inactivated in the cells of all tissues of female embryos (persisting as barr's chromatin) [300] . therefore in normal conditions, one has a cell mosaic that actively expresses for 50% the paternal x chromosome and for the remaining 50% the maternal x chromosome (lionization) [300] (fig. 22 .3a) [355] . in female carriers of xla, the cell mosaic expresses 50% for an x chromosome with btk in an active form and the remaining 50% for an x with a mutated btk (bruton tyrosine kinase). this means that in the carrier mother it is inactivated in preference to the x chromosome carrier of the defective gene in b, which matures therefore in an unbalanced manner (not randomly), while in all other cells activation occurs randomly. it follows that in fixed carriers only the b lymphocytes that have the x carrier of a normal gene complete the differentiating route, while the precursors that express the x chromosome with a mutated btk do not mature into b cells, but remain blocked [100, 413] (fig. 22.3b) . in x-scid, the study of fixed carriers follows the corrected lyon hypothesis, because the cells with a normal active x develop into normal t lymphocytes; however, when t precursors with a mutant x reach the stage where the x is needed, they do not find it and consequently do not develop: thus female carriers have only one normal and active x, instead of the random mixture of cells with one of the two active x [389] . the inactivation test appears predominantly b-cell immunodeficiency inherited in an x-linked trait, only 50% of males have a fh positive for pid; female cases are also known, supporting an ar trait [100] . classically affected subjects present levels of igg at <100 mg/dl, with very low circulating iga, igm and b cells (table 22. 3), in which are found, in addition to bm, pre-b lymphocytes in an almost normal quantity [100] . xla is characterized by a blocking of b-cell differentiation that results in an arrest of the evolution of pre-b1a cells: low levels of cytoplasmic igm and high levels of surrogate light (l) chains (cd179b) into later-stage b cells [348] .the b-cell differentiation arrest in the majority of xla patients appears to be homogeneous, with approximately 80% of the pro b-cell compartment being negative for cytoplasmic igm expression [349] . the size and nature of the residual more mature b-cell population (leakiness) varied among patients, independent of the type of btk mutation. further, it appears that the pro b-cell compartment composition in bone marrow (bm) of some xla patients can be influenced by low levels of wild-type btk mrna [349] . on the contrary, t cells are normal both in function and in number, as is thymus architecture, including hassall's corpuscles and thymus-dependent areas of spleen and lymph nodes. b lymphocyte zones are typically depleted, with an absence of gcs, plasma cells, and cortical and medullar differentiation compared to normal (figs. 22.4 and 22.5) and an absence of adenoidal tissue (fig. 22.6 ). the intestinal lamina shows a similar deficiency [227] , even if both b and t cells use the same recombination (chap. 1). in the bm, increased pre-b lymphocytes without cd19 and cd21 can be observed. the pre-b cells are capable of transcribing and translating microgram intracytoplasmic (ic) h chains, but not the l chains [453] , thus pre-b only form microgram chains not associated with v h , while only 5% of normal cells produce incomplete chains [278] . experimental data currently indicate that the defect lies in the xla gene mutations that codify for btk [505, 513] . the xla gene is expressed by b cells during differentiation, but is not transcribed in the t cells, thereby explaining the b lymphocyte maturative block at the pre-b level [61] (fig. 2.6 ), immediately after their appearance in the bm [302] . xla, however, presents a genetic heterogeneity, explained by mutations in the 5 btk domain (ph, th, sh3, sh2, kinase), with a frequency proportional to the pertinent domain dimensions [514] . the mutation size was ascertained by finding 175 mutations in 236 patients ( fig. 22.7) . equally, genes codifying for marker proteins and receptors that are essential for b-cell maturation and development are also involved: in fact many of these proteins, including btk, hm chains and surface proteins are crucial for b-cell differentiation [395] . studying chil-dren of both sexes with xla, various mutations of hm germline have been identified, in addition to deletions affecting the d, j h and cm genes and other gene alterations capable of blocking h chain synthesis on b lymphocytes [548] . an equivalent molecular defect was observed in an infant girl with xla, with differentiation block preceding the ig gene rearrangements by early pre-b cells [316] . there are also the so-called leaky forms, with absent or few b cells and various antibody deficiencies [240] , which can be attributed to individual mutations of btk [267] , for example in the non-kinase domain, which permits the expression of normal btk levels [427] . however, btk mutations can be even more detrimental for b lymphocyte proliferation compared to the total kinase absence [370] . xla is clinically characterized from its onset in male babies, at 5-6 months of life (but also at the end of the 1st year), when the maternal igg passive protection ceases. it usually attracts attention due to delayed growth and mostly recurrent and severe bacterial infections dominate (sinusitis, otitis, bronchitis, [476] . although representing the phenotypic picture of humoral id, confirmed as a separate deficiency [459] , xla associated with ghd is mapped in the same region as the x chromosome of the isolated xla. the observation of hz deletion of one or more c h genes for the h chains of ig in 5%-10% of normal patients has led to the identification of various polygenic deletions concerning the genes of one or more isotypes and subclasses [282, 414] . some subjects are lacking in genes of all or some igg subclasses, associated with iga 1 and ige deficiency, with no clinical symptoms in 94% of cases [282, 414] . in italy these deletions have a frequency of 2.7% and the expected frequency in hzs is of 1:1,400 [385] . only some of the families that produce l chains and not the k chains are known. in one family the molecular bases of the deficiency were ascribable to two different punctiform mutations, one in each cκ allele that prevented the formation of -s-s bridges between the k and h chains. the k:l ratio in human ig is 2:1, and the relative alterations can be observed in numerous primary or secondary ids [414] . only one patient is known with an l chain deficiency, hgg and rri (upper and lower respiratory tract) [508] . [61, 79, 302] . rotavirus and echo viruses also cause severe meningoencephalitis in 5%-15% of patients [100] . phenotypic variability may occasionally be present, as in a family spanning three generations [332] . in 33 patients with a median age of 9.4 years the median age at the xla onset was 8 months and the median age of diagnosis was 4 years, with a median diagnosis delay of 33 months. the common infectious diseases were pneumonia, otitis, diarrhea, sinusitis, and arthritis. the most common chronic infections were seen in 75.8% of the patients: in the respiratory tract in 93.9%, in the gastrointestinal tract in 75.8%, in the central nervous system (cns) in 33.3%, and in the musculoskeletal system in 21.2% of patients [324] . bronchiectasis, malabsorption, arthritis, autoimmune and tumor-related diseases are the most common complications, as well as edema, contractures, etc. (fig. 22 .8). one must predict the onset of bronchiectasis and intervene quickly with specific physiotherapy, because forms that are initially localized later spread, causing respiratory failure in older children and adolescents. one-third of all cases start with mono-or rheumatoid arthritis (ra) caused by ureaplasma urealyticum with a sterile exudate, which usually regresses following treatment with ivig [355] .anti-polio vaccinations with live attenuated viruses should be forbidden, because they can cause very severe pneumonia [278] . about ten cases of xla associated with ghd are known. in addition to reduced growth, clinical symptoms are typical of xla, though it is not a variant, sporadic cases have been described, occasionally associated with sigad (10%-20%) and more often with ata (80%) and susceptibility to infections [227] or without rris [385] , differentiating patients with probable pid from those with low levels of igg 2 (table 22 .7) [387] , in whom it may represent delayed maturation [450] . selective deficiency of igg subclasses presents three different aspects: ∑ total lack of a subclass ∑ two sd levels below average ∑ inability to produce antibodies relative to the subclass in question, even when hematic concentrations are normal [465] the following selective deficiencies are present [283, 465] : ∑ isolated igg 1 : deficiency in only a few cases has been described, also because this subclass represents 60%-70% of all iggs (the others account for 25% [igg 2 ], 6% [igg 3 ] and 3% [igg 4 ]), its absence is very probably an indication of an evident hgg; these patients usually have a reduced level of total iggs and react normally to antigens with a polysaccharide capsule. ∑ other combined id (cid): for example igg 2 +igg 4 , igg 2 +igg 3 , igg 1 +igg 2 +igg 4 , igg 1 +igg 2 , igg 2 +igg 3 + igg 4 , some of which are associated with a deficiency of iga or its subclasses [153, 465] . the association of sigad and defects of igg subclasses is explainable in view of ig production ontogenesis by b cells: one starts with igm, moving on to igd, and then to igg ending up with iga passing by ige [296] ; therefore the deficiency could originate with an immunological defect involving the t lymphocyte regulating work or b cells secreting ig, with an effect on the final stages of their production. in rare cases, more or less extended deletions in chromosome 14 have been observed, in the region that codifies the h chains; in most cases the genome is instead intact, confirming a possible defect in b lymphocyte switching [367] . very rarely this deficiency depends on gene hz deletions [227] . this pid is probably the most common of all (tables 22.4, 22 .5), especially in nonselected populations of caucasian origin [367] . it is defined by the presence of a serum level of iga <5 mg/dl and the absence of siga in the total deficiency; in the partial sigad levels are <5 mg/dl but <2 sd compared to normal levels for age, with measurable siga [367] . in total deficiencies, igm and igg levels can be normal [414] (table 1. 15), but igg 2 and igg 4 levels are low [153] . in several cases, the partial deficiency is transient [383] , returning to normal levels of iga in 50% of cases by the age of 14 and in 80% by 18 ( fig. 22.9 ) [383] . the sigad is transmitted sporadically; however, cases of multifactorial and dominant ar, with a variable or incomplete expression [105, 536] transmitted within the same family have been reported. functional alterations reflect on the final maturing process of b lymphocytes, given that about 80% of b iga + lymphocytes show an igm+igd+iga+ membrane phenotype, a normal aspect only in newborn babies [103] . studies on chromosome 18 have not led to conclusive results, because deletions in children with sigad are associated with mental retardation, facial dysmorphisms, failure to thrive, etc. an association with hla haplotypes situated on chromosome 6 is instead more consistent, and common in patients with cvid. interesting indications for understanding the pathogenesis come from molecular genetic studies that have allowed the formulation of a hypothesis of multifactorial origin, given that the combinations of more widely involved hla haplotypes and extended haplotypes involve the class i-iii genes, to the extent that they are more often encountered in the general population [105] .among the class iii alleles the most studied is the gene that dictates the c4a, among class i and ii the most common are a1, a28, b8, b13, b40, cw6, dr1, dr3, dr7, dqw1, associated with haplotypes such as a1, b8, dr3; b13, dr7; a1, b14 or a28, b14. other haplotypes are extended, such as b8/sco1/dr3, bw65/sc2 [1, 2] /dr1, bw57/sc61/dr7 and b44f/fc31/dr7, the first of which is increased in patients with a combined iga, igg 2 and ige deficiency [170, 313, 536] . the association with dr3 gives sigad a risk factor of 13 (table 18. 3). one hla supertype is also found in deficiencies of 21-hydroxylase with a late onset, suggesting an important locus for iga differentiation close to class iii hla genes [99] . it has been thought that to induce sigad a non-hla gene or an environmental penetration factor might be necessary, due to the possible sigad discordant expression in hla-identical twins [536] . however, the analyzed sequence of involved alleles showed a significant sigad correlation with some alleles belonging to hla-dq locus, composed of a protective allele with aspartic acid and a susceptible one with valine or alanine in the b chain in position 57 [358] . we have observed that the presence of aspartic acid ensures protection in dm. furthermore, the immunological deregulation extends to the typical formation of auto-antibodies and characterized by the presence of igg anti-iga [61, 196] . in these subjects, there is a wide symptom range, mostly represented by rris, allergic and autoimmune diseases (aids), among which is diabetes. allergic diseases are twice as common in partial deficiencies, unlike aids [507] . from a clinical point of view, the frequency of chronic diarrhea and malabsorption, associated with celiac disorders and giardia lamblia infestation are not surprising, considering siga's prominent iga 1 , igg 2 , igg 4 and ige due to deletion of ig h chain constant region genes were associated with undue susceptibility to infection [384] (see "rri"). a few cases of selective igm deficiency are known, associated with rris and various other symptoms [414] . igm deficiency was detected in four children with rris. isolated igm defect was present in two children, and two more children had an associated igg 3 subclass deficiency [160] . cvid includes a heterogeneous group of unhealthy conditions that have in common hgg and rris; it has an incidence of between 1:50,000 and 1:200,000 [414] . the inheritance of two susceptibility genes within the hla on the short arm of chromosome 6: one located near the class ii region and the other near the junction between the class iii and class i regions is a serious risk for the development of cvid [441] . there are autosomal dominant or ar forms also linked to sex; sporadic cases are the most common [413] . the molecular bases are not totally clarified as yet: the pathogenetic mechanisms may depend on b lymphocyte (80% of patients) and t lymphocyte (20%) defects [227] . the b-cell intrinsic defect is attributable to an alteration of the differentiating line at different stages of maturation, resulting in a poor formation of antibodies, with hgg of variable degrees, while in patients with xla the circulating b lymphocytes are virtually absent. the iggs are <500 mg/dl (with a reduction in all the subclasses: a normal phenotype is observed in only 14% of patients) [367] . more often there is a hierarchical order in the shortage: igg 3 < igg 1 < igg 2 < igg 4 [528] . iga and igm antibodies are <5-50 mg/dl [102] , reflecting the potential cd154 underexpression, implying an activation deficiency [150] or a t-b cooperation defect [232] . a study of t lymphocyte subpopulations indicates various subgroups of patients: 60% have t cells with scarce il 2 , il 4 and il 5 levels, while 30% have a reduced cd4:cd8 ratio, with an increase in cd8 bearing the cd57 marker, which suppresses igg production, elaborates normal il 2 levels and increases ifn-g production [232] . it can also accompany a deficiency of interleukins (ils: il 10 , ifn-g), suggesting a defect in the signaling mechanisms based on the tcr/cd3 [191] . a t-lymphocyte deficiency is therefore difficult to evaluate [527] , also because this could be a vri effect [232] . cvid can also be observed following congenital rubella or ebv infections; it can also be induced by some drugs such as phenytoin [355] . in 2/9 cvid families, 5 subjects were identified with identical large mutations in the icos (inducible costimulator) gene, expressed on the surface role in the formation of a barrier against the penetration of polypeptidic macromolecules through the intestinal mucosa. sigad therefore facilitates the penetration of food antigens through the mucosa followed by the formation of specific antibodies. for example, 50% of patients present cics and precipitins to cm, 23% to bovine anti-serum and 13% to anti-serum of calf fetus [106] . symptoms affecting the respiratory tract are also caused by the absence of siga, as in 30/36 children aged 1-15 with increased susceptibility to rris [327] . patients balance the siga deficiency with the sigm, but in some cases the compensation is insufficient for exempting them from rris and asthma [227] . sigad should be diagnosed on the basis of both serum and secretory iga, because normal levels in adults are achieved at different times (table 1. 15) . some drugs such as phenytoin (an anticonvulsant) can determine sigad, sometimes persisting in time after the drug has been discontinued. the clinical symptoms in these cases are not different from those of patients with sigad [507] . there is no random treatment; these patients do not benefit from therapy with ivig, even when enriched in iga. there are no counter-indications for obligatory and optional vaccinations [507] . whole blood or plasma transfusions containing iga can sensitize patients or cause anaphylactic shock in those already sensitized [105] . life expectancy is excellent; however, the random discovery of sigad in asymptomatic children should not be underestimated. they should in fact undergo periodic clinical and laboratory controls so as to identify as early as possible any possible pertinent symptoms. at the same time, there is the need to ensure a good life quality with adequate prevention of rris in those patients whose respiratory tract is affected [383] . sadni translates into the inability to respond to certain antigens, especially if polysaccharide. while some individuals are normal, others contract sinopulmonary infections. the reduction of igg 2 levels is more of an associative relationship than a random one; igg 2 levels, on the other hand, do not predict antibody responses. subjects who do not respond to anti-hepatitis vaccination may fall into this category [414] . in one retrospective survey at a pediatric tertiary care center, sadni was the most frequent diagnosis, accounting for 23% of id diagnoses [236] . there are cases of patients in good health, without ige due to gene deletion [62] . in two siblings, deficiency of of activated t cells, which interacts with the icos ligand gene expressed on b cells. an additional 181 patients with sporadic cvid were examined, and no mutations were found. only 9 in 226 patients with cvid screened thus far (<4%) have been found to have icos mutations. one unexplained feature of cvid is that the onset of clinical symptoms does not occur until late childhood or adulthood [429] . pid is variable either in the clinical and immunological pattern, or in the onset period, more common during the school years or in adults, but also between the ages of 1 and 3 [102] . the acute bacterial recurrent and/or severe lower respiratory tract infections (lrti) are characteristic: sinusitis (60% of pediatric cases), otitis media (47%), bronchitis, pneumonia (87%) and/or digestive tract infections (diarrhea 57%) [213] . the prevalence of infections caused by mycetes has increased as well as cases of pneumonia caused by pneumocystis carinii, a signal for cell-mediated immunity (cmi) [152] . the gastroenteric tract is dominated by symptoms similar to those seen in celiac disease, with generalized malabsorption, steatorrhea, lactose intolerance, protein-losing enteropathy, inflammatory bowel disease (ibd), saccharidase deficiency and malabsorption of vitamin b 12 and folic acid, supported also in this case by intestinal infestation caused by giardia lamblia [527] . the tumor necrosis factor receptor family (tnfr) member taci (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) mediates isotype switching in b cells. in 4/19 unrelated subjects with cvid and 1/16 subjects with sigad there was a missense mutation in one allele of tnfrsf13b (encoding taci). none of these mutations were present in 50 healthy subjects. tnfrsf13b mutations cosegregated with the phenotype of cvid or sigad in family members of the 4 index subjects. b cells from subjects with taci mutations expressed taci but did not produce igg and iga in response to the taci ligand april (a proliferation-inducing ligand), probably reflecting impaired isotype switching [87] . other characteristics are hemopathies, hepatosplenomegaly, autoimmune hemolytic anemia (aiha) and x-linked lymphoproliferative disease (xlp), and cutaneous and internal organ granulomas (which differentiate it from xla), in particular ra, thrombocytopenia, and neutropenia [102] . offspring of cvid patients are at risk throughout their lives for cvid development and should be monitored with a high index of suspicion [441] . based on experimental evidence, it has been hypothesized that iga-and cvid-associated deficiencies may be the extreme opposites of one clinical spectrum: there is a block of b-cell differentiation, different only in the isotype involved. both defects often appear in different members of the same family groups and more or less the same alleles are present [313] . the most accredited hypothesis is that a number of extended haplotypes of the hla system are shared, to which gene duplications, deletions and polymorphisms codifying for some class ii and iii alleles correspond [22] . in fact, a number of common hla haplotypes, especially belonging to class iii, are observed in patients, and at least two haplotypes in 77% of cases [518] , such as hla-dqb1*0201, hla-dr3, c4b-sf, c4a, g11-15, bf-0.4, c2a, hsp-70-7.5, tnfa-5, hla-b8 and hla-a1, postulating therefore the existence of a common genetic basis [22] , with a susceptible gene (6p21.3) possibly the association marker [61] . for example in five members of a large family with one of the two pids, duplications of the c4 genes were associated with a selected group of hla class ii and iii genes [22] . the fact that four members without pid also had these haplotypes indicates that their presence alone is not sufficient for expressing pid, leaving room therefore for other factors [22] such as overlapping relations with celiac disease. the analysis of linked genes has confirmed a strong association with locus 4a, suggesting that an important role in both pid is played by the gene codifying c4a or an adjacent one [162] . see "x-linked hyper-igm (or hyper-igd) or cd154 deficiency (xhigms)" for further discussion. unlike transient hgg that occurs when the maternal iggs gradually disappear from circulation (table 1 .15), in the original study by taylor et al iga levels had fallen, becoming regular in newborn babies with thi after 1 year, corresponding to the nonatopic levels [493] . it consists therefore of a pathological delay in the normal antibody production maturing process. walker et al have calculated that the prevalence of thi is 23 × 10 6 in children, equal to the prevalence of symptomatic sigad (24 × 10 6 ) [525] . in all 15 children the igg and in 12/15 (80%) the iga were <5th percentile, 9/15 (60%) had igm levels <20th percentile resolved around the 22nd month; further confirmation consisted in the fact that the 12 children had symptoms either of ad or of fa or food intolerance [525] . from table 22 .4 the mean incidence is from 1 to 61 × 10 6 . during 7 years 30 children aged 6-46 months were diagnosed with thi and an incidence of 4.3/year [124] . in other studies the main defect was in the igg: in one it had normalized between 18 and 40 months [129] , in another trial 13/247 babies (5.3%) exhibited at the age of 10 months an absence of serum igg levels and of specific antibodies to viral agents, which in eight children were detected before the serum igg levels returned to normal, whereas in basis is an il 2 r deficiency [529] , more precisely of the g receptor mapped on chromosome xq13 [347] . the sole deficiency of il 2 r is not sufficient for producing an immunological phenotype as devastating as scid [529] . because the g chain of il 2 r (il 2 rg), a shared component of il 4 r, il 7 r, il 9 r, il 13 r, il 15 r, il 21 r and il 23 r [351] , gc mutations interfering with its link to the ils deprive the lymphoid progenitor cells of the crucial signals for normal lymphocyte intrathymic development [424] . mutations in any of the genes: il 2 rg, il 7 ra, jak3, artemis, rag1, rag2, cd38, ada, cd45 cause scid [68, 69, 211, 247, 272, 347, 350, 365, 391, 424, 443] . a total of 264 il 2 rγ gene mutations have been sequenced, of which 169 are unique [341] . each of these mutations has resulted in γc deficiency with varying degrees of id. the mutations are distributed throughout the eight exons of the gene, as well as in the regions necessary for proper transcription and translation. the penetrance of each of the above il 2 rg mutations is unknown. exons 5 and 7 have mutation hot spots. the types of mutations identified include missense, nonsense, insertions, deletions, splice mutations, and mutations that affect rna processing and translation [341]. among 93 mutations in 136 patients, the most numerous (67%) are punctiform mutations (fig. 22 .11) plus one missense related to amino acid residues [390] , with a lack of jak3 and gc interactions [424] . in an atypical form, the substitution with residual cysteine of the arginine at position 115 appears to be decisive for gc chain expression, probably a mutation reversion at the basis of the molecular defect, with a numeric and functional t-cell normalization [475] . the mutations, by inactivating the common g chain, render the t cells of boys with scid-x1 unresponsive to several ils. the result is a block in t-cell development and a severe deficiency of mature t cells. b cells, although pre-two children normal igg levels were detected even before the appearance of specific viral antibodies. igg levels usually normalize at between 15 and 36 months [78] , at the age of 2 years (fig. 22 .10) or before 36 months of age in 33/40 children; however, 7/40 still had low ig levels at 40-57 months of age [253] . at 27 was in 9/30 children ig levels were still <2 sd for age and in 5/9 various igg subclass deficiencies were detected [124] . a prospective study with an 8-year follow-up found that igg and iga deficiency is normalized by the age of 6, but in a minority of cases this may be a prodrome of sigad or another humoral deficiency [315] . a study with a 10-year follow-up of 35 children with igg deficiency as well as iga deficiency in 34% of the cases, observed multiform clinical symptoms. since thi can gradually normalize, some children have low antibody titers, and others low igg levels. however, both groups experienced significant infections [110] . in some cases, thi is asymptomatic; in others infections, especially of the respiratory tract, are present. the designation of thi may be a misnomer, and an alternative designation could be added to thi such as "with recovery" or "with development of other dysgammaglobulinemia" [315] . general characteristics of combined t-cell/b-cell immunodeficiency are summarized in table 22 .8 [453] . t -b + scid is a heterogeneous group with an incidence of between 1:50,000 and 1:75,000 livebirths [509] . xlinked fh is positive in 53% of cases [68] . the genetic sent in normal or even increased numbers than in other forms of scid, are dysfunctional [347] . b cells do not mature or produce antibodies due to a complete b-cell differentiation arrest at the pre-bcr checkpoint, showing the absence of complete vdj recombination [350] . other forms are also known with an attenuated phenotype and a partial t-cell function [162] . typical scid-x1 represents the most common form, with 45.5% of cases [68] (5.5% in tables 22.4, 22.5) . in the thymus, there is a severe hypocellularity, without lymphocytes and hassall's bodies where thymic epithelial cells predominate without grossly evident corticomedullary differentiation (fig. 22.12 ). severe lymphopenia is often associated with eosinophilia; nk cells are within the norm or rare. the majority of in-fants with scid-x1 lack both t and nk cells (t -b + nkphenotype) [68, 391] . cd3 t cells, if present, are of maternal origin, because the block, as also in scid ar, occurs at the level of cd4 -, cd8 -, cd44 -, cd3 + and cd1a + ; developing t cells and cd83 + thymic dc are reduced >50-fold when compared to age-and gendermatched control thymus [209] (fig. 2. 2, pre-t, tn), thus scid t -b + . the study of other subpopulations distinguishes the scid subtypes: t cells are reduced in all variants, the absolute cord blood (cb) number is 158-2,400 lymphocytes/mm 3 (tables 1.34, 1.35, so that any count below 4,000/mm 3 is lymphopenic). moreover, in ada deficiency (adenosine-deaminase) there is a maximum reduction in total lymphocytes, in scid-x1 and in jak3 defi-1284 chapter 22 primary immunodeficiencies alies) and against a common t and nk cell drop [68] . furthermore, in two cohorts [68, 474] the affected females had the same phenotype, indicating a possible complex molecular defect [68] . there is no response to delayed spts, and there is an absence of lymphocyte proliferative responses to mitogens and to a specific antigen such as tetanic toxoid [61, 189, 474] . the average age at diagnosis was 4.4 months in 31 children [21] , similar to the ages reported in >200 children with scid from all causes [68, 474] . the male:female ratio is 3:1 and diagnosis is often missed or occurs too late to save the lives of those infected infants who may manifest gvhd early on with morbilliform eruption in the first few days of life due to the transplacentally acquired maternal t cells, intractable diarrhea resulting in a severe malabsorption ( fig. 22 .13), severe interstitial pneumonia (fig. 22. 14), or giant cells caused by anti-measles vaccination or bcg (bacillus calmette guérin), with death caused by chickenpox or infections caused by pneumocystis carinii, herpes, adenovirus, cmv (cytomegalovirus), etc. [63] . the absence of tonsils is observed and also lymphoid tissue [508] and thymus [453] hypoplasia. these children must be transferred urgently to a specialized center and be placed in a sterile room to receive a bmt [474] . on rare occasions, il 2 rγ mutations have caused an atypical mild scid that presented beyond infancy [390] . up-regulation of bcl-2 by an il 2 r lacking il 2 rb tyrosine residues leads to increased cell survival after il deprivation; astonishingly, this survival signal does not occur when gc tyrosine residues are absent. thus, if ciency, the number of b cells is the highest and that of nk cells is the lowest (b + >t ->nk -); nk cells on the contrary reach their highest levels in the ar form [68] . in scid there can also be b alymphocytosis [474] . this divergent data is, however, characteristic of t -b + nkmolecular defects (gc, jak3 defects), b + t -nk -(ada deficiency), or t and b (possible recombination anomgc-dependent signals are revealed only in the absence of il 2 rb tyrosine, il 2 r engages at least two distinct signaling pathways to regulate apoptosis and ccl-2 expression [293] . in two clinical series, patients with mutations in il 2 rg represent 28%-45% of all scid cases [68, 474] . children with il 2 rg mutations have lymphopenia in 95% of cases, with total lymphocyte counts <2,000/mm 3 (normal levels, 4,000-13,500/mm 3 ), based on clinical case series [68, 474] . all patients have very low or absent t cells, and approximately 88% have low or absent nk cells [390] . ar mutated genes on autosomal chromosomes have been identified in ada deficiency, jak3 deficiency, and rag1 or rag 2 deficiency [65] . the existence of b-and t-lymphocyte lymphoid precursor differentiated defect is particular, in some cases a rag1 and rag2 mutation, the two genes that activate vdj recombination [443] was observed; however, this rag2 gene function has been questioned [411] since a rag defect is more present in t -b -scid and the omenn syndrome [491] . in babies suffering from scid, there is a marked reduction of t and b lymphocytes (table 22. 3) and all in vivo and in vitro responses are absent. onset and clinical and histological pattern is similar to that of x-scid. the jak3 gene mutation (tables 1.31-1.33) variant has a frequency of 5.9%-7.4% [68, 408] among babies affected by scid and in the absence of t (3±2%) and nk cells (1±1%) [407] . the molecular base is the mutation affecting the jak3, which prevents it from associating with the gc chain and from sending signals to the abovementioned ils [354] and to other marker proteins belonging to the jak-stat complex [301] . at the origin is a lack of t lymphocytes that transform into the scid phenotype [424] . these patients present b + t -nk -: the b (70±12%) with iga equal to 2±2% [407] , and those with x-scid present a defective differentiation, but are capable of producing elevated levels of ige in the absence of other isotypes [354] . this data indicates that gc and jak3 are essential for t-and nk-cell development [407] . the clinical characteristics are identical to those in x-scid, with the difference that the scid-jak3 phenotype is also observed in females (50%) [408] . furthermore, a jak3 deficiency could be an important cause of scid ar and should be considered in all patients with the b + t -nkphenotype, without an x-recessive heritage [68] . in a 6-month scid-x1 infant presenting with a history of recurrent infection and failure to thrive, a novel splice mutation, gc-dependent, was described, characterized by near-normal count of functionally deficient nk cells (b + t -nkcell phenotype). cell surface gc expression was undetectable on nk cells and in trace amounts in the minority of b cells. t cells were absent, igg and iga undetectable, and igm were within the normal range [183] . bmt is not a perfect therapy, because b-cell function developed in 3/9 children, and nk functions normalized in 2/9 children after bmt [408] . the family pedigree shows an inbred family with consanguinity across five generations. two brothers were diagnosed with scid. one, at the age of 4 months, presented with persistent oral thrush, oral ulcers, and failure to thrive. he had no palpable lymph nodes and no thymus shadow on a chest x-ray film. the second was diagnosed soon after birth and the third brother has always been healthy. three other male cousins died in infancy from severe infections consistent with scid; a 4 th cousin presented with oral candidiasis at the age of 2 weeks and failure to thrive. no thymic shadow was detected on chest x-ray film and peripheral blood lymphocytes showed persistent lymphopenia. he had no lymph nodes, failed to reject a skin allograft and did not show an increase in the blood igg and igm antibodies for dtp after three vaccinations. the three affected patients were hz for a caet transition at nucleotide 394 in exon 4, leading to a proline to serine substitution (p132s) in the extracellular domain of il 7 r. the cousins and their parents harbored both wild and mutant alleles. this partial deficiency is sufficient to block t-cell development and lead to a scid phenotype. the fh of severe pid with multiple affected male infants strongly suggested an x-linked inheritance. nevertheless, this family consanguinity is in favor of an ar inheritance [410] . defective il 7 r expression caused in three patients a t -b + nk + scid, indicating that the t-cell defect in scid-x1 resulted from inactivation of il 7 ra signaling. thus il 7 r-mediated signaling is required for t cells but not for nk ontogenes. mutations in the gene for the il 7 r chain on chromosome 5p13 were found in all three patients [391] . these infants resemble those with other types of scid with respect to their susceptibility to infection and the absence of functional t cells and b cells. however, they differ in that their circulating lymphocytes are primarily nk cells. rag1 and rag2 are required for the rearrangement of tcr and bcr genes [343] . half of the patients with t -b -scid had mutations in their rag1 or rag2 genes, thus highlighting the crucial role of these genes in normal v(d)j recombination machinery [443] . rag-thymocytes lack a functional pre-tcr and hence arrest at the cd44-/cd 25+ stage of differentation [491] : without rag1 and rag2, mature ig and tcr genes cannot be assembled, and lymphocyte development is arrested at very early stages [53] . abnormalities of the chest, scapula and iliac bones and short and stumpy limbs [219, 224] . x-ray abnormalities are documented in fig. 22 .17: the absent thymic shadow and a notable cupping and flaring of the ribs' ends (arrows) can be observed, while histological studies of the chondrocostal junctions document their total cellular disorganization (fig. 22.18 ). this deficiency is the object of a great deal of attention because it was the first to be treated using gene therapy [313] . the lack of ada is observed in 14.8% of patients with scid [68] . the ada enzyme catalyzes the conversion of adenosine and deoxyadenosine into inosine and deoxynosine; although ada is found in all cells (cd26 anchors ada to the lymphocyte cell surface (table 1. 2), the deficiency damages above all the immune system [219] . table 22 .9 [219] summarizes the biochemical foundations of this pid. more than 50 ada mutations are known, including >30 amino acid substitutions, deletions and punctiform mutations or anomalies of the gene itself, such as exon 1 deletion and exons 4, 5, 7 and 9-11 mutations with a total of 15, nine of these in patients with ada-scid and six in those with a partial deficiency [219] . an additional 29 mutant alleles have been found (28 missense and 1 single-codon deletion) [21] . adenosine and deoxyadenosine are also apparent suicide inactivators of the enzyme s-adenosylhomocysteine (sah) hydrolase, with consequent accumulation of sah, a powerful inhibitor of virtually all cellular methylation reactions [61] . the accumulation of metabolites, including camp, deoxy-atp and 2'-o-methyladenosine, has a toxic effect on the cells by blocking dna synthesis and dividing and resting t lymphocyte proliferation [61] (fig. 22.15 ). four different clinical phenotypes have been described for ada-deficient subjects (table 22 .10) [219] , which cover a broad spectrum of immunological aberrations, from the complete absence of b and t immunity, indicating scid (85%-90% of patients) (the thymus in fig. 22 .16) to forms with a delayed onset or partial deficiency (10%-15%) [219] . in children, the delay between onset of symptoms and diagnosis has been estimated to average 2 months [474] . if clinical symptoms indicate an early onset, in addition to typical scid symptoms, there are also x-ray pathognomonic skeletal abnormalities of the chondrodysplasia type, especially this very rare ar type of scid was observed for the first time in 1959 in identical twin male infants who exhibited a total lack of both lymphocytes and granulocytes in their peripheral blood and bone marrow. it has a frequency of 1% in cases of scid [68] . the children are symptomatic in 90% of cases within the first days after birth [46] and is usually fatal within the 3rd month of life without a bmt [224] . due to the common stem cell (sc) non-maturation [224] , it is characterized by total block in lymphoid and myeloid precursor differentiation, therefore not only by an extraordinary lymphopenia, but also by a marked cytopenia in all sections (table 22 .11) [474] , in the spleen, in the lymph nodes and in the gastroenteric tract, and a high frequency of severe successive infections [474] . the thymus is always much reduced in volume, no hassall's bodies are seen [224] . seven of the eight infants reported by who with this defect died between 3 and 119 days of age from overwhelming infections; the eighth underwent complete immunological reconstitution from a bmt [543] . an additional three of five children who required two hscts (hematopoietic sct stem-cell transplantation) and received intensive conditioning therapy before haploidentical hsct (matched for 3 of the 6 hla loci) are alive and well an activated phenotype and poor functional capacity [117] . studies involving hla typification and dna polymorphism show that t cells belong to the host, ruling out, therefore, the etiology of maternal cell engraftment [117] , unlike other types of scid [474] . the absence of circulating b is also characteristic [117] , equal to 3.8%-7.1% of normal levels [474] , reaching 0% [520] , high ige levels (526 ui/l), hypereosinophilia reaching 3,000¥10 9 cells/l (normal, 0-0.5 cells/l), and low ig levels at the beginning [246] then declining to the point of agammaglobulinemia [520] , comparable to that in reticular digenesis (table 22 .11) [474] . the marked b-cell depletion can also bear rag1 and rag2 gene missense mutations that decrease the efficiency of vdj recombination, which results in impaired but not absent rearrangement of both bcr and tcr. four missense mutations were detected in the rag-2 in 6/8 patients [491] . in 13/16 patients (81%) the mutations affected the rag1 gene, and in 3/16 (19%) the rag2 gene [515] . increased ige is linked to th2 primary infiltration, with spontaneous production of il 2 ifn-g, il 4 , il 5 and il 10 , which is down-regulated by ifn-g therapy [437] . clonal expansion of vb14 + cd3 + , cd4 -cd8secreting high il 5 levels and low il 4 and ifn-g levels [318] could indicate an analogy with the fas (cd95) defect. t lymphocytes show an activated phenotype and a spontaneous apoptosis associated with reduced expression of bcl-2 gene product, and a higher cell death of cd4 + cd45r0 + cells [59] . given that high cd30 levels in the lymph nodes, skin and serum of three children generated th2 lymphocytes [95] , a th2-mediated pathogenesis is possible: the cd30 are th2 markers (chap. 1). as in human scid, b and t cells are found in mice with scid, but with a final repertoire that is decidedly oligoclonal and lacks the heterogeneity characteristic of a normal immune system, so lymphopenic scid and omenn syndrome could be two aspects of the same disease with different clinical expressions, especially of time [224] . clinically, young babies soon after birth show a generalized exudative erythroderma and desquamation, often mistaken as ad, alopecia, widespread lymphadenopathy, hepatosplenomegaly, persistent and profuse diarrhea, failure to thrive with malnutrition ( fig. 22.19) , aiha, recurrent infections caused by common and opportunistic germs ( fig. 22 .20), and markedly elevated serum ige levels [136, 241, 474, 520] . this outline included four babies from the same family with the same symptoms until death occurred at 10-19 months, but who did not present hypereosinophilia and were diagnosed as dm [375] . differential diagnosis may be challenging since omenn syndrome and gvhd show dyskeratosis and basal vacuolation, but the first always shows acanthosis and usually parakeratosis. gvhd shows a flat epidermis and rarely parakeratosis. both can be distinguished after immunohistochemical staining for cd45 and cd68, which shows predominantly lymphocytes in the dermal infiltrate in omenn syndrome, and relatively more macrophages in gvhd [438] . with myeloid and t-and b-cell lymphoid reconstitution [46] ; another child is alive and well after 32 months [13] . b-scid, characterized by increased cell sensitivity to radiation secondary to mutations of the artemis gene, could carry a poorer prognosis because of defective repair of dna breaks [406] , occurring around the time of bmt, from the effects of chemotherapy, infections, and gvhd [206, 247, 332] . one group of patients with scid with an additional sensitivity to radiation was found to harbor large deletions or truncation mutations in the artemis gene mapped on chromosome 10p [65] , implying a role for artemis in dna double-strand break repair, which is mutated in human scid [350] . omenn syndrome is classified as a scid because newborn babies exhibit symptoms similar to a gvhd, due to 1a antigen expression and cd1a absence [241] , and because it can coexist in families with alymphocytosis [117] . this is an ar syndrome with an unknown pathogenesis, sharing characteristic clinical and immunological abnormalities with t + b -scid [515] . severe cutaneous lesions with hyperkeratosis, apoptotic malpighian necrosis and basal membrane destruction can be associated [241] . no lymphoid cells or hassall bodies are found in the thymus [241] . the immunological structure reveals histiocyte infiltration of the skin, bm and lymph nodes, with proliferation of t infiltrating the epidermis and the enteric mucosa, increased t cells with 1289 combined t-cell and b-cell deficiency igg (g/l) 7 2.28-6.16 igm (g/l) 0 neutrophils (cells/ml) 200 1,000-8,500 data from [474] . in a child with scid and circulating t cells within the norm, a gene transcription deficiency was ascertained [414] . a male infant of first cousin parentage presented at the age of 6 months with cmv pneumonia, persistent oral and esophageal candidiasis, adenovirus gastro-enteritis, and failure to thrive. he developed lymphadenopathy, hepatosplenomegaly, iron deficiency anemia with no evidence of hemolytic anemia, and chronic inflammation of his lungs and mandible. biopsies showed extensive lymphocytic infiltration of his lung, liver, gut, and bone. serum igg and igm were elevated, but iga was low. he had t-cell lymphocytopenia, with an abnormal cd4:cd8 ratio of 1:1. the t cells responded poorly to anti-cd3, phytohemagglutinin and other mitogens, and to il 2 . he was found to have a truncated mutation of the il 2 ra chain (cd25). he was given a successful allogeneic bmt after cytoreduction [452] . about 225 cases have been reported, [75, 290, 539] , 78% [75] or 100% [539] of which have the x-linked form of cd154 deficiency [75] . patients are generally male, but there can be a non-x-linked form [224] , in which 22% of patients are females [75] . an estimated minimal incidence was calculated of 1 in 1,030,000 live births. over half of 79 patients developed id symptoms and were diagnosed by 1 year of age, and over 90% by 4 years of age [539] .although carriers of xhigms are considered to be asymptomatic, an extreme lyonization of the normal x can lead to a mild expression of the xhigms which is similar to cvid [118] . it can be secondarily caused by environmental factors and also stem from congenital rubella [278] : this indicates its heterogeneity. mutations in the tnfrsf5 encoding cd154 in xhigm patients result in a lack of b-cell signaling by activated t cells [53] . however, 21 boys out of 56 failed to express cd154, and tnfrsf5 mutations were found in 20 of these boys, whereas no tnfrsf5 mutations were found in 16 boys with weak expression of cd154 [184] . as a result, xmigm b cells fail to undergo isotype switching and produce only igm due to a defect in the rna editing enzyme, activation-induced cytidine deaminase (aicda), an enzyme expressed only in b cells and required for the processes of class-switching and somatic hypermutation of ig genes [357] . the marked reduction of igg (<150 mg/dl), ige and iga is accompanied by a sharp increase in mature igm and circulating igd, but b cells do not express other ig [227] . interestingly, 25% of patients with confirmed xhigms who had tnfrsf5 mutations had low concentrations of igg, iga, and igm. most of the remaining patients with xhigms had the classic pattern of normal or raised igm with low concentrations of iga and igg [184] . the cd154 gene defect is usually expressed on the membrane by activated t lymphocytes, which therefore cannot bind b-cell cd40 [266, 346] . figure 22 .21 shows 75 cd154 localizations and mutation frequencies, in 39.5% of cases mistakenly. for example, a sense codon substitutes for a missense one, creates a premature stop signal: therefore specific pertinent mutations, such as g144e, tunistic infections. this disorder is related to mutations in the gene that encodes the nuclear factor kb (nf-kb), which is required for activation of the transcription factor nf-kb, or nemo (nf-kb essential modifier), also known as ikk (inhibitor of b kinase). the phenotype observed in x-higms-eda patients shows that the putative zinc-finger domain of nemo has a regulatory function and demonstrates the definite requirement of cd40-mediated nf-kb activation for b cell ig classswitching [233] . three other genes, expressed by b cells, have been associated with the higm phenotype giving place to higm 2-4. mutations of activation-induced cytidine deaminase (aicda) (higm2) and uracil glycosylase (ung) (higm4), both expressed by follicular b lymphocytes, lead to defective class switch recombination and somatic hypermutation. mutations of cd40, the cd154 receptor, cause a rare autosomal form with a clinical phenotype similar to cd154 deficiency (higm3). these rare pids may shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes [146, 355] . early treatment with ivig associated with antibiotic prophylaxis have reduced the incidence of life-threatening infections and improved the growth of children with higms [290] . cycles of g-csf (granulocytecolony stimulating factor) in the presence of severe neutropenia are advised [290] . substitute therapies with soluble forms of recombinant or gene type cd154 [76] are being studied. a recent review of cd154-deficient patients showed that 75% develop liver disease and only 20% survive into the third decade of life [290] . bmt has a successful outcome in young children (65%); older patients with more ad-can interfere directly with the link site for cd40 ( fig. 22.22 ). consequently the signal which indicates that b cells should begin isotype switching, limited to the production of low-affinity igm, is missing [346] . without isotype switching, gc formation is minimal [508] (fig. 22 .23) and follicular dendritic cells (fdcs) are reduced in number, also having an abnormal phenotype [147] . as shown by figs. 1.31-1.33, the lack of cross-linking of cd40 by cd154 results in b-cell failure to up-regulate cd80 and cd86, important costimulatory molecules that interact with immunoregulatory molecules on t cells such as cd28 and ctla-4. two patients with normal levels of cd154 have also been described [359] . as in males with xla, infections start during the 12th month, those most often observed are otitis, pneumonia or sepsis cased by pyogenic bacteria, opportunistic infections, in particular caused by pneumocystis carinii [290] , and also ulcerative stomatitis, ra, neutropenia, aiha, lymphoproliferating complications and type b gastroenteric lymphomas with igm [224, 413] . the most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (urti) (49%-87%) including sinusitis (43%) and recurrent otitis (43%), lrti (82.1%) recurrent/protracted diarrhea (34%-55.3%), cns infections (12.5%-14%), sepsis (13%-14.3%), cellulitis (13%), hepatitis (9%-16.3%), and osteomyelitis (1%) [290, 539] . lymphoid tissues are normal or hyperplastic [75] . recently, a rare form of higms associated with hypohydrotic ectodermal dysplasia (eda) characterized by the absence or hypoplasia of hair, teeth, and sweat glands has been described. unlike patients with higms, these patients failed to have a history of oppor purine-nucleoside phosphorylase (pnp) deficiency, ar, for which 35 patients have been reported [53] , is characterized by the absence of an enzyme necessary for the catabolism of purines, which converts inosine, deoxynosine, guanosine and deoxyguanosine into hypoxanthine and guanine ( fig. 22 .15); the responsible gene has been mapped to chromosome 14q at position 13.1 [414] . this has also been observed in 33 patients with nezelof syndrome [304] . a variety of mutations have been found in the pnp gene in patients with pnp deficiency [432] . although ada and pnp are both purine salvage pathway enzymes, pnp deficiency does not lead to as severe an id as ada deficiency. patients have considerably reduced concentrations of serum and urinary uric acid. numbers of t cells fall progressively, more than that of b cells (table 22. 3), just like the proliferating responses to mitogens and antigens, especially because pnp deficiency causes an intracellular accumulation of deoxy-gtp (guanosine triphosphate) inhibiting ribonucleotide-reductase and t-and b-lymphocyte proliferation, so combined t and b defects are critical. pnpdeficient patients are as profoundly lymphopenic as those with ada deficiency, with absolute lymphocyte counts usually <500/mm 3 . ig levels and production of specific antibodies are all normal [19] . onset may be early, as for scid, but also delayed until the age of 3-5 years. the clinical pattern is dominated by recurrent bacterial, viral and fungal infections, with an abnormal susceptibility to opportunisic germs. two-thirds vanced liver disease may die because cryptosporidia infection that has progressed rapidly following pretransplantation cytotoxic conditioning therapy [252] . therefore, a patient with end-stage liver disease related to cd154 deficiency first received a liver graft, and as soon as liver-graft function was satisfactory, bmt was performed with a nonmyeloablative conditioning protocol of fludarabine and melphalan [208] . the screening for cd154 deficiency should include children with severe rri, and with dysgammaglobulinemia with a normal or increased igm level [197] . conventional allogeneic hsct from an hla-matched or a matched unrelated donor (mud) is curative and feasible, if performed before significant infections and organ damage occur [503] . an approach for high-risk patients including nonmyeloablative hsct was workable in a retrospective analysis of 38 european patients undergoing hsct for cd154 deficiency in eight european countries between 1993 and 2002. the donor sc source included 14 hla-identical siblings, 22 muds, and two phenotypically matched parental stem cells (scs) (12 tcd [t-cell depleted]). of these patients, 12 (32%) died from infection-related complications, with a positive result in 68.4% of patients [180] . carriers can be detected, and this is useful for making a prenatal diagnosis [407] . of patients suffer from neurological alterations, ranging from spastic symptoms and alterations, etc., to mental retardation and one-third from aids, the most common of which is aiha. the consequence of severe infections, generalized vaccination, severe chickenpox, lymphosarcoma and gvhd caused by blood transfusions in the first decade of life is death [304, 397] unless bmt is successful [25, 58, 67, 83, 98] . however, poor neurodevelopmental progression may result [25] or may not [98] . since the biochemical bases of pnp and ada deficiencies are similar, it is hoped that genetic treatment will also be effective in children with this pid [76] . this deficiency of hla molecule expression occurs in the more severe forms of pid if they are class ii: about 80 cases [140, 428] are known of this ar syndrome [140] , heterogeneous for the numerous complementation groups the patients are divided into [76] . hla class ii molecules are absent in all tissues [400] , to the extent that the cells of patients maintained in cultures for years preserve the negative phenotype [400] . there is a deficiency of class ii gene transactivator (ciita) codified by chromosome 15, the expression of which plays an important role in t-cell activation: its absence makes class ii gene expression impossible [473] . this function is shared with another protein mapped on chromosome 2, rfx5, with a binding site in the promoter region of genes codifying class ii chains [401] . two additional class ii-specific transcription factors are rfxap and rfxank [314] . these act on the class ii promoter region and are essential and also nonreplaceable, to the extent that alternative routes cannot compensate for their absence [311] . furthermore inactivation, or the deficiency of these factors, has a specific effect on the genes dictating hla class ii, the li chain and hla-dm, because there is no indication that other regulating systems may be involved [401] . the absence of hla class ii is associated with a cd4 lymphopenia. hla class i expression is normal in the patients tested and cd8 lymphocyte numbers are not reduced [428] . interestingly, in a twin study, despite the deficiency, there were antibody responses and class ii-dependent t cells; hence the authors envisage that this represented a hla class ii residual expression below the test sensitivity [540] . the clinical outline is dominated very early on, before the age of 6 months (range, 2 weeks to 12 months) [428] , by severe and recurrent gastroenteric and pulmonary infections, with a severe and prolonged course, associated with malabsorption and failure to thrive [77] . bacterial and viral infections, bronchopneumonia, hepatitis, cholangitis, viral meningoencephalitis and various autoimmune manifestations are common complications [140] . even though an hla class ii deficiency is clinical-ly less severe than scid, the result is uniformly fatal during the first or second decade of life [162] . the most evident immune defect consists in the complete lack of reactivity to exogenous antigens, which in vivo reflects an anergy to spts, as well as the complete lack of hla class ii expression and absence of cellular and antibody responses to antigen stimulation [140] , which are instead positive to mitogens (table 22 .8; fig. 22 .24) [508] . laboratory investigations show a normal b lymphocyte number, but children may be agammaglobulinemic [140] . the thymus and other lymphoid organs are remarkably hypoplastic, with a severe cd4 lymphocyte depletion, while cd8 and b-cell levels are normal. the syndrome involving a deficiency of hla antigens confirms an important hla biological role in the complex system of t-b cooperation [77, 140] . some studies suggest that there are more types of deficiency. when placed together in a culture, the b lymphocytes of these patients, previously transformed by ebv, the lymphocytes correct each other so as to allow hla class ii molecule expression. this has led to the identification of so-called complementary groups [251] . the specification that the gene is mapped on chromosome 19p13.3 can lead to an earlier prenatal diagnosis [166] . longterm survival seems to depend primarily on hla-identical and hla-haploidentical bmt performed in the first 2 years of life, before the acquisition of chronic virus carriage and sequelae of infections [257, 140] . a child recently received a transplant [428] with a novel protocol [208] : the cd4 count increased up to 300 cells/ml [428] . a direct correction of the genetic defect is based on the transduction of cells from patients with lentiviral vectors encoding ciita, rfxank, rfx5, or rfxap. the rfxank vector restored class ii expression in a t-cell line from one patient. the rfxap vector corrected primary cells from a second patient [314] . the study of the common association of hla class i molecule deficiency, already known as bare lymphocyte syndrome, has led to the identification of various patients with an isolated deficiency and of one patient with a deficiency associated with class ii, the most severe [85] . the deficiency is caused by tap-1-tap-2 mutation, accompanied by severe and chronic bacterial rris [115] . in two brothers with the ar hla class i defect, the onset of rris took place between the ages of 4 and 7; the poor expression of nk cells was so severe that it led to the development of bronchiectasis [125] . the immunological structure is characterized by few cd8: the deficient expression of hla class i molecules is diagnostic [115] (tables 22.1, 22.3). mutations with no symptoms referable to an id, therefore integrating a genetic heterogeneity. two other brothers and both parents were healthy [5] . while the ε chain deficiency produces modest clinical symptoms, the other two are severe also from an immunological point of view: in the γ chain deficiency resulting from the profound cd8 and cd45ra decrease caused by altered thymic activity that leaves the cd45ro unaffected [249] , and in those of the ζ chains due to the severe thymic atrophy [5] and thymocytes falling to 15% of normal levels, with limits at between 1% and 50% [249] . the cd3δ deficiency due to a heritable mutation of the cd3 gene that prevents the synthesis of the cd3 protein has been reported in 3 cases hz for the cd3 mutation. two cousins died at 2-3 months of age because of overwhelming infection. the thymus shadow is clearly visible on chest x-rays. the thymus becomes populated with developing thymocytes, with an arrest of differentiation at the cd4 -cd8stage of t-cell development. a girl (3rd patient) survives after a bmt [111] . this rare deficiency transmitted as an ar trait is caused by mutations of the zap-70 gene, a non-src family protein tyrosine kinase (ptc) important in t-cell signaling (tables 1.31-1.33). zap-70, known to be crucial for t cell activation, is a key player in tcr down-modulation and z degradation [136] . zap-70 has an essential role in the cd3g chain deficiency due to g or e gene mutations [19] determines a lack of cd8 and the absence of cd45ra [249] . in the first two cases described, one brother died at 31 months because of viral pneumonia after a clinical history indicating scid with severe aiha, while the other was asymptomatic at the age of 10 years, although with the same molecular defect [18] . the study of these brothers proved that, in spite of the absence of functioning g chains and 50% of the expressive levels of the cd3/tcr complex, the lymphocytes were normal. according to the authors, other chains may act in the place of missing ones; however, the correlated scarcity of cd8 may have negatively interfered with the mechanisms discriminating between self and non-self, while g chain deficiency could have modulated the onset of the deceased brother's severe autoimmune disease (aid) [18] . a cd3e deficiency was found in a 4-year-old child with mild rri symptoms and otitis media; the expression of the cd3/tcr complex was only 10%, but the stimulation with anti-cd3 induced a normal proliferating response. in fact, despite the ongoing mutation, a northern blot analysis showed production of a low amount of transcribed rna, corresponding to a small quantity of e normal chains, even though their dimensions were smaller than normal ones [471, 496] . the z chain deficiency found in the two brothers is similar to the deficient expression of cd3/tcr [5] . in the younger brother, the thymus, markedly reduced, showed no hassall bodies; the elder brother had similar chain [342] . in several babies (most of mennonite origin) with scid [20, 92, 139, 179] , the nonfunctional cd4 t cells (table 22. 3) were either normal or increased (cd3 + cd4 + , 75%). cd8 absence in the thymus and in circulation (cd3 + cd8 + , 0%-2%) [139, 179] suggests that the selective process is arrested during the transition from double-positive (dp) to mono-positive (mp) t cells [20, 140, 179] .arrested thymocytes had terminated rag gene expression and up-regulated tcr and bcl-2 expression, but failed to differentiate into mature cd4 or cd8 mp thymocytes, to be rescued from death by neglect or to sustain il 7 ra expression [294] . zap-70 deficiency results in an impairment of transendothelial migration that can be rescued by the transfection of zap-70 because cross-talk between the zap-70 signaling pathway and the chemokine receptor cxcr4 is required for t-cell migration [502] . although the thymic architecture is normal with presence of hassall bodies [179] and cd8 seem normal in the cortex, very few migrate to the medulla [20] . the near absence of cd8 + cells and an increased cd4:cd8 ratio dominate [27] . the few cd8 coexpress cd56 + , the nk-cell marker; b cells appear normal and functional, cd3 -cd19 + is at a level of 20%-40% [139, 179] , and serum ig values are normal [27] . the same phenotype was found in the brothers [92] ; other relatives were het [20, 139] . the absence of cd8 expression was shown to correlate with a missense mutation in both ig alleles of the cd8 a gene domain in a 25-year-old man and his sister, whereas high percentages of cd4 -cd8 -tcrab + t cells were found in the three siblings [114] . the proliferative responses in vitro to phorbol myristate acetate (pma) and ionomycin, pkc activators (protein kinase c), were normal, unlike pha (phytohemagglutinin), pwm, tetanic toxoid, anti-cd3, etc. [20, 139] . the positives operate below the tcr, while the negatives react directly with the cd3/tcr complex [92, 140, 179] , confirming the zap-70 deficiency [20] . the cd4 are present despite the deficiency because syk, the other member of the family, ensures a compensatory role in the infrathymic cd4 selection, although with a limited efficacy [179] . seven months after bmt, a child was clinically well and immunologically recovered [27] . studies in two siblings hz for a stop mutation in the tap-2 gene suggest that nk cells express still unknown inhibitory receptor(s) (the missing receptor, discussed in chap. 1) capable of down-regulating the nk cell cytotoxicity on binding to surface ligand(s) expressed by t cell blasts. functional analyses were consistent with the concept that this putative inhibitory receptor is expressed by virtually all tap-2/nk cells, whereas it is present only in rare nk cells from healthy persons. another prospect would be that tap-2/nk cells are actually missing this still unidentified triggering receptor involved in nk cell-mediated killing of pha blasts. since cells derived from patients displaying defective expression of either of the tap subunits are characterized by a strong reduction of mature hla class i molecules at the cell surface, a tap deficiency is connected with hla class i deficiency [517] . as discussed in chap. 1, nfat (nuclear factor of the activated t cells) is a transcription factor that forms a powerful transcriptional activating complex and, by linking with specific dna-regulating sites, plays a critical role in the synthesis of various t-cell ils which, due to the deficiency or excessive migratory mobility of nfat, although normal in number and in distribution, are incapable of activating and/or secreting the genes of il 2 , il 4 and ifn-g [86] . a 4-year-old girl with scid presented during infancy with severe recurrent infections and failure to thrive; her mrna was not produced for il 2-5 and ifn-g due to poor t-cell proliferation, although these were normal in number and in distribution, to initiate the transcription of the relative genes, regulated by nfat, with a binding site in the proximity in the 5¢ region. this severe clinical picture is accompanied by evident hgg [19, 86] . nk-cell deficiency is found in scid, cvid, reticular dysgenesis, chédiak-higashi syndrome, xlp, lad in tap-2 deficiency and in cfs (chronic fatigue syndrome), in particular cid such as scid, suggesting an association between nk-and t-cell deficiencies [478] . there is one known case of an adolescent with an isolated numerical and functional deficiency of nk cells and of precursors, recurrent neutropenia, severe and recurrent ebv, cmv, herpes simplex virus (hsv) infections and life-threatening chickenpox. another child, diagnosed at the age of 2.5 years with a cd8 deficiency, suffers from severe viral and bacterial infections although he has antibodies to various viruses [49] . the growing list of human genetic defects that impair nk-cell function has been recently joined by nemo-id [356] which occurs in a group of patients with antibody deficiency combined with exquisite susceptibility to infection with nontuberculous mycobacteria. infectious susceptibilities common to these disorders stress the important role for nk cells in host defense [59] . the natural history of three boys with nemo mutations outside of the 10th exon has been described. including these boys, there have been 22 families described as having nemo-id. the resulting estimated incidence of nemo-id is 1:250,000 live male births, making this disorder significantly less common [356] . cd45ra cells and a marked clinical improvement. these data indicate that the thymus is differentially required in the maintenance of the tcr repertoire complexity [380] . known also as idiopathic lymphocytopenia, primary cd4 t-cell deficiency is revealed by a profound and persistent reduction in circulating cd4 and with a cmi deficiency. it is documented in patients suffering from infections caused by opportunistic germs such as cryptococcus-induced meningitis and oral candidosis, also including ten children and a number of adolescents, for whom the following minimum levels of cd4 per age have been established: <1,000 cells/mm 3 from 0 to 23 months and <300/mm 3 from 2 to 12 years, or a total lymphocyte count of <20% on two separate occasions without being hiv-infected [463] . a family has been reported involving two brothers aged 13 and 18 with t counts between 150 and 200/mm 3 , recurrent respiratory, intestinal and cutaneous infections, and failure to thrive. the mother showed a low cd4:cd8 ratio [122] , while the entire family showed normal levels of ig and subclasses and hla molecules [128] . other symptoms included mental retardation, pansinusitis, bronchiectasis [168] , but no infections caused by opportunistic germs such as those reported by the who scientific group [414] . one case of primary cd7 deficiency is known of a child with scid without genetic transmission of the deficiency. t-cell proliferative responses to mitogens were defective and il 2 r expression was deficient on his t lymphocytes, and b cells did not differentiate into antibodysecreting cells when provided with the help of normal t cells [245] . the index patient for primary cd45 deficiency was the first child of consanguineous kurdish parents. she presented aged 2 months with a rash, pyrexia, hepatosplenomegaly, lymphadenopathy, pneumonitis, pancytopenia, and disseminated cmv infection. laboratory analysis showed absolute lymphopenia, low t cell numbers, with markedly low cd4 + and low cd8 + and normal b cell numbers. she responded well to anti-cmv treatment and at 8 months underwent a mud bmt. t-cell engraftment was demonstrated 3 weeks after bmt. despite continuous anti-cmv treatment, her undifferentiated scid human p56lck deficiency p56lck deficiency is an ar scid due to a defect of an src kinase critical for the generation of mature thymocytes in adult mice. p56lck is important in tcr signaling and phosphorylation of the itams of the cd3/tcr complex proteins. mutant mice lacking p56lck have pronounced thymic atrophy, a critical reduction in dp (cd4 + cd8 + ) thymocytes, no detectable mp thymocytes, and only a few peripheral t cells. both proliferation and development of a given defined cell subpopulation depend on meuse age. the absolute numbers and proliferation of dn and isp (immature single positive) thymocytes only proliferate during fetal and early postnatal life up to 14 days after birth, whereas the proliferation is significantly decreased beyond that age, thus lck may have differential roles in the proliferation and maintenance of dn, isp, and mp/dp thymocyte populations [151] . the first demonstration of a human scid patient with an abnormal expression of p56lck is an scid infant hospitalized at 2 months for dehydration, failure to thrive, and sepsis. the immune phenotype included hgg, selective cd4 lymphopenia, lack of cd28 expression on cd8 + t cells and poor t cell blastogenic responses to various mitogens and il 2 . p56lck protein expression was only minimal with an unusual mrna splicing pattern of the lck gene. the levels of p59fyn were normal and it is therefore possible that p59fyn played a role, albeit incomplete, in the development of his mature t cells. the child has since undergone an allogeneic bmt (at 32 months) from a matched unrelated donor (mud) [185] . unfortunately the boy died 2 months later due to cmv infection and gvhd (fd goldman, pers. comm., 8 nov. 2005 ). whn (winged-helix-nude) encodes for a transcription factor that is crucial for maturation of the thymus microenvironment [185] . nu/nu mice fail to develop a thymus and mature t cells due to a defect in the whn gene encoding a transcription factor necessary for terminal epithelial cell differentiation. a defective whn gene could lead to the disrupted early t cell development in the bm. t cell progenitors were associated with a lack of pta gene expression and a failure to give rise to mature t cells in adoptive euthymic hosts. wild-type hscs rapidly matured into functional t cell progenitors in the marrow of euthymic or thymectomized but not nu/nu hosts. therefore defects in bm prethymic t cell development can contribute to t cell deficiency in nu/nu mice [90] . in two sisters a severe scid caused by mutation of the whn gene was associated with complete alopecia. hla-identical bmt in one of the two girls resulted in a clear reconstitution of cd4 + and cd8 + cmv reactivated, and she died 55 days after bmt [74] . a 6-bp deletion in the gene encoding cd45 resulted in the loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type iii module of the extracellular domain of cd45, identifying a region important for cd45 structural integrity and lack of surface cd45 expression. this was almost certainly responsible for the id in this girl [494] . a second child presented at 2 months of age with severe cid, showing similar t-cell defects. despite normal b-lymphocyte numbers, serum ig levels decreased with age [272] . introduction of a functional cd45 minigene was sufficient to overcome the main scid-associated defects and represents a potential route to a gene therapy for human cd45-deficient scid [516] . two male infants born to consanguineous parents had scid despite phenotypically normal blood lymphocytes. their t cells were unable to produce il 2 , ifn-g, il 4 and tnf-a [154] . another child with scid had defective transcription of il genes encoding il 2 -il 5 [86] . dna binding of activation protein 1 (ap-1), oct, creb, sp1, and nf-k b was normal, but the binding of nfat to its il 2 promoter response element [154] , or the ability of nuclear factors from the child's t lymphocytes to bind response elements present in the il 2 regulatory region [86] was barely detectable [86, 154] both before and after t-cell stimulation [154] . these results indicate that the nfat abnormality may underlie the multiple il deficiency in these boys. nezelof syndrome, also known as cellular id with ig, or combined with a predominant t-cell defect, or as a scid variant, clinically less severe compared to the previous ones, is characterized by a form of ad, concentrations of ige that may also be extremely elevated (table 22. 2), and normal or increased serum levels of other ig classes [62] . the cmi study emphasized the mature t-cell reduction or absence, various expressions of immature cells, with cutaneous anergy to spts and a reduced or absent in vitro lymphocyte response to mitogens. from infancy, patients present recurrent or chronic pulmonary infections, pondostatural retardation, oral and/or cutaneous candidosis, chronic diarrhea, recurrent cutaneous and urinary tract infections, gram-negative bacterial sepsis and a particularly severe form of chickenpox [394] . differential diagnosis must include pediatric aids, also marked by proportionably increased ig and a lack of antibody and t-cell function [79] . inherited through ar modalities, cd95 deficiency has been observed in 8 children, two of whom were brothers, with mutations of the fas gene, one hz and 7 het [166, 281] , as well as in 9 unrelated children [468] . these mutations most often arise as a result of mutations in the gene encoding the lymphocyte apoptosis receptor fas/apo-l/cd95. a novel mutation has been identified in the intracellular apoptosis signaling domain of fas in 11 members of a family, with several members monitored for up to 25 years [228] . thus, the deficiency is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression [228] , but also in an ar fashion [510] . the clinical picture is dominated by imposing hepatosplenomegaly with an early onset, even neonatal, accompanied by t-cell hyperproliferation, chronic and persistent lymphadenopathy, and failure to thrive [468] . an extensive lymphocyte infiltration of lymph nodes, spleen and liver is observed, with t cells reaching 35,000/ml [cd3 + , cd4 -cd8 -(dn) equal to 35-60 cells/ml compared to 0-3 in controls], as in omenn syndrome, also in the bloodstream, with possible oligoclonality of t cellularity. dn t cells expressed the a/b tcr [468] . immune dysregulation is associated with g and a hgg (hypergammaglobulinemia, auto-antibodies and aids, especially of the hematological type, such as aiha, and with a severe and recurrent thrombocytopenia [166, 281] . autoimmune features are discussed in chap. 18. an overlapping mechanism could belong to the etiopathogenesis of xlp and omenn syndrome. was has a prevalence of approximately 4 × 10 6 live births [402] . it is transmitted as a recessive hereditary trait linked to the chromosome x, localized in a pericentrometric position on the short limb of chromosome x (xp11.22-p11.3) [274] . it is therefore possible to identify the female carriers and to provide prenatal diagnosis [61] . the gene that codifies the was defective protein (wasp) has been isolated [458] and has 167 mutations distributed among all 12 exons of the entire gene, 110 of which are unique and 38 familiar, with two large deletions, one embracing exons 1-7 and one intron 8 [275, 444] (fig. 22.25 ). six novel mutations have been identified that involve nonsense mutations, or small deletions, all of which result in predicted truncation of wasp synthesis [57] . a new, recurrent mutation is v75m, due to a cpg island was found in a hz girl, who showed microthrombocytopenia and infections to the same degree as her hemizygous father and brother. the amount of was protein was about 10% in platelets and 15% in mononucleated white cells [388] . involved in ensuring the t lymphocyte functional polyvalence, also explaining why microvilli and platelet defects are absent [152] .wasp and several related proteins (the wasp family) are all involved in the organization of the actin cytoskeleton. to carry out vital functions, cells have to rearrange their actin cytoskeletons [467] . the characteristics peculiar to wasp as a meeting point for the marking pathways is illustrated in fig. 22 .26 [152] . the wasp function is absent in 135 cases of was, in ten with attenuated was and in 23 with xlt [372] . in normal subjects, it is found in the cyto-molecular biology has proven that wasp found only in blood cells binds the small gtpase cdc42h2 in the gtp but not in the gdp [23, 265, 490] . cdc42h2 plays a critical role in the assembly of actin filaments [490] and in t-cell polarization when they encounter a b-lymphocyte apc [481] . wasp activity is regulated by several proteins acting in concert to control wasp configuration. the wasp-interacting protein, when phosphorylated, releases wasp from its grip, allowing wasp to be activated by rho-family gtpases [433] . experimental data also indicate that cdc42, wasp and actin might be plasm but not in the nucleus of various cells such as platelets, t and b lymphocytes and monocytes [477] . the xlt gene is located on the same locus as the was and could therefore be a variant [444] ; the main immunological anomalies are summarized in table 22 .12 [287, 413] . children with was have significantly elevated levels of il 4 and ige (table 22. 2) and decreased levels of ifn-γ [217] . the pathogenetic mechanism unifying the symptom triad is not clear; the glycosylation defect has been proved, primarily concerning sialidation, therefore resulting in an instability on the membranes of platelets, neutrophils and lymphocytes expressing a glycoprotein sialopherin (cd43) [402] , localized on chromosome 16, which makes it an improbable candidate, even though cd54 is indeed the binding agent of cd43 and could therefore play a role in t-cell maturation, differentiation and activation, thereby acquiring marking capacities that are independent of tcr/cd3 [19] . however, the tcr-mediated signaling defect is characteristic of was [259] , in addition to the reduced expression of cd23 [458] , which can explain immune and hematological defects. in the lymph nodes, there is a shortage of lymphatic follicles and the thymus-dependent and -independent areas are depleted, moderately at the age of 4 years ( fig. 22.27 ) and to a greater extent at 8 years ( fig. 22.28 ). the predominant immunological outline is constituted by elevated iga and ige levels, low igm and all igg levels, as well as the absence of a response to polysaccharide antigens, which is why the children's serum lacks isohemagglutinin [278, 528] . in unweaned babies, the most striking finding is the cd4:cd8 ratio =5 [549] , compared to 2.65 in normal children aged 0.63-3.06 (tables 1.36-1.39). was usually starts at 13.7 months (range, 1-58) [132] with hemorrhagic manifestations, petechiae and prolonged bleeding from the umbilical scar or the circumcision site, observed in newborn babies [402] . the clinical triad is characterized by cutaneous lesions that are practically indistinguishable from rather severe ad (70%), congenital thrombocytopenia (100%), a marked susceptibility to rris (91%) [132] (figs. 22.29, 22.30) and gastroenteric symptoms such as hematemesis, melena and chronic diarrhea [132] . other complications may include neutropenia (25%), arthritis (29%), skin vasculitis (22%), cerebral vasculitis (7%), inflammatory bowel disease (9%), and renal disease (3%) [132] . a reduced thrombopoiesis (level <50,000/ml), with microthrombocytes and an accelerated turnover in boys must allow for a suspected diagnosis [413] . it has recently been proven that the classic presentation is more common in children aged 6.8 months than in those aged 7.2 months (60% compared to 25%), unlike platelet counts [549] . however, only 27% of 154 unselected children with persistent thrombocytopenia, positive fh, small platelets and defects associated with t and/or b lines had the classic triad and 20% only thrombocytopenia before diagnosis [484] . primary immunodeficiencies infections, appearing during the first months of life, are often marked by otitis media, pneumonia, meningitis and sepsis, caused by viruses (cmv and herpesvirus) and by bacteria (pneumococci or other capsular polysaccharide). these are followed by more common infections caused by opportunistic germs, pneumocystis carinii and mycetes such as candida albicans. differential diagnosis should also include a rare ar syndrome similar to was, also reported in female patients, characterized by ad, rris and thrombocytopenia with microthrombocytes [62] . when caring for these children one must monitor the platelet count, the immunological structure (ig, lymphocyte and subpopulation counts) and the potential onset of autoimmunity and tumors [224] .aiha may be found in 36% of children [132] . prophylactic treatment for infections is done with ivig; 500 mg/kg every 3 weeks) and sulfamethoxazole (25 mg/ kg/2 days) after diagnosis [132] . splenectomy may decrease the bleeding tendency [224] , but early relapse of thrombocytopenia after splenectomy is predictive of a poor prognosis [132] . on average death occurs around the age of 11 (8 in untreated children), but can occur between 0.5 and 4.5 [549] , with survival also >18. death is caused by massive hemorrhages (23%), tumors (26%) and severe infections (44%) [484] . the second largest group of patients with id given bmts since 1968 are those with was, with 78.8% of children aged <5 years [158] . fourteen out of 18 patients underwent phenoidentical (n=1) or haploidentical (n=13) hscts; the other four died before hsct could be undertaken [132] . boys who had received a mud hsct transplant <5 years had survival rates similar to those receiving hla-identical sibling transplants, but the success rate decreases dramatically at the age of 5-6 [158].wasassociated t-cell signaling defects can be improved upon retrovirally transduced hscts [258] . recently, correcting the t-cell defects has been proposed. the potential for correction of the t-cell defects has recently been demonstrated by transduction with an oncoretroviral vector encoding the wasp, which resulted in correction of the deficient proliferative response to tcr stimulation characteristic of was [483] . ata is a complex ar inherited syndrome, associated with neurological, immunological, endocrinological, hepatic and cutaneous abnormalities, characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, and increased susceptibility to rris [379] with an incidence estimated at 1:100,000-1,300,000 live births [61] . in italy the frequency on the general population, is of 1.3 × 10 6 , with an increase in hets from 1.7% to 3.43% [94] . it is characterized by a genetic heterogeneity, which is reflected in the division into four main groups of complementation, to which one must add the nijmegen and at-fresno variants, perhaps caused by other well-defined id syndromes the same gene, also localized on the long arm of chromosome 11q22.23 [176] . the 12-kb gene, called atm (at mutated) because of its mutations by defective splicing in all patients with ata, permits het identification [435] . a dna clone complementary to atm shows considerable affinity to factors responsible for signals involved in regulating the cell cycle and codifying a protein similar to phosphatidylinositol-3-kinase (pi 3k) [435] , involved in mitotic signal transduction, meiotic recombination, and cell cycle control. a result could be a recombination defect which interferes with b and t lymphocyte gene rearrangement, involving tcr and isotype switching, consequent to a damaged dna triplication and therefore accounting for ig deficiencies [176] . cells from these patients progress too rapidly from the g 1 phase, in which they receive ionizing radiations, to the s phase, then continuing irradiation, to the g 2 /m phase with further delay, evolving in apoptosis [279] . this hypothesis has received further credit after observing that the p53 gene expression does not increase in human cells exposed to radiations [250] . the p53 gene is part of the normal cell cycle and during the s phase provides time for the dna physiological repair after exposure to radiation that may also be cosmic [279] . the thymic tissue is either absent or degenerated with a fetal appearance (fig. 22.31) : some follicles, also with b cells, are visible at the age of 2 (fig. 22.32) , at 8 there is complete cellular depletion (fig. 22.33 ). immune deficiencies are humoral and cellular (cutaneous anergy and depressed proliferative responses) [70] . the karyogram shows that the lymphocytes have common rupture points at the chromosomal level with inversions and translocations involving precisely the tcr and ig genes [320] . most chromosomal translocations involve the genes encoding tcr on chromosome 7 and the ig h chains on chromosome 14: most breakpoints occur at the loci that encode ig and tcr for antigen (regions 7q35, 7p12, 14q32, 14q12) [264] , in areas typical for cod-ification of molecules of immunological importance (chap. 1). an important role is played by genes belonging to ig gene superfamily (igsf) (table 1.4) . possibly the progressive id of ata, like its apparently unlinked manifestations, is at least in part linked to the accumulation of clonal anomalies affecting the tcr and the igsf: this suggests the intervention of "illegitimate" recombinations damaging above all the t cells [162] . t-cell immunological deficiency is completed with lymphopenia, a decreased cd4:cd8 ratio due to the drop in cytotoxic cd8, and a rise of immature forms with tcrgd [80] . another consequence is the isotype deficiency: about 70% of patients present sigad; >50% are also affected by an igg 2 -igg 4 deficiency with igm becoming monoclonal, and 30% by serum igg deficiency [364, 379, 528] . fig. 22 .32,the degree of depletion of lymphocytes is extensive in both thymus-dependent and thymus-independent areas chromosome 11 into cells, the chromosomal aberrations induced by x-rays were suppressed [261] . the rare ar nijmegen breakage syndrome, so called because it was initially seen in two brothers of secondcousin parents living in that city, and at the moment observed in approximately 80 patients, has various characteristics of ata but without ataxia, telangiectasia, or high concentrations of afp. clinical characteristics are singular: short stature and microcephaly with prenatal onset, bird-like profile, prominent midface, a long nose, low-set ears, cutaneous depigmentation with caféau-lait spots, an almost normal intelligence, and also rris and bronchiectasis. humoral and cellular id includes reduction of antibodies and lymphoproliferative responses [70, 224] . during an 8-year period of observation, the id was found to be profound, highly variable, and with a tendency to progress over time in 40/50 children [193] . there is a high proclivity to expressing rearrangements of chromosomes 7 and 14 as in ata [70, 224] . dgs is usually sporadic, with known cases of positive fh [224] . it is caused by a defective development of the 3 rd and 4 th branchial pouches which takes place before the 12 th week of gestation, with consequent thymic hypoplasia or aplasia and parathyroid hypoplasia; the 5 th and 6 th pouches and branchial arches can also be affected [497] . the cause can be found in the neural crest cell incapacity to migrate and interact appropriately with endothermic cells of the brachial pouches and arches [295] . deletions (often microdeletions) at the pericentrometric region of chromosome 22q11-pter have been described in 80%-90% of cases [130] . a microdeletion 22q11.2 was recorded in 112 children aged 4-70 months, 54% of whom had developmental delays, mild hypotonia, as well as language and speech delays [181] . another 80 children had deficits in the areas of attention, story and visuospatial memory, arithmetic performance relative to other areas of achievement, psychosocial functioning [541] , and mental retardation in 73% of 44 children [11] , thus indicating the need for early intervention beginning in infancy [181] . overlapping alterations are present in the syndrome complex known as catch 22, which in turn includes the charge association. other cases of dgs can derive from microdeleted chromosome 10p (fetal-alcoholic syndrome, retinoic embryopathy, maternal diabetes) [414] . this variable phenotype is reliably referred to microdeletion 22q11.2; the greater it is the more complex is the associated phenotype [508] . another difference depends on the variable spectrum of t-cell abnormalities in individuals with dgs who might have normal t-cell numbers and function, low t-cell numbers but fairly normal t-cell proliferative function [32] or no t cells purkinje cells (pcs) and degenerated granular cells. that the number of basket cells, so called because they form with the axons bunches of fibrils distributed so as to form a nest in which the nucleus of each pc settles, is almost normal, proving that pcs are probably normal at birth and degenerate only later [176] . typical clinical manifestations are ataxia, telangiectasia of both auricular lobes and sclera, rris and an elevated incidence of neoplasia [489] . from a review of 331 patients [70] , the percentages of symptoms are as follows: progressive ataxia (100%), typically cerebellar, becomes evident when children start walking or a little later, affecting intentional movement and becoming complicated by dysarthria (100%) and involuntary choreic movements (92%), causing the majority to be unable to walk by about the age of 10-12 [276] . at a later stage it is possible to observe nystagmus (67%), strabismus, oculomotor apraxia (88%), reduction or absence of reflexes (77%), and dyslalia, increasingly amplified and, in some patients, also mental retardation [176] . telangiectasias develop between the ages of 1 and 6 on the bulbar conjunctiva (97%) (fig. 22.34) , on the flexor surfaces of the limbs and areas exposed to sun rays (17%). height and weight are <10th percentile (64%) and the appearance is progeric (63%). severe rris are common (70%), encouraged by antibody deficiencies. the pathogens involved can be bacterial or viral, often resulting in lung bronchiectasis, all starting after the onset of neurological manifestations [276, 489] . associated neoplasia (6%) is usually lymphoreticular, less common than adenocarcinoma, with an eightfold increased trend for all kinds of tumors [224] . in cultures the fibroblasts of these patients are three times as sensitive, compared to controls, to ionizing radiations and to radiomimetic chemical substances, but not to uv rays, unlike what is observed in the cells of subjects affected by xeroderma pigmentosum [70] . in addition, the persistence of elevated serum a-1-fetoprotein (afp) levels was observed in all patients. an interesting in vitro study has reported that by introducing a normal human 1303 other well-defined id syndromes fig. 22.34 . conjunctival telangiectasia in a girl with ata [305] . a second group is referred to as having partial dgs (dgsp) or transient forms (dgst), with mild symptoms. the designation "complete digeorge syndrome" (dgsc) is reserved for the third group of infants who have absence of thymic function in addition to other defects of the 3 rd and 4 th pharyngeal pouches, <1% of patients with dgs, although they can have high t-cell numbers that respond to mitogens [32, 305] . these patients have profound id, with its associated clinical findings [308] . dgst includes cases with a spontaneous quantitative and qualitative t lymphocyte recovery [162] . the thymus can also be ectopic: in dgsc the t zones are depleted, the cd4/cd8 markedly reduced both in number and in function with spt anergy, and b cells appear unaffected or increased [162] . in dgsp, the most common type, t-cell number and function are instead usually normal, as are the cd56/cd16 cells with a nk phenotype, or they may be moderately reduced [162] . the proliferative response to mitogens can be pathologically reduced [224] and the response to polysaccharide antigens may be absent [442] . from neonatal age, there are malformations of other structures that form during the first weeks of embryogenesis, presenting a suggestive but not pathognomonic picture (table 22 .13) [79] . diagnosis is usually suspected within the first 2 days after birth, due to the presence of hypocalcemic tetany caused by hypoparathyroidism and cardiac malformation. the facial dysmorphism is also characterized by a small mouth with thin lips described as fish-like [79, 192] (fig. 22.35) . the two rare cardiopathies indicated in table 22 .13 depend on neural crest nonintegration, as mentioned, which accounts for >50% of the alterations alone [295] . others can be observed affecting the right heart, such as fallot tetralogy, pulmonary athresia with an interventricular septum defect, and pulmonary infundibular stenosis [508] . babies surviving the neonatal period manifest from the very first months an increased susceptibility to infections, particularly those of the respiratory and digestive tract, viral and/or fungal, but also caused by pneumocystis carinii, which can be fatal in dgsc [162] . other findings include gastroesophageal reflux, speech delay, laryngomalacia, absent kidney, conductive or sensorineural deafness, 6th cranial nerve palsy, and hypothyroidism [535] . treatment with high doses of vitamin d and diets enriched with ca gluconate are needed immediately, also ensuring that calcemia remains at the lower limit of normal values so as to avoid snc and renal damage. subsequently the possible correction of cardiac malformations should be evaluated. id may be severe, but can regress spontaneously with reconstitution of cmi and t functions; compensating hyperplasia of the residual parathyroid tissue can make it possible to discontinue ca and vitamin d treatment [192] . dgs natural history is, however, complicated by mental retardation and the difficulties encountered in correcting cardiac malformations and in controlling hypoparathyroidism [224] . because of variability in the id severity, it is difficult to evaluate claimed benefits of bmt: in two cohorts of 8 [305] and 5 transplanted infants [306] , the survivors were 3 out of 13 (23.1%). recently, 5/6 and 7/12 infants underwent postnatal transplantation with cultured unrelated thymic tissue, with immunosuppression, with positive results [307] . del22q11.2 syndrome, characterized by a 3-mb deletion on chromosome 22q11.2 is the most frequent known chromosomal microdeletion syndrome, with an incidence of 1 in 4,000-5,000 livebirths. patients show 1304 chapter 22 primary immunodeficiencies clinical outlines not unlike gvhd [446] (fig. 22.36 ) [508] , suggesting a possible connection to a fas deficiency (cd95) or apoptosis syndrome. the sh2d1a gene was found altered in two families, thus indicating that xlp must be considered when more than one male patient with cvid is encountered in the same family, and sh2d1a must be analyzed in all male patients with cvid [330] . recently a critical revisitation of this experiment in nature has allowed the identification of links between id and allergy [62, 178, 196, 287] . the rare higes is associated with bacterial rris, chronic ad, coarse facial features and very elevated ige levels [60, 250] ( table 22. 2), up to 40,000 iu/ml [549] . linkage to a region on chromosome 4q has been demonstrated in several affected families; however, neither the fundamental host defect nor the defective gene has yet been identified [195] . fh is frequently positive for atopic disease, at times higes is combined with an unusual predisposition to staphylococcus aureus infections [62, 178, 196, 287] . in buckley's study, it was present in 36.4% of cases, of both sexes, indicating an autosomal dominant transmission with incomplete penetrance [62] . onset occurs in the pediatric age in 90% of cases [64] . clinical presentation is unusual: there are no complaints during the first months of life, toward the 3rd-4th month a severe form of chronic ad appears all over the body, which can be associated with other allergic manifestations, including asthma in 13.6% of cases [62] . skin biopsy specimens reveal spongiosis and perivascular dermatitis and/or folliculitis with a predominance of eosinophils [91] . there is an excessive predisposition to cutaneous and respiratory tract infections (deep and superficial abscesses, otitis, pneumonia, sepsis) ( fig. 22 .37), also encouraged by neutrophil chemotactic deficiency caused by defective cellular functions (table 1. 65), which, if present, is so pronounced that it becomes a characteristic, unlike ad where it is secondary [226] . the subcutaneous abscesses, described as cold, not covered by warm and reddened skin, are pathognomonic to higes but not essential to the diagnosis [144] . the abscess is filled with pus that always grows staphylococcus aureus; in some cases mucocutaneous candidosis and chronic herpetic keratitis are associated [178] . infections appear within the first 18 months [62] . the face shows coarse and dysmorphic features, midline facial defects such as a prominent nose and a high, arched palate, and disproportionate cheekbones and mandible; pondostatural growth notably retarded [64] , pneumatocele (fig. 22 .38) and osteoporosis caused by reduced bone density with a tendency to fracture [287] complete the picture. six consanguineous families have been reported with an ar form of higes, including 13 cardiac abnormalities, t-cell deficits, cleft palate facial anomalies, and hypocalcaemia. at least 30 genes have been mapped to the deleted region. recently, in 5/13 patients with del22q11.2 syndrome without 22q11 deletion mutations were found in t-box 1 that is a major genetic determinant of the del22q11.2 syndrome [545] . xlp is caused by a defect in the sh2d1a gene (table 22 .1), which binds to the cytoplasmic domains of cd150 slam (signaling lymphocyte activation molecule) and 2b4, and may regulate signals transmitted by these receptors in t and nk cells, respectively [345] . xlp has been reported in >270 males from >80 families [446, 460] , and in an other 27 males [381] , it is inherited with the x-linked model. it is set off in males aged 5-6 by an ebv infection that became manifest with a very polymorphous pattern, often with unusually severe or fatal infections mononucleosis caused by the immune system incapacity to respond to ebv, or evolving into a hgg with iga and igg deficiency and higms, or medullar aplasia and/or a burkitt type lymphoma [446] . the disease has been reported in 15 female subjects [381] . xlp polymorphism could be explained by the fact that the ebv receptor is expressed on differentiating b lymphocytes starting with the preceding isotypic conversion stage [500] . it has recently been verified that before ebv infection, males already suffer from dys-or pan-hgg, incapable of regulating the expression of ig and/or containing b or t lymphoproliferation. even after ebv infection, the immune system is unable to provide adequate th2 responses, and therefore releases cytotoxic alloreactive cd8 and th1-like t cell ils, causing extensive damage to the entire parenchyma, exemplified by fulminating hepatitis, cellular infiltrations and tissular necrosis. the lymphoid tissues with an altered structure are also affected by necrosis, with a high incidence of mostly nonlocalized lymphomas [381] . the thymus is also affected by thymocyte rarification, with 1305 other well-defined id syndromes fig. 22.36 . bone marrow biopsy specimen in a 3-year-old boy: numerous histiocytes in erythrophagocytosis affected children aged 15 months to 12.5 years, with ar-higes presenting with the classic immunological findings, including rri, eczema, elevated serum ige, hypereosinophilia, and severe recurrent fungal and viral infections [64] . notably, patients with ar-higes did not have skeletal or dental abnormalities and did not develop pneumatoceles, as seen in autosomal dominant-higes [404] . among the immunological characteristics (table 22. 14) [93, 287] , cutaneous anergy to several antigens such as candida and tetanic toxoid is characteristic, which is associated with the anomaly of proliferative responses by the t cells to antigens and mitogens, in contrast with the integrity of other functions tested in vitro [196] . t subpopulations appear to be normal [64] . however, the lymphocyte proliferation to anti-cd3/cd28 monoclonal antibodies can be impaired [226] . as noted, ifn-γ deficiency associated with a pathological th2 prevalence has a fundamental impact on ige hyper-production [178, 287] . in higes, some studies have confirmed ifn-g deficiency compared to controls [120, 368] , also due to an impaired response to il 12 [56] , while others have not [62, 512] ; however, compared to ad, normal levels of t producers of il 4 are characteristic [120] . considering the ifn-g/il 4 + correlation of ad, in higes no specific t-cell anomalies are noted, nor does the hyper-ige explain this pediatric abnormal susceptibility to infections: high ige levels are also seen in children with ad, who do not, however, have an unusual predisposition to abscess formation [226] . one typical characteristic is sige directed against microbial antigens: the anti-staphylococcal sige rise to 8.9% compared to normal levels of 0.2%-0.6%. another constant finding is the increase in 100% of cases of eosinophil concentrations, which make up 6%-12% of leukocytes [64] , reaching 30%-50% [178] . by expressing the cd40-cd154 duo, they stimulate the isotype b-cell switching to ige.we studied children affected by severe ad, chronic fa-induced diarrhea and asthma. the allergens responsible were cm and der p [73] . in case of higes caused by fa, atopic manifestations can clearly improve following an exclusion diet, reducing the frequency of infections and partially correcting the immune defect [420] , revealing how fa can induce several immunological anomalies. diagnosis is made on the basis of the data in table 22 .14; differential diagnosis with ad is schematized in table 22 .15 [287] . treatment with cromolyn is extremely effective, anti-staphylococcal antibiotic treatment [64, 226] and if necessary antifungal therapy provide good results [144] . griscelli disease, mapping to chromosome 15q21 [372] , is an ar syndrome caused by mutations in the myo5a (gs1), rab27a (gs2), or mlph (gs3) genes, all of which lead to a similar pigmentary dilution [50, 312] . the disease is also characterized by partial oculocutaneous albinism, predisposition to pyogenic infections and in most patients by abnormal regulation of the immune system, which results in a syndrome of macrophage hyperactivation, known as hemophagocytic lymophohistiocytosis [15] . mutations in the gtp-binding protein rab27a (gs2), which appears to be involved in an uncontrolled t lymphocyte and macrophage activation syndrome, leading to death in absence of bmt, occur in this syndrome [319] . a mutation was found in the myo5a gene (gs1) associated primarily with neurological impairment [319] . two identical twin boys aged 3 months were reported with persisting fever, mouth ulcers, hepatosplenomegaly, pancytopenia and failure to thrive [431] , as was an 8-month-old infant [397] . both infants had silvery-gray hair and pigment clumps on the hair shafts, and skin biopsy showed accumulation of melanocytes on melanosomes. their parents were first cousins and a sibling with similar manifestations had already died, as did the twins. a genetic study revealed a 5-bp deletion in the rab27a gene (510 del aagcc in exon 5) [431] . in a 4-year-old child with hemophagocytic syndrome, id, and secondary neurological disorders, typical melanosome accumulation was found in skin melanocytes and pigment clumps were observed in hair shafts. two heterozygous mutant alleles of the rab27a gene, a c-t transition (c352t) leading to q118stop and a g-c transversion on the exon 5 splicing donor site (g467+1c) were found [50] . the finding of gray strands of hair, gray eyebrows, and eyelids in childhood should alert pediatricians to considering griscelli syndrome since an early diagnosis is life-and health-saving [203] . the phagocyte system with the biochemical basis of cgd is analyzed within the framework of innate immunity. chronic granulomatous disease (cgd) has an overall prevalence of 1:500,000 to 1:10 6 , although this could be underrated (table 22 .4), considering that some subjects may have a very mild clinical phenotype that escapes diagnosis [501] . a us registry of birth rates found a prevalence of 1:200,000 to 1:250,000 live births for the period 1980-1989 [538] . the youngest patient was 27 days old [337] and in 12 children with cgd the mean age at the onset of infections was 5 months, with a median delay in diagnosis of 2.5 years [371] . otherwise the the clinical features of this rare ar disease include oculocutaneous albinism and susceptibility to especially s. aureus and b-hemolytic streptococcus [549] . approximately 85% of patients develop an accelerated phase of the disease, with deposition of lymphohistiocytes in the liver, spleen, lymph nodes and bm, resulting in hepatosplenomegaly, lymphadenopathy, bm infiltration hemophagocytosis, pancytopenia as well as fever, jaundice, prolonged bleeding, easy bruisability, neurological changes (nystagmus and neuropathy), mild mental retardation, and partial ocular and cutaneous albinism [285, 334, 526] . the cellular hallmarks of the disease include large lysosomal granules in leukocytes, giant melanosomes in melanocytes and affecting other cells of the body such as neural schwann cells, renal tubular cells, gastric mucosa, pneumocytes, hepatocytes, langerhans cells of the skin, and adrenal cells [229, 157] . the fundamental defect in this disorder was found to be caused by mutations in a gene mapped to chromosome 1q42-q43 [31] encoding a cytosolic protein on chromosome 1 named lysosomal-trafficking (lyst) regulator, encoding a 425-kd protein whose function remains unknown [285] . bmt is resolutive in these children [205] . normal protein expression (x91 + form), but with a total absence of oxidase due to incorrect binding [412] . ar-cgd is caused by a mutation in the genes encoding the remaining oxidases of 47 kd (p47 phox ) (phox, phagocytic oxidase) [538] (ncf-1), p22 phox of 22 kd (cyba), and p67 phox of 67 kd (ncf-2) [109, 501] . the ar-cgd forms (18.5%-22% of cases) [285, 458] are identified using the immunoblotting technique, depending on whether they affect the p22 phox , the p47 phox or the p67 phox [84, 97, 109, 501] , with greater prevalence in an american study [97] . patients with the x-cgd appear to have a more serious clinical phenotype than patients with the ar-cgd, based on the fact that they are diagnosed significantly earlier (mean, 3.01 years of age vs 7.81 years of age, respectively), have a significantly higher prevalence of infections and a higher mortality (21.2% vs 8.6%) [537] . mutations in any of the 6 structural molecules (table 22 .16) lead to cgd. mutation of rac2 (see lad), the predominant g protein in neutrophils, leads to defects in so production, as well as in chemotaxis [416] . activation of the nadph oxidase requires complex rearrangements between the protein median age at onset was 1.12 months, and the median age at diagnosis was 1.1 years [81] . the deficiency appears in two forms ( [335, 538] , with an h-chain deficiency, is divided into four x91 subtypes (table 22. 16 [84, 97, 109, 112, 185, 501] ), also identified on the basis of nbt results, depending on whether the x91 is absent (the most common form), reduced or present but inactive; subtype x91is divided into two variants: in one of them the nbt is slightly positive in 80%-100% of cells (6% of patients), in the other in 5%-10% (3% of patients) [84, 109, 412, 501] . more precisely, the four subtypes are caused by mutations in the four gp91 phox regions, many of which depend on cybb gene mutations, causing the x91 0 form, while 17 mutations depend on the nadphoxidase activity (x91form) and eight others lead to a 1309 phagocyte deficiency subunits, which are in part mediated by noncovalent binding between src-homology 3 domains (sh3 domains) and proline-rich motifs [447] . cgd is a hereditary disease (table 22 .16) characterized by severe recurrent pyogenic infections. this marked susceptibility is caused by the phagocytes' incapacity to kill in particular the catalase-positive bacteria, because of a genetic defect of the nadph-oxidase enzymatic system situated in the wall of the phagocytic vacuole. in cgd, phagocytosis occurs normally, but the nadph-oxidase is unable to markedly produce anion superoxide (o 2 •-), h 2 o 2 and other o 2 free radicals, thereby permitting the survival of microorganisms within the cells, where they are protected from the antibodies and from most antibiotics [501] . another consequence of the lack of o 2 radicals is the development with countless inflammatory episodes, which then result in typical granulomas [109] . the nitroblue tetrazolium (nbt) reduction test is based on the chemical characteristics: in fact, the phagocytes without o 2 •are unable to reduce the yellow nbt of products activated by pha aspecifically stimulated phagocyte o 2 , or specifically with corpuscle particles such as preopsonized yeasts (fig. 22.41) . the result was 0% in 14 children [81] . at a molecular level, the genes that codify the two subunits of flavocytochrome b588, gp91 phox and p47 phox have been cloned: respectively the cytochrome, h (b) and l (a) chains situated on the phagosome vacuole membrane, and also the cytosolic factors p40 phox , p22 phox and p67 phox , deriving from the nadph-oxidase activation, all proteins placed inside the cytoplasm and that belong to innate immunity. it has therefore been possible to identify molecular lesions at the cgd origin, with the exception of the p21 rac1 [16, 412, 533] . the clinical pattern is severe in the x91 0 form and variable in the other two x91 forms; onset occurs within the 1st year of life in 2/3 of cases, and in others within the 2nd year [159] , although it can appear also at the age of 16 [335] . purulent recurrent infections, with a granulomatous evolution, predominantly affect the epithelial surfaces normally colonized by bacteria, such as cutaneous, subcutaneous, mucous membranes, the respiratory tract and the intestine: cutaneous and mucosal infections, and lymphadenitis lead to suppuration and fistulation (fig. 22.42) , pneumonia or lung abscesses (fig. 22.43 ) are more frequently characterized by persistent fever and diarrhea [159] (table 22. 17) [109, 538] . pneumonia was the most prevalent infection in 369 patients (79%) (mostly by aspergillus), followed by suppurative adenitis (53%), subcutaneous abscess (42%) and liver abscess (27%); mostly by staphylococcus, osteomyelitis (25%) mostly by serratia, and sepsis (18%), and by salmonella [538] . in a long-term trial, pneumonitis was the most prevalent infection (91%) followed by lymphadenitis (83%), aphthous stomatitis (58%), liver abscesses (25%) and chronic lung disease the rates (%) consist of a first [109] and of a second number related to the european study [84] ; us data regarding ar cgd are in parentheses [97] . data from [84, 97, 109, 185, 501] . x x-linked, ar autosomal recessive, ad autosomal dominant inheritance, nd not done. a the superscript symbols indicate the level of immunoreactive proteins: 0 undetected,diminished, + normal protein levels. granulomas in the entire lung parenchyma, which are formed by mononucleates (fig. 22 .44a) with giant cells (fig. 22.44b) . the chronology of infection onset is summarized in table 22 .18 [335] : lymphadenitis is the earliest. osteomyelitis is usually a worrying complication: (58%) [371] . lymphadenitis, lung infections, enteral infections, and hepatic abscesses were the most frequent infections in a cohort of 48 children [335] . staphylococcal liver abscesses are almost pathognomonic of cgd [447, 538] . because the infections develop in areas drained by lymphatics, they tend to diffuse via the lymphohematogen route, thus causing arthritis and osteomyelitis and abscess formation, especially affecting the bones, which are the most severe manifestation, and hepatitis with common upsurge of hepatosplenomegaly. lung infections are almost the rule: those initially segmented and parallel tend to gradually spread over the entire lobe [109, 538] . histological examination shows widespread gastric outlet obstruction 10 15 urinary obstruction extensive bone destruction involves various segments, for example the vertebra, the metacarpus and the metatarsus, causing widespread damage, which is difficult to treat and is also irreversible [109, 501] . aspergillus, pulmonary, bone (fig. 22 .44c) or encephalic infections constitute a severe therapeutic problem and are threatening events, with a mortality rate of 26%, but with specific treatment the prognosis is good as far as recovery is concerned [335] . the treatment includes prophylaxis with trimethoprim-sulfamethoxazole (tmp/smx) (5 mg/day given in two divided doses), and ifn-g (50 mg/m 2 subcutaneously thrice weekly) in all patients with cgd, regardless of genotype [81, 416] . itraconazole therapy (5 and then 10 mg/kg/day) has an excellent tolerance in all cases and was effective in 29 of 32 children (90.6%) [336] . survival until the age of 21 and beyond is achieved by 20% of patients with cgd xl and 37% of those with cgd ar [339] . because the prognosis is uncertain, as observed, the only possibility for a definite resolution is with a bmt, from family donors who are x-cgd or x-cgd-identical [393] . bmt was successful in 27 children out of 31 (87.1%) (see table 22 .30), including a 4-year-old boy with x-cgd who underwent successful hla-identical peripheral blood sc transplantation during invasive pulmonary aspergillosis and osteomyelitis, which was unresponsive to antifungal treatment [48] . lad is due to mutations in the gene on chromosome 21 at position q22.3 encoding cd18 (table 22 .1). it is divided into five types: lad type i to lad type v [24, 71, 138, 367] . the three subunits of the cd11/cd18 complex are involved in pid (lad type i syndrome), ar, linked to the lack of a m b 2 equal to cd11b/cd18 (table 1.46) surface expression on all leukocyte populations caused by 20 different mutations in the cd18 encoding gene, often severe in infancy [145, 202] . children with a deficiency of these integrins have a defect above all in phagocyte action, suffer from severe infections from the neonatal period [202] due to absent b2-integrin activity, which impairs neutrophil ability to exit the circulation and travel to sites of infection. on the contrary, leukocyte movements are not prevented, indicating the normal involvement of cd54 and cd102 (table 1.4) . the clinical basis for defining this disease, described in over 200 cases [145] , dates back to a study at the soothill school in 1979 [215] . there are two forms of lad type i [71] : if the deficiency is full blown (no detectable cd18), the clinical symptoms (table 22. 19) [71, 138] are dominated by severe and recurrent infections with a negative prognosis in the first years of life unless corrected by an allogenic bmt, the only resolutive treatment [492] . if instead it is a partial deficiency with residual cd18 expression, the clinical outline is less severe and some patients, with appropriate treatment, can live to adult age [24] . lad type ii, ar (cd18 levels are 1%-10% of the normal levels), with a molecular base represented by an slex ligand (cd15s) is a defect common to cd62 e and p, which mediate neutrophil rolling. in the absence of a gdp-fucose transporter, the slex is not made. lad type 2 results from mutations in this transporter that takes fucose into the golgi apparatus for posttranslational fucosylation of newly synthesized proteins. this is the ligand for cd62e; without it, leukocytes cannot make initial attachment to vascular endothelium [7] . lad has been described in two children aged 3 and 5 with mental retardation, from different families, but both with parents who were blood relatives [145] . it has a lower mortality rate [138] . mice with a deficiency of both selectins show a lad-like syndrome, providing a useful model for studying these syndromes [171] . lad type iii shows defective tethering and adhesion and bleeding diathesis. this is a new syndrome where in vitro leukocytes showed normal rolling along endothelial cell cultures but defective tethering and tight adhesion. thus this is a defect in the capability of vascular integrins on circulating leukocytes to rearrange with their endothelial ligands at adhesive contacts and rapidly arrest on target vascular endothelium in response to endothelial-displayed chemoattractants. however, the expression levels of the major integrins on lymphocytes and neutrophils were largely conserved in the patient cells, ruling out a lad-i syndrome. patient leukocytes showed no lad-ii like fucosylation defect, since they expressed normal levels of the fucosylated marker cd15s, comprising the slex carbohydrate selectin ligand [7] . defects in both leukocyte and platelet functions that are biochemically and molecularly distinct from the adhesion disorders previously described suggest a mutation in an early myeloid pathway. the defect is associated with regulation of the gtpase activating protein rap1, as demonstrated by the intact rap1 expression and activation by phorbol esters, thus ruling out an lad defect in rap1 gtp loading [255] . lad type iv manifests defective cd62e expression or tethering. a girl developed pseudomonas omphalitis at 5 weeks of age, recurrent ear and urinary tract infections, and had clinical evidence of impaired pus formation reminiscent of a lad syndrome, but her neutrophils were functionally normal and expressed normal levels of cd18, cd62e, and slex. however, the patient showed an absence of cd62e from the endothelium, although e-selectin mrna was present. in contrast to patients with lad 1, she had mild chronic neutropenia but appropriate leukocyte increases in response to infections or gm-csf. a bm biopsy performed during a period of health showed normal cellularity for her age. her fh is remarkable only for a previous sibling who had died at 32 weeks of gestation of a staphylococcal infection of the fetus, amniotic fluid, and 1313 phagocyte deficiency placenta. she also has two half-sisters who are completely well. the fh is negative for recurrent infections in either parent or more distant relatives [121] . lad type v caused by rac2 deficiency. a 5-week-old boy born to unrelated parents had delayed uc separation, perirectal abscesses, poor wound healing, and absent pus at sites of infection in the setting of neutrophilia, suggesting a neutrophil defect. his neutrophils exhibited decreased chemotaxis, polarization, azurophilic granule secretion, as well as significantly reduced stimulated superoxide production but had normal expression and up-regulation of cd11b. rac2 constitutes more than 96% of the rac in neutrophils [9] . a 1-yearold boy who had multiple recurrent, life-threatening infections characterized by leukocytosis and notable for the absence of pus in the inflamed tissues was reported. the presence and density of cd11b, cd11c, and cd18 were normal. the expression of cd62p and cd62l were also normal. a bmt was curative. the boy shared a phenotype that closely mimicked that of a mouse mutant deficient in the rho gtpase, rac2 [534] . the disease was shown to be attributable to an ad mutation in the rho gtpase rac2 at an amino acid needed for proper interaction with other intracellular proteins. rac2 comprises >96% of the critically important g protein rac in neutrophils. each member of the family appears to control a distinct function of the actin cytoskeleton (chemotaxis and degranulation) and nadph oxidase (superoxide production) function [9] . a male child from the mother's first pregnancy was born at term from parents of arab ethnic origin who were first cousins. he had a severe genetic disorder associated with functional defects in multiple leukocyte integrins, reflected in recurrent infections, profound leukocytosis and a bleeding diathesis. platelet transfusions and antibiotic courses reduced the symptoms, which remained a significant clinical problem. at age 6 years, he died from disseminated fungal infection after a mismatched bmt. a younger brother presented with the same clinical and hematological phenotypes at birth and died at age 1 week from sepsis. g6pd converts g6p to 6-phosphogluconolactone, generating nadph and a h + ion from nadp + . nadph oxidase catalyzes the monovalent reduction of o 2 to o 2 •-, with the subsequent conversion to h 2 o 2 by superoxide dismutase [285] . in the form of a partial deficiency, known as the cause of hemolytic anemia or favism, the enzyme's residual activity (20%-25%) permits nor-mal bactericidal activity. the 400 g6pd variants have been classified by the level of residual enzyme activity and propensity for hemolysis and grouped into five classes: class i, severely deficient with chronic hemolytic anemia; class ii, severely deficient with occasional hemolytic anemia (<10% residual activity); class iii, moderately deficient (10%-60% residual activity); class iv, normal activity (60%-150%); class v, increased activity [310] . in a trial on 161 g6pd-deficient subjects originating from different parts of italy, a greater molecular heterogeneity than described by others was observed, especially in sardinia [310] . in a complete deficiency, sexually transmitted, whose gene is localized on the chromosome x at position p28 and characterized by several mutations and their variants, with a consequent deficiency of bactericidal activity, the neutrophils are unable to kill s. aureus, e. coli and serratia, and therefore there is an increased susceptibility to infections, rather like cgd [109] . the diagnostic work-up of children may reveal a child with recurrent infections who initially received the diagnosis of g6pd deficiency, subsequently shown to have the phenotype of x-linked cgd [3] . the disorder has a higher incidence in mediterranean countries and asia, in japan (10.6%) than in indonesia (4.3%), as ascertained with a novel screening kit [234] , and is low in newborns in tehran, iran (2.1%) [1] . within the framework of oxygen-dependent killing defects, hereditary myeloperoxidase deficiency (mpo) is the most common neutrophil biochemical defect and plays an important role in the host defense mechanism against microbial diseases. the neutrophil disorder characterized by the lack of mpo activity is speculated to be associated with a decreased level of immunity. mpo is unusually accompanied by a specific pathology. ar transmitted, it appears far more common than previously suspected (1:2,000 for the partial deficiency to 1:4,000 for the total deficiency). it is a disorder that is prevalently recorded in entirely healthy patients and therefore, in most cases, a random laboratory finding. in addition to three already-known mutations, the genetic characterization of an italian population showed the presence of six novel mutations: four missense mutations, a deletion of an adenine within exon 3 (c.325dela) and a mutation within the 3¢ splice site of intron 11 (c.2031-2a>c). the c.325dela deletion causes a shift in the reading frame with the occurrence of a premature stop codon within the pro-peptide. the activation of a cryptic 3¢ splice site located 109nt upstream of the authentic 3¢ splice site causes a shift in the reading frame that may lead to the generation of an abnormal mpo precursor lacking the enzymatic activity [303] . in a japanese patient with complete mpo deficiency, neutrophil function analysis revealed that mpo activity was alkaline phosphatase [414] . monocyte functional alterations in the second individual suggest that c/ebph plays a critical role in monocyte/macrophage development of humans and implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of the disorder [455] . severe congenital neutropenia (scn) and cyclic neutropenia are disorders of neutrophil production predisposing patients to recurrent bacterial infections. recently, mutations of the gene encoding neutrophil elastase 2 (ela2) have been indicated as the most common cause for scn as well as the cause for autosomal dominant cyclic neutropenia [225] . deficiency of ela2 leads to regularly fluctuating levels of neutrophils [112] . linkage analysis on 13 affected pedigrees have shown that cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for ela2, located at 19p13.3 [112] . this enzyme is synthesized in neutrophil precursors early in the process of primary granule formation [225] . a mutation in the ela2 gene was detected in one of three apparently autosomal dominant kindreds with familial scn. no mutations were identified in the apparently ar families [12] . these results fit those showing that mutations were found in all five scn families [112] , but they suggest that not all cases of autosomal dominant scn caused by mutations in ela2 [12] . however, the high frequency of het mutations in the neutrophil elastase gene in sporadic scn confirms a previous report [112] . considering that four novel mutations and a low-frequency polymorphism were detected, nearly all cases of sporadic scn may result from de novo het mutations in ela2 [12] . in recurrent scn, an absolute neutrophil count of <200 cells/mm 3 (or <0.1¥10 9 /l) [12] oscillates with an approximate 21-day periodicity. circulating neutrophils vary between almost normal numbers and zero [225] . in about 30% of patients with cyclic neutropenia, however, the cycles range from 14 to 36 days [42] . in 26 children referred during a 22-year period pids were as follows: cyclic neutropenia (30.7%), shwachman-diamond syndrome (26.9%), kostmann syndrome (23%), and chédiak-higashi syndrome (19.2%). the mean absolute neutrophil count of children was 398.2±259.3 cells/mm (range, 74-1,152/mm) at the first visit. the children first experienced symptoms of infection suggesting neutropenia at a median age of 7.5 months (range 1 month to 10 years), also suffering from oral ulcer, otitis, pneumonia, diarrhea, cutaneous abscess, and oral candidiasis [398] . fever, stomatitis, and periodontitis and skin infections occur during periods when the neutrophil count is low. significantly diminished with slightly elevated superoxide production. mutational analysis of the patient revealed a glycine to serine substitution (g501s) in the exon 9 region [356] . because the granulocytes without mpo cannot kill candida, some subjects, presumably carriers of a more extensive mutation and in association with other diseases, present severe and recurrent candida infections. the mpo defect can be diagnosed via a cytochemical investigation or a quantitative count of enzyme levels [303] . neutrophil-specific granule deficiency is a rare autosomal dominant disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins [284] . the markedly decreased level of mrna expression for the bactericidal/permeability-increasing (bpi) protein, the activation factor pu-1 and defensins in these patients suggests a role for ccaat/enhancer binding protein (c/ebpη) gene in earlier phases of the myeloid differentiation program [187] . c/ebpη is a member of the leucine zipper family of transcription factors, expressed primarily in myeloid cells [284] . recessive mutations in the c/ebpη gene were described in one patient; analyses of the c/ebpη locus indicated that the disorder could have resulted from hz recessive inheritance of the mutant allele from an ancestor shared by both parents [187] . loss of c/ebph function is the primary genetic defect in this disease [455] . in a second individual lacking functional c/ebph, analysis of peripheral blood leukocytes revealed aberrant expression of cd45, cd11b, cd14, cd15, and cd16 on the proband cells [455] . a male patient lacking neutrophilspecific granules died from complications of pneumonia at age 20 [284] . neutrophil-specific granules contain important microbicidal components (table 1.23) . among other deficiencies of oxygen-independent killing, this ar defect is characterized by severe recurrent bacterial deep-tissue skin infections without patients showing an increased susceptibility to a particular pathogen. they have defects in chemotaxis, disaggregation, and receptor up-regulation. deficiencies of the oxidoreduction and microorganism-killing mechanisms have also been described. the markedly decreased level of mrna expression for the bactericidal/ permeability-increasing (bpi) protein, the activation factor pu-1 and defensins in these patients suggests a role for c/ebph in earlier phases of the myeloid differentiation program [187] . the defect is identified through a blood test colored with a wright reactive in which polymorphonucleates do not present the specific granules that normally contain lactoferrin. from a morphological point of view, the nuclei appear bilobated and the nuclear membrane may show intro-and extroversions. it is also possible to identify the membrane's lack of cyclic neutropenia is an autosomal dominant disorder in which cyclic hematopoiesis causes intervals of neutropenia and susceptibility to opportunistic infection. in nine families whose children displayed typical blood patterns, pedigrees confirmed dominant inheritance without evidence of heterogeneity or decreased penetrance; three pedigrees suggested new mutations [369] . a wide spectrum of symptom severity, ranging from asymptomatic to life-threatening illness, was observed within the nine families. the phenotype changed with age. children displayed typical neutrophil cycles with symptoms of mucosal ulceration, lymphadenopathy, and infections [369] . patients are usually asymptomatic, but during the period of severe neutropenia, recurrent overwhelming infections, inflammation, and ulcers occur in about 10% of patients and can lead to significant chronic morbidity [298] . severe neutropenia was shown by 21 children, moderate by 4, and mild by 1: 16 of these children had leukopenia, 7 anemia, 2 thrombocytopenia, and 1 monocytosis. during follow-up, respiratory infections developed in 24, oral manifestations in 20 children. the most common infections, in descending order of frequency, were otitis media, abscesses, pneumonia, oral ulcers, acute diarrhea, cutaneous infections, oral candidiasis, and periodontits. sinusitis, cystitis, conjunctivitis, meningitis, and osteomyelitis were less frequently observed. hepatomegaly was also detected in 10 children and splenomegaly in one; 3 children died of recurrent infections. therefore, recurrent infections always deserve further evaluation for detecting such disorders [398] . abdominal pain must be assessed aggressively because of the high frequency of clostridium infections during the period of severe neutropenia [369] . during the course of scn, bm shows lack of maturation of granulocyte precursors beyond myelocytes, and there is myeloid hyperplasia during the remainder of the cycle. occasionally, there is a reduction in the severity of neutropenia and the accompanying infections over time [369] . a complete clearing of symptoms and a significant increase in quality of life is noteworthy in children [298] . however, while the disease is commonly described as benign, four children in three of the nine families died of clostridium or e. coli colitis, documenting the need for urgent evaluation of abdominal pain [369] . pediatric cyclic neutropenia is effectively treated with rhug-csf (recombinant human g-csf), usually at doses of 1-5 mg/kg/day (median dose, 2.5 mg/kg/day) [449] or twice weekly, or once a month. typically, children are noted in early infancy to have persistent scn with absolute neutrophil counts <0.2¥10 9 /l lasting for months or years [12] . in children aged 4 days to 19 months, the initial and lowest median absolute neutrophil counts were 0.29¥10 9 /l and 0.06¥10 9 /l, respectively [289] . usually, children suffer from long-term recurrent bacterial infections, and maturation arrest of myelopoiesis at the promyelocytemyelocyte stage of bm development [12] . the disease begins during the 1st year of life, and its infectious complications include cellulitis, perirectal abscess, peritonitis, stomatitis, and meningitis, commonly as a result of infections with s. aureus, e. coli and pseudomonas aeruginosa [42] . the numbers of circulating monocytes and eosinophils are often increased [42] . missing the most important cells in the defense against bacterial infections, the neutrophil granulocytes, children suffer from episodes of severe, often life-threatening bacterial infections [42] . they spend many days in hospital, requiring iv antibiotic treatment. recurrence of bacterial infections leads to irreversible tissue damage, for example in the lungs, requiring often disabling surgical interventions. a high incidence of significant bone mineral loss was seen in children with scn [545] . the presence of qualitative and quantitative abnormalities of primitive myeloid progenitor cells expressing g-csfr may play an important role in the impairment of granulopoiesis in these patients, thus nearly all patients have a response to pharmacological doses of rhug-csf: neutrophil counts rise, infection rates fall, and mortality is reduced [343] . since the introduction of rhug-csf, most children enjoy a normal life span and a greatly improved quality of life, although they still have problems with infections, especially chronic gingivitis and periodontitis [82] . it is more likely that the bone loss was caused by the pathophysiological features of the underlying disease, but it is possible that rhug-csf accelerates bone mineral loss [545] . prolonged administration of rhug-csf at a dose of 3 u/kg bw twice daily may be associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. in children, the resulting osteopenia can be successfully managed with antiresorptive bisphosphonate therapy with significant improvement in bone density [449] . a child maintained on long-term rhug-csf therapy developed acute myelogenous leukemia associated with a g-csfr mutation.after having undergone successful allogeneic bmt, both ela-2 mutation and g-csfr mutation became undetectable by pcr [237] . shwachman syndrome, a rare ar condition, characterized by pancreatic insufficiency, reduced mobility and neutrophil chemotaxis, cyclic neutropenia, thrombocytopenia, metaphyseal dysostosis, delayed growth and recurrent pyogenic infections, in two cases was associated with isolated gh deficiency [96, 268] . in addition to metaphyseal chondrodysplasia, neutropenia, and pan-poor to absent granuloma formation [242] . salmonella and certain viral infections [hsv, cmv, parainfluenza, and respiratory syncytial virus (rsv)] are also seen [126] . most patients bearing an ifn-gr1 deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome [6] . mortality in these children is high, and infections are severe and recurrent [242] , as in an 8-year-old girl before receiving a bmt [405] . a point mutation may be fatal: an individual, probably hz for the mutation, died from meningitis due to mycobacterium bovis [6] .a hz missense ifn-gr1 mutation was identified in two siblings who did not respond to low or intermediate concentrations, yet responded to high ifn-g concentrations, probably for a reduced affinity of ifn-gr1 for its ligand [243] . otherwise the mutation results in normal surface expression of ifn-gr1 that do not bind ifn-g [244] . a dominant deletion in the ifn-gr1 gene has been reported in a female patient hz for a 4-bp deletion in exon 5 of ifn-gr1 who developed postvaccinal disseminated bcg infection [417] . the ar form of partial ifn-gr1 deficiency was reported in 18 patients of 12 unrelated kindred with susceptibility to mycobacterial infection [403] . an 8-year-old girl with ifn-gr1 deficiency, also with recurrent mycobacterial infections and liver cirrhosis with portal hypertension, received red cell-depleted bmt from her hla-identical sister. the transplantation course was uneventful and 4 years later the child remains in excellent clinical condition and free of mycobacterial infections [405] . a complete ifn-gr2 deficiency was found in a child due to a hz dinucleotide deletion resulting in a premature stop codon in the protein extracellular domain. this gene defect emphasizes the critical role that ifn-g plays in host defense against mycobacteria [126] . a girl with bcg and salmonella enteritidis infection and a hz recessive deletion in the p40 subunit of il 12 leading to a complete il 12 p40 deficiency has been reported. a large hz deletion within the il 12 p40 subunit gene was found, precluding il 12 p70 (composed of p40 and p35 subunits) functional expression by activated dcs and phagocytes. the net result was a markedly impaired ifn-g production by lymphocytes. however, addition of recombinant exogenous il 12 p70 in the assay was able to restore normal ifn-g production in vitro [8] . the girl suffered from well-organized granulomas, possibly due to residual il 12 -independent ifn-g production [8] . another kindred [377] and two siblings and one unrelated patient [142] carried the same large deletion, also accompanied by disseminated infections. a 3-year-old female was repeatedly hospitalized since the age of 5 weeks for recurrent episodes of pneumococcal pneumonia with sepsis and other infections in the absence of creatic exocrine insufficiency, the findings in children are noted as variable extremity shortening, cup deformation of the ribs, metaphyseal widening and hypoplasia of the iliac bones, and increased echogenicity of the pancreas with no change in size [43] . recurrent infections begin during the 1st year of life and commonly involve the sinuses, lungs, bones, skin, and urinary tract [42] . neutropenia, either cyclic or intermittent, occurs in all patients, and 10%-25% of patients also have pancytopenia [464] . immune functions may be involved in this syndrome, including marked pan-hgg, especially of the iga, normal/increased cellular immunity, but depressed humoral and nk cell immunity [268] . in 13 patients diagnosed in infancy, a significant growth improvement and a decreasing frequency of infections were observed over time, in addition to improvement or normalization of exocrine pancreatic function [96] . a continuous spectrum from systemic bcg infection to local recurrent nontuberculous mycobacterial infection covered by the clinical features of affected children has recently helped to identify several genetic defects in the monocyte-macrophage-th1 t-cell pathway [509] . different types of mutations in four genes (ifn-gr1, ifn-gr2, il 12 p40, il 12 rb1) forming the ifn-γ/il 12 axis [123] have revealed both allelic and nonallelic heterogeneity and result in different disorders whose common pathogenic pathway is impaired ifn-g-mediated immunity [123, 403] . several children have been reported who presented a new kind of hereditary id with severe and/or recurrent infections caused by only one microorganism family, in opposition to other patients with classic pid. five new syndromes may encompass these children with a genetic predisposition to infectious diseases. if the ifn-g/il 12 axis is impaired, the host becomes highly susceptible to infection with organisms that replicate intracellularly (susceptibility to mycobacterial disease). stat-1 (signal transducer and activator of transcription-1) deficiency predisposes to viral disease, nemo and irak-4 (il 1 r-activating kinase-4) deficiencies predispose to infections caused by pyogenic bacteria [376] . this pid encompasses several defects: complete, partial, and ar ifn-gr1 deficiency, and complete, partial, and ad ifn-gr2 deficiency [122] . ifn-g and the cellular responses induced by it are essential for controlling mycobacterial infections. patients with ar mutations leading to complete loss of ifn-gr1 or ifn-gr2 expression have the most severe phenotypes, and they present early in life with disseminated severe infections, especially if they have received bcg vaccination, and have fever. she exhibited il 12 deficiency that was associated with an abnormality of the il 12 p40 gene. although present, ifn-g was reduced [211] . a genetic lack of il 12 rb1 surface expression predisposes to severe infections by pathogenic mycobacteria or salmonella and causes strongly decreased, but not completely abrogated ifn-g production [408] . the deficiency may be complete as well as partial [291] . several patients with these features have been reported [291] . three unrelated individuals with severe, idiopathic mycobacterial and salmonella infections were found to lack il 12 rβ1 chain expression. il 12 rβ1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain [116] . a patient with severe infections as above and multiple adverse drug reactions had t cells unable to produce ifn-g or proliferate in response to il 12 , despite the expression of wild-type il 12 rβ1 and il 12 rβ2 [186] . defective il 12 r signaling leads to low t-cell and nk-cell ifn-g production [509] . il 12 rb1 and il 23 rb1 chains are associated in an ar deficiency with susceptibility to mycobacteria and salmonella infections [351] . the stat4 (2 forms, ad and ar [351] ) s721 mutant failed to restore ifn-g production in stat4-deficient il 12 rb2 transgenic cells [329] . stat1, -3, and -5 activation by il 12 was lost, an impairment specific for il 12 ; nor is activation of stat4 alone sufficient for il 12 -induced ifn-g production and proliferation [186] . two unrelated infants hz with respect to mutated stat1 suffered from mycobacterial disease, but unlike patients with ifn-gr deficiency both died of viral disease [133] the complement is an integral part of the humoral defense system against infections and also for promoting inflammatory process (figs. 1.63, 1.65 ). complement deficiency was found in 6/176 dutch patients (3.4%) over a 33-year period (0.1% × year) [156] . from the study of blood donors the prevalence may be of 0.03% in the general population [531] . congenital deficiencies have been described for most of the proteins it is composed of (tables 22.20 and 22 .1f [167, 169, 453, 531] , usually following the ar model. properdin deficiency is the only complement deficiency that is x-linked [531] . hets can be easily identified because their relevant component is present in the serum with a 50% concentration. the lack of one component at the hz level serologically involves the blockage of enzyme release below and the absence of hemolytic activity, while that of controlling proteins causes its uncontrolled activation, consuming the factor that is the object of control and, in various ways, also of successive components [137] . nonfunctional c1q variants have been observed, c1r and c1s deficiencies are often associated, probably because they are mapped on contiguous genes of chromosome 12 (c1q on 1) [167] . the b, c2 and c4 genes, situ-ated on the short limb of chromosome 6, constitute along with others the hla class iii (chap. 1). c6 and c7 are codified on chromosome 5p and have a similar structure; c8 shows a different structure, because the molecule consists in three a, b and g chains, united to form two subunits, a-g and b dictated by different genes [495] . alternative pathway deficiencies are extremely rare [328] . complement deficiencies are accompanied by an increased frequency of infectious pathologies [155] , although it is not rare to come across them in individuals who are apparently in good health, as in the case of c2 hereditary deficiency [422] . also frequent are teens and young adults with autoimmune manifestations (chap. 18). classic pathway deficiencies are often associated with sle-like diseases (systemic lupus erythematosus), id of the early components of complement (c1-c3) are associated with risks of infections caused by encapsulated bacteria such as streptococcus pneumoniae, haemophilus influenzae type b, as well as by meningococci [363] . the incidence of sle in patients with c1q, c4, or c2 deficiency is 90%, 75%, and 15%, respectively [378] . partial c4 deficiency is also associated with sle; 15% of patients with sle exhibit c4a deficiency [531] . several components are associated with development of membranoproliferative glomerulonephritis (table 22 .20 [167, 169, 453, 531] ). in alternative pathway id, the infections recognize pyogens as the most common etiological agents, while final common pathway id (c5-c9) or properdin (p) have been associated with recurrent or invasive infections by neisseria (n) gonorrhoeae or n. meningitidis, gramnegative bacteria, and asplenia, agammaglobulinemia [167, 169, 363, 531] . it is estimated that the frequency of meningitis in subjects with hz deficiency of the final c5-c9 pathway is 10%, 6,000-fold higher than in non-id individuals [363, 488] . some characteristics appear to associate the patients with complement deficiency and meningococcal disease: frequent recurrent episodes, an older age at the first onset, lower mortality compared to patients with a normal complement, and a prevalence of males [167] . over 50 patients with c1q, c1r and c1s deficiencies have been described, c1s deficiency only in two cases [239] . a selective and complete c1s deficiency in a 2-year-old girl with complex aids including sle-like syndrome, hashimoto's thyroiditis, and autoimmune hepatitis has been reported. exon-specific amplification of genomic dna by pcr followed by direct sequence analysis revealed a mz nonsense mutation in the c1s gene exon xii at codon 534. both parents were het for this mutation [127] . a deficiency in one of these proteins is sufficient to block the classic pathway activation; deficiency results as a consequence of non-synthesis, which in the unlike c2, hz c4 deficiency is very rare and is caused by the non-expression of all 4 alleles (2 of c4a and 2 of c4b, 2 maternal and 2 paternal alleles), which can occur due to punctiform mutations, gene deletions, or other gene alterations that prevent gene transcription [28] . the two 4a and 4b genes are polymorphous, just like c2, c3, c6, c4a and c4b and the b factor (bf); polymorphic variants of the other proteins are rare, with 12 different alleles for c4a and 23 for c4b identified at the moment. moreover, two loci c4a and c4b null alleles q0 (quantity 0), do not codify for any phenotype, although often present in the general population [167] . in a 4-year-old caucasian child who suffered from several bouts of pneumonia caused by respiratory viruses, eight episodes of acute otitis media, prolonged respiratory and urinary tract infections, molecular studies of the c4 gene region revealed hz deletion of hla class iii cyp21a-tnxa-rp2-c4b, generating total deficiency of case of c1q amounts to 60% of cases, while in the remaining 40% the molecules are malfunctioning but cross-reacting with the native molecule [328] . c1r and c1s deficiencies are usually combined, due to the contiguity of the two genes; typically in these patients c1r is absent and c1s levels are reduced (20%-40%) [422] . affected patients suffered from a sle-like syndrome and sporadically from an extended predisposition to infections [155] . associated symptoms in c1q deficiency are sle-like syndrome, rheumatic disease, and infection. several children suffered from meningitis, recurrent septicemia, recurrent otitis media, pneumonia, and stomatitis; two died from meningitis septicemia [241] . the incidence is based on the data from [167] ; the inheritance is always ar, with the exception of c1-inh deficiency (autosomal dominant) and factor p deficiency (autosomal recessive or x-linked). data from [167, 169, 453, 531] . gn glomerulonephritis, jra juvenile rheumatoid arthritis. c4b and the flanking 5¢ region up to c4a [230] . moreover, in 7/13 cases the c4a*q0 alleles were related to a c4a/cyp21p gene deletion within the hla-b8 c2c bfs c4aq0b1 dr3 haplotype. in 3/13 cases, the c4b*q0 allele was related to a c4b/cyp21p gene deletion within the hla-b18 c2c bff1 c4a3bq0 dr3 haplotype [212] . the c4 null allele incidence is so elevated that 60% of the population expresses all c4 genes, while 30% lacks 1-3 alleles [328] . the elevated number of q0 probably derives from the marked similitude of the two genes, which facilitates the unequal crossover, but this crossover in the hla can modulate the expression of three c4a alleles and one c4b or vice versa; the c4aq0 allele spreading amplifies the risk of contracting sle and juvenile ra (jra). hz c2 deficiency, the most common in the caucasian population, has an incidence that varies between 1:10,000 and 1:28,000, whereas the het carrier rate is 1.2% [456] . it is usually found in the a25, b18, dr2, bfs, c2q0, c4a, c4b2 haplotype context which, due to its considerable rarity, could assume a predictive value [238] . two different types of c2 deficiency are known: in type i the synthesis is deficient due to the protein nontranslation, in type ii there is a selective absence of secretion but not of synthesis, therefore c2 levels are 0.5%-2% of normal values [238] . hets have a nonfunctioning gene, the complement profile is characterized by serum c2 concentrations equal to 50% of normal values; about 50% are asymptomatic, while the other half exhibit frequent infections and quite a few suffer from sle and correlated syndromes [155] . het c2 deficiency was associated with a 28-bp deletion in the c2 gene (type i), mainly within the hla-a25 b18 c2q0 bfs c4a4b2 dr2 haplotype [212] . in a certain number of cases, a c2 deficiency is accompanied by a partial bf malfunctioning, genetically close to it. hzs can also have a deficient function of the alternative pathway [445] . possibly this deficiency, like other quite common ones, may not always be reported in the literature: the total number of cases therefore underestimates the real prevalence, as is also found in children with c7 deficiency [167] . c2 deficiency must be suspected in all patients presenting pneumococcal infections after the age of 2 years [239] . both c2 and c4 predispose to sle, but this is not the expression of a particular genetic association caused by the same gene localization, because c1q, r, s, deficiencies, which also cause sle, are situated as mentioned outside the hla system [422] . the molecular bases of this pid appear heterogeneous. the c3 gene exists in different allelic forms, some of which have reduced functionality. one must remember the c3 important role in immune responses, also as far as apc and b cells are concerned, as well as the defensive role played in innate immunity along with c4. since both pathways converge in the cleavage and activation of c3, there is no way that this defect can be corrected, and furthermore the opsonic power is greatly deficient, as is the c5 chemotaxis; therefore patients affected by hz deficiency mostly present clinical symptoms totally similar to a congenital hgg with severe recurrent infections and at times the symptoms of cic disease [239] . although id is severe, some patients apparently remain in good health and the syndrome may also in time become less severe, probably due to the higher number of immune experiences that allow a better effector function to antibody reactions mediated by the fc receptor [167] . c3 protein was defective in noninfected nigerian children with protein-energy malnutrition (pem), but rose significantly in the presence of bacterial infection, thus sharing the values found in healthy controls [137] . in its clinical expressions, c5 deficiency does not differ from the other deficiencies discussed here; the clinical consequences of absent c5a anaphylotoxin are unclear [328] . one-fourth of all patients are asymptomatic. in caucasians incidence is 1:60,000 [495] . deficiencies associated with c6-c7 are rare but reflect the close genetic proximity of their pertinent genes; in c6-c8 deficiencies, 63% of patients lacking one component experience at least one severe episode of neisseria infection and 5.5% one aid [239] . rare in europe, c7 deficiency is the second most common complement deficiency in the japanese (0.005%) [339] . in italian children it has a prevalence of 10% and has been identified also in healthy siblings [531] . in japan c7 deficiency is more associated with meningococcal meningitis than with neisseria infections [339] . in a highly inbred arab population, a c7 deficiency was associated with a mutation (g1135c) that is also prevalent among israeli jews of moroccan ancestry [34] . a total deficiency of this 150-kd protein, inherited as an ar trait, has been described in a young patient with a hemolytic-uremic syndrome and in one case in italy whose parents were first cousins [531] . among 21 relatives of the proband studied, encompassing 3 generations, ten had low factor h levels, including her two children, indicating a het factor h deficiency [157] . h deficiency results in uncontrolled breakdown of c3, and in depletion of bf, p and c5 [157] . c3 and c9 components are decreased in varying degrees, while c3 and c5 are found in plasma in traces and only as activated molecules [167] . inheritance of factor d deficiency is for the moment uncertain [488] (table 22 .20): a partial deficiency (6%-12% of normal concentrations) has been described in two mz twins, and a total deficiency in one male. this deficiency, serologically characterized by the non-functionality of the alternative pathway, is clinically accompanied by an increased susceptibility to neisseria infections [239] , leading us once more to emphasize the alternative pathway significance as a substantial means of defense for a broad spectrum of damaging actions caused by bacterial infections. properdin deficiency is the only one inherited as a characteristic linked to the chromosome x and only affects males [190] . at the moment, >50 cases have been described. the deficiency can be materialized by a total p absence, with levels reduced to 10%, with normal levels, however, showing an altered functional activity [239] . specific research has shown a remarkable reduction of c3a and b titers, which represent the c3-convertase proteins, with a consequent heightened consumption due to the alternative pathway spontaneous activation. males are affected by septic episodes caused by neisseria, sometime fulminating, with onset even occurring during the 1st year of life [488] . there is no evidence of increased susceptibility to cic diseases or infections caused by other organisms [155] , thus implying that a functioning alternative pathway is particularly important for a defense against infections [328] . correctly identifying children with complement abnormalities is important and worthwhile if any of the following factors are present: id (such as repeated or unusual infections with other organisms, fh, unusual course of the illness, etc.), repeated neisserial infections, infection with an unusual serogroup, fulminant disease in males (p deficiency), coexisting angioedema, autoimmune, or connective tissue disorders [220] . in the two forms of c8 deficiency (c8a + c8g and c8b mapped on chromosome 1), the subunit not involved is present in the serum, also with reduced levels, and accompanied by altered functionality of the one involved. c8 deficiency has different characteristics due to the diverse associations of the b and a-g chains; therefore caucasians with this deficiency lack the b chain (10%), while colored patients lack the a and g chains (90%) [495] . c9 deficiencies are poorly considered because they are often asymptomatic [339] ; however, in japan there is an incidence of 0.1% [339] and between 33% [155] and 25% of cases [339] present meningococcal meningitis. congenital c9 deficiencies are very common among the japanese (0.036%-0.1%) and represent 11.3% of all deficiencies (table 22 .20). there have been >150 cases of congenital c5-c9 deficiencies reported, distributed unevenly between the various ethnic groups: c5 and c6 deficiencies are prevalent in colored patients and the c7 deficiencies appear to be more common in caucasians [422] . an analysis of published studies shows that 14% of patients with sporadic meningococcal infections may have a c5-c9 deficiency [495] . clinical patterns are overlapping. the most common complement deficiency is c1-inh deficiency (c1 inhibitor), responsible for hereditary angioedema that causes symptoms in hets (chap. 8). at least 15 cases of factor i deficiency are known [328] , with autosomal co-dominant transmission because parents show normal complement levels at 50% of factor i [239] . as in an h deficiency, serologically one has the alternative pathway activation, due to c3b non-catabolization that continuously forms c3 conversion with severe c3 deficiency, the levels of which do not exceed 15% of normal values [155] . in hzs, in addition to subsequent pyogenic infections, as in c3 deficiency [422] , cutaneous rashes and urticaria caused by massive release of histamine and pro-inflammatory cellular products by anaphylotoxic fragments are reported [167] . the fact that a child during the initial period of life should experience a certain number of urtis or lrtis is within the norm: rris are mainly caused by immunological immaturity or inexperience, both transient. a typical symptom outline is difficult to define, and prevalence is also little known. in id children, a basic pathology is present instead, which encourages the recurrence of infections. although a distinction between infection and associated disease is important, childhood infections might have a key role in stimulating the maturation of the immune system, and the microbial burden in early life has been invoked as a protective factor against wheezing and asthma (chap. 4). preschool-age children have an especially high frequency of vris, with most having three to eight infections per year and 10%-15% have ≥12 vris per year. the rate in children aged 0-4 has been about 1 in 200 children compared with about 1 in 500 for children aged 5-10, and about 1 in 1,000 for those aged 11-17 [413] . rris may be defined as >six episodes of urti and/or >3 lrtis in the previous year, or based on age and ≥8 episodes per year if aged <3 or ≥6 episodes per year if aged ≥3. several risk factors can influence the onset and recurrence of infections [217] . it is clear that the younger the child is, the more he/she may fall ill: this is also related to serum ig levels (table 1 .15). the dogma of primary and secondary responses also may not apply to infections, at least those caused by rotavirus, which confers considerable protection only after various infectious events and in children aged 1 [511] . environmental factors in the absence of a basic pathology are important. it is also obvious that the more crowded the environment the child lives in, the more probable that infection becomes. in addition to the number of siblings, other factors such as socioeconomic status, age (preschool children), contact with outside persons, especially babysitter, early social contacts, exposure to passive smoke, indoor and outdoor pollution may be found to be related to the hygiene hypothesis (chap. 4). however, daycare attendance, which was considered to be an indicator of exposure to respiratory pathogens, and the presence of siblings, increased the risk of urti in preschool children aged 4-5 [273] , and in the 1st year of life for children with fha [88] . among children with fha, the protective effect of day care attendance in early life against the development of atopy only begins by 2 years, and against wheezing this may not be observed until after 4 years [89] . the particular ease of smoking parents and/or relatives who fall ill with influenza has been known for some time, to the same extent that the children who live with them are affected by rris (table 4 .24). the impact on rri incidence as it is related to children in kindergartens, has been reflected by a significantly increased morbidity observed in babies aged 3 months to 3 years who go to daycare, who show a number of more severe and longer lasting infections per year [523] , with an incidence of 6.5% in children who stay at home compared to 13.1% of those in kindergartens [524] and an increase of 49% of ome persistence (chap. 15). in children exposed to cigarette smoke, the risk increased 3-fold for lrti [221] or by 3.5-fold, equal to ≤3 episodes of respiratory infections each year [26] . studies on environmental pollution have identified the most damaging agents: conclusive data on fine particles in suspension and polluting derivatives is available, proving a significantly increased risk of infantile rris: table 4 .20 indicates that no 2 reduces immune defenses against rtis, provoking alterations of the epithelium and of the lymph node cells, with negative effects on mucociliary clearance and macrophages. the biological role played by no 2 in the domestic pollution derived from the home has been ascertained to be related to cooking and the smoke released by combustion [26] . using wood for heating leads to so 2 development, while radiators cause the air to dry, which in turn causes potentially infected particles to remain in suspension. pollutants are increasingly responsible for indoor pollution (chap. 4). although levels of micro-pollution are not easily ascertained, significant associations with acute rris and conditions such as polypnea and dyspnea have been reported, especially in <2 year-old children [507] . these children's capacity to evoke adequate responses is genetically controlled; however, it is commonly known that their parents or siblings have suffered similar illness as children. in subjects with physiological immaturity of the immune system, vris more easily cause infectious episodes, which are important factors to be considered only in the presence of recurrent or incompletely cleared conditions [165] . predisposing factors related to a basic pathology derive from perinatal factors, more common in premature babies, which can lead to respiratory tract alterations and consequently to bronchopulmonary dysplasia; anatomical anomalies; cystic fibrosis, which can become recurrent pneumonia; adenoiditis causing otitis and ome; congenital ciliary dyskinesia; humoral deficiency and pid characterized by recurrent sinopulmonary infections [101] (table 22 .21) [79] . viruses are the principal etiological agents, and over 159 a novel member of the coronavirus family has been characterized, which is associated with cases of sars (severe acute respiratory syndrome). phylogenetic analyses and sequence comparisons showed that sarscoronavirus is not closely related to any of the previously characterized coronaviruses [421] . as investigated by a 15-year study the overall prevalence is age-related, and different between children aged 0-4 ( fig. 22.46) [326] and those aged 5-19 ( fig. 22.47 ) [326] : rsv and rhinovirus have a different impact on the first group (58% vs 28%) and the influenza viruses on the second group (9%-48%). incidence in young children was 1.75-fold higher than in those aged 5-19 [326] . rsv causes bronchiolitis in breast-fed babies, with a higher frequency the younger the child is (tables 11. 24, 11.25) , and rhinitis in older siblings. even an infectious agent neglected for some time, such as ureaplasma urealyticum, causes a lung pathology in younger children while sparing those >3 years old [271] . the bacteria most commonly involved are: streptococcus pyogenes (pharynx and larynx); haemophilus in-1323 complement deficiency fluenzae (middle ear and larynx reaching the epiglottis); and streptococcus pneumoniae (middle ear). there are often secondary bacterial infections such as complications caused by vris, which certainly contribute to recurrent infections and/or the onset of chronicity [508] . in chap. 4 we reported several studies which concluded that early infections may protect from atopy development (hygiene hypothesis). we must distinguish pid outlines and pseudo-id in children with rris. summarizing the aforementioned, severe and recurrent lrti and sinusitis are the principal clinical manifestations in children affected by deficiencies prevalently involving humoral immunity (table 22 .1). these children fall ill during the first weeks of their lives and often contract infections caused by opportunistic agents, fungi, protozoa and viruses, and as months go by are also affected by malnutrition and failure to thrive. episodes affecting the airways, particularly common in cellular and combined id, tend to become longer or severe, especially if complicated by pneumonia [44] . chronic disorders such as sinusitis and bronchiectasis (sinobronchial syndrome) are not rare; interstitial pneumonia is in most cases caused by pneumocystis carinii and results in tachypnea and lung hyperinflation [409] . infections supported by the herpes simplex, ebv and cmv are also common: males with xlp exhibit a deficient response to ebv [446] . severe and recurrent sinopulmonary, was, higes and ata infections as well as severe rris in cgd, complement deficiencies and lad 1 to v must also be borne in mind. cases of recurrent pneumonia should be warning signals to rule in 4.8% pediatric cases of pids [392] . the second most important manifestation is chronic diarrhea: in some cases the infections are caused by rotavirus and enterovirus among which the echo: giardia lamblia, salmonella and campylobacter can also cause chronic enteric infection; malabsorption resistant to treatment can be ascribed to cryptosporidium [80] . rris are common in children. they reflect the immaturity of the immune system in its encounter with environmental antigens; this developmental delay during the first years of life fosters the development of rris. thus, rris are part of the growing-up process of any child [47] . the consequences of rris can be of a profound and sometimes protracted alteration of the different immune defense mechanisms, which place the child in an undefended position, similar to the condition observed in children with pids, compromising the phagocytes, lymphocytes, nk cells, antibody production, and ils at every occasion [419] . the responsible viruses for these infections have a development limited to surface mucous cells, spreading from cell to cell due to contiguity, while the viremic stage is absent or remains marginal. the incubation period is therefore brief, normally <3 days; consequently the immune response may not be capable of ensuring a protective function, or it only intervenes partially, clarifying the potentially unlimited number of infectious episodes [392] . from a pathogenetic point of view, the virus works by triggering the development of ige and allergic sensitization and/or damaging the immune structures [322, 519] . in the first case, it is known that experimental infection in mice with rsv is capable of significantly increasing the absorption of ovalbumin (ova) administered by aerosol, of igg, ige and anti-ova siga (fig. 4.26) and of increasing the synthesis of ige and specific igg to ragweed also administered by aerosol. the result is that the majority of infants become infected with rsv, although lrtis develop in only about 20% [382] . approximately 25%-50% of those subsequently experience recurrent acute asthma from vri [530] . the mechanism by which vris induce atopic sensitization in experimental models is identified with antigen penetration and sige synthesis [322] . studies show that viruses increase mucosal permeability, by modulating antigen uptake and altering antigen processing by the mucosa, which results in the ige-suppressor t-cell depression, while ifn-g-modulated histamine release further increases mucosal permeability [162] . it is probable that the immune deficiency is secondary to vris, because many viruses are capable of inducing transient [521] . the lack of nk cells, which are in the front line of defense against viral infections, and with which the altered production of il 2 and factors activating the phagocytes are associated, appears significant, but it is unclear whether the deficiency is primary or secondary to viral infections [419] . the basic question with potential therapeutic consequences therefore remains unanswered, and is probably destined to remain so until more sophisticated tests are available to clarify this issue, although the nk-cell reduction in these children corroborates the first hypothesis. recent data emphasizes the important defensive activity of cytotoxic cd8 t cells and by different ils, including il 10 , il 28 and il 29 active in antiviral defense: if the infected cells express on the surface the viral antigen processed in association with hla class i molecules, cytotoxic cd8 take care of killing the cell. normally the cd8 are activated by the virus itself or by soluble factors released by the infected cells and mediate the cellular lyses after recognizing hla class i antigens on the same cell. however, if the apc is a macrophage, it can be parasitized by the virus, with consequently reduced chemotaxis and microbicidal activity and in particular the capacity to cooperate with t cells [322] . considering that macrophages may have evolved specific mechanisms for directing t-cell development toward the th1, since cmi can solve some infections, it is clear that their dysfunctions appear in the insufficient nk cell activation and inadequate th1 development in response to infections. ifn-g, produced not as a direct consequence of infection, but probably by il 12 and/or il 15 , stimulates the nearby cells to block the nucleic acid transcription and therefore the viral replication, preventing the infection of those cells to which virus spreads due to contiguity. therefore the ifn-g species-specific antiviral activity takes place at the very first stages of the infection, preceding the antibodies [322] . the response to germs' capsular polysaccharides, particularly deficient until the age of 2, although encounters with these germs are abundant during this period of time, still remains to be evaluated [508] . however, selected children, although normal from an immunological point of view, may have a deficient antibody response even aged 4-8 [195] with a percentage of modifications of both humoral and cmi, therefore not only of antibody synthesis or phagocyte and neutrophil functions, but also of t lymphocytes and related ils [457] . it is also possible to hypothesize that persistent vris are capable of inducing th2 activation by antigens or super-antigens: th2 t cells with il 4 help induce virus-specific cd8 + to produce il 5 , which recruits eosinophils in the respiratory tract, thus reducing ifn-g secretion. thus there may be an increased interaction of ige mast cells in these subjects with immunoregulatory alterations, due to a marked lymphoproliferative response and the elaboration of other ils, which consequently amplifies ige production in the respiratory tract. the ige response is thought to lead to a greater production of bronchoconstrictor mediators by effector cells; viral infections themselves may induce these cells to release histamine. it is also known that humoral deficiency, especially of iga, very often opens the way to gram-positive germs causing viral and bacterial infections, thereby completing the circle [409] . interestingly, only 2/13 children have at least a significant production of antigen-specific salivary iga against klebsiella pneumoniae [418] . even if the alterations are transient and aspecific in children with rris, their occurrence and persistence for a number of months, for a year and even longer, leads to believe that the immunosuppressive mechanisms set off by the first episode occasion more severe, profound and lasting consequences for the immune functions than those occurring in their normal peers [36, 273] . having at least one physician-diagnosed lrti in the 1st year of life was significantly associated with recurrent wheezing (or, 2.0) and asthma (or, 2.5) [89] . at the base of this exclusive predisposition in children for contracting rris, there is a nk cell reduction [419] and immune deficiencies related to the global lymphocyte population, the cd4 and the cd4:cd8 ratio, unbalanced toward cd4 t cells, prevalent in children expressing coughing compared to those with bronchial hyperreactivity (bhr) [374] . other t-cell deficiencies in children with humoral anomalies include a considerable spontaneous production of il 2 and il 4 , both generated by th phenotypes, or alternatively by the th0, which express both ils [216] . it is similarly feasible that virus-specific cd8 deprived of cytolytic activity are converted into th2-like t cells when il 4 is present [216] . cmi in these children consists above all in the transient t-cell numeric and functional depression, coinciding with a deficiency of ils necessary for their activation, proliferation and differentiation. the virus toxic effect also acts directly on the t cells, inciting rough structural modifications including giant polynucleate cells, which jeopardize homing and recirculation capacities, to the point of immunosuppression, affecting the specific lymphocytes for that particular virus, thus favoring the attacking organism [552] . a condition of immunosuppression occurs also as a result of superantigen (sa) orchestration, which, stimulating a large num-nonreactive children of 4%-19% [143, 430] , rising to 13%-42% if with an iga and/or igg subclass deficiency [198, 216, 430] . while 50% of children have low antipneumococcus igg 2 , antibody responses are totally absent in 40% of dysimmunoglobulinemics with a virtual absence of iga and igg 2 [430] , confirming previous data [198] . iga and igg 2 -deficient children show a clinical pattern with elevated susceptibility to s. pneumoniae infections [430] . von waldeyer ring (nalt) is a significant constituent of immune response, and of resistance to nalt-dependent infections. among the consequences of chronic adenotonsillitis (table 15. 2) the statistically significant decrease in ig levels, including siga, must be evaluated eventually in relation to rri complications (chap. 15). igg subclass deficiencies can be present in children with chronic and/or severe asthma, associated or not with sigad, in children affected or not by asthma with severe rris or with chronic nonallergic respiratory clinical symptoms, in children with sigad, ata, was, cvid, scid and in healthy subjects [80] . the anti-virus antibodies generally belong to the igg 1 and igg 3 isotypes while the igg 3 protect from microbes with polysaccharide antigens, such as s. pneumoniae and group a and type b h. influenzae [153] . table 22 .7 shows normal values for igg subclasses in subjects aged 0-15. unlike total igg concentrations, igg 1 and igg 3 reach normal levels within the 1st year, igg 2 mature more slowly, ensuring an effective antibody response only after the 2nd year, and igg 4 develop even more slowly. various authors believe that the role played by igg subclasses is unique and vital in defending from infections: igg 2 deficiency is associated with an increased susceptibility to infections by bacteria expressing capsular polysaccharides, such as pneumococci, meningococci, h. influenzae, bordetella pertussis, etc., as well as other factors capable of setting off an inflammation [113, 465] . igg 4 deficiency instead seems associated with a marked predisposition for rris [333] . however, undetectable igg 4 subclass levels are a common finding in normal individuals and an accurate detection of very low levels of igg 4 is technically difficult to achieve [450, 465] . babies aged ≥1 month have levels of circulating lymphocytes secreting all four subclasses in a higher number than adults; therefore the capacity to produce antibodies exists well before a full humoral response is developed. subnormal igg subclass concentrations, especially of igg 2 , are also observed in healthy children who do not present an increased susceptibility to infections. low subclass levels do not necessarily indicate that the subject will experience immune disorders exclusively linked to these, nor do normal concentrations guarantee that the child will be spared complications. sub-jects have been observed both with normal igg 2 levels and with recurrent infections and with a subclass deficiency, which often do not form other types of antibodies [450] . igg subclass determination does not indicate what the humoral level restricted to that molecule is: this is a characteristic in children, unlike adults, even though research was carried out using the same methods in the two studies [465] . interesting hints come from studies involving children with rris: of children aged 2-10, with a confirmed diagnosis of susceptibility to infections, 67/567 (11.8%) had a igg subclass deficiency, almost all concerning igg 4 , with several associations [283] . in other children, the selective igg 4 deficiency was statistically significant compared to atopic controls without rri, associated not so much with a well-defined state of id as to a respiratory tract defense mechanism deficiency, in view of the fact that the relative prevalence of this subclass in secretions may indicate a role in the mucosal defense [333] . other children with typical symptoms of recurrent infections, lymphadenopathies, failure to thrive and hgg exhibited low igg 2 levels, confirming that normal levels of total igg do not exclude a subclass deficiency [454] . in a cohort of young babies, igg 4 deficiency was only present in 78/267 subjects (37%) [198] ; however, the absence of a control group makes the results incomparable. an igg subclass deficiency is therefore able to induce or worsen chronic respiratory symptoms in allergic and nonallergic children, especially if predisposed to developing these affections [113] , or in subjects with sigad [327] . with time these deficiencies, and eventually also those associated with iga, can normalize [29] . in conclusion, transient and persistent iga and/or igg 2 deficiencies have been reported in a small percentage of asymptomatic children [446] , but even if iga and igg subclasses are not always required as such for a normal immune response, their deficiency may predispose to rris [160] . as previously illustrated in chap. 11, the close links between atopy and rris are known, and this is confirmed by the observation that asthmatic children have a higher incidence of rris than their nonasthmatic siblings. it has been known that rris during the early periods of life can play a role in the development of bhr and atopy: in the classic study by frick et al [173] , in 11 out of 13 allergic children sensitization was propitiated by rris. with continued observation, the authors noted the presence of high ige levels, positive rast and histamine released by leukocytes after infections [172] . in a cohort of 73 asthmatic children aged 0.8-3.1, the 21 affected by 20th week of pregnancy is possible, so as to evaluate the immune phenotype in the fetal blood [491] . wccs (white-cell counts) in cb and differential counts can be used to detect the lymphopenia that is commonly present in infants with scid. however, subset analysis by flow cytometry is necessary to enumerate t, b and nk cells. subsequently, scid diagnosis will be suspected when overwhelming opportunistic infections occur [320] . depending on whether one suspects a humoral, cellular or innate immune deficiency, we begin with the algorithm in table 22 .23 [107] , positive if infants or children have ≥2 of these signs, then 478, 522] on laboratory tests can be consulted. however, children with variable levels of antibody id may end up with different diagnosis [269] . children with higms presented initially with a history of an increased susceptibility to infection including pneumocystis carinii pneumonia [539] in 43% of children [290] . in pids affecting phagocytes, because of the relatively narrow spectrum of disease-specific infections (such as aspergillosis in cgd), careful attention to the microbiology laboratory early in the course of evaluation of a patient suspected of having a pid is crucial to orient the work-up in the appropriate direction [416] . in a male newborn referred to hospital at 27 days of age for fever, hemodynamic failure and an inflammation syndrome caused by pulmonary infection, culture of tracheal, bronchoalveolar lavage samples and lung biopsy grew positive for a. fumigatus, enabling the diagnosis of cgd [337] . to investigate whether patients with undiagnosed id could be identified in diverse inpatient hospital populations, a scoring algorithm and computer screening method was updated [107] on the basis of icd-9 codes to survey the discharge diagnoses of all hospitalized patients over periods of time. thus 17 id patients were identified, eight of whom were children aged 2-10 (47%), two with neutropenia, two with igg deficiency, one with lad, one with dgs, etc. [108] . we also suggest including congenital phagocytic defects in the differential diagnosis of recurrent bacterial or fungal infections in a child [285] . a congenital complement deficiency should be suspected if levels of even one component are reduced [167] . early diagnosis is essential for choosing the necessary treatment [44] . the differential diagnosis of pid will emphasize the different characteristics schematized in table 22 .27, to which one must add objective rarity, while fh and child gender become important [10] . in subjects suffering from omenn syndrome, was, severe combined and cellular ids, the screening of clinical symptoms may be useful at birth and during the first few months after birth (table 22. 28) [61, 80, 399] . the localization of infections is multiple, the id child usually appears to be ill, and the peripheral lymph nodes and lymphatic rris had a higher incidence of fh positivity (p=0.015), increased ige (p=0.021), as well as a combined iga (p=0.038) and igg (p=0.018) deficiency [296] . ige hyperproduction could be the result, not only of the wellknown association between igg subclasses and ige and their coregulation of il 2 expression [296] , but also of a virus-caused unbalanced cd4:cd8 ratio [374] . these results link atopy to rris, confirming that the state of chronic inflammation and bhr induced by allergic sensitization is an ideal substratum for the adhesion and chronic evolution of bacterial and/or viral infections. there are no specific clinical outlines for rris. on the contrary, symptoms are extremely varied, with, as previously mentioned, infections caused by bacteria and viruses. urtis are common at age 4. during the last 12 months, 9.5% of the children experienced more than one bout of acute otitis media, 6.9% had more than one pharyngotonsillitis episode, 47.7% contracted >2 common colds, and 3.2% had rhinitis weekly or monthly [273] . there are children who, during the period of maximum exposure due to biological immaturity and immunological inexperience, suffer from one episode each month affecting different organ systems, as well as lymphadenopathies and failure to thrive. the capacity for inducing bhr in normal subjects and worsening the symptoms in those already ill are precisely caused by vri, also facilitating greater penetration of inhaled viral allergens [530] (table 11 .10); rris in turn predispose to sinusitis. lower ifn-g levels produced by 18 of 53 children at 6 months of age were even greater if the comparison was made between children with rris and those with no or maximally one rri during the follow-up period [382] . rhinovirus-induced infections (table 11 .11) take the appearance of common rhinitis, but stimulate mastocytes to release histamine, contributing to bhr development and the perspective of delayed reactions. a differentiating feature is the respiratory infections in the id child that may also result from opportunistic pathogens [80] (table 22 .21). respiratory infections should be under control. a screening of humoral immunity revealed low ig levels in 4.6%, low iga levels in 2.3%, and sigad in 1.3% of children [270] . during the last few years, increasingly sophisticated diagnostic techniques have permitted prenatal diagnosis in many cases (table 22. 22) [61, 166, 389, 406, 414, 491] : in forms supported by rag-1 and/or rag-2 mutations a diagnosis even at the 10th-12th or at the pharyngeal tissue are almost imperceptible [102, 196] . the seriously undernourished appearance should be noted, more often observed in children with scid [162] . rris can be observed in other cmi forms [162] : deficiencies of cd3 g and e chains [18, 249, 471] , zap-70 [92, 139] and hla class ii [77, 256] . finally, children with aids will seem to be in severe general condition and this disease is a paradigmatic example of how hiv can overturn the t lymphocyte immune defense with regards to opportunistic infections [79] . in some cases of pediatric aids there is hgg that is indistinguishable from pid and that belongs to the differential diagnosis of severe recurrent infections during the first few months after birth [79] . as far as tih is concerned, the confirmation of a normal presence of the b lymphocytes and low levels of intrinsically produced ig is resolutive, compared to agammaglobulinemia [61] . an articulate case history often identifies the familiarity of rris, usually with an absent basic pathology and the frequent predisposing environmental factors (table 22 .21), among which passive cigarette smoking stands out. maximum prevalence occurs during the first 2 years of life or during first contacts with school, the disease is limited in time, and there is usually a single location. in most cases the pseudo-immunodepressed child is clinically normal in all other respects [374] . in ten reported sars-infected children from hong kong, fever, cough, and runny nose were 1329 complement deficiency lateral pharyngeal x-ray to visualize adenoidal tissue cytokine production (il 2 , il 3 , il 4 , il 5 , ifn-g, il 12 ) chromosome fragility (ataxia-telangiectasia, bloom's syndrome, etc.) data from [101, 478, 522] . ada adenosine-deaminase, adcc antibody dependent cellmediated cytotoxicity, ctl cytotoxic t lymphocytes, ltt lymphocyte transformation test, pha phytohemagglutinin, pma phorbol myristate acetate, pnp purine nucleoside phosphorylase, ppd purified protein derivative. sars seems to have a less aggressive clinical course in younger children [223] . when in doubt, a broad spectrum of laboratory tests are available: cbc, proteinemia and protidogram, serum ig levels, or in secretions and igg subclasses (table 22 .7), immunoelectrophoresis (homogeneous components, k/l), dosage of isohemagglutinin, five other natural antibodies, the sweat test [10] , in strictly selected cases also a lymphocyte population and subpopulation count (tables 1.34-1.39), and x-ray of paranasal sinuses. analysis of the lymphocyte profile sometimes shows a number of deficiencies, statistically differentiated from those found in other children affected by an asthmatic pathology; however, none of the immunological deficiencies indicated (table 22 .29) are characteristic in pseudo-immunodepressed children. common diagnostic methods may not be capable of revealing a deficiency of igg subclasses or of selective igg 4 : the chance that there may be abnormal igg 2 or igg 4 levels is not excluded by the normality of igg serum concentrations [153] . furthermore, the distribu-tion of igg into four subclasses makes it difficult to identify these deficiencies simply by measuring total serum igg levels [113] ; only for the past few years have there been highly specific reagents for measuring individual subclass levels and methods such as radial immunodiffusion (rid) [198, 317] . the aaaai has recommended not relying on subclass levels [10] , especially igg 4 levels, which seem to be unmeasurable in 25% of the population [198] . rid, which has proven to be more sensitive than the elisa used by the cdc in atlanta, has shown that 25% of normal children have values below normal for at least one subclass [317] ; a similar deficiency was present in 58% of children with rris [198] . a recent study measuring the igg with both methods, has proved that the rid can show higher values of igg 1 and igg 2 in low serum levels of both ig [387] , data with an unquestionable negative effect in pediatrics. in conclusion, at the moment our knowledge suggests that we should also carefully interpret low levels of one or more subclasses, because on the one hand this might indicate a transient or paraphysiological condition, on [174] . igg levels in all patients also rose considerably compared to previous treatment: the average levels in different determinations was >700 mg [174] . finally, all children grew normally; the height achieved by each child is between the 3 rd and 50 th percentile, within the limits of theoretical values calculated on the height of their parents. substituting therapy with ivig has allowed patients to return to their normal activities, with a considerable improvement in quality of life. in all these years, we have never come across substantial unwelcome reactions or infectious complications [174] , as also found by other authors [177, 461] . ivig could also be effective for reducing the allergic symptoms discussed thus far: presuppositions are not lacking, such as the blocking of allergens and mastocyte fcr thanks to the modest quantities of igg 4 present in the preparations [196] . in addition, the increased understanding of the igg transplacental passage (chap. 2) can absolve the function of timing their transfusion in the case of mothers with antibody id, so that the fetal defenses can be complete and quantitatively adequate. in sigad common ivig preparations cannot be used, even if with a low content of iga, nor enriched, both because of the extremely short iga life-span, which would therefore suggest iga administration every 2-3 days, and because the infused iga do not reach the secretions [507] . should ivig be indicated for a deficiency associated with igg 2 , or should transfusions of blood derivatives become necessary, one must first investigate serum antibody anti-iga levels (igg and ige) and, should these be positive, avoid infusions or administer them in a hospital under strict medical supervision, or use washed red blood cells [507] . the same precaution must be taken for subjects with ata for whom ivig, if is appropriately administered, also ensure beneficial effects on quality of life, while there are no known therapies for contrasting neurological symptoms. in patients with humoral deficiency, alongside ivig, if appropriate, an antibiotic prophylaxis is suitable with monthly cycles, alternating amoxicillin, cephalosporin, co-trimoxazole, etc., bearing in mind family compliance. in cvid recurrent infections caused by giardia lamblia should be treated using furazolidone (8 mg/kg/day) or methronidazole (15 mg/kg/day) for 10 days, if necessary to be repeated. cvid treatment in specialized centers involves recombinant il 2 , il 10 and cimetidine [456] . some t-cell pids represent a severe clinical emergency, such as omenn syndrome, in which hypovolemic shock and reticular dysgenesis are immanent in the battle for survival. although precise figures are unavailable, thousands of patients worldwide with different forms of the other a modest deficiency can result in clear hgg [451] . subnormal igg 2 levels can indeed be associated with various manifestations of immune dysfunctions; it is therefore advisable in this case to proceed with specific investigations, measuring the response to polysaccharide antigens and studying the lymphocyte activity in vitro [451] . in children with normal serum levels, who are instead lacking in antibody responses to polysaccharide antigens [143, 430] , this is a conclusive investigation [470] (fig. 22.47) . a study of children aged >5, half atopic and half not, has confirmed this thesis, concluding that the answers were similar in both groups, therefore excluding a greater rri predisposition in the atopic children [344] . many patients with high ige levels do not present atopic manifestations: it is thought that an increased concentration is related to a reduced inhibiting activity of the thymus in ige synthesis [457] . recurrent sinopulmonary infections must make one also consider cystic fibrosis and immotile cilia syndrome [457] . children with malnutrition (chap. 21) suffer from numerous ids, prevalently concerning cmi; their vulnerability makes them succumb to severe bacterial me infections and urtis, often also risking death. obese subjects may also be affected by rris due to a possible adipose tissue hypovascularization or to a defect in the granulocyte microbicidal activity [457] . in the presence of antibody deficiency, antibiotic treatment is chosen as a preventive therapy in less severe cases, otherwise the preferable therapy consists in ivig (fig. 22.48 ). this treatment is restricted to a limited number of diseases, including some forms of id, secondary or cytopenic id, in which effectiveness has been proved in dbpc studies [135, 426, 439] , like other positive forms of intervention described, while it appears to be of no use in uncomplicated thi [426, 439] . two children aged 2.5 and 3 with higes and kawasaki disease were administered 400 mg/die of ivig for 5 days and one 2.5-year-old with higes received only one dose, with ige levels falling from 4,000-14,000 to 600-5,000 ui/ml on the 28th day. hence there was almost a normalization of ige production with symptom relapse after 6 months; similar results using a single dose were also obtained in two children with higes and severe ad [254] . the following data represent a number of clinical and immunological parameters in children suffering from humoral pid and ata, with igg levels <100 mg/dl. treatment with ivig, also at a higher dosage, was very well tolerated by patients: all children presented a clearverely affected by several factors [26] . either hla-identical marrow or t-cell-depleted (tcd) haploidentical parental marrow is the standard of care for scid ( fig. 22.51) . when histocompatible related donor bmt is unavailable, a bmt either with hla-identical unfractionated or tcd haploidentical parental marrow is the standard of care for scid [338] . all but one (95%) of 21 scid infants who received tcd identical or haploiden-genetically determined id have been given bmt in attempts to correct their underlying id [66] , including a recent series [14] . specific treatment for cellular pid consists in a bmt from a hla-compatible donor [10] . the ideal sc donor is normally a sibling who shares identical hla class i and class ii loci. without such a donor, these transplantations usually resulted in fatal gvhd. if death did not occur, event-free survival was se-1335 treatment tical bmt in the first 28 days of life are currently alive, with the period of survival ranging from 8 months to >19.2 years after transplantation. this compares favorably with a 74% survival rate of 96 infants receiving transplants at a median age of 190 days (range, 45-516 days) [338] .a girl with t -b -scid received a full matched bmt from her sister at age 2 weeks [491] . a worldwide survey conducted by buckley from 1994 through 1997, with subsequent additions of published cases from the literature, revealed that 239 of 302 (79%) patients with pid transplanted with hla-identical marrow during a period of 34 years were alive [65] . there are >375 patients worldwide who have survived scid as a result of successful transplantation of hla-identical or haploidentical bm [67] . most importantly, 34 of 35 infants (97%) undergoing transplantation in the first 3.5 months of life are currently alive [69, 338] , compared with a cut-off at 6 months (97% vs 86%, children younger vs those aged >6 months) receiving bmt (or 5.0 [14] ). we stress that neonates developed higher lymphocyte responses to phytohemagglutinin and higher numbers of cd3 + and cd45ra + t cells in the first 3 years of life than those receiving bmts late. t-cell antigens peaked earlier and with higher values in the neonatal bmts (181 days to 1 year) than in the late bmts (1-3 years) [338] . over the past 22 years 78% of all scid patients (110/142) receiving bmt at duke university medical center survive to varying ages up to ≥20 years after bmt. only 16 had an hla-identical donor. all others received rigorously tcd haploidentical bm from a parent, most often the mother. the soy lectin, srbc rosetting technique was used (r. buckley pers. comm. november 20th, 2004 and april 20th, 2005). an uncommon bmt to treat ar scid was undertaken in a 1-month-old girl. the donor was her hla-mismatched 6-year-old sister, who had previously received a bmt from her father [479] : presently, they are aged 5 and 13 and are affected by molloscum contagiosum infection [547] . bmt, both hla identical unfractionated and tcd hla aploidentical [63] .a recent trial found that because only 10%-15% of affected children have a familial hlaidentical donor (rid), the alternative therapeutic options are bmt from a mud or a haploidentical bmt or from hla-mismatched related donors (mmrds). only 40% of these children may find a matched donor; therefore, the remaining pid-affected children are candidates for a tcd haploidentical bmt [277] . mud hsct is successful in young children [132] , but the success rate decreases dramatically above the age of 5-6 years [158] (table 22 .30) [13, 15, 25, 27, 39, 46, 52, 55, 56, 58, 64, 67, 69, 80, 83, 85, 98, 111, 119, 131, 132, 163, 185, 188, 197, 205-208, 231, 233, 235, 237, 245, 252, 256, 257, 259, 260, 277, 280, 286, 288, 290, 305, 307, 334, 360, 366, 380, 405, 408, 428, 440, 448, 452, 456, 466, 474, 491, 496, 499, 503, 534] . bmt survived. compared with mmrd bmt, survival was significantly higher with rid or with mud (45/54 = 83.3%) [201] . when an hla-identical sibling as the donor is unavailable, a phenotypic hla-matched unrelated bmt is needed, also used in cd154 deficiency [290, 499] , with a clinical and immune outline normalization [246] and a variable effect on igg subclasses 1337 treatment [58] . c median (1.5-13 years after bmt). p, at the time of publication. [153] . possibly because of earlier diagnosis before untreatable opportunistic infections develop, the results have improved considerably during the last two decades [65] . bmts have been successful when applied within the first 7-24 days of life in 21 infants with scid, 20 (95%) of those still alive range from 8 months to 19 years, not justifying in utero transplants. a completely normal t-cell function was obtained within 82-118 days [338] and in an other 83 patients was still present after 10-17 years [373] . of the 58 children who received a mismatched parental bmt from 1980 to 1998, 43 (74%) remain alive with t-cell immune reconstitution, a median of 128.8 (range, 13-224. 3) months after bmt [362] . of 96 children out of 117 who received allogeneic bmt after the first 28 days of life, 71 (74%) are alive [69] . three out of five children who received a hsct are alive and well after 18-32 months [13] . breast feeding appeared correlated to an earlier reconstitution when the donor was the mother [338] . intra-amniotic gene transfer has been successfully carried out on a laboratory animal, registering in a dose-dependent manner the fetal gastroenteric and respiratory effects [222] . if confirmed in human beings, this method of treatment will certainly prove useful for prenatal correction of pid. bmt/hsct should be completed by conditioning regimens with busulfan and cyclophosphamide, less toxic than total lymphoid irradiation or a combination of nucleoside analogs and anti-lymphocyte antibody preparations [65] . for example, busulfan (16 mg/kg), melphalan (90 mg/m 2 ) and anti-thymocyte globulin (36 mg/kg) [83] . to enhance the engraftment rate in haploidentical bmt in pid, it was recently suggested to add donor peripheral scs after mobilization with g-csf (16 mg/kg for 5 days) and bm cells. with this procedure the cell load is increased, which allows intensification of the conditioning regimen for induction of faster engraftment [277] . in utero bmt suggested advantages include the sterile environment in utero, and immaturity of the fetal immune system enabling the prevention of clinical manifestations of the disease in the neonate, and the engraftment without the use of cytotoxic conditioning regimens: a child thus treated was well at age 11 months [164] . two series of six and four patients [386, 504] and two additional case reports [182, 532] of in utero transplants have been published, yet failure of b-cell engraftment and function may result in long-term dependence on ivig replacement [248] . better results than those published for in utero bmt for scid were implicit in 13 infants admitted and diagnosed at a median age of 3 days because of a fh of a previously affected infant. bmt was successful and all children are alive and well with follow-up to 11.5 years [248] or <30 days vs approximately 4 months [194] . however, it is suggested that in utero transplants may carry the risks associated with injecting the fetus and the inability to detect gvhd during gestation [65] . umbilical cb transplantation (ucbt) was done in two children affected by a zap-70 deficiency and an omenn-like syndrome. both are alive and well at 4.5 and 2.2 years after ucbt [148] . unrelated ucbt in eight children with severe t-cell id [260] and in three with was [259] resulted in consistent and stable t -, b -, and nk cell development [259, 260] . faster availability of ucbts is a meaningful advantage for patients requiring urgent transplantation: a median of 25 days more rapidly than did those receiving bone marrow [30] . in a large report [423] , 40 patients with scid, seven with was, and other unspecified pid received an unrelated ucbt. ucb was evaluated as a sc source for immune reconstitution in children with severe primary t-cell ids such as scid, reticular dysgenesis, thymic dysplasia, cid, dgs, and was when a matched sibling donor was unavailable, and has been used to date in more than 2,000 patients [194] . three infants who rejected a tcd-mismatched parental bmt without prior cytoreduction engrafted after infusion of ucbt [69] . a 4.5-year-old girl with hla class ii deficiency had a successful related ucbt for graft failure following tcd nonidentical bmt [52] . a girl with reticular dysgenesis failed to engraft following her first transplant, but fully engrafted after a second unrelated ucbt. five of six patients showed grade i gvhd, although one child experienced grade iv skin and gut gvhd. immunological ucbt resulted in consistent and stable t-cell, b-cell, and nk-cell development [260] . long-term event-free survival (≥27 months) with recovery of antigen-specific responses was reported following an unrelated ucbt in a child with omenn's syndrome [38] . gene therapy, which has revolutionized and could revolutionize even more pid treatment in the near future, is analyzed in table 22 .31 [76, 104] . the requisite for applying this form of genetic engineering treatment is that the responsible gene must be cloned; the most common techniques involve knock-out mice and inactivating a particle [104] , or employing retroviral vectors (table 22 .32) [263] , totally deprived of their genomic factors except for the normal copy of the gene to be inserted. this is indispensable for allowing the vector to reach the human nucleus, where it will integrate with the cellular genome [263] . in this case, pbls are collected through leukapheresis and cultivated in vitro with retroviral particles containing a normal gene rna copy: thus the healthy gene is introduced into the cell genome using a vector and the manipulated cells are reinfused, so as to restore normal immune functions. this system has been used to treat two children aged 2 months suffering from scid [508] and from ada deficiency by employing autologous pbls [51] , bm cells [54] , and cb cells [262] . three reports [4, 88, 204] of successful gene therapy in infants with x-linked scid [88, 204] and in t -b -scid [4] are a major step forward among repeated efforts to achieve better immune reconstitution in ada-scid with gene therapy than with bmt/sct [161] . immediately after the diagnosis had been made in two capacity of wild-type, replication-competent retroviruses to cause leukemia in immunologically immature neonatal mice [263] , and in humans (two children out of 11) [63, 88, 204] . retroviruses can cause insertional oncogenesis, a long-known potential complication of retroviral gene transfer attempts, because gene integration occurs at random in the genome, thus deregulating the expression of cellular oncogenes [263] . this complication has been thought to be unlikely with such vectors, because they are capable of inserting only once into the cell's chromosomes and cannot repeatedly reproduce and integrate. lentiviruses may be more effective than murine retroviruses for gene transfer into human hematopoietic scs and t lymphocytes [263] . in ada-scid, the safety and efficacy of hsc gene therapy combined with nonmyeloablative conditioning for the treatment of scid has allowed two children to live at home and clinically well, with normal growth and development [4] . on january 14, 2003, fda placed on "clinical hold" all active gene therapy trials using retroviral vectors to insert genes into blood scs after having learned that a second child treated in the french gene therapy trial developed a leukemia-like condition. gene therapy is on hold despite enormous promise for certain scid/ cid variants. survival. in scid, the european experience with unfractionated hla-identical and tcd or non-tcd haploidentical or mud bmts in patients with scid reported that between 1968 and 1999, a 3-year survival with sustained engraftment was significantly better after hla-identical than after mismatched transplantation (77% vs 54%).within the hla-identical group, survival after bmt from genotypically or phenotypically identical related or muds was 81%, 72%, and 63%, respectively [14] . in non-scid, 3-year survival after genotypically hla-matched, phenotypically hla-matched, mmrd, and mud bmt was 71%, 42%, 42%, and 59%, respectively [14] . in a retrospective analysis of bmts performed between 1977 and 1991 at 13 european centers in 149 children as young as 1 month with 11 different pids (excluding scid), the overall survival among 53 recipients of hla genetically identical bmt was 66%, 45.5% in 22 patients who received closely matched bmt, and 38% in 71 recipients of bmt with two or three mismatched hla antigens. a significant improvement in survival has been achieved in most pids (overall survival, 81.5% vs 51.7%, primarily because of a decrease in the frequency of infectious complications [163] . in the similar analysis performed in 193 children with scid at 18 european centers between 1982 and 1993, 116 out of 193 (60.1%) patients were alive with evidence of engraftment 6 months after bmt. however, 24 patients died >6 months post-bmt, mainly due to cgvhd and/ or viral infection. thus gvhd 6 months after bmt and b -scid vs b + scid were the main factors associated with a poor outcome [206] . the disease-free survival was significantly better for patients with b + scid (60.7%) than for those with b -scid (33.3%) [14] . in a children aged 8 and 11 months including a novel splice imitation in the common gc chain [183] , haploidentical cd34 + peripheral progenitor cells mobilized with gm-csf were isolated to a purity of more than 99%. these cells were infused with no prior chemoablation and no prophylaxis against gvhd. both children showed signs of t-cell reconstitution beginning 3 weeks after the cd34 + infusion and were weaned from continuous cures. they are in excellent health, without gvhd, 34 and 68 months after transplantation. one child does not need replacement ig. the other received a booster infusion of cd34 + scs from the original donor 1 year later to improve b-cell function and now receives ig every 3 months. both were followed for 10 months after gene transfer [88] . however, retroviral vectors have the 1339 treatment data from [4, 76, 104] . ciita class ii transactivator, cgd chronic granulomatous disease, xla x linked agammaglobulinemia; for other abbreviations see table 22 .1. a done with success, see text for details. b in utero transplant of maternal stem cells. trial on children with pid receiving bm from hla-nonidentical related donors or from hla-identical unrelated donors at 13 european centers between august 1990 and june 1993, 22 out of 28 children (76.6%) survived 22-58 months. bm was tcd by use of either erythrocyte rosetting or monoclonal antibodies to prevent gvhd [231] . additional survival rates were reported previously (table 22 .30). in a series of consecutive ud bmts 31/33 children with scid and non-scid pids who received a bmt with reduced-intensity conditioning (ric) regimen between 1998 and 2001 survived after a 3.3-year follow-up, as well as 10/19 children who received a bmt with myeloablative conditioning (mat) between 1994 and 1998 and survived after an 8.6-year follow-up. therefore a ric regimen results in improved survival and reduced bmt-related mortality compared with mat in hr children undergoing an ud bmt [396] . in 170 transplanted patients with was, the 5-year probability of survival differed according to donor type: 87% with hla-identical sibling donors, 52% with other related donors, and 71% with mud. significantly, boys who had received a mud transplant before 5 years of age had survival rates similar to those receiving hlaidentical sibling transplants [158] . however, the time required to develop immune function after haploidentical scts is quite different from that after unfractionated hla-identical bm. lymphocytes with mature t-cell phenotypes and functions fail to rise significantly until 3-4 months after bmt; normal t-cell function is reached between 4 and 7 months [338] . b-cell function develops much more slowly, averaging 2-2.5 years for normalization; many do not have b-cell function, despite normal t-cell function. [338] . ex vivo rigorous depletion of post-thymic t cells from donor marrow that cause gvhd is efficient and feasible, even in haploidentical settings [13] , presumably because of more effective infection-control measures and better transplantation strategy [514] . for non-scid, sct can provide a cure, and grafts from unrelated donors are almost as beneficial as those from genetically hla-identical relatives [45] . in most patients, deficient b-cell function persists after transplantation and requires lifelong ivig therapy [69, 207] , which is necessary to prevent bacterial and common viral infections [69, 514] . some patients also have persistent deficiencies of t-cell function after sct [206, 373] . in children with rris, depending on the nature of the infection, the pediatrician will prescribe the most appropriate symptomatic and/or antibiotic therapy. in the presence of persistent inflammation, or during the winter, when the risk of close acute recurrent episodes is higher, anti-inflammatory preparations will be prescribed via aerosol, chromones, ketotifen, b 2 -adrenergic and if necessary steroids for topical use, strictly depend-ing on the need. we suggest monitoring measures, such as keeping a clinical diary, in which each acute episode should be briefly noted, continuing registration until clinical symptoms have not regressed for at least 15 days and returning to keep notes in the diary each time there is a cough and/or nasal and/or bronchial inflammation, completing this with pef as well as some respiratory parameters right at the beginning and then every 6 months. it is obvious that if medical intervention is not resolutive a center specialized in infantile respiratory physiopathology should be contacted [47] . children with sars were treated with high-dose ribavirin, oral prednisolone, or iv methylprednisolone, with no shortterm adverse effects [223] . antibiotics must be used very carefully in these children because they can influence positively or negatively the innate, cellular or humoral immunity (chap. 18), interaction with ils and growth factors are not known, repeated use often causes phenomena involving allergy/ intolerance [470] , and most infection-prone children suffering from vris are given antibiotics unnecessarily. in italian children (54.6% of males) aged 6 months to 14 years (median, 4 years) with a history of rris, macrolide therapy of acute respiratory infections influenced the natural history of rris, probably because of their elective activity on atypical bacteria [508] . considering the emergence of antibiotic-resistant bacterial stock, as for example s. pneumoniae, immunotherapy has been proposed as a means of preventing rris by providing children with small doses of inactive bacterial antigens liable to trigger specific and protective immune responses (table 22 .33) [36] . for example, om-85 bv significantly reduces the urti rate, particularly in a dbpc study in 232 children aged 3-8 with a history of acute urtis [448] , is active in preventing rri episodes [36] with a meaningful reduction in the number of days of suffering acute urtis [448] . bacterial ribosomal and membrane proteoglycans of s. pneumoniae, which stimulate b cells with secretory responses, as well as memory cells, may be used for responding to future infections [36] . ribosomal immunotherapy appears to be not only well tolerated, but also ideally targeted to induce mucosal responses [37] . among the preparations reserved for specific use, a study of pidotimod in dbpc trials proved its effectiveness in a sample of 101 children with rris, also showing increased cd25, absent in placebo-treated children [72] . the use of immunostimulants should be limited to children with proven high susceptibility to acute urti, or overexposed children attending daycare facilities, or attending kindergarten or elementary school [508] . however, according to a meta-analysis, immunostimulants are an effective treatment for the prevention of acute urti in children [40] . furthermore the indiscriminate and purely empiric use of ivig must be discouraged in every child with rri, whereas in a prospective, dbpc study of ivig and co-trimoxazole, 106 of 130 children <8 years referred for recurrent bacterial rris became infection-free over a 4-month obser-if caused by pneumococci. other kinds of vaccines have provided disappointing results: fig. 22 .52 [340] indicates the immune bases of a specific immunization and the possibility of specific interventions. in children with pid, one should bear in mind all the aforementioned facts. until the past few years, there was a busy motion into the fundamental problems underlying a majority of these conditions. many have now been mapped to specific chromosomal locations, and an impressive number vation period [353] , in addition to having an extremely unfavorable cost-benefit ratio [426] immunization children with rris and deficient antibody responses to germs expressing a capsular polysaccharide can be successfully vaccinated, but avoiding the administration of live virus vaccines and integrating this if necessary with an igg replacement therapy [218] . furthermore, in view of the availability of conjugated vaccines, it will be possible to induce antipneumococcus-igg 2 , providing an effective treatment for children with rris, especially 1341 treatment of the fundamental biological errors have been identified. the pediatrician is entrusted with a more difficult job, that of identifying as early as possible the possible existence of pid, remembering the suggestions for case history in chap. 6, with the exception of clinical emergencies such as omenn syndrome and reticular dysgenesis. this specific research becomes a necessity thanks to the new diagnostic and therapeutic advances that have been conceived over the past few years: the earlier one acts, on the one hand with a prenatal diagnosis and on the other with a bmt or sct therapy, the greater the chance to increase life expectancy for these children, in addition to ensuring better quality of life. the discovery and cloning of the genes for these diseases have obvious implications for the potential of gene therapy. the rapidity of these advances suggests that there will soon be many more to come. one of the most common differential diagnoses will occur with a child affected by rris, for whom we believe the number of infections must be immediately clarified, although evaluated according to different numeric and epidemiologic factors, not associated with those which instead concern the severity and the site of the infection as well as the type of the pathogenic agent that characterize children with pid. however, antibiotics are banned by the supporters of the hygiene hypothesis (chap. 24). an update on the prevalence of glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice in tehran neonates primary immunodeficiency in iran: first report of the national registry of pid in 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diseases bcl10 activates the nf-kappab pathway through ubiquitination of nemo virally induced immunosuppression the xlinked hyper-igm syndrome: clinical and immunologic features of 79 patients brief report: twin boys with major histocompatibility complex class ii deficiency but inducible immune responses neuropsychological profile of children and adolescents with the 22q11.2 microdeletion case definition for surveillance of severe acute respiratory syndrome sars primary immunodeficiency diseases role of tbx1 in human del22q11.2 syndrome high incidence of significant bone loss in patients with severe congenital neutropenia (kostmann's syndrome) key: cord-353519-cmeociax authors: jay miller, j.; niu, chunling; moody, shannon title: child welfare workers and peritraumatic distress: the impact of covid-19 date: 2020-09-25 journal: child youth serv rev doi: 10.1016/j.childyouth.2020.105508 sha: doc_id: 353519 cord_uid: cmeociax whilst there is broad consensus that covid-19 has had a pernicious impact on child welfare services, in general, and child welfare workers, specifically, this notion has not been thoroughly examined in the literature. this exploratory study examined covid-19 related peritraumatic distress among child welfare workers (n=1,996) in one southeastern state in the united states (u.s.). findings suggest that the study sample was experiencing distress levels above normal ranges; 46.4% of participants were experiencing mild or severe distress. sexual orientation, self-reported physical and mental health, relationship status, supervision status, and financial stability impacted distress levels experienced by child welfare workers. overall, data suggest that covid-19 is impacting child welfare workers and there is a need to conceptualize, implement, and evaluate initiatives aimed at assuaging distress among child welfare workers. coronavirus (covid-19) pandemic has fundamentally altered child welfare practice. distancing guidelines, evolving regulatory edicts, and substantial significant restrictions in legal operations (e.g., court processes) have significantly impacted workers' abilities to perform seminal child welfare duties. indeed, as jerry milner, associate commissioner at the children's bureau, aptly concluded in a letter to child welfare leaders: "the covid-19 pandemic has created unprecedented challenges for our health and human services systems in serving our most vulnerable families, children, and youth" (2020, para 1). indubitably, these circumstances have taken a toll on child welfare workers. whilst a plethora of local, state, and federal entities have proffered strategies to assist workers in assuaging the impact of covid-19, personal and professional challenges associated with the pandemic persist. this paper examines the impacts of these challenges. this exploratory study examined peritraumatic distress among child welfare workers (n=1,996) in one southeastern state in the united states (u.s.). to collect primary data, researchers deployed the covid-19 peritraumatic distress index (cpdi; qiu, shen, zhao, wang, xie, & xu, 2020) . cpdi is a self-report instrument designed to measure covid-19 specific distress. this is the first known empirical study to explicitly examine this topic among child welfare workers. after a brief review of pertinent background literature, this paper will explicate results, discuss findings, and proffer salient practice, policy, and research implications. background a well-functioning child welfare system is essential to wellbeing. per the child welfare information gateway (2013), child welfare workers carry out an array of tasks aimed at child and family safety, permanency, and wellbeing. barth (1999) explained that the impact of the work performed by child welfare workers reverberates for generations and extends beyond an individual child or family, but to society as a whole. in short, the importance of the work that child welfare workers perform cannot be overstated. in general, there is a host of problematic occupational concerns related to child welfare practice. suggested that child welfare workers experience higher rates of compassion fatigue and occupational stress, when compared to other social service providers. miller et al made similar assertions (2018) . kim, ji and kao (2011) and blome and steib (2014) reported that child welfare workers experience high caseloads and lower perceptions of personal accomplishment, when juxtaposed with workers in other contexts. lizano, hsiao, barak, and casper (2014) explained that the work-related strain experienced by child welfare workers negatively impacted overall worker wellbeing. others have discussed a host of inimical physical and psychological conditions experienced by child welfare workers (e.g., salloum et al., 2015; griffiths, royse, culver, piescher, & zhang, 2017; schelbe, radey & panisch, 2017) . indeed, even in the best of times, child welfare practice can be challenging. to be clear, empirical research examining the impact of covid-19 among the child welfare workforce is in the nascent stages. however, research conducted in other areas illustrate the impact of covid-19 on an array of practitioners. for instance, in a cross-sectional study of physicians, advanced practice providers, residents/fellows, and nurses, shechter et al. (2020) found that nearly 60% of participants reported acute stress and nearly half of the sample exhibited symptoms for depressive disorder related to covid-19. lai et al. (2020) and xiao, zhang, kong, li, and yang (2020) reached similar conclusions. in a broader review of six articles published about the impact of covid on healthcare workers, spoorthy, pratapa, and mahant (2020) concluded that factors such as gender, age, and lack of social support, among others, were linked to stress, anxiety, and depressive symptoms among study participants. in assessing literature about the impacts of covid-19 on the public, torales, o'higgins, castaldelli-maia, and ventriglio (2020) found that the pandemic has contributed to a host of problematic circumstances. in addition to those noted by spoorthy, pratapa, and mahant (2020) , torales and colleagues (2020) discussed denial, anger, and fear that has been brought about by the pandemic. these authors went on to discuss the impact that these issues may have on prevention and decisionmaking related to the pandemic. empirical studies notwithstanding, several outlets have made assertions about the impact of covid-19 on the child welfare system, more broadly, and workers, more specifically. for example, the national conference on state legislatures (2020) asserted that court restrictions have dramatically slowed child welfare processes and impacted workers' abilities to navigate seminal functions associated with performing their duties. kelly (2020) maintained that these restrictions have presented difficulties in managing child welfare cases. merritt and simmel (2020) explained that many workers experienced abrupt transitions to virtual and/or remote work and service environments. in some instances, child welfare workers, particularly child protective service workers, have continued to initiate and conduct home visits, etc. akin to those in traditional healthcare settings (e.g., hospitals), these workers have been concerned about the availability of adequate personal protective equipment (ppe) and exposure to covid-19 (see fadel, 2020) . given the sweeping impact of the pandemic, it is probable that covid-19 has exacerbated the challenges for engaging in child welfare work. these negative impacts can be felt not only by the child welfare workers, but the children and families they seek to serve. whilst the impact of the pandemic has been explored among other practitioner groups (such as healthcare professionals, etc.), works that examine this impact among child welfare workers is nominal, at best. a thorough review of relevant databases revealed no such studies. this paper seeks to contribute to addressing that limitation in the current literature. the overarching purpose of this exploratory study was to examine covid-19 peritraumatic distress among child welfare workers. this is the first work known to the authors to examine the impact of covid-19 on distress among this population. in so doing, this study offers insight for how to allay distress among child welfare workers during covid-19. specifically, this study was guided by three (3) research questions: research question 1: what are covid-19 related peritraumatic distress levels among child welfare workers? research question 2: are there group differences in covid-19 related peritraumatic distress by participant demographic/professional characteristics? research question 3: what demographic/professional characteristics predict covid-19 related peritraumatic distress? this study employed a cross-sectional design. primary data were collected via an electronic survey administered via an online survey management program (e.g., survey monkey). researchers sought, and were granted, institutional review board (irb) approval and a waiver of documentation of informed consent. all data were collected during summer 2020. to recruit participants for this study, researchers circulated the approved study invitation to statewide child welfare groups and professional membership associations. in turn, participants were asked to forward the invitation to other potential participants. this approach does not permit for the calculation of a response rate. those who participated in the survey were offered a chance to enter a $500 incentive drawing. researchers did utilize features that disabled ip and email address tracking. the incentive link was not connected to the primary survey link. all participants self-identified as a public or private child welfare worker at the time of the survey. primary data pertaining to distress were collected using the covid-19 peritraumatic distress index (cpdi; qiu, shen, zhao, wang, xie, & xu, 2020) . cpdi is a 24-item scale designed to examine covid-19 specific peritraumatic distress. for clarity, peritraumatic distress refers to the physiological and/or emotional distress experienced by an individual during a traumatic event. bunnell, davidson, and ruggiero (2018) explained that peritraumatic distress is related to the development of posttraumatic stress disorder (ptsd). cpdi entails parameters associated with stress, as outlined in the international classification of diseases (11th rev.). each item is anchored at 0 indicating never and 4 indicating most of the time example items include: "compared to usual, i feel more nervous and anxious" and "i feel insecure and bought a lot of masks, medications, sanitizer, gloves and/or other home supplies." in terms of scoring, the cpdi scores range from 0 -100, with higher scores indicating more distress. cut scores are as follows: 0-28 (normal distress); 29-52 (mild distress); and, 53-100 (severe distress). the cronbach's alpha of cpdi for this study was 0.91 (p<0.001). in addition to the cpdi, researchers collected demographic and professional data necessary to adequately describe the sample. variables of interest included: gender; age; years of practice experience; hours worked per week; sexual orientation; race; relationship status; education level; and professional membership group status, among others. participants were asked to self-report their physical health status and mental health status, respectively. response options for both of these variables included excellent, very good, good, fair, or poor. participants were also asked about their current financial situation. response categories included: i cannot make ends meet; i have just enough money to make ends meet; i have enough money, with a little left over; or, i always have money left over. remote work status was operationalized by asking participants if they had worked primarily remotely since march 11, 2020, the date covid-19 was declared a pandemic. participant responses to the instrument are summarized in table 1 . all data were analyzed via spss 26. once data were cleaned, researchers initiated descriptive, bivariate and multivariate inferential analyses. descriptive analysis showed frequency and mean distribution of main variables. bivariate examination included correlation analyses, robust one-way analyses of variances (brown-forsythe tests) or independent sample t-tests. multivariate inferential analysis included hierarchical multiple ordinary least squares regression. a total of 1,996 (n=1,996) child welfare workers participated in this study. of the participants, 800 of them were employed by a private child welfare agency; 1,196 of them were employed by a public child welfare agency. typical survey respondents were aged 41.44 (sd=11.51) years and had been practicing in child welfare for 13.42 (sd=12.7) years. additional demographic information is included in table 1 . the mean cpdi score for participants was 29.06 (sd=13.87); with a range of 86. at an individual level, 53.6% of the sample had cpdi scores within the normal range; 40.5% in the mild range; and, 5.9% in the severe range. correlation analyses between the total distress scores and various continuous demographic variables yielded one significant relationship. specifically, age (r = -.151, p < .001) was significantly correlated with cpdi scores, whereby older participants tended to have lower cpdi scores. due to the exploratory nature of the study, anovas were initiated to assess group differences in cpdi scores. analyses detected significant differences in mean total scores for the following variables: sexual orientation, physical health, mental health, supervision status, current financial status, and current relationship status. table 2 contains a summary of results for these analyses. for sexual orientation, participants were put into two categories for the purpose of analysis: "heterosexual or straight" vs. "not heterosexual or straight" (e.g., gay or lesbian and bisexual). analysis for the purpose of analyses, current marital status was categorized as "married" or "not lastly, differences were detected by financial status. to reduce the sample imbalance across the four levels, those who reported "i cannot make ends meet," and "i have just enough money to make ends meet," were combined into one level. a one-way robust anova (brown-forsythe test) was used to compare mean total distress scores between the different financial status and was found to be statistically results revealed that seven variables significantly predicted total distress: married (p < .01), financial status (p < .001), physical health (p < .001), mental health (p < .001), age (p < .05), and sexual orientation (p < .001). the older and married social workers tended to have lower distress scores by 1.843 and .099 points, respectively. identifying as "heterosexual or straight" seemingly predicted lower total distress scores by 4.787 points. compared to those who reported "excellent physical health", child welfare workers who reported "very good," "good," or "fair/poor" physical health were inclined to score higher on the total covid distress scale by 3.197, 2.737, and 6.499 points, respectively. likewise, those who reported "excellent mental health", when compared to those who reported "very good," "good," or "fair/poor" mental health, scored 5.934, 11.472, and 21.25 points higher, respectively. for those who reported "i cannot make ends meet," "i have just enough to make ends meet," or "i have enough with a little left over" impacted distress scores by 6.305 and 4.537 points respectively, after controlling for all other variables. table 4 for the results of the regression analysis. this study is likely the first to examine covid-19 related distress among child welfare workers. overall, data indicates that child welfare workers in this sample were above normal ranges and fall into the mild distress category. nearly half of all participants scored in a range indicating mild or severe peritraumatic distress stress related to covid-19. in many ways, these findings may not be surprising. in a national examination of the general public, palsson, ballou, and gray (2020) concluded that over half of their sample reported having higher stress levels as a result of covid-19. as well, these findings are somewhat consistent with the aforereferenced literature related to other professional groups, such as healthcare professionals (e.g., shechter et al., 2020) . in addition to professional challenges, child welfare practitioners may be coping with personal challenges, such as homeschooling, caregiving, economic uncertainty, and the like, that may impact their professional roles. these conditions, plus an uncertain prospect for improved conditions in the immediate future, can certainly cause distress among those experiencing them. covid-19 related distress among child welfare workers can be disconcerting for an array of reasons. for example, this distress may lead to professional burnout, which in turn, may contribute to retention issues (lizano, hsiao, barak, & casper, 2014) . as well, it is possible, that covid-19 distress may impact practice decisions. miller, donohue-dioh, niu, and shalash (2018) and suggested that wellness factors, or lack thereof, can negatively impact child welfare workers' abilities to adroitly manage caseloads. that in mind, the level of distress among participants in the current study, specifically, and in the larger child welfare workforce, more broadly, certainly warrants more critical examination and response. that said, the fact that the sample is not experiencing more distress is noteworthy. to be clear, any level of distress among child welfare workers is concerning. however, 53.6% of participants in this study did fall within a "normal" range of distress. while there are no published examinations of peritraumatic distress related to covid-19 among child welfare workers, a recent study of secondary traumatic stress among child welfare workers in three states, rienks (2020) concluded that nearly 60% of the sample experienced moderate, high, or severe stress. given the attention that the impact of the pandemic has had on child welfare, one might have surmised higher levels of distress among the participants in the current study. there are a number of additional factors that may be impacting distress, or lack thereof, among child welfare workers. for example, several outlets have discussed the fact that calls to child protective services have slowed during the pandemic (e.g., welch & haskins, 2020) . moreover, much of the work has shifted to virtual/remote tasks. interestingly, these dynamics may have offered some temporary reprieve associated with high caseloads, volumes, etc. that may cause stress among child welfare workers. among participants in this sample, age did appear to significantly impact distress. age was correlated with distress such that older participants experienced less distress and being older significantly predicted decreases in distress. this is consistent with other research, in general, about age and stress. for instance, jorm, windsor, dear, anstey, christensen, and rodgers (2005) examined generalized psychological distress, by age. these researchers concluded that distress tended to decrease as one got older. it is also possible that older participants may be better able to cope with distress as a result of more financial stability, etc. have better coping skills as it relates to distress (e.g., schieman, van gundy & taylor, 2001) . still yet, age may be related to other factors, such as parenting young child(ren), etc. that may be especially relevant during the pandemic. all told, these findings affirm cursory notions that different age groups may be experiencing covid-19 differently. analyses revealed that several demographic variables impacted covid-19 distress. individuals who were married experienced less distress than did those who were not; marital status was a significant predictor of less distress. several authors have discussed the importance of connectedness and romantic/social relationships to overall wellbeing. for instance, fincham and beach (2010) concluded that marriage is associated with better mental wellbeing and miller, lianekhammy, and grise-owens (2018) found that individuals who are married tend to engage in more frequent self-care practices, when compared to those who are not married. as well, many states, including the one in which this study occurred, implemented strict distancing and isolation mandates. being married may provide additional support, in a time when others are isolated from their social networks. this support can be integral to addressing covid-19 related distress. interestingly, supervisors experienced less distress than did non-supervisors. this is somewhat counter to previous assertions that child welfare supervisors may experience more stress than other child welfare professionals (e.g., dill, 2007) . it is possible that being a supervisor is a proxy for other variables, such as financial status, as supervisors may typically earn more salary. additionally, supervisors may be better informed about agency dynamics and responses associated with the pandemic. or still yet, supervisors' experience may permit them to better navigate or cope with distress specifically associated with covid-19, such as not having to initiate home visits, conduct face-to-face interviews, etc. all of these factors may contribute to less distress for child welfare supervisors. perhaps not surprisingly, physical and mental health appear to impact covid-19 distress. in short, analyses indicate that participants with better physical or mental health, respectively, experience less covid-19 related distress. this finding is consistent with a line of research inquiry linking physical/mental health to overall wellbeing (e.g., perales, del pozo-cruz, & del pozo-cruz, 2014 ). there are a number of factors associated with physical/mental health that may impact current findings. for example, many physical and mental wellbeing routines may be disrupted during covid-19. due to community health guidelines, most gyms and health facilities were closed at periods during the pandemic and counseling/therapy sessions may have been limited or have transitioned to virtual/tele delivery options. veritably, accessibility to resources, and facilities, can impact covid-19 related distress. financial status also seems to be linked to lower distress associated with covid-19. in summary, those reporting more financial stability appear to experience lower distress. intuitively, these findings may be expected. finances are often a life stressor. previous research pertaining to child welfare workers has linked financial status to self-care and wellness practices (miller, donohue-dioh, niu, grise-owens, & poklembova, 2019) . covid-19 has likely exacerbated that stressor. in terms of sexual orientation, identifying as heterosexual or straight appeared to significantly decrease distress. given previous literature about lgbtq* professionals, these findings may not be surprising. evidence suggests lgbtq* individuals face an array of challenges that exacerbate stressors. lgbtq* practitioners must also face issues associated with role encapsulation, tokenism, homophobia, heterosexism, heterocentrism, hostile workplaces, inadequate access to formal and professional mentorship opportunities, professional isolation, and loneliness, (lasala, jenkins, wheeler, & fredriksen-goldsen, 2008; dentato et al., 2016) , among others. this study has several strengths. notably, this is the first known study to explicitly examine covid-19 distress among child welfare workers. the cdc (2020) has discussed the importance of understanding covid-19 associated stressors as a way to better address those stressors. in addition, though exploratory, the study has a more than adequate sample size of child welfare workers and examines the concept of peritraumatic distress related to the pandemic. data from the current study may provide valuable information for child welfare employers to more adeptly support workers during covid-19 and other disasters. this work must also be considered within the context of several limitations. for example, all participants self-selected into the study and self-identified as a public child welfare worker. the sample was overwhelmingly female and white, which may not be reflective of larger child welfare worker populations. a more diverse sample may have yielded different responses, which might have impacted the results. given the nature of this study, and the population, a social desirability bias may be impacting data associated with the current study. the instrument utilized for this study is relatively new. though this is to be expected given the quickly emerging science associated with covid-19, this instrument should be further assessed for use among broader populations, to include child welfare workers. additionally, this study did not examine a number of job-specific factors, such as caseload, etc. given these limitations, assertions based on this study must be made carefully and critically. given that confirmed cases of covid-19 are on the rise in the u.s., it is imperative to conceptualize approaches to supporting child welfare workers in dealing with challenges, and associated consequences, of covid-19. nearly half of the participants in this study were experiencing distress associated with the pandemic. as such, studies that examine the impact of the pandemic on child welfare should identify pragmatic strategies for assuaging distress. the following paragraphs briefly outline salient implications derived from the afore-referenced findings. to be clear, to deal with covid-19 related distress among child welfare workers, responses from both the individual and organizations (e.g., employer) may be necessary. for individual child welfare workers, attention should be focused on developing self-care practices conducive to assuaging distress. several entities (e.g., centers for disease control, 2020; national child traumatic stress network, 2020) have discussed the importance of self-care during the pandemic. this importance has also been discussed in previous research works associated with child welfare workers (e.g., . typical steps in this regard include establishing robust self-care plans, delineating implementation strategies for said plans, and evaluating progress (grise-owens, miller, & eaves, 2016) . from an organizational standpoint, consideration should be given to conceptualizing and implementing broader initiatives aimed at supporting child welfare workers in dealing with the distress associated with covid-19. a host of authors have discussed the importance of workplace culture, to include offering support, for child welfare workers (e.g., ellett, ellis, westbrook, & dews, 2007; madden, scannapieco, & painter, 2014) . there are several ways in which organizations can actualize such initiatives. for example, organizations may look to foster interactions among child welfare workers that extend beyond traditional work spaces. this may take the form of virtual accountability, check-in, and support groups. findings from the current study suggest that certain employee groups (e.g., lgbtq*) experience higher levels of distress. as such, targeted or specialized groups may be impactful in helping to address distress. such initiatives should be conceptualized in a participatory fashion -that is -with the input of child welfare workers. certainly, membership organizations can be helpful in achieving supportive aims for child welfare workers. groups such as the child welfare league of america (see https://www.cwla.org/coronavirus/) and prevent child abuse america (see https://preventchildabuse.org/coronavirus-resources/) have provided web pages, documents, and guidelines to assist workers in dealing with the pandemic. other entities, such as the children's bureau (see https://www.acf.hhs.gov/cb/resource/covid-19-resources) have proffered resource pages. from a macro perspective, it is imperative that regulatory entities continue to promulgate policies directed at providing relief during covid-19. for instance, remote work arrangements may be an ideal approach to assuaging stress among child welfare workers, even absent a pandemic. other edicts related to ppe requirements, virtual visits, etc. should be assessed and weighed as a necessary response to ensure the safety of workers. research implications abound. most importantly, researchers should continue to examine the impact of covid-19 on a variety of stakeholders, including child welfare workers, service recipients, and foster parents, to name a few. what's more, researchers should assess practices and policies, such as remote work arrangements, etc., for efficacy and efficiency. other areas include the impact of age and how covid-19 may impact underrepresented groups, such as lgbtq* and practitioners of color, other jobrelated factors, such as caseload, and how these variables may mediate/moderate distress, to name a few. the critical mission of child welfare workers is laudable and essential. if the wellbeing of children and families served by these workers is to be actualized, the needs of the practitioners must be assessed and addressed. this is particularly true during a pandemic, that by any measure, has had a profound impact on the child welfare system. though this exploratory study fills a unique gap in the current child welfare research literature, it is in no way a definitive work. to understand the true impact of covid-19 on child welfare services, and those who perform those services, workers, employers, researchers, and policy makers must continue to examine the short, medium, and long-term impacts of covid-19. this study can serve as a starting point for that work. after safety, what is the goal of child welfare services: permanency, family continuity or social benefit? the organizational structure of child welfare: staff are working hard, but it is hardly working the peritraumatic distress inventory: factor structure and predictive validity in traumatically injured patients admitted through a level i trauma center employees: how to cope with job stress and build resilience during the covid-19 pandemic department of health and human services homophobia within schools of social work: the critical need for affirming classroom settings and effective preparation for service with the lgbtq community impact of stressors on front-line child welfare supervisors. the clinical supervisor a qualitative study of 369 child welfare professionals' perspectives about factors contributing to employee retention and turnover child welfare services and caretakers grapple with covid-19 effects marriage in the new millennium: a decade in review the a-to-z self-care handbook for social workers and other helping professionals unheard voices: why former child welfare workers left their positions who stays, who goes, who knows? a state-wide survey of child welfare workers age group differences in psychological distress: the role of psychosocial risk factors that vary with age feds lay out minimum expectations for child welfare courts during coronavirus. the chronicle of social change burnout and physical health among social workers: a three-year longitudinal study factors associated with mental health outcomes among health care workers exposed to coronavirus disease lgbt faculty, research, and r esearchers: risks and rewards support in the workplace: buffering the deleterious effects of work-family conflict on child welfare workers' wellbeing and job burnout an examination of retention and length of employment among public child welfare workers barriers to child protection during covid-19: considering the impact on child maltreatment. the chronicle of social change exploring the self-care practices of child welfare workers: a research brief examining self-care among individuals employed in social work capacities: implications for the profession examining the selfcare practices of child welfare workers: a national perspective letter on child welfare leaders as level 1 emergency responders. children's bureau, administration for children and families impact of physical activity on psychological distress: a prospective analysis of an australian national sample a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations an exploration of child welfare caseworkers' experience of secondary trauma and strategies for coping the role of self-care on compassion satisfaction, burnout and secondary trauma among child welfare workers satisfactions and stressors experienced by recently-hired frontline child welfare workers status, role, and resource explanations for age patterns in psychological distress psychological distress, coping behaviors, and preferences for support among new york healthcare workers during the covid-19 pandemic mental health problems faced by healthcare workers due to the covid-19 pandemic-a review the outbreak of covid-19 coronavirus and its impact on global mental health child welfare: hhs could play a greater role in helping child welfare agencies recruit and retain staff what covid-19 means for america's child welfare system the effects of social support on sleep quality of medical staff treating patients with coronavirus disease key: cord-336940-6rgmpy5r authors: russell, b. s.; hutchison, m.; tambling, r.; tomkunas, a. j.; horton, a. l. title: initial challenges of caregiving during covid-19: caregiver burden, mental health, and the parent–child relationship date: 2020-08-04 journal: child psychiatry hum dev doi: 10.1007/s10578-020-01037-x sha: doc_id: 336940 cord_uid: 6rgmpy5r research confirms that the mental health burdens following community-wide disasters are extensive, with pervasive impacts noted in individuals and families. it is clear that child disaster outcomes are worst among children of highly distressed caregivers, or those caregivers who experience their own negative mental health outcomes from the disaster. the current study used path analysis to examine concurrent patterns of parents’ (n = 420) experience from a national sample during the early months of the u.s. covid-19 pandemic. the results of a multi-group path analysis, organized by parent gender, indicate good fit to the data [x(2)(10) = 159.04, p < .01]. results indicate significant linkages between parents’ caregiver burden, mental health, and perceptions of children’s stress; these in turn are significantly linked to child-parent closeness and conflict, indicating possible spillover effects for depressed parents and compensatory effects for anxious parents. the impact of millions of families sheltering in place during the covid-19 pandemic for an undefined period of time may lead to unprecedented impacts on individuals’ mental health with unknown impacts on child-parent relationships. these impacts may be heightened for families whose caregivers experience increased mental health symptoms, as was the case for fathers in the current sample. covid-19 arrived in the united states early in 2020 and quickly altered the daily routines of families nationwide as shelter-in-place recommendations took hold, schools and child care centers closed their physical buildings, and a significant portion of the workforce shifted operations to reduced or remote work from home routines. covid-19 is a novel, highly contagious but preventable disease caused by a coronavirus (sars-cov-2) [1] , mortality rates for covid-19 have surpassed 362,705 deaths worldwide and 103,700 deaths in the united states in may 2020, exceeding rates seen for other recent flu and sars epidemics [2] [3] [4] . time-sensitive research identifies covid-19-related stressors including fears of infection, disruptions to work/learning and daily self-care routines, and lack of access to reliable information and resources [5] . reports from families during the peak of covid-19 in the u.s. indicate these stressors are heightened for those caring for children [5] [6] [7] [8] , though little is known about how this increased stress will impact child-parent relationships [9] . the pattern of affect and behavior that can spillover from parents to children may take several forms, as described by nelson et al. [10] : the spillover hypothesis suggests that affect or behavior can transfer with the same valence within a family system from one relationship to another (i.e., negative affect in the parent is linked to negative affect in the child). a second such impact, called the compensatory hypothesis, suggests that the transfer between family subsystems can occur in the opposite valence, to compensate or protect against negative affect. a final similar process is described as a crossover, where rather than a transfer of affect within one person across subsystems, crossover refers to the transfer of affect or behavior between people (e.g., when the co-parenting stress experienced by one caregiver crosses over to impact the other partner's relationship with their child). research confirms that the mental health burdens following community-wide disasters are extensive, with pervasive impacts noted in individuals and families [11] . among public health officials' covid-19 recommendations [12] to slow the spread of the disease, in addition to a period of quarantine has been instituted in many municipalities, as of this writing on may 25, 2020 48 states, 4 u.s. territories, and washington d.c. had issued notices that all k-12 schools will remain physically closed for the duration of the 2019-2020 academic year, these closures will impact roughly 55.8 million public and private school students [13] . experts caution that the covid-19 pandemic is an instance of traumatic stress and will likely worsen existing mental health difficulties and lead to the development of new disorders in others for an extended period of time [14, 15] . it is clear that exposure to a wide range of disasters negatively impacts mental health and can lead to prolonged periods of increased psychiatric symptomology, including anxiety and depression [16] [17] [18] [19] [20] . further evidence suggests that child disaster outcomes are worst among children of highly distressed caregivers, or those caregivers who experience their own negative mental health outcomes from the disaster [21] [22] [23] . during epidemic conditions, quarantine-related stressors that impact mental health outcomes include prolonged duration of isolation, infection fears, frustration, boredom, inadequate supplies and information, financial loss, and stigma [24] , which are associated with subsequent psychological disorders after brief quarantines of as little as 10 days [25] . the impact of millions of families sheltering in place for an undefined period of time during the current pandemic may lead to unprecedented impacts on individuals' mental health with unknown impacts on child-parent relationships. periods of uncertainty with an indeterminant endpoint [26, 27] , such as quarantines enacted during epidemics, constitute a stressful experience with particular salience for children [28] . when facing adversities like natural disasters, routines for daily activity contribute to stability and predictability which underpin children's mental health outcomes [29] . evidence suggests that compared to those with fewer caregiving responsibilities, parents experience potent, negative responses to disasters more acutely [8, 17] . anxiety and posttraumatic stress may be exacerbated in caregivers who feel an additional caregiving burden during disasters [21, 30] . parents have an important role in shaping disaster outcomes for themselves, in terms of their own coping and self-care, and for their children by modeling coping responses as a primary source of children's coping socialization [31, 32] . for example, a recent study indicates that even when children report lower disaster exposure than their parents, they experienced similar general distress [33] , underscoring reports of exacerbated negative child disaster outcomes among children of highly distressed caregivers [21] [22] [23] . in contrast, supportive parenting, confidence in safety, and discussions about the disaster can provide a buffer against children's subsequent mental health symptoms [20, 34] , indicating positive, responsive parenting can play important protective roles in the development of children's stress-related symptoms [35, 36] . responsive parenting is sensitive to children's needs by responding appropriately and consistently to children's cues [37] , and significantly associated with children's positive psychosocial, cognitive, and behavioral outcomes [23, 38, 39] . in order to meet the unprecedented and indeterminate demands of parenting during covid-19, parents must actively plan new caregiving, work, and education routines, potentially compromising time to tend to their own emotional experience and self-care. family systems' theory and parenting research describes parents' role as complex [40, 41] , given the need to attend and respond the needs of multiple family subsystems (individual self-care, coordination of co-parenting demands, and parenting needs). high levels of psychological distress and caregiver burden may complicate the resulting balance between parallel care responsibilities and create the potential for parents to sacrifice their own well-being to meet caregiving needs of their children, most often noted among mothers who frequently assume the primary caregiving role [42, 43] . parents' mental health symptoms may make this balance harder in two ways: (1) high levels of distress may interfere with parents' perceptions of their children's stress-and therefore impact responsive parenting-as seen in depressed and anxious mothers' overreporting of their children's psychiatric symptoms [44] , and in withdrawn or unavailable patterns of parent-child interaction [36, 45, 46] . (2) leveraging psychological resources to be resilient in the face of stressful challenges like covid-19 is hampered by pre-existing mental health symptoms, which compromise the regulation of stress [5] , including coping with the strains of caregiver burden. the stresses and strains of parenting during disasters may amplify caregiver burden and mental health symptoms, potentially compromising parenting behavior sufficiently to impact the parent child relationship-a significant predictor of children's outcomes during times of prolonged stress [21] [22] [23] . however, there is resilience in family systems, too, as not all children of parents with mental health symptoms experience maladaptive outcomes [47] , and brief periods of less responsive parenting may not detrimentally impact the emotional tenor of the home and parent child relationships [48] [49] [50] . the current study examined concurrent patterns of parents' reported experience from a national sample during the early months of the u.s. covid-19 pandemic. given the multifinality in the effect of parental mental health symptoms on children [47] and the protective influence of positive parent-child relationships [51] , our research questions center on the potential linkages between mental health indicators and parents' report of child-parent relationship outcomes. do we see associations from the sustained burden created by the covid-19 pandemic on mothers' and fathers' relationships with their children? what role do mental health symptoms play? informed by the spill-over hypothesis [10] , we hypothesize that caregiver burden would be positively associated with parents' anxiety and depression symptoms with associations observed with parents' subsequent perceptions of their children's stress. further, each of these stress and mental health variables would also be associated with parent-child relationship qualities, such that we would anticipate positive associations with conflict and negative associations with closeness. data presented here include the baseline survey results collected from april 27-28, 2020, approximately 5 weeks after the first u.s. quarantines were advised. adults 18 years or older living in the u.s. who speak english and were caring for a child under the age of 18 years old in their home at the time of survey administration were eligible to participate through the online worker pool mechanical turk (mturk). mturk workers have been reported as more diverse and otherwise fairly representative of the characteristics of larger online populations, including the u.s. at large [52, 53] . 420 caregivers (average age of 35.53 years) provided complete data for all key variables of interest (see measures below), 202 (48.1%) of the study participants were female, and 117 (27.9%) were of ethnic/racial minority including 45 (10.7%) black/african american respondents, 71(16.9%) asian/asian american respondents, 14 (3.3%) hawaiian/pacific islander respondents, and 38 (9%) of american indian/alaskan native descent. parents were asked to report the age of the focal child in the following categories: birth to 5 years old (n = 169, 40.2%), 6 to 11 years old (n = 146, 34.8%), and 12 to 18 years old (n = 105, 25%; see table 1 for further demographics details). all study materials were approved by the university of connecticut irb (x20-0075) prior to recruitment from mturk's online worker pool for participation in the anonymous baseline study of family experiences and coping during the covid-19 pandemic. mturk has shown recruitment and data collection to be both replicable and valid [54] . participants who consented to participate in the study and met inclusion criteria were able to complete the survey set and were compensated for their time. caregivers were asked to report demographic characteristics including gender, sexual orientation, race/ethnicity, caregiver age, age of focal child on whom caregivers based responses to key variables, partner status (from non-partnered: single, divorced or widowed, or partnered: married or living with a significant other), and financial security ("do you have enough money to meet your needs", rated from 1 = not at all to 5 = completely). burden scale for family caregivers is a 10-item measure that assesses the perceived burden of caregiving responsibilities in the past 2 weeks using a 4-point likert scale ranging from 0 "strongly disagree" to 3 "strongly agree". example items include from time to time i wish i could "run away" from the situation i am in and the care takes a lot of my own strength. items are summed to create a combined score ranging from 0 to 30; higher scores indicate increased burden levels. categories of burden levels for this scale include: 0-4 indicating mild to no burden, 5-14 indicating moderate burden, and scores from 15 to 30 indicate severe to very severe burden. reported cronbach's alphas are excellent (α = 0.92) [55] , as in the present study (α = 0.94). we used the national institutes of health toolkit's emotion resources [57] for parent-reported child stress. the 10-item adaptation cohen developed of the original perceived stress scale [56] asked participants to report their perceptions of their child's general stress using a 5-point likert scale from 0 "never" to 4 "very often". example items include how often have you felt that your child was unable to control the important things in their life and how often has your child felt nervous and stressed. items are summed to create a combined score ranging from 0 to 40; higher scores indicate increased perceived stress. reported cronbach's alpha from a sample of parents of children as young as 8 years of age are good (α = 0.87) [58] , as are those for the current sample (α = 0.81). the gad-7 is a 7-item scale that assesses the severity of generalized anxiety symptoms and the associated disorder by rating the frequency of anxiety symptoms over the past 2 weeks using a 5-point likert scale ranging from 0 "not at all" to 4 "nearly everyday". example items include feeling nervous, anxious or on edge and worrying too much about different things. items are summed to create a combined score ranging from 0 to 21; higher scores indicate greater presence of anxiety symptoms. categories of levels of anxiety for this scale include: 0-5 indicate minimal anxiety, 5-9 indicate mild anxiety, 10-14 indicate moderate anxiety, and 15-21 indicate severe anxiety [59] . reported cronbach's alphas are good (α = 0.90) [59] , and excellent in the current sample (α = 0.93). the mdi is a 12-item scale that assesses depressive symptoms using a 6-point likert scale ranging from 0 "at no time" to 5 "all of the time". example items include have you felt low in spirits or sad and have you felt that life wasn't worth living. items are summed to create a combined score ranging from 0 to 50 that represents overall severity of depression symptoms; higher scores indicate greater presence of depressed symptoms. responses can be matched to diagnostic criteria to determine whether participants currently meet criteria for a major depressive episode [61] . categories of levels of depression for this scale include: 20-24 for mild depression, 25-29 for moderate depression, and 30-50 for severe depression [62] . reported cronbach's alpha is excellent at 0.94 [60] and in the current sample (α = 0.96). the cprs is a 15-item scale that assesses parents' views of their relationship with their child using a 5-point likert scale ranging from 1 "definitely does not apply" to 5 "definitely applies". the cprs contains two subscales, an 8-item conflict subscale that assesses the parents' perceived negativity in the parent-child relationship, and a 7-item closeness subscale that assesses the parents' perception of the warmth, affection and open communication. example items include uncomfortable with physical affection and will seek comfort from me if upset, from the conflict and closeness subscales, respectively. the scale is scored by summing items on the two subscales such that higher scores indicate greater perceived conflict or closeness, respectively. reported cronbach's alpha from samples of parents of children as young as 3 years of age for the two subscales are acceptable (α = 0.83 and 0.72 for conflict and closeness, respectively) [63] , and are good in the current sample (α = 0.85 and 0.91 for conflict and closeness, respectively). online survey data management guidelines suggest removing cases of substandard completion or inattentiveness, determined by abnormally quick response times [64, 65] . the average response time for this dataset was 34 min, thus any entry which fell below the 10 th percentile or above the 90th percentile was examined for adequate completion. two cases were deleted: one response fell below the 10th percentile, completing the survey set in under 5 min, and the other took an excess of 50 h. data analysis concerning survey completion determined a lack of missing data among demographic variables or among measure scale scores; single item-level missingness was less than 0.1% across all key variables of interest such that no single-item was missing for more than a single participant. given the lack of an interpretable pattern in missingness, missing data was determined to be missing completely at random. 12 cases were list-wise deleted for missing values among key variables of interest summed scores, and an additional 5 cases were deleted due to an outlier pattern detected in spss amos output. the resulting data set includes a total sample of 420 cases. data were managed and the path analysis model developed in spss amos [66] using maximum likelihood estimation. the hypothesized path model examined the direct and indirect associations among caregiver burden, generalized anxiety, depression symptomology, perceived child stress, and child-parent conflict and closeness, with parent gender and focal child age categories as controls. a single model, multi-group path analysis was fit to the data. groups were organized by parent gender, thus, there were two groups in the final analysis. model fit was evaluated by considering data from several fit indices. this was done to ensure that fit was evaluated fairly, and without temptation to select only the fit indices that provided the best interpretation for the model. some have argued against the interpretation of fit indices other than the chi square [67] , as they are impacted by a number of factors in addition to the specification of the model. others have cautioned against strict cutoffs for fit indices in that the use of strict cutoffs are often misapplied [68, 69] . thus, we elected to examine and report the following indices with the associated cut off values as noted: model chi square p value of less than 0.05; gfi > 0.90 for acceptable fit and > 0.95 for good fit [70] , cfi 0.90 for good fit [71] , root mean square error of approximation < 0.08 for acceptable fit and < 0.05 for good fit (rmsea) [72] . means for variables of interest were calculated to determine proportions of caregivers' responses that fell above or below relative reported cutoff points. parents reported an average caregiver burden score of 11.00, indicating moderate levels of burden [55] , an average perceived child stress score of 23.79-which is above the 50th percentile of scores and indicates moderate stress [56] . the sample average for generalized anxiety was 7.59, indicating mild anxiety [59] , and an average depression score of 19.16, indicating scores just below mild depression [62] . average scores for child-parent relationship were 19.43 for conflict and 29.66 for closeness, where higher scores indicate greater perceived conflict or closeness, respectively [63] . these averages indicate both lower closeness and greater conflict compared to means from a national sample reported by the cprs authors [63] , these differences may be attributed to younger children sampled during normative circumstances for that study, rather than the present sample which was collected nationwide during a widespread community crisis. bivariate associations (see table 2 ) indicate child-parent relationship conflict was significantly negatively associated with child-parent relationship closeness (r = − 0.37, p < 0.01). importantly, additional positive associations exist between child-parent conflict and generalized anxiety, depression symptomology, caregiver burden, and parent perceived child stress (rs = 0.56 to 0.75, respectively, all p < 0.01). conversely, child-parent closeness was significantly negatively associated with generalized anxiety, depression, caregiver burden, and parent perceived child stress (rs = − 0.17 to − 0.47, respectively, all p < 0.01). independent samples t-tests were then conducted to assess for group differences based on parent gender, financial resources, and single-parent status. several statistically significant group differences are evident (see table 3 ): male caregivers reported significantly higher rates of child-parent relationship conflict (t = 4.02, p < 0.01), depression symptomology (t = 2.73, p < 0.01), caregiver burden (t = 2.02, p < 0.05), and parent perceived child stress (t = 4.86, p < 0.01), whereas female caregivers reported significantly lower rates of child-parent relationship closeness (t = − 4.90, p < 0.01). caregivers whose financial needs were not met reported significantly higher rates of child-parent relationship conflict (t = 4.21, p < 0.01), generalized anxiety (t = 4.15, p < 0.01), depression symptomology (t = 4.91, p < 0.01), caregiver burden (t = 5.44, p < 0.01), and parent perceived child stress (t = 4.10, p < 0.01), whereas parents whose financial needs were met reported significantly lower rates of child-parent relationship closeness (t = − 3.04, p < 0.05). partnered parents reported significantly higher rates of child-parent relationship conflict (t = 3.97, p < 0.01), generalized anxiety (t = 2.65, p < 0.01), depression symptomology (t = 2.29, p < 0.05), and parent perceived child stress (t = 2.72, p < 0.01) compared to those without partners. lastly, one-way anova assessed differences on key variables by child focal age categories: parents of children ages 12 to 18 years old perceived less child stress (f = 3.05, p < 0.05), and experienced lower caregiver burden (f = 3.22, p < 0.05) than parents of younger children (compared to birth to 5 year-olds and 6 to 11 year-olds). the results of a multi-group path analysis, organized by parent gender, is presented. results are presented visually in figs. 1 and 2 , for male and female caregivers, respectively. the multi-group path model had good fit, x 2 (10) = 159.04, p < 0.01, cfi = .91, gfi = 0.92, rmsea = 0.18. taken together, there is evidence of appropriate goodness of fit of the model to the data. the model chi square p value was less than 0.05; and the gfi and cfi had values greater than 0.90. the rmsea is slightly higher than ideal, but this may be an artifact of the complexity of the model. some report that the index can be positively biased and that the bias towards a higher rmsea is associated with both sample size and degrees of freedom [70] . given that there are relatively few degrees of freedom, the rmsea might be expected to be higher in this instance. the multi-group model indicated no significant association between the control (focal child age) and any endogenous variables (parent perceived child stress, child parent relationship conflict and child parent relationship closeness). figures 1 and 2 represent the path analyses for male and female caregivers, respectively. solid lines indicate table 3 means, standard deviations, and group difference effect sizes for the overall sample (n = 420) two-tailed independent samples t-tests were used for categorical group comparisons; one-way anova was used for group categorizations with three or more groups (focal child age: birth to 5 years old, 6 to 11 years old, and 12 to 18 years old); bivariate correlations were used for continuous predictors (age dashed lines indicate nonsignificant paths as hypothesized, caregiver burden was positively associated with generalized anxiety (β = 0.62 and 0.43), depression symptomology (β = 0.69 and 0.51), and parent perceived child stress (β = 0.58 and 0.48) for male and female caregivers, respectively; these results indicate the predictive associations between variables of interests was consistently greater for male caregivers. parents who reported higher rates of caregiver burden also reported higher rates of generalized anxiety, depression, and parent perceived child stress, with male caregivers reporting higher rates overall than female caregivers. caregiver burden was not significantly directly associated with child parent relationship conflict (β = 0.10 and 0.12, p = ns) or child parent relationship closeness (β = − 0.13 and − 0.13, p = ns) for male or female caregivers, respectively. contrary to our hypothesis, generalized anxiety symptoms did not significantly predict child parent relationship conflict (β = − 0.22 and − 0.23, p < 0.01) or child parent relationship closeness (β = 0.21 and 0.26, p = ns) for male or female caregivers, respectively. as hypothesized, depression symptomology was significantly positively associated with child parent relationship conflict (β = 0.72 and 0.50, p < 0.01) for male and female caregivers, respectively, suggesting caregivers with increased depression symptoms reported increased conflict in their parent-child relationship, more so for male caregivers in our sample. contrary to our hypothesis, depression symptoms were not significantly associated with child parent relationship closeness (β = 0.05 and − 0.24, p = ns) for male and female caregivers, respectively. as hypothesized, parents' reports of increased perceived child stress were significantly positively associated with child parent relationship conflict (β = 0.36 and 0.56, p < 0.01) for male and female caregivers, respectively, suggesting caregivers who perceived greater child stress were more likely to report increased conflict in their child-parent relationship, particularly for female caregivers. additionally, parents' increased reports perceived child stress was significantly negatively associated with child parent relationship closeness (β = − 0.47 and − 0.47, p < 0.01) for male and female caregivers, respectively, suggesting caregivers, regardless of their gender, with increased perceptions of child stress were more likely to report reduced closeness in their parent-child relationship. aligned with recent data from the u.s. census bureau and centers for disease control indicating that mental health symptoms are increasing during covid-19 (anxiety more so than depression) [73], the parents in this sample report comparable mental health symptoms that echo rates from a national sample of caregivers during the covid-19 pandemic [8] . parenting is stressful under normative circumstances-its stresses felt by men and women [40, 74] , but crucial time-sensitive data indicate that covid-19 has led to significant increases in the population's general stress, a change felt even more acutely for parents than their non-parent counterparts [8, 75] . our data are among the first to report subgroup differences among parents during covid-19, indicating fathers in our sample report higher rates of burden overall. further, as seen in the betas for each path, the predictive values between variables at each step of the model are strongest for male caregivers. this is in contrast to reports prior to covid-19 that indicate mothers report a disproportionate level of caregiving responsibility and greater caregiver burden than their male counterparts [76] [77] [78] , which may suggest difficulty in adjusting to disaster-related shifts in roles and responsibilities for men. the consistently higher beta weights for men's paths indicates that the associations between caregiver burden and mental health symptoms and perceived child stress, and subsequent linkages to relationship quality are stronger than they are for women. while caregiving roles and responsibilities have increased for all parents by dint of school and childcare closures during the pandemic, women appear to be less distressed by these shifts or note increased conflict and decreased closeness with their children (regardless of the extent of relative change in caregiving roles). similarly, we note significantly higher rates of reported caregiver burden among the nearly half of the sample who indicate a lack of financial resources adequate to meet needs, highlighting the potential heightened mental health needs of known economically vulnerable segments of the population noted by similar covid-19 surveys of the general population [5, 75] . path analysis results report of significant linkages between parents' caregiver burden and mental health and perceptions of children's stress; these in turn are significantly linked to child-parent closeness and conflict. these findings are in line with parent reports of children's experiences from disasters in which the degree of variability in outcomes may be partially explained by children's understanding of the crises at hand and their families' response [79, 80] . as noted by lansford et al. [81] when describing how children respond to parenting, "[c] hildren's conceptions derive at least in part from norms and expectations gleaned from the broader context in which families are situated" (p. 203). given the pervasive, community-wide experience of heightened stress during covid-19, children may be observing context-specific norms for their relationships with parents through the creation of new routines, rules, and expectations during the quarantine and shelter-in-place circumstances. parents are contending with the indefinite parameters of a disaster expected to reach high mortality rates nationwide before the end of children's school year. anxieties about covid-19 fueled municipal recommendations to close workplaces and schools adding caregiving and education challenges to the daily routine adjustments parents must make with very little support [7] . parents reporting higher levels of depression and anxiety in this sample also report higher stress in their children; perhaps this effect is driven by the distortion or overreporting tendency noted by previous researchers [44, 82] . such a result is possible for a number of reasons, for example, parents might overreport child stress out of worry, or fear, or as a result of projection of their own mental health difficulties. or, it is possible that the entire family's coping skills have been challenged and everyone is suffering from an increase in mental health concerns. similarly, the significant group differences between single and partnered parents suggests that the additional demands of managing a co-parenting relationship may be influencing child-parent relationships. future research which untangles sources of relationship stress, and includes partners and children perspectives, would be useful. while the model represents a sound fit to the data, there are some areas of concern that require additional examination. the cfi and gfi indices indicate good fit [70] , while the rmsea does not. it is possible that the rmsea may be less robust for this model, given noted limitations (e.g., small dfs and sample size, or model misspecifications) [83] . rmsea is most accurately a measure of badness of fit [84] , and, as a result, it should be interpreted with caution here. nonetheless, there is the potential that the rmsea has identified some potential misspecification in the model, and future researchers might wish to examine these constructs with different paths, or in other ways that provide more data about associations between these variables. results presented here provide time-sensitive information about families' experiences during the first weeks of the covid-19-pandemic, however, several limitations should be noted. while we lack a pre-pandemic baseline assessment from this sample, our results provide a description of families' early experiences during the peak of the covid-19 pandemic; stronger inferences beyond those possible with cross-sectional data require longitudinal data. while the nih toolkit resources are valuable for creating low-burden, shared data elements for the field of child development, in many cases they are recent adaptations and require further validation [57] . specifically, while cohen's assessment of perceived stress is among the most commonly used global stress measures [56] , the adaptation used in this study has not yet been tested in children younger than 8 years of age. mturk recruitment enables rapid collection of data on a national scale, however, caution is warranted with regards to the sample's generalizability (specifically, the majority of the sample is white and has access to the internet that facilitate mturk data collection). while 47% of this sample reported financial resources insufficient to meet their needs, deliberate recruitment of vulnerable families (e.g., those with chronic medical conditions or complex educational needs), including more robust measures of resources and supportive services in use, would better estimate heightened risk for those at greatest risk for mental health difficulties. results from this mturk sample may not be as representative as those from a probability sample, but nevertheless are among the first national data available on the compounded stresses brought to bear upon american parents during covid-19. attending to mental health indicators for parents is vital for the agile provision of mental health resources to protect high quality parent-child interactions despite the stressful context of the covid-19 pandemic. this study highlights the important spillover link between mental health (i.e., depression, anxiety), perceptions of children's stress, and subsequent impacts on child-parent relationships [10, 82] . clear links exist between mental health indicators and childparent conflict and closeness, such that parents with more severe depression symptoms and who perceive greater child stress also report greater conflict and less closeness, those with more severe anxiety symptoms report less conflict, echoing findings by ginsburg, grover and lalongo [85] that suggest anxious parents may be particularly vigilant to responding to cues of children's distress by encouraging them to express their opinions and providing support and acceptance of their decisions. the pattern of affect and behavior that can carry over from parents to children may take several forms, per the spillover hypothesis [10] : the spillover hypothesis suggests that affect or behavior can transfer within a family system at the same valence, or through compensatory paths that occur with the opposite valence, or finally through a crossover process, where rather than a transfer of affect within one person across subsystems, crossover describes the transfer of affect or behavior between people. our results indicate possible spillover effects for depressed parents and compensatory effects for anxious parents, however, future data on the experiences of other members in the family will help elucidate more precisely the extent of impacts from each form of spillover (e.g., co-parent reports of partner and child-parent relationships). should fatigue and the emotional strains of quarantine and social distance (and related changes in work, education, and child care routines) increase over time, practitioners will need to be focused on providing resources to bolster the energy caregivers have to sustain positive parenting behaviors and provide sensitive interactions for their children that convey a sense of safety, precaution, and protection. these resources may specifically benefit caregivers experiencing heightened anxiety or depression symptoms, as was the case for fathers in this sample. it may be particularly helpful to attend to the demands that new shifts in caregiving roles and responsibilities place on fathers who may be less unaccustomed to navigating the added tasks of work-life balance during times of stress. supportive resources that structure and protect time for self-care that emphasize its value while not stigmatizing help-seeking (formal or informal) may prove especially reassuring to this group. research indicates that exposure to a wide range of disasters negatively impacts mental health for families and can lead to prolonged periods of increased anxiety and depression symptoms. further evidence suggests that child disaster outcomes are worst among children of highly distressed caregivers, or those caregivers who experience their own negative mental health outcomes from the disaster. the impact of millions of families sheltering in place for an undefined period of time, during the current pandemic, may lead to unprecedented impacts on individuals' mental health with unknown impacts on child-parent relationships; periods of uncertainty with an indeterminant endpoint constitute a stressful experience with particular salience for children. the current study used path analysis to examine concurrent patterns of parents' (n = 420) experience from a national sample during the early months of the u.s. covid-19 pandemic. the results of a multigroup path analysis, organized by parent gender, indicates good fit to the data [x 2 (10) = 159.04, p < 0.01], such that parents who reported higher rates of caregiver burden also reported higher rates of generalized anxiety, depression, and parent perceived child stress, with male caregivers reporting higher rates overall than female caregivers and stronger associations across the linkages between variables at each step in the model. specifically, there are significant linkages between parents' caregiver burden, mental health, and perceptions of children's stress; these in turn are significantly linked to child-parent closeness and conflict, such that the strongest betas are seen for male caregivers across all variables of interest. these associations are indicative of spillover effects for depressed parents and compensatory effects for anxious parents. in light of these 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cough does not improve: a review on protracted bacterial bronchitis in children date: 2020-08-07 journal: front pediatr doi: 10.3389/fped.2020.00433 sha: doc_id: 355623 cord_uid: tmr1ieg1 chronic cough is defined as a daily cough that persists longer than 4 weeks. protracted bacterial bronchitis (pbb) is a common cause of chronic wet cough in preschool children with no symptoms or signs of other specific causes, and resolution usually follows a 2-week course of an appropriate oral antibiotic. the diagnosis is mainly clinical; generally, no instrumental examinations are necessary. the most common bacteria found in the bronchoalveolar lavage (bal) of subjects with pbb include haemophilus influenzae, streptococcus pneumoniae, and moraxella catarrhalis. nowadays, there is no certain evidence of the role of viruses in pbb pathogenesis even though different types of viruses have been detected in bal from children with pbb. airway malacia is commonly found in children with pbb; conversely, there is no correlation with any type of immunodeficiency. amoxicillin-clavulanate acid is the most commonly used antibiotic, as first-line, prolonged therapy (longer than 2 weeks) is sometimes required to cough resolution. when the wet cough does not improve despite prolonged antibiotic treatment, an underlying disease should be considered. moreover, there are several hypotheses of a link between pbb and bronchiectasis, as recent evidences show that recurrent pbb (>3 episodes/years) and the presence of h. influenzae infection in the lower airways seem to be significant risk factors to develop bronchiectasis. this underlines the importance of a close follow-up among children with pbb and the need to consider chest computerized tomography (ct) in patients with risk factors for bronchiectasis. in this brief review, we summarize the main clinical and pathogenetic findings of pbb, a disease that may be related to a relevant morbidity and decreased quality of life during the pediatric age. chronic cough in childhood is related to a considerable morbidity and a decreased quality of life (qol) scores, affecting the child's sleep, the ability to play, and the school performance (6) . it may also cause a state of anxiety for parents. nevertheless, the real impact of chronic cough on qol is difficult to quantify (6) . both generic health-related (pedsql) and chronic cough-specific (pc-qol) qol scores among children with pbb are similar to those of children with other respiratory disease such as asthma or bronchiectasis (1) . etiologies of chronic cough include several and heterogenous disease such as asthma, upper airway cough syndrome, and protracted bacterial bronchitis (pbb) (7) . chronic wet cough may also be a symptom of a chronic suppurative airway disease including bronchiectasis (8) . pbb clinical condition was first described by marchant et al. in an australian study among children with a history of chronic wet cough lasting more than 4 weeks, a positive culture of a respiratory pathogen on bal (bacterial growth ≥10 4 cfu/ml in bal) obtained during a flexible bronchoscopy and a clinical response to 2 weeks treatment with antibiotics (amoxicillinclavulanate acid) (9) ( table 1) . currently, this definition has been reclassified as pbb-micro, and new diagnostic criteria have been developed on the basis of clinical symptoms, thus eliminating the need for bal, not performed routinely among the pediatric population. according to the european respiratory society (ers) guidelines new definition, pbb-clinical is based on all three of the following criteria: "presence of chronic (>4 weeks' duration) wet or productive cough; absence of symptoms or signs (i.e., specific cough pointers) suggestive of other causes of wet or productive abbreviations: ba, bronchial aspirate; bal, bronchoalveolar lavage; clds, cystic lung diseases; ct, computerized tomography; ger, gastroesophageal reflux; nthi, haemophilus influenzae non-typeable; pbb, protracted bacterial bronchitis; qol, quality of life; uacs, upper airway cough syndrome. cough ( table 2) ; cough resolution following a 2-4-week course of an appropriate oral antibiotic" (1, 4) . the following additional definitions are used in clinical practice: pbb-extended is pbb-micro or pbb-clinical requiring 4 weeks antibiotic treatment for cough resolution; recurrent pbb is used to define recurrent episodes (>3 per year) of pbb ( table 1 ) (10) . according to the american college of chest physicians (chest) methodological guidelines, too, the definition of microbiologically based pbb (or pbb-micro) should be used "for children aged ≤14 years with pbb with lower airway (bronchoalveolar lavage or sputum) confirmation of clinically important density of respiratory bacteria (≥ 10 4 cfu/ml), " in order to differentiate it from clinically based pbb (3). we know that pbb is a common cause of persistent wet cough in preschool children aged 0-6 years worldwide (although sometimes it may affect even older subjects). it is diagnosed in 11-41% of children consulting a pulmonary specialist. these data are confirmed by two main studies: the first is a prospective multicenter study on the cause of chronic cough including 346 children aged <18 years (mean age of 4.5 years) recruited from five australian major hospitals and three rural-remote clinics newly referred with chronic cough, where it was discovered that the main cause (41%) was pbb (11) . the latter more recent study included 563 children aged <17 (mean age of 5.4 ± 3.8 years), admitted to the pediatric department for chronic cough. among these patients, the most common final diagnoses were asthma (24.9%), asthma-like symptoms (19%), pbb (11.9%), and upper airway cough syndrome (9.1%) (12) . for these reason, in the clinical practice, it is important to know this lung disease in order to start an appropriate therapy before the associated complications arise. as mentioned above, the most frequent symptom in children with pbb is persistent wet cough. generally, the median age ranges from 1.8 to 4.8 years even though pbb can occur also later (>12 years) (11) . frequently, there is neither a correlation with upper airway inflammation such as otitis or sinusitis nor signs of underlying chronic suppurative lung disease (csld) such as digital clubbing, chest wall deformity, and auscultatory wet sound (10, 13) . the prevalence of atopic features is similar to children without pbb, and no specific correlation with the exposure to tobacco smoke has been evidenced (1, 13) nevertheless, tobacco exposure is known to be a risk factor for the development of chronic respiratory diseases (14) . although generally parents report wheezing, auscultatory feedback is rare and more frequently "rattling chest" and crackles are heard (10) . sometimes, the symptoms of pbb are confused with those of asthma because of similar elements, and occasionally, they could coexist. what differentiates the two pictures are mainly the type of cough (wet in pbb and often dry and/or nocturnal in asthma) and the response to antibiotic treatment in pbb. if a child has chronic wet cough and suspected asthma not responding to rescue and background medications, empiric treatment for pbb should be assessed (8) . therefore, diagnosis of pbb is mainly clinical; generally, no instrumental examinations are needed (figure 1 ). among children undergoing chest radiograph, there are no significant changes, so the examination is normal in most cases (sometimes the chest imaging shows only peribronchial changes) (8, 15) . when performed, lung functional test results are usually normal (10) . although pbb may coexist with other diseases such as asthma, no studies assessing objective reversible airflow limitation are available to date (1) . ct scan should only be performed following a treatment failure to evaluate the possible presence of underlying bronchiectasis (8) . bal with a flexible bronchoscope from lower airways should be performed in cases of relapse after three courses of antibiotic; however, the timing is also to be assessed with the parents (16) . according to ers statement, usually bal is carried out in the most affected lung area (identified radiologically and/or endoscopically) (17) . in infants, it is often easier to perform bal in the right lower lobe being, along with lingula, the preferred site because these areas offer better fluid recovery (17, 18) . bal is generally not well-tolerated, and although it is a safe procedure, it may cause hypoxemia; therefore, a recent study compared bal and bronchial aspirate (ba) to investigate if the latter would bring to similar results (19) . both bal and ba cultures provided the same result among the majority of patients (66%). differences affecting the choice of treatment were found just in a small number of subjects with pbb (10% overtreated, 6% undertreated, 4% would have received a different therapy). the study concludes that bal still remains the gold standard, even though ba could be considered in cases where bal is not tolerated, considering that the results are overlapping in the majority of cases (19) . in contrast to the above, bts guidelines suggest that, among children with pbb, underlying conditions should be excluded, and a sputum culture should be performed before the diagnosis (5) . likewise, when a wet cough persists after 4 weeks of appropriate antibiotics, chest guidelines also suggest performing "further investigations (e.g., flexible bronchoscopy with quantitative cultures and sensitivities with or without chest computed tomography)" (3). several studies documented haemophilus influenzae as the most common bacteria found in the bal of subjects with pbb (47-81%), with high bacterial loads (≥10 5 cfu/ml) (1). most h. influenzae are non-typeable (nthi) strains representing different genotypes (10) . streptococcus pneumoniae (24-39%) and moraxella catarrhalis (19-43%) follow with variable percentages among different studies (10) . finally, it should be noted that polymicrobial infections involving more than one pathogenic bacterium have been reported in bal of children with pbb (30-50%) (1, 20, 21) . different studies examined the lower airway microbiota of children with pbb. the first study did not reveal significant differences regarding the microbiota composition between children with bronchiectasis, cystic fibrosis, and pbb; the core microbiota was superimposable with predominance of h. influenzae and oral aerobic and anaerobic (as prevotella melaninogenica) (22) . this contrasted with the data found among adults and suggested that a chronic airway infection starts in a similar way with inadequate airway clearance of normal microbiota, but as time passed, the microbiota in these disease groups progressively diverge from one another as a result of antibiotic drugs and (maybe) as the consequence of the underlying disease (10) . a second study conducted in 2016 found some significant differences between the microbiota of the upper and lower airways between children with pbb, bronchiectasis, and controls (23) . in 2017, a team of uk researchers compared protected brushing of 20 healthy controls and 24 children with pbb, finding that the microbiota of the latter was less different in terms of richness and evenness. bacterial communities in children with pbb were dominated by proteobacteria, and indicator species analysis showed that haemophilus and neisseria were significantly associated with the patient group (24) . a more recent study found out that in bal of children with pbb, one or more respiratory pathogens were detected. moreover, children with pbb showed that a higher bal bacterial biomass strongly correlated with neutrophilic inflammation. pbb-microbiota were different to control-microbiota and clustered into four distinct microbiota patterns where respiratory pathogen or other microbiota species (e.g., prevotella) have been detected (25) . the cultures of respiratory pathogens, inflammatory markers, and bal bacterial biomass were found to not be associated with this variation in alpha diversity among subjects with pbb. this suggest that inflammation and increased bacterial biomass in pbb cannot be caused only by single pathogenic species (25) . differences between the data from these two recent studies may be due to different average age of the patient cohort, geographical differences, or contamination of the bal with upper respiratory flora. finally, a last interesting finding of the study is that prevotella-associated profiles were similar to those of children with pathogen-dominated microbiota, and this could mean that even the microbiota in some cases contributes to inflammation in these patients. this could explain why some children with chronic cough and lower inflammation without respiratory species detected still respond to antibiotic treatment (26) . nevertheless, further studies are needed to establish whether a high relative load of prevotella could explain the need of longer antibiotics (4 weeks) among children with pbb (10, 25) . it is therefore important to understand the role of the microbiota in the pathogenesis of pbbs to identify any other bacteria involved in the recurrence and progression to bronchiectasis (25) . a biofilm is "an assemblage of surface-associated microbial cells that is enclosed in an extracellular polymeric substance matrix; bacterial growth and activity are substantially enhanced by the incorporation of a surface these organisms could tie to" (27) . this matrix decreases antibiotic penetration protecting bacteria against antibiotics (28) . it is reasonable to assume that a chronic bacterial bronchitis develops when one or more pathogens aggregate to form biofilms within the conducting airways dominating a niche. the prevalence of a single species or mixed populations within the biofilms drives a chronic inflammatory state, which induces a favorable environment for some bacteria such as non-typeable h. influenzae (nthi) (29) . viral infection appears not only to enable the starting of both the surface attachment and of biofilms but also to be the trigger for the exacerbations characterized by the release of planktonic organism, which will generate an enhanced inflammatory response (29) . the presence of biofilms can cause the need for prolonged antibiotic therapy, and it has been detected both in bal of children with bronchiectasis and with pbb (10). different types of virus have been detected in bal from children with pbb, but the clinical significance of this is unclear. in a first study on these subjects, high virus detection was reported in pbb patients (67%) compared to controls (38%), and the most common identified virus was adenovirus (adv) in the pbb-bal (23%) compared with controls (4%) frequently encountered with h. influenza coinfection (13) . the same study found other viruses such as rhinovirus (41%), human bocavirus (4%), and human coronavirus (4%) with overlapping prevalence between the two groups (13) . there is only one study in the literature on this topic, published in 2019, whose data are opposed to those already known. this study looks for 10 common viruses in the bal of patients with pbb and controls. the detection rate is almost the same within the two groups (23.5-28.6%) (30) . moreover, no adv in bal in pbb cases were detected, in contrast to previous studies (13, 30) . based on this conflicting data, nowadays, we can say that there is no certain evidence that pbb may be virus induced. the correlation between major airway injuries and recurrent bronchitis is well-known (31) . airway malacia is detected frequently in children with pbb (30) . it may affect airway clearance, therefore predisposing to pbb, although also airway inflammation may predispose to malacia in a vicious circle (10, 32) . kompare et al., in their retrospective study about pbb and tracheobronchomalacia, have assessed 70 children (20 female and 50 male) with protracted cough, wheeze, and/or noisy breathing in whom bal found ≥10 4 cfu/ml of potentially pathogenic bacteria; children with other major conditions were excluded (asthma, cystic fibrosis, and other known chronic diseases) (33) . they reported malacia in 74% of pbb cases (33) . a prospective study by wurzel et al. on a cohort of 104 children with pbb evidenced a correlation with tracheo-and/or bronchomalacia in 68% of (13) . furthermore, airway malacia can both decrease effectiveness of cough and interfere with normal mucous movement, a crucial mechanism for clearing bacteria from the airways (34) . as postulated by donnelly et al., airway malacia could induce an impairment of normal pulmonary defense mechanisms promoting the development of chronic cough and pbb (21) . children with pbb usually do not have immunodeficiencies; therefore, most of them have normal serum immunoglobulin levels by age (igg, iga, igm, and ige) as well as normal antibodymediated response to protein (tetanus) and conjugated proteinpolysaccharide (h. influenzae type b) (9, 13) . nevertheless, several studies report the presence of intense airway neutrophilia with a neutrophil percentage between 25.5 and 44%; no eosinophilia was found, and just one study reported percentage increase in lymphocytes (9, 21, 35, 36) . lymphocyte subsets were normal, except for increased cd56 and cd16 natural killer cell level for age, probably associated with recent viral infection (1, 13, 37) . increased levels of interleukin (il)-8, il-1β, and active matrix metalloproteinase-9 seems to correlate with the degree of neutrophilia (38) . a study of chang et al. detected increased human β-defensin-2 and mannose-binding lectin levels, while activated caspase-1-dependent proinflammatory pathways in response to nthi were also identified in pediatric patients with pbb, because both the innate pathogen recognition and clearance mechanisms were normal (36) . in addition, higher levels of toll-like-receptor 2 (tlr-2) and toll-like-receptor 4 (tlr-4) in the bal of children with pbb are reported compared to controls (38) . finally, another study focuses on the possibility of an impaired clearance of apoptotic cells by alveolar macrophages (efferocytosis). the remaining apoptotic cells may undergo secondary necrosis with proinflammatory effect, thus increasing chronic inflammation and tissue damage (10, 39) . in 2008, chang et al. proposed a paradigm where "pbb, csld and bronchiectasis shared common underlying pathobiological mechanisms and progressed variably along an increasing spectrum of severity" (8) . the similarities are chronic wet cough, rattling breathing, defective mucociliary clearance, endobronchial bacterial infection, and neutrophilic airway inflammation (10) . the major differences between these conditions consist in the clinical severity, the improvement to 2-4 weeks of adequate antibiotic treatment, chest high-resolution ct scan findings, and subsequent management (10, 40) . starting from these observations, analysis were made to address the possible existence of more elements predicting the evolution of pbb in bronchiectasis capable of explaining why among children with recurrent pbb, some subjects do not show pulmonary sequelae, while other children develop bronchiectasis. a recent prospective longitudinal cohort study assessed the 2year outcomes of 161 pediatric patients with pbb and detected two main risk factors for bronchiectasis: recurrent pbb (>3 episodes/years) and a positive bal culture for h. influenzae. this finding correlated with a higher risk of bronchiectasis (more than seven times) compared with no infection (41) . moreover, authors showed that ∼1 of 12 children with pbb are diagnosed with bronchiectasis at 2 years follow-up, with many experiencing recurrent episodes of pbb. this study provides further evidence to support a link between pbb and bronchiectasis in young children. this may also suggest the need to monitor children with pbb over time and to consider chest ct imaging in those with risk factors for bronchiectasis (41) . noteworthy are some evidence showing that lower airways of pbb and bronchiectasis are characterized by marked neutrophilic inflammation with intense proinflammatory mediator responses such as interleukin-8, matrix metalloproteinase-9, and il-1β. all these findings significantly differ to controls and support the hypothesis that lower airway microbiology and pathobiological aspects are similar in pbb and bronchiectasis (35, 38) . according to the 2017 chest guideline and expert panel report, there is high-quality evidence that the administration of appropriate antibiotics among children aged ≤14 years with wet/productive cough improves cough resolution, although further investigation should be undertaken when specific cough pointers (e.g., digital clubbing) are present. when the wet cough does not improve in response to 4 weeks of antibiotic therapy, there is moderate-quality evidence that further investigations such as flexible bronchoscopy, chest ct scan, and immunity tests should be considered to look for an underlying disease (3) . children with pbb should be treated with antibiotic for at least 2 weeks. several studies have been performed, and use of prolonged antibiotic treatment has been shown to facilitate cough resolution compared to placebo (42) . specifically in a randomized controlled trial conducted by marchant et al. (26) , including 50 children (median age, 1.9 years) with chronic wet cough (>3 weeks) a 2-week treatment with amoxicillin-clavulanate acid allowed cough resolution compared with placebo (48 vs. 16%) (26) . amoxicillin-clavulanate acid is the most commonly used antibiotic due to its activity against βlactamase, although other options such as oral second or third generation cephalosporins, trimethoprim-sulfamethoxazole, or a macrolide may be used among patients with ige-mediated reaction to penicillin (1). nevertheless, oral cephalosporins because of its similarity to penicillins (e.g., ampicillin and cefalexin or cefaclor) should be avoided among these patients (1) . some children require up to 4 weeks of treatment. marchant j. et al. in their randomized controlled trial (rct) cited above shows that many of the children not responding after 2 weeks of treatment had underlying tracheobronchomalacia (26) , even though better evidence is needed to determine whether a prolonged course of antibiotics is beneficial, due to the inherent risk of antibiotic therapy. furthermore, during a different study on 144 children eligible upon defined criteria [presence of chronic wet cough >4 weeks and having completed at least 4 weeks of oral antibiotics directed against likely respiratory bacterial pathogens associated with pbb, cystic lung diseases (clds), and bronchiectasis] goyal v. et al. showed that children affected by chronic wet cough not improving after 4 weeks of appropriate treatment have increased likelihood (88/105, 83.8%) of bronchiectasis on a chest ct scan (43) . some clinicians prefer to use prolonged therapies even beyond the resolution of symptoms, and the rationale is that protecting the airways against the common respiratory bacteria for a longer period reduces the risk of reoccurrence and recovers airways integrity (1). however, prolonged antibiotic treatments may cause dysbiosis and the selection of antibiotic-resistant strains (44) . lastly, the role of 1weekly azithromycin in pbb is not clear even though it seems halving the rate of exacerbations in children with either csld or bronchiectasis (1, 45) . bts cough guidelines suggest that all children with pbb should receive both 4-6 weeks of antibiotics (5) and physiotherapy. pbb is a common cause of persistent wet cough in preschool children worldwide; it is frequently underdiagnosed or mistaken for other diseases such as postviral cough or asthma and therefore inadequately treated. considering pbb in the differential diagnosis of chronic wet cough in children allows an early and adequate antibiotic treatment to eradicate the infection. bal and antibiogram generally are not required, as well as chest x-ray, and clinical diagnosis is enough to start an empiric 2 weeks therapy with amoxicillin-clavulanate acid. this therapy is mostly effective against the bacterial species involved, such as h. influenzae (nthi), s. pneumoniae, and m. catarrhalis. moreover, an adequate therapy prevents the onset of a prolonged inflammatory process potentially associated with structural damage of the lower airways, which may be involved in bronchiectasis. several studies provide evidences to support a link between pbb and bronchiectasis in children, and this emphasizes the necessity to consider this possibility of evolution and to carry out some more detailed investigations in the case of a clinical suspicion. ers statement on protracted bacterial bronchitis in children guidelines for evaluating chronic cough in pediatrics management of children with chronic wet cough and protracted bacterial bronchitis: chest guideline and expert panel report ers guidelines on the diagnosis and treatment of chronic cough in adults and children recommendations for the assessment and management of cough in children minimally important change in a parent-proxy quality-of-life questionnaire for pediatric chronic cough update on pediatric cough chronic wet cough: protracted bronchitis, chronic suppurative 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tracheomalacia and bronchomalacia in children: incidence and patient characteristics bronchoscopic findings in children with non-cystic fibrosis chronic suppurative lung disease protracted bacterial bronchitis in young children: association with airway malacia airway mucus function and dysfunction mediators of neutrophil function in children with protracted bacterial bronchitis pulmonary innate immunity in children with protracted bacterial bronchitis clinical characteristics of protracted bacterial bronchitis in chinese infants1 prospective assessment of protracted bacterial bronchitis: airway inflammation and innate immune activation burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease protracted bacterial bronchitis is a precursor for bronchiectasis in children: myth or maxim? breathe protracted bacterial bronchitis in children: natural history and risk factors for bronchiectasis children with chronic wet or productive cough-treatment and investigations does failed chronic wet cough response to antibiotics predict bronchiectasis? the intestinal microbiome in early life: health and disease long-term azithromycin for indigenous children with non-cysticfibrosis bronchiectasis or chronic suppurative lung disease (bronchiectasis intervention study): a multicentre, double-blind, randomised controlled trial mp and mg performed the literature review. gr coordinated the writing group. all authors critically reviewed the manuscript and read and approved the final version. key: cord-351797-b7ywe980 authors: cito, gianmartin; micelli, elisabetta; cocci, andrea; polloni, gaia; coccia, maria elisabetta; carini, marco; minervini, andrea; natali, alessandro title: paternal behaviors in the era of covid-19 date: 2020-04-29 journal: world j mens health doi: 10.5534/wjmh.200071 sha: doc_id: 351797 cord_uid: b7ywe980 nan in recent years, greater attention has been given to the crucial role of fathers in the care and development of their children [1] . several studies have enhanced the understanding of the multitude of paternal behaviors which can affect the health of their children, regardless of marital status [2] . the rapid spread of sars-cov-2 (covid-19) infection has prompted the italian government to declare a national quarantine with restrictive actions, causing a considerably negative socio-economic impact. likewise, several countries have adopted similar measures in order to minimize the spread of the virus. in this warlike condition, all school lessons have been suspended, meaning that childcare is required full-time at home, social and professional meetings have been canceled, public spaces (i.e., parks) locked, the mobility of people restricted to work or health reasons only, and many businesses have been closed. as a result, the quarantine has led many fathers to spend much more time at home with their children. all of this will probably contribute to change the general perception of fatherhood. in the past, some states have developed paid family leave policies in order to support the relationship and attachment of fathers to their infants or young children. however, despite this opportunity, men might experience negative consequences in their professional career when they request family leave [3] . past socioeconomic events gave fathers the opportunity to choose to make their contribution at home and become stayat-home dads in families in which mothers are able to support family income. various researches in the field of mental health, sociology and psychology have provided a critical evaluation of the father's central and irreplaceable role in the health of a child, as well as his effect on maternal well-being. in fact, it has been demonstrated that paternal involvement has a significant impact on the children well-being, especially when it comes to nutrition, exercise, play, and behavioral habits [4] . however, troublesome working hours and the lack of free time could compromise the quality of the parent-child relationship, thus reducing the parental confidence. considering that the stereotype of "father" has changed and is no longer seen as a mere householder, men are now given the opportunity to play a fundamental role in their children's upbringing, influencing their development and family wellbeing. however, fatherhood has to be considered in all of its forms. most children grow up with a father and a mother, but some only have a single father, others have two male parents and therefore two fathers, oth-ers are raised in mixed families where the biological father is living outside and the stepfather living at home, whereas others grow up without a male figure involved in their lives. therefore, a 'father' will be identified with the male figure/s, most involved in the caregiving and development of the child, regardless of the living arrangement, marital status, or biological relationship. a father can be biological, foster or adoptive father, a stepfather, or a grandfather [1] . some authors suggest that a new, broader concept of paternity, which is interposed between the workplace and the domestic context, has been progressively taking place. nevertheless, work and time with children often oppose to each other, and fathers typically tend to spend more time at work, than they can spend at home. according to the italian national statistical institute (istat) data, among employed parents with children under 15 years old, 34.6% of fathers reported difficulties in balancing out work and family. interestingly, in the past few decades, fathers have more than doubled the time that was previously spent doing housework (4 h/wk vs. 10 h/wk) and looking after children (2.5 h/wk vs. 7 h/wk) [1] . this has helped creating a subcategory of "new fathers" who seem able to allow time to stay with children, probably by reducing their leisure or by making children an integral part of their day, especially during the weekends. the engagement of fathers in the early childhood seems to have positive implications on the child's development and psychological profile. notably, at age 3, the father-son interaction is considered a predictive and exclusive factor of enhanced future language development in children. indeed, while mothers adapt the choice of words to the child's known vocabulary, fathers are more likely to introduce new terms [5] . paternal involvement in pre-school age leads to a reduction in the behavioral problems of outsourcing and internalization, as well as greater social adaptation. furthermore, a recent meta-analysis has shown that father involvement during adolescence is related to better cognitive development, reduced behavioral problems in males and psychological problems in females, decreased criminality and better economic circumstances, especially in families with low socio-economic level. the potential role of fatherhood in men's health is expressed through several physiological and psychological reactions in different age groups [6] . for example, in men who become fathers at a young age, trying to compromise between work and family and concerns about preventive health seem to be the most relevant issues. middle-aged fathers may experience the return of adult children at home, while advanced paternal aged men may require the intervention of their adult children to manage aspects of daily life and health care. concerning paternal mental health issues, an active two-way relationship can exist between fathers and children: the father's well-being can positively influence the child's well-being, and vice versa. indeed, children can be a source of happiness as well as deliver feelings of well-being and satisfaction. becoming a father can also be a changing experience for men's physical health: men become more motivated to take better care of themselves, modifying their behaviors. in fact, eating habits usually tend to improve, risky behaviors and alcohol abuse tend to be reduced, and physical activity tend to increase. on the other hand, fathers can become a negative influence if they experience economic difficulties, if they struggle to balance work and family, or if they are emotionally disconnected, as a consequence of physical distance. studies on postpartum male depression show that men are more likely to elude emotional involvement than women, generating unusual depressive behaviors, such as alcohol and drug abuse, antisocial behavior, and interpersonal conflicts. this can result in marital stress and domestic violence, thus compromising the mental health of the child. interestingly, paternal depression is considered a risk factor for excessive infant crying. in addition, depressed parents tend to spend less time with their children, limiting physical contact and expressing lower inclination to education. in this regard, feelings of anxiety, worries and economic uncertainties about the future deriving from the current covid-19 pandemic condition have increased the possibility of depression for both parents, leading to potential negative repercussions on their children care [7] . however, overall, in the era of covid-19, the greater amount of time spent with the children has given rise to a new concept of fatherhood. within a few weeks from the start of the quarantine, some men found themselves at home, having to work remotely and take care of their children at the same time. the lockdown is making paternity an immersive experience, a fullwww.wjmh.org time job that could not have been experienced under normal circumstances, an occupation that deflagrates in all its complexity because hardly compatible with working from home. nevertheless, the belief that only the quality of time spent with children is important is not completely accurate, as the amount of time is equally essential. the more time available can be used to accustom children to the presence of their fathers, highlighting their central roles and their responsibilities. thus, the quarantine is also changing the way children interact with their fathers. given the changing expectations, diversity and changing demographics, a new understanding and insight into the crucial role and powerful influence of fathers on children's health, care and development, has been therefore outlined. several evidences support the positive influence of paternal engagement on offspring behavioral, social and psychological outcomes. fatherhood represents an intrinsic component of men's health. in this dramatic covid-19-related period, in which high mortality rates of the longest-lived generations have been recorded, preserving the children's health becomes more than ever an aspect of fundamental importance. committee on psychosocial aspects of child and family health. fathers' roles in the care and development of their children: the role of pediatricians american academy of pediatrics committee on psychosocial aspects of child and family health. fathers and pediatricians: enhancing men's roles in the care and development of their children from here to paternity: why men are not taking paternity leave under the family and medical leave act urban fathers' involvement in their child's health and healthcare do fathers matter?: what science is telling us about the parent we've overlooked fatherhood as a component of men's health how sexual medicine is facing the outbreak of covid-19: experience of italian urological community and future perspectives the authors have nothing to disclose. key: cord-354974-bh2expef authors: peterson, ingrid; bar-zeev, naor; kennedy, neil; ho, antonia; newberry, laura; sanjoaquin, miguel a.; menyere, mavis; alaerts, maaike; mapurisa, gugulethu; chilombe, moses; mambule, ivan; lalloo, david g.; anderson, suzanne t.; katangwe, thembi; cunliffe, nigel; nagelkerke, nico; mcmorrow, meredith; widdowson, marc-allain; french, neil; everett, dean; heyderman, robert s. title: respiratory virus–associated severe acute respiratory illness and viral clustering in malawian children in a setting with a high prevalence of hiv infection, malaria, and malnutrition date: 2016-09-13 journal: journal of infectious diseases doi: 10.1093/infdis/jiw426 sha: doc_id: 354974 cord_uid: bh2expef background: we used data from 4 years of pediatric severe acute respiratory illness (sari) sentinel surveillance in blantyre, malawi, to identify factors associated with clinical severity and coviral clustering. methods: from january 2011 to december 2014, 2363 children aged 3 months to 14 years presenting to the hospital with sari were enrolled. nasopharyngeal aspirates were tested for influenza virus and other respiratory viruses. we assessed risk factors for clinical severity and conducted clustering analysis to identify viral clusters in children with viral codetection. results: hospital-attended influenza virus–positive sari incidence was 2.0 cases per 10 000 children annually; it was highest among children aged <1 year (6.3 cases per 10 000), and human immunodeficiency virus (hiv)–infected children aged 5–9 years (6.0 cases per 10 000). a total of 605 sari cases (26.8%) had warning signs, which were positively associated with hiv infection (adjusted risk ratio [arr], 2.4; 95% confidence interval [ci], 1.4–3.9), respiratory syncytial virus infection (arr, 1.9; 95% ci, 1.3–3.0) and rainy season (arr, 2.4; 95% ci, 1.6–3.8). we identified 6 coviral clusters; 1 cluster was associated with sari with warning signs. conclusions: influenza vaccination may benefit young children and hiv-infected children in this setting. viral clustering may be associated with sari severity; its assessment should be included in routine sari surveillance. it is estimated that, worldwide, the case-fatality rate of severe pneumonia in children aged <5 years is 8.9%, which, in 2011, amounted to 1.26 million deaths [1] . much of this burden falls on sub-saharan africa, where severe acute respiratory infection (sari), including pneumonia, is a leading cause of childhood hospital attendance and death [2] . although laboratory diagnostic facilities are rarely available in such settings, sentinel surveillance using multiplex molecular diagnostic assays has recently provided considerable insight into the true burden of disease and the complexity of sari etiology. respiratory syncytial virus (rsv), parainfluenza viruses, rhinoviruses, influenza viruses, and adenovirus have been commonly detected in sari surveillance across the african continent [3] [4] [5] [6] [7] [8] . while there are a few viruses for which detection in respiratory disease cases is likely causal (eg, influenza virus and rsv) [9, 10] , for other commonly identified viruses causality has been difficult to determine. use of multiplex assays has led to an increasing realization that children with sari commonly carry multiple viral pathogens that may potentially contribute to disease. in the context of a low-income population with multiple drivers of immune compromise (eg, human immunodeficiency virus [hiv] infection, malnutrition, and malaria) [11] , we conducted active surveillance at a large urban teaching hospital in malawi to estimate the incidence of childhood sari and explore the association of sari clinical severity with hiv infection and clustering of respiratory viral coinfection. while previous studies have focused on children aged <5 years, we included children aged 3 months to 14 years in our analysis, to better capture the total burden and identify age groups particularly at risk. it offers care free at the point of delivery. overall, 13% of children aged <5 years in malawi are moderately to severely underweight, and 4% are experiencing wasting; 80.9% of children aged 12-23 months have received all expanded program on immunization vaccinations [12] . there is no national routine influenza vaccination in malawi. in 2010, a monovalent vaccine campaign targeting 2009 pandemic influenza a(h1n1) virus (a[h1n1]pdm09) achieved 74% coverage in pregnant women and 7% of the overall population [13] . an estimated 2.5% of children aged <15 years are hiv infected [14] ; the hiv prevalence in children aged <5 years on qech nonsurgical pediatric wards is estimated at 6%. blantyre has 2 distinct weather seasons, a rainy season (january-april) and a cool dry season (may-august). overall, 25.2% of paediatric accident and emergency unit (paeu) patients have a malaria parasitepositive blood slide; malaria presentations to the paeu peak from december to may. patients aged 3 months to 14 years presenting during surveillance hours (weekdays, from 8:00 am to 1:00 pm) from january 2011 through december 2014 were screened. consecutive patients fulfilling the sari case definition were recruited (maximum, 5 per day). demographic and clinical data were captured through an electronic data collection system [15] . nasopharyngeal aspirates (npas) were obtained and tested for influenza viruses; from 2011 to 2013, npas were also tested by multiplex assay for respiratory pathogens. thick blood films for detection of malaria parasites were performed for all children. sari was defined as (1) an acute illness with symptom onset <7 days and (2) a reported or recorded fever of ≥38°c (or hypothermia in children <6 months). additional criteria for sari varied by age. in children aged <6 months, additional criteria were (3) cough or apnea or (4) any respiratory symptom requiring hospitalization. in children aged 6-59 months, an additional criterion was (3) clinician-diagnosed lower respiratory infection. in children aged 6-14 years, additional criteria were (3) cough or sore throat and (4) shortness of breath or difficulty breathing. sari with warning signs was considered clinically more severe and defined as the occurrence of one of the following: admission to the hospital, chest recession, or blood oxygen saturation of ≤90%. in this resource-limited setting, some patients with severe illness requiring admission were sent home. thus, hospital attendance (not admission) was required for study enrollment. npas were stored at −80°c in universal transport medium (copan, brescia, italy) [16] and tested in batches for influenza viruses by real-time reverse transcription-polymerase chain reaction (rt-pcr). total nucleic acids were extracted from 300-µl aliquots of each specimen with the qiagen biorobot universal system, using the qiaamp one-for-all nucleic acid kit (qiagen, manchester, united kingdom). the quantity of nucleic acid used per reaction was 5 µl for the centers for disease control and prevention (cdc) human influenza real-time rt-pcr diagnostic panel (cdc influenza division), which detects influenza a and b viruses and influenza a subtypes h1, h3, 2009h1, and h5n1, and 10 µl for the ftd respiratory pathogens 33 kit (fast-track diagnostics, luxembourg). details on sample processing with by ftd real-time rt-pcr are provided in appendix 1. hiv serostatus was assessed by the rapid test (alere determine hiv-1/2 and trinity biotech uni-gold hiv) according to world health organization guidelines [17] . pcr for detection of hiv rna was performed in children aged 3-11 months who had a positive hiv rapid test. hiv infection was defined on the basis of positive results of an hiv rapid test (in the absence of an hiv-negative pcr); data were not collected on hiv exposure. ethics approval for this study was obtained from the liverpool school of tropical medicine research ethics committee (approval reth000790), the university of malawi college of medicine research ethics committee (comrec; approval 958), and the cdc through reliance on the comrec. informed consent was obtained from guardians of all study participants. numerators for minimum sari incidence estimates were generated by summing the number of cases resident in blantyre within strata of age category and hiv status. numerators were adjusted by multiplying by the reciprocal of the daily proportion of recruited cases among all sari cases attending the paeu. denominators for hiv and age strata were derived by applying age-specific hiv prevalence estimates to census figures for blantyre district's population aged 0-14 years [18] . the former were obtained by apportioning the total hiv prevalence among malawian children aged <15 years [14] according to the age distribution of pediatric hiv infections in mozambique, which borders malawi and has a similarly severe hiv epidemic [19, 20] . estimates of age-specific hiv prevalence were unavailable for malawi for the study period. the incidence was obtained by dividing numerators by denominators and multiplying by 10 000; hiv-associated incidence rate ratios (irrs) were calculated by dividing the incidence in hiv-infected strata by the incidence in hiv-uninfected strata; 95% confidence intervals (cis) of incidence and hiv-associated irrs were generated with 1000 bootstrap samples. data analysis was performed using sas 9.3 (sas institute, cary, north carolina). temporal trends in weekly sample counts for sari cases were assessed by plotting 5-week moving averages of sample counts by recruitment week. we developed 2 logistic regression models with a binary outcome factor for the child's clinical status. the first outcome represented sari with warning signs (ie, clinical markers of very severe illness) versus sari without warning signs. the second outcome represented influenza virus-positive sari versus influenza virus-negative sari. autoregressive correlation of residuals was removed by introducing a patient-level kernel weighted moving average of the prior probability of case status. parsimonious models were developed by stepwise logistic regression, retaining age, sex a priori, and explanatory factors with a 2-sided p value of <.05. adjusted relative risk ratios for factors associated with the outcomes were derived from these models. detection of multiple viruses in sari is common, with many possible combinations of viral carriage. conventional statistical techniques (eg, regression models, covariance matrices, and temporal plots) have limited capacity to quantify, characterize or identify factors associated with viral carriage groupings. to assess multiple virus carriage clusters in our setting, we performed nearest-neighbor discrete hierarchical cluster analysis in patients with viral codetection, using the gower distance [21] . distance was based on similarity of viral pathogens detected in the nasopharynx of patients with sari; each patient was a member of only 1 cluster. we defined clusters as those that increased the r 2 value by ≥0.05 (using the ward method); to improve precision, 10% of observations with the lowest densities were discarded. using univariate logistic regression, we identified factors associated with cluster membership. from table 2) . plots of weekly influenza virus-positive sari cases suggest both unimodal and bimodal (2 peaks per year) seasonality. weekly influenza virus-positive sari cases increased during the rainy figure 1 ). incidence estimates for sari and respiratory virus-associated sari sari incidence was 17.5 cases per 10 000 children annually, with the highest incidence in children aged 3-11 months table 5 ), as well as an increased incidence of sari, sari with warning signs, and influenza virus-positive sari (table 4) . hiv-associated irrs rose with increasing age. the hiv-associated irrs for sari with warning signs was 2.6 in children aged 3-11 months as compared to 37.7 in children aged 10-14 years. in children aged >5 years, the incidence of hospital-attended influenza virus-positive sari was at least 8-fold higher in hiv-infected children as compared to hiv-uninfected children. there was no difference in the incidence of rsv-positive sari between hiv-infected and hivuninfected children. in multivariable analysis controlling for etiology, patients with sari recruited during the rainy season (january-april) were more than twice as likely to have warning signs, compared with patients enrolled during september-december (arr, 2.4; 95% ci, 1.6-3.8; table 5 ). peaks in rsv and influenza virus activity corresponded to peaks in the occurrence of sari with warning signs (figure 1 ). detection of rsv in cases of sari warning signs was much higher during the rainy season (39.8%) as compared to other times of year (5.9%). the arr for a positive results of an influenza virus test in patients with sari increased with older age and rainy season of recruitment (table 3 ). after adjustment for age, sex, and hiv status, rainy season recruitment was significantly associated with sari with warning signs in influenza virus-positive patients with sari (arr, 3.42; 95% ci, 1.37-8.53; analysis not shown). in adjusted analysis, a(h1n1)pdm09 was associated with double the risk of sari with warning signs, compared with other influenza virus subtypes (arr, 2.10; 95% ci, .98-4.53; analysis not shown). detection of ≥2 viral pathogens by multiplex pcr occurred in 362 of 1835 sari cases (19.7%). viral codetection was highest in sari cases positive for coronavirus 229 (70.6%) and enterovirus (79.7%). viral codetection was least common in sari cases testing positive for a(h1n1)pdm09 (27.3%), influenza a(h3n2) virus (29.0%), and rsv (29.5%) ( table 2) . viral codetection per se was not associated with warning signs in sari (table 5) . we used discrete hierarchical cluster analysis based on similarity of viral pathogens detected by multiplex pcr assay in sari cases to explore whether particular groupings of viruses were associated with warning signs, host factors, or seasonal factors. we identified 6 clusters, which accounted for 48.3% of the total variation in viral pathogen test results in children with viral codetection. cluster size ranged from 23 to 96 members; smaller clusters had fewer viral pathogens and lower within-cluster heterogeneity. clusters were distinguishable by the type of viral pathogens detected. for example, 80% of influenza a(h3n2) viruses detected were found in cluster a; >65% of bocaviruses detected were found in cluster e (appendix 3). cluster membership was significantly associated with clinical and temporal factors (figure 2 ). among children with viral codetection, membership in cluster d (characterized by abbreviations: ci, confidence interval; irr, hiv-associated incidence rate ratio; rsv, respiratory syncytial virus. a inestimable. hospital-attended sari was common in this urban sub-saharan african setting, particularly in infants aged 3-11 months, in whom the incidence was 91.7 cases per 10 000 children annually. similar to studies from other settings, influenza viruses and rsv were important sari-associated pathogens [5-8, 22, 23] , with prevalence rates of 11% and 12%, respectively. as elsewhere, hiv infection increased the risk of sari and the presence of warning signs in sari cases [24] [25] [26] . among older children, hiv infection greatly increased the risk of influenza virus-positive sari, consistent with data from south africa [25] . viral coinfection occurred in almost 20% of sari cases, highlighting its potential impact in the development or clinical worsening of sari [27] . although viral codetection per se was not associated with clinical severity or season, we found 1 viral cluster, characterized by a high proportion of rsv and a(h1n1)pdm09 infection, which was significantly associated with clinical warning signs and rainy season recruitment. cluster members coinfected with rsv and a(h1n1)pdm09 had a higher rate of warning signs, but the number of coinfected individuals (within the cluster and the entire sample) was too small to formally test for interaction. it is unclear therefore whether clinical severity in this cluster resulted from biological interaction of pathogens, additive risks from each pathogen, or other underlying factors. clusters clearly mapped to peaks and troughs in individual pathogen activity. we suggest that this viral clustering, which was associated temporal dynamics of pathogen activity, may have arisen from complex virus-virus and host-virus pathogen interactions. clinical severity in sari demonstrated seasonal peaks, coinciding with rainy season peaks in rsv activity. rsv was detected in 40% of sari cases with warning signs recruited during the rainy season, compared with 6% recruited at other times of the year. thus, rsv may drive rainy season increases in clinical severity in pediatric sari in our setting, consistent with studies elsewhere in sub-saharan africa [28, 29] . nevertheless, the rainy season remained independently associated with an increased risk of warning signs in sari in figure 2 . dendrogram of coviral clusters. six coviral clusters (a-f) were identified in 362 pediatric sari cases, in whom >2 viral pathogens were detected in the nasopharynx. each severe acute respiratory infection (sari) case is a member of only one cluster; clusters membership is based on similarity of viral pathogens detected. as shown here, characteristics such as sari severity, number of viruses detected per child, and particular season and year of recruitment are more common in some clusters than others. green bars denote sari without warning signs, red bars denote sari with warning signs, bluish-gray bars denote detection of <3 viruses detected, orange bars denote detection of ≥3 viruses, lavender bars denote recruitment in the rainy season, yellow bars denote recruited outside of the rainy season, gray bars denote recruitment in 2011, blue bars denote recruitment in 2012, pink bars denote recruitment in 2013, and light green bars denote recruitment in 2014. multivariable analysis controlling for rsv, hiv, and other viral pathogens. therefore, the observed rainy season excess of clinical severity in sari is in part attributable to unmeasured factors. we speculate that these factors include other intervening illnesses and seasonal malnutrition (in malawi, the rainy season coincides with the so-called lean season after harvest [30] ). however, we cannot exclude seasonal differences in healthcare utilization. we acknowledge that our study has limitations. we did not recruit children aged <3 months, in whom the frequency of sari-related deaths is known to be elevated [31] . we were unable to determine the role of bacterial pathogens in sari, as we lacked laboratory data and systematic radiological data to identify probable infection in the context of a very high prevalence of bacterial carriage. our estimates of sari incidence by hiv strata were based on mozambican pediatric hiv prevalence rates because we lacked data from malawi. nevertheless, malawi and mozambique have similar rates of antenatal hiv prevalence [12, 32, 33] and similarly high rates of hiv-infected pregnant women accessing antiretroviral treatment [34] . we did not assess the impact of hiv exposure on sari risk in hiv-uninfected children. hiv exposure was associated with higher sari incidence and greater sari severity in hiv-uninfected south african children [35] . in conclusion, sari is common in this setting of high hiv prevalence, where influenza viruses, rhinoviruses, and rsv were the most prevalent viruses detected. hiv greatly increased the risk of influenza virus-associated sari in children, and therefore yearly influenza vaccination should be considered in routine pediatric hiv clinical care. influenza vaccination in hiv-infected children is safe, but it has low efficacy (<20%) and may only be immunogenic in older children and adolescents with virological suppression [36] [37] [38] . viral coinfection was common, with 1 coviral cluster associated with clinical severity in sari cases. in this context, there is considerable potential for the use of multiplex respiratory virus assays in tandem with cluster analysis to reveal multiplepathogen-associated outbreaks and disease burden. this approach may expose the potential for synergistic effects of vaccine strategies that disrupt viral clusters. vaccine probe studies to assess the impact of viral coinfection on clinical severity could clarify complex pathogen and host interrelationships and reveal the true burden of disease. global burden of childhood pneumonia and diarrhoea global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis identification of viral and bacterial pathogens from hospitalized children with severe acute respiratory illness in lusaka, zambia incidence of respiratory virus-associated pneumonia in urban poor young children of viral and bacterial causes of severe acute respiratory illness among children aged less than 5 years in a high malaria prevalence area of western kenya viral and bacterial etiology of severe acute respiratory illness among children < 5 years of age without influenza in niger influenza sentinel surveillance among patients with influenza-like-illness and severe acute respiratory illness 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infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis malawi: current issues and what the world food programme is doing global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis mapping hiv prevalence using population and antenatal sentinel-based hiv surveys: a multi-stage approach routine data from prevention of mother-to-child transmission (pmtct) hiv testing not yet ready for hiv surveillance in mozambique: a retrospective analysis of matched test results lessons learned from early implementation of option b+: the elizabeth glaser pediatric aids foundation experience in 11 african countries epidemiology of acute lower respiratory tract infection in hiv-exposed uninfected infants efficacy and immunogenicity of influenza vaccine in hiv-infected children: a randomized, double-blind, placebo controlled trial shedding of live vaccine virus, comparative safety, and influenza-specific antibody responses after administration of live attenuated and inactivated trivalent influenza vaccines to hiv-infected children hiv virological suppression influences response to the as03-adjuvanted monovalent pandemic influenza a h1n1 vaccine in hiv-infected children description of implementation of ftf multiplex assay ftd rrt-pcr assay was used in combination with the agpath one-step qrt-pcr reagents according to the manufacturer's instructions (applied biosystems, carlsad, california, usa) consolidated standards of reporting trials diagram of data analyses. abbreviations: ftd, ftd respiratory pathogens 33 kit; hiv, human immunodeficiency virus sari, severe acute respiratory infection disclaimer. the findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the centers for disease control and prevention (cdc).financial support. this work was supported by with the cdc through a cooperative agreement (grant 5u01ck000146-04).potential conflicts of interest. all authors: no reported conflicts. all authors have submitted the icmje form for disclosure of potential conflicts of interest. conflicts that the editors consider relevant to the content of the manuscript have been disclosed. key: cord-346060-ns6v76rb authors: degli espinosa, francesca; metko, alma; raimondi, marta; impenna, michele; scognamiglio, elena title: a model of support for families of children with autism living in the covid-19 lockdown: lessons from italy date: 2020-06-02 journal: behav anal pract doi: 10.1007/s40617-020-00438-7 sha: doc_id: 346060 cord_uid: ns6v76rb italy has been the european country most affected by the covid-19 pandemic to date and has been in social lockdown for the longest period of time compared to other countries outside china. almost overnight, italian behavior analysts were faced with the challenge of setting up remotely whole-family systems aimed at maintaining adaptive skills and low levels of challenging behavior to be carried out solely by caregivers. given these extraordinary circumstances, the protocols available from the applied behavior-analytic, parent training, and autism literature did not appear to fully meet the needs of parents having to be with their children under extreme levels of stress in a confined space with limited reinforcers for 24 hr a day, 7 days a week. to meet this unprecedented challenge, we developed a dynamic and holistic protocol that extended to the full day and that recognized the need for sustainable intervention delivered solely by parents, who were often looking after more than one child. these practices are presented in this article, together with a discussion of lessons we have learned thus far, which may be useful for behavior analysts working in other regions in which the effects of the pandemic are not yet fully realized. although somewhat unorthodox, we include some parent comments at the end with the goal of sharing the parent perspective in real time as this pandemic unfolds across the world. before discussing responses to the pandemic, it may be helpful to say a few words about the italian health system as it concerns intervention for autism based on applied behavior analysis (aba). italy has a national health system in which autism is recognized as a condition that falls under the care of the state. education is free for all, and mainstream schooling is mandatory and therefore accessible by all children. there are no specialist schools. the delivery of therapeutic and educational services is regulated by registered professional bodies (i.e., psychologists, professional educators, speech and language therapists, neuro-rehabilitation technicians). aba-based intervention is not formally recognized by the italian health authorities, nor is it routinely offered as part of the state autism provision, which typically includes 1 hr per week of psychomotor therapy, 1 hr per week of logotherapy (i.e., speech and language therapy), and school attendance with varying levels of one-to-one educational support. the profession of behavior analysts is not officially regulated. despite the lack of formal governmental recognition of aba interventions for autism and a corresponding professional body, the country has witnessed a steady increase in the number of professionals credentialed by the behavior analyst certification board (bacb) in the past 10 years, verified course sequences, and state-funded health editor's note this manuscript is being published on a highly expedited basis, as part of a series of emergency publications designed to help practitioners of applied behavior analysis take immediate action to adjust to and mitigate the covid-19 crisis. this article was submitted on april 5, 2020, and received final acceptance on april 10, 2020. the journal would like to especially thank julie kornack and courtney tarbox for their expeditious reviews of the manuscript. it is important to note that this article reports the approach taken by a particular group of clinicians operating under completely unprecedented circumstances in one of the hardest hit regions of the world. there are many ways to use the science of applied behavior analysis to support families, and neither the authors nor the journal suggests this is the only approach or the best approach. however, this approach produced positive results for this group of families, and the editorial staff at the journal believes that the rest of the world of applied behavior analysis may benefit from learning from their experience. the views and strategies suggested by the articles in this series do not represent the positions of the association for behavior analysis international or springer nature. rehabilitation centers offering low-intensity (4 to 15 hr per week) aba intervention. as a result of parental demand for aba services, a considerable number of health professionals are enrolling in aba master's programs and consequently incorporating aba-based methods in their therapeutic practices for autism. schools have also begun to open their doors to bacb-credentialed professionals to support the individualized education plans of their students. nevertheless, ababased intervention remains largely privately funded by individual families and is, for the most part, carried out at home during the hours in which the child is not in school. at the time of this writing, the italian authorities have yet to provide statewide guidelines or funding for the continuation of intervention (aba and non-aba) via telehealth for children with autism during the lockdown period. in some regions (e.g., campania, lombardy, marche, emilia romagna), and with considerable variability, individual state-funded centers have begun to set up systems to provide intervention and parental support remotely. italy was one of the first european countries, together with germany, france, and spain, to register the first cases of covid-19 at the end of january 2020 and subsequently to impose movement restrictions on its citizens. for some weeks, it was the second country after china with the largest number of covid-19 cases. presently surpassed by the united states and spain, it currently registers the highest number of deaths related to covid-19 (world health organization, 2020) . on january 31, 2020, the italian government declared a state of national emergency and imposed the first social-distancing restrictions on february 24, with a decree closing all schools and many commercial activities in the northern regions (lombardy and veneto). these restrictions were gradually expanded and eventually extended to the rest of the country, with the period of complete national lockdown commencing on march 9 (ministry of health, 2020) . at the time of writing this paper, italy continues to be in complete lockdown, which includes home isolation, with outside movement restricted to one person per household and solely for the purpose of purchasing food or medicine. deliveries to households are limited to essential goods. outside physical activity is no longer permitted. however, if a child has a disability, she or he can be accompanied outside for brief walks, provided the parent carries a written certificate signed by a health professional attesting to the child's diagnosis and need to be outside. social-distancing measures during the initial lockdown period were less restrictive and were expected to last for a couple of weeks. although children had ceased going to school, and most home sessions had been interrupted, aba practitioners viewed this as a period similar to the summer holidays, where children spend long periods of time with grandparents and are essentially given free access to reinforcement, and parents are given a skeleton program of maintenance to prevent significant skill loss. under usual circumstances, we would expect to see some increase in challenging behavior and some skill loss during the summer months, but not so significant that it could not be addressed within the first few weeks of resuming the typical school and home intervention schedule. by the third week of the lockdown, it became clear that the isolation period would not only be extended to the rest of the country, but that measures would also become much more restrictive. thus, a different approach was required, especially because many parents (all family caregivers in the home are referred to as "parents" hereafter, for brevity) reported that their children were no longer satisfied with the usual reinforcers; were becoming increasingly uncooperative; were engaging in high levels of stereotypy and problem behavior, likely due to being denied access to regular but now unavailable reinforcers (e.g., swimming, going to the playground, taking extended car rides, going to the cinema or ice-cream parlor, participating in physical activity); were demanding high levels of undivided attention; and were becoming more difficult to direct to independent activities. parents also reported that they were struggling to reconcile the demands of distant working required by their employers with the needs of round-the-clock sole care of their children with autism, of siblings, and of their households in the absence of any outside help. although some families lived in the countryside and had access to a privately owned garden (i.e., private yard), many families lived in city apartments, where time spent outside was either prohibited or substantially limited due to the closure of parks and the shared courtyards. even those of us who are not psychologists saw clear early signs of mental health decline, as well as increasing marital conflict. although the latter problems were outside the scope of our practice as behavior analysts who are not also psychologists, referral to paid online psychotherapy or counseling, given the dire financial situation some families were experiencing, was not an option. nonetheless, we believed that the tools of the science of behavior could be extended to the larger family context to alter the repertoires of all its members and to increase contact with positive reinforcement for all. because restrictions in italy happened gradually, with families in the northern regions being in the first cohort, by the time families in the southern region were in lockdown, we had gathered sufficient data on the effects of the first 3 weeks of isolation with minimal structure and free reinforcement access. whereas for the northern families our work in the third week was focused on reducing the negative effects of 2 weeks of "free time," we were able to implement strategies proactively with the southern families to minimize the negative outcomes we observed for the families in the first lockdown cohort. prior to the lockdown period, none of our children displayed severe or unmanageable levels of challenging behavior, and they all had effective behavior management plans in place. after the first 2 weeks of lockdown with limited structure and free reinforcement access, in some of our first cohort families we observed the following during our online meetings: high levels of escape from simple instructions, the loss of independence and communication skills (appropriate mands), satiation (significant reduction in the time children spent with favorite items), an increase in problematic interactions between parents and all children, and unmanageable levels of mands for attention (both appropriate and inappropriate). parents reported being struggling to find new things to entertain their children with autism and siblings. sourcing novel toys or items to create new interests was not possible due to limited deliveries of nonessential items. in the following sections, we describe the protocol that was shaped through the frequent interactions with parents during our online observations and discussions. currently, as a group of professionals, we are serving approximately 30 families with this model. we were consulting with these families prior to lockdown and had been running home-based programs for at least 6 months. in the absence of published literature on interventions that require parents to engage with their children 24 hr per day, 7 days a week, in a confined space for a prolonged and undefined time period, we approached the problem inductively, altering what we did based on principles of learning, on what each individual situation required, and on what parents reported they felt they were able to do. the model developed was a systemic one, in which the client was no longer just the child in sessions working on educational targets but, rather, the whole family in its unique context. we began with an assessment of risk and an evaluation of each child's level of verbal functioning to establish the type of telehealth provision required (direct sessions or parent coaching; see ferguson, craig, & dounavi, 2019, for a review). the two main risks we aimed to mitigate were (a) parental burnout and (b) an increase in socially mediated challenging behavior of the child and siblings. we were less concerned with behavior maintained by automatic reinforcement, unless it was self-injurious. none of our children engaged in such behavior. the assessment was based on our history with the family, data from the child's prelockdown intervention, and direct contingency manipulation and observation via telehealth. for example, we asked the parent to leave his or her child with an activity while he or she talked to us, and we calculated how long the child was engaged without demanding parental attention. the main items included in the risk assessment (see table 1) were parents' prelockdown level of instructional control and social engagement with their children, the duration of the child's and siblings' ability to engage in solitary activities (either reinforcement or instructional, e.g., worksheets, chores, functional play), and parents' tolerance of nondangerous selfstimulation (e.g., flapping, noises, walking up and down, jumping on the sofa). in addition, we considered the child's age, the ability to engage in back-and-forth verbal interaction, the presence of siblings with a disability, and the number of supportive adults always present (i.e., single parent, both parents at home, other family members). for each individual family, we assessed the risk as high, medium, or low. the highest risk families were ones with a single parent or a parent with limited instructional control, who was on his or her own most of the day with two young children, one of whom had autism. in the case of one family, the parent was alone for most of the day with two adolescents with autism, one who was minimally verbal and the other who was verbally interactive. although this situation could have been considered high risk, in this specific case we considered it medium risk because the parent had excellent instructional control over both youngsters, who were both able to engage in solitary activities. as a general rule, the higher the risk, the higher the level of support we provided for the parent and the greater the daily structure. low-risk families included ones with both parents at home who were willing to engage with the child and sibling. in some cases, parents took turns to be with both children, so that one parent could be free. alternatively, each parent looked after one child, and they swapped children every few hours or every day. in these cases, it became crucial to ensure that both parents were involved in the care of the child and sibling, so that the burden of household management did not fall solely on the primary caregiver (parent 1). to achieve the involvement of both parents, provided they were both equally available, we worked separately with each one, setting up individual targets with each and developing a family schedule in which the time of each member was clearly specified. we identified three main learner profiles of the children, in terms of their need for support and perceived amenability to direct sessions over telehealth: 1. preschool-age children (n = 6): children who had not yet started elementary school (up to age 7); 2. minimally verbal children: children with limited adaptive, independent, and verbal skills (n = 16); and 3. verbally interactive children (n = 8). together with the risk assessment, this classification determined the daily family structure we arranged, as well as the type and frequency of support we provided as professionals. verbally interactive children were defined as being able to discriminate wh-questions (tact and intraverbal), follow multiple-step instructions, self-administer tokens, selfmanage interruption of reinforcement based on a timer, and not manifest challenging behavior in and out of sessions. verbally interactive children were those who we predicted would be able to sustain a direct session with their aba tutor (also commonly referred to as a technician or therapist) via telehealth. although none of the tutors had ever delivered interventions in this manner, extensive training was not needed because of their experience with the program targets and their familiarity with the child's home environment. for these families and tutors, contact with the aba consultant (commonly referred to as a supervisor) and/or lead tutor occurred once or twice per week to review targets, ensure that novel problem behavior was not emerging, and continue to provide support to the parents in managing the day. verbally interactive children received sessions in two formats. the first format involved the tutor remotely sharing the computer screen with the child, so what was once the table became the desktop computer. all visual stimuli were placed in individual electronic folders or powerpoint presentations, and the child responded to the materials presented via the tutor's desktop. tutors did not hold up cards to the screen, as it was too cumbersome, and some tutors also did not have the relevant materials at home. the second format was implemented with adolescents who were working on producing written responses; in that case, it was the child who remotely shared his or her screen with the tutor. the data collection system for these children remained unaltered from the prelockdown period, as the only change was the medium of delivery. most children received two 50-min sessions per day. for the two remaining profiles, preschool age and minimally verbal, we implemented a parent coaching system (see parsons, cordier, vaz, & lee, 2017 , for a review). the first telehealth session lasted up to 3 hr and was conducted by the team's aba consultant, with the participation of both parents and the team's lead tutor. subsequently, the consultant or lead tutor met with the family every day during the first and second week and every other day during the third intervention week and thereafter. the following protocol applies to families with preschool-age or minimally verbal children. the youngest child was 4 years old and had been receiving intervention for approximately six months. most of our families had been running an aba home-based program with the support of an aba consultant and tutor(s) for a minimum of 2 years and some for as long as 10 years. parents were not asked to take data, as this seemed unrealistic given how demanding their day was. professionals collected data during the online coaching sessions on the following: & parental report of challenging behavior; & parental report of their ability to maintain the agreed structure; & direct measurements of children's adherence to parental instructions; & direct measurements of challenging behavior during the coaching session; and & parents' procedural fidelity. prior to the lockdown period, children had access to a range of environments, each associated with its unique set of stimuli, signaling a specific reinforcement contingency. for example, children had learned that at school or during home sessions, brief periods of reinforcement were provided contingent on engaging in instructional activities and exchanging tokens. thus, children spent most of their learning time in school and in home sessions, where reinforcement access was regulated. for most of our children, the domestic context with parents signaled prolonged and often uninterrupted access to reinforcement in the evenings and on weekends. although not ideal, prior to the lockdown period, we did not view this as a significant problem because in most of their daily contexts (e.g., school and home sessions), children were able to engage in educational activities appropriately. during lockdown, however, the household became the only living context for all family members. this new set of circumstances created the need to institute an economic system that was sustainable, easy to implement for parents, and positively reinforcing for all members. the system also needed to promote the maintenance of adaptive skills and positive interactions, as well as allow for time off from interaction. during the first consultation session with each family, we worked with parents on structuring the entire day for all children (the child with autism and sibling), dividing it into blocks of activities to meet primary needs (breakfast, morning snack, morning outside time, lunch, afternoon nap for the younger children, afternoon snack, afternoon outside time, bath, and dinner). all times in between were considered dead times and, therefore, high-risk times that needed to be filled with contextually appropriate activities alternated with reinforcement intervals. one important aspect of structuring the day was to decrease the number of waking hours to reduce the fatigue and behavioral irritability that occurred toward the latter part of the day. we achieved two periods of roughly comparable duration between the mornings and afternoons by pushing lunchtime from 12:00 to 13:30-14:00 and bringing bedtime forward to no later than 21:00. as is fairly typical of southern european countries, our children often went to bed around 22:30 prior to the lockdown. we worked with parents to manipulate the stimuli associated with the end of the day (e.g., supper, bath, pajamas, story) to occur earlier than usual and in accordance with the recommendations for the optimal number of sleep hours for the child's chronological age (hirshkowitz et al., 2015) . table 2 shows an example of a daily schedule for a family in which parent 1 was alone most of the day with a 5year-old child with autism with limited independent and selfentertainment skills and a 3-year-old typically developing sibling. the day consisted of a rotation of contextually relevant activities or tasks for both the child and the sibling. we asked parents to identify one target per day in any of the activities, 1-week objectives, and 3-month objectives. we formulated the questions in this way: what would be helpful for you that your child learned? what do you want to teach your child today? what do you want to have taught your child in 1 week? when all this is over, what would you want your child to be able to do? in 1 month? in 3 months? parents chose from four types of activities broadly defined as follows: 1. independent activity: this encompassed any instructional activity the child could engage in without adult support (e.g., puzzles and shape sorters, worksheets, coloring, educational computer programs, domestic skills). visual activity schedules were utilized where useful (mcclannahan & krantz, 1999) . 2. household chores: these included chores the parent felt he or she could carry out with his or her child, giving the child things to do. we asked parents to go to each room and list all the chores that needed doing in each, however big or small. we asked parents to list every chore and not just the chores they thought their child could do or was already able to do. we wanted to identify objectives that were appropriate to the context and in which the parent was more likely to engage their child, as they needed to be done anyway. 3. tabletop discrete-trial teaching (dtt): we did not ask parents to run acquisition targets but only to maintain existing skills, with particular focus on clean responding without behavioral accessories (e.g., stereotypy). although it would be desirable if children maintained specific skill targets in specific programs, our purpose for having parents run dtt was primarily to help ensure that the children maintained some contact with the dtt contingency of rapid and accurate responding. 4. adult-led or shared activity (not dtt): these included activities that required the parent to engage one or both children, in which responses could be more loosely defined. examples of shared activities were completing simple crafts or making cookies. these were not necessarily reinforcing activities for the child with autism but often were reinforcing for the sibling. parents were coached to divide their attention between the two children, shape appropriate attention mands, and provide attention contingent on participation and engagement with the material. the targets for the child with autism were simply to remain in the activity and engage in some relevant responding. we did not include activities based on natural environment teaching (net), in which the parent actively had to manipulate the child's motivation and materials to evoke mands or to generalize language targets. this was because parents reported that they found this type of approach to be too effortful under these extreme circumstances. they reported they did not wish to be in a position to have to follow their child's motivation and to have to signal when that was no longer possible, risking the occurrence of challenging behavior. they also could not risk having to say no to something their child requested because of a lack of materials. although, in general, the daily structure centered on adult-led or shared activities alternated with periods of solitary reinforcement, all parents learned to interact with their children and siblings in a way that worked for them and maintained low rates of problem behavior. it is important to note that previous research exists that supports remote training of parents in net procedures (nefdt, koegel, singer, & gerber, 2010) , so we are not suggesting that this would not be a good approach for some families. two main reinforcement systems were implemented throughout children's waking hours: a token-based economy and an activity-based economy. in the token-based system, tokens were earned throughout the day and exchanged for preferred items. in the activity-based system, engagement in a less preferred activity (i.e., contextually appropriate activities) produced access to a more preferred activity. whether token based or activity based, the common element in both procedures was a system in which contingent relations between target behavior and preferred objects and activities were maintained, and reinforcers were unavailable outside those particular settings. we aimed to help parents establish a closed economy, meaning that engaging with parent-led reinforcement contingencies was the only way in which children could access those reinforcers, which is known to generate higher levels of responding (kodak, lerman, & call, 2007; reed, niileksela, & kaplan, 2013) . because we had already witnessed in our northern families (first cohort) the negative impact of free and prolonged access to reinforcers on (i.e., loss of children's skills and parental fatigue), we organized the household economic system so that reinforcement was accessible contingent on the production of contextually appropriate behavior for all children. this included the siblings, if they were under the age of 10 and not involved in remote schooling. the first step in closing the economy involved teaching parents to be able to limit access to all reinforcers for the child and siblings in every room of the household. parents classified reinforcers in terms of solitary and social for all children. solitary reinforcers were those that the child and sibling could consume on their own, and social reinforcers were those that required an adult and, where possible, were incorporated in the shared and adult-led activities. to help parents identify effective reinforcers, we accompanied them virtually through each room of the house and asked them to identify things their child liked or might like or items with which they had witnessed their child spend some time. every item was removed and placed in boxes, inside wardrobes or bags, or whatever container was available. in some cases, parents took pictures of the items to produce a reinforcer menu for the child (and sibling), whereas at other times, they took the child to the "shop," the place where all reinforcers had been stored. food treats were not available from the shop or the reinforcer menu; these were available at specific times during meals. the reasoning behind this was that food treats were items to be consumed rapidly, so the child was engaged for a very short period of time. our rationale in discontinuing noncontingent access to solitary toys and activities was that these items would hold their value and keep the children occupied longer. if the children were therefore able to be engaged with preferred solitary activities, the parent could safely have time off from the child and sibling. the secondary effect was to reduce escapemaintained problem behavior for both the child and the parent. by engaging with children in structured activities first, parents could access time to themselves and, as a result of contingent reinforcement delivery, also gain greater instructional control. we wished to create a mutually reinforcing situation for both the adults and the children, where parents could experience success in delivering instructions and interacting with their child, given that they would need to engage in this behavior daily in a confined space, over extended periods of time without a break. of course, discontinuing free access to reinforcers could also have the effect of increasing motivating operations that evoke problem behavior, so it was critical to support the children to be frequently successful in meeting the criteria for positive reinforcement, and thereby continuing to earn reinforcement on a frequent basis. many parents implemented the new reinforcement contingencies effectively, and the children learned very quickly that reinforcers were only available after the completion of activities or upon meeting the token schedule requirements. access to the reinforcer menu or shop was not available at any other time. children's mands for these items when they were not available were significantly reduced. because there were clear signals for reinforcement availability, children stopped asking for these items at other times, preventing parents from having to say no, thus reducing the risk of challenging behavior. children learned to mand for items (and receive them) only when the reinforcer menu was presented or when they were taken to the shop. they used whichever communication modality (e.g., vocal, sign, pointing, or selection-based modality) had been achieved prior to the lockdown period. given the level of stress the parents were experiencing after several weeks of lockdown, the likelihood was extremely high that they would reinforce problem behavior by providing the denied item to interrupt contact with the aversive stimulation produced by the child. we wished to reduce the risk by implementing the simplest possible system and not burdening parents with having to teach their child to tolerate denial. we simply removed that risk by giving frequent but contingent access to those items. the token system was implemented mainly for children who had limited verbal and nonverbal skills and who required frequent contact with reinforcement to engage in parent-led activities and instructions. a token system had been in place for all such children prior to the lockdown period, either at school or during home-based sessions. because we had always worked at home, all parents were familiar with the basic techniques; in fact, it was generally parents who manufactured the token boards, so the concept of a token economy system was not new to them. the fact that the system needed to be extended to the entire day was new and, in this sense, paralleled early applications of comprehensive token economy systems (ayllon & azrin, 1965 , 1968 phillips, 1968) . our token schedules consisted of three interrelated components: 1. the token-production schedule (the schedule by which responses earn tokens); 2. the exchange-production schedule (the schedule by which exchange periods are earned); and 3. the token-exchange schedule (the schedule by which the tokens were cashed in for preferred items or activities; see hackenberg, 2018 , for a review). the initial token-production schedule was set at fixed ratio (fr) 1, in which each target response (carrying out the parent's instruction within the activity proposed) produced a token to produce rapid acquisition. this was implemented throughout the day each time the parent gave an instruction. fairly quickly, parents naturally moved to a variable ratio schedule, in which a variable number of responses was required to produce a token, and they learned to adjust it based on the time of day or the difficulty of the task. the exchange-production schedule was fixed at fr 10, in which 10 tokens were needed to reach an exchange period. we did not make this variable, as it would have been too difficult for the parents to manage. the token-exchange schedule was fr 1-handing over the token boardwhereupon the parent presented the reinforcer menu or took the child to the shop to choose one item. during the exchange period, only one item or activity was allowed at a time. if the child wished to change the activity, then tokens had to be earned again for the change to occur. reinforcement duration varied according to parental needs and what was established by the daily schedule. in general, there were two types of reinforcement duration: brief (between 1 and 5 min) and long (up to 30 min). if parents needed their child to be occupied for additional time, they still had to interrupt after 30 min of consumption, place the item back in the shop, run a quick token board, and then open the shop or present the reinforcement menu again. the activity-based system was implemented when the parent had more than one child to look after, and it was extended to all siblings under the age of 10 if they were not involved in remote schooling. the system was based on creating half-hour blocks in which the parent was coached to engage the child and sibling in an adult-led or independent instructional activity for 30 min in order to produce 30 min of reinforcement time for everyone (the child, the sibling, and the parent). in the present article, we have described a model of supporting italian families during the past 6 weeks of lockdown. as professionals, we realized that this was one of the greatest challenges we would face in our careers. it soon became apparent, however, that the published literature and other tools upon which we typically rely were insufficient to deal with the magnitude and urgency of the present crisis. substantial previous research had been published on aspects of aba service delivery via telehealth, but little or no previous research had evaluated systems for transferring entire aba programs from in person to telehealth overnight, especially in the context of families living under total lockdown. in the absence of specific guidelines, we relied on an inductive process dictated by the tradition of our science, adapted published protocols, and derived procedures from principles. the system we were called to develop needed to be comprehensive and efficient. it needed to recognize the complexity of each individual family dynamic and be, at the same time, simple, realistic, and sustainable to maintain parental engagement. some may find the nearly complete elimination of noncontingent reinforcement and the application of a token economy across all waking hours to be somewhat extreme. however, the primary problem reported to us by parents before making this change was a lack of structure and loss of child motivation due to continuous free access to reinforcers. by programming reinforcement contingent on active engagement with the household schedule, we empowered the parents to increase their child's motivation and provide clear direction for everyone involved. if the parents had not been effective in providing sufficient antecedent support in the form of prompting and setting task difficulty at an achievable level, then such a system could have resulted in inadequate access to positive reinforcement. however, with support from their aba consultants, parents were successful in bringing order to their homes and helping their children to be calm, productive, engaged, and happy. despite the difficulties we are all experiencing, as both professionals and human beings, we have learned some valuable lessons that we hope will shape our ability to serve our families more effectively in the future. we have tremendous respect for the courage and dedication shown by the families we work with, who, at a time of adversity and uncertain future, have remained focused on the present. although parents realize that we are all learning as we go, we have seen a level of parental engagement that we had not been able to generate previously. such change, although borne out of crisis, may have enduring positive effects. our task moving forward will be to maintain these novel repertoires under more positive contingencies. we have not yet been able to analyze the data so far collected. we have included ongoing assessment of social validity by asking parents to comment on their experiences so far. we present three representative translated excerpts of parents' feedback: i thought it would be difficult to maintain the daily schedule of alternating instruction with reinforcement, but it has been very successful. i have stuck to it, and it has been all very natural and not too effortful. i am also very happy because i am able to spend time with my 2year-old, who is also making progress. i am able to play more with him and to focus on his speech. it's going well. (vittoria, parent of b, a 6-year-old girl with autism, and g, a 2-year-old boy) we received very simple and clear instructions-take away all reinforcers, engage him all day in simple domestic chores, give him routines, and give the reinforcers only after completing a token board. we saw an immediate change, zero problem behavior, and collaboration from c. if this situation had not happened, my husband and i would never have had such an enriched experience. seeing c so calm and compliant is the biggest reinforcer. (giada and davide, parents of c, a 9-year-old boy with autism) the management of g became very difficult. all his routines and perception of time had been disrupted. g, who was never interested in playing, became satiated with technology and was constantly searching for food, becoming very anxious during mealtimes. creating a closed reinforcer economy and dividing the day in clear sequential moments as to not get to the point of acute problem behavior and prevent boredom were essential. as parents, even in the absence of tutors, we are able to manage our child calmly and maintain learned skills. (veronica and giorgio, parents of g, a 7-year-old boy with autism) conflict of interest the authors declare that they have no conflicts of interest. ethical approval this article does not contain research conducted with human subjects. the measurement and reinforcement of behavior of psychotics the token economy: a motivational system for therapy and rehabilitation telehealth as a model for providing behaviour analytic interventions to individuals with autism spectrum disorder: a systematic review token reinforcement: translational research and application national sleep foundation's updated sleep duration recommendations: final report evaluating the influence of postsession reinforcement on choice of reinforcers activity schedules for children with autism: teaching independent behavior coronavirus, le misure adottate dal governo, provvedimenti attualmente vigenti, approvati dal governo in seguito all'emergenza sanitaria internazionale the use of a selfdirected learning program to provide introductory training in pivotal response treatment to parents of children with autism parent-mediated intervention training delivered remotely for children with autism spectrum disorder living outside of urban areas: systematic review achievement place: token reinforcement procedures in a home-style rehabilitation setting for "pre-delinquent" boys behavioral economics coronavirus disease (covid-19) pandemic publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-027550-yyqsatqw authors: mammas, ioannis n.; drysdale, simon b.; rath, barbara; theodoridou, maria; papaioannou, georgia; papatheodoropoulou, alexia; koutsounaki, eirini; koutsaftiki, chryssie; kozanidou, eleftheria; achtsidis, vassilis; korovessi, paraskevi; chrousos, george p.; spandidos, demetrios a. title: update on current views and advances on rsv infection (review) date: 2020-06-15 journal: int j mol med doi: 10.3892/ijmm.2020.4641 sha: doc_id: 27550 cord_uid: yyqsatqw respiratory syncytial virus (rsv) infection represents an excellent paradigm of precision medicine in modern paediatrics and several clinical trials are currently performed in the prevention and management of rsv infection. a new taxonomic terminology for rsv was recently adopted, while the diagnostic and omics techniques have revealed new modalities in the early identification of rsv infections and for better understanding of the disease pathogenesis. coordinated clinical and research efforts constitute an important step in limiting rsv global predominance, improving epidemiological surveillance, and advancing neonatal and paediatric care. this review article presents the key messages of the plenary lectures, oral presentations and posters of the '5th workshop on paediatric virology' (sparta, greece, 12th october 2019) organized by the paediatric virology study group, focusing on recent advances in the epidemiology, pathogenesis, diagnosis, prognosis, clinical management and prevention of rsv infection in childhood. precision medicine has evolved in recent years allowing the incorporation of novel taxonomies and stratification of patients, and using standardized clinical endpoints, genetic and other biomarker information (1) . its role in paediatric healthcare involves the selection of targeted diagnostic, therapeutic and prevention strategies matched to precise molecular, epidemiological and clinical profile of each patient; the management of respiratory syncytial virus (rsv) infection represents a good paradigm of precision medicine (2) . rsv is a single-stranded rna virus (figs. 1 and 2), which represents the most frequent viral cause of acute lower respiratory tract infection (alrti) in infants, with a worldwide distribution and seasonal occurrence (2) (3) (4) (5) . it was first isolated in 1956 from nasal secretions of chimpanzees with rhinorrhea and coryza; the novel virus was initially named 'chimpanzee coryza agent' (cca) (6, 7) . in the following year, when cca was also isolated from children with alrti, it gained its final name due to the syncytia observed on electron microscopy; syncytia are formed by fusion of infected host cells with neighboring cells leading to the formation of multi-nucleate enlarged cells. although the formation of syncytia is the hallmark of the cytopathic effect of rsv that is associated with host cellular membrane merging, syncytia are not pathognomonic of rsv (8) . syncytia are also observed in cell culture with several other viruses, such as parainfluenza, hsv-1, hiv and mev. recently, the international committee on taxonomy of viruses (ictv), which authorizes and organizes the classification and naming of viral species, grouped rsv under the genus orthopneumovirus within the family pneumoviridae (9, 10) . bronchiolitis is the most common clinical manifestation of rsv infection in infants and although it is usually self-limiting, in infancy it accounts for a significant number of hospitalizations and paediatric intensive care unit (picu) admissions (3) . despite its association with relatively high morbidity and mortality in premature neonates and in certain paediatric populations with underlying conditions, such as immunodeficiency and congenital heart disease, rsv infection may also lead to hospitalization of previously healthy, full-term infants (11, 12) . rsv-positive bronchiolitis is characterized by airway inflammation and oedema, mucus production and debris leading to airway obstruction and turbulent gas flow. even though various therapeutic interventions have been tried, such as bronchodilators, hypertonic saline and corticosteroids, supportive care remains the mainstay in most settings, with gentle suctioning of nasal secretions, prone position, fluid replacement and oxygen or respiratory support, as necessary. several clinical trials on the management and prevention of rsv-positive bronchiolitis have been recently completed, are underway, or in development (3) . currently, there is rapid expansion of rsv vaccine candidate development and there is hope that one will become available in the near future. of course, the safety of vaccines proposed for primary immunization in an antigen naïve child remains the top priority. this review article summarizes the key messages of the plenary lectures, oral presentations and posters of the '5th workshop on paediatric virology' held in sparta (greece) on october 12th, 2019, which was focused on rsv (table i) understanding the burden of rsv infections in real-time. rsv poses significant disease burden in infants and children worldwide (13) , and the international paediatric community is only beginning to appreciate its global impact in both high and low resource settings (4, 14, 15) . the clinical presentation of an rsv infection depends on the patient's age and individual risk factors (16, 17) . the concept of measuring individual-level differences in disease severity has drawn the attention of both public health stakeholders and regulatory agencies in recent years (18) (19) (20) . the impact of rsv infections of course should be differentiated from the disease caused by influenza and other viral respiratory infections (21, 22) . however, a recent extensive literature review and prospective cohort have shown that in infants and children this cannot be done based on clinical symptoms alone; distinguishing rsv from other viral respiratory infections requires laboratory confirmation (23, 24) . with rsv vaccines and antiviral agents in development, it will be important to: a) diagnose rsv infections in a timely manner; b) differentiate rsv from other forms of acute respiratory infections; and c) communicate the test results back to patients and parents/caregivers along with information on the individual disease risk and severity. the pedsidea programme. the vienna vaccine safety initiative (vivi, https://www.vi-vi.org) is an international non-profit research organization which, in collaboration with academic institutions and public health agencies in europe and the united states, has developed digital tools and programs to improve the quality of care for children and adults with alrti or influenza-like illnesses (ili) (13, 25, 26) . taking a person-centered approach, the vivi disease severity score ('vivi score') is a mobile application enabling healthcare professionals to measure disease severity at the point of care within minutes. it was designed to provide a uniform approach to define ad hoc severity at any given time point, based on extensive literature review as well as who criteria for uncomplicated and complicated ili (27) . in collaboration with the robert koch institute, the vivi score was validated in a cohort of 6,000 children (age 0-18) in berlin, germany and subsequently used in a european pilot project entititled 'partnering for enhanced digital surveillance of influenza-like disease and the effectiveness of antivirals and vaccines' (pedsidea) (27, 28) . since then, the pedsidea programme has been implemented in community clinic networks and adult intensive care units in the unites states for the real-time digital surveillance of influenza and rsv disease incidence and severity at the point of care (29) . the programme is expected to continue monitoring, in great detail, the clinical outcomes of 'natural' rsv and other viral respiratory infections in children and adults, including patients at the extremes of age. understanding the real-world disease burden may help facilitate the study of the effectiveness of novel influenza and rsv antiviral agents and vaccines, once they become available (30) . rsv infection: not for children only. rsv was not recognized as a potentially serious problem in older adults until the 1970s, when outbreaks of the virus occurred in long-term care facilities for the elderly (31) (32) (33) . since then, additional studies in hospitalized adults have suggested that rsv may be an important cause of illness in adults. molecular diagnostics suggest that rsv positive specimens are commonly identified in elderly and high-risk adults, in a frequency similar to that of seasonal influenza (31, 34) . even though a positive rsv respiratory panel does not equate pathogenesis, it has been suggested that rsv may account for as much as 10,000 deaths annually in the united states among individuals above the age of 65 years (31) (32) (33) 35) . this, in addition to the morbidity in infants, has stimulated interest in rsv vaccines and antiviral agents. additional natural history studies are needed to better understand the actual burden of rsv infection among the elderly and high-risk adults. the immune response to rsv infection. maternal antibodies may be able to mitigate rsv disease severity in young infants (17, (36) (37) (38) . it is assumed that the transplacental passage of rsv-specific antibodies occurs predominately during the third trimester of pregnancy. high titers can potentially protect term infants up to four months of age (38) . in premature infants, passive immunity may be 'compromised' (39) , but still has a role to play. the degree to which breast feeding may also contribute to passive immunity and to priming of immune system is currently under investigation (40) . once infection is established, the innate immune system plays a dual role in lowering the viral load and in mounting a secondary immune response. prematurity and other conditions that compromise the immune response may lead to reduced levels of antiviral cytokines, such as the interferons (41) . in infants, reduced signaling by tlrs and altered antigen-presenting cell functions, including low interleukin (il)-12 and enhanced il-6 and il-23 production, coupled with reduced activation of regulatory t cells, may result in an adaptive response that is skewed toward th2 and th17 and away from protective th1 and ctl responses (42) . the potential specific role(s) of certain pattern recognition receptors in humans has/ve been suggested by the fact that certain tlr missense mutations are associated to a phenotype with propensity to wheezing (43) . apart from the individual genetics (44), the stage of lung maturation among term and premature infants also impacts on the th1 to th2 switch. in the case of prematurity, the mucosa prior to alveolarization is being deluged with th2 inflammatory responses, even in the earlier stages of bronchopulmonary dysplasia (45) . impaired th1 activation, coupled with little or no b cell memory, and inhibition of antibody production by ifnγ, produces low-titer, low-affinity antibody (46) . the result may be a poorly protective and dysregulated defense mechanism that leads to bronchiolitis in susceptible infants (43) . later, the host immune response is permanently oriented to the direction of wheezing exacerbations, specifically triggered by rsv (47) . micrornas (mirnas) are involved in post-transcriptional gene regulation and play significant roles in the maintenance of the airway epithelial barrier of the respiratory tract (48) (49) (50) (51) (52) (53) (54) (55) (56) . mirnas have been implicated in the modulation of antiviral defense mounted by host innate and adaptive immunity, involving not only immune effector and inflammatory cells, but also parenchymal cells (50) . respiratory viruses, including rsv, attack, as a primary target, the epithelial cells of the respiratory tract causing an altered expression of distinct mirnas in the airway cells. the human innate immune response inhibits rsv replication early after inoculation, mainly through the action of interferons (53) . multiple mirnas are induced by infection in a cell-type-specific fashion (51) . rsv appears to alter host cell gene expression also through regulation of expression of mirnas related to the interferon response (50, 53) . abnormal expression of mirnas has been detected in both peripheral blood cells and airway epithelial cells in rsv-infected infants (54) . understanding alterations in mirna expression profiles and identifying mirna target genes in relation to the pathogenesis of rsv may help clarify the mechanisms of virus-host interactions, and immune dysfunction leading to airway hyper-reactivity and chronic respiratory diseases, such as asthma (49,50,53,54). there are several methods for the purification, quantification and being able to compare severity over time and/or across cohorts is useful in hospital-based qi programmes but also in multi-centre networks, such as pedsidea understanding the real-world disease burden caused by rsv will facilitate the study of the effectiveness of antivirals and vaccines, once they become available recent epidemiological data indicate that rsv infection is an important illness in elderly and high-risk adults, with a disease burden similar to that of non-pandemic influenza rsv and immune response maternal rsv-specific antibodies transmitted transplacentally during the third trimester of pregnancy are related to rsv disease severity in young infants rsv and mirnas a greater understanding of mirnas may enable them to be used as biomarkers of severe rsv infection and as novel targets for treatment or prophylaxis of rsv infection rsv and thrombocytosis thrombocytosis in rsv-positive bronchiolitis does not require routine prophylactic anti-platelet treatment or further investigations rsv and asthma there is compelling evidence that severe respiratory infection induced by rsv is associated with subsequent development of asthma later in childhood further understanding of the role of rsv in asthma pathogenesis will enable our understanding of the impact of future vaccines against rsv in asthma prevention rsv as a cause of pibo there are only few reports in the literature of children with pibo secondary to rsv as a single infection further research is required in order to investigate the potential impact of rsv co-infection in the severity and worse outcome in children with pibo imaging of rsv infection although imaging cannot diagnose rsv infection, it is important to identify the possible pattern of viral disease, in order to avoid unnecessary administration of antibiotic therapy and predict possible late effects standard radiological techniques, including ct, are unable to distinguish between acute bronchiolitis caused by rsv versus that caused by other respiratory viruses hrct of the lungs may be required to assess possible bronchial thickening and remodeling, the development of bronchiectasis and air-trapping antivirals against rsv ribavirin is currently the only licensed antiviral medication used to treat rsv infection; it has very limited efficacy and multiple toxicities, which means its use is usually reserved for severely immunocompromised children due to ethical and technical constraints human challenge models are only undertaken in adults, but if a product is shown to be efficacious in this setting it allows a faster move to trials in children than traditional trials which often take much longer to do a greater understanding of individual data in newly developed pharmaceutical agents against rsv will potentially lead to future personalized treatment regimens rsv and picu hfnc might have a role as a rescue therapy for children with rsv-positive bronchiolitis admitted to picu to reduce their requirement for high-cost intensive care heliox could be useful in addition to standard medical care in the management of children with rsv-positive bronchiolitis admitted to picu characterization of mirna expression profiles in biofluids, whole blood samples and tissue samples obtained in in vivo studies (55) . further research on mirnas is expected to clarify their value as biomarkers of rsv infections and their sequelae (i.e., recurrent wheezing and asthma). thrombocytosis and rsv infection. the most frequent causes of secondary thrombocytosis in childhood are acute respiratory tract infections (57) (58) (59) (60) (61) . to date, several authors have reported significantly higher mean platelet counts in patients with rsv than in patients with other acute respiratory tract infections (61) (62) (63) (64) . thrombocytosis is more likely to occur in younger patients, who have clinical manifestations of wheezing and dyspnoea (62, 64) . moreover, thrombocytosis has been suggested as an early marker of rsv infection (62) . excessive thrombocytosis has also been detected at an early stage in cases of rsv-positive bronchiolitis (65) . it has been proposed that thrombocytotic patients have a more severe clinical course and longer duration of hospitalization and that the platelet count may be a useful clinical marker associated with alrti severity (61, 64, 66, 67) . conversely, other authors have found that platelet counts do not correlate with disease severity and clinical outcome (68, 69) . routine prophylactic anti-platelet treatment or further investigations are not necessary in children with rsv-positive bronchiolitis and thrombocytosis (61, 68, 70) . there is compelling evidence that infants with severe rsv infection in the early months of life have a subsequent increased risk of developing recurrent wheezing and/or asthma, with a prevalence of up to 30% compared with non-rsv groups (71) (72) (73) (74) (75) . whether this association is causal has been the subject of considerable debate on the potential role of rsv infection in the pathogenesis of asthma as well as the impact of asthma predisposition (genetic, environmental exposure, etc.) on the clinical course of rsv infection. a recent large retrospective cohort analysis of australian children born between 2000 and 2010 suggested that different subgroups of high risk children, who developed rsv disease within the first 2 years of life, continued to be at elevated risk of having a first asthma hospitalization beyond the age of 7 years (76). on the other hand, large epidemiological observational studies demonstrate that the vast majority of infants hospitalized for rsv bronchiolitis do not fit into an 'at-risk' group (atopy, family history, etc.), suggesting that viral or host factors not thought of as classical risk factors, may play a role in disease severity (74, 77) . prospective studies with rsv-immunoprophylaxis (e.g., palivizumab) suggest that long-term effects of rsv prophylaxis appear less efficacious in infants with a family history of atopy. in addition, palivizumab decreases parent-reported recurrent wheeze, however the incidence of physician-diagnosed asthma is similar (78) . a recent single-blind, randomized, placebo-controlled trial showed that rsv prevention in otherwise healthy preterm infants, did not have a major effect on asthma or lung function at the age of 6 years (79). considering the above findings, perhaps a more appropriate conclusion would be that rsv infection is important in the mechanism of wheezing development, at least in the first few years of life (80) . rsv possesses the ability to counteract host defense systems through complex mechanisms that facilitate viral replication. this significant increase in asthma frequency seems to be predominantly related to long-term changes in neuroimmune control of airway tone rather than to allergic sensitization. in contrast to rsv bronchiolitis, atopy has been clearly associated with childhood asthma development after rsv-induced early wheezing (81, 82) . high-risk (parental atopy or asthma) birth cohort studies from wisconsin, united states, and australia have shown that young children suffering from rsv-induced wheezing episodes are at high risk of developing school-age asthma (81, 82) . further prospective, follow-up studies are needed to clarify individual and environmental factors that promote more severe viral illnesses and long-term adverse respiratory outcome of children hospitalized for severe rsv infection. developing a greater understanding of the pathophysiological mechanisms through which rsv causes recurrent wheezing/asthma, will lead to an evidence-based prevention strategy and perhaps reduce the subsequent risk for asthma (71) . the biomarker ccl5 (previously known as rantes, a β-chemoattractant for inflammatory cells including t-lymphocyte subsets), in the nasal epithelium during rsv bronchiolitis, is strongly predictive of physician-diagnosed asthma (83, 87) . furthermore, it has been suggested that prematurely born infants have a predisposition to rsv infection-related respiratory morbidity, including subsequent respiratory dysfunction (44,85). single-nucleotide polymorphisms in genes coding for il-8, il-19, il-20, il-13, mannose-binding lectin, ifng and rantes, have been associated with wheezing following rsv lrti in term-born infants (85) . the site of infection might be another important factor related to asthma risk, thus viral alrti in infancy indicates an increased risk of subsequent asthma, while gastrointestinal infections might be protective (86) . asthma after severe rsv bronchiolitis is positively correlated with maternal asthma, exposure to high levels of dog allergen, aeroallergen sensitization and recurrent wheezing; day care attendance and white race have been associated with decreased asthma risk (87) . several host factors, including respiratory allergy and virus-induced interferon responses, viral virulence factors, individual risk factors (e.g., young age, especially the first 6 months of life, small lung size and genetics), and environmental exposures (e.g., exposure to tobacco smoke, airway microbiome) modify the risk of virus-induced wheezing and promote more severe wheezing illnesses and the risk for progression to asthma (86, 88) . the anti-rsv mab palivizumab decreases the risk of severe rsv-induced illness and subsequent recurrent wheeze in prematurely born infants (89) . further understanding of the role of rsv in asthma pathogenesis may help develop vaccines against rsv as a way of asthma prevention. bronchiolitis obliterans (bo) is a chronic and irreversible lung disease leading to the obstruction and/or obliteration of the small airways (90) . most cases of bo in children are post infectious (pibo) and are mainly associated with adenovirus infections, although other viruses may also be implicated, including measles, influenza, parainfluenza and rsv (91) (92) (93) . an extensive search of the current literature in the context of the workshop demonstrated that rsv is detected in children with pibo with an incidence ranging from 4.3 to 30% (94-103); however, there are only a few reports of children with pibo secondary to rsv as a single infection. this creates skepticism about the aetiological role of rsv in pibo. further research is required to investigate the potential impact of rsv co-infection in the severity and outcome of children with pibo. chest radiography and rsv-positive bronchiolitis. although imaging cannot confirm the diagnosis of rsv infection, it is important to identify the possible pattern of viral disease, in order to avoid unnecessary administration of antibiotic therapy and to predict possible late effects (figs. 3-5) (104). the clinical syndrome of bronchiolitis is commonly diagnosed based on the patient's history and physical examination; chest radiography is not routinely recommended to reach the diagnosis due to recommended restriction of radiation exposure in the paediatric age group (104) (105) (106) . chest imaging, however, may be considered when a child with rsv infection and severe alrti is admitted to intensive care to better understand the extent of lung involvement and atelectasis, which is common in acute rsv infection (106). it is important to note that chest radiographs in children with rsv infection may be entirely normal or reveal non-specific findings, which are also encountered in other viral infections: most commonly, perihilar opacities and hyperinflation, atelectasis and rarely consolidation and bronchial cuffing or air-leak (107) . radiography is commonly obtained to rule out atelectasis and foreign body aspiration. guidelines suggest performing a chest radiograph in the presence of significant respiratory distress or hospitalization (108) . in newborns with rsv infection, the radiological pattern on chest radiography may be a predictor of clinical outcome (109) . however, it is highlighted that chest radiographs should not be routinely performed in children with bronchiolitis to avoid radiation exposure (106). it is also important to emphasize that chest radiograph is not the right way to rule out bacterial infection (106); the correct diagnostic approach for bacterial or ventilator-associated pneumonia in children in the picu is to perform respiratory culture or matrix-assisted laser desorption ionization time-of-flight (maldi-tof) mass spectrometry from sputum/aspirate or bronchoalveolar lavage (bal) specimens. chest ct and rsv-positive bronchiolitis. several studies have revealed that standard radiological techniques, including computed tomography (ct), are frequently unable to distinguish between acute bronchiolitis changes caused by rsv vs. those caused by other respiratory viruses (104, 108) . it is interesting that the radiographic findings, especially in high-resolution computed tomography (hrct), reflect the histopathologic changes that rsv infection provokes: plugging or occlusion of the bronchiolar airway lumens by sloughed necrotic and irregular epithelium and exudate, combined with peri-bronchiolar infiltration and reaction with inflammatory cells and submucosal oedema. the infiltration is a combination of neutrophils entering the airway submucosa and epithelial cell debris in the airway lumens. these cellular accumulations are likely to result in acute obstruction of the distal airways, an outcome much more likely to occur in the extremely narrow bronchioles of infants. because this is combined with the inherent loss of mechanical clearance of these small airways, it likely leads to increased spread of infection, augmented inflammation and clinical signs of wheezing/obstruction (110) . consistent with obstruction, the most common ct findings in rsv pneumonia include centrilobular nodules, ground-glass opacities, air-space consolidation, and peribronchial thickening (111) . these findings have a bilateral, usually asymmetric, central and peripheral distribution. up to 40% of children with bronchiolitis will develop further wheezing episodes in the first five years of life. in very severe or atypical cases, hrct of the lungs may be required to assess the extent of bronchial thickening and remodeling, the development of brochiectases and air-trapping (105) . restricted to the airways. case reports have also described clinical pictures resembling viral encephalitis and/or encephalopathic syndromes with severe sequelae in isolated cases (112) . the mechanism of the spread of the rsv infection to the cns compartment remains unclear (112) . brain magnetic resonance imaging (mri) in infants with cns involvement has shown predominantly non-specific findings similar to those also encountered in other viral and/or limbic system encephalitides (113) . in very rare instances, extra-pulmonary findings in rsv infection have also included acute necrotizing encephalopathy (ane) and acute hepatic failure with encephalopathy (114) . clinicians should have a high suspicion of ane in cases of children with a respiratory infection and acute neurological manifestations. antivirals against rsv. thus far, ribavirin is the only antiviral agent that has ever been licensed for the treatment of rsv infection (115) . however, its efficacy is not proven and due to significant toxicity its use has been primarily restricted to severe cases in immunocompromised patients with severe rsv-positive alrti (116) . several other antiviral candidates have been developed since, but none have been licensed as yet. types of molecules being tested include influenza antivirals, such as baloxavir, cc-42344, vis410, immunoglobulin, hyperimmune plasma, mhaa4549a, pimodivir (jnj-63623872), umifenovir, and ha minibinders, rsv antivirals including presatovir (gs-5806), ziresovir (ak0529), lumicitabine (als-008176), jnj-53718678, jnj-64417184, and edp-938, broad spectrum antivirals such as favipiravir, vh244, remdesivir, and eidd-1931/eidd-2801, as well as host directed strategies including nitazoxanide, eritoran, and diltiazem (117-119). novel molecules disrupt various stages of the virus life cycle, including cell entry, viral replication, and polymerization as well as after virus release through rsv neutralizing anti-or nanobodies (120) . the human challenge models. one method used occasionally in phase 2 clinical testing is human challenge models (115) . this method was used in phase 2a clinical testing of the non-fusion inhibitor edp-938 (clinicaltrials.gov identifier: nct03691623). all participants were inoculated with a known strain of rsv and were then randomized to receive the medication or placebo. the advantage of this methodology is the removal of the variability in exposure with natural infection and the collection of samples at precise, known times after infection, which can aid with the understanding of the biological mechanisms of the infection and development of antiviral agents or vaccines (121, 122) . due to ethical and technical constraints, experimental studies are only undertaken in adults, but if a product is shown to be efficacious at this setting, a faster move to trials in paediatrics takes place than in traditional childhood trials. rsv therapeutics and personalized medicine. the current clinical data indicate that rsv disease dynamics may not be identical in all patients (2, 3, 115, 119) . more research is needed to identify uniform clinical endpoints reflecting how patients function, thrive, and survive (us food and drug administration) and to understand inter-individual differences in disease presentation, with the goal of ultimately selecting the right treatment for the right patient. a greater understanding of individual differences may ultimately lead to future personalized treatment strategies. individualized approaches and a well-standardized methodology to assess disease severity at the time of enrolment, as well as during follow-up visits, will require integration of diagnostic, clinical and laboratory markers at the point of care (115) . individualized targeted treatment will constitute an important step in improving outcomes in patients with rsv infection while minimizing toxicity. a greater understanding of individual data in newly developed pharmaceutical agents against rsv will potentially lead to future personalized treatment regimens. applying such co-ordinated diagnostic, clinical and research efforts constitutes an important step in advancing paediatric care, improving outcomes and limiting global rsv morbidity and mortality. over the last decade, high-flow nasal cannula (hfnc) therapy has emerged as a new method to provide respiratory support in children with rsv-positive bronchiolitis (12, (123) (124) (125) (126) . its main advantages include its ease to set up and the fact that it is well tolerated, leading to better compliance, especially in comparison to other devices of non-invasive ventilation (125, 127) . initially, hfnc was trialed in infants with moderate to severe bronchiolitis admitted to picus, but nowadays its application has expanded to paediatric wards, even to emergency departments, in order to avoid a picu admission (127, 128) . recent data have shown that it does not significantly reduce time on oxygen compared with standard therapy, suggesting that early use of hfnc does not modify the underlying disease process (129) . however, the proportion of children who experi-ence treatment failure is lower in hfnc and many of those who experience treatment failure on standard therapy can be rescued by hfnc. additional studies comparing hfnc with continuous positive airway pressure (cpap) in the picu setting led to the same conclusion (130, 131) . consequently, hfnc may reduce the need for intubation and invasive respiratory support, thus potentially lowering costs and adverse effects of mechanical ventilation, such as ventilator-induced lung injury, infections and exposure to sedatives. in addition to effectiveness, most studies have shown no adverse events with hfnc and have concluded that it is a relative safe method for use even in general wards or emergency departments (123) . few cases of pneumothorax have been reported, abdominal distension has been less significant compared with cpap, and the majority of infants have been able to be fed orally or by nasogastric tube (123, 127) . heliox and rsv-positive bronchiolitis. since rsv-positive bronchiolitis is associated with airway obstruction and turbulent gas flow, its clinical course can be improved by heliox, which facilitates gas flow through high-resistance airways (132) (133) (134) (135) (136) (137) (138) . heliox is a mixture of helium-oxygen, which can be administered by all modes of ventilation in spontaneously breathing patients by face mask, hfnc or cpap, and can be adjusted to specific ventilators in intubated children. current evidence suggests that the addition of heliox may significantly reduce clinical scores evaluating respiratory distress and the respiratory rate, and may enhance co 2 elimination in the first hour after starting treatment in infants with acute refractory rsv bronchiolitis (134, 139) . recently, seliem and sultan (140) reported that heliox results in improvement of oxygenation when used with high flow nasal cannula in infants with acute rsv bronchiolitis, during the initial phase of therapy. the combination of heliox with cpap also seems to be beneficial, as the application of cpap may reduce the fio 2 needed in these infants. however, no benefit has been observed in terms of need for intubation and mechanical ventilation, length of treatment or picu stay. in addition, its application in the emergency department does not change the discharge rate (138, 139) . more clinical trials are needed to define the population that may respond to heliox and its place in the therapeutic regimens of rsv bronchiolitis. passive immunization and palivizumab. the prevention of rsv morbidity and mortality remains a global healthcare priority (115, 141) . according to the world health organization (who), the strategic focus for the prevention of rsv infection in children and adults includes the passive administration of immunoglobulins, as well as active immunization. passive immunization is currently the only option available to infants less than 6 months of age, which can be achieved through administration of antibodies to the infant or through active immunization of the mother during pregnancy. passive immunity wanes fast over time, thus, active immunization is the preferred approach for infants above six months of age, as well as older children and adults, including the elderly (141). to date, there is only one product available for prevention of rsv infection, palivizumab, the monoclonal antibody (mab) that has been shown to reduce hospital admission due to rsv infection in some high-risk infants by up to 80% (142) . it is expensive and, thus, reserved for high risk infants, mainly in high income countries. active immunization against rsv: looking back to the past. while antibodies are costly and transitory in their effect, active vaccination would represent the most cost-effective approach for the prevention of rsv infections and their transmission to high-risk individuals (115, 141) . up to date, several vaccine candidates are in development, but none have reached licensure yet (143, 144) . one of the main barriers for the development of rsv vaccines has been the fact that the majority of severe cases in infants occur within the first three months of life, i.e. at a time when active immunization is not really possible (145) . additional caution has been employed during vaccine design because of the failure of a historical vaccine [formalin inactivated rsv (fi-rsv)], which triggered a severe adverse effect, enhanced respiratory disease (erd) (146) . for more than 50 years live-attenuated vaccine approaches have been unsuccessful because of the difficulty in balancing immunogenicity and vaccine safety. it is worth noting that only live-attenuated vaccines have been tested for active infant immunization. active immunization against rsv: perspectives. recent breakthroughs in determining the structure and antigenic content of the rsv fusion (f) glycoprotein has enhanced interest in vaccine development research (115, 141, 147, 148) . the general approaches to vaccine development include engineered viruses that use knowledge of rsv gene function, naturally attenuated chimeric virus combining genes from rsv-related viruses, viral vectors encoding rsv surface antigens, and nucleic acid vaccines using plasmid dna or messenger rna encoding rsv antigens (149, 150) . as of august 2019, 43 rsv vaccines were in development (151). of these, 21 are in clinical trials in humans; 14 in phase 1, five in phase 2 and two (one just completed) in phase 3. twelve vaccines are in trials in children, four in pregnant women and 10 in older adults (some products are undergoing trials in more than one target population). vaccine types under investigation include live-attenuated/chimeric, particle-based, subunit and recombinant vector vaccines. this highlights the variety and breadth of immunization types and different populations that are being investigated to find an answer to the 60-year-old problem of producing a safe and effective rsv prophylactic agent. the resvax. the most advanced candidate vaccine, resvax, is an rsv fusion protein recombinant nanoparticle with aluminum phosphate as an adjuvant (115, 152, 153) . the new approach to develop this vaccine is based on engineering small particles that carry altered rsv proteins. the nanoparticles sensitize the immune system to the virus so that when a person comes in contact with it the immune system delivers a robust response. the phase 3 clinical trial included more than 4,600 pregnant women examining the efficacy of prevention of rsv disease in infants through maternal immunization. although the trial narrowly missed its primary end point of a reduction in medically attended rsv-positive alrti, it showed a 44% vaccine efficacy against rsv hospitalization, 25% efficacy against all respiratory hospitalizations and 39% efficacy against all-cause severe hypoxaemia (152) . a possible route to licensure is currently being sought with the us food and drug administration (fda) and european licensing agencies, bringing hope of a vaccine that could save the lives of countless young infants worldwide. we would like to thank the participants of the '5th workshop on paediatric virology' (sparta, greece, october 12th, 2019) for their comments, corrections and feedback. we would also like to thank the organizing committee the '24th world congress on advances in oncology' and the '24th international symposium on molecular medicine' for the outstanding hosting of the workshop, as well as all members of the pvsg and the newly founded institute of paediatric virology (ipv) based on the island of euboea for their valuable contribution in the preparation of the manuscript. no funding was received. not applicable. all authors (inm, sbd, br, mt, gp, ap, eik, ck, elk, va, pk, gpc and das) contributed to the conception and design of the study, wrote the original draft, edited and critically revised the manuscript, read and approved the final manuscript. not applicable. not applicable. das is the editor-in-chief for the journal, but had no personal involvement in the reviewing process, or any influence in terms of 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force on clinical practice recommendations on preschool wheeze: bronchiolitis needs a revisit: distinguishing between virus entities and their treatments the burden and long-term respiratory morbidity associated with respiratory syncytial virus infection in early childhood association between respiratory syncytial viral disease and the subsequent risk of the first episode of severe asthma in different subgroups of high-risk australian children: a whole-of-population-based cohort study exploring the association between severe respiratory syncytial virus infection and asthma: a registry-based twin study scientific committee for elucidation of infantile asthma: palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. six-year follow-up study respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial iris (infección respiratoria infantil por virus respiratorio sincitial) study group: long-term burden and respiratory effects of respiratory syncytial virus hospitalization in preterm infants -the spring study rhinovirus-induced first wheezing episode predicts atopic but not nonatopic asthma at school age early life rhinovirus wheezing, allergic sensitization, and asthma risk at adolescence koutsaftiki c: predicting asthma following rsv-positive bronchiolitis in early childhood viral lower respiratory tract infections and preterm infants' healthcare utilisation respiratory syncytial virus infection and chronic respiratory morbidity -is there a functional or genetic predisposition? viral respiratory infection and the link to asthma determinants of asthma after severe respiratory syncytial virus bronchiolitis predictors of asthma following severe respiratory syncytial virus (rsv) bronchiolitis in early childhood role of viral infections in the development and exacerbation of asthma in children post infectious bronchiolitis obliterans caused by respiratory syncytial virus (rsv) in children diagnosing and managing bronchiolitis obliterans in children post-infectious bronchiolitis obliterans in children predictors of severity and mortality in children hospitalized with respiratory syncytial virus infection in a tropical region clinical analysis of 28 cases of bronchiolitis obliterans successful lung volume reduction surgery in an infant with emphysema after respiratory syncytial virus-induced obliterative bronchiolitis clinical characteristics of bronchiolitis obliterans in pediatric patients work of breathing to optimize noninvasive ventilation in bronchiolitis obliterans bronchiolitis obliterans: outcome in the medium term clinical studies of children with bronchiolitis obliterans pos-infectious bronchiolitis obliterans in children simultaneous viral infection and childhood bronchiolitis obliterans bronchiectasis and bronchiolitis obliterans post respiratory syncytial virus infection: think again postinfectious bronchiolitis obliterans in children: clinical and radiological profile and prognostic factors imaging in children with rsv infection national institute for health and care excellence (nice): bronchiolitis in children: diagnosis and management, nice guideline respiratory syncytial virus infection of the lower respiratory tract: radiological findings in 108 children chest radiographic features of human metapneumovirus infection in pediatric patients is radiological appearance of lower respiratory tract infection due to respiratory syncytial virus a predictor of clinical outcome? psv and its propensity for causing bronchioloitis imaging of pulmonary viral pneumonia a fatal case associated with respiratory syncytial virus infection in a young child respiratory syncytial virus-related encephalitis: magnetic resonance imaging findings with diffusion-weighted study atypical presentations of respiratory syncytial virus infection: case series management of rsv infection in children: new advances and challenges safety issues related to the administration of ribavirin overview of current therapeutics and novel candidates against influenza, respiratory syncytial virus, and middle east respiratory syndrome coronavirus infections new therapies for acute rsv infections: where are we? advances in respiratory virus therapeutics -a meeting report from the 6th isirv antiviral group conference a review of therapeutics in clinical development for respiratory syncytial virus and influenza in children the future of flu: a review of the human challenge model and systems biology for advancement of influenza vaccinology rsv-specific airway resident memory cd8+ t cells and differential disease severity after experimental human infection high-flow warm humidified oxygen via nasal cannula and rsv-positive bronchiolitis among children admitted to picu high-flow nasal cannula therapy for infants with bronchiolitis paris and predict: early high flow nasal cannula therapy in bronchiolitis, a prospective randomised control trial (protocol): a paediatric acute respiratory intervention study (paris) non-invasive ventilation for the management of children with bronchiolitis (novembr): a feasibility study and core outcome set development protocol high-flow warm humidified oxygen versus standard low-flow nasal cannula oxygen for moderate bronchiolitis (hfwho rct): an open, phase 4, randomised controlled trial a randomized trial of high-flow oxygen therapy in infants with bronchiolitis humidified high-flow nasal cannula oxygen in bronchiolitis reduces need for invasive ventilation but not intensive care admission outcomes of children with bronchiolitis treated with high-flow nasal cannula or noninvasive positive pressure ventilation groupe francophone de réanimation et d'urgences pédiatriques (gfrup): high flow nasal cannula (hfnc) versus nasal continuous positive airway pressure (ncpap) for the initial respiratory management of acute viral bronchiolitis in young infants: a multicenter randomized controlled trial (tramontane study) heliox and rsv-positive bronchiolitis the history and physics of heliox helium-oxygen mixture: clinical applicability in an intensive care unit the therapeutic use of helium use of heliox delivered via high-flow nasal cannula to treat an infant with coronavirus-related respiratory infection and severe acute air-flow obstruction noninvasive ventilation with helium-oxygen in children heliox inhalation therapy for bronchiolitis in infants heliox delivered by high flow nasal cannula improves oxygenation in infants with respiratory syncytial virus acute bronchiolitis prevention of rsv infection: what is new with the vaccines? immunoprophylaxis against respiratory syncytial virus (rsv) with palivizumab in children: a systematic review and economic evaluation who rsv vaccine consultation expert group: who consultation on respiratory syncytial virus vaccine development report from a world health organization meeting global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis development of respiratory syncytial virus (rsv) vaccines for infants enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactivated virus vaccine development for respiratory syncytial virus vaccines against respiratory syncytial virus: the time has finally come recombinant low-seroprevalent adenoviral vectors ad26 and ad35 expressing the respiratory syncytial virus (rsv) fusion protein induce protective immunity against rsv infection in cotton rats nucleoside modified mrna vaccines for infections diseases will the resvax vaccine be key revenue driver for novavax. market realist key: cord-002774-tpqsjjet authors: nan title: section ii: poster sessions date: 2017-12-01 journal: j urban health doi: 10.1093/jurban/jti137 sha: doc_id: 2774 cord_uid: tpqsjjet nan food and nutrition programs in large urban areas have not traditionally followed a systems approach towards mitigating food related health issues, and instead have relied upon specific issue interventions char deal with downstream indicators of illness and disease. in june of 2004, the san francisco food alliance, a group of city agencies, community based organizations and residents, initiated a collahorarive indicator project called rhe san francisco food and agriculture assessment. in order to attend to root causes of food related illnesses and diseases, the purpose of the assessment is to provide a holistic, systemic view of san francisco\'s food system with a focus on three main areas that have a profound affect on urban public health: food assistance, urban agriculture, and food retailing. using participatory, consensus methods, the san francisco food alliance jointly developed a sec of indicators to assess the state of the local food system and co set benchmarks for future analysis. members collected data from various city and stare departments as well as community based organizations. through the use of geographic information systems software, a series of maps were created to illustrate the assets and limitations within the food system in different neighborhoods and throughout the city as a whole. this participatory assessment process illustrates how to more effectively attend to structural food systems issues in large urban areas by ( t) focusing on prevention rather than crisis management, (2) emphasizing collaboration to ensure institutional and structural changes, and (3) aptly translating data into meaningful community driven prevention activities. to ~xplore the strategies to overcome barriers to population sample, we examined the data from three rapid surveys conducted at los angeles county (lac). the surveys were community-based partic· 1patory surveys utilizing a modified two-stage cluster survey method. the field modifications of the method resulted in better design effect than conventional cluster sample survey (design effect dose to that if the survey was done as simple random sample survey of the same size). the surveys were con· ducte~ among parents of hispanic and african american children in lac. geographic area was selected and d1.v1ded int.o small c~usters. in the first stage, 30 clusters were selected with probability proportionate to estimated size of children from the census data. these clusters were enumerated to identify and develop a list of households with eligible children from where a random sample was withdrawn. data collectmn for consented respondents involved 10-15 minutes in-home interview and abstraction of infor· ma~ion from vaccine record card. the survey staff had implemented community outreach activities designed to fost~r an~ maintain community trust and cooperation. the successful strategies included: developing re.lat1on .w.1th local community organizations; recruitment of community personnel and pro· vide them with training to conduct the enumeration and interview; teaming the trained community introduction: though much research has been done on the health and social benefits of pet ownership for many groups, there have been no explorations of what pet ownership can mean to adults who are marginalized, living on fixed incomes or on the street in canada. we are a community group of researchers from downtown toronto. made up of front line staff and community members, we believe that community research is important so that our concerns, visions, views and values are presented by us. we also believe that research can and should lead to social change. method: using qualitative and exploratory methods, we have investigated how pet ownership enriched and challenged the lives of homeless and transitionally housed people. our research team photographed and conducted one-on-one interviews with 11 pet owners who have experienced home· lessncss and live on fixed incomes. we had community participation in the research through a partnership with the fred vicror centre camera club. many of the fred victor centre camera club members have experienced homelessness and being marginalized because of poverty. the members of the dub took the photos and assisted in developing the photos. they also participated in the presenta· tion of our project. results: we found that pet ownership brings important health and social benefits to our partici· pants. in one of the most poignant statements, one participant said that pet ownership " ... stops you from being invisible." another commented that "well, he taught me to slow down, cut down the heavy drugs .. " we also found that pet ownership brings challenges that can at times be difficult when one is liv· ing on a fixed income. we found that the most difficult thing for most of the pet owners was finding affordable vet care for their animals. conclusion: as a group, we decided that research should only be done if we try to make some cha.nges about what we have learned. we continue the project through exploring means of affecting social change--for example, ~eti.tions and informing others about the result of our project. we would like to present our ~mdmgs and experience with community-based participatory action resea.rch m an oral. presentarton at yo~r conference in october. our presentation will include com· mumty representation ~f. both front-hne staff and people with lived experience of marginalization and homdessness. if this is not accepted as an oral presentation, we are willing to present the project m poster format. introduction the concept of a healthy city was adopted by the world health organization some time ago and it includes strong support for local involvement in problem solving and implementation of solutions. while aimed at improving social, economic or environmental conditions in a given community, more significantly the process is considered to be a building block for poliq reform and larger scale 'hange, i.e. "acting locally while thinking globally." neighbourhood planning can he the entry point for citizens to hegin engaging with neighbours on issues of the greater common good. methods: this presentation will outline how two community driven projects have unfolded to address air pollution. the first was an uphill push to create bike lanes where car lanes previously existed and the second is an ongoing, multi-sectoral round table focused on pollution and planning. both dt•monstrate the importance of having support with the process and a health focus. borrowing from traditions of "technical aid"• and community development the health promoter /planner has incorporated a range of "determinants of health" into neighbourhood planning discussions. as in most urban conditions the physical environment is linked to a range of health stressors such as social isolation, crowding, noise, lack of open space /recreation, mobility and safety. however typical planning processes do not hring in a health perspective. health as a focus for neighbourhood planning is a powerful starti_ng point when discussing transportation planning or changing land-uses. by raising awareness on determmants of health, citizens can begin to better understand how to engage in a process and affect change. often local level politics are involved and citizens witness policy change in action. the environmental liaison committee and the dundas east hike lanes project resulted from local level initiatives aimed at finding solutions to air pollution -a priority identified hy the community. srchc supported the process with facilitation and technical aid. _the processs had tangible results that ultimately improve living conditions and health. •tn the united kmgdom plannm in the 60's established "technical aid" offices much like our present day legal aid system to provide professional support and advocacy for communities undergoing change. p2-15 (c) integrating community based research: the experience of street health, a community service agency i.aura cowan and jacqueline wood street health began offering services to homeless men and women in east downtown ~oronto in 1986. nursing stations at drop-in centres and shelters were fo~lowed by hiv/aids prevent10~, harm reduction and mental health outreach, hepatitis c support, sleeping bag exchange, and personal tdennfication replacement and storage programs. as street health's progi;ams expanded, so to~ did the agency:s recognition that more nee~ed t~ be done to. address the underl~ing causes of, th~ soct~l and economic exclusion experienced by its clients. knowing t.h~t. a~voca~y ts. helped by . evtd~nce , street he.alt~ embarked on a community-based research (cbr) initiative to 1dent1fy commumty-dnven research priorities within the homeless and underhoused population. methods: five focus groups were conducted with 46 homeless people, asking participants to identify positive and negative forces in their lives, and which topics were important to take action on and learn more about. findings were validated through a validation meeting with participants. results: participants identified several important positive and negative forces in their lives. key positive forces included caring and respectful service delivery, hopefulness and peer networks. key negative forces included lack of access to adequate housing and income security, poor service delivery and negative perceptions of homeless people. five topics for future research emerged from the process, focusing on funding to address homelessness and housing; use of community services for homeless people; the daily survival needs of homeless people and barriers to transitioning out of homelessness; new approaches to service delivery that foster empowerment; and policy makers' understanding of poverty and homelessness. conclusions: although participants expressed numerous issues and provided much valuable insight, definitive research ideas and action areas were not clearly identified by participants. however, engagement in a cbr process led to some important lessons and benefits for street health. we learned that the community involvement of homeless people and front-line staff is critical to ensuring relevance and validity for a research project; that existing strong relationships with community parmers are essential to the successful implementation of a project involving marginalized groups; and that an action approach focusing on positive change can make research relevant to directly affected people and community agency staff. street health benefited from using a cbr approach, as the research process facilitated capacity building among staff and within the organization as a whole. p2-16 (c) a collaborative process to achieve access to primary health care for black women and women of colour: a model of community based participartory research notisha massaquoi, charmaine williams, amoaba gooden, and tulika agerwal in the current healthcare environment, a significant number of black women and women of color face barriers to accessing effective, high quality services. research has identified several issues that contribute to decreased access to primary health care for this population however racism has emerged as an overarching determinant of health and healthcare access. this is further amplified by simultaneous membership in multiple groups that experience discrimination and barriers to healthcare for example those affected by sexism, homelessness, poverty, homophobia and heterosexism, disability and hiv infection. the collaborative process to achieve access to primary health care for black women and women of colour project was developed with the university of toronto faculty of social work and five community partners using a collaborative methodology to address a pressing need within the community ro increase access to primary health care for black women and women of colour. women's health in women's hands community health centre, sistering, parkdale community health centre, rexdale community health centre and planed parenthood of toronto developed this community-based participatory-action research project to collaboratively barriers affecting these women, and to develop a model of care that will increase their access to health services. this framework was developed using a process which ensured that community members from the target population and service providers working in multiculrural clinical settings, were a part of the research process. they were given the opportunity to shape the course of action, from the design of the project to the evaluation and dissemination phase. empowerment is a goal of the participatory action process, therefore, the research process has deliberately prioritized _ro enabling women to increase control over their health and well-being. in this session, the presenters will explore community-based participatory research and how such a model can be useful for understanding and contextualizing the experiences of black women and women of colour. they will address. the development and use of community parmerships, design and implementation of the research prorect, challenges encountered, lessons learnt and action outcomes. they will examine how the results from a collaborative community-based research project can be used as an action strategy to poster sessions v61 address che social determinants of women health. finally the session will provide tools for service providers and researchers to explore ways to increase partnerships and to integrate strategies to meet the needs of che target population who face multiple barriers to accessing services. lynn scruby and rachel rapaport beck the purpose of this project was ro bring traditionally disenfranchised winnipeg and surrounding area women into decision-making roles. the researchers have built upon the relationships and information gachered from a pilot project and enhanced the role of input from participants on their policy prioriries. the project is guided by an advisory committee consisting of program providers and community representatives, as well as the researchers. participants included program users at four family resource cencres, two in winnipeg and two located rurally, where they participated in focus groups. the participants answered a series of questions relating to their contact with government services and then provided inpuc as to their perceptions for needed changes within government policy. following data analysis, the researchers will return to the four centres to share the information and continue che discussion on methods for advocating for change. recommendations for program planning and policy development and implementation will be discussed and have relevance to all participants in the research program. women's health vera lefranc, louise hara, denise darrell, sonya boyce, and colleen reid women's experiences with paid and unpaid work, and with the formal and informal economies, have shifted over the last 20 years. in british columbia, women's employability is affected by government legislation, federal and provincial policy changes, and local practices. two years ago we formed the coalition ior women's economic advancement to explore ways of dealing with women's worsening economic situations. since the formation of the coalition we have discussed the need for research into women's employabilicy and how women were coping and surviving. we also identified how the need to document the nature of women's employability and reliance on the informal economy bore significanc mechodological and ethical challenges. inherent in our approach is a social model of women's health that recognizes health as containing social, economic, and environmental determinants. we aim to examine the social contexc of women's healch by exploring and legitimizing women's own experiences, challenging medical dominance in understandings of health, and explaining women's health in terms of their subordination and marginalizacion. through using a feminist action research (far) methodology we will explore the relationship between women's employability and health in 4 communities that represent bricish columbia's social, economic, cultural/ethnic, and geographic diversities: skidegate, fort st . .john, lumhy, and surrey. over the course of our 2 year project, in each community we will establish and work with advisory committees, hire and train local researchers, conduct far (including a range of qualitative methods), and support action and advocacy. since the selected communities are diverse, the ways that the research unfolds will 1·ary between communities. expected outcomes, such as the provision of a written report and resources, the establishment of a website for networking among the communities, and a video do.:umentary, are aimed at supporting the research participants, coalition members, and advisory conuniuces in their action efforts. p2t 9 (c) health & housing: assessing the impact of transitional housing for people living with hiv i aids currently, there is a dearth of available literature which examines supporrive housing for phas in the canadian context. using qualitative, one-on-one interviews we investigace the impact of transitional housing for phaswho have lived in the up to nine month long hastings program. our post<'r pr<·senta-t1on will highlight research findings, as well as an examination of transitional housing and th<· imp;kt it has on the everyday lives of phas in canada. this research is one of two ground breaking undertakings within the province of ontario in which fife house is involved. p2-20 (c) eating our way to justice: widening grassroots approaches to food security, the stop community food centre as a working model charles l.evkoe food hanks in north america have come co play a central role as the widespread response to growing rates of hunger. originally thought to be a short term-solution, over the last 25 years, they have v62 poster sessions be · · · 1· d wi'thi'n society by filling the gaps in the social safety net while relieving govemcome mst1tut1ona 1ze . . . t f the ir responsibilities. dependent on corporate donations and sngmauzmg to users, food banks men so th' . ·11 i i . are incapable of addressing the structural cause~ of ~u~ger. 1s pres~ntation w1 e~~ ore a ternanve approaches to addressing urban food security while bmldmg more sustamabl.e c~mmumt1es. i:nrough the f t h st p community food centre, a toronto-based grassroots orgamzanon, a model is presented case 0 e 0 h'l k' b 'id · b that both responds to the emergency food needs of communities w 1 e wor mg to. u1 ~ sustama le and just food system. termed, the community food centre model. (cfc), ~he s~op is worki?g to widen its approach to issues of food insecurity by combining respectful ~1rect service wit~ com~~mty ~evelop ment, social justice and environmental sustainability. through this approach, various critical discourses around hunger converge with different strategic and varied implications for a~ion. as a plac~-based organization, the stop is rooted within a geographical space and connected directly to a neighbourhood. through working to increase access to healthy food, it is active in maintaining people's dignity, building a strong and democratic community and educating for social change. connected to coalitions and alliances, the stop is also active in organizing across scales in connection with the global food justice movement. inner city shelter vicky stergiopoulos, carolyn dewa, katherine rouleau, shawn yoder, and lorne tugg introduction: in the city of toronto there are more than 32,000 hostel users each year, many with mental health and addiction issues. although shelters have responded in various ways to the health needs of their clients, evidence on the effectiveness of programs delivering mental health services to the home· less in canada has been scant. the objective of this community based research was to provide a forma· tive evaluation of a multi-agency collaborative care team providing comprehensive care for high needs clients at toronto's largest shelter for homeless men. methods: a logic model provided the framework for analysis. a chart review of 56 clients referred over a nine month period was completed. demographic data were collected, and process and outcome indicators were identified for which data was obtained and analyzed. the two main outcome measures were mental status and housing status 6 months after referral to the program. improvement or lack of improvement in mental status was established by chart review and team consensus. housing outcomes were determined by chart review and the hostel databases. results: of the clients referred 75% were single and 98% were unemployed. forty four percent had a psychiatric hospitalization within the previous two years. the prevalence of severe and persistent men· tal illness, alcohol and substance use disorders were 60%, 26% and 37% respectively. six months after referral to the program 37% of clients had improved mental status and 41 % were housed. logistic regression controlling for the number of general practitioner and psychiatrist visits, presence of person· ality or substance use disorder and treatment non adherence identified two variables significantly associ· ated mental status improvement: the number of psychiatric visits (or, 1.92; 95% ci, 1.29-2.84) and treatment non adherence (or, 0.086; 95% ci, 0.01-0.78). the same two variables were associated with housing outcomes. history of forensic involvement, the presence of a personality or substance use disorder and the number of visits with a family physician were not significantly associated with either outcome. conclusions: despite the limitations in sample sire and study design, this study can yield useful informa· tion to program planners. our results suggest that strategies to improve treatment adherence and access to mental health specialists can improve outcomes for this population. although within primary care teams the appropriate collaborative care model for this population remains to be established, access to psychiatric follow up, in addition to psychiatric assessment services, may be an important component of a successful program. mount sinai hospital (msh) has become one of the pre-eminent hospitals in the world by contributing to the development of innovative approaches to effective health care and disease prevention. recently, the hospital has dedicated resources towards the development of a strategy aimed at enhancing the hospital's integration with its community partners. this approach will better serve the hospital in the current health care environment where local health integration networks have been struck to enhance and support local capacity to plan, coordinate and integrate service delivery. msh has had early success with developing partnerships. these alliances have been linked to programs serving key target populations with _estabhshe~. points of access to msh. recognizing the need to build upon these achievements to remain compe~mve, the hospital has developed a community integration strategy. at the forefront of this strategy is c.a.r.e (community advisory reference engine): the hospital's compendium of poster sessions v63 community partners. as a single point of access to community partner information, c.a.r.e. is more than a database. c.a.r.e. serves as the foundation for community-focused forecasting and a vehicle for inter and intra-organizational knowledge transfer. information gleaned from the catalog of community parmers can be used to prepare strategic, long-term partnership plans aimed at ensuring that a comprehensive array of services can be provided to the hospital community. c.a.r.e. also houses a permanent record of the hospital's alliances. this prevents administrative duplication and facilitates the formation of new alliances that best serve both the patient and the hospital. c.a.r.e. is not a stand-alone tool and is most powerful when combined with other aspects of the hospital's community integration strategy. it iscxpected that data from the hospital's community advisory committees and performance measurement department will also be stored alongside stakeholder details. this information can then be used to drive discussions at senior management and the board, ensuring congruence between stakeholder, patient and hospital objectives. the patient stands to benefit from this strategy. the unique, distinct point of reference to a wide array of community services provides case managers and discharge planners with the information they need to connect patients with appropriate community services. creating these linkages enhances the patient's capacity to convalesce in their homes or places of residence and fosters long-term connections to neighborhood supports. these connections can be used to assist with identifying patients' ongoing health care needs and potentially prevent readmission to hospital. introduction: recruiting high-risk drug users and sex workers for hiv-prevention research has often been hampered by limited access to hard to reach, socially stigmatized individuals. our recruitment effom have deployed ethnographic methodology to identify and target risk pockets. in particular, ethnographers have modeled their research on a street-outreach model, walking around with hiv-prevention materials and engaging in informal and structured conversations with local residents, and service providers, as well as self-identified drug users and sex workers. while such a methodology identifies people who feel comfortable engaging with outreach workers, it risks missing key connections with those who occupy the margins of even this marginal culture. methods: ethnographers formed a women's laundry group at a laundromat that had a central role as community switchboard and had previously functioned as a party location for the target population. the new manager helped the ethnographers invite women at high risk for hiv back into the space, this time as customers. during weekly laundry sessions, women initiated discussions about hiv-prevention, sexual health, and eventually, the vaccine research for which the center would be recruiting women. ra.its: the benefits of the group included reintroducing women to a familiar locale, this time as customers rather than unwelcome intruders; creating a span of time (wash and dry) to discuss issues important to me women and to gather data for future recruitment efforts; creating a location to meet women encountered during more traditional outreach research; establishing the site as a place for potential retention efforts; and supporting a local business. women who participated in the group completed a necessary household task while learning information that they could then bring back to the community, empowering them to be experts on hiv-prevention and vaccine research. some of these women now assist recruitment efforts. the challenges included keeping the group women-only, especially after lunch was provided, keeping the membership of the group focused on women at risk for hiv, and keeping the women in the group while they did their laundry. conclusion: public health educators and researchers can benefit from identifying alternate congregation sites within risk pockets to provide a comfortable space to discuss hiv prevention issues with high-risk community members. in our presentation, we will describe the context necessary for similar research, document the method's pitfalls and successes, and argue that the laundry group constitutes an ethical, respectful, community-based method for recruitment in an hiv-prevention vaccine trial. p3-0t (c) upgrading inner city infrastructure and services for improved environmental hygiene and health: a case of mirzapur in u.p. india madhusree mazumdar in urgency for agricultural and industrial progress to promote economic d.evelopment follo_wing independence, the government of india had neglected health promotion and given less emphasis on infrastructure to promote public health for enhanced human pro uct1v_ity. ong wit r~p1 m astrucrure development, which has become essential if citie~ are to. act ~s harbmger.s of econ~nuc ~owth, especially after the adoption of the economic liberalization policy, importance _is a_lso ~emg g1ve.n to foster environmental hygiene for preventive healthcare. the world health orga~1sat10~ is also trj:'1!1g to help the government to build a lobby at the local level for the purpose by off~rmg to mrroduce_ its heal.thy city concept to improve public health conditions, so as to reduce th_e disease burden. this pape~ 1s a report of the efforts being made towards such a goal: the paper descr~bes ~ c~se study ?f ~ small city of india called mirzapur, located on the banks of the nver ganga, a ma1or lifeline of india, m the eastern part of the state of uttar pradesh, where action for improvement began by building better sanitation and environmental infrastructure as per the ganga action plan, but continued with an effort to promote pre· ventive healthcare for overall social development through community participation in and around the city. asthma physician visits in toronto, canada tara burra, rahim moineddin, mohammad agha, and richard glazier introduction: air pollution and socio-economic status are both known to be associated with asthma in concentrated urban settings but little is known about the relationship between these factors. this study investigates socio-economic variation in ambulatory physician consultations for asthma and assesses possible effect modification of socio-economic status on the association between physician visits and ambient air pollution levels for children aged 1 to 17 and adults aged 18 to 64 in toronto, canada between 1992 and 2001. methods: generalized additive models were used to estimate the adjusted relative risk of asthma physician visits associated with an interquartile range increase in sulphur dioxide, nitrogen dioxide, pm2.5, and ozone, respectively. results: a consistent socio-economic gradient in the number of physician visits was observed among children and adults and both sexes. positive associations between ambient concentrations of sul· phur dioxide, nitrogen dioxide and pm2.5 and physician visits were observed across age and sex strata, whereas the associations with ozone were negative. the relative risk estimates for the low socio-«onomic group were not significantly greater than those for the high socio-economic group. conclusions: these findings suggest that increased ambulatory physician visits represent another component of the public health impact of exposure to urban air pollution. further, these results did not identify an age, sex, or socio-economic subgroup in which the association between physician visits and air pollution was significantly stronger than in any other population subgroup. eco-life-center (ela) in albania supports a holistic approach to justice, recognizing the environ· mental justice, social justice and economic justice depend upon and support each other. low income cit· izens and minorities suffer disproportionately from environmental hazards in the workplace, at home, and in their communities. inadequate laws, lax enforcement of existing environmental regulations, and ~ea.k penalties for infractions undermine environmental protection. in the last decade, the environmental 1ust1ce m~ve~ent in tirana metropolis has provided a framework for identifying and exposing the links ~tween irrational development practices, disproportionate siting of toxic facilities, economic depres· s1on, and a diminished quality of life in low-income communities and communities of color. the envi· ~onmental justice agenda has always been rooted in economic, racial, and social justice. tirana and the issues su.rroun~ing brow~fields redevelopment are crucial points of advocacy and activism for creating ~ubstantia~ social chan~~ m low-income communities and communities of color. we engaging intensively m prevcnnng co'.'1mumnes, especially low income or minority communities, from being coerced by gov· ernmenta~ age_nc1es or companies into siting hazardous materials, or accepting environmentally hazard· ous_ practices m order to create jobs. although environmental regulations do now exist to address the environmental, health, and social impacts of undesirable land uses, these regulations are difficult to poster sessions v65 enforce because many of these sites have been toxic-ridden for many years and investigation and cleanup of these sites can be expensive. removing health risks must be the main priority of all brown fields action plans. environmental health hazards are disproportionately concentrated in low-income communities of color. policy requirements and enforcement mechanisms to safeguard environmental health should be strengthened for all brownfields projects located in these communities. if sites are potentially endangering the health of the community, all efforts should be made for site remediation to be carried out to the highest cleanup standards possible towards the removal of this risk. the assurance of the health of the community should take precedence over any other benefits, economic or otherwise, expected to result from brownfields redevelopment. it's important to require from companies to observe a "good neighbor" policy that includes on-site visitations by a community watchdog committee, and the appointment of a neighborhood environmentalist to their board of directors in accordance with the environmental principles. vancouver 1976-2001 michael buzzelli, jason su, and nhu le this is the second paper of research programme concerned with the geographical patterning of environmental and population health at the urban neighbourhood scale. based on the vancouver metropolitan region, the aim is to better understand the role of neighbourhoods as epidemiological spaces where environmental and social characteristics combine as health processes and outcomes at the community and individual levels. this paper builds a cohort of commensurate neighbourhoods across all six censuses periods from 1976 to 2001, assembles neighbourhood air pollution data (several criterion/health effects pollutants), and providing an analysis to demonstrate how air pollution systematically and consistently maps onto neighbourhood socioeconomic markers, in this case low education and lone-parent families. we conclude with a discussion of how the neighbourhood cohort can be further developed to address emergent priorities in the population and environmental health literatures, namely the need for temporally matched data, a lifecourse approach, and analyses that control for spatial scale effects. solid waste management and environment in mumbai (india) by uttam jakoji sonkamble and bairam paswan abstract: mumbi is the individual financial capital of india. the population of greater mumbai is 3,326,837 and 437 sq. km. area. the density of population 21, 190 per sq. km. the dayto-day administration and rendering of public services within gr. mumbai is provided by the brihan mumbai mahanagar palika (mumbai corporation of gr. mumbai) that is a body of 221 elected councilors on a 5-year team. mumcial corporation provides varies conservancy services such as street sweeping, collection of solid waste, removal and transportation, disposal of solid waste, disposal of dead bodies of animals, construction, maintance and cleaning of urinals and public sanitary conveniences. the solid waste becoming complicated due to increase in unplanned urbanization and industrialization, the environment has deteriorated significantly due to inter, intra and international migration stream to mumbai. the volume of inter state migration to mumbai is considerably high i.e. 20.89 lakh and international migrant 0.77 lakh have migrated to mumbai. present paper gives the view on solid waste management and its implications to environment and health. pollution from a wide varity of emission, such as from automobiles and industrial activities, has reached critical level in mumbai, causing respiratory, ocular, water born diseases and other health problems. sources of generation of waste are -household waste, commercial waste, institutional waste, street sweeping, silt removed from drain/nallah/cleanings. disposal of solid waste in gr. mumbai done under 1 incineration 2. processing to produce organic manure. 3. vermi-composting 4. landfill the study shows that the quantity of waste disposal of through processing and conversion to organic ~anure is about 200-240 m.t. per day. the processing is done by a private agency m/s excel industries ltd. who had set up a plant at the chincholi dumping ground in western mumbai for this purpose. the corporation is also disposal a plant of its waste mainly market waste through the environment friendly, natural pro-ces~ known as vermi-composing about 100 m.t. of market waste is disposed of in this manner at the various sites. there are four land fill sites are available and 95 percent of the waste matter generated m mumbai is disposed of through landfill. continuous flow of migrant and increa~e in slum population is a complex barrier in the solid waste management whenever community pamc1pat1on work strongly than only we can achieved eco-friendly environment in mumbai. persons exposed to residential craffic have elevated races of respiratory morbidity an~ ~ortality. since poverty is an important determinant of ill-health, some h~ve argued that t~es~ assoc1at1ons may relate to che lower socioeconomic status of those living along ma1or roads. our ob1ect1ve was to evaluate the association between traffic intensity at home and hospital admissions for respiratory diagnoses among montreal residents older than 60 years. morning peak traffic estimates from the emmej2 montreal traffic model (motrem98) were used as an indicator of exposure to road traffic outside the homes of those hospitalised. the influence of socioeconomic status on the relationship between traffic intensity and hospital admissions for respiratory diagnoses was explored through assessment of confounding by lodging value, expressed as the dollar average over road segments. this indicator of socioeconomic status, as calculated from the montreal property assessment database, is available at a finer geographic scale than socioeconomic information accessible from the canadian census. there was an inverse relationship between traffic intensity estimates and lodging values for those hospitalised (rho -0.23, p 3160 vehicles during che 3 hour morning peak), even after adjustment for lodging value (crude or 1.35, cl95% 1.22-1.49; adjusted or 1.13, cl95% 1.02-1.25). in montreal, elderly persons living along major roads are at higher risk of being hospitalised for respiratory illnesses, which appears not simply to reflect the fact that those living along major roads are at relative economic disadvantage. the paper argues that human beings ought to be at the centre of the concern for sustainable development. while acknowledging the importance of protecting natural resources and the ecosystem in order to secure long term global sustainability, the paper maintain that the proper starting point in the quest for urban sustainability in africa is the 'brown agenda' to improve che living and working environment of che people, especially che urban poor who face a more immediate environmental threat to their health and well-being. as the un-habitat has rightly observed, it is absolutely essential "to ensure that all people have a sufficient stake in the present to motivate them to take part in the struggle to secure the future for humanity.~ the human development approach calls for rethinking and broadening the narrow technical focus of conventional town planning and urban management in order to incorporate the emerging new ideas and principles of urban health and sustainability. i will examine how cities in sub-saharan africa have developed over the last fifty years; the extent to which government policies and programmes have facilitated or constrained urban growth, and the strategies needed to achieve better functioning, safer and more inclusive cities. in this regard i will explore insights from the united nations conferences of the 1990s, especially local agenda 21 of the rio summit, and the istanbul declaration/habitat agenda, paying particular attention to the principles of enablement, decentralization and partnership canvassed by these movements. also, i will consider the contributions of the various global initiatives especially the cities alliance for cities without slums sponsored by the world bank and other partners; che sustainable cities programme, the global campaigns for good governance and for secure tenure canvassed by unhabit at, the healthy cities programme promoted by who, and so on. the concluding section will reflect on the future of the african city; what form it will take, and how to bring about the changes needed to make the cities healthier, more productive and equitable, and better able to meet people's needs. heather jones-otazo, john clarke, donald cole, and miriam diamond urban areas, as centers of population and resource consumption, have elevated emissions and concentrations of a wide range of chemical contaminants. we have developed a modeling framework in which we first ~stimate the emissions and transport of contaminants in a city and second, use these estimates along with measured contaminant concentrations in food, to estimate the potential health risk posed by these che.micals. the latter is accomplished using risk assessment. we applied our modeling framework to consider two groups of chemical contaminants, polycyclic aromatic hydrocarbons (pah) a.nd the flame re~ardants polybrominated diphenyl ethers (pbde). pah originate from vehicles and stationary combustion sources. ~veral pah are potent carcinogens and some compounds also cause noncancer effects. pbdes are additive flame retardants used in polyurethane foams (e.g., car seats, furniture) 105fer sessions v67 and cl~ equipm~nt (e.g., compute~~· televisio~s). two out of three pbdes formulations are being voluntarily phased by mdustry due to rmng levels m human tissues and their world-wide distribution. pbdes have been .related to adv.erse neurological, developmental and reproductive effects in laboratory ijlimals. we apphed our modelmg framework to the city of toronto where we considered the southcattral area of 21 by 21 km that has a population of 1.3 million. for pah, local vehicle traffic and area sources contribute at least half of total pah in toronto. local contributions to pbdes range from 57-85%, depending on the assumptions made. air concentrations of both compounds are about 10 times higher downtown than 80 km north of toronto. although measured pah concentrations in food date to the 1980s, we estimate that the greatest exposure and contribution to lifetime cancer risk comes from ingestion of infant formula, which is consistent with toxicological evidence. the next greatest exposure and cancer risk are attributable to eating animal products (e.g. milk, eggs, fish). breathing downtown air contributes an additional 10 percent to one's lifetime cancer risk. eating vegetables from a home garden localed downtown contributes negligibly to exposure and risk. for pbdes, the greatest lifetime exposure comes through breast milk (we did not have data for infant formula), followed by ingestion of dust by the toddler and infant. these results suggest strategies to mitigate exposure and health risk. p4-01 (a) immigration and socioeconomic inequalities in cervical cancer screening in toronto, canada aisha lofters, rahim moineddin, maria creatore, mohammad agha, and richard glazier llltroduction: pap smears are recommended for cervical cancer screening from the onset of sexual activity to age 69. socioeconomic and ethnoracial gradients in self-reported cervical cancer screening have been documented in north america but there have been few direct measures of pap smear use among immigrants or other socially disadvantaged groups. our purpose was to investigate whether immigration and socioeconomic factors are related to cervical cancer screening in toronto, canada. methods: pap smears were identified using fee codes and laboratory codes in ontario physician service claims (ohip) for three years starting in 1999 for women age 18-41 and 42-66. all women with any health system contact during the three years were used as the denominator. social and economic factors were derived from the 2001 canadian census for census tracts and divided into quintiles of roughly equal population. recent registrants, over 80% of whom are expected to be recent immigrants to canada, were identified as women who first registered for health coverage in ontario after january 1, 1993. results: among 397,967 women age 18-41 and 328,885 women age 42-66, 55.3% and 55.5%, rtspcctively, had pap smears within three years. low income, low education, recent immigration, visible minority and non-english language were all associated with lower rates (least advantaged quintile:most advantaged quintile rate ratios were 0.84, 0.90, 0.81, 0.85, 0.83, respectively, p < 0.05 for all). similar gradients were found in both age groups. recent registrants comprised 22.5% of women and had mm;h lower pap smear rates than non-recent registrants (37.2 % versus 63. 7% for women age 18-41 and 35.9% versus 58.2% for women age 42-66). conclnsions: pap smear rates in toronto fall well below those dictated by evidence-based practice. at the area level, immigration, visible minority, language and socioeconomic characteristics are associated with pap smear rates. recent registrants, representing a largely immigrant group, have particularly low rates. efforts to improve coverage of cervical cancer screening need to be directed to all ~omen, their providers and the health system but with special emphasis on women who recently arrived m ontario and those with social and economic disadvantage. challeges faced: a) most of the resources are now being ~pent in ~reventing the sprea.d of hiv/ aids and maintaining the lives of those already affected. b) skilled medical ~rs~nal are dymg under· mining the capacity to provide the required health care services. ~) th.e comphcat1o~s of hiv/aids has complicated the treatment of other diseases e.g. tbs d) the ep1dem1c has led. to mcrease number of h n requiring care and support. this has further stretched the resources available for health care. orp a s d db . . i methods used on our research: 1. a simple community survey con ucte y our orgamzat1on vo · unteers in three urban centres members of the community, workers and health care prov~ders were interviewed ... 2. meeting/discussions were organized in hospitals, commun.ity centre a~d with government officials ... 3. written questionnaires to health workers, doctors and pohcy makers m th.e health sectors. lessors learning: • the biggest-health bigger-go towards hiv/aids prevention • aids are spreading faster in those families which are poor and without education. •women are the most affected. •all health facilities are usually overcrowded with hiv/aids patients. actions needed:• community education oh how to prevent the spread of hiv/aids • hiv/aids testing need to be encouraged to detect early infections for proper medical cover. • people to eat healthy • people should avoid drugs. implications of our research: community members and civic society-introduction of home based care programs to take care of the sick who cannot get a space in the overcrowded public hospitals. prl-v a te sector private sector has established programs to support and care for the staff already affected. government provision of support to care-givers, in terms of resources and finances. training more health workers. introduction: australian prisons contain in excess of 23,000 prisoners. as in most other western countries, reliance on 'deprivation of liberty' is increasing. prisoner numbers are increasing at 7% per annum; incarceration of women has doubled in the last ten years. the impacts on the community are great -4% of children have a parent in custody before their 16th birthday. for aboriginal communities, the harm is greater -aboriginal and/or torres strait islanders are incarcerated at a rate ten times higher than other australians. 25% of their children have a parent in custody before their 16th birthday. australian prisons operate under state and territory jurisdictions, there being no federal prison system. eight independent health systems, supporting the eight custodial systems, have evolved. this variability provides an unique opportunity to assess the capacity of these health providers in addressing the very high service needs of prisoners. results: five models of health service provision are identified -four of which operate in one form or another in australia: • provided by the custodial authority (queensland and western australia)• pro· vided by the health ministry through a secondary agent (south australia, the australian capital territory and tasmania) • provided through tendered contract by a private organization (victoria and northern territory) • provided by an independent health authority (new south wales) • (provided by medics as an integral component of the custodial enterprise) since 1991 the model of the independent health authority has developed in new south wales. the health needs of the prisoner population have been quantified, and attempts are being made to quantify specific health risks /benefits of incarceration. specific enquiry has been conducted into prisoner attitudes to their health care, including issues such as client information confidentiality and access to health services. specific reference will be made to: • two inmate health surveys • two inmate access surveys, and • two service demand studies. conclusions: the model of care provision, with legislative, ethical, funding and operational independence would seem provide the best opportunity to define and then respond to the health needs of prisoners. this model is being adopted in the united kingdom. better health outcomes in this high-risk group, could translate into healthier families and their communities. p4-04 (a) lnregrated ethnic-specific health care systems: their development and role in increasing access to and quality of care for marginalized ethnic minorities joshua yang introduction: changing demographics in urban areas globally have resulted in urban health systems that are racially and ethnically homogenous relative to the patient populations they aim to serve. the resultant disparities in access to and quality of health care experienced by ethnic minority groups have been addressed by short-term, instirutional level strategies. noticeably absent, however, have been structural approaches to reducing culturally-rooted disparities in health care. the development of ethnic-specific h~alth car~ systems i~ a structural, long-term approach to reducing barriers to quality health care for eth· me mmonty populations. methods: this work is based on a qualitative study on the health care experiences of san francisco chinatown in the united states, an ethnic community with a model ethnic-specific health care infrastrucrure. using snowball sampling, interviews were conducted with key stakeholders and archival research was conducted to trace and model the developmental process that led to the current ethnic-specific health care system available to the chinese in san francisco. grounded theory was the methodology ijltd to analysis of qualitative data. the result of the study is four-stage developmental model of ethnic-specific health infrastrueture development that emerged from the data. the first stage of development is the creation of the human capital resources needed for an ethnic-specific health infrastructure, with emphasis on a bilingual and bicultural health care workforce. the second stage is the effective organization of health care resources for maximal access by constituents. the third is the strengthening and stability of those institutional forms through increased organizational capacity. integration of the ethnic-specific health care system into the mainstream health care infrastructure is the final stage of development for an ethnic-specific infrastructure. conclusion: integrated ethnic-specific health care systems are an effective, long-term strategy to address the linguistic and cultural barriers that are being faced by the spectrum of ethnic populations in urban areas, acting as culturally appropriate points of access to the mainstream health care system. the model presented is a roadmap to empower ethnic communities to act on the constraints of their health and political environments to improve their health care experiences. at a policy level, ethnic-specific health care organizations are an effective long-term strategy to increase access to care and improve qualiiy of care for marginalized ethnic groups. each stage of the model serves as a target area for policy interventions to address the access and care issues faced by culturally and linguistically diverse populations. users in baltimore md: 1989-2004 noya galai, gregory lucas, peter o'driscoll, david celentano, david vlahov, gregory kirk, and shruti mehta introduction: frequent use of emergency rooms (er) and hospitalizations among injection drug users (idus) has been reported and has often been attributed to lack of access to primary health care. however, there is little longitudinal data which examine health care utilization over individual drug use careers. we examined factors associated with hospitalizations, er and outpatient (op) visits among idus over 14 years of follow-up. methods: idus were recruited through community outreach into the aids link to lntravenous experience (alive) study and followed semi-annually. 2,551 who had at least 2 follow-up visits were included in this analysis. outcomes were self-reported episodes of hospitalizations and er/op visits in the prior six months. poisson regression was used accounting for intra-person correlation with generalized estimation equations. hits: at enrollment, 73% were male, 95% were african-american, 33% were hiv positive, median age was 35 years, and median duration of drug use was 15 years. over a total of 37,512 visits, mean individual rates of utilization were 11 per 100 person years (py) for hospitalizations and 123 per 100 py for er/op visits. adjusting for age and duration of drug use, factors significantly associated with higher rates of hospitalization included hiv infection (relative incidence [ri(, 1.4), female gender (ri, 1.2), homelessness (ri, 1.6), as well as not being employed, injecting at least daily, snorting heroin, havmg a regular source of health care, having health insurance and being in methadone mainte.nance treatment (mmt). similar associations were observed for er/op visits except for mmt which was not associated with er/op visits. additional factors associated with lower er/op visits were use of alcohol, crack, injecting at least daily and trading sex for drugs. 10% of the cohort accounted for 45% of total er/op visits, while 11 % of the cohort never reported an op visit during follow-up. . . . lgbt) populations. we hypothesized that prov1dmg .appomtments .for p~t1~nts w1thm 24 hours would ensure timely care, increase patient satisfaction, and improve practice eff1c1ency. further, we anticipated that the greatest change would occur amongst our homeless patients.. . methods: we tested an experimental introduction of advanced access scheduling (usmg a 24 hour rule) in the primary care medical clinic. we tracked variables inclu~ing waiting ti~e fo~ next available appointment; number of patients seen; and no-show rates, for an eight week penod pnor to and post introduction of the new scheduling system. both patient and provider satisfaction were assessed using a brief survey (2 questions rated on a 5-pt scale). results and conclusion: preliminary analyses demonstrated shorter waiting times for appointments across the clinic, decreased no-show rates, and increased clinic capacity. introduction of the advanced access scheduling also increased both patient and provider satisfaction. the new scheduling was initiated in july 2005. quantitative analyses to measure initial and sustained changes, and to look at differential responses across populations within our clinic, are currently underway. introduction: there are three recognized approaches to linking socio-economic factors and health: use of census data, gis-based measures of accessibility/availability, and resident self-reported opinion on neighborhood conditions. this research project is primarily concerned with residents' views about their neighborhoods, identifying problems, and proposing policy changes to address them. the other two techniques will be used in future research to build a more comprehensive image of neighborhood depri· vation and health. methods: a telephone survey of 658 london, ontario residents is currently being conducted to assess: a) community resource availability, quality, access and use, b) participation in neighborhood activities, c) perceived quality of neighborhood, d) neighborhood problems, and e) neighborhood cohesion. the survey instrument is composed of indices and scales previously validated and adapted to reflect london specifically. thirty city planning districts are used to define neighborhoods. the sample size for each neighborhood reflects the size of the planning district. responses will be compared within and across neighborhoods. data will be linked with census information to study variation across socio-eco· nomic and demographic groups. linear and gis-based methods will be used for analysis. preliminary results: the survey follows a qualitative study providing a first look at how experts involved in community resource planning and administration and city residents perceive the availability, accessibility, and quality of community resources linked to neighborhood health and wellbeing, and what are the most immediate needs that should be addressed. key-informant interviews and focus groups were used. the survey was pre-tested to ensure that the language and content reflects real experiences of city residents. the qualitative research confirmed our hypothesis that planning districts are an acceptable surrogate for neighborhood, and that the language and content of the survey is appropriate for imple· mentation in london. scales and indices showed good to excellent reliability and validity during the pre· test (cronbach's alpha from 0.57-0.96). preliminary results of the survey will be detailed at the conference. conclusions: this study will help assess where community resources are lacking or need improve· ment, thus contributing to a more effective allocation of public funds. it is also hypothesized that engaged neighborhoods with a well-developed sense of community are more likely to respond to health programs and interventions. it is hoped that this study will allow london residents to better understand the needs and problems of their neighborhoods and provide a research foundation to support local understandmg of community improvement with the goal of promoting healthy neighborhoods. p4-08 (a) hiv positive in new york city and no outpatient care: who and why? hannah wolfe and victoria sharp introduction: there are approximately 1 million hiv positive individuals living in the united sta!es. about. 50% of these know their hiy status and are enrolled in outpatient care. of the remaining 50 yo, approx~mately half do not know their status; the other group frequently know their status but are not enrolled m any .sys~em of outpatient care. this group primarily accesses care through emergency departments. when md1cated, they are admitted to hospitals, receive acute care services and then, upon poster sessions v71 di5'harge, disappear from the health care system until a new crisis occurs, when they return to the emergency department. as a large urban hiv center, caring for over 3000 individuals with hiv we have an active inpatient service ".'ith appr~xi~.ately 1800 discharges annually. we decided to survey our inpatients to better charactenze those md1v1duals who were not enrolled in any system of outpatient care. results: 18% of inpatients were not enrolled in regular outpatient care: 2% at roosevelt hospital and 35% at st.luke\'s hospital. substance abuse and homelessness were highly prevalent in the cohort of patients not enrolled in regular outpatient care. 84% of patients not in care (vs. 33% of those in care) were deemed in need of substance use treatment by the inpatient social worker. 74% of those not in care were homeless (vs. 15% of those in care.) patients not in care did not differ significantly from those in me in terms of age, race, or gender. patients not in care were asked "why not:" the two most frequent responses were: "i haven't really been sick before" and "i'd rather not think about my health. conclusions: this study suggests that there is an opportunity to engage these patients during their stay on the inpatient units and attempt to enroll them in outpatient care. simple referral to an hiv clinic is insufficient, particularly given the burden of homelessness and substance use in this population. efforts are currently underway to design an intervention to focus efforts on this group of patients. p4.q9 (a) healthcare availability and accessibility in an urban area: the case of ibadan city, nigeria in oder to cater for the healthcare need of the populace, for many years after nigeria's politicl independence, empphasis was laid on the construction of teaching, general, and specialist hospital all of which were located in the urban centres. the realisation of the inadequacies of this approach in adequately meeting the healthcare needs of the people made the country to change and adopt the primary health care (phc) system in 1986. the primary health care system which is in line with the alma ata declaration of of 1978, wsa aimed at making health care available to as many people as possible on the basis of of equity and social justice. thus, close to two decades, nigeria has operated primary health care system as a strategy for providing health care for rural and urban dwellers. this study focusing on urban area, examimes the availabilty and accessibility of health care in one of nigeria's urban centre, ibadan city to be specific. this is done within the contest of the country's national heath policy of which pimary health care is the main thrust. the study also offers necessary suggestion for policy consideration. in spite of the accessibility to services provided by educated and trained midwifes in many parts of fars province (iran) there are still some deliveries conducted by untrained traditional birth attendants in rural parts of the province. as a result, a considerable proportion of deliveries are conducted under a higher risk due to unauthorised and uneducated attendants. this study has conducted to reveal the pro· portion of deliveries with un-authorized attendants and some spatial and social factors affecting the selection of delivery attendants. method: this study using a case control design compared some potentially effective parameters indud· ing: spatial, social and educational factors of mothers with deliveries attended by traditional midwifes (n=244) with those assisted by educated and trained midwifes (n=258). the mothers interviewed in our study were selected from rural areas using a cluster sampling method considering each village as a cluster. results: more than 11 % of deliveries in the rural area were assisted by traditional midwifes. there are significant direct relationship between asking a traditional birth attendant for delivery and mother age, the number of previous deliveries and distance to a health facility provided for delivery. significant inverse relationships were found between mother's education and ability to use a vehicle to get to the facilities. conclusion: despite the accessibility of mothers to educated birth attendants and health facilities (according to the government health standards), some mothers still tend to ask traditional birth attendants for help. this is partly because of unrealistic definition of accessibility. the other considerable point is the preference of the traditional attendants for older and less educated mothers showing the necessity of changing theirs knowledge and attitude to understand the risks of deliveries attended by traditional and un-educated midwifes. p4-12 (a) identification and optimization of service patterns provided by assertive community treatment teams in a major urban setting: preliminary findings &om toronto, canada jonathan weyman, peter gozdyra, margaret gehrs, daniela sota, and richard glazier objective: assertive community treatment (act) teams are financed by the ontario ministry of health and long-term care (mohltc) and are mandated to provide treatment, rehabilitation and support services in the community to people with severe and persistent mental illness. there are 13 such teams located in various regions across the city of toronto conducting home visits 1-5 times per week to each of their approximately 80 respective clients. each team consists of multidisciplinary health professionals who assist clients to identify their needs, establish goals and work toward them. due to complex referral patterns, the need for service continuity and the locations of supportive housing, clients of any one team are often found scattered across the city which increases home visit travel times and decreases efficiency of service provision. this project examines the locations of clients in relation to the home bases of all 13 act teams and identifies options for overcoming the geographical challenges which arise in a large urban setting. methods: using geographic information systems (gis) we geocoded all client and act agency addresses and depicted them on location maps. at a later stage using spatial methods of network analysis we plan to calculate average travel rimes for each act team, propose optimization of catchment areas and assess potential travel time savings. resnlts: initial results show a substantial scattering of clients from several act teams and substan· rial overlap of visit travel routes for most teams. conclusions: reallocation of catchment areas and optimization of act teams' travel patterns should lead to substantial savings in travel times, increased service efficiency and better utilization of resourc_~· ~e l'<!tenri~i modifications to catchment areas must be conducted with appropriate attention to specific clients servtce needs, service continuity and applicable regulations by the mohl tc. venice lido is a popular island within and outside italy because it hosts the international cinema festival yearly. only few people remember the island for its hospital, which, in the fifties, was one of the most important hospitals in italy and in europe, being a modern center for wind-, sun-and thermal-therapy. since the sixties, its fame became to drop away, since its structure was no longer adequate for the evolving medicine science. at the end of the seventies all the wards were moved into a new big building in the same area. at present the hospital is made up by about forty 'pavilions' (mostly partially used or empty) and a big building, disseminated in a 10 hectares area, on the sea front, on the 500 m long beach. the aim of my research is to suggest a realistic solution, sustainable on the functional use of the area according to basic local needs and economically realizable. i used a philological and multi-disciplinary method, more in detail: -from historical documents, i found what was the very first call of the property and how it adapted to the needs of the demographic development and the sanitary supply over time; -by contacting some operators from different fields, i realized which functions were suitable to the buildings in existence, to the population's needs and to the present sanitary supply. moreover the planning idea considers: -the debate going on between local people who strongly want to preserve the property, and die ones who want to renew it by different new opportunities; and -the regional sanitary politics, aiming at rationalizing the regional hospitals dislocation, and the budget needs. this plan analyzes and proposes some new alternative solutions to satisfy different needs. the different activities will be dealt out and the environmental fall will be limited as much as possible. after having analyzed its basic call, considered its environmental peculiarities and its position, verified the emerging needs of the local population, the plan proposes 5 different activities: the hospital; the social-rehabilitation center; the elderly house; the thermal center; the residential center; and other activities. such a plan wants to share in the solution of a basic problem by giving architectonic and functional dignity to an historical completely degraded area and by starting again a social-economical broken off process, by bringing in venice lido some fresh necessary elements for its so wished new throw. p4-14 (c) dilemma of free health care in spokane, wa david bunting introduction: the paper reports on the activities of project access spokane [pas], a physician sponsored initiative to provide uncompensated health care to low income, uninsured residents of spokane county wa. program providers included all county hospitals, over 600 physicians, other medical professionals, and specialized clinics. each prescription requires only a $4 co-payment. sponsored and administered by the county medical society, pas is funded by local and national foundations, private corporations, municipalities, civic organizations and individuals. method: the paper is based on a first year assessment report funded by pas, using hcfa [health care financing administration] insurance claim data documenting utilization rates, disease categories and donated charge information and patient cares [centralized applications, referrals and enrollment status) data. results: while essentially free for enrollees, the program involved real costs. an administrative organization to refer over 700 patients to any of over 800 providers had to be developed and staffed, using both paid and unpaid personnel. methods to identify potential patients and veri.fy eligibility. had to ~devised. patient appointments and transportation had to be scheduled and monitored. pu~hc relanons, provider solicitations and fundraising activities were continuous. information requirements regarding program operation were also significant. data reporting the volume. ~nd value of dona~ed medical services were necessary to demonstrate accomplishments and attr~ct addmon~l support. providers required assurances their contributions were both significant and eqmtable. funding sources sought evidence that their support had important consequences. however, generating this ~~ta proved difficult. many providers failed to submit appropriate insurance claims forms because .of a~dmonal donated effort and administrative cost, thereby not only reducing their own apparent conmbut1ons but also the overall significance of the program. conclusions: during its initial year, the estimated cost to deliver free health care was ~bout 5500 per enrollee. the lesson is that without an elaborate administrative structure and record keeping s.yst~~· efforts to provide free health care probably will fail. eligible enrollees c~n not be ~parated from in~hgi ble ones, care will not be accessed or delivered in an efficient manner, neither fundmg nor ~upport "". 1 11 be offered without evidence of tangible benefits, and providers will withdraw if they perceive mequ1table tteannent. v74 p4-1s (c) mobility in prostitution and the impact of health therese van der helm and henk sulman poster sessions introduction: many of the estimated 8.000 commer~ial ~ex wor~ers (c~w)in a'.'1~terdam ~~me from developing countries and eastern europe. to gain ins~ght mto their workmg and_ hvmg condinons the intermediary project (ip) at the municipal health serv1~e _contacts these women via ?utreach work on regular basis. since the new brothel law in october 2000 1s 1~troduc~d, ~sw ~rom outside the eu and who have no dutch residence permit are not allowed to work m prost1tut10n. smee then, many of these csw therefore have gone "underground." the consequences of the new law in the netherlands will be discussed with regard to the accessibility of csw and their risk for stl/hiv acquisition and unplanned pregnancies. methods: topics during outreach work are the interventions to increase the knowledge of safe sex and birth control for csw. written information is handed out in relevant languages and with addresses of health and social services. in conversations with the women, it appeared that many are not aware of these services. to provide easier access to health care for women, staff of the ip carries out free sti control csw working places, in windows brothels and sex houses. also, women are offered vaccination against hepatitis b (hbv). results: from january 2004 till july 2005 we approached 900 csw for first contact. one third was dutch; others were from developing countries, other eu countries and eastern europe. 350 sti consul· rations were done among non-iv drug using sex workers, of whom 50 % was dutch. of these, 2 % was diagnosed with syphilis, 1 % with gonorrhea, and 9% with chlamydia. of 234 women tested for hiv, none were infected. due to the high turnover of csw in .brothels, most wnmen were tested only once. among 845 csw tested for hbv -of whom one third is dutch -22 % had antibodies for hbv, 12 were carrier of hbv, most of whom came from hbv endemic areas. conclusions: sti control and hbv vaccination in brothels is an important support in health care. our findings suggest that csw do not play an important role in the transmission of sti. many csw are highly mobile and often not aware of the existing health and social services. continuous outreach is important to remain in contact with this mobile population. regulations in the new brothel law should not hamper contacts with (illegal) csw. heart disease (cho) is projected to become the leading cause of death. studies conducted in europe and the united states have proven a higher rate of cho in south asians who have migrated from south asia, most notably india, pakistan and bangladesh. approximately 50% of all heart attacks among south asian men occur under the age of 55; 25% of them occur under the age of 40-unheard of in any other population. associated risk factors such as diabetes, high blood pressure and cholesterol are also com· mon in this group. the population of south asians residing in nyc has more than doubled over the past decade to over 300,000, the majority being young, working-class and with limited health care access. many south asian men are employed as taxi drivers (4 out of 10 nyc taxi drivers are from south asial, working daily12 hour plus shifts. methods: acknowledging that this vulnerable, at-risk group was unavailable for outreach through conventional venues, three of the hospitals of the new york city health and hospital corporation, (elmhurst, queens and bellevue) conducted a one day outreach effort at nyc's jfk international air· ~rt's taxi holdin~ ar~a, ~here over one thousand taxis regularly assemble. bringing an outreach event directly to the taxi dnvers workplace, a tent was set up where cardiovascular-related health screenings, in~luding bl~ pressure, sugar, cholesterol, body mass index (bmi), were provided. results were shared with and explamed to the drivers and each participant received a south asian health education brochure. a total of 84 taxi drivers who identified as south asian were involved. rau/ts: participants were all male, ranging from 20 to 61 years; mean age, 41.5. screenings revealed 57% hypertensive; 46% had cholesterols over 200; 26% blood glucose over 160; 91 % had a bmi greater than 25. conc~on: a unique outreach activity, adapting to logistical, occupational limitations, is pre· se~ted. on-site f~back and explanation of results, reiterating and reinforcing the concern that south asia~. men are at mcreased danger for early coronary heart disease, and the dissemination of a culturally sensmve and r~levant brochure, may heighten awareness of prevailing cardiac risk factors in this immi· grant community. p4-17 (c) the community-hospital integration program framework: community-hospital panoenhips to improve the population's health john stevenson, richard blickstead, ann-marie marcolin, and sandi kendal v75 introduction: st. josephs health centre is a catholic community teaching hospital located in the heart of southwest toronto. st. joseph\'s was founded from a community-expressed need for hospital services, and since then has stayed committed to fostering a healthy community through collaboration and parmership. st. joseph's has developed an innovative model, the community-hospital integration program (chip), to strengthen st. joseph's partnerships with community stakeholders, and facilitates the building of links between community needs, service provision, and public policy outcomes to improve the health and wellness of the diverse neighbourhoods they together serve. methods: development of the chip framework st. joseph's health centre developed the chip framework through a multidisciplinary approach that included extensive international literature reviews, consultations, and key informant interviews with community service agencies and academics. to ensure active community voice, st. joseph's has hosted a number of community consultations including a community outreach forum attended by over ninety representatives from 68 community partners. results: the chip framework the chip framework aims to improve the health and wellness of the urban communities served by st. josephs health centre through four intersecting pillars: • raising community voices provides an infrastructure and process that supports community stakeholder input into health care service planning, decision-making, and delivery by the hospital and across the continuum of care; • sharing reciprocal capacity promotes healthy communities through the sharing of our intellectual and physical capacity with our community partners; • cultivating integration initiatives facilitates vertical, horizontal, and intersectoral integration initiatives in support of community-identified needs and gaps; and • facilitating healthy exchange develops best practices in community integration through community-based research, and facilitates community voice in informing public policy. the chip framework drives the complex inter-relationships between community-hospital engagement, reciprocal capacity-building, integration initiatives, and community-based research and evaluation, to create an interconnected network of health care services. the fluidity and simplicity of this framework, and its dedication to balancing community needs and hospital mandate, posits the st. josephs health centre's chip model as an integral component in building healthy and thriving communities. p4-18 (c) home based care promotion: improving acess to quality services and livelihood in the face of aids home based care is a service provided to persons affected/living with hiv/aids, a menu of care/support services at home/community. it is a prominent alternative approach. in uganda, hospital bed ocupacny is high, patient health care worker ratio deteriorating. empowering communities offers solutions to the problems; adressing cost, effectiveness of care. hiv/aids demands changes in attitudes, behaviour, approaches which is enhanced in home/community settings. for example art requires high levels of adherecnce, which medical workers have vety little opportunity to enforce. it also demands other support mechanisims in terms of nutrition, personal displine, etc which work best in stigma free environments. hence the relevance of home based care. this paper highlights the gaps that call for increased action in terms of home based care, examples of whre it has worked key challenges and recommendations for the future. p4-19 (c) health care for one ... health care for alli katharina kovacs burns introduction: at the surface, it appears that every person in canada _has. ~ccess to a publicly funded health care system. those living in urban centers should have the best ava1l~b1hty, chmce, and access to a variety of health care services because of the distribution of health care services, fac1lmes, and health professionals in concentrated in urban centers. this is not true for everyone -people with low income or who are homeless experience the challenges of social exclusion and being marginalized: there are many factors at play making it difficult for the latter group of people to access health care. service they need,.when they need them. health care is not as accessible or inclusive as intended. the quesuon to be explore.cl 1~: if health care is available and accessible to one person, what makes it not available to all people? the ~1gmfic~nce of having marginalized people accessing health care and other services includes e~hanced quality of hfe and decreased risks associated with being homeless, and cost savings in ion~ ter~ w1rh acute health care. methodology: community-based participatory research is applied m a case study on health care access and challenges experienced by low income and homeless people in one urban centre, edmonton, edmonton, and their challenges. the data is being gathered and ana_lyzed usmg basic m1x~d methods. results: the results will focus on how services can be more mtegrated and accessible to all people with low income and who are homeless. there will also be discussion about specific perceptions of not only the service providers but also of people with low income an~ who are homeless~ and vario~s decision makers. the results will be compared to the literature regardmg health care services access mother urban centers in canada and elsewhere. conclusions: recommendations will need to address social exclusion and other factors which can make health care and other services more available to all people in the community. the implications for health care will also be discussed. additional information will be gathered in the next phases of the study to develop a community services access model. p4-20 (c) availability and access exemplified: a case study beth hayhoe and ruth ewert introduction: access to health care in canada requires either the correct documentation or money. street youth have neither. in addition, health services in canada are designed by adults for adults. youth in general are often wary of having trust in adults with respect to their health concerns and frequently feel misunderstood. street youth are even more mistrustful of adults and public organizations, making their contact with health care professionals minimal. this combined with their risky behaviours and dangerous environment creates a population at risk for numerous health issues but with no place to have them investi· gated. at our non-government, not for profit health service designed specifically to provide a broad range of health care to street youth, professional services are provided almost entirely by volunteers. methods: using a retrospective analysis of the 11 years of data gathered from this organization and reviewing the initial reasons gathered from youth about their needs, the success of the health centre was examined. results: all the things youth had listed as being important in a health centre have been implemented, and even more things have been added to improve the breadth and quality of services offered. the use of the health centre has increased by more than six times since its opening in 1994. in addition, tens of thousands of visits have been paid to the health centre, costing the government and taxpayers nothing. as far as we know there is nothing else in canada that offers so many diverse and innovative services to youth in need. conclusion: it is clear from this case, that health care targeted at the needs of specific disadvan· taged populations can successfully provide them with appropriate health care. a model of accessible health care for marginalized populations can easily be developed for high impact and low cost from this successful case. toronto is one of the most ethno-racially diverse cities in the world of the estimated 2,529,280 toronto residents, 24% (597,218) live in scarborough population growth in scarborough is faster than toronto. scarborough's population increased by 6% from 1996 to 2001 while toronto increased only by 4%. toronto's population is projected to increase by 10% (252 000) in 2011 while scarbor· ough's will increase by 12%. (census canada 2001) low income, pove;ty, seniors, hidden homeless, new~omers to canada, the uninsured, are just a few of the issues concerning health care in our community. health care needs in scarborough are greatly impacted by diversity of ethnic and racial groups, poverty and settlement issues. this paper will share how the scarborough hospital (tsh) an urb~n communir_y hospital cares f~~ it~ community. tsh recognizes: •the changing community• b_arriers t~ accessing care • lnequalmes m health care the hospital in caring for its community pro· v1~es services that '!'e~e cu~turally, racially, and linguistically sensitive to our community. the paper will share the hospitals unique program on access and equity. the paper will share the needs in scar· borough and tsh's response to these needs: working in partnership with the local health committee, i:ne scarborough homeless co.mminee, the scarborough network of immigrant services organiza· nons a~d others. 1:'1e paper will also share the many initiatives this urban community hospital has taken viz. community and home programs in service areas such as mental health, haemodialysis day care, t~~ home oxyg~n program, the palliative at-home program, and above all support for the volunteer clinic for the uninsured. j"'"1tllu:lion: in canada's universal health care system it is generally assumed that everyone has equal access to health care. however, some immigrant groups in canada have historically been uninswed. these groups include failed refugee claimants, those overstaying their visas, and new immigrants in transition who are waiting to become eligible for health insurance. some estimates have suggested that at the present time there may be as many as one hundred thousand undocumented and thus uninsured immigrants in toronto alone. understandably, information on the characteristics of this marginalized population is very limited, since undocumented immigrants tend to have little contact with formal institutions. knowledge of the demographic characteristics of this population may aid in the development of health and social programs to better identify and meet the needs of undocumented immigrants in toronto. we conducted a review of all undocumented, uninsured patients, 15 years of age or older at access alliance multicultural community health centre (aamchc) between 1994 and 2004. demographic information such as age, gender, preferred language, length of time living in canada, selfreported education level and household income were recorded. rmdts: 72% of all adult patients at access alliance were undocumented and uninsured. 80% were under40years of age (with a median age of 30 years), 72% were women and only 19% spoke english. this group lived in canada for an average period of 2.2 years before they were first seen at aamchc. 74% of undocumented clients reported having completed at least a secondary or post-secondary education. 81% had self-reported household incomes of less than 20,000$/year, while 97% of households reported earning less than $30,000/year. the mean income per person in an average household was 425$/month. conchuions: uninsured individuals at aamchc were predominantly young females with limited knowledge of the english language. despite having attained a high level of education most were living well below the poverty line. recognition of these characteristics may assist in the development of health and social programs that are better adapted to meet the needs of undocumented immigrants. p4-23 (c) sharing expertise: a role for the hospital lactation consultant in the community. badrgrmuul: st. michael's hospital is a tertiary care hospital that serves a large inner city population in downtown toronto. in order to provide care to this population, the hospital has developed a number of unique outreach roles. one such role was developed to work with pregnant and breastfeeding women living in regent park, a social housing complex located near the hospital. the population of regent park includes new immigrants, refugees and the socially disadvantaged. approach: the outreach lactation consultant provides care, as part of the canada prenatal nutrition program, in the community prenatally, in the hospital during their inpatient stay and postnatally when they return to the community. the continuity of care enhances the probability of long term successful breastfeeding. aside from the health benefits of breastmilk, breastfeeding is especially important for women who are financially needy and must depend on food banks for formula. . . lason learned: aher two years of partnership, the relationship between the an-hospital ~stpar tum experience for breastfeeding mothers and the community postpartum support, the breastfeeding rate ~thin this community is high. the professional support and visibility of the 1:8ctation consultant, both m the hospital and in the community, contributes to the support of breastfee~m~.. . in light of ongoing funding constraints, this ha1son between hospital and community could be at risk and discontinued. in light of the benefits to the mother/baby dyad, the lactation consultant as a community partner in the canada prenatal nutrition program should be safeguarded. . lldpodiu:tion: although the importance of adequate health care in pregna~cy is well recognised, ethnic disparities in utilization of prenatal care still exist in many western coun~~es. a fun~amental factor in these disparities may be language proficiency, as it influences women's ab1hty. to ob~m and understand health information, to find the way in the health care system and to communicate with health care v78 poster sessions providers. we investigated the role of language proficiency in use and knowledge of folic acid as aspect of prenatal care in an urban multi-ethnic pregnancy c?hort. . . design: prospective cohort study. setting and parnc1pants: amsterdam ~regnant women attending obstetric care providers for their first antenatal visit (n= 8050). country of birth defined ethnicity: the netherlands, surinam, antilles, turkey, morocco, ghana, other non-~est~m (nw) and other western (w) country. main outcome measures: knowledge about and use of.fohc a~d (fa) supplements in pregnancy, and determinants of these in diffe~~t ethnic ~~ups. deterrrunants mcl~ded age, ed~ tion, parity, pregnancy intention and dutch prof1c1ency. stansncs: ~2 to co~p~re e~c groups, stranfied logistic regression (forward stepwise method) to explore determmants "'.'thm ethmc groups .. use of fa supplements was significantly lower among ghanaian, moroccan, turkish and other nw women (21%to41 %) than among dutch (86%) or other w women (78%). use amongsurinames and antillean women was intermediate (51%and60%). ethnic differences in fa knowledge were similar. knowledge was the strongest determinant of use in all ethnic groups, with odds ratios (ors) ranging from 10.9 to 42.0. language proficiency was the strongest determi~a~t of kno~ledge in ethnic groups with a mother tongue different from dutch (ors good vs. low proficiency ranging from 3.2 ro 16.0). educational level had a modifying role, as shown by an interaction effect between education and language proficiency in the nw group. here, the odds of having fa knowledge given a high education and good dutch proficiency was 20 times the odds given a good proficiency but low education. conclusions: appropriate periconceptional use of folic acid supplements in non-western ethnic groups is low, reflecting an absence of knowledge that is largely determined by the inability to speak and understand the language of the habitual country. tailored interventions using communication channels most likely to address (pregnant) women from ethnic minority groups are necessary. apan from specific interventions, our results are in support of strong incentives on language education despite current political debate. introduction: recent research suggests living in an economically disadvantaged neighborhood is asso· ciated with decreased likelihood of undergoing mammography and increased risk of late-stage breast can· cer diagnosis. long distances and travel times to facilities offering low-or no-cost mammography may be imponant barriers to adherence to mammography screening recommendations for residents of economically disadvantaged neighborhoods. the purpose of this study was to examine whether facilities providing low-and no-cost screening mammography were less spatially accessible in low-income neighborhoods in chicago, and the extent to which the relationship between neighborhood income and the spatial accessibility of facilities varied by the proponion of african-american residents in the neighborhood. methods: the sample consisted of 343 chicago neighborhoods. for each neighborhood, we con· structed three measures of the spatial accessibility of facilities: street network distance to the nearest facility, public transportation travel time to the nearest facility, and shortest automobile travel time to a facility. using 2000 decennial census data, we characterized the neighborhoods according to proportion of residents with incomes below the poverty line, proportion of residents in each of four raciavethnic groups (african-american, latino, white, and other), and population density. we used ordinary least squares (ols) and spatial exogenous lag regression to examine relationships. model 1 estimated the relationship between neighborhood poverty and the spatial accessibility of facilities, adjusting for raciaveth· nic composition and population density. model 2 added a multiplicative interaction term between neighborhood poverty and african-american. restllts: we identified deven facilities that provided low-or no-cost screening mammography to chicago residents in 2004. we found that the distance and travel times via automobile and public trans· portation to facilities generally decreased as neighborhood poveny increased. however, we also found that the ~egative associations between neighborhood poverty and two of the spatial accessibility mea· sures -distance and public transportation travel time -were less strong in neighborhoods with the highest proponions of african-american residents. among neighborhoods in the highest tertile for poveny, th~ mean distance and mean public transportation travel time to facilities were over twice as long in neighborhoods in the highest tertile than in those in the lowest tenile of african-american residents. . ~ persistent socioeconomic and racial/ethnic disparities in breast cancer stage at diagno-s11 ~nd su~1val suggest that ensuring an equitable distribution of affordable mammography is a worth-w~e policy .goal. the ~~dy sugges~ that ~ture investigations should consider both neighborhood soc1oecono1d1c charactensbes and rac1avethmc composition when examining the spatial distribution of health resources. , 2004) . epidemiological data suggest tha~ hiv prevalence among msm is over 1 % in some metropolitan cities, such .as beijing (ibid.). due to widespread homophobia in chinese society, however, this population remains invisible within current health/social services. lack of research on sexuality, specifically homosexuality, has impaired our understanding of health and health practices of chinese msm. focusing on the illness experiences of chinese msm with hiv/aids, this paper explores the socio-cultural impacts of hiv/ aids on this group. the data used for this paper were collected through semi-constructed in-depth face-toiace interviews with 21 adult plwhas (including 11 msm) in beijing, china. with the permission of the participants, the interviews were audio-taped or recorded in notes. the transcribed interviews and interview notes were analyzed by using n-vivo, a software program for qualitative data analysis. this phenomenological study aimed to understand the experiences chinese plwhas (including msm) from their own perspectives. results: it is found that the illness experiences of chinese msm with hiv/aids are profoundly shaped by the socio-cultural meanings of homosexuality, which are further complicated by the dominant discourses on hiv/aids in china. at a macro level, homophobia in the larger society has decreased the capability of this group to respond to this epidemic in a more efficient way. at a meso level, aids-phobia within the chinese msm circuits has prevented this group from openly confronting this disease and offering support to those who are already affected by it. at a micro level, however, these hiv-infected/ affected msm have tried their best to locate spaces to live and to construct hope for their future lives despite various barriers within family, community, and the larger society. this study suggests that facilitating chinese msm's response to the aids crisis urgently requires bridging awareness, commitment, knowledge and resources both within and without this group. it also illustrates the importance of understanding homosexuality in the local context of hiv i aids, which will be helpful for developing culturally sensitive hiv/aids programs for this population on the community, national and international levels. introduction: having a regular family doctor (rfd) is known to be positively correlated with a good medical follow up, including access to preventive and/or chronic care. inversely, a lack of primary care may lead to high rates of avoidable hospitalizations, especially among poor people and/or in underserved neighbourhoods. in such a matter, a recent comparative study showed that paris was better ranged than other cities, such as nyc, tokyo or london. nevertheless, despite a quasi universal health insurance and a high density of general practitioners, a noticeable fraction of the paris population does not have any regular physician and we aimed to understand who they are and for what reasons rhey don't have any rfd. mdbods: cross sectional population survey among a random sample of households in 2 ~nderpriv ileged neighbourhoods in paris inner city, performed in 2003, using a face-to-face quest10nna1re collecr-1ng more than 400 social and health characteristics. ruults: a quarter (26.3 %) of rhe study popularion did not have any rfd. this proporrion was iignificantly higher among male (or= 2.00, 95%ci = [ 1.41-2.781), younger (e.g. or 18 -29/> .s l _= 4._oo, 95"1.ci = (2.13-7.69)), and/or unemployed (or =2.01, 95%ci = ij .21-3.3411_ people. in multtvanate analysis, after a full adjustment on gender, age, health status, health insura~ce, income, occupat10n and tducation level, we observed significant associations between having no rfd and: ~arrtal and_ pare~t hood status (e.g. or single no kids/in couple+kids = 2.12, 95%ci = ( 1.26-3.59()~ quality of relattonsh1ps with neighbours (or bad/good= 3 .82, 95%ci = [ 1.84-7.94)), and length of residence m the neighbourhood (with a dose/effect statistical relationship). . co11clusion: gender, age, employment status, mariral and parenthood stat~s as well as ~e1gh bourhood anchorage seem to be major predictors of having a rfd, even when um.versa! health i~sur ance has reduced most of financial barriers. in urban contexts, where residential migrattons and single lift (or family ruptures) are frequent, specific information may be conducted to encourage people to ket rfd. :tu~y tries to assess the health effects and costs and also analyse the availability and accessibility to health care for poor. . methods: data for this study was collected by a survey on 300 households of the local community living near the factories and 100 households where radiation hazard w~s n?~ present. ~~art from mor· bidity status and health expenditure, data was collected ~n access, a~ail~b1.hty and eff1c1ency of healrh care. a discriminant analysis was done to identify the vanables that d1scnmmate between the study and control group households in terms of health care pattern. a contingent valuation survey was also undertaken among the study group to find out the factors affecting their willingness to pay for health insurance and was analysed using logit model. results: the health costs and indebtedness in families of the study group was high as compared to control group households and this was mainly due to high health expenditure. the discriminant analysis showed that expenditure incurred by private hospital inpatient and outpatient expenditure were significant variables, which discriminated between the two types of households. the logit analysis showed !hat variables like indebtedness of households, better health care and presence of radiation induced illnesses were significant factors influencing willingness to pay for health insurance. the study showed that study group households were dependent on private sector to get better health care and there were problems with access and availability at the public sector. conclusion: the study found out that the quality of life of the local community is poor due to health effects of radiation and the burden of radiation induced illnesses are so high for them. there is an urgent need for government intervention in this matter. there is also a need for the public sector to be efficient to cater to the needs of the poor. a health insurance or other forms of support to these households will improve the quality for health care services, better and fast access to health care facilities and reduces the financial burden of the local fishing community. the prevalence of substance abuse is an increasing problem among low-income urban women in puerto rico. latina access to treatment may play an important role in remission from substance abuse. little is known, however, about latinas' access to drug treatment. further, the role of social capital in substance abuse treatment utilization is unknown. this study examines the relative roles of social capital and other factors in obtaining substance abuse treatment, in a three-wave longitudinal study of women ages 18-35 living in high-risk urban areas of puerto rico, the inner city latina drug using study (icldus). social capital is measured at the individual level and includes variables from social support and networks, familism, physical environment, and religion instruments of the icdus. the study also elucidates the role of treatment received during the study in bringing about changes in social capital. the theoretical framework used in exploring the utilization of substance abuse treatment is the social support approach to social capital. the research addresses three main questions: ( t) does social capital predict parti~ipating in treatment programs? (2) does participation in drug treatment programs increase social capital?, and (3) is there a significant difference among treatment modalities in affecting change in ~ial capital? the findings revealed no significant association between levels of social capital and gettmg treatment. also, women who received drug treatment did not increase their levels of social capital. the findings, however, revealed a number of significant predictors of social capital and receiving drug ~buse treatment. predictors of social capital at wave iii include employment status, total monthly mcoi:rie, and baseline social capital. predictors of receiving drug abuse treatment include perception of physical health and total amount of money spent on drugs. other different variables were associated to treatment receipt prior to the icldus study. no significant difference in changes of social capital was found among users of different treatment modalities. this research represents an initial attempt to elucidate the two-way relationship between social capital and substance abuse treatment. more work is necessary to unden~nd. ~e role of political forces that promote social inequalities in creating drug abuse problems and ava1lab1hty of treatment; the relationship between the benefits provided by current treatment poster sessions v81 sctrings and treatment-seeking behaviors; the paths of recovery; and the efficacy and effectiveness of the trtaanent. and alejandro jadad health professionals in urban centres must meet the challenge of providing equitable care to a population with diverse needs and abilities to access and use available services. within the canadian health care system, providers are time-pressured and ill-equipped to deal with patients who face barriers of poverty, literacy, language, culture and social isolation. directing patients to needed supportive care services is even more difficult than providing them with appropriate technical care. a large proportion of the population do not have equitable access to services and face major problems navigating complex systems. new approaches are needed to bridge across diverse populations and reach out to underserved patients most in need. the objective of this project was to develop an innovative program to help underserved cancer patients access, understand and use needed health and social services. it implemented and evaluated, a pilot intervention employing trained 'personal health coaches' to assist underserved patients from a variety of ethno-linguistic, socio economic and educational backgrounds to meet their supportive cancer care needs. the intervention was tested with a group of 46 underserved cancer patients at the princess margaret hospital, toronto. personal coaches helped patients identify needs, access information, and use supportive care services. triangulation was used to compare and contrast multiple sources of quantitative and qualitative evaluation data provided by patients, personal health coaches, and health care providers to assess needs, barriers and the effectiveness of the coach program. many patients faced multiple barriers and had complex unmet needs. barriers of poverty and language were the easiest to detect. a formal, systematic method to identify and meet supportive care needs was not in place at the hospital. however, when patients were referred to the program, an overwhelming majority of participants were highly satisfied with the intervention. the service also appeared to have important implications for improved technical health care by ensuring attendance at appointments, arranging transportation and translation services, encouraging adherence to therapy and mitigating financial hardship -using existing community services. this intervention identified a new approach that was effective in helping very needy patients navigate health and social services systems. such programs hold potential to improve both emotional and physical health out· comes. since assistance from a coach at the right time can prevent crises, it can create efficiencies in the health system. the successful use of individuals who were not licensed health professionals for this purpose has implications for health manpower planning. needle exchange programs (neps) have been distributing harm reduction materials in toronto since 1990. counterfit harm reduction program is a small project operated out of a community health centre in south-east toronto. the project is operated by a single full-time coordinator, one pan-rime mobile outreach worker and two peers who work a few hours each week. all of counterfit's staff, peers, and volunteers identify themselves as active illicit drug users. yet the program dis~rib utes more needles and safer crack using kits and serves more illicit drug u~rs t~an the comb1~e~ number of all neps in toronto. this presentation will discuss the reasons behind this success, .s~1f1cally the extended hours of operation, delivery models, and the inclusion of an. extremely marg1~ahzed community in all aspects of program design, implementation and eva.luat1?n. ~ounterfit was recently evaluated by drs. peggy milson and carol strike, two leading ep1dem1olog1st and researchers in the hiv and nep fields in toronto and below are some of their findings: "the program has experienced considerable success in delivering a high quality, accessible and well-used program .... the pro· gram has allowed (service users) to become active participants in providing. services to others and has resulted in true community development in the best sense. " ... counterf1t has ~~n verr succe~sful attracting and retaining clients, developing an effective peer-based model an.d assisting chen~s ~1th a vast range of issues .... the program has become a model for harm red~ctmn progr~ms withm the province of ontario and beyond." in june 2004, the association of ?ntano co~mumty heal~~ <:en· ires recognized counterfit's acheivements with the excellence m community health initiatives award. in kenya, health outcomes and the performance of government health service~ have det~riorated since the late 1980s, trends which coincide with a period of severe resource constramts necessitated by macro-economic stabilization measures after the extreme neo-liberalism of the 1980s. when the govern· ment withdrew from direct service provision as reform trends and donor advocacy suggested, how does it perform its new indirect role of managing relations with new direct health services providers in terms of regulating, enabling, and managing relations with these health services providers? in this paper therefore, we seek to investigate how healthcare access and availability in the slums of nairobi has been impacted upon by the government's withdrawal from direct health care provision. the methodology involved col· leering primary data by conducting field visits to 8 health institutions located in the slum areas of kibera and korogocho in nairobi. purposive random sampling was utilized in this study because this sampling technique allowed the researcher(s) to select those health care seekers and providers who had the required information with respect to the objectives of the study. in-depth interviews using a semi-structured ques· tionnaire were administered ro key informants in health care institutions. this sought to explore ways in which the government and the private sector had responded and addressed in practical terms to new demands of health care provision following the structural adjustment programmes of the 1990s. this was complemented by secondary literature review of publications and records of key governmental, bilateral and multilateral development partners in nairobi. the study notes a number of weaknesses especially of kenya's ministry of health to perform its expected roles such as managing user fee revenue and financial sustainability of health insurance systems. this changing face of health services provision in kenya there· fore creates a complex situation, which demands greater understanding of the roles of competition and choice, regulatory structures and models of financing in shaving the evolution of health services. we rec· ommend that the introduction of user fees, decentralization of service provision and contracting-out of non-clinical to private and voluntary agencies require a new management culture, and new and clear insri· tutional relationships. experience with private sector involvement in health projects underlines the need not only for innovative financial structures to deal with a multitude of contractual, political, market and risks, but also building credible structures to ensure that health services projects are environmentally responsive, socially sensitive, economically viable, and politically feasible. purpose: the purpose of this study is to examine the status of mammography screening utilization and its predictors among muslim women living in southern california. methods: we conducted a cross-sectional study that included 202 women aged ::!: 40 years. we col· leered data using a questionnaire in the primary language of the subjects. the questionnaire included questions on demography; practices of breast self-examination (bse) and clinical breast examination (cbe); utilization of mammography; and family history of breast cancer. bivariate and multiple logistic regression analyses were performed to estimate the odds ratios of mammography use as a function of demographic and other predictor variables. . results: among the 202 women, 78% were married, 68% were 40-50 years old, and 20% had family h1story of breast cancer. thirty-two percent of the participating women never practiced bse and 32% had not undergone cbe during the past two years. the data indicated that 46% of the women did not have mammography in the last two years. logistic regression analysis showed that age (0r=5.1, 95% confi· dcnc~ interval (cl)=l.8-14.2), having clinical breast examination (0r=24.9, 95% cl=8.4-73.7), and practtce of self-breast examination (0r=2.6, 95% cl= 1.1-6.2), were strong predictors of mammography use . . conclusions: the data point to the need for intervention targeting muslim women to inform and motivate th.cm a~ut practices for early detection of breast cancer and screening. further studies are needed to investigate the factors associated with low utilization of mammography among muslim women population in california. we conducted a review of the scientific literature and° government documents to describe ditnational health care program "barrio adentro" (inside the neighborhood). we also conducted qualiurivt interviews with members of the local health committees in urban settings to descrihe the comm unity participation component of the program. rtsmlts: until recently, the venezuelan public health system was characterized by a lack or limited access w health care (70% of the population) and long waiting lists that amounted to denial of service. moit than half of the mds worked in the five wealthiest metropolitan areas of the country. jn the spring oi2003, a pilot program hired 50 cuban mds to live in the slums of caracas to provide health care to piople who had previously been marginalized from social programs. the program underwent a massive expansion and in only two years 20,000 cuban and 6,500 venezuelan health care providers were working acmss the country. they provide a daily average of 20-40 medical consultations and home visits, c1lly out neighborhood rounds, and deliver health prevention initiatives, including immunization programs. they also provide generic medicines at no cost to patients, which treat 80% of presenting ill-ij!m, barrio adentro aims to build 8,000 clinics (primary care), 1,200 diagnostic and rehabilitation ctnrres (secondary care), and upgrade the current hospital infrastructure (tertiary care). local health committees survey the community to identify needs and organize a variety of lobby groups to improve dit material conditions of the community. last year, barrio adentro conducted 3.5 times the medical visits conducted by the ministry of health. the philosophy of care follows an integrated approach where btalrh is related to housing, education, employment, sports, environment, and food security. conclusions: barrio adentro is a unique collaboration between low-middle income countries to provide health care to people who have been traditionally excluded from social programs. this program shows that it is possible to develop an effective international collaboration based on participatory democracy. low-income americans are at the greatest risk of being uninsured and often face multiple health concerns. this evaluation of the neighborhood health initiative (nh!), an organization which uses multiple programmatic approaches to meet the multiple health needs of clients, reflected the program's many activities and the clients' many service needs. nh! serves low-income, underserved, and hard-to-reach residents in the des moines enterprise community. multiple approaches (fourth-generation evaluation, grounded theory, strengths-and needs-based) and methods (staff and client interviews, concept mapping, observations, qualitative and quantitative analysis) were used to achieve that reflection. results indicate good targeting of residents in the 50314 zip code and positive findings in the way of health insurance coverage and reported unmet health needs of clients. program activities were found to match client nttds, validating the organization\'s assessment of clients. important components of nhi were the staff composition and that the organization had become part of both the formal and informal networks. nhi 1 1 positioned as a link between the target population and local health and social sc:rvice agencies, working to connect residents with services and information as well as aid local agencies in reaching this underserved population. p4-36 (c) welfare: definition by new york city maribeth gregory for an individual who resides in new york city, to obtain health insurance under the medicaid policy one must fall under certain criteria .. (new york city's welfare programs 2003) if the individual _is on ssi or earns equal to or less than $934 per month, he is entitled to receive no more than $5,600 m resources. a family the size of two would need to earn less than $942 per month to qualify for no greater than ss,650 worth of medicaid benefits. a family of three would qualify for $5,650 is they earned less than $942 per month and so on. introduction: the vancouver gay communiry has a significant number of asian descendan!l. because of their double minority status of being gay and asian, many asian men who have sex with men (msm) are struggling with unique issues. dealing with racism in both mainstream society and the gay communiry, cultural differences, traditional family relations, and language challenges can be some of their everyday srruggles. however, culturally, sexually, and linguistically specific services for asian msm are very limited. a lack of availability and accessibiliry of culturally appropriate sexual health services isolates asian msm from mainstream society, the gay community, and their own cultural communities, deprives them of self-esteem, and endangers their sexual well-being. this research focuses on the qualita· tive narrative voices of asian msm who express their issues related to their sexualiry and the challenges of asking for help. by listening to their voices, practitioners can get ideas of what we are missing and how we need to intervene in order to reach asian msm and ensure their sexual health. methods: since many asian msm are very discreet, it is crucial to build up trust relationships between the researcher and asian msm in order to collect qualitative data. for this reason, a community based participatory research model was adopted by forming a six week discussion group for asian msm. in each group session, the researcher tape recorded the discussion, observed interactions among the participants, and analyzed the data by focusing on participants' personal thoughts, experiences, and emotions for given discussion topics. ra11lts: many asian msm share challenges such as coping with a language barrier, cultural differ· ences for interpreting issues and problems, and westerncentrism when they approach existing sexual health services. moreover, because of their fear of being disclosed in their small ethnic communities, a lot of asian msm feel insecure about seeking sexual health services when their issues are related to their sexual orientation. conclflsion: sexual health services should contain multilingual and multicultural capacities to meet minority clients' needs. for asian msm, outreach may be a more effective way to provide them with accessible sexual health services since many asian msm are closeted and are therefore reluctant to approach the services. building a communiry for asian msm is also a significant step toward including them in healthcare services. a communiry-based panicipatory approach can help to build a community for asian msm since it creates a rrust relationship between a worker and clients. p4-38 (c) identifying key techniques to sustain interpretation services for assisting newcomers isolated by linguistic and cultural barriers from accessing health services s. gopi krishna lntrodaetion: the greater toronto area (gta) is home to many newcomer immigrants and other vulnerable groups who can't access health resources due to linguistic, cultural and systemic barriers. linguistic and cultural issues are of special concern to suburbs like scarborough, which is home to thousands of newcomer immigrants and refugees lacking fluency in english. multilingual community ~nterpreter. service~ (mcis) is a non-profit social service organization mandated to provide high quality mterpretanon services. to help newcomers access health services, mcis partnered with the scarborough network of immigrant serving organizations (sniso) to recruit and train volunteer interpreters to accompany clienrs lacking fluency in english and interpret for them to access health services at various locati?ns, incl~~ing communiry ~c:-lth centres/social service agencies and hospitals. the model envisioned agencies recruin~ and mcis ~.mm.g and creating an online database of pooled interpreter resources. this da.tabase, acces&1bl~ to all pama~~g ?rganization is to be maintained through administrative/member · ship fees to. be ~1d by each parnapanng organization. this paper analyzes the results of the project, defines and identifies suc:cases before providing a detailed analysis for the reasons for the success . . methods:. this ~per~ q~ntitative (i.e. client numben) and qualitative analysis (i.e. results of key •~ormant m~rv1ews with semce ~sers and interpreters) to analyze the project development, training and 1mplementanon phases of the project. it then identifies the successes and failures through the afore· mentioned analysis. poster sessions vss resljts: the results of the analysis can be summarized as: • the program saw modest success both ia l?lllls of numbers of clients served as well as sustainability at various locations, except in the hospital iririog. o the success of the program rests strongly on the commitment of not just the volunteer interprmr, but on service users acknowledgments through providing transponation allowance, small honororia, letter of reference etc. • the hospital sustained the program better at the hospital due to the iolume and nature of the need, as well as innate capacity for managing and acknowledging volunceers. collc/llsion: it is possible to facilitate and sustain vulnerable newcomer immigrants access to health !ul'ices through the training and commitment of an interpreter volunteer core. acknowledging volunteer commitment is key to the sustenance of the project. this finding is important to immigration and health policy given the significant numbers of newcomer immigrants arriving in canada's urban communities. nity program was established in 1993 to provide support to people dying at home, especially those who were waiting for admission to the resi<lential hospice. with the advent of haart and corresponding challenges for people living with hiv/aids in the community, the community program has developed a unique case management approach. this model features an interdisciplinary team providing a clientdrivcn service. the case manager provides continuity of care to clients in a variety of settings both within and outside of the health care system. a case study is used to demonstrate how formal and informal networks of support facilitate efficient and appropriate resource utilization to promote client health. this case study demonstrates the value of consistent coordination with a client who has complex physical, spiritual, substance use and mental health needs. the authors will show how they liaised with the housing authority, police, social services as well as the family physician, clinic staff and a hospital emergtncy room to ensure this client did not fall between the cracks. tarek hussain recognition of the importance of community involvement and sectoral cooperation in health and !ocial services, formalized in alma-ata declaration in 1978, was reinforced at riga meeting held at the mid·point between alma-ata and the year 2000. then at the 20th anniversary of alma-ata declaration, ir was declared that 'primary health care is everybody's business'. health does not exist in isolation. health cannot be defined only as an outcome of 'medical care' but also as one of 'social action'; the responsibility of disease prevention and health promotion rests not only on governments, but also with don·govemmentorgan izations, the community, and individuals. the major accomplishment to date may be that rhere is growing realization in the health sector that community involvement is more than a political right-it is absolute necessary. lessons have learned during the implementation of disease-specific l'cltical programmes, such as cdd, ari, and epi; first, integrated and holistic approaches to childcare art needed, and second, the need for community involvement has become evident. imc! is a broad inte-gra1ed strategy with an overall objective contributing to reducing child morbidity and mortality in developing countries. and one of the imci components, 'community !mci', which is now broadening ~s an entry point for child-focused community development initiatives. community jmcl/c~1ld health is ~n mtcgrated approach to the promotion of key family and community practices that have impact on: child growth and development, disease prevention, home care for sick, malnourished child~en, a.nd care-seekmg behavior and compliance with advice and treatment. the presentation addres~es, m brief, the ~evel opinent of community !mci, operational aspect of community/im cl, key strategies and tools ava1la~le for implementation of c/imci. the paper draws some successful programme examples on working logether for imc! with the community in various countries which had substantial benefns on programme outcomes. p4-4 t (c) healthy child screening: an innovative service initiative ann-marie marcolin and joyce allen . introduction: with mounting attention for creative and integrated models of c~re .that are populallon and community focused, the healthy child screening initiative achiev.es t~ese pnncipl~s and more! . • parkdale high park rotary (sponsorship) the heal~h ~h1ld scree?1?g is a ~opl~-centred model of care. agency and professional sector-specific silos are ehmmated, ~rov1dmg f~~1hes wit~ one-sto~ access to primary prevention services in a local school gym! children at nsk are rece1vmg early mtervent10n and appropriate referrals to the right care provider, at the right time a~d in t~e right place. further, with a complimentary focus on prevention, the program serves to keep at nsk children healthy. healthy child screening results: the service model is developed around four distinct phases: 1) planned outreach; 2) coordinated intake and registration; 3) interdisciplinary screening; and 4) targeted referral. since the fall 2003 and through six collaborative healthy child screenings 158 children ranging in age from 2 to 6 have benefited from this unique service model of care. conclusion: the presentation will provide practical information on the development and implementation of the model. there will also be a focus on lessons learned in building community service provider-hospital relationships. according to statistics canada (2001) 49% of the toronto population was born outside of canada and 21 % were new immigrants. immigrants often arrive in canada in superior health compared to the canadian born population, but they lose this health advantage over time. changes in immigrant health status over time may be attributed to a variety of factors including barriers to accessing and receiving care as well as limitations in the mainstream health service organizations and their approaches to health care delivery (hyman, 2001 ) . for example, immigrant women are less likely to receive pap tests, which places them at a greater risk for developing cervical cancer. similarly, immigrant women receive less mammography screening than their canadian counterparts. the immigrant women's health centre mobile health unit (mhu) was created as an alternative care delivery model to address the need for increased accessibility as well as culturally and linguistically appropriate reproductive health care. toronto western hospital and the immigrant women's health centre have formed a collaborative partnership which incorporates a primary care nurse practitioner and lay ethnocultural counselors providing care on the mhu. currently, a qualitative ethnonursing study is underway to understand the unique experiences of women using the mhu for their reproductive health care as well as the perspectives of the mhu health care providers. based on a literature review and preliminary findings from provider and participant interviews, the proposed presentation will address the themes of health status for immigrant and refugee women, accessibility issues as well strategies to improve their reproductive health care. we will discuss benefits as well as limitations to health care provision using this alternative service delivery model. michael carden, brian edlin, andrew talal, elizabeth getter, and marla shu lntrod.ction: to date most active drug users have not had access to treatment for hepatitis c virus (hcv) infection and substantial barriers continue to exist that interfere with treatment availability for this population. methods: active illicit drug users interested in pursuing hcv care and treatment were recruited in partnership w~th co~munity-based organizations (cbo's) in new york city. baseline data were collected on quahty of hfe, substance use patterns, depression, health care utilization, hcv health beliefs and other relev.ant variables. medical evaluations were conducted, including liver biopsy when indicated, an~ treatment ts ~ffered when no contraindications are present. participants also receive psychiatric evaluahons to determme the appropriateness of interferon treatment. renlts: fifteen individuals have been recruited to date and received an initial medical evaluation. the mean age was 40 years and _the average age of initial heroin or cocaine use was 16.8. eight (53%) ha~ been homeless at least once m the last 6 months and s (33%) were homeless for most or all of this penod. fourteen (93%) had a history of injection drug use with the mean age at first injection being 21 111s1frsewons v87 ,an. elrven persc.!ns (79%) reported inje~~ng .heroin or cocaine within the last 30 days while the .wing four (21 l'o) reported regular non-m1ect1on use of cocaine and street-obtained benzodiazepines. sijiy seven percent of the sample (n= 10) reported ever being referred to hcv treatment while 2 ( t 3 % ) ftponeddiattreann~nt had been offered by~ ~e.dical provider. none had ever received a liver biopsy or araanent. most believed that hcv was a s1gmf1cant threat to their health (80%) and that there was a pm)dchance they would eventually die if their hepatitis c was not treated (67%). though 7 individuals 147%1 believed that there was no cure for hcv, 13 (87%) reported that they would initiate treatment if i was recommended by their doctor. thirteen (87%) had a current psychiatric diagnosis including «pmsion, anxiety disorder, schizophrenia, schizoaffective disorder, and borderline and antisocial persooaliry disorders. among eight individuals who had the beck depression inventory administered, the mean score was 29.75. attendance rates were 83% (83/100) at scheduled medical and psychiatric 1ppointments and 50% (2/4) at liver biopsy. <andtuions: active drug users, despite experiencing multiple psycho-social problems, can be mgaged in hcv care using a multidisciplinary approach, but require intensive follow-up support. hcv aunnent of active drug users should not be dismissed. n-44 (c) antiretroviral therapy in mv infected infants: when to initiate therapy an african experience kingsley okonkwo, ademola adeyemo, israel sokeye, and nwaife umeike /""°""ction: as technology for early diagnosis of human immunodeficiency virus [hiv] improves, m to commence highly active antiretroviral therapy [haarn is yet to be fully evaluated. this prospective study describes our initial experience with early haart in hiv infected nigerian infants and rqions the outcome. we also analyzed the socioeconomic implications of early haart therapy in infants in the african setting. method: hiv infected infants were started on haart before 6 months and followed up at 4 mkly intervals.we monitored baseline and 3 monthly cd4 . conclusion: initial results suggest early haart before 6 months resulted. in improv~d out~ome in african children. treatment appears to be as effective as in developed counmes. in. a~nca as. m most developing countries with limited resources it is possible and effective to use haart m 1~~ants if p~oper llloniroring facilities are available. however the occurrence of long-term drug related tox1c1ty and mk of emergence of resistant viral strains create need for further evaluation of haart in infants. background: most risk factors for cardiovascular disease (cvd) can be mitigated through ~th clinical interventions and lifestyle change. we used data from a telephone survey of new york city (nyc) adults to characterize health care access and healthy behavior among those with three or more cvd risk factors. methods: the study population included respondents to the nyc community health survey 2002 (n= 9,674) self-reporting~ 3 of the following: smoking, diabetes, high cholesterol level, high blood pres· sure, body mass index >25, and age >45 (males) or >55 (females) (n=2,439). results: based on self-report, an estimated 1.447,000 (24%) of nyc adults have~ 3 or more cvd risk factors. this population is 51 % male, 47% white, 25% black, and 53% with s 12 years of education. most report good access to health care, indicated by having health insurance (95%), regular doctor (89%), their blood pressure checked within last 6 months (91 %), and their choles· terol checked within the past year (90% ). only 29% reported getting at least 20 minutes of exercise ~ 4 times per week and only 9% eating ~ 5 servings of fruits and vegetables the previous day. among current smokers, 59% attempted to quit in past 12 months, but only 32% used medication or counseling. implications: these data suggest that most nyc adults known to be at high risk for cvd have access to regular health care, but most do not engage in healthy lifestyle or, if they smoke, attempt effective quit strategies. more clinic-based and population-level interventions are needed to support lifestyle change among those at high risk of cvd. introduction: recently, much interest has been directed at "obesogenic" (obesity-promoting) (swinburn, egger & raza, 1998) built environments, and at geographic information systems (gis) as a tool for their exploration. a major geographical concept is accessibility, or the ease of moving from an origin to a destination point, which has been recently explored in several health promotion-related stud· ies. there are several methods of calculating accessibility to an urban feature, each with its own strengths, drawbacks and level of precision that can be applied to various health promotion research issues. the purpose of this paper is to describe, compare and contrast four common methods of calculating accessibility to urban amenities in terms of their utility to obesity-related health promotion research. practical and conceptual issues surrounding these methods are introduced and discussed with the intent of providing health promotion researchers with information useful for selecting the most appropria1e accessibility method for their research goal~ ~ethod: this paper describes methodological insights from two studies, both of which assessed the neighbourhood-level accessibility of fast-food establishments in edmonton, canada -one which used a relatively simple coverage method and one which used a more complex minimum cos1 method. res.its: both methods of calculating accessibility revealed similar patterns of high and low access to fast-food outlets. however, a major drawback of both methods is that they assume the characteristics of the a~e~ities and of the populations using them are all the same, and are static. the gravity potential method is introduced as an alternative, since it is ·capable of factoring in measures of quality and choice. a n~mber of conceptual and pr~ctical iss~es, illustrated by the example of situational influences on food choice, make the use of the gravity potential model unwieldy for health promotion research into sociallydetermined conditions such as obesity. co.nclusions: i~ ~ommended that geographical approaches be used in partnership with, or as a foun~ation for, ~admonal exploratory methodologies such as group interviews or other forms of commumty consultation that are more inclusive and representative of the populations of interest. qilhl in los angeles county ,,..ia shaheen, richard casey, fernando cardenas, holman arthurs, and richard baker ~the retinomax autorefractor has been used for vision screening of preschool age childien. ir bas been suggested to be used and test school age children but not been validated in this age poup. ob;taiw: to compare the results of retinomax autorefractor with findings from a comprehensive i!' examination using wet retinoscopy for refractive error. mllhods: children 5-12 years old recruited from elementary schools at los angeles county were iaml with snellen's chart and the retinomax autorefractor and bad comprehensive eye examination with dilation. the proportion of children with abnormal eye examination as well as diesensitiviry and specificity of the screening tools using retinomax autorefractor alone and in combinalion wirh snellen's chart. results of the 258 children enrolled in the study (average age= 8.5± 2.1 years; age range, 5-12 years), 6?% had abnormal eye examination using retinoscopy with dilation. for the lerinomax, the sensitivity was 85% (95% confidence interval [ci] 78%-90%), and the specificity was 31% (95% ci, 22%-41 o/o). simultaneous testing using snellen's chart and retinomax resulted in gain in 111sitiviry (94%, 95% cl= 89, 97), and loss in specificity (28%, 95% cl= 19%-38%). the study showed that screening school age children with retinomax autorefractor could identify most cases with abnormal vision but would be associated with many false-positive results. simuhaneous resting using snellen's chart and retinomax maximize the case finding but with very low specificiry. mdhotjs: a language-stratified, random sample of 2366 members of the college of family physicians of canada received a confidential survey. the questionnaire collected data on socio-demographic characteristics, medical training, practice type, setting and hcv-related care practices. the self-adminisratd questionnaire was also made available to participants for completion on the internet. batdti: response proportion was 33%. median age was 41 years (47% female) and the proporlionoffrench questionnaires was 26%. approximately 88% had completed family medicine residency lllining in canada; median year of training completion was 1995. sixty-seven percent, 38% and 29% work in private offices/clinics, community hospitals and emergency departments, respectively. regarding ~practices, 94% had ever requested a hcv test and 87% of physicians had screened for hcv iafrction in rhe past 12 months· median number of tests was 10. while 17% reported having no hcv-uaed patients in their practic~, 44% had 1-5 hcv-infected patients. regarding the level of hcv care provided, 4.3% provide ongoing advanced hcv care including treatment and dose monitoring for ctmduions: in this sample of canadian family physicians, most had pro~ided hcv screening. to •least one patient in the past year. less than half had 1-5 hcv-infected patients and 41 % provide ~:relared care the role of socio-demographic factors, medical training as wel_i as hcv ca~e percep-lldas 10 rhe provision of appropriate hcv screening will be examined and described at the time of the canference. '4-50 (c) healthcare services: the context of nepal meen poudyal chhetri """1tl.ction healthcare service is related with the human rights and fundamental righ~ of the ci~ ciaaiuntry. however, the growing demand foi health care services, quality heal~care service, accessib1b~ id die mass population and paucity of funds are the different but interrelated issues to .be ~ddressed. m nepat.1n view of this context, public health sector in nepal is among other sectors, which is struggling -.i for scarce resources. . . . nepal, the problems in the field of healthcare servic~s do not bnut ~o the. paucity of faads and resources only, but there are other problems like: rural -urban imbalance, regional unbalance, poster sessio~ f the ll ·m1 ·ted resources poor healthcare services, inequity and inaccessibility of the poor management o , . poor people of the rural, remote and hilly areas for the healthcare services and so on.. . . . · . i f ct the best resource allocation is the one that max1m1zes t e sum o m ivi ua s u11 · ea t services. n a , · h d' ·b · · · h . ·t effi.ciency and efficient management are correlated. it might be t e re istn utmn of mes. ence, equi y, . . . . 1 . income or redistribution of services. moreover, maximizanon of available resources, qua tty healthcare services and efficient management of them are the very important and necessary tools and techmques to meet the growing demand and quality healthcare services in nepal. p4-51 (a) an jn-depth analysis of medical detox clients to assist in evidence based decision making xin li, huiying sun, ajay puri, david marsh, and aslam anis introduction: problematic substance use represents an ever-increasing public health challenge. in the vancouver coastal health (vch) region, there are more than 100,000 individuals having some probability of drug or alcohol dependence. to accommodate this potential demand for addiction related services, vch provides various services and treatment, including four levels of withdrawal management services (wms). clients seeking wms are screened and referred to appropriate services through a central telephone intake service (access i). the present study seeks to rigorously evaluate one of the services, vancouver detox, a medically monitored 24-bed residential detox facility, and its clients. doing so will allow decision makers to utilize evidence based decision-making in order to improve the accessibility and efficiency of wms, and therefore, the health of these clients. methods: we extract one-year data (october 1, 2003 -september 30, 2004 from an efficient and comprehensive database. the occupancy rate of the detox centre along with the clients' wait time for service and length of stay (los) are calculated. in addition, the effect of seasonality on these variables and the impact of the once per month welfare check issuance on the occupancy rate are also evaluated. results: among the 2411 clients (median age 40, 65% male) who were referred by access! to vancouver detox over the one-year period, 1448 were admitted. the majority (81 %) of those who are not admitted are either lost to follow up (i.e., clients not having a fixed address or telephone) or declined service at time of callback. the median wait time was 1 day [q3-ql: 3-1], the median los was 5 days iq3-qt: 6-3], and the average bed occupancy rate was 83%. however, during the threeday welfare check issue period the occupancy rate was lower compared to the other days of the year 175% vs. 84%, p conclusion: our analysis indicates that there was a relatively short wait time at vancouver detox, however 40% of the potential clients were not served. in addition, the occupancy rate declined during the welfare check issuance period and during the summer. this suggests that accessibility and efficiency at vancouver detox could be improved by specifically addressing these factors. background: intimate partner violence (ipv) is associated with acute and chronic physical and men· tal health outcomes for women resulting in greater use of health services. yet, a vast literature attests to cultural variations in perceptions of health and help-seeking behaviour. fewer studies have examined differences in perceptions of ipv among women from ethnocultural communities. the recognition, definition, and understanding of ipv, as well as the language used to describe these experiences, may be different in these communities. as such, a woman's response, including whether or not to disclose or seek help, may vary according to her understanding of the problem. methods: this pilot study explores the influence of cultural factors on perceptions of and responses to ipv among canadian born and immigrant young women. in-depth focus group interviews were con· ducted with women, aged 18 to 24 years, living in toronto. open-ended and semi-structured interview questions were designed to elicit information regarding how young women socially construct jpv and where they would go to receive help. interviews were transcribed, then read and independently coded by the research team. codes were compared and disagreements resolved. qualitative software qsr n6 was used to assist with data management. . ruu~ts_: res~nses_abo~t what constitutes ipv were similar across the study groups. when considering specific ab.us1ve ~1tuanons and types of relationships, participants held fairly relativistic views about ipv, especially with regard to help-seeking behaviour. cultural differences in beliefs about normaive m;ile/femal~ relations. familial.roles, and customs governing acceptable behaviours influenced partictpants perceptions about what 1n1ght be helpful to abused women. interview data highlight the social l05ter srnfons v91 11111 suucrural _impact these factors ha:e on you?g women and provide details regarding the dynamics of cibnocultur~ m~uences on help-~eekmg behav10ur: t~e ro~e of such factors such as gender inequality within rtlaoo?sh1ps and t_he ~erce1ved degree of ~oc1al 1solat1on and support nerworks are highlighted. collc~ the~ findmgs unde~score the _1mporta_nc_e of understanding cultural variations in percrprions of ipv ~ relanon to ~elp-seekmg beha~1':'ur. th1s_mformation is critical for health professionals iodiey may connnue developmg culturally sensmve practices, including screening guidelines and protorol s. ln addition, _this study demonstr~tes that focus group interviews are valuable for engaging young romen in discussions about ipv, helpmg them to 'name' their experiences, and consider sources of help when warranted. p4-s3 (a) health problems and health care use of young drug users in amsterdam .wieke krol, evelien van geffen, angela buchholz, esther welp, erik van ameijden, and maria prins /11trod11ction: recent advances in health care and drug treatment have improved the health of populations with special social and health care needs, such as drug users. however, still a substantial number dots not have access to the type of services required to improve their health status. in the netherlands, tspccially young adult drug users (yad) whose primary drug is cocaine might have limited access to drugrreatment services. in this study we examined the history and current use of (drug associated) treatmmt services, the determinants for loss of contact, and the current health care needs in the young drug mm amsterdam study (yodam). methods: yodam started in 2000 and is embedded in the amsterdam cohort study among drug mm. data were derived from y ad aged < 30 years who had used cocaine, heroin, ampheramines and i or methadone at least 3 days a week during the 2 months prior to enrolment. res11lts:of 195 yao, median age was 27 years (range: 18-30 years), 72% was male and 83% had 1dutch nationality at enrolment. nearly all participants (97%) reported a history of contact with drug llt.lnnent services (methadone maintenance, rehabilitation clinics and judicial treatment), mental health car? (ambulant mental care and psychiatric hospital) or general treatment services (day-care, night-care, hdp for living arrangements, work and finance). however, only 61 % reported contact in the past six l!xlllths. this figure was similar in the first and second follow-up visit. among y ad who reported no current contact with the health care system, 87% would like to have contact with general treatment serl' icts. among participants who have never had contact with drug treatment services, 67% used primarily cocaine compared with 22% and 8% among those who reported past or current contact, respectively. saied on the addiction severity index, 70% reported at least one mental health problem in the past 30 days, but only 11 % had current contact with mental health services. concl11sion: results from this study among young adult drug users show that despite a high contact rm with health care providers, the health care system seems to lose contact with yao. since 87% indicatt the need of general treatment services, especially for arranging house and living conditions, health m services that effectively integrate general health care with drug treatment services and mental health care might be more successful to keep contact with young cocaine users. mtthods: respondents included adults aged 18 and over who met dsm-iv diagn?snc criteria for an anxiety or depressive disorder in the past 12 months. we performed two sets of logisnc regressmns. thtdichotomous dependent variables for each of the regressions indicated whether rhe respondenr_vis-ud a psychiatrist, psychologist, family physician or social worker in the _past_ 12 months. no relationship for income. there was no significant interaction between educatmn an mco~:· r: ::or respondents with at least a high school education to seek help ~rom any of the four servic p were almost twice that for respondents who had not completed high school. th . d ec of analyses found che associacion becween educacion and use of md-provided care e secon s · · be d · · ·f· ly 1 ·n che low income group for non-md care, the assoc1anon cween e ucatlon and was s1gm icant on -· . . . . use of social workers was significant in both income groups, but significant only for use of psychologists in che high-income group. . . . conclusion: we found differences in healch service use by education level. ind1v1duals who have nor compleced high school appeared co use less mental he~lt~ servi~es provided ~y psyc~iatrists, psycholo· gists, family physicians and social workers. we found limited e.v1dence _suggesting the influence of educa· tion on service use varies according to income and type of service provider. results suggesc there may be a need to develop and evaluate progr~ms.designe~ to deliver targeted services to consumers who have noc completed high school. further quahtanve studies about the expen· ence of individuals with low education are needed to clarify whether education's relationship with ser· vice use is provider or consumer driven, and to disentangle the interrelated influences of income and education. system for homeless, hiv-infected patients in nyc? nancy sahler, chinazo cunningham, and kathryn anastos introduction: racial/ethnic disparities in access to health care have been consistently documented. one potential reason for disparities is that the cultural distance between minority patients and their providers discourage chese patients from seeking and continuing care. many institucions have incorporated cultural compecency craining and culturally sensicive models of health care delivery, hoping co encourage better relacionships becween patients and providers, more posicive views about the health care system, and, ulcimacely, improved health outcomes for minority patients. the current scudy tests whether cultural distance between physicians and patients, measured by racial discordance, predicts poorer patient attitudes about their providers and the health care system in a severely disadvantaged hiv-infected population in new york city that typically reports inconsistent patterns of health care. methods: we collected data from 396 unscably housed black and latino/a people with hiv who reported having a regular health care provider. we asked them to report on their attitudes about their provider and the health care system using validated instruments. subjects were categorized as being racially "concordant" or "discordant" with their providers, and attitudes of these two groups were compared. results: the sample consisted of 256 (65%) black and 140 (35%) latino/a people, who reported having 80 (20%) black physicians, 49 (12%) latino/a physicians, 167 (42%) white physicians, and 100 (25%) physicians of another/unknown race/ethnicity. overall, 260 (75%) subjects had physicians of a different race/ethnicity than their own. racial discordance did not predict negative attitudes about rela· tionship with providers: the mean rating of a i-item trust in provider scale (lo=high and o=low) was 8.0 for both concordant and discordant groups, and the mean score in 13-icem relationship with provider scale (4=high and !=low) was 3.5 for both groups. however discordance was significantly associated with distrust in che health care syscem: che mean score on a 7-icem scale (5=high discrust and l=low distrust) was 3.4 for discordant group and 3.0 for che concordant group (t= 2.66, p= 0.008). we further explored these patterns separacely in black and lacino/a subgroups, and using different strategies ro conceptualize racial/ethic discordance. conclusions: in this sample of unscably housed black and latino/a people who receive hiv care in new york city, having a physician from the same racial/ethnic background may be less important for developing a positive doctor-patient relationship than for helping the patients to dispel fear and distrust about the health care system as a whole. we discuss the policy implications of these findings. ilene hyman and samuel noh . .abstract objectiw: this study examines patterns of mental healthcare utilization among ethiopian 1mm1grants living in toronto. methods: a probability sample of 342 ethiopian adults ( 18 years and older) completed structured face-to-face interviews. variables ... define, especially who are non-health care providers. plan of analysis. results: approximately 5% of respondents received memal health services from mainstream healthcare providers and 8% consulted non-healthcare professionals. of those who sought mental health services from mainstream healthcare providers, 3.1 % saw family physicians, 2.1 % visited a psychiatrist. and 0.6% consulted other healthcare providers. compared with males, a significantly higher proportion 1gsfer sessions v93 ri ftlnales consulted non-healthcare_ professionals for emotional or mental health problems (p< 0.01 ). tlbile ethiopian's overall use of mamstream healthcare services for emotional problems (5%) did not prlydiffer from the rate (6%) of the general population of ontario, only a small proportion ( 12.5%) rjerhiopians with mental health needs used services from mainstream healthcare providers. of these, !oj% received family physicians' services, 4.3 % visited a psychiatrist, and 2.2% consulted other healthll/c providers. our data also suggested that ethiopian immigrants were more likely to consult tradioooal healers than health professionals for emotional or mental health problems ( 18.8% vs. 12.5% ). our bivariate analyses found the number of somatic symptoms and stressful life events to be associated with an increased use of medical services and the presence of a mental disorder to be associated with a dfcreased use of medical services for emotional problems. however, using multivariate methods, only die number of somatic symptoms remained significantly associated with use of medical services for emooonal problems. diu#ssion: study findings suggest that there is a need for ethnic-specific and culturally-appropriate mrcrvention programs to help ethiopian immigrants and refugees with mental health needs. since there ~a strong association between somatic symptoms and the use family physicians' services, there appears robe a critical role for community-based family physicians to detect potential mental health problems among their ethiopian patients, and to provide appropriate treatment and/or referral. the authors acknowledge the centre of excellence for research in immigration and settlement (ceris) in toronto and canadian heritage who provided funding for the study. we also acknowledge linn clark whose editorial work has improved significantly the quality of this manuscript. we want to thank all the participants of the study, and the ethiopian community leaders without whose honest contributions the present study would have not been possible. this paper addresses the impact of the rationalization of health-care services on the clinical decision-making of emergency physicians in two urban hospital emergency departments in atlantic canada. using the combined strategies of observational analysis and in-depth interviewing, this study provides a qualitative understanding of how physicians and, by extension, patients are impacred by the increasing ancmpts to make health-care both more efficient and cost-effective. such attempts have resulted in significantly compromised access to primary care within the community. as a consequence, patients are, out of necessity, inappropriately relying upon emergency departments for primary care services as well as access to specialty services. within the hospital, rationalization has resulted in bed closures and severely rmricted access to in-patient services. emergency physicians and their patients are in a tenuous position having many needs but few resources. furthermore, in response to demands for greater accountability, physicians have also adopted rationality in the form of evidence-based medicine. ultimately, ho~ever, rationality whether imposed upon, or adopted by, the profession significantly undermines physu.:1ans' ability to make decisions in the best interests of their patients. johnjasek, gretchen van wye, and bonnie kerker introduction: hispanics comprise an increasing proportion of th.e new york city (nyc) populanon !currently about 25%). like males in the general population, h1spamc males (hm) have a lower prrval,nce of healthcare utilization than females. however, they face additional access barriers such as bnguage differences and high rates of uninsurance. they also bear a heavy burden of health problems lllehasobesity and hiv/aids. this paper examines patterns of healthcare access and ut1hzat1on by hm compared to other nyc adults and identifies key areas for intervention. . . . 148 9 01 5 8 9 01 and older are significantly lower than the nhm popu anon . 10 v. . 10, p<.05), though hi\' screening and immunizations are comparable between the two groups. conclusion: findings suggest that hm have less access t? healthcare than hf or nhm. hown1r, hm ble to obtain certain discrete medical services as easily as other groups, perhapsdueto!rtor are a hm. i i . subsidized programs. for other services, utilization among 1s ower. mprovmg acc~tocareinthis group will help ensure routine, quality care, which can lead to a greater use of prevennve services iii! thus bener health outcomes. introduction: cancer registry is considered as one of the most important issues in cancer epidemiology and prevention. bias or under-reporting of cancer cases can affect the accuracy of the results of epidemiological studies and control programs. the aim of this study was to assess the reliability of the regional cancer report in a relatively small province (yasuj) with almost all facilities needed for c3llcll diagnosis and treatment. methods: finding the total number of cancer cases we reviewed records of all patients diagnoicd with cancer (icd 140-239) and registered in any hospital or pathology centre from1999 until 2001 i n yasuj and all (5) surrounding provinces. results: of 504 patients who were originally residents of yasui province, 43.7% wereaccoulll!d for yasuj province. the proportion varies according to the type of cancer, for exarnplecancetsofdiglstive system, skin and breast were more frequently reported by yasuj's health facilities whereas cancmoi blood, brain and bone were mostly reported by neighbouring provinces. the remaining cases (56.3%1 were diagnosed, treated and recorded by neighbouring provinces as their incident cases. this is partly because of the fact that patients seek medical services from other provinces as they believed that the facil. ities are offered by more experienced and higher quality stuffs and their relative's or temporary acooiii' modation addresses were reported as their place of residence. conclusion: measuring the spatial incidence of cancer according to the location of report ortht current address affected the spatial statistics of cancer. to correct this problem recording the permanm! address of diagnosed cases is important. p4-60 (c). providing primary healthcare to a disadvantaged population at a university-run commumty healthcare facility tracey rickards the. c:ommuni~y .h~alth ~linic (chc) is a university sponsored nurse-managed primary bealthwt (p~c:l clime. the clm1c is an innovative model of healthcare delivery in canada that has integrated tht principles of phc ser · · h' . vices wit ma community development framework. it serves to provide access to phc services for members of th · · illi · dru is ii be . . e community, particularly the poor and those who use or gs, we mg a service-learning facil'ty f d · · · · · · d rionll h . . .,m.:. · t · . meet c ient nee s. chmc nursing and social work staff and srudents r·--· ipa em various phc activities and h .l.hont" less i . f . outreac services in the local shelters and on the streels to'"" popu auon o fredericton as well th chc · model iii fosterin an on oi : . • e promotes and supports a harm reduction . · local d!or an~ h ng ~art:ersh1p with aids new brunswick and their needle exchange program, w1tha ing condoms and :xu:t h:~~~e e~aint~nance therapy clients, and with the clie~ts themselves ~_r; benefits of receiving health f ucation, a place to shower, and a small clothing and food oai~· care rom a nurse p · · d d · --""~'i"· are evidenced in th r research that involved needsaans mvo ves clients, staff, and students. to date the chc has unacn-1 · sessment/enviro i . d ; •• '""""1ll eva uanon. the clinic has also e . d nmenta scan, cost-benefit analysis, an on-go...,,1"".'i'~ facility and compassionate lea x~mme the model of care delivery' focusing on nursing roles wi~ cj rmng among students. finally, the clinic strives to share the resu•p v95 . -arch with the community in which it provides service by distributing a bi-monthly newsletter, and plllicipating in in-services and educational sessions in a variety of situations. the plan for the future is coolinued research and the use of evidence-based practice in order to guide the staff in choosing how much n~ primary healthcare services to marginalized populations will be provided. n-61 (c) tuming up the volume: marginalized women's health concerns tckla hendrickson and betty jane richmond bdrotbu:tion: the marginalization of urban women due to socio-economic status and other determinants negatively affects their health and that of their families. this undermines the overall vitaliry of urban communities. for example, regarding access to primary health care, women of lower economic surus and education levels are less likely to be screened for breast and cervical cancer. what is not as widely reported is how marginalized urban women in ontario understand and articulate their lack of access to health care, how they attribute this, and the solutions that they offer. this paper reports on the rnults of the ontario women's health network (owhn) focus group project highlighting urban women's concerns and suggestions regarding access to health care. it also raises larger issues about urban health, dual-purpose focus group design, community-based research and health planning processes. mdhods: focus group methodology was used to facilitate a total of 30 discussions with 55 urban and 54 rural women across ontario from 2003 to 2005. the women were invited to participate by local women's and health agencies and represented a range of ages, incomes, and access issues. discussions focussed on women's current health concerns, access to health care, and information needs. results were analyzed using grounded theory. the focus groups departed from traditional focus group research goals and had two purposes: 1) data collection and dissemination (representation of women's voices), and 2) fostering closer social ties between women, local agencies, and owhn. the paper provides a discussion and rationale for a dual approach. rax/ts: the results confirm current research on women's health access in women's own voices: urban women report difficulty finding responsive doctors, accessing helpful information such as visual aids in doctors' offices, and prohibitive prescription costs, in contrast with rural women's key concern of finding a family doctor. the research suggests that women's health focus groups can address access issues by helping women to network and initiate collective solutions. the study shows that marginalized urban women are articulate about their health conctrns and those of their families, often understanding them in larger socio-economic frameworks; howtver, women need greater access to primary care and women-friendly information in more languages and in places that they go for other purposes. it is crucial that urban health planning processes consult directly with women as key health care managers, and turn up the volume on marginalized women's voices. women: an evaluation of awareness, attitudes and beliefs introduction: nigeria has one of the highest rates of human immunodeficiency virus ihivi seroprrvalence in the world. as in most developing countries vertical transmission from mother to child account for most hiv infection in nigerian children. the purpose of this study was ro. determine the awareness, attitudes and beliefs of pregnant nigerian women towards voluntary counseling and testing ivct! for hiv. mnbod: a pre-tested questionnaire was used to survey a cross section '.>f.240 pregnant women ~t 2 (lrlleral antenatal clinics in awka, nigeria. data was reviewed based on willingness to ~c~ept or re1ect vct and the reasons for disapproval. knowledge of hiv infection, routes of hiv transm1ssmn and ant1rnroviral therapy iart) was evaluated. hsults: 72% of the women had good knowledge of hiv, i 5% had fair knowledge while 1.1% had poor knowledge of hiv infection.48% of the women were not aware of the association of hreast milk feeding and transmission of hiv to their babies. majority of the women 87% approved v~t while 13% disapproved vct, 93% of those who approved said it was because vct could ~educe risk of rransmission of hiv to their babies. all respondents, 100% who accepted vc.i ~ere willing to be tnted if results are kept confidential only 23% accepted to be tested if vc.t results w.111 be s~ared w1.th pinner and relatives 31 % attributed their refusal to the effect it may have on their marriage whale 69 '-gave the social 'and cultural stigmatization associated with hiv infection for their r~fusal.s 9 % wall accept vct if they will be tested at the same time with their partners.81 ~0 of ~omen wall pref~r to breast feed even if they tested positive to hiv. women with a higher education diploma were 3 times v96 more likely to accept vct. knowledge of art for hiv infected pregnant women as a means of pre. vention of maternal to child transmission [pmtct) was generally poor, 37% of respondents wm aware of art in pregnancy. conclusion: the acceptance of vct by pregnant women seems to depend on their understanding that vct has proven benefits for their unborn child. socio-cultur al factors such as stigmatizationof hiv positive individuals appears to be the maj_or impedi~ent towards widespread acceptanee of ycr in nigeria. involvemen t of male partners may 1mpro~e attitudes t~wa~ds vct:the developmentofm novative health education strategies is essential to provide women with mformanon as regards the benefits of vct and other means of pmtct. p4-63 (c) ethnic health care advisors in information centers on health care and welfare in four districts of amsterdam arlette hesselink, karien stronks, and arnoud verhoeff introduction : in amsterdam, migrants report a "worse actual health and a lower use of health care services than the native dutch population. this difference might be partly caused by problems migrants have with the dutch language and health care and welfare system. to support migrants finding their way through this system, in four districts in amsterdam information centers on health care and welfare were developed in which ethnic health care advisors were employed. their main task is to provide infor· mation to individuals or groups in order to bridge the gap between migrants and health care providers. methods: the implementat ion of the centers is evaluated using a process evaluation in order to give inside in the factors hampering and promoting the implementat ion. information is gathered using reports, attending meetings of local steering groups, and by semi-structu red interviews with persons (in)directly involved in the implementat ion of the centers. in addition, all individual and groupcontaets of the health care advisors are registered extensively. results: since 2003 four information centers, employing 12 ethnic health care advisors, are implemented. the ethnicity of the health care advisors corresponds to the main migrant groups in the different districts (e.g. moroccan, turkeys, surinamese and african). depending on the local steering groups, the focus of the activities of the health care advisors in the centers varies. in total, around 2000 individual and 225 group educational sessions have been registered since the start. most participants were positive about the individual and group sessions. the number of clients and type of questions asked depend highly on the location of the centers (e.g. as part of a welfare centre or as part of a housing corporation). in all districts implementa tion was hampered by lack of ongoing commitment of parties involved (e.g. health care providers, migrant organization s) and lack of integration with existing health care and welfare facilities. discussion: the migrant health advisors seem to have an important role in providing information on health and welfare to migrant clients, and therefore contribute in bridging the gap between migrants and professionals in health care and welfare. however, the lack of integration of the centers with the existing health care and welfare facilities in the different districts hampers further implementation . therefore, in most districts the information centres will be closed down as independent facilicities in the near future, and efforts are made to better connect the position of migrant health advisor in existing facilities. the 2005 who report ranks the philippines as ninth among 22 countries with a high tb prevalence. about a fourth of the country's population is infected, with majority of cases coming from the lower socioeconomic segments of the community. metro manila is not only the economic and political capital of the philippines but also the site of major universities and educational institutions. initial interviews with the school's clinicians have established the need to come up with treatment guidelines and protocols for students and personnel when tb is diagnosed. these cases are often identified during annual physical examinations as part of the school's requirements. in many instances, students and personnel diagnosed with tb are referred to private physicians where they are often lost to follow-up and may have failure of treatment due to un monitored self-administered therapy. this practice ignores the school clinic's great potential as a tb treatment partner. through its single practice network (spn) initiative, the philippine tuberculosis initiatives for the private sector (philippine tips), has established a model wherein school clinics serve as satellite treatment partners of larger clinics in the delivery of the directly observed treatment, short course (dots) protocol. this "treatment at the source" allows school-based patients to get their free government-suppl ied tb medicines from the clinic each day. it also cancels out the difficulty in accessing medicines through the old model where the patient has to go to the larger clinic outside his/her school to get treatment. the model also enables the clinic to monitor the treatment progress of the student and assumes more responsibility over their health. this experience illustrates how social justice in health could be achieved from means other than fund generation. the harnessing of existing health service providers in urban communities through standardized models of treatment delivery increases the probability of treatment success, not only for tb but for other conditions as well. p4-66 (c) voices for vulnerable populations: communalities across cbpr using qualitative methods martha ann carey, aja lesh, jo-ellen asbury, and mickey smith introduction: providing an opportunity to include, in all stages of health studies, the perspectives and experiences of vulnerable and marginalized populations is increasingly being recognized as a necessary component in uncovering new solutions to issues in health care. qualitative methods, especially focus groups, have been used to understand the perspectives and needs of community members and clinical staff in the development of program theory, process evaluation and refinement of interventions, and for understanding and interpreting results. however, little guidance is available for the optimal use of such information. methods: this presentation will draw on diverse experiences with children and their families in an asthma program in california, a preschool latino population in southern california, a small city afterschool prevention program for children in ohio, hiv/aids military personnel across all branches of the service in the united states, and methadone clinic clients in the south bronx in new york city. focus groups were used to elicit information from community members who would not usually have input into problem definitions and solutions. using a fairly common approach, thematic analysis as adapted from grounded theory, was used to identify concerns in each study. next we looked across these studies, in a meta-synthesis approach, to examine communalities in what was learned and in how information was used in program development and refinement. results: while the purposes and populations were diverse, and the type of concerns and the reporting of results varied, the conceptual framework that guided the planning and implementation of each study was similar, which led to a similar data analysis approach. we will briefly present the results of each study, and in more depth we will describe the communalities and how they were generated. conclusions: while some useful guidance for planning future studies of community based research was gained by looking across these diverse studies, it would be useful to pursue a broader examination of the range of populations and purposes to more fully develop guidance. background: the majority of studies examining the relationship between residential environments and cardiovascular disease have used census derived measures of neighborhood ses. there is a need to identify specific features of neighborhoods relevant to cardiovascular disease risk. we aim to 1) develop methods· data on neighborhood conditions were collected from a telephone survey of s,988 fesi· dents in balth:.ore, md; forsyth county, nc; and new york, ny. a sample of 120 of the i.ni~~l l'elpondents was re-interviewed 2-3 weeks after the initial interview t~ measure the tes~-~etest rebab1~1ty of ~e neighborhood scales. information was collected across seven ~e1ghborho~ cond1~ons (aesth~~ ~uah~, walking environment, availability of healthy foods, safety, violence, social cohesion, and acnvmes with neighbors). neighborhoods were defined as census tracts or homogen~us census tra~ clusters. ~sycho metric properties.of the neighborhood scales were accessed by ca~cu~~.ng chronba~h s alpha~ (mtemal consistency) and intraclass correlation coefficients (test-r~test reliabilmes) .. pear~n s .corre~anons were calculated to test for associations between indicators of neighborhood ses (tncludmg d1mens1ons of race/ ethnic composition, family structure, housing, area crowding, residential stability, education, employment, occupation, and income/wealth) and our seven neighborhood scales. . chronbach's alphas ranged from .73 (walking environment) to .83 (violence). intraclass correlations ranged from .60 (waling environment) to .88 (safety) and wer~ high~~~ .7~ for ~urout of the seven neighborhood dimensions. our neighborhood scales (excluding achv1hes with neighbors) were consistently correlated with commonly used census derived indicators of neighborhood ses. the results suggest that neighborhood attributes can be reliably measured. further development of such scales will improve our understanding of neighborhood conditions and their importance to health. childhood to young adulthood in a national u.s. sample jen jen chang lntrodfldion: prior studies indicate higher risk of substance use in children of depressed mothers, but no prior studies have followed up the offspring from childhood into adulthood to obtain more precise estimates of risk. this study aimed to examine the association between early exposure to maternal depl'elsive symptoms (mds) and offspring substance use across time in childhood, adolescence, and young adulthood. methods: data were obtained from the national longitudinal survey of youth. the study sample includes 4,898 mother-child/young adult dyads interviewed biennially between 1992 and 2002 with children aged 4 to 16 years old at baseline. data were gathered using a computer-assisted personal interview method. mds were measured in 1992 using the center for epidemiologic studies depression scale. offspring substance use was assessed biennially between 1994 and 2002. logistic and passion regression models with generalized estimation equation approach was used for parameter estimates to account for possible correlations among repeated measures in a longitudinal study. rnlllta: most mothers in the study sample were whites (42%), urban residents (79%), had a mean age of 31 years with at least a high school degree (82%). the mean child age at baseline was 9 years old. offspring cigarette and alcohol use increased monotonically across childhood, adolescence, and young adulthood. differential risk of substance use by gender was observed. early exposure to mds was associated with increased risk of cigarette (adjusted odds ratio (aor) = 1.52, 95% confidence interval (0): 1.12, 2.08) and marijuana use (aor = 1.46, 95% ci: 1.02, 2.08), but not with alcohol use across childhood, adolescence, and young adulthood, controlling for a child's characteristics, socioeconomic status, ~ligiosity, maternal drug use, and father's involvement. among the covariates, higher levels of father's mvolvement condluion: results from this study confirm previous suggestions that maternal depressive symptoms are associated with adverse child development. findings from the present study on early life experi-e~ce have the potential to inform valuable prevention programs for problem substance use before disturbances become severe and therefore, typically, much more difficult to ameliorate effectively. the ~act (~r-city men~ health study predicting filv/aids, club and other drug transi-b~) study 15 a multi-level study aimed at determining the association between features of the urban enyjronment mental health, drug use, and risky sexual behaviors. the study is randomly sampling foster sessions v99 neighborhood residents and assessing the relations between characteristics of 36 ethnographically defined urban neighborhoods and the health outcomes of interest. a limitation of existing systematic methods for evaluating the physical and social environments of urban neighborhoods is that they are expensive and time-consuming, therefore limiting the number of times such assessments can be conducted. this is particularly problematic for multi-year studies, where neighborhoods may change as a result of seasonality, gentrification, municipal projects, immigration and the like. therefore, we developed a simpler neighborhood assessment scale that systematically assessed the physical and social environment of urban neighborhoods. the impact neighborhood evaluation scale was developed based on existing and validated instruments, including the new york city housing and vacancy survey which is performed by the u.s. census bureau, and the nyc mayor's office of operations scorecard cleanliness program, and modified through pilot testing and cognitive testing with neighborhood residents. aspects of the physical environment assessed in the scale included physical decay, vacancy and construction, municipal investment and green space. aspects of the social environment measured include social disorder, social trust, affluence and formal and informal street economy. the scale assesses features of the neighborhood environment that are determined by personal (e.g., presence of dog feces), community (e.g., presence of a community garden), and municipal (e.g., street cleanliness) factors. the scale is administered systematically block-by-block in a neighborhood. trained research staff start at the northeast corner of an intersection and walk around the blocks in a clockwise direction. staff complete the scale for each street of the block, only evaluating the right side of the street. thus for each block, three or more assessments are completed. we are in the process of assessing psychometric properties of the instrument, including inter-rater reliability and internal consistency, and determining the minimum number of blocks or street segments that need to be assessed in order to provide an accurate estimate of the neighborhood environment. these data will be presented at the conference. obj«tive: to describe and analyze the perceptions of longterm injection drug users (idus) about their initiation into injecting. toronto. purposive sampling was used to seek out an ethnoculturally diverse sample of idus of both genders and from all areas of the city, through recruitment from harm reduction services and from referral by other study participants. interviews asked about drug use history including first use and first injecting, as well as questions about health issues, service utilization and needs. thematic analysis was used to examine initiation of drug use and of injection. results: two conditions appeared necessary for initiation of injection. one was a developed conception of drugs and their (desirable) effects, as suggested by the work of becker for marijuana. thus virtually all panicipants had used drugs by other routes prior to injecting, and had developed expectations about effects they considered pleasureable or beneficial. the second condition was a group and social context in which such use arose. no participants perceived their initiation to injecting as involving peer pressure. rather they suggested that they sought out peers with a similar social situation and interest in using drugs. observing injection by others often served as a means to initiate injection. injection served symbolic purposes for some participants, enhancing their status in their group and marking a transition to a different social world. concl111ion: better understanding of social and contextual factors motivating drug users who initiate injection can assist in prevention efforts. 10 ma!onty of them had higher educational level (57%-highschool or higher).about 20.2 yo adffiltted to have history of alcohol & another 12.4% had history of smoking. only 3.2% people were on hrt & 3.1 % were receiving steroid. majority of them (81.2) did not have history of osteoporosis. 13.6% have difficulty in ambulating. only 8.8% had family history of osteoporosis. bmd measurements as me~sured by dual xray absorptiometry (dexa) were used for the analysis. bmd results were compare~ w1~ rbc folate & serum vitamin b12 levels. no statistical significance found between bmd & serum v1taffiln b12 level but high levels of folate level is associated with normal bmd in bivariate and multivariate analysis. conclusion: in the studied elderly population, there was no relationship between bmd and vitamin b12; but there was a significant association between folate levels & bmd. introduction: adolescence is a critical period for identity formation. western studies have investigated the relationship of identity to adolescent well-being. special emphasis has been placed on the influence of ethnic identity on health, especially among forced migrants in different foreign countries. methodology: this study asses by the means of an open ended question identity categorization among youth in three economically disadvantaged urban communities in beirut, the capital of lebanon. these three communities have different histories of displacement and different socio-demographic makeup. however, they share a history of displacement due to war. results and conclusion: the results indicated that nationality was the major category of identification in all three communities followed by origin and religion. however, the percentages that self-identify by particular identity categories were significantly different among youth in the three communities, perhaps reflecting different context in which they have grown up. mechanical heart valve replacement amanda hu, chi-ming chow, diem dao, lee errett, and mary keith introduction: patients with mechanical heart valves must follow lifelong warfarin therapy. war· farin, however, is a difficult drug to take because it has a narrow therapeutic window with potential seri· ous side effects. successful anticoagulation therapy is dependent upon the patient's knowledge of this drug; however, little is known regarding the determinants of such knowledge. the purpose of this study was to determine the influence of socioeconomic status on patients' knowledge of warfarin therapy. methods: a telephone survey was conducted among 100 patients 3 to 6 months following mechan· ical heart valve replacement. a previously validated 20-item questionnaire was used to measure the patient's knowledge of warfarin, its side effects, and vitamin k food sources. demographic information, socioeconomic status data, and medical education information were also collected. results: sixty-one percent of participants had scores indicative of insufficient knowledge of warfarin therapy (score :s; 80%). age was negatively related to warfarin knowledge scores (r= 0.27, p = 0.007). in univariate analysis, patients with family incomes greater than $25,000, who had greater. than a grade 8 education and who were employed or self employed had significantly higher warfarm knowledge scores (p= 0.007, p= 0.002 and p= 0.001 respectively). gender, ethnicity, and warfar~n therapy prior to surgery were not related to warfarin knowledge scores. furthermore, none of t~e. m-hospital tea~hing practices significantly influenced warfarin knowledge scores. however, panic1~ants who _rece1v~d post discharge co~unity counseling had significantly higher knowledge scores tn comp~r1son with those who did not (p= 0.001 ). multivariate regression analysis revealed that und~r~tandmg the ~oncept of 1?ternational normalized ratio (inr), knowing the acronym, age and receiving ~ommum1!' counseling after discharge were the strongest predictors of warfarin kn~wledge. s~1oeconom1c status was not an important predictor of knowledge scores on the multivanate analysis. poster sessions v101 ~the majority of patients at our institution have insufficient knowledge of warfarin therapy.post-discharge counseling, not socioeconomic status, was found to be an important predictor of warfarin knowledge. since improved knowledge has been associated with improved compliance and control, our findings support the need to develop a comprehensive post-discharge education program or, at least, to ensure that patients have access to a community counselor to compliment the in-hospital educatiop program. brenda stade, tony barozzino, lorna bartholomew, and michael sgro lnttotl#ction: due to the paucity of prospective studies conducted and the inconsistency of results, the effects of prenatal cocaine exposure on functional abilities during childhood remain unclear. unlike the diagnosis of fetal alcohol spectrum disorder, a presentation of prenatal cocaine exposure and developmental and cognitive disabilities does not meet the criteria for specialized services. implications for public policy and services are substantial. objective: to describe the characteristics of children exposed to cocaine during gestation who present to an inner city specialty clinic. mnbods: prospective cohort research design. sample and setting: children ages 5 to 15 years old, referred to an inner city prenatal substance exposure clinic since november, 2003. data collection: data on consecutive children seen in the clinic were collected over an 18 month period. instrument: a thirteen (13) page intake and diagnostic form, and a detailed physical examination were used to collect data on prenatal substance history, school history, behavioral problems, neuro-psychological profile, growth and physical health of each of the participants. data analysis: content analysis of the data obtained was conducted. results: twenty children aged 6 to 14 years (mean= 9.8 years) participated in the study. all participants had a significant history of cocaine exposure and none had maternal history or laboratory (urine, meconium or hair) exposure to alcohol or other substances. none met the criteria of fetal alcohol spectrum disorder. all were greater than the tenth percentile on height, weight, and head circumference, and were physically healthy. twelve of the children had iqs at the 19th percentile or less. for all of the children, keeping up with age appropriate peers was an ongoing challenge because of problems in attention, motivation, motor control, sensory integration and expressive language. seventy-four percent of participants had significant behavioral and/or psychological problems including aggressiveness, hyperactivity, lying, poor peer relationships, extreme anxiety, phobias, and poor self-esteem. conclusion: pilot study results demonstrated that children prenatally exposed to cocaine have significant learning, behavioural, and social problems. further research focusing on the characteristics of children prenatally exposed to cocaine has the potential for changing policy and improving services for this population. methods: trained interviewers conducted anonymous quantitative surveys with a random sample (n= 148) of female detainees upon providing informed consent. the survey focused on: sociodemographic background; health status; housing and neighborhood stability and social resource availability upon release. results: participants were 70% african-american, 16% white, 9% mixed race and 5% native american. participants' median age was 37, the reported median income was <s2,000 year, and 53% reported receiving a high school diploma or equivalent. women reported a number of health conditions rypical of underserved populations, including asthma (42%), sexually transmitted infections (39%), high blood pressure (19%), hcv (14%), diabetes (5%) and hiv (4%). nearly half (46%) did not anticipate having a place to stay for at least 30 days upon release. factors significantly associated housing stability upon release were: high family support score (adjusted odds ratio [aor) 6.15; 95% confidence interval (95% cl) 1.76, 21.61), high neighborhood stability score (aor 4.41; 95% cl 1.25, 15.52), wanting a commercial sex worker (csw) support group (aor 0.25; 95% cl 0.10, 0.62); and identifying as bisexual (aor 0.24; 95% cl 0.07, 0.75). women desired employment (95%), housing (84%), education (77%), drug treattnent (74%), help with custody of children (31 %), childcare (28%), and domestic violence suppon (20%) services. conclusions: female detainees represent one of urban centers' most marginalized pcjpwatioos. short periods of detention represent a unique opportunity for _interven?~ns bri~ co~s and public health institutions. service providers should collaborate ~1th local ~ails to .p~de a con1111uwnof care for female detainees upon release that includes transportation , housing, residential drug treallllcnt, employment, education, family reunification, childcare and domestic viol~nce su~rt. ~pecial attenlion is warranted to lesbian and bisexual women and csws, who may be especially margmalized &om family and service-based support networks. introduction: "health care and ethnic minority immigrants" examines how health care policy dil· ferences between canada and the united states impact the health-related hardships, access and use of preventative care, and health outcomes of urban ethnic minority immigrants in both countries. methods: the findings of this paper build on the results of my qualitative comparative study of hotel workers in vancouver, bc and seattle, wa that revealed greater health related hardships for similarly matched employees in seattle compared to vancouver. in this paper, i examine the generalizability of these findings at the cross-national level for similar ethnic minority immigrant groups. i compare the impact of health care policy differences on specific groups that have emigrated to cities in both canada and the united states. these include immigrants from china, viemam, philippines, west indies, africa, sri lanka, pakistan, and latin america. comparative statistical analysis -utilizing rel· evant data from statistics canada and the u.s. census -reveal the extent to which health policy differ· ences help explain how current health policy in the united states disadvantages urban ethnic minority immigrants. results: many ethnic minority immigrants are a part of the working poor, a group which disproportionately lacks health insurance coverage in the united states. their position in the labour market makes them most vulnerable to exclusion from health care services. the data reveals how current u.s. health policy creates barriers for recently arrived ethnic minority immigrants to access health insurance and care. it remains difficult to ascribe health outcome differences directly to policy differences because of the challenge in disentangling the complex interacting interventing variables, including income inequality, that determine health outcomes. yer suggestive evidence suggests that health policy in the united states is harming the health of urban ethnic minority immigrants. the current health policy regime in the united states harms the health access, care, and outcomes of urban ethnic minority immigrants. comparing the fortunes of similar immigrants in cana· dian and u.s. cities reveals these patterns of disadvantage and some of their consequences. these barriers are an understudied factor in the sociological literature on "segmented assimilation" and social exclu· sion. the paper ends with policy recommendatio ns to improve access to health care among ethnic minor· ity immigrants in both countries, with the goal of reducing health related hardships, and improving health outcomes. mass index deyu pan, richard baker, and keith norris badtgrou~ over the past 3 decades, there has been dramatic increase in prevalence of obesity in the us population. however, the relationship between obesity and the prevalence of cardiovascular dis· ease (cv~) risk factors in different race/ethnic groups over time is not well known. . ik~rgn: _we use 2 cross-sectional , nationally representative surveys: national health and nutri· t10nal examination survey (nhanes iii 1988 -1994 (n= 14 029) and nhanes 1999 nhanes -2002 , including white, black, and hispa~ic races who were no~preg~ant, aged 20 to 74 years. res11lt1: the preval~nce of high cholesterol level (~ 240 mg/dl), untreated high blood pressure (2: l40/90 mm hg) an~ diabetes were calculated according to bmi group (lean, <25; overweight, 25-29; and obese, 2: 30) for different race/ethnicity groups. over the approximately 10 years period (from 1988l ~94 ~o [1999] [2000] [2001] [2002] , reducrion in 3 cvd risk factors in non-hispanic white has been observed. for mmonty race/~hnicity groups, black and hispanic, there had been increases in prevalence in high blood fa pressure and diabetes. the lean group experienced larger increase in prevalence of those cvd risk ctors. . fo~~ the prevalence in cvd risk factors over time had reduced in most of the bmi ca1egoes r t e w ~~e population. however, for black and hispanic, prevalence of 2 of 3 cvd risk factors ave generauy uncreased, especially in overweight and obese groups. methods: strategies identified to achieve these goals include: developing meaningful neighbourhood and district boundaries for comparing health information, providing free access to neighbourhood health profiles (including relevant data at the smallest level for which valid rates could be calculated); mapping relationships of inequality at a variety of nested levels; providing a range of formats (maps, tables) to meet the needs of users; providing technical support; seeking user input to advance and improve the site; and conducting workshops to foster access and use of data for decision-making , advocacy and collaboration. an evaluation strategy is being developed to assess the efforts and impact of these strategies. a preliminary assessment of the results of the first six months of activity will be completed in october 2005. results: significant differences in health are shown at all the geographic levels indicating success in developing the boundaries. results tabulated for the first six months use of the site include: site visits; media use; reference/acknow ledgement of the site in other documents; number of contacts through presentations and workshops; feedback from users identifying strengths and limitations; and, response from health decision makers. members of the partnership are identifying additional tools and services to further support actions that reduce health inequalities. the assessment will be used to develop more specific goals, targets and monitoring mechanisms. conclusions: our experience with paper-based health profiles indicates that they have been used extensively for program planning and advocacy. the greater availability of information in a publiclyavailable web-based format is expected to translate into even greater usefulness and wider application. the web site has had considerable usage to date, extensive media coverage. site users and workshop participants have provided positive feedback and suggestions for next steps. the six month review will be available in october 2005. in india, more than 4 and a half people are hiv-positive and half a million have aids. india currently has the largest number of positive people in the world, oumumbering south africa and accounting for nearly one tenth of the global hiv/aids prevalence. the world bank predicts that by 2015, there will be 35 million hiv/aids cases in india. the central challenge facing hiv prevention efforts in south asia today is learning how to respond to the societal determinants of vulnerability to hiv. hiv/aids is an issue largely engulfed by social stigma. stigma and discrimination are often considered the foremost barriers to effective poster sess10ns v104 prevention and care initiatives. stigma can make a person afraid of disclosing their status~ ~yone el se, and may make them feel depressed or alone. stigma can .also le~d to poor adherence to medicanon, ~ likelihood to access health and social services, and less desire to hve. hiv+ men and women may beafraidtotd! their co-workers that they have hiv for fear of their reactions or for fear of losing their jobs. in a study 1 conducted of people living with hiv/aids in delhi, india ov~r. 2003-~, many respo~ts shared their experiences of discrimination in their families, in their communmes, an~ m health ~e settmgs. these findings will be shared in the workshop, and will be compa~ed to m~ ex~nences workmg as an ~ co~l~ at the center for aids prevention studies in san francisco, cahforma and congreso de lannos unidos m philadelphia, pennsylvania. the workshop will include an overview of hiv/aids in urban contexts in tht united states (los angeles, san francisco, new york, philadelphia) and south asia (delhi, hyderabad, chennai). differences in methods for outreach, prevention and treatment efforts between devdoped world and developing world contexts will be discussed. a large portion of the workshop will be centered on discussion. participants will engage in an exercise to categorize their ideas of stigma. the workshop will also include a powerpoint presentation on the quantitative data gathered from the survey. the number of homeless and runaway youth is increasing in toronto, which is currently home to 3 out of 4 youth in the gt a who live alone, and it is the preferred locale for the street-involved and homeless youth. the city's youth population is expected to grow by nearly 20% by 2011, the school dropout rate is rising, and there are is a paucity of empirical data on what works with these at-risk youth. over a two-year period, (2002) (2003) (2004) , youthlink-inner city, conducted an evaluation of the impact of a harm reduction program aimed at reducing street youth's risk of contracting/infecting others with the hep c virus, which has both short-term and long-term deleterious effects. demographic data from 102 street-youth, along with resources/services used, employment methods, type and frequency of drug use, health status, police contacts, and their views of program impact were analyzed using a standardized sur· vey. additionally, focus groups with youth, agency staff and community key informants were conducted, as well as in-depth interviews with three youth, over a sixth-month period. this paper details study results, which both inform both practice and future study about what works, why it works, and how best to work with these vulnerable youth. sho~ed .that the wasteland in this area was contaminated by as cd zn pb cu simultaneously. the con-ta~matton of as ~d was quit significant. the contamination problems and environmental issues in this region are very. serious. the awareness on environmental and health issues was investigated by spot survey and analysis. overall awareness among the residents in the region is very poor. the measures must be taken to assu~e t~e .sustainable economy development by local and central gorvernments. keywords nandan guangx1; mmmg area; environmental awareness. concern like, epileptic fits, vision problems, earache, cough of more than 3 weeks and urinary problems. ninety-five subjects did not take bath regularly and 42 were exposed to sex. the health problems identified are only of a particular point of time and it may be difficult to interpret the depth of "iceberg" of the street children's world also draw the health-illness continuum. periodic interaction and follow-up is very difficult as they generally disappear from the research setting due to their frequent mobility for survival measures. as per the prediction of the iceberg theory, only some problems may have been identified, larger problems in respect to their health may not have been identified. in spite of various limitations, this attempt had proven that, it is possible to enter the street children world, explore the iceberg of illnesses, and establish data of health-illness continuum through an effective nursing agency. it is recommended to deworm these children, provide nutritional education, establish "condom corners" and "street children help line" in the city and urban slum areas and undertake action research on their health. malnutrition is a serious problem in developing countries like bangladesh. malnutrition causes a great deal of child suffering. malnutrition is one of the major causes of morbidity and mortality among the child. the aim of present study was to investigate the nutritional status and its relation to socioeconomic conditions of urban disadvantaged child of under five years age. nutritional status was determined by anthropoemetric measurement(heig ht, weight, mid-arm circumference etc.). determination of total protein and serum albumin were done for biochemical examination. haematological examination was done by blood haemoglobin profile estimation by cynmethhaemoglob in method and determination of haematocrit value or packed cell volume (pcv). stool examination for ova of hook worm, round worm, trichuris species and other species were also done. relevant information on socioeconomic characteristics was recorded by interviewing the house hold head using pretested questionnaire. our study demonstrated that nutritional status of the children are positively correlated with family income, parents level of formal education and negatively related to the family size. the effect of family income on the nutritional status, haematological and biochemical indices of urban disadvantaged child under five will be discussed in detail which will help us to determine proper way of utilization of health care facilities exists in developing countries. introduction: with the increase in morbidity and reduction in mortality and with the introduction of highly active antiretroviral therapy (haart), there is increasing focus on the determinants of healthrelated quality of life (hrqol) in hiv-infection. the focus on the present study is to examine the relationship between social support, depression, and hiv disease severity, and the extent to which these variables impact on hrqol in adult men with hiv-infection. methods: as part of a larger ongoing natural history study focusing on the neurobehavioural complications of hiv and aids, we administered questionnaires to assess depression (beck depression inventory), social support, and hrqol (mos-hiv) to 366 adult men with hiv-infection. a structured interview was used to collect health information and data on hiv disease severity. physical and mental health summary scores (phs and mhs) were derived through principal components analysis. participants were grouped according to level of social support: "well supported" (n= 180), "moderately supported" (n=90), "little or ineffective support" (n=96). analysis of variance was conducted to assess the effects of three levels of perceived social support, depression status (present vs absent), and hiv disease severity (aids vs non-aids) on mental and physical health dimensions of hrqol. potential interaction effects were also evaluated. results: social support was found to have a significant effect on both mhs and phs. presence of depression was found to have a significant effect on mhs but not phs. hiv disease severity (presence of aids diagnosis) was found to have a significant effect on phs but not mhs. manov a analyses revealed no significant interactions effects. conclusions and implications: level of social support, presence of depression and hiv disease severity were shown to have independent effects on hrqol. feeling "well supported" appears to have significant benefits for mental and physical health. biological indicators of hiv disease appear to have a selective impact on physical health while presence of depression is related to significant reductions in mental health. the development and evaluation of behavioural interventions to improve perceived social support network and depression will likely result in significant improvements in health outcomes of adults with hiv and aids. introduction: ongoing medical advances have greatly enhanced the longevity of penons living with aids (plwa). however, for certain subgroups living with hiv/aids, including, members of minority groups, women and the economically underprivilege d, aids outcomes have not changed so favorably. one obvious factor to consider when explaining disparities in aids outcomes is the environ· ment within which an individual resides. few studies of aids outcomes have focused on how commu· nity setting influences the effectiveness of care delivery. the principle research questions were: 1) what is the relationship between the locations of areas with concentrations of pl wa and the distribution of both primary and ancillary service providers? 2) how has the widespread availability of haart (after 1996) impacted aids outcomes at the community level? 3) how do aids mortality and fatality rates vary when related community characteristics, such as household income, ethnic mix, and geographic access to primary and ancillary hiv/aids services are considered? we examine this issue across residential communities in the los angeles area. methods: los angeles county's comprehensive aids service providers database (compiled and maintained by aids project los angeles) was geo-referenced and distances between weighted mean population centers and the nearest hiv/aids service providers were calculated to provide a measure of access which was then merged with aids diagnosis and mortality data along with relevant socioeconomic and population indicators and for analysis using bivariate and multivariate statistics at the zip code level. results: there is a growing disparity in hiv/aids outcomes between low-income minority areas and affluent non-minority areas in the post-haart era (p = 0.002). ancillary aids services such as case management and counseling and testing are located near the places where low income hiv/aids service consumers are likely to live (p =.000). in spite of having more access to ancillary services low income areas continue to be associated with smaller decreases post-haart aids mortality rates (p=0.301). conclusions: given the increasing disparities in aids outcomes between lower and upper income communities in the post -haart era, more specific research into the capacities of aids services providers and the efficiency of their interventions is required. although it is clear that ancillary services are operating in the areas of greatest need, their effectiveness remains limited. understanding the reasons for t~is, be they lack of adequate resources for inner city service providers, failure to reach target popula· tmns or other causes, requires additional research. in 20?3, y.out~ who were able to speak either french or english and had been absent from their parent's/ c~regivers ~es.1dence for at least three consecutive nights took part in the survey which consisted of inter· viewer-adm1ms tered question~aires. p.arti~i~an~s were recruited from drop in centres in 7 cities across <?-nada.y~uth self-report as either using in1ect1on or non-injection drugs. statistical analyses were car· r1ed out using sas version 8. the 'home' is a contested site for many women living in urban areas. women living in poverty and using illicit drugs are largely excluded from participation in dominant 'home-base' gender roles of wife and mother because of economic disadvantage. they thus 'make home' in ways that are specific to their everyday experiences. while research has established links between housing, health and drug use, this literature does not tend to consider the meanings that home may have within the lives of women who lack access to adequate tenured living spaces. this presentation reports the findings of my master's thesis work. using grounded theory methodology within a poststructuralist feminist conceptual framework, i conducted in-depth, open-ended interviews with 11 women living in the toronto area. the women were recruited from within the community through posters at different social service agencies (e.g., drop-in centres, community health centres). they were asked to describe their housing experiences and what home meant to them over the course of their lives. through the data analysis process, a substantive theory of 'making home' for women living in poverty and using illicit drugs emerged. the central concept of making home is a continual process of learning about and interacting with the environment. the process of making home entails different subprocesses: finding home (knowing what is available and accessible, and accessing home), adaptation, and leaving home. the different meanings of home that women developed from their experiences and knowledge emerged as critical components for the process of making home. the women i interviewed were very mobile and experienced constant change with regards to home. home was not considered only in relation to physical living space. home could be made within a relationship or with regards to a possession. while dominant meanings of home relation to tenured living spaces are generally positive, my research indicated that home could also be a negative context. the presentation will describe my research process and findings as well as the theoretical and policy implications of my results. in the western democracies, social citizenship bundles the right to social provision (defined as a share of the social good, not necessarily proportionate to the market value of a citizen's contribution) with participation in the paid labour force. for this reason, social citizenship rights, which usually involve some kind of redistributive measures, are a key mechanism by which states ensure economic equality, or at least, economic equality of opportunity, but are also a mechanism of social exclusion. social rights are inscribed around a single kind of relationship, that which exists between a male family breadwinner and the paid labor market; those who make economic contributions that fall outside this relationship -such as unpaid care-work, or, work that occurs in shadow or underground economiesare to a greater or lesser degree barred from accessing citizen-based social provisions. furthermore, social provision that occurs outside of the breadwinner/market-eco nomy dyad is very often meanstested and is accompanied by regulatory state apparatuses (this includes a range of social services, from welfare payments, to child-care subsidies, to disability pensions). social citizenship is thus stratified; the legal relationship that is at the heart of social citizenship acts as a form of social closure against claims for a share of the social good made by those who are 'lesser' citizens than others. of particular interest in this paper is how citizenship inequalities translate into inequalities in the social provisions that emerge from economic participation: the right to safety on the job, protection from employer harassment, protection from the vagaries of the market as well the right to adequate, comprehensive, and appropriate health services. drawing on mixed methods, longitudinal data from adult sex workers (n= 170) located in two research sites with different social welfare regimes -one in canada and one in the u.s. -we examine the consequences of working in a "shadow" or "underground" economy on various facets of health and access to health services, taking into consideration the mediating role that citizenship constructs and social welfare regimes play in accessing other key social and economic determinants of health. methods: the study population included methadone patients (re)admitted at the mhs in the period from 1/1/1996 to 31/1/2002, born in the netherlands, morocco, surinam, dutch antilles or turkye, and officially registered in the population register of amsterdam. the population register was used to ascer· rain the vital status. causes of death were provided by the central bureau of statistics. mortality was categorised as hiv related, directly drug related (overdose) and other.mortality. results: the methadone patients had the following characteristics: 38 years of age at entry; 81% male; 37% ethnic minority; 37% ever injected. in total, 9558 personyear (py) of observation time and 173 deaths (18% hiv related, 14% overdose; 57% other) were observed. hence, the crude mortality rate was 18/1000 py (95% ci 16-21/1000 py). the percentage of (ever) injectors was higher among the native dutch than among the ethnic minorities, 51 % and 14 % respectively. higher rates were observed among native dutch drug users compared to those belonging to an ethnic minority (age adjusted hazard ratio (hr) 1.9 (95% ci 1.4-2.7). the age adjusted hr of (ever) injecting drug users versus non injecting users was 3.0 (95% cl 2.2-4.1 ). after additional adjustment for route of administration a non significant difference between the dutch and ethnic minorities remained (hr 1.3, 95% cl 0.9-1.9, p-value 0.151. conclusion: the mortality rate among the heroin users in amsterdam is strongly affected by the high prevalence of non-injecting drug use. moreover, this study confirms that differences in mortality between the native dutch and the ethnic minorities is related to differences in route of administration. the ongoing reduction of injecting drug use (due tot selctieve mortality, and switching route ofadministration and popularity of crack cocaine) may lead to a further reduction of mortality rates among heroin users in amsterdam. interventions preventing the initiation of injecting should be encouraged. . introduction: food insecurity is an inequality that is central in the lives of many low-income cana· d1ans. people lack food security when regular access to nutritious food is limited or variable due to high prices'. low income, lack of transportation or inadequate food distribution, or they become disadvan· taged m other w~ys through the acquisition of food. a group comprising academics, health profession· als, and commumty workers who have experience in food insecurity, developed a pilot study in ottawa that sought to und~rstand the lived experience of food insecurity. the study also used the united states department of agriculture (usda) community food security module. methods: a series of group meetings determined the best research approaches; questionnaires and consent forms were developed by a working group. twenty-three self-identified food insecure respon· dents were interviewed. the data were analysed using frequency distributions· the food security module was coded according to the usda coding guide, and open-ended responses w~re coded using a grounded approach. renlts: preliminary results from our pilot study have given the research team cause for considerable concern. out of 14 households without children, 11 experienced food insecurity with hunger; 5 ~ere at the severe l~vel. out of 9 households with children, 7 experienced food insecurity with hunger. ~•rst person reflecnons commonly featured feelings of depression low self-esteem and despair. participants' account tha d . an 1 cu ty gettmg to the store, severely limited putting knowledge and skills mto practice. l'oster sessions v109 conclusion: based on these early findings, our research team is looking to challenge what appear to be assumptions about poverty and food insecurity and for best ways to use this information. some policy approaches and interventions that encourage people to eat better and exercise more, may be missing the mark for low-income individuals, and may serve to maintain food insecurity. future research will build on this pilot. with methods augmentation, and a comprehensive knowledge dissemination plan, we hope co contribute to research and policy frameworks at all levels. ps-25 (a) mental health and the corrections system: population-based analyses in urban, semi-urban, and rural settings julian somers, robert watts, and michelle patterson introduction: according to recent epidemiological research, rates of mental disorders vary considerably across countries and across regions within countries. nevertheless, rates of mental disorders (including substance use disorders) are consistently higher in populations involved in the corrections sys-1em. courts have long recognized the heavy burden of mental illness within their purview, and have developed innovative programs to better manage the needs of such individuals. the majority of these innovations (e.g., specialized courts) exist in urban settings. however, few studies have examined the degree of variability in rates of different mental disorders between courts in urban and other settings (e.g., semi-urban, rural). variability between courts in different settings, if present, holds implications for needs-based resource planning. the present study was conducted as part of a long-term inter-ministerial collaboration in british columbia (bc). analyses were conducted on linked administrative data regarding population health and correctional services. a database was constructed including all individuals sentenced in bc in a single year (n=49,142). corrections records were matched to records of health services utilization (hospital and outpatient services) for mental disorders and substance use disorders in the years preceding sentencing. services for mental health and substance-related problems were aggregated into three groups: severe mental illness (smi); less-severe mental illness (lsmi); alcohol/other drug (ad). courts were grouped, based on their annual volumes, inro three categories: "urban"; "semi-urban" and "rural." rates of service use for mental disorders were compared between groups for 1-year and 5-years preceding sentencing. results: there were significant differences in the rates of mental disorders in courts of different size (urban, semi-urban, rural) . however, differences between the rates of disorders within each of these groups exceeded the discrepancies between groups. comparatively high and low rates of disorders were observed in courts of each size. moreover, the courts with the highest rates of certain disorders (e.g., ad) did not have the highest rates of other types of mental disorders (e.g., smi). conclusions: rates of mental disorders differed significantly among the annual populations sentenced across courts in bc. urban courts (which process comparatively large numbers of people) have implemented services to address the needs of the mentally ill. the present analyses strongly suggest that program development should be closely linked to the demonstration of need. the results caution that a uniform approach to court programs for the mentally ill is likely to be inefficient, over-supplying services in some settings and underestimating need in others. results: public settings used for injection are characterized by highly unhygienic conditions, the presence of unsafely disposed syringes, limited availability of sterile syringes and a lack of sterile water for injecting. a number of unsafe injection practices observed were common among public injectors. the presence of police officers nearby and the potential of assault by street predators fostered rushed injecting among those consuming drugs in public spaces. the ecological features of these environments encourage unhygienic and unsafe injecting practices, heighten risk for overdose and the transmission of blood borne viruses. introduction: approximately 13% of women experience depression in the first weeks or months after giving birth. although it has been argued that postpartum depression (ppd) is a culture-bound p~ nomenon, experienced only in western, industrialized countries, recent international research studies have confirmed that the prevalence of ppd is similar around the world. however, little is known about variables that may influence the experience of ppd in women from diverse cultures and immigrant women. research is needed to identify the role culture may play in the presentation of ppd (i.e., types of symptoms most commonly reported), how women from various racial, ethnic and cultural backgrounds perceive and attribute their symptoms of ppd, and finally, how culture can be appropriately addressed in ppd treatment programs. method: to examine the role of culture in ppd, semi-structured interviews and self-report question· naires were administered to clients of the women's health centre of st. joseph's health centre, tor· onto. participants were identified as either first generation canadians (relative newcomen) (n=8) or second generation canadian (parents were immigrants to canada) (n=6). data were collected qd these two groups of women based on: severity of depression, symptom presentation, perceived role of social supports and culturally-specific traditions, and barriers and responses to treatment. the interview data were analyzed using qualitative methods (thematic content analysis), and the following themes were identified: 1) stress about passing on their culture to their children, 2) lack of social support and feelings of isolation, 3) perceived importance or lack of importance of cultural based tra· ditions, 4) conflicts with family members. about cultural traditions and beliefs, 5) mental health stigma within ethnic communities and beyond, 6) race-and sex-based discrimination, and 7) language barriers. conclrllion: identifying the role culture plays in the presentation of ppd, and how women from diverse backgrounds perceive and attribute their symptoms of ppd, is critical in order to establishcultur· ally appropriate guidelines for treatment options. furthermore, information gathered from this study can be used to develop policies and resources for delivering culturally competent care for newcomer wo~ who are dealing with ppd as well as the issues around acculturation (i.e., language barriers, racism). llus is of particular importance for urban health centers which provide postpartum care to diverse groups of women, and particularly recent immigrants or newcomers. ps-~8 (al. contaminated 'therapeutic landscape': perceptions of the aamjiwnaang fint nation keyln smith and isaac luginaah . in~: this. paper pres;ents the findings of an ongoing study among the aamjiwnaang f!rst nanon. aam11wnaang is located m the heart of samia's 'chemical valley', surrounded by cherrucal ~(ants such as esso, imperial oil, shell, suncor energy, and canada's largest hazardous waste disposal sate. safety kleen. this fint nation community is located within the st. clair river •area of concem'. as destgna~ by health canada for the population of samia and the surrounding region. although this comm_umty, by way of. its proximity to the numerous chemical plants is already exposed to high levels pollu~on, recent che?ucal dumping in ~mjiwnaang, as well as a failed proposal for another ethanol plant m the community, only helped to mtensify community concerns about potential health impacts of exposure. research on the cultural beliefs and traditions of first nation communities has established that th~ ~isting rel~tionship between first nations people and 'mother earth' is not only physical, but also_ spmtual. in this study we explore how the complex relationship between the aamjiwnaang first naaon and 'mother earth' be ha · · · i .. may c ngmg 111 a contammated 'therapeutic' landscape. the study a so ~lores h?w aam11wnaang residents are coping with these changes and with the probable conramina· boa of their community. ra!jts: aamjiwnaang residents acknowledge that they are living in a contaminated environment and are being impacted by emissions from the surrounding 'chemical valley' especially for future generations, and have expressed concerns that members of the community and mother earth are 'sick' as a result of this exposure. while moving from that 'place' has been discussed, residents have strong personal and generational connections to the land and insist however, that aamjiwnaang is their 'home' and will remain that way despite growing community concerns about the impact from industry. the contribution of this study lies in the direct involvement of community leadership in designing and conducting this research and distributing the results to further local policy development regarding community concerns on the reserve. background: truck driver are at very high risk for drug abuse because the factor contributing to drug abuse among driver are multiple. it is important to gain an understanding of the key factors that contributing to drug abuse among truck drivers. methods: seventy-truck driver aged 25-35 years were conveniently selected from the population. all the participants were male. an interview schedule was developed in the light of literature data and data were collected by personal interview with informed consent in selected urban area of eastern part of nepal. results: a considerable percentage of truck driver have less knowledge about drug abuse, its effect on body and their complication. majority of the participants (90%) explained that lack of education, financial crisis were leading factors of drug abuse. the average numbers of respondents were believed that lack of meaning in life, marital disharmony. friendship with drug abuser, stress, tiredness, modernization of life pattern and freedom from the home pressure were the influencing risk factors to drug abuse. conchuion: this study reveals those truck drivers are at risk in urban area for developing drugs abuse, mostly influenced by social and environmental factors. hence, these groups should undergo certain educational programme to prevent not only drug abuse, but also prevent transmission of infectious disease among these groups. introduction: food insecurity is an inequality that is central in the lives of many low-income canadians. our group of university researchers, health professionals, and community developers conducted a study in ottawa with community workers who work with people identified as food insecure. the purpose of the study was to understand the nature of their work, and their perspectives, perceptions and experiences of the causes and consequences of food insecurity. (a parallel study was conducted with food insecure participants). methods: sampling was through local knowledge of organizations involved in the provision of food to community members. written permission for the researchers to contact workers in confidence was obtained from each organization. thirteen in-depth interviews were conducted. the interviews consisted of a number of open-ended questions. the data were collated, and analysed using a grounded approach. results: workers interviewed represented organizations that offered diverse programming and methods of food distribution intended to address the needs of the community. the provision of food was seen as a necessary response to address hunger that arose for the majority from poverty caused by low income, or levels of government income support and safety nets that were insufficient to support food requirements. workers reported that food requirements varied according to different. ethnic backgrounds, ages of recipients and family configurations, and with food preferences, and d'.etary (health) requirements. workers' observations of the effects of insufficient food on adults and children such as depression, low energy and non-participation or social disengagement matched those of food insecure respondents. food insecurity was cited as "another srressor among the mountain of problems." overall, workers presented a picture of a silent, stigmatized, poor population including children, and a lack of advocacy to address the issues. be tha th · ·ty the results suggest that workers and organizations, like the commuruty mem rs t ey msecun • · · · · f ilab'l' f food · t d ·n thei·r ab1'l1'ty to address food insecurity. l1m1tanons m terms o ava 11ty o , serve, are restnc e 1 . . funding, and donations appeared to set the para?1eters of pr~g:am r.espon~ to commuruty food msecurity. workers were concerned with program des1g": and a~m1mstranon that m general addr~d hunger on an emergency short-term basis, although food msecunty was long-ter_m for ~any. sustainable solutions that include knowledge translation strategies, and health and social pohcy responses were suggested and will be explored in future research that hopes to build on this pilot. background: socioeconomic deprivation as well as low levels of soc!al s.uppoi:r have .been associated with poor outcomes following cardiac surgery. pre-operative depression m ~anents with coron~ry artery disease awaiting cabg ranges from 27-47% and is an independent predictor of post-operanve mortality. since st. michael's hospital has a large inner city population, this study was designed to determine the both the prevalence of depressive symptomatology (ds) in patients awaiting cabg as well as its relationship with socioeconomic status (ses) and social support. methods: consecutive patients referred for isolated cabg were invited to complete the centre for epidemiological studies depression scale (ces-d) as well as a social support scale and a life stressors inventory. a ces-d score of 2: 16 represents mild ds and a score of 2:27 represents moderate to severe ds. participants also recorded information on functional status, perceived progression of heart failure, demographic and ses variables. all participants with ces-d scores 2: 16 were considered to have ds. results: of the 75 patients (75%) who returned the survey, 22 (29.3%) of participants had a ces-d score 2: 16 with 8 (10.7%) of those having scores suggestive of severe depression. females and those with ongoing medical concerns tended to have more ds (p= 0.06 and p= 0.07 respectively). age was not related to ds. perceived worsening of symptoms and increased ccs angina class were significantly related to the presence of ds (p= 0.03 and p= 0.03 respectively) but not the number of diseased heart vessels. satisfaction with personal relationships including having someone to confide in (p=0.01), feeling lonely (p= 0.04) and not having a partner (p= 0.007) were significantly related to ds. being very upset by a recent breakup in the immediate family was also significantly related to ds (p= 0.02). having greater than a grade 9 education was the only ses variable related to ds (p=0.06). multivariate logistic regression suggested that not being partnered and having low education were the most significant predictors of ds. conclnsion: pre-operative depression is present in at least one quarter of patients referred for cabg. since ds is related to poor outcomes following cabg, single patients with few social supports and low education should be considered at high risk for ds. these findings support the need for the development of supportive interventions in patients at risk in order to decrease post-operative morbidity. this study examines the relationship between childhood sexual abuse, sexual assault during adolescence, and hiv-risk-related behaviours in a sample of 919 homeless youths. over the past decade, there has been increasing research devoted to the impact of childhood sexual abuse. some studies have suggested that the experience of childhood sexual abuse is associated with substance use and abuse, at· risk sexual behaviour and subsequent higher rates of hiv infection (ompad et al., 2005; cinq-mars et al., 2003; brown et al., 1997) . other studies have found that childhood abuse, especially sexual abuse, is c_o~n among stree~ youth (noell et al. 1999 ). this study compares sexually abused males and females livtng on the street ~th non-sexually abused street youth, with regards to unsafe sexual behaviours and e~ures to potmnal t:dv sources (e.g., tattooing, body piercing and injection drug use). the hypothe-sis oft~ ~nt study is that the prevalence of hn-risk-related behaviours will be higher among street youth vtctuns of sexual abuse than those who have not been sexually abused. the sample includes 919 youths aged 13 to 25 who met specific criteria's for itinerancy (649 male and 270 female, with a mean ~of 19.4 y· and a standard deviation of 2.9). they were recruited through five organisations working ~th~ you~ and were~ of an ongoing cohort study. all youth completed a 45 to 60 minute ques· ~onnaue on their sexual behaviours, use of drugs and alcohol and other hiv risk behaviours. oral spec· unens for hiv testing were. also collected. a total of 357 (38.9%) youth reported at least one incident of ~i •~use/assault (1~1 girls (67.0% of all the girls) and 176 boys (27.2% of all the boys]). preliminary descnpnve analyses pomt to sexually abused/assaulted youth showing the highest prevalence of sexual poster sessions v113 at-risk behaviours. for example, 43.3% of sexual abuse/assault victims have engaged in prostitution in their lives compared with 13.4% in the non-sexually abused/assaulted group. in addition, 42.6% of sexual abuse/assault victims reported having injected drugs, compared with 32.0% in the non-sexually abused/assaulted group. more statistical analyses will bring other significant factors to light, especially when we analyze separately those victim of childhood sexual abuse as compare to those victim of sexual assault after childhood. elucidating the risk factors for getting involved in hiv-risk-related behaviours is important for the development of comprehensive and appropriate prevention and treatment intervention strategies. introduction: new immigrants and refugees to canada frequently emigrate from regions of the world where intestinal parasitic infections with worms are endemic. of note, some of these parasites area capable of surviving for years to decades within a given host and can have life threatening consequences many years after initial infection. thus, early diagnosis and treatment of intestinal parasitic worms is considered important in high risk immigrant populations, however there remains a lack of consensus regarding the best method of accomplishing this. diagnosing worm infections through stool examinations is costly and has limited sensitivity, while presumptive treatment of all immigrants, although advocated by some, is expensive and results in healthy individuals being unnecessarily treated. herein, we examine the utility of a hematologic marker (i.e. peripheral blood eosinophilia) as a screening instrument to identify parasitic worm infections in new immigrants to toronto. we identified 192 adults, 15 years of age or older, who were screened for intestinal parasitic infections by stool examination as part of a recently developed screening protocol at a downtown toronto community health centre. we examined the prevalence of infections with worms and subsequently evaluated the impact of several demographic factors on the presence of worm infections. we also determined the sensitivity and specificity of peripheral blood eosinophilia (defined as greater than 500 eosinophils per ml) as a marker for intestinal parasitic worm infections. results: overall, 21 % of the 192 immigrants tested had evidence of at least one worm infection on a single stool examination, while 4% of such individuals bad infections with multiple worms concurrently. age did not appear to be associated with the presence of worms, however 29% of males had evidence of worm infections compared with 16% of females (p= 0.03). immigrants from asia, sub-saharan africa, and central america had the highest burden of overall infection. the sensitivity and specificity of peripheral blood eosinophilia for worm infections was 24% and 92% respectively. conclusions: one in five recent immigrants presenting to a community health centre in downtown toronto had evidence of at least one intestinal parasitic worm infection. the highest burden of illness was in men and in those emigrating from less developed regions of the world. peripheral blood eosinophilia is a poor screening test for worm infections however its presence is highly suggestive of the existence of worms in new immigrants. more than a decade ago, the journal of american college health recommended that a national study be conducted to measure the health status of african american college students, 'both health disparities and [their] positive healthful behaviors' (fennell, 1994) . it was later decided that when exploring the level of health risk behaviors for african american students, gender is an important variable and should be included in the research (fennell, 1997) . at historically black college and universities (hbcus) college health researchers must tackle gender disparities through highly-effective health promotion and disease prevention programs. the purpose of this review is to examine the literature that addresses the overarching health behaviors (i.e. risky sexual behavior, poor diet, smoking, physical inactivity, etc.) of african american men who attend hbcus. despite the various social, cultural, and academic benefits of african american students who attend hbcus, the number of research studies that adequately address their health and health behaviors is limited. studies indicate that african american men who attend hbcus are actively engaged in poor health behaviors. compared to females at hbcus, african american men are more likely to behave in ways that could result in injuries and the use tobacco, alcohol, and ~ther dru~. the city of toronto has recently proposed to conduct a street count of the homeless. like proposals that have come before, this most recent proposal is controversial among many homeless advocates and service providers because it is perceived as intrusive, likely to undercount the target population, and unnecessary for addressing the problem. advocates of the count view it as necessary to gauge the scope of the problem and advise city leaders about how to most effectively direct resources ro.the various homeless services. this paper first reviews the history of efforts to count homeless populat10ns m toronto, describing the motivations and arguments of people on both sides of the issue. second, the paper reviews the methodological complexities of counting homeless populations, describing approaches that use shelter-counts, administrative data and street observations. those interested in counts for toronto and elsewhere can benefit from this review of approaches that have been proposed and carried out in other municipalities. third, the paper proposes a new community-base d strategy that joins the skills of methodologists, local experts, and service providers to ensure a fair and accurate count. the method of systematic social observation avoids some of the problems of early counts by utilizing a repeated identification approach to minimize undercount bias. the method also has the advantage of involving and compensating homeless individuals for assisting with the street count estimates. the estimation approach can be implemented on a rolling basis throughout the year. drug transitions) is a multi-level study aimed at examining the associations between features of the urban environment and mental health, drug use, and risky sexual behaviors. research participants are being recruited in 36 new york city (nyc) neighborhoods. an essential first step in the implementation of this study was to delineate boundaries for each target neighborhood that could then be used to establish sampling frames and as key units of analytic interest. although many neighborhood studies rely on pre-established definitions (e.g. those used for the census or administrative purposes), such definitions do not always reflect contemporary settlement patterns. we felt that street level observations were a neces· sary component of the definition process. methods: the procedures used to delineate neighborhoods were: (1) development of census block maps of targeted areas; (2) review of land use maps and census tract data to ensure, prior to going into the field, tha.t particular blocks are residential and likely to have sufficient population for recruitment purposes; and (3) field vislts and observation in each of the targeted areas. field observations focused on: housing characteristics, including housing type and condition; characteristics of commercial areas, such as likely customer base (e.g. local or no~, socio-economic status and ethnicity of customers); pedestrian volume (including con· gregauons of people m parks and outside stores or residences); obstructions to pedestrian traffic (e.g. ma1or thoroughfares, multi-block industry or institutions); and maintenance and use of open spaces. results: in making the final decisions regarding neighborhood boundaries and the inclusion or exclusion of particular. blocks, we considered a broad range of factors including evidence of homogeneity an~ heterogeneity (socmeconomic, ethnic, housing type, environmental) across blocks within and blocks ad1acent to a nei.ghborhood, and across the 36 sample neighborhoods; the potential for efficient recruit· ment of appropriate particip.ants (i.e. sufficient local pedestrian traffic); and boundaries used in reporting census data (s? that population data can be used in our analysis). . altho~gh utilization of field observations for neighborhood definitions is relatively time consuming (ap~~ox1mately 2 hours for a 12 block area, with more diverse neighborhoods taking even longer), we annc1p~t~ that it will substantially improve the quality and consistency of our data gath· ~rmg ~nd analyse~. spec1f1c e?'amples from neighborhoods defined through this process will be given dur· m~ this presentatmn. we will also discuss the merits and limitations of characterizing neighborhoods usmg street level observations. has been no consideration for how social networks are associated with sse. the objective of this study was to identify personal and social network characteristics associated with being a recipient of sse. in this cross-sectional study, idus who injected in the past 6 months were recruited from syringe exchange programs in montreal, canada, between april 2004 and january 2005. information on each participant and on the persons with whom contact had occurred in the past month were elicited using a structured, interviewer-administe red questionnaire. participants provided detailed demographic and drug use information on up to 5 idu members with whom drugs or injecting materials were shared. using logistic regression, personal and network characteristics were examined in relation to receipt of sterile syringes. res.its: of 277 idus, 39% reported receiving sterile syringes in the past month from another idu. the sample mean age was 33 years (range 18-55), 73% male, 91 % caucasian, and 85% cocaine injectors. in multivariate analyses adjusted for age and gender, recipients of sterile syringes were more likely than non-recipients to share drugs after preparation (0r=2.39(1.06-5.42 )), to require help or to have helped inject another idu (or= 3.48(1.60-7.60)), to have asked someone to get sterile syringes from a syringe exchange program (or=2.54[1.20-5.40 )), to lend syringes (or=2.44[1.16-5.16) ) and to use drug preparation water that was previously used by another iou (0r=2.46(1.42-4.28) ) during the past 6 months. recipients also had a higher rate of change (p=0.01) of idus in their drug injecting network during the past month. with respect to social networks, 45% ( 171/348) of idu network members were providers of sterile syringes and were more likely than non-providers to inject everyday (or= 2.50( 1.51-4.15)). when stratified by their role as a sexual partner or as someone who provides support (e.g. friend, family member), further risk behaviours were observed in relation to sharing injecting materials with the participant. conclusion: recipients of sterile syringes and their idu network members had several high-risk behaviours for infection with bloodborne diseases. sse may afford an opportunity for the dissemination of other salutary behaviours such as information sharing on safe injecting practices between recipients and distributors. furthermore, drug injecting networks may be an avenue to reach idus who may not otherwise be exposed to preventive measures. there are numerous sources of stigma and labelling of mental and physical illness. first, the sociocultural dimension to stigma and labelling clearly influences patients, families, health care professionals and society's perception and treatment of illness. this creates multiple challenges related to illness identification and recovery, particularly in culturally diverse societies. second, the media is a major source of stigma and stereotyping with regard to a variety of mental and physical illnesses. despite increased public knowledge of many illnesses, studies have shown that stigma has intensified over the years in certain cases. a third element of stigma and labels appears with the use of diagnosis as a solution to human problems with the result that difficult to treat patients are repudiated and social issues are unaddressed. this presentation will serve to outline the development of stigma, various expressions of stigma, and consequences of stigma. it will provide some practical recommendations for the reduction of stigma related to mental and physical illness. purpose: to assess the knowledge, attitude, and practice about immunization for parent of 2-3 years old hispanic and african american children in los angeles county (lac). methods: we conducted two cluster surveys in lac. the sample was selected with probability proportionate to estimated size at the first stage and simple random sample of children at the second stage. data were collected through interview. we absuacted vaccine coverage data from immunization record card (irc) at home or from clinic records. the participation was 81 % in hispanics and 83% in african americans populations. irc was not available at home for 26% of african american and 16% of hispanic children. results: all parents perceived their children got all necessary vaccine~. fa~orable attitudes to.w~rd immunization were reported by 82 % of african american and 90% of h1s?amc parents. '.he m~1ority of the parents (90% african american and 95% hispanic) agreed that vaccines prevent senous d1se~ses among children. regarding vaccine safety, significantly more hispanic parents (91 %) than african american parents (75%) mentioned that vaccines are safe. introduction: cervical cancer has been shown to be preventable by papanicolau tests in heterosexual women; however, the utility of papanicolau test in lesbians is controversial. cervical cancer is caused by the human papillomavirus (hpv) which is transmitted by sexual _intercourse; howev_er, its' transmission by homosexual intercourse is also controversial. the goal of this study was to review the evidence for papanicolau tests in lesbians. methods: a pub med, ovid ( 1996 ovid ( to 2005 , and cochrane library search was performed using the mesh headings "homosexuality , female," "vaginal smears," and "papillomavirus, human." in pub med, the clinical queries feature was used with "diagnosis" and "broad, sensitive" filters. a google advanced search of the internet was conducted with the terms "lesbian," "cervical cancer," and "pap rest." the url was limited to ".ca," ".edu," or ".gov." results: the search yielded 8 original articles and 4 reviews, but no cochrane reviews. none of the publications were canadian. 111 website hits were found and selected websites were reviewed. studies showed that lesbians have fewer papanicolau tests than heterosexual women; however, many reported risk factors for cervical cancer, including multiple past or current sexual partners (male and female), early age of first coitus, history of sexually transmitted diseases, and cigarette smoking. hpv has been detected in 13-30% of lesbians and 6-19% of lesbians who have never had sex with men. case studies of abnormal papanicolau tests in lesbians who have never had sex with men have also been reponed. sexual transmission of hpv among lesbians can be explained by several factors: 1) 53-99% of lesbians have had sex with men and 21-30% of lesbians continue to have sex with men. 2) hpv may be transmitted by sexual behaviours among women, like digital-vaginal sex, digital-anal sex, oral sex, and the use of insertive sex toys. 3) hpv transmission requires only skin-to-skin contact. genital hpv has been identified on human fingers. some professional organizations, like the society of obstetricians and gynecologists of canada and the american cancer society, recognize the need for papanicolau tests in lesbians. other organizations, like the canadian cancer society, do not have official policy statements. the current ontario cervical screening program does not specifically address lesbians. conclusion: although the data was limited, most studies recommended that lesbians should receive papanicolau tests. the frequency of these tests was controversial. policy makers and professional organizations should address the needs of this special population and make specific recommendations . monique chaaya, ahia sibai, hiam chemaitelly, and zana el roueiheb . literature concerning the mental and physical effect of work at an old age is contradictory. in addinon, urban environments are physically and socially harsh with reduced potential for income generation and employment and increased potential for depression. the present paper is an attempt to study how do work, or lack of work, link to the experience of depression among older adults in underprivileged lebanese urban communities. the data comes from a cross-sectional survey, where 740 elderly residing in 3 underprivileged communities in beirut, including a palestinian refugee camp, were successfully inter-v1ewed through face-to-face interviews. logistic regression was performed to assess the effect of work on depression ad_justing for many other covariates. data showed that 17.5% of people aged 60 years and more were still workmg. there was a highly protective effect of work on depression in elderly males (or= 0.342, 95% cl= 0.128-0.909). the current study is the first of its kind in the arab region and more work shou_ld be _don_e in this area. it is important for the lebanese government to consider elderly rights for social mclus10n m terms of employment opportunities. amam nuru-jeter, nancy adler, and burton singer . l~u~on:_ the socioeconomic gradient is perhaps the most persistent and significant finding in social epidem1ological research. the insistent nature of the ses effect is evidenced by its significance after acc?untmg for ~umerous confounds. the significance and magnitude of the effect, however, varies by ::•al group. evidence_ o_f the relative effect of race and ses is inconclusive. further, less attention has f ~ ptid to the specific interactions of race and ses than to examinations of which is a better predictor 0 d ~ th. ~sues are further complicated by the explanatory complexity of the various measures of ses anl . owht ey relate to the health of various social groups. understanding the specific nature of these re a11ons ips 1s necessary for guiding he ith d · i 1· · h a an soc1a po mes and programs aimed at improving t e poster sessions v117 health of our most disadvantaged groups, and therefore population health, overall. this study examines the synergistic effects of ses with both race and gender in predicting group differences in mortality. methods: analyses use data from the national longitudinal mortality survey (n= 559, 715) for the years 1979, 1980, and 1981-85; and were linked to the national death index for deaths occurring through 1985. results were confirmed using data from the national mortality followback survey for people who died in 1986 (n= 13,491) and the 1986 national health interview survey (denominator). we used correlation analysis and the standardized mortality ratio to examine ses (education and income), race, and gender as predictors of group differences in changes in mortality. results: for the total population, analyses support the income gradient showing significant declines in mortality ratios from low to high income along the income strata. education shows a significant drop in mortality with completion of high school and completion of college, exhibiting a threshold rather than a gradient effect. compared to whites, blacks receive diminishing health returns for each subsequent level of income and education; with whites closely mirroring the total population in ses thresholds. similarly, compared to men, women do not experience the same health gains at comparable ses levels. for education, black men and women only show significant mortality declines upon completion of high school. the ses gradient operates differently among race and gender subgroups. threshold effects suggest resource gains in life opportunities at particular milestones along the ses gradient. further, ses matters less for blacks and women compared to whites and men suggesting differing implications for health and social policy aimed at reducing disparities. objective: we assessed the impact of diabetes in a large puerto rican community of chicago by measuring the prevalence of diagnosed diabetes and calculating the diabetes mortality rate. methods: we analyzed data from a comprehensive health survey conducted in randomly selected households in community areas. questions on diagnosed diabetes and selected risk factors were asked. in addition, mortality data were analyzed in order to calculate the age-adjusted diabetes mortality rate. when possible, rates were compared to those found in other studies. results: the diabetes prevalence located in this community (20.8%: 95% cl= 10.1 %-38.0%) is one of the highest ever reported for puerto ricans. for instance, it is more than three times higher than the prevalence for the us (6.1 %) and twice the prevalence for puerto ricans in new york ( 11.3%) and puerto rico (9.3%-9.6%). diagnosed diabetes was found to be significantly associated with obesity (p=0.023). the prevalence was particularly high among older people, females, those horn in the us, and those with a family history. the diabetes mortality rate (67.6 per 100,000 population) was more than twice the rate for all of chicago (31.2) and the us (25.4). conclusions: understanding why the diabetes and mortality rates for puerto ricans in this commu· nity are so much higher than those of other communities is imperative. collaboration between researchers, service providers and community members can help address the issues of diabetes education, early screening and diagnosis and effective treatment needed in this community. introduction: sars is a respiratory illness that is spread from person to person through dose contact. this infectious disease outbreak was unusual due to the high rate of infection among health care workers. the aim of the study is to explore the demographic and attitudinal determinants of psychological distress due to sars among health care workers of a toronto hospital. methods: a total of 997 adult participants completed questionnaires co assess psychological distress (impact of event scale -jes) and attitudes to sars. of these, 845 participants completed the questionnaire during the sars i outbreak, and 152 participants completed the questionnaire during the sars ii outbreak. participants also provided information on demographic variables, including occupation and exposure to sars. principal components analysis was used to derive eight attitudinal scales: fear: system, protection, prevention, job stress, stigma, instrumental coping, and psychological copm~. l111ear regression analyses were applied to evaluate the associations of the demographic and amtudmal variables, as well as time, with psychological distress. . . regression analyses showed that time and higher scores on fear, 1ob stress, stigma'. and instrumental coping were associated with a higher total ies score: (r2 =.30). contrary to expectations, none of the demographic variables was associated with total ies score. conclusion: the presence of psychological distress in health care workers is indicative of intrusive or avoidant responses to thoughts, feelings, and memories associated with the sars outbreak. this study shows that ( 1) fear for one's health and the he~lth of.others, (2) ex~erien~in~ job stress, (3)_tbe per· ception of stigma, (4) usage of instrumental copmg skills, ~n~ (5) t1m_e s1grufi~an~ly c~nmb~te to increased psychological distress in health care workers. potential mterventmns during mfecttous diseaie outbreaks in health care settings should be targeted to minimize the impact of these factors. purpose: the purpose of this study was to expand knowledge regarding feeding practices, know!· edge and nutritional beliefs of mothers currently residing in the dominican republic (dr). the rising incidence of obesity in children is a major national health concern and obesity in first and second-generation immigrant children also continues to rise. we know that parents (particularly mothers) shape children's early diet patterns and that immigrant mothers experience additional challenges related to acculturation and assimilation into a new culture, however there is a paucity of literature concerning the effect of immigrant adaptation to american culture on the nutrition of children. in addition, new immigrant knowledge about the causes of obesity and the resulting health implications for childhood obesity has not been assessed and reported. this qualitative study used focus group methodology to discuss views and practices related to the introduction of food for infants and feeding practices for young children, along with a discussion on knowledge and beliefs related to the causes and health implications of child· hood obesity. ten dominican mothers' of young children (birth to 6 years old) who reside in a small town in the western frontier area of the dr were participants in the focus group. results from this srudy will be compared to results from an identical study that will be conducted in fall 2005 with new immi· grant mothers from the dr to the boston area. we will compare feeding practices, beliefs and knowledge about nutrition for young children between these two groups. methods: using participatory principles, a focus group design was used to interview a group of mothers in the dr. the investigator along with a bilingual translator conducted the focus group. the session was tape recorded and is currently in the process of being transcribed and translated. transcribed data will be systematically analyzed themes will be identified. a qualitative data analysis software will be used to organize and code the data according to the specific aims of the study. supporting quotations will be selected to substrate each theme. lmpli~tions for urban health practice: an ultimate goal of this study is to lay a foundation for understanding the process of acculturation on feeding practices of mothers when they immigrate to the us. understanding beliefs, knowledge and feeding practices that mothers use with young children will help m ~he ~evelopment of culturally and linguistically appropriate educational strategies and materials for use m primary prevention of pediatric obesity. in canada more than seventy-five percent of immigrants choose to stay in three major urban centers of toronto, montreal and vancouver. approximately fifty percent of the immigrants eventually set· tie m ~~e greater tor<_>nto area. there is mounting evidence that the increasing immigrant population has a_ sigmfic~nt health disadvantage over canadian-born residents. this health disadvantage manifests particularly m the ma1"ority of 1"mm1"gr t h h d be · · h . . . . an s w o a en m canada for longer than ten years. this group as ~n associ~te~ with higher risk of chronic disease such as cardiovascular diseases. this disparity twccb n ma1onty of the immigrant population and the canadian-born population is of great importance to ur an health providers d" · i i · b as isproporttonate y arge immigrant population has settled in the ma1or ur an centers. generally the health stat f · · · · · · h h been . us 0 most 1mm1grants 1s dynamic. recent 1mm1grants w o av_e ant •;ffca~ada _for less ~han ~en years are known to have a health advantage known as 'healthy imm1• ~ants r::r · ~:s eff~ 1~ defined by the observed superior health of both male and female recent immiimmigrant participation in canadian society particularly the labour market. a new explanation of the loss of 'healthy immigrant effect' is given with the help of additional factors. lt appears that the effects of social exclusion from the labour market leading to social inequalities first experienced by recent immigrant has been responsible for the loss of healthy immigrant effect. this loss results in the subsequent health disadvantage observed in the older immigrant population. a study on patients perspectives regarding tuberculosis treatment by s.j.chander, community health cell, bangalore, india. introduction: the national tuberculosis control programme was in place over three decades; still tuberculosis control remains a challenge unmet. every day about 1440 people die of tuberculosis in india. tuberculosis affects the poor more and the poor seek help from more than one place due to various reasons. this adversely affects the treatment outcome and the patient's pocket. many tuberculosis patients become non-adherence to treatment due to many reasons. the goal of the study was to understand the patient's perspective regarding tuberculois treatment provided by the bangalore city corporation. (bmc) under the rntcp (revised national tuberculosis control programme) using dots (directly observed treatment, short course) approach. bmc were identified. the information was collected using an in-depth interview technique. they were both male and female aged between 4-70 years suffering from pulmonary and extra pulmonary tuberculosis. all patients were from the poor socio economic background. results: most patients who first sought help from private practitioners were not diagnosed and treated correctly. they sought help form them as they were easily accessible and available but they. most patients sought help later than four weeks as they lacked awareness. a few of patients sought help from traditional healers and magicians, as it did not help they turned to allopathic practitioners. the patients interviewed were inadequately informed about various aspect of the disease due to fear of stigma. the patient's family members were generally supportive during the treatment period there was no report of negative attitude of neighbours who were aware of tuberculosis patients instead sympathetic attitude was reported. there exists many myth and misconception associated with marriage and sexual relationship while one suffers from tuberculosis. patients who visited referral hospitals reported that money was demanded for providing services. most patients had to borrow money for treatment. patients want health centres to be clean and be opened on time. they don't like the staff shouting at them to cover their mouth while coughing. conclusion: community education would lead to seek help early and to take preventive measures. adequate patient education would remove all myth and conception and help the patients adhere to treatment. since tb thrives among the poor, poverty eradiation measures need to be given more emphasis. mere treatment approach would not help control tuberculosis. lntrod#ction: the main causative factor in cervical cancer is the presence of oncogenic human papillomavitus (hpv). several factors have been identified in the acquisition of hpv infection and cervical cancer and include early coitarche, large number of lifetime sexual partners, tobacco smoking, poor diet, and concomitant sexually transmitted diseases. it is known that street youth are at much higher risk for these factors and are therefore at higher risk of acquiring hpv infection and cervical cancer. thus, we endeavoured to determine the prevalence of oncogenic hpv infection, and pap test abnormalities, in street youth. ~tbods: this quantitative study uses data collected from a non governmental, not for profit dropin centre for street youth in canada. over one hundred females between the ages of sixteen and twentyfour were enrolled in the study. of these females, all underwent pap testing about those with a previous history of an abnormal pap test, or an abnormal-appearing cervix on clinical examination, underwent hpv-deoxyribonucleic (dna) testing with the digene hybrid capture ii. results: data analysis is underway. the following results will be presented: 1) number of positive hpv-dna results, 2) pap test results in this group, 3) recommended follow-up. . the results of this study will provide information about the prevalence of oncogemc hpv-dna infection and pap test abnormalities in a population of street youth. the practice implic~ tions related to our research include the potential for improved gynecologic care of street youth. in addition, our recommendations on the usefulness of hpv testing in this population will be addressed. methods: a health promotion and disease prevention tool was developed over a period of several years to meet the health needs of recent immigrants and refugees seen at access alliance multicultural community health centre (aamchc), an inner city community health centre in downtown toronto. this instrument was derived from the anecdotal experience of health care providers, a review of medical literature, and con· sultations with experts in migration health. herein we present the individual components of this instrument, aimed at promoting health and preventing disease in new immigrants and refugees to toronto. results: the health promotion and disease prevention tool for immigrants focuses on three primary health related areas: 1) globally important infectious diseases including tuberculosis (tb), hiv/aids, syphilis, viral hepatitis, intestinal parasites, and vaccine preventable diseases (vpd), 2) cancers caused by infectious diseases or those endemic to developing regions of the world, and 3) mental illnesses includiog those developing among survivors of torture. the health needs of new immigrants and refugees are complex, heterogeneous, and ohen reflect conditions found in the immigrant's country of origin. ideally, the management of all new immigrants should be adapted to their experiences prior to migration, however the scale and complexity of this strategy prohibits its general use by healthcare providers in industrialized countries. an immigrant specific disease prevention instrument could help quickly identify and potentially prevent the spread of dangerous infectious diseases, detect cancers at earlier stages of development, and inform health care providers and decision makers about the most effective and efficient strategies to prevent serious illness in new immigrants and refugees. lntrodmction: as poverty continues to grip pakistan, the number of urban street children grows and has now reached alarming proportions, demanding far greater action than presently offered. urbanization, natural catastrophe, drought, disease, war and internal conflict, economic breakdown causing unemployment, and homelessness have forced families and children in search of a "better life," often putting children at risk of abuse and exploitation. objectives: to reduce drug use on the streets in particular injectable drug use and to prevent the transmission of stds/hiv/aids among vulnerable youth. methodology: baseline study and situation assessment of health problems particularly hiv and stds among street children of quetta, pakistan. the program launched a peer education program, including: awareness o_f self and body protection focusing on child sexual abuse, stds/hiv/aids , life skills, gender and sexual rights awareness, preventive health measures, and care at work. it also opened care and counseling center for these working and street children ar.d handed these centers over to local communities. relationships among aids-related knowledge and bt:liefs and sexual behavior of young adults were determined. rea.sons for unsafe sex included: misconception about disease etiology, conflicting cultural values, risk demal, partner pressur~, trust and partner significance, accusation of promiscuity, lack of community endorsement of protecnve measures, and barriers to condom access. in addition socio-economic pressure, physiological issues, poor community participation and anitudes and low ~ducation level limited the effectiveness of existing aids prevention education. according to 'the baseline study the male children are ex~ to ~owledge of safe sex through peers, hakims, and blue films. working children found sexual mfor~anon through older children and their teachers (ustad). recommendation s: it was found that working children are highly vulnerable to stds/hiv/aids, as they lack protective meas":res in sexual abuse and are unaware of safe sexual practices. conclusion: non-fatal overdose was a common occurrence for idu in vancouver, and was associated with several factors considered including crystal methamphetamine use. these findings indicate a need for structural interventions that seek to modify the social and contextual risks for overdose, increased access to treatment programs, and trials of novel interventions such as take-home naloxone programs. background: injection drug users (idus) are at elevated risk for involvement in the criminal justice system due to possession of illicit drugs and participation in drug sales or markets. the criminalization of drug use may produce significant social, economic and health consequences for urban poor drug users. injection-related risks have also been associated with criminal justice involvement or risk of such involvement. previous research has identified racial differences in drug-related arrests and incarceration in the general population. we assess whether criminal justice system involvement differs by race/ethnicity among a community sample of idus. we analyzed data collected from idus (n = 1,084) who were recruited in san francisco, and interviewed and tested for hiv. criminal justice system involvement was measured by arrest, incarceration, drug felony, and loss/denial of social services associated with the possession of a drug felony. multivariate analyses compared measures of criminal justice involvement and race/ethnicity after adjusting for socio-demographic and drug-use behaviors including drug preference, years of injection drug use, injection frequency, age, housing status, and gender. the six-month prevalence of arrest was highest for whites (32%), compared to african americans (25%) and latinos (27% ), in addition to the mean number of weeks spent in jail in the past 6 months (7.0 vs. 5.8 and 4.2 weeks). these differences did not remain statistically significant in multivariate analyses. latinos reported the highest prevalence of a lifetime drug felony conviction (48%) and mean years of lifetime incarceration in prison (13.3 years), compared to african americans (48%, 10.7 years) and whites (34%, 6.9 years). being african american was independently associated with having a felony conviction and years of incarceration in prison as compared to whites. the history of involvement in the criminal justice system is widespread in this sample. when looking at racial/ethnic differences over a lifetime including total years of incarceration and drug felony conviction, the involvement of african americans in the criminal justice system is higher as compared to whites. more rigorous examination of these data and others on how criminal justice involvement varies by race, as well as the implications for the health and well-being of idus, is warranted. homelessness is a major social concern that has great im~act on th~se living.in urban commu?ities. metro manila, the capital of the philippines is a highly urbanized ar~ w.1t~ the h1gh~st concentration of urban poor population-an estimated 752,229 families or 3,005,857 md1v1duals. this exploratory study v122 is the first definitive study done in manila that explores the needs and concerns of street dwdlent\omc. less. it aims to establish the demographic profile, lifestyle patterns and needs of the streetdwdlersindit six districts city of manila to establish a database for planning health and other related interventions. based on protocol-guid ed field interviews of 462 street dwellers, the data is useful as a template for ref!!. ence in analyzing urban homelessness in asian developing country contexts. results of the study show that generally, the state of homelessness reflects a feeling of discontent, disenfranchisem ent and pow!!· lessness that contribute to their difficulty in getting out of the streets. the perceived problems andlar dangers in living on the streets are generally associated with their exposure to extreme weather condirioll! and their status of being vagrants making them prone to harassment by the police. the health needs of the street dweller respondents established in this study indicate that the existing health related servias for the homeless poor is ineffective. the street dweller respondents have little or no access to social and health services, if any. some respondents claimed that although they were able to get service from heallh centers or government hospitals, the medicines required for treatment are not usually free and are beyond their means. this group of homeless people needs well-planned interventions to hdp them improve their current situations and support their daily living. the expressed social needs of the sucet dweller respondents were significantly concentrated on the economic aspect, which is, having a perma· nent source of income to afford food, shelter, clothing and education. these reflect the street dweller' s need for personal upliftment and safety. in short, most of their expressed need is a combination of socioeconomic resources that would provide long-term options that are better than the choice of living on the streets. the suggested interventions based on the findings will be discussed. . methods: idu~ aged i 8 and older who injected drugs within the prior month were recruited in 2005 usmg rds which relies on referral networks to generate unbiased prevalence estimates. a diverse and mon· vated g~o~p of idu "seeds." were given three uniquely coded coupons and encouraged to refer up to three other ehgibl~ idu~, for which they received $5 usd per recruit. all subjects provided informed consent, an anonymous 1~t erv1ew and a venous blood sample for serologic testing of hiv, hcv and syphilis anti~!· results. a total of 213 idus were recruited in tijuana and 206 in juarez, of whom the maion!)' were .male < 9 .l.4% and 92.2%) and median age was 34. melhotls: using the data from a multi-site survey on health and well being of a random sample of older chinese in seven canadian cities, this paper examined the effects of size of the chinese community and the health status of the aging chinese. the sample (n=2,272) consisted of aging chinese aged 55 years and older. physical and mental status of the participants was measured by a chinese version medical outcome study short form sf-36. one-way analysis of variance and post-hoc scheffe test were used to test the differences in health status between the participants residing in cities representing three different sizes of the chinese community. regression analysis was also used to examine the contribution of size of the chinese community to physical and mental health status. rmdts: in general, aging chinese who resided in cities with a smaller chinese population were healthier than those who resided in cities with a larger chinese population. the size of the chinese community was significant in predicting both physical and mental health status of the participants. the findings also indicated the potential underlying effects of the variations in country of origin, access barriers, and socio-economic status of the aging chinese in communities with different chinese population size. the study concluded that size of an ethnic community affected the health status of the aging population from the same ethnic community. the intra-group diversity within the aging chinese identified in this study helped to demonstrate the different socio-cultural and structural challenges facing the aging population in different urban settings. urban health and demographic surveillance system, which is implemented by the african population & health research center (aphrc) in two slum settlements of nairobi city. this study focuses on common child illnesses including diarrhea, fever, cough, common cold and malaria, as well as on curative health care service utilization. measures of ses were created using information collected at the household level. other variables of interest included are maternal demographic and cultural factors, and child characteristics. statistical methods appropriate for clustered data were used to identify correlates of child morbidity. preliminary ratdts: morbidity was reported for 1,087 (16.1 %) out of 6,756 children accounting for a total of 2,691 illness episodes. cough, diarrhoea, runny nose/common cold, abdominal pains, malaria and fever made up the top six forms of morbidity. the only factors that had a significant associ· ation with morbidity were the child's age, ethnicity and type of toilet facility. however, all measures of socioeconomic status (mother's education, socioeconomic status, and mother's work status) had a significant effect on seeking outside care. age of child, severity of illness, type of illness and survival of father and mother were also significantly associated with seeking health care outside home. the results of this study have highlighted the need to address environmental conditions, basic amenities, and livelihood circumstances to improve child health in poor communities. the fact that socioeconomic indicators did not have a significant effect on prevalence of morbidity but were significant for health seeking behavior, indicate that while economic resources may have limited effect in preventing child illnesses when children are living in poor environmental conditions, being enlightened and having greater economic resources would mitigate the impact of the poor environmental conditions and reduce child mortality through better treatment of sick children. inequality in human life chances is about the most visible character of the third world urban space. f.conomic variability and social efficiency have often been fingered to justify such inequalities. within this separation households exist that share similar characteristics and are found to inhabit a given spatial unit of the 'city. the residential geography of cities in the third world is thus characterized by native areas whose core is made up of deteriorated slum property, poor living conditions and a decayed environment; features which personify deprivation in its unimaginable ma~t~de. there are .eviden~es that these conditions are manifested through disturbingly high levels of morbidity and mortality. ban · h h d-and a host of other factors (corrupt10n, msens1t1ve leaders 1p, poor ur 1ty on t e one an , . · 1 f · 1 · · th t ) that suggest cracks in the levels and adherence to the prmc1p es o socta 1usnce. ese governance, e c . . . . . ps £factors combine to reinforce the impacts of depnvat10n and perpetuate these unpacts. by 1den· grou o . ·1 "id . . bothh tifying health problems that are caused or driven by either matena _or soc1a e~nvanon or , t e paper concludes that deprivation need not be accepted as a way. of hfe a~d a deliberate effon must be made to stem the tide of the on going levels of abject poverty m the third world. to the extent that income related poverty is about the most important of all ramifications of po~erty, efforts n_iu_st include fiscal empowerment of the poor in deprived areas like the inner c~ty. this will ~p~ove ~he willingness of such people to use facilities of care because they are able to effectively demand 1t, smce m real sense there is no such thing as free medical services. ). there were 322 men with hiv-infection included in the present study (mean age and education of 41.8 (sd=8.4) and 13.9 (sd=2.7), respectively). a series of multiple regressions were used to examine the unique contributions of symptom burden (depression, cognitive, pain, fatigue), neuropsychologic al impairment (psychomotor efficiency), demographics (age and education) and hiv disease (cdc-93 staging) on iirs total score and jirs subscores: ( 1) activities of daily living (work, recreation, diet, health, finances); (2) psychosocial functioning (e.g., self-expression, community involvement); and (3) intimacy (sex life and relationship with partner). resnlts: total iirs score (r 2 "0.43) was associated with aids diagnosis (ii= 0.11, p <0.01) and symptoms of pain (ii= -0.14, p < 0.01 ), fatigue (ji = -0.34, p < 0.001) and cognitive difficulties (p =0.30, p < 0.001 ). for the three dimensions of the iirs, multiple regression results revealed: ( 1) activities of daily living (r2=0.42) were associated with aids diagnosis (ii =0.17, p < 0.01) and symptoms of pain <p =-0j6, p < 0.01 ), fatigue (ji = -0.31, p < 0.001) and cognitive difficulties (ji =0.32, p < 0.001 ); (2) psychosocial functioning (r2=0.31) was associated with was associated with symptoms of fatigue (ii= -0.25, p <0.001) and cognitive difficulties <ii =0.19, p <0.001); and (3) intimacy (r2=0.17) was related to was associated with symptoms of fatigue (ij = -0.17, p < 0.01) and cognitive difficulties (ii= 0.19, p < 0.001 ). methods: the sif evaluation methodology involves a comprehensive database located at the sif, a randomly selected p~o.spective coh~rt of sif users, and two pre-existing external control cohorts. . . ~ts: in addmon to reporting process data and descriptions of the sif users, we report on data indicating that the establishment of the sif has been independently associated with reductions in public ~':°g ~ (p <?.001), and syringe sharing (aor =0.3[95%ci: 0.1 _ 0.7); p =0.013) and other unsafe m1ecnon pract1_ces_ (p ~ 0.010), and increased uptake of detox services (log-rank p =0.017). as well, we report on da~ md1cat1ng that the sif has not prompted adverse changes in community drug use patterns. the vancouver sif has been well accepted by the target population, and while adve~ events s~c~ as overdoses have occurred, these events have been successfully managed. externally compiled data indicate that the sif has been associated with substantial declines in public disorder !'oster sessions v125 associated with injection drug use, syringe sharing, and increased uptake of detox services. as well, the establishment of the sif has not exacerbated community drug use patterns. ongoing evaluation activities wiu involve assessing the impact of the sif on a variety of outcomes, including infectious disease transmission, fatal overdose, and utilization of health and social services. city, brazil, 1996 -2002 maria cristina almeida, waleska caiaffa, renato assum;iio, and fernando proietti dengue cases were described according to time, space, intensity, age, gender, onset of symptoms, residence address and census tract. spatial distribution of two groups (children and women over 64 years old and men aged 20-59) were compared, under assumption that they have distinct behaviors regarding their displacement around the city. analysis included local moran index, ripley\\'s k function and recurrence of census areas over time. about 99,559 cases were identified in seven epidemic waves. concentration of cases in small areas, followed by a spread either in space or time suggested endemic patterns. regarding age-gender groups, distinct patterns suggested that residence might not be a good proxy in determining the local of infection for men aged 20-59. dengue is shifting to endemic pattern in this city and transmission may not be sole related to home environment, suggesting that additional spatial information must be couected aiming efficient control measures. murukan kandamuthan and subodh kandamuthan lnl7uduction: illness or disablement of a child may affect the economic functioning of a family as it alters the employment pattern and earnings of parents this paper tries to assess the health status and the quality of life of disabled children, and how generally, severe disablement in a child affected their fami-lies\' finances, and to quantify any such effects the problems faced by children in their home and to provide information relevant to the formation of criteria for new or increased cash support. methods: a case-control study was done in the thiruvananthapuram district, capital city of kerala by selecting a random sample of 300 families with severely disabled children below 15 years and a random sample of 300 normal children matched for age and occupation of the parents. comparative and subjective data were collected. money spent on children\'s medical care, loss of earnings of the parents, and other economic burden to the family due to the disability of the child in the family. a discriminant analysis along with univariate analysis was done to assess the factors that mostly differentiate the disabled and normal children. the mean expenditure of the families with a disabled child was rs. 852/-per month, which is significantly higher than the corresponding expenditure of rs. 389/-per month of families with normal child, (t= 16.86, p <.00001). of the disabled children, 81 % were not getting any social security payments and 90% had no special concessions for medical and other educational purposes. the analysis of income and expenditure pattern indicated that financial impact of disablement in a child on the family is significant. the discriminant model results revealed that medical expenditure was a significant variable that differentiated the disabled and normal child. the study found that the health status and quality of life of the disabled children were far from satisfactory. this in fact affected the economic status of the disabled children. in addition to reduced earnings, there are extra costs for disabled children for travel, domestic help, medical care, and health care expenditures (hospital care, physician services, dentistry, drugs and others) for disabled individuals. a strong case can be made for their long-term care by improving the financial support to such families possibly through the introduction of an allowance specially to compensate for the earnings lost by parents due to the disability of their children. widows in india are considered disadvantage group of population. because they are characterized by pangs of separation from spouse, and consequently they go through mental agony, social ~s?lation, and economic dislocation. in addition to these, poverty, landlessness, homelessness, malnutr1non etc. endure serious deterioration of their health. according to census 2001, there are 44 million women are widowed and one fourth live in urban areas. there is a noticeable increase of urban widows from the previous census (almost half). the paper examines the type of disability and chronic ailment borne among elderly widows (60 years and above). fifty second round of national sample survey aske~ the individuals three sets of questions regarding their health: their status of health, whether they are physically poster sessions v126 immobile, and whether or not they have had any specific chronic illnesses. although health infrastruc-1 1 ·1 ble 1 ·n urban setting in india as compared to rural counterpart, prevalence of tures are arge y ava1 a . . . . . h · ·11 · h h"gher 1 "n urban areas analysis shows 1omt problems m old age qmte common c romc 1 ness is muc 1 • . . and nearly 44 percent elderly widows are suffering from this ail'.11ent in urban areas. one-fifth of widows are suffering from high/low bp. heart disease, diabetes and urinary problems are much ~ore pre~alent in urban areas though disabilities is comparatively lower in urban areas. however, the d~fference is not statistically significant. disability with respect to vision is more pronounced and one third_ of the total respondents have problems regarding eyesight. one fifths ofdderly widows are _ha.rd of hearing. though disability increases with age, similar trend is not observed with respect to chr~mc illness. the percepnon of self-health among elderly becomes poorer as their age increases. the perceived health status need not be always corrected to objective indicators of health. it is noted that around 27 per~en~ of those perceived their health as "excellenr" or "very good" are found to be suffering from chrome disease of1omts and 17 percent have visual disability. to conclude an elderly widow living in urban areas have similar health problems as she jives in rural areas. this can be easily explained, as they were not made aware to seek treatment from health facility. in addition, the study shows that the economic conditions are deterrent factors for their illness. it is essential that intervention should be taken up improving their economic conditions so that wellbeing of this most vulnerable group of the society can be taken care of. heart failure is a disease that affects nearly 15 million people world wide. the united states alone accounts for one third of this population. blacks are stricken with heart failure twice as often as whites. men are more likely to develop chf than women, however since the majority of the chf population are seniors, there are actually more women than men. congestive heart failure (chf) has become a pandemic. as the baby boomer generation ages, the number of chf cases will rise dramatically. (young, j. & mills, r.,2004). after the age of 45, each proceeding decade doubles the incidence level of chf. the average person has a 1 in 5 chance of developing heart failure within their lifespan according to the framingham study (nih.gov). individuals aging 65 or older compose over half of the entire documented heart failure population. in this age group, chf is the leading cause of hospitalization. many patients are continuously readmitted. it is estimated that the chf population will increase by one million within the next 25 years. mortality was at 50% for a two year period and 70% for five years (young, j. & mills, r.,2004 ). data from: aha as technology evolves, the understanding of the nature of heart failure has become clearer. in the beginning of the 20th century heart failure was diagnosed as a condition that presented with edema (swelling) in the extremities caused by water retention. treatment in the beginning of the past cenrury was limited to abdominal drainage and diuretics. the discovery of the heart's insufficient pumping ability in heart failure patients lead to new surgeries and devices such as heart transplants and ventricular assist devices (bridge until transplant is available). ventricular hypertrophy often occurs before the development of heart failure. hypertrophy is the term given for cardiac remodeling. cardiac remodeling also includes chamber dilation (young, j. & mills, r.,2004) . chf financial burden the us healthcare financing administration has ranked chf as the highest cost illness in the diagnose-related area. direct costs related to chf in the us for 2004 were nearly $26 billion. these costs included hospital admissions, physician fees, home health aids and medications. indirect costs were over $2 billion in 2004. loss of jobs or death due to chf was the criteria for this category (young, j. & mills, r., 2004). . introduction: the injection drug user quality of life scale (iduqol) is a relatively new scale ~es1gned to capture the unique and individual circumstances that determine quality of life among injection drug users (idus). the 20 life areas comprising the instrument were based on the research literature an~ ~ocus group discussions with idus. the purpose of the present study was to evaluate the content validity of t.h~ iduqol using judgmental methods based on subject matter experts' (smes) ratings. content vah~1ty refers to the de~ee to which elements of an assessment tool are representative of the construct of interest and appropnate for a given population. methods: data were obtained from six smes, from the field of idu research and practice, who ~ere. asked t.o evaluate various aspects of the iduqol, including the title of the instrument, administraon instruchons, clarity of the names and descriptions of each life area, response format, scoring instruc-no~s and examples, record form and whether each life area should be included in the instrument. sme ratings were made using either 3 or 4 point scales. sm es were also given the opportunity to comment on poster sessions v127 each section and to suggest whether important life areas had been overlooked, were redundant, not relevant, or in need of revision. (cvi) and the ~v.erage ~eviation index (ad) were used to evaluate smes' agreement on ratings of the content vahd1ty vanables. both measures provided support for the content validity of various aspects of the iduqol, although results from the stricter ad index noted some areas of disagreement, including the description of particular life areas (e.g., being useful, drugs, sex), the inclusion of some life areas (e.g., drug treatment, education, independence and free choice), and the ease of the scoring instructions. the findings from this study provide (a) content validity evidence to support the use of the iduqol as well as (b) recommendations to suengthen both the instrument (e.g., improved descriptions for some items) and the accompanying administration and scoring manual (e.g., an easier scoring template). changes made to the instrument and its manual make the iduqol even easier for researchers, practitioners, and program evaluators to use as a way of assessing, and tracking changes over time or as a result of interventions in, quality of life in injection drug users. introduction: strict adherence to prescribed regimens is required to derive maximal benefit from highly active antireuoviral therapy (haart) in persons living with hiv/aids (phas). adherence is a key determinant of the degree and durability of viral suppression. adherence is also essential in reducing the spread of hiv and ensuring that today's treatments remain effective for as long as possible. the objective of this study is to conduct a systematic review of the research literature on the effectiveness of education and patient support strategies for improving adherence to haart. methods: a systematic search of the core databases was performed from january 1996 until may 2005. randomized controlled trials examining the effectiveness of education and patient support interventions to improve the adherence to haart were considered for inclusion. only those studies that measured adherence at a minimum of six weeks were included. study selection, quality assessments, and data abstraction were performed independently by two reviewers. results: study heterogeneity with respect to differing populations, interventions, outcomes, and length of follow-up did not allow for meta-analysis. we included 19 studies involving 2, 159 ph as. sample sizes ranged from 22 to 367. study duration ranged from a single session to a variable number of sessions delivered over one year. many of the interventions involved the provision of an educational component to improve adherence and often addressed strategies to overcome barriers to adherence and the development of problem-solving skills. they ranged from simple interventions (e.g., the provision of reminder devices) to complex interventions (e.g., cognitive-behavioural therapy delivered by licensed psychologists). eleven of the 19 studies demonstrated a statistically significant advantage associated with the described adherence intervention. the advantage associated with adherence outcomes does not seem to translate into the more clinically relevant outcome of viral suppression. only 4 out of 12 studies that reported virological or immunological results found a significant effect associated with the intervention. the studies had several methodological shortcomings. conclusions: there is a need for standardization and methodological rigour in the conduct of adherence trials. some interventions may have a significant impact on improving adherence. further research is required before any specific adherence improving strategy can confidently be incorporated into standard clinical practice. focus groups were used to collect data from a purposive sample of treatmentexperienced participants. focus group data were analyzed using a grou~ded t~eory appr~ach. i:ne themes identified from the interviews were used to identify the effects of ant1rerrov1rals on quality of hfe. the content of the mos-hiv was appraised against the themes identified from our analysis. participants also completed the mos-hiv survey and were asked whether the survey covered all important aspects of quality of life on antiretroviral medications. results: five key informant interviews and five focus groups with 38 participants were used to identify effects on quality of life that are not directly ~aptu~ed by_ the mos-hiv health survey. our~~ showed that our participants described quality of hfe as mvol~mg_ a set of ~rsonal trad~ffs ~stay alive. in most cases, worsened quality of life was traded-off for gams 1~ longevlty from ~~canon use. these eff~'ts or tradeoffs included: ( 1) downstream consequences of side effects and toxlanes; (2) loss of lrufe. pende~t decision-making privileges, (3) having to choose drugs over ~areer; (~)burden of medication-taking responsibilities; and (5) living life under a pretense and havmg to hide-the net effect of the tradeoffs, or "prices" to pay led to what was described as "longevity with hn without hope and future~. conclusion: our study highlights five major themes summarizing the impact of haart on quality on life, and suggests that currently used scales for measuring quality of life do not a~atd~ cap~e these findings and the associated consequences. the conceptual framework for measuring quality of bfe in hiv should be reconsidered in order to better capture the important effects of the medications on quality of life. this may involve widening the boundaries of the definition of health-related quality oflife to include aspects such as finances, employment, and housing. we should further consider the development of a haart adverse effect specific instrument, using a broad definition of adverse effect in order to capture all types of adverse impacts of hiv treatments on quality of life. introduction: measles (rubeola) is the most contagious vaccine preventable disease of humans. while cases of measles are uncommon in canada today, the disease continues to be a leading cause of morbidity and death in the developing world. as a result of human migration, measles cases still occur in canada, primari~ among immigrants, returning travelers, and other susceptible groups. canada's national advisory council on immunizations (naci) recommends that immigrants without records of measles immunization be considered for vac:cination since these individuals may not have been appropriately vaccinated in their native country. on rhe other hand, natural immunity to measles in immigrants is likely to be high given the high incidence of disease in developing parts of rhe world. thus it remains unclear if the most efficient strategy to achieve high levels of measles immunity in immigrants should entail initial serologic screening followed by vaccination of susceptible individuals or preemptive vaccination of all persons lacking immunization records. understanding the epidemiology of measles immunity in immigrant populations could help guide such decisions. . methods: we identified 527 adults, 15 years of age or older, who were screened for serologtc immunity to measles as part of a recently developed screening protocol at a downtown toronto community health centre. we subsequently determined if these individuals had any immunization records from their native country or from within canada. we then examined the relationship between several demographic factors and immunity to measles. results: 93% of immigrants had no prior immunization records. overall, 93% of the 527 immigrants rested for immunity to measles were found to be immune; 88% of those under the age of 20, 93% of those between 20 and 39 years of age, 99% of those between 40 and 59 years of age, and 100% of those 60 years of age or older. gender, education status, household income, and immigration status were nor ~ssoc1ated wirh immunity to measles. immunity to measles was lowest among immigrants from eastern europe (8~%), whil~ immigrants from other regions of the globe had greater than 90% immunity. c~lusrons: immigrants and refugees appear to have reasonably high levels of immunity to mea· sics, possibly related to natural infection wirh the measles virus. immigrants from eastern europe appear to have slightly. lower l~vel~ of immunity to the measles virus. universal screening for immunity to meales or preemptive vac:cmauon may both be inefficient public health strategies, however further research is needed to corroborate these findings. nancy r~ss, stephane tremblay, saeeda khan, daniel crouse, mark tremblay, and jean-marie berrhelor o~ve: the speed of the rise in obesity in places like canada suggests that rather than a shift in the gcncnc_ com~sirion of the population, the root of the obesity pandemic is an environment that suprrs ~besity. this paper examines the influence of neighbourhood and metropolitan characteristics. bour~lts:. while accounting. for individual socio-demographics and behaviours, residents of neighs with a large proportmn of poorly educated individuals had higher bmis than those living in poster sessions v129 neighbourhoods with more highly educated individuals (p <.01 ). residing in a neighbourhood with a high proportion of recent immigrants was associated with lower bmi for men (p<.01), but not women. neighbourhood dwelling density, a proxy for walkability, was not associated with bm! for either sex. metropolitan sprawl was associated with higher male bmi (p=.02) but the effect was negligible for women (p=.09). bmi was significantly lower for women (p<.01) living in a city in the province of quebec, even after accounting for the influence of individual and neighbourhood covariates. conclusions: bm! was strongly patterned by individual-level social position in urban canada. the incremental influence on bmi of neighbourhood related to the neighbourhood's social conditions and not to their physical form. metropolitan sprawl was associated with higher bm! for men, a group with longer car-dependent commutes than women. the findings suggest that both individuals and their environments (both social and physical) influence the distribution of bmi in urban populations. introduction: urban environments have been linked to a range of human health issues. in singapore, prevalence of end stage renal disease (esrd) is predicted to rise (2633 in 1999 to 6000 in 2010 , kidney international, vol.67, 2005 . the clinical and economic burden of esrd has promoted development of strategies aimed at preventing the development and progression of chronic kidney disease. these include population based screening programs such as the national kidney foundation, sin-gapore\'s (nkfs) "partnership for prevention."the program, aims to reduce incidence of esrd through comprehensive intervention and screening for early detection of urinary abnormalities, blood pressure (bp), and random blood glucose (rbg). objective of this study is to examine gender, race and age wise prevalence of elevated bp, rbg and proteinuria. methodology: this current analysis includes 575,438 subjects, age 18 to 86 years, who underwent screening during september 1999 and december 2004. participants were asked to give demographic information and the history of diseases. tests were given to get clinical information such as proteinuria, blood glucose, sbp, and dbp. blood pressure abnormalities were defined according to ]nc vi criteria. proteinuria was defined as the presence of 1 plus or greater protein (equivalent to> 30 mg/di) on dipstick analysis. results: there were 296, 116 (51.5%) males. racial distribution was chinese (78.8% ), malay (8.8% ), indians (8. 7%) and others (3. 7% ).among participants, who were apparently "healthy" (asymptomatic and without history of dm, ht, or kd), gender and race wise % prevalence of elevated (bp> 140/90), rbg (> 140 mg/di) and positive urine dipstick for protein was as follows male: (20.5;6.9; 3.5) female:(13.6;5.0;3. 2) chinese:( 17.1;6.0;3) malay: (19.4;7.3;5.6) indian:( 15.9;7.5;3.0) others: (15.4;4.5;2.9) total:(l 7.1, 6.1,3.2). percentage of participants with more than one abnormality were as follows. those with bp> 140/90mmhg, 14% also had rbg> 140mg/dl and 6.4% had proteinuria> i. those with rbg> 140mgldl, 11 % also had proteinuria> 1 and 35% had bp> 140/90mmhg. those with proteinuria> 1, 18% also had rbg> 140mg/dl, and 38% had bp> 140/90mmhg. conclusion: we conclude that sub clinical abnormalities in urinalysis, bp and rbg readings are prevalent across all genders and racial groups in the adult population. the overlap of abnormalities, point towards the high risk for esrd as well as cardiovascular disease. this indicates the urgent need for population based programs aimed at creating awareness, and initiatives to control and retard progression of disease. introduction: various theories have been proposed that link differential psychological vulnerability to health outcomes, including developmental theories about attachment, separation, and the formation of psychopathology. research in the area of psychosomatic medicine suggests an association between attachment style and physical illness, with stress as a mediator. there are two main hypotheses explored in the present study: ( t) that individuals living with hiv who were upsychologically vulne~able" at study entry would be more likely to experience symptoms of depression, anxiety and phys1ca! illness over. the course of the 9-month study period; and (2) life stressors and social support would mediate the relat10nship between psychological vulnerability and the psychological ~nd physical outcomes. . (rsles), state-trait anxiety inventory (stai), beck depr~ssi~n lnvento~ (bdi), and~ _21-item pbys~i symptoms inventory. we characterized participants as havmg psychological vulnerability and low resilience" as scoring above 35 on the raas (insecure attachment) or above 120 on the das (negative expectations about oneself). . . . . . " . . ,, . results: at baseline, 55% of parnc1pants were classified as havmg low resilience. focusmg on anxiety, the average cumulative stai score of the low-resilience group was significandy hi~e~ than that of the high-resilience group ( 18.45 sd= 10.6 versus 9.57 sd= 8.6; f(l,80)= 16.74, p <.001). similar results were obtained for bdi and physical symptoms (f( 1,80)= 14.65, p<.001 and f( 1,80)= 5.50, p<.05, respec· tively). after controlling for resilience, the effects of variance in life stres".°rs averaged over time wa~ a_sig· nificant predictor of depressive and physical symptoms, but not of anxiety. ho~e_ver, these assooan~s became non-significant when four participants with high values were removed. s1id1larly, after controlling for resilience, the effects of variance in social support averaged over time became insignificant. conclusion: not only did "low resilience" predict poor psychological and physical outcomes, it was also predictive of life events and social support; that is, individuals who were low in resilience were more likely to experience more life events and poorer social support than individuals who were resilient. for individuals with vulnerability to physical, psychological, and social outcomes, there is need to develop and test interventions to improve health outcomes in this group. rajat kapoor, ruby gupta, and jugal kishore introduction: young people in india represent almost one-fourth of the total population. they face significant risks related to sexual and reproductive health. many lack the information and skills neces· sary to make informed sexual and reproductive health choices. objective: to study the level of awareness about contraceptives among youth residing in urban and rural areas of delhi. method: a sample of 211 youths was selected from barwala (rural; n= 112) and balmiki basti (urban slums; n= 99) the field practice areas of the department of community medicine, maulana azad medical college, in delhi. a pre-tested questionnaire was used to collect the information. when/(calen· dar time), by 2, fisher exact and t were appliedxwhom (authors?). statistical tests such as as appropriate. result: nearly 9 out of 10 (89.1 %) youth had heard of at least one type of contraceptive and majority (81.5%) had heard about condoms. however, awareness regarding usage of contraceptives was as low as 9.4% for terminal methods to 39.3% for condom. condom was the best technique before and after marriage and also after childbirth. the difference in rural and urban groups was statistically signif· icant (p=.0001, give confidence interval too, if you provide the exact p value). youth knew that contra· ceptives were easily available (81 %), mainly at dispensary (68.7%) and chemist shops (65.4%). only 6.6% knew about emergency contraception. only advantage of contraceptives cited was population con· trol (42.6%); however, 3.8% believed that they could also control hiv transmission. awareness of side effects was poor among both the groups but the differences were statistically significant for pills (p=0.003). media was the main source of information (65%). majority of youth was willing to discuss a~ut contraceptive with their spouse (83.4%), but not with others. 51.2% youth believed that people in their age group use contraceptives. 35% of youth accepted that they had used contraceptives at least once. 81 % felt 2 children in family is appropriate, but only 59.7% believed in 3 year spacing. . conclusion: awareness about contraceptives is vital for youth to protect their sexual and reproduc· tive health .. knowledge about terminal methods, emergency contraception, and side effects of various contraceptives need to be strengthened in mass media and contraceptive awareness campaigns. mdbot:ls: 740 elderly aged 60+ were interviewed in 3 poor communities in beirut the capital of f:ebanon, ~e of which is a palestinia~. refugee camp. depression was assessed using the i 5-item geriat· nc depressi~n score (~l?s-15). specific q~estions relating to the 3 aspects of religiosity were asked as well as questions perta1rung to demographic, psychosocial and health-related variables. results: depression was prevalent in 24% of the interviewed elderly with the highest proportion being in the palestinian refugee camp (31 %). mosque attendance significantly reduced the odds of being depressed only for the palestinian respondents. depression was further associated, in particular communities, with low satisfaction with income, functional disability, and illness during last year. condiuion: religious practice, which was only related to depression among the refugee population, is discussed as more of an indicator of social cohesion, solidarity than an aspect of religiosity. furthermore, it has been suggested that minority groups rely on religious stratagems to cope with their pain more than other groups. implications of findings are discussed with particular relevance to the populations studied. nearly thirty percent of india's population lives in urban areas. the outcome of urbanization has resulted in rapid growth of urban slums. in a mega-city chennai, the slum populations (25.6 percent) face greater health hazards due to overcrowding, poor sanitation, lack of access to safe drinking water and environmental pollution. amongst the slum population the health of women and children are most neglected, resulting in burden of both communicable and non-communicable diseases. the focus of the paper is to present the epidemiology profile of children (below 14 years) in slums of chennai, their health status, hygiene and nutritional factors, the social response to health, the trends in child health and urbanization over a decade, the health accessibility factors, the role of gender in health care and assessment impact of health education to children. the available data prove that child health in slums is worse than rural areas. though the slum population is decreasing there is a need to explore the program intervention and carry out surveys for collecting data on some specific health implications of the slum children. objective: during the summer of 2003 there was a heat wave in central europe, producing an excess number of deaths in many countries including spain. the city of barcelona was one of the places in spain where temperatures often surpassed the excess heat threshold related with an increase in mortality. the objective of the study was to determine whether the excess of mortality which occurred in barcelona was dependent on age, gender or educational level, important but often neglected dimensions of heat wave-related studies. methods: barcelona, the second largest city in spain (1,582,738 inhabitants in 2003) , is located on the north eastern coast. we included all deaths of residents of barcelona older than 20 years that occurred in the city during the months of june, july and august of 2003 and also during the same months during the 5 preceding years. all the analyses were performed for each sex separately. the daily number of deaths in the year 2003 was compared with the mean daily number of deaths for the period 1998-2002 for each educational level. poisson regression models were fitted to obtain the rr of death in 2003 with respect to the period 1998-2002 for each educational level and age group. results: the excess of mortality during that summer was more important for women than for men and among older ages. although the increase was observed in all educational groups, in some age-groups the increase was larger for people with less than primary education. for example, for women in the group aged 65-74, the rr of dying for 2003 compared to 1998-2002 for women with no education was 1.30 (95%ci: 1.04-1-63) and for women with primary education or higher was 1.19 (95%ci: 0.90-1.56). when we consider the number of excess deaths, for total mortality (>=20 years) the excess numbers were higher for those with no education ( 17 5. 7 for women and 46. 7 for men) and those with less than primary education (112.5 for women and 11-2 for men) than those with more than primary edm:ation (75.0 for women and -10.3 for men). conclusion: age, gender and educational level were important in the 2003 barcelona heat wave. it is necessary to implement response plans to reduce heat morbidity and mortality. policies should he addressed to all population but also focusing particularly to the oldest population of low educational level. introduction: recently there has been much public discourse on homelessness and its imp~ct on health. measures have intensified to get people off the street into permanent housing. for maximum v132 poster sessions success it is important to first determine the needs of those to be housed. their views on housing and support requirements have to be considered, as th~y ar~ the ones affected. as few res.earch studies mclude the perspectives of homeless people themselves, httle is known on ho~ they e~penence the 1mpacrs on their health and what kinds of supports they believe they need to obtain housing and stay housed. the purpose of this study was to add the perspectives of homeless people to the discourse, based in the assumption that they are the experts on their own situations and needs. housing is seen as a major deter· minant of health. the research questions were: what are the effects of homelessness on health? what kind of supports are needed for homeless people to get off the street? both questions sought the views of homeless individuals on these issues. methods: this study is qualitative, descriptive, exploratory. semi-structured interviews were conducted with homeless persons on street corners, in parks and drop-ins. subsequently a thematic analysis was carried out on the data. results: the findings show that individuals' experiences of homelessness deeply affect their health. apart from physical impacts all talked about how their emotional health and self-esteem are affected. the system itself, rather than being useful, was often perceived as disabling and dehumanizing, resulting in hopelessness and resignation to life on the street. neither welfare nor minimum wage jobs are sufficient to live and pay rent. educational upgrading and job training, rather than enforced idleness, are desired by most initially. in general, the longer persons were homeless, the more they fell into patterned cycles of shelter /street life, temporary employment /unemployment, sometimes addictions and often unsuccessful housing episodes. conclusions: participants believe that resources should be put into training and education for acquisition of job skills and confidence to avoid homelessness or minimize its duration. to afford housing low-income people and welfare recipients need subsidies. early interventions, 'housing first', more humane and efficient processes for negotiating the welfare system, respectful treatment by service providers and some extra financial support in crisis initially, were suggested as helpful for avoiding homelessness altogether or helping most homeless people to leave the street. this study is a national homelessness initiative funded analysis examining the experiences and perceptions of street youth vis-a-vis their health/wellness status. through in-depth interviews with 140 street youth in halifax, montreal, toronto, calgary, ottawa and vancouver, this paper explores healthy and not-so healthy practices of young people living on the street. qualitative interviews with 45 health/ social service providers complement the analysis. more specifically, the investigation uncovers how street youth understand health and wellness; how they define good and bad health; and their experiences in accessing diverse health services. findings suggest that living on the street impacts physical, emotional and spiritual well·being, leading to cycles of despair, anger and helplessness. the majority of street youth services act as "brokers" for young people who desire health care services yet refuse to approach formal heal~h care organizational structures. as such, this study also provides case examples of promising youth services across canada who are emerging as critical spaces for street youth to heal from the ravages of ~treet cultur~. as young people increasingly make up a substantial proportion of the homeless population in canada, it becomes urgent to explore the multiple ways in which we can support them to regain a sense of wellbeing and "citizenship." p5-77 (c) health and livelihood implications of marginalization of slum dwellers in provision of water and sanitation services in nairobi city elizabeth kimani, eliya zulu, and chi-chi undie . ~ntrodfldion: un-habitat estimates that 70% of urban residents in kenya live in slums; yet due to their illegal status, they are not provided with basic services such as water sanitation and health care. ~nseque~tly, the services are provided by vendors who typically provide' poor services at exorbitant prices .. this paper investigates how the inequality in provision of basic services affects health and livelihood circumstances of the poor residents of nairobi slums . . methods: this study uses qualitative and quantitative data collected through the ongoing longitudmal .health and demographic study conducted by the african population and health research center m slum communities in n ·rob" w d · · · · ai 1. e use escnpnve analytical and qualitative techmques to assess h~w concerns relating to water supply and environmental sanitation services rank among the c~mmumty's general and health needs/concerns, and how this context affect their health and livelihood circumstances. results: water (32%) and sanitation (20%) were the most commonly reported health needs and also key among general needs (after unemployment) among slum dwellers. water and sanitation services are mainly provided by exploitative vendors who operate without any regulatory mechanism and charge exorbitantly for their poor services. for instance slum residents pay about 8 times more for water than non-slum households. water supply is irregular and residents often go for a week without water; prices are hiked and hygiene is compromised during such shortages. most houses do not have toilets and residents have to use commercial toilets or adopt unorthodox means such as disposing of their excreta in the nearby bushes or plastic bags that they throw in the open. as a direct result of the poor environmental conditions and inaccessible health services, slum residents are not only sicker, they are also less likely to utilise health services and consequently, more likely to die than non-slum residents. for instance, the prevalence of diarrhoea among children in the slums was 31 % compared to 13 % in nairobi as a whole and 17% in rural areas, while under-five mortality rates were 151/1000, 62/1000 and 113/1000 respectively. the results demonstrate the need for change in governments' policies that deprive the rapidly expanding urban poor population of basic services and regulatory mechanisms that would protect them from exploitation. the poor environmental sanitation and lack of basic services compound slum residents' poverty since they pay much more for the relatively poor services than their non-slum counterparts, and also increase their vulnerability to infectious diseases and mortality. since 1991 iepas've been working in harm reduction becoming the pioneer in latin america that brought this methodology for brazil. nowadays the main goal is to expand this strategy in the region and strive to change the drug policy in brazil. in this way harm reduction: health and citizenship program work in two areas to promote the citizenship of !du and for people living with hiv/aids offering law assistance for this population and outreach work for needle exchange to reduce damages and dissemination of hiv/aids/hepatit is. the methodology used in outreach work is peer education, needle exchange, condoms and folders distribution to reduce damages and the dissemination of diseases like hiv/aids/hepatitis besides counseling to search for basic health and rights are activities in this program. law attendance for the target population at iepas headquarters every week in order to provide law assistance that includes only supply people with correct law information or file a lawsuit. presentations in harm reduction and drug policy to expand these subjects for police chiefs and governmental in the last year attended 150 !du and 403 nidu reached and 26.364 needles and syringes exchanged. in law assistance 740 (420 people living with aids, 247 drug users, 43 inject drug users, 30 were not in profile) people attended. 492 lawsuits filed 218 lawsuits in current activity. broadcasting of the harm reduction strategies by the press helps to move the public opinion, gather supporters and diminish controversies regarding such actions. a majority number of police officer doesn't know the existence of this policy. it's still polemic discuss this subject in this part of population. women remain one of the most under seviced segments of the nigerian populationand a focus on their health and other needs is of special importance.the singular focus of the nigerian family welfare program is mostly on demographic targets by seeking to increase contraceptive prevalence.this has meant the neglect of many areas of of women's reproductive health. reproductive health is affected by a variety of socio-cultural and biological factors on on e hand and the quality of the service delivery system and its responsiveness on the other.a woman's based approach is one which responds to the needs of the adult woman and adolescent girls in a culturally sensitive manner.women's unequal access to resources including health care is well known in nigeria in which stark gender disparities are a reality .maternal health activities are unbalanced,focusi ng on immunisation and provision of iron and folic acid,rather than on sustained care of women or on the detection and referral of high risk cases. a cross-sectional study of a municipal government -owned hospitalfrom each of the 6 geo-political regions in igeria was carried out (atotal of 6 ce~ters) .. as _part ~f t~e re.search, the h~spital records were uesd as a background in addition to a 3-week mtens1ve mvesuganon m the obstemc and gynecology departments. . . . : little is known for example of the extent of gynecological morbtdtty among women; the little known suggest that teh majority suffer from one or more reproductive tr~ct infect~ons. although abortion is widespread, it continues to be performed under ilegal and unsafe condmons. with the growing v134 poster sessions hiv pandemic, while high riskgroups such ascomn;iercial sex workers and their clients have been studied, little has been accomplished in the large populat10ns, and particularly among women, regardmgstd an hiv education. . . conclusions: programs of various governmentalor non-governmental agen,c1es to mvolve strategies to broaden the narrow focus of services, and more importan~, to put wo~en s reproducnve health services and information needs in the forefront are urgently required. there is a n~d to reonent commuication and education activities to incorprate a wider interpretation of reproducnve health, to focus on the varying information needs of women, men, and youth and to the media most suitable to convey information to these diverse groups on reproductive health. introduction: it is estimated that there are 250-300 youths living on the streets, on their own with the assistance of social services or in poverty with a parent in ottawa. this population is under-serviced in many areas including health care. many of these adolescents are uncomfortable or unable to access the health care system through conventional methods and have been treated in walk-in clinics and emergency rooms without ongoing follow up. in march 2004, the ontario government provided the ct lamont institute with a grant to open an interdisciplinary and teaching medical/dental clinic for street youth in a drop-in center in downtown ottawa. bringing 5 community organizations together to provide primary medical care and dental hygiene to the streetyouths of ottawa ages 12-20, it is staffed by a family physician, family medicine residents, a nurse practitioner, 2 public health nurses, a dental hygienist, dental hygiene students and a chiropodist who link to social services already provided at the centre including housing, life skills programs and counselling. project objectives: 1. to improve the health of high risk youth by providing accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. 2. to model and teach interdisciplinary adolescent care to undergraduate medical students, family medicine residents and dental hygiene students. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative:a) semi-structured interviews b) focus groups with youth quantitative:a) electronic medical records for 12 months b) records (budget, photos, project information). results: in progress-results from first 12 months available in august 2005. early results suggest that locating the clinic in a safe and familiar environment is a key factor in attracting the over 130 youths the clinic has seen to date. other findings include the prevalence of preventative interventions including vaccinations, std testing and prenatal care. the poster presentation will present these and other impacts that the clinic has had on the health of the youth in the first year of the study. conclusions: 1) the clinic has improved the health of ottawa streetyouth and will continue beyond the initial pilot project phase. 2) this project demonstrates that with strong community partnerships, it is possible meet make healthcare more accessible for urban youth. right to health care campaign by s.j.chander, community health cell, bangalore, india. introduction: the people's health movement in india launched a campaign known as 'right to health care' during the silver jubilee year of the alma ata declaration of 'health for all' by 2000 ad in collahoration with the national human rights commission (nhrc). the aim of the campaign was to establish the 'right to health care' as a basic human right and to address structural deficiencies in the pubic health care system and unregulated private sector . . methods: as part of the campaign a public hearing was organized in a slum in bangalore. former chairman of the nhrc chaired the hearing panel, consisting of a senior health official and other eminent people in the city. detailed documentation of individual case studies on 'denial of access to health care' in different parts of the city was carried out using a specific format. the focus was on cases where denial of health services has led to loss of life, physical damage or severe financial losses to the patient. results: _fourte_en people, except one who had accessed a private clinic, presented their testimonies of their experiences m accessing the public health care services in government health centres. all the people, e_xcept_ one person who spontaneously shared her testimony, were identified by the organizations worki_ng with the slum dwellers. corruption and ill treatment were the main issues of concern to the people. five of the fourteen testimonies presented resulted in death due to negligence. the public health cen· n:s not only demand money for the supposedly free services but also ill-treats them with verbal abuse. five of these fourteen case studies were presented before the national human right commission. the poster sessions v135 nhrc has asked the government health officials to look into the cases that were presented and to rectify the anomalies in the system. as a result of the public hearing held in the slum, the nhrc identified urban health as one of key areas for focus during the national public hearing. cond#sion: a campaign is necessary to check the corrupted public health care system and a covetous private health care system. it helps people to understand the structure and functioning of public health care system and to assert their right to assess heath care. the public hearings or people's tribunals held during the campaign are an instrument in making the public health system accountable. ps-82 (a) violence among women who inject drugs nadia fairbairn, jo-anne stoltz, evan wood, kathy li, julio montaner, and thomas kerr background/object ives: violence is a major cause of morbidity and mortality among women living in urban settings. though it is widely recognized that violence is endemic to inner-city illicit drug markets, little is known about violence experienced by women injection drug users (!du). therefore, the present analyses were conducted to evaluate the prevalence of, and characteristics associated with, experiencing violence among a cohort of female idu in vancouver. methods: we evaluated factors associated with violence among female participants enrolled in the vancouver injection drug user study (vidus) using univariate analyses. we also examined self-reported relationships with the perpetrator of the attack and the nature of the violent attack. results: of the 346 active iou followed between december 1, 2003 and may 6, 2005, 73 (21.1 %) had experienced violence during the last six months. variables positively associated with experiencing violence included: homelessness (or= 3.46, 95% ci: 1.66-7.21, p < 0.01), public injecting (or= 3.45, 95% ci: 1.43 -8.35, p < 0.01 ), frequent crack use (or= 2.99, 95% ci: 1. 72 -5.17, p < 0.01 ), recent incarceration (or =2.81, 95% cl: 1.38 -5.72, p < 0.01), receiving help injecting (or =2.77, 95% cl: 1.54-5.00, p < 0.01 ), shooting gallery attendance (or =2.46, 95% ci: 1.22 -4.93, p < 0.01 ), sex trade work (or =2.30, 95% cl: 1.35 -3.93, p < 0.01 ), frequent heroin injection (or= 1.96, 95% cl: 1.13 -3.40, p < 0.02), and residence in the downtown eastside (odds ratio [or] = 1.85, 95% ci: 1.09 -3.13, p < 0.02). variables negatively associated with experiencing violence included: being married or common-law (or =0.47. 95% ci: 0.25 -0.87, p < 0.02) and being in methadone treatment (or =0.53, 95% ci: 0.31 -0.91, p < 0.02). the most common perpetrators of the attack were acquaintances (48.0%), strangers (27.4%), police (9.6%), or dealers (8.2%). attacks were most frequently in the form of beatings (65.8%), robberies (21.9%), and assault with a weapon (13.7%). conclusion: violence was a common experience among women !du in this cohort. being the victim of violence was associated with various factors, including homelessness and public injecting. these findings indicate the need for targeted prevention and support services, such as supportive housing programs and safer injection facilities, for women iou. introduction: although research on determinants of tobacco use among arab youth has been carried out at several ecologic levels, such research has included conceptual models and has compared the two different types of tobacco that are most commonly used among the lebanese youth, namely cigarette and argileh. this study uses the ecological model to investigate differences between the genders as related to the determinants of both cigarette and argileh use among youth. methodology: quantitative data was collected from youth in economically disadvantaged urban communities in beirut, the capital of lebanon. results: the results indicated that there are differences by gender at a variety of ecological levels of influence on smoking behavior. for cigarettes, gender differences were found in knowledge, peer, family, and community influences. for argileh, gender differences were found at the peer, family, and community l.evels. the differential prevalence of cigarette and argileh smoking between boys and girls 1s therefore understandable and partially explained by the variation in the interpersonal and community envi.ronment which surrounds them. interventions therefore need to be tailored to the specific needs of boys and girls. introduction: the objective of this study was to assess the relationship between parents' employment status and children' health among professional immigrant families in vancouver. our target communmes v136 poster sessions included immigrants from five ethnicity groups: south korean, indian, chine~e, ~ussian, and irani~ with professional degrees (i.e., mds, lawyers, engineers, ma?~ger~, and uru~ers1ty professors) w11h no relevant job to their professions and those who had been hvmg m the studied area at least for 36 months. methodology: the participants were recruited by collaboration from three local community agencies and were interviewed individually during the fall of 2004. ra#lts: totally, 109 complete interviews were analyzed: 33 from south-east asia, 59 from south asia, 17 from russia and other eastern europe. overall, 14.5% were employed, 38.5% were underemployed, 46% indicated they were unemployed. overall, 58.5% were not satisfied with their current job. russians and other eastern europeans were most likely satisfied with their current job, while south-east asians were most satisfied from their life in canada. about 53% indicated that their spouses were not satisfied with their life in canada, while 55% believed that their children are very satisfied from their life in canada. in addition, around 30% said they were not satisfied from their family relationship in canada. while most of the responders ranked their own and their spouses' health status as either poor or very poor, jut 3% indicated that their first child's health was very poor. in most cases they ranked their children's health as excellent or very good. the results of this pilot study show that there is a need to create culturally specific child health and behavioral scales when conducting research in immigrant communities. for instance, in many asian cultures, it is customary for a parent either to praise their children profusely, or to condemn them. this cultural practice, called "saving face," can affect research results, as it might have affected the present study. necessary steps, therefore, are needed to revise the current standard health and behavioral scales for further studies by developing a new scale that is more relevant and culturally sensitive to the targeted immigrant families. metboda: database: 2003 national health survey (ministry of health www.msc.es). two thousand interviews were performed among madrid population (0.04% of the whole); 593 corresponded to older adults (0.04% of the 1. 7 million aged 50 years and over). study sample constitutes 95.3% (565 out of 593) of those older adults, who live in urban areas. demographic structure (by age and gender) of this population in relation to health services use (medical consultations, dentist visits, emergence services, hospitalisation) was studied using general linear model univariate procedure. a p0.005), while age was associated with emergence services use (26% of the population: 21 %, 28% and 45% of each age group) and hos~italisation (17% .oft~~ population: 13%, 20% and 31%, of each age ~oup) (p0.005) was fou~d with respect to dennst v1s1ts (18% vs 20%), medical consultations (29% vs 36%), and emergence services use (26% vs 26%), while an association (p= 0.005) was found according to hospitalisation (20% vs 16%). age. an~ g~der interaction effect on health services use was not found (p> 0.005), but a trend towards bosp1tal1sanon (p=0.04) could be considered. concl.uions: demographic structure of urban older adults is associated with two of the four health se~ices use studi~. a relation.ship ber_ween age. and hospital services use (emergence units and hospitalisanon), but not with ~ut-hosp1tal sei:vices (medical and dentist consultations), was found. in addition ro age, gender also contnbutes to explam hospitalisation. . sexua experiences. we exammed the prevalence expenences 10 relation to ethnic origin and other sociodemographic variables as wc1i as y1j7 die relation between unwanted sexual experiences, depression and agreuion. we did so for boys and prts separately. mdhods: data on unwanted sexual expcric:nces, depressive symptoms (ce.s-d), aggrc:uion (bohi-di and sociodemographic facron were collected by self-report quescionnairc:s administettd to 35 31 students in the: 2nd grade (aged 12-16) of secondary schools in amsterdam, the netherlands. data on the nature ol unwanted sexual experiences were collected during penonal interviews by trained schoolnursn. ltaijtj: overall prevalences of unwanted sexual experiences for boys and girls were 6.5% and 5.7% respectively. unwanted sexual experiences were more often ttported by turkish ( 17.1 %), moroc· an (10.4%) and surinamese/anrillian boys (7.4%) than by dutch boys (2.2%). moroccan and turkish girls, however, reported fewer unwanted sexual experiences (respectively 2.3 and 2.7%) than durch girls did (6.9%). depressive symptoms(or=4.6, cl=3.1-7.0) covert agression (0r•4.9, cl•3.2-7.7) and cmrt aggression (or= 2.6, cl• 1.6-4.4) were more common in girls with an unwanted sexual experi· met. boys with an unwanted sexual experience reported more depressive symptoms (or= 2.2; cl• i . .l· 3.9) and oven agression (or= 1.5, cl= 1.0-2.4) . of the reported unwanted sexual experiences rnpec· timy 17.5% and 73.5% were confirmed by male and female adolescents during a personal interview. cond11sion: we ..:an conclude that the prevalence of unwanted sexual experiences among turkish and moroccan boys is disturbing. it is possible that unwanted sexual experiences are more reported hy boys who belong to a religion or culture where the virginity of girls is a maner of family honour and talking about sexuality is taboo. more boys than girls did not confirm their initial disdosurc of an lllwalltc:d sexual experience. the low rates of disclosure among boys suggcsu a necd to educ.:atc hcahh care providen and others who work with migrant boys in the recognition and repomng of 1exu.il ... iction. viramin a aupplc:tmntation i1 at .h'yo, 1till far from tafl'eted 100%. feedinit pracn~:n panku· lerty for new born earn demand lot of educatton ernpha111 a• cxdu11ve hrealt fecdtnit for dnared rcnoj of 6 months was observtd in only 6.s% of childrrn thoulh colckturm w.11 givm 1n rn% of mwly horn ct.ildrm. the proportion of children hclow-2 waz (malnounshrdl .con" a• h!jh •• 42.6% anj "rt'i· acimy tc.. 11 compared to 1998 data. mother's ~alth: from all is 10 womm in ttprod~uvr •ill' poup, 83% were married and among marned w~ .\9% only w\"rt' u1mic wmr cnntr.-:cruve mt1h· odl 44% were married bdorc thc •ar of 18 yean and 27% had thnr ftnc prcicnancy hcftitt dlt' •icr nf 21 yean. the lt'f'vicn are not uutfactory or they arc adequate but nae unh1ed opumally. of thote' l'h mothen who had deliverrd in last one year, 80% had nailed 11ntmaral eum1nat1on 11 ira" oncc, .~o-... bad matt rhan four ttmn and ma1ortty had 1heir tetanus toxotd tnin,"t1or"'" nlht "'"'"· ljn1r11ned rn· win ronductrd 12.4% dchvcnn and 26% had home deh\'t'oc'i. ~md~: the tervtcn unbud or u111led are !tu than dnarame. the wr· l'kft provided are inadequate and on dechm reprcwnttng a looun1t ~p of h11hnto good coytti\#' ol wr· ncn. l!.ckground chanpng pnoriry cannoc be ruled out u °"" of thc coatnbutory bc10f. ps-ii ia) dcpn:wioa aad anuccy ia mip'mu ia awccr._ many de wn, witco tui~bmjer. jack dekker, aart·jan lttkman, wim gonmc:n. and amoud verhoeff ~ a dutch commumry-bucd icudy thawed 12-moarh•·prc:yalm«i al 17 .44'1. kw anx1· ay daorden and 13. 7% foi' dqrasion m anmttdam. nm .. 11p1tficantly hlllhn than dwwhrft .. dw ~thew diffamca m pttyalcnca att probably rdarcd to tlk' largr populanoa of napaan 111 ..\mturdam. <turkish 5%, moroccan 9%, and surinam 10%1. lndttd. ic'wt'll ltudla hatt ~ ~ high prevalena rata among migrant poupi in rbe ncdwrlands. howc'ytt au ttlluchn iuffenod from wry low raporne rara, or med screnung talel thac lack a ~y yabdarcd ~ in order to study the prevalence of depression and anxiety, and the (barriers to) use of mental health care among the different ethnic groups the following study was recently conducted: . the study consisted of a two-step approach. the first step was mcl~ded m the ~ h ith survey of 2004 (ahs), and consisted of three screening scales for depression and aruaety (klo, g::q-12 and mhl-5). in this survey all respondents were asked_ permission for~ second app~ 1:' 18t consisted of a structured interview containing the cidi for aruaety and depression, and questtollllalres on health care seeking, amongst others. all respondents who gave permission for a second approachwere invited by jetter for a suuctured interview with multilingual interviewers at home at a preset date and time in the following week. . in total, 439 dutch, 317 turkish, 322 moroccan and 124 surinam respondents took part in the ahs and gave permission for a second approach. in the second step, fo~ 21~ tur~h, 184m~roc can 87 surinamese and 320 dutch respondents, information from the extensive interview was available (res~nse rates between 60 and 70% ). since the data collection was completed only recently (june 2005), prevalence estimates can be presented at the conference for the first time. we have shown that with this approach it is feasible to achieve an acceptable response rate in a study on mental health among migrants. therefore we expect that this study will provide reli· able estimates of depression and anxiety in the turkish, moroccan and surinam migrants in amstw!3~· for the first time. in addition, insight into mechanisms underlying the differences between and within ethnic groups and into barriers to mental health care will provide pretexts for the improvement of pre· vention and mental health care for migrant groups. this study aimed to determine spatial patterns of mortality and morbidity of five major health problems in an urban environment: homicides, pregnancy among adolescents ((<20 years old), asthma hospitalization among young children(< 5 years old) and two mosquito-borne diseasesdengue and visceral leishmaniasis, during 1999-2003. all events were obtained through the city health database and, subsequently, geoproccsscd using the address of residence and the geographical and administrative division of the municipality, composed by 80 unit of planning (up), which in tum were formed, each one, by census tract units. two research questions were investigated: are there spatial patterns to the events dis· tribution, and moreover, are these patterns overlapping across space? we use thematic maps, index of comparative mortality/morbidity by up and the overlapped rank of the 20th worse up rates for each event. a spatial pattern of high rates of homicides, proportion of young mothers and hospitalization of asthma were overlapping in areas social and economically disadvantaged. for mosquito-borne diseases, high rates with great dispersion were found in unprivileged areas in contrast with very low rares among privileged ones. these results pointed toward a coexistence of heavier burden of diseases for those living in areas of the city where misery, poverty, lack of political public health may be modulating social health problems. a possible environmental intervention in one mosquito•bome disease might be playing a role in the occurrence of other. although with limitations, this study may provide useful information for a joint urban planning under the public perspective, articulated for use in health impact assessment. jalil safaei bdrod#aion: the association of socioeconomic status (ses), usually measured by income, and health status is an established result in bcalth studies. the poor and low income individuals have lower health sta· tus then_ those with higher incomes. in general. such finding has been usually obtained from sample surveys on speafic populations. a problem with many sample survey$ is that their results are not comparable aaoss ~ndaries as they may use different sampling methods, ask different questions, categorize the answers differently, or define groups differently. moreover, the sample data need to be standardized using the demographic: katurea of a ~ population. this study, however, uses the national population health survey (nphs) cycle 3 public use mictodata files which is based on a common survey template ·~~three~ area in canada, namely montreal, toronto, and vancouver. it also utili7.es the built-m stanclatdizaaon of the nphs data which accounts for its complex survey design. . ~:the stu~ usc:s two well-known measures of health inequalitythe relative index of meqaality and die concentranon indexto capture the extent of income related health inequality among poster sessions v139 urban female and male populations in each of the three metropolitan areas. personal income is classified into ten groups by the nphs with "no income" as the first group and "more than $60,000" as the last. health status is measured by three variables -having a chronic condition (chc), self assessed health (sah), and health utility index (hui) -using appropriate indices. alternative formulations are used to calculate the standard deviations of the estimated or calculated measures. the findings of the study suggest that the measured health inequality depends on the health measure used. for chc and hui the measured inequality indices do indicate poorer health for lower income individulas, however, they are not statistically insignificant. health inequalities are more pronounced when health is measured by sah. the results do not support any systematic ranking of the three metropolitan areas in terms of health inequalities. they do not reveal any systematic pattern of inequality between men and women, either. conclusions: despite the use of highly aggregated nphs data, income related health disparities are observed in the three metropolitan areas in canada. this is more the case with self perceived (sah) health. such disparities are preventable and call for broader health policies that address poverty and low income among other social determinants of health. introduction: the analysis of health indicators under the spatial perspective is configured as an important instrument in the detection of intra-urban differentials. this study aimed to examine the spatial distribution of the births occurred in belo horizonte, in 2001, analyzing the presence of spatial clusters of health indicators for newborns (rn) and their mothers, using data from the information system on live birth database (sinasc). method: for each covered area of the basic units of health (ubs), we calculated the proportion of: adolescent mothers, mothers with less than 8 years of schooling, first pregnancy, mothers with four or more pregnancies, dead babies born on previous pregnancies, stillbirths, cesarean section, less than four prenatal care attendance, moderate and severe hypoxemia in the 1st and 5th minutes of life, low or very low birth weight. we used empiric bayesian methods for smoothing the estimates. for spatial analysis, the indicators obtained from the global moran (i) index and local indicators of spatial association (lisa) were used. maps were built to allow the visualization of the spatial clusters. in all analysis, significance statistics was considered p~ 0.05. results: a total of 36, 12 7 births of residents in belo horizonte were registered in 200 i. the estimated bayesian proportions for the entire municipality was close to the one observed for all variables. analysis using lisa showed the presence of relevant spatial clusters for adolescent and low educated mothers, dead babies form previous pregnancies, cesarean section, low attendance to the prenatal care especially in area with low socio-demographic characteristics. three areas presented consistent clusters, with important spatial auto-correlation for almost all studied indicators. conclusion: the used methodology was configured as a great instrument of detection risk areas where clustering occurs. it can easily be incorporated in any surveillance system as a mechanism for controlling events related to births in the municipality. moreover, it can be applied to discriminate target areas for prompt public health interventions, such as improving health services access and the consolidation of better obstetric practices. introduction: gentrification, the displacement of low income and non-majority people out of longtime neighborhoods and residences is a global phenomenon. it has been identified as occurring in both developed and less developed countries and as inequality persists or increases, many communities are vulnerable to disruption and loss. while there may be some benefits to gentrification, these benefits are less likely to impact those who have been forced to move out of a gentrifying community or those who remain but economically stressed. . . . . this paper lays out a theoretical framework for 1dent1fymg and ~ddressm~. the_ health consequences of gentrification on residents living in a community prior .to o.r durmg gent~1~1cat.10n. by drawing on the literature of housing, sociology, health and urban plannmg, 1t places genmf1catt~n and neighborhood change into the context of other forces affecting th~ .hea.lth of vulnerable populations. it then proposes solutions to prevent or mitigate the impacts of genmf1cat1on. results: four main categories of consequences potentiallr re~ult from ~entr~fica~~n: !'°°r housing· related issues, spatial effects, mental health impacts and contr1bunons to racial ~spanttes m heal~. the housing issues include increased susceptibility to asthma, lead exposure, allergiesl~topy an~. acetdents/ injuries. spatial effects include reduced access to health ~are, reduce~ access to 1obslttadinonal food sources, decreased physical activity, and increased obesity. the __ pnmary mental health effects_ :ire increased stress increased risk of depression and disruption of trad1t1onal support networks. in addinon to the above he~lth issues, gentrification has the potential to increase racial disparities in health by reduc· ing access to long term and multi-culturally experienced health care provide~s. conclusions: public health practice provides a framework for addressmg the health consequences of gentrification. in this context primary prevention would involve preventing gentrification in the first place along with a renewed commitment to helping distressed communities a~~ im_proving the quality ~f life for long term residents. the next layer of meeting the challenges of gentrification would be to assjst long rime residents to stay in a community and thus potentially allowing them to participate in the bene~ts of gentrification (such as better public services). only if all these efforts fail -and these other prevennon strategies must be a priority, public policy should then work to help people and instirutions move to other communities through grants and the provision of alternative safe affordable housing and neighborhoods. sarah romans, marsha cohen, and tonia forte lnh'odlletion: there has been sustained interest in urban rural (ur) differences in mental health over the last 50 years of epidemiological research, with most studies reporting higher urban rates of mor· bidity, particularly when psychotic disorders have been studied. most recently, in britain, urban rates of non-psychotic disorder were greater than rural and semi-rural rates, both before and after the more adverse circumstances of urban dwellers were considered (paykel et al 2003) . surprisingly, there were no ur differences in help seeking. in canada, wang (2004) found greater urban rates for major depression only after he controlled for the confounding effects of race, immigration, employment and marital status, a result reminiscent of work from the us (blazer et 1985) . rural participants were less likely to have sought help for their mental health problems. in this study, we sought to examine urban/rural differences in rates of depression and help seeking in canada. method; data came from the 2000 canadian community health survey 1.2, a community survey conducted by statistics canada of people aged 15 and older, with the total sample size of 36,984 respon· dents, 77% response. analyses used weighted data; differences were assessed by chi-squared. ra.its: bivariate cross-tabulations showed a modest increase in 12 month depression rates for urban (5.4%) over rural (4.3%, p= 0.03) dwellers; there were no ur differences when the sample was examined separately by gender and age group ( 15-29, 30-44, 45-69) . in general, more urban (10.6%) than rural people (8. 7%, p= 0.002) had sought mental health treatment in the past year. there was no ur difference in helping seeking amongst those with depression (u 58.9%, r 50.1 % ns). amongst the whole population, helping seeking was gendered with more urban men accessing help (7.4%) than rural men (5.4%, p=0.004); this did not apply for women (13.7% vs 12.1% p=0.1). ~ons: the urban-rural demographic continues to generate intriguing findings, even recently when internal migration is common and people can seek out the environment most conducive to their health, ~th physical and mental. people with depression are a disadvantaged, frequently stigmatized group, with ~r quality of life a_nd often impaired function. unlike many other factors associated wi~h urban or rural hfe per se, depression can be treated. the low help seeking rates is a cause for concern, m both the ur~n and_ rural populations. it behooves researchers, policy makers and service planners to ensutt effective services are available for both humane and economic reasons. methods: using united states 2000 census income data, we assigned the 12 manhattan community districts to two major socioeconomic groups, manhattan i and ii. manhattan i is composed of community districts with average household incomes above the median for new york city; manhattan ii is those below. with public new york city department of health 1999 death records and 2000 us census data, we calculated a "standard" new york city population and estimated mortality rate distributions for manhattan i and ii. we then compared these age-adjusted actual mortality distributions with a standard t-test. results: we explored premature deaths using several cut-off points (before the ages of 65, 70, and 75), and with subcomparisons for males and females. every comparison showed the wealthier area, manhattan i, to have significantly lower premature mortality rates than the lower income manhattan ii. further, we compared age-adjusted mortality rates among the city's five boroughs, and found no significant differences based on local geography alone. conclusions: these findings suggest that in manhattan, characterized by its extremes of wealth and poverty, health status, as measured by premature mortality, does vary significantly with the local income level. in manhattan, the relative average income by community district varies as much as 4: 1. this ratio is greater than that found in the other cities we have studied: for example, the range among tokyo's kus is half that in manhattan, or about 2: 1. paris has shown the longest life expectancy and changing premature mortality rates. from our preliminary work, we expect to find less variation in premature mortality rates in comparable cities. this study will continue to explore the relationship of premature mortality rates and life expectancy to income levels and different health systems among wcp cities with a view to measuring health policy options. introduction: according to the world health organization (who), smoking-related illness is currently the world's second major cause of death, currently responsible for one out of ten adult deaths worldwide. the who's framework convention on tobacco control (fctc) aims to reduce tobaccorelated disease and deaths by changing national public policies. mexico, which, according to the who, had smoking prevalences of 32% among adults in 1998 and 23% among health care providers (hcps) in 1997, ratified the fctc in 2004. objective: to examine knowledge of and attitudes towards cigarette smoking and smoking cessation among hcps, and clinical practices regarding smoking cessation. methods: in june 2005, a convenience sample of hcps from one public clinic in urban oaxaca, mexico, part of mexico's national network of public health care clinics, were interviewed in spanish using a verbally administered questionnaire that was standard among all participants. during primary care outpatient visits, hcps were observed treating patients to assess the relative importance of smoking cessation as a health care priority. results: of the 18 hcps interviewed, including ten physicians, three nurses, and five medical students, 67% reported smoking regularly. all hcps reported assessing patients' history of smoking, knowledge of the health risks associated with smoking, and feeling qualified to discuss these risks with patients. all hcps reported counseling patients who currently smoked to quit. all hcps reported recommending nicotine replacement therapy (eg., patch and/or gum) and/or behavioral therapy (eg., psychologist, support groups) to patients who smoked. all hcps reported that there was no government funding for smoking cessation, and that all costs associated with smoking cessation were patients' out-of-pocket expenses. observation of hcp interaction with patients revealed that hcps always inquired about smoking history with new patients and rarely inquired about smoking history with returning patients. hcps were not observed counseling patients who reported current smoking on smoking cessation methods and its benefits. observation of the clinical environment suggested a focus on preventative child health (eg., immunization, water-borne illnesses), family planning, and chronic diseases (eg., diabetes, hypertension). conclusions: while the mexican government has made smoking cessation a public health priority and hcps report addressing smoking cessation, observation of hcps suggests: 1) smoking status is assessed only in new patients; and 2) smoking cessation methods are not addresse~. observ_atio~ of hcps and the clinical environment in a public clinic in oaxaca suggests that smoking cessation 1s of lower priority than other heath care issues. p6-04 (a) urban agriculture and food and nutrition security in kampala, uganda fiona yeudall, renee sebastian, abdelrahman lubowa, selahadin ibrahim, and donald cole introduction: urban agriculture is an important livelihood strategy contributing to household food security by increasing access and availability to food in urban settings (koc et al., 1999) . the purpose of poster sessions v142 rhis study was to examine relationships between child nutritional securiry outcomes, household food security, and urban agriculture activiries in kampala, uga~da. . . questionnaires assessing socio-demographic, farmmg and household food secunry (hfsi characreristics were administered to 270 households. food diversiry was ~lculate~ from ~e number of foods consumed over 24 hours for one child (2-5 years) per household. heigh~ weight,. nud-upper·ann· circumference (muac) and tricep skinfolds (tsf) were measured for the mdex child. z-sc.ores for height-for·age (haz), weighr-for-age (waz) and body mass index (zbmi) were ~~ulated usmg cen· rres for disease control and prevenrion reference data. z-scores for body composition measures were calculated using nhanes i and ii data for african americans. the lms method was used to c~.t for skewed z·score indices. all dara was checked for normaliry and univariable and backward mulnvanablc linear regression analysis conducted. ruwlts: household food securiry was significantly associated with wealth (b= 0. 71, p< 'a acre were more dependenr on assets for hfs. although sex of head of household was ~ot related to j-:ifs, it modi· fied relationships in rhar female headed households had greater food securtry when fai:mmg less than 1,4 acre compared ro male headed households, and vice versa. hfs was significantly associated with food diversiry (s=0.15, p). urbanization, especially in developing countries, has substantially increased the vulnerability of rhe mass of low-income urban dwellers. the livelihoods and quality of life for many of the poor espe· cially in larin america, asia, and africa, have deteriorated significantly over the years. urban areas are increasingly unable to provide for their populations, resulting in poverry, massive unemploymenr, job cuts, poor housing, lack of or poor public services, and a compromised health status. botswana, a country rhat lies in the sourhern parr of africa, has had its share of urban problems such as rhe mush· rooming of squarters and low-income urban sertlements. despite efforts to address the substandard living conditions in low-income urban areas, these problems have continued to grow. these living con· diuons are porenrially stressful to rhe residenrs and likely affects their health. the primary aim of the 11udy wa1 to examine the complex relationship between communiry-level stressors and interveners and health-related quality of life among residents of low-income neighborhoods in francistown, botswana. u1i"" a croa1-icctional quantitative design (both descriptive and explanatory) and using primarily cloae-mded interview• with a random sample of 388 residents, this study examined the role of chrome life 1trnson and environmental quality on overall health status qualiry of life) and the physical, psy· chological and level of independence domains of health. the major hypothesis of the study was that community-levrl stre1sor1 would influence health-related quality of life and that social capital would moderate these relationships. findings indicate that neighborhood quality is a powerful predictor of healrh 1tatu1 rhan socioeconomic status and individual life stressors. social capital was also found to he a 11111ificant positive predictor of healrh and also moderator of structural factors. social capital moderated the effects of low environmental quality on level of indrpendence and on physical health outcomn, but nor on psychological and global health outcomes. these findings suggest that as the environment get1 betttr. stresson are reduced, hence promoting berter health outcomes. the study ends with implication• for social justice, public health and social work practice, and research, focusing mostly on the ~ole of social capital and the environmental quality in predicting health outcomes. spt· cafically • anenhon should be focused on political and civic society's commitment for social justice and poveny alleviation, ~uction of the threat of insecuriry and violence; cultivating social capital and good governance; and improving the health and social environments, especially housing and environ· mental 1aiutanon to name a few. urban and other uprisings by non-elites that lead to transitions, can disrupt sexual and injection "risk" networks that transmit infectious diseases by changing mixing patterns. they can also weaken urban social networks, their associated protective norms and their informal social control mechanisms which can lead to increased sexual and drug risk behaviors and violence (fullilove 2004; wallace & wallace1998, aral 2002 , friedman & reid 2000 hankins et al 2002) . for example, the 1979 revolution and transition to theocratic rule, and subsequent urban and national conflicts, have been followed by many urban youth in iran engaging in clandestine high-risk sexual and drug behaviors. in palestine, conflicts and restrictions on movement have led to increased fatalities from chronic diseases due to limited access to hospitals and modern medical facilities (union of palestinian medical relief committees); and heroin use and violence-related blood exposure have also increased. social movements "from below" that are rooted both in urban social network dynamics and in underlying patterns of injustice can have both protective and risky effects. for example, the social movements that led to the collapse of the ussr and its dependent governments in other countries-with subsequent increases in sex trade, alcoholism, drug use, tuberculosis, hiv, stis, and mortality in many localities-were based originally on such city-based movements in eastern europe. their impacts on health were mediated by urban social dynamics and structures. some urban social movements have improved health by prevent· ing the spread of hiv, hepatitis and other diseases. examples include movements of (a) gays and lesbians and (b) drug users. these have been rooted in social networks that overlap with risk networks. theories of urban health should include social conflict as a core concept. mechanisms that generate conflicts and the pathways by which conflicts affect health should be a major part of urban health research agendas. p6-07 (c) demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital (lasuth) chest clinic john bako, adewale akeredolu, and wale alabi tuberculosis has become a resurgent public health problem in recent times in the world. because resources are limited, control programmes frequently must target population at greatest risk. the purpose of this study was to study the demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital. a total of 76 patients who have been both radiologically and bacteriologically confirmed tuberculosis patients were used for this study between january and march. 57 (75%) were males, while 19 (25%) were females. notable risk factors among patients with tuberculosis were overcrowding (46.1 % ), homelessness ( 11.8%) cigarette smoking (22.4% ), alcoholism (30.3%), non vaccination (25%), secondary contact (36.8%) and poor knowledge (92. l 'x,). man· agement history patterns among the patients were herbs ( 13.2 'yo), orthodox medicine ( .h . .l'x.). intervention targeting early-identified groups may be an effective way to reduce the incidence of tuber· culosis. such intervention should focus on health education, modification of life style and improvement of standard of living. p6-08 (c) profiles in urban health in 9 cities of the americas in the countries of the americas, there is an increasing migration of national and international populations to urban centers. this presentation will focus on some of the issues created by this influx of populations, the ways that 9 cities in 8 countries are dealing with them, and the efforts to promote local participation and solutions in management and decision-making. the methodology used to collect this information has been to draw upon and analyze information produced by the mayor's and ministry of health and development offices in each of the cities under consideration. an analysis of the impact of urbanization on health and health determinants will be presented. the information covers issues such as health status by geographic areas within the cities, highlighting issues such as marginality, barriers and physical, economic and cultural constructs and inequities in the delivery of and access to essential services (such as health, education, water, and basic sanitation). issues of governance and citizen participation will be highlighted to provide insight in~o the balance of power and mechanisms for decision-making at the local level. part of the analysis will show the relationship between democratic processes and social participation. public ~olicies will be reviewed to indicate those that are most beneficial in promoting health and overcoming barriers to it, as well as ways of capitalizing on local assets and resources. final~y, evidence of effectiveness of various strategies will be indicated. the presentation will conclude wuh suggesuons for future strategic directions to improve the quality of life and the promotion of health in large urban centers of the americas. introduction: much of the illicit drug in mexico is concentrated in northern border areas. the 2000 mile border between the u.s. and mexico is also characterized by migration; the border crossing between tijuana, baja california, mexico and san diego, california, u.s.a. is rep~rt~dl~ the busiest land border crossing in the world. we attempt to describe the migration scene among m1ect1on drug users (idus) m tijuana and investigate service needs. methods: migration trends were investigated in a cross-sectional study conducted from february to june 2005 among idus in tijuana. enrollment criteria included informed consent, being 18 years or older, and having injected drugs within the prior month. subjects were recruited by respondent-dnven sampling and were administered a quantitative survey and serology for hiv, hcv, and syphilis. logistic regression was used to compare idus who had migrated to the u.s. versus those who had not. results: of 222 idus enrolled, 91 % were male and median age and age at first injection were 35 and 20, respectively. drug combinations injected most frequently in the past 6 months were heroin (35%1 and crystal methamphetamine mixed with heroin (53%). of those enrolled, 212 responded to quesnons on migration and drug treatment and were included in this analysis. although 76% had resided in tijuana for at least 5 years, 70% of users were born outside of baja california. working outside of mexico was common, with 38% working abroad in the last 10 years (94% in u.s.), and 17% in the past year. in the last 6 months, 10% of idus had crossed the border to the u.s., with 57% crossing at least once per month. those working outside of mexico in the past year were less likely to have ever received substance abuse treatment, [29% vs. 53%, or 0.38, ] and were marginally less likely to have received drug treatment in the past 6 months [6% vs. 18 %, or 0.28, 95% ci (0.06-1.2)]. drug use patterns, age and gender did not differ between migrants and non-migrants, although migrants were more likely to report being in need of substance abuse treatment (68% vs. 57%, respectively). conclusions: migration is common among idus in tijuana. maintaining drug treatment regimens and determining how to best target education and services to a highly mobile population pose challenges to officials on both sides of the border. these data underscore the need to develop coordinated binational prevention and treatment efforts. introduction: despite the expanding literature on the important role public policy plays in influencing the broader determinants of the public\'s health, profound differences exist among jurisdictions in rhe attention placed upon such activities. we take an international perspective on health by examining rhe d?minant public _health paradigms of canada, usa, uk, and sweden and exploring how these paradigms shape public health practice. _method: we carefully analyze governmental and public health agencies documents to discern ~he dommant para~igms driving public health approaches and practices. we also consider the unique paht1· cal and economic contexts within each nation and consider how these contexts drive public health pahcy and approaches. . . ~u~: the canadian and usa public health communities -with some exceptions --focus upon m~ividuahzed approaches to risk management. in contrast, the uk and swedish public health scenes are oriented toward broader approaches to health determinants. we find that the extent to which govern· ments, public health agencies and public health workers concern themselves with public policy approaches £<_> ~ddress ~ro.ad~r .determinants of health depends upon the particular health parad'.~ adhered. ~o withm each 1urisd1ctton. and whether a paradigm is adopted depends upon the ideologi~a and pol~ncal context of each nation. nations such as sweden that have a long tradition of public policies promonng social jus~ce an~ equity are naturally receptive to evolving population health concepts. '[he usa represen~ a ~bey en~ro~~t where such is~ues are clear!~ subordinate. ., our findings mdicate that there 1s a strong political component that influences pubh ~ealth a~proaches and practi~ within the jurisdictions examined. the implications are that those seek· m~ to raise the broader detennmants of the public's health should work in coalition to raise these issues with non-health organizations and age · ca d d th · badrgrollnd: in developed countries, social inequalities in health have endured or even worsened comparatively throughout different social groups since the 1990s. in france, a country where access to medical and surgical care is theoretically affordable for everyone, health inequalities are among the high· est in western europe. in developing countries, health and access to care have remained critical issues. in madagascar, poverty has even increased in recent years, since the country wenr through political crisis and structural adjustment policies. objectives. we aimed to estimate and compare the impact of socio· economic status but also psychosocial characteristics (social integration, health beliefs, expectations and representation, and psychological characteristics) on the risk of having forgone healthcare in these 2 dif· fercnt contexts. methods: population surveys conducted among random samples of households in some under· served paris neighbourhoods (n= 889) and in the whole antananarivo city (n= 2807) in 2003, using a common individual questionnaire in french and malagasy. reslllts: as expected, the impact of socioeconomic status is stronger in antananarivo than in paris. but, after making adjustments for numerous individual socio-economic and health characteristics, we observed in both cities a higher (and statically significant) occurrence of reponed forgone healthcare among people who have experienced childhood and/or adulthood difficulties (with relative risks up to 2 and 3.s respectively in paris and antananarivo) and who complained about unhealthy living conditions. in paris, it is also correlated with a lack of trust in health services. coneluions: aside from purely financial hurdles, other individual factors play a role in the non-use of healthcare services. health insurance or free healthcare seems to be necessary hut not sufficienr to achieve an equitable access to care. therefore, health policies must not only focus on the reduction of the financial barriers to healthcare, but also must be supplemented by programmes (e.g. outreach care ser· vices, health education, health promotion programmes) and discretionary local policies tailored to the needs of those with poor health concern .. acknowledgments. this project was supported by the mal>io project and the national institute of statistics (instat) in madagascar, and hy the development research institute (ird) and the avenir programme of the national institute of health and medical research (inserm) in france. for the cities of developing countries, poverty is often described in terms of the living standard~ of slum populations, and there is good reason to believe that the health risks facing these populations are even greater, in some instances, than those facing rural villagers. yet much remains to be learned ahour the connections between urban poverty and health. it is not known what percentage of all urban poor live in slums, that is, in communities of concentrated poverty; neither is it known what proportion of slum residents are, in fact, poor. funhermore, no quantitative accounting is yet available that would sep· arare the health risks of slum life into those due to a househoid•s own poverty and those stemminic from poveny in the surrounding neighborhood. if urban health interventions are to be effectively targeted in developing countries, substantial progress must be made in addressing these cenrral issues. this paper examines poverty and children's health and survival using two large surveys, one a demographic and health survey fielded in urban egypt (with an oversampling of slums) and the other a survey of the slums of allahabad, india. using multivariate statistical methods. we find, in both settings: ( 11 substan· rial evidence of living standards heterogeneity within the slums; (21 strong evidence indicating that household-level poverty is an imponant influence on health; and (3) staristically significant (though less strong) evidence that with household living standards held constant, neighborhood levels of poverty adversely affect health. the paper doses with a discussion of the implications of these findings for the targeting of health and poverty program interventions. p6-13 (a) urban environment and the changing epidemiological surfacr. the cardiovascular ~ &om dorin, nigeria the emergence of cardiovascular diseases had been explained through the concomitants o_f the demographic transition wherein the prevalent causes of morbidity and monality ~hangr pr~mmant infectious diseases to diseases of lifestyle or chronic disease (see deck, 1979) . a ma1or frustration m the v146 poster sessions case of cvd is its multifactural nature. it is acknowledged that the environment, however defined is the d · f · t' b tween agents and hosts such that chronic disease pathogenesis also reqmre a me 1an o mterac ion e . spatio-temporal coincidence of these two parties. what is not clear is which among ~ever~( potennal fac· · h b pace exacerbate cvd risk more· and to what extent does the ep1dem1olog1cal trans1· tors m t e ur an s ' . . . . tion h othesis relevant in the explanation of urban disease outlook even the developmg cities like nigeri~: thesis paper explorer these within a traditional city in nigeria. . . . the data for the study were obtained from two tertiary level hospitals m the metropolis for 10 years (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) . the data contain reported cases of cvd in the two facilities for the period. adopting a series of parametric and non-parametric statistics, we draw inferences between the observed cases of cvds and various demographic and locational variables of the patients. findings: about 28% of rhe cases occurred in 3 years (1997) (1998) (1999) coinciding with the last year of military rule with great instability. 55.3% occurred among male. 78.8% also occurred among people aged 31-70 years. these are groups who are also likely to engage in most stressful life patterns. ~e study also shows that 63% of all cases occurred in the frontier wards with minor city areas also havmg their •fair' share. our result conformed with many empirical observation on the elusive nature of causation of cvd. this multifactoral nature had precluded the production of a map of hypertension that would be consistent with ideas of spatial prediction. cvd -cardiovascular diseases. mumbai is the commercial capital of india. as the hub of a rapidly transiting economy, mumbai provides an interesting case study into the health of urban populations in a developing country. with high-rise multimillion-dollar construction projects and crowded slums next to each other, mumbai presents a con· trast in development. there are a host of hi-tech hospitals which provide high quality care to the many who can afford it (including many westerners eager to jump the queue in their healthcare systems-'medical tour· ism'), at the same time there is a overcrowded and strained public healthcare system for those who cannot afford to pay. voluntary organizations are engaged in service provision as well as advocacy. the paper will outline role of the voluntary sector in the context of the development of the healthcare system in mumbai. mumbai has distinct upper, middle and lower economic classes, and the health needs and problems of all three have similarities and differences. these will be showcased, and the response of the healthcare system to these will be documented. a rising hiv prevalence rate, among the highest in india, is a challenge to the mumbai public healthcare system. the role of the voluntary sector in service provision, advocacy, and empowerment of local populations with regards to urban health has been paramount. the emergence of the voluntary sector as a major player in the puzzle of urban mumbai health, and it being visualized as voices of civil society or communiry representatives has advantages as well as pitfalls. this paper will be a unique attempt at examining urban health in india as a complex web of players. the influence of everyday socio·polirical-cultural and economic reality of the urban mumbai population will be a cross cutting theme in the analysis. the paper will thus help in filling a critical void in this context. the paper will thus map out issues of social justice, gender, equiry, effect of environment, through the lens of the role of the voluntary sector to construct a quilt of the realiry of healthcare in mumbai. the successes and failures of a long tradi· tion of the active advocacy and participation of the voluntary sector in trying to achieve social justice in the urban mumbai community will be analyzed. this will help in a better understanding of global urban health, and m how the voluntary sector/ngos fir into the larger picture. ba~und: o~er. half _of n~irobi's 2.5 million inhabitants live in illegal informal settlements that compose 5 yo of the city s res1dent1al land area. the majority of slum residents lack access to proper san· iranon and a clean and adequate water supply. this research was designed to gain a clearer understand· mg of what kappr · · · h f . . opnate samtanon means or the urban poor, to determine the linkages between gender, hvehhoods, and access to water and sanitation, and to assess the ability of community sanitation blocks to meet water and sanitation needs in urban areas. m~tbojs_: _a household survey, gender specific focus groups and key informant interviews were conducted m maih saba, a peri-urban informal settlement. qualitative and quantitative research tools were u~ to asses~ the impact and effectiveness of community sanitation blocks in two informal settlements. results ropna e samtarmn me u es not only safe and clean latrines, but also provision ° adequate drainage and access to water supply for cleaning of clothes and homes. safety and cleanliness poster sessions v147 were priorities for women in latrines. levels of poverty within the informal settlements were identified and access to water and sanitation services improved with increased income. environmental health problems related to inadequate water and sanitation remain a problem for all residents. community sanitation blocks have improved the overall local environment and usage is far greater than envisioned in the design phase. women and children use the blocks less than men. this is a result of financial, social, and safety constraints. the results highlight the importance a need to expand participatory approaches for the design of water and sanitation interventions for the urban poor. plans need to recognize "appropriate sanitation" goes beyond provision of latrines and gender and socioeconomic differences must be taken into account. lessons and resources from pilot projects must be learned from, shared and leveraged so that solutions can be scaled up. underlying all the challenges facing improving water and sanitation for the urban poor are issues of land tenure. p6-16 (c) integrating tqm (total quality management), good governance and social mobilization principles in health promotion leadership training programmes for new urban settings in 12 countries/ areas: the prolead experience susan mercado, faren abdelaziz, and dorjursen bayarsaikhan introduction: globalization and urbanization have resulted in "new urban settings" characterized by a radical process of change with positive and negative effects, increased inequities, greater environmental impacts, expanding metropolitan areas and fast-growing slums and vulnerable populations. the key role of municipal health governance in mitigating and modulating these processes cannot be overemphasized. new and more effective ways of working with a wide variety of stakeholders is an underpinning theme for good governance in new urban settings. in relation to this, organizing and sustaining infrastructure and financing to promote health in cities through better governance is of paramount importance. there is a wealth of information on how health promotion can be enhanced in cities. despite this, appropriate capacity building programmes to enable municipal players to effectively respond to the challenges and impacts on health of globalization, urbanization and increasing inequity in new urban settings are deficient. the who kobe centre, (funded by the kobe group( and in collaboration with 3 regional offices (emro, searo, wpro) with initial support from the japan voluntary contribution, developed a health promotion leadership training programme called "prolead" that focuses on new and autonomous structures and sustainable financing for health promotion in the context of new urban settings. methodology: country and/or city-level teams from 12 areas, (china, fiji, india, japan, lebanon, malaysia, mongolia, oman, philippines, republic of korea, tonga and viet nam) worked on projects to advance health promotion infrastructure and financing in their areas over a 9 month period. tools were provided to integrate principles of total quality management, good governance and social mobili1.ation. results: six countries/areas have commenced projects on earmarking of tobacco and alcohol taxes for health, moblization of sports and arts organizations, integration of health promotion and social health insurance, organizational reforms, training in advocacy and lobbying, private sector and corporate mobilization and community mobilization. results from the other six areas will be reported in 01..;obcr. conclusions: total quality management, good governance and social mobilization principles and skills are useful and relevant for helping municipal teams focus on strategic interventions to address complex and overwhelming determinants of health at the municipal level. the prolead training programmes hopes to inform other processes for building health promotion leadership capacity for new urban settings. the impact of city living and urbanization on the health of citizens in developing countries has received increasing attention in recent years. urban areas contribute largely to national economies. however, rapid and unplanned urban growth is often associated with poverty, environmental degradation and population demands that outstrip service capacity which conditions place human health at risk. local and national governments as well as multi national organizations are all grappling with the challenges of urbanization. with limited data and information available, urban health characteristics, including the types, quantities, locations and sources in kampala, are largely unknown. moreover, there is n? basis for assessing the impact of the resultant initiatives to improve health ~onditions amo~g ~o":1":1um ties settled in unplanned areas. since urban areas are more than the aggregation ?f ~?pie w~th md_1v1dual risk factors and health care needs, this paper argues that factors beyond the md1v1dual, mcludmg the poster sessions v148 · i d h · i · ment and systems of health and social services are determinants of the health soc1a an p ys1ca environ . of urban populations. however, as part of an ongoing study? ~s pape~ .addresses the basic concerns of urban health in kampala city. while applying the "urban hvmg conditions and the urban heal~ pen· alty" frameworks, this paper use aggregated urban health d~ta t~ explore the role of place an~ 111st1tu· tions in shaping health and well-being of the population m kampala by understanding how characteristics of the urban environment and specific features of the city are causally related to health of invisible and forgotten urban poor population: results i~dica~e that a .range o~ urb~n he~l~h hazards m the city of kampala include substandard housing, crowdmg, mdoor air poll.ut1on, msuff1c1ent a~d con· taminated water, inadequate sanitation and solid waste management services, vector borne .diseases, industrial waste increased motor vehicle traffic among others. the impact of these on the envtronment and community.health are mutually reinforcing. arising out of the withdra"'.al of city pl~nning systems and service delivery systems or just planning failure, thousands of people part1cularl~ low-mc~me groups have been pushed to the most undesirable sections of the city where they are faced with ~ va_r1ety ~f envj· ronmental insults. the number of initiatives to improve urban health is, however, growing mvolvjng the interaction of many sectors (health, environment, housing, energy, transportation and urban planning) and stakeholders (local government, non governmental organizations, aid donors and local community groups). key words: urban health governance, health risks, kampala. introduction: the viability of urban communities is dependent upon reliable and affordable mass transit. in particular, subway systems play an especially important role in the mass transit network, since they provide service to vast numbers of ridersseven of the 95 subway systems worldwide report over one billion passenger rides each year. surprisingly, given the large number of people potentially affected, very little is known about the health and safety hazards that could affect both passengers and transit workers; these include physical (e.g., noise, vibration, accidents, electrified sources, temperature extremes), biological (e.g., transmission of infectious diseases, either through person-to-person spread or vector-borne, for example, through rodents), chemical (e.g., exposure to toxic and irritant chemicals and metals, gas emissions, fumes), electro-magnetic radiation, and psychosocial (e.g., violence, workstress). more recently, we need to consider the threat of terrorism, which could take the form of a mass casualty event (e.g., resulting from conventional incendiary devices), radiological attack (e.g., "dirty bomb"), chemical terrorist attack (e.g., sarin gas), or bioterrorist attack (e.g., weapons grade anthrax). given the large number of riders and workers potentially at risk, the public health implications are considerable. methods: to assess the hazards associated with subways, a structured review of the (english) litera· ture was conducted. ruults: based on our review, non-violent crime, followed by accidents, and violent crimes are most prevalent. compared to all other forms of mass transit, subways present greater health and safety risks. however, the rate of subway associated fatalities is much lower than the fatality rate associated with automobile travel (0.15 vs. 0.87 per 100 million passenger miles), and cities with high subway ridership rates have a 36% lower per capita rate of transportation related fatalities than low ridership cities (7.5 versus 11.7 annual deaths per 100,000 residents). available data also suggest that subway noise levels and levels of air pollutants may exceed recommended levels. . ~: there is a paucity of published research examining the health and safety hazards associated with subways. most of the available data came from government agencies, who rely on passively reported data. research is warranted on this topic for a number of reasons, not only to address important knowled~ gaps, but also because the population at potential risk is large. importantly, from an urban perspecnve, the benefits of mass transit are optimized by high ridership ratesand these could be adversely affu:ted by unsafe conditions and health and safety concerns. veena joshi, jeremy lim. and benjamin chua ~ ~rban health issues have moved beyond infectious diseases and now centre largely on chrome diseases. diabetes is one of the most prevalent non-communicable diseases globally. 9 % of adult ¥151 benefit in providing splash pads in more parks. given the high temperature and humidity of london summers, this is an important aspect and asset of parks. interviewed parents claimed to visit city parks anywhere between 1 to 6 days per week. corrduion: given that the vast majority of canadian children are insufficiently active to gain health benefits, identifying effective qualities of local parks, that may support and foster physical activity is essential. strategies to promote activity within children's environments are an important health initiative. the results from this study have implications for city planners and policy makers; parents' opinions of, and use of city parks provides feedback as to the state current local parks, and modifications that should be made for new ones being developed. this study may also provide important feedback for health promoters trying to advocate for physical activity among children. introdt1clion: a rapidly increasing proportion of urban dwellers in africa live below the poverty line in overcrowded slums characterized by uncollected garbage, unsafe water, and deficient sanitation and overflowing sewers. this growth of urban poverty challenges the commonly held assumption that urban populations enjoy better health than their rural counterparts. the objectives of this study are (i) to compare the vaccination status, and morbidity and mortality outcomes among children in the slums of nairobi with rural kenya, and (ii) to examine the factors associated with poor child health in the slums. we use data from demographic and health survey representative of all slum settlements in nairobi city carried out in 2000 by the african population & health research center. a total of 3,256 women aged 15-49 from 4,564 households were interviewed. our sample consists of 1,210 children aged 0-35 months. the comparison data are from the 1998 kenya demographic and health survey. the outcomes of interest include child vaccination status, morbidity (diarrhea, fever and cough) and mortality, all dichotomized. socioeconomic, environmental, demographic, and behavioral factors, as well as child and mother characteristics, are included in the multivariate analyses. multilevel logistic regression models are used. l'nlimin11ry rest1lts: about 32 % of children in the slums had diarrhea in the two weeks prior to the survey, compared to 16% of rural children. these disparities between the urban poor anj the rural residents are also observed for fever (64% against 42%), cough (46% versus 20%), infant mortality (91/ 1000 against 76/1000), and complete vaccination (48% against 64%). preliminary multivariate results indicate that health service utilization and maternal education have the strongest predictive power on child morbidity and mortality in the slums, and that household wealth has only minor, statistically insignificant effects. conclruion: the superiority of health of urban children, compared with their rural counterparts, masks significant disparities within urban areas. compared to rural residents, children of slum dwellers in nairobi are sicker, are less likely to utilize health services when sick, and stand greater risk to die. our results suggest policies and programs contributing to the attainment of the millennium development goal on child health should pay particular attention to the urban poor. the insignificance of socioeconomic status suggests that poor health outcomes in these communities are compounded by poor environmental sanitation and behavioral factors that could partly be improved through female education and behavior change communication. introduction: historic trade city surat with its industrial and political peace has remained a center of attraction for people from all the comers of india resulting in to pop.ulatio~ explosio~ a~d stressed social and service infrastructure. the topography,dimate and demographic profile of the city 1s threat to the healthy environment. aim of this analysis is to review the impact of managemt'nt reform on health indicators. method: this paper is an analysis of the changing profile of population, sanitary infr~s~rucrure, local self government management and public health service reform, secondary health stat1st1cs data, health indicator and process monitoring of 25 years. . . health of entire city and challenge to the management system. plague outbr~ak (1994) was the turning point in the history of civic service management including p~blic ~e~lth service management. ~ocal self government management system was revitalized by reg~lar_ field v1s1ts o~ al~ cadre~, _decentraltzanon of power and responsibility, equity, regular vigilant momtormg, commumcanon facility, ream_approach and people participation. reform in public health service management was throu_gh stan~~rd1zed intervention protocol, innovative intervention, public private partnership, community part1c1panon, academic and service institute collaboration and research. sanitation service coverage have reached nearer to universal. area covered by safe water supply reached to 98%(2004) from 40% (1991) and underground drainage to 97% (2004) from 17% ( 1991) the overhauling of the system have reflected on health indicators of vector and water born disease. malaria spr declined to 1.23 (2004) from 23.06'yo(!991) and diarrhea case report declined to 1963(2004) from 3431 (2004). except dengue fever in 2002 no major disease outbreaks are reported after 1991. city is recipient of international/national awards/ranking for these achievements. the health department have developed an evidence and experience based intervention and monitoring system and protocol for routine as well as disaster situation. the health service and management structure of surat city have emerged as an urban health model for the country. introduction: the center for healthy communities (chc) in the department of family and com· munity medicine at the medical college of wisconsin developed a pilot project to: 1) assess the know· ledge, attitudes, and behaviors of female milwaukee public housing residents related to breast cancer; 21 develop culturally and literacy appropriate education and screening modules; 3) implement the developed modules; 4) evaluate the modules; and 5) provide follow-up services. using a community-based participatory research model the chc worked collaboratively with on-site nurse case management to meet these objectives. methods: a "breast health kick off event" was held at four separate milwaukee public housing sites for elderly and disabled adults. female residents were invited to complete a 21-item breast health survey, designed to accommodate various literacy levels. responses were anonymous and voluntary. the survey asked women about their previous physical exams for breast health, and then presented a series of state· ments about breast cancer to determine any existing myths. the final part gathered information about personal risk for breast cancer, the highest level of education completed, and whether the respondents h;td ever used hormone replacement therapy and/or consumed alcohol. responses were collected for descriptive analysis. results: a total of 45 surveys (representing 18% of the total female population in the four sites) were completed and analyzed. 89% reported that they had a physical exam in the previous rwo years. 96% of respondents indicated they never had been diagnosed with breast cancer. 85% reported having had a mammogram and 87% having had a clinical breast exam. those that never had a mammogram reported a fear of what the provider would discover or there were not any current breast problems ro warrant an exam. 80% agreed that finding breast cancer early could lower the chance of dying of cancer. over 92% reported that mammograms were helpful in finding cancer. however, 27% believed that hav· ing a mammogram actually prevents breast cancer. 14% indicated that mammograms actually cause cancer and 16% reported that a woman should get a mammogram only if there is breast cancer in her family. conclusion: this survey indicates that current information about the importance of mammograms and clinical breast exams is reaching traditionally underserved women. yet there are still critical oppor· tunities to provide valuable education on breast health. this pilot study can serve as a tool for shaping future studies of health education messages for underserved populations. located in a yourh serv· ~ng agency m downtow~ ottawa, the clinic brings together community partners to provide primary medical care. and dent~i hygiene t? the street youths of ottawa aged 12-20. the primary goal of the project is to provide accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. these efforts respond to the pre-existing body of evidence suggesting that the principle barrier in accessing such care for these youths are feelings of intimidation and vulnerability in the face of a complex healthcare system. the bruyere fhn satellite clinic is located in the basement of a downtown drop-in and brings together a family medicine physician and her residents, a dental hygienist and her 2nd year students, a nurse practitioner, a chiropodist and 2 public health nurses to provide primary care. the clinic has been extremely busy and well received by the youth. this workshop will demonstrate how five community organizations have come together to meet the needs of high risk youths in ottawa. this presentation will showcase the development of the clinic from its inception through its first year including reaction of the youths, partnerships and lessons learned. it will also focus on its sustainability without continued funding. we hope to have developed a model of service delivery that could be reproduced and sustained in other large cities with faculties of medicine. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative-a) semi structured interviews with providers & partners b)focus groups with youth quantitative a)electronic medical records for 12 months records (budget, photos, project information). results: 1) successfully built and opened a medicaudental clinic which will celebrate its 1 year anniversary in august. 2) over 140 youths have been seen, and we have had over 300 visits. conclusion: 1) the clinic will continue to operate beyond the 18 month project funding. 2) the health of high risk youth in ottawa will continue to improve due to increased access to medical services. p7-11 (a) health services -for the citizens of bangalore -past, present and future savita sathyagala, girish rao, thandavamurthy shetty, and subhash chandra bangalore city, the capital of karnataka with 6.5 million is the 6th most populous city in india; supporting 30% of the urban population of karnataka, it is considered as one of the fastest growing cities in india. known as the 'silicon valley of india', bangalore is nearly 500 years old. bangalore city corporation (bmp), is a local self government and has the statutory commitment to provide to the citizens of bangalore: good roads, sanitation, street lighting, safe drinking water apart from other social obligations, cultural development and poverty alleviation activities. providing preventive and promotive heahh services is also a specific component. the objective of this study was to review the planning process with respect to health care services in the period since india independence; the specific research questions being what has been the strategies adopted by the city planners to address to the growing needs of the population amidst the background of the different strategies adopted by the country as a whole. three broad rime ranges have been considered for analysis: the 1950s, 1970s and the 1990s. the salient results are: major area of focus has been on the maternal and child care with activities ranging from day-care to in-patient-care; though the number of institutions have grown from 5 to the current day 79, their distribution has been far from satisfactory; obtaining support from the india population projects 3 and 8 major upgradarions have been undertaken in terms of infrastructure; over the years, in addition to the dispensaries of modern system of medicine, local traditional systems have also been initiated; the city has partnered with the healthy cities campaign with mixed success; disease surveillance, addressing the problems related to the emerging non-communicable diseases including mental health and road traffic injuries are still in its infancy. isolated attempts have been made to address the risks groups of elderly care and adolescent care. what stands out remarkably amongst the cities achievements is its ability to elicit participation from ngos, cbos and neighbourhood groups. however, the harnessing of this ability into the health sector cannot be said totally successful. the moot question in all the above observed development are: has the city rationally addressed it planning needs? the progress made so far can be considered as stuttered. the analysis and its presentation would identify the key posirive elements in the growth of banglore city and spell a framework for the new public health. introduction: anaemia associated with pregnancy is a major public health problem all over the world. different studies in different parts of india shown prevalence of anaemia between 60-90%. anaemia remains a serious health problem in pregnancy despite of strong action taken by the government of india through national programmes. in the present study we identified th~ social beha~iors, responsible for low compliance of if a tablets consumption in pregnancy at community level and intervention was given with new modified behaviors on trial bases. . in vadodara urban. 60 anganwadies out of 289 were selected from the list by random sampling for tips (trials of improved practices) study. . . participants: 266 pregnant women (132, intervention group+ 134, control. group) registered m the above 60 anganwadies. study was conducted in to three phases: phase: 1. formative research and baseline survey (frbs). data was collected from all 266 pregnant women to identify behaviors that are responsible for low compliance of ifa tablets. both qualitative and quantitative data were collected. haemoglobin was estimated of all pregnant women by haemo-cue. phase: 2. phase of tips. behaviors were identified both social & clinical for low compliance of ifa tablets consumption in pregnancy from frbs and against those, modified behaviors were proposed to pregnant women in the intervention group on trial bases by health education. trial period of 6 weeks was given for trial of new behaviors to pregnant women in the interven· tion group. phase: 3. in this phase, feedbacks on behaviors tried or not tried were taken from pregnant women in intervention group. haemoglobin estimation was carried out again in all 266 pregnant women. at the end of the study, messages were formulated on the bases of feedbacks from the pregnant women. results: all pregnant women in the intervention group had given positive feedback on new modified behaviors after intervention. mean haemoglobin concentration was higher in intervention group (10.04±0.11 gm%) than control group (9.60±0.14 gm%). ifa tablets compliance was improved in intervention group (95.6%) than control group (78.6%). conclusion: all pregnant women got benefits after trial of new modified behaviors in the intervention group. messages were formulated from the new modified behaviors, which can be used for longterm strategies for anaemia control in the community. introduction: in order to develop a comprehensive mch handbook for pregnant women and to assess its effect among them, a pilot study was carried out at the maternal and child health training institute (mchti), in dhaka, bangladesh. methods: from mchti a sample of 600 pregnant women was selected and all subjects were women who were attending the first visit of their current pregnancy by using a random sampling method. of the 600 subjects, 240 women were given the mch handbook as case and 360 women were not given the handbook as control. data on pre and post intervention of the handbook from the 240 cases and 360 controls were taken from data recording forms between the 1st of november 2002 and 31st of october, 2003 and data was analysed by using a multilevel analysis approach. this was a hospital-based action (case-control) research, and was applied in order to measure the outcome of pre and post intervention following the introduction of the handbook. data was used to assess the effects of utilisation of the handbook on women's knowledge, practice and utilisation of mch services. results: this study showed that the change of knowledge about antenatal care visits was 77.1% among case mothers. knowledge of danger signs improved 49.2 %, breast feeding results 31.5%, vaccination 32.0% and family planning results improved 60.3% among case. results showed some positive changes in women's attitudes among case mothers and study showed the change of practice in antenatal care visits was .u.5% in the case. other notable changes were: change of practice in case mother's tetanus toxoid (ti), 55.2%; and family planning 41.2%. in addition, handbook assessment study indicated that most women brought the handbook on subsequent visits (83.3%), the handbook was highly utilised (i.e. it was read by 84.2%, filled-in by 76.1 %, and was used as a health education tool by 80.4%). most women kept the handbook (99.5%) and found it highly useful (78.0%) with a high client satisfaction rate of 88.0%. conclusion: pregnant women in the case group had higher knowledge, better practices, and higher utilisation of mch services than mothers in the control groups who used alternative health cards. if the handbook is developed with a focus on utilising a problem-oriented approach and involving the recomendations .of end~users, it is anticipated that the mch handbook will contribute significantly to ensuring the quahry of hfe of women and their children in bangladesh. after several meetmgs to identify the needs of the community, a faso clinic was opened at ncfs. health care professionals from smh joined with developmental and social service workers from ncfs to implement the faso diagnostic process and to provide culturally appropriate after-care. the clinic is unique in that its focus is the high risk urban aboriginal population of toronto. it accepts referrals of not only children and youth, but also of adults. lessons learned: response to the faso clinic at native child and family services has been overwhelming. aboriginal children with f asd are receiving timely diagnosis and interventions. aboriginal youth and adults who have been struggling with poveny, substance abuse, and homelessness are more willing to enter the ncfs centre for diagnosis and treatment. aboriginal infants prenatally exposed to alcohol born at st. michael's hospital or referred by other centres have access to the developmental programs located in both of the partnering agencies. the presentation will describe the clinic's development, and will detail the outcomes described, including interventions unique to the aboriginal culture. p7-15 (c) seeds, soil, and stories: an exploration of community gardening in southeast toronto carolin taran, sarah wakefield, jennifer reynolds, and fiona yeudall introduction: community gardens are increasingly seen as a mechanism for improving nutrition and increasing food security in urban neighbourhoods, but the evidence available to support these claims is limited. in order to begin to address this gap in a way that is respectful of community knowledge and needs, the urban gardening research opportunities workgroup (ugrow) project explored the benefits and potential risks of community gardening in southeast toronto. the project used a community-based research (cbr) model to assess community gardens as a means of improving local health. the research process included interviews, focus groups, and participant observation (documented in field notes). we also directly engaged the community in the research process, through co-learning activities and community events which allowed participants to express their views and comment on emerging results. most of the research was conducted by a community-based research associate, herself a community gardener. key results were derived from these various sources through line-by-line coding of interview transcripts and field note review, an interactive and iterative process which involved both academic and community partners. results: these various data sources all suggest that enhanced health and access to fresh produce are important components of the gardening experience. they also highlight the central importance of empowering and community-building aspects of gardening to gardeners. community gardens were thought to play a role in developing friendships and social support, sharing food and other resources, appreciating cultural diversity, learning together, enhancing local place attachment and stewardship, and mobilizing to solve local problems (both inside and outside the garden). potential challenges to community gardens as a mechanism for communiry development include bureaucratic resistance to gardens, insecure land tenure and access, concerns about soil contamination, and a lack of awareness and under· standing by community members and decision-makers of all kinds. conclusion: the results highlight many health and broader social benefits experienced by commu· nity gardeners. they also point to the need for greater support for community gardening programs, par· ticularly ongoing the ongoing provision of resources and education programs to support gardens in their many roles. this research project is supported by the wellesley central health corporation and the centre for urban health initiatives, a cihr funded centre for research development hased at the univer· sity of toronto. p7-16 (c) developing resiliency in children living in disadvantaged neighbourhoods sarah farrell, lorna weigand, and wayne hammond the traditional idea of targeting risk reduction by focusing on the development of eff~ctive coping strategies and educational programs has merit in light of the research reportmg_ that_ ~10lupl.e forms of problem behaviour consistently appear to be predicted by increasing exposure to 1den_uf1able risk factors. as a result, many of the disadvantaged child and youth studies have focused on trymg to better _unde.r· stand the multiple risk factors that increase the likelihood of the development of at nsk behaviour m ch1ldren/youth and the potential implications for prevention. this in turn has led t_o. the conclus1on that community and health programs need to focus on risk reduction by helpm~ md1v1duals develop more effective coping strategies and a better understanding of the limitations of cenam pathologies, problematic v156 poster sessions coping behaviours and risk factors potentially inheren~ in high needs co~unities. ~owever, another ai:ea of research has proposed that preventative interventions should cons1de~ .~rotecnve fa~ors alo~~ with reducing risk factors. as opposed to just emphasizing problems, vulnerab1ht1es, and deficits, a res1liencybased perspective holds the belief that children, youth and their families. have strengths, reso~ce.s and the ability to cope with significant adversity in ways that are not only effective, but tend to result m mcreased ability to constructively respond to future adversity. with this in mind, a participatory research project sponsored by the united way of greater toronto was initiated to evaluate and determine the resiliency profiles of children 8 -12 years (n = 500) of recent immigrant families living in significantly disadvantaged communities in the toronto area. the presentation will provide an overview of the identified protective factors (both intrinsic and extrinsic) and resiliency profiles in an aggregated format as well as a summary of how the children and their parents interpreted and explained these strength-based results. as part of the focus groups, current community programs and services were examined by the participants as to what might be best practices for supporting the development and maintaining of resiliency in children, families and communities. it was proposed that the community model of assessing resiliency and protective factors as well as proposed best strength-based practice could serve as a guide for all in the community sector who provide services and programs to those in disadvantaged neighbourhoods. p7-17 (c) naloxone by prescription in san francisco, ca and new york, ny emalie huriaux the harm reduction coalition's overdose project works to reduce the number of fatal overdoses to zero. located in new york, ny and san francisco, ca, the overdose project provides overdose education for social service providers, single-room occupancy hotel (sro) residents, and syringe exchange participants. the project also conducts an innovative naloxone prescription program, providing naloxone, an opiate antagonist traditionally administered by paramedics to temporarily reverse the effects of opiate overdose, to injection drug users (idus). we will describe how naloxone distribution became a reality in new york and san francisco, how the project works, and our results. the naloxone prescription program utilizes multiple models to reach idus, including sro-and street-based trainings, and office-based trainings at syringe exchange sites. trainings include information on overdose prevention, recognition, and response. a clinician conducts a medical intake with participants and provides them with pre-filled units of naloxone. in new york, funding was initially provided by tides foundation. new york city council provides current funding. new york department of mental health and hygiene provides program oversight. while the new york project was initiated in june 2004, over half the trainings have been since march 2005. in san francisco, california endowment, tides foundation, and san francisco department of public health (sfdph) provide funding. in addition, sfdph purchases naloxone and provides clinicians who conduct medical intakes with participants. trainings have been conducted since november 2003. to date, nearly 1000 individuals have been trained and provided with naloxone. approximately 130 of them have returned for refills and reported that they used naloxone to reverse an opiate-related overdose. limited episodes of adverse effects have been reported, including vomiting, seizure, and "loss of friendship." in new york, 400 individuals have been trained and provided with naloxone. over 30 overdose reversals have been reported. over half of the participants in new york have been trained in the south bronx, the area of new york with the highest rate of overdose fatalities. in san francisco, 570 individuals have been trained and provided with naloxone. over 96 overdose reversals have been reported. the majority of the participants in san francisco have been trained in the tenderloin, 6th street corridor, and mission, areas with the highest rates of overdose fatalities. the experience of the overdose project in both cities indicates that providing idus low-threshold access to naloxone and overdose information is a cost-effective, efficient, and safe intervention to prevent accidental death in this population. p7-18 (c) successful strategies to regulate nuisance liquor stores using community mobilization, law enforcement, city council, merchants and researchers tahra goraya presenta~ion _will discuss ~uccessful environmental and public policy strategies employed in one southen:1 cahf?rmna commumty to remedy problems associated with nuisance liquor stores. participants ~111 be given tools to understand the importance of utilizing various substance abuse prevention str~tegi~ to change local policies and the importance of involving various sectors in the community to a~_1st with and advocate for community-wide policy changes. recent policy successes from the commultles of pa~ad~na and altad~na will highlight the collaborative process by which the community mobilized resulnng m several ordmances, how local law enforcement was given more authority to monitor poster sessions v157 nonconforming liquor stores, how collaborative efforts with liquor store owners helped to remove high alcohol content alcohol products from their establishments and how a community-based organiz,uion worked with local legislators to introduce statewide legislation regarding the regulation of nuisance liquor outlets. p7-19 (c) "dialogue on sex and life": a reliable health promotion tool among street-involved youth beth hayhoe and tracey methven introduction: street involved youth are a marginalized population that participate in extremely risky behaviours and have multiple health issues. unfortunately, because of previous abuses and negative experiences, they also have an extreme distrust of the adults who could help them. in 1999, toronto public health granted funding to a non governmental, nor for profit drop-in centre for street youth aged 16-24, to educate them about how to decrease rhe risk of acquiring hiv. since then the funding has been renewed yearly and the program has evolved as needed in order to target the maximum number of youth and provide them with vital information in a candid and enjoyable atmosphere. methods: using a retrospective analysis of the six years of data gathered from the "dialogue on sex and life" program, the researchers examined the number of youth involved, the kinds of things discussed, and the number of youth trained as peer leaders. also reviewed, was written feedback from the weekly logs, and anecdotal outcomes noted by the facilitators and other staff in the organization. results: over the five year period of this program, many of youth have participated in one hour sessions of candid discussion regarding a wide range of topics including sexual health, drug use, harm reduction, relationship issues, parenting, street culture, safety and life skills. many were new youth who had not participated in the program before and were often new to the street. some of the youth were given specific training regarding facilitation skills, sexual anatomy and physiology, birth control, sexually transmitted infections, hiv, substance use/abuse, harm reduction, relationships and discussion of their next steps/future plans following completion of the training. feedback has been overwhelmingly positive and stories of life changing decisions have been reported. conclusion: clearly, this program is a successful tool to reach street involved youth who may otherwise be wary of adults and their beliefs. based on data from the evaluation, recommendations have been made to public health to expand the funding and the training for peer leaders in order ro target between 100-200 new youth per year, increase the total numbers of youth reached and to increase the level of knowledge among the peer leaders. p7-20 (c) access to identification and services jane kali replacing identification has become increasingly more complex as rhe government identification issuing offices introduce new requirements rhar create significant barriers for homeless people to replace their id. new forms of identification have also been introduced that art' not accessible to homekss peoplt-(e.g. the permanent resident card). ar rhe same time, many service providers continue to require identifi· cation ro access supports such as income, housing, food, health care, employment and employmt·nt training programs. street health, as well as a number of other agencies and community health centres, h,1, been assisting with identification replacement for homeless peoplt· for a number of years. the rnrrt·nr challenges inherent within new replacement requirements, as well as the introduction of new forn1' of identification, have resulted in further barriers homeless people encounter when rrring to access t:ssential services. street health has been highlighting these issues to government identification issuing offices, as well as policy makers, in an effort to ensure rhar people who are homeless and marginalized have ac'ess to needed essential services. bandar is a somali word for •·a safe place." the bandar research project is the product of the regent park community health centre. the research looks ar the increasing number of somali and afri· can men in the homeless and precariously house population in the inner city core of down~own toronto. in the first phase of the pilot project, a needs assessment was conducted to 1dennfy barners and issues faced by rhe somali and other african men who are homeless and have add1cr10ns issues. th_e second phase of rhe research project was to identify long rerm resources and service delivery mechamsms that v158 poster sessions would enhance the abiity of this population to better access detox, treatment, and post treatment ser· vices. the final phase of the project was to facilitate the development of a conceptual model of seamless continual services and supports from the streets to detox to treatment to long term rehabilitation to housing. "between the pestle and mortar" -safe place. p7-22 (c) successful methods for studying transient populations while improving public health beth hayhoe, ruth ewert, eileen mcmahon, and dan jang introduction: street youth are a group that do not regularly access healthcare because of their mis· trust of adults. when they do access health care, it is usually for issues severe enough for hospitalization or for episodic care in community clinics. health promotion and illness prevention is rarely a part of their thinking. thus, standard public health measures implemented in a more stable population do not work in this group. for example, pap tests, which have dearly been shown to decrease prevalence of cer· vical cancer, are rarely done and when they are, rarely followed up. methods to meet the health care needs and increase the health of this population are frequently being sought. methods: a drop-in centre for street youth in canada has participated in several studies investigating sexual health in both men and women. we required the sponsoring agencies to pay the youth for their rime, even though the testing they were undergoing was necessary according to public health stan· dards. we surmised that this would increase both initial participation and return. results: many results requiring intervention have been detected. given the transient nature of this population, return rates have been encouraging so far. conclusion: it seems evident that even a small incentive for this population increases participation in needed health examinations and studies. it is possible that matching the initial and follow-up incentives would increase the return rate even further. the fact that the youth were recruited on site, and not from any external advertising, indicates that studies done where youth trust the staff, are more likely to be successful. the presentation will share the results of the "empowering stroke prevention project" which incor· porated self-help mutual aids strategies as a health promotion methodology. the presentation will include project's theoretical basis, methodology, outcomes and evaluation results. self-help methodology has proven successful in consumer involvement and behaviour modification in "at risk," "marginalized" settings. self-help is a process of learning with and from each other which provides participants oppor· tunities for support in dealing with a problem, issue, condition or need. self-help groups are mechanisms for the participants to investigate existing solutions and discover alternatives, empowering themselves in this process. learning dynamic in self-help groups is similar to that of cooperative learning and peertraining, has proven successful, effective and efficient (haller et al, 2000) . the mutual support provided by participation in these groups is documented as contributory factor in the improved health of those involved. cognizant of the above theoretical basis, in 2004 the self-help resource centre initiated the "empowering stroke prevention project." the project was implemented after the input from 32 health organizations, a scan of more than 300 resources and an in-depth analysis of 52 risk-factor-specific stroke prevention materials indicated the need for such a program. the project objectives were:• to develop a holistic and empowering health promotion model for stroke prevention that incorporates selfhelp and peer support strategies. • to develop educational materials that place modifiable risk factors and lifestyle information in a relevant context that validates project participants' life experiences and perspectives.• to educate members of at-risk communities about the modifiable risk factors associated with stroke, and promote healthy living. to achieve the above, a diverse group of community members were engaged as "co-editors" in the development of stroke prevention education materials which reflected and validated their life experiences. these community members received training to become lay health promoters (trained volunteer peer facilitators). in collaboration with local health organizations, these trained lay health promoters were then supported in organizing their own community-based stroke prevention activities. in addition, an educational booklet written in plain language, entitled healthy ways to prevent stroke: a guide for you, and a companion guide called healthy ways to pre· vent stroke: a facilitator's guide were produced. the presentation will include the results of a tw<>tiered evaluation of the program methodology, educational materials and the use of the materials beyond the life of the project. this poster presentation will focus on the development and structure of an innovative street outreach service that assists individuals who struggle mental illness/addictions and are experiencing homelessness. the mental health/outreach team at public health and community services (phcs) of hamilton, ontario assists individuals in reconnecting with health and social services. each worker brings to the ream his or her own skills-set, rendering it extremely effective at addressing the multidimensional and complex needs of clients. using a capacity building framework, each ream member is employed under a service contract between public health and community services and a local grassroots agency. there are public health nurses (phn), two of whom run a street health centre and one of canada's oldest and most successful needle exchange programs, mental health workers, housing specialists, a harm reduction worker, youth workers, and a united church minister, to name a few. a community advisory board, composed of consumers and professionals, advises the program quarterly. the program is featured on raising the roors 'shared learnings on homelessness' website at www.sharedlearnings.ca. through our poster presentation participants will learn how to create effective partnerships between government and grassroots agencies using a capacity building model that builds on existing programs. this study aims to assess the effects of broadcasting a series of documentary and drama videos, intended to provide information about the bc healthguide program in farsi, on the awareness about and the patterns of the service usage among farsi-speaking communities in the greater vancouver area. the major goals of the present study were twofold; ( 1) to compare two methods of communications (direct vs. indirect messages) on the attitudes and perceptions of the viewers regarding the credibility of messengers and the relevance of the information provided in the videos, and (2) to compare and contrast the impact of providing health information (i.e., the produced videos) via local tvs with the same materials when presented in group sessions (using vcr) on participants' attitudes and perceptions cowards the bc healrhguide services. results: through a telephone survey, 545 farsi-speaking adults were interviewed in november and december 2004. the preliminary findings show that 53% of the participants had seen the aired videos, from which, 51 % watched at least one of the 'drama' clips, 8% watched only 'documentary' clip, and 41% watched both types of video. in addition, 27% of the respondents claimed that they were aware about the program before watching the aired videos, while 73% said they leaned about the services only after watching the videos. from this group, 14% said they called the bchg for their own or their "hildren's health problems in the past month. 86% also indicated that they would use the services in the future whenever it would be needed. 48% considered the videos as "very good" and thought they rnuld deliver relevant messages and 21 % expressed their wish to increase the variety of subjects (produ\:e more videos) and increase the frequency of video dips. conclusion: the results of this study will assist public health specialists in bc who want to choose the best medium for disseminating information and apply communication interventions in multi\:ultural communities. introduction: many theorists and practitioners in community-based research (cbr) and knowledge transfer (kt) strongly advocate for involvement of potential users of research in the development of research projects, yet few examples of such involvement exist for urban workplace health interventions. we describe the process of developing a collaborative research program. methods: four different sets of stakeholders were identified as potential contributors to and users of the research: workplace health policy makers, employers, trade unions, and health and safety associations. representatives of these stakeholders formed an advisory committee which met quarterly. over the 13 month research development period, an additional 21 meetings were held between resc:ar~h~rs and stakeholders. in keeping with participant observation approaches, field notes of group and md1v1~ ual meetings were kept by the two co-authors. emails and telephone calls were also documented. qu~h tative approaches to textual analysis were used, with particular attention paid to collaborattve v160 poster sessions relationships established (as per cbr), indicators of stakeholders' knowledge utilization (as per kt), and transformations of the proposed research (as per cbr). results: despite initial strong differences of opinion both among stakeho~ders .an~ between stakeholders and researchers, goodwill was noted among all involved. acts of rec~proc1ty included mu.rual sharing of assessment tools, guidance on data utilization to stakeho~der orga~1zat10ns, and suggestions on workplace recruitment to researchers. stakeholders demonstrated mcreases m concep~ual. un~erstand ing of workplace health e.g. they more commonly discussed more complex,. psychosocial md1cators of organizational health. stakeholders made instrumental use of shared materials based on research e.g. adapting their consulting model to more sophisticated dat~ analysis. sta~ehol?~rs recogni_zed the strategic use of their alliance with researchers e.g., transformational leadership trainmg as a~ inducement to improve health and safety among small service franchises. stakeholders helped re-define the research questions, dramatically changed the method of recruitment from researcher cold call to stakeholderbased recruitment, and strongly influenced pilot research designs. owing a great deal to the elaborate joint development process, the four collaboratively developed pilot project submissions which were all successfully funded. conclusion: the intensive process of collaborative development of a research program among stakeholders and researchers was not a smooth process and was time consuming. nevertheless, the result of the collaborative process was a set of projects that were more responsive to stakeholder needs, more feasible for implementation, and more broadly applicable to relevant workplace health problems. introduction: environmental groups, municipal public health authorities and, increasingly, the general public are advocating for reductions in pesticide use in urban areas, primarily because of concern around potential adverse health impacts in vulnerable populations. however, limited evidence of the relative merits of different intervention strategies in different contexts exists. in a pilot research project, we sought to explore the options for evaluating pesticide reduction interventions across ontario municipalities. methods: the project team and a multi-stakeholder project advisory committee (pac), generated a list of potential key informants (kl) and an open ended interview guide. thirteen ki from municipal government, industry, health care, and environmental organizations completed face to face or telephone interviews lasting 30-40 minutes. in a parallel process, a workshop involving similar representatives and health researchers was held to discuss the role of pesticide exposure monitoring. minutes from pac meetings, field notes taken during ki interviews, and workshop proceedings were synthesized to generate potential evaluation methods and indicators. results: current evaluation activities were limited but all kls supported greater evaluation effons beginning with fuller indicator monitoring. indicators of education and outreach services were imponant for industry representatives changing applicator practices as well as most public health units and environmental organizations. lndictors based on bylaw enforcement were only applicable in the two cities with bylaws, though changing attitudes toward legal approaches were being assessed in many communities. the public health rapid risk factor surveillance system could use historical baseline data to assess changes in community behaviour through reported pesticide uses and practices, though it had limited penetration in immigrant communities not comfortable in english. pesticide sales (economic) data were only available in regional aggregates not useful for city specific change documentation. testing for watercourse or environmental contamination might be helpful, but it is sporadic and expensive. human exposure monitoring was fraught with ethical issues, floor effects from low levels of exposure, and prohibitive costs. clinical episodes of pesticide exposure reported to the regional poison centre (all ages) or the mother risk program (pregnant or breastfeeding women) are likely substantial underestimates that would be need to be supplemented with sentinel practice surveillance. focus on special clinical populations e.g., multiple chemical sensitivity would require additional data collection efforts . . conc~ons: broad support for evaluation and multiple indicators were proposed, though con-s~raints associate~ with access, coverage, sensitivity and feasibility were all raised, demonstrating the difficulty of evaluating such urban primary prevention initiatives. interventionists. an important aim of the youth monitor is to learn more about the health development of children and adolescents and the factors that can influence this development. special attention is paid to emo· tional and behavioural problems. the youth monitor identifies high-risk groups and factors that are associated with health problems. at various stages, the youth monitor chancrs the course of life of a child. the sources of informa· tion and methods of research are different for each age group. the results arc used to generate various kinds of repons: for children and young persons, parents, schools, neighbourhoods, boroughs and the municipality of rotterdam and its environs. any problems can be spotted early, at borough and neigh· bourhood level, based on the type of school or among the young persons and children themselves. together with schools, parents, youngsters and various organisations in the area, the municipal health service aims to really address these problems. on request, an overview is offered of potentially suitable interventions. the authors will present the philosophy, working method, preliminary effects and future developments of this instrument, which serves as the backbone for the rotterdam local youth policy. social workers to be leaders in response to aging urban populations: the practicum partnership program sarah sisco, alissa yarkony, and patricia volland 1"'"1tliu:tion: across the us, 77.5% of those over 65 live in urban areas. these aging urban popu· lations, including the baby boomers, have already begun encounter a range of heahh and mental hcahh conditions. to compound these effects, health and social service delivery fluciuates in cities, whit:h arc increasingly diverse both in their recipients and their systems. common to other disciplines (medicine, nursing, psychology, etc.) the social work profession faces a shortage of workers who are well-equipped to navigate the many systems, services, and requisite care that this vast population requires. in the next two decades, it is projected that nearly 70,000 social workers will be required to provide suppon to our older urban populations. social workers must be prepared to be aging-savvy leaders in their field, whether they specialize in gerontology or work across the life span. mllhotu: in 2000, a study conducted at the new york academy of medicine d<>1:umcntcd the need for improved synchroniciry in two aspects of social work education, classroom instruction and the field experience. with suppon from the john a. hanford foundation, our team created a pilot proj~"t entitled the practicum pannership program (ppp) in 11 master's level schools of social work, to improvt" aginr exposure in field and classroom content through use of the following: i) community-university partnrr· ships, 2) increased, diverse student field rotations, ll infusion of competcn1."}'·drivm coursework, 41 enhancement of field instructors' roles, and 5) concentrated student recruitment. we conductt"d a prr· and post-test survey into students' knowledge, skills. and satisfaction. icarlja: surveys of over 400 graduates and field inltnk."tors rcflected increased numlk-n of .1rrm:y· univmity panncrships, as well as in students placed in aging agencin for field placements. there wa1 11 marked increase in student commitments to an aging specialization. onr year por.t·gradu:nion rcvealrd that 93% of those surveyed were gainfully employed, with 80% employed in the field of aginic. by com· bining curricular enhancement with real-world experiences the ppp instilled a broad exposurr for llu· dents who worked with aging populations in multiple urban settings. coltdtuion: increased exposure to a range of levels of practicr, including clinical, policy/ajvocaq, and community-based can potentially improve service delivery for older adulh who live in elfin, and potentially improve national policy. the hanford foundation has now elected to 1uppon cxpantion of the ppp to 60 schools nationwide (urban and rural) to complement other domntic initiatives to cnhalk"c" holistic services for older adults across the aging spectrum. bodrgnn.ntl: we arc a team of rcscarcbcn and community panncn working tcj8c(her to develop an in"itepth understanding of the mental health needs of homeless youth ~ages 16 to 24) (using qualiutivc and quantitative methods 8' panicipatory rncarch methods). it is readily apparmt that '-neless youth cxpcricnce a range of mental health problems. for youth living on the street, menul illnew may be either a major risk factor for homelessnal or may frequently emcsge in response to coping with rhe multitudinous stressors associated with homclcslllcsi including exposure to violence, prasutt to pamaplte in v162 poster sessions survival sex and/or drug use. the most frequent psychiatric diagnoses amongst the homeless gencrally include: depression, anxiety and psychosis. . . . the ultimate ob1ective of the pr~am of rei:e~ is to ~evelop a plan for intervention to meet the mental health needs of street youth. prior t_o pl~nnmg mtervenbons, .it is necessary to undertake a comprehensive assessment ~f mental health needs m this ~lnerable populanon. thus, the immediate objective of this research study is to undertake a comprehensive assessment of men· tal health needs. . . melbotlology: a mixed methodology triangulating qualitative, participatory acnon and quantitative methods will capture the data related to mental health needs of homeless youth. a purposive sample of approximately 60-80 subjecrs. ages 16 to 24, is currently being ~ted ~participate from the commu.nity agencies covenant house, evergreen centre fo~ srrc;et youth, turning p?1?t and street ~ serv~. youth living on the street or in short -term residennal programs for a mmimum of 1 month pnor to their participation; ages 16 to 24 and able to give infonned consent will be invited to participate in the study. o..tcomes: the expected outcome of this initial survey will be an increased understanding of mental health needs of street youth that will be used to develop effective interventions. it is anticipated that results from this study will contribute to the development of mental health policy, as well as future programs that are relevant to the mental health needs of street youth. note: it is anticipated that preliminary quantitative data (25 subjects) and qualitative data will be available for the conference. the authors intend to present the identification of the research focus, the formation of our community-based team, relevance for policy, as well as preliminary results. p7-31 (a) the need for developing a firm health policy for urban informal worken: the case of despite their critical role in producing food for urban in kenya, urban farmers have largely been ignored by government planners and policymakers. their activity is at best dismissed as peripheral eveo, inappropriate retention of peasant culture in cities and at worst illegal and often some-times criminal· ized. urban agriculture is also condemned for its presumed negative health impact. a myth that contin· ues despite proof to the contrary is that malarial mosquitoes breed in maize grown in east african towns. however, potential health risks are insignificant compared with the benefits of urban food production. recent studies too rightly do point to the commercial value of food produced in the urban area while underscoring the importance of urban farming as a survival strategy among the urban poor, especially women-headed households. since the millennium declaration, health has emerged as one of the most serious casualties consequent on the poverty, social exclusion, marginalisation and lack of sustain· able development in africa. hiv/aids epidemic poses an unprecedented challenge, while malaria, tuber· culosis, communicable diseases of childhood all add to the untenable burden. malnutrition underpins much ill-health and is linked to more than 50 per cent of all childhood deaths. kenya's urban poor people ~ace ~ h~ge burde~ of preventable and treatable health problems, measured by any social and bi~ medical md1cator, which not only cause unnecessary death and suffering, but also undermine econonuc development and damage the country's social fabric. the burden is in spite of the availability of suitable tools and re:c=hnology for prevention and treatment and is largely rooted in poverty and in weak healah •rstems. this pa~ therefore challenges development planners who perceive a dichotomy instead of con· tmuum between informal and formal urban wage earners in so far as access to health services is con· cemed. it i~ this gap that calls for a need to developing and building sustainable health systems among the urban mformal ~wellers. we recommend a focus on an urban health policy that can build and strengthen the capacity of urban dwellers to access health services that is cost-effective and sustainable. such ~ health poli<=>: must strive for equity for the urban poor, displaced or marginalized; mobilise and effect1~ely use sufficient sustainable resources in order to build secure health systems and services. special anenti_on. should ~ afforded hiv/aids in view of the unprecedented challenge that this epidemic poses to africa s economic and social development and to health services on the continent. methods: a review of the literature led us to construct three simple models and a composite model of exposure to traffic. the data were collected with the help of a daily diary of travel activities using a sample of cyclists who went to or come back from work or study. to calculate the distance, the length of journey, and the number of intersections crossed by a cyclist different geographic information systems (gis) were operated. statistical analysis was used to determine the significance between a measure of exposure on the one hand, and the sociodemographic characteristics of the panicipants or their geographic location on the other hand. restlltj: our results indicate that cyclists were significantly exposed to road accidents, no matter of where they live or what are their sociodemographic characteristics. we also stress the point that the fact of having been involved in a road accident was significantly related to the helmet use, but did not reduce the propensity of the cyclists to expose themselves to the road hazards. condlllion: the efforts of the various authorities as regards road safety should not be directed towards the reduction of the exposure of the vulnerable users, but rather towards the reduction of the dangers to which they could face. keywords: cyclist, daily diary of activities, measures of exposure to traffic, island of montreal. p7-33 (a) intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods olumuyiwa akinbamijo intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods abstract urbanization panicularly in nigerian cities, ponends unprecedented crises of grave dimensions. from physical and demographic viewpoints, city growth rates are staggering coupled with gross inabilities to cope with the consequences. environmental and social ills associated with unguarded rapid urbanization characterize nigerian cities and threaten urban existence. this paper repons the findings of a recent study of the relationship between environmental health across inrraurban residential communities of akure, south west nigeria. it discuses the typical urbanization process of nigerian cities and its dynamic spatial-temporal characteristics. physical and socio-demographic attributes as well as the levels and effectiveness of urban infrastructural services are examined across the core residential districts and the elite residential layouts in the town. the incidence rate of cenain environmentally induced tropical diseases across residential neighborhoods and communes is examined. salient environmental variables that are germane to health procurement in the residential districts, incidence of diseases and diseases parasitology, diseases prevention and control were studied. field data were subjected to analysis ranging from the univariate and bivariate analysis. inferential statistics using the chi-square test were done to establish the truthfulness of the guiding hypothesis. given the above, the study affirms that there is strong independence in the studied communities, between the environment and incidence of diseases hence health of residents of the town. this assertion, tested statistically at the district levels revealed that residents of the core districts have very strong independence between the environment and incidences of diseases. the strength of this relationship however thins out towards the city peripheral districts. the study therefore concludes that since most of the city dwellers live in urban deprivation, urban health sensitive policies must be evolved. this is to cater for the urban dwellers who occupy fringe peripheral sites where the extension of facilities often times are illegally done. urban infrastructural facilities and services need be provided as a matter of public good for which there is no exclusive consumption or access even for the poorest of the urban poor. many suffer from low-self esteem, shame and guilt about their drug use. in addition, they often lack suppon or encounter opposition from their panners, family and friends in seeking treatment. these personal barriers are compounded by fragmented addiction, prenatal and social care services, inflexible intake systems and poor communication among sectors. the experience of accessing adequate care between services can be overwhelming and too demanding. the toronto centre for substance use in pregnancy (t-cup) is a unique program developed to minimize barriers by providing kone-stop" comprehensive healthcare. t-cup is a primary care based program located in the department of family medicine at st. joseph\'s health centre, a community teaching hospital in toronto. the interdisciplinary staff provides prenatal and addiction services, case management, as well as care of newborns affected by substance use. regular care plan meetings are held between t-cup, labour and delivery nurses and social workers in the y164 poster sessions maternity and child care program. t-cup also connects "'.omen with. inpatient treatment programs and community agencies such as breaking the cycle, an on-site counselmg group for pregnant substance users. · f · d d h ith method: retrospective chart review, qualitative patient ~ans action stu ~· an ea care provider surveys are used to determine outcomes. primary outcomes mclude changes m maternal su~tance use, psychosocial status and obstetrical complications (e.g. pre-rupture of membrane, pre-eclampsia, placen· ral abruption and hemorrhage). neonatal measures ~~nsisted of .bir~h pa_rame~ers, length of h~spital st.ay and complications (e.g. feral distress, meconium stammg, resuscitation, 1aund1ce, hypoglycemia, seventy of withdrawal and treatment length). chart review consisted of all t-cup patients who met clinical cri· reria for alcohol or drug dependence and received prenatal and intra-partum care at st. joseph's from october 2003 to june 2005. participants in the qualitative study included former and current t-cup patients. provider surveys were distributed on-site and to a local community hospital. raulb: preliminary evaluation has demonstrated positive results. treatment retention and satisfaction rates were high, maternal substance use was markedly reduced and neonatal outcomes have shown to be above those reported in literature. conclusion: this comprehensive, primary care model has shown to be optimal in the management of substance use in pregnancy and for improving neonatal outcomes. future research will focus on how this inexpensive program can be replicated in other health care settings. t-cup may prove to be the optimal model for providing care to pregnant substance users in canada. lntrod11ction: cigarette smoking is one of the most serious health problems in taiwan. the prevalence of smoking in 2002 is 48.1 % in males 5.9% in females aged 18 years and older. although the government of taiwan passed a tobacco hazards control act in 1997, it has not been strongly enforced in many places. therefore, community residents have often reported exposure of second hand smoke. the purpose of the study was to establish a device to build up more smoke-free environments in the city of tainan. methods: unique from traditional intervention studies, the study used a healthy city approach to help build up smoke-free environments. the major concept of the approach is to build up a healthy city platform, including organizing a steering committee, setting up policies and indicators, creating intersectoral collaboration, and increasing community participation. first, more than 80 enthusiastic researchers, experts, governmental officers, city counselors and community leaders in tainan were invited in the healthy city committee. second, smoke-free policies, indicators for smoke-free environments, and mechanisms for inter-departmen· tal inspections were set up. third, community volunteers were recruited and trained for persuading related stakeholders. lastly, both penalties and rewards were used for help build up the environments. raults: aher two-year (2003 aher two-year ( -2005 execution of the project, the results qualitatively showed that smoke-free environments in tainan were widely accepted and established, including smoke-free schools, smoke-free workpla~es, smoke-free households, smoke-free internet shops, and smoke-free restaurants. smoke~s were. effectively educated not to smoke in public places. community residents including adults and children m the smoke-free communities clearly understand the adverse effects of environmental tobacco smoke and actively participated anti-smoking activities. conclruions: healthy city platform is effective to conquer the barrier of limited anti-smoking rc:sources. nor. only can it enlar:ge community actions for anti-smoking campaigns, but also it can provide par_merships for collaboratjon. by establishing related policies and indicators the effects of smoke· free environments can be susta1·ned a d th · · · ' · n e progression can be monitored m a commuruty. these issues are used ~· oi::c it~ goals, weuha identifies issues that put people's health at risk. presently, team com~u:c: ran ee~tion !earns. (iats) that design integrative solutions ~tesj'°~ g om six to fifteen members. methods in order to establish wo-poster sessions v165 projects for weuha, the following approach was undertaken: i. a project-polling template was created and sent to all members of the alliance for their input. each member was asked to identify thdr top two population groups, and to suggest a project on which to focus over a 12-18 month period for each identified population. 2. there was a 47% response to the poll and the top three population groups were identified. data from the toronto community health profile database were utilized to contextualize the information supplied for these populations. a presentation was made to the steering committee and three population-based projects were selected, leaders identified and iats formed. three population-based projects: the population-based projects and health care issues identified are: newcomer prenatal uninsured women; this project will address the challenges faced by providers to a growing number of non-insured prenatal women seeking care. a service model where the barrier of "catchments" is removed to allow enhanced access and improved and co-ordinated service delivery will be pilot-tested. children/obesity/diab etes: using a health promotion model this team will focus on screening, intervention, and promoting healthy lifestyles (physical activity and nutrition) for families as well as for overweight and obese children. seniors health promotion and circle of discharge: this team will develop an early intervention model to assist seniors/family unit/caregivers in accessing information and receiving treatment/care in the community. the circle of discharge initiative will address ways of utilizing community supports to keep seniors in the community and minimize readmissions to acute care facilities. results/expected outcomes: coordinated and enhanced service delivery to identified populations, leading to improved access, improved quality of life, and health care for these targeted populations. introduction: basic human rights are often denied to high-risk populations and people living with hiv/aids. their rights to work and social security, health, privacy, non discrimination, liberty and freedom of movement, marriage and having a family have been compromised due to their sero-positive status and risk of being positive. the spread of hiv/aids has been accelerating due to the lack of general human rights among vulnerable groups. to formulate and implement effective responses needs dialogue and to prevent the epidemic to go underground barriers like stigma need to be overcome. objective: how to reduce the situation of stigma, discrimination and human rights violations experienced by people living with hiv/aids and those who are vulnerable to hiv/aids. methodology and findings: consultation meetings were strm.-rured around presentations, field visits, community meetings and group work to formulate recommendations on how govt and ngos/cbos should move forward based on objective. pakistan being a low prevalence country, the whole sense of compl;u:enc.:y that individuals are not subject to situations of vulnerable to hiv is the major threat to an explosion in th•· epidemic, therefore urgent measures are needed to integrate human rights issues from the very start of the response. the protection and promotion of human rights in an integral component of ;tll responses to the hiv/aids epidemic. it has been recognized that the response to hiv/aios must he multi sectoral and multi faceted, with each group contributing its particular expertise. for this to occur along with other knowlcdg<" more information is required in human rights abuses related to hiv/ aids in a particular scenario. the ~·on sultarion meetings on hiv/aids and human rights were an exemplary effort to achieve the same ohj<..:tivc. recommendations: the need for a comprehensive, integrated and a multi-sectoral appro;u.:h in addressing the issue of hiv/aids was highlighted. the need social, cultural and religious asp•·ct' to he: prominently addressed were identified. it was thought imperative measures even in low prevalence countries. education has a key role to play, there is a need for a code of ethics for media people and h<"alth care providers and violations should be closely monitored and follow up action taken. p7-38 (c) how can community-based funding programs contribute to building community capacity and how can we measure this elusive goal? mary frances maclellan-wright, brenda cantin, mary jane buchanan, and tammy simpson community capacity building is recognized by the public health agency of canada (phac) as an important strategy for improving the overall health of communities by enabling communities to addre~s priority issues such as social and economic determinants of health. in 2004/2005 phac.:, alberta/nwf region's population health fund (phf) supported 12 community-based projects to build community capacity on or across the determinants of health. specifically, this included creating accessible and sup· portive social and physical environments as well as creating tools and processes necessary for healthy policy development and implementation. the objective of this presentation is to highlight how the community capacity building tool, developed by phac ab/nwf region, can demonstrate gains in v166 poster sessions · · the course of a pror· ect and be used as a reflective tool for project planning and community capacity over . . . . i · a art of their reporting requirements, 12 pro1ect sites completed the community caparny eva uanon. s p . . th t i ii i'd d . building tool at the beginning and end of their ~ne-year prorect. e oo ~o ects va 1 an reliable data in the context of community-based health prorects. developed through a vigorous ~nd collabora11ve research process, the tool uses plain languag~ to expl~re nine key f~atures o~ commuruty cap~city with 35 't ch with a section for contextual information, 26 of which also mdude a four-pomt raong 1 ems, ea f fu d · scale. results show an increase in community capacity over the course o the nde prorects. pre and post aggregate data from the one-year projects measure~ statistic.ally si~n~ficant changes for 17 of the 26 scaled items. projects identified key areas of commumty capacity bmldmg that needed strengthemng, such as increasing participation, particularly among people with low incomes; engaging community members in identifying root causes; and linking with community groups. in completing the tool, projects examined root causes of the social and economic determinants of health, thereby exploring social justice issues related to the health of their community. results of the tool also served as a reflec· cion on the process of community capacity building; that is, how the project outcomes were achieved. projects also reported that the tool helped identify gaps and future directions, and was useful as a project planning, needs assessment and evaluation tool. community capacity building is a strategy that can be measured. the community capacity building tool provides a practical means to demonstrate gains in community capacity building. strengthening the elements of community capacity building through community-based funding can serve as building blocks for addressing other community issues. needs of marginalized crack users lorraine barnaby, victoria okazawa, barb panter, alan simpson, and bo yee thom background: the safer crack use coalition of toronto (scuc) was formed in 2000 in response to the growing concern for the health and well-being of marginalized crack users. a central concern was the alarm· ing hepatitis c rate ( 40%) amongst crack smokers and the lack of connection to prevention and health ser· vices. scuc is an innovative grassroots coalition comprised of front-line workers, crack users, researcher! and advocates. despite opposition and without funding, scuc has grown into the largest crack specific harm reduction coalition in canada and developed a nationally recognized sarer crack kit distribution program (involving 16 community-based agencies that provide outreach to users). the success of our coalition derives from our dedication to the issue and from the involvement of those directly affected by crack use. setting: scuc's primary service region is greater toronto, a diverse, large urban centre. much ofour work is done in areas where homeless people, sex trade workers and drug users tend to congregate. recently, scuc has reached out to regional and national stakeholders to provide leadership and education. mandate: our mandate is to advocate for marginalized crack users and support the devdopmentof a com.p.rehensive harm reduction model that addresses the health and social needs facing crack users; and to fac1htare the exchange of information between crack users, service providers, researchers, and policy developers across canada. owrview: the proposed workshop will provide participants with an overview of the devdopment of scuc, our current projects (including research, education, direct intervention and consultation), our challenge~ and s~ccesses and the role of community development and advocacy within the coalition. pre-senter~ will consist of community members who have personal crack use experience and front-line work· ers-, sc.uc conducted a community-based research project (toronto crack users perspectives, 2005) , in w~ich 1 s focus groups with marginalized crack users across toronto were conducted. participants iden· t1f1ed health and social issues affecti h b · · · d " red . . ng t em, arrsers to needed services, personal strategies, an oue recommendations for improved services. presenters will share the methodology, results and recommen· datmns resulting from the research project. conc/usio": research, field observations and consultations with stakeholders have shown that cradck shmoke~s are at an. increased risk for sexually transmitted infections hiv/aids hepatitis c, tb an ot er serious health issues health · ff, · ' ' · · . · issues a ectmg crack users are due to high risk behavmurs, socio· economic factors, such as homeless d. · · · · d · 1 . 1 . ness, 1scrsmmat1on, unemployment, violence incarceraoons, an soc1a 1so at1on, and a lack of comprehe · h i h · ' ns1ve ea t and social services targeting crack users. · · sinct · s, owever arge remains a gross underesurnaoon. poster sessions v167 these are hospital-based reports and many known cases go unreported. however teh case, young age at first intercourse, inconsistent condom use and multiple partnersplace adolescents at high risks for a diverse array of stls, including hiv. about 19% of female nigerian secondary school students report initiating sexual intercourse before age 13 years. 39% of nigerian female secondary school students report not using a condom the last time they had sexual intercourse. more than 60% of urban nigerian teens report inconsistent condom use. methods: 371 adolescents were studied, ages 12 to 19, from benin city in edo state. the models used were mother-daughter(119), mother -son(99), father -son (87), and father-daughter(66). the effect of parent-child sexual communicationat baseline on child\'s report of sexual behavior, 6 to 12 months later were studied. greater amounts of sexual risk communication were asociated with markedly fewer episodes of unprotected sexual intercourse, reduced number of sexual partners and fewer episodes of unprotected sexual intercourse. results: this study proved that parents can exert more influence on the sexual knowledge attitudes and practise of their adolescent children through desired practises or rolemodeling, reiterating their values and appropriate monitoring of the adolescents\' behavior. they also stand to provide information about sexuality and various sexual topics. parental-child sexual communication has been found to be particularly influential and has been associated with later onset of sexual initiation among adolescents, less sexual activity, more responsible sexual attitudes including greater condom use, self efficacy and lower self -reported incidence of stis. conclusions: parents need to be trained to relate more effectively with their children/wards about issues related to sex and sexuality. family -based programs to reduce sexual risk-taking need to be developed. there is also the need to carry out cross-ethnicaland cross-cultural studies to identify how parent-child influences on adolescent sexual risk behavior may vary in different regions or countries, especially inthis era of the hiv pandemic. introduction: public health interventions to identify and eliminate health disparities require evidence-based policy and adequate model specification, which includes individuals within a socioecological context, and requires the integration of biosociomedical information. multiple public and private data sources need to be linked to apportion variation in health disparities ro individual risk factors, the health delivery system, and the geosocial environment. multilevel mapping of health disparities furthers the development of evidence-based interventions through the growth of the public health information network (phin-cdc) by linking clinical and population health data. clinical encounter data, administrative hospital data, population socioenvironmental data, and local health policy were examined in a three-level geocoded multilevel model to establish a tracking system for health disparities. nj has a long established political tradition of "home rule" based in 566 elected municipal governments, which are responsible for the well-being of their populations. municipalities are contained within counties as defined by the us census, and health data are linked mostly at the municipality level. marika schwandt community organizers from the ontario coaliti~n again~t pove~, .along ":ith ~edical practitioners who have endorsed the campaign and have been mvolved m prescnbmg special diet needs for ow and odsp recipients, will discuss the raise the rates campaign. the organizati~n has used a special diet needs supplement as a political tool, meeting the urgent needs o.f .poor ~ople m toront~ while raising the issues of poverty as a primary determinant of health and nutrtnous diet as a preventative health mea· sure. health professionals carry the responsibility to ensure that they use all means available to them to improve the health of the individuals that they serve, and to prevent future disease and health conditions. most health practitioners know that those on social assistance are not able to afford nutritious foods or even sufficient amounts of food, but many are not aware of the extra dietary funds that are available aher consideration by a health practitioner. responsible nurse practitioners and physicians cannot, in good conscience, ignore the special needs diet supplement that is available to all recipients of welfare and disabiliry (ow and odsp). a number of toronto physicians have taken the position that all clients can justifiably benefit from vitamins, organic foods and high fiber diets as a preventative health measure. we know that income is one of the greatest predictors of poor health. the special needs diet is a health promotion intervention which will prevent numerous future health conditions, including chronic conditions such as cardiovascular disease, cancer, diabetes and osteoporosis. many communiry health centres and other providers have chosen to hold clinics to allow many patients to get signed up for the supplement at one time. initiated by the ontario coalition against poverty, these clinics have brought together commu· niry organizers, community health centers, health practitioners, and individuals, who believe that poverty is the primary determinant of poor health. we believe that rates must be increased to address the health problems of all people on social assistance, kids, elders, people with hiv/aids -everyone. even in the context of understaffing, it could be considered a priority activity that has potentially important health promotion benefits. many clients can be processed in a two hour clinic. most providers find it a very interesting, rewarding undertaking. in 2004 the ontario coalition for social justice found that a toronto family with two adults and two kids receives $14,316. this is $21,115 below the poverty line. p7-43 (c) the health of street youth compared to similar aged youth beth hayhoe and ruth ewert . lntrod~on: street youth are at an age normally associated with good health, but due to their risky ~hav1ours and th~ conditions in which they live, they experience health conditions unlike their peer~ an more stable env1r~nments. in addition, the majority of street youth have experienced significant physical, sexual ~nd em.ot1onal abuse as younger children, directly impacting many of the choices they make around their physical and emotional health. we examined how different their health really is. . , methodl: using a retrospective analysis of the 11 years of data gathered from yonge street mis· 510~ 5 • evergreen health centre, the top 10 conditions of youth were examined and compared with national tren~s for similar aged youth. based on knowledge of the risk factors present in the group, rea· sons for the difference were examined. d' ~its: street youth experience more illness than other youth their age and their illnesses can bt . irect t ·~kc~ to the. conditions in which they live. long-term impacts of abus~ contribute to such signif· ~~nt t e t 0 d~slpl air that youth may voluntarily engage in behaviours or lack of self care in the hope at t cir 1ve~ w1 perhaps come to a quicker end. concl11non: although it has ion b k h th' dy clearly shows 3 d'fi . h g ee~ no~n t at poverty negatively affects health, ~siu be used to make ; erence m t .e health of this particular marginalized population. the infonnanon can relates to th . ecommendatio.ns around public policy that affects children and youth, especially as it e1r access to appropriate health care and follow up. p7-44 (cl why do urban children · b gt . tarek hussain 10 an adesh die: how to save our children? the traditional belief that urban child alid. a recent study (dhs d fr 17 r~n are better off than rural children might be no longer v urban migrants are highata th om h c~untn~s i demonstrates that the child survival prospects of rural· er an t ose m their r j · · ·grants. in bangladesh, currently 30 million 0 ~r~ 0~1gm and lower than those of urban non-idi million. health of the urban 1 ~ p~e are hvmg m urban area and by the year 2025, it would be so the popu at1on 1s a key a eals that urban poor have the worse h 1 h . concern. recent study on the urban poor rev ea t situation than the nation as a whole. this study shows that infant poster sessions v169 mortality among the urban poor as 120 per thousand, which are above the rural and national level estimates. the mortality levels of the dhaka poor are well above those of the rest of the city's population but much of the difference in death rates is explained by the experience of children, especially infants. analyzing demographic surveillance data from a large zone of the city containing all sectors of the population, research showed that the one-fifth of the households with the least possessions exhibited u5 child mortality almost three times as high as that recorded by the rest of the population. why children die in bangladesh? because their parents are too poor to provide them with enough food, clean water and other basic needs to help them avoid infection and recover from illness. researchers believed that girls are more at risk than boys, as mothers regularly feed boys first. this reflects the different value placed on girls and boys, as well as resources which may not stretch far enough to provide for everyone. many studies show that housing conditions such as household construction materials and access to safe drinking water and hygienic toilet facilities are the most critical determinants of child survival in urban areas of developing countries. the present situation stressed on the need for renewed emphasis on maternal and child healthcare and child nutrition programs. mapping path for progress to save our children would need be done strategically. we have the policies on hand, we have the means, to change the world so that every child will survive and has the opportunity to develop himself fully as a healthy human being. we need the political will--courage and determination to make that a reality. p7-45 (c) sherbourne health centre: innovation in healthcare for the transgendered community james read introduction: sherbourne health centre (shc), a primary health care centre located in downtown toronto, was established to address health service gaps in the local community. its mission is to reduce barriers to health by working with the people of its diverse urban communities to promote wellness and provide innovative primary health services. in addition to the local communities there are three populations of focus: the lesbian, gay, bisexual, transgendered and transexual communities (lgbtt); people who are homeless or underhoused; and newcomers to canada. shc is dedicated to providing health services in an interdisciplinary manner and its health providers include nurses, a nurse practitioner, mental health counsellors, health promoters, client-resource workers, and physicians. in january 2003 shc began offering medical care. among the challenges faced was how to provide responsive, respectful services to the trans community. providers had considerable expertise in the area of counselling and community work, but little in the area of hormone therapy -a key health service for those who want to transition from one gender to another. method: in preparing to offer community-based health care to the trans community it was clear that shc was being welcomed but also being watched with a critical eye. trans people have traditionally experienced significant barriers in accessing medical care. to respond to this challenge a working group of members of the trans community and health providers was created to develop an overall approach to care and specific protocols for hormone therapy. the group met over a one year period and their work culminated in the development of medical protocols for the provision of hormone therapy to trans individuals. results: shc is currently providing health care to 281 registered clients who identify as trans individuals (march 31 2005) through primary care and mental health programs. in an audit of shc medical charts (january 2003 to september 2004) 55 female-to-male (ftm) and 82 male-to-female (mtf) clients were identified. less than half of the ftm group and just over two-thirds of the mtf group presented specifically for the provision of hormones. based on this chart audit and ongoing experience shc continues to update and refine these protocols to ensure delivery of quality care. conclusion: this program is an example of innovative community-based health delivery to a population who have traditionally faced barriers. shc services also include counselling, health promotion, outreach and education. p7-46 (c) healthy cities for canadian women: a national consultation sandra kerr, kimberly walker, and gail lush on march 4 2005, the national network on environment and women's health held a pan-canadian consultation to identify opportunities for health research, policy change, and action. this consultation also worked to facilitate information sharing and networking between canadian women working as urban planners, policy makers, researchers, and service workers on issues pertaining to the health of women living in canadian cities. methods: for this research project, participants included front-line service workers, policy workers, researchers, and advocates from coast to coast, including francophone women, women with disabilities, racialized women, and other marginalized groups. the following key areas were selected as topics for du.bnes i1 alto kading .:auk of end·sugr ieaal clileue ia singapore, accounting for more than so% of new can singapore (nkfs) to embark on a prevention program (pp) 10 empo~r d1ahc 1j1u1f dieir condition bttter, emphasizing education and disease sdf·managemen1 lkilla a. essennal camponenn of good glycaemic control. we sought 10 explore the effects of a 1pecialijed edu.:a11on pro· pun od glycacmic conuol, as indicated by, serum hba ic values budine serum hba ic values were determined before un<k-rgmng the education progr ;am, which couisted of comprehensive dietary advice, ideal weight goals, and improving lipid profiln. serum hbaic values were obtained ar 3,6,9 months later to determine impact of the program. analy11• wu done uling paired !·tests significant reduction in hba le levels from 0 ro 9 month• was observed in females, chinese race, older age group(> so yean). ohew-ibmi ~ 27.nwm2, wai11 hip ratio> l),up to primary and above secondary level education and those having om urine iclt showed that increasing hbalc levels (9) had increasing urmary protein (38.± 117; .18 ±i ih so± 136) and crearinine (s2.s ± 64 7s ± 71; ioi± 7s) levels fbg rnults showed that the management nf d1abetn m the nkfs preven· tion programme is effec;rive. results also indicated 1har hba le leve11 have a linnr trend wnh unnary protein and creatinine which are imponant determinants of renal diseate tal family-focused cinical palbway1 promoce politivc outcollln for ua inner city canu allicy ipmai jerrnjm1 care llctivirits in preparation for an infanr'' dilchargr honlr, and art m1endnl lo improve effi.:k'fl.:tn of c.are. 11lere i11 paucity of tttran:h, and inconsi1trncy of rnulta on 1ht-•m!*-1 of f1m1ly·fc"-'uw d1nm 1a: to determinr whrthrr implrmentation of family.focuted c:pt 1n 1 ntnn.tt.tl unit w"n mg an inner city 1;ommunity drcl't'aki leftarh of lf•y (i.osi and rromclll'i family uo•fkllon and rt.1j1 nest for dikhargr. md6odt: family-focuk"d cpi 1041 data wm coll«ted for all infant• horn btrwttn 29 and 36 wft"k• 1t"lal111mi atr who wrtt .1dm111ed to the ntonatal unit lmgdl of -.y 111. 9 n. 14.8 day'o p c o.osi ind pma .11 d•mr., ho.nr 137.3 t 1.3 n. 36.4 ± i. i wb, p < o.os) wett n«01fiamly f.lfrt 1n the pre.(]' poup. ~11.fxtmon icofn for famihn wrre high. and families noctd thc:y wnr mott prepued to ah thrar t..lby "'-· thett was .a cosi uving of s 1,814 (cdn) per patient d1teharpd home 1n the pmi-cp poap c.-pated 10 the p"''lfoup· cortclaion· lmplrmrnr.rion of family·foanrd c:p. in a nrona1.1i umt tc"fyidi an 1nnn an com· muniry decre.ned length of'"'" mft with a high dcgrft of family uujamon, and wrre coll~nt at least 35% percent of the kathmandu population lives in slum like conditions with poor access to basic health services. in these disadvantaged areas, a large proportion of children do not receive treatment due to inaccessibility to medical services. in these areas, diarrhea, pneumonia, and measles, are the key determinants of infant mortality. protein energy malnutrition and vitamin a deficiency persists and communicable diseases are compounded by the emergence of diseases like hiv/aids. while the health challenges for disadvantaged populations in kathmandu are substantial, the city has also experienced various forms of innovative and effective community development health programs. for example, there are community primary health centers established by the kathmandu municipality to deliver essential health services to targeted communities. these centers not only provide equal access to health services to the people through an effective management system but also educate them hy organizing health related awareness programs. this program is considered one of the most effective urban health programs. the paper/presentation this paper will review large, innovative, and effective urhan health programs that are operating in kathmandu. most of these programs are currently run by international and national ngos a) early detection of emerging diseases in urban settings through syndromic surveillance: 911 data pilot study kate bassil of community resources, and without adequate follow-up. in november 2003 shelter pr.oviders ~et with hospital social workers and ccac to strike a working group to address some of th~ issues by mcre.asing knowledge among hospital staff of issues surrounding homelessness, and to build a stro?g workmg relationship between both systems in hamilton. to date the hswg has conducted four w~lkmg to~ of downtown shelters for hospital staff and local politicians. recently the hswg launched its ·~ool.k1t for staff working with patients who are homeless', which contains community resources and gu1dehnes to help with effective discharge plans. a scpi proposal has been submitted to incre~se the capacity of the hswg to address education gaps and opportunities with both shelters and hospitals around homelessness and healthcare. the purpose of this poster presentation is to share hamilton's experience and learnings with communities who are experiencing similar issues. it will provide for intera~tion around shared experiences and a chance to network with practitioners across canada re: best practices. introduction and objectives: canadians view health as the biggest priority for the federal government, where health policies are often based on models that rely on abstract definitions of health that provide little assistance in the policy and analytical arena. the main objectives of this paper are to provide a functional definition of health, to create a didactic model for devising policies and determining forms of intervention, to aid health professionals and analysts to strategize and prioritize policy objectives via cost benefit analysis, and to prompt readers to view health in terms of capacity measures as opposed to status measures. this paper provides a different perspective on health, which can be applied to various applications of health such as strategies of aid and poverty reduction, and measuring the health of an individual/ community/country. this paper aims to discuss theoretical, conceptual, methodological, and applied implications associated with different health policies and strategies, which can be extended to urban communities. essentially, our paper touches on the following two main themes of this conference: •health status of disadvantaged populations; and •interventions to improve the health of urban communities.methodology: we initially surveyed other models on this topic, and extrapolated key aspects into our conceptual framework. we then devised a theoretical framework that parallels simple theories of physkal energy, where health is viewed in terms of personal/societal health capacities and effort components.after establishing a theoretical model, we constructed a graphical representation of our model using selfrated health status and life expectancy measures. ultimately, we formulated a new definition of health, and a rudimentary method of conducting cost benefit analysis on policy initiatives. we end the paper with an application example discussing the issues surrounding the introduction of a seniors program.results: this paper provides both a conceptual and theoretical model that outlines how one can go about conducting a cost-benefit analysis when implementing a program. it also devises a new definition and model for health barred on our concept of individual and societal capacities. by devising a definition for health that links with a conceptual and theoretical framework, strategies can be more logically constructed where the repercussions on the general population are minimized. equally important, our model also sets itself up nicely for future microsimulation modeling and analysis.implications: this research enhances one's ability to conduct community-based cost-benefit analysis, and acts as a pedagogical tool when identifying which strategies provide the best outcome. p7-06 (a) good playgrounds are hard to find: parents' perceptions of neighbourhood parks patricia tucker, martin holmes, jennifer irwin, and jason gilliland introduction: neighbourhood opportunities, including public parks and physical activity or sports fields hav~ been. iden.tified as correlates to physical activity among youth. increasingly, physical activity among children 1s bemg acknowledged as a vital component of children's lives as it is a modifiable determinant of childh~d obesity. children's use of parks is mainly under the influence of parents; therefore, the purpose of this study was to assess parents' perspectives of city parks, using london ontario as a case study.m~~: this qualitative study targeted a heterogeneous sample of parents of children using local parks w1thm london. parents with children using the parks were asked for 5 minutes of their time and if willing, a s.hort interview was conducted. the interview guide asked parents for their opinion 'of city parks, particularly the one they were currently using. a sample size of 50 parents is expected by the end of the summer.results: preliminary findings are identifying parents concern with the current jack of shade in local parks. most parents have identified this as a limitation of existing parks, and when asked what would make the parks better, parents agree that shade is vital. additionally, some parents are recognizing the v170 poster sessions focused discussions during the consultation: 1. women in _poverty 2. women with disability 3. immi· grant and racialized women 4. the built and _physica_l environment. . . . . r its· participants voiced the need for integration of the following issues withm the research and policy :::na; t) the intersectional nature of urban women's health i~sues wh~ch reflects the reality of women's complex lives 2) the multisectional aspect of urban wo_m~n s health, 1ss~es, which reflects the diversity within women's lives 3) the interse~roral _dynamics within _womens hves and urban health issues. these concepts span multiple sectors -mdudmg health, educat10n, and economics -when leveraging community, research, and policy support, and engaging all levels of government.policy jmplicatiom: jn order to work towards health equity for women, plans for gender equity must be incorporated nationally and internationally within urban development initiatives: • reintroduce "women" and "gender" as distinct sectors for research, analysis, advocacy, and action. •integrate the multisectional, intersectional, and intersecroral aspects of women's lives within the framework of research and policy development, as well as in the development of action strategies. • develop a strategic framework to house the consultation priorities for future health research and policy development (for example, advocacy, relationship building, evidence-based policy-relevant research, priority initiatives}.note: research conducted by nnewh has been made possible through a financial contribution from health canada. the views expressed herein do not necessarily represent the views of health canada.p7-47 (c) drugs, culture and disadvantaged populations leticia folgar and cecilia rado lntroducci6n: a partir de un proyecto de reducci6n de daiios en una comunidad urbana en situ· aci6n de extrema vulnerahilidad surge la reflexion sobre el lugar prioritario de los elementos sociocuhurales en el acceso a los servicios de salud de diferentes colectivos urbanos. las "formas de hacer, pensar y sentir" orientan las acciones y delimitan las posibilidades que tienen los individuos de definir que algo es o no problema, asf como tambien los mecanismos de pedido de ayuda. el analisis permanenre del campo de "las culturas cotidianas" de los llamados "usuarios de drogas" aporta a la comprension de la complejidad del tema en sus escenarios reales, y colabora en los diseiios contextualizados de politicas y propuestas socio-sanitarias de intervenci6n, tornandolas mas efectivas.mitodos: esta experiencia de investigaci6n-acci6n que utiliza el merodo emografico identifica elementos socio estructurales, patrones de consumo y profundiza en los elementos socio-simb61icos que estructuran los discursos de los usuarios, caracterizandolos y diferenciandolos en tanto constitutivos de identidades socia les que condicionan la implementaci6n del programas de reduccion de daiios.resultados: los resultados que presentaremos dan cuenta de las caracteristicas diferenciadas v relaciones particulares ~ntre los consumidores de drogas en este contexto espedfico. a partir de este e~tudio de caso se mtentara co1?1enzar a responder preguntas que entendemos significativas a la hora de pensar intcrvcnciones a la med1da de poblaciones que comparten ciertas caracteristicas socio-culturales. (cuales serian las .motivaciones para el cambio en estas comunidades?, cque elementos comunitarios nos ayudan a i:nnstnur dema~~a? • cque tenemos para aprender de las "soluciones" que ellos mismos encuenrran a los usos problemat1cos? methods: our study was conducted by a team of two researchers at three different sites. the mapping consisted of filling in a chart of observable neighbourhood features such as graffiti, litter, and boarded housing, and the presence or absence of each feature was noted for each city block. qualitative observations were also recorded throughout the process. researchers analyzed the compiled quantitative and qualitative neighbourhood data and then analyzed the process of data collection itself.results: this study reveals the need for further research into the effects of physical environments on individual health and sense of well-being, and perception of investment in neighbourhoods. the process reveals that perceptions of health and safety are not easily quantified. we make specific recommendations about the mapping methodology including the importance of considering how factors such as researcher social location may impact the experience of neighbourhoods and how similar neighbourhood characteristics are experienced differently in various spaces. further, we discuss some of the practical considerations around the mapping exercise such as recording of findings, time of day, temperature, and researcher safety.conclusion: this study revealed the importance of exploring conceptions of health and well-being beyond basic physical wellness. it suggests the importance of considering one's environment and one's own perception of health, safety, and well-being in determining health. this conclusion suggests that attention needs to be paid to the connection between the workplace and the external environment it is situated in. the individual's workday experience does not start and stop at the front door of their workplace, but rather extends into the neighbourhood and environment around them. our procedural observations and recommendations will allow other researchers interested in the effect of urban environments on health to consider using this innovative methodology. introduction: responding ro protests against poor medical attention for sexually assaulted women and deplorable conviction rates for sex offenders, in the late 1970s, the ontario government established what would become over 30 hospital-based sexual assault care and treatment centres (sactcs) across the province. these centres, staffed around the clock with specially trained heath care providers, have become the centralized locations for the simultaneous health care treatment of and forensic evidence collection from sexually assaulted women for the purpose of facilitating positive social and legal outcomes. since the introduction of these centres, very little evaluative research has been conducted to determine the impact of this intervention. the purpose of our study was to investigate it from the perspectives of sexually assaulted women who have undergone forensic medical examinations at these centres.method: women were referred to our study by sactc coordinators across ontario. we developed an interview schedule composed of both closed and open-ended questions. twenty-two women were interviewed, face-to-face. these interviews were approximately one-to-two hours in length, and were transcribed verbatim. to date, 19 have been analyzed for key themes.results: preliminary findings indicate that most women interviewed were canadian born (79'yo), and ranged in age from 17 to 46 years. a substantial proportion self-identified as a visible minority ( 37'x.). approximately half were single or never married (47%) and living with a spouse or family of origin (53%). most were either students or not employed (68%). two-thirds (68%) had completed high school and onethird (37%) was from a lower socio-economic stratum. almost two-fifths (37%) of women perceived the medical forensic examination as revictimizing citing, for example, the internal examination and having blood drawn. the other two-thirds (63%) indicated that it was an empowering experience, as it gave them a sense of control at a time when they described feeling otherwise powerless. most (68%) women stated that they had presented to a centre due to health care concerns and were very satisfied ( 84 % ) with their experiences and interactions with staff. almost all (89%) women felt supported and understood.conclusions: this research has important implications for clinical practice and for appropriately addressing the needs of sexually assaulted women. what is apparent is that continued high-quality medical attention administered in the milieu of specialized hospital-based services is essential. at the same time, we would suggest that some forensic evidence collection procedures warrant reevaluation. the study will take an experiential, approach by chroruclmg the impa~ of the transition f m the streets to stabilization in a managed alcohol program through the techruque of narrative i~:uiry. in keeping with the shift in thinking in the mental health fie!~ ~his stu~y is based on a paradigm of recovery rather than one of pathology. the "inner views of part1c1pants hves as they portray their worlds, experiences and observations" will be presented (charm~z, 1991, ~· 38~)-"i?e p~ of the study is to: identify barriers to recovery. it will explore the exj?cnence of ~n~t1zanon pnor to entry into the program; and following entry will: explore the meanmg ~nd defirutto~s of r~overy ~~d the impact of the new environment and highlight what supports were instrumental m movmg pan1apants along the recovery paradigm.p7-st (a) treating the "untreatable": the politics of public health in vancouver's inner city introdudion: this paper explores the everyday practices of therapeutic programs in the treadnent of hiv in vancouver's inner city. as anthropologists have shown elsewhere, therapeutic programs do not siinply treat physical ailments but they shape, regulate and manage social lives. in vancouver's inner city, there are few therapeutic options available for the treatment of 1-ilv. public health initiatives in the inner city have instead largely focused on prevention and harm reduction strategies such as needle exchange programs, safe injection sites, and safer-sex education. epidemiological reports suggest that less than a quarter of those living with hiv in the downtown eastside (dtes) are taking antiretroviral therapies raising critical questions regarding the therapeutic economy of antiretrovirals and rights to health care for the urban poor.methods: this paper is drawn from ethnographic fieldwork in vancouver's otes neighborhood focusing on therapeutic programs for hiv treatment among "hard-to-reach" populations. the research includes participant-observation at inner city health clinics specializing in the treatment of hiv; semi· structured interviews with hiv positive participants, health care professionals providing hiv treatment, and administraton working in the field of inner city public health; and, lastly, observation at public meetings and conferences surrounding hiv treatment.r.awlts: hiv prevention and treatment is a central concern in the lives of many residents living in the inner city -although it is just one of many health priorities afflicting the community. concerns about drug resistance, cost of antiretrovirals, and illicit drug use means that hiv therapy for most is characterized by the daily observation of their medicine ingestion at health clinics or pharmacies. daily observed treatment (dot) is increasingly being adopted as a strategy in the therapeutic management of "untreatable" populations. dot programs demand a particular type of subject -one who is "compliant" to the rules and regimes of public health. over emphasis on "risky practices," "chaotic lives," and "~dh~rence" preve~ts the public health system from meaningful engagement with the health of the marginalized who continue to suffer from multiple and serious health conditions and who continue to experience considerable disparities in health.~ the ~ffec~s of hiv in the inner city are compounded by poverty, laclc of safe and affordable houamg, vanous 1llegal underground economies increased rates of violence and outbreaks of ~~~·~ly tr~nsmitted infections, hepatitis, and tuberculosi: but this research suggests 'that public health uunauves aimed at reducing health disparities may be failing the most vulnerable and marginal of citiztl1s. margaret malone 1~ vi~lence that occurs in families and in intimate relationships is a significant urban, ~unity, and pu~hc health problem. it has major consequences and far-reaching effects for women, ~~--renho, you~ sen1on, and families. violence also has significant effects for those who provide and ukllc w receive health care violence · · i · · . all lasses, · is a soc1a act mvolvmg a senous abuse of power. it crosses : ' : ' ~ 11 s;nden, ag~ ~ti~, cultures, sexualities, abilities, and religions. societal responseshali ra y oc:used on identificatton, crisis intervention and services for families and individuajs.promoten are only "-"--:-g to add h · ' · i in intimate relationshi with"-~"'.". ress t e issues of violence against women and vjoence lenga to consider i~ m families. in thi_s p~per, i analyze issues, propose strategies, and note c~· cannot be full -...l'-~ whork towards erad1canng violence, while arguing that social justice and equity y -.1ucvcu w en thett are people wh mnhod: critical social theory, an analysis that addresses culturally and ethnically diverse communities, together with a population health promotion perspective frame this analysis. social determinants of health are used to highlight the extent of the problem of violence and the social and health care costs.the ottawa charter is integrated to focus on strategies for developing personal skills, strengthening community action, creating supportive environments, devdoping healthy public policies, and re-orientating health and social services. attention is directed to approaches for working with individuals, families, groups, communities, populations, and society.ratdts: this analysis demonstrates that a comprehensive interdisciplinary, multisectoral, and multifaceted approach within an overall health promoting perspective helps to focus on the relevant issues, aitical analysis, and strategies required for action. it also illuminates a number of interacting, intersecting, and interconnecting factors related to violence. attention, which is often focused on individuals who are blamed for the problem of violence, is redirected to the expertise of non-health professionals and to community-based solutions. the challenge for health promoters working in the area of violence in families and in intimate relationships is to work to empower ourselves and the communities with whom we work to create health-promoting urban environments. social justice, equiry, and emancipatory possibilities are positioned in relation to recommendations for future community-based participatory research, pedagogical practices for health care practitioners, and policy development in relation to violence and urban health. the mid-main community health center, located in vancouver british columbia (bc), has a diverse patient base reflecting various cultures, languages, abilities, and socio-economic statuses. due to these differences, some mid-main patients experience greater digital divide barriers in accessing computers and reputable, government produced consumer health information (chi) websites, such as the bc healthguide and canadian health network. inequitable access is problematic because patient empowerment is the basis of many government produced chi websites. an internet terminal was introduced at mid-main in the summer of 2005, as part of an action research project to attempt to bridge the digital divide and make government produced chi resources useful to a broad array of patients. multi-level interventions in co-operation with patients, with the clinic and eventually government ministries were envisioned to meet this goal. the idea of implementing multi-level interventions was adopted to counter the tendency in interactive design to implement a universal solution for the 'ideal' end-user [ 1 ), which discounts diversity. to design and execute the interventions, various action-oriented and ethnographic methods were employed before and during the implementation of the internet terminal. upon the introduction of the internet terminal, participant observation and interviews were conducted using a motion capture software program to record a digital video and audio track of patients' internet sessions. this research provided insight into the spectrum of patients' capacities to use technology to fulfil their health information needs and become empowered. at the mid-main clinic it is noteworthy that the most significant intervention to enhance the usefulness of chi websites for patients appeared to be a human rather than a technological presence. as demonstrated in other ethnographic research of community internet access, technical support and capacity building is a significant component of empowerment (2). the mid-main wired waiting room project indicates that medical practitioners, medical administrators, and human intermediaries remain integral to making chi websites useful to patients and their potential empowerment. (1) over the past 5 years the environmental yo~th alliance has been of~ering a.youth as~t. mappin~ program which trains young people in community research and evaluation. wh1~st the positive expenenc~ and relationships that have developed over this time attest to the success of this program, no evaluations has yet been undertaken to find out what works for t.he youth, what ~ould be changed, and what long term outcomes this approach offers for the youth, their local community, and urban governance. these topics will be shared and discussed to help other community disorganizing and uncials governments build better, youth-driven structures in the places they live.p7-55 (a) the world trade center health registry: a unique resource for urban health researchers deborah walker, lorna thorpe, mark farfel, erin gregg, and robert brackbill introduction: the world trade center health registry (wfchr) was developed as a public health response to document and evaluate the long-term physical and mental health effects of the 9/11 disaster on a large, diverse population. over 71,000 people completed a wfchr enrollment baseline survey, creating the largest u.s. health registry. while studies have begun to characterize 9/11 bealth impacts, questions on long-term impacts remain that require additional studies involving carefully selected populations, long-term follow-up and appropriate physical exams and laboratory tests. wtchr provides an exposed population directory valuable for such studies with features that make ita unique resource: (a) a large diverse population of residents, school children/staff, people in lower man· hattan on 9/11 including occupants of damaged/destroyed buildings, and rescue/recovery/cleanup work· ers; (b) consent by 91 % of enrollees to receive information about 9/11-related health studies; (c) represenration of many groups not well-studied by other researchers; (c) email addresses of 62% of enrollees; (d) 30% of enrollees recruited from lists with denominator estimates; and (e) available com· parison data for nyc residents. wfchr strives to maintain up-to-date contact information for all enrollees, an interested pool of potential study participants. follow-up surveys are planned.methods: to promote the wtchr as a public health resource, guidelines for external researcher.; were developed and posted on (www.wtcregistry.org) which include a short application form, a twopage proposal and documentation of irb approval. proposals are limited to medical, public health, or other scientific research. researchers can request de-identified baseline data or have dohmh send information about their studies to selected wfchr enrollees via mail or email. applications are scored by the wtchr review committee, comprised of representatives from dohmh, the agency for toxic subst~nces and disease registry, and wtchr's scientific, community and labor advisory committees. a data file users manual will be available in early fall 2005.~suits: three external applications have been approved in 2005, including one &om a non-u.s. ~esearcher, all requesting information to be sent to selected wtchr enrollees. the one completed mail· mg~~ wtchr enrollee~ (o 3,700 wfc tower evacuees) generated a positive survey response rate. three additional researchers mtend to submit applications in 2005. wfchr encourages collaborations between researchers and labor and community leaders.conclusion: studies involving wtchr enrollees will provide vital information about the long· term health consequences of 9/11. wtchr-related research can inform communities, researcher.;, policy makers, health care providers and public health officials examining and reacting to 9111 and other disasters. t .,. dp'"f'osed: thi is presentation will discuss the findings of attitudes toward the repeat male client iden· 1 ie as su1e1 a and substance us'n p · · · · i · 'd . . -1 g. articipants will learn about some identified effective strategies or service prov1 ers to assist this group of i · f men are oft · d bl men. n emergency care settings, studies show that this group 0 en viewe as pro emaric patient d i r for mental health p bl h h 5 an are more ikely to be discharged without an assessmen 200!) ea 1 1 rofr ems t. an or er, more cooperative patients (forster and wu 2002· hickey er al., · r y resu ts om this study suggest th · · ' ' l · d tel' mining how best to h 1 . d 1 at negative amtudes towards patients, difficu nes e · as well pathways l_e_ p patientsblan ~ck of conrinuity of care influence pathways to mental health care. • uc\:ome pro emat1c when p ti k · che system. m a ems present repeatedly and become "get stuc id methods: semi-structured intervie d . · (n=5), ed nurses (n=5) other ed ;s were con ucted with male ed patients (n=25), ed phys1oans ' sta (n= 7) and family physicians (n= 7). patients also completed a poster sessions v175 diagnostic interview. interviews were tape-recorded, transcribed verbatim and managed using n6. transcripts were coded using an iterative process and memos prepared capture emergent themes. ethics approval was obtained and all participants signed a detailed informed consent form.introduction: urban settings are particularly susceptible to the emergence and rapid spread of nt•w or rare diseases. the emergence of infectious diseases such as sars and increasing concerns over the next influenza pandemic has heightened interest in developing and using a surveillance systt·m which detects emerging public health problems early. syndromic surveillance systems, which use data b,1scd on symptoms rather than disease, offer substantial potential for this by providing near-real-rime data which are linked to an automated warning system. in toronto, we are piloting syndromic data from the 911 · emergency medical services (ems) database to examine how this information can be used on an ongoing basis for the early detection of syndromes including heat-related illness (hri), and influenza-like-illness (ill). this presentation will provide an outline of the planned desi_gn of this system and proposed evaluation. for one year, 911 call codes which reflect heat-related illness or influenza-like-illness will be selected and searched for daily using software with a multifactorial algorithm. calls will he stratified by call code, extracted from the 911-ems database and transferred electronically to toronto public health. the data will be analyzed for clusters and aberrations from the expected with the realtime outbreak and disease surveillance (rods) system, a computer-based public health tool for the early detection of disease outbreaks. this 911-ems surveillance system will be assessed in terms of its specificity and sensitivity through comparisons with the well-established tracking systems already in place for hr! and ill. others sources of data including paramedic ambulance call reports of signs and . this study will introduce complementary data sources t~ the ed ch1e~ complamt an~ o~~rthe-counter pharmacy sales syndromic surveillance data currently bemg evaluated m ~ther ontar~o cltles. . syndromic surveillance is a unique approach to proactive(~ dete~tmg early c.hangesm the health status of urban communities. the proposed study aims to provide evidence of differential effectiveness through investigating the use of 911-ems call data as a source of syndromic surveillance information for hr! and ili in toronto. introduction: there is strong evidence that primary care interventions, including screening, brief advi<:e, treatment referral and pharmacotherapy are effective in reducing morbidity and mortality caused by substance abuse. yet physicians are poor at intervening with substance users, in part because of lack of time, training and support. this study examines the hypothesis that shared care in addictions will result in decreased substance use and improved health status of patients, as well as increased use of primary care interventions by primary care practitioners (pcps). methods: the addiction medicine service (ams) at st. joseph's health centre's family medicine department is in the process of being transformed from its current structure as a traditional consult service into a shared care model called addiction shared care (asc). the program will have three components: education, office systems and clinical shared care. as opposed to a traditional consult service, the patient will be booked with both a primary care liaison worker (pcl) and addictions physician. patients referred from community physicians, the emergency department and inpatient medical and psychiatric wards will be recruited for the study as well as pcps from the surrounding community. the target sample size is 100-150 physicians and a similar number of patients. after initial consult, patient will be recruited into the study with their consent. the shared-case model underlines the interaction and collaboration with the patient's main pcp. asc will provide them with telephone consults, advice, support and re-assessment for their patients, as well as educational sessions and materials such as newsletters and informational kits.results: the impact of this transition on our patient care and on pcp's satisfaction with the asc model is currently being evaluated through a grant provided by the ministry of health & long term care. a retrospective chart review will be conducted using information on the patient's substance use, er/clinic visits, and their health/mood status. pcp satisfaction with the program will be measured through surveys and focus groups. our cost-effectiveness analysis will calculate the overall cost of the program per patient..conclusion: this low-cost service holds promise to serve as an optimal model and strategy to improve outcomes and reduce health care utilization in addict patients. the inner city public health project introduction the inner city public health project (icphp) was desi.gned to explore new an~ innovative ways to reach marginalized inner city populations that par-t1c1pate m high health-nsk beha~1ors. much of this population struggles with poverty, addictions, mental illness and homelessness, creatmg barriers to accessing health services and receiving follow-up. this pro1ect was de~igned to evaluat~ .~e success of offering clinics in the community for testing and followup of communicable diseases uuhzmg an aboriginal outreach worker to build relationships with individuals and agencies. v1n(demographics~ history ~f testi~g ~nd immunization and participation in various health-risk behaviors), records of tesnng and 1mmumzat1ons, and mterviews with partner agency and project staff after one year.. results: t~e chr ~as i~strumental in building relationships with individuals and partner agencies ' .° the c~mmun_1~ re_sultmg m req~ests for on-site outreach clinics from many of the agencies. the increase m parnc1pat10n, the chr mvolvement in the community, and the positive feedback from the agen? staff de~onstrated that.the project was successfully creating partnerships and becoming increasingly integrated m the community. data collected from clients at the initial visit indicated that the project was reaching its target populations and highlighted the unique health needs of clients, the large unmet need for health services and the barriers that exist to accessing those services. ~usion: the outreach clinics were successful at providing services to target populations of high health-nsk groups and had great support from the community agencies. the role of the chr was critical to the success of the project and proved the value of this category of health care worker in an urban aboriginal population. the unmet health needs of this disadvantaged population support the need for more dedicated resources with an emphasis on reducing access barriers. building a caring community old strathcona's whyte avenue, a district in edmonton, brought concern about increases in the population of panhandlers, street people and homeless persons to the attention of all levels of government. the issue was not only the problems of homelessness and related issues, but feelings of insecurity and disempowerment by the neighbourhood residents and businesses. their concerns were acknowledged, and civic support was offered, but it was up to the community itself to solve the problem. within a year of those meetings, an adult outreach worker program was created. the outreach worker, meets people in their own environments, including river valley camps. she provides wrap-around services rooted in harm reduction and health promotion principles. her relationship-based practice establishes the trust for helping clients with appropriate housing, physical and/or mental health issues, who have little or no income and family support to transition from homelessness. the program is an excellent example of collaboration that has been established with the businesses, community residents, community associations, churches, municiple services, and inner-city agencies such as boyle street community services. statistics are tracked using the canadian outcomes research institute homes database, and feedback from participants, including people who are street involved. this includes an annual general meeting for community and people who are homeless. the program's holistic approach to serving the homeless population has been integral, both in creating community awareness and equipping residents and businesses to effectively interact with people who are homeless. through this community development work, the outreach worker engages old strathcona in meeting the financial and material needs of the marginalized community. the success of this program has been surprising -the fact is that homeless people's lives are being changed; one person at a time and the community has been changed in how they view and treat those without homes. over two years, the program has successfully connected with approximately seventy-five individuals who call old strathcona home, but are homeless. thirty-six individuals are now in homes, while numerous others have been assisted in obtaining a healthier and safer lifestyles by becoming connected with other social/health agencies. the program highlights the roots of homelessness, barriers to change and requirements for success. it has been a thriving program and a model that works by showing how a caring community has rallied together to achieve prosperous outcomes. the spn has created models of tb service delivery to be used m part~ers~1p with phannaceunca compa-. · · -. t' ns cooperatives and health maintenance orgamzanons (hmos). for example, the mes, c1v1c orgamza 10 , . · b tb d' · spn has established a system with pharmaceutical companies that help patients to uy me 1cmes at a special discounted rate. this scheme also allows patients to get a free one-_month's worth of~ dru_g supply if they purchase the first 5 months of their regimen. the sy_s~e~s were ~es1gned to be cm~pattble with existing policies for recording and documentation of the ph1hppme national tuberculosis program (ntp). aside from that, stakeholders were also encouraged to be dots-enabled through the use of m~nual~ and on-line training courses. the spn initiative offers an alternative in easing the burden of tb sc:rv1ce delivery from rhe public sector through the harnessing of existing private-sector (dsos). the learnmgs from the spn experience would benefit groups from other locales that _work no~ only on ~ but other health concerns as well. the spn experience showcases how well-coordinated private sector involvements help promote social justice in health delivery in urban communities.p7-63 (c) young people in control; doing it safe. the safe sex comedy juan walter and pepijn v. empelen introduction: high prevalence of chlamydia and gonorrhoea have been reported among migrants youth in amsterdam, originating from the dutch antilles, suriname and sub-sahara africa. in addition, these groups also have high rates of teenage-pregnancy (stuart, 2002) and abortions (rademakers 1995), indicating unsafe sexual behaviour of these young people. young people (aged 12 -30) from the so· called urban scene (young trendsetters in r&b/hip hop music and lifestyle) in amsterdam have been approached by the municipal health service (mhs) to collaborate on a safe sex project. their input was to use comedy as vehicle to get the message a cross. for the mhs this collaboration was a valuable opportunity to reach a hard-to-reach group.mdhods: first we conducted a need assessment by means of a online survey to assess basic knowledge and to similtaneously examine issues of interest concerning sex, sexuality, safer sex and the opposite sex. second, a small literature study was conducted about elements and essential conditions for succesful entertainment & education (e&e) (bouman 1999), with as most important condition to ensure that the message is realistic (buckingham & bragg, 2003) . third a program plan was developed aiming at enhancing the stl/hiv and sexuality knowledge of the young people and addressing communication and educational skills, by means of drama. subsequently a safe sex comedy show was developed, with as main topics: being in love, sexuality, empowerment, stigma, sti, hivand safer sex. the messages where carried by a mix of video presentation, stand up comedy, spoken word, rap and dance.results: there have been two safe sex comedy shows. the attendance was good; the group was divers' with an age range between 14 and 50 year, with the majority being younger than 25 year. more women than men attended the show. the story lines were considered realistic and most of the audients recognised the situations displayed. eighty percent of the audients found the show entertaining and 60% found it edm:arional. from this 60%, one third considers the information as new. almost all respondents pointed our that they would promote this show to their friends.con.clusion: the s.h<_>w reached the hard-to-reach group of young people out of the urban scene and was cons1d_ered entert~mmg, educational and realistic. in addition, the program was able in addressing important issues, and impacted on the percieved personal risk of acquiring an sti when not using condoms, as well as on basic knowledge about stl's. introduction: modernity has contributed mightily to the marginality of adults who live with mental illnesses and the subsequent denial of opportunities to them. limited access to social, vocational, educational, and residential opportunities exacerbates their disenfranchisement, strengthening the stigma that has been associated with mental illness in western society, and resulting in the denial of their basic human rights and their exclusion from active participation in civil society. the clubhouse approach tn recovery has led to the reduction of both marginality and stigma in every locale in which it has been implemented judiciously. its elucidation via the prism of social justice principles will lead to a deeper appreciation of its efficacy and relevance to an array of settings. methods: a review of the literature on social justice and mental health was conducted to determine core principles and relationships between the concepts. in particular, fondacaro and weinberg's (2002) conceptualization of social justice in community psychology suggests the desirability of the clubhouse approach in community mental health practice. a review of clubhouse philosophy and practice has led to the inescapable conclusion that there is a strong connection between clubhouse philosophy-which represents a unique approach co recovery--and social justice principles. placing this highly effective model of community mental health practice within the context of these principles is long overdue. via textual analysis, we will glean the principles of social justice inherent in the rich trove of clubhouse literature, particularly the international standards of clubhouse development.results: fondacarao and weinberg highlight three primary social justice themes within their community psychology framework: prevention and health promotion; empowerment, and a critical pnsp<"<·tive. utilizing the prescriptive principles that inform every detail of clubhouse development and th<" movement toward recovery for individuals at a fully-realized clubhouse, this presentation asserts that both clubhouse philosophy and practice embody these social justice themes, promote human rights, and empower clubhouse members, individuals who live with mental illnesses, to achieve a level of wdl-heing and productivity previously unimagined.conclusion: a social justice framework is critical to and enhances an understanding of the clubhouse model. this model creates inclusive communities that lead to opportunities for full partic1pil!ion 111 civil society of a previously marginalized group. the implication is that clubhouses that an· based on the international standards for clubhouse programs offer an effective intervention strategy to guarantee the human rights of a sizable, worthy, and earnest group of citizens. to a drastic increase in school enrollment from 5.9 million in 2002 to 7.5 million in 200.s. however, while gross enrollment rates increased to 104°/., in the whole country after the introduction of fpe, it remained conspicuously low at 62% in the capital city, nairobi. nairobi city's enrollment rate is lower .than thatof all regions in the country except the nomadic north-eastern province. !h.e.d1sadvantage of children bas_ed in the capital city was also noted in uganda after the introduction of fpe m the late 1990s_-many_ education experts in kenya attribute the city's poor performance to the high propornon of children hvmg m slums, which are grossly underserved as far as social services are concerned. this paper ~xammes the impact of fpe and explores reasons for poor enrollment in informal settlements m na1rob1 city. methods: the study utilizes quantitative and qualitative schooling data from the longitudinal health and demographic study being implemented by the african population and health research center in two informal settlements in nairobi. descriptive statistics are used to depict trends in enrollment rates for children aged 5-19 years in slum settlements for the period 2000-2005. results: the results show that school enrollment has surprisingly steadily declined for children aged 15-19 while it increased marginally for those aged 6-14. the number of new enrollments (among those aged 5 years) did not change much between 2001 and 2004 while it declined consistently among those aged 6-9 since 2002. these results show that the underlying reasons for poor school attendance in poverty-stricken populations go far beyond the lack of school fees. indeed, the results show that lack of finances (for uniform, transportation, and scholastic materials) has continued to be a key barrier to schooling for many children in slums. furthermore, slum children have not benefited from fpe because they mostly attend informal schools since they do not have access to government schools where the policy is being implemented.conclusion: the results show the need for equity considerations in the design and implementation of the fpe program in kenya. without paying particular attention to the schooling needs of the urban poor children, the millennium development goal aimed at achieving universal primary education will remain but a pipe dream for the rapidly increasing number of children living in poor urban neighborhoods.ps-04 (c) programing for hiv/aids in the urban workplace: issues and insights joseph kamoga hiv/aids has had a major effect on the workforce. according to !lo 35million persons who are engaged in some form of production are affectefd by hiv/aids. the working class mises out on programs that take place in communities, yet in a number of jobs, there are high risks to hiv infection. working persons sopend much of their active life time in workplaces and that is where they start getting involved in risky behaviour putting entire families at risk. and when they are infected with hiv, working people face high levels of seclusion, stigmatisation and some miss out on benefits especially in countries where there are no strong workplace programs. adressing hiv/aids in the workplace is key for sucessfull responses. this paper presents a case for workplace programing; the needs, issues and recommendations especially for urban places in developing countries where the private sector workers face major challenges. key: cord-022653-qa1uph35 authors: nan title: poster discussion session pds date: 2017-08-30 journal: allergy doi: 10.1111/all.13251 sha: doc_id: 22653 cord_uid: qa1uph35 nan objectives: since bradykinin is a short-lived, low-abundance mediator in the systemic circulation, the discovery of additional biochemical biomarkers correlating hae disease activity with contact system dysregulation may be useful for further elucidation of hae pathophysiology and pharmacodynamic therapeutic modulation of the contact system. results: activated pkal cleaves single chain high molecular weight kininogen to generate bradykinin and cleaved 2chain hmwk. cleaved 2-chain hmwk was measured in human plasma using both a semi-quantitative western blot assay with fluorescent detection (licor) and a novel elisa with a capture antibody that specifically binds 2-chain hmwk. the western blot assay was previously used to monitor pharmacodynamic activity in hae patients treated with lanadelumab, a fully human antibody inhibitor of pkal that is in clinical development for hae attack prophylaxis. lanadelumab inhibited 2-chain hmwk generation following contact system activation in vitro, confirming that 2-chain hmwk is a product of pkal activity. plasma 2-chain hmwk levels from hae patients during or between attacks were compared to that from healthy volunteers using both the western blot assay and elisa. roc curve analyses with both methods suggest that 2-chain hmwk is a trait-specific biomarker capable of differentiating hae patients from healthy volunteers. the elisa was able to differentiate samples from hae patients collected during an attack from those collected between attacks with moderate sensitivity and specificity (c-statis-tic=0.8176). a comparison of 2-chain hmwk levels in citrated plasma versus plasma that contains protease inhibitors (scat169 plasma) provides estimates of endogenous versus ex vivo activation. the measurement of 2-chain hmwk using the specific assays described may find use in further dissecting the role of the contact system in disease pathology, to identify additional indications for modulators of this pathway, and to investigate therapeutics targeting the contact system. 0206 | g protein coupled receptor kinase 2 (grk2) regulates endothelial permeability induced by bradykinin 0208 | pharmacokinetics (pk) and pharmacodynamics (pd) of c1 esterase inhibitor of chronic urticaria challenges most commonly identified were the following: time of onset of disease; frequency/duration of and provoking factors for wheals; diurnal variation; occurrence in relation to weekends, holidays, and foreign travel; shape, size, and distribution of wheals; associated angioedema; associated subjective symptoms of lesions; family and personal history regarding urticaria, atopy; previous or current allergies, infections, internal diseases, or other possible causes; psychosomatic and psychiatric diseases; surgical implantations and events during surgery; gastric/ intestinal problems; induction by physical agents or exercise; use of drugs; food allergies; relationship to the menstrual cycle; smoking habits; type of work, hobbies; stress; quality of life and emotional impact; previous therapy and response to therapy, and previous diagnostic procedures/results. we included all of these aspects in our guide and as a result we developed a chronic urticaria check list. conclusions: our guide of clinical history for chronic urticaria (gur) contributes to have an easy tool in order to achieve a better diagnosis and evaluation of chronic urticaria. 0213 | clinical and diagnostic features in acquired cold urticaria patients in a coruña sanitary area, spain physicians and dermatologists/allergists; c/sa patients were more likely to visit dermatologists/allergists (51% vs. 47%) and less likely to visit general physicians (32% vs. 57%) than european patients. emergency room visits due to cu were more common in c/sa (40%, mean [sd] number=23.2 [124.3] ) than europe (29%, mean [sd] number=3.7 [11.4] ). conversely, hospital admissions due to cu were more likely to occur in europe (22%) than c/sa (8%), but the average (sd) number of admissions among those hospitalised was greater in c/sa (3.3 [4.7] vs. 2.0 [3.1]). variations were seen in subregion comparisons. mean (sd) overall wpai scores were 7.0 (18.9), 25. 1 (26.8), 27.3 (28.5), and 33.3 (30.8) for absenteeism, presenteeism, work productivity loss, and activity impairment, respectively; patients in c/sa reported a higher rate of impairment (range, 13%-36%) on all domains compared with patients in europe. conclusions: cu is associated with substantial hru and work and activity impairment in both europe and c/sa. general physicians should be considered key members of the treatment team in the care of patients with cu in these regions. objectives: cu patients (n=15) received monthly subcutaneous injections of omalizumab for up to six months. urticaria-related symptoms were assessed by both the urticaria control test (uct) and the chronic urticaria quality of life score (cu-q 2 ol). peripheral blood was drawn prior to each injection for determining the concentration-dependent reactivity of patients' basophils to specific anti-fceri and unspecific fmlp stimulation by basophil activation test. furthermore, the impact of anti-ige treatment on ige-bearing cell populations was characterized by flow cytometry analyzing the surface expression of both fceri (e.g. on monocytes, dendritic cells, basophils) and the low-affinity receptor for ige, fcerii (e.g. on b cells, eosinophils). results: anti-ige treatment of cu patients significantly improved clinical symptoms of cu already after the first injection as evaluated by cu-q 2 ol and uct, the latter of which correlated with an increase of basophil numbers and a decrease of basophil surface bound ige. of note, cell-bound ige on fcerii-expressing cells was not altered. furthermore, while clinical amelioration also was accompanied by reduced fceri expression on basophils, the basophil responsiveness to anti-fceri stimulation increased in 73% (11/15) of treated patients. in contrast, ige-independent activation of basophils by fmlp was unchanged. conclusions: clinical improvement of cu patients treated with omalizumab is associated with characteristic immune alterations in basophils, like rapid, cell-specific reduction of surface bound ige and fceri-expression as well as normalization of basophil responsiveness to fceri-stimulation. while our findings might help to better understand the mode of action of anti-ige therapy in cu, they also can shed new light on the pathomechanisms underlying cu. 0216 | omalizumab in patients with severe active chronic spontaneous urticaria (csu) heavily treated with corticosteroids and cyclosporine introduction: increased levels of blood d-dimers (d-d), the byproducts of fibrin degradation, is linked to the severity of chronic spontaneous urticaria (csu) and to poor response to antihistamines h1 (ah1). omalizumab (oma) is a human monoclonal anti-immunoglobulin-e antibody registered as an add-on treatment of csu in adults and adolescent (≥ 12 years old) and with insufficient response to ah1. the sunrise study assessed the efficacy of omalizumab on csu symptoms and the correlation between d-d levels and response over time to treatment with oma to explore its potential predictive value. objectives: sunrise was a french prospective non comparative phase 4 study. included patients had to have been diagnosed with csu for at least 6 months, be resistant to ah1 treatment, and have a uct score (assessed by patient over the 4 last weeks, values from 0 (maximal disease)to 16 (full control)) <8, indicative of a poorly controlled disease. the widely used uas score (assessed by patients over 1 week which captures intensity of pruritus and number of hives, values ranging from 0 (no disease) to 42 (severe disease)) was further used to evaluate the proportion of patients achieving a well controlled disease(uas≤6). all patients received 300 mg oma by sub-cutaneous injections at day 0, weeks (w) 4 and 8. blood levels of d-d were assessed (turbidimetric immunoassay) at d0, w4 and w8. response to treatment was evaluated at w12 by means of the uas7. results: median level of d-d assessed at d0 in 112 patients was increased at baseline (618 ng/ml, extremes 108-5170) and normalized as early as w4 reaching 286 ng/ml (108-481) at w8. correlation between d-d concentration and uas7 score at w12 was weakly positive (spearman coefficient 0.108). among the 10 patients with a very high baseline de d-d level (>3000 ng/ml) 8 were responder (uas7≤6) at w12. conclusions: baseline d-d levels were increased in more than half of patients of this study in line with relevant literature. a fast normalization was observed with oma as early as w4 of treatment. d-d levels at w8 were weakly correlated with uas7. subgroup analyses may help to better understand the link between d-d and clinical response, as these preliminary results do not yet allow the predictive use as a biomarker. the sunrise study explored for the first time in a prospective way the impact of oma on dd and found weak correlations were measured between dd level and response to oma. further studies will be needed to evaluate its predictive value for response. (crp, esr, il-6, il-10, il-33, ccl2/mcp-1), and the disease severity in patients with chronic spontaneous urticaria introduction: pru p 3 is the primary sensitizer of some fruits and responsible for severe reactions in the mediterranean area. sublingual immunotherapy (slit) using peach extract enriched in pru p 3 (prup3-enriched-slit) brings a new perspective to treat patients with reactions to peach considering that currently the treatment of the allergy to peach is based on avoidable ingestion of fruit. we performed a pilot study to examine the immune modulation by slit in patients with peach allergy over a 1-year treatment period. objectives: we aimed to evaluate the effect of the slit during one year in patients with peach allergy. we analysed the capacity pru p 3enriched-slit to modulate immune response, from a th2 to th1 response with increases of treg cells. we studied three groups of subjects: peach allergic patients who received prup3-enriched-slit for 1 year, peach allergic patients non treated, and healthy controls who tolerated peach. monocyte-derived dendritic cells (dcs) maturation, peripheral blood mononuclear cell phenotype and lymphocyte proliferation after prup3 stimulation were assessed by flow cytometry from samples obtained before, and 1, 6 and 12 months during slit. results: we found statistically significant differences in dcs activation and maturation between allergic patients and controls at the basal state. when we analyzed the effect of prup3-enriched-slit over time, we found a significant reduction of activation and maturation markers (ccr7, cd40, cd80, cd83 and cd86) at the first month of treatment that was maintained after 1 year. concerning lymphocytes, we observed a significant decrease of effector cells immune cells. recent studies showed that fructo-oligosaccharides (fos) increase the efficacy of oral immunotherapy (oit) in a mouse model for cow's milk allergy, however, the mechanism is unknown. objectives: investigating the effect of oit+fos on the effector response and the process of tolerance induction. methods: female c3h/heouj mice (5-6 weeks old, n=8/group) were sensitized to the cow's milk protein whey (20 mg in pbs, intragastrically (i.g.)) with cholera toxin (15 lg) once a week for 5 weeks (d0-d28). the mice received a diet with 1% fos or a control diet from d35-d70. oit (10 mg in pbs or pbs) was provided 5 days a week for 3 weeks (d41-d59). intradermal (i.d.) and i.g. challenges were performed to measure the acute allergic response. serum, bone marrow, caecum content, small intestines and mesenteric lymph nodes (mln) were collected at d50, d63 and d70. spleen-derived t cell fractions (whole spleen, cd4+cd25-and cd4+cd25+, using macs) were transferred to na€ ıve recipient mice at d70. the recipients were sensitized and challenged as described for the donor mice. conclusions: this study shows that oit+fos results in an early induction of functional tregs and a reduction of mast cell degranulation upon challenge. the latter may be caused by inhibition of mast cell activation by galectin-9 and/or butyric acid. moreover, the effect of fos on bone marrow suggests possible epigenetic changes reducing development of mast cells. further research is needed to investigate if this approach may be of potential value to treat food allergies. 0348 | safety and feasibility of slow low-dose oral immunotherapy sugiura s; kitamura k; tajima n; takasato y; kato t; tajima i; ono m; tagami k; sakai k; nakagawa t; ito k aichi children's health and medical center, obu, japan introduction: slow low-dose oral immunotherapy (sloit) is an ongoing clinical trial conducted in our institute (umin registry number 000017416). this is a type of oral immunotherapy with a low dose antigen increased very slowly. objectives: to evaluate the safety and feasibility of the protocol. results: sloit enrolled the patients who were diagnosed as severe egg, milk or wheat allergies, with a threshold dose of 5 g (or ml) or less in the oral food challenge (ofc, 20-minutes boiled egg white, whole milk, udon noodle). subjects were divided into two groups, intervention (sloit) group or elimination (control) group, based on their preference. sloit group began to ingest 1/2 to 1/10 amount of the final dose of the ofc based on the severity of provoked symptoms. intake was continued everyday with an increasing dose less than 1.5 times/ month, expecting a 10 times increase from the starting dose after 12 months. feasibility was evaluated based on the proportion of patients who complied the protocol. safety was evaluated based on the frequency of immediate allergic reactions observed in the programmed intakes. fifty-nine patients were enrolled from april to december 2015, and 36 of them (egg: 23, milk: 4, wheat: 9) preferred the sloit group. among them, 11 patients (30.6%) dropped out from the study protocol because of provoked allergic symptoms (n=2) or the other personal reasons (n=9). among a total of 7090 ingestions by 25 patients who continued the protocol over 10 months, mild symptoms were observed 25 times (0.35%), to which rescue medicine such as oral antihistamines was used in 9 cases (0.13%). no one needed an emergency visit or an adrenalin auto-injector. low threshold dose at the initial ofc (1.0 g or less, n=16) was associated with higher proportion of provoked allergic symptoms in the protocol (low threshold: 0.50%, non-low threshold: 0.12%, p=.019). the level of specific ige titer was not associated with the safety. conclusions: sloit protocol has sufficient safety and feasibility, but low threshold patients should be monitored closely. the efficacy of this protocol is being evaluated by an ofc after 12-15 months of the treatment, and the overall data will be presented after march 2018. objectives: the aim of this phase i, randomized, non-controlled, multicenter, opened, with parallel groups clinical trial, is to evaluate the safety and tolerability of subcutaneous immunotherapy (scit), in a polymerized mixture (100/100) depot presentation. patients with rhino-conjunctivitis polysensitized to olea europaea/ phleum pratense received a schedule consisting of two weeks of initiation with three weekly injections; or a program comprising two administrations in the same day separated by 30 minutes. both treatments continued with a maintenance period of three months with a monthly administration. the primary outcomes are the number, percentage, and severity of adverse reactions. secondary endpoint included subrogate efficacy parameters evaluation: changes in immunoglobulin titers (specific ige, igg and igg4) and changes in cutaneous reactivity at different concentrations. 2 systemic reactions were registered, representing 4.3% of the included patients: one grade 0, described as general discomfort plus dizziness and one grade i, such as rhinoconjunctivitis. there were no local reactions. all were classified as of mild intensity and took place with the cluster schedule. symptomatic treatment was not required. conclusions: both schedules with polymerized mixture of phleum pratense/olea europaea, (100/100), presented a good safety and tolerability. a statistically significant decrease in cutaneous reactivity to olive and grass allergens was observed after immunotherapy. 0351a | design of the pivotal phase iii study to assess the efficacy and safety of subcutaneous hdm allergoid immunotherapy in patients with hdm induced allergic rhinitis/ rhinoconjunctivitis introduction: in order to comply with ema guidelines on development of allergen immunotherapy products, a clinical development program was started to obtain full marketing authorization for a allergoid subcutaneous immunotherapy (scit) product for the treatment of house dust mite (hdm) allergy. previously, the safety and tolerability of increasing doses of this allergoid scit product was evaluated in patients with hdm-induced allergic rhinitis/rhinoconjunctivitis (arc) [eudract 2008-006261-81] . no safety or tolerability issues were identified for doses up to 40 000 aueq. subsequently, a dose-finding study to identify the optimal, i.e. effective and safe dose in hdm arc with or without concomitant asthma was performed [eudract 2011-000393-61; pfaar, allergy 2016] . this study demonstrated a dose response relationship with doses of 10 000 aueq (0.5 ml of 20 000 aueq/ml) up to 50 000 aueq (0.5 ml of 100 000 aueq/ml) showing significant improvements compared to placebo. the current pivotal phase iii study [eudract 2016-000051-27] aims to confirm safety and efficacy of this hdm allergoid scit product at a dose level of 50 000 aueq/ml (0.5 ml) compared to placebo after one year of treatment in patients with hdm-induced arc. objectives: the current study is a multi-center (80 clinical study centers in 7 european countries) randomized, double-blind, placebocontrolled, parallel-group study in 730 adult patients, with moderate to severe hdm induced arc with or without mild to moderate persistent asthma. the primary outcome of the study is the difference in mean combined symptom and medication score (nasal symptoms only) (csms (n)) between 50 000 aueq/ml allergoid scit and placebo treatment, assessed during the last 8 weeks of the approximately 1 year treatment period. results: 211 patients from 14 centers, (mean age 32.9 years) have been included and analyzed. the 49.8% are men, 65.9% presented associated asthma. a large majority of patients have received subcutaneous sit (98.6%), and 58.8% of them containing a single allergenic source. 55.8% in polymerized formulation and 40.9% in depot. accelerated schedule has been the most prescribed (56.9%), followed by clustered one (32.2%). from the 81 patients who have completed the study, 45.7% of them improved from persistent to intermittent rhinoconjunctivitis (p<.01) and 49.4% from moderate/severe to mild intensity (aria) (p<.01). moreover, 21% of asthmatic patients at baseline, did not have any bronchial symptoms after 1-year treatment. the improvement in quality of life was possible to be analyzed in 53 patients. mean values in rqlq questionnaire (total score) decreased from 3.1 to 1.5 points (51.6% of score reduction) in final visit, reflecting a statistically significant improvement (p<.01). mean value of treatment satisfaction was 7.3 (sd=1.7) and 7.2 (sd=1.9) for physician and patients respectively. for safety assessment, out of 199 analyzed patients, only 8 systemic reactions were reported in 8 patients (4.02%). seven of them were classified as grade i, and one as grade ii according to eaaci grading system. strasbourg is a 147 m 3 chamber, located into the university hospital of strasbourg at less than to 5 minutes to the intensive care unit. one of the characteristics of this unit is that the maximum parameters are controlled: temperature, relative humidity, ventilation rate, particles number and particles size, concentration of airborne of der p 1 and airborne voc. mite allergens extract were nebulized through a nebulizer. airborne der p1 concentrations were sampled using 5 glass fiber filters and measured with an elisa assay. particles number and particles size were monitored continuously during nebulization, using 10 particles counters distributed inside the exposure room. the cleaning process was also controlled and validated. objectives: to validate the technical parameters of the environmental exposure chamber (eec) of strasbourg with mite allergens. results: the reproducibility was excellent for the indoor temperature, relative humidity and airflow (5 cv interassay <20%). three concentrations of der p1 were measured: 63, 76, 105 ng/m 3 (n=45). for all 3 concentrations, the cv intra-assay of airborne der p1 was 22ae1.3%, the interassay was less than 30%. for the particle size 0.5-5 and 5-10 lm, the cv interassay was 8 and 13%, respectively (n=19). the cv of the mmad was 2.2% (n=10). no measurable airborne der p1 was detected in the toilets and the medical supervision room (n=6) neither in the exposure room 10 minutes after the end of the allergen exposure (n=9). no airborne voc was measured in the chamber and the other rooms of the clinical unit (n=10). there was no significant change in particles size and number when 2 to 6 persons entered the room (n=4). introduction: pathogenesis of systemic sclerosis (ssc) includes vasculopathy with endothelial dysfunction which is considered to be one of the earliest changes in the pathogenesis of ssc. several biological molecules, including e-selectin (e-sel), inter-cellular adhesion molecule 1 (icam-1), endothelin 1 (et-1), von willebrand factor (vwf) and interleukin 6 (il-6) have been associated with endothelial activation. objectives: we aimed to determine if these vascular biomarkers are associated with distinct capillaroscopic ssc patterns and/or more severe disease in ssc patients. results: correlations between serum levels of all 5 vascular biomarkers were good to moderate and statistically significant, with r indices varying between 0.660 and 0.332, the only exception being et-1 which did not correlate with e-sel. good correlations (r 0.465 to 0.727) were also found between all 5 biomarkers and crp. patients with severe vasculopathy, as reflected by the nfc "late" pattern, had higher levels of il-6 (median 12.06 vs 3.08 pg/ml, p=.001), et-1 (median 2.06 vs 1.59 pg/ml, p=.029), vwf (median 3284 vs 2730 iu/ml, p=.013) and e-sel (median 52.6 vs 42.3 ng/ml, p>.05), compared to patients with nfc "early" or "active" patterns. there was a significant, negative correlation between lung transfer for carbon monoxide (dlco) and e-sel, icam-1 (both p<.001) and vwf (p=.013). et-1 was higher in patients with more severe disease (dcssc, patients positive for anti-topoisomerase antibodies and patients with a history of digital ulcers-all p<.05). conclusions: serum endothelial activation biomarkers are elevated in patients with more severe ssc-associated vasculopathy and correlate with serum crp. together with nfc data they may be used for assessing vasculopathy severity in ssc. objectives: here we present the imagination findings of eye involvement in a family whose 11 members have mws. method: clinical data was collected during the course of ongoing patient care. results: we evaluated the clinical features of 11 patients who were referred to our center. the median age of the patients was 25 years (range: 9-65 years). the ratio of females /males was 1.2 (6/5). all patients had arthritis with exacerbation on exposure to cold and ocular involvement, mostly in the form of conjunctivitis and far less other forms. the median age of onset of ocular involvement was 8 years (2-45 y). chronic eye damage were detected in three patients. corneal involvement and clouding was detected in four patient. two conclusions: in this study, it has been shown that eye findings related to mws can vary from conjunctivitis to severe uveitis. we want to emphasize that ocular involvement in mws should be carefully assessed, since it can lead to visual impairment. 0485 | antiretroviral activity of the conjugates 3'-azido-3'deoxythymidine and derivatives of 1,3-diacylglycerides case report: aids epidemics remain the critical problem due to both their emergent and long development. treatment of aids with azt reduces p24 antigenemia, increases cd4 + lymphocyte counts, reduces the frequency and severity of opportunistic infections and prolongs life. however, zidovudine and other dideoxynucleotides do not decrease the ability to isolate hiv from pbmc, and in addition, these drugs are very toxic. this phenomenon is caused by insufficient inhibition of hiv due to low levels of nucleoside kinases in ccr5-positive cells, including in macrophages, which are a major reservoir of hiv. potential advantages of these liponucleotide prodrugs include: greater in vivo efficacy and lower toxicity due to a greater delivery to monocytes/macrophages, ability to bypass the initial anabolic phosphorylation due to the presence of the phosphorous center in the structure, and the prospect of improved pharmacokinetics and prolonged intracellular persistence. the aim of this work is the study of cytotoxicity and anti-hiv activity of glycerolipids derivatives of azt. evaluation of the cytotoxicity of azt and test compounds was per0488 | bone mineralisation defect in patients with hax-1 deficiency 4 and osteopenia (z score <à1) in 3 patients. bone mineralisation defect was found in all female patients while only one male had osteopenia (table 1) . conclusions: in this study, a significant decrease (87.5%) of bone mineralization was observed in patients with hax-1 deficiency. female patients were found more prone to bone mineralisation defect. to conclude on this subject, more studies are needed with large number of patients having not only hax-1 deficiency but also ela-2 mutations. gene mutation age ( introduction: bronchopulmonary diseases are kept as one of the actual problems of the pediatricians. nevertheless fulfilment of several scientific works on study of these diseases, presently we meet the complication of the respiratory diseases, recurrency, changing to the chronical type. objectives: the main purpose of our work to study the cytokine status and substance p, mutual connection they in frequently ill chilresults: in fic with respiratory diseases in the acute period of the disease increase of levels proinflammatory cytokines il-1beta, il-6, il-8, tnf-alpha and substance p,decrease of levels il-2 and ifngamma was marked. clinical remission in these children is not accompanied by normalization of cytokine status and substance p. the high level of proinflammatory cytokines and substance p testifies to proceeding of inflammatory process that is possible connected with persistence of the infections agent. acute decrease in level of cytokines il-2 and ifn-gamma in these children,most likely, is caused by the presence of a immunodeficiency of cellular type. conclusions: in this connection it is necessary to carry out an adequate therapy of fic with arvi. introduction: atopic diseases are known to be characterized by a t helper (th) 2-skewed immunity. th2-skewed immunity at birth, th2-associated cc chemokine ligand (ccl)-22, appears to be associated with high total ige levels but not of allergic outcomes later in life. the prevalence of asthma increases with a rapid upward trend after age 2; however, there are few studies addressing the changes of ccl22 chemokine levels during infancy related to the development of atopic diseases in early childhood. objectives: we investigated 182 children followed up regularly at the clinic for 5 years in a birth cohort study. the levels of th2 related chemokine ccl22 were quantified in cord blood and age 1.5 by multiplex luminex kits. specific immunoglobulin e antibodies against food (egg white, milk, and wheat) and inhalant allergens (d. pteronyssinus, d. farina, and c. herbarum) were measured at 6 months as well as 1.5, 3, 4 and 5 years of age. results: a total of 125 pairs of ccl22 chemokine levels from birth to age 1.5 were recruited in this study. k-means clustering was performed using r software and package mfuzz and this resulted in 3 groups of ccl22 chemokine levels that declined from around 2000 to 500 pg/ml (cluster a, n=51), from around 1200 to 400 pg/ml (cluster b, n=46) , and raised from around 400 to 600 pg/ml (cluster c, n=28) . in children with raised ccl22 chemokine levels appeared to be associated with a higher prevalence of house dust mite sensitization at age 1.5. furthermore, raised ccl22 levels during infancy were significantly associated with higher risk of asthma at age 3 (p=.026). conclusions: raised ccl22 chemokine levels during infancy appear not only to be associated with an increase in the prevalence of house dust mite sensitization but also the risk of asthma in early childhood. 0520 | serum periostin is "not" a biomarker for pediatric asthma suzuki n 1 ; hirayama j 1 ; nagao m 1 ; kameda k 1 ; kuwabara y 1 ; kainuma k 1 ; ono j 2 ; ohta s 3 ; izuhara k 3 ; fujisawa t 1 1 mie national hospital, tsu, japan; 2 shino-test corporation, kanagawa, japan; 3 saga medical school, saga, japan introduction: periostin is a matricellular protein induced by type 2 helper t-cell cytokines, expressed by airway structural cells and is thought to contribute to airway remodeling and progressive lung function decline in severe asthma in adults. we sought a possible clinical utility of serum periostin in children with asthma. objectives: we recruited volunteer children and adolescents (age range, 3 to 17 years) who were otherwise healthy except for allergic diseases including bronchial asthma. allergic diseases were classified with isaac questionnaire and serum levels of periostin were measured with elisa. abstracts | 167 results: a total of 661 volunteers were enrolled. among them 161 had no allergic diseases (na), 215 had only allergic rhinitis (ar) and the rest of 285 had bronchial asthma (ba) and/or atopic dermatitis (ad) . serum levels of periostin in na younger than 15 were significantly higher than the older counterpart and the levels in children <15 years old were similar across each age. data distribution of serum periostin in ar were very similar with that in na and we defined na and ar groups as reference population. reference values, geometric mean (+2 geometric sd range), for serum periostin were 101 (179) and 82 (151) ng/ml in children/adolescents <15 and ≥15, respectively. there were no gender differences in serum periostin in the reference population. we then compared the serum levels of periostin in ad and/or ba with the reference group and found that serum periostin in ad and ad+ba, not ba, in <15 years old were significantly higher than the reference group. in addition, severity of asthma had no association with serum periostin levels in age group of <15. on the other hand, the levels in ba aged ≥15 were slightly higher than non-ba (statistically significant). conclusions: serum periostin is physiologically high in children and adolescents, possibly in growing age, and the levels are elevated in those with ad, not ba. serum periostin is "not" a useful biomarker for pediatric asthma. 0521 | clinical, biochemical and radiological factors for response to aspirin desensitization in patients with aspirin exacerbated respiratory disease-pilot study introduction: aspirin desensitization is regarded as an effective and well-tolerated therapy for patients with aspirin exacerbated respiratory disease (aerd). despite many studies investigating the pathophysiology of aerd, the underlying mechanism responsible for the beneficial effects of aspirin therapy has not yet been clarified. the aim of the study was to evaluate the influence of aspirin desensitization on clinical, biochemical and radiological changes in aerd individuals. objectives: this is a prospective study of twenty-one aerd patients subjected to one-year aspirin desensitization. all participants were hospitalized three times over the period of one year. at baseline and during each follow-up visit (2 nd and 12 th month) blood, urine, induced sputum (is) and nasal lavage (nl) were collected from all participants. the acquired material was processed in order to evaluate 1) is and nl cell count 2) concentrations of is and nl eicosanoids 3) leukotriene e4 (lte4) in urine and 4) periostin in blood. additionally, participants underwent a ct scan of the paranasal sinuses at baseline and after 12 months of aspirin therapy. the lund-mackay score values were compared. for statistical analysis, summary statistics and repeated measures anova with post-hoc test were applied. results: twenty participants completed a one-year aspirin therapy. there was a statistically significant decrease in the number (p=.007) and percentage (p=.02) of eosinophils in is between baseline and after aspirin desensitisation. significant increase of urine lte4 in the course of aspirin therapy was observed (p=.02). the levels of prostaglandins and leukotrienes in is and nl as well as blood periostin level and the differential cell count in nl did not change during aspirin desensitization. in ct scan images the regression of the lesions in paranasal sinuses was observed in 32%, the worsening in 42% and in 26% of patients no changes were noted. in is count of eosinophils in aspirin-sensitive individuals, which may potentially be used in disease monitoring and tailoring asthma therapy. aspirin desensitization did not lead to significant changes in local eicosanoid levels in is and nl. blood periostin level is not a good marker for patient's response to aspirin desensitization. introduction: one of the main severe asthma phenotype is the "severe eosinophilic" or "eosinophilic refractory" asthma, for which novel biologic agents are emerging as therapeutical options. in this context, blood eosinophils count are one of the most reliable biomarker. objectives: the aim of our study is to evaluate the performance of a point-of-care peripheral blood counter in a clinical setting of severe asthmatics. seventy-six patients with severe asthma were evaluated, for blood cells count, by both a point-of-care and a standard analyser. results: the inter-and intra-assay variation was acceptable for leukocytes, neutrophils, lymphocytes and eosinophils. this was not the case of monocytes and basophils. a significant correlation between blood eosinophils assessed by the two devices was found (r 2 = 0.854, p<.0001); similar correlations were found also for white blood cells, neutrophils and lymphocytes. the point-of-care device showed ability to predict blood eosinophils cutoffs used to select patients for biologic treatments for severe eosinophilic asthma, and the elen index, a composite score useful to predict sputum eosinophilia. introduction: over 10 years ago there was revealed periostin should play an important role in pathogenesis of allergic inflammation including asthma and processes of tissue remodeling and fibrosis. its expression has been observed in the thickened basement membrane as well as in serum of asthmatic patients. thus, measuring of periostin serum levels may shed some light on these elusive asthma features. periostin has already demonstrated a convenient value in clinical studies as a companion diagnostics for lebrikizumab, tralokinumab or omalizumab treatment. however, to date, the changes of periostin serum levels following asthma therapy except for inhaled corticosteroids remain unclear. objectives: to emphasize this issue we have collected clinical and laboratory data including serum periostin of 48 asthma patients (19 males/29 females) in a cross-sectional study. all patients were treated either by conventional therapy comprising inhaled corticosteroids (n=38) or by inhaled corticosteroids with additional biological therapy (omalizumab) (n=10). asthma phenotype, control, complications, comorbidities and other available biomarkers have been assessed and statistically analysed. results: we have observed a weak but statistically significant correlation between serum periostin and total ige levels (p=.039) and absolute eosinophil count (p=.045). association between periostin and total ige had nonlinear character (p=.007), and was expressed particularly in non-severe asthma patients without omalizumab treatment (p=.018). despite mutual correlation between serum periostin a total ige levels, both biomarkers showed different reaction on asthma treatment. multivariate analysis demonstrated, that only periostin levels, in contrast to all other assessed biomarkers, were significantly decreased in severe asthma patients treated by omalizumab (p=.013). this relationship was independent of asthma control (assessed by asthma control test -act), exacerbation rate, hrct or spirometry measurement results or comorbidities, except chronic rhinosinusitis with nasal polyps (crswnp) (p<.001). conclusions: we demonstrate, serum periostin levels are dependent on therapy, thus it may contribute not only to asthma phenotype stratification, prediction of treatment responsiveness, complications such as remodeling but probably more precise monitoring of therapy effect too. 0527 | usefulness of serum pteridines as a biomarker for childhood asthma kasuga s 1 ; hamazaki t 1 ; fujitani h 1 ; fujikawa s 1 ; niihira s 2 ; shintaku h 1 1 department of pediatrics, osaka city university graduate school of medicine, osaka, japan; 2 the national institute of special education, tokyo, japan introduction: reliable and stable biomarker of airway inflammation is essential to determine intensity of asthma treatment. exhaled nitric oxide (feno) has been introduced to assess useful marker of airway inflammation but it fluctuates depending on steroid inhalation. nitric oxide is produced by nitric oxide synthase which requires tetrahydrobiopterin (one of pteridines) as a cofactor. objectives: to assess pteridines as a biomarker of childhood asthma control. results: asthmatic children were recruited for periodical asthma checkup program in japan to assess asthma control status by using objective questionnaire, respiratory function tests, airway resistance, feno, and serum pteridine levels. serum pteridine levels were measured by high performance liquid chromatography. total 131 japanese children (4-17 years) were participated in this program. 36 children who have no asthma attack over three years were divided as remission group to evaluate the long-term asthma control. the other 95 children were divided as asthma group. furthermore, we divided asthma group for three groups by childhood asthma control test (c-act) scores to evaluate the short-term asthma control. and we had 61 age matched children as control group. pteridine levels tended to decrease in patients who showed higher feno in asthma group. asthmatic children showed lower pteridine levels than other groups. there are significant differences between control group and remission groups and asthma groups (p<.001, tukey's honestly significant difference test). but there are no significant differences between the three groups in asthma group (well-controlled group, partly-controlled groups and uncontrolled groups) which were divided by c-act scores. the low concentration of serum pteridines in children with stable asthma may indicate poor long-term control of asthma. but that not indicate poor short-term control of asthma. since pteridine biosynthesis pathways were suppressed by th2 mediated immune response, these results suggest that th2 mediated immune response was dominating the th1 response in asthmatic children. therefore, serum pteridines could be a novel biomarker of stable asthmatic children. introduction: asthma is a syndrome with chronic airway inflammation. the goal in the treatment of asthma is to control the inflammation. however, there has been a scarcity of useful noninvasive tests for monitoring the airway inflammation in clinical setting. metabolites of the eicosanoids pathways in induced sputum of the patients with asthma could be valuable biomarkers that can reflect the airway inflammation. objectives: to investigate eicosanoid metabolites and to find out their phenotypic differences, induced sputum supernatants from 37 patients with refractory asthma, 40 patients with controlled asthma, and 6 normal control subjects were analyzed by using liquid chromatography tandem mass spectrometry. in addition, we evaluated the relationship between asthma exacerbation and eicosanoid metabolites. results: among 43 metabolites which were measured, 26 metabolites were detected in the induced sputum. we found that normal control subjects had higher concentrations of prostaglandin (pg) d2 (normal subjects vs controlled asthma vs refractory asthma, median conclusions: eicosanoid profiles in induced sputum supernatant were different between patients with refractory asthma, those with controlled asthma, and normal control subjects. our findings suggest that they could be biomarkers to differentiate refractory asthma from controllable asthma or non-asthma. this work was supported by the research program funded by the korea centers for disease control and prevention (2016-er7402-00) . 0529 | serum periostin in asthma is related to disease severity, eosinophilia and il-33 introduction: introduction: asthma is a chronic inflammatory disease where more than 100 powerful inflammatory mediators are associated with airway hyperresponsiveness, mucus hypersecretion, activation of fibroblasts and hyperplasia and hypertrophy of smooth muscles of the airways and if they do not use preventive antiasthma treatment can cause irreversible airway remodeling. objectives: the aim of this study was to determine the effect of adding montelukast to combined therapy icss/labas in patients with uncontrolled asthma by analyzing of serum level of il-13, il-5, eosinophils and symptom score. methods: in study we included 29 patients, they were treated with icss/labas (500/50 mcg-twice daily) plus montelukast (10 mgdaily). in each of them were measured serum levels of il-13 and il-5 by the elisa method, value of eosinophils were obtained with visual examination of peripheral blood smear, and assessing symptom scores with 5-point likert scale of breathlessness at the beginning and after 6 months of therapy. objectives: this study has been focussed on a detailed comparison of two samplers-cyclone and chemvol-and on the parameters that could influence their efficiency. results: airborne concentrations of two key olive and grass allergens, ole e 1 and phl p 5, respectively, were monitored over two years with different weather patterns, 2012 and 2014, in c ordoba, located in south-western spain. allergenic particles were quantified by elisa assay and results were compared with pollen concentrations monitored using a hirst-type volumetric spore trap over the same study periods. the influence of weather-related parameters on local airborne pollen and allergen concentrations was also analysed. inter-year differences were observed with regard to pollen season timing and intensity. for both olive and grass, the pollen season was longer and the pollen index (pi) higher in 2014; that year the peak value was higher and it was recorded earlier. although a positive correlation was detected between results obtained using the two samplers during the pollen season, results for the cumulative annual allergen index varied considerably. the two samplers revealed a positive correlation between pollen concentrations and both minimum temperature during the warmer year (2012) and maximum temperature during the cooler year (2014); a negative significant correlation was observed in both cases with rainfall and relative humidity. conclusions: in summary, although differences were observed between the two samplers studied, both samplers may be suitable for allergen detection. objectives: the scientific council of rnsa was asked to update the allergy potency (ap) of plant species that can be established in urban areas. to update the allergy potency of plant species, the rnsa used scientific work on the subject, and also the opinions of allergists and botanists. the pollen grains of anemophilous species are transported by wind; they produce very large quantities of pollen grains so that the fertilization of female flowers has a greater chance of being effective. the majority of allergenic species are anemophilous. results: the pollen allergy potency of a plant species is the ability of its pollen to cause an allergy to a significant part of the population. the allergenic potential can be: low or negligible: no problem to plant them in urban garden moderate: only a few species can be planted in the same garden high: this species cannot be planted in urban places. the table presented on the poster will permit to know the level of allergy potency of more than 30 species. conclusions: species or genus with a strong ap should be labeled as "not to be planted in habitation or residence area ", those with moderate ap should be labeled as "not to be planted in big quantities in habitation or residence area". other species with low or negligible ap may not be affected by public information. gadermaier g 1 ; metz-favre c 2 ; stemeseder t 1 ; de blay f 2 ; pauli g 2 1 universit e de salzbourg, salzbourg, austria; 2 chru strasbourg-allergologie, strasbourg, france introduction: the purpose is to study the profile of cutaneous and molecular sensitization of patients sensitized to plantain pollen living in the north-east of france. objectives: the sera of 28 patients with seasonal pollinosis and cutaneous polysensitization including a positive test to plantain, are investigated through immunoblot (ib), elisa and immunocap. the plantain immunoblot is inhibited with plantain, grass, ash and birch pollen extracts as well as with pla l 1. the specific iges against pla l 1, phl p 1-5 and profilin are measured. results: pla l 1, the major plantain allergen is detected by ib in 10 cases out of 28, either in glycosylated or non-glycosylated form. an allergen of 35 kda is detected in 21 out of 28 cases, always and exclusively inhibited by the grass extract. the intensity of the spot is proportional to the anti-phl p 1 / phl p 5 ige levels, and corresponds to an allergen which is cross-reacting with grass. other cross-reacting allergens with grasses are detected at 30 kda (14/28), and at 50-54 kda (5/28). at the molecular weights of 15 to 17 kda, we detected in addition to pla l 1, cross-reacting allergens with grass, ash and birch pollen which predominantly corresponded to profilin which was confirmed by specific ige measurements in 20 cases. conclusions: among the patients included in this study, only 28% had genuine sensitization to plantago, which never corresponded to a monosensitization in our cohort. most often cutaneous sensitizations to plantain pollen were based on ige cross-reactivity with grass pollen allergens mainly through a 35 kda allergen and/or profilin. the strong environmental grass pollen pressure, compared to the low plantain pollen exposure, seems to be at the origin of this profile of molecular sensitization. these results reinforce the superiority of molecular diagnosis in patients with pollinosis, who are polysensitized. 0536 | sensitisation to peach tree pollen in a highly exposed population results: the 14% of subjects were sensitized to pp, which was the most prevalent after olive tree, grass and cypress pollens, respectively. sensitization to peach fruit was 8%. pru p 3 spt was tested in 30/78 pp positive cases, being 46% positive (14/30). specific ige to pru p 3 was detected in 4/10 pp sensitized individuals. immunoblot showed specific ige to different components in the pp extract, being the most frequent band recognised a 20-25 kda protein. conclusions: pp is a prevalent inhalant allergen in highly exposure areas. in our population pru p 3 was not identified as the major allergen. other pp molecular components need to be identified and their clinical relevance should be further investigated. introduction: allergic respiratory diseases increase after an exposure to airborne pollen, as asthma and allergic rhinitis, are deeply increasing and nowadays, they represent one of the major public health problems. olive pollen is one of the main causes of allergic disease in the mediterranean area, especially in northwest and west of the turkey. olive pollen has been characterized 20 proteins with allergic activity and ole e 1 is the major allergen of olea pollen. objectives: the aim of this study was to estimate the correlation between daily airborne olive pollen and ole e 1 in the atmosphere. aeroallergen load of ole e 1 detected by cascade impactor (chemvol) using prewashed polyurethane foam and pollen counts recorded by hirst trap. chemvol sampler collects particles at 800 l/minutes and it contains 2 impaction stages pm>10 micron and 10>pm>2.5 lm. this sampler is being tested in the frame of the project hialine. results: generally, similar behaviour of pollen count and total allergenic load of ole e1 was observed during the main pollen season. nevertheless, in some occasions, before and later of main period, airborne ole e 1 activity was recorded and some differences between pollen grain/m3 and allergen concentration/m3 were detected. pollen from different days released 11-fold different amounts of ole e1 per pollen. average allergen release from pollen was much higher in 2011 (1.11 pg ole e 1/pollen, r 2 =.44) than in 2012 (0.65 pg ole e 1/pollen, r 2 =.3148). indeed, yearly olive pollen counts in 2011 were 3.8 times higher than in 2012, but ole e1 concentrations were 2.2 times higher. these results have shown that ole e 1 is mostly associated with olive pollen grains but aeroallergen load was not always directly proportional to airborne pollen counts. this suggests that ole e 1 quantification is a better marker for olive allergen exposure. in conclusion, aeroallergen monitoring may contribute to a better understanding of the ole e 1 exposure from airborne pollen. objectives: to describe the clinical profile of the patients sensitized to alt at 6 and to assess the sensitivity of the prick test with the alternaria extract in comparison to the patients sensitized to both allergens alt a 6 and alt a 1. out of the 726 patients, 94 (12.9%) were sensitized to alternaria with specific ige of ≥0.3 isu to alt at 1 or alt a 6. twenty patients (11 females and 9 males, age 6-57 years old) who were sensitized to alt a 6 were selected. we analyzed the clinical profile, total ige values, other co sensitizations as well as the clinical relevance of alternaria sensitization in these patients. : of the 94 patients sensitized to alternaria, 20 (21.3%) were sensitized to alt a 6, of which 9 (9.6%) were monosensitized to alt at 6. the mean age was lower in monosensitized (ẋ 16.2 vs 25.2). among the 9 patients monosensitized to alt a 6, 4 (44%) had prick test negative with the alternaria extract. eight out of 9 patients were polysensitized to more than three different aeroallergens and were asthmatics (6 persistent). the median total ige was higher in monosensitized (859 ku/l vs 479 ku/l). of these 8 patients, alternaria sensitization has clinical relevance in 5 (62%), of which 3 have positive prick test to alternaria. all the patients (12/ 12) sensitized to both allergens have positive prick test to alternaria. ten of them were polysensitized, 8 were asthmatic (3 persistent) and 5 sensitized patients showed clinical relevance. introduction: the role of vitamin d as a potential immune-modulator has been recently elucidated. dendritic cell, a key regulator driving towards th2 immune response in allergic diseases is known to be affected by vitamin d. however, the role of vitamin d in the pathogenesis of allergic rhinitis is unclear and its anti-allergic effect has not been established yet, especially in the mouse model. objectives: the aims of this study are to evaluate 1) the anti-allergic effect of topically applied vitamin d in the allergic rhinitis mouse model, and 2) the effect of vitamin d on dendritic cell activation. results: balb/c mice were intraperitoneally sensitized with ovalbumin (ova) and alum, and they were intranasally challenged with ova. intranasal 1, 25-dihydroxyvitamin d3 was given to treatment group and solvent was given intranasally to sham treatment group. allergic symptom scores, eosinophil infiltration, cytokine mrna levels (il-4, il-5, il-10, il-13, ifn-c) in the nasal mucosa, serum total and ova-specific ige, igg1, and igg2a were analyzed and compared with negative and positive controls. cervical lymph nodes were harvested for flow cytometry analysis. in the treatment group, allergic symptom scores, eosinophil infiltration, and the mrna levels of il-4 and il-13 were significantly reduced compared to positive control. il-5 mrna level, serum total ige, and ova-specific ige and igg1 levels showed a tendency to decrease in the treatment group, but did not reach to a significant level. il-10 did not show a significant difference between groups. cd11c + , mhcii hi , cd86 + activated dendritic cells were significantly reduced in the treatment group. cd4 + , cd25 + , foxp3 + treg cells tended to increase in the treatment group, however it was not significant. the intranasal instillation of 1, 25-dihydroxyvitamin d3 has an anti-allergic effect in the allergic rhinitis mouse model. we believe that the anti-allergic effect of vitamin d is mediated by the inhibition of dendritic cell activation, and therefore decreased objectives: we wanted to assess whether treatment with cyclosporine and tacrolimus allows children with vkc to improve the level of vitamin d due to the higher summer sun exposure for good control of the ocular symptoms. objectives: our objective was to assess the expression of smad2 and smad5 proteins in patients with asthma in correlation with clinical parameters and the expression's changes in response to allergen and methacholine challenge test. the study included 151 patients with asthma and 77 healthy volunteers. spirometry, skin prick tests (spt), allergen and methacholine provocation tests were performed in compliance with standards. personalized clinic surveys including act tm were collected. venous blood was collected before and after provocation. the expression levels of il-5 and il-15 and smads were evaluated by qrt-pcr using isoform-specific primers. results: we showed correlation between the mrna expression of smad2 and the asthma control according to act tm (p<.001). the expression of smad2 is higher in the group of uncontrolled (2 -δct =0.52, p<.001) and in the group of partially controlled patients (2 -δct =0.50, p<.05) in comparison to the group of patients with controlled asthma (2 -δct =0.40). we proved that expression of mrna of smad5 correlates significantly with expression of il-5 and il-15 in patients with asthma (il-5 r=0.34; il-15 r=0.36) and in the control group (il-5 r=0.36; il-15 r=0.27) (p<.05). expression of smad5 elevates more after methacholine provocation test (median 2 -δct =0.69) rather than after allergen provocation test (median 2 -δct =0.51; p=.04). we showed also that skin prick test results correlate positively with smad5 level after the provocation (p<.001). conclusions: the loss of asthma control is connected with expression of smad2, which is part of tgf-ßrii related pathway. il-5 and il-15 correlates with smad5 expression, which can indicate the participation of these cytokines in the regulation of this pathway. the expression of smad5 elevates after methacholine and allergen provocation as well as it correlates positively with skin prick test results, which can be useful clinically. to sum up, tgf-ß-tgfßrii-smad proteins are an important mediators of inflammation in asthma. 0545 | deletion of nfatc1 in t lymphocytes affects th2 and th17 cell differentiation as well as il-9-mediated mast cell activation in allergic asthma objectives: analysing the role of nfatc1 in the allergic trait of human asthma. additionally, we investigated the influence of nfatc1 on t cell differentiation and immunoglobulin class switch and explored its impact on mast cell differentiation in experimental asthma. with the children 0 s hospital in erlangen, we studied nfatc1 mrna expression in freshly isolated pbmcs from pre-school children with and without asthma. in asthmatic children, we found increased nfatc1 mrna expression, especially in those with a positive skin test. these results were confirmed in the asthma bio-repository for integrative genomic exploration (asthma bridge) study, where the isoform a and d of nfatc1 were found significantly increased in asthmatic adults with a positive skin test. moreover, il-9 was also found increased in the supernatants of pbmcs of asthmatic children with a positive skin test. furthermore, mice with a deficiency of nfatc1 in cd4 + t cells display significantly lower levels of il-9. additionally, these mice show reduced numbers of lung th2 and th17 cells. moreover, basic leucine zipper atf like (batf), which is known as an important transcription factor for t cell differentiation as well as immunoglobulin class switch, was found decreased in these mice. consequently, ova-specific ige and total igg1 levels were found significantly decreased after allergen exposure and in the absence of nfatc1. furthermore, nfatc1 deletion also resulted in decreased mast cell numbers. we then analyzed the effect of il-9 on mast cell differentiation and histamine release. we observed that bone marrow differentiated mast cells incubated with ova and il-9 had an induced histamine release. conclusions: thus, nfatc1 deficiency in t cells results in defective ige production affecting ige-orchestrated mast cell activation mediated through il-9. therefore, nfatc1 emerges as a novel target for anti-allergy intervention. 0546 | efficiency of the use of nitric oxide donors for the treatment of bronchial asthma bazarova s; djambekova g center of therapy, tashkent, uzbekistan introduction: to study the influence of nitric oxide donor-l-arginine-on indicators of endothelial system in patients with bronchial asthma. objectives: 58 patients aged 27-55 years (41 ae 4.12 years) with moderate persistent bronchial asthma were examined. ratio of men to women was 30/28. two age-and sex-matched groups were randomly selected. main group (32 patients) received nitric oxide donor -l-arginine in addition to standard background therapy (gina, 2012) . the medication (100 ml of 4.2% solution, tivortin, "yuria-farm", ukraine) was administered intravenously once daily for 10 days. the control group (26 patients) only received the background therapy. the efficiency was assessed with the use of conventional methods of study (clinical laboratory methods, instrumental methods: spirography, peak flow monitoring, bronchomotor tests). concentration of nitric oxide stable metabolites in exhaled breath condensate (ebc) and in blood was studied. their ratio was also assessed. results: baseline data in patients of both groups demonstrated the increase of level of nitric oxide stable metabolites in blood (0.78 ae 0.02 mmol/l) and in ebc (0.43 ae 0.01 mmol/l). after the treatment the positive clinical efficiency of inclusion of l-arginine was much higher than that in the control group (p<.05). in the main group, reduction of requirement for beta2-agonists, decrease of frequency of night-time symptoms, decrease of frequency of lowest pef rate in the morning and improvement of respiratory function were observed on average on the 3rd/4th day compared to the control group were such improvements were evident on the 7th/8th day. in the main group the concentration of nitric oxide stable metabolites significantly increased in blood (0.59 ae 0.02 mmol /l, p<.05) and in ebc (0.21 ae 0.03 mmol/l, p<.05). in the control group the concentration of nitric oxide stable metabolites changed in blood (0.69 ae 0.06 mmol/l) and in ebc (0.32 ae 0.05 mmol/l), but not significantly. introduction: abpa is currently believed to be an exaggerated form of aspergillus sensitization, and is probably the first step in its development. objectives: the aim of this study was to investigate the clinical and immunologic characteristics of fungal-sensitive asthma (fa), nonfungal-sensitive asthma(nfa) and abpa. conclusions: there were different clinical and immunological features among nfa, fa and abpa. the abpa had worse function as well as higher percentage of bronchiectasis, and higher dose of oral corticosteroid. besides, the sensitivity to aspergillus was more severe in abpa. the level of sige-a.f was associated with the damage of lung function. 0548 | self-reported allergic rhinitis and/or allergic conjunctivitis associate with il13 rs20541 genotypes in finnish adult asthma patients introduction: the increased prevalence of asthma and allergic diseases is a major public health problem worldwide. atopy, family history, inhaled irritants, and upper airway inflammation are known risk factors of asthma. a population-based sample of finnish adult asthma patients (n=1156) and matched controls (n=1792) filled a questionnaire. asthma was diagnosed based on a typical history of asthma symptoms and lung function tests. skin prick tests (spt) with 17 aeroallergens and blood tests including analysis of interleukin 13 (il13) rs20541 (g/a) genotypes were performed for a subsample (n=193). objectives: our aim was to observe in adult asthmatics with and without allergic co-morbidities e.g. subject-reported allergic rhinitis and/or allergic conjunctivitis (ar/ac) association with il13 rs20541 genotypes and other factors. results: the proportion of asthmatics reporting ar was 61.9% and ac was 40.7%. after adjustments, the presence of il13 rs20541aallele (or=3.06 ci=1.42-6.58, p=.004) or multi-sensitization (adjusted or=4.59, ci=1.48-14.26, p=.008) associated with ar/ac-asthma. nasal polyps and aspirin-exacerbated respiratory disease associated also with ar/ac-asthma. conclusions: adult ar/ac-asthma could putatively be a phenotype, characterized by the presence of atopic and/or eosinophilic factors and a high prevalence of the il13 rs20541a-allele. studies on the mechanisms behind this and in other populations are needed. 0549 | immunoregulatory role of nfatinteracting protein (nip) 45 in adaptive and innate immune responses in allergic asthma introduction: nfat-interacting protein (nip) 45 is a th2 associated transcription factor. after t cell receptor stimulation, the arginine methylation domain of nip45 supports the interaction with nfat, thereby enhancing the production of the th2 cytokine il-4. moreover, nip45 deficient mice have been shown to be deficient in il-4 and ifn-gamma production indicating that nip45 controls both th1 and th2 cytokine production and might therefore play a protective role in allergic asthma . objectives: we wanted to analyze the importance of nip45 in allergic asthma in pre-school children as well as adults. furthermore, we investigated the role of nip45 in a murine model of allergic asthma to find out more about its contribution to adaptive as well as innate immune responses in the disease. results: in the european study predicta, in collaboration with the children 0 s hospital in erlangen, we analyzed nip45 mrna expression by using quantitative real time pcr in rna extracted from pbmcs isolated from pre-school children with and without asthma. in the pbmcs of the asthmatic children, nip45 mrna expression was found significantly increased compared to healthy control children. furthermore, nip45 mrna expression was also found induced in cd4 + t cells in adult asthmatics from the asthma bio-repository for integrative genomic exploration (asthma bridge) study. we further analyzed the importance of nip45 in a murine model of allergic asthma. after allergen sensitization and challenge nip45 (-/-) mice showed decreased airway hyperresponsiveness, inflammation and mucus production, three of the main patho-physiological features of asthma. additionally, we discovered that nip45 (-/-) mice released decreased th2 type cytokines and also expressed less st2, which is the receptor for il-33, after allergen challenge. furthermore, a defect in innate lymphoid cell type 2 (ilc2) differentiation was observed in the absence of nip45 in allergic asthma and in bone marrow differentiated ilc2s indicating a crucial role for nip45 in mediating asthma via ilc2s. conclusions: in summary, we found that the lack of nip45 influences not only immune responses of the adaptive immune system but also influences components of innate immunity resulting in a abstracts | 181 protective phenotype to allergic diseases such as asthma. objectives: in the study were included 40 ap and 10 healthy controls (hc). fraction of exhaled no (feno), standard lung function parameters, complete blood count and absolute count of cells, serum ige, crp, il-6, il-17a and periostin were measured. results: four clusters were identified by cluster analysis: cluster 1 (c1)(n=14)-late-onset, non-atopic, eosinophilic asthma with impaired lung function, cluster 2 (c2)(n=13)-late-onset, atopic asthma, cluster 3 (c3)(n=6)-late-onset, aspirin sensitivity, eosinophilic asthma and cluster 4 (c4)(n=7)-early-onset, atopic asthma. we have found higher levels of il-6 in all clusters ap as compared to hc (c1: p=.001, c2: p=.017, c3: p=.012 and c4: p=.003). tendency for higher levels of serum il-6 in c1 compared with c2 or c4 (p=.089 or p=.062, respectively) was observed. periostin levels were significantly higher in c1 (p<.001), c2 (p<.001) and c4 (p<.01) as compared to hc. there were no differences in periostin levels between all clusters (anova, p=.389). il-17a levels were significantly higher only in c4 as compared to hc or to c1 and c2 (p<.05, for each comparison). we have found correlation between il-6 and crp (r=.640; p=.014) in c1, il-17a and periostin in c1(r=.631; p=.016) and in c2 (r=.641; p=.018). interestingly, we have observed negative correlation between the duration of asthma and il-17a (r=à.886; p=.019), but positive between the duration of asthma and crp (r=.886, p=.019) in c3. our results have shown higher levels of il-6 in all clusters as compared to hc that are associated with marker for systemic inflammation. periostin levels were significantly elevated in c1, c2 and c4 as compared to hc with no differences between the clusters. a positive correlation between periostin and il-17a in c1 and c2 was observed, that rising the question about their interrelationship in the pathogenesis of late-onset asthma. serum il-17a was significantly higher in c4 in comparison with hc or c1 and c2 suggesting that th17 mediated immunity may be involved in early-onset, atopic asthma. these data support the concept of heterogeneity of the bronchial asthma. 0551 | eosinophil activation with autophagy and extracellular dna traps is involved in severe asthma results: il-5+lps treatment significantly increased autophagy and eet levels from pbes of the study subjects (p<.05 for all), which were in a positive correlation (r=.802, p<.001). compared to nsa patients, both untreated and il-5+lps-treated pbes from sa patients had significantly higher autophagy levels (p=.007 and .002, respectively), while only il-5+lps-treated pbes from sa patients had higher eet level (p=.036). eet level from untreated pbes was correlated with serum eosinophil cationic protein level (r=0.608, p=0.036) and fev1% predicted value (r=à.620, p=.056). co-culture of aec with pbes slightly increased il-8 production, which was significantly enhanced by il-5+lps treatment (p<.001). the il-8 production in co-culture system was reduced by pretreatments with dexamethasone (1 mm, p=.001), antibodies against major basic protein (200 ng/ml), il-5 receptor (1 mm) and il-4 receptor (1 mm, p=.05 for all), but increased by cotreatment with micrococcal nuclease (10 iu/ml, p=.001). conclusions: pbes from sa patients are highly susceptible to be activated to produce high levels of autophagy and eet, which could enhance and maintain airway inflammation. we suggest that steroid and anti-il-5/il-4 receptor antibodies may be beneficial to control airway inflammation in severe eosinophilic asthma via inhibition of eet production, while dna digesting reagents may increase airway inflammation. introduction: it has been demonstrated that exposure to stress induce hyporeactivity of the hpa system by modifying the secretion of cortisol and also that psychosocial stressors such as poor social status are associated with an increased risk of childhood asthma, decreased serum cortisol and high ige response. thus, from this concept it could be postulated that a blunted hpa axis response may increase the risk for allergic inflammatory reaction. objectives: aim of this study was to evaluate the association of serum cortisol in pediatric allergic bronchial asthma and its influence on the ige immune response in a poor children community with psychosocial chronic stress. results: this was a pilot analytical case control study(50 ipa positive subjects and 50 healthy control paired by age and gender, both from poor areas of barranquilla objectives: in order to characterize bp14 an immunoproteomics analysis was conducted, i.e. electrophoretic separation of cypress pollen extracted proteins, ige western blotting using cypress pollen allergic patient's sera and mass spectrometry (lc/ms/ms) for identification of ige-binding proteins. results: ms analysis using chymotrypsin identified in bp14 a peptide also found in the family of protein snakin/gibberellin-regulated protein (grp). the snakin-1, an anti-microbial peptide of potato, produced as a 63 amino-acid recombinant protein (homologous to the c-terminal part of grp), is recognized by ige from cypress pollen allergic patients with ige to bp14. this ige reactivity is abolished after reduction of disulfide bridges and is inhibited by a cypress pollen extract. ige reactivity to bp14 is however barely inhibited by the recombinant potato snakin-1. conclusions: bp14 exhibits a molecular mass closer to grp than to snakin and the absence or very low inhibition of the ige reactivity to bp14 with snakin may be explained by peptidic ige epitopes on the n-terminal part of bp14. the potato snakin-1 share 83% sequence identity with peamaclein, the peach allergen pru p 7, also shown in citrus. these results might explain the peach/cypress and citrus/cypress syndromes described and point out bp14 as the cross reactive allergen. the proteins of snakin/grp family present in many fruits and vegetables might include allergens involved in pollen/food associated syndromes. introduction: exposure to high levels of grass pollen may lead to a high degree of allergic inflammation, sensitization to minor allergens, such as profilin, and development of severe profilin mediated food reactions, similar to those described due to sublingual immunotherapy (slit). objectives: our objective here was to identify genetic biomarkers in order to generate a model that can improve the classification and treatment of patients with a higher probability of developing severe adverse reactions. results: 6 healthy subjects (group 1, control) and 17 patients with mild (group 2) or severe (group 3) profilin mediated food reactions were studied. rna extraction was performed on ficoll-isolated pbmcs using the rneasy ® mini kit (qiagen) and its integrity was analyzed with experion rna stdsens analysis kit (bio-rad). the gene expression profile of all the samples was analyzed using the gene-chip ® wt plus reagent kit (affymetrix) and two specific software: affymetrix ® expression console ™ and affymetrix ® transcriptome analysis console (tac). finally, the microarray data was validated by quantitative real-time pcr (qpcr). the hierarchical clustering of the samples shows the separation of the patients into three clusters coincident with the three established clinical groups (control, mild and severe). genetic profile of patients with mild reactions is similar to healthy patients while severe subjects were significantly different from the other two groups. genes regulated in the severe group were related to histone modification pathways, human complement system, cell adhesion and tgf-b and its receptor. these changes may be associated with the different degree of inflammation between patients in each experimental group. in the course of our study we found out that severe patients had different rna expression patterns compared to mild and non-allergic patients. this lead to the identification of genetic biomarkers useful for the generation of a model able to predict severe reactions and/or adverse reaction during immunotherapy, thus improving the diagnosis and treatment of this type of allergic results: his-tagged recombinant allergens, namely parvalbumin, aldolase, enolase and tropomyosin from c. idella and l. crocea, as well as cod parvalbumin, were synthesized in e. coli and purified using immobilized metal-chelate chromatography. 14 children with history of immediate-type fish allergy were included in this study and their serological ige reactivity to the fish allergen components were measured by elisa. 11 children were positive to at least one allergen component, with nine of them being positive to parvalbumin. despite the high similarity between l. crocea, c. idella and cod parvalbumins (70.6-81.6%), three children only reacted to l. crocea and c. idella parvalbumin but not to cod parvalbumin, while the other six children were positive to all three parvalbumins. competitive inhibition elisa revealed that c. idella parvalbumin inhibited >85% of the binding of specific ige to both l. crocea and cod parvalbumin, while reciprocally only inhibition of 60% and 50% could be achieved respectively. two children were reactive to aldolase and enolase but not parvalbumin. one of them had positive sige to both enolase and aldolase from l. crocea, while the other reacted to aldolase from both species. these two children exhibited relatively mild subjective allergy symptoms (itchy skin and throat). notably, three children were non-reactive to all components tested, and two of them were outgrowing fish allergy clinically. introduction: anti-a-gal antibodies are naturally produced in response to the gastrointestinal flora. in red meat allergy, patients develop ige antibodies towards the a-gal epitope, which itself are structurally closely related to the blood group b antigen. objectives: this study aimed to explore the relationship between a-galand b-antigen-specific antibodies in red meat allergic patients compared to healthy individuals with blood group b or a/o. sera from 39 red meat allergic patients and 84 healthy blood donors of whom 52 belonged to blood group b and 32 to blood group a or o were included. ige reactivity against a-gal and the b-antigen were determined using immunocap. allergen-specific igg, igg1, igg2, igg3, igg4 and ige were assessed by indirect elisa assay. statistical analysis was performed using spearman rank correlation and unpaired t-tests. results: all red meat allergic patients, 12 of the healthy a/o and 3 of the healthy b donors were ige positive to a-gal. however, the ige levels to a-gal were significantly higher in the allergic group compared to the healthy a/o and b individuals. the majority of the meat allergic patients, but none of the healthy individuals had ige antibodies against the b-antigen. a moderate correlation between a-gal and b-antigen specific ige was noted (r 2 =.48). the red meat allergic patients had significantly higher igg levels against a-gal with igg1 and igg4 antibodies as the predominant difference compared to the healthy individuals. the 12 healthy a/o ige positive individuals had significantly higher igg1, igg3 and igg4 compared to the ige negative individuals. the igg response to the b-antigen followed the same pattern as to a-gal. there was a low correlation between the igg levels against a-gal and the b-antigen in both meat allergic patients and healthy a/o individuals (r 2 =.30 and .33). introduction: fx5, a food mixture of milk, egg white, fish, peanut, wheat and soybean, is largely used for food allergy detection. besides the fact that it is questionable if this is the better approach to identify a food allergy, the information that the test provides may represent a pitfall because a positive or negative result does not mean food allergy presence or absence, respectively. objectives: the goal of our study was to access the reason for fx5 request in a pediatric hospital and to analyze its suitability. methods: the fx5 requests, performed in a pediatric population of d. estefânia hospital over a five months' period, were analyzed, concerning demographic data, reason for request and attitude taken due to the result. this test was requested due to respiratory symptoms in 37 patients, gastrointestinal symptoms in 23 patients, cutaneous symptoms in 20 patients and nonspecific complaints in 48 patients. all of these symptoms were not directly related with food intake. a positive result was obtained in 25 patients; of those, only 15 were referenced to our immunoallergology department. in all of them a detailed clinical history was obtained and diagnostic tests (skin prick tests and specific ige) were performed in the ones considered suitable. food allergy was diagnosed in only one patient. conclusions: in the vast majority of patients, fx5 was asked for nonspecific complaints and often without a clinical history suggestive of food allergy. moreover, a positive fx5 test does not mean clinical reactivity or food allergy. on the other hand, the clinical history allows us to identify a suspect trigger in most of the children with food allergy. in such cases, it is preferable to request the specific ige towards the allergen, which gives a more precise and accurate result, instead of the fx5. as our results showed, in the majority of the cases, the fx5 request was often made without complying with a reasonable criterion, implying unnecessary costs. the high number of requests verified may be explained because it is an easily accessible analysis but this attitude should be discouraged. tuppo l 1 ; alessandri c 2 ; pasquariello s 3 ; petriccione m 3 ; giangrieco i 1 ; tamburrini m 1 ; rafaiani c 2 ; ciancamerla m 2 ; mari a 2 ; ciardiello ma 1 1 istituto di bioscienze e biorisorse -ibbr-cnr, naples, italy; 2 caam -centri associati di allergologia molecolare, rome, italy; 3 cra, research unit on fruit trees, caserta, italy introduction: pomegranate, punica granatum l., is one of the oldest cultivated fruit trees. the fruit contains the arils, which are seeds covered by a red pulp, that is a juice sac. the arils are surrounded by the white and fleshy mesocarp. pomegranate can trigger allergic reactions, but the allergenic pattern of this fruit is still poorly characterized and only one allergen, the ltp pun g 1, was reported. objectives: the aim of this study was the investigation of the allergen pattern in pomegranate tissues and cultivars. reported symptoms were food impaction (68%), dysphagia (65%), heartburn (33%) and vomiting (30%). the first 2 symptoms were more frequent in adolescents and adults (96%). children's main complaint was vomiting (73%) and 4 cases presented failure to thrive. most patients had associated allergic diseases (88%), 23% had previous food allergy and 74% were sensitized to aeroallergens. endoscopic evaluation revealed esophageal stricture in 5 patients. at least half of diagnostic esophageal biopsies had >20 eosinophils per highpower field and 33% showed microabscesses. food sensitization was found in 61% of the patients, mainly to cow's milk (46%), nuts and peanut (33%), cereals (30%) and egg (21%). considering therapeutic approach, 88% were treated with swallowed fluticasone and dietary elimination was recommended in 54%. oral corticosteroids were prescribed in 8 patients. at present time 42 patients had done endoscopic reevaluation, 30 (71%) showed histologic resolution. five patients had clinical and histologic relapse during follow-up. conclusions: eoe has a balanced distribution but a distinctly clinical presentation accordingly to age group: children may present unspecific symptoms like vomiting, whereas adolescents and adults complain of food impaction and dysphagia. other atopic diseases and food sensitization is very common. introduction: air pollution, particularly ambient air particulate matter (pm), is considered as one of the most important environmental risks for human health. pm could potentially disrupt immune regulatory mechanisms and predispose exposed individuals to asthma. in contrast, children exposed to traditional farm environment seem to have a natural resistance to asthma. this phenomenon links with exposure to stable dust and subsequent immune regulatory mechanisms initiated in the airways. the underlying exposure agents and definitive pathways determining the risk of asthma are still to be identified. objectives: our aim was to investigate the effect of urban air pm (high risk environment) and farm dust (protective environment) on immune responses in finnish children. briefly, peripheral blood mononuclear cells (pbmcs) of 4-year-old children (n=18) were stimulated with farm dust extract (40 lg/ml, stable in northern savonia, finland) and pm samples (75 lg/ml, pm 2.5-1 , pm 1-0.2 or pm <0.2 , nanjing, china) for 18 hours. expression of immunogenic cd80 and tolerogenic ilt4 in circulating myeloid dendritic cells (mdcs) and plasmacytoid dcs (pdcs) and monocytes were analyzed by flow cytometry. pm samples were analyzed for polycyclic aromatic hydrocarbons (pahs), inorganic ions and elements. farm dust sample will be analyzed for microbial content. results: pm stimulation decreased the percentage of cd80+ monocytes and dcs among children's pbmcs, whereas farm dust stimulation increased the percentage of cells positive for this marker. the percentage of tolerogenic ilt4+ was decreased in all cell types after stimulation with pm. farm dust also decreased the percentage of ilt4+ monocytes, but not dcs. specific metals and pahs in pm associated with the studied immunological parameters. conclusions: samples from high risk and protective environments have differing capacities to influence immunogenic and tolerogenic properties in children's immune cells. the importance of these findings in relation to the risk of asthma in exposed populations will be studied further. introduction: alterations in cell surface glycosylation pattern is a common feature of tumor cells that might be related to immune evasion and malignancy. objectives: to study the capacity of the carbohydrate a10 (ca10) located in the surface of murine ehrlich tumor (et) cells and also in certain human adenocarcinomas to condition the phenotype and function of human dendritic cells (dcs) and the capacity to polarize t cell responses. results: nf-jb/ap-1 are not activated in thp1 cells by ca10, however, this carbohydrate partially impairs the activation of these transcription factors induced by the tlr2 ligand pam3csk. ca10 induces the expression of the tolerogenic marker pdl1 in human monocyte-derived dcs (hmodcs) as well as the production of il-6 and il-10, analyzed by flow cytometry and elisa assays respectively. ca10-activated hmodcs generate functional il-10-producing cd4 + cd25 high cd127 -foxp3 + regulatory t (treg) cells that were able to inhibit the proliferation of cd4 + t cells from pbmcs in a dose-dependent manner. supporting the role of ca10 in the induction of treg cells, our in vivo data showed that the ca10 is present in the sera of tumor bearing mice and the percentage of foxp3 + treg cells is increased in the regional (inguinal) lymph nodes from tumor bearers. our results showed that ca10-activated hmodcs induce the generation of foxp3 + treg cells both in vitro and in vivo, which might well condition the immune response against the tumor and promote the tumor escape. 0567 | assessment of changes in expression of immune system biomarkers to assist the differential diagnosis of acute bacterial infections introduction: biomarkers for acute infections include c-reactive protein, mmp-9, sicam-1, procalcitonin, and neutrophil band counts for bacterial infection. a rapid means of assessment of acute bacterial infections via biomarker assessment was sought. objectives: the expression of toll-like receptors (cd282 and cd284), complement receptors (cd35 and cd88), integrins (cd11b and cd11c), fc-receptors (cd32 and cd64) and l-selectin (cd62l) on the surface of blood neutrophils and monocytes stimulated with inactivated e. coli, l. acidophilus, e. coli derived bacterial ghosts, e. coli lps and l. acidophilus cell walls was assayed using flow cytometry. both the percent of expression and mean fluorescence intensity (mfi) were analyzed for each molecule. results: all the bacterial components used exerted similar activation capabilities even in low concentrations. while the expression of cd11b, cd11c, cd32, cd35 and cd88 was enhanced by both neutrophils and monocytes under activation, the expression of cd64 significantly increased only in neutrophils. the expression of tlr2 and tlr4 was slightly increased by neutrophils and monocytes. the expression of cd62l by monocytes and neutrophils (the percent of activated cells as well as the mfi) was decreased during activation. there was a negative correlation between cd62l expression and integrins (cd11b and cd11b). the activation index was calculated for each molecule as a ratio of expression of molecule by activated cells vs cells used as a negative control (resting). the highest values for the activation index was seen with cd11b, cd11c, cd32, cd35, cd62l and cd88 mfi by neutrophils and monocytes, and the percent of cd64 expression by neutrophils. conclusions: e. coli and bacterial ghosts significantly increased the expression of cd11b, cd11c, cd32, cd35, cd62l and cd88 by neutrophils and monocytes even in very low concentrations, suggesting use as potential biomarkers in the differential diagnosis of the etiology of acute infections. objectives: the aim of this study was to evaluate changes in peripheral blood monocyte expression of cd16, cd163, cd206, cd209, hla-dr, and cd47 in kidney allograft recipients. in total, 88 patients who underwent renal transplantation from a deceased donor were enrolled in the study. the phenotype was evaluated by a multicolor flow cytometry in defined time points and in the case of complications requiring fine needle aspiration biopsy procedure. the results confirmed our pilot data, proportions of peripheral cd14+cd16+ monocytes were downregulated during the first week after the kidney transplantation while the percentage of cd14+cd163+ monocytes dramatically increased early after the kidney transplantation and remained high for at least four months in most patients. the expression of cd206 (marker of m2 macrophages) was limited only to a small population of monocytes (less than 5% in most patients) but the receiver operating characteristic (roc) curve analysis showed its potential importance by significant correlation with acute rejection with a sensitivity of 70% and specificity of 80.33% (area under the roc curve 0.7787, p-value: 0.004973). no correlation between two different m2 markers cd163 and cd206 has been found. the expression of cd209 (dc-sign) was low and did not show any changes in time or association with acute rejection. hla-dr (mhc ii) and cd47 (integrin associated protein) were constitutively expressed without any significant changes in patients with acute rejection of the allograft. we assume from our data that kidney allograft transplantation is associated with early reciprocal modulation of monocyte subpopulations (cd14+cd16+ and cd14+cd163+). a decreased proportion of cd206 positive blood monocytes seems to be associated with an increased risk of acute rejection of kidney allograft. introduction: thioredoxin (trx), a 12-kda oxidoreductase enzyme, is well known to be a redox-active protein that regulates reactive oxidative metabolism. in addition to its anti-oxidative activ0570 | progranulin-dependent regulation of th2 airway inflammation by house dust mite allergen introduction: progranulin is a growth factor that consists of 593 amino acids including 71/2 repeats of cysteine-rich motifs, and produced by variety kinds of cell. progranulin is involved in the regulation and maintenance of inflammatory response, and its role is wellstudied in neuronal and metabolic diseases such as neurodegeneration and type 2 diabetes. however, the role of progranulin during the development of airway inflammation induced by inhaled allergen is still obscure. objectives: in this study, we evaluated the role of progranulin in the development of th2 airway inflammation induced by house dust mite allergen. results: to find the main source of progranulin, we stimulated each cell line with various doses of house dust mite allergens. the production of each cytokine, including progranulin, was estimated in culture supernatant by elisa. to investigate the role of progranulin in airway inflammation, we intranasally administrated house dust mite allergens to 6-week-old female progranulin knock-out mice (macrophage-specific) or littermate mice. lung inflammation and immunological parameters were evaluated at 15 h after first sensitization with allergen or 24 h after final allergen challenge. the production of progranulin was significantly elevated by house dust mite allergen stimulation in innate immune cells, especially in alveolar macrophages over other cells. in the house dust mite allergeninduced airway inflammation model, we found that the level of progranulin increased earlier than other pro-inflammatory cytokines. in addition, in macrophage-specific progranulin knock-out mice, airway inflammation was down-regulated in the earlier phase after exposure to house dust mite allergen. moreover, we stimulated mice with house dust mite allergen for a longer period to observe the changes in the adaptive immune response of th2 airway inflammation, which was found to be decreased in conditional knock-out mice. conclusions: these findings indicate that th2 airway inflammation induced by house dust mite allergen is dependent on progranulin. objectives: the aim of the present study was therefore to investigate the immunomodulatory effect of epinephrine on m2a macrophages and its consequence on cross talk to mast cells in a human model of allergic inflammation. results: primary monocytes from healthy pbmcs were first differentiated into m2a macrophages using m-csf in the presence of il-4 and il-13 cytokines. after overnight incubation with epinephrine, supernatants were collected and analyzed by elisa for il-10, tnf, il-6, ccl1, il-12 and ifn-c, whereas cell surface markers including cd206, cd163 and cd86 were evaluated using flow cytometry. subsequently, both m2a and epinephrine-treated m2a supernatants were transferred onto cord blood-derived mast cells (cbmcs) for further overnight incubation, after which ige-mediated degranulation was assessed by the ß-hexosaminidase release assay. after overnight epinephrine treatment, m2a macrophages showed an increase in il-10, ccl1, tnf and il-6 production, but no ifn-c and il-12 expression was observed. epinephrine treatment also downregulated surface markers cd206 and cd163 and upregulated cd86. when supernatants from epinephrine-treated m2a macrophages were added to cbmc cultures, ige-mediated degranulation was impaired compared to cbmcs treated with supernatants of unstimulated m2a macrophages. conclusions: taken together, epinephrine promoted a phenotypic shift of m2a polarized human macrophages toward an m2b-like regulatory phenotype that was able to reduce the ige-mediated degranulation of cbmcs. we conclude that prolonged acute stress exposure in allergic patients may attenuate symptoms of acute allergy by directing macrophages towards an immunosuppressive phenotype, which can further dampen mast cell degranulation. objectives: a murine local lymph node assay was used to investigate the effect of oa on the immune response to the known skin sensitizer hexyl cinnamic aldehyde (hca, 25% w/v). the ear lobes tape stripped prior to immunization. test solutions (25 ll) were applied on the dorsal side of each ear on three consecutive days. female balb/c mice (8 groups a 6 mice), were exposed to the vehicle acetone:olive oil (4:1) alone, or in combination with hca, with or without oa in the concentrations 5, 10 and 20%, or oa alone (5, 10 and 20%). on day 5, the animals were weighed and exsanguinated by cardiac puncture. the auricular lymph nodes were harvested for single cell preparation, stimulation with cona and cytokine release of il-2 and il-17. the earlobes were excised and fixed for immunohistochemistry. results: no group differences were found for bodyweights or bodyweight change, number of lymph node cells or il-17 secretion. il-2 showed a tendency of dose-related increase, but a significant difference were only found between hca and hca+10% oa (p=.034) in one out of the two experiments. in he stained sections, the epidermal thickness was significantly increased in groups given hca + 10 and 20% oa (p≤0.001). sections immunostained with anti-ly6g showed significant increase in neutrophil influx for the same groups as above (p≤0.001). oa alone showed no effects or effects significantly lower than hca + oa. objectives: we hypothesized that plasma s1p levels in cf patients might be associated with cftr mutations and could influence disease presentation. results: plasma was collected with a defined standard operation procedure to impede unspecific s1p release from blood cells from 20 double lung transplanted adult cf patients as well as 20 sex-and age-matched, non-allergic healthy controls all being fasted overnight. total plasma s1p was measured by mass spectrometry and unbound plasma s1p by elisa. levels were correlated with cftr mutation status, routine laboratory parameters and clinical symptoms. we observed higher total and unbound plasma s1p levels in healthy controls compared to cf patients with the latter value reaching statistical significance (p=.044) after exclusion of two statistical outliers. unbound plasma s1p levels were significantly higher in df508 homozygous cf patients compared to patients with df508 heterozygosity (p=.029). 2 patients with other mutations were excluded. levels of unbound s1p were positively correlated with hemoglobin and negatively correlated with triglyceride levels. additionally, we observed a positive correlation of total plasma s1p levels in cf patients with hba1c. gastrointestinal symptoms were more common in df508 heterozygous (6/8) compared to df508 homozygous cf patients (4/10). fecal calprotectin levels were found to be significantly higher in df508 homozygous compared to heterozygous cf patients (p=.047). differences in unbound s1p levels were not correlated with immunosuppressive treatment after transplantation. conclusions: to the best of our knowledge this is the first clinical study directly correlating plasma s1p levels with cf genotypes and clinical presentation in cf patients. we emphasize to evaluate s1p as a potential novel disease biomarker as well as a therapeutic target for cf in future studies. supported by the austria science fund grant kli 284 (to eu). ochoa-grull on j 1 ; tejera-alhambra m 2 ; guevara k 1 ; guzm an-fulgencio m 2 ; benavente cm 3 ; mart ınez r 3 ; p erez c 3 ; peña a 3 ; rodr ıguez de la peña a 1 ; llano hern andez k 1 ; rodr ıguez-fr ıas e 1 ; s anchez-ram on s 1 objectives: we show preliminary data of one study aimed to evaluate the use of this strategy in the prevention of rrti in infants and preschool children. results: patients: 121 children (70 male and 51 female, age range 6-35 months) were included in a randomized double blind and placebo-controlled study (eudract 2012-002450-24) . all of them showed negative in vivo and in vitro allergy tests. active treatment consisted in a suspension of a mixture of selected strains, grown and inactivated in optimal conditions, of s. aureus (15%), s. epidermidis (15%), s. pneumoniae (60%), k. pneumoniae (4%), m. catarrhalis (3%) and h. influenzae (3%) in physiologic saline solution with 50% glycerol at a concentration of 300 formazin turbidity units (ftu)/ml (equivalent to 10 9 bacteria/ml). placebo did not contain any bacteria. patient were treated for a period of 6 months, receiving 2 daily sublingual puffs of active or placebo and with a follow-up of other 6 months (total period of evaluation was 1 year). symptom (cough, dyspnea, wheeze, mucus, fever, discomfort) and medication (inhaled corticosteroids, beta adrenergics, montelukast, antibiotics) scores were evaluated since the first day of treatment to the end of the study (1 year) . any adverse event was recorded to assess safety. for the comparison between both groups, t test was used. patients who received active treatment experienced an improvement of 39% over placebo in overall symptoms and 38% in medications scores (p<.01). in the combination of symptoms and medication scores the improvement was 38% (p<.0001). no adverse events related to treatment were recorded. conclusions: immunostimulation with these selected strains of bacteria is safe and can be successfully used in infants and preschool children in order to prevent rrti. introduction: to reduce the duration and the risk of the allergen specific immunotherapy using commonly used allergen extracts, new highly immunogenic and non reactogenic vaccines are needed. objectives: the goal of the present study was to employ the ap205 spytag/catcher system to develop a virus-like particle (vlp) vaccine based on the major house dust mite (hdm) allergen der p 2 and to evaluate its reactogenicity in vitro. spycatcher-ap205 vlps and recombinant der p 2, fused at the c-terminus to the 13 amino acid spytag binding-partner, were expressed in e. coli. purified spytagged der p 2 was mixed with spycatcher-vlps, which resulted in covalent conjugation of der p 2 to the surface of spycatcher-vlps. excess unbound der p 2 was removed by dialysis. dynamic lightscattering (dls) was used to analyse the size and aggregation state of vlp-der p 2. the ige reactivity of vlp-der p 2 was assayed by direct elisa and by rat basophil degranulation assays. conclusions: our results demonstrate that coupling of spy-tagged der p 2 to ap205 spycatcher-vlps dramatically reduces the reactogenicity of the allergen, suggesting that vaccination with ap205 vlp-der p 2 may be a safe and effective treatment for hdm allergy. objectives: the qm1s hybrid protein is a qm1 variant where cysteine amino acids have been replaced by serine. the expression of qm1s hybrid protein was performed in e. coli bl21(de3) after iptg induction. the purification of qm1s protein was performed from inclusion bodies by a three-step chromatography process. the stability of qm1s was analyzed by sds-page and total protein assay. qm1s ige-binding capacity was compared with natural der p 1 and der p 2 by elisa-inhibition and allergenicity was studied by mediator release from rbl cells. immunogenicity was evaluated in mice by analysis of the specific igg response to der p 1 and der p 2. results: qm1s was expressed in complex media as inclusion bodies that were solubilized in urea. soluble protein was purified by anionic ion exchange, hydrophobic interaction, and size exclusion chromatography in the presence of a detergent. qm1s purification process was shorter and more efficient than that of qm1. the purity obtained was >95%. elisa inhibition assay showed that qm1s hybrid protein was almost unable to inhibit ige-binding to the hdm extract, less than 10% in all the range of concentrations tested (0.1-10 000 ng/ml) and representing a 40-fold reduction as compared to qm1. qm1s showed a great reduction of the b-hexosaminidase release in rbl cells, compared to der p 1 and der p 2. qm1s was able to induce der p 1-and der p 2-specific lgg antibodies responses comparable with those induced by the mixture of wildtype allergens. mouse igg antibodies induced by the hybrid proteins qm1s and qm1 showed similar ige-blocking antibodies properties to mixture of der p 1 and der p 2. the stability of qm1s was studied in solution at 25°c, 4°c, and -20°c and lyophilized at 4°c, being the frozen and lyophilized forms the best conservation conditions. the qm1s hybrid exhibited less ige-binding activity than qm1 and the natural der p 1 and der p 2 while retained the immunogenicity. these properties together with the improved manufacturability made qm1s a good candidate for sit to hdm allergy. objectives: slit tablets of cockroach, slit tablets of parthenium, slit tablets containing both allergens together (mix) and slit bilayer tablets containing one layer with parthenium allergen and other layer with cockroach allergen, compress to single tablet were prepared. punches and dies of 11 mm were used for compression. slit drops containing cockroach, slit drops of parthenium and slit drops containing both allergens together, were prepared and filled in 10 ml amber colored dropper vials. results: tablet formulations were evaluated for thickness (3.5-3.6 mm), weight variation (357-402 mg), hardness (2.0-2.5 kg/cm 2 ), disintegration time (not more than 2 min.), and biologically active content (90%-110% of the stated label claim). in-vitro dissolution test was performed as per usp using distilled water as the medium and the release was shown between 70 to 80% in 5 minutes. the liquid formulations were analyzed for ph (7.0 -7.5), the biological content (90% -110% of the label claim), specific gravity ( introduction: virtually all patients suffering from the common birch pollen allergy exhibit ige against the bet v 1 relevant allergen. as such, an elisa method for the quantification of bet v 1 was selected and validated as part of the bsp090 project, aiming to establish reference methods for the european pharmacopoeia. herein, we report the mapping of the epitopes recognized on recombinant bet v 1 allergen by the two specific murine monoclonal antibodies (mabs) used for the accurate and precise quantification of bet v 1 within birch pollen extracts. objectives: in order to investigate the ability of mabs 5b4 and 6h4 to recognize various bet v 1 isoallergens, we first carried out immunochromatography combined with electrophoresis. epitope mapping was performed by hydrogen/deuterium exchange (hdx) coupled with mass spectrometry (ms) analysis, using a gmp-grade purified rbet v 1 molecule. results: immunochromatography unveiled that both mab 5b4 and mab 6h4 capture most of bet v 1 isoallergens present within birch pollen natural extracts. those two mabs cross-react with the aln g 1 allergen from alder pollen but do not react with the cas s 1 chestnut pollen allergen. hdx-ms experiments combined with site-directed mutagenesis evidenced that mabs 5b4 and 6h4 target two distinct epitopes. the hdx-defined 5b4 epitope is discontinuous and contains a dominating sequential element (i.e., loop ile56-lys68). the hdx-defined 6h4 epitope is also discontinuous and mainly composed of regions ile44-lys55 and arg70-phe79. conclusions: overall, this study provides a precise molecular characterization of epitopes within bet v 1 recognized by mabs 5b4 and 6h4, confirming that these two antibodies target distinct non-overlapping epitopes and recognize the vast majority of currently introduction: short or common ragweed (ambrosia artemisiifolia), belonging to the aster plant family, sheds enormous amounts of highly allergenic pollen late in the summer. due to its high allergenic potential ambrosia artemisiifolia is becoming a health threat in north america and europe. hal allergy is developing a subcutaneous immunotherapy for patients suffering from ragweed pollen allergy. a standardized ragweed pollen extract, chemically modified and adsorbed to aluminium hydroxide (al(oh) 3 ), is being investigated for its potential use in immunotherapy. objectives: ragweed extract (re) was modified by glutaraldehyde followed by adsorption to al(oh 3 ). in vitro, a mediator release assay (mra) using hurbl (humanized rat basophil leukemia) cells was performed. hurbl cells were pre-sensitized using individual sera of ragweed-allergic patients and challenged with serial dilutions of re and modified re starting at 10 lg/ml followed by eight 1/10 dilutions (0-10.000 ng/ml). antigen-specific release of ß-hexosaminidase was measured and calculated in relation to 100% release values. in vivo, the immunogenic potency of modified re was evaluated by measuring the induction of re-specific igg in mice. female balb/c mice (n=10 per group) were subcutaneously (s.c.) injected with 20.000 aueq/ml re or modified re adsorbed to al(oh) 3 (0.8 mg/ml) per mouse on days 0, 7, 14 and 21. control mice (n=6) were injected with matrix only. specific igg titres were determined in serum obtained at days -1, 13 and 28. results: the potency of modified re in mra was drastically reduced in all patients, with a mean reduction of 1000 fold or more. chemical modification resulted in a later onset of activation as well as a lowering of the maximum release of ß-hexosaminidase. in vivo, both re and modified re show comparable levels of re-specific igg antibodies in mice at day 28 of the immunogenicity model. shown that chemical modification impairs the capacity of re to activate basophils while retaining its capability to be immunogenic. therefore, chemical modification of re may be a promising approach for the development of a safe and effective immunotherapy for ragweed allergy. objectives: the children who had taken subcutaneous conventional venom immunotherapy in our pediatric allergy outpatient clinic between 2002 and 2015 were evaluated with respect to the side effects. in addition, each child was called to ask if the patient was exposed to bee sting and the result of a sting during immunotherapy. introduction: the major unmet needs for allergen immunotherapy (ait) are improved efficacy with good tolerability, and high adherence. to achieve these, allergoids, peptides and recombinant proteins are potentially the answer but their low rate of systemic aes make selection of the optimal dose difficult. to select the dose for an ultra-short course subcutaneous birch ait, the company has adopted the use of a conjunctival provocation test (cpt), a wide range of doses and the multiple comparison procedure -modelling (mcp-mod) statistical analysis to test for a dose response and to determine the shape of the dose response curve. objectives: a range of dose regimens of 5100 su, 15300, 20100 and 27300 su were compared with placebo with respect to reduction of total symptom score elicited by cpt after treatment. patients were administered 6 weekly injections outside the pollen season. cpt was performed at screening, at baseline and 4 weeks after completion of treatment. the study was undertaken in 28 sites in germany and austria with 370 patients. the primary efficacy analysis was performed on a modified full analysis set (fas). the mcp-mod methodology was used to test for a dose-response using the placebo and above doses to describe the shape of the dose response curve. three candidate models were pre-specified: a maximum possible effect for the agonist (emax) model, a logistic model, and a linear in log-dose model. a statistically significant dose-response (p<.01) was shown for the range of cumulative doses, which approached a plateau with the 27300 su dose. the median effective dose (ed-50) was 2600 su. only minor differences were observed between the six active treatment groups in prevalence of treatment-emergent adverse events (between 70.9% and 83.9% of patients with overlapping 95% two-sided confidence intervals), majority of which were local reactions, short-lived and mild. teaes classified as systemic reactions were seen in 2.0% (20100 su group) and in up to 15.1% (5000 su group) of patients in the active treatment groups, and in 11.3% of patients in the placebo group. no treatment related saes were observed. adherence was >90% in all treatment arms. the ed-50 was 2600 su, demonstrating that the currently marketed dose (5100 su) is effective. the highest 27300 su dose will be further investigated in a pivotal phase iii trial having achieved an increase in efficacy by 50% without differences in the onset of aes between the treatment arms. introduction: in order for allergen immunotherapy (ait) to induce long-term immunological and clinical effects prolonged administration is required. therefore adherence to treatment is crucial for its efficacy. there is currently limited data available on ait adherence beyond clinical trials i.e. in real-life clinical practice. objectives: this eaaci immunotherapy interest group endorsed survey aimed to prospectively evaluate adherence to sublingual and subcutaneous immunotherapy in adults with allergic respiratory diseases and hymenoptera venom allergy in real life practice across different european countries. in addition, the reasons for lack of adherence and discontinuation of treatment were explored. this was a prospective, multi-centre, observational survey which took place in eight countries: czech republic, georgia, germany, greece, italy, poland, portugal and spain. data collection involved an online survey that followed participants four-monthly for a period of 36 months from the start date of ait. results: a total of 1336 participants were included in the analysis. introduction: allergic rhinitis is a multiple gene-regulated disease involved in many immune cells such as mast cells and eosinophils, and various inflammatory mediators, and mirna probably plays a critical regulatory role in its pathogenesis. therefore, studies on the functions of critical mirna and its regulatory mechanisms in activated mast cells will lay an important theoretical foundation for our understanding of ar pathogenesis and the development of therapeutic strategies. objectives: to investigate the effect of mir-125a-3p on mast cell activation in an ar mouse model. the number of sneezes and the frequency of nasal rubbing in ar+mir-125a-3p group were significantly reduced compared to those for ar+mir-nc group (p<.05). histological examination showed that inflammation in the nasal mucosa from ar+mir-125a-3p group was slighter than that in ar+mir-nc group. the number of mast cells in ar+mir-125a-3p group was increased compared to ar+mir-nc group (p<.05). the levels of histamine and il-13 in nasal lavage fluid supernatants, histamine in plasmas and il-13 in sera were significantly decreased in ar+mir-125a-3p group compared to ar+mir-nc group (p<.05). conclusions: upregulation of mir-125a-3p can reduce allergic inflammation in the nasal mucosa of ar and alleviate ar symptoms through inhibiting mast cell activation in vivo. mir-125a-3p probably becomes a new target for gene therapy of ar. 0222 | correlation between chronic cough and chronic rhinosinusitis in adults: nationwide, population-based, and cross-sectional study the second hospital of shandong university, ji nan, china; 2 national university of singapore, singapore, singapore introduction: nasal polyp implies a refractory clinical course in case of chronic rhinosinusitis (crs). although hypoxia is believed to be associated with nasal polyposis, little is known about the mechanism underlying polypogenesis. objectives: the aim of this study was to assess mrna and protein introduction: nasal polyp is a multi-factorial disease commonly associated with inactive ciliary beating frequency (cbf), a condition partly attributed to the mis-localization of dnah5, a component of the outer dynein arm in ciliary axoneme. so far however, there have yet to be a systematic histopathological investigation directly linking dnah5 localization pattern in nasal polyps. therefore, we sought to examine the localization of dnah5 in cilia structure of both nasal polyps and inferior turbinates from healthy individuals, and assess whether there are any localization changes that can account for the extensive inactive cbf observed in nasal polyps. objectives: the focus of this work is to compare the localization of dnah5 from the nasal polyps biopsies (n=80) and normal inferior turbinates (n=19) by immunofluorescence. the characterization of each sample was obtained from an average of 10 fields at 4009 magnification. results: from the samples, we observed three distinct localization patterns of dnah5 in the nasal cilia. the three patterns were as follows: 1) the localization of dnah5 in normal cilia is present throughout the entire axoneme (pattern a); 2) the localization of dnah5 is within the axoneme except at their proximal regions (pattern b); 3) the localization of dnah5 is restricted exclusively at the ciliary base and not present in the entire axoneme (pattern c). approximately 96% of the samples exhibited more than one distinct localization patterns for dnah5 within the observed fields. the percentage of pattern a, pattern b and pattern c were observed in 36.5%, 24.7%, and 38.8% fields for samples from nasal polyps. correspondingly, 75.1%, 19.3%, and 5.6% were observed for samples from healthy controls. the results indicated that the predominance of "pattern c" in nasal polyps countered by "pattern a" in inferior turbinates from healthy individuals. conclusions: our study indicated that there is a significant increase in the mis-localization of dnah5 among the cilia in nasal polyps as compared to controls. this mis-localization may account for the inactive cbf, a hallmark characteristic, observed in nasal polyps. zhao l 1 ; zhi l 2 ; jin p 1 ; zi x 1 ; tu y 1 ; li a 1 ; li t 1 ; shi l 1 (3.64, 2.28-5.01, p<.05) and +gc np patients (10.39, 6.00-14.77, p<.05 the results showed that the number of th17 + cells were correlated with eosinophil cells and macrophage (r=.3210, p<.05, r=.3269, p <.05), but no correlation was found between th17 + cells and neutrophil cells. the significantly correlation were found between ilobjectives: this study aimed to reveal if some features of the sinus wall and content (as homogeneity and density of the sinus content, or the continuity, thickness and density of the sinus wall), differ between the afrs and other forms of crs. we tried also to establish early diagnostic parameters for recognition of fungal rhinosinusitis on ct. results: the study included 36 adult patients (mean age: 45.58ae14.29 years, m:f ratio=2.1:1) with clinically diagnosed crs. out of all maxillary sinuses (n=72) from study patients, 62 (86.11%) were opacified, and only these sinuses were included in further analyses. we found out that: (1) positive fungal finding had 33% (12/36) crs patients and 86% (31/36) of these patients had severe forms of crs, (2) patients with positive fungal finding had more often positive specific ige ab than those without fungi in sinuses (43.9% vs. 21.3%, p=.027), (3) foci of non-homogeneity, mean and maximum densities and wall density were more common found in maxillary sinuses with present fungi than those without fungi (p=.037, p=.05, p=.05; respectively) and (4) patients with crs lasting more than 10 years had more often foci of non-homogeneity and presence of hyperattenuation centres, than patients with shorter length of crs. results: neutrophil-related gene mpo and eosinophil recruitment genes ccl13 and ccl18 showed higher expression level in acp than in controls, which were in line with the significantly elevated neutrophils and eosinophils infiltration in acp compared to control. increased cd8 + t cells, macrophages and cd4 + t cells infiltration in acp were also observed. the expression level of t-reg transcription factor foxp3 was significantly higher in patients with acp than in controls, but the expression of th1/th2/th17 transcription factor tbet, gata3 and rorc were significantly decreased in acp vs controls. we further investigated the relationships between these t-cellassociated genes in acp. the expression of foxp3 was positively correlated with t-bet, gata3, il17r and il12a, while no significant correlation with rorc was evident. il6 was observed positively correlated with t-bet, gata3, foxp3, and il17r. il10 had significant correlation with t-bet and il12a. objectives: the aim of this study was to find the olfactory change pattern of crs after ess in short-term and the differences between crswnps and crssnps, secondary aim were to identify the relationship among olfactory dysfunction, ct scores and quality of life(qol). in this study, 48 crs patients who underwent ess were evaluated preoperative by t&t recognition threshold tests, snot-20 score and lund-mackay ct score. patient outcomes were re-evaluated at clinical follow-up 1 month, 3 months and 6 months postoperative. analysis of variance was performed and correlation was calculated, with results analysed separately for crswnp and crssnp subgroups. 1. subgroups of crs differed in the degree of olfactory dysfunction reported before and after the ess. a significant difference in the changes of olfactory dysfunction between the two groups was found at 6 month postoperative. 2. the mean t&t and snot-20 scores showed significant improvement within 6 months after ess in both crswnp and crssnp subgroups, however, no significantly recovery of olfactory dysfunction was observed at 3 months compared to 1 month postoperative. there is a plateau of olfactory recovery at 3 months postoperative. 3. in crswnps, the mean t&t scores preoperative were correlated with lund-mackay ct score significantly(r=.649, p<.001; r=.625, p<.001). however, no relations were found in crssnps and the changes of olfactory dysfunction at the 6 months postoperative with lund-mackay ct score. 4. olfactory scores, before and after the ess, and their changes did not correlate with sont-20 scores. conclusions: olfactory dysfunction was more severe in crswnps. olfaction and qol of crs patients were significantly improved after ess in both groups, but there was a plateau of olfactory recovery at 3 months postoperative. ct scan may predict olfactory disorder, but the olfactory scores were not related with the qol. objectives: in this study, we investigated the effect of hgf, tgf-b1, and pge 2 as effective components for allergic rhinitis treatment using in vitro and in vivo mouse model studies. results: pge 2 decreased infiltration of eosinophil in nasal mucosa. tgf-b1 decreased the infiltration of eosinophil in nasal tissue and increased the number of treg in spleen. however, there was no antiallergic effect of hgf in this experiment condition. in case of the combination treatment group (tgf-b1+pge 2 +hgf), eosinophil infiltrations and the expression of eotaxin-2 were reduced in the nasal tissue, and treg was increased in the spleen. in all treatment group, serum ige and systemic cytokine levels were not decreased due to intranasal administration rather than systemic administration. in vitro study showed that phosphorylation of map kinases such as erk, jnk, and p38 and translocation of p65 were inhibited after treatment of hgf, tgf-b1 and pge 2 , suggesting their anti-allergic mechanism. conclusions: we found that tgf-b1, and pge 2 decreased allergic inflammation and these effects might be derived from changes in the frequency of treg and the activation of map kinase and p65 in the t cell receptor signaling pathway. furthermore, we hypothesized that tgf-b1, and pge 2 would be effective components for allergic rhinitis therapy. introduction: interleukin (il)-10 is implicated in suppression of allergic inflammation. the role of il-10 in the early-phase reaction in type 1 hypersensitivity has been unclear, however. we investigated the contribution of il-10 in a mouse model of the ige-mediated early-phase reaction in allergic conjunctivitis. objectives: ige-mediated allergic conjunctivitis was induced in c57bl/6-kit(+/+) wild-type mice, kit(+/+) il-10-deficient mice, and kit(w-sh/w-sh) mast cell-deficient mice by means of passive conjunctival anaphylaxis. the mice were thus subjected to subconjunctival injection with anti-dinitrophenol ige (dnp-ige) followed after 24 h by intravenous injection with dnp antigen. kit(w-sh/w-sh) mice that had received a subconjunctival graft of cultured bone marrowderived mast cells from kit(+/+) wild-type mice or kit(+/+) il-10deficient mice were similarly treated. vascular permeability of the conjunctiva was examined 30 min after antigen injection by colorimetric evaluation of the extravasation of evans blue dye. results: passive transfer of dnp-ige followed by intravenous antigen injection increased vascular permeability in the conjunctiva of kit(+/+) wild-type mice but not in that of kit(w-sh/w-sh) mice, suggesting that this effect was dependent on mast cells. vascular permeability was increased to a significantly greater extent in kit(+/+) il-10-deficient mice than in kit(+/+) wild-type mice. reconstitution of kit(w-sh/w-sh) mice with kit(+/+) wild-type or kit(+/+) il-10deficient mast cells restored the dnp-ige-and dnp-induced increase in vascular permeability to similar extents. our results suggest that il-10 produced by cells other that mast cells suppresses the mast cell-mediated early-phase reaction in ocular allergy. objectives: our aim was to evaluate the effectiveness and the safety of ccl treatment for keratoconus in children with vkc. forty-two boys (mean age 13.5ae3.3 years) and 17 girls (mean age 11.8ae4 years) with vkc were included in the study. tarsal, limbal and mixed vkc were detected in 55.9%, 8.5% and 35.6% of the subjects, respectively. evaporative dry eye was detected in 23 children out of 43 (53.5%), schirmer test results were <10 mm/ 5 minutes in 20.5% and <5 mm (severe dry eye) in 4 out of 44 children (9.1%) and 39% of the subjects (n=23) had confirmed keratoconus/forme fruste keratoconus with corneal topography (sirius, cso, italy). allergic symptoms were controlled with topical steroids, cyclosporine, dual action antihistaminic/mast cell stabilizers and lubricant agents before the procedure. ccl surgery was performed under topical anesthesia. the children were followed-up at least 1 year and preoperative and postoperative corneal topographic parameters were compared using paired sample t test. results: the visual acuity was between 0.4 and 0.6 (moderate visual loss) in 16.9% of the subjects and less than 0.3 (severe visual loss) in 6.8% of the children. ccl procedure was performed to 19 eyes of 15 children. at the end of one year, the disease was stable in all children with no differences in k1 and k2 corneal parameters before and after cxl (p>.05). there was a statistically significant improvement in maximum keratometry value after the procedure (before 56.57ae4d, after 55.37ae3.5d, p=.005). in one subject, a corneal infiltrate was detected 3 days after ccl, which was treated successfully with topical moxifloxacin. otherwise, no complications were observed in the postoperative period. conclusions: as keratoconus is common in vkc, these children should be referred to ophthalmologists for an eye examination and corneal topography. ccl seems to be a safe and effective option to halt the progression of keratoconus, which might be very aggressive in children with vkc. results: surprisingly, we found among them 11 cases of celiac disease, 7 cases of thyroid dysfunction (thyroiditis), 3 cases of crohn's disease and 1 case of ulcerative colitis, 1 case of anterior uveitis and 1 case of pemphigus respectively. we realized that an average percentage of 7% of the total of vkc cases are affected by an "autoimmune" systemic disease. limbal form of vkc was prevalent and more than 70% of children showed it. we can suppose that a racial and genetic predisposition to systemic diseases can coexist with vkc or that there is a group of vkc affected subjects in which the immune disorder is predominant on the allergic disease. introduction: nasal polyposis (np) is a heterogeneous inflammatory disease of nasal mucosa affecting 1-4% of the population with a high rate of recidivism. polyps arise from nasal sinuses to nasal cavity and are often associated with a strong local eosinophilia. the pathophysiology of np remains controversial, as it seems to be a phenotypic manifestation of multiple possible immunologic processes, such as respiratory allergy, despite a lack of correlated systemic response. here we propose a multiparametric assessment of np patients, in order to shed light on the underlying mechanisms of the disease in allergic and non-allergic patients and aiming to find new predictive biomarkers. objectives: our main aim was to unravel the link between systemic and local allergic inflammation and polyp development, as well as the nasal epithelium condition in polyps and surrounding healthy tissue. methods: four groups of patients were included in the study: healthy donors with or without allergy and np patients with or without allergy. in this regard, several different approaches were followed: a metabolomics serum study, a polyp and nonpolypous nasal epithelium histology and transcriptomic study. results: as for the histological study, luna staining revealed differences in eosinophilia between allergic and non-allergic patients, especially when patients were polysensitized, including perennial allergens; and between nonpolypus tissue and polyps being higher in polyps. pas staining showed differences in epithelium integrity and submucous and goblet cell (pas positive) distribution. immunohistochemistry for cd4+ and cd11c+ reveal a significant inflammatory infiltration in polyps. this inflammatory response was also asses by abstracts | 209 gene expression quantitation. no differences were seen in the metabolic profile in patient sera between groups. for the first time, nasal epithelium from polyps and neighboring tissue were studied. histology techniques and image analysis revealed differences in eosinophil concentration in both mucosa and submucosa areas, as well as different features in epithelium and submucous tissue structure. some of these findings were confirmed by gene expression quantitation. conclusions: our data show an increased eosinophilia and inflammatory infiltration in polyp tissue suggesting a role for allergic inflammation in the progression of np. additionally, we provide clues for the role of inflammation in the damage on nasal mucosa and the following progression of the disease. 0235 | is specific immunotherapy effective in subjects suffering from vkc? a tertiary referral center ten years experience. objectives: our work shows the results of sit additional to usual treatments, in children suffering from vkc and followed in our tertiary referral center (lavagna hospital, genova, italy). we retrospectively analyzed the clinical data of 37 subjects (25 males and 12 females); their mean age at the beginning of treatment was 8 ae 1.2 years. the patients were treated both with scit (sub-cutaneous immune-therapy-56.7%) and slit (sub-lingual immune-therapy -43.3%) depending on patient's wishes. they had to be mono-sensitized to one of the usually more frequent allergens (dust-mites, grass pollen, and pellitory) which was detected by means of recombinant rast, prick test and conjunctival provocation test (cpt); these tests were performed after a complete ophthalmological and allergological history and examination. children selected for sit needed to be positive to all performed allergy tests. systemic involvement included 25 cases of asthma, 5 cases of atopic dermatitis and 1 case of rhinitis; the remaining 6 cases were asymptomatic. local involvement included only vkc cases, the 62% of which were of the limbal type and only 14 subjects were suffering from the tarsal papillary type. mean follow-up was 7.2 years. all the patients included into the study completed their treatment and followed the therapeutic protocol. after one year of sit, no variation in clinical course and treatment was recorded. after the third year of sit, an average improvement in symptoms and signs score (43%) and an average decreased need for allergy systemic medications (63%.) (i.e. antihistamines and corticosteroids) was registered. also topical therapy (including steroid and cyclosporine eye-drops) was discontinued in 43% of children, in this group, short courses of steroid drops were necessary in less than 30% of children (as rescue treatment in the acute phases of the disease). these positive results after sit treatment were stable for the following 5 years. few (only local sub-cutaneous) side effects were recorded and the treatment was generally well-tolerated. conclusions: our experience shows positive results with sit in vkc which can have sensitive-to sit-treatment subtypes. results: 39 deaths occurred in children (21 boys, 54%). median age at death was 11 years (iqr 2-15). pamr of any cause was 0.08 (95%ci, 0.05-0.10) per 10 6 children per year, with a decreasing rate over time (annual change: -2.5%; 95%ci, -5.6 to 0.9). triggers were iatrogenic causes (n=18, 46%), insect venom (n=3, 8%) and food (n=2, 5%). unspecified causes were frequently reported (n=16, 41%). there was no difference in overall pamr between boys and girls (p=.74). there was no age group related differences in fatalities: preschool children (<7 years) (n=14, 36%), school children (7-12 years) (n=12, 31%), adolescent and toddlers (>12 years) (n=13, 39%). the number of fatal cases was similar comparing the southern (n=16, 41%) and the northern regions of france (n=23, 59%) (p=.15). the first episode of anaphylaxis for each patient was captured to calculate incidence. we estimated incidence rate ratios using poisson regression models. results: between 2001 and 2015 there were 523 anaphylaxis episodes in 481 patients younger than 18 years in hong kong. the incidence of admission for anaphylaxis increased markedly from 2.46 to 6.63 per 100 000 person-years during the study period (p<.001). the incidence of food-related anaphylaxis increased significantly from 0.21 to 1.88 (p<.001). increases in anaphylaxis and food-related anaphylaxis were seen in all age groups, with the largest increase in those aged 0 to 4 years. at the beginning of the study period (2001), medication was a more common trigger for anaphylaxis than food (1.61 vs 0.21 per 100 000 person-years). by 2015, food had become the predominant trigger (1.88 vs 0.54 per 100 000 personyears for medication). the incidence of medication-related anaphylaxis decreased significantly (p<.05). the incidence rate of anaphylaxis was significantly higher in boys than girls in the 5-14 and 15-18 year age groups, while there was no significant gender difference in the 0-4 year age group. the most common food triggers of anaphylaxis were peanuts, seafood, eggs, milk products, tree nuts & seeds (in descending order). conclusions: even though the incidence of anaphylaxis among children in hong kong is lower compared with other western countries, it has recently increased significantly, with food-related anaphylaxis predominant. 0238 | prevalence of anaphylaxis and prescription rates of epinephrine self-injector in korea based on national health insurance data results: the prevalence of anaphylaxis over the 5 years were 0.02%. the annual prevalence of anaphylaxis increased over the 5 years. anaphylaxis was more prevalent in male than female (56% vs. 44%) and in population aged 50-59 years old. for the regional prevalence of anaphylaxis in korea, gangwon province showed the highest prevalence of anaphylaxis (41.5 per 100 000 individuals) and relatively low prescription rates (5.8%) of epinephrine self-injector for the patients with anaphylaxis. on the contrary, seoul showed relatively low prevalence of anaphylaxis (14.3 per 100 000 individuals) and the highest prescription rates (26.6%) of epinephrine self-injector for patients with anaphylaxis conclusions: the prevalence of anaphylaxis has increased annually in korea. the prevalence of anaphylaxis and prescription rates of epinephrine self-injector showed regional difference in korea. objectives: the aim of the study was to analyze the prevalence of allergic symptoms and anaphylaxis in mastocytosis patients analyzed in the registry of the ecnm. results: methods: a total of 1513 patient with mastocytosis were enrolled. in these patients, the prevalence of allergy, anaphylaxis, triggers of allergic reaction, and disease subtypes were analyzed. results: symptoms of allergy were observed in 28% of all patients. the most affected group were patients with bone marrow mastocytosis (bmm: 64.52%) and indolent systemic mastocytosis (ism: 32.78%). insect venom allergy (iva) was reported in 14.14% of all subjects. in ism/bmm patients iva affected 22.30% of the cases, while in other patient groups, only 4.3% of the cases were affected (p<.00001). most patients (64%) had wasp allergy, 18% had bee allergy, 2% polistes allergy, and 6.8% allergy to more than one venom. in 9.2% the culprit insect was not identified. food allergy was reported in 3.56%, drug intolerance/allergy in 4.7%, inhalant allergy in 4.43%, and physical triggers in 0.8% of patients. in mastocytosis patients iva is the most prevalent cause of anaphylactic reactions exceeding the prevalence of iva in the general population by far. iva affects mainly bmm and ism patients (22.3% of cases). but 267 (66.1%) subjects didn't know whether adrenaline was administered. only 6 within 44 patients who had adrenaline autoinjectors used their autoinjectors during an anaphylaxis attack. most common symptoms were skin (n=363, 89.9%) and respiratory symptoms (n=327, 80.9%). syncope, hypotension or hypoxemia were present in 273 cases(63.9%), at least three organ dysfunctions in 258 (63.9%) cases; 56 patients (13.9%) had to be hospitalized (f:36, m:20).nearly a third (26.2%) of the patients had stage 1-2 anaphylaxis and 298 patients(73.8%) had stage 3-4 reactions. in 184 cases (45.6%), basal tryptase levels were examined and the average value was correlated with the severity. concomitant drugs being used by the patients were antihypertensives (20.5%),oral antidiabetics (6.2%); angiotensin converting enzyme inhibitors or angiotensin receptor blockers(11.1%), beta blockers(8.4%), diuretics(4.7%) and nsaid's (7.2%). conclusions: male sex was noted as a risk factor for severe reactions and recurrent anaphylaxis. anaphylaxis requiring hospitalization was more frequent in the patients using oral antidiabetics or diuretics. baseline tryptase levels were higher in patients with neurological and gastrointestinal symptoms. cardiovascular symptoms were found to be higher if a cofactor was present. skin symptoms were seen more frequently and higher rate of hospitalization occurred in anaphylaxis in the presence of infections or nsaid use. this study is important to elucidate the factors affecting anaphylaxis severity. 0241 | serum levels of 9a,11ß-pgf2 in combination with apolipoprotein a1 or cysleukotrienes are reliable biomarkers of anaphylaxis objectives: we analyzed mast cell mediators in sera derived from patients with acute anaphylactic symptoms (n=18) versus patients with acute cardiovascular or febrile reactions (n=12) and patients with a history of anaphylaxis but without displaying any symptoms when sera were taken (n=27). in addition, we identified proteins with substantial changes during anaphylaxis. matched serum samples were used to compare basal mediator levels with corresponding levels during acute anaphylaxis in the same patient (n=9). roc curve analysis was performed to determine the sensitivity/specificity of each mediator. results: serum levels of histamine and tryptase were not increased upon anaphylaxis and showed no relation to anaphylaxis severity. however, serum 9a,11ß-pgf 2 , a metabolite of pgd 2 , was significantly increased in acute anaphylactic patients (~8-fold) and abstracts | 213 correlated well with anaphylaxis severity. 9a,11ß-pgf 2 distinguished anaphylaxis from cardiovascular or febrile reactions and showed the highest diagnostic power observed by roc curve analysis. cys-leukotrienes (cys-lts=ltc 4 , ltd 4 , lte 4 ) were increased upon anaphylaxis while apolipoprotein (apo) a1 was significantly decreased. the highest diagnostic power was observed with the combination of 9a,11ß-pgf 2 and apoa1. conclusions: in conclusion, histamine might only be used to detect anaphylaxis when assessed shortly after onset of an anaphylactic response because of its short half-life, whereas tryptase is a useful biomarker if the baseline level of the same patient is known. 9a,11ß-pgf 2 seems to be the most reliable marker as demonstrated by the distinct increase upon anaphylaxis and could be supported by apoa1 or cys-lts. further investigations are needed to prove the suitability of these markers. objectives: objective of this study was to estimate the long-term bv of tryptase using certain chronic disease models and to compare it with those in food and drug allergy. results: serial determinations of tryptase concentrations (n≥5 data points per patient) obtained from patients diagnosed with mastocytosis (n=10) or chronic urticaria (n=1) during a period of sometimes several years were measured by the immunocap assay and evaluated using sigmaplot software. polynomial curve fitting was performed and data points outside the 95% confidence interval of the curve were appointed as outliers and excluded. because the data points were not normally distributed due to long-term fluctuations in homeostatic set-point, a non-linear fitting was applied and used to compute the standard error of the estimate. these standard errors of the fit divided by the estimates themselves were used to calculate the total coefficient of variation within a subject (cv t ). the analytical cv (cv a ) was calculated based on quality control samples (3 levels, n=149 data points) in a conventional way, while the within-subject bv (cv i ) was defined as cv l =(cv t 2 à cv a 2 ) ½ . eleven patients with a chronic disease were selected, of which 1 patient was treated as a potential outlier and 2 patients had to be excluded because of cv t <cv a . the between-subject bv (cv g ) was without the outlier 3.68ae1.92% (n=85 data points during a period 5.6ae2.3 years) and with the outlier 5.75ae6.46% (n=92 data points during a period of 5.3ae2.4 years). as a food and drug allergy control group 2 additional patients were selected with an uncomprehended food (n=1) or drug allergy (n=1). this cv g was calculated under the same conditions and proved to be 9.61ae1.64% (n=16 data points during a period of 4.1ae1.2 years). the long-term between-subject biological variation of tryptase concentrations of patients in chronic disease models was smaller than that of patients with an uncomprehended food or drug allergy. chronic disease models may be of interest to determine the long-term "physiological" biological variation of tryptase. vilà-nadal g; rodr ıguez-sanz a; s anchez-villanueva r; fiandor-roman a; dom ınguez-ortega j; bell on-heredia t introduction: hypersensitivity reactions during hemodialysis sessions have been reported. our aim was to study the mechanisms of the allergic or "pseudoallergic" reactions to synthetic polysulfone (ps) dialysis membranes in "ps-allergic" patients who tolerated cellulose triacetate (cta) membranes. objectives: ten patients with adverse reactions to ps and 8 control non-allergic patients in hemodialysis were studied. 50 ml of blood were collected and an ex-vivo hd were performed on experimental external circuits with low or high priming volumes and pediatric membranes (fx-paed helixone 0.2 m 2 and sureflux). serum tryptase levels, basophil degranulation (hla-dr à cd123 + cd63 + leukocytes), and t cell activation (cd69 expression on cd4 + and cd8 + subpopulations) were analysed in pre-and post-dialysis samples. objectives: the aim was to investigate the influence of asa and alcohol on egg allergy. donor sera from 4 egg allergic patients (i-iv) with s-ige to ovalbumin at (i) 0.1, (ii) 8.87, (iii) 19.5, and (iv) 170 ku/l were injected intracutaneously to the forearm of 11 healthy/nonallergic volunteers. they were then orally challenged separately with: 1) egg white 2) egg white + asa and 3) egg white + alcohol. 'time to wheal' and 'wheal size' were compared between the three experiments. results: two sera (i-ii) with the lowest s-ige to ovalbumin did not react sufficiently and where excluded from further analysis. the 2 remaining sera (iii-iv) significantly decreased 'time to wheal' with both asa (p=.001) and alcohol (p=.019) added as co-factor compared to baseline. increase in 'wheal size' was only found with co-factors added for the less reactive serum (iii) and not for the serum with the highest s-ige (iv). introduction: eaaci have published numerous guidance documents providing evidence-based recommendations for the recognition, risk factor assessment and management of anaphylaxis. these guidelines clearly advocate intra-muscular adrenaline firstline for the treatment of anaphylaxis, and list absolute indications when an adrenaline auto-injector (aai) must always be prescribed; eg for those who have previously experienced an anaphylactic event, those who have a mast cell disorder and for those with co-existing unstable or moderate/severe asthma and a food allergy. furthermore, eaaci recommends that an aai should be prescribed to those at risk of anaphylaxis (termed relative indications), and that 2 aais should be prescribed and carried by patients at all times. despite widespread dissemination of these guidelines, anaphylaxis hospitalizations continue to rise in many european countries. objectives: in this environment eaaci developed the anaphylaxis survey (axis) as part of its allergy awareness initiative to gain insight into guideline awareness. this survey was sent by email to 8720 eaaci members. 873 members from 89 countries responded. data were anonymous and analysed descriptively. results: 81.4% (n=711) reported familiarly with the eaaci anaphylaxis management guidelines, and of these 96.8% (n=688) reported following them. 97.0% (n=847) responded that they would use adrenaline firstline for the treatment of anaphylaxis (although 9.6% (n=84) would still administer it subcutaneously). however, when confronted with a list of indications, only 41.8% (n=365) of eaaci members would prescribe an aai for all absolute indications. furthermore, although 90.1% (n=787) of respondents considered they would prescribe an aai for those at risk, when provided with a list of relative indications, 0% would prescribe an aai for all of them. there was also a lack of consensus about when an aai should actually be used, with 23.8% of respondents (n=208) considering aai use when individuals experienced breathing difficulties and felt that they were going to collapse. conclusions: these results reflect the latest findings that aais are under-prescribed in daily practice. there appears to be a mismatch between perception of guideline compliance and aai prescription behaviour. continued training, further simplification and wider dissemination of guideline messages are required. objectives: the aim of this study was to analyse the clinical practice of emergency physicians concerning the management of anaphylaxis in alsace and lorraine, a region of 3.5 million inhabitants, in france via an electronic survey. results: the response rate was 18.3% (44). fifty percent of physicians were female. 84.1% (37) (1). in case of grade 2 reactions, intramuscular adrenaline injection was performed by 11.2% (5) of physicians as first-line treatment, intravenous adrenaline injection by 8.4% (4), antihistamines (oral route or iv) by 16% (7) and corticosteroids (oral route or iv) by 17.8% (8). in case of grade 3 reactions, intramuscular adrenaline injection was performed by 13.6% (6) of physicians as first-line treatment, intravenous adrenaline injection by 64.3% (28), iv antihistamines by 6.8% (3) and corticosteroids (oral route or iv) by 16% (7). following an acute anaphylaxis episode, only 2.3% (1) of physicians systematically recommended an allergy assessment, 11.2% (5) sometimes, and 86.4% (38) never. conclusions: this study highlights the discrepancies between current guidelines for the management of anaphylaxis in emergency departments and common clinical practice. our results emphasised the need for specific programs to improve clinical management of anaphylaxis in ed. conclusions: a significant number of individuals among those surveyed reported a severe allergic reaction requiring an eai, yet less than a quarter used an eai. the study also identifies most common challenges faced by at-risk individuals including eai availability, cost, and concerns over short expiry dates. objectives: to evaluate the implementation of a stock epinephrine (stock epi) program in a mall setting. stock epinephrine devices are not prescribed for a particular person and can be used in anaphylactic emergencies. methods: a mixed methods approach was used to evaluate the implementation of the stock epinephrine program regarding its acceptability and adoption by diners, food service, mall administration and security personnel; and the appropriateness, costs (included costs for personnel, epinephrine auto-injector devices, and training materials), fidelity, reach, and sustainability (measured by the national health service (nhs) sustainability model, united kingdom) of the program in this setting (hamilton, ontario, canada). the study revealed that individuals with food allergy and food service establishments were in favour of a stock epi program. a total of 1580 individuals with food allergy completed our national online survey. approximately 42% dine out once or twice per month, and one-third had experienced an allergic reaction. we also completed in-person surveys with 120 diners at the mall food court. of these, 24% had a food allergy and 35% reported carrying their epinephrine auto-injector when dining out. the mean nhs sustainability score was 87 among survey participants, well above the mean considered a sustainable program (>55). total cost of the stock epi program over a one-year period varied by ontarian stakeholders: $2155 for the mall, $987 for fast-food restaurants, and $715 for sitdown restaurants. conclusions: this is the first study to evaluate the implementation of a stock epi program. the stock epi program was well received abstracts | 217 and sustainable. implementing a stock epi program provides enhanced access to emergency medication, however it does not replace the responsibility of individuals with food allergy to self-manage. objectives: to identify the optimal needle length for epinephrine prefilled syringe. results: three hundred seventy-two children aged 1 month to 18 years were enrolled. skin to muscle depth (stmd) and skin to bone depth (stbd), which can represent the minimum and maximum needle length respectively, were measured using an ultrasonography at the mid-anterolateral thigh. number of children who had stbd less than needle length (too long needle) and stmd greater than needle length (too short needle) were calculated. one hundred thirty-seven children weight <15 kg, 80 children weight >15-30 kg, and 155 children weight >30 kg were enrolled: 196 (52.7%) children were male. one inch needle was too long in 38 (27.7%) children weight <15 kg, 1 (1.3%) children weight >15-30 kg. it was too short in 8 (5.2%) children weight >30 kg. age≥3 months, weight≥6 kg, height≥59 cm, bmi≥13 kg/m 2 and thigh circumfer-ence≥23 cm, provided the sensitivity of 97-99% in predicting the appropriateness for using 1 inch needle for children weight <15 kg. in children weight >30 kg, thigh circumference≥48.75 cm provided the sensitivity of 86% and specificity of 75% for predicting the inappropriateness for using 1 inch needle. objectives: we present a patient with a probable mdh syndrome to unusual drugs, including ah and cct. results: we report a case of a 23-years-old female, with history of moderate-persistent asthma and chronic urticaria, who experienced angioedema and exacerbation of urticaria hours after the administration of multiple ah (desloratadine, loratadine, cetirizine), systemic cct (hydrocortisone, methylprednisolone, deflazacort) and nonsteroidal anti-inflammatories (nsaids) (paracetamol, ibuprofen, flurbiprofen). patch tests (pt) with excipients (bial arestegui ® ) and drug provocation test (dpt) with placebo were negative. skin prick tests (spt) and intradermal tests (id) with hydroxyzine, hydrocortisone, methylprednisolone and prednisolone were positive to hydroxyzine (5mg/ml) and pt with corticosteroids (bial arestegui ® ) and hydroxyzine were negative. dpts with desloratadine and an alternative ah, dimetindene, were positive with facial angioedema and generalized urticaria within 5 hours. lymphocytic transformation test (ltt) was positive to desloratadine, ebastine and clemastine. dpt with dexamethasone was negative, however, when administered as treatment, a reproducible reaction occurred. since dpt with montelukast was also positive, omalizumab 300mg was initiated to control angioedema and chronic urticaria. after 1 year of treatment, dpt with nimesulide was negative. omalizumab dose was reduced to half after the patient found out she was pregnant. there were no further episodes after anti-ige therapy introduction and pregnancy went uneventfully. conclusions: mdh syndrome is rare, more so when the drugs reported are ah and cct. hr to ah was confirmed, but diagnostic workup remains incomplete, postponed due to the patient's pregnancy. this case is as challenging in terms of diagnosis as it is in terms of therapeutic, so much so that omalizumab was initiated as an off label therapy, maintained during pregnancy based on the premise that risk was lower than benefit. objectives: in this study, we aimed to present our patients who were admitted with oral iron hypersensitivity. conclusions: according to our clinical experience, we think that oral iron salts with different conjugates are safe and acceptable option in patients with suspected oral iron hypersensitivity. introduction: antineoplastic agents are consider nowadays an essential treatment for many kinds of cancer. the increased use of these drugs in recent years is in parallel with a high rise of hypersensitivity reactions to them. these reactions range from mild to severe and as other allergic reactions, are not predictable. a nursing protocol in the desensitization schedules with these drugs is essential in allergy daily hospitals. objectives: the aim of this study are to describe a nursing protocol during desensitization schedules with antineoplastic agents carried out in our allergy unit in order to detect symptoms suggestive an allergic reaction during drug administration and to assess a correct intervention in case of reaction. conclusions: an appropriate nursing protocol in desensitization schedules with antineoplastic agents is essential in order to achieve the correct administration of the treatment in safety conditions. 0255 | long term clinical effects of aspirin desensitization in patients with nerd: comparison of maintenance doses of 300 mg vs 600 mg aspirin çelik ge 1 ; karakaya g 2 ; erkekol f € o 3 ; dursun ba 4 ; gelincik a 5 ; celebioglu e 6 ; y€ ucel t 7 ; yorulmaz i 8 ; dursun e 9 ; tezcaner ç 8 ; s€ ozener zç 10 ; b€ uy€ uk€ ozt€ urk s 11 ; kalyoncu f 12 ; aydin ö 1 introduction: aspirin desensitization (ad) treatment has been shown to be effective in relieving the respiratory symptoms as well in reducing recurrency of nasal polyps in patients with nsaids exacerbated respiratory diseases (nerd). however, a conflict occurs about effective maintenance doses of aspirin on clinical parameters. objectives: in this study, our aim was to compare the effects of two different maintenance doses of aspirin on clinical outcomes for 3 years of ad. this was a multicenter study which involved 4 tertiary centers. patients who completed at least one year of ad treatment were included to analysis. study outcomes were number of nasal surgery, sinus infections, asthma morbidity (number of severe asthma attacks, hospitalization) as well as medication uses for both clinical conditions. the study included 114 subjects, 33 of whom were under 300 mg aspirin daily as maintenance treatment whereas remaining 81 on 600 mg aspirin for a mean of 48.2ae32 months of ad duration. regardless of maintenance doses, number of nasal polyp surgery gradually decreased at 1 (0.04ae0.03/year) and 3 years (0.02ae0.01/year) compared to that of before ad (0.41ae0.06/year) (p<.0001) in all subjects and were comparable in 300 and 600 mg. considering asthma outcomes, decrease in asthma attacks were observed only in 600 mg aspirin group (p<.01) at 1 and 3 years whereas hospitalization due to asthma and systemic corticosteroid use decreased in both groups at 1 and 3 years. conclusions: ad has a reducing effect on nasal polyp recurrence for at least 3 years in patients with nerd. this effect was similar for both 300 and 600 mg maintenance doses of aspirin. considering both treatment arms provided decreased hospitalization due to asthma and systemic corticosteroid use, we think that at 3 years evaluation both 300 and 600 mg/day aspirin has comparable effects on asthma as well. however, reducing effect of ad on asthma attacks was only existed in patients taking 600 mg. aspirin. objectives: pregnant women with syphilis and history of immediate hypersensitivity reaction (hsr) to penicillin were enrolled. according to the risk stratification, which was based on the initial hsr, serum specific ige and skin tests, patients were re-exposed to penicillin either through desensitization or provocation. patients with a clinical history suggestive of penicillin-anaphylaxis and/or positive serum specific ige to penicillin and/or positive immediate skin test were considered at high risk and were desensitized. the remaining patients underwent penicillin provocation test. results: we evaluated 21 pregnant women with latent syphilis and history of penicillin allergy. clinical history was suggestive of immediate hsr in 13 out of these 21 (62%) patients, who were desensitized. all of them had negative serum specific ige to penicillin. intradermal tests were positive in 4/13 (30%). three out of those four were desensitized with an oral protocol and reacted during the procedure. one patient had a severe breakthrough reaction with uterine contraction and did not finish the procedure. the only patient with positive intradermal test that didn't react during the rdd underwent an intravenous protocol. the remaining 9/13 (70%) patients had negative skin tests and an uneventfully rdd. there was a statistically significant association between positive intradermal tests and breakthrough reactions during the rdd (p=.02). the other 8/21 (38%) patients with inconclusive history and negative skin test were submitted to penicillin provocation, which were negative in all of them. conclusions: risk stratification based on the initial clinical reaction and skin testing to guide penicillin re-introduction was safe and effective, as well as rdd. skin testing identified allergic patients to penicillin with increased risk of reactions during rdd. 0257 | utility of basophil activation test for monitoring the acquisition of clinical tolerance after subcutaneous desensitization to brentuximab-vedotin in two patients many hypersensitivity reactions (hsrs) produced by biologic agents have been seen and their true incidence is unknown. desensitization is a method to counter hsrs from monoclonal antibodies in patients with no other adequate alternative options. objectives: we describe a successful rapid desensitization to bv in two patients with scleronodular type hl, refractory to several lines of chemotherapy and asct. this clinical tolerance to bv is easily observed through the basophil activation test (bat) as a decrease in activated basophils after desensitization was done as a treatment of hsrs. because there was no therapeutic alternative in the two patients, we planned to pursue bv administration using a rapid desensitization 12-step protocol. a total dose of 125 mg of bv was given through increasing rate and concentration. the patients completed their infusion without difficulty. after desensitization to bv, bat was done in both patients. the percentage of activated stimulated basophils with bv descended in both patients. both values are similar to their corresponding negative controls. conclusions: the bat continues to be a useful in vitro tool for the study of drug allergic disease. also, the bat in flow cytometry is able to monitor an acquired tolerance induced by a desensitization treatment in hsrs to bv. however, studies involving a larger number of patients will be required to assess the safety and efficacy of this approach to bat as a method to validate rapid desensitization in patients with hsr to bv. objectives: we retrospectively reviewed 166 desensitizations in patients with a history of ihsrs to chemotherapy agents performed in our center from january 2014 to december 2016. the protocol consists of increases in infusion rate every 10 to 15 minutes, in a 10 to 12 steps depending on the drug. in all cases the protocol was performed without premedication (only using regular medication according to instructions for every drug). results: a total of 61 patients with a history of (ihsrs) received 166 desensitization protocol without premedication to chemotherapy agents. the most common involved drug was carboplatin in 24 (39.3%) patients (of these 66% presented positive skin test (st)), followed by paclitaxel in 15 (24.9%) patients (of these 46.6% presented a positive st) and oxaliplatin in 9 (14.75%) patients (of these 11.11% o the st were positive). other chemotherapy agents involved were cetuximab, rituximab, irinotecan, epirrubicin, etoposide, cisplatin and cyclophosphamide. all patients were able to successfully complete the desensitization protocol without premedication and none of them need to withdraw the drug. conclusions: this protocol for rapid desensitization to chemotherapy without premedication is safe and effective. in addition, minimizes secondary effects of the premedication in these patients that are polymedicated. 0259 | rapid desensitization for the management of hypersensitivity reaction to biologicals-infliximab and adalimumab in inflammatory bowel disease patients objectives: to identify barriers to best practice with regards to drug allergy history taking and documentation, and to elaborate the potential strategies to overcome them. results: a total 164 prescribers responded to the survey: doctors in training 47.6% consultants 44.5% non-medical prescribers 7.9% most respondents 56.1% (95%ci 47.9-64.3%) were not aware of the availability of penicillin allergy testing in our trust. among those that were aware of it, 63.9% (95%ci 51.9-76%) had not referred any penicillin-allergic patient to immunology during the past year. barriers to accurate allergy history collection: 55.2% (95%ci 47-63.4%) concurred that often it is not possible to draw a firm conclusion based on history alone. 59.4% (95%ci 51.4-67.5%) agreed with the statement saying that, regardless of the details of the allergy history, it is always better to "play it safe" and not to use alternative beta-lactams in patients labelled as being penicillin-allergic (figure will be attached in the poster). among the interventions proposed; practical educational sessions, an interactive questionnaire to guide allergy history taking and classification and a modified antibiotic policy to guide prescribing based on the allergy classification, were all rated as useful (average score >7 on a scale from 1-not useful at all-to 10-very useful). 0262 | the regulatory role of germinal center maturation during the early b cell response to inhalant allergens investigated in the piama cohort using the medall allergen microarray introduction: in contrast to common belief, igg to airborne allergens is higher in allergic subjects, even before immunotherapy. one of the confusing aspects of the allergic immune response is that not only the igg response, but also the ige response can follow more than a single trajectory (with or without gc maturation). for ige we assume that the direct isotype-switching pathway (igm to ige) is the most relevant for the initial, mature-gc independent phase of sensitization to low-dose airborne allergens (such a pollen, mite). in later phases and for higher exposure situations as well as for other immunization routes, indirect switching is assumed to be the more relevant pathway. methods: ige, igg1 and igg4 antibodies were measured using the medall allergen microarray in 105 children from the piama cohort at age 1 and 4. these results were analyzed in relation to the ige levels at age 4 and 12. objectives: to find support for the hypothesis that the ige/igg ratio reflects not only exposure, but also details on immunological processes during sensitization, such as germinal center maturation. results: sigg1 and sigg4 levels to the major inhalant allergens were low at age 1 and remained in general low at age 4. however, children who at that time were positive for ige an allergen had a significant increased sigg1 to the allergen in question. sigg4 also appeared, but this response was low. the sigg level at age 4 in sigenegative children was not consistently predictive for sige at age 12. conclusions: the initial igg1 response to inhalant allergens is synchronized with the ige response. this result fits with the hypothesis abstracts | 225 that in the initial phase of sensitization to inhalant allergens the allergen initiates a weak and incomplete germinal center response that allows parallel ige-and igg1 production. one of the consequences of the multiplicity of b cell developmental pathways is that the igg/ige ratio is potentially diagnostic: if a subject has sigg levels in the microgram range, and thus a high sigg/sige ratio, this indicates involvement of mature gcs and the indirect class-switching pathway for some or all of the sige in this subject. 0263 | synthetic allergoid consisted of plga nanoparticles covered with synthetic peptides from bet v1 objectives: the aim of this study was to test a hypothesis that the ahr signaling is critical in controlling sl homeostasis through the regulation of key sphingolipid enzymes involved in the s1p synthesis. results: we found that an ahr ligand and a tryptophan photoproduct, 6-formylindolo (3, 2-b) carbazole (ficz; 1 nm), induced a increase in s1p level in a ros and ca 2+ -dependent manner, leading to the degranulation as well as il-13 secretion in mast cells, when compared to those seen in vehicle-treated cells. this was concomitant with an increased level of sphk1 phosphorylation and with a reduction in the enzymatic activity of s1p lyase, which could be reversed by the addition of an anti-oxidant, nac. moreover, s1pl was found to be directly oxidized by ros in vitro and in vivo. conclusions: our findings suggested that ahr-mediated ros and ca 2+ signals are critical for controlling sl homeostasis through regulating sphk1 and s1pl metabolic pathways, providing a new regulatory pathway in mast cells. methods: peptide cytokine mimetics were selected by phage display technology. flow cytometry, elisa, elispot, t cell proliferation, reporter gene, mediator release, intravital microscopy and peritonitis assays were conducted to evaluate the capacity of the mimetic peptides to modulate the immune response. results: the synthetic tgf-b1-like peptide was able to down-regulate the production of tnf-a, il-4, ifn-c and il-8, up-regulate il-10, decrease basophil degranulation and induce t reg cell differentiation. furthermore, this peptide was able to decrease leukocyte rolling and neutrophil migration during an inflammatory condition in vivo. the synthetic il-10-like peptide was able to decrease basophil degranulation and to inhibit the proliferation of allergen-specific t cell lines established from the peripheral blood of birch pollen-allergic patients. conclusions: the peptide cytokine mimetics tested herein, were able to modulate the immune response in the tested conditions. they, thus, represent promising novel candidates for therapeutic approaches. nonetheless, most studies focus on changes occurring early in life and there are rare data on differences in responses between allergic and non allergic subjects. objectives: we aimed to evaluate i) the maturation trajectory of the tlr3 antiviral pathway ii) if this trajectory varies between atopics and non atopics. peripheral blood mononuclear cells (pbmcs) were isolated from otherwise healthy atopic and non atopic subjects. atopy was assessed by medical history and skin prick testing to 8 common aeroallergens and egg white. selected cytokines involved in the antiviral response were measured by luminex multiplexing technology in 24 hour culture supernatants of poly:ic-stimulated pbmcs. data were analyzed by estimating the non-parametric correlation between age and cytokine expression in atopics and non atopics and comparison of regression curves for each cytokine between the 2 groups was performed. results: the analysis comprised data from 39 atopic and 39 non atopic patients (mean age 10.8 years, age range 0-45 and mean 10.3 years, range 0-43.3, respectively). significant age-related increases in the production of ifn-a2, ifn-c, il-1b, il-17a, tnf-a, and mip-1b were found only in non atopics and of il-9 and il-10 in both groups. significant differences in the trajectories (slopes) of cytokine responses over time between atopics and non atopics were observed for ifn-a2, ifn-c, il-10, il-1b, tnf-a and mip-1b, with suboptimal production in atopics. conclusions: age-related increases in cytokines implicated in innate antiviral responses were observed mostly for non atopics. atopy was associated with suboptimal trl-3 induced cytokine responses. differences in the developmental pattern of those cytokines between atopics and non atopics may account for the reported increased susceptibility of atopics to infections. 0271 | a systems-immunology approach identifies a set of micrornas in shaping the th2 phenotype in allergic airway inflammation introduction: mouse allergy is a common disease in inner city households, affecting up to 18% of children who are exposed as determined by house dust analysis. it is associated with allergic rhinitis, atopic dermatitis and asthma and it has been reported that exposure and sensitization to mouse allergens is a strong predictor for asthmatic disease. despite a strong link between mouse exposure and asthmatic disease, the allergic immune response to mouse has been significantly understudied. to date, only one major allergen in mouse, mus m 1, has been identified and very little is known about the targets of the allergic immune response against mouse. objectives: using a proteomic/transcriptomic approach, we sought to identify t cell targets in 24 mouse allergic and asthmatic patients. results: mouse urine and epithelial extracts were analyzed by 2d-ige/igg immunoblots using pooled sera from mouse-sensitized donors. mass spectrometry of selected protein spots identified 30 novel antibody reactive proteins. predicted mhc binding peptides from these novel proteins and mouse homologs to mammalian allergens were screened for t cell reactivity in pbmcs from mouse allergic patients. overlapping peptides from the major mouse allergen mus m 1 and its major urinary protein isoforms were screened in parallel. our screen for t cell responses in pbmc from mouse allergic donors demonstrated that major urinary proteins account for >75% of the total t cell response but they are not the only target of mouse-specific t cell responses. reactivity to mouse peptides homologous to other mammalian allergens, specifically guinea pig, was also detected. conclusions: in summary, our data demonstrates that the cellular and serological targets of the allergic response overlap, with mus m 1 being the major target for both t cells and antibodies. to the best of our knowledge, this is one of the first comprehensive studies of t cell epitope targets in mouse allergy, which provides important insights into cellular and serological targets. this data may form the basis for the development of a mouse-specific immunotherapeutic approach. introduction: food allergy has a complex etiology with many potential underlying factors proposed to contribute to and modify its development and progression. the use of a databases to collect and analyse all relevant data related to incidents of food allergy is essential to fully understand causal factors and improve treatment. objectives: we developed a database using sql, hibernate and java server pages (jsp) that was designed to allow allergy professionals to easily add and modify patient data, including medical history, reaction details and in vitro/in vivo test results. we then filled this database with clinical data relating to reactions to plant-based foods for patients who visited the allergy service of the regional university hospital of malaga between 2012-2016. these data were then analysed in various ways. cluster analysis of skin test results was used to search for relationships between different allergens based on similarities between patient sensitisation profiles; descriptive statistics and graphical analysis were performed to search for relationships between food type, age of first reaction, number of reactions and reaction severity. results: cluster analysis placed the different skin test allergens in distinct groups, which generally correlated with the type of allergen. for example, nuts, rosacea plant-food, mites, trees and weeds formed distinct clusters. analysis of patient history data showed that the first reaction occurred most frequently between ages 10-20, with a right skewed distribution. a relationship was also found between age at first reaction and reaction severity, being urticaria and angioedema more common when the initial reaction occurs at a younger age, and anaphylaxis when the initial reaction occurs later in life. oas remained relatively prevalent at all ranges (around a quarter of all reactions in all age groups). we found fruits to be the most frequent triggers, followed by nuts; within fruits peach and banana were the most frequent. conclusions: this preliminary study show the importance and utility of recording patient allergy information in a well-structured and easily managed database. future work is currently underway to collect a new set of patients from the same geographical area and to analyse similar data from a different area in order to identify what results are replicable within our population and which results are generalizable to other areas. introduction: cow's milk allergy is very common in children and its correct diagnosis is important to prevent possible dangerous allergic reactions. the aim of the present work was to evaluate the prevalence of allergic sensitization to both cow's milk and to its main proteins. with medcalc 9 ® . normality distribution of data was evaluated through the kolmogorov-smirnov test. patients were divided into three age groups (0-2 years, 3-6 years-7-16 years). chi-squared test was performed to verify a statistical difference between sensitization to whole milk and to its main proteins and patients' age. introduction: the order fagales represents an important cause of tree pollen allergy, which is ubiquitous in the northern hemisphere. a high degree of allergenic cross-reactivity has been observed among allergens from these plants, mainly represented by pathogenesis-related protein class 10 (pr-10) pr-10s, including inhalant and food allergens. conclusions: testing ige reactivity to a panel of pr-10s unveils important associations between sensitization profiles and clinical presentation, and allows the identification of novel cluster patterns potentially useful to predict disease severity in patients with pr-10 allergy. results: 11 patients were included, seven boys and four girls, with a median age at diagnosis of six months. the most common offending foods were cow's milk protein (cmp, n=5) and rice (n=2). other foods were fish, egg, chicken, wheat, carrot and potato. average time of symptom onset was 2.5 hours. the most frequent symptoms were vomiting (n=10) and diarrhea (n=4). six patients had a history of hospital admission related to this problem. seven patients had concomitant atopic diseases, being the most frequent allergic comobility atopic eczema (n=5). skin prick tests and/or specific ige to culprit foods were negative at diagnosis, except for one patient with low specific ige to cmp. another patient become sensitized to cmp during follow-up. open food challenges were performed in 10 patients starting from six months of age. resolution was achieved in 6 patients, at a medium age of 36 months. results: a total of 2901 cases of immediate-type fa among 2056 children were reported, with 92.5% involving patients younger than 7 years of age. the major 7 causative foods were hen's egg (27.4%), cow's milk (26.6%), walnut (7.2%), wheat (6.2%), peanut (5.5%), soybean (2.4%), and shrimp (2.2%). the most common causative food in each age group was cow's milk (0-2 years), walnut (3-6 years), walnut and hen's egg (7-12 years), and buckwheat (13-18 years), respectively. the symptom onset time was less than 30 minutes in 65%. food-induced anaphylaxis was reported in 732 (25.2%) out of 2901 cases, and the major 7 causes were cow's milk (26.9%), hen's egg (20.1%), walnut (12.0%), wheat (9.6%), peanut (7.0%), buckwheat (4.0%), and shrimp (2.5%). the proportion of anaphylaxis was highest in buckwheat (60.4%), followed by walnut and pine nut (42.1% each). korean children were hen's egg, cow's milk, walnut, wheat, and peanut, with distinctive distributions according to different age groups. anaphylaxis was reported in 25.2% among immediate-type fa. results: a total of 263 children with a median (inter-quartile) age of 6.13 years (4.27-8.43) were enrolled to the study; (male 66.5%). their ages at diagnosis were 0.50 years (0.40-0.67); follow-up times were 5.63 years (3.57-7.69) and milk specific ige levels at diagnosis were 7.6 ku/l (1.9-27.2). in 30.8% of the children there was only cma; the other children were polyallergic to different foods having most frequently egg white allergy. concomitant diseases were 56.7% atopic dermatitis, 35.4% were asthma, 12.2% were allergic rhinitis. during the follow-up milk tolerance was developed in 43.1%, 65.2% and 68.1% at the ages of 3, 5 and 6 years respectively. the specific ige level at the beginning of the disease was found to be a risk factor for the persistence of the disease (p<.001). conclusions: cma is frequently present with other food allergies. nearly half of the patients develop tolerance to cm up to the age of 3 years; whereas 2/3 becomes tolerant when they are at the age of 5 years. most frequent concomitant diseases are atopic dermatitis and asthma. objectives: two survey tools were used; a questionnaire based on similar surveys done overseas, and the validated food allergy quality of life questionnaire (faqlq). this was distributed throughout paediatric allergy clinics at two metropolitan centres. children and adolescents aged 10-19 completed the questionnaire independently, whilst parents assisted with children aged 5-9 years. results: 102 surveys have been collected at the time of writing of which 64 were answered by parents for young children. overall, 44/ 97 (45%) reported bullying, with a higher portion in older children and adolescents (22/37; 59%). of this group, 10/20 (50%) reported being bullied or teased because of their food allergies. from parental reports, 11/19 (57%) stated that their child had experienced bullying or teasing because of food allergies. for those not bullied, parents mentioned that this may be due to their child having friends at school, being too young for bullying or because other children at school had a good understanding of the severity of allergies and were educated by teachers. the most common location for bullying was "in the playground or sportsground" (36/39). the most common form of bullying involved being "teased, called names or someone has said mean things to me" (31/39). whilst food allergens were involved in bullying in many cases (24/39), there were no reports of children being forced to eat food to which they are allergic. of concern however, two adolescents reported experiencing an allergic reaction as a result of the bullying. the majority reported experiences of sadness from bullying (30/39) while seven stated that it had no effect. conclusions: our current research shows that 45% of children and adolescents with food allergies experience bullying, and that 22% (21/97) experience bullying specifically because of their food allergies. this indicates a significant social problem that requires addressing to positively assist those children living with food allergies. introduction: recently we demonstrated that intake of specific foods, types of fat and micronutrients was associated with inflammation and mucosal integrity in adults with eosinophilic oesophagitis (eoe). the current study aimed to compare dietary intake of these patients with dietary guidelines and intakes of the general dutch population to further investigate our hypotheses on the protective or allergy-provoking role of specific nutrients in eoe. results: the total faqlq score was low when assessed by teenagers and children (4.0 and 3.9, respectively) and moderately low when assessed by parents (2.7). experience of anaphylaxis and having multiple food allergies impaired hrql according to faqlq parent form (p<.05). gender, having prescribed an adrenaline-auto injector, experience of food provocation test, peanut allergy and faim did not contribute to different hrql. hrql in kindergarten and schools were moderately diminished (sum score 2.6 in schools and 2.2 in kindergartens) (p>.05). perceived disease severity was moderately present with total faim scores being 3.4, 3.6 and 3.9, when assessed by children, teenagers and parents, respectively (p>.05). 68% of participants' reported at least some possibility of dying if child/teenagers would accidently eat a food allergen. after fulfilling faqlq and faim, all participants expressed content, ten children/teenagers decided to approach food provocation tests de novo, employees of children's schools/kindergartens were encouraged in written invitations to assess anaphylaxis training programs, and four families accepted additional psychological support. conclusions: food allergies impair hrql in children and teenagers. allergies to multiple foods and experience of anaphylaxis were associated with more severe impairment of hrql. hrqlq and faim are useful, additional tools to assess and discuss child's/teenager's/parent's fears and obstacles because of food allergy and identify further needs of support. introduction: fruit allergy is the most common cause of food allergy in children older than 5 years and adults. regional variations have been observed in europe but there are few studies in pediatric population. objectives: in the context of a prospective and multicentric study on pollen and vegetable food allergy in spain, we enrolled 45 patients (median age 12, range 2-18, female 64%), who had suffered at least two episodes of immediate symptoms after ingestion of fruits and had positive skin test to the implicated fruits. immunocap isac was analyzed in all patients. our aim was to describe the clinical characteristics with the fruits involved and the usefulness of the allergens included in the immunocap isac to improve its characterization. symptoms were categorized into oral allergy syndrome (oas), systemic symptoms (ss) and anaphylaxis. results: a total of 45 patients were included. all of them had symptoms with more than one fruit. 42 patients had pollen sensitization. the main offending food associated with allergic reactions were peach (49%), kiwi (27%), melon (24%), apple (22%) and banana (15%). 5 allergic patients to peach had oas, 13 ss and 4 anaphylaxis, were recognized prup3 in all patients with anaphylaxis, in 4 patients witch oas and in 10 with ss, also prup3 associated with abstracts | 235 prup1 in 2 patients with ss. for allergy to kiwi, 9 patients had oas and 3 ss, were recognized actd2 in 1 patient with sao and 3 patients with ss. actd1 in 1 patient with ss. conclusions: in our population, the most prevalent fruit allergy was the peach, as in spanish adults. patients allergic to peach were the ones that presented the most ss and anaphylaxis, followed by allergic to apple. as previously have been reported most of them had sige to its components in isac; being prup3 the most prevalent (9% had prup1). only patients with ss with kiwi were sensitized to kiwi allergens .the majority of patients allergic to apple, melon and banana were not diagnosed by immunocap isac. introduction: studies have shown that asthma and allergy are prevalent among production workers processing seafood, particularly in workers processing crustaceans. a major ige-reactive proteins is the muscle protein tropomyosin. specific ige to tropomyosin is suggested as a central marker for crustacean allergy, however it is not the only protein characterised as an allergen in crab processing. objectives: the aim of our study was to characterise tropomyosin exposure and prevalence of sensitisation to allergens in workers processing king crab (paralithodes camtschaticus) and edible crab (cancer pagurus) in land based processing plants in norway. results: personal air samplers collected air from the workers' breathing zone during crab processing. workers' blood was collected for ige testing. extracts of both king crab and edible crab raw meat, cooked meat, intestines and shell were made in our lab and used for skin prick testing and immunoblotting. while processing cooked crab yielded highest tropomyosin levels in the edible crab plant, processing raw crab yielded highest levels in king crab plants. ten (12.8%) edible crab and 11 (9.7%) king crab workers had positive ige test (>0.35 ku/l blood, immunocap systems) to crab. four (10%) of skin prick tested king crab workers and 15 (19%) of skin prick tested edible crab workers had one or more positive reactions to edible crab extracts. more workers reacted to cooked crabmeat extracts than to raw crabmeat extracts. immunoblotting showed ige binding to a large number of proteins in all four extracts of both king and edible crab. binding was found to high molecular weight proteins in all four extracts of the crab tested, and the ige-reactive proteins differed between king crab and edible crab. conclusions: workers are exposed to tropomyosin in their breathing zone during crab processing. both king crab and edible crab workers are sensitised to crab, shown with immunocap specific ige test to crab, as well as positive skin prick tests and immunoblots to four different crab extracts made in our lab. workers processing crab in norwegian processing plants have an increased risk for developing sensitisation to crab. objectives: the aim of the study was to assess frequency of skin symptoms in surgery clinic employees, to evaluate burnout as a predictor of the frequency of skin symptoms, and to determine latexspecific ige in surgery nurses with skin symptoms. results: skin symptoms were significantly more frequent in surgery nurses (25%) than in surgeons (2.5%), other physicians (0), and other nurses (6.7%) (v 2 =18.16; p=.001). skin symptoms were also significantly more frequent in workers with high/medium than in workers with low emotional exhaustion (14.3% vs 5.2%; v 2 =4.32; p=.038), as well as in participants with burnout than in subjects without burnout introduction: baker's asthma sensitization pattern is changing due to the introduction of different types of grains and seeds. objectives: a 43 year-old ecuadorian man showing ocular, nasal and pulmonary symptoms when handling grain flours (with or without seeds), while baking for the last 8 years. he tolerated grain flours oral intake, but had oropharyngeal symptoms, rhinoconjunctivitis and dyspnea when eating sunflower and sesame seeds, mustard, and beer with alcohol. he tolerated alcohol-free beer. we performed an allergy study: prick-test with commercial extracts of pollens, dust and storage mite, fungus, animal danders, cereals, yeasts and mustard. prick by prick with patient's products: wheat, multicereals and seeded flour, sunflower seeds, regular and alcoholfree beer spirometry and niox. serial peak flow measurement at and away from work, handling tests with wheat flour and sunflower seeds. laboratory studies: specific ig e to cereals and seeds (cap-isac-microarrays). immunoblot with regular beer (at room temperature and boiled), wheat flour and sunflower seeds, and sequential chromatography. results: skin tests were positive with commercial mustard and all provided products except for the alcohol-free beer. spirometry was normal. niox: 116 ppb. peak-flow monitoring showed a 27% variability during working period, remaining stable during holidays. handling tests with wheat flour and sunflower seeds were positive. specific ig e was positive for grains, malt, gluten, mustard and sunflower seed. the specific determinants were positive to 7s-viciline, 11-s globulin, several prolamins (2s-albumine, alfa-amylase inhibitors and gliadin) and ltp. immunoblot detected a band lower than 14 kda in both regular beer extracts (not detected in alcohol-free beer) identified as barley's ltp, a band of 18 kda in the sunflower seed extract (2salbumine), and two bands lower than 14 kda in wheat flour extract (two kinds of alfa-amylase inhibitors). we present a non-atopic baker with occupational rhinoconjunctivitis and asthma due to prolamins (alfa-amylase inhibitor and gliadin of wheat flour together with 2s-albumin sunflower seed), and anaphylaxis when eating seeds (2s-albumins, 7s-vicilin and 11s-globulin) or drinking beer (sensitization to barley's ltp). it is interesting that the manufacturing process of non-alcoholic beer (high temperature and high pressure) seems to degrade barley's ltp, as suggested by both tolerance to its ingestion and loss of immunoblot band. objectives: the main objective of this study is to evaluate longitudinal change of lung function in workers employed in food preparation and distribution potentially exposed to food allergens. spirometries performed between 2012 and 2015 as part of medical surveillance of 58 food-handlers workers were evaluated. data about occupational task, work years, smoking habits and diagnosis of atopy, asthma and copd were collected from a clinical database. differences in prevalence were calculated by chi-square test, differences in means were calculated using spirola software referred to european predicted values. results: the majority of workers were females (n=49; 84.5%) and caucasians (n=57; 98.3%). 25 (43.1%) subjects were current smokers, 6 (10.3%) were ex smokers, 9 (15.5%) were atopic and no one reported a diagnosis of asthma or chronic obstructive pulmonary disease. 69% workers were canteen service employees and 31% were cookery employees. mean yearly values of the pair-wise within person variation of fev1 and fvc were respectively à248 ml and à266 ml. 6.9% of last observations had a fev1 below lln and 8.6% of last observations had a fvc below lln. conclusions: this study may help in planning preventive programs and in facilitating early recognition and diagnosis of work-related respiratory diseases. wheat, foods and latex allergens may determine decline in fev1 and fvc; furthermore, in our study, a significant proportion of workers reported exposure to tobacco smoke. excessive loss in fev1 over time should be evaluated using a percentage decline (15% plus loss expected due to aging) that we will make afterwards adding more years of follow up spirometries. intervention of smoke avoidance are needed. 0288 | prevalence of wood dust sensitization in occupationally exposed workers in germany-what can be tested? objectives: in 373 serum samples from patients with suspiciously allergic symptoms to wood dust overall 2797 specific (s)ige-tests with standardized wood-dust extracts coupled to streptavidin-immu-nocaps were conducted. additionally, ccd as known source of non-protein ige-target was evaluated. sensitization rates were calculated for 21 different wood species. most frequently requested wood dust allergens were obeche (n=198), beech (n=186), oak (n=173), spruce (n=175) and pine wood (n=147) followed by 80-100 requested sige-tests to mahogany, ash, larch and maple wood. results: overall wood dust sensitization rate was about 11% (range: 0-29%) with obeche, box wood and kambala as most prominent sensitization sources obtaining each more than 20% sensitization. no sensitizations were detectable to red cedar and meranti wood in more than 50 requested tests, respectively. in 81 patients at least one sige-sensitization to any wood was measured. there from 77 were additionally tested with ccd resulting in 47% positive and 53% negative ige responses to ccd. some wood species were exclusively recognized by ccd-positive subjects: ash, maple, alder, mahogany, teak, mansonia and palisander. whereas other woods were recognized by sige of subjects with / or without sige to ccd: obeche, box wood, spruce, oak, beech, limba, pine and kambala. relevance of wood sensitization next to ccd was investigated in eight double positive subjects (wood + / ccd +). specific ige-binding to wood allergens was completely inhibited by ccd in three samples. these subjects were supposed to have no clinically relevant wood sensitization. whereas in five samples sige-binding to selected wood species was not significantly reduced by ccd. in four of these patients skin prick tests (spt) and challenge tests (bronchial and/or nasal) with corresponding wood allergens were performed. three of four challenge tests were positive with the respective wood extract and all spts with wood extracts whose sige-binding was not affected by ccd inhibition showed positive reactions. here clinical relevance of sige-mediated wood sensitization could be demonstrated. conclusions: in summary, our data demonstrate that standardized wood extracts and ccd tools are necessary for valid in-vitro diagnosis of wood dust sensitization. introduction: respiratory symptoms have been reported frequently among seafood processing workers. since seafood processing workers handle the raw material and participate in processing activities during work, they are exposed to inhalable bioaerosols. this put them at risk of developing respiratory symptoms, asthma and allergy. there is little knowledge about the respiratory health status among fish production workers on board fishing trawlers. objectives: the aim of this study was to assess the respiratory health status among norwegian fish production workers, processing fish on board fishing trawlers. the study population consisted of 92 fish production workers, 21 machinists, 22 support crew members and 38 non exposed controls, all were males. written informed consent was the fish production workers had a significantly decreased fev 1% predicted compared to the non-exposed control group, b=à5.9, 95% ci [à11.2, à0.6], when controlling for age, pack-years and family history of asthma/allergy/eczema. the effect did not change when controlling for doctor diagnosed asthma or after dividing fish production workers by doctor diagnosed asthma. machinists and support crew members showed a similar decrease in fev 1% predicted, but the difference from the non-exposed control group was not statistically significant. furthermore fish production workers, reported a non-significantly increased prevalence of wheezing and daily morning cough compared to the non-exposed control group. conclusions: fish production workers, processing fish on board fishing trawlers, showed reduced lung function values compared to a non-exposed control group, and this finding is in accordance with previous findings in seafood industry worker populations from our research group. results: study group comprised 264 patients with work-related respiratory symptoms suggesting wra. the research completion with sic allowed to recognise wra in 164 persons (108 oa and 56 wea) and to exclude asthma in 100 cases qualified to reference group (gr). workers with wea occupationally exposed do lmw-a manifested the highest level of baseline non-specific bronchial hyperresponsiveness (nsbhr) in comparison to the other groups (table 1) . patients with oa exposed to lmw-a more frequently than exposed to hmw-a revealed nsbhr before sic (p=.036) with lower level of median (me) provocative methacholine concentration value causing 20% fall in fev 1 (pc 20 induced sputum (is) was obtained before and 24h after sic from 159 patients (38 gr and 121 wra). in all gr samples and samples possessed before sic from wea subjects exposed to hmw-a, intermediate profile of is (neutrophils (ne)<61% and eosinophils (eo)<2%) dominated ( results: eg: in "granulation" exposure is relatively high and the number of different enzymes handled is low; here the risk of sensitization is highest. in contrast in the pilot plants the exposure compared to granulation in general is lower but the number of enzymes handled concurrently is higher. still the sensitization risk is lower than the range for granulation. conclusions: even though this approach may seem crude and not free from bias and potential misclassification, data does not support the hypothesis that the number of enzymes increases risk of sensitization, whereas increasing exposure level seems to be a risk factor. this suggests that each enzyme exposure acts as a risk in its own right and that the "cocktail effect" seems to be of minor relevance. phospholipids. bioinformatic studies of sequence homology conducted prior to this study showed no similarity between the mpla1s and known allergens including ves v 1. however, the common enzymatic activity in ves v 1 and the mpla1s might still lead to crossreactivity. the goal of this project was therefore to test for possible cross-reactions between sige towards ves v 1 and three different mpla1s. methods: serum from 10 known wasp allergic persons with sige towards ves v 1 spanning from 1.57 ku/l to 1734 ku/l were used for inhibition studies. from each, 125 ll serum was incubated with 125ll of either saline solution (negative control), 50 lg/ml alk802 soluprick solution (positive control) or one of three mpla1s, each in three concentrations (either 0.5 lg/ml, 5 lg/ml and 50 lg/ml (n=3) or 5 lg/ml, 50 lg/ml and 500 lg/ml (n=7)). the level of sige towards ves v 1 was measured using the i211 immunocap, and a decrease in this level was calculated as %inhibition compared to the sige measured from serum incubated with the negative control. inhibition by mpla1s would indicate cross-reactivity. results: the positive control caused 62.5ae28.6% (n=10) inhibition of sige towards ves v 1. this was lower than expected but was found to be caused by a few sera where the fraction of sige towards ves v 1 was <10% of all sige towards wasp venom. in the remaining sera, %inhibition was 78.1ae14.9% (n=7). for all three mpla1s, no inhibition was found for any serum tested (n=10) at the highest concentration tested with %inhibition being 3.5ae2.5%, 3.3ae2.9% and 1.8ae6.0% respectively. conclusions: no inhibition of sige to ves v 1 was found to any of the three microbial phospholipases tested. this indicates that no cross-reaction is found between the phospholipase a1 in wasp, ves v 1, and phospholipase a1 from microorganisms despite the common enzymatic activity. objectives: the aim of study was to evaluate the prevalence and the impact of polyvalent ige-mediated allergy on the course of ad and the occurrence of allergic symptoms from other organs and systems in infants and young children. conclusions: polyvalent ige-mediated allergy is common in young children with ad and seems to be a risk factor for the severe course of the disease. introduction: non-steroid anti-inflammatory drugs (nsaid) are the second most common cause of drug allergies in childhood. objectives: the aim of the study is to determine the frequency of nsaid hypersensitivity in asthmatic children. results: 976 patients who were being followed up for asthma were included in this study. the mean age of the patients was 10.61ae4.21 years, while 59.5% (575) were male. 1% (n=10) of the patients had a reaction history to nsaid (ibuprofen in 4, flurbiprofen in 2, diclofenac potassium in 1, metamizole+acetylsalicylic acid in 1, paracetamol+acetylsalicylic acid in 1 and ibuprofen+acetylsalicylic acid in 1). nsaid sensitivity was confirmed in 9 (0.9%; 9/976) patients who were tested with suspected drugs, while the provocation test was found negative in one patient who described reaction with ibuprofen. of the 2000 children who were assessed as a control group, only 1 had a reaction history to acetylsalicylic acid and no reaction developed in the provocation test. conclusions: nsaid hypersensitivity is more common in patients with asthma. thus, these patients should be evaluated for nsaid hypersensitivity. results: from jan 2012 to dec 2013, 8840 pediatric cases were received by kaers. of 8840 pediatric patients, 56.4% were male, 42.0% were female and 1.6% were unknown. these 8840 pediatric cases included a total of 17 319 adr events with an approximate average of 1.9 adr events per report. of those 8840 cases, 21.2% were in infants (age 0-1 years), 27.8% were in young children (age 2-7 years), 24.3% were in old children (age 8-13 years), 22.7% were in adolescent.(age 14-18 years) and unknown were 4.0%. male to female ratio was 1:0.8 and the mean age was 8.3ae6.3 years. regarding categorical ranking of reported adr agent groups, the most common group were antibiotics (24.4%) followed by antineoplastic agents (14.8%), vaccine (11.6%), antipyretics (7.1%), opioids (5.4%), sedatives (3.1%), antiepileptic drugs (2.9%), contrast media (2.3%), steroids (2.0%). the most common adr symptoms were gastrointestinal system disorder in 33.2%, skin-appendage disorder in 19.5%, abstracts | 249 body as a whole-general disorder in 9.5%, central-peripheral nervous system disorder in 7.5%. regarding seriousness of adrs, 610 events (6.9%) had episodes requiring hospitalization and were considered life threatening. of these, 126 cases had anaphylaxis or anaphylactoid reactions. introduction: multiple drug allergy is an adverse reaction to two or more structurally unrelated drugs that appears to occur by immune mediated mechanism. patients with a history of reaction to two or more drugs often apply to allergy clinics. objectives: the aim of this study is to evaluate the test results of the patients who have a history of multiple drug allergies and underwent drug provocation tests. results: during the study period, drug provocation tests were performed in 889 patients (1014 drug provocation tests). of these patients, 106 (11.9%) had a history of drug reactions to 2 or more drugs. the mean age of the patients who had a history of reactions to two or more drugs was 8.48ae3.94 years, and 58.5% (n=62) toms, and autoimmune manifestation in comparison to igm/iga responders (respectively, pneumonia: 64%, 31% and 0%; chronic diarrhea: 25%, 14% and 0%; autoimmunity 41%, 29% and 0%; autoimmune cytopenias: 17%, 8% and 0%). malignancies were found more frequently in the non-responders and igm-only responders groups in comparison to igm/iga responders (respectively, 23%, 14% and 0%). eleven (15%) patients died during the study time. survival analysis according to the igm/iga responder status showed that the 6-years estimated survival for non-responders vs igm-only vs igm/iga responders was respectively after one year 98%, 87% and 100%; after two year: 93%, 87% and 100%; after three years: 91%, 80% and 100%%; after 4 years: 87%, 80% and 100%; after 5 years: 87%, 80% and 100%; after 6 years: 83%, 80% and 100%. interesting, in our series only two deaths were due to infective complications: five were consequent to malignancies, one to autoimmune cytopenias and three to not-cvid related conditions. between-infusions intervals (10-14 days) than pid patients (6-7 days). finally, a small number of patients with anti-cd20-related sid was able to discontinue scig replacement therapy after recovery of spontaneous igg production. conclusions: this is, to our knowledge, the biggest single center cohort of scig-treated patients ever described. results suggest that safety and effectiveness of scig is similar in pid and sid, irrespective of the mechanisms underlying igg depletion. moreover, in sid a lower igg dosage is required and ig replacement does not always need to be lifelong, with obvious pharmacoeconomic implications. 0685a | should we screen children with bronchial asthma for primary immune deficiencies? miteva d 1 ; perenovska p 1 ; papochieva v 1 ; georgieva b 1 ; lazova s 1 ; naumova e 2 ; petrova g 1 the patient became febrile and cultures were repeated, being positive to campylobacter jejuni, resistant only to ciprofloxacin (blood) and to campylobacter coli, susceptible only to gentamicin and amoxicillin/ clavulanic acid (stools). treatment was thus switched to amoxicillin/ clavulanic acid (1875/125mg 8/8h). the patient became apiretic at day 2 and improvement of local inflammatory signs was noticed, treatment was prolonged for six weeks. one week after cessation, skin lesion worsened again in the same location, in association with fever. blood and stool cultures were repeated and gentamicin (240mg/day; iv) and cefixime (200mg 12/12h) were started, in agreement with previous cultures results. curiously, there was no history of diarrhea, but the patient referred a period of recurrent abdominal colicly pain, before cutaneous lesions appear. conclusion: bacteremia with campylobacter species requires specific laboratory workup. 7diagnosis of campylobacter jejuni bacteremia should be considered in hypogammaglobulinemic patients with recurrent fever, particularly when typical copper color erysipela-like skin lesions occur. campylobacter eradication can only be achieved with prolonged antibiotic therapy guided by antibiogram in cultures. conclusions: in this study, genetic defects of five higm patients have been identified, for other patients further genetic investigation such as next generation sequence (ngs) is required. the study results can help diagnose of the disease more definitively and also can provide valuable information for genetic counseling especially for those who have a history of immunodeficiency in their families and also for prenatal testing. conclusions: mutation analysis of unc13d gene can help the families with hlh patients give genetics counseling for carrier detection and prenatal diagnosis. woelke s 1 ; valesky e 2 ; bakhtiar s 3 ; bader p 3 ; schubert r 1 ; zielen s 1 1 department for children and adolescents, division of allergology, pulmonology and cystic fibrosis, goethe university hospital, frankfurt, germany; 2 department of dermatology, venereology and allergology, goethe university hospital, frankfurt, germany; 3 department for children and adolescents, division for stem cell transplantation and immunology, goethe university hospital, frankfurt, germany introduction: ataxia telangiectasia (a-t) is a devastating multi-system disorder characterized by progressive cerebellar ataxia, growth retardation, immunodeficiency, chronic pulmonary disease and genetic instability with an increased risk for malignoma. as described in other primary immunodeficiencies cutaneous granulomas are a known phenomenon also in a-t. still treatment indication and strategies remain controversial. objectives: from our cohort of 60 classical a-t patients, eight patients in the aged 2 to 11 years presented with granulomas. histopathology of the lesions confirmed the presence of granulomatous inflammation without detection of any microbiological agent in all patients. five patients suffered from cutaneous manifestation, in two patients we detected a bone and in one a joint involvement. both patients with bone involvement (patients 1 and 2) as well as one patient with massive skin manifestation (patient 3) were treated with tnf inhibitors (infliximab). the patient with granulomas in his finger joint (patient 4) was bone marrow transplant (bmt) for other reasons. year led to a total remission for three years now. in patients 2 and 3 treatment with tnf inhibitors led to a partial regression of granulomas. treatment interruptions caused deterioration again. in the course of treatment the effects of infliximab diminished most likely caused by drug antibodies. after changing treatment to subcutaneous adalimumab a further regression could be detected. in patient 4 granulomas totally disappeared with immune reconstitution after successful bmt. partially successful in treatment of granulomas. due to the known immunodeficiency in a-t patients, indication for immunosuppressive therapies as tnfa inhibitors should be held strictly. woelke s 1 ; hess u 1 ; knop v 2 ; krausskopf d 3 ; kieslich m 3 ; schubert r 1 ; zielen s 1 of 1 to 38 years regarding c-reactive protein (crp), liver enzymes, abdominal ultrasound and neurological status (ataxia score). we divided the patients into two age groups of 27 a-t patients aged 1 to 11 years and 26 a-t patients aged 12 years to 38 years. ataxia score (r=0.34), although the underlying pathomechanism is unclear. ultrasound revealed nonalcoholic fatty liver disease in only one young patient (3.7%) compared to 11 older patients (42.3%). one female patient aged 37 years died due to a hcc. conclusions: liver disease is present in almost all older a-t patients. structural changes, nonalcoholic fatty liver disease and fibrosis are frequent findings. there is a considerable risk for hcc. prospective studies are necessary using noninvasive techniques for the assessment of liver fibrosis (eg transient elastography) and to establish the risk of hcc in a-t patients. objectives: in this study, it was aimed to determine the frequency of pollen-food syndrome in children who have sensitization to pollens. results: 672 pollen-sensitized patients were included in this study. the mean age of the patients was 11.82ae3.90 years, while 63.1% (n=424) were male. in 45.2% (n=304) of the patients, allergic rhinitis was concomitant with asthma. 4.3% (n=29) of the patients described symptoms related to pfs. 31% (9/29) of them had a history of anaphylaxis with suspected food. the mean age of the patients describing pfs was 12.22ae4.26 years and 55% (n=16) of them were female. in 17 (58.6%) of these 29 patients, skin tests performed with suspected food was positive, but in one patient the skin test was negative while specific ige was positive. suspected food was fruit/ vegetables in 21 patients. in patients with pollen allergy, oropharyngeal symptoms related to fresh fruit, vegetables, dried fruits and nuts should be enquired. it should be noted that these patients might experience serious systemic reactions including anaphylaxis. patel nb 1 ; vazquez-ortiz m 1 ; lindsley s 1 ; abrantes g 1 ; bartra j 1 ; dunn galvin a 2 ; turner pj 1 conclusions: there is no evidence that the occurrence of anaphylaxis at fc, and self-treatment with an adrenaline auto-injector device, result in adverse impact on hrql measures. the impact of a reaction at food challenge appears to confer greater benefit on the parent than the child. the relationship between confidence in management and hrql needs further assessment, since it is likely that these outcomes will be affected in different ways following therapeutic interventions. results: fifty-one patients (23 females, 28 males) (median age: 6.5 years, range 0-18) with cma were studied. spt to cm was 7.3ae3.3 mm as mean diameter. forty-eight out of fifty-one (94.1%) patients underwent dm-opt (3 patients refused to underwent opt due to positive spt or s-ige to dm introduction: bovine milk is the most common food allergen in children under 3 years of age. milk allergy is treated by eliminating milk from the diet. the milk elimination diet endangers the child's energy intake and also exposes the child to shortage of multiple nutrients. this study was needed because there are no previous systematic reviews about this subject. objectives: the aim of the present study was to examine if the milk allergy or the other factors associated with milk elimination diet have an influence on child's growth. the present study was conducted according to international guidelines for systematic reviews. results: a total of 646 studies were initially identified, of which three fulfilled our criteria. these three studies included 186 children with cow's milk allergy and 122 control children. in all these three studies, children with cow's milk allergy were lighter than controls. in addition, in two studies, the growth of the children with cow's milk allergy was stunted. in two studies the milk elimination was substituted with special infant formula. also in one study where both the growth and the weight were stunted, no major differences in energy or nutrient intake between cow's milk allergic cases and controls were reported. conclusions: current evidence suggests that milk allergy is associated with stunted growth in childhood, but reasons for this are unclear. in order to clarify the effect of cow's milk elimination diet on growth in childhood and the underpinning mechanisms, more studies need to be conducted. in addition, special attention to the diet and growth of children with cow's milk allergy is needed. results: a total of 158 817 children were surveyed in this 6-year period (annual average: 26 470). in 2011, 704 children (2.6%) were diagnosed with food allergy, including 159 cases of pfas, 376 cases of egg allergy, and 235 cases of dairy-product allergy. in 2016, 939 children (3.6%) were diagnosed with food allergy, including 344 cases of pfas, 385 cases of egg allergy, and 249 cases of dairy-product allergy. over this 6-year period, the prevalence of pfas increased 2.2fold (from 0.59% to 1.31%). among the pfas cases, the prevalence of rosacea and apple allergy increased 2.9-and 3.3-fold, respectively. the most prevalent was apple allergy (0.76%), followed by peach (0.59%), loquat (0.53%), plum (0.44%), pear (0.40%), and strawberry (0.18%). the prevalence increased significantly for pfas but not for other types of food allergy (egg and dairy-product allergy). in the future, nationwide studies are needed to further elucidate the relationship between pfas and allergic rhinitis. 0327 | immune profile after oit in children with cow 0 s milk allergy patients with elimination diet, group 3: patients with natural tolerance, group 4: healthy control). in all groups specified laboratory tests were performed at onset and also at 6 month to treatment groups. in desensitization group at 6 month of treatment we evaluated increase in total ige level, sp iga and igg4 antibody responses, decrease in cow's milk spige levels and an increase in il-2, il-10, tgf-b cytokine responses without a difference in cd4+cd25+fox-p3% levels. il-13 levels were similar with pre-treatment levels whereas foxp3 mrna expression was similar with tolerance group. in elimination group at 6 month treatment, there was a decrease in cow's milk spige whereas there was no change in sp iga levels and a minimal increase in igg4 levels. there was no change in il-2 and il-10 cytokine levels. and an increase in tgf-b cytokine response less than group 1, decreased il13 response, a foxp3 mrna expression differed from tolerance group was identified. objectives: although hyperuricemia has a significant prevalence in the general population, and has been related to exercise-induced asthma, could be related to bronchial asthma and nasal polyposis. hitherto, its possible association with hypersensitivity to nsaids and its convenience as biomarker have not been acquainted. conclusions: in our population, hyperuricemia has not demonstrated to be a reliable biomarker related to nsaids allergy and could not be used as a risk factor for assessing the triad nsaids allergy, asthma and nasal polyps. to study the vas of the total score was seen significant variance in: nsaid-cu (3.38pt) and nsaid-pa (6.57pt) (p=.046), nsaid-cu conclusions: data support that cutaneous manifestations have a common response with aerd to cox inhibitors. conclusions: this study showed that in a positive drug oral provocation test, respiratory symptoms were accompanied with nitric oxide changes in both nasal and exhaled way. barrionuevo e 1 ; doña i 1 ; salas m 1 ; bogas g 1 ; guerrero ma 1 ; sanchez mi 1 ; cornejo-garcia ja 2 ; torres mj 1 1 allergy unit, regional university hospital of malaga-ibima, malaga, spain; 2 research laboratory, ibima-regional university hospital of malaga-uma, malaga, spain introduction: non-steroidal anti-inflammatory drugs (nsaids) are the most frequent triggers of drug hypersensitivity reactions, being cross-hypersensitivity reactions (chr) the most frequent. the categories included in chr are nsaids-exacerbated respiratory disease (nerd); nsaids-exacerbated cutaneous disease (necd) and nsaids induced urticaria/angioedema (niua). however, it has been reported patients with chr to nsaids who developed a combination of skin and respiratory symptomatology (blended reactions). objectives: our aim was to analyse the characteristics of patients with blended reactions and compare with those developing symptoms exclusively respiratory (nerd) or cutaneous (niua). episodes of cutaneous and/or respiratory symptoms after the intake abstracts | 265 of ≥3 different nsaids included strong cox-1 inhibitor (acetylsalicylic acid (asa) and/or indomethacin); ii) if they had <3 episodes of cutaneous and/or respiratory symptoms induced by <3 different nsaids, a positive drug provocation test (dpt) with asa was required; iii) if patients had respiratory symptoms accompanied or not by cutaneous involvement, a positive nasal provocation test with lysine aspirin (npt-lasa) was required. atopy was assessed by skin prick test using a panel of inhalant and food allergens. objectives: subjects with nsaids hypersensitivity were divided into two groups: a) those from 2 to 14 years and b) those from 15-20 years. diagnosis was established by a clinical history and controlled challenge with asa. atopic status was verified with a detailed allergological study including skin testing to inhalant allergens. clinical entities were classified in three categories: urticaria/angioedema, anaphylaxis and respiratory (asthma and/or rhinitis). cases. no differences were observed in the atopic status between both groups. there were significant differences between males/ females (p<.05). when we compared the clinical entities there were more cutaneous manifestations, mainly angioedema, in the group a) and more anaphylaxis in group b) although there were no significant differences due to sample size. conclusions: significant sex differences between hypersensitivity reactions to nsaid occurs with predominance of males in the first group (a). although there are also a predominance of clinical entities, an increase number of cases is needed to establish significance. studies on this direction are in progress. show an increase in all age groups. etiologic analysis was limited as the study was carried out using the icd-10 code (nhic records) and database of self reporting systems (kaers). so, further study was needed. introduction: genetic variants from the 17q21 locus are the strongest known genetic determinant for early-onset childhood asthma, and have also been associated with uncontrolled asthma despite asthma treatment. objectives: the aim of the study was to assess whether there is an association between a single nucleotide polymorphism (snp) in the 17q21 locus (rs7216389) and asthma exacerbations despite the objectives: our hypothesis is that the arg16 allele is associated with increased use of prescribed asthma medication, over a 9-year period. to explore this hypothesis, we have undertaken a secondary analysis of breathe, a study of gene-environment associations with asthma severity. breathe data were collected on participants with asthma, aged 3-22 years, between 2003 and 2005, in tayside conclusions: in children and adults, the homozygous arg/arg status is associated with long-term increased prescribing for asthma medication compared to those carrying at least one gly allele. defining subgroups of individuals requiring more medicines could help predict treatment costs and develop targeted management strategies. objectives: considering the role of ptgdr in allergy, the goal of this study was to analyze the effect of ptgdr expression on cytokine levels in the a549 cell line. analyze ptgdr expression in a549 cell cultures. cytokine production assays in the culture supernatant were measured by cytometric bead assay using the bioplexpro tm human cytokine standard 27-plex, group i. the assays were conducted with bioplex high-throughput fluidics system, powered by the luminex technology. every sample was run at least in triplicate. the ptgdr expression in the transfected cells with the haplotypic variants differed by 5 orders of magnitude relative to control cells (p<.001). we found significant differences in ptgdr expression between ctct and cccc haplotypic variants. the cccc (à613 c, à549 c, à441 c, and à197 c) introduction: c159t polymorphism in the cd14 gene has been suggested in susceptibility to asthma. cd14 is a multifunctional receptor endotoxin, which is expressed on the surface of macrophages, monocytes and neutrophils. it is likely to play a role in the inflammation pathway. though data is available regarding association of cd14 gene with asthma but independent studies are in conflict. objectives: the present study was conducted to examine the association of promoter c159t single nucleotide polymorphism (snp) in the cd14 gene for indian children with atopic asthma. we characterize the c159t polymorphism in children with asthma (50), cohort group (20) and healthy control group (50) by pcr rflp. association analysis was performed using v2 tests. we also analyzed the association of cd14 (c159t) with total ige levels by elisa and foxp3 expression using flow cytometry. in this snp a 497 base pair (bp) pcr product was generated using the standard primers. after restriction products showed that homozygous c allele was appeared as a single 497bp band, the homozygous t allele as bands of 144 bp and 353 bp, and heterozygous exhibits all three bands (144, 353 and 497 bp). the or of cc genotype frequency abstracts | 271 was 0.84 in study group and 0.78 in cohort group and the or of c allele frequency was 2.38 in study group and 2.52 in cohort group. total ige level were found to be significantly higher in cc genotype compared to ct and tt genotype. foxp3 level is significantly higher in control group in all genotypes compared to cohort and study group. conclusions: the present study concludes that in cd14 gene polymorphism cc genotype was not significantly associated with asthma but other factors ie total ige and foxp3 showed significant association of cc genotype with asthma. on the other hand, there was significant association of c allele with asthma. 0362 | the disbalance of tlr2, tlr4 gene expression and cytokines production in children with bronchial asthma svitich oa 1 ; gankovskaya lv 2 ; namazova-baranova ls 3 ; bragvadze bg 2 ; alekseeva aa 3 ; gankovskii va 3 objectives: examined were 38 patients with bronchial asthma aged from 3 to 12 years and 10 healthy children of the same age. cytokines were determined by elisa. determination of mrna expression in scrapings from the mucous membranes of the respiratory tract and in peripheral leukocytes was carried out polymerase chain reaction in real time. results: in scrapings from the mucous in patients with moderate to severe asthma found a significant increase in the gene expression of tlr2, 3 times, the gene tlr4 in 10 times in comparison with the control group. in children with severe asthma also found a significant increase in the gene expression of tlr2 4.8 times compared to healthy children, p≤.05). indicators of tlr4 gene expression in this group of patients have a tendency to increase, but not statistically significant. when comparing the indicators of innate immunity in samples with a leukocyte mass in the group of children with severe asthma showed a decreasing expression of tlr2 compared with the index in healthy children. also decreased the expression of tlr4. in children with moderate ba similarly, a significant decrease of tlr4 gene expression in 18 times. the trend towards reduced expression of tlr2 remains in this group, but is not reliable. in washings from the nasopharynx shows that patients with bronchial asthma il-1 is increased 4.5 times compared to the norm, to 45 pcg/ml, tnf increased in 6 times and 18 pcg/mg in severe asthma, and 7.7 pkg/ mg-for mild, il-17 increased in 3 times (16 pcg/mg), pkg of 7.5/ mild blood, il-10 also increased 4.5-fold and equal to 22.5 pkg/mgwith heavier with easy-7.5 pkg/mg, normal à5 pkg/mg. ie is an increase in proinflammatory and anti-inflammatory cytokines. conclusions: the overexpression of tlr2, tlr4 accompanied by increasing, the production of cytokines. this is a violation of mechanisms of innate immunity at the level of the mucous membrane of the nasal cavity on the role of inflammation in the pathogenesis of tlr. 0364 | sustained reduction in risk of experiencing asthma symptoms and using asthma medication in years following grass slittablet treatment-results from the paediatric gap trial were: wheezing, cough (for more than 10 consecutive days), shortness of breath, chest tightness. the odds ratio for having asthma symptoms, using asthma medication, or having asthma symptoms and using asthma medication was significantly lower in the grass slit-tablet group during the 2 followup years. for asthma symptoms, the results were: or=0.52, p=.016 days with csms<2 were defined as "no or minimal symptoms" and days with csms >6 were defined as severe symptoms. csms score was significant lower in the ilit group than in the placebo group for 2014, 2015 and 2016. in 2014 mean csms was 4.05 roth-walter f 1 ; schmutz r 2 ; mothes-luksch n 2 ; zieglmayreer p 2 ; zieglmayer r 2 ; jensen-jarolim e 3 objectives: here, we investigated whether the immune molecule lipocalin 2 (lcn2) may discriminate between allergic and sensitized individuals, and between responding and non-responding patients. results: lcn2-concentrations were assessed in sera of healthy and allergic subjects (n=160) as well as of house dust mite (hdm) allergies that underwent hdm-sublingual immunotherapy (slit) in a randomized, double-blind, placebo controlled trial for 24 weeks. sera pre -, post-slit and at least 3 months after slit were assessed for lcn2 and correlated with total nasal symptom score (tnss) obtained during chamber challenge at week 24 in patients receiving hdm-(n=30) or placebo-slit (n=10). allergic individuals had significant lower lcn2-levels than healthy controls, with women having lower lcn2-levels than men in the patient cohort. hdm-allergic patients who received hdm-slit had a significant increase in hlcn2 6 months after termination of hdm-slit, whereas in subjects receiving placebo no increase in hlcn2 was observed. within the hdm-slit treated group, lcn2-levels were significantly higher in patients whose symptoms improved during slit in contrast to those in which symptoms became more severe. hence, time-course of lcn2 in an allergic individual was predictive to assess clinical reactivity to hdm. objectives: here, we present the benefits of treatment in terms of nnt to prevent one additional child from having asthma symptoms and asthma medication use. children treated with grass slit-tablet had a reduced risk of asthma symptoms and asthma medication use during the 2-year follow-up period compared with placebo (or=0.28 [0.14, 0.57] for sq grass slit-tablet (n=377) vs placebo (n=398), p<.001, relative risk reduc-tion=71%). the risk reduction was independent of age at treatmentstart. younger children had a higher predicted probability of developing asthma symptoms and asthma medication use than older children. thus, the younger the children were at treatment-start, the greater the percentage was prevented from having asthma symptoms and asthma medication use during follow-up off treatment. for children aged 5 at treatment-start, the risk was reduced from 40% to 24% and for those aged 12 it was reduced from 10% to 5%. consequently, the nnt to prevent one additional child from having asthma symptoms and asthma medication use during the 2-year follow-up increased with age, with nnt=6 for children aged 5 and nnt=20 for children aged 12. conclusions: the grass slit-tablet reduced the risk of asthma symptoms and asthma medication use during the 2-year follow-up period; the risk reduction was independent of age. however, the nnt increased with age as younger children had a higher risk of developing asthma symptoms and asthma medication use, emphasising the importance of treatment-start early in life. results: 226 participants were screened for birch and grass allergy, of whom 93 ultimately met randomization criteria and were treated with either slit-t or placebo for 4 months. treatment was preceded by a successful baseline birch pollen challenge in the eeu where a minimum tnss of 6 was achieved in the first 2 of 5 hours of pollen exposure. 87 participants attended the post treatment challenge in the eeu, also 5 hours in duration. no significant differences were noted in the reduction of birch-induced tnss compared to baseline between the slit-t and the placebo treated participants (the primary outcome measure). adverse events with a minimum 5% frequency occurred in 50% of participants in the placebo arm and 70% of participants in the active arm, with upper respiratory tract infection (32% in active arm and 24% in placebo arm) being the most common. oropharyngeal itch was the most common adverse event with causality at least possibly related to study medication (23% in active arm and 2% in placebo). no serious adverse events occurred including no anaphylaxis. objectives: here, we present a pooled subgroup analysis in adolescents from 2 phase ii/iii-iii trials with the hdm slit-tablet (12 sq-hdm dose), p001 in north america and to-203-3-2 in japan. results: to-203-3-2 was a randomised, dbpc phase ii/iii trial investigating the efficacy and safety of the hdm slit-tablet in japanese adolescents and adults (12 to 64 years) with moderate-tosevere hdm ar (n=946, of which 302 were adolescents). subjects were randomised to treatment with the hdm slit-tablet in doses of 6 sq-hdm, 12 sq-hdm or placebo for 1 year. p001 was a randomised dbpc phase iii trial investigating the efficacy and safety of the hdm slit-tablet in north american adolescents and adults (≥12 years) with moderate-severe hdm ar with or without asthma (n=1482, of which 189 were adolescents). subjects were randomised to treatment with 12 sq-hdm or placebo for up to 1 year. in both trials, the primary endpoint was the average total combined rhinitis score (tcrs) during the last 8 weeks of treatment. the pooled analysis was performed on mean values using a linear mixedeffects model. treatment with 12 sq-hdm of the hdm slit-tablet resulted in a statistically significant reduction in the average tcrs of 1.04 (22%, p=.002) compared to placebo in the last 8 weeks of treatment. statistically significant differences were seen for both components of the tcrs, the rhinitis medication score (difference=0.06, p=.038) and rhinitis symptom score (difference=0.87, p=.004). furthermore, treatment with 12 sq-hdm resulted in a statistically significant reduction of the conjunctivitis symptom score compared to placebo (differ-ence=1.10, p=.026). treatment was well tolerated. the most frequent adverse events were mild-to-moderate local allergic reactions. the pooled subgroup analysis showed that the hdm slit-tablet (12 sq-hdm) was effective in treating hdm allergic rhinitis in adolescents (12-17 years old). the reduction in the primary endpoint tcrs was statistically significant and comparable to what has been observed in adults. results: at the time of the data-cut for this analysis, a total of 179 european patients were screened (58% male). 56% of the subjects were aged 4-11, 28% were aged 12-17, and 16% were adults. the mean age of the sample was 11.4 [sd 6.9] years, with a minimum of 4 and a maximum of 49 years. in europe were children. many were allergic to foods other than peanut, and most had at least one other atopic condition. even if allergic to multiple foods, patients and their families were nonetheless keen to participate in the trial. the majority of the screened patients were highly sensitive to peanut, reacting to 144mg (cumulative) or less of peanut protein but a significant proportion of screening failures were due to lack of reactivity to this dose. 0372 | efficacy of 300ir 5-grass pollen sublingual tablet: improvement in subjects with grass pollen-induced allergic rhinoconjunctivitis based on well days and severe days evaluation objectives: four phase ii/iii dbpc studies, 3 in adults and one in children/adolescents, were conducted worldwide. participants were abstracts | 277 randomised to receive the 300ir tablet or placebo starting 4 months (4m) prior to the pollen season and continuing for its duration. data from the first season of the 3 trials in adults were pooled. the well days were defined as those with not more than one moderate symptom or 2 mild symptoms of the 6 evaluated symptoms (sneezing, rhinorrhoea, nasal pruritus, nasal congestion, ocular pruritus, watery eyes) and no use of rescue medication. the severe days were defined as either at least one moderate symptom in subjects using rescue medication, or at least 2 moderate symptoms or one severe symptom whether rescue medication was taken or not. for each subject, the proportions of well days and those of severe days were evaluated during the pollen period while on treatment. treatment groups were compared using a wilcoxon 2-sample test. introduction: the safety of subcutaneous immunotherapy (scit) has been proven in several studies, but the occurrence of side effects (se) remains a concern in daily clinical practice and understanding of their risk factors and avoidance strategies remains limited. objectives: the aim of presented study was to assess the incidence and risk factors of early and late side effects in patients undergoing scit. we conducted a 2 year-long observation of over 1300 patients undergoing scit in our outpatient clinic. we recorded detailed information for each administration and screened subjects for both immediate and late reactions. we compiled the records with medical histories to build a database, which was analyzed using multiple logistic regression. casein is a major cow 0 s milk allergen and very resistant to high temperatures. higher levels of ige towards caseins have been reported to associate with persistent cow 0 s milk allergy and higher risk of adverse reactions before and during the milk oit. a follow-up study on oit to milk started in 2005 with a six-month built-up phase. seventy-six children (mean age 9.7 years) with challenge-verified cma participated the milk oit and their immunological changes were analyzed employing crd. during the year 2016, long-term follow-up report was collected by questionnaires (73%, n=49) and blood samples (46%, n=35). specific antibody responses were characterized before oit and on long term follow up and compared to long-term questionnaire results: milk consumption (yes/no) and side-effects from milk from past 12 months (yes/no). objectives: to define the utility of crd in long-term follow-up after milk oit. results: mean follow-up time was 8 (5-11) years. ten patients (20%) avoided milk completely and 39 patients (80%) reported routine consumption of dairy products. side effects after milk consumption from last 12 months were reported by 39% of the patients. increased specific ige levels towards caseins were seen among patients who did not consume milk at the long-term (p=.03*). there was no significant association between the long-term milk consumption and ige levels to whole milk (p=.08), caseins (p=.06), alpha-lactalbumin (p=.25) and beta-lactoglobulin (p=.08) measured before the oit in this small sample. patients who consumed milk at the longterm follow-up and reported side effects had higher specific ige levels towards caseins before oit (p=.02*). conclusions: there was a high incidence of side effects even after eight years of milk consumption, which may indicate desensitization instead of true tolerance. component-resolved diagnostics may corroborate in predicting prognosis, as suggested by higher incidence of side effects among patients with high levels of ige towards caseins also in the long-term follow-up. objectives: retrospective study of 346 patients who underwent subcutaneous ait for allergic rhinitis (20% had concomitant asthma). patients with less than 4 months of treatment were excluded. large local reactions (wheal≥25 mm) and systemic reactions were defined according to who grading system. patient's satisfaction was defined by vas score. results: the mean age of patients (54% males) was 28ae13 (range 5-72) years (11%<16 years).the most prevalent immunizing allergens were house dust mite (92%), olive (26%) mix of grasses (23%) and pets (17%). 47% of patients were immunized against a single allergen whereas 12% were immunized with≥4 allergens. patients were followed for 24ae18 months. following ait the vas score decreased from 7.2ae2.3 to 3.6ae2.5 (p<.0005). 92% of the patients declared that they will recommend immunotherapy to their relatives. systemic adverse reactions (37% class i, 62% class ii) were observed in 120 introduction: metabolomics, one of the core disciplines of system biology, is a high-dimensional biology method that may allow hypothesis-free profiling of biomarkers, rather than a traditional hypothesis-driven approach. objectives: this study aimed to apply the metabolomic approach to serum to longitudinal alterations during allergy immunotherapy (ait) in dermatophagoides pteronyssinus (der p) sensitized asthmatic children. results: a robust hydroxyeicosatetraenoic acids (hetes) of inflammatory responses was found for discriminating during ait, including 5-hete, 12-hete and 15-hete. 12-hete and 15-hete were significantly decreased continuously from 6 through 12 months of ait. moreover, compared with baseline of ait 5-hete was detected in very low level during 6 and 12 months. the metabolomic profiling could clearly longitudinal alterations biochemical-metabolic profiles in der p-sensitized children during ait. these markers might be involved in asthma pathophysiology but also represent the therapeutic target for ait. background: metabolomics, one of the core disciplines of system biology, is a high-dimensional biology method that may allow hypothesis-free profiling of biomarkers, rather than a traditional hypothesis-driven approach. this study aimed to apply the metabolomic approach to serum to longitudinal alterations during allergy immunotherapy (ait) in dermatophagoides pteronyssinus (der p) sensitized asthmatic children. methods: in this longitudinal study, we recruited 58 der p-sensitized asthmatic children with ait for 12 months. serum samples were analyzed using a metabolomic approach based on mass spectrometry. results: a robust hydroxyeicosatetraenoic acids (hetes) of inflammatory responses was found for discriminating during ait, including 5-hete, 12-hete and 15-hete. 12-hete and 15-hete were significantly decreased continuously from 6 through 12 months of ait. moreover, compared with baseline of ait 5-hete was detected in very low level during 6 and 12 months. the metabolomic profiling could clearly longitudinal alterations biochemical-metabolic profiles in der p-sensitized children during ait. these markers might be involved in asthma pathophysiology but also represent the therapeutic target for ait. we performed desensitization with asa according to the wong protocol (doses of 0. 1, 0.3, 1, 3, 10, 30, 40, 81, 162, 325 mg of asa at intervals of 10-20 min). we pre-medicate with cetirizine 10 mg. our patient successfully reached the necessary dose: 164 mg of asa (0. 1, 0.3, 1, 3, 10, 30, 40, and 80 mg) conclusions: approximately 10% of patients with asthma undergo respiratory symptoms due to exposure to aspirin, meanwhile 0.07% and 0.2% of the population shall undergo hives when exposed to it. desensitization with aspirin is an efficient and safe treatment in patients with hypersensitivity type i, iii and iv. due to the benefits and low toxicity of the wong protocol, we recommend this protocol in order to desensitize patients with allergy to aspirin who undergo rheumatologic or cardiovascular disorders and need antiplatelet treatment. we finally recommend our patients to take 150 mg of asa premedicated with 10 mg of cetirizine every day. we warn that if you interrupt the administration of asa for more than 48 hours, it shall have to be administered again under medical supervision. semedo fm 1 ; cruz c 2 ; reis r 2 ; tomaz e 2 ; in acio f 2 horiuchi t 1 ; takazawa t 2 ; saito s 1 1 department of anesthesiology, gunma university hospital, maebashi, japan; 2 intensive care unit, gunma university hospital, maebashi, japan introduction: sugammadex is a synthetic c-dextrin derivative that is designed to selectively bind to steroidal neuromuscular blocking agent molecules. although sugammadex has been used in many cases of general anesthesia, there are several reports of anaphylaxis following its use. skin testing is the gold standard for detecting the causative agent of anaphylaxis. however, the test itself sometimes precipitates serious complications, including recurrence of anaphylaxis. hence, development of a novel test that can be performed in vitro without causing such complications is desired. recently, the basophil activation test (bat) has been established as a tool to detect the causative agent of anaphylaxis with high sensitivity and specificity. yet, there are few studies examining the utility of the bat in diagnosing sugammadex-induced anaphylaxis, besides our previous report. although both cd63 and cd203c are currently used as the major markers for activated basophils, which one of them is more suitable for the bat depends on the targeted drugs. objectives: the aim of this study was to investigate whether bat could be utilized to diagnose sugammadex-induced anaphylaxis. in addition, we compared the capability of cd203c and cd63 as markers for activated basophils. seven patients with perioperative anaphylaxis demonstrating a positive skin test for sugammadex were included. furthermore, 21 individuals who tolerated sugammadex and had a negative skin test for allergy to this drug were enrolled as controls. results: the ratios of activated basophils in the patients were much higher than those in controls (mann-whitney u test, p<.005). cd203c up-regulation. this was also true for cd63. in the case of cd203c, the sensitivity of bat for sugammadex was 83% and specificity was 100%, while sensitivity and specificity for cd63 were 71% and 100%, respectively. there were no significant differences between cd203c and cd63 in the areas under the roc curve. conclusions: this study showed that bat is a reliable instrument to diagnose sugammadex-induced anaphylaxis. we did not find any difference between cd203c and cd63 as markers for activated basophils in the bat for sugammadex. objectives: we report a retrospective study of 10 patients who were referred to our allergology departments between 2012 and 2016 with a suggestive history of immediate hypersensitivity to ppis. our purpose was the analysis of the clinical presentations and the allergological investigation performed in order to confirm the diagnosis of drug hypersensitivity to ppis and to study the cross-reactivity among ppis. results: the culprit drugs were pantoprazole (n=5), omeprazole (n=3) and lansoprazole (n=2). the allergological investigation confirmed the diagnosis of hypersensitivity to ppis in 5 patients (4 by skin tests and 1 oral challenge). we observed cross-reactions between omeprazole, pantoprazole and esomeprazole (n=1), omeprazole and pantoprazole (n=2), respectively omeprazole and esomeprazole (n=1). in 5 patients the severity and the recurrence of the reaction did not allowed the provocation test with the culprit drug. two oral challenges allowed the use of an alternative ppi (based on the pattern of less cross-reactivity depending on the chemical structure: pantoprazole for a patient who had a grade iii anaphylaxis to lansoprazole and lansoprazole for a patient who had a grade ii anaphylaxis to pantoprazole). conclusions: a complete allergological investigation (skin tests and cautiously, oral challenge) is needed in order to confirm the diagnosis of drug hypersensitivity to ppis and to take a therapeutic decision. the diagnostic approach is limited by the low sensitivity of skin tests and the patient's background (comorbidities and severity of the reaction) which do not always allow the oral provocation test. an ige dependent mechanism may be involved in hypersensitivity reactions to ppis or their metabolites. herrero-lifona l 1 ; muñoz-rom an c 2 1 hospital quironsalud campo de gibraltar, los barrios, spain; 2 hospital regional universitario de m alaga, m alaga, spain introduction: hypersensitivity reactions to beta-lactams are an important problem to study, especially in children, given that these antibiotics are the gold standard for the treatment of many infectious diseases in the infancy. most hypersensitivity reactions to betalactams in children are due to non-immediate response and to diagnose them is essential to perform a drug challenge test. although hypersensitivity is usually ruled out in children by drug challenge test, it is positive test up to 5%-10%. objectives: a 6 year-old boy is suspected to have experienced two drug reactions after the intake of amoxicillin with and without clavulanic acid for pharyngitis treatment. in the first one, he presented a maculopapular eruption in the back after one day treatment with amoxicillin-clavulanic acid. in the second reaction, two hours after the intake of amoxicillin, it appeared an itching maculopapular eruption in the back that was resolved with symptomatic treatment. in both cases, the patient tolerated treatment with cefuroxime afterwards. results: intradermal test with amoxicillin was negative in immediate and delayed reading. oral drug challenge test with amoxicillin (50 mg/kg/day, total cumuoral drug challenge test with penicillin v (total cumulative dose 250 mg): it was well tolerated and the patient continued taking it for epicutaneous patch testing with amoxicillin in the lesion area and in an unaffected area: in the lesion area, it appeared mild erythema, but it was considered a negative result in both areas. conclusions: we report a case of an amoxicillin-induced multiple fixed exanthema: an unusual non-immediate reaction in childhood. most cases of non-immediate hypersensibility need to be confirmed by drug challenge test, given that skin testing lacks sensitivity both intradermal and patch tests. the patient presents a selective hypersensitivity to amoxicillin, being tolerant to penicillin and cephalosporins. jimenez-rodriguez t 1 ; soriano-gomis v 1 ; gonzalez-delgado p 1 ; cueva-oliver b 1 ; venegas-diaz ij 1 ; fernandez j 2 results: data from 62 patients were analyzed, of which 64.5% (40) were women. the overall mean age was 46.1ae16.9 years, with no statistical difference between sexes. the 69.4% (43) of the patients presented symptoms with a single group of nsaids, and 30.7% (19) with 2 or more different groups. the 90% (56) of patients presented a history of atopy. in patients with rhinitis 58% had symptoms with only one nsaid and 42% with two or more groups of nsaid, while patients with asthma, 83% reacted to one nsaid and 17% to two or more groups. the most frequent clinical manifestations were: urticaria/angioedema in 71% (44), pruritus in 35.5% (22), bronchospasm in 19.4% (12), other respiratory symptoms in 16% (10) and anaphylaxis in 13% (7) patients. the most frequently involved nsaids were: metamizole (46.8%) and ibuprofen (37.1%). skin tests were performed in only 24 patients, of whom 13 (54%) were positive to metamizol. dpt was performed in 66.1% (41) objectives: fifty patients diagnosed with "dress" (2012-2016), in a tertiary center were retrospectively analyzed, with 31 cases meeting the regiscar criteria. we collected demographic, clinical, laboratory and therapeutic data from the electronic medical records. results: all cases occurred during hospitalization and in several hospital areas. the mean age was 49.16 years (7-94) with 58.06% women and 95% of caucasian origin. reported clinical manifestations were skin rash (97%), fever (48.39%), digestive symptoms (22.58%), respiratory (12.9%), neurological (9.68%), head and neck (6.45%), urological (6.45%), ophthalmologic (3.23%) and musculoskeletal (3.23%). the most relevant laboratory findings were eosinophilia (77%), elevated transaminase levels (77%), lymphocytosis (53%), altered coagulation (34%) and altered renal function (32%). virus serology was positive in 4 cases (12.9%) involving hhv-6, ebv, cmv and hiv. antinuclear antibodies were positive in 2/13 cases (15.38%). skin biopsy, performed in 12 cases (38.7%) revealed findings suggestive of drug induced skin reaction. suspected culprit drugs were antibiotics (45%), nsaids (26%), antiepileptic drugs (13%), and antiparasitic agents (10%). one case was related to the administration of heparins and other to a monoclonal antibody. in 10% of cases, the episode was not related to a particular drug. treatment was accomplished by the administration of corticosteroids (97%), antihistamines (96%), and immunosuppressant drugs in 2 cases. fluids and other medications were administered attending to symptoms. death occurred in 3 patients, although only in 1 case it was related to dress syndrome. the average time from reaction to death was 4.33 months. allergy evaluation, performed in 11 cases addressed the potential role of drugs. skin tests were positive in 3/11 patients (28.6%) and basophil activation test was negative (2/2 cases). results: from 17 patients admitted with possible diagnosis of scar, only 8 met the inclusion criteria (6f/2m, age 15-81, average 49.1 years-old). they were all admitted to a medicine ward. five patients had diagnosis criteria of dress, 2 of sjs and 1 of ten. as for the drugs related with the reaction, antiepileptic drugs were the most frequent (4 patients); allopurinol (1), betahistine (1), ciprofloxacin+nimesulide (1) were the causative drugs in the remaining patients. average time to the beginning of symptoms was 30.7 days (2 patients unknown). in 1 patient the cause was unknown (he had criteria of ten and also diagnosis of malaria and was transferred to another hospital). there were no deaths. objectives: the objectives of the present study were to determine the efficacy of nfeno to: 1. establish the diagnosis of rhinitis; and 2. discriminate allergic rhinitis (ar) from non-allergic rhinitis (nar). material and methods: prospective and controlled study with healthy subjects, which included patients with rhinitis. ar and nar were phenotypically defined according to positive or negative prick test results, respectively; the control group was collected from people without upper or lower respiratory tract disease and the prick test was negative. in all sample included the following measurements were performed: feno and nfeno (novario analyzer) were performed; spirometry; eosinophil counts in blood and nose (by nasal brushing); bilateral nasal endoscopy; and acoustic rhinometry. results: we included 147 cases (ar=61, nar=53 and controls=33), with a mean age of 37 (sd 11.2) years, 66% men. the table below shows the results of the variables analyzed by group. patients with rhinitis compared to controls had significantly greater feno production, as well as a higher proportion of eosinophils in blood and nose, but not in nfeno production. however, when the two subgroups of rhinitis were compared, ar patients had significantly higher feno and nfeno than nar, in addition to blood and nose eosinophils. there were no differences in acoustic rhinometry values between groups. conclusions: although nfeno does not appear to identify patients with rhinitis, it may be useful in discriminating ar from nar. in routine clinical practice, it could help guide to identify an ar in cases with inconclusive results of the complementary tests commonly used in its diagnosis. introduction: fractionated exhaled nitric oxide (feno) is used as a marker of eosinophilic airway inflammation in asthma, whereas clinical presentation of nasal no (nno) is unknown. objectives: the objective of this study was to evaluate the factors influencing nno levels. in patients with chronic nasal symptoms, total-nasal-symptom-scores (tnss) were calculated; skin-prick-test conclusions: in conclusion nasal no is useful in allergic inflammation in the absence of sinus obstruction in nasal cavity. however, its value is limited with paranasal sinus ostium occlusion. were recruited across australia and the uk via a patient panel. the aim was to assess which ar treatment attribute(s) drove patient preference. results: table 1 shows the willingness to pay (wtp) for each attribute. all attributes were significant predictors of treatment choice, except administration method. however, patients in both countries showed a considerable preference for treatments that were more efficacious, fast acting and affordable. conclusions: although treatment relief remains of primary concern, time to treatment benefit and cost could dictate treatment preference. these data may be of value in optimizing the acceptability of future ar treatments and informing trial endpoint selection. australia ( izquierdo l; chiriac am; molinari n; demoly p introduction: allergic rhinitis is a frequent disease with an important impact on quality of life. self-administrated control assessment tests can help achieve a better management of this disease. however, none of these tools has been validated in teenagers. test in its original version, following the same protocol as the original study in adults. we designed a multicentre, observational, crossconclusions: while the number of included patients is low, the first results are promising. indeed, a significant improvement of the rhinitis control score was found between d1 and d15. this led us to the hypothesis that this questionnaire could be used as is to estimate the control of the allergic rhinitis in teenagers. analyses concerning the validation of the questionnaire itself do not reach at the moment the threshold of significance, the recruitment is on-going, to increase its power. objectives: the objective of this study was to evaluate the role of serum vitamin d in patients with symptomatic allergic rhinitis and active asthma during the allergy season and observe the effect of montelukast 10 mg daily as treatment. results: this study included 130 asthmatic and seasonal allergic rhinitis patients following a single-blind, placebo run-in period of 3-5 days, patients were randomized to oral montelukast 10 mg (n=70) or placebo (n=60) daily during the 2-week, double-blind, active-treatment period. the serum vitamin d was also evaluated in both the groups. the serum vitamin d levels were found to be higher in patients taking montelukast compared to placebo after 2 weeks (p<.001). montelukast reduced the daily rhinitis symptoms score: difference between montelukast and placebo (p<.001). similar improvements were seen in daytime nasal symptoms (p<.001) and nighttime symptoms (p<.001). conclusions: montelukast provides significant relief from symptoms of seasonal allergic rhinitis, while also conferring a benefit for asthma, in patients with both allergic rhinitis and asthma. further, it has a beneficial role in improving vitamin d levels. venegas-diaz ij 1 ; jimenez-rodriguez t 1 ; canto-reig vj 1 ; lindo-gutarra m 1 ; soriano-gomis v 1 ; gonzalez-delgado p 1 ; cueva-oliver b 1 ; fernández j 2 1 allergy section. general hospital alicante. isabial, alicante, spain; 2 allergy section. general hospital alicante. isabial-umh, alicante, spain introduction: local allergic rhinitis is an accepted entity, which only can be recognized by nasal provocation test (npt) in patients with clinical rhinitis with negative skin tests or specific ige (sige). our aim was study this entity in our patients in alicante, spain. objectives: 100 patients with symptoms of rhinitis with skin tests, and sige negative for common aeroallergens were selected, since 2015. half of them (47) most were young adults, 50% belonging to the range of age between 18-30 years; more than 43% had family history of atopy; the mean age of onset of symptoms was 25 years and up to 18.7% had had symptoms before the age of 14 years; 56.2% were nonsmokers. regarding comorbidity, 62.5% of the patients presented with concomitant symptoms of conjunctivitis and 6.2% of asthma. symptoms in 93.7% of the patients were persistent and most of moderate (50%) to severe (43.7%) intensity. the majority of patients (87.5%) presented perennial symptoms and a tpn positive to mites in 37.5%, to salsola pollen in 25% and to cypress pollen in 12.5%. but 3 patients (18.75%) were simultaneously positive to 2 allergens. conclusions: local allergic rhinitis represents an important proportion of patients with clinical rhinitis with negative skin tests and sige. we have to pay attention to identify clinical and demographic factors of ral and to use npt to demonstrate it. objectives: we report the extent of sinus involvement at baseline (bl) in pts with bilateral np refractory to intranasal corticosteroids from a dupilumab phase 2a study (nct01920893). ct scans from enrolled pts, 59 adults <65 years with nasal polyp score of ≥5/8, were pooled and analyzed at bl. for opacification, standard lund-mackay (lmk) scoring (0=normal, 1=partial opacification, 2=total opacification) in maxillary, anterior/posterior ethmoid, sphenoid, frontal sinuses was used. ten sinus scores plus bilateral ostiomeatal complex (omc) score (0=not occluded, 2=occluded) were summed to a bilateral total lmk (0-24). zinreich modified lmk score (zlmk), providing more granularity on opacification degree, was evaluated post-hoc; each sinus was given a 0-5 score based on opacification % from mucosal thickening (0=0%, 1=1%-25%, 2=26%-50%, 3=51%-75%, 4=76%-99%, 5=100%); omc results: the prevalence of asthma at the age of 12 years was 6.4%. 15% of them had an act tm value below 20, ie uncontrolled asthma, median 22.0 (range 12-25). independent risk factors for uncontrolled asthma at the age of 12 were current doctor diagnosed rhinitis (adjusted or, aor 2.8; 95% ci 1.1-7.0), wheeze triggered by exercise (aor 5.6; 1.9-16.6) and cat at home (aor 3.5; 1.2-10.0). if at least one of the parents had higher education the risk of uncontrolled asthma was decreased (aor 0.3; 95% ci 0.1-0.8). six children reported hospitalisation due to asthma during the last 12 months (ie 2.6%) at 12 years of age. hospitalisation was more common in individuals with uncontrolled asthma (or 12.3; 2.2-70.5) or when mites (or 9.8; 1.9-51.5) or pollen (or 5.8; 1.0-32.5) was reported as trigger factors. also, oral corticosteroids (betamethasone), in the last 12 months increased the risk for hospitalisation (or 8.2; 1.4-48.7). to have a parent with asthma (17% compared to 37%, or 0.3; 0.04-2.9) or higher education (40% compared to 62%, or 0.3; 0.07-2.5) was numerically less common for children who were hospitalised for asthma but did not reach statistical significance. conclusions: uncontrolled asthma was associated with current allergic rhinitis, having a cat and exercise as trigger factor. at least one parent with higher education reduced the risk. hospitalisation due to asthma was more common in individuals with uncontrolled asthma. abstracts 0404 | adolescent asthma in relation to severity and gender-data from a prospective population based cohort study introduction: asthma often debuts early in life, but recent studies show that the development of asthma is a dynamic process with disease turnover throughout child-and young adulthood. objectives: to describe adolescents' asthma with focus on severity and gender. the study population consisted of 3115 adolescents participating in the cohort, followed since birth up to 16 years of age with questionnaires and clinical investigations. blood samples from 2452 adolescents (78.7%), sera analyzed for specific ige against common inhalant allergens. asthma at 16 years was defined as fulfilling at least 2 of the following 3 criteria: symptoms of wheeze and/or breathing difficulties in the last 12 months, ever doctor's diagnosis of asthma and/or asthma medicine occasionally or regularly last 12 months. uncontrolled asthma was based on parental information on symptoms of asthma in the last 12 months prior the 16-year follow-up, including 3 or 4 features: nocturnal asthma, activity limitation, wheeze 4 times and hospitalization due to acute asthma. we looked into 2 phenotypes; late-onset, defined as asthma at 8, 12 or 16, but not at 1, 2 and 4 years of age and persistent, defined as asthma at 1, 2 or 4 and 8, 12 or 16 years of age. severe asthma, defined as asthma as above combined with prescribed and dispensed corticosteroids used within the last 18 months plus uncontrolled asthma and/or lung function (fev 1 <80% of predicted). results: at 16 years of age, 14.2% (n=437) fulfilled the study definition of asthma, 49.3% late onset and 50.7% persistent asthma. persistent asthma was more frequent among boys than girls 59.1% vs 43.3% (p=.001). overall ige sensitization was common among adolescents with asthma, 70.1% were sensitised to common inhalant allergens, and equally common in late-onset and persistent asthma (71.7% vs 68.8%, p=.54). however, more boys than girls were sensitised (79.9% vs 62.6%, p<.001). in total 8.1% (n=25) adolescents had severe asthma, 11.2% (n=15) boys and 5.8% (n=10) girls (p=.08). the overall prevalence of severe asthma in the cohort was estimated to 1.0%. severe asthma did not significantly differ among adolescents with late-onset compared to persistent asthma (17/25, 8/25, p=.09). conclusions: among adolescents with asthma, late-onset (age ≥8 years) and persistent asthma were equally common. persistent asthma were more common among boys. there were no difference in asthma severity, or proportion of ige sensitization among adolescents with late-onset or persistent asthma. however, data investigating associations with wheeze and asthma in later childhood are scarce. objectives: our aim was to explore the association of maternal milk fatty acid composition with childhood wheezing phenotypes and asthma up to age 13 years. breast milk was collected 6 weeks and 6 months post-delivery in the ulm birth cohort study (n=720 and n=454, respectively). concentrations of 10-24 carbon atom chain length fatty acids were measured by high-resolution capillary gas-liquid chromatography. to control for constant sum constraint, concentration data were transformed using the centered log ratio method. compositional biplots and correlation matrices were used to group fatty acids based on within sample correlation. adjusted risk ratios with parent-reported wheezing phenotypes and doctor-diagnosed asthma were computed using a modified poisson regression. results: we observed no straightforward evidence of associations between overall breast milk fatty acid composition and specific wheeze phenotypes or doctor-diagnosed asthma. conclusions: despite our use of sophisticated statistical methodology, our results may have been biased toward the null by several cohort-specific factors associated with breast milk collection and fatty acid composition. to overcome potential selection bias by maternal lifestyle, further research should investigate fatty acid intake during the first year of life including sources other than breast milk among children who were never or not exclusively breastfed. introduction: fall is the most common season for asthma exacerbation. previous studies found that exposure and sensitization to house dust mites (hdms) can exacerbate asthma. the seasonal variation in indoor hdm concentration is highest in the fall, correlating with the incidence of asthma exacerbation. most of the studies conducted to date have focused on the effect of hdm exposure on the incidence of acute asthma exacerbation, but reports about the effect of hdm sensitization are few. thus, we aimed to determine whether sensitization to hdms acts as a risk factor of asthma exacerbation in the fall. in addition, we investigated whether asthma exacerbation in the fall had any distinctive features by comparing levels of various cytokines and chemokines with those in other seasons. objectives: we enrolled 55 children aged 3-14 who visited the emergency department because of acute asthma exacerbation from january 2008 to december 2013 (63.6%, males; mean age, 6.0ae2.8 years). they were treated in accordance with the standardized treatment protocol. blood samples were collected from the children during the course of treatment. by using residual sera from the blood samples, we measured the levels of total immunoglobulin e (ige), hdm-specific ige (sige), eosinophil cationic protein (ecp), and various cytokines and chemokines, and classified them according to season. we compared the date divided into fall group (from september to november, n=31) and other season group (from december to august, n=24). ci, confidence interval; or, odds ratio; der f-sige, dermatophagoides farinae -specific immunoglobulin e; der p-sige, dermatophagoides pteronyssinus-specific immunoglobulin e; ecp, eosinophil cationic protein; ige, immunoglobulin e. data are presented as n (%) or as meansaesems and median (range). p value refers to the difference between the fall and "other season" groups and was calculate by the chi-square statistics, fisher's exact test, student's t-test, or wilcoxon rank-sum test. a adjusted for total ige. results: this retrospective study obtained archived nasopharyngeal aspirate (npa) samples from patients aged below 18 years who were hospitalized for acute respiratory illnesses in a university-affiliated hospital during the periods september-november 2014 and january-april 2015. their clinical information was retrieved from computerised record. hrv was detected by rt-pcr, and isolates were sequenced to determine the genogroups and serotypes. ninety patients whose npa was positive for hrv and 160 patients being negative for an extended panel of respiratory viruses by multiplex pcr method were identified. mean age of these groups was 3.6 years and 3.5 years respectively. hrv infection was significantly associated with asthma exacerbation (or 16.54, results: a total of 203 children were included: 73.4% were boys; 26.6% aged 6 months to 2 years, 51.0% aged 3-6 years, 20.1% aged 7-13 years and 2.4% aged 14-18 years; 44.0% were hospitalized, results: the long-term remission (≥5 years without treatment) rate 16 years after initiating early anti-inflammatory therapy was 88.1% (intermittent asthma, 100%; mild persistent asthma, 72.2%; moderate persistent asthma, 90.0%; severe persistent asthma, 66.7%). longterm remission rates improved compared with past asthmatic convaobjectives: the aim of this study is to explore the potential value of feno level for diagnosing chronic cough in children. objectives: in this study, we aimed to compare the efficacy of classical spirometry and impulse oscillometry (ios) in evaluation of late reversibility in children who received treatment with the diagnosis of atopic asthma. we enrolled 83 patients aged 7-17 years who were diagnosed with atopic asthma. exclusion criteria were having received asthma treatment during the previous two months, having acute asthma exacerbation findings, having any other respiratory disease or cardiac disease that may affects the lung function test results. allergic sensitization was determined by skin prick test performed according to eeaci guidelines. lung function test measurements were performed at enrollment and after two months of inhaled steroid treatment. conclusions: classical spirometry is more valuable compared to ios in evaluation of late airway hyperreactivity in children with atopic asthma in children older than seven years age. 0413 | computer bronchophonographyfrequency analysis of the respiratory cycle. objectives: we performed mct in 144 children with symptoms suggestive of asthma and 30 without respiratory symptoms. after each inhalation step oscillometry and spirometry was performed. parameters analysed for ios were z5, r5, r20, x5, x15 and ax (the integrated impedance reactance at r5 and above) and fev1 for spirometry. a fall of 20% in fev1 from baseline after mtc was considered as a positive challenge. pc20-fev1 and pc40 r5, x5 and ax were calculated. results: a total of 174 patients, 79 female, with a mean age of 9.5 (ae3.03) years were enrolled. 132 had a ≥ 20% fall in fev1 after mtc. the mean variation in fev1 was 7% (-12.2%/ +45.8%), the mean variation in z5, r5, r20, x5, x15, ax and fres were 21.88% objectives: the objective of our study was to synthesize cationic peptides and study their antiviral activity (aa) in vitro. results: 16 peptides were synthesized by solid phase method with different structures (linear, helical and dendrimeric). cytotoxicity of the peptides was studied by mtt assay using hela cells. objectives: the aim of the study is to evaluate the changes of ilresults: 48 subjects aged 18-65 years were enrolled in this study, which were divided into 4 groups: 23 patients with diagnosed moderate to severe ba (1st group), 6 ba patients with rvi (2nd group), 8 subjects with rvi only (3rd group) and 11 healthy volunteers (4th group). all patients with ba from group 1 and 2 received inhaled corticosteroids. clinical blood test revealed increase of eosinophils in patients with ba and ba accompanied with rvi up to 7% and 4%, respectively. fev1 was decreased in 1st and 2nd groups to 77% and 79% compared 98% and 97% for 3rd and 4th groups, respectively. conclusions: this study is alarming for asthmatic nosocomial hazards in this govt. hospital. identification of ige specific reactive components of predominant fungal allergens and cross-reactivity among each other, delined in this study could minimize the hazard of therapeutic and diagnostic use of these cross-reactive components, in fungal allergen-specific immunotherapy. objectives: we conducted a longitudinal prospective study to examine the development, composition and diversity of the gut microbiota in healthy and allergic children. we followed 93 children from 4 months to 8 years of age with clinical evaluation; specific ige levels and skin prick testing. fecal samples were collected at 4, 6, 13 months and 8 years. 16s rrna sequencing was used to profile the gut microbiome using illumina miseq. the composition and diversity of the gut microbiome were assessed using quantitative insights into microbial ecology (qiime). comparisons between groups were made using the lefse pipeline; non-parametric factorial kruskal-wallis test, unpaired wilcoxon rank test and linear discriminant analyses (lda) with score >2.0. to assess the interaction effect, the likelihood ratio test (lrt) was applied using r statistical program. p<.05 was considered significant after correction for multiple testing. results: to achieve our aim we divided balb/c mice into 4 groups: mice with viba (1st group), mice with viba treated with nonspecific sirna against gfp (sigfp) (2nd group) and against il-33 (siil-33) (3d group). 4th group was intact mice. groups 1-3 were i.p. sensitized on days 1, 14, 28 with ovalbumin (ova) mixed with aluminum hydroxide and i.n. challenged with ova on days 40-42. the same mice were i.n. infected with 5910 6 tcid 50 /mouse rsv strain a2 on day 39. mice from group 2 and 3 were i.n. treated by sirnas on days 38-42 in dose 120 lg/mouse. on day 43 hyperresponsiveness (ahr) to methacholine was measured. on day 44 and lungs were removed for histological analysis. viral rna (vrna) load and il-33 gene expression were evaluated by qpcr in lungs. bronchoalveolar lavage (bal) was collected for differential cell count by light microscopy. so i.n. administration of siil-33 suppressed il-33 gene expression in lungs by 50% compared to sigfp treated mice. there were no significant changes in body weight and lung vrna amounts between mice received sigfp and siil-33. mice treated with siil-33 demonstrated the tendency to improve lung function compared to mice of group 1-2, that expressed in 13% reduction of specific resistance of airways and 15% increase of peak expiratory flow. bal cell count revealed decrease of total cell number, eosinophils and lymphocytes in mice received siil-33 by 55%, 90% and 63% compared to sigfp treated mice, that indicate reduction of inflammation, that was confirmed by histopathological studies showed 50% leukocyte reduction. downregulation of il-33 resulted in 2-and 1.7-fold decrease of bronchial epithelium metaplasia and hyperplasia. and femur length measurements were collected from routine antenatal screenings. these and derived head to abdominal circumference ratio and estimated fetal weight were converted into z-scores adjusted for gestational age and gender and categorized as "low" (≤1 sd below mean), "normal," or "high" (≥1 sd above mean). ad cases were children with parent-or pediatrician-report of physician ad diagnosis assessed yearly up to age 3 years and supplemented by clinical diagnoses during dermatological exams at 0.5, 1, and 2 years. modified poisson regression models were used to compute risk ratios (rr) adjusted for potential confounders. conclusions: these results provide further evidence for a role of fetal growth as an influence on atopic disease outcomes. unlike previous studies, our data suggests several patterns of fetal growth beginning as early as the 1st trimester may influence ad outcomes. objectives: we aimed to examine the role of eosinophil cationic protein (ecp), eosinophil derived neurotoxin (edn) and total immunoglobulin (ig) e as a bio-marker of disease severity. we examined the difference in level of total ige, ecp and edn between the two groups and whether any correlation existed between disease severity and ecp or edn. objectives: we aimed to identify the subgroup of ad patients with a good clinical response to probiotic treatment. we recruited children who suffered from moderate to severe ad with the scoring ad (scorad) index of 20 or higher. after 2 weeks of washout period, all patients were given lactobacillus plantarum cjlp133 at a dosage of 1910 10 colony-forming units once a day for 12 weeks. we measured eosinophil counts in the peripheral blood, the proportion of cd4 + cd25 + foxp3 + regulatory t (treg) cells in cd4 + t cells, serum total ige levels, and specific ige to common allergens before the start of the treatment (t1) and at discontinuation (t2). logistic regression models were used for the statistical analysis. seventy-six patients (48 boys and 28 girls) with a mean age of 8.7ae4.7 years completed the study. there were 36 responders and 40 non-responders after probiotic treatment. the median scorad was reduced from 29.5 (range 20.6-46.3) at t1 to 16.4 (range 6.3-30.8) at t2 in the responder group (p<.001). in multivariable logistic regression analysis, a good clinical response was significantly associated with high total ige levels (aor 5.1, 95% ci 1.1-23.6), increased expression of , and high proportion of cd4 + cd25 + foxp3 + cells in cd4 + t cells (aor 3.7, 95% ci 1.1-12.7). in responder group, the proportion of cd4 + cd25 + foxp3 + cells of cd4 + t cells were significantly increased after 12 weeks of treatment (p=.004), while the levels of tgf-b mrna expression were decreased (p=.017). there were no differences in total ige levels between t1 and t2 (p=.414) conclusions: the therapeutic effect of l. plantarum cjlp133 on ad is more pronounced in children with high total ige levels, objectives: the objective of the study was to examine the effect of a specific synbiotic mixture of short-chain galacto-, long-chain fructo-oligosaccharides (scgos/lcfos, ratio 9:1) and bifidobacterium breve m-16v on the severity of ad and correlation to serum chemokines in infants with moderate to severe ad and elevated ige. in an exploratory randomized, double-blind, placebo-controlled trial the effect of extensively-hydrolyzed whey-based formula without intervention. serum obtained prior to start and at the end of intervention were analysed using luminex. six chemokines and nine ratio's thereof were correlated to ad severity (sample size=24). introduction: dyshidrotic eczema is one of the most common skin conditions. contact allergy is often associated with dyshidrotic eczema although the exact impact and the influence of contact allergens in different forms of dyshidrotic eczema remain unknown. hypersensitization to nickel is one of the most common contact allergies associated with pompholyx. the standard of care protocol is to use a medical treatment with topical corticosteroids and calcineurin inhibitors to treat the symptoms, together with occlusive barrier creams to avoid skin exposure to the allergens. after the symptoms have been cleared with the topical treatment, the recommendation is to use occlusive barrier creams to prevent recurrence of the symptoms. objectives: a new emollient with specific metal-scavenging agents and no occlusive ingredients has recently been developed and made commercially available. the aim of this study was to evaluate the effect of such cream to provide relief for patients with dyshidrotic eczema associated with nickel allergy. results: thirty-two subjects with dyshidrotic eczema and a positive patch test ppt (contact sensitized) reaction to nickel were selected. these were divided into two randomized groups, group-a was given nickel-scavenging cream (skintifique creamtm, paris) after medical treatment, (n=9) and group-b followed the standard protocol for pompholyx, (n=23). hand eczema was scored according to the dyshidrotic eczema area and severity index (dasi). dasi scores were evaluated at the beginning of the study (day-0), after the medical treatment (day-15) and two months after the end of medical treatment (day-75). results show a significant difference in the efficacy of treatment between the two groups at day-75. a higher percentage of at least 75% reduction of initial dasi score (77.8%) and a higher percentage of total clearance (56%) in patients using nickel-scavenging nonocclusive moisturizing cream was observed as compared to standard-of-care occlusive creams (26.1% and 22%, respectively). objectives: the goal of this study was to investigate whether long-term emollient therapy is associated with alterations of skin barrier function and shifts of the skin microbiome in infants at high risk for developing ad. we prospectively enrolled newborns with a family history of ad to be randomized to either emollient treatment group or control group. at 6 months of age, we tested the skin barrier (transepidermal water loss/tewl, water capacitance/cap, ph) and skin microbiome (16s rdna sequencing of skin swabs from cheek, dorsal and volar forearm). results: the emollient group (n=10) had significantly lower skin ph compared to controls (n=9) (p=.02), but without a statistically significant difference in tewl or cap. the emollient group had higher numbers of different bacterial taxa (chao richness) at cheeks (p=.003), dorsal forearms (p=.008), and volar forearms (p=.003) as compared to controls. both streptococcus pneumoniae and s. salivarius statistically significantly contributed to the observed skin microbiome differences between patient groups. s. salivarius was significantly more abundant in emollient subjects at all sampling sites (p=.02). we then analyzed our previous larger cohort of older children with ad and also observed higher s. salivarius proportions in ad patients with treated and less severe disease (p=.01). objectives: to evaluate the effect of overnight treatment with a temperature-controlled laminar airflow (tla) device in children/adolescents with severe eczema over a 12-month period. in an open-label study, 15 subjects aged 2-16 years (median 10 years) with longstanding severe eczema attended 3 visits during the run-in period lasting 6-10 weeks (median 7.14 weeks) to optimize eczema management. the run-in was followed by a 12month treatment period using overnight tla device (airsonett ® , sweden), which included 8 study visits. we used scorad-index results: the median duration of eczema was 116.5 months (interquartile range 82-145.5). all subjects were sensitised to ≥1 perennial allergen, and had multiple comorbidities (15/15 rhino-conjunctivitis, 14/15 food allergy, 11/15 asthma). there were no significant changes during the run-in period in any of the outcome measures. we observed a significant improvement in scorad after the 12-month tla-treatment period, from 34.9 [28.75-45.15 ] to 17.2 [12.95-32.3] , p=.015. iga improved significantly from a median of 4 [3-4] to 2 [1] [2] [3] , p=.001. improvement in symptoms was paralleled by a significant reduction in medication usage. by 12 months, there was a significant improvement in .0] to 12 [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] , p=.032), and an improvement in cdqli (marginal, p=.084). however, we observed no changes in poem (p=.196) . post-hoc cluster analysis of the patterns of changes in scorad over the 12month treatment period identified two clusters, with 9 participants classified as responders and 6 as non-responders. introduction: intestinal degradation has been shown to determine allergenicity of food allergens. however, it is unclear how allergens are degraded inside pivotal immune cells such as dendritic cells (dc), and how this affects the subsequent immune response to these allergens. in our studies, we determined whether we are able to measure uptake and degradation of allergens inside dc and whether differences in above mentioned factors exist between allergens. objectives: using mouse bone marrow-derived dc and fluorescent-labeled proteins, we studied the cellular uptake of the peanut proteins ara h 1, 2, 3, and 6. results: first, we observed that dc uptake of ara h1 was much higher than ara h2, 3 and 6. using blocking reagents and receptor binding assays for various uptake routes in dc, we observed that one of the principal routes of uptake for ara h 1 was the mannose receptor. other uptake routes, and the routes of uptake for ara h2, 3 and 6 are currently under investigation. second, using proteins coupled to beads we observed that intracellular protein degradation was higher for ara h1 and ara h3 than for ara h2 and 6. finally, cd4+t cells from ara h 1, 2, 3 or 6 sensitized mice were added to matching allergen-pulsed dc. we observed that while ara h1, 3 and to lesser extend ara h6 elicited strong th2 type responses, ara h2 did not elicit any t cell responses. conclusions: together, we show that allergenicity of (peanut) proteins may be, at least partly, determined at the level of allergen uptake and breakdown inside the antigen presenting cell. these findings may be relevant to risk evaluation of existing allergens but also of novel or modified proteins. this also illustrates the usefulness of in vitro, cell based assays to examine initial processes of allergenic sensitization to proteins. 0445 | sensitising capacity of unmodified and acid hydrolysed gluten through the skin-a comparative study in na€ ıve vs tolerant brown norway rats ballegaard ar; madsen cb; bøgh kl national food institute, technical university of denmark, søborg, denmark introduction: allergic sensitisation to foods may occur in infancy without prior oral exposure to the offending food. this has led to the assumption that food allergy sensitisation may occur through alternative routes, such as the skin, supported by the observed correlation between skin barrier disruption and food allergy. recently, concerns have been raised regarding the safety of use of cosmetic and personal care products containing hydrolysed wheat proteins, since these products have been shown to induce allergy towards acid hydrolysed wheat through the skin, and even to cause an abrogation of the already established oral tolerance against unmodified wheat. objectives: the aim of the study was to compare the sensitising capacity of an unmodified and an acid hydrolysed wheat product via slightly damaged skin, in order to evaluate differences in conditions necessary for skin sensitisation in na€ ıve vs tolerant individuals. brown norway rats were raised and bred on either (1) a diet free from wheat, resembling individuals with a na€ ıve immune system, or (2) a conventional wheat containing rat chow, resembling individuals tolerant to wheat. results: in the na€ ıve rats both products were able to induce a statistically significant specific antibody response after application of the products on the slightly damaged skin, whereas in the wheat tolerant rats, only the acid hydrolysed wheat product was able to induce a statistically significant antibody response. for both the na€ ıve and the wheat tolerant rats the response was dose-dependent. in the na€ ıve rats both products were able to sensitise through the skin, inducing a specific ige response, whereas in the tolerant rats only the acid hydrolysed product were able to induce a specific ige response, though this ige response was much lower than in the na€ ıve rats. results from competitive elisas demonstrated that new epitopes had developed as a result of acid hydrolysis, though original epitopes were maintained at the same time. this may explain why only the acid hydrolysed wheat could induce specific antibody responses in the tolerant animals. conclusions: this study showed that the sensitising capacity through the skin of two different wheat products is heavily influenced by the tolerance status of the immune system and the degree of modification of the wheat products. results: using a germ-free c3h/hen mouse model of food allergy, we examined the presence of a major peanut allergen, ara h 2, in the blood after intraperitoneal injection in previously sensitized and control (non-sensitized) mice using an untargeted, quantitative proteomic approach. previously sensitized mice underwent physiological (core temperature decrease, clinical symptoms) and biochemical (mast cell protease increase, ara h 2 specific ige positivity) changes associated with severe allergic reactions. we were able to confidently detect multiple peptides derived from the ara h 2 protein after intraperitoneal injection in both control and ara h 2 sensitized mice. however, the ara h 2 protein was present at 15-40 fold higher levels if mice were previously sensitized, suggesting increased transit across the peritoneal mesothelium with sensitization. an untargeted proteomic approach also allowed changes in the blood proteome of mice undergoing a severe allergic response to be examined. we identified proteins with significantly altered quantity in serum between control and sensitized mice and were therefore apparently associated with the allergic response. we demonstrate the applicability of untargeted proteomics to the study of the allergen transport and proteomic changes which co-occur with a resultant allergic reaction. the transit of allergens into the bloodstream is heavily dependent upon previous sensitization. we are continuing this work to examine the specificity of observed increases in trans-mesothelial transport and to address transport of allergens after intragastric challenge. 0447 | iga to cow's milk differs between breast milk and serum for its epitope specificity objectives: we sought to assess whether the profile of epitopespecific iga differs between mother's serum and bm. we also examined how infants' food epitope-specific iga develops in early infancy and the relationship of iga epitope recognition with development of cow's milk allergy (cma). results: . we measured iga specific to an array of overlapping peptides in major cow's milk allergens (alpha s1-, alpha s2 -, betaand kappa-caseins and beta-lactoglobulin). diversity of peptide-specific iga (ie epitope diversity) was determined in paired maternal and infant sera as well as breast milk samples in 31 mother-infant dyads within the first 15 postpartum months utilizing peptide microarray. microarray data was converted to z-scores and filtered for noise. peptide epitopes were determined based on jaccard distance between neighboring peptides, and intra individual correlation between sample types was estimated using phi coefficient. comparisons between groups and individuals was done using non-parametric tests. we noted marked discordance in epitope recognition in paired breast milk and maternal serum samples. at least one shared epitope was recognized by both milk and serum samples ranging from 13% of mothers for alpha-s1 casein to 73% for kappa-casein. epitopespecific iga was detectable in infants' sera starting at less than 3 months of age. sera of mothers with a cma infant had increased binding of epitope-specific iga to cow's milk proteins compared to those with a non-cma infant (p<.05 for all five proteins). conclusions: these findings support the concept that mothers' milk represents a product of the mucosal immune system that has an antibody repertoire distinct from that of peripheral blood. results: multiple ige-binding proteins were detected in the different wn preparations and many of which were dissemblance in 2dblotting. profiles of detectable proteins (peptides) of raw, roasted and boiled wn extracts were profoundly different in emi analysis. introduction: consumption of tree nuts is on the rise due to their beneficial health effects. however, tree nuts can led to severe allergic reactions in sensitized patients. thermal processing can modify the structure and function of food proteins and may alter (increase or decrease) their allergenic properties. knowledge about the effects of thermal processing on tree nuts such as cashew or pistachio is rare and based on traditional in vitro immunoassays. objectives: to elucidate the influence of thermal treatments (boiling and heat / pressure) on the ige reactivity of cashew and pistachio proteins, by means of traditional in vitro immunoassays and mediator release assays (mra). results: the allergenicity of untreated and treated cashew and pistachio nuts was evaluated by ige-elisa, ige-immunoblot and elisa inhibition assays using sera from spanish patients with clinical allergy to cashew and pistachio. rat basophilic leukaemia cell line transfected with the a-chain from the human high-affinity ige receptor fceri, was sensitized with a pooled sera and used for mra. sensitized cells were stimulated with untreated and treated protein extracts, in order to investigate the capability of untreated and treated cashew and pistachio proteins to cross-link ige on effector cells. the results showed that heat and pressure treatment at the harshest conditions considered in this study produced a higher decrease of the ige-binding capacity of cashew and pistachio proteins than boiling without pressure or soft conditions of heat and pressure. interestingly, although the treatments of heat and pressure seemed to affect cashew allergens to a greater extent than pistachio allergens (evaluated by ige-elisa and elisa inhibition), the results of mra using the cell line rbl-48 indicated that cashew proteins treated with heat and pressure, still retained some capacity to cross-link ige. introduction: previous research has indicated an important role for dietary non-digestible oligosaccharides in decreasing the incidence of atopic dermatitis in children at risk of allergy. it is assumed that these prebiotics promote colonization of beneficial bacteria in the gut. children with atopic dermatitis receiving a diet of galacto-and long chain fructo-oligosaccharides (scgos/lcfos) with bifidobacterium breve m-16v had enhanced serum galectin-9 levels. galectin-9 has ige-binding capacities and can hereby suppress degranulation of mast cells and basophils. next to their function in the gut, oligosaccharides may also affect other immune cells directly, since they were found in plasma and urine. objectives: we investigated whether non-digestible oligosaccharides or galectin-9 can have a direct effect on immune cells, by determining the effect on basophil degranulation in peanut-allergic patients. whole heparinized blood samples were collected from 12 peanut-allergic adult patients and incubated for 24 hours with either a mixture of 0.05% 9:1 scgos/lcfos or scfos/lcfos, or galectin-9 (1 or 5 lg/ml) at 37°c in the presence of il-3 (0.75 ng/ml). after 24 hours, a basophil activation test (bat) was performed. basophils were stimulated for 30 minutes at 37°c with increasing concentrations of whole roasted peanut extract or human anti-ige. degranulating basophils were determined as cd63+ cells and calculated as percentage positive cells. results: in each patient, the concentration of anti-ige or peanut extract that induced maximal degranulation in the untreated control sample was used as reference value to compare degranulation of the samples pretreated with scgos/lcfos, scfos/lcfos, or galectin-9. pre-treatment of whole blood with scgos/lcfos resulted in an average decrease in degranulation of approximately 8%, while a significant reduction of 19% was observed after pre-treatment with scfos/lcfos (p<.05). pre-treatment with 1 lg/ml galectin-9 decreased basophil degranulation with 12%, whereas 5 lg/ml galectin-9 caused a significant decrease of 25% (p<.05). no differences were observed in the ec50, indicating that the basophils are not becoming less sensitive to the peanut extract or anti-ige. the prebiotic mixture scfos/lcfos and galectin-9 can contribute to decreased degranulation of basophils in a igemediated bat assay using whole blood. further analysis is warranted to define the exact working mechanism of these oligosaccharides. introduction: the intestinal mucosa plays a key role in the development of food allergies. we studied the interaction between intestinal epithelial cells (iecs) and pbmcs of peanut-allergic patients in a transwell co-culture model. exposure of iecs to a mixture of galacto-and/or long chain fructo-oligosaccharides (scgos/lcfos) in combination with synthetic cpg dna (tlr9 ligand),modulated the cytokine response of activated pbmcs, driving away from the allergic phenotype. objectives: our aim was to compare the efficacy of scgos/lcfos with a scfos/lcfos mixture and to evaluate these effects in an allergen-specific co-culture model. iecs (ht-29, human colon adenocarcinoma) were grown on transwell filters until confluence. iecs were apically exposed to 0.5% 9:1 scgos/lcfos or scfos/lcfos either or not in combination with 2.5 lmol l à1 cpg dna to mimic presence of dna of beneficial bacterial in the gut. these iecs were co-cultured with basolateral pbmcs from peanut-allergic patients, either activated with anti-cd3/cd28 (24 hours) or peanut-extract (pe, 6 days).cytokines ifn-c, il-10, il-13 and tnf-a were measured in the basolateral supernatant and t-cell polarization of the pbmcs was determined (th2, th1, treg and tfh). results: apical exposure of iecs to cpg dna increased basolateral ifn-c and il-10 production by anti-cd3/cd28 activated pbmcs (p<.01), and was enhanced by both oligosaccharide mixtures (p<.01). cpg exposure in transwells with pe stimulated pbmcs also increased ifn-c and il-10 production, which was further enhanced by scfos/lcfos (p<.05). in this pe-specific model, percentages of th1 and treg cells increased upon cpg exposure of iecs, and th1 frequency was increased by scfos/lcfos (p<.05). cpg dna exposed iecs suppressed il-13 and tnf-a production by anti-cd3/ cd28 activated pbmcs. both scgos/lcfos and scfos/lcfos reduced tnf-a production in combination with cpg dna (p<.01). tfh cells can produce il-21, inhibiting class-switching to ige2. upon cpg exposure of iecs, we observed an increase in tfh cells (p<.01) and similar tendency for cd4 + il-21 + cell frequency in anti-cd3/ cd28 activated pbmcs. conclusions: epithelial exposure to both scgos/lcfos and scfos/lcfos enhances the cpg dna induced th1 and regulatory il-10 response in an anti-cd3/cd28 co-culture model, whereas only scfos/lcfos was effective in an peanut-specific co-culture model. introduction: in areas of spain with high level of grass pollen exposure, 60% of grass allergic patients were sensitized to profilin, and most of them developed severe profilin mediated food reactions. this specific population of patients constitute an ideal model to study the relation among respiratory and food allergy objectives: our aim here was to analyze the links between epithelial barrier integrity and inflammation in oral mucosa. methods: 30 allergic patients and 6 controls were included in the study. allergic patients were stratified into mild or severe according to their clinical history and response to profilin oral challenge test. immunohistochemistry (ihc) for cd11c, cd3, cd4, claudin-1; and dapi nuclear staining were performed in formalin-fixed, paraffin embedded sections of oral mucosa biopsies. rt-pcr was performed to analyze il1b and il33 gene expression and the number of circulating cd4+ cells in pbmc was measured by flow cytometry. additionally, basophil activation test was carried out in whole blood samples upon profilin stimulation and the ec50 was calculated. results: regarding epithelial barrier integrity, claudin-1 expression resulted inversely proportional to pollen-associated food allergy severity. furthermore, by dapi staining, we noticed a lower number of epithelial cells in allergic patients than in non-allergic, and the gene expression of il1b and il33 resulted significantly increased in oral mucosa from severe group. as for immune response in oral mucosa, the number of cd11c and cd3+ cells resulted significantly higher in severe group. in allergic patients, double ihc for cd11c-cd4 showed an increase colocalization of t cells and apcs in the interface between epithelium and connective tissue. a decrease in blood circulating cd4 + cells was detected in allergic patients compared to non-allergic. as for the basophil sensitivity, ec50 in severe patients was 10-times lower than in mild. our results show that damage in oral mucosa epithelium, probably induced by high grass pollen exposure, might allow profilin to penetrate inside oral mucosa and induce inflammation with local recruitment of immune cells. furthermore, analyzing the immune response developed by effector cells, basophils from severe group result more sensitive to profilin as they react to a lower allergen concentration. these data explain the differences in food allergy severity between mild and severe group and propose oral mucosa as a new sensitization route. introduction: th2 cells producing the hallmark cytokines il-4, il-5 and il-13 have been found to constitute the majority of the allergen-specific th cell responses in allergic diseases. subpopulations of the th2 responses have been described with an early primed th2 subtype characterized by production of il-4 and il-13, and a highly differentiated th2 subtype, which in addition produce at least il-5. objectives: we aimed to investigate the polarity of tree nut and peanut allergen-specific th cells in subjects with confirmed tolerance or allergy to multiple nuts, and hereby detect differences in allergenspecific th cell responses within the same study population. we also wanted to stress the question whether a th2 phenotype dominates in asymptomatic sensitization. methods: pbmcs from 35 donors all assessed for clinical reactivity to hazelnut, walnut, cashew nut, pistachio nut and peanut was stained with cfse and stimulated (2910 6 cells/ml) with and without whole nut extracts (50-200 lg/ml) for 7 days. allergen-specific cd4+ t cell phenotypes and cytokine release was analyzed with flow cytometry and luminex, respectively. the allergen-specific th cells of the allergic donors showed a trend of more highly differentiated il-4+il-5+ th2 cells and higher abstracts | 319 release of il-5 than in the tolerant donors. unexpected, except in the cashew nut stimulated cells, no difference was found in the relative percentage of the less differentiated th2 cells (single il-4+ allergen-specific cd4+ t cells) when comparing allergic with tolerant donors. when subdividing the tolerant donors into asymptomatically sensitized or ige-negative (<0.35 kua/l), increased frequency of highly differentiated il-4+il-5+ allergen-specific th2 cells were found in asymptomatically sensitized compared to tolerant-ige-negative donors. interestingly, a positive association of the allergen-specific ige level and the frequencies of allergen-specific il-4+il-5+ and il-4+ th2 cells were found in hazelnut, pistachio nut and cashew nut but not in walnut and peanut allergic subjects. conclusions: an overrepresentation of allergen-specific highly differentiated il-4+il-5+ th2 cells and an elevated il-5 production were observed in allergic subjects compared to subjects that tolerated the nuts. we furthermore found a trend that subjects asymptomatically sensitized to nuts differed from tolerant-ige-negative subjects by having relatively more highly differentiated il-4+il-5+ allergen-specific th2 cells. introduction: it remains largely unknown which features of food proteins that render them allergenic vs tolerogenic. however, it has been suggested that the protein-chemical features affects protein uptake in the intestine, and that protein uptake route may impact on the risk of sensitisation. objectives: the aim of this study was to investigate the interplay between protein-chemical characteristics, the allergenic vs tolerogenic properties and the intestinal uptake of two protein products. the allergenic vs tolerogenic capacity of a heat-treated whey product, consisting of partly denatured and aggregated proteins, was compared to an unmodified whey product in: (1) results: though this study showed that both unmodified and heattreated whey had immunogenic, sensitising and eliciting capacities as well as tolerance inducing capacity, significant differences between the two products were observed. the heat-treated product was found to have a lower allergenicity combined with high tolerogenicity compared to the unmodified product. competitive igg1 elisas indicated that heat-treatment of whey induced de novo epitopes while the original epitopes were maintained. newly established methods to study in vivo intestinal uptake were successfully applied to compare the uptake kinetics of the two products in different small intestinal tissues and serum. collectively the in vivo and in vitro uptake experiments suggested that uptake kinetics and the major intestinal uptake route differed between the heattreated and unmodified product. conclusions: this study showed that heat-treatment, which induces partly protein denaturation and aggregation, changes the immunological properties and intestinal uptake of a whey protein product. the heat-treated product was found to have a lower allergenicity combined with high tolerogenicity compared to the unmodified product, which highlights this products promising potential for induction of cow's milk tolerance. objectives: in this study, we enumerated tregs in esophageal tissue of patient with eoe, gerd and normal controls. ten patients with eoe, 10 patients with gastroesophageal reflux disease (gerd), and 8 patients with normal endoscopy and normal esophageal tissue were included. tregs were enumerated in paraffin embedded esophageal biopsy blocks, using immunohistochemistry assay. tregs were identified as foxp3+, cd3+ cells. results: tregs were counted in 3 high power fields (hpf, 9400) for 28 patients and the average of 3 hpf was recorded. the number of tregs in esophageal tissue of patient with eoe (mean 10.9 cells/ hpf) was significantly more than gerd(mean 2.77 cells/hpf) and control groups(mean 0.37 cells/hpf) (p value <.001). conclusions: there is an increase in number of regulatory t cells in esophagus of patients with eoe in comparison to gerd and control groups. the presence of these cells might be due to eosinophilic inflammation and help controlling the inflammation. objectives: to evaluate whether anti-cd38 (daratumumab) treatment results in a reduction of total and specific ige levels. results: samples from patients with relapsed/refractory multiple myeloma, treated with daratumumab monotherapy or daratumumab plus lenalidomide-dexamethasone in the umc utrecht between april and august 2014, were tested for total ige levels as well as presence of specific ige against common inhalant allergens. in patients with detectable ige at baseline, the total and specific ige levels were evaluated during treatment up to 20 weeks. of eight patients receiving treatment, four had detectable ige levels at baseline. one patient demonstrated sensitization to common inhalant allergens. for this patient, levels of total ige gradually decreased during 20 weeks of treatment (from 356 to 44 ku/l; 88%), as well as specific ige against timothy grass (9.8-1.7 ku/l; 83%) and house dust mite (3.2-0.4 ku/l; 88%). a second patient, not sensitized to common inhalant allergens but with ige levels of 41 ku/l at baseline, also demonstrated a decrease in ige levels, to 5 ku/l (88%). the last two patients had total ige levels <10 ku/l at baseline, which dropped below detection limit after eight weeks of treatment. conclusions: this proof of concept demonstrates that (specific) ige depletion occurred during treatment with anti-cd38 (daratumumab). anti-cd38 could potentially play a role in the management of severe ige-mediated diseases. objectives: following individual and assessment, patients established and stable on omalizumab have been commenced on home therapy. training and education in self-administration has been provided. a service assessment has been carried out to review the ongoing safety, quality and patient experience of the service. results: to date, over 90 doses of omalizumab have been self administered in the community with no adverse events or incidents related to home therapy. conclusions: self-administration of omalizumab at home by patients offers the potential to improve quality of life while also providing efficiency savings. introduction: chronic idiopathic/spontaneous urticaria (csu) is a chronic urticarial subtype, defined as itchy hives that last for at least 6 weeks, with or without angioedema, and that have no apparent external trigger. although csu is more frequent in adult populationup to 0.5%-1%-, it can affect children and generally has a prolonged duration and has a detrimental effect on patients' quality of life. before the fda and ema approval of the anti-ige monoclonal therapy omalizumab for adults and children 12 years and above, nonsedating h1-antihistamines were the only agents licensed for use in patients with csu. however, a majority of patients did not respond to these drugs, even when they were administered at three to four times their licensed dose. objectives: we present 3 pediatric patients (≥12 years old) with csu non-responding to antihistamines, treated with omalizumab. results: at the diagnosis of csu, the patients were 11, 13, 14 years old, respectively. a trial with non-sedating h1-antihistamines, administered up to three to four times their licensed dose, were performed for all patients, without clinical efficacy. omalizumab was started at 12, 14, 14 years, respectively. before anti-ige therapy, the urticaria activity score (uas) was 5, 4, 5 respectively, indicating poor symptom control. omalizumab therapy was administered every 4 weeks for 6 months at the dosage of 300 mg s.c. after 1 month of therapy, all 3 patients were symptom free with uas 0; the patients remained asymptomatic for all the 6 months of duration of monoclonal therapy and antihistamines were discontinued. by now, after 2, 5, 6 months respectively from discontinuation of omalizumab, all 3 patients are asymptomatic with uas 0. introduction: mepolizumab is a humanized monoclonal antibody directed against il-5, and is licensed for the treatment of severe asthma in patients aged >12 years (eu only adults) with an eosinophilic phenotype as an add-on treatment. we were interested to know whether the substance has an antiallergic effect, too. objectives: here, we report the case of a 60 year old man (nonresults: in march 2016 he was switched from omalizumab to mepolizumab (100 mg/month) 4 weeks after the last omalizumab because of two asthma exacerbations under omalizumab in the last 6 months and 380 eosinophils/ll blood under 10 mg prednisolone/day. after two injections of mepolizumab his fev1 increased from 55% to 64% pred., the act from 14 to 21 points, feno decreased from 48 to 32 ppb and the amount of prednisolone from 10 mg to 5 mg/day. but -the patient reported new nasal symptoms after the 2nd injection of mepolizumab, mainly blocked nose which has not been observed under omalizumab. he agreed to be challenged in the mobile gae²len exposure chamber* with house dust mite allergen for 40 min. the total symptom score increased from 2 to 7 points after 20 min exposure time remaining stable till the end, the positive nasal inspiratory flow decreased from 90 to 50 l after 30 min and 40 l after 40 min, the fev1 decreased from 62% to 51% pred. following the inhalation of salbutamol the fev1 reversed. conclusions: mepolizumab has an anti-asthmatic effect but the anti-allergic efficacy seems to be small or absent. methods: all patients treated with omalizumab for severe allergic asthma or chronic spontaneous urticaria at the department of respiratory medicine and allergy at aarhus university hospital (n=64) were grouped after their home municipality. the number of omalizumab treated patients/inhabitant in these municipalities was correlated to the distance to the treatment centre at aarhus university hospital. results: mean distance to the treatment centre was 53.5 km for all inhabitants in the central region, while patients treated with omalizumab lived in average 38.7 km away. we found a negative linear correlation between the number of patients treated with omalizumab/inhabitant and the distance from the municipality to the treatment centre (slope: à0.038 95%ci: à0.072 to à0.003), p=.034, n=64). conclusions: patients living at long distance from the treatment centre are less likely to be offered omalizumab treatment for severe allergic asthma or chronic spontaneous urticaria. objectives: demographics, clinical characteristics, and response to mepolizumab, were evaluated for atopic and non-atopic subgroups. sensitization to any one of the following; house dust mite, dog dander, cat dander, alternaria, or cockroach was considered as atopic, as assessed by specific serum ige of ≥0.35 ku/l. mensa (nct01691521) was a gsk sponsored study. results: of the 576 severe asthma patients, 275 (48%) were considered atopic, 272 (47%) were considered non-atopic and atopic status was missing for 29 (5%) patients. the majority of atopic patients (n=147) were sensitized to ≥3 antigens. compared to the non-atopic sub-group the atopic sub-group was younger with a mean age of 46 vs 54 years of age, had a longer mean duration of asthma (21.6 vs 18.4 years), and a higher total baseline ige level (293 u/ml vs 85 u/ml). mean number of exacerbations in the 12 months prior to the study was similar in the atopic and non-atopic subgroups (3.6 vs 3.8) as was the mean baseline peripheral blood eosinophil level (300 cells/ll vs 300 cells/ll). with mepolizumab an 80% reduction in eosinophils was achieved by week 4 irrespective of atopic status and maintained throughout the treatment period. mepolizumab reduced the rate of exacerbations relative to placebo by 48% in the atopic subgroup and by 54% in the non-atopic subgroup. conclusions: the mensa study recruited an equivalent portion of atopic and non-atopic severe asthma patients. the atopic population was younger and had a longer duration of asthma than the non-atopic subgroup. while the baseline total ige level was >3 times greater in the atopic subgroup, the pharmacodynamic and efficacy response to mepolizumab treatment was similar. introduction: a treatment goal in the management of oral corticosteroid (ocs) dependent severe asthma is to reduce daily ocs use due to the side effects associated with long term use. anti ige treatment is used in atopic patients to reduce daily ocs. this analysis characterizes ocs reduction and asthma control in the sub-set of atopic and non-atopic ocs-dependent severe eosinophilic asthma (sea) patients from the 24-week sirius ocs reduction study. objectives: sirius study participants (n=135) were sub-grouped by atopic status in a post-hoc analysis; demographics, clinical characteristics, and response to mepolizumab were evaluated. sensitization to any one of the following; house dust mite, dog dander, cat dander, alternaria, or cockroach was considered as atopic, as assessed by specific serum ige of ≥0.35 ku/l. sirius (nct01691508) was a gsk sponsored study. results: of the 135 ocs-dependent sea patients, 49 (36%) were considered atopic (61% female), 77 (57%) were considered non-atopic (51% female), atopic status was missing for 9 patients (7%). compared to the non-atopic sub-group, the atopic sub-group was younger; mean age of 46 vs 52 years of age, while the mean duration of asthma was the same irrespective of atopic status (19 years). the mean ocs daily dose and acq-5 score at baseline were similar between subgroups (12.6 mg vs 13.2 mg and 2.16 vs 2.04, in the atopic and non-atopic subgroups respectively). the mean baseline peripheral blood eosinophil level was comparable in both subgroups (250 cells/ll vs 220 cells/ll) while the total ige level was higher in the atopic subgroup (182 u/ml vs 86 u/ml). mepolizumab lead to a ≥ 80% reduction in eosinophils by week 4 irrespective of atopic status and eosinophil reduction was maintained throughout the study. mepolizumab reduced the ocs dose in the atopic group and non-atopic subgroups (odds ratio of a greater ocs reduction category of 5.6 (95% ci 1.71, 18.49) and 1.6 (95% ci 0.66, 3.93), respectively) and led to improvement in asthma control with a change in acq-5 of à0.60 (95% ci à1.20, 0.00) in the atopic subgroup and à0.45 (95% ci à0.94, 0.04) in the non-atopic subgroup. in an ocs dependent sea population mepolizumab reduced eosinophils independent of ige level and atopic status. in this limited post-hoc analysis, mepolizumab was an effective ocs sparing agent while improving asthma control in both atopic and non-atopic patients. patients who responded to retreatment had a similar mean time to response between the 1st dosing period (3.5 weeks) and 2nd dosing period (3.1 weeks). of all patients who were retreated (n=56), symptom control (uas7 ≤ 6) after two doses was achieved in 80% (1st period) and 85% (2nd period) of patients; complete response (uas7=0) occurred in 63% (1st period) and 56% (2nd period) of these patients. omalizumab was well-tolerated during both dosing periods. conclusions: omalizumab retreatment is safe and effective in patients with ciu/csu who respond to initial treatment and relapse after withdrawal, with most patients regaining symptom control after a 2nd course of omalizumab. : total ige reactivity of the grass allergoid formulation was diminished compared with native unmodified extracts. a difference in igg profiles was observed and indicated enhancement of accessible reactive igg epitopes across size distribution profiles of the grass allergoid formulation. detailed analysis of the epitope specificity showed retention of six lol p 1 igg binding epitopes in the grass modified extract. all epitopes were mapped on the solvent exposed area of lol p 1 homology model accessible for igg binding. one of the epitopes was identified as an "immunodominant" lol p 1 igg binding epitope (62-ifkdgrgcgscfeik-76) and classified as a novel epitope. lastly, lol p 1 igg antibodies showed functional capacity to block up to 50% of ige binding sites which provides evidence in protective function of immunotherapy induced antibodies against native allergens. the structural and immunological changes which take place following the grass allergen modification process were further unravelled revealing distinct igg immunological profiles. the results from this study support the concept that modification not only enhances the safety profile of scit but allows shorter-course objectives: design targeted sirna delivery system into liver cells. results: liposome surface was modified by lactose derivatives with different structures: lac(c 16 ) 2 and (lac) 7 lac(c 16 ) 2 . the basic physicochemical and biological properties of the carriers have been examined. it is shown that glycoconjugate introduction has no effect on the physico-chemical characteristics. however the carbohydrate modification of the liposomal surface leads to increasing in transfection efficiency on a specific cell line hepg2. moreover, the introduction of mono-carbohydrate derivative increases the transfection efficiency better than using a branched derivative of lactose. in the pharmacokinetic study target effect also was shown. unmodified liposomes start to be detected in the liver at 10 minutes after administration, whereas modified liposomes were detected at 2 minutes after administration. similarly, the excretion of modified liposomes from the liver was more slowly. also worth noting the high concentration of modified liposomes in the liver. furthermore liposomes modified by carbohydrates reduces the intensity of its accumulation in the lung. conclusions: it was shown that increasing attraction of drugs to the liver cells can be achieved by using liposome modification with lactose derivative. 0472 | sialylated fetuin-a is a candidate predictive biomarker for successful grass pollen allergen immunotherapy objectives: to identify new biomarkers of ait efficacy, pre-treatment sera obtained from 82 grass pollen allergic patients responding or not to sublingual ait were differentially assessed by 2d-dige or label-free mass spectrometry. the role of fetuin-a in allergy physiopathology was studied by using gene silencing in a mouse asthma model, human dendritic cell stimulation assays and surface plasmon resonance. results: using comparative proteomics, we provide evidence for an increased o-linked sialylation of fetuin-a in sera collected before treatment from patients exhibiting clinical responses, when compared with low responders. whereas feta may either inhibit or promote chronic inflammation, no specific role in allergy had been ascribed to it until now. in ovalbumin-sensitized mice, silencing of the fetuin-a gene increased airway hyperresponsiveness and th2 responses. fetuin-a, but not its non sialytated counterpart, synergizes with lps and grass pollen or mite allergens in a tlr4-dependent pathway to enhance the proallergic profile of human monocyte-derived dendritic cells. conclusions: quantification of sialylated fetuin-a glycoforms in the blood before treatment allows to identify patients more likely to benefit from grass pollen immunotherapy. validation of the hypothesis that this marker associated with "an inflammation status" can be used to predict ait efficacy is ongoing in larger cohorts of patients. introduction: kawasaki disease (kd) is a vasculitis that mainly affects small to medium-sized vessels, particularly the coronary arteries, and is a leading cause of acquired heart disease in children. previously, we found that the development of kd is associated with an elevation of both th1 and th2 immunity. gene hypomethylation is abstracts | 329 an important form of epigenetic regulation, which results in increased gene expression. because m1 macrophages are associated with inflammation and th1 immunity while m2 macrophages are associated with immune regulation and th2 immunity, we hypothesize that kd is associated with hypomethylation of both m1 and m2 macrophage related genes. objectives: our objective was to investigate the methylation profile of m1 and m2 related genes in patients with kawasaki disease. twenty-four patients with kd and 12 age-matched healthy controls (hc) were included in this study. in patients with kd, blood was sampled 24 hours before ivig therapy (kd1) and 21 days after ivig therapy (kd2). after dna extraction, samples were analyzed using human methylation bead chip 450 (illumina) to examine the methylation ratios of genes related to m1 macrophages (64 genes, 1536 cpg sites) and m2 macrophages (46 genes, 1329 cpg sites). cpg sites with more than 10% difference in methylation levels and a pvalue less than 0.05 between groups were considered significant. objectives: primary aim of the study is the identification of differentially expressed genes (deg) associated with allergic rhinitis (ar) by using genome-wide transcriptomics data from blood immune cells. this set of candidate genes will then be used to define gene networks relevant for onset, severity and potential treatment outcome of house dust mite associated ar. with different ethnicity or populations exposed to a different environment is currently in preparation. introduction: allergic patients display abnormal immune responses to harmless antigens, leading to various symptoms from hay fever to life-threatening conditions. these responses include abnormal type 2 immunity polarization and induction of allergen-specific memory t and b cells, resulting in development of allergy instead of immune tolerance. allergen-specific immunotherapy (ait) is currently the only causative treatment of allergic disorders. yet, in depth understanding of the underlying differences in allergen-specific cd4+ t cell and treg responses between allergy and tolerance and their changes during immunotherapy is lacking. objectives: we investigated whole-genome transcriptomics of circulating birch (bet v 1) and grass (phl p 5a)-specific cd4+ t cells in allergic patients before and at 3, 6, and 12 months of ait, as well in non-allergic healthy controls in corresponding seasonal time points. detailed immunophenotyping with flow cytometry and cd4+ mhc class ii tetramer staining with low rna/single cell next generation sequencing were performed. results: at baseline, out of the pollen season, there were more allergen-specific cd4+ t cells in allergic patients than in controls. at this time, over 1500 genes were significantly changed in allergenspecific as compared to total cd4+t cells in patients, yet we found substantial differences in signal transduction and inflammatory response gene expression when compared to healthy controls. during ait we noted significant increase of allergen-specific cd4+ cells in patients with subsequent gene expression changes in the immune tolerance pathways. finally, we found increase in allergen-specific treg cells in patients upon ait, but not in tolerant controls in corresponding seasons. of interest yet, at early ait time points, allergenspecific treg cells displayed gene profiles suggesting their insufficient suppressive functions. conclusions: in summary, in vivo allergen exposure causes profound changes in the transcriptomic profiles of allergen-specific t cells. these gene profiles seem to be deficient at baseline in allergic patients, but ait is skewing them into the tolerant controls levels. introduction: the variability of the pharmacological response to beta 2 (b2)-agonists may be due to the polymorphism of the gene of results: singled out statistically significant differences of the genotype distribution. the gly/gly16 homozygous allele was discovered twice as often in the group with an insufficient response to b2-agonists than in the group with a good response (66 vs 38%, p<.001), while the distribution of heterozygous allele was detected the opposite pattern (55 vs 28%, p<.001). in the arg/arg16 genotype distribution, there were no considerable differences in both groups (6% in each group). in the subgroups of children, receiving the high doses of the inhaled glucocorticoids, there was a trend for the prevalence of gly/gly16 homozygous allele prevalence. we have discovered the association of the gly/ gly16 genotype of the adrb2 gene with an insufficient effect of broncholytic therapy by means of short-term b2-agonists; we also revealed the participation of the gly16 allele in the phenotype formation with the severe run of bronchial asthma and tolerance towards the therapy both by b2-agonists and inhaled glucocorticoids. mckenna oe 1 ; posselt g 1 ; lackner p 1 ; schmitt a 2 ; h€ ollbacher b 1 ; briza p 1 ; wessler s 1 ; gadermaier g 1 ; ferreira f 1 1 universit€ at salzburg, salzburg, austria; 2 georg august-universit€ at g€ ottingen, g€ ottingen, germany introduction: an excess of 100 million people worldwide have a reported allergy to birch pollen. proteases in such allergen sources have been suggested to contribute to primary sensitisation and exacerbation of allergic disorders. until now the protease content of betula pendula, a species endemic to the northern hemisphere, has not been studied in detail. hence, we aim to identify and characterise pollen and bacterial derived proteases found within betula pendula pollen. objectives: birch pollen transcriptome was constructed via de novo transcriptome sequencing. reads were assembled using the trinity software suite.. analysis of the birch pollen proteome was achieved via mass spectrometry and use of zymographic gels with the embedded substrates gelatinase and casein, which enabled visualisation of proteolytic activity. further to this, protease activity was quantified using a fluorescently labelled casein substrate protease assay. results: by using mass spectrometry, we were able to identify up to 26 proteases within birch pollen. we could cluster the proteases into specific families based on their distinct proteolytic activities. further comparative analysis of the proteome and transcriptome revealed the relationship between transcript levels and the proteins they encode. zymographic methods enabled distinct visualisation of proteolytic activity for both casein and gelatin substrates. using fluorescently labelled casein, the birch pollen protease activity was quantified as 0.68 lg/ml when compared to a trypsin standard curve. additionally, 26 bacterial isolates of the birch pollen were identified, and the proteolytic activity analysed. we report successful discovery of pollen and bacterial derived proteases endogenous to betula pendula. whilst none of the known birch pollen allergens have been recognised as a protease, we aim to investigate the role of tight junction degradation within epithelial cells and further enhance understanding of proteolytic activity on immune-polarization. objectives: to investigate the frequency and reasons of shortand long-term reintroduction failure in adults after a negative fc. method:: these are preliminary results of an ongoing prospective study. after a negative fc, patients receive standardized aftercare consisting of an introduction scheme to introduce the food at home and consultation by phone for advice and support 24 hours, 1-3 weeks and 6 months after the fc. short-term data about the frequency that patients failed introduction, defined as not completing the introduction scheme or patient-reported allergic complaints repeatedly during introduction, was obtained using a telephone interview. long-term data (5-12 months after negative fc) about frequency and reasons of reintroduction failure in daily diet, defined as not eating the food or only eating products with traces of the food, was obtained using a patient-reported questionnaire. results: from 2014 until now 38 patients were included (mean age: 34 years, male: 26%), who underwent a total of 110 fcs with: hazelnut (23%), other nuts (17%), fruit (7%), composite meals (7%), fish and crustaceans (7%), cow's milk (6%), hen's egg (5%) and other (28%). in 96 (87%) of the negative fcs, introduction using an introduction scheme was advised. in 13%, patients did not receive standardized aftercare for different reasons, eg negative fc with a composite meal. in 19%, introduction with an introduction scheme failed. long-term information was available for 40 fcs. introduction failed in 12 fcs (30%), including 1 patient that even avoided traces of the food. patient-reported reasons for introduction failure were (n=11): symptoms after ingestion of the food (n=8), fear for allergic reactions (n=2) and not like the taste of the food (n=1). conclusions: short term introduction with an introduction scheme failed in 19%. however on the long-term in almost one third of the negative fcs, patients failed to reintroduce the food in daily diet, despite careful aftercare. it is recommended to give these patient even more intensive and tailored support. introduction: in order to help allergic patients manage often severe symptoms, food manufacturers are required to list allergens on labels and take precautions to avoid inadvertent contamination of foods with allergens. existing tools using generic immunoassays do not provide precise identification or quantification of specific food allergens. furthermore, existing elisa immunoassays are not able to be run simultaneously and are often unreliable. objectives: our goal was to develop and validate an accurate, sensitive and high throughput immunoassay that would enable simultaneous quantification of multiple allergens in foods. fluorescent beads coupled to allergen specific monoclonal antibodies were used to develop a multiplex array for simultaneous quantification of major allergens from peanut (ara h 6), milk (bos d 5), egg (gal d 2), and shrimp tropomyosin (pen a 1). target allergens were detected using biotinylated antibodies and streptavidin conjugated fluorochrome. the array was quantified using highly purified natural allergens as standards. allergen content was measured in various samples including samples spiked with purified allergen and allergen incurred food matrices. the results were compared to elisa. a multi laboratory validation was performed to validate the performance characteristics of the assay. results: there was a high correlation between the multiplex array and allergen specific elisa. the limit of detection of the array was as low as 20 pg/ml. no significant cross reactivity was observed between the various food allergen assays. the recovery of allergen from spiked samples was generally between 70 and 130%. inter and intra assay variability was observed to be less than 15%. in conclusion, an accurate, sensitive and reliable multiplex array for major food allergens was developed and validated. the flexibility of the microsphere technology allows for further expansion to produce a comprehensive array for the most important food allergens. this quantitative multiplex array may help to reduce the risk of inadvertent contamination of food. objectives: our aim was to create a food allergy web-based educational program for both schools and restaurants professionals. results: an interactive platform that hosts a free learning program, conclusions: the program and the toolkit are currently available online and are being implemented in schools at the north of portugal. we expect that fac program will give us an important insight on the professionals' knowledge about food allergy. additionally, acting as free integrated service and awareness effort, this program could be an educational tool easily adapted and disseminated, which may improve professionals 'commitment and skills to deal with food allergy in the community. 0495 | development of parallel reaction monitoring (prm) methods for soy and milk detection: consideration of allergen-derived ingredients chen s 1 ; krawitzky m 1 ; yang ct 2 ; downs m 1 1 university of nebraska-lincoln, lincoln, united states; 2 thermo fisher scientific, san jose, united states introduction: the presence of undeclared food allergens poses both regulatory and health risks. in order to assess the magnitude of these risks, accurate quantitative detection methods are required. for some allergenic foods, the food industry uses not only the allergenic source but also a number of source-derived ingredients. some detection methods (both immunoassays and mass spectrometry methods) may fail to accurately detect and quantify these allergen-derived ingredients if they are not taken into consideration during development. objectives: the objective of this work was to select peptide targets for parallel reaction monitoring (prm) mass spectrometry methods that are suitable for detecting a variety of soy-and milk-derived ingredients. six soy-derived and six milk-derived ingredients were obtained for this study. the ingredients were extracted (50 mmol l à1 tris-hcl, ph 8.6, with 6 mol l à1 urea, 20 mmol l à1 dtt, and 1% pvpp) and subjected to in solution trypsin digestion. discovery proteomics analysis was conducted by lc-ms/ms using a q exactive tm plus orbitrap tm running in top 10 data-dependent acquisition mode. peptides were identified using proteome discoverer 2.1 and relative, labelfree quantification was conducted on high-confidence (fdr<0.01) peptides. selected peptides were subsequently analyzed in a targeted prm mode. results: the relative abundance of identified peptides varied among both the soy-derived and milk-derived ingredients. in the case of soy ingredients, for example, there were particularly marked decreases in the abundances of numerous peptides, across different proteins, in a hydrolyzed soy protein isolate. in the milk ingredients, variation in peptide abundance could be more directly attributed to differences in product protein fractionation (eg a decrease in abundance of whey proteins in a sodium caseinate product), although some peptides and proteins maintained consistent abundance across ingredients. after applying specificity and performance criteria, 57 peptides from 14 soy proteins and 64 peptides from 10 milk proteins were selected for further analysis in a targeted prm method. conclusions: peptide abundances vary widely among ingredients derived from allergenic foods. consideration of these peptide differences during ms method development by incorporating discovery proteomics may lead to more versatile and widely-applicable quantitative detection methods for food allergens. introduction: milk and its derivates are usual ingredients in many food products, which must be excluded by cow's milk allergic (cma) patients. oit protocols in patients with cma appear to be safe and effective in inducing desensitization and milk introduction in the diet. objectives: we conducted a survey in cma patients after successful completion of an oit programme, to assess their dietetic profile after introduction of fresh milk and dairy products (unrestricted diet) we considered 42 cma patients (pts), 32 males and 10 females, age 5-29 (median 12.5), who successfully completed the oit protocol. these patients were on an unrestricted diet for milk and derivates, and they had been recommended to assume at least 100 ml of fresh milk or yogurt every day. patients were given an ad hoc questionnaire to assess the milk/dairy products intake at least 24 months after oit completion. results: from our investigation all of the pts have been assuming milk protein everyday without significant reactions after oit. 71% of the interviewee (30 pts) referred to be drinking fresh milk at least three times a week, in a quantity of 100 ml or higher. of note, 85% have to add cocoa powder (14 pts) or coffee (11 pts) to mask milk taste. dislike of milk taste was the cause of the refuse to take fresh milk in 10 pts (over 12 patients that didn't take milk at all); 5 pts who didn't drink milk had at least 125 ml yogurt instead, almost every day. fresh cheese was eaten at least once a week by 50% of all the pts; hard cheese was eaten as main course almost once a week by 62%. 86% of patients consumed biscuits and sweet baked products containing milk/derivates at least once a week, 62% every day. pizza was also present in the diet of the majority of pts (86%), once a week/month. ice cream was appreciated by all the patients and regularly assumed especially during the summer time. conclusions: taste seems to be the main factor that directs the daily choice of milk derivates or milk containing products. all pts easily consume baked products containing milk/derivates, and the majority of them accept fresh milk as advised in order to maintain unresponsiveness. our survey confirms that oit is effective in expanding food choice, but for some patients the change of dietetic habits is hampered due to taste reasons. a more detailed, qualitative and quantitative analysis of the milkunrestricted diet will derive from the 7-days food diary given to these patients. 0497 | frozen-defrosted dried skimmed milk is a suitable product for sublingual immunotherapy for cow's milk allergy introduction: sublingual immunotherapy (slit) is a promising treatment for cow's milk allergy (cma) due to its favourable safety profile. however, its efficacy is limited-probably due to the small volumes and doses that can be delivered sublingually, especially in children. milk products with preserved allergenicity that allow higher protein concentrations in smaller volumes might potentially improve the efficacy of slit for cma. dried skimmed milk (dsm) could fulfill these characteristics. in addition, once dsm is reconstituted, freezing individual vials from the same batch for further administrations could increase dose-consistency throughout the treatment, which would help ensure safety. however, little is known about whether processing to produce dsm, and further freezing-defrosting, may alter its allergenicity. objectives: to evaluate the allergenic protein composition of dsm, including once frozen-defrosted, in comparison to fully-allergenic usually consumed fresh milk. methods: sodium dodecyl sulfate polyacrylamide gel electrophoresis (sds-page) followed by silver staining was performed following the laemmli method to determine the soluble protein composition of the following products: fresh pasteurized milk (friesland campina, amersfoort, the netherlands), dsm (marvel, the premier foods group ltd, london, uk) and frozen-defrosted dsm to identify all protein bands present. western blot with anti-whey and anti-casein antibodies was performed to identify the specific allergenic proteins. results: no significant differences were found amongst the milk products tested, with sds-page displaying all the bands corresponding to the major allergenic proteins in milk (alpha-lactalbumin, beta-lactoglobulin and alpha-, beta-and kappa-caseins) and the western blot showing recognition to all proteins with similar intensity. the major allergenic proteins present in unprocessed milk are well-preserved in dsm, even after freezing-defrosting, making it a convenient product for sublingual immunotherapy. results: nineteen children were randomized into the low dose group (n=11) and the elimination group (n=8). there were no significant differences in background between these groups. after 24 weeks of therapy, the rate of passing the oral food challenge test with 1/8 th of a whole egg was significantly higher in the low dose group (11/11 (100%) vs 4/8 (50%), p=.018). ovomucoid-specific ige levels in the low dose group after 24 weeks were significantly lower than those at baseline. adverse events associated with both therapies did not occur during the study period. conclusions: these results show that low dose ingestion of egg is safe and effective for tolerance or desensitization induction in children with egg allergy, without the need for dose elevation. 0499 | another brick in the wall: toward a national food allergy strategy for canada introduction: the world is experiencing an apparent epidemic of food allergies. with rising prevalence and increasing global spread, basic scientists continue to search for causes while clinical and social scientists continue to study the consequences. these include life-long chronic illness, fear and anxiety, social exclusion and stigma, all of which are underscored by inequalities across vulnerable groups (eg, low income families, immigrants, indigenous peoples). concomitantly, consumer organizations and patient support groups attempt to influence policy in order to maximize choice and minimize risk for individuals and families affected by food allergy, both directly and indirectly. this includes food labeling legislation, food safety regulations, and policies and practices in public places such as schools, restaurants and transportation modes (eg, airplanes). objectives: in canada, with the support of 10+ years of science undertaken by the allergy genes and environment (allergen) networks of centre of excellence in allergic disease, we are leading a national team that aims to establish the building blocks for a national food allergy strategy. conclusions: the greatest challenges to building a national food allergy strategy are not those related to the basic or clinical science, but rather the activities and commitment of individual stakeholders. while gaps remain in the science, the challenges of transdisciplinary integrated knowledge translation hinder progress. we present lesions learned regarding culture shifts that will facilitate the progress we need to maximize choice and minimize risk for canadians affected by food allergy. 0500 | component resolved diagnostics reduces diet restrictions by half among finnish school children savolainen j 1 ; mascialino b 2 ; pensamo e 3 ; hermansson l 4 ; silvan m 3 ; borres mp 4 ; korhonen k 5 1 university of turku, turku, finland; 2 department of allergology, uppsala, sweden; 3 thermo fisher scientific-immunodiagnostics, turku, finland; 4 university of turku, uppsala, sweden; 5 thermo fisher scientific-immunodiagnostics, lieto, finland introduction: there are 50 000-100 000 special diets because of food allergy in finnish schools. the finnish allergy program 2008-2018 was launched to reduce problems and costs induced by allergies. one of the special aims was to reduce diets caused by food allergy will by 50%. the h€ ark€ atie social and health care service region schools have required doctor's certificates for diets for over abstracts | 337 10 years. all diets are listed in a register and checked on a regular basis. objectives: the purposes of this study were to evaluate whether it is possible reduce the special diets when the special diet system appears to be working well and to assess the added value of immu-nocap ® isac allergen component diagnostics in the intervention. results: there were 2885 children attending the schools in the h€ ark€ atie region. there were 205 children with diet due to food allergy. children were recruited to study from the diet register and contacted by a nurse's phone interview. there were 48 children who refused the study leaving 157 children for the assessment of the diet. 23 children were not following any diet and in 44 children the diet was not regarded necessary by the study nurse. 90 children agreed to take part in the study and were referred to laboratory tests for food specific ige and isac. 7 children dropped out leaving 83 children in the study. after the food specific ige results were available, children were contacted by physician. based on the results and/or interview a free diet was allowed for 3 children. 15 children were eating small amounts of the food and were encouraged to increase the use of the foods. 48 children were advised to avoid the foods only if they caused symptoms. only 17 children were advised to continue diet. after the results of isac were available, children conclusions: the study confirmed that it is possible to have diets decreased over 50% in accordance to the finnish allergy program. additionally, the study showed that food allergic children can benefit from the use of component resolved diagnostics. 0501 | omalizumab treatment for severe food allergy caused by lipid transfer protein: a preliminary case series mari a; zennaro d; ferrara r; bernardi ml; alessandri c caam-centri associati di allergologia molecolare, rome, italy introduction: lipid transfer proteins (ltp) are allergens from plantderived foods causing symptoms ranging from oas to anaphylaxis. ltp are present in almost all kind of plant species used for human feeding. ltp allergic patients suffer of reactions to a broad variety of foods, with a very personal reactivity profile which can involve few or many foods. in addition, patients who start to record severe reaction to several foods begin to be afraid of eating any other related or non-related food, leading to a poor diet. omalizumab (ozm) has been documented to be effective in treating food allergies with sensitization to other allergens. objectives: to document the approach for recruiting, studying, monitoring ltp allergic patients, and do a preliminary evaluation of the clinical impact of ozm therapy. results: six adult patients with documented reactions to plantderived foods in the last 12 months and diagnosed to be ige positive to multiple ltp by using multiplex testing, namely isac112 at the beginning and faber244 during the follow up, were recruited. ozm was offered as an off label treatment adopting an open label study design. a questionnaire was submitted to each patient before, during and after the treatment. foods listed as "no more eaten" where considered for reintroduction, starting from those excluded because of fear, going for those with an increasing risk of reactions. re-introduction was done at home after receiving detailed instructions, having all rescue medication at hand. the allergist was connected real time with the patients using one or more ict tools. one patient dropped out because was not complying with the scheduled reintroduction. three patients completed the treatment with a successful re-introduction of all or almost all excluded foods, in two cases peach was reintroduced. the last two patients reintroduced 50%-60% of the excluded foods, including some of those previously causing reactions. the attempt of re-introducing the most risky foods failed causing local allergic reactions promptly controlled by the therapy. all foods re-introduced were tolerated once the treatment was stopped. conclusions: ozm seems to be a promising treatment for severe ltp allergics, improving their qol. starting from the recruitment phase to the re-introduction, the overall procedure looks quite complicated and deserve much resources. ige sensitization to ltp, carefully defined before treatment, can be monitored during the ozm course as the drug doesn't interfere with faber test ige detection. 0502 | oral immunotherapy with peach-juice in lipid transfer protein (ltp) allergy: is it possible to reach tolerance? introduction: food allergy to rosaceae fruits and nuts, due to sensitization to lipid-transfer protein (ltp), is frequent in the mediterranean area countries. based on milk allergy oral immunotherapy (oit) protocols, a study is proposed to obtain an oit regimen in patients allergic to ltp. objectives: we included patients with anaphylactic reactions due to ltp-food allergy, from january/2015 to october/2016. skin prick test (spt) was performed with a food and inhalant battery, ltp bial-aristegui ® (0.1 mg/ml), prick by prick (pbp) with a specific commercial peach-juice (dilutions to endpoint), and determination of pru p3 ige levels (immunocap). the presence of pru p 3 protein in the peach-juice, was confirmed by sds-page and elisa method, and quantified with anti-pru p 3. we elaborated an oit guideline with progressive administration of peach-juice, 1-2-4-5 drops (5drops=0.13 ml), sublingually, starting concentration chosen according to the endpoint spt results, up to 5 ml daily dose. the dose reached at the allergy service, was continued at home, daily, for 1-2 weeks. all the increasing doses were performed at the allergy service, after pbp with peach-juice and ltp control spt. after a time, an oral challenge up to 250 ml peach-juice was performed. patients were instructed on the importance of maintaining regular intakes and avoiding cofactors. results: 16 patients started this protocol (6 male/10 female), aged 7-38 (media 19.67). peach-juice analysis in agarose gel electrophoresis, showed a 10 kda band quantified as 21.16 lg/ml of ltp. there was no difference between wheal diameter on spt for ltp bial-aristegui ® and pbp with commercial peach-juice along all the study. average concentration on pbp to endpoint: 1/1000 (4), 1/100 (8), 1/10 (4). pru p 3 ige level average: 30.22 ku/l. none anaphylactic or serious reactions during the oit protocol appeared. only five patients (31%) reported mild occasional symptoms (oral pruritus and mild located urticaria). 11 patients reached 5 ml daily dose (68.75%), and 4 of them (25%) completed oral food challenge with peach-juice up to 250 ml, with good tolerance. this pattern also allowed us to reintroduce withdrawn foods from the diet due to previous reactions, with good tolerance. results: 60 children (age 10-18 years) sensitized to dog dander extract (median 11.5 ku a /l), with or without known dog induced allergic airway disease, were included. nasal provocation testing with dog dander extract was performed. measurement of ige to dog dander extract and to can f 1-can f 6 was performed with immunocap. an ige level ≥0.1 ku a /l was considered positive. among all 60 children sensitization to can f 1 (65%) and can f5 (62%) was most frequent. corresponding numbers for can f 4, can f 2, can f 6 and can f 3 were 48%, 47%, 47% and 27% respectively. based on the results from the nasal challenges three groups were identified; no (n=21), mild (n=14) and strong reaction (n=25). the median ige levels to dog dander and to all 6 allergen molecules were higher in the strong reaction group than in the mild and the no reaction group. among children with a strong reaction, ige to can f 4 was found in 68% (17/25) compared to 24% (5/21) among children with no reaction (p=.003). ige to can f 6 showed a similar pattern (p=.006). 40% (10/25) of the children with a strong reaction were sensitized to can f 3 compared to 9.5% (2/21) of the patients with no reaction (p=.01). no associations were found between the ige levels to can f 1, can f 2 and can f 5 and the no reaction or strong reaction groups. using multiple regression analysis, with all 6 allergens in the model, sensitization to can f 4 showed a statistically significant difference between the groups. conclusions: molecular allergology may improve diagnostics of dog allergy in children. sensitization to the lipocalin can f 4 was significantly associated to a strong positive nasal reaction implying its usefulness as a marker of clinically relevant dog allergy. tsolakis n 1 ; malinovschi a 2 ; nordvall l 1 ; janson c 2 ; mattson l 3 ; lidholm j 3 ; borres m 3 ; alving k 1 1 uppsala university, women's and children's health, uppsala, sweden; 2 uppsala university, medical sciences, uppsala, sweden; 3 thermo fisher scientific, uppsala, sweden introduction: cat allergy is common worldwide and a major trigger of asthma in many countries. molecular patterns of cat sensitisation vary between individuals but their relationship with allergic inflammation has not been extensively studied. objectives: the aim was to investigate the prevalence of ige to different cat allergen components and their relationship to type-2 inflammation and bronchial responsiveness in young asthmatics. conclusions: ige sensitisation to cat serum albumin (fel d 2) and cat lipocalins (fel d 4, fel d 7) , but not to secretoglobin (fel d 1) or cat dander extract, were independently associated with feno and b-eos count. we suggest that cat serum albumin and cat lipocalins can be used as markers for increased risk of type-2 inflammation in young asthmatics, as shown in multiple regression analyses. 0505 | complete sequence and recombinant production of horse dander allergen equ c 2 lidholm j; lundgren t; larsson h; mattsson l thermo fisher scientific, uppsala, sweden introduction: horse dander is an increasingly important cause of respiratory allergy. equ c 2 was one of the first horse allergens to be recognised but only a small part of its amino acid sequence has been reported. objectives: the aim of this study was to determine the complete sequence of equ c 2 and express it as an immunoreactive recombinant protein. methods: equ c 2 was purified by size exclusion, hydrophobic interaction, anion exchange and reversed phase chromatography. recombinant equ c 2 was expressed as a hexahistidine tagged protein in e. coli and purified by immobilized metal ion affinity and ion exchange chromatography. ige antibody reactivity to natural and recombinant equ c 2 and other horse dander allergens was determined in sera of 25 subjects allergic to horse. results: a putative equ c 2 sequence predicted from genomic data revealed a lipocalin protein of 159 amino acids with a highest sequence identity among known lipocalin allergens of 33% to can f 4. n-terminal sequencing and mass spectrometric analysis of purified natural equ c 2 confirmed 97.5% (155/159 residues) of the predicted sequence. recombinant equ c 2 displayed ige antibody binding activity comparable to that of purified natural equ c 2 (r=.98). of the 25 horse allergic subjects studied, 19 (76%) showed ige antibody binding to equ c 1, 13 (52%) to equ c 2, 5 (20%) to equ c 3 and 7 (28%) to equ c 4. the complete sequence of equ c 2 was established. as a fully immunoreactive recombinant protein, it represents an important addition to the panel of allergens useful in the diagnosis of allergy to horse. 0506 | component resolved diagnosis using guinea-pig allergens elucidates allergen sensitization profiles in allergy to furry animals objectives: to identify major guinea-pig allergens and to evaluate their potential as reliable markers for a specific ige-diagnosis in comparison to dander extracts. results: forty-three patients with a clinical history of allergy to guinea-pig and 45 patients allergic to cat and/or dog were recruited for the study. major guinea-pig allergens were identified by ige-immunoblot and n-terminal sequencing of ige-reactive proteins. corresponding cdnas were cloned and allergens were expressed as recombinant proteins in e. coli. specific ige to animal dander, fel d 2 and can f 3 were determined, specific ige to fel d 4, can f 6 and to guinea-pig allergens were quantified by elisa. two new guinea-pig lipocalin allergens, cav p 1 and cav p 6, were identified in guineapig dander. the combination of 4 guinea-pig allergens, the 2 new allergens and the previously isolated lipocalins cav p 2 and cav p 3, enabled the identification of 39 out of 43 patients sensitized to guinea-pig. the vast majority of the patients had specific ige to cav p 1 (84%). cav p 6 shares 53% sequence identity with fel d 4 and can f 6 and was found to be cross-reactive with these cat and dog allergens. in the group of cat and/or dog allergic patients, 87% had also specific ige to guinea-pig dander. nearly half of those (47%) had ige to cat serum albumin fel d 2 or to fel d 4 (58%) and to can f 6 (56%), explaining the high degree of cross-reactivity to guinea-pig dander. only 25% of the cat/dog allergic patients with a positive isle test to guinea-pig dander had specific ige to any of the non crossreactive guinea-pig allergens cav p 1, cav p 2 or cav p 3. however, none allergen has been characterized from mongolian oak. objectives: in this study, we tried to characterize a major allergen from mongolian oak. results: a molecule homologous to pathogenesis-related protein 10, a putative que m 1, was cloned by rt-pcr and its recombinant protein along with que a 1, an allergen from white oak (q. alba) was produced. cloned que m 1 sequence shares 57.5%-96.2% amino acid sequence identity (96.2%) with pr-10-like allergens from various plants. allergenicity and diagnostic value of recombinant que m abstracts | 341 1, que a 1 and bet v 1 proteins were compared by elisa using sera from oak sensitized subjects. specific ige to recombinant que m 1, que a 1, and bet v 1 were detected in 90.0%, 78.0%, and 94.0% of 50 serum samples from korean tree pollinosis patients. recombinant que m 1 was able to inhibit ige reactivity to que a 1 and bet v 1, indicating its strong cross-reactivity. activation pattern of basophils from five patients was similar in terms of cd203c expression and protein concentration of challenged bet v 1 and que m 1. objectives: over the course of one year, all patients who were seen at our immunoallergology clinic for the first time underwent spt with our standard series, to which four olive tree cultivar extracts were added (arbequina, blanqueta, hojiblanca e picual). we then recorded wheal size diameters, considering a wheal >3 mm to correspond to a positive test. we recorded 832 individual sessions of spts, in which 613 presented at least one positive result. two hundred and thirtysix of these patients (38.5%) had a positive spt for olive tree pollen, only one of them being monosensitized. when looking only at pollen-sensitized patients, twenty-two patients (5.9%) tested positive solely for olive tree pollen. in all allergic patients, the most frequent cultivar sensitization was to the cultivars hojiblanca (31.5%) and arbequina (31.3%), followed by the cultivars picual (29.2%) and blanqueta (27%). twenty-six patients (11% of all olive pollen sensitizations) had a positive spt for the conventional extract and negative spt for the cultivars; 192 patients (81.4%) had a positive spt for both. we noted that 7.6% (n=18) of patients sensitized to olive tree pollen had a negative spt with the conventional extract and positive with one of the cultivar extracts. the cultivar hojiblanca was the most frequent in this group (66.7%, n=12), followed by the arbequina cultivar (55.6%, n=10). in the group as a whole, there was a positive correlation between the results of the spts with the conventional extract and each of the cultivar extracts. this correlation was weaker with the cultivar hojiblanca (r=.785). conclusions: some patients, sensitized only to the pollen of certain olive tree cultivars, are not identified with the conventional extract. spt with the hojiblanca cultivar could identify most of these patients in our country, and therefore should be considered in patients with a history of pollinosis and a negative spt for the common extract of olive tree pollen. 0509 | structural and immunological comparison of heat treated pru p 3 and art v 3, the non-specific lipid transfer proteins of peach and mugwort pollen wildner s 1 ; stock l 1 ; regl c 2 ; alessandri c 3 ; mari a 3 ; huber c 2 ; stutz h 2 ; gadermaier g 4 objectives: recombinant art v 3.0201 and pru p 3.0102 were expressed in e. coli rosetta-gamib plyss and purified using cation exchange chromatography. proteins were analyzed in gel electrophoresis and mass spectrometry. proteins were incubated at 95°c in time intervals up to 120 min using buffers at ph 3.4 and 7.3. physico-chemical properties of native and heated allergens were analyzed by circular dichroism spectroscopy, dynamic light scattering and size exclusion chromatography (sec). using sera from italian patients sensitized to pru p 3 and art v 3 (n=26), ige binding to native and heat-denatured allergens was investigated in elisa. results: highly pure recombinant pru p 3 and art v 3 were obtained as non-tagged proteins from e. coli. identity and formation of disulfide bonds was verified by mass spectrometry. circular dichroism showed high thermal stability of both proteins at acidic ph. the alpha-helical fold of art v 3 was lost upon heating for 15 min at ph 7.3 while pru p 3 was already altered after 5 min. purified pru p 3 and art v 3 are monomeric molecules with a hydrodynamic radius of 1.6 and 1.8 nm, respectively. structural relaxation is observed upon heat treatment which is not attributed to protein aggregation as determined by sec. the ige reactivity to both allergens was largely unaffected upon heating at ph 3.4. notably, ige reactivity to art v 3 was already significantly decreased upon 15 min heating and was completely abrogated to both proteins after 120 min denaturation at neutral conditions. conclusions: even though the fold of pru p 3 is more compact compared to art v 3, susceptibility to structural changes upon thermal treatment at neutral conditions are more pronounced which do however not directly translate to lower ige binding capacities. particularly the buffer environment needs to be considered when formulating ltp-containing products which undergo heat treatment. objectives: we sought to determine the ige binding capacity and potential diagnostic value of a recombinant hybrid molecule. results: the codon-optimized nucleotide sequences of a hybrid molecule comprising the full sequences of blo t 5 and der p 2 at the amino and carboxyl ends respectively, here named bp-2, was cloned into a plasmid vector and expressed in escherichia coli as a 6xhis tag protein. two hundred and thirty three sera from colombian (n=118) and cuban (n=115) allergic patients were tested by elisa for ige reactivity. thirty seven sera from non-allergic subjects and negative skin test (spt) to mites were used as controls. all subjects provided written informed consent to their participation in this study. hdm allergy was diagnosed on the basis of clinical symptoms in combination with mite extract spt. potential diagnostic value of bp-2 specific ige was determined by receiver operating characteristic (roc) analysis and area under roc curve (auc) calculated. positive serum ige values to hybrid molecule were defined as optical density (od) higher than 0.13 (mean od plus 3 standard deviations in 15 nonallergic subjects). in respiratory allergic patients, the overall frequency of positive ige reactivity to bp-2 was 70.9%, in non-allergic subjects the frequency was 21%. serum ige levels to bp-2 were positively correlated to spt to b. tropicalis (spearman r=.54, p=.001), and to d. pteronyssinus (spearman r=.4, p=.001). using spt to mite extracts as gold standard, the sensitivity and specificity of serum ige levels to bp-2 were 71.4% and 94.1% respectively, with an auc of 0.82 (95% confidence interval 0.74-0.89). conclusions: these data suggest that bp-2 could be a useful reagent for identifying allergic patients sensitized to b. tropicalis and/or d. pteronyssinus. 0511 | igg, ige and igg4 specific antibodies to molecular allergens of aspergillus fumigatus introduction: in clinical allergy, alongside with skin prick tests, in vitro determination of specific ige for a particular patient contributes to the diagnosis and helps to estimate the risk associated with different food allergens. however, with commercial methods of specific ige antibodies detection (component-resolved diagnosis, crd), the clinician is typically limited by the list of the available allergens. objectives: to overcome this limitation, we developed two component-resolved diagnostic tests for food allergy in which natural extracts can be used. in the first developed method, the crd is performed using immunoaffinity capillary electrophoresis (iace) coupled with matrixassisted laser desorption/ionization mass spectrometry. meanwhile, the second method is based on in-tube immunomagnetic separation (ims) with mass spectrometry identification (mass spectrometry or peptide mass fingerprinting). in both techniques, magnetic beads coated with antihuman ige antibodies are used to extract the ige antibodies from the blood serum of the allergic patient. then, the immunocomplex, obtained on the magnetic beads, is used to quantify the total ige level or to probe the ige binding with standard allergens or natural allergenic extracts. afterwards, the identification of the extracted proteins, ie potential allergens, is performed by mass spectrometry with or without ce separation. after optimisation, the proposed methods have been successfully applied to a commercial blood sample of a patient with a known allergy to cow's milk, with results confirmed by standard tests. as a proof-of-concept, the sensitization profile of a patient suffering from protein contact dermatitis to the cow's whey fraction has been determined. we confirmed the presence of circulating ige antibodies binding lactoferrin and bovine serum albumin. cross-reactivity tests were also performed using goat and sheep milk and revealed the patient sensitivity to serum albumins from these two milks. such approaches open the possibility for direct identification of ige-bound allergens molecular mass and structure. these methods allow the discovery of yet unknown allergens and could be useful for precise personalized allergy diagnosis, allergens epitope mapping, and cross-reactivity studies. objectives: the objective of this study was to investigate the validity of cord blood ige for predicting atopy at 6 years of age. methods: a total of 385 children born in 2010 participated in the longitudinal investigation of global health in taiwanese schoolchildren (lights) cohort. total ige was measured in umbilical cord blood at birth. perinatal history was collected from medical records in the chang gung memorial hospital, taiwan. total and specific serum ige and questionnaires were carried out at 6 years of age. receiver-operating characteristic (roc) curves were used to determine the validity of cord blood ige for predicting atopy at 6 years of age. logistic regression models were applied to assess the association between cord blood ige and atopy at 6 years of age. results: cord blood ige levels was significantly associated with total serum ige level at 6 years of age (r=.314, p<.001). the cord blood ige levels in atopic children aged 6 years (meanaesd, 1.61ae6.2 ku/l) were significantly higher than those in nonatopic children (0.36ae0.94 ku/l) (p<.001). the area under the receiveroperating characteristic (roc) curve of cord blood ige for predicting atopy at 6 years of age was 0.702. the sensitivity, specificity, and positive and negative predictive values of cord blood at the optimal cutoff of 0.34 ku/l on the roc curve for predicting atopy were 50.9%, 88.1%, 92.1%, and 39.8%, respectively. higher cord blood ige levels (≥0.34 ku/l) was associated with a higher likelihood of atopy at 6 years of age (or=7.66; 95% ci: 2.81-20.90; p<.001). our results indicate that cord blood ige is a potential predictor of atopy at school age, with an optimal cutoff of 0.34 ku/l. bogomolov a vinnitsa national pirogov memorial medical university, vinnitsa, ukraine introduction: allergen sensitization is being diagnosed by commonly available methods in clinical practice-skin prick tests (spts) and specific immunoglobulin e test (sige). recently, a new thermographic (th) method for the assessment of spt was developed, and it was demonstrated that the th measurements of forearm temperature distribution during spt, supported by a mathematical model, offer a new quantification method of allergen-induced skin reactions. objectives: the aim of this study is a comprehensive comparison of the th method with spt and sige techniques. the group of patients who were participated in this study consist of 45 patients. among them were 24 patients (53.3%) with allergic rhinitis and 21 patient (46.7%) with asthma, 35.5% of them were men and 64.5% were women aged 18-53 years (mean age 38.3ae6.5 years). spt and sige testings were performed by the standard techniques. for th analyses, set of thermograms of both forearms were acquired after prick and analyzed with the use of developed software. all results were converted into categorized scale for comparison. after counting patients who were true positive (tp), true negative (tn), false positive (fp), and false negative (fn), the sensitivity, specificity, and accuracy were calculated according to the following formula using the results of spt as the standard; sensitivity=tp/(tp+fn), specificity=tn/(tn+fp), and efficacy=(tp+tn)/(tp+tn+fp+fn). the results showed high correlation coefficients between the methods equal to 0.73-0.97. the sensitivity and accuracy of the th assessment in respect of both the classical methods is at a good level (0.70-0.94). the acceptable level of specificity 0.60-0.88 was also achieved for the majority of allergic reactions. the best accordance was observed between th and sige results (r=.92), while th-spt was the most divergent pair r=.85. in case of particular allergens, the biggest correlation was 0.99, while the smallest value amounted to 0.76. the results of diagnostic indicators of thermographic measurement of skin reactivity in comparison with the classical methods of determining the sensitivity to allergens show the prospect of using the method in routine practice. the main advantages of this method are its higher measuring ability and objectivity, by which the possibility of making error in diagnosis is significantly reduced. introduction: chronic urticaria symptoms may be worsened by factors such as temperature, exercise, hormones and stress. a salicylate rich diet has been reported to worsen symptoms in these patients. the mechanism by which natural salicylates do this is unclear but, like aspirin, is thought to be due to their ability to interfere with the arachidonic pathway via cyclooxygenase inhibition. studies have shown that low dose aspirin increases serum il-3 levels in patients with antiphospholipid syndrome. il-3 is important in basophil and mast cell function, inducing mediator release and cd203c upregulation in the absence of ige stimuli. objectives: the gold standard for diagnosing salicylate exacerbated chronic urticaria is by challenge testing. there is no in vitro laboratory test approved for routine diagnosis. this study investigated whether il-3 levels are raised in patients with chronic urticaria and if these levels were affected by salicylate intake. we aimed to find an optimum method of measuring il-3 levels by comparing levels in serum and salivary samples. the quantikine human il-3 enzyme linked immunosorbent assay (elisa) was validated and used on both saliva and serum of patients with chronic urticaria and normal controls. this was a case control study of 19 medicated patients with chronic urticaria and 26 controls at university hospital southampton, to see whether there were any correlations with il-3, and degree of salicylate intake (based on a questionnaire). introduction: since the introduction of molecular components in allergy, a big challenge of allergy diagnostics is to connect clinical symptoms with optimal test use and correct interpretation of results. objectives: the aim of the study was to (1) develop an algorithm that would meet that need, and (2) to evaluate the effect of introduction of algorithm to clinical practice. the algorithm was developed which groups clinical symptoms into six categories: rhinoconjunctivitis/ asthma, oral allergy syndrome (oas), urticaria/angioedema, eczema, anaphylaxis, and a combination of symptoms and combines them with knowledge of possible allergen specificity. this information is combined with two basic allergen mixtures (panels), reflex testing of selected food molecular components and accompanied by interpretative comments. the introduction of our algorithm led to less inhalation screenings, more food screenings and an increase in the requested molecular components. the oas was seldom recognized or used as a symptom by specialists. the reduction in costs, by using the possibility that the disease presentation may be a consequence of an relatively not dangerous oas, was therefore not achieved. all pr-10 positive proteins in various allergen sources showed also positivity for birch antigen. the screening based on this algorithm has potential to enable clinicians/general practitioners with a tool to increase the pre-test probability of allergy for the most frequently occurring allergens. allergy diagnostics may be more efficient if pr-10 component of birch (r bet v 1) is included in early screening and can help in early recognition of oas. helbling a 2 department of otorhinolaryngology-head and neck surgery 0492 | clinical and immunological evolution of patients who failed milk-oral immunotherapy there is lack of evidence on evolution among failures. objectives: to analyze clinical and immunological evolution of patients who failed milk-oral immunotherapy. data were obtained from medical records of a cohort of 20 patients who failed moit in the past 10 years in hospital infantil universitario niño jesus 14(70%) patients failed during build-up phase [13(92%) due to adverse events (ae) and 1(8%) to family decision. 6 failed during maintenance phase: 3(50%) due to eosinophilic esophagitis, 1(16%) to family decision, 1 to psychiatric disorder and (range 5-1023). the most frequent aes were cutaneous and gastrointestinal symptoms. 10/20 (50%) patients underwent a second moit and was successful in 5. the second moit was performed between 2 and 9 years after the first one. there was no statistical differences between specific ige(ku/l) levels at baseline and 12 months after the moit end portugal introduction: fish allergy is common in countries where consumption is high. parvalbumins present in fish muscle are the major allergens. allergy to multiple fish species is caused by parvalbuminspecific cross-reactive ige. cross-reactivity with parvalbumin from baltic cod retrospective study of patients with fish allergy followed in our immunoallergology department. fish tolerance acquisition was evaluated by oral food challenge. statistical analysis was performed using spss version 23 (descriptive statistics, student test results: 81 pts were included (55 male, 26 female), 62 children and 19 adults (age 14ae9 years). 63(78%) had previous history of rhinitis, 35(43%) of asthma and 54(67%) of eczema age of first contact with fish averaged 8.9ae4.0 months (min4, max36) and the possible types of contact were: oral in 78(96%), cutaneous in 22(27%) and inhalation of cooking fish vapours age of first clinical manifestation (excluding the 4 pts who developed allergy in adulthood) was at 22ae25 months (min4, max132) the clinical manifestation of the reaction was: angioedema/urticaria 58(72%), gastrointestinal symptoms 28(35%), eczema 27(33%), respiratory symptoms 19(23%), oral allergy syndrome 10 (12%), cardiovascular symptoms 2 (2%) age at the first immunoallergology out-patient clinic consult averaged 7ae9 years (min 0.4, max 48) and time from first symptom to first thermo-fisher) was evaluated before and after acquisition of tolerance to at least 1 fish. before tolerance, sige (ku/l) averaged 21 roc curve (area under curve 0.854) showed that, for gad c 1 105 ku/l, pts had a sensitivity of 90.2% and specificity of 62.5% that they would have a negative oral food challenge to a fish an sige<0.635 ku/l had sensitivity of 98% of a negative challenge 34 ku/l had specificity of 92.9% of a positive challenge. conclusions: fish allergy is a common allergy in early childhood however, acquisition of tolerance is possible. rgad c 1 appears to be a good marker for fish tolerance and could help allergologists as to when start testing for fish tolerance key: cord-015306-us58wwmp authors: nan title: abstracts for the ipna congress, 30 august 3 september 2013, shanghai, china date: 2013-06-21 journal: pediatr nephrol doi: 10.1007/s00467-013-2518-4 sha: doc_id: 15306 cord_uid: us58wwmp nan first 5 days after the diagnosis. dwi-mri was performed without application of contrast medium and without general anaesthesia. results: dwi-mri examination confirmed the inflammatory infiltration in kidney parenchyma in all our patients (100 %). on the other hand, static renal scintigraphy confirmed inflammation only in 15 children (60%). six months later, none of the two follow-up examinations showed any signs of inflammation or scarring in 17 children examined so far. conclusion: in conclusion, nuclear magnetic resonance (dwi-mri) imaging seems more beneficial and accurate in the diagnostics of acute pyelonephritis when compared with static renal scintigraphy. moreover, dwi-mri provides more accurate information on the extent of kidney damage. objective: to evaluate the most proper radiologic investigation algorithm in detecting high grade vesicoureteral reflux (vur) and renal cortical scarring after first febrile urinary tract infections in infants aged less than one year . methods: a total of 408 infants aged less than one year with a first febrile urinary tract infection who completed the diagnostic follow up of renal bladder ultrasound (rbus), voiding cystourethrography (vcug) and late 6 months technetium 99 dimercaptosuccinic acid renal scan (dmsa) were enrolled in the study.the most proper radiologic investigation algorithm that could highly detected both high grade vesicoureteral reflux and renal scar in infants after the first febrile urinary tract infection considering high benefit, low cost, low radiation exposure were assessed. results: abnormal renal bladder ultrasound (rbus) was identified in 101 (24.7 %) infants. vesicoureteral reflux (vcug) was identified in 92 (22.5%) with high grade reflux (grade 4 and 5) in 18 (4.4%) infants.abnormal renal parenchyma including renal scar was identified in 32 (7.8%) infants.the top down approach with late 6 months dmsa scan showed high benefit in detecting all abnormal renal parenchyma including renal scars, with high sensitivity ( 72%) in detecting high grade vesicoureteral reflux (vur) whereas reducing the unnecessary investigation for low grade vur (94.6%) and radiation exposure per patient (0.89 msv). conclusion: currently, there is no ideal diagnostic radiologic investigation after a first febrile urinary tract infection in infants and children.the study suggest performing the top down approach with late 6 months dmsa scan that could detect all renal scars and highly detection of high grade vur. abstract# p-sat010 association between postvoid urine bladder volume and urinary tract infection in infants and children: a retrospective cohort study orpheus monakil, ivy avilla department of pediatrics, da la salle university medical, philippines objective: to determine the association between post void urine bladder volume residual and urinary tract infection(uti) in children. methods: medical records of pediatric patients aged 0 to 18 years old with diagnosis of urinary tract infection were reviewed. demographic data, urinalysis and urine culture results and kidney and urinary bladder(kub) ultrasound findings were tabulated and analyzed using the 95% confidence interval. relative risks were computed with a level of significance of p value < 0.05. results: a total of 803 patients were included in the study. five hundred forty-four(67.8%) belongs to age group < 5 years old. majority were females with a 0.97:1 male to female ratio. escherichia coli is the most common organism isolated. patients with post void urine bladder residual are at risk for having growth in the urine culture. in sub group analysis for age and sex, statistically significant results were noted among patients belonging to the 3-5 years with the rr of 1.337, 95% ci (1.082, 1.651) p-value of 0.003 and males with rr 1.186 (95% ci 1.024, 1.374) p value 0.0168. conclusion: there is an association between the occurrence of urinary tract infection and the presence of post void bladder volume residual. males and those patients aged 3 to 5 years of age are more at risk for urinary infection. objective: to evaluate if a relationship exists between renal ultrasound and voiding cystourethrography (vcug) findings among children with uti and determine whether the renal ultrasound findings/results can serve as a guide if a procedure such as vcug is needed to be done in the patient. methods: medical records of infants and children diagnosed as having uti who underwent renal ultrasound and vcug were reviewed. demographic data, urine culture and results of imaging studies were tabulated and analyzed. kappa statistics was used to determine the agreement between renal ultrasound and vcug results. mcnemars test was utilized to determine the statistical significance of the agreement. level of significance was place at p value of < 0.05. results: a total of 146 patients were included in the study. thirtyeight(26%) had vesicoureteral reflux. there were more females with a male to female ratio of 1:1.3 while cases with reflux had a 1:1.5 male to female ratio. most common chief complaint was fever. e. coli is the most commonly isolated etiologic organism from the urine. twenty(52.7%) patients had primary vur while 18(47.3%) were secondary. fifty two of 146 children had abnormal sonogram; of duplex collecting system (dcs) diagnosed during postnatal usc on objective: the aim was to evaluate the relationship of laboratory investigations, therapeutic delay time (tdt), and therapeutic response time (trt) with acute renal damage and to verify these parameters in the presence of non refluxing and refluxing urinary tract infection (uti). methods: a prospective study was conducted in 67 children. all patients received voiding cystourethrography (vcug) and dimercaptosuccinic acid (dmsa) renal scintigraphy. statistical analyses were applied to assess all parameters with dmsa renal scintigraphy. results: abnormal dmsa renal scintigraphy was detected in 20/67 (29.9%) patients. there were no significant differences in peak temperature, tdt and treatment duration. however, white blood cells (wbc) count, percentage of serum polymorphonuclear cells (%pmn) and trt had significant differences at p-values 0.042, <0.001 and 0.001, respectively. the area under roc curve for wbc count, %pmn and trt was 0.653 (95%ci 0.509-0.798) at p-values 0.055, 0.799 (95%ci 0.681-0.888) at p-values <0.001 and 0.760 (95%ci 0.637-0.858) at p-value 0.001, respectively. overall, the optimal cutoff value for %pmn was 56.0 with sensitivity 84.2% (60. 4-96.4 ) and specificity 60. 9% (45.4-74.9 ). the optimal cut-off value for trt was 22 hours with sensitivity 80.0% (56.3-94.1) and specificity 63. 6% (47.8-77.6) . in 50 patients with no vesicoureteral reflux (vur), there was significant difference in trt at p-values 0.002. the area under roc curve for trt was 0.824 (95%ci 0.693-0.955) at p-value 0.004. the optimal cut-off value for trt was 25 hours with sensitivity 88.9 % (95%ci 51.7-98.2) and specificity 68.4% . in vur patients, there were no significant differences in tdt, %pmn and trt between normal and abnormal dmsa renal scintigraphy at p-value 0.750, 0.191 and 0.313, respectively. conclusion: %pmn ≥56% and trt ≥22 hours predict renal damage in the first episode of uti. however, in patients with no vur, trt ≥25 hours predict renal damage. dmsa renal scintigraphy in the first episode of uti should be considered in those patients. susceptibility data. knowledge of local antimicrobial susceptibility all children with the first episode of febrile urinary tract infection traditionally. nowadays it has been revealed that the presence of renal scar is more important than the presence of vur regarding renal and patient outcome. our aim was to assess the relationship between the severity of vur and the severity of dmsa scan changes which is performed in the first week of the first febrile uti. methods: children with the first febrile uti who were admitted in ali asghar children hospital were evaluated prospectively. all dmsa scans have been observed and graded by our nuclear medicine specialist without any knowledge of presence or absence of vur. renal damages in dmsa scan were classified to 8 grades as follows: grade 0: normal kidney, grade 1: decreased uptake in one pole with intact border, grade 2: decreased uptake in two poles with intact borders, grade 3: diffuse decreased uptake with intact border, grade 4: decreased uptake in one pole with scar, grade 5: decreased uptake in two poles with scar, grade 6: multiple scars, grade 7: diffuse decreased uptake with one pole scar, grade 8: diffuse decreased uptake with multiple scars. then dmsa findings in patients with no vur, with low grade vur and high grade or dilating vur were compared with each other. results and conclusion: one hundred and six patients with the first febrile uti were included in this study, thus 212 kidneys were evaluated for the presence or absence of vur and dmsa grading. the mean age of our patients was 4±2.9 years old. 12.3% of our patients were male. 44.8% of kidneys did not have any vur, low grade vur (grades 1,2,3) was seen in 34.4% of kidneys and high grade vur 9grades 4, 5) was found in 20.3% of kidneys. 76.2% of patients with low grade vur and/or without vur had dmsa scoring. abstract# p-sat040 fibronection in reflux nephropathy, is it a marker of grade of reflux? nahid rahimzadeh tehran university of medical science, associated professor, tehran, iran objective: vesicoureteral reflux (vur) is one of the most common urinary tract abnormalities in patients with urinary tract infection. nowadays noninvasive diagnostic methods are suggested to recognize vur and its severity. methods: we measured urinary and serum fibronectin in 51 children with vur. results: the mean serum fibronectin was 318.3±112.1 in children with low grade vur versus 356.1±189.9 in children with high grade vur (pv>0.05). the mean urinary fibronectin was also 31.5±12.9 in low grade vur and 25.9±14.2 in high grade vur (pv>0.05). thus we didn't find any association between the severity of vur and the amount of fibronectin in serum and urine of patients. we also didn't find any relationship between dmsa changes at the acute phase of uti and serum and urine fibronectin. conclusion: in contrast to some previous studies, we showed the serum and urinary fibronectin cannot preclude the severity and grade of vur and hence it is not suitable surrogate marker for imaging techniques for vur diagnosis. abstract# p-sat041 the use of serum procalcitonin level in the prediction of high grade vesicoureteral reflux in urinary tract infection nahid rahimzadeh tehran university of medical science, associated professor, tehran, iran objective: procalcitonin is a reliable and specific marker of bacterial infection such as urinary tract infection. some authors suggest measurement of serum procalcitonin as a predictor of vesicoureteral reflux. we investigated this association in children who admitted because of acute pyelonephritis. methods: forty eight children with the first febrile uti were included. twelve patients had low grade vur, nine patients had high grade vur ((≥ 3) and twenty seven patients didn't have any vur in their imaging assessment. results: there was a significant association between high grade vur and higher levels of procalcitonin (pv=0.04). the sensitivity of procalcitonin level ≥ 0.31 ng/ml was 90% and specificity was 32% for diagnosis of high grade vur. conclusion: we concluded that serum procalcitonin concentration is a sensitive and promising predictor of high grade vesicoureteral reflux. hydronephrosis, parenchymal scarring and to study the rate of resolution of vur on follow up. methods: this was a retrospective study conducted by reviewing case records of all infants and children with primary vur who had minimum follow up of 3 years, at our nephro-urology clinic over the last 10years.the imaging evaluation (renal ultrasound, voiding cystourethrogram, dmsa scan) was done based on the indian society of pediatric nephrology guidelines. severity of vur was classified as mild (grade i, ii), moderate (grade ii, iii) and severe (grade v) results: of the 218 children screened for primary vur, 107 with complete data were included for analysis. the mean age was 25.68 ±22.45 months with male to female ratio of 1.4:1. the age at presentation was significantly lower for moderate to severe vur as compared to mild vur (p=0.033). thirty children (28%) had abnormal antenatal scans. majorities (80%) of children were diagnosed to have vur during evaluation for urinary tract infection.among107 patients, six had solitary kidneys and thus the total number of systems evaluated was 208. of these, 164 systems had vur (24% had mild, 66% had moderate and 10% had severe vur). hydronephrosis was seen in 56% of patients with vur. of these, 45% were unilateral and 55% were bilateral.there was no significant difference in the presence of hydronephrosis and grade of vur. there was no significant difference in presence of scars between mild and mod-severe vur. at the end of 3 years of follow up, complete resolution of reflux was seen in 53%, 43% and 55% of children with mild, moderate and severe vur respectively. conclusion: severity of vur did not necessarily correlate with hydronephrosis and parenchymal scarring. over a 3 year follow up, complete resolution of reflux was seen in nearly 50% of children irrespective of the grade of reflux. abstract# p-sat044 growth in children with dilating vur -a follow up of the swedish reflux trial per brandstrom, sverker hansson pediatricuronephrologic center, university of gothenburg, gothenburg, sweden objective: the swedish reflux trial included 203 children, 1-2 years of age, with vur grade 3-4, diagnosed after uti in 194 and prenatal urinary tract dilatation in 9. dmsa was abnormal at start in 124 children (61%). the children were randomized to antibiotic prophylaxis, endoscopic injection with deflux™ or surveillance. there have been reports on growth retardation in children with vur and catch up after vur resolution. the mechanism behind these findings is unclear. the children of the swedish reflux trial constitute a high risk group with dilating vur, recurrent febrile uti and high prevalence of renal parenchymal defects. we have searched the growth pattern of these children for differences related to gender, treatment group, uti recurrence, vur grade at follow up or renal defects on dmsa. methods: height and weight z-scores, compared to standardized swedish growth charts, were registered during the 2 year follow up in 199 of the children in the trial and at outpatient visits thereafter in 129 patients to the age of 5.3 years (median, range 2.0-11.8). change in height z-score between first and last visit was used to measure growth over time. results: the first and last recorded height and weight z-scores were all within normal range. there was a larger gain of height in children with renal defects compared to those without (z-score difference 0.42 vs. 0.13, p=0.009). there were no differences in growth related to gender, treatment group, vur-grade at follow up or recurrent uti. conclusion: the children of the swedish reflux trial constitute a high risk group with dilating vur, recurrent febrile uti and high prevalence of renal parenchymal defects. they have normal weight, height and height gain at follow up for up to 10 years. there was no sign of growth inhibition in these children related to dilating vur. the larger height gain seen in those with renal defects seem to be due to their slightly shorter stature at study start, although within normal range, which could be related to more severe urinary tract and renal problems during their first 1-2 years of life. engin kose, caner alparslan, serdar saritas, cengizhan elmas, fatma mutlubas ozsan, onder yavascan, nejat aksu tepecik training and research hospital, pediatric nephrology, izmir, turkey objective: the management of vesicoureteral reflux (vur) is varied and remains controversial. conservative therapy is based on the understanding that vur can resolve spontaneously, mostly in young patients with low-grade reflux. in this study, we wanted to evaluate the spontaneousresolution rate of low-grade vur (grades i and ii) in children. methods: children with low-grade (i-ii) vur treated in our hospital from may 2010 to may 2012 were prospectively studied. patients with low-grade (i-ii) vur and those who showed normal dmsa findings were included into the study. initially, a dmsa scintigraphy was performed in all patients and those who experienced acute febrile urinary tract infection (uti) during the follow-up period. treatment success was defined as complete vur resolution. no patients were prescribed antibiotic prophylaxis. all parents were informed by being given an explanation of the clinical significance of personal hygiene methods used after urinating or defecating. our institutional review board approved to collect the data, retrospectively. statistical analysis was made by using ibm spss 20.0 software. results: the study sample comprised 21 infants (10 boys and 11 girls) all of whom showed low-grade reflux (grades i-ii). bilateral reflux was seen in 7 (33.3 %) of cases. median age at diagnosis was 8 months (range: 1-37 months). median follow-up time was 14 months (range: 9-28 months). the spontaneousresolution rate of reflux was 89.3 % (25 out of 28 renal units). the frequency of febrile uti was 0.74±0.7 episode/year (median: 0.8 episode/year). during the follow-up no patients with febrile uti experienced scar on dmsa scintigraphy. conclusion: infants with low-grade reflux show a low risk of febrile uti and a high spontaneous resolution rate without antibiotic prophylaxis. therefore, these children should be managed primarily by conservative therapy. ji-nan sheu 1,2 , hai-lun sun 1, 2 , shan-ming chen 1, 2 , yu-hua chao 1, 2 , min-sho ku 1, 2 , pen-fen liao 1 , ko-huang lue 1, 2 1 pediatrics, chung shan medical unversity hospital, taichung, taiwan 2 school of medicine, chung shan medical university taichung, taiwan objective: to assess the usefulness of procalcitonin (pct) as a marker for predicting dilating (grades iii-v) vesicoureteral reflux (vur) in young children with a first febrile urinary tract infection (uti). methods: children aged≤ 2 years old with a first febrile uti were prospectively evaluated. serum samples were tested for pct measurements upon admission to a tertiary hospital. all children underwent renal ultrasonography (us), 99m tc-dimercaptosuccinic acid renal scan, and voiding cystourethrography. the diagnostic characteristics of pct test for acute pyelonephritis (apn) and dilating vur were calculated. results: of 272 children analyzed (168 boys and 104 girls; median age, 5 months), 169 (62.1%) had apn. there was vur in 97 (35.7%), including 70 (25.7%) with dilating vur. the median pct value was significantly higher in children with vur than in those without (p< 0.001). using a pct cutoff value of ≥1.0ng/ml, the sensitivity and negative predictive value for predicting dilating vur were 94.3% and 95.4%, respectively, for pct, and 97.1% and 97.8%, respectively, for the combined pct and us studies, whereas the positive and negative likelihood ratios were 2.03 and 0.107, respectively, for pct, and 1.72 and 0.067, respectively, for the combined studies. by multivariate analysis, high pct values and abnormalities on us were independent predictors of dilating vur. conclusion: pct is useful for diagnosing apn and predicting dilating vur in young children with a first febrile uti. a voiding cystourethrography is indicated only in children with high pct values (≥1.0 ng/ml) and/or abnormalities found on a us. objective: to evaluate the accuracy of acute 99m tc-dimercaptosuccinic acid (dmsa) scan in predicting dilating vesicoureteral reflux (vur) among young children with febrile urinary tract infection (uti). methods: the medical records of children (age≤2 years), presenting with febrile uti between january 2000 and december 2011, were retrospectively reviewed. the sensitivity, specificity, positive and negative predictive value, positive and negative likelihood ratio of acute dmsa scan in predicting dilating vur in young children with febrile uti were calculated. results: a total of 523 children were included, of which 397(75.9%) had abnormal dmsa results and 178(34.0%) were identified as vur on micturatingcystourethrography (mcu). among all the patients, the number of dilating vur was 151(28.9%). the rate of abnormal results on dmsa of dilating vur group was significantly higher than the rates of non-vur and low-grade vur groups (p<0.01). in age<6 months group and age≥6 months group, the sensitivities of dmsa in predicting dilating vur were 96.15%, 100.0% respectively, while the negative predictive value were 97.26%, 100.0% and negative likelihood ratio were 0.0911,0.0000, respectively. conclusion: for children of age≤2 years with febrile uti, acute dmsa scan possesses certain values in excluding dilating vur. the possibility to detect dilating vur by mcu is rather low when the result of dmsa is negative. cakut: voiding disorders abstract# p-sat048 mono-symptomatic and non-mono symptomatic nocturnal enuresis: a clinical evaluation mitra naseri 1 , mehran hiradfar 2 1 dr sheikh children hospital/pediatric nephrology department, mashhad university of medical sciences, mashhad, iran 2 dr sheikh children hospital/pediatric surgery department, mashhad university of medical sciences, mashhad, iran objective: nocturnal enuresis is divided into mono-symptomatic nocturnal enuresis(mne) and non mono-symptomatic nocturnal enuresis(nmne).this study was conducted to review clinical and ultrasonography findings in enuretic children, and compare organic and functional pathologies of lower urinary tract (lut) in children with mono-mne with those who have nmne. methods: 111 neurologically normal children with chief complaint of enuresis enrolled in the study including 60 boys and 51 girls, aged 5-17 years old, 43 (38.8%) with mne and 68 (61.2%) with nmne. urine analysis, urine culture and kidney bladder ultra sonography was done for all .some patients underwent voiding cystoureterography (vcug), urodynamic study (uds), or both. results: patients were divided in to 3 groups: mne, nmne daytime incontinence and nmne +daytime incontinence. constipation, encopresis and urge incontinence were significantly more frequent in patients with nmne +daytime incontinence (p= 0.011, 0.003, 0.001 respectively) . bladder wall thickness was the most common us findings..one patient with mne and 9 with nmne+ daytime incontinence had vesico -ureteral reflux(vur) )(p=0.016).posterior urethral valve was reported in one patient with nmne. evidences of bladder dysfunction were noted in about half of the patients who underwent uds, with higher prevalence in cases with nmne + daytime urinary incontinence(p=0.297). bowel symptoms and vur were significantly more prevalent in cases with nmne +daytime incontinence. conclusion: we recommend doing vcug in enuretic children who have daytime incontinence.in addition our study revealed that symptoms suggestive of over active bladder are not good indicators for bladder dysfunction. abstract# p-sat049 correspondence between urinary calcium, ca 2+ concentration and osmolality in enuretic children agata korzeniecka-kozerska, tadeusz porowski department of paediatrics and nephrology, medical university of bialystok, bialystok, poland objective: among many factors predisposing to enuresis hypercalciuria may play an important role. hypercalciuria is be observed in patients both in patients with nocturnal polyuria and without. hence, we decided to assess urine concentration of calcium (mmol/l) and ca 2+ (mmol/l) in patients with monosymptomatic enuresis and answer the question if patients with enuresis present calcium balance disturbances methods: the study was conducted on 204 children (83 enuretic aged median 9.66 (4.16-16.98 ) yrs diagnosed with monosymptomatic enuresis after 6 months of unsuccessful non farmacological treatment and 121 healthy children aged median 9.99 (4.15-16.86 ) yrs. we collected 24-h urine samples from all children enrolled to the study. calcium concentration, ca 2+ , ph, osmolality of urine and additionally daily sodium excretion were estimated and compared between two groups. statistical analysis were performed using statistica ver. 10.0 (statsoft,tulsa, ok). the mann-whitney u test was used for comparisons between two independent parameters. correlations were made with spearman test. a p value of <0.05 was considered to be statistically significant. results: there were no differences in age, gender and parameters of physical development between both studied groups and between girls and boys among groups. urinary calcium concentration in enuretic children did not differ compared to reference group ( p=0.993). we found statistically significant differences in urinary ca 2+ concentration (p= 0.001) and osmolality (p=0.02) between both studied group. ca 2+ in urine correlated negatively with age and parameters of physical physical development only in enuretic patients. additionally, positive correlation was found between ca 2+ and calcium concentration (r = 0.7923; p<0.005) and between ca 2+ and osmolality (r=0.2795; p<0.05) in urine of enuretic children. positive correlation was also observed between ca 2+ and daily natrium excretion (r=0.318; p<0.05) in enuretic children. conclusion: disturbed calcium balance may play an important role in pathogenesis of monosymtomatic enuresis. it's a need to assess calcium and natrium excretion in enuretic children. abstract# p-sat050 usefulness of the application of questionnaires to detect attention deficit hyperactivity disorder (adhd) and other psychiatric disorders in children with functional voiding disorders sandra gautreaux pediatric nephrology, complejo asistencial universitario de leon, spain objective: although the relationship between functional voiding disorders (fvd) and the presence of a psychological problem remains controversial, the greater frequency of adhd among children with this condition is well known. the purpose of this study was to determine the diagnostic performance of the application of questionnaires to detect adhd and other psychiatric disorders in children with functional voiding disorders in general pediatrics consultations methods: the study was conducted on 32 children between 6 and 13 years of age (20 males) diagnosed with fvd (patient group) and 32 children of the same age (21 males) who had no urinary symptoms (control group). the parents of these children responded to the questions in two standardized questionnaires: the strengths and difficulties questionnaire (sdq) to screen for mental health disorders and the questionnaire for the detection of adhd of the dsm-iv psychiatric disorders of american academy of psychiatry manual. the variables obtained from the questionnaire responses were compared between the two groups of children using the student's t-test for unpaired samples when variables were quantitative and the chi-square test if the variables were qualitative. it was considered significant when p<0.05 results: no significant differences were found between the two groups in the sdq questionnaire in any of its sections (emotional symptoms, conduct problems, hyperactivity, peer problems and prosocial behavior) or global assessment test, in which only 2 patients of each group had an abnormal result. the questionnaire for the detection of adhd, presented an altered overall result of 17.18% and 14.06% patients in the control group (p=ns). there were also no differences between the two groups on the results of this test concerning the inattention or hyperactivity-impulsivity sections. conclusion: the results of the application of questionnaires to detect adhd and other psychiatric disorders in children with fvd are similar to those of the general population. the routine application of this type of questionnaires to all the patients in pediatrics consultations does not seem necessary. abstract# p-sat051 characterization of voiding dysfunction in chidren with attention deficit-hyperactivity disorder jun yonug kim, kun hee lee, jung won lee department of pediatrics, hallym university kangnam sacred heart hospital, seoul, korea objective: attention deficit hyperacitivity disorder (adhd) has been associated with impairment of frontal inhibitory function and catecholaminergic system. adhd is diagnosed in 3~5 % of children. children with adhd seem to suffer from various forms of urinary problems such as nocturnal enuresis, dysfunctional voiding and diurnal incontinence. however, no data exist to confirm in korean adhd children. we investigate the clinical findings of voiding dysfunction in adhd children. methods: between october 2009 and march 2011, a total of 63 children (33 children with adhd and the other 30 children with upper respiratory infection as control group) were enrolled in gangnam sacred heart hospital, hallymuniversity. adhd children were diagnosed under diagnostic and statistical manual of mental disorders (dsm)-iv criteria. a comprehensive survey of voiding and defecating were administered. results: the patient group included 28 boys and 5 girls, and the control group 15 boys and 15 girls. mean age were 9.09+/−2.8 year in adhd group and 8.58+/−3.1 in control group. children with adhd had statistically significant higher incidence of enuresis (p=0.017), urgency (p=0.017), urge incontinence (p=0.033) and constipation (p=0.007). there was no significant differences in straining, intermitteny, holding maneuvers (p>0.05). conclusion: children with adhd in korea have significantly higher rates of enuresis, urgency, urge incontinence and constipation than those without adhd. the psychological correlates of primary nocturnal enuresis weiran zhou, xiaomei liu, ying shen nephrology, beijing children's hospital, beijing, china objective: previous studies based on clinical samples have reported that enuresis in children is associated with behavioural problems and reduced self-esteem, anxiety, but the relationship remains controversial. this study investigated psychological correlates of enuresis in a group of children suffering primary nocturnal enuresis(pne). methods: this survey involved 98 parents and their children with pne aged 7-14 years. clinical datas of enuresis were collected through parents' reports and individual administrations to all children. parents completed the child behaviour checklist. children completed piers harris children'sself concept scale, the screen for child anxiety-related emotional disorders (scared)and depression self rating scale for children (dsrsc) . results: of the 98 children, 60 are boys and 38 are girls. 65 are monosymptomatic primary nocturnal enuresis and, 33 are nonmonosymptomatic. 72 children accord with the severest form of bedwetting(>=7 times/week). 64.3%(n=63)children have behaviour problems and, girls get higher scores in withdraw and internalizing problems than boys. boys are more aggressive. 42.9%(n=42) get positive results through scared. 9.2%(n=9) get positive results in dsrsc. children with the severest form of bedwetting are likely to have more complex form of psychological problems. they have greater social problems, get higher scores in behaviour problem (p=0.026) and lower scores in piers harris children's self concept scale (p=0.034). but children with or without the severest form of bedwetting have no significant difference in scared . mne have no significant difference with nmne in scores of all the three children's self-evaluated scales. conclusion: most children with pne had different psychological problems. the severer the symptoms are, the more complex the psychological correlates are. these preliminary findings support the view of enuresis closely related with psychological problems. psychological problems are affected by many factors except for enuresis, so further researches need to be conducted to determine whether there is a causal relationship between psychopathology and enuresis. the current situation of treatment of primary nocturnal enuresis in children xiaomei liu, lu chen, weiran zhou nephrology, beijing children's hospital, beijing, china objective: we would like to discuss the treatment of primary nocturnal enuresis in children. methods: children, diagnosed with primary nocturnal enuresis, paid outpatient visits to beijing children's hospital from january 2011 to may 2012, are enrolled in the study. the information of previous clinical experience, compliance and expected treatment goals are collected and analyzed. results: 623 children, with the mean age of 8.69±2.33 are enrolled. 449 children have visited doctors before, 295 have unsatisfied clinical experience, such as late intervention, less standardized treatment and over-treatment. 64.36% have poor compliance with doctor's suggestion of behaviour therapy and alarm therapy. 262 children have been suggested to take medicines such as chinese traditional medicine ddavp, but 17.8% of them refused the suggestion anxious of the side effects or stop the usage on their own. the primary expected treatment goal of parents is to improve the symptoms, accounting for 86.04%. excluding the underlying diseases, alleviating parents' burden, treating the symptoms of hyperactivity or inattention and avoiding adverse effects on intellectual and fertility are also included. for children, they'd like to improve the symptoms so they won't be published by parents or laughed by their fellows. most parents (79.94%) preferred medicines as the first choice. 12.40% parents and children are inconsistent with the behavior therapy (the rate of newly diagnosed and non newly diagnosed children were 8.04%, 14.03% respectly. χ 2 test p>0.05). 38 (6.10%) don't accept alarm therapy (the rate of newly diagnosed and non newly diagnosed children were 2.30%, 8.02% respectly. χ 2 test p>0.05). conclusion: children with primary enuresis need early intervention and standardized treatment. the effect of treatment largely depends on cooperation and joint participation of children and parents. this study found that the compliance of behaviour training and alarm therapy is lower than medicine. the goals of children and parents, living conditions and other factors should be fully considered in the treatment of enuresis to improve short-term remission rates and long-term cure rate of the disease. beware of the sleeping bladder in monosymptomatic nocturnal enuresis (mne) britt borg, konstantinos kamperis, birgitte mahler, soren rittig pediatrics, aarhus university hospital, skejbv, denmark objective: bladder reservoir function in children with nocturnal enuresis is assessed by maximal voided volumes (mvv) registered on frequency-volume charts. although a degree of association is evident, mvv does not always reflect the nocturnal bladder reservoir function in mne. we aimed to evaluate the nocturnal bladder reservoir function during the night in children with apparently normal mvv. methods: data from 557 children aged 5-15 treated for mne in a tertiary referral centre was analyzed. data from 135 children was excluded due to reduced mvv according to iccs standardization and 156 due to lack of home recordings. the remaining were divided into two groups, based on whether mvv was above (n=91) or below (n=175) the average nocturnal urine production during wet nights (nupw) . first morning voids were not included in mvv values. results: 34 % of the children with mne and a normal bladder capacity had an average nocturnal urine production during wet nights below their mvv, one third of these had nupw below 65 % of mvv expected for age. these children did not differ significantly in terms of demographic characteristics, frequency of wet nights or treatment time needed to achieve dryness. urine output during dry nights was not statistical significant between the groups (p=0.077, mean diff.=28.47 ml). the group with mvv>nupwet shared significantly higher mvv to mvv expected for age ratios (mean diff=0.16, p<0.05). urine output during wet nights was lower in the group of children with mvv>nupw (diff: 96.45 ml, p<0.05) . conclusion: children with mne and apparently normal bladder reservoir function during daytime may experience wet nights with urine volumes well below their mvv and mvv expected for age. the fact indicates bladder reservoir function abnormalities during sleep that is not assessed by day recordings. physicians treating children with mne should consider anticholinergic treatment. one year experience of a multidisciplinary investigation on nocturnal enuresis in a brazilian tertiary care facility objective: to characterize a cohort of children, 6-16 yrs old, with nocturnal enuresis, defined by 2010 iccs criteria on the basis of a multidisciplinary evaluation including renal, neurological, psychological and physical therapy approaches. chronic clinical conditions and genetic disorders constituted exclusion criteria. methods: after irb approval, families were invited to participate in the project through press releases, 130 children completed quality of life evaluation through clinically validated questionnaires, followed by a one -day multidisciplinary clinical evaluation. sleep, urinary and intestinal diaries were evaluated. urinary sonography, nocturnal polysomnography, urinary and blood analysis were scheduled. results: 96/130 participants (pts)were male (73,8%), mean age 8 ±1 yrs. twenty two children were excluded due to noncompliance /chronic clinical conditions. 118/130 pts were evaluated. 93/130 parents of children/adolescents, answered the cbcl questionnaire, 25/93 (27%) of which resulted in scores compatible with clinical psychological conditions. monosymptomatic enuresis (moe) was diagnosed in 89/118 children (75.4%). in the moe group, 67/89 pts were diagnosed with intestinal constipation; 7/89 pts with obstructive sleep apnea, 2/89 pts with hipercalciuria and 2/89 were characterized with adhd. area and velocity of center or pressure displacement (vm) were used for postural control evaluation and resulted in 3,67 ±2,95 cm 2 and 20,35±13,04 cm.s-1, respectively; 22/89 pts were also assessed for postural alignment exhibiting pelvic anteversion (10,27 ±3,71 grades) and head protusion (0,40±1,86 grades). these results corroborate with a smaller range of motion found for hip flexion (94,86±17,14 grades) and hip extension (2±3,89 grades) assessed using a goniometer. conclusion: multidisciplinary evaluation of enuretic children may be the key to optimize therapy on the basis of the underlying etiology of the process abstract# p-sat056 weight depending dosing of desmopressin (ddavp) in nocturnal enuresis pauline de bruyne 1 , ann de guchtenaere 1 , charlotte van herzeele 1 , ann raes 1 , jo dehoorne 1 piet hoebeke 2 , erik van laecke 2 , johan vandewalle 1 1 paediatric nephrology, ghent university hospital, ghent, belgium 2 department of urology, ghent university hospital, ghent, belgium objective: in children as well as in adults, a uniform starting dose of desmopressin is prescribed. this uniformity is based on the inability to detect a weight-dependent dose-concentration correlation as this correlation is probably blurred by the wide intra-and interindividual differences in plasma concentration for a fixed desmopressin dose. recently, a smaller variation in plasma concentration was shown for the oral lyophilisate formulation of desmopressin (compared to tablet formulation). therefore, this study assessed a possible correlation between weight-corrected dose and plasma concentration for both formulations. methods: 23 children with monosymptomatic nocturnal enuresis were recruited in a tertiary centre. two tests were performed on two separate days (at two weeks interval) in identical, standardized conditions: on day 1 desmopressin tablet 200μg and on day 2 desmopressin oral lyophilisate 120μg was administered. plasma concentrations were measured at one, two and six hours post dosing. the nonparametric spearman's rank correlation coefficient was used for assessing the correlation between weight corrected dose and plasma concentration. results: mean (sd) age and body weight of the patients were respectively 12.7 (2.9) years and 50.1 (15. 2) kg. a positive correlation between plasma concentration of ddavp was found for the oral lyophilisate formulation at 2 hours (p-value 0,021) and 6 hours (pvalue 0,005) post dosing. this is not the case for the tablet formulation. results are shown graphically in figure 1 and 2. figure 1 and 2: correlation of dose corrected by weight to plasma concentrations at 2 and 6 hours post dosing conclusion: to the best of our knowledge, this is the first pharmacokinetic study showing a significant dose (normalized for size) -concentration correlation for desmopressin. nevertheless, this correlation was only significant for the oral lyophilisate group. this result is clinically important as it is a strong indication for more predictable plasma concentrations for the oral lyophilisate formulation, and thus preventing elevated concentrations of desmopressin. objective: increased nocturnal urine production and/or bladder hyperactivity in primary nocturnal enuretic (ne) patients could possibly be associated with autonomic nervous system dysfunction. reports of studies on autonomic nervous system dysfunction in ne are limited. to investigate autonomic nervous system function in enuretic children by performing ambulatory blood pressure monitorisation (abpm) for 24 hours. methods: children with primary ne were enrolled in this study and they get 24 hour abpm. their results were compared with healthy children. urinalysis,urine electrolyte levels, urinary culture and urinary system ultrasound were carried out in all the children. they also requested to have a diary about daily fluid intake and volume of daily urine. results: the enuretic group consisted of 28 children (m/f:19/9) and the control group of 27 healthy children (m/f:14/13). the mean ages were 7.9±2.2 years and 8.77±2.65 years, respectively. the mean 24-hour bp and daytime dbp did not differ between the groups however, the mean systolic bp was significantly higher in enuretic children (p<0.05). the mean nighttime systolic bp, dbp and map were significantly higher as well in the patient group. daytime bp load did not found to be elevated in both groups.elevated night time systolic bp load was observed in 4 patients and was not observed in control group (14.2 % vs 0%) (p<0.01). nighttime diastolic bp load was elevated in 7 of 28 patients, compared with 1 of 27 control subjects (p<0.01). the nocturnal bp dip was significantly reduced in the patient group compared with control group for diastolic blood pressure ( 67.8 % vs 14.7 %, respectively; p=0.037). patients with elevated night time bp load was found to have higher frequency of urinary incontinence per week as well as per night while compared with enuretic children with normal night time bp load (r=0.72, p<0.01; r=0.69, p<0.01 respectively). conclusion: nocturnal bp loads were significantly higher in children with enuresis. these subtle abnormalities of circadian blood pressure regulation, loss of nocturnal dip and observation of decreased nocturnal pulse rate may reflect autonomic nervous system dysfunction and pathogenesis of en. objective: bladder dysfunction and especially oab plays a major role in nocturnal enuresis, not only in the non monosymptomatic (nmne) but as well in the monosymptomatic patients (mne) . if the enuresis is related to a mismatch in nocturnal diuresis and maximal functional bladder capacity, then the bladder volume should be a major parameter, but is sofar not taken as a parameter for subtyping into nmne in the iccs standardization. maximal voided volume in a diary is the golden standard, although relation with outcome is poorly studied. methods: aim of the study was to evaluate the optimal parameter for estimation of bladder volume as maximal voided volume in a diary, during forced diuresis, bladder volume during 3 uroflow + uroflow), correlating with cystomanometry (if indicated). studypopulation 398 patients age 5 to 18 years, >6/7days wet, only 48 cystomanometries. results: if we compare the data from the bladder volume against the reference frame from rittig (aarhus), then 60,4% of patients had a mvv in diary < 2,5% percentile demonstrating that a majority of patients had a small for age voided volume in their diary. correlation between mvvdiary, mvv forced diuresis, bladder capacity (uroflow+ residu) and cystomanometry show that there is a strong correlation between the 4, but especially for the last 3 parameters (r 2 0.48-0.62, p <0.01),but results with mvv diary are worse (r 2 0.34-0.48, p 0.04-0.018) . there is no sex or gender difference in this observation. correlation with response to therapy at 1 year shows a superior correlation with mvv forced diuresis and during uroflow than mvv diary (p0.04). since cystomanometry is only performed in refractory cases, this voided value had no correlation with clinical outcome. conclusion: bladder volume can be estimated in several ways, each with their advantages and pitfalls. our data demonstrate that the alternative non invasive methods during force diuresis and in center during 3 uroflow correlate best to each other and to the cystomanometricvalues. but as well to the one year outcome (p 0.04). abstract# p-sat060 evaluating nocturnal diuresis (polyuria) claire debusschere, delphine guenter, sophie wouters, johan vandewalle, ann raes, joke dehoorne pediatric, nephrology, gent, belgium objective: nocturnal enuresis is more than bedwetting, but a symptom of a disorder involving multiple pathogenetic factors in circadian rhythm of diuresis/solute excretion and bladder dysfunction. where the sum of diaper weight and morning voided volume, is the standard to evaluate nocturnal diuresis (polyuria), it does not give indices about pathophysiology. the aarhus concept : in center studies during standardised intake, offers the advantage of standardized conditions, and reliability of the values, but is restricted to specific research centres in limited patients for budgetary reasons). the ghent concept : a home based 24 hours concentration prophyle with 4 time daytime and 4 nighttime collections offers an alternative. this one day test was not validated against 14 days diuresis nighttime registration, and was criticized since waking up the patient overnight might increase diuresis and solute excretion, as is demonstrated in sleep deprivation aim of the study: to validate nocturnal diuresis and solution excretion to evaluate nocturnal polyuria against 14 days nighttime diary and 2 days daytime diary. methods: to the study the incidence of nocturnal polyuria, and to evaluate the value of the morning osmolality in the study of nocturnal polyuria. results and conclusion: 401 children (262m), mean age 8 y (5-18y) , 24 h diuresis 1023+/−445 ml, daytime 663+/−367 ml nighttime 365+/−203ml, no sex difference. correlation between volumes in diary and 24 h concentration prophyle during 24 h (p 0.036), night (r 2 0.336 p 0.013) and day (p 0.012). only 13% of patients have a nocturnal polyuria (&gt;130%ebv= absolute nocturnal polyuria), but up to 28% have a nocturnal diuresis higher than 100% ebv and &gt; than their mvv (relative polyuria). there is no correlation between early morning osmolality and nocturnal diuresis-rate (nocturnal polyuria). objectives, methods and results: we present a 16 months old albanian female with fever, urinary retention and constipation. this problems has occurred one week before hospitalization. no history of trauma. life history has no remarkable data. no history of uti or constipation before. physical examination: weight and stature on 50 centile. no respiratory problems. the big overfilled bladder was palpated. on the left sacral region, was a tumorous mass very painful and worm. perianal reflex, bulbocavernosus were weak. other reflexes were normal. there were a hard stools in the rectum. other systems examination was unremarkable. high es rate and pathological urine sed with infection indicators. other laboratory examination was unremarkable. ultrasound examination resulted with dilatation of the left kidney pyelon (9mm), distended and overfilled bladder lumen (>400ml) with thin bladder wall. rectum distended and full with fecal masses.lateroposterior there is a sonolucent cystic formation with (volume 7ml). that cystic formation was supected for ureterocellae first. the urinary catheter and rectal clismas were done. that formation was abscess and it was drained. and two weeks after was better. voiding cystourethrogram and computer tomography was done and resulted that are no anatomical defects in the urinary tract. because of the collapsed bowels there's not good visualization of the region around the sigma and rectum. irigografy resulted: dolihosigma and suspected for hirschprung. two months later the abscess relapsed and needed drainage again. conclusion: since the abscess has repeated the next step will be biopsy. hirschprung, tailgut cysts and other presacral masses should be included in the differential for patients with recurrent abscess in the perisacral space with clinical manifestation of urinary retention and constipation. abstract# p-sat062 treatment failure to enuresis alarms: challenges and factors influencing adherence to treatment indra ganesan 1 , jessica xj hooi 2 , jasmine jy goh 2 , yh ng 1 , sm chao 1 1 nephrology service, kk women's and children's hospital, singapore, singapore 2 department of pediatrics, kk women's and children's hospital, singapore, singapore objective: the study aims to identify factors influencing treatment failure to enuresis alarm and the factors influencing adherence to treatment. methods: all patients aged 6 to 16 years referred to the voiding clinic in kk women's and children's hospital, singapore with primary nocturnal enuresis who opted for enuresis alarm treatment, over 6 year period from 2007-2013, were prospectively studied. data, via direct interview and parental questionnaire was collected on demographics, age at presentation, presence of family history, frequency of nocturnal enuresis per week and per night, on whether child awakens after wetting, or associated constipation in the child and parental perception of why primary enuresis happens. results: seventy-nine of 111 (71%) children with primary nocturnal enuresis with complete data were included. mean age at presentation was 9.6±2.1 years and 45 (57%) were male. twenty-five children had a family history of nocturnal enuresis in a 1 st degree relative. eighteen children had constipation. fifty-one (64 %) children achieved the targeted 21 consecutive dry nights. in the remaining 28 children, the main reasons for treatment failure were non adherence to usage of enuresis alarms mainly due to an inability to wake up to the alarm in deep sleep (71%) and underlying neurobehavioural conditions (21%) (adhd, autism, depression and a chromosomal disorder). the only significant clinical factor predicting treatment failure was the presence of an underlying neurobehavioural condition (or 2.8, and developmental delay . factors such as male gender, family history in first degree relatives, frequency of enuresis, arousal when wet, and the presence of constipation, were not significant. conclusion: in our population, 64% of children achieved nocturnal urinary continence with enuresis alarms. treatment failure of enuresis alarms is higher in the presence of an underlying neurobehavioural condition and developmental delay. non adherence to treatment is mainly due to inability to arouse from deep sleep. long-term follow-up of children with nocturnal enuresis -do enuretics become nocturics? an-sofie goessaert 1 , bente schoenaers 2 , olivier opdenakker 2 , karel everaert 1 , johan vandewalle 3 1 urology, ghent university hospital, ghent, belgium 2 ghent university, ghent, belgium 3 pediatric nephrology, ghent university hospital, ghent, belgium objective: although an overlap between both nocturnal enuresis (ne) and nocturia is known, research on the occurrence of both conditions in one patient is lacking. this study aims to investigate the prevalence of nocturia and other urinary symptoms in patients who have suffered from ne. methods: a questionnaire was sent to 1265 patients treated more than 3 years ago in the university hospital of ghent for ne evaluating the history and current status of enuresis and validated questionnaires on urinary incontinence (iciq-ui) and overactive bladder symptoms (iciq-oab). medical files of all subjects were analysed on the history of enuresis. all subjects were asked to sign an informed consent. results: of the 516 (41%) subjects who completed the questionnaire, 183 reported nocturia (36%), with a sex ratio (m/f) of 101/81 in the nocturic group versus 230/103 in the non-nocturic group, mean age is 18 versus 17 years old, respectively. comparing the nocturic and nonnocturic group, retrospective analysis of the history of enuresis shows an older age at which the subjects were cured (10 vs 9.5, respectively) and a higher percentage of non-monosymptomatic ne (74% vs 63%, respectively) in the nocturic group. no differences in past treatment for ne were found between both groups. prospective analysis shows a significantly higher prevalence (p<0.001) of voiding frequency during daytime, urge and urinary incontinence in nocturics compared to nonnocturics. with an increase in number of nocturic episodes per night, the percentage of female subjects increases (p<0.001) and the percentage of subjects with non-monosymptomatic ne increases as well (p<0.011). conclusion: over one out of 3 former enuretic patients develops nocturia, often accompanied by other urinary symptoms and with significant bother. cure of nocturnal enuresis does not necessarily equals cure of the urological pathology and some of the nocturic patients, who remain to suffer from bothersome symptoms, might benefit from continuous treatment for the underlying urological condition, such as overactive bladder syndrome or nocturnal polyuria. objectives, methods and results: a 3 year old girl was admitted to our hospital due to unusual pattern of voiding. when she wanted to urinate, she was writhing in pain; she cried, became pale and sweated. since the newborn period parents have observed sudden episodes when the girl started to cry and curled up her legs. she stopped when she began to urinate. the girl's father occasionally had pains in the jaw between yawning. the girl's voiding was like parents described: when she was trying to begin urinating, she was squatting on the toilet seat, crying and became pale and sweated. when voiding occurred the girl seemed to relax. the voiding volume was small and the urinary stream was weak. all investigations results were normal. according to the clinical course we assumed that the girl had an unusual expression of paroxysmal extreme pain disorder (pepd). the diagnosis was confirmed by the detection of the heterozygous pathogenic mutation in the scn9a gene, a missense mutation in exon 5. the same mutation was also confirmed in her father. the girl was started on carbamazepine and the pain attacks almost disappeared. pepd is a rare autosomal dominant neuropathy linked to mutation in the scn9a gene which encodes voltage-gated sodium channels. abnormal pain sensitivity occurs due to changes in the properties of the channels. pepd's onset is in the neonatal period with the most characteristic clinical features being attacks of excruciating pain in the rectum, genitalia, face and limbs. in literature we did not find any citation of patients with attacks triggered by the voiding stimulus. carbamazepine has been effective in relieving symptoms but the response is often incomplete (1) (2) (3) , as in our patient. conclusion: the case described is interesting because of the rare clinical expression of pepd with pain triggered by voiding. the same mutation was recently found in patients with sfn (4) . the study of functional importance of this mutation showed that the result of the mutation is increased frequency of firing pain-signaling neurons (5) . rita pavione rodrigues pereira 1 , vera herminakalika koch 2 , simone nascimento fagundes 2 , aline rossi 1 , juliane de oliveira marques vieira 1 , clarice tanaka 1 1 physical therapy, university of são paulo, são paulo, brazil 2 communication disorders and occupational therapy, university of são paulo, são paulo, brazil objective: to assess the postural control in children and teenagers with enuresis compared to a control group methods: 22 enuretic (eg) patients (11 boys and 11 girls) with mean± sd of 10.52±2.77 years, ranging from 7 to 16 years old, and 19.39±3.50 of bmi were paired with assyntomatic kids (cg) of equal age, gender and bmi. three trials of 20 seconds were collected while standing on a forceplate at 60 hz of frequency with standard position of feet in four different sensorial conditions: (1) open eyes and stable surface; (2) closed eyes and stable surface; (3) open eyes and unstable surface, and; (4) closed eyes and unstable surface. the analized variables were area (a) and velocity (vm) of center of pressure displacement (cop). student t-tests were used to compare variables between groups for each sensorial condition. the level of significance was 95% for all the analysis. results: when compared to cg, the eg revealed larger area of cop displacement in the condition (1) (mean± sd of 2,46±2,11 cm 2 for cg and 4,16±2,76 cm 2 for eg; p=0,027), and in condition (4) (mean± sd of 4,29±2,45 cm 2 for cg and 7,33±6,46 cm 2 for eg; p=0,05). no difference in vm were identified. conclusion: when compared to assymptomatic control group, the enuretics children and teenagers presented larger area of cop displacement under normal sensorial input (condition 1) and when vestibular input alone was offered (condition 4). the hip and spine mobility is diminished in enuretic children and teenagers rita pavione rodrigues pereira 1 , vera herminakalika koch 2 , monica maria ribeiro goncalves 2 , thais de souza milhoratti 1 , daniela castro pacheco 1 , clarice tanaka 1 1 physical therapy, university of são paulo, são paulo, brazil 2 communication disorders and occupational therapy, university of são paulo, são paulo, brazil objective: to assess the hip and spine mobility in children and enuretic teenagers compared to a control group. methods: 22 enuretic (eg) patients (11 boys and 11 girls) with mean ± sd of 10.52±2.77 years, ranging from 7 to 16 years old, and 19.39±3.50 of bmi were paired with assyntomatic kids (cg) of equal age, gender and bmi. the range of motion of hip flexion and extension was measured using a goniometer. spine flexibility was measured using schober e stibor test and bank of wells. student t-tests were used to compare variables between groups. the level of significance was 95% for all the analysis. results: when compared to cg, the eg revealed diminished range of motion of hip extension bilaterally (2±3.89 for eg and 10±7.99 for cg at right side; p<0.01; ge 2.05±3.88 for eg and 10.4±7.22 for cg at left side; p<0.01). no difference was found for hip flexion range of motion, however compared to cg, eg showed lower values bilaterally (94.9±17.1 for eg and 100.32±8.52 for cg at right side; 98.3±11.7 for eg and 101±11.1 for cg at left side). the spine flexibility did not presente any difference for schober (14.88±3.18 for eg and 16.18±1.16 for cg; p =0.07), and stibor (50.21±6.2 for eg and 51.93±7.37 for cg; p=0.40) and bank of wells (25.58±7.67 for and 23.66±7.42 for cg; p=0.63). conclusion: when compared to assymptomatic control group, the enuretics children and teenagers presented diminished range of motion of hip extension suggesting transversal misalignment of the pelvis. more concern about enuresis children: an epidemiological study of primary nocturnal enuresis in elementary schools in shanghai yibing zheng 1 , yinv gong 1 , hong xu 1 , keli wang 1, 2 , zhonghui ni 1,2 , dandan he 1,3 1 nephrology and rheumatism, shanghai, china 2 xuhui health bureau, shanghai, china 3 minhang center for disease control and prevention, shanghai, china objective: (1) to assess the prevalence of primary nocturnal enuresis (pne) and its risk factors in children of elementary school age in shanghai. (2) to evaluate the impact of enuresis on these children and their parents, and to identify the methods and effectiveness of managing enuresis. methods: a randomly selected cross-sectional study was conducted in four elementary schools in two districts inshanghai. the parents of these children were asked to complete questionnaires anonymously which included items about the presence and frequency of enuresis, its risk factors and its perceived impact and management. the distress caused to the family by enuresis and the outcome of any management was evaluated using a 5-point visual analogue scale (vas). pns was defined as an involuntary voiding of urine during sleep, with a frequency of more than two times a week for three consecutive months, in the absence of congenital or acquired defects of the central nervous system. results: a total of 7600 questionnaires were distributed. the overall response rate to the questionnaire was 97.1%, girls 45.2% and boys 51.8%. the prevalence of pne declined with age from 6.3% at 7 years old to 0.5% at 11 years old. of all enuresis children, 10.1% had daytime urinary symptoms and 11.7% had a positive family history. 58.8% of parents were concerned and 17.6% were very concerned about enuresis. 41.2% of children were worried about and 5.9% were very worried about enuresis. only 35.3% of pne children sought for treatment and the common strategies (23.5%) were adjusting lifestyle such as restriction of water intake at night, 11.9% used alarm clock and 5.8% were take medication. 48.6% of parents felt that the current treatment was effective. conclusion: we conducted a relatively scientific epidemiological survey on the prevalence of pne in two districts in shanghai. we find enuresis still has great impact on children and their parents, but only a small part of them will seek for treatment. and only half of the parents feel that the current treatment is effective. therefore, it would be desirable to create a series of standardized management and follow-up processes for enuresis children. abstract# p-sat068 renal manifestations of tuberous sclerosis: a descriptive analysis sophy korula 1 , alka ekbote 2 , naresh kumar 1 , sumita danda 2 , indira agarwal 1 , swasti chaturvedi 1 1 paediatrics, christian medical college, vellore, india 2 clinical genetics, christian medical college, vellore, india objective: to describe the renal manifestations in children 0-18 years of age diagnosed with tuberous sclerosis complex (tsc) at a tertiary hospital in south india. methods: data of children with tsc who presented to christian medical college vellore hospital from january 2008 onwards, were analysed by a retrospective chart review. the cases were identified from outpatient records and underwent ultrasonography, urine analysis and serum creatinine to recognize renal involvement. results: twenty-five children with tsc were identified. two children did not imaging studies available and were excluded from the analysis. the age of included children ranged from 5 days to 15 years with a median of 8 years. seventy four percent (17/23) were males. ten of the 23 children had evidence of renal involvement (43.5%). of the ten children with renal involvement, six had angiomyolipoma (60%), five had renal cysts (50%) and one had suspected renal cell carcinoma. in two children both angiomyolipoma (aml) and cysts were noted. none were symptomatic. one child was found to have proteinuria and another had reduced creatinine clearance of 52.5 ml/min/m 2 with normal bp and urinalysis. the rest of children had no evidence of proteinuria and had normal creatinine clearance. conclusion: we conclude that all children with tsc should be screened for renal involvement and regular follow up should be arranged. abstract# p-sat069 sonographic growth charts for kidney length in normal korean children: a prospective observational study objective and methods: kidney length was measured by sonography in a prospective observational study of 343 normal children from 0 to 12 years of age. results and conclusion: there was a good correlation between kidney length and somatic values including age, weight, and height. the rapid growth of height during the first 2 years of life was intimately associated with a similar increase in kidney length. the values of weight and height showed good correlation with kidney length in children from 2 to 12 years of age. height should be considered the important factor to correlate with kidney length. for the children aged 2 years or older, the regression equation was obtained: kidney length (cm) = 2.677 + 0.046 x height (cm). for the younger than 2 years, the equation was: kidney length (cm) = 1.120 + 0.066 x height (cm). objective: the outcome of children with unilateral nonfunctioning mcdk. methods: 24 children (13 pts with right mcdk), afunction confirmed by renal scan, 12 boys, mean age of 6 years (range 1.5 month -21.5 years), mean observation period of 6.7 years with a range of 1.5 month -21.5 years. prenatally diagnosis was made in 83 %. abnormalities of the contralateral kidney were found in 4 /24 pts (13 %) -dystopia (n=2), hydronephrosis due to ureterovesical obstruction (n=1), vacter syndrome (n=1). in 2 pts mcdk had been removed (in period 1991-1997) . collected data include egfr (calculated by cystatin c), urine protein/creatinine ratio, microalbumin/creatinine ratio, a1microglobulin (a1m)/creatinine ratio, urine beta-2microglobulin (b2m), urine ngal, urine nag, blood pressure (bp), renal length. results: hypetrophy of the contralateral kidney (length >2 sds) was detected in 19/24 pts (79%) to 2 years of age. complete involution (in 33 %) or decrease of size (in 30%) of mcdk occured in the first 5 years. hyperfiltration (defined as egfr of 149 ml/min/1.73m2) was seen in 4 pts (17 %). none of 24 pts demonstrated decreased egfr, proteinuria (mean value of 24.8 mg/mmolcreatinine), microalbuminuria (mean value of 2.0 mg/mmolcreatinine).urine a1m (mean value of 5.8 mg/mmolcreatinine), urine b2m (mean value of 0.2 mg/l), urine nag (mean value of 7.3 ukat/mmolcreatinine), urine ngal (mean value of 10.4 ng/l) were in a normal range. all pts were normotensive -bp defined as <95th percentile for age and gender. the combination of hepatoblastoma with renal failure due to congenital dysplastic kidneys in children is extremely rare. we report two children in renal failure since birth due to congenital cystic dysplastic kidneys. hepatoblastoma was subsequently diagnosed in both of them. methods and results: case1 a male infant was born at 35 weeks gestation with an antenatal diagnosis of bilateral dysplastic kidneys and bladder outflow obstruction secondary to a prolapsing ureterocele, anhydramnios, and pulmonary hypoplasia. he underwent surgical repair of other congeniatal abnormality after birth. peritoneal dialysis was initiated at 3 months. treatment with erythropoietin (epo) was commenced at 6 weeks of age. case 2 a male infant with congenital cystic renal dysplasia, bilateral vesicoureteric reflux pulmonary hypoplasia and oligohydramnios was born at 36 weeks gestation. peritoneal dialysis was commenced at day 20 due to anuria from birth. epo was commenced at 6 months of age. both of them required high dose epo to maintain adequate haemoglobin. hepatoblastoma was diagnosed in both of them at 2-3 years, following an incidental finding in abdominal imaging done for different reasons. conclusion: hepatoblastoma has been reported in association with cystic renal dysplasia in 5 children in the literature to date. none of these children had evidence of impaired renal function prior to the diagnosis of hepatoblastoma. in our report both the child were treated with high dose erythropoietin prior to diagnosis of hepatoblastoma. erythropoietin (epo) is the primary regulator of erythropoiesis through specific interaction with its receptor (epo r). epor expression has been demonstrated in common paediatrictumour cells and such expression is reported to promote tumour cell survival through release of angiogenic growth factors. angiogenesis is the primary requirement for tumour growth. epo production has been observed in patients with hepatomas and in the hepg-2 cell line in hepatoblastoma. we report two cases of hepatoblastoma detected incidentally in children with established renal failure and propose a putative role of epo in the development and / or progression of hepatoblastoma in this population. objective: hypercalciuria is the most common metabolic cause of renal stone. long term immobilization is associated with hypercalciuria and bone loss. the effect of short term immobilization on hypercalciuria was the main objective of this study. methods: in a prospective study all orthopedic patients less than 40 years with pelvic fracture who were assigned for immobilization with traction were enrolled in this study. serum (calcium, phosphorous, alkaline phosphatase, sodium, potassium, uric acid, bun, creatinine)and fasting urine calcium, creatinine, sodium, potassium and uric acid were checked within 48hours of hospitalization and also in 1st,2nd and 3rd weeks of immobilization and then after 2to 3months of mobilization. student's t-tests used for statistical analysis. results: fifty five patients 45 male and 10 female with the mean age of 19.4 ± 12.7 years were studied. urine calcium /creatinine (u ca/cr)* ratio before immobilization u ca/cr0 was 0.13±0.06. one, two and 3 weeks following immobilization u ca/cr ratio was 0.17±0.11, 0.22±0.12 and 0.29±0.17respectively.multivariate tests revealed a significant rise in u ca/cr ratio during hospital stay when this value checked before immobilization and throughout immobilization as soon as end of 1st week and following in 2nd and 3rd week ( objective: importance of renal biopsy(rb) in diagnosis and treatment of kidney disease is the same for children as for adults. however there are some differences between institutions in practice of this invasive method. the aim of this study is to identify the current status and complications associated with the renal biopsy of childhood kidney disease. methods: a retrospective study was conducted based on medical records from all patients who had undergone native renal biopsies with 16-gauge needles from april 1997 to november 2012 in our center. we analyzed the number of experiments, sex, age, indication, the types of harvest (percutaneous or open) and anesthesia (general or local), histopathological findings, and complications. results: a total of 158 renal biopsies were performed in 141 patients (82 boys, 59 girls). the mean age at first procedure was 9.4 years. about 70 % of the indications for a biopsy showed moderate proteinuria and hematuria in the annual urinary screening program in japan, and approximately 20 percent of those were refractory childhood nephrotic syndrome. open renal biopsies were practiced in only 3 cases, and the rest of children underwent percutaneous ultrasound-guided kidney biopsies. the most procedures of patients aged 10 or younger were executed under general anesthesia due to the non-cooperation of them. about 30 % of the biopsy-proven kidney diseases showed immunoglobulin a nephropathy, and approximately 20 percent of those were henoch-schonlein purpura nephritis. for the post biopsy complications, 5 out of all performances administered hemostatic agents for moderate hematoma, but none of them required blood transfusion or surgical intervention. conclusion: we suggested that renal biopsy could be supportively performed under local anesthesia in the patients more than the upper grades of elementary school. in addition, 17 patients aged 3 or younger, including 12 months, could undergo the percutaneous ultrasound-guided renal biopsies without procedural and general anesthesia complications. therefore, our results revealed that this procedure was considered safe even in infants. abstract# p-sat084 fifteen years review of indications and results of renal biopsy in children from a single center in egypt there were 20 insufficient biopsies. in pathologically diagnosed 1226 specimens primary glomerulonephritis was the most common finding (n=826, 67.4%) followed by secondary glomerulonephritis (n=238, 19.4%) and end stage renal disease (n=50, 4.1%). the most common causes of primary glomerulonephritis were minimal change disease (n=267, 21.8%), diffuse proliferative glomerulonephritis (n=188, 15.3%), focal proliferative glomerulonephritis (n=164, 13.3%) and focal segmental glomerulosclerosis (n=129, 10.5%). lupus nephritis (n=209, 17%) was the most common cause of secondary glomerulonephritis followed by hemolytic uremic syndrome (n=16, 1.3%) and amyloidosis (n=10, 0.8%). only one mortality has been reported as a complication of renal biopsy (uncontrolled bleeding). conclusion: this study introduces the first biopsy based epidemiological information of pattern of renal diseases in egyptian children from a single tertiary pediatric center in which minimal change disease was the most common histopathological finding and steroid resistant nephrotic syndrome was the most frequent indication for biopsy. results: a total of 112 children were enrolled in the study. most of them (71%) had isolated microhematuria, and were proved mild lesion of glomeruli (60%) by renal biopsy. about 30% of them, however, might have progressive glomerulonephritis, such as iga nephropathy, focal segmental glomerulosclerosis, alport syndrome and so on. these asymptomatic children were found urine abnormalities due to either school urine screening study, health examination, or during diagnosis of non-renal diseases. in center a, iga nephropathy was the most case diagnosed, while in center b and c, minor glomerular abnormalities was the most case diagnosed. the difference among three centers was significant and this variation might be due to different indications of renal biopsy. conclusion: our findings confirm that urinalysis may help early detecting progressive glomerulonephritis in asymptomatic children. children with isolated microhematuria has relatively low risk of severe pathologic lesion of glomeruli, thus isolated microhematuria per se might not be suggested as indication of early renal biopsy. long-term follow-up with appropriate further examination is of great importance for these asymptomatic children. abstract# p-sat089 twenty-three-year review of disease patterns from renal biopsies: an experience from a pediatric renal center there were 59 episode of peritonitis with an incidence of 1 episode per 16.8 patient/months. the commonest organisms isolated were gram negative rods 12(20.3%), followed by staph aureus 11(18.6%). sixteen (27.1%) were culture negative and 3(5.1%) were fungal peritonitis. catheter removal related to peritonitis was performed in 20 patients in whom only one patient returned back to pd. exit site infection (21 episodes) and tunnel infection were reported in 20 and 10 patients respectively. catheter malfunction was the most common non infectious complication seen in 27 (61.3%) children. other noninfectious complications include haemorrahgic effluent 5 (11.3%) children while catheter leak, umbilical hernia and inflow pain where seen in 2 (4.5%) children each. at the end of the study 17 (18.7%) children remained pd active, 26 (28.6%) transferred to hd, 13(14.3%) transplanted, 9(9.9%) suspended from pd, 5(5.5%) lost follow up and 21(23.1%) children died. conclusion: in the setting of our country with limited resources and investment, capd is efficient and successful with complications comparable to most parts of the world. attempts to produce pd fluids locally and to train and educate health care workers will greatly improve the use of pd in developing countries. profile and response to therapy in patients with idiopathic membranous nephropathy from march 2010 to december 2012. renal biopsies were studied for light microscopy, immunofluorescence and electron microscopy. antibodies to the m-type phospholipase a2 receptor (pla2r), bovine serum albumin (bsa), and cationic bsa were measured by western blotting with patient sera (when available) and then detecting for both totaligg as well as specifically for the igg4 subclass. results: 80 renal biopsies were performed during the study period, out of which 11 patients had membranous nephropathy. five were secondary to sle and 6 patients (7.5 %) had idiopathic membranous nephropathy. mean age at presentation was 13.16+/-1.94 years with 50 % having hematuria and 66.6% hypertension at presentation. estimated gfr was 160.57+/-49.33. renal biopsy showed findings consistent with membranous nephropathy on light microscopy with with<5% of the interstitium showing tubular atrophy and interstitial fibrosis. immunofluorescence studies showed granular igg and c3 along the peripheral capillary walls. electron microscopy showed subepithelial deposits, with formation of basement membrane spikes between the deposits. few intramembranous deposits were also present. subendothelial and mesangial deposits were not present. there were no antibodies to bsa or cationic bsa detected in any of the five sera available. one of the five patients had circulating antibodies to pla2r. all patients received prednisolone, angiotensin converting enzyme inhibitors and oral calcium supplements. two patients continued to have nephrotic range proteinuria inspite of prednisolone and were started on cyclosporine. none of the patients developed any complications. conclusion: immunosuppressive therapy is beneficial in children with idiopathic membranous nephropathy. anti-pla2r antibodies can be seen as early as 13 years of age. abstract# p-sat108 hypercalcemic crisis and nephrogenic diabetes insipidus due to vitamin d intoxication methods: twenty-three children (46 kidneys) with first uti with p-fimbriatede.coli were enrolled in the study. children were aged between few months and 10 years. all children were treated with adequate antibiotic therapy. dmsa scintigraphy was performed in a few days after infection and control scintigraphy was performed 5 months to 36 months later. dmsa findings were categorised as normal, generally diminished uptake of activity, focally diminished uptake of activity and clearly pathologic with renal scars. results: the first dmsa scintigraphy immediately after infection was normal in 12 kidneys (26.1%), generally diminished activity was found in 21 kidneys (45.7%) and focally diminished activity in 6 kidneys (13% ). renal scars were present in 7 kidneys (15.2%) . on the control scintigraphy 20 kidneys (43.5%) had normal findings. generally diminished activity were found in 6 kidneys (13%) and focal diminished uptake in 8 kidneys (17.4%). significantly higher number of scars, in 12 kidneys (26.1%), despite of antibiotic treatment were found on the control scintigraphy (p< 0.01). conclusion: dmsa scintigraphy demonstrated that the infection with p-fimbriatede.coli can result in permanent renal damage, which clearly points to uti with p-fimbriatede.coli as a risk factor in renal damage. our results confirm obligatory scintigraphic follow-up of children with positive p-fimbriatede.coli infection. objective: efficacy of mannitol with furosemide was compared with that of albumin with furosemide in the treatment of diuretic resistant oedema in childhood nephrotic syndrome. methods: forty patients fulfilling the criteria for "resistant oedema" in nephrotic syndrome cases were enrolled in this descriptive cross sectional study. resistant oedema was diagnosed based on failure to achieve therapeutic response to diuretics or a weight loss of <1% body weight daily. all nephrotic syndrome patients with severe oedema, age 1 year to 15 years of both sexes were hospitalized and were managed with fluid restriction, no added salt and bed rest. beside these 2 mg/kg/day oral furosemide or combination of furosemide and spironolactone, were given for 3 days to achieve desired diuresis. those patients who did not get response were divided into two groups (group-a, group-b) in consecutive fashion. the group-a study population, was with intravenous mannitol 0.5-1 gm/kg/day in single daily dose over 1-2 hrs followed by intravenous furosemide 1 mg/kg/day for 5 days. the group-b study population was with intravenous albumin, 0.5 -1 gm/ kg /day in single daily dose over 1-2 hrs followed by intravenous furosemide 1 mg/kg/day in every alternate day, total 3 doses. conclusion: this boy presented with rhabdomyolysis, myohemoglobinuria and arf. (similar pr similar presentation can be rarely seen in human being, but often seen in dogs). blood exchange transfusion in time must be necessary for preventing "water fall effect" established, for it can eliminate inflammatory factor and toxic products such as bun, ccr, and creatinasein blood effectively. blood tranfusion in combination with azithromycin and clindamycin must be a good choice replace the "babesia-infected" rbc and eliminate pathogens in blood. beta-2-microglobulinuria in human immunodeficiency virus infected children objective: to determine whether hiv infection in children is associated with increased urinary excretion of β2-microglobulin, which is a marker of tubular defect. methods: a prospective observational study was done of hiv infected children attending outpatient immunology clinics to investigate urinary β2-microglobulin excretion by measuring urine β2-microglobulin to creatinine ratio. in addition serum sodium, potassium, urea, bicarbonate and creatinine levels were documented and urine dipstick test was done to quantify proteinuria. results: thirteen (13) children aged 2 months to 49 months (mean 20+/-4 months) were enrolled. all children had normal estimated glomerular filtration rate. eleven children were on different haart regimes (see table 1), one was receiving nevirapine prophylaxis and one was not on any treatment. the duration of haart use was 1-16 months (mean of 8+/-2 months). seven (7) children were on cotrimoxazole for pneumocystis jiroveci prophylaxis and 4 on anti-tuberculosis drugs, namely rifampicin, ethambutol, isoniazid and pyrazinamide. none received any nephrotoxic drugs. the hiv viral load was >1000 copies/ml in 8 children and <1000 copies/ml in 5 children. of 13 hiv-infected children, 4(31%) had no abnormal urine protein excretion and nine (69%) had elevated urinary levels of β2-microglobulin.of note only 2 (22%) of the 9 children with β2-microglobulinuria had associated proteinuria. ten children ( 76%) had metabolic acidosis with the mean serum bicarbonate (co 2 ) level of 16.9 mmol/l ( range 10-20 mmol/l). conclusion: proteinuria is believed to be the earliest finding for the diagnosis of hiv associated renal diseases. in our study β2microglobulinuria and metabolic acidosis were the prominent findings suggesting that hiv induces tubular dysfunction in children without clinical evidence of renal disease. objective: acute kidney injury (aki) is an important cause of mortality in sub saharan africa because access to renal replacement therapy is limited. there are few reports on haemodialysis in childhood aki in the sub region. we therefore performed a preliminary review of data on children who received intermittent haemodialysis for aki in our centre. method: a retrospective review of case records and haemodialysis registers of children in aki who received haemodialysis in our centre from january 2006 to december 2012. results: 62 children, including a child aged 3years, received haemodialysis for aki over the period but full details were available for 23 children and were further reviewed for this study. there were 13 males (56.5%). the children were aged 5-13 (8.4+/-2.4) years. the primary aetiology of aki was related to intravascular haemolysis (ivh) with massive haemoglobinuria (n=12), septicaemia (n=4), acute glomerulonephritis (n=2), malignancies (n=2), malaria (n=1), hiv (n=1) and haemolyticuraemic syndrome (n=1). the aetiology of ivh was secondary to glucose-6-phosphate dehydrogenase (g6pd) deficiency in 4 patients, autoimmune haemolyticanaemia in 1 and was unknown in the others. one of the patients with ivh secondary to g6pd deficiency also had malaria. the number of sessions of dialysis ranged from 1 to 5 sessions per patient with a modal value of 2 objectives, methods and results: a twelve-day old, formula-fed, full term neonate with unremarkable perinatal history was admitted for poor oral feeding and significant (12%) weight loss. physical examination was otherwise unremarkable. investigation showed normal anion gap metabolic acidosis, hyperkalemia (6.5mmol/l), hyperurecemia (14.5mmol/l) but normal creatinine (28umol/l). metabolic screen and other investigation was unremarkable. on further questioning parents has been feeding baby with goat milkbased formula since day 5. baby was switched back to normal cow milk-based formula with prompt resolution of metabolic disturbance and without recurrence of acidosis on follow-up. conclusions: goat milk is becoming increasing popular to parents because of the myths associated (organic, easier digested, hypoallergenic, better nutrient content etc). however there is good evidence suggesting against these misbelief and there are even reported morbidities associated with ingestion of goat milkbased formula. with increasing appealing but not necessarily accurate information available on the internet, what the public need is education. objective: there have been great inroads made in controlling the scourge of hiv in south africa. the national pmtct program has reduced the mtct rate to 3.5% and children infected prior to these interventions are now on effective treatment programs. these children are now surviving longer and so we are seeing increased numbers of hiv related renal pathology presenting to our clinics. before the widespread availability of arv's in south africa these children would have been denied access to our program but now we are able to offer them crrtand a transplant. the biggest challenge facing our program is one of the social disintergration of much of our indigent population. the vast majority of our patients come from social backgrounds that are incompatible with adhering to the rigours of a chronic renal program. this is compounded when the care givers are themselves ill or when the child has a second serious illness such as hiv to deal with. methods: we would like to present our experience with admitting 8 hiv positive children with ckd5 to our chronic program and will highlight the challenges that face these families and their health care providers. we will describe the social issues affecting each family and how they impact on the child's care. results: all 8 families had serious social issues on top of having to deal with their hiv disease. all 8 families had extreme difficulties in adhering to our program. 2/7 died as a result of non adherence and of the remaining 5 children only 1 is really coping well with the program. 3/7 children have no living parents and 1 is foster care. the rest are either with a single parent or with a family relative. conclusion: the huge difficulties facing these patients is forcing us to rethink the criteria that should be applied to admitting these patients to our program. restricting the program to children with these problem seems cruel and we feel that all options should be considered before denying these children access to life saving care. abstract# most of the patients presented during autumn and winter. the incidence of apsgn has decreased in the past 11 years in shenyang, but the proportion of the patients with acute kidney injury (aki) or nephroticrange proteinuria was increased. the proportion of children with macroscopic hematuria remained almost the same during these years. macroscopic hematuria resolved in 2-3 weeks and non-nephroticproteinuria resolved in 1-3 weeks. the treatment of apsgn patients with nephrotic-proteinuria was the same with the children with primary nephrotic syndrome and prednisone was withdrawn in 3-4 months. some aki patients have been followed up for 5 years and no patients with chronic renal failure. all patients with microscopic hematuria at onset and 30% patients with microscopic hematuria after 2 years. conclusion: the incidence of apsgn was decreased during recent years. the proportion of apsgn patients with aki or nephrotic-range proteinuria was increased. the short-term prognosis of apsgn was good and minority of the patients persisted with microscopic hematuria. abstract# p-sat122 analysis of clinical manifestations and prognosis in 43 children of acute poststreptococcal glomerulonephritis objective: crescentic glomerulonephritis (gn) is characterized by severe infiltration of massive inflammatory cells into glomeruli and crescent formation. although renin angiotensin system (ras) is the key player in renal injury, the impact of direct renin inhibitor on glomerular crescent formation is not elucidated yet. methods: to examine whether direct renin inhibitor ameliorate renal injury in crescentic gn, we investigated renal injury induced by antiglomerular basement membrane (gbm) antibodies in wistar kyoto rats treated with direct renin inhibitor, aliskiren. in addition, using cultured glomerular mesangial cell (mcs) and parietal epithelial cell (pecs), we examined whether recombinant renin could induce monocyte chemoattractant protein-1 (mcp-1) expression and cell proliferation, respectively. results: an anti-gbm nephritis model developed progressive proteinuria and glomerular crescent formation, accompanied by increased expression of mcp-1 and (pro)renin receptor. interestingly, (pro)renin receptor expressed strongly in the crescent formation area in diseased glomeruli. proteinuria was significantly reduced by the treatment of aliskiren. then, aliskiren markedly ameliorated renal injury (% glomerular crescent: 26.0 +/− 1.7 %) compared to vehicle treatment (59.6 +/− 3.6 %). excretion of urinary protein in a group of rats treated with aliskiren were significantly reduced compared to vehicle-treated rats. aliskiren treatment markedly decreased mcp-1 and (pro)renin receptor mrna levels in the diseased kidney. next, primary cultured mcs stimulated by recombinant renin showed significant increases of mcp-1 mrna expression. furthermore, primary cultured pecs showed an increase in recombinant renininduced cell proliferation. conclusion: these data suggest that therapeutic strategy of direct renin inhibitor may prove beneficial for crescentic gn by the suppression of the ras activation and the decrease of inflammation and cell proliferation in glomerular crescent via (pro)renin receptor. an update on management of acute glomerulonephritis in children objective: to analyze the clinical effects, safety, and significance of leflunomide combined with hormone in the treatment of children with refractory nephrotic syndrome. methods: collected 60 cases patients in our hospital in children with refractory nephroticsyndrome,and randomly divided into 30 cases of the control group and treatment group. control group was treated with mycophenolatemofetil (mmf)andhormone,the treatment group was treated with leflunomide (let) and hormone.measured and compared the changes before and after treatment of 24h urinary protein excretion,tc,alt,cr,bun clinical efficacy and complications. results: the two groups after 6 months of treatment, 24 h urinary protein, plasma albumin, total serum cholesterol, serum creatinine and blood urea nitrogen and other indicators were significantly better than before treatment and has a statistically significant (p <0.05); the overall response rate in the control group and treatment group were 83.33% and 86.67%. conclusion: the application of leflunomide combined with hormone treatment of children with refractory nephrotic syndrome can make the disease to be effectively alleviated, the clinical results were satisfactory, safe, and fewer complications, it is worthy of promotion. objective: post-streptococcal acute glomerulonephritis (psagn) is a familiar disease in children. misdiagnosis might occur when it is presented with atypical symptoms. here we report a 12-year-old girl presented with acute heart failure which was finally diagnosed comorbidity of psagn and graves' disease. methods: retrospectively review the history of the patient. the girl was admitted to our hospital with cough, shortness of breath and chest tightness, without any other obvious symptoms and history of illness. the examination of cardiac color ultrasound showed mitral insufficiency with severe mitral regurgitation and heart enlargement. other examinations also found she had hypertention, mild anomalies of urinalysis, hypocomplementemia, hypoalbuminemia, hyperthyroidism and elevated antistreptolysin o. first we diagnosed her illness as rheumatic disease. after two weeks treatment with rest, fluid and sodium restriction, controlling blood pression, diuresis and methimazole, the girl recovered very well. she had no any symptom with normal urinalysis and blood pressure, the result of reexamination of cardiac color ultrasound was normal, her hypocomplementemia and hyperthyroidism were improved significantly. finally she was diagnosed as co-morbidity of psagn and graves' disease. conclusion: psagn with atypical symptoms at presentation should be paid more attention, especially when it is also has co-morbidity. abstract# p-sat128 report of a child with idiopathic cryoglobulinemia idiopathic cryoglobulinemia is rare to see in child. here we report a child with typical manifestations of cryoglobulinemia. the subjected child was male, 6 years and 4 months, he had repeated rashes, itching, desquamation on his fingertips for more than two years, accompanied with recurrent miliary reddish rashes on the trunk and limbs for more than one year, transient arthralgia for 2 weeks, and edema and oliguria for 10 days before he was admitted to our hospital. he was treated as atopic dermatitis all the time. but the rashes were recurrent. erythema could be seen after desquamation. 2 weeks before admission, he had arthralgia on the right knee, 2 days later on left knee without swelling, both were retrieved spontaneously. x-ray of the knees revealed no abnormal. ten days before admission, edema and decreased urine output was notice without gross hematuria. physical examination in local hospital revealed blood pressure 140/108 mmhg, needlelike erythematous maculopapules in his hands and feet. urine test revealed protein 5g/l, rbc 164/ul, no casts. serum bun was 32.41mmol/l, cr 116umol/l, tco2 11mmol/l, c3 0.47g/l. he was sent to another hospital 2 days later. there, prednisone 25mg per day was given. as a result, the urine output increased gradually, but serum bun and cr remained high, so he was referred to our hospital. renal biopsy indicated membrane proliferation glomerular nephritis with abundant microthrombus. the diagnosis of cryoglobulinemia was suggested. after that serum cryoglobulin and serum protein electrophoresis were tested 18 days after prednisone was given, both were normal. etiological examinations, included hepatitis virus a, b, c, d, e, g were all negative; antibodies of hiv, syphilis, toxo, cmv, rvb, rsv, hsv, eb, adv, and rickett's organism were all negative, mp-igm 1:40. antinuclear antibodies of sle, anca and antiphospholipid antibodies were all negative. so idiopathic cyoglobulinemia was more favored. the treatment of prednisone 25mg per day was continued after admission. he restored gradually. prednisone was taped down gradually. now prednisone has been stopped for more than one month, he seems well during that period of time. methods: children with hsp over 3 years of age were enrolled in the study. they were evaluated for demographic, anthropometric, clinical and laboratory data including urinalysis, complete blood count, serum albumin, creatinine, iga levels. in addition, anti-tissue transglutaminase iga (elisa), anti-endomysium iga (ifat), antigliadin (gaf3x, deaminated) iga (ifat) and anti-gliadin (gaf3x, deaminated) igg (elisa) antibody levels were determined. seropositive patients were evaluated by endoscopic small bowel biopsy. the rate of cd seropositivity in hsp patients was compared to the rate in healthy turksih children by the test for the statistical significance of two percentages. results: celiac serology was evaluated in 42 children (25 male, mean age 11.2 +/-3.6 years) with hsp. there was no patient with growth failure or having symptoms associated with cd like abdominal pain, abdominal distention or diarrhea. in addition, none of the patients had iga deficiency, anemia or hypoalbuminemia. celiac serology was positive in 5 (12%) children. endoscopic evaluation was performed in 3 patients and one of them was diagnosed as cd. prevalence of cd in children with hsp was significantly higher compared to healthy turkish children (p<0.001). conclusions: celiac seropositivity was 12% in children with hsp and this rate is significantly higher than the rate in healthy children. although the number of children with hsp is small in this preliminary study, this result suggests that celiac screening may be considered in children with hsp. (14) groups. the glomerular and tubulointerstitial lesions were scored by katafuchi criteria and oxford classification of igan,respectively. results:1.the baseline data of different clincal or pathological groups were no significant differences (p more than 0.05),but 24h protienuria were significant increased in grade 3 and 4 groups than grade 2 group(p less than 0.05).2.according katafuchi critiria,the severity scores of glomerullar and tubulointerstitial lesions were positively correlated with either different clincal or pathological groups(p less than 0.01).3.according to oxford classification, only the severity scores of mesangial hypercellularity and segmental glomerulosclerosis/adhension were positively correlated with different clinical groups(p less than 0.01),but the severity of mesangial hypercellularity, endocapilarity hypercellularity, segmental glomerulosclerosis/adhension,tubular atrophy/interstitial fibrosis and cellular/fibrocellular crecents were all positively correlated with different pathological groups (p less than 0.01). [1990] [1991] [1992] [1993] [1994] [1995] [1996] [1997] [1998] [1999] [2000] [2001] [2002] [2003] [2004] [2005] [2006] [2007] [2008] [2009] were evaluated retrospectively. patients were analyzed comparing those hospitalized during the first and the second ten-year period.the long-term prognosis was evaluated in 60/64 patients (94%) with hsp nephritis followed-up for 1 to 11 years (mean 5.7±3.6 years) based on urine analyses, serum creatinine and blood pressure measurements. results: of 156 patients (mean age 6.9±3.5 years, range 1-17 years, m: f ratio 1.0) with palpable purpura (100%), other symptoms were more common during the first ten-year period including arthralgias (62% vs. 52%, p=0.282), gastrointestinal symptoms (63% vs. 44 %, p=0,018) and renal involvement (55% vs. 21%, p=0.001). among 64 patients (41%) with hsp nephritis, 42 had isolated hematuria and/or non-nephrotic range proteinuria (66%), 15 nephritic syndrome (23%) and 6 nephritic/nephrotic syndrome (10%). hematuria and/or nonnephritic proteinuria was less common (p=0.0005) in the second tenyear period while the incidence of nephritic/nephrotic syndrome was insignificant (p=0.807). recurrences of purpura had 11 patients within 2 years. 6 patients had renal biopsy including one with 30% of crescents and one another with iga nephropathy diagnosed seven years after initial presentation of hsp. long-term prognosis was favourable in most patients with abnormal urine analyses in 12 (20%), in one with hypertension but normal serum creatinine and in all with nephritic/nephrotic syndrome at disease onset. conclusion: clinical evaluation of patients with hsp nephritis treated at our institution showed a good long-term prognosis. urine and blood pressure abnormalities in followed-up patients were associated with nephritis at disease onset. -up (f-up) . egfr was estimated using schwartz formula; decline in renal function was defined as the slope of egfr over the f-up. results: 72% were males, with mean age at renal biopsy of 12.7 ± 3.7 y and a median f-up of 4.7 y (iq range 2.4-7.8 y); more than 80% presented with egfr > 90 ml/min/1.73m 2 . end-stage renal disesase (esrd) was reached by 4% of children, 50% loss of initial egfr by 5%; 7% reached the combined end point (esrd or 50% loss of initial egfr). at renal biopsy 57% presented with mesangial proliferation (m1), 24% with endocapillary proliferation (e1), 35% with segmental glomerulosclerosis (s1) and 9% with tubular atrophy/interstitial fibrosis (ta/if; t1/2). patients with segmental sclerosis and ta/if showed a significantly worse egfr slope over the f-up (s0 vs s1 p=0.04; t0 vs t1/2 p=0.003). at univariate linear regression, clinical data at renal biopsy (egfr, proteinuria and map) were not associated with renal function decline, while data at 6-12 and 12-24 months and ta-proteinuria and map significantly predicted egfr slope.a multivariate linear regression model (including proteinuria and map at 12-24 months together with the difference of egfr at renal biopsy and at 12-24 months as independent variables) performed well in predicting egfr slope (r 2 =0.39). this model was used to derive a formula able to estimate egfr slope with good performance (mean bias between estimated and really observed egfr slope of 0.05 ± 6.6 ml/min/1.73m 2 ). conclusion: the oxford classification of igan was well applicable to this pediatric population. a formula was developed that estimates renal function decline over the f-up based on proteinuria, map and egfr loss after 1-2 years of observation, which will need a validation on other cohorts. sixteen-year experience with pediatric iga nephropathy and validation of the oxford classification as a risk predictor (m1), segmental sclerosis (s1), endocapillary proliferation (e1), and tubulointerstitial fibrosis (t1 or t2) was 32 (35.2%), 15 (16.5%), 9 (9.9%), and 6 (6.6%), respectively. there was no significant decrease in gfr within the entire cohort. however, five patients showed decreased renal function, and of them, two reached stage iii or iv ckd. the five patients' changes in the k/doqi ckd stage were 2 to 4, 1 to 3, 1 to 2, 1 to 2, and 1 to 2. their pathological classifications were haas 4/m1 s1 e0 t0, haas 4/m1 s0 e1 t1 with global sclerosis, haas 1/m0 s1 e0 t0, haas 1/m0 s0 e0 t0, and haas 1/m0 s0 e0 t0 with global sclerosis. in the oxford classification, global sclerosis was the only factor correlated with decreased renal function, whereas the haas classification showed no significant correlation with renal function. conclusions: global sclerosis was correlated with decreased renal function. however, in our cohort, there was no significant decrease in renal function during the follow-up period (p = 0.216). thus, we could not clearly correlate the haas and oxford classifications with renal outcome. the value of the oxford classification as a predictor of renal outcome remains unclear in korean children with iga nephropathy. meng-jie jiang, xiao-yun jiang, ying mo, li-zhi chen, li-ping rong pediatric, the first affiliated hospital of sun yat-sen university, guangzhou, china objective: to analyze the clinicopathological characteristics of primary immunoglobulin a nephropathy (igan) manifested as macroscopic hematuria in children. the clinicopathological characteristics of 48 cases with primary igan manifested as macroscopic hematuria were analyzed retrospectively. according to the lasting time of macroscopic hematuria, 15 cases were assigned to group a (no more than seven days) and 33 cases were assigned to group b (more than seven days). results: the manifestations comprised: acute glomerulonephritis (40% in group a, 33.3% in group b), nephrotic syndrome (20% in group a, 15.1% in group b), hematuria and proteinuria (6.7% in group a, 12.1% in group b) and isolated hematuria (33.3% in group a, 39.4% in group b). 20.0% cases in group a and 21.2% cases in group b were accompanied with abnormal renal function. there was no significant difference between group a and b (p>0.05). the urinary lysozyme or β2-mg increased (6.7% in group a, 30.3% in group b). in group a, subclass ii was the most common histopathological type (53.3%), followed by iii (33.3%) and i (13.3%) while the predominant histopathological types in group b were subclass iii (45.5%), iv (27.3%), ii (21.2%) and i (6.1%). none in group a and 15.2% cases in group b showed crescent. besides, only one glomerulosclerosis was in group a while 8 (24.2%) cases of glomerulosclerosis were in group b. the difference between group a and group b was statistically significant (p<0.05).no differences were found in balloon stenosis between group a (6.7%) and group b (12.1%), as well as the renal tubular and interstitial damage (33.3% in group a, 39.4% in group b). 46.7% cases in group a and 60.1% cases in group b were found with simple iga deposition in mesangial area. there was no significant difference between group a and group b (p>0.05). the children with primary igan manifested as macroscopic hematuria lasting for more than seven days are easily appearing renal tubular damage, crescent formation and glomerulosclerosis. subclass iii and iv are the most common histopathological types. a case report of iga nephropathy accompanying crohn's disease akihiko shirasu 1 , akira ashida 2 , hideki matsumura 2 , hyogo nakakura 2 , tomoki aomatsu 2 , atsushi yoden 2 , motoshi hattori 3 , hiroshi tamai 2 , 1 pediatrics, hirakata city hospital, hirakata, japan 2 pediatrics, osaka medical college, takatsuki, japan 3 pediatric nephrology, tokyo wemen's medical university, tokyo, japan there have been several reports of iga nephropathy accompanying crohn's disease in which the clinical course of the two diseases was linked. we recently experienced a case of iga nephropathy with deterioration of renal function complicated by crohn's disease. a 15year-old boy diagnosed as having crohn's disease underwent total colectomy at the age of 7 years. the patient was referred to pediatric gastroenterology unit at the age of 13, and thereafter maintained a state of remission form crohn's disease while receiving 5-aminosalicylic acid (5-asa). two months prior to referral to our pediatric nephrology unit, when the patient was 15 years old, a school health examination had revealed microscopic hematuria and mild proteinuria. at that time, laboratory tests suggested deterioration of renal function. renal biopsy was performed and histological examination by light microscopy demonstrated focal segmental mesangial proliferation and moderate tubule atrophy with a diffuse interstitial inflammatory infiltrate consisting predominantly of lymphocytes. immunofluorescence assays revealed 2+ diffuse granular staining for iga and 1+ staining for c3 in the mesangium. therefore, the patient was diagnosed as having iga nephropathy and chronic interstitial nephritis. the 5-asa therapy was stopped considering the possibility that it had induced interstitial nephritis. the renal function of the patient has since remained quiescent for 7 months. patients with crohn's disease who present with abnormal urinalysis findings commonly have urological complications, such as urolithiasis and urinary tract infections. however, the possibility of renal parenchymal disease including iga nephropathy should also be considered, even if there is no apparent aggregative linkage of urinalysis findings with gastrointestinal symptoms of crohn's disease. the duration of heavy proteinuria determined long-term outcome of henoch-schönlein purpura nephritis in children results: among the 9 patients, 7 (77.78%) cases presented with hematuria and nephrotic syndrome (ns); 1 (11.11%) with hematuria and nephrotic range proteinuria (>50mg/kg/24h); 1 (11.11%) with hematuria and moderate proteinuria (25~50mg/kg/24h). the typical pathological features, such as the diffuse glomerular mesangial and endocapillary proliferation, mesangial interposition, and double contour formation, were shown in all specimens. moreover, the podocyte hypertrophy, shedding, and cytoplasmic absorption dropletswere also observed in most specimens under light microscopy. the percentage of small cellular crescents varied from 4.25-25%. 9 patients were followed up for 2 to 4 years, and all had recovered. conclusion: the predominant clinical manifestation of iskdc grade vi hspn in children was ns accompanying with hematuria. the well outcome might be associated with the prompt use of steroids and/or immunosuppressive drugs at the onset of iskdc grade vi hspn with very mild glomerulosclerosis and tubulointerstitial lesion. in our future study, all patients should be followed for five or ten years, and more specimens should be observed under electron microscope to investigate whether the podocyte lesions of iskdc grade vihspn should be taken into account in the clinical pathological report and a future new histologic classification of hspn. objective: the aim of the study was to assess efficacy of immunosuppressive treatment in children with iga nephropathy (igan) and henoch-schoenlein nephritis (hsn) based on clinical manifestation and histopathological oxford (o-c) and who (who-c) classifications. the study group consisted of 18 children with igan-9 and hsn -9, (mean age 10.44 ±3.94 years) , treated with azathioprine (aza) 2 mg/kg/day -12 months with prednison (pred) 2mg/kg/day (nephrotic syndrome-ns), 1mg/kg/day (nephritic syndrome -nps) 8 weeks, gradually diminished within 15 months. it recognize clinical remission at normal renal function and absence of proteinuria at the end of treatment. in all patients we estimated: proteinuria, gfrs (calculated using schwartz's formula) at the onset of study and after 15 months. they had performed renal biopsy on average 0.69 ± 0.95 years after the onset of illness and at the end of treatment. we were analyzed the histopathologic evaluation of renal biopsy specimens using the who-c (grade i-v) and oxford classification : (mmesangial hypercellularity, e-endocapillary hypercellularity, ssegmental sclerosis, t-tubular atrophy/interstitial fibrosis; absent =0, present=1). results: in patients with igan we observed: ns-1, nps-8; with hsn : ns-7, nps-2. after the treatment aza/pred we noted clinical remission in all children with igan and 89% with hsn. gfr was normal before and after treatment. at the onset of illness igan patients had: grade iii-6, grade iv-3 according to who-c; hsn had: grade ii -2, grade iii-6, grade iv -1; at the end of therapy we observed positive effect in who-c only in 2 (22%) igan patients and in 5 (56%) hsn , without progression properly 6 (67%) and 4 (44%). in o-c of igan patients we observed nobody with total regression of changes, only 3 children had m0 or e0 or s0 after treatment. in patients with hsn we noted total regression of changes in 4 (44%), in other 3-m0 or e0 or t0. conclusion: aza/pred therapy used in children with igan and hsn can make clinical remission in both groups, but histopathological regression-more frequent in hsn. oxford and who classifications are very useful for estimation of efficiency of treatment. 10-year follow-up of pediatric hennoch schönlein purpura with renal involvement elena tudorache 1 , christine azema 1 , stéphane decramer 2 , georges deschênes 3 , tim ulinski 1 1 pediatric nephrology, armand trousseau hospital, paris, france 2 pediatric nephrology, chu toulouse, toulouse, france 3 pediatric nephrology, robert debré hospital, paris, france objective: the aim of this study was to determine the long-term outcome in children with hsp nephritis who underwent a renal biopsy and to identify possible correlation between disease parameters and treatment. we included retrospectively all patients with renal biopsy proven iga nephropathy related to hsp of three pediatric nephrology centres over a 10-year period. results: 142 patients were included. nephrotic range proteinuria was present in 28% with grade ii, 60% with grade iii and 90% with grade iv lesions. renal function was impaired in 14%. significant proteinuria >500 mg/l was found in 9/48 patients 3 years post renal biopsy, in 8/25 patients at 5 years and in 3/14 patients at 10 years. there was no correlation between risk for proteinuria at 3, 5, or 10 years with initial histological lesions. there was a tendency to higher residual proteinuria in patients with nephrotic proteinuria at disease onset and also for patients who were not treated with steroid pulses at disease onset with 310 vs. 175 mg/l (p=0.06) at three months, 100 vs. 50 mg/l (p=0.93) at one year, 720 vs. 150 mg/l (p=0.1) at five years, and 520 vs. 355 mg/l (p=0.35) at ten years. there was a tendency to less proteinuria in the long term for those with early steroid pulses (<15 days vs. >16 days after proteinuria onset (p=0.16).in patients with acei/arb treatment within 15 days after renal disease onset, compared to those who were treated later (>one month), proteinuria was significantly lower at 6 (p=0.02) and 12 months (p=0.03). among 18 control kidney biopsies, 50% show fibrosis of different degree unrelated to initial histology. conclusion: there is a risk to underestimate long term disease severity in patients with low iskdc classes. there is need for prospective long term studies to explore the benefit of early acei/arb and/or steroid pulses. abstract# p-sat147 good outcome of biopsy-proven henoch-schonlein purpura nephritis in children in shanghai single center objective: severe hsp nephritis considered a risk factor for chronic kidneys disease development especially in patients with nephrotic syndrome (ns). methods: we present our experience with tacrolimus (tac) as a steroid sparing agent for a treatment of severe hsp nephritis in 17 years boy. our patient has been observing at the republic center of pediatric nephrology minsk for 5 years. he presented with a typical purpuric rash with recurrences after infections. one year later during acute pneumonia macrohematuria, proteinuria (1-1.5 g/24h) occured and ace inhibitors (iace) were prescribed. despite this, boy developed nephrotic range proteinuria (3.8-7.7 g/24h), biochemical protein 52g/l, albumin 27g/l, cholesterin 6,5mmol/l. renal biopsie showed mesangial proliferation with iga deposits. prednisolon (pred) 80mg/daily with heparin failed to decrease proteinuria and activity. cyclosporin a 200 mg/daily plus pred on alternate day were started and followed during 8 months with positive dynamic (proteinuria 1,7g/24h, decreased clinical and laboratory activity) after which pathogenic treatment was stopped. arterial hypertension (ag) was treated by iace. 6 months later proteinuria (3.5g/24h) and activity increased again. with the presence of ns resistance to steroids combined with hematuria and ag, medrol (64mg/daily) plus tac 1 mg twice daily were prescribed. duration of tac therapy was 5 months. tac was succesfully withdrawn with no rebound disease activity observed (during 9 months). at present the patient receiving iace only. our results indicate that tac may be a promissing steroid sparing agent for treatment of severe hsp nephritis. anti-proteinuric effect of cyclosporine a treatment for iga deposit diseases objective: to evaluate the therapeutic effect of cyclosporine a (csa) on nephrotic-range proteinuria in children with immunoglobulin a (iga) deposit diseases in mesangium such as iga nephropathy (igan) and henoch-schonlein purpura nephritis (hspn). methods: fifty four children (36 children with igan, 18 children with hspn) who were diagnosed with iga deposit diseases in mesangium at renal biopsy were analyzed retrospectively. all the patients developed nephrotic-range proteinuria (> 40 mg/m2/day) for more than 3 months. the starting dose of csa was 5 mg/kg per day that was given in two divided doses, and the drug level was maintained between 100 and 200 ng/ml. the degree of proteinuria was measured before and after csa treatment. steroids were tapered off and stopped gradually after initiation of csa. results: mean duration of csa treatment was 10.7 +/-5.6 months (range 1.4 -32.7 months). mean follow-up duration was 3.7 +/-3.1 yr (range 0.7 -15.2 yr) from the beginning of csa treatment. the mean ratios of protein to creatinine decreased from 3.7 +/-1.5 to 0.6 +/-0.4 after csa treatment for 12 months. thirty-two (59.2%) patients achieved complete remission. renal function was preserved in all patients 12 months after csa treatment. there were no severe complications in patients with csa treatment. conclusion: our findings indicate that csa is an effective agent to treat nephrotic-range proteinuria of iga deposition glomerular diseases such as igan and hspn and the duration of csa treatment should be at least more than 3 months for efficacy. objective: to observe the therapeutic effects of hemoperfusion combined with corticosteroid in treating children with henoch-schonlein purpura. methods: a total of 180 patients (101 inthe hemoperfusion group (hp) and79 inthe control group) were included and followed up for 12 months. both groups were treated with corticosteroids and other supportive therapy. patients in the hp group received 2 hours of hemoperfusion each day for 3 consecutive days. clinical features at the acute phase, relapses in a year and renal involvement at 1, 3, 6, 12 months were compared. the blood levels of iga and such cytokines as, tnf-alpha-il-1, il-6, ltb4 were measured by elisa technique before and 1, 2, 3 days after hemoperfusion. results: hemoperfusion significantly reduced the severity and duration of abdominal and joint pains. for patients with renal involvement at acute phase the hp group had quicker relief than the control (log rank p=0.000). for patients without renal involvement at acute phase the hp group had less occurrences of renal involvement compared with the control during follow-ups(log rank p=0.001). the rash was also alleviated after hemoperfusion though the difference was not significant. patients' levels of iga were elevated compared with the healthy control before treatment ( day0) patients'levels of cytokines also significantly increased compared with the healthy control on day0, they began to decrease 1 day after hemoperfusion and there were significant differences among those groups. less relapses were seen in the hp group compared with the control (p=0.011). conclusion: hemoperfusion combined with corticosteroid was more effective than corticosteroid alone in improving extrarenal symptoms, alleviating and preventing renal involvement. the effects may be achieved by iga and cytokine reduction after hemoperfusion. the treatment of henoch-schonlein purpura nephritis in children combined with mycophenolate mofetil and corticosteroid nephritic syndrome type, 13 cases(39.4%). about histological degrees, 32 cases were in grade 3 (mesangial proliferation, all accompanied by <50% crescent formation), 1 case was in grade 5 (moderate to severe mesangial proliferation, accompanied by 88% crescent formation). treated with new therapy, 30 cases were complete remission (91%), 2 cases were improved, and one died. the complete remission rate of this therapy was significantly higher than that of the past treatment. objective: steroid pulse therapy (spt) has been reported to be effective for improving urinary abnormalities and preventing renal deterioration in patients with iga nephropathy. however, some patients are refractory to spt or have relapse after spt, resulting in renal impairment. the efficacy of tonsillectomy combined with spt has been discussed. the aim of our study is to evaluate the efficacy of tonsillectomy combined with spt in childhood iga nephropathy. methods: 30 children, aged 3 to 14 years, who had been followed up for more than 3 years after the first biopsy between 2001 and 2009, were enrolled in this study. all patients received spt (methylprednisolone, 20~30 mg/kg intravenously 3 times per week for consecutive 3 weeks). 8 patients received tonsillectomy combined with spt (group a), and 22 patients received spt alone (group b). tonsillectomy was performed one month before or after spt. the therapy was followed by oral prednisolone and tapered off for 12 to 24 months, with warfarin, dipyridamole and ras inhibitor. all of 30 patients underwent repeat biopsy. clinical features and pathological findings were retrospectively analyzed. results: the disappearance rate of proteinuria was 87.5% for group a vs 100% for group b at 1 year, and that of hematuria was 100% vs 72.7% at 2 years. for group a, all the cases which of urinary abnormalities had improved by the treatment could maintain remission, but for group b, 27.3% of the cases had recurrence of proteinuria and 18.2% had recurrence or did not achieve disappearance of hematuria at the last observation. histlogically, the percentage of glomeruli that showed crescents was significantly reduced in both groups. but the cases which still showed crescent formation at the second biopsy were 0% for group a vs 22.7% for group b. conclusion: the differences of recurrence rate for urinary abnormalities after the treatment and disappearance rate of crescents at second biopsy may suggest that tonsillectomy can improve the long-term prognosis. objective: to observe the efficacy and security of tripterygium wilfordii polyglycosidium (twp) in treating children with severe henoch-schonlein purpura nephritis (hspn). methods: 25 children failed to intravenous pulse methylprednisolone for 6 days for their severe hspn entered our study and were given oral twp for 3-6 month. we evaluated the efficacy and security of twp through examinations of urinalysis, blood routine, function of liver and renal, myocardial enzyme series, level of sex hormone and electrocardiogram (ecg) before treatment, 1-2 month after giving twf and 4 weeks after stopping medication respectively. results: proteinuria disappeared in all patients. the remission time was 4 weeks in 22 children, 12 weeks in 2, 15 weeks in 1 respectively. during treatment, elevated glutamic-pyruvic transaminase and glutamic-oxaloacetic occurred in 2 patients and returned to normal after stopping medication. abnormal findings in examination of ecg were observed in 2 patients, one with left ventricular high voltage, another with knot parallel rhythm of the heart. after stopping medication, one patient still had t wave change in ecg. we didn't find any abnormalities of blood routine, renal function and level of sex hormone. conclusion: the twp has good efficacy and security on the treating children with severe hspn. the efficacy and side effects of glucocorticoids in treating children with henoch-schonlein purpura kai-yun liu, ling lu pediatrics, irst affiliated hospital of anhui medical university, anhui, china objective: to observe the efficacy and safety of glucocorticoid in the treatment of children with henoch-schonlein purpura. methods: 50 patients with hsp were divided into mild and severe group according to clinical manifestations. 30 children in mild group were given hydrocortisone sodium succinate (hcss) therapy. 20 children in severe group were given methylprednisolone ( mp ) therapy. a follow-up record system was set up for every patient. we observed the recovery time of clinical symptoms and side effects of glucocorticoid. results: symptoms of skin rashes, joint and gastrointestinal in all children were disappeared within 3 months of treatment. the urinalysis in 13 of 14 patients with renal involvement returned to normal in 4 weeks. the other patient failed to mp therapy was given oral tripterygium and got normal urinalysis in 8 weeks after disease onset. the body mass index (bmi) values in all children after glucocorticoid treatment were significantly higher than before treatment. after stopping medication, there was no significant difference in bmi value compared with before treatment and between two groups. during the treatment, 1 patient in each group had ecg abnormal, and their ecg returned to normal after stopping drug. we didn't find any abnormalities of blood routine, renal function and level of sex hormone. objective: to investigate the role of th17/treg imbalance in the pathogenesis of childhood henoch-schonlein purpura(hsp). and further explore the immunomodulatory affects of compound/lycyrrhizin(gl) on the th17/treg deviation in hsp. methods: 31 hsp patients were chose as gl-treated group, another 5 patients were used as conventional therapy group. besides (0.5-2)ml/kg/l was enjected in l-treated group, other treatments were same, any steroid or immunosuppressants treatment was prohibited. 15 age and sex-matched healthy children were used as healthy controls. blood samples of patients were obtained at the acute stage and after 5 days treatment. using intracellular staining, the frequency of peripheral cd3+cd8-il17+(th17) and cd4+cd25+foxp3+ treg cells was detected by flow cytometry all patients received methyl-prednisone pulses iv (1 g/1.73 m2 for 3 consecutives days) and subsequently oral prednisone with gradual withdrawal in six months, and mmf at dose of 10-20 mg/kg/12 h for 24 months. results: after six months of therapy all patients but one had persistent microscopic hematuria (me), only 3/11 patients had recurrent ma. patients with grade ii hspn showed significant reduction or normal proteinuria. only 3/11 patients with grade iii hspn had proteinuria still >1gr/24 h, 4/11 patients had proteinuria <1g/24 h, in 4/11 proteinuria was normal. mean period of follow-up was 3 years. after one year, only 1 patient had recurrent ma, 10 patients showed persistent me. two patients with persistent proteinuria >1 g/24 h showed a significant reduction (< 1g/24 h in 2 pts, normal in 1 pt). proteinuria did not reappear in all patients.the effect persisted after 2 years and after therapy withdrawal. no side effects was recorded. conclusion: our experience shows the efficacy and safety of mmf in hspn and has to be confirmed by larger controlled studies. the analysis of blood perfusion therapeutic effect on 45 cases of allergic purpura cheng guo-qiang xi 'an children's hospital urology department, xi'an, shanxi, china objective: to observe the auxiliary therapeutic effect on severe allergic purpura. methods: 45 children with severe allergic purpura were randomly divided into the control group (19 cases) and the treatment group (26 cases). the children of control group were treated with conventional therapy (anti-inflammatory, anti-allergic, anticoagulation and symptomatic treatment). the children of treatment group were treated with conventional therapy and blood perfusion. two groups of patients were both treated for 14 days, and were followed up for 9 months. the amelioration time and the regression time of clinical symptoms such as abdominal pain, bloody stool, rash, joint symptoms, visible hematuria and proteinuria, was compared in two groups before and after the treatment. the amelioration time of the clinical symptoms of children in the treatment group, such as acute abdominal pain, bloody stool, rash, joint symptoms, abdominal pain and bloody stool, visible hematuria, proteinuria, and other clinical symptoms, was shorter than the time in the control group (p < 0.05), and the late symptoms such as joint symptoms, abdominal pain and bloody stool iterations was also less than those of the control group (p < 0.05). methods: iga nephropathy model was established in male sprague-dawley rats. at week 10, rats in the model group were randomly assigned to either remain in the model group (n=5), or to receive treatment with rednisone (n=6), 1,25(oh) 2 d 3 group (n=6), or prednisone plus 1,25(oh)2d3 (n=6). at week 12, serum interleukin-17 level was detected by elisa, and the level of treg cells in the blood was assayed using a flow cytometry method. results: (1) the proteinurine and the number of blood cells in urine from rats in the model group was significantly higher than in rats in the control, prednisone, 1,25(oh)2d3, and prednisone plus 1,25(oh)2d3 treatment groups (p < 0.01). (2) serum interleukin-17 in the model group was significantly increased compared with control and treatment groups (p < 0.01), and the levels were decreased in turn in the prednisone treatment group, 1,25(oh)2d3 treatment group, and prednisone plus 1,25(oh)2d3 treatment group. in addition, the 1,25(oh)2d3 and prednisone plus 1,25(oh)2d3 treatment groups showed lower levels than the prednisone treatment group (p < 0.05). (3) the level of treg cells in the model group was significantly decreased compared with the control and treatment groups (p < 0.01), with the levels showing a slight increase in the prednisone treatment group, a larger increase in the 1,25(oh)2d3 treatment group, and the greatest increase in the prednisone plus 1,25(oh)2d3 treatment group when compared with the model group. furthermore, the 1,25(oh)2d3 group and prednisone plus 1,25(oh)2d3 treatment groups showed higher levels than the prednisone treatment group (p < 0.01). conclusion: a th17/treg disorder exists in rats with iga nephropathy, with the levels of interleukin-17 increased and the levels of treg cells decreased. vitamin d3 can regulate the th17/treg balance and reduce the level of protein and blood in the urine in rats with iga nephropathy. objective: to explore the therapeutic effect of prednisone (pred) combined with mycophenolate mofetil (mmf) and cyclosiporin a(csa) in children with severe purpura nephritis (hspn). methods: we collected 6 patients with severe hspn (from iskdc iiia to i) whose proteinuria symptom of nephrotic syndrome did not significantly relieve after 4 weeks which treated with oral pred and mmf (20-30 mg/(kg.d)); and (or) the gross hematuria did not disappear after 2 courses which treated with large doses of methylprednisolone. all patients were treated with oral csa 2-4mg/(kg.d) to induce remission therapy for 3-6 months, then gradually reduced csa to 1-3 mg/(kg.d). the follow-up was 8-30 months. results: combined therapy with immunosuppressant treated a month later, gross hematuria were disappeared in all 5 patients, 1 patient (17%) was partial remission (urinary protein and urine erythrocyte continued to decrease 25%-49% than before),5 patients (83%) were significantly remission (urinary protein and urine erythrocyte continued to decrease over 50% than before), 24-hour urinary protein was 30.50±19.35mg/kg, urine erythrocyte was 15.23±11.39×10 4 /ml.3 months later, 5 patients (83%) were significantly remission, 1 patient was complete remission (urinary protein was completely negative, urinary sediment red blood cells <8000/ml), 24-hour urinary protein was 18.67±10.10mg/kg, urine erythrocyte was 10.71±8.55×10 4 /ml. 6 months later, 5 patients (83%) were significantly remission, 1 patient was complete remission, 24-hour urinary protein was 7.66±6.31mg/kg, urine erythrocyte was 5.18±3.81×10 4 /ml. 4 patients were complete remission at last and the median duration of complete remission was 8.5±4.93 months. 2 patients had not been reached complete remission, which follow-up was 8-9 months. 3 patients were relapse during withdraw or reduction, other side effects included hairy (4 patients objective: increasing evidence suggest that the cosmc(1-beta-3galactosyltransferase-specific molecular chaperone ) might play a vital role in the pathogenesis of iga nephropathy (igan). however, the mechanism is not clear. methods: we investigated whether cosmc gene( c1galt1c1 )methylation is an important mechanism in igan in children. methods 33(m:f=25:8) primaryigan children and 39(m:f=28:11) healthy controls were enrolled randomly. the methylation status of the c1galt1c1 was detected using bisulfite-specific polymerase chain reaction (bsp)-based sequencing analysis. results: the male patients had obviousely high methylation percentage than the male controls(p=0.047). three significant hypermethylation sites were identified in the male patients: cpg site 20 (p = 0.034), site 21 (p = 0.039), andsite 26 (p = 0.047). in the female groups,the patients and the normal controls all had high level methylation without significance (p=0.947). conclusion: methylation of c1galt1c1 might have the vital significance in the susceptibility to the male igan patients. objective: the aim of this research is to investigate the value of serum and urinary tgf-β1and mmp-9 level, the noninvasive and easy repeatable biomarker, for assessing the severity and disease progression in igan children. methods: 54 children with biopsy-proven igan and 55 normal children(control group) were enrolled between july 2009 and january 2013.(fingure 1)the igan group was divided into 3 clinical groups according to their clinical features: isolated hematuria group (ih group, 20 patients), hematuria and proteinuria group (hp group, 16), and nephritic syndrome group (ns group, 18). patients were divided into two groups according to their lee's pathologic classification: grade i+ii (lee's i+ii, 39 patients), grade iii+ iv (lee's iii+ iv ,15) groups. igan group was classified according to the renal function into two groups(renal failure group vs normal group). igan group was also divided into four groups according to their immunophenotype: iga(7patients),iga+igg(9),iga+igm(10),iga+igg+igm(28) group. results: the level of tgf-β1 and mmp-9 inserum and urinary of the igan group was significantly higher than that in the control group (p<0.05). both the level of tgf-β1 and mmp-9 inserum and urinary of the three clinical groups in the igan children were not statistically different. the serum tgf-β1 and mmp-9 levels were significantly higher in lee' s iii+ iv group compared to that in lee's i+ii group(p<0.05). the difference was not statistically significant between urinary tgf-β1 and mmp-9 levels in the two lee's group.the serum tgf-β1 and mmp-9 levels of renal failure group were significantly higher than that of normal renal function group in igan children(p<0.05),and the urinary tgf-β1 and mmp-9 levels of the two group were not statistically significant different. the serum and urinary tgf-β1 and mmp-9 levels were not statistically different in all immune classification. conclusion: the serum tgf-β1 and mmp-9 plays an important role in the severity and progression of children with igan. tgf-β1 and mmp-9 may be two more noninvasive and easy repeatable biomarkers to be used in evaluating the progression of igan in children. abstract# p-sat163 glomerular ace2 expression is enhanced in pediatric iga nephropathy yusuke seki, maki urushihara, takahiro tayama, takashi nagai, ariunbold jamba, shuji kondo, shoji kagami department of pediatrics, the university of tokushima graduate school, tokushima, japan objective: angiotensin converting enzyme (ace)2 is a homolog of ace and is thought to be a potent counter-regulator against ace activity. while renin-angiotensin system (ras) plays a critical role in the progression of iga nephropathy (igan), the role of ace2 has not been investigated in pediatric patients with igan. this study was performed to examine the relationship between ace2 expression and the development of pediatric igan. methods: we performed immunohistochemical analysis of ace2 and ace in kidney tissues from 39 patients with pediatric igan and 14 patients with minor glomerular abnormalities (mga) using specific antibodies and examined the correlation with clinical parameters and pathological findings. in addition, we elucidated the effects of various cytokines on ace2 expression in cultured human mesangial cells (mcs) by quantitative real time pcr and western blot analyses. results: ace2 expression levels in glomeruli (r = 0.5732, p < 0.0001) and tubules (r = 0.4917, p = 0.0002) were positively correlated with the mesangial hypercellularity score, while ace expression levels in glomeruli (r = 0.1331, p = 0.3420) and tubules (r = 0.0743, p < 0.5959) are not. multiple regression analysis showed that the mesangial hypercellularity score correlated with ace2 expression level in glomeruli and urinary protein-creatinine ratio (r = 0.6295, p < 0.0001). in igan patients not treated with a ras blocker (ace inhibitors or angiotensin ii type 1 receptor blockers), ace2 expression levels in glomeruli were significantly increased compared to patients with mga (p < 0.0001). iga patients treated with a ras blocker did not show this increase in ace2 exrepssion. furthermore, ace2 mrna and protein expression was enhanced by interleukin-1 beta, a pro-inlammatory cytokine, and suppressed by transforming growth factor-beta 1 , a pro-fibotic factor in the progression of igan. conclusion: these data indicate that ace2 expression in glomeruli is associated with mesangial hypercellularity in the active phase of pediatric igan. abstract# p-sat164 increased serum interleukin-17 and peripheral th17 cells in children with henoch-schonlein purpura nephrology (hspn) xiaoshan shao nephrology, guiyang children's hospital, guizhou, china objective: interleukin (il)-17 and th17 cells have been involved in many autoimmune diseases. the aim of this study is to investigate the involvement ofil-17 and th17 cells in the pathogenesis of childhood henoch-schonlein purpura (hspn). methods: serum and supernatant levels ofcytokines and chemokines were analyzed by enzyme-linked immunosorbent assay (elisa). using intracellular staining, the frequency ofperipheral th17 and th1 cells was studied by flow cytometry. results: children with hspn had significantly higher serum levels of il-17, il-6and transforming growth factor-beta than healthy controls. the il-17 levels in culture supernatants of peripheral blood mononuclear cells with anti-cd3 and cd28 antibody stimulation were much higher in patients with hspn (212.2 +/− 71.4 vs. 34.7 +/− 12.6 pg/ml, p = 0.021). thepatients also had more th17 cells (1.47 +/− 0.23% vs. 0.61 +/− 0.10%, p = 0.012) but not th1 cells in peripheral blood. moreover, il-17 could promote human endothelial cells to produce chemoattractants il-8 and monocyte chemotactic protein-1. the increased frequency of peripheral th17 cells and serum il-17 levels are shown in childhood hspn that may in part contribute to vascular inflammation, suggesting cellular immunity is likely to be involved in the process of hspn. expression and significance of tgf-beta, smad7, fn, ub and smurf2 in the renal tissues of children with iga nephropathy chen li-zhi, jiang xiao-yun, ling yi-hong, mo ying, sun liang-zhong pediatrics, the first affiliated hospital of sun yat-sen university, guangzhou, china objective: in this study, we investigated the expression of tgf-beta 1, smad7, snon, fn, ub and smurf2 inthe renal tissues in children with igan, in order to explore the potential cross-talk between ubiquitinproteasome pathway and tgf-beta 1 signaling and even their role in the progressive renal fibrogenesis of igan. methods: sixty children with igan were divided into three groups according to their clinical features: isolated haematuria group (ihgroup, 20 patients), hematuria and proteinuria group (hp group, 21), and nephrotic syndrome group (ns group, 19) . patients were also divided into three groups according to pathologic grades: grade 2 (26 patients), grade 3 (20) and grade 4 (14) groups. six normal renal specimens (four was non-tumor kidney tissues from patients who had renal tumor and underwent nehprectomy, another two was healthmismatched donor renal tissues before renal transplantation) were used as the control group. the expression of ub, smurf2, tgf-1, smad7, snon, and fn in renal tissues were determined by immunohistochemistry (two-step powervisiontm) and semi-quantitatively analyzed by the software of image-pro plus 6.0. the degrees of glomerular and tubulointerstitial lesions were scored according to the katafuchi semi-quantitative criteria. results: the expression of tgf-beta 1, fn, ub and smurf2 inigan kidneys was significantly higher than that in the control group(pless than 0.01), while the increased expression of smad7 was only found in glomeruli but not in renal tubular interstitium(p less than 0.01). the highest expression of tgf-beta 1, fn, and ub were found in the ns and grade 4 groups(p less than 0.01), smurf2 in the ih and grade 2 groups(p less than 0.01), while the lowest expression of smad7 was found in the grade 4 group(p less than 0.01), closely associated with different clinical and pathological groups. (p less than 0.01) conclusion: these results demonstrate that upp and tgf-beta 1/smads signaling pathway were both activated in children with igan.both upp and tgf-beta 1/smads signaling pathway may play an important role in the progress of glomerular sclerosis, renal tubular injury and renal interstitial fibrosis in children with igan. abstract# p-sat166 objective: the proteasome (ps) plays a key role in the activation of transcriptional factors, cytokines and presentation of hla-i restricted peptides. in immune mature cells, particularly dendritic cells, the ps, under the action of interferon gamma and alpha, becomes an immunoproteasome (ips), by substituting 3 catalytic units beta1, beta2, beta5 with other low molecular weight proteins (lmp2 and lmp7) and an endopeptidase-like complex (mecl-1). this modification confers an optimal catalytic property for professional presentation of specific peptides to mhc class i. our group previously demonstrated that adult patients with iga-nephropathy (igan) have an increased expression of ips catalytic subunit, which correlated with the severity of renal disease.aim of this study was to investigate the switch from ps to ips in children with primary igan and with henoch-schoenlein purpura (hsp), a vasculitis sharing with igan several immune system abnormalities. methods: peripheral lymphomonocytes (pbmc) from 18 children with igan, 57 with hsp and 33 healthy control subjects (hc), isolated by centrifugation gradient, were tested with real time prc (taqman) to assess quantitatively the mrna levels of ps alpha subunit (constitutive), of the active subunit of ps (beta1, beta2, beta5) and of ips (lmp2, lmp7 and mecl-1). results: objective: recent studies suggest that dysregulated innate immunity plays an important role in the pathogenesis of iganephropathy (igan). interleukin-20 subfamily and its receptor, interleukin-22 receptor alpha-1 (il-22r1), were recently identified as immunomodulators in human diseases, acting as mediators of mucosal host defense. however, the potential role of il-22r1 in the pathogenesis of igan has not been explored. methods: in the current study, one hundred ninety four patients with igan and 287 normal controls were genotyped for coding polymorphisms of the il-22r1 gene and the association between the polymorphisms and igan was investigated. local expression of il-22r1 was examined in patients with igan and healthy controls using immunohistochemistry. results: our case-control analysis showed that genotypes of rs3795299 were associated with childhood igan. individuals with the cc genotype of rs3795299 had about three fold reduced risk of igan compared with those with the gg genotype in the codominant model (p=0.0028) and those with the genotypes containing g allele (gg or gc) in the recessive model (p=0.002).after bonferroni correction, the association between rs3795299 cc genotype and reduced risk of developing igan remained significant. furthermore, the renal expression of il-22r1 was significantly higher in healthy controls compared with subjects with igan. conclusion: our data suggest that the cc genotype of rs3795299 polymorphism in il-22r1 gene is associated with the reduced risk of igan, and this genetic association was supported by the higher renal expression of il-22r1 in healthy controls compared with patients with igan. abstract# p-sat168 toll-like receptor 9 gene polymorphisms contribute to development of proteinuria in childhood iga nephropathy henoch-schoenlein purpura (hsp) is the most common form of immune-mediated systemic vasculitis in children, which mainly affects skin, joints, gastrointestinal tract and kidney. the overall prognosis of hsp is favorable, but the long-term outcome is dependent on the degree of renal involvement. the incidence of renal involvement varies from 20 to 60% and there have been some reports showing that nephritis might be related to an older age at onset, persistent purpura (> 1 month), severe abdominal pain, and relapsing disease.recently, several studies have shown that galactose-deficient iga1 (gd-iga1) is recognized by anti-glycan antibodies, resulting in the formation of the circulating immune complexes and their mesangial deposition causing renal injury in hsp nephritis and serum galactose-deficient iga1 levels were highly inherited in children with hsp nephritis.regarding the treatment of hsp, one randomized double-blinded controlled study recently showed that patients with abdiminal pain or arthralgia may benefit from early treatment with prednisone, but the drug has not been proven to be capable of preventing the development of renal symptoms. however, it was effective in altering the course of renal involvementmild henoch-schoenlein purpura nephritis (hspn) generally does not require aggressive treatment due to a favorable course of the disease, but severe nephritis has a high risk of progression to end stage renal failure. although several intensive therapies, such as intravenous high-dose methylprednisolone pulse, immunosuppressive/cytotoxic drugs, fibrinolytic therapy, anticoagulants, antiplatelet agent and plasma exchange, have been used in children with severe hspn, treatment of hspn still remains controversial due to the rarity of randomized controlled studies in this field. expressions and significance of mtor, p70s6k1 and e-cadherin in glomeruli of children with iga nephropathy objective: to investigated the expressions of mtor, p70s6k1, and e-cadherin in glomeruli of children with igan to explore the role of mtor/p70s6k1 signaling pathway in the progressive renal glomeruli fibrosis of igan. methods: seventy-two children with igan were divided into three groups according to their clinical features: isolated hematuria group (ih group, 24 patients), hematuria and proteinuria(hp group, 26 patients), and nephritic syndrome group (ns group, 22 patients). patients were also also divided into three groups according to their pathologic grades: grade ii(33 patients), grade iii(25 patients) and grade iv(14 patients). six normal renal specimens were used as control group. the expressions of mtor, p70s6k1, and e-cadherin in glomeruli were determined by immunohistochemistry method and the relationship between these indexes and the clinical pathology indexes were analyzed. results: the highest expressions of mtor and p70s6k1 inglomeruli were found in the ns group, both of which in tubulointerstitium were higher in grade iii and iv group than that in grade ii group and control group while the lowest expressions of e-cadherin was found in the grade iv group. the glomerular lesion level degree was positively correlated with expressions of mtor and p70s6k1 inglomeruli. the quantitative urinary protein of 24 h was positively correlated with expressionsss of mtor in glomeruli. the concentration of serum iga was negatively correlated with the expressionss level of mtor in glomeruli. there was no significant correlation between the expressions of ang ii, mtor, p70s6k1, e-cadherin and α-sma in igan glomeruli and their courses from duration of illness as well as iga depositional strength. conclusion: the mtor/p70s6k1 signaling pathway was actived in the children with igan and it may play an important role in the progress of renal glomeruli fibrosis in children with igan. abstract# p-sat171 iga1 from hsp patients trigger apoptosis and inhibit cytoskeletal proteins in huvec objective: henoch-schonlein purpura (hsp) is the most common form of small-vessel vasculitis in children, and its etiology is believed to be associated with immune injury. a polymorphism in the gene encoding heat shock protein 70-2 (hsp70-2) is known to be associated with immune diseases. the purpose of this study was to investigate the correlation between the hsp70-2gene polymorphism (+ 1267 a/g) and hsp in children. the polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) method was used to detect the hsp70-2 polymorphism in 205 cases of children with hsp and 53 controls, and the association of this polymorphism with hsp and hsp nephritis (hspn) was analyzed. results: in patients with hsp, the a/a, a/g, and g/g genotypic frequencies at the +1267a/g position of hsp70-2 were 25.9%, 51.2%, and 22.9%, respectively. in the control group, the a/a, a/g, and g/g genotypic frequencies at the +1267a/g position of hsp70-2 were 30.2%, 60.4%, and 9.4%, respectively. thus, the g/g genotypic frequency in the hsp group was significantly higher than that in the healthy control group (χ2=4.764, p<0.05). the frequencies of the a and the g allele were 51.5% and 48.5%, respectively, in the hsp group and were 60.4% and 39.6%, respectively, in the control group. the frequencies of the a/a, a/g, and g/g genotypes in patients with hsp were 24.8%, 52.9%, and 22.3%, respectively. in hspn, the frequencies of the a/a, a/g, and g/g genotype were 27.4%, 48.8%, and 23.8%, respectively. conclusion: the +1267a/g polymorphism in the hsp70-2 gene is associated with hsp in children. the g/g homozygous genotype may be a genetic factor that predisposes individuals to hsp, but it is not significantly associated with the development of renal impairment. abstract# p-sat174 investigation of the correlation between tumor necrosis factoralpha gene polymorphism and henoch-schonlein purpura in children fei zhao 1,2 , songming huang 1, 2 , huaying bao 1 , guixia ding 1 , ying chen 1 , hongmei wu 1 , aihua zhang 1 1 nephrology, nanjing children's hospital, nanjing, china 2 institute of pediatrics, nanjing medical university, nanjing, china objective: to investigate the association between serum tumor necrosis factor-α (tnf-α) gene polymorphism and the occurrence and development of henoch-schoenlein purpura (hsp) in children. the polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) method was utilized to detect and compare the genotype and allele frequencies at the tnf-α -308 locus in 205 hsp child patients and 53 non-hsp child patients. furthermore, the relationship between the genotypic and allelic frequencies at the tnf-α -308 locus and the susceptibility to hsp and henoch-schonlein purpura nephritis (hspn) was analyzed. results: 1. the g/g, g/a, and a/a genotype frequencies at the tnf-α gene (−308g/a) locus in the hsp group and the control group were 59.5%, 32.2%, and 8.3% and 77.4%, 20.8%, and 1.9%, respectively; among them, the a/a genotype frequency in the hsp group was higher than that in the healthy control group, with a statistically significant difference (x 2 = 6.447, p < 0.05). the g and a allele frequencies in the hsp group and the control group were 75.6% and 24.4% and 87.7% and 12.3%, respectively. the a allele frequency in the hsp group was higher than that in the healthy control group, with a statistically significant difference (x 2 = 7.241, p < 0.05). 2. the g/g, g/a, and a/a genotype frequencies in the hsp non-renal impairment group and the nephritis group were 64.5%, 26.4%, and 9.1% and 52.4%, 40.5%, and 7.1%, respectively, but these differences were not statistically significant (x 2 = 4.474, p > 0.05). the g and a allele frequencies in the hsp non-renal impairment group and the nephritis group were 77.7% and 22.3% and 72.6% and 27.4%, respectively; the difference in the frequency of the a allele in the hsp non-renal-damage group and the nephritis group was not statistically significant (x 2 = 0.240, p > 0.05). conclusion: the tnf-α (−308g/a) gene polymorphism was associated with hsp in children. a/a homozygosity may be a genetic predisposing factor for hsp; however, this factor was not significantly correlated with the development of kidney damage. abstract# p-sat175 objective: the nephrotic syndrome (ns) is characterized by proteinuria, hypoalbuminemia and generalized edema. although the pathophysiological mechanisms of ns remain unknown, studies with animal models and patients have associated the ns with changes in immune response. the present study investigated the expression of molecules related to cell activation, such as the beta-2 integrin (cd18) and cd80 on peripheral blood leukocytes and renal production of reactive oxygen species in rats with ns induced by doxorubicin. meathods: male wistar rats, 250-300g, were divided into two groups: animals receiving intravenous injection of doxorubicin (7.5 mg/kg) (dox, n=32) and control animals that received saline (con, n=32). the animals were sacrificed at days 7, 14, 21 and 28 after injection, and 24 hour urine and blood samples were collected for biochemical and immunological analyzes. the phenotypic analysis of leukocytes was performed by flow cytometry. the expression of cd18 in monocytes, cd4+, cd8+ and nk cells and the expression of cd80 in monocytes were measured. in renal tissue samples, the oxidative activity was evaluated by tbars production and antioxidant activity of sod and catalase. results: the dox group animals showed significant increase in cellular cd18 expression and in the percentage of cytotoxic t lymphocytes, nk cells and monocytes that expressed cd18 as well as raised cd80 expression on peripheral blood monocytes when compared to the con group. the increased production of reactive oxygen species in renal tissue of dox group animals was positively correlated with the cd80 expression on monocytes and serum levels of creatinine. conclusion: these findings indicate a potential link between increased activation of peripheral monocytes and kidney damage in animals with ns. additional studies analyzing the effects of the blockade of integrins and co-stimulatory molecules may offer new therapeutic opportunities to treat human ns. abstract# p-sat182 cyclosporine a protects podocyte via upregulating the expression of cofilin-1 li xiaoyan, zhang xiaoyan, li xuejuan, wang xuejing, wang suxia, ding jie pediatric, peking university first hospital, beijing, china objective: podocyte foot process is dysregulated in nephrotic syndrome. the effacement of podocyte foot processes typically arises owing to perturbations in the actin cytoskeleton. calcineurin inhibitor cyclosporien a (csa) is currently used in the treatment of nephrotic syndrome. recent data suggest that the effects of csa on nephrotic syndrome are independent of its effects on the immune system. they identified that csa can stabilize the actin cytoskeleton through stabilizing synaptopodin in podocytes and thereby reduce proteinuria directly. other studies also showed that csa induced cofilin phosphorylation and promoted stress fiber generation in proximal tubular cells. however, whether the antiproteinuric role of csa is played by regulating cofilin-1 in podocyte has not been studied. methods: acute podocyte injury and nephrotic syndrome were induced by puromycin aminonucleoside (pan) injection in rats with or without csa. cultured podocytes were exposed to pan with or without csa treatment. cofilin-1, nephrin, synaptopodin expression were determined by western blot or immunofluorescence. the cofilin-1 specific effect was determined using cofilin-1 sirna. results: csa reduced proteinuria, restored expression of cofilin-1, nephrin, syanptopodin and repaired foot process effacement of pan induced nephropathy in vivo. in vitro studies showed that exposure of csa restored the expression of cofilin-1 and nephrin which decreased by pan. csa also repaired actin cytoskeleton impaired by pan. the protective effect of csa was disappeared partially when cultured podocytes were exposed to cofilin-1 sirna. objective: to find a probably mechanism of immune disorder in rsv nephropathy in rats which resembled the change of minimal change nephrotic syndrome. methods: 1. rsv mrnas (g, f, m2, ns1, ns2) and proteins (g and f) were detected with fluorogenic quantitative rt-pcr and indirect immunofluorescence assay (ifa) to find the evidence of viral persistence. 2. dc-sign mrna and protein were detected with rt-pcr and ifa to find the trend of its change. 3. the levels of il-12/il-10 and cd4/cd8 were measured by elisa and flowcytometry. results: the course could be divided into two stages: 1. first stage (4d-14d) the mrna of rsv f, g, m2, ns-1 and ns-2 in kidneys, lungs and spleens expressed and arrived at the highest on 14d, which accorded with the expression of rsv f and g proteins in ifa. the positively fluorescent luminance and mrna of dc-sign expressed stronger than that in the control, especially from 8d (ct kidney =18.50±3.12) to 14d (ct kidney =11.40±2.07). compared with the control, the secretion of il-12 in renal tissues was rising from 4d (1205.46±262.07pg/ml) to 14d (1054.68±154.18pg/ml). the expression of cd4 and cd8 in peripheral blood was lower than that in normal control. 2. second stage (30d-120d) rsv mrna and viral proteins in the tissues were persistently expressed; it showed that partial rsv survived through immune escape. after 30d, the fluorescent luminance of dc-sign was gradually reduced in the three tissues. the expression of dc-sign mrna in kidneys, lungs and spleens on 60d (ct kidney =14.10±8.32) and 120d (ct kidney =14.92±1.80) was higher, except that in spleens on 30d (ct= 21.90±1.43) was significantly lower than the control. the secretion of il-12 in tissues decreased after 30d (583.40±199.26pg/ml), but that of il-10 gradully increased after 30d (3832.38±88.20pg/ml). although the expression of cd4 and cd8 in peripheral blood was increased gradually after inoculation, the level was still lower than that in normal control. conclusion: there was rsv persistence in rats which likely attributed to the rsv-induced immune escape. rsv interacts with dc-sign to make dcs inhibit the immune ability of cytotoxic t cells, caused t cell immune dysfunction and finally induced the immune tolerance. abstract# p-sat185 evaluation of the migratory and regulatory profile of leukocytes from peripheral blood in pediatric patients with idiopathic nephrotic syndrome objective: dynamic regulation of the podocyte cytoskeleton plays an important role in maintaining the glomerular filtration barrier. severe glomerular disorders are associated with perturbed organization of the podocyte actin cytoskeleton. the therapy is based on immunosuppressive agents, in particular cyclosporine a, whose beneficial effect seems also related to the stabilization of the actin cytoskeleton in podocytes. previous studies of our group demonstrated, that the mtor inhibitor everolimus (ev) might similarly involve the recovery of the actin cytoskeleton in a puromycin (pan) experimental model of proteinuric disease. methods: in the present study, inhibitory effects of ev on mtor complex 1 (mtorc1) and −2 (mtorc2) were analyzed by western blotting in human differentiated podocytes. downstream of mtorc2 the activity of rhoa (gtpase pull-down assay) and myosin light chain (mlc) was studied. to identify further signaling pathways affected by ev, we performed affymetrix microarray expression analysis followed by verification using real-time rt-pcr. results: biochemical studies revealed a substantially decreased phosphorylation level of both mtor effector proteins mtorc1 (reduced p-akt) and mtorc2 (reduced p-p70s6k) by ev. objective: notch constitutes an evolutionarily conserved intercellular signaling pathway that determines cell fate in various organs. activation of notch1 and notch2 has been implicated in human glomerular diseases. notch1 was reported to play a critical role in development of glomerular diseases; however, a function of notch2 remains unclear. our aim of the study is to clarify notch2 pathway's contribution to developing proteinuria and glomerulosclerosis. methods: we injected either jagged1 antagonistic antibody (mab) or notch1 agonistic mab or notch2 agonistic mab intraperitoneally to mice with adriamycin (adr) nephropathy, a model of nephrotic syndrome and focal segmental glomerulosclerosis, and evaluated the levels of proteinuria and the ratios of sclerotic glomeruli. next, we treated cultured podocytes with adr in the presence or absence of notch2 agonistic mab, and we assessed the effect on cell survival and examined the pathways involved. then, we evaluated a correlation between notch2 activation and podocyte loss in human kidney specimen of nephrosis, minimal change disease (mcns) and focal segmental glomerulosclerosis (fsgs). results: administration of notch2 agonistic mab ameliorated nephrosis and glomerulosclerosis in mice with adr nephropathy, even when notch2 agonistic mab was administered therapeutically after the onset of nephrosis. in vitro, notch2 agonistic mab protected adr-damaged podocytes from apoptotic cell death. the specific knockdown of notch2 led to increased apoptosis in damaged podocytes. notch2 rescued damaged podocytes from apoptosis through akt pathway. human kidney specimens of nephrosis showed a positive linear correlation between the number of podocytes expressing activated notch2 and the number of residual podocytes. the glomeruli with mcns showed more activated notch2 and more podocytes, conclusions: whereas those with fsgs showed less activated notch2 and less podocytes. notch2 pathway has a pivotal role in preventing apoptosis of damaged podocytes. specific activation of notch2 may represent a novel clinical strategy for the amelioration of nephrosis and glomerulosclerosis. abstract# p-sat191 proliferation and apoptosis of tubular cells in initial and advanced stages of focal segmental glomerulosclerosis (fsgs) objective: to analyze processes of proliferation, apoptosis and ciliogenesis in proximal tubular cells during initial and advanced stages of fsgs associated with cystogenesis. methods: normal kidney tissues and tissues of fsgs kidneys were immunohistochemically analyzed using ki-67 proliferation marker and caspase-3 apoptotic marker. diameters of dilated and cystic proximal tubules were measured and correlated with proliferation index of tubular cells. data were analysed by the kruskal-wallis and dunn's post hoc test and expressed as mean+/−sd. significance was accepted at p<0.05. results: normal kidney tissue showed absence of proliferation in proximal tubules. initial stages of fsgs were characterized by intermingling areas of healthy non-proliferating proximal tubules, and pathologically changes, mildly dilated (15um diameter) proximal tubules showing proliferation index of 15.92%. advances stages of fsgs displayed different stages of cystogenesis: while mildly dilated tubules (diameter 12+/−1.4um) contained 36,18% of proliferating cells, their number increased to 45,23% in cysts with diameters from 21+/−1.8um to 54+/−1.1um, and then decreased to 13,76% in cysts with diameter 73+/−2.1um. while in the largest cysts proliferation index was lowest and the primary cilia short and distorted, in distal tubules and collecting ducts, primary cilia were extremely long and branching. apoptotic caspase-3 positive cells were observed within the tubular and interstitial cells. conclusion: deterioration of proliferation and apoptosis, and primary cilia formation characterizes cystogenesis in fsgs kidneys. we suggest that changes in primary cilia length might cause alterations in transfer of signaling pathways which control proliferation, differentiation and apoptosis of proximal tubules cells. advanced stages of fsgs are associated with cyst formation and increased proteinuria leading to nephrotic syndorme objective: to investigate effect of prednisone on the expression of ezrin and neph1 in rats with adriamycin-induced nephrosis. methods: adr model was induced by a tail intravenous injection of adr.the rats were divided into three groups, which were control group, model group and prednisone group. serum index and 24h urinary protein were measured at 4 and 8 weeks. observe pathologic changes of renal tissues at 8 weeks. the expression of ezrin and neph1 in glomerulus was evaluated by immunohistochemistry respectively. results: compared with control group, at 4 weeks, 24h urinary protein and total cholesterol in model group and prednisone group were significantly increased(p<0.05),albumin and total protein were significantly decreased(p<0.01),which indicated that the model was successfully established;compared with control group, at 8 weeks, the expression of ezrin and neph1 in the model group were significantly decreased(p<0.01).compared with the model group, the expression of ezrin and neph1 in prednisone group were significantly increased(p<0.01),24h urinary protein and total cholesterol were significantly decreased(p<0.01),albumin and total protein were significantly increased(p<0.05), renal pathology and ecm/ga were significantly increased(p<0.01). conclusion: the expression of ezrin and neph1 were reduced in rats with adriamycin-induced nephrosis which were negatively related to proteinuria and renal pathological damage. prednisone can reduce the proteinuria and relieve the renal pathological damage by improving the expression of ezrin and neph1. objective: the activation of the complement system plays an important role in various kidney diseases, such as antibody-mediated rejection or membranous glomerulopathy. the majority of the circulating complement components are produced in the liver. but in the last decade the local production of complement components by other cells is highly debated. the aim of our study was to proof the ability of human podocytes to produce and secrete complement components. methods: immortalized human podocytes were analyzed with western blot (wb), immunofluorescence (if) or/and pcr for their ability to produce components (c1/ c1q, c2, c3, c4, c5) inhibitors (factor h, mcp, cd 55, cd59) and activators (factor b, properdin) of the complement system. secretion of components was measured in the medium, and functionality of c3 was tested in a specific c3convertase assay. stimulation of the cells was done with interferon-γ, interleukin 6 and human albumin. results: pcr-studies revealed that human podocytes express on mrna level the components c2, c3, c4, c5, the inhibitors factor h, mcp, cd 55 and cd59, and the activators properdin and factor b. on protein levels c2, c3, factor b, properdin, factor h, cd 55 and cd59 were detected. in immunofluorescence all the components showed either intra-plasmatic, perinuclear or peri-membranous distribution. in addition, we could show that podocytes secrete the factors c2, c3, c4, c5, factor b and factor h into the medium. the secreted c3 was clearly functionally active and could further enhanced by stimulation with interferon-γ. objective: to construct the eukaryotic expression plasmid and its shrna plasmids of il-17 of mice, and to investigate their ability of expression or inhibitory effects on il-17. methods: the rna from spleen cells of bal b/c mouse was reversed to cdna, and the full-length cds fragment of il-17 was amplified. the target segment was cloned into the expression vector plvx-ires-zsgreen1, then, the recombinant plasmid plvx-il-17-ires-zsgreen1 was obtained. three pairs of shrna chains targeting il-17 gene and one pair control shrna chain were designed and synthesized, then annealed to form double strand ,and inserted into the expression vector plvx-shrna2. three shrna plasmids and one control plasmid were constructed ,which were called shrna1/shrna2/shrna3/shrnac, respectively. these plasmids were identified by restriction analysis and sequencing, and then they were transfected or co-transfected into 293t cells in mediation of liposome. the transcription levels of il-17 mrna were detected by fluorescent quantitative pcr, while expression levels of il-17 protein were detected by elisa. results: restriction analysis and sequencing proved that the recombinant plasmid were constructed correctly. the plasmid of plvx-il-17-ires-zsg reen1 could expression il-17; when cotransfected with expression plasmid, il-17 expression levels were significantly reduced in the group of shrna1/shrna2/shrna3 as compared with the shrnac group, and the group of shrna1 had the least expression. conclusion: il-17 eukaryotic expression plasmid and its specific shrna plasmids were constructed successfully, and plasmid shrna1 had the best inhibitory effects. abstract# p-sat195 reno-protective effect of all-trans retinoic acid on adriamycininduced nephropathy mice xiaoli wang, jingjing cui, qiu li nephrology and immunology department, children's hospital of chongqing medical university, chongqing, china objective: to investigate the reno-protective effect of all-trans retinoic acid on adriamycin-induced nephropathy mice. methods: balb/c mice were randomly divided into nephrosis(a single adriamycin 10.5mg/kg,n=20) and control(tail intravenous injection the same amount of saline,n=10). after two weeks nephrosis divided into atra-treated(intraperitoneal injection all-trans retinoic acid 20mg/kg, three times a week,n=10) and adr nephrosis. then, we chose five mice each group randomly after treatment 6 weeks and 10 weeks to collect 24-hours-urine, blood, kidney for detection. results: all-trans retinoic acid significantly decreased 24-h urinary protein excretion, serum tc and tg(p<0.05). fas/fasl shows by immunohistochemistry and fluorescence quantitative pcr is decreased sifnificantly(p<0.01). conclusion: all-trans retinoic acid has anti-apoptosis on adriamycin induced nephropathy mice to protect kidney damage and delay fibrosis process. abstract# p-sat196 molecular mechanism of ers induced by lipid accumulation in human mesangial cells (hmcs) objective: dehydroxymethylepoxyquinomicin (dhmeq) is a novel nf-κb inhibitor that potently inhibits the dna-binding activity of nf-κb, resulting in therapeutic effects for various pathological conditions. to elucidate the pathogenetic role of nf-κb in minimalchange nephrotic syndrome (mcns), we examined whether dhmeq could ameliorate the nephrosis in mice induced by puromycin aminonucleoside (pan), which is considered to be an animal model for mcns. methods: mice were injected with dhmeq or only vehicle 2 hours before pan injection on day 0. mice without pan injection served as controls. the dhmeq or vehicle was injected on 5 consecutive days. the daily urine was collected from day 0 to day 30, and the urinary concentrations of albumin and creatinine were measured. some mice were sacrificed 7 days after pan-injection, and their serum concentrations of cholesterol, total protein, albumin and il-6 were measured and the pathological changes of the kidneys were observed. results: pan injection without dhmeq in the mice induced albuminuria which gradually increased up to day 10 and gradually decreased thereafter. in contrast, pre-treatment with dhmeq was associated with no significant increase in the amount of albuminuria during the first 2 weeks. in the serological tests, pan-injection induced an increase in the cholesterol level, a decrease in the total protein, a decrease in the albumin and an increase in the il-6 in the serum compared to controls 7 days after injection, but dhmeq ameliorated these changes. an electron microscopic analysis indicated an effacement of the foot processes of the podocytes in the pan-injected mice, but this was rarely observed in the pan-injected mice pre-treated with dhmeq. further immunohistochemical analysis showed that dhmeq can inhibit the pan-induced translocation of nf-κb from cytoplasm into nucleus. conclusion: these results suggest that dhmeq can be a candidate therapeutic agent for mcns, because the activation of nf-κb of podocytes may be associated with pan-induced nephrosis. knocking-down stim1 gene expression inhibits some podocyte molecules jingjing yan, meigui wang, siguang lu the first people's hospital, lianyungang, jiangsu, china objective: to study the effect of knocking-down stim1 on nephrin,podocin,cd-2ap and α-actinin-4 in murine podocytes in vitro. methods: conditionally immortalized murine podocyte cells were cultured in rpmi1640 medium at 33°c permissive condition.then the cells were shifted to non-permissive condition at37°c and cultured for ten-fourteen days, and were transfected with stim1 small interfering rna(sirna) using transfection reagent lipofectamine 2000.transfection efficiency was measured by flow cytometer and inhibitory effect of stim1 sirna was determined by rt-pcr and western blot at fourty-eight, senventy-two hours after transfection respectively. results: (1)the transfection efficiency of fam-sirna was about 75.5%. (2)after transfection with specific sirna,the expression levels of stim1 mrna and protein were down-regulated by 80.7% and 49.8% respectively. (3) the expression levels of nephrin,podocin and α-actinin-4 mrna were decreased by 62%, 35%, 60% respectively, whereas cd-2ap showed no-change.both podocin and α-actinin-4 protein were decreased by 45%, 20% respectively. objective: one of the most common causes of nephrotic syndromes in children is the minimal-change-glomerulonephritis (mcgn). typically, mcgn results in foot processes effacement of podocytes. their plate-shaped flattening very likely results in dysfunction of the filtration barrier and may underlie the increase in urine albumin concentrations. notably, mcgn often disappears at the onset of puberty, thus in parallel with increasing peripheral hormone levels. this is particularly true in girls. methods: podocytes were studied by western blot analysis, immunofluorescence and by radioimmunoassay for their ability to secrete and bind estrogens. results: podocytes express estrogen receptors both, estrogen receptor alpha and beta, suggesting that increasing levels of estradiol during puberty potentially maintains and restores morphological integrity of podocytes. this protective function could be mediated by stabilization of the podocyte cytoskeleton by estradiol, as evidenced in vitro by the increase in phosphorylation of cofilin, very similar to the effects of estradiol in neurons. furthermore, we show that dissociated podocytes express aromatase, the final enzyme of estrogen synthesis, and that podocytes in fact synthesize estradiol, as evidenced by measuring estradiol content in the supernatant. conclusion: as it was shown that estrogen synthesis in cells other than those in gonads becomes stimulated during puberty, an autocrine mechanism of estrogen action could underlie decreasing frequency of mcgn at the onset of puberty. overexpression of pgc-1α inhibits aldosterone-induced podocyte phenotypic changes and detachment by blocking mitochondrial dysfunction objective: to explore the role of heparanase in the pathogenesis of rat respiratory syncytial virus (rsv) nephropathy. methods: 150~200g sprague-dawley(sd) rats (n=5 per group) were inoculated with 6×10 6 (plaque-forming units, pfu) rsv and sacrificed on days 4,8,14 and 28 postinoculation (rsv 4 ,rsv 8 ,rsv l4 and rsv 28 ). five normal sd rats inoculated with dulbecco's minimum essential medium were served as normal control. the expression level of heparanase protein and mrna in kidney of each group was determined by immunohistochemical staining and real-time quantitative rt-pcr respectively. the proteinurina was measured and the relationship between the expression level of heparanase and the 24hour urinary protein was studied. results: rats with rsv nephropathy exhibited higher proteinuria by comparison with normal rats. there was a significant difference between each group(rsv 14 >rsv 8 >rsv 28 >rsv 4 ). compared with normal control, rats with rsv nephropathy showed up-regulated expression of heparanase protein in glomeruli. the expression level of heparanase protein in rsv 8 and rsv 14 group was higher than that in rsv 4 and rsv 28 group. there was a linear positive correlation between the expression level of glomerular heparanase protein and the quantity of urinary protein(r =0.783,p<0.05).compared with normal control group, the expression level of heparanase mrna in kidney f r o m r s v 4 , rsv 8 , rsv 1 4 a n d r s v 2 8 g r o u p w a s elevated(rsv 14 >rsv 8 >rsv 4 >rsv 28 ).there was a linear positive correlation between the expression level of renal heparanase mrna and the 24-hour urinary protein(r=0.725,p<0.05). the increased heparanase in kidney may be important to the loss of glomerular negative charge in glomerular basement membrane and is involved in the pathogenesis of rsv nephropathy. podocyte morphology andautophagosomes were viewed using electron microscopy. podocyte numerical density was estimated by weibel-gomez method. expressions of autophagy markers and ersassociated proteins were analyzed by western blot. results: the expression level of ers-associated protein grp78 was up-regulated from day 4 to day 21 post-injection. the results also showed that autophagosomes were massively accumulated and the autophagy marker lc3 was up-regulated in the models on day 7 and 14. furthermore, rapamycin was given to phn rats to further explore the role of autophagy in the process of complement-dependent podocyte injury. results revealed that rapamycin, which enhanced autophagy in podocyte, could reduce proteinuria, lighten podocyte lesionsand prevent podocyte loss on day 21. conclusion: taken together, our results demonstrated that ers plays an important role in completment-dependent podocyte damage, and in another aspect, autophagy induced byers can alleviate injury as a protective mechanism. this provides an important basis for a thorough understanding of the role of autophagy in the process of podocyte damage and the pathogenesis of mn. abstract# p-sat209 the cytoprotective role of autophagy under oxidative stress in human podocyte objective: autophagy is a ubiquitous catabolic process involving selective degradation of cellular components. it shows cytoprotective effects in different cell types and helps to maintain cell homeostasis. some studies demonstrated that cell stress, generated by starvation or some chemical reagents, can initiate autophagy which responsively resists harmful stimuli at the early stage. however, little is known about autophagy in human podocytes under oxidative stress. since the apoptosis and autophagy pathways share some common molecules, we investigated the role of autophagy induced by puromycin aminonucleoside (pan) in human podocytes. methods: human conditional immortalized podocytes were treated with pan, the generation of reactive oxygen species (ros) was measured by immunofluorescence. then, autophagy was assayed by immunofluorecence staining for lc3 puncta and western blotting for lc3. in addition, the mammalian target of rapamycin (mtor) and its substrates which play critical roles in autophagy inhibition were investigated for elucidating the mechanism of pan induced autophagy. podocyte apoptosis was assessed by flow cytometry (yo-pro-1/pi and active caspase 3 assays). to study the effects of autophagy on podocyte apoptosis, 3-methyladenine (3-ma) and chloroquine were used to inhibit autophagy. results: autophagy was detected in pan-treated podocytes in a dose and time dependent manner and prior to apoptosis which was accompanied with increased ros generation. lc3 aggregates were observed in the cytoplasm and the expression of lc3 ii was significantly elevated. intriguingly, phospho-mtor and its substrates (phospho-p70 s6 kinase and phospho-4e-bp1) increased when the autophagy was activated. when autophagy was inhibited by 3ma and chloroquine, podocyte apoptosis increased significantly. conclusion: pan induced both apoptosis and autophagy in human podocytes. our results suggested that this in vitro model will be useful for the study of crosstalk between apoptosis and autophagy in podocytes. autophagy may be the adaptive cytoprotective mechanism for podocytes under oxidative stress. further studies directed at identifying the role of mtor are essential. abstract# p-sat210 impact of angptl3 knock-out on adriamycin-induced nephropathy mice objective: idiopathic focal segmental glomerulosclerosis (fsgs) is associated with recurrence after transplantation due to a circulating permeability factor or factors (n engl j med, 334:878-883, 1996) . we have shown the effects of fsgs plasma and its fractions on glomerular permeability in vitro and in vivo and have used state-of-the-art proteomics to identify cardiotrophin-like cytokine-1 (clcf1), a member of the il-6 family, as a candidate for the active substance. we hypothesize that a new model of fsgs can be based on the effects of clcf1 in mice. methods: rclcf1 (r&d systems) was injected intraperitoneally (ip), one dose, 10 μg/kg, or infused by minipump for 28 days, 40 μg /kg/day. a construct containing clcf-1 was administered by electroporation. all studies were done in c57bl6 mice. urinary albumin/creatinine, pjak1, pstat3, patk, and perk in peripheral blood cells (pbc) and in kidney homogenate were measured and glomerular histology was assessed. results: albuminuria was induced promptly by rclcf1 after either injection or electroporation. peak albuminuria occurred by 7 days of expression and was 3-5 fold increased vs. baseline. ip administration of rclcf-1 increased pjak2 and pstat3 of pbc within 15 min. and renal pjak1 and pstat3 remained upregulated for at least 72 hours after injection. kidney pjak2 and pstat3 as well as perk/12 and pakt were markedly increased after 28 days of infusion. mesangial matrix was increased at that time. conclusion: we conclude that clcf1 mimics many of the renal effects of the active fraction of plasma from patients with idiopathic fsgs and may play an important role in its etiology. its relationship to other candidates such as circulating urokinase receptor (supar) is not known. a murine model based on administration or overexpression of clcf1 may permit us to define mechanisms of injury and to test potential therapeutic agents prior to use in clinical trials. over-expression of myo1e in mouse podocytes enhance cellular endocytosis, migration, and adhesion objective: to investigate the effects of tacrolimus (fk506) on hepatocyte growth factor and transforming growth factor β1 in kidneys of fsgs rats. methods: establish unilateral nephrectomy combined adriamycin double tail vein injection of fsgs model in rats divided to model group and treatment group ,then treatment group rats were treated withtacrolimus 8 weeks. the protein expression and site of hgf and tgf-β1 in renal of each group were assayed by western blot and immunohistochemistry after animals were sacrificed. urine protein, serum albumin, blood lipoids and kidney function were tested automatic biochemical analysis system. results compared with the normal control group , model group and treatment group rats 24h urinary protein excretion , serum creatinine , blood urea nitrogen , cholesterol significantly increased serum albumin significantly reduced severe renal pathological changes and tgf-β1 protein expression was significantly increased , and the differences were statistically significant ( p <0.05 ) ; compared with the model group , in experiments 9 weekend , the treated rats 24h urinary protein excretion , relevant serum biochemical indicators of renal pathological changes varying degree of improvement in renal tissue hgf protein expression was increased and tgf-β1 protein expression was decreased , the above differences were statistically significant ( p < 0.05 ). objective: the cellular mechanisms of kidney injury caused by obstructive nephropathy are interstitial inflammation, fibrosis, and apoptosis. rodent models can be used to simulate obstructive nephropathy in the human kidney. we developed shear-thinning hydrogels for the local delivery of il-10 to abate the progression of inflammation and fibrosis that leads to ckd. methods: injectable dock-n-lock gels were developed as previously reported 1 (fig. 1) . il-10 was added to the gel or phosphate buffered saline solution at a concentration of 0.33 ug/ul. study design: eight cohorts were studied (7, 21, 35 days, n=4): healthy, sham operation, healthy injected with msa, healthy + gel, unilateral ureteral obstruction (uuo), uuo + il-10, uuo + gel, uuo + gel/il-10. 15 ul of il-10 solution, gel, or gel/il-10 was injected into the left kidney via retroperitoneal approach 3 days after the initial uuo or sham operation. histology: immunohistochemistry (ihc) was performed on paraffin sections to identify macrophages and apoptotic cells, and trichrome stain was used to evaluate fibrosis. cells and total area were quantified for ihc and total fibrotic area was quantified for trichrome. results: comparing the treatment groups to the untreated uuo, macrophage infiltration and apoptosis were significantly reduced at day 21 and 35. by day 35, adding the il-10 via gel injection reduced macrophage infiltration more than il-10 alone and il-10 alone did not reduce apoptosis. fibrosis was decreased by day 35 in all three treatment groups (fig. 2) . conclusion: injectable hydrogels were synthesized that permit facile local delivery of immunotherapy to both healthy and obstructed kidneys. renal inflammation and scarring was reduced in an animal model of ckd by using an injectable hydrogel for drug delivery. logistic regression reveled that apd was the main parameter significantly associated with surgery treated upjo cases (roc plot was 0.79). a possible threshold of 14mm apd may be used as a cut-off value of surgery treated upjo group with a sensitivity of 77% and a specificity of 69%. conclusion: apd dilatation was the strongest predictor of surgery treated upjo. pt and renal length also significantly discriminate the two groups and correlate with apd, only with lower predictive power. our findings expand the clinical knowledge in the field of prenatal consult by highlighting a threshold of apd, which predicts the need for surgery in prenatally detected hn cases. abstract# p-sat221 survival and renal outcome in fetuses with lower urinary obstruction (luto) with and without intra-uterine vesicoamniotic shunting.a ten years experience of a cohort. objective: ureteropelvic junction obstruction (upjo) is the most common cause of hydronephrosis in children. the significant role of the surgical relieving of high grade obstruction is indisputable. nevertheless, the effect of pyeloplasty on the function of the involved kidney remains controversial, especially in upjo with significantly reduced relative renal function (rrf) before surgery. to evaluate the effect of pyeloplasty on the relative function of kidneys in children with upjo and decreased rrf. methods: the records of children who underwent pyeloplasty for upjo during a 10 year period in schneider children's medical center of israel were reviewed. the study group included 40 children who underwent pyeloplasty for upjo and had an initial rrf <40%. children with bilateral upjo, solitary kidney or other genito urinary abnormalities were excluded. the control group included 38 children with non obstructive hydronephrosis and an initial rrf<40%. results: the average initial rrf in the study group was 26% (range 8-39%), and the final renal function was 32% (1-55%). in the control group, the initial rrf was 23% (2-40%), and the final function was 22% (0-44%). the final rrf of the study group was significantly higher comparing to the control group (p value<0.05). in the subgroup of patients with upjo and initial rrf<30% (24 patients) the average initial function was 20% (8-30%) and the final function was 27% (3-55%). in the control subgroup with initial rrf<30% (26 patients) the initial average function was 17% (2-30%) and the final function was 17% (0-44%). conclusion: pyeloplasty is associated with an improvement of renal function in children with upjo and an initial rrf <40%. this is also true for patients with rrf<30% before surgery. our results support the need for pyeloplasty in children with upjo and reduced rrf. objective: common cause of chronic kidney disease (ckd) in children. kidney damage occurs in utero, and kidney disease progresses postnatally. the objective of this project was to identify clinical biomarkers, in particular antenatal variables, which predicted long-term renal outcome in boys with puv. methods: this was a retrospective cohort analysis. primary outcome was the development of end stage renal disease (esrd) as defined as starting dialysis or preemptive transplantation. clinical variables studied included antenatal factors, postnatal renal function, and modifiable variables. continuous data for the two outcome groups were compared, receiver-operating characteristic (roc), kaplan-meier, and logistic regression analyses were conducted to assess the robustness of each candidate biomarker as a predictor of outcome. results: in this cohort 15 cases reached the primary outcome of end stage renal disease at a mean age of 7.0 ± 6.7 yrs. compared to those who didn't, those who progressed to esrd had younger age at diagnosis (0.6 ± 1.5 vs 3.3 ± 7.3 yrs, p<0.05), valve ablation ( . fsgs rate was found as 60% in biopsied subjects. nephrotic syndrome was defined by edema, massive proteinuria (>40 mg/m 2 per hour or a protein/creatinine ratio >2.0 mg/mg), hypoalbuminemia (<2.5 g/dl), and hyperlipidemia. remission was defined as a urinary protein excretion below 4 mg/m 2 per hour or a protein/creatinine ratio below 0.2 mg/mg for three consecutive days. steroid resistance was accepted as no achievement of remission in spite of treatment with prednisolone, 2 mg/kg per day for 4 weeks. if steroid resistance was seen, patients were also treated with cyclosporine a (csa) (3-5mg/kg per day for least 6 months) and, thereafter, if required, with cyclophosphamide(cp) (2.5-3.0 mg/kg per day for 10-12 weeks). renal failure was defined as a glomerular filtration rate (gfr) below 80 ml/min per 1.73 m 2 body surface area, and esrd was defined as a gfr below 10 ml/min per 1.73 m 2 or the necessity for any renal replacement therapy. bidirectional dna cycle sequencing analysis of entire coding exons and adjacent intronic segments of nphs2 gene was performed.nphs2 gene mutation analysis has been also performed in 100 healthy children. results: pathogenic nphs2 mutations were found in 127 patients (18%) from the totally 700 srns children group. mutation rate was 29% in familial group, and 16.5% in sporadic group. a total of 53 mutations were determined in the nphs2 gene, and 37 of which were characterized as a novel mutation presented at hgmd databank. in the mutation positive nphs2 group, most of the mutations were found out to harbor in exons 1, 4, and 5 while no mutation were found in exon 6 of the respective gene. patients with p118l, r138q, r138x, r168h, s211a, a212t, v218g, h228d, ivs7+5g>a, c.460-467inst, c.503delg mutations were progressed to end-stage renal disease (esrd). also, age at onset of proteinuria (years) was 4.2+/-0.5 in the mutation (-) (n=573) group; 3.6+/-3.08 in the mutation (+) (n=127) group. for the mutation negative patients, effects of other disease causing genes involving nphs1, wt1, trpc6, cd2ap, and actn4 for different molecular subtypes of srns may be considered. nphs1 mutation screening was performed for all the patients who had proteinuria up to two years of age. as a causative srns gene, we should consider nphs2 gene mutation screening in early diagnosis and the follow-up of the clinical course. conclusion: in relation to homozygous or compound heterozygous nphs2 mutated patients who have the lack of response to standard steroid therapy we suggest to perform nphs2 gene mutation analysis for every child (if consent can be obtained) soon after the first episode of ns. for the newly diagnosed patients, the crucial certain determination of the causative disease gene mutation will enable clinicians to avoid redundant immunosuppressive therapeutic trials. we then performed next generation sequencing in the 5 affected patients and in one of their unaffected relatives. exome enrichment was conducted using the agilent sureselect human all exon v4+ utrs capture kit. the multiplex libraries were then sequenced on an illumina hiseq2000 instrument with a 2x76 bp read length. results: we unexpectedly identified a novel lmx1b mutation segregating with the disease in the family. subsequently, we screened 74 additional unrelated families from our international cohort of autosomal dominant fsgs and found mutations of the same residue in 2 families. none of the probands had any sign of dysplasia of nails, patellae or elbows, iliac horns or glaucoma, or any ultrastructural changes suggestive of nail-patella-like renal lesions. lmx1b encodes a homeodomain-containing transcription factor that is essential during development. a lmx1b in silicohomology model suggests the mutated residue plays an important role in strengthening the interaction between the lmx1b homeodomain and dna. both mutations are expected to diminish such interactions. conclusions: our data demonstrate that isolated fsgs could be due to mutations in genes also involved in syndromic forms and highlights the need to include these genes in all next-generation sequencing diagnosis approaches in fsgs. .in 24/37 patients mutations were identified by ngs (detection rate 65%). in 8/24 patients sequence variants were found in two different genes (33%) suggesting oligogenic inheritance. in 6 of these 8 patients the causative mutation was located in a gene following an autosomal dominant inheritance pattern. these patients showed a more severe form of the disease compared to affected family members who showed only the causative mutation without additional modifier variants. one additional patient of this cohort with pierson syndrome had two single heterozygous mutations in nphs1 and lamb2, respectively (both genes following an autosomal recessive pattern of inheritance). a further patient showed two mutations in nphs1 and the non-neutral polymorphism p.arg229gln in nphs2. structural and/or functional analysis of all mutations identified in patients with mutations in two genes suggested impaired protein function of the particular gene products. conclusion: the influence of modifier genes or digenic inheritance seems to play an important role in the pathogenicity of srns. the application of ngs is therefore of special interest and highly efficient in the diagnostics of patients with srns. abstract# p-sat232 mutation analysis in japanese patients with congenital and infantile nephrotic syndrome objective: mutations in podocyte genes (nphs1, nphs2, wt1, and lamb2) are associated with congenital (<3 months) and infantile (3-12 months) nephrotic syndrome (ns). the purpose of this study is to investigate the frequency of causative mutations in these genes in ns manifesting in the first year of life in japan. methods: all exons and exon-intron boundaries were investigated in consecutive, unrelated 37 patients from regional pediatric kidney disease centers, by pcr-direct sequencing. results: we detected disease-causing mutations in 64.9% (24 of 37) patients (75% in congenital and 25% in infantile) (table) . objective: hypercoagulability along with thrombosis are prevalent complications of nephrotic syndrome. in cases of refractory nephrotic syndrome, intracardiac thrombus, although rare, is a serious complication because of its association with morbidity and high mortality herein, we report a case of a patient with a right atrial thrombus associated with nephrotic syndrome who responded well to corticosteroid therapy and attained quick remission. case presentation: a 12-year-old japanese boy was referred to our hospital for a right atrial thrombus associated with idiopathic nephrotic syndrome diagnosed 1 month ago. the patient had attained the partial remission within the 10 days of the corticosteroid therapy initiation. he was asymptomatic otherwise at the time of admission. the patient's vitals were stable and laboratory values were almost within the normal range. an echocardiogram showed a large isolated hyperechoic mass in the right atrium, which originated from the superior right atrial wall. the mass measured 31 × 26 mm in diameter and traversed through the tricuspid valve in a to-and-fro motion. the patient underwent emergency surgical thrombectomy on day 1 and anticoagulation therapy was started 7 days after the operation. the subsequent hospital stay was uneventful, and the patient was discharged on day 87. objective: nephrotic syndrome features proteinuria and severe sodium retention which is implicated in ascites and edema formation. previous works realized in nephrotic rats (pan) clearly highlighted that, the increase of sodium absorption in the ccd is associated with an increase activity of the na/k atpase; sodium absorption is independent of aldosterone, activation of epithelial sodium channel enac is not necessary and sodium absorption is inhibited by amiloride. our hypothesis is that, in nephrotic syndrome, another apical sodium channel sensitive to amiloride and independent of saar pathway is implicated in sodium absorption in the ccd. methods: transcriptome of ccds from control rats (ct) and pan treated clamped rats (adx pan) was analyzed using a high-resolution quantitative and comparative analysis of gene expression. subsequently, transcriptional (rt-qpcr) and proteic expression (western blot and immunohistochemistry) of channel were analyzed. sodium handling in vivo and in vitro microperfused collecting ducts in different conditions (ph 6 and 7.4, apical zinc 0.3mm and amiloride 0.1mm) was analyzed. results: metabolic study confirmed previous results: sodium absorption and ascites were similar in pan and adxpan rats suggesting that sodium absorption in nephrotic syndrome was independent of saar. transcriptome analyses highlighted an increased expression of accn1 mrna only in adx pan at day 6. rt-qpcr confirmed an increased expression of accn1 only in the ccd of adx pan (about eight time compared to adx ct). subsequently, protein shows an increase expression of accn1 (adx pan 0.72+/-0.12 vs adx ct 0.31+/-0.03, p 0.03) and immunohistochemistry on microdissecated ccd highlighted a strong apical expression of accn1 only in adx pan rats. schimke immuno-osseous dysplasia (siod) is a rare autosomalrecessive multisystem disorder, characterised by: disproportionate growth deficiency, defective cellular immunity, nephrotic syndrome and progressive renal disease.siod is caused by bi-allelic mutations of smarcal1 gene, which encodes the hepa-related protein (harp), a member of the snf2 family of atpases, acting as chromatin remodelers within multi-protein complexes. a 5-year-old patient was hospitalized in november 2011, after detection of proteinuria (1.5 g/day). at our first clinical examination: height-weightgrowth retardation, thinning hair, thin and hypopigmented skin, arched palate and normal neuro-psychological development.serological examination showed proteinuria (1.7 g/day), hyperchol. (col tot 242 mg/dl, ldl-col 165 mg/dl) and lymphocyte deficiency (17.6%).renal function and complement levels were normal. lymphocyte subpopulations showed a decrease of t lymphocytes and an increase of nk cells(cd16 + cd56 +).the patient had also a detour back-lumbar scoliosis and normal kidneys in size, but with reduced corticomedullarydifferentiation. we started therapy with ramipril 2.5 mg/day. the 24 hrs urine exams performed monthly showed persistent proteinuria (500-800 mg/day). at the end of april 2012, for the persistence of proteinuria, we performed renal biopsy, which showed focal and segmental glomerulosclerosis. at discharge, she started therapy with irbesartan 75 mg/day with significant reduction of proteinuria (140 mg/day). after 6 months of therapy, thepatient did not present proteinuria and her renal function was normal. the molecular genetic study of smarcal1 gene revealed that patient was compound heterozygous for two mutations: a novel missense mutation in exon 3, inherited by mother, and a nonsense paternally-derived mutation in exon 17, leading to a truncated smarcal1 protein. our data allow us to diagnose a schimke immuno-osseous dysplasia (siod). in most patients, life expectancy is limited to childhood or early adolescence, due to the onset of stroke, infections,hematopoietic bone marrow failure and renal failure. only patients with milder and late onset forms can survive until adulthood. gain of glycosylation in integrin-alpha-3 causes nephrotic syndrome and lung disease objective: congenital nephrotic syndrome and interstitial lung disease is a rare multiorgan disorder, characterized by disrupted basement membrane structures. itga3 gene mutations were recently identified as the genetic cause of this disorder, but the disease mechanism remains poorly understood. methods: we describe a patient who presented with neonatal respiratory distress, glomerulosclerosis, proteinuria, pulmonary hypoplasia and alveolar glycogenosis, who died 7 months after birth due to respiratory insufficiency. a genome-wide screening for deletions and duplications revealed a large homozygous region that included the itga3 gene. we sequenced the gene and then conductedin vitro characterization studies to investigate the effect of the variant on the protein function. results: a novel homozygous missense mutation was identified in the coding region of the itga3 gene, which introduces an n-glycosylation motif to the protein sequence. thereby, the mutant integrin alpha-3 protein becomes hyperglycosylated. functional studies demonstrated that the conformation of integrin alpha-3 is affected and the mutant alpha-3 precursor is targeted for degradation. consistent with these findings, alpha-3 integrin was not detected in the patient glomeruli. furthermore, integrin alpha-3 protein expression was absent in murine podocytes that lack endogenous integrin alpha-3 and transfected with mutant itga3. conclusion: our findings underscore the role of the integrin alpha-3beta-1 complex as the main regulator of podocyte basement membrane integrity. here, we show that hyperglycosylation of the integrin alpha-3 subunit, causing the complete lack of alpha-3-beta-1 expression on the basement membrane, is a new pathogenic mechanism underlying congenital nephrotic syndrome and interstitial lung disease. itga3 mutation screening was directly implemented in dna diagnostics, facilitating early diagnosis, recurrence risk estimation, and genetic counselling. the clinical study on pkhd1 gene-based testing for the diagnosis of arpkd objective: in order to study the implications of pkhd1 gene-based testing for arpkd diagnosis in clinical practice, we performed a prospective study to apply pkhd1-based genetic testing to the suspected arpkd patients. methods: 12 suspected arpkd patients from 10 unrelated families were detected on mutations of pkhd1 gene by pcr direct sequencing. these patients were evaluated by combining the testing results and their clinical materials. results: in the 6 detected children, 4 mutations (p137s, v836a, q1574h, l2658x) were novel and 7 mutations (t36m, r559w, r760c, n830s, a1262v, q3899r, q4048r) were previously described. 4 of the 11 variants were definite pathogenic mutations. two pathogenic mutations in both chromosomes were found in 2 out of 6 families (30%), which greatly aid to making definite diagnoses. the 4 families with perinatal presentation consisted of 2 fetuses and 2 couples. one definite pathogenic mutation (s3457c) was found in the wife of family no.9, however, it was still difficult in conforming the diagnosis owing to lack of the pathogenic mutation from the husband. for the other families, only some potential mutations were found.two in four children with congenital hepatic fibrosis were detected two pathogenic mutations in both chromosomes, and their liver functions were obviously lower than the other two children without pathogenic mutations. conclusion: pkhd1 gene-based testing is an effective means for the diagnosis of arpkd, at the same time it could improve the understanding of this disease by analysing the testing results and their clinical materials. objective: to present a case of schimke immuno-osseous dysplasia (siod) which is the first to be reported from egypt. methods and results: this article presents a case from egypt with mild form of siod presented at the age of 14.5 years with disproportionate short stature, srns (focal segmental glomerulosclerosis), laboratory evidence of cellular immune deficiency and radiologic characteristics of spondyloepiphyseal dysplasia and died at the age of 16.5 years with bone marrow failure and severe pneumonia. conclusion: we emphasize that siod is to be considered in children with growth retardation, srns and bone abnormalities and that inherited nephrotic syndrome may be presented in late childhood or even adolescence and siod suspected patients even before full picture development should be closely monitored for proteinuria, hypertension, cellular immunity and opportunistic infections especially with the need to start immune suppressive therapy for nephrotic syndrome. abstract# p-sat244 denys-drash syndrome presenting with polycystic kidneys objective: denys-drash syndrome (dds) is characterized by a congenital or infantile nephrotic syndrome due to diffuse mesangial sclerosis, male pseudohermaphroditism and a strong predisposition to develop wilm's tumors and gonadoblastoma's. the syndrome is caused by a dominant mutation in the wt1 gene. we report a case of dds associated with renal cysts, which has never been described so far. we report a case of dds in a 3 months old girl presenting with proteinuria and bilateral cortical cysts on renal ultrasound. autosomal recessive polycystic kidney disease was excluded by a normal liver biopsy. a kidney biopsy showed diffuse mesangial sclerosis. at the age of 7 months, she developed a unilateral wilm's tumor, which was treated by heminephrectomy and chemotherapy. the renal cysts were still present on ultrasound. histological examination of a cyst (located in the resected specimen, but separate from the wilm's tumor) showed one layer of flattened epithelial cells, without any evidence of malignancy. the combination of diffuse mesangial sclerosis and a wilm's tumor pointed to the diagnosis of dds. genetic analysis showed a de novo heterozygous missense mutation c.1186g>a (p.asp396asn) in the wt1 gene, previously described in patients with dds, confirming the diagnosis. because polycystic kidneys have never been reported in dds, we explored several genes responsible for these renal manifestations, such as hnf-1β, pax2, pkd1 and pkd2. remarkably, we identified a heterozygous missense variant c.12439a>g (p.lys4147glu) in the pkd1 gene. mutations in pkd1 lead to autosomal dominant polycystic kidney disease (adpkd). the pathogenicity of the newly identified missense variant in our case was evaluated by different mutation prediction software programs and was classified as being 'likely pathogenic'. the same variant was found in the patient's mother, having no renal cysts on ultrasound and in the grandfather, having bilaterally renal cysts. conclusion: this is the first case of dds in combination with polycystic kidneys. we hypothesize that pkd1 c.12439a>g variant might be an incompletely penetrant allele that can cause a severe phenotype of adpkd in association with a wt1 gene mutation. the phosphatase and tensine homolog (pten) gene is a tumor suppressor gene located on the long arm of chromosome 10 (10q22-23). the pten protein is broadly expressed in cells throughout the body, acting as both lipid and protein phosphatases, and regulates intracellular signaling via various pathways. reduced pten protein resulting from a pten gene mutation may enhance cell proliferation, resist from apoptosis. in addition, it has became clear that, in vascular endothelial cells, pten gene abnormalities lead to increased expressions of vascular growth factors, such as angiotensin ii (ang ii), that are essential to angiogenesis. recent reports revealed a germline mutation of the pten gene to cause several syndromes with generalized, multiple hamartomatous lesions of tridermic origin. thus, the new concept of pten hamartoma tumor syndrome (phts) has been proposed. to the best of our knowledge, we describe here for the first time a case of focal segmental glomerulosclerosis (fsgs) with phts. a 3-year-old girl was found to have proteinuria and hematuria on health examination and referred to us for persistent urinary abnormalities. igm nephropathy were diagnosed by renal biopsy, and she started taking an angiotensin-converting enzyme inhibitor. however, proteinuria was not reduced, and an oral angiotensin ii receptor blocker (arb) was administered. proteinuria persisted and she underwent renal biopsy again, yielding a diagnosis of fsgs. despite continued oral arb treatment, proteinuria is ongoing with a urine protein-to-creatinine ratio of approximately 0.5, and mild renal impairment. at age 13 years, 2 years ago, a neck mass prompted a detailed examination which revealed multiple thyroid nodules, ovarian cysts (mucinous cystadenoma), hemangiomas in the plantar and femoral regions, spinal cord lipoma, and renal nodular lesions, necessitating follow-up. subsequently, additional workup detected a pten gene heterozygous mutation (exon 8 codon 335 cga(arg) tga(stop)) and she was diagnosed with phts. methods: a 7-day-old girl, the first child of non-consanguineous chinese parents, was hospitalized due to edema, gross proteinuria, and progressive renal failure. she was delivered spontaneously at 36 weeks of gestation with a birth weight of 2700gand a body length of48cm. during the delivery, she was experienced mild asphyxia. placental weight was large, and the amniotic fluid was meconium-stained. pregnancy was unremarkable and had included routine prenatal ultrasound evaluation. the family history of proteinuria or renal failure was negative. on admission, the findings from physical examination showed the patient had bilateral microcoria and limb hypotonia. results of serological testing for torch infections were negative. since pierson syndrome was suspected, a kidney biopsy was performed when she was aged 10 days. meanwhile, all coding exons of lamb2 were analyzed by using pcr and direct sequencing. results: electron microscopy revealed some glomerular basement membranes were thick and thinning, with splitting of the lamina densa. in addition, the foot processes of podocytes were diffusely effaced, and the number of podocytes increased. two different novel nonsense mutations (trp16x and gln748x) of lamb2 were detected in the patient. these mutations were inherited from her parents respectively. conclusions: newborn with unexplained renal insufficiency or nephrotic syndrome should consider pierson syndrome. our report extends the genotypic spectrum of pierson syndrome. a familial wt1 mutation associated with incomplete denys-drash syndrome we report a familial wt1 missense mutation in exon 9 (1180c>t, r394w) in three members of one family. patient 1, a 2 years old boy, was born at ambiguous genitalia (46, xy karyotype), penoscrotal hypospadias and bilateral inguinal hernias. he was found proteinuria on the preoperative examination and renal biopsy showed diffuse mesangial sclerosis. patient 2, a 3 years old, is the older sister of patient 1, who has normal genitalia. she was found proteinuria and renal biopsy showed focal mesangial sclerosis. wilms's tumor was not found in both of them. a wt1 mutation was detected in both the two patients and their farther. the patients are considered as incomplete dds and they can inherit mutations from their father. so, this finding will provide new evidence for a better understanding of dds and further familial studies in patients of dds are need. ying chen 1 , songming huang 1, 2 , guixia ding 1, 2 , hongmei wu 1 , aihua zhang 1, 2 1 nephrology, nanjing children's hospital, nanjing, china 2 institute of pediatrics, nanjing medical university, nanjing, china objective: to investigate the correlations between peroxisome proliferator-activated receptor (ppar)-α, ppar-γ, and ppar-γ coactivator-1α (pgc-1α) gene polymorphisms and susceptibility to primary nephrotic syndrome (pns). methods: patient genotypes were determined using the polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) technique for the pro12ala and val290met polymorphisms of the ppar-γ gene, the gly482ser polymorphism of the pgc-1α gene, and the leu62val polymorphism of the ppar-α gene. the gene polymorphisms in 111 cases of pns in children and 111 normal controls (nc) were analyzed and compared to examine the differences in the clinical metabolism index, proteinuria, renal pathological types, and hormone treatment responses among pns children with different genotypes. results: the ppar-γ pro12ala and pgc-1α gly482ser mutations were not associated with the occurrence, blood pressure, total cholesterol, a decrease in glomerular filtration rate (gfr), urine protein excretion at the onset of disease, renal pathological type, or hormone treatment response in children with pns. although the homa-ir values for children with the a allele did not differ significantly from those of children with the pp genotype of the ppar-γ gene, their insulin levels were decreased and their isi values were significantly increased (p=0.012 and 0.006, respectively). the triglycerides (tg) levels of children with the aa genotype of the pgc-1α gene were significantly increased (p=0.026). in addition, the ppar-γ (val290met) and ppar-α (leu162val) gene polymorphisms did not show any mutations in the 111 cases of pns in children or the 111 nc children. conclusion: the pro12ala mutation of the ppar-γ gene may be correlated with a decrease in insulin secretion and an increase in insulin sensitivity and the pgc-1α (gly482ser) gene polymorphism may be a causative genetic factor for the triglyceride abnormalities in children with pns. the relationship between endothelin-1 gene polymorphisms and primary nephrotic syndrome in children objective: nphs1 mutations have been reported in cns. however, no hot mutation has been described in chinese family. in this study, nphs1 mutations were analyzed in a chinese family with two siblings died of cns. methods: genomic dna samples were extracted from peripheral blood of the proband, her parents, and 150 unrelated normal individuals. all 29 exons of nphs1 were detected by polymerase chain reaction(pcr) and direct dna sequencing. results: the proband, a 15-day-old girl, weighed 3500g at birth. the placenta was one time heavier than usual. she was hospitalized with edema of legs, heavy proteinuria(+++), and hematuresis(+++). two compound heterozygous mutations were identified in exon 15 (c.2020c>t, p.p674s), which was detected in her father, and in exon 16(c.2207t>c, p.v736a), which was also detected in her mother. these two new mutations were not found in the 150 chinese controls. conclusion: new compound heterozygous nphs1 mutations (c.2020c>t and c.2207t>c) were identified in a chinese family with two siblings of congenital nephrotic syndrome, which were suggested to be the causative mutations in this family. the compound heterozygous mutations (c.2020c>t and c.2207t>c) lie between ig6 and ig7 domain which has a free cysteine residues. these mutations might cause misfolding and defective intracellular transport, with consequent absence of the mutant nephrin on the plasma membrane. abstract# p-sat255 sporadic myh9-related disease: a case report and mutational analysis of myh9 gene .genetic analysis confirmed that these three cases had intron 9 (+kts) mutation.after confirmation of fs, cytogenetic analysis showed xy in girls though phenotypically there were females.abdominal ultrasound in them showed normal uterus with streak gonads and gonadectomy was done for both and histologically reported as dysgerminoma stage i. familial girl aged 12 entered esrd and received live related renal transplant from her mother. the sporadic girl aged 9 years also entered end stage renal disease rapidly and died. the third was a nephrotic boy aged 9 years with fs. he had bilateral hypoplastic testes. his chromosome was xy. renal biopsy showed mcd with igm deposits and partially responding to therapy. a six year old girl presented at the emergency department with a history of 3 episodes of vomiting in 24 hours. she had a history of polyuria and polydipsia with a current daily intake of 3 liters. physical examination revealed signs of mild dehydration. plasma electrolytes revealed hyponatremia (128 mmol/l), hypokaliemia (1.6 mmol/l), metabolic acidosis with normal anion gap (14 mmol/l), hypophosphatemia (0.86 mmol/l), hypouricemia (90 umol/l) and normal serum creatinine (29 umol/l). urinalysis confirmed the na, k, ph and acid uric losses: na (67 mmol/l, fractional excretion 2%), k (83 mmol/l, ttkg 30), tubular phosphate reabsorption of 18%, and fractional excretion of uric acid of 30%. cystine level in leucocytes was normal. she was discharged six days later with oral supplementation of potassium and phosphorus. laboratory studies 3 weeks later revealed surprising findings with persistent hypokaliemia (3 mmol/l), metabolic alcalosis (hco3 30 mmol/l), hypomagnesemia (0.65 mmol/l), and hypocalciuria (calcium/creatinine 0.06 mmol/mmol). we therefore sequenced the slc12a3 gene and we found that she is compound heterozygous for 2 known missense mutations (p.thr304met and p.gly439ser). conclusion: gs can have atypical presentations including severe polyuria; it should be suspected in case of severe hypokaliemia even in the absence of the other classical features. this case report emphasizes the need for repeated laboratory tests in unclear tubular disorders, especially outside of confusing intercurrent illness. a single basepair mutation causes cystinosis in the majority of western cape patients. conclusion: renaltube is being used by pediatric nephrologists over the world for the study of their patients with primary tubular disorders. renaltube will likely contribute to a better care of these children and to a better scientific understanding of primary tubular diseases. the creation and development of this sort of international collaborative efforts must be encouraged within the pediatric nephrology community. objective: to study molecular mechanism of hypercalcemia-induced nephrogenic diabetes insipidus (ndi) by identification of proteins in inner medullary collecting duct (imcd) responsible for this syndrome. methods: the effect on rat kidney medullary collecting duct of early onset ndi resulting from parathyroid hormone-induced hypercalcemia was studied using proteomics and phosphoproteomics in native inner medullary collecting duct (imcd) cells. imcd tryptic peptides and phosphopeptides were identified and quantified by mass spectrometry using a label-free methodology. the major findings were confirmed by selected reaction monitoring study, immunoblot, and immunohistochemistry. results: a total of 5,866 peptides corresponding to 1,107 proteins and 1,388 phosphopeptides of 580 proteins were identified, with significant changes in abundance of 69 proteins and 49 phosphopeptides in early onset ndi versus vehicle controls. gene ontology terms and pathway analysis revealed that hypercalcemiaaffected proteins and phosphoproteins are associated with integrin signaling, and actin cytoskeleton organization. immunoblot and selected reaction monitoring lc-ms/ms studies confirmed the hypercalcemia-regulated proteins (agrin, arcp1b, capg, erm, itgb1, lamb2, and lamc1) and phosphoproteins (myh9, add1, dync1li1, cgnl1, aqp2). hypercalcemia induced changes in abundance of vasopressin-regulated phosphorylation of aquaporin-2 (aqp2) at ser256 and ser261, but not total aqp2, and decreased abundances of slc14a2 urea transporters ut-a1, ut-a3, and phospho-ser486-ut-a1. the major findings were also identified in imcd of rats with vitamin d-induced hypercalcemia. filamentous actin aggregation was firstly demonstrated in imcd of rats with hypercalcemia-induced ndi from both pth and vitamin d. conclusions: early increasing in water excretion in response to hypercalcemia are dependent of changes in abundances of aqp2 phosphorylations, ut-a and its phosphorylations are consistent with prior literature pointing to key roles of the integrin signaling and the actin cytoskeleton in maintenance of collecting duct function. objective: to study molecular mechanism of hypokalemia-induced nephrogenic diabetes insipidus (ndi) by identification of proteins in inner medullary collecting duct (imcd) responsible for this syndrome. methods: the effect on rat kidney medullary collecting duct of early onset ndi resulting from hypokalemia was studied using proteomics in native inner medullary collecting duct (imcd) cells. imcd tryptic peptides were identified and quantified by mass spectrometry using a label-free methodology. the major findings were confirmed by selected reaction monitoring study, immunoblot and immunohistochemistry. results: a total of 2,477 peptides corresponding to 821 proteins were identified with significant changes in abundance of 189 proteins in early onset ndi versus vehicle controls.gene ontology terms and pathway analysis revealed that hypokalemia-affected proteins are associated with generation of precursor metabolite and energy and regulation of actin cytoskeleton. immunoblot and selected reaction objective: inherited distal rta (drta) is a rare condition and is almost always observed in children as a primary entity. mutations in genes encoding transporter or channel proteins operating along the renal tubule may result in a variety of functional defects. the identification of the molecular defects in drta may provide a basis for future design of targeted therapeutic interventions and, possibly, strategies for gene therapy of these complex disorders. for this reason, we evaluated mutations in slc4a1 and atp6v1b1 genes. methods genomic dna from 20 pediatric patients diagnosed with drta was extracted from peripheral blood samples. sequencing was performed for five exons of slc4a1 (14, 15, 17, 19, 20) and two exons of atp6v1b1 (1, 7). all the selected exons are considered hotspots for mutations associated to this tubular disorder. results silent mutations were identified in both studied genes. the mutation c.2688t>c was identified in exon 20 of slc4a1 in one patient and the second variation (c.27t>c) was found in exon 1 of atp6v1b1 in two patients. although previously described, these silent variations are not highly frequent in the overall population. also in slc4a1, exon 19, two nonsynonymous variations were identified in the same patient (p.pro854leu and p.val862ile). the p.val862ile variation was also found in three other patients. it has been shown that these variations are rare polymorphisms in the population, but they have already been associated to diego group erythrocyte antigen. in exon 1 of atp6v1b1 the variation p.met2? was presented in twelve patients and the mutation p.thr30ile was found in six patients. although they occur in the coding region of atp6v1b1, these variations have been described as highly frequent in the population. dent's disease is an x -linked renal proximal tubulopathy associated with mutations in clcn5 (dent's type 1) and ocrl1 (dent's type 2).ocrl1 mutations also cause the oculocerebrorenal syndrome of lowe. we report the case of a 5 year old boy with dent's disease associated with a novel hemizygous change, c.2t>c p.(met1) in exon 1 of ocrl. our patient presented at 3 years of age with incidental finding of non-nephrotic range proteinuria. he had elevated urinary beta -2 microglobulin, retinol binding protein and hypercalciuria. he was developmentally normal and is otherwise of good general health. slit lamp examination and vision were normal. he had normal renal function but had very poor renal accumulation of 99mtc-dmsa on renoscintigraphy. genetic testing identified a hemizygous change, c.2t>c p.(met1), in exon 1 of ocrl, which affects the translation initiation codon. his healthy 8 year old brother who was also found to have low -molecular weight proteinuria and hypercalciuria, is currently being investigated. to the best of our knowledge, the hemizygous change, c.2t>c p.(met1?) in exon 1 of the ocrl gene which was identified in our patient with dent's disease represents a novel variant which has not been previously reported in a dent's disease patient. abstract# p-sat274 enamel-renal syndrome associated to splenic and ovarian calcifications: a case report sameh mabrouk, noura zouari, houda ajmi, jalel chemli, menair tfifha, saida hassayoun, saoussen abroug , abdelaziz harbi pediatrics, university hospital of sahloul, sousse, tunisia enamel-renal syndrome (omim204690) is a rare condition characterized by amelogenosis imperfecta and nephrocalcinosis.we report a new pediatric case of this rare association with the particularity of associated splenic and ovarian calcifications. this report concerns a 13-year-old girl, born to consanguineous parents (first degree cousins). she has no family history of nephrocalcinosis or kidneydisease. her unique brother, aged 8 years, is in good health and has no dental or renal problems. she was first seen at the age of 12 years in dentistrydepartment because of dental abnormalities, the diagnosis of amelogenosis imperfecta was made and the patient was further investigated. a renal ultrasound showed a bilateral medullary nephrocalcinosis. ct confirmed bilateral nephrocalcinosis which was associated to ovarian and splenic calcifications. besides this young girl has a normal growth, her puberty began at the age of 12 years. laboratory findings including serum electrolytes, urea, creatinine, calcium, phosphate, parathormone and alkaline phosphatase were within normal ranges. on urine examination we found a hypocalciuria, with normal sodium and phosphate excretion. the patient is regularly seen in both dentistry department and pediatrics. the aim of this report is to highlight the important role of pediatricians as well as dentists in recognizing this rare and uncommon syndrome. objective: ipex syndrome, a hereditary (x-linked) immune dysregulation with autoimmune polyendocrinopathy and enteropathy, as the basic manifestations, presents a rare and severe disease. the objective of this case report is to highlight the pleomorphism of the syndrome. methods: the authors report the case of a male infant, with a family history of three male siblings affected by ipex syndrome. the patients' medical records were reviewed in order to describe the case of the youngest one. results: during the follow-up of the youngest of three siblings, who presented eczema and intestinal manifestation, without compromised pancreatic and thyroid function, different from other two siblings, it was noticed the pattern of dent's disease. we registered hypophosphatemia, hypercalciuria, glycosuria, low molecular weight proteinuria and ultrasound revealed second stage bilateral nephrocalcinosis. in this child there was no apparent glomerular involvement, as it was seen in the eldest sibling. conclusion: dent's disease is an x-linked renal proximal tubulopathy associated with mutations in the chloride channel gene clcn5 (xp11.22), which is next to foxp3 gene on the x chromosome (xp11.23-q13.3). it seems that in this sibling mutations occurred in exons of both of these genes. this case is to remind on pleomorphic potential of mutations that occur near the coding regions of the foxp3 gene. objective: multiple target organ defects (mtod) is a subgroup of pseudohypoaldosteronism (pha) type i and salt wasting is more severe in this form of pha i. it has a poorer outcome than the renal form, and therapy must be maintained throughout life. here, we reported an infant with mtod who had severe hyperkalemia resistant to classical treatment of pha. hyperkalemia was normalized only by peritoneal dialysis (pd). case: a 4 month-old boy was admitted to our hospital with persistent vomiting, metabolic acidosis, and severe hyperkalemia. there was consanguinity between parents and he had a healthy sister and brother. there was no history of medication. physical examination revealed the signs of volume depletion and acidosis. results: in laboratory examination, blood urea nitrogen was 71 mg/dl, creatinine 0.43 mg/dl, sodium 114meq/l, potassium 9.5meq/l, and chloride 97meq/l. blood ph was 7.33, base excess -12meq/l, and hco3 11meq/l. urinary analysis revealed low specific gravity (1003) with ph 8.0, and normal urinary sediment. urinary sodium was 68meq/l, potassium 1meq/l, and plasma renin activity 80.2ng/ml (2.7-37.0), aldosterone 2800pg/ml (50-900), cortisol 11.1 mg/dl (7-17.5), and acth 5.5pg/ml (10-469). renal ultrasonography did not show any abnormalities. sweet-test showed high sodium waste from sweet glands (144meq/l). the patient diagnosed as mtod. severe hyperkalemia persisted and was resistant to all treatment options for pha, including high-sodium and low-potassium diet, fluid resuscitation, potassiumbinding resins, indomethacin, fludrocortisone, and hydrochlorothiazide. nutritional status of the patient was also not good, and parents did not accept gastrostomy. hyperkalemia was corrected only after pd treatment, and his nutritional status improved dramatically. conclusion: in the case of type iv renal tubular acidosis resistant to therapy, mtod could be considered as a cause of acidosis. if the classical treatment options fail to correct hyperkalemia in these patients, pd may be a reasonable choice to normalize severe hyperkalemia. gülsün gülay yılmaz 1 erta yilmaz 1, 2 1 pediatric nephrology, md, antalya, turkey 2 akdeniz univercity, prof. dr, antalya, turkey tuberous sclerosis, which has an autosomal dominant hereditary disease with a high rate of spotaneous mutation, especially occupies the nervous system and many other organs like kidney, heart and lung. the case presented here was initially diagnosed as congenital heart and polycycystic kidney diasease, because of its characteristics which were quite different than expected for tuberous sclerosis. finally, it was evaluated at our pediatric department together with its dermatological and radiological aspects and defined as a tuberous sclerosis of delateddiagnosis. the case was discussed with its former and actual findings and presented as a warning for early diagnosis. abstract# p-sat285 the effect of bone marrow stem cells mobilization on expression of hif-1α and egf in ischemia/reperfusion-induced renal injury objective: to investigate the therapeutic effects of bone marrow stem cells which has been mobilized by g-csf and stem scf on expression of acute tubular necrosis hypoxia inducible factor-1a (hif-1α) and epidermal growth factor (egf), and to investigate the mechanism of scf and g-csf on the treatment of ischemia/reperfusion-induced renal injury. methods: 160 male sprague-dawley rats that are 8-10 weeks old were randomly allocated into 4 groups (n =40 ineach group): control group (group a), ischemic-reperfusion group (group b), scf + g-csf + ischemic-reperfusion group (group c) and scf + g-csf + control group (group d). detection index: hif-1α was measured by immunohistochemistry technique, the expression of egf and cd34 + cells in kidney was measured by strept avidin-biotin-peroxidase(sabc) and egf mrna by rt-pcr . results: (1) at 5 days postoperative, the cd34 + cells of group b and c was conspicuous higher than group a and d(p<0.05), group c was higher than group b(p<0.05). they gradually descended from 5 days with the time prolonged. (2)at 5 days postoperative, there was significant difference of the expression of hif-1α between group a and d (p<0.05). the expression of hif-1α of group b and c showed higher positive reaction at 5 days postoperative then decent to normal. at each time the expression of hif-1α of group c was significant higher than other groups (p<0.05). (3)the egf expression of group b and c showed higher positive reaction at 5 days postoperative and decent to normal with the time prolonged, group b peaks at 17 days and higher than group a, group c peaks at 10 days, and it is the highest (p<0.05 results: in contrast to model group, atn treated with adscs displayed: cells expressing green fluorescent protein were dectected in injured tubule in kidney . treatment group were significantly higher than model group, p<0.05; renal damage is lighter; kidney damages were relative gently and histopathologic lesion scores was relative lower; while ki-67 positivece cells in treatment group were more than those in model group (p<0.05); the expression of bax, bcl-2 and cell apoptotic index(ai) in treatment group was lower than those in model group , p<0.05, but bax/bcl-2 ratio was higher than those in model group. conclusion: allogenic adscs transplantation can accelerate proliferation of renal tubular epithelial cell and suppress apeptosis injury through up-regulating the ratio of bcl-2/ bax and down-regulating the expression of bax protein in acute kidney injury. objective: previously we showed that pretreatment with the antidepressant fluvoxamine (flu) improves postischemic survival and ameliorates functional and structural kidney damage after renal ischemia/reperfusion (ir). in heart ir injury flu is protective through activating the sigma-1 receptor (s1r) -nitric-oxide synthase (nos) system. here we studied the intrarenal vasoregulatory effect of flu and analyzed the renal s1r-nos cascade. methods: male wistar rats were were treated i.p. either with (1) vehiculum (veh); (2) flu (20 mg/bwkg; flu); (3) flu+ s1r antagonist ne-100 (1mg/bwkg; fn); (4) flu+ non-selective nos blocker l-name (10mg/bwkg); (5) flu + selective endothelial (e) nos blocker l-nio (20mg/bwkg); (6) flu and selective neuronal (n) nos blocker 7-ni (25mg/bwkg). 30 minutes later rats were either harvested or subjected to 50 minutes of ischemia followed by 24 hours of reperfusion. sham-operated animals served as controls (n=10/group). renal s1r, akt, enos and nnos protein levels were measured, the alteration of renal capillary diameters was determined in vivo using muliphoton microscopy. results: ir induced renal vasoconstriction, which was ameliorated by flu. this increase was neutralized by all nos blockers, mostly by 7-ni. after ir all measured protein levels increased. s1r expression was similar in all treatment groups. akt and enos levels were lower, while nnos levels were higher in the flu treated group compared to veh and fn. the acute vasodilatative effect of flu 30 minutes after treatment was suspended by l-name and 7-ni and even reversed by l-nio. s1r, akt and enos protein levels were elevated 30min after flu treatment, while nnos levels remained unchanged. discussion: pretreatment with the s1r agonist flu -used chronically without notable side-effects -improves postischemic renal perfusion through the activation of s1r -nos system in a time and nos isoform specific manner. based on this data one can hope to find a new therapeutic target in the treatment of renal ir damage through the modulation of the s1r. methods: 36 sd rats were randomly divided into model group, intervention group and normal group, 12 rats in each group. intraperitoneal injection with gentamicin for 7 days to establish renal tubular injury rat model. then the intervention group rats were transplanted with 4×10 6 /ml bm-mscs via tail vein. 7 days after transplanted with bm-mscs, took blood and kidney specimen of rats for testing. serum creatinine (scr), urea (bun), malondialdehyde (mda), superoxide dismutase (sod), glutathione peroxidase (gpx), heme oxygenase -1 (ho-1) were detected by spectrophotometry. he staining was used to evaluate the change of renal tissue pathology, then score the renal tubular injury according to the nangaku semiquantitative scoring method. tunel method was used to detect the apoptosis of epithelial cell rate in renal tubular, while immunohistochemistry was used to detect the proliferation of renal tubular epithelial cells (pcna labeling index). results: 1. scr and bun of intervention group rats were lower than those in the model group, the difference was statistically significant (p <0.01); 2. renal tubule pathological score of intervention group rats were lower than those in the model group, the difference was statistically significant (p< 0.01); 3. apoptosis ratio of renal tubular epithelial cell in intervention group rats were lower than the model group, the difference was statistically significant (p<0.01); 4. the pcna labeling index of intervention group rats were higher than those in the model group, the difference was significant (p<0.05); 5. the mda level was significantly reduced in intervention group rats than in the model group (p < 0.01); 6. the sod, gpx and ho-1 inintervention group rats were significantly increased than those in the model group (p < 0.01). conclusion: antioxidant factors such as sod, gpx and ho-1 were significant increased after bm-mscs transplanted into rats. it means that bm-mscs may have antioxidant effect to heal the renal tubular damage. the effect on regeneration and repair in renal tubular epithelial cell after injury deal with at2r antagonist pd123319 objective: to study the effect of proliferation of renal tubular epithelial cell after injury deal with at2r antagonist pd123319,and to explore the function and mechanism of at2r in the regeneration and repair after acute kidney injury. methods: to establish the human renal proximal tubule cells (hk-2 cells) hypoxia /reoxygenation model. hk-2 cells were divided into two groups. (1) (1) these results suggest that the renal proximal tubule epithelial cells after hypoxia/reoxygenation can be simulated tubular epithelial cell process damage; (2) the proliferation of renal tubular epithelial cell after injury was inhibited by pd123319.at2r may play an important role in the regeneration and repair in the kidney by means of promoting the proliferation of renal tubular epithelial cells. (3) arb have no significantly inhibit the proliferation of renal tubular epithelial cell after injury, suggesting that at1r may not have major role in regeneration and repair after acute kidney injury. the effect and mechanism on regeneration and repair in renal tubular epithelial cell after injury by the inhibitory proliferation effect of acei and arb objective: to study the effect of regeneration and repair of renal tubular epithelial cell after injury deal with fosinopril and valsartan, and to explore the function and mechanism of acei and arb induced acute kidney injury by suppressing proliferation. objective: ischemia-reperfusion injury (iri) is a major cause of acute kidney injury (aki) and both innate and adaptive immunity contribute to the pathogenesis. t cell immunoglobulin-3 (tim-3) has been reported as an important regulatory molecule and plays a pivotal role in several inflammatory diseases. however, it keeps unknown whether tim-3 is involved in renal iri. to investigate the expression of tim-3 on kidney mononuclear cells (kmncs) from mice with renal iri and explored its role in the pathogenesis of renal iri. methods: the left renal pedicle was clamped in c57bl6 mice for 45 min, followed by reperfusion. animals were sacrificed at baseline, day 1,3. flow cytometry was used to quantify tim-3 expression on kmncs ,cd4 + t cell,cd8 + t cell,foxp3 + tregs and cd19 + b cell. the levels of tnf-α, ifn-γ, il-4 and il-10 in kidney tissue were measured using elisa. results: at day 1, the increased expression of tim-3 on kmncs ,cd4 + t cell,cd8 + t cell,foxp3 + tregs in the injured kidney from mice with renal iri compared to those from uninjured kidney tissues and baseline (p<0. 05). percentage of tim-3 + cells in kmncs showed an inverse correlation with kidney injury score and kidney tnf-α level. similar negative correlations were found between kidney injury score and tim-3 levels on cd4 + t, cd8 + t cells. consistently, tim-3 expression on cd3 + t cells was further increased in mice at day 3. tim-3 expression on foxp3 + tregs negatively correlates with kindey tnf-α. conclusion: tim-3 might participate in the proceeding of renal iri by regulation on various cd4 + t cell subsets. tim-3 might be a potential new marker for assessing severity of renal iri. expression of galectin-9 and tim-3 in kidney of mice with renal ischemia reperfusion injury objective: t cell immunoglobulin-3 (tim-3) is a surface molecule expressed on various immune cells which plays a central role in immune regulation. identification of galectin-9 (gal-9) as a ligand for tim-3 has established that the tim-3/gal-9 pathway has been linked to several inflammatory diseases by regulating adaptive and innate immunity. to study the expression of gal-9 and tim-3 in kidney of mice with renal ischemia reperfusion injury (iri). methods: thirty c57bl6 male mice were randomized into renal iri groups with and without recombinant gal-9. the left renal pedicle was clamped in c57bl6 mice for 45 min, followed by reperfusion. animals were sacrificed at baseline, day 1,3,10, 21 after iri. gal-9 and tim-3 mrna levels in kidney tissues were determined using real-time rt-pcr. expression of gal-9 in kidney were detected by immunohistochemistry staining .the levels of tnf-α, ifn-γ,il-4 and il-10 in kidney tissue were measured using elisa. results: the expression of gal-9 and tim-3 mrna in the injured kidney tissues increased significantly compared with uninjured kidney tissues and baseline (p<0. 05). compared with the uninjured control and baseline control, the expression of tnf-α and ifn-γ increased significantly in the injured kidney. the expression of gal-9 and tim-3 mrna was positively correlated with renal il-4 and il-10 level (r=0.792, r=0.79 respectively; p<0. 05), but negatively correlated with kidney tnf-α and ifn-γ level (r=-0.69,r=-0.75 respectively,p<0.05). after recombinant gal-9 treatment for three days, the kidney injury ameliorated and inflammatory cytokines (tnf-α and ifn-γ) decreased. the expression of gal-9 and tim-3 in kidney tissues increase in mice with kidney iri. tim-3/gal-9 pathway are closely related to inflammatory process in renal iri. objective: we previously found that rgc-32(response gene to complement-32), a key factor in regulating cell cycle, plays an important role in dealing with epithelial-mesenchymal transition (emt). this study aimed to evaluate the effects of rgc-32 regulating cell cycle in renal tubular epithelial cells injury and repair. methods: (1) objective: autophagy is a lysosomal degradation pathway that is essential for cellular stress adaptation and normal homeostasis. increased level of autophagy has been reported in the post-ischemic kidneys by static analysis. this study aimed to understand the dynamics of epithelial autophagy in kidneys following acute ischemic injury and during renal repair. methods: taking the advantage of differential ph sensitivity of rfp (pka 4.5) and egfp (pka 5.9) fluorescence, we generated a new strain of cag-rfp-egfp-lc3 mice to distinguish early autophagic vacuoles from autolysosomes and to monitor autophagic process in the kidneys with ischemia-reperfusion injury (iri). results: renal epithelial cells responded to nutrient deprivation with easily detectable fluorescent puncta that represented autophagic vacuoles and corresponded to lc3-ii and atg5 protein levels. the majority of the egfp lost its fluorescence in the acidic environment of the autolysosomes where bright rfp signals remained. in normal kidneys, few egfp and rfp puncta were present in the nephron. iri led to dynamic changes in autophagic process in the proximal tubules with the number of egfp puncta reaching the peak at 1 day and returning to the control level at 3 days whereas rfp puncta persisted at a high level through 3 days post injury, indicating autophagy initiation at 1 day but autophagosome clearance at 3 days as kidneys were recovering. since rfp puncta persisted in cells with recent autophagy, we examined ki67 expression and found significantly lower proliferation in cells that contained rfp puncta, suggesting that autophagic cells were less likely to divide for tubular repair. furthermore, 87% proximal tubular cells with mtor activation indicated by p-s6 kinase expression contained no rfp puncta. inhibition of mtorc1 activity with rapamycin caused a 2-fold decrease in cell proliferation. conclusion: our results highlight the dynamic regulation of autophagy in post-ischemic kidneys and suggest a role of mtor in autophagy resolution during renal repair. abstract# p-sat297 novel mechanisms by which heparin can regulate the vascular activity of angiotensin ii (ang-ii) and fibroblast growth factor-2 (fgf-2) and affect the outcome of acute kidney injury (aki) objective: critically ill children treated with extracorporeal membrane oxygenation (ecmo) and/or cardiopulmonary bypass (cpb) frequently develop hypertension, endothelial dysfunction, and acute kidney injury (aki). these patients show high serum levels of ang-ii and fgf-2, and are treated with heparin to prevent clotting disorders. however, the mechanisms by which heparin may affect the vascular activity of ang-ii and fgf-2 are not clearly understood. we carried out this study to determine whether heparin can modulate the vascular activity of ang-ii and fgf-2 by affecting the rho-a, rac-1, src, and pkc signaling pathways. methods: normal fvb/n mice were injected with adenoviral vectors carrying a secreted form of human fgf-2 or lac z vectors, and treated with heparin (5,000 u/kg) or control buffer (n=5 per group). vascular contractility was studied in pressurized isolated resistance-sized mouse mesenteric arteries, in the presence and absence of ang-ii and fgf-2. the activation of the src, rho-a, rac-1, and pkc signaling pathways were assessed by pull-down assays and western blots, both in vivo and in vitro. permeability changes were explored in cultured human renal glomerular endothelial cells (hrgec) using fitc-dextran. results: heparin significantly enhanced the fgf-2-induced activation of rho-a and rac-1 in the kidney and isolated mouse mesenteric vessels. in addition, heparin antagonized the ang ii-induced contractility of isolated mouse mesenteric vessels through rho-a and pkc-dependent pathways. these changes were reverted by fgf-2, and abolished by the rho kinase inhibitor y27632. both heparin and fgf-2, acting in a synergistic manner, increased the permeability of hrec by activating the rho-a and src signaling pathways. conclusion: we conclude that heparin and fgf-2, acting in a synergistic manner, can modulate the activity of ang-ii in the kidney, isolated resistance vessels, and cultured hrgec. these findings clearly identify novel mechanisms by which heparin, acting alone or in combination with fgf-2, may affect the control of blood pressure, renal perfussion, and capillary permeability in critically ill children treated with ecmo and cpb. abstract# p-sat298 cisplatinum (cis) toxicity in immortalized human kidney (hk-2) proximal tubular epithelial cells is independent of dna strand breaks and has implications for biology and therapy of renal cell carcinoma (rcc) results: viability of huh-7 and hk-2 cells decreased similarly after ic50 doses of cis with morphology and mtt assays. many dna damage genes, including atm-related genes, were expressed less at mrna and protein levels in both cell types. however, p53 expression decreased in hk-2 cells. comet assays showed extensive dna strand breaks in huh-7 but not in hk-2 cells. atm promoter activity increased in only huh-7 cells. also, s and g2/m populations were depleted by facs in huh-7 but not hk-2 cells. conclusion: hk-2 cells transformed by hpv e6/7 oncogenes displayed independence from cis-induced dna breaks and atmmediated cell cycle arrest. such independence from genotoxicity will help explain mechanisms imparting resistance to chemo-or radiotherapy and invasiveness in rcc. abstract# p-sat299 renal neutrophil gelatinase-associated lipocalin and kidney injury molecule-1 expression in children with acute kidney injury on henoch-schonlein purpura nephritis yue du, jinjie guo, ling hou, yubin wu, tingting sun paediatrics, post graduate trainee, china objective: to evaluate serum, urinary and renal neutrophil gelatinaseassociated lipocalin(ngal) and kidney injury molecule-1(kim-1) in children with aki on hspn by prifle or hspn with nephroticrange proteinuria. methods: we performed a prospective single-center evaluation of serum, urinary and renal ngal and kim-1 in a cohort of children. we recorded any relevant data including age, gender, weight, hemoglobin(hb), serum creatinine(scr), cystatine c(cysc), serum beta2-mg, albumine, urine beta2-mg, urine protein in all patients. each patient's estimated creatinine clearance was calculated using the original schwartz formula. blood sample and five ml of urine sample from each participating patient were collected for ngal and kim-1 using an enzyme-linked immunosorbent assay. analysis of proteins ngal and kim-1 using sabc immunohistochemical assay. results: twenty five patients were enrolled in the study. nine patients with aki-on-hspn(a-on-c) and six were done renal biopsy, sixteen patients with hspn with nephrotic-range proteinuria and ten were done renal biopsy. blood cystatinc, beta2-mg , scr, ngal and kim-1 were increased significantly in patients with a-on-c than those with hspn, and so do urine ngal, kim-1 and beta2-mg. there was no significant difference of proteinuria between the patient with a-on-c and the patients with hspn. immunohistochemical results showed that ngal and kim-1 were expressed in proximal tubule and their expression were significantly higher in a-on-c group than in hspn group. the correlation analysis showed that urine ngal and kim-1 were negative correlated with gfr and they were uncorrelated with proteinuria. conclusion: blood, urine and renal ngal and kim-1 were significantly increased in patients with a-on-c than those with hspn, and they were negative correlated with gfr. we may conclude that ngal and kim-1 may diagnose a-on-c patients more sensitive than scr. abstract# p-sat300 objective: neonatal period is an important stage in the development of renal function at the children. the frequency of renal damage in infants undergoing resuscitation is high, but non-specific clinical symptoms and low information existing survey methods impede their timely diagnosis. purpose -evaluation of diagnostic importance of determining the level of carbonic anhydrase ix (ca9) in the urine of newborns in critical states. methods: we evaluated human carbonic anhydrase ix in the urine of 40 newborns who had asphyxia at birth and receiving treatment in the intensive care unit -the main group. the control group consisted from healthy newborns (13 people). for the study used a sample of newborn urine collected at 1-2 days of age. carbonic anhydrase was determined using enzyme immunoassay kit. results: human carbonic anhydrase ix (ca9) -trans membrane protein, the main physiological function of which is to regulate the ph by the reversible hydration of carbon dioxide. the main pathogenic factor causing kidney damage of fetus is chronic fetal hypoxia. there is a single study hif-i alpha (hypoxia inducible factor-i alpha) in the blood, increased expression of which occurs during hypoxia. this is connected with damage of tubules and interstitial cells of the kidneys, their proliferation, synthesis of cytokines and extracellular matrix. in this case, activity of ca9 is reduced in the blood. normally, ca9 is missing in the urine, so its definition can be a marker of early renal dysfunction. the authentic increase of ca9 level in the main group was revealed in comparison with the control group ( and β2-mg, 59,723/ 32,616/ 1511/ 996/ 1084/ 600 μg/g cr. levels of each marker were very high in nb and 1m children, and subsequently decreased gradually. urinary α1-mg levels reduced the quickest, and became the same as at >=3 years old by 6 months after birth. conclusion: renal tubular function can be evaluated in children <3 years old using these normal values. the most stable and useful marker from early infancy seems to be urinary α1-mg. urinary biomarkers for gentamicin-induced acute kidney injury in the neonatal intensive care unit objective: gentamicin (gm) is an aminoglycoside frequently used in the neonatal intensive care unit (nicu). gm is nephrotoxic and may cause acute kidney injury (aki). serum creatinine (scr) appears to be an insensitive and unreliable marker for detecting aki. to determine whether urine biomarkers are useful for early detection of gm-induced aki in neonates in the nicu. methods: prospective, clinical, observational study. forty-six neonates (32m/14f) without pre-existent kidney disease were divided in a gm group (n=26) and a reference group (n=20). demographics, vital signs and clinical conditions were recorded. only neonates with a bladder catheter in place were included. urine samples were collected every two hours. biomarkers (gsta1-1, gstp1-1, kim-1, nag, ngal) were determined. residual blood samples were used to measure scr. results: the gm and reference group were comparable for gestational age, weight and mortality. neonates treated with gm are admitted longer than neonates in the reference group. treatment with gm resulted in higher scr compared to the reference group (58. 5 [44.8-58.5] vs. 34.0 [28.3-58.8]; p<0.05). higher levels of scr correspond with higher urinary excretion of all biomarkers, especially in neonates treated with gm. the average time until the highest peak was shorter for all biomarkers compared with scr (p<0.05). there was no difference in produced urine volume between the gm and the reference group. conclusion: higher scr levels correspond with higher urinary excretion of all biomarkers, especially in neonates treated with gm. gstp1-1 seems the most useful marker for early detection of aki in neonates. seong heon kim, sang wook mun, su young kim 1 1. pediatrics, pusan national university children's hospital, yangsan, korea objective: spontaneous tumor lysis syndrome (stls) before cancer treatment is rare and develop mostly in burkitt lymphoma and non-hodgkin lymphoma. here we report a case of stls secondary to tcell acute lymphoblastic leukemia(all) which presented with renal stone and subsequent aki. methods and results: a 6-year-old boy was admitted to our hospital for generalized tonic clonic seizure. one month ago, he visited other hospital for episodic right-sided flank pain and evaluations revealed microscopic hematuria, hyperuricemia and stone on right uretero-pelvic junction. his blood pressure was 160/90 mmhg and he did not have any dysmorphic features and he had developed normally. physical examination showed tender hepatomegaly (2 cm below costal margin) and no splenomegaly. his initial laboratory findings were as follows : bun 119.3 mg/dl, creatinine 4.77 mg/dl, uric acid 47.6 mg/dl, ldh 460 iu/l, wbc 11,900 /ul, hb 9.9 g/d l, platelet 242k /u l. there was no blast on his peripheral blood smear test. emergent hemodialysis was started because of aki, hypertension and seizure. his renal function, blood pressure, uric acid and electrolyte abnormalities gradually improved with appropriate therapy after 2 times of hemodialysis. but serum uric acid level increased again (from 6.1 mg/dl to 12.9 mg/dl), so allopurinol was added on. the cause of aki was unclear and we thought that aki presumed to be secondary to acute uric acid nephropathy caused by stls. after few days, bone marrow biopsy was done and demonstrated normocellular marrow without evidence of malignancy. after day 15 of hospitalization, abdominal pain with hepatomegaly was getting worse than before and uncontrolled high fever occurred. 20% of blasts were seen on his peripheral blood smear and subsequent second bone marrow biopsy demonstrated acute t cell lymphoblastic leukemia. then, he was referred to division of pediatric hemato-oncology on our hospital and induction chemotherapy was started. conclusion: stls with aki is very uncommon initial presentation of leukemia and stls presenting with renal stone is extremely rare. in a clinical situation of marked hyperuricemia with acute kidney injury, we need to consider occult malignancy and stls. the application of serum beta-2-microglobulin (beta-2-mg) and cystatin c(cysc)concentration to evaluation of renal function impairment in patients withneonatal jaundice yanan xin, cairong jiang, junfeng yang, hui xu, yuan zhang the fourth hospital of baotou, baotou, china objective: to explore the application of serum beta-2-microglobulin (beta-2-mg) and cystatin c(cysc)concentration to evaluation of renal function impairment in patients with neonatal jaundice. methods: 60 neonates with hyperbilirubinemia from jan. of 2012 to dec.of 2012 in pediatric department and 34 full term infants were chosen as research object, hyperbilirubinemia divided into mild group (bilirubin<256.5umol/l) and moderate severe (bilirubin> 256.5umol/l) group according to the level of bilirubin. the different of sex and age were not significant between neonates with hyperbilirubinemia and control group. serum beta-2-mg, cysc, cr and bun were measured in the two groups. results: serum beta-2-mg and cysc in 60 neonates of hyperbilirubinemia were significantly higher (p<0.01) than healthy neonates, meanwhile, serum cr and bun were significantly lower (p<0.01) than healthy neonates. after treatment, serum beta-2-mg and cysc of neonates with hyperbilirubinemia were significantly lower (p<0.01) than pretreatment. however, serum beta-2-mg were higher (p>0.05) abeta-d cysc were significantly higher (p<0.01) than normal group. but there was no significant difference between mild and moderate severe group in the level of serum beta-2-mg, cysc, cr and bun(p>0.05). the result implied that neonates with hyperbilirubinemia suffered for renal function to varying degrees. howerer, the damage can partially recovered after energetic treatment. clinical and pathological analysis of iga nephropathy with acute kidney injury minguang chen, xiaohua ye, qing yang nephrology, yuying children's hospital, wenzhou, china objective: to investigate the incidence, etiology, clinical pathological characteristics and prognosis in primary iga nephropathy(igan) children with acute kidney injury(aki). methods: retrospectively analysis the clinical and pathological manifestations and follow-up results of chlidren with primary igan and aki in our department from january,1996 to jun, 2012. results: there were 19 cases with aki in 196 chlidren with igan(9.7%), the peak serum creatinine were from 94.5umol/ to 282 umol/l. histological changes: with the formation of crescent in 10 cases, diffuse endocapillary proliferation in 5 example, 15 cases of renal tubular injury, 10 cases of red blood cell and protein cast, 1 cases with acute interstitial nephritis. multivariate logistic regression analysis showed: with massive proteinuria were independent risk factors of igan in children with aki (or = 27.370, 95% confidence interval was 3.151-237.740, p<0.01). the etiology of aki except with massive proteinuria, include: 1. iga nephropathy with severe glomerular damage, including crescentic glomerulonephritis and diffuse endocapillary proliferation; 2 complicated acute interstitial nephritis; 3 drugs causing decreased glomerular filtration rate; 4. renal tubular injury induced by gross hematuria. all of the patients were not on dialysis, hormone therapy in 13 cases (including 7 cases of methylprednisolone pulse therapy), 6 cases combined with cyclophosphamide treatment. except 1 cases no significant improvement, the renal functiones of all patients recovered or improved within 1-2 months after treatment. follow-up from 1 month to 7 years, 3 cases had renal function improved, but 2 were lost to follow-up and after 3 years enter to the chronic renal failure, 1 case with renal function loss after 32 months and repeated renal biopsy showed glomerular sclerosis of 31.6% during the follow-up period. conclusion: aki is not uncommon in children with igan, the causes are varied and massive proteinuria is independent risk factor among them. we should adopt different treatment strategy according to different causes and the short term prognosis is good. abstract# p-sat307 biopsy proven acute interstitial nephritis in children objective: biopsy proven acute interstitial nephritis (ain) is an uncommon cause of acute renal failure in children. the cause of ain most is commonly due to medications such as antibiotics or infections. we reviewed our experience of biopsy proven ain in children. the biopsy database of all native renal biopsies over a 15 year period was reviewed. all biopsies which listed acute interstitial nephritis were selected and clinical and laboratory data were extracted from clinical records. results: 16 cases of ain from 540 biopsies,(2.9%) was identified. median age 11.5 years, range 1-14 12/16 cases presented with acute renal failure without an obvious cause. 13/16 cases had non specific constitutional symptoms and oliguria was reported by 6 patients. antibiotics were the most common medications implicated (5/16 patients) three patients were on multiple medications with one having chronic epilepsy and the other crohn's disease. five patients required short term dialysis ranging from 2 to 7 days.13 patients were treated with corticosteroids and at last follow up, 4 had reduced gfr 45-74ml/min/1.73m 2 . conclusion: acute interstitial nephritis is uncommon in childhood but when it occurs, antibiotics are the single commonest cause. there is significant morbidity associated with the illness with not all patients making a full recovery. abstract# p-sat308 acute kidney injury as presentation of burkitt's lymphoma eva greta ter haar 1 , anne uyttebroeck 2 , marleen renard 2 , veerle labarque 2 , djalila mekahli 1 1 pediatric nephorlogy, university hospital leuven, leuven, belgium 2 pediatric hemato-oncology, university hospitals leuven, belgium objective: acute kidney injury (aki) has become increasingly prevalent. approximately 2-3% of children admitted to pediatric tertiary care centers present with this life-threatening condition. the most common causes are post-operative septic shock, organ or bone marrow transplantations and intrinsic renal disease. the latter comprises multiple disorders, but tumor invasion due to a lymphoproliferative malignancy is very exceptional. methods and results: we report two cases of aki caused by infiltration of burkitt's lymphoma. both four-year-old male patients presented with abdominal pain, nausea, vomiting, weight loss and overall weakness since a few weeks. clinical examination showed hepatosplenomegaly and impressive bilateral nephromegaly. both had malignant hypertension. blood analysis showed severe renal impairment in both patients. the first had creatinine of 2.9 mg/dl (egfr 21 ml/min/1.73m 2 ), urea of 97 mg/dl and uric acid of 8.9mg/dl. the second had creatinine of 5.97mg/dl (egfr 10 ml/min/1.73m 2 ), urea of 215mg/dl and uric acid of 12mg/dl. lactate dehydrogenase was extremely elevated in both cases (5860 u/l; 758 u/l respectively). urinary sediment was normal. ultrasound showed bilateral nephromegaly in both patients (patient 1:+12sd and +11sd; patient 2: +10sd and +9sd, for right and left kidney respectively). mri demonstrated a homogenous renal enlargement with features of an infiltrative lesion. bone marrow was inconclusive and diagnosis of burkitt's lymphoma was confirmed by a renal biopsy. after starting chemotherapy according to the inter-b-nhl ritux 2010 protocol, both children developed a tumor lysis syndrome and required hemodialysis. at last follow-up both children still had hypertension. nevertheless, renal size and function were normalized. conclusion: lymphomatous infiltration due to burkitt's lymphoma is a rare cause of aki. however, it should be considered in a patient presenting with unexplained renal failure and bilateral nephromegaly with normal urinary sediment. renal biopsy may be needed to confirm diagnosis. abstract# p-sat309 does malnutrition interact with acute kidney injury in children? objective: to investigate the interaction between malnutrition and acute kidney injury (aki) assessed by prifle criteria and to assess the effects of these factors on the outcomes of pediatric intensive care unit (picu) patients. methods: prospective cohort study conducted on children. outcome variables: mortality, need for dialysis, picu free days (the number of days alive from icu discharge to day 28) and ventilator-free days (the number of days alive and breathing without assistance from admission to day 28). exposure variables: malnutrition on admission (who growth standards) and any change in prifle criteria during the first icu 14 days. results: of 98 patients (median age =19 iqr =50 months, 35 girls) enrolled, 39 (40%) were malnourished and 34 (35%) developed aki. among the malnourished, 19/39 cases (49%) had aki, while this complication occurred in 15/59 (25%) of patients without malnutrition resulting in a risk ratio of 1.9 (95%ci 1.1 -3.3). the 28 days mortality rate was 10/98 cases (10%) and aki was associated with higher risk (8/34 versus 2/64 cases -rr=7.5 95%ci 1.7-33.5). concurrent malnutrition and aki was present in 19/98 cases (19%) producing a tendency (p=0.2) to a further increased risk of death (rr=9.4 95%ci 1.5-58.0). 9/98 (9%) patients needed dialysis and malnutrition increased the risk for this outcome (rr=5.3 95%ci 1.2-24.2). aki was associated with significantly higher icu free days (19±7 vs. 15±10) and ventilator-free days (22±9 vs. 13±12) but concomitant malnutrition did not reduce either of these outcomes. conclusion: malnutrition and aki are common in children admitted to the icu and the presence of malnutrition is associated with increased risk of developing aki. the need for dialysis was increased in malnourished patients and more powered studies are demanded to test whether the tendency to higher mortality observed in patients with concomitant aki and malnutrition is confirmed. urine erythropoietin level is associated with kidney and brain injury in critically ill neonates yanhong li, jie yan, xiaozhong li department of nephrology, children's hospital affiliated to soochow university, suzhou, china objective: erythropoietin (epo) is a glycoprotein hormone produced predominantly in the kidneys. the protective effect of exogenous epo in hypoxic-ischemic brain injury has been thoroughly examined in neonates. however, the metabolism of endogenous epo in neonates remains unclear. we aimed to evaluate the concentration of urinary epo (uepo) in critically ill neonates and to identify possible clinical and laboratory variables that may be associated with uepo levels. methods: the concentrations of epo, cystatin-c, microalbumin, and α 1 -microglobulin in the first available urine sample during the initial 72 hours of life were measured in 103 critically ill neonates. clinical and laboratory data were collected for each neonate. results: there was a positive correlation between uepo levels and urinary levels of cystatin-c (r =0.265, p =0.008), microalbumin (r =0.422, p <0.001), andα 1 -microglobulin (r =0.421, p <0.001). the concentration of uepo was elevated in neonates who developed acute kidney injury (aki) during the first week of life compared with those without aki (p =0.002) and was also elevated in neonates with brain injury, as demonstrated by ultrasound or magnetic resonance imaging, compared to neonates without brain injury (p =0.008). an increased log 10 uepo level was associated with the occurrence of aki (odds ratio of 2.70, p =0.007) and brain injury (odds ratio of 2.33, p =0.016). conclusion: an increased urinary epo level in the early postnatal period is significantly associated with kidney and brain injury in critically ill neonates. abstract# p-sat311 acute kidney injury following extracorporeal membrane oxygenation support and concomitant hemofiltration -the role of diuretics objective: fluid overload (fo) is common during extracorporeal membrane oxygenation (ecmo) and can be managed by continuous hemofiltration (hf) and/or diuretic therapy. although combination therapy of hf and diuretics in particular can be most effectively for fo removal during ecmo, it may also increase the risk for prerenal acute kidney injury (aki) post-ecmo. our objective was to describe the incidence of aki post-ecmo in patients treated with ecmo and hf who received concurrent diuretics. methods: in this cohort study all neonates (≤28 days after birth) treated with ecmo and concomitant hf between 2007 and 2011 were included. patients were divided into two groups based on diuretic regimen: group-1, patients who received no or one single diuretic dose during ecmo and group-2, patients who repeatedly received diuretics. both groups were compared using mann-whitney u test for nonparametric data and chisquare test for categorical data. aki was defined as the highest serum creatinine (scr)-based rifle class reached on post-ecmo day 1 up to post-ecmo day 4 (risk, injury, or failure being 150%, 200% or 300% of median scr reference values for age). results: 56 neonates received ecmo support with hf, 6 died immediately following decannulation and 6 others were lost to followup since they were transferred back to their referring hospitals within 3 days post-ecmo. of the 18 patients in group-1, 3 (17%) qualified as risk and 1 (6%) as injury. of the 26 patients in group-2, 3 (12%) qualified as risk, 4 (15%) as injury and 9 (35%) as failure (group-1 vs. group-2, p=0.039). patients in group-2 had an increased ecmo duration (p=0.001) and number of ventilator days (p=0.002). no differences were observed in baseline characteristics (e.g. age at the start of ecmo, underlying diagnosis, severity of illness scoring using the pim and prism risk adjustment systems), hf flow rate, and fluid balance between both study groups. conclusion: the incidence and severity of aki immediately post-ecmo was significantly higher in patients who repeatedly received diuretics in addition to hf during ecmo. valentina sitnikova, yuliya pashkova, tatiana zvyagina, elena kulakova, alexandra nastausheva voronezh state medical academy, voronezh, russia objective: it is actually to find the new markers of kidney damage and spread them in practice. cystatine c (cys) is one of these, but there are only few data about it in children with urinary tract infection (uti) according to the age. the aim of our study was to evaluate serum concentration of cys in children with uti of different age. we investigated 83 patients (47 girls and 36 boys) with uti from 1 month to 17 years among them 32 children were under 1 years old. methods: concentration of cys were measured by immunoenzime method (elisa) with test-system biovendor (check republic). results: the mean cys concentration in children with uti under 1 year was 1.43± 0.37 mg/l, in older children it was lower: 1.23 ± 0.36 mg/l, p= 0.025 (mann-whitney). in 16 girls before 1 year cys concentration was 1.47± 0.32 mg/l and in 16 boys of the same age it was 1.40±0.43 mg/l, p>0.05. in 31 girls over 1 year cys concentration in serum was 1.31± 0.41 mg/l, in 20 boys -1.3± 0.33 mg/l, p>0.05. the results of our study showed that among children with uti serum concentration of cys was higher in children of the first year of life and did not depend on sex. probably, higher level of cys in infants connects with low glomerular filtration rate in children of this age. microalbuminuria can prognosticate outcome in the critically ill children biplab maji, surupa basu, rajiv sinha paediatrics, post graduate trainee, kolkata, india objective: microalbuminuria [albumin creatinine ratio (acr) >30 mg/g] increases in acute inflammatory conditions as a result of glomerular endothelial dysfunction. the study evaluated its prognostic potential in the critically ill child. methods: an ongoing prospective observational study (oct 2012-mar 2012) of random urine acr (mg/g) estimated on day1 and day 3 of pediatric intensive care unit (picu) admission, of a tertiary care pediatric hospital. demographic, laboratory data, vasopressor use, mechanical ventilation, length of stay, outcome and pelod scores were recorded. results: of 113 children, 72 children (median age 4.5years, 68% male) recruited. the commonest cause of admission was pneumonia, infection associated hemophagocytic lymphohistiocytosis followed by meningitis. day1 acr (median 70.8 mg/g) significantly correlated with day 3 total leukocyte count (p=0.016). both day 1 and day 3 acr correlated with pelod scores [median 8] (p=0.002 & p= 0.003 respectively) and duration of mechanical ventilation (p=0.003 and p=0.001 respectively). both median day 1 acr, and day 3 acr were significantly different between survivors (n= 29) and non-survivors (n=11) (p=0.0001 and p<0.0001, respectively). roc curve analysis for mortality prediction revealed the highest area under curve (auc) of 0.963 for acr3, followed by 0.928 for acr1 and 0.867 for pelod scoring (p>0.05, non-significant for auc comparisions) (fig. 1.) . a cut-off value of day 3 acr of 102.4mg/g had a positive predictive value of 95.8% for negative outcome conclusion: microalbuminuria is an early inflammatory marker that correlates with organ dysfunction. significant levels reliably predict negative outcome early into intensive care admission, as accurately as pelod scores, which can help counsel patients, plan treatment and triage, and allocate resources judiciously. abstract# p-sat314 an unusual presentation of congenital nephrotic syndrome caused by wt1 mutation ann raes, sofie maebe, joke dehoorne, bert callewaert, johan vande walle pediatric nephrology, university hospital, gent, belgium objective, methods and results: a caucasian girl was admitted at the age of 28 days because of progressive lethargy, poor feeding, oliguria en peri-orbital edema. extreme hyponatremia (89 mmol/l), severe renal insufficiency (creat 1.9 mg/dl, p 10.7 mg/dl), low plasma albumin (1.5 g/dl), respiratory compensated metabolic acidosis (arterial ph 7.31 pco 2 27 mmhg, bicarbonate 13.5 mmol/l, be -10.9 mmol/l) and massive proteinuria (12 g/l). clinical examination was normal without anomalies of the external genitals or other dysmorphic features. despite supportive therapy (sodium, bicarbonate, albumin and furosemide) she progressed to respiratory failure and renal failure with need for mechanical ventilation and peritoneal dialysis. congenital infections and thrombosis was ruled out. histological examination showed diffuse mesangial sclerosis (dms). the combination of congenital nephritic syndrome and dms on biopsy was suggestive for mutations in the wilms' tumor 1 (wt1) gene. genetic analysis showed normal female karyotype and conformed a heterozygosity for the c.1223c>g or p.his441gln mutation within the zinc finger 2 domain. after a long and complicated icu episode, a stable situation with home choice peritoneal dialysis was achieved. due to the important risk for comparision of auc of pelod with acr 3, p= 0.766 for comparison with acr 1) for the prediction of mortality in the pediatric intensive care unit. development of wilms' tumor, bilateral nefrectomy was performed and kidney transplantation will be planned. we present an unusual case of congenital nephrotic syndrome with extreme hyponatremia at presentation and fast progression to esrd, due to mutation in wt1 gene. several genes have been implicated in congenital nephrotic syndrome. genetic testing is mandatory and can add important information such as risk of malignancy. renal histology can play an important role in the approach for appropriate mutational screening. mutations in the wt1 gene are associated with denish drash syndrome and frasier syndrome, but also with isolated and sporadic steroid resistant nephrotic syndrome. in the last category the majority of patients is female, the age of onset and time to esrd is variable, although the vast majority of cases are older at presentation and time to esrd is longer than in our case. objective, methods and results: a 8-year-old girl, affected by b thalassemia major, was admitted for proteinuria detected at the emergency unit. fever, hyporexia and diarrhea had been present in the last three days. on physical examination she presented with decreased skin turgor and hypertension. laboratory examinations showed: hyponatremia (124 meq/l), hypokalaemia (2.9 meq/l), hypophosphatemia (1.1 mg/dl), hyperazotemia (60 mg/dl), reduced creatinine clearance (crcl = 68 ml/min/1.73 m 2 ) and metabolic acidosis (hco 3 -12.8 mmol/l). urine analysis revealed: proteinuria, glycosuria, hypercalciuria, hyperuricuria, hyperphosphaturia and aminoaciduria. she had been under treatment for five years with deferasirox (dfx) 26 mg/kg/die. we stopped dfx and gave supplementation of potassium, phosphate, sodium bicarbonate and sodium chloride with electrolyte and renal function (crcl 130 ml/min/1.73 m 2 ) normalization in 6 days. after one month only minimal proteinuria persisted. conclusion: in so far a fanconi syndrome (fs) has been reported in 11 patients (6 children), while mild renal insufficiency (ri) has been documented only in 2 children. in our case dehydration seems to be responsible for the ri, while an interstitial nephritis cannot be excluded. close monitoring of renal function should be done in children on dfx. objective: to test the hypothesis that neutrophil gelatinase-associated lipocalin (ngal) and interleukin-18 (il-18) are early biomarkers for aki in critically ill patients and evaluate the predictive value of them in patients with established aki at inception of crrt. methods: children from picu and health examination center in guangzhou women's and children's medical center were divided into four groups: critically ill patients with aki recevied crrt group (group1 ), critically ill patients with non-aki recevied crrt group(group2) , critically ill patients with aki don't recevie crrt group (group 3),healthy control group (group4). 1.5 ml venous blood and urine specimens were collected and was kept under -70°c.from each patient in picu untill they were discharged, transferred or die . serum creatinine (scr) and urine ngal and urine il-18 were analyzed . results: compared with group2 and group4, the urine ngal and urine il-18 increases obviously in group1 and group3 (p<0.05). there is no significance of urine ngal and urine il-18 between group2 and group 4.(p> 0.05).the concentration of urine ngal increased more than10 times obviously 2 days before diagnosed of aki under the akin standard with auc 0.841(p <0.05) , and the concentration of urine il-18 increased more than 5 times 2 day before aki with auc 0.808(p <0.05). the auc was 0.943(p <0.01) when they were combined. the level of urine ngaland il-18 at initiation of rrt were higher in in non-survivors compared to survivors. conclusion: urine ngal and urine il-18 are useful indicators to predict and early diagnose aki. the level of urine ngal and il-18 at initiation of rrt.were negative correlation with the outcome of renal prognosis and survival rate . objective: the aim of this study was to evaluate the rate of early kidney injury in infants with congenital heart disease (chd). neutrophil gelatinase associated with lipocalin (ngal) which can be measured both in serum (sngal) and in urine (ungal), is at the moment the most promising marker directed to discover early kidney injury within the glomeruli and distal and proximal tubules. less known is cathepsine l as a marker of tubule necrosis. methods: the study group consisted of patients (22 boys and 12 girls) with congenital heart disease. all patients were under 3 years of age (mean 8.2 months). blood and urine samples were obtained during routine checkups. all patients had normal serum creatinine level at the day of collecting samples. the control group (n = 20) was age-and gender-matched. levels of sngal, ungal and cathepsine were compared in whole group. the study group was divided depending on the nature of the defect (cyanotic/acyanotic) and the treatment (surgical/conservative treatment). results: chlidren with congenital heart disease had significantly higher concentration of sngal, ungal and urine cathepsine than the control group. no significant difference was observed in the urine cathepsine and urine and serum ngal level between patients with acyanotic and cyanotic chd. there were also no significant differences in patients who underwent surgery and on conservative treatment in ngal level (both in urine and serum). cathepsine level was significantly higher in group after surgical treatment. conclusion: patients with chd are at higher risk of early kidney damage. this process is independent on the etiology and nature of the defect. ngal determined in the serum and urine of these patients may be used to detect kidney injury or monitoring disease progression. urine cathepsine is more efficient marker of early kidney injury in patients after cardiac surgery. abstract# p-sat318 tim-3 expression in kidney mononuclear cells and its relationship with foxp3+ tregs from mice with renal ischemia reperfusion injury yamei wang, yuhong tao, li ye department of pediatrics, west china second university hospital, chengdu, china objective: foxp3 + tregs participate in the repair of renal ischemia reperfusion injury. t cell immunoglobulin-3 (tim-3) plays a pivotal role in several inflammatory diseases by modulation of foxp3 + regulatory t (treg) cells. to detect the expression of tim-3 in kidney mononuclear cells (kmncs) from mice with renal iri and analyze the relationship with foxp3 + tregs, to explore the role of tim-3 in repair of renal iri. methods: the left renal pedicle was clamped in c57bl6 mice for 45 min, followed by reperfusion. animals were sacrificed at baseline, day 1,3,10, 21 after iri. tim-3 expression in kmncs were determined using real-time rt-pcr and flow cytometry. the percentage of foxp3 + treg in cd4 + t cells was quantified by flow cytometry. the levels of tnf-α、ifn-γ、il-4 and il-10 in kidney tissue were measured using elisa. the correlation among tim-3 expression, foxp3 + treg and cytokine level was analyzed. results: the expression of tim-3 expression in kmncs from injured kidney at acute stage(day 1) was significantly higher than those from uninjured kidney at acute stage and lower than those from injured kidney at repair stage (day 3,10, 21). the percentage of foxp3 + treg in cd4 + t cells was up-regulated with time. compared with the uninjured kidney, the expression of tnf-α and ifn-γ increased significantly in the injured kidney at acute stage and the expression of il-4 and il-10 increased significantly in the injured kidney at repair stage. the tim-3 expression in kmncs at iri repair stage was positively related with the level of foxp3 + treg, il-10 (r=0.81, r=0.79 respectively; p<0. 05), but negatively related with the level of tnf-α and ifn-γ. conclusion: the increased expression of tim-3 in kmncs may take part in the repair of renal iri and contribute to the development of foxp3 + treg. objective: (d+)hus is a critical health problem in argentina since it is the main cause of acute renal failure in children and the second cause of chronic renal failure. fecal contamination of food and drinking water by asymptomatic cattle is often the source although secondary infection through personto-person contact may also occur. occasionally in (d+) hus, the onset among affected siblings occurred within a short time of each other. to evaluate the risk and clinical severity of illness for childhood (d+)hus in siblings. methods: we retrospectively analyzed the clinical records of 133 children with d+hus that were admitted in our pediatric department between march 1997 and december 2012. results: (d+) hus occurred in 2 siblings in 4 of the 129 families studied (3%). 16 patients had an affected sibling with diarrhea and 4 progressed to hus (25%). family cases: mean age: 28 months, 5 were girls. the mean duration of interval between hus episodes was 4 days. second family members had prolonged oligoanuria (3 vs 12 days) and a most of them developed neurological complications. long-term renal complications were more frequent in this group, but differences were not statistically significant. conclusion: these findings emphasize the potential for extensive intra-familiar transmission of stec, especially between siblings. a second family member might also develop an even more severe hus episode, so siblings should be kept under close surveillance. objective: kawasaki disease (kd) is a common cause of systemic vasculitis in children. other than well known complications like coronary artery aneurysm, there have been few reports of this disease involvement in renal system. according to the study from wang jn et.al, 52% (26 out of 50) of the patients who suffered from kd showed renal inflammatory foci in dmsa renal spect which suggested a possibility of renal scar formation subsequent to kd. therefore, this study was performed to verify the renal inflammation following kd. methods: from march 2011 to october 2011, 15 patients who were diagnosed as kd at national health insurance service ilsan hospital were enrolled to the study. all of the patients underwent dmsa renal spect to evaluate renal involvement during their acute phase of kd. echocardiography was performed to assess cardiac involvement such as coronary artery aneurysm. complete blood cell counts, aspartate amino-transferase, alanin amino-transferase, albumin, c-reactive protein, and bun/creatinine were measured. also urine β2microglobulin was measured to assess renal tubular function. addition to fever of more than five days of duration, 4 of the following symptoms, rash, conjunctival injection, changes of lips or oral mucosa, erythema and swelling of hands and feet and cervical lymphadenopathy, was the diagnostic criteria for kd. results: among the 15 patients, 80% showed increased white blood cell s (wbc) and 47% showed elevated ast/alt level. serum albumin was below 4.0 g/dl in 93% of the patients. all of the patients presented normal renal function test. in urinalysis, hematuria and pyuria were observed in 13% and 33% respectively. echocardiography revealed coronary artery aneurysm in 33% of the patients. urine β2-microglobulin was elevated in 46%. regardless abnormal findings in urinalysis and elevated β2microglobulin, no significant findings were observed in dmsa renal spect. conclusion: according to the study, mild abnormality in the urinalysis and elevated β2-microglobulin were the only findings of renal involvement in kd. however there was no aggressive renal manifestation which could be detected in dmsa renal spect. objective: in this study, the question remains if ngal is a culprit or only bystander in aki due to sepsis in children. methods: twenty seven children, (m-17, f-10) admitted to intensive care diagnosed with sepsis, severe sepsis or septic shock were enrolled in this study. the concentration of ngal, protein c and s, antithrombin iii and basic parameters were measured in the plasma at diagnosis and after 10 days of treatment. results: mean creatinine concentration in septic children at admission was higher than in reference group (p <0.05). there was statistically significant difference in aptt, prothrombin time, prothrombin ratio, thrombocytes count, heart rate, and systolic blood pressure between study groups in first and after 10 days (p<0.005, p<0.001, p<0.001, p<0.01, p<0.05, p<0.05 respectively). the pc concentration in the septic patients was significantly lower than those of the references (p<0.0001), and during intensive 10 days treatment raised (p<0.01). also protein s concentration rose during the treatment (p<0.005), and was lower in septic children then reference group (p<0.0001). ngal concentration was significantly higher in study group on the admission day comparing with reference group (p<0.05). plasma ngal was correlated at admission and after 10 days of treatment with protein c (respectively: r=-0.48, p<0.00005; r=-0.53, p<0.05). multivariate regression revealed that ngal was significantly predicted by creatinine (β=0.39, p<0.01) and protein c (β=-0.38; p<0.01), yielding a model r2 =0.34 (p<0.001). conclusions: it is possible that kidney binding of pathogenic antibodies stimulates local expression of ngal, which plays a crucial role in the pathogenesis of aki. objective: the aim of the study was to assess the impact of perinatal risk factors (prfs) on serum ngal level in term neonates. methods: the study group consist of 62 term neonates with prfs, and 14 healthy neonatescontrol group (cg). serum ngal (elisa) was measured in samples of cord blood (cngal) and peripheral blood (pngal) taken within first 5 days of life, and stored in -80°c until elisa procedure was performed. prfs were divided into 3 groups: 1. pathology of pregnancy or mother: diabetes (d) n=23, infection (i) -elevated crp or wbc n=20, positive vaginal culture (vc) n=21, hypertension (ht) n=7, others n=5; 2. labor pathology: instrumental delivery (id) n=41, premature rupture of membranes, >6 hours (prom) n=26, fetal distress (fd) n=26; 3. neonatal pathology: intrauterine infection (ii) n=10, cakut n=5, perinatal asphyxia (pa) n=4. the results were shown as median; values of cngal, pngal were logtransformed before analysis. statistical analysis was performed with t-student, manova tests with help of statistica 10. statistical significance: p<0.05. results: in 62 term neonates, median cngal was 117.69ng/ml vs 64.37ng/ml in cg. mean log cngal was significantly higher (p<0.01) vs cg, pngal was ns. mean log cngal correlated positively with mean log pngal (r=0.36, p<0.01). univariate analyzes of log ngal in neonates with chosen prfs vs neonates without particular factor showed significantly higher (p<0.05) mean log cngal in id and fd group (median cngal: 126.47 vs 67.50 and 122.30 vs 77.01ng/ml respectively), whereas in ii group significantly higher were mean log cngal and mean log pngal (median cngal 209.69 vs 96.52ng/ml, pngal 457.35 vs 156.37ng/ml). multivariate analysis showed that the impact of id was significant in groups: d (f=9.84; p<0.002), i (f=4.56; p<0.04), prom (f=6.01; p<0.02) and fd (f=5.36; p<0.02). conclusion: 1. intrauterine infection may have a significant influence on ngal in cord and peripheral blood whereas fetal distress and instrumental delivery only in cord blood. 2. the instrumental termination of pregnancy has an import impact on ngal level in cord blood of neonates whose mothers had diabetes or infection, with prom or fetal distress. objective: acute kidney injury (aki) is a common problem and associated with significant morbidity and mortality in neonates. pediatric-modified rifle (prifle) classification system was developed to standardize the definition of aki in children. we aimed to evaluate the performance of prifle score diagnosis, severity and prognosis of aki in term and preterm neonates. methods: in this retrospective study, charts of 820 patients who were admitted to neonatal intensive care unit (nicu) over a 4 year period were reviewed for development of aki. a diagnosis of aki was determined for 254 patients (30.9 %) according to the prifle criteria results: of the 254patients included in this study, 101 of them were girls and 153-were boys. mean age was 4.12days (min-max: 0-49), mean birth week was 33.6 ±5.1 weeks (min-max: 24-42), mean birth weight was 2166 ± 1045 gr (min-max: 580-4600 gr), length of nicu stay was 37.3 ± 33.5(min-max: 2-165days). two hundred fifty four patients with aki were classified according to prifle criteria. ninetyeight patients (38.5%) achieved an 'r' level of aki severity, 86 patients (33.5%) an "i" level, 66 patients (26%) an "f" level, 4 patients (1,5%) an "l" level. the most common etiologies of aki -were prematurity, congenital heart disease, hypoxic ischemic injury, sepsis and usage of nephrotoxic agents. patients classified with a higher prifle score had a longer nicu stay and required a greater number of mechanical ventilation (p<0.05). renal replacement therapy (rrt) was needed for 30 patients (11.8%). mortality rate was 26% and all deceased patients were classified as prifle 'i','f' or 'l',p < 0.05) conclusion: using prifle criteria in neonates with aki is an efficient way to assess the severity and prognosis of the disease. objective, methods and results: i present a case of a 11 years albanian old boy, 25th centile of development. presented with abdominal pain, vomiting. four days after, was addmited in the surgery clinic for uregent apendicitectomy. wbc: 23.0, se: 64/, bun: 6.1, cre: 60, urine: normal. after the intervention medications that were used were: gentamycin, metronidazol, cephtriaxon, h2 blocators. two days after he was better. thereafter he had polyuria and frequent urinating. the fifth day he had oliguria to seventh day, when he couldn't urinate. nativ rtg of abdomen resulted normal. he was transferede to pediatric clinic-nephrology department as an akute kidney injory. he looked very sick, consious, stratified tongue, ecg: 50b/min, bp: 115/60 mmhg, breathing sounds were normal, periferal edemas and cold extremities. lab resultrs: cre: 624, bun: 16.6, k: 5.1, na: 131, egfr: 8.8 ml/min oer 1.73m2. ultrasound resulterd with urinary stasis: hydronephrosis, huge bladder. first was suspected for acute obstruction and aki couse of a medication. we changed a bladder cathether which we find out that was blocked and took out 2700 ml urine/24h. we dialysed him for three days and cre was stabilized to 266, when we stoped dialyse. bp was stabile, his weight droped from 32kg to 27.5 kg. he had proteinuria 2 g/24 h. schintigraphy was done (biopsy we couldn't do) and resulted: egfr was 12% less than adecuat for age, suspected for nephritis tubulointestialis. he had some toxoalergic exanthema spread to the body. repeted us resulted with ascaridosis in the gallbladder, which was treated with mebendazole and in the feces were found the parasites. imune ab were negativ, ige: positive, periferal blood smear had eosinophils, wastage of na and mg with urine. cre after four weeks was 58, bun:5, negative proteinuria. no changes of uveitis in the eyes. importance of this case is cause this is the first case in kosova that was dialysed and has recovered and now is free of dialyse (all other cases have traveled abroad until then). conclusion: we have to think for parasites as a cause of a tubulointesticial nephritis but also of a abdominal pain or fatigue. surgery team should have a close cooperation with pediatricians, in order to identifye in time complications of the surgery. urine output in first 48 hours after birth in relation to akin criteria saroj kumar patnaik, gaurav aggarwal, uday kumar, vempati venkateshwar, shamsher singh dalal pediatrics, command hospital air force, bangalore, india objective: applicability of akin urinary output (uo) criteria in neonates during first 48 hours of life remains contentious since nonpassage of urine during this time has traditionally been considered 'normal'. we hypothesize that 'physiological' oliguria in first 48 hours of life is mostly prerenal in origin related to poor fluid intake during transition and uo criteria should be applicable in the 1st 48 hours of life too. we aimed a) to investigate pattern of uo in babies admitted to nicu with underlying morbidity but regulated fluid intake versus roomed-in babies in postnatal ward on breastfeeds in first 48 hours of life; b) to relate uo till 48 hrs of life with development of aki methods: prospectively timing of first void and 6 hourly uo from birth till 48 hours age was compared between consecutive postnatal ward and nicu admissions. neonates with structural malformations and requiring ventilatory/vasopressor support were excluded. outcomes-primary : time of first void after birth secondary: uo in 1st 48 hrs in relation to subsequent aki results: amongst eligible 87 postnatal breastfed babies (mean bwt 2.86 kg ; sga 18; 27 lscs born) and 110 nicu admissions (median birthweight 2.01 kg,mean ga 34 wks (26-43 wks); 67 prematures (10 < 30 wks); 82 sga (6 elbw) recruited after informed consent, first voiding was significantly earlier for nicu babies (mean(95%ci) (hrs) postnatal 4.12 (3.29, 4 .93) vs nicu 2.31 (1.50,3.12) hrs). nonvaginal delivery(lscs 3.00 (1.89,4.11) vs vaginal 4.68 (3.60,5.75 ) and normal birthweight (aga 4.08(3.10, 5.06) vs sga 4.22(2.81, 5.63) ) had a trend for earlier voiding. 80% babies voided within 6 hrs of birth -more in nicu babies (90.4% nicu vs 76.7% postnatal (p<0.004) (fig) .asphyxia with mas in nicu and iugr and poor feeding in postnatal ward had delayed first void beyond 12 hours. 6 postnatal and 7 nicu neonates anuric in 1st 6hrs met stage i akin creatinine criteria. 2 asphyxiated babies anuric beyond 12 hours in nicu developed stage iii aki. conclusion: 'physiological' anuria in 1st 48 hrs of life is misnomer and is related to fluid intake. most babies are nonoliguric by 6 h; anuria >12 h needs investigation. akin urinary criteria should be applicable in neonates. odillha morales maglalang-reed nephrology, philippine children's medical center, quezon city, philippines objective: the precise mechanism of renal injury among dengue patients is not known. patients who have atn will usually require early dialysis. however, on admission to the hospital, it is difficult to distinguish dss patients with atn from patients with reversible prerenal causes that will respond to simple hydration. our understanding of the complex pathogenesis of tubular injury in dengue aki is very limited that until it is sufficiently increased, therapeutic strategies will continue to fail.therefore we sought to explore the limitations of serum creatinine in this setting. general objective is to determine the clinical and diagnostic factors which are predictive for the need for dialysis among dss patients at pcmc. specific objective is to determine if the following factors are predictive of the need for dialysis: decrease in estimated creatinine clearance by 75% or <35 ml/min/bsa with urine output of <0.3ml/kg/hr. x 24 hours or anuria of 12 hours, assess the usefulness of urinary sediment scoring (uss) in predicting the need for dialysis, methods: this retrospective study covered 60 newly admitted cases of dengue shock syndrome lll and lv at the philippine children's medical center between january 2010 to december 2011. results: data from 60 patients were available for analysis. comparison of the demographic characteristics between patients who required dialysis and those who did not showed no significant difference as proven by all p values >0.05. of the differentclinical and laboratory parameters, there was a significant difference in the hr, rr, o 2 saturation, bicarbonate and base excess as proven by all p values <0.05. the hr an rr were significantly higher among those who needed dialysis than those who did not o 2 saturation, bicarbonate and base excess were significantly lower among those who needed dialysis than those who did not. the estimated creatinine clearance was significantly lower among those who needed dialysis than those who did not. urine sediment score (uss) ≥3 was significantly higher among those who needed dialysis than those who did not. conclusion: our data indicate that a decrease in estimated creatinine clearance by 75% or <35 ml/min/bsa with urine output of <0.3ml/kg/hr. x 24 hours or anuria of 12 hours is not predictive of dialysis among dss-induced aki as well as other clinical and laboratory indices. but rather, relatively lower serum creatinine level among dssinduced aki who needed dialysis is associated with greater urine sediment scorecompared with those who did not. a uss ≥ 3 correlated with atn and was predictive of early dialysis.however, estimated crea < 50 is the only factor predictive of dialysis, since this is the only one that was positive after logistic regression. abstract# p-sat327 pre-operative fgf23 predicts acute kidney injury in pediatric cardiac surgery patients: a prospective study mark r hanudel, myke federman, barbara gales, georgina ramos, vicky campbell, kristen ethridge, mary scotti, brian reemtsen, isidro b salusky, katherine wesseling-perry pediatrics, ucla, los angeles, usa objective: fibroblast growth factor 23 (fgf23) is a phosphaturic hormone that predicts renal disease progression in ckd. however, in the setting of aki, there is a paucity of prospective data on fgf23, especially in the pediatric population. thus, we prospectively measured fgf23 levels in pediatric patients undergoing cardiopulmonary bypass (cpb) and assessed the ability of fgf23 to predict aki. methods: pediatric patients, age newborn to 21 years, without underlying ckd, undergoing cardiac surgery requiring cpb were eligible for the study. plasma fgf23 levels (2nd generation cterminal, immunotopics) were measured pre-operatively and at 2, 6, 12, 24, 48, and 96 hours post-reperfusion. serum creatinine was obtained at baseline and daily post-reperfusion. aki was defined by the akin criteria, estimated gfr was calculated using the schwartz formula, and cardiac surgery complexity was classified via rachs-1 score. results: of the 20 enrolled patients, 13 developed at least stage 1 aki. gender, weight sds, height sds, baseline egfr, cardiac surgery complexity, and cpb duration did not differ between the aki group and the non-aki group. patients who developed postoperative aki were younger than those who did not. preoperative fgf23 levels were inversely related to age (r = -0.67, p = 0.001). pre-operative fgf23 levels were significantly higher in patients who developed aki than in those who did not; this remained significant upon correcting for age. post-operatively, fgf23 levels increased in all patients. conclusion: pre-operative fgf23 levels predict the development of post-operative cpb-associated aki. fgf23 levels increase in non-ckd patients undergoing cpb, even in patients without significant changes in serum creatinine, suggesting that fgf23 may be a more sensitive marker of aki than serum creatinine. non-aki pateints p value objective: improved perinatal care increased not only the survival rate but also the frequency of acute kidney injury (aki) in newborns. we aimed to determine the frequency, etiology, clinical course and mortality of aki in a third level neonatal intensive care unit (nicu). methods: medical records of all patients admitted to a nicu in western turkey during 2007-2011 were evaluated and those having aki within 0-30 days of life were determined. birth weight, gestational age, mode of delivery, gender, maternal morbidity, hospitalization period, accompanying morbidities and mortality of all patients; and primary disease causing aki, highest serum creatinine and prognosis of patients with aki were recorded. results: there were 677 patients (m/f:392/285) and 94 (13,9%) had aki of which 80% developed during 0-7 days of life mostly due to birth asphyxia, hypovolemia, cardiac disease, sepsis and urinary system anomalies. aki incidence and total mortality rate were higher in patients with birth weight <1000 g and with gestational age <28 week. however, mortality in patients with aki was increased independent on birth weight (42,1% in <1000 g vs 32,1% in >1000 g; p=0,324) and gestational age (44,1% in <28 week vs 31,7% in >28 week; p=0,227). mortality tended to increase in the presence of aki independent on the underlying cause, but this was significant only for sepsis (33, 3% vs 5, 9%, p<0, 001; or 7, 9) and cardiac diseases (50,0 %vs 15,0%, p=0,001; or 5, 6) . hospitalization period was increased if aki was present (39,1 vs 20,5 days, p<0,001). serum creatinine in deceased patients with aki was higher than those who survived (2,0 vs 1,6 mg/dl, p<0,05). chronic kidney disease was developed in 6 (10%) patients of whom 3 had urinary tract anomalies and 3 had birth asphyxia. conclusion: aki incidence in nicu was 14%, and 80% of aki developed during the first week of life. aki is associated with low birth weight, prematurity, birth asphyxia, sepsis, hypovolemia, cardiac diseases and urinary tract anomalies. mortality in patients with aki is increased independent on the birth weight, gestational age and underlying etiology. objective: cisplatin (cddp) is one of the antineoplastic agents widely used for solid tumors in adults and children. an excessive dose due to medical error causes severe nephrotoxicity, ototoxicity and myelosuppression. previous reports described the effects of plasma exchange, sodium thiosulfate, n-acetylcysteine and other interventions. however, the strategy for over-dose patients, as regards the selection or intensity of therapies and the target of cisplatin removal, remains uncertain in children. a 12 year-old girl was admitted for headache and vomiting. she was found to have a right cerebellar tumor and underwent total extirpation of this medulloblastoma. next, we administered chemotherapy mainly using cddp. however, she developed renal insufficiency and hearing loss on the fourth day. we then realized that we had been administering cddp 90 mg/m 2 for 4 days, instead of the intended 1 day. we promptly discontinued the cddp and began plasma exchange and sodium thiosulfate administration. nonoligiric renal failure was confirmed by a urea nitrogen value of 63.6 mg/dl and creatinine level of 4.4 mg/dl. with 4 cycles of plasma exchange and 2 weeks of sodium thiosulfate, renal function improved and the cddp concentration decreased from 6.04 to 0.99 mg/ml. after 1 month, the concentration was 0.34 mg/ml. we switched from cddp to carboplatin, and chemotherapy was continued for 4 courses and then radiation therapy was added. ultimately, she had mild renal insufficiency and moderate hearing loss. we evaluated the relationship between renal function and the cddp concentration. severe renal failure and hyponatremia were observed at a cddp concentration of 1 mg/ml or more. creatinine clearance of 60 ml/min/1.73 m 2 was maintained at a cddp concentration below 0.5 mg/ml. conclusion: in children with a cddp over-dose, plasma exchange and sodium thiosulfate administration are effective. also, monitoring of cddp concentrations is recommended in patients with acute renal failure. in over-dose patients, early severe renal failure can be prevented when the cddp concentration is reduced to less than 0.5 mg/ml with these therapies. abstract# p-sat331 peritoneal dialysis in children with acute kidney injury: a developing country experience om p mishra 1 , aditya k gupta 1 , vishal pooniya 1 , rajniti prasad 1 , narendra k tiwary 1 , franz schaefer 2 1 pediatrics and medicine, institute of medical sciences, varanasi, india 2 division of pediatric nephrology, heidelberg university medical centre, heidelberg, germany objective: peritoneal dialysis (pd) is the preferred and convenient treatment modality for acute kidney injury (aki) in children and hemodynamically unstable patients. the present study analyzed the efficacy of pd in patients with aki and factors contributing to mortality. methods: the outcome of acute pd was studied in 57 children (39 males) with aki, aged 1 month to 12 years, at a tertiary care centre of a teaching hospital in india. results: there were 14 patients less than 1 year of age, 23 patients 1-5 years of age, and 20 patients more than 5 years of age. per the rifle criteria, 5 patients were classified at the risk stage; 13, at the injury stage; and 39, at the failure stage at the time of the decision to start pd. hemolytic uremic syndrome was the most common cause of aki (36.8%), followed by septicemia (24.6%) and acute tubular necrosis (19.3%). treatment with pd was highly effective in lowering retention markers (blood urea decreased by 40% and serum creatinine by 34% during the course of dialysis therapy, both trends significant at p < 0.001). overall mortality was 36.8%. deaths occurred 2-7 days after hospitalization. significantly higher proportion of non-survivors had fluid overload (66.7% vs 25%, p= 0.002) and septicemia (47.6% vs 11.1% , p< 0.001) than survivors at presentation. the risk of mortality by multivariate analysis was higher when patients were anuric [odds ratio (or) 8.2, 95% confidence interval (ci) 1.3-49, p<0.05), had septicemia (or 3.79, 95% ci 1.55-25.8, p<0.05), or severe infectious complications (or 8.2, 95% ci 1.5-42.9, p<001). conclusion: because of its simplicity and feasibility, acute pd is still an appropriate treatment choice for children with aki in resource-poor settings. septicemia and severity of aki are contributory factors to high mortality in pediatric acute kidney injury. outcome of acute kidney injury managed in a regional paediatric nephrology centre shivaram hegde, sabina pahari paediatric nephrology, university hospital of wales, cardiff, uk objective: this study reviewed the aetiology, treatment modalities and outcome of children with aki managed in our tertiary paediatric nephrology unit. method: retrospective analysis of referral practices, aetiology, and management of 38 children treated for aki over the last 5 years. children primarily treated in intensive care units were excluded. outcomes noted as complete recovery, residual renal injury, renal replacement therapy (rrt) dependency or death. they were followed up until their renal function normalised and any proteinuria or hypertension resolved. result: out of the total 38 children aged 5 months to 16 years, 34% were under 5 years. haemolytic uremic syndrome (hus) was the commonest aetiology in 18 cases (47%), 15 of them secondary to ecoli 0157 and 3 with atypical hus. obstruction was second most common (5) and renal function improved following relief of obstruction. supportive management sufficed in 23 (60%) cases and 15 (37.5%) received renal replacement therapy (rrt); peritoneal dialysis being the commonest mode. most children needing dialysis were oliguric (14). at discharge there were no deaths, 5 patients showed complete recovery of renal function, one was dialysis dependant and renal function was improving in the rest. at 3 months we found normal renal function in 26 (68%) children and chronic kidney disease (ckd) stage ii in 7 (18%) and ckd stage iii in 4. the dialysis dependent child underwent renal transplantation. based on the data from 12 patients currently under follow up (for 12-62 months, mean 41 months), 32 (84%) children have recovered completely and 5 have developed ckd; stage i in 2 and stage ii in 3. conclusion: prognosis following aki was excellent in our patients, probably because of lack of multiorgan dysfunction. hus was the commonest cause and urgent renal imaging needed when obstruction is suspected. oliguric patients are more likely to require dialysis and need early referral to the regional unit. all cases should have long-term follow up to ensure renal recovery and detect delayed complications. clinical course and outcome of acute kidney injury (aki) due to childhood haemolytic uremic syndrome (hus): a single centre experience shivaram hegde, sabina pahari paediatric nephrology, university hospital of wales, cardiff, uk objective: clinical data, along with the management and outcome of 15 children with aki due to hus, caused by shigatoxin-producing ecoli (stx-hus) are described. method: we analysed the data of children with stx-hus induced aki, managed in our unit over the last 5 years. outcomes noted as complete recovery, residual renal injury, dialysis dependency or death. all patients were followed up at least for a year and further monitoring continued until their renal function normalised and any proteinuria or hypertension resolved. methods and results: stx-hus was the commonest cause of aki in our unit, accounting for 15 of the total 38 cases (39.5 %) treated for aki during this period. 11 patients were less than 10 years of age. all children presented with blood in stool and 11 with oligoanuria. all showed microangiopathic haemolytic anaemia and thrombocytopenia. positive stool cultures (for ecoli 0157) were obtained in 11 and 4 had ecoli 0157 lipopolysaccharide serum antibodies. 10 patients required dialysis (peritoneal dialysis in 7, haemodialysis in 1 and both modes in 2) and one child needed plasma exchange. the remaining responded to supportive management. morbidities encountered included bowel perforation (1), hypertension (2), seizures (2) and diabetes mellitus (1) and three of these children needed intensive care management. at discharge there were no deaths, none with dialysis dependency or complete renal recovery but all showing improving renal function. at 3 months we found normal renal function in 12 (80%) and chronic kidney disease (ckd) stage ii in 2 and ckd stage iii in 1. a 13 year old girl with an unknown myopathy presented for the third time with clinical and laboratory features of rhabdomyolysis. on day two of admission, her renal function deteriorated with decreased urine output, increasing creatinine of 380 μmol/l and ck of 240,220 iu/l. she was commenced on haemodialysis and started on calcium supplements, as her calcium levels were 1.6 mmol/l. three week into her illness, she was symptomatic with high blood pressure of 170 mm of hg leading to a generalised seizure. her serum calcium was 4.01 mmol/l. the ct brain did not reveal any evidence of haemorrhage or infarction. there were no other trigger factors identified for the seizure and the hypertension, apart from the hypercalcaemia. the hypercalcaemia was managed with low calcium dialysate, calcitonin and sevalamer. despite the above treatments, she continued to be hypercalcemic and developed erythematous palms and soles and an injected conjunctiva. in view of the refractory hypercalcaemia, she received two doses of intravenous pamidronate (0.5 -1 mg/kg) when the creatinine was 317 mmol/l. following this, her calcium levels normalised to 2.59 mmol/l. her renal function improved and was discharged a week later. there was no nephrocalcinosis seen on follow up. bisphosphonates are used in children with caution, as there is little evidence on its safety and efficacy. they act by binding to the surface of calcium phosphate crystals and inhibiting osteoclast formation, aggregation and dissolution. it is nephrotoxic causing acute tubular necrosis and collapsing focal segmental glomerulosclerosis. pamidronate is usually used in children with chronic kidney disease but this was the first time it was used in a child recovering from acute kidney injury secondary to rhabdomyolysis. there were no complications with the use of pamidronate in our patient. chronic kidney disease during long-term follow-up in children treated with neonatal extracorporeal membrane oxygenation: do we need to worry? objective: acute kidney injury (aki) is a common complication in children receiving extracorporeal membrane oxygenation (ecmo) support. as aki may cause loss of a significant number of functioning nephrons, these children are at risk of developing chronic kidney disease (ckd) post-ecmo. therapeutic interventions might be needed to prevent further renal function deterioration or comorbidity of ckd in these patients. the objective of our study was to determine the prevalence of ckd during long-term follow-up (fup) of children treated with ecmo. methods: this was a cross-sectional study performed between 2010 and 2013. all children previously treated with neonatal ecmo who visited our fup clinic at the age of 1, 2, 5, 8, 12 and 18 years were screened for ckd. if more check-ups were available per patient, only the latter one was used for the study. ckd screening included height (ht) and blood pressure measurements (bp), and laboratory parameters including serum creatinine (scr) (schwartz formula [0.413*ht (cm)/scr (mg/dl)] or mdrd formula were used to estimate gfr) and urinary protein/creatinine (up/c) ratio. ckd was suspected in patients with hypertension (>95th percentile of reference values according to height and age), abnormal egfr (<90 ml/min/1.73m 2 ) or proteinuria (up/c ratio >30 mg/mmol creatinine). patients were excluded if scr was lacking. results: to date, 132 children visited the fup clinic. of these, 4 (3%) were excluded because of pre-existent kidney disease and 6 (5%) because of missing scr data. hence, 122 children (44% female) were screened for ckd. the number of patients per fup age category was 17 <5 years, 56 between 5-12 years, and 49 >12 years. bp was within normal ranges in all children. in 13 (11%) children either an abnormal up/c ratio or egfr was observed. up/c ratio was increased (median 36 [iqr 32-38 mg/mmol creatinine]) in 8 (7%) children, of which 1 was explained by low muscle mass. only 5 (4%) children had an abnormal egfr but all >60 ml/min/1.73m 2 . conclusion: the prevalence of ckd and its clinical implication in children previously treated with neonatal ecmo seems to be limited. future research will focus on identifying risk factors for ckd following ecmo support. abstract# p-sat336 10 years clinical retrospective analysis in children of acute poisoning inpatient man jiang, qiu li nephrology and immunology department, children's hospital of chongqing medical university, chongqing, china objective: acute poisoning is the common critical and emergency disease in children. since childhood is the special life stage with continuous growth, clinical features are different from the adult and changes were happened in resent years. the change rules, clinical features, treatments and the outcomes of acute pediatric poisonings inpatients were investigated in this article. methods: retrospective evaluated the 1005 cases of pediatric acute poisonings admitted to the children's hospital of chongqing medical university. cases were divided into 5 groups by ages, or divided into 2 groups based on different origins (urban or suburban), different causes and routes of poisonings in different groups were calculated. the clinical manifestations, treatments and prognosis in acute intoxication were also studied. results and conclusion: pediatric acute poisoning mainly happened in 1-4 years old children (50.02%), there was no statistical difference between genders. the common causes of poisonings were pharmacological poisoning (26.07%), food poisoning (19.50%), animal bites and stings (16.92%) and pesticide poisoning (14.73%). in the resent five years, pharmacological poisoning rose to be the top reason of poisonings, and was mainly composed by children≤3 years old (p < 0.001),and urban children were more than children from suburban(p < 0.001). neurological and psychiatric drugs were the most common (32.06%) in drug poisoning. rural children with animal bites and stings, pesticide poisonings and rodenticide poisonings were more than the urban children (p < 0.001, p < 0.001, p < 0.05). the main poisoning causes in 6-12 years old group and >12 years old group children were food poisoning (29.20%) and pesticide poisoning ( objective: little is known about cardiac surgery-associated acute kidney injury (cs-aki) in children in developing regions of the world. the study aimed to determine the prevalence of cs-aki, associated factors and its impact on mortality and utilization of hospital services. methods: hospital records of children aged 0-17 years that underwent cardiac surgery (other than device closure procedures and pacemaker insertion only) at an indian hospital between 2011 and 2012 were reviewed. cs-aki was defined as a rise in serum creatinine of ≥0.3 mg/dl in any 48 hours and or by urine output less than 0.5ml/kg/hr for an 8-hour period in the first 5 days after cardiac surgery. results: the study included 323 children with a median age of 1 year (0.04-17), of which 22 (6.8%) were neonates and 18.3% had single ventricle. about 60% of the children had rachs-1 1 or 2 interventions. cs-aki occurred in 39 children (12.1%), most often in the first 48 hours after cardiac surgery. on univariate analysis cs-aki was associated with sepsis and intra and post-operative hypotension. in-hospital mortality was 6-fold higher in children who developed cs-aki. cs-aki was associated with 2-3 days longer duration of mechanical ventilation, inotropic support and icu stay. conclusion: cs-aki occurs in children in developing countries but at a lower frequency mainly due to older children with less complex congenital heart disease undergoing cardiac surgery. cs-aki was associated with higher in-hospital mortality and increased utilization of hospital services. factors associated with cs-aki included intra and post-operative hypotension and sepsis. objective: data on long term effects of newborns after acute kidney injury is limited. the aim of the study was to evaluate long term effects of acute kidney injury (aki) in neonatal period. methods: inclusion criteria were as follows: oligo-anuria or plasma creatinine >1.5 mg/dl during first three postnatal days or >0.7 mg/dl after third postnatal day or ≥25% increase in plasma creatinine within 48 hours during hospitalization in neonatal period. three hundred sixty children who had aki during neonatal period (between january 2000 and december 2009) and survived to hospital discharge were invited; 106 of them accepted to participate. patients' characteristics during aki and during follow-up were recorded; a physical examination and laboratory studies, including acr (urine microalbumin/creatinine ratio) were performed. schwartz formula was used to estimate gfr; hyperfiltration was defined as a gfr >160 ml/min/1.73 m 2 . hypertension was defined as blood pressure ≥95 th percentile for age, gender and length. results: the mean age on evaluation was 6.78±2.9 years. 15.8-15.8-12 .2% of patients. all these children were dialyzed for more than 7 days on acute phase of the disease. at time of discharge from hospital proteinuria remained in 53 (85.5%), hypertension -in 47 (75.8%) patients. after 1 year, 5years and >10 years period proteinuria was detected accordingly to 26.3-7.9-33.3%, hypertension to 11.3-6.5-12.9% of patients. after >10 years from the onset of disease hypertension was detected more often in the group of children who were < 1 years old on acute phase of the disease (40% vs 11.1%, p=0.05). in the group of patients who hadn't proteinuria on the acute phase, after >10 years period proteinuria was observed to 25% of them. after 1 year period renal impairment of various degree was observed to 26.3%, after 5 years -to 39.5 %, after >10 years-to 33. . on admission his mean arterial pressure was 35 mmhg, his creatinine was 5.8, potassium 6.5 and sodium 121. usual medical management for aki was initiated but even by late d5 he continued to be anuric with a rising creatinine. his uric acid was grossly elevated at 14 mg/dl. dialysis was considered but as the parents were not in favour of it they were offered the option of rasburicase. rasburicase was given on late d5 and within 12 hrs he started to produce urine which peaked at 4 ml/kg/hr by d9. the creatinine also showed a concomitant fall and by discharge (d10) it was 2.1 mg/dl and normalized at 0.5 mg/dl by d30. uric acid was 0.5 mg/dl on d7 and 2.8 mg/dl on d9. case 2: 6 years old boy with multiple special needs was transferred from another hospital intubated, anuric and in multi organ failure (mof). creatinine was elevated at 3.7 mg/dl and uric acid was also found to be raised at 9.1 mg/dl. in view of mof along with disseminated intravascular coagulopathy (dic) dialysis was considered a risky process and parents were offered the option of rasburicase. rasburicase was given on d2 of admission and although the repeat uric acid was 0.3 mg/dl and he did produce 5 ml of urine within 6 hours no further improvement in renal parameters was noticed. dialysis (sled) was initiated on d3. although the creatinine improved with sled he continued to be oligo-anuric and died of mof by d5. conclusion: although rasburicase seemed to work in case1, it was not beneficial in case 2. the exact mechanism for rasburicase is still hypothetical and the few case reports have all documented positive results. although it seemed to have worked in case 1, to the best of our knowledge case 2 is the first documented case wherein it did not work. proper randomized control trial is needed before advocating rasburicase as a novel therapy for aki. results: age, sex, diagnosis, baseline and post-surgery hemoglobin, total leukocyte count, platelet count and biochemistry were recorded. baseline and post-operative, urea (mg/dl), creatinine (mg/dl), urine output (ml/kg/hr) and inotrope dose were also recorded daily. the duration of cpb was noted. post-operatively cardiac, renal, hepatic, neurological and respiratory dysfunctions were recorded. conclusion: fifteen (7.2%) children developed aki stage i, one child (0.5%) developed aki stage ii and four children developed aki stage iii (2%). all patients with aki had a longer stay in hospital. eight children required dialysis for aki; two required dialysis to maintain the fluid balance post operatively. none developed chronic renal impairment. using stepwise regression, younger age (<1 year), weight < 10kg, pump failure, sepsis and duration of cpb more than 60 minutes were significant risk factor for developing aki. results: most of the patients were male, with less than 28 days old and weighing less than 5kg.in the majority of cases (77%), arf was diagnosed in the first 6 days after surgery, demonstrating influence of the procedure itself. all of them were treated by peritoneal dialysis(pd) for a mean time of 255 hours; 58.3% of them died. there was no statistical significant difference between age, time on extracorporeal circulation and duration of dialysis, comparing the patients who survived and the deceased ones. conclusion: acute renal failure is a common complication in children with congenital heart disease and pd is a safe dialytic method. the mortality rate is high and influenced by aspects related to the child, underlying disease, type of surgery and many other associated aspects. abstract# p-sat344 acute kidney injury epidemiology and associated factors in a pediatric intensive care unit. conclusion: acute kidney injury (aki) is associated with significant morbidity and mortality in pediatric patients with critical illness. the main causes associated to aki were sepsis and shock. we found no association with cardiac surgery, probably explained by the low level of complexity that is performed in our center. almost half of our patients with aki were in failure and the mortality was high as previously reported. objective: fibroblast growth factor-23 (fgf-23), a phosphaturic hormone involved in calcium phosphate homeostasis, appears to predict renal disease progression in adults with non-diabetic ckd (fliser, jasn 2007) . this study aimed to determine renal survival according to fgf-23 serum levels in children with ckd stage ii-iv. methods: 232 children participating in the escape trial (age 11.5±4 yrs, gfr 45±18 ml/min/1.73m 2 ; underlying renal disease: hypo/dysplasia (71%), glomerulopathies (12%), hereditary or other (17%)) were analyzed. all patients received fixed dose ace inhibition and were followed prospectively by 2-monthly examinations for up to 5 years. the study endpoint was defined by egfr loss >50% from baseline, gfr <10ml or start of renal replacement therapy. fgf-23 levels were determined at baseline (c-terminal human fgf-23 elisa (immutopics, san clemente,ca,usa objective: the long-term outcome of patients born with unilateral renal agenesis (ura) and of those who underwent therapeutic unilateral nephrectomy (un) remains a topic of concern and debate. children with a solitary functioning kidney (sfk) have an increased risk of developing hypertension, albuminuria and chronic kidney disease in later life. the purpose of this study was to identify whether plasma symmetric dimethylarginine (psdma) is an useful biomarker reflecting the level of renal injury in children with solitary functioning kidney (sfk). methods: we measured circulating psdma in 51 patients with sfk and no other urinary defects. patients were subdivided for two groups: primary sfk (psfk)-unilateral renal agenesis (ura) and secondary sfk (ssfk) after unilateral nephrectomy. the control group (c) consisted of 21 healthy children, aged mean 9.92 ± 4.85 yrs. immunoenzymatic elisa commercial kits was used to measure psdma concentration. data analysis was performed using computer program statistica 9.0. results: the age and sex of studied children did not differ from healthy controls (p> 0.05). plasma sdma levels in sfk children were higher than in healthy participants (p< 0.05). there was no difference in psdma concentrations between psfk and ssfk patients (p> 0.05). sdma plasma levels correlated significantly with c cr (r= -0.32, p< 0.01) in all participants. roc analyses performed in order to define the diagnostic efficiency of serum creatinine and psdma in identifying children with c cr < 90ml/ min/ 1.73m 2 among sfk and healthy participants revealed no difference between all two aucs (p> 0.05). conclusion: in children with a solitary functioning kidney increased psdma levels were observed, however the sensitivity and specificity of this marker in detecting the decrease in c cr was not better than creatinine. objective: renal osteodystrophy encompasses a variety of skeletal disorder ranging from high turnover lesions of secondary hyperparathyroidism (shpt), to low turnover lesionsof diverse etiology that are usually associated with normal or reduced pth levels. so our aim was to assess by dexa which is a precise , rapid and noninvasive procedure the degree of osteopenia in patients with crf. methods: 53 children aged (11-3.84) years, 17 on conservative treatment and 36 on hemodialysis were included in the study bmd of lumbar spine and wrist were measured by (dexa) and compared with age and sex matched controls. results: shows that out of 53 patients, 25 (47%) are osteopenic 22 (88%) on hemodialysis and 3 (12%) on conservative treatment, of these 13 (24.4%) had severe osteopenia as regard bmd of the spine, while dexawrist shows 11 (21%) are osteopenic, 7 (64%) on regular hemodialysis and 4 (36%) on conservative iii, of these 3 (5.66%) had severe osteopenia ,correlation between z-score spine in the osteopenic group and different biochemical parameters shows non-significant correlation except -ve correlation with duration and age of the patients, while z-score wrist of the same group shows +ve correlation with bicarbonate. our result shows that group with ipth >= 200 pg/ml are more osteopenic than those with lower ipht levels, although difference did not reach level of statistical significance p > 0.05. conclusion: we can conclude that osteopenia is frequent in patients with crf more in the dialyzed group, with longer duration of the disease, older age and severe acidosis, irrespective of the severity of the disease. although, degree of osteopenia is not correlated with biochemical findings of (shpt) but still patients with (shpt) are more osteopenic and have lower cortical bone density. mineral and bone disorders were defined according to k/doqi guidelines. results: during the study period 95% of stage i-iv ckd patients and all esrd patients and renal allograft recipients had at least one type of mbd. high turnover bone disease with hyperphosphatemia, hyperparathyroidism and hypocalcemia was the most frequent type of mbd in stage i-iv ckd and esrd patient. adynamic bone disease was seen in only one esrd patient. hypophasphatemia was the most common disorder in renal allograft recipients. vitamin d deficiency/insufficiency was seen in 55% of stage i-iv ckd, 65% of esrd patients and all renal allograft recipients. all patients with stage i-iv ckd and esrd were treated with calsitriol and renal allograft recipients were treated with vitamin d3 supplementation. conclusion: mineral and bone disorders especially high turnerover type is common in children with ckd and esrd. although successful kidney transplantation corrects many of the metabolic abnormalities associated with the development of mbds, renal allograft recipients had increased risk of vitamin d deficiency/insufficiency. objective: calciphylaxis is a complication of chronic kidney disease that characterized by necrotic lesion in the skin and in histological examination reveals microcalcification of medium sized blood vessels. materials and methods: we report on a 21-month old girl with end stage renal disease due to diffuse mesangial sclerosis referred for tenckhoff catheter implantation. laboratory tests on admission were: bun = 150 mg/dl, cr= 5 mg/dl, uric acid = 10 mg/dl, calcium= 4 mg/dl, phosphate = 40 mg/dl, alkaline phosphatase= 1017, pth= 700 pm/l,vitd= 21 mg/ml. calciphylaxis process started when she received calcium gluconate iv the day before surgery and continued progressively when oral calcium carbonate and oral calcium gluconate were given. hourly peritoneal dialysis was started and all calcium containing medications were stopped. but the process continued progressively. surgical detriment of the necrotic tissue of right wrist was done. comfeel dressing had no effect and the circulation of tissue was poor. therefore the left wrist was kept as control. pamidronate 0.5 mg/kg/day prescribed for 6 days and then once a week for 5 weeks. after one week of starting pamidronate skin lesion began to heal, circulation improved and after six weeks all skin lesions completely recovered. as shown in figure one debridement cause skin scar on right wrist. conclusion: pamidronate is effective to stop calciphylaxis in children with advance renal insufficiency and severe calcium-phosphate imbalance. medical or surgical debridement are not suggested and lesions will recover without scar by pamidronate objective: fibroblast growth factor 23 (fgf23) is a key player in kidney-bone axis and regulation of calcium and phosphate homeostasis. most of the recent research has focused on fgf23 in chronic kidney disease and there is paucity of data in healthy children. hence we initiated a study on the various biomarkers of calcium-phosphate metabolism including fgf23 in healthy children and present here the interim report of our findings as of now. methods: a total 100 healthy school children and adolescents aged 6-16 years, were enrolled in this cross-sectional study, after a written consent from their parents. height, weight and pubertal staging were assessed. blood was collected and calcium, phosphate, pth and vitamin d were estimated by standard methods. plasma c-terminal fragment of fgf23 was quantitated using a commercial elisa kit (immutopics, usa). three day dietary recall was done to calculate mean daily calcium, phosphate and protein intake. results: of the 100 children enrolled 60% were males. the mean age was 12.3 yrs, mean height was144 cms and mean weight was 34kgs. the mean blood biochemistry values of the children tested so far for ca, p, pth and vitamin d shown in table 1. the parameters of the children were normal for their respective ages however fgf23 levels were found to be lower compared to reports in literature. conclusions: from the results available as of now all of the children had normal biochemistry for their ages. the fgf23 levels were found to be lower than reports in the literature. whether it can be attributed to the dietary differences from the children of the west needs further investigation. testing of the entire cohort will reveal if this lower fgf23 is a universal phenomenon among all children in our study. on the contrary, all dxa parameters showed a decreased in their mean zscore bmd values that reached statistically significance. finally, multivariate stepwise regression analyses showed that estimated glomerular filtration rate at the beginning of the study was the best predictor of the difference in bmd z-scores measured at lumbar spine. additionally, values of ipth at the beginning of the study and the change of ipth throughout the study predicted the 72.3% of the difference in z-score of sos measured at radius with an inverse relationship. conclusion: the use of two different techniques have shown bipolar changes of bone properties after renal transplantation. reversal of renal osteodystrophy and consequently correction of many of the underlying metabolic abnormalities, mainly normalization of ipth, strengths cortical bone as this is best illustrated by qus assessment. however, reduction in bmd, is predominantly considered as an adverse effect of steroid immunosuppression. age 3.3 yr) (group 1), 33 patients with ckd stage 5 on pd or hemo (mean age 9 yr, mean time on dialysis 2 yr) (group 2) and 29 patients with ckd stages 2-4 (mean age 7 yr, mean gfr 37 ml/min/1.73 m 2 ) (group 3). 25ohd levels were deficient in 20% and insufficient in 35% of the group 1 patients, 48% were deficient and 15% were insufficient in group 2, and 7 % were deficient and 17% were insufficient in group 3. results: intact pth (ipth) was above the target level by different ckd stages in 52 % of the group 1 patients, in 58% of the group 2 and in 52% of the group 3 and showed an inverse correlation with 25ohd levels (p<0.05, r=−0.25). there was inverse correlation with age in the complete cohort of patients (p=0.0005, r =−0.33) height standard deviation score (sds) was associated with 25ohd only in group 2 (p=0.025, r=0.45). there was direct correlation between 25ohd levels and gfr in group 1 and 2. conclusion: our data suggest that 25ohd deficiency is common in pediatric renal transplant and ckd children of any stage even in an area with year-long sunshine, especially in adolescents. hyperparathyroidism was also frequent in all groups. it would be advisable to monitor vitamin d status in these patients. 3) years, 28 with ckd 5 (2 on hd, 9 on pd and 17 tx) mean age 13 (5.4-17.5) and 113 healthy children, mean age 11.5 (5-17.9 objective: the aim of our study was to analyze twelve single nucleotide polymorphisms (snp) of gene lrp5 potentially associated with osteoporosis risk in children with routine steroidotherapy in the course of the idiopathic nephrotic syndrome. methods and results: glucocorticosteroids are important risk factors for drug induced osteoporosis. decrease in bone mineral density (bmd) and increased risk for pathological fractures are caused by direct division of steroids at the cellular level by inhibiting the replication of osteoblasts and stimulation of its apoptosis. also proven its effects on the inhibition of type i collagen synthesis. lrp5 is one of the wnt signaling pathway proteins coreceptors involved through the rank-rankl system in regulation of the osteoblasts function. lrp5 is included to the osteoporosis phenotype genes group and its selected single nucleotide polymorphisms can be responsible for bmd decrease in patients with glucocorticoid therapy. the study group was composed of 38 children with idiopathic nephrotic syndrome, 21 boys and 17 girls beetwen the age of five to twelve years old , 14 with osteoporosis and 24 with normal bone mass density. study also included the control group consists of 102 healthy individuals at the same age not treated with glucocorticoids. the analysis was carried out with polimerase chain reaction (pcr) and taqman molecular probe designed for 12 single nucleotide polymorphisms (snps) nearby investigated mutations in lrp5 gene that can be connected with osteoporosis fenotype. odds ratio value (or) was based on frequencies of single nucleotide polymorphisms in lrp5 gene and its haplotype analysis. the results showed significant differences in or value among the three groups. it was also found the differences in the lrp5 gene structure. based on gabriel algorytm single nucleotide polymorphisms pairs analysis in children with osteoporosis and nephrotic syndrome we proved the correlation between selected snps pairs presence and decretion of bone mineral density in studied group. objective: growth hormone (gh) and insulin-like growth factors are essential for normal growth and development. chronic renal failure (crf) results in major changes in the circulating growth hormone /insulin-like growth factor (igf) system. our aim isto study: to assess clinical and laboratory parameters of growth and osteodystrophy including igf1 and igfbp2 as part of the somatotropic hormone axis in egyptian children suffering from crf on conservative therapy. methods: 62 egyptian children (47 boys and 15 girls) with a mean age of 9.7y (0.47 to 21.12y) suffering from crf on conservative therapy and 21 controls were included in the study. ht, wt and tsf were measured ,pubertal staging was assessed and followed up for a period of 6 months. at the end of the follow up period serum for igf1 and igfbp2, renal function, electrolytes, ca, p ,and alkaline phosphatase and acid base balance were measured and an x-ray of the left hand and wrist was done to determine their bone age by tanner and whitehouse. results: our study shows that children suffering from crf in egyptian conservative therapy have growth retardation with a mean ht of -3.7 sds, a mean wt of -2.24 sds. tsf mean was -1.3 sds. on the average the patients had a delay of 2.95y (+/-2.0) in their bone age. their height was retarded more than their bone age with a height age/bone age of 0.8 (+/-0.18). alkaline phosphatase as a markers of renal osteodystrophy is significantly correlated to the height, height age , bone age and to the ph. the mean igf1sds (-0.6 +/-1.8) did not differ from that of controls while the mean igfbp2sds (2.4 +/-4.6) was significantly higher in patients with crf than in controls. height and weight were significantly correlated to igf1 but not igfbp2. there is a significant correlation between igfbp2 level and the glomerular filtration rate. conclusion: the imbalance between normal insulin-like growth factor-i (igf-i) and markedly increased igfbp2 plasma levels plays a pathogenic role for growth retardation in children with chronic renal failure. the lower the gfr the higher the igfbp2 level. the latters inhibitory action may provide hope for improving growth in cases of crf by reducing the level of igfbp2 or displacing igf1 from it. objective: anemia is one of the most common complications of chronic kidney disease (ckd) and renal transplantation. this study evaluated the prevelance and the etiology of anemia in children with stage i-iv ckd, end-stage renal disease (esrd) and renal allograft recipients. methods: between 2010 and 2012, we prospectively followed 21 pediatric stage i-iv ckd, 20 esrd patients and 27 renal allograft recipients. anemia was defined according to k/doqi guidelines as hb is less than the fifth percentile of the normal, adjusted for age and sex. results: during the study period52.3% of stage i-iv ckd, 100% of esrd patients and 48.1% of renal allograft recipients developed anemia. the mean hb levels were 11.30+/-1.72 g/dl, 9.62+/-1.94 g/dl and 11.95+/-1.88 g/dl in stage i-iv ckd, esrd patients and renal allograft recipients, respectively. the mean hb levels were significantly lower in esrd patients as compared to stage i-iv ckd patients and renal allograft recipients (p<0.0081, p<0.002). erythropoetine (epo) deficiency was the most frequent cause of anemia in stage i-iv ckd and esrd patients, followed by iron deficiency. in addition to epo and iron deficiency, bone marrow suppression and parvovirus infection were the causes of anemia in renal allograft recipients. erythropoietic stimulating agents were used in 27% of stage i-iv ckd, 100% of esrd patients and 23% of the renal allograft recipients. conclusion: although anemia is one the most common problems seen in children with ckd and esrd, the prevelance is also high in renal allograft recipients. these patients should be evaluated and treated accordingly to the underlying causes. abstract# p-sat375 determinants and prevalence of anaemia among preschool children in highly focussed states of india results: about more than 60 % child is anaemic among all eag states. the prevalence of severe anaemia is 6.7 % in rajasthan followed by uttar pradesh (3.6 %) and madhya pradesh (3.4 %). those children aged 12 to 17 months are 7 times significantly more likely to be severe anaemic as compare to the 36 to 59 months aged children. those mothers have severe anaemia, their children are also found to be severe anaemic (16 times more than not anaemic mothers). mothers who are highly educated and belong to richest quintile their children are less likely to be anaemic. the finding of the study shows that demographic and socio-economic indicators play significant role in determining the prevalence of anaemia in eag states which needs focused programme to reduce the prevalence of anaemia in preschool children. abstract# p-sat376 impaired renal growth hormone mediated jak/stat5 signaling in juvenile rats with chronic kidney disease objective: linear growth retardation is a major problem in children with chronic kidney disease (ckd) and is ascribed to gh insensitivity. treatment with exogenous gh has been accepted as standard therapy in children with ckd and short stature. however, concerns have been raised in the past on the potential fibrogenic effects of gh. there is no information regarding renal ghr signaling pathway in ckd. methods and results: to investigate this pathway, surgically 5/6 nephrectomized (ckd) and pair-fed control (c) juvenile (3 wk old) rats were sacrificed after 2 weeks of ckd. serum creatinine and albumin excretion were significantly elevated (associated with glomerulomegaly and early fibrosis) while body weight and length gain were reduced in ckd rats. serum igf-i levels were decreased in ckd, even though serum gh levels were unchanged. kidney ghr mrna and protein levels were reduced and phosphorylation of jak2 and stat5 was significantly impaired. supressor of cytokine signaling (socs3) mrna was increased in association of increase in renal il6 mrna. renal igf-1 mrna was unaltered in ckd. thus, in the remnant kidney of ckd growth retarded juvenile rats there is impaired gh mediated jak2/stat5 signaling. this defect may be due to a reduction in gh receptor expression and signaling together with an increase in socs3 expression. conclusion: we suggest that the insensitivity of the remnant kidney to gh may serve to protect against the potential adverse renal effects of exogenous gh in ckd patients. objective: concerns have been raised about possible adverse effects of growth hormone(gh) in short children with chronic renal diseases. six cases of short children with chronic renal diseases ckd were studied in our hospital, the microalbuminuria as a sensitive parameter of early glomerular damage was detected during the treatment of recombinant human growth hormone. the individual growth response to gh was also observed. methods: of the 6 cases, male were 4 , female 2, the onset age ranged from 4 to 14 years old, all were diagnosed as growth retarded children with various chronic renal diseases. the dosage of gh was 0.1 iu/kg/d. the follow-up period was from 3 months to 1years. microalbuminuria was measured by a commercially available elisa kit, as a sensitive parameter of early glomerular damage in children being treated with recombinant human growth hormone. serum insulin-like growth factor igf-i concentration and igfbp3 were also measured before and during the treatment with gh. results: there was no statistically difference on the level of microalbuminuria compared with that of pretreatment. linear growth were 1.0 cm/month with an increment in height sds by 1.5 at the end of the first year of gh treatment. growth retardation in children with ckd is associated with normal to slightly low concentrations of (igf)-i and igfbp3. objective: iron deficiency anaemia is common in chronic haemodialysis patients and is the most common factor of resistance to erythropoeitin treatment. kdoqi clinical practice guidelines and recommendations for anaemia in ckd suggest maintaining hb levels between 11-12 g/dl, tsats >20% and serum ferritin above 100 ng/ml. our unit's previous practice provided 1-2 mg/kg/week of elemental iron intravenously to our haemodialysis population and monitored blood parameters monthly. from july 2012, we changed our practice to withhold routine administration of iv iron, unless blood parameters (monitored fortnightly) suggested iron deficiency. we assessed the change in our practice in safely reducing the frequency of iv iron administration in our haemodialysis population. methods: we included all 9 children attending our haemodialysis unit (july 2012). we used %hypochromia of >4%, correlating with hb level of <11 g/dl as a marker for initiating iv iron sucrose (3mg/kg/week) until improvement of the above parameters. serum hb and %hypochromia were monitored at the start of change-over and fortnightly thereafter. all patients received routine erythropoietin at recommended doses of between 50-300 units/kg/week. results: at initiation of change-over, there were 9 patients with mean hb 11.3 g/dl, mean %hypochromia 1.2% and mean tsats 27.7%. from july 2012 -mar 2013, four patients required iv iron therapy (mean hb 9.2 g/dl, mean %hypochromia 6.2%, mean tsats 16.3%). three patients had 4 weeks and one patient had 7 weeks of iv iron sucrose 3 mg/kg/week to achieve normalisation of serum hb (mean 11.5 g/dl), %hypochromia (mean 2.73%) and tsats (mean 26%). at time of reporting (mar 2013), there were 7 patients with mean hb 11.22 g/dl, mean %hypochromia 2.07% and mean tsats 28.2%. two patients received transplants. conclusion: a novel change in our practice has resulted in a safe reduction of iv iron therapy in our population of children undergoing haemodialysis. from our findings, we suggest avoiding routine iron infusions in paediatrichaemodialysis, which is unlikely to have an adverse effect on the incidence of anaemia and will reduce the risk of inadvertent iron overload. abstract# p-sat380 reversible portal ascitis after bilateral nephrectomy in infant with polycystic kidney disease we report here on a newborn with moderate renal failure and severe hypertension due to autosomal recessive polycystic kidney disease (arpkd). antihypertensive therapy associating minoxidil, labetalol, amlodipine and lasilix were not able to control adequately blood pressure. due to massive kidney enlargement, inadequate respiratory function and inability to tolerate enteral nutrition, parenteral nutrition was initiated at 2 months to maintain adequate calories intake. at 4 months of life, the infant presented severe viral pneumonia complicated by cardio respiratory arrest . he required cardio respiratory resuscitation and hospitalization in icu for several days. unilateral right nephrectomy was decided after this severe complication in order to avoid similar accidents due to massive kidney volume and to improve respiratory and nutrition status. one week after unilateral nephrectomy, we noted rapid increase volume of the left kidney and important ascitis having the biological characteristics of portal hypertension. repeated aspiration of more than 100 ml of portal ascitis was performed every day. in parallel daily perfusion of albumin for more than 3 weeks and complete parenteral nutrition did not succeed in treating ascitis. faced to resistant ascitis and persisting difficulties in maintaining enteral nutrition and adequate respiratory ventilation , left nepherctomy was decided and performed. automated peritoneal dialysis was rapidly initiated in our anuric infant (weight after binephrectomy4kgs). portal ascitis disappeared in 48 hours with rapid normalization of respiratory ventilation and return to normal and well tolerated enteral nutrition. conclusion: to our knowledge, this is the first case reported of portal ascitis noted after palliative unilateral nephrectomy to facilitate pulmonary expansion and gastrointestinal function in arpkd. ascitis was resistant to daily albumin perfusion and repeated aspirations but was completely reversible after bilateral nephrectomy and initiation of peritoneal dialysis. early bilateral nephrectomy at 2 months of life was probably the ideal choice to avoid many complications in our infant due to abdominal and thoracic compression by massive kidney compression. ethical considerations, therapeutic possibilities, and parent consent should be discussed in such challenging and very difficult cases. abstract# p-sat381 serum hepcidin 25 levels and anemia in pediatric chronic kidney disease objective: hepcidin restricts the availability of iron from its stores for erythropoiesis resulting in a functional deficiency of iron and hyporesponsiveness to erythropoiesis stimulating agents. the objectives were to estimate the serum hepcidin 25 in children with chronic kidney disease stage ii to iv and correlate it with hemoglobin, iron status (serum ferritin and transferrin saturation), inflammation (c reactive protein) and estimated glomerular filtration rate (egfr). methods: it was a cross sectional study. children aged 2 to 18 years with ckd stage 2-4 on stable dose of iron and or erythropoetin for the last 4 weeks were included. children with anemia due to other causes, severe acute infection, chronic cardiac or respiratory conditions and those who received parenteral iron and or blood transfusion in last 4 weeks were excluded. hemoglobin, serum ferritin, transferrin saturation, c reactive protein were assessed. serum hepcidin 25 levels were estimated using a elisa based kit in the cohort as well as in 15 age and sex matched normal children to estimate the levels in normal population. multivariate regression analysis was used to assess the relationship between hepcidin and hemoglobin, iron status, inflammation and egfr. results: forty children were recruited into the study. the mean age of children was 9.1+ 4.5 years. around 30%, 28% and 42% of children had ckd stage ii, iii and iv respectively. the mean serum hepcidinlevels in children with ckd (55.87+14.27ng/ml) was significantly higher than controls (11.17+4.38ng/ml). conclusion: serum hepcidin levels showed an increasing trend with decrease in egfr, but this was not statistically significant. the mean haemoglobin was 10.76+1.59g/dl, the mean ferritin was 43.27+38.3ng/ml , the mean transferrin saturation was 21.68+11.5%. anemia and absolute iron deficiency was seen in 100% of our cohort and worsened with increasing stages of ckd. serumhepcidin levels did not correlate significantly with haemoglobin, ferritin or with c-reactive protein. objectives, methods and results: presenting a 16-year old armenian patient who developed a secondary amyloidosis on top of a familial mediterranean fever (fmf) and moved to germany 4 years ago. at the time of the move the patient had already a terminal renal insufficiency and received intermittent hemodialysis. despite the therapy with colchicine moderate attacks of the fmf occurred with an interval of 4 weeks and inflammatory parameters were permanently elevated. the dosage of colchicine was titrated up to 3 mg per day. as a consequence diarrhea occurred and the dosage had to be decreased. over the course the amyloidosis progressed and affected all internal organs including heart and bowel. the combination of inflammation, uremia and amyloidosis led to malnutrition (bmi 14 kg/m2). at the age of 16 years the most severe colitis with peritonitis and paralytic ileus occurred. the treatment with colchicine was paused in assumption of a toxic effect. after improvement of the diarrhea but still persisting abdominal pain the colchicine treatment was slowly started again. shortly afterwards a very severe attack of the fmf developed with an accompanied cardiovascular insufficiency. the treatment with a single high-dose of methylprednisolone and the inhibition of interleukin 1 with anakinra (1 mg/kg, given after dialysis) led only to a short remission. the high-dose methylprednisolone treatment was therefore repeated three times and anakinra was given on a daily basis. since then no new attack of the fmf occurred and the combination of lowdose colchicine and anakinra improved the general status of the patient the elevated inflammatory parameters including serum amyloid a have almost normalized. objectives: invasive aspergillosis is almost exclusively occurs in immunocompromised hosts. the central nervous system (cns) is one of the most frequent sites of invaziveaspergillozis after the lungs. we report a case of invasive aspergillosis in a boy with end stage renal failure. methods and results: a 15-year-old boy was admitted to the hospital for abdominal pain, fewer and cough. he suffered from chronic kidney failure (crf) known for a year and he was on peritoneal dialysis for seven months. he was initially treated with iv. ceftriaxone for lobar pneumonia, intraperitonealceftazidime and cefazolin for peritonitis. the peritoneal fluid was also cultured for fungus and mycobacteria and all cultures were negative. on the seventh day, the patient complained for lower extremity weakness, and bilateral hyperactive deep tendon reflexes and positive babinski reflex were found. cranial magnetic resonance imaging (mri) was normal, but the spinal cord was compressed between c7-t5 by a solid mass which was originated from right lung on spinal mri. computed tomography-guided tru-cut lung biopsy was performed for the solid mass. repeated peritoneal fluid culteres were also negative. two days later, when unconsiousness and convulsions were seen, intraparenchymal multiple hemorrhagic abscesses were found on his second mri. typical hyphae of aspergillusfumigatus was present in pathologic specimens and galactomannan test was positive. cerebral abscesses were evaluated as cns involvement of invasive aspergillosis. anti fungal therapy was began immediately as amphotericin b and caspofungin. the peritoneal catheter was removed and continuous veno-venous hemodiafiltration was performed. however his condition kept deteriorating and death ensued on the fourth day of anti fungal therapy. conclusion: invasive aspergillosis may rarely occur in immunocompetent patients and diagnosis may be missed or delayed due to lack of the particular clinical signs. we should be careful about diagnosis of fungal infections in patients with crf since early treatment before the invasion and dissemination of aspergillosis to adjacent tissues and/or organs offers a higher survival chance for the patient. questionnaire and to find a way to increase reliability for healthy children aged 8-12 years especially, according to iranian culture. objective: we lunch this study to compare the parent and children's behavior problem in pediatric patients suffering from ckd referring arak amir kabir hospital. methods: to perform this case control study, we recruit 116 children with ckd and compared them with other 116 non affected children age between 5 to 16 years old. the child behavior checklist cbcl4/18 for child behavior assessment and general assessment function gaf for the evaluation of their parent's behavior were completed by the parent's data was analyzed using qualitative variables and chi-square formula. results: among 116 patients with ckd, 10 case 8.6% showed behavioral problem while this figure was 3 case 2.6% in the control group, denoting a significant difference p-0.04. moreover 20 children 17/2% in the case group and 9 children 7.8% in the control group had internalizing problem p-0.02. 22 children 19% with ckd and 8 children 6.9% in the healthy group had externalizing problem which was also a significant difference p-0.0003. as a significant p-0.0001 the parent's average stress and behavior scores in case and control were 3.65 & 3.76, respectively. conclusion: the higher prevalence of behavioral problem in the children suffering from ckd and their parent's functional impairment highlights the important of early treatment and subsequently prevention of future behavioral problem in their sibling. abstract# p-sat391 development in 6-year-old children with and without ckd objective: ckd is a pathophysiologic process with multiple etiologies, resulting in the inexorable attrition of nephron number and function and frequently leading to esrd. a number of studies have suggested that children with ckd have problem in development than other children our goal was to compare development of children with ckd with normal children within the common age range for the disease. methods: in this descriptive-analytical study, we selected 30 children with 6-year-old children whom were diagnosed with ckd as our case group and studied their developmental status by ages and stages questionnaire (asq). the control group was selected from 6-year-old children who attended the clinic for reasons other than ckd. conclusion & application to practice: the eleven key areas of responsibility used to measure sc in a periodic evaluation demonstrated a strong correlation to the increasing extent of qpdo. additionally, as the nurses progressed to becoming expert a direct correlation to the qpdo was notable. the study became the foundation for staff training and developing a competency appraisal framework in renal nursing practice thereby promoting quality assurance procedures while attaining qpdo. objective: urinary incontinence is a child health problem that affect both the child and the family in psychological and social aspect and that leads to a decrease in quality of life of the child and his caregiver. patients with higher ckd stage had significantly lower qol score in all domains in the child-self reports, but not parent-proxy reports. whereas there was no difference between patents with stage i and stage ii. according to gender, boys had a tendency to present better qol than girls, but there was no significant difference between these two groups. age discrepancy was not a significant factor to decide qol in children with ckd. in addition, there was significant difference between parent-proxy reports and child-self reports and qol scores in the child-self reports was significantly higher than in the parent-proxy reports, especially in the domains of emotional, school functioning and psychosocial health score. conclusion: residual renal function in children with ckd is a important factor to decide qol. in addition, emotional and psychosocial support for their parents can be necessary to improve qol in children with ckd. abstract# p-sat398 results: the mean period of post-transplant follow-up was 4.7+/-2.1years(range: 0.8-9 years). in the first year of transplantation, 14 (15.2%) recipients had obesity obese patients had higher serum ggt levels than non-obese patients (21.2+/-6.2 u/l vs 14.9+/-3.8u/l, p=0.01). there was a positive correlation between bmi and ggt and tg levels in obese patients (r=0.61, and r=0.5, p<0.01 respectively). patients with dyslipidemia were found to have significantly higher mean ggt level (14.2+/-3.6 u/l vs. 19.2+/-6.2 u/l, p=0.016) and bmi (18.6+/-3.4 vs. 29.4+/-6.3 p=0.04). we could not find any correlation between bmi, and gender, post-transplant follow-up, duration of crf, primary disease, donor status and graft loss. in the first year of transplantation, gfr was significantly lower in obese patients than non-obese recipients (p<0.05) conclusion: our data has suggested that, even within its normal range, elevated serum ggt concentrations and hyperlipidemia are closely associated with obesity in transplanted patients and obesity has negative effects on graft functions. the relationship between the graft function and the serum and urine ngal in children with renal transplantation tehran university of medical science, associated professor, tehran, iran objective: the evaluation of graft function long term after transplantation is important. serum creatinine is the most common used marker for graft function in renal transplantation. the level of serum and urine ngal may predict graft function in renal transplant recipients. methods: we evaluated 21 pediatric renal transplant recipients by measurement of serum and urine ngal, serum creatinine concurrently. the gfr of the patients was also estimated by schwartz formula. results and conclusion: the time after transplantation was 3-12 years (mean: 6.8+/-2.47 years). the mean serum ngal was 140+/-94.2 ng/ml (15.4-324) . the mean urine ngal was 17.8+/-20 ng/ml (32-68). we didn't find any association between serum creatinine, gfr estimated by schwarz and serum ngal. we also didn'y find any association between urine creatinine, gfr estimated by schwarz and serum ngal. glomerular filtration rate measured by dtpa scan of fourteen patients were available. we also didn't any association between gfr measured by dtpa scan and serum and urine ngal. abstract# p-sat409 racial disparities in paediatric kidney transplantation in australia glomerulonephritis and late referral were more common in non-caucasian patients. among patients who did receive a transplant, caucasians had overall better hla matches to their graft and were less sensitised. conclusion: caucasian australian paediatric patients have greater access to kidney transplantation, particularly from living donors, and are likely to have the better graft survival. some racial disparities may be inevitable due to differences in kidney diseases, however further work is required to understand barriers to live donation and address disparities. abstract# p-sat410 cost-effectiveness of renal transplantation in paediatric and adult transplant recipients. [1.4-4.8] ), were associated with a lower inscription probability 6 months after reaching esrd. the national inscription rate was 69% with a significant center variability (median 69% [iqr 51-80]) that remained after adjustment on patient characteristics (p<0.0001). preemptive transplantation rate explained 19% of the inter-center variability (p=0.06). probability of transplantation 12 months after inscription decreased with time of waiting list inactivity (p<0.0001) and with the probability of finding a compatible transplant considering patient's hla and abo groups. underweight (bmi <-2sd) was associated with lower transplant probability (or 0.3 [0.1-0.9]). at 12 months, 81% of patients were transplanted with a significant center variability (median 80% [iqr 72-88] that remained after adjustment (p=0.02). conclusion: as expected patients' characteristics contribute to intercenter variability as well as centers' attitude towards the inscription of younger children, management of specific primary renal diseases and preemptive transplantation. despite national allocation rules we found a significant inter-center variability in the probability of being transplanted after inscription on the list, which was not explained by either the patient or center characteristics of our study. abstract# p-sat414 ten year outcomes of paediatric renal transplantation: the irish experience objective: focal segmental glomerulosclerosis is the most common cause of steroid-resistant nephrotic syndrome in children and adolescents. within 10 years of initial presentation, 50-70% of patients will progress to end stage kidney disease requiring kidney transplant. recurrence rate after transplantation is high and may be associated with early graft loss. methods: we analysed demographic and transplant data collected by the australian and new zealand dialysis and transplant registry (anzdata) on children and adolescents with a diagnosis of primary fsgs who were 20 years of age or younger at the time of transplant. kaplan-meier analysis was performed to compare graft survival according to recurrence of fsgs and donor characteristics. results: during the 20-year period from 1st january 1992 to 31st december 2011, 80 transplants were performed in 74 patients (age range 3-20 years, median 15 years). twenty seven patients developed recurrent fsgs, with one child developing recurrent disease in 2 grafts (overall recurrence rate 36%). the median time to recurrence was 15 days, with loss of graft function in 12/28 transplants (43%). median graft survival in patients with recurrence was significantly shorter than in patients with no recurrence (2.3 years vs >10 years, respectively; p<0.01). there was no significant difference in recurrence rate in recipients receiving deceased donor (dd) versus live donor (ld) transplants (p=0.24) and median graft survival was significantly better in recipients with live donors (11.7 yrs vs 1.6 yrs for dd, p<0.01) conclusion: the rate of recurrent fsgs and graft loss in this retrospective cohort study of children and adolescents transplanted within the australasian region, was similar to previously reported studies. however, in contrast to previous studies, there was no significant difference in rate of recurrence for live versus deceased donors. additionally, live donor recipients had longer median graft survival compared to deceased donor recipients. outcomes of calcineurin inhibitors conversion to mammalian target of rapamycin inhibitors in children with renal transplantation nuntawan piyaphanee, suroj supavekin, anirut pattaragarn pediatrics, siriaj hospital, bangkok, thailand objective: to study outcomes of pediatric renal transplant recipients who underwent cni elimination and conversion to mtor inhibitors. methods: we performed retrospective analysis of all pediatric renal transplant recipients who underwent cni elimination and conversion to mtor inhibitor at siriraj hospital, a tertiary care center in thailand. indications for conversion were defined. graft function prior and post conversion, history of acute rejection, and cni elimination failure were reviewed. results: nine of 32 pediatric renal transplant recipients underwent complete cni conversion to mtor inhibitor. triple-drug regimen including prednisolone, cni and mmf/mpa was basically prescribed to the recipients. eight with tacrolimus and 1 with cyclosporine were conversed to everolimus. mean ages at transplantation, conversion and last follow up were 12.1±2.4, 13.6±2.1 and 14.5±1.8 years, respectively. everolimus was initiated within 3 months in 4 patients. each patient due to cni induced hemolytic uremic syndrome, posttransplant diabetes mellitus, graft impairment with early onset nephrocalcinosis and graft impairment with renal artery stenosis. everolimus was initiated after 3 months in 5 patients due to 1 chronic cni nephrotoxicity, 2 chronic allograft nephropathy (can) and 2 unfavorable graft functions with history of delay graft function. median duration from transplantation to cni conversion was 4.5 months (range 0.8-88) and median time from conversion to the last follow-up was 8 months (range 2-26). mean creatinine clearance (crcl) prior to the cni elimination was 33.0±13.2, as compared to mean crcl of 49.0±16.3 ml/min/1.73m 2 at last follow up (p =0.069). three patients had acute rejection (ar) before the conversion, but only 1 patient had ar post cni elimination. there were no patients with graft loss or cni-elimination failure. conclusion: conversion from cni to everolimus was safe without increasing risk of acute rejection in pediatric kidney transplant patients who experienced early and late cni associated complications. objective: due to a severe shortage of suitable deceased-donor kidneys for children awaiting kidney transplants (kt), we have performed a series of abo-incompatible (abo-i) living kt since 1989. historically, abo-i kt was performed using several session of plasmapheresis (pp) to remove existing anti-a or anti-b antibodies, followed by splenectomy to prevent rebound of antibodies. because splenectomy had risks of surgical complications including bleeding and pancreatic pseudocyst, we introduced a new protocol, for abo-i kt, in january 2006. the new protocol without splenectomy utilizes the anti-cd20 monoclonal antibody (rituximab) and pp. this study retrospectivery examined the efficacy and safety of this protocol. methods: eight de novo abo-i kt (5 males and 3 females) were performed between january 2006 and december 2012. the mean age at transplantation was 15.3±4.0 years (range 9.9-20.5 years). the immunosuppressive protocol consisted of cyclospolin or tacrolimus, mycophenolate mofetil, and methylprednisolone. all patients received induction therapy with basiliximab. the preconditioning protocol included pp or double filtration plasmapheresis (dfpp) and a single dose of rituximab (average dosage 179 mg/m 2 ). all patients who underwent kt achieved a isoagglutinin titer less than 1:16 with 1-4 sessions of pp/dfpp treatment before transplant. results: the patients were followed for 5 to 82 months with a mean follow-up of 36 months. patient and graft survival rates were 100%. one non-adherent patient experienced antibody mediated rejection. figure1 ). in the rtr who had graft loss, there was no significant difference in graft survival time (6.0, 3.1 years, dsa negative vs dsa positive), grade 1 rejection (0.5, 0.7 episodes per patient), grade 2 rejection (0.5, 0.7 episodes per patient) or c4d staining (100%, 57% patients). one patient in each group had bk virus associated nephropathy. two patients had plasma cell infiltrates on biopsy and lost their grafts within 6 months of dsa detection. results: fifty-one kidney recipients (male 32 cases; female 19cases) were enrolled in this study. the median age was 15 years, the youngest kidney recipient was 3years old with a body weight of 10.0kg). there were 11 recipients less than equal 10 years, including one children with congenital renal dysplasia and one with congenital renal artery malformation. about 73.7% kidney recipients came from guangdongprovince. about 1 to 7 pediatric patients accepted renal transplatation each year from 2003 to 2011, but there were13 in2012, which showed a significant increase than in each previous sigle year.the policy that children had a kidney recipients priority may contribute to this increase. the kidney donors were cadaveric kidneys(72.5%) and living kidneys(27.4%), only one patient accepted auto-renal-transplatation. all kidney recipients were survival to present with the treatment of glucocorticoid and or immunosuppressants,such as csa, fk506, mmf,ect. only two patients accepted retransplatation due to losing function of the renal grafts. conclusion: renal transplantation in children increased significantly in 2012 in our hospital, and it seemed an effective treatment to children with esrd. recent adult studies have shown that low levels of immunosuppression (is) are associated with dndsa. however, limited data is available on significance of dndsa and its management in paediatric population. to assess relationship between dndsa with renal function, histological findings, immunosuppression levels and graft outcome in paediatric renal transplant recipients (rtr). in our centre, at the time of the study, dsa were tested if deterioration in graft function was found necessitating renal biopsy. methods: retrospective review of all rtrs in a single tertiary nephrology centre tested for dndsa. data collected included dndsa, histological findings, egfr as marker of renal function, baseline immunosuppression, subsequent treatment and outcome. results: 27/88 patients had dsa tested; 12/27 had dndsa detected. median time for measured of dndsa was 7.6 years post-transplant (range 1.07-13.02).histology: 8/12 biopsies in dndsa+ve subgroup had antibody mediated rejection (abmr) of which 6 were active abmr (3 were c4d positive) compared to 1/16 in dndsa-ve subgroup. the following treatments were used in the dndsa+ve group: increase in is+ pulsed methylprednisolone (mp) (5 patients), increase in existing is (2), rituximab (2), pulsed mp (1), sirolimus added+pulsed mp (1) . in one patient no change was made. at last follow up, in 9/12 patients with dndsa an improvement in egfr was observed. on re-testing for dndsas, 3/12 patients tested negative, 2/12 had lower and 3/12 increased levels. 3/12 had not yet had repeat dndsa testing. conclusion: despite previous reports of dndsa conferring poor prognosis, in our cohort with allograft dysfunction and positive dndsa an improvement in renal function was observed in 75%. however, larger prospective studies are required to further evaluate these findings. abstract# p-sat425 anuria since birth: does it impact outcome of kidney transplant in infants? shefali vyas, maria isabel roberti pediatric nephrology, saint barnabas medical center, livingston, usa objective: scarcity of data exists for allograft outcomes and urological problems in children with long term de functionalized bladders. however, even less is known about the outcome of infants anuric since birth and whose bladders underwent "forced rehabilitation" after a successful renal transplant. methods: in this retrospective study we compared urological events and allograft outcome in infants with esrd mainly due to urological problems. they were grouped according to the history of pre-txp urine out put: group a with urine output prior to txp and group b anuric since birth (all had visible small bladders by ultra sonogram). results: there were no significant differences regarding birth history or ethnicity . group a had 13 boys (87%) and group b had all girls; all but one child in group b received lrd txp. all received induction followed by triple therapy (tacrolimus, steroids and mmf). group a: 8/15 had v-u reflux and 13/15 were on pd prior to txp (mean time= 7 mos). all patients in group b were started on pd in the neonatal period (mean =9.8 days). pre txp native nephrectomies were done in 3 patients (2 in group a and 1 in group b). group a had 2 acute rejections and none in group b. conclusion: anuric young infants had higher rates of post txp utis and v-u reflux, a direct consequence of their inherent small bladders. however, the 3 year graft survival, patient survival and gfr remained excellent in anuric infants (group b )compared to young infants transplanted with higher rates of v-u reflux and dysfunctional bladders pre txp. abstract# p-sat426 kidney transplantation in a child with bladder dysfunction who underwent prior bladder augmentation: a case report 1 tepecik training and research hospital, pediatric nephrology, they were divided into 2 groups; 12pts with esrd on dialysis (d), 4/12 with history of kidney transplant, and 9 kidney transplant recipients with good graft function (t). all subjects were tested for anti-hla antibody 1 month prior to and 1 month and 6 months after administration of the combination vaccine of influenza a/ h1n1. results: among the t group, no pt tested positive for either anti-hla class i or class ii antibodies before or after influenza a/ h1n1 vaccine. in the d group, of the 4 pts with a history of graft failure who were sensitized before immunization; 2 showed no change in class i & ii, one patient had mild increase in class i after vaccination, and one patient had an increase in class i by 24%. [figure] conclusion: none of the t pts had clinical evidence of either cell mediated or humoral rejection after the influenza a/h1n1 vaccine. in the d group, no pt had any statistically significant increase in anti-hla antibody following vaccination. our study suggests that influenza a/h1n1 vaccination may be safe and tolerable in pediatric dialysis pts with or without a failed kidney allograft. the effect of dipping blood pressure status on structural and diastolic heart function in renal transplant recipients mitra basiratnia 1 , gholamhossein ajami 2 1 shiraz nephrology urology research center, shiraz university of medical sciences, shiraz, iran 2 department of pediatric cardiology, shiraz university of medical sciences, shiraz, iran objectives: non dipping has been linked to cardiovascular disease in adults, however the impact of non-dipping on cardiovascular status of the adolescents with renal transplantation has not been well established. the aim of this study was to evaluate the influence of non dipping status on left ventricular mass index and diastolic function in subjects with renal transplantation. methods: sixty six stable renal transplant patients (34 females, 32 males), aged 7 to 25 years (mean 17.4±4.3 years) were enrolled in this study. cardiac function assessed by tissue doppler echocardiography and blood pressure measurement performed using ambulatory method. dipping was defined as at least 10% bp decline during the night and was calculated as (mean daytime -mean night time/mean daytime)*% 100. left ventricular mass (lvm) was calculated by standard 2dimensional directed m-mode echocardiography according to the formula of devereux and was indexed to height in meters to the 2.7 power to allow the comparison between recipients of different sizes. left ventricular hypertrophy was defined as lvmi>38.6g/m 2.7 in patients younger than 18 years and 51g/m 2.7 in patients > 18 years. data analysis was performed by spss-15. a p<0.05 was considered statistically significant. results: non-dipping was identified in 48 (73%) patients. five recipients were systolic non-dippers, 1 diastolic non-dipper, and 42 both systolic and diastolic non-dippers. left ventricular hypertrophy (lvh) was found in 37.1% of the renal allograft recipients. lvh was present in 41% of the systolic nondippers and 27.8% of the systolic dippers (p=0.33) . forty five percent of the diastolic non dippers and 22.7% of the diastolic dippers had lvh (p=0.08) . there was no correlation between systolic and diastolic dipping status and lvh, respectively (p=0.33, p= 0.08). there were no significant differences in terms of diastolic function [measured by early diastolic inflow velocity (e), e/a ratio, and early diastolic mitral inflow velocity to earlydiastolic annular velocity (e/ea)] between dipper and non dippergroups(p= >0.05). conclusion: non dipping is common among renal transplant recipients, but is not always related to diastolic dysfunction and lvh. prospective longitudinal studies are required to determine the impact of dipping status on diastolic and structural heart function in renal transplant recipients. parsa yousefi chaijan, parvin soltani, farshid haghverdi, masood fazelimoslehabadee nephrology, arak university of medical sciences, arak, iran objective: nephrolithiasis in renal grafts is a relatively common phenomenon which can induce organ damage; hence early diagnosis and management of predisposing factors can preclude subsequent complications. the aim of this analytic cross-sectional study is to determine the contributory factors to nephrolithiasis after renal transplantation. method: 56 renal-transplanted patients (10-40 years old) were enrolled in the study, being divided into two groups of 28 transplanted patients suffering from nephrolithiasis (within first 5 years after surgery) and 28 transplanted patients free from renal stone with the same age and gender and similar gfr. data were collected and arranged in excellmicrosoft program and the statistic analysis was carried by spss v17. pvalue < 0.05 were considered statistically significant. result: the studied showed that male gender (p = 0.048), age group of 15-25 years (p=0.021), hyper cholesterolemia (p=0.007), hyper triglyceridemia (p=0.031), 3 rd year after surgery (p=0.023), hyperuricosuria (p=0.012) , hypocitraturia (p=0.001) and anemia (p=0.006) were significantly more common in patients with nephrolithiasis. conclusion: it is better to evaluate hyperuricosuria and hypocitraturia in kidney donors, moreover all patients had better undergo serial sonography for early screen and management of renal stone as well as treatment for hyperlipidemia and anemia. it also seems prudent to further assess the donors of transplanted patients suffering from renal stone and possbile relation between cni & nephrolithiasis ( regardinghyperuricusuria) objective: epstein-barr virus-associated smooth muscle tumor (ebv-smt) in immuno-compromised patients has recently been reported. but there were no evidence about the treatment of ebv-smt. we report a 6-year-old girl treated for multiple ebv-smt by using rituximab. methods: case report results: she was suffering from end stage renal disease due to congenital nephrotic syndrome induced by wt1 mutation. renal transplantation (tx) was performed at the age of 2 years, and immunosuppressive therapy was performed her. soon after performing tx, she was infected cytomegalovirus(cmv), bkv and ebv. she was reduced in amount of immunosuppresive therapy, and she recovered from viremia of cmv and bkv. her ebv titer did not become negative, but we did not perform any medication because of no symptom. four years after tx, she was pointed out 1cm of cholecystic polyp in a protocol abdomen ultrasonic examination. we soon performed cholecystectomy and extirpation of swelling mesenteric lymph nodes. the pathological finding of cholecystic polyp was ebv encoded small rna (eber) positive smooth muscle tumor but there was no finding about post-transplant lymphoproliferative disorder in mesenteric lymph nodes. positron-emission tomography (pet) showed accumulation of 1cm mass around 12th of thoracic vertebra and ct scan showed three small masses in the lung and one in the liver. we diagnosed her suffering multiple infection of ebv-smt. immunosuppression therapy was reduced, but there was no change about size of her tumor. rituximab was administered for keep away from repetition of tumor after proving infection of ebv only in b cells by using flow cytometry. after medication of rituximab, the ebv dna counts were normalized. ultrasonic examination detected three small masses in liver and one lymph node around main artery. but her mass around 12th of thoracic vertebra was disappeared and whole body ct scan detected only one small residual mass in the lung. we report a case of an ebv-smt presenting multiple infections, which was treated with rituximab. rituximab may be an effective treatment for multiple ebv-smt but careful observation is also needed for the reappearence of ebv-smt. the usefulness of monitoring of epstein-barr viral load after renal transplantation in pediatric recipients with ebv seronegative objective: the purpose of this study are to establish a protocol for monitoring epstein-barr virus (ebv) infection for identification of pediatric renal transplant recipients with a high risk of developing posttransplantlymphoproliferative disorder (ptld) and to predict the development of ptld. methods: peripheral blood mononuclear cells (pbmcs) and plasma ebv loads were measured by nested pcr (n-pcr) and real-time pcr (r-pcr) every 1-3 months after grafting in 17 pediatric recipients who were seronegative for ebv before grafting (4 with ebv-associated symptoms, including 2 with ptld (group a); 6 with asymptomatic persistent high ebv loads in pbmcs of >1,000 copies/ug dna for over 6 months (group b); and 7 with neither ebv-associated symptoms nor persistent high ebv loads in pbmcs (group c). ebv-ctls were also measured in 13 patients without ebv-associated symptoms. results: the ebv genome detected by n-pcr was present in plasma in 3 (75%), 1 (17%), and 0 (0%) in groups a, b and c (p<0.01 for a vs. b and a vs. c). ebv loads detected by r-pcr in pbmcs were significantly higher in groups a (p<0.05) and b (p<0.01) compared to group c. ebv genomes in plasma were detected by n-and r-pcr in only the 2 cases with ptld. one patient with lymphadenitis in group a and 1 patient in group b had ebv-dna in plasma based on n-pcr, but the viral loads using r-pcr were <250 copies/ml. the ctls' percentage was significantly lower in group b when ebv loads first rose above 100 copies/ugdna. conclusion: plasma ebv loads (over 250 copies/ml) estimated by r-pcr and ctls' monitoring may be useful to distinguish ptld from other ebv-associated diseases or asymptomatic viremia, and to avoid ptld as patients with asymptomatic persistent high ebv loads had higher ebv loads and lower percentages of ctls. abstract# p-sat437 risk factors for post-transplant lymphoproliferative disorder (ptld) in children with kidney transplantation (ktx) -a single center survey since the introduction of tacrolimus (tac) since pre-transplant evaluation showed complete obstruction of ivc/ iliac vein below diaphragm, she had been managed with peritoneal dialysis for 7 years until january 2012 when she received a living donor kidney allograft from her mother. the graft was transplanted in a left orthotopic position. venous drainage was to the left ascending lumber vein. in addition, a venous bypass was made using donor ovarian vein between graft vein and splenc vein after splenectomy. such double venous drainage was working very well after transplantation. there was no surgical complication and the serum creatinine (s-cr) during the hospital stay was 0.54mg/dl. at second month after the transplantation, she developed an increase of s-cr with edema and hypertention. however, biopsies of kidney allograft performed at 2 nd and 4 th month after the transplantation revealed no evidence of acute rejection. hypertention was difficult to control even with a maximum dose of calcium blocker, and a temporary increase of the s-cr up to 1.30 mg/dl was noted when angiotensin ii receptor blocker was administrated. by the ultrasonography, the maximum arterial blood flow of the kidney allograft was high enough (459cm/s) to suggest renal arterial stenosis. moreover, severe renal arterial stenosis was clearly shown for about 10mm length from the anastomosed site of aorta by the contrasting ct.for the treatment of artery stenosis of the kidney allograft, percutaneous transluminal renal angioplasty (ptra) was performed at 8 th month after the transplantation. the stenotic lesion was expanded using the special dilatation balloon from 1.7mm through 2.0mm in diameter. because intravascular ultrasonography showed no intimal thickening of the blood vessel, a vascular stent was not placed. after the ptra, s-cr was decreased to 0.5mg/dl, and the blood pressure became controllable by antihypertensive agents. moreover, the angiography performed 4 months after the ptra revealed no progression of arterial stenosis. the s-cr of this patient is now stable in 0.7 mg/dl. post-transplant encapsulating peritoneal sclerosis in children: a single center experience kei nishiyama tokyo women's mdical university, pediatric nephrology, tokyo, japan objective: a substantial proportion of encapsulating peritoneal sclerosis (eps) cases develop after renal transplantation (rt), an entity known as post-transplant eps. although risk factors for eps include prolonged pd, recurrent peritonitis, decreased ultrafiltration and prolonged administration of hypertonic glucose or icodextrin, the pathophysiology of post-transplant eps is largely unknown. however it has been postulated that the use of calcineurin inhibitors (cnis) after transplantation may promote eps, as these drugs are considered profibrotic. a recent scottish study showed that the contribution of post-transplant eps might be even as much as 50% of the total eps patients. by contrast pediatric cases are very rare. therefore we examined the incidence of post-transplant eps in pediatric renal transplant recipients. methods: in this study, we retrospectively investigated clinical records from 52 consecutive pediatric renal transplant recipients in our center between 2007 to 2012, who performed pd before transplantation. clinical parameters and pd-related risk factors of eps were collected at the time of rt. transplant-related variables were also collected. eps cases who met ispd diagnostic criteria including clinical feature and either radiologic and/or histopathological confirmation were examined. results: the median duration of pd was 2.0 yr (range 0.5 to 7.9). twelve patients (23.1%) had at least one episode of peritonitis. ten patients (19.2%) were administered hypertonic glucose and/or icodextrin. the median follow-up period after transplantation was 2.3 yr (range 0.3 to 5.8). all patients were administered cni, and 2 patients discontinued corticosteroid during the follow-up period. although 5 patients had ultrafiltration failure at the time of rt, there was no case who developed post-transplant eps. conclusion: the case of eps after rt was not seen in this study. possible explanation of this result might be associated with shorter durations of pd and small sample size. since post-transplant eps is rare but carries a high mortality, caution should be paid to developing post-transplant eps even in pediatric patients with a relatively long pre-transplant duration of pd. asli kantar, kaan gulleroglu, esra baskin, umut bayrakci, zafer ecevit, hande arslan, aydincan akdur, gokhan moray, mehmet haberal pediatric nephrology, baskent university, ankara, turkey objective: viral infections remain a significant cause of morbidity and mortality following renal transplantation. although cytomegalovirus is the most common opportunisticpathogenesis in transplant recipients, numerous other viruses may affect clinical outcome. viral infections are potentially severe complications of transplantation, as they not only induce specific diseases, but they also favor the development of allograft damage, opportunistic infections and acute rejection. we evaluated the major viral infections seen following kidney transplantation and allograft outcomes in our pediatric patients. methods: we evaluated retrospectively 94 pediatric renal transplant recipients for the occurrence of viral infections and compared outcomes among these patients. patients were divided in to two groups those who developed an infection and those who did not. inthese groups, we recorded induction therapy used at transplantation, immunosuppressive therapy given at discharge, acute rejection rate, patient and graft survival rates. results: the mean age of the patients was15.5±5.3 years. viral infection was found in 32 patients. cytomegalovirus infections were the leading causes; ebv and bk virus were following causes in our study. any significant correlation could not be shown between viral infections and immunosuppressive therapy. we did not observe any correlation between acute rejection and viral infections. lowest gfr at 6 th month was shown in patients with bk virus infection. a significant correlation was shown between viral infection and graftloss (r: 0.22 p: 0.028). conclusion: viral infections are common after kidney transplantation. patients should be monitored more carefully for provide against damage in transplanted kidney. objective: anemia is a frequent condition in kidney transplant recipients and it has a negative long term impact on graft and patient outcomes. recently it has been shown that treatment with angiotensinconverting enzyme inhibitors (acei), angiotensin ii receptor blockers (arb) and mtor inhibitors could be the leading causes of anemia in renal transplant recipients.to study the association of hemoglobin (hb) and ferric parameters with gfr, immunosuppressive drugs, acei, arb and clinical features of kidney recipients. method: hospital records of 94 (f/m:48/46) kidney recipients were reviewed retrospectively. the mean age of the study group was 15.5±5.3 years. the mean follow-up was 52.6±36.31 months. results: thirty six (38%) patients were found to be anemic. mean hb levels of anemic and non anemic patients were 10.2±1.15 mg/dl vs 13.87±3.41 mg/dl respectively. ferritin and iron levels as well as transferrin saturation index, rdw and mcv did not differ among the groups. anemia was not found to be correlated with immunosuppressive or antihypertensive drugs including acei and arb. donor status did not also have any influence on anemia. mean gfr of patients at posttransplant 6 months and 1 year follow-up was found to be significantly lover than patients without anemia (74.4±34.1 vs 99.1±28.9 ml/min/1.73m2 respectively). graft loss was also found to be significantly higher in anemic patients (16% vs 6%, p<0.018). conclusion: in this study we examined the prevalence of anemia and its risk factors in kidney transplanted patients. its incidence is quite high in our patients. we found that anemia in kidney recipients is neither related to iron status nor medications like acei, arb or immunosuppressive drugs. the major determinant of hb level, especially during the first year of transplantation is the graft function. the most important conclusion of this study is the considerable controversial impact of anemia on graft survival. there was no significant effect on blood pressure ; 4 patients 7±2 modigraf® administration days in the converted group. in the whole series, mean creatinine level was 0.7±0.5 mg/dl throughout the observational period, and no rejection episodes were detected. blood pressure was well controlled and no proteinuria was seen. the equivalent dose ratio between modigraf® and liquid tacrolimus was 1.28. conclusion: modigraf® appears to be a safe and sustainable way to administer tacrolimus in kidney transplanted infants. in our experience required modigraf® dose was 1.28 times the oral liquid tacrolimus one, and therapeutic levels were attained in one week. objective: prescribing of medications in paediatric practice is problematic as many drugs remain unlicensed. this is especially true of immunosuppressive medications. however, there is now a licensed product for tacrolimus called modigraf® with data available on bioavailability. we undertook a single centre prospective study of conversion to modigraf®, an oral liquid available in granule formulation (1mg and 0.2mg) that allows for dosing according to body weight. methods: all paediatric renal transplant recipients (rtr) under the care of a single centre were considered for conversion to modigraf® from their current tacrolimus regimen. inclusion criteria included all rtr under 18 years of age who were on tacrolimus suspension. exclusion criteria included recipients of multi-organ grafts, patients with lactose intolerance and patient choice to continue with their current suspension. patients were then seen by the multi-disciplinary team. after equivalent dose conversion, patients were monitored with blood tests one week after conversion with subsequent doses adjusted accordingly. patients continue to be monitored with blood levels over a 3 month period after conversion with renal allograft function, renal allograft loss and side-effect profiles recorded. results: forty-three (27% of 158) rtr were considered for conversion to modigraf®. the families of four patients requested to stay on their current tacrolimus suspension, three patients were deemed unsuitable due to lactose intolerance and three patients were excluded due to low doses (incompatibility with the granule dosing). thirty-three patients were then converted to modigraf® and closely monitored. after blood level monitoring one week after conversion, 12% (4) patients had their doses increased due to lower than anticipated 12-hour trough tacrolimus levels. there was stable renal allograft function without renal allograft loss after conversion. conclusion: conversion to modigraf® immunosuppression can be safely undertaken in paediatric rtr, although regular monitoring in the immediate period of conversion is required to provide accurate immunosuppression dosing. escort trial -effects of strict control of blood pressure in pediatric renal transplant recipients -baseline characteristics of patients from a randomized controlled trial tomas seeman, jiri dusek, nadezda simankova, karel vondrak, jakub zieg dpt. of pediatrics, university hospital motol, prague, czech republic objective: arterial hypertension is a known risk factor for impaired graft survival in patients after renal transplantation (rtx). strict control of blood pressure (bp <50 th percentile) delays progression of chronic kidney diseases in children (escape trial). it is not known whether strict bp control has renoprotective effect also in children after rtx. the aim of this randomized controlled trial was to investigate whether strict bp control can protect kidney graft in children after rtx. methods: all children from our pediatric renal transplantation center were screened for eligibility for the study (children 3-16 years at least 1 year after rtx, no acute rejection in the last 3 months, egfr>15 ml/min/1.73m2, 24hr mean bp >50 th percentile using ambulatory blood pressure monitoring abpm). altogether 23 children fulfilled the inclusion criteria. they were randomized to intensified bp control group (intens, target 24hr map <50 th percentile, n=12) or standard bp control group (stand, target 24hr map 50-95 th percentile, n=11). all antihypertensive drugs are allowed to reach the target bp. the study period is 3 years. the primary endpoint is the yearly change in egfr (schwartz formula, ml/min/1.73m2/year), the secondary endpoints are graft failure, change in proteinuria, left ventricular mass and safety of strict control of bp. results: the baseline characteristics of the patients are given in the allelic variants. tac dose (mg/kg/day) and tac exposure normalized for dose (tac co/d) (ng/ml/mg/kg/day) were analyzed with respect to cyp3a5 genotype and for interaction with azoles and corticosteroids, for a period of one year post-transplant. over time, tac co/d was significantly lower in recipients with a cyp3a5*1/*3 genotype compared to those being homozygous for the cyp3a5*3 allele (55.33 +/-21.30 versus 83.07 +/-9.9 ng/ml/mg/kg/day, p= 0.0068). the dose requirement was significantly higher in children with a cyp3a5*1/*3 genotype compared to those being cyp3*3/*3 (0.21 +/-0.02 versus 0.17 +/-0.01 mg/kg day, p=0.0079). the tac co/d was significantly higher for patients receiving azoles (n=17) than those not receiving azoles (n=40) (117.21 +/-1.06 and 62.01 +/-0.52 ng/ml/mg/kg/day, p= 0.002) and consequently the required tac dose was lower in patients receiving azoles overtime (0.08 +/-0.00 versus 0.22 +/-0.01 mg/kg/day, p < 0.001). in children receiving steroids without azoles the tac co/d was significantly different between the cyp3a5*1/*3and cyp3a5*3/*3 genotypes, respectively (52.86 +/-1.71 vs. 58.68 +/-0.85 ng/ml/mg/kg/day, p=0.0044) but the tac co/d was not different for those receiving steroid versus those not receiving steroid with cyp3a5*3/*3 genotype ( 84.91 +/-12.7 and 84.21 +/-1.41 ng/ml/mg/kg/day, p=0.16). conclusion: in conclusion, the tac dose is influenced by the cyp3a5 genotype and drugs such as azoles, while steroids may not impact tac dose. while therapeutic drug monitoring of tac remains necessary, integrated knowledge of patient genotype and comedication use provides the opportunity to refine tac dosing in children receiving kidney transplant. abstract# p-sat458 basiliximab induction therapy in pediatric renal transplantation, a double blind clinical trial hasan otukesh tehran university of medical science, associated professor, tehran, iran this is an open, single center, randomized study to compare induction therapy with basilixamb with no induction therapy in children with renal living transplantation. in this trial 20 pediatric renal transplant recipients enrolled randomly to one group with basiliximab as induction therapy and another group without basiliximab induction therapy. both group received prednisolone, cyclosporine and cellcept. we assessed graft function at 3 months after transplant and compared this item between these two groups. in the congress the data and results of this randomized trial will be presented. abstract# p-sat459 legalization of the organ donation and optimal utilization of young pediatric donor kidneys into pediatric recipients in china objective: china has started to establish a new national system for organ donation and transplantation since march 2010 by the ministry of health and the red cross society of china. the aim of this study was to describe our initial experience of pediatric renal transplantation using organ donations from pediatric patients no more than 6 years old. methods: the procedure of organ donation includes: 1. judgment of brain death, or circulatory death, or brain death followed by circulatory death by doctors; 2. organ donation informed consent form signed by family (children's parents); 3. approval by the hospital ethics committee; 4.organ donation to the red cross society and allocation by the china organ transplant response system (cotrs). the red cross society has been commissioned by the ministry of health to run this system. clinical data of 8 children who underwent renal transplantation using organ donations from pediatric patients no more than 6 years between september 2011 and march 2013 were retrospectively analyzed. results: the age at transplantation for these 8 patients was 4.5 years to 14 years and the weight was 14 kg to 35 kg. among these 8 cases, 7 donors were used aged from 33 days to 6 years and all diagnosed with circulatory death. 5 recipients received en bloc kidney transplantation and the other 3 recipients received one single kidney according to the size of both recipient and donor. the duration of follow-up after the transplantation was 1 month to 18 months. patient survival rate was 100% and graft survival rate was 7/9 (77.8%, one graft loss due to the hemorrhagic complication and the other one due to the thrombosis). at latest follow-up, the median serum creatinine level was 92umol/l and the median egfr was 80ml/(min·1.73m 2 ). conclusion: organ transplantation legislation is necessary to ensure the rights and obligations of donors, recipients and medical institutions. we believe young pediatric donors can be expanded further to increase the number of pediatric renal transplants. this pediatric to pediatric combination on the one hand efficiently lower the discarding ratio of the kidneys from small donor, and give more chances to the younger recipient on the other. to assess the normalization of serum 25 (oh)d level (>30 ng/ml) after standard treatment dosing among primary hypertension (ph) and chronic kidney disease (ckd) methods: we enrolled 144 patients aged 2-19 yrs we collected retrospective data on age, sex,race, cause of kidney disease, egfr, ht, wt, bmi, bp z-scores, lipid panel, 25(oh) d level, pth, calcium, phosphorus, magnesium, medications, type and dosing of vitamin d supplements and follow up serum vitamin d level three months post treatment. results: mean age (yrs) was (12.99±5.05). white(2) prevalence of vitamin d deficiency was (88%); 60% had level <20 ng/ml. mean pretreatment 25(oh) d (ng/ml) was (19.25±10.69) after completion of standard treatment almost 64 % patients had 25 (oh) d level <30 ng/ml; ph(28.02±9.22) and ckd(25.38±9.8). none were in toxic range. conclusion: the standard treatment dose of vitamin d doesn abstract# p-sat360 mineral metabolism in european children with end-stage renal disease marjolein bonthuis 1 the netherlands 2 pediatrics, nephrology and dialysis unit results: hypocalcaemia was found in 22% of hd, 18% of pd, and 48% of transplanted patients, with a mean time on transplantation of 4.3 years. hyperphosphataemia was found in 47% of hd, 37% of pd, and 5% of transplanted patients. pth was outside target in 56% of hd, 58% of pd and 14% of transplanted patients. in dialysis patients, calcium and pth were inversely associated with age; 53% of adolescents were hyperphosphataemic resulting in a significantly higher risk compared to 3-5 year olds (or:1.77, 95%ci:1.43-2.19). patients transplanted pre-emptively had a lower risk of hypocalcaemia compared fgf23 is modulated by calcium in children under chronic peritoneal dialysis azocar 1 , maria l. ceballos 1 , angelica m. rojo 1 luis calvo mackenna children's hospital human intact fgf-23 levels (pg/ml, immutopics) were determined through a 2-site elisa kit. klotho levels were determined by a solid phase sandwich elisa kit (pg/ml). descriptive statistics, univariate and multivariate analysis were performed methods: we measured serum calcium, phosphorus, intact parathyroid hormone, alkaline phosphatase (alp), 25-hydroxy vitamin d3 (25d3), 1, 25-hydroxy vitamin d3 (1,25d3), and fgf-23 from 233 children (male:female = 157:76, mean age 10.2 years) with ckd stage i-v predialysis in korea with 0.5-1 year intervals since 2011. results: hypocalcemia was observed in 23.8%, 32.4%, 21.8%, 22.4% and 31.8% of patients with cdk i to v (the rest is the same as above) 3%, 8.3%, 47.1%, 68.1% and 40.9%. 25d3 level was below fgf-23 (ru/ml) was 38.0, 44.9, 54.4, 67.3 and 119.6. serum p had positive correlation with alp (p < 0.0001), ipth (p = 0.0489) and fgf-23 levels (p < 0.0001) and was inversely correlated with urine phosphorus conclusion: the prevalence of hypocalcemia, hyperphosphatemia and hyperparathyroidism increased as ckd progressed. serum ipth and fgf-23 increased and 1,25d3 level decreased in proportion to the progression of ckd malaysia 6 national transplant resource centre, national transplant resource centre, kuala lumpur, malaysia objective: to analyse the cost-effectiveness of paediatric and adult living related renal transplantation (lrt) and deceased donor renal transplantation (drt) the time horizon was the lifetime of transplant recipient from transplant to death. data for survival analysis was obtained from national renal registry. statistical analysis was performed using stata se version 11.2. the costs was discounted at 3% p.a. results: we reviewed 206 medical records. there were 88 children (39 lrt, 49 drt) and 118 adults (63 lrt, 55 drt). the paediatric recipients mean age was 12.3 +/-3.4 (lrt) and 14.0 +/-2.4 years (drt), whereas the adult recipients mean age was 33.4 +/-10.3 (lrt) and 41.8 ±8.9 years (drt). the 5 and 10-year patient survival rates for both paediatric lrt and drt were 95% and 85% respectively. the 5 and 10-year patient survival rate for adult lrt was 92.5% and 90% respectively, whereas adult drt was 77.5% and 70% respectively. mean cost per paediatric transplant at first year was rm 81,000 (lrt) and 90,000 (crt), from second year onwards was at 20,000 per year (lrt) and 37,000 per year (drt) . the total lifetime cost was rm 650,000 (lrt) and 630,000 (drt) their serum creatinine, egfr, cholesterol, ldl, proteinuria, full blood counts and liver function were profiled to compare the pre-/post-conversion changes. common adverse effects, acute rejection, opportunistic infection and need of treatment for hypercholesterolaemia and proteinuria were investigated. results: we have 15 eligible patients with m: f = 7 : 8. the mean age at renal transplantation was 12 sirolimus was started at a mean age of 15.4 +/-5.0, at a mean time period of +/-2.5 years after renal transplantation, and used for a mean duration of we observed new onset hyperlipidaemia in 9 patients (60%) and needed statin treatment. we found significant proteinuria (spot pr/cr > 1.0 mg/mg) in 4 (27%) patients and needed acei treatment. there was no adverse effect on blood counts and liver function. there was no opportunistic infection observed after conversion to sirolimus in the study period. there was one acute cellular rejection (ia) one month after conversion to sirolimus and responded to pulse methylprednisolone. conclusion: converting from a cni based immunosuppressant protocol for paediatric renal transplantation patients to a sirolimus based one was effective and the benefit was shown up to 54 months post-transplantation one patient received a desensitisation regime with rituximab and plasmaexhange pre-transplant and iv immunoglobulin post-operatively. surgical complications occurred in 7 patients; 2 lymphocoeles, 3 ureteric leaks and 2 renal vein thromboses. early post-operative medical complications included hypertension (47), pulmonary oedema (13), seizures (9), reaction to basiliximab (3), sepsis (5), acute tubular necrosis (8), delayed graft function (5), acute rejection (2) and diabetic ketoacidosis (1). primary ebv infection occurred in 38 patients -1 developed ptld. there were 9 (12%) graft failures; renal vein thrombosis (2), acute humoral rejection (1), acute tubulointerstitial nephritis and tacrolimus toxicity (1), de-novo acute glomerulonephritis (1), chronic rejection (2) and non-compliance (2). graft survival rates were 95% at one year, 93% at 3 years, 89% at 5 years and 88% at 10 years. patient survival was 100% at 10 years. conclusion: our outcomes compare well with international figures a desensitisation program for paediatric renal transplant patients in nsw one child received atg in addition. results: complications/ patient outcomes:1: 2 yo boy, donation from mother. dsa antibodies mfi 658. no complications. no infections. good renal function, creatinine 45 at 2yrs. 2: 14 yo boy, previous transplant from biological father. donation from foster father. dsa antibodies mfi 2602. post operative complication of pseudomonas pneumonia/bronchiectasis, cmv, acute cellular rejection x2. good renal function creatinine 120 at 1 yr. 3: 17 yo boy, donation from father. dsa antibodies mfi 724. early e-coli urine infection. no other complications, creatinine 117 at 1 yr. 4: 14 yo girl, recipient of 3 liver transplants. maternal donor with positive b cell cxm and dsa mfi 6488. no complications. good renal function four of them had subsequently increasing needs in bicarbonate and/or sodium supplementation, and f was reintroduced in 3 of them. conclusion: f is effective in most cases of severe tubulopathy after rtx. however, side-effects can occur. further prospective studies are needed to validate this indication methods: eighty-one (f/m: 41/40)pediatrictransplant patients were included to the study.demographic characteristics and laboratory parameters were recorded.risk factors for hyperuricemia and the effects of plasma uric acid levels at 3 rd and 6t h months, 1 st and 3 th years on allograft outcomes were evaluated. results: mean age was 16.9±5.6 years.mean follow-up time after transplant was 3.5±0.47 years. hyperuricemia was detected in 17.6% of patients. a significant negative correlation was found between 6 th month uric acid leveland 3 th year of gfr value (r = -0.33, p = 0.04 and r = -0.33, p = 0.017). a significant positive correlation between 3 th and 6 th months uric acid levels and3 th year plasma creatinine level was demonstrated conclusion: uric acid levels may have predictive value in the long term assessment of renal function.posttransplanthyperuricemia can be used as a long term prognostic marker of poor renal outcome.patients with hyperuricemia should be monitored closely for renal functions abstract# p-sat447 tuberculosis in paediatric renal transplant patients -single centre experience methods: retrospective descriptive folder review of tb in paediatric renal transplantation at red cross children's hospital, university of cape town from 1994 -2012. results: 14 paediatric renal transplant with tb identified. male 11: female 3. ages 3.4 -18.8yrs(mean 12.0; median 13.2). all patients screened for tb prior to transplant polycystic kidney disease, 2 dysplasia, 2 chronic glomerular nephritis, 2 unknown cause, 1 systemic lupus erythematosis and 1 all patients were on steroids and 8 had recent intensification of immunosuppression. tb treatment included conventional drugs in all but 1 case. levels of calcineurin inhibitors were affected in 12/14 patients and required increased dosing(up to 3 times baseline) according to levels in all. rejection was seen in 7 patients(all biopsy proven). successful treatment of tb in all patients with retention of graft. graft and patient survival 100% post treatment. conclusion: tb is a significant problem in paediatric renal transplants in developing countries. our series shows that with careful investigation and diagnosis of tb as well as careful monitoring of immunosuppressant levels objective: to evaluate the reliability, validity and feasibility of the persian version of the pediatric quality of life inventory (pedsql tm 4.0tm 4.0) generic core scales in iranian healthy students ages 7-15 and chronically ill children ages 2-18. methods: we followed the translation methodology proposed by developer to validate persian version of pedsql tm 4.0tm 4.0 generic core scales for children. six hundred and sixty children and adolescents and their parents were enrolled. sample of 160 healthy students were chosen by random cluster method between 4 regions of isfahan education offices and 60 chronically ill children were recruited from st. alzahra hospital private clinics. the questionnaires were fulfilled by the participants. results: the persian version of pedsql tm 4.0tm 4.0 generic core scales discriminated between healthy and chronically ill children (healthy students mean score was 12.3 better than chronically ill children, p< 0.001). cronbachs alpha internal consistency values exceeded 0.7 for children self reports and proxy reports of children 5-7 years old and 13-18 years old. reliability of proxy reports for 2-4 years old was much lower than 0.7. although, proxy reports for chronically ill children 8-12 years old was more than 0.7, these reports for healthy children with same age group was slightly lower than 0.7. constructive, criterion face and content validity were acceptable. in addition, the persian version of pedsql tm 4.0tm 4.0 generic core scales was feasible and easy to complete. conclusion: results showed that persian version of pedsql tm 4.0tm 4.0 generic core scales is valid and acceptable for pediatric health researches. it is necessary to alternate scoring for 2-4 years old objective: bisphosphonates are widely used in the management of children with steroid induced osteoporosis (sio). with the increasing use of bisphosphonates, there have been reports of abnormal radiological findings in the growing skeleton. therefore, their use in pediatric patients remains controversial. the present study was conducted to evaluate the long term follow-up results of radiographic features especially metaphyseal sclerotic lines, associated with pamidronate therapy in pediatric patients with nephropathy. methods: twenty two children with nephropathy receiving oral calcium and pamidronate (mean duration: 7.9 months, dose: 125mg daily) were evaluated restrospectively. all patients had soi because of chronic glucocorticoid therapy for the treatment of nephropathy. biochemical tests, long bone radiography and bone mineral density (bmd) were performed before the treatment of pamidronate and followed up several years later. the physeal growth rates were estimated by measuring the distance that the sclerotic lines moved on the radiographs during the corresponding time intervals. results: the mean follow-up period was 9.5 years. in all patients, the well-defined sclerotic lines at the metaphyseal ends were observed and progressively moved from physeal plate to diaphysis on the radiographs of long bones. the mean moving rates of the sclerotic lines was 7.95 mm per year and in twelve patients, the lines disappeared. and the mean growth rate of height was 4.50 cm per year. conclusion: our long-term follow-up results suggest that the metaphyseal sclerotic lines associated with pamidronate treatment tend to disappear without affecting the skeletal growth. bisphosphonate treatment for soi in pediatric patients with nephropathy seems to be safe although further studies for larger number of patients are needed abstract# p-sat366 clinical effectiveness and safety of the high dose active vitamin d therapy on severe hyperparathyroidism in children with esrd eun gu kang, su-yon kim, joo hoon lee, young seo park department of pediatrics, asan medical center children's hospital, seoul, korea objective: a potent inhibiting effect of active vitamin d on parathyroid hormone is well known, but there is uncertainty on the dose to be used in hyperparathyroidism. the aim of this study is to assess the effectiveness and safety of high dose active vitamin d treatment on severe hyperparathyroidism in children with end stage renal disease (esrd). methods: fifty-four patients underwent dialysis for more than 1 year between may 2002 and feb 2013 in asan medical center. among them, patients who were administered high dose of active vitamin d (dose of alfacalcidol 1mcg/day to 3mcg/day) with severe hyperparathyroidism(intact parathyroid hormone (ipth) >800pg/ml) were selected. changes of ipth, plasma albumin-corrected calcium, phosphorus and 1,25 (oh)2 vitamin d were analysed. results: fourteen patients (10 boys and 4 girls) with median age of 12.5 years (6-19 years) were included. the mean duration of dialysis was 49±32 months and the median duration of the high dose alfacalcidol therapy was 5 months(3-22months). the ipth level significantly decreased in 10 patients (71%) from 1206.3±387.6 to 215.2±117 during the high dose alfacalcidol therapy (p<0.001). serum phosphorus (5.9±1.3mg/dl vs. 6.0±1.8mg/dl, p=0.88) and calciumphosphorus product (53.4±11.9mg2/dl2 vs. 59.8±18.4mg2/dl2, p=0.20) were not significantly changed and 1,25 (oh)2 vitamin d was low or normal after therapy. plasma albumin-corrected calcium significantly increased (9.4±0.64mg/dl vs. 10.2±0.75mg/dl, p=0.016). four patients (29%) had persistent severe hyperparathyroidism despite treatment with high dose of alfacalcidol, which was controlled after kidney transplantation (2 patients) or after parathyroidectomy (2 patients).conclusion: high dose active vitamin d therapy controlled severe hyperparathyroidism in the most children with esrd without significant adverse events. clinical features and treatment of ckd-mbd in children with ckd i-v predialysis objective: vitamin d is known to have multiple effects on the cardiovascular system, renal function, hyperparathyroidism and growth, its deficiency is common in adults and children with chronic renal disease (ckd), but data in kidney transplant children are scarce. the aim of the present study was to investigate the vitamin d status in 3 groups of children and adolescents with ckd and to establish the association between 25(oh) vitamin d (25ohd) levels, age, hyperparathyroidism, short stature, and renal function. methods: we recruited 105 children: 44 renal transplant patients with a functioning graft for at least 6 months (mean age 12 yr, mean graft abstract# p-sat386 the expression and significance of il-6 、ip-10 and il-17 in serum and synovial fluid with juvenile idiopathic arthritis. objective: to detect the disparity of three cytokines about interleukin-6(il-6),interferon-inducible protein 10(ip-10) and in peripheral blood(pb) and synovial fluid(sf) of patients with juvenile idiopathic arthritis (jia). method: serum concentrations of the three cytokines were measured in 27 patients with 13 systemic-onset jia(sjia), 14 polyarticular jia(pjia) and 28 healthy controls using enzyme-linked immunoabsorbent assays (elisa). 19 patients being no marked arthritis symptom or only temporary arthralgia enrolled in probable sjia group. sf from 18 patients with 7 sjia,11pjia were examined for cytokine levels. objective: the aim of the present study is to evaluate serum concentrations of ghrelin and leptin, and their associations with fat mass and insulin homeostasis in children undergoing chronic dialysis. methods: the study population consisted of 40 patients on maintenance dialysis (22 pd and 18 hd) aged between 5-19 years and 20 age-and sex-matched healthy children. serum levels of total ghrelin and leptin were measured in all patients and controls. fasting serum glucose and insulin levels were also measured in the patients; insulin resistance was estimated by the homeostasis model assessment of insulin resistance (homa-ir). nutritional status was assessed by measuring body mass index (bmi), triceps skinfold thickness (tsf) and multi-frequency bioimpedance analysis (bia). body fat mass was estimated by the bia method. results: the mean total ghrelin level was significantly higher in the patients than the controls (1671±1317 vs. 543±365 pg/ml, p<0.001). higher total ghrelin levels in dialysis patients were significantly associated with younger age (p=0.015), lower bmi-sds (p=0.050) and lower bia-based fat mass-z score (p=0.007). the mean leptin level was also higher in dialysis patients compared to the controls but the difference was not statistically significant (15.5±29.2 vs. 6.48±5.51 ng/ml). however, the ratio of leptin levels to fat mass was significantly higher in dialysis patients than the controls (1.16±1.31 vs. 0.50±0.12, p=0.041). serum levels of leptin in dialysis patients positively correlated with bmi-sds, tsf-z score and bia-based fat mass-z score (p<0.001 for all). serum leptin levels also had a positive correlation with serum insulin (p=0.001) and homa-ir (p<0.001), and an inverse correlation with total ghrelin level (p=0.005). conclusion: children on maintenance dialysis have high levels of total ghrelin that are closely related to decreased fat mass and poor nutritional status. in contrast to ghrelin, leptin is associated with increased fat mass and insulin resistance; however, these patients have inappropriately elevated leptin levels in relation to body fat mass that may be related to wasting. objective: this study investigated the influence of social support and other psychosocial factors upon mortality, adherence to medical care recommendations, and physical qol amongst hemodialysis patients. method: 272 hd patients were examined using the qol questionnaire to determine self-reported inclinations. logistics regression through weighted k was used to analyze data. results: 53.5% of patients reported health had interfered with their social activities demonstrating a strong associated with risk towards all-cause (sp=1.33) and cause-specific mortality including cardiac diseases (sp=1.28). these patients had a greater risk of withdrawing (sp=1.67) from treatment, non-adherence to phosphorus (sp=1.06) greater than 7.5 mg/dl and increased risk towards an albumin of less than 3.5 g/dl (sp=1.23). patients reporting dissatisfied with family support (12.0%) were at highest risk to non-adherence to intra-dialytic weight gain (sp=1.27), shortening the dialysis session (sp=1.21) and increased risk of potassium level greater than 6 meq/l (sp=1.14). however, patients reporting dissatisfied with staff support (14.1%) revealed a higher risk of decreased physical qol (sp=0.76). conclusion: this study demonstrated that physical qol was not only affected by medications and other laboratory work-ups but also with additional psychosocial support. the study led to the development of programs empowering patients and families to participate in their treatment plans. the program includes various counselling approaches directed to patient, families, and health team. objective: the aim of the study was to analyze health-related quality of live (hrqol) in children with chronic kidney disease (ckd) dependent on the ckd stage, treatment modality and selected social life elements in families of the patients. furthermore, potential differences between self-and parent/proxy reports and the factors influencing them were assessed. methods: 203 ckd children (on hemodialysis-hd, peritoneal dialysis-pd and conservative treatment-ct) and their 388 parentproxies were enrolled into a cross-sectional national study. a semistructured interview form was used to determine the demographic and social characteristics of the participants. we used the pediatric quality of life inventory (pedsql) 4.0 generic core scales to assess the hrqol in children. results: hrqol scores for all ckd groups were significantly lower in all domains compared with population norms, the lowest one being in the hd group. in ct children, hrqol did not depend on the ckd stage. children with ckd reported problems with education and emotional functioning. both parents assessed the hrqol of their children differently depending on their involvement in the care. there are differences between the hrqol scores of the children and their parents. conclusion: the hrqol in children with ckd is lower than in healthy children. this is already observed in the early stages of the disease. the disease itself influences the child's mental state. children on hd require special support on account of the lowest demonstrated overall hrqol. children's lower rating of the quality of life observed by their parents may render the patients unmotivated and adversely affect their adjustment to life in later years. it may also create conflicts between the parents and the children. objective: chronic medical illness is a significant risk factor for the development of psychiatric disorders. the aims of the study were: to investigate the level of anxiety in children with chronic kidney disease (ckd) and to identify factors associated with the presence of that emotional problem. methods: ckd children on hemodialysis (hd, n=22), peritoneal dialysis (pd, n=20,) and on conservative treatment (ct, n=95), and healthy subjects (n=100) were enrolled in the study. we used state-trait anxiety inventory (stai) for adolescents and stai-c for children. socio-demographic and physical factors were assessed. results: there was a significantly higher level of anxiety-state among hd children (8-12 years) compared with other groups of participants of the same age. the level of anxiety among adolescents (13-18 years), both anxiety-state and anxiety-trait, was significantly higher in the hd group compared with other groups, which did not differ among themselves. in the hd adolescents, there was a correlation between the anxiety-state and the duration of the disease as well as with the number of hospitalizations. pd adolescents in the mainstream education had higher levels of anxietystate and anxiety-trait compared with home schooled patients. conclusion: even though children and adolescents with ckd are at risk of developing a variety of emotional disorders, the level of anxiety among the researched group, with the exception of hd patients, was not significantly different than the level of anxiety among healthy subjects. adolescents on hd who present a high level of anxiety should undergo long-term psychological treatment. ipek akil objective: compare medication adherence and kidney graft loss rate before and after transition in a single-center cohort of pediatric patients. methods: records of the patients transplanted in our center between 1990 and 2011 were screened and patients who remained in the program by their 18th birthday were included in the analysis. adherence and graft function were assessed for the period of 2 years prior and 2 years after transition. undetectable and/or sub-therapeutic levels of calcineurin inhibitors and their level variability were used as measures of adherence. graft survival analysis was performed for the period of 4 years before and 4 years after transition. results: out of 197 screened patients, 71 were eligible and 25 of them were transitioned (tg -transitioned group). the remaining 46 patients were used as a comparison group (cg), 27 of them did not reach the age of transition by the time of the analysis. the median age at transplantation was 17.7 [15.1-19.1] years in the tg and 15.8 [13.5-17.6] years in the cg, median age at transition was 22. 5 [21.7-23 .3] years. overall, there was no significant difference in adherence within tg before and after transition (p=0.5 for low drug levels and p=0.6 for drug levels variability); however, patients with lower pre-transition adherence (tertile i) showed improvement of their adherence following transition when compared with those with high pre-transition adherence (tertile iii), p=0.02. there were 4 graft losses per 67.9 patient-years in tg vs 19 losses per 102.4 person-years in cg (p=0.02). the peak graft loss in all pediatric transplant recipients in our center (n=105 losses) occurred 3 years (sd 5.7 years) prior to the transition. conclusion: at our institution, transition was not associated with worsening adherence or graft loss. this may be in part do to the fact that the transition occurred at a later age than in other institutions. a report on 7-years experience in the use of mtor-inhibitor (sirolimus) in paediatric renal transplantation patients with calcineurin inhibitor (cni) toxicity the management of children with end-stage renal disease (esrd) deu to congenital urological abnormalities is more problematic and difficult than in patients with esrd due to other causes. kidney transplantation in neurogenic bladder patients with small capacity and defunctionionalized urinary bladders is a challenging issue in the field of pediatric transplantation. in these patients with severe bladder dysfunction, augmentation cystoplasty can protect the transplanted kidney by reducing intravesical pressure and creating an appropriate capacity. 8-year-old boy who presented urinary tract infection with fever at 2 year-old and while his investigation, stage 3 chronic kidney disease secondary to bilateral grade 5 reflux disease was found (blood urea: 81 mg/dl, creatinin: 1.5 mg/dl, creatinin clerance: 32 ml/min/1.73m 2 ). his mixiocystoureterographic and urodynamic study were showed bladder wall irregularity and trabeculation; decreased bladder capacity and compliance, respectively. at 8-month of followup he was putted into dialysis programme about 6 years. thereafter, normal bladder capacity was achieved after bladder augmentation implementation. he was achieved renal transplantation from his mother, after 6-month of augmentation operation. now, he still got uneventfull follow-up period about 24 months. consequently, bladder augmentation application with timely and rationally could be a chance to kidney transplantation in children with bladder dysfunction. the effect of anti-hla antibodies on renal graft functions esra baskin 1 , asli kantar 1 umut bayrakci 1 , kaan gulleroglu 1 , mahir kirnap 1, 2 , feza karakayali 1, 2 , aysegul haberal 1, 3 , gokhan moray 1, 2 , mehmet haberal 1, 2 1 pediatric nephrology, baskent university, ankara, turkey 2 general surgery, baskent university, ankara, turkey 3 immunology, baskent university, ankara, turkeyobjective: the identification of suitable donor kidneys for transplant candidates with high levels of circulating antibodies against human leukocyte antigen (hla) is a major challenge and results in adverse graft outcome. methods: seventy four kidney transplanted children without any shown hla antibody in the pre-transplant period were enrolled in the study. their anti hla antibody status was checked by luminex during post transplant period and its relation with the graft function and prognosis of the patients is studied. results: mean age of the patients was 13.5±5.2 years. mean follow-up time was 3.8±1.1 years. pre-transplant cytotoxicity tests and pra was negative in all patients. nine (12.1%) patients were found to have anti hla antibodies after kidney transplantation. mean time for the detection of antibodies was found as 11±4.8 months. patients with anti hla antibodies were similar with patients without antibodies in the terms of age, sex, hla mismatch, transfusions and immunosuppressive drugs as well as the presence of viral infections. mean serum creatinine level was found to be higher in patients with anti hla antibodies. the antibody mediated rejection rate was found to be 7.2% (5/65) in patients without anti hla antibodies while it was 55.1% (5/9) and remained dialysis dependent. all 6 were dialysis dependent by 6 months post diagnosis. time from anca gn diagnosis to kidney transplant (mean±sd) was 31±12 months (range 17 -48 months). all patients received induction therapy and maintenance immunosuppression with prednisone, mycophenolate mofetil, and tacrolimus. median duration of follow up post transplantation was 3.5 years (range 1.25 -6.9). egfr at last follow up was 71.9 ± 34.7 ml/min/1.73m 2 (range 5.7 -100.5). 1 patient lost her transplant to biopsy-proven, severe acute cellular rejection due to complete non-adherence to medications after 21 months of stable transplant function. no patient had recurrence of vasculitis. conclusion: short-term patient and allograft survival in paediatric patients with eskd secondary to anca gn is excellent despite aggressive disease, with no recurrence of vasculitis post transplant.abstract# p-sat429 en-bloc kidneys from infant donors less than 5 kg transplantation into pediatric recipients at school age objective: given the shortage of donor kidneys in china, the use of grafts from deceased infant donors (weight < 5kg) is a potential approach to expand the donor pool. in this study, we reviewed the results of the first cohort of en bloc kidney transplantation of infant donors to pediatric recipients at school age in our center.methods: from february 2012 to march 2013, 4 infant en bloc kidney transplants in pediatric recipients were performed in our center. en bloc kidneys from 4 infant donors (maastricht category iii) who died of severe congenital disease were recovered and donated to the red cross society of tianjin and allocated to our center by china organ transplant response system (corts). donor age ranged from 33 to 56 days with weight ranging from 2.5 to 5.0 kg. recipients included 2 females and 2 males with age ranging from 5 to 11 yr. the en bloc graft was implanted extraperitoneally in the right iliac fossa. the distal end of the donor aorta was anastomosed end-to-end to the internal iliac artery, while the donor vena cava was anastomosed to the external iliac vein. the donor ureters were implanted separately onto the bladder with double-j stents placement. after the operation, the recipients received basiliximab as an induction therapy. maintenance immunosuppression consisted of tacrolimus and myfortic. prophylactic anticoagulation with heparin was used for the first week after transplantation. results: patient survival was 100%. complications included delayed graft function in 1 patient (managed by pd for one week), urine leak in 1, and anticoagulation-related hemorrhage in 1. due to discontinued anticoagulation, one graft was lost early from vascular thrombosis. of the remaining 3 recipients, all had immediate and excellent long-term function with average creatinine of 1.13±0.31 mg/dl at 5 months follow-up (range 1-12 months). conclusion: this is the first report of en bloc kidney transplantation from infant donors into pediatric recipients in china. many improvements by our transplant teams had improved the survival of patients and grafts. based on our experience, albeit very limited, we concluded that favorable outcomes can be obtained from en bloc transplantation from infant donors. objective: to describe the rates and outcomes of renal transplantation in children with intellectual disability (id). methods: we performed a retrospective analysis of all children receiving a first kidney alone transplant in the united network for organ sharing (unos) dataset from january 1, 2008 to october 31, 2011. recipients with definite, probable, and without id were compared using chi-square and fisher's exact tests. kaplan meier curves were constructed for patient and graft survival. results: over the study period, 218 children with definite (90) or probable (128) intellectual disability underwent first renal transplant accounting for 17% of all first pediatric renal transplants (total n=1280). children with definite or probable id did not significantly differ from other recipients on the basis of gender or ethnicity but tended to be younger. children with definite id had higher rates of structural kidney disease and lower rates of glomerulonephritis. children with id were not significantly different than children without id with respect to rate of preemptive transplant, donor source, or number of episodes of acute rejection. graft and patient survival were similar between children with definite or probable id and without id. in cox regression, intellectual disability was not significantly associated with patient or graft survival. conclusion: in this first large-scale study, 17% of all first pediatric renal transplants are performed in children identified as having intellectual disability. early outcomes after transplant appear to be equivalent between children with and without id. further research is needed on long-term outcomes and quality of life effects of transplant in this population. mariana guerra duarte rosa de lima, ana cristina simoes e silva, nadine marcia de faria, eleonora moreira lima pediatrics, universidade federal de minas gerais, belo horizonte, brazilobjective: the aim of this study was to evaluate the clinical course of children and adolescents undergoing renal transplantation at federal university of minas gerais between 2000 and 2011 and to identify possible factors that could interfere with graft survival. methods: a retrospective observational cohort study through analysis of medical records of patients below 18 years submitted to renal transplant were performed. data were analyzed in spss, version 19.0. the results were expressed by descriptive variables and survival analysis was performed using the kaplan-meier method. comparisons between subgroups were made using the log-rank test. p level was set at below 5%. results: we analyzed 64 patients who underwent 66 transplants. the mean age was 10.5 ± 3.9 years. the main causes of chronic kidney disease were cakut (32.8%) and glomerular diseases (26.6%). most patients were submitted to dialysis before transplantation (81.9%) with a mean duration of 36.5 ± 25.5 months. deceased donor was used in 57.6% and the average cold ischemia time was 22.2 ± 6.3 hours. dialysis after renal transplantation was performed in 22.7% of cases. the median survival of patients 1, 5 and 10 years was 98.3%, 95.8% and 92.8%. there were four deaths in this population, two after graft loss. twelve patients lost their grafts (19.7%). the median survival of the graft was 9.2 years and 1, 5 and 10 years survival was 91.7%, 81.2% and 75.6%, respectively. no statistical difference was detected in graft survival between the deceased versus. living donor recipients, the different age groups, the occurrence of hypertension or not, the preemptive transplantation vs. preceded by dialysis (p=0.97) and those with more than three versus less than three hla mismatches. a significant reduction in graft survival was associated with cold ischemia time associated with 24h, need for dialysis after transplantation, early acute or late rejection and creatinine greater than 1mg per dl after the first year os transplantation. conclusion: in our center, graft survival was similar to that described in the literature. however, further studies are needed to address the variables that negatively impacted the results of transplantation. objective: the aim of this study is to assess whether there is an increase in anti-hla antibodies after the influenza a/h1n1 vaccine given to pediatric pts with esrd on dialysis (d) and with kidney transplant (t). methods: 21 pediatric pts were enrolled. mean age was 15.5 years old, 29% female, 71% male, 57% african american, 29% hispanic.objective: ptld is the most common malignancy and important complication of pediatric solid organ transplantation. the rates of pltd have been increasing through 1990s in ktx recipients. we conducted a survey of ptld in children who received ktx since the introduction of tac. methods: from 1975, ktx was performed in 463 recipients at our center. among them, we analyzed data from children who had undergone ktx since the introduction of tac and retrospectively studied incidence of ptld and risk factors, including immunosuppression protocol and pre-ktx ebv serology. results: we retrieved the data of 188 pediatric recipients since 1997 (110 boys, median age at ktx 8.2 years, living ktx 170, pre-emptive ktx 26, ebv-seronegative 82). among them, 11 cases (10 ebvrelated, 1 non-ebv) of ptld were diagnosed in 10 recipients (5.3%), and all cases were ebv-seronegative at ktx. the median duration from ktx to the onset of ptld was 7 months (range: 4-101 months). the most common presenting symptom of ptld was abdominal complaints in 9 cases, followed by fever in 3, superficial lymphadenopathy in 3 and nasal congestion in 1. immunosuppressants were reduced in all cases; the subsequent treatment consisted of antiviral agents + ivig (3/11), anti-cd20 monoclonal antibody (5/11), and anti-cd20 monoclonal antibody + chemotherapy (2/11). only one recipient died due to ptld. assessing the correlation between ptld and immunosuppressants in 82 ebv-seronegative recipients (median age at ktx 5.7 years, cya 39, tac 43, mzr 26, mmf 56, il-2 receptor antibody 56), a significantly higher incidence of ptld was associated with tac (9/43) than cya (1/39) [or 18.3, p=0 .003] in multiple logistic regression analysis. we compared the incidence of ptld, median age at ktx, and rate of ebv-seronegativity in 3 eras (a: 1997-2001, b: 2002-2006, c: 2007-2011) of the study period and found 4%/8.2 yrs/32% in a, 3%/7.1 yrs/43% in b, and 10%/9.0 yrs/55% in c. thus the incidence of ptld increased with the increase in ebv-seronegative recipients. conclusion: in our study, maintenance treatment with tac (compared with cya) is associated with a higher risk for developing ptld. attention should be paid to the increase in the ebv-seronegative recipients.abstract# p-sat438 acute graft dysfunction and encephalitis post renal transplant: the role of epstein-barr virus objective: epstein-barr virus (ebv) has been described as a rare cause of acute kidney injury and encephalitis in children. methods: we report a case of a 5 year old renal transplant recipient who developed acute graft dysfunction and a significant neurological insult with evidence of primary ebv infection. results: the patient had been diagnosed with posterior urethral valves prenatally and received a live related renal transplant aged 4 years. seven months post-transplant he presented fluid overloaded, oliguric, with significant uraemia and hyponatraemia. there was a history of lower urine output and sore throat 4 days before admission with evidence of anaemia with red blood cell fragments, thrombocytopenia, mild monocytosis, raised ldh, alt and splenomegaly on presentation. haemodialysis was commenced. primary ebv infection was subsequently detected by serology and pcr.renal biopsy showed a picture of acute glomerular thrombotic microangiopathy(figure above) and acute tubular injury secondary to haemoglobinuria.scanty eber+ lymphocytes containing ebvencoded small nuclear rna were also present. within 3 days of presentation patient deteriorated neurologically developing a reduced conscious level, dysarthria, decreased motor power peripherally and an inability to upward gaze. an mri brain demonstrated increased t2 signal and mild diffusion restriction in in the caudate nuclei, putamina and ventro-lateral thalami. this picture has been previously described in ebv encephalitis. there was a gradual neurological improvement and by day 7 of admission, and 6 doses of i.v. methylprednisolone, the patient had a full neurological recovery. the number of ebv copies has subsequently decreased on lower dose of immunosuppression. by week 4 after presentation he was no longer dialysis dependent with creatinine 3-fold higher than the previous baseline. conclusion: this is the first report of acute graft dysfunction and encephalitis due to primary ebv infection in renal transplant recipient.abstract# p-sat439 indoleamine 2,3-dioxygenase (ido) as a new immunological marker in kidney elisa loiacono 1 , barbara votta 2 , alessandro amore 1 , licia peruzzi 1 , maria paola puccinelli 2 , roberta camilla 1 , luca vergano 1 , giuliana guido 3 , maria elena donadi 1 , rosanna coppo 1 1 nephrology, cittàdella salute e dellascienza. regina margherita children's hospital, turin, italy 2 nephrology, cittàdella salute e dellascienza, turin, italy 3 nephrology, sapienza university of rome, rome, italyobjective: the enzyme indoleamine 2,3dioxygenase (ido), induced by interferon-gamma (ifn-gamma) and toll-like receptors (tlrs) ligands in dendritic cells, degrades the essential aminoacid tryptophan (trp) to kinurenine (kyn). its activity is estimated by the ratio of kyn to trp concentration (kyn/trp).t-cell activation and proliferation are affected by trp deprivation and accumulation of kyn. therefore, activating ido during immune responses counter balances mechanism of negative feedback loop of ifn-gamma and acts as a tool to downregulate overwhelming immune activation. ido activation has been reported to be increased in acute rejection and downregulated in vitro by the immunesuppressants adopted for organ transplantation. objective: to determine the prevalence of mycophenolic acid (myfortic) use as part of the immunosuppressant regime in our current paediatric renal transplant recipients in a single tertiary paediatric nephrology centre and examine the demography of these cases. method: case note and pharmacy record review of all paediatric renal transplant recipients' history, immunosuppressant medication and current renal allograft function in january 2013. indication for medication switch from mycophenolatemofetil to enteric-coated mycophenolic acid tablets (myfortic) was noted. data presented as median (range). results: 14 (10 male) out of a total of 88 patients with renal transplants are currently receiving myfortic in our centre. age and time from transplant was 12.3 (8. 1-17.4 ) years and 4.3 (0.68-10.6) years. the most common cause of end stage renal disease requiring transplantation in this subgroup was posterior urethral valves in 5/14 cases. two of these recipients had abo incompatible living related transplants. current egfr was 46.7 (20.9-82.3) ml/min/1.73m2. 13/14 patients receiving myfortic were also receiving prednisolone and tacrolimus as part of their immunosuppression regime. one patient was on tacrolimus and myforctic only (history of idiopathic intracranial hypertension). dosage of myfortic varied based on patient size from 180mg twice daily to 720mg twice daily. the indication for carrying out a medication switch from mycophenolatemofetil to myfortic was related to gastrointestinal symptoms in all cases; specifically diarrhoea in 9 cases, abdominal pain in 2 cases and both symptoms in 3 cases. these symptoms improved on myfortic with renal allograft function remaining stable, however in view of neutropenia in one patient her myfortic is currently suspended and under review. we have found that enteric-coated mycophenolic acid (myfortic) was a well-tolerated alternative in paediatric renal allograft recipients who developed gastrointestinal symptoms whilst receiving mycophenolatemofetil. its usage should be considered in such patients who are able to take tablet preparations. ferretti alfonso, ilaria luongo, bruno minale, gabriele malgieri, carmine pecoraro nephrology and urology, santobono children' hospital, naples, italyobjective: uti represent one of the main complications after kt and have an important role in graft funcion impairment. this retrospective report is aimed to evaluate the incidence of uti in a group of patients attending our hospital for post transplant usual medical controls. methods and results: we incuded in our study 75 children who underwent kt between 2000 and 2011: 42 m and 33 f, mean age 11.6 +/-5.3 . four children received a graft from a living related donor and 71 from a deceased donor. first morning sterile urine sample to the microbiology laboratory was obtained when attending the hospital for its usual medical control or immunesuppressive drug detection levels. results: in 41 patients (54.7%) esrd was secondary to cakut. thirty-six patients (48%) presented at least one episode of uti occurred in the first 6 months after kt, mainly in females (1.2:1) . uti developed in the first period were caused mainly by gram negative bacteria (91%). e. coli was the main agent (66.1%), the other uropathogens involved were: proteus (9%), enterobacter cloacae (9%), pseudomonas aeruginosa (6%), candida albicans (3.3%) and klebsiella (3.3%). later infections were caused mainly by candida, klebsiella, proteusansdenterobacterfaecalis. one patient at the 15th month post-transplantation manifested uti caused by corinebacterium urealyticum associated with concretions of baldder mucosae. eight patients (5m and 3 f) experienced the graft loss: 4 patients were affected by cakut and had febrile uti posttx. one patient left the second graft by a an acute deterioration of renal function during an uti by bkv. conclusion: uti in kidney transplanted children represent a main complaint as demonstrated by the high incidence (48%) in total population mainly in females. a significant role is played by primary uropathy and immunosuppression as demonstrated by the high frequency also in non uropathic patients. the role of uti in longterm outcome of kt remains controversial. factors associated with elevated pulse wave velocity in children after renal transplantation objective: even after successful transplantation children with underlying chronic kidney disease (ckd) still carry a high cardiovascular risk. this is also documented by cardiovascular death being the second leading cause of death after transplantation in this patient cohort.methods: in a cross-sectional approach 109 renal transplant recipients at three german transplant centres were enrolled. we measured pulse wave velocity (pwv), a strong predictor for cardiovascular events, as our primary end point. in all participants we assessed classical (e.g. blood pressure, cholesterol) and non-classical (e.g. crp, pth) cardiovascular risk parameters. results: patients were 13 ± 3 years of age and had received their transplant 5 ± 4 years ago. pwv-sds adjusted to height was 0.4 ± 1.5. in order to identify predictors of elevated pwv, we performed a univariate screen and introduced factors with a p-value below 0.2 into a stepwise forward linear regression analysis. we found that systolic blood pressure in the ambulatory blood pressure measurement and gfr independently predicted pwv-sds (table) . conclusion: our results show a large variability in aortic stiffness in children after renal transplantation. we found elevated pwv to be associated with classical as well as non-classical risk factors. the wide range of cardiovascular comorbidity seen in these patients highlights the need for individualized risk factor monitoring and management. objective: renal transplantation is the optimal treatment for end-stage renal disease in children,. however, it remains technically challenging in small recipients, especially with adult-sized graft. we report on two 4-year-old children, undergoing living donor kidney transplantation, and describe our management after failure to close the abdominal wall. method: both children weighed < 15kg and received their father's kidney. the recipient/donor weight ratios were 1/5 and 1/6. surgical procedure was an extra peritoneal approach to the iliac fossa, with vascular anastomosis on the aorta and vena cava. they recieved intensive fluid replacement during surgery to optimize hemodynamic status and graft perfusion. after initial successful reperfusion, all attempts to close the abdominal wall (even simple skin closure or superficial muscle layer closure) led to graft hypoperfusion, diagnosed on graft colour change and doppler ultrasound. closure with resorbablevicryl?mesh gave the same results and failure. finally, we had to close with a synthetic non resorbable plate (goretex?), without skin closure.results: the first patient presented acute tubular necrosis and required continuous hemofiltration from day 2 to 6. the second one had immediate diuresis and with a decrease of serum creatinine to 65μmol/l at day 2. in both cases, kidney was successfully replaced intra abdominally at day 6, with superficial closure of facia and skin in one child and with vicryl? mesh and skin in the second one. no effect on clinical graft perfusion or doppler parameters were observed after final closure. in patient 2, a limited necrotic area 3x3cm, on direct contact with the goretex?plate, was noticed during the second surgery procedure but it remained very superficial. finally, with a follow-up of respectively 1 year and 1 month, recipients and grafts are doing well without any other events and a serum creatinine of 40-50 μmol/l. conclusion: in conclusion, in small patients kidney size discrepancy and tissue oedema can lead to renal allograft compartment syndrome. in this situation, goretex? plate is an option for initial wound closure and graft salvaging. objective: amr in the transplant is one of the most complicated form of rejection, which do not respond to the standard therapy. survival of the transplant exposed to amr is still low. this is a clinical report of an amr-treatment in children in our centre. methods: 4 girls with amr after the deceased donor renal transplantation were observed of age10, 13, 15, 16 from 2009 to 2012 in our centre. all had a negative "cross-match" at the time of transplantation, the quantity of discordant antigens varied from 3 to 6. for 1 girl it was the 2 transplantation. 3 children had an immediate function of the graft,1-delayed. induction of the immunosuppressive therapy: polyclonal antibodies and methylprednisolone, maintenance: tacrolimus, prednisolone, mmf. 2 children had high level of preexisting antibodies (more than 30%) at the time of transplantation. there were morphological confirmation and decrease of the graft function for the moment of amr. the treatment of amr included: pulse therapy of methylprednisolone, polyclonal antibodies, rituximab, immunoglobulin iv. function of the graft was evaluated by the cr levels, gfr, the level of dsa.results: the cr of children was 483±256 umol/l for the moment of developing of amr. function of the graft has been restored to satisfied: cr fall to 121±28 umol/l, there were no proteinuria. it was noted a significant reduction of dsa i and ii class in 3 from 4 patients. conclusion: thus, treatment of an amr of the graft with methylprednisolone, rituximab and immunoglobulin intravenously let us achieve 100% 1-year graft and recipient survival after deceased donor kidney transplantation in children. since the risk of amrdevelopment is high in children with high levels of preexisting antibodies, addition of one-time rituximab and immunoglobulin intraveneously in therapy seems reasonable.abstract# p-sat454 tacrolimus granules use in kidney transplanted infants. dose and safety.ramon vilalta, enrique lara, alvaro madrid, marina munoz, sara chocron, gema ariceta paediatric nephrology, hospvalld'hebron, barcelona, spainobjective: tacrolimus in infants has been administered as an extemporaneously compounded oral liquid made by hospital pharmacy. modigraf® is a new tacrolimus formulation available as sachets containing granules (0.2 mg and 1 mg), that are made up with water, prepared by parents or caregivers. modigraf® is considered at least as safe and practical than the compounded oral tacrolimus liquid. furthermore, it is easier to be stored and ready to use, and promotes patient's autonomy, preventing potential medication errors. 9 kidney transplanted infants, 3 de-novo and 6 converted from oral liquid to modigraf® were evaluated to assess its safety and adequate dose. methods: after induction with basiliximab or atg, de novo's3 patients were treated with modigraf® associated with mmf and with tapered steroids. 6 infants with similar immunosuppression regimen were converted from oral tacrolimus to modigraf®. target tacrolimus through level was 8-10 ng/ml. mean patients' age at transplantation was 2.2 years old, and mean follow-up period with modigraf® was 10±8 months.results: in the de-novogroup the stable modigraf® dose needed to reach target levels was 0.28±0.12 mg/kg/day. in the converted group, the initial oral tacrolimus liquid dose was 0.20±0.12 mg/kg/day, whereas modigraf® stable required dose was higher: 0.30±0.10 mg/kg/day (p =0.0003). target levels of tacrolimus were reached after key: cord-022448-ungitgh9 authors: sergueef, nicette title: clinical conditions date: 2009-05-15 journal: cranial osteopathy for infants, children and adolescents doi: 10.1016/b978-0-443-10352-0.50013-4 sha: doc_id: 22448 cord_uid: ungitgh9 nan this chapter addresses some clinical conditions than can be effectively treated using manipulative procedures. such treatment, however, is not intended to replace defi nitive medical or surgical treatments. rather this therapeutic option is offered as a gentle, alternative, non-invasive approach, with essentially no untoward side effects, to be employed as a fi rst line of therapy. patients respond quickly to a specifi c technique when it is appropriately applied following a precise diagnosis. it is the responsibility of the practitioner to ensure that underlying pathologies requiring more aggressive medical or surgical treatment have been ruled out or appropriately addressed. it should also be borne in mind that when a patient fails to respond to treatment as anticipated, they should be completely reassessed. if the osteopathic practitioner does not see a signifi cant functional change in the patient's condition by the third to fi fth treatment, the probability of misdiagnosis is likely. for each clinical condition, the specifi c features of the condition are addressed. for the basic treatment protocols and descriptions of individual procedures, see chapters 5 (examination of the patient) and 6 (treatment of the patient). congenital muscular torticollis and plagiocephaly are the most frequently occurring asymmetries of infancy. brachial plexus injury, fracture of the clavicle, pectus excavatum and carinatum, scoliosis, kyphosis and vertebral somatic dysfunctions are other commonly encountered conditions with structural and functional consequences that can be addressed with osteopathic manipulative treatment. torticollis may be subdivided into congenital torticollis and congenital muscular torticollis (cmt). the patient with congenital torticollis presents at birth with their head tilted toward the involved side and rotated toward the opposite side. they commonly have associated medical conditions, such as osseous malformations, basilar impression or atlantooccipital anomalies, and neurologic disorders such as arnold-chiari malformations. 1 these underlying conditions should be diagnosed and appropriate treatment initiated before osteopathic manipulation is considered. the patient with cmt, on the other hand, is symmetric at birth, and the asymmetry develops in the fi rst weeks of life. cmt presents with a tight sternocleidomastoid (scm) muscle, causing the child's head to be tilted toward the side of the tight muscle and rotated in the opposite direction. a mass, or fi bromastosis colli, can eventually be palpated within the muscle. the incidence of cmt ranges from 0.3 to 1.9%, but is as high as 3.92% when cases are diagnosed sonographically. 2 cmt occurs more often among boys than girls. 2,3 some authors report a higher incidence on the right side, 1, 4 whereas others report that it is more frequently encountered on the left. 2 primiparity, assisted delivery 2,3 and breech presentation 3,5 frequently appear in the birth history. the larger the infant, birth body length and shoulder width, with more associated delivery trauma, the higher the incidence of cmt. 2 multiple theories to explain the etiology of cmt have been proposed. van roonhysen (1670) postulated abnormal uterine pressure as a cause of torticollis. 4 pommerol, in the 19th century, attributed the unilateral shortening of the scm to abnormal fetal position. 6 these 'intrauterine' theories have also attempted to explain the presence of several other deformities present at birth. many authors have commented on aberrant constraint of the infant within the uterus and the association between torticollis, plagiocephaly, bat ears, scoliosis and congenital hip dislocation, [7] [8] [9] [10] or hip dysplasia. 3 other theories link cmt to birth trauma. the high incidence of breech presentation associated with cmt may document the role of birth trauma in its occurrence. others suggest that intrauterine torticollis predisposes the infant to breech presentation or forceps delivery. 11 it has been proposed that birth trauma with injury of the scm and a resultant hematoma, which is then replaced with fi brous tissue, causes cmt. histologic studies have, however, failed to support this proposition. proposed compressive arterial occlusion as an etiology 12 has also been dismissed. vascular compromise does not occur because there is abundant arterial and venous supply to the scm that follows no regular or segmental pattern and has multiple anastomoses. 13 among more recent theories, cmt is proposed as the sequela of an intrauterine or perinatal compartment syndrome. 14 a bilateral imbalance of structures responsible for control of head posture may play a role -for example, as may be the case for the interstitial nucleus of cajal, a neural integrator for head posture. 15 because the torticollis is not present at birth but appears later, it is possible that it results from improper handling of the child or incorrect positioning as in a car seat. resultant dysfunction of the occipito-atlanto-axial joints may, therefore, occur and has been proposed as a cause for cmt. 16 several clinical variants are observed. the scm mass is not always present. 17 smaller masses may be found on the occipital bone below the superior nuchal line. when an scm mass is palpable, usually in the fi rst 2 months of life, it appears well circumscribed within the muscle, is located in the midportion of the scm and ranges in size from 8 to 15.8 mm on maximal transverse diameter and from 13.7 to 45.8 mm in length (measured with ultrasound). 18 this mass typically disappears during the 1st year of life without any correlation with the resolution of the cmt. 3 although the fi ndings of head tilt toward the involved side with head rotation toward the opposite side are consistent, the amount of rotation can differ between subjects. contractures of the semispinalis capitis and the splenius capitis are sometimes present. cmt is probably the consequence of several concomitant factors. the problem may begin with a faulty intrauterine position that weakens the scm, making it vulnerable to birth trauma and thus creating the dysfunction. osteopathic practitioners use their knowledge of anatomy to develop a rationale for treatment. the scm arises, by two heads, from the sternum and clavicle ( fig. 7.1.1 ). the medial (or sternal) head has its origin on the upper part of the anterior surface of the manubrium sterni and the lateral (or clavicular) head arises from the anterior surface and superior border of the medial third of the clavicle. initially, the two heads are separated from one another. they gradually join, below the middle of the neck, to form the body of a thick, rounded muscle. the scm is inserted into the lateral surface of the mastoid process by a strong tendon and into the lateral half of the superior nuchal line of the occipital bone by a thin aponeurosis. the two heads of the scm consist of different types of fi ber, the sternal head being more tendinous and the clavicular head being composed of fl eshy and aponeurotic fi bers. the clavicle is more mobile than the sternum and is subject to signifi cant stress during the birth process, which may explain a different strain being put on the two parts of the scm. a distinction between 'sternal torticollis' and 'clavicular torticollis' has been proposed. 19 the insertion of the scm covers the occipitomastoid suture; therefore, scm tightness should be released whenever attempting to treat this suture. conversely, somatic dysfunction between the temporal and the occipital bones will affect the scm. the jugular foramen -located at the anterior end of the occipitomastoid suture, between the petrous portion of the temporal bone and the occiput -will also be affected. the jugular foramen contains the inferior petrosal sinus and the sigmoid sinus that unite to form the internal jugular vein. it also contains the glossopharyngeal (cn ix), the vagus (cn x) and the accessory (cn xi) nerves. cn xi provides the motor supply to the scm, its proprioceptive fi bers passing through branches from the anterior divisions of the second and third cervical nerves to innervate the scm. thus, sutherland stated: 'you will probably fi nd the source of the torticollis to be entrapment neuropathy of the eleventh cranial nerve at the jugular foramen.' 20 jacquemart and piedallu, in 1964 , recommended that osteopathic manipulation for cmt be directed at somatic dysfunction of the occiput and upper cervical spine. 16 the mastoid process is not fully developed in the newborn and is totally covered by the tendon of the scm from its apex to its superior border. the development of the mastoid process is linked to the traction of the scm; asymmetric sidebending and rotation of the head, as in cmt, will cause the mastoid processes to develop asymmetrically. cephalometric analysis demonstrates that, left untreated, persistent torticollis can lead to skull and facial asymmetry. 21 when it occurs, the cranial base deformation appears early, the changes being more signifi cant in the posterior cranial fossa, whereas the facial deformity will develop later in childhood. both the cranial base and facial deformities tend to increase with age. 22 furthermore, the asymmetric function of the neck muscles stresses the mechanisms of postural control. abnormal sensory input to the cns and a sense of instability occurs that has to be compensated for with vision. 23 this can affect the infant's developing visual function. to prevent these sequelae, osteopathic procedures should be employed to address cmt as early as possible. observe the child for spontaneous rotation and sidebending of the cervical region. a good way to evaluate the range of motion in rotation and sidebending is to have the baby visually follow a toy moved in the directions to be tested. the child can also be held in the arms of the practitioner, facing the parents. the practitioner then pivots to the right and to the left, holding the infant in such a way that, in order to continue to observe their parents, the child must actively turn their head fi rst to the left in response to the practitioner's pivoting right, and then to the right in response to the practitioner's pivoting left. having the parents participate in this procedure allows them to understand the extent of the child's restriction of motion; repeating the procedure after treating the child allows one to evaluate the effect of the treatment. the size of the scm mass (when present) and the tension of the muscle fi bers should be evaluated. palpate the infant to identify membranous, myofascial and interosseous somatic dysfunction, particularly in the upper thoracic spine, pectoral girdle, cervico-occipital area and cranium (temporal bone, occiput, occipitomastoid suture and jugular foramen). treatment should use indirect principles. because the mass associated with cmt often develops at the conjunction of the two heads of the scm, in order to release the dysfunction the bones to which the muscle is attached (clavicle, sternum, occiput and temporal bone) should be balanced. indirect myofascial release of the scm may be employed. if the infant is treated early, before a dysfunctional pattern becomes engrained, osteopathic manipulation can rapidly alleviate the asymmetry of scm. the caregiver should be taught an active positioning program to be employed at home. for example, approaching the infant from the side opposite the rotation during daily activities, such as feeding and playing, head turning and lengthening of the scm can be facilitated. the infant should be placed in a sleeping position that avoids reinforcement of the scm shortening. it is improper to attempt to accomplish this by propping the infant's head with a pillow in such a way as to lengthen the scm. although this may appear to hold the head in the desired position, it induces a stretch refl ex in the tight muscle, maintaining the shortening. gentle stretching exercises that induce active scm stretching can be taught. these should be employed to rotate the head toward, and sidebend the neck away, from the side of the tight scm. such exercises are indicated until a full range of movement has been obtained. the term plagiocephaly -derived from the greek plagios (oblique) and kephalê (head) -indicates distortion of the head and refers clinically to cranial asymmetry. cranial deformations have been (and still are) produced intentionally, depending on the period and country, as signs of distinction, beauty, health, courage, freedom and nobility. the oldest known example is from iraq, c.45 000 bc, and the earliest written reference is from hippocrates, around 400 bc (airs, waters, places), describing the macrocephales who practiced head deformation. 24 inten-tional plagiocephaly was obtained by pressure applied to an infant's skull, either through manual molding or with boards, pads or stones. different deformities were induced depending on the methods employed. 25 the use of cradleboards and the wearing of headdresses are examples of other traditions that also resulted in head deformation. non-intentional plagiocephaly can be associated with premature sutural closure or craniosynostosis. premature synostosis of one or several cranial sutures may be the result of genetic or metabolic conditions. 26, 27 the fused suture does not allow bone growth and the shape of the skull refl ects this anomaly: a brachycephaly develops when the coronal suture fuses, a dolichocephaly or a scaphocephaly when the sagittal suture fuses, and a trigonocephaly when the metopic suture fuses. unilateral synostosis of the lambdoid or coronal suture (fig. 7.1.2) results in a posterior or anterior plagiocephaly, respectively. although any suture may be involved in synostotic plagiocephaly, true lambdoid synostosis with posterior plagiocephaly rarely occurs 28 and represents only 3.1% of all synostoses. 29 in the general population, the incidence of craniosynostosis has been estimated to be as low as 1 in 2100-3000 live births; 27, 30 however, it is imperative that the diagnosis of synostotic plagiocephaly, which is most specifi cally accomplished by radiologic means, be made when the condition is present. children presenting with craniosynostosis should be monitored closely by a pediatric neurosurgeon for signs and symptoms of increased intracranial pressure. treatment may require surgery, particularly for severe cases. non-synostotic plagiocephaly (nsp), also referred to as functional plagiocephaly, must be differentiated from craniosynostosis. the prevalence of nsp is estimated to be as high as 9.9% of all children under the age of 6 months. 31 nsp is identifi ed as either frontal 32 or occipital 33 (figs 7.1.3 and 7.1.4) depending on the site of the deformation. in 1992, the 'back to sleep' campaign was instituted in the usa for prevention of sudden infant death syndrome (sids). parents were encouraged to put infants to sleep in the supine position. following this, a shift occurred in the location of the deformity of nsp, from frontal plagiocephaly being more frequently encountered before the 'supine' directive, to occipital plagiocephaly more commonly encountered now. nsp results from a variety of extrinsic and intrinsic factors affecting the infant before, during and after birth. these various factors may be isolated or may exert a cumulative effect. associated risk factors for nsp include premature birth, 34 fi rstborn, 31, 35 prolonged labor, unusual birth position, 35 use of forceps and vacuum extraction. 36 male gender is also a risk factor because fetal distress during labor, with a consequently higher incidence of operative delivery, is more common with males than with females. 37 before birth, nsp may result from abnormal constraint on the fetal head in the intrauterine environment, as with a unicornuate uterus, uterine fi broids or oligohydramnios. 9 multiple births are another risk factor, with deformational plagiocephaly being frequently encountered in these children. extrauterine constraints placed on the fetus can be responsible for nsp. this may be the result of pressure from neighboring abdominal organs. with athletic mothers, increased tonus of the abdominal muscles can compress the uterus back against the spine. lack of abdominal muscle strength, on the other hand, will produce an increase in the already increased lumbar lordosis that is very common in late pregnancy. the increased lordosis is associated with anatomic fl exion of the sacrum that displaces the sacral promontory forward, with resultant external pressure on the uterus. during the birth process, the uterus contracts regularly to allow the descent of the fetus through the birth canal. prolonged periods of uterine contraction may increase the mechanical forces applied to the infant's head. when the head enters the pelvic cavity, anatomic extension between the sacrum and the pelvic bones normally occurs to increase the diameters of the pelvic outlet. dysfunction of the maternal sacroiliac joints can result in a reduction of that increase and further constraint on the infant's head. in the left occiput-anterior position -the most frequent birth presentation -the right side of the infant's occipital bone is in contact with the maternal pubic symphysis while the left frontal bone is compressed against the sacrum (fig. 7.1.5 ). asynclitism further increases the pressure of the infant's head against the pelvic bones with resulting occipital fl attening on the right and frontal fl attening on the left. the reverse -occipital fl attening on the left and frontal fl attening on the right -would result from the left occiput-posterior position. at the end of the descent, the head contacts the pelvic fl oor and turns in such a way as to position the occiput under the pubic symphysis. in the left occiput-anterior position, the right side of the occiput and the occipitomastoid area can be exposed to greater pressure. later, during expulsion, compressive forces are applied on the occiput by the pubic symphysis. after birth the pressure of the mattress on the infant's head is thought to contribute to occipital fl attening. 38 sleeping habits affect the cranial shape. when infants consistently sleep supine, as in asiatic countries, posterior fl attening of the skull occurs. 35 babies should be able to turn their head symmetrically to both sides. asymmetric cervical rotation should be considered anomalous 39 and, if present, should be resolved by 12 weeks of age. 40 although a preferred rotation of the head to the right side is present at birth in 59% of infants, this does not seem to be related to the fetal position. often, infants may demonstrate asymmetric preferential motions, but a preferred motion should be differentiated from somatic dysfunction. concern should arise when a rotational dysfunction is present. early restriction of cervical motion is an identifi ed risk factor for positional plagiocephaly, 41 particularly if the child is less active, staying in the same position to the point where an area of alopecia develops on the scalp. upper thoracic and cervical restrictions, and scm imbalance or torticollis, very often accompany plagiocephalies. 34, 42, 43 furthermore, when the fl attening has developed, it reinforces the preferential positional pattern with automatic positioning of the head on the fl at area. by defi nition, plagiocephalic children have irregularly shaped heads. since infants now sleep supine because of the 'back to sleep' campaign, the most commonly encountered forms of plagiocephaly are posterior, with either medial or lateral occipital deformity. when compressive forces are applied to the squamous portion of the occiput, usually in the area of the lambda (superior angle of the occiput), the posterior portion of the head is fl attened and assumes a brachycephalic shape. in severe cases, the fl attening can demonstrate a slight depression, usually near the superior part of the occiput. an asymmetric plagiocephaly results when dysfunctional rotation of the head is associated with the compressive forces. because of the rotation, pressure from the weight of the infant's head on the mattress is asymmetric, and the occipitoparietal area on the side toward which the head is chronically rotated becomes fl attened, while the other side develops excessively. this results in occipital fl attening on one side and occipital bossing on the other. anteriorly, the skull demonstrates frontal bossing on the same side as the occipital fl attening, with frontal fl attening on the opposite side. when the head is seen from above, it has a 'parallelogram' shape ( fig. 7.1.6) . the parallelogram cranial shape is commonly described in allopathic medical literature 28, 33, [44] [45] [46] [47] as well as in osteopathic medical literature. [48] [49] [50] this pattern is also referred to as 'cranial obliquity'. 51 in the cranial concept, the parallelogram cranial shape is associated with a pattern of lateral strain in the sphenobasilar synchondrosis (sbs) (fig. 4.10) . shearing between the posterior part of the body of the sphenoid, which is displaced laterally, and the anterior part of the occiput, displaced in the opposite direction, is lateral strain of the sbs and is found in children with nsp. 36 the temporal bones of three parts. when occipital fl attening occurs, the deformity is obvious in the squamous portion of the occiput where the compression has occurred; however, the compressive forces have also been directed against the non-visible parts of the occipital bone, i.e. the anterior intraoccipital synchondrosis that lies between the two parts of the condylar facets. when such a compression of the occipital condyles occurs, it most often occurs asymmetrically. the hypoglossal canals are located bilaterally in the anterior intraoccipital synchondroses, between the basiocciput and the bilateral exocciputs. they contain the hypoglossal nerves that provide the motor supply to the tongue. compressive force on one side can have an impact on tongue motor function, with resultant problems such as suckling diffi culties. asymmetry of the cranial base can also affect the shape of the foramina therein, with potential for various entrapment neuropathies and vascular compressions. the jugular foramen, the right usually being larger than the left, contains the glossopharyngeal nerve (cn ix), the vagus nerve (cn x), the accessory nerve (cn xi) and the inferior petrosal and sigmoid venous sinuses. a broad spectrum of functions depends on these structures. compression of cn ix is associated with altered sensation of the pharynx, fauces, palatine tonsil, pharyngotympanic tube (pt) and the posterior third of the tongue. disturbances of cn x result in a wide range of symptoms including dysautonomia, colic and regurgitation. according to magoun, 'the occipitomastoid suture and the jugular foramen should be considered as of signifi cance with "pukey" parallelogram shape of the head, with the basilar portion of the occiput displaced away from the side of the posterior fl attening. the relationship between the cranial bones is disturbed, as described in lateral strain of the sbs, but this is not the only dysfunction associated with nsp. the compressive forces responsible for nsp can affect the relationship between different portions of the cranial bones, producing intraosseous dysfunctions. the occiput and temporal bones are the most common bones that demonstrate intraosseous dysfunction in the presence of nsp. at birth, the occipital bone is composed of four parts and each of babies'. 52 compression of cn xi can compromise the motor supply to the upper and middle portions of the trapezius and to the scm. the trapezius receives a portion of its motor supply from cn xi; the scm depends mainly on cn xi. cn xi can also affect swallowing through its impact on the pharyngeal constrictor muscles that receive their nervous supply from the cranial portion of the accessory nerve. with the resultant asymmetry in the cranial base, a difference in tension between the two scm muscles is palpable. there are multiple myofascial attachments on the cranial base that can be similarly affected, resulting in a multiplicity of dysfunctional patterns in distant areas. asymmetric tensions in the trapezius and semispinalis capitis muscles can cause thoracic spine dysfunction, asymmetries of the stylopharyngeus and stylohyoideus muscles can affect the pharynx, and the styloglossus muscle can dysfunctionally infl uence the tongue. the compressive forces applied to the fetal head also affect the temporal bones. when occipital fl attening occurs on one side, the ipsilateral temporal bone and attached ear are moved forward and the mastoid portion is compressed. this deformation can be demonstrated with computerized tomography of the skull base. the long axis of the petrous portion of the temporal bone is displaced in the direction of the coronal plane, 53 thus placing the temporal bone in a position resembling external rotation. embedded in the petrous portion of the temporal bone are the bony portion of the pt and the vestibular apparatus. compressive forces affecting the temporal bone may increase the risk of otitis. the bony portion of the pt, the vertical portion of the tensor veli palatini and the mastoid air cell system have been found to be smaller than normal in children with secretory otitis. 54 temporal bone dysfunction may have further implications. children with nsp present with a higher risk of auditory processing disorders, which is thought to lead to subtle problems of cerebral dysfunction later at school. 55 these problems include language disorders and learning disabilities, as well as attention defi cits. 56 plagiocephalic children also have a higher incidence of sleep disorders. 36 nsp infants have been described as less active when sleeping on their backs than non-nsp infants, who move actively, turning their head and torso when developmental landmarks are achieved. 56 on the other hand, infants who sleep supine do not need to use their upper trunk and shoulder girdle muscles as much. consequently, there is a delay in acquisition of early motor milestones. 57 tripod sitting, creeping and crawling are particularly delayed, which contributes further to weakening of the core muscles. scoliosis has been associated with plagiocephaly where sleeping supine was identifi ed as a causative factor. 51, 58, 59 in the netherlands, where the supine sleeping position has been encouraged since 1989, approximately 2.4% of 2-3-yearold children have cervical restriction of motion and/or plagiocephaly. 31 interestingly, the habit of always bottle feeding a child on the same side seems to contribute to the pattern of asymmetric cervical rotation. alternating right-and left-sided bottle feeding is consequently an imperative for every baby, particularly nsp infants. the facial skeleton adapts to the cranial base asymmetry. facial asymmetries and facial disharmonies are associated with nsp. 44, 60, 61 on the side of the occipital fl attening, the maxillary bone develops less well, with less distance separating the nasion and the temporomandibular joint. this reduction is proportional to the amount of posterior occipital deformation. 62 the growth of the neurocranium and the viscerocranium occurs at different rates. consequently, compensatory developmental disorders of the viscerocranium will appear later in childhood than the original nsp, and the association, therefore, is not commonly recognized. it is a common observation that infants will sleep preferentially with their head turned toward one side, and that will be the side of the occipital fl attening of the nsp. daily activities such as diffi culty nursing or accepting bottle feeding bilaterally will also refl ect dysfunctions because of diffi culty in turning the head to both sides. associated disorders such as regurgitation, colic or sleep disorders are also often present. otitis media can be part of the picture if the child is over 3 months of age. while taking the history, the infant's appearance, posture and range of motion are studied. when observing the child, the osteopathic practitioner assesses what dysfunctional mechanics are involved in the present nsp. where is the dysfunction? is it only in the cervical spine or are other areas involved? what is the primary dysfunction? three mechanisms are quite frequent: occipitocervical somatic dysfunction, thoracic somatic dysfunction and cranial somatic dysfunction: 1. is there a pattern of restricted cervical spinal rotation that has obliged the child to lay their head on one side that explains the head fl attening? if the head moves freely in all clinical conditions directions, no cervical spinal dysfunction is present. 2. is there a pattern of thoracic somatic dysfunction? does the child rotate their head with a movement involving only one side of the pectoral girdle, indicative of thoracic dysfunction? in this case, asymmetry of the movements of the arms may also be present. 3 . is there a cranial dysfunction, such as a lateral strain of the sbs that explains the parallelogram shape of the head? these questions should be kept in mind in the following examination. observe the relationship between the head and the pelvis. in the presence of a 'total body' dysfunctional pattern, the pelvis and the head of the child are rotated in opposite directions on the vertical axis of the spine. palpation and motion testing will confi rm these observations and treatment should be applied accordingly. evaluate the skull. infants usually do not present with thick hair as encountered in most adults, making observation of the neurocranium easier. look for any bald spots that indicate chronic contact between that area of the head and the bed during sleep. look for posterior and anterior fl attening; in the presence of posterior plagiocephaly these are usually on opposite sides. this results in a parallelogram-shaped head that is easier to see from above when the child is held on the practitioner's or parent's lap. observe the child's face and frontal bones. a pattern of compressive forces applied directly to the frontal bone, with no occipital deformity, would indicate a frontal dysfunction. frontal fl attening opposite to the occipital fl attening is consistent with a pattern of lateral strain of the sbs. symmetry of the frontal bone with occipital deformity on one side is an indication of synostotic posterior plagiocephaly, where the forehead may be symmetric or fl attened on the side of the occipital fl attening. 63 when a frontal dysfunction is present, this may affect the eyes. observe the size and shape of the orbital cavities, as well as the ocular bulbs. the orbital diameter is the distance between the superior medial and inferior lateral angles of the orbit. an increase in the orbital diameter results in an orbital cavity that appears to be wider than it is high and is associated with a cranial fl exion-external rotation pattern. conversely, if the orbital cavity appears to be narrower, this is associated with a cranial extension-internal rotation pattern. frontal dysfunction, in turn, affects the rest of the facial bones and is particularly important when problem solving dysfunctions of the nasal bones and the maxillae. observe the positions of the ears. they are very indicative of the positions of the temporal bones. in cases of nsp, the ear located on the side of the occipital fl attening is displaced more anteriorly than the contralateral ear. if the ear is displaced more posteriorly on the fl attened side, further diagnostic investigation is warranted because the displacement might be a sign of synostotic plagiocephaly. 29 this sign, however, is not an exclusive indicator and synostotic plagiocephaly may also present with an anterior ear position. 28, 63 observe the size and shape of the ears. usually, on the side of the occipital fl attening of nsp, the ear may, for example, have been compressed against the uterine wall and, therefore, may be smaller. in this instance, expect to fi nd intraosseous dysfunctions of the temporal bone on that side. this is the ear that the child will usually rub and that eventually may present with an otitis media. after observation, the osteopathic practitioner gently palpates (i.e. caresses) the child's head, looking for depressions, bossing and irregularities of contour. sutures are palpated for ridges, overlapping or irregularities in shape. a thick ridge over a suture calls for attention, because it may be a sign of a synostotic suture. flattenings are the result of compressive forces. tissues are palpated to evaluate for tissue texture abnormality and increased tenderness. palpation of osseous tissues gives a sense of density that might be different between the two sides of the suture; increased tenderness is usually proportional to the strength of the compressive forces. posterior occipital muscles are evaluated by palpation for tension and asymmetry. although the vault and the back of the head, the parietals and the squamous portion of the occiput are quite accessible to palpation, palpation of the frontal and facial bones necessitates a little more patience and delicacy in order to avoid disturbing the child. the base of the skull is not directly accessible to palpation for structure. the lateral parts of the occiput or exocciputs and the basilar part, as well as the sphenoid bone and the petrous portions of the temporal bones, should be assessed by palpating for function. to visualize these areas correctly while palpating them, knowledge of anatomy is of paramount importance. motion testing will confi rm the fi ndings of palpation and observation. dysfunctional head rotation is a treatment priority. it is of considerable importance that the child leaves the offi ce with a freer range of motion and an increased ability to turn their head. if not treated, the dysfunctional rotation will maintain the nsp. look for any somatic dysfunction of the occipitocervical junction and the cervical and thoracic spine, and treat utilizing indirect principles. structure will follow function, and if bilateral rotation is recovered, the traction of the muscles that insert on the occipital squama will help to reshape the fl attened areas. membranous patterns of the cranial mechanism should be assessed and dysfunctions balanced. particular attention should be given to the poles of attachment of the dura, the falx cerebri on the occipital squama and the tentorium cerebelli on the superior borders of the petrous portions of the temporal bones. motion of the sbs, occipitomastoid and lambdoid sutures should be assessed and treated accordingly. check the frontal bones and their relationships with the facial bones. any dysfunction should be treated. special attention should be directed at the cranial base, with the assessment and treatment of the compressed occipital condyles and compressed jugular foramina, when present. molding procedures can be applied, with intraosseous balancing of the occiput, temporal bones, frontal bones, sphenoid and parietal bones as dictated by the patient's needs. very often parents will comment on the fact that the fl attening was not present at birth and say that they do not understand why nsp has developed. to succeed in the treatment of plagiocephaly, it is worthwhile explaining the mechanism of nsp and stressing the importance of parental participation in the following months. explain that the initial asymmetry may have been present at birth in a very subtle way that has been exacerbated by a persistent positional preference. explain that it is of paramount importance to encourage the child in activities that promote bilateral cervical rotation, as well as promoting sleeping positions that avoid pressure on the already fl attened area. successful treatment depends on this. proper sleeping position may be obtained by elevating one side of the bed approximately 5 cm (2 inches). this can be accomplished by placing a rolled bath towel beneath the entire length of the mattress, on the side of the occipital fl attening. this will encourage the infant to turn their head in the other direction. toys and other attention-getting objects, soliciting the rotation of the child's head when lying supine, should be placed on the side opposite to the occipital fl attening. encourage play in the prone position. it can be explained to the parents that activities in the prone position stimulate the posterior axial musculature. muscular extension of the neck results in traction on the squamous portion of the occiput, helping to create a round head. to stimulate the child's curiosity and open them to the world, while encouraging them to turn their head symmetrically left and right, carry the child facing forward, held in the midline of the parent's chest. one parental hand should support the child's bottom while the other hand contacts the front of the child's torso, holding them against the parent's chest. the prolonged use of a car seat or other similar such carrying device should be discouraged because it tends to maintain the child in a chronic position, usually that of the dysfunctional asymmetry. thumb sucking should be discouraged because the child assumes an asymmetric position while preferentially sucking one thumb. if oral gratifi cation is necessary, an orthodontically shaped pacifi er should be employed. encourage the parents to gently caress the child's head bilaterally, behind the ears, in the areas over the occipitomastoid sutures and over the superior nuchal line of the occiput. this will help to reduce any dysfunctional tenderness. scoliosis is a lateral deviation of the spine. a structural scoliosis is a spinal deformation that is not totally reducible, while a functional scoliosis is totally reducible. the diagnosis of scoliosis is confi rmed by radiographic analysis. a functional scoliosis is usually associated with pelvic or postural asymmetry, a difference in the length of the lower limbs or vestibular or visual disorders. a structural scoliosis presents a spinal deformation in the three planes of space involving sidebending, rotation and fl exion or extension of the vertebrae. the side of convexity of the spinal curve defi nes the scoliosisfor example, a left scoliosis consists of a spinal curve that is convex on the left side. cobb's angle is a measurement of the degree of scoliosis between the most tilted vertebrae above and below the apex of the curve. this angle is obtained by measuring the angle of intersection between lines drawn perpendicular to the top of the most superior vertebra, and the bottom of the most inferior vertebra, of the curve. a scoliosis is identifi ed as idiopathic when no recognizable pathology explains its origin. it is identifi ed as secondary in the presence of spinal anomaly or neuromuscular dysfunction. the classifi cation of scoliosis is based on the age of the patient when the spinal curvature is fi rst identifi ed: congenital scoliosis is present at birth, infantile scoliosis is diagnosed under the age of 3 years, juvenile idiopathic scoliosis between 3 and 10 years, and adolescent idiopathic scoliosis (ais) between 10 years and the end of skeletal growth. the cause of idiopathic scoliosis has not been established, but seems to be a multifactorial interaction of environmental and genetic factors. studies have shown scoliosis as a single-gene disorder that follows the simple patterns of mendelian genetics. 64, 65 traits can be dominant or recessive. genetic links exist, with 3% of parents and 3% of siblings having a scoliosis. 64 further, a correlated incidence of scoliosis has been described in twins. 66 older maternal age is a risk factor for greater progression of the curve of ais. 58 maternal age of 27 years or more at the time of the child's birth is associated with a higher incidence of ais, whereas paternal age has no significant effect. 67 changes in the extracellular matrix of the connective tissues (e.g. collagen distribution and elastic fi bers) have been found among patients with scoliosis, but most researchers do not consider these changes to be the etiology of the deformity. 68 similarly, a change in muscle fi ber composition or chronic muscle overuse might explained the hyperintense signal intensity shown on mri in the multifi dus muscle on the concave side of the scoliosis associated with greater degrees of curve severity. 69 myopathy involving impaired calcium pump activity is among other proposed etiologies that require further study. the progression of ais is associated with increased calmodulin (calcium-binding receptor protein) levels in platelets, with a possible modulation of the calcium-activated calmodulin by melatonin. 68 the level of melatonin has been proposed as a predictor for progression of spinal curvature in idiopathic scoliosis. 70 melatonin is produced and released by the pineal body at night, and its production is inhibited by environmental light. it is proposed that a deficiency of melatonin could disturb equilibrium and postural mechanisms. 71 neurologic origins have also been proposed as etiologies of scoliosis. hearing-impaired children who have a high incidence of vestibular dysfunction have signifi cantly less idiopathic scoliosis than children with normal hearing, resulting in the suggestion that idiopathic scoliosis has a neural etiology. 72 a sensory input defi ciency of the spatial orientation system, involving visual and vestibular dysfunction, is believed to cause motor cortex and axial posture control disturbances. 73, 74 another hypothesis is that developmental disorders in the central nervous system, followed by asymmetry of the spinal rotators and other trunk muscles, results in ais. a less effi cient postural regulation system with a diminished quality of standing stability has been demonstrated in some scoliotic patients. 75 developmental disorders have also been considered at the level of the spinal cord. differences between the growth of the vertebral column and the growth of the spinal cord -'uncoupled neuro-osseous growth' -either with asymmetric nerve root tension or with reduced growth of the cord, are suggested etiologies for scoliosis. 76 more rapid growth of vertebral bodies that occurs through endochondral ossifi cation, as well as slower circumferential growth of the vertebral bodies and pedicles that occurs through membranous ossifi cation, is observed in ais patients. 77 furthermore, the length of the vertebral canal is shorter than the length of the vertebral column. this leads to the hypothesis that the thoracic spine is tethered by a tight spinal cord, with a resultant diminution of the kyphosis. this, in turn, results in a displacement of the spinal cord to one side of the vertebral canal with an associated sidebending of the spine and lastly a rotation of the vertebral bodies to allow for their growth while the vertebral canal stays in the midline. 78 the base of the vertebral canal remains at a right angle to the sagittal plane of the patient, in its original position, and does not follow the rotation of the vertebral body. 78 the tension of the core link -the strong dural membranes covering the cord, between the pelvic and cranial bowls 79 -may play a role in this mechanism. the relationships between the different parts of the craniosacral mechanism, therefore, should be considered, and any dysfunction of the dura and/or the vertebral ligaments should be treated. biomechanical factors can affect spinal alignment. sidebending-rotation and torsion of the sbs, for example, can modify the level position of the orbits through the sphenoid and thereby modify the occipital neutral position, again altering balance mechanics in the spine below. pelvic obliquity is considered a cause of imbalance in the axial skeleton. pelvic obliquity has been associated with unequal leg length. if this imbalance appears early in the growth process, it will result in abnormal asymmetric weight-bearing pressures on the vertebrae. a 'dangerous triad' of joint laxity, delayed growth and persistence of asymmetric overloading of the spine has been described in rhythmic gymnasts who develop scolioses. 80 this group shows an incidence of scoliosis of 12%, compared to 1.1% in the general population of the same age group. pelvic obliquity has also been associated with the 'molded baby syndrome', where intrauterine molding determines a vertebral curve, having a sacral tilt inferiorly on the side of the spinal convexity. mechanical compressive forces acting on the infant during the prenatal, perinatal and postnatal periods have been proposed as an etiology for scoliosis. more breech presentations have been found among infants developing scoliosis during the fi rst 6 months of life. 58 plagiocephaly is frequently associated with infantile scoliosis. 58,81-84 a facial and cranial distortion, always on the side of the curve of the scoliosis and linked to the intrauterine position, has been described. 85 mcmaster noted that the scoliosis was rarely present at birth and, like plagiocephaly, develops very often within the fi rst months of life. he proposed an explanation for the association between plagiocephaly and scoliosis, as follows. infants prefer to turn toward their right side when in a supine position. light but asymmetric pressures from the mattress on the skull as well as on the growing spine can create asymmetries, particularly when applied over a prolonged time or during a critical period of growth. with chronic right rotation of the head, the back of the head will fl atten on the right, allowing growth of the skull on the left. the thorax follows the same pattern, the left side expanding freely backwards with a left rotation of the thoracic vertebrae. 83 infantile scoliosis is sometimes found in association with imbalance of the occiput or with dysfunction of the sbs. intraosseous dysfunction of the occiput can produce asymmetry of the occipital condylar parts, resulting in altered balance mechanics in the spine below. the compressive forces applied to the occipital bone at the time of delivery have been described and suggested to be the causes for future compensatory scoliotic curves. 59, 86 thus, the child may prefer to sidebend their head slightly to one side and, as time goes on, with potential new injuries and therefore more diffi culties for compensation, the adolescent will develop a scoliosis. ventura et al. state: 'even small deformities present at, or soon after, birth may get worse in infants whose connective tissues do not have a potential for recovery.' 84 to this we could add one or more of the components described above -the etiology is multifactorial. congenital scoliosis may be associated with neurologic pathology or a vertebral structural defect (failure of formation and/or segmentation), as well as associated abnormalities of the head, neck, pelvis and hips. a thorough medical examination should be performed to rule out these disorders. hemivertebra is the most common anomaly that causes nonidiopathic congenital scoliosis 87 and is sometimes associated with posterior midline cutaneous abnormalities. neural axis abnormalities have been demonstrated in 21.7% of otherwise asymptomatic patients with infantile scoliosis. 88 congenital scoliosis is more common in females than in males, occurring in the ratio of 1.27 : 1. 87 among children with congenital spinal anomalies, 30-60% have other anomalies located most commonly in the genitourinary tract, cardiovascular system, spinal cord or cervical spine. 89 since the time of hippocrates, congenital and infantile scolioses have been described as potentially the result of mechanical factors operating during fetal life. 9 these scolioses are more common in males, presenting more often as a left thoracic curve. 83, 85 some resolve spontaneously, while others progress. harrenstein in 1930, 90 quoted by mehta, 91 stated: 'spontaneous correction does occur without treatment but at the moment it is not possible to distinguish between the two at the time of the diagnosis.' thus, in order to differentiate between progressive and non-progressive congenital and infantile idiopathic scoliosis, mehta proposed a method of measurement of the rib-vertebra angle (rva). 91 in an anteroposterior radiograph, the rva is 'the angle formed between each side of the apical thoracic vertebra and its corresponding rib'. the rvas are equal on a normal spine and a gap of 2-4 mm normally separates the head of the rib and the upper corner of the adjacent vertebra. mehta states that the most progressive infantile scoliosis presents an rva difference between the two sides equal to or greater than 20°. when this radiographic measurement is repeated after 3 months, the rva remains unchanged or increases with a progressive scoliosis, whereas it decreases with a resolving curve. furthermore, with time, in the anteroposterior radiograph, a progressive scoliosis demonstrates overlap of the rib shadow with the upper corner of the vertebra. the relationship between the rib and the vertebra and the tissue response to any stress during growth periods is of great importance. curve progression is the major concern in every type of scoliosis, and the differentiation between progressive and non-progressive congenital scoliosis and infantile idiopathic scoliosis has been confi rmed through sequential comparisons of rvas over time. 84, 92 when spontaneous resolution occurs in non-progressive infantile scoliosis, it does so between the ages of 12 and 18 months. 84 spontaneous resolution of infantile idiopathic scoliosis varies between 17% 93 and 92%. 94 therefore, it is appropriate to detect the scoliosis at its earliest stage and to treat all affected babies within the fi rst 6 months of life. 95 it is typical to employ a wait-and-watch approach to the progressive category because orthopedic treatment is complex and diffi cult to initiate before the age of 18 months. 96 osteopathic procedures, on another hand, may be begun immediately, with potentially good results being obtained in cases of congenital and infantile idiopathic scoliosis. observe the baby for spontaneous positioning and areas of restricted mobility. look for positional asymmetries of the torso, head and neck, arms and legs. look also for a bulky back on the convex side of the thorax and creases in the skin laterally on the concave side. skin creases are a sign of fi xed scoliosis. 97 observe the baby for clumsy movement in the maintenance of head position and in general coordination. palpate the infant to identify membranous, myofascial and interosseous somatic dysfunction contributing to the visually observed functional restrictions. the infant may be treated utilizing indirect principles to release any restriction of motion, particularly in the pelvis, upper thoracic spine, ribs, sternum, thoracic diaphragm, pectoral girdle, cervico-occipital area and cranium. intraosseous dysfunctions -most commonly encountered in the sacrum, lumbar and thoracic vertebrae and occiput -may be addressed using molding procedures. at home, following treatment, it is important to avoid movements and positions that will reinforce the scoliotic pattern. in considering daily activities, such as feeding and play, and when putting the infant to sleep, encourage the parents to position the infant correctly and to solicit movement from the infant that promotes symmetry. a child should sleep on their back to prevent sids, but should play in the prone position to develop the vertebral musculature of tonic posture. prevention is the best therapy. osteopathy, as a non-invasive treatment, facilitates the spontaneous recovery process or regression as quickly as possible. this allows the child to progress through the developmental milestones of infancy without interference from a dysfunctional musculoskeletal system. scoliosis is present between 10 and 16 years of age in 2-4% of children. 98 these patients differ from those with infantile scoliosis in that there is predominance among females and for the curvature to be a right thoracic curve. 83, 85 the vertebral rotation is associated with a 'rib hump' on the side of the convexity, with most curves convex on the right in the thoracic area and on the left in the lumbar area. cobb's angle is sometimes debated as a true assessment of the scoliosis. ais is a three-dimensional deformity of the spine, with morphologic changes in the trunk and rib cage. vertebral rotation should be considered in the evaluation. the presence of severe pain or neurologic symptoms would be atypical for idiopathic scoliosis and should raise concern for spinal cord pathology. idiopathic scoliosis, if left untreated, increases in adult life. the period of puberty should be considered as a high-risk interval, and regular screening is recommended. a signifi cant correlation between growth in height and progression of cobb's angle has been found, with a possible increase until 2.5 years after menarche. 99 current studies have indicated that the younger the patient at the time of diagnosis by pubertal or skeletal maturation landmarks, the greater the chance of curve progression. a curve measuring less than 30° at skeletal maturity is least likely to progress, whereas curves measuring 30-50° may gain another 10-15°. 65 thoracic curves deteriorate most, followed by thoracolumbar curves and double curves. 100 less than 25% of adolescent idiopathic scoliosis resolves without treatment. 101 orthopedic treatment with a cast or a brace might be indicated to limit the progression of the curve and to employ surgery to correct the scoliosis. bracing for at least 23 hours per day appears to be optimal for interdicting progression of the curve. 102 watchful waiting is suggested as an alternative treatment to bracing because bracing does not decrease the incidence of surgery and often results in adverse psychological effects. 103 manipulative treatment associated with exercise has been shown to stop curve progression in ais. 104,105 exercise may be used to effectively reverse the signs and symptoms of scolioses and to prevent progression of spinal curves in children and adults. 106 as scoliosis is a risk factor for the impairment of physical wellbeing and quality of life, treatment is important. the physical examination begins with observation of the patient standing. observe placement of the feet for asymmetries. from behind, note the level of the iliac crests and the symmetry of the pelvis and waist triangles. leg length discrepancy as a contributing factor should be considered. further, observe the relationship between the pelvic and pectoral girdles, and look for shoulder and scapular asymmetries. elevation of the right shoulder compared to the left is associated with a thoracic curve convex on the right. note the position of the patient's head. a vertical line dropped from the external occipital protuberance should fall in the middle of the intergluteal crease. the patient is next observed in profi le for increased or decreased thoracic kyphosis, forward head posture and lumbar lordosis. the adam's forward bending test is employed to help identify scoliosis. the child bends forward, holding palms together with arms extended. the examiner looks from behind and from the side, along the horizontal plane of the back, to detect an asymmetry as a rotational deformity or 'rib hump' (fig. 7.1.8) . this deformity is associated with spinal curves and may be further delineated with radiographic evaluation. with the child remaining forward bent, observe the distance between tips of the fi ngers and the ground as an indication of general spinal fl exibility. the palpatory examination of the patient with ais is directed at the identifi cation of membranous, myofascial and interosseous somatic dysfunction. the patient may be treated utilizing indirect principles to address any identifi ed dysfunction. begin by treating the area of greatest motion restriction. this will often be in the upper thoracic and craniocervical regions. the presence of proprioceptive sensory endings in the ligaments and fascia of the upper cervical area contributes to postural balance. primary high cervical somatic dysfunction can consequently impact postural balance. somatic dysfunction in the upper thoracic region can result in compensatory dysfunction in the upper cervical spine. once these areas have been treated, dysfunction of the thoracic spine, ribs, lumbar spine, sacrum and pelvis should be addressed. normalization of the diaphragm, to increase vital capacity, should always be part of the treatment of scolioses. dysfunction of the thoracic diaphragm, because of the attachments of the crura on the lumbar spine, affects the mobility of the spine and may be linked to dysfunction in the pelvic and cranial diaphragms through the core link. any dysfunctional pattern present in the skull should be treated. dysfunction in the occiput can affect the proprioceptive input from the craniocervical region. the vestibular apparatus located inside the petrous portions of the temporal bones contributes to balance mechanics and symmetric muscle tension. dysfunction between the sphenoid, occiput and temporal bones should, therefore, be treated. by virtue of the fact that fusion of the sbs does not typically occur before late adolescence, there remains mobility in the base of the skull of younger ais patients, making them particularly receptive to cranial treatment. cranial dysfunction may also affect the scoliotic patient through the reciprocal tension membranes. dysfunctional tensions in the dura have been proposed as an etiology of scoliosis. 76 equilibration of intracranial and intraspinal membranes should, therefore, be employed. in younger patients where active bone growth is still present, intraosseous dysfunctions -most commonly encountered in the sacrum, lumbar and thoracic vertebrae and occiput -may be addressed using molding procedures. exercises are an important component of the treatment protocol. a properly employed exercise program should teach the patient to breathe effectively, increasing vital capacity and enhancing thoracic cage mobility. it should facilitate the establishment of the fullest range of motion possible and the development of symmetry of movement, particularly spinal rotation, while strengthening the core musculature and stabilizing the spine. it should allow the patient to develop proprioception and establish good postural habits. kyphosis is an increase of the spinal curve in the sagittal plane that results in a greater than normal posterior convexity (anterior concavity). an increased kyphotic curve is encountered more often in the thoracic spine, where it produces a rounded upper back, or 'humped back'. in the cervical and lumbar spines, normal curves present with posterior concavity or lordosis. under dysfunctional circumstances, the lumbar and cervical curves are reversed and become kyphotic. at the lower portion of the spine, a kyphosis can be ascribed to the sacrum, when its usual posterior convexity is increased. a thoracic kyphosis of >45° is considered pathologic. congenital kyphotic deformities are infrequent and can be caused by a failure of formation of the vertebral body or a failure of segmentation, for which the treatment is surgical. 107 in the infant, tumor of the spine is also a potential cause of kyphosis that requires specifi c medical attention. in the juvenile period, scheuermann's disease is a cause of kyphosis resulting from an alteration of the vertebral development. wedging of the vertebral bodies, the posterior height being greater than the anterior height, produces the kyphotic deformity. boys are more frequently affected and the resultant back pain might be the trigger for an x-ray where the diagnosis is made. irregularities in the endplates of the vertebrae can be observed, particularly at the level of the lower thoracic and upper lumbar spine. scheuermann's disease may also be associated with scoliosis. 108 because kyphosis is a spinal deformity, it should not be confused with poor posture. when examining an infant who is seated without support, it is normal to fi nd a kyphosis of the thoracic and lumbar spine. proprioception and muscular tone develop with age to maintain adequate sagittal balance. sagittal spinal curves change as a child grows. 109, 110 the thoracic kyphosis is more pronounced in males, 111 at a mean age of 12.8 years. 112 more often, the exaggerated kyphotic curve is associated with dysfunctional posture. juvenile and adolescent kyphosis can be the result of poor posture, as a compensatory pattern to an extension dysfunction elsewhere. anterior displacement of the occipital bone on the superior articular surface of the atlas will project the chin forward, and the ensuing postural compensation will result in an increased thoracic kyphosis. this pattern is commonly found in individuals who demonstrate oral breathing. when encountered in a child, an apparent kyphosis may also be the result of protraction of the pectoral girdle. in this case, the thoracic curve is not fi xed in the kyphotic position and spinal backward bending can be achieved on demand, although lack of fl exibility is common. the child is usually shy, and an extension-internal rotation pattern may be present, either at the level of the pelvis or at the level of the sbs, the temporal or occipital bones. a thoracoabdominal diaphragmatic dysfunction is very often associated with diminished thoracic fl exibility and reduced vital capacity. the areas of the diaphragmatic attachments onto the inferior portion of the sternum and adjacent ribs might be the causative dysfunctional agents. an increased thoracic kyphotic curve is usually compensated for by an increase in the lumbar lordosis. kyphosis and lumbar lordosis generally compensate each other. a correlation between these two spinal curves has been found in most age groups. 113 the cervical and lumbar regions are normally lordotic. hyperlordosis is an increase of the lumbar lordosis and is considered pathologic. it can be associated with other conditions, such as developmental dysplasia of the hip or neuromuscular disorders. there may be a family history of hyperlordosis, but it can also follow trauma, commonly from athletic activities, particularly highly competitive sports, during periods of growth. adolescents may also present with hyperlordosis as a consequence of a developmental spondylolisthesis. with this disorder, studies have shown an increase of hyperlordosis and sacral inclination, but a decrease of thoracic kyphosis. 114 the degree of lumbar lordosis is correlated with sacral position. sacral anatomic extension (craniosacral fl exion) is normally associated with decreased lordosis; sacral anatomic fl exion (craniosacral extension) is associated with increased lordosis. the global amplitude of the vertebral curves, cervical lordosis, thoracic kyphosis and lumbar lordosis changes with growth, but the association with the position of the sacrum is constant under normal conditions. the relationship between the cranial and the pelvic bowls, through the core link, is a fundamental principle within the cranial concept. cranial fl exion is associated with sacral craniosacral fl exion, and cranial extension is associated with sacral craniosacral extension. the vertebral anteroposterior curves are decreased when fl exion of the cranial base is present; conversely, there is an increase of the lordotic or kyphotic curves with extension of the cranial base. 115 early detection of kyphotic and lordotic curves is important for successful treatment. the child should be considered from a total body approach and the posture of the whole body should be evaluated in the standing position: • observe the pattern of weight-bearing mechanics. • observe the feet for a pattern of inversion or eversion. a pattern toward eversion of the feet, and eventually fl at feet, is consistent with increased sagittal curves and cranial extensioninternal rotation. • observe the knees. genu valgum is consistent with increased sagittal curves and cranial extension-internal rotation. • observe the pelvis for an increase of anterior tilt, with the sacrum in craniosacral extension. • observe for pelvic asymmetry and any difference in the greater trochanter and innominate crest heights. • observe the spine for an increase of the anterior-posterior curves. a pattern involving all of the curves might be the consequence of a cranial or sacral dysfunction with extension and internal rotation. a pattern of increased curvature limited to a portion of the spine may be associated with a dysfunction within the curve, in an adjacent spinal curve or adjacent junctions between the spinal ap curves. • observe the pectoral girdle for protraction or an associated asymmetric pattern. a difference in shoulder heights is common. this suggests somatic dysfunction in the thoracic spine with associated sidebending and rotational components. • observe the position of the head in relation of the rest of the body, in both the frontal and the sagittal plane. forward displacement of the head is often associated with somatic dysfunction of the craniocervical or upper thoracic vertebrae. next, observe the child while they are moving. if necessary, have the child demonstrate active fl exion-extension, sidebending and rotation of the spine to confi rm previous observations. muscles may show a difference in tension between anterior and posterior groups. hyperlordotic children will present with increased tension in the hamstrings and hip fl exors, while at the same time their abdominal muscles will lack tension. tests of listening are performed on the innominates, the sacrum, the lumbar and cervical vertebrae and the cranium. the treatment of any identifi ed dysfunctional areas should follow using indirect principles. the postural response to effective manipulation is almost immediate. you should be able to see improvement in the posture of the child after the fi rst treatment. simple exercises may be recommended, particularly if poor posture is present. pelvic tilt is useful, as are stretching the hamstrings and proprioceptive exercises to increase body posture awareness. the child should be encouraged to judiciously practice athletic activities, such as swimming and tai chi, which will strengthen and balance the core muscles and improve fl exibility and coordination. advice should be given that appropriately addresses daily living conditions. for example, the patient should avoid carrying a backpack on one shoulder; rather, they should carry it using both shoulders. they should avoid reading and writing on a fl at horizontal surface and should work instead on a surface that is tilted approximately 20° to limit cervicothoracic fl exion. once the problem has been effectively addressed, the child may then be treated as needed, but they should be followed on a regular basis, at least annually, until they have stopped growing. pectus excavatum is a deformity of the anterior thoracic cage in which the sternum is depressed in a concave shape, whereas in pectus carinatum the sternum is protruded in a convex shape. these deformities may or may not be associated with genetic disorders or with scolioses. decreased thoracic cage compliance and reduced vital capacity may be present, although the heart and lungs develop normally. pectus excavatum and pectus carinatum are present at birth, but the parents usually do not become aware of the deformity until it becomes more apparent with growth. severe cases often result in signifi cant psychological impact, usually in early adolescence. pectus excavatum is frequently associated with an sbs extension pattern. this results in internal rotation of the paired structures, specifi cally the pectoral girdle. these individuals may also demonstrate direct mechanical derangement of the internal fascial structure of the thoracic cage and intraosseous dysfunction of the ribs and sternum. a diaphragmatic dysfunction is almost always associated with this condition. in pectus carinatum, similar mechanisms exist but with a tendency for sbs fl exion. the evaluation of the patient commences by examining the interrelationship between the sternum and the thoracic spine, and between the sternum and the occiput. next, examine all myofascial structures attached to the sternum, including the pectoral girdle and the diaphragm. the anterior abdominal wall should be evaluated for dysfunctional tension, and, if present, contributory mechanics should be sought out in the lumbar spine, sacrum and pelvis. visceral abdominal dysfunction should also be considered. treatment consists of myofascial release applied to identifi ed dysfunctions. if possible, molding procedures directed at the sternum should be employed simultaneously with the myofascial release modalities to enhance the effi cacy of both. the application of these procedures should be done in synchrony with, and with the intent to enhance, the inherent motility of the body. the younger the patient when treatment is initiated, the greater the potential for positive outcome. vertebral somatic dysfunction in infants and children can be found at any level of the spine. it will, however, be more commonly encountered in the lumbar, upper thoracic and cervical regions. it usually results from the day-to-day physical activities and traumas of childhood. in younger children, dysfunction in the cervical region will often present as cervical pain and, eventually, as torticollis. in the lumbar region, somatic dysfunction may remain quiescent for a protracted period, in time manifesting through a somatovisceral mechanism as abdominal pain. in older children and adolescents, the initial complaint from vertebral dysfunction is usually localized or referred musculoskeletal pain. because of the young patient's ability to compensate for somatic dysfunction, any vertebral somatic dysfunction should be thoroughly evaluated to rule out a viscerosomatic origin. the mechanics of vertebral somatic dysfunction manifest in children and adolescents is the same as that encountered in adults, showing the coupled relationships between fl exion-extension, sidebending and rotation as described by fryette. 116 however, because of the fl exibility of the soft tissues in these young patients, dysfunctional barriers are more compliant, lending to the application of indirect techniques in their treatment. somatic dysfunction may also exist as a refl ex manifestation of visceral dysfunction and disease. although the precise locations of viscerosomatic refl exes in infants and young children have not been specifi cally reported, it is reasonable to anticipate locations similar to those in adults. the facilitated state of the segmental spinal cord in the presence of visceral input can, in turn, result in a somatovisceral response. a listing of viscerosomatic locations as they have been reported in the osteopathic literature is summarized in box 7.1.1. because of the growth potential of these patients, vertebral somatic dysfunction can exert disproportionate impact on their developing posture as well as on the viscera through somatovisceral refl exes. -the parasympathetic refl ex from the gastrointestinal tract proximal to the mid-transverse colon is vagal, occiput, c1, c2; the parasympathetic refl ex from the distal half of the transverse colon to the rectum is sacropelvic s2-s4 -the esophagus has a right-sided sympathetic refl ex from t3 to t6 -the stomach has a left-sided sympathetic refl ex from t5 to t10 -the duodenum has a right-sided sympathetic refl ex from t6 to t8 -the small intestine sympathetic refl ex is bilateral from t8 to t10 -the appendix and cecum sympathetic refl ex is from t9 to t12 on the right -the ascending colon sympathetic refl ex is from t11 to l1 on the right -the descending colon to rectum sympathetic refl ex is from l1 to l3 on the left. the clavicle is the bone most frequently fractured during the birth process. clavicular fractures occur in about 1.6% of all vaginal deliveries 1,2 and 0.5% when considering all live births. 3 both males and females are affected equally, with equal left versus right-sided incidence. 3 there is, however, a slightly increased incidence of right-sided fractures in left occiput-anterior deliveries. 4 reported risk factors for clavicular fractures include increased duration of the second stage of labor, increased birth weight and neonatal length (macrosomia), instrumental delivery 2 and shoulder dystocia. 3 in cephalic presentation, the compression of the infant's anterior shoulder against the maternal symphysis is responsible for the trauma. 4 direct pressure or torsion applied to the clavicles to facilitate delivery can also result in fracture. complete or incomplete greenstick fractures are most frequent. they present with edema, crepitus, a palpable bony bump and tissue texture changes over the fracture site. decreased or absent movement of the affected arm is present, as may become apparent when eliciting the moro refl ex. asymptomatic or incomplete clavicular fractures may not be initially identifi ed until after discharge from the hospital. usually, the caregiver will notice that the child demonstrates irritability with discomfort and pain when putting the child's arm through the sleeve of a garment or when lifting the child by holding them under their arms. they are also liable to report that the child cries when positioned on the affected side. shoulder dislocation, humeral fracture and brachial plexus injury are part of the differential diagnoses. the diagnosis is confi rmed radiographically. associated complications, such as erb's palsy, are present in 11.3% of newborns with fractures of the clavicle, 2 although clavicular fracture may actually reduce the potential nerve injury from traction on the brachial plexus. 4 usually no orthopedic treatment is necessary for asymptomatic and incomplete clavicular fractures. when the neonate presents with pain or discomfort, the affected arm may be immobilized by pinning the sleeve to the front of the shirt for 7-10 days. 5 a large callus typically forms at the fracture site within a week, and recovery is usually considered to be complete. osteopathic procedures may be employed to assist the recovery process and address the dysfunctions usually associated with a fracture of the clavicle. the clavicle is of importance because of its myofascial attachments. it serves as a junction between the fasciae of the thorax, arm and neck. the investing layer of the deep cervical fascia completely surrounds the neck. superiorly, it is attached to the external occipital protuberance and the superior nuchal line, the mastoid processes, zygomatic arches and the inferior borders of mandible. it splits to surround the trapezius and sternocleidomastoid muscles. inferiorly, it is attached to the manubrium of the sternum, the acromion and the spine of the scapula. the clavicle is the link in the fascial continuity between the investing layer of the deep cervical fascia and the fascia of the thorax and the arm. the clavipectoral fascia attaches on the clavicle, as does the deltoid fascia. the deltoid fascia is in continuity with the brachial fascia. the clavicle, therefore, plays an important role in the equilibrium of the fascia of the thorax, arm and neck, and should be balanced, as should the myofascial structures attached to it. forces applied during the delivery that are great enough to fracture the clavicle also affect the neck and upper thoracic vertebrae of the neonate. therefore the osteopathic practitioner should evaluate these structures and treat any dysfunctions accordingly, using indirect principles. furthermore, because of pain from the fractured clavicle, the child will prefer to lie on the opposite side, thereby fostering the development of asymmetric fascial tensions. these asymmetries can, in turn, induce the child to select a chronic position of comfort, long after the clavicle has healed. the chronic asymmetric positioning can then predispose the child to the development of plagiocephaly. fractures of the clavicle that occur during childhood are usually the result of rough play or athletic activities. in childhood, the forces that result in clavicular fractures are usually violent, most often involving impact on the hand with the arm extended or impact on the shoulder. in 75% of cases the site of fracture involves the medial third of the bone. the standard orthopedic treatment reduces the displacement at the fracture site by maintaining the shoulder in an upward and backward position with a bandage or plaster. osteopathic procedures applied to the older child follow the same anatomic principles as for the infant, i.e. to alleviate myofascial imbalances and upper thoracic and cervical dysfunction. the acromioclavicular junction may demonstrate somatic dysfunction; it should, therefore, be evaluated and treated following indirect principles. it is of importance to allow for normal function of the growing upper extremity. acromioclavicular dysfunction is the source of many adult shoulder disorders. a brachial plexus injury occurs most commonly as a result of a diffi cult birth, fetal malpresentation, 5 shoulder dystocia, macrosomia 6 or assisted vaginal delivery. 7 fracture of the clavicle(s) or humerus, 8 shoulder dislocation, torticollis, hematomas of the sternocleidomastoid muscle or paralysis of the diaphragm may be associated with injury of the brachial plexus. 5 a commonly believed etiology of brachial plexus injury is excessive traction on the fetal head during birth. in vaginal delivery, during the attempt to deliver the anterior shoulder, the applied downward traction can damage the brachial plexus. this theory, however, is questionable because, in almost half the cases of brachial plexus injury, delivery of the shoulders occurs without diffi culty. therefore, an in utero, atraumatic theory is also proposed. 8 when asymmetry and diminished movement of the arm are observed on the fetal ultrasound, a vulnerable plexus may be injured without traction during delivery. 9 the brachial plexus is formed by the union of the anterior divisions of the lower four cervical nerves and part of the anterior division of the fi rst thoracic nerve. in addition, the fi fth cervical nerve frequently receives a branch from the fourth cervical, and the fi rst thoracic a branch from the second thoracic. the plexus extends from the inferior aspect of the side of the neck to the axilla. the fi fth and sixth cervical nerves unite to form the upper trunk; the eighth cervical and fi rst thoracic nerves form the lower trunk, while the seventh cervical nerve runs out alone as the middle trunk. these three trunks pass beneath the clavicle and split into the anterior and posterior divisions. the plexus is attached to the fi rst rib and to the coracoid process by the costocoracoid membrane and is subject to any force that disturbs the relationship between the cervical vertebrae, the fi rst thoracic vertebra and ribs, the clavicle and the scapula (fig. 7.2.1) . most of the time brachial plexus injury is unilateral and immediately recognizable. brachial plexus injury can affect different spinal nerve roots and is identifi ed as follows: • upper type, with involvement of c5 and c6, or erb-duchenne palsy that affects muscles of the shoulder and elbow. the child presents with adduction of the upper extremity and internal clinical conditions rotation of the shoulder, but grasp remains intact. it represents most of the brachial plexus paralyses 10 and is considered to have a good prognosis. • lower type, with involvement of c7, c8 and t1, or klumpke's palsy that affects muscles of the forearm and hand. the child presents with a paralysis of the hand and wrist. the presence of an ipsilateral horner's syndrome (anhidrosis, miosis and ptosis) indicates an involvement of the sympathetic fi bers associated with an intraspinal avulsion of the root of t1. • whole arm type, with involvement of c5-t1, with no movement of the upper extremity and often associated with sensory loss. extreme lateral fl exion and traction of the head may be responsible for the stretch applied to the brachial plexus. the injury results in anything from a mild edema or hemorrhage within the affected nerves, to tearing of the nerve(s) that could be as extensive as to produce a total avulsion of the complete plexus. the c5 and c6 spinal nerves are located in the sulcus nervi spinali of the transverse processes. in that location they are strongly attached by various fi brous slips as extensions of the prevertebral fascia and surrounding structures attached to the spinous processes, and are, therefore, more likely to be ruptured. 11 the c8 and t1 spinal nerves may, more often, be subject to avulsion. 11 neuronal injury associated with brachial plexus injury may be of different degrees of severity: • neuropraxic lesions are failure of conduction without the axon having been affected, and are reversible. • axonotmetic lesions involve disruption of both the myelin sheath and the axon, but with the surrounding neuronal elements kept intact. wallerian degeneration of the axon distal to the injury occurs. • neurotmetic lesions are total sectioning of the nerve with its myelin sheath and supporting connective tissue. • avulsion is a separation of the plexus from the spinal cord. obstetric brachial plexus palsy occurs in 0.4-2.5 per 1000 live births with an upper root (c5-c6) involvement in 50% of cases; c5, c6 and c7 involvement in 25%; and the whole plexus in 25%. 6, 8, 12 neuropraxic and axonotmetic lesions have better prognoses. the diagnosis is made by physical examination. the moro refl ex is asymmetric and the biceps' deep tendon refl ex is absent. the grasp refl ex is, however, normal. the child should be moved very gently: the injuries are painful and the tissues very fragile. initial treatment is usually conservative with regular assessment. if the patient fails to show signifi cant improvement by 3 months of age, surgical opinion should be sought. 13 physical therapy, consisting of gentle passive mobilization, may be employed to maintain range of motion and prevent contractures while the infant is recovering active motion. specifi c motor training can be initiated within the fi rst 2 weeks, with facilitation of active movement. the persistent neurologic defi cits may result in the development of internal rotation and adduction contractures of the arm. gentle stretching of internal rotators should be performed to reduce this risk while avoiding reinforcement of forearm supination. osteopathic procedures should be employed as early as possible in the treatment of brachial plexus injury. traumatic forces may have injured the brachial plexus, but other areas, such as the upper thoracic spine, the fi rst rib, the cervical spine, clavicle and all of the myofascial components of the thoracic outlet, have been stressed as well. dysautonomia may also be present because somatic dysfunction of the cranial base and occipitoatlantal region can affect the parasympathetic tone through the vagus nerve, while somatic dysfunction in the upper thoracic spine can affect sympathetic nervous function. direct compression of the venous and lymphatic drainage of the brachial plexus, as well as somatovisceral refl exes, should be considered when attempting to facilitate nerve regeneration. osteopathic procedures aim to promote fl uid, electrolyte and metabolic exchange within the tissues to facilitate drainage of edema and to prevent or reduce tissue scarring. treatment is intended to optimize nerve regeneration and prevent the development of muscular imbalance. recuperation of the common motor defi cits, such as the absence of active external rotation, fl exion and abduction of the shoulder, and function of the biceps should be addressed to minimize bony deformities and joint contractures. the neonate with possible brachial plexus injury may be examined on the treatment table. observe for spontaneous movements of the head, trunk, pelvis and limbs. check for subtle facial palsy that may be found as a concomitant result of birth trauma. inspect shoulders and limbs for deformities. evaluate range of motion of every joint of the affected limb. palpate for tissue texture changes in the upper extremities. look for signs of shoulder instability such as a palpable or audible click during movement. palpate for tissue texture changes in the suboccipital, neck and upper thoracic areas. the connective tissues are responsible for the maintenance of shape against both external and internal stresses. 14 mechanical forces contribute to the development and evolution of the extracellular matrices found in the connective tissues. 15 as tissue texture changes follow trauma, osteopathic procedures should help in resetting structure and function of traumatized connective tissues. evaluate, through tests of listening, the function of the humerus, scapula, clavicle, sternum, upper thoracic spine, fi rst ribs, cervical spine and craniocervical joints. this method of assessment is of particular value with this type of pathology because it is so gentle. anatomic visualization is, as always, important. as you evaluate the patient, visualize the different layers of soft tissue: fascia superfi cialis, cervical fascia, costocoracoid membrane, sternocleidomastoid and scalene muscles. evaluate and visualize the different bones involved. listen to the inherent motions in order to defi ne the dysfunctional area. study the relationship between the shoulder and the vertebral column. for instance, in the case of a klumpke's palsy, place the pad of the fi ngers of one hand on the spinous processes of c6, c7, t1 and t2, and place the other hand on the ipsilateral shoulder. listen, and look for dysfunctional motion. one vertebral segment may be more dysfunctional than others. the relationship between the humerus and the shoulder should also be balanced. treat the dysfunctions you identify by applying indirect principles. improvement should be rapid and most cases have a favorable prognosis. injuries involving the fi fth and sixth cervical nerve roots have the best prognosis, whereas lower plexus and total plexus injuries have a poorer prognosis. signifi cant defi cit persisting after 3 months should be explored surgically. prognosis is excellent if antigravity movement of biceps and shoulder abductor is present by 3 months of age. assessment may be performed by testing the biceps' strength in a supine position while simultaneously palpating the muscle. bicipital activity should not be confused with fl exion of the elbow obtained by the action of the supinator muscle. surgery is considered by some authors when antigravity movement of the biceps is not present by 3 months of age. 16 surgery is considered to be justifi ed by others when an initial involvement of the c7 nerve root is present, with a birth weight above the 90th percentile and there is only poor elbow fl exion at 6 and 9 months of age. 12 the plasticity of the glenohumeral joint in the newborn makes it subject to shoulder dysplasia and, in more severe cases, dislocation. these disorders may be compared to similar disorders occurring in the hip joint -hip dysplasia and hip dislocationand in some cases the etiology may be similar. intrauterine forces applied to the fetus can result in shoulder dysplasia. during the latter part of pregnancy any compression of the upper fetal torso within the uterus may affect the glenohumeral joint and the surrounding soft tissues. stresses during the birth process can also contribute to the development of shoulder dysplasia. increased duration of the second stage of labor, greater than 2 hours, has been described as a factor contributing to shoulder dystocia. 17 additionally, macrosomia that results in a size discrepancy between the fetal shoulders and the maternal pelvic inlet can, in severe cases, lead to signifi cant neonatal morbidity including asphyxia and trauma, particularly to the brachial plexus. a large fetal trunk, or increased bisacromial diameter, prevents the rotation of the fetal shoulders into the oblique pelvic diameter during delivery. 18 as a consequence, certain obstetrical maneuvers may have to be employed to alleviate the impaction of the fetal shoulders within the maternal pelvis. 19 as stressful as such a disproportionate relationship between the fetus and the maternal pelvis can be, it does not always result in overt trauma to the brachial plexus. it can, however, cause injury to the shoulder that can lead to shoulder dysplasia. this type of injury to the shoulder can occur even from the stresses of an otherwise normal delivery. dysplasia of the shoulder may also result from postpartum conditions. the presence of dysfunctional asymmetries in the newborn, congenital muscular torticollis, non-synostotic plagiocephaly and brachial plexus injuries may contribute to abnormal development of the glenohumeral joint. contractures of the muscles of internal rotation in neonatal brachial plexus palsy are responsible for posterior dislocation of the humerus from the glenoid fossa, 20-22 requiring orthopedic repair. milder cases of dysplasia without dislocation may be treated using osteopathic procedures. if untreated, these glenohumeral dysfunctions can increase with age, becoming the cause of adult scapulothoracic problems. therefore, the scapula and the glenohumeral joint should be evaluated at birth for any signs of dysplasia, as precisely as the pelvis is evaluated. particular attention should be directed at the identifi cation of signs of shoulder instability, such as a palpable or audible click during movement. observe and compare the size and shape of both shoulders. the examination may reveal asymmetry in the number of skin folds in the proximal part of the arms. observe the freedom and range of motion of both shoulders. note any restriction, stiffness of movement and asymmetry in movement, particularly external rotation and abduction of the arm. the malposition of the humeral head may result in an apparent difference in the length of the arms, with the arm on the side of the dysplasia appearing to be shorter. compare the anterior and posterior aspects of the shoulders and look for any posterior fullness that may be indicative of a posteriorly displaced humeral head, necessitating orthopedic attention. treat any somatic dysfunction identifi ed using indirect principles. stabilization of the humeral head in the glenoid fossa may be facilitated when myofascial procedures are applied to the periarticular muscles of the shoulder. nursemaid's elbow, also called pulled elbow, is a radial head subluxation that occurs in younger children when traction is applied suddenly to their hand or forearm. this commonly occurs when an adult is attempting to lift a child up by pulling upward while holding the child's hand. traumas such as falls or when the infant initiates rolling over are other possible causes of this condition. the head of the radius articulates with the radial notch of the ulna and the surrounding annular ligament. under normal conditions, the annular ligament encircles the head of the radius with a certain amount of tension that maintains the contact with the radial notch. the normal movements of the head of the radius, within the ring formed by the annular ligament and the radial notch of the ulna, are anterior and posterior motion. pronation is associated with posterior radial motion and supination with anterior radial motion. in nursemaid's elbow a subluxation of the developing radial head from the annular ligament of the elbow joint occurs. a combination of pronation and traction on an extended elbow causes a proximal slip of the annular ligament over the top of the radial head with resultant interposition of some fi bers of the anterior joint capsule between the two bones. 23 the most common symptoms of nursemaid's elbow are immediate pain and an inability to move the arm. the child will have a partially fl exed elbow with pronation of the forearm. most of the time anxiety is also present. the intention of osteopathic treatment is to restore motion between the head of the radius and the radial notch of the ulna and surrounding annular ligament. ligamentous articular strains may be balanced utilizing indirect principles that apply perfectly to this condition. balancing the annular ligament and the radial collateral ligament of the elbow may prevent recurrence of a posterior radial head subluxation. the caregiver should be told to avoid pulling or lifting their child by the arms or hands. a frequent complaint in an osteopathic practice is intoeing, i.e. the child's feet turn in when walking or running. malposition of the feet, developmental dysplasia of the hip and toe walking are among the other complaints encountered with infants, while sprains are more frequently encountered with the older children and teenagers. metatarsus adductus is an adduction of the forefoot that occurs in 1 : 5000 live births. 24 the classic view of it resulting from intrauterine positioning is debated, since genetic factors may contribute. 25 sleeping in the prone position also seems to promote it. this is a frequent cause of intoeing during the fi rst year of life and is more frequently encountered on the left side. 24 normally, in the neutral position, the heel-bisector line drawn through the midline axis of the hindfoot passes through the forefoot at the second web space. in cases of metatarsus adductus, the line passes lateral to the third toe. therefore, an angulation exists medially between the forefoot, or metatarsals, and the hindfoot. sometimes a transverse crease is present on the medial side of the foot and the lateral border of the foot is convex (fig. 7 metatarsus adductus associated with an inversion of the foot is named metatarsus varus and adduction of the fi rst metatarsal is metatarsus primus varus. metatarsus adductus is frequently associated with internal tibial torsion. metatarsus adductus associated with retracted equinus -the inability to dorsifl ex at the ankle -is indicative of a diagnosis of clubfoot. dysfunctions of the feet might not seem grave, but left untreated they will lead to postural dysfunctions and compensatory dysfunctions of the feet, with diffi culty wearing shoes and the development of bunions and hammer toes. a group of children with metatarsus varus, followed an average of 7 years, showed that 10% maintained a moderate, although asymptomatic, deformity and 4% demonstrated residual deformity and dysfunction (stiffness). 25 the opinion is that metatarsus adductus left untreated will persist into adulthood in 4-5% of cases. 26, 27 furthermore, some cases only appear to be clinically improved because of a compensatory pronation of the midtarsal joints and rearfoot. 28 metatarsus adductus is classifi ed according to its fl exibility. normally, an infant should extend and abduct the foot when being tickled (e.g. with a toothbrush) along the lateral border of the foot, particularly over the fi fth metatarsal head. the inability of the infant to react in such a way is indicative of metatarsus adductus. the physician should consider the total body approach and treat any dysfunctional mechanics, particularly of lisfranc's joints (tarsometatarsal) following the principles of functional procedures. the parents should be encouraged to stimulate abduction of the forefoot, using a toothbrush or similar stimulus, as described above. in more severe cases it should be proposed that stretching exercises be practiced several times a day (e.g. at each diaper change). the calcaneus is maintained between the thumb and index fi nger, while the forefoot is gently pulled into a corrected position, holding the correction for 10 seconds and repeating the process about fi ve times. it should be stressed that this exercise should be done properly, without creating a valgus of the hindfoot. if these treatments fail, and also in cases of clinical conditions severely rigid feet, a series of casts are used to gradually straighten out the deformity. ctev, or clubfoot, is a complex deformity of unknown pathogenesis with several etiologic hypotheses that range from genetic to intrauterine factors. 29 the head-body angle of the talus (declination angle) which normally increases after the 16th week of gestation has been found to be decreased in ctev, associated with hypoplasia of the talus. 30 more recently, studies indicate that talar deformity is not the primary lesion, but follows loss of spatial orientation of the deltoid and spring ligaments and tibialis posterior tendon insertion, with contracted soft tissues. 31 ctev is a relatively common congenital deformity that occurs with geographical differences ranging from 0.5 : 1000 live births in japan to 7 : 1000 in the south pacifi c (1.2 : 1000 live births among caucasians). 32 about 50% of the cases are bilateral. the male-to-female ratio for affected children is 2.5 : 1. 32, 33 clubfoot deformity presents with different components: hindfoot equinus (inability to dorsifl ex), hindfoot varus and metatarsus adductus. the fl exibility of the deformity is important to determine the degree of severity. classic treatment consists of manipulation of the foot followed by casting. 34 generally, casting is attempted for 3 months; if unsuccessful, surgery is planned. osteopathic procedures should be employed as early as possible for best results. every bone of the hindfoot -the calcaneus, talus, navicular and cuboid bones -should be evaluated and treated to release any dysfunctional relationships between them and to equilibrate the soft tissues surrounding them. the deltoid and plantar calcaneonavicular (spring) ligaments are of particular importance and should be balanced with gentle fascial release procedures. pes cavus, or high-arched or hollow foot, should fi rst make you think of ruling out an underlying neurologic disorder as the primary etiology. anterior pes cavus, where both the medial and lateral longitudinal arches are high, is benign. medial pes cavus is more severe, often with claw foot deformity of the toes. the two may be differentiated by dorsifl exing the foot. in the presence of medial pes cavus the claw foot deformity of the toes increases with dorsifl exion of the foot. the position and range of motion of the hindfoot bones, particularly the talus, should be evaluated. hollow foot is often associated with a fl exionexternal rotation pattern of the craniosacral mechanism. you must differentiate total fl at foot or total hollow foot from partially fl at foot or partially hollow foot. in the latter, only the posterior portion of the longitudinal arch is involved, resulting from an imbalance of the subtalar, calcaneocuboid or cuneocuboid articulation. a rigid pes planus is a pathologic fl at foot, also named tarsal coalition, in which one or more of the tarsal bones that should have a joint between them become fused. in infants the fused joints are cartilaginous and are still relatively fl exible. thus the condition is typically not symptomatic before adolescence. physiologic pes planus is a loss or reduction of the longitudinal arch ( fig. 7.2. 3) that can be reestablished when the child stands on their toes. physiologic pes planus is fl exible and often associated with generalized ligamentous laxity. in a sample of primary school children, 2.7% demonstrated fl at feet, and being overweight was shown to increase the prevalence of the condition. 35 because of ligamentous laxity and/or obesity, the child's ankles cave in. the plantar calcaneonavicular ligament plays an important role in maintaining the arch of the foot ( fig. 7. 2.4). it supports the head of the talus and is part of the astragalonavicular joint. any dysfunction of the plantar calcaneonavicular ligament affects the head of the talus that tends to be displaced downward, medially and forward by the weight of the body. the tibialis posterior, an inversion muscle, lies directly below the plantar calcaneonavicular ligament and participates considerably in maintaining the longitudinal arch of the foot. in cases of dysfunction of these structures, the foot becomes fl attened, expanded and turned laterally. this condition has been suggested as a cause for tarsal tunnel syndrome. 28 it has also been suggested as contributing to back and knee problems later in life, but no evidence supports this contention. flat feet and dysfunction of the spine are, however, very often two components of the same problem, where postural mechanics are involved. flat foot is usually associated with an extension-internal rotation pattern of the craniosacral mechanism. the treatment of physiologic pes planus with orthotic devices is controversial. 36 insole arch supports diminish some of the muscular activity that maintains the arch and tend to weaken the muscles. 35 two studies suggest an association between wearing shoes at an early age and fl at feet. 37, 38 this stresses the importance of allowing the feet to grow and develop without constraint. parents should be reassured about their concerns regarding the child's appearance and gait. this condition tends to improve between 2 and 6 years of age. 39 to promote optimal growth without dysfunctional mechanics, the osteopathic practitioner should consider the global posture of the child. check for rearfoot valgus by assessing the position and freedom of the calcaneus and talus. check also for internal rotation dysfunction of any of the tarsal bones. encourage the child, through their parents, to maintain a healthy lifestyle, to go barefoot as much as possible and not to become overweight. physical activities that strengthen foot inversion, such as walking on the lateral borders of the feet or picking objects with the toes, should be recommended. positional calcaneovalgus, the result of intrauterine malposition, is a fl exible dorsifl exion of the ankle with a mild subtalar joint eversion. it is frequently associated with external tibial torsion and has the appearance of fl at feet. treatment follows the principles of functional procedures to address the subtalar dysfunction. sprains and strains are common in the pediatric population. young athletes are particularly vulnerable. activities that involve jumping and landing, as in skateboarding, often result in such injuries. these injuries are, however, not limited to young athletes. young children can sustain sprains and strains with activities of daily living, such as ascending or descending stairs. these injuries may be overlooked because of the child's tendency to get up and resume activity unless severely injured; however, if not properly addressed, such injuries can be the source of functional asymmetry and somatic dysfunction, often with sequelae in other anatomic areas at a later date. following a foot or ankle sprain that causes excessive or prolonged midfoot pronation, abnormal patellofemoral mechanics may result. 40 traumatic twisting of the forefoot, most often inversion, commonly causes ankle injuries, often resulting in, but not limited to, sprains or strains involving the tibia, fi bula and talus. it should be remembered that these stresses may also result in specifi c dysfunctions between the fi bula and talus, the talus and calcaneus, the talus and navicular bone, and the calcaneus and cuboid, as well as dysfunctions between any of the other adjacent tarsal and metatarsal bones (figs 7.2.5, 7.2.6). on physical examination, the acutely injured ankle presents with pain and swelling and, with more severe injuries, ecchymosis. ecchymosis indicates possible ligamentous tears or bony fracture necessitating radiographic evaluation. further, if the subject is not willing to bear weight on the injured ankle, or if signifi cant edema is present, radiographic evaluation is also appropriate to evaluate the extent of injury. 41 once bony fracture has been ruled out, soft tissue injuries may be treated with osteopathic manipula-tion by employing indirect principles. under these circumstances, the patient should experience no aggravation of discomfort during the treatment procedure and will often feel a signifi cant reduction of pain and swelling following the intervention. posttreatment reduced weight bearing and avoidance of stressful activities should be recommended. immobilization of the injured area with strapping methods should be considered for adolescents and individuals likely to be involved in weight-bearing activities. when there is no more pain for a week, a rehabilitation program can be organized to work the injured ankle in full range of motion with progressive resistance exercises. exercises with a balance board, to strengthen proprioception, function and coordination, are also indicated. the patient places the foot on the board and fi rst does fl exion-extension movements, followed by rotation of the ankle around the ball (fig. 7.2.7) . a thorough history and physical examination should be performed to rule out diagnoses such as cerebral palsy, which can present with rotational misalignment of the legs. internal tibial torsion is said to be the result of intrauterine positioning or from the child's habit of sitting on their feet. this is often noticed by the parents between 1 and 2 years of age and is a common cause of intoeing in children under 3 years of age. internal tibial torsion is more often bilateral; when unilateral, the deformity most commonly affects the left side. 24 parents complain that their child is clumsy, trips and falls easily, although intoeing in athletes has been suggested as benefi cial in activities like sprinting. 42 about 90-95% of all torsional deformities resolve spontaneously by maturity. 43 when it does not resolve, however, dysfunctional rotation results in improper alignment of the lower limb and is associated with arthrosis of the hip, knee and ankle. 44 external tibial torsion is usually diagnosed later and demonstrates a tendency to increase with age. it is associated with conditions of the extensor apparatus as unstable patellofemoral joints and osgood-schlatter disease. 45, 46 examination of rotation of the tibia is best done with the child in the prone position with their knee fl exed to 90°. this allows measurement of the footthigh angle, the angle formed between the long axes of the femur and the foot. the osteopathic practitioner should consider a total body approach with specifi c attention to intraosseous and myofascial tensions in the lower limbs. the relationships between the fi bula and the tibia, as well as between the tibia and the femur and the tibia and the talus, should be balanced. osteopathic procedures directed at functional alignment and balance of the lower extremity improve function and should reduce stressful compensatory patterns that may later result in patellar tendonitis and arthritis. femoral torsion is defi ned by the angle between the femoral neck axis and the transcondylar axis of the distal femur. femoral torsion can be internal (femoral anteversion) or external (femoral retroversion) and results in the knees pointing toward or away from each other, respectively. a normal femur is anteverted, i.e. the femoral head and neck are rotated anteriorly with respect to the femoral condyles. babies have 30° of femoral anteversion. this decreases by about 1.5° per year to reach 10° in adult life. 33 femoral anteversion is also a very common cause of intoeing in children under 3 years of age, the child being obliged to internally rotate the femurs in order to re-center the femoral heads in the acetabula. observation of the child's gait allows one to differentiate between intoeing that is the result of internal tibial torsion as compared to femoral anteversion where the patellae are positioned more medially on the knees. the child trips and falls frequently and does not like to sit with their legs crossed, preferring to sit in a 'w' position (fig. 7.2.8) . parents note that the child's shoes are very quickly worn out in an asymmetric pattern. studies in adults in whom the condition remained uncorrected found a correlation between femoral anteversion and arthritis of the knee. 47 normally, hip range of motion shows greater amplitude in medial rotation than in lateral rotation. abnormal femoral anteversion can be predicted (±2 sd from the mean) if the difference between medial and lateral rotation is 45° or more. 48 the osteopathic practitioner should consider a total body approach and release intraosseous and myofascial tension in the lower limbs. the pelvis should be diagnosed and treated if necessary, as well as the coxofemoral joint. somatic dysfunction of the innominate, particularly during periods of growth, is signifi cant because of the infl uence it can have on the position of the femur. genu varum and genu valgum -also known as bowlegs and knock-knees, respectively -are common angular deformities of the lower extremities in children. all babies are born bowlegged. between the ages of 2 and 3 years the bowlegging gradually decreases, and by 3 years the average child is maximally knock-kneed. the knock-kneeing straightens minimally over the next several years and, by age 7 years, most children have reached the typical adult confi guration, which is slightly knock-kneed. persistent genu varum is better tolerated functionally than valgus, which causes stress to the medial aspect of the knee joint with the subsequent development of pain. the wider the varus or the valgus, the greater the shear stress (lateral-medial forces) on the joint. an angular deformity is not physiologic when it is asymmetric or painful and radiographs might be necessary. bilateral varus is associated with craniosacral fl exion of the sacrum, and bilateral valgus with a sacrum in craniosacral extension. unilateral varus problems are very often associated with fl exion-external rotation patterns on the same side at the level of the pelvis, the temporal bone or the occipital bone. similarly, unilateral valgus problems are associated with extension-internal rotation patterns of these same areas. using indirect procedures from a total body perspective, treatment is directed at specifi cally diagnosed dysfunctional mechanics. the distance between the knees (with the ankles together) of children who have varus, or between the ankles (with the knees together) of children who have valgus, can be measured to follow the response to treatment. the knee can also present minor strains. a commonly found pattern occurs when an increased medial femoral torsion is combined with excessive lateral torsion of the tibia. this is found more often as the result of physical activities, such as in skiing, when the ski is stuck in the snow, slightly abducted, and the rest of the body moves forward. the relationship between the tibia and the femur should be balanced to address these strains. congenital dislocation of the patella is rare and may be isolated or associated with other limb malformations. 49 patellar instability is not a congenital condition, although anatomic confi gurations such as patella alta, trochlear dysplasia and ligamentous laxity are thought to participate in the instability. mri permits visualization of the nonosseous components of the patellofemoral articulation in the child. the cartilaginous composition of the articulation provides less restraint to lateral movement of the patella that allows instability. 40 the trilaminar soft-tissue structures 50 surrounding the patella present interconnections with the fi bers of the iliotibial tract, lateral hamstrings and lateral quadriceps retinaculum. tightness in these structures has been suggested as causing excessive posterior and lateral pull, contributing to patellar instability, especially if the medial patellofemoral ligament is injured and cannot stabilize the knee. 40 these structures are linked to the pelvic bone, and recurrent dislocation of the patella can be associated with pelvic dysfunctions that interfere with the balance transmission of weight-bearing forces. osgood-schlatter disease occurs mainly in athletic adolescent boys. it is suggested that a welldeveloped and inelastic quadriceps creates a traction apophysitis on the tibia, with the development of loose ossicles and elongation of the patellar ligament leading to patella alta. 51 patients with osgood-schlatter disease also present with increased external tibial torsion that, in association with other factors, has been suggested to predispose to the onset of the disease. 46 the osteopathic practitioner will consider a total body approach and release the pelvis, the hips, the knees and the patellofemoral articulations ( fig. 7. 2.9). myofascial release should be considered for the thigh and patella. gentle and pain-free stretch-ing exercises should be done at home on a regular basis and should address tension in the quadriceps, the upper and lower iliotibial tract, the hamstrings, the hip fl exors, the hip abductors, the gastrocnemius and the soleus. a long-term maintenance program should include strengthening in terminal knee extension in association with isometric exercises of the above muscles. patellar knee sleeves are sometimes useful. they might have proprioceptive effects offering support. patients feel less pain and the support provides some kind of reassurance. different terms describe hip dysfunctions. 'developmental displacement of the hip' (ddh) is proposed in replacement for 'congenital dislocation of the hip' to stress the fact that the condition can occur prenatally or postnatally. 52 the different variants of the abnormalities of the hip joint include shallowness of the acetabulum and capsular laxity with resultant instability and propensity for dislocation. ddh refers to a defi cient development of the acetabulum that could lead to subluxation and dislocation. the femoral head remains well covered by the acetabulum in the early fetal period (between 6 and 20 weeks) and dislocation does not occur at this early time. 53 however, at birth, the human acetabulum is shallower than at any other time during development and is consequently vulnerable for hip instability. 54 mechanical factors seem to play a role in neonatal hip instability. moderate loading of the hips at 45° of fl exion maintained for 3 hours has been shown to distend the articular capsule and to produce deformation and dislocation of the joint resembling that found in ddh. 55 modifi cations in the pressure on the cartilaginous acetabulum are thought to interfere with normal bone growth. 56 uterine constraint is proposed by numerous authors as an explanation for the association between ddh and other deformations. foot deformity, 57 congenital torticollis, congenital postural scoliosis 56, 58 and plagiocephaly 59 are frequently associated with ddh. the sleeping position of the infant, with a preference to lie on one side (the 'side-lying syndrome'), has also been proposed as a contributing factor to ddh. 60 leg postures, associating extension and lateral rotation, critically predispose the infant to hip dislocation during fetal life and at birth. interestingly, the newborn psoas muscle is totally relaxed in full abduction, fl exion and lateral rotation. this muscle is always a lateral rotator of the hip, but exerts a much greater effect when the femur is abducted. 61 extending the hip results in a levering action that is potentially critical if associated with other contributing factors such as acetabular or femoral ante-version and dysplasia. 62 caution should, therefore, be exerted when moving the leg into combined extension and lateral rotation. ddh occurs in 1 : 1000 live births and is more frequently encountered on the left side. being female, fi rst-born, having been carried or delivered in the breech position 57,63,64 and having a family history of acetabular dysplasia or ligamentous laxity are the main risk factors. 60 dislocation of the hip requires orthopedic attention. clinical examination reveals asymmetries in the number of skin folds on the thigh and the inability to completely abduct the thigh when the knee and hip are fl exed. the malposition of the femoral head may cause the leg on that side to look shorter than the other. barlow and ortolani positive tests confi rm the diagnosis and are performed with the child supine on a fl at pad, placing the fi ngers on the baby's greater trochanters and the thumbs on the inside of the lower portion of the thighs and knees. the hips and knees are fl exed to 90°. the barlow test consists of adducting the legs and pushing down gently on the knees in an attempt to disengage the femoral head from the acetabulum. a 'clunk' will be felt as the femoral head dislocates. the ortolani test relocates a dislocated hip and is performed by slowly abducting the thighs while maintaining axial pressure. the fi ngers on the greater trochanter exert a movement in the opposite direction to assist the return of the femoral head to the acetabulum. the examiner will again feel, and hear, a 'clunk.' diagnostic ultrasonography may be carried out after 4-6 weeks and radiographs after 4-6 months; before these ages there is insuffi cient ossifi cation for the tests to be diagnostic. different methods of treatment are proposed for ddh, with good results. abduction devices (pavlik harness) and traction followed by plaster immobilization are always done with special care because of the risk of aseptic necrosis of the femoral head. a program of home abduction-adduction exercises administered by the parents has been successful in infants with limited abduction and acetabular dysplasia without dislocation. 57 developmental dysplasia of the hip -insuffi cient depth of the acetabulum to accommodate the femoral head -in the infant can be associated with pelvic imbalance, such as intraosseous dysfunction of the innominates and sacrum, coxofemoral dysfunctions and eventually with craniosacral dysfunctions. the innominate bone needs to be in a neutral position in order to provide a satisfactory acetabular placement. an internally rotated innominate results in a higher position of the acetabulum, leading to an apparently shorter leg on that side. this can be confused with the apparent inequity of leg length found in association with hip dislocation. osteopathic procedures attempt to balance the craniosacral mechanism of these children. the relationship between the sacrum and the occiput, the temporal bones and the innominates should be balanced. special care is given to myofascial structures responsible for pelvic tensions or pelvic asymmetry. myofascial procedures should be applied to the periarticular muscles of the hip, in particular the iliopsoas, the adductors and the abductors, to release contracture of the joint and improve restrictions of motion in adduction or abduction. the treatment of dysplasia is intended to stabilize the femoral head in the acetabulum and to allow the growth of a symmetric pelvis with a balanced sacrum, innominates and hips. dysfunctional interosseous relationships between the sacrum and the innominates, and between the innominates and the femurs, should be identifi ed and treated. any dysfunctional intraosseous relationship between the ilium, ischium and pubes should be also balanced, and, if present, intraosseous dysfunction of the sacrum treated. clinical examination of these children should be repeated during the 1st year, with an annual follow-up, until full skeletal maturity. dysplasia may result in early development of osteoarthritis of the hip. [65] [66] [67] [68] treatment should be directed at promotion of function and prevention of future degenerative changes. by the age of 4 years children should be walking with a heel-toe gait. after this age, toewalking is abnormal and can be due to an underlying neurologic disorder. a tight achilles tendon may be present, but in other cases nothing will be found. look for any extension dysfunction of the craniosacral mechanism. balance the sacrum and the craniocervical junction. release the posterior myofascial components of the spine and inferior limbs. teach the child to walk heel-toe. because serious medical and orthopedic conditions may be responsible for limping, any such underlying pathology should be ruled out before using manipulation as a primary treatment. for example, a limp or a waddling gait between the ages of 2 and 6 years might be associated with a congenital coxa vara, where the angle between the femoral neck and the femoral shaft is less than normal (<130°). coxa valga is an increase in that angle (>135°) and, in this case, the child may present with increased internal rotation and adduction of the hips. observation of the child while walking allows one to determine what area is dysfunctional. it is better to have the child bare legged to best visualize the different components of the lower extremity. observe the foot angle, the direction in which the child's feet point when they walk. observe for tibial and femoral torsions and the movements of the hips. determine which part is not following the global movement of the limb or if one side does not contact the fl oor in the same fashion. the postural balance should be evaluated and any dysfunctional asymmetries treated. an asymmetry of leg length might be present as the cumulative result of several dysfunctions. for example, an innominate in external rotation on the right side, combined with an innominate in internal rotation on the left side, will give the appearance of a longer leg on the right side. evaluate the range of motion of the different joints of the lower limbs and, utilizing appropriate manipulative procedures, treat any dysfunction identifi ed. otitis media (om) is among the most common of illnesses affecting preschool children. 1 almost every child experiences om at least once before their third birthday 2 and 20% of children experience recurrent om. 3 its prevalence has increased considerably recently, resulting in an enormous economic burden to society. 4 clinical classifi cations include acute otitis media (aom) and chronic otitis media with effusion (come). aom is a viral or bacterial infection, commonly secondary to an upper respiratory infection and usually occurring in young children from the age 3 months to 3 years. it presents with a sudden infl ammation in the middle ear, fever, pain and irritability. an incomplete resolution of aom or an obstruction of the pharyngotympanic tube (pt), also called the eustachian or auditory tube, may lead to an effusion in the middle ear containing common pathogenic bacteria. repeated episodes of acute symptoms are considered to be recurrent aom. come is a chronic infl ammation of the middle ear mucosa, with the retention of fl uid within the middle ear space that lasts more than 3 months. it is a condition wherein irreversible changes have occurred, affecting the tympanic membrane, the pt or the middle ear. the multitude of studies attempting to identify the causative factors of om have provided multiple, and often opposite, results. this is probably because the etiology of individual cases of om is often multifactorial, including genetic, environmental, nutritional and behavioral factors. thus, the number of variables necessary for consideration makes such studies extremely diffi cult. the following have, however, been identifi ed as risk factors for the onset of om: genetic predisposition, 5,6 low birth weight, 7 male gender, 8 number of siblings, 9 day-care attendance, 10 not being breastfed, 1 use of a pacifi er, 11, 12 season of the year, 10,13 passive exposure to smoking 14 and low socioeconomic status. 15 on the other hand, breastfeeding, even for periods as short as 3 months, has been shown to reduce the incidence of om in childhood. 16 anatomic factors should also be considered. the ear, particularly the middle ear, and adjacent structures provide a site where genetic, environmental, nutritional and behavioral factors can interact, resulting in the development of om. the three parts of the ear -external, middle and internal ( fig. 7. 3.1) -are related anatomically and functionally to the temporal bone. the external ear consists of the auricle (pinna) and external acoustic meatus. the auricle on the lateral aspect of the head, at the level of the temporal bone, refl ects the global position of the temporal bone. a protruding auricle, for example, are often associated with external rotation of the homolateral temporal bone. the auricle functions to collect sound waves. the external acoustic meatus terminates in the tympanic membrane. its lateral part is membranous, continuous with the auricle. the medial part is surrounded by the squamous portion of the temporal bone above and the tympanic portion in front and below. the middle ear or tympanic cavity, an air-fi lled space, is located between the tympanic membrane laterally and the lateral wall of the internal ear medially. it contains three bones, or ossicles -the malleus, incus and stapes -that transmit vibrations from the tympanic membrane to the cochlea of the internal ear. the tympanic cavity is open posteriorly to the mastoid antrum, an air sinus located in the petrous portion of the temporal bone, and to the interconnected mastoid air cells. anteriorly, the tympanic cavity communicates with the nasopharynx through the pt. a mucosa covers the complete cavity, including its contents, the three ossicles and the two muscles (tensor tympani and stapedius), and forms the inner layer of the tympanic membrane. this mucosa is in continuity with that of the pharynx. the mastoid cavity, mastoid antrum and auditory ossicles are nearly completely developed at birth. the internal ear consists of several bony cavities, the vestibule, the semicircular canals and the cochlea that form the bony labyrinth. it contains the membranous labyrinth with the organ of hearing (the cochlear duct) and the organs of balance (the semi-circular ducts). the membranous labyrinth fl oats in the perilymph, the fl uid fi lling the bony labyrinth. the structures that form the internal ear are also nearly completely developed at birth. most of the above structures of the ear can be found nesting within the petrous portion of the temporal bone. in diseases of the ear such as om, as well as in balance and hearing disorders, this anatomic relationship confers great signifi cance on the temporal bone and its function and dysfunction. the temporal bone is formed by the squamous, petromastoid, tympanic and styloid parts. the petromastoid part develops in the cartilaginous otic capsule of the cranial base. the squamous and the tympanic portions are ossifi ed from mesenchyme. the tympanic portion (the tympanic ring) unites with the squama just before birth. 17 total fusion of the temporal bone, except the distal part of the styloid, is complete by the end of the 1st year. nevertheless, the mastoid portion is completely fl at at birth. the mastoid process, a postnatal petrous development, begins to develop with the growth of the mastoid air cells and because of the traction from the tendon of the sternocleidomastoid (scm) muscle. the development of the mastoid process is dependent on the child's ability to lift their head (extend their cervical spine) and to rotate their cervical spine symmetrically. for this reason the prone position, recommended in the statement 'back to sleep, prone to play' is important. in this case, function determines structure, and children with torticollis will present with asymmetry in the shape and size of the mastoid processes. alternatively, infants with non-synostotic plagiocephaly may present with a fl attening in the area of the occipitomastoid suture, where compressive forces inhibit mastoid development. the expansion of the mastoid process is of particular signifi cance. the mastoid air cells that develop inside the mastoid during the growth period are important components of the complex system that regulates and buffers the fl uctuations of middle ear pressure. 18 the volume of the mastoid air cells is about 20 times the volume of the tympanic cavity. often compared to an air reservoir, the mastoid cavity is an active space for gas exchange through its submucosal capillary network 19 the submastoid cell structure in humans is histologically similar to that found in the pulmonary alveolar and nasal membranes, and, therefore, is suitable for gaseous effusion and diffusion. the production of gas within the tympanomastoid cavity keeps the internal pressure at the same level, or higher, than atmospheric pressure. 20 swallowing allows gas to be expelled through the pt into the pharynx. this positive pressure gradient prevents bacteria from entering the tympanomastoid cavity. 20 the depth of the mastoid air cell system has been found to be shorter in children with secretory om compared with healthy individuals. 21 decreased mastoid pneumatization has been proposed as a prognostic indicator for chronic infl ammation of the middle ear, as has poor outcome with om when the mastoid is poorly pneumatized. 22 the mastoid cells connect to the tympanic cavity and through the pt to the nasopharynx. both mastoid cells and pt are of paramount importance in the normal function of the ear and, consequently, the pathogenesis of om. the pt connects the middle ear to the nasopharynx, balances pressure between the middle ear and ambient air, clears debris and secretions toward the nasopharynx and also protects the middle ear against nasopharyngeal secretions and noxious agents from the airways. it begins on the anterior wall of the tympanic cavity and extends forward, medially and downward to the nasopharynx posterior to the inferior meatus of the nasal cavity (figs 7.3.3, 7.3.4). because of these close relationships between the middle ear and the nasopharynx, om, frequently described as a complication of rhinitis, may be considered to be a disease of the upper respiratory tract. descriptive and functional anatomy of the nose and nasopharynx is discussed in 'rhinitis' and 'sinusitis' below. the pt is shaped like two cones joined together at their apices. the posterolateral cone, shorter, approximately one-third of the pt, is osseous (protympanum), located inside the petrous temporal bone. it ends at the junction of the petrous and squamous parts of the temporal bone, immediately posterior to the foramen spinosum. the remaining two-thirds of the pt are fi brocartilaginous, partially fi xed to the cranial base, in a furrow following the sphenopetrosal synchondrosis, between the petrous portion of the temporal bone and the posterior border of the greater wing of the sphenoid. the upper border of the cartilaginous pt is arched laterally and looks like a hook on transverse section. a fi brous membrane completes the tube. the tubal isthmus, where the pt diameter is smallest, joins the two cones of the pt. the cartilaginous portion has a greater vertical inclination than the osseous portion. the length of the pt in the adult is approximately 35-45 mm. the pt in the newborn is approximately half its adult length and reaches approximately 98% of its adult length by 7 years of age. the ratio of the length of the cartilaginous and junctional portions of the pt to the length of the bony portion is 8 : 1 in infants and 4 : 1 in adults. 23 the pt in infants is not only shorter, it is also more horizontal, and, therefore, the clearance function is less effective. additionally, when the bony portion of the pt of children with secretory om is compared to that of healthy children, it is found to be even shorter. 21 the pt connecting the middle ear and nasopharynx has been compared to the bronchial tree connecting the lung to the nasopharynx. 8 the mucosal lining of the pt contains mucus-producing cells, ciliated cells, 24 infants and children demonstrate an increase in the density and size of the folds in the tissues lining the pt and it has been suggested that this plays a role in protecting the middle ear. 25 the gas exchange through the submucosal connective tissue seems to be accelerated when the submucosal vasculature dilates and blood fl ow is augmented due to middle ear infl ammation. alternatively, gas exchange can be diminished when the mucosa thickens and submucosal tissue proliferates due to extended infl ammation. 26 in normal tubal function at rest, the pt is usually collapsed, fulfi lling its protective role against retrograde infection from the nasopharynx. 27 the tensor veli palatini (tvp), the dilatator tubae (dt), the levator veli palatini (lvp) and the salpingopharyngeus muscles are all attached to the pt. the tvp arises from the scaphoid fossa, from the spina angularis of the sphenoid and from the lateral wall of the cartilage of the auditory tube. it then descends verti-cally, becomes tendinous and inserts onto the pterygoid hamulus, the lower extremity of the medial pterygoid plate of the sphenoid, and medially onto the posterior border of the hard palate to form part of the palatine aponeurosis. the dt is attached above to the pt, particularly to its membranous portion. it intermingles below with the tvp and rounds the pterygoid hamulus. most authors agree that contraction of the tvp opens the pt lumen and therefore ventilates the middle ear; 24,28 this action is particularly signifi cant for the fi bers of the dt. 29 the lvp arises from the medial lamina of the cartilaginous pt and from under the apex of the petrous portion of the temporal bone. it extends into the palatine velum, its fi bers broadening to the middle line, where they blend with those of the opposite side. the salpingopharyngeus arises from the inferior part of the pt, is directed downward and blends with the posterior fasciculus of the pharyngopalatinus ( fig. 7 open it -for example, swallowing, crying or yawning. this balances the pressure gradient between the atmosphere and the tympanic cavity. when the mechanism of swallowing is dysfunctional, opening of the pt is not effi cient. sustained collapse follows with the development of negative middle ear pressure and retraction of the tympanic membrane. the subsequent potential for aspiration of nasopharyngeal secretions into the middle ear may result in om. furthermore, dysfunctional swallowing may also cause gastroesophageal refl ux, another risk factor for om. in addition, if present, the frequent use of a pacifi er may encourage infantile deglutition, i.e. forward tongue thrust when swallowing. although the use of a pacifi er does not increase the incidence of respiratory infections, there is evidence that constant use affects the occurrence of aom, possibly because of alteration in the pressure equilibrating function of the pt. 12 dysfunction of the pt may result in negative middle ear pressure that, in turn, impairs auditory sound conduction to the cochlea of the internal ear affecting hearing. pt dysfunction can also affect hearing through its impact on the tensor tympani muscle. the tensor tympani muscle is continuous with the tvp. it arises from the cartilaginous portion of the pt and the adjoining sphenoid, and inserts on the manubrium of the malleus. 24, 29 tensor tympani contraction draws the malleus medially, increasing tympanic membrane tension while pushing the incus and stapes medially against the fenestra vestibuli. this results in an increased intravestibular pressure that, under normal circumstances, serves to dampen violent noises. consequently, dysfunction of the pt may be associated with both negative middle ear pressure and spasm of the tensor tympani with resultant disturbance of hearing. anatomic developmental delays such as immaturities of the pt and surrounding structures or of the neuromuscular system may result in dysfunctional opening of the pt in infants and children. 30 most of the time, the dysfunctional opening of the pt improves with age as the base of the neurocranium and the viscerocranium develop. this too, however, can contribute to the complex interaction of phenomena that predispose the child to develop om. the base of the skull (figs 7.3.6, 7.3.7) goes through signifi cant developmental changes during the fi rst years of life. two critical phenomena participate in this development. first, the diverse stimulation produced by normal orofacial functions, such as suckling and swallowing, spurs the growth of structures, particularly the pterygoid processes in which the involved muscles insert. secondly, but concomitant with the above, the progressive fl exion of the cranial base, associated with the anteroposterior growth of the skull, contributes to positional changes of both the pterygoid processes, which become longer and more vertical, and the petrous portions of the temporal bones, which become externally rotated. additionally, several changes occur in the viscerocranium, such as the increase in height of the vomer that accompanies the expansion of the nasal cavity. these developmental changes are concomitant with the development of the pt and its associated muscles. therefore, any structural imbalance that develops in association with the development of the base of the skull or viscerocranium may adversely affect the ventilation and drainage of the ear. a dysfunctional tongue posture may affect the tongue's pumping function on the palatine aponeurosis and, therefore, the associated pt ventilation that occurs during swallowing. tongue posture adapts to oral development and pt function appears to be diminished in long-faced adenoidal children. 31 additionally, children with signifi cant overbites are found to be more predisposed to develop pt dysfunction. 32 body position also seems to infl uence pt opening. evidence shows a correlation between the lateral recumbent position, where one ear is positioned downwards, and a lower pt opening function on that side. 20 this reinforces the need to avoid the repeated use of the same sleep position for infants. any cranial somatic dysfunction of the base of the skull may disrupt its developmental sequence as well as affecting tongue posture, with resultant impact on pt growth and function. this may be a cranial somatic dysfunction of the bony constituents of the cranial base, the occiput, sphenoid and temporal bones, or dysfunction of any component linked to the vascular supply and innervation of the myofascial structures involved in suckling and swallowing. the tvp and the tensor tympani are innervated by branches from the otic ganglion, located immediately below the foramen ovale, on the medial surface of the mandibular nerve (cn v 3 ). the glossopharyngeal nerve (cn ix) innervates the stylopharyngeus, and the accessory nerve (cn xi) innervates the palatal muscles through the pharyngeal plexus. they both exit the skull through the jugular foramen. the hypoglossal nerve (cn xii) innervates the intrinsic and extrinsic tongue muscles. it exits the skull through the anterior intraoccipital synchondrosis, the site of the hypoglossal canal of the occipital bone when ossifi cation occurs. consequently, effi cient pt function requires equilibrium among surrounding bony structures, such as the temporal bones, occiput, sphenoid and mandible. it also requires that associated myofascial structures be free of dysfunction. a dysfunctional pt creates a terrain where other risk factors are reinforced. recurrent bilateral om with effusion develops when poor pt function is allied with diminished immune status. 33 the allergic infl ammatory response that often occurs in the nasopharynx also occurs in the middle ear, 34 and the prevalence of allergic rhinitis is signifi cantly higher in children with om with effusion than in healthy children. 35, 36 the allergic infl ammation in atopic children is not localized in one area only, but manifests itself in the middle ear on both sides, as well as in the nasopharynx, demonstrating totally the united airways concept. 37 mucosal infl ammation with release of histamine and other mediators following nasopharyngeal exposure to an allergen may, consequently, be responsible for pt obstruction and dysfunction. chronic allergic infl ammation of the upper airway may lead to lymphoid hypertrophy with increased size of adenoidal and tonsillar tissue. 38 in such a case, with edema and infl ammation of the posterior nasopharynx, the enlarged adenoids may obstruct the pharyngeal ostium of the pt. tubal tonsil hypertrophy is a possible etiology for om, when recurrence appears after adenoidectomy. 39 the pt mucociliary apparatus contains components that have an important role in eliminating middle ear debris by moving it toward the nasopharyngeal orifi ce. additionally, specialized epithelial cells express and secrete surface-active materials that appear to facilitate the muscular action of the pt opening and to protect the middle ear against infections. 3 conversely, many viruses impair the mucociliary function of the pt epithelium and perturb the nasopharyngeal bacterial fl ora, increasing the adherence of bacteria to the epithelial cells. 40 bacteria and respiratory viruses (e.g. the respiratory syncytial virus or infl uenza viruses) are common causes of middle ear infection. [40] [41] [42] because of the connection between the upper and lower airways, the pathophysiologic site of origin is frequently the nasal pathway. babies born in the fall begin their lives during the peak seasons for viral exposure and the development of respiratory infections, a risk factor for om. 13 additionally, impaired or decreased nasal mucociliary activity may also cause pt mucociliary dysfunction. 43 thus osteopathic procedures that facilitate the clearance of secretions and the mucociliary action of the pt and upper airways are indicated. blood fl ow to the region should also be improved. gastroesophageal refl ux may also predispose to bacterial infection. 44 possibly because of refl ux, infants fed in the supine position demonstrate abnormal postfeeding tympanographic results compared to infants fed in the semi-upright position. 45 signs of aom include fever, insomnia and the presence of pus in the middle ear with a tympanic membrane that appears bulging and erythematous when observed by otoscopic examination. ear infections may be painful, causing irritability, rubbing of the affected ear, loss of balance and impaired hearing with lack of response to moderate sounds. although it is generally thought that om causes permanent hearing loss, this has not been demonstrated. 46 transient mild to moderate hearing loss associated with om has, however, been shown to cause delays in communicative development. 47 osteopathic considerations for the treatment of om are directed at augmenting the body's defenses against infection and its recuperative power after infection is present. mainstream medical interventions are often fraught with controversy. because the infectious agents responsible for om are both viral and bacterial, antibiotic therapy, although appropriate for bacterial infection, is not universally effective. guidelines for determining when to employ antibiotics and other modalities are available. 2, 4, 48, 49 the use of tympanostomy tubes is controversial. 50, 51 consequently, non-toxic interventions like osteopathic treatment, which appear to reduce the need for antibiotics, have been shown to be of potential benefi t as adjuvant therapy for children with recurrent aom. 52 diagnosis should begin with observation. start with an overall evaluation of the child's posture. look at the pectoral girdle, often protracted in patients with ent infections. observe the cervicothoracic junction, the cervical spine and its relationship to the skull for lack of mobility and vertical compression. these patients may demonstrate a shrugged shoulder posture, with the appearance of a shortened neck. observe the auricles of the ear bilaterally for deformity, asymmetry of position and relative external or internal rotation. the appearance of the ear follows the temporal bone which, in turn, affects the function of the pt. examine the parietomastoid and occipitomastoid sutures bilaterally. look for fl attening or compression of the area. because ear position refl ects temporal bone position, asymmetry of the ears is often associated with asymmetry of cranial shape. non-synostotic plagiocephaly has been shown to be associated with an increased incidence of om. enquire if the child repeatedly pulls at one ear. this will often occur on the side of compression of the parietomastoid and occipitomastoid suture. study the face. open mouth facies are indicative of mouth breathing and nasal obstruction, predisposing to om. diagnosis and treatment of dysfunction in this area is discussed in part 7.4, 'mouth breathing'. next, perform a palpatory examination. begin by evaluating the upper thoracic spine, ribs and pectoral girdle for somatic dysfunction. the viscerosomatic refl exes from the upper respiratory tract, including the ear, are to be found at level of t1-t4. somatic dysfunction in this area results in increased sympathetic tone with vasoconstriction affecting the ears, nose and throat through somatovisceral refl exes. mechanical dysfunction of the upper thoracic spine (t1 and t2), associated ribs, sternum and clavicles impairs lymphatic drainage from the head and neck. further evaluate the remainder of the thoracic cage and thoracoabdominal diaphragm which, when dysfunctional, can also impair lymphatic circulation. utilizing indirect principles, treat any dysfunction identifi ed in the above areas. examine the cervical region for somatic dysfunction. pay particular attention to the occipitoatlantal and atlantoaxial articulations, to the myofascial structures for their relation to lymphatic nodes and vasculature, and to the scm muscles that, when dysfunctional, impact the function of the temporal bone. treat any identifi ed dysfunction. evaluate the skull. begin by assessing the cranial base, paying attention to the sphenobasilar synchondrosis and temporal bones. the articulations of the temporal bones should be examined. the occipitomastoid sutures are important for their impact on the contents of the jugular foramen: cranial nerves ix, x and xi. the petrobasilar suture and sphenopetrosal synchondrosis are often dysfunctional in the infant's skull. dysfunction of these articulations may affect the petrous portion of the temporal bone containing the osseous part of the pt. furthermore, the cartilaginous portion of the pt is located beneath the sphenopetrosal synchondrosis and free motion of the petrous portion of the temporal bone, in external and internal rotation, facilitates the clearance of secretion from the pt. next, evaluate the temporal bones for intraosseous dysfunctions between the petrous, squamous and tympanic portions. palpate for the cranial rhythmic impulse (cri) at the level of the mastoid. intraosseous mastoid cranial respiration may promote mastoid cell function. examine the relationship between the mandible and the temporal bones. there is usually tenderness in the area. any temporomandibular dysfunction can affect the mobility of the temporal bones and the myofascial structures of the anterior neck below. the pt is commonly cleared by the actions of swallowing and yawning. these actions can be impaired by dysfunction of the mandible and its relationship to the tongue and soft palate. treat identifi ed dysfunction. specifi c attention should be paid to the effi cient clearance of secretions from the pt and mastoid cavities. this activity may be stimulated by the mastoid pump procedure and the galbreath technique. when possible, the rate and amplitude of the cri should be monitored during the above procedures. following the cri during the mastoid pump enhances the effi cacy of the procedure. the specifi c treatment of cranial dysfunctional patterns will augment the amplitude of the cri, improving fl uid mobility and affecting low frequency oscillations in autonomic nervous system (ans) physiology. counsel the caregivers to maintain a healthy lifestyle for the child. maintain a regular sleep-wake cycle. provide a balanced diet with adequate hydration and avoiding refi ned carbohydrate as much as possible. bottle feed and nurse in a semi-upright position and never put the infant to bed with a bottle. as much as possible, limit pacifi er use to moments when the infant falls asleep and try to eliminate its use after the age of 6 months. avoid exposure to passive smoke. when bathing the infant, limit the amount of water entering their ears. caregivers should be instructed to lay the child on their side, with the problem ear up. they should then massage the mandibular region, applying gentle skin traction from the area anterior to the ear in the direction of the chin. this tends to open the pt and the position employs gravity to facilitate drainage. they can also gently caress around the ear, particularly over the mastoid region. these actions allow the caregiver to actively participate in the child's recovery. they sensitize the caregiver to the health status of the child and promote relaxation for the child. encourage the caregiver to play with the child in a fashion that promotes mimicry of the production of sounds in the throat and the clicking of the tongue by pulling it quickly from the hard palate. all activities encouraging action of the myofascial structures connected to the pt will tend to open it and facilitate its drainage. rhinitis is the infl ammation of the nasal mucous membranes. acute rhinitis may be the consequence of a viral infection, whereas allergic rhinitis is caused by an immune-mediated response to any one or more of a myriad of allergens. other classifi cations include atrophic rhinitis and vasomotor rhinitis. although these conditions are the result of differing etiologies, they are all affected by the presence of somatic dysfunction. it is an established osteopathic dictum that the body possesses the inherent ability to heal itself. the presence of somatic dysfunction can predispose the individual to develop rhinitis or interfere with the body's recuperative mechanisms. knowledge of the anatomy and physiology of the nasal cavities and the mucosa lining their walls is absolutely necessary to understand the etiologies of nasal dysfunction and how osteopathic principles may be applied to promote health in this area. the nose is divided by the nasal septum into two cavities, or fossae. the two nasal cavities open anteriorly by way of the anterior naris, or nostril. they are continuous posteriorly by way of the posterior nasal apertures, or choanae, into the nasopharynx. the nasal septum represents the medial wall of each nasal cavity. it is formed by the perpendicular plate of the ethmoid, the vomer and the septal cartilage ( fig. 7.3.8) . the roof of the nasal cavities is formed anteriorly by the nasal spine of the frontal bone and the two nasal bones. the cribriform plate of the ethmoid, with numerous perforations for the olfactory nerves, is located behind the nasal bones. more posteriorly, the anterior aspect of the body of the sphenoid causes the roof of the nasal cavities to slope downward. the sphenoidal sinuses open into the nasal cavities from above, on each side of the nasal septum ( fig. 7. 3.9). the fl oor of the nasal cavities is the upper surface of the osseous palate. the maxillary palatine processes form the anterior two-thirds, while the palatine horizontal plates form the posterior one-third ( fig. 7. 3.10). the lateral walls of the nasal cavities demonstrate numerous structures. they are formed anteriorly by the maxilla, posteriorly by the palatine bone and superiorly by the ethmoid labyrinth and lacrimal bone. the inferior, middle and superior nasal conchae (turbinates), the most central portion of this lateral wall, by virtue of their curled shape add a great amount of surface area to the nasal cavities. the space below each turbinate is referred to as a meatus (fig. 7.3.11) . the nasal vestibules, just inside the nares, are the anterior-most aspect of the nasal cavities. the nares and vestibules are bounded laterally by the alar and lateral cartilages, and medially by the cartilaginous septum and the connective tissue septum, the columella (fig. 7.3.12) . the vestibule is lined with skin that contains sebaceous and sweat glands and coarse hairs (vibrissae) that assist in air fi ltration. the nasal cavities are completely covered with a lining that varies histologically in different areas. at the anterior part of the nasal cavities, in the vestibules, the lining is continuous with the facial skin. above, at the level of the upper border of the alar cartilages, the limen nasi defi nes the beginning of a lining formed by a non-keratinizing stratifi ed squamous transitional epithelium that evolves further into a pseudostratifi ed ciliated epithelium, the respiratory mucosa. this mucosa covers the remaining surface of the nasal cavities, except for the olfactory area that is covered with olfactory epithelium. this mucosa is also present in many other parts of the upper respiratory tract. several additional cavities communicate with the nasal cavities and demonstrate a continuum of the nasal respiratory mucosa. each of the nasal cavities communicates directly with the nasopharynx below, the nasopharynx continues to become the oropharynx, the laryngopharynx and the esophagus. the mucous membrane of the pharynx is continuous with that lining the mouth and larynx, as well as, through the trachea and bronchi, into the lungs. this continuum is a perfect example of the interrelationship between the different structures of the human body and exemplifi es the concept of the body as a unit. the respiratory mucosa plays a signifi cant part in the physiology of the nose, as well as in its pathologies, as is the case in rhinitis. the mucosa acts as a selective barrier, essential for the defense of the airways against inhaled pathogens. the respiratory pseudostratifi ed ciliated epithelium is formed by ciliated columnar or cuboidal epithelia with goblets cells, non-ciliated columnar cells and basal cells. mast cells and migrating lymphocytes, mainly t cells, are also present. under the basal lamina of this epithelium, the submucosa is adherent to the periosteum of the adjacent cranial bones and includes a fi brous layer with diffuse lymphoid tissue and a layer of mucous, seromucous and serous glands. an abundant mucous fi lm is produced by these glands and by the goblets cells. additional plasma exudation may occur, particularly in the presence of infl ammatory states. this fi lm gathers the particles and debris from the air that is inspired to sweep them away. almost all particles greater than 5 μm and about 50% of those between 2 and 5 μm are collected. they end up either in the nasopharynx and oropharynx to be periodically swallowed, or in the anterior nasal vestibules. mucociliary clearance depends on the beating function of the respiratory cilia. they beat about 1000 times per minute. 53 the frequency of the mucociliary transport rate is subject to various infl uences, such as mucus viscoelastic properties, airway epithelia alkalization that appears to be a stimulator or airway epithelia acidifi cation that decreases the rate. 54 healthy function of the respiratory cilia results in constant motion of the mucous fi lm. the nasal ciliary beating propels the mucus secretions posteriorly in the direction of the nasopharynx. conversely, dysfunction of the drainage of the nasal respiratory epithelium leads to stasis and the accumulation of secretions within the nasal cavities. cranial somatic dysfunction -particularly of the frontal bones, sphenoid, ethmoid, maxillae and vomer, with resultant loss of their inherent motility -is a possible cause of mucociliary stasis. septal deviations are known to infl uence the dynamics of the nasal cavity and are often associated with a 'stuffy' nose. histologic studies confi rm this observation. loss of cilia, increased infl ammation and decreased density of the glandular acini are reported affecting the mucosa on the concave side of the septal deviation. 55 the vasculature of the respiratory epithelium contributes signifi cantly to the function and dysfunction of the nasal cavities. the nasal mucosa contains a profuse subepithelial capillary network that supplies nutrients and water that through its evaporation contributes to the conditioning of inspired air. the vascular supply also includes a number of different capacitance vessels, i.e. the veins, venules and cavernous sinusoids that modulate blood fl ow. constriction and relaxation of these sinusoid vessels produce shrinkage or swelling of the mucosal surfaces that consequently regulates airfl ow and alters nasal patency. most of the venous cavernous sinusoids are located on the inferior conchae, major sites for nasal congestion. air conditioning is a major function of the nose. on inspiration, the air contacts the nasal mucosa and is brought to the appropriately conditioned temperature and humidity. by virtue of their contour, the conchae, located on the lateral walls of the nasal cavities, provide an increased surface area for the fl owing air to be in contact with the nasal mucosa. during expiration, some of the heat may be returned to the mucosa. when an individual is in a setting of 23°c, the nasal cavities warm the inspired air to 33°c. 56 the air is also humidifi ed and this allows gas exchange within the alveoli of the lungs that takes place at 37°c and 100% relative humidity. 57 therefore, nasal air conditioning requires large amounts of heat and water for conditioning the inspired air and the capacitance vessels seem perfectly designed to fulfi ll that need. they might also operate as a short-term reservoir, either for heat or for water. special conditions (e.g. hyperventilation) call for these reserves in order to provide cooling and evaporation. 58 under normal circumstances and normal vasculature, a healthy nose succeeds in warming and humidifying the inspired air in order to protect the lungs. conversely, paucity in blood supply or moistening may reduce the effi ciency of the air conditioning system of the nasal cavity. 56 the nasal vasculature also contains an extensive system of arteriovenous anastomoses. this allows for the rapid passage of blood through the mucosa without reducing the nasal patency. great amounts of arterial blood may fl ow through these anastomoses, providing heat exchange similar to hot water in a radiator. 53 brain cooling appears to be the result of several mechanisms including a possible nasal and paranasal convection process. this latter process involves the transfer of cool venous blood from the respiratory mucosa to venous structures of the brain, such as the superior sagittal sinus between the parietal bones or the cavernous sinuses on each side of the body of the sphenoid, where arterial thermoregulation may then occur. on both sides, the cavernous sinus drains venous blood from the skin of the face and from the nose and mouth areas, and is in intimate contact with the internal carotid artery. 59 the direction of fl ow in these sinuses is reversible. 17 countercurrent mechanisms are suggested, where the arteriovenous anastomoses, present in the nasal vasculature, may also participate, allowing enhanced thermoregulation and brain cooling in hot conditions. 60 changes in craniofacial morphology have been observed as adaptations to weather conditions. wider nasal cavities and larger paranasal sinuses are considered to be adaptive mechanisms that, under hot conditions, offer more evaporating surface and consequently greater cooling capacity, thus protecting the brain. 61 orofacial dysfunction may alter nasal breathing and consequently the above functions. body position also affects the nasal vasculature. the supine position increases vascular congestion, thus decreasing nasal patency and the ability of the clinical conditions nose to condition cold, dry air. conversely, the upright position decreases vascular congestion. 62 consequently, it is appropriate to enquire if the patient experiences excessive increased nasal congestion when they lie down as it may result in snoring and sleep disorders. furthermore, the nasal vascular supply is under the infl uence of hormones, psychological stress and diverse substances (e.g. gases or infl ammatory molecules) that once in contact with the nasal mucosa seem to produce vascular congestion with edema and plasma exudation. it should be noted that children and teenagers often report nasal vascular congestion as nasal obstruction. an alternation of breathing between the two nares is known as the nasal cycle. it has been observed as early as 3 years of age, with the duration of a cycle ranging from 40 to 215 minutes. 63 alternation of the side of nasal breathing has been associated with the central mechanism regulating the dominance of the cerebral hemispheres. increased sympathetic activity in the nasal mucosa appears to be linked to greater sympathetic tone in the ipsilateral hemisphere and thus with decreased blood fl ow and mental activity in that hemisphere. 64 changes in the tone of the nasal vascular supply are regulated by the ans. parasympathetic nerves are vasodilator, sympathetic nerves are vasoconstrictor. therefore, predominance of parasympathetic activity causes a vasodilatation and nasal congestion, whereas increased sympathetic activity produces a vasoconstriction that decreases nasal airfl ow resistance. the preganglionic fi bers of the cranial portion of the sympathetic nervous system originate from axons of somata in the lateral gray column of the upper thoracic spinal segments. the fi bers enter the superior cervical ganglion adjacent to the second and third cervical vertebrae where they synapse. the postganglionic fi bers ascend, following the course of the internal carotid artery, forming the internal carotid plexus. the greater petrosal nerve, a branch of the facial nerve (cn vii), contains the preganglionic parasympathetic fi bers traveling to the pterygopalatine (sphenopalatine) ganglion. located deeply in the pterygopalatine fossa, between the pterygoid process and maxilla, anterior to the pterygoid canal, the pterygopalatine ganglion is one of the major peripheral parasympathetic ganglia. at the level of the foramen lacerum, the greater petrosal nerve is joined by the deep petrosal nerve from the internal carotid plexus (sympathetic) to form the nerve of the pterygoid canal (vidian nerve). these fi bers synapse in the pterygopalatine ganglion; the postganglionic parasympathetic fi bers are secretomotor and supply the glands of the nasal mucosa. additionally, the nasal cavities are densely innervated by the sensory nervous system. nerves are present in respiratory mucosa, particularly in the walls of the venous vessels and the gland acini. glands are innervated by both parasympathetic and sensory nerve fi bers. sensory nerves are stimulated by mechanical, thermal or chemical stimulation and afferent fi bers run in the trigeminal nerve. sensory nerve stimulation instigates different refl exes, such as the sneeze refl ex. 65 nasal thermal stimulation, as occurs with inhalation of cold dry, dry or moist air, produces a nasopulmonary bronchoconstrictor refl ex in normal healthy individuals, inducing changes in airway resistance. 66 activation of temperaturesensitive nerve endings in the nasal mucosa generates this response and the decrease of airfl ow through the nose and trachea protect the lungs from insufficiently conditioned air. 66 the ans controls several aspects of nasal function, i.e. nasal secretions, mucociliary function, blood fl ow, microvascular permeability, release of infl ammatory cells and nasal patency. the modulation and balance of nasal functions necessitate an interaction between the sympathetic and parasympathetic systems, as well as a well-tuned sensory nervous system. dysfunction may lead to pathologic nasal syndromes. because of the relationships between the sympathetic nervous system and the upper thoracic spinal segments, the second and third cervical vertebrae, and between the parasympathetic nervous system and the sphenoid, maxilla or palatine bones, somatic dysfunction of any of these vertebral and cranial areas can result in dysfunction of the ans with impact on nasal function. furthermore, because of the role of the trigeminal nerve, particularly the fi rst and second divisions, in the sensory function of the nose, the temporal bone should be added to that list. osteopathic procedures may be applied to balance the ans and promote healthy nasal functions. unpaired and paired structures form the nasal cavities, as in the remainder of the skull. as such, during the prm inspiratory phase, the midline unpaired structures of the nasal cavities (i.e. the sphenoid, ethmoid, vomer and septal cartilage) demonstrate cranial fl exion and the paired structures (i.e. maxillae, palatine, nasal and lacrimal bones and conchae) externally rotate. in the reciprocal prm expiratory phase, the midline structures move in the direction of cranial extension and the paired structures internally rotate. therefore, in health, the nasal cavities follow each cycle of the prm, with a resultant widening of the cavities during fl exionexternal rotation of the inspiratory phase and narrowing during extension-internal rotation of the expiratory phase. cranial somatic dysfunction very frequently follows asymmetric patterns. thus, the nasal cavity will be wider on one side than on the other. this can be observed by nasoscopic examination, as well as by simply looking at the patient to note asymmetry in the facial features. it may also be observed by comparing the relative size of the nares. one side is usually more open than the other. the open side is the side of the external rotation, whereas the other side is associated with internal rotation. the patient often reports more nasal congestion on the smaller side and in cases of small children the mothers comment on the increase of nasal secretion on that side. the alternation of cranial fl exion and extension, with all cranial structures free to follow this movement, is necessary to ensure effective tissue perfusion of the nasal mucosa. it also promotes venous and lymphatic drainage of the nose, as well as the removal of secretions from the nasal cavities and sinuses. under these circumstances, mucosal infl ammation and hyperreactivity associated with rhinitis may be reduced. in neurogenic infl ammation of the upper airway mucosa, such as in chronic rhinosinusitis, sensory nerves are excited and mediators are released, including histamine, prostaglandins and various neuropeptides such as substance p. 67 they may then cause vasodilatation, vascular congestion, extravasation of plasma with edema, and recruitment and activation of infl ammatory cells. secretion from the submucosal glands may also be increased. these exaggerated sensory and parasympathetic defensive refl exes form the pathophysiologic basis of rhinitis. acute rhinitis, one of the symptoms of the common cold, is the result of a viral infection. numerous viruses cause infections in the respiratory tract and any region of the tract may be infl amedthe nose, the paranasal sinuses, the throat, the larynx, the trachea and the bronchi. acute rhinitis represents one of the most frequent upper respiratory infections. allergic rhinitis is considered to be the most common allergic airway disease, with about 10% of the population experiencing this condition. 53 allergic rhinitis is common in children and most of the time this condition fi rst develops during childhood or adolescence. 68 typical behaviors are usually observed such as grimacing and picking of the nose. older children are likely to blow their noses more often than younger children who present with constant clearing of the throat because of postnasal drip, frequent sniffi ng or snorting. 69 rhinorrhea, nasal obstruction, sneezing, itching of the eyes, nose and palate, and watery eyes are typical symptoms associated with allergic rhinitis. the disease results from exposure to various allergens including foods, pollens, molds, dust mites and animal dander. two groups are described: seasonal allergic rhinitis, often the result of pollen exposure, and perennial allergic rhinitis, lasting for at least 9 months of the year. allergic individuals demonstrate a decreased capacity to warm and humidify inhaled air. 57 they also are prone to develop other diseases of the upper and lower respiratory tract such as sinusitis, otitis media with effusion and asthma that may complicate allergic rhinitis. 70 although the reason why individuals develop allergic rhinitis is uncertain, a genetic predisposition to develop the allergic response has been suggested. 69 it is thought that these individuals probably have a greater sensitivity to allergens and are predisposed to develop mucosal infl ammation and hyperreactivity. a 'microfl ora hypothesis' has also been suggested. it is thought that the disturbance of the normal microbiota in the gastrointestinal tract, in part due to the use of antibiotics and dietary changes in industrialized countries over the past two decades, is a factor that may lead to modifi ed airway tolerance to allergens and atopic disorders. 71 genetics and microbiotic disruption would then be considered as predisposing factors, increasing an individual's susceptibility to develop airway hypersensitivity and allergy. the nasal dysfunction associated with allergic rhinitis results in various symptoms. nasal congestion with increased airfl ow resistance, particularly in the supine position, causes sleep-disordered breathing. it is a risk factor for snoring, affecting teenage males more frequently than females. 72 it is also linked to various systemic symptoms such as headaches, irritability and fatigue that diminish functional capacity. thus, allergies are one of the main reasons for missed school days in the us. 73 school performance may be decreased because of inattention and decreased concentration. 74 physical and emotional impairments associated with the allergic condition make it a whole body dysfunction. 75 because allergic rhinitis can affect the patient's quality of life to such an extent, and because of its economic impact, prevention and treatment are essential. 73 osteopathic procedures may be seen as a valuable complement to traditional medical treatment. the examination for somatic dysfunction is begun by observing the global postural pattern and/or how the cervical and thoracic regions are, or are not, integrated into this pattern. the child should be observed from behind, from the side and from the front. from behind, observe upper body postural mechanics. look for cervical and thoracic sidebending, occipitocervical rotation and slumping of the pectoral girdle. from the side, observe cervical and thoracic anteroposterior mechanics. there is often upper thoracic fl exion with increased cervical lordosis. in this position, the head will very commonly be thrust forward with signifi cant tension placed on the anterior cervical soft tissues. observe specifi cally the submandibular myofascial structures and the position of the hyoid bone. the child with rhinitis may have to compensate by mouth breathing. as such, they may demonstrate the associated mouth breathing posture to a variable degree, depending on the chronicity of the condition. a double-chin appearance and the demonstration of a slack-jawed posture are indicative of chronic mouth breathing. from the front, observe and confi rm the sidebending and rotation observed from behind. again look for the presence of mouth breathing and the associated orofacial characteristics. children who mouth breath demonstrate a lack of tonicity of their facial tissues. the lower lip is typically everted and the tongue slightly protruded. observe the relationship between the tongue and the teeth. persistent protrusion of the tongue results in anterior displacement of the upper incisors with an eventual overbite. the child with allergic rhinitis will demonstrate puffi ness of the facial soft tissues, particularly noticeable around the eyes, as well as darkening of the tissues beneath the eyes. the nasion is often recessed in the face. because of the chronic lack of nasal breathing, the bony structures of the nasal cavities are small, resulting in narrowed nasal apertures. children with persistent nasal congestion demonstrate an observable transverse crease in the skin across the lower third of the nose, at the junction between the nasal bones and cartilages. this develops as the result of repeatedly rubbing and pushing the tip of the nose vertically or laterally with their fi ngers or hand in response to nasal itching -the 'allergic salute'. following observation, the palpatory examination is best performed with the child supine. begin by palpating the upper thoracic region for structure and employ the tests of listening to assess function, paying particular attention to the motion of the vertebrae and ribs. examine the clavicles in similar fashion. next, evaluate the cervical spine, with attention to the structural and functional relationships between the occiput, c1, c2, c3 and c4. palpate the soft tissues in this area for the presence of edema. in acute upper respiratory conditions, the trigeminally mediated upper cervical refl ex (occiput, c1) will result in acute tissue texture changes. assess the anterior cervical soft tissues and midline structures with attention to the hyoid bone. identify somatic dysfunction and treat it using the principles of indirect technique. examine the cranial base. note the pattern demonstrated between the sphenoid and occiput. sbs compression and inferior vertical strain are often encountered in association with nasal dysfunction. note the relationship between the occiput and temporal bone. visualize how this relationship impacts the jugular foramina and consequently cn x. the functional status of the sphenoid bone exerts significant infl uence on the frontal bone and the facial bones below, and should be assessed. also assess the frontal bone. any dysfunctional motion restriction will result in diminished movement, and consequently diminished drainage, of the nasal cavities. in particular, dysfunctional frontal internal rotation causes the ethmoidal notch to be narrowed, restricting the movement of the ethmoid below. when evaluating the relationships between the sphenoid, frontal bone and the facial bones with the tests of listening, fi rst assess the global motion of the region and then proceed to assess the individual bones and their interosseous relationships. during this assessment, localized motion restriction may be perceived that requires further identifi cation through visualization. the following sutures are potential sites of interosseous dysfunctions: frontoethmoidal, frontomaxillary, frontonasal and sphenoethmoidal. the relationships between the vomer and the sphenoid, ethmoid, maxillae and palatine bones, as well as the articulation between the two maxillae, should be evaluated. the nasal cartilages should be assessed in their relationship with the nasal bones and perpendicular plate of the ethmoid. following indirect principles, treat any dysfunctions found. address the upper thoracic and cervical regions for their effect on the ans. treat cranial dysfunctions for their effect on the autonomic and sensory nervous systems, venous and lymphatic drainage, and to promote the production and drainage of nasal secretions. treatment of nasal structures will affect the total body through the cranial mechanism. the nasal septum consists of the vomer and the perpendicular plate of the ethmoid. posteriorly, it is continuous with the sphenoidal sagittal septum that divides the body of the sphenoid into two sinus cavities. posteriorly and superiorly, it is continuous with the falx cerebri and falx cerebelli. these structures combined constitute a vertical septum that separates the paired structures of the head and unites the viscerocranium and the neurocranium and, through the core link, the body below. the nasal mucosa contains a rich supply of nerve endings and a dense network of microvasculature. for these reasons, it is highly sensitive. this should be kept in mind during the physical examination and treatment. it makes tests of listening and methods of treatment employing indirect principles the techniques of choice. further, to follow the prm, its rhythm and potency within nasal tissue, and to employ treatment when appropriate to enhance its potency, may help to modulate the autonomic dysfunction present in rhinitis, as well as help to reduce stasis and edema on a macro level in the mucosa and a micro level in the neuronal synapses. recurrent and chronic rhinitis is commonly triggered or aggravated by environmental circumstances. as such, the caregiver should be provided with information as to potentially irritating conditions and substances that will allow them to identify and remove these triggers from the child's environment. allergens should be sought out, identifi ed and, if possible, removed. the most common allergens include pollens, foods, molds, dusts and animal dander. a detailed list of these substances may be found by doing an internet search. conversely, dietary considerations and respiratory exercises may be employed to improve the function of the immune system. it has been suggested that disruption of the normal microbiota in the gastrointestinal tract contributes to decreased airway tolerance to allergens. 71 refi ned foods should be avoided as much as possible, while a diet rich in fresh fruit and vegetables and antioxidants such as vitamins c and e should be recommended. a diet high in probiotics that promote the growth of benefi cial bacteria (bifi dobacterium, lactobacillus, bacteroides) is recommended. this includes prebiotic carbohydrates such as inulin and oligofructose, plant carbohydrates that are not digestible in the small intestine but rather are fermented by bac-teria in the colon. 76 lactose intolerance should be considered. respiratory exercises are intended to enhance nasal breathing, promote mucus drainage and reduce vascular stasis in the nasal mucosa. they should be initiated in such a way that they can be successfully performed and yet avoid frustrating the child. nasal congestion impairs nasal respiration and if the child is simply told to breathe through their nose, the diffi culty of the experience usually limits the success of the exercise. the child will feel frustrated at best, and at worst may experience anxiety and a sense of suffocation. and they will stop doing the exercises. begin by explaining to the child the importance of nasal breathing. explain that breathing through their nose cleans the air they breathe and gives them more oxygen in their blood, and that this will, in turn, enhance their performance in school and in sports. next, have the child breathe through their nose and become aware of the sensation of nasal airfl ow. have them palpate the lateral aspects of the nasal cartilages as they breathe. teach them to actively fl are the nose by contracting the dilatator nostril muscles as they inhale. palpating the nose during this process reinforces their awareness of nasal fl aring. after 2 or 3 minutes of active nasal breathing the child should observe the difference in the sensation of nasal airfl ow. they may now be instructed to repeat the above process at home, exercising for 5 minutes at least three times daily. the child should also be taught to breathe using their thoracoabdominal diaphragm. successfully implementing these exercises not only allows the child to improve nasal respiratory function, it further teaches them a sense of control over their own respiration. this will reduce and eventually eliminate the sense of suffocation the child experiences when they attempt to breathe through congested nasal passages because, even thought they may experience nasal congestion, they will have been empowered to alleviate it. it is estimated that children get an average of six to eight colds annually, and that 5-10% of all upper respiratory tract infections are complicated by sinusitis. 77 the application of osteopathic principles in the treatment and prevention of sinusitis in children should be utilized, as it is particularly effi cient. it is based on an understanding of the anatomic and functional aspects of the nasal cavities and sinuses as part of the upper respiratory tract. a description of the nasal cavities, mucosa and its main characteristics has already been provided in 'rhinitis' above. we shall, therefore, only consider the description of the paranasal sinuses and the pathophysiology that explains their dysfunction. many speculative theories exist concerning the function of paranasal sinuses. some 2000 years ago, galen hypothesized that they were 'porous bones' reducing the skull's weight. since then, other theories have described the paranasal sinuses as shock absorbers, resonance chambers, air conditioning areas or the result of the evolutionary process and parts of the facial development. there are four paranasal air sinuses associated with each nasal cavity: the ethmoidal, frontal, sphenoidal and maxillary sinuses, all of which open into the lateral walls of the nasal cavities by small apertures that differ from one individual to another. the lateral wall of the nasal cavity is formed anteriorly by the frontal process of the maxilla and the lacrimal bone; centrally by the ethmoid, maxilla and inferior nasal concha; and posteriorly by the vertical plate of the palatine bone and the medial pterygoid plate of the sphenoid. three meatuses are located in this wall. they consist of three irregular passages directed anteroposteriorly -the superior, middle and inferior meatuses of the nose. the superior meatus is the smallest. located between the superior and middle nasal conchae, it occupies the middle third of the lateral wall of the nasal cavity. the middle meatus is between the middle and inferior conchae. the inferior meatus is the largest of the three. it lies in the space between the inferior concha and the fl oor of the nasal cavity. only the nasolacrimal duct drains into the inferior meatus in the anterior part of the nasal cavity. the ethmoidal sinuses, on each side, are formed by 3-15 air cells, fi lling the ethmoidal labyrinth. they are divided into three groups: anterior, middle and posterior. the anterior and middle ethmoidal cells drain into the middle meatus, whereas the posterior ethmoidal cells drain into the superior meatus. the frontal sinuses are the highest. each frontal sinus develops from an anterior ethmoidal cell that extends posteriorly along the medial part of the orbital roof and laterally above the internal part of the eyebrow at about 5 or 6 years of age. on each side, through the frontonasal duct and the ethmoidal labyrinth, the frontal sinus drains into the middle meatus. the maxillary sinuses are the largest. they form large pyramidal cavities within the bodies of the maxillae and drain into the middle meatus on each side. the sphenoidal sinuses are within the body of the sphenoid, their apertures being on the upper portion of the anterior walls of the sphenoidal body. the sphenoid sinuses drain into the superior meatus, near the roof of the nasal cavities (figs 7.3.14, 7.3.15). the pneumatization of the paranasal sinuses occurs at different rates, with a great deal of variation between individuals. the maxillary and sphenoidal sinuses are the fi rst ones to develop in the fourth gestational month, followed by the frontal and ethmoid cells that appear in the sixth month. at birth, the parasinuses are quite small. the ethmoid cells measure 2-5 mm in diameter while the maxillary sinuses appear as furrows 7 mm in length and 4 mm in width. 78 the sphenoid sinuses are usually pneumatized around 5 years of age 79 and the frontal sinuses have developed to the extent that they are radiographically apparent by about the age of 6. around this time, the growth of the cerebral mass slows down. the inner table of the frontal bone is stabilized while the outer table is still dragged forward by nasomaxillary growth. a space forms between both plates, where the frontal sinus expands. mechanical forces associated with mastication and the actions of growth hormones are linked with the increase in the size of the sinus. 80 sinusal development normally continues until late adolescence. the paranasal sinuses are innervated by branches from the trigeminal nerve (cn v). the frontal and sphenoidal sinuses are innervated by branches from the ophthalmic nerve (cn v 1 ), the maxillary sinuses from the maxillary nerve (cn v 2 ), and the ethmoid cells from both the ophthalmic and maxillary nerves. as in the remainder of the nasal cavity, described previously, the paranasal sinuses are lined with a respiratory mucosa, ciliated and mucus-secreting, that is continuous with that of the respiratory tract. additionally, the paranasal sinuses seem to be an anatomic source for the excretion of nasal nitric oxide (no). mammals lacking paranasal sinuses (e.g. baboons) demonstrate lower exhaled concentrations of this molecule. 81 no is involved in vasodilatation, neural transmission and immunologic activity, and appears also to participate in local host defense, even before allergens reach the respiratory mucosa. it may also regulate the mucociliary motility of the respiratory mucosa, thereby participating in the drainage of nasal secretions and the defense mechanisms of the mucosa. from the paranasal sinuses, no may also play distal functions. throughout normal nasal breathing, no is constantly excreted into the upper airway, acting as an 'aerocrine' messenger. 82 it follows the airfl ow to the lungs where it modulates pulmonary function through regulation of blood fl ow and oxygen uptake. 83 nasal breathing, therefore, becomes crucial for these vital functions. when compared to oral breathing in healthy individuals, nasal breathing results in an improvement of arterial oxygenation 84 with a reduction of pulmonary vascular resistance. in this manner, no would be an airborne messenger. it is of prime importance to improve nasal respiration in infants and children as soon as possible. nasal breathing promotes healthier conditions in association with inspiration. additionally, it stimulates the development of the maxillofacial skeleton and, therefore, of the nasal cavities. 85 the paranasal sinuses are a common site for infection in children and adolescents. the most common sinusitis is maxillary, followed by ethmoidal and then frontal sinusitis. the tendency to develop sinusitis can be explained in part by anatomy. proper ventilation is critical for preservation of sinus integrity. the maxillary sinuses are ventilated, but the ostium of each sinus is positioned high on the lateral wall of the nasal cavity. this encumbers gravitational drainage and probably predisposes patients to infections of the maxillary sinus. the frontal sinus is ventilated and because of the location of its ostium at its base, this sinus benefi ts the most from gravity. sphenoidal sinusitis rarely occurs as an isolated infection, being found more often as a part of complete sinusal involvement. viral infections of the upper respiratory tract commonly result in an infl ammation of the sinuses and nasal mucosa to produce the rhinosinusitis. 86 bacterial infections with purulent nasal drainage are most often located in the paranasal sinuses. 79 viral rhinosinusitis precedes about 80% of bacterial sinus infections while the remaining 20% most often follow allergic rhinitis. 77 persistence of nasal symptoms, such as discharge or congestion, cough and headaches, particularly when awakening, for more than 30 days is defi ned as chronic sinusitis. the sinus ostium is a common structure shared by all of the paranasal sinuses. its function has been compared to that of the pharyngotympanic tube. they both permit drainage. the ostia of the sinuses allow drainage of the paranasal sinuses whereas the pts drain the tympanic cavities. 87 therefore, following the same principles as those used to treat otitis media, osteopathic procedures may be applied to affect the bones of the paranasal sinuses to improve their compliance and promote sinus drainage. interand intraosseous techniques for the frontal bones, ethmoid, sphenoid and maxillae are very effi cient in the treatment of sinusitis. the normal size of the sinus ostia is approximately 2.4 mm. 88 the ostia are lined with mucosa and infl ammation and swelling of that mucosa may decrease or occlude ostial patency and consequently the drainage of the paranasal sinuses. obstruction of a paranasal sinus ostium will initially produce an increase of the pressure within the sinus. this is followed by intrasinusal gas absorption that consequently results in negative pressure within the sinus. this condition predisposes aspiration of bacterialaden secretions into the ethmoid or maxillary sinuses from the nasal cavity, particularly when an individual sniffs or blows their nose. 87 obstructed drainage generates stasis of mucus in the paranasal sinuses that, in turn, becomes an ideal culture medium for bacteria. more infl ammation follows, with a self-perpetuating condition that leads to chronicity. additionally, somatic dysfunction may contribute to impaired nasal secretion. parasympathetic stimulation results in vasodilatation and increased activity of the seromucous glands and goblet cells, with symptoms such as rhinorrhea and nasal congestion. on the other hand, increased sympathetic activity produces vasoconstriction and dryness of the nasal mucosa. 89 cranial somatic dysfunction of the maxilla, palatine bone and sphenoid can affect the pterygopalatine ganglion and both parasympathetic and sympathetic supply of the nose and paranasal sinuses (see 'rhinitis' above). dysfunction of the cranial base and craniocervical junction will refl exly affect the trigeminal nerve and, through it, sympathetic and parasympathetic refl exes. somatic dysfunction in the cervical and upper thoracic spine can affect sympathetic activity, as well as lymphatic drainage of the facial area. once again, normal motion of skeletal structures, functional ciliary motion and autonomic regulation are required for a healthy upper respiratory system. it should be stressed that cranial somatic dysfunction, although it may originate very early in life, may not manifest until years later. nasal septal asymmetry may affect as many as 1% of newborns as the result of compression of the tip of the baby's nose during vaginal delivery. 90 nasal suction bulbs or nasogastric tubes may also be traumatic to the nose. a nasal septal deviation may affect the middle concha and predispose to the obstruction of the osteomeatal area. 87 cranial base dysfunction and vertebral somatic dysfunction may result from diffi cult labor. obviously, for all these reasons, a whole body osteopathic evaluation and treatment of the newborn should be performed, including attention to the facial bones, particularly those of the nose. left untreated, facial somatic dysfunction may restrict full development of the paranasal sinuses. furthermore, nasal obstruction will lead to mouth breathing and sleep-disordered breathing. 85 sore throat and sinusitis may follow. nasal obstruction is frequently associated with chronic maxillary sinusitis, adenotonsillar hypertrophy and otitis media as well as dental malocclusion and facial maldevelopment. 31 later in childhood and adolescence, somatic dysfunction can occur as the result of traumatic forces from physical bumps, falls, athletic strains and the like. the resultant dysfunction, depending on the direction of the traumatic force, may be established in the pattern of the individual's underlying postural balance or completely independent of it. somatic dysfunctions of the facial bones and upper thoracic region are of particular consequence in the development and maintenance of sinus dysfunction. the cranial respiration of the prm differs from the thoracoabdominal respiration. however, they may entrain each other. this happens during states of relaxation, where the rate of the pulmonary respiration decreases to that approximating the rate of the prm. thereby, the two respirations combine their action to affect the entire body. this principle is particularly signifi cant in the upper airway to promote movement of the nasal secretions, the gaseous contents of the paranasal sinuses, blood and lymph. the normal cranial motion associated with the prm consists of an inspiratory phase (fl exionexternal rotation) during which the paranasal sinuses as paired structures expand laterally and decrease in height. conversely, during the expiratory phase of the prm (extension-internal rotation), the sinuses decrease their lateral dimension and increase their height. during cranial inspiration, the maxilla and the zygomatic bone move in external rotation, but at the same time a slight twisting occurs between them that contributes to the drainage of the maxillary sinus. the movements of all bones in association with the biphasic prm may be described as the result of the combined movements in the three cardinal planes. the twisting between the zygomatic bone and the maxilla occurs predominantly in the sagittal plane. during external rotation, the zygoma demonstrates a component of anterior rotation, while the maxilla simultaneously demonstrates posterior rotation. the reverse occurs during internal rotation. this motion may be compared to the wringing out of a wet rag. the zygomatic bones are an interface between the greater wing of the sphenoid, the maxilla, the frontal and the temporal bones. their position is strategic and they play a key role in the balance of the face. the vomer is located between the sphenoidal body and the hard palate. its inferior border articulates anteriorly with the intermaxillary suture between the palatine processes of the maxillae and posteriorly with the interpalatine suture between the horizontal plates of the palatine bones. the vomer rotates posteriorly during cranial fl exion or inhalation, when the body of the sphenoid rotates anteriorly. conversely, the vomer rotates anteriorly during cranial extension or expiration, when the body of the sphenoid rotates posteriorly. accordingly, sutherland stated: 'during inhalation the zygomatic bones and the vomer function somewhat like a plumber's plunger on the sphenoidal sinus and the maxillary sinuses.' 91 every component of the facial skeleton is involved as part of the global functional pattern and should be assessed. again according to sutherland, even the smallest structures should be considered: 'see the turbinates on the side of the nose as they are in the living body, curling and uncurling during inhalation and exhalation.' 92 the treatment of sinusitis is intended to promote the prm. the osseous structures as well as the potency of the prm should be considered. manipulative treatment of the somatic dysfunction associated with sinusitis should be employed in conjunction with standard medical treatments. the sooner it is initiated, the more rapid and successful the response. failure to treat chronic sinusitis effectively will result in altered growth patterns of the viscerocranium. nasal breathing will be impaired with concomitant malposition of the tongue and resultant dental malalignment. osteopathic examination and treatment of sinusitis are very similar to that of rhinitis. examination is directed at the identifi cation of somatic dysfunction that affects normal mucociliary clearance and impairs blood and lymphatic circulation, as well as ans function. for this and the associated treatment discussion, the reader is directed to 'rhinitis' above. manipulative treatment for sinusitis should focus on the reduction of mucosal edema, which will increase osteal patency. procedures should be employed to drain the sinuses and provide symptomatic relief. treatment should also include procedures that address sympathetic and parasympathetic somatovisceral refl ex activity affecting the sinuses. the sympathetic supply of the paranasal sinuses emanates from the upper thoracic spine. when examining the child with sinusitis, it is all too easy to become focused on dysfunction of the viscerocranium and forget this signifi cant area. additionally, when working with children it is less intrusive to begin in an area away from the face. perform tests of listening to evaluate the motion of the upper thoracic vertebrae and associated ribs. because of its relationship with the trigeminal nerve, the occipitocervical region should also be assessed. the rhythmic motion of the cranial bones under the infl uence of the prm signifi cantly facilitates sinus drainage. it is, therefore, appropriate to examine the global cranial pattern, looking specifically for dysfunction that reduces the motion of the sphenoid, ethmoid, vomer, palatine and zygomatic bones, maxillae and conchae. observe the face of the child, looking for puffi ness in the nasal area. look for asymmetry of the nares and asymmetric nasal respiration. compare the degree of nasal alar fl are with inspiration. in addition, inspect the nasal cavity, noting secretions, edema and erythema of the mucosa. observe the child for open mouth posture that may be indicative of enlarged adenoids. listen to the child's speech for hyponasality. utilizing tests of listening, evaluate the sphenoid and frontal bones. proceed to assess the facial bones, paying particular attention to the ethmoid, maxillae and zygomatic bones. the function of the vomer, palatine bones and conchae should also be considered. the zygomatic bones are easily accessible and their manipulation readily results in drainage of the maxillary sinuses. this procedure (see chapter 6) is straightforward and easily mastered by the novice. manipulation of the zygoma, in turn, affects the ipsilateral maxilla and greater wing of the sphenoid. the motion of the sphenoid should be assessed. it exerts signifi cant infl uence on the facial bones and on proper drainage of the sphenoid sinuses whose ostia are located in the upper portion of the anterior walls of the sphenoidal body. the ethmoid bone is a common site of dysfunction in children and adolescents, and should be assessed in its relationships with the frontal bones, sphenoid and maxillae. proper motion of the ethmoid bone is necessary to facilitate the emptying of secretions from the ethmoid air cells. intra-and interosseous motion of the maxilla should be assessed because it is necessary for the effective drainage of the maxillary sinus. additionally, in conjunction with the pterygoid process of the sphenoid and the palatine bone, it forms the pterygopalatine fossa where the pterygopalatine (sphenopalatine) ganglion is located. any dysfunc-tion of these bones may affect the ganglion and its effects on mucosal secretions. the vomer's contribution is very important to the mechanism of the pumping action of the paranasal sinuses. its assessment is often performed with one fi nger placed intraorally. when treating very young children, this procedure should be done only when absolutely necessary and then only with the greatest delicacy. the examiner should never attempt intraoral palpation of the vomer if the child is not completely cooperative. an alternative procedure is to employ visualization of the vomer while palpating the anterior edge of the nasal septal cartilage. treat any dysfunctional areas identifi ed. treatment is normally performed in continuity with assessment. because indirect treatment procedures are used preferentially for children and adolescents, the effective treatment of a given area results in further relaxation of the patient, thereby facilitating the treatment of the next area to be evaluated and treated. furthermore, when performing indirect techniques, tissue responses are continuously monitored, so that in acute conditions the patient's tolerance to the procedure is also continuously assessed. the tissues dictate the treatment; they guide your actions and determine the dosage. the upper thoracic region should be treated for its sympathetic somatovisceral effects, to facilitate lymphatic drainage of the head and neck, and for functional reasons because it is the foundation on which the above structures rest. the occipitocervical junction should be treated for its refl ex impact on the trigeminal nerve and its relationship to the cranial base. the sphenoid, frontal and facial bones should be treated for their direct effect on the paranasal sinuses. paranasal sinuses are intraosseous cavities and their drainage is dependent on the inherent motility of their respective bones: frontal, sphenoid, ethmoid and maxillae. as such, intraosseous dysfunctions of any of these bones can impact the associated sinus. specifi cally pumping the individual bones may be employed to facilitate drainage of their sinuses. positioning the patient contributes to the drainage of the paranasal sinuses by using gravity. drainage of the sinuses is best performed as follows: • drainage of the frontal sinus in the seated position • drainage of the sphenoidal sinus in the seated position with the head of the patient bent forward • drainage of the maxillary sinus in the supine position with the patient's head rotated to the opposite side so that the sinus to be drained is up. when treating the vomer, if the child resists the digital intraoral approach, the child's pacifi er, if they have one, may be utilized. by allowing the child to actively suck on the pacifi er the resultant alternation of intraoral pressure and tongue movement, pressing the pacifi er on the roof of the child's mouth, may be employed to manipulate the vomer, while the practitioner works on the adjacent sphenoid and ethmoid bones. the caregiver should be encouraged to maintain a healthy lifestyle for the child, including a balanced diet with adequate hydration and the avoidance, as much as possible, of refi ned carbohydrate. respiratory exercises including nasal respiration and diaphragmatic breathing may be taught. vocal activities such as humming can be benefi cially employed to increase sinus ventilation. 93 the pharynx is a musculomembranous half-cylinder that connects the nasal and oral cavities with the larynx and esophagus. it extends from the base of the skull to the level of the sixth cervical vertebra where it joins the esophagus. the pharynx is divided into three portions: the nasopharynx located above the hard palate, the oropharynx that extends from the hard palate to the base of the epiglottis and the laryngopharynx from the base of the tongue to the larynx. the oropharynx can be further subdivided into the retropalatal or velopharynx from the hard palate to the caudal margin of the soft palate and retroglossal from the most inferior tip of the soft palate to the base of the epiglottis (fig. 7.3.16) . the pharyngeal wall consists of an internal mucous layer, an intermediate fi brous layer and an external layer of skeletal muscle. in the superior part of the pharynx, the pharyngobasilar fascia is the thickest portion of the intermediate fi brous layer of the pharyngeal wall and is fi rmly attached to the base of the skull. the attachment forms an irregular u-shaped line. the anterior part inserts on the posterior margin of the medial plate of the sphenoidal pterygoid process. it then curves under the cartilaginous part of the pts where it inserts onto the petrous part of the temporal bone and continues to the pharyngeal tubercle of the occipital basilar part to meet the attachment from the other side (fig. 7.3.17) . the anterior part of the pharyngeal wall is not continuous; rather, it has multiple attachments to the medial pterygoid plate, the pterygomandibular raphe, the mandible, the tongue, the hyoid bone, and the thyroid and cricoid cartilages. six muscles contribute to constitute the pharyngeal wall. the bilateral superior, middle and inferior constrictor muscles constrict the pharyngeal cavity and, on each side, three longitudinal muscles -the stylopharyngeus, salpingopharyngeus and palatopharyngeus -elevate the pharyngeal wall and participate in swallowing (figs 7.3.18, 7.3.19) . the fi bers of the three constrictor muscles fan out posteriorly into the median pharyngeal raphe, a fi brous band that is attached above to the pharyngeal tubercle of the occipital basilar part. the pharyngeal raphe descends to the level of the sixth cervical vertebra where it blends into the posterior wall of the esophagus. a thin retropharyngeal space fi lled by loose areolar tissue connects the pharynx with the cervical portion of the vertebral column and the prevertebral fascia covering the longus colli and longus capitis muscles. the pharynx is the common route for air and food, and seven cavities communicate with it: the two nasal cavities, the mouth, the larynx, the two tympanic cavities and the esophagus (fig. 7.3.20) . the nasal cavities open posteriorly into the nasopharynx through the choanae. the oral cavity also opens posteriorly through the oropharyngeal isthmus the internal mucous layer of the pharyngeal cavity is continuous with that of the mouth and larynx and that lining the nasal cavities and pts. it contains a large collection of lymphoid tissue, arranged in a circular orientation around the wall of the throat, the waldeyer's tonsillar ring that represents the primary defense against pathogens at the entry of the upper respiratory and alimentary tract. the constituent parts of this defensive annulus are the nasopharyngeal, palatine, tubal and lingual tonsils, plus lymphoid tissue in the intertonsillar intervals. the nasopharyngeal tonsil is located in the area of the nasopharyngeal roof and posterior wall, where the mucosa covers the inferior part of the sphenoidal body and the basilar part of the occipital bone. the palatine tonsil constitutes the major part of waldeyer's ring. the paired palatine tonsils are located in the lateral wall of the oropharynx, in the tonsillar fossae, posterior to the base of the tongue between the anterior and posterior pillars, the palatoglossal and palatopharyngeal folds, respectively. they can be observed through the open mouth with the tongue depressed (fig. 7.3.21 ). they are located slightly higher in the neonate and descend during the 2nd and 3rd years of age. the lingual tonsils are multiple lymphoid nodules situated on the posterior one-third of the tongue while additional small nodules beneath the mucosa of the pt form the tubal tonsils. the nasopharyngeal tonsil increases in size in the fi rst years of life to reach its peak around 6 years of age. thereafter, it starts to involute until almost completely atrophied by puberty. when the nasopharyngeal tonsil is enlarged it is referred to as adenoid or adenoids; 'tonsils' is usually the common name for the palatine tonsils. waldeyer's tonsillar ring is located at a strategic point where numerous antigens, both foodsupported and airborne, fi rst come into contact with the body. thus, it plays an important role in the immune system as a site of antigen recognition and synthesis of antibodies, including ige. 94 the nasopharyngeal and palatine tonsils are major sources of t lymphocytes that participate in cell-mediated immunity and b lymphocytes that produce immunoglobulins. 95 the nasopharyngeal tonsil also seems to participate in immune peripheral tolerance to harmless foreign antigens commonly inhaled or present in digested nutrients. 96 bacterial, or less frequently viral, infections are most often responsible for tonsillitis, where the tonsils may be acutely infl amed. bacterial infections are often streptococcal, usually from group a streptococci, the most virulent species in humans. differential diagnosis between viral and bacterial infection, based on physical examination alone, is diffi cult. tonsillitis is characterized by sore throat and pain, particularly during swallowing, which may involve the ears. headaches, vomiting and high fever may be associated. it should be noted that bacterial infections are correctly treated with appropriate antibiotics and that in these instances the diagnosis and treatment of somatic dysfunction should be considered as adjunctive. pharyngitis, an acute infl ammation of the pharynx, is usually the result of a viral infection, although it may be bacterial. the pharyngeal mucous membranes may be infl amed with purulent exudates. sore throat and pain during swallowing are also present, associated with fever, cervical adenopathy and leukocytosis. susceptibility to infections differs between individuals. host genetic components that adjust immune responses to pathogens seem to play an important role. 97, 98 nevertheless, the peritonsillar location is the most common of head and neck space infections in children in 49% of cases. 99 the american academy of otolaryngology-head and neck surgery currently proposes adenoidectomy as a guideline after '3 or more infections of tonsils and/ or adenoids per year despite adequate medical therapy'. 100 adenoidectomy is currently one of the most common operations performed on children in the united states. 39, 101 besides bacterial and viral infections, allergies such as allergic rhinitis are considered to be common risk factors for adenoid hypertrophy. 102 the continuity between the internal mucous layer of the pharyngeal cavity, the nasal cavities, the mouth, the larynx, the tympanic cavities and the esophagus explains the interrelationship and diversity of clinical presentations in allergic conditions. increased immune activity results in hypertrophy of waldeyer's tonsillar ring, in particular at the level of the nasopharyngeal tonsil. chronic nasal airway obstruction may follow a condition quite common in childhood that leads to a persistent mouth-open posture and mouth breathing. adenotonsillar hypertrophy has also been associated with a myriad of symptoms such as obstructive sleep disorder syndrome, nocturnal snoring, rhinosinusitis, hyponasal speech and impairment of the ability to smell. 103 furthermore, hypertrophy of the nasopharyngeal tonsil or adenoids predisposes the individual to recurrent otitis media or otitis media with effusion, in part because of the diminution of the patency of the orifi ces of the pt, located just laterally to the nasopharyngeal tonsil. tonsillectomy and adenoidectomy in children is reported to improve symptoms associated with obstructive sleep apnea syndrome, such as snoring and restless sleep, as well as behavioral, emotional and neurocognitive diffi culties. 104 these procedures are also associated with improvement of the nasal cavity geometry by reducing the venous stasis and congestion of the inferior turbinate present in adenotonsillar hypertrophy. 105 nasopharyngeal tonsil hypertrophy and the associated mouth breathing are usually believed to impact craniofacial development. experiments conducted in primates have established that a persistent mouth-open posture and associated oral respiration leads to dental malocclusions such as cross-bite. 106 mouth-breather children may present with a narrow, elevated palate and a decreased nasopharyngeal space. in such cases, they may demonstrate a receding chin (retrognathia) with crowding of the maxillary and mandibular teeth, and increased lower anterior vertical face height. following adenoidectomies and establishment of nasal breathing, changes are reported, with a more anterior growth of the mandible, improvement of retrognathia and diminution of lower anterior vertical face height. 107 the commonly used terminology 'adenoid' facies to describe longer lower face heights, open mouth and more retrognathic mandibles has led people to believe that adenoid hypertrophy was solely responsible for mouth breathing and associated disorders. this is an overly simplifi ed conclusion. once again, a multifactorial approach to diagnosis and, consequently, treatment may be necessary. a study of children 12 years after adenotonsillectomy showed that upper airway narrowing during sleep was still present, although some resolution of sleep disturbance was obtained 6 months postoperatively. 108 not all children who snore demonstrate adenotonsillar hypertrophy and such hypertrophy is not the only cause of sleep apnea. pharyngeal collapsibility is implicated with anatomic predisposition 109 such as changes in the longitudinal tension within the pharyngeal airway. 109 although adenoidectomy is considered to be an effective treatment for children who are mouth breathers, recurrence of breathing diffi culties in these individuals occurs and has been attributed to their craniofacial anatomic pattern. 110 in upper airway narrowing, sleep apnea, mouth breathing and adenotonsillar hypertrophy, the craniocervical membranous, myofascial, ligamentous and interosseous somatic dysfunction may contribute to the pharyngeal dysfunction. the upper part of the pharynx is attached to the sphenoid, the temporal bones and the occiput. through the prevertebral fascia the pharynx is linked to the cervical spine and movements of the cervical spine are associated with changes of pharyngeal size: cervical fl exion decreases clinical conditions oropharyngeal size; cervical extension does the opposite. [111] [112] [113] any dysfunction of the cervical spine or of any of the structures on which the pharynx is inserted can impair normal pharyngeal function. movement is necessary to mobilize body fl uids, particularly lymph, and somatic dysfunction affecting the structures surrounding lymph nodes and vessels is associated with impaired motion and can thus interfere with lymph fl ow. lymphatic vessels from the pharynx drain into the deep cervical lymph nodes through the retropharyngeal, paratracheal and infrahyoid nodes. the retropharyngeal nodes consist of a median and two lateral groups located in front of the lateral masses of the atlas. they are positioned between the pharyngeal and prevertebral fasciae and drain the nasopharynx and pt, as well as the two upper cervical joints. the deep cervical lymph nodes are beneath the scm muscle. among them, a large node surrounded with several small ones forms the jugulodigastric group that receives drainage from most of the lymphatic vessels from the tonsil. the tonsils differ from the lymph nodes in that they do not receive afferent lymphatic vessels. small lymphatic vessels organize as efferents from the tonsils that traverse the superior constrictor muscle before draining to the jugulodigastric nodes. located against the posterior belly of the digastric muscle, these nodes swell during tonsillitis and may be palpable in front of the anterior border of the digastric muscle, below the mandibular angle. the vessels that supply the pharyngeal wall come from the external carotid artery. the tonsillar branch of the facial artery (external maxillary) is the main blood supply to the palatine tonsil. the veins of the pharynx drain through the pterygoid plexus in the infratemporal fossa and into the facial and internal jugular veins. because the pharynx is so intimately linked to the cervical spine and the cranial base, as well as associated muscles and fasciae, optimal pharyngeal function necessitates that these areas are unimpaired. the upper thoracic spine is the anatomic origin of the sympathetic supply to the pharynx and, consequently, along with associated ribs, should also be considered when addressing pharyngeal dysfunction and disease. finally, the functional freedom of the clavicles, thoracic inlet and cervical spine, together with associated soft tissues above, is necessary to facilitate lymphatic drainage of the pharynx. having performed a total body structural examination to identify the global postural pattern and its relationship to the pharyngeal complaint, with the child in a supine position, it is appropriate to begin the local examination by evaluating the cervical and upper thoracic regions. first, palpate for tissue texture abnormalities in the paravertebral muscles and superfi cial soft tissues, looking for areas of muscular tension and subcutaneous edema. similarly, palpate the anterior and lateral aspects of the neck. observe and palpate the location of the hyoid bone and larynx that should be in the midline. palpation of the anterior neck structures should be done with great delicacy to prevent irritating already infl amed tissues and because this is an area of increased sensitivity, particularly in infants who were born with a nuchal cord. assess the anterior and lateral cervical musculature, paying specifi c attention to the scm muscle because of its relationship to the deep cervical lymph nodes. follow the scm inferiorly to its attachment on the clavicles and assess clavicular motion. evaluate the cervical vertebrae, noting the alignment of the spinous processes. clinical experience has shown a strong association between pharyngitis and cervical articular somatic dysfunction that, when treated, appears to prevent recurrent pharyngitis. next, evaluate the upper thoracic vertebrae and associated ribs. assess the functional status of the cranial base, noting the relationships between the occiput, temporal bones and sphenoid. the pharynx is suspended beneath the skull and tone of the pharyngeal musculature is impacted by cranial dysfunction. for proper function, the pharyngeal muscles require precise interrelationships between their origins and insertions. dysfunctional mechanics that affect these relationships will impair function of the pharynx and associated waldeyer's tonsillar ring. the pharyngeal tonsil is located directly beneath the cranial base, at the level of the sphenobasilar junction. as such, freedom of motion of the cranial base may facilitate lymphatic drainage of the adenoids. mandibular function should also be examined. dysfunction of the mandible may impact anterior cervical myofascial function, contribute to impaired lymphatic drainage of the jugulodigastric node and participate in chronic mouth breathing. apply indirect principles to treat any identifi ed articular dysfunction of the spine, ribs and clavicles. myofascial release techniques may be employed to address pharyngeal, anterior cervical and spinal muscular dysfunctions. normalizing the cranial and thoracoabdominal diaphragms and the thoracic inlet may be employed to promote lymphatic and venous circulation. following the inherent motility of the prm may enhance all of these interventions. this slow, gentle rhythm is soothing to the child and is integral in the maintenance of homeostasis. 114 18. humans may breathe through their noses, mouths or intermittently through both. it is commonly held that, between birth and at least 2 months of age, infants breathe exclusively through their noses. this belief has, however, been challenged and some authors propose that infants are 'preferential nasal breathers' rather than 'obligate nasal breathers'. 1 in older children and adults, under normal conditions and at rest, the nasal respiratory route is used, and oronasal breathing occurs typically when a higher degree of ventilation is necessary, as during exercise. in order to breathe through the nose, the nasal airway (nostril, nasal cavity and nasopharynx) should be patent. nasal obstruction consists of partial or complete blockage of one or more of these components of the air passages. in the newborn, the posterior nasal aperture may be blocked by choanal atresia. because of the infant's preferential nasal breathing route, such total nasal obstruction is a medical emergency. 2 in the young infant, and later in life, several other factors can cause nasal airway obstruction. 'stuffy nose' or rhinitis is a common cause of nasal obstruction in young infants that results in mouth breathing (see p. 224). viral upper respiratory tract infections, foreign body, deviated nasal septum, hypertrophy of the inferior turbinates and nasal polyps are other factors that can also predispose to mouth breathing and produce an open mouth posture. nasal endoscopy may be necessary to assess children with severe nasal obstruction that may require surgical repair. 3 tonsillar hypertrophy is believed by many to be the main cause of nasal obstruction in children. the pharyngeal tonsil, or adenoids, is a large collection of lymphoid tissue located beneath the roof of the nasopharynx, at the level of the sbs. enlargement of the pharyngeal tonsil commonly occurs as the result of frequent bacterial or viral infections and can obstruct the nasopharyngeal route so that mouth breathing is the only possible alternative. 'tonsils' is the common name for the palatine tonsils, which are lymphoid tissue located laterally on the oropharyngeal walls, just posterior to the base of the tongue. children with enlarged adenoids are described as having 'adenoidal facies' (long faces). they share common features with other mouth breathers, having low body weight and short stature, circles around their eyes, receding chins, small mouths, dry, large lower lips and short upper lips that are held apart from one another. they also tend to have multiple allergies and to demonstrate a specifi c postural confi guration, the most commonly described feature of which is the anteriorly displaced or extended position of the head. 4 effi cient respiration is the result of multiple intricate neurophysiologic processes and several anatomic structures contribute to this complex system. the extended, or forward, head posture may follow nasal obstruction as a solution to compromised nasal breathing. experimental studies have shown that cervical extension increases maximum oropharyngeal airway size. 5 therefore, children with nasal obstruction will spontaneously tend to assume the extended or forward head posture. an extended head position is associated with an anterior displacement of the condyles of the occiput on the superior articular surfaces of the atlas, while the squamous portion of the occiput is lowered. the distance between the occiput and dorsal arch of the fi rst cervical vertebra has been shown to be decreased in mouth breathers. 6 the condyles of the occiput are convex and the superior articular surfaces of the atlas are concave. extension of the head for the shift from nasal to mouth breathing results in anterior and ascending displacement of the occipital condyles on the superior articular surfaces of the atlas. this causes the horizontal line of sight of the orbits to be angled upward, with resultant shift of the visual fi eld and the need for postural compensation. one way to accomplish this, which is commonly observed in mouth breathers, is to increase the thoracic kyphosis. another way -possible with young children when the synchondroses of the cranial base are still patent -is to increase the amount of fl exion in the cranial base. such an increase of cranial base fl exion is present in mouth-breathing children. 7 interestingly, an increase in cranial base fl exion in primates has been shown to result in a decrease of the anteroposterior length of the nasopharynx and shortening of the anteroposterior length of the mandibular ramus. 8 the decrease of the anteroposterior length of the nasopharynx reinforces the tendency for mouth breathing, while the shortening of the anteroposterior length of the mandibular ramus correlates with the receding of the chin (retrognathia) that is observed in children who are mouth breathers. adenoidectomy is considered to be an effective treatment for children with enlarged adenoids who are mouth breathers. however, recurrence of breathing diffi culties in these children has been observed and is attributed to their craniofacial anatomic pattern. 7 an extended craniocervical junction, or any dysfunctional pattern in the surrounding myofascial structures, may, therefore, be considered a primary dysfunction that could, in turn, predispose the child to chronic mouth breathing. this is confi rmed by clinical observations that some children present with chronic mouth breathing secondary to nasal airway obstruction, while others tend to be mouth breathers without any obvious obstruction of the nasal airway. mouth breathing has also been correlated with an inferoposterior displacement of the hyoid bone and an anteroinferior positioning of the tongue. 4, 7, 9 the hyoid bone, a 'u-shaped' bone with an anterior convexity, is not directly articulated with any other skeletal structures. through its myofascial attachments it acts as an interface between the tongue, the pharynx, the larynx and the skull and thorax. therefore its position is infl uenced by dysfunction of any of these related structures and it can, in turn, exert infl uence on them. in mouth breathers, both the hyoid bone and the tongue are displaced to a position lower than normal. chronic mouth breathers often demonstrate premature molar eruption. mouth breathing also infl uences the growth of the mandible, resulting in anterior mandibular rotation 9 and increase of the gonial angle between the ramus and the body of the mandible. 7 consequently, the vertical height of the lower face of mouth breathers is usually increased, with a resultant open bite that is an augmentation of the vertical dimension separating the jaws. 9 nose breathing performs several functions of importance, such as warming and humidifi cation of the inspired air, facilitation of arterial oxygenation 10 and regulation of pulmonary function. 11 nasal obstruction is linked to obstructive sleep apnea in children as well as in adults. therefore, nasal obstruction is a signifi cant dysfunction and osteopathic procedures can often be applied to improve the patency of the nasal airway. preventive treatment should be carried out for infants and toddlers to ensure normal development of the cranial base and craniocervical junction. mouth breathing is present with and without nasal obstruction and the child should be evaluated to determine if nasal obstruction is present. in severe cases, nasal endoscopy and medical treatment may be necessary. hyponasal speech usually indicates an obstructed airway. a simple way to check for nasal patency is to ask the child to breathe, at least 10 times, through their nose while keeping their mouth closed. the child should be able to perform this test without becoming short of breath. diffi culty in achieving the test may be associated with rhinitis or chronic sinusitis. successfully completing the test indicates that the prognosis for a positive response to manipulative treatment is good. an alternative method to assess nasal patency is to hold a mirror under the nostrils of the subject. normally patent nasal respiration will fog the mirror. if nasal obstruction is not demonstrated, the child should be examined to defi ne somatic dysfunction possibly responsible for mouth breathing. identifi ed somatic dysfunction should be treated and then procedures to establish nasal breathing should be taught to the child. the objective of treatment is to obtain optimal posture, improve function of the cervical and thoracic spine, balance the cranial base and its relationships with the hyoid bone and mandible, and facilitate nasal passage patency. as the pharyngeal tonsil is located immediately below the cranial base, at the level of the sphenobasilar junction, augmentation of the motion of the cranial base may increase tonsilar lymphatic drainage. when treating the child it is best to begin by addressing their global standing posture. observe the relationship between the head and the remainder of the body. look for any asymmetries of cervical rotation and sidebending. look for an exaggerated position of cervical extension or fl exion and for increased thoracic kyphosis and lumbar lordosis. next, with the child in the supine position, palpate for tissue texture change in the suboccipital area and in the cervical and thoracic spine below. palpate the soft tissue in the submandibular area; look for any lack of tonicity of the genioglossus muscles. palpate for texture change in the tissues surrounding the mouth and the nose. assess the motion of the suboccipital area, cervical and thoracic spine. the cranial base, sphenobasilar synchondrosis and sphenoid should be evaluated next. the motions of the frontal bone, ethmoid and facial bones, particularly the maxillae, are considered next. identify any membranous myofascial dysfunction that might also be present and treat accordingly, following indirect principles. teaching the child activities for the rehabilitation of normal breathing habits should complete the treatment. the child should be trained to breathe through their nose. they should be taught to control the nasalis muscle that compresses the nasal aperture with its transverse part and laterally opens the nostril with its alar part. with their index fi nger and thumb bilaterally contacting their nose, lateral to the nasal ala, they can be taught to feel the expansion of the nares when breathing. next, they can be encouraged to open their nostrils more dynamically during inhalation while palpating the resultant nasal expansion. encouraging them to smell pleasant odors such as fl owers or favorite foods may further increase awareness of nasal function. small children may be taught to intermittently fl are and relax their nostrils by telling them to move their noses as a rabbit does, while keeping their mouths closed, but not so tight as to purse their lips by constricting the orbicularis oris muscle. the upper airway is a very complex area that participates in several physiologic functions as diverse as deglutition, vocalization and respiration. multiple anatomic structures take part in the mechanics of respiration. consequently, more than one specifi c site of the upper airway can be blocked in obstructive disorders such as sleepdisordered breathing (sdb) where the different parts of the pharynx, the base of the tongue and the esophagus may be involved. 12 in sdb, several factors may be present along with the obstructive phenomenon. these include abnormalities or diseases of the paranasal sinuses, tonsilses, soft palate and tongue, as well as obesity. [13] [14] [15] a review of the development and relationships between the multiple constituents of the upper respiratory system is helpful in understanding the dysfunctional patterns of the region. the respiratory system consists of the larynx, trachea, bronchi, lungs and pleura. the larynx is situated between the trachea and the root of the tongue. it forms the lower part of the anterior wall of the pharynx and is the organ of voice. in the infant, during the fi rst 2 months of life, the larynx is located in a high position and, throughout both deglutition and respiration, contact is maintained between the epiglottis and the soft palate. 16 by approximately 6 months of age, however, this contact is maintained only during deglutition and separation occurs during respiration. the larynx progressively descends from a high position in the neck at the level of c1-c3 during the fi rst 2½-3 years of life to a lower position in the adult, where it is located between the upper border of c4 and the upper border of c7. 16 during the fi rst 2 years of life the descent of the larynx is associated with important changes in the relationships of the structures that constitute the pharynx. in the newborn and the very young infant, the tongue is located totally within the oral cavity. as the larynx descends, the posterior part of the tongue is drawn posteriorly and inferiorly to participate in the constitution of the superior part of the anterior wall of the pharynx, i.e. the oropharynx. the pharynx is shaped like a funnel, having a length of about 12.5 cm. the upper wide end of the pharynx is tipped forward and consists of the oral and nasal cavities, whereas the lower part, at about the level of c6, is continuous with the esophagus. superiorly, it is attached above to the base of the skull on the posterior borders of the medial plates of the pterygoid processes of the sphenoid bone, on the petrous parts of the temporal bones and on the pharyngeal tubercle of the occipital bone. laterally, the pharynx is connected to the styloid processes of the temporal bones and posteriorly to the cervical spine and the prevertebral fascia that envelops the longus colli and longus capitis muscles. the anterior portions of the pharynx are attached to the medial pterygoid plates of the sphenoid bone, the pterygomandibular raphes, the mandible, the tongue, the hyoid bone, and the thyroid and cricoid cartilages. the pharyngeal wall consists of two groups of muscles, the constrictor muscles and the longitudinal muscles, grouped according to the arrangement of the muscle fi bers. the three constrictor muscles -the inferior, middle and superior -function to constrict the pharyngeal cavity. the longitudinal muscles are the paired stylopharyngeus muscles that connect the pharynx with the styloid processes of the temporal bones, the salpingopharyngeus muscles that connect the pharynx with the cartilaginous part of the pharyngotympanic tubes and the palatopharyngeus muscles that connect the pharynx with the soft palate. the three longitudinal muscles elevate the pharyngeal wall. the pharyngeal muscles are innervated by the vagus nerve (cn x), except for the stylopharyngeus muscles that are innervated by the glossopharyngeal nerve (cn ix). the pharynx consists of three parts: the nasopharynx into which the choanae of the nasal cavity open, the oropharynx that constitutes the posterior portion of the oral cavity and the laryngopharynx into which the superior portion of the larynx opens. the soft palate is located between the nasopharynx and the oropharynx. the soft palate is a determining factor in the establishment of the breathing route. it is compared to a curtain hanging from the posterior border of the hard palate, i.e. the posterior borders of the two palatine bones. the soft palate extends downwards and backwards between the mouth and pharynx. it consists of muscular fi bers, aponeurosis, vasculature, nerves, adenoid tissue and mucous glands enclosed in a fold of mucous membrane. its posterior surface is convex and is continuous with the fl oor of the nasal cavities. its anterior surface is concave and is continuous with the roof of the mouth (fig. 7.4.1) . the position of the soft palate determines the route of breathing. it acts as a valve hanging over the oropharyngeal isthmus. in its more horizontal position it separates the nasopharynx from the oropharynx, its posterior tip being closer to the posterior wall of the pharynx, facilitating the oral route of breathing. when it is depressed against the base of the tongue, the oropharyngeal isthmus is closed and the nasal breathing route is made possible. when respiration is through both mouth and nose, the position of the soft palate is shown to be between the tongue and the posterior pharyngeal wall. 13 the soft palate is under the control of fi ve pairs of muscles. the levator veli palatini (lvp) and tensor veli palatini (tvp) arise from the base of the skull. the lvp originates from the apex of the petrous part of the temporal bone and from the cartilage of the pt and spreads in the palatine velum to blend with the muscle of the opposite side. the tvp arises from the scaphoid fossa of the medial pterygoid plate, from the spina angularis of the sphenoid and from the lateral wall of the cartilage of the pt. it descends vertically and then turns around the pterygoid hamulus to insert into the palatine aponeurosis. the musculus uvulae is related to the uvula. the palatopharyngeus arises from the pharynx and the palatoglossus from the tongue. all the soft palate muscles are innervated by the vagus nerve (cn x) except the tvp that is innervated by the mandibular nerve (cn v 3 ) . the tvp muscles tense the soft palate; the lvp muscles elevate the soft palate and, therefore, close the nasopharynx. the palatopharyngeus muscles depress the soft palate and participate in the closing of the oropharyngeal isthmus. the palatoglossus muscles depress the soft palate caudally and ventrally and elevate the root of the tongue. the function of the soft palate is supposed to be actively determined, with dominant activity of the palatoglossus muscle when a subject is breathing quietly, and more activity from the lvp muscle during forced expiration. 13 some activities such as breathing exercises or singing require both the nasal and oral breathing routes and the position of the soft palate consequently adapts to the situation. normal breathing relies on a patent nasal and pharyngeal airway. this patency depends on neural regulatory mechanisms as well as normal anatomic structures. the neural regulation is in part under the control of refl exes mediated through the trigeminal nerve (cn v) or the vagus nerve (cn x). the role of the vagus nerve is of paramount importance in the preservation of pharyngeal airway patency and any dysfunction of the upper cervical spine, in particular at the level of the jugular foramen, should be considered when airway patency is functionally compromised. considering the anatomic structures, the soft palate has been found to be the most common site of obstruction in infants presenting with signifi cant obstructive sleep apnea (osa). 17 furthermore, an increase of cranial base fl exion has also been demonstrated in mouth breathing or sdb children. 7 one can assume that, because of the insertion of the soft palate muscles, a dysfunction of the cranial base would lead to modifi ed soft palate mechanics. the soft palate occupies a strategic position, an intersection between the muscles arising from the base of the skull and the muscles connected to the tongue and the pharynx. considering these relationships, it is logical that any disturbance in the anatomic features infl uencing the soft palate, the tongue and the pharynx may also play a role in the development of sdb. adenotonsillar hypertrophy is described as being the most common cause of osa in children; its importance correlates with the dimension of the adenoids. 18 osa, the result of airfl ow obstruction, occurs in older children as well as in infants, where symptoms may include apneic spells. 17 pharyngeal collapse is involved and it is proposed that airway muscle dysfunction 19 or anatomic alterations predispose to that collapse. 20 loss of longitudinal tension within the pharyngeal airway is suggested as being responsible for the collapsibility. 20 subtle abnormalities in upper airway neuromuscular function or structure are proposed additions to the etiology of adenotonsillar hypertrophy. 21, 22 the craniocervical junction is under great stress in the infant and dysfunction of the pharynx, which is attached to the base of the skull and to the cervical spine and prevertebral fascia, may be associated with any somatic dysfunction of the craniocervical junction and cranial base. the position of the cervical spine is correlated with pharyngeal changes: cervical fl exion reduces oropharyngeal size; cervical extension increases it. 5, 23, 24 studies have demonstrated that patients with obstructive sdb present a narrower or more obstructed oropharynx and laryngopharynx than controls, particularly during sleep. 15 besides the effect of cervical posture, alteration of refl exes due to sleepiness may play a role. when present, nasal obstruction also disturbs nasopharynx refl exes, mediated through the trigeminal or vagus nerves, which may result in decreased patency of the oropharynx. 25 multiple sites are considered as potential causes for sdb. in view of the intricate anatomic relationships of the soft palate, the pharyngeal wall, the tongue and the mandible, any dysfunction of one affects the associated structures and their positions. biomechanical interactions between the tongue and lateral pharyngeal walls have been described 26 and displacement of the mandible also affects oropharyngeal size. 5 mouth opening reduces oropharyngeal size. 27 the modifi ed mandible position affects the function of the genioglossus, one of the tongue muscles that protrude the anterior part of the tongue out of the mouth. this, in turn, increases upper airway collapsibility, the position of the tongue being a strong determinant of the patency of the oropharynx. this explains why mouth breathers present with snoring and sdb. 7 alterations in the electromyographic activity of the geniohyoid and genioglossus muscles follow experimental nasal obstruction in monkeys with affected mandibular growth as a result. similar mechanisms are believed to exist in humans 27 where mouth breathing in children, associated with sdb, may cause developmental facial abnormalities. 25 maxillary and mandibular protrusions are smaller in children with osa and the position of the hyoid bone is lower. 28 mouth breathing generates the development of a craniofacial type that includes an increased value of the anterior facial height and an open bite. 29 the increased respiratory effort that these children must exert is responsible for functional impairment and eventually structural changes in their craniofacial anatomy. osa is also associated with poor sleep quality, failure to thrive, impaired daytime psychomotor performance, irreversible developmental delay 17 and enuresis. 30 osteopathic procedures should consequently be employed at the earliest possible time to avoid the establishment of dysfunctional patterns and their sequelae. begin by assessing for, and treating, any dysfunctional imbalances in the global postural pattern, particularly the craniocervical junction and upper aspects of the thoracic region including clavicle, sternum, upper thoracic vertebrae and associated ribs. next, attention should be paid to the mechanics of the hyoid bone, including the infra-and suprahyoid muscles because of their relationship with the pharynx and tongue. the synchondroses of the cranial base, the occipitomastoid sutures and the relationship between the sphenoid and temporal bones should be considered next. any dysfunction of the temporal bones should be addressed in the treatment of sdb because of the connection between the longitudinal muscles of the pharynx and the styloid processes of the temporal bones. evaluate the temporomandibular joint, the mandible and surrounding myofascial elements. the inferior part of the pharynx is continuous with the esophagus that connects the pharynx to the stomach. possible stomach as well as tracheal visceral dysfunctions may affect the pharynx, either through mechanical imbalance or through disturbed vagal refl ex; therefore, they should be treated if present. teaching the child activities that strengthen and tone the soft palate and tongue can complete the treatment. vocal exercises employed in singing are benefi cial. the tongue, particularly the genioglossus muscles, can be strengthened by having the child alternately attempt to touch the tip of their tongue up to the tip of their nose and down to their chin. bronchiolitis is an acute viral infection of the lower respiratory tract that affects infants and young children. in europe, australasia and north america, an average of 3% of all children born every year present with bronchiolitis. 31 respiratory syncitial virus (rsv) and infl uenza a virus are the most important viral causes of lower respiratory tract infection in young children. infections with infl uenza viruses b and coronavirus may also be common. 32 infl uenza viruses are highly contagious and are responsible for epidemics presenting various degrees of severity, although only a small proportion of children infected with the virus develop severe disease. risk factors are childcare attendance, exposure to environmental pollutants, school-aged siblings, congenital abnormalities of the airways and neuromuscular disease. 33 rsv is so named because, in tissue culture, it grows as a giant syncytia, a mass of protoplasm containing several nuclei. multiple genotypes of rsv cocirculate every year, 34 along with an important variability in infl uenza virus occurrence from year to year. 32 the infecting virus fi rst establishes in the upper respiratory tract and then spreads to the medium and small bronchi and bronchioles, resulting in infl ammation of the epithelium with edema and bronchial obstruction that manifests principally during expiration. air is trapped within the alveoli and hyperinfl ation of the lungs follows. respiratory distress appears with tachypnea and tachycardia. expiration is diffi cult and prolonged, and when the infant presents with severe tachypnea, breath is rapid and short, with poor air exchange. wheezing, crepitus and fever may be present. rsv is an important childhood pathogen in infants younger than 24 months of age. 35 once infected, an infant does not develop complete immunity and recurrence of infection is common. pneumonia and bacterial superinfections of the respiratory tract are frequent complications. 32 rsv may be severe in infants under 3 months of age and is an important cause of hospitalization for acute lower respiratory tract infection in infants and young children. 36 bronchiolitis, particularly when due to rsv, may be a precursor of the later development of asthma. allergic rhinitis also exacerbates bronchial infl ammation and may be a risk factor for the development of asthma. 37 young children who have more than three episodes of infectious bronchiolitis, and those with a family history of asthma who have more than two episodes of infectious bronchiolitis, may also be predisposed to asthma. widespread respiratory viruses like rsv are also possible factors in the cause of acute otitis media in young children. 38, 39 consequently, preventive considerations should be applied. the primary defense against common pathogens of acute lower respiratory infections is waldeyer's (circumpharyngeal) tonsillar ring, a collection of lymphoid tissue in the mucosa of the nasopharynx. it consists of the pharyngeal tonsil, the palatine tonsils and the lingual tonsil that are the multiple lymphoid nodules located on the posterior part of the tongue, plus small other nodules in the pt and lymphoid tissue in the intertonsillar intervals. the nasopharyngeal tonsil increases in size in the fi rst years of life, are largest at 6 years and atrophies by the time of puberty. the efferent lymphatics of these mucosa-associated lymphoid tissues start in plexuses surrounding every lymphoid follicle and drain through the retropharyngeal lymph nodes or directly into the upper deep cervical nodes. the retropharyngeal nodes consist of three groups, two of which are located on either side, anterior to the lateral masses of c1, following the lateral borders of the longi capitis. somatic dysfunction of the cervical spine, the frontal bone, the maxillae, the ethmoid bone, the nasal bones and the zygomatic bones can alter the function of the upper respiratory tract as a primary defense against common pathogens. dysfunction of the thoracic cage and diaphragm can impair effi cient return of lymph to the general circulation and the ciliary clearance current of mucus in the bronchial tree. thus, somatic dysfunction can contribute to the creation of a fertile environment wherein pathogens can thrive. it has been shown that osteopathic manipulative treatment (omt), particularly the lymphatic pump, results in decreased morbidity and mortality in patients with infl uenza. 40, 41 the ans is of prime importance in the regulation of bronchial secretion and its dysfunction may facilitate bronchiolitis. the sympathetic postganglionic fi bers between t2 and t4 stimulate bronchial and bronchiolar dilatation and decrease fl uidity of the secretions. the pulmonary branches of the vagus nerve are motor to the muscles fi bers of the bronchi and bronchioles and are consequently bronchoconstrictor. thus, somatic dysfunction of the upper thoracic, upper cervical and cranial regions can affect the lower respiratory tract through somatovisceral refl ex action. the objective of osteopathic treatment in the acutely ill, non-emergent child with bronchiolitis is to stimulate the expectoration of mucus, reduce air trapping and promote homeostasis by balancing the ans and enhancing the venous and lymphatic drainage of the lungs. furthermore, it is important to reduce somatic dysfunction that can predispose the child to the recurrence of the illness. observe the chest and the way the child is breathing, paying particular attention to the mobility of the ribs and sternum. children with respiratory obstruction may demonstrate suprasternal, infrasternal, subcostal and intercostal retraction when breathing. on percussion, the chest is hyperresonnant. prolonged expiration, wheezing, and fi ne moist crackles may be observed at auscultation. it is important to auscult the lungs before and after the osteopathic treatment. using indirect principles, restore thoracic spine and rib motion. thoracic pumping may be used to loosen mucus, stimulate expectoration and decrease bronchial obstruction. the thoracic diaphragm and thoracic inlet should be evaluated and treated as fi ndings dictate. rib raising and sternal molding may be applied to further mobilize the thoracic cage, increase ventilation, loosen mucus and stimulate expectoration. sympathetic activity should be balanced by treating any dysfunction of the upper thoracic spine (t2-t4). parasympathetic tone can be normalized with treatment of the suboccipital area. using indirect principles, treat any cervical somatic dysfunction that is present. improve lymphatic drainage from the upper deep cervical lymph nodes with soft tissue techniques applied to the cervical myofascial structures. observe the child's face. the frontal bone, the maxillae, the ethmoid bone, the nasal bones and the zygomatic bones form the upper respiratory tract. look for asymmetries of these structures and for any tissue texture change. palpation and motion testing will confi rm these observations and treatment should be applied accordingly. it is imperative that the child is breathing through their nose, so any dysfunction that impairs nasal respiration should be addressed. following manipulative treatment it is important to re-evaluate the child. re-evaluate the musculoskeletal areas treated and auscult the lungs again to check clearance of the secretions and progress of airfl ow. it is important to maintain hydration of the respiratory tract. the caregivers should be advised to encourage consumption of fl uids and to maintain suffi cient humidifi cation of the child's environment. asthma is the most frequently encountered chronic disease in childhood. allergic disorders and asthma in childhood have increased in prevalence in many countries over the past 20-30 years. 42, 43 asthma is characterized by chronic infl ammation leading to airway hyperreactivity and recurrent reversible airfl ow obstruction. a multifaceted interaction of genetic and environmental factors appears to cause asthma. a genetic predisposition seems to exist 42, 44, 45 and the risk is greater if both parents present with the disease. 46 in the predisposed host, immune responses to different exposures such as allergens and air pollutants may trigger pathogenic infl ammation. 47 children from lower socioeconomic groups more often present with asthma, rhinitis and allergic sensitization, especially to food allergens. 48 different factors may explain this susceptibility, the quality of food being one of them. evaluation of different diets demonstrates the asthma preventive effect of dietary management for children with a family history of asthma. of demonstrable benefi t are diets with increased anti-infl ammatory 'n-3' polyunsaturated fatty acids (omega-3 polyunsaturated fatty acids), alone 49 and in combination with house dust mite allergen prevention. 50 there is also some evidence that dietary omega-3 polyunsaturated fatty acid supplementation during pregnancy and early childhood may potentially reduce infant atopy and asthma. 51, 52 the controversial 'hygiene hypothesis' was developed in the late 1980s to explain the high prevalence of allergic diseases and asthma in industrialized countries. 53 the attention to hygiene in these countries is associated with reductions in microbial exposures and decreased incidence of infectious diseases. microbial encounters in infancy and early childhood stimulate the development of the immune system and the 'hygiene hypothesis' states that atopic disorders are the consequences of the lack of early life infections. 54 alternatively, the use of antibiotics in the 1st year of life may increase the risk of asthma. 55 opposite to the hygiene hypothesis, however, there is evidence that the pathogenesis of asthma may include early exposure to viruses and bacteria. 56, 57 a high frequency of respiratory tract infections in the 1st year of life is a predictor of asthma between the ages of 6 and 8 years. 46, 58 elevated ige levels at 6 months are also a predictor. 46 alternatively, the association of atopy with asthma is controversial and the onset of eczema during the 1st year of life is not always found to be associated with the later development of asthma in childhood. 46 a clinical association between rhinosinusitis and asthma is strongly suggested. furthermore, effective treatment of rhinosinusitis has a positive effect on concomitant asthma. 59 elements that contribute to the concept of 'united airway' disease include the dissemination of postnasal drip of infl ammatory cells into the lungs. a vascular circulatory route with the migration of infl ammatory cells to the lungs is another suggested pathway to explain the connection. another possible link between the upper and lower airways is through the nervous system, with naso-pharyngo-bronchial refl exes involving the trigeminal and the vagus nerves. 60 upper airway infl ammation may have an effect on receptors in the nose and pharynx. afferent (sensory) fi bers from these receptors participate in the constitution of the trigeminal nerve that connects with the dorsal vagal nucleus in the brainstem through the reticular formation. the vagus sends parasympathetic efferent fi bers to the bronchi to preserve bronchial muscle tone and modulate bronchospastic responses. in asthmatic children, bronchoconstriction and mucus secretion is increased due to augmented parasympathetic nerve activity. 61 a neurogenic infl ammation activated by infl ammatory mediators and environmental irritants along the neural refl ex pathway may be the cause of a neuronal dysfunction. 62 the osteopathic principle of holistic integration of the different parts of the body applies perfectly to this hypothesis where an initial body reaction is followed by distant manifestations. the theory of 'one airway -one response' states that the common histopathology in both upper and lower airways results in a global allergic infl ammation of the whole airway. the total body allergic response is also illustrated through interactions between the respiratory system, the skin and the gastrointestinal tract. the lung and the gut are part of a unifi ed mucosal system. the circulation of cells of the blood, from the bone marrow and the mucosal lymphoid tissue explain a possible interaction between these different areas and allergens. 63 the intestine is one of the most signifi cant immune organs of the body. the composition of its microfl ora differs between infants with and without atopy, and the differences are verifi able before the occurrence of some clinical manifestation such as asthma. 64 alternatively, there is a link between the mode of obstetrical delivery and the maturation of the humoral immune system. infants delivered by cesarean section demonstrate a delay in intestinal colonization. 65 the initial stimulation by the gut microfl ora may possibly be more signifi cant than that of a sporadic infection and there is evidence of a relationship between cesarean section delivery and increased occurrence of atopic asthma. 66 there is another connection between the lung and the guts with asthmatic patients. about 50-80% of adults and children with asthma present with gastroesophageal refl ux -refl ux of gastric contents into the esophagus -which may not be clinically obvious. 67 intracellular acidifi cation diminishes the ciliary beat frequency of the epithelial cells of the human tracheobronchial apparatus. 68 this point is signifi cant in asthma, as well as in other respiratory dysfunction, as a factor contributing to decreased mucociliary clearance. the lungs and esophagus are both innervated by the vagus and upper thoracic distribution of the sympathetic nervous system. autonomic dysfunction may explain symptoms related to both gastroesophageal refl ux and asthma. 69 under normal conditions, the parasympathetic nervous system through the vagus sustains bronchial muscle tone while sympathetic fi bers evoke bronchodilatation. sympathetic nerve fi bers also innervate the bronchial and gutassociated lymphoid tissue that seems to be essential in neuroimmune interactions. 70 the parasympathetic visceral sensory system collects internal information that, in turn, infl uences emotions as much as emotional states impact autonomic function. 71 the infl uence of stress is potentially negative on neuroimmunoregulation. 70 in asthmatic patients, there is evidence that stress experienced prenatally or in the 1st years of life may participate in the development of asthma. 72, 73 increased psychological stress may impact respiratory illnesses in children and contribute to immune deregulation. there is evidence that stress facilitates susceptibility to infections 74 and may be associated with the development of asthma. very often, asthmatic children present with anxious facial expression. most of the time, an asthmatic reaction is triggered by exposure to numerous environmental agents. asthmatic children have hyperresponsive or hyperreactive airways. various stimuli such as dust mites, pollutants and tobacco smoke produce an exaggerated bronchoconstrictor response with sensations of shortness of breath and chest tightness. there is evidence that the pathogenic development occurs early in the lungs, producing architecturally altered lungs later in life. 47 treatment, therefore, should be initiated as soon as possible. asthma presents in different forms. the patient may demonstrate prodromal symptoms such as itching over the upper part of the chest and associated dry cough. this can be followed by episodes of dyspnea, tachypnea and tightness in the chest with wheezing and coughing that result from exposure to allergens, air pollution 75 or exercise. in asthmatic patients, a bronchoconstrictor response follows nasal inhalation of cold air. 76 other patients present with chronic coughing and wheezing, associated with shortness of breath and decrease of vital capacity. anxiety may occur related to the sensations of shortness of breath and chest tightness. osteopathic considerations for the treatment of asthma, although directed as a whole body intervention, are specifi cally focused on somatic dysfunctions of the thoracoabdominal diaphragm, thoracic cage, upper thoracic spine, cervical spine, sacrum, cranium and face. the goals of treatment are to encourage expectoration of mucus, reduce the mechanical impact of somatic dysfunction, enhance the recuperative effect of balanced sympathetic and parasympathetic tone, and facilitate the arterial, venous and lymphatic components of tissue perfusion. because signs and symptoms are often observed fi rst by the parents, these children may present to the osteopathic practitioner before the diagnosis of asthma has been formally made. it must be stressed that asthma is a potentially life-threatening condition, and although the treatment of somatic dysfunction can greatly benefi t the patient, 77,78 the need for other methods of medical management should never be dismissed. the earlier somatic dysfunction is effectively addressed, the better the possible outcome. manipulative treatment should begin with the area most easily accessible without distressing the child. the sequence of treatment is determined by the patient's acceptance of the intervention. older children are commonly tolerant and treatment may be begun on the treatment table. for younger children, it is often easier to begin with the evaluation and treatment of the upper thoracic cage because this can be done with the child seated, even in the caregiver's lap. after a trusting physicianpatient relationship has been established, the child may then be transferred to the treatment table for further treatment. with the child seated or supine, observe the upper thoracic cage, looking for decreased compliance to respiratory excursion, i.e. tension of the scalene, trapezius and sternocleidomastoid muscles in the region of the supraclavicular triangle. evalu-ate sternoclavicular motion and fl exibility of the sternum for dysfunction. articular motion of this region becomes mechanically discrete as the skeletal structures become more developed around 7 years of age. palpate the thoracic spine and ribs for somatic dysfunction, paying attention to the area from t2 to t4 because of viscerosomatic input and somatovisceral impact with the lungs in this region. utilizing indirect principles, treat identifi ed somatic dysfunctions. following this, with the child, if possible, in the supine position, evaluate the lower thoracic cage and thoracoabdominal diaphragm. observe the mechanical pattern of respiration. asthmatic children tend to demonstrate forced expiration. palpate for lower thoracic cage compliance, comparing the inspiratory and expiratory phases of respiration. greater resistance will typically be appreciated during the expiratory phase and the child will often manifest shallow, rapid respiration. palpating the lower thoracic cage bilaterally, evaluate for general tension and asymmetry in the excursion of the thoracoabdominal diaphragm. assess the lumbar spine for dysfunction that can impact the diaphragm through the diaphragmatic crura. examine the sacrum and pelvis to identify dysfunctional mechanics that can affect the asthmatic through the core link. treat identifi ed somatic dysfunction with indirect procedures. entraining the movement of the manipulative treatment with the patient's breathing allows the practitioner to follow and gradually augment the amplitude of respiratory excursion. next, evaluate the cervical spine and myofascial structures of the neck. after general screening for dysfunction, attention should be directed at the upper cervical spine because of the viscerosomatic and somatovisceral vagal infl uence of the area. treat identifi ed dysfunction. examination can now proceed to the cranial base. using your preferred hand placement, evaluate the motion of the sbs. anecdotally, children with asthma and eczema seem to present frequently with sbs compression and decreased amplitude of the cri. assess the relationship between the occiput and temporal bones for compromise of the jugular foramen with its potential to interfere with vagal function. evaluate the temporal bones where part of the tentorium cerebelli attaches. dysfunction at this level affects the respiratory breathing pattern. an external rotation of one temporal bone tends to limit the freedom of expiration. examine the relationship between the sphenoid, frontal and facial bones. the bones of the face -ethmoid, lacrimal, maxillary and nasal bones, which contribute to the structure of the nasal airway -are suspended beneath the frontal bones. additionally, the ethmoid bone articulates posteriorly with the sphenoid. it is not uncommon to encounter compression between the frontal bones and the bones of the face. treat specifi cally identifi ed dysfunctional patterns. it is important that the nasal airway is unobstructed because of the effect of nasal respiration on inspired air and thoracopulmonary function. the interrelationship between rhinosinusitis and asthma further stresses the importance of appropriate function of the facial bones in asthmatic children. treatment of the cranial mechanism with attention to the inherent rhythm augments the cri with a resultant total body effect. following manipulative treatment, various activities can be prescribed to facilitate the results of the intervention. for small children the caregiver should be encouraged to regularly gently stroke the thoracic paravertebral region, particularly t1-t5, bilaterally. the child can be encouraged to perform expiratory activities like blowing soap bubbles. older children can be taught breathing exercises to improve lung function to increase vital capacity, facilitate the clearing of airway secretions and enhance the quality of life. begin by encouraging the child to breathe slowly and deeply, employing the thoracoabdominal diaphragm and with the least possible utilization of the accessory muscles of respirationscalene, sternocleidomastoid, trapezius and abdominal wall muscles. they should learn to breathe on demand with particular attention to control of expiration. further, they should be taught to hold their breath in the most relaxed possible way. this allows them to experience apnea without anxiety. as they become experienced in these activities, they can be encouraged to practice this method of respiratory relaxation at the fi rst perception of an asthma attack. because controlled breathing is an integral part of singing, they may benefi t from participation in a choral group. teach them to maintain good posture. a simple procedure is to have the child walk with a book balanced on the top of their head. finally, children and adolescents with asthma should participate in regular physical activity. 79, 80 diet considerations should be initiated. daily intake of fresh fruit and vegetables should be recommended. processed sugars and foods that increase gastric acidity should be limited. dairy products (e.g. ice cream) which increase mucus production should be consumed moderately and preferably before 5 p.m. to facilitate gastric emptying before bedtime and avoid gastroesophageal refl ux. approximately 20% of infants demonstrate symptoms of imperfect lacrimal drainage during their fi rst months of life. most of the time spontaneous resolution takes place and by their 1st birthday only about 0.7% of infants still present with the condition. 1 congenital nasolacrimal duct obstruction (dacryostenosis) may result from an abnormality in the lacrimal drainage system or from an infection. the diagnosis of congenital nasolacrimal duct obstruction is clinical. it is based on a history of epiphora (tearing), mucopurulent discharge, or both, in the presence of non-infl amed conjunctiva, usually affecting only one eye and occurring in the fi rst few weeks of life. the condition may be continuous or intermittent and crusting on the lid margins is common. parents will often report that the eyelids are stuck together on the child's awakening or that the child has a persistently watering or sticky eye. digital pressure applied medial to the eye over the lacrimal sac will produce increased discharge from the excretory puncta. there is much debate regarding a standard medical approach for the management of congenital nasolac-rimal duct obstruction. 2 the availability of multiple therapeutic approaches for any given condition indicates that none of them works particularly well in all cases. the list of procedures that are employed as standard to correct symptomatic nasolacrimal duct obstruction includes probing and irrigation, intubation with a silicone tube, balloon dilatation of the nasolacrimal duct and infracture of the inferior turbinate. 3 osteopathic manipulation offers an alternative approach and, since it is benign, it should be attempted before more aggressive procedures are employed. the earlier the infant or child is treated, the better the chance of rapid resolution of the obstruction. additionally, a good mental image of the anatomy of the nasolacrimal duct and lacrimal drainage system, on the part of the practitioner, will provide the basis necessary to improve the effi cacy of manipulation. the lacrimal apparatus consists of several parts that develop simultaneously. the lacrimal gland secretes the tears and the excretory ducts (lacrimal canaliculi) deliver the fl uid to the surface of the eye, while the lacrimal sac and the nasolacrimal duct collect and transport the fl uid into the nasal cavity. the lacrimal gland consists of two portions: the superior orbital part and the inferior lacrimal part. the superior orbital part is located in the lacrimal fossa, in the superolateral part of the orbit, on the medial side of the zygomatic process of the frontal bone. shaped like an almond, it is connected to the periosteum of the orbit and rests on the levator palpebrae superioris and the lateral rectus. the inferior lacrimal gland is separated from the superior by a fi brous septum and projects into the lateral part of the upper eyelid. although the lacrimal gland reaches full development at about 3-4 years of age, the production of tears in infants is similar to that in adults. 4 on each eyelid, the lacrimal canaliculus originates at a lacrimal punctum, a minuscule orifi ce on the medial margins of the lids. the superior canaliculus is the smaller and shorter. first it goes up, then turns at an acute angle to meet the lacrimal sac, while the inferior canaliculus descends, then turns upward toward the lacrimal sac ( fig. 7.5.1 ). at their angles the canaliculi are dilated and form ampullae. their mucous lining is covered by stratifi ed squamous epithelium, positioned on a basement membrane. the external wall consists of a layer of skeletal muscle fi bers, continuous with the lacrimal part of the orbicularis oculi. the lacrimal sac is the upper dilated end of the nasolacrimal duct. it is located in a fossa formed by the lacrimal bone, the frontal process of the maxilla and the lacrimal fascia. it measures from 12 to 15 mm in length and extends to form the nasolacri-mal duct. its superfi cial surface is sheltered by the lacrimal fascia (an extension of the orbital periosteum) and by the medial palpebral ligament. its deep surface is crossed by the lacrimal part of the orbicularis oculi, which is attached to the posterior lacrimal crest on the lacrimal bone. the lacrimal sac is lined by a mucosal membrane continuous with the conjunctiva through the lacrimal canals and with the nasal cavity through the nasolacrimal duct. the relationship with the orbicularis oculi is of particular interest. this muscle surrounds the circumference of the orbit, with osseous attachments on the frontal bone, the frontal process of the maxilla and the lacrimal bone. when it contracts, as during 'blinking', compression of the lacrimal sac occurs through the lacrimal part of the muscle, pushing fl uid into the nasolacrimal duct to drain into the inferior meatus of the nasal cavity. during muscular relaxation, fl uids are drawn into the canaliculi and the expanded lacrimal sac. 5 the nasolacrimal duct extends from the lacrimal sac caudally to open in the inferior nasal meatus. both ends of the duct are wider than its middle portion, where it is enclosed in an osseous canal formed by the maxilla, the lacrimal bone and the inferior nasal concha. it is directed downward, backward and slightly laterally. the nasolacrimal duct is formed embryologically from ectodermal cells enclosed between the maxillary and lateral nasal processes. during the 3rd month of gestation a canal appears in the center of this epithelial cord. it will develop progressively in a cephalocaudal direction from the 6th month of gestation until birth. in the third trimester of gestation the lower portion of the duct opens into the inferior meatus of the nasal cavity to constitute the nasolacrimal duct, while the epithelium from the nasal cavity invests the duct in a caudocephalad direction. a mucosal fold -the valve of hasner -is located just above the nasal opening of the nasolacrimal duct. total canalization of the epithelial cord may fail to occur with the persistence of membranous tissue that should normally disappear at birth or in the fi rst days of life. in congenital nasolacrimal duct obstruction, the lower part of the duct may be closed at birth by fusion of the mucosa covering the nasal folds. the resultant obstruction is usually observed in infants at about the 10th or 12th day of life. nasolacrimal duct obstruction is frequently associated with dysfunction of the bones forming the osseous canal in which the nasolacrimal duct is located, i.e. the maxilla, the lacrimal bone and the inferior nasal concha. it frequently follows compression of the frontal bone and may also be associated with an inferior vertical strain of the sbs. consequently, the relationships between the frontal bone, maxilla and lacrimal bone are affected, potentially modifying the patency of the nasolacrimal duct. this type of compression occurs frequently during pregnancy, diffi cult labor or delivery and appears to be a prediposing factor. furthermore, dysfunction of the frontal bone, maxilla and lacrimal bone changes the relationship between the points of attachment of the orbicularis oculi, predisposing to muscular dysfunction. when treating nasolacrimal duct obstruction, the delicacy of the intervention necessitates that the infant moves as little as possible. this may be accomplished by arranging to see the infant at a time that coincides with their nap time. the best approach is to have the caregiver arrive with the infant about 30 minutes before the scheduled appointment. place the infant and caregiver in a quiet examining room and allow the infant to have their bottle or to nurse. allow suffi cient time thereafter for the infant to go to sleep, preferably in a supine position on the examining table. once the infant is asleep, quietly commence treatment. first observe the frontal bones. often the frontal bone on the side of the lacrimal duct obstruction will be found to be lower than the other side. look next at the area of the nasion, nasal bones and frontal processes of the maxillae, noting asymmetry and compression of these structures. the forces commonly involved in lacrimal duct obstruction are most often vertical compression between the frontal and nasal bones, sometimes with sidebending and rotation of the facial block beneath the frontal bone, with the obstruction on the side of the facial concavity. confi rm the observations with tests of listening, paying close attention to the frontal bones, nasal bones, maxillae and lacrimal bones. keep a mental picture of the minute details of the area to help this process. defi ne areas of restricted motility and employing the inherent forces of the prm and its rhythm, utilize the most delicate indirect treatment procedure. the treatment procedure should be so gentle as not to awaken the infant. encourage the caregiver to regularly clean the secretions from the eye to avoid the development of an infection. to promote drainage into the nasolacrimal duct, the caregiver can milk the lacrimal sac by intermittently applying gentle digital pressure medial to the punctum of the eye in a superior to inferior direction. actively playing with the child to encourage facial expression stimulates the function of the orbicularis oculi. if the child is old enough, have them blink tightly and make faces. contracting the orbicularis oculi promotes drainage by placing pressure on the lacrimal sac. strabismus -the deviation of the alignment of one eye in relation to the other -is a condition frequently encountered in infants and children. it is a very complex subject and its complete discussion is beyond the focus of this text. however, the treatment of somatic dysfunction can prove very beneficial in certain presentations of the condition. strabismus must be taken seriously and signifi cant underlying pathologies, such as congenital cataract and retinoblastoma, ruled out. it is imperative that, on presentation, every case of strabismus, no matter what the age of the patient, has a thorough ocular examination, including cornea, lens, retina and optic nerve, as well as the neurologic status of the eye and extraocular muscles (eom). treatment of strabismus should be initiated at the earliest possible time to avoid loss of the ocular stimulation that normally contributes to the maturation of the visual system. the eyeball -the organ of sight -is contained in the skeletal cavity of the orbit, which provides a protective space for the eyeball and associated structures, i.e. fasciae, eyelids, conjunctiva, lacrimal apparatus and eom. the eyeballs start to develop from neuroectoderm of the lateral aspects of the forebrain as a pair of diverticulae at approximately the 22nd day of gestation. at the 25th day, two optic vesicles are formed. around the 4th week, they invaginate and create the optic cups in which mesenchymal and vascular tissues enter the globe. the different parts of the future eyeball and surrounding orbital cavity are intimately interrelated. at the beginning of the fetal period -the end of the 2nd month of gestation -eom are present, surrounding the eyeball. growth will continue with a signifi cant correlation between gestational age and fetal eye biometry, including lens, orbital diameters, circumferences and surfaces. 6 surrounding the eyeball, the constituents of the orbital cavity consist of the frontal, lacrimal, palatine and zygomatic bones, ethmoid, maxilla and sphenoid. they develop in membrane and are quite responsive to the growth stimulation of the eyeball. thus, the orbital cavity is growing as a result of the increase of the volume of the eyeball and the activity of the eom, with more and more elaborate eye movements. from this time up to 5 years of age, the eyeballs will continue to grow, acting continuously as a growth stimulator for the skeletal cavity of the orbit. at birth, the orbit height is already 55% of its adult height. at 3 years of age it is 79%, while at 7 years of age it is about 94%, nearly its adult size. 7 evidence of the importance of this stimulating factor is demonstrated by conditions like microphthalmia, where the development of the eyeball does not occur correctly, or when an individual is enucleated in early childhood. underdevelopment of the orbital cavity is typically associated with these conditions. an anophthalmic bony orbit may be 14.5% smaller when compared to the other orbit. 8 the concept that function affects structure, one of the basic osteopathic principles, is perfectly illustrated in this instance. at the same time, structure affects function. in this case, the structures forming the orbital cavity may affect the ocular function of sight, associated vascular and neurologic aspects, and extra-and intraocular muscular activity. therefore, it is appropriate to consider the protective case for the eye, i.e. the orbital cavity, and to see how its osseous components play a part in the etiology of ocular dysfunction. the orbits are located in the upper and anterior part of the viscerocranium. they are shaped like pyramids, with their apices and long axes directed backward and medially. each orbit consists of a roof, a fl oor, a medial and a lateral wall, a base and an apex. the roof is concave, directed downward and slightly forward. the orbital plate of the frontal bone forms most of the roof, while the lesser wing of the sphenoid forms its posterior part. therefore, there is a suture on the roof of the orbital cavity between the frontal bone and the lesser wing of the sphenoid. the lacrimal fossa for the lacrimal gland is located laterally on the orbital surface of the frontal plate. medially, below and behind the end of the supraorbital margin of the frontal bone, is the trochlear fovea for the attachment of the cartilaginous pulley of the superior oblique muscle. this feature is of particular interest in understanding ocular dysfunction, since the frontal bone is frequently under stress from fetal positioning, diffi cult labor or trauma sustained by young children, such as a fall on the head. although most of this anatomy is not directly palpable, the supraorbital margin of the frontal bone is completely accessible and its position should always be evaluated in strabismus. the fl oor of the orbit is directed upward and laterally. it consists mostly of the orbital surface of the maxilla; behind that and medially, the orbital process of the palatine; and in front and laterally, the orbital process of the zygomatic bone (fig. 7.5.2) . the maxilla articulates with both the palatine and the zygomatic bones. the lacrimal notch is located anteriorly, on the medial border of the maxilla, and provides the superior opening of the nasolacrimal canal. on this border the maxilla articulates with the lacrimal bone and the ethmoid's orbital plate behind. a depression situated just lateral to the lacrimal notch is the location of the origin of the inferior oblique muscle. the posterior border of the maxilla forms most of the anterior edge of the inferior orbital fi ssure, discussed further below. the medial wall of the orbit is formed anteriorly by the frontal process of the maxilla, the lacrimal bone, the orbital plate of the ethmoid and a tiny part of the body of the sphenoid in front of the optic foramen. the lacrimal groove for the lacrimal sac is located anteriorly. it is limited behind by the posterior lacrimal crest, from which the lacrimal part of the orbicularis oculi arises. three vertical sutures -the lacrimomaxillary, lacrimoethmoidal and sphenoethmoidal -are present, while the frontomaxillary, frontolacrimal, and frontoethmoidal sutures are situated between the superior border of the medial wall and the orbital roof. the lateral wall of the orbit is directed medially and forward. it consists of the orbital process of the zygomatic and the orbital surface of the greater wing of the sphenoid. the sphenozygomatic suture unites them. this is another site of particular interest since the zygomatic bone is easily palpable. through palpation of the zygoma one can visualize, indirectly assess and treat the less accessible greater wing of the sphenoid. the sphenozygomatic suture ends below at the anterior end of the inferior orbital fi ssure. the upper end of the sphenozygomatic suture meets with two other sutures, creating a sutural crossroads for consideration in the treatment of any ocular dysfunction. anteriorly, the frontozygomatic suture can be observed, and posteriorly the suture between the frontal bone and the greater wing of the sphenoid. just under the frontozygomatic suture, on the orbital process of the zygomatic bone, is a tubercle for the attachment of the levator palpebrae superioris' aponeurosis. the inferior orbital fi ssure lies between the lateral wall and fl oor of the orbit, posterior to the zygomaticomaxillary suture. it communicates with the pterygopalatine and infratemporal fossae, and transmits the infraorbital vessels, the maxillary nerve (cn v 2 ) and the ascending branches from the pterygopalatine ganglion. the superior orbital fi ssure separates the roof and lateral wall of the orbit in its medial portion. the oculomotor (cn iii), the trochlear (cn iv), the ophthalmic division of the trigeminal (cn v 1 ) and the abducent (cn vi) nerves enter the orbital cavity through this fi ssure, accompanied by some fi laments from the cavernous sympathetic plexus and the orbital branches of the middle meningeal artery. additionally, the superior ophthalmic vein drains into the cavernous sinus through this fi ssure. the apex of the orbit corresponds to the medial end of the superior orbital fi ssure, close to the origin of the eom, just below the optic foramen. the cylindrical optic canal forms by surrounding the optic nerve and ophthalmic artery where the two roots of the lesser wing of the sphenoid join the sphenoidal body. through the optic canal and superior orbital fi ssure, the cranial cavity communicates with the orbital cavity. the cranial dura mater lines the internal surface of every cranial bone, with a fi rm adhesion at the sutures, and extends outside the cranial cavity through foramina and fi ssures, forming tubular sheaths for the cranial nerves as they leave the neurocranium. thus, the endosteal layer of the cranial dura mater is continuous through the superior orbital fi ssure with the orbital periosteum. in addition, a tubular dural sheath from the meningeal layer of the dura surrounds the optic nerve as it passes through the optic canal. this dural layer blends with the ocular sclera and adheres intimately to the common annular tendon of the four recti muscles. there is an anatomic continuity between the dura and the lining and structures of the orbital cavity, such as the eyeball and the eom. the seven extraocular, or extrinsic, muscles include the levator palpebrae superioris, superior rectus, inferior rectus, medial rectus, lateral rectus, superior oblique and inferior oblique muscles (fig. 7.5.3) . they control the movements of the upper lid and eyeball. all the eom are tied together in a complex fashion by fascial sheaths. there are also intrinsic muscles within the eyeball that are responsible of the shape of the lens and size of the pupil. the levator palpebrae superioris arises from the lesser wing of the sphenoid, above and in front of the optic foramen, from which it is separated by the origin of the rectus superior. from a narrow tendon it soon broadens into a fl at, triangular shape that ends anteriorly in a wide aponeurosis. the superficial fi bers are prolonged forward, piercing the orbicularis oculi muscle, to insert on the deep surface of the skin of the upper eyelid. the deepest fi bers blend with an expansion from the sheath of the rectus superior. some fi bers also attach to the upper margin of the superior tarsus and are referred to as the superior tarsal muscle. a thickening of the sheath of the levator palpebrae superioris is referred to as the superior transverse ligament of whitnall. it extends laterally and medially to insert in the orbital walls just behind the superior orbital rim. medially, it attaches to the trochlea of the superior oblique muscle and to the frontal bone. laterally, it is fi xed to the capsule of the lacrimal gland and to the frontal bone. when the levator palpebrae superioris contracts, it raises the upper eyelid. it is innervated by a superior branch of the oculomotor nerve (cn iii). interestingly, the superior tarsal muscle is innervated by postganglionic sympathetic fi bers from the superior cervical ganglion. therefore, a complete ptosis refl ects the loss of oculomotor function, whereas a partial ptosis is associated with loss of sympathetic supply. 5 the four rectus muscles arise from a fi brous ring -the common tendinous annulus of zinn -that extends across the superior orbital fi ssure and clinical conditions surrounds the upper, medial and lower margins of the optic foramen, where it adheres strongly to the tubular dural sheath surrounding the optic nerve. the common tendinous annulus consists of two parts. superiorly, the tendon of lockwood gives origin to the superior rectus muscle, part of the medial rectus and the upper fi bers of the lateral rectus; inferiorly, the tendon of zinn gives origin to the inferior, medial and lateral rectus muscles. at their origin, the rectus muscles are tightly set in zinn's annulus and start to separate at about 8 mm anterior to the optic canal. 9 the medial rectus is the broadest while the lateral rectus is the longest. the four rectus muscles go forward and insert through tendinous expansions into the sclera, the superior and inferior recti passing anterolaterally. the superior oblique muscle originates from the body of the sphenoid, above and medial to the margin of the optic foramen and origin of the superior rectus. it passes forward, ending in a round tendon, which goes through a fi brocartilaginous ring or trochlea attached to the frontal bone. from that point, the tendon turns backward, laterally and downward beneath the superior rectus to insert into the sclera, behind the equator of the eyeball in its superolateral posterior quadrant. the inferior oblique muscle originates from the orbital surface of the maxilla, just posterior to the orbital rim and lateral to the lacrimal groove. it tra-verses the fl oor of the orbit in a lateral, backward and upward direction, and inserts into the inferolateral posterior quadrant of the eyeball. the eom produce mobility of the eyeball with extreme amplitude in all directions (fig. 7.5.4) . this is because the type of attachment they demonstrate to the periorbita -an interlocking of tendinous and muscular fi bers -provides them with a strong anchor. 10 the contraction of the eom rotates the eyeball according to their insertions and the orientation of their fi bers. however, in all cases it should be remembered that these muscles function together and not as isolated entities. the ocular movements of individual muscles can be simplifi ed as follows: 5 • the superior and inferior recti adduct the eyeball, in association with elevation and intorsion from the superior rectus and depression and extorsion from the inferior rectus. • the medial rectus adducts the eyeball while abduction is the result of contraction of the lateral rectus. • the superior oblique is considered to act from the trochlea. • both the superior and inferior oblique abduct the eye, with a component of depression and intorsion from the superior oblique and elevation and extorsion from the inferior oblique. being described in 1806. 13 this capsule is a fascial sheath completely covering the eyeball. it extends from the optic nerve to the corneoscleral junction and separates the eyeball from the orbital fat. it is perforated by the tendons of the eom on which it refl ects to form tubular sheaths. tenon described this capsule as a 'muscle pulley'. 13 after much controversy, this theory is again accepted, and further studies have established that each rectus and inferior oblique muscle passes through a pulley formed by a ring or sheath of collagen, elastin and smooth muscle that is located close to the equator of the eyeball, in tenon's capsule. 14 in this manner, the rectus and the inferior oblique muscles have their paths constrained by pulleys that serve as functional origins for the muscles, in a fashion similar to that of the trochlea for the superior oblique muscle. 15 thus, the position of a pulley insertion relative to the eyeball affects the forces of the eom, and a translation of the eyeball of 1.5 mm modifi es the pulling direction of the rectus muscle by 6°. 16 these pulleys are under active muscular control, allowing for constant ocular adjustments. 14 conversely, their instability and modifi cation of location are associated with ocular dysfunction. 16 the eom connective tissue sleeves that act as pulleys are fi rmly attached to each other and, through extensions, to the orbital walls. those from the lateral and medial rectus are anchored to the orbital tubercle of the zygomatic bone and posterior to the lacrimal crest of the lacrimal bone, respectively. they are referred to as check ligaments. this point is of great signifi cance. the zygomatic bone should not be overshadowed as a site of insertion for the eom sheaths by the sphenoid on which the common tendinous annulus of zinn inserts. in subjects with it should be noted that while the longitudinal axis of the orbit deviates laterally in a posterior to anterior direction, the axis of the eyeball approximates the sagittal plane (fig. 7.5.5) . therefore, muscular activity between medial and lateral muscles is not equal. at birth, infants tend to demonstrate intermittent ocular misalignments. this is associated with lack of maturity in visual function. it should disappear by 4 months of age when orthotropic ocular alignment and sensory binocularity should be present. 11 transitory esotropic misalignments are usually considered to be typical in infants. however, if the condition is permanent with a fi xed restriction of any of the eom movements, or if it persists after 6 months of age, further evaluation is necessary. 12 in any case, osteopathic examination and treatment are indicated to balance the bony components of the orbit and their relationship with other parts of the skull. dysfunction can also manifest through myofascial and membranous components. entrapment neuropathy can result. evaluation and treatment of these components are indicated to promote the best possible muscular activity and ocular function. although the study of eom function is complex, it is imperative that it includes the orbital connective tissues that sheath the muscles. these tissues have long been recognized, the capsule of tenon clinical conditions strabismus or other ocular misalignments, the consideration of the orbital bones on which the eom insert should include the zygomatic bone. its location makes it vulnerable to being struck during the course of normal childhood activities. this may, in turn, affect the diameter of the orbit and the functional balance of the eom, particularly the lateral rectus. another site of importance is the trochlea for the superior oblique muscle on the frontal bone. frontal dysfunctions are often found in infants, with one side lower than the other resulting in frontal trochlear asymmetry. this may be seen with a superior-medial deviation of the eye encountered with dysfunction of the superior oblique muscle. dysfunction of the maxilla can also infl uence visual activity through its effect on the insertion of the inferior oblique muscle. through these complex interactions the orbit functions as a unit and each part, when dysfunctional, is a potential site for muscular instability and resultant ocular dysfunction. the somatic components of ocular dysfunction also involve oculomotor supply. the oculomotor nerve (cn iii) exits the brain medially to the cerebral peduncles. it traverses the dura at the top of the clivus, enters the cavernous sinus and courses forward in the lateral wall of the cavernous sinus where it receives sympathetic fi bers from the internal carotid plexus and connects with the ophthalmic division of the trigeminal nerve (cn v 1 ). it then divides into two branches that enter the orbit through the superior orbital fi ssure. the general somatic efferent fi bers of the oculomotor nerve innervate nearly all of the eom. the superior division innervates the superior rectus and the levator palpebrae muscles, whereas the inferior division innervates the medial and inferior rectus and inferior oblique muscles. the general visceral efferent fi bers of cn iii are part of the parasympathetic ans and supply the sphincter of the iris that regulates the size and shape of the pupil and the ciliary muscle that modulates the shape of the lens. the trochlear nerve (cn iv) is the only cranial nerve to emerge from the dorsal surface of the brainstem. it curves around the midbrain, pierces the dura between the lesser and greater circumferences of the tentorium cerebelli, enters the lateral border of the cavernous sinus, receives sympathetic fi bers from the internal carotid plexus and traverses the superior orbital fi ssure to the orbit. it carries somatic efferent fi bers to the superior oblique muscle. the abducent nerve (cn vi) emerges from the brainstem between the pons and medulla oblongata. it pierces the dura covering the clivus and passes over the ridge of the petrous apex of the temporal bone through an osteofi brous canal underneath gruber's petrosphenoidal ligament. it then enters the cavernous sinus where it receives sympathetic fi bers from the internal carotid plexus and the orbit through the medial end of the superior orbital fi ssure and within the annulus of zinn. cn vi carries somatic efferent fi bers to the lateral rectus muscle. additionally, the eom contain proprioceptive receptors that provide input as to the position and movement of the eye in the orbit. 17 this contributes to the control of eye's movements and facilitates central control of the direction of gaze and the relationship of the child to their environment. these afferent fi bers appear to travel with the motor cn iii, iv and vi before joining the ophthalmic branch of cn v to enter the cns. afferent input from these receptors not only affects static eye position but can also modify linear visual tracking, saccadic eye movement and the vestibulo-ocular refl ex. 18 each of these nerves is subject to intracranial entrapment from osseous compression, membranous tension, ligamentous pull or the pressure of edema from venous congestion. 19 the anterior attachments of the tentorium cerebelli are a site with particularly great potential to cause such neurologic dysfunction. the ganglion of the trigeminal nerve may become entrapped by the tentorium in the trigeminal cave formed at the apex of the petrous part of the temporal bone. bilaterally, the anterior fi bers of the tentorium twine on each side as the fi bers of the lesser circumference attach to the anterior clinoid processes and the fi bers of the greater circumference attach to the posterior clinoid processes. between these two attachments, the fi bers of the tentorium cerebelli are oriented horizontally and contribute to the formation of the roof of the cavernous sinus. cn iii and iv pierce the dura at this level to enter the cavernous sinus. any dural membranous strains in these areas can result in entrapment neuropathy and each bone on which the tentorium cerebelli attaches should be considered as potentially critical in the development of ocular dysfunction. the petrosphenoidal ligament is another signifi cant site under which cn vi may be compressed. furthermore, as the nerve bends sharply in its course over the petrous ridge, it is, therefore, vulnerable to the changes in position of the petrous portion of the temporal bone. adequate arterial supply and drainage are necessary for healthy nervous function. edema and stasis encumber this function, as is the case with a jugular foramen dysfunction and impediment of the drainage from the cavernous sinus, resulting in venous congestion. this, in turn, will affect the cranial nerves passing through the cavernous sinuses to the orbits. the same rationale applies to the superior orbital fi ssure. intraosseous dysfunction in infants between the greater and lesser wings of the sphenoid, or narrowing of the fi ssure because of greater wing dysfunction with surrounding structures, such as the temporal bone, impairs venous drainage or impulse conduction of the nerves passing through the fi ssure. 19 additionally, lymphatic stases outside the skull can also entrap nerves at their foramina of exit. 19 multiple theories exist concerning the cause of non-paralytic or concomitant strabismus, including sensorimotor, anatomic and mechanical or muscular origins. 10 prematurity 20 and diffi cult labor are considered to be risk factors. a supranuclear developmental abnormality in the cns is thought to be the cause of strabismus occurring in the fi rst 6 months of life. impaired vision and amblyopia may also cause strabismus. it is abnormal for an infant or child to have strabismus and, if present, a thorough ocular and neurologic examination by a specialist should be performed. osteopathic procedures may, however, be applied to provide balance to the musculoskeletal and nervous systems. such balance improves the self-healing capacities of the body and contributes to the success of other treatments. osteopathic treatment should be initiated at the earliest possible time because the prognosis of strabismus is correlated to the time when the strabismus fi rst appears and the time when treatment is initiated. additionally, early treatment may positively impact the vestibulo-ocular refl exes and thereby the child's posture. young children and infants are most likely to present for the treatment of strabismus. as such the following treatment description must be appropriately adapted to fi t the age of the patient. the following is not intended to treat organic pathologies of the eye; it is directed at problems of functional balance. the examination and treatment for the eye should address different levels of anatomic dysfunction. these include osseous, myofascial, neurologic and vascular dysfunction and the intrinsic structure of the eye. observation and palpation are directed at determining on which of these levels treatment should focus. observe the relationship between the eye and the functional pattern of the skull. if the functional pattern of eye position and movement is consistent with the dysfunctional pattern of the skull, the focus of treatment should be on the cranial dysfunction. if eye position and movement is not consistent with the pattern of the skull, treatment should focus directly on the eye, eom and associated fascial structures. start with observation of the bony orbit, relative to how it fi ts the global pattern of the skull. look at the shape of the face and skull of the child to determine if a global pattern of cranial fl exion-external rotation, extension-internal rotation, sidebendingrotation or torsion is present. observe the orbital diameter, the distance between the superior medial and inferior lateral angles of the orbit. it is increased with cranial fl exion-external rotation, resulting in an orbital cavity that is wider. cranial extensioninternal rotation decreases the orbital diameter, with a resultant orbital cavity that is narrower. look for asymmetry between the visible constituents of the bony orbits, specifi cally the frontal bones, zygomae and maxillae. look at the eyes and observe for difference in size and shape. cranial fl exion-external rotation is associated with a prominent eyeball and an almondshaped eye. in cranial extension-internal rotation, the eyeball is less prominent, with a smaller, rounder shaped eye. epicanthus -a vertical fold of skin covering the medial portion of the eye -may give the impression of esotropia. active motion testing will, however, demonstrate normal function of the eye. next, observe the spontaneous movements and neutral resting position of the eyes. note the direction of gaze, the presence of esotropia or exotropia. the easiest way to evaluate the ocular movement of younger children is to hold a toy or some interesting object in front of the child to catch their attention. move the object horizontally, vertically and in both diagonals, and observe the movement of the child's eyes as they follow the moving object. note any asymmetric movement of the cervical spine that can be employed to compensate for the absence of ocular movement. this may be a sign of amblyopia that requires further evaluation. if possible, assess both eyes together and each eye separately by covering one eye with the child's or caregiver's hand and pretending to play 'peek-a-boo'. comparatively note the speed and ease with which the eyes move to follow the object. convergence may be determined by observing as the toy is brought closer to the infant's face. this procedure tests the actions of the eom and normal responses are illustrated in figure 7 .5.4. determine if a correlation exists between the dysfunction of the eom and the pattern of cranial dysfunction. the two most commonly encountered types of strabismus that are amenable to cranial clinical conditions manipulation are the consequence of dysfunction involving the superior oblique muscle and the lateral rectus. a superior-medial-oblique deviation of the eye resulting from dysfunction of the superior oblique muscle may be associated with ipsilateral dysfunction of the frontal bone affecting its relationship to the muscle at the trochlea. medial deviation of the eye resulting from dysfunction of the lateral rectus may be associated with ipsilateral temporal bone or sphenoid dysfunction that affects cn vi as it passes beneath the petrosphenoidal ligament. palpate for function to confi rm the above observations. tests of listening should be performed with specifi c attention to the anatomic structures associated with the eyes in order to defi ne the dysfunctional area responsible for ocular deviation. areas of specifi c interest include the bones on which the eom are attached: the sphenoid, frontal, maxillae and zygomae. assess the anatomic areas of neurovascular passage to the orbital cavity. these include the superior orbital fi ssure between the greater and lesser wing of the sphenoid and the cavernous sinus for their contents. also evaluate the apex of the petrous portion of the temporal bone and the sphenoid for their relationship to the petrosphenoidal ligament. in actual practice, these assessments and the treatment of identifi ed dysfunction fl ow seamlessly into one another. diagnostic palpation of the sphenoid, and to a lesser degree of the frontal bone, is complex because the movements of the eom are transmitted to these bones. these additional movements on top of the biphasic prm create multifaceted palpatory sensations that can be confusing to the inexperienced examiner. consequently, it is desirable to evaluate the child when they are quiet with minimal eye movement. this occurs most readily when the child is sleeping. if the examiner is skilled with indirect procedures, the act of palpation will often soothe the child enough to bring them to a quiet state. complete examination of the sphenoid is somewhat diffi cult because of the limited surface area of the bone that is available for direct palpation. the areas of contact over the lateral-most aspects of the membranous greater wings, because of their fl exibility, transmit an incomplete representation of the movement of the body of the sphenoid. for this reason, the lightest touch must be employed when evaluating the sphenoid and even then information about the body must be obtained indirectly. to assess the sphenoid body and associated lesser wings more effectively, visualize the relationship between the frontal bone and the sphenoid behind. the body and lesser wings of the sphenoid are in continuity with the orbital plates of the frontal bone. when palpating, one hand can be placed transversely on the frontal bone with the thumb and middle fi nger contacting the greater wings on either side. the movement of the lesser wings and body of the sphenoid is transmitted through the orbital plates of the frontal bone. this provides a method of augmenting the palpatory sensations from the body of the sphenoid through the frontal bone. similarly, the sensation of movement of the greater wings of the sphenoid may be enhanced through the zygomatic bones and their relationship with the greater wings at the sphenozygomatic sutures. these visualization procedures may be employed during both tests of listening and treatment, and require that the bones being palpated in association with the sphenoid are themselves free of somatic dysfunction. in infants and younger children, intraosseous dysfunctions of the frontal bone and sphenoid should be considered. listen to the movement between the two halves of the frontal bone. palpate for deformation affecting the trochlea of the superior oblique muscle. visualize and listen to the synchondroses between the greater wings and the body of the sphenoid. listen to the relationship between the greater and lesser wings at the superior orbital fi ssure, visualizing the neurovascular content, and try to promote the inherent forces of the prm in the area. similarly, assess the cavernous sinus because of its relation with the nerves and venous drainage of the eyes. visualize the dura that constitutes the walls of the cavernous sinus and its relationship to the remainder of the reciprocal tension membranes. finally, if the child permits, and while utilizing the gentlest of indirect methods, palpate the globes of the eyes. evaluate the tone and quality of the myofascial structures surrounding the eyeballs. identify the functional point of balance between the eom. treat any dysfunction as identifi ed above, using indirect principles. only after any osseous, membranous and fascial dysfunctions have been treated, and the eom have been balanced, employ myofascial rehabilitation. in the patient with ocular deviation, the eom provide dysfunctional proprioception to the cns. the child should learn to experience the sensations of the normal range of ocular movements. older children can be taught to move their eye while the practitioner gently applies digital contact intended to guide the eye through the normal range of ocular movements. in this exercise, particular attention should be directed at establishing awareness of the sensation of eye movements in the directions that they are defi cient. the process of myofascial rehabilitation is accomplished with greater ease once pre-existing osseous, membranous and fascial dysfunctions have been treated. a description of the anatomy of the bony orbit and the eom has already been provided in 'strabismus' above. we shall, therefore, only consider the description of the eyeball and somatic dysfunction as they relate to the pathophysiology of astigmatism, myopia and hyperopia. the eyeball occupies the anterior part of the cavity of the orbit. it is surrounded by the eom and embedded in the fat of the orbit. two spheres of different diameters form the eyeball. the anterior cornea is smaller, transparent, bulging outward and represents approximately one-sixth of the eyeball. posteriorly, a larger opaque sphere constitutes the rest of the eyeball. anatomically, the eyeball may be described as being formed by three tunics or walls that are, from front to back, the fi brous tunic, the vascular pigmented tunic and the nervous tunic, and by internal components or refracting media, the aqueous humor, the vitreous body and the crystalline lens. the outside fi brous tunic of the eyeball is formed by the sclera and cornea. in the front, the sclera is continuous with the cornea at the sclerocorneal junction. the sclera is a dense and fi rm membrane that preserves the shape of the eyeball. it is covered with a fascial membrane, the capsule of tenon, posteriorly from the optic nerve to the corneoscleral junction anteriorly. this fascial membrane refl ects onto each of the eom tendons as they perforate tenon's capsule to attach on the sclera. posteriorly, the sclera is pierced by the nervous fi laments of the optic nerve (cn ii), forming the lamina cribrosa sclerae. the sclera is continuous with the fi brous sheath of cn ii and, therefore, with the meningeal layer of the dura mater. several small apertures exist around the lamina cribrosa sclerae for the ciliary vessels and nerves. the central artery and vein of the retina pass through cn ii. the cornea projecting in front of the sclera is almost circular, with its width slightly greater than its height. its anterior convexity demonstrates varying degrees of curvature throughout life and between individuals. a rapid change in the corneal curvature occurs during the fi rst 2-4 weeks of life. this rate of change then decreases considerably after the 8th week. 21 the corneal curvature usually stabilizes at approximately the end of the 1st year of life. 5 its coating of tears constitutes the most important site of refraction of the eyeball. the middle tunic of the eyeball is a vascular pigmented layer consisting of the choroid posteriorly and the ciliary body and iris anteriorly. the choroid is a thin, highly vascular membrane that constitutes approximately the posterior fi ve-sixths of the globe. its outer surface adheres fi rmly to the sclera while its inner surface is attached to the retina. this layer provides a signifi cant percentage of the vascular supply to the retina. the ciliary body consists of the ciliary processes and the ciliary muscle. the ciliary processes are circularly arranged as a ruche behind the iris surrounding the lens. they are continuous at their periphery with the layers of the choroid and anteriorly with the periphery of the iris. posteriorly, they are connected with the zonule that is the suspensory ligament of the lens. the ciliary muscle plays an important role in accommodation. it adjusts the shape of the lens in order to change the focus of the eye. when the ciliary muscle contracts, it draws forward the ciliary body, thus reducing tension in the fi bers of the suspensory ligament. this results in a relaxation of the lens' capsule with resultant increased convexity of the lens. the parasympathetic stimulation of fi bers from cn iii produces contraction of the ciliary muscle. the iris is a thin, circular, contractile disk, located between the cornea and lens, and continuous peripherally with the ciliary body. the iris differs in color among individuals, and at birth is light blue because of a lack of pigment. iris pigmentation is well developed at 6 months of age. the iris divides the space between the cornea and lens into an anterior and a posterior chamber that communicates through the center of the iris, the pupil. pupillary dilatation or constriction results from the contraction of the dilatator or sphincter pupillae. responses to light and accommodation produce the two dominant pupilloconstrictor refl exes. axons from preganglionic parasympathetic fi bers course with cn iii to the ciliary ganglion, located behind the eyeball. from there, postganglionic fi bers supply the smooth muscle of the iris; this may result in pupillary constriction. inhibition of the tonic activity of the oculomotor system in the midbrain edinger-westphal nucleus leads to pupillary dilatation. extreme pupillary dilatation is referred to as mydriasis, extreme constriction as miosis. the nervous tunic, i.e. the retina or inner layer of the walls of the eyeball, is truly a sensory extension of the brain. during embryogenesis, the optic vesicles develop from the lateral aspects of the forebrain. when they invaginate, forming two optic cups, the inner walls of the cups become the retinal sensory mesh and send axons back to the optic stalk. on activation of the receptors of this sensory stratum, brain activity starts the visual sensory processing. light and images of external objects are received on the retinal receptors, stimulating a chemical reaction and action potentials transmitted through the optic nerve to the visual cortex within the occipital lobe. the vascular supply of the retina comes partly from the choroid that is in contact with the external layer of the retina. internally, the retina lies in contact with the vitreous body. the thickness of the retina varies, its thickest portion being located in the back of the eye, near the central retinal area or macula lutea. the fovea centralis, the center of the macula lutea, is a point of maximum vision and could be considered as the posterior point of the eyeball's axis. it is approximately 3-4 mm lateral and 1 mm inferior to the center of the optic disc, a point where the retina is insensitive to light, referred to as the blind spot. the macula continues to develop until 16-18 weeks after birth. fully developed visual acuity is normally established by 2 years of age. 22 light passes through various refracting media in the eye, the aqueous humor, the lens and the vitreous body. the aqueous humor fi lls the anterior and posterior chambers of the eyeball. it is secreted into the posterior chamber by the ciliary processes. it fl ows into the anterior chamber through the pupil and is absorbed into the scleral venous sinus between the iris and cornea. the lens is situated directly behind the iris and in front of the vitreous body. it is a transparent, biconvex structure surrounded by a capsule and is connected to the ciliary muscle through the suspensory ligament. it measures approximately 6 mm in diameter at birth and from the fi rst years of life offers excellent refractive power. as the child grows, more layers are added on the lens periphery, and around 14 years of age it reaches its adult size. from then on, progressively, it will loose its hydration and thereby its fl exibility and refractive power. accommodation, normally occurring when tension of the lens' capsule decreases, becomes more diffi cult. this leads, for most individuals in their fi fties, to the need for glasses to compensate. the postrenal (vitreous) chamber forms about four-fi fths of the eyeball and is fi lled with the vitreous body (vitreous humor) that is situated between the retina and the lens. it is transparent, of a gel-like consistency, and is composed of about 99% water. when light enters the eye, the cornea and crystalline lens normally focus the rays of light through accommodation specifi cally on the retina. when properly functioning, this is referred to as the emmetropic state and requires that normal ocular growth occurred resulting in normal eye biometry. the central point of the anterior curvature of the eyeball is referred to as the anterior pole; the central point of the posterior curvature is the posterior pole. a line joining the two poles is referred to as the optic axis. the optic axes of the two eyeballs are almost parallel, approximating in the sagittal plane, while the longitudinal axes of the orbits are directed forward and laterally (fig. 7.5.5) . therefore, for each eye, these two axes are aligned in different directions. the optic nerves enter the orbit with the ophthalmic artery, through the optic canal, and follow the direction of the axes of the orbits. this explains why the optic disc is medial to the fovea centralis in the center of the macula lutea. the transverse and anteroposterior diameters of the eyeball are slightly greater (24 mm) than its vertical diameter (23.5 mm). at birth the anteroposterior diameter is about 17.5 mm and at puberty is between 20 and 21 mm. ocular growth and refraction are dynamic processes evolving during infancy and childhood, well through adult life. color vision develops rapidly after birth and in most individuals some color vision is usually present at 3 months of age. 23 although diffi cult to evaluate in infants, normal visual acuity is thought to be present by 2 years of age. 22 even though complete anatomic and functional maturity of the visual system is reached around 10 years of age, many important milestones occur during the fi rst 2 years of life. for these reasons, when examining and treating infants and children, an osteopathic practitioner should pay close attention to any somatic dysfunction that may potentially alter the normal shift of the refractive state of the eye to emmetropia. the sites of dysfunction with potential for alteration of the visual system are the different bony components of the orbit, the eyeball, eom and surrounding fascial and dural sheaths. because the vestibulo-ocular refl exes link the individual's posture with ocular function, the axial skeleton and postural balance of the child should also be addressed. any disturbance in the visual components may alter vision, usually asymmetrically. if this occurs during the developmental process, the resulting absence of stimulation in the visual part of the cortex will cause partial loss of sight, or amblyopia. this could be associated with an important difference of visual acuity between both eyes. normally orthotropic ocular alignment and sensory binocularity should be present by 4 months of age. 11 if there are signs of misalignment and lack of sensory binocularity, further evaluation should be carried out. emmetropization allows a distant object to be projected as a focused image on the retina without accommodative effort. 24 this is possible when the optical power and the axial length of the eye are balanced. normally, in the emmetropic eye with relaxed accommodation, objects are focused on the retina. if the point of focus falls behind the retina, increased accommodation is necessary to bring the point of focus on the retina. this occurs with hyperopia and has been associated with decrease of the axial length of the eyeball. conversely, in myopia, the point of focus falls in front of the retina and this is associated with increase of the axial length of the eyeball (fig. 7.5.6 ). some compensation usually occurs in these conditions, since eyes with decreased axial length are associated with a more rounded cornea, whereas increased axial length is associated with fl attening of the cornea. typically, infants demonstrate hyperopic eyes that tend to improve with ocular growth and, by the age of 5-8 years, they are emmetropic. by age 6 years, only a few children are myopic, but between the ages of 6 and 7 years, myopic children have the fastest progression of all age groups. 25 myopia is a common condition affecting approximately 4.4% of caucasian children, 13.2% of hispanics and demonstrates the highest prevalence in asians (18.5%). 26 this condition and its progression are infl uenced by various factors such as demography and the environment 27 . the etiology of myopia seems to be multifactorial, with a genetic component since myopic individuals are more likely to have myopic parents. 29 a greater reading exposure in childhood has often been suggested as a contributing factor and is especially associated with myopia in asian children, more often encountered around 7-9 years. 30 intrinsic ocular factors are also associated with myopias. greater dimensions are present in myopic eyes than in emmetropic eyes when the vitreous chambers are measured along the axial direction, i.e. the optical and visual axes. 31, 32 heavier newborns with large heads have longer optical axial lengths, deeper vitreous chambers and fl atter corneas. however, refraction is maintained and satisfactory, suggesting the presence of accommodative mechanisms in the cornea that compensate for the longer axial length. 24 myopia usually develops because of a lack of coordination between postnatal growth and the refractive power of the eyeball components. there is some probability that the cns infl uences the development of myopia. 28 unequal curvature(s) along the meridians of the refractive surfaces of the eye -cornea, anterior or posterior surfaces of the lens -result in astigmatism. thus, when light enters the eye, instead of having the cornea and the crystalline lens focusing the rays of light at a single point on the retina, they are spread out as a line in one direction or another. the orientation of the axis of corneal astigmatism is affected by the mode of delivery. infants delivered vaginally when compared to those delivered by cesarean section demonstrate a higher frequency of with-the-rule astigmatism, with the greater curvature of that astigmatism tending to be in the vertical meridian. 33 these astigmatic corneas usually fl atten signifi cantly by the age of 6 months. because astigmatism, myopia and hyperopia are associated with anatomic variations in the biometry of the eye, any form of treatment that may affect the refractive power and shape of the eye is desirable. this is particularly important in children less than 1 year of age, when the eye is still growing and the ocular refl exes are not totally developed. prevention of the ocular complications of myopia, such as retinal detachment and glaucoma, may be facilitated by relaxation of tension in surrounding ocular structures. addressing somatic dysfunction of the upper thoracic and cervical vertebrae may further assist relaxation of ocular tension. for these reasons, osteopathic procedures may be applied directly to the eyeball itself or the structures surrounding the eyeball including the orbit and its myofascial contents. procedures may also be employed to affect the control of refractive mechanisms through the impact that the ans has on the intrinsic ocular muscles. the osteopathic structural examination of the eye and orbit for the patient with astigmatism, myopia and hyperopia is essentially the same as that described above for strabismus. the patient should be thoroughly evaluated for dysfunction affecting the component bones of the orbit, the eom and associated fascial sheaths. in addition, because these ocular conditions involve changes in the shape of the eyeball, the physical evaluation of the individual with myopia or hyperopia should specifi cally include the search for any somatic dysfunction that affects the axial length of the eyeball. for the patient with astigmatism, somatic dysfunction responsible for changes in orbital shape and tension of myofascial structures that affect the curvatures along the meridians of the refractive surfaces of the eye should be identifi ed. cranial fl exion-external rotation is associated with a decrease of the orbital depth, whereas extension-internal rotation is associated with increased orbital depth. for these reasons, potentially contributory craniosacral somatic dysfunction should be sought out and treated. this includes dysfunction involving the sbs and bony components of the orbit as well as all components of the craniosacral mechanism, including, but not limited to, the sacrum and pelvis. a posture in which the child projects their head forward may be the result of poor sight. on the other hand, dysfunction affecting the posture, because of its effect on the cervical myofascial structures, particularly those attaching to the base of the skull, will tend to impair the inherent motility of the skull and potentially the components of the orbit. a craniosacral somatic dysfunction of the sacrum in fl exion will produce a decrease of spinal ap curves and a tendency toward cranial fl exion. this can, in turn, favor decreased orbital depth that is particularly signifi cant in infants and young children at a time when ocular growth is occurring. as such, a complete postural assessment is appropriate when examining a child with ocular dysfunction. it is also appropriate in these individuals to begin working on the global postural pattern because vestibulo-ocular refl exes link posture with ocular function. using an indirect approach, begin with the treatment of postural dysfunction. because of their action on the prm, the use of indirect techniques will relax the patient. the treatment of ocular dysfunction requires the most delicate touch and as the patient relaxes it becomes easier to treat the eyes. after addressing the global postural pattern, proceed to the examination of the neurocranium and viscerocranium. assess the sbs with tests of listening, then progress to observe the size and shape of the orbit. look at the relationship of the eyeball to the orbit. prominence of the eyeball is associated with a wider orbit and a pattern of cranial fl exion-external rotation, whereas a recessed eye is associated with a narrower orbit and cranial extension-internal rotation. also observe the patient in profi le bilaterally, comparing the amount of corneal curvature. determine if the dysfunctional mechanics identifi ed at the sbs is consistent with the pattern of orbit and eyeball. if so, treat the sbs; if not, look for dysfunction in the orbit. (note: in infants the state of development of the frontal bone with small brow ridges causes the eyeballs to appear as if they are bulging.) next, assess the different bones that constitute the orbit, particularly the frontal bone, zygomae, maxillae and sphenoid. the effect of cranial dysfunction on the depth and shape of the orbit is signifi cant in astigmatism, myopia and hyperopia. the apex of the orbit is situated at the medial end of the superior orbital fi ssure between the lesser and greater wings of the sphenoid, near the origin of the eom and inferior to the optic foramen. thus, the length and direction of the orbital axes are infl uenced by the sphenoid. dysfunctions of the sphenoid that can affect the orbit include dysfunction of the sbs, dysfunction between the sphenoid and the bones articulating with its wings and intraosseous dysfunction. with cranial fl exion the apex of the orbit moves forward, thus decreasing the ap orbital diameter, whereas in extension the apex is displaced posteriorly, increasing the ap orbital diameter. with sbs torsion or sidebending-rotation, on the side of associated external rotation, the ap orbital diameter is decreased and on the side of associated internal rotation it is increased. intraosseous dysfunctions of the sphenoid have variable effects on the orbit and eyeball. they must be identifi ed and treated as early as possible, sphenoid ossifi cation being essentially complete by 1 year of age. dysfunction of the frontal bones, zygomae and maxillae, either individually or in conjunction with the sphenoid, can affect the shape of the orbit and, when present, should be treated using indirect principles. an extension of the dura surrounds the optic nerve and is attached to the optic canal. intraosseous dysfunction of the sphenoid can affect the cylin-drical optic canal that is formed where the two roots of the lesser wing of the sphenoid join the sphenoidal body. the dura also extends through the superior orbital fi ssure and blends with the orbital periosteum. consequently, membranous strain can affect the sphenoid and through the sphenoid the shape of the orbit. dural membranous dysfunction should thus be sought out and treated at the youngest possible age. to ensure autonomic balance for the orbital contents, the rhythmic motility of the orbit and neurocranium is necessary. change of the ap diameter of the orbit is associated with altered tension of the intraorbital soft tissues with resultant stasis, edema and compression. this, in turn, will affect the function of nervous structures, in this case cn iii and the ciliary ganglion. treatment of regional dysfunction, ensuring the rhythmic fl exion-extension of the prm in the orbit, fi ssures and foramina, provides a pumping action mobilizing the extracellular fl uids surrounding the nerves and facilitating their function. the sympathetic supply to the orbit originates in the upper thoracic spine and, through the upper cervical ganglia, reaches the ciliary ganglia via the carotid plexus. somatic dysfunction affecting these structures in the upper thoracic and cervical spine and the cranial base should be sought out and treated to ensure optimal sympathetic function. sucking and swallowing are complex activities that are partially conscious and partially unconscious. they require the participation of many structures, including a signifi cant percentage of the cranial nerves, and should be considered in the context of a sensory-motor complex that begins to develop well before birth. swallowing appears in utero after 11 weeks 1 with movements of the fetal tongue visible after 14 weeks. at that time, fetuses suck their thumbs refl exively in response to oral stimulation from the digital extremities. 2 protrusion of the upper lip appears after the 17th week of gestation and protrusion of the lower lip at the 20th week. the real activity of sucking is seen at the 24th week. after that time, sucking and swallowing become more and more developed and appear as coordinated movements around 33 weeks. 1 at term, the fetus swallows about 500-900 ml of amniotic fl uid per day. this daily exercise stimulates the maturation of oral structures, including the tongue, lips, soft palate and pharynx, and, therefore, prepares the fetus to perform the orofacial functions that will be vital at birth. sucking is one of the primitive refl exes that are totally present at birth in term infants. in the fi rst days of life, oral feeding is almost entirely refl ex, apparently without suprabulbar activity for rooting, latching, sucking and swallowing. 3 these refl exes are functionally important in infants to ensure successful ingestion. the primitive sucking refl ex lasts for about a year, and then becomes more diffi cult to obtain because of central nervous system maturation and the development of voluntary motor activity. the tongue is one of the major participants in the process of sucking. it is a muscular structure with intrinsic and extrinsic muscles. the intrinsic muscles allow the precise movements necessary for sucking, swallowing and speech. they are the superior longitudinal, inferior longitudinal, transverse and vertical muscles. the extrinsic muscles originate from other parts of the skull and hyoid bone, and consist of four paired muscles: • the genioglossus muscles originate from the mandible, attach to the hyoid bone and blend with the intrinsic muscles of the tongue • the hyoglossus muscles originate from the hyoid bone and insert into the tongue • the styloglossus muscles originate from the styloid processes of the temporal bones and insert into the lateral part of the tongue • the palatoglossus muscles originate from the soft palate aponeurosis and insert into the lateral part of the tongue. a midline fi brous sagittal septum divides the tongue into two halves and attaches to the body of the hyoid bone. additionally, on the undersurface of the tongue, the frenulum linguae -a vertical fold of mucous membrane -connects the tongue to the fl oor of the mouth. as such, although anchored at its root, the tongue is mobile, allowing the different functions of sucking, suckling, latching, swallowing and eating, and later speech. in infants, the tongue is totally contained in the oral cavity, although it is quite wide in proportion to the container and protrudes beyond the alveolar gum pads. however, its development is far from being complete and its position will go through many changes before the end of adolescence. one of the biggest changes occurs in the fi rst years of life, as the child grows, the posterior third of the tongue descends following the larynx. 1 when evaluating tongue malposition in children, the bony attachments of the tongue muscles should be evaluated for somatic dysfunction. dysfunction of the mandible, the temporal bones through the styloid processes and the hyoid bone may potentially interfere with the position of the tongue. one of the most common lingual dysfunctions is forward and inferior displacement of the tongue. this predisposes to malocclusion and mouth breathing. mouth breathing and a low posture of the tongue are also associated with an inferoposterior displacement of the anterior convexity of the hyoid bone. [4] [5] [6] to ensure the lingual mobility necessary in the infant for feeding and the development of proper speech, the frenulum linguae should not be too short. ankyloglossia, or tongue-tie, is a congenital anomaly characterized by an unusually short frenulum linguae. breastfeeding is more diffi cult in the presence of ankyloglossia, and children have more diffi culty pronouncing lingual and sibilant sounds such as t, d, z, s, th, n and l. 7 furthermore, the tongue affects the growth and development of the maxillae and mandible and, therefore, the teeth in the alveolar processes, acting as a natural orthodontic appliance 'for better or for worse'. 8 its position should be unencumbered as early in life as possible in order to play a satisfactory functional role. as such, clipping of the frenulum (frenuloplasty) may be necessary in association with osteopathic procedures to ensure a correct tongue placement. sucking has been classifi ed in two categories: nutritive and non-nutritive sucking (nns). 9 nutritive sucking results in the delivery of milk and exhibits a slower rate of sucks that are continuous, whereas nns consists of a series of bursts of rapid sucks, approximately twice the rate of nutritive sucking, followed by rest periods. during breastfeeding, before the initiation of sucking, the tongue protrudes beyond the lower gum and then retracts, repeating this protrusive and retrusive displacement of the tongue to draw the nipple into the mouth. if the newborn recognizes the odor of the breast's nipple, frequent sucking is initiated that, in turn, will stimulate the mechanism of lactation. the mother's milk odor results in increased sucking and stronger pressure than when the infant is fed formula or water. 10 successful sucking is produced by a peristaltic wave in the medial portion of the tongue moving from the front to the back of the tongue. 11, 12 this is the result of successive contraction and relaxation of the genioglossus and transverse muscles of the tongue. at the same time, a repetitive thrust of the mandible participates in the compressive action on the nipple to produce milk. sucking results from the combined actions of the masseters, orbicularis oris and buccinator muscles, as well as from the muscles of the tongue and the mandible, in particular the lateral pterygoid muscles. this activity of the pterygoid muscles is important. at birth the pterygoid processes of the sphenoid are not fully developed, and because the activity of sucking requires a signifi cant effort from the infant, the stimulation produced contributes to their development. at approximately the 10th month of life, a new sucking pattern appears. it resembles that of later years, as when sucking from a straw, and demonstrates less movement of the tongue. 13 refl exes are of paramount importance in the actions of the oral cavity. they facilitate various vital functions, including suckling and swallowing, but also breathing, eating and drinking. sucking elicits a swallowing refl ex in the infant by stimulating the lips and the oral cavity. this refl ex results from sensory input that induces a series of motor responses. it is mediated through neural receptors located on sensory fi bers, the afferent pathway of sensory fi bers, central synaptic connections and interneurons, and the efferent pathway composed of motoneurons or autonomic postganglionic neurons innervating the effector organ. in a somatic refl ex, the effector is the striated muscle innervated by the alpha motoneuron. in an autonomic refl ex, the effector includes a peripheral neuron extending its postganglionic axon to visceral structures. in sucking and swallowing, the sensory receptors -the tongue, gums, palate and pharynx -are located in the oral cavity. the sensory input passes through the superior laryngeal nerve, trigeminal nerve (cn v) and glossopharyngeal nerve (cn ix) to the brainstem, in the nucleus tractus solitarius (nts) and adjacent reticular formation. from there, second order neurons engage brainstem deglutitive pharyngeal and laryngeal motoneurons in the nucleus ambiguus and in the facial, trigeminal and hypoglossal nuclei. the palate and palatopharyngeal muscles respond, separating the mouth from the nasal cavity to prevent passage of food from the oral cavity to the nasal cavity during the swallowing process. 14 the integrity of the infant's oral cavity is of signifi cance when considering the development of orofacial refl exes. the concept that structure affects function, and vice-versa, is perfectly illustrated in this area. the different structures that constitute the oral cavity evolve as the infant is developing, thus producing changes in function that will, in turn, further affect those structures. conversely, malposition of any of the structures contributing to the oral cavity, such as lingual malposition, will affect function and consequently viscerocranial development in infants and children. breastfeeding differs from bottle feeding. breastfed infants have better control of the amount of milk obtained than bottle-fed infants. bottle feeding is greatly infl uenced by the force of gravity, with higher volumes resulting in faster fl ow of milk. in order to control this increased fl uid fl ow, the newborn tends to adapt with a lingual and mandibular posture that is less protrusive. this decreases muscular participation and bottle-fed infants demonstrate a reduction of masseter muscle activity. 15 the positive effect of muscular traction on bony development and thus on orofacial development 16 is decreased and may, in turn, contribute to malocclusion. 17 the type of nipple employed during bottle feeding, i.e. its material, density and location of holes, requires different adaptive patterns from the infant. most of the time, the root of the tongue does not come up to the tip of the nipple, as is the case with breastfeeding, but rather demonstrates a more posterior position. sucking is considered to be a determining factor in orofacial morphogenesis. it infl uences mandibular growth through the traction of myofascial attachments. the upper head of the lateral pterygoid muscle inserts into the developing condyle of the mandible. active sucking as produced by breastfeeding is considered to be of paramount importance in mandibular development. it contributes to the change from the retrognathic mandibular posture seen in infants to a more centered position at 1 year of age. 18, 19 during breastfeeding, the shape of the breast and the sucking pressure of the infant's tongue against their palate has a modeling effect on the palate. the pressure of the tongue on the anterior portion of the palate produces a pattern of cranial fl exion-external rotation. the rhythmic sucking pressure on the infant's palate results in a pumping action that may contribute to the balancing of their skull and cranial mechanism. additionally, breastfeeding seems to have a positive effect on orofacial morphogenesis, 20 and a protective effect for the development of posterior cross-bite in deciduous dentition. 21 human milk is a complex fl uid that contains more than 200 components and is highly effective for the health and wellbeing of the infant. 22 breastfeeding provides multiple benefi ts, such as decreased gastrointestinal and respiratory infections in childhood, 23 in particular otitis media, as well as protection against atopic disease. 24, 25 it also seems to reduce pain in infants 26 and to enhance cognitive and visual development, as well as to have a potentially positive impact on the mother's health. 22 breastfeeding is thus recommended as the optimal source of nutrition for infants during the fi rst 6 months of life. although thought of as a natural process, it is not always easy, and some infants demonstrate diffi culties. such is the case for preterm infants, or infants with developmental anomalies such as micrognathia or ankyloglossia. nursing diffi culties may also be related to developmental anomalies of the mother's breast or variations of nipple size or shape that reduce the effectiveness of sucking. when developmental anomalies are not present, but nursing diffi culties persist, an evaluation for somatic dysfunction should be performed. the oral structures, including the mandible, should be assessed, and the function of the tongue should be checked. the intrinsic muscles of the tongue are all innervated by the hypoglossal nerve (cn xii), as are all the extrinsic muscles, with the exception of the palatoglossus muscle which is innervated by the vagus nerve (cn x). the hypoglossal nerve leaves the skull through the hypoglossal canal, situated in the anterior intraoccipital synchondrosis, between the basiocciput and the exocciput. the hypoglossal nerve may be subject to compressive forces during a diffi cult labor, with consequent impact on tongue motor function and resultant suckling diffi culties. feeding is a highly complex activity in young infants since it requires the integration of sucking, swallowing and breathing. normally, coordination of the buccopharyngeal functions takes place by 35 weeks postconceptional age, 14 although refl ex swallowing occurs when sucking stimulates the lips and the oral cavity. a spoon of food placed on the tongue of term infants will also produce a refl ex where the tongue pushes against the spoon. 1 it is only around the 4th or 5th month of age that infants open their mouth when a spoon is brought before them or touches their lips, and approximately 2 weeks later that they use their tongue to move food to the back of the mouth to swallow. 27 the mechanism of deglutition is divided into oral, pharyngeal and esophageal stages. the oral stage occurs when the milk or food is in the mouth and when the child tastes, plays, experiments with the food and forms a bolus to be pushed into the pharynx and esophagus. at that time, the anterior part of the tongue presses against the hard palate, while in infants the buccinator muscles participate with resultant suction. next, the tongue propels the bolus in the back of the mouth into the pharynx and the swallowing refl ex is elicited. multiple receptors around the opening of the pharynx are stimulated by the bolus, resulting in sensory impulses conducted to the swallowing center via cn v, ix and x. consequent motor activity is triggered by cn ix and x. during this pharyngeal stage, while the tongue propels the bolus posteriorly, the hyoid is displaced anteriorly, the larynx superiorly and anteriorly toward the base of the tongue, and the epiglottis moves to cover the superior opening of the larynx. the displacement of the epiglottis and the approxi-mation of the vocal cords of the larynx combine to prevent the passage of food into the trachea. thus, the bolus passes into the pharynx, dividing around the epiglottis while the soft palate moves against the posterior pharyngeal wall to close the nasopharyngeal entrance. the stylopharyngeus muscles draw the sides of the pharynx superiorly and laterally. this stretches the opening of the esophagus, and the bolus, always under the infl uence of gravity and contractions of the pharyngeal constrictors, enters into the esophagus. this third stage of the mechanism of swallowing -the esophageal phase -is totally under the infl uence of the ans via the vagus nerves and the cervical and thoracic sympathetic ganglia. several differences in the coordination of swallowing are observed between infants and adults. human infants, like non-human primates, demonstrate the ability to breathe and suckle simultaneously with swallowing phases between respirations ( fig. 7 .6.1). they will keep this ability until approximately 2 years of age when the neuromuscular system matures. at that time, the larynx and tongue have completed their descent and the posterior third of the tongue is more vertical, forming the upper anterior wall of the pharynx. 28 the larynx and hyoid bones are involved in the descent, with separation of the epiglottis away from the uvula of the soft palate. the tip of the epiglottis is located at the level of the fi rst cervical vertebra at 4 months of age and at the level of the third vertebra between 12 and 18 months of age. 29 nasal cavity in infants, swallowing is immature, different from that of the adult and characterized by an important anterior displacement of the posterior pharyngeal wall. during immature swallowing, the tongue protrudes over the lower lip with active contraction of the facial muscles, in particular the orbicularis oris and mentalis muscles. with progression of time, the teeth erupt in surroundings that can have an infl uence on their development, as much as they can infl uence the adjacent structures. therefore, with maturation, the tongue rests lower in the mouth and is located between the teeth. now, during swallowing, the tip of the tongue is posterior to the incisors, the lips are sealed and facial muscles relaxed. infantile or immature swallowing should disappear around 2-3 years of age, and the positioning of the tongue against the palate will contribute to the development of a broad palate and a well-developed facies. the act of swallowing is complex, involving the lips, jaw, tongue, palate, pharynx, larynx and esophagus, and each of these structures may be affected by somatic dysfunction. conversely, the functions of sucking and swallowing are of paramount importance for the development of structures to which they are related. oropharyngeal development is infl uenced by the functional posture of the tongue, lips and jaws. the pharynx is attached superiorly to the base of the skull, the pterygoid processes of the sphenoid bone, the petrous portions of the temporal bones and the pharyngeal tubercle of the occipital bone. laterally, the pharynx is connected to the styloid processes of the temporal bones and posteriorly to the cervical spine. consequently, any dysfunction of the cranial base, cervical spine, hyoid bone and mandible should be considered when evaluating dysfunctional swallowing. craniocervical dysfunctions are very frequently associated with an anterior displacement of the tongue, predisposing the individual to tongue thrusting. furthermore, because cn ix and x trigger the motor activity of swallowing, the relationship between the occiput and temporal bones should be assessed for its effect on the jugular foramina. the process of maturation of swallowing is not always established, leading to swallowing dysfunction or immature swallowing. many individuals swallow with their tongues barely touching the palate or with their tongues between their teeth, in a dysfunctional manner. swallowing occurs between 1500 and 2000 times a day, and, when dysfunctional, the thrusting force applied on the incisors with every swallow results in labial tilting. the child or adolescent who swallows immaturely also demonstrates some contraction in the orbicularis oris and mentalis muscles, failure to contact the molars and tongue protrusion when swallowing. 30 furthermore, they have a narrow, high, palatal arch, and thus do not benefi t from the pumping action of the tongue on the palate, and the palatine aponeurosis, which is suggested as being necessary for aeration of the pharyngotympanic tube (eustachian tube). 31 begin by observing the face, specifi cally noting the proportion between the upper, middle and lower thirds of the face. the lower two regions are proportionately smaller in newborns than in older children, adolescents and adults. observe the tonicity of the lips and note whether or not pursing is present. observe the tonicity of the perioral musculature. have the child open the mouth and observe the position of the tongue; note any protrusion and if the tongue is at rest or demonstrates slight muscular activity. assess the length of the frenulum linguae. it may be too short, inserting near the tip of the tongue, sometimes giving the tongue a heart-shaped appearance due to it. observe the movements of the tongue and, if the child is old enough, have them protrude the tongue to note its mobility. ask them to pretend they are going to touch the tip of their nose with their tongue to observe its undersurface. with severe ankyloglossia, the tongue will tend to curl under during protrusion and will not be able to protrude because the tip is tied down by the short frenulum. in infants, test the suck response by introducing a cotted fi nger, with the palmar surface in the direction of the hard palate, into the infant's mouth and allow them to suckle. the infant should respond by latching tightly. feel coordination and strength of tongue movements. note any oral habits, such as tongue sucking, thumb or fi nger sucking, pacifi er sucking or nail biting. when present, observe the position the child assumes when sucking a fi nger, thumb or pacifi er and note in what direction the object being sucked is oriented. these positions will usually be taken to reinforce a dysfunctional pattern. for example, placement of an index fi nger relatively vertically in the mouth is associated with a narrow, high, palatal arch. thumb sucking with the index fi nger curled over the nose is consistent with a cranial pattern in extension because the ethmoid bone is placed in anterior rotation as during extension. utilizing tests of listening, assess the cranial base, noting the movement of the occiput and the temporal bones. intraosseous dysfunction of the occipital bone at the anterior intraoccipital synchondrosis will compress cn xii in the hypoglossal canal, while interosseous dysfunction between the occiput and temporal bones can affect the jugular foramen, entrapping cn ix and x. also examine the temporal bones because they affect the position of the mandible and because of the insertion of the styloglossus muscles on the styloid processes. assess the mandible, temporomandibular joint, hyoid bone and cervical spine. these areas should be balanced to ensure satisfactory function of the associated myofascial structures. patient education should be approached in three steps: 1. instruct them to consciously keep their tongue in their mouth. 2. they must learn to swallow with their lips closed. 3. while keeping their lips closed, they must learn to swallow with the tip of their tongue resting against the palate behind their upper incisors. an exercise to accomplish this is to place a small piece of food between the tongue and palate and keep it there while attempting to swallow several times. this may be repeated up to the point where swallowing with the tip of the tongue resting against the palate becomes an automatic refl ex. in young children with minor ankyloglossia, have them perform exercises to mobilize the tongue as much as possible in order to stretch the frenulum. stress that mispronunciation often associated with baby talk may appear to be cute, but that it is actually dysfunctional and should not be encouraged. insist, when speaking, that the child repeats incorrectly articulated sounds as correctly as possible to improve tongue mobility. have them play soundmaking games where they repeat certain sounds that cause the tongue to make a clicking noise against the palate. be aware that functional asymmetries are often associated with repetitive asymmetric activities, such as unilateral bottle feeding or thumb sucking. educate the caregiver and patient to lose these habits. the use of a pacifi er should be limited as much as possible. suggest that pacifi ers should be used only during the fi rst 10 months of life, when the need for sucking is strongest. 32 gastroesophageal refl ux (ger) is the retrograde fl ow of gastric contents into the esophagus and above. it is rather frequent during infancy and is often considered as 'physiologic' under 2 months of age with a benign prognosis in the majority of cases. however, it is a problem of considerable concern for the parents that ranges from minimal regurgitation with the bringing up of small amounts after feeds, to signifi cant vomiting with failure to thrive. because the latter may be indicative of a serious condition, it requires further medical evaluation. ger is one of the most recurrent symptomatic clinical disorders affecting the gastrointestinal tract of infants and children, and regurgitation in infancy is a complaint in 5.8% of children seen in osteopathic practice. 33 daily regurgitation is present in 50% of infants in the fi rst 3 months of life, with a peak incidence at 4 months. 34 most of the time, the condition resolves before the end of the 1st year and only 5% of infants still bring up their food between 13 and 14 months of age; however, when the condition is present for at least 90 days before 2 years of age, children are predisposed to demonstrate ger symptoms into middle childhood. 35 there is no association with gender, 35, 36 nor with the mode of feeding the infant, breast or bottle; nevertheless, a genetic component seems to be present and a correlation exists between maternal symptoms of ger and the occurrence of regurgitation in infancy and ger in middle childhood. 35 additionally, there is a stronger prevalence of ger among caucasian infants. 36, 37 normal gastroesophageal function is a complex mechanism where the relaxation and contractility of the lower esophageal sphincter are important factors. the esophagus is a tube connecting the pharynx and stomach, with muscular sphincters -the upper and lower esophageal sphincters. the upper portion of the esophagus (the cervical esophagus) consists of skeletal muscle; the remainder (the thoracic esophagus) consists of smooth muscle. after swallowing, the bolus of food passes through the pharynx to enter the esophagus. a primary wave of contraction starts in the pharynx and travels along the whole length of the esophagus, reinforced by secondary waves in the body of the esophagus. these peristaltic waves assist gravity to propel the bolus through the esophagus and into the stomach. normally, at the gastroesophageal junction (gej), the lower esophageal sphincter (les) relaxes to allow the bolus of liquid or food to pass into the stomach. in ger, the gej is a critical site. the les is formed by circular smooth muscle surrounding the terminal esophagus. the les is under tonic contraction that relaxes during swallowing as well as following esophageal distension by a bolus of liquid or food. additionally, the crura of the diaphragm participate in this sphincteric mechanism. the esophagus traverses the diaphragm through an opening in the right diaphragmatic crus, the esophageal hiatus, which is located between the central tendon and the hiatus aorticus. the two vagus nerves (cn x) also traverse the diaphragm through the esophageal hiatus. at this hiatus, one crus, most often the right crus, surrounds the esophagus forming an external sphincter; however, the fi bers from the crus are not directly connected to the esophageal wall. rather, fi bers coming from the transversalis fascia, and thus continuing to form a fascia under the diaphragm, pass into the esophageal hiatus and surround the esophagus to blend into its walls 2-3 cm above the gej. some of the elastic fi bers of the fascia extend into the esophageal submucosa. 1 this connection between the diaphragm and esophagus is called the phrenoesophageal ligament. this ligament simultaneously allows gej mobility, permitting the displacement associated with respiration and swallowing, while providing restriction of upward movement of the esophagus. additionally, during pulmonary inspiration, the diaphragmatic esophageal hiatus contracts in response to increased intra-abdominal pressure. 1 the fascial relationships between the esophagus and the diaphragm must be balanced when addressing dysfunction of the gej. the transversalis fascia is a vast layer of fascia lying between the peritoneum and the abdominal walls, in continuation below with the pelvic fasciae, behind with the thoracolumbar fascia and above with the fascial sheet covering the undersurface of the diaphragm. the phrenoesophageal ligament, described above, consists of fi bers extending from this layer to form the cone surrounding the gej. furthermore, the stomach is connected to the diaphragm through the gastrophrenic ligament, i.e. the portion of the greater omentum that extends from the greater curvature of the stomach to the inferior surface of the diaphragm. from a functional point of view, the diaphragm must be balanced to allow satisfactory gej function. the smooth muscle of the les generates a tonic pressure at the gej that is the major barrier to refl ux of gastric contents into the esophagus. thus, refl ux of acidic fl uid backward, out of the stomach and into the esophagus, is normally controlled at the gej. at birth, neuromuscular activity and esophageal and les peristalsis are undeveloped, resulting in frequent retrograde spilling out of gastric contents. the achievement of full development of the les occurs as the infant matures, with the pressure at the les reaching adult levels between 3 and 6 months of age. at the same time, the average capacity of the stomach at birth, i.e. around 30 ml, will rise to 100 ml at the end of the fi rst month and will reach 1000 ml in the adolescent. in order to act as a protective barrier against refl ux from the stomach, pressure in the gej has to be higher than in the adjacent stomach or esophagus. inhibitory and excitatory factors infl uence the tone of the les. as mentioned above, a bolus of liquid or food initiates the relaxation of the sphincter in response to esophageal distension. this mechanism is under the control of intramural plexuses of the enteric nervous system. the motor fi bers start in the dorsal motor nucleus of the vagus and the nucleus ambiguus, and the neural release of nitric oxide and vasoactive intestinal peptide among others by postganglionic fi bers triggers the relaxation of the les. additionally, neurological activity from the dorsal motor nucleus of the vagus and nucleus ambiguus is also sent to the crura of the diaphragm. 14 thus, both the esophageal and crural musculature are inhibited. embryologically, both the esophagus and stomach develop from the foregut. the dilatation of the foregut for the stomach starts in the sagittal plane at 4 weeks of gestation. several spatial changes occur before the stomach reaches its fi nal position. because growth is greater along the dorsal border of the stomach, the greater and lesser curvatures are formed. this is followed by rotation, with the greater curvature moving to the left and the lesser curvature moving to the right. the two vagus nerves follow this rotation. thus, the right vagus becomes posterior and supplies the dorsal part of the stomach, while the left vagus is anterior and supplies the ventral part of the stomach. some torsion of the stomach occurs between the lower part of the esophagus and the pyloric canal, which are consequently no longer in the same plane. this has been suggested as a risk factor for ger. 38 this developmental process results in what is felt when the stomach is palpated. the identifi cation of a strong torsional sensation in this region of the gut is an indication for osteopathic treatment that should be directed at the alleviation of the identifi ed torsional dysfunction. the etiology of ger is multifactorial, with often more than one factor being present in children with this condition. however, a transient les relaxation (tlesr) as the result of a vasovagal refl ex appears to be frequently associated with ger, producing a complete relaxation of the les without pharyngeal swallowing. 39, 40 other factors for ger include ineffective esophageal motility or delayed gastric emptying. 41 a high fat diet can contribute to an increase in the number of episodes of tlesr. 42 additionally, in infants, gravitational and positional factors associated with the supine position may exacerbate the refl ux. most infants spend more time in this recommended position since the 'back to sleep' campaign to prevent sudden infant death syndrome (sids). the return of the gastric acid contents into the esophagus predisposes the infant and the child to esophagitis; for these patients, crying becomes common. 43 acid refl ux into the esophagus can reach the upper esophagus, the pharynx and larynx, and may possibly be aspirated into the trachea. chemoreceptors in the mid or upper esophageal mucosa are stimulated, resulting in refl ex respiratory inhibition, hypertension and bradycardia. approximately 1% of infants demonstrate refl ux-induced apnea with airway closure or laryngospasm. 44 the severity of these reactions may lead to sids. 43 bronchospasm may also occur and, in turn, accentuate the symptoms of asthma, although ger does not seem to increase the risk of developing asthma. 45 recurrent bronchitis or pneumonia is frequent and can be caused by repeated pulmonary aspiration of acid refl ux. ent problems such as nasal obstruction are sometimes related to ger, with secondary infl ammation and narrowing of the posterior nasal apertures. 46, 47 with premature infants, the most common complication of recurrent ger is failure to thrive. in children and adolescents, ger is frequently associated with abdominal pain in the midepigastrium, eventually substernal heartburn and possible chronic irritative coughing. furthermore, regurgitation of gastric contents into the oral cavity is responsible for dental erosion and dental caries. 48 the vagus nerve (cn x) is essential in the control of les tone. it contains both motor and sensory fi bers, with a course and distribution more widespread than any of the other cranial nerves, passing through the neck and thorax to the abdomen. about 80% of vagal fi bers are afferent fi bers and may be general somatic, general visceral or special afferent. they provide signifi cant sensory input from the viscera. in infants, children and adolescents with ger, there is a defi nitive dysfunctional viscerosomatic and/or somatovisceral component. this may, in turn, lead to altered behavioral responses. possible dysfunction affecting cn x in its extensive course may facilitate ger. critical sites are the jugular foramina and the passages through the diaphragm at the esophageal hiatus. additionally, the stomach and esophagus may demonstrate visceral dysfunction in relation to somatic dysfunction in the surrounding structures, i.e. diaphragm, fasciae and ligaments. the osteopathic approach to ger consists, therefore, of addressing any dysfunction that can impede the vagus, balancing the stomach and esophagus together and in their relationships with surrounding structures -the diaphragm, fasciae and ligaments. inspect the abdomen, noting its shape, contour and movement with respiration. the abdomen should be rounded and dome-shaped in infants because of the lack of abdominal muscular tone. observe for abdominal asymmetry, noting areas of tension under the inferior border of the thoracic cage, in particular under the xiphoid process. note if the umbilicus is centered or displaced or if it is protruded. in children and adolescents, observe the inside of the mouth for dental caries. examine and treat the craniocervical junction, with particular attention to the relationship between the occiput and temporal bones because compression of the jugular foramen can impact the exit of cn x. check and balance the cervical area (c3, c4, c5) because of the phrenic nerve and its action on the diaphragm. examine and treat identifi ed somatic dysfunction affecting the thoracolumbar junction because of its potential to affect the crura of the diaphragm. evaluate and treat the diaphragm, paying particular attention to the freedom and symmetry of its excursion and its attachment around the xiphoid process as well as its anterior costal attachments. balance the fasciae at the level of the les by balancing the area below the xiphoid process with the diaphragm. balance the relationship between the stomach and diaphragm. the stomach itself demonstrates curling and uncurling movements, similar to those that created its curvatures. palpation should reveal a balance between these curling and uncurling movements. a predominance of one phase can be treated using indirect procedures. balance the torsional relationship between the stomach and the esophagus. address somatic dysfunction related to both viscerosomatic and somatovisceral refl exes: occiput, c1, c2 for the vagus; upper thoracic for the esophagus; midthoracic for the stomach. 49 infants should have small and frequent feeds, and should be fed in a semi-upright position. feeding should occur under calm circumstances. instruct children and adolescents to eat slowly and to avoid swallowing air. they should eat and drink small amounts to prevent distension of the stomach. they should also be instructed to avoid the consumption of fatty foods, caffeinated beverages and chocolate. lifestyle changes such as avoiding eating before bedtime and, if appropriate, weight loss should be encouraged. the term colic is derived from the greek, kblikos, meaning in relation to the colon. in the list of the most frequent gastrointestinal (gi) dysfunctions encountered in infants, colic is second only to regurgitation. it occurs in 10-40% of infants [50] [51] [52] and is one of the most common complaints for which parents seek professional advice. the colicky infant presents with abdominal distension, frequent gas emissions, apparent abdominal pain, irritability and excessive crying. the mechanisms that explain this disorder are not entirely understood. they may be discussed in anatomic or physiologic terms, refl ecting dysfunction at one or more levels of the brain-gut axis. additionally, because the ontogeny of the gi system is under multiple infl uences -genetic heritage, intrinsic development, endogenous regulatory mechanisms and the environment 53 -the etiology of colic is commonly multifactorial. thus, various etiologies have been proposed, including gi diseases such as allergy to cow's milk protein, lactose intolerance and intestinal hyperperistalsis, as well as neurodevelopmental dysmaturation or psychological diffi culties in the parent-child relationship. on average, it is estimated that infants cry for 2.2 hours per day during the fi rst 2 months of life, with a peak around 6 weeks of age. 54 crying time then slowly decreases to less than 1 hour a day by 12 weeks of age. the 'rule of three' proposed by wessel et al. in 1954 is usually the reference employed to identify colicky children. these children are said to cry for more than 3 hours per day, more than 3 days per week and for longer than 3 weeks. 55 colic usually starts in the 1st month of life and may persist until 3 or 4 months of age. crying is commonly concentrated in the late afternoon and evening, occurs in prolonged bouts and is unpredictable and spontaneous. colicky children are described as crying without identifi able cause, fussing and hard-to-soothe, although being otherwise healthy infants, well fed and showing no signs of failure to thrive. individual variation may be present in the cries, such as duration or intensity, associated fussing or the resulting parental distress, adding complexity to the defi nition. 56 colic cries convey acoustic information that the infant is highly aroused or distressed. 57 during a crying episode, the infant usually positions their legs fl exed over their abdomen, in association with a hard distended abdomen, gurgling noises from the abdomen (borborygmi), sometimes gas and regurgitation, as well as facial grimacing and clenched fi sts. this presentation is indicative of a gi etiology for colic. when evaluating the colicky infant, several aspects of gi development and associated neurohormonal factors should be considered. bacterial colonization of the sterile gi tract of the neonate starts quickly on delivery. a fl ora develops, resulting from microbial and host interactions. the main factors that infl uence this developing microbial population are the maternal intestinal fl ora, the use of antibiotics by the mother during pregnancy and when nursing, the mode of delivery (vaginal or cesarean) and the mode of feeding (bottle feeding or breastfeeding). the bacterial fl ora in breastfed infants is composed typically of bifi dobacteria, whereas in bottle-fed infants anaerobic bacteria as well as aerobic species are present. 58 it is also recognized that the fl ora of breastfed infants includes far fewer species that are liable to be pathogenic. 59 the developing bacterial fl ora usually becomes stable by the end of the fi rst week of life. by 2 years of age the infantile fl ora resembles that of the normal adult. this process is one of the main components, along with host cells and nutrients, that form the complex ecosystem of the intestine. the intestinal lumina are lined by a very large surface of mucosa that is the principal interface with the external environment. besides its function of digestion and absorption of the nutrients contained in food, the intestinal mucosa forms a protective barrier against foreign substances and potentially pathogenic microorganisms from the external environment. the mucosal barrier consists of cellular and stromal components covered by a mucus layer. within the mucosal barrier various secretions form a viscoelastic gel, creating a site for bacteria-bacteria interactions. thus, the microbiota play an important role in the development of the endogenous barrier mechanism in the gut and are involved in the maturation of humoral immunity in humans. 60 the intestine can be considered the primary immune organ, housing more than 70% of all immune cells. 25 the gut-associated lymphoid tissue (galt) develops through innate and acquired immunity and consists of organized and diffuse lymphoid tissues that constitute the aggregated lymphoid follicles (peyer's patches) and the mesenteric lymph nodes. this arrangement permits rapid response to any challenge in order to maintain the integrity and protective functions of the immune barrier at the gi mucosal surface. the galt contains b lymphocytes, implicated in the synthesis of secretory antibodies of the immunoglobulin a (iga) class, and t lymphocytes. in this ecosystem, the equilibrium of the microbiota is important in the maintenance of homeostasis and intestinal immune responses. it is also of paramount importance in the prevention of food allergies, and it is during the fi rst 2 years of life, when the infantile fl ora is not well diversifi ed, that food allergies and enteropathies are more apt to be established. particular circumstances in infants, such as prematurity, cesarean section delivery and antimicrobial treatment, delay intestinal colonization and its important immunostimulating effect. 60, 61 on the other hand, breastfeeding is considered to confer benefi cial effects on the microbiota, explaining its protective role against atopic disease, although it does not appear to have a protective effect on the development of colic. 62 differences in the gut microbiota of breastfed colicky infants have been shown to exist when compared to non-colicky, and lactobacilli are present less than in controls. 63 that breastfed infants may suffer from colic might be explained by the fact that breast milk contains intact proteins similar to those of cow's milk and that colic often appears to be related to a food allergy, particularly to cow's milk protein. 64, 65 this exposure would trigger the production of specifi c ige to milk protein and may be considered a manifestation of an allergic predisposition. this is, however, subject to debate because no data support the hypothesis that infantile colic leads to an increased risk for subsequent allergic disease or atopy, 66 although more irritability during the 7th week and colic-type crying during the 12th week has been observed in children with atopic disease at 2 years of age. 67 furthermore, lactose intolerance also contributes to infantile colic. 68 incomplete lactose absorption encourages bacterial growth with resultant fl atulence and cramping. as the etiology of infantile colic is multifactorial, cow's milk protein elimination may be an effective treatment for infantile colic, 64 and for colicky breastfed infants a maternal diet free of cow's milk may be considered. 69 other maternal dietary modifi cations during breastfeeding should include reduction of cruciferous vegetables, onion and chocolate, foods that are associated with colic symptoms in infants. 70 hyperperistalsis is another theory included in the gi disorder etiology to explain abdominal cramping and colic. intestinal smooth muscle normally generates rhythmic peristaltic activity. movements of the intestine with the regulation of gut motility are the result of complex neural and muscular interactions that take place at several levels and under the infl uence of neurotransmitters and hormones. 71 the innervation of the gut consists of intrinsic and extrinsic nerves. ganglionated and non-ganglionated plexi, part of the enteric nervous system (ens), form the intrinsic innervation, while the vagus, splanchnic and pelvic nerves form the extrinsic innervation. the intrinsic afferent neurons project within the myenteric and submucous plexuses and information from activated sensory receptors reaches the cns through vagal and spinal afferent nerves. the gut interacts constantly with the cns through either somatic or autonomic neurons (brain-gut axis). consequently, the cns modulates the gut motor activity through the ans (sympathetic and parasympathetic), maintaining the normal rhythm of activity in the gi tract as well as adjusting autonomic output to accommodate any external challenge. the release of acetylcholine by the parasympathetic fi bers increases gut motility, whereas the release of norepinephrine, somatostatin and neuropeptide y by sympathetic fi bers decreases the motility. multiple factors, such as emotion, stress, nervousness, fasting or eating, can also infl uence the activity of the ans. additionally, communication occurs between the different parts of the gi tract through myogenic and neurogenic signals along the gut, and through refl ex arcs transmitted via autonomic neurons. individual differences are present in the functioning of the cns. accordingly, an increased sensitivity to stimuli, such as distension of the gut, is demonstrable in patients with functional gi disorders, 72 and excessive crying in colicky infants may be the result of hypersensitivity in the perception of gut stimuli or excessive afferent responses to these stimuli. 73 genetic susceptibility to functional gi disorders may exist. supporting this theory, a correlation is found between high responsiveness of the newborn during neurobehavioral assessment in the fi rst days of life and crying behavior at home. 74 additionally, intestinal hypersensitivity may alter motility of the gi tract by increasing intestinal afferent-efferent refl exes. 75 cranial osteopathy offers a therapeutic option for these patients. osteopathic treatment of colicky infants has been demonstrated to decrease crying and increase sleep time. 76 somatic dysfunction affects the ans. the resulting state of facilitation, in turn, increases the perception of either mechanical or chemical intestinal stimuli, and visceral hypersensitivity or dysfunction follows. somatic dysfunction can involve any osseous, articular, ligamentous, membranous, fascial, muscular, visceral and vascular component associated with the gi tract. vagal viscerosensory neurons have their cell bodies in the inferior ganglion located under the jugular foramen. the spinal sensory input takes place through perivascular nerves passing through the prevertebral ganglia to the dorsal horn of the spinal cord, and these neurons have their cell bodies in the dorsal root ganglia. pain perception is thought to be mediated essentially by the spinal innervation. 77 the craniocervical junction (parasympathetic), the thoracic and thoracolumbar spine (sympathetic) and sacropelvic region (parasympathetic) may be sites of somatic dysfunction resulting in somatovisceral dysfunction. treating these areas may contribute to balance the gut function of the colicky infant. changes in internal sensory states, acting in a bidirectional manner between the viscera and the brain, are obviously related to interoception and visceral hypersensitivity, and are considered as the key pathogenetic factors underlying the emotional state present in subjects with functional gi disorders. 78 stress, in a broad sense, as with any menace to one's individual homeostasis, may come from the external or internal environment. 78 as such, visceral hypersensitivity, milk allergy or somatic dysfunction may be stressful, and colicky infants are quite often described as demonstrating diffi cult temperament. an infant who is crying is expressing distress without indication of its origin. this can be a signifi cant source of stress for parents and caregivers. they respond differently to these cries according to cultural and sociodemographic factors that, in turn, may affect the amount of infant crying. responses of mothers to infant crying diverge from putting the child to bed, to holding and carrying them, riding around in the car, rocking or swaddling. 79 globally, fi rst-born babies are usually reported as crying more excessively, and the western caregiving style is associated with a higher incidence of reported crying. 79, 80 touching, holding and caressing a child results in positive effects on the emotion regulation and stress reactivity in the infant. 81 maternal care facilitates the development of central corticotropin-releasing factor (crf) systems which regulate the expression of behavioral, endocrine and autonomic responses to stress. 82 it is well established that infant-maternal contact is of paramount importance in mediating infant emotional reactivity. gut-brain peptide cholecystokinin (cck) and endogenous opioid analgesic agent production are increased following contact. 81 this contributes to the development of attachment through the 'interactive regulation of biological synchronicity between organisms'. 83 under normal conditions, this relationship between mother and infant contributes to the wellbeing of both. conversely, infantile irritability can prove to be a major source of distress to caregivers. in extreme circumstances the irritability of the child can prove so stressful as to create an impulse to shake the child. 73 a potential psychosocial etiology for colic in the 1st year of life is associated with pre-existing maternal anxiety. 62 if the caregiver is stressed, the child will cry more, and the caregiver will be further worried by their incapacity to help the child. furthermore, a baby is frequently described as crying excessively when the crying distresses the parents. infants' cries can also be indicative of a behavioral problem resulting from a less than optimal parentinfant interaction. this complex interrelationship between the child and caregiver has led to a behavioral hypothesis for the etiology of colic where interventions such as modifying parental responsiveness, using motion and sound to calm the baby, and reducing stimuli have been suggested. 64 these caregivers do not need to be told that they are bad parents; they need to be supported and managed with understanding. the circumstances must be discussed and the caregiver given the opportunity to vent their anxiety and frustration. behavioral adaptations, when appropriate, should be encouraged. maternal smoking may contribute to the disorder. 84 one hypothesis for colic suggests that it is the result of transient developmental dysmaturation based on the fact that infantile colic often stops after 5 or 6 months. 85 it is important, nonetheless, to treat these children and help the parents, because persistent behavioral diffi culties, including crying, sleeping or feeding behavior in infancy, are precursors of hyperactivity or behavioral problems and academic diffi culties in childhood. 86 it is important to perform a thorough physical examination to rule out other causes for persistent crying to ensure that there is no organic cause for the crying. once this has been done, osteopathic manipulation may be employed to reduce the somatic afferent load of somatovisceral refl exes into the cns as well as to alleviate the mechanical impact that somatic dysfunction can have on the gi tract. treatment is appropriate not only for infants, but also for children and adolescents, because colic may persist later in life as a functional gi disorder. 87 the osteopathic component of the examination should begin with observation of the infant's posture. the infant may position themselves with their legs fl exed to their chest. if the patient is a child, they might present with an apparent increased lumbar lordosis that occurs when bowel dysfunction creates a distended abdomen with consequent relaxation of the abdominal muscles. observe the abdomen to see if it is tense with bowel distension from fl atulence. note the power and rhythm of the inherent motility of the prm in the head and throughout the body, particularly noting the abdomen. somatic dysfunction should be sought out, especially in the regions of, but not limited to, the posterior neurocranium; the occipitocervical junction and upper cervical spine; the thoracic spine, ribs and upper lumbar spine; the thoracoabdominal diaphragm, the anterior abdominal wall and the sacrum and pelvis. treatment should employ indirect principles and manipulation should be directed at somatic dysfunction, when identifi ed, involving the temporooccipital relationship for its impact on the jugular foramen, and the occipitocervical junction and upper cervical spine for their effect on the vagus and parasympathetic somatovisceral refl exes. somatic dysfunction of the thoracic spine, ribs and upper lumbar spine may be treated to affect sympathetic somatovisceral refl exes. in acute cases, practice inhibition in the lumbothoracic area. avoid active massage of the abdomen which can be irritating. dysfunction of the thoracic spine, ribs and thoracoabdominal diaphragm should be addressed for its impact on the lymphatic and venous drainage of the contents of the abdomen. diaphragmatic, abdominal wall and pelvic dysfunction should be treated to alleviate the impact of dysfunctional fascial tensions on the gi tract. dysfunction of the thoracoabdominal diaphragm is related to the function of the mesenteric plexus. sacropelvic somatic dysfunction may be treated to affect pelvic splanchnic parasympathetic somatovisceral refl exes. using indirect principles, release the periumbilical area and intestine. in every treatment procedure pay attention to the inherent motility of the prm as manifest throughout the body. treating this mechanism affects the ans and probably facilitates tissue perfusion, reducing congestion. 88 the caregiver should be encouraged to create an environment of comfort, calm and relaxation for the infant. gently caressing the frontal area of the neurocranium will often facilitate this. obtaining relaxation of the infant will also have a calming effect on the caregiver(s) that will, in turn, further relax the infant. this relaxation will often make it easier to obtain such a state of calm in the future and will also demonstrate to the caregiver(s) that it can be obtained. avoid, however, active massage of the abdomen which can be irritating. dietary considerations may be employed to improve the function of the gi and the immune system. breastfeeding should, if at all possible, be encouraged. the mother should pay attention to her diet, avoiding cow's milk, cruciferous vegetables, onion and chocolate. in colicky children, lactose intolerance should be considered. a diet rich in fresh fruit and vegetables and antioxidants such as vitamins c and e should be recommended, while refi ned foods should be avoided as much as possible. constipation is the chief complaint in 3% of all pediatric outpatient visits and defecation disorder is present in 10-25% of children referred to pediatric gastroenterologists. 89 constipation in children is usually defi ned as abdominal pain, diffi culty or pain when passing stool, with the passage of feces that are either large and too hard or in small pebble-like pieces, with diffi culty defecating and a frequency of two times or less per week. the fi rst intestinal discharge, meconium, is passed in healthy newborns within 24 hours. 90 after that, the mode of feeding determines the frequency and quality of stools. bottle-fed infants demonstrate less frequent stools than breastfed infants, who have soft yellow stools up to fi ve times a day. however, breastfed infants may go for 3 or more days without defecation. weaning -the commencement of nourishment with food other than milk -usually occurs between 4 and 6 months of age and results in fi rmer feces. although the frequency of bowel evacuation varies from one infant to another, it is generally admitted that a frequency of less than one stool a day before 6 months of age, and three times or less per week after 6 months, may be considered as pathologic. in preschool children, constipation is present when the child has less than two stools per week. most of the time, constipation is functional, without any objective evidence of an underlying pathologic condition and a thorough history and physical examination are suffi cient to make the diagnosis. it is, however, important to rule out failure to thrive or endocrine, metabolic or structural disease such as hirschsprung's disease. children presenting with this latter condition, characterized by the total absence of ganglion cells in meissner's and auerbach's plexuses, suffer from constipation with massive colonic dilatation proximal to the segment of affected bowel. the onset, however, occurs at birth with delayed passage of meconium and children suffering from the disease demonstrate poor growth. 91 functional constipation has also been described as functional fecal retention, voluntary withholding, psychogenic megacolon or idiopathic constipation. it affects boys more often than girls, contrary to the adolescent and adult populations where women suffer more often from constipation. another difference between children and the adult population is the presence of fecal incontinence in children, which is not present in adults with functional constipation. 91 during the fi rst months of life, infants may present with dyschezia, i.e. diffi culty in defecation. in this case they experience severe problems when trying to defecate and strain and scream during prolonged endeavors. this behavior may last up to 20 minutes, until they successfully pass stools that are usually soft or liquid. the cause is hypothesized to be the failure to coordinate the augmentation of intra-abdominal pressure with the relaxation of the pelvic muscles. 89 painful defecation quite often results in chronic fecal retention with fecal impaction (the immovable collection of compressed or hardened feces in the colon or rectum) and resultant fecal soiling (the passage of liquid stool around the impaction). more than 50% of school-aged children suffering constipation have a history of painful defecation before 36 months of age. 92 toddlers may succeed in avoiding defecation for several days. the evacuation that then occurs is often painful and may be associated with bleeding, thereby strengthening the behavior of fear and retention. fecal retention, in turn, is associated with subsequent abnormal contraction of the anal sphincters (anismus) and contraction of the pelvic fl oor during attempted retention. the child develops a retentive posture with contraction of the gluteal muscles. with overstretching of the rectal wall and muscle fatigue in the pelvic fl oor, incompetent anal function results in spontaneous relaxation of the sphincters, with consequent fecal soiling with soft or liquid stool. fecal soiling often follows constipation facilitated by rectal distension. 93 constipated children demonstrate several associated symptoms including irritability, abdominal cramps and decreased appetite. most of the time, children with constipation have a withholding type of behavior and very often feel ashamed. they demonstrate more behavioral problems than children who are not constipated; however, these accompanying symptoms disappear immediately following the effective treatment of constipation. 94 the role of psychological and emotional components in the etiology of defecation disorders is subject to debate. it is uncertain which problem comes fi rst: the emotional disorder or the defecation disorder. 94 toilet training is normally initiated between the ages of 18 months and 3 years. when conducted in an overly coercive and stressful fashion, the associated stress has been proposed as a cause of fecal retention. however, when hard bowel movements or painful defecation are present in association with stool toilet training refusal, constipation should be considered because the fi rst episode of constipation in children usually occurs before stool toilet training refusal. 95 familial environmental factors, or added parental anxiety because they want their child to be able to go to school, may add a psychological factor to a physical predisposition to constipation. a decrease in colonic peristalsis has been proposed as a cause of constipation in childhood. it is well recognized that reduction of physical activity and reduction of fl uid intake in adults can be associated with constipation. because children tend to be normally physically active, inactivity is not a major cause of constipation for this population. however, food allergy, particularly cow's milk allergy with cow's milk protein hypersensitivity, seems to be associated with constipation in children. 96, 97 constipation may certainly be multifactorial. the behavioral approach does not explain every case of constipation. furthermore, children with constipation demonstrate a higher incidence of bladder disorders such as urinary incontinence, bladder overactivity, dyscoordinated voiding, large bladder capacity, poorly emptying bladder, recurrent urinary tract infection and vesicoureteral refl ux. 98 this constitutes a syndrome, an aggregate of associated symptoms and signs that may be addressed by an osteopathic approach. most cases of functional constipation respond well to osteopathic manipulative procedures. defecation is a complex process that involves a mixture of voluntary and involuntary actions. it is triggered by the excitation of anorectal mechanoreceptors sensitive to distension of the rectum. it is followed by coordinated voluntary activity of the abdominal and pelvic musculature and involuntary relaxation of anal sphincters. as the fecal mass moves, the pelvic fl oor muscles relax in order to allow alignment of the rectum with the anal canal. defecation can be inhibited by voluntary contraction of the external anal sphincter and pelvic fl oor muscles. normally, the anal canal is occluded by the internal and external anal sphincters. additionally, the puborectalis muscle, the medial part of the levator ani muscle, contributes to the loop surrounding the anorectal junction by mixing some of its fi bers with the deep part of the external sphincter of the anal sphincters. additional fi bers of the levator ani muscle join the conjoint longitudinal coat that surrounds the anal canal between the internal and external canal. behind the rectum, the pubococcygeal fi bers of the levator ani muscles attach to the anterior surface of the coccyx. the internal anal sphincter has an autonomic innervation: the sympathetic fi bers are from the hypogastric plexus and the plexuses located around the superior rectal artery; the parasympathetic fi bers are from the pelvic splanchnic nerves (s2-s4). the external sphincter has a voluntary motor supply that comes from the inferior rectal branch of the pudendal nerve (s2-s3) and the perineal branch of the fourth sacral nerve. if the child is old enough to be standing and walking, observe their postural mechanics, noting particularly the degree of abdominal protrusion, thoracolumbar mechanics as they relate to psoas muscle mechanics, the degree of lumbar lordosis as it relates to abdominal protrusion and psoas muscle mechanics. with the patient supine, observe the abdomen, noting its contour and possible distension. palpate the abdomen, looking for tension in the abdominal wall and for palpable stool. in many cases of chronic constipation, stool will be palpable throughout the colon. defi ne stool consistency and assess the quantity of the rectal fecal mass by looking at the height of transabdominally palpable stool above the pelvic brim. diagnostic digital rectal examination should be performed gently to avoid perpetuation of dyschezia. maneuvers that result in rectal stimulation produce potentially noxious sensory experiences and should be discouraged. 89 specifi cally look for somatic dysfunction affecting the thoracolumbar junction that can be associated with psoas muscle dysfunction and sympathetic somatovisceral refl exes. examine the sacrum, coccyx and pelvis for dysfunction that can affect the pelvic fl oor and also be the source of parasympathetic somatovisceral refl exes. the general medical treatment approach includes dietary changes with behavioral modifi cation techniques (cognitive and behavioral interventions such as toilet training, which diminishes phobia and provides positive reinforcement through a rewards system). this approach is often combined with prolonged courses of laxatives. treatment is usually successful, but may take up to 6-12 months. 93 when somatic dysfunction has been identifi ed, the correct osteopathic treatment can result in signifi cantly faster results with a resolution of constipation, often in one or two treatments. therefore, treat any somatic dysfunction as identifi ed. treat somatic dysfunction of the sacrum for its relation with pelvic splanchnic nerves and the pudendal nerve. release sacroiliac joints and surrounding myofascial structures. it is important to remember that the sacrum is not completely ossifi ed in infants and children and that intraosseous dysfunction may be present between the different sacral segments. in the infant the sacral molding procedure often provides good results. treat somatic dysfunction of the coccyx, paying attention to its relationship to the insertion of the levator ani muscles. treat somatic dysfunction of the thoracolumbar area for its somatovisceral effect on the sympathetic output to the intestine. with hypersympathetic drive, the bowel becomes less active and may result in constipation. it is also important to be sure that child's posture is balanced, without dysfunctional tension at the level of the psoas for its relationship with the sympathetic chain near the psoas muscle origin. it is important to increase the amount of fl uid that the child drinks every day. infants may be given fruit juices such as prune and pear which contain fructose and sorbitol for their mild laxative effect. if the child is old enough to be eating solid foods, increase bran cereal and fruits and vegetables that are high in fi ber. encourage the consumption of meals at regular times. if the child is relatively sedentary, as tends to occur these days with the playing of computer games, encourage increased physical activity. tell the parents to watch for infrequent, diffi cult or painful defecation that heralds the recurrence of constipation. when identifi ed, they should respond quickly, encouraging the child to go to the bathroom more frequently and modifying the child's diet and physical activities. in a holistic approach to health care, any one area of the body is linked directly or indirectly to all the other areas of the body. consequently, observation of the oral cavity not only provides information about the mouth, it also provides knowledge as to many other aspects of the individual. the oral cavity provides access to the posterior nasal cavity, pharynx, esophagus and lower respiratory tract. it contains an ecosystem that refl ects the overall health status of the individual. dental occlusion refl ects the functional balance of the musculoskeletal system, both locally and at distant areas of the body. muscular tone, facial expression and orofacial habits mirror the individual's psychoemotional status. the oral cavity is also an area that allows communication with others through facial expression and speech. it is the major point of entry for nutrition and hydration and a secondary portal for respiration. optimal function of the area is essential for the very survival of the individual. the main osseous structures of the oral cavity are the mandible, maxillae and palatine bones. the latter two bones are part of the viscerocranium and as such their growth and development extend through adolescence. this process is under genetic infl uence as well as epigenetic factors in which orofacial functions play a signifi cant part. the long period through which development occurs allows extensive opportunities for dysfunction to be established. thus, a thorough understanding of the structure and function involved in this evolution, combined with attentive observation of the infant and growing child, is imperative to identify somatic dysfunction, the effective treatment of which is necessary to promote health and balance. the oral cavity, the mouth, is surrounded by the lips and cheeks and consists of two parts: the oral cavity proper and the vestibule. the oral cavity proper is limited anteriorly and laterally by the alveolar arches, teeth and gums, and above by the hard and soft palate; posteriorly, it communicates with the pharynx through the oropharyngeal isthmus. it includes the tongue, which is totally contained in the oral cavity in infants. as the child grows, only the anterior two-thirds remain in the oral cavity while the posterior third descends following the larynx. 1 the vestibule is located between the lips and cheeks externally, and the gums and teeth internally. it connects with the outside through the oral fi ssure between the lips. the entire oral cavity is covered by mucosa, starting at the labial margins and consisting of three portions: the lining and the masticatory and specialized mucosae. 1 these portions demonstrate different properties according to their location. the oral mucosa is in continuity with the pharyngeal mucosa at the oropharyngeal isthmus. several bones within the viscerocranium defi ne the oral cavity. the maxillae are the fi rst to come to mind; together with the mandible, they are among the largest of the facial bones. nevertheless, all of the components that constitute the skeletal framework of the oral cavity must be taken into consideration. myofascial structures attached to this framework affect it and are, in turn, affected by it. besides the mandible and maxillae, these bony boundaries include the paired palatine and temporal bones, and unpaired sphenoid and hyoid bones. the maxilla consists of a body with zygomatic, frontal, alveolar and palatine processes. bilaterally their bodies contain the maxillary sinuses, the largest of the paranasal sinuses. although these cavities are large in the adolescent, at birth they are small furrows 7 mm in length and 4 mm in width. 2 consequently, in the infant, the vertical diameter of the maxilla is smaller than the transverse and anteroposterior diameters. the maxillary body is shaped as a pyramid, having four surfaces: anterior, posterior (infratemporal), superior (orbital) and medial (nasal). the lower part of the anterior surface demonstrates multiple eminences above the roots of the teeth. several facial muscles insert on the anterior surface of the maxilla and their traction during orofacial activities such as sucking and chewing contributes to the development of the maxilla. the depressor septi nasi muscle arises above the eminences of the incisor teeth. a slip of the orbicularis oris muscle is attached on the alveolar border below this incisive fossa, and the nasalis muscle is attached superiorly. the levator anguli oris muscle arises from the canine fossa, lateral to the incisive fossa. above the canine fossa is the infraorbital foramen, the anterior end of the infraorbital canal, which transmits the infraorbital vessels and nerve. above the foramen on the margin of the orbit is attached part of the levator labii superioris. the nasal notch medially limits the anterior surface of the maxilla and nearby the nasalis and depressor septi muscles are attached. bilaterally the two nasal notches join to form a pointed process, the anterior nasal spine. laterally, the convex infratemporal surface of the maxilla forms the inferior part of the infratemporal fossa. the maxillary tuberosity forms the lower part of this surface and on its medial side articulates with the pyramidal process of the palatine bone. inconstantly, it articulates with the lateral pterygoid plate of the sphenoid and gives origin to a few fi bers of the medial pterygoid muscle. just above this is the pterygopalatine fossa, with a groove for the maxillary nerve. the maxillary orbital surface forms part of the fl oor of the orbit. medially, behind the lacrimal notch, the margin articulates with the lacrimal bone, the ethmoid's orbital plate and the palatine's orbital process. posteriorly, it constitutes the poste-rior border of the inferior orbital fi ssure. anteriorly it forms part of the orbital margin, which is continuous medially with the frontal process and laterally with the zygomatic process. anteriorly and medially, the inferior oblique muscle originates just lateral to the lacrimal groove. on the nasal surface is the maxillary hiatus, the large opening of the maxillary sinus. the superior border of the maxillary nasal surface articulates with the ethmoid and lacrimal bones. the inferior meatus of the nasal cavity is located below the maxillary hiatus and behind a surface for articulation with the perpendicular plate of the palatine bone. a groove crosses this surface, running obliquely downward and forward, and forms, with the palatine bone, the greater palatine canal. anterior to the maxillary hiatus a deep groove forms part of the nasolacrimal canal. the zygomatic process of the maxilla is triangular and is situated at the convergence of the anterior, posterior and orbital surfaces. the frontal process forms part of the lateral boundary of the nose projecting posterosuperiorly. it gives attachment to part of the orbicularis oculi and levator labii superioris alaeque nasi. its medial surface forms part of the lateral wall of the nasal cavity. the upper border articulates with the frontal bone, the anterior border with the nasal bone and the posterior border with the lacrimal bone. the alveolar process is very thick, being broader behind than it is in front. it contains eight deep cavities for the roots of the teeth. these cavities vary in size and depth: the cavities for the canine teeth are the deepest; the cavities for the molars are the widest. the alveolar processes of the maxillae articulated together form the alveolar arch. the buccinator muscle arises from the lateral surface of the alveolar process, as far forward as the fi rst molar. the palatine process projects horizontally and medially from the nasal surface of the maxilla. it constitutes an important part of the fl oor of the nasal cavity and the roof of the mouth. its inferior surface is concave and forms, with the palatine process of the opposite side, the anterior three-quarters of the osseous plate of the palate. in young skulls, a fi ne linear suture, the incisive suture, may be observed. it extends from the incisive fossa, behind the incisor teeth, to the space between the lateral incisor and canine teeth. the small part in front of this suture forms the premaxilla (os incisivum) that contains the sockets of the incisor teeth. the two palatine processes join to form the median intermaxillary palatal suture. the margins are sometimes raised and form a prominent palatine torus. the medial border of the superior surface of the palatine process forms a ridge, the nasal crest. with the opposite side, it forms a groove for the vomer. the posterior border is articulated with the horizontal plate of the palatine bone (figs 7.7.1, 3.5) . the maxilla ossifi es in a mesenchymatous sheet. the number of ossifi cation centers is debated and between two and four such centers may appear during the 7th week of fetal life. they form a premaxilla (os incisivum) and a maxilla that start to unite at the beginning of the 3rd month of development. the identifi cation of the junction between these two parts as a suture is also debated, 3 and information is lacking to demonstrate its role as a growth site. 4 a line or cleft, however, may be observed in the anterior part of the palate until the middle decades of life. 1 this site -be it suture, line or cleft -is of consequence in osteopathic practice because it provides a hinge-like location where intraosseous maxillary somatic dysfunction can develop. such dysfunction is commonly found in infants and children as the result of activities such as thumb sucking and from falls where the area is injured. if not treated, this dysfunction will have a signifi cant impact that can only increase as the structures grow. orofacial dysfunctions such as malocclusion or speech disorders may follow. the maxillary sinus, described as a small furrow at birth, reaches its full size after the second dentition. as such, the size of the maxillary body at birth is small, the teeth sockets located almost at the level of the fl oor of the orbit. the relatively small length of the maxillary vertical dimension, when compared to that of the adult, gives the infant the appearance of having large eyes. augmentation in volume of the maxillary sinus and development of the alveolar processes will contribute to an increase in the vertical dimension of the maxillary body ( fig. 2.13 ). the maxilla articulates with nine bones including the frontal, ethmoid, zygomatic, nasal, lacrimal, inferior nasal concha, palatine, vomer and the opposite maxilla. the articulation with the orbital surface or with the lateral pterygoid plate of the sphenoid is inconstant. on the other hand, the mandible articulates only with the two temporal bones. it consists of a curved horizontal body and two perpendicular portions, the rami. it is the largest and strongest bone of the face and contains the alveoli for the roots of the lower teeth. its shape and position determine the positional arrangement of the lower teeth and as such it contributes to the relationship between the occlusal surfaces of the maxillary and mandibular teeth when they are in contact. the mandibular body has two surfaces and two borders. in the midline of the external surface is a small ridge, the remnant of the line of fusion between the two halves of the mandible at the symphysis menti. this ridge divides inferiorly to surround the mental protuberance. the mentalis muscle and a small portion of the orbicularis oris are inserted below the incisor teeth on either side of the ridge. laterally, the depressor labii inferioris, depressor anguli oris and platysma muscles are attached. the internal surface is concave and the paired superior and inferior mental spines are situated on either side of the symphysis menti. the genioglossi muscles have their origins on the superior spines and insert on the lingual fascia beneath the mucous membrane and on the hyoid bone. they depress and protrude the tongue. if their origin on the mandible is dysfunctionally positioned, their leverage will be altered and consequently their effect on the tongue will, in turn, be dysfunctional. the geniohyoid muscles insert on the inferior mental spines, and the anterior belly of the digastric insert below the mental spines, on either side of the midline. on either side, an oblique line, the mylohyoid line, runs from a point inferior to the mental spine upward and backward to the ramus behind the third molar tooth. it gives attachment to the mylohyoid muscle, the lower-most part of the superior constrictor of the pharynx, and the pterygomandibular raphe. the superior constrictor, pterygomandibular raphe and buccinator are intimately joined together to the mandibular periosteum. furthermore, they form a continuous band that unites the orofacial structures with the cranial base and cervical spine (fig. 7.7.3) . thus, postural imbalances in the axial skeleton can affect the orofacial structures, potentially leading to orofacial dysfunction and malocclusion. the upper or alveolar border contains 16 cavities for the roots of the teeth. on either side, the buccinator muscle is attached on the outer lip of the superior border, as far forward as the fi rst molar tooth. the buccinator has its origin posteriorly on the lateral aspect of the maxilla and oblique line of the mandible, the pterygoid hamulus and pterygomandibular raphe (figs 7.7.2, 7.7.3). it inserts anteriorly on the angle of the mouth, the middle fi bers of the muscle crossing in the region of the modiolus, the lower set passing to the upper lip, the upper set to the lower lip. 5 the modiolus located near the corner of the mouth represents a convergence of several muscles of facial expression and, as such, observation of this area is highly indicative of the psychoemotional state of the individual. the fi bers of the buccinator muscle are interspersed with more horizontal portions of the orbicularis oris muscle. the buccinator fl attens the cheek, retracts the angle of the mouth and plays an important role in mastication in conjunction with the tongue and orbicularis oris muscle to form a belt on each side of the oral cavity, preventing food from accumulating in the oral vestibule. the quadrilaterally shaped mandibular ramus consists of two surfaces, four borders and two processes. the lateral surface is fl at and gives attachment to the masseter muscle. the masseter muscle is attached above on the inferior border of the anterior two-thirds of the zygomatic arch and the medial surface of the zygomatic arch. it inserts inferiorly on the lateral surface of the ramus and the coronoid process of the mandible. it elevates the mandible and its function is of paramount importance in the development, growth and maturation of the mandibular condyles and fossae. a reduction of masseter muscle activity in bottle-fed babies has been observed 6 and, with the loss of chewing behavior, may predispose to chewing/swallowing disorders and malocclusions. 7 located on the medial surface of the mandibular ramus, approximately in its center, is the mandibular foramen leading to the mandibular canal. it contains the alveolar nerve and vessels. a sharp spine on the anterior margin of the foramen, the lingula (spix spine), provides attachment for the sphenomandibular ligament. this site is of particular interest in mandibular kinematics because mandibular motion is centered on a point located near the lingula. the vascular-neural bundle is, therefore, protected from injury caused by normal mandibular motion. 8 the medial pterygoid muscle inserts below the mandibular foramen, on the medial surface of the mandibular angle. thus, the mandibular angle is affected by the action of the masseter laterally and medial pterygoid medially. traction from these muscles dynamically infl uences the growth of the mandible. this infl uence has to be balanced unilaterally between the masseter and medial pterygoid, as well as bilaterally. the coronoid process is a thin, fl attened piece that forms the anterior limit of the mandibular incisure. the temporalis and masseter muscles are attached on its lateral surface; the temporalis also covers part of the medial surface and anterior border of the ramus. the temporalis muscle has its origin on the temporal fossa and functions to elevate the mandible and close the jaw. its posterior, almost horizontally oriented fi bers are the primary retractors of the protruded mandible. these muscles determine chewing action and, when dysfunctional, can have signifi cant impact on the mandible. the condylar process provides an articular surface with the disk of the temporomandibular joint (tmj). its long axis is slightly oblique and directed medially and posteriorly. the neck that unites the head or condylar process to the ramus has the pterygoid fovea (anteriorly) for the attachment of the lateral pterygoid muscle. this masticatory muscle has two heads: the inferior head has its origin on the lateral plate of the pterygoid process; the superior head originates on the infratemporal crest and adjacent greater wing of the sphenoid. in addition to its insertion on the mandible, some of its fi bers join the articular disk and capsule of the tmj. it acts to protrude the lower jaw and also contributes to the opening of the mouth. unilateral pterygoid contraction deviates the chin laterally, enabling grinding motion for chewing. this muscle is important in the development of children's orofacial structures, where unilateral functional patterns will stimulate growth in an asymmetric fashion. alternatively, structural asymmetries may, in turn, prevent the individual from having symmetric functional patterns. ossifi cation of the mandible occurs in the fi brous membrane covering the outer surfaces of meckel's cartilages. these cartilages develop bilaterally in the fi rst pharyngeal arches. the primitive tmj starts to organize during the 7th week of development, concomitantly with the emergence of muscular activity in the masticatory apparatus. at birth the mandible consists of two parts separated by a cartilaginous symphysis menti not yet ossifi ed. the body, although rather underdeveloped, is much larger than the rami. it consists of relatively thin cortices with tooth buds almost totally occupying its volume. 9 each side contains the sockets of the two incisors, the canine and the two deciduous molar teeth. the angle between the body and the ramus is obtuse (175°), and the coronoid process, of rather large size, projects above the level of the condyle. at birth, the tmj is slack. the mandibular fossa of the temporal bone in which the condylar process of the mandible is located is almost fl at, providing little stability. 10 during the fi rst years of life growth will occur through bony deposition and resorption. bone deposition occurs on the mandibular labial side, whereas resorption occurs on the lingual side, thus allowing for elongation of the mandible and more space for the deciduous dentition. 11 the two halves of the mandible join during the 1st year, although a line of separation may still be seen in the beginning of the 2nd year. concomitant development of mastication stimulates growth of the alveolar and subdental portions of the mandibular body, allowing in turn more powerful traction from the masticatory muscles. during the fi rst 3 years of life, mandibular bicondylar width grows rapidly, in synchrony with cranial base growth. it is the fastest growth period of the mandible. with the development of permanent dentition, the angle becomes less obtuse -140° at about the 4th year. crown formation of the permanent teeth, and their following eruption, is a time of possible occlusal instability, lasting up to 10-12 years of age when the majority of the permanent teeth have erupted. after puberty, the mandibular angle is 120° (fig. 7.4.4) . development of the teeth, like the development of the other components of the craniofacial complex -jaws, dental arches, tongue and myofascial structures -is under the infl uence of genetic and environmental factors. this development is largely infl uenced by the surrounding structures of the cranium, particularly the temporal bones with which the mandible articulates, and the sphenoid and hyoid bones that are part of the skeletal framework of the oral cavity. at the root of the zygomatic process, in the squamous portion of the temporal bone, is the mandibular fossa, with which the condylar process of the mandible articulates. this fossa, also called the glenoid cavity, is a deep hollow in the adult but is almost fl at in the infant. a disk separates the mandibular condylar process from the temporal glenoid cavity, and a fi brous capsule and synovial membrane surround the joint. the position of the condylar process of the mandible is greatly infl uenced by the position of the mandibular fossa of the temporal bone. the relationship can be potentially dysfunctional if one or several components of the tmj demonstrate somatic dysfunction. in the cranial concept, during cranial external rotation, the mandibular condyles move somewhat posteromedially, following the mandibular fossae of the temporal bones, and the chin recedes. concomitantly, the mandibular angles move laterally. the opposite occurs during cranial internal rotation when the mandibular fossae of the temporal bones move anteriorly. as a result, the mandible moves anteriorly, with the chin becoming more prominent. the deep cervical fascia and stylomandibular ligament also contribute to the relationship between the temporal bones and mandible. the deep fascia of the neck is divided into an external or investing layer and a pretracheal layer. the former surrounds the neck and encloses the trapezius and sternocleidomastoid muscles. above, it fuses with the periosteum along the superior nuchal line of the occipital bone, on the mastoid and styloid processes of the temporal bone and the complete base of the mandible. 1 the stylomandibular ligament, a condensation of the deep cervical fascia, extends from the tip of the styloid process of the temporal bone to the posterior border of the angle of the mandible. this fascia links the mandible to the base of the skull. thus, dysfunction of the cranial base may affect the mandible, and vice versa. it is of great signifi cance in the fi rst years of life, when structures have not yet completed their growth. as such, torticollis or plagiocephaly, if untreated, may predispose to somatic dysfunction of the mandible and viscerocranium, leading to malocclusion. 12 as it belongs to the cranial base, the sphenoid also infl uences the mandible through its muscular and ligamentous relations. the sphenomandibular ligament is of particular importance. this fi brous band, a remnant of meckel's cartilage, runs from the spine of the sphenoid's greater wing to the lingula of the mandible. it constitutes the primary passive support of the mandible, with the area of the lingula acting as an anchor. an artifi cial axis passing through the two lingulae may be proposed, around which motions of the mandible occur. these motions include depression of the mandible during opening of the mouth and elevation during closure, as well as protraction and retraction. the mandible may be compared to a swing hanging under the sphenoid's greater wings. this comparison is particularly valid in infants and young children, where the tmj is quite loose and the sphenomandibular ligament well defi ned. other links between the mandible and sphenoid include the bilateral pterygomandibular raphe and pterygoid muscles joining the pterygoid process to the mandible. the pterygomandibular raphe, also referred to as the pterygomandibular ligament, is a thickening of the buccopharyngeal fascia. it separates and gives origin to the buccinator muscle anteriorly and the superior constrictor of the pharynx posteriorly. the pterygomandibular raphe is attached superiorly to the pterygoid hamulus, the hookshaped inferior extremity of the medial plate of the pterygoid process. below, it is attached above the mylohyoid line behind the third molar tooth. indeed, multiple infl uences exist between the cranial base and the facial bones, potentially affecting the orofacial structures. the human profi le and the position of the mandible have been correlated postnatally with the basicranial shape. 13 furthermore, facial morphology is more related to variation of the lateral part of the basicranium than to fl exion occurring in the midline. 14 epigenetic factors play a signifi cant role in this process. this role is largely fulfi lled by several orofacial functions that start as early as the fi rst weeks of development. it is hypothesized that, around 8 weeks of development, early mandibular movement participates in the differentiation of the primary mandible from meckel's cartilage. 15 consideration of orofacial function is of great signifi cance in the understanding and treatment of any orofacial disorder or malocclusion. to a large extent, orofacial function, interconnected with the musculoskeletal apparatus in a complex system, contributes to the formation of the oral cavity and viscerocranium. deglutition, sucking, ventilation, facial expression, mastication and speech are the sequential events that, through dynamic processes, constantly infl uence the growth and development of the orofacial components. for most of these activities, the tongue plays a central and vital part. in feeding, it moves food through the oral cavity for chewing and then to the pharynx for swallowing. in respiration, its position, relative to the posterior pharyngeal wall, determines the dimensions and shape of the airway for air to fl ow between the palate and the posterior tongue. with the larynx, the tongue contributes to the production of sounds and speech. finally, the tongue seems to play an important proprioceptive role that, in turn, functionally or dysfunctionally regulates all of these activities. 1 the tongue consists of a mass of muscle covered by mucous membrane, where the papillae of the gustatory organ are located. the lingual musculature is divided into intrinsic and extrinsic muscles. the intrinsic muscles, which are totally contained inside the tongue, are the bilateral superior and inferior longitudinal, the transverse and the vertical lingual muscles. conversely, the extrinsic muscles extend outside the tongue and consist of the genioglossus, hyoglossus, styloglossus and palatoglossus muscles. the lingual musculature matures quite early in life, transforming the tongue into a powerful growth stimulator for the surrounding structures. at birth, the infant tongue is totally intraoral and its extrinsic muscles are short. in the infant, the tongue fi lls the oral cavity, contacting the soft and osseous palates, the cheeks and lower lip. although mobile, the tongue is solidly anchored at its base on the mandible by the paired genioglossi and on the hyoid bone by the genioglossi and hyoglossi muscles. in addition, the lateral surfaces of the tongue are suspended from the soft palate by the palatoglossi and from the styloid processes of the temporal bones by the styloglossi muscles. the fi bers of these muscles blend with the superior portion of the tongue. as in other primates, the larynx of the newborn is positioned high, with the epiglottis in direct contact with the soft palate. during the fi rst years of life, in association with the growth of the cervical spine, the hyoid bone migrates from the level of c1-c2 at birth to c3-c4 after puberty. 16 the posterior third of the tongue follows this caudal migration, consequently stretching its superior attachments. this contributes to change the orientation of the soft palate from horizontal in the infant to more vertical in the adult. 17 although the positional changes occur mainly during the fi rst years of life, the reciprocal infl uences, from the cranial base and hyoid bone acting on the tongue and soft palate, should be kept in mind, no matter the age of the patient. normally, at about 4 or 5 years of age, after the descent of the larynx and tongue, the tongue rests lower in the mouth. 18 at this time it forms part of the fl oor of the oral cavity and part of the anterior wall of the oropharynx. 1 it is contained inside the mandibular arch and the functions of swallowing, sucking, ventilation, facial expression, chewing and phonation should be performed without diffi culty. dysfunction develops when lingual mobility and function are impaired. this may be the result of somatic dysfunction affecting the cranial base, hyoid bone or mandible, or accommodation of these areas to dysfunction in more distant body areas. tongue-tie, or ankyloglossia, is a partial or complete adhesion of the tongue to the fl oor of the mouth. because of abnormal shortness, the frenulum linguae tethers the tongue to the fl oor of the mouth, impairs lingual mobility and, in severe cases, prohibits its extension beyond the lower gum. although it may present as part of several craniofacial syndromes, in most cases the child is perfectly healthy. 19 ankyloglossia is, however, associated with up to 12.8% of serious breastfeeding problems. 20 it is also a potential etiology for speech disorders 21 and dental problems, 22 such as diastasis between the lower incisors due to the lingual pressure. 23 furthermore, impaired lingual mobility is related to diffi culty with intraoral toileting and later with the playing of wind instruments. 23 although surgical treatment (frenuloplasty or tongue-tie division) remains debated, in specifi c indications it is reported to improve diffi cult breastfeeding and to protect the maternal nipple, 24 and to alleviate speech disorders and improve tongue mobility. 25 swallowing, or deglutition, is one of the fi rst orofacial functions to appear in utero and has been observed after 11 weeks, when the child refl exively swallows amniotic fl uid. 1 at birth, new habits develop with feeding, allowing the evolution of the pattern of deglutition. in the infant, sucking and swallowing are the results of a pumping action in the hyolingual complex, with a rhythmic tongue thrust, the tip of the tongue showing regularly between the alveolar processes. musculoskeletal growth and maturation of the neuromuscular system result in the development of a more mature or adult swallowing pattern. at around 2-3 years of age, at rest and during swallowing, the apex of the tongue is normally located on the palate, behind the upper incisor teeth. when swallowing, the lips are closed, but the perioral musculature, particularly the orbicularis oris and mentalis muscles, is relaxed. lingual pressure applied against the palate contributes to the development of a broad palate and well-developed maxillae. the tongue works as a natural orthodontic appliance 'for better or for worse'. 26 in the cheeks, the muscular bands formed by the buccinator and superior constrictor muscles, joined together through the pterygomandibular raphe, bilaterally act to constrain the tongue within the oral cavity. thus, functional balance or dysfunction of the cervical spine and cranial base, the sites of origin of the superior constrictor, contributes significantly to lingual posture. in addition, because the tongue is anchored on the mandible, it affects and is affected by mandibular position and growth. when mature or adult swallowing does not develop successfully, immature or atypical swallowing will continue. chewing forces also contribute to maxillofacial growth. first, mastication occurs purely in the sagittal plane, with the mandible moving up and down, and demonstrating propulsion and retraction. then, progressively, an alternating unilateral chewing pattern appears, with diagonal movements of the mandible. 8 the masticatory muscles develop in response to this demand. at around 9 months of age, a child can chew soft food and keep it in their mouth; 1 year later they can chew more solid foods. 27 as such, their diet should include food that requires suffi cient chewing to allow satisfactory occlusal force per chew that can, in turn, stimulate periosteal growth. symmetric chewing is a requisite for adequate muscular stimulation of the digastric, temporal and pterygoid muscles. the traction of these muscles will, in turn, stimulate bone growth. at this time cranial balance is necessary to facilitate the establishment of symmetric masticatory patterns that are learned and practiced throughout the rest of life, making early identifi cation and treatment of somatic dysfunction essential. besides swallowing and chewing, ventilation, speech and facial expression also contribute to the development and growth of the maxillofacial structures. ventilation, as a vital function, is present from birth onwards. in the fi rst months, the infant is normally a nasal breather. at this time, observed respiration should be unencumbered. it is imperative that airfl ow be quiet and through both nares equally. dysfunctional nasal respiration will impact the development of the orofacial structures, potentially leading to mouth breathing. establishment of the route of respiration is partly under the control of the soft palate. this muscular fold, suspended from the posterior border of the bony palate, extends inferiorly and posteriorly into the oropharynx. under normal circumstances the soft palate and tongue act in apposition to close the oropharyngeal isthmus; conversely, when the soft palate rises and contacts the posterior pharyngeal wall, the nasopharynx is closed. thus, the position of the soft palate determines the route of respiration and regulation of airfl ow through the nose or mouth. the soft palate is united with the tongue through the palatoglossi muscles and with the pharynx through the palatopharyngei muscles. for optimal function of all of the structures that contribute to upper airway respiration, somatic dysfunction affecting the sites of origin of these muscles should be identifi ed and treated. for optimal breathing, the cranial base, hyoid bone and mandible should be balanced. it is well established that an inferoposterior displacement of the hyoid bone and an anteroinferior positioning of the tongue are correlated with mouth breathing. [28] [29] [30] normally, the tongue demonstrates large movements in all three planes of space. 31 in the production of sounds and speech, the tongue must change shape and the dorsum of the tongue must contact the palate. shortening of the base of the tongue results from anterior displacement of the hyoid bone, whereas lengthening of the base of the tongue results from its posterior displacement. by employing the activity of the lingual muscles, speech contributes to the overall function and development of the orofacial cavity. although the hyoid bone has no direct articulation with other skeletal structures, it is an interface between the mandible and tongue above and the upper thoracic area below. consequently, its position and motion are infl uenced by changes occurring at the level of the mandible or anywhere in the thorax. a hyolingual complex -a 'kinetic chain' -may be described, 32 part of a more global oropharyngeal complex where every structure is interdependent with others as part of the system. begin by noting the relationship between the head and the remainder of the body. the skull should be centered above the spine. note any tension in the posterior, lateral and anterior (submandibular) cervical musculature. divide the viscerocranium into three regions: frontal, nasal and buccal. observe the relationship between these three regions and the relative harmony between them. in newborns, the lower two regions are proportionately smaller than in older children, adolescents and adults because the paranasal sinuses are not yet developed and the teeth have not erupted. observe facial expression and orofacial functions such as breathing, sucking (in infants) and swallowing. look for coordination of the tongue and orofacial musculature, the rate of sucking if the patient is a baby, and possible tongue sucking or tongue thrusting. note the ease of swallowing without any concomitant inappropriate muscular contraction if the patient is a child. if they are old enough to respond, ask them to describe the location of the tip of their tongue during swallowing; normally it should contact the hard palate behind the upper incisors. observe the resting respiration. nasal patency of airfl ow can be assessed easily with a wisp of cotton held adjacent to each nasal aperture or look for fogging with exhalation on the convex side of a cold metal spoon or a cold mirror. observe the midline of the face, the metopic suture, nose and symphysis menti. all of these landmarks should be aligned in a straight line observe the maxillae and compare size and shape: in external rotation the maxilla appears wider; in internal rotation it appears narrower. observe the position of the mandible. note its relationship with the maxillae, particularly its centric position. observe the location of the gnathion; newborns are normally retrognathic. with the infant, an open mouth posture with tongue forward may be observed with dysfunction of the cranial base, mandible or hyoid bone. with children, observe the mouth area and the lips for symmetry and tonicity. the upper lip refl ects the functional pattern of the maxillae, whereas the lower lip refl ects the mandible. look for the capacity to keep the lips closed and in soft contact. there should be no tension, in particular in the orbicularis oris or mentalis muscle, and no protrusion, retraction or pursing of the lips. note any abnormal perioral muscle function or nervous habits such as fi nger and nail picking or nail biting. compare the nasolabial sulci for depth and obliquity. increased sulcus depth is associated with external rotation of the ipsilateral maxilla and/or the zygoma, whereas decreased depth is associated with internal rotation of these bones. look inside the mouth. assess the position and function of the tongue. note the presence of a large frenulum linguae. if the child is old enough to voluntarily open the mouth, look at the relative position of the tongue within the oral cavity. it should be inside the mandibular arch and should not cover the lower teeth. again, if possible, have the child slightly protract their tongue to look for the presence of dental imprints on the lateral aspects of the tongue, unilateral or bilateral, indicating lingual malposition and/or dental malalignment. with the tongue protracted, look for tongue deviation. assess the mobility of the tongue, looking for limitation of movement. dysfunctional tongue posture is often accompanied by decreased tone and eversion of the lower lip. observe the teeth as to position, dental attrition and progression of dental development according to the child's age. observe clenching of the teeth and observe the occlusion of the teeth. the upper and lower midline between the incisors should be in alignment. normally, the upper incisors should slightly override the lower incisors and upper molars should rest on the lower molars. note misalignment or protrusion of the upper or lower incisors. note any crowding of the teeth. if asymmetric crowding is present, look to see if there is ipsilateral cranial internal rotation. note the potential association with impaired ipsilateral nasal breathing and/or dysfunctional mastication. observe the shape and symmetry of the palate: a lower, fl attened palate with everted teeth is associated with external rotation; a high arched palate with inwardly directed teeth is associated with internal rotation. observe the mandible. it should appear balanced under the cheeks. if not, differentiate between asymmetry of position and asymmetry of size and shape. asymmetry of mandibular position is associated with asymmetry of the temporal bones: external rotation of the temporal bone results in posterior displacement of the mandibular fossa; internal rotation results in anterior fossa displacement. the chin will be displaced toward the side of temporal external rotation. if asymmetry of mandibular size and shape is noted, look for a potential cause. structural asym-metry may result from intraosseous mandibular dysfunction, dental malalignment or asymmetric orofacial function, such as mastication occurring only on one side. note the consistency between orofacial fi ndings and the cranial pattern. if they are in concordance, a cranial osteopathic approach may be indicated. palpation for function and treatment of identifi ed dysfunction should follow. when treating orofacial problems, don't forget to check and treat somatic dysfunction of other areas, frequently the cranial base, craniocervical junction and upper thoracic area. cranial procedures directed at release of the global membranous strain pattern, the sbs, vault and facial bones to ensure optimal freedom of movement are anecdotally associated with facilitation of the teething process. it is also important to remember that all tooth buds are present in the maxillae and mandible, even though not yet erupted. any fi nger or object placed inside the mouth of a child can act as an orthodontic device and move the teeth. therefore, it is inappropriate to employ force when examining the patient or using osteopathic manipulation to treat children's orofacial somatic dysfunction. the earlier osteopathic treatment of orofacial dysfunction is initiated, the better. results may be enhanced when osteopathic treatment is employed in conjunction with appropriate orthodontic treatment. dental development begins in the 3rd month of intrauterine life and ends at approximately 25 years of age. throughout this period profound occlusal events occur, resulting in potential sources of stress for the orofacial structures. to understand the evolution of the occlusal mechanism, it is important to begin with the infant and to follow the eruption and arrangement of the teeth along the dental arches. during the fi rst months, the absence of teeth allows total freedom in the displacement of the mandible and the child can experiment and discover objects surrounding them by bringing everything to their mouth. the lower central incisors are normally the fi rst to appear between 6 and 8 months of age. when the upper central incisors emerge, the fi rst occlusal relationship appears, associated with new constraint for mandibular mobility. the upper and lower lateral incisors are almost completely erupted at around 14 months, the time when the fi rst molars appear. just before the end of the 2nd year of life, the central and lateral incisors and the fi rst molars are in occlusion, the canines have erupted and the second molars are beginning to emerge. in the 2nd year of life, the 20 deciduous teeth are present, with occlusion between the incisors, canines and fi rst molars. at the same time, the child's orofacial functions have matured and their food is becoming more solid. mouthing (active oral interaction with the environment by sucking different objects) is still quite frequent up to 3 years of age. several explanations -from a means of exploring their environment to proactively exposing the naive gi tract to environmental antigens -have been offered for this behavior. 33 whatever the reason, mouthing effectively contributes to dental attrition, thereby eliminating any dysfunctional occlusal contact and facilitating functional adaptation. smoothing of the occlusal surfaces results in proprioception important in establishing functional balance of mandibular motion patterns. conversely, any dysfunctional occlusal contact will result in dysfunctional mandibular motion patterns and stimulate abnormal mandibular and maxillary growth. 34 it will also prevent the establishment of alternating unilateral mastication. the teeth develop in sockets in the alveolar parts of the maxillae and mandible. they are each held in their respective socket by a periodontal ligament. this anchors the teeth solidly while still allowing micromovements. it is also the site for periodontal innervation that is of paramount importance in the development and control of orofacial praxis. proprioceptive input from the periodontal ligament in association with proprioception from the tmj and surrounding myofascial structures provides constant information to the cns. this allows the individual to adjust to the challenges of mastication as well as to global postural mechanics. 35 deciduous teeth are small, with thin enamel coverage, allowing rapid wearing out. on the other hand, permanent teeth are the hardest of all tissues in the body. each consists of a crown and a root, meeting at the cervical margin. dentine forms most of the tooth, with a central pulp cavity ending in a pulp chamber and canal. the side of the tooth in contact with the lips and cheeks is the labial or buccal surface while the side in contact with the tongue is the lingual or palatal surface. when the jaws are brought together the teeth meet, or occlude; thus, dental occlusion occurs. occlusion is qualifi ed according to the respective positions of the teeth. a centric occlusion takes place when the relation of opposing occlusal surfaces of mandibular and maxillary teeth provides the maximum contact, or inter-cuspation. in such circumstances, the mandible is in centric relation to the maxillae. infants usually demonstrate a retrusive mandibular position. when the fi rst teeth erupt, the relationship will tend to show a horizontal protrusion, or overjet, of upper incisors beyond the lower incisors. however, at this early age tongue thrusting will result in a functional edge-to-edge repositioning of the teeth. in the fi rst years of life, during eruption of the deciduous teeth, changes in the orofacial osseous and myofascial structures normally allow suffi cient space for the teeth to emerge. typically, by approximately 6 years of age, there is occlusion between all deciduous teeth that already gives a good idea of the occlusal pattern of the future permanent teeth. the overjet and overbite relationship should have resolved in order to allow for freedom of mandibular diduction, which is only possible if the mandible can slide forward slightly. this sequence occurs as the result of an alternating chewing pattern, enhanced by chewing the solid foods found in the correct type of diet. it is important for the osteopathic practitioner to observe the oral cavity and teeth in order to identify their eruptive pattern, position, occlusal contacts and any asymmetric wear that may be associated with cranial somatic dysfunction. in addition, any asymmetry of function that predisposes the child to mouth and then chew using only one side, as might occur with a neurologic impairment, a child with one handicapped upper extremity or simply a child with a torticollis, will result in asymmetric wear of the occlusive surfaces of the teeth and eventually asymmetric mandibular growth. the permanent incisors are signifi cantly wider than the deciduous incisors that they have replaced by approximately 8 years of age. there might be a tendency for overjet or overbite, either positive or negative. while a horizontal protrusion of upper incisors beyond the lower ones is named overjet, a vertical overlap is named overbite (fig. 7.7 .5). at this age, the child's temporary canines, the two temporary molars and the fi rst permanent molars are in occlusion. around 10 years of age, occlusion exists between the permanent incisors, the temporary canines and the fi rst permanent molars. at 12 years of age, occlusion is typically present between the permanent incisors, permanent canines and fi rst permanent molars. in mixed dentition, if the child has developed an asymmetric pattern of chewing, with a tendency to chew only on one side, they may wear out the teeth in a way that will not allow functional and symmetric development. unsatisfactory occlusal contact will create points of resistance that will, in turn, control and guide the movement of the mandible in asymmetric patterns. the masticatory, perioral and craniocervical muscles, as well as the highly elaborate tmj structures, result in engrams of the repetitive dysfunctional pattern. if no change occurs, this will be the permanent pattern ingrained in the cns. thus, it is important to recognize asymmetric patterns and to identify and treat any underlying somatic dysfunction. because patterns of function become fi xed as the child ages, for the best therapeutic outcomes the cranial osteopathic approach should be employed at the earliest opportunity. at the end of the 19th century, edward angle proposed that a defi nitive nomenclature was necessary in orthodontia as in anatomy. 36 he felt that the term malocclusion was far more expressive than 'irregularities of the teeth' to describe not only the relationship between the maxillary and mandibular arches, but also of the individual teeth to one another. as a result, a classifi cation was born, referred to as angle's classifi cation. angle's classifi cation is based on the mesiodistal relationship of the permanent molars. in dentistry, distal means away from the median sagittal plane of the face, following the curvature of the dental arch, while mesial means proximal. three classes of dental arrangement are described. class i identifi es the normal relationship of the jaws, where the mesiobuccal cusp of the maxillary fi rst molar occludes in the buccal groove of the mandibular fi rst molar. in the individual with normal dentition and centric occlusion, the lower incisors bite against the lingual surfaces of the upper incisors, the crowns of the lower incisors being covered in their superior third. in addition, from the canine teeth backwards, each lower tooth is slightly in front of its upper fellow. classes ii and iii categorize variations of malocclusion. in class ii, all the lower teeth occlude distal to normal, wherein the distobuccal cusp of the maxillary fi rst molar occludes in the buccal groove of the mandibular fi rst molar. in addition, this class is further subdivided into division 1, labioversion of maxillary incisor teeth, and division 2, linguoversion of maxillary central incisors. this may occur unilaterally of bilaterally. class ii is the most frequently encountered type of malocclusion. in class iii, all the lower teeth occlude mesial to normal, wherein the mesiobuccal cusp of the maxillary fi rst molar occludes in the embrasure between the mandibular fi rst and second permanent molars. class iii may further be classifi ed as a unilateral condition. the origin of malocclusion is highly debated, again with multifactorial origins proposed. besides the genetic aspect of malocclusion, in particular for class iii, 37 malocclusal patterns are felt to result from an imbalance between intrinsic forces such as from the tongue and lips and extrinsic forces such as stressful orofacial habits. a large number of studies have considered the infl uence of epigenetic factors such as the orofacial functions of deglutition, sucking, ventilation, mastication and phonation (see below). in fact, it is more the orofacial dysfunctions and parafunctions or orofacial habits that are the source of malocclusion. edward angle said: 'orthodontic treatments are very unlikely to succeed, if the functional disorders are still going on.' 38 class ii malocclusion represents a heterogeneous collection of conditions with malocclusion that may be the result of purely skeletal or combined skeletal and dental origin; they are, however, more often purely dental in nature. 39 the teeth and alveolar bone constitute an interface between opposing forces and pressures, primarily from muscular function -the perioral musculature of the lips and cheeks on the one hand and intraoral forces from the tongue on the other. pressures are applied to the teeth with varying distribution according to the oral function involved. 40 under appropriate circumstances these pressures should affect the teeth from multiple, yet balanced, directions. when dysfunction results in chronically repeated patterns of activity, limiting the directions that these muscular pressures are applied to the teeth, dental malocclusion can be the result. the development of class ii malocclusion has also been correlated with non-nutritive sucking habits such as thumb sucking. [41] [42] [43] [44] [45] in the early years of life the premaxillae may be easily pushed forward by non-nutritive sucking, pushing the upper incisors along with them. thumb sucking creates an anterior opening between the dental arches, which facilitates the forward displacement of the tongue that occurs during tongue thrusting. it consequently results in dysfunctional forward placement of the tongue. this will, in turn, promote maxillary prognathism because, with every deglutition, which occurs approximately 1500 times per day, the tip of the tongue will move forward between the teeth, applying pressure to the premaxillae and upper incisors, pushing them forward. for similar reasons, the sucking of a pacifi er is also commonly associated with malocclusion, followed by the practice of sucking fi ngers. 46 prolonged pacifi er habits result in changes to the dental arches with a prevalence of posterior cross-bite and increased amount of overjet. 47 until the age of 2-3 years the risk of developing a dysfunctional occlusion may be reduced proportionally to the reduction of time that the child uses the pacifi er, and under these circumstances the dental arches should be regularly evaluated. 48 signifi cant maxillary prognathism has also been correlated with persistent digit sucking habits. 48, 49 among other sucking habits, a trend toward association of bottle feeding with the need for orthodontic treatment has been found. 50 on the other hand, breastfeeding seems to have a positive effect on orofacial morphogenesis, 51,52 with a protective effect for the development of posterior crossbite in deciduous dentition. 45 not only the mode of feeding but also the type of food is associated with malocclusion. there are suggestions that changes in diet and food processing are associated with variations in facial size and shape. 53 the prevalence of occlusal disorders in subjects born in the 1950s has been found to be lower than in individuals born in the 1990s. it is thought that this is probably because of dietary habits resulting from the increased consumption of processed foods. 54 at the same time, there is an increased prevalence of allergies that result in mouth breathing. there is a 3% incidence of mouth breathers in individuals born in the 1950s and 21% in those born in the 1990s. 54 when mouth breathing is associated with nasal obstruction, it results in an inferior position of the mandible. in addition, the tongue is maintained lower in the oral cavity (fig. 7.7.6 ). this posture is associated with compensations in the perioral musculature, such as hypotonicity, as well as compensations at the level of the vertebral spine. mouth breathers tend to assume an extended or forward head posture. respiratory dysfunctions are also associated with malocclusion. premature molar eruption is often present in chronic mouth breathers. mandibular growth is affected, with resulting anterior mandibular rotation 29 and an increase of the mandibular angle. 30 thus, the vertical dimension of the lower face is increased, with resultant open bite. 29 the term 'adenoidal facies' (long faces) describes infants with an open mouth, a short upper lip and prominent and crowded anterior teeth. lip hypotonicity -decreased tonicity of the orbicularis oris muscle -is typically found in patients with class ii, division 1 malocclusion. 55 in this presentation, hypotonicity of the orbicularis oris muscle is balanced by compensatory contraction in the mentalis muscles. it is this aspect that can be observed in patients with 'adenoidal facies' syndrome. in addition, the maxillae are narrow and the palate high arched with concomittant increase in the mandibular angle; thus the face appears longer. 56 these individuals also demonstrate a lack of development of the masseter muscles as well as of the maxillary bones. 57 alternatively, hypertonic and bulbous masseter muscles with reduced facial height are correlated with a tendency to clench the teeth. 57 these fi ndings are commonly identifi ed in association with cranial somatic dysfunction involving the temporal bones and/or tmjs. the cranial concept lends itself well to the understanding of functional orofacial disorders. children who have dysfunctional extension of the sbs will present with a long narrow head. the resultant internal rotation of the maxillae is associated with a palate that is narrow and high arched. this orofacial cranial pattern fails to provide suffi cient space for the teeth in the dental arches, predisposing the child to dental crowding. in young children, class ii malocclusion may be found in association with an intraosseous dysfunction between the premaxilla and the maxilla. the premaxilla can be pushed forward or backward as the result of stress patterns occurring during intrauterine life or at the time of delivery. postpartum behaviors, such as thumb sucking, can also push the premaxilla forward, while a fall forward striking the face, particularly the upper incisors, will push the premaxilla in a posterior direction. cranial maxillary dysfunction can be the beginning of a sequence of events that act to reinforce each other. maxillary dysfunction can reduce nasal patency and predispose to mouth breathing. it can affect the dental arch with potential consequences for occlusion. maxillary dysfunction can also trigger a compensatory pattern in the position and development of the mandible. the mandible itself may demonstrate several types of dysfunction. similar to maxillary dysfunction, mandibular dysfunction may result from strains or traumas. it can also occur as accommodation to internal or external rotation dysfunction of the temporal bones. temporal bone dysfunction may be unilateral or bilateral, with the mandible moving anteriorly on the side of temporal internal rotation or posteriorly on the side of temporal external rotation. the resultant mandibular displacement will, in turn, affect occlusion. in fact, any facial strain or trauma may impact the symmetry of the occlusal pattern. the area of the nasion -the junction between the frontonasal and internasal sutures -as well as the frontomaxillary sutures, may suffer compression from intrauterine pressures or as the result of a diffi cult delivery. the nasal bones should be attentively evaluated. with the maxillae, they are suspended from the frontal bone and as such will demonstrate restriction of movement following any trauma of the frontal bone. furthermore, an impact on the frontal bone may result in a decrease in the vertical height of the maxillae with potential intraosseous dysfunction and resultant compromise of nasal respiration. discrepancy in size between the maxilla and mandible may result from insuffi cient growth of these structures, potentially producing overjet or overbite. positioning of the child during the fi rst months of life infl uences the growth pattern of the cranial bones. non-synostotic plagiocephaly is associated with chronic sleep position and is most often visible in the fi rst months of life. 58 it has also been shown that when a child sleeps in the same position for months, changes in the dental arches are observed. 59 deformation of the face, however, because the growth of the viscerocranium continues later in life than the growth of the neurocranium, is not common rotational variations in children predictive model for congenital muscular torticollis: analysis of 1021 infants with sonography sternocleidomastoid pseudotumor and congenital muscular torticollis in infants: a prospective study of 510 cases sternomastoid tumour and muscular torticollis breech deformation complex in neonates endocranial suture closure. its progress and age relationship. part i. adult males and white stock a study of the relationship between fetal position and certain congenital deformities relationship between side of plagiocephaly, dislocation of hip, scoliosis, bat ears and sternomastoid tumors congenital postural deformities the hip in the moulded baby syndrome congenital muscular torticollis in infancy; some observations regarding treatment pathologic changes in muscle as a result of disturbances of circulation congenital' muscular torticollis congenital muscular torticollis: sequela of intrauterine or perinatal compartment syndrome midbrain control of three-dimensional head orientation le torticolis 'congénital' est-il simplement un torticolis obstétrical? clinical determinants of the outcome of manual stretching in the treatment of congenital muscular torticollis in infants. a prospective study of eight hundred and twenty-one cases fracture of the clavicle in the newborn following normal labor and delivery reappraisal of neonatal clavicular fracture: relationship between infant size and neonatal morbidity newborn clavicle fractures clavicle fractures in the newborn management of birth injuries associated factors in 1611 cases of brachial plexus injury the effect of sequential use of vacuum and forceps for assisted vaginal delivery on neonatal and maternal outcomes brachial plexus injury: a 23-year experience from a tertiary center intrauterine shoulder weakness and obstetric brachial plexus palsy birth trauma in the head and neck mechanisms of cervical nerve root avulsion in injuries of the neck and shoulder obstetrical brachial plexus palsy. prediction of outcome in upper root injuries management of infant brachial plexus injuries supramolecular organization of extracellular matrix glycosaminoglycans, in vitro and in the tissues invited review: role of mechanophysiology in aging of ecm: effects of changes in mechanochemical transduction paralysie obstétricale du membre supérieur is abnormal labor associated with shoulder dystocia in nulliparous women? shoulder dystocia: prevention and management comparing mcroberts' and rubin's maneuvers for initial management of shoulder dystocia: an objective evaluation glenoid deformity secondary to brachial plexus birth palsy glenohumeral deformity secondary to brachial plexus birth palsy posterior shoulder dislocation in infants with neonatal brachial plexus palsy pulled elbow in childhood common rotational variations in children the natural history of hooked forefoot intoeing -fact, fi ction and opinion foot deformities at birth: a longitudinal prospective study over a 16 year period guidelines for evaluation and management of fi ve common podopediatric conditions the newborn foot congenital club foot. an anatomical study the pathogenesis of club foot. a histomorphometric and immunohistochemical study of fetuses congenital idiopathic talipes equinovarus common lower extremity problems in children the ponseti technique for correction of congenital clubfoot flexible fl at feet in children: a real problem planovalgus foot deformity. current status the infl uence of footwear on the prevalence of fl at foot. a survey of 2300 children the infl uence of footwear on the prevalence of fl at foot. a survey of 1846 skeletally mature persons footprint analysis during the growth period acute and recurrent patellar instability in the young athlete sprain or fracture? an analysis of 2000 ankle injuries sprinting and intoeing torsional and angular deformities effect of limb malrotation on malalignment and osteoarthritis the effect of tibial torsion of the pathology of the knee increased external tibial torsion in osgood-schlatter disease femoral anteversion and arthritis of the knee femoral anteversion related to side differences in hip rotation. passive rotation in 1140 children aged 8-9 years congenital dislocation of the patella. part i: pathologic anatomy soft-tissue anatomy anterior to the human patella does osgood-schlatter disease infl uence the position of the patella? congenital dislocation of the hip -a misleading term: brief report the fetal acetabulum. a histomorphometric study of acetabular anteversion and femoral head coverage increasing prevalence of recurrent otitis media among children in the united states otitis media surfactant proteins a and d in eustachian tube epithelium american academy of pediatrics subcommittee on management of acute otitis media. diagnosis and management of acute otitis media susceptibility to otitis media: strong evidence that genetics plays a role the genetic component of middle ear disease in the fi rst 5 years of life upper respiratory morbidity in preschool children: a cross-sectional study otitis media and eustachian tube dysfunction: connection to allergic rhinitis prognostic factors for persistent otitis media with effusion in infants epidemiology of otitis media onset by six months of age a pacifi er increases the risk of recurrent acute otitis media in children in day care centers pacifi er as a risk factor for acute otitis media: a randomized, controlled trial of parental counseling risk factors for chronic otitis media with effusion in infancy. each acute otitis media episode induces a high but transient risk accumulation of factors infl uencing children's middle ear disease: risk factor modelling on a large population cohort otitis media in 2253 pittsburgh-area infants: prevalence and risk factors during the fi rst two years of life exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media gray's anatomy, 38th edn selective hemispheric stimulation by unilateral forced nostril breathing neuropeptides and nasal secretion changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals chronic rhinosinusitis and neuropeptides neuronal plasticity in persistant perennial allergic rhinitis allergic rhinitis: defi nition, epidemiology, pathophysiology, detection, and diagnosis complications of allergic rhinitis the 'microfl ora hypothesis' of allergic diseases allergic rhinitis as a risk factor for habitual snoring in children economic impact and quality-of-life burden of allergic rhinitis allergic rhinitis and impairment issues in schoolchildren: a consensus report assessment of quality of life in adolescents with allergic rhinoconjunctivitis: development and testing of a questionnaire for clinical trials infants are not obligatory nasal breathers consultation with the specialist: diagnosis and management of the newborn and young infant who have nasal obstruction endoscopy in the assessment of children with nasal obstruction posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils infl uences of head positions and bite opening on collapsibility of the passive pharynx hyoid bone and atlas vertebra in established mouth breathers: a cephalometric study anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction posterior maxillary (pm) plane and anterior cranial architecture in primates upper airway obstruction and craniofacial morphology oronasal obstruction, lung volumes, and arterial oxygenation decreased pulmonary vascular resistance during nasal breathing: modulation by endogenous nitric oxide from the paranasal sinuses site of upper airway obstruction in obstructive apnoea and infl uence of sleep stage soft palate and oronasal breathing in humans upper airway imaging anatomy of oral respiration: morphology of the oral cavity and pharynx developmental change in the upper respiratory system of human infants site and mechanics of spontaneous, sleep-associated obstructive apnea in infants polysomnographic studies in children undergoing adenoidectomy and/or tonsillectomy upper airway stability and apnea during nasal occlusion in newborn infants pharyngeal airway obstruction in obstructive sleep apnea: pathophysiology and clinical implications upper airway collapsibility in children with obstructive sleep apnea syndrome evidence for persistence of upper airway narrowing during sleep, 12 years after adenotonsillectomy factors infl uencing regional patency and confi guration of the human infant upper airway tracheal and neck position infl uence upper airway airfl ow dynamics by altering airway length the nose and sleep-disordered breathing: what we know and what we do not know state-related changes in upper airway caliber and surrounding soft-tissue structures in normal subjects nasal obstruction in sleep-disordered breathing adenotonsillar hypertrophy and skeletal morphology of children with obstructive sleep apnea syndrome craniofacial modifi cations in children with habitual snoring and obstructive sleep apnoea: a case-control study enuresis in children with sleep apnea preventing respiratory syncitial virus bronchiolitis surveillance of communityacquired viral infections due to respiratory viruses in rhone-alpes (france) during winter 1994 to 1995 respiratory syncytial virus activity -united states molecular epidemiology of respiratory syncytial virus infections among children with acute respiratory symptoms in a community over three seasons rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. ige and eosinophil analyses respiratory syncytial virus infection in children hospitalised with acute lower respiratory tract infection the unifi ed immune system: respiratory tract-nasobronchial interaction mechanisms in allergic airway disease detection of rhinovirus, respiratory syncytial virus, and coronavirus infections in acute otitis media by reverse transcriptase polymerase chain reaction otitis media one hundred thousand cases of infl uenza with a death rate of one-fortieth of that reported under conventional medical treatment more about the use of omt during infl uenza epidemics genetics of allergic disease british thoracic society research committee. asthma prevalence in 1973 impact of il8 and il8-receptor alpha polymorphisms on the genetics of bronchial asthma and severe rsv infections advances in adult and pediatric asthma onset and persistence of childhood asthma: predictors from infancy consider the child: how early should we treat? low socioeconomic status as a risk factor for asthma, rhinitis and sensitization at 4 years in a birth cohort dietary supplementation with fi sh oil rich in omega-3 polyunsaturated fatty acids in children with bronchial asthma three-year outcomes of dietary fatty acid modifi cation and house dust mite reduction in the childhood asthma prevention study diet as a risk factor for atopy and asthma fish oil supplementation in pregnancy modifi es neonatal allergen-specifi c immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial infection, allergy and the hygiene hypothesis: historical perspective infections and autoimmunity -good or bad? infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood clinical patterns and natural history of asthma respiratory infections and asthma infl uence of early life exposures on incidence and remission of asthma throughout life rhinosinusitis and pediatric asthma systemic effects of local allergic disease muscarinic acetylcholine receptors and airway diseases the role of nerves in asthma the unifi ed immune system: respiratory tract-nasobronchial interaction mechanisms in allergic airway disease allergy development and the intestinal microfl ora during the fi rst year of life importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0-6 months mode of delivery and asthma -is there a connection? gastroesophageal refl ux: a potential asthma trigger regulation of human airway ciliary beat frequency by intracellular ph refl ex mechanisms in gastroesophageal refl ux disease and asthma the sympathetic nerve -an integrative interface between two supersystems: the brain and the immune system the central autonomic nervous system: conscious visceral perception and autonomic pattern generation stress and atopic disorders socioeconomic status, stress, and immune markers in adolescents with asthma streptococcal infections in families. factors altering individual susceptibility asthma, genes, and air pollution changes in airway resistance induced by nasal inhalation of cold dry, dry, or moist air in normal individuals quantifi able effects of osteopathic manipulative techniques on patients with chronic asthma effects of osteopathic manipulative treatment on pediatric patients with asthma: a randomized controlled trial training of aerobic and anaerobic fi tness in children with asthma physical activity and exercise in asthma: relevance to etiology and treatment epiphora during the fi rst year of life outcome of probing for congenital nasolacrimal duct obstruction in older children a simple model for practicing surgery on the nasolacrimal drainage system development of tearing in preterm and term neonates gray's anatomy, 38th edn growth of the fetal lens and orbit the growth of human face bony orbital development after early enucleation in humans anatomy of the orbital apex and cavernous sinus on high-resolution magnetic resonance images the origins and insertions of the extraocular muscles: development, histologic features, and clinical signifi cance the development of eye alignment, convergence, and sensory binocularity in young infants effect of developmental status on the approach to physical examination la fonction de la capsule de tenon revisitée evidence for active control of rectus extraocular muscle pulleys pivotal role of orbital connective tissues in binocular alignment and strabismus: the friedenwald lecture incomitant strabismus associated with instability of rectus pulleys the functions of the proprioceptors of the eye muscles does extraocular muscle proprioception infl uence oculomotor control? entrapment neuropathy of the central nervous system. ii factors associated with childhood strabismus: fi ndings from a population-based study the rapid change of corneal curvature in the neonatal period and infancy anatomy, development, and physiology of the visual system development of visual sensitivity to light and color vision in human infants: a critical review the relation between birth size and the results of refractive error and biometry measurements in children relationship of age, sex, and ethnicity with myopia progression and axial elongation in the correction of myopia evaluation trial collaborative longitudinal evaluation of ethnicity and refractive error study group. refractive error and ethnicity in children a synopsis of the prevalence rates and environmental risk factors for myopia iq and the association with myopia in children prevalence and risk factors for refractive errors in adult chinese in singapore nearwork in earlyonset myopia baseline refractive and ocular component measures of children enrolled in the correction of myopia evaluation trial (comet) eye shape in emmetropia and myopia corneal topography of neonates and infants gray's anatomy, 38th edn acquisition et exercice de la fonction masticatrice chez l'enfant et l'adolescent. première partie the development of normal feeding and swallowing posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils upper airway obstruction and craniofacial morphology anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction ankyloglossia: does it matter? la langue, appareil naturel d'orthopédie dentofaciale 'pour le meilleur et pour le pire the serial organization of sucking in the young infant antenatal olfactory learning infl uences infant feeding ultrasound demonstration of tongue motions during suckle feeding ultrasonographic analysis of sucking behavior of newborn infants: the driving force of sucking pressure neonatal sucking behaviour and its development until 14 months relationship between respiratory control and feeding in the developing infant reduction of masseter muscle activity in bottle-fed babies infl uence of breast feeding on facial development approche fonctionnelle de l'allaitement et malocclusions morphogenèse temporo-mandibulaire structure fonctionnelle du condyle mandibulaire humain en croissance does breast-feeding protect against malocclusion? an analysis of the 1981 child health supplement to the national health interview survey breast feeding, bottle feeding, and non-nutritive sucking; effects on occlusion in deciduous dentition exclusive breastfeeding protects against bacterial colonization and day care exposure to otitis media promotion of breastfeeding intervention trial (probit): a randomized trial in the republic of belarus the 'microfl ora hypothesis' of allergic diseases breastfeeding reduces pain in neonates feeding behaviors and other motor development in healthy children (2-24 months) developmental change in a basicranial line and its relationship to the upper respiratory system in living primates postnatal descent of the epiglottis in man. a preliminary report oral habits -studies in form, function, and therapy middle ear effusion: an orthodontic perspective a pacifi er increases the risk of recurrent acute otitis media in children in day care centers palpatory diagnosis of plagiocephaly prevalence of symptoms of gastroesophageal refl ux during infancy. a pediatric practice-based survey. pediatric practice research group natural history and familial relationships of infant spilling to 9 years of age ethnicity and gender related differences in extended intraesophageal ph monitoring parameters in infants: a retrospective study gastroesophageal refl ux disease: review of presenting symptoms, evaluation, management, and outcome in infants embryonic origins of the relation of gastroesophageal refl ux disease and airway disease transient lower esophageal sphincter relaxation overview of the mechanisms of gastroesophageal refl ux gastric emptying: a contributory factor in gastro-oesophageal refl ux activity? the natural course of infantile refl ux regurgitation: a non-western perspective gastroesophageal refl ux in childhood an overview of refl ux-associated disorders in infants: apnea, laryngospasm, and aspiration gastroesophageal refl ux disease and asthma: a longitudinal study in uk general practice consultation with the specialist: diagnosis and management of the newborn and young infant who have nasal obstruction humans are born too soon: impact on pediatric otolaryngology dental erosion in children: a literature review osteopathic family practice: an application of the primary care model eléments cliniques du diagnostic de coliques du nourrisson. enquête chez 2773 nourrissons âgés de 15 à 119 jours systematic review of the occurrence of infantile colic in the community paediatric study group on gastrointestinal symptoms in infancy. gastrointestinal symptoms in infancy: a population-based prospective study the ontogeny of the small intestinal epithelium crying in infancy paroxysmal fussing in infancy, sometimes called colic excessive infant crying: the impact of varying defi nitions what is distinct about infants' 'colic' cries? intestinal microfl ora in early infancy: composition and development the intestine and its microfl ora are partners for the protection of the host: report on the danone symposium "the intelligent intestine importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0-6 months factors infl uencing the composition of the intestinal microbiota in early infancy infant colic: empirical evidence of the absence of an association with source of early infant nutrition intestinal microfl ora in breastfed colicky and non-colicky infants effectiveness of treatments for infantile colic: systematic review infantile colic and small intestinal function: a nutritional problem? relation between infantile colic and asthma/atopy: a prospective study in an unselected population extent of fussing and colic type crying preceding atopic disease improvement of symptoms in infant colic following reduction of lactose load with lactase cow's milk as a cause of infantile colic in breast-fed infants maternal intake of cruciferous vegetables and other foods and colic symptoms in exclusively breast-fed infants neurohumoral control of gastrointestinal motility principles of applied neurogastroenterology: physiology/motility-sensation changing our understanding of infant colic individual differences in responsivity to a neurobehavioural examination predict crying patterns of 1-week-old infants at home role of the brain and sensory pathways in gastrointestinal sensory disorders in humans a preliminary assessment of the impact of cranial osteopathy for the relief of infantile colic understanding and controlling the enteric nervous system central nervous system involvement in functional gastrointestinal disorders mothers' reports of infant crying and soothing in a multicultural population crying, feeding and sleeping patterns in 1 to 12-month-old infants emotion regulation and touch in infants: the role of cholecystokinin and opioids the role of corticotropin-releasing factor-norepinephrine systems in mediating the effects of early experience on the development of behavioral and endocrine responses to stress attachment and the regulation of the right brain infantile colic: maternal smoking as potential risk factor colic and crying syndromes in infants persistent infant crying and hyperactivity problems in middle childhood clinical conditions the clinical signifi cance of disaccharide maldigestion the primary respiratory mechanism childhood functional gastrointestinal disorders times of fi rst void and fi rst stool in 500 newborns gastrointestinal motility in neonatal and pediatric practice painful defecation and fecal soiling in children constipation and toileting issues in children colonic transit times and behaviour profi les in children with defecation disorders during toilet training, constipation occurs before stool toileting refusal intolerance of cow's milk and chronic constipation in children review article. chronic constipation and food hypersensitivity -an intriguing relationship functional constipation in children gray's anatomy, 38th edn pediatric skull base surgery. 1. embryology and developmental anatomy incisive suture (fi ssure) in the human fetus: radiographic and histologic study prémaxillaire et croissance faciale 68 ans après the anatomy of buccinator -insights from functional casts of the oral vestibule reduction of masseter muscle activity in bottle-fed babies approche fonctionnelle de l'allaitement et malocclusions acquisition et exercice de la fonction masticatrice chez l'enfant et l'adolescent the pediatric mandible: i. a primer on growth and development a propos de l'articulation temporo-mandibulaire du nouveau-né. les relations oto-méniscales remodeling reversals in anterior parts of the human mandible and maxilla skeletal and functional craniofacial adaptations in plagiocephaly post-natal growth of the human skull base facial heights: evolutionary relevance of postnatal ontogeny for facial orientation and skull morphology in humans and chimpanzees prenatal development of the human mandible developmental change in the upper respiratory system of human infants développement de l'oropharynx: évolution de la paroi ventrale du pharynx developmental change in a basicranial line and its relationship to the upper respiratory system in living primates orodigitofacial syndromes type i and ii: clinical and surgical studies ankyloglossia: assessment, incidence, and effect of frenuloplasty on the breastfeeding dyad the effect of ankyloglossia on speech in children tongue-tie ankyloglossia: does it matter? tongue tie division in infants with breast feeding diffi culties ankyloglossia: the adolescent and adult perspective la langue, appareil naturel d'orthopédie dentofaciale 'pour le meilleur et pour le pire feeding behaviors and other motor development in healthy children (2-24 months) posture of the head, the hyoid bone, and the tongue in children with and without enlarged tonsils upper airway obstruction and craniofacial morphology anatomical basis of sleep-related breathing abnormalities in children with nasal obstruction the part played by the tongue in mastication and deglutition tongue movements in feeding and speech infant mouthing behavior: the immunocalibration hypothesis deciduous dentition and the establishment of functional occlusal patterns the effect of occlusal alteration and masticatory imbalance on the cervical spine classifi cation of malocclusion morphologic determinants in the etiology of class iii malocclusions: a review angle's system, 7th edn. philadelphia: s.s. white dental manufacturing company skeletal maturation and cephalofacial development muscular forces exerted on the normal deciduous dentition tongue thrust classifi cation oral habits -studies in form, function, and therapy cephalometric characteristics of class ii division 1 and class ii division 2 malocclusions: a comparative study in children effects of oral habits' duration on dental characteristics in the primary dentition breast feeding, bottle feeding, and non-nutritive sucking; effects on occlusion in deciduous dentition relação entre hábitos bucais e má oclusão em pré-escolares duration of nutritive and nonnutritive sucking behaviors and their effects on the dental arches in the primary dentition sucking, chewing, and feeding habits and the development of crossbite: a longitudinal study of girls from birth to 3 years of age a cephalometric evaluation of patients presenting with persistent digit sucking habits bottle-feeding and malocclusion: is there an association? does breast-feeding protect against malocclusion? an analysis of the 1981 child health supplement to the national health interview survey early weaning: implications to oral motor development effects of food processing on masticatory strain and craniofacial growth in a retrognathic face tooth wear in the mixed dentition: a comparative study between children born in the 1950s and the 1990s effects of upper lip closing force on craniofacial structures the nose and sleep-disordered breathing: what we know and what we do not know middle ear effusion: an orthodontic perspective observations on a recent increase in plagiocephaly without synostosis skull morphology affected by different sleep positions in infancy cranio-facial surgery: international society for craniomaxillofacial surgery importance of early recognition and treatment of deformational plagiocephaly with orthotic cranioplasty diagnosis and management of positional head deformity artifi cial deformation and cranio-facial asymmetry in ancient peruvians head posture and craniofacial morphology growth changes in head posture related to craniofacial development the application of cephalometrics to cinefl uorography: comparative analysis of hyoid movement patterns during deglutition in class i and class ii orthodontic patients commonly observable by the non-trained examiner before several years of age. facial asymmetries are, however, frequently associated with plagiocephalies. [60] [61] [62] with asymmetric occipital deformation, compensatory changes may occur in the maxillae, with resultant mandibular asymmetry. 63 the relationship between the neurocranium, cranial base and viscerocranium has been studied extensively. an increase in anterior facial height is observed in subjects maintaining a forward-bent head position; a decrease is associated with a backward-bent head posture. 64, 65 changes in the position of the hyoid bone are observed in class ii malocclusion where the hyoid bone is higher and more forward relative to the mandible. 66 the posture of the cervical spine changes in response to changes in the occlusal plane as well as to imbalance between right and left masticatory muscles. 35 modifi cations of the cranial base are linked to class iii malocclusion where a decrease in the angle between the clivus (surface from the dorsum sellae of the body of the sphenoid to the foramen magnum) and the cribriform plate of the ethmoid has been observed. 13 the child's occlusal pattern should be assessed. if abnormal occlusion or malocclusion is identifi ed, the somatic dysfunction that may be responsible should be sought out and treated. the etiology of malocclusion is multifactorial and osteopathic procedures may be employed when cranial somatic dysfunction contributing to the establishment of the malocclusive pattern is present. to be effective, these procedures should be employed at the earliest possible age. cranial manipulation is in no way intended to be a replacement for standard orthodontic treatment. however, orthodontic treatments are less likely to be fully successful if somatic dysfunction affecting the child's occlusal pattern persists.when examining the child with malocclusion, the principles of examination discussed above in 'oral cavity and orofacial functions' apply. in addition, when looking for contributory somatic dysfunction, the practitioner should pay attention to the standing postural mechanics and their impact, particularly on the upper thoracic and occipitoatlantal areas. even in cases where orthodontic treatment has been initiated, the child's posture should be addressed. the identifi cation and treatment of dysfunctional postural mechanics resulting in functional balance of the orofacial complex will accelerate the effect of the orthodontic treatment. furthermore, orthodontic treatment in itself serves as a source of stress, affecting the overall mechanics of the body. thus, the release of existing dysfunctional mechanics will provide comfort to the child, making the orthodontic process more tolerable, as well as facilitating the effect of the orthodontic procedure.with the child seated, it is appropriate to observe the occlusal pattern. have the child actively open their mouth while observing for displacement of the symphysis menti. this motion normally should follow a straight vertical path, without a distorted pattern. next, have the child move their mandible laterally to the right and left sides to compare ease of movement and degree of displacement bilaterally. if appropriate, give the child some chewing gum to observe the presence or absence of an alternating masticatory pattern. observe and note the presence of a dominant side to the masticatory pattern. check the presence of immature swallowing by observing and asking the child to describe the location of the tip of their tongue within their mouth during swallowing. assess the musculature of the lips and cheeks by placing your thumbs inside the child's mouth, such that their palmar surfaces are in contact with the inside of the cheeks. ask the child to close their mouth and swallow, and with your thumbs appreciate the strength of contraction of the buccinator muscles. next, with the child lying supine, palpate the clavicles, sternum and hyoid bone, assessing their myofascial attachments. go on to assess the myofascial structures of the upper thoracic and cervical spine for somatic dysfunction, noting the relationship between the occiput and atlas. palpate the myofascial structures of the skull, paying attention to the orofacial muscles and tmj area for dysfunctional asymmetric tension. check the tmjs and proceed with tests of listening. evaluate the cranial base, looking for patterns of predominant cranial fl exion or extension, as well as torsion, sidebending-rotation, compression and strain patterns. by placing one hand on the frontal bone with the index and middle fi ngers controlling the greater wings of the sphenoid and the other hand cradling the mandible, note the balance between the mandible and greater wings of the sphenoid. listen to the different bones of the skull that may be involved in the malocclusion, paying particular attention to the temporal bones, sphenoid, frontal bones and maxillae, looking for intra-and interosseous cranial somatic dysfunctions. treat all identifi ed somatic dysfunction using indirect principles. intraosseous molding may be considered if the child is young enough.all of these relationships are often reciprocal and illustrate the integration of all parts of the body, local and distant, into a united system. osteopathic treatment may be employed to address the somatic dysfunction that is found in association with orofacial dysfunction. when indirect principles of treatment are respectfully employed, these procedures may be used to treat from the very youngest patient on through adolescence. the earlier the dysfunction is recognized, the younger the patient and the more plastic the tissues, the greater the possibility to affect the structure and to re-establish satisfactory functional patterns, thereby activating the body's inherent ability to heal itself. involve the parents or caregivers; empower them to help the child to succeed in dealing with the dysfunction. take the time to explain to the child why it is necessary to breathe through the nose and eat slowly. encourage the child to promote correct function, such as nasal breathing and learning how to blow their nose. encourage the child to practice activities that promote breathing, such as singing with good articulation of the words.young children with dysfunctional tongue mechanics or with minor cases of ankyloglossia can perform exercises to mobilize the tongue and to stretch the frenulum as much as possible. encourage the parents or caregivers to correct the child when there is mispronunciation. it may appear to be cute, but is actually dysfunctional. the child should repeat incorrectly pronounced words as correctly as possible to improve tongue mobility. infants can be encouraged to play sound-making games by repeating sounds that cause the tongue to make a clicking noise against the palate.teach effi cient swallowing without tongue thrusting by instructing the child to consciously keep their tongue in their mouth and to learn to swallow with the tip of their tongue resting against the palate behind their upper incisors. to practice this, the child can hold a small piece of food between the tongue and palate while attempting to swallow several times. this exercise should be repeated until the act of swallowing with the tip of the tongue resting against the palate becomes automatic.insist on alternate unilateral mastication and that the child takes suffi cient time to chew their food thoroughly. those children who are old enough should be encouraged to eat food that is as unrefi ned as possible. soft refi ned junk food often does not require suffi cient chewing.caution the parent or caregiver to watch for functional asymmetries that are associated with repetitive asymmetrical activities, such as unilateral bottle feeding or thumb sucking. instruct the parent or caregiver and the patient, when old enough to understand, to avoid these activities or perform them in a fashion that alternates sides. key: cord-345222-otfnrarh authors: ciccarelli, simona; stolfi, ilaria; caramia, giuseppe title: management strategies in the treatment of neonatal and pediatric gastroenteritis date: 2013-10-29 journal: infect drug resist doi: 10.2147/idr.s12718 sha: doc_id: 345222 cord_uid: otfnrarh acute gastroenteritis, characterized by the onset of diarrhea with or without vomiting, continues to be a major cause of morbidity and mortality in children in mostly resource-constrained nations. although generally a mild and self-limiting disease, gastroenteritis is one of the most common causes of hospitalization and is associated with a substantial disease burden. worldwide, up to 40% of children aged less than 5 years with diarrhea are hospitalized with rotavirus. also, some microorganisms have been found predominantly in resource-constrained nations, including shigella spp, vibrio cholerae, and the protozoan infections. prevention remains essential, and the rotavirus vaccines have demonstrated good safety and efficacy profiles in large clinical trials. because dehydration is the major complication associated with gastroenteritis, appropriate fluid management (oral or intravenous) is an effective and safe strategy for rehydration. continuation of breastfeeding is strongly recommended. new treatments such as antiemetics (ondansetron), some antidiarrheal agents (racecadotril), and chemotherapeutic agents are often proposed, but not yet universally recommended. probiotics, also known as “food supplement,” seem to improve intestinal microbial balance, reducing the duration and the severity of acute infectious diarrhea. the european society for paediatric gastroenterology, hepatology and nutrition and the european society of paediatric infectious diseases guidelines make a stronger recommendation for the use of probiotics for the management of acute gastroenteritis, particularly those with documented efficacy such as lactobacillus rhamnosus gg, lactobacillus reuteri, and saccharomyces boulardii. to date, the management of acute gastroenteritis has been based on the option of “doing the least”: oral rehydration-solution administration, early refeeding, no testing, no unnecessary drugs. acute gastroenteritis (age), characterized by the onset of diarrhea with or without vomiting, continues to be a major cause of morbidity and mortality in children mostly in resource-constrained nations. although generally it is a mild and self-limiting disease, gastroenteritis is one of the most common causes of hospitalization and is associated with a substantial disease burden. 1, 2 according to the world health organization (who), diarrhea is defined as the passage of three or more loose or liquid stools per day, or more frequently than is normal for the individual. 3 when young children suddenly experience an episode of acute diarrhea, with or without vomiting, infectious gastroenteritis is by far the most common explanation. 4 viewed from a global perspective, gastroenteritis in children is of enormous public health importance. worldwide, about 10.6 million children still die every year before reaching their fifth birthday. gastroenteritis alone is responsible for almost 20% of the deaths. 4 in spite of the intense promotion of oral rehydration solution (ors) at the community level and the training of health care workers, diarrhea mortality remains unacceptably high: more than 2 million children aged less than 5 years die each year from gastroenteritis, almost all living in resource-constrained nations, where acute diarrhea represents a leading cause of child mortality, second only to pneumonia. 2 age causes 1.5 million visits to primary care providers each year and 220,000 hospital admissions for children under the age of 5 years; that is 10% of all the hospital admissions of children in the us. 5 in general, resource-constrained nations have a higher rate of hospital admissions compared to rich nations. 6 in the us, the admission rate is nine per 1000, per year, for children younger than 5 years old. 5 in england each year, 9.4 million cases of gastroenteritis occur in the community and 1.5 million present to their primary care doctor. 4 in europe, rotavirus infection accounts for more than 50% of hospitalizations for gastroenteritis and about one-third of emergency department visits. 2, 6, 7 not surprisingly, the economic burden of acute diarrhea is substantial, not only in management costs but also in indirect costs, such as absence from work by parents or caregivers of sick children. 2 the severity of acute diarrhea is related to etiology, with rotavirus infection disproportionately implicated in severe cases that frequently require hospitalization. 2, 8 worldwide, up to 40% of children aged less than 5 years with diarrhea are hospitalized with rotavirus: while most of the episodes are mild, about 10% of cases lead to dehydration requiring a doctor visit, and in resource-constrained nations, one in 250 children will die from this dehydration. [7] [8] [9] [10] [11] in europe, rotavirus infection accounts for more than 50% of hospitalizations for gastroenteritis and about one-third of emergency department visits. 2, 7 otherwise, some agents have been found predominantly in resource-constrained nations, including shigella spp, vibrio cholerae, and the protozoan infections. mode of transmission is mainly horizontal, through physical contact with an infected person or with their excretions. the pathogens, most frequently transmitted during the passage through the birth canal, are enteropathogenic escherichia coli, salmonella, and enterovirus. although rare, the passage of the germ can also occur transplacentally during bacteremia. several maternal infections are asymptomatic. horizontal transmission can occur through direct contact with siblings, parents, or health care workers. some cases of transmission through the ingestion of contaminated water or infant formula are also reported. some viral infectious agents, such as adenovirus and rotavirus, can be transmitted by air. 12 the relatively low incidence of the disease in newborns is the result of several factors: breastfeeding and the universal practice of giving birth at home in rural villages, and improvements in social and educational standards and medical care in advanced countries. 13, 14 otherwise, newborns are particularly susceptible to enteric infections in early life, due to reduced local and systemic immune response, absence of an adequate intestinal flora, and reduced gastric acidity. in the newborn, the protective role of gastric motility and of the intestinal mucus is still uncertain. other external factors contribute to the balance of the intestinal ecosystem: nutrition, type of delivery, hygiene habits, use of antibiotics in the mother and infant and the supplementation with probiotics and/or prebiotic oligosaccharides in the newborn. [15] [16] [17] the mortality risk for very low-birth-weight infants (less than 1500 g) due to acute diarrhea is 100 times higher than for infants of low or appropriate birth weight (more than 1500 g). acute diarrhea has several risks and complications; it may lead to lifethreatening dehydration and electrolyte disturbances. when diarrhea is not halted, there is a risk of disturbed digestion and absorption of nutrients with nutritional deterioration. 13 prevention is essential, and all health professionals should ensure caregiver education in the following main principles of prevention: 13 • full and exclusive breastfeeding that protects against intestinal infections and prevents exposure to environmental contamination. 18, 19 thriving breastfed babies under 6 months of age do not require water supplements, even in hot weather. 19 ,20 • provision of safe water for drinking and food preparation. • proper hand-washing hygiene after toilet use and before food preparation and feeding. • safe disposal of human and other waste. table 1a-c shows the main characteristics of the principal bacterial, viral, fungal, and parasitic enteropathogens, respectively: typical age of presentation, type of diarrhea, duration of symptoms, clinical features, transmission, and seasonality. not always well defined, because some agents use both these pathogenetic strategies to induce disease. in europe, the most common bacterial agent is either salmonella or campylobacter, depending on country. 6 aeromonas hydrophila and plesiomonas shigelloides (previously also known as aeromonas shigelloides) belonging to the family of vibronacee, can cause watery diarrhea. the pathogenic role of a. hydrophila as an enteric pathogen causing gastroenteritis is difficult to confirm, because of the frequency of other pathogens isolated with a. hydrophila in symptomatic and asymptomatic subjects. but a. hydrophila is recognized increasingly as a clinically significant enteric pathogen associated with diarrhea also in children younger than 2 years of age living in a rural community, and is linked to local drinking water sources. 21 campylobacter is the most common enteropathogen after 5 years of age, particularly in northern european countries. 6 c. jejuni and c. coli infections are endemic worldwide and hyperendemic in resource-constrained nations. infants and young adults are most often infected. 22 c. jejuni, followed by c. coli and c. lari, are the most common bacterial causes of acute diarrheal illnesses in rich nations. 22 c. jejuni has invasive properties, leading to epithelial ulceration and inflammatory infiltrates in the lamina propria, mainly in the colon, ileum, and jejunum. some c. jejuni isolates elaborate very low levels of cytotoxins, similar to shiga toxin. some isolates have been reported to elaborate an enterotoxin similar to cholera toxin. enterotoxin production has been more frequently observed in isolates from resource-constrained nations, where infection by c. jejuni has been associated with watery diarrhea. however, the clinical significance of the toxigenicity of these organisms is still unclear. 23 symptoms and signs of c. enteritis are not distinctive enough to differentiate it from illness caused by many other enteric pathogens. diarrhea is often associated with blood, but it can be difficult to distinguish from other invasive forms. a cholera-like illness with massive watery diarrhea may also occur. bacteremia is uncommon (less than 1%) in immunocompetent patients with c. jejuni infection. 22 newborn infection by campylobacter spp is rare; most cases were born to mothers with campylobacter diarrhea at the time of delivery. the transplacental passage of campylobacter fetus is responsible for abortion, premature birth, bacteremia, and meningitis. c. jejuni/coli infections can cause a series of complications as reactive arthritis, irritable bowel syndrome, and guillain-barré syndrome (gbs), an acute neurologic disease driven by autoimmunity and molecular mimicry in which the body stages a cell-mediated and humoral immunological response against peripheral nerve myelin. a recent systematic review of gbs estimated that 40%-70% of all cases are preceded by an acute infectious illness, of which 22%-53% are upper respiratory infections and 6%-26% are gastrointestinal infections, one of the most common being enteritis due to campylobacter. 24, 25 several studies have shown that patients with gbs (most of cases associated with the variant acute motor axonal neuropathy) have a recent history of infection due to c. jejuni. 26 clostridium difficile is a major nosocomial pathogen that causes a spectrum of intestinal disease from uncomplicated antibiotic-associated diarrhea to severe, possibly fatal, antibiotic-associated colitis. 27 in the last 5-7 years, a change in the epidemiologic pattern of c. difficile infection characterized by an increasing incidence and severity of infection has been observed. a few epidemiological studies recently conducted in the pediatric population demonstrated a twofold increase in the incidence of c. difficile infection in the last 5 years, but with no increase in the incidence of severe complications, such as the need for colectomy or mortality. 28, 29 the clinical presentation of c. difficile-associated disease can range from asymptomatic carriage in the gastrointestinal tract and mild diarrhea to potentially fatal pseudomembranous colitis. 30 diarrhea is watery and usually nonbloody, but approximately 5%-10% of patients have bloody diarrhea. fecal material typically contains excess mucus, and pus or blood may also be noted. 31 the disease may progress to a pseudomembranous colitis, possibly including intestinal perforation and toxic megacolon. neonatal infections by c. difficile can be asymptomatic, but usually display fever, diarrhea, and irritability within 48 hours after production of the toxins. 32 escherichia coli are the predominant nonpathogenic facultative anaerobe of human colonic flora and usually remain harmlessly confined to the intestinal lumen. some e. coli have evolved the ability to cause a broad spectrum of human diseases, and different types associated with enteric infections are classified into five groups according to their virulence properties and are briefly described here. enteroaggregative e. coli (eaec) serotypes exhibit a characteristic aggregative pattern of adherence and produce persistent gastroenteritis and diarrhea in infants and children in resource-constrained nations. 22 enteroinvasive e. coli serotypes have properties similar to invasive salmonella, but the presence of blood in the stool is less frequent. these can also produce an enterotoxin that cause watery diarrhea, resembling the effects of shigella in children and adults. enteropathogenic e. coli (epec) serotypes in the past were 33 serotypes number about 50, and in rich countries are primarily responsible for gastroenteritis with bloody diarrhea, severe abdominal pain, and cramps that resolve in a few days with an adequate oral rehydration. since 1982, gastroenteritis from shiga toxin-producing e. coli (stec), an e. coli strain with the capacity to produce a cytotoxin similar to that produced by shigella spp, has been identified as a significant health problem in the developed world. 34, 35 infections with stec, of which ehec o157 is the most well-known serotype, have been recorded in many regions, including north america, western europe, central and south america, the middle and far east, africa and australia; also, eaec serotype o104:h4 can produce shiga toxins (stec). [36] [37] [38] infections by stec are characterized by abdominal cramps and acute bloody diarrhea; 39 however, more serious sequelae may also result, including hemolytic uremic syndrome (hus), thrombocytopenia, and associated complications, which can lead to kidney failure and death in some individuals. 36, 40 most outbreaks and sporadic cases of bloody diarrhea and hus have been attributed to strains of stec serotype o157:h7. however, in europe and recently in the us, the role of non-o157 stec strains (eg, o26:h11/h-, o91:h21/h-, o103:h2, o104:h4, o111:h-, o111:nm, o113:h21, o121:h19, o128:h2/h-, and o145:h28/h-) as causes of hus, bloody diarrhea, and other gastrointestinal illnesses is being increasingly recognized. 33, 41 in many studies, a significant association between illness and the consumption of pink or undercooked hamburgers, pinkish ground beef, undercooked meat, or barbecued food has been demonstrated. 38, 41, 42 the natural reservoirs of stec are ruminant animals, especially cattle, and transmission to humans usually occurs via contaminated food or water. helicobacter pylori (previously named campylobacter pyloridis)-infected children may have no symptoms or a wide variety of symptoms, and rarely potentially life-threatening complications, such as gastroduodenal ulcers and bleeding. symptoms of ulcers may include pain or discomfort (usually in the upper abdomen), bloating, an early sense of fullness with eating, lack of appetite, nausea, vomiting, blood in the stools, and diarrhea. in the last 10 years, various studies have been performed investigating its role to modify the susceptibility to gastroenteritis in children. 43 a study reported an increased risk of chronic diarrhea, compared with healthy control subjects, among infected age-matched gambian children with malnutrition. 44 in a nested case-control design, the authors found an increased risk of severe cholera among h. pylori-infected subjects without vibriocidal antibodies. 45 similarly, in an urban slum, h. pylori infection was twice as common among subjects with typhoid fever (salmonella typhi) 46 than in neighborhood control subjects. another study reported increased diarrhea episodes among peruvian infants with recent h. pylori seroconversion. 47 conversely, in a thai orphanage, no association was found between seroconversion and diarrheal disease. 48 some investigators have even speculated that local inflammatory factors induced by infection may be protective. 49 in a cross-sectional study of elementary school-age children in germany, the infection seemed associated with a reduced frequency of diarrheal illnesses. 50 these epidemiological discrepancies could be explained, because h. pylori could be argued to increase or decrease susceptibility to enteric pathogens. depending on the age at acquisition and the anatomical site of colonization, for example, h. pylori decreases gastric acid secretion in some people, thereby potentially reducing the effectiveness of the gastric acid barrier to intestinal pathogens, but increases gastric acid secretion in others. 51 in this prospective study, h. pylori did not seem to increase the risk of gastroenteritis in people more than 2 years old. 43 these data have recently been confirmed. 52 klebsiella, enterobacter, citrobacter, and streptococcus group d have been isolated from feces of sick newborns and associated with intestinal disease, but there is insufficient evidence to define the pathogenic role of these agents. proteus and providencia, although rarely, may be responsible for intestinal infections in newborns. providencia species occur in normal feces and have been isolated from epidemic and sporadic causes of diarrhea, though their importance in the causation of diarrheal disease is not easy to assess. 53 pseudomonas aeruginosa can colonize (0%-10%) the intestine of the newborn during the first days of life. 54 clinically, the infection may be asymptomatic at first, later developing into grayish-blue stool color or watery diarrhea, profuse vomiting, and systemic symptoms. salmonella pass through the intestinal mucosa and multiply within the lamina propria, may invade mesenteric lymphonodes, and systemic spread of the organisms can occur, giving rise to enteric fever. 55 in fact, 3%-5% of infants may have extraintestinal symptoms. the colonization and initial invasion probably occur at the distal ileum, while the mucosal edema and cryptic abscesses are frequently in the colon. the diarrhea is due to secretion of fluid and electrolytes by the small and large intestines. the incubation period is usually 12-48 hours, rarely for a few days. 22 salmonella spp is normally acquired through the birth canal, and the mother can be an asymptomatic carrier. 55 shigella spp are the leading bacterial causes of diarrhea worldwide and are relatively common in children. they cause invasive gastroenteritis, and symptoms can take as long as a week to show up, but most often begin 2-4 days after ingestion. mild symptoms are self-limiting, but s. dysenteriae serotype 1 resistance to multiple antibiotics has the ability to elaborate the potent shiga toxin, which may lead to extraintestinal complications, including hus and death. 56 cases of neonatal infections from staphylococcus aureus are reported in the literature. the pathogen produces two enterotoxins, g and i, that cause atrophy of intestinal villi, diarrhea, and poor growth during the first weeks of life. vibrio cholerae causes watery diarrhea through the production of cholera toxin without invading the intestinal mucosa. yersinia enterocolitica is a common enteropathogen usually causing relatively mild disease. y. enterocolitica crosses the intestinal mucosa, replicates in peyer's patches, and children infected present acute diarrhea associated with fever and pharyngitis, chronic or recurrent diarrhea, or abdominal pain associated with mesenteric adenitis. this infection looks like salmonella infections, with feces containing mucus with or without blood. the pathogen, within phagocytes, can reach other sites through the bloodstream. some of the y. enterocolitica pathogenic biotypes express the yst gene encoding for an heat-stable enterotoxin that may contribute to the pathogenesis of diarrhea. 57, 58 viral enteritis (table 1b) viruses are responsible for approximately 70% of the episodes of acute gastroenteritis in children. viral gastroenteritis is of shorter duration than bacterial gastroenteritis and associated with an increased risk of vomiting and dehydration compared with those without viral infection. the severity of dehydration is significantly higher in children infected with either astrovirus or rotavirus group a. prolonged hospitalization is also more likely to occur with rotavirus infection. 4, 22, 55, 59, 60 enteric adenoviruses are a common cause of viral gastroenteritis in infants and young children. although there are many serotypes of adenovirus that can be found in the stool especially during and after typical infections of the upper respiratory tract, only serotypes 40 and 41 cause gastroenteritis and are very difficult to grow in tissue culture. 61 adenovirus directly infects intestinal enterocytes, causing villous hypoplasia and crypt hypertrophy. the virus causes a massive infiltration of the lamina propria of the villi by mononuclear cells. enteric adenovirus is associated with longer lasting diarrhoea, compared to other viral gents. 4, 22, 55 maternal antibodies are certainly protective; however, among premature and/or low-birth-weight infants the infection spreads rapidly and can be associated with a poor prognosis and high morbidity. 5 cytomegalovirus and herpes virus (cmv or hh5 and hhv6-7; family herpesviridae, subfamily betaherpesviridae) can cause gastrointestinal symptoms such as diarrhea or colitis with profuse hematochezia and bowel perforation. 62 most people who are infected with a non-polio enterovirus (ev; family picornaviridae, genus enterovirus) have no disease, but all ev may cause diarrhea. 63 human ev 68 (ev-d68) is a historically rarely reported virus linked with respiratory disease. in the last 3 years, a large increase in respiratory disease associated with ev-d68 has been reported, with documented outbreaks in north america, europe, and asia. 64 ev71 infections can be asymptomatic or can cause diarrhea, rashes, and hand, foot, and mouth disease. however, ev71 may be responsible for severe complications, including meningitis, encephalitis, cardiovascular and respiratory problems as pulmonary edema, or heart failure. cases of fatal ev71 encephalitis have occurred during outbreaks. most ev71 infections occur under 3 years of age. coxsackie (family picornaviridae, genus enterovirus)-a16 and ev71 are two of the major pathogens responsible for hand, foot, and mouth disease, but the most severe cases are associated with ev71. 65, 66 pleconaril, a viral agent active against enteroviruses, has demonstrated efficacy against neonatal infection with systemic symptoms. however, further confirmatory studies are needed. 67 results of phase i clinical trials suggest an ev71 vaccine has a clinically acceptable safety profile and immunogenicity. outbreaks of ev71 are a serious socioeconomic burden not only in the western pacific region. for this reason, an ev71 vaccine is now being tested and seems to submit your manuscript | www.dovepress.com have an acceptable safety profile and clinically acceptable immunogenicity. 68 human astrovirus (family astroviridae, genus mamastrovirus) may also be responsible for sporadic infections or epidemics, occasionally in newborns and children. 61, 63 human bocavirus (family parvoviridae, genus bocavirus), recently discovered, has been suggested to be involved in a large spectrum of clinical manifestations, including gastroenteritis. 63, 69 human coronaviruses (hcovs; family coronaviridae, genus coronavirus) are common causes of upper respiratory tract infections. a new coronavirus was found to be a causative agent of severe acute respiratory syndrome (sars). sars-hcov caused a serious lower respiratory tract infection with high mortality. diarrhea is common in this condition, and in one study was registered in 38.4% of patients. in the same study, sars-hcov was also isolated from intestinal tissue, and viral rna was detected in stool samples. moreover, non-sars hcovs can be found in stool samples of children with age. however, most of the hcov findings were coinfections with well-known enteric pathogens -norovirus and rotavirus. it is also difficult to determine whether hcovs in the respiratory tract in cases of age were primarily causing the respiratory or gastrointestinal symptoms. hcovs may also be found in occasional stool samples of children without gastroenteritis. these findings suggest that known hcovs may at most have a minor etiologic role in age of children. 70 human rotavirus (family reoviridae, genus rotavirus) in the past was considered to be responsible for the most severe episodes of diarrhea in children. 71, 72 there have been reports of epidemics in neonatal intensive care units caused by rotavirus or enterovirus that can determine cases of necrotizing enterocolitis or necrotizing enterocolitis-like symptoms: abdominal distention, bloody diarrhea, and septicemia secondary to enteric bacteria. improved diagnostic tools for norovirus (family caliciviridae, genus norovirus): have shown that it has a major role in both epidemic and sporadic cases of gastroenteritis. 59, 73 sapoviruses (family caliciviridae, genus sapovirus): mainly infect children younger than 5 years of age. 59 the illness is milder than that caused by noroviruses. 73 antibody prevalence studies show that virtually all children are infected with sapoviruses by the time they are 5 years of age, indicating that sapovirus infection is widespread, although the illness most likely is sporadic with a high rate of asymptomatic infection. 59, 74, 75 torque teno midi virus/small anellovirus (ttmdv/sav) is a member of the family anelloviridae. although human ttv infection is ubiquitous and several infecting genogroups of the virus have been identified, to date there is no consistent evidence of a link between ttv infection of humans and specific disease. [76] [77] [78] [79] in a recent hungarian study, viral shedding, molecular epidemiology, and genetic diversity of ttmdv/ sav were studied in human body fluids (nasopharyngeal aspirates of children with acute respiratory diseases and serum, stool and urine samples collected from eight healthy children with previous ttmdv/sav infection). in this study, shedding of ttmdv/sav and related viruses was detected in two other human body fluids, feces and urine, suggesting the existence of fecal-oral/urinary-oral transmission routes beyond the originally presumed blood-borne and later-suggested respiratory route. this finding extends the number of possible successful transmission routes. fungal enteritis (table 1c) the pathogenic role of candida in neonatal diarrhea is still difficult to prove. symptoms ascribed to candida-associated diarrhea in the literature include prolonged secretory diarrhea with abdominal pain and cramping but without blood, mucus, fever, nausea, or vomiting. 80 disseminated candida infection can cause intestinal symptoms similar to necrotizing enterocolitis, especially in premature infants and in infants treated with antibiotics (especially third-generation cephalosporins) and with central venous catheters or in surgical patients. 81, 82 candida infections frequently develop into systemic forms, and are a major cause of morbidity and mortality in neonatal intensive care units. 83 the incidence of candidemia in the neonatal intensive care unit is steadily increasing, with an estimated incidence of 1%-2% in very low-birth-weight infants and of 2%-23% in extremely low-birth-weight infants. 84 infection-associated mortality following candida bloodstream infections is as high as 40% (very low birth weight 2%-30%, extremely low birth weight 12%-50%), and neurodevelopmental impairment is common among survivors (extremely low birth weight 57%). [84] [85] [86] [87] [88] because invasive fungal infections are common and extremely difficult to diagnose, prevention (decrease of risk factors that contribute to increased colonization and concentration of fungal organisms like maternal vertical transmission or nosocomial acquisition) and antifungal prophylaxis should be considered. 89 parasitic enteritis -protozoan (table 1c) some waterborne protozoan parasites induce enteritis through their membrane-associated functional structures and virulence factors that alter host cellular molecules and submit your manuscript | www.dovepress.com dovepress dovepress signaling pathways, leading to structural and functional lesions in the intestinal barrier. 90 cryptosporidium parvum has a high infectivity with significant enteric disease: rarely is asymptomatic. there have been reported cases of infection in the first month of life; the passage of the maternal antibodies and breastfeeding are a protective factor against infection. 91 giardiasis is one of the intestinal protozoa that cause public health problems in most resource-constrained nations, as well as some resource-rich countries. many infected persons can be asymptomatic, leading to difficulties in the eradication and control of this parasite due to the number of potential carriers, such as school children. giardia lamblia is observed almost three times more in asymptomatic children than in symptomatic children. the first signs of acute giardiasis include nausea, loss of appetite and an upper gastro-intestinal uneasiness, followed or accompanied by a sudden onset of explosive, watery, foul-smelling diarrhea. stools associated with giardia infection are generally described as loose, bulky, frothy and/or greasy with the absence of blood or mucus, which may help distinguish giardiasis from other acute diarrheas. other gastro-intestinal disturbances may include: flatulence, bloating, anorexia, cramps. the acute stage usually resolves spontaneously in a few days. occasionally an acute infection will persist and lead to malabsorption, steatorrhea, loss of strength and weight loss. it has been estimated that about 200 million people are infected each year in africa, asia and latin america. in the resource-rich countries the prevalence rate of giardiasis is 2-5%. however, in resorce-constrained countries, giardia lamblia infects children early in life thus a prevalence rate of 15-20% in children younger than 10 years is common. children who are malnourished are more frequently infected. 92 cryptosporidium and giardia most often cause diarrhea in immunocompromised children or in children from resource-constrained nations, and diarrhea tends to be chronic in both settings. 60, 92, 93 although e histolytica generally causes bloody diarrhea, some studies have demonstrated that e histolytica could also be responsible for watery diarrhea, particularly in infants. that nondysenteric diarrhea is a common presentation of amebiasis in children less than 2 years of age but it was also reported among children aged 2-12 years of age. 94, 95 isospora belli is an opportunistic protozoan more frequent in developing countries of tropical and subtropical regions and should be monitored in both immunocompromised and immunocompetent patients with gastrointestinal complaints such as abdominal pain, nausea, and diarrhea. several helminths can also cause diarrhea, and their importance depends on geographic location, climatic conditions, poor sanitation, unsafe drinking water, and the immune status of the child. 6, 60 strongyloidiasis is an infection caused by the intestinal nematode strongyloides stercoralis. infected healthy individuals are usually asymptomatic; however, it can cause watery or chronic diarrhea, abdominal cramping, failure to thrive, and cachexia. it is potentially fatal in immunocompromised hosts, due to its capacity to cause an overwhelming hyperinfection. a screening assay for strongyloides infection in suspected patients is needed for early detection and successful cure. 96 trichuris trichiura infections are widespread globally, with prevalence and intensity-of-infection peaks in school age. nevertheless, as soon as infants start to explore their environment, thus coming into contact with contaminated soil, they are at risk of infection according to the levels of transmission in the area. the pathogen can cause inflammatory damage to mucosa, bloody diarrhea, iron deficiency, and anemia. most children with gastroenteritis do not require any laboratory investigations. many infants and children experience brief episodes of diarrhea, and are managed by their parents without seeking professional advice. even if advice is sought, health care professionals often consider that a clinical assessment is all that is required, and laboratory investigations are not undertaken. 4 however, there may be particular circumstances when investigations may be helpful in diagnosis. frequently the signs and symptoms are not sufficient to make an etiological diagnosis as they often are nonspecific. the localization of the pathogen in the small intestine or in the colon, the characteristics of the feces (table 2) , the clinical history of the disease, and environmental risk factors can support the diagnostic evaluation. it would be also important to be aware of any history of recent contact with someone with acute diarrhoea and/or vomiting and exposure to a known source of enteric infection (possibly contaminated water or food) or a recent travel abroad. 4 severe watery diarrhea in the absence of mucus, pus, or blood suggests secretory diarrhea or malabsorption (such as by noninvasive vibrio cholera, etec, or by rotavirus, adenovirus, or astrovirus), while the presence of blood and mucus are more indicative of an invasive germ, such as salmonella, shigella, campylobacter jejuni, or yersinia enterocolitica. 60 the presence of vomiting and fever with diarrhea is nonspecific and cannot help in the diagnosis. 4 it would be also important to be aware of any history of recent contact with submit your manuscript | www.dovepress.com 1 year and a few percent of adults. although these data support the potential for endogenous sources of human infection, there was early cir cumstantial evidence to suggest that this pathogen could be transmissible and acquired from external sources. 97 therefore the possibility of other disorders would require careful consideration in such cases of diarrhea and/or vomiting as shown in table 3 . regarding collection and transport of stool specimens, for stool culture for bacterial pathogens: one stool specimen is sufficient in most cases: • c. difficile toxin testing: one stool specimen is sufficient in most cases. • ova and parasite testing: specimen must be submitted in an appropriate preservative (sodium acetate-acetic acidformalin fixative). • viral pathogens: stool for viral pathogens are not routinely tested; for a suspected outbreak of viral gastroenteritis, one stool specimen submitted in a sterile container is sufficient in most cases. for the investigation of bacterial pathogens, stool specimens should be delivered to the laboratory as soon as possible, as a delay may compromise bacterial pathogen recovery. a single stool specimen, properly collected and promptly submitted, will identify most patients with a bacterial pathogen. additional stool specimens need to be submitted if the culture results are negative, symptoms persist, and other causes cannot be found. if there are concerns regarding timing or transport of the specimen, consult the laboratory. submit your manuscript | www.dovepress.com for physical and chemical study of feces, fecal ph less than or equal to 5.5 or the presence of reducing substances is a sign of intolerance to carbohydrates, mostly secondary to viral infection. for microscopic examination of stool, the presence of leukocytes is suggestive of an enteroinvasive infection, although the absence of leukocytes cannot exclude it. however, infections mediated by enterotoxins (etec, vibrio cholerae, and viruses) have no white blood cells in stool. for fecal culture, various culture media are used to isolate the bacteria. the clinical history, physicochemical characteristics of the stool, and laboratory tests thus allow the choice of an appropriate culture medium. in the presence of clinical signs and leukocytes in the stool, it is always necessary to perform culture for salmonella, shigella, and campylobacter. if stool cultures are not performed within 2 hours of sample collection, it is necessary to keep the stool at 4°c. blood cultures are examined for evidence of bacteremia. research of bacterial toxins is conducted through enzyme-linked immunosorbent assay (elisa). 42 the fecal rotavirus antigen is examined through elisa and latex agglutination test; search of adenovirus fecal antigen is performed using elisa. 98 polymerase chain reaction (pcr) or other molecular investigations are performed for viral research, especially on stools for norovirus, adenovirus, sapovirus, and human bocavirus, and pcr of stool and blood is used for the detection of enteroviruses. 63 a providencia genus-specific pcr method has been developed, and its specificity and sensitivity was evaluated to be 100% with various bacterial strains. 99 recently, pcr methods have been applied to investigate the prevalence of the virulence genes specific for five major pathogroups of diarrheagenic escherichia coli in primary cultures from feces of animals slaughtered for human consumption in burkina faso that revealed the common occurrence of the diarrheal virulence genes in feces of food animals. 100 another study investigated using pcr for the incidence, antimicrobial resistance, and genetic relationships of epec in children with diarrhea. 101 regarding parasitic infection and study of trophozoites or oocysts, antigen detection of stool through elisa is used; the serological study can be helpful in rare systemic infections. 60, 82, 91 for intestinal infection by enteroinvasive agents, it is possible to find low blood levels of albumin and high levels of alpha-l-antitrypsin in the stool, and an index of extended intestinal inflammation with dispersion of proteins. 22 parents, caregivers, and children should be informed that it is possible to prevent the spread of gastroenteritis using some simple rules: • wash hands with soap and water, especially after using toilet or changing diapers and before preparing, serving, or eating food • do not share towels used by infected children • children should not attend any school or other child-care facility while they have gastroenteritis; they can go back to school from at least 48 hours after the last episode of diarrhea or vomiting • children should not use swimming pools for 2 weeks after the last episode of diarrhea 102,103 • implementing rotavirus vaccination: the new rotavirus vaccines are safe and reduce the severity of infection and prevent deaths, but they do not prevent all cases of rotavirus diarrhea. 104 two live, oral, attenuated rotavirus vaccines were licensed in 2006: a pentavalent bovine-human recombinant vaccine and a monovalent human rotavirus vaccine. both vaccines have demonstrated good safety and efficacy profiles in large clinical trials in resource-rich countries and in latin america. 105, 106 immunization against rotavirus is recommended in europe and the us. 107, 108 the protective effects of breastfeeding against gastroenteritis infections have been demonstrated in several studies. 109, 110 antibacterial substances, such as lactoferrin, lysozyme, phagocytes, and specific secretory immunoglobulins plays a protective role. 111 the ligand-specific action of κ-casein inhibits helicobacter pylori adherence to the gastric mucosa. human milk also has antiviral action through the lactoferrin and products of digestion of lactoferrin and milk fatty acids. 112 all of these elements suggest that exclusive breastfeeding contributes to protection against common infections during infancy and lessens the frequency and severity of infectious episodes. 113 breastfeeding promotes the colonization of the intestinal ecosystem with a predominance of bifidobacteria and lactobacilli (probiotics) rather than coliforms, enterococci, and bacteroides that characterize the intestinal microflora of infants fed with formula. 114 some authors have demonstrated that the use of formulas supplemented with probiotics (bifidobacterium lactis and lactobacillus gg) have decreased the incidence (up to 57%) and severity of diarrhea. the probiotics, also submit your manuscript | www.dovepress.com dovepress dovepress defined as food supplements, improve intestinal balance, have beneficial effects on health, and are able to balance the intestinal ecosystem and reduce the duration and severity of diarrheal infections, especially in the course of rotavirus infections. the probiotics in the intestine determine resistance to colonization by other potentially pathogenic microbes through mechanisms of competition or inhibition, and the effects are expressed both on nonspecific innate and acquired immunity. 115 lactobacillus rhamnosus gg (lgg) is considered particularly effective in the management of age; this is confirmed by a recent cochrane review documenting that lgg reduced the duration of diarrhea, mean stool frequency on day 2, and the risk of diarrhea lasting $4 days. 1, 116 according to a recent cochrane review, saccharomyces boulardii reduces the risk of diarrhea lasting $4 days, and a more recent review confirmed that s. boulardii significantly reduced the duration of diarrhea and hospitalization. a recent randomized controlled trial evaluated the efficacy of treatment with lactobacillus reuteri dsm 17938 compared with placebo: the administration of l. reuteri reduced the duration of watery diarrhea, the risk of diarrhea on days 2 and 3, and the relapse rate of diarrhea. 1 it has been suggested that probiotics may decrease infant mortality and nosocomial infections because of their ability to suppress colonization and translocation of bacterial pathogens in the gastrointestinal tract. several meta-analyses evaluating probiotics in preterm infants suggest a beneficial effect for the prevention of necrotizing enterocolitis and death, but less for nosocomial infection. l. reuteri may reduce these outcomes because of its immunomodulation and bactericidal properties. a large, double-blinded, randomized controlled trial (rct) using l. reuteri was performed to test this hypothesis in preterm infants. this study suggested that although l. reuteri did not appear to decrease the rate of death or nosocomial infection, the trends suggest a protective role consistent with what has been observed in the literature: a protective role for mortality, nosocomial infection, and necrotizing enterocolitis. feeding intolerance and duration of hospitalization were significantly decreased in premature infants less than 1500 g. 117 the use of formulas supplemented with probiotics (particularly bifidobacterium lactis and lactobacillus gg) seems to decrease the incidence (up to 57%) and severity of infectious acute diarrhea. symbiotics, a combination of prebiotics and probiotics that beneficially affect the host by improving survival and implantation of live microbial dietary supplements in the gastrointestinal tract, has recently been evaluated by two european rcts for the management of age. these studies are promising, but presently it would not be appropriate to recommend the use of symbiotics until confirmatory data are available. 1 dehydration is probably the main complication of gastroenteritis in childhood. who classification of patients' hydration status is based on the presence of symptoms and signs. the presence of one of these signs or symptoms immediately classifies the patient as a more severe case. table 4 summarizes the who management of rehydration. 118, 119 all moderate and severe patients require close monitoring, but patients at the extreme ages of life, especially children under 18 months, require meticulous observation and immediate measures if their condition worsens. according to current who recommendations, oral rehydration therapy (ort) is considered the treatment of choice to replace fluid and electrolyte losses caused by diarrhea in children with mild to moderate dehydration. intravenous rehydration is the treatment of choice in cases of failure of ort, and it has to be reserved for patients with severe dehydration or who eliminate more than 10-20 ml/ kg/hour. in the 1960s, efforts by young scientists and researchers led to the development of ort for the treatment of dehydration that often accompanies acute attacks of diarrhea. many members of the research team responsible for this discovery were associated with noteworthy universities and medical research centers in the us. the goal of their research was to devise effective therapies for cholera-induced diarrhea; as a result of their hard work, they developed a new framework for treatment that would soon be adopted throughout the developing world as a key element in the overall strategy to combat acute diarrhea and the potentially fatal dehydration that accompanies the disease. in an article published in 1968 in the lancet, it was confirmed that cholera patients could be rehydrated orally with a simple solution of water, salt, and sugar, and equally importantly that field staff could easily be trained to administer the therapy. as stated in the article, ort also offers a practical treatment for large numbers of patients in the developing world who do not have access to traditional intravenous drip therapy. at first, studies on the efficacy of ort, when compared with intravenous therapy (ivt), were conducted only in patients with cholera. [120] [121] [122] following that, other studies established the effectiveness of ort in children with acute diarrhea from other causes. 123 some trials also compared the effectiveness of oral rehydration submit your manuscript | www.dovepress.com with ivt in children with different degrees and types of dehydration (mild, moderate, severe, and hypernatremic dehydration), and they concluded that the use of ors to rehydrate children is safe and that there are no significant differences in incidences of hyponatremia, hypernatremia, mean duration of diarrhea, weight gain, or total fluid intake if compared with ivt. in terms of outcomes, ort was associated with a higher risk of rehydration failure, while babies treated with ivt had a significantly longer stay in hospital and a higher risk of phlebitis, but no statistically significant differences were seen. 124 the main reason for this failure is that ors neither reduces the frequency of bowel movements and fluid loss nor shortens the duration of illness; moreover, the unpalatability of regular ors (strong salty taste) also decreases this acceptance. however, the most important aspect of treatment of gastroenteritis is the water and electrolyte balance. it must be adjusted according to serum electrolytes, body water content (greater the younger the child), and the water demand must be calculated on the weight of the newborn infant (table 5a and b). different ors are now commercially available (table 6 ). 125 recently, some companies have added probiotics to the saline solution to obtain a quick balance of intestinal bacterial flora. the infant should be monitored closely to check the status of nutrition and hydration. infants with moderate dehydration, suspected infected by ehec, with bloody diarrhea, or systemic symptoms should be hospitalized. these newborns are at high risk of secondary complications. during ort, milk-feeding is often temporarily suspended. among all the oral solutions, the ideal one has a low osmolarity (210-250 mosm/l) and a sodium content of 50-60 mmol/l to avoid high levels of serum sodium. the solution should be administered frequently and in small amounts to prevent vomiting. initial oral rehydration is 50-100 ml/kg in the first 4 hours. 126 also consider giving the ors via a nasogastric tube if patients are unable to drink it or if they vomit persistently and to monitor them by regular clinical assessment. in cases of failure of oral rehydration, it is necessary to establish an appropriate parenteral rehydration fluid and electrolyte solutions (table 7) . 127 pediatric presentations of racecadotril were first authorized in france in 1999, and today it is approved and widely used in seven european countries (france, spain, italy, portugal, greece, bulgaria, and romania) and outside europe. 128 this antisecretory drug is a peripherally acting enkephalinase inhibitor that reduces intestinal water and electrolyte hypersecretion acting on the enkephalins (neurotransmitters of the gastrointestinal tract) through the selective stimulation of delta receptors inhibit adenylate cyclase activity by reducing the intracellular concentration of camp, thus reducing the secretion of water and electrolyte in the intestinal lumen. the result is a reduction of water and electrolyte secretion without changes in intestinal motility. moreover, the action of racecadotril takes place only when there is a hypersecretion and has no effect on the activity secretory baseline. new data have reconfirmed that racecadotril is an effective adjunctive therapy to oral rehydration in watery diarrhea. 1 a recent individual patient data meta-analysis 129 assessed the efficacy of the use of racecadotril as an adjunct to ors compared with ors alone or with placebo. raw data from nine rcts involving 1348 children aged 1 month to 15 years with age were available for the analysis. two trials compared the effect of racecadotril with placebo 130, 131 with no treatment (two rcts), or with kaolin-pectin (two rcts). compared with placebo, racecadotril significantly reduced the duration of diarrhea after inclusion. almost two times more patients recovered at any time in the racecadotril group vs the placebo group (p , 0.001). there were no interactions between treatment and dehydration, rotavirus infection, type of study (outpatient/inpatient), or country. in the studies evaluating inpatients, the ratio of mean stool output racecadotril/placebo was reduced (p , 0.001). in outpatient studies, the number of diarrheal stools was lower in the racecadotril group (p , 0.001). in the responder analysis (defined as a duration of diarrhea of less than 2 days), the proportion of responders was significantly higher in the racecadotril group compared with the placebo group. by adjusting for dehydration and rotavirus, the absolute risk difference was 24.7% (95% confidence interval 19.8-29.7), and the associated number needed to treat was four. the secondary need for care in outpatients was significantly in favor of racecadotril in two studies. also, the need for ivt was lower in the racecadotril group compared with the placebo group. there was no difference in the incidence of adverse events between the groups. the results of this recent meta-analysis support the use of racecadotril as an adjunct to ors for the management of age in children. in addition, the safety of racecadotril in children has been demonstrated in clinical studies, including a large pre-and postaccess study showing that racecadotril has a favorable adverse-event profile in children. [128] [129] [130] despite racecadotril's proven safety and efficacy in treating acute watery diarrhea, its cost-effectiveness for infants and children has not yet been determined in europe. 128 the uk model highlights the potential savings arising from reduction in diarrhea duration and avoidance of reconsultation and referral rates in children with diarrhea. 128 children presenting with age often have high levels of vomiting that can interfere with the oral rehydration process, which could limit the success of the oral therapy. ondansetron is widely used in the pediatric emergency department for vomiting and age; it can help with the successful delivery of ort, thereby reducing the need to treat with ivt. a recent study evaluated the spectrum of diagnoses for which ondansetron is used in the pediatric emergency room. medical records of patients 3 months to 18 years of age given ondansetron for 2 years were retrospectively reviewed. patients without a primary discharge diagnosis of vomiting or gastroenteritis were defined as non-gastroenteritis, and they were compared to the gastroenteritis group. the non-gastroenteritis group includes 38% of the subjects, and they were older (8.3 vs 4.3 years) than the gastroenteritis patients. the most common primary diagnoses for non-gastroenteritis discharged patients were fever (15%), abdominal pain/ tenderness (13%), head injury/concussion (7%), pharyngitis (6%), viral infection (6%), migraine variants (5%), and otitis media (5%). although ondansetron is a widely accepted treatment for gastroenteritis submit your manuscript | www.dovepress.com in children -62% of total use -this study identifies a broader spectrum of primary diagnoses for which ondansetron is being used. 132 another study used rcts comparing antiemetics with placebo or no treatment in children and adolescents under the age of 18 years, for vomiting due to gastroenteritis. the proportion of patients with cessation of vomiting in 24 hours was 58% with intravenous ondansetron, 17% placebo, and 33% in the metoclopramide group (p = 0.039). in this case, the authors' conclusions were that oral ondansetron increased the proportion of patients who had ceased vomiting and reduced the number needing intravenous rehydration and so immediate hospital admissions. 1, 133 today, it is still unclear if in spite of an improvement in the vomiting, ondansetron worsens diarrhea. some trials report a statistically significant increase in its frequency as an adverse event. in cochrane reviews, diarrhea was reported as a side effect in four of the five ondansetron studies. [133] [134] [135] according to who, of the antiemetics available, those with the greatest evidence of efficacy in the prevention of nausea and vomiting (particularly in the treatment of postsurgery nausea and vomiting) were ondansetron and dexamethasone, ondansetron as first-line treatment with the addition of dexamethasone as required. 136 zinc is an important trace element, as over 300 enzymes require zinc for their activation and nearly 2000 transcription factors require zinc for gene expression. zinc is essential for epithelial barrier integrity, tissue repair, cell-mediated immunity, and immune function. zinc as an antioxidant and antiinflammatory agent is effective in gastrointestinal structure and function. 137 diarrhea is associated with significant zinc loss, and the use of zinc supplements can reduce the duration and severity of diarrhea in children. in areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged 6 months or more. the current evidence does not support the use of zinc supplementation in children below 6 months of age. 138 the who has recommended zinc supplementation in children with gastroenteritis. supplements should be started at the beginning of the symptoms. recommended doses and duration: • for children less than 6 months of age, 10 mg daily for 10 days • for children from 6 months to 5 years of age, 20 mg daily for 10 days. this therapy decreases the severity and reduces the number of episodes of diarrhea occurring within 2-3 months following the intake of zinc. 139 the physiological composition of intestinal microflora is essential to maintain an appropriate balance of microbiota and the intestinal barrier. probiotics, also defined as food supplements, improve the intestinal microbial balance of the host, have beneficial effects on health, prevent outbreaks of community-acquired diarrhea, reduce colonization of infants with pathogenic microorganisms, and reduce the duration and severity of diarrheal infections, balancing the intestinal ecosystem. in large clinical trials, lactobacillus reuteri, lgg, and saccharomyces boulardii have shown the best therapeutic effects (reducing mean duration and frequency of watery diarrhea and number of watery stools per day, and improving stool's consistency). [140] [141] [142] particularly, a recent randomized double blind study carried out in three italian pediatric centers showed that l. reuteri dsm 17938, taken together with a standard ors, significantly reduced the duration of watery diarrhea compared with placebo (2.1 ± 1.7 days vs 3.3 ± 2.1 days, p , 0.03). on days two and three of treatment, watery diarrhea persisted in 82% and 74% of the placebo and 55% and 45% of the l. reuteri recipients, respectively (p , 0.01, p , 0.03). moreover, children receiving l. reuteri dsm 17938 had a significantly lower relapse rate of diarrhea (15% vs 42%, p , 0.03). 143 the european society of gastroenterology, hepatology, and nutrition and the national institute for health and clinical excellence have suggested the use of probiotic strains with proven efficacy and in appropriate doses for the management of children with acute gastroenteritis as an adjunct to rehydration therapy. 144, 145 probiotics and symbiotics are of interest as they elicit healthpromoting properties to the host, release various soluble low-molecular-weight molecules of different nature (surface and exogenous proteins, peptides, amines, lectins, sirtuines, nucleases, other enzymes, bacteriocines, fatty and amino acids, lactones, nitric oxide, etc), are able to interact with corresponding cell receptors, to reply quickly by induction of special sets of genes, to support stability of host genome and microbiome, to modulate epigenomic regulation of gene phenotypic expression, and to ensure information exchange in numerous bacterial and bacteria-host systems. all this plays an important role in the control for many physiological, biochemical, and genetic functions in supporting host health. recently, probiotic l. reuteri strain atcc pta 6475 demonstrated the ability to potently suppress human tumor necrosis-factor production by lipopolysaccharide-activated monocytes and primary monocyte-derived macrophages from children with crohn's disease: the primary mechanism of probiotic-mediated immunomodulation is transcriptional regulation. 146 other researchers have confirmed these results, and it has been shown that l. reuteri produce biologically active small compounds, previously unknown, that can modulate host mucosal immunity. the identification of bacterial bioactive metabolites and their corresponding mechanisms of action with respect to immunomodulation may lead to improved anti-inflammatory strategies for chronic immunomediated diseases. 147 antibiotic therapy bacteria most cases of age in children are viral, self-limited, and need only supportive treatment. antibacterial therapy serves as an adjunct, to shorten the clinical course, eradicate causative organisms, reduce transmission, and prevent invasive comsubmit your manuscript | www.dovepress.com dovepress dovepress plications. selection of antibacterials to use in acute bacterial gastroenteritis is based on clinical diagnosis of the likely pathogen prior to definitive laboratory results. antibacterial therapy should be restricted to specific bacterial pathogens and disease presentations. in general, infections with shigella spp and vibrio cholera should usually be treated with antibacterials, while antibacterials are only used in severe unresponsive infections with salmonella, yersinia, aeromonas, campylobacter, plesiomonas spp, and clostridium difficile. antibacterials should be avoided in ehec infection. 148 there is no evidence of benefit for antibiotics in nontyphoidal salmonella diarrhea in otherwise healthy people. the effects in very young people, very old people, and in people with severe and extraintestinal disease are not always so clear, and a slightly higher number of adverse events are noted in people who receive antibiotic treatment for nontyphoidal salmonella diarrhea. 149 however, empiric therapy may be appropriate in the presence of a severe illness with bloody diarrhea and stool leucocytes, and particularly in patients with risk factors (ill-fed or debilitated patients), the use of systemic antibiotics has been recommended (table 8) . 148, 150 the benefits and risks of adverse drug reactions should be weighed before prescribing antibacterials. moreover, a major concern is the emergence of antibacterial-resistant strains due to the widespread use of antibacterial agents. aeromonas spp produce a β-lactamase that induces resistance to penicillin and first-generation cephalosporins. in fact, several studies have demonstrated a relatively high resistance rates for cephalothin and for trimethoprimsulfamethoxazole; low rates of resistance has been found to third generation cephalosporin (cefotaxime), to ciprofloxacin and to chloramphenicol. with high levels of resistance to many antibiotics, resistance of a. hydrophila to ciprofloxacin is still very low, which may suggest that ciprofloxacin and other quinolone class antimicrobials may be considered as potential drugs for the treatment of bacterial diarrhea caused by a. hydrophila. 21, 151, 152 for campylobacter jejuni, antibiotics are initiated in cases of febrile diarrheas, especially those believed to have moderate to severe disease. considering the increased incidence of c. jejuni and the resistance of the great majority of isolated strains to quinolones, the administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate. 153, 154 moreover, erythromycin treatment of acute c. jejuni diarrhea demonstrated antibacterial efficacy by reducing the mean number of days until first negative stool culture. 4 according to recent studies, the management of clostridium difficile infections involves three basic principles: supportive care, discontinuing the precipitating antibiotic(s), and the initiation of effective anti-c. difficile therapy. discontinuation of the offending antibiotic may be sufficient for the resolution of mild symptoms and facilitates the reconstitution of the normal enteric flora. 154 for mild-moderate c. difficile infection in children, metronidazole is the drug of choice, with efficacy similar to vancomycin. for severe infection, oral vancomycin with intravenous metronidazole is recommended. linezolid also has a potential impact, and in adults, recurrence is less frequent with fidaxomicin than with vancomycin. [155] [156] [157] [158] a vaccine against c. difficile is desirable and being developed for prevention. 159 regarding enterobacteriaceae, an antibiotic-susceptibility profile indicated that enteropathogens are generally susceptible to meropenem and ceftriaxone, followed by amikacin and ciprofloxacin. almost all enteropathogens were resistant to ampicillin and amoxicillin. 160 epec infection is primarily a disease of infants younger than 2 years of age, often contracted during travel in hot countries. in moderate-severe forms of gastroenteritis caused by epec in nurseries, the use of antibiotics such as imipenem, amikacin, gentamicin, and fluoroquinolone seem to be useful in reducing morbidity, mortality, and time of excretion, but few studies have evaluated in a systematic manner the value of antimicrobials for the management of epec infection in children. 161, 162 etec has been reported to be the most important pathogen responsible in traveler's diarrhea. eaec also plays an important role in traveler's diarrhea. pathogen-and geographic-based approaches to traveler's diarrhea treatment should be encouraged. fluoroquinolones and nonabsorbable rifaximin are the drugs of choice for travelers to high-risk areas in which e. coli is the predominant etiologic agent (latin america, the caribbean [haiti and the dominican republic], and africa), leaving azithromycin for travelers to south and southeast asia as well as patients with febrile dysenteric illnesses acquired in any region. 163 antibiotic therapy for stec is complicated. the growth of o157:h7 in the intestinal tract leads to diarrhea, and patients would presumably benefit if antibiotic treatment eliminated the bacteria. however, systemic dissemination of shiga toxin type 2 produced by the bacteria in the intestinal tract can lead to life-threatening complications, including neurological damage and hus. antibiotic treatments that induce the phage lytic cycle, resulting in increased shiga toxin production, could lead to more serious disease. recent studies suggest that normal flora can have a profound impact on shiga toxin production. subinhibitory levels of antibiotics that target dna synthesis, including ciprofloxacin and sulfamethoxazole-trimethoprim, increased shiga toxin production, while antibiotics that target the cell wall, transcription, or translation did not. so ciprofloxacin and sulfamethoxazole-trimethoprim are not appropriate for treatment of o157:h7. in contrast, azithromycin significantly reduced shiga toxin levels, even when relatively high levels of o157:h7 were recovered. 164 moreover, the eradication rate reported in stec o104:h4 infections is 86%. azithromycin might be considered a potentially effective and safe antibiotic, and may be used safely for decolonization of stec o104:h4 long-term carriage. 165 numerous outbreaks, as well as sporadic cases of stec infections and hus, have been documented worldwide. there are numerous reports on stec o157:h7 as the most common serotype associated with hus, especially in children. several reports on non-o157 stec underline their potential to cause sporadic disease as well as epidemics. during 2011, there was a large outbreak in northern germany, with a satellite outbreak in western france caused by an eaec of serotype o104:h4 expressing a phage-encoded shiga toxin 2: clinicians were confronted with a large number of mainly adult patients with hus associated with severe hemolysis and neurological complications. 166 medical centers used varying therapeutic regimens, including plasmapheresis, glucocorticoids, and the submit your manuscript | www.dovepress.com dovepress dovepress anti-c5 monoclonal antibody eculizumab, but currently there is no effective prophylaxis or treatment available for stec infections and hus. 166 the probiotic escherichia coli strain nissle 1917 (ecn) seemed to have very efficient antagonistic activity on the ehec strains of serotype o104:h4 and o157:h7, with reduced growth of pathogens. 167 the 2011 outbreak strains perfectly showed the genome plasticity and evolution of e. coli as a result of horizontal gene transfer. these strains combine the virulence mechanisms of two pathotypes (eaec and ehec), leading to an improved ability to adhere to and infect host cells. furthermore, the acquisition of mechanisms mediating increased antibiotic resistance hampered patient treatment and recovery. these strains have conserved most of the virulence factors of an eaec strain, but several mobile genetic elements were responsible for the acquisition of new functions involved in high-frequency recombination, mobilization, and transfer of genes. despite the alternative mechanisms that have evolved to colonize and adapt to new niches, e. coli strains have maintained a core genome sequence, and therefore share several components that could be useful targets for a universal vaccine against e. coli. considering the increasing antibiotic resistance present among e. coli strains, which is derived from an uncontrolled use of antibiotics, vaccination is the most promising approach to control disease. 168 helicobacter pylori is a leading cause of chronic gastritis, peptic ulcers, nonulcer dyspepsia, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. eradication of the pathogen has a failure rate of more than 30% in pediatric patients, particularly because of poor compliance, antibiotic resistance, and occurrence of side effects. 169 treatment regimens generally include a proton-pump inhibitor (lansoprazole, omeprazole, pantoprazole, rabeprazole, dexlansoprazole, or esomeprazole), which allows the tissues damaged by the infection to heal, and two antibiotics to reduce the risk of treatment failure and antibiotic resistance. treatment requires several medications for 7-14 days. in pediatric patients, gastric mucosal lesion-caused h. pylori infection is a reversible process, and the eradication of this infection not only stops the activity of the inflammatory process but also restores the mucous membranes, reduces the incidence of recurrence of gastritis and peptic ulcer disease, and can lead to prevention of malignant disease in 70%-80% of cases. 170 adjuvant therapy with probiotics has been studied in recent years. 169 in a recent randomized, placebo-controlled, double-blind study, children on h. pylori eradication therapy receiving seven strains of probiotic in addition to the standard triple regimen (omeprazole + amoxicillin + claritromicin or omeprazole + amoxycillin + furazolidon) were compared with patients on the same triple regimen receiving placebo. the findings reported a significant reduction in treatment complications and an improved therapeutic outcome: the rate of eradication was significantly higher, and children had a lower rate of nausea/vomiting and diarrhea during treatment. 168 the long-term success of h. pylori eradication interventions for preventing gastric cancer, depends on the recurrence determinants (nonadherence and demographics) that are as important as a specific antibiotic regimen. 171 despite plesiomonas shigelloides seeming to be a minor cause of bacterial enteritis, the pathogen has been implicated in gastroenteritis outbreaks in tropical regions and in cases of traveler's diarrhea. antibacterials are used only in cases of severe and unresponsive infections: the most effective are ciprofloxacin and azythromycin, and partially trimethoprimsulfamethoxazole. with salmonella spp, antibiotics are initiated in cases of febrile diarrhea, especially in case of moderate to severe disease. the administration of azithromycin empirically for acute diarrhea, when indicated, could be appropriate. 4, 153 consistent evidence from several clinical trials suggests that antibiotic treatment (ampicillin, amoxicillin, cefixime, azithromycin, cotrimoxazole) did not shorten the duration of diarrhea or lead to an earlier resolution of clinical symptoms. intramuscular ampicillin protects children against relapse and reduces the carriage of salmonella infection significantly better than placebo, oral ampicillin, or amoxicillin. 4 antibiotics are usually avoided in mild shigella illness, because mild forms of shigella dysentery are said to be self limiting, some shigella strains are resistant to antibiotics, and their use may lead to increased resistance. if necessary, in severe cases, the choice of antibiotic to use as first line against shigella dysentery should be governed by periodically updated local antibiotic sensitivity patterns of shigella isolates. other supportive and preventive measures recommended by the who should also be instituted along with antibiotics (eg, health education and hand-washing). ciprofloxacin has been recommended by the who as the drug of choice for all patients with bloody diarrhea, irrespective of their ages. 172 according to a recent cochrane review, the authors did not find robust evidence to suggest that antibiotics of a particular class are better than those belonging to a different class. trials report that at various periods of time, different antibiotics have been effective against isolates of shigella dysentery in different parts of the world. these are ampicillin, cotrimoxazole, nalidixic acid, fluoroquinolones submit your manuscript | www.dovepress.com dovepress dovepress like ciprofloxacin, pivmecillinam, ceftriaxone, and azithromycin. however, limited data from a subgroup of studies suggest that a fluoroquinolone (ciprofloxacin) would be more effective than a beta-lactam (ampicillin) in reducing diarrhea among adults, and that beta-lactams would be more effective than fluoroquinolones in reducing diarrhea among children with proven shigella dysentery. emerging drug resistance to ciprofloxacin and second-line drugs such as pivmecillinam, ceftriaxone, and azithromycin is increasingly being reported in many parts of the world, as is multiple-drug resistance. 173, 174 in india, for example, several shigella strains (s. flexneri, s. dysenteriae, s. boydii, and s. sonnei) isolated from children # 15 years of age are resistant to ampicillin, cotrimoxazole, ciprofloxacin, and nalidixic acid. alternatives include ceftriaxone and azithromycin, but ceftriaxone is an injectable drug and azithromycin has limited therapeutic benefit, as organisms easily develop resistance to it. 175 it has been noted that all shigella spp utilize a type iii secretion system to translocate bacterial proteins -invasins ipaa-d and ipgd -into host eukaryotic cells to initiate infection. because they are common to all virulent shigella spp, they seem to be ideal candidate antigens for a subunit-based broad-spectrum protective vaccine for prevention of shigellosis. 176 vibrio cholerae strains from endemic outbreaks within the last decade revealed patterns of antibiotic resistance to ampicillin, tetracycline, and trimethoprim correlated with widespread therapeutic and prophylactic administration of antibiotics. 177 treating severe cases of cholera with antibiotics is important, but the continuing spread of resistance to the most important therapeutic agents is a matter of concern, as some strains have either intermediate resistance or are resistant to ceftriaxone, ciprofloxacin, and tetracycline. 178 the most common clinical manifestation of a yersinia enterocolitica infection is a self-limited gastroenteritis that resolved spontaneously within 2 weeks. 179 y. enterocolitica usually shows in vitro susceptibility to aminoglycosides, chloramphenicol, doxycycline, cotrimoxazole, third-generation cephalosporins, carabapenems, and fluoroquinolones. 180 recently, in a case-control study conducted among children aged less than 12 years, it was found that y. enterocolitica is generally susceptible to meropenem (100%), ceftriaxone (94%), and ciprofloxacin (94%), followed by ceftazidime (88%) and amikacin (81%). almost all y. enterocolitica was resistant to ampicillin. 57 fungal fungal infections of the gastrointestinal tract are not common in children, especially in immunocompetent ones. in the neonatal period, candida infections frequently develop into systemic forms. 82 fluconazole prophylaxis in infants , 1000 g (3 mg/kg twice a week), while intravenous access is required, appears to be safe and effective in preventing invasive candida infections with or without diarrhea, while attenuating the emergence of fungal resistance. 88, 181 new echinocandines -anidulafungin, caspofungin, and micafungin, recently introduced -seem to have some advantages over fluconazole and amphotericin b, as they better meet the needs of pediatric patients, neonates, and in particular preterm infants with invasive candidiasis and/or diarrhea from candida spp infection. micafungin, a dose-dependent candidacidal agent with excellent in vitro efficacy against most candida spp, including species resistant to amphotericin b, is approved for the treatment of invasive candidiasis in children, including preterm infants aged less than 3 months. efficacy and safety were demonstrated in comparison with liposomal amphotericin b and fluconazole. the most appropriate dose in children weighing less than 40 kg is 2 mg/kg/day in the treatment of invasive candidiasis and or gastroenteritis and 1 mg/kg/day as prophylaxis. in premature infants, the most appropriate doses to achieve appropriate levels in the brain parenchyma are 7 mg/kg/day in infants weighing more than 1,000 g and 10 mg/kg/day in those weighing less than 1,000 g, respectively. micafungin has few drug-drug interactions and an acceptable safety profile thus providing a promising drug in the prophylactic and therapeutic management of invasive candidiasis. micafungin has few drug-drug interactions, and an acceptable safety profile. [182] [183] [184] data from randomized trials conducted in pediatric and adult patients showed through a subgroup analysis that both caspofungin and micafungin are effective and well tolerated also in neonates. 185, 186 parasitic -protozoan the major causes of diarrhea worldwide in children are cryptosporidium parvum, giardia lamblia, and entamoeba histolytica: "the neglected parasitic disease." cryptosporidium is a diarrheagenic protozoan pathogen for children, and immunosuppressed individuals are disproportionately affected. until a few years ago, the most commonly used treatments, only partially effective, were paromomycin and azithromycin. recent investigations have focused on nitazoxanide, as it significantly shortens the duration of diarrhea and decreases mortality in malnourished children. nitazoxanide is not effective without an appropriate immune response, as in aids patients. 187, 188 giardia lamblia is a diarrheagenic protozoan pathogen most commonly treated with metronidazole (mtz) or tinidazole submit your manuscript | www.dovepress.com dovepress dovepress but failures occur in 10%-20% of cases. albendazole may be of similar effectiveness to metronidazole, may have fewer side effects, and has the advantage of a simplified regimen. nitazoxanide is a viable therapeutic option as an effective alternative to mtz in reducing the duration of diarrhea. 61, 188, 189 auranofin, a gold complex classified by the who as an antirheumatic agent, has been revealed to be active against multiple mtz-resistant strains blocking a critical enzyme involved in maintaining normal protein function. these results indicate that auranofin could be developed as an antigiardial drug, particularly against mtz-resistant strains. 190 entamoeba histolytica amebiasis is the fourth-leading cause of death and the third-leading cause of morbidity due to protozoan infections worldwide. in children, effective drugs for diarrhea are mtz and other nitroimidazoles. however, eradication of e. histolytica infection after completion of mtz requires additional therapy with luminal amebicides, such as paramomycin. nitazoxanide is a recent therapeutic advance, due to its action against luminal and invasive parasite forms. 191 nitazoxanide-treated patients had statistically shorter durations of diarrheal illness. auranofin could represent a promising therapy for amebiasis. 187 parasitic -helminths nematodes strongyloides stercoralis and trichuris trichiura are causes of diarrhea. strongyloides stercoralis can penetrate host skin and parasitize human intestines, leading to burning pain, tissue damage, ulcers, edema and obstruction of the intestinal tract, and diarrhea, as well as loss of peristaltic contractions. ivermectin is the first-choice therapy because of its higher tolerance, and albendazole is the second-choice therapy. 61, 192 trichuris trichiura is chiefly a tropical infection, and children are especially vulnerable to infection due to their high exposure risk. light infestations (, 100 worms) are frequently asymptomatic, but heavy infestations may cause mechanical or inflammatory damage to the mucosa, abdominal pain, profuse or chronic diarrhea, and bloody diarrhea. mebendazole seems to be the first-choice therapy and albendazole the second-choice therapy, while nitazoxanide shows no effect. an albendazole and nitazoxanide-albendazole combination showed only a minimal effect. there is a need to develop new anthelmintics against trichuriasis. 193 age remains a major problem in children and still represents one of the leading causes of illness costs and of deaths, as an estimated 2.5 million gastroenteritis deaths occur each year in children less than 5 years of age throughout the world, especially in resource-constrained countries. in rich countries, transmission occurs much more frequently from contaminated food compared to direct person-to-person contact, except for enteric viruses, which can also be transmitted by aerosol formation after vomiting. most cases of age in children are viral, self-limited, and need only supportive treatment. rehydration (oral or intravenous) with an appropriate fluid-and-electrolyte balance, with close attention to nutrition, remains central to therapy: this may turn into an additional benefit in limiting hospitalizations. intestinal infections often require drugs such as antiemetics, antidiarrheal agents, and probiotics that may deeply change the impact, severity, and duration of acute diarrhea. in cases of severe infectious diarrhea with a prolonged course, signs of inflammation, bloody stool, immunosuppression, and comorbidity, and in suspected outbreaks, fecal microbial analysis, should always be performed, and a specific therapy should be considered if indicated to shorten the clinical course, eradicate causative organisms, reduce transmission, and prevent invasive complications. selection of antibacterials to use in acute bacterial gastroenteritis is based on clinical diagnosis of the likely pathogen and on definitive laboratory results. based on epidemiological data and after collecting organic materials for etiological diagnosis (often a single fecal sample studied for etiologic agents is the customary way to make an etiologic diagnosis), an initial empiric therapy may be appropriate in case of a severe illness, particularly in infancy and the immunocompromised. in case of suspected ehec serotype o157 and eaec serotype o104:h4 (but also of shigella dysenteriae serotype 1), as it is estimated that 5%-8% of infected individuals will develop hus following stec infection with e. coli o157:h7 the most commonly involved serotype, antibiotics should be prescribed according to more recent guidelines. moreover, a major concern is the emergence of antibacterialresistant strains due to the widespread use of antibacterial agents: a continuous monitoring of antibiotic resistance in diarrhea-related bacterial pathogens is recommended. the benefits and risks of adverse drug reactions should be weighed before prescribing any kind of drug. the authors report no conflicts of interest in this work. review article: the management of acute gastroenteritis in children the management of acute diarrhea in children in developed and developing areas: from evidence base to clinical practice national collaborating centre for women's and children's health. diarrhea and vomiting caused by gastroenteritis: diagnosis, assessment and management in children younger than 5 years acute gastroenteritis: from guidelines to real life european society for paediatric gastroenterology, hepatology, and nutrition/european society for paediatric infectious diseases evidence-based guidelines for the management of acute gastroenteritis in children in europe hospital-based surveillance to estimate the burden of rotavirus gastroenteritis among european children younger than 5 years of age rotavirus and not age determines gastroenteritis severity in children: a hospital-based 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hydrophilaassociated diarrhea among children younger than 2 years in rural egyptian community acute gastroenteritis in children the role of campylobacter jejuni cytolethal distending toxin in gastroenteritis: toxin detection, antibody production, and clinical outcome the epidemiology of guillain-barré syndrome worldwide. a systematic literature review guillain-barré syndrome and campylobacter infection quantifying the association between campylobacter infection and guillain-barré syndrome: a systematic review antibiotic associated diarrhea in children increase in clostridium difficilerelated hospitalizations among infants in the united states epidemiological features of clostridium difficile-associated disease among inpatients at children's hospitals in the united states rapid stool-based diagnosis of clostridium difficile infection by real-time pcr in a children's hospital galveston (tx): university of texas medical branch at galveston pyrosequencing-based molecular monitoring of the 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pylori and risk of gastroenteritis helicobacter pylori in gambian children with chronic diarrhoea and malnutrition impact of infection by helicobacter pylori on the risk and severity of endemic cholera association between helicobacter pylori infection and increased risk of typhoid fever acute helicobacter pylori infection is followed by an increase in diarrheal disease among peruvian children prospective study of the incidence of diarrheal disease and helicobacter pylori infection among children in an orphanage in thailand antibacterial peptide from h. pylori inverse relationship between gastric colonization of helicobacter pylori and diarrheal illnesses in children: results of a population-based cross-sectional study the gastric biology of helicobacter pylori gastrointestinal symptoms and helicobacter pylori infection in school-age children residing in porto torres epidemiological studies on proteeae isolates from clinical specimens in the laquintinie hospital in douala, cameroon pseudomonas aeruginosa in a neonatal intensive care unit: molecular epidemiology and infection control measures infectious gastroenteritis. from: neonatal infectious diseases study group of the italian society of neonatology. manual of neonatal infectious diseases live attenuated shigella dysenteriae type 1 vaccine strains overexpressing shiga toxin b subunit yersinia enterocolitica infection among children aged less than 12 years: a case-control study the pathogenic potential of yersinia enterocolitica 1a viral gastroenteritis in children diagnosis and treatment of acute or persistent diarrhea infections and pediatric pharmacotheray viral infections of the gastrointestinal tract epidemiological and clinical characteristics of pediatric gastroenteritis associated with new viral agents worldwide emergence of multiple clades of enterovirus 68 diversity in the enteric viruses detected in outbreaks of gastroenteritis from mumbai, western india excretion of enterovirus 71 in persons infected with hand, foot and mouth disease pleconaril revisited: clinical course of chronic enteroviral meningoencephalitis after treatment correlates with in vitro susceptibility immunogenicity and safety of an enterovirus 71 vaccine in healthy chinese children and infants: a randomised, double-blind, placebo-controlled phase 2 clinical trial viral load of human bocavirus-1 in stools from children with viral diarrhoea in paraguay detection of human coronaviruses in children with acute gastroenteritis prevalence of norwalk-like virus infections in cases of viral gastroenteritis among children in osaka city epidemiological aspects of human rotavirus infection in children hospitalized with acute gastroenteritis in an area of northern italy human caliciviruses and pediatric gastroenteritis outbreak of gastroenteritis due to sapovirus human sapovirus classification based on complete capsid nucleotide sequences detection and follow-up of torque teno midi virus ("small anelloviruses") in nasopharyngeal aspirates and three other human body fluids in children isolation of multiple tt virus genotypes from spleen biopsy tissue from a hodgkin's disease patient: genome reorganization and diversity in the hypervariable region analysis of the entire genomes of thirteen tt virus variants classifiable into the fourth and fifth genetic groups, isolated from viremic infants torque teno virus infection in the pig and its potential role as a model of human infection an unusual case report of small bowel candida overgrowth as a cause of diarrhea and review of the literature invasive candida enteritis of the newborn prevalence of candida colonization in preterm newborns and vlbw in neonatal intensive care unit: role of maternal colonization as a risk factor in transmission of disease candida colonization in the nursery antifungal therapy for neonatal candidiasis safety and pharmacokinetics of repeat-dose micafungin in young infants pediatric antifungal therapy. part ii: neonatal infections neonatal fungal infections: when to treat? getting to zero": preventing invasive candida infections and eliminating infection-related mortality and morbidity in extremely preterm infants strategies for the prevention of neonatal candidiasis dysfunctions at human intestinal barrier by water-borne protozoan parasites: lessons from cultured human fully-differentiated colon cancer cell lines investigation of cryptosporidium spp. antigen by elisa method in stool specimens obtained from patients with diarrhea giardia intestinalis giardia lamblia: a major parasitic cause of childhood diarrhoea in patients attending a district hospital in ghana prevalence and species distribution of e. histolytica and e. dispar in the venda region prospective case-control study of the association between common enteric protozoal parasites and diarrhea in bangladesh symptomatic chronic strongyloidiasis in children following treatment for solid organ malignancies: case reports and literature review clostridium difficile infection: essential information for nurses rotavirus infection in a tertiary hospital: laboratory diagnosis and impact of immunization on pediatric hospitalization prevalence of providencia strains among children with diarrhea in japan prevalence of diarrheagenic escherichia coli virulence genes in the feces of slaughtered cattle, chickens, and pigs in burkina faso molecular analysis of typical and atypical enteropathogenic escherichia coli (epec) isolated from children with diarrhoea guidance on infection control in schools and other childcare settings preventing person-to-person spread following gastrointestinal infections: guidelines for public health physicians and environmental health officers association between pentavalent rotavirus vaccine and severe rotavirus diarrhoea among children in nicaragua uptake, impact, and effectiveness of rotavirus vaccination in the united states: review of the first 3 years of postlicensure data the effect of rotavirus vaccine on diarrhea mortality european society for paediatric infectious diseases/european society for paediatric gastroenterology, hepatology, and nutrition evidence-based recommendations for rotavirus vaccination in europe prevention of rotavirus gastroenteritis among infants and children. recommendations of the advisory committee on immunization practices (acip) effect on clinical outcome of breast feeding during acute diarrhoea management of infectious diarrhoea breast milk as the gold standard for protective nutrients breastfeeding protects against acute gastroenteritis due to rotavirus in infants protective effect of exclusive breastfeeding against infections during infancy: a prospective study gastroenteric pathology and probiotics: from myth to scientific evidence. current aspects probiotics: from the ancient wisdom to the actual therapeutical and nutraceutical perspective probiotics for treating acute infectious diarrhoea prophylactic probiotics to prevent death and nosocomial infection in preterm infants world health organization. first steps for managing an outbreak of acute diarrhea. geneva: who protocolo de vigilancia epidemiológica de cólera. lima: oficina general de epidemiologia reduced osmolarity oral rehydration solution for treating cholera decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions replacement of water and electrolyte losses in cholera by an oral glucose-electrolyte solution randomized controlled trial comparing oral and intravenous rehydration therapy in children with diarrhea oral versus intravenous rehydration for treating dehydration due to gastroenteritis in children dehydration and rehydration. state of the art and therapeutic interventions giardia intestinalis la gastroenterite acuta: reidratazione, alimentazione e terapia al pronto soccorso evaluating the cost utility of racecadotril for the treatment of acute watery diarrhea in children: the rawd model racecadotril for childhood gastroenteritis: an individual patient data meta-analysis racecadotril in the treatment of acute watery diarrhea in children efficacy and tolerability of racecadotril in acute diarrhea in children ondansetron use in the pediatric emergency room for diagnoses other than acute gastroenteritis antiemetics for reducing vomiting related to acute gastroenteritis in children and adolescents oral ondansetron for gastroenteritis in a pediatric emergency department a randomized clinical trial comparing oral ondansetron with placebo in children with vomiting from acute gastroenteritis unedited draft report of the 17th expert committee on the selection and use of essential medicines. geneva: who discovery of human zinc deficiency: 50 years later oral zinc for treating diarrhoea in children zinc and diarrhea in children under 5 years: who recommendations implemented in switzerland probiotics for treating infectious diarrhoea probiotics and prebiotics in pediatrics: where are we now? meta-analysis: saccharomyces boulardii for treating acute diarrhoea in children randomised clinical trial: lactobacillus reuteri dsm 17938 vs placebo in children with acute diarrhoea -a double-blind study health impact of probiotics -vision and opportunities probiotics for children with diarrhea: an update probiotic lactobacillus reuteri suppress proinflammatory cytokines via c-jun histamine derived from probiotic lactobacillus reuteri suppresses tnf via modulation of pka and erk signaling acute gastroenteritis in children: what role for antibacterials? antimicrobials for treating symptomatic non-typhoidal salmonella infection the patient presenting with acute dysentery -a systematic review infections following the application of leeches: two case reports and review of the literature the role of leech water sampling in choice of prophylactic antibiotics in medical leech therapy. microsurgery empiric antimicrobial therapy and infectious diarrhea. do we need local guidelines? resistance mechanisms in campylobacter jejuni clostridium difficile: an emerging pathogen in children potential protective role of linezolid against clostridium difficile infection fidaxomicin for the treatment of clostridium difficile infections clostridium difficile infection: new insights into management clostridium difficile: development of a novel candidate vaccine bacterial enteropathogens and risk factors associated with childhood diarrhea enteropathogenic escherichia coli associated with diarrhea in children in cairo enteropathogenic escherichia coli infection in children new developments in traveler's diarrhea different classes of antibiotics differentially influence shiga toxin production association between azithromycin therapy and duration of bacterial shedding among patients with shiga toxin-producing enteroaggregative escherichia coli o104:h4 lessons learned from outbreaks of shiga toxin producing escherichia coli antagonistic effects of probiotic escherichia coli nissle 1917 on ehec strains of serotype o104:h4 and o157:h7 escherichia coli: great diversity around a common core probiotics for the treatment of pediatric helicobacter pylori infection: a randomized double blind clinical trial childhood and coress model of carcinogenesis risk of recurrent helicobacter pylori infection 1 year after initial eradication therapy in 7 latin american communities world health organization. guidelines for the control of shigellosis, including the epidemics which were caused by shigella dysenteriae type 1. geneva: who antibiotic therapy for shigella dysentery a multi centre study of shigella diarrhoea in six asian countries: disease burden, clinical manifestations, and microbiology the recent trends of shigellosis: a jipmer perspective broadly protective shigella vaccine based on type iii secretion apparatus proteins cholera epidemiology in nigeria: an overview increasing antimicrobial resistance of vibrio cholerae oi biotype e1 tor strains isolated in a tertiary-care centre in india symptoms and sources of yersinia enterocolitica-infection: a case-control study clinical characteristics and response to prophylactic fluconazole of preterm vlbw neonates with baseline and acquired fungal colonisation in nicu: data from a multicentre rct why might micafungin be the drug of choice in pediatric patients? population pharmacokinetics of micafungin in neonates and young infants scientific evidence supporting the use of micafungin in the treatment of invasive candidiasis echinocandins for the nursery: an update micafungin: a review of its use in the prophylaxis and treatment of invasive candida infections reprofiled drug targets ancient protozoans: drug discovery for parasitic diarrheal diseases nitazoxanide for the empiric treatment of pediatric infectious diarrhea drugs for treating giardiasis a reprofiled drug, auranofin, is effective against metronidazole-resistant giardia lamblia current pharmacotherapy of amebiasis, advances in new drugs, and design of a vaccine a research agenda for helminth diseases of humans: intervention for control and elimination efficacy and safety of nitazoxanide, albendazole, and nitazoxanide-albendazole against trichuris trichiura infection: a randomized controlled trial submit your manuscript here: http://www.dovepress.com/infection-and-drug-resistance-journal infection and drug resistance is an international, peer-reviewed openaccess journal that focuses on the optimal treatment of infection (bacterial, fungal and viral) and the development and institution of preventive strategies to minimize the development and spread of resistance. the journal is specifically concerned with the epidemiology of antibiotic resistance and the mechanisms of resistance development and diffusion in both hospitals and the community. the manuscript management system is completely online and includes a very quick and fair peerreview system, which is all easy to use. visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors. key: cord-253799-lzbeaf2p authors: garcía‐salido, alberto title: sars‐cov‐2 children transmission: the evidence is that today we do not have enough evidence date: 2020-06-07 journal: acta paediatr doi: 10.1111/apa.15396 sha: doc_id: 253799 cord_uid: lzbeaf2p i have read with interest the review by ludvigsson on the role of children as transmitters of the new coronavirus (sars‐cov‐2). an in‐depth review of the current literature focused on 40 published articles and 7 non‐peer reviewed papers(1). all the papers included have been done under lockdown conditions. as a consequence, we should not ignore a main bias of this review(1). the main conclusion we can draw now is that under confined conditions, children are not the main drivers of the covid‐19 pandemic. and “confined" is not a normal situation. dear editors, i have read with interest the review by ludvigsson on the role of children as transmitters of the new coronavirus (sars-cov-2). an in-depth review of the current literature focused on 40 published articles and 7 non-peer reviewed papers 1 . all the papers included have been done under lockdown conditions. as a consequence, we should not ignore a main bias of this review 1 . the main conclusion we can draw now is that under confined conditions, children are not the main drivers of the covid-19 pandemic. and "confined" is not a normal situation. in the review, we can read a section called "real world evidence". in this section only two papers are included 1 . even in the context of our need for knowledge, we cannot ignore the fact that conclusions drawn from partial knowledge can only be partial. there is also described the sweden experience and we are obliged to check the external validity of what we state. schooling, the teacher-pupil ratio and physical spaces will be of great importance in controlling transmission. and they differ between countries and cultures. for example in my country, spain, this will be probably different from the author's. what will happen with multiple social and structural conditions? we don't know, we can only guess. in turn, one of the author's fundamental assertions is that the opening of schools would unlikely to modify the mortality of the fragile population. i understand this point, but another way of approaching this would be to say that certain mortality must be assumed if the schools are reopened under unsuitable conditions. on this fact, studies like the done by zhang et al. estimate that closure of schools would delay the epidemic peak by 40-60% 2 . this effect could be fundamental to avoid the collapse of health care, and consequently, to reduce morbidity and mortality especially in at-risk populations. children are suffering side effects from this pandemic on both education and clinical care 3 . in the latter, the drop in vaccination rates is a cause for concern. the schools reopening must be done in compliance with public health measures 1, 3 . in turn, it should be done assuming that the knowledge we have today about the this article is protected by copyright. all rights reserved transmission of sars-cov-2 among children or from children to adults is scarce. as the author states "it is highly likely that children can transmit the sars-cov-2 virus, which causes covid-19, and even asymptomatic children can have viral loads" 1 . we can't say that they don't have a role, but at the same time, announcing the opposite. hesitation is logical. children will return to school, and data of their role on transmission will emerge from that gradual return. i do not mean that i think that they are effective transmitters, i am only stating that based on the current evidence we are unable to make a firm statement one way or the other. they have not been the "main drivers" in this first wave, but we must adjust to the evidence to avoid be drowning by the second. bibliography. children are unlikely to be the main drivers of the covid-19 pandemic -a systematic review changes in contact patterns shape the dynamics of the covid-19 outbreak in china covid-19: delaying school reopening by two weeks would halve risks to children, says isage accepted article key: cord-261424-t0yulofo authors: feltman, dalia m.; moore, gregory p.; beck, andrew f.; siffermann, emily; bellieni, carlo; lantos, john title: seeking normalcy as the curve flattens: ethical considerations for pediatricians managing collateral damage of covid-19 date: 2020-06-26 journal: j pediatr doi: 10.1016/j.jpeds.2020.06.067 sha: doc_id: 261424 cord_uid: t0yulofo nan fearful. uncertain. overwhelmed. committed. hopeful. pediatricians around the world have cycled through these emotions when considering the health and safety of patients and families during this coronavirus disease 2019 (covid19) pandemic. we worry about the direct medical effects of covid-19. we also worry about the ancillary effects of the lockdowns, stayat-home orders, closed clinics, schools, and daycare centers, and newly unemployed parents on the well-being of children. we will focuse on those concerns. we believe that responding to these ancillary effects of covid-19 will be a bigger challenge for pediatricians than the clinical care of children with covid-19. these challenges will be with us for the foreseeable future. the covid-19 pandemic presents quickly-evolving ethical challenges for pediatricians. some of the issues are not specific to covid-19. they include moral distress, reprioritizing clinical goals, responding to unique vulnerabilities of children, addressing uncertainty in shared decision-making, and considering how and when to proceed with pediatric clinical research. covid-19 puts a new spin on all of them. it also offers opportunities to rethink solutions. how we respond will matter. we must use the challenges of this pandemic as opportunities to improve the health of our children now and even after covid-19 recedes. this pandemic highlights long-standing deficiencies and inefficiencies in our current system of child health care. as advocates for children, pediatricians are in a unique position to redesign the system in a way that prioritizes children and families, addresses the social determinants of health, reduces inequalities and health disparities, and ensures ethical research on treatment and prevention of covid-19. moral distress and utilitarian prioritization in the throes of crisis 3 the covid-19 pandemic has created experiences of moral distress in our lives at home, in the clinical setting, and as citizens in our communities. 1 moral distress is the psychological discomfort experienced when we feel that we must act in ways that violate our own deep moral commitments. as clinicians and as members of communities in this pandemic, our actions have initially and rightfully centered on crisis-mode utilitarian goals of saving the most lives. however, actions to conserve the medical resources that prevent iatrogenic spread of infection and protect health professionals and other patients have shifted priorities away from the best practices that are part of our usual care for children. we are committed to holistic and familycentered care. but the conditions of the pandemic constrain us; we cannot do what we know is best. therein lies our distress. we all prioritize goals of care within resource constraints. however, pandemic-era care is different in two ways. first, prioritization in the midst of a pandemic considers foremost the overall needs of groups of people instead of our usual prioritization of the individual person in front of us. second, the limited resources we must protect include us as healthcare workers. we are uncomfortable delaying a reintubation to don personal protective equipment (ppe) even though we know we must protect ourselves so that we can continue to treat our patients. we similarly worry about the patients we do not see because of decreased staffing levels in our clinics, or because families opt to reasonably defer medical care because of stay-at-home orders or fear of getting infected in a clinic. in our communities, we are conflicted in our inclinations to "reopen" or to remain "sheltered." we know lives have been saved by nonpharmaceutical interventions like transmission prevention measures. that said, we also recognize that many people have suffered because of school, business, and government shut-downs. there are clearly trade-offs. if everyone stayed home all the time, no one would become infected with covid-19. but our children would not be educated, our stores would not be stocked, and our economy would grind to a halt. we seek the optimum balance between the risks of infection and the risks of perfect protection. our hearts ache for all children, but especially for those who have situational vulnerabilities that put them at greatest risk of adverse effects both from illness and from a shutdown society. situational vulnerabilities are conditions such as poverty or family instability that can worsen how individuals experience problems such as the current pandemic. these vulnerabilities deserve special ethical consideration because they often exist due to societal injustices. 2 whether children are our patients or are outside of our immediate communities, we feel a sense of responsibility and with that, a deep uncertainty and powerlessness. we may not always know the best course of action, but we must help find that balance. we will gradually move out of a crisis mode; we can begin to shape a new normal right now. as we begin to imagine that new normal, we consider three domains that require attention to help children to stay well: medical, mental health, and educational needs. during the covid-19 crisis, many hospitals and clinics have limited procedures, numbers of staff, and patients, cancelling elective surgeries 3 and nonessential pediatric visits. although this was necessary to reduce the risk of inadvertently spreading the virus and to conserve ppe, these practices have had unintended negative consequences. children have experienced delays in clinical care. immunization rates have fallen. 4 children are at risk for health problems that are not directly related to covid-19 but that are a result of our necessary response to the pandemic. pediatricians and pediatric subspecialists are now required to triage patient procedures and visits, raising the question of what, exactly, is "elective." some surgical procedures that can be delayed without an immediate risk to the life or health of the patient may still have adverse consequences from waiting, as in the case of pyeloplasty 5 and adolescent herniorrhaphy. 6, 7 lengthy delays already exist for families trying to gain access to pediatric subspecialty appointments, such as for children with cleft palate. 8 such delays increase anxiety and stress for families 9 and could result in a worsening of the patient's clinical condition. 10 temporary cessation of home health services for children with chronic medical conditions may increase the occurrence of acute-on-chronic complications. infants experiencing postponement of necessary early intensive developmental supports (e.g., speech and language therapy, occupational therapy, physical therapy) may lose a benefit proven to support their development, 11 possibly lengthening time to advancement and/or stunting their ability to reach their true potential. to overcome covid-19-mediated effects on medical care, primary care pediatricians, and pediatric subspecialists can respond with several measures. outreach, in order to check-in on patients and families regarding both their physical and mental health, will re-establish connections, nurture trust, and allow personalized counseling about needed services. 12 virtual in-home physical, occupational, or speech therapies can keep children on track. primary care pediatricians, pediatric subspecialists, and pediatric surgeons must collaborate and carefully monitor all patients whose treatment was postponed to ensure that they are not getting worse. 13, 14 communicating with patients on processes to make clinic visits safe may reassure anxious parents. all pediatricians should notify families about the options to connect with their care providers whether in person or via telephone, email, or telemedicine. 15, 16 mobile clinics to reach children in underserved areas could decrease lags in immunizations. 17 sometimes, home visits with adequate ppe might be necessary. finally, in looking further ahead, pediatricians can collaborate with allied healthcare professionals 18 to facilitate "catch up" on the inevitable wait lists for those providers who have been limited to providing emergency services. 19 alongside medical needs, pediatricians understand the relevance of social factors to their patients' health. 20, 21 medical providers must acknowledge and address the needs of children whose situational vulnerabilities put them at greatest risks of harm during this pandemic. 22 such a consideration is critical to prevent further widening, and to ideally narrow, existing health and socioeconomic disparities. the pandemic has already drastically altered fundamental disparities in the social determinants of health, defined by the world health organization as "conditions in which people are born, grow, work, live, and age, and the wider set of forces and systems shaping the conditions of daily life." 23 there are ways that pediatricians can respond to mitigate the harmful effects of these changes, but we will need to be creative and proactive. we can leverage existing partnerships or forge new ones to best meet the needs of our patients and their families. for example, medical-legal partnerships (mlps) are local links between medical professionals and legal advocates. they can protect low-income families' legal rights that may be at risk in the current pandemic. they can help guard against eviction and utility shut-offs; 24 help families navigate public benefit sign-ups, and ensure access to critical educational resources. other clinical-community partnerships (eg, with food banks) may have a similar, bold effect. 25, 26 pediatricians may refer families to key social service agencies within their community that are responding in earnest to covid-19's harmful effects (e.g., united way 211, a free resource that can link families to local resources). 27 we can also avail ourselves to help community groups that may benefit from a clinician's assistance. 28 mental health needs within families. children in families with mental health needs will be vulnerable to further disruptions to their psychosocial stability due to covid-19 control measures. shuttered community resources upon which people rely will increase the risk for the most vulnerable children. a family member with mental illness or substance misuse may therefore experience barriers to their own usual coping supports. this could further endanger children in the home. these can all contribute to a dangerous escalating cycle if a family's coping skills were already precarious. 29 stress also increases the risk of child maltreatment. rates of physical abuse increase during periods of economic crises 30 and after natural disasters. 31 maladaptive disciplinary behaviors, which put families at risk for escalating violence in the home, increase during recessions. 32 as child sexual abuse is often perpetrated by someone known and trusted by the child, stay-at-home orders may increase perpetrators' access to children. abuse may go unreported, however. we were concerned to learn that, during the early weeks of the recent stay-at-home orders in illinois, there were sharply decreased call volumes to child maltreatment hotlines. 33 we suspect that this is the result of children isolated from teachers, counselors, and health providers like pediatricians who typically generate most of the reports. 34 not all abuse is going unnoticed, however. a tip line for reporting of online sexual exploitation of children noted a 5-fold increase in calls. 35 social distancing will also affect visitation and placement for youth entering foster care. for those children who require alternative safe placements or children who need to be removed from a home due to maltreatment, foster parents and extended family members may be more hesitant to increase covid-19 exposures by accepting new children and child protection caseworkers into their homes. for many children, mortality and illness are unfamiliar concepts and they will be especially vulnerable to the psychological stresses caused by the disturbing news and images generated by stories about covid-19. 36 children may also see their parents worrying for the first time about their families' medical and economic health. some children may find themselves in difficult situations from being forcedly separated from one parent (e.g., children of separated couples 37 or with a parent in jail). pediatricians can provide education to parents on using honest, age-appropriate language to discuss difficult topics such as disturbing news stories, illness and death, and unemployment. parents and older children can also learn from their pediatricians about moderating screen time and video gaming to minimize maladaptive effects on neurocognitive development, 38 obesity, body malposition, and eye problems. 39, 40 pediatricians need to review their records, identify children with mental health concerns or a history of maltreatment, and reach out to the families of these children. self-care to mitigate anxiety and stress will be protective and can build resilience. 26 pediatricians can proactively provide education on mental health and effective discipline strategies. 41 parents can also be directed to sites of professional organizations such as the american academy of pediatrics' healthychildren.org. pediatricians can connect patients to mental health professionals 42 who develop and disseminate mental health interventions to support families with pandemic-driven stresses. 43, 44 educational needs. some children's educational needs will be fulfilled more easily than others with the transition to learning at home. children with access to technology -personal devices and local internet connectivity 45 -may make the transition to home-based or electronic learning more easily. children who usually receive learning accommodations in the classroom may find that their needs are not easily met with technology, further widening educational gaps between them and their peers. 46 the so-called "summer slide" -the loss of educational progress -may be accelerated, and may persist, for as long as children find themselves homebound. children with autism or special needs who are unable to adhere to their routines may have particular difficulty during shelter-in-place regulations, 47 and we can direct families to resources in their areas. 48 pediatricians may be able to assist schools in finding children (e.g., over 2,000 in chicago) whom educators have been unable to be contact since the start of the pandemic. 49 although all children are at risk for challenges during the pandemic, poor children are at higher risk. poverty makes shelter-at-home regulations more difficult. 50, 51 the risks are both medical and non-medical. covid-19 infection and death rates are higher among people of color and those of low income. 52 factors at the root of this disparity include: densely population living areas (where disease transmission is overall more prevalent), sub-optimal housing, and more difficulties meeting basic needs. 53, 54 elderly family members living in multigenerational homes will be at greatest risk of severe illness. children with limited safe outdoor spaces and cramped living quarters may have adverse psychological effects 55 while prolonged exposure to indoor pollutants and pests may exacerbate medical problems. 56, 57 many children normally receive nutrition at school -with free or reduced-price breakfast and lunch 58 -a provision that continues in many cities despite school closures. 59 access to cleaning supplies, masks, and hand sanitizer may also be more challenging for families with limited financial means or private transportation. 60 outside of our clinics, we can address the aforementioned situational vulnerabilities that put children at risk by advocating in the public policy arena. we can work for housing-related programs with mlps. we can advocate for employment protections, paid sick leave regulations, and economic stimulus for those most in need. 61 we can similarly lend our voice to food access programs for children and families, partnering with those who distribute public benefits and with businesses and non-profits that bolster the underlying safety net. 30 during the quarantine, many families have discovered that their homes are better-suited to sleep in rather than to live in continuously. online lessons have been challenging or impossible for children, because most families live in 2 or 3-room homes where isolation and silence are impossible. over the longer term, we can advocate to city and building planners to design living spaces that allow easier social distancing in future pandemics with family-friendly areas for safe physical activity. we as pediatricians may not always be the ones in the lead, but we can always be in support, helping to prioritize fundamental needs for those most at-risk populations. 22, 39, 62 because covid-19 is new, we do not yet understand the natural history or the factors that influence prognosis. we do not yet know the best treatments. everything is innovative. if we had more time, we could do more studies, but the rapid spread of the pandemic makes that impossible. we do not yet understand all of the ways the virus is transmitted, the best practices to slow or halt transmission, the range of illness manifestations, or the sensitivity and specificity of different diagnostic tests. we desperately need more research on all aspects of this new disease. the international medical community has adapted quickly to collect data and disseminate findings to help guide clinical practices. we are beginning to understand covid-19's clinical course. we are identifying complications afflicting certain children, like the kawasaki-disease-type sequelae after covid-19 infection 63 now being called multisystem inflammatory syndrome in children. 64 registries now enable sharing of data to better elucidate perinatal transmission and covid-19 illness in newborns. 65 in the meantime, when we talk to families, we must be transparent about our knowledge gaps while still providing best evidence to parents when sharing decisions for the care of their children. guidance from professional organizations can support discussions with covid-19 positive mothers deliberating between post-delivery separation from newborns vs. cautious "rooming in" and directly breastfeeding vs. providing expressed breastmilk. screening, tracing, and asymptomatic transmission require elucidation 66 to inform which practices will best prevent transmission of the virus in daycare, school, and sports settings so that we can help guide parents and administrators institute safe plans for reopening. the zeal for learning how to combat covid-19 will require temperance, however, with ethical principles that govern research in non-pandemic related areas. 67 as investigators develop studies to test new treatments, they will need to clearly explain what is known, what is not known, the reasons why research is being done, the risks and benefits of participating in research, and the risks of being treated with therapies that have not been validated by rigorous clinical studies. there is no risk-free choice between participation in clinical research or opting for standard care when there is no standard of care. with either choice, parents may have unrealistic expectations about risks and benefits. doctors must guide them to understand the risks and benefits of either option. the ethics of research will become more complicated as candidate vaccines enter clinical trials. vaccine studies are technically and ethically complex. studies require large numbers of participants in order to assess both efficacy and safety. rushing development and endorsement of a covid-19 vaccine before establishing efficacy and safety could endanger not only recipients but also uptake of current safe vaccines. 68 but holding off on vaccine use while completing studies will be stressful for both doctors and families. pediatricians will need to help design studies in ways that minimize risk and generate useful data as quickly as possible, and then help families understand the choices that they face. children have encountered and will continue to encounter unique challenges as the covid-19 pandemic continues. we cannot ignore discrepancies in social determinants of health. keeping families and communities safe, and our patients healthy is no small task. but we have an opportunity, if we pay close attention to the vulnerabilities exposed by this pandemic, to make conditions better for children than before the pandemic began. 69, 70, 71 justice is a key value we need to be attentive to health disparities as we develop new programs to respond to covid-19 and covid-related health challenges. pediatricians have a fiduciary responsibility to each patient and family that they serve, but they also have a broader responsibility to the population of children in our communities. we must ensure that no subgroup is overlooked or left out. because some patients suffer unjustly due to situational vulnerabilities, fairness may require we focus more efforts toward those children at risk of greatest harms. transparency will mean making clear that despite uncertainty, our decisions and choices are reasoned, evidence-based, and strive for equity. maintaining rigorous ethical standards for research will produce knowledge we can confidently endorse. the positive downstream effects of early interventions on health are familiar to pediatricians. the challenges are daunting but they are not insurmountable. pediatricians can transform them into powerful opportunities for improving the lives of children. un policy brief: the impact of covid-19 on children ethics, poverty and children's vulnerability doctors fret over surgery backlog after immediate covid-19 crisis. the globe and mail effects of the covid-19 pandemic on routine pediatric vaccine ordering and administration -united states functional and morphological outcomes of pyeloplasty at different ages in prenatally diagnosed society of fetal urology grades 3-4 ureteropelvic junction obstruction: is it safe to wait? urology impact of wait time on outcome for inguinal hernia repair in infants mortality after groin hernia surgery a cross-sectional analysis of the bc children's hospital cleft palate program waitlist. plast surg (oakv) waiting for an operation: parents' perspectives impact of surgical waiting time on paediatric spinal deformity patients early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants does screening for and intervening with multiple health compromising behaviours and mental health disorders amongst young people attending primary care improve health outcomes? a systematic review use of electronic consultation system to improve access to care in pediatric hematology/oncology the impact of electronic consultation on a canadian tertiary care pediatric specialty referral system: a prospective singlecenter observational study initial assessment, treatment, and follow-up of minor pediatric burn wounds in four patients remotely: a preliminary communication computerized automatic diagnosis of innocent and pathologic murmurs in pediatrics: a pilot study utilizing lean principles to improve immunization administration efficiency in a pediatric mobile clinic program. pediatr qual saf the effect of a non-surgical orthopaedic physician on wait times to see a paediatric orthopaedic surgeon american dental association center for professional success covid-19 state mandates and recommendations redefining "medical care protecting the most vulnerable children from the impact of coronavirus: an agenda for action what are social determinants of health? 2020 partnering with families experiencing housing instability: considerations for interdisciplinary teams based in massachusetts and beyond hospital -food bank partnerships: a recipe for community health forging a pediatric primary care-community partnership to support food-insecure families a road map to address the social determinants of health through community collaboration prevalence and predictors of mental health distress post-katrina: findings from the gulf coast child and family health study abusive head trauma during a time of increased unemployment; a multicenter analysis increased incidence of inflicted traumatic brain injury in children after a natural disaster the great recession and the risk for child maltreatment calls to illinois' child abuse hotline dropped by nearly half amid coronavirus spread. here's why that's not good news. the southern illinoisan department of health & human services, administration for children and families, administration on children, youth and families child protection organizations seeing 'significant uptick' in predators using covid-19 as opportunity to exploit online. the globe and mail affective temperament, attachment style, and the psychological impact of the covid-19 outbreak: an early report on the italian general population co-parenting in the time of coronavirus: if you and your ex don't agree, what are your rights? the conversation tv watching and computer use in u.s. youth aged 12-15 screen media exposure and obesity in children and adolescents an investigation of children's posture and discomfort during computer use council on child abuse and neglect & committee on psychosocial aspects of child and family health. effective discipline to raise healthy children mental health in the coronavirus disease 2019 emergency-the italia response healthy children.org signs your teen may need more support in some illinois towns, internet shortfalls and lack of computers putting students at a disadvantage during an extended period away from the classroom. 'a poverty issue, pure and simple updates on coronavirus and the disabled community. forbes handle the autism spectrum condition during coronavirus (covid-19) stay at home period: ten tips for helping parents and caregivers of young children autism speaks covid-19 information and resources for families since cps shut, 2k kids went mia. chicago tribune covid-19: vulnerability and the power of privilege in a pandemic covid-19 community stabilization and sustainability framework: an integration of the maslow hierarchy of needs and social determinants of health the covid-19 pandemic: a call to action to identify and address racial and ethnic disparities. j racial ethn health disparities health justice strategies to combat covid-19: protecting vulnerable communities during a pandemic covid-19: the painful price of ignoring health inequities mental health status among children in home confinement during the coronavirus disease 2019 outbreak in hubei province epub ahead of print indoor allergens and allergic respiratory disease housing code violation density associated with emergency department and hospital use by children with asthma feeding low-income children during the covid-19 pandemic covid-19 information and resources for families supporting equitable food access during national emergencies-the promise of online grocery shopping and food delivery services primary care pediatrics and public health: meeting the needs of today's children mitigating the impacts of the covid-19 pandemic response on at-risk children sars-cov-2-induced kawasaki-like hyperinflammatory syndrome: a novel covid phenotype in children acute heart failure in multisystem inflammatory syndrome in children (mis-c) in the context of global sars-cov-2 pandemic. circulation coronavirus infections in children including covid-19 clinical features, diagnosis, treatment and prevention options in children for lowering scientific standards adverse consequences of rushing a sars-cov-2 vaccine implications for public trust after hurricane floyd passed investigating the social determinants of disaster preparedness and recovery don't let disaster recovery perpetuate injustice this time must be different: disparities during the covid-19 the authors declare no conflicts of interest. abbreviations: covid-19: coronavirus disease 2019; mlp: medical-legal partnership; ppe: personal protective equipment key: cord-021951-xxvol17t authors: amos, louella b. title: cough date: 2017-05-12 journal: nelson pediatric symptom-based diagnosis doi: 10.1016/b978-0-323-39956-2.00002-9 sha: doc_id: 21951 cord_uid: xxvol17t nan cough is an important defense mechanism of the lungs and is a common symptom, particularly during winter months. in most patients, it is self-limited. however, cough can be ominous, indicating serious underlying disease, because of accompanying problems (hemoptysis) or because of serious consequences of the cough itself (e.g., syncope and hemorrhage). the cough reflex serves to prevent the entry of harmful substances into the tracheobronchial tree and to expel excess secretions and retained material from the tracheobronchial tree. cough begins with stimulation of cough receptors, located in the upper and lower airways, and in many other sites such as the ear canal, tympanic membrane, sinuses, nose, pericardium, pleura, and diaphragm. receptors send messages via vagal, phrenic, glossopharyngeal, or trigeminal nerves to the "cough center," which is in the medulla. because cough is not only an involuntary reflex activity but also one that can be initiated or suppressed voluntarily, "higher centers" must also be involved in the afferent limb of the responsible pathway. the neural impulses go from the medulla to the appropriate efferent pathways to the larynx, tracheobronchial tree, and expiratory muscles. the act of coughing ( fig. 2 .1) begins with an inspiration, followed by expiration against a closed glottis (compressive phase), resulting in the buildup of impressive intrathoracic pressures (50-300 cm h 2 o). these pressures may be transmitted to vascular, cerebrospinal, and intraocular spaces. finally, the glottis opens, allowing for explosive expiratory airflow (300 m/sec) and expulsion of mucus, particularly from the larger, central airways. the inability to seal the upper airway (tracheostomy) impairs, but does not abolish, the effectiveness of cough. weak ventilatory muscles (muscular dystrophy) impair both the inspiratory and the compressive phase. the patient history often provides the most important body of information about a child's cough. a diagnosis can often be discerned with relative certainty from the family history, the environmental and exposure history, and the acute nature and characterization of the cough. the patient's age (table 2 .1) helps to focus the diagnostic possibilities. congenital anatomic abnormalities may be symptomatic from birth, whereas toddlers, who may have incomplete neurologic control over swallowing and often put small objects in their mouths, are at risk for foreign body aspiration; adolescents may experiment with smoking or inhaled drugs. socioeconomic factors must be considered; a family that cannot afford central heating may use a smoky wood-burning stove; spending time at a daycare center may expose an infant to respiratory viruses; and several adult smokers in a small home expose children to a high concentration of respiratory irritants. the various cough characteristics can help determine the cause of cough. the causes of acute, recurrent, and chronic coughs may be quite different from each other ( fig. 2. 2; see also table 2 .1). a cough can be paroxysmal, brassy, productive, weak, volitional, and "throatclearing," and it may occur at different times of the day (tables 2.2 and 2.3). the previous response or lack of response to some therapies for recurrent and chronic cough can provide important information (see table 2 .3). furthermore, some coughs may be caused or worsened by medications (table 2 .4). a history of accompanying signs or symptoms, whether localized to the respiratory tract (wheeze, stridor) or elsewhere (failure to thrive, frequent malodorous stools) can give important clues (table 2 .5; see also tables 2.2 and 2.3). it is essential to remember that the daily language of the physician is full of jargon that may be adopted by parents but with a different meaning from that understood by physicians. if a parent says that a child "wheezes" or "croups" or is "short of breath," it is important to find out what the parent means by that term. because many disorders of childhood have genetic or nongenetic familial components, the family history can provide helpful information: • are there older siblings with cystic fibrosis (cf) or asthma? • is there a coughing sibling whose kindergarten class has been closed because of pertussis? • is there an adolescent or adult with chronic cough (bronchitis) who may have pertussis or tuberculosis? • was the child premature, and, if so, did he or she spend a month on the ventilator, and does he or she now have chronic lung disease (bronchopulmonary dysplasia)? • did the toddler choke on a carrot or other food 3 months ago? • did the child have rsv, bronchiolitis, or rhinovirus infection as an infant? • did the child receive a bone marrow transplant a year ago? • is the child immunized? • did the infant have a tracheoesophageal fistula repaired in the neonatal period? chest, abdomen, and spine. the shape of the chest gives information. is the anteroposterior (ap) diameter increased, which indicates hyperinflation of the lungs from obstruction of small airways (asthma, bronchiolitis, cf)? is this diameter small, as can be seen with some restrictive lung diseases with small lung volumes (muscular dystrophy, spinal muscular atrophy)? the normal infant has a "round" chest configuration, with the ap diameter of the chest about 84% of the transverse (lateral) diameter. with growth, the chest becomes more flattened in the ap dimension, and the ap-to-transverse ratio is between 70% and 75%. although obstetric calipers can be used to give an objective assessment of the ap diameter of the chest, most clinicians rely on their initial inspection often reveals the seriousness of an illness: • is the child struggling to breathe (dyspnea)? • does the child have an anxious look? • can the child be calmed or engaged in play? • is the child's skin blue (representing cyanosis) or ashen? • does the child appear wasted, with poor growth that may indicate a chronic illness? the respiratory rate is often elevated with parenchymal lung disease or extrathoracic obstruction. respiratory rates vary with the age of the child (fig. 2 .3) and with pulmonary infection, airway obstruction, activity, wakefulness and sleep, fever, metabolic acidosis, and anxiety. odors may also give helpful clues. does the examining room or the clothing smell of stale cigarette smoke? is there a foul odor from a diaper with a fatty stool, which may suggest pancreatic insufficiency and cf? is the child's breath malodorous, as can be noticed in sinusitis, nasal foreign body, lung abscess, or bronchiectasis? fingers. cyanotic nail beds suggest hypoxemia, poor peripheral circulation, or both. the examiner looks for the presence of digital clubbing (fig. 2.4) , which makes asthma or acute pneumonia extremely unlikely. the absence of digital clubbing but a history of severe chronic cough in an older child makes cf unlikely. † anatomic abnormality includes tracheobronchomalacia, tracheoesophageal fistula, vascular ring, abnormal position or take-off of large bronchi. 1 common; 2 less common; 3 much less common. cf, cystic fibrosis; ger, gastroesophageal reflux. less easy to notice than intercostal retractions is their bulging out with expiration in a child with expiratory obstruction (asthma). contraction of the abdominal muscles with expiration is easier to notice and is another indication that a child is working harder than normal to push air out through obstructed airways. inspection of the spine may reveal kyphosis or scoliosis. there is a risk of restrictive lung disease if the curvature is severe. palpating the trachea, particularly in infants, may reveal a shift to one side, which suggests loss of volume of the lung on that side or extrapulmonary gas (pneumothorax) on the other side. placing one hand on each side of the chest while the patient breathes may enable the examiner to detect asymmetry of chest wall movement, either in timing or in degree of expansion. the former indicates a partial bronchial obstruction, and the latter suggests a smaller lung volume, voluntary guarding, or diminished muscle function on one side. palpating the abdomen gently during expiration may allow the examiner to feel the contraction of the abdominal muscles in cases of expiratory obstruction. hyperinflation may push the liver down making it palpable below the costal margin. palpation for tactile fremitus, the transmitted vibrations of the spoken word ("ninety-nine" is the word often used to accentuate these subjective assessment of whether the diameter is increased: does the patient look "barrel-chested"? intercostal, subcostal, suprasternal, and supraclavicular retractions (inspiratory sinking in of the soft tissues) indicate increased effort of breathing and reflect both the contraction of the accessory muscles of respiration and the resulting difference between intrapleural and extrathoracic pressure. retractions occur most commonly with obstructed airways (upper or lower), but they may occur with any condition leading to the use of the accessory muscles. any retractions other than the mild normal depressions seen between an infant's lower ribs indicate a greater than normal work of breathing. because lung sounds tend to be higher-pitched than heart sounds, the diaphragm of the stethoscope is better suited to pulmonary auscultation than is the bell, whose target is primarily the lower-pitched heart sounds (table 2 .6). the adult-sized stethoscope generally is superior to the smaller pediatric or neonatal diaphragms, even for listening to small chests, because its acoustics are better (figs. 2.5 and 2.6). adventitious sounds come in a few varieties, namely, stridor, crackles, rhonchi, and wheezes. other sounds should be described in clear, everyday language. • stridor is a continuous musical sound usually heard on inspiration and is caused by narrowing in the extrathoracic airway, as with croup or laryngomalacia. • crackles are discontinuous, representing the popping open of air-fluid menisci as the airways dilate with inspiration. fluid in larger airways causes crackles early in inspiration (congestive heart failure). crackles that tend to be a bit lower in pitch ("coarse" crackles) than the early, higher-pitched ("fine") crackles are associated with fluid in small airways (pneumonia). although crackles usually signal the presence of excess airway fluid (pneumonia, pulmonary edema), they may also be produced by the popping open of noninfected fibrotic or atelectatic airways. fine crackles are not audible at the mouth, whereas coarse crackles may be. crackles is the preferred term, rather than the previously popular "rales." • rhonchi, or "large airway sounds," are continuous gurgling or bubbling sounds typically heard during both inhalation and exhalation. these sounds are caused by movement of fluid and secretions in larger airways (asthma, viral uri). rhonchi, unlike other sounds, may clear with coughing. , or the phalangeal depth ratio, is normally less than 1 but increases to more than 1 with finger clubbing. the dpd/ipd ratio can be measured with calipers or, more accurately, with finger casts. the hyponychial angle is measured from lateral projections of the finger contour on a magnifying screen and is normally less than 180 degrees but greater than 195 degrees with finger clubbing. schamroth sign is useful for bedside assessment. the dorsal surfaces of the terminal phalanges of similar fingers are placed together. with clubbing, the normal diamond-shaped aperture or "window" at the bases of the nail beds disappears, and a prominent distal angle forms between the end of the nails. in normal subjects, this angle is minimal or nonexistent. ( • wheezes are continuous musical sounds (lasting longer than 200 msec), caused by vibration of narrowed airway walls, as with asthma, and perhaps vibration of material within airway lumens. these sounds are much more commonly heard during expiration than inspiration. the chest radiograph is often the most useful diagnostic test in the evaluation of the child with cough. table 2 .7 highlights some of the radiographic features of the most common causes of cough in pediatric patients. radiographic findings are often similar for a number of disorders, and thus these studies may not indicate a definitive diagnosis. chest radiographs are normal in children with psychogenic (habit) cough and in children with sinusitis or gastroesophageal reflux (ger) as the primary cause of cough. a normal chest radiograph indicates the unlikelihood of pneumonia caused by respiratory syncytial virus (rsv), influenza, parainfluenza, adenovirus, chlamydia species, or bacteria. although children with cough resulting from cystic fibrosis (cf), mycoplasma species, tuberculosis, aspiration, a bronchial foreign body, or an anatomic abnormality usually have abnormal chest radiographs, a normal radiograph does not exclude these diagnoses. hyperinflation of the lungs is commonly seen on chest radiographs of infants with rsv bronchiolitis or chlamydia pneumonia, and a lobar or round (coin lesion) infiltrate is the radiographic hallmark of bacterial pneumonia. the diagnosis of sinusitis cannot be sustained with normal sinuses on radiograph or computed tomography (ct) scan. the white blood cell (wbc) count may help exclude or include certain entities for a differential diagnosis. for example, a wbc count of infections are the most common cause of acute cough in all age groups and are responsible for some chronic coughs. the age of the patient has a large impact on the frequency of the type of infection. viral upper respiratory infections (common cold); croup (laryngotracheobronchitis); viral bronchiolitis, particularly with rsv or human metapneumovirus; and viral pneumonia are the most frequently encountered respiratory tract infections and hence the most common causes of cough in infancy. viral illness may predispose to bacterial superinfection (croup and staphylococcus aureus tracheitis or influenza and h. influenzae or s. aureus pneumonia). viral upper respiratory infections (uri). viral uri symptoms and signs usually include stuffy nose with nasal discharge, sore throat, and sneezing. there may be fever, constitutional signs (irritability, myalgias, and headache), or both. cough is common and may persist for 5-7 days. the mechanism by which uris cause cough in children is undetermined. in adults, it is generally thought that "postnasal drip"-that is, nasal or sinus secretions draining into the posterior nasopharynx-causes cough and, in fact, may be one of the most frequent causes of cough. indeed, sinus ct in older patients with uris often reveals unexpected involvement of the sinus mucosa. other authorities believe that cough in a child with a uri indicates involvement (inflammation or bronchospasm) of the lower respiratory tract. over-the-counter cough and cold medications are commonly used. evidence of efficacy of these medications for children with uri is lacking. because of the known risk for unintentional overdose from these medications, their use is not recommended in children under age 4 years. 35,000 with 85% lymphocytes strongly suggests pertussis, but not every child with pertussis presents such a clear hematologic picture. the presence of a high number or large proportions of immature forms of wbcs suggests an acute process, such as a bacterial infection. immunoglobulins provide supportive evidence for a few diagnoses, such as chlamydial infection, which rarely occurs without elevated serum concentrations of immunoglobulins g and m. specific bacteriologic or virologic diagnoses can be made in a number of disorders causing cough, including rsv, influenza, parainfluenza, adenovirus, and chlamydia pneumonia. in most cases, the viruses can be rapidly identified with amplification of the viral genome through polymerase chain reaction (pcr). in bacterial pneumonia, the offending organism can be cultured from the blood in a small proportion (10%) of patients. a positive culture provides definitive diagnosis, but a negative culture specimen is not helpful. throat cultures are seldom helpful (except in cf) in identifying lower respiratory tract bacterial organisms. sputum cultures and gram stains may help guide initial empirical therapy in older children with pneumonia or purulent bronchitis, but their ability to identify specific causative organisms with certainty (with the exception of cf) has not been shown clearly. infants and young children usually do not expectorate but rather swallow their sputum. specimens obtained via bronchoscopy may be contaminated by mouth flora, but heavy growth of a single organism in the presence of polymorphonuclear neutrophils certainly supports the organism's role in disease. if pleural fluid or fluid obtained directly from the lung via needle aspiration is cultured, the same rules apply: positive cultures are definitive, but negative cultures are not. a number of specific tests can help to establish diagnoses in a child with cough (see table 2 .7). these include a positive response to bronchodilators in a child with asthma; visualizing the red, swollen epiglottis in epiglottitis (to be done only under very controlled conditions); the bronchoscopic visualization of the peanut, plastic toy, or other offender in foreign body aspiration; a positive purified protein diaphragm, with an enlarged retrosternal air space in as many as 60% of patients, peribronchial thickening in approximately 50%, and consolidation and/or atelectasis in 10-25%. the diagnosis is confirmed with demonstration of rsv by pcr of nasopharyngeal secretions. in most cases, no treatment is needed because the disease does not interfere with the infant's eating or breathing. apnea is a common complication of rsv bronchiolitis in neonates and may necessitate close monitoring. in severe cases, often those in which there is underlying chronic heart, lung, or immunodeficiency disease, rsv can be life-threatening. in severe cases, hospital care with supplemental oxygen and intravenous fluids is indicated. suctioning of secretions is an essential part of the treatment. many other treatment modalities have been tried for hospitalized infants with bronchiolitis. aerosolized bronchodilators and systemic glucocorticoids do not seem to alter clinical outcome and are not recommended in most patients. nebulized saline may reduce the length of hospitalization. use of high-flow nasal cannula may reduce the need for more invasive forms of respiratory support in infants with impending respiratory failure. viral pneumonia. viral pneumonia can be similar to bronchiolitis in its manifestation, with cough and tachypnea, after a few days of apparent uri. there can be variable degrees of fever and of overall illness. infants and children with viral pneumonia may appear relatively well or, particularly with adenovirus or influenza, may have a rapidly progressive course. frequent symptoms include poor feeding, cough, cyanosis, fever (some patients may be afebrile), apnea, and rhinorrhea. frequent signs include tachypnea, retractions, crackles, and cough. cyanosis is less common. the most common agents causing viral pneumonia in infancy and childhood are rsv, influenza, and parainfluenza. adenovirus is less common, but it is important because it can be severe and leave residua, including bronchiectasis and bronchiolitis obliterans. adenovirus pneumonia is often accompanied by conjunctivitis and pharyngitis, in addition to leukocytosis and an elevated erythrocyte sedimentation rate (esr); the esr and leukocyte count are usually not elevated in other types of viral pneumonia. additional viral agents include enteroviruses, human metapneumovirus and rhinovirus. radiographs most often reveal diffuse, bilateral peribronchial infiltrates, with a predilection for the perihilar regions, but occasionally lobar infiltrates are present. pleural effusions are not common. on occasion, if an infant is extremely ill, bronchoscopy with bronchoalveolar lavage may be indicated to isolate the virus responsible for the pneumonia. treatment is largely supportive, with oxygen and intravenous fluids. mechanical ventilation may be necessary in a small minority of infants. in young infants, the afebrile pneumonia syndrome may be caused by chlamydia, ureaplasma, or mycoplasma species; cytomegalovirus; or pneumocystis jiroveci. in this syndrome, cough and tachypnea are common. severe pneumonia may develop in neonates as a result of herpes simplex. pertussis (whooping cough). pertussis is a relatively common cause of lower respiratory tract infection in infants, children, adolescents, and adults, especially in those who are underimmunized or not immunized. the causative organism, bordetella pertussis, has a tropism for tracheal and bronchial ciliated epithelial cells; thus the disease is primarily bronchitis, but spread of the organism to alveoli, or secondary invasion by other bacteria, can cause pneumonia. the disease can occur at any age, from early infancy onward, although its manifestations in young infants and in those who have been partially immunized may be atypical. most commonly, pertussis has three stages: • catarrhal, in which symptoms are indistinguishable from a viral uri common viral pathogens include rhinovirus, rsv, coronaviruses, and parainfluenza viruses. the differential diagnosis includes allergic rhinitis, which often demonstrates clear nasal secretions with eosinophils and pale nasal mucosa, and sinusitis, which presents with mucopurulent nasal secretions containing neutrophils and erythematous mucosa. croup (laryngotracheobronchitis). infectious croup (see chapter 3) is most common in the first 2 years of life. its most dramatic components are the barking ("croupy") cough and inspiratory stridor, which appear a few days after the onset of a cold. in most cases, the patient has a low-grade fever, and the disease resolves within a day or two. in severe cases, the child can be extremely ill and is at risk for complete laryngeal obstruction. there may be marked intercostal and suprasternal retractions and cyanosis. stridor at rest signifies significant obstruction. diminishing stridor in a child who is becoming more comfortable is a good sign, but diminishing stridor in and of itself is not necessarily good: if the child becomes fatigued because of the tremendous work of breathing through an obstructed airway and can no longer breathe effectively, smaller-than-needed tidal volumes make less noise. it is important to distinguish croup from epiglottitis in the child with harsh, barking cough and inspiratory stridor because the natural histories of the two diseases are quite different (see table 2 .7). epiglottitis occurs more commonly in unimmunized toddlers than in infants (see chapter 3). treatment of mild croup is usually not needed. for decades, pediatricians have recommended putting a child with croup in a steamy bathroom or driving to the office or emergency department with the car windows rolled down. it is likely that these remedies are effective because of the heat exchange properties of the upper airway; air that is cooler or more humid than the airway mucosa will serve to cool the mucosa, thus causing local vasoconstriction and probably decreasing local edema. in a child who has stridor at rest, evaluation is indicated. symptomatic, often dramatic relief through decreased laryngeal edema can usually be achieved with aerosolized racemic epinephrine (2.25% solution, 0.25 to 0.5 ml/dose). it is essential to remember that the effects of the epinephrine are transient, lasting only a few hours, although the course of the illness is often longer. the result is that when the racemic epinephrine's effect has worn off, the child's cough and stridor will probably be as bad or even worse than before the aerosol was administered. this is not a "rebound" effect: the symptoms are not worse because of the treatment but, rather, because of the natural progression of the viral illness. repeating the aerosol will probably again have a beneficial effect. a child who responds favorably to such an aerosol needs to be observed for several hours because further treatment may be needed. a single dose of dexamethasone (0.6 mg/kg orally, intramuscularly, or intravenously) reduces the severity and hastens recovery. aerosolized steroids (budesonide) may also be effective in patients with mild to moderately severe croup. bronchiolitis. bronchiolitis is a common and potentially serious lower respiratory tract disorder in infants (see chapter 3). it is caused usually by rsv but on occasion by parainfluenza, influenza, human metapneumovirus, adenovirus, enterovirus, and human rhinovirus. it mostly occurs in the winter months, often in epidemics. rsv bronchiolitis is seen uncommonly in children older than 4 years. typically, "cold-like" symptoms of rhinorrhea precede the harsh cough, increased respiratory rate, and retractions. respiratory distress and cyanosis can be severe. the child's temperature is seldom elevated above 38°c. the chest is hyperinflated, widespread crackles are audible on inspiration, and wheezing marks expiration. the chest radiograph invariably reveals hyperinflation, as depicted by a depressed 23.e1 (see nelson textbook of pediatrics, p. 2032.) (see nelson textbook of pediatrics, p. 2091.) colds and cough in infants (see previous discussion) apply to this older age group. the differential diagnosis of rhinorrhea is noted in table 2 .10. sinusitis. the sinuses may become the site for viral and subsequent secondary bacterial infection spreading from the nasopharynx (fig. 2.7) . the signs and symptoms are usually localized, including nasal congestion, a feeling of "fullness" or pain in the face (fig. 2.8) , headache, sinus tenderness, day or night cough, and fever. maxillary toothache, purulent nasal discharge for more than 10 days, and a positive transillumination (opacification) are important clues. sinus radiographs or (more accurate) ct scan may facilitate the diagnosis of sinusitis by demonstrating opacification of the sinus with mucosal thickening. sinusitis is thought to be a cause of cough in adults and can probably be listed, with lower certainty, as a cause of cough in children. sinusitis is frequently seen in other conditions known to cause cough, especially cf, asthma, ciliary dyskinesia, and granulomatosis with polyangiitis with or without eosinophilia. it may be difficult to ascertain whether the cough is a direct result of the sinus infection or the underlying problem (purulent bronchitis in the child with cf or ciliary dyskinesia, exacerbation of asthma). in the first two situations, it may not matter because treatment is the same. in the case of the child with asthma, it is important to treat the asthma with bronchodilating and antiinflammatory agents, as well as to treat the infected sinuses with antibiotics. • paroxysmal, dominated by repeated forceful, paroxysmal coughing spells; spells may be punctuated by an inspiratory "whoop," posttussive emesis, or both • convalescent, in which the intensity and frequency of coughing spells gradually diminish each stage typically lasts 1-2 weeks, except the paroxysmal stage, which lasts many weeks. (pertussis is known as the "100 day cough" in china.) most children are entirely well between coughing spells, when physical findings are remarkably benign. infants younger than 6 months of age are at highest risk for complications. the majority of infants with pertussis need to be hospitalized. diagnosis can be difficult because the definitive result-namely, culturing the organism from nasopharyngeal secretions-requires special culture medium (bordet-gengou, which must be prepared fresh for each collection). culture specimens are much less likely to be positive during the paroxysmal stage than during the catarrhal stage, when the diagnosis is not being considered. pcr assay of an adequate nasopharyngeal (np) specimen is the most commonly used test because of improved sensitivity and faster turnaround time compared to culture. an elevated wbc count, as high as 20,000-50,000, with lymphocytes predominating is suggestive of pertussis in infants and children but often absent in adolescents. chest radiographic findings are nonspecific. infants with severe disease may require hospitalization. treatment is largely supportive, with oxygen, fluids, and small frequent feedings for patients who do not tolerate their normal feedings. treatment with azithromycin decreases infectivity and may ameliorate the course of the disease if given during the catarrhal stage. complications include those related to severe coughing (table 2 .9) and those specific to pertussis, such as seizures and encephalopathy. the risk of acquiring pertussis is markedly reduced by immunizations (three primary immunizations and regular booster immunizations). neither pertussis infection nor immunization produces lifelong immunity. chlamydial infection. chlamydia trachomatis can cause pneumonia in young infants, particularly those aged 3-12 weeks. cough, nasal congestion, low-grade or no fever, and tachypnea are common. conjunctivitis is an important clue to chlamydial disease but is present in only 50% of infants with chlamydial pneumonia at the time of presentation. affected infants may have a paroxysmal cough similar to that of pertussis, but post-tussive emesis is less common. crackles are commonly heard on auscultation, but wheezing is much less common than the overinflated appearance of the lungs on radiographs would suggest. the organism may be recovered from the nasopharynx by culture or antigen testing. the complete blood cell count may reveal eosinophilia. chlamydial infection responds to oral erythromycin therapy. ureaplasmal infection. ureaplasma urealyticum pneumonia is difficult to diagnose but causes cough in some infants. there are no particularly outstanding features to distinguish this relatively uncommon infection from viral pneumonias. bacterial pneumonia. bacterial pneumonia is relatively less common in infants than is viral pneumonia but can cause severe illness, with cough, respiratory distress, and fever. chest radiographs are abnormal, and the wbc count is elevated. treatment is with antibiotics effective against pneumococci, group a streptococci, and, if illness is severe, s. aureus. viral uris. in early childhood, as children attend daycare and nursery schools, they are constantly exposed to respiratory viruses to which they have little or no immunity (e.g., rsv, rhinoviruses, adenoviruses, parainfluenza, and enteroviruses). young children may have as many as 6-8 or even more uris in a year. the remarks concerning the treatment of sinusitis involves the use of oral antibiotics active against the common pathogens (i.e., streptococcus pneumoniae, nontypable h. influenzae, moraxella catarrhalis, and, in rare cases, anaerobic bacteria or streptococcus pyogenes). treatment regimens include the use of amoxicillin, amoxicillin-clavulanate, cefuroxime, cefpodoxime, or cefdinir. amoxicillin is considered the initial agent of choice. oral (pseudoephedrine, phenylephrine) or topical (phenylephrine, oxymetazoline) decongestants may be of benefit by increasing the patency of the sinus ostia, which permits drainage of the infected and obstructed sinuses. oral antihistamines may benefit patients with an allergic history. treatment with antimicrobial agents should continue for at least 7 days after the patient has responded. this may require 14-21 days of therapy. many patients with presumed sinusitis recover without antibiotic therapy. complications of acute sinusitis include orbital cellulitis, abscesses (orbital, cerebral), cranial (frontal) osteomyelitis (pott puffy tumor), empyema (subdural, epidural), and thrombosis (sagittal or cavernous sinus). pneumonia. the features discussed for viral pneumonia in infants are relevant for viral pneumonia in older children. the differentiation of viral or atypical pneumonia from classical bacterial pneumonia is noted in table 2 .11. adenovirus and influenza pneumonia may present similar to bacterial pneumonia in severity and acuteness. bacterial pneumonia is more common in toddlers and older children than in infants. the most common pathogen is s. pneumoniae. (table 2 .12). cough may not be as prominent a presenting symptom or sign as tachypnea and grunting. raised respiratory rates (>50 in infants 2-12 months old, >40 in children 1-5 years old) plus retractions and grunting with or without hypoxia (oxygen saturation <90%) have a high specificity and sensitivity for pneumonia. chest pain, abdominal pain, headache, or any combination of these symptoms may occur. upper lobe pneumonia may produce meningeal signs, and lower lobe involvement may cause abdominal pain and an ileus. examination of the chest shows tachypnea but may be otherwise surprisingly normal. in older children, there may be localized dullness to percussion, with crackles or amphoric (bronchial) breath sounds over a consolidated lobe. the chest radiograph may be normal in the first hours of the illness, inasmuch as the radiographic findings often lag behind the clinical manifestations. nonetheless, both anteriorposterior and lateral views are the main diagnostic tools; lobar consolidation is usual, with or without pleural effusion. in infants, the pattern may be more diffuse and extensive. *atypical pneumonia syndrome (see table 2 .11); atypical in terms of extrapulmonary manifestations, low-grade fever, patchy diffuse infiltrates, poor response to penicillin-type antibiotics, and negative sputum gram stain. sars, severe acute respiratory syndrome. some clinical and radiographic features may be suggestive of the bacterial cause of pneumonia. children (especially infants) with staphylococcal pneumonia are more likely to have a rapid overwhelming course. staphylococcal pneumonia may be accompanied by more extensive radiographic abnormalities, including multilobar consolidation, pneumatocele formation, and extensive pleural (empyema) fluid. the presence of a pleural effusion is not helpful in indicating the specific bacterial diagnosis because other bacterial pneumonias may be accompanied by pleural effusion. pleural effusions may represent a reactive parapneumonic effusion or an empyema. pleural fluid may be characterized as transudate, exudate, or empyema (table 2 .13). if the effusion is of sufficient size, as demonstrated by a lateral decubitus radiograph or ultrasonography, a thoracentesis may be indicated to differentiate the nature of the effusion and to identify possible pathogens. for young children who require sedation for thoracentesis and who have an effusion needing drainage, a primary chest tube placement is preferred over thoracentesis to decrease the risks from multiple procedures with sedation. differentiating among the causes of bacterial pneumonia can be done with certainty only with positive cultures from blood, pleural fluid, fluid obtained by direct lung tap, or, in rare cases, sputum. current or previous antibiotic treatment diminishes the yield of such cultures. bronchoscopy with or without lavage may yield helpful specimens from the progressively ill child or the child who has not responded promptly to empirical antibiotics. treatment of uncomplicated presumed bacterial pneumonia is with antibiotics. ampicillin is the drug of choice for the previously healthy child who requires hospitalization with lobar pneumonia who is fully immunized. if the child is not fully immunized, either cefotaxime or ceftriaxone is indicated. for the critically ill child, vancomycin and cefotaxime/ceftriaxone may be considered for possible drug-resistant s. pneumoniae and methicillin-resistant s aureus (mrsa). many children with pneumonia do well with oral antibiotics and respond within hours to the first dose. repeated or follow-up chest radiographs may remain abnormal for 4-6 weeks after appropriate treatment and are not indicated for a single episode of uncomplicated pneumonia (i.e., to an adult with active tuberculosis. nonetheless, tuberculosis is an infrequent cause of cough in children, even in those with active disease. the diagnosis is made primarily by skin testing (purified protein derivative [ppd]) or a positive quantiferon test; a history of contact with a person who has tuberculosis; and recovery of the organism from sputum, bronchoalveolar lavage, pleural fluid or biopsy, or morning gastric aspirates (table 2 .14). the yield from these procedures is relatively low, even from children with active pulmonary tuberculosis. no effusion, no abscess, and good response to treatment). mycoplasma pneumoniae is a common cause of pneumonia among school-aged children. the disease often occurs in community outbreaks in the fall. the illness typically begins with extrapulmonary symptoms (i.e., sore throat, myalgias, headache, fever), which then progress to include cough, which can be paroxysmal at times. patients do not often appear acutely ill, but cough may persist for weeks. there may be no specific abnormalities on the chest examination, although a few crackles may be heard, and about one third of younger patients wheeze. the radiographic findings in mycoplasmal pneumonia can mimic almost any intrathoracic disease; scattered infiltrates with nonspecific "dirty" lung fields, predominantly perihilar or lower lobes, are common, and lobar infiltrates and pleural effusion are occasionally seen. laboratory data (complete blood cell count, esr, sputum culture) may not be helpful. a rise in antimycoplasma immunoglobulin g over 1-2 weeks may be demonstrated but is seldom helpful in guiding therapy. a positive immunoglobulin m response may be useful, although it can persist in serum for several months and, consequently, may not indicate current infection. pcr is helpful. the cold agglutinin test yields positive results in about 70% of patients with mycoplasmal pneumonia, but they are also positive in other conditions, including adenovirus infection. the more severe the illness is, the greater is the frequency of positive cold agglutinins. the diagnosis is often made from the history of an older child who has a lingering coughing illness in the setting of a community outbreak, unresponsive to most (nonerythromycin) antibiotic regimens. treatment with azithromycin, clarithromycin, or erythromycin in children <8 years old or tetracycline or doxycycline in children ≥8 years old usually shortens the course of illness. extrapulmonary complications of mycoplasmal infection include aseptic meningitis, transverse myelitis, peripheral neuropathy, erythema multiforme, myocarditis, pericarditis, hemolytic anemia, and bullous otitis media (myringitis). in patients with sickle cell anemia, severe respiratory failure and acute chest syndrome may develop. infection with chlamydia pneumoniae mimics respiratory disease resulting from m. pneumoniae, inasmuch as it occurs in epidemics, is seen in older children, and produces an atypical pneumonia syndrome and pharyngitis. tuberculosis. tuberculosis is uncommon in developed countries; 95% of the disease burden worldwide is in developing countries. tuberculosis must be considered in the child with chest disease that is not easily explained by other diagnoses, especially if the child lives in or has migrated from an endemic area of the world or has been exposed cutaneous induration ≥5 mm • close exposure to known or suspected active tb • chest radiograph consistent with tb (old or active) • clinical evidence of tb • children receiving immunosuppresive therapy or with immunosuppressive conditions cutaneous induration ≥10 mm children at increased risk • age < 4 yr of age • medical high risks (chronic renal failure, malnutrition, diabetes mellitus, lymphoma) children with likelihood of increased exposure • children born in high-prevalence regions of the world • children who travel to high-prevalence regions of the world • children frequently exposed to adults who are hiv infected, homeless, users of illicit drugs, residents of nursing homes, incarcerated, or institutionalized cutaneous induration ≥15 mm • all children ≥4 yr of age without any identifiable risk the patterns of disease in normal hosts include primary pulmonary tuberculosis, with subsequent inactivation usually noted in young children and reactivation pulmonary disease among adolescents. primary pulmonary disease is often noted as a lower or middle lobe infiltrate during the period of t lymphocyte reaction to the initial infection. before resolution, the mycobacterium tuberculosis infection may disseminate to the better oxygenated upper lobes and extrathoracic sites, such as bone, or the central nervous system. if the immune response contains the initial infection, the radiographic findings may be indistinguishable from those of any other pneumonic process. with altered immune function, however, there may be progressive local disease, dissemination to miliary pulmonary disease, or early reactivation (months to 5 years) at distal sites, which produces tuberculous meningitis or osteomyelitis. reactivation of upper lobe pulmonary disease may produce cavities that are similar to the disease among adults. cavitary and endobronchial lymph node involvement are highly infectious, in contrast to the much less contagious nature of the hypersensitivity reaction noted in primary pulmonary disease. inhaling food, mouth or gastric secretions, or foreign bodies into the tracheobronchial tree causes acute, recurrent, or chronic cough. interference with normal swallowing disrupts the coordination of swallowing and breathing that prevents aspiration. structural causes of disordered swallowing include esophageal atresia (in neonates), strictures, webs, or congenital stenoses. mediastinal lesions (tumors, lymph nodes), including vascular rings, may compromise the esophageal lumen and esophageal peristalsis, increasing the likelihood of aspiration. functional disorders include central nervous system dysfunction or immaturity, dysautonomia, achalasia, and diffuse esophageal spasm. prior neck surgery, including tracheostomy, may alter normal swallowing. tracheoesophageal fistula and laryngeal clefts are congenital malformations with direct physical connections between the tracheobronchial tree and the upper gastrointestinal tract; thus oral contents enter the lungs directly. making the diagnosis of aspiration as the cause of cough may be difficult. barium contrast studies during swallowing may help characterize these disorders if barium enters the trachea. because most patients aspirate sporadically, a normal barium swallow does not rule out aspiration. radionuclide studies can be helpful if ingested radiolabeled milk or formula is demonstrated over the lung fields at severalhour intervals after the meal. bronchoscopy and bronchoalveolar lavage that recover large numbers of lipid-laden macrophages suggest that aspiration has taken place; however, the finding is neither sensitive nor specific for aspiration. treatment depends largely on the cause of aspiration. because many patients who aspirate do so because of lack of neurologic control of swallowing and breathing, it is often difficult to prevent. even gastrostomy feedings cannot prevent aspiration of oral secretions. in extreme cases, tracheostomy with ligation of the proximal trachea has been employed. this not only prevents aspiration but also prevents phonation, and it must be considered only in unusual situations. aspiration pneumonia is often treated with intravenous ampicillinsulbactam or clindamycin to cover mouth flora of predominant anaerobes. additional coverage against gram-negative organisms may be indicated if the aspiration is nosocomial. any child with cough of abrupt onset should be suspected of having inhaled a foreign body into the airway. toddlers, who by nature put all types of things into their mouths and who have incompletely matured swallowing and airway protective mechanisms, are at high risk. infants with toddlers or young children in the household who may "feed" the baby are also at risk. in older children, it is usually possible to obtain an accurate history of the aspiration event. these events are described as choking, gagging, and coughing while something (e.g., peanuts, popcorn, small toys, sunflower seeds) is in the mouth. the child may come to the physician with cough and wheeze immediately after the event, with a clear history and a straightforward diagnosis. in many children with a tracheobronchial foreign body, however, the initial episode is not recognized; these children may not come to medical attention for days, weeks, or even months. the initial episode may be followed by a relatively symptom-free period lasting days or even weeks, until infection develops behind an obstructed segmental or lobar bronchus. at this point, cough, perhaps with hemoptysis, with or without wheeze, recurs. on physical examination early after an aspiration episode, there is cough, wheeze, or both, often with asymmetry of auscultatory findings. there may be locally diminished breath sounds. later, localized wheeze or crackles may be detected. the triad of wheezing, coughing, and decreased breath sounds is present in fewer than 50% of patients. the presence of laryngotracheal foreign bodies often manifests with stridor, retractions, aphonia, cough, and normal radiographs. chest radiographs may be normal in 15% of patients with intrathoracic foreign bodies but should be obtained in both inspiration and expiration because in some cases the only abnormality is unilateral or unilobar air trapping, which is occasionally more clearly identified with an expiratory radiograph. in this view, an overdistended lung that had appeared normal on the inspiratory view does not empty, but the normal, unobstructed lung empties normally. this phenomenon causes a shift of the mediastinum toward the emptying lung, away from the side with the obstructing foreign body (fig. 2.9) . in other patients, localized infiltrate or atelectasis may be present behind the obstructing object. in a few patients, it may be possible to identify the foreign body itself; nonetheless, most inhaled food particles are not radiopaque and cannot be seen on radiographs. aspiration is usually unilateral (80%); 50-60% of the objects are in the right lung (the lobe depends on body position-supine versus standing-but is often the right middle lobe). the definitive diagnostic and therapeutic maneuver is bronchoscopy; either the flexible or rigid open-tube bronchoscope enables direct visualization of the object; the rigid instrument also enables its removal. ger is a common cause of cough in all age groups (see chapter 12). the typical patient is an infant in the first 6 months of life who spits up small amounts of milk frequently after feedings. this "regurgitant reflux" most commonly resolves by 1 year of age. however, many toddlers and children continue to have reflux, although it may be "silent" or nonregurgitant (without spitting up). in most people with ger, it is merely a nuisance or not noticed. in some there are sequelae, and this condition is designated gastroesophageal reflux disease (gerd). one manifestation is cough; the mechanisms for the cough are not fully understood. aspiration of refluxed material is one mechanism for cough but is probably not very common in neurologically intact children. a major mechanism for gerd with cough is mediated by vagal esophagobronchial reflexes (bronchoconstriction), stimulated by acid in the esophagus. whether acid in the esophagus is sufficient stimulus to cause bronchoconstriction by itself or whether it merely heightens bronchial reactivity to other stimuli is not yet clear. many children with reactive airways disease have cough or wheeze that is difficult to control until their concurrent ger is also treated. many episodes of cough caused by gerd occur in children with asthma that is difficult to control. (cftr), which acts as a chloride channel and affects other aspects of membrane transport of ions and water. not all the consequences of the defective gene and protein have been determined. in general, however, the defective gene product results in the long-observed clinical manifestations of the disease, including thick, viscid mucus in the tracheobronchial tree, leading to purulent bronchiolitis and bronchitis with subsequent bronchiectasis, pulmonary fibrosis, and respiratory failure; pancreatic duct obstruction, leading to pancreatic insufficiency with steatorrhea and failure to thrive; and abnormally high sweat chloride and sodium concentrations. the airway disease in cf is characterized by infection, inflammation, and endobronchial obstruction. the infection begins with s. aureus, h. influenzae, escherichia coli, klebsiella species, or combinations of these organisms but eventually is dominated by nonmucoid or mucoid pseudomonas aeruginosa. other organisms, such as burkholderia cepacia, stenotrophomonas maltophilia, alcaligenes xylosoxidans, aspergillus fumigatus, or nontuberculous mycobacteria may also appear; their significance remains undetermined. in some patients, b. cepacia has been associated with rapid deterioration and death, and in others, aspergillus species has caused allergic bronchopulmonary aspergillosis (abpa). the airway inflammation in all patients with cf appears to be the result of toxic substances, including elastase, released by neutrophils as they respond fig. 387.2.) a b the diagnosis of gerd must also be considered in the child with chronic or recurrent cough with no other obvious explanation. the child who coughs after meals or at night, when the supine position may provoke ger, should be evaluated for ger. if ger is confirmed, the next step is a therapeutic trial of antireflux therapy. treatment in a child whose cough is related to ger may be accomplished by treating the reflux (see chapter 12) or by a combination of antireflux and antiasthma treatment (see chapter 3). on occasion, the cough may be abolished by stopping all antiasthma medications. in such cases, the cough was a manifestation of reactive airways with esophageal acidification as the trigger for bronchospasm; the esophageal acidification was caused by the bronchodilator effects on the lower esophageal sphincter. cough is frequently the sole or most prominent manifestation of asthma; wheezing may be entirely absent. in fact, asthma is almost certainly the most common cause of recurrent and chronic cough in childhood (see chapter 3). some of the features that characterize the cough of a child with asthma are listed in table 2 .15. treatment for asthma manifesting as cough is the same as the treatment for asthma. cystic fibrosis (cf) is a common cause of recurrent or chronic cough in infancy and childhood. cf occurs in 1 in 2000-3000 live births among white persons, is far less common among african americans (1 in 15,000), and is rare among native americans and asians. early diagnosis improves the prognosis for untreated cf; if untreated, many patients die in infancy or early childhood. with current state-of-the-art care, median length of survival is upper 30s. cf is a genetic disorder, inherited as an autosomal recessive trait. the cf gene is on the long arm of chromosome 7; more than 1900 mutations have been identified at the cf locus. of these mutations, one (δf508, indicating a deletion, δ, of a single phenylalanine, f, at position 508 of the protein product) is the most common, responsible for 70-75% of all cf chromosomes. the mutation affects the gene's protein product, termed cystic fibrosis transmembrane regulator any age (even infants) coexistence of allergy increases likelihood, but absence of allergy does not decrease likelihood wheeze need not be present ↑cough with upper respiratory infections ↑cough with (and especially after) exercise ↑cough with hard laughing or crying ↑cough with exposure to cold ↑cough with exposure to cigarette smoke usually a history of dramatic response to inhaled β-agonists cf may manifest at birth with meconium ileus (10-15% of patients), or later, with steatorrhea and failure to thrive despite a voracious appetite, in an apparent effort to make up for the calories that are lost in the stool (see chapter 11). the most common presenting symptom is cough, which may appear within the first weeks of life or may be delayed for decades. the cough can be dry, productive, or paroxysmal. cough may respond to antibiotics or perhaps steroids, but it is less likely to improve with bronchodilators (see tables 2.3 and 2.5). although cf is a genetic disease, there is often no family history. furthermore, in atypical cases, patients may not have pancreatic insufficiency (~10% of patients) and thus may not demonstrate steatorrhea and failure to thrive. in addition, malabsorption may not be evident in the neonatal period. there is no such thing as a child who looks "too good" to have cf; common abnormalities found on physical examination are noted in table 2 .16. one of the most important physical findings is digital clubbing. in most patients with cf, clubbing develops within the first few years of life. although the list of conditions associated with digital clubbing (table 2 .17) is long, they are less common than cf, or the incidence of digital clubbing with these conditions is low. there is some relationship between the degree of pulmonary disease severity and the degree of digital clubbing. a child who has had years of severe respiratory symptoms without digital clubbing is not likely to have cf. the diagnosis is confirmed by a positive sweat test or confirming the presence of two cf mutations on chromosome 7. the sweat test, if not performed correctly in a laboratory with extensive experience with the technique (as, for example, in an accredited cf center), yields many false-positive and false-negative results. the proper technique is to use quantitative analysis of the concentration of chloride in the sweat produced after pilocarpine iontophoretic stimulation. chloride concentrations higher than 60 mmol/l are considered positive, and those lower than 40 mmol/l are negative (normal). healthy adults have slightly higher sweat chloride concentrations than do children, but the same guidelines hold for positive tests in adults. the non-cf conditions yielding elevated sweat chloride concentrations are listed in table 2 .18. false-negative results of sweat tests can be seen in cf children presenting with edema or hypoproteinemia and in samples from children with an inadequate sweat rate. sweat testing can be performed at any age. newborns within the first few weeks of life may not produce a large enough volume of sweat to analyze (75 mg minimum), but in those who do (the majority), the results are accurate. indications for sweat testing are noted in table 2 .19. in patients for whom sweat testing is difficult (e.g., because of distance from an experienced laboratory, small infants who have not produced enough sweat, patients with extreme dermatitis, or patients with intermediate-range sweat chloride concentrations), dna mutation testing can be useful. demonstration of two known cf mutations confirms the diagnosis. finding one or no known mutation makes the diagnosis less likely but is not exclusive, inasmuch as there are patients all 50 states are using a neonatal screen for cf. the cf screen assays include measuring serum immunoreactive trypsinogen (irt) levels, which are elevated in most infants with cf for the first several weeks of life, and dna analysis for cftr mutations. the main drawback of the irt assay is that it has relatively poor specificity; as many as 90% of the positive results on the initial screen are false-positive results. if an infant's irt screen is positive, the test should be repeated, or dna analysis for the 23 most common cftr mutations should be performed. at 2-3 weeks of age, which is when the irt is repeated, the false-positive rate has fallen dramatically but is still quite high (25%). definitive testing with the sweat chloride test needs to be carried out on infants with positive screening results. laboratory data that may support the diagnosis of cf include low levels of fecal elastase. this suggests pancreatic insufficiency, which occurs most commonly in cf but can be seen in other diseases. the test is not perfect for confirming cf as some cf patients have sufficient pancreatic function. pulmonary function test findings with an obstructive pattern, incompletely responsive to bronchodilators, are consistent with cf but, of course, can be seen in other conditions. conversely, some patients with cf also have asthma and may show a marked response to a bronchodilator. complications of cf that should suggest the diagnosis are noted in table 2 .20. the treatment of patients with cf requires a comprehensive approach, best performed in, or in conjunction with, an approved cf center. several studies have shown survival to be significantly better in center-based care than in non-center-based care. table 2 .21 lists the main anatomic abnormalities that cause cough. vascular rings and slings. vascular rings and slings are often associated with inspiratory stridor because the abnormal vessels compress central airways, most commonly the trachea (see chapter 3). the patient may also have difficulty swallowing if the esophagus is compressed. the diagnosis may be suspected from plain radiographs of the chest, especially those showing tracheal deviation and a right-sided aortic arch. further support for the diagnosis can be found at bronchoscopy (which shows extrinsic compression of the trachea or a main stem bronchus), barium esophagram (which shows esophageal compression), or both. the definitive diagnosis is made with computed tomographic angiography or magnetic resonance angiography. treatment is surgical. pulmonary sequestration. pulmonary sequestration is relatively unusual, occurring in 1 in 60,000 children. it occurs most commonly in the left lower lobe and can manifest in several ways (fig. 2. 10; see also table 2 .21). the chest radiograph usually shows a density in the left lower lobe; this density often appears to contain cysts (fig. 2.11) . the feature distinguishing a sequestered lobe from a complicated pneumonia is that the blood supply arises from the aorta and not the pulmonary circulation. doppler ultrasonography and ct angiography provide the definitive diagnosis. the treatment is surgical removal. congenital pulmonary airway malformation (cpam). congenital pulmonary airway malformations (formerly known as congenital cystadenomatoid malformations or ccams) are rare. they manifest in infancy with respiratory distress in nearly 50% of cases; the other half may manifest as cough with recurrent infection later in childhood or even adulthood. the chest radiograph reveals multiple cysts, separated by dense areas. chest ct scans can help make the diagnosis with near certainty. surgical removal is the treatment of choice if the lesion is symptomatic. congenital lobar emphysema. congenital lobar emphysema occurs in one of 50,000 live births. it can manifest dramatically with with not-yet-characterized mutations. furthermore, commercial laboratories do not identify all of the mutations. recovery of mucoid pseudomonas aeruginosa from respiratory tract secretions is strongly suggestive of cf. similarly pansinusitis is nearly universal among cf patients but is quite uncommon in other children. respiratory distress in the neonatal period or later (fig. 2.12) , with cough or wheeze, or as an incidental finding on a chest radiograph. radiography shows localized overinflation, often dramatic, with compression of adjacent lung tissue and occasionally atelectasis of the contralateral lung because of mediastinal shift away from the involved side. the appearance on chest ct scan is typical, with widely spaced blood vessels (as opposed to congenital cysts, for example, which have no blood vessels within the overinflated area). bronchoscopy can document patent bronchi and should probably be performed in older children in whom congenital lobar emphysema can be confused with acquired overinflation of a lobe as the result of bronchial obstruction, as with a foreign body. if the disease is symptomatic, treatment is surgical. tracheoesophageal fistula. tracheoesophageal fistula is common, with an incidence of about one in 5000 live births. of these fistulas, the large majority (85%) are associated with esophageal atresia; only 3% are the isolated, h-type fistula (a patent esophagus with fistulous tract connecting the esophagus and trachea). a neonate with esophageal atresia experiences respiratory distress, excessive drooling, and choking and gagging with feeding. the h-type fistula causes more subtle signs and may be undiagnosed for months or even years. the child may have only intermittent feeding trouble, especially with liquids. there may be recurrent lower respiratory tract infections. the diagnosis is not challenging in the infant with esophageal atresia; a nasogastric tube cannot be passed, and swallowed barium outlines the trachea. in the older child with h-type fistula, a barium esophagogram may or may not reveal the fistula. bronchoscopy and esophagoscopy should permit direct visualization of the fistula; however, the opening may be hidden in mucosal folds. treatment is surgical. many children born with tracheoesophageal fistula have recurrent cough and lower respiratory tract infection for many years, even after successful surgical correction. the cough is characteristically the harsh cough of tracheomalacia, which is present at the site of the fistula. the infections result from several causes, including ger, with or without aspiration, and altered mucociliary transport. treatment involves regular chest physiotherapy and early and aggressive use of antibiotics whenever there is evidence of increased pulmonary symptoms. hemangiomas. hemangiomas may be present within the airway and can cause cough, rarely with hemoptysis. stridor (if the hemangioma is high in the airway) and respiratory distress (if the hemangioma is large) may also occur. in rare cases, with very large airway hemangiomas, there may even be dysphagia from extrinsic compression. children with cutaneous hemangiomas in the mandibular or neck region ("beard" distribution) are at risk for an airway hemangioma. the diagnosis is made with bronchoscopy. these lesions may resolve spontaneously over the first year or so. however, if they cause symptoms, it may not be advisable or possible to wait for them to resolve. many airway hemangiomas regress with steroid treatment; however, due to the side effect profile, propranolol is considered the treatment of choice. asthma is a contraindication for propranolol treatment due to its beta-blocking effect and potential to worsen asthma. laser ablation may be indicated in some refractory cases that do not respond to first-line treatment. in the case of a large subglottic hemangioma, a tracheostomy is performed and maintained until the mass regresses. enlarged lymph nodes. enlarged mediastinal lymph nodes, such as those resulting from tuberculosis, leukemia, other hematologic malignancies, or other infections, are occasionally a cause of cough in children ( plain radiographs of the chest. the x-ray study or bronchoscopy may show extrinsic compression of the trachea. treatment is directed at the underlying cause. bronchial stenosis. occasionally bronchial stenosis, either congenital or acquired, may cause cough. the diagnosis is made with bronchoscopy, after suspicion has been raised by the child having recurrent infiltrates in the same lobe, especially with localized wheeze. treatment may be difficult. in some cases, endoscopic balloon dilatation or airway stent placement is successful; in others, surgical resection of stenotic areas may be necessary. bronchogenic cysts. bronchogenic cysts are uncommon, but they can cause cough, wheeze, stridor, or any combination of these. they may also cause recurrent or persistent pneumonia if they block a bronchus sufficiently to interfere with normal drainage of the segment or lobe. radiography may show localized overinflation if the cyst causes a ball-valve-type obstruction. the cyst itself may or may not be seen on plain radiographs. bronchoscopy reveals extrinsic compression of the airway. ct studies often definitively show the lesion. surgical removal is indicated. on occasion, a school-aged child may develop a cough that lasts for weeks, often after a fairly typical cold. this cough occurs only during wakefulness, never during sleep. in many cases, the cough is harsh and foghorn-like. it often disrupts the classroom, and the child is asked to leave. the child is otherwise well and may seem rather unbothered by the spectacle created. there is no response to medications. it seems that this type of cough, previously termed "psychogenic," or "psychogenic cough tic," but now called habit cough, has given the child valuable attention. this attention then serves as the sustaining force, and the cough persists beyond the original airway inflammation. in the small minority of cases, there may be deep-seated emotional problems of which the cough is the physical expression. during the history or physical examination, the child appears completely well and may cough when attention is drawn to the child or when the word "cough" is uttered. the physical examination findings are otherwise completely normal, as are laboratory values. because this may occur in any child, evidence of mild reactive airways disease (history or pulmonary function testing) does not rule out the diagnosis. once a physician has seen a child with this problem, it is usually possible to make the diagnosis with certainty on entering the examining room or, indeed, from the hallway outside the room. treatment can prove more difficult. the child and family should be reassured that the child is well. suggestion therapy empowers and encourages the patient to suppress the cough for short increments of time. the goal is for them to gradually lengthen the cough-free intervals. speech therapy may be helpful ( infiltrates, and there is invariably iron deficiency anemia. the diagnosis is based on lung biopsy findings. tumors. tumors causing cough are rare in childhood. cough occurs because of bronchial blockage, either extrinsic or endobronchial (see table 2 .22). the diagnosis is usually made from bronchoscopy, chest ct, or both. treatment depends on the cell type, but it usually involves at least some surgical removal. chemotherapy or radiation may be used in some cases. tracheomalacia and bronchomalacia. isolated tracheomalacia or bronchomalacia is uncommon but can cause cough in some children. the cough of tracheomalacia is typically harsh and brassy. treatment is difficult but, fortunately, is seldom needed. spasmodic croup. some children, usually preschoolers, may episodically awaken at night with stridor and a harsh, barking cough indistinguishable from that of viral croup. this entity is termed spasmodic croup and is of unclear origin. viral and allergic causes have been postulated. ger may be the cause in some patients. treatment with cool mist or racemic epinephrine is effective in most patients. if ger is the underlying cause, antireflux treatment is beneficial. obliterative bronchiolitis. obliterative bronchiolitis is very rare except in lung transplant recipients. in other instances, it may arise after adenovirus, measles, or influenza pneumonia; after exposure to certain toxins; or in other rare circumstances. children may exhibit cough, respiratory distress, and exercise intolerance. the diagnosis is suggested by the pulmonary function test or radiographic evidence of small airways obstruction; however, these findings are not always present. not all chest radiographs show overinflated lungs, and not all pulmonary function tests show decreased small airways function. the definitive diagnosis is histologic via open or transbronchial biopsy. no specific treatment is available. most children with obliterative bronchiolitis recover, but many progress to chronic disability or death. the child who coughs out blood or bloody mucus presents special diagnostic and therapeutic challenges. although hemoptysis is relatively uncommon in children, particularly among those without cf, many conditions can cause it (table 2 .25). it is important (and not always easy) to distinguish cases in which blood has originated in the tracheobronchial tree (true hemoptysis), the nose (epistaxis), and the gastrointestinal tract (hematemesis). table 2 .26 gives some guidelines to help localize sites of origin of blood that has been reported or suspected as hemoptysis. none of these guidelines is foolproof, partly because blood that has originated in one of these sites might well end up in another before being expelled from the body; for instance, blood from the nose can be swallowed and vomited or aspirated and expectorated. infection is among the most common causes of hemoptysis. lung abscess and tuberculosis need to be considered. bronchiectasis can readily cause erosion into bronchial vessels, often made tortuous by years of local inflammation, and produce hemoptysis. other infectious causes are less common and include necrotizing pneumonias and fungal and parasitic lung invasion. foreign bodies in the airway can cause hemoptysis by direct irritation, by erosion of airway mucosa, or by secondary infection. pulmonary embolus is uncommon in children and adolescents, but it needs to be considered in the differential diagnosis of an adolescent with hemoptysis of unclear origin. clues to the diagnosis of pulmonary embolus include a positive family history, severe dyspnea, chest pain, hypoxia, a normal chest radiograph, an accentuated second bronchiectasis. bronchiectasis is defined as an abnormal dilation of the subsegmental bronchi and is usually associated with chronic cough and purulent sputum production. it occasionally occurs after severe pneumonias (bacterial or viral); it eventually develops in nearly all patients with cf. diagnosis may, on occasion, be made with plainchest radiographs, but high-resolution ct scanning is the diagnostic procedure of choice. treatment of bronchiectasis consists of airway clearance with chest physiotherapy with postural drainage or highfrequency chest wall oscillation, occasionally bronchodilators and mucolytic agents, and antibiotic therapy during exacerbations. surgical resection may be indicated in cases that are progressive and localized when medical therapy has failed. the prognosis of bronchiectasis depends on the underlying cause. cf-associated bronchiectasis is a major cause of cf-related morbidity and mortality; whereas, non-cf bronchiectasis may remain stable or even regress with therapy. ciliary dyskinesia. conditions in which the cilia do not function properly (immotile cilia or ciliary dyskinesia) lead to cough, usually because infection (and bronchiectasis) occurs in the absence of normal mucociliary transport. treatment is similar to that for cf, with regular chest physiotherapy and frequent and aggressive use of antibiotics at the first sign of airways infection, most commonly increased cough. interstitial lung disease. interstitial lung diseases are now classified based on those that occur during the neonatal period and those that are not as prevalent in infancy. interstitial lung diseases that manifest with cough include aspiration (chronic and recurrent) pneumonitis, hypersensitivity pneumonitis, bronchiolitis obliterans, and cryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia or boop). lung biopsy may be required for a diagnosis. pulmonary hemosiderosis. pulmonary hemosiderosis is a rare, and often fatal, condition of bleeding into the lung that can manifest with cough. if sputum is produced, it is often frothy and blood-tinged. there may be frank hemoptysis. however, the cough may be nonproductive, or the sputum may be swallowed. some cases are associated with milk hypersensitivity (heiner syndrome), and affected children may have upper airway obstruction. some cases are associated with collagen vascular disorders. radiographs usually show diffuse fluffy postnasal drip (?) bronchiectasis ciliary dyskinesia interstitial lung disease heart failure/pulmonary edema pulmonary hemosiderosis drug-induced (see table 2 bronchoscopy can sometimes localize a bleeding site, identify a cause (e.g., a foreign body or endobronchial tumor), or recover an offending bacterial, fungal, or parasitic pathogen. in many instances, bronchoscopy does not help except by excluding some possibilities, because either no blood or blood throughout the tracheobronchial tree is found. bronchial artery angiography may help to identify the involved vessel or vessels. treatment of hemoptysis depends on the underlying cause. it can be a terrifying symptom to children and their parents, and a calm, reassuring approach is essential. because hemoptysis is seldom fatal in children, reassurance is usually warranted. furthermore, hemoptysis most often resolves, and treatment of the bleeding itself is not often needed. what is required is treatment of the underlying cause of the hemoptysis, such as therapy for infection, removal of a foreign body, or control of collagen vascular disease. when death occurs from hemoptysis, it is more likely to be from suffocation than from exsanguination. in cases of massive bleeding, the rigid open-tube bronchoscope may help suction large amounts of blood while ventilating and keeping unaffected portions of lung clear of blood. interventional radiologists treat as well as localize a bleeding site by injecting the offending vessel with occlusive substances (embolization). in extremely rare instances, emergency lobectomy may be indicated. heart sound, an abnormal compression ultrasonographic study of the leg veins, a positive homans sign, a positive helical ct scan, and a high-probability lung ventilation-perfusion scan. the diagnosis of several causes of hemoptysis is straightforward. for example, hemoptysis that occurs immediately after a surgical or invasive diagnostic procedure in the chest should suggest an iatrogenic problem. the chest radiograph can help suggest lung abscess, pulmonary sequestration, bronchogenic cyst, or tumor. chest ct can help with cases of arteriovenous malformations, and additional laboratory values can support the diagnosis of collagen vascular disease. cough that may produce significant complications (see table 2 .9). for most diseases, suppressing the cough offers no advantage. disadvantages include narcotic addiction and loss of the protective cough reflex with subsequent mucous retention and possible superinfection. demulcent preparations (sugar-containing, bland soothing agents or honey) temporarily suppress the cough response from pharyngeal sources, and decongestant-antihistamine combinations may reduce postnasal drip. cough itself seldom necessitates specific treatment. nonetheless, cough is not always completely benign (see table 2 .9). most complications are uncommon, and most accompany only very severe cough, but some are serious enough to justify treatment of the cough itself. cough suppressants include codeine and hydrocodone (two narcotics) and dextromethorphan (a nonnarcotic d-isomer of the codeine analog of levorphanol). such agents should be used only for severe cough is important because it is a symptom and sign of underlying disease that frequently merits treatment. in the acute setting, severe disease, including massive hemoptysis or profound dyspnea or hypoxemia, warrants immediate attention, rapid diagnosis, and rapid management. certain chronic conditions, including those that suggest cf and those in which symptoms have persisted and interfere with a child's daily activities and quality of life, warrant further evaluation and treatment. finally, a child whose cough fails to respond to what should have been reasonable treatment should be referred to a pulmonary specialist (table 2 .27). evaluation of chronic or recurrent cough guidelines for evaluating chronic cough in pediatrics recommendations for the assessment and management of cough in children upper respiratory infection bacterial tracheitis: report of eight new cases and review the common cold adverse events from cough and cold medication in children does this patient have sinusitis? diagnosing acute sinusitis by history and physical examination pertussis (whooping cough) report of the committee on infectious diseases bts guidelines for the management of pleural infection in children chlamydial respiratory infections the management of communityacquired pneumonia in infants and children older than 3 months of age: clinical practice guidelines by the pediatric infectious diseases society and the infectious diseases society of america infant pneumonitis associated with cytomegalovirus, chlamydia, pneumocystis, and ureaplasma: follow-up value of radiological follow-up of childhood pneumonia british thoracic society guidelines for the management of community acquired pneumonia in children: update tuberculosis (myconbacterium tuberculosis) etiology and treatment of pneumonia pulmonary manifestations of acquired immunodeficiency syndrome standardized diagnosis of pneumonia in developing countries hypoxaemia in young kenyan children with acute lower respiratory infection tuberculosis in children clinical practice guideline: the diagnosis, management, and prevention of bronchiolitis the evaluation of the child with recurrent chest infections nebulised hypertonic saline solution for acute bronchiolitis in infants bronchoscopic removal of aspirated foreign bodies in children tracheobronchial foreign bodies subglottic foreign bodies in pediatric patients tracheobronchial foreign bodies cystic fibrosis the cystic fibrosis genotype-phenotype consortium. correlation between genotype and phenotype in patients with cystic fibrosis cystic fibrosis therapeutics. the road ahead wheezing in infants with cystic fibrosis: clinical course, pulmonary function, and survival analysis cystic fibrosis physiotherapy in cystic fibrosis efficacy and safety of short-term administration of aerosolised recombinant human dnase i in adults with stable stage cystic fibrosis the diagnosis of cystic fibrosis: a consensus statement emerging therapies for cystic fibrosis pseudomonas cepacia: pulmonary infection in patients with cystic fibrosis effect of long-term treatment with inhaled budesonide on adult height in children with asthma a clinical index to define risk of asthma in young children with recurrent wheezing airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age statement: asthma control and exacerbations. standardizing endpoints for clinical asthma trials and clinical practice low-dose inhaled corticosteroids and the prevention of death from asthma venous thromboembolic complications in children clinical assessment and management of massive hemoptysis massive haemoptysis: medical management will usually arrest the bleeding pathogenesis and management of hemoptysis in children key: cord-015352-2d02eq3y authors: nan title: espr 2017 date: 2017-04-26 journal: pediatr radiol doi: 10.1007/s00247-017-3820-2 sha: doc_id: 15352 cord_uid: 2d02eq3y nan prof. michael riccabona undertook his medical school & university training at the university of innsbruck, tirol, austria, completing his md at karl franzens university in graz, austria. following an internship in neurology, surgery and internal medicine he then specialized in paediatrics at the dept. of paediatrics, university hospital in graz. there he took charge of the paediatric radiology and sonography sections at university hospital in graz, as associate professor of paediatrics. in 1993 he additionally started to specialise in radiology, becoming associate professor of radiology in 1998 -then taking charge of the subsection of paediatric sonography at the dept. of radiology, university hospital in graz, where in march 2006 he was appointed full univ. prof at the medical university graz, austria. he has a distinguished academic career and written over 200 papers, more than 50 chapters and several textbooks, and is a very popular international speaker, delivering numerous lectures at many high profile scientific meetings. he is an active member of several reputable international societies, has been chair of the paediatric ultrasound section of the austrian ultrasound society since 2003 , and president of the society of german speaking paediatric radiologists (2010) (2011) (2012) (2013) (2014) (2015) (2016) . he is a constant source of inspiration within his subspecialist areas of interest in ultrasound and abdominal radiology in children. he has been course director at several important meetings and served as president of espr in graz in 2015 and as lead of the paediatric subcommittee at ecr in 2012. he has provided inspirational leadership as chair of the espr task force on uroradiology since 2002writing state of the art guidelines and procedural recommendations to facilitate standardised best practice for imaging within paediatric uroradiology. he has been a reviewer for many international journals. he has on-going active roles in postgraduate education for medical colleagues from eastern europe, including basic ultrasound education and refresher courses, and workshops. michael riccabona is very deserving of honorary membership of espr, which reflects his seminal role within paediatric radiology in europe and his tireless dedication working for the good of children. & to discuss how to optimally adapt the various imaging techniques minimising radiation exposure and risks during diagnostic imaging in children. & to consider common restrictions, challenges, and possible solutions in paediatric radiology within the different settings in different countries, regions, continents and clinical scenarios -discussing all these aspects with colleagues, and to mingle with experts from all over the world learning from each other and fostering networking in paediatric radiology to try to grant optimal imaging for all children. an application for the 53 rd annual meeting as well as for the 39 th post graduate course has been submitted to the eaccme® for cme accreditation of this event. the eaccme is an institution of the uems (www.uems.net). the number of cme points will be announced at the espr 2017 congress website. each medical specialist should only claim those hours of credit that he/she actually spent in the educational activity. certificates of attendance will be available in the espr myuserarea after the meeting. the answers right away is: yes we can and we constantly have to. it is part of human nature to recognize problems and to find solutions. we define ideals but we also face reality. being aware of the gap in between we are constantly driven to improve. this overview will highlight some milestones and disputes throughout the 100 years of development in the use of plain x-ray imaging. it will hint on scientific literature and sources of information. and it will hint on some swiss contributions as the espr meeting 2017 will be held in davos, switzerland. fighting the glow not the fire -122 years of x-ray imaging development and improvement: in the beginning of the clinical use of x-ray imaging, there was great enthusiasm in its potential without knowing the unfavorable dangers of uncontrolled use of x-ray. the dangers were recognized and the 'beast' was tamed and domesticated. in respect to radiation protection, the most significant achievements took place in the first half of that development. throughout the recent decades, some further considerable steps in dose reduction took place mainly by the improvement of film-screen systems and the recent introduction of computed (cr) and digitized radiography (dr). even if the early computerized x-ray imaging brought a slight increase in patient doses (which was overcompensated later on by direct digital radiography) a whole new world of further advantages launched the digital era in which we live today. as we all know new dangers arose with these techniques as the uncontrolled distribution of images and thereby confidential patient data over hospital departments and across borders throughout. also, the risk of an evitable overexposure in digital radiography is a significant issue. throughout the process of taming the radiation and controlling it, today's doses are attained within the lowest range of the danger scale. this range still is perceived as a black box within which we do not exactly know which concept reflects the potential harm best. the linear no-threshold model [lnt] is acknowledged as the concept which most reliably supports the idea of radiation protection. other concepts partly oppose the linear idea and question the relevance of that dose range because there lie so much greater health benefits in the appropriate use of diagnostic x-rays. several scientists even propagate the idea that very low levels are producing health benefits instead of physical harm [hormesis model]. nevertheless, the lnt model is widely accepted as the most helpful in the context of diagnostic radiology. some recent studies were able to support the idea of potential harm at very low dose levels as they were able to prove the induction of attributable cancers in the pediatric age group. so today we are fighting the glow, not the fire. as trained medical professionals we are fully aware of the fact that there is only little potential harm to the patient by using x-rays in the current state of the art. but on the other hand, we also have to be aware of the fact that our patients and their parents still fear the fire. one of our main tasks, therefore, is to explain the risks and benefits to the patients and their advocates and to educate the public. developed straight from the first radiographic technique's digital radiography today is state-of-the-art in plain 2d-imaging. throughout the last decade, it has replaced cr and conventional radiography in many institutions. in the united states of america, one of the most developed healthcare systems, healthcare authorities propagate incentives to abolish cr and older imaging systems by making them financially unattractive. the market is fully concentrated on the spread of dr systems. momentarily there are no real milestones but many refinements of existing systems such as tomosynthesis, dual energy subtraction and advanced auto-stitching, fluoroscopy capability, basic angiography applications and 3-d cone-beam ct images are made available. combinations of these features can be found in some recently designed x-ray machines. grid-less imaging software can reduce patient dose significantly. concerning detectors, there are cr retrofit systems which will support the easy upgrade of existing systems to dr capability. wireless detectors with large internal storage, different sizes and high resolutions of 100 microns are available. dr is becoming a part of the system in the current era of full digitalization of our lives and big data, digital radiology is a cornerstone of our healthcare systems. ris and pacs as part of integrated healthcare (ihs) systems are widely disseminated. at the next step, all accessible data will be used for analyses. the major vendors of imaging systems, as well as pacs suppliers and independent companies, offer readymade software tools for reports and evaluations of all kind. the doses from different x-ray sources can be screened internally and be used for optimization purposes. they also can be sent to remote servers for dose monitoring, comparison and optimization in multi-hospital health care provider settings or to comprehensive databases like the american college of radiology dose index registry, cancer registries, or for central billing. has everything been invented? many technologies have been declared dead before a new transformation appeared. this was the case for example with single slice ct before the invention of spiral ct by willi kalender, germany and peter vock, switzerland in 1988. often the plain x-ray image was meant to be needless or redundant as newer technologies like ct or mri approached. but it still is of value because of different reasons as the low dose, high availability, well known and easy interpretation to name a few. there are some new and sophisticated techniques on the way like the "smart x-ray source" which uses coherent beams of x-rays from an array of micronsized point sources, developed by scientists at the massachusetts institute of technology (mit). the developers promise less radiation, less weight of the equipment and a far better soft tissue resolution. another promising approach is phase contrast x-ray imaging which has the potential to reduce the dose up to 1/100 of the actual value. it also has its strengths in additional soft tissue information as recent experimental publications show (paul scherrer institute switzerland) e. g. in functional evaluation of lung fluid (munich, germany). functional imaging of the lungs can also be achieved without any radiation as the development of the known concept of electrical impedance tomography highlights. this functional imaging method usually is not within the modality spectrum of radiologists. dose control and reduction -local -regional -international the most effective measures to achieve significant dose reductions in your own department are still the same strategies which are based on the "eternal rules" as we know them from our teachers: avoiding unnecessary exposures by strictly controlling the appropriateness of a referral. justification is a shared responsibility between radiologists and clinicians. there are many tools available for justification like the appropriateness criteria, guidelines or rules (like wrist or ankle rules) of several national societies and different study groups. the process of optimization is mainly in the hands of the technicians. as many studies show, the proper collimation still has the greatest effect on dose reduction. other important factors are the positioning of the patient and the shielding of radiosensitive organs which are not relevant for image interpretation so that they may be covered by lead shields. the proper use of the grid in bigger children can now partially be replaced by software solutions. in digital radiography, a profound knowledge of postprocessing possibilities is mandatory as well as the active control of the exposure indices. dose limitation procedures should be regularly checked in a team-based approach to avoid overexposure by less experienced staff or "exposure creep". existing standards should be actively used to guarantee a constant satisfactory image quality. in 2011, the image gently campaign released a safety checklist for performing digital radiography examinations on pediatric patients which is easily applicable to every radiology service. organizational improvements: at regional and national level, efforts should be made to check for best practice use in the departments and to compare and discuss imaging strategies. the establishment of national and international dose reference levels helps to keep the overall doses low and to protect the population from unnecessary overexposure. the pidrl project prepared the "european diagnostic reference levels for pediatric imaging" as part of the eurosafe project. momentarily the results of pidrl-workgroup are harmonized with international organizations. the european guidelines on drls for paediatric imaging can be accessed as a preliminary final for workshop drafts on the internet. on a worldwide basis, the world health organization has published a fundamental information brochure concerning radiation risks and the communication of health professionals and patients. health care professionals have a shared responsibility for communicating risks and benefits of imaging procedures to patients, especially in the case of pediatric patients. the document "communicating radiation risks in paediatric imaging-information to support health care discussions about benefit and risk" is intended to serve as a tool for health care providers, to communicate known or potential radiation risks associated with pediatric imaging procedures and to support risk-benefit dialogue in health care settings. as said before we are fighting the glow, not the fire. the paper of the swiss pediatric oncology group stirred a broad discussion. among other issues, there was a question if it shouldn't be a logical consequence to transfer kids from areas with higher background radiation to safer areas. the author's answers were clear: that swiss health authorities better concentrate their efforts more effectively and with greater benefit for more people by supporting prevention "toward modifiable environmental factors leading to larger numbers of deaths from several causes, such as exposure to radon, air pollution, and second-hand tobacco smoke". this leads to the conclusion that we as medical radiological professionals do have the obligation to make every effort to prevent our patients and personnel from harm of the usage or non-usage of radiation. as health specialists, we also should support the fields of prevention with broad mass effects as far as we have the opportunity. and as human beings, we are summoned to do so in respect to other beings, to our environment and to the resources we all share. radiation protection and quality improvement is just a small part of it all, but it is our field -and 'yes we can'. "communicating radiation risks in paediatric imaging. freely available at the who homepage." computed tomography: are we doing enough? e. sorantin; graz/at summary: already in 1912 the alara principle was publishedbut the implementation is still far from complete. according to the surveys of the ec tender project "pidrl -european diagnostic reference levels for paediatric imaging" the most frequent computed tomography (ct) examinations in children are, in descending order, head/neck, chest and abdomen thus counting for about 75% of all pediatric ct's. therefore it makes sense to optimize these examinations first. surveys of the "international atomic energy agency (iaea)" in 40 countries have shown, there is considerable lack of organizationeg in about 50% of facilities protocols for children were missing, indication based protocols available only in 57%, ctdi values for head and chest two to five times of those for adults. all of these simple facts indicate we are not doing enough for radiation protection in pediatric ct. actions to lower dose in ct can be categorized in organisational, optimization and alternatives. the interdisciplinary implementation of international guidelines for ct in minor head trauma with trauma surgeons could serve as an example of organisational actions. for dose optimization knowledge about dose relevant factors according the "imaging chain" is mandatory as well as adjusting kv to pediatric needs. dose influence on image quality must be known, by exploiting the fact, that, if all ct parameters are kept constant but hte slice thickness is just halve there must be an increase in noisein particular about two times more. therefore if a standard examination is reconstructed at half slice thickness and image quality is still appropriate the amount of waste radiation is in the range of 100%. therefore if the next examination will be reduced with eg 20% mas setting less will be for sure in appropriate quality and the process can be started again. after a couple of examinations the optimal dose will be reached. thus the "half slice thickness" approach is easy to do, does not need special equipment or human resources and will help to find the appropriate dose. the third point is alternatives -ultrasound and mri being the candidates in the first row. new, radiation free, techniques like electrical impedance tomography and others are already developed and can be expected to be release soon. take home points: & we are not doing enough for ct dose savingeven more than 100 years after release of alara principle & dose saving actions can be categorized inthe subtasks organisation, optimization and alternatives & "the half slice thickness approach" is an easy to do technique to elaborate the optimal dose on an particular ct machine. prenatal thoracic mr l. alamo; lausanne/ch the generalization of screening us has considerably increased the detection of congenital anomalies in utero. in the last years, important technological advances and especially, the development of fast heavily t2-weighted sequences has led to an increasing use of prenatal mri as additional diagnostic imaging method. mri is increasingly used for evaluation of thoracic pathology, including tumours and vascular malformations as well as anomalies of the diaphragm, the lungs and more recently, even of the foetal heart: -thoracic tumours and vascular malformations: the diagnosis of a congenital tumor during pregnancy involves a tremendous emotional impact for a family. the most frequently observed thoracic tumours are teratoma, myocardial rhabdomyoma and exceptionally, pleuropulmonary blastomas. mri may provide relevant additional information concerning the origin of the lesion and its real anatomical extent. -diaphragmatic pathology: congenital hernia is by far the most commonly reported foetal diaphragmatic anomaly. the large field of view and the multiplanar possibilities of mri may help to clarify the position of the herniated organs and to evaluate the severity of lung hypoplasia, considered the most important parameter for predicting outcome. other rare pathologies include eventration, paralysis and diaphragmatic lung sequestrations. -lung anomalies: congenital lung abnormalities are a heterogeneous group of pathologies consisting of isolated bronchopulmonary or vascular anomalies or a combination of both of them. congenital pulmonary airway malformation, bronchopulmonary sequestration and bronchial atresia are the most often observed pathologies but they present significant overlap imaging findings. mri allows accurate information concerning the location and extension of the lesion and the volume of the normal and abnormal lung. -heart pathology: the evaluation of the foetal heart remains extremely difficult because of its small size and high rate of battements. the unpredictable foetal motions during data acquisition and the absence of a foetal ecg signal to synchronize data acquisition are additional problems. in the last years, different approaches have been made to overcome these challenges. radiologists should know the typical imaging findings of the thoracic pathology most often observed in foetuses. prenatal mri may provide additional relevant information in a wide spectrum of congenital thoracic anomalies, but in general, it should only be performed if it is considered that additional results might influence the management of the pregnancy and/or the therapeutic approach. therefore, it is important to know the right indications for mri and to recognize the limits of the method. interruptions during embryogenesis of the muellerian or wolffian ducts result in various, potentially complex genitourinary abnormalities of a wide spectrum or combinations. multiple imaging modalities are employed to evaluate patients with these abnormalities. ultrasound is the frontline imaging modality. mr imaging is mostly reserved for complex cases and may incorporate an mr urography, too. other imaging modalities are less frequently used or provide only ancillary information. this presentation will demonstrate the utility of ultrasound and mr imaging, in particular, in the routine diagnostic imaging of patients with the wide spectrum of muellerian and wolffian duct abnormalities. & mr imaging is reserved for more complex cases. neonatal hepatic tumors and vascular malformations d. pariente, s. franchi-abella; le kremlin bicêtre/fr neonatal hepatic tumours and vascular malformations are rare but imaging plays a key role in diagnosis and treatment. the most frequent hepatic tumour is haemangioma (fig1) which often is asymptomatic but may be complicated by cardiac failure, coagulopathy or compartment syndrome. the differential diagnosis mainly includes hepatoblastoma, hematoma (fig2), abscess, mesenchymal hamartoma, choriocarcinoma in the solitary form and metastatic neuroblastoma, cirrhosis, neonatal leukemia in the multifocal form. pertinent biological data are alpha-fetoprotein (but level may be normally high in neonate), betahcg, and urinary catechol amines. hepatic vascular malformations are rarer and include intra or extra porto-systemic shunts (pss), arterio-portal fistula or complex mixed forms. intrahepatic pss may be associated with haemangioma and regress in most cases rapidly (fig3). on the contrary the extrahepatic pss which are located below the portal vein, should be urgently closed to avoid occurrence of agenesis of the portal vein. the best imaging modality is us which must be performed with high frequency probes and colour doppler to identify hepatic vessels and assess patency, direction of flow, abnormal communication. mri and ct with contrast injection may also be useful. hepatic mass in a 12 do neonate with increased crp and afp. us showing a hyperechoic mass with thrombosis of the left portal vein (black arrow) and a track (white) extending to the mass: hematoma due to malposition of an umbilical vein catheter. hemangioma of antenatal diagnosis on d1. the mass is composed of a large anterior vascular lake corresponding to a porto-systemic shunt and a tissular hyperechoic part. the infant has remained asymptomatic. intrahepatic porto-systemic shunt between the left portal branch of segment 2 (white arrow) and the left hepatic vein (black arrow) in a neonate. at 3 months of age this shunt has completely resolved. haemangioma is the most frequent hepatic tumour in the neonate and is often asymptomatic with spontaneous resolution. levels of alphafetoprotein are physiologically high in the neonate, and can be misleading. hepatic hematoma can be secondary to traumatic delivery, to coagulation disorders or to umbilical vein catheterization. intrahepatic porto-hepatic shunts are the most frequent vascular malformations and regress in most of the cases in the first year of life. us with colour doppler remains the best imaging modality in the neonatal period. imaging in crohn disease: state of the art in diagnosis, prognosis and followup n. colavolpe, a. aschero, b. bourliere-najean, c. roman, f. khachab, h. pico, m. kheiri, g. gorincour, c. desvignes, p. petit; marseille/fr summary: during the past years the inflammatory bowed diseases (ibd) have increase in frequency (1). less than twenty-five percent of them occur in children of less than 18 years (2) and crohn's disease (cd) is twice as frequent than ulcerative colitis (uc) in the pediatric age group. specific phenotypic and genotypic subtype of ibd occur in younger children. early onset (eo) pediatric ibd (before 5 years of age) represent 11% of childhood ibd (3) . uc and undetermined colitis are more frequent in this age group. eo cd showed a more frequent isolated colonic and upper gastrointestinal involvement than later-onset disease where locations are predominantly colic and terminal ileum later on childhood. some pediatric ibd specificities exist than can interfere with the imaging findings: -cd can be limited to the terminal ileum or to the colon in up to 20% of children (4) . isolated jejunal involvement is reported to occur in 5-6% of children. this location is more frequent in the youngest and is more at risk of complicated course of disease (2) . for auvin et al. (3) the small bowel is involved in 80% of cases with less involvement of the terminal ileum than in the adult population. -uc: the classical contiguous alteration of the bowel wall from the rectum to the caecum is inconstant. a macroscopic rectal sparing is reported from 5 et 30% and the absence of continuous disease from rectum to caecum (caecal patch) described in 2% of children. transmural inflammation may be present in severe form as well as terminal ileitis without granulomata (backwash ileitis) (2) . in order to assess these pathologies, and more specifically cd small bowel locations which are difficulty explored by others modalities, small bowel follow-through, barium enema, ultrasound, computed tomography and mr imaging have been widely used. among them, mr-enterography has gained worldwide acceptance due to multiple factors including: a high contrast resolution, a multiplanar ability, an absence of radiation, the possibility to explore in the same exploration the whole bowel and the extra-bowel diseases (perianal fistulae, sacroiliac joint, biliary tract), the ability to compare of side by side consecutive studies in a reproducible manner, a more easily understood exploration by the clinicians than ultrasound, and first of all for its performances. in order to technically harmonize this exploration a recent consensus statements on mre protocol has been published by the esgar and the espr societies (5) . preparation: -depending on their age children must not have solid oral intake from 2 to 6 hours prior to the examination to reduce bowel wall motility. morning mr appointment is more favorable for this purpose. no gasless fluid restriction is recommended but is reabsorbed too quickly to distend enough the small bowel. none hyperosmolar non absorbable solution is superior to another. its ingestion must start 45 to 60 minutes prior to mre. the recommended volume is 20 ml/kg with a maximum up to 25 ml/kg. explanations long before the mre concerning the importance of such absorption and the use of a refreshed product mixed with aromatized flavors will facilitate the child's participation. -the use of spasmolytic agents is optional. however, there are recommended in adults by multiple societies including esgar (5) , the society of abdominal radiology (6) and the acr (www.acr.org/ quality-safety/standards-guidelines). but, mre without antiperistaltic agents result has reached a high diagnostic confidence and excellent agreement with ct enterography for the presence of cd (7) . if used, they need to be administered immediately prior to motion sensitive sequence (t1w dynamic enhanced sequences). if the pictures obtain with these medications are of better quality, there is no evidence that they change the final diagnosis and the children's therapeutic management (8) . the use of these products increase the length of the exploration and their side effects are frequent (nausea > vomiting) which balance their visual benefice (8) . if a spasmolytic agent is used, the recommended first line spasmolytic agent is i.v. hyoscine butylbromide (0.5mg/kg i.v). the recommended second line agent is i.v. glucagon, 0.5mg (<24.9kg) and 1mg (>24.9kg), given as a slow infusion with i.v. saline at an infusion rate at 1ml/s. -no rectal enema is needed. -exploration can be performed either at 1.5tesla or 3testla. more chemical shift and susceptibility artifacts are present with the latter. prone position has been demonstrated to allow better small bowel distension than the supine one with reduction of the peristaltism but without better lesion detections (9, 10) . large multi-elements coils are needed to cover with high resolution from the perineum up to the left colonic flexure. sequences: both morphologic steady state free precession gradient echo and 2d -t2-weighted images are needed in the axial and coronal planes. fat saturation in one of this plane is recommended and maximal slice thickness of 5 mm is required. nowadays, non-enhanced then enhanced 3d t1-fat saturation weighted sequences are mandatory. slice thickness does not exceed 3 mm. enhance sequence need to be acquired at the portal phase of injection. however, in recent studies the need for gadolinium has been questioned when dwi is added to the morphologic sequences. dwi sequences have been considered optional (5,6) but we consider their place essential in pediatric practice. they must be done with high b values, from 600 up to 800 in the coronal and axial planes with 5 to 8 mm contiguous cut in free breathing. axial plane is less prone to artefact than the coronal plane. interestingly enough shenoy et al (11) report in 27 pediatric patients that dwi does not perform as well as standard mre for detection of active crohn disease but the combination of dwi and mre increases imaging accuracy for determining disease activity compared with either technique alone. seo et al (12) in 44 young adults said that dwi mre was noninferior to contrast-enhanced mre for the evaluation of inflammation in cd. based on the exploration of 130 cd adult and pediatric population, dwi proved to be efficient and would avoid gadolinium injection (14) . sirin et al. (14) report in 37 children that dwi revealed lesions that were not detectable with mre done with gadolinium injection. finally, respectively dubron et al. (15) in 48 children and neubauer et al (16) in 33 children and young adults demonstrate better performance of dwi than gadolinium enhanced imaging. like the existing mr protocols for suspected appendicitis (17) it will not be surprising to see fast mr ibd explorations becoming an alternative to emergency us as already proposed (16) . this fast mr limited to a morphologic t2 sequence in two planes associated with dwi sequences will allow a positive diagnosis and the ibd work up. apart from bowel obstruction and its spontaneous bowel distension one of the limiting factors will be the need for an oral water agent uptake in a potential surgical patient. however, it has been published in the adult literature than an oral or rectal preparation was not necessary to rule out uc (18) nor a cd (19) . the other limiting factor is the length of exploration. mre can be shorten especially if the patient's positioning is easy to do (dorsal decubitus) (20) and if there is no need for injection, either for spasmolotytic agent and for gadolinium chelates. the suppression of the iv line, the absence of potential side effects (nausea, vomiting) of paralytic agents and the decreased of repeated long apneas with no loss of significant information will be strong progresses toward the holy grail. -positive diagnosis, disease activity, prognosis and follow-up: mre has a better accuracy to detect inflammation for the small bowel than for the colon (21) . one of its goal is to try to accurately identify features of active inflammation vs fibrotic disease. this is of paramount importance since the former may respond to medical treatment and the latter may need surgical resection. however, inflammation and fibrosis are associated within the same bowel segment and progress in a parallel way making the goal difficult to reach (22) (23) (24) . in their study based on the analyze of 20 children operated for cd strictures, barkmeier et al. (24) report than strictures demonstrating >3 cm upstream dilatation with associated feces sign were highly associated with transmural fibrosis. the most severely fibrotic strictures were associated to the greatest amount of inflammation and there was no significant correlation between stricture length, mural thickness, degree of post-contrast enhancement (arterial and delayed venous phases), diffusion-weighted imaging apparent diffusion coefficient, pattern of post-contrast enhancement, or normalized t2-weighted signal intensity and histological fibrosis or inflammation scores. however, correlation with histological specimens of cd done on a other series s312 (2017) 47 (suppl 2):s297-s pediatr radiol demonstrated that the enhancement ratio of the wall is positively correlated with disease chronicity due to a possible increasing microvessels permeability and inversely correlated to acute disease (25). on the other hand, several authors have tried to correlate the adc values to cd activity. fibrotic tissue does not restrict diffusion and presents a decrease of signal at high b values and high adc values whether acute inflammation shows decrease adc values. variable thresholds from 1.6 x10 -3 mm 2 /s to 2.4 x10 -3 mm 2 /s have been proposed to separate active vs non active disease (21) . however, others authors have reported low adc value of fibrosis compare to histology (26). even if promising results have been published with high correlation with the crohn disease endoscopic index of severity (13) , adc measurements are associated with sever limitation factors including sample size overlap between the bowel wall and its atmosphere, lack of reproducibility between mri-units and mri-vendors, non-standardized sequence b-values parameters (21) . two mre scores are available to quantify the activity of cd. one is using gadolinium injection (27) and the other dwi (13) . due to the complexity of the formula, both are difficult to use in daily practice and have not been evaluated in paediatric practice. interestingly enough if a simplify mre paediatric protocol appears to become a reality, us stays a good imaging challenger and (28). in a recent meta-analysis, based on adult and pediatric series, calabrese et al (29) reported that bowel us showed 79.7% sensitivity and 96.7% specificity for the diagnosis of suspected cd, and 89% sensitivity and 94.3% specificity for initial assessment in established patients with cd. bowel us identified ileal cd with 92.7% sensitivity, 88.2% specificity, and colon cd with 81.8% sensitivity, 95.3% specificity, with lower accuracy for detecting proximal lesions. the absence of abnormal thickness wall would have a negative predictive value, high enough to exclude the need for further exploration, especially when cd is concerned (30,31). concordance between us and mre have been variably reported from excellent (32) to just correct (33). rosembaum and al (22) report that the us findings present in children operated for cd include: bowel wall thickness above 4.3 mm (mean, 6.1 mm) and an increased frequency of loss of mural stratification and fibrofatty proliferation. others us technologies are used in children to better approach the disease activity. it includes, hydrosonograpy using specific oral agents (mannitol, sorbitol, polyethylene glycol, etc…), contrast-enhanced ultrasound and dynamic contrast-enhanced ultrasound (nowadays, contrast agent is offlabel in children) (34) and elastography (35). their enthusiastic results and their efficiency to assess disease activity need to be confirmed (36). in conclusion, as we suspected 7 years ago (37), mre has dramatically modified our approach of pediatric ibd especially when considering its orientation toward a less invasive exploration and the increasing importance of dwi imaging. a cost benefice between mre and us remains to be done on this increasing disease. heterotaxy and isomerism c. lapierre; montreal/ca summary: objectives: to review the classification of visceroatrial situs to describe the associated cardiac and non-cardiac anomalies to illustrate typical findings in fetuses, neonates and children to discuss the surgical consideration and the long-term follow-up in these patients abstract: by definition, the type of situs is determined by the relationship between the atria and the adjacent organs. anatomically, the atrial chamber differentiation is based on the morphologic aspect of the atrial appendages, earlike extensions of the atria. three types of situs exist: solitus (normal), inversus (mirror image) and ambiguus. a single type of situs is present in a patient. when the situs is neither solitus nor inversus, it is referred to as situs ambiguus or heterotaxy. heterotaxy may manifest with various abnormal visceroatrial configurations that are associated with cardiac (in 90-100% of cases) and extracardiac anomalies such as splenic abnormalities, biliary atresia and intestinal malrotation. two subsets of situs ambiguus are well-recognized: right isomerism (asplenia) and left isomerism (polysplenia). in heterotaxy, the venoatrial connections are frequently abnormal. left isomerism is usually indicated by bilateral bilobed lungs, interruption of the ivc and multiple spleens. the more likely found cardiac anomalies are: pulmonary or aortic stenosis, isolated atrial and ventricular septal defects, cardiac arrhythmia due to sinus node dysfunction as well as pulmonary veins that drain into both the right and the left atria. in the presence of right isomerism, bilateral trilobed lungs, a large symmetric liver, and absence of the spleen are frequently observed. at the cardiac level, patients are more likely to have a common atrioventricular defect, a double outlet right ventricle and pulmonary stenosis. total anomaly of the pulmonary venous return and absence of coronary sinus will always be present in right isomerism. heterotaxy can be diagnosed with high accuracy by prenatal echography. a diagnosis should be suggested in the presence of congenital heart disease, visceroatrial heterotaxy and interruption of inferior vena cava with azygos continuation for left isomerism or abnormally closed juxtaposition of inferior vena cava and descending aorta in right isomerism. the mortality in fetuses is high in the presence of heart block and hydrops whereas the cardiac anomalies influence the long-term outcome. as discussed in the literature, the clinical outcomes and long-term prognosis in these patients are relatively poor when compared with non-heterotaxy patients. the risk factors are cardiac (underlying anatomy and arrhythmia risk) and non-cardiac. based on the cardiac anatomy, one of the main determinants is left versus right isomerism. with right isomerism, the cardiac malformation is more severe and an univentricular correction is more frequent. another predictor of mortality is pulmonary vein stenosis/obstruction. whatever the severity of cardiac lesions, the postoperative or discharge mortality is higher in patients with heterotaxy. prenatal diagnosis seems not improve the survival. extracardiac anomalies also contribute to the increased morbidity and mortality. three of the more challenging entities are respiratory, immunologic and gastrointestinal. recurrent respiratory infections, failed extubation or chronic respiratory failure are frequently observed in patients with heterotaxy. recent studies revealed an association between heterotaxy and primary ciliary dyskinesia which can explain the increased postoperative respiratory complications. the spleen is important for the bacterial clearance. patients with asplenia or polysplenia are thought to have "functional asplenia". so, they are at risk for sepsis and severe bacterial infection. the incidence of intestinal malrotation is high, approximately 40% to 90%. observation versus prophylactic ladd procedure and screening for asymptomatic intestinal malrotation are a growing area of debate. the trend seems to go along conservative management and surveillance of malrotation. bronchopulmonary malformations, such as congenital pulmonary airway malformation (cpam), bronchopulmonary sequestration (bps), and congenital lobar emphysema (currently known as congenital lobar overinflation [clo] ), are common congenital lung diseases. these conditions are detected prenatally, usually in the second trimester, in countries where obstetric sonography is routinely performed. the malformations are seen as hyperechoic images with respect to normal fetal lung parenchyma, with a mass effect and homogenous appearance or with coexisting cysts. the lesions usually decrease in size along gestation. a residual mass is seen on postnatal chest radiography, the first imaging technique performed, in only 40% of cases. cpam and bps are predominantly located in the posterior lower chest and can be identified postnatally on ultrasound using a small vector probe and a subcostal and subxiphoid approach. potential feeding arteries can be visualized using color or power doppler. based on clinical and sonographic findings, the differential diagnosis between congenital lung malformations and tumors such as neuroblastoma, type i pleuropulmonary blastoma, and myofibroblastic tumor will be discussed. postnatal management and imaging of newborns with congenital lung malformations is controversial, particularly in asymptomatic patients (approximately 80% of cases). chest radiography is mandatory at birth and chest ultrasound is also recommended to confirm the prenatal diagnosis. computed tomography (ct) or magnetic resonance imaging (mri) using angiographic techniques should be performed some months (8 months) after birth in asymptomatic patients. these techniques are also recommended in symptomatic newborns and before surgery to characterize the arterial supply and venous drainage in cpam and bps, as ultrasound is limited in this regard. in premature infants, sonography complements radiography in the study of prematurity-related lung diseases such as respiratory distress syndrome and its pulmonary complications (eg, pneumothorax), in predicting bronchopulmonary dysplasia, and in diagnosing transient tachypnea of the newborn when clinical and radiographic features are inconclusive. the main ultrasound finding in these conditions is visualization of numerous "b-lines", vertical narrow-based hyperechoic bands extending from the pleural surface to the end of the field of view, representing what is currently known as "sonographic interstitial syndrome". b-lines are artifacts originating from variations in the air-fluid relationship of the lung and are better seen using high-frequency linear probes . use of sonography for follow-up of these patients will reduce the number of the chest plain films performed, and therefore, the amount of radiation exposure in this vulnerable population. for proper interpretation of the sonographic findings in these conditions, the radiologist should be familiar with current related terms, such as lines a, lines b, comet tail artifact, interstitial-alveolar syndrome, septal syndrome, and white lung. trauma is the leading cause of mortality and morbidity in children after the first year of life. motor vehicle accidents are the leading cause of death from unintentional injury in children up to the age of 15. of these cases, the abdomen is the fourth most commonly injured area. in pediatric patients non-operative management of these injuries predominate, hence the importance of early radiologic assessment for appropriate clinical follow-up. anatomically, compared to adults, childrens' abdomens are more square, less muscular and with less intraperitoneal and subcutaneous fat to absorb impact. the diaphragm is more horizontal causing downward displacement of the liver and the spleen outside the protective casement of the ribs. the pelvis is smaller and hence the bladder is displaced upward, also resulting in more vulnerability to this organ. the organ surface area is larger in children and they have a smaller body mass-hence more force applied per-unit of body surface area. the ribs are flexible, and although we see fewer rib fractures, this results in more internal damage. physiologically, children maintain hemodynamic stability longer, often presenting with only mild tachycardia, even when in severe hemodynamic shock. decrease in blood pressure may not be evident before the loss of 30% blood volume. nevertheless, bleeding is less severe and operative intervention is rarely performed. mechanics of blunt abdominal trauma include organ compression from seat belt injury with the presence of erythema, ecchymossis or abrasion on the abdominal wall increasing the likelihood of internal organ injury (55% likelihood of injury). other common mechanisms include pedestrian-car collisions( 4% with intra-abdominal injuries), falls (4% with intra-abdominal injuries), or handle bar injuries (54% with intraabdominal injuries). after the child arrives in the hospital, a trauma algorithm is initiated. generally, for the unstable patient, algorithms are similar and require a rapid atls protocol, followed by a fast ultrasound to confirm free fluid prior to operation. in stable patients, institutional algorithms vary greatly between countries and in different centers. some rely solely on mechanism to determine the need for fast vs ct (not complete ultrasound), others will rely on clinical exam (in a conscious patient with reliable exam) and blood work to determine the need for imaging (ct or us) and others may chose to perform an initial us and complete the exam with a constrastenhanced us during work hours. in the literature many management prediction rules exist based on the history, physical examination, mechanism of injury and are supplemented by blood work and/or intial imaging. most are based on retrospective reviews, with only a few controlled clinical trials. however, the validity of these studies is limited because of different populations, institutional policies and variable radiological practices in terms of when imaging is performed, which modalities are most beneficial and which are less valuable, all the while, considering the utilization of the least irradiating techniques. a representative sample of such algorithms will be discussed. routine and extensive initial trauma panels are not required according to a number of studies. abdominal ultrasound and urinalysis together have been found to confirm 98% of all intra-abdominal injures, in some studies. serial haemoglobins/hematocrit is valuable for determining ongoing s315 (2017) 47 (suppl 2):s297-s pediatr radiol blood loss and assists clinical surveillance. electrolyte abnormalities are uncommon in children unless severe shock is present (metabolic acidosis). liver function tests are elevated in most cases of blunt abdominal trauma, hence, are often performed for its high sensitivity, to avoid ct if the liver panel is negative. imaging, however, is needed for grading of the potential liver injury if the liver panel is positive. abdominal xray is not useful in blunt abdominal trauma, and is usually normal. ultrasound has an important role in the pediatric community, as a sensitive and non-irradiating modality. however, this sensitivity is dependent on the type of ultrasound performed (fast vs. complete abdominal ultrasound vs. contrast-enhanced ultrasound) but also on the qualifications and experience of the performing physician. a meta-analysis of fast in pediatrics demonstrates that it has a sensitivity of 66% (grade i-ii evidence) for identifying hemoperitoneum. a negative fast is not sufficient to rule out intra-abdominal trauma. one prospective observational trial demonstrasted that 34 % of patients without free fluid on fast (performed by formally trained pediatric truama surgeons demonstrated at least grade iii liver or splenic injuries on ct). we know that pediatric ultrasound is operator-dependent, and generally an ultrasound performed by the skillful hand of a pediatric radiologist is more sensitive than that performed by surgeons or by adult radiologists. furthermore, we know that the benefits of contrast-enhanced ultrasound in pediatric trauma exist-highly accurate in visualising lesions, hence avoiding non-contributive ct imaging, however, the feasibility of providing 24-hr contrast-enhanced ultrasound by a qualified radiologist is resource intesive: both structurally and with respect to personnel. published indications for abdominal ct in stable pediatric patients included suspected mechanism of blunt abdominal trauma, significant fluid resusitation without apparant blood loss, hemoglobin <100mg/l without obvious blood loss, multisystem trauma and unreliable abdominal exam. one series with 1500 children undergoing ct for blunt abdominal trauma demonstrate postive findings in 388 (26%), of which all solid organ injuries and 96% of hollow viscus injuries were identified on ct. however, ct has its limitations: it was found to identify gastrointestinal perforation in only 47% of patients with known perforation, but with findings of free fluid, wall thickening and/or bowel dilatation. it is also less accurate in identifying pancreatic trauma, with normal scans in 33-53% of children with pancreatic trauma. again, findings of pancreatic trauma can be non-specific: free fluid or, less commonly, thickening of the gerota's fascia, presence of mesenteric fluid or of fluid between the pancreas and the superior mesenteric vein. when and where to perform ct depends on the imaging algorithms established by individual centers. generally, unstable patients with very high grade visceral injuries are taken to surgery. the stable patients are treated with non-operative management. the literature on angiographic embolization in pediatric blunt trauma is limited to case series that demonstrate a limited utility in hemodynamically stable patients with ongoing blood loss or for the definitive treatment of traumatic pseudoanevryms. a dialogue with the interventional radiologist is imperative in such cases. common imaging findings and pitfalls will be illustrated with case examples. in conclusion, a child's anatomy and physiology must be taken into account when determing the level of urgency and appropriate imaging work-up in blunt abdominal trauma. imaging of these patients cannot follow a standard algorithm as institutions vary with respect to types of personel, training, frequency of trauma, emergency department trauma protocols and availability of an in-house pediatric radiologist. ultrasound and ct have their advantages and disadvantages with associated pitfalls that the pediatric radiologist must recognize to provide an optimal diagnostic workup with minium irradiation. take home points: a child's anatomy and physiology must be taken into account when determing the level of urgency and appropriate imaging work-up in blunt abdominal trauma. imaging of pediatric abdominal trauma cannot follow a standard algorithm as institutions vary with respect to types of personel, training, frequency of trauma, emergency department trauma protocols and availability of a pediatric radiologist. ultrasound and ct have their advantages and disadvantages with associated pitfalls that the pediatric radiologist must recognize to provide an optimal diagnostic workup with minium irradiation. sport injuries d. jaramillo; miami, fl/us the growing skeleton has unique vulnerabilities to acute and chronic injuries due to sports. the practice of intensive sports during puberty and adolescence has led to a great increase in the incidence of sportsrelated injuries. during the growth spurt of early adolescence, the physis becomes weak, and is the site of fractures and avulsions (particularly in the apophyses) and of physeal widening due to repeated stresses, such as the wrist in gymnasts or the proximal humerus of baseball pitchers. both lesions can result in growth arrest. the chondro-osseous junctions of the ossifying epiphyses and apophyses are also vulnerable to avulsions, and the avulsed fragment may be entirely cartilaginous and not visible radiographically (such as in the patellar sleeve fracture). repeated trauma to epiphyses or round bones can lead to osteonecrosis (panner's disease) but more often to osteochondritis dissecans (ocd). in adolescents, ocd occurs most frequently in the medial femoral condyle, the capitellum of the elbow and the talar dome. juvenile ocd has a better prognosis than the adult form. when the skeleton begins to mature, there are fractures unique to partially closing physes such as the triplane and tillaux fracture. some sturctures have propensity to unique injuries during adolescence. a stress on the anterior cruciate ligament (acl) can lead to a tibial eminence avulsion in puberty ( figure) , an incomplete acl tear in early adolescence or a complete acl tear later. meniscal tears are almost always vertical and often involve large meniscal fragments that can flip. patellar dislocations often result in osteochondral injuries. this review will cover the main types of sports-related injuries and the imaging modalities used to diagnose them. 11 year-old with pain and popping sensation during a fall on a football game. ap radiograph is normal & it is important to take into account the specific sport in order to anticipate subtle injuries that may be difficult to detect. a. c. offiah; sheffield/uk the radiographs obtained when inflicted injury is suspected are collectively termed the "skeletal survey". a full skeletal survey should be performed in all children below 2 years of age in whom abuse is suspected. the investigation is not complete until follow-up skeletal imaging has been performed in the 11 to 14 days following the initial survey. children below one year of age should also receive a ct brain. neurological imaging in older children will depend on the clinical scenario. ct chest/abdomen is indicated when visceral injury is suspected. in terms of imaging in suspected abuse, espr has adopted the rcr guidelines. in the absence of a history of significant trauma, fractures highly specific for abuse in pre-ambulatory children include rib, metaphyseal and diaphyseal fractures. simple linear skull fractures have a relatively low specificity for abuse. the combination of subdural haemorrhage, retinal haemorrhage and diffuse cerebral oedema/encephalopathy (the so-called, "triad") suggests shaking. whereas the presence of a skull fracture implies impact. visceral injury often results from direct blunt trauma and may therefore be accompanied by anterior and/or costochondral rib fractures. the posterior rib arcs are protected by soft tissue and posterior rib fractures result from compressive/squeezing forces rather than direct trauma. the dating of fractures has a subjective element and it is more important to recognise that fractures are in different stages of healing, rather than to assign a definite age/age range to the injuries. the major differential diagnoses are accidental trauma and osteogenesis imperfecta. if rickets is the cause of the fractures, then radiology and/or biochemistry will show evidence of rickets. a low vitamin d level, in the absence of rachitic features, is not the cause of fractures. close liaison between radiologists and paediatricians is vital and any siblings/children in the same household who are below 2 years of age should also receive a skeletal survey. remember that the presence of injury does not always mean abuse and that the absence of injury does not always exclude abuse. scoliosis may be primitive, structural, particularly during adolescence; during this period, careful follow-up is mandatory, because worsening is frequent. clinical examination with evaluation of a hump (gibbosity) with a scoliometer is mandatory, with also neurological assessment. beside radiography, additional tools have been developed to avoid xray exposure: "spinal mouse", back surface topography systems, ultrasound and other computer-assisted systems. but scoliosis can also be secondary, and imaging is important to find a cause and adapt management. among the etiologies, radiologist must recognize spine malformations, dysplastic and neuromuscular scoliosis. in addition, scoliosis may also be in relation with a primitive lesion, tumor-related or not, whether the initial disease could be within the spinal canal, spinal or paravertebral. imaging studies lies first on pa and lateral full spine x-rays, if possible with a low dose device (flat panel, slot-scanning system), keeping in mind that follow-up with repetitive exposures may be necessary. reproducible measures of different curvatures help to assess the overall static spine and the importance of scoliosis with cobb angle. the assessment of axial rotation can be obtained through 3d simulations, with frontal and axial views (see figure) . morphologic evaluation of the s317 (2017) 47 (suppl 2):s297-s pediatr radiol spine is mandatory: if a secondary scoliosis is suspected, the research to etiology needs to perform ct or mri, depending on the clinical signs and the results of plain x rays evaluation. similarly, these explorations are useful in the preoperative assessment when surgical treatment is necessary. girl scoliosis, pa and lateral views with eos®, 3d simulation, coronal and axial views take home points: clinical evaluation is always the first step in subject with suspected scoliosis radiation burning is quite low with new devices, but repetitive exposures for follow-up need to carefully respect justification for x-rays exposures new tools are available to appreciate 3d spinal deformation and evaluate prognosis and surgical procedures ct and/or mri are useful in presurgical assessment and to look for etiologies in suspected secondary scoliosis malformations of the spine and spinal cord a. rossi; genoa/it summary: embryology and classification: spinal cord development occurs through three consecutive periods: (i) gastrulation (2 nd gestational week): the embryonic disk is converted from a bilaminar into a trilaminar arrangement, with formation of the intervening mesoderm; the notochord is laid down along the midline, identifying the craniocaudal embryonic axis; (ii) primary neurulation (18 th -27 th day): under the induction of the notochord, the midline ectoderm specializes into neural ectoderm. the initially flat neural plate progressively bends and folds until it fuses in the midline to form the neural tube. the primary neural tube produces the uppermost 9/10 of spinal cord; (iii) secondary neurulation (28 th -48 th day): a secondary neural tube is laid down caudad to the termination of the primary neural tube. retrogressive differentiation of the secondary neural tube results in the tip of the conus medullaris and filum terminale. defects in one of these three embryological steps produce spinal dysraphisms, characterized by anomalous differentiation and fusion of dorsal midline structures. spinal dysraphisms may be categorized clinically in two subsets: open and closed spinal dysraphisms. in open spinal dysraphisms (osd) the placode (non-neurulated neural tissue) is exposed to the environment through a cutaneous defect along the child's back. osd include myelomeningocele, myelocele, hemimyelomeningocele and hemimyelocele, and are associated with a chiari ii malformation. myelomeningocele is by far the most common of these forms; the placode protrudes through a posterior defect and is elevated above the skin surface due to concurrent dilatation of the subarachnoid spaces. closed spinal dysraphisms (csd) are covered by intact skin, although cutaneous stigmata usually indicate their presence. two subsets may be identified based on whether a subcutaneous mass is present. csd with tumefaction comprise lipomas with dural defect (lipomyelocele and lipomyelomeningocele), meningocele, and myelocystocele. lipomas with dural defect are more common; they are differentiated from one another based on the position of the cord-lipoma interface, that lies within the spinal canal in lipomyelocele, and outside the spinal canal (ie, into a meningocele) in lipomyelomeningocele. csd without tumefaction comprise complex dysraphic states (ranging from complete dorsal enteric fistula to neurenteric cysts, diastematomyelia, dermal sinuses, caudal agenesis, and spinal segmental dysgenesis), bony spina bifida, tight filum terminale, filar and intradural lipomas, and persisting terminal ventricle. the most complicated forms (complex dysraphic states), including diastematomyelia, caudal regression, and segmental spinal dysgenesis) are related to faulty gastrulation. diastematomyelia (literally, split cord) is caused by failure of midline notochordal integration, resulting into two separate hemineural plates. caudal agenesis and segmental spinal dysgenesis are related to defective notochordal formation, characterized by absence or hypoplasia of a segment of the notochord, in turn resulting into absence or hypoplasia of a corresponding segment of the spinal cord. functional neuroimaging of cns is a fast advancing field with frequent new developments in scanner's hardware, protocols, clinical indications, and post-processing techniques. for radiation safety reasons in the case of children, functional neuroimaging is mostly based on mr techniques especially designed to focus on the assessment of functional tissue characteristics, such as neuronal activity (fmri),, metabolism (mrs) and perfusion (dsc perfusion, asl). pediatric coils with multiple elements, multiple slice excitation, 3d spectroscopy, 3d asl, reduced fov (zoom) and improved motion compensation techniques are important tools available to meet the permanent challenges of pediatric mr functional imaging: fast motionless acquisitions and increased resolution. functional mri (fmri) reveals brain activation during performance of behavioral tasks, based on the blood oxygen level dependent (bold) mri signal, which is modulated by neural activity via a process of neurovascular coupling. for children, especially of younger age unable to follow a task, resting-state fmri (rfmri) can be performed and correlates brain areas with similar spontaneous fluctuations in the bold signalthereby enabling estimates of 'functional connectivity.' main clinical applications of fmri are the delineation of eloquent cortex near a space-occupying lesion and the determination of the "dominant hemisphere" for language. intense research is conducted in the areas of language organization and development, brain plasticity, and neurobehavioral disorders (e.g. adhd). magnetic resonance spectroscopy (mrs) is a noninvasive mr technique, that detects intracellular metabolites, and may provide neuroimaging biomarkers of normal biological and pathological processes or response to a therapeutic intervention. although the main field of application of mrs is the brain tumors, it has also been of particular (2017) 47 (suppl 2):s297-s pediatr radiol usefulness in assessing ischemic or traumatic brain injury and neurometabolic disorders. perfusion mr imaging methods detect signal changes that accompany the passage of a tracer through the cerebrovascular system. a less invasive approach is arterial spin labeling (asl) that uses arterial water as an endogenous tracer to measure cbf and thus it is more suitable for pediatric studies. mr perfusion is applied in the evaluation of brain tumors, neurological diseases and developmental disorders. functional neuroimaging clinical applications are expected to expand greatly in the future due to the increasing availability of their techniques, as well as the continuous advancements in the field of pediatric research. good knowledge of these techniques will become more necessary for an effective clinical practice and will enhance the role of radiology in the healthcare system. functional neuroimaging advanced techniques based on mri allow us to study complex cns processes such as cerebral perfusion (dsc, asl), metabolic activity (mrs) and brain activation (fmri). functional neuroimaging techniques already have significant clinical pediatric applications and assisted by recent advances in mr technology are expected to become even more powerful in the near future. kidney: perfusion, excretion, obstruction k. darge; philadelphia/us the functional imaging of the urinary tract entails the evaluation of the renal perfusion and excretion. in this complex process the sites of the main abnormalities could be pre-renal, renal parenchymal, renal pelvicalyceal or post-renal or even a combination at different sites. functional mr urography (fmru) is an advanced tool that not only allows the exquisite morphological depiction of the urinary tract, but also makes it possible to generate comprehensive functional data. these provide information about the function of the kidney as well as the excretion of urine from the renal parenchyma into the pelvicalyces and ureter. the functional results are mainly divided into two groups: 1. transit timesthese are recorded in minutes and a side comparison gives idea how much time it takes for the contrast to go through the renal parenchymathe longer the more abnormal in general. 2. differential renal functionsthese can be based on the enhanced renal parenchymal volume or the patalk number generated from this area and provides in percentage the split renal function. this presentation will discuss in detail the functional aspect of mr urography and demonstrate its utility in routine pediatric uroradiologic imaging. in chronic childhood lung disease (e.g. cystic fibrosis) global pulmonary function tests (pft) can be normal although lung damage is already present. moreover, in comparison to imaging, pft is challenging in young children. thus, cross-sectional imaging became more important in the past two decades. regarding morphological evaluation, multidetector computed tomography (mdct) serves as the most sensitive and reproducible modality. for functional evaluation perfusion/ventilation scintigraphy remains the reference standard. although the individual radiation burden by a single chest ct has decreased significantly in the past, radiation doses can cumulate considerably when repeated examinations are performed in a longterm follow-up. pulmonary mri exists as an alternative method, especially for paediatric patients. however, standard h+mr sequences do not demonstrate small airway disease due to inherent limitations of low signal and rapid t2* signal decay of lung tissue. for comprehensive diagnosis, functional mri offers the unique possibility to measure regional ventilation and perfusion, and mapping relaxation times and diffusion. focussing on research applications, a variety of methods are available for these purposes. in this context, ventilation imaging using inert fluorinated gas indicates to overcome the limitations of the expensive setting necessary for imaging with hyperpolarized noble gasses. regarding lung perfusion, dynamic contrast-enhanced mri (dce-mri) is the most established method in clinical practice. however, especially in children, techniques that are completely non-invasive and do not require i.v.-contrast agents administration or gas inhalation could be promising to achieve broad acceptance. concerning non-invasive methods, ventilation can be assessed by sequences with ultra-short echo times (ute), perfusion by arterial-spin-labeling (asl) and both by fourier decomposition mri (fd-mri). in conclusion, pulmonary mri offers both, the assessment of morphology and the unique possibility to measure regional ventilation and perfusion, and mapping relaxation times and diffusion. new mr techniques that are completely non-invasive are now available. however, further scientific evaluation is needed. ibd and related arthropaties d. jaramillo; miami, fl/us musculoskeletal diseases affect about 5% of patients with crohn's disease and are the most frequent extra-intestinal manifestation of inflammatory disease. the articular manifestations of inflammatory bowel disease (ibd) are one of the seronegative arthritides, although they have a lower incidence of hla -b27 than other seronegative arthritis such as ankylosing spondylitis. there are manifestations in the joints of the extremities, and findings in the pelvis, especially in the sacro-iliac joints, and spine. involvement of the extremities occurs in about 10% of patients with ibd related arthropathies, are more common with crohn's disease, and can have either manifestations related olygoarticular jia, or can have symmetrical involvement of smaller joints. the axial manifestations include ankylosing spondylitis and sacro-iliitis. sacroilliitis is typically bilateral (figure) and often has radiographic as well as mri abnormalities. enthesitis, tenosynovitis and dactylitis can occur with ibd just as they occur with other arthritides. it is important to differentiate ibd related arthritis from septic arthritis due to extension of an enteric fistula. deceased bone mineral density is a common finding in inflammatory disease. it occurs as a combination of malabsorption of vitamin d due to intestinal involvement and the effects of therapy, particularly corticosteroids. insufficiency fractures of the spine, sacrum and extremities can mimic the symptoms of arthritis. finally, ibd can be associated with chronic non-bacterial osteomyelitis, although this association is relatively rare. this review will illustrate several of the skeletal manifestations of ibd, focusing on the arthropathies. juvenile idiopathic arthritis (jia) can be defined as an arthritis of unknown cause occuring in children younger than 16 years and of at least 6 weeks duration. juvenile spondyloarthritis (jspa) is a subset of jia and is characterized by enthesitis (inflammation at the attachment of tendons, ligaments and the joint capsule), arthritis and an increased risk of axial disease. there is also a strong association with human leukocyte antigen b27. jspa accounts for approximately 10-15% of juveniles arthritis cases in europe and is the most common form of juvenile arthritis in asia. the condition is associated with significant long-term morbidity, high health-care costs and poorer outcomes compared with other forms of juvenile arthritis as well as its adult counterpart. up to 40% of patients continue to be at risk of developing ankylosing spondylitis (as) during the disease course. recognizing spondyloarthritis (spa) in children is challenging, particularly early in the course of disease, as the signs and symptoms at disease onset differ from those seen in adults. jspa typically presents with hip and lower limb arthritis in conjunction with enthesitis. inflammatory back pain as a presenting symptom is less common. as a consequence, jspa may be missed or confused with other juvenile arthritides and patients often experience prolonged delays in diagnosis. currently there is no single diagnostic or classification system that is representative of the jspa population. according to the international league of associations for rheumatology (ilar) classification system, most childhood spa's are classified as enthesitis-related arthritis (era), psoriatic arthritis or undifferentiated arthritis. recent studies indicate that there are two clinical phenotypes of era: those with early axial disease often associated with hip arthritis in addition to peripheral arthritis; and those who follow a more peripheral disease course with arthritis and enthesitis and do not develop axial disease. the ilar classification system places patients with both axial and peripheral involvement into the era subtype, and does not specifically address children who meet the criteria for as. the correct approach to the classification of era is uncertain, and this issue is confusing to both pediatric and adult rheumatologists. unlike other categories of juvenile arthritis, jspa affects boys more often than girls, and peak age of onset is early adolescence. enthesitis is a defining characteristic of jspa. it is more common and affects more sites in the paediatric population compared with the adult one. the most commonly tender entheses are the insertions of the patellar ligament at the inferior patella, plantar fascia at the calcaneus, and the achilles tendon. arthritis in jspa is typically asymmetrical, oligoarticular (< 5 joints) and involves predominantely the weightbearing joints. isolated hip joint arthritis may be the presenting feature and predicts early axial disease. involvement of the small toe joints is common in jspa but rare in other forms of jia. midfoot arthritis and tarsitis (inflammation of the intertarsal bones, overlying tendons, entheses and soft tissue) is highly suggestive of spondyloarthritis. in adults, inflammatory back pain typically heralds the onset of sacroiliitis, whereas children seldom present with symptoms of axial disease. however, according to several studies, sacroilitis can be asymptomatic in jspa and only detectable by imaging. other axial manifestations in jspa are inflammation of the lumbar apophyseal joints and interspinous ligaments, corner lesions of the spine and other sites of axial enthesitis-osteitis including the various ligamentous and muscular attachments of the pelvis. extraarticular manifestations of jspa are highly associated with axial disease and include acute anterior uveitis, bowel inflammation, psoriasis, and cardiac disease. clinical diagnosis of jspa can be difficult and the role of imaging may be more critical than in adult disease. the major goal of imaging in jspa is to identify children with early signs of axial disease, as this group is at the greatest risk for progression to as. the presence of axial disease in spa has also major implications for treatment decisions, since traditional firstline therapies appear to have minimal effectiveness in the management of axial inflammation. in addition, recent studies in adults suggest that earlier initiation of biologic agents (anti-tnfs) may slow radiographic progression. x-rays are not sensitive to acute inflammatory changes and will only show advanced disease in the sacroiliac joints. for these reasons plain radiographs are not useful in children or adolescents. ultrasound is a non-invasive, non-ionizing and relatively inexpensive technique that can be performed in a clinical setting. it is emerging as a valid diagnostic tool in spa and can be used to visualize peripheral synovitis, tendonitis and enthesitis, but the method is heavily operator-dependent and there does not yet exist a clear definition for the diagnosis and grading of enthesitis in children. secondary changes (calcifications, enthesophytes) have been observed much less in children compared with adults. there is a need for better consensus on abnormal ultrasonographic findings that define enthesitis lesions and standardization of methods. magnetic resonance imaging (mri) is a radiation free and sensitive imaging modality for detection of synovitis as well as cartilage and bone destruction. mri of the sacroiliac joints is increasingly obtained for early detection of inflammatory changes, as it shows active inflammatory (bone marrow edema, osteitis, enthesitis and capsulitis) and structural (erosions, subchondral sclerosis, subchondral fatty change and bony ankylosis) lesions of sacroiliitis long before radiographic changes become evident. in adults, mri has become the gold standard imaging modality for detecting arthritis and enthesitis. consensus definitions of lesions indicating pathology on mri are now incorporated into diagnostic criteria for adult with spa. in children and adolescents there is no gold standard mri technique and it is therefore not clearly defined whether changes s320 (2017) 47 (suppl 2):s297-s pediatr radiol seen in the sacroiliac joints are pathologic or part of normal maturation in the growing skeleton. the use of contrast enhanced imaging for the detection of active sacroiliitis on mri in jspa is a major controversy. synovial enhancement can be detected without accompanying bone marrow edema in children, and it can be argued that contrast should be administered in order not to miss the diagnosis. some authors argue that contrast administration does not change or add substantially to the mri findings made on non-enhanced scans. certainly, given the risks associated with gadolinium administration, contrast should be used with caution. perhaps the use of contrast agents should be limited to selected cases when high stir signal in the joint is the only finding in order to confirm the presence of synovitis, and when the differential diagnosis includes etiologies such as infection or tumor. the development of new mri techniques has made it possible to perform whole body mri scans (wbmri) that allow assessment of the full range of affected entheses and joints. there is limited data on the utility of wbmri in the pediatric population. it is worth noting that edema-like changes seen in the marrow of healthy children is an important potential pitfall to consider during interpretation and further studies are required in order to establish specific reference standards for mri of the pediatric skeleton. diffusion-weighted imaging (dwi) offers a new approach to detect inflammation. inflammation produces an increase in the apparent diffusion coefficient (adc) of water molecules in affected tissues. several studies in adults and a few recent studies in children have demonstrated that adc is elevated in sacroilitis versus controls and that diffusion scores correlates well with stir images. dwi is promising as a potential biomarker of disease activity in jia and presents a novel approach to contrast-free imaging of synovitis. however, further studies are needed before it can be implemented in clinical practice. jspa is distinct from adult spa and manifests more frequently as peripheral arthritis and enthesitis. symptoms involving the spine and sacroiliac joints often occures later in this population. clinical diagnosis of jspa can be difficult, and imaging therefore plays an important role in the diagnostic workup of disease. identifying early signs of axial disease has major implications for treatment decisions and mri of the sacroiliac joints is increasingly obtained for early detection of inflammatory changes. however, mri criteria for sacroilitis in children are lacking. a major controversy in imaging of sacroilitis in jspa is the use of contrast, as children can have sacroilitis without accompanying bone-marrow edema. dwi presents a novel approach to contrast-free imaging of synovitis but further studies are needed before it can be used in clinical practice.wbmri has been shown to be more sensitive than clinical examination in the assessment of both disease activity and extent, but there is limited data on wbmri in children. normal variants in the growing skeleton may mimic pathologic changes and potentially cause overdiagnosing and -staging of disease. hence, there is an urgent need to establish specific reference standards for mri of the pediatric skeleton and to develop a gold standard mri technique for the axial skeleton in children and adolescents. juvenile idiopathic arthritis o. olsen; london/uk summary: juvenile idiopathic arthritis (jia) is common (about 1:1,000 children). diagnosis and classification are based on clinical criteria. these criteria are in flux depending on 1) contemporaneous knowledge about aetiology and 2) available treatment options. radiology has currently no role in establishing the diagnosis. the clinical classification rests on whether the child has few joints affected (oligo jia), many joints (poly jia), has a condition similar to adult spondyloarthritis (entesitis-related arthritis) or other clinical presentations (systemic-onset jia, psoriatic jia, etc). radiology can potentially assess expressions of jia, such as synovitis, tenosynovitis, systemic manifestations and permanent damage caused by inflammation. it is therefore thought to play a part in gauging the disease activity. the clinical care aims at optimising the child's everyday function, reducing acute symptoms (pain, swelling, joint restriction), allowing normal growth, minimising long-term sequelae (joint deformity) and minimising adverse effects of medical treatment. medical treatment in jia is systemic (immuno-modulation) and local (steroid injection to joints and tendon sheaths). both modes of therapy may to some degree be guided by imaging. however, there currently is no evidence that any form of whole-body imaging is efficacious for guiding treatment. this means that, in principle, indication for imaging should be 1) specific clinical questions, e.g. uncertainty regarding active inflammation at specific sites, or 2) a high pre-test likelihood of inflammation at a site which is difficult to assess clinically and where imaging offers reasonable accuracy. one example of the latter are the temporo-mandibular joints where destruction is frequently seen at an early stage, often without prior symptomatic warning. there is one fundamental challenge for imaging research in jia: what is the reference standard? for lack of anything better, a standardised clinical examination is often used as 'ground truth'. the dilemma is obvious. if clinical examination is reliable and accurate, then why bother with imaging? but we think imaging offers an improvement, then we cannot use an inferior method to set the standard. this problem is not unique to jia. as is often the case, radiology in jia is all about: knowing your clinicians (i.e. the pretest likelihood for disease) being technically eloquent (e.g. using high-resolution us probes, not delaying post-contrast mri acquisitions) knowing what is normal (e.g. normal undulations in the articular surface, focal bone marrow signal variation) not being dogmatic about individual observations or measurements interpreting your findings in a clinical context the lecture will demonstrate similarities and differences among joints and modalities in children with variable-severity jia. the following points will be made: focal areas in the bone marrow with high signal (t2) and corresponding enhancement are often seen in healthy children. in isolation, these do not signify active inflammation. active synovitis in children often is not associated with (much) effusion the combination of synovial thickening with hyperaemia (us)/abnormal contrast enhancement (mri) and surrounding softtissue swelling suggests active inflammation, however there is (yet) no established system for quantifying hyperaemia/enhancement focal pits in the carpal bones do not represent erosions unless there is an associated cartilage defect radiographs are useful for detection of destructive abnormality in mri, scan fairly soon after injecting contrast. gadolinium physiologically leaks into the synovial fluid making it difficult to delineate the synovium a few differential diagnoses to keep in mind when there is mass-like swelling within or adjacent to a joint: vascular and neoplastic lesion, pigmented villonodular synovitis, synovial chondromatosis, lipoma arborescens. synovial inflammation is not always primary. even when there is an established diagnosis of jia, do consider that it may be secondary to biomechanical abnormality (erosion, osteochondral lesion, deformity). focal areas in the bone marrow with high signal (t2) and corresponding enhancement are often seen in healthy children. in isolation, these do not signify active inflammation. active synovitis in children often is not associated with (much) effusion the combination of synovial thickening with hyperaemia (us)/abnormal contrast enhancement (mri) and surrounding soft-tissue swelling suggests active inflammation, however there is (yet) no established system for quantifying hyperaemia/enhancement focal pits in the carpal s321 (2017) 47 (suppl 2):s297-s pediatr radiol bones do not represent erosions unless there is an associated cartilage defect radiographs are useful for detection of destructive abnormality in mri, scan fairly soon after injecting contrast. gadolinium physiologically leaks into the synovial fluid making it difficult to delineate the synovium pulmonary manifestation of connective tissue disorders c. m. owens; london/uk summary: connective tissue diseases are an important cause of morbidity and mortality in children with very varied presentations. nomenclature is confusing and a more appropriate descriptive term would be "multisystem inflammatory disorder +/-autoimmunity". it is important for the radiologist to be aware of the protean radiological appearances and clinical manifestations. take home points: different patterns of diffuse lung disease (eg, desquamative interstitial pneumonia, non specific interstitial pneumonia, lymphocytic interstitial pneumonia, organising pneumonia, diffuse alveolar damage) may be present in several forms of collagen vascular disease, (and indeed other rheumatological conditions such as jia) including scleroderma, systemic lupus erythematosis, juvenile dermato and polymyositis, sjogren's syndrome and mixed connective tissue disease. these will be discussed in detail with illustrations for thin section high resolution ct with histopathological correlation. the clinical presentation, prognosis and response to therapy vary depending on the histological pattern of diffuse lung disease, as well as on the underlying collagen vascular disease. whole body imaging in children: sonography, ct, mri, nuclear medicine -what and when? r. a. nievelstein; utrecht/nl there are several (benign and malignant) disease processes in children that frequently involve more than one organ system or body region. diagnostic imaging of children with such multifocal or multisystem diseases has been quite challenging, often requiring a combination of different imaging techniques for a whole body coverage. the recent technical developments in computed tomography (ct), magnetic resonance imaging (mri) and nuclear medicine (nm) have changed the role of imaging in these children revolutionary. in the past, imaging techniques have been mainly used as a tool to detect the cause of illness and to assess the extent of disease spread before, during and after therapy (i.e. structural imaging). but nowadays, it has also become possible to use imaging techniques to gain information on the biological behavior of diseases before and during therapy (i.e. functional imaging). plain radiography, ultrasonography (us) and computed tomography (ct) have been the structural imaging techniques of choice for many decades, more recently supplemented by functional imaging techniques like single-photon emission tomography (spect) and positron emission tomography (pet). a major disadvantage of most of these techniques is the use of ionizing radiation, which may be associated with induction of second cancers later during life. this small but not negligible health risk is of particular concern in children as their tissues are more radiosensitive than adults and they have more years ahead in which cancerous changes might occur. that is why there is an increasing interest in the use of alternative imaging techniques that do not use ionizing radiation. with mri it is nowadays possible to acquire images with a high spatial resolution and excellent soft tissue contrast throughout the body, which makes it an ideal radiation-free tool for the detection of pathology, especially in soft tissue, parenchymal and bone marrow locations. moreover, recent technological advances have resulted in fast diagnostic sequences for whole-body mr imaging (wb-mri), including functional techniques such as diffusion weighted imaging (dwi). as a result, wb-mri has become a clinically feasible imaging modality for diagnosis and follow-up of multifocal and multisystem diseases in children. in this scope, the recent development of integrated pet/mri systems is very interesting, combining the superior structural imaging of mri with the functional (molecular) information of both imaging techniques while decreasing the radiation dose. traditionally, whole body imaging techniques have been mainly used for oncological indications, such as staging of malignancies, and monitoring of the effectiveness of therapy. however, whole-body imaging techniques are increasingly used for the diagnostic imaging of other benign multisystem diseases and indications, including chronic recurrent multifocal osteomyelitis (crmo), rheumatological diseases, neuromuscular diseases, neurofibromatosis type 1, generalized vascular malformations, multifocal osteonecrosis after intensive chemotherapy, fever of unknown origin, and post-mortem imaging. finally, these imaging techniques may be used for the screening of children with a cancer predisposition syndrome. during this lecture, imaging protocols and indications of the different whole body imaging techniques will be discussed with a focus on their clinical application in children with benign and malignant multifocal or multisystem diseases. (2017) 47 (suppl 2):s297-s pediatr radiol appearances is important for any radiologist involved in child imaging, because we have an important role in characterizing the lesions and guiding purposeful and minimally invasive but successful diagnostic procedures. most head and neck masses in children are benign and have an inflammatory, infective, vascular or congenital cause (cf. special presentation on vascular malformations). malignant lesions are less common, however, early diagnosis is paramount as many of these cancers are readily treatable and often curable. differential diagnosis is guided by patient age, clinical presentation, tumour localisation, and imaging characteristics. while some masses such as (epi-)dermoids, fibromatosis colli and swollen lymph nodes including atypical mycobacterial infections (mott) may be readily diagnosed by clinical inspection und ultrasound, others present special diagnostic challenges. fibromatosis, for example, is a benign lesion with an often complex and potentially destructive local spread. some malignant lesions tend to be localised such as the embryonal rhabdomyosarcoma, while others may be part of a systemic disease such as lymphoma and langerhans cell histiocytosis (lchc). in case of a suspected malignancy, patients should be referred to a specialized centre which will be able to provide the full spectrum of multidisciplinary evaluation and treatment according to the guidelines of an international oncology study group. this is also important for image guided or surgical biopsies as long term outcome and survival of many of the young patients are directly associated with these initial diagnostic and therapeutic strategies. with its excellent spatial resolution in the near field, ultrasound is the method of choice for all superficial masses. an experienced paediatric radiologist will be able to identify most of the benign lesions and in other cases will be able to guide further diagnostic decisions. tumours in the midline require thorough workup to exclude an encephalocele or a dermal sinus with connection to the intracranial space. high resolution mri is required if such an extension cannot be ruled out by ultrasound or if a tumour is larger than the transducer's scan area. soft tissue tumours in the deeper parts of face and neck as well as tumours of osseous origin are also best delineated by mri. in lesions adjacent to the skull base contrast enhanced and fat saturated mr images with high spatial resolution are of utmost importance to completely depict the tumour's extension through the foramina and along the meninges (fig. 1) . ct can provide additional information on the involvement of osseous structures. embryonal rhabdomyosarcoma. high resolution mri with fat saturation after contrast injection depicts the tumour's extension through the foramen ovale (long arrow) and along the meninges (short arrows). skull base and face lesions are less frequent in children than in adults. symptoms may be subtle or unspecific. depending on their localization, clinical findings may be common (nasal obstruction, otitis…) or more disturbing (cranial nerves palsies, exophthalmos, vision loss …). clinical history and physical examination findings are important to reduce the spectrum of differential diagnosis, but imaging data are the key features to determine the nature of these lesions. ct and mri play an important role in diagnosis, treatment survey and surgery planning of skull base and face lesions. skull base and face bone lesions are either intrinsic lesions of the bone or secondary to soft-tissue tumors or pseudo tumors invasion. this lecture will focus on bone intrinsic lesions, and include soft-tissue and pseudo tumors only as differential diagnoses. computed tomography plays the role for skull base and face of plain radiograph for long bones. therefore, the same semiology may be used to determine if the lesion is slowly or rapidly growing, aggressive or looks benign. helical ct allows reconstructions with both soft-tissue and bone algorithms as well as multiplanar reformations. it gives a good visualization of the anatomy of the skull base and allows a good depiction of the bone architecture. ct is first used for the initial work up of the disease but also for surgery and therapeutic planning (endoscopic sinus surgery with navigation). however, ct analysis may be challenging in children due to growth changes: normal process of pneumatization according to age, sutures not yet fused has to be recognized. some variations in pneumatization must not be mistaken for pathology: asymmetrical pneumatization of the petrous apex and arrested pneumatization of the sphenoid mimicking intraosseous lesion are the most common. both ct and mr imaging are complementary: most preferably, contrast-enhanced mr is associated with non-contrast high resolution ct. mri allows a good delineation of bone involvement of skull base lesion due to bone marrow changes, whether ct can fail to detect subtle extension within the bone. in addition to t1 and t2 weighted sequences, the use of specific sequences and/or techniques such as fat-saturation, diffusion, dynamic-contrast-enhanced sequences, and mr angiography helps to characterize the lesions. t1 spin echo sequence is mandatory to appreciate bone marrow infiltration in adults and older children. but when red bone marrow has not yet be replaced by fatty bone marrow, in young children, this can be challenging. it is useful to know the bone marrow fatty conversion of the skull base chronology. cranial mr can also be associated to whole body mr to look for multifocal or metastatic disease. epidemiologic data concerning bone tumors of the skull base are scarce due the rarity of these lesions. they can be classified according to their location within anterior, middle or posterior cranial fossa or classified according to their origin: osteogenic (osteoblastoma, osteoma, osteosarcoma...), chondrogenic (chondroma, chondrosarcoma), fibrous ( fibrous dysplasia, fibro-s323 (2017) 47 (suppl 2):s297-s pediatr radiol osseous lesions..), notochord (chordoma), hematopoietic (leukemia, histiocytosis ), vascular (hemangioma), neuro ectodermic ( ewing sarcoma) or unknown origin (aneurysmal cyst, giant cell tumor). the aim of this presentation is to draw attention to skull base growth changes that can mimic pathology and to describe the imaging specificities of the most common bone tumors of the skull base and face in children. because conflicted nomenclature can cause confusion, accurate diagnosis and classification of these anomalies is important for proper clinical evaluation and management. many of these patients require multidisciplinary care, consequently the usage of a correct nomenclature across all disciplines is a sine qua non. the international society for the study of vascular anomalies (issva) classification, updated in 2014, offers a comprehensive classification accepted by many subspecialities. this approach/ classification has facilitated correct communication for all medical subspecialties involved in the care of these complex vascular anomalies. pediatric radiologists play a critical role in evaluating these patients since the majority present during childhood. in this presentation, we present a state of the art mri imaging protocol with exemplary cases of the most common types of vascular anomalies in the pediatric trunk and extremities, using the current issva classification. in addition, we discuss the common syndromes associated with vascular anomalies such as klippel-trenaunay and lumbar syndrome. genetic skeletal disorders (gsd's) are a heterogeneous group of syndromes characterized by an intrinsic abnormality in growth and (re-)modeling of cartilage and bone. a large sub-group of gsd's may have additional involvement of other structures/organs beside the skeleton, such as the central nervous system (cns). cns abnormalities have an important role in long-term prognosis of children with gsd's and should consequently not be missed. sensitive and specific identification of cns lesions while evaluating a child with a gsd requires a detailed knowledge of the possible associated cns abnormalities. here, we will present and discuss a pattern-recognition approach for identifying relevant neuroimaging findings in gsd's guided by the obvious skeletal manifestations of gsd. in particular, we will discuss which cns findings should be ruled out for the various gsd. to facilitate this diagnostic approach the multiple gsd are classified based on the pattern of skeletal involvement (1. abnormal metaphysis or epiphysis, 2) abnormal size/number of bones, 3) abnormal shape of bones and joints, and 4) abnormal dynamic or structural changes). skeletal involvement is defined in accordance with online mendelian inheritance in man. the spectrum of co-existing cns involvement is extracted from an extensive literature search. selected examples will be shown based on prevalence of the diseases and significance of the cns involvement. cns involvement is common in gsd's. a wide spectrum of morphological abnormalities is associated with gsd's. early diagnosis of cns involvement is important in the management of children with gsd's. this pattern-recognition approach aims to assist and guide physicians in the diagnostic work-up of cns involvement in children with gsd's and their management. not infrequently the correct radiological differentiation of skeletal and/or central nervous system findings secondary to non-accidental injury versus inherited genetic and/or metabolic disorders may be challenging. imaging findings may be non-specific, can result in incorrect diagnosis and subsequently inadequate patient management or initiation of faulty treatment. the diagnostic work-up of children suspected of non-accidental injury or genetic/metabolic disorders requires a multi-disciplinary approach involving many key players including physicans of various disciplines, nurses, psychologists, social workers and many more. a proper and detailed medical history and physical examination of the patient, collection of the relevant family history, a metabolic and genetic work up, a detailed interview of care givers, friends and family are essential for the correct and comprehensive evaluation of imaging findings. in the current session, various exemplary and possibly confusing cases will be interactively discussed with the audience by a panel of experts (susan blaser, thierry a.g.m. huisman and andrea superti-furga). goal is to offer a case based approach to challenging patients with discussion of the best diagnostic approach including differential considerations. the zikv is transmitted mainly by the bite of female aedes aegypti and aedes albopictus mosquitoes. other forms of transmission, including through sexual intercourse, blood transfusion, and neonatal, are currently under evaluation, although more elements are still needed to assess the real importance of these transmission routes 4 . the course of the zikv infection is self-limited. so far, no specific symptoms have been attributed to the disease, and a wide variety of manifestations ranging from absent to mild symptoms (in 25% of cases) have been described. when symptoms are present, they may lead to a misdiagnosis of other bacterial and viral infections, especially other arboviroses in endemic areas. the most frequently reported symptoms are mild fever, cutaneous rash, fatigue, arthralgia/myalgia, and conjunctivitis. dizziness, malaise, edema of the extremities, anorexia, retro orbital pain, photophobia, gastrointestinal disorders, sore throat, cough, sweating, and lymphadenopathy have also been reported. infection by the zikv in adults may be associated with autoimmune complications such as guillain-barré syndrome 9 . the laboratory diagnosis of zikv infection is based on the demonstration of the virus in the urine and blood using real-time reverse transcription polymerase chain reaction (rt-pcr). the main limitation of this diagnostic method is a false-negative result after the viremia is resolved. the serological diagnosis of the disease is limited due to cross-reactivity of the zikv with other viruses of the flavivirus genus, especially those causing dengue and chikungunya. physicians should be aware of this fact when the diagnosis of zikv infection relies solely on serological results. the diagnosis is also possible by igm measurement in serum, urine, or cerebrospinal fluid using enzyme-linked immunosorbent assay (elisa) 9 . the prevention against zikv infection is similar to that of other arboviroses, including vector control and mosquito bite prevention. the first major zikv epidemics were reported in the french polynesia in 2013 and 2015. at that time, some neurological changes were observed in neonates of infected pregnant women but were not associated with a maternal-fetal transmission of the virus. the growing increase in the number of cases and the severity of the infection specific to this subpopulation then led to the evidence of a congenital disease 9 . in brazil, the situation became alarming with the report of a high number of infected individuals in the second half of 2015 2, 5 . the brazilian ministry of health attributed to congenital zikv infection the 20-fold increase in cases of neonatal microcephaly in the northeastern part of the country, particularly in the state of pernambuco. this led the world health organization (who) to declare the zikv infection a "public health emergency of international concern" in february 2016 6 . the main challenge for radiologists practicing in regions of endemic zikv infection is to become familiarized with findings of congenital zikv infection in perinatal imaging studies; this is particularly important for the prenatal screening of pregnant women 3, 6 . the diagnosis of zikv infection in the fetus by neuroimaging is based on prenatal ultrasound (us), especially in the third trimester, and complemented with magnetic resonance imaging (mri). postnatal imaging was obtained by transfontanellar us, ct or mri. the main imaging findings on ct are microcephaly, an exuberant external occipital protuberance, rectification of the frontonasal angle, and a redundant scalp skin. three-dimensional (3d) reconstruction of al skull permits a better evaluation of these findings and enhances the parents' understanding of the disease. moreover, ct scan data may yield a 3d virtual physical model that can maybe obtained from ct scan data and printed onto using thermoplastic acrylonitrile butadiene styrene 7 . the aim of this study was to describe the perinatal imaging findings in cases of congenital zikv infection. we studied 18 mothers diagnosed with zikv infection from october 2015 to november 2016. they had all presented a maculopapular rash and fever during the first or second trimester of pregnancy, and their neonates presented neurological defects that were attributed to intrauterine transmission of the zikv. the maternal diagnosis of zikv infection was confirmed by serology (n=4) or rt-pcr (n=14). all patients were torch (toxoplasma, rubella, cytomegalovirus, herpes simplex) negative. prenatal us was performed every 3 weeks after the first imaging findings, and fetal mri was obtained in all cases. microcephaly was considered present when the infant's head circumference was two standard deviations below the mean value for age and sex or below the second percentile. postnatal imaging follow-up was obtained in all cases by transfontanellar us, ct or mri. we found several cns malformations, including lissencephaly, pachygyria and/or polymicrogyria, cerebral atrophy (panel 1), enlarged cisterna magna with abnormalities of the corpus callosum, ventriculomegaly, brainstem hypoplasia, malformation of the cortical development, and cortical and/or periventricular calcifications mainly in the junction between the cortical and subcortical white matter (panel 2). the skull of the infants had a collapsed appearance, with overlapping sutures and redundant skinfolds (panel 3). craniofacial disproportion was easily identifiable, and arthrogryposis was identified in one case. similar neurological findings were observed in the infected patients and seemed to differ from findings of other infectious diseases. the finding of microcephaly in neonates with congenital zikv infection seems to be only the tip of the iceberg, as several cns malformations have been identified in connection with the disease. in brazil, a spectrum of imaging findings associated with congenital zikv infection has been observed. such findings are useful in helping radiologists to identify suspected cases of the disease. panel 1: prenatal ultrasound (37 weeks) shows calcifications (arrows) and microcephaly. axial and sagittal t2 shows relative smoothness of the brain surface (arrows) and assymmetric colpocephaly. panel 2:ax t1-wi multiple cortical-subcortical fronto-parietal hyperintense foci (arrows) and markedly hypointense on swi. sagittal t2: dysgenesis of the corpus callosum, with dilation of the posterior horns of the lateral ventricles (colpocephaly). pre-and postnatal imaging in zika virus: where are we? early insights into zika's microcephaly physiopathology, from the epicenter of the outbreak: a case for teratogenic apoptosis of central nervous system. p. jungmann; recife/br early insights into zika's microcephaly physiopathology, from the epicenter of the outbreak: a case for teratogenic apoptosis of central nervous system. in mid-october 2015, intense interaction among surgical pathology and fetal medicine specialists from university of pernambuco was only focused on the dramatic and non explained ultrasonographic (us) findings and hopelessness due to lack of explanations on the odd us discoveries on the first gestational cases of zika's microcephaly. this is the field of our history of a physiopathological hypothesis on zika virus (zikv) related microcephaly when it first struck pernambuco state (pe), northeast brazil, the place that has been at the front line of the global response to the microcephaly and responsible for a large amount of data from affected children. the outbreak onset came with a sudden increase in microcephalic newborns being reported in pe state from august 2015 (panel, fig. 1) . zikv was previously thought to cause a relatively mild disease, but was recently accepted to lead to severe and diverse neurologic conditions in s329 (2017) 47 (suppl 2):s297-s pediatr radiol some children born from infected mothers and in adults 1 . the scientific community is actively trying to uncover the extent of these disorders but little has been reported on the early days of the outbreak when doctors were approaching the unknown. while evidence that zikv is related to microcephaly in newborns is accumulating, the mechanisms of how the virus affects the fetus is still uncertain. in the outbreak onset we had to face daunting challenges to search the cause of microcephaly and the emotional toll on the families. we took a very early approach from 9 microcephalic fetuses on gestation and 46 microcephalic babies on clinical follow-up from different pe areas, evaluated between 15 october and 17 december 2015 in oswaldo cruz hospital, to propose the early physiopathologic hypothesis that, a viral-related brain developmental disruption could be the basic neuropathogenesis in zikv babies instead of a direct injurious process due to viral insult followed by active inflammation. the eight pregnant women were all in the 3 rd gestational trimester and had had normal us follow-ups till week 20 th . crucially, we were facing a temporal-geographic association of cases presenting an unanticipated pattern of us alterations. because of their late alarming findings they were re-examined and the us scans revealed sudden encephalic alterations after 28 th gestational week. such devastating us clustering images were not seen here before, but are now considered as part of the "congenital zika syndrome". we observed late appearing severe dysmorphic encephalic changes in 9 out of 9 fetuses, including small skull, small brain, sub arachnoidal space enlargement, ventricular dilation, brain calcifications of varied shape and distribution, inclined frontal bone, progressive decline of head growth potential, early fontanels closure and redundant scalp (panel, figs. 2a, 2b). we had no clues on the causes and mechanisms responsible for this phenotype of severe alterations. thus, we had no explanation to offer to patients, in particular, or to the medical community. both as physicians and human beings, we were committed straightaway to continue the study of these victims of an unknown medical tragedy, engaging our expertise in fetal imaging and immunopathology. from beginning october, the first microcephalic babies were referred to the upe pediatric infectology service for initial investigation. strikingly, the newborns exhibited "healthy" appearance, excluded the microcephaly itself and motor sequels. we then looked for csf analysis of the microcephalic babies. for that, we obtained from dr. patricia travassos, a csf specialist at upe, a cohort of 120 csf samples that have been studied for signs of meningitis or encephalitis. about 87% (42 cases) of the csf analyzed looked normal for any signs of central nervous system ongoing inflammatory responses (panel, fig. 3 ). the babies had been examined by outpatient clinic dr angela rocha, from the upe hospital infectology reference center that have stated that although small, the babies were near to full term gestation (36-39 weeks gestation), had good apgar scores and variable degrees of microcephaly and neurologic impairments, i.e. contractures, spasms, irritability and in some retinal macular atrophy. during the follow-up, the babies were cared at home, breastfeeding, gaining weight and having routine vaccines. none of them expressed signs of ongoing inflammatory reaction in the cns (panel, fig. 4 ) or alterations on peripheral blood count and other routine laboratory tests up to 3 months of age. despite the striking neurological phenotype, 80% of the babies were negative for torch agents, no deaths were recorded. furthermore only in january 2016, the first evidence associating zikv to microcephaly from rt-pcr test on amniotic fluid was reported 2 . astonishingly, a particular kind of physiopathological process linked to fetal brain development was arising without clinical manifestation of inflammatory reactions or necrotic processes in these babies. unfortunately, no necroscopic samples of affected brain tissues were available to us to monitor the presence of putative neural dysgenesis and the very nature of brain calcifications background offering histological support for our hypothesis. nevertheless, with this restricted dataset we hypothesized that whatever the etiologic agent involved in these cases, its physiopathologic mechanism must trigger the cellular death programthe apoptotic process -at a particular development window on the cns, assuming clinically that the agent was not encephaalitogenic but silently tertogenic. if not, the clinical outcome of affected babies would not be so mild as far as signs of inflammation on cns was concerned. consequently, the inflammation-free clinical status of patients suggested us that a massive enhanced apoptotic cell death during the window of telencephalic expansion was the most probable physiopathologic process operating this microcephaly phenotype, with no direct direct lytic brain lesion or significant necrosis due to usual injury. furthermore, knowles and penn 3 stated that this window is very active to select the "fittest" neural cells by a constitutive apoptotic pathway. we so hypothetized that during this developmental time window, the "fit or not fit" status of the rapid, transient amplifying neural progenitors cells facing zikv, would heavily shift the selective process toward the self-elimination of virusbearing cells through apoptotic pathways. thus, zikv-enhanced constitutive apoptotic mechanisms would lead a massive loss of developing telencephalic neuronal precursors and, consequently, provoking losses of dividing cells and the arrest of further brain development. this could be particularly inferred by the absence of the characteristic morphology of late stages structures of neocortex, according with our us images of zikv microcephalics in gestation. similar processo could also be inferred to neurocrest derivatives as deformities in the viscercrany always accompany the cephalic malformation. our initial understandings based on clinical examination on the field, when no specific laboratory test, necroscopic data or experimental evidence on the disease causality were available, conducted our physiopathological approach to the "apoptosis hypothesis" for zika microcephaly that is now gaining strong support. in february, mlarkar et al 4 showed clear connection between zikv and microcephaly, presenting cns histopathologic analyses, revealing remnants of neural germinative matrix, intense gliosis, alterations in cortical ribbon, calcifications in gray and white matters without associated necrosis, encephalitis or meningitis and the presence of the virus, further supporting neurodevelopmental arrest. similar results were showed by driggers et al 5 . the ct scans from microcephalic babies from hazin at al 6 , have added details of brain development arrest with no radiological signs of brain destruction or active inflammation. finally, experimental models have provided a body of evidence f or neuroprogenitors permissiveness to zikv and viralinduced apoptotic process. tang et al 7 demonstrated by icq that the zikv infection of cortical neural progenitors attenuates their growth and increases caspase-3 activation, calling for an apoptotic process. this finding was corroborated by the up regulations of caspase-3 genes by rna sequencing. nowakowsky et al 8 demonstrated that zikv may hijack axl protein as an entryway to infection. interestingly, axl is highly abundant on the surface of neural stem cells but not on differentiated neurons in the developing brain. recently, cugola et al 9 demonstrated that zikv was able to cause cns congenital brain dysgenesis upon vertical transmission in mice. in parallel, human brain organoids infected by zikv show a reduction of proliferative zones and disrupted cortical layers, so targeting cortical progenitors and inducing apoptotic cell death with impaired development. for babies born with zikv-related microcephaly, the many expected consequences besides the evolving congenital neurosequels, are the unanticipated pattern of persistence of zikv in cns host cells, unsafe maintenance of neuron genome stability on remaining arrested populations, implying risks for brain tumors, risks for impaired adult type neuron wiring and neuron survival in an affected neuronal circuitry. in brief, evolve life with a wide vulnerable brain. the outbreak of zikv in the americas will eventually decline as herd immunity increases, but the world remains at risk of further waves of infection in affected countries and spread into new territories 1 . while experimental studies will be carried out to fully understand the pathophysiology of zikv infection in the developing fetus, our findings provide a coherent and testable physiopathological hypothesis for cns teratogenic phenotype linked to zikv congenital infection, which may be critical for the clinical care of pregnant mothers and their babies before and after birth. take home points: fetal dysmorphisms detected by ultrassonographic and mri images in congenital zika syndrome are late findings, usually after the 20 th gestational week and requires acurate analyses. clinically, zika's virus microcephaly is an infectiuos congenital condition that is not encephalitogenic but primarily teratogenic on the nervous system. the most important process leading to zika's virus microcephaly is pathologically induced apoptosis in telencephalic neuroprecursosrs cells and neurocrest precurssors cells. viral induced autophagy and low antiviral responses during the fetal period are linked to zika virus persistence in the central nervous system of affected new borns and babies a. vossough; philadelphia/us summary: susceptibility-weighted imaging (swi) has proven to be a valuable mr imaging sequence in a variety of applications. pediatric imaging has also immensely benefitted from this technique. in this presentation we will review pediatric neuroimaging applications in trauma, arterial and venous vascular disorders, hypoxic-anoxic injury, congenital malformations, congenital heart disorders, neoplasms, and pediatric degenerative disease. use of swi in pediatrics other than demonstrating hemorrhage and calcification will be reviewed. challenges in the clinical use of swi in pediatrics, interpretive pitfalls, and sources of clinical misinterpretation of swi will also be explored. we will also briefly present ongoing research and clinical use of swi in pediatrics and potentials for future collaborative investigations. & swi is highly sensitive in detection of susceptibility effects on mri. & in many cases, but not all, swi processing can differentiate between calclium and blood products. & quantitation information can also be obtained from swi with further processing. state of the art imaging of the single ventricle d.m. biko; philadelphia/us there are many congenital heart defects that result in a functional single ventricle. this may be functional or anatomical as a result of a dysfunctional valve or absent or ineffective pumping chamber. the repair of single ventricle physiology most often involves a staged reconstruction due to changing physiology ultimately resulting in a total cavopulomonary connection or fontan procedure. to appropriately image the single ventricle throughout its stages of palliation, familiarity with the physiology of the various steps in surgical palliation of the single ventricle is essential although echocardiography is a mainstay of cardiac imaging, cross sectional imaging has a vital role in the evaluation of the single ventricle. the role of ct angiography is mostly for anatomic evaluation. although it is fast and has high spatial resolution for evaluation of vasculature, ct has lower temporal resolution than mri and is unable to quantify flow. ventricular performance along with quantification of flow can be performed with mri. systemic to pulmonary collateral flow, which has been shown to result in adverse outcomes after fontan, can be quantified. valvular insufficiency and myocardial scarring can also be assessed. additionally, high anatomic vascular detail can be obtained with mri, particularly with the recent investigational use of the blood pool agent ferumoxytol. mri also has the ability to assess the lymphatics either through non-contrast t2 weighted imaging and/or dynamic contrast mr lymphangiography as lymphatic pathology may play a role in postsurgical hemodynamics in single ventricle patients. this lecture will focus on the use of ct and mri in the evaluation of the single ventricle particularly concentrating on the developing use of mri for anatomic and physiologic assessment. take home points: in single ventricle physiology, there is only one effective pumping chamber. familiarity with the physiology of the various steps in surgical palliation of the single ventricle is essential in imaging this disorder ct angiography provides high anatomic detail but limited in its assessment of physiology since it cannot quantify flow and has lower temporal resolution than mri. mri can evaluate ventricular performance, quantify flow and valvular insufficiency, and assess myocardial scarring. high anatomic vascular detail can also be obtained with mri particularly with the emerging investigational use of ferumoxytol. with non-contrast t2 weighted mri and/or dynamic contrast mr lymphangiography, lymphatic evaluation can be performed which may play a role in post-surgical hemodynamics in single ventricle patients. neuroimaging in head trauma m. argyropoulou, g. alexiou; ioannina/gr summary: objective: head trauma in children is one of the most common reasons for visiting emergency department. however, only a small portion of patients will have a traumatic brain injury. patients with moderate or severe head trauma should undergo ct scan, however, a debate exists for the indication and yield of neuroimaging for minor head trauma. we performed a systematic literature review on the accuracy of symptoms and signs in children with minor head trauma in order to identify those with severe intracranial injuries. materials: a systematic literature search of medline (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) was performed to identify studies assessing the diagnosis of intracranial injuries in children. the authors independently performed critical appraisal and data extraction. results: we identified studies that evaluated the performance of findings for detecting intracranial injury using the reference standard of neuroimaging or follow-up examination. mechanism of injury, multiple vomiting episodes and decline in gcs score were more commonly associated with severe intracranial injury on ct. normal variations in the amount of joint fluid, ganglion cysts, bone marrow edema, and bony depressions that resemble erosions are frequent in the wrists of children. the results of a follow-up of a healthy cohort aged 6-17 will be presented. the cohort was examined twice with mr of the wrist, and the second time also with a cartilage sequence for better visualization of the bony depressions. knowledge of these normal variations is important because they can resemble disease. bone marrow edema, joint fluid more than 2 mm, and bony depressions that can resemble erosion are frequent findings in the normal wrist. take home points: bone marrow edema, joint fluid more than 2 mm, and bony depressions that can resemble erosion are frequent findings in the normal wrist. these findings can not be attributed to dissease without additional findings of synovitis. a cartilage sequence can be of use in the differentiation between true erosions and bony depressions. mri scoring of the wrist in patients with jia-current status and future perspectives c. nusman; amsterdam/nl the wrist is a frequently affected joint in patients with juvenile idiopathic arthritis. due to recent improvements in treatment strategies, permanent damage is not that common anymore. also, imaging has been playing a key role in monitoring the disease activity in the wrist of jia patients. the past years lots of efforts have been made to improve the assessment of acute and permanent changes of the jia wrist. requisites and recommendations for the mri protocol to use for of the jia wrist are available in literature. currently, the features of scoring the jia wrist are synovitis, tenosynovitis, bone marrow edema and bone erosions. the repeatability of the above-mentioned scoring features proved to be acceptable. recent studies showed that the appearance of the wrist in healthy children can mimic pathology. therefore, construct validity of the scoring features needs to be assessed by comparing wrists of healthy children with the wrists of jia patients. & construct validity of the scoring features needs to be assessed by comparing wrists of healthy children with the wrists of jia patients a novel radiographic scoring system for permanent hip involvement l. tanturri de horatio 1 , p.l. di paolo 1 , s.c. shelmerdine 2 , p. toma 1 , k. rosendahl 3 ; 1 rome/it, 2 london/uk, 3 approximately 20-50% of children with jia, particularly those with systemic onset disease, will have hip-involvement within 1-6 years after disease onset. as scoring systems for radiographic changes in children with hip involvement are lacking, we aimed to examine the reliability of potential markers and suggest a novel scoring system. a set of 75 hip-radiographs from 75 children with jia and clinical hipinvolvement: 59 seen at the outpatient clinic at great ormond street hospital (gosh), london, and 16 seen at ospedale pediatrico bambino gesù, rome, was used. all hip radiographs were scored in a blinded fashion, once by an experienced paediatric radiologist and a paediatric radiologist with minor experience in musculo-skeletal imaging in rome, and twice by an experienced radiologist and a research fellow in bergen/ london. radiographic findings suggestive of 1) destructive change (bone erosion, flattening of the femoral head, squaring of the femoral head contour, presence of sclerosis, joint space height, and 2) growth abnormality (length and width of the femoral neck, varus/valgus deformity, the ccd angle and the trochanteric-femoral head height) were assessed. assessment of erosions of the femoral head, femoral neck and the acetabulum showed moderate to good agreement for the same reader. the inter-reader agreement was, however lower. there was a high to moderate (2017) 47 (suppl 2):s297-s pediatr radiol agreement for the assessment of femoral head flattening using the mose' circle. the measurements of femoral neck length and width, the ccd and trochanteric-femoral head lengths were precise, with 95% limits of agreements within 10-15% of the mean. we have identified a set of relative robust radiographic findings suggestive of growth abnormalities and destructive change in children with hip-jia, and suggested a novel scoring system. x-ray of a 21 years-old jia patient with severe chronic hip involvement. x-ray of a 6 years-old boy with growth abnormalities on hips (bilateral coxa magna). in jia hip involvement is often a predictor of a severe disease course. radiographic findings vary according to mode of onset and age: in younger children the initial findings may be developmental rather than destructive while children with later onset jia may have destruction/narrowed joint space as the first feature. several of the commonly used radiographic findings for chronic hipchange are inaccurate. we have identified a set of relative robust radiographic findings suggestive of growth abnormalities and destructive changes in children with hip-jia, and suggested a novel scoring system. bone age assessment -statement from the msk task force k. rosendahl; bergen/no summary: age assessment is an important, yet complex and challenging issue that authorities may need to perform to determine whether an individual is an adult or a child in circumstances where their age is unknown. there is currently no method which can identify the exact age of an individual and there are concerns about the invasiveness and accuracy of the methods in use, namely analysis of documentary evidence, interviews, physical or other form of medical examination such as imaging. the main imaging methods include carpal, collar bone and dental examinations. whilst many countries make use of these methods they do not apply them in the same way and often use different combinations and/or order. one of the main reasons for this is the fact that age assessment procedures remain to a large extent determined by national legislation, with procedures evolving through national jurisprudence (ref.: european asylum support office (easo age assessment practice in europe)). the ethical and legal aspects of using bone age to determine age will be addressed in a statement from the msk task force. the ethical and legal aspects of using bone age to determine age will be addressed in a statement from the msk task force. & the application of drls should be the responsibility of all providers of x-ray imaging. this means that drls should also be applied to imaging performed outside the radiology department. & the physical quantity used to establish drls should be an easily measurable quantity, usually directly obtainable from the x-ray equipment console, obtained either by manual recording or preferably by automatic recording and analysis. organ doses and effective dose are not considered feasible as a drl quantity because these cannot be easily determined. the ultimate mission of eurosafe imaging is to support and strengthen medical radiation protection across europe following a holistic, inclusive approach. most common imaging procedures in children and their contribution to collective dose e. sorantin 1 , c. granata 2 ; 1 graz/at, 2 genova/it summary: several countries have released "diagnostic reference levels (drl)" for imaging procedures using ionizing radiation. unfortunately those drl differ in types of procedures and granularity as well as information about the proportion of pediatric patients within the different examinations are sparse. therefore an more evidence based approach seems to be feasable -meaning releasing drl first for frequent and radiation burdened examinations. therefore a survey within europe was conducted and a questionnaire was sent to key persons of the european society of pediatric radiology (www.espr.org) as well to members of a large academic, interdisciplinary, international network within the ceepus programme (central european exchange programm for university studieswww.ceepus.info). alltogether 33 centers were contacted and an response was received from 18 (54.5.%). from one center only frequencies for interventional radiology was sent. plain films: most frequent procedures are extremities (48.5%), followed by chest films (31.4%) -both account together for more than ¾. flouroscopy: voding cysto urethrography (vcu) 37.2%, followed by upper gastro intestinal (gi) series with 32.1% -again representing 2/3 of those examinations. computed tomography: head & neck 46.8%, chest 27.8%, abdomen 13.7% -together almost 90%. interventional radiology and cardiac interventions: only limited data available and procedures quite hardly standardize and comparable. it seems adviseable, that only a few procedures are suitable for drl like peripheral insertion of vascular lines, occlusion of ductus arteriosus botalli or stent implantation for coarctation. in order to estimate the contribution to the relative collective dose all values were normalized to a chest xrays (1.0) and the following numbers could be calculated: abdominal plain film 0.1, skull 0.01, ct head 2.6, ct chest 10.2, ct abdomen 4.5. the most frequent imaging procedures using on ionizing radiation are: in plain films extremities and chest xrays in flouroscopy vcu and upper gi series in ct head, chest and abdomen therefore eu wide drl should be released for those examinations. as it could be expected chest ct is the main contributor to the collective dose. since the espr abdominal (gi and gu) imaging task force has changed its name and agenda, extending from initially only genitourinary queries to also other abdominal imaging topics, new projects have been added such as for example imaging in anorectal and cloacal malformations, imaging in paediatric inflammatory bowel disease (ibd, a joint project with esgar), or paediatric abdominal ceus applications. results of these new projects will be presented in the upcoming talkshoping that again (as the last procedural recommendations and proposed imaging algorithms) our proposals and recommendations will help to standardise paediatric imaging, to reduce radiation burden, and to facilitate comparable imaging data for future research. other topics in this session are a proposal for a more standardised approach to gastrointestinal ultrasonography, and considerations on gadolinium applications in children in the light of new observations (i.e., gadolinium deposit in tissue even in children with normal renal function). the work goes ononly achievable with active participation of interested and competent members. many interesting topics for either recommendations or joint research are on the list such as addressing late decompensating pujo or specific imaging needs in ibd in early childhood; other new ones may be proposed by any task force member. thus all espr members are invited to join the group, work with us and share their expertise. (2017) 47 (suppl 2):s297-s pediatr radiol contrast enhanced us in childhood -applications in children: literature review and results from the questionnaire c. bruno; verona/it in adults, following the characterization of focal liver lesions, several applications of contrast-enhanced ultrasound (ceus) have emerged in the last two decades, since second-generation contrast agents have been introduced and approved for use in most european countries. from many points of view, children represent an ideal population for ceus, because of the absence of radiation exposure and of need of sedation. moreover, due to the small body size many anatomical targets in children can be adequately explored with high-frequency ultrasound, obtaining images with higher spatial resolution than in adults. however, to date comparatively few data on pediatric ceus are available. although very rare and usually mild, possible adverse effects of contrast agents probably limit their use in many centers. in addition, the intravenous administration of ultrasound contrast agents in children is still off-label in europe, which makes informed consent necessary in every case. finally, for unclear reasons information on this topic does not flow easily. & from the comparison between the data available, similar or better results are likely to be obtained with ceus in children than in adults, and some specific pediatric indications might be proposed. imaging in ibd-joint recommendation statement with esgar f.e. avni 1 , m. napolitano 2 , p. petit 3 ; 1 brussels/be, 2 milan/it, 3 marseille/fr the first joint esgar/espr consensus statement on the technical performance of cross-sectional small bowel and colonic imaging (1) objective: to develop guidelines describing a standardized approach to patient preparation and acquisition protocols for magnetic resonance imaging (mri), computed tomography (ct) and ultrasound (us) of the small bowel and colon, with an emphasis on imaging inflammatory bowel disease. methods: an expert consensus committee of 13 members from the european society of gastrointestinal and abdominal radiology (esgar) and european society of paediatric radiology (espr) undertook a six-stage modified delphi process, including a detailed literature review, to create a series of consensus statements concerning patient preparation, imaging hardware and image acquisition protocols in pediatric and adult patients. the delphi process is constructed as follow: step 1 questionnaire construction to includes all contents relevant to the guideline and set up of working groups; step 2 questionnaire completed by all committee member, step 3 literature search; step 4 draft consensus produced by each wg based on the literature review and questionnaire responses; step 5 committee members indicate agreement or otherwise for each individual draft consensus; step 6 acceptance of agreed statements (more than 80% of members), face to face meeting to modify statements without agreement. committee members indicate agreement or otherwise for each modified consensus statement and final consensus statements. the questionnaire was split into four broad topics, each of them treated by a subgroup including in each of them a pediatric radiologist: (1) patient preparation for mre/mr enteroclysis/cte/ct enteroclysis, (2) mre/ mr enteroclysis technique and sequence selection, (3) cte/ct enteroclysis technique, and (4) enteric us patient preparation and technique. after an extensive literature research each member were instructed to always base their statements on the retrieved literature wherever possible, and to this end graded the strength of retrieved relevant publications from i (high) to v (low) using the criteria of the oxford centre for evidence based medicine (2) during their review process. if no relevant literature was available for a particular item, members used expert opinion to construct the consensus statements. the pediatric guidelines were based on the opinion of 3 pediatric radiologists and 4 adult radiologists who have experience in pediatric practice. & it is recommended that children aged 6-9 should not eat any solid & it is recommended that the use of a spasmolytic agent is optional. unlike adult practice, the use of spasmolytic prior to mre is considered optional in paediatric patients and use is likely dependent on the age of the patient, with older children more likely to tolerate spasmolytic injection. there are data supporting the benefits of glucagon on image quality, at the expense of prolonged imaging time and precipitation of nausea in just under half of paediatric patients (3, 4) . however, high diagnostic accuracy can also be achieved without spasmolytic (5) . & it is recommended that children aged over 9years should be nil by mouth for carbonated and milk beverages for 4-6h. ingestion of still water or non-carbonated fruit juice is recommended. & it is recommended that for dedicated colonic evaluation, a standard protocol without specific modification is used. & use of a spasmolytic agent is not recommended. & the use of i.v. us contrast is not recommended. & it is recommended that scan coverage should include an abdominal and pelvic examination, including the liver. there are no specific recommendations as to the use of hydro us in the paediatric patient as practice is not well developed. if oral contrast is given prior to us, it would seem sensible to follow the recommendations for mre in the paediatric population & it is recommended that if ct scanning is used in the paediatric population, no specific preparation is usually required although administration of positive oral contrast could be considered; for example, prior to percutaneous drainage of abscesses. limitations: there is little evidence in the literature to ascertain all these proposals. the recommendations were mainly based on expert opinion. no recommendations have been proposed for children before 6 years of age. especially the benefice of mre under sedation (6) in the younger compare to us doppler need to be explored. contrast media application is essential for a number of mri studies in children. there is some evidence that gadolinium-based contrast agents (gbca) are well tolerated in infants and children. the risk of adverse reaction is no higher in children than in adults. there are only few data available about pharamakokinetics in children, especially for the use of gbca in neonates. age-adapted reference values of the glomerular filtration rate (gfr) have to be used to identify children with a potential risk. in the past few years there was some attention toward the potential cellular toxicity of gadolinium and its role in the development of nephrogenic systemic fibrosis (nsf). there were only few children identified with proof of nsf. but, particulary renal insufficiency, poor hydration, acidosis and inflammation increase the risk for nsf. because the cases of nsf have been observed with linear componds the guidelines (2017) 47 (suppl 2):s297-s pediatr radiol from the esur and the espr and others propose to avoid linear compounds and to prefer macrocyclic gbca. in the past year several studies have described observations about possible gadolinium retention in the brain; hyperintense brain structures in native t1 weighted sequences were verified -globus pallidum and dentate nucleaus -also in children undergoing multiple mri examinations with gbca application. so, repeated mr investigations within a short time should be avoided -the cumulative dose of gbca should be recorded. consider all these points, the benefit of a contrast-enhanced study should be weighted against the potential risks before administering a gbca for each child separately. but, never deny a child an indicated cemri study. use single dose application (0.05-0.1 ml/kg body weight), improve renal function and hydration, balance acidosis -and ask your pediatric nephrologist íf necessary. gadolinium-based contrast agents are safe. macrocyclic compounds should be used in children. avoid contrast media in neonates and be careful in infants. identify risk factors. avoid repetivite application. procedural recommendation: how to perform pediatric gastrointestinal us m.l. lobo 1 , m. riccabona 2 ; 1 lisbon/pt, 2 graz/at summary: ultrasound (us) is the first imaging modality applied in the investigation of abdominal complaints in children, and an increasingly valuable imaging tool in the assessment of the gastrointestinal (gi) tract in neonates, infants and children. a comprehensive us examination is a critical first-step to optimize the potential of us diagnostic yield in many paediatric gi conditions. using proper high resolution transducers and graded compression technique is an essential part of gi us examination. a methodical and systematic analysis is crucial to facilitate a thorough evaluation of the bowel segments as complete as possible: follow bowel in a cross section, complete by longitudinal and oblique views. for some bowel sections filling is essentialsuch as stomach for gastroesophageal reflux and pyloric function, and distensibility and size of the colon by enema (e.g. for query microcolon). modern us methods are valuable, but not a pre-requisite. proper documentation of abnormal size of the gi tract segments, their luminal content, peristalsis, bowel wall characteristics and its surroundings, as well as local tenderness should be noted. a proposal for recommendation on how to perform paediatric gastrointestinal us will be presented for public discussion. & careful and dedicated us examination is crucial to obtain maximum anatomic and functional information in many gastrointestinal disorders in children. & systematic and methodical analysis helps to assess the bowel as complete as possible. & satndardization of us technique is essential to optimize us diagnostic capabilities and to allow for comparable examinations wich is essential to improve future evidence-based knowledge. hominid evo-devo: reconstructing the evolution of human development c. zollikofer; zurich/ch from an evolutionary biologist's perspective, modern humans represent the only surviving species of a group of highly specialized "bipedal great apes". they evolved more than seven million years ago in africa and managed to spread over the entire globe. in this talk, i will trace the history of our species with an emphasis on key developmental innovations that underlie major evolutionary innovations. why are we born with brains that have the size of adult great ape brains? and why do we grow up so slowly and get so old? i will highlight how advanced biomedical imaging methods help addressing these questions, and show how combined fossil, clinical and great ape data yield surprising insights into the evolution of our development. to present our experience with innovative imaging in pediatric interventional radiology. imaging technologies presented will include: 1. use of bubble contrast (lumeson) for indicatons including; complex pleural effusion and abdominal collection assessment pre and post therapy, primary g tube placement, renal perfusion pre and post rena artery angioplasty, vascular patency during central venous line placement, vascular malformation therapy and biliary tube assessment. 2. intravascular us (ivus) in arterial intervention pre and post angioplasty and venous thrombolysis intervention. 3. optical coherence tomography pilot study assesssment for renal artery intervention -validation in normal subjects. currently this imagng which uses laser light technology to assess vascular mural detail at the micron level, is only validated in coronary artery intervention in adults. 4. mr overlay -a technology that fuses mr imaging with low dose fluoroscopy and can faciltate biopsy of mr positive/ct negative lesions in the ir suite. focus will be on bone lesion biopsy and vascular malformation therapy. critical structures to be avoided can be outlined on the mr and transposed onto the fluoroscopic image during biopsy. in our experience this technology has promise in the pediatric setting with significant dose reduction when compared to ct. 5. mr fusion and i guide fusion technology enables an mr positive/ct negative lesion that would require ct guided imaging to be biopsed, using low dose c -arm ct, with fusion of the ct and mri images performed using landmarks, facilitating fluoroscopically guided biopsy in the ir suite. critical landmarks/structures to be avoided can be outlined on the ct or mr and transposed onto the fluoroscopic image during biopsy path planning and orchestration. focus will be on bone lesion biopsy. 6. color parametric flow related imaging in vascular interventionthis software enables time to peak opacification of arterial or venous contrast to be color coded in time and can provide adjunctive information for assessent of perfusion change during vascular intervention such as renal artery angioplasty, dialysis access intervention and cerebral embolization. 7. mr guided intervention -this focus will be on the initial development of an mr interventional program and our initial experience with mr arthrography. discussion will also involve the use of this modality for vascular malformation sclerotherapy and other msk interventions such as biopsy and nerve injections. 8. high frequency us imaging-focus will be on the use of a 40mhz us probe in the ir suite for various indications including visualization of smaller targets such as neonatal central venous access, superficial vascular malformation therapy and thyroid fine needle biopsy. 1. participants will become more familiar with exisitng and emerging innovative imaging technologies for pediatric intervention. participants will learn about the various indications and limitations of these technologies. 3. participants will gain insight into the process of introducing new imaging modalities into their pediatric interventional practice. increasing evidence supports the notion that autism spectrum disorder is associated with anomalies of brain function and connectivity. it is also evident that there are atypicalities in development/maturation of brain systems. particular promise arises from findings of atypical electrophysiology -indexing brain neuronal activity in real time. in particular, this talk will address a characteristic electrophsyiologic signature of delayed auditory evoked response latency (at~100ms). this, and related timing anomalies, have been proposed as biomarkers for asd -with candidate use for diagnosis, prognosis, stratification and therapy monitoring. progress along each of these axes will be discussed. however, to justify the term "biomarker", we demonstrate converging evidence from spectrally-edited (megapress) mrs and diffusion-mri. mrs offers insights into neurotransmitter levels, especially gaba and glutamate, imbalance of which may be associated with anomalous electrophysiologic oscillations in the gamma band. diffusion offers insights into the white matter of the brain (auditory pathway will be illustrated) and an interpretation of diffusion parameters as an index of central conduction velocity will be offered. combining these mechanistic measures with the spectrospatio-temporal capabilities of magnetoencephalography (meg), this talk will present a state of the art review of multimodal biomarker development in asd. take home points: meg captures brain activity in space and time as well as showing sensitivity to activity at different frequencies (where, when and what) delays in cortical neuronal response latency are evidence in asd atypical coupling between diffusion evidence of conduction velocity and timing of cortical responses in shown in asd oscillatory activity is atypical in asd (elevated "noise", decreased "synchrony") diminished inhibitory neurotransmitter (gaba) levels are shown in asd disturbance of teh typical coupling between gaba and gamma-band oscillations in development leads to anomalous adult oscillatory activity (taken to index local circuit function). multimodal and longitudinal approaches may be required to tackjle the complex and heterogeneous landscape of asd the paediatric radiologist can play an important role in establishing vascular access in paediatric patients ranging from neonates to teenagers. a breadth of knowledge and skills are needed to deal with changing body morphology and varied pathology in this age range. some of the skills particular to performing and managing vascular access in children will be discussed. different devices which can be placed, their indications, advantages and disadvantages will be reviewed. choice of access vessel is important in children, because there are known long term complication such as central venous stenosis and thrombosis, which can have a huge impact for future venous procedures or potential creation of an arteriovenous fistula of the arm for dialysis. preserving venous access sites is a (2017) 47 (suppl 2):s297-s pediatr radiol key responsibility especially in children with complex medical and surgical co-morbidities. because vascular access in children has associated morbidity it's important to manage and maintain devices that are placed. the risk of infection when repairing or exchanging a broken line will be highlighted. image guided biopsy is a very frequent procedure in pediatric patients. they range from random organ parenchyma for the diagnosis of medical disease up to tumor biopsies for histopathology analysis. different imaging modalities can be used for guidance as well as different biopsy devices and needles. ultrasound guidance is the most common modality used for this purpose in the pediatric population. the success of this procedure depends on multiple factors: from pain control up to choosing the correct device and area to sample. the radiologist performing the procedure also needs to be familiar with the potential complications of the intervention, how to prevent them and how to manage them. the intention is to perform the safer procedure as possible, obtaining the best quality of sample. the goal of this lecture is to present in a didactic way technical tips to perform safe and effective image guided pediatric biopsies, which may be applicable to different groups of operators, ranging from general pediatric radiologists performing occasional biopsies up to pediatric interventional radiologists. the objectives will be: to identify the safest approach to different types of biopsies; to describe ways to obtain the better quality of sample as possible; to demonstrate the use of different approaches in challenging clinical scenarios; to illustrate new devices currently used in specific applications; to discuss potential complications and its management and to show imaging modality integration applied to biopsy planning an performance. image guided biopsy is a frequent procedure in pediatric patients. a pre-procedure planning is fundamental in the success of the intervention. the operator must be aware of the aims of the biopsy and based on this choose the best approach, device and site for sampling. preparation and competency to manage complications is mandatory. pediatric interventional oncology: big cases in little people m. heran; vancouver/ca summary: the pediatric patient presents unique challenges in diagnosis and management of oncologic disorders. interventional radiology (ir) has a prominent role in the care of these children, with improvements in imaging and equipment offering better and safer options to traditional diagnostic and therapeutic procedures. as cancer can involve any organ system, consultations to the ir service can involve any part of the body, and can be non-vascular and vascular, simple and complex. the most common ir procedures in the pediatric oncology patient are enteric tube placement/change, vascular access, and percutaneous image-guided tissue/organ biopsy. however, with the explosion of interventional oncology in the adult setting, the variety and complexity of ir in pediatric oncology has begun to increase as well. ir techniques, such as thermal ablation, transarterial pharmacotherapy, and preoperative embolization, are now increasingly discussed in multi-disciplinary conferences as complementary or primary modes of treatment of oncologic disorders or related diseases/complications. however, although the principles of these diagnostic and therapeutic ir procedures remain essentially the same in their translation from adults to children, well recognized differences in pediatric physiology and metabolism, as well as the range in weight, size, and age of children, result in a practical question of "how do we do this?" the aim of this presentation is to provide an overview of the role of ir in the pediatric oncology patient, and to highlight areas of research and innovation. vascular anomalies encompass a spectrum of disorders including vascular tumours and vascular malformations. incorrect nomenclature and misdiagnoses resulting in inappropriate treatment are commonly experienced by patients with vascular anomalies. the currently accepted method for classification of vascular anomalies is straightforward and clinically relevant. vascular malformations can be divided into high flow lesions such as arteriovenous malformation or low flow lesions such as venous or lymphatic malformations. in children, a diagnosis can often be made with the history, examination and ultrasound. the classification of vascular anomalies will be briefly reviewed with examples of commonly encountered pathologies. a multidisciplinary team approach to the management of these conditions is vital. paediatric radiologists can play a key role not only in diagnosis but also in management, principally by injection sclerotherapy of low flow lesions and embolization of the much rarer arteriovenous malformation. many sclerotherapy agents are available with sodium tetradecyl sulphate the most commonly used for venous malformations and doxycycline for lymphatic malformations. different sclerotherapy agents have different characteristics and uses which will be covered. symptomatic relief is often achieved with treatment but multiple treatment episodes may be needed to achieve the desired outcome. ensuring the child and family understand this is vital to ensure they are satisfied with the management of the condition. contrast media is commonly used during imaging in children whatever their age and whatever the pathologic conditions. still, youngest patients are vulnerable and unstable. therefore, in neonates and infants the use of s339 (2017) 47 (suppl 2):s297-s pediatr radiol contrast media should be carefully evaluated and customized putting in balance the risk versus the benefit of its use. when using contrast media in neonates and infants, several features should be highlighted: -prematures and neonates have rather immature kidneys and some contrast media might be difficult harmful -the thyroid gland in prematures may be (transitorily) depressed by iodinated contrast media -the use of high osmolar contrast may induce a fluid shift and dehydration especially in premature and neonates -most contrast media are used off label; almost none has obtained the authorization to be used in neonates. -there are very few studies evaluating the short and long term adverse reactions in neonates and infants below the age of two. fortunately these reactions seem very rare in these age groups. -using contrast extends the duration of the examination and the need for sedation different types of techniques will potentially need ingestion, instillation or injection of contrast media: 1) opacification of the entire gi tract pre-and post-operatively 2) retrograde uretro-cystography 3) contrast enhanced ct 4) contrast enhanced mr imaging 5) contrast enhanced us 6) angiography furthermore, different types of contrast media can be used to achieve these purposes 1) barium (sulfate) 2) iodinated water-soluble contrast media (hyper-, iso-or hypoosmolar) remarks regarding opacification of the upper gi tract: -the upper or lower gi tract should be opacified using water soluble contrast in the immediate postoperative period or whenever a bowel perforation is suspected. -air can be used to confirm esophageal atresia and duodenal atresia -barium should be preferred in case of t-e fistula -either barium or water soluble iodinate contrast can be used in order to opacify (sub)obstructed upper gi tract remarks regarding the opacification of the lower gi tract -iodinated iso/hypo osmolar contrast should be used to opacify the colon in case of obstruction -a higher osmolarity iodinated contrast can be used in case of suspected meconium ileus or plug; still this contrast should be used diluted and under close clinical surveillance and adequate hydration. -in some more specific cases, for instance whenever hirschprung disease or a stenosis post nectotizing enterocolitis are suspected, barium enema can be used remarks regarding ct scan -contrast enhancement may help for the global assessment of various pathologies especially in case of cardio-vascular malformations or for the evaluation of abdominal masses. any iodinate contrast among those available is acceptable in neonates. higher osmolality contrast allows to inject a lower volume -injected volumes of 1.5 ml/kg seem adequate using 22-24 gauge needles -power injectors are acceptable as long as adequate catheters can be used -allergic or side effects are very rare and should be managed similarly to adults. remarks regarding mr imaging -the use of gd chelates in neonates remains controversial as there is no data available on the long term effects of gd injected so early in life -gd should be used only when enhancement may provide additional information compared to the non-enhanced study (cns infections, tumors, cardiovascular imaging, abdominal tumors, uro-mr imaging...) -only gd with low nsf risk should be used -gd should not be used in children with renal failure remarks regarding contrast enhanced us -little is known about the use of ce-us in neonates -indications seem equal to older children -there are very few side or allergic effects -doses suggested are 0.1 ml/year of age children present varied histological types of brain tumours. it's now possible to combine different information and image techniques to improve the diagnosis of paediatric brain tumours. the multimodal approach has increased the diagnostic specificity and permits, in most cases, the pre-operative differentiation between low and grade tumours. children with low grade lesions, and in particular the less accessible tumours, would benefit the most from avoiding biopsy. in addition, preoperative spinal mri evaluation to rule out drop metastases should be performed in patients with suspected high grade tumours. in general paediatric brain tumours are less necrotic, i.e. aggressive tumours in paediatric patients tend to be more hypercellular and homogeneous. because of its ready availability and speed, computed tomography (2017) 47 (suppl 2):s297-s pediatr radiol (ct) is the first investigation generally performed for a suspected brain tumour. ct can rule out haemorrhage or calcifications, but can also be used to evaluate tumour cellularity. a hyperdense tumour on ct reflects hypercellularity and is very often high grade. medulloblastoma are, for example, typically hyperdense on ct scans and paediatric low-grade astrocytomas are almost always hypodense. mri plays a major role in the evaluation of brain tumours. in conventional mri, the "general aspect" is the single most important parameter in predicting high-grade tumours in children. the same does not hold true for low-grade tumours, of which only 67% can be predicted using the general aspect. in our previous study, hyperintensity on t2-w and the lack of diffusion changes were the most important single parameters with 83% positive prediction. embryonic tumours, such as medulloblastoma or pnet have high tumour cellularity with consequent very low adc and hypo/isointense t2 compared to the cortex. adc values derived from dwi have been shown to be decrease in highly cellular tumours. adc values cannot reliably be used in individual cases due to the substantial overlap between tumour types previously described in the literature. nevertheless, adc has a higher predictive value in children and increases the accuracy of preoperative differentiation between low grade and high grade paediatric tumours. the cut-off values for differentiating between low and high grade paediatric brain tumours are 0.7 x 10 3 mm 2 /s and 1.0 x 10 3 mm 2 /s for minimum adc and average adc values, respectively. perfusion with relative cerebral blood volume (rcbv) is considered a marker of angiogenesis and is helpful in distinguishing high and low grade tumours. however, perfusion can be difficult to perform in small children; small catheters with manual injection are therefore used in such cases (or, as an alternative, arterial labelling). it should however be taken into account that choroid plexus tumours can have high rcbvs resulting from highly leaky capillaries. mr spectroscopy (mrs) shows the metabolic profile of the tumour. high grade tumours show elevated choline (cho) -reflecting increase in cell membrane turnover -and decreased n-acetylaspartate (naa), which represents a neuronal marker. the absolute values of the mrs peaks are not used by us; we favour to normalize the signal intensities of metabolites to their values in contralateral brain tissue. mrs is helpful not only as guidance for stereotactic biopsy (cho hot spot) but also for determining whether the tumour is high or low grade. as a rule of thumb, a 200% increase of cho when compared to the contralateral brain tissue is highly suggestive of a high-grade tumour. however, in children, increased cho levels can also be found in pilocytic astrocytoma; in this case the typical aspect with cystic component and location can suggest the diagnosis, despite the mrs result. therefore, in children, high cho levels do not necessarily imply the presence of a malignant tumour. task based functional mri (fmri) can be used for pre-operative localization of the eloquent cortex together with the identification of the language and somatomotor function. in the future, small children who are unable to cooperate will probably profit from resting-state fmri. pet mri has the advantage of integrating structural mr imaging with physiologic pet. take home points: take home points although the histology of paediatric brain tumours is diverse, their general morphological aspect on mri has a very high diagnostic reliability. unlike adult grade iv brain tumours, malignant paediatric brain tumours are less necrotic, but are highly cellular with high nuclear-to-cytoplasmic ratios. adding information on signal intensities on t2w and dwi further increases the diagnostic accuracy of conventional mri. the solid areas of high-grade tumours are iso-or hypointense on t2w and hyperintense on dwi, whereas low-grade tumours show inverse signal characteristics. advanced mr techniques (perfusion and spectroscopy) provide important biological information which can be used to correctly identify grading (high vs. low) and to guide biopsy. in children high cho levels, although suggestive, do not necessarily mean a malignant tumour. experience with central review of paediatric renal tumours g. khanna; st louis/us summary: central imaging review of pediatric renal tumors has been performed in children's oncology group since 2006. to date, more than 5500 cases of pediatric renal tumors have been centrally reviewed real time by the study radiologists. the mean time for central review was <8 days. discrepancies between local and central risk stratification were identified for detection of bilateral disease and pulmonary metastasis. in addition, central archiving of images has created a rich repository of cases for future research. the role of imaging in detection of key diagnostic features in pediatric renal tumors will be reviewed. the diagnostic performance of imaging for staging, detection of vascular invasion and tumor rupture will be discussed. real time central review of imaging is feasible in pediatric oncology wilms tumor remains the most common pediatric renal malignancy, followed by renal cell carcinoma cystic nephroma typically presents as a bosniak 3 lesion, and has high association with dicer-1 mutations is there a role for dwi in nephroblastoma? a.s. littooij; utrecht/nl wilms tumour or nephroblastoma is the most common malignant renal tumour in children. ultrasound is usually the first line investigation. mri of the abdomen is often performed to further delineate the tumor and its surroundings. the addition of diffusion-weighted imaging (dwi) to the standard mri protocol may enable subtype characterisation and allows assessing treatment response beyond necrosis and volume change. overall, the survival rate in patients with nephroblastoma is relatively good and the current focus is on finding biomarkers to further improve outcomes while reducing therapy-related side effects in these children. therefore, identifying low-or high-risk type nephroblastoma might be relevant for treatment planning. diffuse anaplastic nephroblastoma and extensive blastema in residual tumour after preoperative chemotherapy may require more intensive treatment. the limited available literature suggest a linear relation between adc values and subtypes nephroblastoma at histopathology. furthermore, the addition of dwi to the standard mri protocol may detect lesions (e.g. nephrogenic rests of nephroblastomatosis) that remain undetected at post contrast t1-weighted images. unfortunately, there is a considerable heterogeneity in acquisition techniques and methods of adc measurements. nephroblastoma often contains areas of necrosis and/or hemorrhage that can demonstrate very low adc values and consequently mimic highly cellular portions of tumours. therefore these areas should be excluded from further analysis. this lecture will highlight the potential additional benefit and limitations of dwi in children presenting with renal tumour. significantly lower radiation exposure even in comparison to low-dose pet/ct, (b) the higher diagnostic accuracy as compared to pet/ct even when using diagnostic contrast-enhanced ct, (c) the unique possibility to combine distinct mr-inherent contrasts (e.g. dwi) with specific pettracers (e.g. 64cu-labeled antibody imaging) for the evaluation of novel targeted therapies, and (d) the opportunity to stage local and systemic tumour burden within a single and highly resolved examination. on the other hand, many circumstances are challenging the extensive use of pet/mri in children. in general, the availability of pet/mri systems is low, particularly for children. thus, only a few sites in europe have experience with this technique in children, and therefore the generated scientific evidence is limited. moreover, whole-body-mri is still not a broadly adopted method for the combined assessment of local disease extent and whole-body staging, potentially replacing other whole-body modalities like the bone scan. in this context, especially the detection of pulmonary metastases is biased also against pet/mri. finally harmonized sequence protocols and specific recommendations for trace dosage are not available for pet/mri. in conclusion, further efforts are needed to keep the promises of pet-mri in the daily practice. common artefacts in paediatric mri-how to recognise, avoid or take advantage of them c. kellenberger; zurich/ch summary: while mri is a robust and radiation free imaging technique for assessing anatomy and pathology of most tissues and organs throughout the body, it is inherently prone to artefacts as no other imaging modality is. mri artefacts may impair image quality potentially leading to difficulties or errors in interpretation, but in some instances can contribute diagnostic information. main sources of image degradation are motion, disturbances of the local magnetic field and other factors inherent to image acquisition. strategies to reduce effects from various kinds of motion and adjustment of sequence parameters for eliminating artefacts will be discussed. & understanding the origin and effects of artefacts encountered in paediatric mri is essential for modification of mri protocols, so that artefacts and associated errors can be avoided. & for safely and successfully imaging children with implants and devices, the composition, location and functionality of the foreign body needs to be known. injuries to the central nervous system in abusive head trauma are responsible for the primary cause of morbidity and mortality in infants. neuroradiology has an important role in diagnosis but also in depicting injury and extent of brain damage of poor outcome. computerized tomography (ct) and magnetic resonance imaging (mri) are the primary imaging techniques. ct is usually performed in the acute phase while mri is performed the following days after injury. some injuries are better identified on mri such as diffuse axonal injury and cerebral edema with susceptibility and diffusion weighted images. abusive head trauma (aht) is the primary cause of morbidity and mortality in infancy, especially during the first year of life. aht is clinically characterized by a triad consisting of subdural hematoma, retinal hemorrhage and encephalopathy caused by brain swelling (1). the most common mechanism responsible for brain damage is thought to be caused by whiplash shaking injury explaining that abusive head trauma is also referred as shaken baby syndrome. impaction, compression and penetrating injury are also possible mechanisms as well as strangulation. however because of the variability of types and severity of injury, clinical symptoms vary from subtle to severe such as alteration of consciousness or coma (2) . the most common symptoms include vomiting, seizure, lethargy, poor feeding and apnea of which vomiting and respiratory pauses are non-specific (3). poor feeding, irritability or lethargy is also nonspecific signs. however apnea and/or retinal hemorrhages seen in children with brain injury are strongly associated with inflicted trauma (4) . in contrast to acute injury some children may manifest with increased head circumference related to chronic subdural hematomas. neuroimaging is therefore playing a crucial role to assess infants and children with a suspicion of abusive head trauma. computerized tomography (ct) and magnetic resonance imaging (mri) are the primary imaging techniques. ct is performed for the initial evaluation in cases with acute symptoms to look for hemorrhagic intracranial injury as subdural hematoma. mri is more often performed in the following days to further evaluate brain injury and to look for spine and spinal cord damage (5, 6) or in the presence of normal or equivocal ct findings (7) . however brain mri may be the first option in children presenting with increased head circumference. recently the study from flom et al showed the high sensitivity of mri for intracranial hemorrhage in well appearing infants at risk for abusive head trauma suggesting mri as a screening tool with 3 pulse sequences (axial t2, axial gradient recalled echo and coronal t1 weighted inversion recovery) (8) . ct is generally performed without intravenous contrast injection with 3d volume rendering (vr) reconstructions for identification of fractures. in some cases postcontrast images are also obtained specially to rule out deep venous thrombosis especially when children present with nonspecific clinical symptoms. mri protocol should include axial t2, t2* or susceptibility weighted images, coronal t1 images, diffusion or diffusion tensor images, and postcontrast 3dt1 images including mip reconstructions to evaluate the venous structures. mr venography can also be performed. susceptibility-weighted images are usually preferred because they allow the depiction of smaller hemorrhagic dai lesions and greater number of lesions compared to gre t2 (9) . it was also reported by colbert et al (10) that the presence of micro-hemorrhages alone was useful for outcome prediction in abusive head trauma with significant poor long-term outcome. the sensitivity and specificity of microhemorrhages was also higher than the other clinical (such as retinal hemorrhages and glasgow coma scale score) and other imaging findings for prediction of outcome. diffusion tensor imaging (dti) measurements were reported in abusive head trauma by imagawa et al: decreased axial diffusivity related to axonal injury with consequent reduced mean diffusivity did correlate with poor outcomes (11) . magnetic resonance spectroscopy (mrs) is usually not part of the standard protocol. however aaen et al (12) showed that n-acetylaspartate/creatine and/or nacetylaspartate/choline ratios were decreased significantly in the corpus callosum, frontal white matter, parieto-occipital white matter, and parietooccipital gray matter in children with poor outcomes. this study mentioned above also reported that the prediction of outcome was accurate in 100% of patients by using a logistic regression model that include age, initial glasgow coma scale score, presence of retinal hemorrhage, lactate on mrs, and mean total n-acetylaspartate/creatine. functional mri, (2017) 47 (suppl 2):s297-s pediatr radiol volumetry may be performed in long-term follow up of victims of child abuse. physical abuse is associated with altered emotion with greater activation in the salience network in response to negative stimuli, that includes amygdala, thalamus, putamen and anterior insula (13) . increased responsiveness of the right amygdala to fearful and angry faces (negative stimuli) and structural changes as reduced hippocampal volume, are reported by dannlowski et al (14) . impaired attention was also reported in patients with childhood abuse (15) with reduced activation during attention tasks in the left hemispheric ventral and dorsolateral prefrontal regions. intracranial injuries include extracerebral hemorrhages and parenchymal damage as brain swelling and ischemia, venous infarction, diffuse axonal injury, contusions and intraparenchymal hematomas (7, 16) . extracerebral hemorrhages subdural hematoma is a characteristic finding of inflicted traumatic brain injury, is generally multifocal and most commonly seen along the posterior interhemispheric scissure, over de convexities at the vertex level and/ or in the posterior fossa (17) (18) (19) . subdural hematomas are most likely bilateral but may be unilateral. all locations are related to disruption of bridging veins. the identification of bridging vein rupture allows the diagnosis of traumatism in relation to acceleration/deceleration, rotational and shearing forces due to violent shaking (20) . a mixed density appearance of subdural hematomas is frequent but is also seen in accidental traumatic brain injury (21) (22) (23) . indeed this feature is often present in the very early hours following trauma and is thought to be secondary to early sedimentation of blood clots and supernatant serum. tubular high density is often seen on non-contrast ct over the convexities in abusive head trauma. this ct feature is related to a clot secondary to venous disruption (24, 25) that can end up in thrombophlebitis. this tubular high density was reported more recently as tadpole sign (26) and lollipop sign (27) respectively seen in 40 and 44% of abusive head trauma. this appearance is strongly associated to inflicted trauma and much less frequent in accidental trauma (3 out of 83 cases (3,6%) of accidental trauma in our experience). associated venous infarction is reported in 12% of cases of abusive head trauma (24) and often located in the parieto-occipital region, unilaterally at the site of venous disruption of bridging veins. subdural hemorrhages, when multiple, in the convexity and interhemispheric, or in the posterior fossa were found significantly associated with abusive head trauma in the meta-analysis reported by kemp et al (28). in addition subdural hematoma, cerebral ischemia, skull fracture, retinal hemorrhage and intracranial injury were significantly associated with abusive head trauma in the review from piteau et al (29). subarachnoid hemorrhages (sah) and epidural hematomas are also found in inflicted trauma and are not considered discriminant-imaging features. however epidural hemorrhages, isolated skull fracture and scalp swelling were reported as significantly associated with accidental traumatic brain injury (29). sah in shaking injury is usually caused by tears of the vessels within the pia and arachnoid predominantly in the interhemispheric fissure and high convexity (7). parenchymal injury parenchymal injury include brain swelling and ischemia, venous infarction (discussed above), diffuse axonal injury related to rotationallyinduced shear-strain injury with different inertia for grey and white matter due to their different specific gravities, contusions seen in deceleration trauma with friction between the skull and brain, and in blunt trauma and intraparenchymal hematomas related to lacerated vessels. brain swelling/ischemia may be related to increased blood volume (congestive swelling), increased presence of water in the nervous tissue, and the combination of both. increased water in the nervous tissue may manifest as vasogenic edema located in the white matter due to extravasation of plasma like fluid related to incompetent blood-brain-barrier and as cytotoxic edema located in the grey matter, related to ionic imbalance. cerebral edema can be recognize on ct within the 12 hours following injury as loss of gray-white matter differentiation and decreased attenuation of grey and white matter. cytotoxic and vasogenic edema are better characterized on mri with diffusion-weighted imaging. brain swelling and edema occur early after trauma with consequent underestimation of subdural hematoma. therefore imaging should be repeated (ct or mri) especially when neurologic symptoms change rapidly. brain swelling/ edema may also involve the posterior fossa and is better identified on brain mri. two frequent patterns have been reported in abusive head trauma (24). diffuse supratentorial brain swelling (infarction) involving the cortex and white matter was reported in 39% of cases and is considered as severe hypoxic-ischemic injury with poor outcome (30). watershed infarction was reported in 36% of cases and considered a less severe form of hypoxia-ischemia. apparent diffusion coefficient (adc) values are strongly associated with poor neurodevelopmental outcomes in the acute phase (within 4 days) especially basal ganglia, thalamus, brainstem, cerebral cortex, cerebellar vermis, cerebellar cortex and mean total brain (31). during the early phase up to 1 month adc values in fewer regions (basal ganglia, thalamus, brainstem and corpus callosum) were associated with poor outcome. when patients with and without parenchymal lesions are compared, the detection of diffuse lesions during the first 3 months as well as beyond 3 months is significantly associated with severe developmental outcome (32). late mri (beyond 3 months after injury) also showed that recovery depends on the extent of brain damage. patients with diffuse lesions show more severe motor and intellectual impairments and are more likely to have blindness and epilepsy than patients with focal or hemispheric lesions (32). diffuse axonal injury (dai) is related to shear-strain injury of small medullary veins and was reported in 6% of cases of abusive head trauma (24). it is encountered in trauma with sudden acceleration-deceleration associated with rotational angular forces and in shaking-impact trauma. the lesions may be hemorrhagic or non hemorrhagic (related to axonal swelling). dai is most often located in the subcortical white matter at the gray-white matter junction, corpus callosum, basal ganglia, brainstem and internal capsule. if the lesions are large enough and hemorrhagic dai may be seen on ct. however dai is usually better identified on mri with susceptibility and diffusion weighted images. the detection of changes in the basal ganglia or brainstem during the first 3 days as well as during the first month after injury is significantly associated with poor long-term outcome in survivors (30). the presence of intraparenchymal brain micro-haemorrhages detected on swi in children with abusive head trauma correlates with significantly poor long-term neurologic outcome (10) contusion is also reported in abusive head trauma and is seen in blunt trauma with impact with or without contrecoup contusion. contusions are located at the surface of the brain (crest of gyri) and may be pial and haemorrhagic (disruption of cortical arteries). they are also found in the frontal and temporal regions related to impact of the brain on the roof of the orbit, middle cranial fossa and sphenoid wing. white matter tears are also seen in the frontal and temporal area related to the vulnerability of unmyelinated and soft white matter in infants. skull fractures are seen in blunt impact and are less frequent than long bones and rib fractures in non-accidental trauma. the most common site is the parietal bone (because of bulging of parietal bones below 1 year of age). the fracture may be linear as in accidental trauma. radiologic features significant for inflicted trauma are multiple fractures, bilateral fractures and fractures that cross suture lines (28, 33). focal underlying brain damage can be seen such as subdural hematoma and hemorrhagic contusion. hypoxic-ischemic encephalopathy is seen in strangulation injury with involvement of the territories of the internal carotid artery related to their anatomic vulnerability. neuroradiology (ct and mr) is crucial for the diagnosis of trauma, to predict outcome when showing edema and hypoxic-ischemic injury. this presentation will present an update on post mortem mri (pmmr) with relevance to clinical developments over the last 2 years. in particular, reference will be made to diagnostic accuracy of pmmr across different body parts, the current limitations of post mortem mr, and protocol development at different field strengths. imaging correlates of post mortem interval are also being investigated. maceration (autolysis within intrauterine fluid) and perimortem hypoxic brain changes caused difficulties in image interpretation, which more advanced and quantitative techniques may be able to address. jawad take home points: below 500g, 1.5-t pmmr shows a significant reduction in diagnostic yield, compared with conventional autopsy, and therefore its clinical usefulness in this setting will depend on individual circumstances. 3t pmmr performs better than 1.5 t particularly <20 weeks gestation, and particularly for the chest, heart and abdomen. diffusion characteristics in different fetal brain areas are multifactorial, with maceration the strongest predictor in most areas. international pm ct protocols c.y. gerrard 1 , o.j. arthurs 2 ; 1 albuquerque, nm/us, 2 london/uk the european society of pediatric radiology (espr) taskforce and the international society of forensic radiology and imaging (isfri) pediatric working group have combined efforts to establish best practice standards for performing perinatal and pediatric post mortem computed tomography (pmct) examinations. use of pmct in the investigation of pediatric death has increased significantly in the past decade. due to quick acquisition times and the ability to acquire thin slice, high detailed images of the whole body, (2017) 47 (suppl 2):s297-s pediatr radiol many hospitals and forensic institutes have implemented pmct into daily practice. however, there lack an overall standardization of how cases are triaged and the acquisition methods when comparing institutes using pmct. in an effort to address inconsistencies in acquisition parameters, post processing, and case selection, pmct protocols were compiled from international institutes and centres currently performing pediatric imaging. this paper will describe both the uniform and divergent elements of image acquisition and procedural uses identified among the participating centres. the outcome is to provide a single source of information that can guide already established and new centres on the best practice standards for implementing pediatric pmct. take home points: describe how pediatric post mortem computed tomography (pmct) has increased in utility over the past decade. identify the differences in acquisition methods for clinical computed tomography versus post mortem computed tomography. discuss the overall consensus of case triage and scan acquisitions when comparing institutes in aggregate. provide comprehensive statement of best practice standards for pediatric pmct. post mortem imaging research: updates and future proposals o.j. arthurs; london/uk paediatric and perinatal post mortem imaging is a new and rapidly growing field, and the post mortem imaging taskforce was founded in graz at espr 2015. the pmi taskforce aims to help reach consensus and guidance regarding imaging protocols and the potential yield of post mortem ultrasound, ct and mr. the key priorities are the themes of collaboration, image acquisition, best practice guidelines, training and education, raising awareness and access to imaging. this presentation will give updates on the latest developments in perinatal and paediatric imaging, with particular focus on where the pmi taskforce can help. in particular, protocol development is underway, and the espr meeting acts as an opportunity for collaborative working and network development, to facilitate best clinical practice and welcome new members. arthurs oj et al., espr post mortem imaging task force: where we begin. pediatr radiol (2016) ; 46: 1363 -1369 take home points: post mortem imaging is an exciting sub-specialty which requires a combination of in depth fetal medicine, perinatal autopsy and pediatric imaging knowledge to help shape and grow the clinical and research arena. dedicated personnel have an opportunity to create the evidence-based behind a growing clinical service, with clear benefits to patients, families and referring clinicians. abstracts appear as submitted to the online submission system and have not been checked for correctness and completeness. sequences, are an emerging tool for evaluating intracranial vessel disease. improved survival due to emended treatment protocols results in an increasing number of long-term medulloblastoma survivors who experience delayed treatment effects. microbleedings, developement of cavernomas, vasculitis and atherosclerotic lesions are cerebrovascular structures affecting sequelae of the applied radiochemotherapy. this study evaluates radiation-induced intracranial vascular changes. twenty-two long-term pediatric medulloblastoma survivors (mean age 25.8 years, range 10-53 years; mean years after primary radiochemotherapy 16.3 years, range 1-45 years) underwent mri. the scan protocol included precontrast 3-dimensional time of flight (tof)magnetic resonance angiography (mra), precontrast 2d t1-and 2d t2-vwisequences and postcontrast 2d t1-vwi-sequences of the medium and large intracranial arteries. vessel wall thickening, contrast enhancement and luminal narrowing were analyzed. additionally precontrast t1-, t2-swi and t1-weighted images of the supra-and infratentorial brain were acquired. results: vwi-sequences: vessel wall changes could be found in 12 (54%) and 14 patients (63%) of the right and left ica, respectively. for the ba 4 (18%) patients revealed vessel wall changes; for the left and right va 2 (9%) patients were detected with vessel wall changes, respectively. in the tof angiography no alteration of the ica, ba or vas could be identified. in total vessel wall changes for the vertebrobasilar system and the icas could be found in 16 (72%) patients. swi-sequences: all patients (100%) revealed swi lesions, the smallest lesion measuring less than 2 mm, the biggest up to 5 mm. sixteen patients (72%) were presented with lesions > 4 mm, suspicious for cavernomas. to ensure quality of life in long term childhood medulloblastoma survivors, monitoring of long-term effects, like vascular changes after rct is gaining in importance. high resolution mri, including swi and vwisequences could be used here for. this study images, asymptomatic vessel wall alterations in former childhood medulloblastoma patients through vwi sequences and micro bleedings through swi sequences. vessel wall alterations, revealing rct induced arteriosclerosis, can lead to symptomatic intracranial stenosis which is associated with ischemia, furthermore micro bleedings and cavernomas can lead to intracranial hemorrhage. however further studies are needed to standardize mri sequence protocols to ensure a high standard follow up protocol, detecting clinically still asymptomatic vascular changes. fast "black-bone" mr imaging in evaluation of craniofacial abnormalities: comparison with high resolution ct z. habib, a. talib, c. parks, s. avula, l.j. abernethy; liverpool/uk to evaluate the feasibility and diagnostic value of a fast field echo, "black bone" mri sequence in children with craniofacial abnormalities. a fast "black bone" mri sequence has been used in addition to standard brain mri in 16 children (mean age 17 months, age range 3 months to 5 years and 5 months) referred to the supra-regional craniofacial surgery unit at alder hey children's hospital, liverpool, uk. a subgroup of 10 of these patients with complex craniofacial abnormalities additionally had high resolution volume ct performed at the same visit. "black bone" mr imaging was performed on philips ingenia 3t and 1.5t scanners, using a 3d fast field echo sequence (tr=8.3 ms, te=4.6 ms, flip angle 5 0 ). this sequence can be performed with an acquisition time of less than 2 minutes. the "black bone" sequences were assessed for accuracy in evaluating the patency of the sagittal, coronal and lambdoid sutures, and, where applicable, were compared with high resolution ct. the fast "black bone" mri sequence was shown to be technically feasible in all cases. the resultant images successfully demonstrated both patent sutures, which were confidently seen, and prematurely fused sutures which were confidently not seen. visualisation of patent sutures was found to be further enhanced by the use of minimum intensity projection. in the subgroup of patients with complex craniofacial abnormalities, comparison with high resolution volume ct confirmed good sensitivity for patency of cranial sutures. there was complete agreement in 50 out of 50 sutures assessed. the "black bone" mr images were also found to produce good-quality surface-rendered images and were also suitable for 3-d printing of models for pre-operative planning. fast "black-bone" mri has proven to be technically feasible and to demonstrate cranial suture patency with good agreement with high resolution ct. additionally "black-bone" mri can be used to produce good quality surface-rendered images and 3-d printed models for surgical planning. main symptom of mucopolysaccharidosis type iva (mps iva) is progressive systemic skeletal dysplasia. this is routinely monitored by cerebral and spinal mri. the vascular system is generally not in the primary focus of interest. in our population of mps iva patients we observed vessel shape alterations of the vertebrobasilar arteries, which has not been described before materials: mri-datasets of 26 patients with mps iva acquired between 2008 and 2015 were eligible for retrospective analysis of the vertebrobasilar arteries. the vessel length and angle of the basilar artery (ba) and both vertebral arteries (va) were analyzed. a deflection angle between 90°and 130°in the vessel course was defined as tortuosity, less than 90°as kinking. the results were compared to an matched control group of 23 patients not suffering from mps. the deflection angle [°] of the va and ba was significantly decreased in the majority (85%) of mps iva patients (fig. 1) mps iva is associated with significantly increased tortuosity of vertebrobasilar arteries. therefore the vascular system of mps iva patients should be monitored on routinely basis, as vessel shape alterations had been associated with dissections, leading to a higher risk of cerebrovascular events. in the pediatric population, intraspinal cysts (arachnoid or neurenteric cysts) are rare lesions mainly located in the thoracic region, whose acute onset is not well described in the literature. (2017) 47 (suppl 2):s297-s pediatr radiol we present a series of four children seen in the last two years as spinal cord emergencies and discuss the clinical aspects, imaging diagnosis, and management approaches, particularly in the emergency setting. a comparison of our cases with those reported in the literature is also provided. as in other types of spinal cord lesions, mr imaging is the diagnostic procedure of choice, because of its potential to demonstrate the exact location and extent of the cyst and its relationship to the spinal cord, valuable information for planning surgical treatment. this is a retrospective review of 4 cases of pediatric intraspinal cyst occurring in 4 boys and 1 girl, aged 2 to 6 years, treated at our institution between 2014 and 2016. onset was sudden in all cases and mimicked transverse myelitis or infarction. all our affected patients had no preceding history of trauma and presented with signs of spinal cord compression-back pain and less commonly abdominal pain-followed by weakness. all patients underwent emergent mr imaging, including t1, t2, t2*, 3d ciss, diffusion imaging and enhanced t1 sequences, mainly in the sagittal and axial planes. in each sequence, mr imaging showed a well-defined cystic lesion with signal intensity similar to cerebrospinal fluid, and secondary spinal cord compression that was severe in most cases. blood remnants were not visualized within or around the arachnoid cyst in any patient, which correlated with the absence of trauma antecedents. three of the four cysts were located in an anterior position relative to the spinal cord, and only one was located posteriorly; this latter had an associated subdural effusion. none of our patients had an associated neural tube defect. all patients were urgently treated with cyst wall fenestration or resection. the symptoms improved in all except one patient, whose symptoms did not abate, but ceased to progress. a prompt emergent diagnosis with mr imaging is important, as the symptoms can resolve if surgical treatment is performed before the spinal cord becomes irreversibly damaged. urgent surgery is essential in these cases, particularly if progressive neurological dysfunction develops over the course of spinal cord compression. the outcome following surgical fenestration or excision is excellent in most cases. nevertheless, a long-term imaging follow-up is recommended to detect possible recurrence. the objective of this study was to evaluate the usefulness of multiparametric quantitative mri model for myelination quantification in children. twenty-two children (age range: 9-5,400 days) were scanned with multiparametric quantitative mri. total volume of myelin water fraction (mwf) (msum), the percentage of msum within the whole brain parenchyma (mbpv), and the percentage of msum within intracranial volume (micv) were obtained. mwf values of brain regions were acquired by drawing regions of interests. the values were fitted to representative models of myelin maturation. spatiotemporal pattern of mwf mapping was visually assessed. values of msum, mbpv, and micv well fitted to a developmental model of myelination. mwf of brain regions well fitted to a developmental model with high r 2 values: pons (r 2 =74.6), middle cerebeller peduncle (r 2 =75.5), genu of corpus callosum (r 2 =93.6), splenium of corpus callosum (r 2 =79.7), thalamus (r 2 =85.8), frontal white matter (wm) (r 2 =95.7), parietal wm (r 2 =95.1), temporal wm (r 2 =93.7), occipital wm (r 2 =94.5), and centrum semiovale (r 2 =82.1). mwf mapping followed the known spatiotemporal pattern of myelination. multiparametric quantitative mri is a useful tool for mwf quantification in children. retinoblastoma is the most common intraocular tumour of childhood. it is a highly malignant. retinoblastoma is curable. if detected while still confined to the globe and if there are no metastatic risk factors, the child will nearly always survive following appropriate treatment. our aim is to assess diagnostic accuracy of preoperatively performed magnetic resonance (mr) imaging for detection of tumor extent in patients with histopathologically proved retinoblastoma. local ethics committee approval and informed consent were required for reviewing of patients' images and records. fifty-eight eyes in 30 girls and 27 boys with retinoblastoma (mean age at diagnosis was 23 months ±18.9) were reviewed on unenhanced t1wi, t2wi, and gadolinium-enhanced t1-weighted mri with and without fat suppression. mri parameters such as anterior chamber hyperintensity, involvement of choroid, ciliary body, optic nerve, sclera, orbital fat, and pineal gland were determined. maximum tumor diameter was measured and correlated to metastatic risk factors. imaging and pathologic findings were compared. choroidal invasion was suspected with mr imaging in 47/58 eyes; findings were false-positive in 6 eyes and false-negative in two (accuracy, 86.2%; sensitivity, 95.3%; specificity, 60%). mr imaging findings were true-positive in 10 of 17 eyes with proved prelaminar optic nerve invasion (60% sensitivity) and false-positive in 7 (82.9% specificity, 75.8% accuracy). postlaminar optic nerve invasion was correctly detected in 23 eyes; 4 eyes were false positive, in other 4 eyes, this metastatic risk factor was missed (accuracy, 86.2%; sensitivity, 85.2%; specificity, 87%). of nine eyes with histologically proven scleral invasion, 5 eyes were true positive . in the other 4 eyes, scleral involvement was missed on mri (accuracy, 93%; sensitivity, 55.6%; specificity, 100%).extraocular fat invasion was suspected on mri in 5/58 eyes. of these, findings were truly positive in 4 eyes (80%) and in 1 eye (20%) was incorrect (false positive) (accuracy, 98.3%; sensitivity, 100%; specificity, 98%).anterior chamber hyperintensity on t1-weighted mr images obtained after contrast agent administration correlated well with main mri and histolopathology findings. tumor size (assessed in our study by the maximum diameter in mm) was statistically associated with postlaminar optic nerve invasion (ρ=.002) and choroidal invasion (ρ=.007). mr imaging shows promising role for tumor staging and detection of metastatic risk factors. tumor diameter, measured with mr imaging, is associated with postlaminar optic nerve and choroidal involvement. patterns of the cortical watershed continuum of term gestation hypoxic ischaemic injurythe "wish-bone sign" a. chacko 1 , s. andronikou 2 , s. vedajallam 1 , j. thai 2 ; 1 east london/za, 2 bristol/uk objective: background partial-prolonged term hypoxic ischaemic injury (hii) involves the cortical and subcortical watershed zones of the brain, which are visually difficult to conceive. new innovative methods of demonstrating watershed cortical atrophy using flattened maps of the brain surface gives added insight into distribution of the watershed zone by demonstrating the entire brain surface. aim determining and validating patterns of hii sustained at birth in term infants using cross-sectional mri and the innovative mercator and scroll map views of cortical surface anatomy, to define the distribution of the watershed zones in children with partial-prolonged injury. one hundred paediatric mri brain scans with an mri and clinical diagnosis of chronic term hypoxic injury were read by 3 radiologists independently. all sites of abnormality were recorded and patterns classified. (2017) 47 (suppl 2):s297-s pediatr radiol patients with partial-prolonged and combined patterns were evaluated using mercator and scroll map reconstructions, generating schematics of the watershed zone. predominant patterns of disease were partial-prolonged and acuteprofound types. the watershed zone was demonstrated, on the derived maps, representing a continuum of involvement in the shape of a 'wish-bone' extending bilateral from frontal lobes to posterior parietal lobes in band-like fashion along the para-falcine cortex and intersected by another band of atrophy in the peri-rolandic regions extending along peri-sylvian cortices. this is defined in schematics as a visual aid. predominant patterns of injury in term hypoxic ischaemic injury are described and quantified, with the 'wish-bone sign' introduced to describe the typical distribution pattern of partial-prolonged hii in the watershed zone. correlation of brain edema degree and biochemical parameters in pediatric posterior reversible encephalopathy syndrome with hematologic/oncologic diseases t. akbas 1 , s. ulus 2 , b. karagun 1 , t. arpaci 1 , c. kalayci 2 , b. antmen 1 ; 1 adana/tr, 2 istanbul/tr posterior reversible encephalopathy syndrome (pres) often associated with hypertension is characterized by typical transient parietooccipital predominantly brain edema on magnetic resonance imaging (mri) with neurological symptoms such as seizures, headache and visual disturbances. even if endothelial dysfunction, increased blood-brain barrier permeability and hyper-hypoperfusion remain as controversial mechanisms to explain, the pathophysiology of pres is unremain. the aim of our study was to investigate the correlation between brain edema degree on mri and serum biochemical parameters such as lactate dehydrogenase (ldh), albumin (alb), creatinine, uric acid (ua) and urea. a total of 27 pediatric hematology and oncology patients (19 male, 8 female, aged 3-17, mean age: 11 years 6 months) diagnosed with pres during treatment and after hematopoietic stem cell transplantation (hsct) were included in this retrospective study. underlying diseases were beta thalassemia (n:14), aplastic anemia (n:4), acute lymphoblastic leukemia (n:4), acute myeloid leukemia (n:3), lymphoid leukemia (n:1) and burkitt's lymphoma (n:1). pres was seen after undergoing hsct in 21 patients. the brain edema degree according to specified anatomical regions on fluid attenuation inversion recovery (flair) mri sequence was scored by two radiologists blinded to patients' records. the levels of serum biochemical parameters at onset of symptoms were correlated with score of brain edema degree on mri. serum ldh concentration was statistically correlated with the score of brain edema degree (spearman's rho correlation, r=0.459, p=0.016). no relationship was found between other biochemical parameters and the score of brain edema degree. our results suggest that increased serum ldh as a marker of endothelial dysfunction is the main biomarker for development of brain edema in pediatric pres patients under treatment and after hsct with underlying hematologic and oncologic diseases. objective: gadolinium based contrast agents (gbcas) have been associated with increasing signal intensities in deep brain nuclei on unenhanced t1-weighted brain imaging. until now, most studies have been performed in adults, while results on pediatric patients are sparse. therefore, the aim of this study was to evaluate if there is any difference between signs of gadolinium retention in pediatric and adult patients. in this irb-approved, single center retrospective study, we extracted all patients with at least 5 contrast-enhanced mris archived on pacs between 2009-16. all patients with gadobenate dimeglumine only enhanced mris were reviewed. seventy-six pediatric patients with the most injections and 86 adult patients with the most injections were included in the final evaluation. therapies were documented. t1 signal intensity measurements for the initial and last unenhanced brain mris were performed for dentate nucleus, pons, globus pallidus and thalamus. signal intensity ratios for dentate-to-pons (dnp) and globus pallidus-to-thalamus (gpt) were calculated and correlated with number of injections and time interval as well as therapy. differences between adults and pediatrics were assessed. mean age for the pediatric group was 9.3 years compared to 47.7 years in the adults. no significant difference was found for gender distribution (47 vs. 43% females) and follow up time (3.1 vs. 3 years). there was no difference concerning the signal intensities on first and last mri in children and adults (p=0.81/0.84, respectively). for each additional year of follow-up the change in ratio increases by 0.016 for adults but only 0.002 for peds (p=0.002). comparing therapies, in children a statistically significant difference between patients with and without former radiation was found (p<0.001) while there was no difference in adult patients with and without therapy (p=0.65). children and adults show a similar increase in t1 signal in deep brain nuclei ascribed to gadolinium deposition. in children, radiation and chemotherapy) seem to have a higher influence on gadolinium deposition. this correlation cannot be found in our adult cohort, indicating therapies have no (additional) influence. kearns-sayre syndrome (kss) is a rare mitochondrial dna-deletion syndrome characterized by early onset (<20 years), progressive external ophthalmoplegia and pigmentary retinopathy, often associated with cerebellar ataxia, muscle weakness, bilateral sensorineural hearing loss and cardiomyopathy. pyramidal symptoms may be present in kss, but they are poorly reported in the literature. through this case series, we aim to evaluate the concordance with the imaging patterns proposed by literature, correlating them with clinical and laboratory data, and to investigate possible microstructural damage with diffusion tensor imaging (dti) and magnetic resonance spectroscopy (mrs). we evaluated eight patients (8-19 years of age) with genetically confirmed diagnosis of kss. all pts. were studied with 3t/1.5t mri. in 5/8 pts. the study was completed by mrs and in 7/8 by dti imaging with reconstruction of cortico-spinal tracts (cst) using a 2-rois approach. a t-test comparative study between mean fractional anisotropy (fa) of cst in the 7 kss patients with dti and a group of 4 healthy controls was performed. cst reconstruction in a patient suffering from kss (images a-c), compared to an healthy control (images d-f). the dti study showed significantly reduced fa values, pointing out a possible microstructural damage. the disease showed an mr pattern of mixed white and gray matter signal abnormality, with periventricular and/or subcortical white matter hyperintense lesions, which in 1/8 patient presented a "tigroid pattern" (fig.2 ) three patients displayed a disease extension to the cervical spinal cord. (fig.2 ) dwi images demonstrated restricted diffusivity in almost all lesions (fig.3) , with persistence of low adc values. mrs study documented a high lactate peak in 2/8 pts. and a naa reduction in 5/8 pts; an increment of gsh was noted in one patient (fig.3) . the t-test comparative study of cst showed a significant reduction of mean fa value in kss patients compared to healthy controls (p= 0,004). involvement of the spinal cord (a-c, yellow arrows). comorbidity was suspected in "a" (myelitis). below (d-f): pale nuclei (d, green arrows) and subcortical white matter (e) alterations. right image displays the "tigroid pattern" (purple arrow). mrs showing the presence of a gsh peak, which may suggest an augmented antioxidative activity within the encephalic tissue. below: dwi hyperintensity in many regions of the brain in patients suffering from kss, due to diffusion resctriction. the integration of neuroimaging with clinical data can implement the diagnosis of mitochondrial diseases such as kss. according to our experience, comorbidities can delay the achievement of a correct diagnosis. the finding of an altered signal in the spinal cord of 2/8 pts. may suggest a new possible localization of the disease, while in one patient was referable to myelitis (fig.2, a) the evidence of a "tigroid patter" in should be taken in count in the differential diagnosis with lysosomal disorders. the presence of a prominent gsh peak may represent an augmented antioxidant activity, which may correlate with a more favorable outcome. an involvment of cst can be speculated even if pyramidal symptoms are poorly represented in kss. remotely distractible, magnetically controlled growing rod (mcgr, fig. 1 ) system has been developed to allow for gradual lengthening on an outpatient basis. this allows for safe spinal lengthening with continuous neurologic monitoring and real-time feedback by the patient. this study aims to evaluate retrospectively our ultrasound (us) geometric method and his accuracy compared with the plain radiograph (gold standard) for assessing mcgr distractions. this is a retrospective study that includes patients with early-onset scoliosis undergoing multiple consecutive distractions after mcgr implant. the rods length was measured for with us, for each distraction (3-months interval), and compared with plain radiograph follow-up (1-year interval). all patients included were treated with dual-rod systems. distraction length was monitored by a senior radiologist with us at each visit, one rod at a (2017) 47 (suppl 2):s297-s pediatr radiol time, before and after magnetic lengthening, with our geometric measurement method (fig.2) . low-dose upright two-projections radiograph were taken immediately after surgery and at 1-year intervals and measured by two radiologists (1 and 10 years of experience respectfully) (fig.3) . we compared measurements with the wilcoxon signed-rank test. from january 2014 to october 2016, a total of 5 patients (4 females and 1 male), which diagnoses included mitochondrial encephalopathy syndrome (n=1), spina bifida (n=1), ataxia of unknown cause (n=1), juvenile idiopathic scoliosis (n=1) and trisomy 8 (n=1), with a mean of 10 distractions per patient (standard deviation [sd] ±1,2), were recruited. fifty distractions for each system (95 measurements in total) were performed, targeting different lengths of distraction (from -2.0 mm to +4.6 mm) on each occasion. a total of 21 sets of plain radiographs were taken. from these, 18 sets of data points were used for correlation analysis. the mean distracted length per year on plain radiographs was 10,1 mm (sd ± 3,8 mm) and the mean distracted length on us per 6-months interval was 4,5 mm (sd ± 2,9 mm). excellent correlation was observed between radiographic and ultrasound measurements. in particular, correlation between rx measurements and ultrasound was excellent both for junior (0.001<p<0.005, w=70) and senior radiologist (p<0.001, w=28,5). there were no rod's breaches identified neither in ultrasound or radiographs in this series. the measured changes in rod length between the two imaging modalities were highly correlated. thus, ultrasonography is at least as accurate as radiographs in measuring changes in rod length. our geometric measurement method adds reproducibility to an effective, non-ionizing and lowcost procedure for monitoring distraction of mcgr in children population. refuting child abuse denialistshealing rickets is clearly different from child abuse metaphyseal fracture a.e. oestreich; cincinnati/us objective: child abuse denialists, who testify against the diagnosis of child abuse, often claim that radiographic findings generally recognized by pediatric radiologists as likely due to abusive trauma are instead a consequence of rickets, including healing rickets. in particular, bucket handle transverse bony density at metaphyses are declared by some denialists to be identical to the pattern of healing rickets. i demonstrate by reviewing the details of these different patterns that this is an incorrect declaration. additionally, concave distal ulna margins alone are not a sign of rickets. rickets is radiologically distinct from classic metaphyseal fractures. i reviewed medicolegal documents and published articles by several well known physicians who claim that certain children suspected of having suffered child abuse instead demonstrate rachitic bone disease. their statements and images in support of their opinions are critically reviewed and contrasted with known examples of rickets, including healing rickets. at the physeal region of long bones in rickets, the zone of provisional calcification (zpc) is not calcified and the normal metaphyseal collar shaftward from that zone is not maintained. in metaphyseal fractures from abuse, the zpc and collar are maintained. in early healing rickets, the zone of provisional calcification calcifies first, giving a transverse calcification separated from the already ossified metaphysis. this calcification is different from a bucket handle fracture pattern without signs of rickets. moreover, concave distal margin of the ulna without other signs of rickets is seen in about 20% of normal infants. repeatedly, denialists have testified against the diagnosis of child abuse, claiming rickets in the absence of radiographic evidence -i critique one well known child abuse is a serious diagnosisclaiming by denialists of an alternate diagnosis, such as rickets, when radiographically no rickets is present, should be refuted. a clear understanding of the differences between abuse fractures and rickets is obligatory. when no rickets is seen at other growth sites, including seeing the presence of zones of provisional calcification, rickets is not present. simultaneous multi-slice turbo spin echo: a 2-fold time-saving alternative to conventional tse in mr imaging of the pediatric knee s. benali, a. gholipour, p.r. johnston, s.d. bixby; boston/us objective: simultaneous multi-slice (sms) is a novel iteration of parallel imaging in mri that reduces acquisition time at least two-fold over conventional turbo spin echo (tse) acquisitions. the aim of this study is to determine whether 2-dimensional (2d) sms tse can replace conventional 2d tse in imaging of the knee in pediatric patients without compromising diagnostic quality. this was an irb-approved retrospective study. subjects included all pediatric patients referred for routine 3-tesla mri of the knee between october through december 2016. mri examination consisted of institutional basic protocol with both traditional t2 tse and sms t2 tse in axial and sagittal planes with fat suppression. two anonymized study folders were created for each subject, one containing all basic sequences (basic exam), and one in which t2 tse sequences were substituted with t2 sms sequences (sms exam). two pediatric radiologists independently and blindly reviewed each study and noted presence or absence of 15 pre-determined abnormalities (table 1) . discrepancies between radiologists were settled by consensus. qualitative assessment was performed using a likert scale to evaluate edge blurring, contrast resolution, image noise, and flow artifact. thirty-five subjects comprised the study population (mean age 14.6 years, range 8-20, 26 female, 9 male). diagnostic performance was assessed by comparing findings (table 1) from basic exam to sms exam based on absolute agreement and cohen's kappa statistic. for all findings, the proportion of absolute agreements between basic and sms exam was >0.96 for reader 1, > 0.88 for reader 2, and 1.00 for consensus between readers. kappas for consensus reads were 1.00 on all 15 structures (p< 0.001, lower 95% confidence limit >0.97). for reader 1, kappas were 1.00 for 14/15 structures (p< 0.001) and 0.00 for pcl. for reader 2, kappas were 1.00 for 14/15 structures (p< 0.001) and 0.45 for cartilage defects. paired t-test was used to compare mean likert scores for image quality characteristics. for both readers, sms was preferred for flow artifacts whereas tse was preferred for the three remaining image quality characteristics (p< 0.05). our primary assessment suggests that sms t2 tse is comparable to standard tse in terms of diagnostic performance in the evaluation of the pediatric knee despite modest decrease in overall image quality. the 2-fold decreased acquisition time of sms is a significant advantage which is felt to offset the mild decrease in image quality, particularly as it increases the likelihood that children will tolerate the examination without motion. mri for sacroiliitis in children: panel findings and inter-observer evaluation using standardised reporting k.e. orr 1 , m.j. bramham 1 , s. andronikou 2 ; 1 plymouth/uk, 2 bristol/uk there is little evidence regarding mri for diagnosing sacroiliitis in children with juvenile idiopathic arthritis (jia). the limited literature presents varied opinions but no published recommendations for standardisation of reporting. axial disease in jia responds poorly to conventional first-line treatments but identifying these children using history and examination findings is unreliable. standardised mri reporting (2017) 47 (suppl 2):s297-s pediatr radiol may improve diagnosis and selection of patients in whom newer biologic treatments are indicated. the aim was to use a standardised reporting proforma based on published definitions for recording mri findings in suspected sacroiliitis to evaluate inter-observer agreement and determine the reliability of findings according to specific sequences. ninety-nine sacroiliac joint mris (198 joints) were included, 80 were initial examinations and 19 were follow-up mris. the age range was between 6.6 and 20.3 years (mean age 15.4 years). three readers retrospectively reported all 99 mris using the standardised proforma. 'reader 1' was the study group panel while readers 2 and 3 were specialist paediatric radiology consultants working in the united kingdom. readers were blinded to additional clinical information and other imaging. inter-reader variation was evaluated for the presence of bone marrow oedema, erosions, effusions, ankylosis, sclerosis and enhancement, as well as the presence or absence of sacroiliitis. the quality of mri examinations was evaluated, including presence and adequacy of sequences performed and alignment of the coronal/oblique studies. mri findings were correlated with clinical details and final diagnosis. there is significant variability in sacroiliac joint mri protocols. refinement of these to include only necessary sequences based on inter-reader reliability and reinforcement of good positioning will improve reporting and result in universal standardisation. there is inconsistency in current reporting practice of sacroiliac joint mri in children but increasingly, clinicians rely on imaging to select patients with sacroiliitis and guide appropriate treatment. using a standardised reporting proforma may improve the quality and consistency of reporting. ultrasound-guided steroid tendon sheath injections in juvenile idiopathic arthritis s. peters, d.a. parra; toronto/ca objective: juvenile idiopathic arthritis (jia) is the most common chronic rheumatic disease in childhood. tenosynovitis is one of the manifestations of jia, which can explain the absence of response to treatment when adjacent joints are injected. steroid injection is one of the treatment options for tenosynovitis and it has been shown to be effective in the literature. utilizing ultrasound (us) guidance for injections into tendon sheaths has shown clinical advantage to conventional blind injections in the adult rheumatoid arthritis population. the aims of this study are to: (a) identify tendon sheaths most commonly treated in our patient population with jia referred for steroid injections; (b) describe technical aspects of the procedure; (c) characterize sonographic appearance of tenosynovitis in jia; (d) assess agreement between clinical request and sites injected. this was a 10 year single-center retrospective study ( may 2006 -april 2016 in which we recruited patients with jia referred by rheumatology for us-guided tendon sheath injections. we collected patient demographics, clinical assessment information, sonographic appearance of the tendons and technical aspects of the intervention from the procedure records. we collected data from 308 visits of 244 patients (75% female, mean age 9 years 8 months) with a total of 926 injections. the ankle region was most commonly injected (85%), specifically the tendon sheaths of tibialis posterior (22%), peroneus longus (20%) and brevis (20%). 63% of the procedures were performed under general anesthesia and triamcinolone hexacetonide was used in 97% of the injections. an "out of plane" approach was used in 86% of the interventions and the 15 mhz "hockey stick" us probe was preferred for guidance (86%). we found 2 minor intra-procedure complications without sequelae. the majority of treated sites (92%) showed peritendinous fluid and sheath thickening on us. other findings were increased color-doppler signal and echogenic peritendinous fluid. a strong agreement between clinical request and sites injected was observed and most patients required one visit (78%). us-guided tendon sheath injections are used frequently to treat patients with jia. it is a safe intervention with a high technical success rate. the ankle region, specifically the medial compartment, is the area most commonly injected in this cohort of patients. the most common sonographic finding is peritendinous fluid and sheath thickening. these findings might assist radiologists and rheumatologists to characterize and more effectively manage tenosynovitis in patients with jia. to evaluate the accuracy of the software for automatic bone age (ba) estimation based on deep learning technique, and to validate the feasibility of this system in clinical practice. the software for automatic ba estimation was developed based on deep learning technique using 18,940 left hand radiographs and estimated ba of each radiograph based on greulich-pyle method. ba estimation was done for left hand radiographs of 100 consecutive patients (9 months -17 years; 42 boys and 58 girls) in three methods: (1) ai bone age (assessed by the software), (2) ai-assisted ba (assessed by two radiologists with the assistance of the software), (3) gp atlas-assisted ba (assessed by two radiologists with only gp atlas but the software). the reference ba was determined by two radiologists by consensus. the accuracy of the estimated ba by each method was assessed using concordance rate (%), pearson's correlation analysis, the root mean square error (rmse), and bland-altman plot. reading time for ba estimation by each method was evaluated. ai bone age showed 61% of concordance rate, and a significant correlation with reference ba (r2=0.986, p<0.05). the bland-altman plot of agreement between the reference ba and ai bone age showed the mean difference of -0.20 years (95% limit of agreement, ±1.22 years). rmse was 0.42 years. in reviewer 1, concordance rates were same between both gp atlasassisted ba and ai-assisted ba (72%), and rmse of ai-assisted ba (0.20) was slightly lower than that of gp atlas-assisted ba s353 (2017) 47 (suppl 2):s297-s pediatr radiol (0.23). in reviewer 2, concordance rate was slightly higher in aiassisted ba (60%) than gp atlas-assisted ba (58%), and rmse was almost the same (0.54 in ai-assisted ba, 0.55 in gp atlasassisted ba). the reading time was reduced 20.0% in reviewer 1 and 62.7% in reviewer 2. the software for automatic ba estimation based on deep learning technique showed high accuracy and may enhance work efficiency in ba estimation by allowing radiologists to save reading time and to improve accuracy. temporomandibular joint mri findings in adolescents with primary disk displacement in comparison to those in juvenile idiopathic arthritis j. bucheli, d. ettlin, c. kellenberger; zurich/ch to investigate potential differences of morphology and degree of inflammation in temporomandibular joints (tmjs) affected by primary anterior disk displacement (add) and juvenile idiopathic arthritis (jia). in 18 adolescents (15 female, age 15 ± 2 y), contrast enhanced magnetic resonance images (fig. a) of tmjs with add were retrospectively compared to those of age-and gender-matched controls with jia. morphology of articular disk and bony structures were described. osseous deformity and inflammation were qualitatively scored with progressive 4-grade scales and compared between groups with mann-whitney-u test. mandibular ramus length, measured on gradient echo minimum intensity projection images (fig. b) , was compared between groups and to normal values with independent samples t-test. in the add-group, 31/36 disks were dislocated anteriorly and showed thickening of the posterior band (27/31). in contrast, tmj disks of jia patients were mainly flattened (n=23) and/or centrally perforated (n=12) and rarely dislocated (n=1). tmjs with add showed similar overall grades of inflammation (p=0.39) and osseous deformation (p=0.53) as tmjs in the jia group. while erosions were frequent in both groups (add 25/31; jia 32/36, p=0.55), the mandibular condyle (p<0.001) and glenoid fossa (p<0.001) were less flattened in tmjs with add. in add tmjs, bone marrow oedema was less frequent (p=0.001) and grades of joint enhancement slightly lower (p=0.03), but presence of synovial thickening (p=0.43) and degree of effusion (p=0.87) were not significantly different between groups. mandibular ramus length was not significantly different (p=0.72) between groups, but in both groups clearly decreased compared to mean normal values (p<0.0001). articular disks in tmjs affected by jia are rarely dislocated. surprisingly, tmjs with primary add show considerable inflammatory change including condylar erosions. still, chronic systemic inflammation in jia joints results in considerable higher deformity of the mandibular condyle and the temporal joint surface. observation of the mostly preserved normal shape of the temporal bone may help differentiating primary add from jia. retrospective magnetic resonance imaging (mri) study of 49 consecutive jia patients (35 female, median age 14 y) with at least two consecutive tmj mri examinations ≥ 2y apart and no csi. degree of tmj inflammation was determined on t2-weighted and contrast-enhanced t1weighted fast spin echo images (fig. a) , and degree of osseous deformity on gradient echo images (fig. b) by progressive 4-grade scales (0-3). change of respective grades was assessed with wilcoxon test. mandibular growth was determined by ramus length change and compared to normal values. over a median period of 3.4 y (interquartile range, 2.4 -4.6 y), degree of tmj inflammation improved (p<0.001) with decrease in frequency of grade 3 (4.1% to 0%) and grade 2 (19.4% to 4.1%). inflammatory grades improved both in patients with (n=39, p=0.007) and without (n=10, p=0.02) systemic disease modifying medication. the degree of osseous deformation slightly improved (p=0.04), with decrease in frequency of grade 3 (5.1% to 3.1%) and grade 2 (9.2% to 6.1%), and increase of grade 0 (48% to 54.1%). overall growth rates of mandibular ramus (median, 1.3 mm/y) were not significantly different from normal growth rates (p=0.27) (fig. c) . growth rates of tmjs from patients only receiving non-steroidal anti-inflammatory drugs (median, 1.25mm/y) were not significantly different (p=0.9) compared to patients treated with systemic disease modifying drugs (median, 1.35mm/y). in patients with systemic treatment of jia, both the degree of tmj inflammation and osseous deformity as seen on mri improved at midterm follow-up. normal growth of the mandibular ramus was maintained. these results are in contrast to those from an earlier cohort treated with csi, in which on average deformities deteriorated and growth was impaired. objective: pediatric ileocolic intussusception, ici, is a common abdominal condition for which pediatric radiologists are asked to attempt emergency pneumatic reduction. because of the high success and low complication rates of pneumatic reductions, radiologists are able to make several attempts at reduction in stable patients if the initial enema attempt is unsuccessful. we have observed patients with successful reductions with rather long periods between initial symptoms of ici and performance of the air enema. we hypothesize that successful pneumatic reduction rates are independent of length of symptoms and in stable patients, repeated reduction attempts can be performed with the expectation of successful reduction. we performed an irb-approved retrospective review of all ici with a pneumatic reduction attempt between 2008-2016 at xxx. clinical, imaging and surgical data was reviewed. time to enema was defined as the time from first symptom to first air enema attempt. linear and second order polynomial statistical analysis was performed to assess the relationship between time to enema and enema outcome. results: 66 ici were identified in 61 patients. air enema was successful in 46 ici, 77%. the mean time to enema was 37.5 hours, range 4-168 hours with sd of 42.2 hours for successfully reduced ici and 35.1 hours, range 2-336 hours with sd of 53.9 hours for unsuccessfully reduced ici. surgical resection was required in 4 patients with ischemic bowel including one with an irreducible meckel's diverticulum as lead point. there was no correlation between time to enema and successful reduction, fig 1. no patient with a successful pneumatic reduction of a ici required subsequent bowel resection. conclusions: air enema for ici can be safely performed despite prolonged time to enema with the anticipation of a successful reduction. the lack of correlation of pneumatic reducibility and time to enema suggests that in surgically cleared patients with ici, the pneumatic reduction attempt may not be a true emergency and that repeated attempts at reduction are safe. additionally, though our numbers are small, they suggest that an ici is reducible or not from the beginning and do not "become irreducible" with prolongation of the time to enema. evaluation of splenic stiffness measurements for the diagnosis and the follow-up of portal stenosis after paediatric liver transplantation c. escalard 1 , a. dabadie 2 , s. chapeliere 1 , d. pariente 1 , c. adamsbaum 1 , s. franchi 1 ; 1 le kremlin-bicêtre, paris/fr, 2 la timone, marseille/fr to report our preliminary findings about the role of splenic and hepatic supersonic shear-wave elastography (sswe) in the diagnosis and followup after treatment of portal stenosis in paediatric liver graft recipients. all paediatric liver recipients with portal stenosis treated by the interventional radiology procedure, and who underwent splenic and hepatic sswe pre and post interventional procedures, were retrospectively reviewed. demographics, data about the portal stenosis (delay post transplantation, clinical presentation, initial radiological findings, hemoglobin and platelet counts), ir procedure performed, clinical and ultrasonographic follow-up and spleen stiffness pre and post ir procedure were collected. four patients were included, median age 6,5 years (range 0,9 months to 8 years) and median delay post transplantation 3,9 years (range 1 month to 4.5 years). two patients presented with anemia, associated in one case with progressive splenomegaly. one patient had liver test abnormalities, and one had decreased portal flow found on systematic doppler followup. spleen stiffness was elevated pre-procedure in all 4 patients, from 36 to 65 kpa (normal <20 kpa), and liver stiffness was normal or mildly elevated in all. portal stenosis was successfully treated by ir in 3 patients. spleen stiffness decreased rapidly, ranging from 38 to 53% (figure 1) . however, the size of the spleen remained unchanged. in the last patient, angioplasty of the portal stenosis failed leading to portal thrombosis. spleen stiffness increased on the subsequent ultrasound ( figure 2 ). mr elastography (mre) is a novel imaging technique that provides a non-invasive evaluation of liver fibrosis. the standard sequence used for this purpose on a siemens scanner has been gradient echo (gre). we also implemented echo planar imaging (epi) available as a work-in-progress (wip). our aim is to compare the liver elastogram values between gre and epi in children. after consent from both research and referred clinical subjects, a dedicated mre of the liver was performed on a 3t mr scanner (magnetom® skyra, siemens) with a pediatric mechanical driver over the right upper quadrant. an axial t2 blade with fat saturation, coronal t1 vibe dixon and axial diffusion weighted imaging (dwi) were obtained. elastograms were obtained using both standard gre and epi, in the axial plane. for the gre sequence, 5 different slices were selected and each scanned sequentially. the epi sequence incorporated 5 different slices in just one series. images were post-processed placing regions-of-interest (roi) and measuring the stiffness in kilopascals (kpa). for each sequence and each slice the mean stiffness and then the average of the means was calculated. a spleen elastogram was simultaneously generated, without changing the mechanical driver location, and the mean stiffness was also calculated. increased stiffness was defined as >2.9 kpa in the liver and >3.6 kpa in the spleen. we focused on a technical comparison between the sequences without clinical or histological correlation of findings. we included 15 subjects that had elastogram measurements of liver and 11 of them spleen stiffness on both gre and epi sequences. mean liver stiffness on gre was 2.4 (sd+/-0.71) and on epi was 2.8 (sd+/-1.04), with a pearson's correlation of r= 0.92 (p<0.001). increased liver stiffness was found in 4/15 (26.6%) of the cases in gre and 9/15 (60%) of the cases in epi. mean spleen stiffness on gre was 3.9 (sd+/-1.39) and on epi was 4.8 (sd +/-1.45) with a pearson's correlation of r=0.69 (p= 0.01). epi reported consistently higher values than gre in both liver and spleen stiffness. our preliminary data shows a moderate to high correlation between gre and epi sequences; however, the epi values were higher in both liver and spleen. in the future, larger studies are needed to validate these thresholds and patterns among different sequences. were also reviewed if done. patient's medical & surgical treatment, and clinical progress were also reviewed. active telephone follow-up 3 days after cevus was performed. results: 120 patients giving a total of 240 pelviureteric units were referred for vus study during the study period, with age ranging from 1 month to 7 years old. no contrast-related complication was encountered. except 2 cases with failed catheterization, 108 were investigations of urinary tract infection (uti), antenatal hydronephrosis and congenital anomalies etc., and remaining 10 were follow up studies of known reflux. of all cases of uti, 36 refluxing units were picked up by vus, ranging from grade i to v. of the 36 refluxing units diagnosed by cevus, 17 were missed on mcu, among which 12 were high grade refluxes (grade iii to v) requiring treatment; whereas cevus only missed one grade i refluxing unit detected by mcu. besides, one grade iv refluxing unit identified on vus was under graded by mcu to grade i. regarding patient outcomes, one patient with mcu-missed refluxing unit presented with breakthrough uti on follow up. two refluxing units that were missed on mcu but detected on cevus demonstrated scarring on dmsa. conclusion: cevus is shown to be more sensitive in detecting vesicoureteric reflux than mcu. the fact that mcu-missed refluxes detected by cevus were associated with breakthrough urinary tract infection and scarring on dmsa indicated that the extra sensitivity brought by cevus did translate to clinical significance. difficulty in visualizing low-grade reflux is a potential limitation of this technique. with favourable diagnostic performance and safety profile, cevus can be further applied in this community in the era of radiation reduction. percutaneous transbiliary needle or forceps biopsy in hepatic masses with biliary dilatation a. dabadie 1 , s. franchi 2 , d. pariente 2 ; 1 la timone, marseille/fr, 2 le kremlin-bicêtre, paris/fr hepatic masses with biliary dilatation are rare in children and mainly include rhabdomyosarcoma of the biliary ducts, but also other masses or pseudo-masses compressing the hepatic hilum. in these patients histological diagnosis of the lesion as well as temporary biliary drainage are warranted. the objective of this study is to report our experience in percutaneous transbiliary biopsy performed simultaneously and using the same access as the percutaneous biliary drainage in children with hepatic mass obstructing the biliary ducts. children presenting with a hepatic mass causing biliary obstruction, with need for biliary drainage, were considered candidates for percutaneous transbiliary biopsy of the lesion performed at the same time. the biopsy was performed under ultrasound guidance, through a sheath introduced in the dilated biliary system, using a semi-automatic 16 gauge needle or the transluminal biliary biopsy forceps set (cook medical, bloomington, usa). between 2009 and 2016, four patients were included, three females and one male, median age 5.5 years (range 2.5-11.5). all presented with jaundice and were diagnosed with a hepatic mass with secondary biliary obstruction. percutaneous transbiliary biopsy was performed in all 4 patients using the 16 gauge needle. in one patient, the biopsy did not demonstrate any tumoral cells and a second biopsy was performed using the forceps device through the same biliary access. the samples deemed adequate for analysis by the pathology department in all patients, however the samples were larger when using the needle. a retrospective -prospective study included 62 patients of both sexes (13,72 +/-3,17 y), in a two-year span. patients were divided into two groups according to the used diagnostic method (positivegroup a on us and a1 on mri, with intestine mural thickness above 3mm, and negativegroup b on us and b1 on mri, with mural thickness below 3mm). overall sensitivity and specificity of us and mri in diagnosing ibd was calculated in comparison to pathohistological (ph) findings. us examination showed an average intestinal mural thickness of 4.93 ±1.39mm and 2.7+0.18mm in group a (28 patients) and group b (34 patients) respectively. mri examination showed an average intestinal mural thickness of 6.50±1.45mm and 2,8+0,16mm in group a1 (27 patients) and group b1 (35 patients) respectively. out of 28 patients from group a, 15 (52%) had irregular mural architecture, contrary to group b in which mural architecture irregularities have not been observed. in groups a1 and b1 14 (51.9%) and 2 (5.7%) patients had irregular mural architecture respectively. average length of affected intestinal segment on us and mri was 103mm and 105mm respectively. five patients from group a and four from group a1 had signs of fibrosis. color doppler showed hyperemia in 17 and 22 patients of group a and a1 respectively. transmural signs of inflammation were found in 59% of patients on us, and 61.3% of patients on mri. average longer diameter of mesentery lymph nodes measured by us and mri was 13.29 ±3.74mm and 12.7±5.68mm, respectively. overall sensitivity of us and mri was 88.4% and 92.31% respectively. both us and mri showed a specificity of 88%. us and mri are reliable and compatible methods in diagnosing ibd, with mri being slightly more accurate. us is an extremely valuable and widely available imaging modality in every-day clinical work, both in diagnosing and follow-up of therapy effects in children with ibd. findings in percutaneous transhepatic cholecysto-cholangiography in neonates and young infants presenting with conjugated hyperbilirubinemia d.a. parra, s. peters, j. amaral; toronto/ca objective: conjugated hyperbilirubinemia is a concerning finding in neonates and young infants, biliary atresia (ba) being one of the main diagnostic considerations. ba is a rare disease characterized by fibrosis of the biliary tree. the obliteration of the biliary system leads to cholestasis and ultimately liver parenchymal injury, cirrhosis and death. an early diagnosis of ba along with a kasai portoenterostomy operation significantly improves the long-term prognosis. percutaneous transhepatic cholecysto-cholangiography (ptcc) is one of the options described in the diagnostic algorithm of ba. the aims of this study are to: (a) describe ptcc findings in patients with conjugated hyperbilirubinemia; (b) identify the abnormal patterns encountered that justify further investigations; (c) analyze technical aspects of the procedure. this is a 16 year single-center retrospective study (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) in which we recruited patients with the diagnosis of cholestasis (less than 6 months old) referred for ptcc. we collected patient demographics, clinical information, findings in ptcc, post-procedure management and long term clinical outcome. eigthy-nine patients were referred for ptcc in the study period. the procedure was technically feasible and successfully performed in 73 patients (68% male, mean age 2.2 months). forty-one had a pre-procedure hida scan suggestive of ba. fifty-nine patients had an ultrasound-guided biopsy in conjunction with the ptcc and in all of them the cholangiography was performed through a needle placed using ultrasound guidance in the gallbladder. 53% (39) of the patients had a normal ptcc. abnormal patterns encountered were: 1) variable degrees of hypoplastic bile ducts seen in 25%; 2) atretic gallbladder without demonstration of communication with bile ducts seen in 18%; and 3) gallbladder communication with a cystic structure not communicated with the biliary ducts (cystic biliary atresia) seen in 4%. the most common diagnosis in the abnormal group was ba (71%). alagille's syndrome, alpha-1 antitrypsin deficiency and progressive familial intrahepatic cholestasis were other diagnoses in this group. no complications related to the procedure were observed. ptcc is a safe and effective option in the diagnostic algorithm of patients presenting with cholestasis early in life. visualization of the gallbladder is fundamental to perform the procedure. the majority of studies were normal in our patient population preventing further invasive investigations. three types of abnormal ptcc patters were encountered, with ba being the most common diagnosis in this group of patients. to evaluate the additive role of shear wave elastography in the sonographic distinction of biliary atresia from other causes of neonatal/ infantile cholestatic liver disease. neonates and infants with clinical and biochemical diagnosis of cholestatic jaundice were enrolled in our study after obtaining informed written consent from the parents. grey scale, doppler and shear wave elastographic findings were recorded after 4 hours of fasting using aixplorer® ultrasound system (supersonic imagine, aix en provence, france). sedation was not needed during the study. for obtaining elastographic values, linear transducer (4-15hz) was used and after image stabilization a q-box measuring 3mm was placed in the most homogenous vessel free area. the mean of three elastographic values were recorded. hida scan, liver biopsy, intra-operative cholangiogram and histopathological evaluation of resected specimens was done wherever feasible and clinically indicated. the prospectively obtained elastographic values were retrospectively evaluated. eleven of 25 patients included in our study were proven to be biliary atresia (ba) by intra operative cholangiogram and histopathological reports. the diagnosis in the remaining 14 patients included other causes of infantile cholestatic jaundice like infantile choledochal cyst, neonatal idiopathic hepatitis, progressive familial intrahepatic cholestasis, abernathy malformation, cmv hepatitis etc. the elastographic values of ba and non-ba patients were compared. six of 25 infants were younger than 60 days which included four patients with ba and their elastographic values (18.75±2.9kpa) were significantly different from that of non-biliary atresia (7±1kpa) in the same age group (p value <0.05). similarly, for patients aged >60 days also we had a significant difference (p value <0.05) in elastographic stiffness between ba (45.7±11kpa; n=7) and non-ba (19.4±3.6kpa; n=12) groups. the mean echogenic area anterior to right portal vein (earpv) was 4.45 ±0.84mm in ba and 1.47±0.36mm in non-ba group (p value <0.05). the mean gall bladder (gb) length was 1.82±0.26 mm in biliary atresia group in contrast to 3.2±0.26mm in the rest (p value <0.05). the roc plot for earpv and gb length gave a youden index cut off value of >2.7mm (sensitivity 72.7 & specificity 71.4%) and <3.32 cm (sensitivity 100 & specificity 42.9%) respectively. infants with biliary atresia have a significantly higher elastographic value when compared to age matched patients with other causes of neonatal cholestasis. we expect to validate the findings in our ongoing study with a larger sample size. to retrospectively define in a large pediatric population the association between testicular microlithiasis and testicular neoplasia. retrospective multicenter study of scrotal ultrasounds performed between january 2000 and april 2014 in subjects <18 years of age. all unique subject scrotal ultrasound reports from each institution were reviewed for mention of microlithiasis. for subjects with serial exams, the most recent exam performed was included in the analysis. all exams mentioning microlithiasis were reviewed by site-specific investigators to confirm the presence of ≥5 punctate calcifications in the testicle on a single image. the presence of testicular germ cell and stromal tumors were determined for subjects with and without microlithiasis through review of institutional pathology and imaging databases. the risk of testicular neoplasia in the context of microlithiasis was expressed in terms of odds ratios with (a-or) and without adjustment (u-or) for fixed study site (institution) effects by logistic regression. the study population included 37,863 unique subjects with confirmed microlithiasis in 1,097 (2.9%). mean subject age was 11.1±4.7 years for subjects with microlithiasis and 9.1±5.9 years for subjects without (p<0.0001). one hundred thirty-nine subjects (0. this large, multicenter study confirms that there is a significant, strong association between testicular microlithiasis and testicular neoplasia, particularly malignant germ cell tumors. children with microlithiasis have approximately 22x greater odds of having a malignant germ cell tumor than children without microlithiasis. this reinforces the need for a large prospective study assessing the risk of developing testicular neoplasia in children with incidentally identified diffuse microlithiasis. do adc-values reflect renal function or obstruction in children with uretero-pelvic-junction obstruction? p. grehten, a.c. eichenberger, c. kellenberger; zurich/ch the use of diffusion weighted imaging (dwi) in renal mri is increasing. in adults as well as in infants a positive linear correlation between adcvalues and glomerular filtration rate has been demonstrated. the aim of our study was to assess whether renal dwi can provide information on the grade of urinary tract obstruction or renal function in children with uretero-pelvic-junction (upj)-obstruction. retrospective analysis of 19 children (age 3.1+/-4.5y) with unilateral upj-obstruction who underwent pre-and postoperative mri at 1.5t and 6 normal controls (age 6.6+/-4.0y). functional mr-urography and multiple b-value dwi were part of the mr-protocol. renal adc-values were correlated to measures of obstruction and function, and compared between obstructed and non-obstructed kidneys and between pre-and postoperative studies. no correlation was found between mean parenchymal, cortical or medullary adc-values and calyceal transit time (ctt), renal transit time (rtt) and measures of differential renal function (%parenchymal s359 (2017) 47 (suppl 2):s297-s pediatr radiol volume, vdrf, pdrf). there was moderate correlation with absolute parenchymal volume and total kidney volume, and low correlation with pelvic volume. adc-values showed high correlation with age and patient's weight. adc-values normalized for age or weight showed low correlation with rtt and ctt, but no correlation with functional measures. adc-values were not significantly different between obstructed and contralateral normal kidneys (p=0.2-0.9) or between pre-and postoperative studies (p=0.3-1). renal adc is dependent on age and weight in young children and does not correlate with differential renal function. for assessing urinary tract obstruction with adc normative values need to be established. to determine the level of knowledge and awareness of medical staff, medical students and parents concerning possible risks associated with ionizing radiation. a prospective study has been conducted at children's hospital, center for adult's radiology, and medical faculty, by filling out two anonymous questionnaires (questionnaire 1medical staff and medical students, questionnaire 2parents of the children exposed to x-ray based procedures), and it included 254 participants. statistical analysis was performed using the spss 21.0. the majority of examinees assessed their knowledge about ionizing radiation as moderate. knowledge level was statistically significantly higher only in the group of medical students who passed the course of radiology, in comparison to the group of those who have not attended the course yet. only 45% of radiologists and up to 37.5% of pediatricians, pediatric surgeons and anesthesiologists are informed about "image gently" campaign. up to 80% of radiologists, and up to 22% of clinicians, both specialists and residents, are aware of alara principle. over 60% of medical doctors think that diagnostic radiology procedures are very often performed unnecessarily among children, while only 12.5% of parents share this opinion. most of the radiologists and clinicians consider it necessary to inform parents about potentially harmful effects of ionizing radiation, but even though 60-80% of clinicians claim they do inform parents in every-day clinical practice, over 70% of parents affirm that they had never been informed about effects of ionizing radiation before diagnostic procedures were performed on their children. only 26% of pediatric surgeons and pediatricians, but 72.7% of radiologist and 60% of anesthesiologists are concerned that informing parents about ionizing radiation would cause problems in every-day work. nearly 71% of parents claimed that they would not refuse to expose their child to x-ray based diagnostic procedure, after the given information about potential harmful effects. over 70% of radiologists and less than 50% of pediatric surgeons and pediatricians support the initiative to calculate the total effective dose child was exposed to during hospitalization, and place it on the discharge list. between 50% and 85% of pediatricians and pediatric surgeons greatly underestimated the effective doses in ct and fluoroscopy procedures. there are 58-100% of clinicians who are aware that ct increases the risk of carcinoma development. this study showed that general knowledge about ionizing radiation, potential risks and effective doses in pediatric population is poor, and that organized education is required. fluoroscopy in pediatric radiology -how important is an individual impact to radiation exposure of children? j. lovrenski, i. varga; novi sad/rs to determine whether there are differences between different pediatric radiologists and radiology residents in exposure of pediatric population to ionizing radiation during fluoroscopy procedures. a retrospective study has been conducted at the regional children's hospital, and included all the diagnostic fluoroscopy examinations performed within a one-year period. the fluoroscopic data along with the names of pediatric radiologists/radiology residents performing these examinations were retrieved from the evidentiary notebooks, and included: dose-area product (dap), skin dose, and fluoroscopy time. there were 4 radiologists (r1-r4), and 4 radiology residents (r5-r8) involved in fluoroscopic examinations. we found all the fluoroscopic findings in the hospital's data base, which enabled a differentiation between positive and negative findings. statistical analysis was performed using the spss 21.0. a p-value less than 0.05 was considered statistically significant. a total of 191 fluoroscopy procedures in children (mean age 4,5y, 107 males and 84 females) have been performed within a one-year period, most of which were voiding cystourethrograms (vcug) -93, and an upper gastrointestinal (gi) series -79 examinations. radiology residents and radiologists carried out 82 and 109 examinations respectively. duration of fluoroscopy procedures performed by residents (av. 32.5s) was statistically significantly shorter in comparison with duration of fluoroscopy examinations performed by radiologists (av. 53s). dap and skin dose did not show statistically significant difference between these two groups, as well as the number of positive and negative fluoroscopic findings in groups of examinations performed by radiologists and radiology residents. mean dap value ranged from 0.82μgym 2 (r2) to 7.5μgym 2 (r7) when performing vcugs, and from 1.35μgym 2 (r2) to 4.79μgym 2 (r1) for upper gi series. mean skin dose ranged from 14.33mgy (r2) to 151.48mgy (r3) for vcugs, and from 28.66mgy (r2) to 120.54mgy (r4) for upper gi series. mean fluoroscopy time ranged from 11.76s (r2) to 48.5s (r3) for vcug, and from 26.22s (r2) to 125.75s (r3) for upper gi series. statistically significant difference was shown only between radiologists r2 and r3 for dap and skin dose values in performing vcug, and for fluoroscopy time in performing an upper gi series. for all examinations dap and skin dose were statistically significantly higher in the group of positive fluoroscopic findings. this study has shown that exposure of children to ionizing radiation during fluoroscopy procedures significantly depends on radiologist/ radiology resident and the nature of fluoroscopic finding. to evaluate image quality and radiation exposure of non-contrast pediatric chest ct with automated tube voltage selection (atvs), in combination with automated tube current modulation (atcm). non-contrast chest ct scans of 160 children (91 male and 69 female; mean age, 8.7 ± 5.4 years) were analysed retrospectively with regard to radiation exposure and image quality before and after the implementation of an automated tube voltage selection. correlations of volume ct dose index (ctdi vol ) and the effective diameter (edm), before and after the implementation of atvs were compared, and confidence intervals related to the change in correlations with and without atvs were determined using fisher's z-transformation. image quality was assessed by mean signal-difference-tonoise ratios (snrs) in the aorta and in the left principal bronchus with the independent samples t-test. subjective image quality was rated by two pediatric radiologists and a general radiologist on a 10point scale. agreement between the readers was assessed using weighted kappa coefficients. a p<0.05 were considered significant. automated tube voltage selection, in combination with an automated tube current modulation, resulted in optimization of scan protocols, homogeneity of image quality, and reduction of radiation exposure for pediatric patients. advantages and disadvantages of cone beam ct for pediatric interventions l. dance, r.b. towbin, d. aria, c. schaefer, r. kaye; phoenix/us objective: illustrate the advantages and disadvantages of cone beam ct (cbct) as an alternative to conventional ct guidance and an adjunct to angiography. there is a steep learning curve to optimize utilization of cbct. we found that cbct reliably identifies high-contrast lesions. however, the lower dose and decreased penetration of cbct resulted in poorer visualization of low-contrast lesions. also cbct can be degraded by streak artifact from hardware or dense contrast. the relatively narrow field of view can be restrictive for peripherally located lesions in larger patients. however, the anatomic display is adequate for guidance in most instances. these findings are illustrated in a series of cbct-guided cases including pulmonary nodule localization, osteoid osteoma ablation, abc sclerotherapy, renal av fistula embolization, and liver lesion biopsy. the advent of cbct as an adjunct modality in the ir suite has significantly decreased the use of conventional ct guidance and significantly decreased the radiation dose in children. we have found cbct to be a practice changer. the aim of this study is to review our local drl in pediatric fluoroscopy and to compare them to values proposed by pidrl guidelines and recent international litterature. data were prospectively collected on consecutive procedures (750 total) performed from january 2016 to december 2016 on 2 different fluoroscopy units (siemens iconos r200, luminos drf). of each procedure patients data (name, weight and birth date), examination-data (kind of procedure, date, dap [cgy*cm2], total fluoroscopy time, number of images) were recorded. data from micturating-cystourethrography(mcu), barium meal/swallow(bs) and most commonly performed procedures were divided into 4 weight-groups (<10kg,10-15kg,15-30kg,30-60kg) and of each one 75th-percentile was calculated. data were compared to europeandrl and recent literature data (by age:newborn,1-,5-,10years old). weight-groups are considered a representative sample if at least 20-patients per procedure-type and per patient-group are included. our local-drl for mcu are 7(<10kg), 10(10-15kg), 24(15-30kg) and 57(30-60kg). they results to be lower than pidrls values (30, 70, 80, 75) but higher if compared to a previous local survey of 2014 (4, 9, 18, 29) . bs data are 9(<10kg), 32(10-15kg), 28(15-30kg); these data are lower than that of a previous local survey of 2014 (23, 34, 68) . the update of local-drl is helpful in daily practice to identify (and solve) critical issues such as incorrect technique or poor practice with new flat-panel equipment. pidrl guidelines: a review of local drl for pediatric head, thorax and abdomen ct in a italian referral center a. magistrelli, v. cannatà, e. genovese, m. cirillo, r. lombardi, p. toma; rome/it the aim of this study is to review our local drl in pediatric ct and to compare them to values proposed by pidrl guidelines and recent international litterature. data were prospectively collected on consecutive procedures (347 total) performed from january 2016 to june 2016 on a somatom definition flash siemens. of each procedure patients data (name, weight and birth date), examination-data (kind of procedure, clincal question, date, ctdivol16/32 and dlp16/32) were recorded. ctdivo/dlp16 from head ct were divided into 4 age-groups (<4weeks,4weeks-1y,1-6y,≥6y) and of each one 75th-percentile was calculated. ctdivol/dlp32 from thorax (chest, cardiovascular ct angiography) and abdomen+pelvis ct examination were divided into 5 weightgroups (<10kg,10-15kg,15-30kg,30-60kg,>60kg) and of each one 75th-percentile was calculated. data were compared to europeandrl and recent literature data. weight-groups are considered a representative sample if at least 20patients per procedure-type and per patient-group are included. our local drl are substantially lower than that proposed by pidrl guidelines. specifically ctdivol/dlp32 for chest ct are 1/22(<5kg), 1,52/42(5-15kg), 1,83/56(15-30kg), 2,99/113(30-60kg), 6,07/ 239(>60kg) respectively. for cardiovascular ct angiography are 0,71/ 15(<5kg), 1,01/21(5-15kg), 2,44/36(15-30kg), 2,87/90(30-60kg), 13,72/311(>60kg). while for abdomen+pelvis ct are 1,9/47(<5kg), 2,68/83(5-15kg), 3,25/131(15-30kg), 7,77/320(30-60kg), 11,21/ 532(>60kg). data for trunk sere not collected. for head ct local drl are higher in age-group 0 and 1 but lower in other age-group if compared to routine head ct pidrl ones. the update of local-drl allowed us to identify (and solve) some critical issues such as incorrect technique. drl-curve in optimization of pediatric body ct r. seuri 1 , p. laarne 2 , a. nikkola-sihto 3 , k. nygaard bolstad 4 , m.s. perhomaa 5 , a. thilander klang 6 , k. rosendahl 4 , j. ruohonen 3 , e. tyrvainen 7 ; 1 helsinki/fi, 2 tampere/fi, 3 seinäjoki/fi, 4 bergen/no, 5 oulu/fi, 6 gothenburg/se, 7 kuopio/fi objective: diagnostic reference levels (drls) in medical imaging represent valuable tools to study dose optimization in clinical practice. this is particularly important in pediatric computed tomography (ct) as the number of the examinations in many institutions is low. drls are typically given as a percentile point, usually as 75% or 3 rd quartile of the observed distribution of patient dose. in pediatric practice drls are often given for each age-or weight group separately. we present continuous drl-curve as a feasible way to compare dose levels in pediatric body ct. during 2016-2017 a selected group of nordic hospitals collected dose values (ct dose index by volume, ctdi vol , and dose-length product, dlp) from pediatric body ct examinations on children aged 5-16 years. the dose values were imported into a dynamic excel table, previously established by the radiation and nuclear safety authority in finland, stuk (fig 1) . the stuk-table includes a graphic presentation of a continuous drl-curve presented as a function of body weight, and the program automatically calculates a dose curve and compares it to the established reference level (fig 2) . the dose values were easily exported to the excel tables, and the graphic presentation and comparison with an established drl-curve was clear and readily understandable for both radiologists and radiographers. in some of the institutions included in the present study, the weight of the patient was not recorded routinely. this represents a challenge for the use of the drl-curves provided by stuk. the drl-curves provided by stuk were feasible for clinical practice. the automatic calculation of the dose curve and graphic presentation were helpful to interpret the results. the drl-curve also allows relevant comparison even with a smaller number of patients. fifty randomly selected ct chest studies performed over 10 years to assess diffuse lung disease were included in the study sample (25 females, 25 males; mean age 9.9 years + 6.6 years), comprising 9 disorders. two pediatric radiologists and a pediatric radiology fellow blinded to the results of the cts evaluated four subsets of complete chest cts (3 slices, every third slice, every other slice, and all images below the thyroid) and compared the subsets with the entire chest ct, interpreted as the control. accuracy of evaluating the primary diagnosis and determination if significant diagnoses were missed in the reduced slice ct subsets were rendered. we assume linear distribution of dose across the anatomy to estimate dose reduction on reduced slice subsets. most significant findings were present on all reduced slice ct subsets. all relevant findings were present in 100% of subthyroid, 96% of every other slice, 86% of every 3 rd slice, and 50% of 3 regional slice subsets respectively. excluded findings included small foci of ground glass opacity, consolidation, focal mosaic attenuation, and linear parenchymal bands; peribronchial thickening, dextrocardia vs dextropositioning, tree-in-bud opacities, extent of mild bronchiectasis. with the exception of consolidation in 1 of the studies, these findings were not thought to inhibit diagnostic assessment. the underlying diagnosis was correctly identified in most of the subsets: 100% subthyroid and every other slice, 90% every 3 rd slice, and 80% of 3 regional slice subsets. dose is significantly decreased by using any of these methods. while some findings are excluded with increasing gaps between slices, equivalent diagnostic information can be provided on reduced slice ct and can serve as a viable strategy to reduce lifetime radiation dose to children and young adults with diffuse lung disease imaged for routine follow-up. as findings are missed with larger gaps, this strategy should be used with caution in patients presenting with acute symptoms 3. to extrapolate the significance of early diagnosis which will compliment to treatment planning and management. case presentation: types a and b niemann-pick disease are lysosomal storage disorders that result from deficient acid sphingomyelinase activity and lead to the accumulation of sphingomyelin, primarily in tissues of the reticuloendothelial system. type b niemann-pick disease manifestations are hepatosplenomegaly, excess bleeding and bruising, growth retardation, and recurrent respiratory infections. features of hrct include thickened peribronchovascular and interlobular septal thickening, ground-glass opacities. the intermixed regions could be characterized as showing crazy paving, although this is not the predominant pattern. type b niemann-pick disease should be added to the list of clinical entities that can demonstrate crazy paving. our patient is a sevenyear old girl, presented with dry cough and fever. physical examination revealed hepato splenomegaly. radiological work up included abdominal ultrasound examination, which showed mild hepatosplenomegaly. chest radiography revealed diffuse reticulonodular infiltration in both lungs. chest hrct was done for more comprehensive evaluation which showed multilobar bilateral peribronchovascular interstitial thickening and interlobular septal thickening with ground-glass opacities and crazy paving appearance. no honeycomb pattern was seen. no sizable pulmonary nodule or sizable mediastinal lymphadenopathy was seen. no pleural effusion was seen. finding were indicating extensive pulmonary intestitial disease. a corroborative analysis along with lab tests and genetic studies revealed the diagnosis of type b niemann pick disease. 2. the spectra of hrct features including crazy paving pattern may be encountered; though not frequent. hence should be included in the differential diagnosis of crazy paving pattern. blast from the past: lemierre's syndrome in adolescents with sore throat o. kvist; stockholm/se a minor ailment such as a sore throat could prove to be a severe disorder known as lemierre's syndrome. this syndrome mostly affects previously healthy adolescents and young adults and in its classical form should meet four diagnostic criteria; primary infection of the oropharynx, septicemia, clinical-or radiographic evidence of thrombosis of the internal jugular vein (ijv) plus secondary metastatic abscesses. the infection is caused by fusobacterium necrophorum, a species of obligate anaerobe bacteria forming part of the normal human flora. the syndrome should be suspected in any patient with pharyngitis, cervicalgia and pulmonary symptoms. the incidence of lemierre's syndrome decreased dramatically after the introduction of antibiotics but has, of unknown reasons, increased over the past 15 years. we will present four patients diagnosed with lemierre's syndrome in our department during the last 8 years. the purpose of this case report is to raise awareness of this "forgotten disease". of the four patients diagnosed with lemierre's syndrome two fulfilled all 4 criteria while two fulfilled 3 out of 4. (table 1 ). the first two presented at the emergency department with one week's history of a sore throat, left sided cervical lymphadenopathy, erythematous tonsils, leukocytosis and elevated crp. in both cases the clinical condition deteriorated and they were referred to the icu. one developed ards and required initiation of ecmo. in both patients, chest ct revealed multiple pulmonary consolidations with cavitations, findings consistent with septic emboli (image 1,2 and 3). incidentally ct-neck revealed thrombosis in the left ejvand ijv (image 4). ultrasound of the neck veins confirmed the finding (image 5 and 6). blood cultures taken on admission later proved positive to f. necrophorum. the third and fourth case, with similar clinical histories but with a less aggressive development, had positive blood cultures but no thrombosis and vice versa. (table 1 and all four patients recovered and could be discharged with oral antibiotics and anticoagulants. unique teaching points: in conclusion, lemierre's syndrome is less common today thanks to antibiotics but may still occur in previously healthy adolescents and may lead to a fatal outcome. the pediatric radiologist should be aware of typical findings like septic emboli in the lungs and thrombosis in the ijv. unicameral bone cyst associated with secondary aneurysmal bone cyst of clavicle i. dasic, g.j. djuricic, s. ducic; belgrade/rs objective: aneurysmal bone cyst (abc) accounts for 2,5 % of all bone tumors. they are benign but locally destructive lesion of the bone characterized by presence of spongy or multiloculated cystic tissue filled with blood. abcs are metaphyseal, excentric, bulging, fluid-filled and multicameral, and may develop in all bones of the skeleton. most common locations include the proximal humerus, distal femur, proximal tibia, and spine. clavicle is a very rare site for aneurysmal bone cyst with only few cases reported in literature. a 10-year-old boy reported to the university children's hospital for detailed examination of swelling of right shoulder. 2-3 days before admission parents noticed tumefaction of right shoulder. there was no history of trauma or fever. physical examination revealed tumefaction of the right shoulder, in projection of acromial end of clavicle, measuring approximately 8x8cm, which was tender and fixed. the swelling was not hot to the touch, and there was no skin discoloration over that area. regional lymph nodes were not palpable. (fig. 1a) x-ray revealed osteolytic, expansible lesion in the lateral end of clavicle and there was no pathological fracture. (fig. 1b) laboratory analyzes were within normal limits. blood cultures remained sterile. chest x ray and abdominal ultrasound were normal. computed tomography (ct) revealed a thinwalled multiloculate lesion in lateral end of right clavicle. (fig. 2a) there was no extension in the soft tissues on magnetic resonance imaging (mri). mri shows the multiloculate cavities and fluid levels. (fig. 2b) . the open biopsy was done. histopathological examination confirmed the secondary aneurysmal bone cyst on the field of simple bone cyst of clavicle. the clavicle is an uncommon site for bone tumors. review of literature shows clavicle accounts for less than 1 % of all bone tumors. the patient with an aneurysmal bone cyst generally presents with pain and swelling, which may vary in duration from weeks to several years. up to 8 % of bone tumors occur in less than 20 years of age with peak incidence in second decade. radiologically, lesion is lytic and may have a soap-bubble appearance with ballooned distension of the periosteum. the differential diagnosis for aneurysmal bone cyst include giant cell tumor, chondromyxoid fibroma and telangiectatic osteosarcoma. distinction from telangiectatic osteosarcoma is difficult because the conditions have overlapping clinical and radiologic features. the differentiation is made from the histologic features. imaging of glomus tumor of liver in a child (case report) n. tewattanarat, j. srinakarind, j. wongwiwatchai, p. komvilaisak, s. areemit, p. ungarereevittaya, p. intarawichian; khonkaen/th objective: glomus tumors occur preferentially in subcutaneous tissue of fingers and toes, but extremely rare in visceral organs. most cases of the tumors are diagnosed in adults. several cases of glomus tumors in liver have been reported in adults. a literature review, no case of glomus tumor in liver in children was published. therefore, we present clinical, imaging findings of the first case of pediatric patient with glomus tumor in liver and also histopathological features. a previously healthy 11 year-old-girl was admitted with a twoweek history of progressive dyspnea on exertion and vomiting. family history was unremarkable. physical examination revealed hypertension and smooth and firm mass at epigastrium. systolic apical murmur on heart examination was noted. liver function test (2017) 47 (suppl 2):s297-s pediatr radiol showed elevated cholesterol (396 mg/dl). other laboratory tests (complete blood count, blood chemistry, renal and liver function test, coagulation test, hepatitis profiles and alpha-fetoprotein) were within normal limits. echocardiogram found mitral and tricuspid regurgitation and poor left ventricular systolic dysfunction. abdominal mri demonstrated a 12-cm well-defined exophytic hypervascular mass with intratumoral hemorrhage at segment 3/4b of the liver. there were no other suspicious lesions in other organs. the biopsy was done and revealed glomus tumor. patient underwent preoperative embolization and the liver mass revealed decreased size to 8-cm after 1-month follow up with ultrasound. after that, exploratory laparotomy with left lateral segmentectomy was performed. the pathological results showed dilated vascular channels surrounded by uniform neoplastic cells, uniform with round nuclei, fine chromatin, inconspicuous nucleoli, and pale eosinophilic cytoplasm, and well-defined cytoplasmic border. no mitotic figures and necrosis are identified. immunohistochemical (ihc) staining of tumor was positive for cd34, smooth muscle actin (sma) and h-caldesmon. others ihc including ae1/ae3, heppar1, cd31, desmin and myogenin were negative. from these findings, the tumor was finally diagnosed as glomus tumor of uncertain malignant potential due to deep location and large size. primary glomus tumor is a rare entity of liver tumor diagnosed in children. however, it should be considered in the differential diagnosis of a hypervascular liver mass. most of these tumors are benign, however tumor in liver have malignant potential due to deep seated position. therefore, tumor removal with pre-operative embolization should be considered. brain mri in a pediatric patient with linear scleroderma en coup de sabre m. mortilla, a. rosati, e. canale, c. filippi; florence/it objective: linear scleroderma "en coup de sabre" (ecds) is a rare subset of localized scleroderma. affected individuals typically have a characteristic atrophic skin lesion involving the fronto-parietal scalp. the disease usually has a benign course but rare neurologic symptoms can be seen associated: the most common described is epilepsy. intracranial mri findings described in the literature include: focal brain atrophy, calcifications and t2-hyperintense white matter lesions that may demonstrate contrast enhancement. white matter lesions and calcifications are found in the cerebral hemisphere ipsilateral to the skin abnormality. in the literature only a few pediatric cases have been described. a 4yrs. old girl was hospitalized at our institution for evaluation of a lesion of the frontal skin associated to a history of febrile seizures and mri alterations. she presented febrile seizures at the age of 2 on april 2013. on january 2014 parents noted a frontal cutaneous lesion that was defined as "linear scleroderma, port-wine stain type". on november 2014 she performed an mri at another institution showing a diffuse white matter alteration in the left emisphere with focal lesions with high susceptibility and mild contrast enhancement. she was addressed to immunosuppresive therapy with steroids and methotrexate, with steroids stopped after 6 months. a clinical cutaneous improvement was noted. on july 2016 a second mri showed a worsening of the findings. we describe a case of a little girl with ecds with no neurologic deficits or symptoms that shows extensive and progressive neuroradiologic alterations. only a few pediatric cases have been described, but it has to be known that also in absence of symptoms, patients with linear scleroderma should be screened with mri to look for cns involvement in this immune disease. brain mri can also be used to monitor the progression of the disease and the response to therapy. mals is a vascular compression syndrome which symptoms can overlap chronic functional abdominal pain. in mals the proximal part of the celiac artery is compressed by the too low located median arcuate ligament during expiration resulting in hemodynamically significant symptoms. we report two cases with mals diagnosed primarily by ultrasonography. case 1 18-year-old girl was admitted to tartu university children's clinic (tucc) due to recurrent acute epigastric pain episodes with nausea and loss of appetite during 7 years. previous analyses were normal, abdominal uss and gastroscopy did not show any abnormalities. she was referred to paediatric radiology department for doppler us (dus) which showed narrowed proximal celiac artery (ca) with turbulent flow, increased peak-systolic and end-diastolic velocities on deep inspiration and expiration, and positive ca deflexion angle on expiration. superior mesenteric artery (sma) was markedly widened, indicating possible collateral blood-supply due to severe ca stenosis. according us findings mals was suspected. abdominal mra showed proximal ca kinking, stenosis and poststenotic dilatation and confirmed diagnosis. during dsa collateral blood-supply from sma via pancreaticoduodenale arcade (pda) was seen. laparoscopic release of mal resulted in relief of patient's symptoms, she has been pain-free for two years. case 2 16-year-old girl applied to tucc due to recurrent abdominal pain episodes for 2-3 years. usually, pain occurred 2-3 times per week about 15 minutes after the start of intense cycling training or competitions, and passed about 5 minutes resting in squat position. mild mid-epigastric bruit was audible at physical examination. dus showed two-fold increase in expiratory peak-systolic and enddiastolic blood flow velocities compared to inspiratory velocities which indicated to the hemodynamically significant worsening of ca compression by mal during expiration. mra showed proximal ca compression, upward angulation and poststenotic dilatation. preoperative ct-angiography depicted collateral supply via pda. during laparoscopic surgery ca was released by transecting mal and surrounding fibrous tissue. after surgery the girl has been pain-free for one year except single pain episode during intense competition. the diagnosis of median arcuate ligament syndrome should be considered in patients with postprandial abdominal pain that does not have other clearly established etiology. colour doppler us should be the first choice imaging method. to confirm diagnosis in pediatric patients abdominal mra is preferred in our institution, but as mra may still have a tendency to movement artifacts and inadequate spatial resolution for smaller blood vessels, in these two cases mra was followed by cta or dsa. understand the unique predilection of infantile malignancies to metastasize and present as skin-based masses, most commonly lymphoma/leukemia. case presentation: an otherwise healthy 37 day old male presented to dermatology with a pedunculated, friable red glabellar mass (centered between the eyes). first noticed as a flat, bluish lesion at 10 days, its subsequent rapid growth led to an emergency department visit where dermatology diagnosed a hemangioma and initiated propranolol treatment. despite this, the mass continued to grow rapidly, encroaching upon the patient's right eye. the patient was admitted for further workup. an elevated beta hcg, anemia (7.4 mg/dl), and thrombocytopenia (92,000) suggested an alternate diagnosis. an mri and ultrasound led to a percutaneous biopsy; pathology was consistent with choriocarcinoma. pet ct found fdg-avid glabellar, liver and lung lesions. maternal and placental testing was negative for choriocarcinoma. ultrasound demonstrates a hypoechoic hypervascular mass. mri brain demonstrates cutaneous confinement of the solid avidly enhancing glabellar mass. ct shows a peripherally enhancing liver mass with a masslike area of consolidation in the right lung. initial pet/ct demonstrated fdg avid liver and lung metastases with a small focus of residual activity at the glabella consistent with incomplete resection. follow-up pet/ct showed astoundingly rapid re-growth of the glabellar mass and enlargement of the hepatic and pulmonary masses just 12 days later demonstrating the extremely aggressive nature of this cancer. 3month follow-up pet/ct showed significantly decreased size and activity of the metastases consistent with a treatment response. in a series of 208 infants with cutaneous metastases, the following diseases presented with cutaneous involvement (ordered most to least common): leukemia, langerhans cell histiocytosis, neuroblastoma, rhabdoid tumor, rhabdomyosarcoma, primitive neuroectodermal tumor, choriocarcinoma, and adrenocortical carcinoma. pathology slides (2017) 47 (suppl 2):s297-s pediatr radiol unique teaching points: considered one of the fastest growing tumors, infantile choriocarcinoma classically presents with hepatomegaly, anemia, failure to thrive, and precocious puberty between 0 days and 5 months of life. left untreated, the disease is usually fatal within 3 weeks of presentation. a solitary cutaneous metastasis can be mistaken for infantile hemangioma both clinically and radiographically. atypical mri appearance is one important clue that can suggest an alternative diagnosis. pet/ct may be useful for staging and follow-up. a rare case of ovarian juvenile granulosa cell tumor associated with ollier's disease -generalised mesodermal dysplasia p. joshi; pune/in to demonstrate a rare case of mesodermal dysplasia -association of ovarian granulosa cell tumour with enchondromatosis case presentation: two year 8 month old girl presented with precocious puberty i.e thelarche. left hand radiograph showed the radiological age corresponding to chronological age, suggestive of peripheral precious puberty. the patient subsequently underwent a sonography which revealed a pelvic mass probably arising from the right ovary ? sex cord stromal tumour. a mri of the abdomen and pelvis confirmed the pelvic mass and revealed multiple bone lesions in the right hemipelvis -on the side of the tumour she was later operated. hpe of pelvis mass revealed juvenile granulosa cell tumour. ultrasound pelvis images reveal a solid pelvic mass, probably ovarian in etiology mri pelvis also reveals multiple bone lesions unique teaching points: the aim of the poster is to create awareness about this association. the bone lesions should not be mistaken for metastasis juvenile granulosa cell tumour of the ovary (jgct) is a well-known sexcord stromal ovarian neoplasm. ollier's disease is a rare, non hereditary mesosermal dysplasia consisting of multiple enchondromas. the association of granulosa call tumour with asymmetric ipsilateral hemiskeletal distribution may indicate generalised mesodermal dysplasia as there is also association of jgct with maffucci's syndrome, other dysplastic conditions such as microcephaly, facial asymmetry,' and potter's syndrome. review of literature showed 11 previous cases of juvenile granulosa cell tumor associated with enchondromatosis, three associated with maffucci's syndrome, and the rest with ollier's disease goldbloom's syndrome is a paediatric idiopathic disease characterized by transient bone marrow oedema with recurrent crisis of bone pain, periosteal hyperostosis, fever, increased inflammatory markers and dysproteinaemia. a case series of wbmr studies in goldbloom's syndrome is reported and differential diagnosis discussed. case presentation: a 9-year-old female girl was admitted to our paediatric department because of daily crisis of bone pain of the lower limbs, associated with fever spikes, limping and nocturnal awakenings. no history of trauma was reported. laboratory tests showed mild anaemia (hb 8.2 g/dl), thrombocytosis (plt 680000/mmc), increased inflammatory markers (ers 75 mm/h, crp 7 mg/dl), high streptolysine o and dnase-b antibody levels (aso 4280 iu/ml and adn-b 6310 ui/ml, respectively). throat swab was positive for group a β-haemolytic streptococcus (gas). unusual dysproteinaemia, characterized by hypoalbuminemia (2.8 g/dl) with increased a1, a2 and g globulinaemia, was noted. x-ray examinations of both legs resulted normal. wbmri showed markedly delineated, high and homogeneous hyper-hypointensity respectively in stir/t1 of the distal tibialperoneal meta-diaphysis of both legs (fig1a,b). distal metaphysis of femur, humerus, radius-ulna and proximal tibia were also homogeneously mildly hyperintense on stir sequences bilaterally (fig1a). bone biopsy revealed signs of chronic inflammation. infectious and neoplastic diseases were ruled out and the diagnosis of gs with dysproteinaemia seemed conceivable. steroid treatment was started in association with indomethacin, leading to a prompt resolution of the clinical picture within a few days. the follow-up stir total body mri, performed after 10 months, showed the complete resolution of bone oedema. (fig2 a,b) the sock sign is a pathognomonic whole-body magnetic resonance imaging (wbmri) feature of goldbloom's syndrome (gs).it is a well marked, symmetric, homogeneous and high bone marrow hyperintensity, localized both at the distal tibial and peroneal meta-diaphysis, which looks like a pair of socks. objective: left ventricle hypoplasia is generally thought as a part of hypoplastic left ventricle syndrome or aortic hypoplasia. it is estimated that about 15-20 ml/m2 left ventricle volume is needed in order to support systemic circulation. less than that volume generally precludes biventricular repair. however conditions associated with severe preload decrease such as total anomolous pulmonary venous return (tapvr) should be considered in the differential diagnosis. tapvr presenting as hypoplastic left ventricle syndrome is presented in this study. six month old female patient admitted to emergency service with symptoms of fever, dyspnea and coughing. emergency staff started intravenous antibiotic theraphy and from medical records learned that she has been followed for partial anomolous pulmonary venous return (papvr) and atrial septal defect (asd). lung x-rays revealed pulmonary edema. echocardiography was performed and revealed very small left ventricle, papvr and 13 mm wide asd. ecg gated cardiac ct was requested with the prediagnosis of hypoplastic left ventricle syndrome. ct images revealed dilated right cavities, very small left ventricle, pulmonary edema, tapvd and peritoneal fluid plus hepatomegaly. we then retrospectively searched our archive and found she was diagnosed as papvr when she was 10 days old. all the cavities that time, were normal sized. according to these we confirmed our diagnosis as tapvr and hypoplastic appearing cavities due to reduced preload and right chamber dilatation due pulmonary overcirculation. surgical team decided to perform corrective operation and they confirmed our diagnosis unique teaching points: small left ventricle cavity in an infant need not to be due to intrinsic hypoplasia. whenever we experience such a situtation we should search for other reasons of pseudohypoplasia in order to give a chance for corrective surgery instead of palliative procesures. we present a case report of kimura disease, a rare benign chronic inflammatory disease that involves the deep subcutaneous tissues and lymph nodes of the head and neck. we report the case of a thirteen year old male who presented with a right sided facial mass which had been present for two years but had enlarged rapidly in the preceding three months. us and mr were interpreted locally as an arteriovenous malformation. review of these examinations and catheter angiography performed at this quaternary referral centre favoured a vascular tumour. subsequent percutaneous biopsy demonstrated angiolymphoid hyperplasia with eosinophilia and blood tests showed a serum eosinophilia, consistent with kimura disease. us shows a mass consisting of scattered heterogenous foci within the fat with multiple large feeding vessels. contrast enhanced mri demonstrated a solid, homogenously enhancing, mass with multiple vascular flow voids from the right external carotid artery branches. catheter angiography showed tumour blood supply from branches of the right transverse facial artery and distal right ima. the dominant supply arose superficially from the transverse facial artery. kimura disease is a rare chronic inflammatory disorder of unknown aetiology that involves the deep subcutaneous tissues and lymph nodes of the head and neck region, most common in asian men in the third decade and sporadic in the non-asian population. the histopathological and biochemical characteristics are eosinophilic lymphfolliculoid granuloma, increased eosinophils in the peripheral blood and increased ige levels. whilst ultrasound and mri are effective imaging modalities, imaging alone does not allow confident differentiation from malignant lesions and biopsy is necessitated. kimura disease has a benign indolent course with an excellent prognosis following surgical excision although local recurrence has been reported. increased naa: is it surely canavan disease? e. varga, p. barsi, g. rudas; budapest/hu leukodystrophies are a group of rare genetic, metabolic diseases that affect the central nervous system, mainly the brain. each type of them is caused by a specific gene abnormality that leads to abnormal development or destruction of the white matter of the brain. the differential diagnosis are made on the basis of clinical and neuroradiological signs. there are some diseases which show typical changes on mr spectroscopy. we present a case of a 12 year-old boy, who has been investigated due to somatomental retardation and muscle dystrophy since his six months of age. his perinatal period was normal except of a nystagmus visible from his birth. the child has muscle dystrophy, spastic quadriparesis, contractures, scoliosis, truncal hypotonia and ataxia and mental retardation. we started examinations to find out the background pathology of his idiopathic encephalo-myopathy. the brain mri showed a bilateral, symmetrical white matter signal alteration, which referred to some kind of metabolic (2017) 47 (suppl 2):s297-s pediatr radiol disease. the mr spectroscopy revealed decreased cholin and increased naa levels, which are typical of canavan disease. despite of this, the clinical aspects and the location of the involved brain areas were more typical of pelizaeus-merzbacher disease (pmd). the pmd is a genetic disorder, which is originated of the mutation of the proteolipid protein gene (plp1) located on long arm of x-chromosome (xq21-22) . this gene has an impact on growth of the myelin sheath. various types of mutations (deletion, duplication, point mutation, insertion) of plp1 gene lead to various severity of clinical picture. all form of mutations show decreased naa level on spectroscopy, except the duplication of plp1 gene. in connection with our case, we present briefly the clinical and neuroradiological differences between the two entities. magnetic resonance imaging findings in medium-chain acyl-coenzyme a dehydrogenase (mcad) deficiency l. talamanca, d. narese, m.c. rossi espagnet, l. pasquini, d. longo; rome/it we report serial brain magnetic resonance (mri) in a patient with medium-chain acyl-coenzyme a dehydrogenase (mcad) deficiency who developed acute encephalopathy. a 12-months-old girl was admitted in the emergency department of our hospital with sudden onset of acute encephalopathy with drowsiness. baseline laboratory investigations revealed severe hypoglycemia, hyperammonemia, hyperchloremic metabolic acidosis and hyperuricemia. the patient was treated with glucose solution infusion that resulted in a gradual resolution of symptoms. the first brain mri, performed within 6 hours of onset of symptoms showed bilateral symmetric restricted diffusion on diffusion-weighted imaging (dwi) in the middle cerebellar peduncle, nucleus caudatus, putamen and periventricular white matter; the adc map showed reduced diffusivity (fig 1) . the second mri, at 72 hours after the onset, revealed bilateral and symmetric hyperintensity on t2-weighted images in the middle cerebellar peduncle, nucleus caudatus, putamen and periventricular white matter. dwi showed restricted diffusion in both globus pallidus (fig 2) . a single voxel h-mrs study performed by placing a roi in the right nucleus lenticularis revealed increased values of gaba and glutamine (fig 3) . a further mri was performed 4 weeks after the first neuroimaging and indicated widespread atrophy and the appearance of a hyperintense signal in t2-wi in both globus pallidus while dwi did not reveal any remarkable signal abnormality. single-voxel mrs of the same region showed a normalization of gaba and glutamine values. brain mri showed bilateral symmetric restricted diffusion on diffusionweighted imaging (dwi) in the middle cerebellar peduncle, nucleus caudatus, putamen and periventricular white matter; the adc map showed reduced diffusivity the second mri, at 72 hours after the onset, revealed bilateral symmetric restricted diffusion on diffusion-weighted imaging (dwi) in both globus pallidus. a single voxel h-mrs study performed by placing a roi in the right nucleus lenticularis revealed increased values of gaba and glutamine. mcad is an enzyme of the mitochondrial b-oxidation of fatty acids, an essential source of energy for cells during stress. mcad deficiency is the most common genetic disorder of fatty acid oxidation. the clinical manifestation of the disorder is typically precipitated by stress due to fasting, vomiting, fever or muscular exertion and occurs in the majority of cases before the age of 2 with the onset of acute hypoketotic hypoglycemia. clinical features of this decompensated state include seizures and lethargy proceeding to coma and death in the absence of prompt treatment with intravenous dextrose infusion. mcad deficiency usually appears in an acute form and has high morbidity and mortality rates; early diagnosis is therefore extremely important in order to promptly begin treatment and obtain a complete recovery from symptoms. mr can play a significant role in the early diagnosis of the decompensated state of the disease; in our case dwi revealed the presence of lesions with a bilateral symmetric topographic distribution that strongly suggested a metabolic disease leading to acute encephalopathy. a full-term male neonate (3 days old) with external perineal anomalies was referred to our hospital. the physical perineal examination revealed a bifid scrotum containing palpable testis and a normal configured penis located at the bottom of the bifid scrotum. two soft masses of 3 and 2 cm respectively, divided from a cutaneous notch, were located below the bifid scrotum and on the right of the midline. the rear biggest mass was normal epithelized, instead the other one was a rugged pigmented mass, which resembled the scrotum (figure 1 ). there were no additional abnormalities of the external genitalia. the other peduncolar mass, located between the right scrotum and the posterior mass, had fluid content. a mild hydrocele in the right scrotum and a sliding testis on the left side were also revealed. us examination showed a hyperechoic solid tissue, corresponding to the rear biggest perineal mass. the other peduncolar mass, located between the right scrotum and the posterior mass, had fluid content (figure 2) . a mild hydrocele in the right scrotum and a sliding testis on the left side were also revealed. mri also confirmed two perineal peduncolar masses: the biggest and posterior one, was made up by homogeneous fatty matter without contrast-enhancement after intravenous gadolinium injection (figure 3 ). the patient underwent excision of perineal masses and no complications occurred in the surgery. the histopathological examination of the perineal masses revealed two areas with different histological features: the first one was characterized by the presence of smooth muscle bundles dispersed in the dermal collagen, instead the other contiguous area showed abundant mature adipose tissue in the deep dermis and hypodermis ( figure 5 ). at last the rugged swelling mass was definitively diagnosed as as without testis tissue inside, and the rear mass was diagnosed as lipoma. the physical perineal examination revealed a bifid scrotum containing palpable testis. two soft masses of 3 and 2 cm respectively, divided from a cutaneous notch, were located below the bifid scrotum. us examination showed a hyperechoic solid tissue, corresponding to the rear biggest perineal mass. the other peduncolar mass, located between the right scrotum and the posterior mass, had fluid content mri confirmed the presence of two perineal peduncolar masses: the biggest and posterior one, was made up by homogeneous fatty matter without contrast-enhancement after intravenous gadolinium injection. neonates presenting with perineal masses are uncommon. these anomalies can occur isolated or more rarely in combination with other abnormalities such as uro-genital or ano-rectal anomalies or with contiguous subcutaneous tumors. when perineal masses are found, with prenatal diagnosis or during a newborn physical examination, it is important to look for any associated congenital anomalies or subcutaneous tumors by using imaging. to describe and emphasize the significance of the "half-moon" sign in pelvic mri. a 13-year-old adolescent, karate athlete, was submitted with left hip pain, decreased range of movement and asymmetry in thigh circumference. markers for infection or inflammation were negative. frog-leg radiograph was negative for hip effusion, slipped epiphysis and equivocal for a left trochanteric abnormality. mri demonstrated a half-moon pattern of bone marrow edema at the left intertrochanteric area and at the major trochanter, surrounding an apophyseal low-intensity lesion. ap radiograph and limited ct confirmed the presence of a lytic lesion with sclerotic margins, containing calcified chondroid matrix. chondroblastoma was histologically confirmed following excision. mri, coronal stir sequence, demonstrates semilunar-shaped hyperintense area abutting the growth plate and the cortex of the femoral neck, consistent with the half-moon sign. note edema surrounding an apophyseal low-intensity lesion and soft-tissue edema. ct confirms a typical apophyseal lesion with sclerotic margins containing chondroid matrix. unique teaching points: "half-moon" sign refers to a semilunar shape of bone marrow edema at the intertrochanteric area of the hip with its base located at the cortex of the femoral neck. this distribution differs from the distribution of edema in metaphyseal and metaphyseal-equivalent osteomyelitis. "half-moon" sign has been described in patients with stress fractures and osteoid osteomas. to our knowledge, this is the first case of chondroblastoma exhibiting this sign. whenever the "half-moon" pattern of edema is identified at pelvic mri scans, a thorough search for an occult fracture line or a nidus corresponding to an osteoid osteoma or a chondroblastoma is mandatory. mr elastography (mre) is a noninvasive imaging technique that quantitatively measures liver stiffness and provides an estimate of the degree of fibrosis. our aim was to evaluate the feasibility of performing mre using both gradient echo (gre) and echo planar (epi) sequences on siemens scanners. a dedicated mre of the liver was performed on a 3t mr scanner (magnetom® skyra, siemens) with a pediatric mechanical (2017) 47 (suppl 2):s297-s pediatr radiol driver (courtesy of mayo clinic) over the right upper quadrant. an axial t2 blade with fat saturation, a coronal t1 vibe dixon and axial diffusion weighted imaging (dwi) were obtained. elastograms were obtained using both an axial standard gre and a works in-progress (wip) epi sequence. for the gre sequence, 5 different slices were selected and each scanned sequentially. the epi sequence incorporated 5 different slices in just one series. images were post-processed placing regions-of-interest (roi) and measuring the stiffness in kilopascals (kpa). for each sequence and each slice the stiffness mean was measured and then the average of the means was obtained. a spleen elastogram was simultaneously generated, without changing the mechanical driver location, and mean stiffness was also calculated. based on cutoffs in the literature, values were considered abnormal if liver stiffness >2.9 kpa and spleen stiffness >3.6 kpa. our initial experience shows that mre is feasible on siemens scanners using both gre and epi sequences. epi sequences are a promising addition to standard gre. prone versus supine ultrasound positioning for evaluation of urinary tract dilation (utd) in children c. maya 1 , y. gorfu 2 , e. dunn 1 , k. darge 1 , s. back 1 ; 1 philadelphia/us, 2 addis ababa/et objective: ultrasound (us) is used in the initial evaluation and surveillance of utd in children. utd classification systems, including the 2014 multidisciplinary consensus, assess anterior-posterior renal pelvic diameter (aprpd) and calyceal dilation. there is currently no consensus regarding optimal patient positioning-prone versus supine-during us assessment of utd. this study was performed to determine if there is a significant difference in the measurement of the aprpd, presence of calyceal dilation, or resulting utd consensus score obtained between supine and prone positions. two raters retrospectively reviewed renal bladder ultrasounds of patients with utd of one or both kidneys. technically adequate ultrasound examinations of orthotopic kidneys that were imaged in both supine and prone positions were included. those with renal anomalies or prior surgery were excluded. aprpd measurements, as well as central and peripheral calyceal dilation, were documented in both prone and supine positions. a postnatal utd consensus score was assigned to each kidney based only on these features. 146 kidneys (77 left) in 89 subjects had utd in either the supine or prone position. mean age was 0.41 years (range: 0.01 -1.97 y). female to male ratio was 1:3 (21/68). the interclass correlation (icc) of the aprpd between raters was 0.88 and 0.87 in the supine and prone positions respectively (ps<0.001). central calyceal dilation was found in 97/146 supine kidneys and 102/146 prone kidneys by rater 1 and 94/146 supine and 99/146 prone kidneys by rater 2 (kappa 0.92). peripheral calyceal dilation was found in 54/146 supine kidneys and 65/146 prone kidneys by rater 1 and 50/146 supine kidneys and 62/146 prone kidneys by rater 2 (kappa 0.89). as such the results are presented as one. the aprpd tended to be greater when prone with a strong correlation between prone and supine measurements (0.92, p<0.001). the mean difference between supine and prone aprpd was 1.1 mm (p< 2.2). in 15 kidneys, calyceal dilation was seen in the prone position and not supine while 1 kidney had central calyceal dilation only when supine. the utd score differed between supine and prone in 13/149 kidneys, with all but one higher when prone. in 10 other kidneys, the aprpd differed between positions however concurrent calyceal dilation resulted in no change in utd class. as a screening tool, performing ultrasounds in the prone position may help identify more kidneys with utd. further research is needed to determine if these differences are clinically significant. during the evaluation of magnetic resonance enterography (mre), diffusion restriction (dr) has been utilized as a marker for bowel inflammation, but in our practice we commonly see dr in otherwise normal segments of jejunum. the purpose of this article is to assess the dr in normal loops of jejunum on mre and to determine if there is a correlation between dr and luminal distention, age, magnet field strength, and bowel segment location. a retrospective analysis of subjects with a normal mre and normal clinical work up (based on available clinical history, endoscopy reports, serum white blood cell count and inflammatory markers, and stool samples) was performed. the abdomen was divided into 4 quadrants. if available, 2 loops of jejunum were randomly chosen in each quadrant. two radiologists independently evaluated these same loops of jejunum for the following: luminal distension, wall thickness, and enhancement pattern. additionally, the loops were then evaluated for the presence or absence of dr. inter-rater reliability was determined. disagreement was resolved by consensus. presence or absence of dr was correlated with luminal distension, age, magnet field strength (1.5 versus 3 tesla), and abdominal quadrant. one hundred ninety-seven loops of jejunum were evaluated in 39 patients. not all subjects had jejunal loops in all quadrants. sixteen subjects (41%) had jejunal loops with dr for a total of 29 loops. one loop had increased wall thickness and another increased enhancement but both did not demonstrate dr. no other loops demonstrate increased enhancement or wall thickening. for the presence or absence of dr, inter-rater reliability was fair (kappa=0.39). there was no correlation between the presence/ absence of dr in relation to luminal distension, age, magnet field strength, or quadrant location. of the 16 subjects who had a single loop with dr, a 2 nd loop with dr was found in 50%. 14 year old who presented with nausea. mr enterography demonstrates no bowel thickening or abnormal enhancement. a. coronal haste demonstrates the craniocaudal position of the axial diffusion sequence for reference (line). 14 year old who presented with nausea. mr enterography demonstrates no bowel thickening or abnormal enhancement. b. axial diffusion weighted seqeunce (b=800) shows diffusion restriction within loops of jejunum (arrow) within the anterior abdomen. 14 year old who presented with nausea. mr enterography demonstrates no bowel thickening or abnormal enhancement. c. corresponding adc map demonstrates low signal within the jejunal wall consistent with diffusion restriction (arrow). diffusion restriction in normal loops of jejunum on mre was present in 41% of patients. if dr is seen in an otherwise normal segment of jejunum, this can be considered non-pathologic. a patient with a loop of jejunum with dr is likely to have an additional loop of jejunum demonstrating dr. there is no correlation with dr of normal jejunum with luminal distension, magnet field strength, or patient age. our data may help reduce overestimation of disease burden when clinically applied. imaging findings in the newborn with meconium peritonitis that require surgery p. caro dominguez 1 , a. zani 2 , a. daneman 2 ; 1 cordoba/es, 2 toronto/ca objective: meconium peritonitis is a rare condition caused by an in-utero bowel perforation resulting in spillage of meconium into the peritoneal cavity and subsequent calcification. the role of prenatal and postnatal imaging is to identify infants who require surgery. the aim of this study was to evaluate the role of postnatal imaging in meconium peritonitis and to correlate the radiologic and sonographic patterns with the need for surgery. imaging studies in infants with meconium peritonitis performed between 1999 and 2014 at our institution were reviewed separately by a pediatric radiologist, a pediatric radiology fellow and a pediatric surgeon. patients were divided in a surgical and a non-surgical group. clinical, surgical and pathology reports were reviewed to validate the diagnosis. statistical analysis: comparisons between sonographic and radiographic findings and patterns in the surgical and non-surgical groups were performed using unpaired t-test and chi-square. during the study period, there were 37 infants with meconium peritonitis managed at our institution. in the 23 (62%) who needed surgery, the most frequent surgical findings were idiopathic perforation, jejunal and ileal atresia. ultrasound identified more cases with hepatic calcifications, meconium pseudocyst, ascites and pneumoperitoneum than radiography and radiography more cases of small bowel obstruction. ascites identified with ultrasound (p=0.01) [fig 1] and bowel obstruction [fig 2] diagnosed either with ultrasound (p=0.04) or radiography (p=0.01) were associated with the need for surgical intervention. one third of children with meconium pseudocysts (4/12) [fig 3] , did not require surgery. diffuse peritoneal or hepatic calcifications as an isolated postnatal finding were not associated with the need for surgery. both radiography and ultrasonography give valuable information to the surgeon to take the decision for surgery. dilatation of bowel loops and ascites detected postnatally with radiography and/or ultrasound require surgical intervention in children with meconium peritonitis. interestingly, a large proportion of infants with meconium peritonitis can be managed conservatively. 0.17 -17.4) . those included had complete fmru analysis, dti (b=0 and b=400, 20 directions), and upjo configuration in at least 1 kidney. cases with motion artifact (n=9), post-pyeloplasty (n=3) or duplex collecting systems (n=3) were excluded. pelvicalyceal dilation grade (pcd), corticomedullary differentiation (cmd), and functional parameters were included. pyeloplasty following fmru was recorded. dti tractography was reconstructed using a fractional anisotropy (fa) and an angle threshold of 0.10 and 55°, respectively (figure 1) . user-defined regions-of-interest (roi) of the renal parenchyma, excluding the collecting system, were drawn to quantify dti parameters: mean fa, apparent diffusion coefficient (adc), tract length and tract volume. the relationships between dti quantitative parameters and fmru parameters were analyzed. age and adc (roi) (p<0.01, r 2 =0.36), tract volume (p<0.01, r 2 =0.77) and tract length (p<0.01, r 2 =0.60) were positively correlated. age and fa (roi) (p<0.01, r 2 =0.46) were negatively correlated. there was a correlation between fmru parenchymal volume and tract volume (p<0.01, r 2 =0.80), but median volumes were higher on dti (tractography=98.5 cm 3 vs. fmru=60.52 cm 3 ; p<0.01). of the 16 children, 12 had pyeloplasty, 1 had nephrectomy, 2 were managed conservatively and 1 was lost to follow-up. fa was significantly lower in kidneys that went on to have pyeloplasty in comparison to those without pyeloplasty, but the 95%ci and the iqr overlapped (table 1) . the adc, tract length and tract volume were similar between these groups (table 1) . there was no difference between the adc of fa values in kidneys with and without pcd or cmd (p>0.11). linear hierarchical regressions controlling the age did not show a significant relation between adc and cortical or renal transit times (p>0.68), but lower fa values were related to a higher renal transit time (p<0.01, r 2 =0.103). table 1 . quantitative dti parameters between kidneys with and without pyeloplasty following fmru. renal adc, fa, tract volume and tract length change with age but tractography overestimates renal parenchymal volume. there was a tendency towards a lower fa in kidneys that went on to pyeloplasty. otherwise, none of the quantitative parameters evaluated in this study differentiated degrees of upjo. echo-enhanced voiding urosonography (eevus) has become an important imaging tool in urodiagnostics; however, it has been observed that during eevus the premature destruction of ultrasound contrast agent microbubbles might occur. the purpose of this study was to evaluate the possible causes of contrast vanishing during investigations and propose the protocol to avoid false negative results. eevus was performed in 163 children from april to december 2016. sonovue mixed with saline solution in a plastic bottle is applied by continuous flow through the urine catheter. the collected data according to the protocol in this prospective study was completed in 105 children, aged from 2 weeks to 10.25 years. the protocol included general patient information, indication for eevus, duration of eevus in minutes, and the presence of vesicoureteric reflux. extensive data about sonovue were recorded: charge number, expiration date, time since opening, amount of initially administered contrast (ml sonovue/ml saline solution), grading of the initial contrast opacification of the bladder, the need for immediate readministration of contrast (dose), grading of contrast opacification during examination, and the need for readministration of contrast later in the course of the examination (dose). in addition, the data regarding bladder (ratio real/predicted bladder volume, wall thickness, ureter dilatation), saline solution, the size of urine catheter (french), and the type of antibiotic prophylaxis were collected. child observation included grading of crying and muscle stiffness. normal contrast opacification of urinary tract during examination was found in 87/105 children, while in 18/105 (17.2%) the contrast opacification was insufficient. in 12/18 (72.2%) microbubble destruction occurred during the first minute, in 4 (22.2%) in 5 minutes, and in 1 in 13 minutes after the beginning of contrast administration. the reason for unsatisfactory contrast opacification at the beginning of the eevus is probably due to small urine catheter size (25% of children with fr6 catheter had insufficient opacification compared to 13.3% with fr8 in whole cohort), time since the contrast is opened (more than 3 hours in 4 children), and insufficient bladder emptying at the beginning of the procedure. the reason for microbubble destruction later in the course of the examination is bladder overfilling in combination with increased muscle stiffness and strong crying, which led to increased bladder pressure. there was no correlation between the type of antibiotics and microbubble destruction. we should be aware of possible false negative vur results during eevus caused by premature microbubble destruction. patients with fontan-type palliation of univentricular congenital heart disease have elevated central venous pressure due to their passive pulmonary flow. the altered circulation has a negative impact on several visceral organs, and these patients have chronic liver congestion. they are at risk of developing hepatic fibrosis and cirrhosis with potential malignant transformation. these changes can occur from only a few years after fontan palliation, making early detection and grading of major importance. the patchy pattern of hepatic changes makes liver biopsy an unreliable diagnostic tool. magnetic resonance imaging (mri) t1 mapping has been suggested as a technique for non-invasive assessment and quantification of hepatic fibrosis/cirrhosis. the aim of this study was to compare two different t1 mapping sequences of the liver in adolescents with fontan palliation, and in healthy controls. materials: 15 adolescents (15-17 y) with fontan circulation and 7 young healthy adults (18-24 y) were included as a part of an ongoing national population-based study. all underwent mri (1.5 tesla) pre-and post-gadolinium contrast, including two types of t1 mapping of the liver. a 3d t1 volumetric interpolated breath-hold examination (3d vibe) sequence with dual flips with b1 correction and a modified look-locker inversion recovery (molli) sequence. t1 relaxation times (ms) were measured by placing five standardized circular regions of interest (roi) in the mid-section of the liver and one in the spleen (fig 1) . statistical analysis was performed comparing measurements pre-and post-contrast, between sequences, and patients and controls. there was a significant difference in the measurements between molli and 3d vibe with increased values for the latter. within each sequence there were small, but significant regional differences in relaxation times (table 1). the same pattern was seen in pre-and post-contrast images in both groups. there were significantly increased native t1 times on both sequences in all regions in the fontan group as compared to the controls, but not post contrast. t1 relaxation times differ between the t1 mapping sequences, molli and 3d vibe, pre-and post-contrast. t1 mapping of the liver revealed significantly increased native t1 times in adolescents with fontan palliation compared to healthy slightly older controls. these findings suggest hepatic fibrosis/cirrhosis, but may also represent a component of congestion. diagnostic accuracy of ultrasound, computed tomography and wedge portography in the work-up for mesenterico-rex bypass in children with extrahepatic portal hypertension s. toso, r. breguet, m. annoshiravani, s. terraz; geneva/ch to identify the diagnostic accuracy of ultrasound (us), computed tomography (ct) scan and portography (wedge hepatic vein portography or direct portography) in the pre-operative work-up of mesenterico-rex bypass performed for extrahepatic portal hypertension in children. we conducted a retrospective analysis of pre-operative imaging for mesenterico-rex bypass in our tertiary hospital over the last 12 years. we analyzed all patients between the ages of 0-16 years, with extrahepatic portal hypertension necessitating surgical treatment that underwent us, ct and portography. three reviewers independently analysed the patency of the left portal vein, mesenteric vein, splenic vein and the presence of communication between the left and right portal vein on preoperative imaging with correlation to surgical findings. statistical analysis of diagnostic accuracy was performed. eleven patients underwent mesenterico-rex bypass for portal hypertension secondary to portal vein thrombosis. two patients had partial liver transplant. ct with ultrasound correlation was sufficient in responding to the preoperative criteria in 72% (8/11) cases. portography was useful in the 27% (3/11) cases where ct could not respond to preoperative criteria, in particular the presence of left-right communication. there was good inter-rater correlation for each modality and good correlation of findings between modalities. in the majority of cases the use of ultrasound and ct is sufficient for preoperative planning for mesentrico-rex bypass. portography is mandatory in cases with large intra-hepatic cavernoma, where the left-right communication could not be confirmed on ct. contemporaneous clinical data was reviewed where available, and a clinical decision on disease severity and activity on a likert scale made with and without imaging. fifty-three patients underwent mre and bowel us in the specified timeframe (29 male; median age 13.02 years, range 4-16 years). twenty patients had sufficient contemporaneous clinical information to be analysed. inter-observer variability for the imaging scores was assessed using bland-altman plots. where variability was beyond pre-determined limits, the studies were consensus reviewed. mean scores were used for the studies within accepted limits of variability. there was no significant difference between total mre and us scores (wilcoxon signed-rank test z=1.13, p=0.26). at the bowel segment level, there was no significant difference between the mre and us segment scores for the ileum and terminal ileum (wilcoxon-signed rank test, z=0.72, p= 0.472), but significant differences were present between the imaging scores for other bowel segments, with mre identifying more abnormalities. there is a significant positive correlation between mre and clinical consensus scores (spearman's rho=0.598, p=0.0053) and between us and clinical consensus scores (spearman's rho =0.657, p=0.0016). imaging caused a refinement to the original clinical assessment in 8 of the 20 cases, with jejunal and ileal disease the most common reason for 'upgrading' a score and absence of any detectable abnormality on us and mre the most common reason for 'downgrading' a score. we found good agreement between mre and us for total patient imaging scores, ileal and terminal ileal scores. both mre and us scores correlated well with the gold standard clinical consensus, with imaging altering the original clinical decision in 40% of cases. although us detected fewer abnormalities than mr, it correlates marginally better with the clinical consensus, suggesting it is at least equally clinically valuable. background: differentiating between acute osteomyelitis (om) and acute bone infarct (bi) in children with sickle cell disease (scd) is a challenge for clinicians and radiologists, particularly when blood cultures are negative. although bone aspiration is the gold standard test for om diagnosis, it is an invasive procedure and infrequently performed. magnetic resonance imaging (mri) has shown a potential role in differentiating between acute bi and acute om. the goal of this case series is to evaluate the utility of fluid signal on unenhanced fat-suppressed (fs) t1-weighted mr sequence in distinguishing acute bi and om in children with scd. methods: we reviewed a total of 22 children with scd admitted with long bone pain during the one -year study period 2015-2016 attributed to either an acute bi or an acute om. twelve of 22 patients with available bone aspiration, blood culture, and mri data were evaluated for fluid signal, marrow signal and other criteria. of 12 patients, nine patients were diagnosed as acute bi and two patients had acute om and one with coexisting bi and om. the diagnosis was based on the fluid signal on t1 unenhanced t1 fs mr images as compared to aspiration cytology in which eight of nine patients with bi had hyperintense fluid signal on non-contrast t1 fs mr images while one of two patients with om demonstrated hypointense fluid signal. the last patient was diagnosed as a probable coexisting lesion (om&bi) based on a giant well demarcated hypointense marrow signal with an extraosseous hyperintense fluid signal. in acute bi, an abnormal hyperintense subperiosteal or paraosteal fluid signal is frequently observed on unenhanced t1-fs weighted images. this finding was present in the majority of cases in our study population regardless of age, sex or site in the appendicular skeleton. mri fluid signal characteristic on unenhanced t1 fs shows promise as a criterion to differentiate between acute bi and om. role of mri to assess skeletal age in pediatric celiac disease s. bernardo, m. martino, a. laghi, e. tomei; rome/it objective: coeliac children are often subject to weight loss and lower somatic growth rate, compared to healthy children of the same age. the purpose of this study was to asses the feasibility of magnetic resonance imaging (mri) of the hand and the wrist to assess skeletal age and growth delay. we enrolled in our study 39 coeliac children (13 males and 26 females) affected by histological proven coeliac disease, with a chronological age ranged between 5 years and 1 month and 16 years and 4 months (mean age of 10years, +/3 years and 8 months standard deviation). a single mri sequence (t13d se, acquisition time: 1 minute 31 seconds) of the hand and wrist in coronal plane was performed of each patient to estimate the skeletal age. patients' data were compared with a population of normal subjects. the preliminary results showed a delay in skeletal age in children affected by coeliac disease in 85,7% of the simple study, with a delay of maturity of 0.83 years (+/-2,2 years of sd). only 3 children showed advance mri skeletal age when compared to normal subjects. mri of hand/wrist to assess skeletal age may be considered as a reliable indicator of somatic growth. mri, without radiation exposure, can be an used as a diagnostic tool in skeletal delay. it could play an important role in the follow up of coeliac children, after glutenfree diet. the prevalence of metaphyseal injury and its mimickers in otherwise healthy children under two years of age p. eide, å. djuve, r.e. gjøsaeter, k.f. forseth, a. nøttveit, c. brudvik, k. rosendahl; bergen/no objective: metaphyseal lesions in infants and toddlers are believed to have a high specificity for inflicted injury, however, normal metaphyseal irregularities may mimic pathology and lead to overdiagnosis. during the period 2010-2015 all children between 0 and 2 years, seen at the a&e department in bergen (bergen legevakt) due to an injury, and who had radiographs taken, were included. data on previous injury, age, sex and injury mechanism were drawn from the medical notes and pacs archive. all radiographs were reviewed by two researchers and an experienced paediatric radiologist, registering the following: number, site and type of fractures, signs of healing (yes, no), bone structure (normal, pathological) and metaphyseal appearances (shape (normal, metaphyseal collar, metaphyseal irregularity), injury). the study was approved by the institutional review board. six hundred one children (293 girls) between 2 and 24 months of age (mean 17.8 months) were included, of whom 218 (109 girls) had a total of 275 fractures. one hundred eight of the fractures (39.3%) involved the forearm, followed by leg-fractures (59/275, 21.5%) and fractures to the clavicle (37/275, 13.5%). one epiphyseal separation and one metaphyseal lesion (without a history of trauma) were seen. one thousand three hundred twenty metaphysis were analysed, of which 212 (16.1 %) were defined as either irregular (105/1320, 8.0 %) or demonstrating a metaphyseal collar (107/1320, 8.1 %). metaphyseal lesions with a history of trauma did not occur in otherwise healthy neonates and infants under 2 years of age, indicating that this type of fracture has a particular mechanism. metaphyseal irregularities are frequent, particularly around the knee, and should not be mistaken for clms to evaluate whether mri might be used for age estimation, based on greulich-pyle (gp) atlas criteria. 1.5tesla mri of the left hand was conducted in 60 adolescents, and subjectively evaluated by two blinded radiologists. for sequence optimization, coronal mri sequences (t1 tirm, t1 vibe-3d-we, and t1 se) and a left hand x-ray were compared in ten patients (eight male, two female; mean age, 13.5 years). the ages of 50 healthy volunteers (17 s375 (2017) 47 (suppl 2):s297-s pediatr radiol male, 33 female; mean age, 15 years) were assessed from coronal t1 vibe-3d-we. bland-altman plots, intraclass correlation coefficients (icc), and logistic regression models were calculated. coronal t1 vibe-3d-we achieved the best image quality. the correlation between estimated patients' ages on x-ray and mri was high. icc showed high inter-observer agreement (0.95 for x-ray, 0.97 for mri). the estimated age of the healthy volunteers tended to be older than their chronological age. the probability of overestimation was higher in girls than in boys. coronal t1 vibe-3d-we of the left hand is feasible for skeletal age estimation by gp criteria with a high readers' agreement. the likelihood of overestimation of healthy children makes it necessary to develop a new hand atlas representing changes since the 1950s. to assess the relationship between the radiographic findings of metabolic bone disease (mbd) and serum biochemical markers in preterm infants. preterm infants in our neonatal intensive care unit between january 2014 and september 2016 were included. two readers retrospectively reviewed the wrist radiography for grading according to mbd severity. we recorded the levels of alkaline phosphatase (alp) and phosphorous (p) immediately after birth, on the same day of the first wrist radiography (alp-s, p-s), the highest alp levels before the first wrist radiography (alp-hb) and during follow-up (alp-h), and the lowest p levels before the first wrist radiography (p-lb) and during follow-up (p-l). patients were subdivided into four groups according to mbd severity determined by wrist radiography for the first analysis, and were divided into two groups according to mbd presence for the second analysis. one-way analysis of variance with a tukey multiple comparison and the student's t-test were used for statistical comparisons in the two analyses, respectively. a receiver operator characteristic (roc) curve was constructed to determine the optimal cut-off values of the biochemical markers for the radiological prediction of mbd. of the 159 patients, 94, 39, 19, and 7 infants were classified into grades 0 1, 2, and 3, respectively. in the first analysis, alp-s, alp-hb, and alp-h were significantly different between grades 0-1 and 2-3 (all p<0.001). plb was significantly different between grades 0 and 2 (p=0.001) and p-l was significantly different between grades 0 and 2 or 3 (p<0.001 or p=0.001). in the second analysis, alp-s, alp-hb, alp-h, p-s, p-lb, and p-l were all significantly different between the two groups (p<0.001). the roc curve of alp-h showed the largest area under the curve values (0.752, 95% confidence interval=0.676-0.828; p=0.039) for detection of a radiographic change. the optimal cut-off value of alp-h was 473.5 u/l, and the sensitivity and specificity were 81.5% and 47.9%, respectively. the first wrist radiography was obtained at 8.3 ± 5.1 weeks after birth, and alp-h was measured at 6.9 ± 5.3 weeks after birth. the cut-off value of alp for the prediction of abnormal radiological changes in wrist radiography was determined to be was 473.5 u/l. our findings indicate that the highest alp level at around 6.9 weeks after birth could be a valuable predictor of radiological mbd in preterm infants, including those with very low and extremely low birth weights. quantitative grading of tmj synovitis in children with jia-influence of mr-coil, timing after contrast-injection and location of measurements on joint-to-muscle enhancement ratio a. hamardzumyan schmid, c. kellenberger; zurich/ch objective: assessment of signal intensity ratio between joint space and longus capitis muscle on contrast-enhanced mri has been proposed as reliable method across different mr-scanners and protocols for grading temporomandibular joint (tmj) arthritis in juvenile idiopathic arthritis (jia) with a cut-off of 1.55 for diagnosing synovitis. the aim of this study was to investigate potential influences on such enhancement ratios (er). retrospective evaluation of 14 contrast-enhanced mr-studies of 28 tmjs in 7 girls with jia (age 11.3±4.3y) obtained at two occasions with two different coils on a 1.5t scanner. joint-to-muscle er were calculated from signal intensity measurements in different joint compartments, muscles and sequences obtained with varying delay after contrast-injection, and compared with paired sample t-test. er of tmjs without synovitis (n=10) and tmjs with synovitis (n=18), determined by qualitative criteria, were compared to er reported in the literature. superior and inferior joint space to longus capitis muscle er for normal tmjs (2.2±0.9; 2.6±0.7 respectively) exceeded 1.55 in all but one case (figure) and for tmjs with synovitis (3.3±1.1, 3.8 ±1.1) were significantly higher than in 211 cases with synovitis from the literature (2.5±0.8, p≤0001). the same er were higher when obtained with dual-ring coil (3.7±1.1; 4.1±0.9) than with multichannel surface coil (2.2±0.7; 2.6±0.8; p≤0.0002). while er to longus capitis muscle were higher than those to pterygoideus muscle for both coils (p≤0.008), er to pterygoideus muscle did not differ between coils (p>0.2). not considering the timing of the scan, er to pterygoideus muscle were highest in the inferior joint space (1.65 ±0.63), followed by the anterior joint recess (1.52±0.44) and superior joint space (1.49±0.62). comparing images acquired immediately after contrast injection to later images (median delay 11min, range 5-15min), pterygoideus muscle er in the superior (1.2±0.4 to 1.8 ±0.7) and inferior (1.2±0.3 to 2.0±0.6) joint space increased substantially (p<0.0001), while er in anterior recess showed no significant increase (1.5±0.4 to 1.6±0.5, p=0.18). conclusion: joint-to-muscle er are clearly dependent on 1) the signal profile of the mr coil with muscles located further away from the coil providing higher er, 2) the time of image acquisition after contrast-injection with later obtained images providing higher er, and 3) where the joint signal intensity is measured. as these factors need to be accounted for, the described normal and pathologic ranges of joint to longus capitis muscle er cannot be generalised for every mr-system and imaging protocol. integration of 3d c-arm ct images with navigational software provides real-time fluoroscopic guidance during percutaneous interventions in the interventional radiology (ir) suite. a trajectory, drawn from skin entry point to the target lesion on the 3d c-arm ct data, is overlaid on intraprocedural fluoroscopy for real-time needle guidance. this study describes our experience with syngo iguide (siemens) needle guidance software in a range of clinical applications in the pediatric ir suite, including technical success, radiation dose and procedure time. in this irb approved study, all percutaneous interventions performed in the ir suite using syngo iguide over a 3-year period were included. cases were classified by procedure type; for each type, mean effective radiation dose (msv) was estimated using pcxmc program (v2.0.1.3, stuk) and procedure times were evaluated. forty-five patients (25 male, 20 female; mean age: 11±6 years) underwent iguide-assisted interventions including: bone biopsies -35/45 (22 pelvic, 7 lumbar, and 6 lower extremity), intra-articular steroid injections -5/45 (4 sacroiliac, and 1 temporomandibular joint), lumbar punctures -2/45, percutaneous catheter placements -2/45 (cecostomy, and chest tube placement) and bone biopsy with radiofrequency (rf) ablation -1/45. iguide was used in particular for the cecostomy procedure due to high sub-hepatic cecal pole position, and in the chest tube procedure due to the presence of loculated pneumothoraces. all procedures were technically successful. the diagnostic bone biopsy rate was 97.7%. the mean estimated dose and procedure times for each procedure type are listed in table 1 . sonography of neonatal spine (sus) is a simple, non-invasive, quick, relatively inexpensive method to evaluate lumbar spine anomalies in infants less than 4 months of age. unossified posterior neural arches allow beam penetration to obtain high-resolution images of the intra-spinal contents. sus is carried out at the bedside, does not utilize radiation & requires no sedation. linear array transducers with extended field-of-view permit diagnostic sensitivity equal to mri. factors affecting mri resolution like patient movement, pulsation & vascular flow do not affect sus. we use sus as first-line screening test in neonates with lumbosacral cutaneous stigmata & spinal dysraphism (sd) associated syndromes. this was a prospective study approved by the institutional ethics committee. thirty five children (age range of 5 to 15 years) with clinically suspected and complicated pulmonary tb were enrolled in the study. lung mri and ct scan was performed in all the patients. the sensitivity, specificity, positive predictive value (ppv), and negative predictive value (npv) of lung mri in detection of radiological findings that were considered highly suggestive or diagnostic for tb, were calculated, with ct as the standard of reference. lung mri performed equivalent to ct in detection of pleural effusion, mediastinal/hilar lymphadenopathy and lung cavitation with sensitivity and specificity of 100%. agreement between ct and mri in detection of each finding was almost perfect (k: 0.8-1). lung mri was found to be comparable to ct scan for detecting various radiological abnormalities which were highly suggestive for tuberculosis. being a radiation free imaging modality, it has the potential, particularly in children, to replace chest radiographs and ct scan in the coming years. to evaluate differences of myocardial strain assessed by feature tracking using ssfp cardiac mri sequences between pectus excavatum (pe) patients and healthy volunteers. in this prospective study, cardiac mri was performed in 10 pe patients (with a pathologic haller-index above 3.25) and 10 healthy volunteers (5 males and females, respectively; age range 13-30 years) including short-and long-axis cine-ssfp sequences on a 3t scanner. post-examination analysis included standard cardiac volumetry with measurements of the biventricular ejection fractions (ef). additionally, manual biventricular contouring by an experienced radiologist, and subsequent automated strain assessment using dedicated software (circle cvi 42 ®) was performed. longitudinal, radial, and circumferential peak systolic strain and strain rates were analyzed for both ventricles. left-ventricular ef was normal in all patients. five pe patients had a normal right-ventricular ef, in 5 pe patients rvef was slightly impaired (40-44%), all healthy volunteers had a normal rvef. compared with healthy volunteers, pe patients showed a significantly higher apical left-ventricular strain (radial: 53±16.8 vs. 26±8%, p<0.001; circumferential: -23.7±4.8 vs. -15.3±3%, p=0.001) and strain rate (radial: 3.76±1.05 vs 1.71±0.33s -1 , p<0.001; circumferential: -1.92±0.51 vs. -1.08±0.48s -1 , p=0.002). mid right-ventricular strain (radial: 14.4±6.5 vs. 8.2±2.6%, p=0.019; circumferential: -9.7±3.3 vs. -6.4±1.5%, p=0.019) and strain rate (radial: 1.07±0.45 vs. 0.63±0.24s -1 , p=0.015; circumferential: -0.79±0.27 vs. -0.5 ±0.14s -1 , p=0.011), as well as apical right-ventricular strain (radial: 25.6±8.6 vs. 16.5±8.6%, p=0.009; circumferential: -15.9±3.8 vs. -11.1±4%, p=0.019) and circumferential strain rate (-1±0.26 vs. -0.72±0.24s -1 , p=0.029) were also significantly higher in pe patients than in healthy volunteers. left-and especially right-ventricular radial and circumferential strain and strain rate increased from the bases to apices in pe patients. longitudinal strain and strain rate did not differ significantly between pe patients and healthy volunteers. myocardial strain assessed by cardiac mri differs significantly between pe patients and healthy volunteers. as the chest wall deformity usually leads to a compression of the basal parts of the ventricles, higher values of myocardial strain in the mid and apical ventricles in pe patients might indicate a compensation mechanism to enhance especially right ventricular output against sternal compression. to determine the normal range of the haller index (hi) value, and its dependence on the age, sex, and respiratory phase. evaluate the possibility of reduction of the effective dose (ed) of ionizing radiation using a single-slice ct scan technique. the retrospective-prospective study included 165 patients (av. 12y, sd 5y). it consisted of 3 parts. the prospective study included evaluation of ct scans performed by single-slice technique in 30 patients with pectus excavatum both in inspiratory and expiratory phase, without topogram. hi was measured in each patient in both respiratory phases. in retrospective study, 100 ct scans of the chest in children without pectus excavatum were analyzed to determine normal range of hi values depending on the age (0-5y, 5-10y, 10-15y, 15-18y) and gender. the retrospective study also included the analysis of another 30 ct scans in patients who were operated or diagnosed with pectus excavatum. in the latter group of patients the average value of ed of ionizing radiation was calculated, and the values were compared with the average ed obtained using low-dose ct examinations applied in the new protocol (single-slice technique). the normal value of hi was 2.23±0.32. a significant positive correlation between age and value of hi was found. older patients had higher hi (0-5y: 2.01±0.29, 15-18y: 2.35±0.33). results of mann-whitney test did not demonstrate any difference between gender in the observed group, however girls had generally higher hi in all age groups. in the group of patients who were operated/diagnosed with pectus excavatum, hi was 3.34±0.88. the average value of hi in inspirium in children with diagnosed deformity was 2.69±0.76, while in expirium it was 3.49±1.19. only 3/32 (9%) patients had hi value over 3.25 (a boundary value for surgical treatment) during inspirium, while 13/32 (41%) patients had it in expirium, which showed statistically significant difference (p=0.012). single-slice ct technique during the inspiratory and expiratory phase showed average ed of 0.02msv, which is an equivalent of 1 chest xray. it reduced ed more than 20 times in comparison with low-dose whole chest ct. the value of haller index increases with the age and in expiratory phase. we propose the single-slice ct technique without topogram in expiratory phase, as a sufficient and reliable technique in evaluation of haller index and preoperative preparation. mps iva is a lysosomal storage disorder caused by a deficiency of nacetylgalactosamine-sulfatase. main symptom is a systemic skeletal dysplasia. affection of the vascular system has not been described yet. our goal is the analysis of the vascular system in patients with mps iva, based on the example of the aorta. in a retrospective study, 32 patients with mps iva were included. the aorta in its course from 4 th thoracic vertebrae to 10 th was analyzed on the basis of 49 craniospinal mr and 4 ct examinations. to describe the course of the aorta, the area around the vertebral body was devided into 5 equal parts (fig.1) . high buckled arteries in relation to the length of the affected aortal part were indicated as aortal kinking, and a moderate twist in relation to the length of the affected aortal part as aortal tortuosity. results: twelve of 32 patients had an aortal kinking, 10 of 32 patients an aortal tortuosity, 4 of these had moderate and 3 strongly tortuous aortae. seven patients had a normal aortal course, 4 couldn't be analyzed. one patient revealed both, aortal kinking and tortuosity. this study reveals the occurrence of aortic tortuosity in patients with mps iva. we suggest that this complication could be due to glycosaminoglycane deposition in the aortic intima, which may be s379 (2017) 47 (suppl 2):s297-s pediatr radiol associated with an increased vulnerability of the vascular wall. we conclude that the examination of the vascular system should be included in regular follow-up protocols. lung ultrasound in the diagnosis and follow-up of pneumonia in children -is it really as reliable as chest x-ray? s. balj-barbir, j. lovrenski, s. petrović; novi sad/rs to investigate the role of lung ultrasound (lus) both in the diagnosis and follow-up of pneumonia in children. a prospective study was carried out in the regional children's hospital, and included 130 children (av. 2.9y, sd 2.93y) with clinically suspected pneumonia, in whom initial lus and subsequent chest x-ray (cxr) were performed within 24h. the final diagnosis of pneumonia at discharge was used as a reference test to determine the reliability of lus, cxr, clinical and laboratory findings in the diagnosis of pneumonia. children with pneumonia formed a study group, while the control group consisted of children without diagnosed pneumonia. lus finding of subpleural lung consolidation was considered a diagnostic sign for pneumonia. the children with lus signs of pneumonia were followed-up until complete resolution of the lus findings. there were from one to five follow-up lus examinations performed. a final diagnosis of pneumonia was confirmed in 105/130 (80.8%) patients, and 77/105 (73.33%) were hospitalized (av. 10.84, sd 6.19 hospital days). in diagnosis of pneumonia lus, cxr, auscultation, elevated crp, and tachypnea showed sensitivity of 94.3%, 93.3%, 79%, 80% and 32.38%, and specificity of 100%, 92%, 56%, 48% and 100% respectively. lus detected lung consolidations in 99 of 105 children with final diagnosis of pneumonia, and in 84/99 patients lus showed air-bronchogram (figures 1, 2) . lus was superior to cxr in the detection of lung consolidations smaller than 15mm. interstitial lung changes were detected by lus in 50/105 (47.62%) patients, and by cxr in 21/105 (20%). lus and cxr detected pleural effusion in 24/105 (22.86%) and 14/105 (13.33%) patients respectively. mcnemar's test showed no statistically significant difference, and cohen's kappa coefficient showed almost perfect agreement (0.864) between us diagnosis of pneumonia and final diagnosis of pneumonia. during the follow-ups, moderate to substantial agreement between lus and clinical evaluation of the course of the disease was obtained (k=0.406-0.621). in children with complete clinical and incomplete us regression of pneumonia, consolidations of less than 15mm were the most prevalent finding. the average time period until complete resolution of the lus findings was 16.3±10.24 days. children with us detected pulmonary consolidations larger than 50mm were statistically significantly longer hospitalized than others. lung ultrasound in the diagnosis of pneumonia in children is just as reliable as radiography, and should be included in the standard diagnostic protocol. the latest uk nice guidelines for childhood tb contact screening require that a chest x-ray (cxr) be requested only when mantoux or igra testing is positive or if there is a documented reason e.g. clinical concern. nice clarifies the role of cxr in determining treatment choice. we aimed to review cxr referral and treatment in the current climate of european migrant screening. retrospective review of 148 paediatric referrals to the infectious diseases clinic for tb contact screening of whom 125 had cxrs, from october 2009 to august 2015 and correlation with the medical notes. a panel of 3 paediatric radiologists independently interpreted radiographs in the clinical context of tb contact screening and a majority decision was reached. of 148 patients referred to the infectious diseases unit, 125 underwent cxr in addition to a mantoux and igra test. of those 125 cxr's, 20 were reported as having features of pulmonary tb but only 16/20 (80%) were treated as active tb. eighteen of the 105 (17%) cxr's which were reported as having no features of pulmonary tb, were treated as active tb. of those 18, only 6/18 (33.3%) had a clearly documented reason. review of the 125 radiographs (mean age 14 years) by the panel of radiologists noted that all were of readable quality, 20 radiographs were in keeping with a diagnosis of tb, 6 were inconclusive and 99 were normal. the diagnosis of tb was based on lymphadenopathy in 19 and (2017) 47 (suppl 2):s297-s pediatr radiol milliary nodules in 1. parenchymal abnormality was seen in 8 patients [one was the milliary] and effusion was seen in 3. this correlated well with the initial radiology reports of duty radiologists. of the 125 who underwent cxr, referral information was available in 120.109 (90.8%) of these had been appropriately referred because of a +ve mantoux/igra. only 8 out of 11 (72.7%) of those who had cxr despite a -ve mantoux or igra, had a documented reason. according to nice guidelines, 20% of cxr reported positive for tb were not treated for active tb. this may represent a lack of clarity regarding the definition of 'latent tb'. furthermore, only a third of the 17% of patients who received treatment despite negative radiographs had a documented reason. the current migrant crisis requires clarity of x-ray definitions of latent tb to avoid the 20% under-treatment and 17% overtreatment identified in our population. is there really no cardiac problem for performing sports ö.i̇. koska, p. bayindir, h. alper; izmir/tr objective: sudden death in young is a rare condition excluding known anomalies and sudden infant death sydrome; but its consequences are devastating because they are so unexpected. %25 of them occur in a context of sports event. everyday parents of millions of children admit hospitals in order to get permission for participating in sports events. and after physical examination and ecg, physicians are expected to decide such an important issue. however there are a number of silent reasons that may lead to child to sudden death. altough we don't perform ct scans for such indications, we have encountered several cases with abnormalities that can lead to sudden child death and while reporting an examination, awareness of these devastating conditions may be usefull. we searched our database from 01.01.2016 to 01.01.2017 in order to see how often we diagnosed such a silent reason from the ct images that are performed for some reasons. as our center is a tertiary center we have performed 452 cardiac ct examinations in that period that are mainly for excluding or defining complex cardiac anomalies. in order to prepare a pictorial review of unexpected but ct detectable sudden cardiac death reasons, we excluded congenital heart diseases (namely obstructive, shunting or complex anomalies) and ecg detectable arrhytmic diseases. the non arrhytmic, non traumatic reasons for sudden cardiac death excluding congenital heart diseases in the papers are: hypertrophic cardiomyopathy (cmp) (%36), some coronary artery path and origin anomalies (mainly abnormal left coronary artery from pulmonary artery (alcapa), and interarterial path)(%24), increased cardiac mass (%10), dilated cmp (%9), marfan disease (%6), myocarditis (%3), ischemic heart disease (%2). we detected 18 examinations according to our inclusion criteria and selected one cases of each; rca path anomaly, alcapa, dilated cmp, hypertrophic cmp, subaortic discrete membrane and increased cardiac mass for presentation although sudden cardiac death is rare in young children it is a so devastating condition that it must be taken into account for every situation. awareness of silent conditions and active search of them may protect professionals from medicolegal issues and unpleasent results. to describe the spectrum of chest ct scan findings of pulmonary involvement in childhood langerhans cell histiocytosis (lch) and propose a simple scoring system to evaluate the profusion and distribution of the main lung lesions. one hundred forty-six chest ct scans of the 48 pediatric patients with pulmonary lch enrolled in the french national database for lch until april 2016, could be retrospectively and independently reviewed by 3 pediatric radiologists. for each ct scan a semi-quantitative analysis was performed for nodular opacities and cystic abnormalities. the chest was divided in 6 fields (upper, medium and lower field of the left and the right lung) and for each field, both for the nodules and the cysts the score was 0=no lesion, 1= lesions involving up to 25% of the parenchyma, 2=25-50%, 3= 50-75% and 4=more than 75%. of 29 patients evaluated at diagnosis, 18 patients (62%) presented with nodules, 13 patients (45%) presented with cysts and 6 patients (21%) presented a combination of both nodular and cystic lesions. on the initial ct scan, median nodules total score was 1 and median cysts total score was 0. during subsequent ct scans almost the same percentage of patients with nodules (30 patients, 62 %) was found but we observed an increase number of patients with cysts (30 patients, 62 %), median nodules total score was 1 and median cysts total score was 2. the distribution of nodules and cysts was symmetric in the upper, medium and lower fields with an involvement of costo-phrenic angles in 68% of the cases. patients with pneumothorax (13 patients, 27%) had a higher cysts median score (10) than patients without pneumothorax (1). we found alveolar condensation in 12 patients (25%). none of them showed signs of infection at bal examination or any improvement after a treatment with a standard antibiotic therapy while they did show regression under the lch standard regimen of chemotherapy. we proposed a score for semiquantitative analysis of distribution and profusion of nodular and cystic lesions on chest ct scans that can be a useful tool in pediatric population to monitor lung involvement. we found a significant correlation between pneumothorax and a high cysts median score. alveolar condensation could be considered as a possible manifestation of plch in children. lung bases involvement was found in 68% of the cases, representing an important different imaging feature from adult plch. high resolution computed tomography for chronic small airway disease in hiv infected adolescents a.-m. du plessis 1 , s. andronikou 2 , h. zar 1 ; 1 cape town/za, 2 bristol/uk early treatment with antiretroviral therapy (art) and decline in infected infants due to prevention of mother-to-child transmission has resulted in an increase in the population of hiv-infected adolescents. pulmonary disease is common among them. cxr is considered insensitive and terminology inconsistent. therefore, despite concerns related to radiation dose in paediatric patients, high resolution computed tomography (hrct) is the modality of choice for the evaluation of small and large airway pathology, prominent in chronic pulmonary disease. hrct findings are used for prognosis, treatment decisions and defining anatomic extent of bronchiectasis for surgical intervention. the aim of this paper is to demonstrate the spectrum, frequency and extent of airway pathology in hiv-infected adolescents using hrct. a nested sub study was undertaken within the cape town adolescent antiretroviral cohort (ctaac); a prospective, descriptive cohort study of 520 hiv-infected adolescents on art and 120 age matched hiv-s381 (2017) 47 (suppl 2):s297-s pediatr radiol negative controls. hrct was performed on 100 patients who demonstrated abnormal lung function (defined by forced expiratory volume in 1 second (fev1) of <85% and/or low lung diffusion capacity (dlco)). single phase, contrasted multi-detector volume acquisitions were performed from the thoracic inlet to the diaphragms at full inspiration and image data postprocessed to yield thin (0,6mm) and thicker slice images (5mm). three 1mm slices at 3 cm intervals were performed in full expiration. three radiologists interpreted the c t scans independently, with strict imaging definitions, and a majority decision was generated for each finding. ages of patients ranged from between 10 to 17 years with a mean of 14,2. there were 53 females and 47 males with a ratio of 1:0,8. bronchiolitis obliterans was seen in 70% of patients and bronchiectasis was demonstrated in 39%, 12% of which was classified as severe (involving either an entire lobe or more than 50% of at least 2 lobes). there was an absence of lymphadenopathy (a sign of primary tuberculosis (tb)), lymphocytic interstitial pneumonitis (lip) and post tuberculous apical architechtural distortion. miliary tb was identified in a single patient. ground glass was seen in 10% and consolidation in 13%. the majority of hiv infected adolescents with poor lung function demonstrated bronchiolitis obliterans strongly emphasizing the use of hrct for confirming small airways disease. hrct was also useful for demonstrating extent of associated bronchiectasis in 39%. hrct allows classification of patients into those with diffuse small airways disease requiring medical management and those with local disease requiring surgery. background: chronic recurrent multifocal osteomyelitis (crmo) is an autoinflammatory paediatric non-infectious bone disease. presenting symptoms are non-specific, prolonging diagnosis, and leading to deformity, morbidity and unnecessary procedures. imaging is critical to diagnosis, with whole-body mri (wbmri) commonly used in all stages of care. in our institution, a baseline whole-body coronal stir sequence is routinely obtained. aim: to determine lesion distribution and extent on baseline wbmri via retrospective panel review of all patients clinically diagnosed with crmo, and to determine any patterns of involvement that could facilitate earlier radiological diagnosis. method: all patients diagnosed with crmo since december 2009 using published bristol criteria were identified and baseline whole body mris reviewed. the reviewing radiologists were blinded to the original report and previous investigations. each mri was reviewed for focal lesions consistent with crmo. the extent of metaphyseal and epiphyseal lesions was categorized into involvement of thirds of the width of the structure. the wbmri of forty children (28 girls, 12 boys), averaging 12 years (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) were reviewed by the panel using a majority decision rule. three hundred three lesions were recorded, averaging 7.6 lesions (0-26). the tibia was most affected (83 lesions), most commonly the distal tibial metaphysis (25 lesions in 16 patients, 9 bilateral). rib, metatarsals and distal femoral epiphyseals lesions were common. humeral, hand and skull lesions were few. complete metaphyseal involvement, the 'smouldering physis', was most prevalent within the proximal and distal tibial metaphyses. although ranked seventh, the reportedly more common clavicular lesions were the site of the most florid lesions, demonstrating bone expansion and periosteal reactions. two clear patterns of involvement emerged. in patients with clavicular lesions, fewer overall lesions were observed (average 6.4), mainly affecting the axial skeleton and feet. patients with tibial involvement had a higher number of overall lesions (average 9.3), but few lesions outside the lower limbs. only four patients had a both clavicular and tibial lesions. twelve vertebral lesions and four cases of spodylo-discitis were identified; two at t5/6 level, one at t6/7 level, and one involving both t5/6 and t6/7. our series of 40 cases of crmo with baseline wbmri, one of the largest in the published literature, identifies the common sites that should be interrogated for involvement. this study also demonstrates potential as-yet undescribed patterns of skeletal involvement that can be used to aid radiological diagnosis and highlights a non-infective cause for spondylo-discitis. hepatic hemangiomas (hh) are the most common benign vascular tumors encountered in the pediatric population. two main types have been described congenital and infantile, which both display distinct clinical courses and biological features. hemangioendothelioma in differential diagnosis of hh is controversy. recent literature suggests that congenital hepatic hemangiomas present in a focal form, whereas infantile hepatic hemangiomas present in either a multifocal or diffuse form. the goal of this study is to evaluate the features associated with focal and multifocal hh. the records of 45 patients diagnosed with a hepatic hemangioma at a tertiary pediatric hospital from 1994 to 2015 were reviewed. we divided our series into 2 groups: focal or multifocal including diffuse form. clinical endpoints are: age of diagnosis, presence of cutaneous hemangioma, alpha-fetoprotein, thrombocytopenia, cardiac insufficiency. imaging endpoints were echogenicity on us (hypoechoic, hyperechoic or mixed), vessels density on color doppler (<2; 2-5, >5 cm 2 ). presence of calcifications, venous lakes, visible vessels and aortic tapering were assessed on us, ct-scan, mr and angio. treatment and outcome were analyzed. univariate and bivariate analysis were done. this study included 24 focal (9m, 15f) and 21 multifocal (17m, 28f) hh. antenatal diagnosis was done in 6 focal and 1 multifocal hh. focal lesions were associated with the presence of cutaneous hemangiomas (p<0.001) and calcifications (p<0.05). no other variable was significant. conservative management was decided in 12 focal and 11 multifocal hh. steroids (focal: 6, multifocal: 3), steroid-interferon (focal: 1, multifocal: 3), propranolol-steroid (focal:4, multifocal: 4) and surgery in one focal form. complete regression was observed in most lesions (focal: n=19, multifocal n=20), whereas incomplete regression <50% was observed in 4 patients (focal: n=3, multifocal: n=1) and 3 patients in the focal group with the pathology diagnosis of hemangioendothelioma. hepatic hemangiomas demonstrate a wide range of radiological features, with important overlaps in focal, multifocal or diffuse forms. focal and multifocal hh can be seen in congenital hemangioma, infantile hemangioma or hemangioendothelioma. the association of cutaneous infantile hemangioma in the focal group confirmed that the focal lesion can be seen in infantile hemangioma. however, calcifications are more frequent in focal hh which is described in congenital hemangioma or hemangioendothelioma. (2017) 47 (suppl 2):s297-s pediatr radiol symptomatic and asymptomatic meckel's diverticulum in the pediatric population -a retrospective analysis of imaging findings with histopathologic correlation n. abu ata, r. cytter-kuint, j. bar-ziv, i. hadas-halpern; jerusalem/il objective: though meckel's diverticulum (md) is a relatively common gastrointestinal anomaly, many of the symptomatic and most of the asymptomatic md's are often missed on abdominal imaging. our purpose is to describe the radiologic appearance of symptomatic and asymptomatic md in the pediatric population and to correlate the radiologic findings with histopathology. a retrospective analysis of all children diagnosed with md between 1/2004-10/2016 and had relevant imaging (n=38) was done. imaging studies-ultrasound (us), computed tomography (ct) and magnetic resonance imaging (mri) were retrospectively reviewed and evaluated for visualization of md in symptomatic and asymptomatic patients. findings were compared with the preoperative radiology report and the pathology specimen. symptomatic group (n=24): mean age 8.6±6 years, nineteen males. md presented with abdominal pain in 9 patients, small bowel obstruction (sbo) in 6 patients, gastrointestinal bleeding or anemia in 5 patients and intussusception in 2 cases. md was identified in 13 preoperative reports (54.16%) and retrospectively identified in 4 more cases (overall 17 patients, 70.1%). in 7 cases, an inflamed or perforated md were found. in 4 cases, mucosal lining resembling gastric folds was seen. inverted meckel and prominent tissue surrounding the diverticula were seen in 2 patients. in a single case md was misdiagnosed as a duplication cyst. asymptomatic group (n=14): mean age 10.9±6, eight males. md was not mentioned in any of the original reports and only 3 md's were identified retrospectively (21.4%). no mucosal abnormality or irregularity were noted. histopathology: ectopic gastric mucosa was found in 16/24 (66.67%) of the symptomatic patients vs. 2/14 (14.29%) in the asymptomatic group. all 4 patients with sonographic appearance of gastric mucosa had gastric mucosa in pathology (specificity-100%, positive predictive value-100%). md has a variety of radiologic appearances. it can be detected in most of the symptomatic patients but is almost undetectable in asymptomatic patients. heterotopic gastric mucosa is more common in the symptomatic group. inflamed gastric mucosa may have a typical appearance resembling a small stomach, a sign that was not described before and has both high specificity and high positive predictive value for gastric mucosa within a meckel diverticulum. preliminary results on dna damage from ct irradiation in pediatric patients i. dilevska, e. nagy, w. schwinger, e. sorantin; graz/at the increased radiation sensitivity in children, compared to adults, is a well-recognised fact in the pediatric radiology community. the high-dose irradiation induced dna damage has been well established, however the dosages that are clinically used in everyday ct procedures are so low, that it remains unclear how this severely affects the dna and can induce cancer in the long run. the aim of this study is to assess the effects of lowdose ionizing radiation from ct in children by establishing a standardization curve ranging from the high to the low, medically significant ctdi values. this is done by measuring the phosphorylation of the h2ax histone (γh2ax), which is considered a biomarker for quantification of radiation induced dna double-strand breaks (ddsbs). the detection of the γh2ax histone was done by two methods: immunofluorescence microscopy (im), which is an established method for detection and quantification of this histone and the new, promising flow cytometry technique (facs). for this study, 35 leucocyte samples ("buffy coats") were provided by the local transfusion department and these samples were irradiated with a clinical ct scanner (aqilionone, tmse) with values ranging from 2153,6 to 0,16 mgy ctdi. afterwards the samples were processed with both methods. for the immunofluorescence, twostep immunostaining was used with two different antibodies and the cell and foci counting were done on an olympus xc10 microscope, while the facs staining was done with a one-step antibody and the samples were measured on a navios flow cytometer (beckman coulter). comparable results were detected with both methods, with a good correlation between the facs and im, with a linear incline (r 2 >0.95) in the high and in the low dosages from 0,16 to 5.0 mgy ctdi. however, in the samples irradiated with doses below 5.0 mgy ctdi, there seems to be less phosphorylated h2ax than in the native samples. two possible explanations arise: a) low dose irradiation initiates repair that extends to ddsbs occurring naturally or b) low dose irradiation doesn´t cause phosphorylation of this histone, but affects other dna damage and repair pathways. the preliminary findings show that the facs analysis can be used as a valid replacement method for the labor-intensive if method in the higher dosages. however more analysis should be done to establish its accuracy in the lower regions since underlying mechanisms are not clear yet. a. turkaj 1 , g. cicero 2 , e. sorantin 1 , r. coroiu 3 ; 1 graz/at, 2 mesina/it, 3 cluj-napoca/ro there is only little information available regarding imaging procedures in the trauma setting of pediatric patients. such data can serve as a rational basis for running pediatric trauma units. the purpose of the paper is to investigate the number, types and distribution of imaging procedures in a tertiary pediatric trauma center serving children of about 1.2 million inhabitants with approximately 225.000 children. all trauma-caused admission to the emergency room and their imaging procedures were analyzed retrospectively occurring within a period of 15 months. a cohort of 263 patients (m:f=1.9:1) were analyzed. patients were grouped according to age into the following categories: neonates, infants, middle childhood, early adolescence, late adolescence. imaging procedures were classified into plain films, us, ct and mri. furthermore, the time of admission was noted and categorized in time slots 07:00-15:00, 15:00-20:00, 20:00-24:00 and 24:00-07:00. referral cause was divided in domestic accidents, motor-scooter-bicycle accidents, car accidents, sport injuries, falls from height and others. the average age was 9.5 ± 5.4 years, aligned in the following age-groups neonates 13 (5%), infants 68 (26%), middle childhood 42 (16%), early adolescence 58 (22%), late adolescence 82 (31%). a total of 364 imaging procedures were performed, of which 210 plain films (58%), us 81 (22%), ct 69 (19%) and mri 4 (1%). there was a statistically significant difference of imaging procedures due to age in particular in us and ct. regarding the timeslots: 07:00-15:00 ;111 patients (42%), 15:00-20:00; 118 patients (45%), 20:00-00:00; 31 patients (12%), 00:00-07:00;3 patients (1%). domestic accidents were the leading referral cause with 82 cases (31%) prevailed age groups were infants and middle childhoods corresponding for more than 75%. motorscooter/bicycle accidents accounted for 51 cases (19%) of which most were early and late adolescence (more than 85%), s383 (2017) 47 (suppl 2):s297-s pediatr radiol sport's accidents 38 (14.4%) equally shared among middle childhood, early and late adolescences. car accidents 37 (14.0%) cases and fall from height 22 (8,3%) did not show any prevalence according to the age groups. for the first time detailed data about imaging procedures at the emergency room for pediatric patients are now available. over half of the admissions (55%) occur outside regular work hours thus representing a challenge for the staff in duty and this fact should be considered in working schedules. due to strict interdisciplinary developed diagnostic pathways the number of ct examinations was reasonable low. head ct in a regional children's hospital without mri -effective doses and justification of clinical indications j. lovrenski, n. milenković; novi sad/rs to calculate effective doses (ed) for pediatric head computed tomography (ct), to determine the most common referral diagnoses, and the share of normal and pathological ct findings. a retrospectiveprospective study comprised all the children with performed ct examination (16-slice scanner) within a one-year period. pediatric ct protocols were used. the values of ed for head cts were calculated based on the two different models (shrimpton's and icrp publication 103). average ed for different age groups was expressed as the number of chest x-rays (cxrs) (1cxr 0.02msv). the most common non-traumatic referral diagnoses for head cts were determined, as well as percentage and type of pathological ct findings. a share of pathological ct findings was also determined for trauma as a referral diagnosis. head cts were represented with 649 (71%) in total number of 924 ct examinations within a one-year period. the different calculation models have shown the difference in ed values of up to 20.5%. eds for head cts were equivalent of 66 (15 years of age and older) to 140 (younger than 3 months of age) cxrs for one sequence of scanning. the most common non-traumatic referral diagnoses for head cts were: loss of consciousness, epilepsy, headache, convulsions, and vertigo. in this group of 273 patients, 86% of completely normal ct findings were found. pathological findings in this group consisted of the patients with the most common non-traumatic referral diagnoses were as follows: cortical atrophy (15 patients), arachnoid cyst (10), ischemia (6), porencephalic cyst (3), agenesis of the corpus callosum (1), chiari malformation -type i (1), open-lip schizencephaly (1), and tumor of the posterior cranial fossa (1). most common incidental, extracerebral pathology discovered included sinusitis and otomastoiditis. in patients with trauma as referral diagnosis, the share of pathological ct findings was 59.5%. it is necessary to get clinicians familiar with the extent of ionizing radiation that children are exposed to during the head ct examinations. a more careful selection of children for head cts is necessary in an every-day clinical practice, especially for patients with non-traumatic referral diagnoses. diffuse and symmetric diffusion restriction involving the white matter of the brain in patients with neonatal seizures j.-y. hwang 1 , y.j. lee 2 , y.-w. kim 2 ; 1 yangsan-si, gyeongsangnam-do/ kr, 2 yangsan-si/kr this study aimed to evaluate magnetic resonance (mr) imaging findings in patients with neonatal seizures focused on the diffuse white matter lesions on diffusion weighted image (dwi) in addition to clinical manifestations. a total of 55 neonates aged less than 1-week old underwent brain mr imaging for evaluation of neonatal seizures between november 2008 and december 2016. among them, 12 patients showed diffuse and symmetric pattern of high signal intensity on dwi. clinical, laboratory, and mr images were analyzed retrospectively. nine patients were males and three patients were females. patient age was 5.2 ± 0.8 days (range, 3-6 days). all the patients were born at full term. the most frequent month of the hospital visit was march (n=4) and january (n=3). eight patients showed generalized clonic seizure and four patients showed partial clonic seizure. stool viral test was performed in nine patients. among them, five patients were positive for the rotavirus and one patient was positive for the astrovirus. nine patients underwent cerebrospinal fluid analysis, however, all showed negative results. mr imaging was performed at 2.2 ± 1.6 days after onset of seizures. diffuse and symmetric diffusion restriction were distributed along the cerebral white matter tracts and both thalami (fig 1) accompanied with high signal intensity on either t2-weighted images or on the fluid-attenuated inversion recovery (flair) sequence. multiple foci of high signal intensity on t1-weighted images at the centrum semiovale that was affected on dwi were also observed. follow-up period was 11.3 ± 9.6 months (range, 1.8 -30.9 months) and developmental delay was encountered in three patients. six patients underwent follow-up mr imaging at the age of 8.4 ± 4.2 months (median, 8.5 months; range, 3.7-13 months). five patients showed volume loss in cerebral white matter on both sides of the brain and four patients showed high signal intensity of the periventricular white matter on either t2weighted images or flair sequences (fig 2) . myelination delay was not observed in follow-up mr images. diffuse and symmetric diffusion restriction involving the cerebral white matters can be seen in patients with neonatal seizures on mr imaging. our study shows that rotavirus is commonly encountered, but not exclusively detected in these patients. nevertheless, viral infection-associated encephalopathy should be considered when a patient is presented with characteristic clinical and mr findings. whole body mri on diagnosis and follow-up of neurofibromatosis type 1 d. grassi, v. tostes, e. caran, h.m. lederman; sao paulo/br demonstrate that whole body mri is effective on showing neurofibromatosis type 1 involvement of different regions of the body not known by the clinicians. review of 41 patients with neurofibromatosis type 1 (nf1) who underwent whole body mri throughout their follow-up with the majority of them had only brain and spine imaging studies. it was possible to demonstrate that whole body mri provides an overview of nf1 systemic manifestations and neurofibroma's extension beyond the clinic expectation. despite being rare, sarcomatous degeneration was suspected when there was any difference on the characteristics of the neurofibromas. whole body overview where its possible to see the neurofibroma's extension in right cervical region, scoliosis and multiple plexiform neurofibromas. only the biggest neurofibroma was detected by clinical exam. however it is possible to identify two others neurofibromas. whole body view of multiple plexiform neurofibromas. whole body mri is a radiation-free exam and it is useful on the diagnosis of nf1 and on patient's follow-up. it provides an overview of the systemic s385 (2017) 47 (suppl 2):s297-s pediatr radiol involvement and neurofibroma's extension beyond the clinical expectation. during patients follow up, it could also show tumor's characteristics modification, which was considered as a possible sarcomatous degeneration. accuracy of non-radiologists and lay-persons for identifying children with cerebral cortical atrophy from 'mercator map' curved reconstructions of the brain s. vedajallam 1 , a. chacko 1 , s. andronikou 2 , e. simpson 2 , j. thai 2 ; 1 east london/za, 2 bristol/uk objective: background: communication of cortical brain atrophy in children with term hypoxic ischaemic injury (hii) to parents and the legal fraternity contesting compensation rights can be very difficult using text and standard cross-sectional images. when demonstrating the cortex in hii, a single image of the brain surface, much like the way a map of the earth is derived from a globe, can be generated from curved reconstruction of coronal magnetic resonance imaging (mri) scans i.e. a mercator map. lay people's ability to identify abnormal scans from such maps without prior training requires evaluation before routine use. aim: to determine the sensitivity and specificity of lay people in detecting abnormal brain scans through review of mercator flat-earth maps of the brain, without prior training. ten mercator map images were provided to 100 participants with a distribution of 5 hii, 1 cortical dysplasia and 4 reported normal. participants were required to identify abnormal scans. sensitivity and specificity overall and for sub-groups were derived by averaging true positives and negatives; false positives and negatives. the results show a strong ability for lay-people to identify normal versus abnormal mri brain studies using mercator maps. the sensitivity and specificity in this group is 67% and 73% respectively. non-radiologist physicians and radiographers performed slightly better than lay people as expected. radiologists of course had very high sensitivity and specificity of 86% and 100%. the mercator map is therefore a viable tool in the communication of complex mr imaging to the lay-person. safety and efficacy of sphenopalatine ganglion blockade in childreninitial experience l. dance, c. schaefer, d. aria, r. kaye, r.b. towbin; phoenix/us objective: sphenopalatine ganglion (spg) blockade is known to be a safe and effective migraine headache treatment among adults. this paper will report the initial experience in the pediatric population with spg blockade. one hundred thirty-three procedures were performed in 85 patients ages 7 to 18 from february through november 2015. pre-intervention headache scores were recorded on a scale of 1 to 10. the procedure was performed supine with neck in hyperextension. anesthesia of the bilateral nares was accomplished with lidocaine spray and gel. contrast was injected using a sphenocath confirming catheter position. 4% lidocaine was injected. patients remained supine with neck in hyperextension for 10 minutes. post-intervention headache scores were recorded. mean pre-treatment score of 5.55 decreased to 3.28 post-treatment (δ2.27, 95% ci 1.34-3.20, p<0.0001). there were no complications. spg blockade is a safe and effective treatment for migraine headaches in children which results in decreased reliance on intravenous drug therapy. orbital masses represent a spectrum of benign and malignant lesions in children that can be challenging to diagnose and treat. imaging plays an important role in diagnosis, due to a potentially limited clinical examination and risks associated with biopsy. mr imaging is a powerful tool for imaging the orbit, due to the excellent tissue contrast it provides. yet conventional mri has a limitation in discriminate the benign from malignant lesions. diffusion-weighted imaging (dwi) is non-invasive rapid technique uses the water diffusibility to produce contrast among different kinds of tissues. our propose was to assess the role of dwi and calculated apparent diffusion coefficient (adc) values in characterization of the pediatric orbital masses regarding benignancy or malignancy. one hundred and thirty patients with recently diagnosed orbital masses and who underwent preoperative conventional mri and dwi were included in this study. the orbit was divided into six compartments: the eye globe, retroocular fat, optic nerve, lacrimal system, bony boundaries and extra-ocular muscles. the average adc obtained from each tumor was compared with the histopathological diagnosis determined from subsequent surgical sample. seventy girls and sixty boys with orbital masses were included in this study. their age was ranged from 1 month to 18 years. the globe is the seat of lesions in 43/130 cases, optic nerve in 27/130 case. seven cases have lesions in the lacrimal gland. forty-five of cases was diagnosed as having benign masses & 85 of cases have malignant lesions. there is a statistically significant difference between the mean adc value of the benign lesions (1.39±0.52 x10 -3 mm 2 /s) and the mean adc value of the malignant lesions (0.69±0.22 x10 -3 mm 2 /s) (p<0.001). the optimal adc cutoff value that was determined for discrimination between these lesions is: 1.075 x10 -3 mm 2 /s), with sensitivity of 97.14% and specificity of 75%. using conventional mri alone in predicting benign and malignant lesions has the sensitivity of 76% and specificity of 91% with 94% positive predictive value and 67% negative predicative value. combining dwi and conventional mri has increased accuracy, as the sensitivity and specificity were 95%, 86% respectively with 93% positive predictive value and 90% negative predicative value. (2017) 47 (suppl 2):s297-s pediatr radiol adc values provide an accurate, sensitive, fast, and non-invasive mean of characterization of pediatric orbital tumors. a priori tumor characterization is useful in timing and treatment planning for orbital tumors. utiliy of resting state fmri in children for preoperative language mapping l.-m. leiber, m. delion, a. ter minassian; angers/fr to assess if resting state fmri is able to detect language eloquent areas in childrens. six children, from 8 to 15 years old suffering from brain lesions were enrolled in this study. they underwent mri with one 3dt1 morphology session and three 10 minutes fmri sessions, including one resting state fmri and two language task induced activity fmri sessions. analysis was performed using a generalized linear model for the first one and a spatial independent component analysis approach for the two others. language maps were compared with cortical mapping obtained by intraoperative direct stimulation. language network was identified systematically by resting state session but not by task induced activity sessions. moreover, in two of the six patients, resting state fmri was able to detect eloquent areas found during intraoperative cortical mapping that were not present in task induced activity sessions. resting state fmri appears superior to task induced activity fmri in detecting language eloquent areas. is sclerotherapy an effective treatment option for ranulas or thyroglossal duct cysts in children? d. aria, l. dance, c. schaefer, r. kaye, r.b. towbin; phoenix/us to assess the utility of sclerotherapy in the treatment of ranulas and thyroglossal duct cysts materials: from 2015-2016, 8 patients varying in age from 16 months to 32 years were referred to the ir department for sclerotherapy. of the 8 patients, 6 had a diagnosis of ranula while 2 had the diagnosis of thyroglossal duct cyst by either mr, ct, or us. sclerotherapy treatments were performed with standard sclerosing agents, i.e. sotradecol 3% foam, absolute ethanol, and bleomycin. in the subset of patients with ranulas, sclerotherapy was commonly performed in accordance with salivary (submandibular and/or sublingual) gland botox injection or ethanol ablation. 22-gauge or 5f sheathed needles were used for us-guided access to the lesions, with ranula sclerotherapy being performed after placement of side-hole drainage catheters (5-10f) due to their increased viscosity. the preferred sclerosing agent was injected with dwell times ranging from 15 mins to 3 hours. salivary gland injection/ablation was performed under usguidance using a 22-gauge needle with volume injection targeted centrally within the gland or in the portion of the gland abutting the ranula. after treatment, all patients were scheduled for follow-up ultrasounds at a minimum of 8 weeks to assess lesion response or residual disease. a total of 23 sclerotherapy treatments were performed. of the 8 patients, 2 were lost to follow-up after single sessions for ranula and thyroglossal duct cyst. the other 6 patients all had follow-up ultrasounds after each of the remaining 21 sclerotherapy sessions. four of these patients showed initial improvement with either decreased size of lesion or lesion resolution while the other 2 showed no improvement with either stable or increased size on initial follow-up. the 4 patients who initially showed promising response unfortunately had recurrence on follow-up imaging and ultimately, demonstrated no favorable response to sclerotherapy after subsequent treatments regardless of whether treatment was combined with ethanol/botox salivary gland injection. in summary, all 6 patients who were successfully followed show no appreciable response to treatment for ranula or thyroglossal duct cyst. despite the emergence of clinical requests for sclerotherapy of ranulas and thyroglossal duct cysts, in our case series, sclerotherapy has not proven to be an effective treatment option using our current drug regimen. role of the susceptibility-weighted imaging (swi) in the neuroimaging of term newborns g. rudas, e. varga, p. barsi, l. kozák, ü. méder; budapest/hu objective: susceptibility-weighted imaging (swi) was introduced in the neonatal neuroimaging only a few years ago. we can find only a few publications about its advantages and disadvantages. according to our experience, swi is extremely useful not only for detecting bleedings but for the diagnosis of other diseases as well. during the last year we had 164 mri examinations on term newborns (0-14 days of life) and the swi gave additional information in 54 cases. we used a 3t philips insignia scanner. in the case of the questionable hypoxic-ischemic-encephalopathy (19 cases) and the metabolic diseases (5 cases) we could find increased signal intensity in the cortex; in the case of stroke we could find the thrombus itself in 6 cases; the avm were much clearer using the swi in 3 cases; at the pvl in 3 cases we could visualize the cysts better using swi; in the case of congenital heart disease (11 cases) and in the case of sinus thrombosis (4) we could find microbleedings and/or dilated veins; in 3 cases the position of the lateral ventricle drain or shunt was much clearer using the swi. the swi gave important additional information in 54/164 (33%). the swi is a strongly recommended new sequence at the mri examination of the term newborns' brain. a disadvantage of swi is that it requires ca. three minutes examination time (in contrast to t2* which is only 1 minute long). mechanical birth-related trauma: imaging of the "accidents of birth" a. chaturvedi, j.g. blickman; rochester/us objective: 1. to discuss definition, incidence and risk factors leading to "mechanical birth-related trauma" and compare these with existing literature. offer an organ-system based classification scheme encompassing the varied manifestations of birth-related trauma and describing the implications on care decisions. materials: the hospital imaging department database was searched for neonates who presented with history of difficult/traumatic birth at our obstetric center between january 1, 2013-june 30, 2016. search software used was primordial customised radiology solutions, san mateo, ca. the search terms used were "macrosomia", "shoulder dystocia", "instrumental delivery", "malpresentation", "cephalopelvic disproportion", "forceps" and "vacuum". initial and follow-up imaging and clinical data on these neonates was reviewed and compiled by two board-certified pediatric radiologists. the relevant literature was reviewed and findings compared. organ-system based classification scheme for birth-realted trauma. in our study, mechanical trauma of birth was seen to manifest within different organ systems, which have been listed below in the order of occurrence within our sample. injuries to the skull (sutural overlap, dents and fractures), scalp hemorrhages (subgaleal hematoma, cephalhematoma, caput). intracranial intraand extra-axial hemorrhages (subdural, subarachnoid, epidural, intraparenchymal). clavicle fractures neonatal brachial plexus injury. sternocleidomastoid hematomas. adrenal hemorrhages. cervical spinal cord contusions. schematic diagram depicting intra-and extracranial hemorrhages by location. 6-year-old with history of calvarial fracture at birth-fracture did not heal but enlarged secondary to leptomeningeal entrapment at the fracture sitean entity called "growing fracture" or "leptomeningeal cyst". multiple newborn organ systems can be injured from mechanical trauma of birth. our numbers compare favourably with the existing literature. mechanical birth-related trauma can occur simultaneously with hypoxic-ischemic birth injury. although most of these injuries spontaneously and completely resolve, long-term complications can be seen in some cases. few of these injuries are life-threatening. imaging plays a crucial role in diagnosis and follow-up, and can assist in decision making as well as in counselling the parents. ewing sarcoma of tibia in an infant girl a. seehofnerova, j. skotáková, i. červinková; brno/cz objective: ewing sarcoma (es) is the second most common primary bone malignancy in children. it histologically originates from neuroectodermal tissue and consists of small round blue cells. ewing tumour family is very close to primitive neuroectoderm tumour (pnet) family with diverse stage of differentiation, ewing sarcoma being less differentiated. approximately 50 % of the cases occur between ten and twenty years of age with slightly higher prevalence in male gender. nine-month-old caucasian girl presented to local surgery department after she had wedged her lower leg in a bed. the right lower leg was swollen and painful. she was initially diagnosed with a ligament injury and underwent standard treatment. oedema gradually disappeared, but swelling and pain increased after three weeks. she also suffered from a fever of 38.1°c (100.58 o f). at that point x-ray of her right lower leg was performed with report describing pathologically changed structure of tibia and she was referred to our university centre. (2017) 47 (suppl 2):s297-s pediatr radiol we made a second reading of the plain film, reporting sclerotic heterogeneous bone structure of the right tibial diaphysis and distal metaphysis, onion-like periosteal reaction with sunburst spiculation and cortical bone destruction. her laboratory results were: crp 7.2 mg/l, ld 6.2 μkat/l, nse 44.3 μg/l, ferritin 18 μg/l. crp has been raising for a week to 25 mg/ l, then decreased to normal level. differential diagnosis was established as a primary bone malignancy (especially es) or, less likely, an osteomyelitis. mri revealed pathological signal of bone marrow of diaphysis of the whole tibia with cortical scalloping and periosteal spiculated apposition. epiphyses were spared. dorsal cortical bone was interrupted with extraosseal spread of the process. intraosseal part enhanced heterogeneously, whereas extraosseal component enhanced almost homogeneously after contrast medium administration. total size of the tumour was assessed as 97x23.5x20 mm (22.8 ml) . adjacent muscles were oedematous with post-contrast enhancement. there were also few enlarged lymph nodes in popliteal region. results from the biopsy confirmed ews with positive ews/fli1 gene. tumour was assessed as a localized disease, enneking iib. patient underwent chemotherapy according to aews1031doc protocol and a knee-exarticulation with no traces of tumour in resection lines. nowadays she is in the first complete remission. x-ray: ap view mri: etw1_tse postcontrast, sagittal view, pre-treatment mri: etw1_tse postcontrast, sagittal view, after initial treatment unique teaching points: ewing sarcoma belongs to common primary bone tumours in children but is a very rare unit in infants. despite the age predilection it is necessary to consider this diagnosis even in children younger than one year of age. scimitar syndrome together with pulmonary sequestration and horseshoe lung: congenital pulmonary venolobar syndrome b.e. derinkuyu, h.n. özcan, y. tasci-yildiz, h g. cınar, u.a. orun; ankara/tr objective: congenital pulmonary venolobar syndrome (cpvls) comprises of a spectrum of pulmonary developmental anomalies. the main components of cpvls are hypogenetic lung partial anomalous pulmonary venous return, absence of pulmonary artery, pulmonary sequestration, systemic arterialization of lung, absence of inferior vena cava. minor components of cpvls include tracheal trifurcation, eventration and partial absence of the diaphragm, phrenic cyst, horseshoe lung, esophageal and gastric lung, anomalous superior vena cava, and absence of the pericardium. in this case presentation, we present a baby with scimitar syndrome, pulmonary sequestration, horseshoe lung and right aberran subclavian artery. a 3 month-old girl was admitted to our hospital with the suspicion of scimitar syndrome from a different hospital. she did not have any symptoms. the physical examination was unremarkable. on plain radiograph, the baby had dextrocardia. there was a doubtful tubular structure with the shape of scimitar and a nodular radioopacity behind the heart (figure 1 ). transthoracic echocardiography demonstrated the dextrocardia, atrial septal defect and the right pulmonary artery hypoplasia. afterwards, the ct angiography was done for confirmation of scimitar syndrome and other accompanying abnormalities. on the ct angiography, there was a partial anomalous pulmonary venous return to the suprahepatic inferior vena cava known as scimitar syndrome. besides this, there was a right pulmonary extralobar sequestration in the lung base. the arterial supply was arising from the celiac trunk, while the venous drainage was going directly to the inferior vena cava. therefore, the right lung was hypoplastic of which the tongue of the right pulmonary parenchyma passing between the aorta and heart, appearing confluent with the left lung in a horseshoe configuration. there was dextrocardia and right aberran s389 (2017) 47 (suppl 2):s297-s pediatr radiol subclavian artery. the patient was subjected to catheterization and angiography for treatment. on plain radiograph, the baby had dextrocardia. there was a doubtful tubular structure with the shape of scimitar and a nodular radioopacity behind the heart unique teaching points: the term cpvls is an umbrella to a group of pulmonary parenchymal and vascular anomalies that may present in combination. mdct is a helpful diagnostic tool in the preoperative evaluation for delineation of the components of this syndrome. congenital pulmonary venolobar syndrome refers to a wide spectrum of pulmonary developmental anomalies that may appear single or in combination. the main components of congenital pulmonary venolobar syndrome are hypogenetic lung (including lobar agenesis, aplasia, or hypoplasia), partial anomalous pulmonary venous return, absence of pulmonary artery, pulmonary sequestration, systemic arterialization of lung, absence of inferior vena cava, and accessory diaphragm. in this case presentation, we describe a child with scimitar syndrome, bilateral sequestration, hypogenetic lung (single lobed left lung) and right aberran subclavian artery. an 8 year-old syrian girl was admitted to our hospital with the history of heart defect. she did not have syncope or ciyanosis whereas she has easy fatigue and palpitation. on plain radiograph the anomalous draining vein was seen as a tubular structure paralleling the right heart border in the shape of a turkish sword ("scimitar") ( figure 1) . transthoracic echocardiography demonstrated the scimitar vein as well as large patent ductus arteriosus (pda), atrial septal defect and left pulmonary hypoplasia. afterwards, the ct angiography was done for confirmation of scimitar syndrome and other accompanying abnormalities. on the ct angiography, there was a partial anomalous pulmonary venous return to the suprahepatic inferior vena cava known as scimitar syndrome. besides this, there was a bilateral intralobar pulmonary sequestration in the lung bases. the arterial supply of the right side was arising from the celiac trunk, while the left side feeding artery was originating directly from the descending aorta. therefore, the left lung had a single lobe with single pulmonary vein draining to left atrium. there was a large pda and right aberran subclavian artery. the patient was subjected to catheterization and angiography for treatment. the right sided anomalous draining pulmonary vein and the feeding artery of the right sequestration were closed in the first session. the procedure was completed without any complication. afterwards, the closure of the feeding artery of the left pulmonary sequestration and the pda were planned in the next sessions. on plain radiograph the anomalous draining vein was seen as a tubular structure paralleling the right heart border in the shape of a turkish sword ("scimitar") unique teaching points: congenital pulmonary venolobar syndrome comprises a heterogeneous group of uncommon abnormalities that may occur in combination. diagnosis of congenital pulmonary venolobar syndrome can be confirmed by ct angiography that allows detailed evaluation of vascular, tracheobronchial, and pulmonary parenchymal abnormalities with a single short, noninvasive procedure. neck infection disclosing diagnosis of congenital fourth branchial arc anomaly in a girl h.n. özcan, z. aycan, b. ardıclı, m. haliloglu; ankara/tr objective: congenital branchial arc anomalies are rare entities. herein, we describe the imaging findings of acute suppurative infection of the neck caused by fourth branchial fistula in a child. case presentation: an 11-year-old girl presented to our pediatric emergency department with fever, left sided neck swelling and redness. her complaints were started five days ago. on her physical examination, there was a 4x4 cm, stiff, painful mass lesion with redness on the left side of the neck. blood count and thyroid function tests were in normal range; however, c-reactive protein level and erythrocyte sedimentation rate were elevated. neck ultrasonography revealed diffuse soft tissue swelling, a hypoechoic mass consistent with abscess in the left thyroid lobe and perithyroid tissue. the left lobe of the thyroid gland had poorly defined margin and a focus of air. contrast-enhanced neck mr imaging demonstrated an abscess in the left thyroid and perithyroid tissue ( figure 1) and enhancement of the soft tissue plane around the left pyriform fossa (figure 2 ). barium swallow revealed the sinus tract originating from the left pyriform sinus apex. the patient was operated after antibiotic treatment and sinus tract was surgically excised. the aim of this report is to describe three cases of right kidney wilms' tumor with cavoatrial tumor extension, referred to our institution between january and september 2016. case presentation: three children, two girls (3 and 7 years old) and one boy (2 years old) were admitted at the emergency service with cardiac failure symptoms; the latter had also liver failure. echocardiography showed right atrial thrombus in all three patients, as an extension of massive obstructive thrombosis of the inferior vena cava (ivc). abdominal ultrasonography revealed in all patients a right renal mass, associated to right renal vein thrombosis that extended to the ivc and to the right hepatic vein. contrast enhenced computed tomography confirmed findings. patients were treated primarily with chemotherapy before surgery, with partial regression of the thrombus in two patients and no response in one. (2017) 47 (suppl 2):s297-s pediatr radiol unique teaching points: wilms' tumor is the most common renal malignancy in children and its intravascular extension is a well-recognized event. incidence of tumor extension to inferior vena cava (ivc) is reported to be of 2-5% and intra-atrial extension of 0,2-1,2%. it occurs most commonly in tumors located in the right kidney (probably due to the shorter path of the right renal vein compared to the left one). this complication does not directly influence the prognosis of malignancy, but the degree of intravascular extension determines technical surgical strategy and increases difficulty of the surgical procedure, especially when there is intracardiac involvement, which increases morbidity. several classifications have been proposed in the adult age group, but due to the similarity of the degree of intraoperative difficulty, the same classifications are used in children. pritchett et al. (1986) described the relation between thrombus and hepatic vessels: level i -intrahepatic intravascular extension; level iiintrahepatic extension; and level iii -suprahepatic or atrial extension. staehler et al. (1987) proposed a different classification that was posteriorly modified and detailed by daum (1994) : stage i -small extension (thrombus size within ivc <5 cm); stage iilarge thrombus (> 5 cm within the ivc), but still below the hepatic vessels; stage iii -thrombus extending to the level and above the hepatic vessels; stage iv -intra-atrial thrombus. a 4 year old boy presented with a soft tissue mass in his forearm which appeared to have grown quickly in size over a period of three to four months. physical examination demonstrated a welldefined mass in the dorsal aspect of the forearm with no pulsatile bruit. intial differentials included a vascular anomaly or a sarcomatous lesion. the patient proceeded to have an ultrasound examination which revealed a very well-defined heterogenous subcutaneous mass, mostly solid in substance. the lesion measured 3.5 cm x 1.6 cm x 3.5 cm (transverse x length x depth). there was no evidence of muscle invasion. prominent internal arterial vascularisation was demonstrated and the mass was classed as inderminate in nature. subsequent mr findings demonstrated a mass with t1 signal isointense to muscle, hyperintense t2 signal and marked homogenous enhancement. small foci of intralesional t1 hyperintensity and larger areas of t2* gradient hypointensity were noted, in keeping with small areas of intralesional blood. vessels were seen to extend from the subcutaneous fat into the lesion. the mass slightly distorted the underlying extensor muscles and tendons of the forearm but there was no deep extension across the fascia. findings deemed the lesion to be more malignant in nature. the patient underwent incisional biopsy and histological findings confirmed a diagnosis of angiomatous fibrous histiocytoma. these tumours are rare soft tissue tumours which most commonly occur in children, adolescents and young adults. while it is rare, there is a potential for local recurrence and metastasis. therefore, it is essential to identify these tumours where possible or at least consider them as a differential for a soft tissue mass in a child. the surgeon commented that the imaging findings and report were essential in making the initial decision about whether to perform an incisional or excisional biopsy as the best treatment for the tumour is wide surgical excision with clearance of margins. unique teaching points: angiomatous fibrous histiocytomas are rare lesions with potential for recurrence and metastasis and therefore should be identified and managed appropriately as a malignant tumour. they are often confused as soft tissue haemangiomas or complex haematomas. it is very important to be aware of the presentation and imaging findings, remembering this form of tumour as a key differential for a soft tissue mass. nasopharyngeal anlage tumor in a neonate with the initial presentation of respiratory difficulty: correlation between imaging and clinicopathologic findings p.-s. tsai, d.-c. lin, s.-l. shih; taipei/tw the etiologies of nasal or nasopharygeal obstruction are variable in neonates. the respiratory symptoms are varied in these cases. mass lesions in nasal cavity or nasopharynx are extremely rare during the neonatal period. however, we must keep it in mind when respiratory problems occur in the neonatal period. here, we report a case presenting with sleep apnea resulting from nasal obstruction by a rare benign salivary anlage tumor in nasopharynx and discuss the imaging findings as well as clinicopathologic characteristics. the 28-day-old female infant had loud breathing sound, slow feeding and sleep apnea since birth. nasal endoscope and laryngoscope disclosed a polypoid tumor in nasopharyngeal cavity with a stalk connecting with posterior nasal septum. further magnetic resonance imaging (mri) revealed a lobulated mass about 1.6 cm in greatest diameter occupying posterior nasal cavity to the nasopharynx that was intermediate signal intensity on t1-weighted/t2-weighted images and heterogeneous gadolinium enhancement. the patient then received endoscopic resection. the tumor was shown locating in nasopharyngeal cavity and having a stalk from posterior nasal septum, partially occluding the choanae as well. resected tissue fragments displayed tan and whitish in color grossly. microscopic examination demonstrated duct-like structures and mesenchymal elements in a nodular pattern which are typical features of salivary gland anlage tumor. until now, there is no tumor recurrence for four years. unique teaching points: "salivary gland anlage tumor (sgat)" was firstly introduced in a report by dehner et al in 1994 . the tumor that has histologic resemblance to the developing salivary gland, is believed to be a hamartoma originating from minor salivary gland rather than a true neoplasm. congenital sgat displays male predilection and is a rare cause of neonatal airway obstruction. the mass is usual in the midline and attached to the posterior nasal septum or posterior nasopharygeal wall by a delicate pedicle. favorable results with simple excision are obtained. once massrelated airway obstruction is established, further examination with computed tomography (ct) or mri is helpful in anatomic evaluation, size measurement, characteristics definition and intracranial involvement. if mass induced airway obstruction is suspected in a neonate and sgat is considered based on imaging studies, invasive procedure should be careful due to the potential of tumor dislodgement from its fine pedicle resulting in complete airway obstruction. the association of intussusception with malrotation is referred to as waugh syndrome. [1] malrotation occurs in approximately 1 in 500 live births. [2] the incidence of malrotation amongchildren with intussusception is 40%. we hereby present a case report of waugh's syndrome associated with midgut volvulus. case presentation: a 5 month old male child reported to the emergency department with the clinical history of vomiting, abdominal distension, bloody mucoid stools and incessant cry. routine blood examination revealed hb: 12.9 gm%, tlc: 14500/cu mm, plt-2. 9lac/cu. mm. ultrasound (us) examination was performed and it revealed dilated fluid-filled small bowel loops with moderate amount of free fluid, right iliac fossa showed bowel within bowel appearance suggestive of target/pseudo kidney sign of bowel intussusception. no pathologic lead point was identified. transverse ultrasound image through the upper abdomen showed superior mesenteric vein noted to the left of the superior mesenteric artery hence malrotation should be considered. in view of surgical emergency non contrast enhanced ct was done and axial image showed target/sausage shaped soft tissue density mass it had alternating areas of low and high attenuation due to bowel wall and mesentry. on emergency laparotomy patient was found to have intestinal malrotation with duodenojejunal junction on the right of the midline and 180 mid gut volvulus in clockwise direction. intussusception with terminal ileum (gangrenous), caecum, appendix, whole of ascending colon, transverse colon were telescoping into descending and sigmoid colon. the volvulus was derotated and the in tussusceptum was reduced. the gangrenous terminal ileum and appendix was resected and ladd's procedure was done, a diverting ileostomy was created. the patient recovered uneventfully after which an ileo-colonic anastomosis was created transverse ultrasound shows a mass with a swirled appearance of alternating hypoechoic and hyperechoic "bowel-within-bowel" appearance (target sign) unique teaching points: on ultrasonography multiple, concentric, target like appearance of wall layers of invaginated segments (target sign) on axial scan, as well as pseudokidney sign (sandwich sign) on longitudinal scans were accepted as diagnostic criteria for intussusception. [8] it can assess the relative positions of the smv and sma which are mostly abnormal in malrotation. upper gastrointestinal contrast study is the imaging reference standard for diagnosis of malrotation with or without volvulus. abnormal position of the duodeno-jejunal junction. spiral, "corkscrew" or z-shaped course of the distal duodenum and proximal jejunum, and location of the proximal jejunum in the right abdomen. [2] a high degree of clinical suspicion and radiologist's awareness of this entity is helpful in guiding the surgeons towards diagnosis and prevention of morbidity and mortality. a rare case of epidermal naevus syndrome p. joshi; pune/in to acquaint the radiologists with the entity of epidermal nevus syndromes (enss) which are a group of rare complex disorders characterized by the presence of skin lesions known as epidermal nevi associated with additional extra-cutaneous abnormalities, most often affecting the brain, eye and skeletal systems case presentation: this one and a half year old child was referred to us for neuroimaging. he had multiple hairy naevi over his face, limbs including the palms, since birth, associated with blackish discolouration of his entire trunk. unique teaching points: epidermal nevi are overgrowths of structures and tissue of the epidermis, the outermost layer of the skin. the different types of epidermal nevi can vary in size, number, location, distribution and appearance. neurological abnormalities that can be associated with enss can include seizures, cognitive impairment, developmental delays and paralysis of one side of the body (hemiparesis). skeletal abnormalities can include abnormal curvature of the spine, the term "epidermal nevus syndrome" has generated significant controversy and confusion in the medical literature. originally, the term was used to denote a disorder that was actually several different disorders erroneously grouped together. in the recent past, the term was used to denote a specific disorder now known as schimmelpenning syndrome. however, the term epidermal nevus syndrome could be correctly applied to several different disorders. therefore, the umbrella term "epidermal nevus syndromes" now represents a group of distinct disorders that have in common the presence of one of the various types of epidermal nevi. however, there is so far no general agreement how to classify the types of this diverse group of disorders, adding to the confusion within the medical literature. these disorders are quite different from one another and are not "variants" of each other as is sometimes mistakenly stated in the medical literature. in the future, as the genetic molecular basis of these disorders is better understood, the classification may change or expand. bilateral axillary lump in a newborn diagnosed as hematoma h.n. özcan, u. aydingoz, m. haliloglu; ankara/tr objective: most birth traumas are self-limiting and have a favorable outcome. injuries to the infant that result from mechanical forces during the birth process are not uncommon. they occur most commonly on head and neck after vaginal breech delivery. however, soft tissue hematomas can be rarely seen after caesarian section (c/s). herein, we describe imaging findings of a newborn with bilateral axillary lump diagnosed as hematoma. case presentation: a 31-year-old woman was admitted to an outside hospital at 38 weeks' gestation for c/s due to prior caesarean operation. it was her fourth pregnancy (g4 p2). the pregnancy was unremarkable and she had normal ultrasounds at gestation. there was no history of trauma or fall during antenatal period. according to the c/s reports, the process of operation was uneventful any undue prolongation and without having used any other instrumentation. the weight of the female baby was 3.1kg at birth. on the 3 rd postnatal day, her mother noticed a left axillary swelling, then admitted to a tertiary children's hospital. her physical examination revealed, bilateral axillary asymmetry with a fluctuant, nontender swellings. there was no redness or discoloration of the skin. there was no clinical feature suggestive of trauma or bleeding diathesis. a superficial ultrasonography showed solid heterogeneous, hyperechogenic masses 38x35 mm in the left axillary region and 15x13 mm in the right side. doppler study did not reveal any flow in the masses. contrast enhanced mr imaging demonstrated, bilateral axillary mass lesions with fluid levels and smooth contours (figure 1 and 2) . t1w images demonstrated hyperintense component suggesting hemorrhage. after the administration of the gadolinium-based contrast material, lesions showed peripheral enhancement (figure 3) . a diagnosis of hematoma was entertained. the child was managed non-operatively. she was monitored clinically and radiologically. follow-up ultrasounds scan revealed significant regression of the swellings. unique teaching points: soft tissue hematomas can be rarely seen in newborns. the formation of axillary hematoma on the background of c/s is a rare complication, which, to the best of our knowledge, has not been previously reported. ultrasonography and mr imaging readily depicts hematoma and aids in the differential diagnosis. colorectal carcinoma (crc) is extremely rare in pediatric age, with an estimated annual incidence of approximately 1 case per million individuals. the majority of reported cases occur in adolescence, while the incidence is further lower for children under 10 years. the distribution between males and females is not equal, with higher prevalence in males (ratio of 2:1). the etiology in children is unclear as these tumors are often sporadic and not linked to a preexisting adenomatous polyp, unlike adults. predisposing factors such as familial polyposis of the colon, other polyposis syndromes, ulcerative colitis and familial multiple cancer syndromes were reported in 10 % of cases. advanced stage at diagnosis, aggressive histologic subtypes (poorly differentiated, signet ring and mucinous adenocarcinoma) and poor survival are the hallmarks of pediatric crc. case presentation: a 15-year-old male presented with a history of dyspeptic symptoms (recurrent epigastric-right flank colic pain and heartburn) for the last eight months, without evidence of irregular bowel function. after a prior diagnosis of esophagitis secondary to a gastroesophageal reflux disease, physical and laboratory examinations revealed anorexia, progressive body weight loss, microcytic iron deficiency anemia and positive fecal occult blood test. during an emergency access, abdominal ultrasound identified rounded target liver lesions and circumferential heterogeneous mural thickening of the ascending colon. contrast-enhanced computed tomography scan (cect) demonstrated a marked circumferential wall thickening of the ascending colon and cecum with a longitudinal extension of 85 mm and thickness of 22 mm; the mass contained lowdensity areas and calcifications. furthermore 5 hypovascular hepatic lesions along with lymph node metastases containing calcifications were identified. no lung metastases were found. histopathological analysis confirmed the diagnosis of metastatic colon adenocarcinoma. after chemo-and radio-therapy, only the hepatic lesions showed reduction in size and number. the patient subsequently underwent right hemicolectomy. one month after surgery he is in a rigorous follow-up through ultrasonographic evaluation of pleural effusion and ascites and cect. unique teaching points: crc, although rare, should be suspected in children presenting with unexplained persistent abdominal pain, progressive body weight loss and positive fecal occult blood test. ultrasound imaging can be appropriate in the preliminary detection of abnormal bowel wall thickening, lymph node and liver metastases; cect is mandatory to confirm the radiological diagnosis and complete the staging. to increase awareness of this rare syndrome and its varied presentation in order to facilitate its early diagnosis and treatment to prevent poor prognostic outcomes. case presentation: lemierre syndrome is a rare disease characterized by an initial infection of the head and neck leading to the development of a septic thrombophlebitis which has a propensity to spread and involve the jugular and facial veins. this progressive infection then leads to the development of metastatic septic emboli to the respiratory tract. we present the case of a 7 year old boy who attended with a 1 week history of fever and a cough. initial imaging on admission demonstrated a large left sided hydropneumothorax with multiple cavitating lesions throughout the lung parenchyma in addition to thrombosis of some of the segmental pulmonary veins. the hydropneumothorax was surgically drained and the patient was transferred to the paediatric intensive care unit after further deterioration with the development of a broncho-pleural fistula. following a short course of antibiotics there was no clinical or radiological improvement and sputum cultures grew coliform organisms which raised suspicion for a more distant source. when pus was noted to be discharging from the left ear, a contrast enhanced ct of the head and neck revealed a left mastoiditis with multiple cerebral abscesses and occlusive thrombi in the left jugular vein, transverse venous sinus, sagittal and straight sinuses. following this diagnosis antibiotic therapy was modified and targeted at anaerobes, which was vital in assisting the patients recovery and successful discharge home. unique teaching points: clasically the majority of lemierres syndrome begins in the oropharynxinvolving the palantine tonsils and peritonsillar tissue often presenting with fever, sore throat and neck pain. our case demonstrates an atypical presentation with sepsis and respiratory symptoms as a result of the septic emboli which delayed diagnosis. we have learnt from this case the importance of considering lemierres syndrome in patients presenting with signs of a respiratory infectionin particular cavitating pulmonary lesions-that have not improved with conventional therapy and to have a low threshold to investigate the head and neck as a potential source of infection. when the working hypothesis of meningitis could not help e. kovacs 1 , n. pinter 2 , g. balázs 1 , a. machovitsch 1 , a. arany 1 , z. liptai 1 , l. fonyad 1 , p. benke 1 ; 1 budapest/hu, 2 amherst/us objective: neuroinfection still represents a diagnostic challenge in the everyday practice, where clinical evaluation, imaging, laboratory and pathological workup and treatment goes hand in hand under the pressure of time. we summarized a case in which, despite the extensive multilateral collaboration the battle was lost, to bring attention to the possible causes. a two year old, previously healthy female was taken to the emergency department for altered state of consciousness and fever. she also suffered from gingivitis. the unconscious child underwent an emergency ct scan: hydrocephalus with signs of raised intraventricular pressure was detected. subsequently mri of the head and spine was performed, and showed signs of diffuse leptomeningeal enhancement with basal predominance. multiple dwi restricted parenchymal lesions with basal predominance were also found. repeated csf and blood tests did not reveal any causative organism, although the gradually increasing crp suggested infection. two weeks after the onset of symptoms a follow up mri study showed extensive cerebral and spinal swelling with no focal lesion. the child passed away three days later due to cardiac failure. autopsy and neuropathological evaluation could not reveal the cause of the disease, which was identified only weeks after the child died, by culturing sputum and csf. unique teaching points: an overview of the clinical and radiological presentation of meningitis basilaris is carried out. attention is given to the circumstances, when tuberculotic infection should be suspected, and antituberculotic treatment should be started, even before the confirmation of the presence of mycobacteria can be obtained. to describe the clinical, laboratory and mri findings of chronic nonbacterial osteomyelitis(cno) in a patient with a negative radiograph and emphasize useful imaging findings, including an unusual radial pattern of edema in both femoral heads. case presentation: a 14-year-old adolescent, was referred with progressive debilitating hip pain and inability to walk since 5 days, that was unsuccessfully treated with non-steroidal anti-inflammatory drugs. during hospitalization he developed fever up to 38 ο with normal full blood count and smear, elevated esr (95mm/h) and crp (12.8 mg/dl), positive serologic markers for streptococcus (asto) and ebv and received antibiotics with relative good response. blood cultures did not grow any pathogens, the rest of serology was negative for acute infection, tuberculin skin test was negative and immunological investigation was unremarkable. pelvic radiographs were negative. mri showed a symmetric pattern of bone marrow involvement around both triradiate cartillages, at both femoral heads and (2017) 47 (suppl 2):s297-s pediatr radiol major trochanters. complementary evaluation of tibial areas with a limited protocol disclosed asymptomatic involvement of tibial epiphyses and apophyses. a radial pattern of edema was seen at the femoral heads with alternating stripes of involved and uninvolved areas. clinical course and imaging appearances were highly suggestive of cno. rapid clinical improvement occurred during hospitalization while a repeat mri 6 months later showed complete resolution of hip findings and the patient was free of any symptoms or signs. coronal stir sequence at presentation showing the radial pattern of bone marrow edema (arrowheads) alternating with stripes of normal marrow (*) at both femoral epiphyses. note hyperinense edema (arrows) around triradial cartillages. coronal stir sequence showing the predilection of bone marrow edema symmetrically around triradial cartillages (arrows) and at major and minor trochanters (arrowheads). coronal stir sequence at 6-months follow-up shows resolution of edema. unique teaching points: cno is a not well known chronic autoinflammatory bone disorder affecting primarily children and adolescents. positive serology for streptococcus or other infectious agents has been previously reported as in our case and may be a triggering factor. striking mri findings with a negative radiograph may occur at initial stages. symmetrical distribution of non-specific bone marrow edema around epiphyses and apophyses is highly suggestive of the diagnosis in the appropriate clinical setting and following exclusion of suppurative bone infections as well as bone or hematologic malignancies. the radial pattern of edema in our patient is unusual and considered to comply with the direction of main trabecular systems in femoral heads. in 26/31 chest cts, 103 nodules (median size 2.0 mm) were detected. display mode a with 5 mm mip yielded the best interreader variability (κ=0.294) and the highest sensitivity (73.9%) compared to mode b and c (κ=0.218, sensitivity 61.2% and κ=0.238, sensitivity 59.3%, respectively). perifissural nodules were detected in all subgroups. conclusion: mip improves the detection of pulmonary nodules in chest cts of young children, but overall interreader agreement is only fair. nodules, including perifissural nodules, occur in children with and without malignancy. images were subsequently read and interpreted by board-certified radiologists and nuclear medicine physicians in communal reading. in case of identifying suspicious lesions in cect additional imaging (mri) or biopsy was performed. compared to pet/ct employing only low dose ct (ldct), the use of cect resulted in the identification of 19 additional suspicious lesions in 13 patients. furthermore the use of cect allowed us to qualify 3 lesions as benign/ physiologic which in pet/ldct were identified as suspicious and 16 lesions suspect for metastases or tumor. in those 37 patients who received combined integrated fdg pet/ct including both ldct and cect the ctdi ranged in between 1,3-15.5 mgy (n= 10.2 mgy) and the dose length product (dlp) ranged in between 82.4-2464 mgy *cm (n= 812.6 mgy *cm) specificity was significantly higher combining pet and ct compared to stand-alone ct and pet. our study showed that the acquisition of cect in combined integrated pet/ct leads to an increased specificity and thus represents an essential component of a good fdg pet/ct in pediatric oncology. in assessment of lymph nodes, inflammatory foci and liver lesions diagnostic contrast enhanced ct is essential. comparison of the detectability of ubos in neurofibromatosis type i patients with proton density-weighted and flair sequences in 3t mri l. porto, s. lescher, n. hillenbrand; frankfurt/de objective: neurofibromatosis type 1 (nf1) is an autosomal-dominant congenital disease. in nf1 patients, significant numbers of so-called unidentified bright objects (ubos) can be found in brain imaging, with predilection sites at the basal ganglia and the dentate nucleus. ubos seem to develop at a very early age, contrary to other criteria leading to diagnosis. the detection of ubos might therefore prove helpful in the early diagnosis of nf1, complementing the clinical diagnosis based on criteria of the "national institutes of health consensus development conference". the aim of the study was to investigate whether the detectability of ubos increases at 3t by comparing proton density-weighted images (pdw) with fluid-attenuated inversion recovery (flair) sequences. a total of 14 nf1 patients (7 male, 7 female, between 8 and 26 years old, mean age 15.4 years) were examined by a 3t magnetic resonance scanner. the presence of ubos was evaluated on pd-w and flair images by 4 evaluators (2 experienced neuroradiologists, 1 junior radiologist and 1 student in his final year). detectability was rated by a three-point scoring system for dedicated regions: lesions which were "well defined/detectable", "suspicious" or "detected after a second look". the wilcoxon signed-rank test was used for comparisons between the raters. the level of significance was p<0.05. significantly more lesions were marked as "well defined/detectable" in the pd-w sequence compared to flair (p<0,001 for all four evaluators together, as well as for each evaluator separately). in particular, pd-w proved to be superior for detecting ubos located in the medulla oblongata (p=0,001) dentate nucleus (p=0,002) and hippocampal region (p=0,007), regardless of the level of the raters' experience. this is the first study that compares flair and pd-w at t3 for the diagnosis of ubos in nf1. significantly more ubos are detected in the pd-w compared to flair sequences, especially for the infratentorial regions. as ubos occur at very early stages of the disease in patients with suspected nf1, pd-w might aid an early diagnosis in these patients. assessment of radiation doses from diagnostic imaging in the followup of paediatric oncology patients p. logan 1 , r. harbron 2 , k. mchugh 1 ; 1 london/uk, 2 newcastle-upon-tyne/uk objective: previous literature (1,2) has suggested paediatric oncology patients accumulate a large radiation burden as a consequence of routine diagnostic imaging examinations during therapy. we retrospectively looked at the effective doses from routine ct and nuclear medicine in three cohorts of children, namely patients with hepatoblastoma, wilms' tumours and rhabdomyosarcoma (rms). of note, in our centre we rely on repeated mris of the primary site for many tumours. effective doses (e), in millisieverts (msv), were estimated using the ncict dose estimation tool (lee et al 2015) , based on details specific to each procedure: patient age, scan region, scanner type and ct dose index (ctdi -an indicator of radiation exposure recorded at the time of each scan). doses for general radiography were estimated using pcxmc v2.0 monte carlo simulations, assuming standard exposure factors and field size. there were 59 patients in total (18 hepatoblastoma, 21 wilms', 20 rms). there were 33 boys. the mean age was 3 years 2 months (ranging from 14 days -11 years 10 months). the mean and median cumulative effective doses from ct for the whole cohort were 7.88 msv and 4.24 msv respectively. four patients in the wilms' cohort had a dmsa nuclear scintigram (0.7 -1.0 msv), no hepatoblastoma patient had any nuclear medicine imaging, and 16 patients with rms received a bone scan (3 -3.5 msv) or a pet scan (approximately 8msv). cumulative radiation doses from routine radiological investigations in paediatric oncology can be kept in a much lower range than reported in the literature (1,2). in our institution, the followup of solid intra-abdominal tumours with mri, with additional ct or nuclear medicine only when clinically justified, has resulted in a significantly low radiation exposure in these patient cohorts. mri of the primary tumour site should be implemented as a replacement for ct imaging when there is no significant detriment to the diagnostic information obtained. (2017) 47 (suppl 2):s297-s pediatr radiol mri-based evaluation of multiorgan iron overload is a predictor of adverse outcomes in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation f. zennaro 1 , d. zanon 2 , r. simeone 2 , g. boz 2 , f. degrassi 2 , m. gregori 2 , g. schillani 2 , c. boyer 1 , n. maximova 2 ; 1 nice/fr, 2 trieste/it objective: iron overload is associated with poor clinical outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation (hsct). although the effects of hepatic and cardiac siderosis on patient outcomes have been extensively studied, less is known about the effects of siderosis in other organs. the medical records of 44 consecutive pediatric patients who underwent allogeneic hsct in our institute from 2011 to 2015 were retrospectively reviewed. mri was used to measure iron concentrations in the liver, spleen, pancreas and bone. these patients were divided into two groups, 18 with non-elevated (<100 μmol/g; group 1) and 26 with elevated (>100 μmol/g; group 2) liver iron concentration (lic) at baseline. in group 1, only two patients had normal iron concentrations in all organs. none of the patients of group 2 presented with pathological iron concentrations in only two organs. comparisons of baseline data with results of the first follow-up mri performed 1-6 months after hsct, showed a general worsening of iron accumulation. in group 1, none of the patients showed complete absence of iron overload in a single organ. in group 2, none of the patients showed a total absence of siderosis involving fewer than three organs. this study confirms the correlations between iron overload and the risks of transplant-related complications, such as transplant related mortality, sinusoidal obstruction syndrome, infections, pancreatic insufficiency, and metabolic syndrome, in transplant recipients with systemic siderosis. another important finding of this study was the close correlations between pre-transplant bic and times to neutrophil and platelet engraftment (p<0.001 each). (15), ganglioneuromas (gn, 2) and ganglioneuroblastoma (gnb, 1), examined by 3t mri were retrospectively grouped according to tumor entity, risk factors (bone marrow metastasis, mycn amplification or 1p36 deletion) and therapeutic regime (observation versus chemotherapy). dw (b values 0, 400 and 800) and conventional mri images (t2, t1 pre and post contrast) were analyzed for tumor size, relative si-and absolute adc-values at baseline (base; no therapy), and after 3 (fu1) and 12 (fu2) months. adc values in nb were lower than in gnb and gn (0.75*10 -3 mm 2 /s versus 1.28*10 -3 mm 2 /s; p<0.05). there was a tendency towards lower adc values in tumors with risk factors (n=6) versus no risk factors (n=7) at baseline, which did not reach statistical significance (p=0.08). during follow-up shrinkage of tumor volume was noted (baseline 1206 ml, fu1 159 ml, fu2 51 ml; p<0.05 baseline vs. fu1; p=0.08 baseline vs. fu2). in the observation group, tumor adc values rose without relapse (0.89*10 -3 to 1.07 *10 -3 mm 2 /s). only in eventually relapsing tumors adc values tended to decrease further (0.95*10 -3 to 0.71*10 -3 mm 2 /s, p=0.17), despite initial reduction in tumor size. to establish inter and intra-observer variability in the radiological detection and assessment of pulmonary nodules at diagnosis in children with wilms tumours. a test set of ct thoraxes at diagnosis from 15 patients enrolled in the multicentre 'improving population outcomes of renal tumours of childhood' (import) study in the uk were assessed. five radiologists (3 chest, 2 paediatric) from 5 different centres (4 uk, 1 netherlands) completed a scoring sheet for nodule assessment on the same studies on two occasions, 6 months apart. the readers were blinded to patient respiratory symptoms, the original radiology reports and also that they were scoring identical cases. descriptive statistics, modified bland altman graph and fleiss kappa scores were used for statistical assessment. in total, 93 different pulmonary nodules across the 15 ct thoraces at both rounds were scored by at least one reader. 81 (87%) were seen by at least one reader in round 1 and 81 (87%) in round 2, 69 (85.2%) nodules were seen by at least one reader in both rounds. only 20 (21%) nodules were scored by all 5 readers in round 1, 16 (17%) by all 5 readers in round 2, and 14 (7%) nodules by all 5 readers in both rounds. of the 20 nodules seen in the first round, 11 were measured to be >5mm in at least one dimension and of these, 7 were classified as malignant by all 5 readers. the limits of agreement for mean difference in nodule size in anterior-posterior, transverse and longitudinal measurements were ±1.85mm, ±1.76mm and ±1.88mm respectively. the fleiss kappa scores ranked from poor to fair agreement for nodule border smoothness (0.03), nodule shape (0.2), solidity (0.2) and impression of malignancy (0.4). within the same readers for both rounds, nodule detection rates of agreement were between 60.7-82.9%. the average intra-reader percentage of observed agreements for nodule border smoothness, shape, solidity and impression of malignancy were 84.2%,63.9%, 90.6% and 84.8% respectively. conclusion: detection and characterisation of pulmonary nodules on ct thorax shows both intra-and inter-observer variability. this has important implications for the interpretation of metastatic disease at presentation. fever without a focus is defined as febrile illness without an initial obvious cause or localizing signs. our aim is to assess the diagnostic value of whole-body mri (wb-mri) in the diagnostic work-up of children with fever without a focus. we retrospectively searched for subjects who underwent wb-mri for fever without a focus. a total of 29 children (m=17, f=12), mean age 6.1 years (range: 0.08 -17.61) were included. 8/29 (27.6%) subjects were immunosuppressed and 6/29 (20.7%) subjects were hospitalized at onset of fever. the reference standard was based on positive cultures, biopsy or surgery. when this was not possible, a probable diagnosis was made based on clinical follow-up or serology. initially, the wb-mri images were reviewed independently by 2 pediatric radiologists blinded to all clinical information. at the end of each case the final diagnosis and the diagnostic category (5 categories: a. normal, b. infection, c. oncologic, d. rheumatologic, e. miscellaneous) was recorded. this was followed by a consensus read for comparison with the reference standard. for statistical analyses all subjects were treated as fever without a focus. results: reference standard: the diagnostic category of the reference standard was as follows: infectious 12/29 (44.8%), oncologic 1/29 (3.4%), rheumatologic 8/29 (27.6%), miscellaneous. 1/29 (3.4%). even after extensive work-up in 7/29 (20.7%) no clear cause for the fever was found table 1 . wb-mri: wb-mri diagnosed the cause of fever without a focus in 7/29 subjects (24.1%) ( table 1 ). in 2 subjects (6.8%) wb-mri results were falsely positive (1 jia and 1 myositis), and in the remaining 20 subjects no imaging findings compatible a cause of febrile disease were found. interobserver agreement was fair (kappa 0.53). in children with fever without a focus wb-mri provided the diagnosis in in almost a quarter of the cases. given the multiplicity of causes of fever without a focus, some of them not possible to visualize on mr imaging, wb-mri may be considered in routine imaging practice when evaluating pediatric patients with fever without a focus. to compare linear measurement/volume to direct volumetric measurements using 3 dimensional(3d) post-processing software. for this irb approved study initial diagnostic ct or mr exams in 100 patients(11mo-20yr) with solid tumors were reviewed by 11 radiologists and 3 technologists. radiologists recorded measurements in 3 axes in their routine method, described tumor shape (sphere, ellipse, cone) and surface texture (smooth, almost smooth, or mildly, moderately, markedly irregular). three technologists individually, and 3 radiologists by consensus, used 3d processing software (intellispace portal, philips, cleveland, oh) to directly measure tumor volume. tumor volume (v) was calculated from linear measuments using the following equations: sphere v=4/3πr 3 , ellipsoid v=8πr 2 or 16πr 2 , conicalv=2πr 2 or 4πr 2 , and cuboid v=(xyz). inter-reader variability in tumor measurement in all tumors and for tumors divided by surface characteristics was assessed amongst radiologists and technologists, and radiologist consensus using coefficient of variation (cov). tumor shape analysis was reported as 14 sphere, 84 ellipse, 2 cone, and surface texture 8 smooth, 10 almost smooth, 32 mildly irregular, 31 moderately irregular, 19 markedly irregular. inter-reader variability of as much as 1,119cc above to 383cc below the mean tumor volume was found when using radiologist determined linear measurements, with standard deviation (sd), range 0.65-413. inter-reader variability amongst technologist derived volumes was considerably less, range 102cc above to 90cc below the mean, with sd, range 0.03-97. cov analysis shows a greater degree of variation in tumor volume calculated from linear measurements [smooth(7%), almost smooth(12%), mildly(20%), moderately(18%), markedly(27%) irregular] than direct volume determination [smooth(5%), almost smooth(6%), mildly(3%), moderately(3%), markedly(5%) irregular]. variation was significant only for tumor with irregular surface texture [smooth (p=0.26), almost smooth (p=0.23), mildly (p=0.003), moderately (p=0.001), or markedly (p=0.002) irregular]. variation in linear/volume measurements in very irregular tumors. light blue=middle 50% tumor volume measurements by pediatric radiologists. whiskers mark limits of range. ▲♦ • markers =measurements by technologists. note broad degree of variation. (2017) 47 (suppl 2):s297-s pediatr radiol variation in linear/volume measurements in almost smooth tumors. light blue=middle 50% tumor volume measurements by pediatric radiologists. whiskers mark limits of range. ▲♦ • markers =measurements by technologists. note narrow degree of variation. both graphs show the same informationthe % relative variation in tumor volume measurements determined by 3 dimensional linear measurements (11 pediatric radiologists) v. volumetric processing (technologists & consensus group). radiologist generated measurements are subjective and unreliable. variation in measurement technique leads to differences in calculated tumor volume which significantly over or under estimate volume in tumors with irregular texture and is not significant in smooth tumors. quail-quantitative mri-based evaluation of pancreatic iron overload in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation f. zennaro 1 , m. gregori 1 , f. degrassi 1 , e. cattaruzzi 2 , y. diascorn 3 , c. boyer 3 , n. maximova 1 ; 1 trieste/it, 2 muggia/it, 3 nice/fr objective: iron overload (io) is a relatively common but often neglected transplantrelated complication and has been associated with poor prognosis in patients undergoing allogeneic hsct for hemato-oncological disease. pancreatic io is frequent among patients with transfusion-dependent anemias, but is uncommon among patients with hematologic malignancies. the causes of pancreatic io and the potential effects of pancreas iron deposits on transplant outcomes or on the risk of developing significant late effects in long-term hsct survivors have not been yet determined. our institute routinely uses magnetic resonance imaging (mri) with various gradient-recalled-echo (gre) sequences to quantitatively measure the iron concentration in abdominal parenchymal organs in all pediatric patients before and after allogeneic hsct. this study retrospectively analyzes the correlations of pancreas io with the type of conditioning regimen and pretransplant liver iron concentration (lic) in 50 pediatric patients who underwent allogeneic hsct in our transplant unit over the last 5 years. we enrolled 50 patients, age 1-17 years. pre-transplant mean lic was 147,55 μmol/g (normal values 36 μmol/g). 3 (6%) patients had mild liver io and 25 (50%) had moderate or severe io. pretransplant mean pancreatic iron concentration (pic) was 29,59 μmol/g, whose only 4 (8%) had mild pancreatic io and none had severe io. post-transplant mean lic was 162,6 μmol/g, only one patient had mild liver io but 36 patients (72%) had moderate or severe io. post-transplant mean pic was 66,22 μmol/g, 12 (22%) patients had moderate or severe io. mean pre-transplant pancreatic volume was 33,41 cm 3 , while mean post-transplant pancreatic volume (evaluated 30 days after transplantation) was 25,41 cm 3 . 11 (91,7%, p<0,001) patients with post-transplant moderate or severe pancreatic io underwent tbi-based conditioning. mean reduction of pancreas volume in tbi group was 12,02 cm 3 (p< 0,001). no pancreatic volume reduction was observed in chemotherapy-based group. all patients with pancreatic io have had exocrine pancreatic insufficiency and 9 (83,3%) patients have had metabolic syndrome. volume reduction well correlate (mean 49,8%, p<0,0001) with pancreatic io. this study confirms that pancreatic iron overload is not so rare in patients with hematologic malignancy underwent allogeneic hsct, with increased risk of metabolic syndrome and total deficit of exocrine pancreatic activity, but not of endocrine activity. iron overload monitoring allows for chelation therapy optimization. mr is fast, reproducible and more reliable compared to serum ferritin and transfusional history and allows a multi organ evaluation. pulmonary tb is common in south africa, with many children affected. diagnosis can be challenging and chest x-ray remains fundamental for diagnosis. interpretation is difficult and shown to have wide inter-reader variability. no study however has compared cxr findings and interreader agreement between ambulatory and hospitalised patients. this study compares the frequency of cxr changes, as well as interreader agreement in ambulatory compared to hospitalised children with suspected tb. from nolungile clinic and red cross children's hospital respectively was done. each sample contained 50% proven tb and 50% negative controls. two paediatric radiologists and one paediatrician served as blinded, independent readers for the database using standardised ticksheets. our study demonstrated no significant difference in lymphadenopathy, but an increase in parenchymal change in the hospitalised group. we otherwise showed similar results to literature regarding finding frequency, but poor inter-observer agreement. if the least expert reader were removed, results were comparable with available literature. this highlights the need for development and study of explicit cxr criteria for lymphadenopathy to improve the value of cxr for paediatric tb in all settings. lung ultrasound in pediatric pneumonia -why is it necessary to use the additional trans-abdominal approach? j. lovrenski; novi sad/rs objective: to emphasize the need of lung ultrasound (lus) technique modification, which enables detection of pneumonia in children not visualized by using solely the standard trans-thoracic approach. a prospective study was carried out in the regional children's hospital, and comprised a 2-year period. the inclusion criterion was us finding of pneumonia detected by trans-abdominal, and not with trans-thoracic approach. lus examinations were performed using a combined, trans-abdominal and trans-thoracic approach. longitudinal, transversal (intercostal), and oblique sections were used. trans-abdominal examination included transhepatic and trans-splenic approach. the ultrasound probe was angulated from the most anterior to the most posterior sections while examining the lung bases by trans-abdominal approach. a pneumonia-positive lus finding included subpleural consolidation with air-bronchogram, or with an adjacent area of interstitial/ alveolar-interstitial edema. lus was always performed before the other diagnostic modalities (chest x-ray (cxr) and computed tomography (ct)), if they were indicated by pediatrician or radiologist. within a 2-year period in 14 children (mean age 3.9y, sd 2.3y) the pneumonic focus was discovered using the trans-abdominal approach, while the trans-thoracic approach showed a normal lus pattern. all the children had the clinical symptoms of pneumonia (fever and cough, with or without dyspnea/tachypnea). the auscultatory finding was positive in 4 children. cxr was performed in three children, showed a right-sided pneumonia in two, and was negative in one patient. one child had a contrastenhanced chest ct, which confirmed a left-sided pulmonary base abscess detected during lus examination by trans-splenic approach only (figures 1, 2) . apart from pulmonary symptoms, there has not been any other associated diseases found, apart from otitis media in two children. each child responded to the antibiotics treatment with resolution of infection and us signs of pneumonia. in this oral presentation we will explain and give anatomical and technical reasons for pneumonia-positive us findings within lung bases, that remained undetected by the trans-thoracic approach. left-sided abscess abutted on the spleen (s), and was detected by trans-splenic us approach. it did not contact the pleural surface approachable by trans-thoracic ultrasound (black semi-lunar mark). l-liver. conclusion: trans-abdominal (trans-hepatic and trans-splenic) approach should become an inseparable part of each lus examination, along with a standard trans-thoracic approach. this modification of technique is expected to result in a further increase of lus sensitivity in diagnosing pneumonia. is thoracic ultrasound really competitive to computed tomography in children -a two-year retrospective study j. lovrenski, k. antolović; novi sad/rs to compare diagnostic accuracy of thoracic ultrasound (us) and computed tomography (ct) in children. a retrospective study was conducted in the regional children's hospital, and comprised a 2-year period. the inclusion criteria were: chest ct performed within 24h after the us examination of thorax, and us and ct examinations in the same patient performed by different pediatric radiologists. all us examinations were performed using a combined transabdominal-transthoracic approach. ct examinations were done (2017) 47 (suppl 2):s297-s pediatr radiol according to the body mass based pediatric ct protocols. each hemithorax was analyzed separately in terms of comparison between us and ct findings. statistical analysis included the calculation of sensitivity, specificity, positive predictive value (ppv) and negative predictive value (npv) of ultrasound in diagnosis of pulmonary pathological entities. out of 176 children with chest ct, 21 of them (mean age 8,2y, sd 5,6y) fulfilled the criteria to enter the study group. lung us showed sensitivity, specificity, ppv and npv in diagnosis of pleural effusion: 100%, 96,4%, 91%, 100%; lung consolidation: 100%, 100%, 100%, 100%; lung abscess: 75%, 100%, 100%, 97%; and interstitial lung disease: 57%, 100%, 100%, 91%, respectively. within 3 hemithoraces multiseptation of pleural effusion was observed by us only. air bronchogram within lung consolidation was observed in 5 hemithoraces both by us and ct examinations. necrotic areas within pulmonary consolidations were detected by us in 4 hemithoraces, which was later confirmed by ct examination. lung abscesses were diagnosed in 3 hemithoraces by both us and ct. two small lung abscesses filled with air (1 hemithorax) and bronchiectasis (2 hemithoraces) were detected only by ct examinations. other pathological findings detected both by us and ct examinations were: congenital pulmonary airway malformation (cpam) (1 hemithorax), pulmonary sequestration (1 hemithorax), partial pneumothorax (2 hemithoraces), hidropneumotorax (1 hemithorax), inflamed pneumatocele (1 hemithorax), hydatid cyst (1 hemithorax), pericardial effusion (2 patients), soft tissue masses of thoracic wall with initial bone destruction (2 patients), and lymphomas (2 patients) (figures 1-3) . in one patient us and ct revealed cysts and an extremely dilated bronchus within lung consolidation (pathohistological finding: cpam type 2 combined with subsegmental bronchial atresia, and extensive bronchopneumonia). us examination, unlike ct, could not differentiate between eventration of the left hemidiaphragm and diaphragmatic hernia in one patient. to determine and compare the accuracy of frontal cxrs alone and 'combination frontal-lateral' set of cxrs for diagnosing lymphadenopathy in children with tb using patients with confirmed tb and controls without tb, and to compare findings in hiv-infected and hiv-uninfected children. a total of 172 children (ie: 88 children with gene xpert confirmed tb and 84 control patients admitted with lower respiratory tract infections), which were part of a larger south african study, who had both frontal and lateral cxrs, were included. three qualified radiologists read the cxrs in 2 separate sittings one month apart (one for the frontal x-ray alone and one for the 'combination frontal-lateral' cxrs) for the presence of lymphadenopathy. odds ratios and 95% confidence intervals were calculated to determine the presence of lymphadenopathy using a consensus reading on the frontal cxr and frontal-lateral cxr combination according to the final diagnosis of tb. inter reader agreement was determined using the kappa statistic. lymphadenopathy was reported in 86 (50%) patients on the frontal cxr alone and in 143 (83%) patients on the frontal-lateral cxr combination. 52 (60%) of the 86 patients with lymphadenopathy on the frontal cxr alone were gene xpert positive versus 72 (50%) of the 143 patients with lymphadenopathy on the frontal-lateral cxr combination. in all patients, the consensus reading using a frontal-lateral cxr combination resulted in a 5-fold increase (or 4,9; 95% ci 2, 4) in calling lymphadenopathy compared to using a frontal cxr only in the gene xpert positive group, the consensus reading using a frontal and lateral cxr combination resulted in a 3 fold increase (or 3,1; 95% ci 1,5-6,6) in calling lymphadenopathy compared to a frontal cxr only. overall inter reader agreement for all 3 readers when evaluating for lymphadenopathy was 'fair' on both the frontal cxr (k= 0,2088) and the frontal-lateral cxr combination (k=0,273). the addition of a lateral view to the standard frontal cxr increased the rate of calling lymphadenopathy. however, the accuracy of diagnosing lymphadenopathy on chest x-ray as a marker for tb was poor. this poor accuracy was further hampered by only 'fair' inter reader agreement for the presence of lymphadenopathy on chest x-ray. dynamic 4d ct imaging in children has significant advantages over routine ct scanning, bronchography and bronchoscopy for diagnosing trachebronchomalacia because it can be performed during free breathing without anaesthesia or invasive airwayaccess.itcanalsodemonstratevascularcausesoftracheo-bronchomalaciain the same sitting. the technique is currently performed in 1 paediatric center in the uk. we aimed to report pitfalls encountered while setting up a dynamic 4d ct imaging service for children and report the findings of studies performed. materials: dynamic 4d ctscanning was introduced after installation of a large array (320 slice) ct scanner, applications specialist training and review of the literature. imaging parameters in use by greenberg and colleagues (arkansas children's hospital, usa) were applied. referral indications, pitfalls encountered, quality of scanning and imaging findings/diagnoses were reviewed and enumerated. results: nineteen paediatric dynamic 4d ct scans (9 females, 10 males; 11 days -3 years 9 months; mean 12 months) were performed over 15 months. the first 4 studies were performed without ivi contrast due to lack of experience and 13 subsequent studies were performed with contrast ( figure 1 major pitfalls included initial failure to perform contrasted studies for simultaneous evaluation of vessels, initial failure to withdraw the endotracheal tube, patient motion under care of nurses and clinicians, failure to appreciate the value of imaging the full lung volume while trying to keep dose length product to a minimum and failure to appreciate that collapse of the airway is often in the ap plane and not appreciated on coronal slab projections -rotating 3d volume rendered images is a requirement ( figure 3 ). additional obstacles were initial clinician and radiologist lack of support after early failures and colleague concerns regarding the radiation dose. objective: diagnosis of pulmonary tuberculosis (ptb) in children relies on chest radiography, however there is wide inter-observer agreement in detecting lymphadenopathy, the hallmark of ptb. paediatric airways are pliable, thus detection of airway compression may be a more objective criterion for the presence of lymphadenopathy. thus the objctive was to assess the usefulness of airway compression on chest radiographs for diagnosis of ptb in children. chest radiographs of children admitted to red cross children's hospital with suspected ptb were read by two readers according to a standardised format and a 3 rd when there was disagreement. radiographs of children with definite ptb were compared to those with lower respiratory tract infection (lrti) from another cause. the prevalence and location of airway compression was evaluated. findings were correlated with hiv status and age. inter-observer agreement was assessed using kappa statistic. 13 .9% in older children (or 1.7; 95%ci 1.00-3.00). no association with airway compression and hiv infection was found. inter-observer agreement ranged from 0.0-0.4. eighteen-month-old male patient diagnosed with ptb; hiv negative. majority agreement of airway compression at lmb indicative of lymphadenopathy. left upper lobe opacity is in keeping with a ghon focus. there is a strong association between airway compression on chest radiographs and confirmed ptb, particularly in infants, irrespective of hiv status. however, clinical use is limited by poor inter-observer agreement. paediatric ultrasound-guided biopsies in a tertiary oncology centre: five years experience n. parvizi, m. smedley, s. chakraborty; oxford/uk objective: histological diagnosis is almost always essential to guide appropriate therapy for children diagnosed with cancer. tissue can either be obtained by surgical/open or image-guided percutaneous biopsy. the aim of this study is to assess the safety and diagnostic accuracy of ultrasound-guided biopsies in a tertiary oncology referral centre. a retrospective analysis of clinical data, imaging findings and histological diagnosis of patients aged 0 to 18 years between january 2010 and december 2015 was carried out. a total of 113 ultrasound-guided biopsies were performed in our institution on 110 patients. most of the biopsies were performed in theatre with the patient under general anesthetic and with an 18-gauge spring-loaded core biopsy needle with a minimum of two cores per patient. in 99% of lesions the needle biopsy was diagnostic. the single nondiagnostic case did not have sufficient material to make a full diagnosis and a surgical biopsy was required. eighty-two of the biopsied lesions were malignant and 31 were benign. in no cases was a repeat biopsy required. the vast majority of the biopsies were performed within one week of request with over half performed within 3 days. all biopsies were performed without complication and in the majority of cases the patients were discharged the same day or following an overnight stay. ultrasound-guided percutaneous biopsy is an accurate and safe technique in order to acquire tissue from suspected malignant lesions in children. these can be performed instead of or in addition to open biopsy and will often result in a shorter hospital admission and recovery time. the role of imaging in the diagnosis of thymoma in paediatric patients with myasthenia gravis j. adu, t. a. watson; london/uk thymomas are exceedingly rare tumours in the paediatric age group, with only very few cases having been reported in the literature. thymomas are commonly associated with myasthenia gravis (mg), with thymectomy being potentially curative. ct is the mainstay imaging modality for thymoma diagnosis in the adult population. while, chemical shift mr imaging can be helpful to distinguish thymoma from other anterior mediastinal abnormalities. currently, there is no consensus on the imaging pathway for children with mg with suspected thymoma. our aim is to review the imaging of patients who were referred to our institution for management of mg, and suggest an imaging pathway in cases where thymoma is suspected. we performed a retrospective search of the local pacs system of cases between 2000 and 2016 using the search terms "thymoma" and "myasthenia gravis" in the clinical indication for the study and the body of the final report. forty-three cases were identified using the search criteria. eight cases were excluded owing to an absence of cardiothoracic imaging. 20/35 of all cases (57%) had chest x-rays (cxr's), of these 17/20 (85%) were normal. the three remaining patients who had abnormal cxr's went on to have ct scans, which confirmed an anterior mediastinal mass (amm) in all three cases. 26/35 of all cases (74%) had cross-sectional imaging (mri 15/26 cases, ct 11/26 cases). of those, 21/26 of cases (81%) had normal studies. specifically, all 15 mri studies (100% of cases) were normal, while only 5/15 ct scans (66%) demonstrated an anterior mediastinal abnormality. 12/35 of all cases (34%) had both cxr and cross sectional studies. 9/12 of these cases (75%) had a normal ct or mri. in the remaining three cases, the amm was clearly demonstrated on both cxr and the crosssectional imaging. in our series, radiography, ct and mri studies were normal in the vast majority of cases. however, given that thymectomy is potentially s405 (2017) 47 (suppl 2):s297-s pediatr radiol curative, it is appreciated that clinicians may still be keen to radiologically investigate paediatric patients with myasthenia gravis. cxr is not an efficacious imaging modality in this context, as patients with a normal cxr may be falsely negative, and patients with an abnormal cxr may undergo cross-sectional imaging regardless. we propose that mri should be used as first line investigation for patients in this population. this approach will negate the need for ionizing radiation, maximize diagnostic yield, and facilitate surgical planning if deemed clinically appropriate. increased risk of venous thrombosis of the arm with multiple peripherally inserted central catheters insertion in paediatric patients r. gnannt 1 , n. waespe 2 , j. donnellan 2 , k. liu 2 , l. brandao 2 , b. connolly 2 ; 1 zurich/ch, 2 toronto/ca objective: peripherally inserted central catheters (piccs) are associated with superficial and deep venous thrombosis of the arm. the impact on the incidence of developing a thrombosis of the arm when inserting a subsequent picc remains unclear. the purpose of this study was to analyze the incidence of deep, upper limb thrombosis of repeated upper limb piccs in children. the study population included all patients who underwent their first successful arm picc insertion between january 2010 and december 2015. subsequent ipsilateral arm piccs were included in the analysis. patients were followed until march 2016 or until any alternative central venous line insertion (jugular, femoral, saphenous or umbilical vein lines -because of their thrombogenic effect). for each picc insertion the following data were collected: date of insertion and removal, weight of the patient, type of picc (1.9fr, 2.6fr, 3fr, 4fr, 5fr), left or right arm, and vein cannulated (basilic, brachial, cephalic). all symptomatic deep and superficial thrombosis of the arm were correlated with the picc database. four thousand one hundred thirty-eight piccs were inserted. applying inclusion and exclusion criteria, 1955 piccs remained for analysis. first, 2 nd , 3 rd , and 4 th picc insertions in the same arm were identified in 1773, 146, 30 and 6 patients, respectively. in total there were 57 upper body deep symptomatic thrombotic events diagnosed with ultrasound. a 1 st , 2 nd , 3 rd , and 4 th picc insertion was associated with 46/1773 (incidence 2.6%), 6/146 (4.1%), 4/30 (13.3%), and 1/6 (16.7%) thrombotic events, respectively. an increasing hazard ratio was seen with higher numbers of picc insertions, which was significant when comparing the 1 st with the 3 rd picc insertion in the same arm (hr 3.9, ci95%1.3-11.4, p=0.01). after excluding any confounder, double lumen piccs were associated with a significantly higher risk of thrombosis than single lumen (or 5.3, ci 1.2 -23.4, p=0.026). repetitive picc insertions in the same arm are associated with an increased risk of thrombosis. double lumen piccs are associated with a higher risk of thrombosis compared to single lumen lines. diagnostic performance of lung ultrasound for the detection of community acquired pneumonia in children j.a.m. stadler 1 , s. androunikou 2 , h. zar 3 ; 1 paarl/za, 2 bristol/uk, 3 cape town/za objective: chest radiographs (cxr) are considered the first line imaging modality when investigating cases of suspected community acquired pneumonia (cap) in children. however, cxr interpretation is limited by moderate sensitivity and specificity and poor inter-and intra-rater reliability and expose children to potentially harmful ionizing radiation. point-of-care lung ultrasound (lus) has been proposed as alternative to cxr for diagnosis of pneumonia in children and some published data suggest accuracy and reliability as good as or better than cxr. most of these studies however, were performed in in-hospital settings creating a bias for selceting more severe disease and consequently more overt radiological findings. the mean age of children in most of these studies were also well above one year, while the highest incidence and risk of complicated pneumonia occurs during the first year of life. the purpose of our study was to assess the diagnostic performance of lus for the diagnosis of pneumonia in both hospitalised and non-hospitalised children in an age group representative of the most at risk segment of the population. we performed a lus on 147 children who presented with clinical signs consistent with the who case definition for childhood pneumonia. one hundred of these patients also had chest radiographs performed as part of routine clinical care. inter-rater reliability (irr) between a general practitioner and an expert paediatric radiologist were assessed for the interpretation of lus findings consistent with pneumonia. where radiographs were available concordance between lus and cxr findings of pneumonia were also assessed. results: seventy-four hospitalised and 73 non-hospitalised clinically defined pneumonia cases were included with a median age of 10.3 years. our general practitioner reported lus findings consistent with pneumonia in 77/147 (52%) compared with 66/147 (45%) by the paediatric radiologist. substantial overall agreement between the reporters was found with an overall agreement proportion of 0.79 and kappa=0.62. agreement for the presence of lung consolidation or for a normal scan was also substantial with kappa of 0.67 and 0.68 respectively. agreement on the finding of interstitial syndrome was moderate with kappa=0.45. agreement was higher in hospitalised than in non-hospitalised cases with kappa of 0.62 and 0.56 for the respective categories. results showing concordance between lus and cxr findings are pending. conclusion: lus shows substantial irr for the diagnosis of pneumonia in children. irr are higher for the detection of consolidation or for no pathology than for interstitial syndrome. irr also appears to be lower in clinically less severe disease. 'white-out' on plain chest radiograph-a late presentation of congenital diaphragmatic hernia a. fagan 1 , c. stewart 2 , k. halliday 3 , s. rao 2 , d.t. chang kwok 2 ; 1 peterborough/uk, 2 lincoln/uk, 3 objective: awareness of the limitations of plain radiograph and computed tomography in diagnosis of late presentation of congenital diaphragmatic hernia. case presentation: a 2 year old boy presented with a 6 day history of pyrexia, vomiting and respiratory distress. he was haemodynamically stable, and had no audible air entry over his upper left thorax with occasional wheeze over the left base. he had bronchiolitis previously but did not require ventilatory support. he was otherwise well with unremarkable antenatal scans. initial chest x-ray showed a large air collection with fluid or soft tissue density within the left hemi-thorax and mediastinal shift to the right. repeat x-ray (figure 1 ) demonstrated the nasogastric tube below the diaphragm. complicated pneumonia was suspected but as the findings were atypical a non-contrast ct was performed. this was interpreted as showing a large hydropneumothorax. (figure 2) . a chest drain was inserted which drained only a small volume of fluid, and a repeat chest film showed no change. ct chest and abdomen with oral and intravenous contrast revealed a bochdalek diaphragmatic hernia (figure 3) . fortunately the chest drain had not entered the herniated stomach. the hernia was surgically corrected and the child recovered well. (2017) 47 (suppl 2):s297-s pediatr radiol bochdalek is the most common congenital diaphragmatic hernia (cdh). it is often diagnosed on prenatal ultrasound, with mri used for confirmation. cdh which is not diagnosed in the perinatal period may be asymptomatic and imaging findings can be confusing. postnatal x-ray typically shows an opacified hemi-thorax with or without gas bubbles. there can be mass effect with mediastinal shift. the position of an ng tube can be helpful in localising the stomach, but in this case the infradiaphragmatic position of the tube gave false reassurance. in neonates, the position of an umbilical venous catheter may demonstrate abnormal location of the liver. computed tomography generally demonstrates a posterolateral defect (foramen of bochdalek), which is located on the left in 80% of cases. ct is useful for excluding lung masses or bronchopulmonary foregut malformations, which may appear similar to cdh on x-ray. ct can also identify anatomical abnormalities associated with cdh. late presenting cdh is often misdiagnosed as pleural effusion or pneumothorax. there are other case reports published where chest drains were inserted before cdh was diagnosed. it is important to keep cdh in mind as a potential cause of unilateral hemithorax opacification, even in previously asymptomatic older children. ct with oral contrast can be useful in diagnosis. ovarian tuberculosis with peritoneal dissemination mimicking ovarian tumor with peritoneal seeding d. grassi, v. tostes, a. duarte, s. abib, h.m. lederman; sao paulo/br consider tuberculosis (tb) as a differential diagnosis whenever the case enrolls in an endemic region. case presentation: female, 13 years old adolescent, who presents with abdominal pain and weight loss. abdominal sonography was performed in a public family practice location and bilateral ovarian masses were detected. she was referred to an oncology pediatric facility for further investigation. abdominal mri and chest ct were performed where dissemination through the peritoneal and mesenteric lymph nodes could be detected; chest ct was normal. the patient underwent surgical intervention for diagnosis and on pathology the findings in the bilateral ovarian masses were secondary to tb involvement. sonography showing bilateral pelvic masses. t2-weighted coronal overview bilateral ovarian masses. unique teaching points: whenever a case enrolls in an endemic region of tuberculosis, it is important to consider it as a possible differential diagnosis. in this case, the initial presentation mimicked ovarian tumor with mesenteric seeding. however, only after surgical approach was possible to diagnose ovarian tuberculosis with mesenteric lymph nodes and peritoneal involvement. retrospectively, patient's uncle was discovered as having pulmonary tb. langerhans'-cell histiocytosis with thoracic involvement in infant and young child: ct findings s.-l. shih 1 , k. tsai 1 , w. huang 2 , f.-s. yang 1 ; 1 taipei/tw, 2 taitung/tw the purpose of the study was to evaluate the ct changes of thorax in the patients with langerhans'-cell histiocytosis. the 3-month-old female infant presented with generalized hemorrhagic macular rash over the skin for 2 months. the laboratory findings showed hemoglobin 7.8gm/dl (normal 11.0~16.0gm/dl). the chest radiograph showed bilateral reticulonodular infiltration. high-resolution computed tomography (hrct) of chest showed multiple cystic-like lesions (1-6mm) in the right middle and bilateral lower lobes. the pathological report was langerhans'-cell histiocytosis after skin biopsy from upper chest. then she was on scheduled chemotherapy. she was in remission after one-year treatment. the 1y10m-old girl presented with fever for 3 months. the physical examination revealed hemorrhagic-macular rash over the skin in the anterior chest wall and hepatosplenomegaly. the laboratory findings revealed albumin 2.5g/dl (normal 3.8-4.7g/dl) and hemoglobin 7.0g/dl (normal 11.0-16.0g/dl). hrct of chest showed multiple cystic-like lesions (1-6mm) in the bilateral lower lobes with left pleural effusion as well as multiple osteolytic lesions in the vertebral bodies of t7, t8, t11 and t12. the pathological report was langerhans'-cell histiocytosis after skin biopy from anterior chest wall. then she was on scheduled chemotherapy. she was doing well 10 years after treatment. the 1y6m-old girl presented with yellowish discoloration of skin for one month. the laboratory findings revealed direct/total bilirubin 4.4/7.9mg/dl (normal 0.1-0.5/0.3-1.2mg/dl), got 223iu/l (24-46iu/l) and gpt 220iu/l (12-27iu/l). the chest radiograph revealed enlargement of upper mediastinum. the ct scan of chest and upper abdomen showed punctuate calcification with heterogeneous enhancement in the upper mediastinum and several minute cysts in the lower lobes of lung (hrct) as well as dilatation of bilateral intrahepatic bile ducts in the liver. the pathological report was langerhans'-cell histiocytosis after biopsy from thymus and liver. then she was on scheduled chemotherapy and got initial response. unique teaching points: langerhans'-cell histiocytosis affecting the lungs and thymus may be in isolation or as part of a multiorgan disease. the pulmonary changes on ct scan may not have corresponding respiratory symptoms. ct scan of thorax may have multiple minute cysts (1-6mm) in the lungs, pleural effusion, calcification in the thymus and osteolytic lesions in the thoracic spine. case of fungal infection of the soft tissue in a child with acute myeloid leukemia (ultrasound aspects of diagnosis) i. begun, s. kondaurova; minsk region/by objective: early diagnosis of fungal infections of the tissues is essential for a successful and complete recovery. we describe a clinical case of fungal infection of the soft tissue in a child with acute myeloid leukemia (aml). ultrasound were made for the characteristics of the structural changes in the area of interest to perform biopsies followed by bacteriological culture studies. case presentation: patient k., 13 years old, diagnosed with aml, from which after a course of induction chemotherapy with neutropenia about 3 weeks on the skin of the foreskin appeared removable hard white coating. cultures of plaque it possible to establish the presence of fungi of the genus trichosporon spp. after 4 days, there were hyperemia, compaction and ulceration of the glans penis, which led to extensive tissue defects. with help ultrasound were determined the structural deformation of the glans penis with the pronounced around changed tissues vascularization. after 7 days in the rear surface projection of the left thigh and the lateral surface of the left calf were defined erythematous papules which progressed to ulceration with central black scab. by standard ultrasound were visualized: subcutaneous nodal education oval 1,0х0,4 sm on hip and echogenic skin thickened portion having an average degree of severity of dorsal acoustic shadow on the lower leg (weakening of the signal behind scab). in cultures of biopsies of subcutaneous foci were revealed fungi of the genus trichosporon spp too. the patient received the combination treatment (intravenous liposomal amphotericin b and surgical rehabilitation of lesions of glans and corpus cavernosum of penis). after the stabilization of patient state the treatment of the underlying disease was continued. unique teaching points: for some patients, lesions of superficial tissues may be the only sign of systemic fungal infections, and rapid recognition of these lesions may contribute to early diagnosis and treatment. ultrasound examination in such a situation naturally becomes an main imaging tool and by choice method. the scanning high-resolution of foci of the thigh of the patient k. in grayscale made possibility to determine the configuration consisting of the central echogenic focus surrounded by a hypoechoic rim (fig. 1) with peripheral changes in the type of "infiltrative" according by the active fungal infection at the exit of cytopenia. duplex and triplex ultrasound scanning were indicating to the perifocal vascularization with low level vascular resistance around of the affected area (see fig.2-3) . to increase knowledge and awareness of rare cases and diseases in order to be able to better manage and treat patients in the future. case presentation: an 3-month-old female was presented to our hospital with abdominal distention that increased in the past 3 months associated with low-grade fever, loss of weight and mild respiratory distress. abdominal ultrasonography revealed an enlarged liver with multifocal hypoechoic lesions scattered all over the liver (fig 1) . a ct scan with iv contrast (mri was not available at that time in our district) revealed severe hepatomegaly with the presence of multiple, variable in size, hepatic hypodense lesions which had peripheral (ring) enhancement after contrast injection in the arterial phase (fig 2) . progressive centripetal filling in portal phase is seen and in the delayed images many of the lesions were completely filled (fig 3) . reduction in the aortic caliber (mid-aortic syndrome) below the level of celiac branch was noted. a diagnosis of hemangioendothelioma was made although liver biopsy was not done due to fear of hemorrhage. alternative diagnosis to infantile hemangioendothelioma in this age group is hepatoblastoma, mesenchymal hamartoma and metastatic neuroblastoma. the patient was transferred to another city to a hospital with pediatric oncology department for follow up and treatment. unfortunately the lack of experience and knowledge of such rare cases led to mismanagement and delayed treatment and after less than 2 months the patient was brought back to our hospital to the pediatric icu due to deterioration of her status due to congestive heart failure. unfortunately the patient died shortly afterwards. hemangioendothelioma is twice as common in girls and can have complications due to high output chf secondary to arteriovenous shunting hemangioendotheliomas tend to involute spontaneously without therapy over a course of months to years. they are followed with sequential ultrasounds. medical therapy is reserved for severely symptomatic lesions (e.g. anemia, consumptive coagulopathy, high-output chf) and includes high-dose steroids or alpha-interferon. in cases of failed medical management, surgical resection should be performed. if partial hepatectomy is not technically achievable, transarterial embolization should be used either as definitive therapy or as a temporizing measure until liver transplantation is possible. the sad outcome of this case was mainly due to mismanagment due to lack of medical experience and knowledge of such rare cases so we suggest that such rare cases should be catalogued in a national data bank for future consultation and teaching purposes. fatal outcome of acute gastric dilatation causing acute abdomen compartment syndrome in a child: a case review c.s. yoon; seoul/kr to describe and review presumed acute abdominal compartment syndrome in a child. case presentation: a 3 years and 5months old boy was admitted to emergency room due to abdominal distention. he suffered abdominal pain and vomited since yesterday after lunch. on physical examination, his abdomen was rigid and distended. body temperature is 37.2°c. the white cell count was increased (24,140/μl). esr is 25 mm/hr and c-reactive protein was 123.4 mg/l. creatinine was increased (1.24mg/dl). amylase and lipase were increased (164 u/l and 104 u/l respectively). prothrombin time was prolonged (15.5 sec). plain abdomen radiograph shows markedly distended stomach with air-fluid level (fig.1) . first trial of nasogastric tube insertion was failed due to kinking of tube at gastroesophageal junction. contrast-enhanced abdomen ctscan shows marked distensionofstomachwithlargeamountoffoodmaterialsandintraluminalairwith prominent external compression in the duodenal 3rd-4th junction. esophageal air distention is also markedly noted with l-tube insertion. no opacification of large vessel with contrast media, without contrast enhancement of spleen, pancreas and left kidney is noted (fig.2) . prob. markedly compressed and poorly defined lower abdominal aorta with faintly visible both common iliac arteries and femoral arteries. after ctscan, nasogastric tube exchange was performed due to poor drainage of gastric fluid. about 700cc of gastric fluid was drained. however, sudden cardiac arrest of the patient was developed. although vigorous cardiopulmonary resuscitation was performed, the patient was died. (2017) 47 (suppl 2):s297-s pediatr radiol unique teaching points: acute abdomen compartment syndrome is a very serious and lifethreatening disease. as soon as possible, rapid diagnosis and adequate treatment are necessary for good prognosis. delayed diagnosis and treatment may result in fatal outcome. pleuroperitoneal fistula in a pediatric patient with primary hyperoxaluria type 1 w.p. chu; hang hau/hk to illustrate the imaging features of pleuroperitoneal fistula in a pediatric patient suffering from primary hyperoxaluria type 1 case presentation: an 11-year-old girl with the history of primary hyperoxaluria type 1 was repeatedly admitted to the hospital for recurrent right pleural effusion despite chest drain insertion. the right pleural fluid was transudative in nature and the microbiological cultures for bacteria and mycobacterial species were negative. the radiographic examination [ figure 1 ] showed moderate right pleural effusion a n d f e a t u r e s o f o x a l o s i s i n c l u d i n g b i l a t e r a l c o r t i c a l nephrocalcinosis and generalized increased in bone sclerosis. delayed planar images of the peritoneal scinitigraphy [ figure 2 ] obtained 3 and 5 hours after injection of technetium-99 m suphlur colloid found diffuse tracer activity at the right hemithorax, suggestive of pleuro-peritoneal fistula. the patient subsequently required thoracoscopy and surgical decortication at the right hemithorax and renal transplantation. primary hyperoxaluria is due to defective glyoxylate metabolism and results in increased synthesis of oxalic acid. cortical nephrocalcinosis and diffusely increased bone sclerosis are characteristic radiographic features. pleuroperitoneal fistula is unusual in patients without peritoneal dialysis. possible cause in this patient is increased intra-abdominal pressure related to portal hypertension and cirrhosis. osteosarcoma with pulmonary intra-arterial tumor embolism metastasis a. alzaher, f. alzaher; dammam/sa objective: osteosarcoma rarely invade the veins and small number of cases has been reported with venous invasion at the presentation. however, to our knowledge, no case has been reported with venous invasion and isolated distal metastasis as intra-arterial pulmonary embolisms. we are presenting a case of pediatric pelvic osteosarcoma with venous invasion and pulmonary arterial tumor embolisms as isolated distant metastasis at the presentation. the purpose of this case report is to describe the rare presentation of distant metastasis as isolated pulmonary arterial embolism that might be overlooked radiological. additionally, such tumor embolism might cause respiratory symptoms and differentiating tumor emblism from pulmonary thromboembolism is crucial to avoid the unnecessary anticoagulation. case presentation: fourteen year old boy who presented with 3 months history of right hip and lower limb pain after trauma. this was associated with lower limb swelling. the plain radiography showed right pelvic iliac bone aggressive mass, along with lobulated, soft-tissue components, extensive areas of osseous matrix, and malignant periosteal reaction. the patient could not tolerate the mri and ct scan was performed and it showed that the mass was invading the right external and internal iliac vein with imaging appearance was most consistent with osteosarcoma. patient staging was then carried on with mri under anesthesia and chest, abdomen and pelvic ct scan. the unenhanced and iv contrast enhanced chest ct scan showed multiple beaded expansion of sub segmental pulmonary arteries with soft tissue destinies and calcification suggestive of intra-arterial pulmonary tumor embolisms. there was no isolated pulmonary nodule or any other site of distant metastasis. unique teaching points: we present this case to increase the awareness of isolated intra-arterial pulmonary tumor embolisms as osteosarcoma metastasis especially with the present of venous invasion. additionally, such condition might be with respiratory symptoms and differentiating the tumor embolism from pulmonary thromboembolism is crucial to avoid the unnecessary anticoagulation. case presentation: a 14-year old boy with acute myelodysplastic syndrome presented with recurrent, acute severe anemia (hemoglobin 68 g/dl) and melena. his past history was significant for bone marrow transplant twice followed by graft-versus-host-disease of intestines, bilateral lung transplants for bronchiolitis obliterans, renal failure, scleroderma and acute pancreatitis. ct angiography performed previously did not identify active extravasation. several days before, upper gi endoscopy had demonstrated ulceration of the greater curvature of the gastric wall that was initially treated with epinephrine injection and surgical clip placement. at the time of referral, endoscopic interventions were unsuccessful leading to progressive clinical deterioration. a decision was taken to proceed to angiography to isolate the arterial source of hemorrhage, with an intention to embolize, if feasible. catheter angiography via transfemoral 4fr access revealed a left gastric artery pseudoaneurysm with active extravasation into the gastric lumen through the ulcer. after selecting the feeding pedicle of the left gastric artery with a microcatheter, the pseudoaneurysm was embolized using 40% nbca in lipiodol, resulting in complete angiographic obliteration of the bleeding source. on repeat cbc 6 hours post-procedure, the hemoglobin had increased from 80 to 115 g/dl. the patient remained hemodynamically stable in the intensive care unit. there is no evidence of bleeding recurrence 25 days later. unique teaching points: catheter angiography can define the bleeding source with greater accuracy than cta in children. there should be a low threshold to perform catheter angiography, with an intention to proceed to treatment. nbca embolization is a feasible and effective option for treatment of acute gi bleeding in children. case presentation: an infant born by cesarean section at 38 weeks of gestation, after nonreassuring cardiotocoghraphy, with meconium aspiration at birth, severe hepatocellular failure with hyperbilirubinemia, signs of hemorrhage, edema, ascites, hypoglycemia, increased ferritin values, and lactic acidosis was referred for ultrasound and magnetic resonance. both examinations showed signs of liver cirrhosis with portal hypertension; in addition, on t2-weighted images and gradient-echo images, the signal intensity of the liver and the pancreas was lower than that of the spleen and skeletal muscle, a finding consistent with abnormal iron deposition in those organs. a biopsy of the lower lip confirmed the diagnosis of neonatal hemochromatosis. unique teaching points: although the diagnosis may be suspected clinically, it must be confirmed by demonstrating the generalized iron overload affecting, among other organs, the salivary glands, liver and pancreas, with sparing of the reticuloendothelial system. the underlying cause may be associated with an an alloimmune mechanism; thus, intravenous immunoglobulin during gestation is administered in selected cases to prevent the severity of neonatal hemochromatosis. diagnosis is then crucial not only for management of the affected infant, but also for prevention in the future offspring. fishing for the answer -a rare case of paediatric exogenous lipoid pneumonia secondary to fish oil aspiration h. moodley, d. white, g.d. baker; johannesburg/za objective: lipoid pneumonia is a rare condition caused by the intrapulmonary accumulation of endogenous or exogenous fat containing substances. in the acute exogenous form secondary to aspiration of oil, it is important to make the diagnosis and remove the causative agent to prevent or arrest the progression of pulmonary fibrosis. radiopathological findings usually prompt the diagnosis, as aspiration of mineral oils is usually unnoticed due to the lack of reactive airway symptoms and patients present with vague chronic respiratory symptoms. case presentation: we present the clinical, radiological and pathological correlation of exogenous lipoid pneumonia in a 4-month-old male patient with recurrent respiratory tract infections. a ct chest demonstrated an extensive crazy paving pattern of the dependent lung segments bilaterally. the lung biopsy findings of occasional intra -alveolar macrophages with larger (2017) 47 (suppl 2):s297-s pediatr radiol foamy cytoplasmic vacuoles, raised the possibility of an exogenous lipoid pneumonia secondary to aspiration. on further history, the patient was found to have been fed fish oil by his mother, confirming the diagnosis. unique teaching points: the rare diagnosis of exogenous lipoid pneumonia can be confirmed on ct chest by measuring the hounsfield units in the most hyperdense components of consolidation (typically -150 to -30 hu). histopathological confirmation can be obtained provided that the specimens are not embedded in paraffin. the possible role of visual evaluation of dwibs in childhood renal masses based on our five cases e. varga, g. rudas; budapest/hu objective: nowadays, the diffusion-weighted mri has a great importance not only in the differential diagnosis and follow-ups of childhood renal tumors, but in the early detection of recurrence of the disease as well. the dwibs with appropriate b-values and the adc calculation can be helpful in distinguishing between benign and malignant processes. however, the adc calculation is a time consuming method and in addition, there are cases when we cannot use this technique, but we can still apply the visual evaluation of diffusion. case presentation: between 2013-2016, we had 5 cases in which the visual assessment of dwibs was the best method which helped to make the appropriate therapeutic decisions. left kidney of an infant with nephroblastomatosis was removed because of an arising wilms tumor. 2,5 years later, in the contralateral kidney, a small area of diffusion restriction appeared on the dwibs in one of the cystic residual lesions, but the anatomic sequences haven't showed any changes comparing with the previous examinations. in another patient with beckwidt-wiedemann syndrome, the follow-up ultrasound examination showed a little bulging of the surface of the left kidney. accordingly, the mri showed a barely distinguishable nodule, but the dwibs referred to a wilms tumor. in a 17-month-old child, more nodules were visible in both kidney on the dwibs than on other sequences. with the help of visual evaluation of dwibs, we were able to detect the malignant lesion easily and quickly, among a lot of cystic and solid nodules of the kidneys in a seven years old patient with sclerosis tuberosa. an 8-month-old infant was followed with a benign cystic renal disease and a new small solid nodule was found on the last ultrasound examination. instead, the visual assessment of dwibs indicated a multilocular cystic wilms' tumor. unique teaching points: the diffusion-weighted mri is suitable for differentiate benign and malignant renal lesions in children. the dwibs (with appropriate b-values) and the adc calculation are very sensitive methods in pediatric oncoradiology. the adc calculation is a long process andas our cases demonstrated -we cannot apply in every cases. the visual evaluation of dwibs is a time saving method which is spared from limitations of adc histogram-based assessment, so it may become very useful in the everyday practice. we can use it in the differential diagnosis and follow-ups of childhood renal tumors and we can detect the recurrence of the malgnancy very early and easily. mr urography in a 9-years-old female with unusual urinary dribbling m.c. terranova, c. tudisca, d. narese, g. li voti, s. salerno; palermo/it objective: congenital anomalies of kidney and urinary tract (cakut) occurs in up to 3.2% of infants, and clinically they can range from asymptomatic patients, in which anomaly is detected incidentally even in adulthood, to ante-natal or post-natal mortality due to bilateral kidney agenesis or acute renal failure. dmsa renal scintigraphy is considered gold standard, for evaluation of those cases electable for surgery, in order to assess renal function, depict and locate ectopic kidney and guide surgical management, but has the important limit of radiation exposure and may undetect poorly functional renal moieties. the advent of modern magnetic resonance technics proven to be able to assess anatomical malformations and renal function, overcoming the limits of dmsa scintigraphy, may be used as a valid alternative, especially in vulnerable pediatric population. we herein describe a case of a young girl with small left renal bud and ectopic ureter, draining in vagina, discovered by mr and undetected by previous dsma scintigraphy. case presentation: a 9 years old girl was referred for continuous urinary dribbling, after starting toilet training, with normal bladder voiding pattern, unrelated to any physical and psychological events, and no history of urinary tract infections. physical examination revealed vaginal septa and micturition training was practiced, with no symptoms improvement. abdominal us study was performed, reporting empty left renal fossa and hypertrophic right kidney; no ectopic kidney nor sign of urine stasis or other urogenital anomalies were detected, and dmsa renal scintigraphy was planned. it depicted only normal right kidney radionuclide uptake but no evidence of left renal or ectopic renal tissues activity. patient then underwent mr evaluation for suspected genito urinary malformation, that revealed a small cystic formation, with a slight cortex, at the level of the iv lumbar vertebra -that represented the left immature renal bud -supplied by a short fluid-filled tubular structure, located postero-medially to the bladder -that configured the left ectopic ureter, draining in left vaginal wall. bladder was normal, and regularly connected with the right orthotopic ureter (fig 1) . pre-surgical cystoscopy and vaginoscopy, followed by left ascending urethrogram were performed, confirmed previous mr findings, and patient underwent successfull laparoscopic left nephron-ureterectomy. unique teaching points: mr urography has proven to be a rapid, safe, radiation free, systematic diagnostic tool especially in the evaluation of poorly functioning renal systems, and of collecting system, bladder and ureteral abnormalities, overcoming the limits of conventional imaging technics agenesis of the dorsal pancreas: case report c. lanza, g. pieroni, l. amici, a. giovagnoni; ancona/it objective: agenesis of the dorsal pancreas (adp) is a rare malformation. since 1911 and until 2008, 53 cases have been reported. majority of the patients with this anomaly are asymptomatic or associated with abdominal pain, hyperglycemia, diabetes mellitus, and acute or chronic pancreatitis. case presentation: we present a case report of a 11-year-old girl with adp, diagnosed incidentally during radiological evaluation for abdominal pain. she was hospitalized in the pediatric department for recurrent abdominal pain for the past 10 months. there was no history of nausea, vomiting or trauma. biochemical investigations showed a normal random serum glucose, serum amylase levels slightly increased (149 u/l; reference value 28-100 u/l) and slightly elevated serum pancreatic lipase levels (138 u/l; reference value 22-51 u/l). the day after serum amylase levels decresed up to 80 u/l and lipase levels to 78 u/l. us revealed increased -size pancreatic head with normal contour and echotexture with no parenchymal calcification or duct dilatation. the body and the tail of the pancreas were poorly visualized. mr imaging examinations revealed only a partial visualization of the pancreas: the pancreatic head and the uncinate process were visualized with defined margins with peripancreatic fat stranding, but the distal neck, body, and tail of the pancreas were absent. on mrcp, the dorsal pancreatic duct of santorini and the minor duodenal papilla could not be visualized. the ventral pancreatic duct of wirsung and the common bile duct were normal and clearly visualized. these findings were compatible with complete adp, eliminating the need for ercp. unique teaching points: the clinical presentation of dpa varies greatly ranging from incidental detection on x-ray, surgery or autopsy through to the development of a ductal adenocarcinoma of the pancreas. abdominal pain and diabetes are the most frequent clinical manifestations reflecting exocrine and endocrine insufficiency as most of the islands of langerhans are located in the tail of the pancreas. there have also been reports of an increase in the size of the remnant pancreas and recurrent acute pancreatitis as a form of presentation. diagnosis requires confirmation of the absence of the neck, body and tail of the pancreas and duct of wirsung using endoscopic retrograde cholangiopancreatography (ercp) or mrcp. one hundred four mr images of foetal cns with a us suspicion of acc were retrospectively reviewed. foetal mri was performed at 1.5 t magnetom avanto (siemens, erlangen, germany) without motherfoetal sedation. polymicrogyria, lissencephaly, schizencephaly, subependymal heterotopias and migration disorders were evaluated. cortical findings were compared to three types of acc (complete agenesis, partial agenesis and hypoplasia). genetic tests were collected. postnatal mri or foetopsy for diagnostic confirmation were collected. on 104 foetuses, fetal mri was able to detect cortical malformations in 32 cases even in early gestational ages (<24gw). the mean gestational weeks (gw) at mr diagnosis was 26 (range: 22-36gw). mr imaging found 13/32 polymicrogyria, 7/32 lissencephaly, 5/32 schizencephaly, 4/32 subependymal heterotopias and 3/32 neuronal migration disorders. 22/32 had complete acc, 4/32 had partial acc and 6/32 had cc hypoplasia. statistically significant correlations (p<0.005) between complete acc, focal polymicrogyria and cortical dysmorphism affecting frontal lobes were found. fetal cns mri can detect cortical development malformations in complex acc, providing further information for the clinician to assess the severity of perinatal outcome. mri is a useful tool in improving obstetrical genetic prenatal counselling to predict pregnancy and foetal prognosis. clinical signs of the neonatal lymphatic flow disorder (nlfd) are a combination of the congenital chylothorax, chylous ascites and body edema. it can present as neonatal chylothorax (nc), neonatal chylous ascites, or congenital lymphatic dysplasia (cld). the prenatal appearance of lymphangiectasia has been described as nutmeg lung. the purpose of this study is to describe prenatal and postnatal imaging features and outcomes of neonates with nlfd. materials: this is a retrospective case series of neonates in our institution that had pre-and postnatal lymphatic imaging and nlfd. all patients had prenatal imaging (fetal mri and us) and underwent postnatal dynamic contrast mr lymphangiography (dcmrl) with a three-dimensional (3d) t2 space. conventional lymphangiography (cl) when performed was also reviewed. six patients with nlfd were identified (3 with nc and 3 with cld). one patient had congenital heart disease. nutmeg lung was seen in all patients on fetal mri and 4 patients on fetal us. 5/6 patients had pleural effusions, 2/6 had ascites and 1/6 had body wall edema prenatally. postnatal mri with 3d t2 space revealed soft tissue edema in the upper chest and neck (5/6 patients), mediastinal edema (5/6 patients), interstitial lung edema (6/6 patients), retroperitoneal edema (5/6 patients), and ascites (6/6 patients). dcmrl demonstrated lymphatic flow to the pleural space (5/6 patients) and to the abdominal cavity (1/6 patients) and dermal backflow (2/6 patients). cl was performed in 4 patients, all of which had collateral lymphatic flow to the lung. lymphatic intervention was performed in 3 patients, lipiodol injection for 2 patients with nc and thoracic duct embolization (tde) for 1 patient with cld. mean hospital duration in the first 4 months of life was 51 days (range 5-113) for nc and 105 days (range 75-120) for cld. all 3 patients with cld died after 4 months of age due to respiratory distress including the patient that had tde and both with findings of dermal backflow. the pleural effusions in the 2 patients with nc resolved post lipiodol injection and in the other patient with nc it resolved with conservative therapy. conclusion: nlfd is a disorder that can be recognized on prenatal and postnatal imaging. in this small series, nutmeg lung was present in all patients with nlfd and may be easier to recognize with fetal mr than us. dermal backflow on dcmrl suggests a poor prognosis. both prenatal and postnatal imaging may guide treatment and interventions in nlfd. fetal mri and postnatal ct scans of prenatally diagnosed bpms from 10 patients with available histology were analyzed retrospectively. the fetal mri and ct images were reviewed by two radiologists blinded to histological findings. specific diagnosis was assigned based on predetermined criteria. the accuracy of fetal mri was evaluated. the agreement rate in fetal mri diagnosis between two radiologists was 100 %. an overlap of 80% in fetal mri and histopathological diagnosis was reached. when comparing fetal mri and postnatal ct examinations, the agreement of the results was also 80%. the least matching histological diagnosis was bronchopulmonary sequestration (bps). fetal mri is very accurate in characterizing the bpm spectrum and provides important information on lesion type and structure when compared with histology. with relatively small number of patients high correlation between prenatal mri and postnatal ct was reached. therefore, further investigation with more patients is needed. we hypotethise that fetal mri in late pregnancy could in the future replace early (neonatal) ct examinations if fetal mri provides sufficient inforfmation for clinical management. real time virtual sonography: a new integrated approach for the evaluation of fetal cerebral pathologies? s. bernardo, a. antonelli, v. vinci, m. saldari, c. catalano, l. manganaro; rome/it objective: real-time virtual sonography (rvs) is a new technique that uses magnetic navigation and computer software for the synchronized display of real-time us and multiplanar reconstruction mri images. the purpose of this study was to evaluate the feasibility and ability of rvs to assess the main cerebral pathologies in fetuses with suspected us anomalies. materials: this is a prospective study. fusion imaging (hitachi hi vision ascendus) was offered to 35 patients undergone fetal mri for a us suspicion of cerebral pathology. the mri image dataset acquired was loaded into the fusion system using a cd support and displayed together with the us image. both sets of images were then manually synchronized and images were registered. the possibility to record the images in a video format allowed, however, the possibility to re-evaluated the examination. results: rvs was technically possible in all cases. data registration, matching and fusion imaging were performed in 25 minutes at the beginning and in less than 15-20 minutes after practice. the ability of rvs imaging to assess the main anatomical sites and fetal anomalies was evaluated and compared with standard us and mri images. the principal application of rvs was the study of midline, cerebral gyration and vascular malformations because it also allowed adding a real time doppler signal on mri images. fusion imaging helped the diagnosis in 25%. in the 25/ 35 cases of encephalic pathology, fusion imaging improved the diagnosis; in the other cases mri was superior to us even using the rvs. this is a preliminary study on the feasibility and practical use of a fetal mri-us real-time fusion imaging. both techniques are complementary but still independent and the retrospective synthesis of these exams allows optimal analysis of fetal cerebral anomalies. this technique has many advantages especially on the pedagogic plan. however, rvs is currently limited to the research area. role of foetal mri in the evaluation of ischaemic-haemorrhagic lesions of the foetal brain s. bernardo, a. antonelli, v. vinci, m. saldari, c. catalano, l. manganaro; rome/it the aim of this study was to define the role of fetal magnetic resonance imaging in the evaluation of cerebral ischaemic-haemorrhagic lesions and the extension of parenchymal injuries. from september 2010 to december 2016 we performed 271 fetal mri of cerebral region in foetuses with suspected abnormalities on ultrasound or cmv infection and toxoplasma serum conversion. fetal mri was performed with a 1.5-t magnet system without materno-fetal sedation. fetal mri detected ischaemic-haemorrhagic lesions in 14/271 fetuses, revealing a 5% pathology incidence. mri confirmed the diagnosis in 3/14 cases with us suspect of ischaemic-haemorrhagic lesions associated with ventriculomegaly. in 1/14 cases with us findings of cerebellar haemorrhage, mri confirmed and provided additional information regarding the parenchymal ischaemic injury. in 8/14 cases with us suspect of ventriculomegaly (n=3), corpus callosum agenesis (2), cerebellar vermis hypoplasia (1), holoprosencephaly (1), spina bifida (1) mri detected ischaemic and haemorrhagic lesions unidentified at us examination. in 2/14 fetuses with us suspicion of intracerebral tissue space-occupying lesion, mri modified the diagnosis to extra-axial haematoma associated with dural sinus malformation. results were compared to fetopsy or after-birth follow up. fetal mri is an additional imaging modality in the diagnosis of cerebral ischaemic-haemorrhagic lesions and it is useful in providing further information on the extension of parenchyma injury and associated abnormalities and in improving delivery management. the contribution of mid-trimester virtual autopsy with mr imaging a. d'hondt, n. d'haene, j. rommens, m. cassart, f.e. avni; brussels/be the aim of the study was to assess the potential contribution of fetal virtopsy (post-mortem mr imaging (pm-mri)) in the second trimester of pregnancy. during a one-year period, post-mortem mr imaging (pm-mri) was performed in all fetuses who died in utero or whose pregnancy was interrupted due to major malformations. the study was performed in agreement with the local ethical committee. fetuses of <26 weeks that underwent obstetrical ultrasound and pm-mr were included. mr imaging examination was performed on a 1.5 tesla magnet with a standardized protocol. the findings on pm-mri were compared to obstetrical sonographic findings (and to pathology when available). we have analyzed separately the findings in the central nervous system and those in the rest of the fetus (chest, abdomen and skeleton). the results were classified in three categories according to the diagnostic accuracy: ultrasound>pm-mri, ultrasound=pm-mri and pm-mri>ultrasound. the us and pm-mri data of ten fetuses were analyzed. their gestational age ranged from 17.6-26 weeks and their bodyweight ranged from 160-930g. for the cns malformation: pm-mri offered a better diagnostic accuracy than us in 7 cases (70%) (e.g. agenesis of the corpus callosum and holoprosencephaly). in 3 cases (30%) us offered the same information than pm-mri. there was no case where us was more accurate than pm-mri. for the rest of the body malformations: pm-mri offered a better diagnostic accuracy in 5 cases (50%) (e.g. heterotaxy anomalies or vertebral segmentation anomalies). in 3 cases (30%), us offered the same information as pm-mri. there were 2 cases (20%) where us showed major malformations that were not diagnosed on the pm-mri (two cases of cardiac malformation). post mortem mr imaging is more accurate than obstetrical ultrasound in detecting major malformations in the cns as well as in the rest of the body. the present exceptions are cardiac malformations. the examination offers an easy evaluation of the deceased fetus. it provides, in most cases, important additional information. diffusion coefficient and perfusion fraction parameters correlate with gestational age in normal human in vivo placenta: a preliminary study a. antonelli, m. guerreri, s. bernardo, s. capuani, c. catalano, l. manganaro; rome/it to investigate the potential of diffusion parameters derived from a biexponential analysis as marker to evaluate the perfusion quality of normal in vivo placenta. eighteen normal pregnancies, fulfilling the study inclusion criteria, have been analysed at 1.5 t magnetom avanto (siemens, erlangen, germany) without mother-foetal sedation. dw imaging was collected using seven b values: 0, 50, 100, 150, 400, 700, 1000 (s/mm 2 ). three regions of interest (rois) have been considered -central (c), peripheral (p) and umbilical (u) regions. a bi-exponential model was used to obtain perfusion fraction (f), pseudo-perfusion (d*) and apparent diffusion (d) coefficients. pearson test was performed to investigate correlation between diffusion parameters and gestation weeks (gw), body mass index (bmi) and basal glycaemia (bg). the average values on all rois were d=1.41±0.16•10 -3 (mm 2 /s), d*=1.81 ±1.28•10 -2 (mm 2 /s), f=3.28±0.18•10 -1 , in good agreement with the literature. in the c roi, a positive correlation (p<0.04) was observed between f and gw. after 30 gw in the p roi a positive correlation between f and gw (p<0.05) and a negative correlation between d and gw (p<0.0001) were found. no correlation was found between d, d*, f, bmi and bg. conclusion: the f increase reflects normal placenta perfusion physiology. on the other hand, the decrease of d highlights placental parenchyma maturation becoming more fibrotic during late gestational age. bi-exponential model provides more and useful information about placental morphological changes compared to mono-exponential diffusion model. to demonstrate the diagnostic value of fetal mri in the detection of fetal central nervous system (cns) impairment in prenatally echocardiographic diagnosed congenital heart diseases. we retrospectively examined 24 fetuses between 19 gestational weeks and 33 gestational weeks who performed a fetal mri in our institution after a second-line ultrasonography, between april 2010 and october 2015. fetal heart and cns studies were performed with a 1.5 tesla magnet (siemens magnetm avanto) without maternal sedation. prenatal findings were compared to fetopsy results, fetal mri after 30 gw or postnatal mri. in our sample of 24 cases, 7/24 had interatrial septal defect (iasd),intervertricular septal defect (ivsd), and atrioventricular canal defect (cavc), 6/24 had cardiac rhabdomyomas, 3/24 had hypoplastic left heart syndrome and hypoplastic aorta, 2/24 had transposition of the great vessels, 2/24 had fallot tetralogy, 2/24 had aorta coartation and 2/24 had intracardiac masses of uncertain significance. magnetic resonance imaging was able to detect cns impairment: we recognize 11/24 corpus callosum (cc) dysgenesis (4/13 cc hypoplasia, 4/13 complete cc agenesis, 3/13 partial cc agenesis), 7/24 ventriculomegalies or hydrocephalus, 3/24 subtentorial anomalies (dandy-walker, vermian hypoplasia and vermian malrotation) and 3/24 gyration anomalies. due to the high risk of cns involvement in prenatal congenital heart diseases, it is essential to suggest an mri study of the evolving fetal brain especially in complexes forms that suggest a syndromic background. fetal mri of the cns is mandatory in the study of congenital heart disease due to the high rate of encephalic anomalies associated, particularly in iasd, ivsd and cavc. first experiences and diagnostic utility of micro-ct for fetal autopsy j.c. hutchinson 1 , x. kang 2 , s.c. shelmerdine 3 , m. cannie 2 , v. segers 2 , n. sebire 3 , j. jani 2 , o.j. arthurs 3 ; 1 newcastle upon tyne/uk, 2 brussels/ be, 3 london/uk perinatal autopsy remains poorly accepted by parents, despite yielding information that affects the management of future pregnancies in around 30% of cases. microcomputed tomography (micro-ct) has shown promising results in the examination of ex-vivo fetal organs, and may provide diagnostic imaging in cases where traditional autopsy is challenging, and s416 (2017) 47 (suppl 2):s297-s pediatr radiol existing post mortem imaging techniques (ct and mri) provide insufficient diagnostic resolution. our objective was to examine whole fetuses non-invasively using micro-ct, and compare the findings with standard autopsy as the gold standard. in this ethically approved double blinded study, terminated fetuses or miscarriages underwent iodinated micro-ct examination followed by conventional autopsy. images were acquired using a nikon xth225st microfocus-ct scanner with individual specimen image optimisation. forty indices normally assessed at perinatal autopsy were evaluated for each imaging dataset by two independent reporters and a consensus report produced. autopsies were performed blinded to the imaging findings by one of two perinatal pathologists. we examined 8 fetuses, with a gestational age range of 11-16 gestational weeks. 36/320 indices were non-diagnostic (11%), but there was agreement for 271/284 diagnostic indices (overall concordance of 95.4% (95% ci 92.3, 97.3%). in seven out of eight fetuses (87.5%), the same final diagnosis was made following micro-ct examination and autopsy examination; in one case, micro-ct was non-diagnostic. ten false negatives indices included a vsd, laryngeal anomaly, ambiguous genitalia and incomplete bowel rotation, none of which changed the overall diagnosis. three apparent false positives on micro ct were a cloacal anomaly, incidental cystic neck lesion and thymic atrophy, which were not detected at autopsy. micro-ct of early gestation whole fetuses can provide highly accurate datasets with three-dimensional renderings of complex disease processes. this approach confirms the potential of this technology for non-invasive examination of small fetuses. investigation of perinatal body organ diffusion-weighted post mortem mri s.c. shelmerdine 1 , m. cheryl 2 , j.c. hutchinson 1 , n. sebire 1 , o.j. arthurs 1 ; 1 london/uk, 2 southampton/uk objective: diffusion weighted magnetic resonance imaging (dwi) uses water molecule diffusion to generate mr contrast images, and can reveal microstructural or functional changes in tissues, quantified by measuring the apparent diffusion coefficient (adc). the application of dwi to the post mortem setting is appealing as it does not require the administration of an exogenous contrast agent. a recent pilot study of 15 paediatric cases suggested that lung adc values at pm mri may be a useful marker of post mortem interval (time since death; pmi) which has forensic relevance, but other body organs have not been comprehensively evaluated. the aim of this study was therefore to evaluate the relationship between pmi and body organ adc values in a larger cohort of subjects across a wider gestational range in the setting of perinatal death. whole body perinatal postmortem mri with dwi sequences were performed at 1.5t, with b values of 0, 500, 1000 mm 2 /s. mean adc values were calculated from regions of interest (rois) placed in the lungs, myocardium, spleen, renal cortex, liver and psoas muscle. the values were measured by two independent readers, correlated against gestational age and post mortem interval (pmi) using the pearson product-moment correlation coefficient. bland-altman plots were created, and the limits of agreement used to assess the inter-observer agreement of mean adc values. results: eighty fetal deaths and stillbirths were imaged with mean gestational age 31.5 weeks (range: 20 -41 weeks). the mean pmi was 8.9 days (range 2-20 days). there was a weakly positive correlation between pmi and mean lung adc (r 2 =0.03) and spleen adc (r 2 =0.08). no correlation was found with between adc and pmi for the other body organs. there was reasonable inter-observer agreement between the two readers, with mean adc difference 11.8 mm 2 /s (+/-135.1 mm 2 /s). perinatal lung and splenic adc values show a mild increase with increasing pmi. together with other imaging parameters, this may be useful to evaluate organ-specific changes which occur in the post mortem period, particularly in a forensic setting. further research is needed to understand the organ-specific changes which occur in the post-mortem period. usefulness of combined grey-scale and color doppler ultrasonography(us) findings in the evaluation of acute pyelonephritis in children k. lee, j.h. lee; anyang/kr objective: us diagnosis of apn in children can give a valuable information to the clinicians for the early treatment. but the problem of us in the diagnosis of apn is wide range of sensitivity, which is 11-69%. the purpose of this presentation is to evaluate the usefulness of grey-scale us and color doppler us in the diagnosis of acute pyelonephritis in children. from march 2007 to february 2014, 154 children(308 kidneys), 108 boys and 46 girls, aged 2 weeks to 9 years (mean age, 7.7 months) underwent kidney us as an initial diagnostic tool for acute pyelonephritis and follow up dmsa scintigraphy within a week. criteria for acute pyelonephritis on grey-scale image were focal/diffusely increased/decreased echogenicity or loss of corticomedullary differentiation. on color doppler sonography, the criterion was decreased color flow. we classified the us diagnosis of apn into 4 categories. definite, suggestive, possible and normal. when above two grey-scale us criteria and color doppler us criterion are seen, we classified it as 'definite'. when one of greyscale us and color doppler us finding are seen, it was classified as 'suggestive' of apn. 'possible' apn was abnormal finding either on grey-scale or color doppler us. 'normal' was no abnormal findings on grey-scale and color doppler us. we compared above findings with dmsa scan, which is considered as gold standard for diagnosing apn. statistical analysis was performed on all 308 kidneys. the overall sensitivity of our study was 68%(88/129) and specificity was 72%(123/177). the positive predictive value for each definite, suggestive, possible groups were 86%, 60%, and 38% respectively. the negative predictive value for normal group was 75%, which means the false ppv was 25%. the p-value of the definite and suggestive was statistically significant, but the possible was statistically insignificant. in the diagnosis of apn in children, abnormal us finding either on greyscale or color doppler us is not optimal. abnormal us findings both grey-scale us and color doppler us showed good association with dmsa scan and statistically significant. combined grey-scale and color doppler us findings can give a more reliable information in the diagnosis of apn in children. the greater degree of gastric and/or duodenal wall thickening and increased echogenicity are helpful sonographic features in differentiating congenital duodenal anomalies from malrotation. our findings confirm the superiority of us vs ugi for evaluation of duodenal obstruction in neonates and evaluation of gastric and duodenal wall must be added to the constellation of other features to be assessed on us examinations. a measure of renal morphology as an indicator for potential renal failure a.c. eichenberger, p. grehten, c. kellenberger; zurich/ch this study introduces a measure of renal morphology, herein labelled split renal volume (srv), that should be applied as an indicator for potential renal failure and eventual surgical treatment of obstructive uropathy in children. current practice applies dynamic contrast enhanced functional renal imaging (fri) with complex post-processing methods. fri generates a measure of split renal function (srf). reduced values of srf under 45% are currently considered to be an indicator for surgical treatment. this retrospective study compares the accuracy of srv with the accuracy of srf as methods for assessing potential renal failure. materials: srv is a quotient of volumetric measurements. total renal volume is described by the sum of parenchymal volume and intra-renal collecting system volume. srv is designated in this study as the quotient of two ratios: first, the ratio of total renal volume to parenchymal volume of the left kidney; and second, the ratio of total renal volume to parenchymal volume of the right kidney. twenty-two children were studied: 16 (age 3.1±4.5y) with unilateral asymptomatic intrinsic uretero-pelvic-junction obstruction (upjo), and 6 normal controls (age 6.6±4.0y). all subjects underwent mr urography at 1.5t, which provided estimates of srf and srv for each of the 44 examined kidneys. the sensitivity and specificity of both srf and srv for predicting surgical management were determined by comparing the indicators with an expert review panel's decision to operate. the panel was blinded to values of srv. results: when a cut-off value of 45% for srf was used, the resultant sensitivity and specificity of srf for the detection of kidneys at risk were found to be 44% and 86%. the values of srv ranged between 0.3 and 3.5. it was found that a value greater than 1.1 indicated kidneys at risk. when the cut-off value of 1.1 for srv was used, the resultant sensitivity and specificity of srv for the detection of kidneys at risk were both 100%. in this small population, srv proved to be 100% accurate and is superior to srf for detecting kidneys at risk of failure due to obstruction. routine application of srv promises to simplify mr urography by obviating dynamic contrast enhanced imaging studies. further prospective studies are necessary in order to select an optimal cut-off value of srv. factors that can distort the dj flexure mimicking malrotation v. bhalla 1 , s. mohan 2 , k.a. bradshaw 2 , m. thyagarajan 2 ; 1 stoke-on-trent/uk, 2 birmingham/uk to highlight the varied radiological appearances and position of the duodenal-jejunal flexure in children and to discuss its importance in assessing for malrotation materials: retrospective analysis of the multiple fluoroscopic examinations performed in the assessment for malrotation over the past 5 years in a busy tertiary centre results: the classic position of the dj flexure is to the left of left pedicle of l1 and at the level of the duodenal bulb on frontal views and posterior (retroperitoneal) on lateral views. however variations of the normal location can appear, particularly on frontal views, in the upper gi series that can mimic malrotation which has shown to be more common in neonates. we present cases with examples to illustrate the variability in position due to various causes and its implications in the diagnosis of malrotation and volvulus. our case mix includes patients with excessively distended stomachs, large bowel obstruction, renal pelvic dilatation, repeated naso-jejunal and gastro-jejunal tube insertion and in patients post liver transplantation. malrotation and its assessment have serious management and prognostic implications. this presentation demonstrates that the imaging features can be varied, and knowledge about factors distorting the position of the dj flexure is vital in the accurate management of neonates presenting with bilious vomits. retrospective study of prospectively collected data performed at a single tertiary paediatric institution over a 16.5 year period. a total of 1000 consecutive patients, aged <18 years, were reviewed who underwent native renal biopsy. all biopsies were performed within the interventional radiology department. all patients had renal disease requiring a renal biopsy for diagnosis. outcome measures include technical success, early and late complications and the adequacy of histological samples. in addition, age, body weight, glomeruli number, histological data, number of cores, size of the biopsy needle, use of co-axial needle and the rate of tract embolisation/plugging were recorded. results: from september 1999 to april 2016, 1000 patients (mean age: 10.07 years +/-4.65; range 0.14 -18.0 years) underwent native renal biopsy. one hundred ninety-one patients were <5 years of age. nine hundred forty-six patients (94.6%) had a biopsy of the right kidney, 53 patients (5.3%) had a biopsy of the left kidney and 1 patient (0.1%) had a biopsy of a horseshoe kidney. five hundred fifteen patients were female (51.5%). seven hundred sixtynine patients (76.9%) had the procedure performed under general anaes-thetic and 227 of patients (22.7%) had the procedure performed under local anaesthetic (+/-sedation/entonox). mean number of passes of the core biopsy needle through the renal capsule was 2.7. a 16 gauge core biopsy needle was used in 100% of the patients. 81.9% of the patients had three or less passes of the biopsy needle though the renal capsule. the overall complication rate was 2.6% (n= 26). 1.2% (n= 12) of patients had a non-diagnostic biopsy. fifty-five patients underwent a post biopsy ultrasound due to clinical concerns. twenty patients developed perinephric haematoma (19 were treated conservatively; one underwent embolisation and subsequent nephrectomy). four patients developed arteriovenous fistulas. two patients developed post procedure infections (one at the skin site and one a perinephric collection). histology results were reviewed in all patients. the mean number of glomeruli obtained was 26.97 (range 2-87). glomerulonephritis was the most common histological diagnosis (n=464; 46.4%) conclusion: renal biopsy is an extremely useful diagnostic tool for renal disease. there is no published data of this size assessing the outcome of native renal biopsies in the paediatric population. jr usa 1979 a. lassrich germany 1979 j. sauvegrain france 1982 c. fauré france 1982 a. giedion switzerland 1983 e. willich germany 1984 r. astley united kingdom ringertz sweden 1994 d.g. shaw united kingdom 1996 r. lebowitz usa 1996 b. lombay hungary pena spain gold medallists london/united kingdom the dutch group of paediatric radiologists, the hague/the netherlands 1981 g. stake ringertz (espr) & d. kirks (spr) chicago/united states future espr meeting italy european courses of paediatric radiology (ecpr) genoa/italy (neuroradiology) 2000 r.fotter, graz/austria (abdomen) brussels/belgium (thorax) 2006 j-n. dacher paediatric musculoskeletal imaging) references: 1. 2014-stellungnahme-lnt-modell.pdf [internet]. [zitiert 2 an evaluation of paediatric projection radiography in ireland contrast imaging -> application -dectris background ionizing radiation and the risk of childhood cancer: a census-based nationwide cohort study best practices in digital radiography communicating radiation risks in paediatric imaging kinderradiologie-besonderheiten des strahlenschutzes diagnostic imaging and ionizing radiation -canadian nuclear safety commission epidemiology without biology: false paradigms, unfounded assumptions, and specious statistics in radiation science (with commentaries by inge schmitz-feuerhake and christopher busby and a reply by the authors) european guidelines for ap/pa chest x-rays: routinely satisfiable in a paediatric radiology division? eurosafe imaging together -for patient safety image gently campaign back to basics initiative: ten steps to help manage radiation dose in pediatric digital radiography hostens j, u. a. in-vivo dark-field and phase-contrast x-ray imaging safety commission cn. linear-non-threshold model optimisation of paediatric chest radiography optimizing digital radiography of children radiation exposure in diagnostic imaging: wisdom and prudence, but still a lot to understand radiation shielding for diagnostic radiology strahlenhygienische aspekte bei der röntgenuntersuchung des thorax the image gently pediatric digital radiography safety checklist: tools for improving pediatric radiography the standardized exposure index for digital radiography: an opportunity for optimization of radiation dose to the pediatric population gastroenterology and radiology records were searched to identify ibd patients with colonic strictures. all patients underwent an mre within 3 months of colonoscopy. the following colonic parameters were evaluated: bowel wall thickening with luminal narrowing, pre-stenotic bowel dilatation, bowel wall enhancement, and diffusion restriction (if performed). colonoscopy and operative notes were correlated. results: fourteen patients met the inclusion criteria, one with 2 colonic strictures. bowel wall thickening with luminal narrowing at the site of the reported stricture was present in all cases. pre-stenotic bowel dilatation (>3.0 cm) proximal to the reported stricture was present in 11/15 cases. using luminal narrowing and prestenotic dilatation as criteria for diagnosis of a colonic stricture, 11/15 cases were therefore positive on mre. when comparing to colonoscopy, mre diagnosed colonic strictures in 8/12 cases (67%). in the six patients who had surgery, mre accurately diagnosed colonic strictures in 5/6 cases (83%). conclusion: mre is not the primary modality for colonic evaluation, yet diagnosing colonic pathology on mre, particularly strictures, may be beneficial for the referring gastroenterologist in the assessment of these patients. potential strictures on colonoscopy did not agree with mre in all cases, but when correlating with surgery 83% of colonic strictures were accurately diagnosed in a small subset. although mre is not optimized for the evaluation of the colon, colonic strictures can be recongnized in children with crohn's disease.disorders of sexual differentiations in neonates: standardized sonographic evaluation and proposal of a reading grid h. lerisson, e. amzallag -bellenger, f.e. avni, m. cartigny; lille/fr to propose a systematic and structured sonographic approach in neonates with disorders of sexual differentiation (dsd) materials: review of the us pelvic, external genital and adrenal findings in 20 consecutive patients with clinical suspicion of dsd evaluated in the neonatal period. the us survey included: the uterus (absent or visible -with or without hormonal impregnation), the vagina (absent or present (complete or partial)), the gonads (ovaries, testis or unsetermineddysgenetic ) as well as the adrenals (normal, too small or enlarged). the us conclusions were correlated with the endocrinological and genetical work-up of each patient results: twenty cases of dsd have been included us had correctly identified the presence of a uterus in 11 patients. there was one false positive case; 6 among the 11 patients did not show the physiological hormonal impregnation. the 5 vaginal anomalies were correctly evaluated. the gonads were defined correctly as normal testis in 6 patients, normal ovaries in 4 and dysgenetic gonads in 4. they could not be visualized in 6 patients. adrenals were considered normal in 17 patients (one false negative), hypertrophied in 2 and small in one patient. to compare hepatic 2d shear wave elastography (2d swe) in children between free-breathing and breath-hold conditions, in terms of measurement agreement and time expenditure. a cohort of 57 children (12.7±4.3 years) who underwent standardized 2d swe between may and october 2015 were retrospectively evaluated. liver elastograms were obtained under free-breathing and breath-hold conditions and time expenditure was measured. median stiffness, interquartile range (iqr), and iqr/median ratio were calculated based on 12, six, and three elastograms. results were compared using pearson correlation coefficient, intraclass correlation coefficient (icc), bland-altman analysis, and student's t. median liver stiffness under free-breathing and breath-hold conditions correlated strongly (7.22±4.5kpa vs. 7.21±4.11kpa; r=0.97, p<0.001). time to acquire 12 elastograms with free-breathing was lower than that with breath-holding (79.3±32.5sec vs. 143.7±51.8sec, p<0.001). results for median liver stiffness based of 12, six, and three elastograms demonstrated very high agreement for free-breathing (icc 0.993) and for breath-hold conditions (icc 0.994). hepatic 2d swe performed with free-breathing yields results similar to the breath-hold condition. with a substantially lower time requirement, which can be further reduced by lowering the number of elastograms, the free-breathing technique may be suitable for infants and less cooperative children not capable of breath-holding. abstract: pelvi-ureteric junction obstruction (pujo), classified into intrinsic and estrinsic is one of the most frequent urological diseases affecting the pediatric population. extrinsic causes include the presence of crossing vessels, kinks or adhesions. in cases with extrinsic obstruction of puj, colour doppler ultrasound (cd-us) can detect the presence of crossing vessels. in presence of crossing vessels pyeloplasty or vascular hitch can be performed. the aim of the study is to analyze the sensitivity of cd-us and magnetic resonance urography (mru) in visualizing crossing vessels in extrinsic pediatric hydronephrosis in order to decide the correct diagnostic pathway and evaluate in the pre-operative phase which surgical technique and approach (open, laparoscopic or robotic) is the ideal to be performed. a retrospective review of medical records for patients who underwent surgical treatment for hydronephrosis from august 2006 to february 2016 was performed. a descriptive statistical analysis was performed. the presence of crossing vessels at surgery was considered the gold standard. the sensitivity was calculated for both the imaging techniques as a measure of accuracy, evaluating the ratio between the positive cases divided by the those with aberrant vessels identified at surgery. results 220 clinical charts were reviewed. crossing vessels identified at surgery were 73 (33,2% of pujo). the median age was higher in the group with crossing vessels compared to the group without crossing vessels (p< 0,0001). the sensitivity of cd-us was higher compared to mru (93,3% vs 71,7%). before the surgical time knowing which technique and approach have to be managed in hydronephrotic patients with crossing vessels could be very important. according to our preliminary datacollection cd-us has got a higher sensitivity and could be the gold standard technique. study limitations include the absence of specificity, positive and negative predictive values. in the future it could be useful to perform a double blind trial in which children with moderate-severe hydronephrosis will be subjected to both imaging techniques to evaluate not only the sensitivity, but also the specificity, the positive predictive value and the negative predictive value conclusion: conclusions in the pre-operative phase, cd-us could be sufficient for the surgeon to discern between pujo with the presence or the absence of crossing vessels, as it has a higher sensitivity and lower costs compared to mru.urosonography -nonradiant alternative for voiding cystourethrography o.m. fufezan, c.a. asavoaie, s. tatar; cluj-napoca/ro voiding cystourethrography (vcug) was considered the gold standard in the diagnosis and monitoring of vesicoureteric reflux (vur). this method is invasive due to the radiation exposure. in the present the diagnosis of vur can also be established by contrast ultrasound examination, also known as voiding urosnography (vus). the authors will present the role of vus in the diagnosis and grading of the vur and the role of patient position in the detection of vur. the infants and children with congenital anomalies of the urinary tract and/or urinary tract infection have been evaluated with vus. iatrogenic vur, neurogenic bladder and urogenital sinus anomalies were excluded. the presence and the degree of the vur were evaluated. vus has been performed using a protocol similar to the one used for vcug. in conditions of sterile urine, 0.5 ml sonovue and saline solution have been introduced into the bladder until voiding started. the patients were examined both in a supine and an upright position and the following structures have been scanned: urinary bladder, distal part of the ureters and both pelvicaliceal systems during bladder filling, during and after voiding. the visualisation of the ultrasound contrast agent in the upper urinary tract represented a positive vur diagnosis. the grading of the vur has been established based on the same criteria as in vcug. sixty five patients (130 renal units), ages between 2 weeks and 17 years were evaluated (median age ± sd: 3 years ± 4 years and 2 months) through vus. vcug was performed in 6 patients in a maximum of 48 hours after vus. vur has been identified in 35 patients (40.7% renal units). a high vur grade (iv-v) was identified in 19.2% of renal units. for the patients investigated with both methods, the results were concordant in 4 patients. in two patients vur has not been identified by vcug, but was detected during vus. the upright position (in addition to decubitus) revealed vur in 3 renal units in which the reflux was not detected in decubitus. conclusion: vus is extremely useful and reliable in diagnosing and grading vur in pediatrics. the changing of the patient position during examination can improve vur detection.new sonographic features useful in differentiating congenital duodenal anomalies from malrotation: gastric and duodenal wall thickening and hyperechogenicity p. caro dominguez 1 , s. hameed 2 , a. zani 3 , r. moineddin 3 , o.m. navarro kunstmann 3 , a. daneman 3 ; 1 cordoba/es, 2 london/uk, 3 toronto/ca the clinical and plain radiographic differentiation of congenital duodenal anomalies (atresia, web, stenosis) and intestinal malrotation is not always clear. although sonography has been documented as an important diagnostic tool to differentiate these two entities, its role is still not widely appreciated. the purpose of this study was to assess the sonographic features of the gastric and duodenal wall in a large series of neonates with congenital duodenal obstruction as these have not been reported previously. neonates who had surgically proven congenital duodenal anomalies or malrotation were identified from the surgical database in a tertiary pediatric hospital in a period of 15 years (2000) (2001) (2002) (2003) (2004) (2005) (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) . those with an ultrasound performed within 48 hours of surgery were included in the study. imaging was retrospectively and independently reviewed by two readers in chronological order blinded to final diagnosis. a wall thickness of ≥ 2 mm of a distended loop was considered abnormal. hyperechogenicity was recorded when the wall of the stomach or duodenum was brighter than liver or splenic parenchyma. imaging findings in the group with congenital duodenal anomalies was compared to the group with malrotation using fisher's exact test. one hundred eight neonates were included in the study, 40 with a congenital duodenal anomaly, 49 with malrotation (36 with volvulus) and 19 with both. ugi was performed in 61 neonates who had us. the correct diagnosis was provided only by us in 24 of these 61 newborns (39%), only by ugi in 5 (8%), by both in 26 (43%) and by neither in 6 (10%). ugi was performed in 21 children with malrotation and volvulus, eight were diagnosed only by us, four only by ugi and nine by both. the gastric and/or duodenal wall was significantly thicker and more hyperechoic in neonates with congenital duodenal anomalies than those with malrotation (p<0.0001) [fig 1, table 1 ]. conversely an abnormal relationship between the superior mesenteric artery and vein, abnormal position of the third part of the duodenum and the whirlpool sign were found more commonly in neonates with malrotation than those with congenital anomalies (p<0.0001). key: cord-257778-xwu1gdak authors: link-gelles, ruth; dellagrotta, amanda l.; molina, caitlin; clyne, ailis; campagna, kristine; lanzieri, tatiana m.; hast, marisa a.; palipudi, krishna; dirlikov, emilio; bandy, utpala title: limited secondary transmission of sars-cov-2 in child care programs — rhode island, june 1–july 31, 2020 date: 2020-08-28 journal: mmwr morb mortal wkly rep doi: 10.15585/mmwr.mm6934e2 sha: doc_id: 257778 cord_uid: xwu1gdak on june 1, 2020, with declines in coronavirus disease 2019 (covid-19) cases and hospitalizations in rhode island,* child care programs in the state reopened after a nearly 3-month closure implemented as part of mitigation efforts. to reopen safely, the rhode island department of human services (ridhs) required licensed centerand home-based child care programs to reduce enrollment, initially to a maximum of 12 persons, including staff members, in stable groups (i.e., staff members and students not switching between groups) in physically separated spaces, increasing to a maximum of 20 persons on june 29. additional requirements included universal use of masks for adults, daily symptom screening of adults and children, and enhanced cleaning and disinfection according to cdc guidelines.† as of july 31, 666 of 891 (75%) programs were approved to reopen, with capacity for 18,945 children, representing 74% of the state's january 2020 child care program population (25,749 children). * h t t p s : / / w w w . b o s t o n g l o b e . c o m / 2 0 2 0 / 0 5 / 2 9 / m e t r o / new-covid-19-cases-hospitalizations-fall-ri-governor-gives-update-friday/. † https://www.cdc.gov/coronavirus/2019-ncov/community/schools-childcare/ guidance-for-childcare.html#cleandisinfect. § https://wwwn.cdc.gov/nndss/conditions/coronavirus-disease-2019-covid-19/ case-definition/2020/. the case could be ruled out by a negative rt-pcr test result. ridoh quarantined contacts ¶ and conducted symptom monitoring via a weekly phone call or daily text message; symptomatic contacts were referred for testing. a total of 101 possible child care-associated covid-19 cases were reported during june 1-july 31. among them, 49 (49%) symptomatic persons were excluded after receiving negative laboratory test results, 33 persons (33%) had confirmed cases, and 19 (19%) were classified as having probable cases. among the 52 confirmed and probable cases, 30 (58%) were among children (median age = 5 years), and 22 (42%) were among adults (20 teachers and two parents [median age = 30 years]) (table) . overall, 39 (75%) cases occurred from mid-to late july, when incidence in the state was increasing (figure) . cases were confirmed a median of 2 days (range = 0-11 days) after specimen collection. the identification of 101 possible child care-associated covid-19 cases resulted in closures of 89 classes and quarantine of 687 children and 166 staff members, including contacts. cases occurred in 29 child care programs, 20 (69%) of which had a single case with no apparent secondary transmission. five (15%) programs had two to five cases; however, ridoh excluded child care-related transmission because of the timing of symptom onset. in late june, a child aged 2 years attended child care for 6 days while potentially infectious, including 3 days before symptom onset (parent-reported fever to 100.3°f [37.9°c] and chills) and 3 days after symptom resolution. ten of 11 child care contacts were tested for sars-cov-2 a median of 2 days after last exposure (range = 1-3 days); none had a positive test result. epidemiologic investigation by ridoh indicated adherence to ridhs regulations. secondary transmission in four child care programs after july 15 could not be ruled out. in one program, ridoh epidemiologic investigation identified lack of adherence to ridhs regulations, including switching between groups. ten confirmed cases (five children, four staff members, and one parent) were identified among contacts in the program. the program was closed, and 60 children and 21 staff members were quarantined for 14 days. in the second program, three confirmed cases were identified from a single classroom; 26 students and 17 staff members were quarantined. the third program had two cases with symptom onset dates indicating potential transmission; however, no epidemiologic link was identified. the fourth program had two cases, one in a staff member and the other in a child contact of the staff member. the staff member moved among all classrooms, exposing adults and children in the entire program, which was subsequently closed; 37 students and 16 staff members were quarantined. rhode island reopened child care programs in the context of low sars-cov-2 transmission relative to other u.s. states. possible secondary transmission was identified in four of the 666 programs that had been allowed to reopen, all in the last 2 weeks of july, when community transmission in rhode island increased. the apparent absence of secondary transmission within the other 662 child care programs was likely the result of ridoh response efforts to contain transmission and child care programs' adherence to ridhs requirements, in particular maximum class sizes and use of face masks for adults (1) . however, case ascertainment among children is challenging, given high rates of asymptomatic infection or mild disease (2, 3) , and sars-cov-2 infections were likely undetected. despite limited identified secondary transmission, the impact on child care programs was substantial, with 853 children and staff members quarantined, which highlights the importance of community mitigation efforts to safeguard child care programs. adherence to current cdc recommendations remains critical to reducing transmission in child care settings, including wearing of masks by adults, limiting mixing between established student-teacher groups, staying home when ill, and cleaning and disinfecting frequently touched surfaces.** timely public health action, including case investigation and contact tracing, is critical to minimizing outbreaks in child care programs. † † ** https://www.cdc.gov/coronavirus/2019-ncov/downloads/php/open-america/ community-mitigation-quicklinks.pdf. † † https://www.cdc.gov/coronavirus/2019-ncov/php/contact-tracing/contacttracing-plan/contact-tracing.html. absence of apparent transmission of sars-cov-2 from two stylists after exposure at a hair salon with a universal face covering policy epidemiology of covid-19 among children in china rapid asymptomatic transmission of covid-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside wuhan and characteristics of young patients with covid-19: a prospective contact-tracing study all authors have completed and submitted the international committee of medical journal editors form for disclosure of potential conflicts of interest. no potential conflicts of interest were disclosed. key: cord-014687-0am4l5ms authors: nan title: spr 2012 date: 2012-03-29 journal: pediatr radiol doi: 10.1007/s00247-012-2356-8 sha: doc_id: 14687 cord_uid: 0am4l5ms nan dear colleagues, i confess i haven't read many "welcome letters" at the beginning of the spr program book over the years. perhaps the only defensible benefit of this is that there is no preconception about the content of this message…or the length. i will be brief. this meeting is about building bridges…bridges from our past to the future and bridges between all of us who believe fundamentally in maintaining or improving the health of our children. the content, which is detailed on subsequent pages, speaks for itself. this material will be presented during the sessions with an appreciative look back at past accomplishments-the legacy of our subspecialty-with a vision to the future of pediatric imaging. we can only measure how broad and deep our successes have been by connecting with these beginnings. looking beyond the titles (and the speakers), i think you will see that the material is not only about techniques and tactics but about ideas, insights, energy, all conspiring in the creative process … an aggregate for excellence in pediatric imaging. the content is also punctuated by a strong presence of our clinical colleagues. again, this builds bridges. how can we maintain and expand these relationships? moreover, the connections between science and clinical practice are evident in the structured blending of scientific papers and topical presentations by both imaging and clinical experts. this blending is also "fraternal" in that there will sometimes be disagreement and critical commentary, but this is essential in the advancement of medicine. support and criticism make a stronger mortar. in the end, this gathering is about fostering a connected community, including technologists, nurses, physicists and other allied health experts including industry experts. finally, the emblem of pediatric radiology has always been embossed by cooperation, passion, commitment, and humanistic care. i believe the program content, the presenters and you, the participants, all embrace this. i hope that you will feel the spirit and the passion of the meeting and all of us will in many ways be better able to care for children because of this-even if you never read this message! donald p. frush the gold medal of the society for pediatric radiology is our most distinguished honor. the spr medal is awarded to pediatric radiologists who have contributed greatly to the spr and our subspecialty of pediatric radiology as a scientist, teacher, personal mentor and leader. marilyn goske has always wanted to make a differenceand what a difference she has made! her role as an educator, and her lifelong commitment to improving training for residents, fellows, faculty, medical staff and radiologic technologists has resulted in many wonderful initiatives that have benefited all in pediatric radiology. the work she is most proud of-the cleveland clinic web based curriculum, working with the leadership of spr's philanthropic campaign for children, launching the image gently campaign and the pediatric research component within the american college of radiology's dose index registry share a common theme: educating others in providing the best care possible for children. born in berea, ohio, marilyn's father, george, was a chemical engineer. her mother, cornelia aka "corky", loved writing as one of the first women journalists for the associated press and later teaching, passions she passed on to her daughter. while marilyn was blessed with a strong female role model in her mother, it was her brother, james, who was her cheerleader, always pushing her to dream big. he encouraged her to follow in his footsteps first at ohio university, then on to the ohio state college of medicine to pursue an md degree during an era when nursing would have been a more conventional goal. marilyn met her husband rick on a double date in college-unfortunately, they were with different dates! luckily, they were able to get together for an actual date with each other 18 months later. they quickly became engaged and married within a year of that first true date. when rick started his residency in internal medicine, marilyn transferred to the university of connecticut school of medicine in farmington. it was here that she met her first pediatric radiologist-and what a giant-mike ozonoff! when rick moved on to a neurology residency in rochester, new york, marilyn followed and met another pediatric radiology giant: beverly wood, at strong memorial hospital. beverly proved to be a wonderful teacher, mentor, co-researcher and lifelong friend. marilyn describes beverly as inspirational and "fearless" in trying new technologies. it was during her time in rochester that marilyn went to her first spr meeting and, not surprisingly, won the 1984 caffey award for her work on "experimental neonatal intraventricular hemorrhage: clinical, radiographic and pathologic features." by then marilyn had two young children and moved on to the private sector, practicing part-time for several years first in rochester, then in cleveland, ohio. her years in private practice were particularly helpful in learning the importance of patient oriented service-and paved the way for her intuitive public relations strategies when designing the image gently campaign in later years. dr. goske was asked to join the cleveland clinic in 1990, as the first full-time section head of pediatric radiology. it was here that she built a new section and spearheaded the web based education program for pediatric radiology residents with co-founder janet reid. this important free web site with 65 modules is used widely by over 200 radiology residencies nationally and internationally. her passion for education continued, inspiring her to complete a medical education fellowship focused on professionalism within the cleveland clinic lerner college of medicine. her work towards this fellowship has led to many creative educational initiatives including yearly educational summits at the spr. she was named chair of the professionalism committee of the rsna where she along with her committee have sponsored interactive workshops on this topic dear to her heart. dr. goske's energy and effective leadership skills brought her to become involved in the society for pediatric radiology, first as the coordinator for spr's first video-taped course in 1994. mentors diane babcock and carol rumack proposed her for the nominating committee. this was followed by chair of the membership committee, where she organized the first formal survey of the society, then as a board member, then as secretary, and finally as president and chair of the board of directors, completing 12 years on the spr board. working together with stuart royal, she successfully energized the campaign for children raising funds for the research and education foundation of the spr and expanded the work of prior presidents in further organizing the corporate support committee. marilyn's years as president and chairman of the board of the spr were highly successful with many unique strategic goals. she was instrumental in the founding of the junior spr. she led the wonderful 2007 spr national meeting in miami which included the first educational summit to enhance knowledge in adult learning and resident competencies. most people would rest after completing their arduous year as president but as chairman of the board, marilyn was just beginning! she moved to cincinnati children's hospital, joining the radiology department and was named the dr. corning benton endowed chair for radiology education where she got to work with dr. janet strife, another influential mentor and friend. acknowledging spr's long focus on reducing radiation doses in the imaging of children but concerned about the lack of change in practice by a majority of radiologists despite increasing reports of possible side effects, marilyn developed a public relations and awareness campaign. her goal was to inspire all to work towards decreasing radiation exposure to children when possible. with the help of many, she founded the alliance for radiation safety in pediatric imaging and the image gently campaign, initially focusing on ct. her ability to encourage numerous experts and societies to work together and get involved in "child sizing the amount of radiation used" has resulted in a groundswell of research and activity in this area. currently 69 organizations with over 800,000 members have joined the alliance including 24 international societies. the web site, www.imagegently.org, has been immensely successful filled with free information pamphlets in over 12 languages, pqi projects, and modules for parents, physicians, and technologists. the image gently campaign has received several awards including the associations advance america honor roll, rt image magazine group with the "most influence in radiology" and the most effective philanthropy program from aunt minnie. image gently has spawned the creation of the adult-focused image wisely campaign. the alliance has been named by the joint commission, u.s. food and drug administration, and the american medical association in their influential statements on radiation dose as providing much needed guidance and information. marilyn's exceptional talent is inspiring and coordinating experts in multiple fields to work together towards common goals. she continues to work hard on the image gently campaign with more safety and quality messages planned for the coming years. she is also proud of her work with the acr dose index registry and quality improvement registry in ct scans in children in working toward developing diagnostic reference levels with a talented consortium of pediatric radiologists, medical physicists and technologists. she has acted as a national and international expert in her work with the international atomic energy agency, the world health organization and the national council on radiation protection in medicine and the fda. dr. goske's multiple committee appointments are taken seriously, and her work is always meticulous, well thought out, and brought to successful completion. she has been an active member of numerous national and international societies including the john caffey honorary society, acr, rsna, espr, aawr, and scorch. it is important to remember that dr. goske is also a successful researcher with numerous grants obtained through the spr ref including the thorne griscom education award and the rsna scholar grant. she has published over 80 peer-reviewed articles, 19 electronic publications, 7 chapters, and presented 26 scientific exhibits as well as given numerous scientific presentations. an articulate and engaging speaker, she has been invited to give over 130 lectures locally, nationally and internationally. while marilyn has been very focused on her work with the spr, she believes that it is her amazing family and their love that really fuels her life. her husband rick is an internationally known neurologist and researcher in multiple sclerosis. her adult children jamie and brian, both in manhattan, remain close, and spending quality time together as a family remains the joy of her life. whether it is relaxing together in florida cooking or fishing, or taking an exotic vacation to india, being with rick, jamie and brian makes her the happiest. marilyn's genius is partly refusing to take "no" as an answer. along the way, at every turn there were those who believed that what she wanted to do couldn't be done. her approach was to draft the nay-sayers to the team and charge ahead with their willing and enthusiastic help. daniel burnham might have been talking about marilyn and not about his plan for the city of chicago when he said: make no little plans; they have no magic to stir men's blood and probably themselves will not be realized. make big plans; aim high in hope and work, remembering that a noble, logical diagram once recorded will not die, but long after we are gone be a living thing, asserting itself with evergrowing insistence. as an amazing change agent, inspirational leader, and wonderful role model, the spr is proud to honor marilyn goske with the 2012 gold medal. she made big plans! dorothy i. bulas, md pioneer honorees were first acknowledged in 1990 as a means to honor certain physicians who made special contributions to the early development of our specialty. it is time to reevaluate the meaning of the pioneer honoree. the subspecialty of pediatric radiology has been in existence now for more than 50 years. we are beyond "the early development"; we must recognize other pioneering paths and should consider contributions to the subspecialty beyond the bounds of a modality, a technique, an observation or a change in practice. whatever this advancement is, it must be forged with vision, innovative ideas, and the ability to enable and sustain science and application. george s. bisset, iii, m.d. why george bisset? has he been part of the pediatric radiology landscape these last ten years? been part of the dialogue that has been increasingly influential across all of radiology, a conversation steeped in a deep tradition of excellence in diagnosis and treatment, and the safety and welfare of our children? been a leader in science and application? part of the landscape? no. but he has been beyond that and has worked tirelessly within the horizon, surveying…a step before, but guiding us on towards our destiny. a conversant? part of the dialogue? maybe. but he has been defining thought and concept upon which such conversation is born and nurtured. part of the science and application? yes, as much as anyone who promotes, who facilitates and sustains discovery, then here we are. horizons, innovation, and the gift of en-abling…what else is needed to define a true pioneer? how was this done? simply stated, george bisset has devoted at least the last decade to the advancement of our specialty in truly novel ways through his leadership, especially in rsna and the abr. in the rsna, as the scientific program committee chair several years ago he was instrumental in the conception, development and implementation of the integration of scientific papers and refresher course topics. this has been a resounding success, is currently used in other categories during rsna and is a model for other meetings, including the annual meeting for the society for pediatric radiology over the past few years. pediatric radiology was first in this effort. george continued to endorse topics that were marquees for pediatric radiology over the year in his education role on the rsna board of directors. he endorsed and implemented the pediatric campus concept at the 2011 rsna. early returns are that this was an extremely successful model to consolidate experts in pediatric radiology (and those interested in this subspecialty), pertinent science, education and administration. george is now the president of rsna, perhaps the most widely respected scientific and educational organization for our profession across the globe…and i would argue, with more promise for our future success in pediatric radiology than has ever existed. and george bisset, who through two terms as the pediatric trustee for the board of trustees for the abr, again, was on the horizon of a critical, sometimes perilous, and complete transformation of our certification examination process, always mindful of his constituency and colleagues, his duty as a physician, and the public and patients. this required delicate diplomacy, forward thinking, professionalism, and enlistment of a cadre of experts from within our subspecialty to assure excellence in pediatric radiology through abr certification. he was also a leader in the development, validation and implementation of the imagerich computer based examination model (the pediatric caq) now the standard for the new abr examinations. with these successes in mind, who better to embody the concept of bridging horizons that is the theme for this entire meeting? if you were looking for more numbers and accolades, i apologize. here are some: more than 225 contributions to medical and scientific literature, advancing care through pediatric body ct and mr imaging research, a litany of presentations and invited lectures, vice chairs, chairs, chiefs, boards of directors, committee member and committee leader, clinical excellence including as a pediatric cardiologist and interventional radiologist, a superb speaker and author.… all are on his cv but i believe serve really as signposts for his gifts, some of those mentioned above, that a cv simply cannot convey. he could have played it safe with all of these successes on his cv. but pioneers don't play it safe. they are on the horizon, too busy defining thought and enabling (our) advancement-building bridges. i believe it is time to reevaluate the meaning of the pioneer honoree and i have the greatest honor and pleasure of introducing george s. bisset, iii for the pioneer award for 2012. linked with past awardees, he continues an exceptional legacy and i don't believe his explorations and discoveries are finished… donald p. frush, md the society bestows presidential recognition awards on members or other individuals whose energy and creativity have made a significant impact on the work of the society and its service to its members. in 1999, david kushner was recognized by the spr with its first presidential recognition award for his vision and foresight in working with both the american college of radiology (acr) and the society for pediatric radiology (spr) in developing an important new relationship and for his service to the spr. in summarizing his considerable efforts for that award, i noted that he "contributed substantively to the increased visibility of the spr within the acr. his tenure as our treasurer placed our organization on a firm financial foundation." with the current award, the society recognizes his indefatigable continuing efforts on our behalf including: his work with the acr: 1. establishing a pediatric radiology caucus at the annual acr meeting, 2. convincing the acr of the value of managing specialty societies by making the spr its first successful new model for imaging society management, 3. advocating tirelessly for pediatrics and children's health within the acr by serving on the council steering committee and then as acr council vice speaker and speaker, 4. helping establish the first pediatric commission, assuring that pediatric issues will receive support of the college and its resources while serving on the board of chancellors of the acr for the past five years. the spr's "image gently" campaign was a beneficiary of this pediatric commission of the board of chancellors, 5. continuing to shepherd and contribute to the pediatric component of the acr practice guideline process. his work with the spr: since his earlier award, david has served as: foundation from 2000 to 2003, including the launch of the formal fundraising effort, "the campaign for children," 2. spr president 2003 -2004 , organizing and running a very successful meeting in savannah, 3. chair of the board of directors of the spr from 2004 to 2005, including leading a strategic planning process that resulted in a new, more focused division of labor amongst board members and defined board responsibilities. david was born in fargo, north dakota, received a ba from the university of minnesota, and received his medical education at the university of pennsylvania. this was followed by two years of training in pediatrics at children's hospital, boston. he then did a two-year fellowship at the national institute of health in bethesda, performing research in embryology and teratology. he returned to massachusetts general hospital for training in diagnostic radiology. this was followed by a year of residency in pediatric radiology at children's hospital boston, followed by a one-year fellowship. he then became director of the pediatric radiology section at massachusetts general hospital, a position he held from 1979 to 1988. from 1988 to 2005, david was chief of the division of diagnostic imaging and radiology at children's national medical center in washington, dc attracting a strong faculty, training many fellows and promoting research. during that time, he served as a volunteer radiologist and pediatrician to inner city healthcare systems aiding the indigent and homeless, and developing telemedicine capabilities linking free clinics with radiology experts. in 2005, our man inside the beltway moved a bit outside by accepting the medical directorship of radiology at the children's hospital of the king's daughters in norfolk, virginia, and professor of radiology and pediatrics at the eastern virginia medical school. he assures me that life there is good, being a bit more "laid back" with fishing and sailing just outside the door. he also finds time for italian cooking and practicing jazz on his several guitars. fortunately for all of us in the spr, david is close enough to our central office and the acr that he will be able to continue work on our behalf for many years to come. the society bestows presidential recognition awards on members or other individuals whose energy and creativity have made a significant impact on the work of the society and its service to its members. the 2012 spr presidential award is given in recognition of stuart's numerous significant and outstanding contributions to the spr over many years of service. the awardee is selected by the honors committee, a committee comprised of the three most recent past presidents of the society. dr. royal is a proud native of birmingham, alabama. he is a second generation physician who came naturally to his desire to care for children as the son of a pediatrician, arnold royal, who took care of children in the birmingham community until he was 79 years old. dr. royal attended rice university in houston, texas followed by md and ms degrees from the university of alabama at birmingham. he subsequently moved to san francisco, where he completed a pediatric internship followed by a diagnostic radiology residency at the university of california, san francisco. dr. royal credits dr. charles gooding at ucsf for influencing his decision to pursue a career in pediatric radiology. during his internship stuart observed dr. gooding make a plain film diagnosis of tapvr, type 3 on a severely ill and perplexing newborn, and he was immediately hooked into radiology. while at ucsf dr. royal was also appointed as a national institute of health research fellow in the department of radiology. following residency, stuart completed a fellowship in pediatric radiology at the children's hospital medical center in boston. from boston, stuart returned to his roots in birmingham, alabama in 1980, where he was appointed as a pediatric radiologist at the university of alabama and subsequently the children's hospital in birmingham. in recognition of his outstanding leadership skills and accomplishments at the children's hospital, dr. royal was appointed as the radiologist-in-chief in 1987 , and subsequently the harry m. burns endowed chair of pediatric radiology. he also holds appointments as clinical professor of radiology and pediatrics at the university of alabama at birmingham and serves on the children's hospital board of trustees. at alabama dr. royal has earned the high esteem of his colleagues, referring physicians, and staff for his outstanding clinical acumen as a diagnostic radiologist and for his undaunting commitment to excellent care of children. colleagues describe stuart as one who fosters a strong work ethic, high commitment to teaching, and sincere compassion for children. in 2006, stuart was the recipient of the children's advocate award by childcare resources for improving the quality of care and access to radiological services for underserved children in birmingham. stuart has been married to the love of his life, barbara royal, for the past 40 years. stuart and barbara are the proud parents of two very accomplished children, jeremy a budding radiologist in training at the university of alabama, and rachael, who has an mba and works as a vice president for moody's in new york. stuart and barbara are also the proud grandparents of three grandchildren. in conversation, stuart is quick to pull out his iphone and share the latest pictures of family members while recounting their latest activities and milestones. throughout his professional career, dr. royal has worked tirelessly to advance the mission of the society for pediatric radiology. he is past president and chairman of the board of the spr and has served on numerous spr committees. he ran a highly successful spr meeting in new orleans in 2005. those in attendance will recall the jubilant parade stuart led through the streets of new orleans to culminate the meeting. as president and then chair of the spr board, stuart played a critical and instrumental role in bringing the spr management contract under the umbrella of the acr. the synergy achieved by the spr-acr relationship has yielded results well beyond a simple management contract. pediatric radiology and spr now have a voice at the "radiology table." stuart has also been a strong advocate for supporting translational research to advance the care of children via imaging. to help achieve this goal, he has worked aggressively to secure increased funding for the society of pediatric radiology research and education foundation. following the launch of the ref's campaign for children in 2000, stuart made it his personal mission to work with the leadership of the society, both past and present, to discuss major gifts to the foundation. through stuart's personal effort, the foundation received pledges for many significant leadership gifts, including from spr pioneers drs. hooshang taybi and ed singleton and from himself and barbara. the spr is highly fortunate to have benefited from stuart's numerous contributions and dedication to the care of children. the society is very proud to bestow the 2012 president's award on dr. stuart a. royal. the society extends honorary membership to individuals outside of pediatric radiology who have made outstanding contributions to the care of children. this evening, dr. harvey l. neiman, whose leadership of the american college of radiology is resoundingly praised, is the recipient of the 2012 honorary member award. for 2012, as in 2007 when his contributions were similarly recognized, dr. neiman's selection by the society for pediatric radiology honors committee was made in appreciation for the strength of his efforts to further the spr's philosophy, goals, and programs for responsible diagnosis and treatment of the young patient as embodied in the acr and spr's "image gently" campaign. image gently has succeeded not only in raising awareness of the great diagnostic benefits we can offer to pediatric patients but also directs us to acknowledge the downside of overzealous diagnostic efforts where excessive radiation becomes a risk. importantly, the "image gently" campaign, an upbeat, positive program rather than a punitive one, a smile rather than a frown, makes pediatric and all radiologists aware that their best practice reflects balanced, educated, up-to-date utilization of state-of-the art technology with exercise of responsible leadership in protecting the pediatric patient. for adults, awareness of the need for patient protection is communicated in image wisely. dr. neiman's vision and successful achievements are evident on every page of his curriculum vitae. a consummate strategist in assembling teams to make forward-looking goals a reality, harvey now stands at the top of our specialty as the first physician executive director of the american college of radiology. at this time in big-business medicine, as we see the physician, leader of the patient care team, being diminished to one of many "providers," it is so important for our patients' well-being for us to recognize the obligations commanded by our training, clinical experience and commitment. dr. neiman's recognition of the need for physicians' leadership in improving the quality of patient services and his development of programs in all areas of the college's activities have been just short of miraculous-image wisely for adults, quality and safety including the performance guidelines and accreditations, education, government relations, economics, imaging metrix, acrin, and the new radiology leadership institute-to name only a few. all have contributed significantly to the care of our patients and the stature of our specialty. dr. neiman was born in detroit and attended mumford high school. from wayne state university, he received his b.s. in 1964 and his md in 1968. harvey's postgraduate training was at the university of michigan, where he was a resident in radiology (1969 -1972 ), chief resident (1971 , and a 1972-73 fellow in angiography (cardiovascular radiology), receiving abr certification in 1973 and a caq in vascular and interventional radiology in february 1995. dr. neiman often expresses his gratitude to and profound respect for his mentor and beloved chief at the university of michigan, dr. william martel. dr. neiman was chief of cardiovascular radiology at walter reed army hospital and a lecturer in cardiovascular radiology at the afip from 1973 -1975 . in 1975 , he joined the northwestern radiology faculty, rising to professor in 1981, and for ten years he headed up the section of angiography and sectional imaging, advancing its technology and honing the skills of northwestern's radiology residents. harvey also offered a highly sought-after fellowship in interventional radiology, us, and ct. in 1985, dr. neiman left northwestern to assume the chair in medical imaging at the western pennsylvania in pittsburgh. i was the first woman to have completed his fellowship in us, ct, and interventional radiology at northwestern and accompanied him to pittsburgh. his tenure at west penn attests to his talent in making his visions a reality: the department became a highly respected, successful academic private practice notable in many areas including ultrasound, breast and women's imaging, and interventional radiology. harvey instituted an excellent radiology residency program in 1988 as well as fellowship programs in 1986 in the areas of excellence noted above. during the 40 years since harvey received his md, he has been awarded honors from many national, international, and specialty societies, has been an invited lecturer over 181 times on ultrasound, interventional radiologic, radiologic educational, management, turf issues, disruptive and new technology topics to name just a few. dr. neiman, who was a founder of the sru (society of radiologists in ultrasound), has to his credit 122 peer-reviewed articles, 69 scientific presentations and 20 exhibits, a text co-authored with dr. james yao, angiography of vascular disease (1984) , and 26 book chapters. he has received many honors including fellowship in the american college of radiology, american institute of ultrasound in medicine, society of radiologists in ultrasound and the society of cardiovascular and interventional radiology (now sir). as part of his strong commitment to the future leaders of radiology, for diagnostic radiology he has served as a member of the residency review committee of the accreditation council for graduate medical education. he has been a member of the american college of radiology and its committees and commissions for many years including the commissions on education, ultrasound, and economics. he also served as chair of the commissions on ultrasound and economics. from 1994 to 2002 , he was a member on the acr board of chancellors, serving as its chairman 2000-2002. he was president of the radiology advocacy alliance from 1998 to 2000. in 2003, nine years ago, dr. neiman became the acr's executive director. he currently serves in this position, where his excellent business skills, knowledge of health policy and economic issues, and strong administrative background have furthered our specialty. his goal, to ensure that the acr's resources benefit all radiologists and patients across all economic strata, is evident in his actions at the college. harvey has a devoted, wonderful family that often included me and my youngest daughter on many pittsburgh occasions. his beautiful, elegant wife of many years, ellie neiman, is here tonight to celebrate with him the spr's recognition of his many achievements. dr. neiman has two accomplished, lovely daughters, jennifer, extremely successful in her marketing career, and hilary, an attorney. jennie's husband, dr. seth kligerman, one of many young radiologists whom harvey has mentored, is on the radiology staff at the university of maryland. how harvey has had time between, through, and among all of these achievements to have become mentor, colleague, and friend to me and to so many others who have been inspired by his ability to see into the future and to shape it in a positive way is remarkable. now that dr. neiman has taken all of radiology under his wing, not just its component parts, the future of our specialty, one of the best, can be assured but also recognized for its centrality to all of medicine. it is my honor and privilege to introduce to you harvey l. neiman md, facr as this year's society for pediatric radiology honorary member. the singleton-taybi award is given in honor of edward singleton and hooshang taybi, in recognition of their personal commitment to the educational goals of the spr. initiated in 2006, the award is presented annually to a senior member of the spr whose professional lifetime dedication to the education of medical students, residents, fellows, and colleagues has brought honor to him/her and to the discipline of pediatric radiology. it comes as no surprise to those who know him that dr. daneman, "dr. d" as some of us call him, has been named the 2012 recipient of the singleton-taybi award in recognition of his many years of dedication to the education of residents, fellows, and colleagues. born in south africa in 1947, he received his medical degree at the university of the witwatersrand, johannesburg, receiving the harwood-nash award for the most successful student in surgery. initially, dr. d thought he would become a pediatric surgeon; but after passing the part i examination offered by the royal australasian college of surgeons, he changed his mind and began his training in diagnostic radiology. he chose a radiology residency at the royal prince alfred hospital, in sydney, australia. this included a year in pediatric radiology at the royal alexandra hospital for children in sydney where his interest and love of pediatric radiology began. dr. d then had the foresight to pursue pediatric radiology fellowship training at the hospital for sick children in toronto, canada. after completing the fellowship, he was immediately offered a position as staff radiologist at "sick kids." he became director of body imaging in 1984 and radiologist-in-chief in 1988 serving in that capacity for 7 years. his management style was simple but effective. he chose staff that were young, but smart and innovative. he nurtured them and provided them with all the tools they needed to become successful professionals, like him. but contributing to his own department was not enough for him. he also found the time and strength to contribute, teach, train, and help pediatric radiologists in the most remote portions of the globe in every continent, which resulted in recognition from prestigious organizations in places such as south america, israel, europe, taiwan and australia: he is an honorary member of the european society for pediatric radiology and the sociedad latinoamericana de radiologia pediatrica as well as other national societies. dr. d is an "institution" inside the great institution that is sick kids. his teaching is unique and praiseworthy in being enthusiastic, provocative, and fun at the same time. his lectures have been regarded as both instructive and practical by his students and trainees due to his special gift of making the most complicated things look as simple as possible. in sharing his diagnostic knowledge and know-how, he passes his own, innate teaching spirit on to his apprentices. he has earned several awards for this, including the outstanding teacher award granted by the university of toronto fellows at sick kids for the past 5 consecutive years. dr. d receives numerous invitations to present at national and international meetings and symposia and has been invited as a visiting professor to more than a hundred institutions across the globe. he does not only teach us the ins and outs of pediatric radiology, but he makes sure that we learn to love it and understand the importance not only of good practice but also the imperative to pass knowledge on by teaching and publishing. dr. d is someone who inspires us to reach beyond our limits, someone we want to emulate. he shares his knowledge, his wisdom, and his advice freely. he shares with us the most incredible secrets of his own career, so we understand from his personal experience. dr. d never tells you what to do, he suggests to you, in an incredible articulate fashion, what you want to do yourself. dr. d has been and is for many of us, more than an educator, more than a mentor, he is our "coach." well before this concept was introduced into medicine by a. gawande 1 , dr. d intuitively had the vision to "coach" his trainees, trying to get the best out of them, without pressure, but with love and passion, and especially emphasizing the importance of achieving a worklife balance in order to prevent the now so common "stress and burnout" affecting the radiology community 2 . he warned us that many high achievers reach their goals only at the expense of their personal lives, but dr. d has been as successful personally as he is professionally. his wonderful wife of 40 years, louise, his two daughters and his recently newborn granddaughter serve as sources of strength and pride. he is a truthful and generous friend to many, both in and out of radiology. it is not uncommon for many of us, who came through sick kids, to come back and visit and be invited to his house to share a wonderful dinner with other invitees, who may be radiologists from north america or from other parts of the globe visiting sick kids to learn from him. dr. daneman's research has widely influenced the field of pediatric radiology. examples include the work of dr. daneman and his colleagues on intussusception, which has promulgated the use of ultrasound for diagnosis, and the use of air enema for reduction. this approach has been adopted as standard practice at many institutions in north america and across the globe. to share his research with others in the field, dr. daneman has authored or co-authored more than 200 publications, including peer reviewed articles and book chapters on a wide range of topics related to the imaging of children. dr. d is one of those rare people who are irreplaceable. he is a superb teacher, a gifted academician, a capable administrator, and a person called "friend" by so many of us. we are thrilled and proud to present our society's singleton-taybi award to dr alan daneman in recognition of his lifelong accomplishments and personal commitment to the educational goals of the spr. we cannot imagine anyone more deserving of this award than dr. d. thank you "coach"! monica epelman, md and oscar navarro, md john caffey, md 1895 -1978 dr. caffey was regarded throughout the world as the father of pediatric radiology. his classic textbook, pediatric x-ray diagnosis, which was first published in 1945, has become the recognized bible and authority in its field. the seventh edition of this book was completed several months before his death in 1978. it has been among the most successful books of its kind in the medical field. dr. caffey was born in castle gate, utah on march 30, 1895 . it is interesting that he was born in the same year that roentgen discovered the x-ray. dr. caffey was graduated from university of michigan medical school in 1919, following which he served an internship in internal medicine at barnes hospital in st. louis. he spent three years in eastern europe with the american red cross and the american relief administration, and returned to the united states for additional training in medicine and in pediatrics at the universities of michigan and columbia, respectively. while in the private practice of pediatrics in new york city at the old babies hospital of columbia university college of physicians and surgeons, he become interested in radiology and was charged with developing a department of pediatric radiology in 1929. he frequently expressed appreciation and admiration for the late ross golden, chairman of radiology at columbia presbyterian hospital, who allowed him to develop a separate department of diagnostic radiology without undue interference, and who was always available to help and advise him. dr. caffey's keen intelligence and inquiring mind quickly established him as the leader in the fields of pediatric x-ray diagnosis, which recognition became worldwide almost instantaneously with the publication of his book in 1945. dr. caffey received many awards in recognition of his achievements. outstanding among these were the mackenzie davidson medical of the british institute of radiology in 1956, the distinguished service award of the columbia presbyterian medical center in 1962, the outstanding achievement award of the university of michigan in 1965, the howland award of the american pediatric society in 1967, the jacobi award of the american medical association in 1972, and the gold medal award of the american college of radiology in 1975. he had been a member of the american journal of roentgenology. he was a counselor of the society for pediatric radiology and was an honorary member of the european society of pediatric radiology. dr. caffey's contributions to the pediatric radiologic literature were many. he was instrumental in directing attention to the fact that a prominent thymic shadow was a sign of good health and not of disease, an observation that literally spelled the end to the practice of thymic irradiation in infancy. infantile cortical hyperostosis was described by him and is called "caffey's disease." dr. caffey in 1946 first recognized the telltale radiographic changes that characterize the battered child, and his students helped disseminate his teachings about these findings. it was dr. caffey who first recognized and descried the characteristic bony changes in vitamin a poisoning. he recognized and described the findings associated with prenatal bowing of the skeleton. in 1963, three years after his retirement from babies hospital, he joined the staff of the children's hospital of pittsburgh as associate radiologist and as visiting professor of radiology and pediatrics at the university of pittsburgh school of medicine. although dr. caffey came to children's hospital and the university of pittsburgh in an emeritus position, he worked daily and on weekends throughout the years he was there. in pittsburgh, he made four major new contributions to the medical literature. he described the entity, "idiopathic familial hyperphosphatasemia." he recognized and described the earliest radiological changes in perthes' disease. he called attention to the potentially serious effects of shaking children, and used this as a subject of his jacobi award lecture. he described, with the late dr. kenny, a hitherto unrecognized form of dwarfism that is now known as the caffey-kenny dwarf. the john caffey society, which includes as its members pediatric radiologists who have been intimately associated with dr. caffey, or who have been trained by his students, was established in 1961. this society is now among the most prestigious in the field of radiology. his book and the society named in his honor will live on as important memorials to this great man. his greatness was obvious to all who worked with him. he was warm, kind, stimulating, argumentative, and above all, honest in his approach to medicine and to x-ray diagnoses. his dedication to the truth was expressed in his abiding interest in the limitations of x-ray signs in pediatric diagnosis and in his interest in normal variation in the growing skeleton. he was concerned with the written and spoken word and was a skilled semanticist. his book and his articles are masterpieces of language and construction. he stimulated and was stimulated and loved by all who had the privilege of working with him. radiology and pediatrics have lost a great man, but they shall ever have been enriched by his presence. interstitial lung disease, which is more common in infants than older children, is defined as a rare heterogeneous group of parenchymal lung conditions primarily due to underlying developmental or genetic disorders. affected infants typically present with clinical syndromes characterized by dyspnea, tachypnea, crackles, and hypoxemia. mainly due to a lack of evidence based information regarding underlying pathogenesis, natural history, imaging findings, and histopathologic features of interstitial lung disease, the understanding of interstitial lung disease in infants has been limited in the past. however, in recent years, the understanding of interstitial lung disease in infants has been substantially improved primarily due to: 1) advances in imaging technology for better detection; 2) improvement of thoracoscopic techniques for lung biopsy; 3) established pathologic criteria for consistent diagnosis; and 4) development of new classification system based on underlying etiology of the interstitial lung disease. in fact, several forms of interstitial lung disease in infants that exhibit distinct clinical, radiological, and pathological patterns are currently emerging. the overarching goal of this article is to review a new classification system, imaging findings, and pathological correlation of interstitial lung disease in infants. improved understanding of this often challenging disorder can aid in early and accurate diagnosis, which in turn, will result in improved patient care. large airway disease in pediatric patients: impact of advanced post-processing techniques catherine m. owens, bsc mbbs mrcp frcr the introduction of multidetector row computed tomography (mdct) scanners has altered the approach to imaging the pediatric thorax. in an environment where the rapid acquisition of ct data allows general hospitals to image children instead of referring them to specialist pediatric centers, it is vital that general radiologists have access to protocols appropriate for pediatric applications. this lecture will focus on the main principles of volumetric ct imaging that apply generically to all mdct scanners and in particular we describe the reconstruction techniques for imaging the pediatric thorax and the low-dose protocols used in our institution on a 64-slice dual source ct scanner. examples of important clinical applications with the impact and added value of post processing are also given. neoplasms, by definition, comprise an abnormal uncoordinated proliferation of cells that persists even after the inciting stimulus as ceased. the resulting mass may be benign or malignant and arise from any tissue that is normally found in the location where the mass develops. thus, tumors of the chest may arise from bone, lung, pleura, lymphatics, muscle, etc. whether benign or malignant, chest masses may be incidental findings on imaging obtained for other reasons. this presentation will focus on malignant tumors of the chest, address the imaging characteristics and staging of the most common chest malignancies and discuss characteristics that may aid in distinguishing these lesions from their corresponding benign or infectious counterparts. included in this presentation will be the most common chest wall malignancies (ewing family of tumors and rhabdomyosarcoma), mediastinal malignancies (lymphoma, germ cell tumors, and neurogenic malignancies) and pulmonary primary malignancies (pleuropulmonary blastoma and carcinoid). the changing appearance of selected tumors in patients treated with new targeted therapies will be introduced. lung disease is the most common chronic disease of childhood, but young children cannot perform the breathing maneuvers required for the most commonly used method for assessing lung function, spirometry. ct provides exquisite structure information about the lung but concerns regarding the long-term consequences of the relatively high radiation dose limit its use particularly in the pediatric population. magnetic resonance imaging (mri) has the potential to provide regional information about the lung without the use of ionizing radiation. while conventional proton mri has found widespread clinical application in most organs of the body, mri of the lung lags behind because the lung is intrinsically difficult to image with mri. the strength of the mr signal depends on the physical density of protons in the tissue being imaged and the local environment of the protons. the lung has a low physical density and thus a low proton density so little mr signal is generated by the lung. furthermore, the magnetic susceptibility effects from its many air-tissue interfaces cause what little signal is generated to rapidly decay so that the lung typically appears dark on conventional proton mr images. a variety of strategies have been developed to overcome the inherent difficulties of mri of the lung, resulting in recent substantial improvements in image quality. additionally by administering an inhaled gaseous contrast agent, such as the hyperpolarized noble gases helium-3 or xenon-129, direct visualization of lung airspaces in an mr image is possible. a number of unique strategies for evaluating the structure and function of the human lung using hyperpolarized gas mri have been developed. although the level of structure detail possible with lung mri may never equal that of ct, mri may nonetheless has the potential to provide clinically useful information and be a sensitive, effort independent test of pediatric lung disease. for a matter of time, we will focus in this presentation only on the following: intestinal malrotation a normal visceral situs can be inferred sonographically in relation to the right-sidedness of the superior mesenteric vein, to the retromesenteric location of d3 and to the right iliac position of the ileocecal valve. conversely, intestinal malrotation is likely when the 3 aforementioned features are reversed. in addition, cdu can display the whirlpool pattern in case of midgut volvulus or internal hernia, alleviating the need for preoperative opacification. the reliability of us in diagnosing intussusception is well documented since the early 1990s. the value of us in predicting the success or failure of pneumatic reduction and/or bowel necrosis is more debatable, based upon a coexisting bowel occlusion, the presence of interloop fluid, bowel wall changes (intramural air, dilated mural vascular channels), absent blood flow at cdu. the continuous down-grading of us in comparison to ct, and the opposite conclusions of various series regarding imaging of pediatric appendicitis are based upon different prerequisites and definitions. historically and in most usa institutions, sonography reports are either negative (entire normal appendix), positive (abnormal inflamed appendix), or equivocal (non-visualization or partial visualization of appendix). the equivocal group is then logically investigated by a subsequent abdominal ct. in europe, some usa centers, and in our practice, us reporting include 4 groups and take into account ancillary findings: 1. normal appendix (blind-ended, lamellated, compressible, <6 mm in diameter, without peristalsis; 2. appendix not depicted, no secondary signs; 3. appendix not depicted, with one of the following: hyperchoic mesenteric fat, fluid collection, local dilated small bowel loop; 4. appendix inflamed. group 3 represents most cases of perforated appendicitis, groups 1 and 2 the negative sonogram. ct is then indicated only in obese patients and to assess the feasibility of percutaneous interventions. inflammatory bowel disease in the recent literature, mr enterography is often preferred to ct enterography. small bowel series look prehistoric and us is rarely mentioned. sonography however is very valuable both for screening children presenting with abdominal pain, diarrhea, weight loss, or gi bleeding and for following the course of the disease and searching for complication. hypervascularization has been proved to parallel the disease activity. initially mentioned by dr. rita teele, the interest of us for differentiating high-intermediate/low varieties of imperforated anus has been re-emphasized more recently. a perineal rectal cul de sac distance of 15 mm is quoted as the significant cut-off value. us can also display rectourinary fistulae outlined by air. update on mdct and mri of hepatobiliary disease in children: what's new lisa h. lowe, md a variety of disorders may affect the pediatric liver. recent advances in histopathological knowledge and imaging techniques have led to important changes that radiologists must be aware of in order to allow for an accurate limited differential, and in some cases, specific, diagnosis. this presentation will focus on recent developments that have lead to a better understanding of the embryopathogenesis for fibropolycystic liver diseases (including choledochal cysts and caroli disease), histopathological findings that have led to new classification systems for of pediatric vascular anomalies, technological advances and contrast agents in magnetic resonance imaging that are useful to characterize and limit the differential diagnosis of hepatic masses. diagnostic errors in pediatric abdominal imaging: diagnostic pearls and pitfalls george a. taylor, md this presentation reviews the types of diagnostic errors in abdominal imaging occurring over a 13-year period in an academic pediatric radiology practice. radiologists engage in two interrelated processes when interpreting imaging studies: perception and analysis. failures in perception (failure to identify an important finding) are a common source of diagnostic error in pediatric imaging, while failures in the analytic portion of the process (over-or faulty interpretation of a finding) are not as common. under-interpretation of findings can be related to a number of perceptual and visual phenomena including visual isolation where attention is selectively focused on a main area of the image while less or no attention is given to secondary areas, and satisfaction of search which occurs when additional lesions remain undetected after detection of an initial lesion. many analytic errors are the result of commonly used heuristics or shortcuts in reasoning. these include the availability heuristic in which likelihoods are based on memory of a similar case, the framing effect in which a different diagnosis is reached based on how the information is presented, and the anchoring heuristic in which the initial impression is difficult to change, despite conflicting new information. another recognized pitfall is blind obedience, in which a diagnostician stops thinking when confronted by authority. this authority can be human or technical (reliance on a laboratory value). finally, diagnostic errors can result from an attitude of overconfidence. examples of these heuristics and strategies to minimize cognitive errors will be discussed. marta hernanz-schulman, md, faap, facr this session will consider abdominal masses that present in the neonatal period, spanning developmental, inflammatory and neoplastic conditions. time constraints do not allow an exhaustive list or description, but the more important or frequent lesions are discussed. the presentation is subdivided by systems. the renal section discusses various conditions presenting with hydronephrosis, such as ureteropelvic junction obstruction and duplication anomalies, followed by autosomal recessive polycystic kidney disease and multicystic dysplastic kidney, cystic entities commonly presenting in the perinatal period. neoplastic renal entities include lesions with benign behavior, such as ossifying renal tumor of infancy, with the discussion extending to entities with very poor prognosis such as clear cell sarcoma and rhabdoid tumor, while discussing the congenital mesoblastic nephroma, its histologic subtypes and the differences in their presentation, imaging findings and clinical behavior. suprarenal lesions include the adrenal hemorrhage, congenital neuroblastoma and subdiaphragmatic sequestration. hepatic lesions include developmental anomalies that present as mass lesions, such as choledochal cysts, vascular lesions such as congenital and infantile hemangiomas, and neoplastic lesions such as the mesenchymal hamartoma and hepatoblastoma. differences in clinical presentation, imaging characteristics and behavior of the lesions are discussed. the section on pancreatic lesions discusses pancreatic cysts and pancreaticoblastoma. gi tract and mesenteric lesions include duplication cysts, lymphangioma, and meconium pseudocyst, and their relationship to bowel obstruction and persistent perforation. ovarian cysts can present as large masses in neonatal girls, and should be high in the differential diagnosis of large masses encountered in female infants; the imaging characteristics of simple and complicated cysts are described, as well as their course and potential complications. pediatric procedures: from imaging to intervention the spectrum of vascular anomalies in pediatric patients: multimodality imaging evaluation and current treatment patricia e. burrows, md vascular anomalies are categorized into two main groups, vascular tumors and vascular malformations. genetic and molecular regulation of vascular genesis of angiogenesis, and mutations responsible for some of the vascular malformations, have been delineated. in order to implement future targeted treatment of vascular lesions, accurate diagnosis is important. imaging modalities that are effective in distinguishing the various types of vascular anomalies and demonstrating the extent include ultrasonography with doppler interrogation, mri and various forms of mr vascular flow imaging, conventional angiography and venography. techniques used to image lymphatic channel anomalies, conventional lymphangiography, lymphoscintigraphy and infrared fluorescent lymphangiography. in this presentation, common forms of vascular anomalies will be described and rare or recently recognized anomalies will be mentioned. current treatment of the different forms of vascular anomalies will also be discussed, including pharmacotherapy using beta blockers, angiogenesis inhibitors and mtor inhibitors. endovascular techniques used in treating vascular malformations, including embolization and sclerotherapy will be presented. pediatric vascular disease is extremely varied, with a wide range of conditions requiring diagnostic or therapeutic intervention. technological improvements in non-invasive imaging modalities such as mri and ct have reduced the need for diagnostic angiography; however, with advances in interventional techniques, arteriography in the pediatric patient is now often performed for therapeutic reasons. pediatric arteriography presents unique issues and challenges. tremendous variability in patient size and physical maturity limits the ability to standardize technical aspects of performing arteriography. in addition, radiation protection, sedation/anesthetic support, monitoring of fluid balance, and maintaining patient warmth must be considered. a regimented protocol for assessment of the pediatric patient must be followed, with review of the indications for the study requested, and review of patient-specific issues such as coagulation profile, concurrent medical disease, patient weight, and anesthetic concerns. appropriate patient monitoring is imperative to ensure patient safety. vascular access can be quite challenging. ultrasound and micropuncture access techniques have tremendously improved successful access while reducing associated complications. the smallest catheter that can accomplish procedure objectives should be used. for most diagnostic cases, 4 french systems can be used for children>10 kilograms, while 3 french catheters are preferred in those <10 kg. intraprocedural heparinization (75-100 iu/kg) is also more often used, especially in children weighing less than 10-15 kg. rates and volumes of contrast injected for pediatric arteriography are not standardized, as in adult patients. in general, contrast dose should be limited to 6-8 ml/kg, and 4-5 ml/kg in premature infants and neonates. all these new technique are less invasive, improve patients' outcomes and reduce morbidity. they are also cost-effective as patients are discharged home earlier and recover faster from the intervention. the future holds promising new technologies such as high-intensity focused ultrasound (non-invasive method of thermal ablation) and nanoparticles for drug delivery. pediatric interventional radiology will continue to be an essential part of these minimally invasive therapies. musculoskeletal imaging: from planning to performance kirsten ecklund, md the purpose of this talk is to review advanced mr imaging techniques currently being used in the evaluation of pediatric musculoskeletal tumors. the goals of these techniques include improved image resolution and quality, lesion tissue characterization, and increased acquisition speed. diffusionweighted (dw) and perfusion imaging will be emphasized; however, whole body, metallic artifact mitigation, and volumetric sequences will also be discussed. dw mri is based upon the brownian motion of water within extra and intra-cellular spaces which depends upon tissue cellularity. dwi can aid in the differentiation of benign from malignant lesions, which generally have restricted diffusion. there is even greater potential for dwi in the assessment of tumor response to therapy. the apparent diffusion coefficient (adc) maps are critical to accurate interpretation of diffusion sequences. adc maps distinguish between restricted diffusion and t2 effect, both of which appear bright on dwi. both qualitative and quantitative tissue assessments can be made with dwi. challenges for dwi in the pediatric musculoskeleton include susceptibility artifacts from bone, motion vulnerability, and geometric distortion at larger fields of view. our current protocols and parameters for dwi will be presented. contrast-enhanced (dce) mr using one of a variety of vendor specific sequences. qualitative and quantitative assessments of inflow and distribution of contrast have been shown to help differentiate between benign and malignant lesions and to evaluate drug efficacy during therapy. this technique is especially promising in those patients undergoing antivascular and antiangiogenic therapy. tal laor, md congenital abnormalities of the musculoskeletal system can result in alterations of limb size, configuration, and/or segmentation. these disorders often affect both the osteocartilaginous skeleton as well as the surrounding soft tissues and can be localized or diffuse. in this session, we will focus on the imaging features of several congenital abnormalities that result in a small or short limb, in altered configuration of a limb, or in abnormal segmentation. deformities of both upper and lower limbs will be examined. like congenital abnormalities, developmental disorders of the pediatric musculoskeletal system can be limited to a single area or can affect numerous sites within the body. for example, neonatal brachial plexopathy is a localized disorder that produces characteristic musculoskeletal alterations about the shoulder girdle and elbow of affected children. the alterations of morphology and function of the shoulder develop over time with growth of the child and change in response to a variety of therapies. we will review the features of developmental anomalies of the pediatric musculoskeletal system and evaluate the role that imaging plays in the initial evaluation and in the subsequent assessment of these children during treatment. multimodality imaging of skeletal trauma in children: using all of the tools peter j. strouse, md skeletal trauma is a common indication for imaging throughout the pediatric age range. newborns may suffer birth trauma. infants and toddlers may be subject to abusive injury. children of all ages may suffer accidental injury. older children and adolescents are increasing hurt in sporting activity and vehicular accidents. fracture patterns vary with maturation of the child. interference with normal growth is a potential complication. imaging of skeletal trauma begins with radiography. proper anatomic and age specific radiographic technique assures optimal diagnostic yield. radiography suffices in most cases to diagnose fracture or confirm normalcy. "clinical correlation" aids in diagnosis. ultrasound, ct, mri and nuclear medicine may play a role in specific instances where plain radiographs are non-diagnostic or to better delineate certain fractures. arthrography and conventional tomography have occasionally been used in the past and tomosynthesis may prove useful. follow-up radiographs may be useful for diagnosis or confirmation of some fractures. this presentation will focus on the imaging of acute skeletal injury. technique and approach for plain radiography will be emphasized. specific indications and roles for ancillary imaging techniques will be defined and illustrated with representative cases. although classically thought of as a disease of adulthood, stroke is much more common in the pediatric population than was once appreciated. this may be due to many factors, not the least of which is increased awareness due to the presence of subspecialty stroke teams now fairly commonplace in many children's hospitals, and the fairly recent advent of more advanced imaging technique such as diffusion-weighted imaging (dwi) and its routine use in imaging the central nervous system (cns) in the child and adolescent. causes of stroke in children can be protean, and range from idiopathic on one end of the spectrum, to traumatic on the other, with many causes in between, many of which may not be intuitive to the clinician without further research. moyamoya disease and its many causes, such as sickle cell disease (scd), trisomy 21 and neurofibromatosis type i (nf i) can all lead to stroke in children, as can congenital clotting deficiencies such as factor v leiden deficiency and congenital cardiac lesions with their resultant shunting of blood between the left and right cardiac circulations. although usually arterial in nature, strokes may arise from the venous system in clinical scenario of venous thrombosis with resultant venous infarctions. factors contributing to venous thrombosis in children and adolescents can be due to dehydration (especially in the very young), severe iron deficiency anemia, inflammatory bowel disease and exogenous hormone ingestion such as is seen with oral contraceptives (ocp) in young women. advanced imaging techniques for neuroimaging in pediatric patients: where are we now? blaise v. jones, md the past decade has seen a large number of advanced imaging techniques introduced to the clinical armamentarium of the pediatric radiologist. from the development of multidetector ct scanners that can obtain whole head diagnostic studies in less than 2 s to the routine use of 3 t mr imaging, technical advances have dramatically changed our ability to diagnose and manage neurological disorders in children. however, all of these advances are not of equal clinical utility, and it is imperative that the pediatric radiologist be well versed in their judicious and appropriate application. this presentation will discuss the effective use of volume ct scanning, cta, swi, asl, fmr, pmr, and other advanced imaging techniques in the diagnosis of neurological disorders presenting in childhood. at the conclusion of the presentation the attendee will have a better understanding of how to ideally apply these technologies in practice. a spectrum of abnormality in pediatric neck: practical imaging choices and interpretation caroline d. robson, mbchb learning objectives: 1. become familiar with an optimized imaging approach for head and neck infections 2. recognize the complications of head and neck infections 3. recognize the utility and interpretation of imaging for neck masses this talk will cover the imaging approach and interpretation of findings in head and neck infection and neck masses. infection includes acute complicated sinusitis, coalescent mastoiditis, neck infection and local and intracranial complications. optimized imaging protocols and image interpretation for neck masses will also be discussed and illustrated. acute complicated sinusitis is diagnosed when acute sinusitis is accompanied by orbital symptoms (e.g. proptosis) and/or mental status changes, seizures or other neurological findings. coalescent mastoiditis is diagnosed when otomastoiditis is accompanied by tenderness and/or swelling over the mastoid process. ct and mr provide complementary information. ct is obtained with contrast. mr sequences include fatsuppressed t2, t1, diffusion, and fat-suppressed contrastenhanced t1 weighted images with mr venography. intracranial complications include epidural abscess, subdural empyema, meningitis, cerebritis, brain abscess, venous thrombosis and venous infarction. the limitations and usefulness of ct in the diagnosis of neck abscess will be illustrated. the imaging approach to masses depends on patient age, and the size and location of the mass. us, ct, mr, and nuclear medicine studies provide complementary information. as for infection, optimized imaging approaches and key imaging features for various masses will be discussed. embryology and diagnostic approach in spinal dysraphism l. santiago medina, md, mph and esperanza pacheco-jacome, md congenital anomalies of the spine are malformations that can be confusing due to the complexity of their embryology, and to the sometimes unclear classifications and terminology. the purpose of this review is to give a clear and basic understanding of the different stages of the embryological development of the spinal cord, starting with the bilaminar disc in the first week of gestation. during the second week, the formation of a trilaminar disc (gastrulation), the notochord, and the formation of the neural tube or neurulation. also, a review of the development of the distal cord: conus medullaris, filum terminale, ventriculus terminalis, by a different mechanism, canalization and retrogressive differentiation. beside the embryological review, a case correlation will be presented using mr imaging to demonstrate these malformations. open spina bifida entities include meningocele and myelomeningicele. closed or occult spinal dysraphism (osd) is characterized by a spinal anomaly covered with skin and hence with no exposed neural tissue. osd spectrum includes dorsal dermal sinus, thickened filum terminale, diastematomyelia, caudal regression syndrome, intradural lipoma, lipomyelocele, lipomyelomeningocele, anterior spinal meningocele and other forms of myelodysplasia. several studies have shown that mri and ultrasound have better overall diagnostic performances (i.e., sensitivity and specificity) than plain radiographs for detection of occult spinal dysraphism. for h1n1, most patients had mild illness but a small percentage required mechanical ventilation and icu admission. the high risk groups include children <5 years old and those with chronic medical conditions in particular neurodevelopmental impairment. pediatric mortality was 7.5% of all deaths associated with the pandemic reported in the u.s. in both conditions, the most prominent radiographic and ct features were airspace disease including ground glass opacities (ggo) and consolidation, commonly with multi-focal and bilateral involvement. pleural effusion, adenopathy and cavities were absent. in some patients with viral infection, respiratory symptoms may be mild but are complicated by neurological manifestations. a brief review of mri features in h1n1 related encephalopathy including acute necrotizing encephalopathy (ane) will be given. bernard f. laya, do tuberculosis (tb) is a worldwide major public health problem with one-third of the world's population being infected. it is a leading cause of death and disability from infection worldwide. children are amongst the most vulnerable group because of their immature immune status. a child usually gets tb infection after being exposed to a sputum-positive adult. depending on many factors, the infection can lead to latency or tb disease. it can affect virtually any organ in the body and can be devastating if left untreated. tb in children remains a diagnostic challenge. in addition to history of tb exposure, signs and symptoms, laboratory and microbiologic tests, medical imaging remains a valuable tool in its diagnosis. although findings are nonspecific, the radiograph is the most commonly ordered initial imaging tool for screening and diagnosis of pulmonary and musculoskeletal involvement. computed tomography and magnetic resonance imaging offer more detailed assessment especially in cranial and abdominal involvement. medical imaging is also utilized to follow up patients during or after anti-tb treatment. knowledge of the common imaging patterns, pitfalls and dilemma are very important in establishing the diagnosis of tb in children. the pathophysiology of pediatric tb will be discussed as it correlates with imaging findings. the wide spectrum of imaging manifestations in various modalities will be presented. imaging updates along with pitfalls and dilemma in the interpretation will also be discussed. tb can affect almost every organ system but the author will present cases that are more commonly encountered. and concurrent ct/ pet-ct (k00.33) panels. there were more indeterminate nodule predictions by pet-ct (n038 of 75; 51%) and concurrent ct/pet-ct (n 023; 31%) than by ct alone (n012; 16%). the overall accuracy of ct alone was 71%, pet-ct alone 45% and concurrent review 60%. worst case sensitivity and specificity were 85% and 44% for ct alone, 60% and 19% for pet-ct alone, and 67% and 48% for concurrent ct/pet-ct. conclusions: pet-ct assessment of pulmonary nodules in children is feasible but limited by non-diagnostic quality ct images and atelectasis caused by sedation. subjective assessment of nodules by pet-ct does not appear to improve the ability to distinguish benign from malignant histology in children with solid malignancies. semi-quantitative nodule assessment using the standardized uptake value may improve the performance of pet-ct in this setting and will be investigated in the future. purpose or case report: nec is the most common lifethreatening medical/surgical emergency of the gastrointestinal (gi) system in neonates, with an incidence up to 10% in infants weighing <1500 g. with advances in treatment of nec, increased survival rates result in rise in post-nec gi complications such as feeding intolerance. development of post-nec bowel strictures results from healing of involved bowel and can result in bowel obstruction. it has been routine to study the bowel of infants after medical treatment for nec by contrast enema and small bowel follow-through prior to initiating feeding. however, in order to "image gently" we are attempting to decrease the radiation exposure to these patients. we postulate that in patients with no abnormal bowel dilation prior to initiation of feeds, the incidence of colonic stricture would be so low that routine enemas would be unnecessary and could be eliminated from the workup. recorded as present or absent in 6 anatomic abdominal regions defined as: 1 and 2-from the dome of the diaphragm to top of l2 to the right and left of midline, respectively; 3 and 4-from top of l2 to the iliac crest to the right and left of midline, respectively; 5-from the iliac crest to the top of the sacrosciatic notch; 6-below the top of the sacrosciatic notch. we assessed the frequency of findings in each region and how often findings in regions 5 and 6 were associated with findings in regions 1-4. 95% confidence intervals were calculated. results: the fewest pertinent findings were present in region 6 in 10.2% (51/501) (95% ci: 7.7-13.1%) of radiographs. findings included: abnormal bowel 6% (n031), bowel gas paucity 1.4% (n07), pneumatosis 0.4% (n02), inguinal hernia 0.8% (n04) and osseous abnormalities 1.2% (n06). pertinent findings were present in region 5 in 67.7% (339/501) (95% ci: 63.4-71.8%). findings included: abnormal bowel 43.7% (n0 219), bowel gas paucity gas 19.6% (n098), pneumatosis 1.6% (n08), free air 0.2% (n01), and abnormal bowel with pneumatosis 2.6% (n013). among 51 patients with an abnormality in region 6, 49 (96.1%) also had an abnormality within at least one of regions 1 through 4. among the 342 patients with an abnormality in region 5 or 6, 338 (98.3%) also had an abnormality within at least one of regions 1 through 4. catheter/tube tips were located in region 5 in 6.8% (n034) and region 6 in 1.4% (n07) of radiographs, respectively. pneumatosis was present most frequently in regions 3 (5.8%), 4 (4.0%), and 5 (4.2%). free air was present most frequently in regions 1 (1.6%), regions 2 and 3 (0.6% each). conclusions: our preliminary data suggest that pertinent findings on neonatal portable abdominal radiographs are rarely isolated to the pelvis, implying that gonadal shielding of regions 5 and 6 should not compromise diagnostic accuracy. purpose or case report: the purpose of this study was to determine the sensitivity, specificity, and positive and negative predictive value of ultrasound in diagnosing appendicitis when the appendix is visualized, using three diagnostic categories: positive, negative, and equivocal. the 3-category diagnostic accuracies for appendiceal diameter and radiologist impression were compared. methods & materials: a retrospective study was performed evaluating all right lower quadrant ultrasound reports dictated over a 5-month period. included studies were interpreted as positive, negative, or equivocal for appendicitis. report impressions that did not specify one of these categories and studies where the appendix was not seen were excluded. the pathologic diagnosis of appendicitis was considered the gold standard for a positive diagnosis. because virtually all pediatric surgical cases in the region are referred to our hospital, it was assumed that the patient did not have appendicitis if surgery was not performed. logistic modeling using appendiceal diameter as the independent variable established cutoff diameters of ≤6 mm0negative, >8 mm0positive, and 6<x≤ 8 mm0equivocal. sensitivity, specificity, and positive and negative predictive values were calculated for both methods. results: of the 571 patients imaged during the study period, 255 (45%) met the inclusion criteria; 34 (6%) reports did not categorize the impression and in 282 (49%) studies the appendix was not seen. surgery was performed on 122 (48%) subjects, of which 101 (83%) had a pathologic diagnosis of acute appendicitis. using the radiologist impression, there were 68 true positives (tp), 2 false positives (fp), 8 false negatives (fn), and 150 true negatives (tn), for a sensitivity of 97% (95% ci090-100%), specificity of 95% (ci090-98%), ppv of 89% (ci080-95%), and npv of 99% (ci095-100%). there were 27 (11%) cases reported as equivocal; of these, 7 (26%) had a pathologic diagnosis of appendicitis. using appendiceal diameter, there were 46 tp, 6 fp, 2 fn, and 161 tn, for a sensitivity of 88% (ci077-96%), specificity of 99% (ci096-100%), ppv of 96% (ci0 86-99%), and npv of 96% (ci092-99%). there were 41 (16%) cases categorized as equivocal; of these, 25 (61%) had a pathologic diagnosis of appendicitis. conclusions: the use of diagnostic categories enables high ppv and npv with a relatively low number of equivocal cases. using appendiceal diameter alone results in higher ppv than that of the radiologist impression, but also yields a higher number of equivocal cases. purpose or case report: intussusception is an obstructive condition that a segment of the bowel invaginates into adjacent bowel and is an urgency that needs to be reduced as soon as possible to prevent bowel ischemia or necrosis. when it occurs in the infants and young child, it usually develops idiopathically and reduced by the technique such as air enema under the fluoroscopic guidance or saline enema under the ultrasound guidance. the success rate of the non-surgical reduction has reported over 95%. the pneumatic reduction is to introduce air into the patients' rectum via a ballooned foley catheter by hand pump. a mercury manometer connecting with the foley catheter calibrates the pressure of insufflation, and the recommended maximum pressure is 120 mmhg. the hydrostatic reduction is to drip saline from a bag at the height of 3 ft that may be different according to the institute's guidelines. until recently, in both techniques, the precise measurement of the intraluminal pressure was not possible. with the purpose of intraluminal pressure monitoring, we introduced a specific digital pressure gauge that can measure both pneumatic and hydrostatic pressure in various units and can give the collected data to our workstation. with the data, we purpose to make the curve of intraluminal pressure during the procedure and to compare the pattern and difference in both techniques of reduction, which permits suggesting the better technique for reducing the intussusception. from february 2011, we performed the intraluminal pressure monitoring in 8 children; 4 cases of pneumatic reduction and 4 cases hydrostatic reduction. the results indicated that the curves were similar in both techniques. however, the hydrostatic reduction tended to need longer time and higher pressure difference than the pneumatic reduction. we assumed that a higher flow rate and more fluctuating introduction of pressure in the pneumatic reduction made the difference between both methods. purpose or case report: anecdotal evidence suggests that some pediatric brain tumors, particularly pilocytic astrocytomas, demonstrate greater enhancement on delayed post-contrast t1 weighted mr imaging compared to early post-contrast imaging. our goal was to compare immediate post-contrast imaging with delayed post-contrast imaging in pediatric brain tumors. methods & materials: the research protocol was granted exempt status by the institutional review board (comirb# 10-1354). between november 2010 and march 2011, all patients for whom an mri of the brain was ordered to follow-up known brain tumor or to evaluate new brain tumor underwent a modified protocol that included both immediate and 10 min delay post-gadolinium images. the modified protocol sequence order was dwi, t1 mprage, contrast injection, immediate post-contrast t1 mprage, t2, flair, 10 min delayed post-contrast t1 mprage. this sequence allowed both immediate and delayed post-contrast imaging to be performed without scanner downtime. a total of 67 unique patients met inclusion criteria of an enhancing primary brain tumor with the delayed imaging performed within a window of 6-19 min. these studies were evaluated independently by 2 pediatric neuroradiologists (ns and lf) and a radiology resident (jm) to compare the degree of lesion conspicuity and edge discrimination, and to determine an overall preference. in cases of discrepancy between reviewers, final grading was determined by group consensus. results: delayed post-contrast images were preferred in 55/67 tumors (82%), immediate post-contrast images were not preferred in any case, and 12/67 cases were graded as equivalent (18%). notably, delayed imaging was preferred for 19/20 pilocytic astrocytomas (95%). in 9/67 cases (13%), the improvement in conspicuity and edge discrimination on delayed imaging was felt to have a potential impact on clinical management, e.g. by extending resectable or treatable tumor margin. conclusions: delayed post-contrast imaging can be performed easily by reordering existing mri protocols, and no scanner downtime is required for this protocol change. our results indicate that pediatric brain tumors (particularly pilocytic astrocytomas) often enhance more conspicuously on delayed imaging, that no diagnostic confidence is lost on delayed imaging, and that clinical management may be more accurately guided. 3-directions) were retrospectively reviewed, after irb approval. both sporadic (n07) and nf-1 associated optic gliomas (n06) were included. tumors confined to intraconal optic nerve were excluded due to technical limitation of epi dwi within the bony orbit. apparent diffusion coefficient (adc) of the solid portions of the tumor was measured using the region of interest method both at baseline and on follow-up mri. results: for the 13 patients, 7 required treatment (surgery and/or chemotherapy) for symptomatic tumor progression (5 sporadic opg and 2 cases of nf-1). median follow-up interval was 3.1 years (range: 7 months to 10.5 years, sd 2.7 years). there was no difference in adc values between sporadic and nf-1 associated opg. opg that required therapy had significantly higher baseline mean adc (1589 x 10-6 mm2/s, sd 0.22), whereas opg with low mean adc (1255 x 10-6 mm2/s, sd 0.18) remained clinically asymptomatic or stable (stratified mann-whitney test, p00.0002). an increase in mean adc of 100 x 10-6 mm2/s doubled the odds the patient will require treatment (or02.16, 95% ci: 1.51-3.10, p<0.0001). enhancement patterns did not predict tumor behavior or nf-1 status (fisher's exact test, p00.192). conclusions: significantly higher mean adc was seen in opg that required therapy for tumor progression. mri may be a useful prognostic tool in further defining a subset clinically significant sporadic or nf-1 associated opg. purpose or case report: fast brain mri imaging has recently been introduced for assessing brain ventricles in patients with ventriculo-peritoneal shunts (vps). however, there is minimal literature on how this method could be beneficial for other indications. compared to ct, this method reduces lifetime cumulative radiation dose and has multiplanar capabilities. it is much faster than full brain mri, reducing exam costs and potentially reducing the need for sedation. however, fast brain mri has lower resolution than a standard brain mri and cannot detect hemorrhage. the goal of our study is to retrospectively assess additional clinical applications for fast brain mri. methods & materials: patients who had undergone fast brain mri were found in xenobase, a database which references deidentified electronic medical records at our institution. xenobase was then used to identify subgroups by diagnosis. one of the most common diagnoses was arachnoid cyst. after irb approval, patients with fast brain mri and arachnoid cyst were identified so that their fast brain mri could be compared to any full brain mri and to clinical outcomes. fast brain mri findings were excluded if there was not a full brain mri within 1 year. agreement with full brain mri, and documented effect on clinical management were coded for statistical review. results: between 2008 and 2011, there were 14 arachnoid cyst patients with 16 fast brain mri exams. in 12 members of this group, fast brain mri was used alone or in comparison with a full brain mri in the decision to follow or discharge the patient. 2 exams failed to report a pituitary cyst and mass effect which were reported on prior exams. 6 patients had no complications in the year following their fast brain mri. the most common complication was headache (4 cases). conclusions: fast brain mri reduces radiation exposure, time, cost, and the need for sedation in vps patients. these benefits may cautiously be extended to other patient groups also requiring routine imaging, such as those with arachnoid cysts. disclosure: the authors disclose that they will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: susceptibility-weighted imaging (swi) is a new technique that exploits susceptibility differences in different tissues, to provide a different type of tissue contrast. swi is a gradient echo sequence utilizing both phase and magnitude data to achieve exquisite sensitivity to tissue magnetic susceptibility effects. it is extremely sensitive to even minute amounts of paramagnetic substances and therefore for detection of blood products (hemosiderin, ferritin), deoxygenated blood, calcium, iron, and small vein depiction. it is particularly suited for vascular imaging, especially in cerebral ischemia. swi has been shown to be more sensitive in detecting cerebral microbleeds than is conventional t2*-weighted gradient-recalled echo imaging (gre) partly because of its inherent sensitivity, increased spatial resolution and the thinner slices acquired. recent studies have shown that swi detected more microbleeds in more patients, irrespective of their location and that swi may be more sensitive in detecting traumatic lesions than ct or mri. methods & materials: between january 2011 and october 2011 we have performed swi on 75 pediatric patients (from 1 day to 15 yrs old) affected with different pathologies. mri was performed using either a 3-or 1.5-t magnet (achieva ; philips healthcare, best, the netherlands). among these patients 62 also received a classic gre sequence. results: our experience confirms a greater sensibility of swi than gre in detecting microbleedings and larger bleedings. swi is much more helpful in patients younger than 1 year since it can distinguish hemorrhagic and non hemorrhagic punctuate white matter lesions detected as hyperintensities on t1-w images. it is more accurate in distinguishing petechial hemorrhages and ischemic foci in patients with germinal matrix hemorrhages. swi can provide important diagnostic information not only in vascular pathologies but also in tumors showing the altered tumor microvascularity, the degree of intratumoral necrosis and the presence of subtle defects of the bbb within the surrounding parenchymal tissue. the technique also allows the detection of possible bleedings in infectious lesions. conclusions: swi is a valuable technique in the evaluation of a wide variety of intracranial pathologies in the pediatric population and its use is advisable on a routine basis. purpose or case report: a common problem with pediatric mr imaging is motion. diffusion-weighted imaging (dwi) is highly sensitive to the effects of both rigid-body motion and brain pulsation. the resulting motion artifacts can manifest in several ways, and include blurring (motion between volumes), slice 'drop-outs' (motion during the diffusion encoding), and aliasing (motion during the parallel imaging/ghost calibration scan). in order to improve image quality in pediatric dwi and avoid the potential for repeat scans, we have implemented our grappa-accelerated diffusion tensor (dt)-epi sequence on over 1,600 pediatric patients at our institution, and have developed tailored reconstruction software to correct for large motion and reduce the need for general anesthesia (ga). methods & materials: grappa-accelerated epi dti data was collected on 100 patients at 1.5 t and 1,500 patients at 3 t between the ages of 1 month and 18 years old. with these data, we investigate the use of a method to select the best grappa and ghost calibration weights; 3d rigid-body realignment with importance weighting; a new volume rejection criterion for large motion; together with other procedures to lower image noise and reduce phase artifacts. all image reconstruction was performed using compiled threaded matlab code on the vendor's (ge) multiprocessor reconstruction hardware. results: using the maximum motion detected from the 3d realignment procedure on the 1,600 dti exams, 51% of patients did not move (either through co-operation or ga, denoted here by <1 mm of motion); 28% of patients moved between 1-3 mm; 13% between 3-5 mm; 6% between 5-10 mm; and 2% between 10-18 mm. except for 3 patients in total, the motion correction steps employed here were extremely robust in correcting for motion. in addition, the motion correction steps employed here do not blur or negatively affect the data on non-moving patients. conclusions: our proposed integrated reconstruction scheme suggests that correcting for different types of motion at different stages of the dti acquisition is critical to provide scans of diagnostic quality. apart from the very rare instance (0.2%) where the patient moved continuously an extensively throughout the scan, our motion correction procedures employed here are extremely robust. using this scheme, we show that highly diagnostic motion-corrected dti data can routinely be read on our patient database within 10 min. . participating sites followed mutually agreed upon vendor-specific dti protocols used for neonates in clinical practice: ss-epi; b 0700;~2 mm3 voxel; 30-32 directions; te~84 msec; 1 acquisition; parallel imaging; multi-channel (8-32) head coil. tensor data was analyzed at one site using internally developed software in idl. b0 and eddy current distortion were assessed by analyzing grid line distortion on acr slice 5 ; deviations from linearity were measured in the phase encoding direction. acr slice 7 was used to assess snr of the center and periphery of the b00 image, and fractional anisotropy (fa) of the phantom, which should approach 0. deviations from specified sequence parameters were recorded. results: both siemens scanners had some image degradation due to vibration susequently corrected by the vendor. nonlinear gridline distortion was highest on the ge followed by philips but was corrected with the use of 2nd order shimming. eddy current distortion was consistently smaller than acquisition voxel size after image registration. te varied from 74-92 msec; acquisition bandwidth range was 1563-2928 hz/pixel. the 2 mm slice thickness was problematic on clinical ge scanners resulting in non-isotropic voxels. across vendors, snr was consistently higher in the image periphery than center by a factor of 1. 30-0.45 ). the greatest difference was showed in patients with fhc. no association was found between the value of ldl-c and imt. the 62.5% received drug treatment at the time of evaluation. in dbt-1 a no association was found between the imt and the levels of hba1c and lipids. and in the ob group found no association between imt and bmi z score. fhc 31%, 8% of dbt-1 and 6% of ob showed atherosclerotic plaques and intima irregularities. conclusions: the imt ultrasonography was able to demonstrate that patients with chronic diseases, with increased cardiovascular risk in adulthood, showed early alterations of carotid intima media in children. this allows clinical applications of preventive and therapeutic guidance. a benchmark for precision of flow assessment was determined from differences between aortic and pulmonary arterial flows, which should agree. the precision of flow when utilizing a slow flow structure (vein) and a fast flow structure (artery) was then determined, serving as an indicator of the precision of slow flow measurements. this was done in pairs for the upper body (svc flow vs difference between ascending and descending aortic flow), lower body (ivc flow vs descending aortic flow) & total body (svc flow+ivc flow vs ascending aortic flow). paired t-tests were used to identify significant differences in the respective arterial and venous flow rates. with an f-test, the relative precision of the arterial flow (determined from aortic and pulmonary arterial flow) was compared against the precision of agreement between upper, lower, and total body flows, each of which has a slow flow venous component, thus assessing precision of venous flow measurement. results: arterial & venous flow measurements were strongly correlated for the upper body (r00.89), lower body (r00.96) and total body flow (r00.97); net aortic and net pulmonary trunk flow rates were also tightly correlated (r00.97). moreover, there was no significant difference in the precision of arterial & venous flow measurements (t-test, p00.31). lower venc (200 cm/s or lower) improves the accuracy and precision associated with low velocity venous flow, a finding that tended to but it did not reach statistical significance. conclusions: with 4-d pc mri, the accuracy and precision of venous flow quantification are comparable to arterial flow quantification, though venc settings may improve venous flow assessment. disclosure: dr. tariq has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. the spatial resolution requirements for imaging tiny target vessels in neonates have so far precluded its use of cemra in this patient population. the purpose of our study, therefore, was to explore the potential of high resolution cemra at 3.0 t in neonates with suspected congenital vascular anomalies methods & materials: 16 neonates (mean age 9.4 days, range 1-28 days; mean weight 2.7 kg, range 1.5 kg-4.2 kg) underwent cemra at 3.0 t. cemra was performed under controlled apnea on a 32-channel 3.0 t system using either a 12-channel head-neck coil (9 pts) or a 15-channel adult knee coil (7 pts). gd contrast delivery was calculated based on a total dose of 0.2 mmol /kg. parallel imaging factors of 4-6 were used, generating 0.7 x 0.5 x 0.6 mm voxels in an acquisition time of 17-22 s. images were scored for quality and the presence of artifacts independently by two observers. the cemra series were evaluated to identify pulmonary arterial and venous anatomy. extra-pulmonary vascular anatomy was divided into 12 sections for image quality assessment on mpr. results: the mra data sets had high mean image quality and low mean artifact grading scores. no significant difference was evident between the two observers for scoring image quality and artifact (p00.9), and there was good interobserver agreement (k00.66, 95% ci: 0.26-0.81). the pulmonary arteries were confidently visualized to at least the 2nd order branches in all 16 patients, at least the 3 rd order branches in 15 (93%). out of 176 evaluated segments, 164 (93%) were graded as the vessel "very well visualized with excellent definition of vessel" pa abnormalities were diagnosed in 10 patients and pv anomalies in 6 patients. correlation was made with open surgical findings in 12 cases, confirming the cemra diagnoses with no discrepancy between the operative and imaging conclusions. the results of our study suggest that high resolution cemra at 3.0 t is extremely promising in neonatal cchd and, in combination with echocardiography, may often provide comprehensive information for treatment planning. with appropriate use of physiological motion compensation, parallel imaging and coil configuration, voxel volumes less than 0.5 mm3 are routinely achievable. purpose or case report: it is not well understood whether transfusion-dependent children (mainly those who have hereditary anemias subject to excessive iron levels from regular blood transfusions) with no or mild cardiac iron overload and without signs of heart failure exhibit early changes in cardiac dysfunction. this study aims to evaluate intramyocardial deformation and subsequent cardiac dysfunction in such patients using the cardiovascular magnetic resonance technique of myocardial tagging as well as assess iron overload by another cardiovascular magnetic resonance technique of t2 star (t2*). we hypothesize that transfusion dependent children undergoing chelation therapy will be at high-risk for cardiomyopathy despite normal or slightly elevated iron levels and no signs of heart failure due to progressive myocardial deformation as assessed by myocardial tagging; that is, we expect abnormal mechanical parameters to exist despite t2* values which correspond to normal or slightly elevated myocardial iron levels. methods & materials: 8 patients (mean age 15 yrs) requiring regular blood transfusions for various reasons (e.g. thalassemia, sickle cell disease, other anemias) were investigated using harmonic phase magnetic resonance tagging and t2* imaging. various myocardial mechanical parameters were quantified and correlated to cardiac iron levels as measured by t2*. results: 2 children with no overt signs of heart failure (as measured by ejection fraction and volume indices) exhibited normal t2* iron levels in combination with global circumferential abnormal myocardial strain and 4 children exhibited regional strain. conclusions: this preliminary data suggests that transfusiondependent children without overt signs of heart failure exhibit early signs of cardiac dysfunction (an effect of strain as assessed by myocardial tagging) in direct relation to normal or slightly elevated myocardial iron levels (as measured by t2*). a larger sample size of children could support the idea of abnormal myocardial mechanics being a diagnostic imaging marker for the development of myocardial iron overload and eventual iron-mediated cardiomyopathy. the choice of coil and field of view varied according to the age and size of the patient. imaging was performed on a 1.5 t magnet (philips mri system). after the cine gradient echo time of flight sequences were acquired, the dynamic keyhole mr angiographic sequence was applied in the coronal orientation. this sequence commenced 2-5 s after initiation of the first bolus administration of 2-10 ml of undiluted gadopentetate dimeglumine (0.5 mmol/ml, magnevist) at a rate of 2-3 ml/sec followed by 10-20 ml of saline at a rate of 2 ml/sec. image acquisition was repeated multiple times without delay for 60 s during shallow breathing. contrast material was administered through a peripheral or central venous line, and sometimes via simultaneous bilateral extremity injections. rarely manual hand injection was performed. the parameters were as follows: centra k-space filling, acquired voxel size 1-1.2 x 1-1.2 x 2-3, reconstructed voxel size 0.4-1 x 0.4-1 x 1-1.5, number of dynamics 8-20, keyhole percentage 25-38%, sense (parallel imaging) factor 2x1-2x2, dynamic times 1-3.6 s, and injection rate 1-3 cc/second. image analysis was based on original contrast-enhanced data sets, mip and volume rendering. the quality of the mrv was graded by a subjective scale from 1-5 (10excellent, no limitations; 50nondiagnostic). comparison with unenhanced mr venographic sequences and doppler ultrasound were available in all cases. results: 4d mrv provided diagnostic information on patency of venous segments in all cases, including the presence of venous occlusion or stenosis, the segments involved, and collateral venous pathways. conclusions: 4d mr venography using the method outlined is a reliable means of estimating central venous thrombosis in children, using short dynamic scan times with high spatial and temporal resolution, creating an effect similar to conventional venography. paper #: pa-033 analysis of optimal phase interval for prospective ekg-triggered cardiac ct in children prakash masand, md, texas children's hospital, savivek bogale, lorna browne, rajesh krishnamurthy purpose or case report: evaluate high temporal resolution cine mri of the heart in children to determine relationship of heart rate to the optimal motion free interval during the cardiac cycle, and to derive a chart depicting optimal reconstruction intervals across a range of heart rates which could be applied for prospective ekg triggered ct imaging of the heart. methods & materials: pediatric patients who had high temporal resolution cine steady state free precession sequence (50 frames acquired across a single cardiac cycle) performed as part of a mri/mra of the heart from 2005-2011 were included. a single reader analyzed the high temporal resolution cine data to determine the location and duration of the motion-free phase interval in systole and diastole for heart rates ranging from 60-140 bpm. the following information was collected: age, heart rate, duration of systole and diastole, ekg phase and phase percentage of motion-free interval, and duration of motion-free interval. heart rates were grouped in ranges of 10 (61-70, 71-80, 81-90 etc.), with at least 25 patients in each group. wilcoxon sum rank test was performed to compare the static durations of systolic and diastolic phases for each heart rate group. two-tailed p-values<0.05 were considered to indicate statistical significance. a chart matching heart rate range to the optimal phase of image acquisition and reconstruction was created. results: optimal reconstruction intervals for motion-free imaging of the heart in systole and diastole, and single best phase for a given heart rate are as follows: (please see table 1 ) mean duration of the motionless phase in systole and diastole for a given heart rate is as follows: (please see table 2 ) conclusions: this is the first time that variability in location of the motion-free interval within the cardiac cycle with respect to heart rate in children has been studied in rigorous fashion. this chart will have immediate application in the so-called 'target scan', which uses prospective ekg triggered acquisition of data in combination with half-scan reconstruction to minimize radiation dose with respect to retrospective ekg gated imaging. results: a total of 10 patients were found to have aberrant pda by ccta. nine patients had a pda emanating from the brachiocephalic artery to the pulmonary arteries and one patient had pda emanating from the carotid or the subclavian artery according to the operative report. all ten patients had echocardiography in addition to ccta. nine of the ten patients underwent surgery. one patient was lost to follow up. comparison between ccta and echocardiography to operative report showed the following: 3 out of the 10 echocardiograms agreed completely with ccta and operative report. 7 out of the 10 echocardiograms did not report aberrant pdas which were seen on ccta and confirmed during surgery. in one patient, the echocardiogram reported a double aortic arch which was found to be an aberrant pda from the left brachiocephalic artery; a finding that changed the surgical management and pre-surgical planning. the results were statistically significant with a p value of <0.05. conclusions: diagnostic accuracy of ductus arteriosus anatomy is important in pre-surgical planning and management of patients with ductal dependent pulmonary circulation. cardiac ct angiography is more accurate as compared to echocardiography in diagnosis of aberrant patent ductus arteriosus. ) in patients younger than 1 year of age. the prospective ecg-gated protocol scanned 50% of the cardiac cycle with 10 msec padding in patients with heart rates greater than 100 bpm. two experienced radiologists evaluated the image quality and course of the coronary arteries. image quality was assessed based on the degree of homogeneity of vascular enhancement, presence of stair-step artifacts, image signal and noise as well as the overall subjective image quality based on a 4 point scale. the course of the left and right coronary arteries was also evaluated based on a 4 point scale, focusing on how well the evaluator was able to visually follow the coronary artery from its origin to its termination. radiation dose was recorded and compared. results: the mean score of the homogeneity of vascular enhancement, stair step artifacts, image noise and signal, overall image quality, and score given to visualization of the course of the coronary arteries showed no significant difference (p>0.35) in the retrospective and prospective ecg gated groups. the mean estimated effective dose was significantly lower for the prospective ecg gated group compared to the retrospective group, (0.83 msv vs 2.39 msv) respectively (p<0.0005). conclusions: prospective ecg-gated cardiac mdct provides comparable assessment of coronary anatomy, image quality with significantly less radiation dose when compared to the retrospective ecg-gated mdct. prospective ecg gated cardiac mdct is a powerful adjunct to the treatment and surgical planning of pediatric patients with congenital heart disease less than 1 yr of age with lower radiation dose. methods & materials: 3 pediatric neuroradiology lectures were recorded and made available to 29 radiology residents at a university program through on-line streaming video viewed through an internet link. topics included brain tumors, phakomatosis, and congenital brain malformations. one lecture per week was recommended prior to case conferences that reviewed the same topic. pre-and post-tests and a feedback survey were administered. nonparametric paired sign test and analysis of covariance were used to evaluate changes in test scores overall and according to feedback responses. spearman's partial rank correlation coefficient was used to evaluate the relationship between the number of viewed videos and test scores. results: twenty-nine residents completed the pre-test and 28 the post-test. the means (sd) scores were 59.3% (12.0%) and 64.8% (14.2%) respectively. there was a significant improvement in test scores (p 00.019). residents that agreed/strongly agreed that the streaming technology lectures were convenient had greater improvement than those who did not (14.0 vs. -3.2%, p00.001). similarly, those who agreed/strongly agreed that being able to replay a lecture was helpful had greater improvement than those who did not (10.9 vs. -6.7%, p 00.001). finally, those who agreed/ strongly agreed that the streaming technology lecture format was a better teaching tool had greater improvement than those who did not (10.8 vs. -4.7%, p00.003). significant positive correlation between number of videos watched postconference and improvement was present (spearman's rho0 0.48, p00.013). conclusions: on-line streaming video with live case conferences enhances radiology resident learning of pediatric neuroradiology. step (mpps) software provided an accurate measurement of scan time. visual charting made gaps in utilization apparent. technologists and nursing notes correlated to gaps identified barriers and opportunities for improvement. nursing and anesthesiology reduced redundancies. standardized protocols lead to more consistent scan times. appointment access for sedated mri was measured by the third available appointment. results: manually entered data points were time consuming, inconsistent and unreliable. the process improvement was most effective when fewer more reliable data points were used to evaluate the effect of change. the program resulted in a reduction of appointment access for sedated mri from 30 days to 2 days with no change in the hours of operation. magnet utilization was increased from 58% to 73%. induction outside the scan room provided the most efficient process tested. we ranked first in utilization in a children's healthcare cooperation of america (chca) survey as measured by exams per scanner. patient preference for a.m. scheduling was shown by survey and corroborated by scheduling data. consistent scan times were achieved by protocol standardization augmented by indication driven decision support. conclusions: a consise definition of mr utilization established a metric that was used in the process cycle of analyze-optimize-measure. anesthesia induction outside the magnet was the most efficient practice but required collaboration between nursing, mr technologists and anesthesiology. protocol standardization were valuable aspects of process improvement essential to optimizing parallel sedation. these adjustments reduced appointment access from 30 days to 2 days, increased utilization from 58% to 73% and produced a number one rank in utilization by chca survey. we exploited the synonym option in epic order entry to translate indications into procedures mapped to specific protocols for mri neuroimaging. the order screen allows the provider to enter an indication. that indication is linked through a synonym option to a specific exam and protocol. the recommendation is based upon institutionally created clinical care guidelines, and can be accepted with a single click to complete the order. the requesting provider retains the option to override the recommendation. an step in process development utilized an order queue established within the epic inbasket. a pediatric radiologist monitored the queue and communicated with referring providers to obtain additional history and educate toward best imaging practice. these interactions facilitated development of a robust index of clinical indications used to create the synonym pool. results: mri neuroimaging indications were expanded into a robust data set linked to specific mri exams aligned with specific protocols. the synonym option within epic created the opportunity for the requesting provider to simply enter an indication which drives the procedure and recommended protocol. provider satisfaction has been high and concurrence with recommendations nearly universal. conclusions: indication driven order entry was achieved through the synonym option in order entry within the epic emr. imaging recommendations are based upon institutional clinical care guidelines developed through consensus. a robust compilation of pediatric mri neuroimaging indications has been created and linked to specific exams and protocols. compliance with the indication driven recommendation has been high. modifications of the current system are currently under development for all cross sectional modalities and organ systems. paper #: pa-039 cost-effectiveness of routine neonatal renal ultrasound in non-syndromic complex congenital heart disease elfrides traipe, tch, extraipe@texaschildrens.org; jill v. hunter, marthe munden purpose or case report: to assess the prevalence of abnormal renal ultrasound in non-syndromic complex congenital heart disease (cchd) and assess the cost-effectiveness of routine renal ultrasound in this population. we restrospectively reviewed the initial neonatal renal ultrasound and any subsequent renal imaging in 97 patients with non-syndromic cchd. etiologies included hypoplastic left heart syndrome (hlhs), transposition of the great vessels (tga), coarctation of the aorta (coa), truncus arteriosos (ta), double outlet right ventricle (dorv) with or without patent ductus arteriosus. patients were recruited consecutively as part of a prospective trial for pre-and post-operative magnetic resonance imaging of the brain. results: the neonatal pre-operative renal ultrasounds were analyzed in 41 female and 56 male patients. only 1 of the 97 patients showed any congenital renal anomaly. this patient was born with hypospadias, that would have routinely stimulated neonatal follow up. conclusions: knowledge of embryology would not lead us to anticipate a high co-incidence of congenital renal and cardiac pathology. based on this statement and our findings, our recommendation to improve cost-effectiveness is not to perform routine neonatal renal ultrasound in non-syndromic cchd, but only if otherwise clinically indicated. purpose or case report: to conduct a meta-analysis of the diagnostic performance of contrast enhanced voiding urosonography (cevus) in comparison to voiding cystourethrography (vcug) or direct radionuclide cystography (drnc). a literature search was conducted for studies published on cevus in the pediatric age group. studies were included if the ultrasound contrast agents (usca) levovist® (bayer-schering pharma, germany) or sonovue® (bracco, italy) were used and enough data was available to extract 2x2 tables. if the cevus was compared to both vcug and drnc in the same patients the results for each were analyzed separately. a bivariate hierarchical model that takes into account the heterogeneity in cevus sensitivity and specificity in different studies was used for the assessment of the summary diagnostic metrics. the summary roc curve was derived and presented graphically from the parameters of the model. additionally, the 95% confidence intervals (ci) and the positive (lr+) and negative (lr-) likelihood ratios were calculated. results: out of 127 publications only 30 comparative studies fulfilled the inclusion criteria. these encompassed 26 cevus studies in comparison with vcug and 4 with drnc with regards to detection of vesicoureteric reflux. in 26 studies the usca levovist® and in 4 sonovue® were used. a total of 2549 children with 5078 pelvi-ureteral-units (puus) were included in the meta-analysis. cevus compared to vcug and drnc had a sensitivity of 90% (ci: 85-93) and a specificity of 92% (ci: 89-94) with lr+and lr-of 11.7 and 0.11, respectively. the performance of cevus was better when compared to drnc than to vcug (sensitivity 94%, specificity 95% versus 90% and 92%, respectively. the meta-analysis of the diagnostic performance of cevus regarding the urethra included 880 patients (682 boys). excellent imaging of urethral anatomy was reported in over 97% of the patients. however, currently there is only one comparative study with 146 patients available. in this study 100% sensitivity and 100% specificity were reported. conclusions: sufficient evidence is available clearly demonstrating the high diagnostic performance of cevus compared to vcug or drnc regarding the detection or exclusion of vur in children. these findings combined with the absence of radiation should be convincing reasons for promoting the widespread use of cevus in children. disclosure: dr. darge has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: prenatal ultrasound (us) has increased identification of infants with asymptomatic renal pelvic dilatation. society for fetal urology (sfu) grading is used in the sonographic evaluation of pediatric hydronephrosis. based on us findings, a nuclear medicine diuretic renogram may assess renal function, which could result in operative intervention. standardized protocols for diuresis renography, the "welltempered renogram," already exist; however, no current study has assessed effect of intravenous hydration (iv) status with us in the evaluation of childhood hydronephrosis. our study assesses the effect of hydration on sfu grading. in this prospective irb approved study, pediatric patients diagnosed with pelvicaliectasis requiring a diuretic renogram were recruited to undergo pre and post hydration renal us. a urinary catheter was placed followed by renal us pre and post iv hydration (10 ml/kg normal saline bolus). imaging was performed by the same sonographer on the same us machine. a well-tempered renogram was then performed. all images were reviewed by two blinded radiologists, one pediatric radiologist who assigned sfu grades to each kidney. results: data were collected from 34 studies, with ages ranging from 6 weeks-16 years, with an average age of 22 months. there were 28 unique patients. of these, 23 underwent a single renogram, 4 underwent two renograms, and 1 underwent 3 renograms. one patient had a solitary kidney due to mcdk. thus, there were 33 usable paired sonograms (67 kidneys) for analysis. sfu grades were compared in the pre-and post-hydration us for each kidney. two-sided statistical tests were done to assess whether sfu grades changed significantly after hydration (sign test). 52 of 67 (78%) kidneys remained the same grade post hydration. when there was a difference, most demonstrated an increase (13 of 15 kidneys and p<0.01). no change in sfu grade pre-and post-hydration differed by more than 1. only 1 kidney went from grade 2 to grade 3. sfu above grade 2 is considered clinically significant. no kidney that was grade 3-4 pre-hydration became grade 0-2 post-hydration. when sfu is dichotomized grade 0-2 vs. 3-4, there was no significant change in grade from pre to post hydration (p01). conclusions: hydration does not appear to have a clinically significant effect on sfu grade. therefore, performance of a "well-tempered" us is unnecessary. disclosure: dr. lee has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. study type was significantly associated with both total and weighted score (both p < 0.0001). rus was better and mag3 was worse than vcug, rnc, and dmsa, which did not differ from each other. other factors associated with worse total scores included patient age 1-3 years (p<0.001) and non-white race (p00.04). gender, prior testing history, wait time, and parent education were not associated with total scores. in the multivariate model, rus remained the best, mag3 the worst, and dmsa, vcug, and rnc in the middle (p<0.0001). compared directly, dmsa and vcug total score did not differ (p00.59). conclusions: this study documents significant differences among gui studies with respect to the patient and family experience, but there was no overall difference between dmsa and vcug. these findings may be useful to aid decision-making when considering gui for pediatric patients. we retrospectively reviewed the imaging findings of 29 consecutive patients with histologic diagnosis of cd (17 males, 12 females; mean age 14.6 years; age range 5-24 years) who underwent mre between 1/21/ 2011 and 10/10/2011. the mre was performed in a siemens avanto 1.5 tesla scanner. standard departmental volume of polyethylene glycol and fluid were administered for bowel distention. the imaging protocol included dwi with eight b values ranging between 0 sec/mm2 and 800 sec/ mm2 and gadolinium enhanced dynamic 3d vibe (volume interpolated breath hold exam) in the coronal plane. the studies were qualitatively evaluated in a blinded fashion by two board certified radiologists. disease activity was defined as bowel wall thickening and enhancement in the gadolinium enhanced images. dwi abnormality was defined as bowel thickening, increase signal on dwi images and decrease signal on adc maps of the ileum. intra voxel incoherent motion (ivim) dwi parameters were used as quantitative biomarkers for the analysis of slow diffusion (d) and fast diffusion fraction (f). results: gadolinium enhanced vibe images identified abnormal thickening and enhancement of the ileum in 11/29 (38%) patients. dwi identified abnormal signal in 11/29 (38%) patients. the sensitivity and specificity of the qualitative dwi for identifying ileitis, as shown by gadolinium enhanced imaging, were 82% and 89%, respectively. quantitative analysis showed statistically significant difference in ivim maximal values for f (fast diffusion fraction) between abnormal (mean00.67, std00.17) and normal (mean00.8, std00.14) ileum segments (p00.012). there was statistically significant difference in ivim maximal values for d (slow diffusion) between abnormal (mean 02.2 μm2/ms, std 0 0.7 μm2/ms) and normal (mean 02.7 μm2/ms, std 0 0.6 μm2/ms) ileum segments (p00.0084). abnormal loops of bowel had decreased slow and fast diffusion parameters. conclusions: diffusion weighted imaging has excellent sensitivity and specificity for the detection of active ileitis in pediatric cd. furthermore, quantitative ivim model parameters provide effective biomarkers for this condition. ivim dwi has the potential to assess bowel inflammation without intravenous contrast enhancement and further increase our understanding of cd. methods & materials: forty pediatric patients (median age 13.8 years, range 10.0-17.7) with suspected (n035) or confirmed ibd (n05) were included and underwent gastroileocolonoscopy with biopsies followed by mre (median interval 20 days, range 6-55). the mre results were compared with macroscopic and microscopic assessment of the ileum. the clinical importance of the mre results was registered. results: crohn disease (cd) was diagnosed in 25 cases, ulcerative colitis (uc) in 12, and ibd unclassified (ibdu) in three. macroscopic ileitis was detected in 15/25 (60%) of cd cases and in 2/12 (17%) of uc (backwash ileitis). microscopic inflammation was found in another four cd cases and one ibdu patient. in total, discrepancy between macroscopic and microscopic inflammation was found in 9 cd, 2 uc and one ibdu patients. the sensitivity of mri was 64% (against macroscopy and/or microscopy) to 71% (against macroscopy alone), while the specificity was 100% and 92%, respectivley. mre findings was decisive for diagnosis in 4/40 (10%) and led to treatment adjustments in 11/40 (28%) in the following six months. conclusions: mre is a reliable method for imaging of intestinal inflammation in pediatric ibd, and can be supportive or essential for clinical treatment decisions. results: of 15 children with ec, 7 had ct imaging of the abdomen and pelvis. these 7 children ranged in age from 15 months to 16 years (mean 10.2 years +/− 6.3) with a male predominance (n04, 57%). the most common presenting symptoms were abdominal pain (n06), bloody diarrhea (n03), and rectal bleeding (n03). ec was characterized as a dense and predominant eosinophilic inflammatory infiltrate in the lamina propria and/or epithelium without granulomas. ct scans were abnormal in 6 (86%). no colonic luminal contrast was present in 2 patients, and in one of these, the colon appeared normal. abnormal ct findings included cecal wall thickening (n05, 71%), mucosal enhancement without colonic wall thickening, (n01, 14%), mesenteric lymph node enlargement (n02, 29%), terminal ileal thickening (n02, 29%), jejunal and ileal thickening (n01, 14%), and pneumatosis (n01, 14%). of the 5 patients with cecal involvement, 4 primarily involved the cecum with less severe or no ileal or downstream colonic involvement. pneumatosis extended along the length of the colon with rectal predominance. conclusions: the predominant ct finding in our ec series was wall thickening, most severe in the cecum with variable extent downstream with mild or no involvement of the terminal ileum. although there is overlap, these findings are different from the most common patterns encountered with ulcerative colitis or crohn disease and should raise the possibility of ec in children presenting with abdominal pain and bloody diarrhea. purpose or case report: timely identification of childhood arterial ischemic stroke (ais) is critical to development of acute treatment strategies. we present our experience prior to and following development of a pediatric stroke alert system (sas). through multi-disciplinary collaboration in a tertiary care setting, a pediatric sas was established in 2008. we describe the system, imaging protocol evolution, and impact upon the time between admission and mri initiation (time-to-mri) in patients with childhood ais. of 74 patients in our stroke database (comirb #05-0339), 27% met inclusion criteria for stroke alert initiation (acute focal neurological deficit within 12 h). eleven pre-2008 and nine post-2008 patients met criteria. we compared the time-to-mri between these two groups, utilizing a two-tailed t-test. results: the pediatric sas has two phases: i-neurological evaluation and ii-imaging and treatment consideration. phase i stroke alert is initiated when a child presents with an acute focal neurologic deficit. if neurology confirms stroke symptoms and ct head is negative for an alternative etiology, a stroke alert is called prompting an emergent brain mri. if mri confirms an acute stroke, hyperacute therapies are considered. initial mri protocol included dwi, t2, flair, 3d tof cow mra, 2d tof neck mra and fat saturated t1 neck imaging. after internal quality review, t1 mprage brain and contrast enhanced 3d neck mra were added. the sequence order was also altered so diagnostic sequences were scanned first (dwi and cow mra). there was a trend towards decreased time-to-mri in the post-2008 group (mean0152 min, sd +/− 120) as compared to the pre-2008 group (mean 340 min, sd0+/−304; p00.10). conclusions: institution of a pediatric sas improved urgent neurologic evaluation and demonstrated a trend towards shorter time-to-mri. ongoing quality review has enhanced imaging quality and decreased time-to-mri. continued refinement of pediatric sas's will be critical to the success of recently funded phase i clinical trials in the evaluation of hyperacute therapies. results: there were 6 female and 3 male infants. the mean post-gestational age at presentation was 20 days (range 0-90 days), while the corrected age was less than 30 days for all patients. 7 patients presented with seizures and signs of infection; 1 presented with lethargy and later proved to have protein c deficiency. mri was performed 0-12 days from presentation in these 8 patients. another patient with known protein c deficiency underwent mri at 3d for followup of screening us abnormalities. there were a total of 27 deep cerebral white matter lesions: 21 frontal, 4 parietal, 2 temporal lobe. lesions were fluid signal cavities with restricted diffusion. larger lesions had dependent debris. all lesions had associated hemorrhage and most lesions had evidence of adjacent small vessel venous thrombosis. lesions imaged after gad showed peripheral enhancement. three lesions were seen to increase in size on follow-up imaging. three patients, 2 with meningitis confirmed via microbiology and 1 with presumed meningitis by csf counts, underwent surgical aspiration of a total of 6 lesions. all specimens were sent for pathology and culture and were negative for microorganisms. conclusions: recognizing the mr appearance of necrosis and liquefaction after deep white matter cerebral venous infarction in neonates can distinguish this entity from cerebral abscess and potentially avoid an unnecessary neurosurgical aspiration procedure. all four children were initially treated with aspirin but experienced recurrent events on therapy. all four were subsequently anticoagulated. two children have remained on warfarin for 6-7 years without recurrent events, while the other two had recurrent events despite adequate anticoagulation. these two children underwent uncomplicated coil embolization of the affected vertebral artery segment, and they have remained symptom-free for five and 20 months since then. conclusions: dava was diagnosed by ca in 3/4 patients. all four children with dava in our series suffered recurrent strokes despite aspirin therapy. two of the four experienced further strokes on anticoagulation, necessitating endovascular therapy. these findings suggest that dava in children may require ca to diagnose, and that it may be refractory to standard adult therapies. ongoing multicenter efforts in childhood ais should further evaluate the diagnostic approach and recurrence risk of childhood dava. ) and cerebral gray matter abnormalities were present in 6 (1%). posterior fossa lesions were seen on us in 1.6% , but mastoid views were included in only 50% of the centrally read us. conclusions: in the largest extreme preterm cohort to date with near-term mri and serial us, 19% had mod-severe wma on brain mri, similar to previous reports. cerebellar abnormalities were detected more frequently by mri than by us. neurodevelopmental outcomes at 18-22 months and school age will assess the relative and combined values of mri and us as outcome predictors. , an analysis technique based on task-free resting state fmri recording, can be useful in assessing disruption of connectivity in certain disease states, including epilepsy. in healthy control subjects, functional connectivity reveals strong bilateral interhemispheric connectivity in such system as sensory-motor, visual, auditory as well as dorsal attention and default mode networks. in patients with epilepsy associated with unilateral diffuse hemispheric disease such data is limited. differences in the pattern of activation would suggest alteration in connectivity in these entities. this finding would impact the typical interpretation of this data that is becoming routinely collected for epilepsy pre-surgical evaluation. methods & materials: siemens (erlangen, germany) system, 3-tesla (trio) scanner was used for imaging (epibold sequence, te030 ms, flip angle090°). resting state fmri scan were performed in both awake and anesthetized patient. awake patients were instructed to relax and rest while keeping their eyes open. analysis was performed using 1000 functional connectomes project scripts based on afni and fsl software packages. resting state data were analyzed for connectivity with the following seeds: somatomotor, visual, auditory, and default mode (posterior cingulated cortex (pcc)). results: we applied this technique to evaluate 12 patients with hemispheric seizure disorders, including rasmussen's, neonatal infarct and migration disorders. all the subjects demonstrated some deviation from typical interhemispheric connectivity with a spectrum of findings. the figure below shows connectivity patterns in a patient with cortical dysplasia. while some interhemispheric connectivity remained in somatomotor (sm) and auditory (a1) systems, it was disrupted in visual (v1) and default mode (pcc) networks. variable patterns were found across the cases that corresponded to lesion side, supportive of disruption in interhemispheric connectivity as measured by fmri. conclusions: resting state functional connectivity patterns are well documented in healthy subjects. these results suggest that interhemispheric connectivity disruption is a typical feature of unilateral diffuse hemispheric disease though variable in presentation, either being limited to select systems or demonstrating broad disconnect between the two hemispheres. these results should be carefully considered when evaluating data for pre-surgical epilepsy evaluation. purpose or case report: premature birth is associated with white matter injury leading to a wide ventricular system. however,normative standards for ventricular size are lacking for this particular group.aims: we aimed to, in a controlled, population based norwegian cohort of ex-prematures without major handicaps, and for men and women separately,to 1) create standards for radiological indices of ventricular dilatation, 2)investigate associations of these measurements with subjectively assessed ventricular size,3) examine differences in ventricular size between ex-prematures and healthy controls methods & materials: the initial birth cohort included 217 neonates, birth weight below 2000 g (low birth weight)born within hordaland county, norway, between april 1st 1986 and august 8th 1988. 113 of 174 eligible survivors (without major handicaps)underwent mr examination during the period january 2006 to may 2007. 103 of these were expremature (born before gestational age 37 weeks) and were included in this sub-study. based on t2 weighted images, the ventricular size was subjectively judged as being normal, mildly, moderately or severely dilated by an experienced paediatric neuroradiologist, while objective measurements were performed in a blinded fashion, by a second observer (sma) using an imaging software program (nordic ice®). results: the normative standards for the ventricular system in ex-premature young adults showed wide variations, in particular for the occipital horns. the agreement between subjective and objective assessment of ventricular size was good. ex-prematures had smaller heads than those born term (control group). there was no difference in ventricular size between the two groups, even after adjusting for head size. ex-premature males had larger ventricles than females; however, the difference disappeared after adjusting for head size. conclusions: young adults born prematurely with a birth weight below 2000 g do not have larger lateral ventricles than healthy controls born term, even after correcting for a smaller head size. paper #: pa-057 best practice for reproducibility when measuring t2*: implications for liver and cardiac iron assessment mark ferguson, md, radiology, seattle children's hospital, markferg@uw.edu; randolph otto, seth d. friedman purpose or case report: patients with red blood cell transfusion-dependent conditions receive high amounts of iron that can lead to abnormal iron accumulation in tissues resulting in organ damage. while the liver is the dominant excess iron storage organ, iron related cardiotoxicity is a leading cause of morbidity and mortality in patients with transfusion-dependent thalassemia. therefore, accurate determination and tracking of tissue iron levels in both the liver and the myocardium is important for patient prognostication as well as monitoring treatment changes. while multi-echo gradient echo mri (t2*) is widely used and validated method employed for iron assessment, less attention has been given to derived metrics. specifically, the literature almost exclusively reports and uses the mean value for t2* from a pixel-wise (pw) map. infrequently used is the median. the median is a potentially superior metric than the mean because it is insensitive to outliers. outliers will always occur in data because of either noise or imperfect vessel exclusion. to compare mean versus median on reproducibility of t2* measurement, 23 subjects who had paired heart/liver measurements were examined. the entire liver (excluding vessels) and the interventricular septum myocardium were traced on representative images from each series. mean and median t2* values were generated from the pixel maps. r2* (1000/ t2*) and coefficient of variation (cv) were computed on a patient-by-patient basis. these measures were then summarized for the group. results: markedly higher r2* values were observed in both heart and liver using median summary measures (liver: t0−2.79, p0.01, heart: t0−2.8, p0.01). these findings were accompanied by lower cv's (better reproducibility) for the median approach (liver: t01.89, p0.07; heart: t01.91, p0.07). conclusions: the consistent difference in derived t2* values between the methods (median>mean) should be considered when comparing derived r2* values to established normal ranges. cv data support that using the median as the final summary metric will always outperform mean metrics for measuring change in r2*. this finding has immediate implications for the scientific literature and for guiding therapeutic management over time. results: twelve children (age 5mo-13yo; m:f 6:6) with gsds (7 abca mutations, 4 sp-c mutations, 1 undefined mutation) and 16 children (age 2wk-18yo; m:f 10:6) with other dlds (including pulmonary interstitial glycogenosis, neuroendocrine cell hyperplasia of infancy, lymphocytic interstitial pneumonia, lipoid pneumonia, diffuse alveolar damage, granulomatous infection, capillaritis and other pulmonary hemorrhage syndromes) were identified. ct findings with highest sensitivity for gsds were ground glass attenuation (83%), parenchymal cysts (67%), and interstitial thickening (58%). parenchymal cysts, honeycombing, and pectus excavatum were more specific for gsds compared to other dlds (p<0.05). the combination of either parenchymal cysts and honeycombing or ground glass attenuation and pectus excavatum provided the highest specificity (100%) but low sensitivity (25%). the combination of parenchymal cysts and ground glass attenuation provided good specificity (81%) and modest sensitivity (50%). no combination of findings provided both high sensitivity and specificity. conclusions: ground glass attenuation is the most sensitive finding for gsds, while parenchymal cysts, honeycombing, and pectus excavatum are more specific findings for gsds than other chronic dlds of childhood. however, no single finding or combination of findings on chest ct is both highly sensitive and specific for gsds, and chest ct cannot substitute for genetic testing or lung biopsy for the differentiation of gsds from other dlds. pes were observed in 33 scans of patients without a history of congenital heart disease (chd), and 26 pes in 12 scans of patients with a history of chd. z-axis scan lengths for the chest ct exams ranged from 10.1-33.3 cm. a z-axis scan length of 14 cm centered 3.5 cm below the carina captured all pes in all patients, and a length of 12 cm centered 3.5-4 cm below the carina in patients with chd. a z-axis scan length of 8 cm centered 5 cm below the carina was sufficient to capture at least one pe in all patients, and a length of 8 cm centered 4-5 cm below the carina in patients with chd. the radiation effective dose of the chest ctpa exams ranged from 3-10 msv. limiting the z-axis scan length on ctpa exams to 14 cm or 8 cm would have resulted in a 20% or 40% decrease in z-axis coverage, respectively, and estimated radiation effective dose reduction of 21-42% due to less radiation exposure to the intrathoracic structures, thyroid gland and upper abdominal viscera. conclusions: limiting the z-axis scan length coverage for ctpa exams based on a model of the typical anatomic distribution of pes relative to the reference level of the carina permits a substantial reduction of radiation dose in children without reducing the sensitivity for detection of pulmonary emboli. purpose or case report: to determine whether the addition of multiplanar reformation mdct images affects reader performance parameters and provides added diagnostic value compared to the use of axial ct mdct images alone for diagnosing pe in children. this was an institutional review board-approved retrospective study of 60 consecutive pediatric patients who underwent ctpa for clinically suspected pe. two faculty pediatric radiologists and two radiology residents independently reviewed each study initially using only axial mdct images and later using mpr mdct images in any x-, y-, or z-axis for detecting pe. diagnostic accuracy, confidence level, and interpretation time of mpr mdct images were compared to axial mdct images using mcnemar's test and paired t-tests. the kappa coefficient was calculated to assess interobserver agreement. diagnostic accuracy was compared between faculty pediatric radiologists and radiology residents by logistic regression whereas confidence level, interpretation time, and added diagnostic value were evaluated with analysis of variance (anova). results: the final study cohort consisted of 60 ctpa studies from 60 children (28 m/32 f; mean age 14.7 years). nine (15%) of 60 ctpa studies were found to have pe. diagnostic accuracy in correctly detecting pe ranged from 91.7 to 100% (mean096.7%), with no significant differences between the use of axial and mpr mdct images. logistic regression indicated no significant difference in diagnostic accuracy of detecting pe between faculty pediatric radiologists and radiology residents for axial mdct images (p0.48) or mpr mdct images (p0.24). confidence level and interobserver agreement were significantly higher and average interpretation time was longer in evaluating pe with mpr mdct images compared to axial mdct images for all reviewers (p<.001). compared to faculty pediatric radiologists, significantly greater increases in confidence level, interobserver agreement, interpretation time, and added diagnostic value using mpr mdct images compared to axial mdct images to diagnose pe were found for radiology residents (p<0.001). conclusions: use of mpr mdct images in diagnosing pe on ctpa in children significantly increases confidence, interobserver agreement, and interpretation time among faculty pediatric radiologists and radiology residents. because mpr mdct images provide significantly greater improvements in reading parameters for residents than for faculty members, their routine use should be encouraged for trainees. paper #: pa-062 chest ct in children, anesthesia and atelectasis beverley newman, md, radiology, stanford university, bev.newman@stanford.edu; elliot krane, terry e. robinson purpose or case report: in spite of advances in ct equipment and speed, sedation/ anesthesia is required in many young children for optimal quality ct for detailed parenchymal evaluation; resultant atelectasis is a common and important quality issue. our purpose was to evaluate the safety and effectiveness of a standardized lung recruitment technique. methods & materials: with irb approval and parental informed consent, 49 controlled ventilation, low dose, chest ct's (cooperative effort between anesthesia, pulmonology and radiology) were performed in 38 children (7 had 2-4 cts) (21 f, 16 m; ages .02-5.13 yrs, mean 2.5 yrs). indications included cystic fibrosis 8; ciliary dyskinesia 4; chronic or interstitial lung disease 16; evaluate pulmonary metastases 10. ct parameters were 80-100kvp, 25-80mas, iv contrast 11. various prior methods employed by the pediatric anesthesiologists to maintain lung inflation had unpredictable results (a brief survey showed 5/9 nonintubated anesthetized cases had problematic atelectasis). a standardized intubation technique was therefore adopted: 1.use of a tight fitting face mask during induction and iv placement, inspiratory pressures of 20-25 and peep of 5. 2. introduction as early as possible using an appropriately sized cuffed endotracheal tube. 3. alveolar recruitment maneuvers-10-12 3 s breaths to 40 cm h2o/5 (32-35 in 1st 6 cases). 4. three breaths at 25/5, inspiratory breathold followed by 25-30 cm on 4th breath for scout and inspiratory scan, and complete ventilator disconnection for expiratory scan. recruitment breaths repeated before each scan. two experienced readers reviewed and scored the images on a 5 point scale for overall quality and atelectasis. results: all studies were completed safely with no procedural complications. one child had propofol-related postoperative emergence delirium. all ct scans were diagnostically good to excellent with small subsegmental atelectasis in 8 (6/8 were the initial cases with lower recruitment pressures) and segmental atelectasis in 2. 13 cases had prior cts, without this technique, that were suboptimal due to moderate procedural atelectasis, in spite of tracheal intubation in the majority of cases. conclusions: an intubation lung recruitment technique can be performed safely and consistently by different individuals using a standardized protocol. procedural atelectasis that affects quality is reliably absent and repeat sequences are not needed. obtaining a high-quality dynamic airway imaging study is critical for accurate interpretation and subsequent medical decision-making. the ideal mri sleep study is one that allows successful completion while maintaining spontaneous breathing without artificial airway, which can be an anesthesia challenge. dexmedetomidine has been shown to have sedative properties paralleling natural sleep with minimal respiratory depression. we hypothesized that dexmedetomidine compared to propofol would have less effect on upper airway tone and airway collapsibility and provide favorable conditions with less airway interventions required during dynamic mri airway imaging in children with osa. in this prospective study, we examined the requirement for airway intervention for propofol (100-200 mcg/kg/m) and dexmedetomidine(1-3 mcg/kg/h) in children and adolescents with osa. severity of osa was analyzed by overnight polysomnography. for children with history of mild osa there was no intervention unless oxygen saturation decreases below 90%; while for children with history of moderate/severe osa, an artificial airway was placed when oxygen saturation decreased below 85%. results: demographics and osa severity by polysomnography were comparable. requirement for artificial airway by severity of osa as documented by polysomnography will be shown. mri sleep studies required airway intervention in 3/26(12%) children in the dexmedetomidine group versus 7/ 29 (24%) children in the propofol group. mri sleep studies were successfully completed without the use of artificial airways in 23 children (88%) in the dexmedetomidine group versus 22 children (76%) in the propofol group. conclusions: safe and effective anesthetic management is a key factor in obtaining good quality mr images of the airway. although there was no statistical significant difference in the need for airway intervention between drugs, dexmedetomidine provided acceptable sedation for mri sleep studies with less airway intervention in children with osa. dexmedetomidine may be the preferred agent for sedation during mri sleep studies in children, and may offer benefits to children with sleep disordered breathing requiring anesthesia or sedation for other diagnostic imaging studies. an open mouth and administration of cpap resulted in smaller ap diameter of the retroglossal airway compared to images without cpap due to cpap pressure pushing the tongue posteriorly. in patient 1 volume of oral cavity anterior to the tongue increased from 7.41 ml to 11.74 ml. meanwhile, the ap diameter of the retroglossal airway decreased from 4.8 to 1.4 mm (71% decrease). in patient 2 the mouth was initially closed but parted when the pressure of cpap was added with the oral volume increasing from 3.69 ml to 15.80 ml. the ap measure of the retroglossal airway decreased from 8.3 mm to 2.8 mm (66% decrease). in patient 2 the mouth was then closed and cpap reapplied resulting in an ap measurement of 11.0 mm (33% increase). the ap diameter difference between cpap and no cpap were tested with paired t-test, but were not statistically significant (p00.1475). conclusions: positive airway pressure on a patient by full facemask and an open mouth can have an adverse effect on the retroglossal airway. this adverse effect is an important consideration in the use of positive airway pressure to support airways for osa, or during emergency resuscitation when a full facemask is used. paper #: pa-065 the purpose or case report: a nanoparticle blood pool iodinated contrast agent (nctx) has been designed and tested in preclinical animal models. we report data in animal models exemplifying its advantages over conventional contrast in the setting of ct pulmonary angiography methods & materials: nctx blood pool nanoparticles of 125 nm diameter with an encapsulated total iodine concentration of~125mgi/ml were administered by intravenous injection to mice, rabbits, dogs, pigs and sheep. (these studies were actually conducted for other purposes and a review of the data revealed the similarities that motivated this paper.) total injected volumes were~5 ml/kg in large animals, and as high as 10 ml/kg in small animals to provide satisfactory vessel enhancement. iohexol or iopamidol was administered for comparative studies with conventional contrast. in a subset of pigs, iatrogenic pulmonary arterial emboli were introduced prior to contrast administration. toxicity studies were conducted in mice and monkeys. results: the visualization of pulmonary vessels using nctx blood pool nanoparticles was generally at least equivalent to using conventional contrast, and superior in several cases, particularly in small veins and when bolus timing of the conventional contrast was suboptimal. in all cases, satisfactory vessel enhancement was achieved for a duration of several hours following a single infusion of nctx blood pool nanoparticles. there was no evidence of renal toxicity, and only transient elevation of hepatic enzymes at relevant dose levels. conclusions: nctx nanoparticle blood pool agents demonstrate several advantages over conventional glomerularfiltered iodinated contrast agents for ct pulmonary angiography in animal models, including no nephrotoxicity, no dependence on bolus injection technique, superior depiction of small veins, and capability of re-imaging for follow-up studies without needing contrast re-injection. potential applications in human pediatric subjects include the diagnostic and post-therapeutic evaluation of cardiopulmonary anomalies and pulmonary embolism, especially in patients with renal insufficiency or tenuous vascular access. disclosure: dr. annapragada has indicated that he is a stock holder and consultant for marval biosciences inc. paper #: pa-067 cardiovascular image quality using a nanoparticle ct contrast agent: preliminary studies in a pig model rajesh krishnamurthy, radiology, texas children's hospital, rxkrishn@texaschildrens.org; ketan ghaghada, prakash masand, abhay divekar, eric hoffman, ananth annapragada purpose or case report: image quality in a separate study using a long circulating, liposomal-based nanoscale blood pool iodinated contrast agent (nctx) suggests clinical utility in pediatrics, potentially reducing difficulties in contrast-ct of children with congenital heart disease (chd) including the size of intravenous cannula, need for accurate timing, inability to simultaneously opacify multiple targets of interest (requiring repeated contrast administration and/or repeated imaging). methods & materials: six pigs (average weight 30 kg) were imaged after slow intravenous infusion of nctx (105 mg i/ml) at an iodine dose of approximately 900 mg i/ kg (8.5 ml/kg). retrospective ekg gated ct imaging was performed 3 h later using a 128-slice dual-source ct scanner at 80 and 120 kvp. two radiologists analyzed and graded (on a 5-point scale with 1: unreadable, 5: excellent) images aimed at anatomic structures relevant to chd. quality of images obtained at 80 and 120 kvp were compared. uniformity of contrast opacification was measured using a roi-based ctnumber method at various intracardiac and extracardiac sites and mean non-uniformity was calculated. results: there was excellent agreement between the two readers on all counts at 120 kvp. 80 kvp images received lower scores for coronary morphology (4/5), and aortic valve visualization (3.5/5), but were comparable in other aspects. pulmonary artery and pulmonary vein branch visualization extended up to the 5th generation in all cases. visualization of coronary artery branches was possible up to the second generation, with good arteriovenous separation. subtle morphologic features including crista terminalis, thebesian valve, foramen ovale, membranous septum, and chordae of the mitral valve were demonstrated in all cases. automated functional analysis and myocardial mass quantitation was feasible in all cases. there was no significant difference in blood pool attenuation between the atria, ventricles, and extracardiac vasculature on quantitative assessment. no image artifacts were visible on the reconstructed images. conclusions: these findings suggest that nctx promises to be superior to conventional contrast agents for ct imaging of complex congenital heart disease, due to the absence of nephrotoxicity, avoidance of repeated contrast administration, and reduced number of scans performed. avoiding the need for accurately timed scans precludes the need for large bore intravenous access. these attributes make it a promising agent that warrants further studies. disclosure: dr. annapragada has indicated that he is a stock holder and consultant for marval biosciences inc. paper #: pa-068 theoretical cost and x-ray dose reduction in pediatric congenital heart disease imaging by the use of a nanoparticle contrast agent robert bell, the university of texas-houston; rajesh krishnamurthy, gabriela espinosa, christopher petit, ananth annapragada purpose or case report: the purpose of this study is to determine the effective, population averaged reduction in costs and radiation dose that can be achieved in the diagnosis of congenital heart disease by use of a nanoparticle long circulating blood pool contrast agent. methods & materials: a markov model of the decision tree followed at the texas children's hospital in the image based diagnosis of congenital heart disease was constructed in treeage software. the model included ct angiography, mr angiography, cardiac catheterization, and echocardiography diagnostic modalities. patient records, accumulated between 2003 and 2011 were examined to inform the model. the radiation dose and cost for each step were encoded as penalty functions. markov simulations were run for two decision trees: (1) utilizing ct angiography and (2) replacing conventional ct angiography with blood-pool agent based ct angiography. the overall population x-ray dose and accrued cost was calculated for each pass through the model. results: x-ray dose distributions for the example populations showed substantial reductions per ct study, as much as 50%. averaged over the population, since a sizeable fraction of patients are diagnosed without ever being exposed to any x-ray based modality, reductions were more modest, but still substantial. costs per ct study were slightly higher when the blood pool contrast agent was used. when the diagnostic probability using the blood pool agent increased, it led to an automatic overall cost reduction. conversely when the diagnostic probability remained unchanged, costs rose, commensurate with the increased cost of the contrast agent. conclusions: the use of a blood pool contrast agent for ct angiography leads to substantial reduction in radiation dose in the setting of congenital heart disease. cost reductions are more modest, and are driven almost completely by the reduction in the number of mr and invasive angiography procedures resulting from increased diagnostic success using blood pool based ct angiography. the model as constructed does not account for potential workflow changes that might result from the use of a new contrast agent. actual reductions realized may therefore be higher. disclosure: dr. annapragada has indicated that he is a stock holder and consultant for marval biosciences inc. paper #: pa-069 frequencies and patterns of situs discordance in chest and abdomen justin boe, stanford, justinj.boe@gmail.com; beverley newman, shreyas vasanawala, frandics chan purpose or case report: incidence of situs anomalies, including heterotaxy and situs inversus, is estimated at 0.02% of population. as the first step in the segmental analysis of structural heart disease, the determination situs position is of fundamental importance. abdominal situs, as defined by splenic position and morphology, and cardiac situs, as defined by atrial morphology, are usually but not always in agreement. echocardiographers also employ the relative position of the great arteries and vein at the hiatus to determine cardiac situs. we evaluate the frequencies of discordances among abdominal, hiatal and cardiac situses. methods & materials: with retrospective irb approval, imaging records from 2001 to 2011 were reviewed for the diagnosis of cardiac situs inversus and heterotaxy. patients who had cardiac ct or mri were included. images were evaluated on a 3d-processing station by a cardiac radiologist. cardiac situs was determined by the morphology of the atrial appendages. when an atrial appendage was not adequately visualized, cardiac situs was assessed by the relative position of the main pulmonary artery and bronchi. hiatal situs was determined by the relative position of the aorta and the systemic venous return, and abdominal situs by the position and morphology of the spleen. results: thirty-five cases were identified, with 23 cardiac ct and 12 mri. patients' age ranged from 1 day to 35 years old. in the abdomen, the numbers of situs inversus, asplenia, and polysplenia were 11 (32%), 12 (34%), and 12 (34%). for the heart, the numbers of situs solitus, inversus, rightisomerism, and left-isomerism were 2 (6%), 13 (37%), 11 (31%) and 9 (26%). the abdominal and cardiac situses were discordant in 5 (14%) cases. polysplenia had the highest number of discordance with the heart. hiatal situs was discordant with the abdomen in 5 cases (16%) and with the heart in 8 (25%) cases. conclusions: situs disagreement between the abdomen and the heart is not uncommon and they should be documented separately in radiology reports. hiatal situs, as used by echocardiographer, disagrees with the cardiac situs in a quarter of the cases. it should be used with caution in the segmental analysis. paper #: pa-070 diminished asl intracranial perfusion in children with neurofibromatosis type 1 kristen yeom, md, stanford university, kyeom@stanford. edu; cynthia campen, patrick barnes purpose or case report: neurofibromatosis type 1 (nf1), a neuro-cutaneous syndrome affecting 1/3500 children is associated with moyamoya syndrome (mms). however, no comparisons of cerebral perfusion in patients with nf1 and nf1-associated mms to healthy controls exist. we hypothesize cerebral blood flow (cbf), as measured by magnetic resonance imaging (mri) arterial-spin-labeled (asl), is diminished in children with nf1 compared to healthy controls, with the lowest levels seen in patients with nf1-associated mms. methods & materials: twenty children aged 2-18 years with nf1, four with mms, and 26 age-matched controls underwent asl cbf on a 3 t magnet. pseudocontinuousspin-echo-asl technique was used. measurements were taken bilaterally in cerebral cortical-subcortical regions, and the deep gray nuclei. trends in measurements as a function of disease severity were tested with the jonckheere-terpstra test for ordered alternatives. a bonferroni-adjusted p-value less than 0.0013 was considered significant. results: we identified 6/12 areas with significantly diminished asl cbf (ml/100 g/min) in patients with nf1 (midrange), and nf1-associated mms (lowest) compared to healthy controls (highest). these included the: thalami (left: p00.0002, right: p00.0004); superior/middle temporal lobes (left: p 00.0012, right: p 00.0009); temporooccipital lobes (left: p00.0006, right: p00.0003); occipital poles (left: p 00.0008, right: p 00.0001); centrum semiovale (left: p00.0022, right: p00.0005); and left parietal lobe (p00.0012). conclusions: cerebral perfusion diminishes in a graded fashion in children with nf1 and nf1-associated mms, particularly in the posterior circulation and the mca-pca posterior watershed zones. future studies may demonstrate an important role for asl in the presymptomatic diagnosis of cerebral vasculopathy, and the definition of nf1-related vasculopathy patterns. paper #: pa-071 cingulate gyrus mri sign in pediatric nf1 patients: a novel imaging marker nadja kadom, md, radiology, children's national medical center, nkadom@childrensnational.org; nabila hai, rhea udyavar , amir noor, gilbert l. vezina, maria t. acosta purpose or case report: we observed a magnetic resonance imaging (mri) signal abnormality in the anterior cingulate gyrus of pediatric patients with neurofibromatosis type 1 (nf1). the cingulate gyrus could play a role in cognitive deficits of nf1 patients. the first objective here is to document inter-rater reliability scores for visual detection of this sign. the second objective is comparing adc values of the cingulate gyrus in areas of visually abnormal mri signal in nf1 patients to matched normal mris to confirm a pathophysiological basis of the visual mri sign. methods & materials: retrospective analysis, irb approved, 61 nf1 patients and 38 matched controls. in the visual assessment part, two blinded neuroradiologists rated presence or absence of mri signal abnormality in the cingulate gyrus in three different age groups of nf1 patients mixed with normal controls. cohen's kappa inter-rater reliability coefficients were calculated. the same blinded neuroradiologists evaluated the cohort one year later, this time by agreement at the workstation. in the adc measurements part, two researchers, one blinded, manually placed roi's in the anterior and posterior cingulate regions of 26 nf1 patients and their matched controls, and student t-test was used to assess for significance of differences in measured values. results: cohen's kappa for the three age groups showed very good agreement (kappa coefficients were either 0.9 or 1.0). rater agreement at the workstation was 100%. all subjects with a positive finding also had nf1 and the sign was not seen in any of the normal controls. the prevalence of the sign was 43%. adc measurements showed significantly higher adc values in the anterior cingulate gyrus of nf1 patients when compared to normal controls and also when compared to the posterior cingulate gyrus in nf1 patients. conclusions: our results show that visual t2/flair mri abnormalities in the anterior cingulate gyrus are present in 43% of patients with nf1 from ages 2 to 19 years. adc measurements confirm a pathophysiological basis for this finding. future correlation with clinical manifestations, such as learning and behavioral manifestations in patients with nf1, are under way to further evaluate the clinical importance of this finding. tract-based spatial statistical analysis of diffusion tensor imaging in pediatric patients with mitochondrial disease seth friedman, phd, seattle children's, seth.friedman@ seattlechildrens.org; andrew v. poliakov, sandra l. poliachik, dennis w. shaw purpose or case report: often diagnosed at birth or in early childhood, mitochondrial disease presents with a variety of clinical symptoms, particularly in organs and tissues that require high energetic demand such as brain, heart, liver, and skeletal muscles. in a group of pediatric patients identified to have complex i or i/iii deficits, but with white matter tissue appearing qualitatively normal for age, we hypothesized that quantitative dti analyses might unmask deficits in microstructural integrity. methods & materials: dti and structural mr brain imaging data were collected in 10 pediatric patients with confirmed mitochondrial disease and 10 clinical control subjects matched for age, gender, scanning parameters, and date of exam. paired tract-based spatial statistics (tbss) were performed to evaluate differences in fractional anisotropy (fa) and mean diffusivity (md). results: in patients with mitochondrial disease, significant widespread reductions in fa values were shown in white matter tracts. md values were significantly increased in patients, having a sparser distribution of affected regions compared to fa. results of tbss statistical analysis will be shown. to be shown in green is the mean fa skeleton which represents the centers of main white matter tracts. all results p<.05. red and yellow represent a significant increase, blue and light blue represent a significant decrease. conclusions: despite qualitatively normal appearing white matter tissues, patients with confirmed mitochondrial disease have widespread microstructural changes measurable with quantitative dti. this supports the evaluation of such metrics in other populations where gross imaging features may be normal. to extend our studies to patients with other plp1 mutations, we analyzed the brains of 52 male pmd patients (ranging in age from 2 to 45) and 9 female carriers for whom the plp1 genotype had been determined and analyzed by mri. for each patient we measured, white matter volume (wmv) and the intercaudate distance (icd). the mri data were correlated with functional disability scores (fds) using a system we developed for clinical evaluation of pmd patients and which was validated by assessments of 22 pmd patients. brain volume and segmentation were measured using nih image 1.62. the average number of coronal slices analyzed from each patients mri was 60 slices. when graywhite contrast was not adequate, then the intercaudate distance (icd) and intercaudate ratio were measured as described in caon et. al., (2003) . results: comparison of the mr measurements and the fds demonstrated that white matter volume inversely correlates with functional disability, suggesting that the initial disability does correlate with the extent of myelination. the intercaudate distance also correlated with the fds, and may usefully substitute when gray-white matter segmentation is not possible. conclusions: pmd is a clinically and genetically heterogeneous disease caused by mutations in the gene encoding the major cns myelin protein, proteolipid protein (plp). myelin is a major target of disease pathogenesis in most cases of pmd, but how the various mutations cause clinical disability is not fully understood. our data demonstrate that the extent of brain white matter atrophy, measured directly by volumetric fractionation, or indirectly by analyzing the intercaudate ratio, is significantly correlated with the patient's functional disability. white matter atrophy is thus the main cause of clinical disability in patients with pmd of all ages and mutation type. paper #: pa-074 maturational effects on language localization in children demonstrated by fmri susan palasis, md, children's healthcare of atlanta at scottish rite, spalasis@yahoo.com; binjian sun, laura l. hayes, richard a. jones purpose or case report: language localization is of paramount importance when contemplating surgery in children with intractable epilepsy or brain tumors. the potential risk of injury to language centers in the developing pediatric brain needs to be weighed against the potential benefits of surgery. in the past, language localization was crudely and invasively determined using the wada test. most institutions are now transitioning to non invasive localization using functional mri (fmri). the purpose of our study was to analyze language localization relative to age in children using age appropriate language paradigms and fmri. methods & materials: forty three healthy, english speaking, right handed children underwent fmri evaluation for language localization. the studies were performed on a 3 t system. three novel age appropriate language block paradigms were utilized, targeted both to expressive and receptive language processing. these paradigms were the auditory category decision task (audcat), the auditory description decision task (addt), and the listening task. the spatial statistical maps generated by the fmri data were fused to the 3d anatomical mri dataset. language areas were localized and statistical analysis was performed with age as the variable in a general linear model. results: our results demonstrate a distinct trend in language localization and lateralization with brain maturation. in the young age groups (less than 12 years) the localization tended to be less focused and bilateral in the frontal and temporal regions of the brain. in the older age groups (greater than 12 years), language became more localized and lateralized to the expected left sided pattern. the findings were more robustly demonstrated with the addt task and were statistically significant (p<0.05). conclusions: our study clearly demonstrates the plasticity of language centers in the maturing pediatric brain. this observation is significant for neurosurgical planning and rehabilitation in the pediatric population. (3) no slc26a4 mutations were found in 16, 12 and 47 subjects, respectively. significantly higher association with slc26a4 mutations was found in bilateral eva+v/c dysplasia (16/18). double mutations of slc26a4 is more often associated with combined eva+ v/c dysplasia, while a single mutation with eva only. cochlear aplasia without eva (0/2) and snhl with normal imaging (3/21) are less likely associated with slc26a4 mutation. conclusions: slc26a4 mutation is highly associated with eva and v/c dysplasia. once eva with or without v/c dysplasia are found at imaging, genetic investigation is recommended for slc26a4 mutation because of possible thyroid involvement. moderate-severe hie who were randomized to cooling (33.5°c for 72 h). there were 73 in the hypothermia group and 63 in the control group. all mris were reviewed by a cental reader masked to the clinical findings, groupings, and outcomes. the mri findings were scored according to pattern and extent of injury, including involvement of the cerebral hemispheres, basal ganglia, thalami, internal capsules, and other structures. brain injury scores were correlated with death or disability at 18 months postnatal age. results: no mri abnormalities were observed in 38 of 73 infants (52%) in the hypothermia group and in 22 of 63 infants (35%) in the control group (p00.08). infants in the hypothermia group had fewer areas of injury (12%) as compared with the control group (22%, p0 0.02). there were 51 of the 136 infants with death or disability at 18 months. the brain injury score correlated with outcome of death or disability (p00.001) and disability among survivors (p00.0001). conclusions: fewer areas of brain injury on mri were observed following whole-body hypothermia. the mri brain injury score is a marker of death or disability at 18 months following hypothermia for term hie. . presence or absence of the "red dot" on fa color maps was correlated to clinical (ataxia, oculomotor abnormalities etc.) and morphological data, and to fa and md measurements. results: the "red dot" was absent in js and hgpps (genetic cross wiring impairment diseases) and present in coma and wvs (no reported gene abnormalities so far) as in normal controls. js and coma presented on mri molar tooth appearance. hgpps presented "split pons" appearance. js and coma patients presented oculomotor apraxia, wvs and hgpps palsy of the horizontal gaze. mirror movements were found in 2 js and in wvs. ipsilateral responses are present in hgpps. wvs presented multiple cranial nerves impairment. in js, fa and md values of scp, pt and pc were significantly lower than in normal controls (p >0.01). in hgpps high fa and low md were found in pc and pt (p >0.01) and normal in scp. conclusions: the "red dot" absence is unrelated to morphological or clinical abnormalities. absence of the "red dot" is associated to abnormal measurements of fa and md in pc and pt( low in js and high in hgpps). these findings indicate a pivotal role for the pc in the physiopathology of these diseases. the "red dot" absence seems to be a marker of genetic cross wiring diseases. in this view, coma and wvs should not be considered as part of these diseases. sonographic predictors of intermittant testicular torsion in the pediatric patient jennifer williams, md, pediatric radiology, texas children's hospital, jlwilli1@texaschildrens.org; marthe munden purpose or case report: intermittent testicular torsion (itt), defined as sudden onset unilateral scrotal pain with spontaneous resolution, is difficult to confirm both clinically and sonographically. the purpose of this study was to determine if sonographic predictors exist for diagnosing itt in the pediatric patient. methods & materials: a search of the pacs data system for patients presenting with suspected intermittent testicular torsion was performed. fifteen patients with a total of 20 episodes presenting over a 2 year period were found. a retrospective review of the medical records for clinical presentation, surgical outcome, and comorbidities was performed. scrotal ultrasound images and reports were reviewed for testicular size and echotexture, testicular flow, epididymal appearance, vascular bundle appearance, and presence of hydrocele. results: an abnormal appearance of the vascular bundle was found in 85% of episodes (17/20). initial absence of testicular flow followed by reperfusion during the scan was seen in 30% of episodes (6/20); 45% had increased flow (9/ 20), 10% had decreased flow (2/20), and 15% had normal flow (3/20) . nine of the 15 patients had surgery; of these 8 were found to have evidence of itt and 1 was found to have acute testicular torsion. of patients with itt, 88% (7/8) had an abnormal vascular bundle. testicular flow was not initially visualized but returned during the exam in 50% of patients (4/8), was increased in 38% of patients (3/7) and was decreased in 13% patients (1/8). conclusions: itt is a difficult diagnosis. the most reliable sonographic indicator is an abnormal spermatic cord, found in 85% of episodes and 88% of surgically proven itt. dedicated views of the spermatic cord must be obtained in order to differentiate an abnormal epididymis from an engorged vascular bundle (the so-called pseudomass). attention to testicular flow is of particular importance. while visualization of a transition from no or decreased testicular flow to normal flow during the sonogram is certainly diagnostic of itt, increased testicular flow should not lead to false reassurance. purpose or case report: testicular torsion is a common acute condition in boys requiring prompt and accurate diagnosis. the objective was to evaluate ultrasound accuracy and findings, and clinical predictors in testicular torsion in boys presenting to the stollery pediatric emergency department (ed) with acute scrotal pain. methods & materials: retrospective review of us, surgical and ed records for boys aged 1 month to 17 years, presenting with acute scrotum from 2008 to 2011, was performed. age, demographics, clinical symptoms, physical findings, us and surgical techniques, findings and diagnoses were recorded. surgical results and follow-up were used as the gold standard as all pediatric urology in our region is performed at our centre. results: 343 patients presented to ed with acute scrotum with the following diagnoses: 35 testicular torsion, 11 possible torsion-detorsion, 3 torsion of appendix testes, 135 epididymo-orchitis, and 159 other. of 266 us performed, 29 boys had torsion confirmed by surgery. there were 8 inconclusive us reports, none of which had torsion at surgery or follow-up. the false positive rate of us was 1.5% (4 patients), and there were no false negatives. six torsion patients had no us. median time from ed to us and surgery for torsion patients was 159 and 303 min. six patients had non-salvageable testes. diagnostic accuracy of us compared to surgery was 96% for torsion and 67% for other. sonographic heterogeneity was seen in 80% of patients with testes that the surgeon felt were non-viable at surgery and 72% of patients with viable testes (p00.35). sudden-onset scrotal pain (92%), abnormal position (86%) and absent cremasteric reflex (91%,) were most prevalent in torsion patients. conclusions: color doppler us is accurate and sensitive for diagnosis of torsion in the setting of acute scrotum. despite heterogeneity on pre-operative us, many testes were felt to be salvageable at surgery. rate of salvage of torsion was high. common symptoms and findings of torsion were sudden onset of pain, abnormal testicular position and absent cremasteric reflex. paper #: pa-080 diagnostic twists of tubal torsion srikala narayanan, md, children's national medical center, snarayan@childrensnational.org; anjum n. bandarkar, dorothy bulas purpose or case report: fallopian tube torsion is a rare cause of acute pelvic pain in a young female and requires prompt diagnosis for immediate surgical intervention. our purpose is to review varied imaging findings of surgically proven cases of tubal torsion. methods & materials: retrospective review of our data base from 2007 to 2011 revealed 7 cases of surgically proven fallopian tube torsion. ages ranged from 9 to 15 years of age. all had pelvic ultrasound performed, 3 cases had additional ct performed for acute pelvic pain. results: us findings included thickened dilated tubular hypoechoic structure (5), cystic mass (4); adnexal (3), midline (1). five cases had normal ovaries bilaterally (2 with paratubal cysts). ct imaging findings include dilated, fluid filled, thickwalled tube with internal hyperdensity (40hu) likely debris/ hemorrhage in 1 case. additional findings included cystic adnexal mass (3 cases), beak sign (1 case) and increased vascularity (1 case). secondary signs included free fluid (5), peritubular fat stranding (1), vascular congestion and thickening of the broad ligament (1) and enlarged draining vein (1). laparoscopic salphingectomy was performed in 3 cases (including 2 cases with isolated tubal torsion). laparoscopic detorsion was performed in a total of 4 cases. in addition, laparoscopic cyst drainage was performed in 2 out of these 4 cases. detorsion with paratubal cystectomy and hemorrhagic ovarian cystectomy was performed in 1 of the 4 cases. conclusions: imaging diagnosis of tubal torsion can be difficult. it can occur in isolation with a dilated thickened tubular structure adjacent to a normal ovary or potentially mimic appendicitis, pyosalpinx, complex adnexal cyst or cystic adnexal neoplasm. presence of normal ovaries, beaked tapered tubular structure with intratubal fluid level and hemorrhage may help in making the diagnosis. it is important to recognize this entity in a patient with acute pelvic pain to facilitate prompt tubal sparing surgery. paper #: pa-081 adjusted renal length in pediatric bone marrow transplant recipients nicholas bodmer, md, university of washington, nbodmer@gmail.com; teresa chapman, sangeeta hingorani, marguerite parisi purpose or case report: bilateral nephromegaly has been observed in the bone marrow transplant (bmt) patients at our institution. this study aims to quantify this observation, thereby providing radiologists with an adjusted baseline agedetermined renal growth curve for bmt patients. methods & materials: a retrospective clinical chart and imaging review was performed on 185 patients who underwent bmt between 2006 and 2010 and who had abdominal imaging including the kidneys. ultrasound, ct, and mri exams were used for renal length measurement. renal lengths were assessed for each age group, first as an average length of all the patients within that age group overall, and subsequently as an average renal length by age group divided into the following time frames after transplantation: 0-30 days, 31-90 days, 91-180 days, and 181+ days. clinic chart information collected included bun, creatinine, weight, and medication use. results: renal length was measured using 278 imaging cases, distributed across each age group as follows: 6-12 months, n 011; 13 months-2.5 years, n 030; 2.6-4.5 years, n033; 4.6-7.5 years, n038; 7.6-11.5 years, n0 51; 11.6 years and higher, n0115. renal lengths were greater, on average, within every age group, compared with previously established normative age-related renal lengths (rosenbaum et al.) . the augmented renal lengths universally were observed in the 0-30 day post-transplantation timeframe. return to normal renal lengths typically occurred by 6 months post transplant. clinic chart review revealed that the majority (87%) of patients received nephrotoxic medication within two weeks of imaging. conclusions: pediatric bmt patients have larger kidneys in the absence of known renal disease than age-matched peers. a revised, age-based renal length chart for post-bmt patients has been generated which should help prevent the misdiagnosis of nephromegaly in this population, eliminating unnecessary diagnostic evaluations. multiple etiologies to explain renal enlargement in these patients are possible, including fluid overload, nephrotoxic medication, or direct effect of the transplant. purpose or case report: mr urography can be a comprehensive exam for anatomical and functional pediatric renal evaluation. quantification of renal function may benefit when dynamic contrast enhanced images can be obtained at high spatiotemporal resolution and with minimal respiratory motion artifacts. though respiratory triggering may decrease motion artifacts, it results in loss of temporal resolution by a factor of about three. a two-echo gradient echo sequence with segmented outer k-space sampling and view-sharing/dixon image reconstruction (disco, differential subsampling with cartesian ordering) was chosen as a starting point due to its high temporal resolution. it was then modified to enable respiratory triggering while maintaining temporal resolution of one temporal frame every one to two respirations, with segments of k-space only acquired in the expiratory phase of respiration. imaging parameters were: 12°flip angle, ± 167 khz bandwidth, tr~3.56, matrix 256x200, fov 28-34 cm, slice thickness 4 mm, and 2x2 spatial acceleration. with irb approval and informed patient consent 9 consecutive patients referred for mri renal function evaluation were recruited (age range; 0.5 to 9.6 years, mean±sd: 3.99±3.6 years; males 78% females 22%), and scanned on a ge 3 t mr using a 32-channel torso array with the respiratory-triggered high spatiotemporal resolution technique to extract regional gfr maps. two readers by consensus assessed image qualitative snr, motion artifacts and volumetric fat-water suppression performance. results: data acquisition was obtained to completion in all subjects without triggering failure. temporal resolution was approximately 12 s for two respiratory cycles. no case had major fat suppression failure, whereas minor fat suppression failure was seen in 11% (95% c.i. 0 to 37%). all cases had diagnostically acceptable snr. no motion artifacts were noted in 7/9 cases, while some artifacts with ghosting in 2/9 cases. regional gfr maps could be successfully extracted for each patient without the need for image registration. attached figure shows image quality. conclusions: view-sharing offsets loss of temporal resolution from respiratory triggering. thus, high spatiotemporal resolution renal dynamic contrast enhanced respiratory triggered images can be obtained with minimal motion artifacts in a pediatric clinical setting to evaluate renal function. disclosure: dr. chowdhury has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. methods & materials: the study cohort was selected from the irb approved children's oncology group aren03b2 study. cases are evaluated for pre-operative wt rupture based on central review of surgical/pathology findings. 70 wt cases with rupture were matched to 70 wt controls by age and tumor weight (within 6 months and 50 g). ct scans were independently reviewed by 2 blinded radiologists, for presence/absence of rupture and the following ct signs: poorly circumscribed mass, perinephric fat stranding, peritumoral fat planes obscured, retroperitoneal fluid, ascites beyond cul-de-sac, peritoneal implants, ipsilateral pleural effusion, intratumor hemorrhage. sensitivity, specificity of ct for assessing pre-operative wt rupture was determined. the relationship between ct signs and rupture was assessed by mcnemar's test, and the most predictive ct signs determined by backward selection multivariate logistic regression. results: sensitivity, specificity for detecting wt rupture were: reviewer 1-53.7%, 88.4%, reviewer 2-70.2%, 88.4%. kappa coefficient for interobserver agreement was substantial: 0.76 (p<0.0001). all ct signs tested, except peritoneal implants and intratumoral hemorrhage, had significant association with tumor rupture (p<0.01). for reviewer 1, ascites and fat stranding around tumor were most predictive (odds ratio 18.359 and 10.554, p<0.01). for reviewer 2, ascites and retroperitoneal fluid were most predictive (or 8.345 and 4.916, p<0.01). conclusions: ct has high specificity but relatively low sensitivity for detecting preoperative wt rupture. the presence of ascites beyond cul-de-sac is the best indicator of preoperative rupture, followed by fat stranding and retroperitoneal fluid. paper #: pa-084 the failed pyeloplasty: evaluation with mr urography damien grattan-smith, children's healthcare of atlanta, damien.grattansmith@mac.com; ricahrd jones, stephen little, wolfgang cerwinka, hal scherz, andrew kirsch purpose or case report: to identify imaging characteristics associated with failed pyeloplasty seen with mr urography. we have performed mr urography in 142 children following pyeloplasty. from this group, 16 children had follow-up surgical intervention with repeat pyeloplasty or balloon dilatation of the upj. imaging features reviewed included degree of hydronephrosis, calyceal transit times, renal transit times, signal intensity versus time curves, as well as functional analysis based on volumetric and patlak differential function and change in the asymmetry index. results: all children who underwent a second surgical procedure had delayed calyceal transit times. the degree of hydronephrosis and renal transit times were either stable or worse when compared to pre-operative evaluation. functional derangement could show stability, slight improvement or deterioration. the asymmetry index estimated the severity of the obstruction. conclusions: mr urography is valuable in the evaluation of children who have undergone pyeloplasty. the calyceal transit time appears to be the most reliable discriminator when comparing successful and failed pyeloplasty. calyceal transit times may be prolonged before the hydronephrosis becomes progressive. disclosure: dr. grattan-smith has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: initial attempts at interpreting functional mr urography (fmru) can be challenging. a time intensive navigation through a multitude of both subjective and objective functional results is necessary to render a useful interpretation. this is a guided review of fmru, noting the important functional findings in high-grade unilateral pelvicalyceal dilatation (pcd), in the absence of ureterectasis, with a contralateral normal kidney allowing for an optimal functional comparison. methods & materials: a retrospective functional evaluation of 16 cases with unilateral pelvicalyceal dilatation (pcd), without prior pyeloplasty, was conducted. the fmru studies were carried out according to a standard protocol and post-processing using the chop-fmru software. this included iv hydration, bladder catheterization and iv furosemide administration. fifteen minutes after diuretic administration, a dynamic coronal 3d fat saturated t1 sequence was performed in a supine position over 15 min. a sagittal 3d t1 and delayed single coronal t1, both fat saturated, followed in a supine and/or prone position. the following functional features were evaluated: visualization of the ureter, the presence of a contrast-urine level and swirling of contrast in the dilated renal pelvis. the functional results included in the analysis were calyceal transit time (ctt), renal transit time (rtt), time-to-peak (ttp), parenchymal volume (pv), differential renal functions (volumetric-vdrf, patlak-pdrf and volumetric patlak-vpdrf) and the difference between vdrf and pdrf. results: 16 patients were comprised of 8 males and 8 females with an age range of 0.1-17.0 years (median 0.8 yrs). of the kidneys with pcd, the ureter was visualized in 10, 3 during the dynamic sequence, 4/9 during supine delay and 3/7 only in prone position. a contrast-urine level was present in 14 of the dilated systems, and swirling in 6. the ureter was visualized during dynamic sequence in all contralateral normal kidneys and at no time was swirling or a contrast-urine level identified. the average functional parameters are seen in table 1 . a statistically significant (p<0.05) difference between the normal and dilated pelvicalyceal systems was achieved in ttp, pdrf and vpdrf for this small sample size. conclusions: awareness of multiple functional features and the range of calculated results may aid in subsequent combined interpretation of the fmru with the morphologic analysis. disclosure: dr. lecompte has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. 2007 and 2011. demographics, clinical presentation , diagnostic studies and treatment outcomes were evaluated. post-procedure imaging was evaluated for clot burden reduction (patency) and residual venous stenosis by two-reader consensus. results: ten patients (5 male; 5 female, mean age 16 years, range 15-18) presenting with acute upper extremity swelling and pre-procedure imaging revealing 100% occlusion of the axillary and subclavian veins received successful endovascular therapy. all 10 patients underwent infusion catheter placement for thrombolysis with tissue plasminogen activator or urokinase. 6 patients received additional pharmacomechanical treatment. angioplasty was also performed in all patients. the mean treatment duration was 33 h (range 16-62). post-procedural imaging revealed that 9 of 10 patients achieved 75-100% patency (clot burden reduction) and 1 patient achieved 50-75% patency. the residual venous stenosis was graded: 5 patients had 0-25% stenosis, 2 patients had 25-50% stenosis and 3 patients had 75-100% stenosis. all patients were discharged on full anticoagulation therapy with low molecular weight heparin. 9 patients had surgical rib resection postthrombolysis with an average length of time from thrombolytic therapy to surgery being 32 days (range 14-73). 3 patients had re-thrombosis events during the follow-up period (mean 10 months; range 1-34), with one re-thrombosis event occurring within one week of thrombolytic therapy, prior to surgery and the other two occurring 3-5 weeks post-rib resection. there were no procedure related complications. one patient was lost to follow-up after initial successful catheter directed therapy. conclusions: percutaneous endovascular techniques such as pharmacomechanical thrombolysis and angioplasty appear to be feasible and safe options for paget schroetter syndrome in otherwise healthy adolescent patients. in attempt to prevent rethrombosis and chronic symptoms, we refer all patients for adjunctive surgical decompression. future larger studies are needed to address optimal strategies for these patients. combined 3d fluoroscopy image guided percutaneous intervention with real-time optical sensing at the tip of a needle for tissue characterization rami nachabe, philips, rami.nachabe@philips.com; john m. racadio, drazenko babic, ross schierling, jasmine hales, benno hendriks purpose or case report: to investigate the feasibility and potential of real-time tissue characterization at the tip of a needle with diffuse optical spectroscopy (dos) sensing capabilities during 3d fluoroscopy guidance using cone beam ct and dedicated needle path planning software. methods & materials: a c-arm x-ray system that combines fluoroscopy and 3d imaging from a cone beam ct was used to image a woodchuck with hepatocellular carcinoma (hcc). the imaging system enabled needle path planning, which was used to perform insertion and navigation of a needle toward the liver tumor. the needle was integrated with optical fibers for real-time tissue spectral sensing at its tip. optical spectra measurements were obtained continuously as the needle passed through healthy liver tissue and then into the tumor. from the diffuse optical spectra measurements, the following clinical parameters were extracted for tissue characterization: blood volume fraction, blood oxygenation, lipid volume fraction and tissue light scattering (related to tissue density). the tissue parameters were compared for healthy liver and tumor using the kruskal-wallis test. results: the tissue density of the healthy liver was lower than that of the tumor. higher blood and lipid volume fractions as well as oxygenation levels were observed in the healthy liver as compared to the tumor. all differences were statistically significant (p<0.01). additionally, a much wider heterogeneity in tissue density was observed in the tumor as opposed to the healthy liver. conclusions: differences in tissue properties between tumor and healthy liver enable discrimination between these two types of tissues. adding real-time optical sensing at the tip of a needle to 3d fluoroscopy image guidance is a feasible technique that complements the imaging information with relevant physiological parameters; it facilitates more precise definition of tumor boundaries despite any target motion during needle insertion. disclosure: dr. racadio has disclosed that he is a consultant for philips healthcare and receives travel reimbursement. rami nachabe, drazenko babic and benno hendriks are employees of philips healthcare. methods & materials: two children aged 6 months and 3 months were treated at this institution for liver failure resulting from urea cycle disorders, with a hepatocyte transplant procedure. the recipient liver was irradiated prior to transplant to facilitate engraftment. the procedure involves the injection of prepared hepatocytes from a suitably screened, compatible donor, via a main portal vein branch into the recipient liver. in both procedures access to the umbilical vein was achieved by the surgery service and a 4 french arterial sheath was placed. a 4 french angled catheter was used for diagnostic runs and to access the right and left main portal vein. a 3 french fogarty catheter (edwards lifesciences, irvine, ca) was placed to isolate each portal vein branch in turn and hepatocytes injected using hand injections. pressures in the main, right and left portal veins were measured and hand injections of contrast made at regular intervals. careful attention must be paid for evidence of pruning of portal branches, indicating occlusion of small portal branches, or portal to hepatic vein shunting. if shunting is seen, infusion must be stopped as embolism of hepatocytes into pulmonary arteries may result with serious clinical sequelae results: in both patients, the desired number of hepatocytes were successfully delivered into the recipient liver. in both cases, mild pruning of the portal vein branches was evident at the end of the procedure. portal vein presssures remained steady. there was no venographic or clinical evidence of pulmonary arterial embolization. conclusions: the interventional radiologist plays a central role in the hepatocyte transplant procedure. familiarity with catheterizing portal branches from an umbilical vein approach, measuring venous pressures, using small occlusion catheters and recognizing venographic end points such as portal vein pruning and portal to hepatic vein shunting are necessary to the safe and successful completion of this new technique. purpose or case report: the aim of the study was to evaluate the trends in term of type of tube placed, number of procedures per year, number and age of the patients as well as the number of procedures per patient and the interval of time between two placements, and finally the irradiation burden borne by the patients. methods & materials: after reb approval the radiologic files of the patients who underwent naso-duodenal-jejunal (ndj) or gastro-jejunal (gj) or jejunal (j) tube placement under fluoroscopy over the past five years (2006 to 2010) were extracted from the ris and reviewed. the results were tabulated as a single batch and stratified by year. results: eighty-nine patients representing 234 procedures (155 ndj, 77, gj, 2 j) were included. only 38 patients underwent a single procedure. the average number of procedures per patient was 2.6 with a maximum of 12 during the study period. the average patient's age was 55.3 months (sd074.88, median0 11.43). the average fluoro time per procedure was 7.2 min (sd08.3, median05.0). the average interval between two procedures was 58 days (sd0108,44, median018). the average fluoroscopy time per patient combining those having a single procedure and those having multiple ones, was 19.57 min (range 0.3 to 151.7, sd024.36, median012.45). conclusions: fluoroscopic placement of enteric tubes delivers a significant amount of irradiation. our data led to two interventions with respect to insertion and management of the tubes. on one hand, when the attempt pursued by a radiologist is not successful after 10 min of fluoroscopy other strategies should be considered including another operator or an alternative technique for tube positioning. on the other hand, information will be distributed toward the clinicians and nurses in order to improve the management of these tubes and avoid fortuitous displacement which was responsible of a significant amount of repeated procedures leading to undue irradiation. purpose or case report: to evaluate drug elution pharmacodynamics of doxycycline in an albumin-based solution, as used in percutaneous imaging-directed therapy of aneurysmal bone cyst (abc) and microcystic lymphatic malformation (lm) methods & materials: doxycycline mixed with 25% human serum albumin (hsa), and doxycycline mixed with saline solution (both 20 mg/ml) were evaluated using a fluid diffusion chamber system over 8 h, recording ph and doxycycline concentration. static ph and doxycycline concentrations were recorded every 5 min for the first 180 min, then every 30 min for a total of 8 h, averaged over 3 trials in each of the hsa and saline systems. statistical analysis evaluated standard deviation and rate of change for the 3 trials in each system. drug elution dynamics data were correlated with clinical experience in the doxycycline/albumin treatment of 49 patients (233 treatments) with aneurysmal bone cyst (abc) and 63 patients with 1263 lymphatic malformation microcysts. results: drug elution was linear in both the hsa and saline systems, with statistically significant (p<.001) slower elution drug release from the albumin system as compared with the doxycycline and saline solution, both over 3 and 8 h. purpose or case report: to describe a successful interventional radiologic approach to the management of paget schroetter syndrome presenting as acute arm swelling in adolecent athletes. methods & materials: institutional review board approval was obtained for this retrospective study. five patients aged 14 to 18 years (mean 16.5 years) were treated at this institution over a 2 year period all presenting with acute arm swelling (july 2009 -july 2011). ultrasound confirmed subclavian vein thrombosis in all cases. all were treated with placement of an infusion catheter (ev3, plymouth, mn), infusion of tissue plasminogen activator (tpa) at a rate of 1 mg/hour overnight and aspiration of remaining clot with a "trellis" (bacchus vascular, santa clara, ca, usa) thrombectomy device. results: clot was successfully removed in all five patients. complete clearance of clot was confirmed by contrarst venography in all cases. in four patients balloon angioplasty of a narrrowing at the junction of the subclavian and brachiocephalic veins was carried out. in one, the thrombus recurred within 6 h. the patient was retreated the next day with aspiration of clot using the "trellis" device and an infusion catheter placed with low dose (0.5mgs/hour) tpa commenced until surgical review; this patient was operated on within 48 h of final thrombolysis. all patients were seen by a vascular surgeon with an interest in this condition. all underwent surgical decompression; at end of the study period all patients were asymptomatic. conclusions: interventional radiologic management of acute axillo-subclavian thrombosis due to paget schroetter syndrome is safe and highly successful in the adolescent population. early recurrence of thrombus is not uncommon and prompt surgical consultation with a view to early surgical decompression is recommended. purpose or case report: diagnostic reference levels (drl) or target radiation dose ranges for pediatric ct scans are needed in the u.s. the first u.s. pediatric ct dose index registry (quircc) within the american college of radiology recorded estimates of patient radiation dose using a new method (ssde) based on body width(bw) for the purpose of developing diagnostic reference levels (drl). in addition to developing drl at the 75th percentile, the purpose of this study was to determine the ssdes associated with the lower range of acceptable image quality through subjective image quality evaluation. methods & materials: six children's hospitals participated in a retrospective review of abdominal ct with iv contrast on patients <18 yrs of age. from 939 exams, each site submitted de-identified images for selected cases based on ssde and patient width. a total of 106 cases were selected from the lowest, first quartile and median ssde. six investigators reviewed 3 images from each case under identical viewing conditions and rated them for subjective quality according to a score sheet and reference scale of images with known quantum mottle. cases were considered non-diagnostic if at least 3 of 6 reviewers ranked them as such. results: first, second, and third quartile ssde and ctdi-vol32 values from 6 sites for each bw will be shown. 6/ 106 cases were ranked non-diagnostic by the reviewers. 4/6 non-diagnostic cases were below the 10th percentile based on ssde. 5/6 of "non-diagnostic" cases had ssde less than the 25th percentile. the unacceptable case with ssde above the 25th percentile (16 cm, ssde 8.2 mgy) was due to subcutaneous metal implant with artifact. the quircc 75th percentile using ctdivol 32 for a 5 yr old is 7.1 mgy which is 30% lower than the acr ct accreditation data's published 75th percentile. conclusions: this consortium developed target dose ranges (drls) for ct of the abdomen with iv contrast for routine exam indications based on evaluation of image quality that establish lower and upper ranges (25-75 percentile) of patient dose(using ssde) associated with clinically acceptable images. this study demonstrates that pediatric radiologists in this consortium are comfortable interpreting images at or above the 25 percentile ssde and judged all but one image within this target range as diagnostically acceptable. table 1 ). with the exception of neonate chest, most used age-based techniques; only two centers reported using thickness. no survey used grids for wrist images, while 2/3 of the surveys used grids for chest and abdomen exams in 5-year-olds. at the most common sid there was up to a 60 kvp variation (5year-old chest ap) and up to 8-fold variation in mas (13 year old scoli lat). only two surveys used equipment that displayed the new iec exposure index. conclusions: participants report variability in the techniques and methods used to acquire common radiographic studies, reflecting differences between detector types and users. radiologists, technologists, medical physicists, manufacturers, and the fda have an opportunity to work together to standardize the techniques based on detector type to optimize radiation exposure for pediatric radiographic exams. disclosure: dr. don has indicated that he performs contract research for carestream and that he is on the speaker's bureau for siemens and receives an honoraria. purpose or case report: this study assesses community adoption of ct radiation dose guidelines after a 10-year international initiative to reduce medical radiation exposure in children. size-specific dose estimates (ssde) from community pediatric body ct scans are compared to ssde from matched scans obtained at a children's hospital that adheres to image gently campaign principles. we reviewed 112 pediatric ct scans (14 chest (c), 80 abdomen/pelvis (ap),18 chest/abdomen/ pelvis (cap)) transferred from 32 community imaging centers to our university children's hospital between july 2010 and february 2011. community scans were acquired with variable parameters and reconstructed with traditional filtered back projection (fbp). comparison was made to 432 children's hospital ct scans, performed in accordance with principles of the image gently campaign. because iterative reconstruction (ir) software was added to our scanner during the study, enabling us to reduce ctdivol by 60%, children's hospital scans were divided into two groups: a) 213 scans obtained with standard weightbased pediatric protocols and fbp (october 2009-october 2010; 58 c, 110 ap, 45 cap) and b) 219 scans obtained with reduced-dose weight-based pediatric protocols and blended ir/ fbp (october 2010-april 2011; 85 c, 104 ap, 30 cap). ctdivol and greatest lateral dimension were recorded from each scan and were used to calculate ssde. mean ssde from community scans was compared to mean ssde from children's hospital groups a and b. statistical analysis was performed with student's t-test. results: patient age range was 0-17 years in both community and children's hospital groups. mean ssde for community c, ap, and cap scans was 1.7, 1.3, and 1.6 times higher than mean ssde for matched scans in control group a (p<0.001) and 5.0, 2.8, and 3.7 times higher than mean ssde for matched scans in control group b (p<0.0001). conclusions: ssde was significantly higher for community pediatric body ct scans than for matched scans performed at a children's hospital that adheres to image gently campaign principles. results suggest that more community outreach and education are required in implementation of low-dose ct protocols outside of children's hospitals. concurrent use of ir provides a means of achieving even greater ssde reduction than is possible with fbp alone and should be encouraged. paper #: pa-095 optimization of tube voltage and current in size-based pediatric ct imaging: a phantom study boaz karmazyn, md, radiology, riley hospital for children, bkarmazy@iupui.edu; yun liang, keith kaser, peter johnson, mervyn cohen purpose or case report: determine the change in ct dose index (ctdivol) required to maintain the same quantum mottle noise when using lower tube voltages (80 and 100 kvp) relative to 120 kvp in different sized cylinder water phantoms (cwp) representing a wide range of pediatric body sizes. we performed 256 mdct scans of 10, 20, 25, and 35 cm cwp. thirty scans were performed for each phantom. the tube currents ranged from 50 to 500 mas with increments of 50 mas, and the tube voltage levels were 80, 100, and 120 kvp. the noise (standard deviation in hu) was measured using center region of interest (roi) that was 80% of phantom's area. two other rois (each 2% of the area) were placed at the center and periphery of the phantom images to measure noise gradient. results: in the smallest (10 cm) cwp, approximately the same noise level was maintained with all three tube voltages without a significant change in ctdivol. for the 20, 25, and 35 cm phantoms, the average ctdivol needed to be increased by 2%, 4%, and 19%, respectively, to maintain same noise level when the voltage was decreased from 120 to 100 kvp. the average ctdivol needed to be increased by 15%, 22% and 52% to maintain the same noise level in the 20, 25, and 35 cm cwp when the tube voltage was decreased from 120 to 80 kvp. the difference between central and peripheral noise increased on average by 11.1%, 19.6%, 23.7%, and 28.0% in the cwp of 10, 20, 25, and 35 cm, respectively. in each cwp, the central to peripheral noise difference was more pronounced (up to 3.7% more) with decrease in kvp from 120 to 100 or 80. conclusions: noise measurements in the water phantom model indicate that tube voltage could be decreased from 120 to 80 in cwp of 10 cm without significant change in ctdivol. it is also possible to decrease the voltage from 120 to 100 kvp with a minimal (< average 5%) increase in dose in cwps of 10, 20, and 25 cm. the noise gradient increases with larger cwp and smaller kvp. paper #: pa-096 comparison of radiation dose estimates, image noise, and scan duration in pediatric body imaging using 320-row and 64-row ct jennifer johnston, md, radiology, cincinnati children's hospital medical center, jhtai@yahoo.com; daniel j. podberesky, erin angels, terry t. yoshizumi, greta toncheva, donald p. frush purpose or case report: to compare effective dose (ed) estimates, image noise, and scan duration for pediatric chest, abdomen and pelvis protocols using 320-row and 64-row ct scanners in various acquisition modes. methods & materials: organ doses were measured using 20 mosfet dosimeters. dose, scan duration, and noise measurements were made in a 5-year-old anthropomorphic phantom for conventional helical, 160-detector helical and volume acquisition modes for chest, abdomen and pelvis protocols on a 320-row ct, and for helical mode on a 64row ct (aquilion one and aquilion 64, toshiba medical systems, otawara, japan) using similar scan parameters representing currently used clinical protocols. mean organ doses from three runs for each protocol, in combination with icrp 103 tissue weighting factors, were used to obtain ed for each protocol. noise was measured as the standard deviation of hounsfield units in 3 equivalent locations at 4 levels for each protocol with an roi tool. ed and noise were compared with a paired t-test or sign test. results: compared to helical acquisitions on the 64-row ct, ed of all tested acquisition modes on the 320-row volume ct were significantly lower for chest, abdomen/pelvis (ap) and chest/abdomen/pelvis (cap) protocols (table) . scan durations were lower across the board on the 320-row volume ct. compared to acquisitions on the 64-row ct, noise was in general similar to those on 320-row ct protocols, but some acquisition protocols on the 320-row ct produced greater noise (table) , specifically volume acquisition for chest ct and 160-detector helical and volume modes for ap and cap protocols. conclusions: dose savings can be achieved for chest, ap and cap ct examinations on a 320-row ct scanner compared to helical acquisition on a 64-row ct, with shorter scan durations. image noise was in general comparable between protocols. although noise differences between some modes did reach statistical significance, the impact on overall image quality will need to be studied further. paper #: pa-097 the observed to expected total fetal lung volume as a predictor of short-and long-term morbidity in surviving infants with congenital diaphragmatic hernia emily stenhouse, the royal hospital for sick children, emilysten@doctors.org.uk; neil patel, judith simpson, watt andrew, gregor walker, carl davis purpose or case report: observed-to-expected total fetal lung volume (o:e tflv) is a validated mr measure which we have previously demonstrated to be significantly reduced in non-surviving infants with congenital diaphragmatic hernia (cdh). our aim was to investigate the relationship between o:e tflv and short-and long-term morbidity outcomes in surviving infants with cdh. methods & materials: a retrospective analysis of cases of isolated left-side cdh referred to our institution for fetal mr evaluation between 24-35 weeks. mr imaging studies were performed on a 1.5 t philips system using a phased array body coil. the observed tflv was calculated by multiplying the summed area of the region of interest by the section thickness. the expected tflv was calculated with a formula previously described in the literature using the gestational age of the fetus. the observed tflv was expressed as a percentage of the expected tflv at a given gestation. morbidity outcome data was obtained from the case records of all surviving infants. specific measures of illness severity relating to short-term intensive care management and long-term outpatient management were recorded. differences in o:e tflv between outcome groups were assessed by t-test. results: 18 liveborn infants with isolated left-side cdh and antenatal mr scans were identified. scans were performed at 24-35 weeks gestation. 12 infants survived to discharge; gestation 38.5 (36.0 -39) weeks, birth weight 3.17 (2.03-3.66) kg. median length of admission was 38 (23-103) days, median duration of follow-up was 3.1 (0.7-5.4) years. o:e tflv was significantly lower in non-surviving infants; 23 vs. 37%, p0 0.005. o:e tflv was significantly lower in infants who received high frequency oscillation ventilation (hfov) versus those who were conventionally ventilated (29% vs 41%, p00.05). o:e tflv was also significantly lower in those infants who had a length of admission greater than the median of 38 days (29% vs. 43%, p00.02). o:e tflv trended lower with other measures of increased morbidity; inhaled nitric oxide use, patch repair of diaphragm, rehospitalisation within 1 year, supplemental feeding at discharge, gastro-oesophageal reflux, and developmental delay. conclusions: as well as predicting survival, lung volume measurement by o:e tflv is a promising predictor of outcome and morbidity in surviving infants with cdh. further studies in larger populations are required to provide quantitative predictive risk data. characterization of the inherent acoustic noise of a dedicated nicu mri system jean tkach, phd, cincinnati children's hospital medical center, jean.tkach@cchmc.org; yu li, ron g. pratt, christopher villa, beth m. kline-fath, charles dumoulin purpose or case report: we have developed a small foot print 1.5 t mri scanner specifically for neonatal imaging that can be easily installed in a neonatal intensive care unit (nicu). the scanner has a maximum patient bore diameter of 21.8 cm (without rf coil), and roughly twice the gradient performance of the best conventional adult whole-body 1.5 t mr systems. it is known that sensory stimulation such as acoustic noise can elicit autonomic instability in both term and preterm neonates. the inherent noise properties of the nicu mri system were measured as part of the initial safety evaluation of the system and compared against that of a conventional 1.5 t mri system. to evaluate the inherent acoustic noise characteristics of the nicu mri scanner, sound pressure level (spl) measurements were performed on it and on a conventional adult sized whole body 1.5 t hdx ge mri system (ge healthcare, waukesha, wi). a brüel & kjaer model 2250 sound level meter (brüel & kjaer sound & vibration measurement a/s, denmark) was used to perform the spl measurements for 6 several different mr acquisitions (spin echo, gradient echo, fast rf spoiled gradient echo, fully balanced steady state free precession, gradient echo echo planar, and diffusion weighted) using acquisition parameters consistent with clinical protocols. the mr sequences, acquisition parameters, noise measurement equipment and methodology were identical for the two mr systems. the maximum spl in units of a weighted decibels (dba) was recorded for each of the mr acquisition/mr system combinations evaluated. results: the maximum spl values measured during each of the 6 mr acquisitions were lower for all sequences (average 11.33dba (range05-18dba)) for the nicu mri unit as compared to the conventional mri scanner ( table 1 ). the average measured maximum spl value, reported in dba, across all 6 acquisitions was 86.2±2.6 for the nicu scanner, and 97.5±2.9 for the conventional mri scanner. the highest spl values were measured for the diffusion-weighted sequence: 85 and 103dba, for the nicu and conventional mri scanner respectively. conclusions: because of the smaller dimensions of the gradient coils in the nicu mri system, acoustic noise is less than that of conventional mri scanners despite the superior gradient performance of the smaller coils. the lower inherent acoustic noise level of the nicu system provides improved safety for the neonate, and facilitates siting of the unit in the nicu. disclosure: dr. tkach has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. paper #: pa-099 late neurologic events in extremely premature infants carlos guevara, md, radiology, duke university, cjg7@duke.edu; brett bartz, caroline l. hollingsworth, caroline w. carrico, michael c. cotten, charles m. maxfield purpose or case report: germinal matrix hemorrhage (gmh) is a major complication of prematurity. persistence of germinal matrix and immature neurovascular autonomic regulation in the premature neonate is thought to predispose to gmh. most gmh in premature population occurs during the first 4 days of life, and yet the persistence of the germinal matrix to 32 weeks gestation may allow for post-natal gmh outside of the immediate perinatal period. to our knowledge, this is the first systematic review of late gmh (after the first week of life) in a large population of extremely preterm neonates (less than 28 weeks of gestation). this irb approved retrospective review included patients weighing less than 750 g or born at less than 28 weeks of gestation from 2008 through 2010. the study population included 150 infants who had a head ultrasound (hus) within the first week of life and at least one follow hus after the first week of life. all hus were reviewed by three experienced pediatric radiologists for the presence and grade of ich or late developing hemorrhagelike lesions (hll). infants with and without hll were evaluated for several clinical variables, including neurodevelopmental outcomes (bayley scales). results: average gestational age of study population was 25.1 weeks. the incidence of gmh in the first week of life was 34% grade 1, 38.6% grade 2, 4.9% grade 3/ 4, and 2.2% posterior fossa. new echogenic foci (hll) at the caudothalamic groove were seen in 13.3% after the first week of life. 70% of these lesions were bilateral. a four-fold increase in incidence of hll was seen in infants <750 g compared to those> 750 g. higher grade hemorrhages were not seen in this patient population, although 6% of infants had late posterior fossa hemorrhages. the clinical course of infants with hll trended towards a higher incidence of stressors, but this was not statistically significant. the psychomotor development index scores were lower than those infants without hemorrhage. conclusions: small hll at the caudothalamic groove are common in extremely preterm infants after the first week of life. higher grade (2-4) hemorrhages were not seen. there were no cases of intraventricular extension and no direct complications. if isolated, this finding necessitates no follow-up imaging, but may be associated with poor neurodevelopmental outcome. disclosure: dr. guevara has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: tof/apv is a rare congenital heart lesion in which pulmonary arteries may become aneurysmally dilated and compress adjacent airways. pulmonary arterioplasty is often required to relieve tracheobronchial compression in addition to intracardiac repair. the purpose of this study was to review pre and postnatal imaging findings and their impact on patient management and clinical course. methods & materials: a retrospective database search identified 9 infants with tof/apv between 2005-2011 (4 fetal diagnosed cases and 5 diagnosed postnatally). for fdc, prenatal ultrasound (us) and fetal mri were correlated with postnatal ct for the size of the central pulmonary arteries, airway compression, and presence / distribution of air trapping/atelectasis. for all cases postnatal ct findings (between 3-9 days of age) were correlated with clinical management and outcome. results: prenatal diagnosis of tof/apv was suggested sonographically, based on dilated central pas, between 21-28 weeks gestational age (ga). fetal mri, performed between 32-37 weeks ga confirmed the diagnosis and aneurysmal central pas and demonstrated air trapping &/or atelectasis in 3/4 with normal appearing lungs in 1 fetus. size of the pas (4/4) and presence and distribution of lung abnormality (3/4) correlated closely between fetal mri and postnatal ct, although detailed visualization of the central airway/ vascular relationships were better defined on ct. fetal mri identified an unexpected diaphragmatic hernia (dh) not seen on us. for the pnd cases, ct showed aneurysmal pas and airway compression with air trapping &/or atelectasis in 4/5 infants. seven infants with airway obstruction on ct required pulmonary arterioplasty; 1 infant with no air trapping did not have arterioplasty. 7/8 operative patients survived, one with concomitant dh died at age 22 days due to hemorrhagic shock. one fdc was inoperable due to poor cardiac function and died at age 7 days. conclusions: prenatal mri correlates well with postnatal ct for assessing pulmonary artery size and location and severity of lung abnormality in patients with tof/apv, this allows for appropriate management planning and may negate the need for an immediate postnatal ct. ct accurately depicts the location and extent of airway compression and resultant air trapping or atelectasis, serving to guide the need for and extent of the arterioplasty procedure. paper #: pa-101 craniosynostosis syndromes: prenatal findings by us and mri eva rubio, md, cnmc, rubioeva@yahoo.com; anna blask, alexia egloff, dorothy bulas purpose or case report: craniosynostosis with associated malformations is a feature of several related syndromes resulting from a fgfr or twist genetic mutation. syndromes include apert, crouzon, pfeiffer, and carpenter syndromes. our purpose was to review imaging findings which aid in suggesting the diagnosis prenatally. we retrospectively reviewed prenatal us and mri findings in 6 cases with prenatal (5 with postnatal/molecular) diagnosis of a craniosynostosis syndrome: 3 cases of apert, 1 case of carpenter, and 2 cases of pfeiffer syndrome. results: 5/6 cases were correctly diagnosed prenatally. in the second trimester findings may be subtle, with mild calvarial changes; digit abnormalities, in particular, may elude the imager in unsuspected cases. although the diagnosis could be made with either modality, the full spectrum of abnormalities was best appreciated using a combined imaging approach of mri and us. by us many salient features were depicted: turribrachycephaly/trigonocephaly/cloverleaf (6/6); syndactyly (4/4); polydactyly (1/1). agenesis of the corpus callosum was identified by us in (2/2) cases. conversely, mri, performed in all cases, contributed additional observations not well seen by us: the fetal airway was well delineated in all cases (6/6); a low lying spinal cord was noted (1/1), midface hypoplasia (6/6) and migrational/sulcation abnormality (1/1). additional findings of absent ductus venosus with biliary atresia (1/1), abdominal wall defect (1/1) and renal anomalies (1/1) were seen with both modalities. reimaging in later pregnancy depicted important changes (2/2), including worsening hydrocephalus and resolution of suspected airway occlusion. conclusions: us and mri are complementary modalities in evaluating fetuses with craniosynostosis. airway patency, midface hypoplasia, spinal cord abnormalities and intracranial abnormalities are often better seen with mri. fetal activity, digits, bone detail, and cardiac anomalies are better appreciated by us. findings may be subtle in the second trimester. repeat imaging in later pregnancy may reveal specific information affecting delivery planning. paper #: pa-102 pcpra best paper 2011 hyperpolarized carbon-13 mrsi for pediatric disease john mackenzie, md, department of radiology and biomedical imaging, ucsf, john.mackenzie@ucsf.edu; yi-fen yen, linda nguyen, jeffrey gu, john kurhanewicz purpose or case report: to study the potential of carbon-13 mr spectroscopic imaging (13 c-mrsi)-a radiation free molecular imaging strategy-for the detection and treatment monitoring of pediatric disease. methods & materials: the potential of 13 c-mrsi to detect pediatric disease was tested in rodent models of pediatric arthritis. animals were induced with arthritis and subsequently given intravenous hyperpolarized 13 c-pyruvate, and imaged. the amount of 13 c-lactate produced from pyruvate in normal and arthritic joints was measured both at single points in time and dynamically at either 3 or 14 tesla. the 13 c-mrsi data were compared with clinical measures of arthritis, cell stimulation studies, and joint changes on conventional anatomic mri and histology. results: alterations in lactate production as measured by 13 c-mrsi appear to depict sites of arthritis and correlate with other more established but potentially less reliable or more invasive measures of disease status. imaging robust mouse models of pediatric disease may be feasible at 14 telsa. this method may also be translated from high-field to clinical equipment with reasonable hardware and software modifications that allow detection of hyperpolarized 13 c compounds. 13 c-mrsi depicts increased lactate production at specific regions of inflammation within arthritic joints and is confirmed by histological inspection and anatomic mri. on average, lactate production is increased by 60% in areas affected by inflammation. conclusions: the intravenous injection of hyperpolarized carbon-13 compounds and subsequent imaging with 13 c-mrsi provides a unique molecular imaging strategy to noninvasively monitor pediatric disease. this non-invasive imaging strategy may eventually provide clinical utility for several pediatric diseases involving inflammation, infection and tumor. disclosure: dr. mackenzie has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. methods & materials: using the hemangioma-vascular malformation clinic registry at cincinnati children's hospital, we searched for patients diagnosed with khe whose evaluation included mri. twenty such patients were found, although three of the patients had no pre-therapy mris. the imaging studies were reviewed by the authors with assessment of the following characteristics: location, margin definition, soft tissue involvement, and pre and post contrast signal intensity. results: location: lesion location was as follows: trunk (9), extremity (3), extremity plus trunk (3), and head/neck (2). signal: all lesions were dark on t1 weighted sequences with diffuse enhancement after contrast administration. the majority of the lesions were bright on t2 weighted sequences, but there were 3 cases that had heterogenous to low t2 signal (with all involving the retroperitoneum). of the 17 cases, only one had both high arterial and venous flow by mri. margin definition: four of the lesions had well defined borders (greater than 50% well circumscribed) with minimal to no adjacent infiltration/edema. two of those four cases were exophytic masses. the remaining 13 cases were poorly defined lesions with adjacent infiltrative fluid signal intensity and enhancement. tissue/organ involvement: tissue/organ involvement was counted if abnormal fluid-signal intensity or enhancement was identified at that site. review of these cases showed fifteen patients with muscular involvement. dermal and subcutaneous involvement was observed in all but 4 cases, with the uninvolved lesions being isolated and deep. additional sites of suspected involvement included bone (3), pleura (1), penis (1), and pancreas (2). conclusions: khe is a rare neoplasm of infancy with a spectrum of features by mri. poorly defined lesions are much more frequent than well-circumscribed masses. however, pathologic correlation of such infiltrative margins is usually not available as treatments after biopsy are primarily medical rather than surgical. common additional mri features include predominant involvement of muscle, subcutaneous fat, and skin over viscera and bone with lesions generally showing increased t2 signal and enhancement. is dedicated chest ct needed in addition to pet ct for evaluation of pediatric oncology patients? ibrahim tuna, montefiore medical center, dristuna@yahoo. com; jeffrey levsky, jeremy rosenblum, rosanna ricafort, benjamin taragin purpose or case report: to evaluate the diagnostic accuracy of low dose ct performed during pet-ct as compared to dedicated chest ct in the assessment of pulmonary findings in children with malignancy. the institutional review board approved this hipaa compliant research. pediatric oncology patients, ages between 0-21, with known solid malignant tumors who were referred to pet-ct and standard chest ct within 30 days for staging or assessment of treatment response between 01-2008 and 01-2011 were eligible for this retrospective study. radiology reports were reviewed for potential discrepancies. two radiologists re-evaluated the standard chest ct and low dose chest ct portion of the pet ct of the discordant cases, while comparing with the most recent prior studies. studies were scored for pulmonary nodules, bony metastasis, adenopathy, and pleural effusions. true discrepancies were assessed by a panel of pediatric oncologists to judge whether the differences in reports might lead to a significant change in management. results: 120 (57 female, 63 male) patients were identified. 31 radiologic reports of 16 different patients (8 female, 8 male) had potential discrepancies based on review of the reports. the primary tumors were rhabdomyosarcoma (n0 6), hodgkin's lymphoma (n 03) and others (n 07). reevaluation of the original images showed true discrepancies in 3.3% (4/ total 120). in 2 studies, the discrepancy had no clinical significance. in 2 studies, a pulmonary nodule was identified on standard chest ct which was not described on the pet-ct. both of these patients had rhabdomyosarcoma. one of these patients had findings that pediatric oncologists considered significant enough to alter patient management. conclusions: we found a low false negative rate for clinically significant findings on the low dose portion of pet-ct as compared to standard chest ct. in the future, improvements in acquisition technique and post processing of the ct portion of the pet-ct may further improve its diagnostic utility, obviating the need for a routine separate diagnostic ct, thereby minimizing radiation exposure in these young patients. methods & materials: 98 low-dose cta examinations were performed in pediatric patients over a three year period to evaluate suspected vascular traumatic injury with some patients receiving scans of more than one area of the body. areas scanned in this include the head and/or neck (n054), chest (n017), abdomen and/or pelvis (n013), upper extremity (n08) and lower extremity (n017). in 80 of these patients, suspected vascular injury was due to a history of either blunt (n 041) or penetrating (n 039) trauma. 64 patients were referred directly from the emergency department, while 27 were inpatients and the remaining 7 were referred from an outpatient setting. patients (32 f:66 m) ranged in age from 0 to 23 years old (mean age 11). studies were performed on a 64-channel mdct scanner with 80 or 100 kv, 40 to 200mas, 1.0 to 1.5 mm section thickness, reconstructed with 50% overlap, and 0.8 to 1.5 pitch. contrast medium was power-injected using weight-based protocols to optimize iodine delivery. exams were interpreted on a workstation using advanced imaging techniques. patient radiation dose was calculated in all cases. clinical outcome was assessed through a 6 month follow-up when possible. results: all studies were technically adequate. 76.5% (n078) of studies revealed no vascular injury, while 23.5% (n023) revealed acute vascular pathology. vascular injuries included vascular occlusion (n012), vasospasm (n03), narrowing/dissection (n04), pseudoaneurysm (n02), and transection (n0 1). extravascular traumatic findings were demonstrated in 51.0% (n050), including fractures, lung injury, soft tissue hematomas, and a ruptured baker's cyst. of the patients with acute vascular findings, 43.4% (n010) underwent surgical management (including 6 for vascular injury), while 52.1% (n012) were managed conservatively. one patient with active extravasation was managed with angiographically-guided embolization. in no case was catheter angiography required to confirm cta findings. conclusions: low dose cta is a reliable means to screen pediatric patients emergently for acute vascular injury. vascular and non-vascular pathology can be diagnosed noninvasively for efficient patient management. paper #: pa-106 elasticity measurement by acoustic radiation force impulse (arfi) technique of normal liver, kidney and spleen in healthy children mi-jung lee, radiology, severance children's hospital, mjl1213@yumc.yonsei.ac.kr; myung-joon kim purpose or case report: there are many previous studies about using acoustic radiation foce impulse (arfi) value to measure the elasticity of tissue, mainly the liver in adult patients. however, there was limited study about arfi measurement in the children. the purpose of this study is to evaluate the arfi value in the normal liver, kidney and spleen in healthy children and to evaluate the effect of sex, age, and body mass index (bmi). the study prospectively enrolled healthy pediatric volunteers who are under 18 years old, and underwent abdominal ultrasonography and arfi between july 2011 and august 2011. arfi velocity measuring was performed by 4-9 mhz linear probe for children under 5 years old and 1-4 mhz convex probe for older children. arfi velocity was measured three times at each organ. however this measurement was stopped if the child cannot tolerate. results: two hundred two children (m:f092:110; mean age, 8±4.7 years) were enrolled. and arfi measurement was performed only two time for some organs in three children. the mean arfi value was 1.12±0.20 m/s in liver, 2.20±0.49 m/s in right kidney, 2.33±0.53 m/s in left kidney, and 2.25 ± 0.41 m/s in spleen. arfi velocity was not different between boys and girls. however, arfi velocity was different between right and left kidneys (p00.001). the arfi value of right kidney, left kidney and spleen was correlated with age, height, weight and bmi (p<0.001). however, the arfi value of liver was not correlated with these parameters. conclusions: arfi measurement is feasible in children with only three times acquisition for each abdominal organ. the mean arfi velocity was increased according to the age, height, weight and bmi in kidney and spleen, but it was constant in liver. disclosure: dr. lee has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: diagnostic image quality can be achieved over a wide range of radiation exposure in digital radiography. "exposure factor creep" or "dose creep'" in which technologists tend to increase dose to avoid the appearance of noise has been well described. using the alara principle, acceptable images can be achieved while minimizing dose. at our institution "dose creep" has been observed in bedside pediatric chest radiography. to address this we coupled a data mining tool with a continuous quality improvement (cqi) initiative which educates individual technologists on appropriate technique. methods & materials: radiation dose in digital radiography is estimated from an exposure index, a proprietary format that varies among manufacturers. our institution uses a fuji computed radiography system which calculates an s, or sensitivity value, that provides an approximation of the radiation dose to the imaging plate, using an inverse scale. overexposed bedside chest radiographs were defined by a s value less than 150. a data-mining program was developed to extract from the dicom header the s value and other relevant information, on a monthly basis. these data were used to provide training and feedback on a one-on-one-basis. results: with ad hoc feedback and group training initiatives prior to implementation of this new system, approximately 16.7% (344/2057) of bedside chest radiographs were overexposed over a four month period. after one-on-one intervention with the technologists, preliminary findings reveal a trend towards fewer overexposed radiographs with approximately 9.2% (40/435) with s<150. conclusions: our tool provides a simple method for systematically identifying overexposed radiographs and the corresponding responsible technologists. we anticipate that this personalized educational program will continue to reduce the proportion of overexposed radiographs and thus the radiation dose to our pediatric patients. purpose or case report: ensuring radiation protection for children undergoing ct scans is challenging due to rapidly changing technology, differences in ct equipment and potential lack of understanding of unique aspects of scanning children. the joint commission has named technologists' training as an "action" item. we developed 8 online training modules to fill potential gaps in ct technologists' education. methods & materials: four modules were created by pediatric radiologists, radiologic technologists and medical physicists; 4 were developed by education/training experts from major ct vendors (ge, philips, toshiba, siemens) through the medical imaging technology alliance. 4 modules were created as microsoft word documents containing de-identified images and edited by education specialists at the american society of radiologic technologists and the alliance for radiation safety in pediatric imaging. they were converted to audio/video format using question/answer narration.4 vendor modules were created in microsoft powerpoint format and edited. all 8 modules were converted into adobe captivate learning program to achieve uniformity of appearance. modules are hosted on the asrt server and linked to the image gently website. a certificate may be printed as documentation of completion. results: all 8 modules are available at www.imagegently.org. two introductory modules discuss basics of ct equipment and medical physics related to radiation dose in children. the third and fourth modules discuss dose-saving strategies for neu-roct and body ct. four vendor-produced modules address unique aspects of equipment design such as automatic exposure control and dose saving strategies for children. conclusions: through collaborative efforts with medical imaging professionals and vendors, we have developed 8 free online modules addressing radiation protection for children. ct technologist training in specific dose saving strategies for children is variable and limited. these modules have the potential to improve ct technologists' understanding of equipment. end confusion which focused attention on improving communication with patients and families. there is little research regarding health literacy (hl) in radiology. the purpose of our study was to determine if an educational intervention (brochure) improves hl for parents whose child will undergo a fluoroscopic study. methods & materials: an education exemption was obtained from the irb. a multidisciplinary team developed brochures for 5 fluoroscopic procedures. participants were randomly selected and asked to complete a survey to assess their knowledge of the procedure and use of radiation both before and after reading a brochure. a final survey to rate and gain feedback about the brochure was completed. results: median age of children whose parents participated (n0120) was 4 years. vcug was most commonly performed (46%). prior to the brochure, 92% of participants knew the name of the test their child was having. after the brochure, 99% knew the name (p < .0001). prior to the brochure, 81% felt informed about the test, whereas 99% felt informed after (p<.0001). test scores showed an improvement in parent knowledge about the procedure with a median increase of 20 points after the brochure (scale of 1-70; p<.0001). even after reading the brochure, 23% of parents wanted more information. prior to the brochure, 68% of parents knew the test involved radiation compared to 100% afterwards (p<.0001). parents improved their understanding of the relative amount of radiation compared to background from 25% before to 79% after the brochure (p<.0001). overall, 99% rated the brochure >2 on a 3-point scale with 92% rating the brochure 3 (p<.0001). written feedback was uniformly excellent. conclusions: improving hl for parents is part of the mission of radiology medical professionals. our study demonstrates that there is room for improvement in communicating with parents about fluoroscopy. straightforward information for parents provided as a brochure improves their understanding of radiologic fluoroscopic procedures. paper #: pa-110 compendium of resources for radiation safety in medical imaging anum minhas, duke university, anum.minhas@duke.edu; donald frush purpose or case report: diagnostic imaging, including ionizing radiation modalities, maintains a foremost role in evaluation of medical disorders. there is increasing awareness and need for information across varied sectors about low level radiation and potential risks. many medical/scientific organizations have resources discussing radiation risk and management. however, there is no one resource compiling the same available information. methods & materials: websites, including those of national and international medical organizations (e.g., acr, "image gently" alliance, iaea) were reviewed for information on radiation dose, risk, justification, optimization, guidelines (which included general information about improvement in quality and dose reduction without specific mention of optimization techniques), appropriateness criteria, and general principles of radiation safety for radiography, fluoroscopy/angiography, and ct. this information was divided by modalities and separated into adult and pediatric populations. information from organizations that were not arbitrarily considered to be national (e.g., subspecialty society, regional organization, individual institution/practice) was not reviewed. the resources were then organized into 8 tables, organized by modality. websites with training modules were noted as well. results: 29 websites were explored. overall, less information is available about medical radiation safety in children compared to adults. across both, most information is available on ct, then fluoroscopy, and finally radiography. across all groups and modalities, there is no information available for patients/parents on optimization, appropriateness, or guidelines, with the exception of adult radiography where there were some guidelines. conclusions: this compendium on medical imaging radiation serves as a collective resource for communities including the public and regulatory organizations. additionally, the compendium can be used to determine redundant or deficient areas, providing opportunities for more comprehensive and efficient efforts in medical radiation protection for patients. inappropriate and cloned histories in children: how big a problem is it? leann linam, md, radiology, uams/ach, llinam@uams. edu; chetan c. shah, s bruce greenberg purpose or case report: acr standards require appropriate clinical history for obtaining imaging examinations. cloning clinical histories is a federal violation. our purpose is to determine the frequency of inappropriate histories (ih) and/or cloning histories (ch) at a tertiary children's hospital. methods & materials: three pediatric moc radiologists reviewed clinical histories for radiographs obtained at a tertiary children's hospital on 3 randomly selected dates (2 weekdays and 1weekend day) for appropriateness and cloning. appropriate histories have associated icd-9 codes. cloning is defined by identical clinical histories occurring on 3 consecutive days and could be clinically appropriate or inappropriate. only the first patient radiograph on a day was included. χ2 testing was performed to determine significant differences. results: 14% (54/388) of exams had ih. ih were significantly more common in inpatients than outpatients (p< 0.0001). nicu examinations accounted for 52% of all ih and were significantly more frequent than other inpatient locations (p0.006). the cvicu examinations accounted for 11% of all ih and was the second most common patient location for ih, but not significantly different from other inpatient locations (p00.09). the increased frequency in ih on the weekend reflects a change in patient mix with fewer outpatient examinations performed than on weekdays and was not significant (p00.07). the most common ih included: evaluate ett or evaluate lungs (15 each). cloning only occurs in inpatients and was combined with ih in 48% of patients with ch. the nicu accounted 63% of ch which was significantly greater than other inpatient locations (p00.026). conclusions: 1 in 7 radiographs had ih which can lead to misdiagnoses or nonpayment by insurance companies. inpatients, especially the nicu were the most common patient locations. cloning was also a common problem and was frequently combined with ih. identifying the extent of ih allows for corrective educational measures to be instituted which should improve compliance with existing medical and legal standards for ordering radiographs. paper #: in vivo validation of size-specific dose estimates (ssde) through breast entrance skin dosimetry (esd) during pediatric chest ct angiography sjirk westra, md, radiology, massachusetts general hospital, swestra@partners.org; xinhua li, mannudeep kalra, bob liu, suhny abbara purpose or case report: ssde is a new ct dose measure that corrects scanner console ct dose index (ctdi) for cross-sectional body diameter, being a better estimate of absorbed dose in individual patients of varying body size. ssde has been developed through phantom studies and computer simulations of ct dose, but has not yet been validated in vivo. the purpose of our study was to determine correlation between ssde and measured breast entrance skin dose (esd) for pediatric chest cta across a variety of scanning techniques, scanner models and patient sizes. methods & materials: our study was irb-approved, with waiver of written informed consent. during 42 consecutive chest cta exams done on 4 different scanners over a period of 7 years, we measured mid-sternal esd as an approximation of breast dose with skin dosimeters, which was also expressed as mammogram equivalents. for each scan, we recorded patient age, weight, effective ma, kvp, console ctdivol-32 cm and dlp-32 cm (from which we calculated age-adjusted effective dose (ed)). we measured effective chest diameter ø to convert ctdi to ssde, and we correlated ssde with measured breast esd, using linear regression. we evaluated image quality with regard to answering the clinical question. (table) , due to systematic introduction of automatic exposure control, low kv and high pitch scanning techniques. all studies were of diagnostic image quality to address the clinical question. conclusions: ssde is a valid measure of ct dose in pediatric patients undergoing chest cta over a wide range of scanner platforms, techniques, and patient sizes, and may be used to model breast and other organ dose, and to document results of dose reduction strategies over time. purpose or case report: the purpose of this project was to create an automated system capable of quantifying slice-byslice ct image quality and radiation dose data based on patient size. the information generated from this system should enable size-specific optimization of ct scan parameters in order to obtain images of diagnostic quality at the lowest possible radiation doses. methods & materials: a mathematical model was developed to predict ct image noise based on kvp, effective mas, and water-equivalent diameter of the patient. a conical water phantom was used to calibrate the model on multiple scanners and accounting for different operational modes and scan parameters, including tube voltage (kvp), tube current (effective mas), bowtie filter, and focal spot size. a software application was created to process image data from the scout topogram and incorporate dicom metadata from the axial images. a database and data viewing application were developed to display individual and aggregate study data. all of these systems were integrated and automated to enable real-time monitoring of image quality and radiation dose as a function of patient size. results: since the completion of the automated system, 565 ct exams have been processed. a search application allows the user to find an individual study or a collection of studies based on parameters such as body part imaged or study protocol. the viewing application displays slice-by-slice patient diameter, radiation dose, and image quality for each study. radiation dose estimates are adjusted for patient size, yielding size-specific dose estimates. the application also graphs individual study data compared to those of comparative studies that are included in the search. conclusions: we have successfully developed an automated system that monitors ct image quality and radiation dose data based on patient size. the system enables simultaneous real-time monitoring of all studies performed on all ct scanners at our institution. specifically, the system enables size-specific radiation dose estimates at every scan level. this system will be used to guide protocol adjustments in order to optimize ct image quality and thus optimize radiation dose. disclosure: dr. larson has disclosed that he has a patent application in process through cchmc for ct radiation dose reduction. purpose or case report: at many institutions, ct scan parameters for children are determined by patient age or weight. aapm task group 204 recommends cross sectional body dimension, such as patient width to determine size specific dose estimates. the purpose of our study was to develop prediction models of body width based on patient age and weight and compare these models with actual measured body widths for children undergoing body ct. methods & materials: 6 children's hospitals participated in a 3-month retrospective review of abdominal ct scans on patients <18 years of age after local irb approval. recorded values included patient width(cm) from an axial image at the level of the splenic vein, patient age (yrs) and patient weight (lbs). a regression model for predicting patient width as a function of age and weight was determined. results: 939 exams, 472 had all 3 measurements. both age and weight were significant predictors of patient width (p<.0001). there was also a significant interaction between weight and age (p<.0001), indicating that the relationship between patient width and weight depended on the age of the patient. the r2 for the regression model for predicting patient width from age and weight individually were 0.65 and 0.83 respectively. the r2 for the model including both age and weight and their interaction was 0.86 leaving 14% of the variation unexplained. the regression equation for this model is: patient width 014.1 + 0.34 x age(yrs)+ 0.12 x weight(lbs)-0.003 x age x weight. despite the r2 of 0.86 for the model using both age and weight, the average error (rmse) for predicting patient width compared to a direct measurement of width was 1.9 cm. the plot of observed minus predicted values (residuals) versus predicted values indicates that the best model (combination of weight and age) results in measurable errors of predicted patient width relative to direct measurement. conclusions: a combination of both patient age and weight results in a more accurate patient width prediction than using age or weight alone. while age and weight can be used to predict body width, this is not sufficiently accurate for generating ct protocols. therefore, direct measurement of body width form either physical measurement on the patient or from the scout view or an axial image is preferred to select appropriate scan parameters for pediatric abdominal ct. paper #: pa-115 automated size-adjusted dose monitoring for pediatric ct dosimetry olav christianson, clinical imaging physics group, olav. christianson@duke.edu; ehsan samei, donald frush purpose or case report: the potential health risks associated with low levels of ionizing radiation have created a movement in the radiology community to minimize radiation dose during ct imaging; this is especially important for pediatric patients due to their increased sensitivity to radiation. it is thus essential to accurately assess the risks to pediatric patients undergoing ct imaging. current efforts to monitor radiation dose, however, are limited because they do not account for differences in risk from ionizing radiation due to variability in patient size, age, and gender. in this context, we developed an automated size-adjusted dose monitoring program capable of performing patient-specific risk estimation to facilitate protocol optimization. methods & materials: dicom routing software was used to send dose reports and scout images to an image repository on a dosimetry server. optical character recognition was used to extract dose-relevant data from dose reports; patient size was determined from corresponding scout images. based on anatomical location, risk estimation conversion coefficients (qfactors) were determined for each series in the dose reports. the q-factors were adjusted according to patient size, age, and gender and then multiplied by the dlp to estimate the risk to each patient. this process was applied to the cohort of pediatric patients undergoing ct examination at our institution. to evaluate the impact of including patient size, age, and gender, risk estimates were obtained excluding and including the dependencies on size, age, and gender. the results were computed in units of cancer incidence per 1000 cases exposed (cpt). results: the average patient-generic risk estimate for a pilot group of patients undergoing body ct was 0.15±0.14 cpt. by including patient size, the risk estimate was increased to 0.26 cpt±0.27 cpt. by including patient age and gender, the average risk estimate was further increased to 1.0 cpt±0.72 cpt. conclusions: we developed a new size-adjusted dose monitoring program for pediatric ct dosimetry. comparisons between patient-generic and our new patient-specific risk estimates show that failure to consider patient size, age, and gender resulted in risk estimates that were too low by a factor of seven. additionally, the increase in standard deviation we observed demonstrates that our method of including patient size, age, and gender is sensitive to the inherent variability in the patient population. disclosure: dr. christianson has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: treatment of prenatally diagnosed lung masses is controversial, with many specialists recommending elective surgical removal in the first year of life because of a reported or perceived increased risk of infection and malignancy, while other centers recommend a conservative approach to management. the natural history of unresected lung masses is not clear. in our center, our standard recommendation is prophylactic resection of asymptomatic lesions, although not all families choose this option. we asked whether respiratory morbidity increased during the time prior to elective resection of prenatally diagnosed lung masses. methods & materials: ninety-eight pregnant women carrying fetuses with chest masses were imaged by ultrasound (us) and magnetic resonance imaging (mri). medical records of the liveborn infants were retrospectively reviewed. results: fetal diagnosis of a lung mass was made at a mean of 27 weeks gestation (range 17-32 wks). intrauterine fetal demise was documented in 4 pregnancies. there was one elective termination of pregnancy. three infants were lost to follow up. thus, outcomes were available for 90 children (59% m, 41% f) with prenatally diagnosed lung masses. significant respiratory morbidity (rm) was defined as the occurrence of pneumonia, asthma, chronic coughing or wheezing, or respiratory symptoms severe enough to require an emergency room visit or hospitalization. of the 76 children who had surgical removal of their lung mass, 34 (45%) had rm prior to surgery. fifteen out of 90 children did not have surgery but have been followed expectantly, and 3 of 14 (21%) developed some form of rm. fifteen of 76 (20%) infants had immediate and significant rm (tachypnea, grunting, increased work of breathing, increased oxygen requirements or need for intubation) in the newborn period leading to urgent surgery (range of age at surgery: 1-10 d; mean 2.5 d). of the 61 initially asymptomatic infants, 17 (28%) developed rm prior to elective removal of the mass (range 6-96 weeks, mean 17 weeks). of the lesions removed, histology revealed: cystic adenomatoid malformation (ccam) 59%, ccam + sequestration 21%, sequestration 8%, congenital lobar emphysema (cle) 7%, ccam+cle 1%, other 3%. conclusions: the risk of respiratory morbidity appears to be increased during the time prior to elective resection of prenatally diagnosed lung masses, which may be important for parents and pediatric specialists to consider when deciding whether to remove an initially asymptomatic lung mass. purpose or case report: it is now accepted that fetal mri with its superior tissue resolution can be very helpful in clarifying anomalies detected during obstetrical ultrasound. this is particularly the case with intracranial abnormalities, although indications are expanding. the current english medical literature, though, appears to be focused on evolving mri techniques and how mri compares to ultrasound with regards to image quality and detection of additional findings which may alter the diagnosis. however, we found no study specifically evaluating the clinical relevance and impact of the information obtained by fetal mri to the specialists who counsel and treat these patients. a "satisfaction and clinical impact" survey was created and sent to all the members of our fetal diagnosis and treatment group, asking specifically how the clinicians rated their satisfaction with this type of imaging, its influence on their counseling and on various clinical decisions, both prenatal and postnatal. results: we received responses from 37 specialists in 10 different clinical disciplines. the greatest number of respondents came from our obstetricians (28%), many of whom perform their own ultrasounds, and from members of our medical geneticists/genetic counselors (27%), although 46% of respondents were from various other clinical disciplines, both medical and surgical. there was a surprisingly high degree of satisfaction overall with the quality of the images and with the type and amount of information provided. most respondents indicated they felt fetal mri was "moderately" or "extremely" useful for their particular clinical decisions, and most respondents agreed that fetal mri impacted "moderately" or "significantly" on counseling and management of these pregnancies. impact appeared greatest on the counseling of the parents and their decision to terminate/pursue the pregnancy, and the least impact was on issues around delivery. conclusions: fetal mri, in addition to providing images of better quality, particularly in certain conditions, has clinical value in that it directly impacts on the counseling of parents and on clinical decisions. 2006-2011. ultrasound reports were reviewed to determine sonographic diagnoses. selected patients from this cohort underwent mri using ge 1.5 tesla magnet without contrast (sequences included ssfse, fiesta, fgre or dual echo in 3 planes). the images were reviewed and multiple characteristics were assessed for specifiying the area of obstruction. the features included: presence of normal fluid-filled bowel, small rectum for gestational age, signal of meconium in the rectum, and meconium filled dilated bowel. results: 46 cases of sonographically suspected bowel obstruction were identified during the study period; 27 of these underwent fetal mri. of these 27 cases, 4 had normal mri and postnatal outcomes, 2 cases did not have postnatal findings available, and 2 had postnatal meconium peritonitis but no obstruction. one case of congenital chloride diarrhea was diagnosed by fetal mri. a variety of bowel abnormalities were observed amongst the remaining 18 cases. proximal obstruction was diagnosed in 8 cases: jejunal atresia (n07) and multiple atresia (n01). distal obstruction was diagnosed in 10 cases: ileal atresia (n03), meconium plugging (n04), closed gastroschisis (n01), enteral duplication cyst (n01), and imperforate anus (n01). characteristic patterns of features were identified amongst these 18 cases that specified the location of obstruction. these patterns of findings allowed accurate localization of the level of obstruction in all cases when compared to postnatal findings. distal obstruction was characterized by normal fluid-filled small bowel and high t1 signal in distended loops. jejunal atresia was characterized by multiple loops of dilated bowel with high t2 signal primarily in the left upper quadrant. small rectum for gestational age was not consistently associated with proximal or distal atresia. conclusions: evaluation of fetal mri with attention to specific features allows localization of bowel obstruction. this may aid in counseling and postnatal management, including the need and type of postnatal imaging study. early diagnosis and treatment of ph may prevent clinical deterioration. pvt may produce a spectrum of imaging appearances, which has not been fully recorded in the literature. the goal of this paper is to review the spectrum of imaging appearances of neonates and survivors of neonatal pvt with special emphasis on the role of us and to correlate these findings with the clinical findings including outcome. methods & materials: a retrospective review of 133 consecutive neonates admitted between 1999-2003 and diagnosed with pvt was conducted. diagnosis was established by us at a mean age of 9 days (range: 1-40). health records, initial and follow-up (f/u) imaging were reviewed. findings were classified as non occlusive, single branch, pvt (grade 1); occlusive pvt (grade 2) and pvt with extensive parenchymal ischemia (grade 3). results: pvt was diagnosed in 133 patients, 70 of whom were followed up to for 2 years or longer. twelve patients were excluded due to liver disease, 22 expired and 29 were lost to f/u. of the 70 in whom f/u was available, at the time of initial diagnosis, grade 1 pvt was present in 27, all were on the left. grade 2 pvt was diagnosed in 28 and grade 3 pvt in 15. on f/u physical exam, findings were unremarkable in 68/70 patients. liver function tests (lft) and thrombophilia assessment were available in 25 children, mild lft abnormalities were noted in 9 and 6 children had evidence of thrombophilia. us exams were available in 37/70 children. among the 37 survivors of neonatal pvt, us was regarded as normal in only 14 children; 16 showed left lobar atrophy (lla), 5 had slowly progressive splenomegaly without other signs of ph, and 2 developed clinically significant ph requiring shunting. conclusions: pvt has a wide spectrum of imaging appearances, it is possibly underdiagnosed and clinically unsuspected. varying degrees of lla are likely a sequela of clinically silent left pvt. us is a sensitive method for the detection of disease and assessment of progression. paper #: pa-120 fetal mri in arthrogryposis hedieh eslamy, md, radiology, lucile packard children's hospital, hkeslamy@gmail.com; erika rubesova, louanne hudgins, britton rink, richard a. barth purpose or case report: to present the fetal mri findings in fetuses with a prenatal diagnosis of arthrogryposis and correlate with postnatal outcome or autopsy results. arthrogryposis refers to contractures involving more than one joint which often represent deformational changes secondary to decreased or absent fetal movement. prognosis varies widely dependent on diagnosis, ranging from isolated contractures in amyoplasia to lethality in some cases. we hypothesized that fetal mri may demonstrate central nervous system (cns) pathology and muscle abnormalities which are important for predicting postnatal outcome. methods & materials: we identified 6 fetuses with a diagnosis of arthrogryposis between january 2010 and october 2011. all had fetal mri which was performed on a ge 1.5 tesla magnet, with ssfse, fiesta and fgre sequences in 3 planes. the fetal mri's were evaluated for cns and muscle abnormalities. the extremities were evaluated for: muscle mass, increase in subcutaneous fat (indicative of muscle atrophy), and extremity joint positioning. these findings were subsequently correlated with the clinical exam of the neonates, pathology in the abortus and karyotype when available. results: results of fetal us, amniocentesis, fetal mri and post-natal or post-termination outcomes will be summarized. five fetuses had ≥2 limb joint contractures. a sixth case had neck hyperextension and lateral flexion associated with akinesia and hydrops. on mri, no structural brain or spine abnormalities were identified. the abnormalities detected in the extremities were: severe decrease in muscle mass associated with increased subcutaneous fat (3 cases); normal muscle mass (2 cases); moderate decreased muscle mass associated with increased subcutaneous fat (1 case). in the 3 cases that delivered, the diagnoses were amyoplasia (2) and distal arthrogryposis (1). in a fourth case that underwent elective termination, autopsy was consistent with amyoplasia. two cases are pending delivery. conclusions: while fetal mri can be useful to rule out cns anomalies, it may also provide important information on decreased muscle mass as an important prognostic sign in a fetus with arthrogryposis. in our series, severely decreased muscle mass was predictive of amyoplasia, and joint contractures limited to hands and feet with preserved proximal muscle mass was predictive of distal arthrogryposis. both diagnoses are associated with relatively good prognosis and usually normal intelligence. purpose or case report: the purpose of this study is to assess the effects of iterative reconstruction technique (irt) on image quality metrics measured in child-sized anthropomorphic phantoms as kvp is changed. methods & materials: ct scans were performed on anthropomorphic phantoms with sizes of 1, 5 & 10 years (atom phantoms, cirs, norfolk virginia) using low dose pediatric chest protocols (1.6, 3 & 6 msv) to determine baseline noise and dose levels. subsequently three voltage levels (120, 100 & 80 kvp) were used while adjusting mas to maintain baseline ctdivol and without mas adjustment which allowed varied ctdivol. images were reconstructed using 100% filtered back projection (fbp) and blends fbp: ir (80:20, 60:40, & 40:60) . parameters including ctdivol, dose length product, scan length, kvp, and mas, were recorded for each scan. image noise, contrast:noise (cnr), and signal:noise (snr) data were recorded from rois in phantoms and dilute iodine contrast filled syringes (5, 3, 1.5%). results: as kv is lowered from 120 to 80, image noise is doubled if mas is not increased to maintain ctdivol, and cnr is increased but snr is decreased due to the increased image noise. as kvp is lowered from 120 to 80, image noise is increased nominally (8-21%) if mas is increased to maintain ctdivol; therefore the increase in cnr and decrease in snr is negligible. ctdivol is reduced >300% in all phantom scans as kv is reduced from 120 to 80. irt reduces image noise by up to 36% [range 10-41%] in all phantom sizes and in clinical images. as ctdivol is maintained in patient scans, image noise, cnr, and snr are reduced in patients (p<0.05), resulting in improved image quality. conclusions: when lowering kvp, compensation with increases in mas is necessary to maintain ctdivol. however, lower target ctdivol can be achieved when adding irt as image noise can be decreased. for these phantoms, cnr and snr improved using all [selected] levels of ir, even when kv was reduced, resulting in lower ctdivol in phantoms. at all kvp settings when irt is applied, image noise is reduced, resulting in improved cnr and snr for all phantoms. disclosure: dr. bardo has indicated she is in the speaker's bureau and receives an honorarium from koninklijke philips. paper #: pa-122 adaptive iterative dose reduction in evaluation of the pediatric abdomen with ultra-helical 320-channel mdct jeffrey hellinger, md, stony brook university, jeffrey. hellinger@yahoo.com; bernice hoppel, richard mather, monica epelman purpose or case report: radiation reduction is paramount for pediatric patients. ultra-helical 320-channel mdct allows for rapid acquisitions at low dose. we evaluated the ability of a new adaptive iterative dose reduction algorithm (aidr) to reduce noise in low-dose ultra-helical pediatric abdominal ct scans. aidr is an iterative algorithm that adaptively reduces noise in the raw and image domains while preserving image structure. the raw data from 14 consecutive low-dose pediatric abdomen exams was gathered. a dose simulation tool which adds noise to raw projection data was employed to simulate tube current at 1/4 of baseline ma. data were reconstructed with both standard filtered back projection and with aidr. regions of interest were drawn in the liver and lumbar musculature to determine the signalto-noise (snr), contrast-to-noise (cnr) and overall diagnostic quality of each data set. statistical significance was determined using a student's t-test. subjective image quality was evaluated by two reader blind review using a five point scale (50excellent, 10unacceptable). results: the snr and cnr were significantly lower for the 75% dose reduction datasets compared to the original filtered back projection reconstructions (snr: 3.59 vs 2.20, p<0.001; cnr: 1.24 vs 0.75, p00.01). when aidr was applied to the 75% dose reduction data, the snr and cnr improved to be superior to the native case (snr: 3.59 vs 5.48, p<0.001; cnr: 1.24 vs 1.95, p00.02). the average image quality score for the low dose datasets with aidr was 4.2 compared to 3.4 with standard filtered back projection at the baseline ma conclusions: aidr significantly improves the image quality of pediatric abdominal ct images. with a simulated 75% reduction in dose, aidr produces images with significantly greater snr and cnr. the subjective image quality scores for aidr showed dramatic improvement over standard filtered back projection. aidr processing algorithms with ultra-helical 320 mdct will allow 75% reduction in radiation exposure while achieving the same diagnostic quality as compared to routine pediatric abdomen mdct radiation protocols with filtered back projection processing algorithms. purpose or case report: to explore incorporating asir into pediatric head ct protocols, to reduce patient radiation dose while maintaining image quality. methods & materials: an alderson rando head phantom was estimated to approximate the size of a 7-year-old child's head, and was scanned at decreasing 10% ma intervals (100 to 50%, 150 to 75 ma) relative to this institution's age-based head ct protocols. each of these studies was then was reconstructed at 10% asir intervals (0% to 100%), and a 100 mm2 roi was obtained in a consistent location behind the frontal bone to estimate noise (sd). using this phantom data, our ventriculoperitoneal (vp) shunt follow-up ct protocol was modified, and patients were scanned at 20% asir with approximately 20% ma reductions relative to our normal age-based mas. these asir studies were then anonymously compared to older non-asir head ct studies from the same patients (with identical kvp/slice thickness) by two blinded attending pediatric neuroradiologists. all studies were evaluated subjectively for diagnostic utility (1-4), sharpness (1-5), noise (1-4), and artifacts (1-4). 50-100 mm2 rois were drawn in consistent locations to estimate noise in air, bone, csf, and white matter (wm). results: the phantom study suggested similar same noise levels at 100% ma/0% asir (3.9) and 80% ma/20% asir (3.7). 12 patients (average09, range01 to 17 years) were then scanned at approximately 20% ma reductions, with an average of 349 days (range027 to 871 days) between the asir study and prior non-asir study. the average ctdivol and dlp values of the 20% asir studies were 22.4 mgy and 338.4 mgy-cm, and for the non-asir studies were 28.8 mgy and 444.5 mgy-cm, representing statistically significant decreases in the ctdivol (22.1%, p00.00007) and dlp (23.9%, p00.0005) values. there were no significant differences between the asir studies and non-asir studies in respect to diagnostic acceptability (p00.33), sharpness (p0 0.45), or noise (p00.84). there was a non-significant trend that the asir studies had a lower artifact score (1.8 vs 2.1, p0 0.06). there was good to perfect (kappa00.5 to 1.0) agreement. the asir studies had statistically significant decreased csf noise (3.0 vs 4.4, p00.0000008), but no noise differences were seen in air (p00.46), bone (p00.26), or wm (p00.22). conclusions: our findings suggest that asir can provide dose reductions in pediatric head ct without affecting image quality. purpose or case report: to validate the t2 map as a noninvasive quantitative biomarker of fatty infiltration of muscles and to determine whether the t2 map can differentiate between boys with dmd and healthy boys. methods & materials: two groups of boys with similar ages (range 5-15 years) were evaluated: 42 boys with dmd (mean age 10.4 years) and 29 healthy boys (mean age 11.7 years). mr images were performed at 3 t. fatty infiltration of the pelvic and thigh muscles on t1-weighted images (wi) was graded from 0 to 4. on t2 maps with and without fat suppression, the muscle with the greatest fatty infiltration on t1-wi was selected, and a region of interest was placed to obtain t2 values. t2 values from t2 maps with fat suppression were subtracted from values of t2 maps without fat suppression and designated as the "t2 fat value." t2 fat values were obtained from the same muscles in all boys. comparison was made between the t2 fat values of the two groups. the upper reference limit of the reference interval (ri) of t2 fat values was obtained from the control group to establish the normal range and applied to both groups to determine the accuracy of the t2 map. results: the gluteus maximus muscle had the greatest fatty infiltration on t1-wi. median t2 fat value was 73.0 msec for dmd (95% ri 193.8, range 29.2-175.6) and 7.5 msec for the control group (95% ri 19.2, range 1.4-21.6). when applied to the two groups, the upper reference limit of the ri for control patients yielded 100% sensitivity, 93% specificity, 95% positive predictive value, and 100% negative predictive value. conclusions: utilization of t2 maps for the quantitative measurement of fatty infiltration of muscles can clearly differentiate between dmd and normal control boys with a high degree of accuracy and precision. this advanced noninvasive technique may potentially replace invasive muscle biopsies currently used for diagnosis. purpose or case report: prior work has shown that the gluteus maximus muscle has the greatest t2 relaxation time on mr imaging using t2 mapping in boys with duchenne muscular dystrophy (dmd). however, an increased t2 value on t2 relaxation time mapping may reflect both fatty infiltration and inflammation of the muscle. fatty infiltration characteristically follows inflammation in this disease process. therefore, the purpose of this study was to determine the contribution of each component (fat and inflammation) within gluteus maximus muscles and to correlate each component to clinical assessments. methods & materials: forty-six boys with dmd (ages: 5-15 years) were recruited. mr imaging of the pelvis using t2 maps with and without fat suppression were performed. the t2 map "fat values" (t2 value calculated from the t2 map without fat suppression [fs] minus t2 map with fs) and the t2 map "inflammation value" (t2 value from the t2 map with fs) were obtained. clinical assessments typically used to evaluate dmd patients (including clinical functional score, 30 ft run, gower score, and 4 step-up time) were also performed. spearman correlation coefficients between fat and inflammation values and the clinical assessments were calculated. results: there was a statistically significant correlation between the fat value of the gluteus maximus muscle and each clinical assessment test (p<0.05). however, the inflammation value of the gluteus maximus muscle did not correlate with any clinical assessment. conclusions: in dmd, the amount of fatty infiltration of the gluteus maximus muscle has excellent correlation with clinical assessment. the amount of inflammation of the gluteus maximus muscle, however, does not correlate with clinical function. therefore, further study is needed to determine whether components (fatty infiltration or muscle inflammation) of the single most involved muscle reflect the components of all the muscles of the pelvis and thighs and whether the cumulative muscle involvement of each component represents clinical disease severity. utility of contrast-enhanced mr imaging in children with osteonecrosis: does gadolinium help? lamya atweh, md, radiology, texas children's hospital, laatweh@texaschildrens.org; robert c. orth, wei zhang, r. paul guillerman, herman kan purpose or case report: at our institution, gadolinium contrast-enhanced mr sequences are often obtained to assess epiphyseal and non-epiphyseal osteonecrosis in children. several studies have shown that dynamic contrast-enhanced sequences may provide prognostic information about long-term complications and healing of osteonecrosis. to our knowledge, no studies have determined the added value of routine post-contrast mr imaging in assessing acute complications related to chronic osteonecrosis. the purpose of this study was to evaluate the utility of intravenous gadolinium contrast in the mri identification of complications in children with an established diagnosis of osteonecrosis. methods & materials: 64 patients were restrospectively identified (age range: 1.75 years to 25.75 year; m:f 0 59:80) with an imaging diagnosis of chronic osteonecrosis who underwent 139 contrast-enhanced mr studies between 1/2000 and 9/2011. the pre-and post-contrast mr images were consensus reviewed by two caq pediatric radiologists. pre-and post-contrast images were reviewed at separate times. the pre-contrast images were available during the review of post contrast images. studies were assessed for: osteonecrosis location (epiphyseal, non-epiphyseal osteonecrosis, or both), joint effusion, marrow edema, and epiphyseal collapse. 95% confidence interval (ci) and cohen's kappa coefficient(κ) was calculated to assess observed agreement. results: the diagnosis of osteonecrosis without complicating features was made in 49.6% (ci: 41.3-58.0%) (69/139) of pre-contrast studies and 53.2% (ci: 45.0%-61.5%) (74/ 139) of post-contrast studies. when chronic osteonecrosis with complicating features was identified,pre-and postcontrast images idenfied joint effusion in 44.9% (57/127) and 51.2% (65/127) (κ00.686, p<0.001); marrow edema in 50.4% (70/139) and 46.8% (65/139) (κ00.727, p<0.001); and epiphyseal collapse in 51.2% (65/127) and 42.5% (54/ 127) (κ00.796, p<0.001), respectively. myositis or muscle strain was incidentally diagnosed in 12.2% (17/139) pre-contrast and 10.1% (14/139) post-contrast (κ 0 0.674, p <0.001) studies. conclusions: the high observed agreement between the pre-and post-contrast mr images shows that the addition of intravenous gadolinium may not be necessary in the majority of children with chronic osteonecrosis. paper #: pa-127 systematic protocol for assessment of the validity of bold mri in a rabbit model of inflammatory arthritis at 1.5 tesla michael chan, bhsc, university of toronto, mw.chan@ utoronto.ca; afsaneh amirabadi, anguo zhong, antonella kis, rahim moineddin, andrea s. doria purpose or case report: blood oxygen level-dependent (bold) mri has the potential to identify regions of early hypoxic and vascular joint changes in inflammatory arthritis. at this point, there is no standard protocol for data analysis of bold mri measurements in musculoskeletal disorders. standardization of the technique is paramount to compare results between studies and assess the validity of this technique in tissues outside the blood-brain barrier. our objective is to optimize bold mri reading parameters in a rabbit model of inflammatory arthritis by determining the diagnostic accuracy of (1) statistical threshold values (r>0.01 vs r>0.2), (2) summary measures of bold mri contrast [ the mean of the % bold signal differences within the region of interest (roi) (diff_on_off) and the percentage of suprathreshold voxels within the roi (pt%)], and (3) voxel activation algorithm (positive, negative, and positive_negative). methods & materials: using bold mri protocols with a carbogen stimulus on a 1.5 t magnet, we imaged injected and contralateral knee joints of 21 juvenile rabbits at baseline, and days 1, 14 and 28 after a unilateral intra-articular injection of carrageenin. nine non-injected rabbits served as controls. receiver operating characteristic (roc) curves were plotted to determine the diagnostic accuracy of the reading parameters. the bold measures from [(injected knee-control knees)/control knees] were counted as positive cases, while the bold measures from [(contralateral knees-control knees)/control knees] were regarded as negative cases. areas under the curve (aucs) were calculated to determine the most accurate parameters. results: using diff_on_off and positive_negative activations as constants, r>0.01 was found to be more accurate than r>0.2 (p00.03 at day 28). comparison of diff_on_off and pt% yielded no statistically significant difference (p> 0.05). finally, positive_negative activations for diff_on_off and negative activations for pt% using r>0.01 were the most diagnostically accurate (auc00.78, p<0.01 at day 28, and auc00.90, p<0.01). conclusions: from the results of this study, the most diagnostically accurate and clinically relevant reading parameters included the use of a more lenient threshold of r>0.01, a diff_on_off measure of bold contrast, and a positive_negative voxel activation algorithm. pt% may used as an ancillary measure of bold contrast. quantitative versus semi-quantitative mr imaging of cartilage in blood-induced arthritic ankles andrea doria, md, phd, diagnostic imaging, the hospital for sick children, andrea.doria@sickkids.ca; ningning zhang, carina man, pamela hilliard, ann marie stain, victor blanchette purpose or case report: to cross-sectionally compare the ability of a scoring system (semi-quantitative method) with a manual segmentation technique (quantitative method) to evaluate the status of the articular cartilage of growing ankles of children with blood-induced arthritis. methods & materials: 12 boys, 11 with hemophilia (a, n09; b, n02) and 1 with von willebrand disease, median age 13 (range, 6-17) underwent a high resolution mri protocol at 1.5 tesla, x-rays, and physical examination using the hemophilia joint health score (hjhs) system. two blinded radiologists scored the mri examinations for cartilage items (horizontal component: surface erosions, scores 0-2 and vertical component: cartilage degradation, scores 0-4) according to the semiquantitative method (international prophylaxis study group mri scale). an experienced operator applied a validated quantitative 3d-mri method (horizontal components: ac, vc, vctab, thctab; vertical component: thccab) to corresponding high resolution mr images of ankles. results: internal correlation of the semi-quantitative method components was substantial (r00.72, p<0.0001, tibia) to high (r00.91, p<0.0001, talus) in any site of investigation, but it was site-specific with the quantitative method, being significant only in the talar trochlea (r00.86, p<0.0001). external correlation of corresponding components of the semiquantitative and quantitative methods was moderate (r00.55, p00.005) to poor (r00.39, p00.05) for horizontal components, and non-existent for vertical components. components of the semi-quantitative method highly correlated with lifetime number of previous ankle bleeds (r00.74-0.84, p<0.0001), pettersson x-ray (r00.87-0.94, p<0.0001), and hjhs scores (r00.91, p<0.0001). this correlation was poor (r00.42, p0 0.04) to moderate (r0−0.56, p00.004) for horizontal components of the quantitative method. conclusions: the biologic concepts of the semi-quantitative and quantitative mri methods are distinct for assessment of ankles. the semi-quantitative method is valid for assessing cartilage changes in cross-sectional studies of blood-induced arthropathy, however the quantitative method is suboptimal or less powerful for this purpose. paper #: pa-129 shoulder mr arthrography in skeletally immature patients nancy chauvin, md, department of radiology, the children's hospital of philadelphia, chauvinn@email. chop.edu; camilo jaimes, victor ho-fung, diego jaramillo purpose or case report: there has been a well documented increase in sports participation in children which has lead to an increase in sports-related injuries. to date, there are no studies describing the value of shoulder mr arthrography compared with the gold standard, arthroscopy. we retrospectively reviewed 80 mr shoulder arthrograms obtained in pediatric patients between 2004 and 2010 who underwent subsequent shoulder arthroscopy. interpretation of the images was performed by three pediatric radiologists who were blinded to the arthroscopy findings. images were evaluated in consensus and independently. assessment included evaluation of the osseous structures, labral-ligamentous complex, joint space and the rotator cuff interval. the mr results were compared with reported surgical findings. sensitivity and specificity were calculated. results: nine patients were excluded due to technical reasons. of the remaining 71 patients, 48 were boys (9.7-18.5 years, mean 15.7 years) and 23 were girls (12.7-19.3 years, mean 15.6 years). at arthroscopy, 53 patients (74%) had injury to the anterior inferior glenoid labrum. mr sensitivity was 92% for depiction of bankart-type injuries with a specificity of 94%. 37 patients (52%) had hill sach lesions and mr had sensitivity of 86% with specificity of 88%. 24 superior labrum anterior posterior (slap) tears (33%) were identified at arthroscopy with mr sensitivity of 67% and specificity of 89%. overall, mr arthrography had a positive predictive value of 96% for identification of a surgical lesion. agreement between the observers was high. interobserver reliability was calculated with an intraclass correlation coefficient (icc)of 0.638 with a cronbach's alpha of 0.841. conclusions: mr shoulder arthrography can accurately depict labral and osseous injury and provides pertinent preoperative information. a novel multi-channel mr coil for improved pediatric elbow coil imaging suraj serai, phd, cchmc, suraj.serai@cchmc.org; randy giaquinto, kathleen emery, charles dumoulin purpose or case report: single flex coils or adult size coils are currently used for imaging the pediatric elbow. this frequently results in uncomfortable patient positioning, motion, poor fat suppression, low snr and there is currently lack of a dedicated pediatric elbow coil in the commercial market. our goal was to explore the usefulness of a new coil array dedicated for pediatric elbow imaging and to compare quantitative & qualitative imaging findings to commercially available coils. methods & materials: an eight channel elbow coil was designed. the coil frame was designed to be rigid and lightweight. seven identical loop coils were built into a polycarbonate frame and an eighth coil built into a paddle that fits into the top frame. the coil elements were constructed with heavy copper to provide a high q-factor and increased snr. the complete coil including electronics & covering, weighs only 1.4 kg. mr imaging under irb approval was performed on a ge 1.5 t scanner using a routine clinical elbow protocol including t1w, pdw, t2w, fat-sat, non-fat-sat, 2d & 3d sequences. subjects were positioned feet-first with the elbow on the side & were subjectively assessed for comfort level. images obtained from the new coil & from the current commercial coils were compared for snr. results: scan positioning was reported to be comfortable. snr was between 20-25% higher as compared to the routine coils. fat saturation was uniform, indicating that the magnetic susceptibility of the coil is well-matched to human anatomy. anatomical detail depiction was subjectively better for anatomic features such as trochlea. detection & diagnostic confidence of elbow disorders were improved with the new coil & greatly decreased motion artifacts were observed. conclusions: the new pediatric elbow coil provided excellent image quality, patient acceptance and clinical performance improvements over existing coils. the open coil design also allows for imaging of the elbow in a partially flexed position or in a cast. the advantages provided by the new coil are expected to include shortened image acquisition times (via parallel imaging) & increased snr. disclosure: dr. serai has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. incremental value of knee radiography in the interpretation of pediatric knee mri yen-ying wu, texas children's hospital, yxwu@ texaschildrens.org; robert c. orth, wei zhang, r. p. guillerman, herman kan purpose or case report: the acr appropriateness criteria recommendation for the imaging work-up of knee pain is radiography followed by mri. in many cases, mri is performed prior to review of radiographs or the referring subspecialist does not feel radiographs add value, particularly when ligamentous injury is suspected. the purpose of this study is to determine if radiography adds incremental value in the interpretation of knee mr studies electively referred by pediatric sports medicine and orthopedic subspecialists. knee mri studies referred from pediatric sports medicine physicians or pediatric orthopedic surgeons between 9/2008 and 9/2011 (n0194, ages 4-18 years, m:f087:107) with accompanying radiographs were identified. patients were separated into 3 groups based on mri findings: normal, ligamentous injury, or osteochondral injury (osteochondral lesions, bone contusions/fracture, and avulsion injury). knee radiographs were consensus reviewed by two caq pediatric radiologists blinded to mri findings and categorized into the same groups. radiograph and mri findings were compared and categorized into 3 groups: neutral if radiograph and mri findings were the same, misleading if findings were discordant, or helpful if radiographs improved mr interpretation. the latter group was analyzed for impact on mr diagnosis. results: for 194 knee radiographs, 166 were normal, 2 showed ligamentous injuries, and 26 showed osteochondral injuries. when radiographs were interpreted as normal (n0 166), by mr 44% were normal, 33% had ligamentous injury, 10% had osteochondral injury, and 13% had both ligamentous and osteochondral injury. when radiographs were interpreted as ligamentous injury (n02), by mr 50% were normal and 50% had ligamentous injury. when radiographs were interpreted as osteochondral injuries, by mr 8% had ligamentous injury, 38% had osteochondral injury, and 54% had both ligamentous and osteochondral injury. subset analysis of true positive radiographs (n025) found 56% to be helpful and 44% to be neutral in mr diagnosis. for radiographs considered helpful, 0% resulted in a change in mr diagnosis. in regards to the influence of radiographs on mr interpretation, 37% (72/194) were misleading, 56% (108/194) were neutral, and 7% (14/194) were helpful. conclusions: a minority of pediatric knee radiographs aided mr diagnosis, and none resulted in a change in diagnosis. pediatric knee mri and interpretation should not be predicated on radiologist review of knee radiographs in this subset of patients. paper #: pa-132 sonographic evaluation of pediatric skeletal lesions: is it worthwhile? henrietta rosenberg, md, radiology, the mt. sinai medical school, henrietta.rosenberg@mountsinai.org; amish patel, neil lester purpose or case report: the purpose of this paper is to demonstrate how ultrasound(us) may serve as a readily available, cost-effective, non-invasive, non-ionizing, practical tool for the evaluation of a variety of skeletal abnormalities in the pediatric age range. we reviewed the clinical and imaging findings in 31 patients seen during the past 2 years in whom us demonstrated abnormalities related to the skeletal system, excluding patients with hip joint effusions or ddh. results: us proved useful in the following situations: evaluation hard superficial immobile mass (osteoma shin) (1), absent medial end clavicle on x-ray in region of neck mass (us showed abc medial end clavicle)(1), to determine if soft tissue mass involves adjacent bone nodular fasciitis surrounding clavicular head (1), for diagnosis and followup fracture (displaced/non-displaced) in infants (4), diagnosis osteomyelitis in patients with cellulitis (4), question of fracture underlying cephalohematoma or subgaleal hematoma (4), rib mass (osteochondroma) (1) or mass costochondral junctions (contour deformities costochondral cartilage) (6), firm posterior knee mass (baker's cyst) (1), firm anterior knee mass (septated cystic mass suprapatella region due to rheumatoid disease) (1), immobile hard scalp mass due to epidermoid cranial vault (1), painful mass occipital bone with soft tissue components extending through the skull externally and internally due to langerhan's histiocytosis (1), indeterminate mass clavicle clinically thought to be post-traumatic sequellae, resolved on follow-up (1), assessment craniosynostosis (3), for differentiation of pathological entity from normal anatomic structure (lump on back of slender baby proved to be normal posterior spinous process) (1). conclusions: us is worthwhile for evaluation of wide range of pediatric skeletal abnormalities and helps to determine if the a lesion is one that is "touch" or "don't touch". to maximize diagnostic accuracy, the imager should have thorough knowledge of the clinical history, physical findings, laboratory and other imaging findings. in equivocal cases or in those patients in whom the field of view (fov) is insufficient for complete visualization of an obvious lesion or if malignancy is suspected, us serves to triage those patients in whom further imaging is necessary. high incidence of vertebral fractures in children with acute lymphoblastic leukemia 12 months after the initiation of therapy mary ann matzinger, md frcp(c), university of ottawa, matzinger@cheo.on.ca; nazih shenouda , brian lentle, josée dubois, helen r. nadel purpose or case report: vertebral fractures due to osteoporosis are a potential complication of childhood acute lymphoblastic leukemia (all). to date, the incidence of vertebral fractures during all treatment has not been reported methods & materials: we prospectively evaluated 155 children with all during the first 12 months of leukemia therapy. lateral thoracolumbar spine radiographs were obtained at diagnosis and 12 months. vertebral bodies were assessed for incident vertebral fractures using the genant semi-quantitative method, and relevant clinical indices such as spine bone mineral density (bmd), back pain and the presence of vertebral fractures at diagnosis were analyzed for association with incident vertebral fractures. results: of the 155 children, 25 (16%, 95% confidence interval [ci] 11% to 23%) had a total of 61 incident vertebral fractures, of which 32 (52%) were moderate or severe. thirteen of the 25 children with incident vertebral fractures (52%) also had fractures at the time of diagnosis. vertebral fractures at diagnosis increased the odds of an incident fracture at 12 months by an odds ratio of 7.3 (95% ci 2.3 to 23.1, p00.001). in addition, for every 1.0 standard deviation reduction in spine bmd z-score at diagnosis, there was 1.8-fold increased odds for incident vertebral fracture at 12 months (95% ci 1.2 to 2.7%, p00.006). conclusions: children with all have a high incidence of vertebral fractures 12 months after diagnosis, and the presence of vertebral fractures and reductions in spine bmd zscores at diagnosis are highly associated clinical features. purpose or case report: to provide objective measures of acetabular morphology utilizing volume-rendered ct and to better characterize normal acetabular development in adolescents. implications for the diagnosis of femoroacetabular impingement (fai) will be discussed. methods & materials: 146 hips in 73 consecutive patients (36 female, 37 male; ages 13-20 years) who underwent abdominal and pelvic ct for non-hip related complaints were retrospectively examined. examinations were performed for a variety of complaints, including abdominal pain, nephrolithiasis, vomiting etc. patients with obvious hip pathology were excluded. pelvic rotation was eliminated, and pelvic inclination was measured and corrected to 60°u tilizing a volume rendered ct model. measurements of femoral head diameter (fhd), anterior femoral head coverage (fhca), and posterior femoral head coverage (fhcp) were obtained. femoral head area (fha) was defined as π(fhd/2)2. percent anterior femoral head coverage (%fhca) was defined as (fhca/fha)*100. percent posterior femoral head coverage (%fhcp) was defined as (fhcp/fha)*100. acetabular version by volume-rendered ct (avvr) was defined as (fhcp/fhca). results: average pelvic inclination angle (sd) was 70.9 (5.6) for females and 64.8 (6.3) for males. average (sd) %fhca was 22.7 (4.9) for males and 18.6 (5.6) for females. average (sd) avvr was 2.39 (0.57) for males and 3.42 (1.19) for females. among males, average avvr decreased with subject age. on the other hand, there was little change in average avvr with age among females. conclusions: average avvr is greater for females than males, and this difference becomes more striking with increasing subject age. this represents an unexpected finding given the reported increased incidence of "pincer" type fai among females. characterization of acetabular morphology among adolescents with clinical fai should consider subject age and gender. in this regard, volumerendered ct is capable of providing an objective measure of acetabular morphology. mistakes in musculoskeletal plain film interpretation james crowe, pediatric radiology, texas children's hospital, jecrowe@texaschildrens.org; george s. bisset purpose or case report: to evaluate the mistakes made by trained pediatric radiologists when interpreting radiographs of the extremities obtained for the evaluation of outpatient acute pain (mostly post-traumatic). we retrospectively evaluated all radiographs and associated interpretations obtained during a 6 month period from april 15, 2011, to october 15, 2011, of the elbows, wrists, knees and ankles in pediatric outpatients who presented with acute pain in the affected area. all radiographs were previously interpreted by a caq-certified pediatric radiologist varying in experience from 1 year to 57 years. 745 abnormals were identified, including 305 elbows, 168 wrists, 175 knees and 97 ankles. all radiographs were determined to be "as dictated", missed significant finding, or overcall. attention was focused on the missed findings and overcalls. results: findings were as follows: elbow radiographs-14 missed findings and 10 overcalls, wrist radiographs-12 missed findings and 5 overcalls, knee radiographs-9 missed findings and 0 overcalls, ankle radiographs-14 missed findings and 10 overcalls. this resulted in a total of 49 missed findings (6.6% of abnormals) and 25 overcalls (3.4% of abnormals). of the 49 misses, 49% were fractures. the highest mistake percentage occured in the ankles where the combined misses and overcalls approached 25%. this was also the location where we found the highest percentage of missed fractures (9.0%) conclusions: when just abnormal cases were considered, fully trained pediatric radiologists have a mistake rate of approximately 9.8%, if misses and overcalls are included. from a quality improvement perspective, we will review all of the types of misses and overcalls to expose common themes. longitudinal assessment of osteoporosis in a blood-induced hemophilia rabbit model using quantitative ultrasound kuan-chieh wang, university of toronto, kc.wang@ utoronto.ca; afsaneh amirabadi, anguo zhong, christopher tomlinson, andrea s. doria purpose or case report: the reduction of physical activities in hemophilic patients may lead to bone demineralization and consequent osteoporosis. quantitative ultrasound (qus) is free of ionizing-radiation, relatively inexpensive, and easy to use that making this technique suitable for follow-up of hemophilic children with clinical suspicion of osteoporosis. to our knowledge, no previous study has investigated the value of qus for longitudinal assessment of growing bones in an animal model which is paramount for clinical translation of the technique once change in measurements could relate to either the baseline pathology or physiologic bone growth variability. the objective of this study is to investigate the intra-and inter-operator reliability of qus over time, and its ability to discriminate bone loss in pathologic vs control knees of a rabbit model of blood induced arthritis. methods & materials: sixteen juvenile white new zealand rabbits distributed into two groups: 8 received 8 intraarticular blood injections over 17 weeks (n 0 8 pathologic and 8 contralateral knees), and 8 noninjected rabbits were used as controls (n 016 knees). midshaft tibia speed-of-sound (sos) was measured at baseline, and weeks 8 and 17 of the experiment. two operators scanned each site twice at each time point. qus measurements were compared to microct (reference standard) on week 17 to validate the study results. results: the sos measured in the control group increased significantly (p<0.001) over the 17 week period. there was not such an increase in the arthritis sos value (p>0.05). in both groups the overall intra-operator coefficient of variation of sos measurements was 6% at baseline and decreased to 2% at week 17 likely due to increased tibia size. the inter-operator reliability was 6% at baseline and 3% at week 17. with regard to the effect of bone growth on qus measurements for the control group (n 016), sos values increased by 419.13 m/s, whereas for the pathologic group (n08), they only increased by 195 m/s. statistically significant differences in ratios of sos between final/baseline results were noted (p 00.016) between the pathologic and control groups. conclusions: the longitudinal use of qus has an acceptable intra-and inter-operator reliability. even accounting for the significant impact that bone growth has on qus measurements over time, qus can differentiate pathologic from control knees in the proposed animal model and holds potential for clinical use in the assessment of osteoporosis in hemophilic children. methods & materials: the study was approved by the institutional review board. 68 pediatric patients with 73 abdominal tumors (34 malignant and 39 benign lesions) underwent diffusion-weighted mr imaging (dwi) on clinical 1.5 t (n039) and 3 t (n029) mri scanners. adc maps were generated from b0500 dwi and adc values were retrospectively and independently measured by two radiologists. adc values of benign and malignant tumors were compared with the welch two sample t-test. a p value of 0.05 was considered to indicate statistical significant differences. in addition, a receiver operating curve analysis (roc) was performed to determine the optimal cut-off adc value for differentiating benign and malignant tumors. results: the mean adc value (mm2/sec) of benign tumors was 1.681 x 10-3 for the first reader and 1.679 x 10-3 for the second reader. the mean adc value (mm2/sec) of malignant abdominal tumors was 1.018 x 10-3 for the first reader and 1.113 x 10-3 for the second reader. the differences between benign and malignant tumors were statistically significant (p<0.001 for both readers). roc analysis revealed an optimal cut-off adc value for differentiating malignant and solid tumors as 1.1 x 10-3 mm2/sec. conclusions: diffusion-weighted imaging with adc maps can be used to differentiate between benign and malignant pediatric abdominal tumors. creation of a database to evaluate imaging findings in long-term survivors of pediatric malignancy alexander towbin, md, radiology, cincinnati children's hospital medical center, alexander.towbin@cchmc.org; seth hall purpose or case report: over the past 20 years, there have been significant improvements in the treatment of pediatric malignancies. improved therapy has led to an increase in the number of long-term survivors. many of these survivors are now experiencing late effects as a result of the original disease process or its treatment. these late effects are frequently identified on imaging. the purpose of this study is to create a database of the imaging findings of long-term survivors of pediatric malignancy in an attempt to begin to classify the findings and identify associations. methods & materials: after irb approval, the institutional cancer registry was searched to identify all patients younger than 20 years of age who were diagnosed with a solid tumor between 1980 and 2005. patients were included in the database if they survived for more than 2 years from the date of their initial diagnosis. the electronic medical record system was then used to obtain demographic and treatment information for each included patient. the dictated reports from all cross-sectional imaging studies evaluating the chest, abdomen, or pelvis performed more than two years from the date of diagnosis were then reviewed. each positive imaging finding was classified by the involved organ. results: after querying the institutional cancer registry, 909 patients were identified who met the inclusion criteria for this database. the most common neoplasms were neuroblastoma, wilms tumor, and astrocytoma. of the included subjects, 420 had imaging of the chest, abdomen, or pelvis. overall, 2851 reports were evaluated and classified. findings were most commonly identified in the lungs, musculoskeletal system, kidneys, liver, and lymph nodes. conclusions: a database examining the late effects in longterm survivors of pediatric malignancies was created. this database has the potential to help identify the radiologic manifestations of the complications of cancer therapy and thus help guide rationally determined long-term risk-benefit ratios in the treatment of pediatric malignancies. imaging followup of lymphoma in pediatric patients: is pelvic ct necessary? javier lopez bueno, md, children's hospital of eastern ontario, jlopezbueno@cheo.on.ca; nishard abdeen purpose or case report: pelvic ct is often included in the imaging followup of patient with lymphoma before, during and after treatment to assess response to treatment and monitoring for relapses. while such followup is expected to improve detection of relapse, there is little objective evidence of its effectiveness in lymphoma. anecdotally, there are few pelvic relapses in pediatric patients with lymphoma regardless of primary site. we hypothesize that pelvic ct could be avoided as part of the followup without adverse impact on survival or in the detection rate of relapses, and with subsequent significant reduction in the radiation dose, particularly to the gonads. methods & materials: research ethics board approval was obtained. patients diagnosed with lymphoma and with at least one year of followup at our tertiary care pediatric hospital were included. sex, age, type of lymphoma, stage, primary site, site of relapse if any as well as the number of ct scans of the head, neck, chest, abdomen and pelvis were recorded. results: a total of 29 patients met study criteria. there were 21 males and 8 females, with an average age of 11.9 years (range 3-17 years). eighteen patients had hodgkin disease (62%) and eleven had non-hodgkin lymphoma (38%). mean length of followup was 3.8 years (range 1-12 years). an average of 4.5 pelvic scans per patient were performed for surveillance (range 0-12). three relapses were detected. of these only one was in the pelvis, in a patient whose initial t cell non-hodgkin lymphoma was extensive and involved the neck, chest, abdomen and pelvis. conclusions: this study suggests a low incidence of pelvic relapse in pediatric patients with lymphoma. the routine use of pelvic ct in surveillance protocols may therefore be of little benefit while imposing a significant radiation burden. our study is limited by small sample size and short length of followup. further large scale studies are required. (esft) is performed by measuring the size of the tumors before and after chemotherapy. the proposed method of measuring tumor size, however, differs amongst recist 1.1 (response evaluation criteria in solid tumors), who (world health organization) and cog (children's oncology group) response criteria. in our project, we assessed whether response classification differs between the three different methods. methods & materials: after irb approval, we retrospectively analyzed mri studies of 55 patients with ewing sarcoma who were treated at stanford and ucsf medical centers. tumor size was assessed before and after therapy. tumor measurements were obtained using recist 1.1 (longest single diameter), who (longest diameter and perpendicular diameter), and cog criteria (three measurements to calculate tumor volume). tumor response was assessed by the differences in sizes of the tumors before and after treatment using four response categories: progressive disease (pd), stable disease (sd), partial response (pr), and complete response (cr). concordance between the three response classification systems was assessed using cohen's kappa (k) coefficient and percentage of disagreement per response category. results: the k statistic for concordance in cog/who, cog/ recist and recist/who were 0.663, 0.210 and 0.166 respectively. disagreement rates for recist/who, cog/ who, and cog/recist were 12.73, 34.55, and 47.27% respectively. using tumor volume, twenty-six patients were reclassified: twenty-four cases of stable disease coded by recist were reclassified as progressive disease by cog and two cases of partial response coded by recist were reclassified as complete response by cog. conclusions: this study demonstrates poor agreement between the recist 1.1 and cog response criteria in esft. given the degree of discordance between response criteria in esft, evaluation of the prognostic impact of each of these classification systems may guide selection of the optimal system for future use in this disease. imaging recognition of chylous ascites following surgery for abdominal neuroblastoma zeyad metwalli, md, baylor college of medicine, metwalli@bcm.edu; r. p. guillerman, heidi v. russell, eugene s. kim purpose or case report: surgical resection is a standard part of multimodality treatment of neuroblastoma, the most common abdominal malignancy of infancy and early childhood. chylous ascites is a rarely reported complication of surgery for abdominal neuroblastoma, and is likely underrecognized, posing the risk of nutritional deterioration and sepsis. to facilitate early diagnosis and institution of appropriate therapy, we present the salient imaging findings of the largest known series of chylous ascites following surgery for abdominal neuroblastoma. methods & materials: all patients with abdominal neuroblastoma complicated by post-operative chylous ascites over a five-year period at a large children's hospital were identified by a database search. a retrospective review of the imaging studies and clinical charts was conducted. results: chylous ascites developed following surgical resection of abdominal neuroblastoma in 5 of 36 patients, with the diagnosis made between postoperative days 20 and 33. four cases were high-risk neuroblastoma and one was intermediaterisk neuroblastoma. all 5 cases involved resection of an adrenal mass and dissection around the abdominal great vessels. all 5 cases manifested with abdominal distention on physical exam, and ascites was suspected clinically in 3 cases. computed tomography (ct) in all 5 cases revealed a large volume of ascites of near-water attenuation (range of −3 to 16.5 hounsfield units). the 3 cases imaged with ultrasound (us) showed hypoechoic or anechoic ascites without septations. the chylous ascites resolved after 1-4 months of treatment with dietary fat restriction, medium chain triglycerides, intravenous octreotide, or peritoneal catheter drainage. conclusions: chylous ascites is an under-recognized complication of surgical resection for abdominal neuroblastoma, occurring in 14% of patients in this series. the diagnosis is supported by the demonstration on ct or us of a large volume of ascites causing abdominal distention 3-5 weeks post-operatively. the ascites is typically near-water in attenuation rather than fatty in attenuation and should not be misattributed to peritonitis, hemorrhage, bowel leak, or early tumor recurrence. cervical spine injuries in patients with suspected physical abuse nadja kadom, md, radiology, children's national medical center, nkadom@childrensnational.org; zarir p. khademian, tanya hinds, katherine deye, allison m. jackson, eglal shalaby-rana purpose or case report: to evaluate the incidence and nature of cervical spine injuries and relationship to posterior fossa abnormalities in children who underwent brain and cervical spine mri as part of the clinical workup for suspected physical abuse. methods & materials: authors retrospectively analyzed records of eighty-five children less than three years of age who were documented by the child protective services at a level one pediatric trauma center over a period of four years (2006) (2007) (2008) (2009) (2010) . only patients who underwent both mri imaging of the cervical spines (c-spine) in addition to brain imaging as part of the clinical workup were included. cspine and posterior fossa of brain mris were independently reviewed by two pediatric neuroradiologists, both blinded to clinical details. c-spine abnormalities (bone marrow edema, cord edema, intrathecal blood, disc pathology, soft tissue/ ligamentous injury, vascular injury) were documented and correlated with abnormalities seen in the posterior fossa (blood, brainstem edema, cerebellar edema). results: at this time, 40/82 patients have been reviewed. twenty patients (50%) had both cervical spine injuries and posterior fossa abnormalities. there were no patients with isolated cervical spine injuries without posterior fossa abnormalities, but there were five patients (12.5%) that had posterior fossa abnormalities in the absence of c-spine injuries. fifteen patients (37.5%) did not have any spinal or posterior fossa imaging abnormality. none of the patients had bone marrow edema, disc pathology, or intrathecal blood. one patient had vascular neck injury and cord edema. conclusions: our results show that the incidence of cervical spine injury in children under investigation for abusive head trauma is as high as 50%. our data show further that cervical spine injury predicted posterior fossa injury in all patients, while presence of posterior fossa injury predicted concomitant c-spine injury in only 75%. the incidence of c-spine trauma we found in these patients is higher than reported elsewhere in the literature and may impact whether or not routine c-spine mri will be included in national imaging guidelines for children under investigation of abusive head trauma. pediatric skull fracture andre loyd, phd, biomedical engineering, duke university, aml6@duke.edu purpose or case report: skull fractures are often seen in the setting of non accidental trauma (abuse) abuse, and are usually attributed to falls from heights above 1 m. part of the difficulty in assessing height is due to uncertainties in actual distance. objective: to determine what types of skull fractures can occur in pediatric and adult post-mortem human specimens during controlled impacts on hard surfaces from various heights. methods & materials: skull fracture patterns in postmortem human specimens from a unique bank of pediatric specimens (30-week gestation to 16-years-old, n013) were subjected to controlled drops from both arbitrarily low heights (15 and 30 cm) and high heights (2 m) onto an aluminum platen. the specimens were dissected from the neck at the occipital condyles and intracranial were sealed inside the head using pmma. the heads were dropped on to five different impact locations. fractures were identified using palpation and high resolution mdct. results: no specimens between 33-weeks-gestation and 24days-old sustained fractures from the 15-30 cm drops. three out of four (75%) specimens ages between 5-and 22-months old fractured due to the 15 or 30 cm drops. the 9-and 16-year-old specimens and all adult specimens survived the 15-30 cm drops. all specimens subjected to the 2 m drop fractured. the specimen between 11-months and 22-months sustained either a linear fractures or diastatic fractures from the 15 cm and 30 cm drops. the results indicate that some aged infants and young children can sustain skull fractures by being dropped or falling from relatively low heights. drops, as low as 15 cm, can cause linear and diastatic fractures in pediatric skulls. the presences of compliant sutures and fontanelles in neonatal heads allow the head to deform during impact. these data add very important information to mechanisms of skull fractures across ages, including ages in which child abuse is a consideration. evaluation of a new classification system for temporal bone fractures in children aimed at increasing prognostic value badriya al-qassabi, md, mcgill university, albahlania1@ yahoo.com; lucia carpineta, rania ywakim, bahar torabi, andrew m. zakhari, lily h p. nguyen purpose or case report: to compare a new classification of temporal bone fractures which specifically evaluates involvement of the otic capsule against the traditional classification system (transverse versus oblique versus longitudinal), to evaluate whether this new classification is able to better identify patients at risk of adverse otologic outcome and neurologic complications in the pediatric population. methods & materials: a retrospective hospital chart review was performed by ent colleagues searching for all patients with temporal bone fractures seen at our center over the past 10 years. this was followed by a blinded review of the ct heads by a resident and a trained pediatric radiologist with neuro expertise. these cts were evaluated for petrous involvement, otic capsule involvement and any associated intracranial lesions. this information was then correlated with clinical outcome measures including post-traumatic hearing deficit, facial nerve palsy, persisting csf leak and global neurologic sequelae. the new classification was compared to the traditional one, and specifically analysed for the ability to better predict the clinical outcomes. results: expectedly, pediatric temporal bone fractures were infrequent and otic involvement even more rare. fractures with involvement of the otic capsule (versus otic sparing) were found more frequently in boys. they were also more likely to be associated with immediate otologic signs and neurologic findings on presentation. these fractures also had the highest association with conductive hearing deficit (>60%) and were twice as likely as otic sparing fractures to be associated with immediate facial nerve palsy and with more important concomitant intracranial injuries such as midline shift. conclusions: while our numbers are small, our results suggest a trend that when temporal bone fractures show involvement of the otic capsule, there is higher risk of adverse otologic outcome and neurologic complications even in the pediatric population. absence of a causal relationship between mr detected subdural hematomas (sdh) in neonates with hypoxic-ischemic encephalopathy (hie) deniz altinok, children's hospital of michigan; jay shah, harut haroyan, gulcin altinok, nitin chouthai purpose or case report: the existing controversy regarding subdural hemorrhages noted in patients with hie is an important discussion in the medical, legal and child-welfare realms. it is our goal to provide additional information to this critical debate through mr findings on patients with clinically diagnosed hie. methods & materials: all patients born with clinically diagnosed hie, and treated at children's hospital of michigan in the past 8 years were examined; those with head mri taken within 19 days of life were selected. in total, 41 patients fit the criteria, this included: 22 males and 19 females, and an age range of 2-19 days at scan (average age of 10 days at scan). all traumatic births, coagulopathies, and other pertinent clinical findings were noted. mr imaging was reviewed and reported by a blinded pediatric neuroradiologist, these reports were then compared to the "original read". results: all 41 patients were confirmed radiologically to have hie. the causes of hie in all cases examined were either intrauterine/delivery asphyxia, aspiration, or congenital disease. of these 41 cases, the findings were: 6 sdh, 11 parenchymal hemorrhages, 4 intraventricular hemorrhages, 4 cephalohematomas, 3 subarachnoids, 1 large subcutaneous hemorrhage and 1 instance of mca stroke. all 6 patients with mr detectable sdh had 1 or more confounding factors (1 meningitis, 3 coagulopathies, 4 chest compressions, 1 cardiac malformation, 1 pph, 1 severe pulmonary hemorrhage requiring transfusion of plasma and prbc). conclusions: it has been hypothesized that sdh is often found incidentally in children diagnosed with hie, this is however a dubious conclusion considering our results. in fact, the presence of sdh and hie concomitantly is low even when including a population with traumatic births such as ours. sports-related concussion in children: an mri and mrs study kim cecil, phd, cincinnati children's hospital medical center, kim.cecil@cchmc.org; todd a. maugans, james l. leach, mekibib altaye purpose or case report: the pathophysiology of sportsrelated concussion (src) is poorly understood, especially for children. following src and mild traumatic brain injury in adults, a few mri and proton mrs studies have identified axonal injury with declines in the neurometabolite n-acetyl aspartate (naa). we wanted to examine a src adolescent population with proton mrs, diffusion tensor imaging (dti) and other mri methods within 72 h of concussion and with short term followup to determine if there were differences in imaging metrics with age and sex matched healthy control participants. methods & materials: twelve children, ages 11-15 years, who experienced src were evaluated with impact neurocognitive testing, t1-weighted mri, susceptibility weighted imaging (swi), dti, proton mrs, and phase contrast angiography (pca) at less than 72 h, 14 days and 30 days or greater post-concussion. healthy, age and sex matched controls for each src participant were recruited and evaluated at a single time point. quantitative imaging metrics included fractional anisotropy, metabolite concentrations, and global cerebral blood flow (cbf). group comparisons were examined by paired t-test or wilcoxon signed rank test. correlational data employed spearman rank correlation. results: impact results revealed significant differences in initial total symptom score (tss), and reaction time (rt) for the src group compared with the control group, with tss resolving by a mean of 14 days and rt at 30 days. no evidence of structural injury was observed qualitatively for either group. analyses between groups or over time within the src group found no decreases in naa or elevation of lactic acid upon mrs, and no changes in fractional anisotropy upon dti. within the src group, significant changes in the global cbf were observed. improvement towards control values occurred by 14 days for 27% and by 30 days for 64% of src group participants. conclusions: pediatric src affects global cbf without evidence of structural or metabolic injury. predictive value of high resolution mr imaging of brain and sella in children with clinical optic nerve hypoplasia for hypopituitarism charles glasier, radiology, arkansas childrens hospital, glasiercharlesm@uams.edu; raghu h. ramakrishnaiah, julie shelton, chetan c. shah, paul h. philips purpose or case report: to review the spectrum of cns abnormalities and their incidence in children with optic nerve hypoplasia and to calculate the sensitivity and specificity of magnetic resonance imaging in predicting endocrine abnormalities. methods & materials: this is an irb approved retrospective study of 44 children with clinical optic nerve hypoplasia who underwent mri of the brain and orbits as part of the clinical workup in a tertiary care pediatric hospital. high resolution mri studies were performed on 1.5 tesla scanners. mri studies were reviewed for optic nerve hypoplasia, absent or ectopic posterior pituitary, absent pituitary infundibulum, absent septum pellucidum, migration anomalies and hemispheric injury.radiologists were blinded to patients endocrinologic status.all patients had clinical evaluation by a pediatric neuro-ophtalmologist and endocrinologist. a standardized panel of serologic testing that included serum cortisol, acth, tsh, and free t4 levels were performed on all patients. statistical analysis was performed to determine the sensitivity and specificity of mr findings in predicting endocrinologic deficiency. results: study included 44 children(26 males and 18 females) who had clinical optic nerve hypoplasia. the mean age of the study population was 3 yr (sd:4.7 yr).15 children had unilateral and 29 children had bilateral optic nerve hypoplasia by mri.6 children had absent posterior pituitary bright spot and 9 had ectopic posterior pituitary,7 had absent infundibulum,1 had complete callosal agenesis,3 partial callosal agenesis and 16 had callosal thinning. 9 had absent septum pellucidum. 2 had hypopituitarism. of the 12 patients with hypopituitarism 8 had abnormal abnormal pituitary on mri, 3 had absent septum pellucidum, and 1 child had migration abnormality. none had corpus callosal abnormality. the sensitivity and specificity of mri in predicting hypopituitarism by demonstration of abnormal pituitary is 75% and 81% respectively. the positive predictive value and the negative predictive value is 60% and 90% respectively. among the 32 patients with normal endocrinologic function, none had pituitary abnormalities on mri. conclusions: pituitary abnormalities are the most common intracranial abnormality in patients with optic nerve hypoplasia followed by absent septum pellucidum. detection of pituitary abnormalities by the mri has high specificity and high negative predictive value for endocrine abnormality. paper #: pa-148 ct imaging pearls for shunted pediatric brains srikala narayanan, md, children's national medical center, snarayan@childrensnational.org; nadja kadom purpose or case report: shunted pediatric patients frequently present emergently with symptoms that could indicate shunt malfunction, such as headache and vomiting. here, we present imaging pearls on non-contrast head ct in shunted children. methods & materials: illustration of each of the following: 1. shunt tip and volume averaging-consider location of side holes and use of multiplanar reformatted images. 2. shunt at burr hole-consider radiolucent shunt parts. 3. shunt rupture in the neck-remember to investigate the lower extracranial shunt parts. 4. shunt in cyst/subdural shunt (vs dislocation)-consider primary shunt location in a cyst rather than shunt dislocation. 5. enlarged temporal horns-look for it. in infants occipital horns may dilate first. 6. enlarged 3 rd ventricle-look for bulging of lateral walls. 7. sulcal effacement-use the "three shades of gray" rule. 8. small cisterns-detecting shape distortion can help. 9. periventricular edema-easily overlooked because of similar low density compared to ventricular fluid. 10. slit-ventricle -requires cautious reporting. conclusions: careful evaluation of ct images in shunted pediatric patients can reveal important clues for making an accurate diagnosis, even when prior images are not available. successful treatment of mice with creatine transporter deficiency kim cecil, phd, cincinnati children's hospital medical center, kim.cecil@cchmc.org; diana m. lindquist, matthew r. skelton, gail j. pyne-geithman, joseph f. clark purpose or case report: creatine transporter deficiency (ctd) is an untreatable x-linked mental retardation syndrome with severe cognitive and speech impairment. patients are identified by an absence of creatine in the brain on mr spectroscopy (mrs) and distinguished from two creatine synthesis deficiency syndromes with genetic testing. for ctd, the absence of the transporter (slc6a8) prevents creatine from crossing the blood brain barrier and entering brain cells. a brain specific ctd knockout mouse was developed replicating key features of the human disease and establishing an animal model for treatment of ctd. we report the successful treatment of the ctd knockout mouse and present confirmation by mrs. methods & materials: brain specific knockout and littermate control mice were randomly assigned and treated with on one of three supplements: agentx (confidential), creatine or maltodextrine as placebo. 1h and 31p mrs data were collected on a 7 t mr system (bruker). mice (n016) were studied with mrs after 9 weeks of supplementation. single voxel 1h data were acquired on a 144 ul voxel covering the cerebrum using a double spin echo sequence. 31p data were acquired with an isis sequence from the same voxel. metabolite quantification was performed with jmrui and compared between groups and over time with statistical tests for significance (t-tests, anova). results: creatine and phosphocreatine levels in the brain were all significantly higher after 9 weeks supplementation of agentx in knockout mice, compared to creatine and placebo fed knockout mice (phosphorus mrs [144 ul brain voxel] with phosphocreatine (pcr) (0 ppm) observed only in agentx treated knockout mice. adenosine triphospate (atp) gamma (−2.5 ppm), alpha (−7.5 ppm) and beta (−17 ppm) peaks are noted in all three knockouts. conclusions: successful treatment was achieved in a slc6a8 brain specific knockout mouse for the second largest known cause of x-linked mental retardation in humans, ctd. disclosure: dr. cecil has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. prevalence of abusive injuries in siblings and contacts of abused children kenneth feldman, md, general pediatrics/children's protection program, university of washington/seattle children's, kfeldman@u.washington.edu purpose or case report: siblings and children who share a home with a physically abused child are thought to be at high risk for abuse. however, rates of injury in these children are unknown. disagreements between medical and cps professionals are common and screening is highly variable. our objective was to measure the rates of occult abusive injuries detected in contacts of abused children using a common screening protocol. this was a multi-center, observational cohort study of 20 child abuse teams who shared a common screening protocol. data were collected for all children <10 years undergoing evaluation for physical abuse and their contacts. for contacts of abused children, the protocol recommended physical examination for all children <5 years, skeletal survey and physical exam for children <24 months, and physical exam, skeletal survey and neuroimaging for children <6 months old. results: among 2,825 children evaluated for abuse, 618 met criteria as "physically abused" and these had 477 contacts. for each screening modality, screening was completed as recommended by the protocol in approximately 75% of cases. of 133 contacts who met criteria for skeletal survey, new injuries were identified in 16 (12.0%). none of these fractures had associated findings on physical examination. physical examination identified new injuries in 6.2% of 257 eligible, examined contacts. neuroimaging failed to identify new injuries among 19 imaged, eligible contacts less than 6 months old. twins were at significantly increased risk of fracture relative to other non-twin contacts (56.3% vs 11.9%, or 19.9). conclusions: these results support physical examinations and skeletal survey, regardless of physical examination results, for contacts of abused children <24 months of age. too few children had cranial imaging to change recommendations to image contact children less than 6 months old. even for children where no injuries are identified, these results demonstrate that abuse is common among children who share a home with an abused child. they support including contacts in evaluations and interventions (foster care, safety planning, social support) designed to protect physically abused children. the project was supported by the health resources and services administration/maternal shown that pediatric rib fractures may be a marker for significant intrathoracic injury. this information has been used to suggest that children with rib fractures and no underlying intrathoracic injury may have sustained them due to insufficient bony mineralization and minor trauma rather than inflicted injury. methods & materials: irb approval was obtained for a retrospective review of all children under 3 years of age with imaging diagnosis of rib fracture over a 6-year period at two university hospitals. children with prior thoracotomy, previously recognized metabolic bone disease, and prematurity <36 weeks were excluded. medical records were reviewed and children with documented abuse or accidental trauma were evaluated. children with indeterminate injury mechanisms were excluded. sixty-six patients with rib fractures were included in analysis, 47 due to abusive injury and 19 due to accidental trauma. children were analyzed for associated intrathoracic, abdominal or intracranial injury, additional fractures and retinal hemorrhage. results: abused children were younger (4.7+/−6.1 months) than accidentally injured children (18.9+/−11.1 months, p< 0.001). children with rib fractures due to accidental trauma had a higher incidence of intrathoracic injury compared to those due to abusive injury (53% vs 13%,p<0.001). there was no difference in the incidence of abdominal or intracranial injury between groups. mortality and icu admission rates were similar. abused children had a higher total number of rib fractures (mean 5.5 vs 3.0, p<0.009) and were more likely to sustain additional fractures outside of the thoracic cavity (77% vs 63%, p<0.001). conclusions: abuse is a more common cause of rib fractures in young children than accidents. children with rib fractures due to abusive trauma are less likely to have intrathoracic injury compared to those sustaining rib fractures due to accidental trauma. this suggests differences in mechanism of injury between groups. pediatric elbow fractures: a different angle on an old topic shannon zingula, md, pediatric radiology, cincinnati children's hospital medical center; kathleen emery, christopher g. anton purpose or case report: the 3 most common elbow fractures classically reported in pediatric orthopedic texts are supracondylar (sc) (50-70%), lateral condylar (lc) (20%), and medial epicondylar (me) fractures (10%) with fractures of the proximal radius (including but not limited to fractures of the radial neck) being relatively uncommon (5-10%). our experience at a large children's hospital suggests a different distribution. purpose: 1) to describe the frequency of different elbow fracture types in a large pediatric population, and 2) to determine the fracture types that were occult on initial radiographs but detected on follow-up. methods & materials: review of medical records identified 468 children, median age 6 years and interquartile range for age of 4-8 years (range, 0.8-18 years) diagnosed with elbow fractures at our institution from october 2010 through july 2011. initial and follow-up radiographs were reviewed in blinded fashion independently by two experienced pediatric musculoskeletal radiologists to identify fracture type(s) on initial and follow up radiographs. note was made of fractures identified on follow up only. results: the most common fractures included sc (n0254, 54%), radial neck (rn) (n080, 17%), and lc fractures (n066, 14%). as compared to classically referenced incidences, rn fractures were seen significantly more (p<0.0001) and me fractures (n025, 5%) significantly less (p0.0008) than would be predicted. in 26 patients without fracture seen on initial films, occult fractures were seen on follow up; sc (n012, 46%) and rn fractures (n08, 31%) were most common. the frequency of rn fractures compared to the overall group (31% vs. 17%) approached but did not reach statistical significance (p00.06). 34 patients with one fracture had additional fractures seen on follow-up not seen initially with olecranon fractures most frequent (n018, 53%.) this was significantly more common than the number identified on initial radiographs (n033, 7%) (p<0.0001). conclusions: sc fractures are the most frequent elbow fracture seen initially and in follow up followed by rn and lc fractures in a distribution different than classically described. the relatively high frequency of rn and olecranon fractures detected on follow up speaks to their potentially occult nature. careful attention to these areas is warranted in patients with initially normal radiographs. purpose or case report: previous studies have found that fractures involving the spine, hands and feet are rare on skeletal surveys for suspected child abuse, leading some authors to suggest eliminating views of these regions from the initial skeletal survey protocol. the purpose of this study was to assess this recommendation by performing a historical review of these injuries in a population undergoing screen-film based skeletal surveys for suspected abuse. this cross-sectional, retrospective irb approved study reviewed the reports of the initial skeletal surveys of all children <2 years of age with suspected abuse imaged between april, 1988 and december, 2001 . infants underwent skeletal surveys according to acr standards acquired on a mammographic type screen-film imaging system with at least 13 line pairs per millimeter resolution. studies in toddlers were performed using a par speed screenfilm system. results: 62% (225/365) of all skeletal surveys demonstrated positive findings, and 44% (98/225) had >1 fracture. 5.5% (20/365) of all studies had fractures involving the spine, hands or feet. of all positive skeletal surveys, 8.9% (20/ 225) had fractures involving the spine, hands or feet, and 20.4% (20/98) of all patients with >1 fracture on skeletal survey had fractures involving these regions. conclusions: these data, acquired in the screen-film era, suggest that fractures of the spine, hands and feet may not be rare in infants and toddlers in cases of suspected child abuse. the benefits of eliminating views of these regions from the initial skeletal survey should be carefully weighed against the cost of missing these potentially important injuries in at-risk pediatric populations. purpose or case report: dating fractures is critical in cases of suspected infant abuse, but there are little scientific data to guide radiologists, and dating is generally based on personal experience and conventional wisdom. we previously reported a scientific scheme for dating fractures in infants based on an analysis of subperiosteal new bone and callus formation in birth-related clavicular fractures. we hypothesize that when used as a guide this system can significantly improve the ability of radiologists to accurately date fractures in young infants. methods & materials: 103 radiographs of presumed birthrelated clavicular fractures in infants 0-3 months were reviewed by 2 pediatric radiologists with 2 (reader a) and 15 (reader b) years experience in two reading sessions separated by one year. for the first read, no guidelines were provided. training was carried out prior to the second session, and readers were given the dating scheme as a guide during fracture analysis. readers were asked to provide an estimate of the minimum and maximum fracture age in both sessions. the primary outcome was whether or not the reader's estimated range for fracture age included the actual fracture age. a secondary outcome was the width of the estimate of fracture age. these outcomes were compared across the two reading sessions. results: the rate of correct response significantly increased after training for each reader (reader a: 66% to 89%, p<.0001; reader b: 76% to 86%, p0.041). the width of estimated fracture age after training was significantly smaller for each reader (reader a: mean width 17 days to 13 days, p<.0001; reader b: 25 days to 15 days, p0.001). conclusions: our results suggest that the ability of a radiologist to accurately date fractures can improve significantly when provided with a scientifically based system outlining patterns of fracture healing. this scheme can be applied in radiologic practice and may prove particularly useful in cases of suspected abuse, where fracture dating often has forensic implications. purpose or case report: to demonstrate the acute and subacute features of proximal femoral physeal fractures in the abused child. also to demonstrate how to recognize this injury in patients with unossified femoral heads. the database of patients with suspected non-accidental trauma, accumulated over 12 years, was reviewed. 254 out of a total of 599 patients (43%) were proven to be cases of non-accidental trauma, as determined by the child abuse pediatrician. from these 254 patients, the cases of proximal femur growth plate fractures were identified. results: 7 patients with proximal femur growth plate fractures were identified for a prevalence of 2.8%. one patient had bilateral proximal femoral fractures, for a total of 8 fractures in 7 patients. 5 were boys, 2 were girls with ages ranging from 2.5 mos to 2 yrs 2mos. in 4 patients, the fracture was revealed on imaging performed because of refusal to bear weight; in the other 3 patients, the fracture was found during imaging for the skeletal survey. the fracture was on the left side in 7 cases and on the right side in 1 (the patient with bilateral fractures). in all of the fractures, there was lateral displacement of the femoral shaft. in 3 fractures, the femoral head was not yet ossified simulating the appearance of a dislocation. location of the femoral head in the hip joint was verified by ultrasound or ct (ct abdomen had already been done in 1 patient) thus delineating the presence of a physeal fracture. 6/8 fractures were salter-harris i and the other 2 were salter-harris ii fractures. the fracture was acute in 2 cases and subacute in 6 cases. in these 6 subacute cases, periosteal reaction and/or calcifying subperiosteal hemorrhage was present in 3, and irregularity and scalloping of the metaphysis was present in the other 3. conclusions: proximal femoral growth plate fractures are quite uncommon in non-accidental trauma. the injuries are typically salter-harris i or ii fractures, seen more often in the healing phase. in the presence of an unossified femoral head, the laterally displaced femoral shaft can simulate hip dislocation; this can be clarified with hip sonogram. purpose or case report: in recent years, metal stents have been used to overcome airway obstruction in children for whom no better surgical option is available. these devices are not designed for use in the airway, however, and may cause significant complications. bioabsorbable airway stents may avoid some of the problems associated with metal stents. methods & materials: this is a retrospective review of all endoluminal insertions of bioabsorbable airway stents at a single institution from april 2010 to september 2011. custom-made polydioxanone stents of various sizes (ella dv, ella, czech republic) were used. results: twelve stents were inserted in the airways of seven children. indications were: recurrent obstruction after slide tracheoplasty (2), persistent airway compression after correction of a congenital cardiac lesion (2), collapse of stem cell supported tracheal homograft, tracheomegaly following fetal balloon insertion, and syndromic tracheobronchomalacia (tbm). eleven stents (diameters 6 to 12 mm) were placed in the trachea and one in the left main bronchus. two stents had to be removed and replaced for technical reasons (one was too long and the other too narrow). the child with syndromic tbm died when treatment was withdrawn because she could not be weaned from the ventilator. the remaining children are alive at a median follow-up of nine months (range 1 to 17 months). the granulation tissue response was similar to that seen after placement of metal stents. the stents were observed to absorb gradually over a period of approximately three months, requiring serial stenting in two children. conclusions: bioabsorbable airway stents are more difficult to insert than metal stents. they cause similar early complications, especially granulation tissue formation, but appear to avoid potential long-term complications of metal stents, including vascular erosion and growth limitation. disclosure: dr. mcclaren has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: renal angiomyolipomas (amls) in tuberous sclerosis complex (tsc) grow at a faster rate, exhibit a wider and more problematic range of symptoms, and hemorrhage more frequently than sporadic amls. we examined the efficacy of prophylactic embolization of renal amls in tsc in decreasing tumor size, alleviating symptoms, and preventing hemorrhage while preserving renal function. we retrospectively reviewed the charts and imaging studies of 47 consecutive patients who underwent transarterial, transcatheter embolization of 52 amls. tumor volume was measured from available ct or mri imaging before and after embolization. pre-and postembolization symptoms and creatinine levels were documented. results: 37 patients had available follow-up imaging at a mean of 63 months post-embolization. the mean preembolization tumor volume was 581 ml and postembolization was 284 ml; median decrease in volume was 76%. using the schwartz method, the mean glomerular filtration rate before embolization was calculated to be 95.75 ml/min/1.73 m2. after embolization the mean value was statistically unchanged at 101.97 ml/min/1.73 m2. none of the patients experienced renal hemorrhage or symptom recurrence during the follow-up period. conclusions: selective embolization of renal amls in patients with tsc decreases tumor volume, relieves symptoms and reduces the risk of future hemorrhage while preserving renal function. etoh was injected percutaneously with 25 g needle; transductal ablation performed through a 4 f micropuncture sheath. drug volumes, technical difficulties, percentage reduction in saliva production, family reported clinical significance, and complications were recorded. results: salivary gland ablation (sga) included bilateral smg and slg ablation without parotid gland ablation in 20 cases, and with unilateral parotid gland ablation in 4 cases. one case of bilateral parotid gland ablation following surgical resection of bilateral smgs. mean etoh dose for smg04.2 ml, and 3.1 ml for slg. one case of focal skin necrosis was noted; no other complications. patient families reported response to sga in 24/25 cases (96%) with mean saliva production of 66%. greatest health and family impact was reported with elimination of hospitalizations for recurring aspiration pneumonia (2 cases), elimination of choking in bed (3 cases) , and improved patient sense of self-hygiene in 8 cases. one complication occurred with temporary marginal mandibular nerve paralysis (resolution in 6 months). conclusions: percutaneous and transductal sga is feasible, safe, and effective in this small patient series, offering an alternative to surgical salivary gland resection, or treatment option following failed surgical intervention. paper #: pa-159 mr-guided procedures in children: initial experience joao amaral, md, diagnostic imaging, the hospital for sick children, joao.amaral@sickkids.ca; michael temple, dimitri parra, philip john, bairbre connolly purpose or case report: the primary purpose of this study was to review our initial experience with mr-guided procedures in children. our secondary objective was to share some aspects on how to start an mr-guided program in a tertiary pediatric center. patients with lesions identified only on magnetic resonance (mr) imaging were selected to undergo an mr-guided procedure. patients' demographic data, primary diagnosis, referring team's clinical suspicion, lesion's anatomical location, tissue adequacy for pathology, final diagnosis and clinical follow up were reviewed. aspects of starting a program of mr-guided procedures, safety concerns, imaging and technical challenges, and mr compatible materials were also addressed. results: to date, 7 procedures (5 bone biopsies, 1 soft tissue biopsy and 1 pre-surgical needle localization) were performed in 6 patients during 9 months. there were 4 girls and 2 boys with a mean age of 10.2 years (3y5mo-17 yrs). one patient had a nasopharyngeal carcinoma, 1 cardiofacial syndrome, 1 wilm's tumor and 3 had no previous medical issues. the clinical suspicion for 2 procedures in 2 patients was metastatic disease and for 5 procedures in 4 patients was primary malignancy or infection. lesions were located in the tibia (2-metaphysis and diaphysis), femur (2 -metaphysis and epiphysis), thigh (1-soft tissues), sacrum (1) and retroperitoneum (1). all biopsies provided adequate tissue for diagnosis. needle localization and hook deployment was also accurate. malignancy was excluded in all patients. final diagnosis included 1 chronic recurrent multifocal osteomyelitis (crmo), 3 osteomyelytis, 1 fibrous tissue, 1 osteoid osteoma, and 1 scar tissue. mean follow up was 6.6 months. no patient required a second procedure to confirm the diagnosis. conclusions: mr with its unique soft tissue resolution and lack of ionizing radiation is an excellent method to guide interventions in children. one of the greatest advantages of this method is the precise target localization especially in lesions located in the bone marrow or lesions better identified on mr. special safety measures, specific mr compatible material (needles, surgical instruments), dedicated imaging techniques to reduce or increase material/needle artifact and careful technique are paramount. 2006-2011. 11 m, 15 f; 2 .5-59 months, mean 8.3 months, median 5 months, mode 5 months. sonographic approach expanded as our experience grew over 71 months. 25 studies performed by a single pediatric radiologist. bilateral sonography included: interscalene and supraclavicular neck, nerve roots at neural foramina, cervical spinal canal, diaphragm during spontaneous respiration, rhomboid muscle, serratus anterior muscle, posterior shoulder, all performed and interpreted blind to other imaging. results: interscalene and supraclavicular neck evaluated in all patients. all exhibited echogenic interscalene portion of brachial plexus.size and extent of traction neuroma varied. nerve roots at foramina noted in axial and coronal planes. in 11 cases enlarged root(s)noted. cervical spinal canal studied in 19 patients: cord oscillated normally, no syrinx, cord concentric in canal. intracanalicular traction pseudomeningoceles on concurrent ct myelography or mri were not apparent on us. in 2 cases a "clumped" retracted nerve root on the cervical cord was later found to correspond to a pseudo-meningocele on ct myelogram. otherwise, cervical spinal canal us was unremarkable in 24 cases. diaphragm motion was evaluated in 23 patients during spontaneous respiration; no phrenic nerve palsy. rhomboid muscle was evaluated for atrophy in 16 patients; 4 had atrophy. the rhomboids are innervated by the dorsal scapular nerve which arises solely from c5, prior to c5 joining the brachial plexus. intact rhomboid indicates that the central c5 root is intact. serratus anterior muscle, innervated by the long thoracic nerve (c5,c6,c7), was evaluated for atrophy in 12 patients; 6 had atrophy. dynamic evaluation of the posterior shoulder looking for posterior laxity was evaluated in 10 patients; 4 had laxity. posterior shoulder dislocation or subluxation is a known sequela of brachioplexopathy which sometimes requires muscle transfer when the child is older. conclusions: comprehensive us evaluation of perinatal brachioplexopathy detects: extent of traction neuromafibroma from the interscalene region peripherally toward clavicles (important for neurosurgeon), thick nerve roots, phrenic nerve diaphragm palsy, muscle atrophy from denervation, and posterior shoulder subluxation. us misses: intracanalicular traction pseudomeningoceles. paper #: alt-001 impact of the image gently campaigns in adult-focused hospitals: a survey of practice leaders brett bartz, duke university medical center; donald frush, kimberly applegate, michael callahan, laura coombs, marilyn goske purpose or case report: the alliance for radiation safety in pediatric imaging is an organization that uses social marketing to promote radiation protection for children and effect change across radiology practices. the impact of the alliance's image gently campaigns on practice patterns in radiology practices has yet to be assessed, especially outside of freestanding children's hospitals. the purpose of this investigation was to assess the impact of the image gently campaigns on academic and private practices/institutions that treat children but primarily serve adults. a web-based survey was emailed to leaders in radiology practices (n01186) who do not practice at freestanding children's hospitals utilizing the acr's pred database. the survey consisted of 18 questions designed to measure the recognition and impact of the image gently campaigns, including the impact on practice patterns. results: a total of 186 practice leaders in 41 u.s. states and territories responded for a response rate of 15.7%. the majority (94%) of sites image pediatric patients in their practices. respondents consisted of department chairs (60%), group presidents/ceos (33%), and division chiefs (13%). the majority (52%) of respondents described their practice as a hospital-based private practice without a dedicated pediatric radiology division. the vast majority (95%) of respondents was familiar with the image gently campaigns; 55% of respondents reported that image gently had effected a change on how they imaged children. specifically, respondents (%) reported that the campaign caused a modification to lower dose protocols for head ct (57%), chest ct (66%), and abdominal/pelvic ct (69%). slightly more than half of respondents (55%), however, estimated that the image gently campaign resulted in no modification of pediatric fluoroscopy exposure. conclusions: to our knowledge, this is the first survey evaluating the impact of the image gently campaigns. there is near universal recognition of the campaigns, which have impacted practice patterns beyond the freestanding children's hospital in ct, but not in fluoroscopy. reliability of shear-wave velocity using different frequencies in acoustic radiation force impulse (arfi) elastography mi-jung lee, radiology, severance children's hospital, mjl1213@yumc.yonsei.ac.kr; suyon chang, myung-joon kim purpose or case report: although there are many studies about acoustic radiation force impulse (arfi) measurement, standard protocol has not been established. and a new probe with high frequency has been developed which can be applied for pediatric patients. the purpose of this study was to assess the reliability of shear-wave velocity (swv) at various depths using different frequencies to suggest standard measurement in arfi elastography. methods & materials: arfi elastography of both the elasticity phantom and normal liver was performed at different depths (2-5 cm) with convex (1-4 mhz) and linear (4-9 mhz) probes. ten valid swv measurements at each depth were performed. it was repeated ten times with the phantom and it was done in 8 healthy volunteers (m:f03:5, age 20-34 years; mean 25.5). the mean value and standard deviation of swv were calculated. results: in both the elasticity phantom and the liver, variability of swv was different between the depths in both probes. the depth with lower variability in the phantom was 4 and 5 cm with the convex probe and 2 cm with the linear probe. in the liver, the depth with lower variability was 4 cm with the convex probe and 3 and 4 cm with the linear probe. in comparison of two probes, the linear probe showed lower variability at 2 and 3 cm depth in the phantom and at 3 cm depth in the liver whereas the convex probe showed it at 4 cm depth in both the phantom and the liver. conclusions: in arfi elastography, measurement of depth shows different variability in both low and high frequency probes. to obtain the most reliable measurement of swv, using high frequency probe is recommended for 2-3 cm depth and using low frequency probe is recommended for 4-5 cm depth. disclosure: dr. lee has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. imaging 100-year-old fetuses sabah servaes, children's hospital of philadelphia; teresa victoria, ann johnson, sandra kramer, richard markowitz, diego jaramillo purpose or case report: to demonstrate normal anatomy and pathology of medical museum specimens without disturbing the specimens. methods & materials: nine fetal specimens from a medical museum were imaged with ct and mri (1.5 t and 3.0 t) when possible with the specimens in their preserving fluid and containers. results: the 9 fetal specimens are estimated to be approximately 100 years old. one specimen is from the first trimester, seven are from the second trimester, and one is from the third trimester. normal anatomical structures at various stages of development including the brain (and varied sulcation pattern), lungs (lobar anatomy), and skeletal structures (several developmental features such as the ossification centers, perichondrial structures, and marrow cavitation) can be evaluated using imaging without causing harm to the specimens. pathologic entities including anencephaly and sirenomelia are also evaluated demonstrating features of these entities. conclusions: imaging historical fetal specimens provide an opportunity to evaluate normal developmental changes and pathological entities and also to gain a better understanding of the museum pieces without damaging the museum specimens. pediatric ct interpretations: does a tertiary care radiologist make a difference? wendy d. ellis, monroe carell jr. children's hospital at vanderbilt university; sumit pruthi, david johnson, christopher eakins, chang yu, marta hernanz-schulman purpose or case report: to determine whether a substantive difference exists between the pediatric imaging reports of community radiologists and reinterpretations by tertiary care radiologists at a free-standing children's hospital; and how those interpretations were related to the final diagnosis. methods & materials: this retrospective review examined the computed tomography (ct) reports of all pediatric patients referred to our tertiary care children's hospital over a 17 month period (1/1/2009-5/31/2010). the outside reports and the requested second interpretation reports were compared and their content categorized as "agreement" vs. "disagreement: major or minor". a representative sample of 92 major disagreements in which there was reliable followup information was correlated with the final diagnosis to determine if there was added value provided by the reinterpretation. results: ct scans from 732 patients were submitted for reinterpretation. disagreements were found in 301/732 cases (41.1%); with 50.5% (152/301) classified as major disagreements. among the 427 neurologic cases, major disagreements occurred in 53 patients (12.4%) and minor disagreements in 92 patients (21.5%). among the 305 body scans, major disagreements occurred in 99 cases (32.5%) and minor disagreements in 57 cases (18.7%). in the cohort of cases reviewed for final diagnosis, the second read interpretation was more accurate in 90.2% of cases with a p-value of <0.0001 (neurologic 84.4%, p0<0.0001; body 95.7%, p0<0.0001). conclusions: in our review, discrepancy rates between community and tertiary care radiologists in interpretation of pediatric ct scans were substantial, with discrepancies occurring in more than 40% of cases. further review of the cases for final diagnosis, showed that a significant number of the tertiary care interpretations were more accurate. possibilities that may account for this discrepancy include subspecialty training and elapsed time since performance of the study, which might provide additional clinical data in some cases. diagnostic ct scans performed at outside institutions should not be repeated considering added radiation burden to the child and additional expense. our data indicates there is added value to the reinterpretation which impacts the accuracy of the report (as assessed by the final diagnosis), and should be recognized by payors as integral to optimal patient care. ionizing radiation exposure from radiography in the neonatal intensive care unit-per-patient cumulative effective doses amaya basta, radiology and biomedical imaging, ucsf; jesse courtier, john mackenzie purpose or case report: to better understand the levels of exposure to ionizing radiation for infants in the neonatal intensive care unit (nicu). we retrospectively collected the number and types of radiographs performed per infant in our nicu by searching our radiology information system database over a five-year period. we focused on the most common examinations (98% of all radiographs) and assigned each an estimated equivalent dose based on published literature: chest and abdomen021.3 micro sieverts (μsv), one-view chest013.3 μsv, abdomen013.5 μsv, twoview chest026.6 μsv, two-view abdomen027 μsv. we then calculated a cumulative equivalent dose (ced) for each infant based on the number of each type of examination they received. descriptive statistics were generated to depict the distribution of number of examinations and ced. results: over five years, 2,626 infants cared for in our nicu received at least one radiograph of the chest and/or abdomen. the number of examinations obtained on these infants was 9.6, 4, 1, 137 (mean, median, minimum, maximum). the 1st quartile was 1 and the 3 rd quartile was 11 examinations. the cumulative equivalent dose these infants received was 157.9, 61.2, 13.3, 2, 092.2 μsv (mean, median, minimum, maximum) . the 1st quartile was 21.3 and the 3 rd quartile was 61.2 μsv. two hundred infants (7.6% of the study population) received a ced of over 500 μsv. conclusions: descriptive statistics provide a valuable assessment for the broad range of radiation that infants receive in the nicu. although the distribution is skewed towards a low level of exposure, a subset of patients (7.6%) received a ced of over 500 μsv. identification of factors that cause infants to enter this group will be important for future dose reduction strategies. poster #: cr-001 congenital cardiac fibroma: a case report earic bonner, meharry medical college, ebonner07@email. mmc.edu; seth crapp, david parra purpose or case report: a 5-week-old male presented to his pediatrician with a ii/vi systolic ejection murmur along the left sternal border. he had mild tachypnea without cyanosis. his oral intake was adequate with no evidence of failure to thrive. he was referred to a pediatric cardiologist who performed an ecg and a transthoracic echocardiogram. the ecg showed normal sinus rhythm at 135 beats per minute with no abnormalities. the transthoracic echocardiogram showed a 25 x 25 x 14 mm homogeneous mass originating from the anterior free wall of the right ventricle, and mild dilation of the right ventricle. mild dynamic subpulmonary stenosis and a secundum atrial septal defect were also noted. although the murmur was significantly louder at one month follow-up, a repeat echocardiogram did not reveal any increase in the size of the mass. at 2 months of age, a cardiovascular magnetic resonance imaging (cmri) study under general anesthesia was performed. cmri revealed a 16 x 21 x 22 mm cardiac tumor that was causing narrowing of the right ventricular outflow tract. the tumor was hypointense on t2-weighted imaging and hyperintense on t1weighted imaging, with positive delayed enhancement. these findings, along with the size and location of the mass, are consistent with a diagnosis of a cardiac fibroma. chest mra, that was also performed, showed normal extracardiac vascular anatomy with no evidence of peripheral branch pulmonary stenosis. cardiac fibromas do not usually increase in size; however, the concern is the child's risk of arrhythmias. frequent holter monitoring was recommended for this patient. considerations were also made for an electrophysiology study in the next 1-2 years to determine the risk of ventricular ectopy. at that point, the patient can be assessed for the possibility of resection of the fibroma. purpose or case report: treatment of pulmonary atresia is complex and demands intricate solutions. one solution is the creation of a conduit between the right ventricle and the main pulmonary artery. the lifespan of these conduits is limited by progressive occlusion over time, which can be treated with endovascular stent placement in lieu of surgical re-intervention. however, these stents are at high (40%) risk for fracture, typically at the stent waist. the radiologist should be aware of this complication, as they may be the first to identify it on chest radiograph. the purpose of this electronic poster is to familiarize radiologists with this entity by presenting 3 cases of stent fracture and migration. methods & materials: over a 6 month period, we identified three children with rv-pa stent fractures and associated stent migrations on chest radiography. imaging analysis was focused on the appearances of these fractured stents. patient management and outcomes were reviewed. results: three children, 2 males, 1 female (ages 4, 3, and 3 years) were found to have asymptomatic rv-pa conduit stent fractures with fragment migration. one chest xray was performed in the er for fever and cough; one was pre-op for gi surgery; one was done to confirm abnormal findings seen on a routine cardiac echo. the time between stent placement and fracture detection ranged from 1 to 22 months. two patients had stent fractures and embolizations to the right ventricle that required open surgery to remove stent fragments. the third patient had embolization to both pulmonary arteries, but did not require treatment. all patients did well. conclusions: stent fractures and migrations are a relatively common complication of rv-pa conduit stent placement. pediatric radiologists need to be aware of this complication in order to provide value-added interpretations. purpose or case report: we describe the case of a 23 week stillborn fetus with a 5.5 cm diameter craniopharyngioma detected by ultrasonography. a g1p0 woman in her third decade had ultrasonographic examination showing hydrocephalus, polyhydramnios and an intracerebral mass. the nature of the mass was uncertain and intracerebral hemorrhage was considered. the pregnancy was terminated at 23 weeks gestation. at postmortem examination the decedent was a 650 g male fetus with a head circumference of 24.5 cm and a crown-rump length of 21.8 cm. anterior and posterior fontanelles appeared large. no other external abnormality was found. the placenta was unremarkable and cytogenetics on placental tissue showed a normal male karyotype. examination of fetal viscera was remarkable for mildly underweight adrenal glands (0.75 g, expected 1.5 g) and hepatomegaly (66.4 g, expected 21.7 g). intracranial csf was increased in volume. there was a suprasellar 5.5 cm diameter somewhat gritty, but smooth-surfaced tumor. the brain and tumor together weighed 135 g. the floor of the cranium and sella turcica were grossly normal. histologic examination of the tumor showed an adamantinomatous type craniopharyngioma with characteristic epithelium, stellate reticulum, focal keratinizing squamous epithelium and calcification. pre-and postnatal mri of caudal regression syndrome claire b. beaumont, md, university of arkansas for medical sciences, cbbeaumont@uams.edu; nafisa k. dajani, leann e. linam purpose or case report: caudal regression syndrome is a rare form of caudal dysplasia characterized by a spectrum of findings including agenesis of the lumbosacral vertebra, multiple orthopedic deformities in the lower limbs, as well as anomalies of the gastrointestinal and genitourinary tracts. the mechansim of caudal regression syndrome is not completely understood but is believed to be secondary to a defect in the induction of caudal elements. mri is a valuable tool for identifying the specific anomalies involved with caudal regression syndrome on a case-by-case basis. the following is a case from our institution which includes both pre-and postnatal mri. unsuspecting tuberous sclerosis diagnosed on neonatal cranial ultrasound vikas menghani, md, pediatric radiology, women's and children's hospital, drvikasmenghani@gmail.com; puneet gupta, richard thomas, vaseem iqbal, jan najdzionek. purpose or case report: tuberous sclerosis (ts) is a rare autosomal dominant genetic disorder causing hamartomatous proliferation in number of organ systems. because the classical triad of epilepsy, mental retardation and adenoma sebaceum is not commonly seen on clinical examination, imaging plays a central role in the diagnosis and treatment of tuberous sclerosis. central nervous system features of ts include subependymal nodules, cortical tubers, subependymal giant cell astrocytoma, white matter bands and cysts. in patients with ts, cerebral involvement in the form of subependymal nodules is seen in 95% to 100% and white matter abnormalities are noted in 40% to 90% of cases. knowledge of expected radiological features is thus important in making the correct diagnosis. recent studies have indicated that earlier appearance of brain lesions indicate a greater risk of mental retardation and a more severe clinical course. we present a case of a 23-day-old neonate who was referred to us with concerns for hydrocephalus. the cranial ultrasound demonstrated multiple echogenic subependymal nodules of varying sizes and mild asymmetry of the ventricles. the differential diagnosis included ts, torch infections, and x-linked subependymal heterotropia. areas of increased echogenicity were noted within the white matter of the left frontal lobe, which favored ts. subsequently, an mri was performed to validate these findings and assess for additional white matter lesions. the mri showed classic manifestations of ts that included periventricular lesions and streaky, linear, wedge-shaped hyperintensities on flair imaging. a noncontrast ct scan was also performed which revealed classic calcified subependymal nodules. cardiac rhabdomyoma and renal angiomyolipoma are the other recognized manifestations of ts and were respectively excluded by subsequent echocardiogram and renal ultrasound. pyloric atresia with epidermolysis bullosa: fetal mri diagnosis with postnatal correlation arnold c. merrow, md, radiology, cincinnati children's hospital medical center, carl.merrow@cchmc.org; jason s. frischer, anne w. lucky purpose or case report: pyloric atresia (pa) is an uncommon disorder, accounting for 1% of congenital gastrointestinal atresias. up to 55% of cases have associated anomalies, the most common of which is epidermolysis bullosa (eb). prenatal findings have been reported sonographically for each of these anomalies, both in isolation and in the rare case of association. a case of isolated pa has been reported by fetal mri. we present the first reported case of pa with eb diagnosed by fetal mri with corroborative postnatal imaging and surgical findings. the mother of this child was initially referred to the fetal care center of cincinnati at 21 weeks gestation for a possible myelomeningocele diagnosed by prenatal ultrasound at an outside facility. these ultrasound images were not available for review at the time of our workup. a fetal mri was the first study to be obtained at our institution. the mri showed no myelomeningocele or brain anomalies. the stomach was moderately enlarged throughout the exam and did not empty. subjective polyhydramnios was also noted. no duodenal dilation was seen, and there was minimal fluid in the distal bowel loops. this constellation of findings raised concern for pyloric atresia, resulting in a careful search for any sign of epidermolysis bullosa due to a known association of these disorders. prominent debris was seen layering dependently in the amniotic fluid and in the dilated fetal stomach, and the external ears were abnormally small and misshapen. the pa-eb association was proposed as the underlying diagnosis based on our mri findings. it was also postulated that skin blistering over the lumbosacral spine at the time of the prior outside ultrasound could have mimicked a myelomeningocele, thus prompting the referral to our center. at delivery, the baby had numerous skin defects, and the ears were malformed. an abdominal radiograph obtained after nasogastric tube placement and air injection showed no gas beyond the stomach. a pyloric ultrasound showed a distended stomach without a patent pyloric channel to the duodenal bulb, consistent with pyloric atresia. a skin biopsy confirmed epidermolysis bullosa, and the patient underwent a resection of the pa with gastroduodenostomy. the baby subsequently expired less than two weeks later, most likely due to sepsis based on wound cultures and autopsy results. our case demonstrates the ability of fetal mri to diagnose this rare condition and highlights the key imaging manifestations of the pa-eb association. disclosure: dr. merrow has indicated that he is an author for amirsys and receives a royalty accordingly. purpose or case report: we demonstrate a case where the changing position of the contrast filled appendix lead to the diagnosis of malrotation, with review of the embriology of intestinal rotation. a newborn preterm female presented with a golf ball sized umbilical mass, that reduced by itself, thought to represent an umbilical hernia vs omphalocele. she was unstable to undergo an upper gi exam under fluoroscopy, therefore a limited contrast study was performed at bedside and was inconclusive for malrotation. subsequent nicu radiographs showed changing position of the appendix filled with residual contrast, visiting all quadrants of the abdomen in a random pattern over a few days period. this confirmed our suspicion for malrotation. it is well know that in malrotation the position of the cecum can be variable, most commonly located in the right upper quadrant or left lower quadrant. to our knowledge it has not been described yet that the changing position of the appendix can lead to the diagnosis of malrotation. through this case we display the embriology of the intestinal rotation and the radiologic signs of malrotation. poster #: cr-008 mr imaging patters of liver transplant complications in the pediatric population edward richer, md, emory university, richerej@gmail. com; adina alazraki, jonathan loewen purpose or case report: pediatric liver transplantation is a relatively common surgery, with more than 500 transplants in the united status annually. the spectrum of post transplant complications has been previously described, primarily utilizing ultrasound. as mri has become a more widely used technique in pediatric imaging, and ultrasound findings may be non-specific, knowledge of mr imaging patterns is an important adjunct in the post-transplant evaluation. we present a spectrum of complications, including vascular, biliary, hepatic parenchymal, and systemic complications. methods & materials: using an electronic record system, we identified pediatric patients with prior liver transplantation who subsequently underwent abdominal mri at our institution and were found to have a post transplant complication. patient management and outcomes were reviewed. results: our review of a subset of the available patients shows vascular complications to be the most commonly encountered abnormality at our institution, including hepatic artery stenosis/thrombosis, and portal vein stenosis/ thrombosis, cavernous transformation of the portal vein. biliary complications were relatively common, including bilary stenoses and bilomas. hepatic parenchymal and systemic complications, such as ptld, were less common. we demonstrate the mr imaging patterns of these complications. conclusions: pediatric liver transplantation is a relatively common surgery, and the mri appeance of post transplant complications warrants illustration as abdominal mri becomes more widely used in pediatric imaging. we present a pictorial review of common patterns of complication. imaging of progressive familial intrahepatic cholestasis (pfic) matthew d. dobbs, md , radiology, vanderbilt university medical center, matthew.dobbs@vanderbilt.edu; sumit pruthi, stephanie e. spottswood purpose or case report: progressive familial intrahepatic cholestasis (pfic) is a relatively rare pediatric liver disease due to a genetic mutation (abcb11 gene on chromosome 2q24-31) in a bile salt export protein causing cholestasis leading to chronic inflammation within the biliary system. the diagnosis is made clinically with detection of a low ggt in the face of an elevated bilirubin and alkaline phosphatase. genetic testing confirms the diagnosis. one of the 3 subtypes, type 2, was shown in 2006 to be highly related to the development of hepatocellular carcinoma. the vast majority in children in this study developed hcc at less than 2 years of age. radiological contribution to the management of these chronic liver disease patients is to perform surveillance imaging to detect hcc. due to the rarity of this condition, almost no reports exist in the radiological literature describing the imaging features or management of this condition. our presentation will review the imaging findings in our small population of pfic type 2 patients on us, ct, and mri. we will also review suggested surveillance imaging techniques and imaging algorithms. renal rhabdoid mimics wilms tumor vikas menghani, md, pediatric radiology, women's and children's hospital, drvikasmenghani@gmail.com; paul montgomery, jan najdzionek, vaseem iqbal purpose or case report: in the past most pediatric renal tumors have been classified together under the umbrella of wilms tumor. however, over the last decade with advancement in imaging, several distinctive imaging features specific to renal tumors have been recognized which aid in their classification as being distinct pathologically. we present a case of rhabdoid tumor where in the primary tumor arose from the kidney. it had classical imaging features of wilms tumor. we want to highlight that even with the most sophisticated imaging techniques, specific renal tumors cannot always be diagnosed with preoperative imaging and how this alters the management and prognosis for child with a renal mass. in our case, the postoperative findings, pathology and immunohistochemical techniques confirmed a rhabdoid tumor. differentiation of these two tumors is essential since in patients with rhabdoid tumor survival is poor with 4-year overall survival rates of 42% for stages i and ii and 16% for stages iii, iv, and v. on imaging, there are several features that suggest the diagnosis of rhaboid tumor. these include subcapsular fluid collections, linear calcifications outlining tumor lobules, and vascular invasion. also, a pertinent feature of rhabdoid tumor due to its aggressive nature is the presence of lung metastasis (83%) and synchronous malignant brain lesions (15%). these findings were not present on our case, which led us in formulating a diagnosis of wilms. our patient is unusual in the fact that the local renal findings and absence of metastasis, synchronous malignant lesions, and vascular invasion led us to an incorrect diagnosis of wilms tumor. in conclusion, we would like to stress that diagnosis of rhabdoid tumor of the kidney on imaging presents a challenge because of its imaging similarity to wilms tumor. ectopic ureters in young infants: mru findings shin-lin shih, md, department of radiology, mackay memorial hospital; yi-fang chen, chun-chao huang, fei-shih yang purpose or case report: to localize the terminations of ectopic ureters by mri methods & materials: mr urography (mru) was conducted in four female patients with hydroureter and a suspected ectopic orifice. mr imaging was performed with a 3 t mr scanner (achieva; philips). the imaging protocol mainly consisted of a single-shot t2-weighted turbo spin echo sequence with a slice thickness of 4 mm and multiplanar reformations. the ages of the four patients were 1 day, 3 days and 2 months (for two). the latter two patients presented with urinary tract infection. the newborn patients presented with abnormal prenatal examination. the pertinent findings and descriptions of a variety of renal anomalies were described. results: the locations of the ectopic ureters were two in the vagina, one in the uterus and one in the bladder neck. the associated renal anomalies were a right duplex kidney in four, a left duplex kidney in one, a left ectopic dysplastic kidney in one and vesicoureteral reflux in one (confirmed by vcug). conclusions: mru may demonstrate the exact point of termination of an ectopic ureter and also the associated renal anomalies. poster #: cr-012 acquired polycystic kidneys in neuroblastoma survivors richard bellah, , radiology, the children's hospital of philadelphia, bellah@email.chop.edu; bernard kaplan, camilo jaimes, yael p. mosse, jill p. ginsberg, kevin e. meyers purpose or case report: neuroblastoma (nbl) is the most common extracranial solid malignancy of childhood. with current therapy, the prognosis and long term survival of patients affected by this condition has dramatically improved. nevertheless, the treatment for nbl may account for some complications further in life. in patients with neuroblastoma, acute renal failure can occur usually as a result of a thrombotic microangiopathy associated with bone marrow transplantation. in addition, end-stage renal disease has been reported in long-term survivors of nbl. this exhibit describes and illustrates the first case series of five patients with treated nbl in whom the imaging features of polycystic kidney disease (pkd) developed over time, and in some cases, as progressive renal failure ensued. methods & materials: medical and imaging records were reviewed (irb approved) of patients with treated nbl in whom pkd became apparent during the course of followup imaging. results: five patients displayed findings of pkd on us and/or ct. three of the five patients (where images were available) had normal renal imaging at time of nbl diagnosis. the mean age at nbl diagnosis was 2.4 years (range 1.3-3.3 yr). the mean age at time pkd was detected was 14.6 years (range 8-18 yrs). none of the patients had a family history of pkd, or had previously undergone dialysis. all patients received chemotherapy and total body irradiation prior to bone marrow transplantation. four patients survived nbl therapy but eventually developed end-stage renal disease. conclusions: an association between acquired pkd and nbl has not been previously reported. the etiology of this observation is still unclear, but a toxic insult is likely to account for the renal changes. further research is needed to establish the epidemiology, prognosis, and etiology of this association. abnormal migration of the retention anchor suture in a case following gastrostomy tube insertion surendra narayanam, mbbs, dmrd, dnb, division of image guided therapy, department of diagnostic imaging, the hospital for sick children, nrssbabu@gmail.com; joao amaral, luke toh, bairbre connolly, vicente deoliveira, dimitri parra purpose or case report: during percutaneous gastrostomy tube placement, retention anchor suture(s) are deployed into the stomach to tack the anterior gastric wall to the abdominal wall. in our practice the thread of the retention anchor suture is cut at 14 days and the metallic portion passes pre rectum. we report an interesting and very rare migration of the metallic portion of the retention anchor suture in post-primary gastrostomy tube insertion. an 8-month-old girl, with a mitochondrial disease and severe hypotonia underwent percutaneous gastrostomy placement. during the procedure the retention anchor suture thread snapped and the metallic portion of the suture remained within the stomach. day1 post procedure, the child became uncomfortable, so a gastrostomy tube check was performed. the suture was not visible in the abdomen on abdominal x-ray or fluoroscopically. on close review of the images, the suture was found projected over the distal esophagus. initial impression was the anchor suture had refluxed into the esopahgeal lumen. careful attempts were made to remove it along with the nasogastric tube, from above under fluoroscopic control. however on withdrawal of the nastogastric tube, the retention anchor suture moved enbloc with the nasogastric tube. once removed the retention anchor suture was confirmed to be within the nasogastric tube. this case illustrates the importance of examining the chest x-ray carefully before assuming a retention anchor suture has passed. to understand the appropriate post procedural radiographic workup and its technique for timely diagnosis. 3. to learn the potential complications of delayed diagnosis. pediatric retroperitoneal synovial sarcoma ahmad aouthmany, university of toledo medical center, ahmad.aouthmany@utoledo.edu; asif abdullah purpose or case report: pediatric synovial sarcoma most commonly affects the extremities, especially the lower thigh and knee region; other primary sites such as the retroperitoneum have been only infrequently reported. we report an extremely rare case of a retroperitoneal synovial sarcoma masquerading as retroperitoneal hematoma in a 16-year-old white female with non-traumatic back pain and non-contrast enhanced ct findings of right quadratus lumborum and psoas region presumed hematoma. coagulation studies revealed factor xi deficiency also known as hemophilia c. however, on follow-up imaging, the presumed retroperitoneal bleed persisted and a subsequent mr examination revealed a solid enhancing mass. ct, mr, and fdg-pet findings as well as a brief histopathology are discussed. our case is rare in the regards that the tumor occurred in an uncommon retroperitoneal location in a pediatric patient and was mimicking a retroperitoneal hematoma which posed a significant diagnostic challenge. despite a rare entity, synovial sarcoma among other sarcomatous lesions maybe considered in the differential consideration of a spontaneous retroperitoneal hematoma even in hemophiliac patients. longitudinal bracket epiphysis michael jubang, geisinger, mjjubang@geisinger.edu; farzad sedaghat, william j. malone, george wu, william mirenda purpose or case report: longitudinal bracket epiphysis is a rare anomaly with multiple synonyms such as delta bone, triangular bone, and congenital angular deformity. the purpose of this case report poster is to discuss an 11-month-old male born with an adducted right great toe with a broad nail and a notch in the center of the distal phalanx. the review will discuss radiographic findings, the natural progression of the disease, the treatment options, the mri findings used for pre-surgical planning, and associated pathology. whole body mri in pediatric non oncologic diseases: pictorial review ramy el jalbout, md, radiology, chu sainte justine, ramy.jalbout@yahoo.com; vijay moorjani purpose or case report: with the advances in scanning techniques and the scanning sequences, the role of wbmri is expanding. mri has a great role in the pediatric population owing to its inherent advantages namely lack of radiation, high tissue specificity, and high diagnostic yield at the level of the entire body under a single sedation. unlike the application of wbmri in the assessment of metastasis and bone marrow involvement in leukemia, its role in systemic diseases is yet to be further investigated. certain diseases such as crmo are very often multifocal. the extent of osteonecrosis in patients on steroids, dermatomyositis and the lesions related to child abuse are very often wide spread in the skeleton. we intend to present some of the findings of these pediatric systemic and multifocal diseases on wbmri. chronic relapsing multifocal osteomyelitis (crmo): crmo can be acute or chronic and is multifocal. the abnormality manifests as high signal intensity. wbmri can guide for the best site for biopsy and provides monitoring for response to treatment. osteonecrosis: only few small studies evaluated the usefulness of wbmri in the diagnosis of both the symptomatic and asymptomatic sites of osteonecrosis in all patients on steroid therapy. wbmri is more sensitive than conventional radiographs. the abnormalities are typically geographical areas of high stir signal intensity. myopathies: wbmri has also the role of detecting the extent of idiopathic inflammatory myopathies such as dermatomyositis in the entire skeleton. child abuse: wbmri has a low sensitivity for the highly specific fractures that are pathognomonic for child abuse. conclusions: wbmri is a useful examination in the pediatric patient that is radiation free, quick and allows imaging of the entire body. it is an adjunct to dedicated mris to look for multifocality and extent of systemic diseases such as crmo, osteonecrosis in patients on steroids and dermatomyositis. it has a great potential as a screening examination but at the same time can detect both the symptomatic and the asymptomatic lesions in the bone marrow and muscles that are otherwise not seen on conventional radiography. it also allows guidance for biopsy and monitors response to treatment. mobile "cerebroliths" in hemihydranencephaly: a case report usha d. nagaraj, md, the ohio state university medial center, usha.nagaraj@osumc.edu; brent adler purpose or case report: hydranencephaly is a congenital central nervous system disorder manifested by the replacement of the cerebral hemispheres with a thin membranous sac filled with cerebrospinal fluid and necrotic debris. hemihydranencephaly is an extremely rare brain condition in which the vascular anomaly is unilateral, with fewer than 10 cases previously reported in the literature. this is a case of a 4-month-old male who presented to the ophthalmologist for evaluation of possible leukocoria of the right eye. the patient had a history of a difficult vaginal delivery that required forceps delivery with possible associated trauma to the right eye. dilated fundoscopic exam revealed retinal calcifications. this caused a clinical concern for retinoblastoma and ct and mri of the orbits were obtained. ct demonstrated profound dilatation of the left lateral ventricle with only a thin rim of cortex surrounding it. there was some midline shift to the right with mild dilatation of the right lateral ventricle. the thalami and brainstem were spared. there were multiple soft tissue bodies that layered in the dependent portion of the left lateral ventricle, which were isodense to grey matter. mri revealed similar findings consistent with hemihydranencephaly involving the left cerebral hemisphere. there were multiple round soft tissue masses that measured up to 1 cm in size that layered posteriorly in the left lateral ventricle. these masses were isointense to grey matter on t2 and hyperintense on t1. when the patient was placed with his head turned to the left, these masses moved to the dependent portion of the left lateral ventricle. the orbits were normal on both ct and mr. these soft tissue collections are presumed to be mobile collections of infarcted brain tissue. this unusual appearance has not been described in the radiology literature. we review the ct and mr findings and review the relevant literature. purpose or case report: citrullinemia type i is a rare inborn error of urea cycle metabolism resulting in hyperammonemia. in the classic form, the newborn presents with poor feeding, vomiting, progressive lethargy and signs of increasing intracranial pressure 3-7 days after birth, rapidly progressing to apnea, coma and death if left untreated. we present a case of a term infant who presented to the hospital on the 5th day of life with a typical history of poor feeding and profound hypotonia. upon admission he had multiple episodes of apnea and hemodynamic instability prompting intubation and intensive support. laboratory evaluation revealed multiple abnormalities, most notably, hyperammonemia (910umol/l) and elevated citrulline (>800umol/l). mri of the brain performed on the 7th day of life showed findings consistent with term hypoxic ischemic encephalopathy with restricted diffusion in bilateral rolandic cortex and subcortical white matter, bilateral caudate heads and lenticular nuclei, bilateral insular cortex, and bilateral cerebral peduncles. the genu of the corpus callosum, bilateral deep frontal white matter, and the left parietal white matter also demonstrated restricted diffusion suggesting infarction secondary to thrombosis of deep intramedullary veins. an area of restricted diffusion in the right parietal cortex was suspicious for superficial venous infarct. review of the literature reveals that this case of neonatal citrillunemia has unique mri findings. while our patient had diffusion changes with some shared similarities to the previous two cases in the literature, there are also findings consistent with deep intramedullary venous thrombosis and infarction. poster #: cr-020 duplicated internal auditory canal: a rare anomaly of the temporal bone ahmad aouthmany, university of toledo medical center, ahmad.aouthmany@utoledo.edu; asif abdullah purpose or case report: duplicated internal auditory canal (iac) is a rare anomaly of the temporal bone, which is usually associated with sensorineural hearing loss. only a few cases have been previously described in literature. we describe an extremely rare case of duplicated right internal auditory canal in a six month-old patient with a history of down syndrome. a six month-old male with trisomy 21 presented with profound bilateral sensorineural hearing loss. the patient failed the newborn hearing screening tests. past medical history was unremarkable for recurrent ear infections. on focused physical examination, the auricles were normal appearing. external auditory canals were patent bilaterally revealing clear and translucent tympanic membranes. patient did not reveal a facial palsy. subsequently, a high resolution computed tomography (hrct) of the temporal bone was performed. duplicated appearance of the right internal auditory canal with separation of facial and vestibulocochlear segments was noted. the facial nerve canal demonstrated normal caliber while there was significant narrowing of the cochlear canal near the fundus. significant stenosis of the vestibulocochlear segment of the duplicated iac was identified at the porus acousticus. dehiscent right posterior semicircular canal was also seen. an enlarged right vestibule was also noted. a single iac was identified on the contralateral side with significant stenosis at the porus acousticus. high-resolution magnetic resonance imaging of iac was recommended which revealed normal appearance of the bilateral cochlear and vestibular nerves. duplication of the iac is an extremely rare anomaly involving a redundant osseous canal extending from the cerebellopontine angle through the otic capsule bone toward the labyrinth or cochlea. a duplicated iac may or may not be associated with congenital sensorineural hearing loss secondary to aplasia or hypoplasia of the vestibulocochlear nerve. to evaluate for structural abnormalities that may preclude cochlear implantation, it is important to evaluate pediatric patients with sensorineural hearing loss radiologically. although hrct is the best imaging modality for evaluation of osseous iac, the iac contents are best viewed on mri in oblique sagittal planes of the iac using a 3-d volumetric steady state sequence. neuroimaging in hemiplegic migraine: cases and review of the literature nicholas v. stence, md, children's hospital colorado-radiology, nicholas.stence@childrenscolorado.org; sita kedia, john a. maloney, jennifer armstrong-wells, timothy bernard purpose or case report: hemiplegic migraine (hm) is a rare variant of migraine with aura. it is characterized by a motor deficit lasting up to 24 h that is fully reversible. little neuroimaging data for hm exists in the literature. we report our experience with two pediatric cases of hemiplegic migraine. we also review published cases of pediatric hm with abnormal findings on neuroimaging. methods & materials: cases 1 and 2 presented to our institution with severe headache (ha), acute right-side weakness, aphasia, and altered mental status (ams), which did not resolve after 24 h. magnetic resonance imaging (mri) and genetic testing are reviewed for these cases. the literature was reviewed for pediatric cases with neuroimaging changes during hm attacks. results: initial mri, including diffusion-weighted imaging (dwi), was negative in both patients within 24 h of onset. repeat mris at 93 h (case 1) and 75 h (case 2) were both positive for mild hyperintensity on trace diffusion images, and corresponding reduced diffusion on adc maps, involving regions of the cortex and juxtacortical white matter in left middle cerebral artery distributions. these findings completely resolved at 3 months in both cases. mr angiograms (mra) were negative in both cases. case 1 had a family history of migraines and was found to have an unreported mutation in atp1a2 gene at a highly conserved location in vertebrates. case 2 had a family history of hm and was found to have an indeterminant mutation in the cacna1a gene. infectious, metabolic and hypercoagubility work up was negative. case 1 required inpatient rehabilitation and at 1 year follow up was requiring speech therapy. case 2 resolved completely. in the literature, 6 cases of hemiplegic migraine with neuroimaging changes were reported. all cases had prolonged hemiplegic migraines (symptoms>24 h) and showed cerebral edema with or without restricted diffusion. conclusions: all eight hm cases in the literature with abnormal findings on neuroimaging had prolonged attacks. mris for our two cases and two cases reported in the literature were initially normal at admission. mild swelling and restricted diffusion developed in our two cases after 24 h, and resolved on follow up mris. subtle findings on diffusion and t2 imaging may lag behind the clinical picture in hm, therefore serial neuroimaging may be useful in individuals with prolonged symptoms. most cases eventually show resolution clinically and on mri. correlation of neurosonographic anatomy with matching mr scan planes denise castro, hospital for sick children, denisecastro22@ gmail.com; pam rasalingham, omar islam, don soboleski purpose or case report: new high-resolution mr sequences have allowed for exquisive anatomic detail and enables reconstruction of images in any scan plane desired. this ability allows for precise matching of mr image planes with the standard oblique coronal, sagittal and axial images obtained during routine neurosonography. the purpose of this poster is to correlate the morphology demonstrated on neurosonography with the mr image, utilizing this ability in order to enhance our understanding of the neuroanatomy distinguishable on sonographic imaging. we believe this will allow a better appreciation of the subtle differences in echotexture of neuroanatomic structures which are often ignored or overlooked on neurosonography and help improve our detection of subtle sonographic abnormalies. ectopic cerebellum in the posterior cranial fossa: report of a case and review of the literature usha d. nagaraj, md, the ohio state university medical center, usha.nagaraj@osumc.edu; daniel boue, lisa martin purpose or case report: cerebellar heterotopia is a common congenital anomaly frequently encountered in the form of cell rests around the fourth ventricle. however, isolated well-differentiated cerebellar ectopia is extremely rare. of the 8 previously reported cases in the literature, only 4 have presented as a discrete, extraaxial mass and none have been described in the posterior cranial fossa. we present a case of a 5-year-old male who initially presented with persistent daily headaches. physical exam including a detailed neurologic exam was within normal limits. non-contrast computed tomography (ct) of the brain was initially performed, demonstrating no abnormalities. further work-up with magnetic resonance imaging (mri) was performed, which revealed a well-defined, extra-axial mass superior to the cerebellum and inferior to the tentorium, immediately beneath the vein of galen. the mass was isointense to grey matter on t1 and t2 sequences and there was no significant enhancement on post-contrast images. there was mass effect on the vermis and the cerebellar tonsils were displaced 3 mm below the foramen magnum. neurosurgery was consulted and the mass was removed for diagnosis and treatment of the patient's symptoms. the mass was easily identified intra-operatively and gross total resection was accomplished successfully. pathologic analysis of the mass revealed well-formed cerebellar tissue without evidence of neoplasia. to the best of our knowledge this is the only case of ectopic cerebellum presenting as a discrete extra-axial mass in the posterior cranial fossa. our case shows that an extra-axial mass that parallels grey matter on all sequences can be a presentation of ectopic cerebellum. we describe the ct and mri findings, surgical and histopatholgical results and review the relevant literature. pediatric isodense acute subdural hemorrhage jeffrey s. kao, md, msee, university of kansas-wichita, run4boston@gmail.com; debbie desilet-dobbs purpose or case report: the density (attenuation coefficient) of subdural hemorrhage (sdh) in computed tomography (ct) is important in assessing the acuity of sdhs. an acute sdh is traditionally described as hyperdense and then becoming isodense in approximately 3 weeks when entering the subacute phase. in this report, we document the case of a pediatric patient with the new appearance of an acute sdh within 40 h of the prior ct that was isodense. greater than 95% of the collection was isodense, with a small focus of hyperdensity. acute sdhs are known to be isodense to gray matter in patients with anemia (wp smith, am j neurorad 1981). however, the hemoglobin and hematocrit was within normal limits. in addition, acute sdhs that are only a few hours old can have a mixed hyperdense and hypodense appearance because of uncoagulated blood before clotting takes place (j provenzale, ajr 2007) . thus, an acute sdh can have an isodense appearance in a non-anemic patient. radiologists should consider the possibility of an acute sdh with an isodense appearance, especially in case of possible non-accidental trauma where timing of an injury is important. undifferentiated sarcoma of the esophagus in an 11year-old male: case report and radiologic/pathologic correlation michael e. daniel, md, ut southwestern / children's medical center dallas, michael.daniel@utsouthwestern. edu; lisa sutton, sandy cope-yokoyama, neil j. fernandes purpose or case report: mesenchymal neoplasms of the gastrointestinal (gi) tract occur infrequently in the adult and are extremely rare in the pediatric population. the occurrence of these lesions in the esophagus is limited to a collection of case reports in the available literature. most esophageal mesenchymal tumors in the pediatric gi tract are benign leiomyomas. the vast majority of malignant mesenchymal tumors in children are categorized as either sarcomas or gastrointestinal stromal tumors (gist). we report a case of a high grade undifferentiated sarcoma of the distal esophagus in an 11year-old male. while this tumor most closely resembles a gist, the immunohistochemical profile of the lesion is not typical of any distinct mesenchymal neoplasm. a review of the literature demonstrates a single case report of a likely benign undifferentiated mesenchymal neoplasm of the distal esophagus in an adolescent. to our knowledge, this is the first reported case of an undifferentiated esophageal sarcoma in a pediatric patient. we provide radiologic and pathologic features of the above lesion, and review the typical imaging and pathologic characteristics of mesenchymal gi neoplasms. potential airway management issues in sedated children kimberly fagen, md, ms, children's national medical center, kfagen@childrensnational.org; nadja kadom, ira cohen purpose or case report: many pediatric imaging studies require sedation. it has been shown that a variety of health care professionals other than anethesiologists may provide sedation, including advanced practice registered nurses, nurse practitioners, physician assistants, fellow level trainees, emergency medicine physicians, intensivists, pediatricians and, last but not least, radiologists. moderate sedation, also called "conscious sedation", does generally not require an anesthesiologist as there is usually adequate spontaneous ventilation and no airway intervention required. however, in case of a complication during the imaging study intubation may become necessary. for patients with certain congenital or acquired conditions emergent intubation may be very difficult and should be brought to the attention of an anesthesiologist prior to inducing moderate sedation. the four "d's" is a quick way to assess potentially difficult airways that necessitate consultation with anesthesia prior to moderate sedation: dentition (incisor/tooth size, dental alignment, and macroglossia), distortion (swelling from infection, tumor, or trauma), disproportion (hyoid-chin ratio, such as with micrognathia), and dysmobility (jaw or cervical spine movement issues, i.e. trauma or atlanto-occipital instability). presence of some of these features may be an indication to consider general anesthesia for sedation; at the very least, anesthesiologist's awareness of a potentially difficult intubation adds to patient safety during moderate sedation. purpose or case report: lymphangiomatosis describes the presence of multiple lymphangiomas often with multiorgan involvement; typically bones, spleen, mediastinum and lungs. although lymphangiomatosis has been described in patients ranging from birth up to 80 years, it most frequently presents in childhood. the lesions can occur in any tissue in which lymphatics are normally found, with a predilection for neck and chest involvement. the clinical presentation is variable including pleural or pericardial effusion, hemoptysis, protein wasting enteropathy, peripheral edema, hemihypertrophy and disseminated intravascular coagulopathy. the coexistence of lytic bone lesions and chylothorax serves as an important diagnostic clue. we describe typical radiographic, ct and mri findings in the appropritate clinical setting that narrow the differential diagnosis and raise concern for this rare entity as the etiology for the patient's symptoms. we report a 12-year-old girl and 2year-old boy with pulmonary lymphangiomatosis with typical presentation and imaging findings. results: bilateral interstitial infiltrates, pericardial and pleural effusions are evident on chest radiograph. sampling of the pleural fluid demonstrates chylous effusion. ct scans of the thorax reveal diffuse smooth thickening of interlobular septa and bronchovascular bundles with extensive infiltrative involvement of mediastinal fat. osseous and splenic lesions are demonstrated both on ct and mr. differential diagnosis includes interstitial edema, lymphoma and sarcoidosis. conclusions: the natural history of pulmonary lymphangiomatosis is characterized by progressive growth and compression of adjacent structures. therapy should aim to decrease the compressive effects, to control chylous effusions, and to maintain cosmesis. the success of surgical resection is limited by inability to separate lymph collections from normal structures. characteristic clinical and radiographic presentation, chylothorax, and extrathoracic lymphatic dysfunction should prompt a consideration of lymphangiomatosis and prevent delay in diagnosis. aortic arch congenital anomalies: what the radiologist needs to know luana stanescu, radiology, seattle children's hospital, stanescu@u.washington.edu; stephen done purpose or case report: 1. review classic imaging findings in congenital aortic arch anomalies which can improve detection on radiographs and barium esophagogram 2. describe pertinent embryologic basis of the radiologic findings 3. describe correlative imaging findings on ct and/or mri in dedicated cases 4. describe common diagnostic pitfalls methods & materials: after obtaining institutional irb approval we reviewed various patients presentations with this condition and analyzed images to characterize this particular entity and it's manifestations for better definition of diagnostic criteria. results: radiographs and barium esophagogram: algorithmic approach in reviewing chest radiographs in order to improve detection of aortic arch anomalies; classic findings and common pitfalls. cross-sectional imaging (ct and mri): what the surgeons need to know before surgical repair; detection of associated cardiac anomalies. sample cases: double aortic arch, double aortic arch with complete or partial atresia of one of the arches. conclusions: major teaching points of this exhibit are: 1. review of classic features of congenital aortic anomalies on radiographs, esophagogram, ct and mri with pertinent embryologic basis 2. describe the utility of various imaging modalities in congenital aortic anomalies, emphasizing common pitfalls. cardiovascular and mediastinal imaging in children with unexpected clinical presentation shunsuke nosaka, md, radiology, national center for child health and development, nosaka-s@ncchd.go.jp purpose or case report: children with cardiovascular and mediastinal diseases can be congenital or acquired in etiology. they usually present with straightforward clinical course. in certain situation, however, some of the children show unexpected clinical presentation predominantly with those of neighboring organs such as respiratory tract, hepatobiliary system, and gastrointestinal tract. these unexpected presentations can be the cause of delay in proper diagnosis and treatment. the purpose of this exhibit is demonstrate a variety of imaging findings of cardiovascular and mediastinal diseases in children with unexpected clinical presentation. this exhibit is case based presentation of cardiovascular and mediastinal imaging in children including tips, pitfalls and lessons learned among patients presented with unexpected clinical presentation. diagnostic imaging modalities for cardiovascular disease usually consist of various combinations of plain radiography, ultrasound, ct, mr imaging, fluoroscopy, nuclear medicine, and angiography. the general concept of alara-as low as reasonably achievable-should always be utilized when radiation-producing modalities are indicated in children. the diseases included will be double aortic arch found during workup for the cause of aspiration pneumonia, unilateral pulmonary vein atresia presented with recurrent episodes of pneumonia, severe mitral regurgitation secondary to chordal rupture mimicking fluminant hepatic failure, myocarditis initially present as acute abdomen, cardiomyopathy as unusual initial presentation of neuroblastoma, and thymolipoma mimicking gradual development of cardiomegaly. conclusions: it is important for radiologist to be familiar with imaging findings of cardiovascular and mediastinal diseases in children with unexpected clinical presentation. cardiac embryology made easy: a novel teaching approach using claymation andrew phelps, children's hospital boston, aphelpsmd@ gmail.com; purpose or case report: congenital heart disease can be an intimidating subject for radiology residents, and cardiac embryology is key to its understanding. however, this can be an equally intimidating topic to teach! various diagrams and animations are available in textbooks and online, but much like advanced origami, many of these resources suffer from being visually too complex for the first-time learner. to overcome this teaching obstacle, i created my own cardiac embryology animations using modeling clay and incorporated them into a comprehensive didactic lecture on congenital heart disease. methods & materials: cardiac embryology animations were created using modeling clay, a digital camera, and microsoft powerpoint. surface and cross-sectional views were generated, depicting the key events in cardiac embryology: heart tube formation, cardiac looping, chamber division, truncus arteriosus division, and pulmonary venous connection. example models are shown in figure 1 . results: in this lecture, the animations are presented alongside actual embryonic heart photographs. the lecture then uses the embryology knowledge as a basis to explain the common congenital heart diseases and their mri appearances. examples of septal defects, ventricular hypoplasia, and transposition of the great arteries are presented, among others. conclusions: understanding cardiac embryology is required in order to approach congenital heart disease in a logical fashion. modeling clay animations are a cheap and easy way to simplify this complex topic. arterial tortuosity syndrome: an introduction to the clinical and radiologic manifestations in the pediatric population neal desai, umkc som, neal540@gmail.com; suchit patel, ayushi gupta, marius hubbel, doug rivard purpose or case report: 1. to describe the clinical findings of arterial tortuosity syndrome and give a brief discussion of the disease process. 2. to describe the radiologic manifestations of arterial tortuosity syndrome. 3. to give a brief discussion of loeys-dietz syndrome-a disease with similar arterial findings, but with unique molecular characteristics from arterial tortuosity syndrome. 4. to use this knowledge to help establish the diagnosis and reduce mortality. methods & materials: arterial tortuosity syndrome overview • epidemiology • molecular basis • pathophysiology • review of signs, symptoms and presentation • brief discussion of treatment differential diagnosis of arterial tortuosity syndrome • loeys-dietz syndrome-similarities and differences radiologic findings and discussion • chest radiograph • computed tomographic angiography • magnetic resonance angiography-neck • magnetic resonance angiography-head • conventional angiography making a diagnosis • sample case report • review questions conclusions: arterial tortuosity syndrome is a rare disease whose chief manifestation is severe cardiovascular connective tissue defects. due to the nature of these defects and the significance of rapid intervention, it is important to be aware of and recognize the radiologic manifestations associated with arterial tortuosity syndrome in the presence of appropriate clinical history to help offer a better prognosis to the patient. dynamic pulmonary computed tomography for evaluation of cardiopulmonary disease shilpa v. hegde, md, arkansas childrens hospital, university of arkansas, shilpavhegde@gmail.com; s. bruce greenberg purpose or case report: dynamic pulmonary computed tomography (dpct) is a wide-detector ct technique that allows for continuous chest imaging during respiration. when combined with intravenous contrast, the technique is a unique tool for evaluation of cardiopulmonary abnormalities in children with cardiopulmonary abnormalities. the purpose of this poster is to illustrate the technique of dpct for evaluation of cardiopulmonary disease in children with congenital heart disease and persistent respiratory distress. methods & materials: methods and materials: 8 dpct exams with intravenous contrast were performed on 5 infants with a history of congenital heart disease and palliative surgery. four continuous 350 msec gantry rotations were obtained with respiratory rates set at 40/minute. the imaging was accomplished during the time of a single respiratory cycle. 80 kvp and low ma resulted in effective dose of≈1.5 msv. eight respiratory phases were reconstructed to create 3d and mpr cine loops for evaluation of cardiopulmonary abnormalities. results: cardiopulmonary abnormalities were detected in all patients. patency of sano shunt, blalock tausig shunt or patent ductus arteriosus stent was established. intimal thickening was identified in one sano shunt. hypoplastic branch pulmonary arteries were present in 3 infants and pulmonary vein thrombosis in 1 infant. left bronchomalacia was identified in four of five infants and best or only identified on the expiratory phase of respiration. left lung air trapping was present in two patients. conclusions: dpct with intravenous contrast is the ideal study for evaluation of the post-operative infant with congenital heart disease and persistent respiratory distress. the role of low-dose ct angiography in the evaluation of renovascular hypertension in children jessica kurian, md, chop, kurianj@email.chop.edu; monica epelman, kassa darge, els nijs, jeffrey hellinger purpose or case report: historically, the evaluation of renovascular hypertension has been accomplished via us and conventional angiography. based on the reported adult experience we introduced renal ct angiography (cta) for the evaluation of renovascular hypertension in mid-2006. our institution has a robust, well-established protocol, which results in reproducible, high quality images. we aim to present our imaging strategies for the evaluation of these patients and to discuss and illustrate the role of low-dose cta with 3-d imaging as a noninvasive alternative in the evaluation of pediatric renovascular hypertension. methods & materials: we used our department information system to identify pediatric patients (< 18 years of age) who had documented renovascular hypertension confirmed either by conventional angiography and/or surgery during a 5-year period. we present our protocol and discuss the indications, limitations and benefits of renal cta. ct thin slice data, obtained employing dose reduction strategies, was reviewed and reconstructed in 2d and 3d renderings. pertinent us and mr studies as well as demographic and clinical data were reviewed and recorded. several causes for renovascular hypertension were documented and relevant ct angiographic findings were selected for presentation. results: radiation dose ranged 0.58-4 msv. fibromuscular dysplasia was the most common diagnosis followed by neurofibromatosis type 1. vascular pathology included stenoses, beading, occlusions, and aneurysms. disease was noted in the extraparenchymal renal arteries in approximately 70% of the cases. the choice of the imaging modality for the investigation of renovascular hypertension in pediatric patients remains controversial. in the authors' experience, cta with 3-d imaging is a valuable, non-invasive diagnostic tool for the evaluation of pediatric renovascular hypertension. low dose protocols can reduce the radiation exposure associated with ct. this method can spare patients the complications associated with conventional angiography. fetal mri: brain, head and neck malformations-a pictorial essay sumit singh, md, children's hospital of wisconsin, sumitsingh78@yahoo.com; mohit maheshwari, teresa c. gross kelly, tushar chandra, ibrahim s. tuna, craig johnson purpose or case report: the purpose of the exhibit is to illustrate various brain, head and neck massses/vascular anomalies on fetal mri. we will also briefly discuss the normal fetal brain anatomy as seen on fetal mri. methods & materials: major indications for fetal mri include evaluation of inconclusive sonographic findings in cases of cns malformations. in our institute patients are scanned on 1.5 t mr scanner. a body surface six channel phased array coil is used to maximize signal to noise. all the scans are checked by a neuroradiologist to make sure adequate 3 plane imaging of the brain or other lesion in question were performed. 3 plane scanning of the fetal body is also performed for the laterality determination of the lesion and also screen for other congenital anomalies. results: prenatal usg is frequently inconclusive for evaluation of complex fetal brain and head and neck anomalies. most studies suggest that mri after first trimester is safe. in addition, advent of rapid mri sequences like single shot fast spin echo (ssfse) have helped in reducing scan time and motion artifacts leading to availability of diagnostic quality images. these have led to increasing use of mri as supplemental tool to further investigate inconclusive fetal sonographic findings. mri provides better anatomical delineation of these complex abnormalities. it helps in making appropriate diagnosis with high confidence and aids in appropriate obstetric and prenatal/neonatal surgical planning or intervention. this educational exhibit will illustrate few common fetal anomalies. these will include agenesis of corpus callosum, malformation of cortical development, posterior fossa malformations, ventriculomegaly, in-utero stroke, orbital abnormalities and some fetal neck masses/ vascular malformation. correlation and confirmation with the postnatal mri will also be provided for some cases. conclusions: technical and therapeutic advances have driven the development of fetal mri. it is an important adjunctive tool for prenatal imaging in those instances in which a complex anomaly is suspected by sonography, when fetal surgery is contemplated, or when a definitive diagnosis cannot be determined. it has prognostic implications and may help in optimal and timely obstetric and neonatal management. purpose or case report: this educational report will provide a review of the imaging appearance of intradiaphragmatic and subdiaphragmatic pulmonary sequestrations on fetal mri. the proposed pathophysiology, review of sequestration subtypes, and surgical management options will also be described. case examples will be provided to illustrate the fetal mr imaging findings of these variants of pulmonary sequestration that help support the diagnosis. specifically a "triangle sign" of t2 hyperintense tissue directed toward the diaphragm will be demonstrated. illustrative case examples will be placed in the context of a differential diagnosis for subdiaphragmatic masses seen on prenatal imaging. imaging signs that help make a diagnosis of these pulmonary sequestration variants and separate this entity from other lesions will be emphasized. poster #: edu-009 mri of the fetal head and neck masses alok jaju, md, mallinckrodt institute of radiology, alokjaju@gmail.com; joshua shimony, per amundson purpose or case report: fetal magnetic resonance imaging (mri) is a useful problem solving tool for abnormalities detected by prenatal ultrasound (us). masses of the head and neck region can vary from benign incidental lesions to devastating neurological lesions and life threatening tumors. we share our experience in characterizing these lesions by prenatal mri, that can have a bearing on follow up imaging, perinatal management and overall prognosis. we did a retrospective review of all fetal mri studies performed at our tertiary care children's hospital between 11/2002 and 06/2011, to identify fetuses with head and neck masses. we reviewed the maternal demographic and clinical data, prenatal ultrasound, fetal outcomes and post natal imaging (when available). results: out of the 351 fetal mri studies, 20 had dominant head and neck masses. majority were encephaloceles (9 occipital, 1 parietal). the remaining included variety of masses such as nasal glioma, teratoma (3), epidermoid cyst, hemangioma and lymphatic malformation (3) . mri played a useful role in distinguishing encephaloceles from other masses based on underlying bone defect and intracranial extension. it also helped in characterizing other masses based on location and signal characteristics. the presence and degree of airway compromise was determined. intracranial anomalies associated with encephaloceles including callosal dysgenesis, cerebral and cerebellar hypoplasias, migrational disorders and spinal anomalies were also correctly identified. conclusions: we present the prenatal mr imaging findings of a spectrum of head and neck lesions, correlating with prenatal ultrasound, postnatal imaging and clinical or pathological outcomes. purpose or case report: the immaturity of the cns in neonatal infants makes neurologic assessment difficult. neuroimaging plays an essential role in the assessment of brain injury by helping to indentify the injury and expected neurologic outcome. cranial ultrasound (us) is usually the first neuroimaging modality used since the technique is portable, does not involve radiation and can be used sequentially. magnetic resonance imaging (mri), however, is the most sensitive imaging modality for the detection of hypoxic brain injury. the goal of this presentation is to compare the us and mri performed within a 24-hour interval, and evaluate these findings to improve the interpretation of the us which is usually the first methodology used to evaluated these patients. we performed a retrospective review of the neonatal imaging studies with us and mri performed within 24-hour interval on 72 preterm and term newborns with clinical history of hypoxia-ischemia. the imaging findings of the two modalities, mri and us, were correlated with the pattern and severity of the injury and brain maturity. results: diffuse white matter abnormalities were observed in 60% of the patients by us or mri. the ultrasound identified diffuse increased echogenicity which did not show correlation with mri in 30% of patients. focal white matter abnormalities were better identified by mri on non-cavitary leukomalacia which is the most common pvl observed in premature neonates with low birth weight and the most difficult to identified using us. cavitary leukomalacia showed strong agreement in both methodologies. the mri identified 6% more cases of intraventricular hemorrhage, however, the corresponding increase in hemorrhage was of minimal clinical significance. in most cases extra axial hemorrhage was better identified by mri. conclusions: after viewing this exhibit, the viewer will gain a better appreciation and understanding of the neuroimaging characteristics of hypoxia-ischemia in us and mri, and thus improving the interpretation of the us which is usually the first imaging modality used to evaluate this patient population. purpose or case report: the most common thoracic lesions found on prenatal imaging, congenital pulmonary airway malformation (cpam), bronchopulmonary sequestration (bps), and congenital diaphragmatic hernia (cdh), usually have characteristic imaging findings previously described in detail. however, common entities presenting with atypical findings and rarer thoracic entities do occur and can be characterized by fetal magnetic resonance (mr) imaging. the purpose of this educational exhibit is to show examples of atypical presentations of common thoracic lesions and more unusual thoracic entities on fetal mr. when applicable, prenatal mr is compared with prenatal ultrasound, postnatal imaging, operative findings, or pathology. methods & materials: using a radiology information system database, the reports of all fetal mr exams at our institution from january 2005 through january 2011 were reviewed. when unusual thoracic findings were described in the report, all prenatal and postnatal images (when available) were evaluated. in the cases selected, medical charts were reviewed for operative findings and pathologic reports. results: the cases to be described, both pulmonary and extrapulmonary in location, include: hybrid lesion in a horseshoe lung, cpam extending across the midline, bilateral bps, bps located within the mediastinum, bps located within the leaves of the diaphragm, ectopia cordis and cdh as components in pentalogy of cantrell, cdh with herniation of liver into the pericardium, elongated esophageal duplication cyst, chest wall lymphatic malformation, and tight double aortic arch causing congenital high airway obstruction syndrome (chaos). conclusions: after studying this educational exhibit, the reader will be acquainted with a variety of unusual fetal pulmonary and extrapulmonary lesions, with emphasis on fetal mr. prenatal and postnatal imaging findings in megacystis-microcolon-intestinal hypoperistalsis syndrome (mmihs) mary kitazono, chop, mkitazono@gmail.com; richard bellah purpose or case report: to review the classic constellation of findings seen in prenatal and postnatal imaging of megacystis-microcolon-intestinal-hypoperistalsis syndrome (mmihs), as well as to illustrate additional imaging features that are variably seen in this syndrome. the imaging database at our children's hospital was searched for all cases of mmihs diagnosed since 2002. all available prenatal and postnatal imaging studies were reviewed in patients with a diagnosis of mmihs, and representative images are provided with a description of the findings. results: since 2002, 6 patients (5 girls, 1 boy) have been diagnosed with mmihs at our institution, including 4 on prenatal mri and us. the characteristic prenatal imaging findings include marked urinary bladder distension, bilateral pelvicaliectasis, and dilated, tortuous ureters, as well as a diminutive colon containing no or minimal t1w-hyperintense meconium on mri. postnatal imaging studies also characteristically demonstrate a massively distended urinary bladder (with no apparent mechanical cause of obstruction) as well as a small, unused colon with dilated, hypoperistaltic small bowel seen proximal to the microcolon. additional findings which are variably seen include intestinal malrotation, stomach and esophageal hypoperistalsis or aperistalsis, gastroesophageal reflux, and biliary stasis. conclusions: although a rare syndrome, the constellation of imaging findings in mmihs is pathognomonic, and recognition of the classic pattern of findings can allow the radiologist to make a diagnosis of mmihs in both the in-utero and postnatal setting. early diagnosis is essential for allowing prenatal counseling regarding this generally fatal disorder, as well as to optimize early management options. purpose or case report: gastric mass lesion are uncommon. this presentation is an educational review of pediatric gastric mass lesions including gastro-intestinal stromal tumor (gist), inflammatory myofibroblastic tumor (pseudotumor). burkitt's lymphoma, squamous cell carcinoma, gastric teratoma, gastric varices, gastric hamartoma, gastric polyp and hypertrophic pyloric stenosis (hps). clinical presentation is varied with upper gi bleeding, feeding intolerance, pain, weight loss and fatigue manifesting. the imaging work-up might initially have been endoscopy or ultrasound. cross section imaging (ct mr) can be invaluable. the role and impact of fdg pet on the management, staging and follow up of the oncologic pathology will be emphasized. imaging findings in megacystic microcolon intestinal hypoperistalsis syndrome, a rare disease kiery braithwaite, pediatric radiology, emory-egleston, kieryb@yahoo.com; kiery braithwaite, paula dickson, marianne m. ballisty purpose or case report: megacystis microcolon intestinal hypoperistalsis (mmih) syndrome is a rare congenital form of severe functional intestinal obstruction which is more commonly found in females. the presenting clinical and imaging features of this disease can often mimic other causes of proximal bowel obstruction in the neonate. in combination with its common association with intestinal malrotation, the clinical picture of mmih syndrome may be confusing at times. awareness of additional imaging features characteristic of mmih syndrome may help the radiologist suggest this diagnosis. the purpose of this study is to enhance the ability of the pediatric radiologist to suggest this rare diagnosis by recognizing this unusual constellation of imaging features. we retrospectively reviewed the clinical data and imaging studies of four patients with mmih syndrome at our institution. imaging studies included plain radiography, ultrasonography, fluoroscopy, and cross sectional imaging. the initial presentation and clinical outcome was also reviewed. results: the clinical presentations of our patients, who were all female, were somewhat varied but typically included symptoms of intestinal obstruction. the diagnosis of mmih syndrome was made in our patients from the first few weeks of life through early childhood. the four patients demonstrated imaging features characteristic of this disease including a very large dilated bladder, severe bilateral hydroureteronephrosis, gaseous distention of the stomach and proximal small bowel, intestinal hypoperistalsis, and a very small colon. the clinical course of these patients that we observed was also quite variable, with some patients dying in neonatal period while another patient continues to do reasonably well at 14 years old after a multi-organ transplant. conclusions: mmih syndrome is a rare and frequently lethal disease. the ability of the pediatric radiologist to recognize this constellation of imaging findings can help the clinical team arrive at a diagnosis of mmih syndrome. more prompt diagnosis can aid in the development of a long term management plan for the patient and in counseling the family regarding the prognostic implications of this disorder. pathologies of omphalomesenteric duct remnant: radiologic-surgical correlation swapnil bagade, md, pediatric radiology, mallinckrodt institute of radiology, bagades@mir.wustl.edu; geetika khanna, rebecca hulett purpose or case report: 1. to facilitate understanding of embryology of the omphalomesenteric(vitelline) duct and normal anatomy of the umbilicus. 2. review the spectrum of omphalomesenteric duct malformations and diversity of clinical presentations of these remnants. 3. illustrate the imaging findings of omphalomesenteric remnants, from the common such as meckel's diverticulum to the uncommon such as the omphalomesenteric duct cyst, with surgical correlation. methods & materials: cases with complications of persistent omphalomesenteric duct were collected from the joint surgery/radiology conferences at a tertiary level children's hospital. imaging features were correlated with intraoperative findings. conclusions: preoperative diagnosis of complications related to the omphalomesenteric duct remnants can be challenging because clinical and imaging features overlap with other etiologies of acute abdomen. knowledge of the embryologic, clinical, radiologic, and surgical characteristics of omphalomesenteric duct remnants will aid in early and accurate diagnosis. neonatal bowel obstruction-a pictorial essay tanmay patel, university of kentucky; harigovinda challa purpose or case report: bowel obstruction is the most common abdominal emergency in the newborn period and in most cases is secondary to a congenital anomaly requiring early surgical intervention. however not every case of abdominal distension or dilated bowel is secondary to mechanical bowel obstruction or underlying surgical condition. radiologic imaging forms a central role in the work up of newborns with suspected intestinal obstruction. the role of the radiologist is to identify whether or not mechanical obstruction is present; if obstruction is identified on initial radiographs, to determine the level of obstruction, and finally to identify the etiology of obstruction. initial plain radiographic evaluation also helps to determine the subsequent diagnostic or therapeutic approach. methods & materials: a retrospective review of multiple radiographic and fluroscopic examinations in patients with diagnosis of neonatal bowel obstruction was performed at kentucky children's hospital. multiple examples of classical imaging findings were compiled and placed into a pictorial review. results: neonatal intestinal obstruction generally presents with nonspecific symptoms such as abdominal distention, vomiting, or failure to pass meconium depending on the level of obstruction and time of occurrence of underlying congenital lesion/atresia in the intrauterine life. initial plain radiographs of the abdomen reveal dilated bowel loops when obstruction is present. high intestinal obstruction is suspected when only few dilated loops are identified, while multiple dilated bowel loops are seen in low obstruction. most cases of high obstruction may not need another diagnostic imaging test. all cases of distal intestinal obstruction require water soluble enema to identify the etiology of obstruction. in conditions like functional immaturity of the colon, and meconium ileus water soluble enema is therapeutic and thus surgery can be avoided in most cases. the objective of this presentation is to present an educational exhibit of classical imaging findings of various types of neonatal bowel obstructions, and how to differentiate between them. conclusions: bowel obstruction is the most common abdominal emergency in the new born period. most cases are secondary to a congenital surgical condition and early diagnosis and treatment significantly reduces mortality and morbidity. radiographic evaluation plays a central role in the diagnosis and treatment of these conditions. poster #: edu-017 3d t2-weighted mrcp in the pediatric population-a pictorial review nathan egbert, mbbs mph, university of michigan, nathaneg@med.umich.edu; jonathan r. dillman, peter j. strouse purpose or case report: to demonstrate the utility of 3d t2-weighted magnetic resonance cholangiopancreatography (mrcp) in the pediatric population, and to illustrate the mrcp findings of various conditions affecting in the pediatric pancreaticobiliary system. we identified all mrcp exams performed on pediatric patients (< 18 years of age) from january 1, 2000 through august 1, 2011 by searching institutional electronic medical records. we then identified representative 3d t2-weighted mrcp images of various conditions affecting the pediatric pancreaticobiliary system. results: representative 3d t2-weighted mrcp images (including source, maximum intensity projection, and volume rendered images) from the following conditions will be presented: abnormal biliary narrowing/stricture (including sclerosing cholangitis, anastomotic strictures following kasai procedure & liver transplantation, and "pseudostricture"), biliary atresia, choledochal cyst (including various subtypes, based on todani classification), choledocholithiasis & cholelithiasis, congenital anomalies of the pancreaticobiliary system (including pancreas divisum and anomalous pancreaticobiliary junction), pancreatobiliary system trauma (including main pancreatic duct transection), and other rare conditions affecting the pancreaticobiliary system (including rhabdomyosarcoma of the biliary tree). conclusions: 3d t2-weighted mrcp has become an extremely useful tool in the evaluation of children with suspected disorders of the pancreaticobiliary system. since mrcp has distinct advantages over alternative diagnostic techniques, such as endoscopic retrograde cholangiopancreatography (ercp) or percutaneous cholangiography, including lack of ionizing radiation and noninvasiveness, mrcp is a much preferred initial study for pediatric pancreaticobiliary imaging. this pictorial review is intended to highlight the 3d t2weighted mrcp appearances of various pancreaticobiliary conditions occurring in the pediatric population. purpose or case report: magnetic resonance enterography (mre) is rapidly emerging as an important imaging tool for the diagnosis and follow-up of inflammatory bowel disease (ibd). its lack of ionizing radiation makes this imaging modality especially vital to the pediatric population. using a casebased approach, we will demonstrate the usefulness of diffusion-weighted imaging (dwi) as part of a comprehensive mre protocol for the assessment of ibd in children. the basics of dwi will be discussed with particular attention to abdominopelvic techniques. the role of mre dwi for the evaluation of pediatric crohn disease (cd) and ulcerative colitis (uc) will be reviewed using a case-based approach. key images from pertinent imaging studies will be identified by searching institutional electronic medical records and presented with relevant clinical data. results: a review of pediatric mre examinations suggests dwi can be used to detect the following: 1) small and large bowel segments affected by ibd (both cd and uc) 2) abdominopelvic abscesses (including within the mesentery, body wall, iliopsoas muscle, and liver) 3) abnormal lymph nodes 4) sacroiliitis 5) perianal disease (including abscesses and other penetrating complications). conclusions: dwi has the potential to play a very important role in the diagnosis and follow-up of pediatric ibd. this mre technique is particularly useful for detecting a variety of disease-related complications. as the exact meaning of bowel wall restricted diffusion is poorly understood to date, continued investigation will be necessary to determine the clinical and histologic significance of this finding. cases of cf involving the gi tract were collected from clinical workflow encounters of the authors and from the main hospital medical records database. relevant imaging studies were reviewed for known gi manifestations of cf. these imaging studies were correlated with clinical histories and available intraoperative and pathologic findings. results: cf involvement of the gi tract presents over a wide range of ages, organs involved, and associated symptoms. these manifestations can generally be divided anatomically into those involving the alimentary tract, hepatobiliary system, and pancreas. alimentary tract manifestations consist of meconium ileus in uncomplicated and complicated forms (with the latter including secondary intestinal atresia, volvulus, and perforation with meconium peritonitisdistal intestinal obstruction syndrome, constipation, rectal prolapse, duodenal fold thickening, and appendiceal dilation. hepatobiliary disorders secondary to cf include microgallbladder, cholelithiasis, biliary ductal abnormalities, neonatal hepatitis, and cirrhosis (including complications such as portal vein thrombosis and ascites). pancreatic expressions of cf include fatty infiltration, calcifications, and cysts/ cystosis, frequently in the setting of malnutrition and/or stooling abnormalities. this exhibit will demonstrate the spectrum of clinical and radiologic gi findings in this disease from the fetal and neonatal period through adolescence across a range of imaging modalities. conclusions: gastrointestinal manifestations of cystic fibrosis occur frequently in the pediatric population and may be the earliest clinical expression of the disease. familiarity with the variety of gastrointestinal imaging findings of cystic fibrosis can expedite appropriate diagnosis and therapy, particularly in those children in whom the primary disease is not clinically suspected. beyond acute appendicitis: imaging of additional pathologies of the pediatric appendix kelly dietz, md, cincinnati children's hospital; arnold c. merrow, daniel j. podberesky, alexander j. towbin purpose or case report: primary acute appendicitis (or appendiceal inflammation caused by a superimposed bacterial infection in the setting of appendiceal obstruction) is by far the most common pathology of the appendix, and imaging evaluations to exclude this diagnosis occur daily in the pediatric radiology setting. the clinical and imaging differential diagnosis in a patient with right lower quadrant pain and suspected appendicitis is a broad but well-recognized list that predominantly involves structures adjacent to the appendix including the ovaries, small and large bowel, and ureters. there are, however, less common pathologies primarily involving the appendix which can create an imaging diagnostic dilemma in the setting of right lower quadrant symptoms. our goal is to review the imaging and clinical manifestations of these less commonly encountered appendiceal abnormalities. methods & materials: cases of appendices that were abnormal by imaging but ultimately determined not to be due to primary acute appendicitis were collected from clinical encounters by the authors as well as through a search of the radiology and pathology report databases. clinical course, surgical findings, and pathology reports (if available) were subsequently reviewed through the main hospital medical records system. results: the collected cases demonstrate a wide range of additional pathologies of the appendix outside of primary acute appendicitis. a variety of imaging modalities were employed in the workup of these cases. examples reviewed in this exhibit include crohn's disease, ulcerative colitis, cystic fibrosis, carcinoid tumor, inguinal hernia with incarceration, retained foreign body, pinworm infestation, and ileocolic intussusception. conclusions: despite the frequency of primary acute appendicitis, there is a differential diagnosis when an abnormal appendix is found by imaging. familiarity with these alternative diagnoses may be particularly helpful in guiding management of the patient whose clinical presentation is not typical for primary acute appendicitis. methods & materials: a hospital pacs database search from the past 10 years for patients with bws. selected cases, with multimodality imaging, were cross-referenced with pathology reports from patient records database. results: intricate abdominal pathologies are depicted utilizing multimodality imaging, such as plain films, us, ct, mri and pet/ct, and with pathologic correlation. cases with highlight the following: liver: hepatoblastoma, nonspecific hepatobiliary cysts, multiple hemangiomas mimicking metastatic disease; adrenal: dysplastic organomegaly mimicking neoplasm; pancreas: diffuse and focal hyperplasia in the setting of hyperinsulinism, organomegaly; renal: neprocalcinosis, including medullary sponge kidney, nephroblastomatosis, organomegaly; adnexal: ectopic paraovarian adrenal tissue mimicking metastatic lymph node; urinary bladder: benign fibro-uroepithelial polyp. conclusions: diagnosis of bws can be difficult when the classic clinical and radiological findings are not present. these few cases highlight the unusual abdominal pathologies, so when detected, a radiologist can aid in the appropriate diagnosis and help guide therapy for these young patients. this poster will discuss pharmaceuticals the fda considers investigational for their intended use. disclosure: dr. lecompte has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. radiologic-pathologic review of pancreatic masses encountered at a tertiary pediatric hospital over a 10-year period no kwak, md, radiology, long island jewish medical center, kwak_nb@yahoo.com; karen naar, jeanne choi-rosen, lee collins, sukhjinder singh, anna thomas purpose or case report: review of pathologically proven pancreatic masses in pediatric patients encountered at a tertiary pediatric hospital over a 10-year period. describe the key morphologic features and other pertinent findings using various imaging modalities. correlate pathologic and radiologic findings. methods & materials: illustrate the various imaging characteristics of pathologically proven pancreatic masses including pseudocyst, pancreatoblastoma, solid pseudopapillary tumor, acinar cell carcinoma, ductal adenocarcinoma, lymphoma, pancreatic neuroblastoma, and inflammatory myofibroblastic tumor. correlate pathologic and radiologic findings. identify the key imaging features that allow narrower differential diagnosis. results: pancreatoblastoma and solid pseudopapillary tumor are the more commonly encountered pediatric primary pancreatic tumors. both are bulky and heterogeneously enhancing tumors with solid and cystic elements. pancreatoblastoma occurs more commonly in young children. internal hemorrhage and fibrous capsule favor solid pseudopapillary tumor which more commonly occurs in adolescent girls. ductal adenocarcinoma, acinar cell carcinoma and an inflammatory myofibroblastic tumor, which were pathologically proven in our pediatric patients, are exceedingly rare entities. the imaging findings of these cases and their pathology when available will be presented, as well as a quick literature review of these rare tumors. illustration and correlation of the pathologic and radiologic findings. conclusions: pancreatic masses in children are rare but in general have a better prognosis than in adults. salient imaging findings for the various tumors encountered at a tertiary care center with pathologic and radiologic correlation. evaluation of hepatoblastoma with gadoxetate disodium-typical, atypical, pre and post treatment evaluation arthur b. meyers, radiology, cincinnati children's hospital, arthurbmeyers@yahoo.com; alexander j. towbin, daniel j. podberesky purpose or case report: gadoxetate disodium (gd-eob-dtpa) is a hepatobilliary mri contrast agent that is widely used in adults for characterization of liver tumors and is being increasingly used in pediatric patients. hepatoblastoma is the most common primary hepatic malignancy of childhood. the purpose of this presentation is to describe our experience with the use of this agent in the mri evaluation both before and after initiating therapy in patients with hepatoblastoma. methods & materials: the radiology report system at our institution was queried for all patients with pathology proven hepatoblastomas who underwent a liver mr with administration of gadoxetate disodium between 8/1/10 and 2/28/ 2011. the mr imaging characteristics of the patient's primary hepatoblastoma pre-and post-therapy (when available) and post treatment findings (when available) were reviewed. results: 22 mri studies in 9 different patients were reviewed. the patients ranged in age from 4 months to 12 years. 6 patients had pre and post treatment evaluation with gd-eob-dtpa enhanced mri, 1 patient had only pretreatment evaluation and 2 patients had only post treatment evaluation. 6 of the hepatoblastomas did not take up gd-eob-dtpa during the hepatocyte phase and were therefore low signal intensity during the hepatocyte phase of imaging. this was useful in the pretreatment evaluation of hepatoblastoma, particularly in defining the relationship of the tumor to hepatic and portal veins. post treatment gd-eob-dtpa imaging allowed characterization of the biliary anatomy and demonstrated the communication of a postoperative fluid collection with the biliary tree, consistent with biloma. 1 atypical hepatoblastoma showed uptake of gd-eob-dtpa on hepatocyte phase imaging, similar to what has been described in adults with atypical hepatocellular carcinoma. conclusions: gadoxetate disodium enhanced mri is useful in the imaging evaluation of hepatoblastoma, particularly in defining the relationship of tumor to vascular and biliary anatomy and in characterizing post-treatment complications. disclosure: dr. meyers has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. imaging of the gallbladder and biliary tree in pediatric age group ihsan mamoun, md, cleveland clinic, ihsanmamoun@ yahoo.com; s. pinar karakas, unni udayasankar, neil vachhani, ellen park purpose or case report: interactive educational exhibit to illustrate the embryology, anatomical variants as well as congenital and acquired diseases of the bile ducts and gallbladder in pediatric patients. methods & materials: a)the embryology of the gallbladder and biliary tree will be demonstrated with diagrams. b) imaging techniques for gallbladder and biliary tree including us, ct, mri, ercp and intraoperative cholangiogram will be discussed. c)imaging findings of various lesions with special emphasis on key findings that can lead to accurate diagnosis will be discussed. d)an appropriate list of differential diagnosis will be provided. e)an algorithm for the assessment of suspected biliary pathology will be presented. f)the exhibit will be interactive and the reader will answer questions about the discussed entity, related imaging algorithm and management. results: a)discuss congenital anomalies including duplicated and septated gallbladder, choledochal cyst, caroli disease, situs abnormalities and biliary atresia. b)discuss infectious and inflammatory conditions including cholecystitis, kawasaki's disease, sclerosing cholangitis and hepatitis. c)discuss iatrogenic complications including post transplant biliary stricture and leak. d)discuss benign and malignant neoplasms invoving the gallbladder including polyps, ptld and rhabdomyosarcoma. conclusions: this exhibit will demonstrate a logical approach to imaging of the congenital and acquired diseases of the gallbladder and biliary tree based on the embryology and underlying pathology. postnatal work up of congenital uronephropathies-a pictorial essay harigovinda r. challa, radiology, university of kentucky, hch229@uky.edu purpose or case report: the use of obstetric ultrasound routinely in the prenatal care has lead to the discovery of many fetal anomalies. uronephropathies in the newborn represent one of the largest groups of anomalies amenable to neonatal management. since these uropathies are detected mostly in asymptomatic patients the treatment is mainly preventive. the pediatric radiologist has a key role in the post natal work up and management of these patients with prenatally diagnosed neprhouropathies and familiarity with the congenital urinary tract abnormalities is necessary. methods & materials: a retrospective review of multiple radiographic, sonographic and fluroscopic examinations performed in the newborn babies and infants with prenatal diagnosis of urinary tract abnormalities was performed at kentucky children's hospital. multiple examples of classical imaging findings were compiled and placed into a pictorial review. results: numerous anomalies can be detected in utero, including anomalies of renal number, position, morphology, collecting system dilation and bladder, urethral abnormalities. of these postnatal work of congenital hydronephrosis is the most common routinely encountered clinical entity. renal ultrasound is the initial examination in the evaluation in all cases of prenatal hydronephrosis, which is best performed around postnatal day 5. if collecting system dilatation persists on postnatal ultrasound, further imaging work up with vcug, radionuclide imaging may be required depending on degree of dilatation. conclusions: uroneprhopathies are increasingly detected in the prenatal life with increasing use of obstetric ultrasound. the objective of this presentation is to demonstrate in a pictorial essay of different neprhouropathies and their workup in newborns. isolated fallopian tubal torsion: causes, imaging findings, and how to suggest the diagnosis jesse courtier, md, ucsf dept of radiology, jesse. courtier@ucsf.edu; amaya m. basta, rebecca maine, pierre-alain cohen, shinjiro hirose, john d. mackenzie purpose or case report: the purpose of this educational report is to describe the rare entity of isolated fallopian tubal torsion in the pediatric population and depict the cross sectional imaging findings that help make a diagnosis and guide management. the proposed pathophysiology, predisposing factors, and surgical management will be described. an illustrative case example of 12-year-old female patient will be provided with surgical correlation. the exhibit will review imaging findings on us, ct and mri that help support the diagnosis including, dilated tubular structure in the pelvis, normal ovaries, and corkscrewing and beaking of the proximal fallopian tube. isolated fallopian tubal torsion will be placed in the context of a differential diagnosis for girls presenting with pelvic pain and the imaging signs that help make a diagnosis of isolated tubal torsion and separate this entity from other causes of pediatric pelvic pain will be emphasized. multimodality imaging characteristics of genitourinary rhabdomyosarcoma rhea udyavar, md, george washington university medical center, rudyavar@gwmail.gwu.edu; amir noor, pranav k. vyas purpose or case report: in this pictorial essay, we will demonstrate salient imaging features of mr, us, and ct modalities for the diagnosis of genitourinary rhabdomyosarcoma in male (n04) and female (n04) children ages 2-14 years, evaluated at our institution over the past 6 years. background information, including tumor biology, staging, and treatment will also be discussed. the swollen scrotum: ultrasound technique and differential diagnosis kelli r. schmitz, md, oregon health & science university, schmitzk@ohsu.edu; roya sohaey purpose or case report: to review the ultrasound protocol for the performance of scrotal ultrasound and illustrate the ultrasound appearance of conditions resulting in scrotal swelling in pediatric patients. a retrospective review of the imaging database at a tertiary pediatric referral center was performed to identify pediatric patients who presented with scrotal swelling and underwent diagnostic ultrasound. when available, surgical/pathologic correlation was obtained. results: a variety of pathologic processes result in scrotal swelling. causes illustrated include: testicular torsion, epididymitis/orchitis, hydrocele, varicocele, inguinal hernia, trauma, adrenal rest, and testicular or paratesticular neoplasm. conclusions: the causes of scrotal swelling are myriad, including infectious/inflammatory, developmental, traumatic, and neoplastic etiologies. in children, the clinical presentation of a swollen scrotum is nonspecific, and ultrasound plays a key role in making the correct diagnosis. experiences of starting a functional mr urography program at a university hospital: trials and tribulations steven l. blumer, bsc, montefiore medical center/albert einstein college of medicine, sblumer@montefiore.org; ibrahim tuna, amanda north, benjamin taragin, netta blitman, terry l. levin purpose or case report: starting a functional mru program can be challenging as there are numerous potential hurdles to overcome. this presentation describes the process of starting a functional mr urography (fmru) program at a university hospital and discusses the difficulties encountered starting such a program. selecting a sufficient patient referral base, resolving common and uncommon technological issues, and education of clinicians, patients and technical staff are some of the challenges that will be discussed. conclusions: awareness of the common pitfalls in fmru imaging and close partnering with referring physicians can make establishing a functional mru program easier. despite many potential obstacles, the benefit of exquisite anatomical and functional information provided by fmru in children, without exposure to ionizing radiation, greatly outweighs any challenges. disclosure: dr. blumer has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. pictorial review of ultrasound findings in boys presenting to emergency department/urology with acute scrotum teresa liang, faculty of medicine, university of british columbia, teresaliang86@gmail.com; peter metcalfe, william sevcik, michelle noga purpose or case report: testicular torsion is a common acute condition in adolescent boys. rapid and accurate diagnosis is critical. diagnosis is currently based on history, physical findings, and ultrasound (u/s) with doppler. the objective of this poster is to demonstrate ultrasound findings from a retrospective review of acute scrotum over 3 years, and to demonstrate some pitfalls of the technique with regard to testicular torsion diagnosis. we reviewed the u/s, surgical and ed records at the stollery children's hospital for boys aged 1 month to 17 years, presenting with acute scrotum from july 1, 2008 to 2011. age, demographics, clinical symptoms, and physical findings, u/s and surgical techniques, findings, diagnoses and follow-up were also recorded. results: 343 patients presented to uah stollery ed with acute scrotum: 35 were diagnosed with testicular torsion (2 inguinal torsion), 11 were suspected of a torsion-detorsion, 3 torsion of appendix testes, 135 epididymitis/orchitis, and 159 other diagnoses including hydroceles, varicoceles, epididymal cysts, abscesses, cellulitis and hematomas. for the 266 patients who had ultrasound,100% sensitivity and 88% specificity for testicular torsion. the ultrasound findings including size, vascularity and echogenicity associated with both salvageable and necrotic testicles including use of color and pulse doppler will be reviewed. the sonographic findings and pictorial examples associated with the more common acute scrotum etiologies will be presented. sonographic findings from problematic cases (those with inconclusive ultrasound reports or false positive reports) will also be addressed. conclusions: ultrasound imaging problem case examples and characteristic findings of common acute scrotum presentations at stollery hospital at the university of alberta are reviewed in this poster. primary and secondary amenorrhea in pediatric patients: from the beginning to the end cesar cortes, md, miami children's hospital, n4c03@ hotmail.com; yanerys ramos, ricardo restrepo, alejandro diaz, lorena sequeira, edward lee purpose or case report: to describe the role of imaging in evaluating patients with primary and secondary amenorrhea and to illustrate the normal imaging findings of the reproductive organs in the pediatric population as well as the imaging findings of the different etiologies causing amenorrhea. a search of the literature is done to determine the different etiologies of amenorrhea and the role of imaging in their evaluation. first, we will focus on the normal physiologic hormonal influence and changes of the girl's reproductive organs since birth until adolescence on ultrasound and mri. images of the normal appearance of the female reproductive organs as well as imaging findings of the different common and uncommon etiologies of amenorrhea will be shown. then, specific reference will be made to crucial related concepts such as minipuberty of infancy, latest criteria for polycystic ovarian disease and ovarian failure syndrome among others. finally, the treatment, either medical or surgical will be briefly discussed. results: causes of amenorrhea in children range from disorders affecting the hypothalamus, pituitary gland, adrenal glands, and ovaries, as well as uterine and vaginal structural abnormalities. even though history and clinical exam are essential in evaluating a patient with amenorrhea, the pediatric radiologist plays a pivotal role helping guide the area to be imaged and thus the modality that should be used. mri and ultrasound are the main modalities in the evaluation of amenorrhea. conclusions: ultrasound and mri are the main imaging modalities used in the evaluation of amenorrhea in children and are usually part of the work up. amenorrhea in children can have implications in girl's fertility allowing pediatric radiologists to play an important role in helping not only the patient but also their offspring. imaging of mullerian duct anomalies in children kelly k. horst, md, radiology, university of michigan, khorst@med.umich.edu; maryam ghadimi mahani, deepa pai, jonathan r. dillman, peter j. strouse purpose or case report: the purpose of this educational exhibit is to provide an up-to-date appraisal of mullerian duct anomalies presenting in the pediatric population. the appearances of anatomic variants on ultrasound and mri will be used to illustrate the strengths and potential pitfalls of these imaging modalities. methods & materials: patients who have previously undergone ultrasound and/or mri in the course of their clinical workup within the university of michigan health system (umhs) were identified using electronic medical records. imaging reports were reviewed by a single author in order to identify relevant imaging findings (interesting anatomic variations, associated anomalies, etc.). pertinent images from these imaging examinations were de-identified and saved to a secure hard drive. the medical record was accessed by a single researcher to obtain relevant information regarding the patients' clinical presentations. in cases of corrective surgery, pathology reports were reviewed, if available, for correlation with the imaging findings. results: cases of mullerian duct anomalies were reviewed within the pediatric population. clinical manifestations were correlated with imaging appearances. conclusions: mullerian duct anomalies represent a range of developmental variants. although functioning ovaries and age-appropriate external genitalia are characteristic, there may be anomalies ranging from uterine and vaginal agenesis, to duplication of the uterus and vagina, to minor uterine cavity abnormalities. müllerian malformations are frequently associated with abnormalities of the renal and axial skeletal systems, and pediatric patients in particular may present with these associated anomalies. menstrual abnormalities may represent a more typical presentation in the adolescent age group. this is in contrast to the adult population, which may be more likely to present with infertility. the variation in clinical presentations make mullerian duct anomalies difficult to diagnose and, because surgical techniques for correction and treatment depend on the underlying anatomy, understanding these variants in the context of imaging studies is important to their diagnosis and management. patient 2 had radiographs which showed an irregular left humeral metaphysis with an associated fracture. patient 3 had a 3 phase bone scan that showed slightly increased uptake on the angiographic and blood pool phases and increased activity on the delayed phase in the right femur. radiographs showed a moth eaten appearance of the right femur with soft tissue swelling. patient 4 had radiographs that showed periosteal reaction in the right tibia with an associated fracture. patient 5, in addition to radiographs, had an mri that showed osteomyelitis of the left humerus and scapula with an associated subperiosteal abscess. patient 6 had multi focal osteomyelitis that was demonstrated on radiographs by irregular cortices and periosteal reaction involving the upper and lower extremities. conclusions: neonatal osteomyelitis is an uncommon entity that can have severe complications if not diagnosis and treated promptly. it is important to review cases and to review the appearance of neonatal osteomyelitis on multiple modalities. radiographs will usually demonstrate periosteal reaction and possibly soft tissue swelling. additional studies may be obtained to evaluate for complications, such as abscesses or involvement of the joint space. purpose or case report: review the epidemiology of ddh. describe the critical diagnostic imaging findings of ddh. understand the role of imaging accompanying treatment. methods & materials: images including radiographs, ultrasound, ct and mri will be used to demonstrate the current and historical role of imaging in caring for patients with ddh. discussion of the importance of reducing radiation exposure when choosing imaging studies will be included. results: radiographs and ultrasound are used primarily in making the diagnosis of ddh. ultrasound and mri are most often used during the course of treatment to assess its effectiveness. mri is increasingly utilized without sedation for patients in spica cast. conclusions: imaging is critical in the care of patients with ddh. pediatric musculoskeletal ultrasound of the proximal lower extremity (pelvis to thigh) julia rissmiller, md, dept of radiology, children's hospital boston, julia.rissmiller@childrens.harvard.edu; howard christianson, michael j. callahan purpose or case report: to review indications for ultrasound of the proximal lower extremity (pelvis, hip and thigh), and to illustrate the practical use of ultrasound in evaluation of the proximal lower extremity, emphasizing the sonographic appearance of various musculoskeletal disorders. ultrasound is a well-established modality for the evaluation of painful hip, developmental hip dysplasia, soft tissue infection, palpable masses, and foreign bodies in children. in general, ultrasound has a more limited role for the primary evaluation of other pediatric musculoskeletal disorders including trauma, articular and periarticular diseases and tumors or tumor-like processes. advantages of ultrasound, a relatively non-invasive technique, include excellent spatial resolution, low cost, lack of ionizing radiation, lack of need for sedation, and the ability to image the patient in real-time. the major disadvantage of ultrasound is operator dependency, which is particularly evident in musculoskeletal applications. we present ultrasound examples of pathology involving the proximal lower extremity (pelvis, hip and thigh). cases include developmental hip dysplasia, hip effusion, osseous metastasis to the iliac bone, osteomyelitis of the hip, femoral acetabular impingement, rectus femoris hernia, vascular malformation, ewing's sarcoma and myositis ossificans. results: a range of images from pediatric diagnostic ultrasounds performed of the proximal lower extremity (pelvis to thigh) will be presented emphasizing the sonographic appearance of various musculoskeletal disorders. conclusions: ultrasound is an excellent modality for evaluating the proximal lower extremity in children, beyond the current indications of painful hip, developmental hip dysplasia, soft tissue infection, palpable masses, and foreign bodies in children. a multi-modality pictorial review of lesions of the epiphysis in infants and children ernesto i. blanco, md, st. christopher's hospital for children, eiblanco74@gmail.com; jacqueline urbine, evan geller, peter pizzutillo purpose or case report: to review the imaging spectrum of epiphyseal lesions in infants and children. a retrospective review of our imaging database was performed to identify studies with either primary lesions of the epiphysis or processes that affect the epiphysis. results: multiple epiphyseal lesions were elucidated primarily by radiography, with cross-sectional imaging included where clinically necessary. congenital lesions include the epiphyseal dysplasias represented here by chondrodysplasia punctata. epiphyseal infarction may due to multiple etiologies including slipped capitol femoral epiphysis, developmental dysplasia of the hip, sickle cell disease, or idiopathic reasons. neoplasms may occur in the epiphysis, including chondroblastoma and histiocytosis. traumatic lesions include fracture and avulsion. osteomyelitis can occur in the epiphysis as well. pseudolesions that mimic pathology will also be reviewed. other pathologies that can affect the epiphysis include juvenile idiopathic arthritis and hemophilia. conclusions: a wide spectrum of congenital and acquired pathologies may affect the epiphysis in the infant and child. plain radiography, computed tomography, and magnetic resonance imaging all contribute to the diagnosis of these varied lesions. purpose or case report: we aim to present the spectrum of common and uncommon hip disorders in pediatric population. we will formulate a systematic approach and present a flowchart to workup and characterize hip diseases. methods & materials: relevant imaging appearances of normal as well as pathological hip will be presented. normal hip anatomy will be discussed through anatomic drawings and radiological images (plain radiographs, ct, usg, and mri). we will illustrate the various anatomic landmarks, measurements and lines on plain radiographs and ultrasound of hip. results: evaluation of limp and hip pain in the pediatric population has undergone rapid evolution. surgical treatment for these disorders continues to be refined, and our ability to identify patients along the spectrum of disease continues to improve. yet, despite our advances, obtaining an accurate diagnosis can remain challenging, especially in the setting of mild structural abnormalities. many imaging studies can be used to evaluate the bones and soft tissues, but conventional radiography is the primary imaging modality for most clinical conditions. plain radiographs usually are obtained first because they are sensitive and specific for a wide range of bone pathology. more sophisticated imaging modalities including radionuclide scintigraphy (bone scan), ultrasonography (usg), computed tomography (ct) and magnetic resonance imaging (mri) are reserved for specific clinical situations. each of these imaging modalities has specific advantages and disadvantages. it is the aim of this review to guide in selecting and interpreting the appropriate imaging modality for a variety of common disorders. this exhibit will illustrate imaging features of developmental dysplasia of hip, perthes disease, slipped capital femoral epiphyses, hip malformations in syndromes, femoral acetabural impingement, labral disorders, septic arthrits and other disorders. the role of various imaging modalities in evaluation of these disorders will be discussed, along with common imaging pearls and pitfalls. conclusions: a systematic approach is necessary for evaluation of pediatric hip disorders. familiarity with normal appearances, pitfalls and specific imaging of these entities is essential for proper diagnosis and management. osteoid osteomas: a pain in the "night" diagnosis nancy k. laurence, md, the children's hospital of philadelphia, nkang26@gmail.com; monica epelman, richard markowitz, camilo jaimes, diego jaramillo, nancy chauvin purpose or case report: a common benign bone-forming lesion, osteoid osteoma comprises approximately 12% of all benign bone tumors. the tumor is composed of a nidus of vascular osteoid tissue and woven bone lined by osteoblasts, frequently with considerable surrounding inflammation. the radiolucent nidus surrounded by variable degrees of reactive sclerosis usually leads to a straightforward diagnosis; however, sometimes the diagnosis of osteoid osteoma can be challenging, as it may have a non-specific and misleading appearance on different imaging modalities, particularly on mri. the purpose of this exhibit is to review the typical and atypical features of osteoid osteomas on different imaging modalities. we present diagnostic dilemmas of osteoid osteomas from our institution and how imaging characteristics can aid in diagnosis. we performed a retrospective review of our imaging database to identify cases of typical and atypical osteoid osteomas, with special emphasis on cases which posed a diagnostic dilemma on imaging. results: when osteoid osteomas occur in atypical locations the diagnosis can be elusive. when located in the intraarticular space there is often minimal or absent cortical thickening and there may be a joint effusion with synovial hypertrophy. phalangeal lesions may cause extensive bone marrow edema and surrounding soft tissue swelling. both of these types of osteoid osteomas can be mistaken for infection. the recently described "ct vessel" or "vascular groove" sign, a low density vascular groove adjacent to the nidus, is highly specific for osteoid osteoma. in the authors' experience, a rim of sclerosis surrounding the nidus may aid in diagnosis on mri and can be identified as an outer hypointense halo on all sequences. we illustrate the findings in cases of atypical osteoid osteomas which may be difficult to diagnose including intraarticular, phalangeal, and vertebral osteoid osteomas. we also show examples of the newly described sign which has high specificity for osteoid osteoma. conclusions: imaging findings in osteoid osteomas can be misleading and cause misdiagnosis, especially in atypical cases. knowledge of their appearance in atypical locations and specific findings can aid in the correct diagnosis. ultrasound of normal entheses in the growing skeleton nancy chauvin, md, department of radiology, the children's hospital of philadelphia, chauvinn@email.chop. edu; pamela f. weiss, monica epelman, diego jaramillo purpose or case report: ultrasound is an underutilized modality in the evaluation of the pediatric musculoskeletal system. evaluation of tendon insertions about the elbow, knee and foot can be easily performed with ultrasonography. a good knowledge of the age dependent normal ultrasound appearance of the entheses is crucial in order to evaluate for pathology, such as trauma or ethesitis-related arthritis. this exhibit will serve to provide the reader with a practical approach to imaging when assessing tendon insertions. optimal patient positioning and transducer selection will be discussed. in addition, important anatomic landmarks will be described to allow for reproducibility and avoiding pitfalls. methods & materials: transverse and longitudinal ultrasound images of 12 entheseal insertion sites were performed on 20 healthy girls and boys between the ages of 5 and 17 years. ultrasound of the elbow was performed while in full extension and the insertions of the common flexor and common extensor tendons were evaluated. the quadriceps and patellar insertions were imaged with patients in the supine position, with the knees flexed at 30 degrees. the achilles tendon and plantar fascia insertion were evaluated with the patient prone, with the feet hanging off the edge of the table. results: tendons demonstrated the expected fibrillar pattern with parallel echogenic lines. the appearance of the entheses changed as the insertion matured from sonolucent cartilage to echogenic bone. conclusions: using a systematic approach and knowledge of the normal anatomy, sonography of the tendons of the elbow, knee and foot can easily be performed in children. pediatric musculoskeletal ultrasound of the distal lower extremity (knee to ankle) howard christianson, md, radiology, children's hospital boston, howard.christianson@childrens.harvard.edu; julia rissmiller, michael j. callahan purpose or case report: ultrasound is a well-established technique in children for evaluation of the painful hip, developmental dysplasia of the hip, soft tissue infection, palpable masses and foreign bodies. in general, ultrasound has a somewhat more limited role for the primary evaluation of several other pediatric musculoskeletal disorders in the setting of trauma, articular and periarticular diseases and tumors and tumor-like conditions. inherent advantages of ultrasound include excellent spatial resolution, a lack of ionizing radiation, a relatively non-invasive technique and lack of a need for sedation. real-time imaging allows problem solving not available with other modalities which is well suited for musculoskeletal applications, particularly in the setting of trauma. the major disadvantage of ultrasound is operator dependency, which is particularly evident in musculoskeletal applications. the purpose of this study is to illustrate the practical use of ultrasound in the evaluation of the distal lower extremity (knee to ankle) emphasizing the sonographic appearance of various musculoskeletal disorders. examples include: 1) cystic lesions around the joints: baker's cyst, synovial cyst, ganglion cyst and suprapatellar bursitis; 2) infectious processes: pretibial, subperiosteal and intramuscular abscess; 3) tumor and tumor like lesions: nerve sheath tumor, tumoral calcinosis; 4) trauma related injuries: sinding larsen johansson, tibialis anterior muscle herniation, hematoma. methods & materials: cases selected for presentation from a series of diagnostic musculoskeletal ultrasounds performed at our institution. results: a range of images from diagnostic ultrasounds performed of the distal lower extremity (knee to ankle) will be presented emphasizing the sonographic appearance of various musculoskeletal disorders. conclusions: selected musculoskeletal ultrasounds of the distal lower extremity are presented to familiarize the audience with the sonographic appearance of various musculoskeletal disorders and to highlight the tremendous potential of ultrasound in evaluating musculoskeletal disease in children and adolescents. role of conventional and dynamic contrast enhanced magnetic resonance imaging in diagnosis of hemihypertrophy syndromes in children shrey k. thawait, md, phd , radiology, yale university-bridgeport hospital, sthawai2@jhmi.edu; gaurav k. thawait, sally e. mitchell, laura m. fayad, john a. carrino, kate puttgen purpose or case report: hemihypertrophy syndromes in children are complex and there is some overlap among these conditions. hence, establishing a diagnosis can be challenging. identification of the correct vascular anomaly associated with these overgrowth disorders helps to correctly classify the disease into one of the several syndromes, which in turn guides management. in this educational poster, we will review the definition, clinical presentation, conventional magnetic resonance imaging (mri) and contrast enhanced magnetic resonance angiography and venography (mra / mrv) features of hemihypertrophy syndromes in children. methods & materials: 1. learn the diagnostic criteria for overgrowth syndromes in children such as klippel-trenaunay syndrome (kts) and parkes weber syndrome (pws) with special emphasis on associated vascular anomalies. 2. gain knowledge of high resolution mri technique for evaluation of vascular anomalies associated with the hemihypertrophy syndromes. 3. understand the additional value of dynamic contrast enhanced mra / mrv in the differentiation of the hemihypertrophy syndromes in the pediatric age group. results: 1. mri technique for a dedicated "vascular anomaly protocol" consisting of fat saturated t2 weighted, pre contrast axial t1 weighted, and post contrast triplanar t1 weighted fat saturated imaging will be described. 2. special emphasis will be provided on dynamic contrast enhanced mra/mrv. 3. conventional and dynamic mri features of clinically proven cases of hemihypertrophy syndromes will be demonstrated. conclusions: systematic mri interpretation utilizing a dedicated vascular anomaly protocol enables the radiologist to correctly identify the hemihypertrophy syndrome, and provide detailed extent of disease. correlative ultrasound, mri imaging and physical examination of elbows in hemophilic children andrea s. doria, md, the hospital for sick children-diagnostic imaging, andrea.doria@sickkids.ca; frederico xavier, arun mohanta, carina man, ningning zhang, pamela hilliard purpose or case report: 1.to report a systematic ultrasound (us) protocol for assessment of hemophilic elbows. 2. to discuss advantages and disadvantages of us and mri for evaluating hemophilic elbows in comparison with physical examination. 3.to illustrate us and mri findings and associated pitfalls in hemophilic joints. background: the value of physical examination for assessment of early arthropathic changes in hemophilic joints is unknown. us does not require sedation in young children, but involves operator training and standardized technique. mri is the reference standard imaging modality for assessment of pathology in hemophilic joints. standardization of a systematic protocol for data acquisition and interpretation of us findings and understanding of the correlation of findings between physical examination, us and mri in hemophilic elbows is essential for the use us as an outcome measure both in clinical practice and research. so far such information is not available for growing elbow joints. methods & materials: eight hemophilic boys (age range/ median, 7-17/13 years) with a history of prior elbow bleeds underwent us and mr imaging, and physical examination on the same day. corresponding images on us and mri were highlighted to illustrate abnormalities and pitfalls. soft tissues (effusion/hemarthrosis,synovial hypertrophy,hemosiderin deposition) changes were characterized as small, moderate, or large. erosions, cartilage and subchondral abnormalities were graded based on depth or extent of articular changes. results: 1. us is helpful for discriminating synovial hypertrophy, joint effusion/hemarthrosis, and large hemosiderin deposition which otherwise generates susceptibility artifacts on gradient-echo mri obscuring adjacent tissues. 2. us can visualize erosions, cartilage and subchondral abnormalities at the joint periphery. however,differentiation between subchondral cysts and erosions is usually unfeasible by us. 3. prior knowledge of the degree of joint maturation is essential for an accurate evaluation of cartilage loss by us. 4. physical examination has limitations for assessment of early joint changes in contrast to us. conclusions: us can be useful for assessing hemophilic elbows, with advantages over mri in the evaluation of soft tissues. further development of an us-mri atlas on normal cartilage in growing joints is needed for definition of the value of us in the assessment of minimal osteochondral abnormalities. digital atlas of skeletal surveys of common skeletal dysplasias shawn parnell, mbbs, md, dnb, radiology, seattle children's hospital, shawn.parnell@seattlechildrens.org; corey wall, edward weinberger purpose or case report: skeletal dysplasias are conditions of abnormal bone and cartilage growth which result in short stature. developing expertise in the radiographic evaluation of skeletal dysplasias can be difficult, as more than 250 dysplasias exist. exhaustive description of individual dysplasias can be found in hard copy textbooks, without the ability to compare individual dysplasias side by side. by providing radiographic images and descriptive text of thirteen common skeletal dysplasias and two comparative normal skeletal surveys, we aim to facilitate understanding of the terminology and highlight the differences in imaging appearances one may commonly encounter in interpreting skeletal dysplasias. methods & materials: initial skeletal surveys and/or follow up radiographs obtained for evaluation of skeletal dysplasias at our institution from 2005 to 2011 were compiled and reviewed for best quality images. selected images for each case were labeled according to body part and view, to include ap and lateral views of the spine and skull and ap views of the extremities and pelvis. for neonates, ap and lateral babygram images were used. the software program used for viewing the atlas, written in c#, may be freely downloaded. it permits linked scrolling and resizing of the images, and simultaneous comparison of different cases is available. cases may be viewed as unknowns or in a selfteaching mode. results: radiographic images for thirteen common skeletal dysplasias and two comparative normal skeletons (neonate and child) are provided within an interactive digital atlas. cases include achondroplasia, pseudoachondroplasia, cleidocranial dysplasia, thanatophoric dysplasia, diaphyseal dysplasia, multiple epiphyseal dysplasia, osteopetrosis, osteogenesis imperfecta, multiple hereditary exostoses, dysostosis multiplex, fibrous dysplasia, asphyxiating thoracic dysplasia (jeune syndrome), and spondyloepiphyseal dysplasia. conclusions: by displaying radiographic images of several common skeletal dysplasias in an interactive and comparative format with descriptive text, understanding of basic radiographic terminology and appearances will be facilitated. purpose or case report: 1. to classify various pediatric msk soft tissue masses 2. to describe pathogenesis, imaging appearances and differential diagnosis of these lesions methods & materials: radiology and clinical medical records were reviewed and pediatric patients with musculoskeletal soft tissue masses were identified. representative images were collected as examples of each lesion. the lesions were then classified into different groups based on the similar pathology and etiology. brief discussion is done for each of these masses with their multimodality imaging appearances. results: the search yielded pediatric soft tissue masses of multiple different etiologies, including post-traumatic (hematoma, fat necrosis, fibromatosis coli, myositis ossificans), inflammatory or infectious (cellulitis, abscess, granuloma annulare, retained foreign bodies), pseudotumors (synovial cysts, ganglion cysts, vascular malformations) and neoplastic lesions (fatty, vascular, neural, fibrous, muscular). multiple different imaging modalities were used to evaluate these masses, including ultrasound, ct and mri. representative examples of different lesions and their appearances on different imaging modalities will be presented and an organized approach to the diagnosis of these lesions will be discussed. conclusions: musculoskeletal soft tissue masses are relatively common in children. majority of these are benign; however, up to 6% of these lesions can be malignant "sarcomas". multiple different imaging modalities often provide complimentary information in the work-up of these lesions. despite multimodality imaging approach, tissue diagnosis or short interval follow-up is still often required when the mass does not show typical features of a benign etiology. pediatric radiologists should be familiar with various pediatric msk soft tissue masses and their imaging appearances, and should be able to guide appropriate management. results: 199 elbow mri examinations were reviewed on children aged 4 months to 18 years with 28 (14%) of these investigating clinical instability in 25 children. mechanism of injuries included congenital dislocation 10 (36%), traumatic dislocation 13 (46%), fracture or avulsion 2 (7%) and other injuries 3 (11%). the patient's with congenital elbow dislocations most commonly presented with radial head dislocation and associated dysplasia or flattening, effusion and less frequently dysplasia of the olecranon or capitellum. patient's with traumatic dislocations were frequently associated with ligamentous or capsular disruption, bone oedema and epicondylar avulsion with effusion, loose osseous bodies and fractures less often. the epicondylar avulsions and ligamentous or tendon injuries occurred equally often in those few patients with unspecified injury mechanism. conclusions: a number of the bony, ligamentous, articular and developmental anomalies evident on elbow mri have been illustrated highlighting the importance of careful and systematic review of all elbow structures when presented with a child with elbow instability. accurate identification of these abnormalities is vital to facilitate their appropriate management. methods & materials: from our computerized radiology information system, we retrieved all patients that have foot ultrasound for evaluation of vertical or oblique talus deformities in the last 6 years (10/2005-10/2011). the us was performed by a pediatric radiologist using a high resolution linear and tight convex curve probes with foot in neutral, plantar flexion and dorsiflexion. all medical charts, ultrasound scans and foot radiographs were reviewed by a pediatric radiologist. results: we identified nine patients' with foot deformities who were suspected of vertical or oblique talus and were evaluated by ultrasound. seven patients are male; two of them had initial foot radiographs that were not diagnostic. two female patients had unilateral oblique talus deformity. there were 7 patients with vertical talus deformity; three of them had bilateral deformities. conclusions: us can directly visualize the unossified navicular, the talar cartilage and their alignment. dynamic us can. ultrasound evaluation of costal chrondral pathologies in children presented as anterior chest wall mass or pain nucharin supakul, md, radiology, riley hospital for children, tanyasupakul@yahoo.com; boaz karmazyn purpose or case report: to summarize our experience with the use of ultrasonography (us) for evaluation of costal cartilage pathology presented as anterior chest wall mass. methods & materials: from our computerized radiology information system, we retrieved all patients that have chest wall ultrasound for evaluation of a mass in the last 4.5 years (4/2007-8/2011) . the us was performed by a pediatric radiologist using a localized scan with high resolution linear probe. all medical charts, pathology results, ultrasound scans and other imaging studies were reviewed by a pediatric radiologist. results: ten patients were found with costal chrondral pathologies. nine patients presented with anterior chest wall mass and one with chest wall pain. eight patients had angular deformity of a single costal cartilage and one patient had biopsy proven osteochrondroma, presented with anterior chest wall mass. one patient had a non-union fracture after motor vehicle accident, presented with anterior chest wall pain. in patients with rib deformity, the mass was non-tender. nine patients had prior imaging study including chest x-rays (n08), ct scan (n0 2), breast mr (n01). all these studies were negative. conclusions: us optimally demonstrated costal cartilage abnormities. chest radiographs and cross sectional studies were negative. we therefore recommend using high resolution chest wall us in children with negative chest radiograph and anterior hard chest wall mass. challenges in pediatric marrow imaging-boning up on current mr techniques srikala narayanan, md, division of radiology, children's national medical center, snarayan@childrensnational.org; neha kwatra, nabile safdar purpose or case report: a wide range of pathologies demonstrate similar findings when imaged using conventional mr sequences. however, pediatric musculoskeletal imagers are increasingly leveraging newer techniques to add specificity to their diagnoses when abnormal marrow signal is detected. the purpose of this educational exhibit is to review the application of current mr techniques to pediatric marrow imaging across the spectrum of normal, variant, and pathologic processes. methods & materials: cases with potentially overlapping imaging appearances on conventional mr sequences, including hematopoetic marrow, sickle cell disease, osteomyelitis, chronic recurrent multifocal osteomyelitis, and infiltrative neoplasms, will be presented. the basis of various mr techniques including chemical shift imaging, "whole body" marrow imaging, diffusion weighted imaging, and fat-water separation techniques such as dixon or ideal (ge) will be reviewed. the strengths and weaknesses of such techniques in differentiating between infection, neoplasm, and normal variation will be emphasized through the case examples. challenges and pitfalls in the imaging of these pathologies using such techniques will be discussed. results: current mr imaging techniques add specificity to diagnoses of marrow pathology which are otherwise difficult to differentiate using traditional sequences alone. the use of opposed phase imaging can be helpful in differentiate hematopoietic marrow or infection from infiltrative and neoplastic conditions. "whole body" marrow imaging may serve as an alternative to other modalities which involve significant radiation exposure. the use of diffusion weighted imaging is a promising, but developing, technique being applied to marrow pathology. conclusions: pediatric bone marrow mr imaging is a challenging area for a vast majority of the radiologists. understanding normal developmental bone marrow changes and being aware of the pitfalls is crucial to render accurate diagnosis. current techniques such as ideal, chemical shift imaging, and "whole body" mri have a potentially important role in further characterization of marrow abnormalities. radiologists beware: unusual imaging manifestations in child abuse eglal shalaby-rana, mbbs (hons), children's national medical center, erana@childrensnational.org; allison m. jackson, tanya hinds, katherine deye purpose or case report: to present less common imaging manifestations of injuries in child abuse that may not be readily recognized as possibly abusive injury. methods & materials: through bi-monthly review of cases with the child protection team over a period of 12 years, the imaging studies of patients with suspected non-accidental trauma were recorded. of the 654 pts with suspected nonaccidental trauma, outcomes were available in 599 patients. the child protection team concluded 254 (43%) were cases of non-accidental trauma with reasonable medical certainty. this data base was reviewed for less common injuries that were found in these medically confirmed cases of child abuse. results: less common manifestations of abuse identified by radiographs included salter-harris injuries in the proximal humerus, and proximal femur. pelvic fractures were rare and when present were associated with sexual abuse. severe chest wall injury, with associated rib fractures, causing complete or near-complete white-out of the chest was occasionally encountered. soft tissue injures, such as hematomas were found in various locations in the body including the buttocks and anterior abdominal wall, were imaged on ultrasound and ct. paraor prevertebral injuries, with or without associated bone injury were identified; one infant presented with retropharyngeal soft tissue swelling. mri identified cervical spine injuries which included ligamentous injury and intrathecal hematomas. conclusions: while classic metaphyseal lesions and rib fractures are the most common, specific injuries documented by radiologic work up of suspected non-accidental trauma, less common injuries to the soft tissue and skeletal system may occur as a result of child abuse. the ability of the radiologist to recognize these uncommon manifestations of demonstrated in axial, coronal, and sagittal planes. the ligament of interest will be denoted by arrows. at the conclusion of the anatomy section, there will be a self assessment exam. the participants then will be asked to identify the ligament. if answered correctly, a summary slide will be displayed and, if common, images of the relevant pathology will be demonstrated. if an incorrect answer is indicated, a slide will appear denoting the incorrect answer with explanation. conclusions: hopefully, with review of this educational exhibit, the participant will have a better understanding of the relevant ligamentous anatomy of the ankle and hindfoot. purpose or case report: the purpose of this educational exhibit is to demonstrate the pathologic sonographic findings, one might encounter in the pediatric ankle. a systematic methodological approach including patient positioning, transducer orientation and sonographic technique are vital for ideal sonographic assessment of the pediatric ankle. using a data search program from a large academic institution, pediatric ankle ultrasounds performed in the last 10 years were reviewed. pathologies include trauma, inflammation/infection, masses and congenital abnormalities. examples of normal anatomy will be included particularly when demonstrating ligament and tendon pathology. the normal side was often assessed for comparison purposes. results: ankle sonography is a useful modality to evaluate commonly encountered pathologies in the pediatric ankle. radiographically occult fractures may be discovered. ligament and tendon pathology, such as tears of the anterior talofibular ligament, high ankle sprain and peroneus longus tendon tears, can be easily detected. signs of infection that can be radiographically occult such as subtle periosteal reaction or fluid collections can be identified. finally, "lumps and bumps" can be characterized. for example, one of the most commonly encountered masses in the pediatric ankle is a ganglion cyst which can be well characterized sonographically. awareness of imaging pitfalls is also critical to avoid misdiagnosis and to guide appropriate management. conclusions: with basic ultrasound skills and knowledge of normal anatomy, sonography of the pediatric ankle is a useful modality to evaluate soft tissue structures and other pathologies. it is comparable to mri and allows for dynamic evaluation without need for anesthesia. resonance angiography (mra) using time resolved imaging is a relatively new technique that has become increasingly utilized in the diagnosis of vascular anomalies. we will describe the technique used at our institution, time resolved imaging of contrast kinetics (tricks, ge healthcare, milwaukee, wi), and the parameters that can be adjusted to optimize the exam. we will review key imaging features of hemangiomas and vascular malformations in various modalities, with a special emphasis on the tricks appearance. we performed a retrospective review of all the tricks studies performed at our institution for suspected vascular anomalies. in addition to the mr imaging features, we specifically analyzed the t1 weighted with fat saturation post tricks enhancement and the temporal tricks enhancement pattern. we reviewed all additional imaging including plain film, ultrasound, and ct and correlated the radiographic imaging with the available clinical and histopathologic features. results: we present illustrative cases of hemangiomas, kaposiform hemangioendothelioma, venous malformations, arteriovenous malformations, lymphatic malformations, and other pitfall lesions. we propose a diagnostic algorithm that relies heavily on the post contrast t1 weighted with fat saturation post tricks enhancement pattern and the temporal tricks enhancement pattern. conclusions: time resolved contrast-enhanced mra has become an increasingly important adjunct in the diagnosis of vascular anomalies. optimization of the exam technique and familiarity of the tricks imaging appearance is essential and can often assist in accurate lesion characterization. purpose or case report: vertical expandable prosthetic titanium rib (veptr) is increasingly used in the treatment of thoracic insufficiency, scoliosis, and chest wall defects in children. in contrast to spinal fusion surgery, veptr allows for growth while stabilizing the deformity. we review the indications, pre-operative imaging, normal radiographic appearance, and complications of this device. methods & materials: on review of the literature, the indications for veptr have expanded in the past several years to include thoracic insufficiency, idiopathic and neuromuscular scoliosis, and chest wall defects. we illustrate the normal radiographic appearance of the three common configurations of veptr (cradle-to-cradle assembly, cradle with lumbar extension assembly; cradle-to-ala hook assembly). we discuss the potential complications of veptr, including infection, rib fracture, dislodged hardware, and neurological injury, with an emphasis on imaging diagnosis. results: there is a relatively high rate of reported complications with veptr in the literature. therefore, awareness of the growing number of indications, as well as the expected and unexpected appearance of this device, aids in radiographic diagnosis of complications. conclusions: vertical expandable prosthetic titanium rib (veptr) is gaining acceptance in the treatment of thoracic insufficiency, scoliosis, and chest wall defects in children. recognition of the indications, normal radiographic appearance, and complications of this device will facilitate timely and accurate diagnosis. disclosure: dr. philips has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. spectrum of pediatric spinal neoplasms: an interactive tutorial benjamin t. haverkamp, md, radiology, university of missouri-kansas city, haverkampbt@umkc.edu; salvador f. iloreta, maha jarmakani, lisa lowe, seth gibson purpose or case report: the objective of this educational electronic exhibit is to provide the radiologist with an approach to pediatric spinal neoplasms. emphasis will be placed on narrowing the differential diagnosis using a combination of lesion location, characteristic imaging findings, relevant history, and associations. the exhibit format will include a casebased review of various pediatric spinal neoplasms, radiologicpathologic correlation, and a brief discussion of imaging findings useful in guiding surgical management. an interactive selfassessment exam will be presented at the end of the exhibit. results: a review of the specific etiologies will be presented with classification as intra-and extra-medullary and extradural lesions. radiologic images will be related to gross and microscopic pathology. conclusions: after viewing this exhibit, the learner will be able to: 1. recognize the clinical, imaging, and pathologic characteristics of pediatric spinal neoplasms. 2. understand relevant imaging findings useful in surgical management. 3. test their understanding of the presented material through an interactive exam. poster #: edu-057 craniosynostosis jason tsai, mbchb, children's hospital boston, jason. tsai@childrens.harvard.edu; diana p. rodriguez purpose or case report: to review the normal developmental appearance of the cranial sutures with computed tomography (ct) and to describe ct findings of the various forms of craniosynostoses. in this irb-approved retrospective study we reviewed ct images of subjects diagnosed with craniosynostosis between 2006 and september 2011. we included patients with single-suture synostosis, isolated bilateral coronal synostosis, pansynostosis, and combined craniosynotoses. additionally, we identified individuals with normal appearing sutures from 0 to 5 years of age imaged with head ct to describe the pattern of normal development of the cranial sutures. results: a description of the normal developmental ct appearance of the cranial sutures using computed tomography has been provided. of the group of patients with craniosynostosis the following variables were recorded: age at presentation, the pattern of sutural fusion, skull shape, presence of hydrocephalus, genetic testing, and types of surgical correction. conclusions: we have demonstrated the normal developmental ct appearance of the cranial sutures and the ct patterns of the various forms of craniosynostoses, with clinical, genetic and surgical correlation. posterior fossa tumours: a pictorial review sam byott, md, manchester children's hospital, sambyott@ hotmail.com; neville wright, vivian tang, abdu shabani, stavros stivaros purpose or case report: posterior fossa tumours account for 54-70% of childhood brain tumours. the most common differentials include pilocytic astrocytoma, medulloblastoma and ependymoma. mr imaging is crucial to diagnosis, staging and identification of complications such as hydrocephalus and haemorrhage. soft tissue characteristics alongside tumour location, invasion and clinical history facilitate radiological discrimination prior to surgery. however, there is significant clinical equipoise with regards to the imaging appearances in a significant proportion of cases making definite diagnosis difficult. the aim of this study is to evaluate the radiological findings and correlate with histological data. this will allow identification of the key morphological features that discriminate different tumours. these can then be presented to educate fellow radiologists. methods & materials: radiology pacs and patient notes were used to collate radiological, histological and clinical data. results: there were 27 patients presenting at our institution with posterior fossa tumours. 12 had pilocytic astrocytomas, 8 had medulloblastomas and 7 had ependymomas. one patient had an atypical teratoid rhabdoid tumour (atrt). traditional features alongside more advanced mr characteristics were correlated with histology, and the features allowing for discrimination of tumour types are presented in this pictorial review. conclusions: posterior fossa tumours have a highly variable radiological appearance. we present a range of appearances and describe the important morphological features that allow radiological discrimination of tumour type. poster #: edu-059 3dt1 imaging of the pediatric spine teresa c. gross kelly, children's hospital of wisconsin, tkelly@chw.org; ibrahim s. tuna, mia s. kelly, tushar chandra, sumit singh, mohit maheshwari, hervey d. segall purpose or case report: some abnormalities of the pediatric spine can be challenging. we have discovered that in many such cases, diagnosis of spinal lesions can be faciliated by using the 3dt1 weighted sequence. the purpose of this educational poster is to demonstrate the remarkable usefulness of 3dt1 weighted images for delineating pathology of the pediatric spine. methods & materials: lesions of the spine that will be reivewed in this educational exhibit will be categorized as: (1) vascular (2) due to infection/inflammation (3) neoplastic/ neurogenic (4) congenital (5) traumatic/iatrogenic (6) endocrine/metabolic. the imaging characteristics of lesions found in the pediatric spine will be described and the utility of 3d t1-weighted mr sequences for the evaluation of these lesions will be discussed. finally the role of imaging in the treatment planning of abnormalities of the pediatric spine will be addressed. results: this educational exhibit will provide numerous examples of how 3d t1-weighted imaging can elucidate diagnosis of lesions involving the spine. examples include enhancement of the cauda equina in guillain barre syndrome, lipomatous malformations, spondylolysis in children with low back pain, thecal cysts, filar cysts, metastasis, hydromyelia and ventriculus terminalis. conclusions: 3d t1-weighted images of the spine performed in the sagittal plane with coronal and axial reformations, as well sagittal oblique reformations (scotty dog reformations) for evaluation of spondylolysis, can facilitate the evaluation of lesions involving the pediatric spine. the normal pediatric spine: a pictorial review of mr anatomy and development in the infant, child and adolescent ibrahim s. tuna, md, radiology, children's hospital of wisconsin, dristuna@yahoo.com; teresa c. gross kelly, tushar chandra, mohit maheshwari, sumit singh, hervey d. segall purpose or case report: radiological evaluation of the pediatric spine can be more challenging in child than in the adult patient due to the wide range of normal anatomic variants and synchondroses, combined with the unique effects of trauma in children. mri is an excellent imaging modality for the evaluation of the pediatric spine. however, in order to provide an accurate interpretation of acute posttraumatic changes in the pediatric spine, particularly in the setting of abusive head trauma, a fundamental knowledge of normal anatomy, variants and pathology of the pediatric spine is required. the aim of this educational exhibit is to illustrate normal mri anatomy of the spine in the infant, child and adolescent. methods & materials: this exhibit will first describe basic spinal embryology and development of the vertebra and spinal cord, followed by mri depiction of the developmental anatomy of the spine from infancy through adolescence. the changing appearance of the spinal canal, spinal cord and vertebral bodies with age will be illustrated using normal cases from the radiology database. sagittal and transverse diameter of vertebral bodies, thickness of the dural thecal sac, dimensions of the spinal canal, normal bone marrow signal changes, vertebral body heights, level of conus medullaris, prevertebral and paraspinous soft tissues and epidural fat thickness will be described and changes according to age will be pointed out. results: in early life, the spinal cord extends to the inferior aspect of the bony spinal column. because the vertebral bodies grow longitudinally faster than the spinal cord does, the conus medullaris may change. ossification of the vertebral bodies and posterior elements is nearly complete by age 10, with a resultant decrease in the spinal canal diameter. the nucleus pulposus becomes smaller after 10 years and spans approximately half the disk space in the sagittal plane. the spinal cord is elliptical in cross section in the cervical spine and demonstrates a difference in signal between the normal gray and white matter of the spinal cord which should not be mistaken for intramedullary pathology. conclusions: a solid understanding of normal spine anatomy and embryological development is essential in evaluation of pediatric spine, mainly in the setting of trauma. familiarity with normal anatomic variants is essential to provide an accurate interpretation of pathology in the pediatric spine. spectrum of intracranial cystic lesions in infants and children ernesto i. blanco, md, st. christopher's hospital for children, eiblanco74@gmail.com; eric faerber purpose or case report: to review the imaging spectrum of intracranial cystic lesions in the pediatric population. methods & materials: a retrospective review of our imaging database was performed to identify studies obtained in which the findings included intracranial cystic lesions. results: multiple cystic lesions were elucidated primarily by computed tomography or magnetic resonance imaging. these lesions can be divided into nonneoplastic and nonneoplastic tumor-associated cysts. the nonneoplastic cysts, which is the largest group, include: cavum septi pellucidi and cavum veli interpositi, choroid plexus cyst, enlarged peri-vascular spaces, pineal cyst, the large spectrum of arachnoid cysts, colloid cyst, epidermoid cyst, rathke cleft cyst, and porencephalic cyst. nonneoplastic tumor-associated cysts include: craniopharyngioma, optic glioma, pilocytic astrocytoma, hemangioblastoma, and ganglioglioma. conclusions: intracranial cystic lesions are relatively common entities in the pediatric population. a wide spectrum of nonneoplastic and nonneoplastic tumor associated pathologies are presented using both computed tomography and magnetic resonance imaging. kelly, sumit singh, ibrahim s. tuna, hervey d. segall purpose or case report: the aim of this educational exhibit is to provide a comprehensive review of imaging features, classification and management of pediatric spinal cord tumors. we also aim to elicit the differences between pediatric spinal cord tumors and their adult counterparts. we will summarize the differences between the individual tumors based on histological cell types and the pertinent implications on management and outcome methods & materials: this exhibit will provide an overview of the common as well as uncommon tumors of the pediatric spinal cord. various classification systems for these tumors-anatomical as well as histological will be discussed. we will illustrate the relevant imaging findings that can help in differentiating these tumors. results: pediatric spinal cord tumors account for 1% to 10% of all pediatric central nervous system tumors. mri is the mainstay for the initial diagnosis as well as the post surgical evaluation and surveillance of these tumors. pediatric and adult spinal cord tumours differ both in terms of anatomical location as well as histology. the disease and treatment related morbidities are also different in children as compared to adults. astrocytomas, ependymomas, glioneural tumors and csf metastasis represent the vast majority of cord neoplasms in the pediatric age group. some of cord tumors may also be associated with inherited syndromes (like neurofibromatosis type 2) or may have genetic predisposition. these would also be discussed. we will also illustrate and discuss common non neoplastic spinal masses that may mimic tumors. conclusions: pediatric spinal cord tumors have varied clinical presentations, imaging appearance and outcome. this review would improve the understanding of these tumors thereby helping in diagnosis, management and follow up of these uncommon neoplasms. multi-modality imaging of pediatric head and neck lesions jason au, md, oklahoma university health sciences center, jasonmau@gmail.com; anthony alleman, mahmoud elkaissi, roy jacob purpose or case report: the purpose of this study is to present a side by side comparison of the multi-modality imaging features of pediatric masses. using cases that have been imaged with multiple modalities, the exhibit will delineate the sonographic, mr, and ct appearance of congenital, infectious, and neoplastic head and neck lesions in the pediatric population. methods & materials: a restrospective search of pacs was performed on studies completed at the oklahoma university medical center on the oklahoma university health science center campus from january 2008 to the present. ultrasound, ct, and mr examinations were selected that depicted relevant pediatric head and neck pathology. all studies were de-identified prior to image export. results: over twenty representative cases of pediatric infections, fibrous tumors, cystic neoplasms, vascular malformation, bony tumors, developmental anomalies, and other neoplasms were selected for inclusion. results: pictorial review of cases including the following representative cases: myelonmeningocele associated with arnold chiari malformation, lipomyelomeningocele, tethered cord with spinal lipoma/fibrofatty filum, tethered cord and dermal sinus tract, and chiari i with syringohydromyelia. several unique cases including the following will be presented as well: thoracic meningocele with arnold chiari malformation, terminal myelocystocele, diastematomyelia, and myelomeningocele without arnold chiari malformation. while mri demonstrates the cranio-cervical junction and the cervicothoracic spinal cord better than ultrasound, ultrasound often allows for improved resolution of the distal spinal cord, lumbosacral spinal canal, and spinal dysraphism structures near the skin surface in the neonate. conclusions: congenital spinal malformations are complex and variable in imaging appearance. it is important to understand the classification in order to determine the appropriate management and prognosis. in the neonatal period imaging should be performed with ultrasound and mri studies, as they may provide different and complementary information. conclusions: hypoxic ischemic injury is a common condition resulting in a wide spectrum of severe neurological defects. while in the past treatment only consisted of supportive care for hii, recent advances have yielded promising treatment options if initiated within a limited time window. thus due to the severity of the disease and the need for rapid intervention, it is important to recognize radiological manifestations of hii along with its clinical signs and symptoms to offer a better prognosis to the patient. craniosynostosis: looking beyond the sutures tushar chandra, md, children's hospital of wisconsin, drtusharchandra@gmail.com; teresa c. gross kelly, mohit maheshwari, sumit singh, ibrahim s. tuna, hervey d. segall purpose or case report: the aim of this educational exhibit is to provide a framework upon which the diagnosis of the various types of craniosynostosis can be facilitated. our goal is to provide an efficient way to evaluate craniosynostosis for the radiologist in clinical practice. we plan to accomplish this goal by providing a succinct review of the sutures, an overview of the various classification schemes for craniosynostosis and potential complications associated with premature sutural closure. the role of imaging in the evaluation of craniosynostosis will be described and the features of craniosynostosis that are most important to the craniofacial surgeon will be elucidated. finally, surgical strategies for the repair of craniosynostosis and postoperative findings will be described. results: some of the forms of craniosynostosis may have a genetic basis, but many are spontaneous in nature. untreated progressive craniosynostosis can lead to inhibition of brain growth, and an increase in intracranial pressure. mdct with mip and 3d surface reformations is the preferred modality for diagnostic evaluation of craniosynostosis. it is also a robust modality for post operative assessment and long-term follow up. mri is a useful adjunct for assessment of associated intracranial anomalies and complications. timely and appropriate imaging is essential to assess for potential complications of craniosynostosis which may include intracranial hypertension, anomalies of external and middle ear, hydrocephalus, chronic tonsillar herniation, cranial base deformity, impaired venous drainage, enlarged emissary foramina and veins and optic atrophy. on the other hand, positional plagiocephaly should not be misinterpreted as craniosynostosis. surgical management is typical for nonsyndromic craniosynostosis, which involves correction of craniosynostosis between three to six months of age. conservative management is the mainstay for syndromic craniosynostosis. postoperative follow up imaging for surveillance for ventricular size and signs of raised intracranial pressure are necessary. conclusions: craniosynostosis is a challenging area of pediatric neuroimaging. knowledge of the sutural anatomy, an understanding of the potential intracranial complications caused by premature sutural closure, as well as the role that imaging plays in presurgical planning, can provide a practical way for the radiologist to evaluate craniosynostosis in a fast-paced clinical setting. poster #: edu-067 the perinatal brain and spinal cord-imaging across a life border: a case-based approach anand dorai raju, md, radiology university of tennessee, araju@uthsc.edu; harris l. cohen, matthew whitehead, asim choudhri purpose or case report: to review normal and abnormal perinatal ultrasound (us) and magnetic resonance (mr) imaging findings and note their significance for the analysis of the fetal and neonatal brain as well as spinal cord and vertebral column using a case based approach. to highlight us and mr capabilities in allowing correct perinatal diagnosis of congenital and acquired central nervous system abnormalities. methods & materials: cases will be shown of normal and abnormal anatomic findings in fetal and neonatal brain and spinal cord imaging. key teaching points necessary for the diagnosis of such brain abnormalities as ventriculomegaly, chiari malformations, holoprosencephaly, and agenesis of the corpus callosum as well as dandy walker malformations and avms will be discussed. intraventricular hemorrhage, periventricular leukomalacia, anoxic injuries and infectious abnormalities will be reviewed. abnormal anatomic findings in fetal and neonatal spine evaluations for congenital and acquired abnormalities and key teaching points necessary for the accurate diagnosis of tethered cord, myelomeninocele, caudal regression syndrome, hydromyelia, diastomatomyelia and sacrococcygeal teratoma will be reviewed. some diagnostic difficulties and controversies will be addressed. conclusions: ultrasound aided by mri can provide ready diagnosis to many central nervous system abnormalities involving fetuses and neonates. ever improving perinatal imaging experience and technique allow for better prenatal as well as postnatal diagnosis. cases showing such imaging and key points helping such imaging diagnoses will be reviewed. overview of imaging of pediatric extraocular orbital tumors srikala narayanan, md, division of radiology, children's national medical center, snarayan@childrensnational.org; nadja kadom, gilbert l. vezina purpose or case report: to show the spectrum of benign and malignant extraocular orbital tumors in children. methods & materials: we reviewed the cross-sectional imaging of orbit (ct and mr) done in the last 5 years. specific imaging signs of extraocular tumors including benign and malignant tumors such as hemangiomas, lymphangiomas, optic nerve glioma, optic nerve sheath meningioma, pseudotumors, rhabdomyosarcoma, orbital myofibroma, eosinophilic granuloma and neuroblastoma metastases will be shown. important imaging features that should be considered when formulating a differential diagnosis will be described. conclusions: the spectrum of diseases affecting pediatric orbit is substantially different from what we see in the adults. it is not easy always to differentiate between different tumors. important imaging characteristics will help us towards better differential diagnosis. in this exhibit, we will illustrate ultrasound anatomy of the neonatal spinal cord. discussion of the normal anatomic variants and pathological conditions of the spinal cord will be provided. representative images of a variety of common and uncommon pathological conditions of the spine will be presented to illustrate teaching points. in abnormal cases, follow up mri images will also be illustrated for comparison. results: ultrasound is a robust screening modality for evaluation of the lumbosacral spine in neonates. it is cheaper, readily available, safer first line imaging modality in neonates suspected to have spinal malformations. under able and well trained operator, diagnostic accuracy of spinal ultrasound approaches mri. however, mri remains the gold standard for imaging evaluation of spine. normal variants that simulate disease processes like ventriculus terminalis, prominent filum terminale and central echo complex will be presented. congenital malformations of the cord such as tethered cord, hydromyelia, lipoma, diastematomyelia, myelomeningocele, lateral meningocele and presacral masses will also be discussed. conclusions: ultrasound is a very useful screening technique for evaluation of pathological conditions of lumbosacral spine in neonates. this review would improve the understanding of utility and limitations of ultrasound in evaluation of neonatal spinal malformations. purpose or case report: although mri is the standard for detecting epilepsy and brain tumor abnormalities, pet-ct is performed to ascertain metabolism related to epileptogenic regions or characterize tumor metabolic activity. asymmetric metabolism often correlates to structural abnormalities like cortical dysplasia. metabolic activity often correlates with tumor aggressiveness or grade. fdg pet is commonly used to assess seizure and tumor metabolism. the lesser utilized amino acid pet tracers (c11 methionine, fdopa) show increasing value with lower grade tumors due to high tumor to normal tissue contrast. literature is accumulating regarding c11 methionine (cmet) in the detection of lesions like cortical dysplasia and its ability to delineate low grade seizure related tumor lesions. despite the established fdg and accumulating cmet literature, little information exists about the imaging seen with both in pediatrics. as these studies are increasingly viewed as part of fusion mri images, there is more scrutiny of focal metabolism correlating with mri findings and less interpretative reliance on abnormality based solely on asymmetry. methods & materials: review of 110 patients who underwent cmet and fdg brain pet-ct was performed. each was imaged on a philips scanner and had prior mri. studies demonstrating a variety of tumors, postoperative findings of residual or recurrent tumor, and pseudoprogression were selected. epilepsy cases with structural cortical abnormalities or seizure-associated tumors were also selected. cmet and fdg studies were analyzed by 3 pediatric neuroradiologists and the imaging findings correlated with prior mri and any pathology or follow-up imaging. pictorial galleries of the cmet and fdg imaging patterns were created. results: pathologically proven low-grade glial tumors showed increased cmet uptake and no hypermetabolism on fdg. high-grade tumors showed increased uptake on cmet and hypermetabolism on fdg. patients with residual or recurrent tumors showed uptake similar to their original tumor. granulation tissue and pseudoprogression changes showed increased uptake on cmet and no hypermetabolism on fdg. epilepsy surgery patients with cortical dysplasia or low grade glial tumors showed increased uptake on cmet and fdg hypometabolism. conclusions: this study illustrates the variety of findings on cmet and fdg pet-ct in pediatric patients clinically evaluated for brain tumor and epilepsy. this atlas provides readers with a guide to the appearance of these findings on an emerging imaging technique. pediatric head and neck neoplasms: a multimodality pictorial review alok jaju, md, mallinckrodt institute of radiology, alokjaju@gmail.com; marilyn j. siegel purpose or case report: neck masses are common in children and most occur in the suprahyoid region. knowledge of the fascial spaces involved in conjunction with imaging features can help in diagnosis. in this pictorial review, we present a multimodality imaging approach based on anatomy of the suprahyoid fascial spaces for evaluation of pediatric neck tumors. methods & materials: radiology information system (ris) at our tertiary care children's hospital was queried to identify patients with suprahyoid neck masses who had imaging performed between july 2004 and present. a variety of conditions having congenital, inflammatory, neoplastic, or vascular origin were identified and the anatomic location in the neck as well as imaging and clinical findings were retrospectively reviewed. results: the imaging evaluation included ultrasound, ct and mri. lesions arose within the following fascial spaces of the suprahyoid neck: superficial, carotid, masticator, submandibular, sublingual, parotid, parapharyngeal, visceral, retropharyngeal and prevertebral. key imaging features important in diagnosis included lesion vascularity, calcification, necrosis and bone invasion. we discuss and illustrate these imaging findings and relate them to specific suprahyoid fascial spaces. specific lesions include vascular and lymphatic malformations, teratoma, nerve sheath tumors, thyroglossal duct and branchial cleft cysts, pleomorphic adenoma, dermoid cyst, ranula, lymphadenopathy, abscess, lymphoma, rhabdomyosarcoma, neuroblastoma and nasopharyngeal carcinoma. conclusions: knowledge of fascial spaces of the suprahyoid compartment and key imaging features on multiple modalities can aid in the diagnosis of pediatric neck masses. pediatric sinusitis: spectrum of imaging findings with clinicopathologic correlation roy jacob, md, university of oklahoma, drjacobr@gmail. com; paul digoy, robert s. glade, anthony alleman purpose or case report: the clinical spectrum of sinusitis in children can range from uncomplicated bacterial sinusitis to invasive fungal sinusitis. most cases respond favorably to medical management. however, complications occasionally occur due to the spread to adjacent structures. imaging plays an important role in characterizing the disease and guiding the clinical and surgical planning and treatment. this electronic presentation outlines the following-1. review radiologic anatomy and unique characteristics of pediatric sinuses. 2. review the clinical features, pathophysiology, and microbiology of sinusitis. 3. review of ct and mri imaging characteristics of sinusitis with representative cases such as complicated sinusitis and invasive fungal sinusitis. 4. review the treatment approaches of sinusitis. methods & materials: a retrospective search of pacs was performed on studies completed at the ou children's hospital in oklahoma city for the last three years. ct and mr examinations were selected that depicted relevant disease processes. corresponding nasal endoscopic pictures were obtained from cases which required surgical management. all studies were de-identified prior to image export. results: over fifteen representative cases of the clinical spectrum of sinusitis and its complications were selected for inclusion. conclusions: this educational exhibit provides a concise review of imaging, clinical features, and treatment of pediatric sinusitis. findings will be richly illustrated with radiological and clinical images. microcephaly or hydrocephalus. knowing the embryology of the cerebellum and 4th ventricle is important to perceive the development of posterior fossa malformations and to further understand the imaging findings. several classifications schemes have been proposed from a pure embryologic to an imaging-based approach using some essential findings such as the size of the posterior fossa, the presence of csf collection or expansion of csf space, and the size and morphology of the cerebellum. mr is the gold-standard for adequately access and characterize the posterior fossa structures. this pictorial essay will review the mr findings of some of the most common posterior fossa malformations including dandy-walker malformation, persistent blakes pouch, mega cisterna magna, arachnoid cyst, paleocerebellar hypoplasia, cerebellar agenesis, cerebellar and pontocerebellar hypoplasia, cerebelar cortical malformations, isolated brainstem hypoplasia/dysplasia and chiari malformations. we will provide a practical approach to the mr findings of posterior fossa malformations in children. conclusions: mr plays a crucial role in identifying and characterizing malformations of the posterior fossa structures. it should give a logical approach to these complex malformations thus guiding the refereeing physician into the clinical approach and in determining further investigations. results: neuroimaging features of abnormal thalami as encountered in the pediatric population were detailed, and wherever applicable, the relevance of additional mr imaging sequences and techniques to determine etiology was described. while there was considerable overlap in imaging appearances, making a precise diagnosis was found to be challenging in difficult cases, and by and large, a stepwise approach was successfully formulated and used to: 1. diagnose the more emergent conditions and to 2. devise a management algorithm for the less acute abnormalities. conclusions: bilateral thalamic lesions are occasionally encountered in pediatric neuroimaging and have a limited differential; a good knowledge base and adequate technique are imperative to tease out the precise diagnosis and institute appropriate management. cortical developmental abnormalities in pediatric seizure patients ibrahim s. tuna, md, radiology, children's hospital of wisconsin, dristuna@yahoo.com; mohit maheshwari, teresa c. gross kelly, sumit singh, tushar chandra, hervey d. segall purpose or case report: to describe various cortical malformations with illustrative examples. we will also briefly discuss the embryology, genetic basis, classification schemes and characteristic imaging findings . methods & materials: this exhibit will illustrate three main categories of cortical malformations: neuronal proliferation, migration and organization. understanding of this complex topic would be facilitated by brief discussion on the embryological basis and proposed genetic causes of some of these cortical malformations. classification schemes on embryology and imaging will be discussed. characteristic imaging findings of these malformations will be discussed and examples from the authors database will be shown. results: neuroimaging in pediatric seizures is challenging. mri is considered the imaging modality of choice because of superior soft tissue contrast and better ability to characterize the pathologic process. we will also discuss the dedicated seizure protocol which is used in our institute. pet-ct imaging can also provides additional information in cases where mri is negative, inconclusive or does not correlate with eeg/clinical findings. brief discussion on advanced imaging techniques will also be presented. malformations are frequently detected in infancy. however, if the initial mri scan performed in infancy is negative, a repeat scan after 2 years of age may be helpful. conclusions: evaluation of cortical malformation in seizure patients still remains a challenging area of pediatric neuroimaging. reviewing of the embryological basis, classification schemes and characteristic imaging findings would improve the understanding the cortical malformations and interpreting the images. poster #: edu-079 sprs best poster 2011 cystic neonatal lesions associated with the spinal cord: discussion and differential diagnosis for these uncommon lesions jacob pirkle, md, jpirkle@mc.utmck.edu, james boyd, brian dupree purpose or case report: to review intradural cystic neonatal spine lesions and discuss the various causes and appearance of these lesions. this poster presentation provides a brief review of neonatal cystic spine lesions, including their etiologies, and presents the targeted audience (radiology resdients, fellows, and practicing radiologists) a helpful differential diagnosis of these lesions based upon their imaging appearance. methods & materials: a brief overview of neonatal cystic spine lesions, their etiology, and imaging appearance is presented in poster format utilizing both literature search and printed reference material. images from several cases of cystic neonatal spine lesions are presented. results: a brief overview of neonatal cystic spine lesions, their etiology, and imaging appearance is presented in poster format utilizing both literature search and printed reference material. images from several cases of cystic neonatal spine lesions are presented. conclusions: neonatal spine ultrasound is often performed to evaluate for abnormalities related to the presence of sacral dimples, cutaneous stigmata, skin tags, hairy tufts, during the evaluation of other congenital anomalies, or when prenatal ultrasound/mri demonstrates an abnormality warranting postnatal follow-up. the identification of cystic spinal cord lesions is relatively rare in the neonate. however, the etiology of these lesions can often be deduced or surmised based upon the location and the imaging appearance of the lesion. the most common cause of a cystic intramedullary spinal lesion is ventriculus terminalis, with a reported incidence of 2.6%. additional lesions include transient dilatation of the central canal, filar cyst, syringohydromyelia, intramedullary arachnoid cyst, and myelomalacia related to in utero/birth trauma. extremely rare etiologies in the neonate include epidermoid/dermoid, cavernous malformation, intranatal cystic infections etiologies, neuroepithelial cysts, and cystic neoplasms. mimics include diastematamyelia, spinal lipomas, and intramedullary hematomas. numerous imaging examples of these lesions are provided in the accompanying poster. brain mri in peroxisomal disorders: a pictorial essay bruno p. soares, md, radiology and biomedical imaging, university of california at san francisco, bruno.soares@ucsf. edu; leonardo vedolin, guido gonzalez purpose or case report: our presentation aims to illustrate the brain mri patterns in peroxisomal disorders. peroxisomes are intracellular organelles involved in important cellular processes including beta-oxidation of very-longchain fatty acids and plasmalogen production. peroxisomal disorders can be categorized into disorders of peroxisomal biogenesis, in which the peroxisomes are abnormally formed and several peroxisomal functions are deficient, and in defects involving a single peroxisomal function, in which the structure of the peroxisome is intact. disorders of peroxisomal biogenesis include zellweger syndrome, neonatal adrenoleukodystrophy, infantile refsum disease and rhizomelic chondrodysplasia punctata. numerous disorders are caused by loss of a single peroxisomal function including x-linked adrenoleukodystrophy and acyl-coa oxidase deficiency. clinical findings in peroxisomal disorders include dysmorphic features, hepatic dysfunction, neurodevelopmental delay, retinopathy and hearing impairment. methods & materials: pictorial essay illustrating brain mri patterns in peroxisomal disorders, including disorders of peroxisomal biogenesis and disorders with loss of a single peroxisomal function. results: brain abnormalities in peroxisomal disorders have a wide spectrum of patterns. neuronal migration disorders with abnormal myelination are typically seen in zellweger disease and neonatal adrenoleukodystrophy. specifically, the association of abnormal myelination with germinolytic cysts is suggestive of zellweger syndrome. classic x-linked adrenoleukodystrophy typically shows posterior central white matter involvement and symmetric demyelination also involving the corticospinal tracts and corpus callosum. a similar pattern of white matter involvement is seen in acyl-coa oxidase deficiency and infantile refsum disease. conclusions: brain mri helps narrow the differential diagnosis and guides subsequent evaluation in infants presenting with clinical features concerning for peroxisomal disorders. therefore, knowledge of the brain mri patterns in peroxisomal disorders is important for the radiologist interpreting neuroimaging studies. clots in tots: role of imaging in diagnosis of acute stroke and its causes in children asif abdullah, c.s. mott children's hospital of the university of michigan, asifa@med.umich.edu; ellen hoeffner, augusto elias purpose or case report: stroke is a major cause of morbidity and mortality in children. long-term neurologic deficits occur in 50% to 85% of infants and children after arterial ischemic stroke. limited awareness regarding pediatric stroke among physicians and in general community is a major concern. imaging plays crucial role in the diagnosis of pediatric stroke. the goal of this presentation is to provide awareness to the reader about the role of imaging in childhood stroke and its myriad causes in children. we will provide a case based approach to imaging diagnosis of acute pediatric stroke based on three categories: (1) arterial ischemic stroke, (2) cerebral venous thrombosis, and (3) hemorrhagic. arterial ischemic stroke (ais) is classified according to the pediatric stroke classification (psc). psc includes eight subtypes of ais: (1) sickle cell disease, (2) cardioembolic disease, (3) moyamoya syndrome, (4) cervical arterial dissection, (5) stenoocclusive cerebral arteriopathy, (6) other determined etiology, (7) multiple probable etiologies, and (8) undetermined etiology. we will describe the role of computed tomography (ct) and magnetic resonance imaging including angiography (mri/mra) in identifying these causes in relation to available clinical data. the etiologies of cerebral venous thrombosis related infarction would be discussed from an imaging perspective with a case-based approach with emphasis on mrv and swi techniques. finally, we will focus on hemorrhagic causes of childhood stroke such as vascular malformation, aneurysm, neurocutaneous disorders, coagulopathy, and a variety of other causes from an imaging standpoint. perfusion imaging in pediatric stroke demonstrates flow within the brain and can detect areas that are at risk of ischemia; however, further studies in the pediatric population need to be validated for the role of this technique in pediatric stroke. results: the most important factors in the diagnosis of childhood stroke are causal investigation, appropriate laboratory tests, and imaging studies. imaging is frequently the first step in the evaluation of an acutely ill child. conclusions: pediatric stroke is a debilitating disease that requires urgent multidisciplinary approach for diagnosis and treatment. in cases of both ischemic and hemorrhagic origin, the radiological approach to be obtained in emergency setting leads to the initial screening and the first therapeutic possibility. methods & materials: this exhibit will illustrate the characteristic imaging findings of vascular anomalies in the head and neck region. vascular anomalies are divided into vascular tumors and vascular malformations which include slow flow malformations (capillary malformations, venous malformations, lymphatic malformations and their combinations) and high flow malformations (arteriovenous fistula and arteriovenous malformations). complex malformations are also seen in several syndromes including klippel-trenaunay syndrome, phace syndrome, etc. cases from author's database will be used for illustration. results: a review of clinical manifestations, characteristic imaging findings and interventional treatment strategies in cases of head and neck vascular anomalies will be presented with pre and post treatment imaging features. ultrasonography and mri are the mainstay in diagnosis of these malformations. ct scan and catheter angiography may occasionally be needed for diagnosis and treatment planning. various imaging findings and main treatment options will be listed. conclusions: head and neck vascular malformations are common in pediatric population. understanding the characteristic imaging findings and clinical presentation is essential in evaluating the vascular malformations. interventional procedures are generally the preferred treatment modality, either alone or in association with surgery in majority of these cases. isolated cortical diffusion restriction in pediatric brain mri ihsan mamoun, md, cleveland clinic, ihsanmamoun@ yahoo.com; sarah stock, s. pinar karakas, unni udayasankar, janet r. reid purpose or case report: diffusion-weighted imaging continues to emerge as a powerful neuroimaging tool. isolated cortical restricted diffusion is a particularly striking pattern with specific differential in the pediatric population. we aim to review this specific imaging pattern supplemented by case examples and key physiologic and imaging concepts. methods & materials: review the concept of diffusion restriction a) pathophysiology b) specific imaging appearances pictorial review of pediatric conditions that lead to cortical restricted diffusion: a) post ictal change b) infection-i. meningoencephaliitis ii. herpes c) hypoxic ischemic injury d) infarct: venous and arterial e) posterior reversible leukoencephalopathy f) mitrochondrial cytopathy g) metabolic: hypoglycemia. discuss certain artifacts. summary table and differential clues conclusions: the pattern of isolated cortical restricted diffusion has specific differential diagnosis in the pediatric population. the radiologist should be aware of this as use of dwi continues to grow. this exhibit with familiarize the reader with common conditions that specifically affect the cortex and produces true restricted diffusion. methods & materials: high resolution ct scan and mri are mainstay of diagnosis and assessment in patients with sensorineural hearing loss. in this exhibit we will present a pictorial review of ct scan and mri images of various causes of sensorineural hearing loss (snhl) that are seen on imaging. reviewing the embryologic basis of these anomalies would enable better understanding of this complex subject. results: the new system classifies these malformations according to descending order of severity into complete labyrinthine aplasia, cochlear aplasia, common cavity, cystic cochleovestibular malformation or incomplete partition-i (ip-i), cochleovestibular hypoplasia, and incomplete partition-ii (ip-ii). there is a lot of confusion in literature pertaining to mondini deformity. the new classification divides incomplete partition into ip-i representing cystic cochleovestibular malformation and ip-ii representing the classic mondini deformity with three components (cystic cochlear apex, dilated vestibule, and large vestibular aqeduct). recently a subclassification of ip-i and ip-ii has been proposed (subdividing into typical and atypical subtypes)[2]. this will be discussed briefly. isolated large vestibular aqueduct without associated cochlear abnormalities will also be discussed. we will discuss the relevant embryology with correlations of malformations to the timing of embryologic insult. conclusions: the new classification system provides precision in description of inner ear malformation. this also helps in providing a uniform scale for comparison of effectiveness of cochlear implant for different malformations. purpose or case report: congenital cranial nerve anomalies often present as sensory and/or motor deficits of unknown etiology in the pediatric age group. the early recognition of a definitive cranial nerve abnormality using high-resolution imaging can focus further clinical investigation and shorten the time to diagnosis. methods & materials: to promote appropriate recognition of cranial nerve anomalies, we present the imaging findings of the most commonly affected cranial nerves and provide correlation with clinical presentation. all studies were performed on a 1.5 t magnet with dedicated high resolution imaging of cranial nerve exit zones. results: ours is a tertiary care pediatric hospital with an extensive neuroimaging database. we intend to review all known cases of cranial nerve anomalies from the prior 5 years and present interesting and representative images including optic nerve hypoplasia as part of septo-optic dysplasia, kallman syndrome, duane retraction syndrome, and mobius syndrome. conclusions: congenital cranial nerve anomalies present with varied symptomatology including anosmia, impaired vision, occulomotor deficits, and hearing loss. additionally, clinical manifestations of cranial nerve anomalies can be difficult to recognize in the pediatric age group. effective imaging and prompt diagnosis is crucial to initiate appropriate clinical management. purpose or case report: mr is the standard for evaluation of tumors or epilepsy. pet-ct imaging is often performed to ascertain metabolic asymmetries related to epileptogenic regions or to better characterize the metabolic activity of tumors. a baseline for normals with pet-ct fdg-18 and c11 methionine does not exist. methods & materials: retrospective review was performed of the 110 pediatric patients who underwent pet-ct with c11 methionine and fdg. representative studies were selected for patients imaged during infancy (<1 yr), early childhood (1-4), childhood (4-7), late childhood (7-12), teenage (13-18). c11 methionine and fdg studies were analyzed for normal patterns of uptake and any trends identified across the stratified age groups. representative pictorial image galleries of the c11 methionine and fdg imaging patterns through development were created. results: the pattern of radiotracer uptake on c11 methionine differed from that of fdg. the c11 uptake remained low level throughout development compared to fdg uptake, which was robust in much of the cortex. the cortical fdg uptake within the frontal lobes progressively increased with age. the c11 uptake within the brainstem and thalamus was equal to cortex throughout development. the fdg uptake within the basal ganglia was equal to cortex while the brainstem and thalamic uptake was generally less than cortex. several anatomic structures showed robust c11 uptake not seen on fdg. these included the lacrimal, submandibular and parotid glands. incidentally, the pituitary gland and hippocampus consistently showed c11 uptake equal to cortex contrary to their appearance on fdg. our institutional protocol regarding the performance of combination c11 methionine and fdg brain pet-ct studies is presented. conclusions: this study illustrated the normal appearance of brain pet-ct imaging performed with c11 methionine and fdg in a representative cohort of the pediatric patients through development. normal variance imaging patterns and developmental trends seen with each radiotracer was demonstrated. the pediatric cerebellum: a pictorial review of normal anatomy using mri and diffusion tensor imaging ibrahim s. tuna, md, radiology, children's hospital of wisconsin, dristuna@yahoo.com; sumit singh, teresa c. gross kelly, mohit maheshwari, tushar chandra, hervey d. segall purpose or case report: the aim of this educational exhibit is to illustrate normal anatomical and functional anatomy of the cerebellum in the pediatric patient. the cerebellum receives sensory input from the brain and spinal cord and integrates this information to coordinate motor control. in addition, the cerebellum also plays a role in some cognitive functions such as attention and language. the first step toward understanding how cerebellar abnormalities can lead to neurological dysfunction, is to provide a solid understanding of the neuroanatomy and functional pathways of the cerebellum. we will describe basic cerebellar embryology, the various cell types and gross anatomy using mr images as well as dti fiber tractography. methods & materials: this exhibit will describe the microstructure, gross anatomy and functional pathways of the cerebellum through illustrations, mr images, diffusion tensor imaging (dti) and pathological correlation. first embryology of the cerebellum will be described, followed by mri depiction of the developmental anatomy of the cerebellum from infancy through adolescence. finally dti tractography images will be used to delineate functional pathways to and from, as well as within, the cerebellum. pathological specimens will be photographed to further illustrate gross anatomy. results: afferent white matter pathways travel mainly via the inferior and middle cerebellar peduncles. the main efferent cerebellar white matter pathway is through the superior cerebellar peduncle. transverse fiber tracts are present in the vermis. there are mainly two main systems of cerebellar white matter fibers which are easily visualized with dti color mapping; however more anterior components of dti tracts are intermixed with afferent white matter projections following the middle cerebellar peduncle. conclusions: knowledge of the precise neuroanatomy and white matter tracts of cerebellum may elucidate our ability to comprehend the clinical manifestations of cerebellar diseases in children. a solid understanding of normal cerebellar anatomy, development and functional fiber tracts in the pediatric patient can provide a baseline that may help predict the clinical outcome of various diseases or interventional procedures. gastroesophageal reflux scintigraphy: a low radiation alternative to gerd evaluation in children vikas menghani, md, pediatric radiology, women's and children's hospital, drvikasmenghani@gmail.com; feraas jabi, jan najdzionek, vaseem iqbal purpose or case report: gastroesophageal reflux disease (gerd) is among the common causes for failure to thrive, recurrent cough and aspiration in children. early diagnosis of gerd is essential in avoiding long-term sequelae such as growth delay, chronic lung disease, esophageal stricture, and esophagitis. gastroesophageal reflux scintigraphy, a noninvasive imaging modality, has been applied for detection of gerd and gastric emptying in children over the past few decades. the radiation burden is considerably small given that a very low dose of radioactivity via a short half-life radioisotope like technetium-99 m tagged to oral sulfur colloid is administered to a patient. this feature makes reflux scintigraphy especially attractive as the patient can be scanned for prolonged and delayed periods without increasing radiation dose permitting not only identification but also assessment of severity of gerd. characterizing gerd severity is essential in determining how aggressive the pediatrician should be with therapy. gastroesophageal reflux scintigraphy also allows a child to be fed their regular meal tagged to radiopharmaceutical without altering food taste. qualitative and quantitative parameters like gastrointestinal transit and gastric emptying time can be measured, respectively. scintigraphy is highly sensitive to low grade reflux making it very desirable for monitoring response to therapy. while scintigraphy like all other imaging modalities,has limitations, it continues to be an excellent technique for gerd identification and characterization as well as in monitoring response to gerd therapy. the pediatric kidney-a review of common and uncommon renal anomalies ruby lukse, staten island university hospital, drjosemorey@gmail.com; josé morey, jeremy neuman, arnold brenner, oren herman, adam bernheim purpose or case report: renal parenchymal imaging in nuclear medicine has long been performed with 99mtcdimercaptosuccinic acid (dmsa) due to its sufficient binding to the renal tubules to permit renal cortical imaging. dmsa is of particular value when high-resolution images of the renal cortex are needed. this poster will be a pictorial review of common and uncommon congenital anomalies evaluated on dmsa imaging, such as horseshoe kidney, pelvic kidney, sshaped kidney and crossed-fused ectopia. the poster will also correlate planar imaging findingss with appropriate additional imaging including computed tomography (ct), magnetic resonance imaging (mri), fluoroscopic imaging and plain film radiographs when clinically warranted and in keeping with the as low as reasonably achievable (alara) principle set forth by the american college of radiology (acr). purpose or case report: in this poster we will review the differential diagnoses of congenital anomalies that give the appearance of hydronephrosis on renal imaging of the pediatric patient. we will show a pictorial review of both common and uncommon congenital anomalies such as congenital megaureter, ureterocele, uretero-pelvic junction (upj) obstruction, uretero-vesicular junction (uvj) obstruction and posterior urethral valves (puv). we will also review common mimickers of hydronephrosis such as multicystic dysplastic kidney (mcdk) and pseudo-obstruction secondary to bladder overdistention. the poster will also correlate planar imaging finds with appropriate additional imaging including computed tomography (ct), magnetic resonance imaging (mri), fluoroscopic imaging and plain film radiographs when clinically warranted and in keeping with the as low as reasonably achievable (alara) principle set forth by the american college of radiology (acr). the pediatric bone scan-a review of neoplastic pathology shrita smith, staten island university hospital, drjosemorey @gmail.com; josé morey, jeremy neuman, arnold brenner, daniel klein, purpose or case report: bone imaging continues to be the second greatest-volume of nuclear imaging procedure performed today, offering the advantage of total body examination, low cost, and high sensitivity. the diagnostic utility, sensitivity, specificity and predictive value of 99 m-tc bone imaging of malignant conditions have long been established. in fact, more than 3,450,000 bone scans were performed in the united states in 2005. in this poster we will review the current indications for planar bone imaging for the evaluation of malignant and benign neoplasms in the pediatric population, such as osteoid osteoma, langerhan cell histiocytosis (lch), osteoblastoma, ewing's sarcoma, lymphoma, osteosarcoma and osseous/hepatic metastatic disease from neuroblastoma. the poster will also correlate planar and single-photon emission computed tomography (spect) imaging findings with appropriate additional imaging including computed tomography (ct), magnetic resonance imaging (mri), positron emission tomography (pet), and plain film radiographs when clinically warranted and in keeping with the as low as reasonably achievable (alara) principle set forth by the american college of radiology (acr). the many faces of duplex kidneys on dmsa scans-a pictorial essay neha kwatra, children's national medical center, nskwatra@childrensnational.org; massoud majd purpose or case report: renal duplication is the most common malformation of the urinary tract and is often seen in children with urinary tract infections (uti). the purpose of this study is to learn to recognize duplex kidneys on dimercaptosuccinic acid (dmsa) scintigraphy, review their entire spectrum of findings and correlate with other imaging modalities. methods & materials: dmsa scintigraphy is routinely performed in the nuclear medicine department with a single-head gamma camera (siemens e.cam, schaumberg, illinois). about 1.5 h after injection of dmsa, posterior and posterior oblique images are obtained using parallel and pin hole collimators. differential renal function is also calculated. dmsa scan reports containing the words "duplex" or "duplicated" from 2006-2011 were populated using a radiology search engine (montage health care solutions inc.). the images were then reviewed in pacs and representative examples were selected for the poster. the scans were evaluated for renal position, size, contour, any evidence of duplication and parenchymal damage. results: patterns of duplication included non complicated duplex kidney recognized by asymmetric renal size and a prominent cortical bar separating the two moieties, complicated duplex systems with hydronephrosis, scarring or pyelonephritis of one or both moieties. a small nonfunctioning upper moiety was sometimes evidenced by just an indentation along the superomedial aspect of the larger lower moiety. cases with bilateral duplex kidneys were also seen. illustrative examples of each will be provided. correlating findings on other imaging modalities will also be included. conclusions: establishing the diagnosis of duplex kidney on a dmsa scan requires a careful systematic review of the images. the findings can be subtle and it is important for the radiologist to recognize them. correlation with other modalities such as ultrasound or voiding cystogram can be complementary. the assessment of parenchymal function of the upper and lower moieties separately on dmsa scintigraphy can be of immense value in patient management and in choosing surgical options. poster #: edu-094 18 f-fdg pet/ct imaging of pediatric brain tumors, neurofibromatosis 1(nf1) and non-lymphomatous head and neck tumors. lisa states, md, radiology, chop, states@email.chop.edu; purpose or case report: this educational poster will review the current literature and summarize the value of 18 f-fdg pet/ct in standard clinical practice in the evaluation of pediatric brain tumors, nf1 plexiform neurofibromas and malignant peripheral nerve sheath tumors, and nonlymphomatous head and neck tumors. normal variants and pitfalls will be reviewed. comparison with other pet tracers will be briefly discussed. case examples will be used to illustrate the value of 18 f-fdg pet/ct in grading, staging, assessment of therapeutic response and detection of residual or recurrent disease in various pathologic entities. results: examples of cases will include: benign brain tumor, residual brain tumor in the post-operative bed, brain metastasis, malignant peripheral nerve sheath tumor in nf1, head and neck rhabdomyosarcoma, mandibular osteosarcoma, and infection. conclusions: an understanding of the value of pet molecular imaging is essential to the success of the next phase of hybrid imaging with pet/mri which has the potential to play an important role in the development of new diagnostic and therapeutic approaches for the treatment of pediatric brain tumors, nf1, and pediatric head and neck tumors. disclosure: dr. states has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. the pediatric bone scan-a review of non-malignant pathology josé morey, staten island university hospital, drjosemorey@ gmail.com; jeremy neuman, arnold brenner, vinh phan, cheryl lin purpose or case report: bone imaging continues to be the second most performed nuclear imaging procedure, offering the advantage of total body examination, low cost, and high sensitivity. the diagnostic utility, sensitivity, specificity and predictive value of 99 m-tc bone imaging of benign conditions have long been established. in fact, more than 3,450,000 bone scans were performed in the united states in 2005. in this poster we will review the current indications for planar bone imaging for the evaluation of non-malignant diseases in the pediatric population, such as acute osteomyelitis secondary to salmonella enterobacteriaceae and tubercle bacillus (tb), chronic osteomyelitis, reflex sympathetic dystrophy, spondylolysis, bone infarcts in the setting of sickle cell disease, fractures (occult/stress), ankylosing spondylitis, dermatomyositis and non-accidental trauma. the poster will also correlate planar and single-photon emission computed tomography (spect) imaging findings with appropriate additional imaging including computed tomography (ct), magnetic resonance imaging (mri), positron emission tomography (pet), and plain film radiographs when clinically warranted and in keeping with the as low as reasonably achievable (alara) principle set forth by the american college of radiology (acr). purpose or case report: we review the radiologic features of pathologic conditions linked to diesel exposure. the hydraulic fracturing ("fracking") technique is increasingly used in many areas of the country to extract natural gas from rock formations. diesel fuel, or fluids containing diesel, are one component of fracking fluid and create a potential for ground water contamination and risk to air quality. the toxic effects of diesel exhaust are described in the literature, and include asthma, hydrocarbon pneumonitis, and leukemia. there are no scientific data currently available on the effects of chronic diesel ingestion. methods & materials: multi-modality examples of pathology were obtained from a radiology database at a tertiary care pediatric hospital. the specific cases displayed are not known to have diesel exposure, but are intended to serve as representative examples of the type of pathology that may be encountered in the setting of chronic diesel exposure. results: imaging findings of asthma include hyperexpansion, atelectasis, peribronchial thickening, and air-trapping. hydrocarbon pneumonitis may demonstrate low attenuation consolidation and subsequent pneumoatocoeles with ct. leukemia may present on plain radiographs with lucent metaphyseal bands and with marrow infiltration on mri. conclusions: in conjunction with other symptoms not necessarily evaluated in the radiology department, including rhinitis, laryngitis, acute coronary syndrome, and dementia, the radiologist may suggest the diagnosis of diesel toxicity, particularly in populations that may be at high risk of exposure. pediatric radiology in the philadelphia region: a historical review* richard markowitz, md, children's hospital of philadelphia, markowitz@email.chop.edu purpose or case report: the specialty of pediatric radiology in the philadelphia region has grown and evolved over the past eight decades originating from early "visiting" radiologists to drs. hope and kirkpatrick, the "giants" of the 1950s and '60s, to over fifty practicing pediatric radiologists today. clinical excellence, commitment to teaching, and advancement of knowledge through research remain the goals and ideals, much as they were many years ago. philadelphia has been a fertile home and environment for this evolution, mostly because of outstanding leaders and role models who have trained and influenced generations of pediatric radiologists. developments and leadership at the children's hospital of philadelphia, st. christopher's hospital for children, and a.i. dupont institute are highlighted. the purpose of this poster is to tell the story of the growth and development of pediatric radiology in this area and to explore the intellectual origins, professional "genealogy," and legacies left by those who created and those who have carried on this tradition. *note: this material is based on a previously published article: pediatric radiology (2009) 39:969-981 and "addendum" (pediatric radiology 2010: 1454-1455), but never presented at spr. superficial lumps and bumps henrietta k. rosenberg, md, radiology, the mt. sinai medical school, henrietta.rosenberg@mountsinai.org; diane belvin, neil lester purpose or case report: superficial soft tissue masses in the pediatric age range can be quite challenging to the pediatrician and the imager. the purpose of this presentation is to demonstrate the efficacy of duplex/color doppler ultrasound for the diagnosis and follow up of a large gamut of superficial lumps and bumps. methods & materials: we reviewed our experience during the past 6 years using ultrasound to evaluate superficial soft tissue masses that had been encountered in many parts of the body, from the skull to the soles of the feet, in a large group of patients ranging in age from newborn to 21 years. all sonograms were performed after obtaining pertinent clinical information as well information regarding the clinical characteristics of each of the masses, e.g. location, consistency (firm [solid], compressible [cystic]), fixed or easily movable, smooth or irregular surface, tenderness. the masses were palpated by the imaging team and duplex/color doppler ultrasound was performed. comparison sonographic views of the opposite side were obtained as needed. clinical followup and surgical/pathological correlation was obtained in most of the patients. results: most of the masses were benign and included a wide variety of etiologies. most often, us was sufficient for assessment of soft tissue masses if the entire mass was included in the field of view. if the lesion was too large for the field of view or malignancy was suspected, ct/mri were required preoperatively. nuclear medicine studies are reserved for midline masses likely due to ectopic thyroid and pet was used for more complete evaluation of a lesion that was likely malignant. conclusions: duplex/color doppler ultrasound (us) is the modality of choice for evaluation of superficial lumps and bumps! this modality allows for rapid acquisition of information without the use of ionizing radiation, intravenous contrast material, or sedation/anesthesia. reliable information can be rapidly acquired regarding the size, shape, borders, location, internal consistency, vascularity, vascular encasement/displacement. correlation of the ultrasound and clinical findings helps narrow differential diagnosis. sonography helps to determine what is the next best step: watchful waiting (clinical observation, follow-up us), surgical resection, or us guided interventional procedure. present day imaging of down syndrome rupa radhakrishnan, md, radiology, university of cincinnati college of medicine, radhakrp@ucmail.uc.edu; alexander j. towbin purpose or case report: down syndrome is a common genetic condition characterized by unique physical traits and multisystem anomalies. the purpose of this exhibit is to portray the imaging findings of down syndrome and discuss with illustrative examples, the use of imaging in multidisciplinary management. methods & materials: published literature was reviewed to identify the multisystem imaging findings in down syndrome. the electronic medical record system was then searched to find illustrative case examples from our institution. results: in patients with down syndrome, abnormalities can be found in the musculoskeletal, cardiovascular, respiratory, gastrointestinal, and central nervous systems. abnormalities can range from emergent, life threatening conditions such as malrotation with midgut volvulus to chronic conditions such as scoliosis. examples of abnormalities from each organ system and the modalities used for diagnosis and management are described. cardiovascular system: echocardiogram and cardiac mri and ct are useful in evaluating congenital heart disease associated with down syndrome. respiratory system: micrognathia with macroglossia and hypotonia predisposes patients to sleep apnea which can be evaluated with dynamic mri. chest ct demonstrates subpleural cysts which are characteristic of this syndrome. gastrointestinal system: fluoroscopy and/or radiographs are the mainstay in diagnosing many gastrointestinal disorders including duodenal atresia, malrotation, annular pancreas, imperforate anus, and hirschsprung disease. central nervous system: choroid plexus cysts may be identified on prenatal ultrasound in a fetus with down syndrome. imaging is used in the evaluation of epilepsy, hearing loss and alzheimer disease that is more common in these individuals. musculoskeletal system: multiple skeletal anomalies can be present in patients with down syndrome. radiographs are often used as the method of identifying and, if needed, following the anomalies. prenatal imaging: increased nuchal translucency is the earliest imaging finding. other features of down syndrome can be identified on prenatal ultrasound or mri. prenatal imaging is helpful in determining the prognosis of the fetus and in guiding management. conclusions: modern day multidisciplinary management has improved quality of life and survival in individuals with down syndrome. imaging plays a critical role in guiding management in these individuals. imaging the spectrum of lymphatic malformations in the pediatric patient andrew schapiro, md, radiology, university of wisconsin, aschapiro@uwhealth.org; kara gill, bradley maxfield purpose or case report: lymphatic malformations (lm) occur as a result of abnormal development of the lymphatic system during embryogenesis. as 90% of lm present by 2 years of age, these lesions represent an important pediatric entity. lm can often be suspected clinically in an infant with the classic presentation of an asymptomatic, soft mass in the head, neck, or axilla. however, myriad presentations are possible as lm occur in numerous other anatomic locations, can be multiple, and can be a component of mixed vascular malformations. in addition, the true extent of lm is often not apparent clinically. given these considerations and the implications for proper management, imaging plays an important role in the assessment of lm. the purpose of this exhibit is to review the spectrum of radiographic, ct, sonographic, and mr imaging findings of a variety of lm presentations. methods & materials: cases of lymphatic malformation in pediatric patients identified at a single institution over the past ten years with available imaging were reviewed utilizing pacs. results: images of lm involving the head and neck, chest, abdomen, retroperitoneum, extremities, and skeletal system were identified. in addition, cases of lymphangiomatosis and mixed venolymphatic malformation were identified. various imaging modalities including radiography, ct, sonography, and mr were represented. conclusions: adequate knowledge of the imaging characteristics of lm across multiple modalities enables proper diagnosis, assessment of disease extent, and guidance of appropriate therapy in pediatric patients. results: ct and mr imaging findings in nine cases will be presented. they include 1) congenital absence of the inferior vena cava with thrombosis of the external iliac vein secondary to venous stasis 2) pyelophlebitis complicating ruptured appendicitis 3) left iliac vein thrombosis in a patient with may-thurner syndrome 4) splenic vein thrombosis complicating pancreatitis 5) splenic vein thrombosis following splenectomy 6) renal vein thrombosis in an infant of a diabetic mother 7) adrenal vein thrombosis as the presenting sign of antiphospholipid syndrome 8) budd-chiari syndrome associated with underlying myeloproliferative disease 9) iliac vein thrombosis as a manifestation of behcet's syndrome (hughes-stovin syndrome, a variant of behcet's syndrome, which presents with systemic venous thrombosis and pulmonary artery aneurysms will also be discussed). conclusions: thrombosis of large abdominal and pelvic veins in children and adolescents is uncommon. certain conditions, both congenital and acquired, predispose to the development of venous thrombosis. ct/mr imaging defines the extent of thrombosis, and demonstrates additional findings that may elucidate the nature of the underlying condition leading to clot formation. purpose or case report: because abnormal gait in a young child has a wide range of causes, imaging plays a critical role in establishing the definitive diagnosis. the purpose of this exhibit is to review the clinical clues (age, duration, laboratory markers) and imaging findings of the causes of abnormal gait in a toddler and to assess the strengths and limitations of radiographs, ultrasound, magnetic resonance imaging (mri), and computed tomography (ct). methods & materials: cases, from a single institution experience with various causes for abnormal gait in a toddler, are reviewed and categorized into congenital, traumatic, inflammatory, neoplastic, or neuromuscular etiologies. results: there are various causes of abnormal gait in a toddler. the congenital causes include spinal dysraphism, proximal and distal skeletal deformities and dysplasias. the traumatic causes include non-accidental trauma, toddler's fracture, foreign body, and soft tissue injuries. the inflammatory causes include juvenile idiopathic arthritis, transient synovitis, and infection, including osteomyelitis, septic arthritis, discitis, cellulitis, and abscess. the neoplastic causes include various neurogenic, bone, and soft tissue tumors. the neuromuscular causes include cerebral palsy and spinal bifida. the combination of clinical presentation, supporting laboratory findings, and classic imaging findings help to distinguish the possibilities and often allows confident diagnosis. conclusions: knowledge of imaging findings and clinical factors can demystify the diagnosis of abnormal gait in a toddler. familiarity with the clinical presentation can ensure the performance of the appropriate diagnostic studies, timely diagnosis, and effective treatment. nonaccidental causes should never be overlooked. ultrasonography has become an important tool in the radiologist's armamentarium, augmenting radiography, mri, and ct. approximately 20 different contrast agents for mri and ct are now commercially available for use. although most of them are fda approved in adults, information on usage and safety in children is not readily available. the most important reason is lack of controlled studies in children, especially for the age of 0-2 years. however, the lack of fda approval has not limited the use of these promising agents in children. in fact, there is widespread off-label use of these agents in most major pediatric hospitals in the country. based on a review of relevant literature in children, and based on a survey of radiology faculty at major pediatric hospitals, this poster will address the gap between approved use and reality in the setting of pediatrics. results: using a tabular format, this poster will provide a list of mr and ct contrast agents that are available for clinical use, their relevant clinical properties (ionic or nonionic, viscosity, linear or macrocyclic, degree of relaxivity for mri, iodine concentration for ct, cost, dosage, halftime, incidence of allergic reactions, nephrogenic systemic fibrosis and other adverse reactions), fda approval status (for ages 0-30 days, 30 days-2 years, and 2-17 years), common pediatric applications, and contrast injection protocols for common applications. conclusions: to enlighten imaging personnel about usage and safety of contrast agents in children. disclosure: dr. krishnamurthy has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. a pictorial essay and literature review of the spleen in sickle cell disease david hindson, md, boston medical center, david. hindson@bmc.org; heather imsande, philippa sprinz, ilse castro-aragon purpose or case report: the morbidity and mortality of sickle cell disease (scd) results from acute and chronic infarction events that affect almost every organ. repeated infarction has some of its greatest visual and physiologic impact within the spleen. continuous hemolysis, sequestration and vaso-occlusion within the spleen result in loss of splenic function early in life and frequently autosplenectomy thereafter. by 2 years of age, approximately 90% of children with hemoglobin ss disease will have diminished splenic function, putting them at increased risk for infections. treatments for scd have evolved over the last 20 years, and among others include penicillin prophylaxis and immunizations, hydroxyurea and transfusion therapy (or hypertransfusion program). imaging findings are a reflection of the different treatments and their efficacy. methods & materials: our institution cares for a large group of patients with sickle cell disease, from birth to adulthood. this offers an unprecedented opportunity to document the imaging findings of the spleen with different treatment regimens, and over many years. the splenic size and morphology can be followed, by ultrasound, in a very straightforward way. we have compiled a pictorial essay of the various imaging characteristics of spleens from infants to adults. we also performed a literature review to compare and supplement the findings of our images. results: there is a spectrum of imaging findings in the spleen of patients with scd that changes from birth to childhood. the findings range from the normal appearance of a spleen to a calcified spleen, and include regenerative nodules, fibrosis, altered parenchymal echotexture, increased echogenicity, and changes in size, including enlargement secondary to sequestration. the ultrasound characteristics not only change with advancing age, but also appear to depend on whether or not the patient has received specific treatments, and at what age treatment was initiated. conclusions: the ultrasound appearance of the spleen in patients with scd is variable. treatments such as blood transfusions and hydroxyurea, patient compliance with therapy and type and severity of the disease are some of the factors that affect imaging characteristics. cystic fibrosis: not just for children cindy miller, md, radiology, yale-new haven hospital, cindy.miller@yale.edu purpose or case report: cystic fibrosis has been recognized for hundreds of years with the first descriptions of it including such anecdotes as mothers licking the foreheads of their children and knowing that if it tasted salty, an early death could be predicted. it was not until 1939 that the disease was first named by dr. dorothy andersen, and for the following 50 years, treatment was largely supportive, and imaging was essentially done with plain films alone. in 1989 with the elucidation of the cftr gene, there was an explosion of knowledge which included the range of increased awareness and understanding of the suspected etiology, imaging findings and significance of the ductus bump. the contribution of 3d imaging for evaluation of the pediatric central airways jessica kurian, md, the children's hospital of philadelphia, kurianj@email.chop.edu; monica epelman, david a. mong purpose or case report: evaluation of the central airways in children has historically been accomplished by flexible bronchoscopy, an invasive technique associated with inherent risks and complications. multidetector ct (mdct) with volume rendering offers a noninvasive alternative for airway evaluation. in this educational exhibit, we will review imaging techniques and clinical applications of mdct for the assessment of large airway maladies in children. methods & materials: mdct imaging in children with a variety of tracheobronchial disorders is reviewed. for each entity, the characteristic clinical features are described, and key imaging features are illustrated. emphasis is placed on the contribution of 3d techniques for characterizing complex airway anomalies. dose reduction strategies are also highlighted. results: the entities reviewed in this exhibit include, but are not limited to, congenital anomalies of tracheobronchial branching, airway malformations associated with situs, and congenital or acquired airway compression and/or obstruction. conclusions: mdct with volume visualization is a useful adjunct for evaluation of the pediatric central airways in a variety of pathologies. as a noninvasive technique, it avoids sedation risks and spare patients from complications associated with conventional flexible bronchoscopy. low dose protocols should be used to minimize radiation exposure. bronchopulmonary foregut malformation that result from abnormal budding of the primitive foregut. currently, many such anomalies are initially detected by prenatal ultrasound and are further delineated by fetal magnetic resonance imaging (mri), while others may be incidentally detected on postnatal radiologic examinations or later in life in the setting recurrent pulmonary infection. imaging plays a very important role in the diagnosis and characterization of these lesions and assists surgical planning. the purpose of our educational exhibit is to illustrate the common and uncommon radiologic appearances of cpams using various imaging modalities, including radiography, computed tomography, prenatal and postnatal ultrasound, and prenatal and postnatal mri. methods & materials: all pediatric and adult cpam (including both sequestration and ccam) patients were identified using electronic medical records. pertinent imaging reports (including radiography, prenatal and postnatal ultrasound, ct, and prenatal and postnatal mri) were reviewed by a single author in order to identify relevant imaging findings. relevant images from these imaging examinations were de-identified and saved to a secure hard drive. medical records were accessed by a single researcher to obtain relevant demographic information as well as data regarding the patients' clinical presentations. in cases of corrective surgery, operative and pathology reports were reviewed, if available, for correlation with the imaging findings. results: cases of pediatric and adult cpam were identified and presented in a variety of clinical contexts. their appearances were reviewed through multiple imaging modalities. conclusions: congenital pulmonary airway malformations are varied in their clinical presentation and imaging appearance. the purpose of this pictorial essay is to enhance understanding of their diagnosis and to use a multidisciplinary approach in order to highlight imaging aspects that may alter clinical management. disclosure: dr. horst has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. the imaging evaluation of cystic lung disease in children: an evidence-based approach jordan caplan, md, pediatric radiology, lucile packard children's hospital, stanford university, caplan@stanford. edu; beverley newman purpose or case report: the goal of the poster is to provide a framework for use when confronted with cystic lung disease in a child. methods & materials: the differential diagnosis for the types and causes of cystic lung disease in children will be presented using an evidence-based, age appropriate approach. categories of disease discussed and illustrated with case examples will include: a. congenital cystic bronchopulmonary malformations b. infectious cysts c. autoimmune/inflammatory/vasculitic disease with cavitating lesions d. neoplastic conditions e. collagen/soft tissue abnormalities f. mimics of cystic lung disease results: the pathophysiology, imaging appearance, and demographics of the above entities will be reviewed with attention to relevant recent literature. important educational points include the differentiation of bronchopulmonary malformations from neoplasm, notably pleuropulmonary blastoma (ppb), the relationship between lung cysts and ppb, and the management and surveillance of lung cysts in children. conclusions: an evidence-based approach to the broad spectrum of causes of cystic lung disease in children is a useful starting point in forming a concise and pertinent differential diagnosis. an understanding of the pathophysiology, imaging appearance, and demographics of these entities is essential in guiding patient management. pediatric interstitial lung disease (ild): a pictorial review with radiologic and pathologic correlation hollie west, md, diagnostic radiology, vanderbilt university, hollie.c.west@vanderbilt.edu; melissa a. hilmes, sudha p. singh, jennifer soares, lisa young purpose or case report: while adult interstitial lung disease is a well-described and fairly well understood group of disease processes, pediatric interstitial lung disease (ild) remains a subject of uncertainty and misunderstanding for many clinicians and radiologists. confusion surrounding the phenomenon of pediatric ild stems not only from the rarity of the disease, but also from the extensive list of disease entities that can produce ild, the existence of certain patterns that are restricted to infants and children and the fact that patterns of ild manifest differently in a child's developing lung than in an already developed adult lung. imaging plays an important role in diagnostic work-up of this disease and can guide lung biopsy in specific patient populations. methods & materials: the irb approved retrospective study will show patients at our institution over a 10 year period diagnosed with various types of ild, including pulmonary insterstitial glycogenolysis (pig), diffuse neuroendocrine cell hyperplasia (nehi), surfactant deficiency diseases, and lung diseases associated with other systemic processes such as downs syndrome and inflammatory bowel disease. we will include patients with biopsy proven ild and will provide examples of the major ilds, including clinical, radiologic and pathologic correlation. our pictorial review will describe the radiologic patterns associated with the different forms of ild, emphasizing what the radiologist needs to know and how to be helpful to a multidisciplinary team in the diagnosis and treatment of these diseases. results: the study will report the frequency of ild at our institution, including a breakdown of the various subtypes of ild. we will show examples of the subtypes with correlative chest radiography, computed tomography, and pathology. we plan to highlight specific differentiating factors between the different diseases and demonstrate how a radiologist can be helpful in collborating with clinicians in diagnosing and treating these diseases. conclusions: pediatric ild can be a confusing topic for radiologists. increasing knowledge and awareness of these diseases, their clinincal presentation, work up, and treatment is important for pediatric radiologists who work as part of of a multidiciplinary team. poster #: sci-001 ct radiation dose delivered by community hospitals and imaging centers stephen little, children's healthcare of atlanta, stephen. little@choa.org; damien grattan-smith, bonnie johnson purpose or case report: to evaluate and compare ct radiation dose for pediatric abdominal and cranial ct examinations performed by community hospitals and imaging centers. methods & materials: 148 consecutive ct examinations (49 cranial, 99 abdominal) from 41 community hospitals and imaging centers were reviewed following transfer of care. the examinations were performed between january and july 2011. 433 consecutive ct examinations (241 cranial, 192 abdominal) performed at our own institution were also reviewed. ctdivol and dlp were obtained from the dose report for each examination (32 cm-phantom for abdominal exams, 16 cm-phantom for cranial exams). patient age and weight were obtained from the medical record. results: average ctdivol for abdominal ct performed by local community hospitals and imaging centers was 8.7 mgy, while average ctdivol was 4.3 mgy for abdominal ct performed at choa. there was a wide variation in ct radiation dose delivered. while some sites delivered a ct radiation dose comparable to our own, others delivered a substantially greater dose. in fact, 23% of pediatric abdominal ct exams performed by local community hospitals and imaging centers exceeded the notification value recommended by the aapm (10 mgy using the 32cm phantom). low kvp technique for imaging small children was infrequent. multi-phase examinations were more often performed, resulting in additional elevation in ct radiation dose when dlp is considered. average ctdivol delivered by local community hospitals and imaging centers for cranial ct was 44 mgy compared to a ctdivol of 30 mgy for cranial ct performed at choa. 8% of pediatric cranial ct exams performed by local community hospitals and imaging centers exceeded the notification value recommended by the aapm (60 mgy for 2-5 years, 80 mgy for >5 years). conclusions: despite ongoing efforts at education, there is wide variation in ct radiation dose delivered for pediatric abdominal and cranial ct examinations performed by local community hospitals and imaging centers. appropriate use of dose check software on newer scanners may help reduce the number of children subjected to excessive ct radiation dose. ultimately, each site performing pediatric ct must take responsibility for minimizing radiation dose while producing diagnostic quality exams. the impact of adaptive statistical iterative reconstruction on ct image quality parameters -a phantom study karen thomas, md, radiology, hospital for sick children, karen.thomas@sickkids.ca; nancy ford, angjelina protik, paul babyn purpose or case report: to quantify the effect of adaptive statistical iterative reconstruction (asir) on ct image quality parameters. methods & materials: phantom (catphan 600) studies were performed on a ge hd750 64-slice scanner to investigate the impact of a) 50% asir compared to routine filtered back projection using variable kvp (80-140) and mas (5-200), and b) incremental asir % (0, 30, 50, 70, 100%), scanning at 75mas and variable kvp (80-120). pitch, acquisition fov and detector width were kept constant. image noise, spatial and contrast resolution, contrast noise ratio (cnr) and wiener spectrum analysis were performed on 0.625 mm ax, 5 mm ax mpr and 2 mm cor mpr series. results: 50% asir resulted in a mean decrease in noise of 30% (0.625 mm ax), 26% (ax mpr) and 28% (cor mpr) and improvement in cnr of 38-49%. incremental advantage was seen with stepwise increase in asir %. however, application of asir was associated with a small reduction in spatial resolution (2-8% at 50% asir). low contrast detectability (lcd) improved except at the smallest target lesion size. image quality effects at very low mas and at high asir % will be presented. conclusions: image noise reduction and improvements in cnr and lcd with asir hold considerable potential for dose reduction in pediatric ct. this study provides quantitative data that may be used to design asir-enhanced protocols with consideration of diagnostic task, balancing image quality benefits and potential pitfalls. pictorial essay on cardiac mr for congenital heart disease on 3 t mr scanner with rf multi-transmit technology (tx) taylor chung, md, diagnostic imaging, children's hospital & research center oakland, taylorchung12@gmail.com purpose or case report: this is a pictorial essay (e-poster) to show artifacts on cine ssfp images pre-tx and post-tx upgrade on congenital heart disease cardiac mr; to illustrate methods prior to tx-upgrade to minimize artifacts. disclosure: dr. chung has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. revisiting the relationship between anthropometric parameters and left ventricular mass abdullahi adamu, md, phd, ahmadu bello university, scorpion68kd@yahoo.com purpose or case report: the purpose of this study was to find the correlation between anthropometric parameters and left ventricular mass in normal adolescents and young adults. methods & materials: 147 healthy individuals in the age range 17 to 23 years (73 males and 74 females) were included in this study. anthropometry was performed with standard anthropometry kit and measurements of height, weight, body surface area (bsa), upper arm circumference and upper hip circumference were taken. echocardiography was performed and the american society of echocardiography (ase)-recommended method was employed for calculation of left ventricular mass (lvm). statistical analysis was performed using statistica 6.0 (stat soft, usa). results: the mean value of lvm for all our subjects was found to be 124.53±2.79 g. there was significant correlation between lvm and height (r00.52, p<0.0001), weight (r00.63, p<0.00001) and bsa (r00.64, p<0.00001). correlation with upper arm circumference was moderate (r0 0.46, p<0.0001), while it was found to be weak with upper hip circumference (r00.23, p<0.01). diagnostic. both field strengths can be used successfully for cardiac and vascular imaging. the decision as to which to use is weighted by local availability and the relative requirement for detailed vascular vs intra-cardiac imaging. disclosure: dr. nguyen has indicated that she will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. poster #: sci-006 color coded 3d cardiac cta of congenital heart disease: a five year experience nhi huynh, md, radiology, st. joseph hospital and medical center, e.nhihuynh@gmail.com; randy richardson purpose or case report: post-processing of cardiac computed tomography angiograms can be performed on a commercially available workstation to create color coded 3d volume rendered images of the segmented heart and great vessel anatomy in patients with congenital heart disease. these studies optimally demonstrate complex anatomy, streamlining communication between members of the healthcare team and providing a tool for communicating complex anatomy and treatment options with families. these studies have been ordered with more frequency over the past five years. we retrospectively reviewed the types of congenital heart disease demonstrated by cardiac 3d cta over the past five years at a congenital heart center. methods & materials: color coded cardiac cta postprocessing was performed from ecg gated prospective and retrospective cta data on a commercially available workstation for 333/395 patients over the past three years. the anatomy was initially segmented and colored into individual parts of the anatomy of the heart and great vessels as follows rv 0 purple, lv 0 light red, aorta 0 red, pulmonary arteries 0 blue, systemic veins and right atrium 0 aqua, pulmonary veins and left atrium 0 pink, pda or collaterals 0 green, airway 0 yellow, coronary arteries 0 neutral. the anatomy was then reassembled and images obtained every 3°in a 360°rotation for display. results: 3d color coded cta images were used in the treatment and care of congenital heart patients for the following types of congenital heart diseases: 124 cases of complex anatomy (tga, truncus arteriosus, hlhs, tricuspid atresia, tof…), 67 coronary artery anomalies, 68 cases of pulmonary atresia or stenosis, 44 cases of systemic and venous anomalies, 40 cases of coarctation or interruption of the aortic arch, and 56 tracheobronchial tree anomalies. conclusions: color coded cardiac cta post-processing is an effective and viable method for demonstrating anatomy in complex congenital heart patients. it is an excellent tool for demonstrating anatomy which is difficult to see by echocardiography such as: coronary artery anomalies, pulmonic atresia, aortic arch coarctation or interruption, and tracheobronchial anomalies and/or stenosis. neuroimaging in the evaluation of hie in term neonates post hypothermia therapy julio m. araque, md, radiology, medical college of georgia, jaraque@georgiahealth.edu; jatinder bhatia, leann vanlandingham purpose or case report: to illustrate and review the potential utility of brain mri, ct and ultrasound in hypoxic ischemic encephalopathy in newborns treated with hypothermia. neuroimaging studies including brain ultrasound, ct and mri of fifteen term newborns treated in our institution with therapeutic hypothermia, since april 2010 were evaluated retrospectively. more relevant lesions are depicted and the diagnostic and prognostic value of the findings is discussed and compared with a review of the literature. results: recent studies showed that patients treated with cooling had a more favorable prognosis than was suggested by the clinical grade of encephalopathy compared with infants treated with standard care. our institutional protocol includes the performance of mri, and ultrasound. ct is performed when is a clinical impossibility of perform mri. brain ultrasound was performed in all the 15 patients. mri scans were obtained in 11 neonates. ct was obtained in 3 patients. all mri studies included dwi. the utility of dwi and adc maps as an aid in diagnosis of non-ischemic lesions is becoming increasingly established. mri evidence of brain injury was visible on basal ganglia in 8 cases with negative ultrasound. abnormal signal intensity in the posterior limb of the internal capsule coexists with lesions in the basal ganglia and thalami have been associated with abnormal motor outcome. the remaining 3 newborns did not develop significant mri evidence of brain injury. it has been suggested that the ability of mri to predict subsequent neurological impairment is unaltered by therapeutic hypothermia. further research is needed for defining the relation between mri findings and cooling. it is possible that imaging findings might be delayed in cooled infants. conclusions: mri offers the highest sensitivity in detecting anoxic injury of the neonatal brain. mr biomarkers in combination with clinical markers may identify patients with adverse outcome with therapeutic implications. disclosure: dr. araque has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. purpose or case report: to correlate bowel wall diffusionweighted imaging (dwi) apparent diffusion coefficient (adc) values with multiple mr enterography (mre) and clinical findings in pediatric small bowel crohn disease. methods & materials: 54 pediatric crohn disease patients with mre exams containing diffusion-weighted imaging and demonstrating terminal ileitis were identified. minimum bowel wall adc values were tested for correlation/association with other mri findings and clinical parameters (including laboratory values). results: there is negative correlation between adc value and degree of bowel wall thickening (r0(−)0.27; p00.048). lower adc values were significantly associated with striated pattern of arterial phase postcontrast enhancement (p0 0.007), greater degree of arterial phase postcontrast enhancement (p00.006), and presence of stricture (p00.005). adc values were not associated with diseased bowel length, degree/pattern of delayed postcontrast enhancement, degree of mesenteric inflammation or fibrofatty proliferation, or clinical markers of inflammation. conclusions: restricted diffusion in pediatric small bowel crohn disease is associated with other mri findings of that are suggestive of active disease, including degree of bowel wall thickening and degree and pattern of arterial phase postcontrast enhancement. our data also suggests that dwi may be useful when attempting to characterize small bowel strictures as either predominantly inflammatory or fibrotic, although further investigation is needed. quantification of blood flow into and out of the liver with 4 d phase contrast mri in the pediatric patient binh huynh, md, radiology, stanford, bhuynh@stanford. edu; shreyas vasanawala, albert hsiao purpose or case report: the ability to probe blood flow dynamics in the liver may aid management of children with liver disease, including shunt fractions in portal hypertension and arterial flow fraction in diffuse liver disease. the purpose of this study is to evaluate the ability to measure blood flow into and out of the liver with time resolved volumetric (4d) phase contrast mri in the pediatric patient. methods & materials: nineteen consecutive patients were retrospectively identified who underwent 4d flow imaging through the level of the hepatic vessels on 1.5 t and 3 t magnets. a software enabling 4d flow program was utilized to first assess for the feasibility of measurement of flow in the hepatic artery (ha), portal vein (pv), splenic vein (spv), superior mesenteric vein (smv), supra (sivc) and infrahepatic (iivc) inferior vena cava. if measurable, calculations were performed to evaluate for internal consistency by comparing the sum of smv and spv flow to pv flow. calculations were then performed to compare hepatic inflow (pv+ha) to hepatic outflow (sivc-iivc) and for the percentage of pv and ha contribution to hepatic inflow. results: of the nineteen patients, all of the above mentioned six vessels were visualized and measurable in two patients, both of which were imaged on the 1.5 t magnet. in the remaining patients, flow measurements were limited by respiratory motion artifacts obscuring the smaller vessels, and severe eddy currents, particularly in patients imaged with the 3 t magnet. the evaluation for internal consistency demonstrated an average of 1.2% (0.06% & -1.5%) difference between smv+spv and pv flow. hepatic inflow was found to closely match the measured hepatic outflow with an average difference of 11.1% (19.1% & 3.1%). the portal vein was found to contribute 82.9% and 87.3% to hepatic inflow, while the hepatic artery contributed 17.1% and 12.7%. conclusions: measurement of hepatic flow with phase contrast mri is more challenging than assessment of thoracic flow. when respiratory artifacts are minimal, vessels can be identified and measurements have internal consistency and good agreement between hepatic inflow and outflow at 1.5 t. conversely, flow measurements were limited at 3 t by eddy currents. thus, ongoing efforts are aimed at mitigating respiratory motion artifacts at 1.5 t. poster #: sci-011 mri findings in post-fontan hepatopathy adina alazraki, md, radiology, emory university/children's healthcare of atlanta, adina.alazraki@choa.org; pinar bulut, kiery braithwaite, miriam vos, rene romero, nitika a. gupta purpose or case report: as advances in congenital heart disease continue to improve both mortality and quality of life, associated complications are becoming more prevalent. amongst patients who have had fontan repair for hypoplastic left heart syndrome, tricuspic atresia, or other right heart dysfunction, it is well known that liver disease is a complication. we describe the mri findings in post-fontan patients and propose mri as a useful tool to the hepatologist's evaluation of these patients. methods & materials: irb approval was obtained for a retrospective review of 29 patients who underwent fontan repair and were subsequently referred for hepatology evaluation between 2010-2011. all but one patient was scanned on a siemenstriotrim 3 t magnet; one patient was scanned on a ge twinspeed 1.5 t magnet with an equivalent protocol due to orthodontics. a standardized departmental protocol was utilized. mri findings were correlated with age at surgery and years since surgery. mr images were reviewed independently by 2 pediatric radiologists and compared with the dictated report in the patients record. results: 17 patients underwent mri of the abdomen. 4 patients had mri incompatible hardware and 8 patients were not scanned secondary to insurance denial. patients were divided into 4 groups based on elapsed time since surgery: less than 5 years, 5-10 years, 10-15 years, and greater than 15 years.(table 1) mr images were evaluated for the presence of fibrosis, congestion and any other hepatic abnormalities. fibrosis was determined based on a specific pattern of delayed reticular enhancement in combination with liver morphology. congestion was deemed present if there was increased t2 signal in the liver parenchyma or periportal regions in combination with cloud-like enhancement on dynamic post-contrast images. all patients demonstrated morphologic changes in the liver with varying degrees of hepatic fibrosis and hepatic congestion. fibrotic changes were often non-uniform, and thus could be underdiagnosed by biopsy. interestingly, 4 patients, 24%, had focal arterially enhancing lesions speculated to represent vascular proliferative lesions, however, none warranted biopsy. conclusions: it is established that patients who undergo fontan develop hepatic abnormalities. mri is a reliable, non invasive technique that accurately demonstrates these findings. mri may be a more sensitive method to evaluate the etiology and full extent of hepatic disease. poster #: sci-012 complications within the interventional radiology division of a tertiary care children's hospital: initiatives for ongoing quality and practice improvement brian dillon, children's hospital boston, brian. dillon@childrens.harvard.edu; pamela sanborn, yolanda milliman-richard, darren orbach, stephan voss purpose or case report: between 2004 and 2010, procedure-related complications occurring within the division of interventional radiology at our institution were recorded and classified according to level of severity. the goals of this study were to determine rates of procedurebased complications based on severity, to establish thresholds for complications, and to determine whether measurable trends in complications over time were evident. methods & materials: between 2004 and 2010, 14,042 interventional procedures were performed within the division of interventional radiology at our institution. adverse events were characterized both according to level of severity (using an institutional 5 point severity scale), and with brief descriptions of individual events. adverse events were reviewed monthly at the division's morbidity and mortality conference, with respect to procedure type and operator. based on review of our interventional radiology data and benchmarks rates used for diagnostic errors, threshold complication rates were established by consensus between the department quality improvement committee and the division of interventional radiology. for severe events (level 4 and 5) there is no allowable threshold; all such events were subjected to both internal and institutional review. results: the overall complication rate was less than 1% for all procedures performed. the complication rates for the respective severity levels were: level 1 (0.235), level 2 (0.3), level 3 (0.1), level 4 (0.249), and level 5 (0.028). the severity of a given complication was not associated with procedural complexity. no operator-specific trends were identified. conclusions: since 2003, the society of interventional radiology has offered guidelines and strategies for improving safety and quality in interventional radiology. however, no specific benchmark data or procedural recommendations are available for pediatric interventional procedures. our results demonstrate rates of complications well below published overall complication rates for interventional radiologic procedures. this database of procedure-based complications serves as a foundation for a quality improvement program that allows review of complications with respect to specific procedure types, individual operators, and procedural complexity, in an effort to institute an ongoing and continuous process of quality improvement within interventional radiology. purpose or case report: dysosteosclerosis (dss), an extremely rare dense bone disease, features short stature and fractures and sometimes optic atrophy, cranial nerve palsy, developmental delay, and failure of tooth eruption in infancy or early childhood consistent with osteopetrosis (opt). bone histology during childhood shows unresorbed primary spongiosa from deficient osteoclast action. additionally, there is remarkable progressive flattening of all vertebrae mimic ppi blocking mineralization. during ehdp treatment for gaci, in our patient prolonged high dose ehdp resulted in severe skeletal deformity resembling hypophosphatasia which was reversable with drug stoppage. methods & materials: a 7-year-old boy with gaci referred for profound, acquired, progressive skeletal deformity. he was receiving 200 mg/day of ehdp and was wheelchair bound. we studied him and his response to stopping ehdp. results: skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, widened physes with metaphyseal osteosclerosis, "tongues" of radiolucency, along with cupping and fraying, and long-bone bowing. in addition there were large intra and extraarticular calcifications. radiographic features of bp-induced opt included femoral erlenmeyer flask deformity and osteosclerosis (lumbar sine dxa z-score +5.7). biochemical parameters of mineral homeostasis were essentially normal although serum osteocalcin was low and he had markedly elevated serum levels of creatine kinase and trap-5b consistent with osteopetrosis (opt). after stopping ehdp, he improved quickly with remarkable healing of his rachitic appearing skeleton and decreased joint calcifications. conclusions: our patient with gaci had profound skeletal deformities from high-dose ehdp therapy that significatly improved with drug stoppage. magnetic resonance imaging in the evaluation of infants with hypoxic ischemic encephalopathy julio m. araque, md, radiology, medical college of georgia, jaraque@georgiahealth.edu purpose or case report: to illustrate and review a spectrum of brain abnormalities of infants with hie. defining the most useful approaches and mri sequences, to facilitate identification and early diagnosis of lesions with the potential to predict outcome and abnormal neurodevelopment. methods & materials: reviewed available evidence on mri strategies for evaluating infants with hypoxic ischemic encephalopathy. different cases illustrating lesions are presented and discussed for proper diagnosis correlating physiopathology and imaging appearance. more relevant findings are depicted with didactic illustrations. identifying studies where new techniques such as dwi, adc, dti, swi, or mrs adds significant diagnostic value to the overall interpretation. results: mri is routinely performed as a very sensitive method for detection of hie lesions. advanced mr techniques, such as dti, dwi, adc, mrs, swi offer the possibility of detecting injuries at a time when intervention is theoretically possible. the understanding of the physiopathology allows for prediction of the location and extent of lesions, facilitating identification and appropriate classification. the identification of infants with potentially abnormal neurodevelopment, offers the opportunity to provide therapeutic neurodevelopmental interventions in early childhood. mrs is the best mr biomarker to predict neurodevelopmental outcome in asphyxiated full-term neonates. brain metabolite ratios and regional adc values may vary between mr systems and coils. development of normal values for each institution is required, and support of physicists is mandatory. conclusions: mri continues to evolve as a valuable adjunctive tool routinely obtained in nearly all cases of hie. advanced mri techniques increase sensitivity of conventional t1 and t2-w images and outperform computer tomography and ultrasound for confirming the diagnosis of hypoxic-ischemic brain injury or providing prognostic information for the care of patient with hie. disclosure: dr. araque has indicated that he will discuss or describe, in the educational content, a use of a medical device or pharmaceutical that is classified by the food and drug administration (fda) as investigational for intended use. posterior fossa abnormalities in children amit gupta, mbbs, radiodiagnosis, r.n.t. medical college, udaipur, rajasthan, india, amitsensation@yahoo.co.in purpose or case report: the aim of this exhibit is to demonstrate various conditions involving the posterior fossa in children with emphasis on importance of embryologic development of cerebellum in reaching a correct diagnosis. methods & materials: this pictographic presentation displays the imaging features of cases encountered in our clinical practice on 1.5 tesla magnetic resonance (mr) imaging. results: with the advent of mr imaging, there has been a revolution in identification and characterization of malformations of the brain this is especially true in posterior fossa, where the sensitivity and specificity of mr imaging with its multidimensional imaging capability are far superior to those of computed tomography (ct) in the detection of subtle morphologic abnormalities. however, there is still a great deal of confusion regarding their classification, terminology, and spectrum of expression and this is where neuroembryology is of great help. this exhibit demonstrates : 1) review of embryology and normal anatomy of cerebellum. 2) mr appearance of spectrum of conditions involving posterior fossa in children which includes developmental abnormalities (dandy-walker complex, arnold chiari malformations, cerebellar dysplasia/ hypoplasia, joubert's syndrome, etc.), cysts (arachnoid cyst, giant cisterna magna etc.), tumours (medulloblastoma, ependymoma, hemangioblastoma etc.) and miscellaneous conditions. significantly reduces dose (1/3 of other gadolinium based contrast agents), and doesn't require trigger imaging. conventional mri provides important information regarding the anatomical extent, size, and relation to critical anatomical structures thus when combined with twist, mri provides the best information without use of radiation in children. functional connectivity mri in pediatric brain tumor patients with and without epilepsy andrew v. poliakov, phd, radiology, seattle children's hospital; david bauer, edward novotny, seth d. friedman, dennis shaw, jeff ojemann purpose or case report: functional connectivity mri (fcmri) is a way to evaluate cortical networks across different modalities such as motor, sensory, vision, and the default mode network using functional magnetic resonance imaging. fcmri relies on correlation in fmri image intensity that occurs between functionally connected regions. this effect can be seen in awake as well as anesthetized patients. we evaluated these pathways in pediatric patients with brain tumors. methods & materials: patients were randomly selected from our tumor database. inclusion criteria included age less than 18, history of brain tumor resection, and complete fcmri data. imaging was performed on a 3 t siemens trio system. functional mri data were acquired as part of a clinical imaging protocol over 6.5 -8 min using a gradient echo, echo-planar sequence. preprocessing of fmri data followed by independent component analysis (ica) was performed using fsl software. functional connectivity analysis was performed using software provided by 1000 functional connectomes project, based on afni and fsl software packages. correlation maps were produced by extracting the bold time course from a seed region, computing the correlation coefficient between that time course and the time course from all other brain voxels, correcting for multiple sampling and degrees of freedom and thresholded at a z value of 3.0. results: fourteen patients were included in the study, eight female and six male. tumor types include ganglioglioma (5), pleomorphic xanthoastrocytoma (2), juvenile pilocytic astrocytoma (2), ependymoma (1), anaplastic astrocytoma (1), glioblastoma multiforme (2), and primitive neuroectodermal tumor (1). seven patients had tumor-associated epilepsy, and seven patients did not. the figure shows connectivity patterns in the motor network in patients without (a) and with (b) epilepsy. in the patients without epilepsy, functional connectivity was often displaced but not decreased or absent. in the patients with epilepsy, we observed decreased or absent functional connectivity. similar results were found for default mode network: connectivity was diminished or absent in the patients affected by epilepsy. conclusions: fcmri is a novel technique that may prove useful for evaluation and presurgical planning by giving us insight into how tumors disrupt function. functional connectivity was often displaced but relatively preserved in the patients without epilepsy. it was disrupted or absent in the patients with epilepsy. poster #: sci-022 corpus callosum dti measurements in neurofibromatosis type 1 and normal controls nadja kadom, md, radiology, children's national medical center, nkadom@childrensnational.org; amir noor, rhea udyavar, marine bouyssi-kobar, iordanis evangelou, maria t. acosta purpose or case report: many patients with neurofibromatosis type 1 (nf1) have corpus callosum enlargement; pathogenesis and underlying pathophysiology are unclear. the goal of our study is to investigate the pathophysiological basis of corpus callosum enlargement in nf1 patients through mri diffusion tensor (dti) measurements. methods & materials: retrospective study, irb approved. patients consecutively selected from institutional data base; inclusion criteria: established diagnosis of nf1, brain imaging with dti sequence, abnormally high corpus callosum to skull ratio; excluded were patients with complications of nf1 that could affect size of the corpus callosum. age and gender matched normal controls were randomly selected from the radiology data base. roi were placed manually over the corpus callosum for dti measurements using dti-studio by two independent researchers, one blinded to diagnosis. results: fifteen nf1 patients and matched controls were analyzed. the corpus callosum to skull ratio was found to be significantly different between the experimental and control group (p00.0001). for nf1 patients we found: a trend to lower apparent diffusion coefficient (adc, p00.067), significantly higher radial diffusivity (p00.023), significantly lower axial diffusivity (p00.0002), and significantly lower fractional anisotropy (fa, p00.0012). conclusions: the significantly lower axial diffusivity in nf1 can indicate that there are more crossing fibers in the corpus callosum of nf1 patients than in normal controls. further studies using comparative dti tractography may be helpful in further investigating this stipulation. the significant increase in radial diffusivity can be explained by a variety of factors, including thinner myelin sheaths, increased interstitial fluid, smaller axons, or a combination thereof. the trend of lower adc may indicate low axonal diameter, as adc has been shown to more strongly correlate with axonal diameter without the myelin sheath. in future studies we will correlate abnormal corpus callosum dti markers with cognitive functions in nf1 patients to see if relationships exist that can be used as predictors of cognitive deficits in nf1 patients. screening for vitamin d deficiency in children with suspected non-accidental fracture conor kain, md, tripler army medical center; veronica rooks, laura keller, jordan pinsker, allyson cordoni, sarah frioux purpose or case report: determine if routine screening of vitamin d levels after suspected non-accidental fracture detects vitamin d deficiency and changes clinical outcomes. methods & materials: after irb approval we reviewed all skeletal surveys performed at tripler army medical center (tamc) in the last 10 years and selected the children who were evaluated for suspected non-accidental fracture. we determined if 25-hydroxyvitamin d [25(oh)d] level was requested for these patients and characterized the provider's clinical suspicion of vitamin d deficiency as high or low. per the 2010 institute of medicine report and 2011 endocrine society guidelines we defined vitamin d deficiency as a 25 (oh)d level of less than 20 ng/ml. we calculated the prevalence of children with low 25(oh)d levels whose providers had low clinical suspicion for vitamin d deficiency. results: 396 skeletal surveys were done at tamc from november 2000 to july 2011. 99 were performed after identifying a suspected non-accidental fracture. of these patients 11 children from ages 1 to 7 months had 25(oh)d levels requested. for children whose providers had a low pre-test suspicion for vitamin d deficiency, the prevalence of vitamin d deficiency was 12.5% (95% binomial ci 0.003-0.524, 1 of 8 cases. these results indicate that at least one out of every three hundred children evaluated for nonaccidental fracture could have vitamin d deficiency despite a low clinical suspicion by their provider, although the actual rate is likely much higher given that we found one in eight cases. the child we identified with a low vitamin d level whose provider had no suspicion for rickets was treated with ergocalciferol and continued to be evaluated for abuse. conclusions: routine vitamin d level screening after nonaccidental fracture may detect vitamin d deficiency in children for whom there is low clinical suspicion. as our population resides at a low latitude and receives greater than average sun exposure, the rate of deficiency in children with suspected non-accidental fracture may be much greater in other areas. comet tails and dirty shadows: the secrets behind artifacts in pediatric ultrasound adam edelstein, pediatric radiology, massachusetts general hospital; anuradha shenoy-bhangle, katherine nimkin purpose or case report: to review common ultrasonographic artifacts, explain what causes them, and show how they can be used to aid in diagnosis in a variety of pediatric conditions, including less common entities. methods & materials: ultrasonographic images in patients less than 18 years of age were reviewed. cases were selected that showed classic artifacts which helped with the diagnosis of a variety of entities. results: ultrasound artifacts include comet tail, reverberation, ring down and "dirty" shadowing. these can be used to help characterize a variety of pediatric conditions including gossypiboma, bezoar, subcutaneous foreign body, complications of nec, and staghorn calculus. artifacts can also be used to confirm the presence of stool or bowel gas. conclusions: familiarity with ultrasonographic artifacts is critical for tissue characterization and can help narrow the differential diagnosis in difficult pediatric cases. cardiac cta: non-vascular ring tracheobronchial compression secondary to enlarged patent ductus arteriosus in infants with congenital heart disease. nhi huynh, md, radiology, st. joseph hospital and medical center, e.nhihuynh@gmail.com; todd chapman, randy richardson purpose or case report: tracheobronchial compression or narrowing secondary to a vascular ring has been well documented. the purpose of this study is to describe the frequency of airway compression secondary to an enlarged patent ductus arteriosus detected by ccta without the presence of a vascular ring. methods & materials: a retrospective study of 282 ccta exams in infants was performed over the period between 03/ 28/2007 and 09/28/2011. ccta was performed with a 64-slice mdct, with ekg gating, followed by three-dimensional reformations. results: of the 282 congenital heart disease infant patients, there are 49 patients with tracheobronchial compression or narrowing. of these 49 patients, 20 patients reported to have patent ductus arteriosus as the primary cause of tracheobronchial compression or narrowing. approximately 41% of patients with airway compression in patients with congenital heart disease are secondary to an enlarged and/or tortuous patent ductus arteriosus. none of these cases were due to a vascular ring. of these 20 patients, 10, 6, and 4 patients demonstrated to have mild, moderate, and severe airway compression respectively. conclusions: tracheobronchial compression or narrowing secondary to vascular ring with a patent ductus arteriosus has been well documented. in this study, we demonstrate that a significant percentage of airway compression in patients with congenital heart disease without a vascular ring is due to a tortuous enlarged patent ductus arteriosus. cardiac cta is uniquely equipped to evaluate airway compression due to an enlarged patent ductus arteriosus and can help improve patient care in congenital heart disease patients with respiratory symptomatology. pediatric liver mr elastography: a primer suraj serai, phd, cchmc, suraj.serai@cchmc.org; daniel j. podberesky, alexander j. towbin purpose or case report: a wide variety of pediatric liver disorders may be complicated by the development of liver fibrosis and ultimately cirrhosis. with early interventions, the progression to hepatic fibrosis can be slowed, halted, and in some cases reversed. liver biopsy has long been considered the gold standard for assessing the presence and degree of liver fibrosis. however, liver biopsy has disadvantages, due to its potential sampling error, risk of complications, relatively high cost, intra-and inter-observer variability, and, in general, poor acceptance by pediatric patients and their parents. mr elastography (mre) is a relatively new, non-invasive technique that provides a safe, rapid and cost-effective method for objectively evaluating of a wide variety of hepatic diseases by quantitative stiffness evaluation of the liver-parenchyma. the purpose of this exhibit is to review our clinical experience with this technique and illustrate the application of liver mre in the pediatric population at our medical center. methods & materials: a review of pathogenesis and staging of liver fibrosis in children and current methods available for assessing liver fibrosis will be provided. a review of mre physics and technique, including the specific liver mre protocol used at our institution will be illustrated. we will review widely-used and emerging clinical indications for liver mre, as well as benefits and limitations to the technique, supported by brief literature review. results: in addition to sharing our liver mre technique, we will illustrate clinical case examples from our institution of a variety of liver disorders including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, storage disorders, cardiac disease, and idiopathic elevated liver enzymes. conclusions: this educational exhibit will review our experience with liver mre, a safe, newly available technique which will play an increasingly important role in the noninvasive evaluation of pediatric liver disease. poster #: sci-027 spectrum of tuberculosis in children amit gupta, mbbs, radiodiagnosis, r.n.t. medical college, udaipur, rajasthan, india, amitsensation@yahoo.co.in purpose or case report: the aim of this exhibit is to present a spectrum of tuberculosis (tb) in the human body which commonly involves pulmonary, nervous, musculoskeletal, gastrointestinal and genitourinary systems. this pictographic presentation displays the imaging features of tb cases encountered in our clinical practice with reference to plain x-rays, ct and mri as appropriate. results: with the advent of the newer modalities, the utility of the plain skaigram has been largely limited a initial screening tool only. whereas ct scores over mri in pulmonary tb (parenchymal disease, lymphadenopathy, pleural effusion, empyema, miliary disease) and abdominal tb (spectrum from mesenteric lymphadenitis to visceral involvement), the magnetic resonance (mr) imaging is much better in diagnosing cns tb (tuberculoma, abscess, meningitis, subdural empyema and myelitis). in musculoskeletal and genitourinary tb, ct and mr imaging may be preferred based on the stage of disease and the character of the lesion. cardiac involvement (pericarditis) is among the less common affections of tb. conclusions: tuberculosis is a multisystem disease that can affect virtually any part of the body from head to toe. tb demonstrates a variety of clinical and radiologic findings and has a known propensity for dissemination from its primary site and therefore can mimic numerous other disease entities. hence it is imperative for radiologists to understand the typical disease distribution, patterns and imaging manifestations of tb. 2010 janet l. strife, md 2011 carol m. rumack md 1987 ole a. eklof, md 1987 clement c. faure, md 1987 andres giedion, md 1987 denis lallemand, md 1987 arnold lassrich md 1992 donald r. kirks, md 1992 beverly p. wood, md 1993 hooshang taybi md 2008 marta hernanz-schulman, md, facr 2009 m. ines boechat, md, facr 2010 neil d. johnson, mbbs 2011 dorothy i. bulas, md *deceased singleton-taybi award investigator award this award is given to the author of the best paper presented by a resident or fellow at the spr meeting md 2002 ricardo faingold, md 2003 andrea doria, md 2004 nina m. menezes, phd anthropometric parameters are a strong determinant of lvm in healthy individuals kiyarash mohajer, pierangelo renella, paul j. finn purpose or case report: despite theoretical advantages of higher field strength ssfp cine imaging, time-resolved magnetic resonance angiography (tr-mra), and high resolution contrast-enhanced mra (ce-mra) were performed. two readers independently evaluated the data for image quality, vessel and cardiac chamber definition, and presence of artifacts. snr and cnr were calculated. results: 95% of ssfp cine images at 3 t were rated as good or excellent quality with 73% having mild and 24% having moderate artifacts (k00.07) 100% of arterial and venous phase ce-mra images were considered good or excellent cardiac chamber definition was considered good or excellent in 95% of arterial and venous phase ce-mra images (k00.08). 100% ce-mra images showed good or excellent definition of the thoraco-abdominal vessels on average, both readers scored cine ssfp images higher at 1.5 t and cemra images higher at 3.0 t. overall diagnostic performance was high at both field strengths. conclusions: mri of pediatric patients with chd and vascular abnormalities at 3.0 t is feasible. relative to 1.5 t, snr and cnr are both improved at higher field strength and higher resolution cemra is achievable t are more prevalent, they rarely render cine imaging non-poster # exclusion criteria were lack of correlating us or follow up information. two pediatric radiologists blinded to us findings reviewed the mr images and analyzed the contents of abdominal wall defect, organ location and attachment; spine anomalies; umbilical cord and limb anomalies. results: our search yielded 16 patients. all fetuses had ventral wall defects, small thorax and eviscerated liver and bowel. in two cases kidneys were in extracorporeal location. in 12/16 there was no membrane covering extruded organs. in five mr showed organs attached to the placenta or uterine wall (mainly bowel and liver) mahmoud al-hawary and, by adolescence, paradoxical metaphyseal osteopenia with thin cortical bone. reports of consanguinity indicate autosomal recessive inheritance our studies, spanning ages 11-44 mo, showed weight 50%, but length diminishing from~30% to −2.3 sd. head circumference was +4 sd. she had frontal bossing, blue sclera, normal teeth, genu valgum, and unremarkable joints. radiographs showed orbital and facial sclerosis, basilar thickening, "bone-in-bone" appearance in the pelvis, sclerotic long bone ends, and fractures of ribs and extremities. progressive metaphyseal widening occurred as vertebrae changed from ovoid to flattened and became beaked anteriorly. consistent with opt, serum pth concentrations reflected dietary calcium levels. serum bone alkaline phosphatase, osteocalcin, and trap5b were sub-normal. iliac crest contained excessive primary spongiosa and no osteoclasts. splice sites and exons were intact for the genes encoding cholride channel 7, t-cell immune regulator 1, opt-associated transmembrane protein 1 the hallmarks include stippled epiphyses, nasal hypoplasia, and hypoplastic distal phalanges and developmental delay. punctate calcifications are seen not only in the epiphyses but also in the paravertebral regions. paravertebral puncta are commonly associated with defective ossifications in the cervical spine. the malformation of the cervical spine causes spinal canal stenosis and instability, which occasionally necessitate surgical intervention none of the cases had brain infarction. conclusions: tortuousity and luminal narrowing of the cervical arteries is a common finding in cdp-bt. this previously unknown malformation is an important factor to discriminate patients at increased risk of cerebral ischemia, particularly in patients undergoing surgical intervention. disclosure: dr. okabe has indicated that she will discuss or describe severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy william h. mcalister, md, mallinckrodt institute of radiology campbell sheen purpose or case report: generalized arterial calcification of infancy (gaci) is an autosomal recessive disorder caused by deactivating mutations within the gene for ectonucleotide pyrophosphatase phosphodiesterase-1 (enpp1). enpp1 on osteoblasts, chondrocytes, and vascular smooth muscle cells hydrolyzes nucleotide triphosphates to nucleotide monophosphates and inorganic pyrophosphate (ppi) can time-resolved contrast-enhanced mra (twist) classify soft tissue vascular anomalies in the head and neck in children accurately? aylin tekes, md 28 children from 0-17 years of age were enrolled. twist and conventional mri was performed (triplanar t2-weighted [t2-w] imaging with fat saturation, pre-contrast axial t1-weighted [t1-w] imaging, and post contrast triplanar fat-suppressed t1-w imaging). twist was performed in coronal plane using blood-pool mr contrast agent (ablavar-lantheus) to enhance image quality and spatial resolution of mra. two pediatric neuroradiologists evaluated all patients in two different sessions, 15 days apart: one session conventional mri with contrast was evaluated, in the second session twist was evaluated. clinical evaluation and/or percutaneous venogram/lymphogram data were the gold standard. results: our patients had diagnosis of infantile hemangioma (n04), venous malformation (n012), and lymphatic malformation (n012). twist alone could accurately classify 26/ 28, conventional mri with contrast could accurately classify 22/28. conventional mri with contrast combined with twist could accurately classify all cases. conclusions: twist offers high temporal resolution in the order of seconds, and provides functional data about the dynamics of contrast enhancement comprising the arterial, venous and delayed venous phases kiery cr-2, sci-11 edu-91, edu-92 edu-35, edu-40, pa-045 edu-86, pa-036 a-092, pa-093, pa-108, pa-109, pa-113 edu-7, edu-59, edu-60, edu-62, edu-66, edu-69, edu-78 edu-59, edu-60, edu-62, edu-66, edu-69, edu-78 suraj sci-26, pa-124, pa-125 edu-98 pa-147, edu-86, pa-036 the society for pediatric radiology gratefully acknowledges the support of the following companies in presenting the 55th annual meeting and postgraduate course: cme committee reviewers for this activity have disclosed any relevant financial relationships. no conflicts of interest exist.abuse and offer potential mechanisms of injury may help make the diagnosis of child abuse. the pediatric elbow-mri findings with multimodality correlation michael guandalini, md, royal children's hospital; murray bartlett purpose or case report: to describe and illustrate elbow abnormalities identified by mri performed in a cohort of pediatric patients with multimodality correlation. methods & materials: retrospective review of mri elbow studies performed at the royal children's hospital, melbourne between 2003 and . the studies were reviewed by a pediatric musculoskeletal radiologist and pediatric radiology fellow with patient demographics, clinical indication, findings and selected images recorded. results: 199 elbow mri examinations were reviewed on children aged 4 months to 18 years (123 boys, 76 girls) with equal numbers of left and right sides examined. clinical indications included previous trauma in 147 cases (74%) and nontraumatic conditions in 52 (26%). the most common traumatic indication was suspected or confirmed fractures or avulsions (21%) followed by osteochondral or cartilage injuries (18%), growth arrest (16%), loose bodies (14%) and ligament injuries (10%). hemophilia (38%) was the most frequent nontraumatic indication followed by neoplasm (17%). mild to severe arthropathy, fractures, physeal growth arrest, subluxations, osteochondral lesions and loose bodies were the most frequently demonstrated abnormalities. ligament strains and tears, bone oedema, neuromuscular abnormalities, infections and several neoplasms including lipomas, vascular/lymphatic malformations and bone tumors also featured. conclusions: this pictorial review illustrates the broad range of abnormalities one might expect to encounter on pediatric elbow mri studies, highlighting the major features and corresponding appearances on ct and plain x-ray. spectrum of patellar tendon avulsive injury on mri in children: differentiation between acute and chronic avulsive injuries of the inferior patellar pole and tibial tuberosity zeyad metwalli, md, baylor college of medicine, metwalli@ bcm.edu; herman kan, scott rosenfeld, r. p. guillerman purpose or case report: the extensor mechanism of the knee is an intricate component of the joint and is frequently injured in pediatric athletes. due to the strength of the patella tendon, trauma to the anterior knee is often manifested by avulsive injuries, which may occur on an acute or chronic repetitive basis. purpose: this pictorial review will illustrate differentiating radiographic and mri features of acute and chronic avulsive injuries of the pediatric knee. outline: 1. anatomy and physiology a. discuss the anatomic differences of the pediatric and adult knee extensor mechanism b. pathophysiology and biomechanical basis for chondro-osseous avulsion injuries versus tendon tears in the skeletally immature. purpose or case report: the purpose of this educational exhibit is to demonstrate the magnetic resonance imaging (mri) appearance of the ankle and hindfoot ligaments using an interactive approach. methods & materials: a 3 tesla siemens mri scanner with a multichannel ankle coil was utilized in the acquisition of images of ankle and hindfoot. three dimensional volume acquisition proton density images will be used to demonstrate the ligamentous anatomy of the ankle and hindfoot in axial, axial oblique, coronal, and sagittal planes. results: the exhibit will begin with an interactive review of the ankle and hindfoot ligamentous anatomy with each ligament poster #: edu-073 cns imaging findings in hemophagocytic lymphohistiocytic syndrome rupa radhakrishnan, mbbs, md, dnb, radiology, university of cincinnati college of medicine, radhakrp@ucmail. uc.edu; marcia k. kukreja, alexandra filipovich, alexander j. towbin purpose or case report: hemophagocytic lymphohistiocytosis (hlh) is a rare, life threatening condition caused by an uncontrolled proliferation of activated lymphocytes and histiocytes with high levels of inflammatory cytokines. the organs most commonly involved in this disorder include the liver, spleen, lymph nodes, bone marrow and central nervous system (cns). the purpose of this exhibit is to review the cns imaging findings associated with hlh, its complications, and its management. the published literature was reviewed to identify the potential imaging findings hlh. the electronic medical record system was then searched to find illustrative case examples from our institution. cases demonstrating the primary imaging findings as well cases highlighting complications of the disease or its therapy were selected. results: cns involvement is common in hlh with approximately 75% of patients demonstrating neurological symptoms. ct findings of cns involvement include diffuse parenchymal atrophy, low attenuation lesions in the white matter and calcifications. mr findings include diffuse leptomeningeal and perivascular enhancement, t2 hyperintense lesions with nodular or rim enhancement as well as confluent white matter lesions, and diffuse parenchymal volume loss of the cerebrum and cerebellum. restricted diffusion has been demonstrated in some lesions. ring enhancing parenchymal lesions have been described representing active demyelination. intracranial hemorrhage may occur as a result of thrombocytopenia and coagulation abnormalities. sepsis with opportunistic organisms can involve the cns and produce intracranial findings such as parenchymal abscesses. cns changes, such as posterior reversible encephalopathy syndrome, are also seen with the commonly used immunomodulatory regimen used in the treatment of hlh. conclusions: this exhibit will aid the viewer in identifying the cns imaging findings of hlh as well as the complications of the disease and its therapy. while the cns imaging findings are not specific, they may help the radiologist formulate a diagnosis in association with the other clinical and imaging findings; furthermore, imaging can help the clinical team in managing the disease and its complications. methods & materials: medical records of our pediatric patients with palpable head masses over the last 5 years, were reviewed and images were collected. correlation of us of these lesions with other imaging modalities and/or pathologic diagnosis was done. results: us appearances of various head masses including congenital/developmental (encephalocele, meningocele, dermoid, occipital protuberance), traumatic (cephalhematoma, subgaleal hematoma, calvarial fracture), inflammatory/infectious (sebaceous cyst, histiocytosis, dermatitis), vascular (malformations, pseudoaneurysm) and neoplastic (benign and malignant lesions including metastases) etiologies, will be illustrated with case based approach. mri and/or ct or tissue diagnosis can be problem solving. role of ultrasound guidance for percutaneous procedures (biopsy, sclerotherapy) will also be described. conclusions: ultrasound can play an important role in the delineation, diagnosis and guiding further management of pediatric palpable head masses. us can differentiate various scalp lesions and suggest the underlying calvarial defect or involvement to some extent, helping to narrow the differential diagnosis for such lesions. color doppler us can be useful to detect vascularity within the lesion or vascular lesions. given that us is often requested for the evaluation of palpable head masses, pediatric radiologists should be familiar with their sonographic features. posterior fossa malformations-a pictorial review rui santos, md, bc children's hospital, ruiradiologia@gmail. com; khalid khashoggi, angela t. byrne purpose or case report: posterior fossa malformations are a group of central nervous system anomalies that may be detected during pregnancy or present early infancy with features that include hypotonia, developmental delay, mutations responsible for the disease and proposals as to mechanism of action of the mutation with respect to disease manifestations. this preceded the development of hypotheses regarding the relationship between genotype and phenotype and the attempt to utilize imaging modalities that could better assess disease activity as it related to functional status. the purpose of this exhibit is to briefly review the history pre-1989 and to focus on the numerous ways in which the understanding has improved since that time. conclusions: 1. there are over 1000 different mutations of the cftr gene responsible for cystic fibrosis with varying prevalence throughout the world. 2. the class of mutation often dictates its particular mechanism of action. 3. there is some relationship between genotype and phenotype-particularly with respect to pancreatic involvement. 4. newer imaging modalities including ct and mri with or without hyperpolarized helium are better predictors of disease severity than is plain film. imaging pulmonary tuberculosis in infants: what are the most useful diagnostic radiological findings? handan cakmakci, pediatric radiology, dokuz eylul university hospital, handancakmakci@gmail.com; nevin uzuner, filiz tetik purpose or case report: early diagnosis and treatment are very important for infants with tuberculosis. infantile pulmonary tuberculosis is more symptomatic, and the risk of severe and life-threatening complications such as tuberculous meningitis or miliary tuberculosis is higher. bacteriologic confirmation of the disease in children is difficult and in younger infants (<3 months), the tuberculin skin test is frequently negative. therefore, radiological findings play important role in diagnosing tuberculosis in infants. the purposes of this study are to identify chest x-ray and lung ct findings in pulmonary tuberculosis of infants and consider the most useful diagnostic findings of these age group patients.methods & materials: chest radiographs and chest ct images of 7 infants who were diagnosed in our hospital from 2005 to 2011 were retrospectively reviewed. the study group included 2 boys and 5 girls ranging in age from 2 to 12 months (mean age, 6 months). chest x-ray and computed tomography images were analyzed considering air space consolidation, nodular lesions, cavitating lesions, mediastinal enlargement, hyperinflation, bronchial narrowing, atelectasis pleural effusion on plain radiography and additional mediastinal calcific or caseating lymph nodes on ct images.results: air space consolidation was seen on 5 out of 7 chest x-ray and computed tomography images. nodular lesions were seen 2 out of 7 chest x-ray and computed tomography images. cavitating lesion was seen on 1 out of 7 chest x-ray and computed tomography images. mediastinal enlargement suggesting lymph node was seen 5 out of 7 chest x-ray and computed tomography images. hyperinflation, bronchial narrowing was seen 2 out of 7 chest x-ray and computed tomography images. atelectasis, pleural effusion was seen 1 out of 7 chest x-ray and 2 out of 7 computed tomography images. mediastinal caseating lymph nodes, mediastinal calcific lymph nodes were seen 3 out of 7 computed tomography images. conclusions: frequent and the most useful diagnostic radiological findings of pulmonary tuberculosis in infants are mediastinal or hilar lymphadenopathy with central necrosis and air space consolidations. disseminated nodules including miliary lesions and airway complications are also detected in this age group. ct can show detailed parenchymal lesions and tuberculous lymphnodes especially calcified ones. the ductus bump: radiographic findings of this normal variant and differential diagnoses anusuya mokashi, staten island university hospital, anusuya.mokashi@gmail.com; jeremy neuman, cheryl lin purpose or case report: the ductus bump: review of radiographic findings, differential diagnoses and current controversies. the ductus bump was first described in 1965 by berdon et al as a transient physiologic mass in the chest in newborn infants. some controversy remains as to the exact etiology and clinical significance. although initially thought to represent a dilated ductus arteriosus, recently it has been suggested that it actually represents a ductus arteriosus aneurysm that spontaneously resolves. others contend it represents dilation of the infundibulum of the closing ductus. regardless of etiology, the time of discovery, location, and rapid resolution are characteristic of this entity. in this presentation we will review the radiographic and echocardiogram findings of the ductus bump, as well as discuss the differential diagnosis. the frontal radiographic findings are a round mass to the left of the vertebral spine projecting from the mediastinum near the aortic arch. this mass does not indent the esophagus and it cannot be seen on the lateral view. it is classically said to resolve within the first few days of life. the controversy regarding the etiology has also led to some disagreement involving the clinical significance and appropriate follow up, which will also be discussed. after reviewing this educational poster, the reader will have conclusions: abnormalities of the posterior fossa are often difficult to differentiate solely on the basis of their radiologic appearances alone. however, an accurate diagnosis is essential for proper treatment planning and genetic counselling. therefore it is imperative for radiologists to be well versed with the normal anatomy and development of cerebellum so as to correctly diagnose the various posterior fossa abnormalities.poster #: sci-019imaging of oculoauriculofrontonasal syndrome with low-dose 3-dimensional computed tomography paritosh c. khanna, md, radiology, seattle children's hospital, pkhanna@uw.edu; kelly evans, gisele ishak, joseph gruss, michael cunningham, anne hing purpose or case report: oculoauriculofrontonasal syndrome (oafns) combines elements of abnormal morphology of the frontonasal and maxillary processes of the face. the aim of our exhibit is to demonstrate the low-dose computed tomography (ct) features of this syndrome, in seven patients who have been followed at seattle children's hospital (sch) over 18 years. we underscore the imaging features of this condition, and describe additional features including bony nasal abnormalities not previously described in the literature, to improve imaging recognition of this spectrum. we present 3d ct imaging features of a series of eight patients with oafns. in keeping with the alara (as low as reasonably achievable) concept and the image gently recommendations (www.imagegently. org), ct head and face studies were obtained on six of eight patients at sch, while two had prior exams at outside institutions. using a 64-slice multidetector ct scanner (ge lightspeed vct, waukesha wi), low-dose ct (120 kv, 150 mas or lower depending on age) of the head and face was obtained. planar bone window and 3d surface rendered images were analyzed. results: our series of patients demonstrated bifid nasal bones, uni-or bilateral mandibular hypoplasia, temporomandibular and zygomatic dysplasia and bony external auditory canal abnormalities. one patient had an interfrontal bone with a frontal bony defect that was contiguous with the metopic suture. we describe additional previously unidentified ct anomalies of the nasal bones, anterior nasal spine and nasal septum. these structures are involved in all patients who had ct imaging available, although unique features are present in each case. conclusions: ct is the mainstay of imaging of craniofacial anomalies in the post-natal period, both pre-and postoperatively. in addition to our low-dose ct imaging findings of oafns, novel nasal bone anomalies identified by our group serve to identify a new subset of patients with this syndrome and may help refine the phenotype of the oafns spectrum. key: cord-009997-oecpqf1j authors: nan title: 2018 aspho abstracts date: 2018-03-31 journal: pediatr blood cancer doi: 10.1002/pbc.27057 sha: doc_id: 9997 cord_uid: oecpqf1j nan myelodysplastic syndrome (mds) and frequently arise in the context of inherited bone marrow failure (bmf) syndromes, such as shwachman diamond syndrome (sds). monosomy 7/del(7q) is associated with high grade mds and propensity to progress to acute myelogenous leukemia, a major cause of morbidity and mortality for patients with inherited bmf. development of non-transplant strategies to treat bone marrow failure without simultaneously stimulating outgrowth of malignant clones remains a major challenge. objectives: the aim of this study is to investigate the molecular consequences of del(7q) in the context of bmf with the goal of developing more effective treatments. design/method: to study the biological and molecular consequences of monosomy/del(7q) in bmf, induced pluripotent stem cells were generated from sds patients (sds-ipsc) . a deletion of the mds-associated region of the long arm of chromosome 7 was then introduced using a previously published modified cre-lox approach. results: the sds ipsc phenocopied bone marrow failure with slow proliferation and impaired hematopoietic differentiation. we next explored whether deletion of 7q conferred a relative fitness advantage within the context of bone marrow failure. proliferation of the sds-del(7q) ipscs was reduced below that of both the isogenic sds ipscs and normal controls without an increase in cell death. sds-del(7q) demonstrated reduced hematopoietic differentiation compared with isogenic sds cells. these data demonstrate that deletion of 7q fails to confer a relative growth advantage relative to isogenic sds ipscs and results in further impairment of hematopoiesis. to gain insight into the mechanisms of del7q-associated clonal evolution in sds, we performed rna sequencing (rnaseq) of sds+/-del(7q) ipsc. expression of tgf pathways and their downstream targets were reduced in sds-del(7q) ipscs compared to isogenic sds ipsc. single cell rnaseq analysis of primary sds bone marrow cells confirmed that the tgf pathway is hyperactivated in sds. western blot analysis showed increased phospho-smad2 levels in sds ipscs compared to sds-del(7q) and normal controls, while total levels of smad2 were unchanged. pharmacological targeting of tfg with small molecule inhibitors resulted in selective improvement of sds hematopoietic colony formation and myeloid differentiation without stimulating outgrowth of the isogenic sds-del(7q) cells or normal controls. these results demonstrate that del(7q) reverses the tgf pathway hyperactivation of sds. furthermore, inhibition of tgf selectively rescues hematopoiesis in sds but not in isogenic del7q cells, suggesting a potential strategy to treat bone marrow failure without stimulating del7q clonal outgrowth. background: standard therapy of medulloblastoma consists of treatment with alkylating agents and radiation after surgical resection. although a statistically significant increase in survival is reported with this regimen, 1/3rd recur and become resistant this class of agents ultimately leading to mortality. large numbers of somatic mutations were observed in recurrent medulloblastoma (rm) after alkylating agent and radiation treatment. high mutation rates in tumors can have twofold effect; 1) a large number of non-synonymous mutations that have no role as drivers can still cause functional tumor antigens increasing the neoantigen burden and immunogenicity. moreover, 2) such tumors can gain mutations in canonical or non-canonical dna repair pathways leading to a gain in the number of mutations as seen in case of glioblastoma, this can lead to even higher accelerated mutational rate. evidences suggest that high mutational load can cause higher neoantigen burden thereby making the tumor more susceptible to immune checkpoint inhibition. we propose that post therapy recurrent medulloblastoma gain mutational signature and immunophenotype of malignancies demonstrating clinical response to immune checkpoint therapy. objectives: 1) rm has molecular signatures identical to tumors with high immunogenicity and clinical response to immune check point inhibition. 2) rm has the immune inflammatory phenotype; harboring high percentage of tumor infiltrating lymphocytes (tils), macrophages and monocytes. design/method: to test our hypothesis, we downloaded the raw bam files of previously published data from international cancer genome consortium (icgc) . this set of about 30 matched primaries and recurrent medulloblastoma cases forms our discovery cohort. we have called somatic variants using the gatk pipeline by the broad institute. to validate our key findings, we have procured human medulloblastoma specimens and are conducting whole exome sequencing. the primary assays utilized to assess immunogenicity are immunohistochemical (ihc) staining of formalin fixed and embedded recurrent medulloblastoma tissue to identify tils, tumor associated macrophages and other markers. 300 mg/m2 had dlts of dyspnea (grade 4)/hypoxia (grade 3) but no dlts were observed in any other cohort. adverse events were generally mild to moderate, consistent with the safety profile observed in adults. across the desc cohorts, plasma concentrations were dose-proportional and steady state concentrations were lower on day 15 vs. day 1. mean systemic exposure in the 1200 mg/m2 cohort was ∼ 4-fold greater compared with the adult rp2d of 800 mg bid. a pk:pd relationship between tazemetostat exposure and h3k27me3 levels in peripheral blood monocytes and granulocytes was observed in the desc phase. consistent and significant post-dose reductions in h3k27me3 occurred at doses ≥900 mg/m2. further analysis of twelve patients treated at the rp2d confirmed that h3k27me3 inhibition was maximally inhibited. doses 520-900 mg/m2 showed confirmed objective responses (cr/pr) per recist/rano in patients with es (n = 1), chordoma (n = 2), and atrt (n = 1). background: previous studies established that the platelet/ fibrin(ogen) axis promotes metastatic potential by impeding the clearance of newly formed micrometastases by natural killer (nk) cells. however, multiple important questions remain, including the potential of fibrin(ogen) to promote metastasis through interactions with cells other than platelets (e.g., inflammatory cells), and the fundamental question of whether fibrin polymerization is required for metastasis. objectives: determine the role of fibrin polymerization and fibrin(ogen) engagement of integrins iib 3 and m 2 in metastasis. design/method: we performed experimental and spontaneous metastasis assays in immunocompetent mice carrying specific fibrinogen structure/function alterations. results: expression of a mutant fibrinogen lacking the binding motif for the leukocyte integrin m 2 (fib 390-396a) significantly decreased metastatic potential relative to wildtype fibrinogen, suggesting a role for fibrin(ogen)inflammatory cell interactions mediated by m 2 in metastasis. to directly determine the importance of thrombinmediated fibrin polymerization in metastasis, we analyzed metastatic potential in fibaek mice, which carry a form of fibrinogen essentially "locked" in the soluble state due to a mutation in the a chain thrombin cleavage site. metastatic potential in fibaek mice was diminished relative to control mice, speaking to the importance of thrombin-mediated fibrin polymerization in the metastatic process. however, the fibaek mice retained significant metastatic potential relative to complete fibrinogen deficiency, indicating that fibrinogen monomer retains significant prometastatic properties. in order to better define the role of fibrin(ogen)-platelet interactions in metastasis, we compared metastatic potential in control and fib δ5 mice, carrying a form of fibrinogen lacking the chain binding motif for the platelet integrin iib 3. surprisingly, this mutation had no impact on metastatic potential. together, these studies suggest fibrinogen plays a multifaceted role in metastasis. fibrin(ogen)-leukocyte interactions mediated by m 2 appear to have a role in metastasis. previous studies showed that macrophages promote the metastatic potential of circulating tumor cells, which may represent at least one important m 2 expressing cell type whose prometastatic behavior is influenced by fibrin(ogen) interactions. these studies show that thrombin-mediated fibrin polymerization promotes metastasis, but soluble fibrinogen retains some significant prometastatic capacity. surprisingly, loss of the fibrinogen chain iib 3 binding motif had no impact on metastasis. given the established importance of platelets in metastasis, these findings suggest that fibrin (ogen) is capable of platelet stabilization through mechanism(s) independent of this iib 3 binding motif. platelets may bind polymerized fibrin at other sites, and/or fibrin interactions with other matrix proteins capable of binding iib 3 are sufficient to support platelet functions required for metastasis. the role of platelets in hemostasis and thrombosis is well defined, but it is becoming increasingly evident that platelets also assist in host defense and inflammation. platelets participate in the innate immune system through direct antimicrobial activity and interactions with effector cells (chapman2012, garlanda2013, kapur 2016). in the adaptive immune system, platelets recruit and costimulate t-cells, and promote b-cell differentiation and antibody class switching (kapur2016, morrell2017). the question remains: which mechanisms influence platelet immune function and are they developmentally regulated? preliminary studies in the palis lab have revealed significant dif-ferences in embryonic versus adult platelet gene expression, including regulators of immune and inflammatory responses such as beta2-microglobulin (b2m) and major histocompatibility complex class i (mhc1). mhc1 is expressed on all cell surfaces except red blood cells and its molecular chaperone b2m is a marker of inflammation highly expressed in platelet alpha granules (zufferey2014). preliminary data from the morrell lab reveals a mass release of b2m during platelet activation, which drives monocyte differentiation to an inflammatory phenotype through tgfb receptor signaling. we therefore sought to determine whether developmental changes in platelet b2m expression mediate differences in platelet-mediated monocyte activation. with trilineage hematopoiesis with a predominance of early myeloid precursors, with full maturation. microarray, elane and sbds sequencing and deletion/duplication analyses were negative. immunologic evaluation was significant for agammaglobulinemia and an absence of memory (cd19+cd27+) b cells. a 207 gene primary immunodeficiency panel revealed two variants of unknown significance-c.1957g>a and c.2292g>t in dnmt3b; one previously reported in association with icf1. parental testing demonstrated parental heterozygosity. centromeric instability was confirmed in mitogen stimulated lymphocytes showing characteristic, multibranched chromosomes containing at least 3 arms of chromosome 1 and 16 joined near the centromere. decondensation of the 1qh and 16qh regions and triradial configuration of chromosome1 was noted, and a diagnosis of icf1 syndrome was made. the patient was started on monthly intravenous immunoglobulin (ivig). prophylaxis for pneumocystis jiroveci pneumonia and respiratory syncytial virus was initiated. a 10/10 matched sibling hsct is being planned. demonstrated the diagnosis of high grade osteosarcoma. the patient was started on multi-agent chemotherapy with planned a whole femur prosthesis at time of local control. 7 cases of osteosarcoma have been described in the literature in patients with nf1 (median age; 25 years, range 17-37 years) with slightly male predominance (4 cases). the femur was the most common site of involvement (5 cases). four patients died of metastatic disease despite surgery and multi-agent chemotherapy. conclusion: nf1 represents a major risk factor for development of malignancy and uncommonly osteosarcoma in adolescents and adults. we report a rare case of an extensive involvement of osteosarcoma of the left femur in a child with known diagnosis nf1. this presentation should alert the pediatric oncologists to monitor for bone tumors in patients with nf1 by physical exam and detailed medical history. hasbro children's hospital, providence, rhode island, united states background: dysautonomia is a paraneoplastic syndrome most commonly described in adult malignancies. despite current therapies aimed at symptoms management, it is often debilitating. we present a case of a 16-year-old girl who initially presented with autonomic dysfunction and was subsequently found to have hodgkin lymphoma. objectives: describe hodgkin lymphoma presenting with dysautonomia and discuss symptom management with rituximab design/method: case report a 16 year-old-girl presented with severe symptoms of orthostatic hypotension necessitating prone positioning to prevent syncopal episodes. additionally, she reported anhidrosis, xerostomia, urinary retention, and constipation. she had unmanageable peripheral neuropathic pain despite multiple analgesia medications. initially, it was suspected that her symptoms were caused by an atypical presentation of guillain-barre syndrome. she was treated with intravenous immunoglobulin g, without response. due to a suspicion of a paraneoplastic syndrome a positron emission test/cat scan (pet/ct) was performed and revealed widespread fdg-avid nodal and splenic disease. pathology from a thoracoscopic biopsy of a mediastinal lymph node demonstrated classical hodgkin lymphoma. she was classified as stage ivb. a paraneoplastic panel obtained during the first cycle of chemotherapy revealed elevated anti-amphiphysin antibodies and glutamic acid decarboxylase (gad) antibodies. therapy was initiated with abe-pc (doxorubicin, bleomycin, etoposide, prednisone, cyclophosphamide) ; vincristine was held given her significant neuropathy. due to persistence of autonomic symptoms following her first cycle and presence of antiamphiphysin and gad antibodies, rituximab was incorporated into her treatment. following two cycles abe-pc, she had a rapid early response by fdg-pet/ct. she completed an additional three cycles of abd-pc. end of therapy imaging demonstrated complete response with a single persistent mildly fdg-pet avid lymph node (deauville 2) and her antibodies were negative. she continues treatment of maintenance rituximab with significant improvement, but not resolution, of her orthostatic hypotension. at this time, the patient can ambulate with assistance. constipation and urinary retention have fully resolved and, her peripheral neuropathy, xerostomia, anhidrosis have improved. conclusion: this is rare case of a pediatric hodgkin lymphoma patient developing dysautonomia associated with antiamphiphysin and glutamic acid decarboxylase antibodies and subsequently managed with chemotherapy and rituximab. clinicians should be suspicious of a paraneoplastic syndrome when a neurologic disorder fails to improve with standard treatment. results: labs obtained at an outside hospital one month prior to presentation showed absolute neutrophil count (anc) 78 and hemoglobin 10.2 g/dl. she presented to our institution with 11 days of fever, hepatomegaly 1 cm below costal margin, a white plaque on her tongue, and circumferential perianal ulceration. labs were significant for anc 0 and hemoglobin 7.8 g/dl. anti-granulocyte antibody testing was positive. bone marrow biopsy showed arrest of neutrophil maturation. after initiation of filgrastim (2.7 mcg/kg/day), her anc increased to >500 and repeat bone marrow biopsy demonstrated left shifted myelopoiesis. biopsy of her oral lesion demonstrated invasive actinomyces prompting a prolonged course of antibiotics. biopsies of her oral and anal lesions were reported as myeloid sarcoma without mll rearrangement. chemotherapy was not initiated due to complete resolution of both lesions within 6 weeks of initiating filgrastim and appropriate antibiotic coverage. she has not developed any further lesions concerning for malignancy. testing for common genes associated with severe congenital neutropenia and autoimmune lymphoproliferative syndrome was negative. her immunoglobulin levels and the measurement of age-appropriate vaccine responses were normal. after her lymphocyte subpopulation analysis indicated a selective deficiency in cd8 positive t-lymphocytes (absolute cd8 cell count 185), the severe combined immunodeficiency panel from genedx showed compound heterozygous mutations in results: a male infant was born with a large thigh mass. the child was clinically well aside from restricted movement of affected leg. mri showed mass expanding into pelvis without other lesions. an interventional-radiology guided core biopsy of the mass was reported as high-grade spindle cell sarcoma without etv6 rearrangement. surgery was deferred because of concern that it would result in excessive morbidity. the mass was treated with vincristine and dactinomycin per infantile fibrosarcoma protocols. after 3 months of therapy, no significant change in size of the mass was noted on physical exam or imaging. repeat biopsy was obtained to confirm diagnosis and allow for expanded tumor testing. this biopsy showed triphasic distribution of adipose, fibrous and mesenchymal tissue consistent with fhi with rare sarcomatous foci. additional chemotherapy was deferred and the child was followed clinically. his tumor has remained approximately the same size and still unresectable. next generation sequencing of tumor utilizing panel based technology revealed braf-erc1 fusion consistent with braf activating mutation. this mutation was confirmed by fluorescent in situ hybridization (fish) probe for braf. braf and mek inhibitors have been pursued as treatments to decrease size of tumor and allow for resection. conclusion: braf mutations have been characterized in a variety of malignancies. inhibition of braf and downstream signaling components has produced promising results in a variety of patients. this is the first case report of a braf mutation in a fhi. although management of fhi is typically surgical, this does suggest a potential therapeutic target and may allow for improved surgical outcomes especially in cases where up-front surgery would result in unacceptable morbidity. genetic sequencing of fhi and other rare tumors is an important tool and has the potential to identify mutations amenable to targeted therapies. background: icf is a rare autosomal recessive disorder characterized by hypo-or agammaglobulinemia and often opportunistic infections suggesting t-cell dysfunction. it is further categorized into subtypes 1-4 based on mutations in dna methylation. mutations in the helicase-lymphoid specific (hells) gene, which is required for t-cell proliferation and participates in de novo dna methylation, are characteristic of icf type 4 (icf4). of approximately 70 reported cases of icf, less than 10 percent are characterized as icf4. while malignancy has been reported in icf1 (angiosarcoma, acute lymphoblastic leukemia), and icf2 (hodgkin lymphoma), here we describe the diagnosis and management of an icf4 patient with neuroblastoma and neutropenia, which has not been previously described. objectives: describe a novel phenotype and mutation of icf4 and its management to further expand our understanding of this disease. results: a 6 month ex-31 week premature male with bronchopulmonary disease and failure to thrive presented with acute respiratory failure in the setting of recent viral bronchiolitis with associated chronic diarrhea. he was subsequently diagnosed with multiple infections including pjp pneumonia, norovirus, parainfluenza, rhinovirus, and pseudemonal cellulitis. he presented with profound neutropenia and agammaglobulinemia with presence of b and t cells on lymphocyte phenotyping. ct revealed a paraspinal mass that was mibg-avid on further study, strongly suggesting neuroblastoma. bone marrow was normocellular and negative for malignancy, however revealed marked granulocytic hypoplasia and maturation arrest concerning for severe congenital or, less likely, immune-mediated neutropenia. metastatic workup was negative. whole exome sequencing revealed a homozygous variant of unknown significance (c. 668t>c) in the hells gene, portending a working diagnosis of icf4 syndrome. immunoglobulin supplementation, pentamidine prophylaxis, and g-csf were initiated. he was able discontinue g-csf after 4 months of treatment. his neuroblastoma, initially categorized as l1, met criteria for observation. however, followup mri revealed interval growth nearing the spinal canal. he underwent tumor resection, confirming mycn non-amplified, favorable histology neuroblastoma. after infectious prophylaxis and immunologic support were initiated, he incurred two other hospitalizations, the first for g-tube cellulitis and the second for parainfluenza respiratory illness. he now has stable neutrophil counts off g-csf and remains in remission from neuroblastoma. current plan is to proceed with bone marrow transplantation for immunodeficiency. conclusion: icf4 has not previously been described with neutropenia or neuroblastoma. this report not only describes a novel mutation and phenotype of icf4 and the management thereof, but also reveals the potential curative role of bone marrow transplantation in such disease. staten island university hospital -northwell health, staten island, new york, united states background: desmoid tumors are rare tumors that arise from highly differentiated fibroblasts. they occur in isolation or as part of the disease spectrum of familial adenomatous polyposis (fap) . fap mutations between codons 1445-1578 typically correlate with increased extraintestinal disease such as desmoid tumors and upper gastrointestinal polyps. we describe a patient with a large intra-abdominal desmoid tumor who is heterozygous for a c.8161c>t (p.arg2721cys) apc gene mutation. we are not aware of any other patients reported with this germline apc mutation presenting with a desmoid tumor. objectives: to discuss a novel apc mutation and the presentation of a rare case. design/method: review of clinical presentation, genetic analysis and management of a rare tumor. a 17-year-old female with no significant medical history presented with abdominal asymmetry and intermittent pain. she reported urinary urgency, shortness of breath, early satiety, decreased appetite and a 20-pound weight loss over the course of 7 months. ct scan of the abdomen demonstrated a 24 × 15cm abdominal tumor abutting the local organs but no presence of bowel obstruction. a biopsy revealed a spindle cell neoplasm favoring fibromatosis. there was no known family history of fap, colon cancer, or desmoid tumors. apc gene mutation analysis demonstrated a c.8161c>t (p.arg2721cys) heterozygous gene variant. due to size and location of the tumor, it was initially deemed unresectable. the patient was started on a course of monthly liposomal doxorubicin. she tolerated the initial cycles well and interval ct after 3 cycles of chemotherapy revealed a 40% decrease in tumor volume. variability exists in phenotypic presentation with regards to the location of the afp mutation locus. while fap mutations associated with desmoid tumors typically have changes in the 1445-1645 codon region, our patient presented with a heterozygous mutation resulting in a missense mutation at codon 2721. due to the change in polarity and size, the mutation is not considered to be of conservative nature. we are only aware of one other report of this mutation, which occurred in an individual with a personal and family history of colon cancer. we are not aware of any patients with desmoid tumors who also have this germline apc gene mutation. our case report highlights an apc gene mutation that is not well-described; we are not aware of any other cases of this mutation reported in patients with desmoid tumors. future evaluation and tracking of this mutation may lead to the determination of further clinical significance. background: over time, advanced care planning for location of death has been associated with increased deaths at home rather than in the hospital. in some cases, however, complex management and symptom control can prevent families from achieving their goal of keeping their child out of the hospital and at home at the end of life. ascites is a sequelae of many conditions including malignancy that might lead to significant morbidity. increasingly, interventional procedures are being utilized. peritoneovenous "denver" shunts are placed internally with one end in the peritoneal space and the other buried within a major vessel such as the svc. a one-way valve and pump buried under the skin allows the patient to pump fluid from the peritoneal to the vascular space. the shunt is used frequently in adults, but has not seen much use in pediatric oncology patients. objectives: to describe a case of a terminally ill patient with refractory wilms tumor with ivc involvement who received symptomatic relief with denver shunt placement. results: an 8-year-old female was diagnosed with relapsed, refractory, metastatic wilms tumor with pulmonary and hepatic involvement, with tumor extension to the hepatic veins and ivc. multiple chemotherapeutic regimens and palliative radiation to the ivc were administered, but her disease continued to progress, leading to pressure on the portal vein and portal hypertension. the resulting ascites was causing the patient significant pain and was difficult to manage. the patient's code status was changed to dnr/dni after discussion with her mother, who identified a desire to have the child die at home as comfortably as possible. a peritoneovenous shunt was placed in order to control the patient's pain and avoid frequent medical procedures and therapies. despite initial anxiety, the patient was able to utilize the pump and achieve significant improvement in her ascites and pain. she was able to spend the remaining six weeks of her life at home. ascites is a common phenomenon of end stage disease. peritoneovenous shunts are a treatment modality that may be considered to allow for pain control at the end of life for pediatric oncology patients with ascites. the procedure is relatively low risk, allows for self-control of the pump to maintain comfort, and is easy enough to use by the patient or family. background: extraneural metastases (enm) from pediatric glioblastoma multiforme (gbm) are rare, with an estimated frequency of 0.3%. etiologic factors include multiple neurosurgical procedures and sarcomatous dedifferentiation. their occurrence can seriously affect the patient's quality of life and survival. while enms have been well documented in adults, pediatric cases have not been previously summarized. a 15 year old male with a cerebral gbm developed extension of disease outside of the neuraxis approximately 18 months post initial presentation and at the time of disease progression. metastases included exracranial temporal lesions, cervical and mediastinal lymph nodes and s29 of s301 bilateral lung nodules. a large pleural-based soft tissue metastatic focus was identified on imaging when the patient presented with respiratory distress secondary to a right tension pneumothorax, which was recognized and managed promptly. we summarize the main reported cases in literature to better define risk factors for and evaluate the proposed mechanisms underlying these systemic metastases. design/method: we performed a literature review on the pubmed database using the terms gbm and enm. patients under 21 years of age who met the weiss criteria for the diagnosis of enm from primary cns tumors were included. results: our patient fulfilled two of the three weiss criteria with confirmed gbm at the primary site with all enm in the temporal soft tissue and cervical lymph nodes displaying histopathologic features similar to the primary cns tumor. the intrathoracic adenopathy and lung nodules detected upon chest imaging during workup for respiratory distress were assumed to represent additional metastatic foci. our literature review identified 22 pediatric patients with enm from gbm with a median age of 12 years (range 3.5 -21 years) and a slight female predominance (55% females vs. 45% males). the most common sites of metastases reported were pleura/lungs, bones, lymph nodes and liver. in 9 of 22 patients, metastases were associated with csf shunting. conclusion: pediatric oncologists should have an increased index of suspicion when caring for patients with gbm, particularly those who have undergone shunting procedures and present with systemic symptoms including bony pain, respiratory changes, transaminitis or cytopenias which should prompt timely investigation for enm. although enm of cns tumors carry very poor prognosis, their diagnosis has potential therapeutic importance because treatment of metastatic lesions may alleviate symptoms and improve the quality of life. additional studies may be warranted to evaluate the incidence of enm that can provide valuable insight into the pathogenesis and biology of high-grade gliomas. nicklaus children's hospital, miami, florida, united states background: sinusoidal obstruction syndrome (sos) has been reported in patients undergoing intensive chemotherapy and as a complication post-hematopoietic stem cell transplan-tation. sos may be complicated by portal hypertension, hepatorenal disease or multi-organ failure. however, despite treatment, there may be further potential complications that can be anticipated in patients with history sos. we report two patients with history of sos presented with post-procedural bleeding after gastric tube placement. we believe that their presentations may be associated to their previous diagnosis of sos. design/method: pubmed search was done with search for terminology including "sinusoidal obstruction syndrome" "defibrotide", and "bleeding". papers relevant to our cases were selected for literature review. results: case 1: a 4 year-old female with history of desmosplastic medulloblastoma status-post resection and intensive chemotherapy was diagnosed with sos one month after her second part of planned tandem transplant. she was managed with paracentesis and defibrotide. due to malnourishment, patient had a gastric tube placement 5 months after she completed therapy and had an episode of upper gastrointestinal bleeding postoperatively from the g tube site. case 2: similarly, a 4 year-old male diagnosed with anaplastic medulloblastoma status post resection and adjuvant multiagent chemotherapy. his treatment course was complicated with sos after the second cycle of induction chemotherapy which responded to 21-day course of defibrotide. likewise, the patient had a major bleeding event from the g-tube site approximately two months after sos diagnosis. defibrotide was discontinued in both cases before g-tube placement. both patients had no previous history of bleeding disorders or relevant family history. in addition, comprehensive laboratory evaluations were within normal limits before both procedures. in sos, there is blockage of fluid out of the liver that leads to congestion, ascites, ischemia of the liver, and post-sinusoidal portal hypertension. two related causes of sos should be considered as an explanation for g-tube bleeding. similar patients should have close monitoring postoperatively or if possible surgical intervention should be delayed until the sos process has been evolved. nicklaus children's hospital, miami, florida, united states background: the development of treatment related acute myeloid leukemia (t-aml) and myelodysplastic syndromes (t-mds) is a potential complication after cytotoxic chemotherapy or radiation therapy. the incidence of development of t-aml/t-mds varies from 1-20% depending on the treatment regimen used. cutaneous myeloid sarcoma (ms) is a common presentation of extramedullary leukemia and usually occurs in the setting of aml. we report a rare case of cutaneous ms in an adolescent female after successful treatment for ovarian yolk sac tumor (yst) stage i with bep (bleomycin, etoposide and cisplatin) therapy. the ms was managed only with biopsy and close observation. design/method: a pubmed search was conducted for queries including t-aml/t-mds, cytotoxic agents, cutaneous myeloid sarcoma, regression. relevant papers were selected for literature review. a 13 year-old female was diagnosed with a left ovarian yolk sac tumor, for which she underwent left salpingooophorectomy and successfully completed 4 cycles of bep over 4 months. during routine follow-up 8 months after initiation of treatment for ovarian yst, she was noted to have a small, non-tender, indurated nodule on the left side of her upper back approximately 1cm in diameter. punch biopsy of the skin nodule was performed and pathology was positive for cutaneous myeloid sarcoma. at the time of next follow-up less than one month later, the skin lesion had resolved. two subsequent bone marrow aspirates were performed one month apart and were negative for leukemic involvement or mds. examinations and work-up including whole body pet with ct scan were negative for evidence of disease. although cutaneous ms can be regarded as the herald of systemic myeloid disease rather than a localized process, our patient was monitored periodically with physical exam and laboratory evaluations. she remains free of disease more than four years after the presentation of cutaneous ms without any further treatment. spontaneous regression ms has been previously reported. the authors would like to stress that a conservative approach with close observation could be an option in cutaneous ms even with history of chemotherapy exposure. nesreen ali, iman sidhom, sonia soliman, sherine salem national cancer institute, cairouniversity, egypt children cancer hospital egypt, egypt background: acute leukemia is the commonest malignancy in childhood. the coincidental occurrence of leukemia with hemophilia is extremely rare. hemophilia is a congenital rare x linked bleeding disorder. the main complication of the two diseases is bleeding diathesis which may be lifethreatening due to many factors, deficiency of coagulation factors in hemophilic patients, thrombocytopenia from disease and chemotherapy in leukemic patients, certain cytotoxic drugs such as asparaginase which may result in coagulation disorders and infection which may lead to disseminated intravascular coagulation. objectives: reporting such a case is imperative to set up treatment guidelines for prevention of bleeding and to optimize the therapeutic approach for these patients. design/method: seventeen years old boy, presented to children cancer hospital egypt in june 2015 with pallor and multiple ecchymoses.he was diagnosed with precursor b acute lymphoblastic leukemia, cerebrospinal fluid (csf) was free, the chromosomal analysis revealed hypodiploidy 36, xy. he had moderate type of hemophilia a since birth, factor viii level was 1.5 % at time of diagnosis, coagulation profile revealed prolonged partial thromboplastin time 89 (normal 26-45), factor viii was low 1%, prothrombin concentration and prothrombin time were normal100% and 13 seconds, virology screening for hepatitis b core igg/igm, hbs ag, hiv and hc igg /igm were negative.the patient started induction total xv sjcrh protocol, factor viii 40 unit/kg was given at presentation before doing bone marrow aspiration(bma), csf and as a prophylactic before intramuscular asparaginase injection, intrathecal and bma. it was given immediately within 2 hours before the procedures and platelets transfusion was given regularly to maintain platelets count about 50,000. the minimal residual disease by flow cytometry was 0.81% and 0.11% at d15 and d42 induction. results: our patient received his induction and reintensification chemotherapy without any major bleeding event which reveals the success of our guidelines for the prevention of bleeding. he developed very early relapse at w7 maintenance by the same clone. he received salvage chemotherapy but didn't achieve remission and died out of disease and resistant clone. the development of leukemia on top of hemophilia is a major problem. bleeding complication during chemotherapy can be prevented by regular prophylactic factor viii and platelets concentrate transfusion with good supportive care. life threating bleeding complication may be correlated with the severity of hemophilia. we need to collect data about the biology of leukemic cells, complications, and cause of death to optimize care for these patients. background: mucoepidermoid carcinoma (mec) is a rare malignancy that arises from exocrine glands in the upper aerodigestive tract and tracheobronchial tree. conventionally, mec diagnosis is based on histology, with prognosis based on the extent of resection and detection of metastases. mec is characterized by a translocation of chromosomes 11q and 19p resulting in a fusion between the mect1 and maml2 genes, that occurs in 38-81% of cases. this fusion transcript has been recognized to have a favorable impact on disease features and prognosis of mec. however, recent studies indicate that high grade mec can have mect1-maml2 fusion positivity and multiple other genomic imbalances that have not been studied in much detail. owing to the rarity of mec tumors, more definitive data related to the clinical and prognostic significance of these molecular markers are limited. objectives: 1. identify the presence or absence of mect1-maml2 fusion in the tissue of our patient. 2. analyze the incidence of the fusion in 25 mec cases in children and young adults retrieved from the iowa cancer registry. 3. determine if fusion status correlates with clinical, pathological and outcome data in our cohort. design/method: we describe the case of a 12 year-old caucasian male who presented with recurrent pneumonia, persistent cough and radiographic evidence of right lobar collapse. bronchoscopy revealed an endobronchial lesion and the patient underwent right upper lobe sleeve resection. pathology report was consistent with low grade muco-epidermoid carcinoma. we retrieved 25 archived formalin-fixed paraffinembedded (ffpe) specimens of pediatric and young adult mec cases (ages 0-29) reported in iowa from 1973-2016 using the iowa cancer registry. testing for the mect1-maml2 fusion in the index case and 25 ffpe specimens will be done using a custom-designed laboratory validated next generation sequencing (ngs) assay with the ability to detect novel fusion partners. clinical, pathological and outcome data (age, sex, tumor site, tumor size, nodal metastases, clinical stage, histologic grade, treatment and follow up) will be analyzed to correlate with fusion status. the mect1-maml2 fusion tested positive in our index patient. we will obtain irb approval to test for the fusion in the 25 archived ffpe specimens and correlate clinical, pathological and outcome data. conclusion: mect1-maml2 fusion is a frequent event in mec that has prognostic and potential therapeutic applications in adults. the results of this study may enlighten the clinical management of mec in children and young adults. children 's mercy hospital, kansas city, missouri, united states background: mutations in the samd9 gene are associated with a rare syndrome comprising of myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy (mirage syndrome). diagnosis is made through exome sequencing. in the largest reported case series, of eleven patients diagnosed with mirage syndrome, two developed loss of chromosome 7. given the potent growth restricting activity of samd9 mutants, the loss of chromosome 7 is considered the first documentation of adaptation by aneuploidy mechanisms in humans and led to myelodysplastic syndrome (mds), with deaths occurring from related complications at 2 and 5 years of age. objectives: to report a case of mirage syndrome with congenital thrombocytopenia progressing to bone marrow failure, managed uniquely with bone marrow transplantation. results: male born at 29 weeks gestation with prenatal diagnosis of iugr, two vessel cord, oligohydramnios was found to have ambiguous genitalia, adrenal insufficiency, partial panhypopituitarism and congenital thrombocytopenia with bone marrow showing absence of megakaryocytic precursors. severe thrombocytopenia was present from birth. bone marrow evaluation demonstrated a hypocellular marrow with markedly reduced megakaryocytic and myeloid precursors and no evidence of myelodysplasia. he required gastric tube placement for failure to thrive, had a laryngeal cleft repaired and developed focal segmental glomerulosclerosis. mpl gene testing for congenital amegakaryocytic thrombocytopenia was negative. testing for fanconi anemia, shwachman-diamond syndrome and dyskeratosis congenita was also negative. approximately 30% of cells had loss of heterozygosity on chromosome 7q. exome sequencing showed that he is heterozygous for a de novo gain of function variant, c.2471g>a (p.arg824gln), identified in the samd9 gene, confirmed by sanger sequencing and consistent with a diagnosis of mirage syndrome. at 6 years of age, he developed pancytopenia requiring frequent transfusions with platelets and packed red blood cells. he underwent a successful bone marrow transplant at 7 years of age without significant complications, and remains transfusion independent without cytopenias greater than 18 months from bone marrow transplantation. conclusion: it is imperative to pursue work up for persistent congenital thrombocytopenia in a stepwise multidisciplinary manner. to the best of our knowledge, this is the first case of mirage syndrome associated bone marrow failure treated with bone marrow transplant. due to the individual rarity of mirage syndrome and pediatric myelodysplastic syndrome, it is important to maintain an index of suspicion given their association and explore bone marrow transplant as a therapeutic option. results: the patient demonstrated disease regression, initially, and continued without disease progression for 36 months. the regimen has been well tolerated with only minimal side effects of dry skin (ctcae grade 1) and a transient episode of brief erythrodysesthesia (ctacae grade 2) that resolved spontaneously. the combination of sorafenib and capecitabine was effective and well tolerated in this adolescent patient with fl-hcc. our observations, although in a single patient, lend support for further testing of this novel oral chemotherapy regimen in patients with fl-hcc, a disease for which there is no effective standard chemotherapy approach. background: epstein-barr virus (ebv) is a ubiquitous virus associated with a broad range of malignancies due to its oncogenic potential. history of organ or bone marrow transplantation, immunosuppressive therapy, and primary or acquired immunodeficiency syndromes increases the risk of ebvassociated tumors. epstein-barr virus associated smooth muscle tumors (ebv-smt) are unique and rare neoplasms typically discovered in immunocompromised patients. most information related to pathogenesis and therapeutic options is limited to case reports and case series of adult patients. there are several gene expression pathways that ebv utilizes, the most notable of which is the mammalian target of rapamycin (mtor) pathway. the mtor pathway performs a key role through integrating various cell growth signals and factors to regulate protein synthesis and metabolism related to smooth muscle proliferation. sirolimus is an immune modulating therapy that targets the mtor pathway to block activation of lymphocytes. objectives: several case reports have demonstrated shortterm clinical remission of ebv-smt in adult patients with the use of sirolimus. we report the first case of long-term background: bilateral neuroblastoma is characterized as neuroblastoma arising in both adrenal glands, a rare presentation with little data on its genetic make-up. a two-monthold patient was diagnosed with bilateral neuroblastoma in our clinic. her risk assignment was based on biopsy of the left adrenal lesion, which showed mycn amplification, an unfavorable genetic marker. treatment regimen was intensified accordingly and after 5 courses of chemotherapy tumors were excised. patient went on to receive a stem cell transplant and immunotherapy. with no knowledge of genetic similarity between the two tumors it is unclear whether biopsy of the right lesion would have yielded similar results or whether bilateral biopsies are needed for risk assessment of bilateral neuroblastoma. objectives: utilize whole exome sequencing (wes) to characterize the genomic signature of bilateral adrenal neuroblastomas excised following chemotherapy treatment. design/method: paraffin-embedded samples from left (l) and right (r) tumors underwent wes at the broad institute. we analyzed resulting data including somatic variant calls, indel mutations, and copy number variants (cnvs) using ingenuity software to evaluate and compare differences between the two tumor samples. preliminary analysis of the data shows important descriptive information on the two tumor samples. out of 29 somatic mutations in the r tumor cells and 25 mutations in the l tumor cells, only two common somatic mutations were present. out of 40 cnv calls in the r tumor and 60 in the l tumor, 31 cnvs were common between the two tumors, or 73% of each tumor's cnv calls. there was a 14 fold higher frequency in gains versus losses. the median size of the common cnvs was 56,683 (range 220 to 3,323,064 bp). cancerrelated genes with increased copy numbers included transcription factors, receptors for signal transduction pathways, and histone methylation proteins. conclusion: preliminary analysis of the wes results of the two adrenal tumors show some genomic divergence. because the tumor tissue was exposed to chemotherapy prior to excision it is difficult to determine whether genomic divergence is a result of independently originated tumors or subsequent adaptation to chemotherapy of a clonal cell population. the high number of common cnvs in the two tumors points to a common cell of origin, however the low number of common somatic mutations does not fit that picture. a future study to help elucidate the question will be wes of the original biopsy tissue to provide information on tumor mutations prior to the effects of chemotherapy. baylor college of medicine, houston, texas, united states background: although there has been significant improvement in the overall survival rates of children with cancer many children will still die from their illness or complications secondary to treatment. research surrounding the deaths of children who succumb to their disease is warranted to ensure we are providing the best care possible for these patients. objectives: this case series aims to explore pediatric cancer deaths by focusing on perhaps the most extreme cases of high intensity end of life care. we explore those patients whom we know are dying or our very likely to die as evidence by their do not resuscitate (dnr) orders. in all of these cases despite the patients very grim prognosis, their great likelihood of death and limitations placed of resuscitation methods all patients continued end of life care in the pediatric intensive care unit (picu). the primary medical records of all children with a cancer diagnosis who died between february 1, 2011 and january 31, 2017 in the picu with a dnr order seven days or earlier prior to death. each medical history included disease-directed treatment history and response with particular attention to the events surrounding the terminal admission. results: eight patients met criteria for this study representing 1.9% of all cancer patients who died during this time period and 7.4% of those who died in the icu. the average time between dnr and death is 19.6 days (7 days -32 days). the average length of terminal admission was 43.5 days (1 day -153 days). the average time between diagnosis and dnr is 10.75 months (0 months -22 months). the average time between diagnosis and death is 11.25 months (0 months -23 months). conclusion: these cases highlight the journey that patients, families and providers endure leading up to death. medical care is complex, there are very few absolutes that are encountered when caring for patients and decisions around limiting or withdrawing medical care are made in a context of the prior journey. . these cases help to understand the complexity of death and how two seemingly opposite ideals can be congruent in the event of an anticipated death. most of these cases show the need for improved anticipatory guidance surrounding death and greater consideration for de-escalation of care when death is expected. the hospital for sick children, toronto, ontario, canada background: rhabdomyosarcoma (rms) is the most common soft tissue sarcoma in children, with embryonal (erms) and alveolar (arms) representing the most common subtypes. arms tumors are associated with inferior outcome when compared to erms, and they are characterized in about 80% of the cases by a t (2;13) or t(1;13) chromosomal translocation with creation of a pax3-foxo1 or pax7-foxo1 fusion gene, respectively. it is increasingly clear that the pax-foxo1 fusion status is an important poor prognostic factor, thus the histological classification tends to be replaced by the fusion status, particularly in terms of risk stratifica-tion in contrast to arms, there are no recurrent chromosome alterations in erms; however, there are multiple numerical chromosome changes that are frequent in these tumours: gain of chromosome 2,8, 12 and 13 have been found in 25 to 50 % of emrs karyotypes. moreover, erms tumors show frequently allelic loss, the 11.p15.5 chromosomal region being the most frequently involved. recently, novel gene fusions have been described also in erms tumours. these fusions involved mainly the ncoa2 and or the vggl2 genes. the rearrangement partners are variable, and include, i.e. pax 3 (2q35), srf (8q11) and tead 1 (11p15). objectives: to present a patient who died as a consequence of brain metastases while on therapy in the setting of an foxo1negative rms and the identification of a new translocation t(2;15)(q21;q22). design/method: case report and retrospective review of the literature. we report a case of pelvic embryonal rhabdomyosarcoma in a 3-month old boy. he was treated as per cog arst 0531 intermediate risk group, but unfortunately was found to have a large cerebellar tumour during the course of his chemotherapy treatment and he subsequently passed away. a novel translocation between chromosomes 2 and 15 was observed in 11 of 20 metaphase cells by g-band analysis in the autopsy sample of the brain lesion. breakpoints of the translocation were estimated to be at 2q21 and 15q22. there were no additional clonal chromosome abnormalities in the tumour cells. conclusion: erms tumors with fusion genes involved have been exclusively described in patients less than 12 months of age; they seem to be associated with spindle cell histology and, a favorable outcome. in our patient, a novel (2;15) translocation was found and clinically, the patient had a dismal outcome. further studies are indicated to inquire whether this finding is of significance in term of prognosis for these patients. children 's national medical center, washington, district of columbia, united states background: iatrogenic immunodeficiency-associated lymphoproliferative disorders (lpds) are a group of lymphoid s35 of s301 proliferations or lymphomas that are well known to be associated with an immunosuppressed state. these disorders most commonly occur following hematopoietic or solid organ transplantation (called post-transplant lymphoproliferative disorders or ptld), but cases have also been described during the treatment of autoimmune and rheumatologic disorders by immunosuppressive and immunomodulatory medications. these disorders are strongly associated with infection by the epstein-barr virus (ebv) as a result of impaired immune function in the immunosuppressed state. while this phenomenon has been well documented in autoimmune conditions, cases affecting pediatric patients while on antileukemia chemotherapy are lacking. background: atypical teratoid/rhabdoid tumor (at/rt) of the central nervous system (cns) in children younger than 3 years old has a prevalence of 1% to 2% and accounts for 1.6% of all pediatric cns tumors. only 15-30% of patients have leptomeningeal dissemination. rhabdomyosarcoma is the most common soft tissue tumor in childhood, but represent only 3-4% of all pediatric cancers. rarely, it can metastasize or even directly extend into the cns, but typically, cases of cns involvement arise either from parameningeal areas or other primary sites. primary spinal or meningeal rhabdomyosarcoma is extremely rare. objectives: our objective is to describe two unique cns malignancies presenting as rare, primary leptomeningeal disease. design/method: case 1 a 19-month-old female presented with vomiting, fatigue and listlessness, despite a normal head ct and brain mri. csf showed hypoglycorrhachia and mild pleocytosis. ceftriaxone was started, but she developed nuchal rigidity and cranial nerve vii palsy. repeat brain mri showed evolving leptomeningeal enhancement concerning for meningitis. she gradually developed worsening opisthotonus and ultimately a brain biopsy of the temporal lobe was consistent with at/rt. case 2 a 3-year-old male presented with new generalized tonic-clonic seizure activity and intermittent headaches with photophobia, phonophobia, and vomiting. brain mri was significant for enhancement of interpenducular and suprasellar cisterns extending to the optic nerves and chiasm most consistent with meningitis. neurosurgery ultimately placed a lumbar drain for hydrocephalus, and a tissue biopsy demonstrated primary meningeal rhabdomyosacroma. results: in case 1, our patient's temporal lobe biopsy demonstrated grade iv malignant tumor cells consistent with atypical teratoid/rhabdoid tumor. fish demonstrated a homozygous deletion of smarcb1 (22q11.23). she was started on chemotherapy per the dana farber at/rt protocol but ultimately was discharged home on hospice. in case 2, our patient's lumbar arachnoid biopsy demonstrated cellular tumor consistent with group iiia embryonal rhabdomyosarcoma. immunostaining was positive for cd99, desmin, myogenin, and myo-d1 with neural markers ema and gfap highlighting the meninges but without a neural component to the tumor. he completed craniospinal radiation to 36gy total with lumbar boost to 50.4gy total. he is currently receiving chemotherapy per arst0431 protocol. conclusion: these two cases are particularly instructive because of their similar initial presentations and neuroimaging, but with very different and unique diagnoses. university of iowa, iowa city, iowa, united states background: ebf1-pdgfrb fusion causes ph-like b-cell acute lymphoblastic leukemia (b-all), which has a philadelphia positive phenotype without the bcr-abl translocation. this is one of several mutations associated with ph-like b-all and leads to downstream overexpression of tyrosine kinase. ebf1-pdgfrb fusion accounts for about 8% of children with ph-like b-all. patients with ph-like b-all previously had poorer outcomes with conventional chemotherapy. the addition of tyrosine kinase inhibitors (tki), like imatinib, has improved the outcome for many patients predicted to have tki sensitive mutations. objectives: to review clinical characteristics and outcomes of two cases of ph-like b-all at the university of iowa stead family children's hospital and to compare these outcomes to similar cases reported in the literature. design/method: a retrospective chart review was performed for two cases of ph-like b-all diagnosed and treated at the university of iowa stead family children's hospital. results: both patients were males diagnosed at 8 years of age with high wbc count (110,700 and 347,200) and positive for ebf1-pdgfrb gene fusion. patient 1 (pt1) was cns 2b at presentation while patient 2 (pt2) was cns negative; neither had testicular involvement. both started treatment according to cog protocol aall1131. peripheral blasts cleared by induction day 22 for pt1 and induction day 14 for pt2. at end of induction, pt1 had m3 bone marrow and pt2 had m1 bone marrow but mrd 8%. dasatinib was started induction day 13 for pt1 and induction day 31 for pt2. pt1 was still not in remission at end of consolidation; bone marrow cell culture for tki resistance showed best response to dasatinib. pt1 proceeded to anti-cd19 car t-cell therapy followed by tbi-based matched unrelated donor bone marrow transplant. pt2 had negative mrd at the end of consolidation and continues chemotherapy according to aall1131, dasatinib arm. both patients are currently clinically well. our patients had the same tyrosine kinase gene fusion and similar initial clinical courses. while both patients had persistent disease at end of induction, pt1 had almost 80% blasts while pt2 had significant reduction of disease burden before starting tki. pt2 showed good response with the addition of dasatinib while pt1 did not. these findings suggest that response to conventional chemotherapy may potentiate the effect of tki and may predict overall outcome. there are likely additional factors which must be taken into account when determining response to tki for patients with ph-like b-all which have not yet been identified. background: medulloblastoma is the most common malignant brain tumor of childhood. classically, medulloblastoma presents as a well-defined mass lesion in the cerebellum, with a high rate of metastatic dissemination. primary leptomeningeal medulloblastoma (plmb) is an exceedingly rare type of medulloblastoma presentation with a dismal prognosis in which patients present with isolated leptomeningeal disease without an associated mass. to our knowledge, only three pediatric and three adult cases of plmb (ages 5 -30 years) have been reported, all of which died within 6 months of diagnosis. this is the first case of plmb to report a molecular classification. objectives: to report the case of a pediatric patient with plmb in which histopathologic and molecular characterization was performed and to describe the patient's treatment and clinical course. design/method: retrospective review of the patient's electronic medical record and review of the literature. a 9-year-old boy presented with headache, vomiting, diplopia, and fatigue. physical examination revealed upward gaze palsy, left-sided extremity and facial weakness, and ataxia. magnetic resonance imaging (mri) of the brain revealed diffuse cerebellar leptomeningeal enhancement and edema without an identifiable mass and moderate hydrocephalus. mri of the spine and cerebral spinal fluid analysis were normal. a diagnosis of cerebellitis was rendered, and the patient underwent placement of a ventriculoperitoneal shunt. an extensive infectious, neurologic, rheumatologic, and oncologic workup did not identify an etiology. empiric antibiotics, high-dose steroids, and intravenous immunoglobulin therapy yielded minimal improvement. two months later, repeat mri of the brain performed for declining mental status demonstrated progressive thickening of cerebellar leptomeningeal disease. a suboccipital craniectomy with decompression and cerebellar biopsy were performed. pathologic examination revealed a diagnosis of plmb, classic histology, non-wnt/non-shh, without gain/amplification of myc/mycn, and p53 wild type pattern. craniospinal radiation to 4140 cgy with a 1440 cgy boost to the posterior fossa was delivered with concurrent carboplatin/vincristine over six weeks. two months following chemoradiation, mri of s37 of s301 the brain demonstrates significantly reduced pathological leptomeningeal enhancement of the cerebellum, and the patient is awaiting initiation of systemic chemotherapy while recovering from a surgical wound infection. conclusion: plmb is extremely rare but should be considered in patients with cerebellitis and diffuse leptomeningeal involvement who are refractory to medical management or in whom an etiology has not been identified. cerebellar biopsy is recommended early to enable timely treatment and improved outcomes. molecular classification should be performed in cases of plmb to further characterize this disease, inform treatment decisions, and improve clinical outcomes. background: primary intracerebral osteosarcoma is extremely rare and limited to case reports. ptpn11 gain of function is associated with noonan syndrome, which has increased risk of multiple cancer types including brain tumors, but osteosarcoma has never been described. ptpn11 mutations have been reported in many cancers as both oncogenes and tumor suppressors, however no ptpn11 mutations have been described in osteosarcoma. pdgfr-a is a growth factor receptor whose activation is implicated in several malignancies. pdgfr-a and ptpn11 concurrent mutations are described in glioblastoma. there is no known link between holoprosencephaly, noonan syndrome, and osteosarcoma. we report a case of multifocal intracerebral osteosarcoma in a child with lobar holoprosencephaly and chronic subdural hemorrhage and discuss the genetic changes found in the tumor. design/method: a seven-year-old caucasian female, with a known diagnosis of lobar holoprosencephaly, chronic subdural hemorrhage and well controlled seizure disorder presented with status epilepticus shortly after completing antibiotic therapy for infection of subdural hematoma. mri showed diffuse dural thickening with mass lesions in the frontal lobe, temporal lobe, and the parasagittal region, the largest of which was contiguous with the subdural space but none of the lesions were associated with bone on mri or by direct neurosurgical visualization. tissue obtained for concern for recurrent infec-tion resulted in a diagnosis of high grade osteosarcoma. dna analysis was performed to help guide treatment choice. results: standard metastatic work-up was negative for skeletal primary tumor or metastatic lesions outside of the brain. she was treated with high dose methotrexate for two cycles per modified aost1331. despite maximal supportive care, she quickly developed rapid tumor growth as well as intratumoral hemorrhage with resultant herniation and death from respiratory failure just three months after diagnosis. tumor gene sequencing discovered three mutations with described roles in cancer: pdgfra d842>vr, kdm6a loss of exons 1-4, and ptpn11 a72v. conclusion: to our knowledge, primary multifocal extraosseus intracerebral osteosarcoma has not been previously described. despite known cns penetration of high dose methotrexate, this tumor proved resistant and aggressive. holoprosencephaly is associated with a multitude of known genetic drivers, but none are found in this case. furthermore, the genetic changes in this tumor are not typical for osteosarcoma. pdgfr-a over-expression is described in osteosarcoma, but is not clearly correlated with worse overall survival. further research is required to determine the role of ptpn11 in osteosarcoma. background: anaplastic lymphoma kinase (alk) encodes a receptor tyrosine kinase whose activation induces pathways associated with cell proliferation, angiogenesis, and cell survival. alk rearrangements are rare in neuroblastoma, while alk mutations and gene amplification occur more frequently. alk mutations have been found to be associated with increased alk protein expression that is associated with a worse prognosis. alk is commonly mutated in neuroblastoma at three hotspots (f1174, r1275, and f1245). the eml4-alk rearrangement has mostly been associated with lung adenocarcinomas, with only a few cases of non-lung cancers found. it has never been reported in neuroblastoma. multimodal therapy and to report the successful management of treatment related iron overload. results: a 10-year old male presented with abdominal swelling and ct showed a right kidney mass and bilateral lung nodules. he underwent right radical nephrectomy with lymph node sampling. pathology was reviewed centrally and revealed wilms tumor with diffuse anaplasia with rhabdomyosarcoma arising within the stromal component and 3 of 13 nodes positive. he received adjuvant intensive chemotherapy and radiation to the hemiabdomen and whole lungs. the 49-week chemotherapy regimen was vincristine, doxorubicin, cyclophosphamide (per cog arst0431) alternating with carboplatin and etoposide (per cog aren0321 revised uh-1). treatment was complicated by multiple episodes of fever and neutropenia and anorexia requiring g-tube placement. post-therapy, he had persistent neutropenia and thrombocytopenia without related complications. every 6 months for 3 evaluations he underwent a bone marrow which revealed normocellular marrow with maturing trilineage hematopoiesis. evaluation for a bone marrow failure syndrome was unrevealing. starting at 6 months into therapy and all posttherapy imaging showed splenomegaly. he received 29 units of packed red blood cells through the duration of therapy. he was diagnosed with iron overload based on serum ferritin and imaging, including t2*mri. he received therapeutic phlebotomy for 2 years with normalization of serum iron studies, t2* of the heart, and liver iron concentration. he is more than 6 years from completing therapy with no evidence of recurrent disease. asymptomatic cytopenias persist and he has no evidence of iron overload. conclusion: though a rare development, clonal sarcomatous transformation can occur in wilms tumor. our patient's tumor was successfully treated with intensive multimodal therapy targeting the diffusely anaplastic wilms and the rhabdomyosarcomatous component. treatment-related iron overload in a pediatric patient with a solid tumor was successfully treated with phlebotomy. consideration should be given to screen patients with solid tumors who receive multiple packed red cell transfusions for iron overload at the completion of cancer therapy. primary children's hospital, university of utah, salt lake city, utah, united states background: malignant solid tumors are less frequently encountered in infants. primitive myxoid mesenchymal tumors of infancy (pmmti) are a myofibroblastic malignancy and cases are rarely reported in the literature. cure is achieved in the majority of cases with surgical resection, however treatment for unresectable cases remains an enigma. recently published literature postulates that the newly discovered bcor duplication found in pmmti is tumorigenic via an epigenetic pathway. this molecular signature resembles that of clear cell sarcoma of the kidney (ccsk) and the growing number of bcor mutated sarcomas. a similar chemotherapeutic backbone and local control used for ccsk, has been proposed for the unresectable subset of pmmti. utilizing this approach a 19 month-old with relapsed disease has remained disease free for 12 months. however, given the rarity of this disease and the lack of published literature, there is no known standard of care treatment for unresectable and/or recurrent ppmti. we report a case of unresectable recurrent pmmti, a rare infant tumor, with less than 20 cases reported. design/method: medical record, radiological studies, pathology and literature was reviewed. results: our patient is a now 12 month-old female who presented with constipation and lower extremity weakness in the first weeks of life. an mri demonstrated a large lumbar epidural mass with spinal cord impingement. given prolonged (>14 days) neurological symptoms and location, emergent chemotherapy was initiated. biopsy showed a bcor positive, primitive myxoid mesenchymal tumor of infancy (pmmti). she was treated with ifosfamide, carboplatin and etoposide, and demonstrated clinical and radiographic response. we gave two additional cycles of cyclophosphamide, carboplatin and etoposide until surgical resection was feasible followed by two post-surgical cycles of chemotherapy. unfortunately, four month post-therapy mri demonstrated two new lesions; an unresectable paraspinal soft tissue mass and a left iliopsoas groove mass. given bcor association and reported successful therapy with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide and etoposide, we elected to incorporate vinca-alkaloid and anthracycline into her regimen. she is being treated with vdc/ie with plan for radiation consolidation. conclusion: pmmti is a locally aggressive tumor, for which surgical resection is curative. for those not amendable to resection, best care practices are still being determined. we report a case of pmmti initially responsive to chemotherapy, but not curative. this is the second case to conclusively demonstrate chemo-responsiveness. bcor mutation seems to be a common feature of this cancer; its role in the pathogenesis and as a target is an area of investigation. medical college of wisconsin, milwaukee, wisconsin, united states background: atypical teratoid/rhabdoid tumors (atrt) are central nervous system (cns) tumors that most commonly occur in very young children. there is no widely accepted standard of care for atrt patients, and while survival rates are improving they are historically poor. patients with metastatic disease to the spine at diagnosis have a worse prognosis, and for patients >3 years old, the presence of metastatic disease often results in the use of craniospinal radiation. the importance of correctly identifying metastatic disease at diagnosis aids in decision making and can have both prognostic and therapeutic implications. mr imaging at diagnosis is used to identify metastatic disease; however, here we present a case of diffuse leptomeningeal enhancement that spontaneously resolved after resection of a primary supratentorial atrt. objectives: to describe the resolution of diffuse leptomeningeal enhancement after resection of a primary atrt tumor in a 12-month-old prior to any adjuvant therapy. results: a 12-month-old male presented with a 2 month history of vomiting and weight loss, regression of gross motor developmental milestones, and left hemiparesis. a brain mri demonstrated a 7 × 5.8 × 5.7 cm solid and cystic right atrial mass with diffusion restriction and post-contrast enhancement. smooth diffuse enhancement was noted along the surface of the brainstem and within the interpeduncular fossa. a spine mri demonstrated diffuse circumferential post-contrast enhancement along the surface of the entire spinal cord. the patient underwent a successful near total surgical resection of the primary mass. pathology confirmed the loss of ini-1 staining in tumor cells, consistent with a diagnosis of atrt. no immediate adjuvant radiation or chemotherapy was given. repeat imaging was completed 15 days after resection. brain mr demonstrated expected post-operative changes within the surgical cavity without definitive residual mass or leptomeningeal enhancement. spine mr demonstrated complete resolution of the previously seen circumferential enhance-ment along the entire spinal cord. csf evaluation at that time was negative for tumor cells. after recovery from surgery, chemotherapy treatment was initiated. conclusion: leptomeningeal enhancement at the time of diagnosis of atrt has historically been considered clear evidence of metastatic disease. this case raises questions about the previously accepted etiology of these imaging changes and suggests that widespread leptomeningeal enhancement should be carefully interpreted in future patients with similar imaging findings. in this setting, clinicians should consider repeat imaging following primary surgical resection in order to provide appropriate prognostic information and inform therapeutic decisions. poster # 047 primary ewings sarcoma of cervical cord mimicking cauda equina syndrome sucharita bhaumik, joshua chan nyu winthrop hospital, mineola, new york, united states background: ewing's sarcoma (es) is a malignant primary bone tumor usually involving long bones. primary es of spine is quite uncommon (0.9%) and its location in the cervical spine is even more rare. cauda equina syndrome (ces) is symptoms due to damage to the bundle of nerves below the end of the spinal cord known as the cauda equina (low back pain, radiating shooting pain down the legs, paraplegia, and loss of bowel or bladder control). it often occurs with lesions of lumbosacral spine. treatment with high-dose steroids may provide pain relief and improved neurologic function (by reducing edema) while awaiting diagnostic studies objectives: to demonstrate an unusual clinical presentation and emergent management of cervical es presenting with ces like symptoms. : 15 year old male presented with a left sided posterior neck mass. soon after, he developed weakness of left arm, urinary and stool retention and inability to walk or bear weight in both legs. on physical exam a left tempero-occipital 6 × 4cm fixed, non-tender, non-fluctuant mass was noted as well as motor and sensory impairment of left upper extremity, bilateral spastic paraplegia and loss of sphincter control. mri cervical spine showed a left cervical tumor with moth eaten appearance involving the vertebral bodies of c2-c3, adjacent muscles, displacing vital structures of the neck and compressing the cervical spinal cord. the thoracic and lumbosacral spine had no disease involvement. due to rapidly worsening spinal cord compression he was emergently treated with high dose steroids. he gained back all function in his extremities and regained bowel and bladder control. this eliminated need for urgent neurosurgical intervention. results: biopsy of the neck mass showed small blue round cells consistent with es with ewsr1 gene rearrangement. staging work up revealed no additional metastatic involvement. he then initiated treatment for localized es with systemic chemotherapy and radiotherapy and has had excellent response to treatment so far. conclusion: this is the first known case of non metastatic primary cervical es mimicking ces where an acutely enlarging mass presented with rapidly progressive neurologic deficits due to compression of anterior spinothalamic tract. in these unusual presentations of ces without lumbodorsal involvement it is important to consider cervical lesions. early rapid steroid initiation should be considered while awaiting biopsy results to prevent worsening cord compression followed by es focused treatments. this increases the chance of a successful outcome. the initial improvement with steroids may confuse the tumor with being a lymphoma children 's mercy hospital, kansas city, missouri, united states background: von willebrand disease (vwd) is a relatively common bleeding disorder with a high degree of genotypic and phenotypic variation. bleeding is usually mucocutaneous but can be severe and include muscle and joint bleeds especially in type 3 vwd patients. most common bleeding management consists of desmopressin, anti-fibrinolytics, and/or plasma-derived antihemophilic factor/von willebrand factor (ahf/vwf) complex. a recombinant vwf has become available in the last few years. anaphylaxis and inhibitor development in vwd are rare. objectives: to describe the rare clinical manifestation of anaphylaxis to factor concentrate in a patient with severe type 1 vwd. results: a 13-year-old female with severe type 1 vwd [baseline vwag 10%, activity < 10%, factor viii (fviii) 26%] originally presented with heavy menstrual bleeding (hmb) leading to anemia requiring blood transfusion. she underwent placement of a levonorgestrel-releasing intrauterine device (lngiud) and began norethindrone. her hmb continued despite the lngiud and an increase in norethindrone dosing. plasma derived ahf/vwf complex was administered, which she had previously received. following the infusion, the patient developed anaphylaxis with hives, wheezing, tachycardia, and itching requiring 2 doses of diphenhydramine and 1 dose of hydrocortisone with resolution of symptoms. subsequently, she received recombinant vwf without incident. however, due to her low fviii level, she also required treatment with a full length recombinant fviii product. she again developed hives and itching after this infusion. she has since received recombinant vwf with recombinant fviii/fc fusion protein without further allergic reaction. there was no evidence of an inhibitor with her most recent post-infusion vwf level was 101%, factor viii 199%. conclusion: anaphylaxis to plasma derived factor products has been documented far less frequently within the vwd population compared to those with hemophilia and is typically seen in those with large gene deletions, usually with type 3 disease. therefore, similar type 1 vwd patients with severe disease may benefit from gene sequencing. it is unclear in this patient's case to which aspect of her treatment she is allergic, as she reacted to plasma-derived ahf/vwf and full length recombinant fviii, but not recombinant vwf or recombinant fviii/fc fusion protein. we hypothesize that she may be allergic to an epitope in the fviii b domain, or that the presence of fc fusion may have had a protective effect. further investigation including genetic analysis is planned. nodules. biopsies were consistent with neuroendocrine carcinoma, large cell type (g3). next generation sequencing revealed a khdrbs2-braf fusion. he received conventional cytotoxic chemotherapy regimens both with cisplatin/doxorubicin, capecitabine/temozolomide, and doxorubicin/etoposide, but achieved a minimal response followed by rapid disease progression, massive ascites, and renal failure secondary to bilateral ureteral obstruction. results: based on his prior genomic testing, therapy with single agent mek inhibitor (trametinib) was initiated. this produced a rapid, dramatic response with greatly reduced disease burden at all sites, resolution of ascites and return to completely normal activity within 2 months. this response lasted for approximately 6 months before the tumor again progressed. further therapy with an erk inhibitor was ineffective, and the patient expired from progressive disease. located on the chromosome 7q34, the braf oncogene, as part of the ras/mapk pathway, is involved in cellular proliferation, differentiation, migration, and apoptosis. braf mutations are recognized in a wide range of adult malignancies: thyroid cancers, non-small cell lung cancer, cholangiocarcinoma, ovarian cancers, and multiple myeloma. braf mutations have also been described in adult neuroendocrine carcinoma of the colon. trametinib is a highly specific inhibitor of mek1/mek2, a downstream mediator in the braf pathway. it has demonstrated activity in a number of tumors including advanced melanoma and gliomas. trametinib was chosen for this patient based on his atypical braf fusion. we believe this is the first documented case of its successful use in neuroendocrine carcinoma in the pediatric population. conclusion: this case demonstrates the presence of braf fusion in a case of pediatric neuroendocrine carcinoma and significant response to single agent mek inhibition in this context. this cases raises the question as to whether the combination of a targeted inhibitor, in addition to either conventional chemotherapy or other braf inhibitors, might offer a better approach to therapy than current treatment options. albany medical center, albany, new york, united states background: warm autoimmune hemolytic anemia (waiha) is characterized by autoantibody, and occasional complement binding of protein antigens, on the surface of red blood cells at temperatures ≥37 oc resulting in targeted destruction. we describe the case of a 17 year old male with a history of evan's syndrome, poor immune response to vaccines and lymphoid hyperplasia, presenting with altered mental status and severe anemia, found to have a warm igg pan agglutinin with evidence of both intra and extravascular hemolysis. his course was complicated by respiratory failure requiring intubation, pulmonary emboli, enterococcus bacteremia and hypertension. he received multiple transfusions with only transient increases in hemoglobin. the aiha was refractory to multiple rounds of treatment with high dose steroids, ivig, rituximab, cyclophosphamide, bortezomib, plasma exchange and mycophenolate mofetil (mmf). objectives: given the refractory nature of our patient's aiha the decision was made to trial eculizumab, a monoclonal antibody targeting c5 complement, preventing its cleavage and activation, and shown to be effective in treatment of atypical hemolytic uremic syndrome and hemolysis due to an igm cold agglutinin. prior to eculizumab infusion, ch50 and sc5b-9 assays were significantly elevated. design/method: the patient was given two doses of eculizimab 6 days apart. results: his hemoglobin steadily rose independent of red cell transfusions with a corresponding decrease in reticulocyte count, ldh and ch50 levels. the patient has remained stable with a normal hemoglobin (12-14 g/dl) on maintenance steroids and mmf. although we cannot definitively conclude that eculizumab directly caused his recovery, the clinical course post-eculizumab suggests this may be an efficacious treatment for aiha. genetic testing showed monoallelic frameshift mutation of the nfkb1 gene and monoallelic missense mutation of the dock2 gene. given the role of nfkb1 in both immunodeficiency and autoimmunity, it is thought that the patient's phenotype is due to nfkb1 haploinsufficiency and he is currently considering hematopoietic stem cell transplant. st. joseph's regional medical center, paterson, new jersey, united states background: heterozygous -thalassemia typically manifests as thalassemia minor, characterized by mild microcytic hypochromic anemia with minimal clinical ramifications. coinheritance of -globin gene triplication has been reported to exacerbate the clinical and hematological phenotype ofthalassemia trait, due to increase in the alpha/non-alpha-chain imbalance. reported phenotypes range from asymptomatic thalassemia minor to moderate thalassemia intermedia, usually diagnosed in adulthood without transfusion dependence. this combination has been described in mediterranean, european and asian populations, but rarely reported in hispanics. objectives: to report two cases of unusually severethalassemia intermedia in hispanic patients with heterozygosity for triplicated -globin gene and a (0)-thalassemia allele. results: case 1: sixteen-month-old male of mexican descent presented with persistent microcytic anemia and jaundice. peripheral smear showed nucleated rbcs with basophilic stippling and target cells. hemoglobin electrophoresis revealed: hba-79%, hbf-17%, hba2-4.3%. -globin gene testing revealed heterozygosity for (0) mutation (ivsi-i, g→a). given the unusually severe anemia, -gene testing was performed which showed -globin gene(anti 3.7) triplication ( / ). at four years, he had splenomegaly and bilateral maxillary prominence. head ct showed irregular contour of the parieto-occipital region due to medullary expansion. due to significant persistent anemia (6-8g/dl) and progressive bony deformities of the skull, patient began chronic transfusions at age eight after family declined splenectomy.case 2: fifteen-year-old female, of peruvian and honduran descent, presented for evaluation prior to cholecystectomy for gallstones and recurrent ruq pain. father had known thalassemia trait. her hb was 9.2 g/dl with hypochromia, microcytosis, and target cells. electrophoresis indicated -thalassemia trait (hba-94%, hba2-4.7%, hbf-1.3%), confirmed by gene testing (heterozygous for a (0) mutation in codon 39 c>t). given jaundice and gallstones, -globin gene analysis was ordered showing triplication ( / ). ruq pain resolved post-cholecystectomy, but she developed persistent painful splenomegaly. she began hydroxyurea to increase gamma-globin production and decrease excess alpha chains, but it was discontinued due to hematological toxicity. due to recurrent luq pain and progressive splenomegaly, she underwent laparoscopic splenectomy at age 22 with resolution of symptoms and improved hemoglobin. conclusion: -globin gene testing should be considered in -thalassemia carriers with an atypical clinical presentation including hispanic patients. the wide variability in the phenotypic expression of (anti 3.7) mutation andthalassemia trait suggest interplay of other genetic factors which remain undefined. the clinically significant presentation amongst certain subjects, as in our two cases, makes it imperative to identify these factors to aid in phenotype prediction and genetic counseling. ashley bonheur, shivakumar subramaniyam, jogarao vedula, sucharita bhaumik nyu winthrop hospital, mineola, new york, united states background: wilms tumor (wt) is one of the most common solid malignant neoplasms in children. a diverse range of genes and mechanisms are implicated in wt pathogenesis. predisposing syndromes result from a disruption of wt1 gene, crucial for renal and gonadal embryogenesis. another gene is wt2 gene locus at 11p15, an area of imprinting. the p53 tumor suppressor gene on chromosome 17p13.1 is seen in patients with anaplastic histology. in addition to these genes, whole and partial chromosome gains of 1q, 2, 7q, 8, 12, & 13 and losses of 1p, 7p, 16q, 22q, as well as loss of heterozygosity (loh) are commonly seen. some genetic markers appear to be predictive of outcome and are now incorporated into the assigning of risk-directed therapy. patients with loh at chromosome 1p and 16q are treated with more intensive chemotherapy, as they have been associated with increased risk of relapse and mortality. objectives: to describe a new complex translocation involving chromosome 2, 7, and 12 in a case of pediatric wt. design/method: a four-year old female presented with abdominal pain and emesis. on exam, patient had a firm and large abdominal mass. radiologic studies revealed a complex lobulated right renal mass. right radical nephrectomy was performed. histopathologic studies showed wt with triphasic histologic features with blastema predominance, invasion of the lymphovascular and perinephric adipose tissues, perinephric lymph node involvement and no anaplasia. chest ct scan showed bilateral lung metastases. tumor cytogenetics showed an abnormal karyotype, a complex translocation of 2, 7, and 12. the rearrangement occurred due to translocation between chromosomal bands 7q22 and 12q15, with an insertion of 7q22-32 on the 2q21 region. pcr based genotyping using microsatellite markers additionally identified loh for chromosome 1p36 and 16q22. the patient was treated for high risk stage iv wilms tumor with favorable histology and received intensive chemotherapy and radiation therapy to the flank and the lungs. she is now in remission 8 months after, with no evidence of recurrence on surveillance scans. complex translocations associated with wt have not been rigorously studied. a question for further study is whether there is any relationship between recurrence potential with a complex translocation compared to common chromosomal abnormalities. further knowledge of the molecular pathology and genetic changes in wt will help the development of new targeted therapies, as well as new biomarkers to aid diagnosis, risk stratification, and monitoring of treatment and relapse. results: a 4 week-old girl was referred for evaluation of an abnormal newborn screen. mother was a known carrier of hb khartoum trait while father was a known carrier of thalassemia trait. patient's hemoglobin quantification performed by capillary zone electrophoresis showed hbf 92%, hb variant 8%, and no detectable hba. the hb variant ran in the d zone, a pattern consistent with mother's hb. alkaline agarose gel electrophoresis banding pattern showed f/s. acid agarose gel electrophoresis pattern showed v/f. later testing revealed abnormal isopropanol stability with 3+ precipitation at 20 minutes. this electrophoresis pattern is consistent with the pattern previously reported of hb khartoum. clinically, the patient is a healthy, active child whom we have followed for two years. she has not had any significant anemia outside of her physiologic nadir. she has not had any hemolytic episodes, and her bilirubin levels have always been within the normal range conclusion: to the best of our knowledge, this is the only reported case of hb khartoum/ thalassemia. the proline to arginine substitution of hb khartoum introduces a charged group on the chain at the site of 1 1 contact. the resulting unstable 1 1 chains can dissociate into monomers and favor the formation of methemoglobin, leading to hemoglobin instability. we had wondered if this unstable hemoglobin might result in clinical hemolysis when challenged with oxidative stress, such as in periods of infection. however, in the two years we have followed this patient, she has never had a hemolytic episode. at two years of age, she has hbf 7.8%, hb khartoum 85.5%, and hba2 6.7%. whether hbf elevation is protective from oxidative stress remains to be determined as we continue to follow this child. university of puerto rico -medical science campus, san juan, puerto rico, united states background: gm1 gangliosidosis is a lysosomal disorder caused by -galactosidase deficiency due to mutations in the glb1 gene. it is a rare autosomal recessive neurodegenerative disorder with an incidence of about 1:100,000-1:200,000 live births worldwide. this neurological disorder has three clinical forms. gm1 type 1, or infantile form is characterized by psychomotor regression by the age of 6 months, visceromegaly (hepatosplenomegaly), macular cherry red spot, facial and skeletal abnormalities, seizures, and profound intellectual disability. we present a 4-year-old female with gm1 type 1 and acute lymphocytic leukemia (all). design/method: she was diagnosed with gm 1 type 1 at the 1st months of age and family history was remarkable for an older sister with gm 1 type 1. diagnostic studies reveal homozygous exon 7 of the glb1 gene for a sequence variant defined as c.622c>t, predicted to an amino acid substitution p.aarg208cs. results: patient presented to our hospital with petechiae in lower extremities, pallor and intermittent tracheal bleeding. physical examination shows a hemodynamically stable girl that is chronically ill dependent of mechanical ventilation, severe mental retardation and scatter petechiae at upper and lower extremities. laboratory workup revealed severe normocytic anemia (hgb: 5.7g/dl) with immature peripheral cells and thrombocytopenia (81 × 109/l). serum chemistry revealed increase ldh (695u/l), increase hepatic enzymes (ast: 63u/l), normal uric acid level. there was no evidence coagulopathy. chest x ray was unremarkable except for evidence of chronic pulmonary illness. abdominal sonogram hepatosplenomegaly. during hospitalization, bone marrow aspirate and biopsy was performed which was diagnostic of b cell acute lymphoblastic leukemia (all) with 26.5% lymphoblast and orderly myeloid/erythroid maturation. flow cytometry: 26% b lymphoblast with aberrant phenotype c/w b-acute lymphoblastic leukemia. karyotype revealed hyperdiploid female of favorable prognosis. cytogenetic by fish: hyperdiploid all with extra copies of runx1 and igh (no bcr-abl translocation). family was oriented about the new diagnosis and the dismal prognosis in conjunction to her primary condition. parents agree on no chemotherapy treatment for all with only supportive treatment. to this date, there is no evidence in literature that has previously described association of gm1 and leukemia. life expectancy of patient's primary condition is null therefore, correlation with leukemia might not be a coincidental finding. this patient opens the possibility of malignancy as part of gm1 type 1 thus, malignancy diagnosis should be considered as part of their medical lifetime course. university of south florida, tampa, florida, united states background: hematological manifestations related to hiv infection are not uncommon, with thrombocytopenia having an estimated prevalence of 5-15%. the pathophysiology is likely multifactorial. studies suggest that the primary mechanism may be immunologic resulting in accelerated platelet destruction. additional theories suggest that infection of megakaryocytes may also play a role causing inadequate platelet production. treatment of hiv-related thrombocytopenia is challenging. first-line treatments include initiation and optimization of antiretroviral therapies, immunoglobulin (ivig), and glucocorticoids. however, this approach is not effective in all patients and second line treatment options are less well studied, particularly in the pediatric population. objectives: we aim to present and discuss the case of a 13 year old patient with perinatally acquired hiv-1 infection and persistent thrombocytopenia who, after failing first line therapies, showed normalization of platelet count on the novel thrombopoietin receptor agonist, eltrombopag. design/method: a retrospective chart review of the case patient's medical record was conducted. additionally, a thorough literature review was performed on this topic including the pathophysiology of hiv related thrombocytopenia and its treatment modalities. the patient required monthly ivig infusions for about 1 year, but did not show a sustained response, often with platelet count dropping to less than 10,000 in between infusions. after initiation of 50 mg eltrombopag daily the patient showed a sustained increase in platelet count (range 32,000-88,000). during a brief 2 week lapse in eltrombopag treatment his platelet count dropped to 17,000. upon re-initiation of therapy his count increased to 84,000. the patient has remained asymptomatic, off of ivig for over one year, with undetectable hiv viral load and greater than 500 cd4 t cell counts. no side effects or grade 2 laboratory abnormalities were reported. conclusion: treatment of hiv-related thrombocytopenia can be challenging. first line therapies, including ivig and glucocorticoids, are not effective in all patients. several other treatment modalities have been utilized, including anti-d immunoglobulin, dapsone, danazol, interferon alfa, vincristine, thrombopoetic growth factors including romiplostim and eltrombopag, or splenectomy, but these are less well studied. this represents the first reported case of a pediatric patient with hiv who showed a positive response to eltrombopag with a sustained improvement in platelet count and no adverse effects from treatment. eltrombopag may be a safe alternative to first line therapies in those patients with hiv and refractory thrombocytopenia, however additional studies are needed. university of illinois college of medicine at peoria, peoria, illinois, united states background: achromobacter xylosoxidans is a gram negative rod with peritrichous flagella which causes rare opportunistic infections most commonly encountered by immunocompromised patients. it is primarily associated with uncomplicated bacteremia, cather-associated infections, and pneumonia. most reports of bacteremia associated with a. xylosoxidans are nosocomial, associated with neoplasm, and occurring mainly in adults. most reported infections with a. xylosoxidans in children are associated with cystic fibrosis. there are very few reported cases of septic shock from a. xylosoxidans bacteremia and pneumonia in the pediatric oncology population. objectives: to describe a rare case of a. xylosoxidans septic shock in a pediatric patient with relapsed neuroblastoma results: a 4-year old boy with history of stage iv highrisk neuroblastoma underwent standard frontline therapy with chemotherapy, hematopoietic stem cell transplant, radiation therapy, and immunotherapy, followed by a dfmo trial for maintenance. his 3-month follow-up scans demonstrated relapse and he was subsequently treated with additional chemotherapy, surgical resection, and mibg therapy, crizotinib for an eml4-alk fusion and finally ifosfamide, carboplatin and etoposide (ice). he developed neutropenic fevers and was started on cefepime, vancomycin and fluconazole. blood cultures were initially negative. on the 4th day of fever, his previously scheduled pet scan was performed during hospitalization and showed new pulmonary opacities. he did not have respiratory symptoms, but therapy was escalated to meropenem, vancomycin and amphotericin. emergent bronchoscopy was performed the same day, with all bacterial and fungal cultures remaining negative. overnight, he developed tachypnea and saturations in the upper 80s, requiring nasal cannula. ir-guided lung biopsy was performed the next day, a flexible bronchoscopy was done to remove blood clots in the airway, the patient was placed on a ventilator, femoral lines were placed, granulocytes ordered and pressors were started for deterioration to presumed septic shock. arterial and femoral lines were placed but patient continued to have hemodynamic instability on multiple pressors. the following day, blood and respiratory cultures returned positive for results: at 33 days after the start of iti, the inhibitor was <0.1 bu and continued undetectable 6 months after initiation of iti therapy. in this patient, iti with high-dose plasma-derived factor viii and von willebrand factor (vwf) complex was well tolerated and effective. genetic analysis confirmed a large factor viii gene duplication of exons 7 to 22. we believe our patient developed inhibitor so quickly (14 exposure days) due to the possibility of this mutation causing a frameshift that introduces a premature termination codon. this might be functionally similar to a deletion in the factor viii gene which poses the highest risk for inhibitor development in patients with severe hemophilia a. this variant has only been identified previously in two unrelated patients diagnosed with severe hemophilia a. this duplication is not listed in dbsnp variant database, nor observed in the general population database. our case proves the effectiveness of this method for patients with severe hemophilia a and an inhibitor. it also shows that more research is needed to identify patients at risk for inhibitor development. background: mercaptopurine (6-mp) is a prodrug that is a core component of maintenance chemotherapy for patients with a diagnosis of acute lymphoblastic leukemia (all). suppression of the neutrophil count is used to demonstrate adequate dosing of 6-mp during this phase of therapy. bone marrow suppression is mediated by the active metabolite 6-thioguanine (6-tgn), whereas the metabolite 6-methylmercaptopurine nucleotides (6-mmpn) has been shown to cause hepatotoxicity. allopurinol has been used infrequently in all maintenance therapy in the setting of skewed metabolism when adequate myelosuppression is difficult to achieve due to excessive hepatic toxicity. when given in combination with allopurinol a reduced dose of 6-mp may result in both increased 6-tgn levels and decreased 6-mmpn levels. objectives: describe the characteristics and clinical course of patients treated with allopurinol and reduced dose 6-mp during maintenance chemotherapy for all. we performed a retrospective chart review of patients at aflac cancer and blood disorders center of children's healthcare of atlanta with new diagnoses of b or t-cell all who received allopurinol during maintenance chemotherapy. we identified eleven patients with b-cell or tcell all who received allopurinol adjunctive therapy during maintenance chemotherapy at a single institution between 2014-2017. these 11 patients received adjunctive allopurinol for 2-120 weeks (median 52 weeks) with reduced 6-mp (25-65% of full dose). all ten patients with genetic testing for thiopurine s-methyltransferase (tpmt) had wildtype genotype associated with normal enzyme levels. indications for allopurinol use were most commonly unfavorable 6-mp metabolite levels, transaminitis (n = 8), pancreatitis (n = 3) and hyperbilirubinemia (n = 3). favorable metabolite shift was achieved in all patients. liver enzymes improved in 6 of 10 patients with transaminitis after initiation of allopurinol/reduced 6-mp. three patients who experienced pancreatitis during maintenance did not have recurrence after initiation of allopurinol (2 of these patients previously reported). six patients developed pancytopenia while on allopurinol, and two of those patients developed pancytopenia severe enough to require allopurinol cessation. four patients developed isolated anemia (hgb <11.0 g/dl) without thrombocytopenia or severe neutropenia. no patient has experienced a recurrence of leukemia. overall, treatment with allopurinol and reduced dose 6-mp was successful in producing a favorable 6-mp metabolite distribution and reducing toxicity. therapy was generally tolerated; however a major and notable side effect was pancytopenia, in two cases severe enough to stop allopurinol treatment. anemia may be more prominent with allopurinol usage. allopurinol effect is variable among individual patients despite normal tpmt genotypes. baylor college of medicine, houston, texas, united states background: congenital sideroblastic anemia, b-cell immunodeficiency, periodic fevers and developmental delay syndrome (sifd) is a rare inherited sideroblastic anemia syndrome, first described in 2013 with 12 clinically similar cases. genetic variations of trnt1 were identified as causative. objectives: to present an unusual presentation of a patient with sifd complicated by diagnosis of concomitant alpha thalassemia trait. design/method: retrospective chart review. a five month old male infant was referred to our hematology center for evaluation of elevated hemoglobin barts identified on newborn screen. despite numerous attempts, blood work was unable to be collected. at seven months of age he had microcytic anemia (hemoglobin 7.5 g/dl, mean corpuscular volume 44 fl) more severe than what would be expected with alpha thalassemia trait. no variant hemoglobin was identified with isoelectric focusing or high performance liquid chromatography. by nine months of age he developed growth failure, intermittent emesis with fevers, developmental delays (predominantly gross motor), hearing loss, a disproportionally large head and coarse, thinning hair. over the next ten months, he was seen by numerous specialists for seemingly unconnected problems including sensorineural hearing loss, elevated liver enzymes and growth hormone deficiency. alpha globin analysis revealed deletion of two alpha globin genes. at 20 months of age, he was admitted with one week of fevers, jaundice, and emesis. peripheral blood smear showed microcytic hypochromic anemia with marked anisopoikilocytosis including target cells, elliptocytes, tear drops, spherocytes, poikilocytes, marked polychromasia, and coarse basophilic stippling. given the inconsistency of his laboratory findings with the diagnosis of alpha thalassemia trait and clinical syndromic findings, bone marrow biopsy was performed which revealed rare ringed sideroblasts. one month later whole exome sequencing revealed trnt1 splicing variant c.1057-7c>g and novel missense variant c.1092a>t consistent with sifd. hemoglobin barts on newborn screen with moderate to severe microcytic anemia directed initial diagnostic work-up towards variant alpha thalassemia. as additional medical conditions developed the focus shifted to a unifying syndrome. compared to previously described cases, our patient was diagnosed at an older age, presented with anemia rather than episodes of febrile illnesses, and had rare sideroblasts on bone marrow examination. diagnosis in this case led to identification of the novel c.1092a>t variant in his sister who had similar, but milder, features. sifd is a rare disease with variable phenotypic severity making diagnosis challenging without high index of suspicion which is crucial for appropriate management. wiseman, blood, 2013 . chakraborty, blood, 2014 background: cholelithiasis is uncommon in childhood. cholelithiasis is known to occur more frequently in children with predispositions, including female sex, obesity, parenteral nutrition, previous abdominal surgery, use of oral contraceptives, family history of gallstones, chronic hemolytic anemias, hepatobiliary disease, or exposure to specific drugs. although there have been occasional case reports linking cholelithiasis to childhood leukemia or leukemia therapy, the prevalence and risk factors of cholelithiasis in patients with childhood leukemia remain unclear. objectives: to estimate the prevalence of cholelithiasis in patients diagnosed with childhood acute lymphoblastic leukemia (all), and to evaluate possible risk factors for the development of cholelithiasis in patients with childhood all. we performed a computer-assisted review of the electronic medical records of 503 patients diagnosed for b or t-cell all at children's healthcare of atlanta in the period from 2010 to 2016. patients with diagnoses of cholelithiasis, cholecystitis or who had a cholecystectomy were identified. possible risk factors of age, sex, bmi, history of abdominal surgery and parenteral nutrition use were abstracted. patients with underlying chronic hemolytic anemia or pre-existing gallbladder disease were excluded. results: seventeen cases of cholelithiasis and 2 cases of cholecystitis without documented cholelithiasis were identified. among patients with cholelithiasis, 8 were female. median age at diagnosis of cholelithiasis was 14.0 (range 2.7 -21.6) years. seven patients had no symptoms referable to cholelithiasis at the time of diagnosis. the median age of leukemia diagnosis among these patients was 12.1 (range 0.9 -18.8) years. the median interval from diagnosis of leukemia to gallbladder disease was 1.0 years. four patients had bmi over the 95th percentile for age. two patients had a prior history of intraabdominal surgery. no patient received oral contraceptive pills. six patients received parenteral nutrition for more than 30 days. there was no documented family history of cholelithiasis. seven patients did not receive any cholelithiasis directed therapy. two patients were managed with medical management only, 1 with endoscopic retrograde cholangiopancreatogram with stone extraction, and 7 with cholecystectomy. our study estimates the prevalence of cholelithiasis in childhood lymphoblastic leukemia to be 3.3%, higher than the reported prevalence in the general pediatric population of 0.13-0.22%. although our cohort size is small, it appears that all therapy and supportive care modalities associated with all are likely to play a larger role in the development of cholelithiasis than known predisposing factors in the general population. further studies are warranted. background: an uncommon side effect of intravenous immunoglobulin (ivig) administration is clinically apparent, sometimes severe hemolysis. we describe a severe case of coombs-positive hemolytic anemia secondary to ivig administration. ivig is a blood derivative manufactured from pools of 5,000 to 10,000 individual plasma donations. ivig is not abo-type restricted, so anti-a, anti-b and anti-a,b isoagglutinins are detectable. objectives: to describe a rare but serious type of transfusion reaction leading to gross hemolysis after ivig administration. results: a 16-year-old male with a past medical history of obstructive sleep apnea and obesity was admitted to the pediatric intensive care unit for adenoviral pneumonia and subsequent respiratory failure requiring mechanical ventilation. he had a complex hospital course with many complications including acute respiratory distress syndrome (ards), septic-shock, and coombs-positive hemolytic anemia. the patient was treated with commercial ivig (baxter/baxalta) 400-mg/kg daily for five days. he had two isolated episodes of severe hemolysis in relation to ivig administration requiring multiple transfusions of packed red blood cells (prbc). examination of pre-transfusion peripheral blood smear showed spherocytosis with rouleaux formation and large clumped rbc aggregates. the patient's blood type was classified as blood group a, rh-negative and his initial prbc transfusions were of this type. subsequently, the patient's coombs test was found to be positive using polyspecific and anti-igg typing sera. the patient's antibody screen against reagent group o screening cells was negative ruling out autoimmune hemolytic anemia. however, type specific anti-a antibodies were detected in his plasma as well as the acid eludate prepared from the coombs-positive red blood cells. it was concluded that the patient's hemolysis was due to anti-a antibodies presumed to arise from ivig. the patient's rbc transfusions were changed to o-negative blood and the hemolytic process resolved. the patient ultimately died due to complications of ards. although hemolysis is a known side effect of ivig, it is rarely considered when deciding to administer ivig. in addition, it has rarely been described in the pediatric population. ivig is used in the treatment of a growing number of medical conditions. due to the critical nature of many of these patients, hemolysis secondary to ivig may not be considered and continued blood transfusions with the patient's specific blood type may be used. it is crucial to remember that severe hemolysis can occur from ivig, and the importance of transfusing with blood group o, rh-negative blood when applicable. university of maryland medical center, children's hospital, baltimore, maryland, united states background: coagulopathy is a well-described complication of acute promyelocytic leukemia (apml), and remains a leading cause in induction failure. with treatment, coagulopathy associated with apml has been shown to rapidly improve. multiple organ dysfunction syndrome (mods) in apml, including acute respiratory distress syndrome (ards), has been associated with infection, traumatic injury, malignant infiltration, and cytokine release syndrome. when mechanical ventilation is no longer sufficient, extracorporeal membrane oxygenation (ecmo) can be considered; however, coagulopathy, severe end-organ damage, and malignancy are all relative contraindications to initiation of treatment. we report the case of a 17-year-old female presenting in respiratory failure, disseminated intravascular coagulopathy (dic), with intracranial hemorrhage, and mods, diagnosed with apml, successfully treated with ecmo therapy. design/method: retrospective case analysis and literature review. our patient, a 17-year-old female was admitted in respiratory failure and altered mental status, following a fall shortly prior to presentation. initial laboratory values were notable for pancytopenia, dic, and acute renal failure. a non-contrast head ct showed left temporal lobe intraparenchymal hemorrhage. she was diagnosed with apml by peripheral smear, later confirmed by fish for t(15:17), and was started immediately on high-risk induction chemotherapy as per cog protocol aaml1331, including all-trans retinoic acid, arsenic trioxide, idarubicin, and dexamethasone. cvvhd was required for acute renal failure. despite maximal respiratory support, she remained hypoxemic, with oxygenation index of 46, pao2/fio2 ratio of 70. ecmo was initiated 24 hours after start of induction, 48 hours after admission. coagulopathy resolved on day 6 of induction, ecmo was discontinued after 9 days, mechanical ventilation and cvvhd were stopped after 15 days and she continued to improve, eventually achieving remission with few neurologic side effects. despite relative contraindications to ecmo, this patient was successfully treated with ecmo without significant neurologic side effects. the correction of her coagulopathy was multifactorial: 1) restoration of adequate oxygen delivery via ecmo improving endothelial function; 2) successful organ support to allow sufficient response to induction chemotherapy with atra leading to the terminal differentiation of leukemic blasts; 3) complement and contact system activation through contact with ecmo circuitry. this case illustrates that ecmo can still be considered in patients despite coagulopathy and end organ damage. sinai hospital of baltimore, baltimore, maryland, united states background: primary polycythemia vera is an extremely rare diagnosis in the pediatric patient and is defined by a marked elevation of red blood cells due to erythropoietin-independent mechanisms. presentations of this disorder range from the asymptomatic person to severe thrombotic events, such as budd-chiari syndrome or cerebrovascular stroke. mutations in the jak2 gene are found in adult and pediatric patients with polycythemia vera; however, the jak2 v617f mutation is less commonly identified in pediatric patients. we describe an otherwise healthy 16-year-old female who presented with a significantly elevated total erythrocyte count, hemoglobin, and platelets, incidentally discovered upon routine annual blood work obtained by her pediatrician. design/method: this is a report and discussion of a rare case. demonstrated cellular marrow with trilineage hematopoiesis and no dysplasia. cytogenetics were not assessed. his hemoglobin and platelet count recovered but leukopenia and neutropenia persisted. follow-up evaluation at three months revealed fevers, ongoing cytopenias, a one-month of a nodular skin rash on the trunk and extremities resembling erythema nodosum, and hepatitis (peak alt and ast of 1,176 and 1,008, respectively). following clinical evaluation, a skin biopsy was performed and was remarkable for atypical lymphocytes within the subcutis with t-cell markers, a high ki-67, and positive tia-1, perforin, and -f1 immunoperoxidase stains. negative stains for cd56, cd30, and ebv were noted. these results are consistent with sptcl. additional evaluation did not support a diagnosis of hlh. a staging evaluation was performed. pet-ct showed widespread hypermetabolic subcutaneous activity in the legs, trunk and skull and diffuse marrow hyperplasia. bone marrow demonstrated involvement with precursor b-cell acute lymphoblastic leukemia, with a mll gene rearranagement. his skin biopsy was retrospectively stained with tdt, cd34, pax-5, cd79a, and cd20 with negative results, and a blood smear taken at the time of the skin biopsy did not demonstrate leukemic cells. conclusion: this is the first report of a patient with sptcl having a synchronous malignancy. the patient is doing well, currently in the maintenance phase of treatment for his all, and his skin disease has resolved on pet-ct. while it is possible that his presentation was a function of chance, the possibility of an underlying immune dysfunction or cancer predisposition warrants further investigation. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hereditary xerocytosis (hx) is a rare red blood cell (rbc) dehydration disorder, characterized by variable hemolysis and propensity to iron overload. hx is often misdiagnosed as hereditary spherocytosis (hs). while splenectomy is curative for hs, it is relatively contraindicated in hx due to a substantial thromboembolism risk, signifying the importance of delineating these diseases. blood smear abnormalities are variable and often insufficient to make an accurate diagnosis. osmotic-gradient ektacytometry and genetic confirmation are critical in distinguishing these overlapping disorders. objectives: describe a family with hx, initially misdiagnosed as hs. discuss the importance of distinguishing these disorders and the utility of ektacytometry in making this distinction. design/method: a 13-year-old caucasian male was diagnosed with hs after presenting with prolonged neonatal jaundice starting on the first day of life. he described mild scleral icterus and history of intermittent jaundice and dark urine, without need for transfusions. his father, paternal uncle and paternal grandmother were all diagnosed with hs during childhood and underwent cholecystectomy. additionally, his father underwent splenectomy for abdominal pain. the child's blood counts revealed compensated anemia (hb 12.9 gm/dl) and reticulocytosis (arc 347 × 103/mcl) with increased mcv (96.6 fl) and mchc (38.2 gm/dl). blood smear showed increased polychromasia and poikilocytosis with rare spherocytes and few stomatocytes. while the child had normal ferritin, his father had iron overload (ferritin 800 ng/ml) despite no prior transfusions. osmotic-gradient ektacytometry profile of the child and father's rbcs showed a characteristic left-shifted, bell-shaped curve with decreased omin and ohyp, diagnostic of hx. the family is currently undergoing genetic studies. despite clinical similarities between hs and hx, distinguishing these diseases has significant management implications. hx is a disorder of rbc permeability, causing shortened rbc survival. stomatocytes on blood smear can raise suspicion for hx, but are insufficient to make an accurate diagnosis. identifying characteristic biomechanical membrane properties using osmotic-gradient ektacytometry is the gold standard for clinical diagnosis, which can then be confirmed by molecular studies. hs and hx can be easily and reliably distinguished using ektacytometry, as both disorders have very distinctive curves representing different rbc deformability patterns. after hx diagnosis was made, we counseled the family against splenectomy, as the risk of thromboembolism is significantly increased in hx compared to hs, and the father was diagnosed with iron overload. conclusion: hx is commonly misdiagnosed as hs. this case highlights the importance of making this distinction, and the utility of osmotic-gradient ektacytometry in reliably distinguishing these conditions. penn state health children's hospital, hershey, pennsylvania, united states background: relapsed acute myeloid leukemia (aml) presenting as an isolated central nervous system myeloid sarcoma (cns ms) is very rare and its treatment is not well-defined. thiotepa, vinorelbine, topotecan and clofarabine (tvtc) has been successful for re-induction therapy to induce remission prior to hematopoietic stem cell transplant (hsct). objectives: to describe our experience in utilizing tvtc therapy in two children with no extramedullary disease at initial diagnosis who presented with relapsed aml as intracranial myeloid sarcomas. results: case 1: 34 month-old female was diagnosed with flt3 negative aml and completed treatment per the children's oncology group (cog) aaml1031 study on the low risk arm without bortezomib. cerebral spinal fluid (csf) negative at diagnosis. fish testing positive for tcf3 gene deletion of unknown significance. mrd was undetectable after induction i and remained undetectable after each cycle. nine months off therapy, recurrent headaches prompted mri imaging which revealed two posterior fossa masses. csf and bone marrow testing were negative. stereotactic biopsy of the larger mass confirmed recurrence of aml. patient underwent two cycles of tvtc with a total of seven doses of intrathecal cytarabine with almost near resolution of the cns ms. completed cranial radiation and proceeded to allogeneic stem cell transplant with unrelated cord marrow donor and is disease free at approximately day +200.case 2: 5 year-old female diagnosed with flt3 and mll negative aml and completed treatment per cog aaml1031 study on the low risk arm without bortezomib. csf negative at diagnosis. mrd was undetectable after induction i and completed therapy without complications. two months off therapy, a retrospective analysis of her diagnostic bone marrow by the cytogenetic laboratory to test a new panel identifying novel 11q partners revealed a cryptic insertional 10:11(mllt10/mll(kmt2a) translocation. at four months off therapy, acute mental status changes prompted mri imaging which revealed two intracranial ms and lumbar spine involvement. resection of the larger lesion for symptomatic relief confirmed the mllt10/mll(kmt2a) fusion. csf positive for blasts and marrow negative for relapsed disease. patient completed two cycles of tvtc with a total of seven doses of it cytarabine with near resolution of cns disease (only 3 mm contrast enhancement in the medulla). she received craniospinal radiation and is awaiting improvement in her cardiac function before proceeding to hsct. conclusion: tvtc is a successful reinduction regimen for relapsed aml with cns ms prior to hsct. background: acute severe anemia can be a life-threatening medical condition. the differential is quite broad for possible etiologies of acute severe anemia, including autoimmune hemolytic anemia (aiha) and atypical hemolytic uremic syndrome (ahus). autoimmune hemolytic anemia is an antibody-mediated process that targets the protein antigens located on the surface of red blood cells. treatment options for aiha include corticosteroids, with up to 80% of patients being responsive, with some requiring splenectomy. atypical hemolytic uremic syndrome is a medical urgency, defined as the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. the etiology is usually due to genetic causes, or less commonly, due to autoantibodies or idiopathic reasons. prognosis is very poor. objectives: differentiating between autoimmune hemolytic anemia and atypical hemolytic uremic syndrome can be a time-sensitive diagnostic dilemma while the patient is in critical condition, but this important delineation can vastly alter therapeutic options. design/method: here we discuss two cases highlighting the diagnostic workup involved in differentiating between atypical hemolytic uremic syndrome and autoimmune hemolytic anemia. patient a is a 3-year-old male who presented in extremis with severe anemia, uremic encephalopathy, and severe acute renal injury requiring hemodialysis and multiple blood transfusions. patient b is a 10-month-old male, who also presented in extremis with respiratory failure secondary to adenovirus/rhinovirus/enterovirus, with acute progressive renal failure and microangiopathic hemolytic anemia, requiring hemodialysis and cardiorespiratory support. : patient a underwent a full hematologic and infectious disease workup. subsequent laboratory studies confirmed enteropathogenic e.coli (epec) in the patient's stool; blood cultures remained negative. renal biopsy results were consistent pigment nephropathy. bloodwork indicated positive direct coombs. patient a was ultimately treated with steroids 2mg/kg/day, with significant improvement. patient b also included a full hematologic work-up, including adamts13 activity and ahus genetic panel, as well as full infectious disease work-up. subsequent laboratory test-ing revealed blood cultures growing streptococcus pneumoniae, with adamts13 activity at 41% (adult ref range: >/ = 70%), and normal complement levels. imaging findings also supported diagnosis of ahus. the management of a critically ill patient with acute severe anemia requires a thorough hematologic and infectious disease work-up. while molecular and genetic are helpful in definitive diagnosis of ahus, the utility of such results is limited by time. overlapping clinical presentation of a patient in extremis due to acute severe hemolytic anemia with progressive renal failure presents a rather broad differential, with time-sensitive treatment and prognostic implications. the favorable response to steroids delineates aiha from hus. background: d-2-hydroxyglutaric aciduria (d-2-hga) is a rare metabolic disorder characterized by developmental delay, hypotonia, and bi-allelic mutations in d-2hydroxyglutarate dehydrogenase (d2hgdh) or isocitrate dehydrogenase 2 (idh2). metaphyseal chondromatosis with d-2-hydroxyglutaric aciduria (mc-hga) is a type of d-2-hga that has been previously reported in seven patients (omim 614875; pmid 24049096), three of whom had somatic mosaicism for r132 variants in isocitrate dehydrogenase 1 (idh1). we describe a 3-year-old boy with mc-hga who subsequently developed acute myeloid leukemia (aml) and was found to have a r132 variant in idh1 in a leukemic bone marrow sample. we report the first case of aml with this metabolic disorder. design/method: a 1-year-old hispanic boy presented with short stature, developmental delay, abnormal skin pigmentation, and unilateral congenital cataract. workup revealed multiple skeletal enchondromatosis and elevated urine d-2-hydroxyglutaric acid levels. he was diagnosed with mc-hga. no pathogenic variants in d2hgdh, idh1 and idh2 were identified in peripheral blood. germline testing with biopsies of skin lesions was declined by the family. two years later, he presented with streptococcal sepsis and pancytopenia. blasts were noted on peripheral smear. bone marrow morphology was consistent with acute myelomonocytic leukemia (∼23% blasts). chromosome analysis showed normal 46 xy, and molecular testing by pyrosequencing idh1 and idh2 revealed a r132c variant in idh1 (25% mosaicism). the patient is being treated as per the cog study aaml1031. end of induction i bone marrow aspirate was hemodiluted, but there was no obvious residual disease by flow cytometry (0.01-0.01% sensitivity) or morphology. the previously identified idh1 variant was no longer detectable (limit of detection <10%). although targeted therapy for aml with idh1 mutation is currently in phase i clinical trials in adults, there is no safety or efficacy data for using idh1 inhibitors in children. treatment with ivosidenib is therefore not currently an option for our patient. conclusion: this is the first case of aml reported with this rare metabolic disorder. somatic r132 variants in idh1 have been identified in three other mc-hga cases. this same mutation leads to the accumulation of d-2-hydroxyglutarate in gliomas and aml. without any confirmed germline mutation or somatic mosaicism testing of multiple specimen sources, we can only speculate that the patient has an underlying somatic idh1 mutation associated with mc-hga which subsequently led to leukemogenesis. we present the first case of this association, to increase index of suspicion for development of aml in children with metabolic disorders associated with variants in idh1. background: congenital combined deficiency of the vitamin k-dependent coagulating factors (vkcfd) is a rare heterogeneous autosomal recessive bleeding disorder. vkcfd is caused by mutations in the genes of either gamma-glutamyl carboxylase (ggcx) or vitamin k epoxide reductase complex (vkorc), which are responsible for the gammacarboxylation of vitamin k dependent proteins (vkdps) allowing for their activation. the clinical presentation ranges from no bleeding to intracranial hemorrhage. to date, vkcfd has been reported in few patients worldwide. objectives: we report a case of a girl with novel homozygous mutation of the ggcx gene, highlighting her clinical and biochemical characteristics with a review of the literature. a 3-month-old girl of consanguineous emirati parents, presented to our hospital with a history of bleeding from puncture site after receiving her second-month vaccine. that was associated with episodes of mild mucosal bleeding. review of systems was negative for jaundice, steatorrhea and failure to thrive and physical exam was unremarkable. investigations revealed markedly prolonged pt and aptt with high inr. fibrinogen, hemoglobin and platelets were always normal. activities of vitamin k-dependent factors including fii, fvii, fix, fx, protein c and s were all low. a measurement of proteins induced by vitamin k absence (pivka-ii) was done and came very high. this was associated with a mild elevation in liver enzymes but normal liver function test. the picture was supporting vitamin k deficiency, and as a result, she was started on oral vitamin k supplements of 1 mg/day. she responded partially to vitamin k and required higher doses to stabilize her inr. after excluding acquired causes and due to her requirement of high doses of vitamin k, a mutation in either ggcx or vkorc genes was suspected. genetic analysis was conducted for her which revealed a novel missense homozygous mutation in the ggcx gene (c.548a>t) confirming the diagnosis of combined deficiency of vitamin k-dependent clotting factors type 1. the asymptomatic parents were both heterozygous for the same mutation. results: she is currently stable on 10 mg/day of vitamin k supplements. conclusion: vkcfd is a rare bleeding disorder with an overall good prognosis due to the availability of several effective therapeutic options. the function of the mutated gene is unknown. our patient demonstrated a partial response to vitamin k supplements suggesting presence of a residual carboxylation capacity and a possible role of this gene in the enzymesubstrate interactions. university of alabama at birmingham, birmingham, alabama, united states s55 of s301 background: gata2 is a zinc finger transcription factor that plays a critical role in the regulation of hematopoiesis and lymphatic angiogenesis. mutations leading to gata2 deficiency (gd) have been linked to a variety of clinical conditions. patients with gd have a striking predisposition to develop myelodysplastic syndrome (mds), acute myeloid leukemia (aml), or chronic myelomonocytic leukemia (cmml). acute lymphoblastic leukemia (all) has not been associated with gd, although the association of bcell all and gd has been previously reported. objectives: to describe a unique association of gata2 deficiency and t-cell all in a young child. results: an 8-year-old female presented with a one-week history of fever and malaise. she had a significant past medical history of verruca plantaris and self-resolving leukopenia associated with febrile illnesses. significant family history included sister with neutropenia and human papilloma virus (hpv) infection, and mother with neutropenia, monocytopenia, atypical mycobacterial infections, and hpv infection. peripheral blood revealed hemoglobin 9.3 g/dl, hematocrit 26.7%, platelets 176,000/ul, and white blood cell 1,740/ul (neutrophils 122/ul, lymphocytes 1601/ul, monocytes 17/ul). patient underwent a bone marrow biopsy demonstrating lymphoblast infiltration. flow cytometry analysis demonstrated monoclonal lymphoid blast population that co-expressed cd117, cd34, cd13, nuclear tdt, cd2, however, lacked expression of cd33, cd10, cd3, cd19, hla-dr, or myeloperoxidase. findings were consistent with tcell all with aberrant myeloid markers. cytogenetics analysis revealed 45,xx,dic(21;22)(p11.2;p11.2). patient began treatment as per children's oncology group aall0434 and achieved remission at the end of induction. course of therapy was complicated by episodes of fever, reciprocating junctional tachycardia, asparaginase-associated thrombosis, viral meningitis, recurrent episodes of verruca plantaris, and resistant streptococcus pneumoniae or haemophilus parainfluenza infections causing chronic cough. later, she was also found to have low igm levels; after completion of therapy, she developed monocytopenia. lymphocyte subset panel revealed absent b cells, decreased number of natural killer (nk) cells, and cd4/cd8 inversion. further work-up included gata2 sequence analysis that showed heterozygous nonsense mutation (c.58c > t/c; reference nm_001145661) likely resulting in gata2 haploinsufficiency. patient continues to be in remission, is receiving monthly immunoglobulin replacement and is on azithromycin for atypical mycobacterial prophylaxis. surveillance bone marrow biopsies have shown no evidence of mds or leukemia, however, have demonstrated persistent hypocellularity. the possibility of undergoing an allogeneic bone marrow transplant is actively being discussed given its curative potential. clinicians should be aware that t-cell all may be associated with gata2 deficiency. cincinnati children's hospital medical center, cincinnati, ohio, united states background: treatment for severe hemophilia a is centered on factor viii (fviii) replacement therapy. development of an alloantibody (inhibitor) against fviii is a significant treatment complication occurring in as many as 25-30% of patients. high titer inhibitors render treatment with factor viii ineffective, necessitating the use of bypass agents that may not achieve hemostasis with the same efficacy. considering the substantial ramifications of inhibitor development on treatment, eradication of inhibitors is of great importance to achieve adequate hemostasis in this patient population. desensitization by immune tolerance induction (iti) is the primary method of inhibitor elimination. however, not all patients respond to iti. immunomodulation may be considered as the next line of therapy, although controversy remains in regards to agent selection and use. objectives: there is incomplete data on the use of immunomodulation therapy for inhibitor eradication in severe hemophilia a. we present a case of a pediatric patient with severe hemophilia a and high titer inhibitor who failed initial iti therapy to better illustrate potential treatment options for the future. design/method: a retrospective chart review was performed on a patient with severe hemophilia a at cincinnati children's hospital medical center. results: an 8-year-old caucasian male with severe hemophilia a secondary to intron 22 inversion, was initially diagnosed following extensive bleeding after circumcision at birth. he was identified as having an inhibitor (312 bethesda units (bu)) at 12 months of age after 15 exposure days of treatment. he failed multiple attempts of iti, with recombinant and plasma-derived (pd) fviii. he was advanced to immunomodulation therapy in combination with pdfviii, however demonstrated anaphylaxis to rituximab and ofatumumab. he underwent tolerization to rituximab, and received a six month course with a partial response (nadir of 0.56 bu). 12 months following last dose of rituximab, a rising inhibitor titer (7.44 bu) was found. mycophenolate mofetil (mmf) was initiated with subsequent inhibitor stabilization and a decreasing titer (1.48 bu) over the course of the following year. mmf has been well tolerated without major side effects or infection throughout therapy. conclusion: development of an inhibitor against fviii is a considerable complication in patients with severe hemophilia a. use of immunomodulatory therapies following iti failure remains controversial. mmf has not been well studied in this patient population. we report a case of a patient who is being successfully treated with mmf with minimal side effects. further prospective studies should be considered to further define the role of mmf immunomodulation therapy. background: down syndrome (ds) children with aml (ds aml) have higher cure rates than their non-ds counterparts. outcomes for refractory/relapsed cases, however, remain dismal. somatic mutations of the gene encoding the transcription factor gata1 in ds aml patients are responsible for the observed hypersensitivity of ds aml blasts to cytosine arabinoside (ara-c). in view of excellent survival rates (approaching 90%) of ds aml patients, the ongoing children's oncology group (cog) aaml1531 study seeks to determine the feasibility of treating standard risk (minimal residual disease/mrd negative) ds aml patients using a reduced dose (7-fold decrease) ara-c backbone. although results from japanese trials with this approach are promising, north american and european data are conflicting. although chromosome 7 rearrangements in ds aml do not appear to carry the same adverse prognostic significance as in non-ds aml, monosomy 7 in ds aml patients has been associated with a moderately worse outcome. isochromosome 7q, however, is rare and has only been reported in 3 previous cases of ds aml. objectives: to report our institutional experience of very early relapse involving 2 cases of ds aml patients treated per the reduced dose ara-c arm (3.8 g/m2) of the aaml1531 study. design/method: we hereby report the disease course and cytogenetics of the above 2 ds aml patients. : patient 1 is a 20 month old caucasian female who had gata1 mutation negative aml. patient 2 is a 3-year old caucasian male whose chromosomal analysis revealed isochromosome 7q (3 copies of the long arm of chromosome 7). both patients achieved negative mrd (<0.05%) after induction i chemotherapy with thioguanine, low-dose ara-c and daunorubicin and proceeded per the reduced dose ara-c arm of aaml1531. patient 1 relapsed immediately after completion of chemotherapy. salvage chemotherapy with mitoxantrone/high dose ara-c (hidac) failed to induce a second remission and the patient subsequently died of disease. patient 2 relapsed within 4 months from end of therapy. the patient underwent salvage chemotherapy utilizing a hidac backbone and remains in disease remission. the noted very early relapse following a reduced dose ara-c regimen in our 2 above ds aml children suggests that testing for gata 1 mutation and chromosome 7 rearrangements may play a useful role in the development of future risk-stratified treatment strategies for ds aml. university of rochester, rochester, new york, united states background: in developed countries in the 21st century, severe nutritional deficiency is not an often considered differential diagnosis of unexplained childhood anemia. aside from iron deficiency anemia, vitamin deficiency severe enough to impact hematopoiesis is uncommon in the general pediatric population. here we present the unique case of a 10-monthold infant who presented with intermittent emesis, failure to thrive (ftt), developmental delay, macrocytic anemia, and neutropenia which was initially concerning for a congenital bone marrow failure syndrome. instead, she was discovered to have an underlying, potentially familial deficiency of b12. objectives: 1. to describe the unique case of an infant with b12 deficiency. 2. to outline the importance of including b12 deficiency in the differential diagnosis of unexplained megaloblastic anemia in children. a 10-month-old exclusively breastfed infant presented for gastroenterology evaluation due to persistent emesis and poor weight gain over the course of 2 months. her history was notable for delayed developmental s57 of s301 milestones and hypoactivity. marked pallor prompted hematologic evaluation, which revealed concern for macrocytic anemia (hemoglobin 7.1 g/dl, mcv 107), reticulocytopenia (48.1 × 10^3/ l), and neutropenia (anc 0.4 × 10^9/l). an otherwise reassuring physical examination and laboratory evaluation was notable only for the discovery of an undetectable b12 level and marked hyperhomocysteinemia (162 mol/l). her hemoglobin (hgb) continued to decline (to 5.9 g/dl) over the first few days after presentation, and she required red blood cell (rbc) transfusion. within only a few days of initiation, daily cyanocobalamin injections resulted in a robust reticulocytosis response, improved hgb, immediate normalization in the neutrophil count, and resolution of hyperhomocysteinemia. additional history and laboratory evaluation from the patient's mother revealed a concurrent, asymptomatic maternal b12 deficiency as well as a history of a need for b12 supplementation in the maternal grandfather, raising concern for an inherited etiology. despite the rarity of vitamin-deficient hematologic abnormalities in the general pediatric population, b12 deficiency should be considered as a potential cause of an otherwise unexplained megaloblastic anemia, especially in the setting of concurrent ftt and neurodevelopmental delay. a detailed family history should be obtained in such cases and may have helped to prevent this patient's clinical sequelae had the deficiency been discovered sooner. our patient has experienced a favorable clinical response to b12 supplementation, attesting to the importance of vitamin b12 in early childhood growth and development. background: peg-asparaginase is universally utilized in the treatment of pediatric acute lymphoblastic leukemia (all). despite its high efficacy in this disease, it is associated with hypersensitivity and allergy in 10 -20% of patients. protracted anaphylaxis has been described in circumstances such as severe food allergy with ongoing allergen exposure; however, it has not yet been described in relation to peg-asparaginase. we describe the first reported case of protracted anaphylaxis after peg-asparaginase administration, provide guidance as to time course and management of protracted anaphylaxis, as well as evidence that erwinia asparaginase may be safely administered even in this high risk population. objectives: to provide guidance regarding the duration, course and management of protracted, severe anaphylaxis after peg-asparaginase therapy. a 15 year old male with very high risk all presented for consolidation therapy with peg-asparaginase (intramuscular) and vincristine. one hour after administration, he developed generalized hives and angioedema, for which he was given diphenhydramine. he then quickly developed progressive hives, angioedema, subjective throat and chest tightness, and wheezing. he was treated with diphenhydramine, epinephrine, albuterol, and methylprednisolone with resolution of symptoms. one hour later, symptoms recurred and the patient became hypotensive; he was retreated with methylprednisolone and epinephrine, and was transferred to the pediatric intensive care unit (picu). in the picu, he was placed on an epinephrine drip, and continued on methylprednisolone, diphenhydramine, cetirizine, albuterol, and ranitidine. the epinephrine drip was successfully discontinued after 48 hours, and his other medications were gradually weaned over the course of two weeks. of note, the patient did have st segment changes in his electrocardiogram during the first 48 hours of anaphylaxis. these were associated with normal ventricular function as per echocardiogram, and resolved within one week. this patient has subsequently tolerated multiple doses of erwinia asparaginase (intramuscular) without premedication. this patient was acutely managed in the pediatric intensive care unit with steroids, anti-histamines, and continuous infusion epinephrine. symptoms consistent with severe anaphylaxis including hives, angioedema, throat and chest tightness, wheezing, and hypotension persisted for a total of four days before finally resolving. he has thus far tolerated multiple doses of erwinia asparaginase without any symptoms of allergy, hypersensitivity, or anaphylaxis. protracted severe anaphylaxis after peg-asparaginase therapy can be successfully managed with multi-agent therapy, including antihistamines, steroids, and continuous infusion epinephrine. re-challenge with an alternate form of asparaginase may be tolerated, even in a patient with protracted anaphylaxis to peg-asparaginase. ucsf benioff children's hospital oakland, oakland, california, united states background: vincristine (vcr) is widely used in pediatric cancers. unlike most cytotoxic agents, hematopoietic toxicity is uncommon. vcr-induced anemia has been observed but its mechanism has not been well studied. vinca alkaloid-induced membrane changes were seen in early studies of hereditary spherocytosis (hs) and anecdotal cases suggest vcr may increase hemolysis in such patients. here we describe a case involving severe vcr-induced anemia in a patient with hs and an explanation as to the mechanism. objectives: to describe the mechanism of vcr-induced anemia in hs. design/method: case report. a 6 year-old female with hs was diagnosed with t-lymphoblastic lymphoma. she had required 2 packed red blood cell (prbc) transfusions as a neonate and thereafter had done well without episodes of acute hemolysis or aplasia. complete blood counts (cbc's) demonstrated a compensated hemolysis, and she did not require further transfusions until she commenced chemotherapy. by the start of maintenance she had received many more prbc transfusions than the average patient. intermittent drops in hemoglobin (hb) did not correlate with any particular agent, and she had stable, mild splenomegaly. a clear pattern emerged during maintenance. her hb was 8-9 g/dl at monthly clinic visits, when she received vcr, intermittent intrathecal methotrexate, and corticosteroids. within 3-4 days, her hb dropped to 5.8±0.6 g/dl, and reticulocyte count decreased from 13.4 to 4.3±0.7%. transfusion at day 4 corrected hb, and the reticulocytes and hb returned to baseline. white blood cell and platelet counts did not change after vcr. blood samples from pre, immediately post, and 4 days post vcr were analyzed and rbc characteristics and markers of hemolysis were not significantly different. ektacytometry showed identical curves, indicating no change in rbc deformability. in vitro incubation of patient blood samples with vcr also did not affect the osmotic deformability, confirming that a change in rbc rigidity was unlikely the reason for the drop in hb. these data indicate that a dysregulation of erythropoiesis was responsible for the anemia after vcr, rather than damage of peripheral rbc's. in most patients, maintenance therapy for lymphoblastic lymphoma does not cause severe anemia, likely because a temporary reduction in erythropoiesis in patients with a normal rbc survival and low reticulocyte count is not noticed. however, in a patient with decreased rbc survival and a brisk reticulocytosis, a disruption in rbc generation is more apparent. in conclusion, vcr administration to patients with an rbc disorder warrants close observation for potentially severe vcr-induced anemia. background: the addition of tyrosine kinase inhibitors (tki) to conventional chemotherapy has improved outcomes for pediatric patients with philadelphia chromosome-positive (ph+) acute lymphoblastic leukemia (all), however there remains an increased risk of relapse compared to other types of childhood all. typically, in relapsed disease the philadelphia chromosome persists and several mechanisms of resistance involving acquired mutations of the bcr-abl1 chimeric oncoprotein have been reported. objectives: describe a unique case of a pediatric patient with ph+ b-precursor all relapsing with b-precursor all without the philadelphia chromosome. results: an 8-year-old boy was diagnosed with ph+ bprecursor all with the presence of the t(9;22)/bcr-abl1 translocation by cytogenetics and fluorescence in situ hybridization (fish), respectively. additional abnormalities included gains of runx1 and loss of one copy of etv6. a remission bone marrow with negative minimal residual disease (mrd) was achieved at the end of induction with dasatinib and the esphall chemotherapy backbone. duration of tki therapy was two years post diagnosis. nearly one year after the completion of therapy, cytopenias prompted a bone marrow investigation. relapsed b-precursor all was established by immunophenotyping, however fish analysis did not identify the bcr-abl1 rearrangement. moreover, quantitative reverse transcriptase pcr was negative for the bcr-abl1 fusion transcript. again fish analysis of the bone marrow revealed multiple additional copies of runx1 and mono-allelic loss of etv6, similar to the initial diagnostic sample. the patient was re-induced per aall0232 anticipating a ph+ all relapse. however, with confirmation of the loss of the ph+ clone, tki therapy was not re-initiated. due to positive mrd of 3.5% at the end of re-induction therapy, the patient was salvaged with blinatumomab therapy and subsequently underwent an allogenic stem cell transplant with a sibling donor. conclusion: this is the first known report of a pediatric patient with ph+ b-precursor all who developed recurrent b-precursor all without the philadelphia chromosome. the persistent findings of gain of runx1 and loss of etv6 makes it unlikely that a second unrelated b-precursor all developed following successful treatment of the original disease. this case highlights the possibility of a genetically distinct subclone present at the onset of disease that shared abnormalities of runx1 and etv6 but did not contain the philadelphia chromosome. nevertheless, the subclone harbored leukemogenic potential in the absence bcr-abl1 expression. it is plausible that the predominant clone present at diagnosis was effectively treated with dasatinib and extinguished, but the bcr-abl1-negative clone persisted in the face of tki therapy. background: ligneous conjunctivitis is a rare form of pseudomembranous conjunctivitis that develops specifically in patients with type 1 plasminogen deficiency. lack of plasmin activity in those patients result in defective fibrinolysis and formation of fibrin-rich membranous material/ masses that develops on the palpebral conjunctiva as well as other sites in the body.current management involve surgical excision of the masses that is usually complicated by multiple recurrences. recently, use of topical plasminogen concentrates helped delaying recurrence, but currently, those concentrates are not commercially available. we report on a 7-year-old omani girl, with hypoplasminogenemia who required optimization of plasminogen level at the time of surgery to delay/ prevent recurrence. objectives: case report on the peri-operative use of ffp versus cryopricipitate transfusion as an alternative replacement of plasminogen during surgical excision of ligneous conjunctivitis. design/method: pharmacokinetic study was performed to assess plasminogen recovery after ffp (15 ml/kg) and precipitate (1 bag/5kg) transfusion results: plasminogen levels remained subnormal after either ffp or cryoprecipitate administration. with ffp, the maximum concentration reached was almost 50% of normal. although half-life of plasminogen is known to be 2-2.5 days, the patient seemed to have a high catabolic rate after receiv-ing cryoprecipitate, with plasminogen levels reaching basal levels within 4 hours. because of the better recovery profile with ffp, we opted to give ffp before and after surgery. peri-operative management included ffp transfusion at 20 ml/kg/12 hours one day before and for 3 days post operatively, followed by 10 ml/kg once daily from day 4-6, then 20 ml/kg on 7th post-operative day. topical treatment was initiated using antibiotic and steroids ed on the day of surgery, followed by heparin ed on the second day. on follow up, she used topical heparin, cyclosporine, prednisolone, and topical lubricant eye drops for variable duration. clinical picture remained stable for almost 1 year post operatively, when she started to develop recurrence of ligneous lesions again. background: ponatinib (inclusig®, ariad pharmaceutical) is a 3rd generation multi-targeted tyrosine kinase inhibitor (tki) approved for treatment of adults with chronic myeloid leukemia (cml) and philadelphia chromosomepositive acute lymphoblastic leukemia (ph+ all) resistant to or intolerant of other tkis. ponatinib has numerous drug-drug interactions and a black box warning for associated serious adverse vascular events and hepatotoxicity. for this reason, ponatinib use has been confined to specific high-risk populations. however, in patients who prove refractory to other therapies, the potential benefits of ponatinib may outweigh risks. to date, ponatinib has not been studied in the pediatric/adolescent and young adult (aya) population. furthermore, literature describing the use of ponatinib alone or in combination with other agents in pediatric oncology patients is scarce. objectives: to describe a single institutional experience using ponatinib in the pediatric patients with ph+ all. design/method: two cases of ponatinib use in pediatric ph+ patients resistant to other tkis were identified at our institution and are described. peripheral blood samples obtained from both patients identified bcr-abl1 p190 fusion transcripts and sanger sequencing was used to identify resistant mutations. results: our first case is a 15-year-old female who received upfront multi-agent chemotherapy plus dasatinib for ph+ all. relapse was confirmed on end-of-therapy bone marrow evaluation, thus bcr-abl mutation testing was performed and revealed a t315i mutation. ponatinib was initiated then discontinued after one week due to clinically significant fluid retention with peripheral edema and bilateral pleural/pericardial effusions. the second case is a lateadolescent female with ph+ all who relapsed 4-years after stem cell transplant (sct). following relapse, tki therapy included both imatinib and dasatinib. due to persistence of bcr-abl fusion transcript despite tki therapy she was switched to ponatinib. shortly following initiation of ponatinib she developed a diffuse, maculopapular rash, which persisted despite dose reduction, resulting in ultimate discontinuation of the drug. bcr-abl mutation testing identified f317l and f357v resistance-conferring mutations. to date, there is scant existing literature detailing the use of ponatinib in pediatric patients. appropriate dosing is undefined and side effect profile not well described, particularly when used concurrently with other chemotherapeutic agents. thus, this case series reporting the response to and toxicity of ponatinib in pediatric ph+ all patients has important clinical implications. additionally, this is the first report of a pediatric ph+ all patient with documented t315i mutation underscoring the importance of bcr-abl mutational testing, particularly at the time of relapse. cooper university hospital, camden, new jersey, united states background: myh9-related disorder is a rare autosomal dominant disease, encompassing several subtypes: may hegglin anomaly, epstein syndrome, fechtner's syndrome, and sebastian syndrome. heterozygous mutations are seen in the gene encoding non-muscle myosin heavy chain iia (nmmhc-iia) which is involved in cell motility as well as functions to maintain cellular shape and integrity. the presentation of myh9-rd is mainly characterized by macrothrombocytopenia, but various related expressions exist: nephritis often leading to renal failure, cataracts and sensorineural deafness (1). a 4-year-old girl with history of extensive dental caries, hyperactivity, and speech delay due to suspected hearing loss was incidentally found to have thrombocytopenia at the time of genetic evaluation. she did not have any bruising or excessive bleeding. she did not respond to observation, immunoglobulins, or steroid therapy. her platelet count remained persistently low (4-23 k/ul). she underwent extensive evaluation to rule out platelet disorder vs. coagulation defect. her peripheral smear showed enlarged platelets by giemsa stain but no inclusion bodies were noted in granulocytes. her platelet aggregation and platelet surface glycoprotein by flow cytometry were negative. her coagulation profile was also normal. objectives: this case report summarizes the complexity in diagnosing myh9-rd in a pediatric patient. design/method: since a unifying diagnosis for her clinical presentation was not apparent, whole exome sequencing (wes) was undertaken. results: wes revealed the r702c heterozygous pathogenic variant, located in exon 17 in the myh9 gene. myh9 gene alteration explained the patient's clinical features of macrothrombocytopenia and hearing loss. this mutation was paternally inherited, and her father demonstrates mosaicism. he was asymptomatic with normal platelet count but his morphology showed enlarged platelets with no inclusion bodies in granulocytes. when dealing with patients who have mild or no symptoms of bleeding diathesis but evidence of persistent macrothrombocytopenia, considering a platelet disorder belonging to myh9-rd can help delineate certain predisposing syndromes and guide clinical management. patients are likely to benefit from early genetic testing while receiving supportive therapy. wes can highlight syndromes and provide information on recurrence risk for families. the renal and hearing abnormalities are indistinguishable between epstein and fechtner's syndromes, but the pathogenic variants differ (2). the genotype-phenotype correlation implies that our patient may have either syndrome, although clinical features compatible with nephritis have yet to manifest. patients should be monitored closely for long-term progression of myh9 disease, and treatments should be initiated accordingly. we present an 11-year old female evaluated by genetics at birth due to prenatal microcephaly. chromosomes and microarray were normal. at age 3 she developed standard risk pre-b-cell acute lymphoblastic leukemia (all). she completed treatment in 2012 and has been doing well in the interim, remaining in complete clinical remission. during and after treatment she exhibited developmental delay and neurocognitive deficits. at age 11 her height and weight were at or below the 5th centile and head circumference was below the 2nd centile (approximately 6 standard deviations below the mean and corresponding to the 50th centile for a 9-month-old girl). bone age was appropriate. she had a distinctive triangular face with micrognathia and a pointed nose resembling a seckel-like syndrome. the patient also had clinodactyly of the 4th toes, zygodactylous triradius involving the 2nd and 3rd left toes, tendency to sydney line in the right palm and a radial loop in the left middle finger. the patient's unique clinical presentation prompted a more thorough genetic evaluation, which led to a novel finding we feel is clinically significant with regard to the development of malignancy. design/method: whole exome sequencing (wes) was performed on the patient as well as her biological parents (trio). a de novo heterozygous mutation in the gene pcdh17 with potential relation to the phenotype was discovered. this c.716dupa variant causes a frameshift starting with codon asparagine239, changing this amino acid to a lysine residue and creating a premature stop codon at position 34 of the new reading frame denoted p.asn239lysfsx34. this variant is predicted to cause loss of normal protein function via protein truncation or nonsense-mediated mrna decay. conclusion: pcdh17 is a member of the protocadherins family which is important in cell-to-cell adhesion and synaptic function in the central nervous system and is highly expressed in areas of the brain involved in higher cortical function and speech. aberrant expression of protocadherins has been associated with the development of malignancies in many organ systems. with regards to leukemia, the methylation status of this gene at diagnosis has been implicated in the prognosis of all and could be used as a biomarker to predict relapse. this patient's de novo mutation and clinical presentation are unique to what has been previously presented in the literature. we feel that this mutation is a clinically significant finding that may shed light on the role of this gene in the development of hematopoeitic malignancies. background: acquired hemophilia a (aha) is an uncommon and potentially life-threatening hemorrhagic disease characterized by sudden onset of bleeding in patients with neither personal nor family history of bleeding dyscrasia. it is usually seen in adults with autoimmune diseases, solid tumors, lymphoproliferative diseases, pregnancy or during the postpartum period; occurrence in the pediatric population has rarely been reported. we report a case of an otherwise healthy teenager who was found to have aha when he presented with acute onset of atraumatic soft tissue hematoma. results: a 13-year old male of middle eastern descent with history of congenital absence of the right external ear, but otherwise in good general health, presented to our emergency department with a three day history of progressive worsening of right lower leg pain, swelling, and paresthesia, without preceding history of trauma. evaluation by the pediatric orthopedics service documented significantly elevated compartment pressures, necessitating immediate four-compartment fasciotomy. pre-operative labs were significant for prolonged activated partial thromboplastin time (aptt) of 67.7 (23.4-38.9) seconds with normal prothrombin time (pt) and international normalized ratio (inr). ptt did not correct on mixing studies, suggesting the presence of a circulating anticoagulant. factors xii and xi were in the normal range; factor ix was elevated, 247 (60-150). factor viii level was 4% and fviii inhibitor level was 5.3 bethesda units (<0.8), confirming the diagnosis of aha. work up for autoimmune disease was negative. his bleeding and surgical hemostasis were managed with recombinant factor vii (novoseven) 90 mcg/kg every 3 hours for 24 hours post operatively, with gradual interval prolongation. factor viii antibody eradication was managed with prednisone 1 mg/kg/day. factor viii and inhibitor levels normalized by day 5 of hospitalization. recombinant factor vii was discontinued; steroids were gradually tapered and discontinued at discharge (hospital day 15). conclusion: acquired hemophilia is likely an underdiagnosed condition in pediatrics. while it is typically seen in adults with underlying autoimmune disease, solid tumors, lymphoproliferative disease, or during pregnancy or the postpartum period, pediatric cases may have no identifiable etiology. this case highlights the importance of considering this diagnosis in any patient with unexplained bleeding regardless of their age, so as to intervene early and prevent adverse consequences. university of oklahoma, oklahoma city, oklahoma, united states background: myeloid neoplasms associated with eosinophilia is a rare subtype of chronic leukemia characterized by clonal eosinophilia. the true incidence is unknown due to its rarity and possible classification as idiopathic hypereosinophilia syndrome. the most common chromosomal aberrations involve platelet-derived growth factor receptors (pdgfrs). we report one such rare case in a pediatric patient. most of the pediatric management of this entity is derived from adult case reports and case series. objectives: to describe a case of chronic leukemia presenting as eosinophilia results: a previously healthy 15 year old caucasian male presented with a several week history of migrating joint pain, splenomegaly, and abnormal blood counts with leukocytosis, thrombocytopenia and absolute eosinophilia. white blood cell differential showed myeloid precursors suggestive of chronic myeloid leukemia. bone marrow evaluation showed 10% blasts and 18% eosinophils. bcr-abl testing was negative, ruling out cml. fish analysis for eosinophilic clonality revealed deletion of chic2 gene, resulting in fip1l1/pdgfra fusion gene, diagnostic for myeloid neoplasm with eosinophilia associated with pdgfr abnormalities. treatment was started with tyrosine kinase inhibitor (tki), imatinib 100mg daily. within 3 months, fish analysis for fusion gene was negative. after approximately 18 months of daily imatinib, he was switched to maintenance dose of 200mg weekly. he is approximately 36 months since diagnosis and doing well on maintenance imatinib. in 2008, the who revised its classification of some chronic eosinophilic leukemias to myeloid and lymphoid neoplasms associated with eosinophilia and rearrangement of pdgfra, pdgfrb, fgfr1. the most common abnormality is the fip1l1/pdgfra fusion gene. other less common abnormalities include fusion genes kif5b-pdgfra and etv6-pdgfrb and point mutations in pdgfra22. some features of chronic eosinophilic leukemia include absolute eosinophilia, splenomegaly, elevated vitamin b12 and tryptase levels, and organ damage from eosinophil infiltrates and cytokine release. patients with rearrangements or mutations involving pdgfra are usually very responsive to imatinib. starting doses have not been well studied or established. experts recommend co-administration of corticosteroids during the first few days of imatinib therapy in patients with a history of cardiac involvement and/or elevated serum troponin levels to prevent myocardial necrosis, a rare complication of imatinib therapy in eosinophilic patients. fortunately our patient did not have cardiac involvement and to date has not exhibited signs of chronic tki toxicity. conclusion: myeloid neoplasms with eosinophilia constitute a rare form of chronic leukemias. they are often associated with pdgfr abnormalities and are usually very responsive to tyrosine kinase inhibitor therapy. walter reed national military medical center, bethesda, maryland, united states background: germline samd9l mutation is a rare cause of constitutional bone marrow failure with a unique propensity for clonal evolution to monosomy 7 and mds. objectives: previous case series have demonstrated diverse clinical outcomes in patients with a germline samd9l mutation. our case presents a novel samd9l mutation (p.val1551leu). additionally, the case highlights the challenges in clinical decision making for a patient with a gene mutation that is known for clonal evolution towards monosomy 7 with risk of progression to myeloid malignancy, but also known for self-correction through uniparental disomy or inactivating mutations which results in disease remission. design/method: a retrospective chart review and review of the literature was performed. dna was isolated from peripheral blood and used for whole exome sequencing. a peripheral blood sample from the patient's mother and father showed no samd9l mutation. skin biopsies of the patient and parents were evaluated for uniparental disomy or new mutations. to determine the pathogenicity of this novel mutation, the specific samd9l mutant dna was transfected into the 293human embryonic kidney cell line to assess its role in inhibiting cell proliferation. our patient presented at 8 months of age with pancytopenia and hypocellular bone marrow in the setting of s63 of s301 sepsis. he had evidence of dysfunctional immune activation with hemophagocytosis and elevated soluble il2 with simultaneous severe hypogammaglobulinemia. analysis of the peripheral blood showed no increase in chromosomal breakage, normal telomere length, and normal flow cytometry. gene testing for primary hemophagocytic lymphohistiocytosis and inherited bone marrow failure were negative. after the patient recovered from his presenting illness, a repeat bone marrow biopsy demonstrated improved cellularity with myelodysplasia and cytogenetics significant for monsomy 7.whole exome testing demonstrated a novel samd9l mutation. the patient continued to require intermittent ivig and failed to demonstrate appropriate leukocytosis with intermittent infections. on repeat bone marrow evaluation over the course of 9 months, the patient demonstrated no evidence of evolution towards self-correction and had a persistent monosomy 7 clone. the patient is scheduled to undergo a matched unrelated donor bone marrow transplant. our case highlights the unique clinical picture associated with constitutional marrow failure and clonal evolution secondary to a novel samd9l mutation which is thought to cause pancytopenia by inhibiting cellular proliferation and often results in the development of monosomy 7 which rescues hematopoiesis but with a risk for malignancy. background: notable labs developed a flow cytometricbased assay with a custom robotic platform to test fdaapproved drugs for anti-cancer activity against individual patient's tumor cells. this personalized assay is a potential method for identifying novel agents and drug combinations to treat aml patients who have failed standard therapies. objectives: to present the case of a teen who underwent successful treatment of relapsed aml post-sct with bortezomib, panobinostat, and dexamethasone-a regimen selected based upon results of notable lab testing. results: a 15-year-old male with m4-aml had an isolated bone marrow relapse 8 months after completion of scheduled therapy. at relapse, his aml was flt3-itd positive. he achieved a second remission with negative mrd and underwent matched sibling donor bmt after busulfan/cyclophosphamide conditioning. bma performed on day +180 was mrd positive (0.13%). repeat bma done on day +204 showed 5.7% mrd. he started sorafenib on day +212. he received donor lymphocyte infusion (dli) on day +246, then received 2 cycles of azacitadine (aza) followed by dli. marrow mrd by flow after sorafenib alone, sorafenib with dli, and sorafenib with aza/dli were 16%, 15.7%, and 0.16%, respectively. treatment was complicated by varicella meningitis, grade i skin agvhd, febrile neutropenia and c. difficile colitis, and metapneumovirus pneumonia. despite extremely low levels of leukemia (marrow mrd 0.16%), notable lab testing performed on the patient's leukemia cells from marrow collected after aza/dli/sorafenib revealed sensitivity of his leukemic blasts to a combination of bortezomib, panobinostat, and dexamethasone. because of prolonged cytopenias, multiple infectious complications, and persistently positive mrd, he discontinued aza/dli/sorafenib and on day +368 started bortezomib 1.3 mg/m2 iv on days 1, 4, 8, and 9; panobinostat 20 mg po on days 1, 3, 5, 8, 10, 12; and dexamethasone 20 mg po on days 1, 2, 4, 5, 8, 9, 11, and 12 . chemotherapy cycle 2 started 21 days later. he tolerated treatment without side effects and with resolution of rash and cytopenias. he achieved full donor chimerism, negative flt3-itd, and complete remission by morphology and flow after two cycles. notable lab testing is a powerful tool for evaluating the sensitivity of small populations of leukemic blasts to novel drug therapy. results from notable lab testing may serve as a useful guide for treatment selection after failure of standard aml therapy. this patient achieved morphologic and mrd remission post-sct with bortezomib, panobinostat, and dexamethasone-a regimen predicted to be efficacious based upon notable lab results. maria ahmad-nabi, christine knoll, sanjay shah, esteban gomez, lori wagner phoenix children's hospital, phoenix, arizona, united states background: development of inhibitors in patients with factor ix deficiency (fixd) is a well-recognized complication occurring in 1-3% of patients. within this subset a small percentage can develop anaphylaxis to factor. desensitization with cyclophosphamide, an alkylating agent used in the management of various oncologic malignancies, and reported for use in factor viii desensitization has been previously unreported for use in desensitization in patients with fixd. rituximab, an anti-cd 20 antibody, however has been used. objectives: to induce immune tolerance (it) in patients with inhibitors to factor ix with either novel or under reported methods using cyclophosphamide and/or rituximab. we report a case series of 2 patients at phoenix children's hospital with fixd who achieved it with cyclophosphamide and/or rituximab. results: patient one was a 14 year old male with severe fixd, who at the time of desensitization had inhibitor levels of 12 bu. he was desensitized with cyclophosphamide, then admitted for infusion of recombinant factor ix. he experienced a few minor symptoms of intolerance including an urticarial rash which was self-limited, and hemarthrosis of the right elbow on day 1 which responded to novo 7. he tolerated the remainder of his infusion without issues. he continued recombinant factor ix daily, and returned to clinic for monthly cyclophosphamide for 6 months. he did develop urticaria with hemarthrosis and spontaneous muscle bleeds which were tempered with zantac, zyrtec, solumedrol, and benadryl. he remained without a recurrence of inhibitors, however did have intermittent hemarthrosis of his ankles thereafter requiring prophylactic twice daily dosing recombinant factor ix. patient two was a 10 year old male with severe fixd and a family history of anaphylaxis to factor causing early death in all male relatives with the disease. he had never received factor ix and did not have a detectable inhibitor prior to desensitization. he successfully underwent desensitization to recombinant factor ix with rituximab in the icu, and returned to clinic for weekly infusions x 4. he experienced no adverse reactions concerning for anaphylaxis. he continued to tolerate factor ix products without evidence of intolerance, development of inhibitors, and continues on as prophylactic dosing of recombinant factor ix every other day. our experience at a single institution proves cyclophosphamide as a novel agent for inducing it in those with fixd and anaphylaxis. it also provides further evidence that rituximab can desensitize patients with severe fixd. differences include longer duration for cyclophosphamide therapy (6 months vs 1 month). background: cartilage-hair hypoplasia (chh) is an autosomal recessive chondrodysplasia associated with defective cell-mediated immunity caused by mutations in the ribonuclease mitochondrial rna processing (rmrp) gene. cancer incidence is 7-fold higher in patients with chh than in the general population, especially non-hodgkin lymphoma. the use of rituximab, an anti cd20 antibody, results in decreased host b-cell number and impaired humoral function for 6-9 months. the safety of rituximab in pediatric patients with cancer and immunodeficiency is not well documented. a diagnosis of underlying immunodeficiency may discourage physicians from using rituximab due to the risk of severe bacterial infection or viral re-activation. objectives: to report a case of burkitt lymphoma in a young adult female with chh and defective cellular immunity successfully treated with rituximab. results: an 18-year old amish female with disproportionate short stature presented to our center for management of stage iv biopsy proven burkitt lymphoma with myc rearrangement. she had presented a week earlier with cervical, occipital, and submandibular lymphadenopathy, splenomegaly; fevers, night sweats, and weight loss for 2-4 weeks. on exam, her height was three feet associated with brachydactyly, mild bowing of the legs, normal size head without frontal bossing, fine and sparse hair. she had normal intelligence. her pattern of dysmorphisms was suggestive of chh (genetic testing not performed at time of diagnosis). pet-ct scan showed stage iv disease with involvement of cervical lymph nodes, spleen, iliac bone and bone marrow. treatment with standardintensity fab/lmb therapy (group c) with the addition of rituximab was initiated. she had an incomplete response to cop (∼80% reduction of tumoral masses) but achieved complete remission after copadam1. her course was complicated with severe varicella zoster but she completed therapy and remains in complete disease remission for 24 months after treatment completion. genetic testing subsequently performed proved homozygosity for chh with a n.71a>g variant. she had no other opportunistic infections during or after therapy. conclusion: the use of rituximab was both safe and beneficial in our patient despite defective cell mediated immunity secondary to chh suggesting that rituximab may be safe to use in patients with cellular immune deficiencies. background: hemophilia a and b are bleeding disorders characterized by deficiency in factor viii or ix, respectively. spontaneous or provoked hemarthrosis is a known complication of hemophilia. repetitive episodes of hemarthrosis can lead to debilitating hemophilic arthropathy. lyme disease is a tick-born infection which is endemic to increasing parts of the united states. chronic lyme disease, the phase in which lyme arthritis typically develops, occurs months to years after initial infection and is characterized by swelling of one or more large joints generally in the absence of systemic symptoms. objectives: review cases of hemophilia a and b patients with episodes of provoked hemarthrosis refractory to intensive recombinant factor replacement therapy found to have concurrent lyme arthritis. design/method: we report two clinical cases and review relevant literature. results: first, we report a 12 year-old male with moderate hemophilia a with a provoked knee hemarthrosis which failed to improve despite 3 months of intense factor replacement therapy requiring multiple hospitalizations. factor replacement regimens included twice daily standard half-life recombinant factor viii products or daily to every other day extended half-life recombinant factor viii products with trough levels aimed as high as 50-80%. factor viii pk studies were obtained for dosing, to confirm adherence, and to evaluate for subclinical inhibitors (inhibitor testing was negative). given protracted symptoms additional workup for hemarthrosis was pursed. lyme titers were positive for (8)igg, though negative for igm. he was treated with 28 days of doxycycline during which time hemarthrosis greatly improved on examination and imaging, and he was able to recover function through physical therapy. second, we report a 6 year-old male with moderate hemophilia b who required multiple hospital admissions for a provoked knee hemarthro-sis with no improvement in symptoms despite weeks of daily or twice daily factor replacement with standard halflife recombinant factor ix products aiming for 100% correction. we performed inhibitor testing (which was negative) and pk studies to assess for non-detectable inhibitors, dosing and adherence. lyme testing was positive for (6)igg, though negative for igm. he was treated with amoxicillin for 28 days during which time hemarthrosis significantly improved on examination and imaging. diagnosis and follow-up imaging studies for both patients included mri and serial bedside ultrasounds performed as per uc san diego school of medicine mskus guidelines. background: relapse/refractory aml following allogeneic hematopoietic stem cell transplant (hsct) holds a high mortality rate. current relapse/refractory therapy modalities for younger patients may include re-induction with a clofarabinebased regimen followed by second allogeneic hsct. even for patients who undergo second hsct, the five-year survival rate is dismal. new therapies, including small molecule inhibitors, are being studied in the post-hsct relapse setting or those unfit for hsct with promising results. venetoclax is a small molecule inhibitor that has received breakthrough designation for aml treatment in elderly patients objectives: to report a young adult aml patient with relapse post hsct who was successfully re-induced with topotecan, vinorelbine, thiotepa, clofarabine (tvtc) and has sustained remission with venetoclax maintenance therapy. this approach appears to be unique in terms of reported literature. results: our patient is now a 23-year-old female noted to have mll rearranged aml at initial diagnosis when she was 21 years old. she underwent chemotherapy consisting of cytarabine/daunorubicin according to standard 7+3. due to persistent disease, she was re-induced with g-csf, clofarabine, and high-dose cytarabine (gclac) which put her in cr. her course was complicated by sepsis, colitis, gastrointestinal bleed, deep venous thrombosis, and transfusionassociated circulatory overload. given her co-morbidities, she received another cycle of clofarabine/cytarabine, and then proceeded to reduced intensity allogeneic hsct, according to bmt ctn 1101. the patient tolerated hsct well and experienced no transplant-related complications, including no acute or chronic gvhd. unfortunately, she relapsed about 10 month's post-hsct. initial salvage therapy consisted of another course of g-clac, but due to persistent disease the decision was made to re-induce her with topotecan, vinorelbine, thiotepa, and clofarabine (tvtc). during this time however, she was found to have extensive infection with a fusarium species requiring a course of anti-fungal therapy. bone marrow evaluation showed no residual disease with an mrd of <0.1%. once the absolute neutrophil count recovered, the patient was started on single-agent venetoclax for maintenance therapy, which has been well-tolerated. she remains in morphologic remission for over 8 months. we describe herein a young adult with multiply relapsed aml wherein tvtc re-induction, followed by maintenance with venetoclax were safely used in the post-hsct setting. venetoclax therapy in the relapsed aml setting warrants further study. background: vitamin b12 deficiency is uncommon in children in developed countries, especially in the absence of risk factors like malabsorption or inadequate dietary intake. it often presents with non-specific symptoms and signs and can elude diagnosis. the recognition and treatment of vitamin b12 deficiency is critical as it can lead to bone marrow failure as well as severe neurological and developmental problems in children. to increase index of suspicion of vitamin b12 deficiency anemia in children. we report a rare case of vita-min b12 deficiency anemia in a child who presented with a severe macrocytic anemia, with signs of hemolysis and concern of malignancy. design/method: an almost three-year-old previously healthy girl presented with a few day history of fever, emesis, fatigue and pallor. she had no dysmorphic features, hepatosplenomegaly or lymphadenopathy on exam, growth and development were normal. laboratory findings showed severe macrocytic anemia (hemoglobin 4.4 grams/dl; mcv 104.1 fl) with reticulocytopenia. signs of intravascular hemolysis were present with elevated lactate dehydrogenase (3,842 units/l) and haptoglobin below assay limit. immune-mediated hemolysis was ruled out. initial picture of a hemolytic anemia was compounded by other findings of moderate neutropenia, mild thrombocytopenia and peripheral smear showing occasional blasts. further workup was done with a broad differential diagnosis that included leukemias, hemolytic anemias, bone marrow failure syndromes, and specific deficiencies. results: workup revealed abnormally low vitamin b12 levels along with significantly elevated homocysteine and methylmalonic acid levels indicating functional vitamin b12 deficiency. bone marrow evaluation showed megaloblastic anemia and dyserythropoiesis consistent with vitamin b12 deficiency, and ruled out leukemia. vitamin b12 deficiency can cause a hemolytic anemia like picture secondary to intramedullary hemolysis due to ineffective erythropoiesis. myeloid precursors are also affected which can lead to neutropenia, thrombocytopenia, and abnormal peripheral blood cells. in our patient, initial symptomatic anemia was treated with blood transfusion, followed by intramuscular vitamin b12 injections with normalizing lab values. so far, workup for an etiology for vitamin b12 deficiency is negative except for an equivocal range of anti-parietal cell antibodies raising concerns for pernicious anemia; however it is rare in this age group. another rare condition is an inborn error of the cobalamin transporter. she is currently on oral vitamin b12 supplementation and further workup will be planned based on response. conclusion: this case highlights the importance of early consideration and thorough evaluation of vitamin b12 deficiency in children with unclear etiology of anemia, so that prompt treatment can be initiated. memorial hospital/ university of miami, miami, florida, united states background: despite great success in the treatment of acute lymphoblastic leukemia (all), the outcomes for patients with relapsed all remain poor. prognostic indicators include timing and site of relapse. blinatumomab, is the first agent in its class that simultaneously binds cd3-positive cytotoxic t cells to cd19-positive b cells resulting in lysis of malignant cells. however, mechanisms of leukemia resistance to blinatumomab are unclear. objectives: to describe a case with multiple sites of extramedullary (em) relapse during blinatumomab therapy. results: a 9-year-old hispanic male with philadelphia positive, cd19-positive b-precursor cell all refractory to chemotherapy, had failed a bone marrow (bm) and was placed on blinatumomab and imatinib. he achieved minimal residual disease (mrd)-negative systemic remission, but during his fifth cycle developed bilateral periorbital masses. biopsies confirmed cd19-negative isolated em relapsed disease, which was treated with radiation therapy (rt). there was notable resolution of em disease and he continued systemic therapy. subsequently, he presented with a painful left scapular swelling. imaging showed muscle and lung parenchymal em relapse with cd19-positivity confirmed on histology. he continued on blinatumomab with localized rt while awaiting car-t cell therapy. his bm mrd remained negative until he developed systemic mrd-positivity with cd19-positive blasts following the sixth cycle. primary resistance to blinatumomab is poorly understood. it is proposed that expansion of cd19-negative clones or downregulation of cd19 following blinatumomab may play a role. this was observed in our patient's periorbital relapse; but subsequent em and systemic relapses were cd19-positive, consistent with the co-existence of multiple clones in relapsed all. it has also been postulated that em relapse could be linked to the failure of blinatumomab or t cells to migrate to em sites of disease or drug inactivation by the microenvironment. the second em relapse in our patient, with cd19-positive disease suggests this as a possible mechanism of relapse. this was reported in patients with cd19 positive non-hodgkin lymphoma (nhl), and higher doses of blinatumomab however, have shown promising results in this population. despite blinatumomab's effectiveness in inducing remissions in patients with refractory/relapsed all, it appears to have limitations in patients with em disease. these may arise either from the multiclonality associated with relapsed all or due to the emergence of resistance to blinatumomab, including failure to migrate to em sites. background: cyclic neutropenia is a rare hereditary disorder, characterized by recurrent neutropenia, cycling at about 3 week intervals, with variable associated symptoms including oral ulcers and fever. there are 4 reported cases of cyclic neutropenia associated with chronic inflammation leading to development of reactive aa amyloidosis. one patient also presented with amyloid goiter. we report a new case of cyclic neutropenia with associated renal and thyroid amyloid. design/method: a 12-year-old female presented with a 1 month history of thyromegaly, and recurrent aphthous ulcers associated with fevers. laboratory workup showed severe neutropenia, anemia, azotemia, and abnormal thyroid function, with an absolute neutrophil count -0/ l, hemoglobin -9.0 g/dl, serum creatinine -1.89 mg/dl, and uric acid -9.0 mg/dl. thyroid stimulating hormone was elevated -12.5 iu/ml, and normal free t4. urinalysis showed 2+ protein, 2+ blood, and 5-10 urine red blood cells/hpf. chest radiograph showed mild narrowing of the trachea from thyroid compression. bone marrow biopsy showed a hypocellular marrow, with tri-lineage hematopoiesis, left shifted myeloid maturation with very rare mature neutrophils. both renal biopsy and thyroid fine needle aspiration revealed abundant amyloid. of note, her father had aa amyloidosis, resulting in end-stage renal disease (esrd) requiring hemodialysis, and recurrent aphthous ulcers. the family history suggested a familial predisposition. genetic testing revealed a pathogenic elane c.358 a>t gene mutation with autosomal dominant inheritance confirming the diagnosis of cyclic neutropenia. we treated our patient with daily granulocyte colony stimulating factor to reduce the burden of chronic inflammation induced by cyclic neutropenia, and to preserve renal and other end organ function affected by further amyloid deposition. results: proband with elane gene mutation positive cyclic neutropenia, amyloidosis of thyroid and kidney, with a positive paternal history of aa amyloidosis resulting in esrd. cyclic neutropenia may result in chronic inflammatory states leading to secondary amyloidosis. university of kentucky, lexington, kentucky, united states background: overall survival of burkitt lymphoma (bl), regardless of stage, is greater than 85% in the pediatric population when treated with multi-agent chemotherapy. adenovirus is a common, usually self-limited infection within the pediatric population; however, findings can vary within an immunocompromised host. hepatitis is a rare complication, with very few reports of radiologic findings in this patient population. we discuss a three year old male with history of bl who presented with clinical and radiographic evidence of relapse but was found to have adenovirus hepatitis. design/method: a case report of a patient with bl in complete remission after completion of standard of care chemotherapy, who presented with return of high fever, elevated ldh, transaminitis and hepatic lesions. we describe the hepatic imaging and pathology consistent with adenovirus hepatitis in this immunocompromised host. our patient presented at three years old with a six week history of worsening abdominal pain and fevers. he was found to have a right sided pleural effusion, multiple lesions of the liver, and diffuse abdominal lymphadenopathy; biopsy of lymph tissue was consistent with bl. he completed therapy per anhl1131 arm b and was in a complete remission at the end of planned therapy. one month after completion of therapy, he returned with high fever, abdominal pain and transaminitis, similar to his initial presentation. ct scan showed multiple hypodense discrete lesions throughout the liver and re-accumulation of right sided pleural effusion. ldh peaked at 3580 u/l (uln 370 u/l). uric acid remained within normal limits. bilirubin peaked at 4.0 mg/dl, conjugated 3.2mg/dl. liver biopsy was performed, showing smudgy nuclei with immunohistochemical staining positive for adenovirus. there was no evidence of lymphomatous involvement. resolution of hepatic lesions and transaminitis, with normalization of ldh and fever, occurred with symptomatic treatment alone. adenovirus is known to cause systemic disease in immunocompromised patients and rarely hepatitis. no pediatric patients with discrete hepatic lesions secondary to adenovirus have been reported in the literature. three cases of discrete hepatic lesions have been reported in adult immunocompromised patients, two with fatal fulminant liver failure and one who required cidofovir. this case demonstrates that a common pediatric viral infection can present with lesions concerning for metastatic disease in a pediatric lymphoma patient. prompt diagnosis is vital in the management of these patients when recurrent lymphoma is in the differential. background: heparin induced thrombocytopenia (hit) is an immunologic process in which antibodies bind a heparin complex and cause a paradoxical hypercoagulable state. ramifications of this process may include a multitude of thrombotic events and bleeding complications secondary to platelet consumption. in our patient, hit manifested as increased bruising, an acute decrease in platelet count, and continual clotting of her crrt circuit. hit, although rare in pediatrics, should be included in the differential for children with thrombocytopenia who have received heparin products. to present a unique case report of a critically ill pediatric patient who developed hit in the presence of multiorgan system failure and to discuss the challenges encountered with identification of an alternative anti-coagulant. results: a 12yo obese, caucasian female child presented to our facility with bilateral pulmonary emboli (of unclear etiology). initially, she was started on a continuous heparin infusion, but was transitioned to enoxaparin within 3 days without issue. five days after enoxaparin was initiated, the patient developed acute kidney injury (evidenced by increasing creatinine) attributable to her biventricular heart failure. due to her need for continuous renal replacement therapy (crrt), she was transitioned back to a continuous heparin infusion. whereas her initial platelet count on transition was normal, she developed severe thrombocytopenia (15,000ul) within 48 hours. due to intermediate risk but low suspicion for hit, pf4 antibodies were sent which were positive. after much discussion, she was transitioned to an argatroban infusion which was titrated according to ptt levels. within 48 hours, her platelet count normalized. at discharge, she was prescribed apixaban for anti-coagulant management. conclusion: hit is an uncommon presentation in the pediatric population. given its rarity, there is often a delay in diagnosis which increases risk of complications such as bleeding, stroke, and limb ischemia. even if the diagnosis is suspected or proven, there may be challenges in initiating alternative agents as limited data exists on pediatric options. as argatroban remains the treatment of choice for patients with hit, experience in pediatric patients is limited, and dosing recommendations have been extrapolated from adult studies. anecdotal data exists for use of bivalirudin in children, although studies, primarily, focus on use in specific cardiac cases. in our patient's case, choice was further complicated by renal failure. this case study highlights the need for further research regarding the identification of a secondary anti-coagulant agent for use in pediatric patients with hit. background: subcutaneous panniculitis-like t-cell lymphoma (sptl) is a rare form of non-hodgkin's lymphoma characterized by infiltration of cytotoxic t-cells into subcutaneous tissue. sptl occurs in both adults and children and can present in both patient populations as either alpha/beta or gamma/delta subtypes. patients with the gamma-delta phenotype have an overall poorer survival, although the exact etiology is unclear. interestingly, both subtypes of sptl can present with secondary hemophagocytic lymphohistiocytosis (hlh), and this is associated with a worse prognosis. currently, there are no standardized treatment protocols for sptl, and clinical management includes watchful waiting, corticosteroids/immunosuppression, chemotherapy, and stem cell transplant. the primary objective was to compare how two patients with the same diagnosis responded acutely to therapy. we performed a retrospective chart review of two pediatric patients at our institution who were diagnosed with alpha/beta sptl and secondary hlh. we examined each presentation, treatment course, and outcome. we then completed a brief review of the current literature describing treatment of and outcomes for sptl with secondary hlh. results: these two patients presented in a similar manner with signs and symptoms of hlh. each was then subse-quently diagnosed with alpha/beta sptl after biopsy of cutaneous nodules and each had diffuse disease, as measured by pet. however, they demonstrated vastly different acute responses to therapy. one patient was pre-treated with systemic glucocorticoids before receiving definitive chemotherapy and tolerated therapy well as an outpatient. the other patient started systemic chemotherapy without steroid pretreatment and developed severe cytokine storm characterized by hypotension, cardiac dysfunction, multi-organ failure and cytokine elevation. both patients achieved complete remission (cr) after treatment with chop chemotherapy and remain disease-free 12-24 months off therapy. in patients presenting with sptl and secondary hlh, we propose that initial treatment with antiinflammatory or anti-cytokine therapy can decrease, or even prevent, the possibility of life threatening cytokine release as a result of cytotoxic chemotherapy. background: congenital dyserythropoietic anemia type ii (cda ii) is a rare autosomal recessive disorder, rarely presenting in the neonatal period. iron overload often occurs as a late sequela of ineffective erythropoiesis and intramedullary hemolysis. objectives: to report the novel use of iron chelation in an infant with cda ii associated with severe iron overload. the patient is a 3-month-old, former 27-week infant with prenatal non-immune hydrops and transfusion-dependent fetal anemia who presented with persistent anemia, reticulocytopenia, hyperbilirubinemia, liver dysfunction, and hyperferritinemia. his initial ferritin was 4822.3 ng/ml, tibc 185 ug/dl, and transferrin 116 mg/dl. his bone marrow biopsy showed trilineage hematopoiesis and erythroid dyspoiesis characterized by binucleation of late-stage precursors. genetic testing revealed a compound heterozygous missense mutation and splice site mutation in the sec23b gene, confirming the diagnosis of cda ii. initial liver biopsy revealed mild portal fibrous expansion, and abundant hepatic iron deposition. his ferritin continued to increase, peaking at 21,114 ng/ml, along with liver enzymes peaking at an alanine aminotransferase (alt) of 505 u/l and aspartate aminotransferase (ast) of 776 u/l. ferriscan showed an elevated estimated liver concentration of 2.8 mg/g dry tissue. repeat liver biopsy 3 months later showed giant cell hepatitis with worsening mild portal fibrosis and hemosiderosis. additionally, tissue liver iron concentration was 4755 mcg/g dry weight. cardiac t2* mri revealed mild cardiac iron deposition. given his significant degree of iron overload, deferoxamine was used to reduce hemosiderosis and liver morbidity in preparation for bone marrow transplantation. the patient received deferoxamine 15 mg/kg/day iv x 5 days/week for three months, without any clinically significant adverse events. blood counts and hepatic and renal function were monitored weekly without any abnormalities. growth parameters and liver enzymes significantly improved while receiving chelation therapy. as a noninvasive, cost-effective method, serum ferritin levels were monitored monthly to gauge response to treatment. despite receiving blood transfusions every 3-4 weeks, serum ferritin decreased to 344 ng/ml and liver enzymes decreased to alt 29 u/l and ast 26 u/l prior to bone marrow transplantation. we report the use of deferoxamine in a patient with cda ii less than 2 years of age, for treatment of iron overload. our patient tolerated deferoxamine well without significant adverse events or organ toxicity. deferoxamine may be a well-tolerated method of reducing iron burden in young patients with iron-loading pathologies. background: low grade gliomas with kiaa-1549-braf fusions typically have a favorable prognosis with infrequent rates of high grade transformation, low rates of metastasis and even lower rates of extra cns metastasis. while highgrade transformation has been reported for tumors with braf v600e mutations and cdkn2a deletions, it has not been pre-viously reported in gliomas with kiaa-1549-braf fusions. while there are case reports of high-grade cns malignancies metastasizing through a ventriculo-peritoneal (vp) shunt, low-grade gliomas metastasizing in this manner are extremely rare. objectives: to describe a unique case of peritoneal tumor dissemination of a braf fusion positive high grade neuroepithelial tumor in a child with a vp shunt placed for multifocal braf fusion positive low grade astrocytomas results: an eight-year-old male was initially diagnosed with multifocal low-grade astrocytomas of the hypothalamus and c2-c4 spinal cord. initial testing revealed the kiaa-1549-braf fusion, but no cdkn2a or braf v600e mutation. initial surgical management included a vp shunt and resection of the cervical spinal lesion. he received vincristine and carboplatin, followed by transition to vinblastine given new thoracic metastatic lesions after 10 months of therapy. at 15 months after diagnosis, scans were concerning for diffuse leptomeningeal progressive disease and new intracranial lesions, necessitating craniospinal radiation. following a near cr, he presented 13 months later with acute onset of abdominal pain. a ct scan revealed peri-renal and perirectal soft tissue masses, confirmed by exploratory laparotomy to be peritoneal tumor dissemination of high grade neuroepithelial tumor. a kiaa1549-braf fusion was noted and confirmed by rt-pcr, identical to that seen in the original cns tumors. additional findings included deletion of chromosome 1p (without 19q loss) and heterozygous and homozygous deletion of cdkn2a found by fish. brisk mitotic activity justified a high-grade designation. salvage chemotherapy consisted of 4 cycles of ice with subsequent resolution of pet-avid disease and only minimal peri-nephric tissue remaining. given the favorable response, surgical resection and multiple tissue biopsies were performed which documented no residual active disease. the shunt was revised and he started trametinib for maintenance. we present a unique case of peritoneal dissemination of high grade neuroepitheial tumors with the same kiaa-1549-braf fusion as multifocal low grade astrocytomas in a child with a vp shunt. this raises suspicion for tumor metastasis and transformation to a higher grade malignancy versus two distinct diseases, which may be indicative of an underlying cancer predisposition. texas children's hospital, houston, texas, united states background: polycythemia is a common referral to hematology. it is important to evaluate for a high oxygen affinity hemoglobinopathy, ensuring appropriate testing is performed for early diagnosis and avoidance of additional tests and procedures. a 17 year old mexican female presented with an elevated hemoglobin and hematocrit, symptoms of plethora of her hands and feet, chest pain, palpitations, and fatigue. further confounding the picture, she also had significant menorrhagia and iron deficiency. she was diagnosed with the rare high oxygen affinity hemoglobin new mexico variant, only previously described once in the literature in a 4 year old black boy. objectives: the patient initially presented at age 14 with a hemoglobin of 16.7g/dl and a hematocrit of 52.4%. initial work up consisted of a hemoglobin electrophoresis which diagnosed sickle cell trait, a co-oximetry panel which was normal, and erythropoietin level of 7mu/ml, also normal. she was then lost to follow up and re-referred at age 17. she is a competitive basketball athlete, and at that time, she presented with a hemoglobin of 17.1g/dl, and hematocrit of 50%. erythropoietin level continued to be normal at 13mu/ml. design/method: cardiology was consulted regarding chest pain and palpitations with a normal evaluation. chest x-ray was also normal. a bone marrow aspirate and biopsy was performed with results significant for mild erythroid hyperplasia and mild reticulin fibrosis. jak 2 mutation, von hippel lindau, bpgm, and hereditary erythrocytosis mutations including phd2, hif2a, and epor mutation analysis were sent, all of which were normal. testing to mayo clinic for p50 rbc oxygen dissociation returned low at 19mmhg (24-30mmhg normal range) and subsequently a hemoglobin electrophoresis identified a hemoglobin variant leading to beta globin gene sequencing. results: patient found to be heterozygous for hemoglobin new mexico, with 41.9% hb new mexico and 54.5% hba, and 3.6% hba2. there was no evidence of hbs. when evaluating patients with polycythemia, maintaining a high index of suspicion for high affinity hemoglobinopathies may eliminate further unnecessary and invasive testing for patients. caution should be used when using hemoglobin electrophoresis testing since hb new mexico is known to migrate similarly to hbs on hplc with minimal change that may not be detected in regular laboratories. most high affinity hemoglobinopathies are reported to not have significant symptoms. in this case, our patient complains of fatigue, occasional palpitations and plethora of hands and feet. we will need to further follow this patient for possible attributable symptomatology. divya keerthy, simone chang, warren alperstein, patricia delgado, claudia rojas, ofelia alvarez, matteo trucco university of miami jackson memorial hospital, miami, florida, united states background: improved technology is enabling detection of previously unidentified translocations and mutations in otherwise unclassified sarcomas. one such mutation is the bcl-6 co-repressor -internal tandem duplication (bcor-itd) allowing for the new classification of bcor positive undifferentiated round cell sarcomas (urcs). this sarcoma has a similar appearance to clear cell sarcoma of the kidney (ccsk), potentially representing an extra-renal manifestation of this tumor, but their clinical pathologic features are not identical. objectives: this case highlights how recombinant polymerase chain reaction (rt-pcr) and bcor immunohistochemical staining can ease the diagnosis of this rare sarcoma. results: a 5 month-old female presented for right sided pre-septal cellulitis and a temporal subcutaneous mass. the detection of multiple other subcutaneous nodules on exam raised the concern for malignancy and she was admitted for evaluation. she had two subcutaneous masses on her abdomen, with more cutaneous masses on her legs, back, shoulder, cheek and submandibular areas. she lacked spontaneous lower limb movement and had bilateral clonus. imaging confirmed multiple masses throughout the body including paravertebral area from t3 to l2, bilateral adrenal glands, left kidney and muscles of upper and lower extremities. initial differential included neuroblastoma, infantile myofibromatosis, rhabdomyosarcoma or atypical presentation of a renal tumor. however, synaptophysin and chromogranin stains were negative. with standard immunohistochemistry, the tumor could be only broadly classified as "undifferentiated sarcoma" maintaining the diagnostic challenge. using rt-pcr in the setting of a morphologically primitive round cell neoplasm with strong bcor expression, two external institutes simultaneously diagnosed the tumor as bcor-urcs. the primary lesion is unknown but potentially may have arose from the kidney. bcor-urcs has a heterogeneous histology with tumor cells appearing monomorphic in nests of 6-10 cells separated by septa with uniform nuclei. there is frequently an "orphan annie eye" appearance and sparse cytoplasm to the cells. diagnosis cannot be made solely on evaluation of this nonspecific histology. rt-pcr uses the genetic abnormality in undifferentiated sarcomas to narrow the differential and bcor immunohistochemical staining provides further context. bcor has significant diagnostic value given its sensitivity and specificity in urcs. another potential marker includes ywhae-nutm2b fusions, which occur in smaller subset of cases, but requires further study. rt-pcr has helped further classify tumors leading to the diagnosis of a rare undifferentiated sarcoma with bcor overexpression. while this technology is beneficial, its availability is limited. if accessibility improves, earlier identification and treatment may be possible maximizing the chance for a positive outcome. background: hematohidrosis is a rare condition that mimics bleeding disorders. cases present with oozing blood tinged fluid from various sites like eyes, ears, nose, skin, etc. reported causes of this condition were stress or fear, physical activity, psychological disorders. the condition is self-limited and don't affect the general condition of the patients, but it may contributes to psychosocial problems and may increases their stress and anxiety. so this condition needs to be promptly treated. to test the response of this disease and the associated headache to propranolol treatment. design/method: our case female patient 11 years old 1st offspring of non consanguineous marriage, was admitted with recurrent episodes of oozing blood tinged fluid from eyes, ears and nose 2 months before admission, about 0.5-1 ml from each orifice, lasted 5-10 minutes and subsided spontaneously. it could involve the 3 sites simultaneously or 1-2 sites. the number of attacks was 3-4 times per day then gradually increased to 15-20 times per day. later on the patient developed a bleeding attack from umbilicus. these attacks were aggravated by stress and physical activity and decreased with rest and sleep. the condition was associated with severe headache involving the whole head, throbbing in nature of gradual onset, increased by physical activity and relieved by analgesics. the condition was not associated with vomiting, blurring or diminution of vision, ocular pain, eye discoloration. no earache, tinnitus or diminution of hearing. there was no other form of discharge from eyes, ears or nose. no history of ecchymotic patches, bleeding from other orifices or blood product transfusion. no history of trauma, drug intake, fever or rash. no symptoms of other system affection. past history of recurrent attacks of epistaxis and two operations were done that passed without remarkable bleeding. no similar condition in the family physical examination was free, no evidence of psychological problems. complete blood count, coagulation profile, platelets function, factor 13 and c.t brain were normal. oozing fluid from the patient was analyzed showed the same components as blood. results: our case started oral propranolol 0.5mg/kg/day based on its use in similar cases in literature. the frequency of attacks and headache reduced then stopped after 2 months of treatment and didn't recur after stoppage of propranolol. propranolol can treat this condition successfully. further investigations are needed to determine the link between this condition and severe headache our case was suffering from. background: wilms tumor is the most common renal solid tumors of childhood and is derived from primitive metanephric cells located in the kidney. primary extra-renal wilms tumors (erwt) are extremely rare, estimated to comprise 0.5-1% of all wilms tumors. despite similar histologic appearance intrarenal and erwts differ in embryologic tissues of origin. erwts arise from the more primitive mesonephric or pronephric origin and, therefore, can develop anywhere along the craniocaudal migration pathway of these primitive tissues, most often retroperitoneal, inguinal/genital, lumbosacral/pelvic and mediastinal. these tumors are typically staged and treated per national wilms tumor study (nwts) guidelines, and, by definition, are stage ii or greater due to location beyond the kidney borders. based on the cases reported in the literature, outcomes for erwt are comparable to renal wilms tumors with an 11% local recurrence rate and an 85% two-year event-free survival. we report the first case of a stage iii testicular extrarenal wilms tumor in an 8-month-old male with an intrabdominal undescended testis who underwent complete surgical excision followed by chemotherapy and inguinal radiation. results: a full term 8-month old male underwent orchipexy for an undescended left testicle. the testicle was noted to be grossly abnormal with a pea-sized thickened tissue adherent to the upper pole and a separate mass outside of the scrotum on the superior epididymis. both masses were removed, and s73 of s301 pathology demonstrated wilms tumor with favorable histology and negative margins. ct imaging of the chest, abdomen and pelvis were negative for a primary renal tumor, local residual disease, pathologic lymph node enlargement or distant metastases. the tumor was classified per nwts as stage iii due to tumor removal in multiple pieces. the patient completed dd-4a treatment with vincristine, doxorubicin and dactinomycin per aren0534 with 10 cgy left inguinal radiation. he is currently 15 months off therapy without clinical or radiographic evidence of recurrent disease. primary erwt is an extremely rare malignant neoplasm associated with challenges in diagnosis, staging and treatment. based on the 80 cases reported in the literature, outcomes are similar to that of intrarenal wilms tumor. there are four pediatric paratesticular wilms tumors reported in the literature and, to the best of our knowledge, this is the first case of stage iii testicular wilms tumor successfully treated with dd-4a chemotherapy and radiation. in erwt, nwts guidelines for staging and treatment should be applied with evaluation of both kidneys to exclude an intrarenal primary tumor. background: patient is a 20 yo f, with esrd secondary to atypical hus versus ttp, who presented with thrombotic microangiopathy, aki, thrombocytopenia and anemia after a living unrelated donor kidney transplant. patient initially had downtrending creatinine. on post-op day 2, hematology was consulted for an increasing ldh and drop in platelets. peripheral smear was notable for an absence of schistocytes. yet, biopsy of the kidney revealed microthrombi. the patient was diagnosed with a thrombotic microangiopathy. plasmapharesis was initiated on day #3, at which time ms r was noted to have significantly elevated creatinine. plasmapharesis did not yield any correction in labs and significant bruising developed. patient was started on eculizimab; plasmapharesis was stopped. shortly after, creatinine, anemia and thrombocytopenia corrected to levels at which she was discharged. overall, patient was found to have progressive anemia, thrombocytopenia, an increasing creatinine and ldh (600s) concerning for atypical hus, despite absence of schistocytes on peripheral smear. she responded well to eculizimab, with correction of hematologic changes during induction. she was discharged on eculizimab and continued to respond with normalizing platelet counts and hemoglobin. the differential in light of patient's thrombotic microangiopathy and thrombocytope-nia also included ttp. yet, adamts13 remained normal. dic was unlikely given normal fibrinogen level and d-dimer. objectives: presentations of atypical hus vs ttp. discuss eculizumab as a treatment of atypical hus. highlight atypical presentations of illness in transplant patients. results: despite absence of schistocytes by smear, pt was diagnosed with atypical hus based on presentation and after failing plasmapharesis, she responded well to eculizumab. though her presentation was abnormal, her response to this antibody that blocks the complement cascade suggests that she was experiencing a complement-mediated process. there are rare documented cases in the literature of atypical hus without schistocytes. hemolytic uremic syndrome (hus) is characterized by hemolytic anemia, thrombocytopenia and acute kidney injury. atypical hus is a diagnosis of exclusion, not due common etiologies such as shiga toxin. among atypical causes are complement-mediated forms, caused by an antibody to complement factor. in addition to plasmapharesis, renal transplant and supportive care, the mainstay of treatment for atypical hus is eculizumab (an antibody that blocks the complement terminal cascade). this case describes a patient unique in that, she was diagnosed with atypical hus without any schistocytes by smear. secondly, she responded to eculizumab, with unremarkable gene studies. finally, this case highlights that transplant patients often have unique presentations. nicklaus children's hospital, miami, florida, united states background: synovial sarcoma is a spindle cell tumor categorized as a soft tissue sarcoma. the chromosomal translocation t(x;18) leading to the ss18-ssx fusion protein is unique to this sarcoma. it is a slow growing tumor with common recurrences and often, at presentation, with evidence of metastatic disease. if resection is not feasible, then neoadjuvant with adjuvant chemotherapy is recommended. metastasis carries an unfavorable prognosis given synovial sarcoma historically does not respond well to chemotherapy. trabectedin is a well-tolerated alkylating agent currently indicated for the treatment of liposarcoma and leiomyosarcoma. we present a 17-year-old male with metastatic synovial sarcoma to the lungs that progressed and was refractory to chemotherapy. he was administered trabectedin as a form of palliative chemotherapy, with significant clinical and radiographic response. design/method: pubmed search was done with search for terminology including "synovial sarcoma" and "trabectedin". papers relevant to our case were selected for literature review. a 17-year-old male patient presented with a large right axillary mass. initial imaging showed a heterogeneous multiseptated mass invading the subscapularis and teres major muscles along with innumerable lung nodules. biopsy confirmed diagnosis of monophasic synovial sarcoma. the patient was started on protocol arst 0332 with ifosfomide, mesna, doxorubicin. he completed 4 cycles followed by radical resection and 33 sessions of radiation. due to progression of disease multiple chemotherapy regimens were tried including topotecan and cyclophosphamide, protocol advl 1522 with lorvotuzumab, and pazopanib. imaging of the chest continued to show significant progression of metastasis. the patient's clinical status deteriorated with worsening respiratory status, requiring 10l of oxygen therapy, and inability to ambulate. he was started on trabectedin 1.2mg/m2 for palliative care. after 2 cycles of treatment patient was no longer requiring oxygen and was ambulating without assistance. radiological imaging showed significant reduction in number and size of lung nodules. trabectedin is a recently approved alkylating agent for the management of sarcomas resistant to first line treatment. response in synovial sarcoma is scarcely documented in the pediatric population. epidemiology places the most common age group in the young adults and children. our case opens the doors to further consideration of the use of trabectedin in the pediatric patient with metastatic synovial sarcoma. background: gata1 is an x-linked gene that plays critical role in hematopoiesis. mutations of gata1 gene can be associated to various blood disorders including diamond blackfan anemia, cytopenia, congenital dyserythropoietc anemia and acute megakaryoblastic leukemia. we report a patient with macrocytic anemia and platelet dysfunction who carries a novel gata1 mutation that has not been reported. results: a now 28-month-old male with complex medical history including prematurity at 33 weeks, dysmorphic features, global developmental delay, hyperinsulinism, hypogonadotropic hypogonadism, growth hormone deficiency, micropenis, failure to thrive, patent ductus arteriosus status post ligation, and severe hypotonia, was referred to hematology at 16 months old for resolved, transient thrombocytopenia and macrocytic anemia since 1 month of age. chromosomal microarray showed chromosome deletion of 14q21.3, which is the rps29 gene. he doesn't have a family history of diamond blackfan anemia (dba), despite mom having the same rps29 mutation. he was then diagnosed with dba. his lab workup showed mild macrocytic anemia (hgb 9.1 g/dl, mcv 95fl), normal to inappropriately low reticulocyte count, normal white blood cell and platelet counts, hgf 0%, erythroid ada 1.39 eu/gm hgb (elevated). he has abnormal pfa-100, with prolonged closure time of both adp and epinephrine. he had low von willebrand antigen and ristocetin cofactor activity. he has severe pancreatic insufficiency. bone marrow biopsy showed normocellular marrow with trilineage hematopoietic maturation, without ringed sideroblasts. since mother has the same rps29 gene mutation, maternal labs were done and showed no evidence of macroytosis or anemia. the diagnosis of dba was questioned. whole exome sequencing did not identify any pathogenic sequence changes in the coding regions of rps29 gene, but detected a gata1 mutation r140w, which was reported variant of uncertain significance. his mother shares the same mutation and is asymptomatic, but she may not be affected since gata1 iis xlinked. his father doesn't harbor the gata1 mutation. conclusion: gata1 gene encodes zinc finger dna binding hematopoietic transcription factor, which is important during erythroid differentiation. gata1 mutation r140w has not been reported in literature and is a novel variant of gata1 mutation, which might be contributing to this patient's clinical picture. further studies are warranted to confirm gata1 mutation r140w to be a pathogenic sequence change. alexander boucher, tomoyuki mizuno, alexander vinks, greg tiao, stuart goldstein, james geller cincinnati children's hospital medical center, cincinnati, ohio, united states background: hepatoblastoma (hb), the most common pediatric primary hepatic malignancy, can be associated with specific congenital syndromes. recently, chronic kidney disease and genitourinary anomalies have been linked to hb. cisplatin is a key chemotherapeutic agent in treating hb but its renal clearance and toxicity profile can limit its use for those with end-stage renal disease (esrd). objectives: using an institutional case series, we present data using cisplatin for hb in dialysis-dependent esrd and define recommended dosing for future use. design/method: a chart review of patients with concurrent hb and esrd on dialysis treated with cisplatin at our institution was undertaken. demographic data, diagnostic history, tumor pathology, alpha fetoprotein (afp), hearing assessments, dosing schema, treatment outcomes, and therapyrelated toxicities were reviewed. total cisplatin levels were collected at 5 time points within 10 days after each infusion. free cisplatin levels were also collected for 2 infusions, as were dialysate cisplatin levels. pk parameters were generated using bayesian estimation with a published population pk model as a priori information. results: three patients meeting these criteria were identified. each had "low risk" (non-metastatic resectable) disease at presentation and underwent upfront resections. all had congenital renal anomalies with esrd prior to their hb diagnosis. all cisplatin infusions were given over 3 hours, followed 3 hours later by hemodialysis. patients 1 and 3 received cisplatin at 50% of children's oncology group's ahep0731 weight-based dosing (1.67 mg/kg). patient 2 received 50% of ahep0731 body surface area-based dosing (50 mg/m2) during cycle 1 but required a second dose reduction (25 mg/m2) for cycle 2 due to prolonged cisplatin exposure (total area under the curve 342 mg⋅h/l; average for all seven evaluable cycles 238 mg⋅h/l) and early sensorineural hearing loss at 2000-4000 hz. no other hearing loss in any patient was identified; mild toxicities also included grade 1-2 emesis and grade 1 neutropenia and thrombocytopenia. the median (range) of clearance, volume of distribution at steady-state, and elimination half-life at terminal phase for total platinum were 0.19 (0.15-0.31) l/hour/70 kg, 69.1 (59.0-105.7) l/70 kg and 155 (102-185) hours, respectively. patients 1 and 2 received 2 cycles with rapid afp normalization. patient 3 required an additional 2 cycles, for a likely second primary hb 1 year after initial therapy. cisplatin can be used successfully in pediatric patients with esrd on hemodialysis to treat hb with minimal morbidity using 50% standard mg/kg-based dosing (1.67 mg/kg), achieving pharmacologically appropriate cisplatin exposures. background: treatment for immune thrombocytopenia (itp) has been grouped into rescue and maintenance therapy and often is reserved for patients with bleeding, severe thrombocytopenia, or for improvement in quality of life. splenectomy is considered one of the more invasive but definitive treatments with success rates of 70-80%. treatment of itp can be more difficult in the setting of previous treatment with immune modulation or when the patient is immunocompromised and not a candidate for splenectomy. objectives: present an interesting case of a patient with an autoimmune disease that presented with severe thrombocytopenia, un-responsive to rescue therapy, and requiring emergent splenectomy in the setting of acute intracranial hemorrhage (ich). a 13 year old female with a history of juvenile dermatomyositis presented with a fine purpuric rash on her extremities, wet purpura, and a platelet count of 1k/ l. bone marrow evaluation at that time was consistent with itp. she was on cyclosporine and plaquenil for dermatomyositis. platelets failed to increase after three doses of intravenous immunoglobulin and high dose steroids. following a two week course of oral prednisone and eltrombopag, she presented with persistent severe thrombocytopenia of 1k/ l, anemia of 6.4 g/dl, and a lower gi bleed. she was started on amicar, novo-seven, rituximab, and given platelet transfusions with no improvement in bleeding. subsequently, she developed a subdural hematoma with midline shift. surgery performed an emergent open splenectomy with concurrent continuous platelet transfusion. results: she was monitored closely post operatively and, due to ich, transfused to maintain platelets greater than 100k/ l. by 1 week post-op she had normal platelet counts off transfusions. all medications were stopped within three days of discharge. she represented eight days later with abdominal pain and thrombocytosis and was found to have a portal vein, splenic vein and mesenteric vein thrombosis. she was started on lovenox therapy and admitted for monitoring due to her history of ich. it is unknown whether our patient's underlying immune dysregulation and history of treatment with immunosuppressive medications may have contributed to her unresponsiveness to multiple therapeutic agents. in addition, her significant bleeding did not allow us to fully evaluate her response to second tier therapy. this adds to the scarcity of literature of itp response in pediatric patients with autoimmune disease, and may support more aggressive therapy upfront in these patients. background: multivisceral organ transplantation involves concurrent transplantation of the stomach, pancreas, liver, and intestine with splenectomy, and has been classically used in the pediatric population for infants with intestinal failure from disorders affecting foregut integrity. while there is some data demonstrating its efficacy in adults with low-grade abdominal malignancies, it has not been traditionally used for hepatocellular carcinoma treatment. to describe a unique pediatric case of multivisceral organ transplantation as definitive therapy for refractory fibrolamellar hepatocellular carcinoma in an adolescent male. a 16 year old male presents with a history of fibrolamellar hepatocellular carcinoma, tumor invasion of the portal vein, severe portal hypertension complicated by bleeding esophageal varices and hypersplenism. he had two treatments with yttrium-90 radioembolization, without significant response. he completed six cycles of traditional chemotherapy in combination with sorafenib with resolution of petavidity, but minimal decrease in tumor size and continued portal hypertension. since his disease remained relatively stable for over 2 years, he was evaluated and listed for multivisceral organ transplantation. at approximately 2 years and 7 months after diagnosis, he underwent en bloc liver, pancreas, stomach, small bowel, and colon transplant with splenectomy. a single lymph node was positive for malignancy at the time of resection. in addition to expected post-transplant complications, he also developed skin only acute graft versus host disease at 2 weeks after transplant, treated successfully with a thymoglobulin course. he clinically improved and was back to his baseline activity level, on full oral feedings within 3 months post-transplantation. at three and six month post-transplantation, there is no concern for relapsed hepatocellular carcinoma on comprehensive imaging and evaluation. he is maintained on protocol immunosuppression and posttransplant support. we present the first known case of successful multivisceral organ transplantation in the treatment of refractory pediatric fibrolamellar hepatocellular carcinoma. background: hematohidrosis is a rare disorder that presents with spontaneous excretion of whole blood from intact skin or mucosa. diagnosis is based on clinical observation of the occurrence with the proven presence of erythrocytes and other blood components, without other abnormalities to account for the phenomenon. the existing literature is scarce and consists of primarily case studies. most reports describe bleeding from facial sites around the eyes, ears, and nose. the available literature suggests anxiety and physical or emotional stress reactions as the most common inciting events. little evidence exists regarding the ideal therapeutic approach, however propranolol has been used successfully to reduce bleeding frequency and severity in multiple case reports. a specific genetic etiology has not been elucidated, and no familial cases have previously been reported. we present a pair of half-siblings, both of whom presented with spontaneous cutaneous and mucosal bleeding before two years of age, and report on preliminary results of propranolol therapy. tanzania. at 20 months of age, he became ill and developed spontaneous bleeding from his ears, nose, and scalp. he continued to have frequent bleeding episodes, usually related to illness or physical distress. a bleeding diathesis work-up was unremarkable, however some episodes were severe enough to require transfusions. the patient was subsequently diagnosed with hiv and hepatitis b, presumably acquired via unscreened blood product transfusions. patient b is an infant female born to the same mother as patient a, with a different father. she was healthy until two months of age when she developed spontaneous bleeding from the hairline, eyelids, ears and genital/rectal area. bleeding episodes were nearly always associated with irritability and crying. extensive coagulation workup was unremarkable. results: propranolol therapy was started in both patients, titrated to a goal of 2 mg/kg/day. in both patients, the frequency and duration of bleeding episodes significantly improved. patient b continues to have milder occasional bleeding episodes from her eyes, ears and scalp but has significantly less discomfort and irritability during the episodes. conclusion: to our knowledge, there are no prior reports involving two related patients with hematohidrosis. this case series suggests that there may be a genetic predisposition which has yet to be identified. propranolol has shown effectiveness in reducing symptom frequency and severity. background: gliomas are the most common central nervous system tumors in children. they are classified into different grades based on genotype (idh, braf, tsc, etc.). lowgrade gliomas such as oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas are classified as grades i and ii. of the molecular level alterations this case report focuses on the braf v600e mutation. braf is a member of the raf family of serine/threonine protein kinases and it plays an important role in cell survival, proliferation and terminal differentiation. objectives: here we discuss two cases where dabrafenib, a braf kinase inhibitor, was utilized in the management of gliomas. the cases focus on the use of dabrafenib late versus early in disease course. design/method: patient jl is a 20 year old female who was diagnosed with a low-grade glioneuronal tumor (c7-t1 with a metastatic lesion to the brain) in 2007. jl was treated with chemotherapy, radiation, and surgical resection. despite treatment, the patient's disease progressed. she developed lower extremity dysfunction, urinary incontinence, poor truncal control, and hydrocephalus. dabrafenib was started after the braf v600e mutation was confirmed. patient lg is a 12 year old female who presented in november 2016 with left facial and upper extremity weakness. ct and mri scans demonstrated a mixed solid and cystic lesion extending from the optic chiasm and hypothalamus to the right thalamus and posterior basal ganglia with additional involvement of the right cerebral peduncle. neurosurgical intervention was undertaken and dabrafenib was started after the braf v600e mutation was confirmed. results: patient jl's mri scans have demonstrated improvement of the spine with diminished areas of enhancement along thecal margins, decreased volume and enhancement within the trigeminal plate cistern and resolution of ependymal enhancement within the right ventricle. the patient's most recent mri exhibits no disease progression in head or spine. jl has shown improvement clinically since starting dabrafenib. patient lg has shown improvement in strength and recent mri of the brain has shown resolution of enhancement along surgical resection margins, decreased hyperintensity along the inferomedial aspect of the right basal ganglia and no new enhancements. conclusion: low grade gliomas can alter a person's quality of life and even lead to life threatening complications. often the standard chemotherapy, radiation and surgery don't prevent these complications. genetic analysis can help clinicians target therapy towards certain mutations such as braf v600e. dabrafenib has shown to decrease tumor burden, early utilization as therapy can help prevent morbidity and mortality. children's hospital of pittsburgh of upmc, pittsburgh, pennsylvania, united states background: copper is an essential cofactor in enzymatic reactions essential to proper hematologic, skeletal, neurologic and vascular function. copper requirements in children over the age of 4 are 15 mg/day, which is readily acquired in a typical diet. copper deficiency is known to occur in patients with the rare x-linked mutation and in older individuals with gastrointestinal bypass surgery; however, it is rarely reported in other conditions. objectives: to highlight individuals with autism spectrum disorders or developmental delay with a limited dietary repertoire are at risk for copper deficiency, thus a high index of suspicion must exist in order to diagnose the disorder. design/method: a 15 y/o boy with a prior diagnosis of global developmental delay and oral aversion presented with slowly progressive fatigue, weakness, gait instability, and weight loss. his longstanding feeding difficulties were refractory to intensive feeding programs. his daily diet consisted of 50-60oz of milk and 25-30 individual servings of butterscotch pudding (1680-1880calories/day, 0.7mg iron/day). initial complete blood count demonstrated white blood cell count of 3.3, absolute neutrophil count of 760, hemoglobin of 4.4, mean corpuscular volume of <50, reticulocyte count of 0.5, platelet count of 392. review of his peripheral blood smear revealed microcytic, hypochromic red cells without marked fragmentation, anisopoikilocytosis and ringed sideroblasts; there were no morphologic abnormalities of his leukocytes or platelets. iron studies demonstrated ferritin of 45, total iron binding capacity of 514, and 2% iron saturation. he had no evidence of b12, folate deficiency or blood loss. additional evaluation revealed a serum copper level of 6 (range 60-190), and cerulosplasmin of 2.1 (range 22-58). results: once a diagnosis of copper deficiency was made, the patient promptly began a course of parenteral copper repletion. he received iv copper 35mcg/kg/day x 3 days then weekly intravenous infusions. given his malnutrition, a gtube was placed to begin oral copper repletion and enteral nutrition. within 3 weeks his copper level improved as well as his blood counts. unfortunately, although his blood counts and copper levels normalized, his neurologic status remains below his old baseline although, he has made gains in his gross and fine motor abilities. conclusion: acquired copper deficiency in the pediatric population is a rare event but given the hematologic and neurologic consequences, prompt recognition and treatment is important. this patient's clinical course demonstrates the need to have a high index of suspicion of concomitant nutritional deficiencies other than those routinely evaluated such as iron, b12 and folate. background: lymphoepithelioma-like thymic carcinoma (lelc) is a rare, aggressive neoplasm with a high rate of invasion, metastasis and recurrence. there are no known curative therapies for metastatic lelc. we report the case of a 16-year-old male who presented with metastatic ebv positive lelc. sites of disease included a large primary anterior mediastinal mass and metastases to hilar lymph nodes, lungs and liver. he was initially treated with cisplatin and 5fluorouracil followed by mediastinal radiation. he had a partial response to therapy but his end of therapy scans showed disease progression in lungs, liver, and hilar, supraclavicular and axillary lymph nodes. objectives: molecularly targeted therapies tailored to the patient's genetic profile offer a novel approach to obtain improved survival outcomes. design/method: the patient enrolled on a precision medicine trial, nmtrc009: molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancer (nct02162732). in this study, tumor/normal whole exome sequencing and tumor rna sequencing were performed and a molecular report detailing the results of genomic and gene expression analysis was generated. a treatment plan was designed within a molecular tumor board comprising oncologists, pharmacists, genomicists, and molecular biologists with domain expertise. results: exome sequencing revealed 26 somatic coding point mutations and no structural mutations (focal copy number changes or translocations). candidate somatic driver mutations included tp53 s94x and r248w as well as kit n655k. both genes have been previously implicated in thymic carcinoma. rna expression analysis demonstrated aberrant activation of biological pathways, including overexpression of kit, hdac1, 2 and 9, tyms, and dhfr. the molecular tumor board selected the combination of pemetrexed (500 mg/m2) on day 1 of a 21 day cycle, imatinib (400 mg daily), and vorinostat (400 mg days 1-5, 8-12, and 15-19) . on day 8 of cycle 1, he was admitted with a herpes zoster infection and imatinib was discontinued in order to reduce risk of herpes zoster recurrence. imaging after 2 cycles showed a complete metabolic response on f-18 fdg pet and a partial response by ct size criteria. as of december 2017, the patient had received 15 cycles of pemetrexed and vorinostat. scans in december 2017 showed an increase in the size and metabolic activity of two right lower lobe pulmonary nodules. there were no new sites of disease and imatinib was re-started. background: systemic lupus erythematosus (sle) is a chronic autoimmune disease that affects multiple organ systems and is associated with many different autoantibodies. patients can present with vague constitutional symptoms including fever, rash, fatigue, and weight loss. some of the various hematologic manifestations of sle include anemia of chronic disease, leukopenia, autoimmune hemolytic anemia (aiha), and idiopathic thrombocytopenic purpura (itp). these can be the presenting signs of sle. evans syndrome (es), a disease characterized by itp and aiha, is a rare hematologic manifestation of sle. neurofibromatosis 1 (nf1) is a relatively common neurocutaneous disorder. these patients are at risk of developing benign and malignant tumors. its association with autoimmune disorders, including sle, remains rare. objectives: there are few cases in the literature that have patients with the combination of sle and nf1. this is the only case that has a patient with sle, nf1, and es. results: a 16-year-old caucasian female presents with two months of vaginal bleeding, weight loss and petechiae. her exam is remarkable for petechiae and café au lait macules. laboratory findings show severe anemia and thrombocytopenia. she receives blood and platelet transfusions during stabilization, and a bone marrow aspirate is performed to rule out a malignancy which is negative. based on the presence of thrombocytopenia and a positive coombs test, an autoimmune process such as es is considered. screening tests for sle reveal positive antinuclear and anti-double stranded dna antibodies as well as low complement. she receives intravenous immunoglobulin and methylprednisolone and eventually her vaginal bleeding slows and her counts recover. she begins sle therapy with hydroxychloroquine and azathioprine. due to the presence of café au lait macules on her exam, a genetics evaluation is performed and the patient is also diagnosed with nf1. to date, there are seven cases of sle with nf1 reported in the literature, only two of which are pediatric cases. there are no reports of the combination of sle, nf1, and es. conclusion: es is a rare hematologic manifestation of sle but can be the initial presentation of this disease. one large study estimates 2% of childhood-onset sle cases are observed to have es. screening for sle should be considered in all es patients even in the absence of typical clinical findings. association of nf1 and sle has been rarely described. whether this association reflects a causal relationship or is coincidental needs more investigation. (lube, ped blood & cancer, 2016) . university of california san diego, la jolla, california, united states background: high grade glioma (hgg) has poor outcomes in adults and children. extraneural metastases are very rare in hgg, and poorly characterized with only a few small case series in adults and only isolated case reports in pediatrics. no genomic data has previously been published for any children with hgg who develop extraneural metastases. objectives: our objective is to describe the natural history of two children with hgg and bony extraneural metastases, comparing their clinical characteristics as well as whole exome sequencing data for both tumors. this information would suggest similar patients should be monitored closely for extraneural metastasis and may benefit from more systemic therapy. design/method: we present a case series of two patients who presented with hgg and had development of bony metastases less than six months after initial diagnosis. both patients had molecular profiling with whole exome sequencing (wes). the first patient was an 11-year-old male with a tumor found in the left lateral ventricle invading into the fornices, hypothalamus, and left midbrain, who had subtotal resection. bony metastasis were found at 3.5 months after diagnosis, and he died 9 months after diagnosis. he initially received radiation, followed by nivolimuab. the second was a 12-year-old female with a tectal/pineal tumor and multiple spinal cord metastases, who had subtotal resection. she developed bony metastasis at 5.5 months after diagnosis and died 13 months after diagnosis. her histologic diagnosis was pineoblastoma, revised to hgg after whole exome sequencing. she received craniospinal radiation followed by chemotherapy per acns0332 (cisplatin, vincristine, and cyclophosphamide) for 2 cycles. when she failed to respond satisfactorily to this therapy, wes of tumor was performed and the findings were consistent with hgg. treatment was transitioned to temodar and lomustine after hgg diagnosis was given. she had ongoing progressive disease despite this therapy as well as trials of nivolumab, everolimus, and vorinostat. neither patient had extraneural metastasis at presentation. in both tumors, whole exome sequencing identified the h3f3a k27m mutation. both tumors also had additional known mutations associated with hgg but no other overlapping mutations. this case series represents the first description of the genetic alterations of pediatric hgg patients who developed extraneural metastases. while h3f3a k27m is a common mutation in pediatric midline hgg, especially dipg, and is associated with more aggressive disease, there has not been an association with extraneural metastasis prior to this series. background: deferiprone-induced agranulocytosis is a well -known albeit rare side effect of the drug. incidence of agranulocytosis varies from 0.5-3.6%, while milder neutropenia is reported in 8.5% of patients treated with deferiprone. deferasirox is unknown to cause such a complication. clinical trials and post marketing side effect monitoring studied possible correlations between different risk factors and development of agranulocytosis. unfortunately, no studies directly addressed a special risk in a community with background of ethnic neutropenia, like oman. objectives: to report on the incidence of neutropenia among omani children with b thalassemia using different iron chelators design/method: a retrospective study conducted on patients < 21 year-old with b thalassemia treated with different iron chelators. electronic patients records were reviewed to detect episodes of neutropenia either mild (anc 1.0-<1.5/cmm), moderate (anc 0.5-<1), severe < 0.5, or agranulocytosis anc = 0). data were collected including sex, age, personal or family history of ethnic neutropenia, iron chelating agent, infective complications, management and outcome. detailed clinical, laboratory ± radiological information were reported for patients who developed life-threatening agranulocytosis. among 179 young patients with b thalassemia, treated between 2007-2017 in squh, neutropenia, was reported in 78 patients (43.6%).severe neutropenia was encountered on 14 occasions in 11 patients (11/179: 6.1%) (8 on deferiprone including 5 episodes of agranulocytosis, 1 on defersirox, 1 on combined chelation, and 5 off chelation). moderate neutropenia was encountered in 29 patients (29/179: 16.2%), on 36 occasions: deferiprone (15), deferasirox (8), combined chelation (4), and 9 episodes off chelation. mild neutropenia was more prevalent, encountered in 59 patients (32.9%) on 124 occasions (30 on deferiprone, 44 on defersirox, 19 on combined chelation, and 31 off chelation) of 85 patients exposed to deferiprone, 35 patients had neutropenia (41%), higher than previously reported. deferiproneinduced agranulocytosis was encountered in 4 patients (4/85 = 4.7%). three of them had life threatening complications. one patient developed pneumonia complicated by rupture of pulmonary artery aneurysm-massive hemoptysis, who recovered fully after catheter embolization. the second had facial cellulitis and treatment with gcsf was complicated by frequent ventricular extrasystoles. the third had sepsis, disseminated herpes simplex and required admission to icu for inotropic support. in a community with background ethnic neutropenia, neutropenia is more common to be encountered among thalassemic patients, both on and off chelation therapy. careful monitoring of anc and rational choice/modification of chelating agents is required for optimal management of iron overload and to avoid life threatening complications. objectives: this case control study aimed to evaluate the systolic and diastolic cardiac function in 2 groups of children with ti: non transfused group and a group that received early regular blood transfusion comparing them to healthy controls. design/method: thirteen regularly transfused patients with ti with a mean age of 11.8+5.6 years were compared with eight patients who are non-transfused or minimally transfused (< 3 rbcs transfusion/year); mean age 11.8+9.4 years and 18 healthy controls with a mean age of 8.8 ± 3.9 years. clinical parameters and standard echocardiographic and tissue doppler imaging (tdi) were compared. results: young non-transfused ti patients had a statistically significant higher peak late diastolic velocity of the left ventricular inflow doppler, a mitral valve a wave duration over the pulmonary vein a wave duration ratio and the pulmonary s81 of s301 vein s/d velocities ratio compared to the transfused group with p values of 0.028, 0.01, 0.01 respectively. in addition, they have a lower e/a ratio of the mitral valve inflow and a larger left atrial to aortic diameter ratio compared to the control group with p values of 0.025 and 0.01 respectively. the diameters of the right and left outflow tract were significantly larger in the non transfused group with a trend to have a higher cardiac index compare to the transfused group. systolic function was similar in the 3 studied groups and none of the patients had evidence of pulmonary hypertension. young patients with ti who are receiving early regular blood transfusion have normal systolic function. diastolic function assessment revealed indicators of an abnormal relaxation of the left ventricle in the non transfused group which indicate diastolic dysfunction. the abnormalities affected multiple diastolic function parameters which give an indication that the changes are clinically significant. a statistically significant increase in the diameters of the outflow tracts are likely attributed to high cardiac output status in nontransfused ti patients as they had a trend to have a higher cardiac index. these findings support the early commencing of regular blood transfusion therapy for ti patients to prevent serious cardiac complications in adult life. background: in the 52-week sustain study, crizanlizumab 5.0 mg/kg significantly reduced the frequency of scpcs versus placebo (1.6 vs 3.0, p = 0.01) and increased the time to first on-treatment scpc (4.1 vs 1.4 months, p = 0.001) in patients with sickle cell disease (scd). to evaluate time to first scpc in sustain study subgroups and the likelihood of not experiencing scpc for the duration of the trial using post hoc analyses. design/method: sustain was a randomized, double-blind, placebo-controlled, phase 2 study (nct01895361). inclusion criteria were: scd patients aged 16-65 years; 2-10 scpcs in previous 12 months; concomitant hydroxyurea use permitted if ≥6 months and stable dose for ≥3 months. patients were randomized 1:1:1 to receive intravenous crizanlizumab 5.0 mg/kg, 2.5 mg/kg, or placebo. study treatments were administered on days 1 and 15, then every 4 weeks to week 50, with the final assessment at week 52. median time to first scpc after first dose was summarized for crizanlizumab 5.0 mg/kg or placebo in these subgroups: 2-4 or 5-10 scpcs in previous 12 months; scd genotype; and hydroxyurea use at baseline. hazard ratios (hrs) for crizanlizumab 5.0 mg/kg versus placebo were calculated based on cox regression analysis, with treatment as a covariate. descriptive statistics were used to summarize the frequency of patients who were scpc event-free for the duration of the study by prior scpc events, scd genotype, and hydroxyurea use at baseline. : 67 patients received crizanlizumab 5.0 mg/kg and 65 received placebo. there was a meaningful delay in time to first scpc with crizanlizumab 5.0 mg/kg versus placebo observed in the entire study population. the effect was present in both scpc subgroups, and the largest treatment difference was observed in hbss scd versus other genotypes (4.1 vs 1.1 months; hr: 0.50). in patients taking hydroxyurea who experienced 2-10 scpcs in the previous year, time to first onstudy scpc was longer with crizanlizumab 5.0 mg/kg versus placebo (2.4 vs 1.2 months; hr: 0.58). a greater proportion of patients treated with crizanlizumab 5.0 mg/kg were scpc event-free versus placebo in each of the analyzed subgroups. one third of patients who were taking hydroxyurea and treated with crizanlizumab 5.0 mg/kg were scpc event-free during the study versus 17.5% with placebo, possibly suggesting an additive effect. with crizanlizumab 5.0 mg/kg, there was a clinically meaningful delay in time to first scpc and an increased likelihood of being scpc-free versus placebo in all subgroups investigated. cincinnati children's hospital medical center, cincinnati, ohio, united states background: shwachman-diamond syndrome (sds) is an inherited marrow failure syndrome associated with increased risk of myelodysplasia (mds) and acute myeloid leukemia (aml). objectives: this multi-institutional retrospective study investigated clinical features, treatment, and outcomes of 38 sds patients who developed mds or aml by central pathology review. design/method: nine individuals presented with aml (4 male, 5 female), 5 mds-eb1/2 (3 males, 2 females, 23 with mds (11 male and 12 female), and one male with isolated persistent somatic tp53 mutation. one mds-eb1 and 1 mds patient progressed to aml. median age (years) at diagnosis of mds was 16 (range 0.5-30), mds-eb1/2 was 9 (range 0.7-20) and aml was 28.8 (range 5.5-47). complex cytogenetics were noted in 10/11 aml cases, with one having normal cytogenetics. complex clonal cytogenetic abnormalities were noted in 4 of 5 mds-eb1/eb2 patients and clonal abnormalities in 17 of 18 mds patients. follow up was available for 10 aml patients; 9 are deceased. 9 received chemotherapy with intent to proceed to hematopoietic stem cell transplant (hsct). four failed to achieve remission and died with disease without proceeding to transplant. one patient proceeded to hsct without prior chemotherapy. four of six transplanted subjects died with relapsed disease. treatment related mortality was largely infectious or gvhd. the sole surviving aml patient had normal cytogenetics, achieved remission with chemotherapy and underwent hscts with 3 separate stem cell infusions due to two primary graft failures. he remains alive in remission more than 4 years after diagnosis. of the 5 mds-eb1/2 patients, 4 underwent ric hsct, three of whom are alive, one died of infection. the fifth patient has stable disease on continued decitabine monotherapy for 4.75 years. of 19 mds patients with treatment data, 13 had upfront hsct therapy, 2 upfront chemotherapy and 4 had no therapy. three patients required ≥2 hscts all due to graft failure. follow up is available for 18, 11 of whom are deceased, 6 with relapsed disease. treatment related mortality was largely infectious or graft failure. one individual died of hepatic failure unrelated to mds. seven mds patients are alive in remission. in summary, prognosis is poor for patients with sds who develop aml due to resistant disease and treatment-related complications. better markers for risk stratification are needed to identify patients who would benefit from early transplant. novel therapeutic strategies are urgently needed to improve outcomes of sds patients with mds or aml. background: unlike primary myelofibrosis (pmf) in adults, which is associated with somatic mutations in jak2, mpl, or calr, myelofibrosis in children is rare and the underlying genetic mechanisms remain elusive. here we describe 3 families with autosomal recessive congenital macrothrombocytopenia with focal myelofibrosis (cmtfm) due to germline mutations in the megakaryocyte-specific immune receptor tyrosine-based inhibitory motif (itim) receptor g6b-b. objectives: to characterize the clinical phenotype, histological features and identify the causative gene for cmtfm. we performed affymetrix snp 6.0 genotyping on the index family to identify shared regions of homozygosity by descent. whole exome sequencing (ws) was performed on all three pedigrees to identify potentially causative mutations. we studied 6 affected children from 3 families, with macrothrombocytopenia, anemia, mild leukocytosis and a distinctive pattern of bone marrow (bm) fibrosis centered around clusters of atypical megakaryocytes. affected children had mild to moderate bleeding symptoms and required platelet and red cell transfusions. none showed evidence of extramedullary hematopoiesis, and all were negative for mutations in jak2, mpl, and calr. snp genotyping identified multiple statistically non-significant genomic loci, including the region of the major histocompatibility locus (mhc) on chromosome 6p (lod = 2.01). we focused on this region because affected individuals in two families shared a common homozygous human leukocyte antigen (hla) type and had congenital adrenal hyperplasia (cah) due to 21-hydroxylase (cyp21a2) mutation; the cyp21a2 and hla loci are located at 6p21.33 and 6p21.32-6p22.1. wes revealed homozygous frameshift mutations in the megakaryocyte and platelet inhibitory receptor g6b-b, encoded within the candidate linkage region. we identified two distinct g6b-b frameshift mutations (c.61_61+1dup; p.20fs and c.147inst; p.49fs) in 7 individuals within these three families. no other mutations that segregated with the phenotype were identified. to validate g6b-b as a potential disease-causing gene, we evaluated g6b-b expression in bm biopsy specimens from affected patient and control samples by immunohistochemical staining using a monoclonal antibody. g6b-b was strongly s83 of s301 and selectively expressed in megakaryocytes of control samples, but completely absent in clinically affected individuals. a murine knockout that lacks g6b-b has a strikingly similar phenotype with macrothrombocytopenia, myelofibrosis and aberrant platelet production and function, further affirming the causality of g6b-b mutations. we showed that autosomal recessive loss-offunction mutations in g6b-b cause cmtfm, uncovering the molecular basis of this rare disease. loss of g6b-b-dependent inhibition of megakaryocyte activation likely underlies the distinctive focal myelofibrotic phenotype and might be important in other forms of marrow fibrosis. cardinal glennon, saint louis, missouri, united states background: intrauterine transfusion is the method of choice for management of fetal anemia due to red blood cell alloimmunization. despite the decrease in prevalence of anemia due to rhesus d alloimmunization with prophylactic administration of anti-rhd immunoglobulin in rh d negative patients, maternal red red blood cell alloimmunization with other type of red blood cell antigens remains an important cause of fetal anemia. newborn who received intrauterine transfusion for hemolytic disease may have prolonged postnatal transfusion requirement. objectives: 1-to evaluate clinical outcome of fetuses and newborns who received intrauterine transfusions. 2-to determine the need of packed red blood cell transfusions until 6 months of age. we conducted a retrospective case series study of all intrauterine transfusions due to anemia secondary to red blood cell alloimmunization performed in our regional center ssm in st louis missouri, between april 2011 and january 2016. we evaluated the indications, diagnosis, gestational age, and frequency of intrauterine transfusions, along with the infant's gestational age at birth, duration of admission, timing of blood transfusion and monitoring of hemoglobin. results: 37 intrauterine transfusions were performed in 14 patients. the most common causes of alloimmunization were due to d antibodies (n = 7, 50%) and kell antibodies (n = 5, 35.7%). the median gestational age of the first intrauterine transfusion was 28.1 weeks, and the median pre-transfusion hemoglobin was 8.9 g/dl. the gestational age at the first intrauterine transfusions was found to be significantly correlated with the number of postnatal transfusions (r = 0.8. p = 0.001). the median gestational age at birth was found to be 35 weeks (28.6-36.9 weeks), with a hemoglobin of 13.1 (10.8-14.1). in our population, 6 patients (42%) received postnatal transfusions, of which 4 were during the first 3 weeks of life, and close monitoring follow up with a hematologist was established in 6 patients at their discharge from the nursery/nicu. one neonatal death occurred and severe morbidity due to severe anemia occurred in one infant. despite the continuing risk factor for persistent anemia, only 8 patients had follow up hemoglobin monitored by their primary care provider. conclusion: infants with anemia due to red blood cell alloimmunization treated with intrauterine transfusion should be monitored closely via regular complete blood count for persistent anemia due to suppression of fetal erythropoiesis. sebastian hesse, piotr grabowski, juri rappsilber, christoph klein dr. von hauner childen's hospital, lmu university hospital, munich, munich, germany background: neutrophil granulocytes are the most abundant leukocytes in the peripheral blood. validated diagnostic options for these cells are limited, leaving many patients with functional neutrophil defects without a defined diagnosis. objectives: here we evaluate proteomics as a new diagnostic tool to investigate defects of neutrophil granulocytes. we analyzed neutrophil granulocytes from 6 children with severe congenital neutropenia (scn) associated with elane mutations, 4 children with chronic granulomatous disease (cgd) with cyba (2) or cybb (2) mutations and 2 children with leukocyte adhesion deficiency (lad) due to itgb2 mutations. in addition we collected samples of children with genetically undetermined neutrophil defects. neutrophils from 68 healthy individuals served as controls. cells were isolated from fresh venous blood using negative selection (purity >99%). whole cell proteome analysis was done by data-independent acquisition. showed a correlation coefficient of ∼0.9. principal component analysis demonstrated unequivocal separation of the proteome of healthy and diseased cells. differential expression analysis showed minimal proteome aberrations in lad with deficiency in cell surface receptors and upregulation of alpl (total downregulated proteins: 7/ total upregulated proteins: 5). analysis of neutrophils from cgd patients also showed limited proteome aberration. cyba and cybb were both diminished independent of genotype, whereas protein clusters around a stat1/2 centered network were increased (total down: 11/ up: 23). neutrophils with elane mutations showed the gravest proteome disturbance (total down: 47/ up: 93) with an upregulated translational apparatus (srpdependent ribosomes and protein folding complexes) and increased mitochondrial proteins. proteins of each granule subset were dysregulated and metabolic pathways upregulated. a detailed analysis of the proteome from patients with genetically undefined diseases is currently ongoing. one patient with clinical phenotype of cgd was found to have no mutations of nadph oxidase members in whole exome sequencing but critically low levels of ncf1 on protein level. heterozygosity mapping showed autozytocity in the ncf1 region warranting current efforts to sequence promoters and intronic regions of the gene. mass spectrometry based proteomics promises exciting new insights into monogenic disease of neutrophil granulocytes and may offer new diagnostic options, in particular in synergy with genome sequencing. by virtue of our international care-for-rare alliance, open to new partners, we hope that our proteome focus may lead to better delineation of as yet unknown disease of neutrophil granulocytes. background: warm autoimmune hemolytic anemia (aiha) is an igg mediated disease. although it can be post-viral, it is often idiopathic and can also be a forme fruste for malignancy or an autoimmune disease. initial management includes steroids. it often relapses on steroid wean and can be refractory to the use of second line treatment such as rituximab. objectives: abatacept (ctla-4-ig fusion protein, ctla-4 mimetic) has been used to ameliorate autoimmune manifestation associated with ctla-4 haploinsufficiency. we used abatacept as a novel therapeutic agent to manage patients with refractory aiha. design/method: a retrospective case series of two patients at phoenix children's hospital with severe refractory aiha. results: patient 1, a previously healthy 12 year old female, presented with 8 weeks of icterus, fatigue, and hemoglobinuria. spleen was enlarged 8cm below the costal margin. laboratory evaluation demonstrated: hemoglobin 3.8 g/dl, mild leukopenia 3200/microliter, platelets 99,000/microliter, reticulocytosis 14.3%, positive direct coombs' test, mycoplasma igm and igg positive. bone marrow evaluation showed a hypercellular marrow. she continued to need packed red blood cell (prbc) transfusions despite receiving high dose steroids, ivig and rituximab from may-july 2017. in august, she started sirolimus decreasing her transfusion requirement. after starting abatacept (10mg/kg/dose bi-monthly for three doses and then monthly) in october, she maintained hemoglobin of 9-10 g/dl without transfusion. patient 2, a previously healthy 2 month old male, presented with one week of progressive fatigue, jaundice, and poor feeding. splenomegaly was absent. laboratory evaluation revealed hemoglobin 3.8g/dl, leukocytosis 20,200/microliter, platelets 324,000/microliter, reticulocytosis 16.1%, negative direct coombs' test, and non-specific reactivity on antibody screen. evaluation for inherited hemolytic anemia including a next generation sequencing panel was negative. further evaluation by blood bank showed 2+ positive coombs' for c3d due to a warm antibody. cold agglutinin disease was ruled out. bone marrow evaluation was normal. he received high dose ivig as a steroid sparing agent but continued to require prbc transfusions weekly. when prednisone did not seem to slow down hemolysis, treatment with abatacept was initiated and he has not required transfusions for two months. steroids are being weaned. we present successful treatment of two refractory aiha cases with abatacept. patient 1 is steroid and transfusion free and continues on monthly abatacept and sirolimus. patient 2 is also transfusion free and continues on a steroid taper. ctla-4 is crucial for suppressive function of treg cells. abatacept by binding to cd80/86 seems to enhance treg activity ameliorating autoimmune hemolysis. children's minnesota, minneapolis, minnesota, united states s85 of s301 background: transfusional iron overload is common in patients receiving chronic red cell transfusions. as a result, iron chelation is required to minimize toxicity from iron overload. chelation with a single agent can be inadequate at controlling or reducing iron burden. when combination therapy is required deferoxamine may be added to oral chelation. deferoxamine is generally given subcutaneous over 8-12 hours for 5-6 days a week at 25-60mg/kg/day. many patients struggle to remain compliant with this schedule which has prompted trials of intravenous high-dose (hd) deferoxamine. prior reports of short-term hd deferoxamine have shown minimal side effects however, prolonged use of hd deferoxamine has known toxicity. when compliance is a concern, our center has used hd deferoxamine infusions at 15mg/kg/hr x 48hours every 2 to 4 weeks. objectives: evaluate the safety and efficacy of hd deferoxamine at our institution to help guide future therapy. design/method: a retrospective review was completed of patients previously treated with hd deferoxamine between april 2011 and september 2017 at children's minnesota. final sample included 8 patients ages 3 to 14 years with underlying diagnosis of thalassemia (7) and diamond-blackfan anemia (1). deferoxamine infusions were given for 48 hours every 24-35 days with a mean length of treatment of 279 days. results: all patients were on combination therapy with deferasirox, however deferasirox was held during deferoxamine infusion. mean pre-deferoxamine liver iron concentration (lic) was 31.75mg/g and mean post lic was 12.11mg/g (p = 0.0008). ferritin mean pre-deferoxamine was 2677ng/ml compared with mean post 1594ng/ml (p = 0.0107). two patients had possible allergy, leading to deferoxamine discontinuation. one patient developed hives, eye swelling and cough while the other had emesis and cough. another patient experienced facial nerve palsy of unclear etiology, which did not recur with resumption of deferoxamine. no respiratory complications were seen. results showed significant decrease in iron burden following combination therapy with high dose deferoxamine and deferasirox. no significant pulmonary, liver, renal, vision, or hearing toxicities were observed. three patients reported reactions to deferoxamine infusions. however, one of these was able to successfully continue deferoxamine without further incident. short-term, hd deferoxamine was effective at reducing lic in combination with oral chelation but requires further evaluation to assess for potential increased risk of toxicity. short-term hd deferoxamine may be considered in the setting of poor compliance of subcutaneous administration or inadequate chelation with single agent therapy. further studies are needed to clarify ideal dosing, timing and risk of toxicity. background: immune thrombocytopenia (itp) is the most common cause of symptomatic thrombocytopenia in childhood but remains a diagnosis of exclusion warranting further evaluation if atypical findings are present. two male children (15 months and 3 years old) with newly diagnosed immune thrombocytopenia (itp) were found on initial evaluation to have persistent elevations of lactate dehydrogenase (ldh), alanine aminotransferase (alt), and aspartate aminotransferase (ast). these serum enzyme abnormalities cannot be attributed to itp. in the setting of thrombocytopenia, elevated transaminases and ldh create diagnostic complexity for the hematology/oncology provider as their elevation raises concern for malignancy, hemolytic disease, and other systemic diseases. to raise awareness about an unexpected pattern of duchenne muscular dystrophy in patients undergoing evaluation for itp. to expand the differential of a hematologist/oncologist when abnormal labs support a nonhematologic diagnosis design/method: this case-series of two patients with their clinical and laboratory findings were discovered with retrospective chart review. results: after a thorough evaluation for hemolytic anemias, liver disease and infectious etiologies was negative, bone marrow and liver biopsies were considered. eventually, both children were found to have severely elevated serum creatine kinase (ck). skeletal muscle has the highest concentration of ck of any tissue. thus, significant ck elevation is almost exclusively attributable to muscle injury and is the most sensitive and specific enzyme for diagnosis of muscle disease. referral to a neuromuscular specialist and further genetic testing confirmed the diagnosis of duchenne muscular dystrophy in both children allowing initiation of appropriate interventions. to date, there is no clear genetic predisposition to itp in patients with muscular dystrophy although further investigation may be needed. hematology/oncology providers should consider obtaining a serum ck to rule out muscle disease in any male child with unexplained elevations of serum ldh and/or aminotransferases, as it provides an easy and inexpensive, non-invasive approach to screening. additionally, clinical history and physical examination can aid in the diagnosis of muscular dystrophy, with gross motor delay, abnormal muscle bulk, gower's sign, and proximal muscle weakness all possible findings. objectives: to identify the range of cbcs in patients with ds without infections, hematologic or immune disorders and to create more accurate reference ranges for total white blood count; hemoglobin; hematocrit; mcv; platelet count and absolute neutrophils (anc), lymphocytes, monocytes, eosinophils, and basophils. design/method: a retrospective investigation of healthy pediatric patients with ds who received a cbc between 2011 and 2017 as part of their medical care at a single, large, pediatric teaching hospital. the study group consisted of 562 children with ds (male = 310, 55.2%; mean age = 2.10 years, sd = 3.17) at time of blood draw. initially 692 children were reviewed for possible participation in the study; however, 130 patients were excluded due to not meeting the study's inclusion criteria. descriptive statistics were performed on demographic and clinical characteristics. kruskal-wallis h tests, anova, and t-tests were run to determine the significant associations between independent means. results: a significant difference in absolute neutrophils between racial groups, f(2, 183.553) = 3.990, p = 0.020, was observed. there was an increase in anc from 2.5 +/-1.1 with african americans to 3.0 +/-1.6 in the other racial groups and to 2.9 +/-2.0 with caucasians. differences were also found in anc in hispanics/latinos versus non-hispanic/latinos. the results were higher in non-hispanics and latinos, a significant difference of -.584 (95% ci, -.791 to -.376), t(1255) = 2.572, p = 0.001. preliminary kruskal-wallis h tests run determined that there were significant differences between age groups for total white blood cell, hemoglobin, hematocrit, platelets, lymphocytes and anc. further studies are being run to evaluate in which age groups these differences lie and create reference ranges by age, race and sex. conclusion: among patients with ds, there are differences between racial groups and age groups. this data has been compared to previously established reference ranges for cbcs, but we are currently establishing healthy cbc controls which we will use to validate the reference ranges. these ranges will be published to help guide providers in workup and management of patients with ds. background: transfusion is a critical part of the care provided in the neonatal intensive care unit, but it is not without risks. low birth weight and premature infants can become anaemic from an immature haematopoietic system and frequent phlebotomy. these infants often receive multiple red blood cell transfusions. identifying infants more likely to require such intervention is important in ensuring the appropriate usage of this scarce resource. to determine whether birth weight, gestational age, gender, length of stay and mode of delivery can predict red cell concentrate (rcc) transfusion, units required, donor exposure and time to exposure. design/method: a retrospective chart review of all infants born below 32 weeks gestation and/or birth weight less than 1,500g who received a red blood cell transfusion between july 2009 and july 2012 in the cork university maternity hospital neonatal unit. results: 224 infants met the inclusion criteria, 105 (46.87%) received a rcc transfusion. our study showed lower gestational age (p<0.01) and lower birth weight (p<0.01) infants are more likely to be transfused. donor exposure increases with a lower birth weight (p = 0.016). multivariate analysis showed infants with a lower gestational age (or -0.019 per day; p<0.05); lower birth weight (or -0.002 per 1g; p<0.01) and a longer length of stay (or 0.016 per day; p<0.05) are more likely to receive a higher number of rcc transfusions. the time to first rcc transfusion is shorter in those with lower birth weight (or 0.013 per 1g; p<0.05) and lower gestational age (or 0.356 per day; p<0.01). gender and mode of delivery were not found to be predictors of red blood cell transfusion in this study. conclusion: low birth weight and premature infants are more likely to receive a rcc transfusion during admission to the neonatal unit. our study highlights predictors of rcc transfusion, donor exposure and time to transfusion. these can be used in identifying at risk infants, counselling parents and in anticipating transfusion requirements. emily southard, r. grant rowe, david williams, akiko shimamura, taizo nakano children's hospital colorado, aurora, colorado, united states background: the mecom locus encodes transcription factors that regulate hematopoietic stem cell self-renewal and maintenance. overexpression of mecom has been noted in 5-10% of acute myeloid leukemia, several solid tumors, and denotes a poor prognosis. mutations that reduce mecom expression or that disrupt protein function, however, have been implicated in the development of bone marrow failure (bmf) through undefined pathways. an association between mecom mutations and radioulnar synostosis with amegakaryocytic thrombocytopenia (rusat) syndrome has been reported, however further characterization of this phenotype has yet to be explored. to characterize the phenotypic spectrum of a cohort of pediatric patients with novel mecom mutations. we performed a retrospective review of five patients with mecom mutations who were referred to hematology at children's hospital colorado or boston children's hospital. clinical, laboratory, and genetic data was collected on subjects and available family members. results: four of 5 subjects were identified in infancy presenting with congenital cytopenias or physical dysmorphisms that prompted broad genetic screening. platforms for genetic detection included microarray, targeted genetic panels, and whole exome sequencing. three of 4 subjects with cytopenias presented with congenital thrombocytopenia, 1 of whom rapidly progressed to severe aplastic anemia. four of 5 subjects presented with congenital anomalies, 3 of whom demonstrated radioulnar synostosis. additional dysmorphic features identified include craniofacial (low set ears x1), cardiac (pda x1, vsd x1, aortic root dilation x1), pulmonary (pulmonary hypertension x1, arteriovenous malformations x1), and developmental delay. one subject presented at age 13 years with acute pancytopenia, hypocellular marrow, no dysmorphisms, and a mecom variant of unknown signif-icance. the identified mecom mutations include one 4.1 mb deletion involving several genes including mecom, one variant affecting a splice acceptor consensus sequence predicted to disrupt splicing, and three novel missense mutations, tyr949cys, arg950thr, and tyr1118cys, all of which were absent from public databases and were predicted in silico to be deleterious. we describe the phenotypic spectrum of 5 patients with novel mecom variants. a subset of patients lacked radio-ulnar synostosis and had presence of additional systemic anomalies, demonstrating a varied clinical phenotype that is not isolated to rusat syndrome. a centralized publically accessible database to share clinically annotated mecom variants, together with analysis by experts in mecom function would advance our understanding of the clinical interpretation of mecom variants. mecom should be considered in the differential diagnosis of bone marrow failure and we advocate for the inclusion of mecom in targeted sequencing panels. cairo university, cairo, egypt background: beta thalassemia is regarded as a serious public health problem in the mediterranean region, southeast asia, and the middle east. however, very few studies have been conducted to assess the quality of life (qol) among thalassemia major patients. objectives: to assess the quality of life among b-thalassemia major patients using short form (sf)-36 questionnaire and to determine the factors associated with their quality of life. design/method: a cross-sectional study was conducted among thalassemia major patients who were attending the hematology outpatient clinic at cairo university hospital, during the study period. data were collected between october 2016 and march 2017. the quality of life was assessed for patients aged ≥17 years. the mean age of the studied group was 18.32± 1.33 years. the majority (93.63%) had one monthly blood transfusion. the mean total score of sf-36 was 44.90±7.54. general health perception domain was the most affected domain with mean score, while vitality was the least affected one. there was no statistically significant difference between males and females regarding different quality domains except for vitality where the mean score was significantly higher in males than females (p = 0.05). age at onset of disease, and at first blood transfusion were the most documented factors positively correlated with the quality of life among the enrolled thalassemia patients. conclusion: the quality of life in thalassemia major patient was found to be compromised. all thalassemia patients should undergo assessment of the quality of life so that interventions focusing on the affected domains can be implemented. background: international adoption of children with special needs has become more prevalent in recent years leading to tremendous growth in the number of u.s. thalassemia patients adopted from foreign countries. currently 13% of the 1,119 thalassemia patients registered in the cooley's anemia foundation (caf) patient database have been adopted from foreign countries, primarily china. as this population continues to grow, further information is needed in order to provide these families with best supportive care. the primary goal of this study is to characterize the socio-demographics and health statuses of adopted children with thalassemia and their families. a secondary goal is to describe adoptive families' motivations, experiences, challenges, and support resources. design/method: a redcap survey was accessed by families of adopted children with thalassemia through the caf website and caf social media from january to august 2017. following a four-question screen, eligible subjects were directed to complete an adoption questionnaire. families who had at least one adopted child with thalassemia receiving care at a participating thalassemia treatment center or hematology office in the u.s. were considered eligible. descriptive statistics were analyzed using sas 9.4. respondents who were ineligible or who provided incomplete data were removed from the dataset prior to analysis. of 78 survey respondents, 67 qualified and completed the survey. these households had adopted a total of 74 children with thalassemia (33.8% male), most from china (93.2%), where they had been living in orphanages (73.0%). legal guardians identified primarily as christian (87.3%). the majority had completed post-secondary education (76.9%) with reported household incomes greater than $80,000 (76.1%). most adoptive families were connected to an adoption group or community including online groups, local support groups, and adoption networks (98.5%). commonly cited challenges were: 1) volume of frequent medical appointments, 2) insufficient support from their local care centers, and 3) financial burdens. the reality of care for the population of adopted patients with thalassemia in the u.s does not seem to match the expectations set by their providers. we are hopeful this data will be used to assist adoptive families navigating the complexities of thalassemia care. the findings suggest that this population would benefit from additional outreach, education, guidance, and advocacy resources -especially in the early stages of adoption and during initiation of post-adoption medical care. background: in many higher-income countries, thalassemia major has become a chronic disorder; many outcomes are different in emerging countries with more limited resources. most analyzes of health-related quality of life (qofl) in thalassemia have been conducted in high-income settings. objectives: to assess the impact of health status on qofl in thalassemia patients in an emerging country. we assessed qofl in 110 randomly-selected patients (72 thalassemia major; 33 with hemoglobin e thalassemia; five thalassemia intermedia) at the national thalassemia center in kurunegala, sri lanka where approximately 800 patients are managed. treatment is free, but compared to north america/europe, access to tertiary staff and other resources are limited. overall, control of body iron as estimated by serum ferritin concentration (mean± sem, 2906±267 g/l) was not optimal in many patients. to understand the impact of health status on qofl, we used the sf36v2 health survey, analyzing scores of physical function, pain, general health, social functioning, emotional and mental health, to generate overall physical and mental component scores. results: compared to reports from higher-income countries (american journal of hematology 2011; 86:92-5), physical function scores (mean±sd, 48.16±10.72) were similar in sri lankan patients; indeed, in three categories (physical role, social function, emotional role), sri lankan scores were slightly higher. by contrast, compared to scores from higherincome settings, those estimating bodily pain, general health, and mental health were significantly lower, resulting overall in a significantly lower physical component score in sri lankan patients. male sri lankan patients reported higher scores than females, and somewhat surprisingly, in four categories (physical function, physical role, social function and emotional role) reported higher scores than those obtained in higher-income settings. lower scores in physical functioning, leading to an overall lower physical component score, were recorded by females. patients with hemoglobin e thalassemia reported generally poorer qofl than those with thalassemia major. the lack of differences in qofl in patients with "high" and "low" hemoglobins was likely related to low pre-transfusion hbs (mean±sem, 8.31 ± 0.14 g/dl) in nearly all patients. these early data in a small cohort of thalassemia patients in an emerging setting suggest that in many patients bodily pain, reduced mental health, and poorer views of general health affect overall qofl. prospective studies in larger cohorts including evaluation of adequacy of transfusions and chelation therapy, complications, and overall accessibility of care may guide approaches to improve qofl in lower-income settings of thalassemia care. geetanjali bora, anand prakash dubey, tarun sekhri, mammen puliyel, aparna roy maulana azad medical college, new delhi, delhi, india background: in the last two decades, the presence of osteopenia has been described in optimally treated patients with transfusion dependent thalassemia, the pathogenesis of which seems to differ from osteopenia in non-transfused patients. the prevalence rate of low bone mineral density (bmd) in pediatric population is highly variable amongst studies done worldwide. furthermore, the role of metabolic and endocrine factors in determining bone mass in this population is not well understood. objectives: to assess bmd in subjects with transfusion dependent beta thalassemia by dual-energy-x rayabsorptiometry and find its co-relation with clinical, biochemical and hematological parameters. design/method: this is a comparative cross-sectional study and includes patients with transfusion dependent beta thalassemia between ages 6 to 16 years enrolled from a thalassemia day care center in the year 2012 -2013. at the time of enrollment age, sex, bmi z scores, pubertal staging, duration and type of chelation therapy were noted. enrolled subjects were scanned for bmd at lumbar spine l2-3 and left femoral neck using dexa scan. the bmd was expressed in mean values and z scores. age, bmi, ethnicity and gender matched historic controls were used to generate z scores. 5 ml of pre transfusion fasting venous blood samples were obtained to test for serum calcium, phosphate, alkaline phosphatase, pth, thyroid function panel, serum ferritin and serum igf-1 levels. mean values for pretransfusion hemoglobin and serum ferritin over last 12 months were calculated. results: total no of subjects 50, median age 11.6 years, male 32 (64%), female 18 (36%), ethnicity 100 % asian, bmi < 3rd centile 13 (26%), pre pubertal 50%, all receiving transfusion and chelation therapy. prevalence of low (z score < -1 sd) and very low (< -2.5 sd) bmd was 74%, 52 % at l1-l2 respectively and 66 %, 24% at left femoral neck respectively. there was trend of lower bmd z scores with advancing age. statistically significant co-relation (p value < 0.05) was found between low bmd and low mean pretransfusion hemoglobin, serum phosphate, igf -1 and vitamin d levels conclusion: a sizable proportion of children and adolescents with transfusion dependent thalassemia have suboptimal bone mineral density and this decline may start as early as 6-7 years of age despite being on transfusion regimen highlighting the importance of yearly dexa screening and optimization of pre-transfusion hemoglobin, vitamin d and igf 1 levels. vanderbilt university medical center, nashville, tennessee, united states background: it is well described that iron deficiency anemia (ida) can co-present with thrombocytosis or thrombocytopenia, though cases of thrombocytopenia are less frequent than thrombocytosis. prior reports of thrombocytopenia have included adult and pediatric patients with menorrhagia (1-2), menorrhagia due to uterine fibroids (3), or other gynecologic abnormalities (4). our cases highlight the pattern of ida, thrombocytopenia, and menorrhagia in the setting of significant menstrual clotting without observed gynecologic abnormalities in african-american adolescents. objectives: to describe the clinical course of three adolescent females with severe ida, menorrhagia, and thrombocytopenia. results: our cases included three female african-american patients ages 12-17 who presented with severe anemia and concurrent thrombocytopenia in the setting of menorrhagia. all three patients reported heavy and prolonged menstrual cycle bleeding with significant clots. two of the three were admitted for transfusions at presentation and noted to have significant menstrual bleeding with continued blood loss requiring additional transfusions until bleeding was controlled with estrogen therapy. these two patients were evaluated with pelvic ultrasounds revealing a prominent endometrium in both patients and hyperechoic material consistent with a clot in one patient. average hemoglobin on presentation was 4.3 gm/dl (2.8-6.5), average platelet count was 70,000/mcl (18,000-99,000), and average mcv was 63 (54-68). all had severe iron deficiency with an average ferritin of 4 ng/ml (2-7) subsequently treated with oral iron. one patient had a prior history of ida that required transfusion and had subsequent normalization of her complete blood count. two patients had subsequent thrombocytosis before normalization of their platelet counts. two patients received platelet transfusions: one due to recent neurosurgical intervention with a higher goal platelet count and the other to help control menstrual bleeding after a nadir platelet count of 9,000. a review of the clinical history and red cell indices pointed to ida and ongoing blood loss from menorrhagia as the reason for the bicytopenias. the thrombocytopenia in these cases may have been exacerbated by consumption of platelets in the significant clots all three patients reported. it is reasonable to treat with iron supplementation and supportive care which may include transfusions or management of menorrhagia with oral contraceptives or other hormonal methods. background: sickle cell disease is one of the most common inherited red blood cell disorders, yet many are not aware of their carrier status. the american college of obstetricians and gynecologists' guidelines recommend that pregnant women of african, mediterranean and southeast asian descent be screened for hemoglobinopathies with a cbc and hemoglobin electrophoresis1. however, adherence to this practice and frequency of improper screening with sickledex is unknown. proper screening and counseling can impact families' knowledge, allowing for establishing relationships with pediatric hematology providers earlier. objectives: we sought to assess prenatal hemoglobinopathy screening practice patterns and methods of obstetrics & gynecology (obgyn) and family medicine providers in the nyc regional area. design/method: a cross-sectional electronic survey was administered to obgyn and family medicine practitioners from four nyc institutions. questions focused on prenatal hemoglobinopathy screening practices using case scenarios with variations on parental trait status and ethnicities. chisquare analyses were used to compare the two provider groups on categorical variables. there were 98 total responses; 71 surveys were complete, of which 48 were obgyn and 23 family medicine providers. respondents were mainly from academic medical centers, with the majority being faculty (68% of the obgyns and 41% of family medicine). no significant difference was found in frequencies of screening patients with a positive family history of a hemoglobinopathy. when asked about screening practices for patients without a personal/family history of a hemoglobinopathy, 92% of obgyns versus 70% of family medicine providers "always" screened for hemoglobinpathies (p = 0.03). when analyzed by ethnic background, there were significant differences by group in screening patients of white (92% vs 70%), black (94% vs 74%), mediterranean (94% vs 74%), and asian descent (94% vs 70%) (p≤0.05 for all). however, in cases where the hemoglobinopathy carrier status of both parents was known, there was no difference in screening with a hemoglobin electrophoresis. furthermore, >20% of all respondents use sickledex for screening in the case scenarios. conclusion: this pilot survey highlights a difference in the methods and likelihood of prenatal hemoglobinopathy screening based on the type of prenatal care provider. screening differences can lead to variations in prenatal guidance, diagnostic procedures, informed decision-making and knowledge of families referred to pediatric hematology clinics. this is the first study analyzing prenatal screening for hemoglobinopathies in obgyn and family medicine. improving prenatal screening practices by collaborating with hematologists may decrease health care disparities and allow for earlier relationship building with pediatric hematology. 1. acog, opinion#691, 2017 poster # 220 hermansky-pudlak syndrome: spectrum in oman background: hermansky-pudlak syndrome (hps) is a rare autosomal recessive disorder, characterized by the triad of oculocutaneous albinism, a hemorrhagic diathesis resulting from storage pool-deficient platelets, and accumulation of ceroid/lipofuscin-like material in various tissues. before 2016, nine different types of hermansky-pudlak syndrome were identified, which can be distinguished by their signs and symptoms and underlying genetic cause. in 2016, a tenth type was defined based on mutations in the ap3d1 gene. hps type 2 is characterized in addition by severe neutropenia and recurrent sinopulmonary infection. the disease is more common in puerto rico, and this is the first report from oman. to describe the clinical, laboratory and genetic characteristics of hps sub-types in oman, including the first 2 cases of hps type 2. design/method: this is a retrospective study, including 7 cases with hps that had been suspected clinically and confirmed through genetic mutation analysis. clinical data included sex, age at presentation, initial clinical presentation (skin, eyes, development, neurological involvement, bleeding tendency, recurrent infections) and course of disease. laboratory data (complete blood counts, platelet and absolute neutrophil counts, coagulation screening, platelet function tests by platelet function analyzer, and platelet aggregation studies using different agonist had been recorded. pcr and next generation sequencing for genetic confirmation by testing mutations in hps1, ap3b1, hps3, hps4, hps5, hps6, dtnbp1,, bloc1s3, bloc1s6 genes had been done. results: seven omani cases with hps have been identified (4 males and 3 females). their age ranged between 0 (at birth) to 10 years. two patients had hps type 2, 1 patient had type 6, while the other 4 cases had hps type 3. no other sub-types were encountered in oman. all patients were products of consanguineous marriage. one patient had adrenal hge, while the others had mild hemorrhagic phenotype, characterized by recurrent bruising and mild epistaxis. laboratory testing confirmed variable platelet aggregation defects with different platelet agonists. all patients had characteristic hypopigmentation, iris transillumination, nystagmus, and foveal hypoplasia. both patients with hps type 2 had the same homozygous mutation in the ap3b1 gene (c.12_13delta), and presented with severe neutropenia. early diagnosis and initiation of gcsf on one of them improved outcome and prevented the development of complications. late diagnosis in the other patient resulted in the development of bronchiectasis as a result of recurrent sinopulmonary infections. background: sickle cell disease (scd), a genetic disorder characterized by defective sickle hemoglobin (hbs), triggers red blood cell sickling, hemolysis, vaso-occlusion, and inflammation. ischemic injury from scd starts in infancy and accumulates over a lifetime, causing pain, fatigue, and progressive end-organ damage that culminates in early mortality. voxelotor (gbt440) is an oral, once-daily therapy that modulates hemoglobin's oxygen affinity, thereby inhibiting hemoglobin polymerization. objectives: to assess the safety, pharmacokinetics, and efficacy of voxelotor in pediatric patients with scd. design/method: this ongoing study is being conducted in 2 parts: part a: a single dose of voxelotor 600 mg in pediatric and adolescent patients; part b: multiple doses of voxelotor 900 mg/d or 1500 mg/d for 24 weeks in adolescents. part b's primary objective is to assess the effect of voxelotor on modifying anemia. secondary objectives include measuring other markers of disease modification, such as hemolysis; daily scd symptoms, using a patient-reported outcome (pro) measure; and safety. results: as of november 6, 2017, 24 patients (10 females) had received voxelotor 900 mg and 12 patients (6 females) had received voxelotor for ≥16 weeks. the median age for the 12 patients was 13 years, 92% were receiving hydroxyurea (hu), and 41% had ≥1 painful crises in the past year. data for hemolysis measures are available for 11 patients who received voxelotor for 16 weeks. six of the 11 patients achieved a hemoglobin (hb) response of >1 g/dl increase. laboratory markers of hemolysis improved concordantly; the median reductions in reticulocytes and indirect bilirubin were 11% and 40%, respectively. ten of 12 patients showed reduction in total symptom scores (tss) at week 16, with a 94% median reduction in tss from baseline. there were no treatmentrelated serious adverse events (aes) or drug discontinuations due to aes. voxelotor 900 mg for 16 weeks in adolescents with scd, the majority receiving hu, demonstrated consistent, sustained efficacy on hb levels and measures of hemolysis; >50% of patients showed a >1 g/dl improvement in hb. improvement in tss in mildly symptomatic patients suggests that the pro is sensitive to treatment effect and supports use in the ongoing hope phase 3 study. voxelotor's reassuring safety profile is consistent with results in adults. these interim results support ongoing clinical evaluation of voxelotor as a potential disease-modifying therapy for adults and children with scd. supported by global blood therapeutics. background: acute kidney injury (aki) is a common complication in sickle cell disease (scd), and a potential risk factor for sickle nephropathy. aki is associated with acute decline in hemoglobin (hb) during vaso-occlusive pain crisis and acute chest syndrome (acs). it is unclear which pathologic factor plays a stronger role in aki development during hb drop: increase in free heme during vaso-occlusive events secondary to hemolysis or hb decline itself. objectives: to investigate if hb decline alone is associated with aki, we tested if the renal function of patients with scd worsened during parvovirus b19-induced transient aplastic crisis (tac), in the absence of accentuated hemolysis. design/method: with irb approval, a retrospective study of patients who had laboratory confirmed parvovirus-b19 was conducted. serum creatinine (scr), both during and within 12 months from the tac event, was collected. comparisons of the clinical and laboratory characteristics were analyzed using the wilcoxon test for continuous variables. aki was defined as an increase in scr by ≥0.3 mg/dl or a 50% increase in scr from baseline. to evaluate differences in change in hb on aki risk, changes in scr during tac were compared to those during pain crisis or acs admissions by fitting a generalized linear mixed model for binary outcome. a comparative sample of 149 acs events and 197 vaso-occlusive pain crisis were used to estimate rates of aki according to hb levels. results: three (9%) of the 34 patients with scd developed aki during tac. no association was identified between change in hb from baseline to tac event (p = 0.08). no cases of aki were identified until hb decreased <5.0 g/dl or the change in hb was ≥4.5 g/dl from baseline. next, we developed a model to evaluate the impact of change in hb from baseline for patients admitted with tac, pain crisis or acs on aki. with a 2 g/dl decrease in admission hb from baseline, patients with tac had a 3% probability of developing aki, while acute chest syndrome and pain crisis would have a 9% and 27% probability, respectively. our data suggest that aki is still prevalent during parvovirus b19-induced tac. however, the risk of aki during a tac event is 3 and 9 times lower than that from severe anemia induced by acute chest syndrome and vasoocclusive pain events, respectively. hemolysis-induced anemia during scd crisis appears to have a more significant role in the development of aki as compared to agenerative anemia. background: the natural history of hemoglobin e beta thalassemia (hbethal), the commonest form of severe beta thalassemia worldwide, has been examined in very few longterm studies. previously, we reported findings in 109 hbethal patients in sri lanka.1 objectives: to evaluate longterm requirements for transfusion and splenectomy, complications and death in hbethal patients. design/method: all available patients were reviewed 1-4 times annually over 12 years. results: 33 patients (30%) died, aged (mean ± sem) 29.3 ± 4.2 years; the (known) causes commonly included iron overload (9) and infection (12); 76 patients surviving patients are aged 33.4 ± 1.2 years. of 109 patients originally classified by severity (group 1 the mildest, and group 5 the most severe, phenotypes), 62 (57%) were assessed as mild (groups 1 and 2), of whom transfusions had been discontinued in 46. ultimately, 23/46 (50%) resumed transfusions, often following shifts to increasingly severe phenotypes including increasing intolerance to anemia. age at resumption of transfusions (following a transfusion-free interval of 14.9 ± 1.6 years) was 32.8 ± 2.7 years; in the more severe groups 4 and 5, regular transfusions were stopped in 27/33 patients and resumed in 22/27 (81%), at younger ages (19.9±1.8 years) and after shorter transfusion-free periods (10.1±1.4 years) than in "milder" patients. mid-parental height (mph) was ultimately achieved in 53%. 84 patients (77%) were splenectomized; updated analysis of responses to splenectomy (originally "group 3" patients), showed that splenectomy (at 9.0 ± 0.9 years) was followed by an extended, but impermanent, transfusion-free interval (11.1 ± 1.4 years); 50% patients resumed transfusions, usually related to exercise intolerance or poor growth. in groups 1 and 2, complications of anemia and ineffective erythropoiesis, including leg ulcers (in 38% and 50%) and gallstones (44% and 54%), were more frequent than in groups 4 and 5; fractures were observed (25-48%) across all groups, except for regularly-transfused group 5 patients (0%). pulmonary artery pressures >30 mm were recorded in 39% patients. evaluation of patients with hbethal requires observations over years, without which definition of patients as "mild" or "severe" may be misleading. while in many patients transfusions may be withheld or reduced in frequency, troublesome complications may surface with advancing age even in "milder" patients. although individual consideration of transfusion requirements is critical, the availability of effective chelation, where this can be provided without prohibitive cost, may alter the balance of risks and benefits of regular transfusions in hbethal. 1(premawardhena a. lancet 2005). background: social determinants of health (sdh) are environmental and socioeconomic factors, such as access to food and housing that affect health outcomes. pediatricians are increasingly screening for sdh as part of primary care visits, however less is known about screening for sdh in pediatric hematology. evidence suggests that sdh play a role in disease severity for children with scd, who face significant socio-economic and racial disparities. the goal of our quality improvement (qi) project was to increase the percentage of patients with scd who were connected to community resources for unmet social needs. design/method: we based our intervention on the successful implementation of wecare in our institution's pediatric primary care clinic. eligible patients were identified at the start of each clinic session. on arrival the parent was given a self-reported screening tool for six sdh (childcare, education, employment, food, utilities and housing). results were entered in the electronic health record by the physician or social worker who then printed a pre-existing resource list for patients with a positive screen. we used a series of plan-do-study-act (pdsa) cycles to study tests of change. we tracked process measures (percentage of patients screened, percentage of patients with an unmet social need who received a resource sheet), outcome measures (percentage of patients with an unmet social need who connected with a community resource) and balancing measures (staff, patient and provider satisfaction). run charts were reviewed weekly and then monthly to inform further tests of change. examples of pdsa cycles include who gave the paper survey to patients (social worker or physician versus medical assistant) and length of time between surveys (3 to 6 months). results: between august and december 2017 screening rates improved from 57% to 88%. of the patients screened, 67% report at least one unmet social need; of those 33% received a targeted list of community resources in the first month of the project, and 92% in the fifth month. finally, 44% of patients reached by phone had connected with a community resource within 2 weeks of the clinic visit. we have successfully implemented universal screening for sdh for patients with scd in our urban pediatric hematology clinic without requiring extra staff. next steps include further pdsa cycles to connect more patients to appropriate resources, and tracking improvement in health care utilization outcomes from addressing sdh in this vulnerable patient population. background: the clinical manifestations of sickle cell disease (scd), chronic hemolytic anemia, and vaso-occlusion occur as a direct result of sickle hemoglobin (hbs) polymerization. voxelotor (gbt440) is a first-in-class, oral, oncedaily investigational agent designed to modulate hemoglobin's oxygen affinity in a targeted approach to inhibit hbs polymerization. objectives: to examine the pharmacokinetics (pk), safety, and dosing of voxelotor in children (aged 6-11 years) and adolescents (aged 12-17 years) with scd from part a of the gbt440-007 study. design/method: gbt440-007 is an ongoing, open-label, phase 2a study in patients aged 6-17 years with scd (sickle cell anemia or sickle beta zero thalassemia). part a of this study (the focus of this abstract) is examining pk of singledose (600 mg) voxelotor. pk samples to measure whole blood and plasma voxelotor concentrations were collected up to 15 days following single-dose administration. separate population pk (ppk) models were developed to describe the concentration versus time profiles of voxelotor in whole blood and plasma using nonlinear mixed effects modeling (non-mem, version 7.3). ppk modeling and physiologically based pk (pbpk) modeling were used to simulate voxelotor pk parameters and support dose selection for future evaluation in younger children. : part a included 7 adolescents (4 females; median age 16 years [range 14-16]) and 6 children (3 females; median age 8.5 years [range 6-10]). mean weight was 52.8 kg (range 45-66 kg) and 21.1 kg (range 16-38 kg) in adolescents and children, respectively. voxelotor was well tolerated with no drugrelated grade ≥3 adverse events (ae) or serious aes. a 2compartment model with first-order absorption best described the pk of voxelotor (and was the same model structure used for adults with scd). voxelotor pk exposures in adolescents were comparable to those observed in adults, but higher exposures were observed in children. ppk and pbpk modeling support the use of a weight-based dosing strategy in younger children (aged <12 years) in future trials. adult voxelotor doses can be used in adolescents. however, based on higher pk exposures, a lower weight-based dosing strategy is recommended in children. ppk and pbpk modeling provides an innovative approach to minimize experimental dosing in children and accelerate dose selection of voxelotor in ongoing and future clinical studies. this abstract is supported by global blood therapeutics. background: hydroxyurea (hu) reduces rates of acute complications, and improves long term outcomes in patients with sickle cell disease (scd) and is now fda approved for children. through previous work we have increased the number of eligible patients on hu in our clinic, however accessing a compounding pharmacy remained a significant barrier to hu adherence for infants and children who cannot swallow capsules. objectives: the objective of our quality improvement project was to improve adherence to hu among pediatric patients with scd at our urban safety net hospital by addressing barriers to obtaining liquid hu. design/method: to begin we met with the leadership of our outpatient pharmacy which offers mail order delivery. however, like most retail pharmacies, they do not have the necessary protective equipment to compound liquid hu. through a series of discussions, we began a unique partnership with our institution's inpatient chemotherapy pharmacy who compounds the liquid hu and delivers it to the outpatient s95 of s301 pharmacy, who then dispenses liquid hu to families. using a series of plan-do-study-act (pdsa) cycles we tracked adherence by calculating the medication possession ratio (mpr), defined as the percentage of days in a given period of time that each patient had their medication on hand. the mpr for liquid hu mpr among enrolled patients was tracked by pharmacy staff and reviewed monthly. additional pdsa cycles included adding automatic refills and reminder calls by pharmacy staff and improving communication about delivery. we also tracked patient satisfaction. results: between march 2016 and december 2017, a total of thirty pediatric patients were enrolled in our program for on-site compounding and free mail order delivery of liquid hu. mpr for liquid hu is currently 93.8% among enrolled patients, significantly higher than the mpr of 60% reported in the literature, and has risen steadily since the beginning of the project. families are highly satisfied with the program, specifically appreciating the convenience of mail order delivery, saving on delivery fees, and reminder calls when refills were due. by compounding and dispensing liquid hu directly from our institution's outpatient pharmacy we have significantly improved adherence to this hu therapy in our high-risk population. next steps include analysis of change in clinical outcomes for patients enrolled in this program. as adherence to hydroxyurea is associated with decreased acute care utilization and cost, programs such as ours could play a crucial role in reducing the excessive costs and ed utilization among this patient population. background: experience with the iron-chelator deferasirox is reported widely in higher-income settings. by contrast, real-life experiences in emerging countries are infrequently reported. objectives: to evaluate, in a non-trial setting, the real-life response to deferasirox in an emerging country. design/method: in sri lanka's national thalassemia center which manages 800 patients without tertiary staff, quantitative evaluations of body iron or estimates of extra-hepatic iron, the records of 328 patients who began deferasirox in 2010/11 were retrospectively reviewed. results: baseline assessments (mean±sem) indicated substantial iron loading [serum ferritin (sf) 4,529±125 ug/l; serum alt 111±3.5 u/l (normal ≤ 40 u/l)]. deferasirox was introduced at low doses (21.2 ± 0.3 mg/kg/day); many patients started at <20 mg/kg and, after 12 months, doses remained ≤30 mg/kg/day in 60% patients. after 24 months, sf in 50% patients remained >2,500 ug/l; only by 48 months had (mean) sf declined to <2,500 ug/l (2475±344; p<0.001). similarly, mean alt normalized (to 35 ± 5 u/l) only by 60 months. death and complications were not systematically recorded by staff who had been charged, without provision of additional resources, with the introduction of this new drug in hundreds of patients. these results contrast to those in sri lanka's tertiary thalassemia center where, in 107 patients following the introduction of deferasirox 32 ± 0.1mg/kg/day, sf declined rapidly, even in relatively less ironloaded patients (from 3,231±278 to 2,153±218 g/l after 24 months; p = 0.0002). these findings underscore the importance, during the implementation of new drug regimens in lowerincome centers with marginal resources, for investments in methods to quantitate body iron burden, hands-on educational initiatives to guide day-to-day management by competent but non-expert staff, and data systems to record efficacy, effectiveness, toxicity and compliance. such investment is critical to optimising therapy and improving complications in thalassemia patients worldwide: even in sri lanka, where resources directed to thalassemia management are greater than in most of asia, results in the oldest living cohort (born 1980-1990) indicate under-treatment [elevated iron burdens (sf 3,565±323 ug/l) and high prevalences of diabetes (27%) and hypothyroidism (29%)]. even in a younger cohort (born 1990-2000) which has benefitted from improved treatments, the prevalence of many complications exceeds those reported from high-income settings. over the next decade, and two decades after the 2006 who declaration that the impact of thalassemia on global mortality and morbidity is underrecognized, increased investments by governmental and nongovernmental sources will be necessary to improve outcomes for asian patients with thalassemia. background: a major barrier to success in hydroxyurea (hu) treatment of patients with sickle cell disease (scd) is non-adherence. objectives: to optimize hu adherence in patients with scd. design/method: a care model was designed by the sickle cell (qi) team at children's hospital to improve hu adherence among scd patients. the original model included bimonthly family phone contact, monthly dispensing pharmacy phone contact and lab monitoring. adherence measures included obtaining hu from pharmacy monthly, completion of monthly labs, hb f percentage and mcv, and mtd achievement. from 6/2016 -6/2017, several pdsa cycles refined our care model. a one-year follow-up survey gathered feedback on the care model. the first-year data involved ∼ 30 patients. the biggest improvements resulted from making pharmacy calls before patient/family calls, shipping liquid hu to outlying patients, and tracking call time/content. the qi goal was 75 % hu adherence by 12/2017. the 33% baseline adherence rate increased to 80% by 12/2016, and has remained in that range. the completion rate of patient/parent phone calls increased from 33% the first month to 77% at six months. pharmacy prescription pick-up has increased from 50 % to 77% per month. lack of liquid hu availability was overcome by shipping the medication to the patient's home. parental hesitance to share information by phone, especially with qi team members with whom they had no established relationship, was overcome by having the longtime sickle cell nurse do many of the early calls. however, survey feedback showed families became comfortable with several clinic personnel calling. the calls gave families the opportunity to ask questions about their child and/or get additional information about scd. the calls also provided an opportunity for seasonal flu shot or tcd testing reminders. the surveys gave information on the optimal time of day to reach each family, providing individualization and further increasing the percentage of completed calls. two families surveyed said they no longer needed two calls a month because they were now able to remember to pick up hu, administer it, and get labs on their own. this qi project has not only improved hu adherence, but also fostered health education/counseling, increased patient/parent satisfaction, and enhanced service utilization. medical team member and patient/family comments demonstrate that it has helped build relationships and trust between families and the medical care system. based on survey feedback, we will further individualize care to increase adherence rate and sustain improvements. cincinnati children's hospital medical center, cincinnati, ohio, united states background: the thalassemias are a heterogeneous group of genetic blood disorders caused by mutations that decrease or eliminate the synthesis of the -and/or -globin subunits of hemoglobin. the phenotype of thalassemia depends on the interaction of the -and -globin gene clusters, because both loci determine the -/ -chain balance. for example, a -thalassemia phenotype can be more severe than expected when coinherited with -globin gene triplication (copy number gain), which exacerbates the -/ -globin imbalance. objectives: describe four individuals with an incorrect diagnosis of -thalassemia trait who were later properly diagnosed by comprehensive genetic testing to have -thalassemia intermedia caused by heterozygous -thalassemia mutations coinherited with triplicated -globin loci. design/method: sequence analysis of the -globin (hba1/hba2) and -globin (hbb) genes, and copy number variation analysis of the -and -globin gene clusters by multiplex ligand-dependent probe amplification. results: four unrelated individuals of northern european ancestry were evaluated for signs and symptoms not explained by a diagnosis of -thalassemia trait (previously made by a pediatric hematologist), including growth delay, splenomegaly, moderate anemia, marked elevation of hemoglobin f, thalassemic facies, reticulocytosis, and/or indirect hyperbilirubinemia. genetic testing revealed that all were heterozygous ( / 0) for the same, single -globin mutation [hbb.c.118c>t (p.q40*)] and also heterozygous for an -globin triplication ( / anti-3.7). their previous diagnoses of thalassemia trait had been made by complete blood counts, hemoglobin electrophoresis, and/or sequence analysis of the -globin genes only. these individuals' phenotypes ranged from moderate anemia only to multiple stigmata of thalassemia, demonstrating the phenotypic variation of a thalassemia genotype. correct diagnosis was made at an average age of 8.9 years. a trial of chronic transfusions was initiated for one patient for growth failure. all were educated about the potential for exacerbations of anemia, gallstones, osteoporosis, and iron overload (even without transfusions). parental genetic testing was recommended to assess reproductive risk, because inheritance of this complex genotype can be apparently autosomal dominant. conclusion: heterozygosity for a -thalassemia mutation does not necessarily indicate -thalassemia minor or "trait". when coinherited with -globin gene triplication, a symptomatic form of -thalassemia can occur. correct and timely diagnosis of thalassemia requires careful consideration of the degree of anemia and examination for organomegaly, bony changes, and jaundice. sequence analysis and copy number variation analysis of both the -and -globin gene clusters is key. hematologists need to be aware of this diagnostic possibility and how to test for it to prevent inaccurate or delayed diagnosis. background: the burden of healthcare costs for sickle cell disease (scd) is nationally estimated at over $488 billion. the major components of these costs are inpatient and emergency center (ec) visits, many of which are potentially avoidable. in several chronic conditions, a subset of patients account for most of the avoidable encounters. identifying these patients is the first step in targeted care delivery. objectives: to measure and analyze scd patient utilization patterns in the ec and inpatient at texas children's hospital (tch). we identified all individuals under 21 years old with any encounter at tch associated with an international classification of disease (icd)-9 or 10 code for scd, including hgb ss, hgb sc, and hgb s/beta thalassemia. for each patient, we identified all inpatient and ec encounters in the 365 days prior to their most recent encounter. finally, each encounter was classified as associated with pain, acute chest syndrome (acs), or "other" using an algorithm of discharge diagnosis codes and pharmaceutical delivery. the total number of scd-associated ec and inpatient encounters over the prior year was calculated for each patient. we stratified each patient according to their utilization patterns: low (0-1 encounters), intermediate (2-3 encounters), and high (≥4 encounters). we identified 952 unique patients with scd that had at least one encounter from july 2016 until june 2017. there were 1,100 scd-related encounters in the 365 days prior to their most recent encounter. most (74%, n = 701) patients exhibited low-utilization patterns and 18% (n = 174) were intermediate. finally, a small subset (8%, n = 77) demonstrated high-utilization patterns and accounted for 41% of all encounters. high-utilization was associated with older age and public payment mechanisms. pain encounters were predominantly in pre-adolescents and teenagers with high-and intermediate-utilization patterns. acs was most frequent in pre-teens and younger teens in the intermediate-utilization group. finally, the youngest-aged high and intermediate users presented for other reasons such as febrile episodes and splenic sequestration. our findings reflect national trends in that a significant portion of encounters are attributed to a small subset of patients exhibiting a high-or "super-" utilization pattern. at our institution, scd super-utilization is associated with older age and pain. we also identified a group of infants and toddlers with frequent encounters for fever. to comprehensively address this burden, it will be important to design interventions targeted toward age and specific medical needs. background: background: the rarity of diamond blackfan anemia (dba) has hindered describing the spectrum of disease, identifying predictive correlations, and guiding datadriven recommendations. long-term toxicities from steroid or transfusion therapy that start in childhood remain the major clinical problems in patients with dba who do not receive stem cell transplant. objectives: objective: to define the dba patient population at st. jude children's research hospital including treatment responses and toxicities to help inform recommendations on treatment and monitoring. design/method: method: medical records were reviewed for all patients with dba treated at st. jude between 1997 and 2017 for diagnostic testing, treatment types and regimens, and outcomes. two-sample t-test or wilcoxon rank sum test was used to compare continuous variables in two groups depending on the normality of the data tested by shapiro-wilk test. results: a total of 22 patients with dba were identified with a median age of 8.29 years (range 3 months -35 years) at last follow up. a ribosomal protein gene mutation was identified in 15/22 patients (68%) with an rps19 mutation 8/22 (36%). thirteen different congenital malformations were described in 9/22 patients (41%). fourteen of twenty (70%) patients treated with corticosteroids had an initial response and 3 of those achieved full remission. three patients became steroid-refractory and 2 were unable to wean to an acceptable dose. five of twenty patients continue on lower-dose steroids. five patients currently require no therapy. univariate analysis revealed no statistically significant genetic predictors of response or remission, however, 3/3 rpl11 patients responded to steroids with 2/3 (66%) in long-term remission. ten patients are maintained on chronic transfusions and 2 have undergone successful hematopoietic stem cell transplant. nineteen of 20 treated patients (95%) had a treatment-related toxicity. patients on steroids were more likely to have short stature than patients on transfusions or in remission (p = 0.005). severe bone mineral density deficit occurred in 4/20 (20%) patients, in 2 before age 7 years. eight patients had hepatic iron overload, in one documented by age 2 years. other severe toxicities included restrictive cardiomyopathy from iron overload, pathologic fracture, diabetes mellitus, and premature ovarian failure in one patient each. this genotypically and phenotypically heterogeneous dba cohort had a high rate of treatment-related toxicities, notably growth retardation, bone density loss, and hepatic iron overload even in very young children. these findings underscore the need for early standardized monitoring. background: patients with sickle cell disease (scd) face worsening morbidity and mortality between ages 18 and 30, when they must transition from pediatric to adult healthcare.(1) an effective curriculum addressing disease knowledge, educational and vocational skills, self-efficacy, and social supports is critical to a successful transition. traditional didactic approaches have not led to durable knowledge retention. (2) technology-based methods have been attempted, but the best educational approach remains unknown. objectives: 1. to understand how adolescent and young adult (aya) patients with scd view existing transition education. 2. to include patient preferences in improving our transition curriculum. we developed a qualitative survey to assess patient views of existing approaches for learning about scd and their opinions about preferred transition topics. thirty patients with scd aged 12 to 24 years old were recruited between january and december 2017. responses were managed using redcap electronic data tools hosted at the university of rochester.(3,4) qualitative and quantitative data analyses were performed, including independent t-testing to compare responses between age groups. results: approximately 68% of subjects were under 18 years of age, while 32% were 18 or older. seventy-one percent had a computer, and 93.5% had a cell phone, with most reporting daily use. subjects reported greatest satisfaction with learning from their doctor during clinic visits (83.9% agree or strongly agree) and websites on a cell phone (77.4% agree or strongly agree); the least popular methods were online chat rooms and microsoft® powerpoint presentations. satisfaction was similar across age groups. recommended transition topics were viewed positively, with subjects ranking highest understanding their bloodwork (87.1% agree or strongly agree) and understanding laws protecting students with chronic disease (93.6% agree or strongly agree). older subjects (18-24 years old) agreed more strongly with learning about opioid addiction and understanding differences between adult and pediatric doctors than did younger subjects (12-17 years old) (p < 0.05). this pilot study was successful in helping us to understand the educational needs of aya patients with scd. preliminary data underscore the importance of education provided by the pediatric hematologist. our results also suggest that the optimal use of technology-based methods requires further investigation and that tailoring transition education by age group may be useful. background: similar to patients with transfusion-dependent beta-thalassemias (tdt-beta), survivors of hemoglobin barts hydrops fetalis (homozygous alpha-0-thalassemia, tdtalpha) will require lifelong transfusions of erythrocytes. we have previously shown that a transfusion strategy that is based on the guidelines developed for tdt-beta (conventional transfusion) is suboptimal for these patients owing to the differences in the pathophysiology of anemia in the two conditions: in tdt-alpha, conventional transfusion strategy will lead to a gradual increase in non-functional hbh with subsequent tissue hypoxia and hemolysis. an aggressive transfusion strategy that was based on reduction of hbh and increase in "functional" hemoglobin level resulted in improvement of tissue oxygenation and reduction of hemolysis but was associated with significant increase in transfusional iron burden [amid et al, blood 2016] . objectives: to define the optimal chronic blood transfusion targets for hbh% and functional hemoglobin in patients with tdt-alpha. design/method: following research ethics board approval, longitudinal data of 6 patients with tdt-alpha (2 males, median age 11.5 (2.1-18.0) were retrospectively collected. variables of interest included total pre-transfusion hemoglobin, hbh%, and "functional" hemoglobin [measured as total hemoglobin x (1-hbh/100)]. outcome variables were lactate dehydrogenase (ldh, marker of hemolysis), and soluble transferrin receptor (str, marker of erythropoiesis). hemoglobin analysis was done using high-performance liquid chromatography and capillary zone electrophoresis. we examined the association of "functional" hemoglobin with str, and hbh% with ldh, using repeated-measures anova to adjust for the effect of multiple testing. we constructed receiver operating characteristic curve and calculated the area under the curve to define the best cut-off values for variables of interests. there was a strong association between functional hb and str, as well as hbh and ldh. the optimal cut-off for "functional" hemoglobin that was associated with str <2.0 mg/l was 98 g/l (auc = 0.94, sensitivity and specificity of 82.76% and 100% respectively). the optimal cut-off for hbh to supress ldh to <1000 u/l was 18% (auc = 0.94, sensitivity and specificity of 87.5% and 87% respectively). the optimal pre-transfusion hbh% for reduction of hemolysis was 18% and the optimal "functional" hemoglobin to adequately supress erythropoiesis was 98 g/l. to meet these hbh% and functional hb targets by simple blood transfusions, patients with tdt-alpha would require a hypertransfusion regimen with a minimum pre-transfusion total hb of 116 g/l and consequently high transfusional iron burden. an alternative approach using exchange transfusion to reduce hbh% and improve functional hemoglobin would be associated with less volume of transfusion and potentially better long-term outcome. hospital sacre coeur, milot, haiti background: initial results of work developing a pediatric sickle cell disease (scd) clinic at the hôpital sacré coeur (hsc) in milot, northern haiti were presented at aspho 2017. the purpose of this clinic is for a pediatrician with a special interest in scd to provide scd care, advising on trait and managing disease with penicillin prophylaxis (pcn) and hydroxyurea therapy (hu) for select patients. this clinic was started in collaboration with a us based hematologist and support from yale-new haven hospital. objectives: to describe the success and challenges of providing pcn and hu in the scd clinic at hsc through a review of patient records. design/method: since this clinic's inception, a database of patients, with basic clinical information has been kept and made accessible, through 'drop-box', to the us hematologist. the records of those that presented to the clinic were reviewed. the hemoglobin diagnosis was made either by clinical history and sickle cell prep or by hemoglobin electrophoresis through alpha laboratory, port-au-prince, haiti. results: ninety-nine individuals were seen in the first 2 years of the program. fifty-six underwent a hemoglobin electrophoresis. of these 99, 49 are ≤ 6 years old. thirty-two were started on pcn vk, of which 10/32 (31%) were ≤ 3 years old. eleven patients were started hu therapy. all patients on hu have shown progressive increases in hemoglobin. there have been no clinical complications of hu therapy. none of the patients taking hu have required hospitalization or transfusion in 2017. three patients (not on hu) were hospitalized in 2017 for complications of scd (osteomyelitis, pain). in 2016, with less than half the numbers in the program, there were 7 admissions for severe anemia, pain, stroke and splenic sequestration. with ongoing external support and a local reputation for excellence in sickle cell care, the clinic at hsc has been able to expand services and improve the health of a growing number of patients with scd. early data suggests that pcn and hu therapies are helping to reduce complications and improve quality of life. challenges to date have included lack of funding for transportation to clinics, for hospitalizations and to cover the cost of electrophoreses. at the same time as continuing providing excellent care and gathering data, it is crucial to explore opportunities for collaboration and cooperation in ways that will assure that the clinic can become independently sustainable while continuing to improve the quality of life for the individuals it serves. background: ykl-40 is an inflammatory glycoprotein expressed by infiltrating macrophages in various inflammatory conditions. it has been found to be elevated in patients with different pathological conditions like acute and chronic inflammations, increased remodeling of the extracellular matrix (ecm), development of fibrosis and cancer. several studies have found elevated ykl-40 concentrations in sera of patients with liver diseases such as hepatic fibrosis by hepatitis c virus. it has been suggested that ykl-40 concentrations reflect the degree of liver fibrosis. to evaluate serum ykl-40 levels in patients with -thalassemia and its relation to viral hepatitis, liver stiffness as assessed by transient elastography (fibroscan, fs) and hepatic iron concentration. design/method: a prospective study included 100 patients with -tm (43 males and 57 females) with mean age 13.8 ± 2.7 years (range: 5-18 years). serum ferritin level, liver enzymes (alt and ast), hbs ag, anti hcv ab and serum ykl-40 using elisa kit were evaluated. all patients were subjected to liver mri t2* to detect liver iron content by the sequence and transient elastography (fibroscan, fs) to assess degree of liver stiffness. results: mean fibroscan value was (10.99±11.5) kpa with a median 6.7 (range 1.3 to 47) kpa. 64 (64%) patients were categorized as f0-1 and 17 (17%) were stage f2-3, 19 (19%) patients had severe fibrosis. their median serum ferritin was 3100 ng∖ml, with 61 (61%) patients had values exceeding 2500 g/l. median cardiac t2* was 24.2 with 30 patients had values below 20 ms, and the median lic was 16.21 mg/g dw with 68 patients showed readings above 7 mg/g dw. nyl-40 was evaluated as a marker of inflammation and liver fibrosis and showed mean value 1505.1 (±960.9) pg/ml, and range from 500 to 3529 pg/ml. mean ykl-40 was significantly higher among males (p = 0.03), patients on chelation therapy (p = 0.002), patients on dfs (p≤0.001), in those with abnormal liver enzymes, splenectomised patients, patients with hbv sero-positivity, those with moderate elevation of t2* and patients with high grades of liver fibrosis (p<0.05). ykl-40 showed positive correlation with the rate of transfusion, lic, ferritin, alt and ast but negative correlation with weight, height and t2*. roc curve analysis revealed that the cutoff value of ykl-40 at 1500 pg/ml could differentiate -tm patients with and without viral hepatitis with 86.7% sensitivity and specificity of 91.4%, area under the curve (auc) 0.933, positive predictive value 81.2 and negative predictive value 94.1 (p<0.001). roc curve analysis revealed that the cutoff value of ykl-40 at 1600 pg/ml could detect -tm patients with liver cirrhosis with 93.4% sensitivity and specificity of 97.1%, area under the curve (auc) 0.972, positive predictive value 93.7 and negative predictive value 97.1 (p<0.001). conclusion: serum ykl-40 levels are elevated in patients with -thalassemia and can detect patients with active viral hepatitis and liver stiffness. background: the most common splenic complication in pediatric patients with sickle cell disease (scd) is acute splenic sequestration (ass), which has often been managed with splenectomy. although splenectomy has been a treatment of choice for years, long-term vascular complications have not been thoroughly evaluated. pulmonary hypertension (phtn) is a severe complication of scd. in adults with scd, phtn has been associated with a 40-month mortality rate of approximately 40%. it has been reported that splenectomized patients with hemolytic disorders are at even greater risk of phtn. several medications exist to treat phtn, but with few studies of their efficacy or toxicities in patients with scd. additionally, these patients are often treated with either chronic prbc transfusions or hydroxyurea (hu) to raise hemoglobin, reduce hemolysis, and prevent vaso-occlusive events. objectives: to evaluate effect of chronic prbc or hu vs. no intervention, on tricuspid regurgitant jet velocities (trv) in pediatric patients with scd and history of splenectomy. design/method: retrospective chart review of splenectomized patients with hbss followed at marian anderson center at st. christopher's hospital for children, philadelphia, between 1999 and 2017. we analyzed 73 trvs (16 hu, 40 prbc, and 17 from control group receiving neither treatment) from 35 patients (10 hu, 13 prbc, 12 neither). mean age at echo was 13.31 +/-5.1. data was analyzed with linear correlations and analysis of variance (anova), including the post hoc test of least significant difference (lsd) for all pairs of treatment groups. results: trv was not significantly correlated with age at time of assessment or with time between splenectomy and trv. univariate anova among groups yielded trv means of: 214.0 +/-36.0 cm/s (hu), 231.3 +/-28.1 (prbc), 231.3 +/-25.4 (neither). we found a notable difference as the mean of the hu group was almost 18 cm/s lower than the others, but no overall statistically significant association for any of the groups exists. however, when we performed post hoc tests to adjust for multiple comparisons and looked at all 3 pairings within the anova, we found that the lsd between the hu and the prbc groups was statistically significant (p = .051), and that a trend exists between the hu group and the neither treatment group (p = .095). our data suggests that treatment with hu is correlated with a reduction in trv in pediatric patients with scd who underwent splenectomy. given these promising results, we believe our data warrants further study with larger treatment groups. nancy olivieri, gaurav sharma, susmita nath, rajib de, tuphan kanti dolai, prakas kumar mandal, abhijit phukan, amir sabouhanian, robert yamashita, angela allen, david weatherall, prantar chakrabarti background: hemoglobin e thalassemia (hbethal), which accounts for 50% of all severe beta thalassemia worldwide, has an estimated prevalence of 1.4/10,000 in west bengal, from which little information about clinical findings has been reported. objectives: to document clinical and laboratory findings in patients with hbethal, ultimately to improve resources for clinical management. design/method: we reviewed records from: a database recording patient names; clinic charts; "special" charts containing additional details; and, in transfused patients, transfusion day-care records. additionally, because in india's public hospitals original lab/imaging reports are commonly retained at home, 20% of families were interviewed to provide additional information. we excluded records of patients aged <5 years and patients aged <30 years who had not been reviewed since 2014. results: while at least one visit had been recorded in 1,398 hbethal patients at nrs hospital, most patients are not regularly reviewed there. we examined 219 charts [84 (38%) aged ≥30 years; 135 (62%) aged 5-29 years; 61% male], representing approximately 70% of regularly-reviewed patients. most families (84.9%) reported monthly incomes (<5,000 indian rupees), below the monthly cost of living (70,000 rupees) in kolkata. mean (±sem) hemoglobin was 6.9±1.1 g/dl. 43% patients were receiving eight or more transfusions per year; from 2013, 40% had been treated with deferasirox, 26.5±8.5 mg/kg/day. iron control estimated by serum ferritin concentration (1357.2±1187 g/l) was highly variable. a total of 24% patients were splenectomized. a substantial obstacle to documenting complications was the lack of recording, in any of the five sources, of many relevant parameters: for example, the status of sexual maturation (normal, delayed, or absent) was documented in less than 60%, and measurements of fasting blood glucose in less than 50%, of records. where recorded, complication rates were high: delayed/abnormal sexual maturation was recorded in 15% patients aged >30 years; in the patients aged >30 years and those aged 5-29 years, respectively, hypothyroidism was recorded in 31% and 44%, and elevated serum alt in 30% and 35%. in most evaluable patients >30 years, height was measured between the 3rd-10th percentiles. cardiac findings, rarely documented, included pulmonary hypertension and reduced left ventricular ejection fractions in a few patients. despite dedicated attention to many aspects of thalassemia care, insufficient documentation limited a clear understanding of the current morbidity in hbethal patients. investment in personnel and technology will be critical to record relevant information, ultimately to improve clinical management, over the next decade. children's hospital of richmond at vcu health, richmond, virginia, united states background: sepsis is a common cause of death in children with sickle cell disease (scd). recommendations for care of fever in children with scd include immediate medical evaluation including blood culture and initiation of broad-spectrum antibiotic therapy. the increasing availability of pcr-based respiratory pathogen panels (rpp) provide the opportunity to rapidly identify viral causes of fever. the role for rpps in identifying the source of fever in children with scd and how it affects provider practice is not well studied. (1) to determine the epidemiology of respiratory virus-associated fever in children with scd and (2) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all children with scd seen in our emergency department (ed) with temperature ≥38.3oc at home or in the ed from january 1, 2016, through september 30, 2017, as well as, all febrile children for whom rpps were sent since the introduction of rpps april 2014. we reviewed the results of blood cultures, rpps, chest radiographs, and ed notes and discharge summaries to identify sources of infections. independent t test and chi-square analysis were used as appropriate to compare results using spss©. overall, the rate of bacteremia was 1%. there were no cases of bacteremia among children with positive rpps. 4% of children with negative rpps had true bacteremia. a positive rpp did not reduce the likelihood of bacteremia (p 0.11). patients with bacteremia had higher presenting temperatures than those without bacteremia (39.5oc vs 37.9oc, p 0.017). the most common rpp findings were rhinovirus/enterovirus (38%), human metapneumovirus (13%), and influenza a (10%). sending an rpp did not affect admission rate (29% and 26% respectively, p 0.70); however, likelihood of admission was lower in patients with positive rpps (21% vs 49%, or 0.27 [0.13-0.56], p 0.004). length of stay (los) was shorter in patients for whom an rpp was not sent (3.1 vs 4.5 days, p 0.036). as previously reported, bacteremia in febrile children with scd is very low, but remains a serious concern, particularly in the setting of high fever (>39oc). a positive rpp did not reduce the odds of bacteremia, but did have a sta-tistically significant impact on both admission rate and los. more work is needed to understand how rpp results impact provider decision-making and care for children with scd. cincinnati children's hospital medical center, cincinnati, ohio, united states background: diffuse myocardial fibrosis is a common, if not defining, feature of the heart in sickle cell anemia (sca) that is strongly associated with diastolic dysfunction. we found diffuse myocardial fibrosis in every patient in a sca cohort (n = 25) ranging in age from 6 to 61 years (niss 2017). the treatment and prevention of this complication of sca has not been studied before. objectives: because diffuse myocardial fibrosis must begin in early childhood, we hypothesized that early initiation and uninterrupted use of disease-modifying therapy for sca can prevent it. design/method: we use cardiac magnetic resonance imaging (cmr) to measure the myocardial extracellular volume fraction (ecv) to quantify diffuse myocardial fibrosis in individuals with sca who have been treated, uninterrupted, with hydroxyurea or chronic transfusion therapy since ≤4 years of age. two comparison groups were used: individuals with sca who have not been treated with disease-modifying therapy since ≤4 years of age (n = 25) and controls without sca (n = 16). results: we studied 7 individuals (3m/4f) with a mean age of 13.4 years (range 7 -24). mean age at the start of diseasemodifying therapy was 2.5 ± 0.4 years (range 1-4). only 1 had evidence of mild diffuse myocardial fibrosis (ecv 0.339); the other 6 had no detectable diffuse fibrosis (all had ecv <0.304, the upper limit of normal). mean ecv was 0.283 ± 0.012, which was significantly lower than the ecv of individuals with sca who have not received early uninterrupted therapy (0.441 ± 0.016; p = 0.009) and not statistically different from normal controls (0.257 ± 0.004; p = 0.898). none had macroscopic fibrosis by late gadolinium enhancement or evidence of myocardial hemosiderosis by t2* imaging. no patient had diastolic dysfunction by echocardiographic classification, right heart catheterization, or both. disease-modifying therapy for sca can prevent diffuse myocardial fibrosis, and possibly diastolic dysfunction, if started in early childhood. prospective trials of disease-modifying and anti-fibrotic therapy are planned to prevent diffuse myocardial fibrosis, which can be monitored noninvasively by cmr, and improve outcomes in sca. (niss, blood, 2017) . background: a statewide sickle cell surveillance system (sscss) was developed with the goal of determining the prevalence of sickle cell disease (scd) in indiana and the level of care that patients receive throughout the state. persons with scd are at high risk of infection, especially with encapsulated organisms, as well as at increased complications from influenza. utilizing sscss data, the relationship between vaccination status and mortality was explored. to determine if vaccination status is associated with mortality in persons with scd. the project was granted a waiver of consent by the st. vincent irb. death certificates were obtained to identify cause of death. deceased patients (cases) were matched by age, gender, and sickle genotype to living patients (controls). vaccination data were collected from the medical record and the children and hoosier immunization registry program (chirp) through the date of death for each case. cases and controls were assigned a point for completion of the pneumococcus, meningococcus and haemophilus influenza type b (hib) vaccine series and one point if the influenza vaccine was given within a year prior to death of the cases [max vaccine status score (vss): 4]. total points were compared between the cases and controls. two tailed t-tests to compare means of continuous data and wilcoxon signed-rank test to compare ordinal data. one thousand forty-eight individuals were included in the sscss. six hundred and seven (48.6%) were seen at one institution and included in this analysis (mean age = 21 years). thirty-three of the 607 (5.4%) were deceased at the time of analysis. six point one (6.1)% of controls and 12.1% of cases received a vss of 4. the mean vss for cases was 0.7±1.3 and 0.6±1.1 for controls. thirty point three (30.3) % of controls had a vss of one or more, compared to 27% of cases (p = 0.41). patients who died of infection [streptococ-cus (n = 1), pseudomonas (n = 1) and unidentified organisms (n = 4)] were not up to date on vaccination against encapsulated organisms, but two had received the influenza vaccine in the year prior to death. in this sample, mortality occurred exclusively among adult patients, which is consistent with current patterns in developed countries. among these adults, vss and mortality rates were not related. limitations to the study include small sample size and potential incompleteness of vaccine records. vaccination rates and other standard of care indicators should be explored in a larger cohort of patients to determine associations with mortality. background: sickle cell disease (scd) is a genetic disorder resulting in acute and chronic complications, including delayed puberty. delayed puberty can have adverse physical and psychosocial effects on affected children and families. there are no published reports from ghana on pubertal timing in children with scd. the aim of this cross-sectional study was to describe pubertal changes in children with scd at korle bu teaching hospital (kbth), accra, and compare these findings to those in a control group without scd. design/method: 178 children with scd and 174 children with hb aa, ages 8-19 years, were consecutively recruited and matched for age, sex and socioeconomic status. investigator-administered questionnaires were used to obtain demographic data for all participants and information on menarche (girls only). pubertal status was assessed by physical examination using tanner staging. testicular volumes were determined in boys using a prader orchidometer. body mass index (bmi) and socioeconomic status (ses) of participants were analyzed to determine if there were any associations with tanner stage. of the 178 with scd, 133 (74.7%) were hb ss and 45 (25.3%) hb sc. females comprised 51.1% (cases and controls). mean age at onset of breast development was significantly delayed in girls with scd (13.1 ± 1.9 years) compared to controls (10.8 ± 1.9 years) but there was no significant age difference at onset of pubic hair development. mean age at menarche was significantly delayed in girls with hb ss (14.0 ± 1.8 years) and hb sc (13.5 ± 1.5 years), compared to those with hb aa (12.5 ± 1.3 years). in boys, the mean ages at onset of puberty were significantly delayed in those with scd (13.6 ± 2.7 years, for genital development and 15.1 ± 2.2 years, for pubic hair development), compared to those without scd (11.3 ± 1.9 years and 11.4 ± 1.9 years, respectively). mean testicular volumes were significantly lower in cases compared to controls, across all age ranges (p<0.001). mean bmi in both cases and controls were similar at onset of breast development in girls. however, in boys with and without scd, mean bmi values were significantly different at pubertal onset. in univariate analysis, ses was not associated with tanner stage for both genital and breast development. mean ages at pubertal onset were significantly delayed in children with scd. longitudinal studies are needed to further characterize any associations with bmi and determine potentially modifiable risk factors affecting pubertal onset in scd. background: sickle-cell disease (scd) is a life-threatening genetic disorder associated with multiple chronic and acute complications. specific monitoring and treatment for children is a major part of the medical focus, but there remains a lack of real-world evidence of the disease burden and practice patterns among the pediatric scd population. objectives: to examine the clinical burden and management of scd among pediatric patients. design/method: a retrospective claims study was conducted using the medicaid analytic extracts database from 01jan2009-31dec2013. pediatric patients (aged <18 years) with scd were identified using icd-9-cm diagnosis codes (282.41-282.42, 282.60-282.69 ). the first observed scd diagnosis during the identification period was designated as the index date. patients were required to have continuous medical and pharmacy benefits for at least 6 months pre-and 12 months post-index period. patient data were assessed until the earliest occurrence of the following events: disenrollment, death, or the end of the study period. patient demographic and baseline clinical characteristics, clinical outcomes (mortality, incidence of pain crisis, complications), scd management, and healthcare utilization were examined. all variables were analyzed descriptively. results: a total of 12,388 patients met the study inclusion criteria, with a mean age of 7.7 years. most patients were black (59.9%) and had a charlson comorbidity index score of 0 (80.9%). mortality during follow-up was 0.1 in 100 personyears, and the event rate of pain crisis in the inpatient setting was 54.0 in 100 person-years. the three most common complications after pain crisis (highest rates in 100 person-years) were fever (31.9), infectious and parasitic diseases (27.7), and asthma (14.5). rates of life-threatening complications were also examined in 100 person-years, including acute chest syndrome (7.0), stroke (1.8), splenic sequestration (1.1), pulmonary hypertension (0.3), and pulmonary embolism (0.1). 83.9% of patients were prescribed antibiotics during the one-year post-index period. other frequent medications utilized among children were folic acid (39.2%), nonsteroidal anti-inflammatory drugs (37.4%), opioids (11.2%), and hydroxyurea (11.5%). 16.0% of patients had a blood transfusion within one year post-index date. patients had frequent health care utilizations in the inpatient (1 visit), emergency room (2 visits), office (7 visits), and pharmacy (11 visits) settings during the one-year follow-up period. pediatric scd patients are burdened with a high rate of complications including pain crisis. in addition, patients utilized a substantial amount of health care resources including outpatient office care and acute care visits. background: novel use of hydroxyurea in an african region with malaria (noharm, nct01976416) is a randomized controlled trial of hydroxyurea for very young children with sickle cell anemia living in uganda. during year 1, study participants received blinded study treatment of hydroxyurea or placebo; those receiving hydroxyurea had no increased risk of malaria, but had both laboratory and clinical benefits. during year 2, all study participants received openlabel hydroxyurea treatment. to assess the effects of open-label hydroxyurea treatment in a very young population of children with sickle s105 of s301 cell anemia living in uganda. study endpoints included the rates and severity of malaria infections, clinical sickle-related events, and laboratory effects. design/method: all children in the noharm trial were enrolled at mulago hospital sickle cell clinic in kampala uganda. during year 2, all children received open-label fixeddose hydroxyurea (20 mg/kg/day) for 12 months, after previously receiving either hydroxyurea or placebo for 12 months. results: a total of 198 children entered year 2 of the noharm trial and received fixed-dose hydroxyurea, including 107 males and 91 females, at an average age of 3.3 ± 0.9 years. among 99 children previously on placebo, there were 6 malaria events in 6 children, including 3 with severity grade ≥3, and three deaths (two acute chest syndrome, one sepsis). clinical adverse event rates dropped from 3.0 to 1.6 per patient year, and hospitalizations were reduced from 35 to 7. expected hematological benefits of increased hemoglobin, mcv, and fetal hemoglobin, along with decreased neutrophils and reticulocytes, were rapidly achieved. laboratory adverse events were infrequent at 0.2 events per patient-year, and only half of those were dose-limiting hematological toxicities. among 99 children previously on hydroxyurea, there were 7 malaria events in 5 children, including 2 with severity grade ≥3, and two deaths (one acute chest syndrome, one sepsis). clinical adverse event rates and hospitalizations were maintained at low rates, the hematological benefits of hydroxyurea continued throughout the extended treatment period, and dose-limiting toxicities remained infrequent. fixed-dose hydroxyurea treatment of young children with sickle cell anemia living in uganda is associated with no increased risk for malaria. clinical and laboratory benefits occur, including children previously on placebo who crossed-over to hydroxyurea treatment. future studies should focus on the optimal dosing and monitoring strategies, in an effort to determine the overall feasibility and safety of introducing hydroxyurea therapy across sub-saharan africa. background: acute chest syndrome (acs) is the second most common cause of hospitalization in patients with sickle cell disease and is a leading cause of morbidity and mortality. in mid-2009, an algorithm was implemented at cohen children's medical center to initiate transfusions within four hours of diagnosis of acs in order to improve patient outcomes. objectives: the aim of this project was to analyze the effect of early blood transfusion on the outcomes of patients with acs. we focused on the number of total transfusions, need for exchange transfusion, need for intensive care unit (icu) stay, and length of hospitalization. design/method: a retrospective chart review was completed on patients admitted to ccmc with a primary diagnosis of sickle cell disease and a secondary diagnosis of either acs or pneumonia during the years of 2006-2012. data from the three years directly prior to implementation of the algorithm was compared to data from the three years directly after implementation of the algorithm. a total of 118 patients were analyzed, of which 45 belonged to the pre-algorithm group and 73 to the postalgorithm group. patients from the post-algorithm group had a higher incidence of transfusions (78% with a mean transfusion number of 1.49 pre versus 86% with a mean of 1.83 post) as well as exchange transfusion (17% pre versus 27% post). the post-algorithm group had a shorter overall length of stay (mean of 6.0 days pre versus 5.0 days post). while the overall percentage of patients requiring an icu admission was similar in each group (27% pre versus 29% post), the post-protocol group had a lower likelihood of requiring an icu admission for reasons outside of line placement for exchange transfusion, most commonly for icu-level respiratory support (13% pre versus 4% post). despite a higher total number of transfusions, early recognition and transfusion for acs can lead to decreased lengths of hospitalization as well as decreased need for icu-level respiratory support. further studies comparing different center's clinical practice guidelines are necessary to improve the standard of care. background: novel use of hydroxyurea in an african region with malaria (noharm) was the first placebocontrolled randomized clinical trial of hydroxyurea in sub-saharan africa. in noharm, young children with sca received either hydroxyurea or placebo during year 1, followed by open-label hydroxyurea for all study participants during year 2. an ancillary noharm project was designed to determine if hydroxyurea treatment lowers transcranial doppler (tcd) velocities and possibly reduces stroke risk in this very young cohort. objectives: to perform tcd screening on the noharm cohort, measuring the time-averaged mean velocity (tamv) at the end of both year 1 and year 2. we hypothesized that the maximum tamv would be lower for noharm study participants receiving hydroxyurea compared to those receiving placebo, and that key clinical and laboratory parameters would also influence tcd velocities. design/method: all children enrolled in noharm were eligible to undergo tcd examination at two study time points: month 10-12 when they were completing the blinded treatment phase, and again at month 22-24 at the end of the open-label treatment phase. tcd measurements included tamv readings from the main intracranial arteries: middle cerebral artery, distal internal carotid artery, and bifurcation on tcd. all tcd examinations were scored and classified as normal (less than 170 cm/sec), conditional (170-199 cm/sec) or abnormal (greater than or equal to 200 cm/sec), with higher scores correlating to greater risk of stroke. results: at the end of year 1, 185 tcd exams were conducted of which 164 were suitable for analysis (81 hydroxyurea, 83 placebo). based on the maximum tamv, the median velocity was 138 cm/sec (iqr 120 -159) for children on hydroxyurea and 150 cm/sec (iqr 134 -168) on placebo, p = 0.0509. maximum tamv values had negative correlations with hemoglobin concentration (-0.47), fetal hemoglobin (-0.32), and oxygen saturation (-0.27); positive correlations were noted with age (0.27) and absolute neutrophil count (0.27). at the end of year 2, 187 tcd exams were conducted and all were suitable for analysis; the median velocity was 137 cm/sec on open-label hydroxyurea treatment, regardless of previous blinded treatment. all correlations with tamv were maintained except for age. conclusion: compared to placebo, hydroxyurea treatment for young children with sca living in uganda was associated with lower tcd velocities, which have been correlated in other studies with lower risk of primary stroke. tcd velocities were correlated with hematological and clinical parameters that can be improved by hydroxyurea therapy. children's hospital of richmond at virginia commonwealth university, richmond, virginia, united states background: acute chest syndrome (acs), defined by respiratory symptoms and a new pulmonary infiltrate, is a serious complication of sickle cell disease (scd). acs can occur during hospitalization for non-pulmonary conditions, such as a vaso-occlusive crisis or after surgery. nih clinical practice guidelines encourage incentive spirometry (is) which decreases the incidence of acs. it is additionally widely accepted that early, frequent ambulation in post-operative and pneumonia patients decreases the length of stay (los). to decrease acs events in children with scd at our children's hospital, we aimed for is use in 100% of ageappropriate pediatric sickle cell admissions. design/method: a multidisciplinary team examined inpatient acs prevention practices, including is, at children's hospital of richmond. key drivers were identified, including educational awareness of patients and healthcare staff, order placement, and documentation. we aimed for all scd patients ≥ 15 months of age hospitalized with any admission diagnosis to participate in is with the use of a traditional incentive spirometer or similar age-and ability-appropriate devices (e.g. positive expiratory pressure devices, bubbles, and pinwheels). we secondarily aimed to increase activity events, specifically ambulation and out of bed time. educational and outreach tools included patient informational brochure and incentive program, and staff informational sessions and reference materials at workstations. a disease-specific order set was implemented including desired is and activity orders. data were collected prospectively may through november 2017, during which 3 pdsa cycles were conducted. admissions during the corresponding months of the previous year were reviewed for comparison. independent t-test analysis was performed using graftpad prism 6 statistical analysis software. results: improvements reaching statistical significance included increase in is order placement from 44% to 89% of admissions (p < 0.01), and admissions with documented is use increased from 32% to 59% (p < 0.01). los decreased from a mean of 3.7 days to 2.7 days (p 0.02). post-admission development of acs also decreased from 12% to 4% of admissions, but did not reach statistical significance (p 0.18). there was an additional increase in appropriate activity order placement and documentation of activity events. conclusion: improving education and outreach to patients and staff, including implementation of a disease-specific order set, can improve is use and activity events. the decline seen in incidence of acs development during hospitalization, though not statistically significant, and the decreased los are encouraging, and efforts continue to improve on these trends. background: painful vaso-occlusive crises (voc) are a frequent and debilitating complication of sickle cell disease (scd) and are thought to occur due to progressive blockage of the microvasculature with rigid sickle shaped red blood cells. any trigger that decreases the microvascular blood flow (mbf) can promote entrapment of sickled cells in the microvasculature and progression to voc. exposure to cold wind and changes in weather are common triggers of voc and are associated with increased frequency of hospitalizations for pain in patients with scd. there is limited experimental data on the physiologic effects of these factors on peripheral perfusion in scd. to study the effect of graded thermal stimuli on the peripheral mbf in scd. design/method: 17 scd and 16 control (healthy or sickle trait) subjects aging 13 to 39 years were exposed to their individual threshold temperatures for heat and cold detection, heat and cold pain via tsa-ii thermode that was placed on the thenar eminence. mbf was measured on the contralateral thumb using photo-plethysmography (ppg). the vasoconstriction response within the complex ppg signal was detected using cross-correlation technique. mean mbf was derived from the ppg amplitude during each of these stimuli and compared to baseline mbf. cross correlation analysis showed that cold pain caused significant vasoconstriction response in 67% of the subjects, followed by heat pain (58%), cold detection (36%) and heat detection (18%).there was a significant drop in the mbf during cold pain (p <0.0001), heat pain (p <0.0001), heat detection (p = 0.0005) and cold detection (p = 0.02) when compared to baseline mbf, with cold pain causing the greatest drop in mbf. thermal sensitivity and mbf responses were comparable between scd and controls. conclusion: exposure to graded thermal stimuli causes a progressive drop in mbf with exposure to cold pain eliciting the strongest vasoconstriction response. vasoconstriction occurred in the contralateral hand at an average of 11 seconds after the stimuli, suggesting a neurally mediated mechanism. although there was no significant difference in vasoconstriction responses between scd and controls, the drop in mbf in patients with sickle cell disease can increase the likelihood of entrapment of the sickled red blood cells, leading to vaso-occlusion. these findings are consistent with extensive reports in literature that exposure to cold weather is associated with a higher frequency of voc. this suggests that neurally mediated vasoconstriction is likely an important factor in the pathophysiology behind cold exposure leading to voc in scd. background: vaso-occlusive crisis (voc) is a major cause of hospital admissions in children with sickle cell disease (scd). although the use of clinical biomarkers in voc has been studied, especially with regards to acute chest syndrome (acs), there is less data regarding overall voc severity prediction. in addition new biomarkers such as platelet to lymphocyte ratio (plr), neutrophil to lymphocyte ratio (nlr), and lymphocyte to monocyte ratio (lmr) have been little studied with regards to scd. objectives: to identify whether admission laboratory values, changes from well baseline laboratory values, and new biomarkers such as plr, nlr, and lmr could predict severity of vaso-occlusive crisis in children with sickle cell disease admitted with voc. design/method: this was a retrospective single center observational study of admissions of voc in children aged 1 -21 years with hbss or hbs-b0thal from september 2014 to november 2017 excluding those on hyper-transfusion protocol or having an admission diagnosis of acs. univariate analysis was done using student's t-test, mann-whitney non parametric test, or fischer's exact test as appropriate depending on the distribution between admission laboratory data of complete blood count (cbc), reticulocyte count, comprehensive metabolic panel, lactate dehydrogenase (ldh), change from well baseline cbc values within 6 months previously, plr, nlr, lmr, and the development of complicated voc. complicated voc was defined as the development of secondary acute chest syndrome, prolonged admission duration > 5 days (120 hours), requirement of blood transfusion, and readmission within 30 days. results: a total of 109 admissions were studied. fifty-nine (54.1%) were female. of the 109, 50 (45.9%) were complicated with no significant differences in sex (p 0.447) or age (p 0.435). univariate analysis revealed significant elevations in total bilirubin (p 0.017), ldh (p 0.010), and platelet count (p 0.019) in those with complicated voc. there is also significant difference in the percentage change of platelet count from baseline with greater decline in uncomplicated voc (p 0.014). there were no significant differences in plr (p 0.186), nlr (p 0.775), or lmr (p 0.445). conclusion: elevations in total bilirubin, ldh, and platelet count in admission laboratory values are associated with developing complicated voc. in addition, those with complicated voc present with significantly less decline in platelet count from baseline well cbc. plr, nlr, and lmr do not seem to be useful predictive biomarkers for severity of voc. background: sickle cell disease (scd) causes health problems of varying frequency and severity. the only validated biomarker for children with scd is transcranial doppler. if reliable predictors existed for scd severity, children with scd could be treated according to risk category. many patients with scd face psychosocial or economic hardships, but these factors have not been evaluated as risk markers for medical or functional severity of scd. objectives: the goal of this project was to develop and stratify a preliminary list of psychosocial risk factors for health outcomes that could be used as scd severity predictors. st. vincent institutional review board. a list of potential psychosocial risk factors for adverse health outcomes was compiled based on assessment materials utilized by the sickle safe program (indiana's hemoglobinopathy newborn screening follow-up program). this list of 39 items was distributed to child abuse prevention (12) and scd (17) experts, who ranked each item on a likert scale of 1 (least important) to 5 (most important). mean scores were calculated using spss version 24; 163 assessments were retrospectively analyzed to determine psychosocial risk factor frequency. risk factors occurring in ≥15% of homes were considered high frequency events. overall, there was high agreement among experts on the risk factors that were considered the most important predictors of severe scd outcomes. the risk factor with the highest frequency (92%) was eligibility for public assistance programs. fifteen risk factors were rated ≥4 by the experts. four (26.7%) were high frequency events occurring in ≥15% of homes: a child with hbss or hbs 0thalassemia not taking hydroxyurea (15%); parent report that they had treated a fever (>101®f) at home in the past 6 months (25%); tobacco use by someone in the household (23%); and the family reporting significant psychosocial stressors in the past year (30%). tobacco use in the home was significantly correlated with several other risk factors (smoking during pregnancy [r = 0.503], other health concerns in the child [r = 0.459], and child having health insurance [r = -0.459]), suggesting that it is part of a constellation of health risk. in general, the risk factors that were rated as most important for health outcomes occurred less frequently in the sample. this study represents important progress toward identifying a group of psychosocial risk factors for scd severity, which is a necessary first step for future investigation of empirical relationships between candidate risk factors and scd outcomes. unitversity of cartagena, cartagena, bolivar, colombia s109 of s301 background: sickle cell disease is an autosomal recessive disorder characterized by a mutation in the -globin chain, which produces hbs. acute and chronic complications as aplastic crisis, acute chest syndrome, priapism, stroke, leg ulcers and primary/secondary prevention of stroke can be treated with simple transfusion or exchange transfusion. the latter offers advantages as lower iron overload, post-treatment hbs goal control, lower viscosity and improved microvascular circulation. but it is not a widely-used option because is associated with technical difficulties. objectives: standardization of a new partial exchange transfusion protocol in a group of patients with sickle cell disease, within the framework of a chronic transfusion program. design/method: this is a prospective descriptive study, which included 25 patients under 18 years with sickle cell disease (20 hbss, 5 hbs-tal), with indication of partial exchange transfusion in a chronic transfusion program, according to the institutional protocol; patients who fulfilled the inclusion criteria were enrolled in the study between february 2016 and december 2017. a registry of the medical and technical complications was made in each of the procedures. a database was constructed in excel, and the graph-pad prism® version 6 oc software was used for statistical analysis. the sequence is as follows: isovolemic phlebotomy and transfusion of packed red cells. depending of the recent hemoglobin level (48 hrs), we do the phlebotomy there: hb:7-7.9: 10 cc/kg, hb: 8-8.9: 15 cc/kg, hb>9: 15 cc/kg; isovolemic solution (ns 0,9%) there: hb:7-7.9: 10 cc/kg, hb: 8-8.9: 15 cc/kg, hb>9: 15 cc/kg and packed red cell transfusion there: hb:7-7.9: 15 cc/kg, hb: 8-8.9: 15 cc/kg, hb>9: 10 cc/kg. the safety of this exchange transfusion protocol was analyzed in 25 patients with sickle cell disease (176 procedures). there were no differences in the sex distribution, and the median age was 8 years. 80% of the population was homozygous. the indication of transfusion was 52.27%(92/176) primary stroke prevention, 44.31%(78/176) secondary stroke prevention and 2.84%(5/176) was other reason. a low percentage of complications was found (7.3%); of which, those of medical origin (hypotension and nausea/vomiting) were only presented in 2.2% of the total procedures. the standardization of this protocol was safe and its use could be extended to other low-income centers that treat patients with sickle cell disease that need chronic transfusion program including patient with hemoglobin level until 7gr/dl. we suggest do studies for measure the security and efficacy of this protocol in patients with acute complications. background: clinical trials that aim to achieve pain reduction have challenges achieving clinical endpoints as pain has no quantifiable biomarkers and may be unrelated to scd. furthermore, the threshold of seeking medical care differs between patients and vocs that occur at home are missed. we present a non-interventional, longitudinal study to identify vocs in patients with scd. objectives: to examine the longitudinal relationship between pros and biomarkers in subjects with scd before, during, and after a self-reported voc event, in order to build a model of in-home and clinical voc and to collect longitudinal pros and biomarker data from subjects that span voc events in the home, clinic and the hospital. design/method: longitudinal measures of pain, fatigue, function, activity, and biomarkers from scd patients in steady state and voc were studied over a six month period. patients self-reported pain, fatigue, function, and medication use using a novel epro tool. voc was reported in real-time, triggering a mobile phlebotomy team. blood was collected sequentially after self-reported voc (at home or hospital). blood samples were drawn two days after resolution of voc, as reported by the patient. during non-voc periods, blood was drawn every 3 weeks to establish a baseline. biomarkers included leukocyte-platelet aggregates and circulating microparticles, cell and soluble adhesion molecules, cytokines, inflammatory mediators and coagulation factors. patients wore an actigraphy device to track sleep and activity and rest. results: twenty-seven of thirty-five patients experienced a total of 286 days with voc >4 hr, of which only 58 days resulted in healthcare utilization. voc days had significantly higher pain and fatigue scores. voc days were associated with significantly decreased functional scores, with significantly greater decreases during vocs requiring medical contact compared to at-home vocs. different activity profiles were identified for non-voc, at-home voc and medical contact voc days by actigraphy monitoring. at-home voc days exhibited increased daytime resting compared to non-voc days. medical contact vocs had decreased average and peak activity, and increased daytime resting compared to non-voc days. a sleep fragmentation index trended up for both at-home (16%) and medical contact voc days (18%). significant changes during voc days were observed in: c-reactive protein (54% increase), nucleated rbc (34% increase), monocyte-platelet aggregates (25% increase) and neutrophil-platelet aggregates (35% increase), interleukin-6 (112% increase), interleukin-10 (19% increase) and tnfalpha (14% increase). the identification and assessment of at-home vocs through use of epros, actigraphy and biomarkers is feasible as demonstrated by this innovative at-home study design. background: risk-stratifying sickle cell disease (scd) patients and demonstrating response to disease-modifying therapies is challenging due to the phenotypical heterogeneity of scd. a pathogenic role for procoagulant von willebrand factor (vwf) via excess vwf high molecular weight multimers (hmwm) has been proposed, with variable reports of increased vwf and hmwm in crisis vs. steady-state in adults, but less so for vwf in children with scd. moreover, vwf and multimers have not been studied in sickle trait. objectives: our pilot study evaluated the potential for vwf antigen (vwf:ag) and hmwm on densitometric tracings to serve as biomarkers for disease severity or treatment response in children and young adults with scd compared to sickle trait (hbas) siblings. design/method: we evaluated vwf:ag, vwf multimers and retrospective clinical data from 10 hbss, 3 hbsc and 5 hbas subjects at steady state. one hbsc subject also had a crisis sample. median scd age was 17 years (8.0-20.1 years). 46% were female. scd severity was judged by annual vasoocclusive and acute chest events, or stroke/elevated tcd. eight of 13 (6 hbss and 2 hbsc) took hydroxyurea. four hbss subjects had severe scd, all of whom were chronically transfused. results: mean vwf:ag (normal 50-160 iu/dl) was higher for hbss (175+/-17.4) and severe hbss (195+/-33.5) compared to hbsc (103+/-3.2, p = 0.049 and 0.044, respectively); however, lacked statistical significance when compared to hbas (152+/-34.5, p = 0.52 and 0.41, respectively). vwf:ag was elevated in 7/10 (70%) steady-state, including 3/4 (75%) with "severe" disease on chronic transfusion and 4/6 (67%) taking hydroxyurea, in 1 hbsc crisis but no hbsc 3/3 (100%) at baseline. vwf:ag was high in 2/5 (40%) hbas siblings. four (31%) had increased hmwm at baseline: 1 hbss/severe disease/chronic transfusion, 2 hbss/hydroxyurea and 1 hbsc untreated. hmwm were increased only during vaso-occlusive crisis in 1 hydroxyureatreated hbsc subject. no ultra-large hmwm were observed. in this preliminary study, in young scd subjects, vwf:ag trended higher in hbss vs. hbsc and in severe hbss participants at a single time-point, but serial evaluations at baseline, in crisis and with optimized diseasemodifying therapy are needed to determine the potential of vwf:ag and hmwm as biomarkers for severity or treatment response. surprisingly, vwf:ag was high in some sickle trait subjects. since hbas is associated with some health challenges such as increased thrombosis risk, further examination of vwf and endothelial dysfunction in sickle trait may provide novel insights into its role as a biomarker. background: the 2014 national heart lung & blood institute(nhlbi) guidelines for acute management of voe recommends rapid evaluation and treatment of pain, including administration of a parenteral opioid within 30-minutes of triage or 60-minutes from registration, pain reassessment & repeat opioid delivery within 15-30-minutes. inf use has been increasing in peds due to its rapid onset and ease of administration. objectives: to evaluate ped utilization of inf & its effect on intravenous (iv) opioid administration and pain control for the treatment of voe. design/method: a retrospective review of 250 emr was performed on children with scd±2years presenting to a ped with voe (pain scores 6 on a 0-10 scale) from jan-june 2017. variables studied were median time (iqr,95%ci) from ped arrival to first-parenteral-opioid-administration, time-to-first-iv-opioid, first & final pain score, disposition and readmission rate. time-to-first-iv-opioid was also compared to historical data (jan-dec2012,n = 231) prior to inf protocol initiation. . additionally, 15% patients received iv opioids within 60 minutes of ed arrival in the inf+iv opioid vs. 40% in the iv opioids alone group (p<0.01). no differences in 72-hour-returnrates were found in any of the groups, including inf alone group. conclusion: use of inf in the ped for voe is an excellent strategy to shorten time-to-first-parenteral-opioidadministration, improve pain scores & improve adherence to the nhlbi guidelines. however we had 2 distinct unexpected findings: (1) delays in iv opioid delivery after inf use & (2) inf alone appeared to provide sufficient pain control without iv opioids for disposition home in 17% of voe patients. whether the latter reflects insufficient pain management or that there is a milder subgroup for whom inf alone is sufficient, requires further investigation. this study illustrates our experience with a ped-based inf protocol in terms of unanticipated delays in iv opioids and also discharges after inf alone. efforts are underway to further improve use of inf in voe management. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: folate supplementation is commonly included as standard management in patients with sickle cell disease. however, clear evidence supporting the clinical benefits of this practice is lacking. a single study demonstrated improvement on the occurrence of repeat dactylitis at a higher dose of folic acid. to compare clinical outcomes in pediatric patients with sickle cell disease treated with folate supplementation versus those who were not. design/method: this study was a retrospective chart review that included patients 3 to 23 years old with sickle cell disease type ss and s 0 followed at st. christopher's hospital for children. data collected included information about folate supplementation, red cell indices and the presence or absence of clinical outcomes including vaso-occlusive crisis requiring hospitalization in the last six months, acute chest syndrome, infections, asthma, sleep apnea, nephropathy, cerebral vascular disease, stroke and avascular necrosis. analysis of variance (anova) was used to evaluate mean differences between age, number of infections, number of voc events, hemoglobin, reticulocyte count, and mean corpuscular volumes. additionally, chi square analysis was implemented to evaluate differences in folate and non-folate groups for left ventricular remodeling (lvr), sickle cell nephropathy, asthma, obstructive sleep apnea (osa), nocturnal hypoxia, and avascular necrosis (avn). mean differences between the folate and non-folate groups were compared for patients on and off hydroxyurea therapy. one hundred and seven patients met inclusion criteria following review of clinical data. of the patients included in the study, 45 patients were found to be taking folate (42%), while 62 patients were not (58%). statistical analysis showed that there were no significant differences in the incidence of clinical outcomes between patients on folate versus those who were not on folate. of the patients who were not on hydroxyurea, hemoglobin levels were significantly higher in patients on folate versus those who were not (p = 0.053), but not significantly different for the patients on hydroxyurea. this study suggests that folate supplementation makes no significant impact on the red blood cell indices of anemia nor on the incidence of adverse clinical outcomes in children with sickle cell disease. however, a larger prospective study is needed to guide future considerations for folate supplementation in sickle cell patients in the clinical setting. background: tanzania ranks 3rd globally for the number of infants born annually with sickle cell disease (scd) but lacks a national newborn screening program. the prevalence of sickle cell trait (sct) and scd is highest in the northwestern regions around lake victoria served by bugando medical centre (bmc) a teaching and consultancy hospital in mwanza. bmc also houses the hiv early infant diagnosis (eid) laboratory that tests dried blood spots (dbs) from hivexposed infants. dbs can be tested for hiv and then retested for sickle cell trait and disease. to determine the prevalence of sickle trait and disease by region and district in northwestern tanzania using existing public health infrastructure. secondary objectives explored associations between sct, scd, malaria and hiv. design/method: the tanzania sickle surveillance study (ts3) is a prospective year-long cross-sectional study of hivexposed infants born in northwestern tanzania, whose dbs collected by the eid program are tested at bmc and available for further testing of sct and scd. samples from children ≤24 months of age were tested by isoelectric focusing (ief) and scored independently by two tanzanian staff as normal, sct, scd, variant, or uninterpretable. dbs samples scored as disease or variant were repeated. over the course of 9 months, 157 ief gels have been run. a total of 10,019 dbs samples have been scored, including 9,567 from children less than 24-months old. the overall prevalence of sct is 20.65% and the prevalence of scd is 0.99%, along with 0.10% hemoglobin variants. quality of the laboratory results is extremely high, with only 0.15% dbs samples yielding an uninterpretable result. geospatial mapping of the first 5,900 samples revealed a regional scd prevalence ranging from 0.3% up to 2.0% among the 9 regions served by bmc. the prevalence of sct and scd is very high in northwestern tanzania. geospatial mapping will identify high prevalence areas where targeted newborn screening can be started using existing public health infrastructure with minimal start-up cost and training. further data will enhance the accuracy of the map to the district level. background: pediatric patients with sickle cell disease (scd) could develop obstructive, restrictive or mixed abnormalities of pulmonary function (pf). several publications report progressive worsening of pf over time, which could lead to severe morbidity in adult patients with sickle cell disease. in adults with sickle cell anemia up to 20-30 % of mortality is related to lung disease. early intervention aimed at improvement of lung function could significantly decrease morbidity and possibly improve life expectancy. among disease modifying approaches commonly used in scd are hydroxyurea (hu) and chronic prbc transfusions. both interventions lead to increase of hemoglobin, decrease of hbs fraction, leading to decreased hemolysis. reports of effect of hu on pulmonary function are conflicting with some suggesting no effect and others proposing a slower decline of pulmonary function. the goal of our study is to evaluate effect of disease modifying therapies, like hu and chronic prbc on change of pulmonary function in pediatric patients with sickle cell disease. design/method: this study utilized a retrospective chart review of children with scd who had multiple pfts. we analyzed 286 pfts from 80 patients done during clinic visits. scd patients were divided into three treatment groups: hydroxyurea, chronic transfusions or neither. data was analyzed with linear correlations and analysis of variance (anova). comparison were made between the three groups specifically observing the changes in absolute numbers on pfts over time using the first and last pft the patient had. results: there were a total of 80 patients with multiple pfts (ranging from 2-7); control (40), hydroxyurea (23) and chronic transfusion (10). the mean changes of the control, and hydroxyurea for the pft parameters fev1 (-5.53 the chronic transfusion group demonstrated a small improvement in pfts over time for fev1 (0.300), fvc (1.300), fef25-75 (0.400), however there was a decline in fev1/fvc (-0.013). however, there was no statistically significant (p-value <0.005) in the difference in any pfts parameters between any of the groups. in children with scd there is a decline of pf parameters over time. although no significant differences were seen between the three groups it appears chronic transfusion may improve or limit the decline in pfts. larger studies need to be done to evaluate difference in pf decline in patients with scd patients. background: the use of mobile technology in health care has been a growing trend. patients with chronic diseases such as sickle cell disease (scd) require close monitoring to provide appropriate treatment recommendations and avoid complications. we conducted a feasibility study for patients with scd hospitalized for pain using our self-developed mobile application (tru-pain: technology resources to better understand pain) and a wearable activity tracker. subjective symptoms such as pain and objective data such as heart rate (hr) were measured. we aimed to 1) correlate nursing recordings with mobile technology recordings; 2) get feedback from patients about usability. design/method: we enrolled patients with scd >8 years old and <36 hours from admission for uncomplicated vasoocclusive crisis, excluding patients admitted to icu. patients were given an ipad and a wearable device. they were instructed to record in the application at least once per day and to keep the wearable on, removing only to charge. prior to discharge, patients completed a feasibility questionnaire. we enrolled 20 patients, 40% females, median age 17.5 (range 13 to 54) who were admitted for a median 5 days (range 2 to 8) for uncomplicated pain crisis. patients used the application throughout hospitalization and made one entry/day (range 0 to 2). pain scores recorded via tru-pain correlated well (r = 0.74, p<0.005) with pain scores recorded in emr. there was an average of 10,930 data points recorded per day, by the wearable, with a maximum of 54,693 data points/day. the median amount of hours of wearable data per day was 4.21 (maximum of 18.05). the hr recorded via the wearable correlated significantly with the hr recorded in emr (r = 0.69, p-value < 0.005). as for usability, 70% of patients indicated never having a problem with the technology, 90% found tru-pain 'very easy' or 'somewhat easy' to use, and 60% were 'very satisfied' with their participation in the study, indicating that it helped them track their pain. our pilot study during hospitalization shows strong potential for using tru-pain for patients with scd. pain data from application and hr from wearable correlated well to the emr data. according to the feedback received, our application was easy to use and helped patients track their pain. despite limitations of battery life, the use of wearable technology is feasible, providing additional data such as activity. we are optimistic that we can continue to improve our tru-pain system to help improve care in patients with scd. background: hydroxyurea, chronic blood transfusion, and bone marrow transplantation can reduce complications, and improve survival in sickle cell disease (scd), but are associated with a significant decisional dilemma because of the inherent risk-benefit tradeoffs, and the lack of comparative studies. these treatments are underutilized leading to avoidable morbidity and premature mortality. there is a need for tools to provide patients high-quality information about their treatment options, the associated risks, and benefits, help them clarify their values, and allow them to share in the process of informed medical decision making. objectives: to develop a health literacy sensitive, web-based, decision aid (ptda) to help patients with scd make informed choices about treatments, and to estimate in a randomized clinical trial the acceptability and effectiveness of the ptda in improving patient knowledge, involvement in decisionmaking and decision-making quality. design/method: we conducted qualitative interviews of scd patients, caregivers, stakeholders, and healthcare providers for a decisional needs assessment to identify decisional conflict, knowledge, expectations, values, support, resources, decision types, timing, stages, and learning, and personal clinical characteristics, and to guide the development of a ptda. transcripts were coded using qsr nvivo 10. stakeholders completed alpha and beta testing of ptda. we conducted a randomized clinical trial of adults, and of caregivers of pediatric patients to evaluate the comparative efficacy of the ptda, vs. standard of care. results: ptda (www.sickleoptions.org) was developed per decisional needs described by 223 stakeholders and finalized following alpha testing, and beta testing by 68 and 87 stakeholders respectively. in a randomized trial of 120 subjects considering various treatment options, qualitative interviews revealed a high level of usability, acceptability, and utility in education, values clarification, and preparedness for decision making of the ptda. a median 68% rated the acceptability of ptda as good or excellent and provided narrative comments endorsing the acceptability, ease of use, and utility in preparation for decision making. the ptda met international standards for content, development process, and efficacy with the exception of having a full range of positive and negative experiences in patient stories. compared to baseline ptda group had statistically significant improvement in preparedness for decision making (p = 0.005) and informed subscale of decisional conflict (p = 0.02) but not for decisional self-efficacy, knowledge, choice predisposition, or stages of decision-making. a ptda for patients with scd developed following extensive engagement of key stakeholders was found to be acceptable, useful, easy to use, to improve preparedness for decision making, and decrease decisional conflict. background: painful vaso-occlusive crisis (voc) accounts for the majority of emergency department (ed) visits and hos-pitalizations in sickle cell disease (scd). we are interested in studying mental stress and associated autonomic nervous system (ans) imbalance that cause vaso-constriction as possible triggers of scd pain. to this end, we developed a mobile phone application (app) to record daily pain frequency and intensity as clinical endpoints that might be predicted by ans parameters measured in the laboratory. in particular, we think that the aura may represent ans instability that precedes or even triggers change in blood flow and voc. objectives: to assess the feasibility of using an app to evaluate frequency and severity of voc and its potential association with mental stress and presence of aura. design/method: an app was developed for both ios and android systems to allow patients to track pain, stress, and aura. the idea was to create an app that was easy to use with the intent to only capture pain episodes, rather than detailed description of the pain. all scd patients were eligible and a parent version was available for younger children. de-identified data was automatically transferred to a hipaa compliant database via a cloud-based server interfaced to the main research project database. a feedback questionnaire was implemented after at least a month of utilization to assess usability. of the 51 scd patients enrolled, 39 participants utilized the app and 21 of the 23 participants that provided feedback indicated the app was easy to navigate. the mean pain scale was 6 out of 10 (standard deviation 1.97) for those that entered they had pain that day. although the mean stress level was 3 out of 10, there was a statistically significant correlation between increasing stress levels and increasing pain scores (p < 0.05). aura was reported by 26 patients, with 5 patients reporting more than 10 episodes. moreover, on days aura was present there was greater incidence that pain was present as well (p < 0.05). however, there was no statistically significant association between pain intensity and presence of an aura (p = 0.14). conclusion: consistent with prior research, reported pain intensity is significantly associated with reported stress intensity. although there was an association between presence of aura and pain, it did not seem to correlate with pain intensity. this uniquely designed app can monitor scd pain clinically and help understand the role of sickle dysautonomia in the genesis of scd pain. university of florida college of medicine, gainesville, florida, united states background: evidenced-based guidelines recommend the emergent evaluation of fever in children with sickle cell disease (scd). as the prevalence of bacteremia has decreased, outpatient management has become more common. however, fever can sometimes herald other complications of scd, such as acute chest syndrome, vaso-occlusive pain crisis, splenic sequestration, or aplastic crisis. institutional practices regarding fever management in scd remain variable, and little is known about the clinical outcomes of children hospitalized for uncomplicated fever. objectives: the primary objective was to determine the rate of bacteremia or scd-related complications per febrile episode in children with scd admitted to a single institution between january 2014 and june 2017 for uncomplicated fever. this was a retrospective cohort study of febrile patients up to 21 years of age with scd, any genotype, admitted to the university of florida during the defined study period. eligible patients were identified by a database search using admitting diagnosis codes for scd and fever based on the international classification of diseases 9th and 10th revisions. encounters were manually reviewed to confirm eligibility. patients were excluded if they had other indications for hospitalization apparent at the time of admission, such as an acute vaso-occlusive episode requiring parental narcotics, asthma exacerbation, or additional complications of scd. the database search identified 211 encounters, of which 83 were excluded based on confounding indications for hospitalization. sixty-three eligible patients accounted for 128 hospitalizations. the median age was 2 years (range 5 weeks-17 years); 60.2% were male. mean duration of hospitalization was 2.6 days (range 1-13 days). eight positive blood cultures were identified; six of these were classified as contaminants. bacteremia or the development of a scd-related complication was identified in 18 (14.06%) admissions. these included acute chest syndrome (n = 4), bacteremia (n = 2), splenic sequestration (n = 1), and red cell transfusion (n = 11). exploratory analyses of potential predictors of bacteremia or scd-related complications showed no association with the presenting white blood cell count or degree of fever (p = 0.36). of the patients classified as having a scd-related complication, 94% had hemoglobin ss disease and 78% had at least one prior documented complication. 64% of the patients transfused had at least one prior transfusion. conclusion: while improvements in preventative care have substantially lowered rates of bacteremia in children with scd, fever warrants careful evaluation for other acute scdrelated complications. providers should consider inpatient observation in select cases. additional studies are warranted to define subsets of patients suitable for outpatient fever management. background: children with sickle cell disease (scd) exhibit lower neurocognitive functioning than healthy peers, even in the absence of stroke. among the domains commonly affected, working memory (wm) seems particularly affected by disease processes and wm deficits have significant implications for academic achievement and disease selfmanagement. few interventions to improve working memory in pediatric scd have been evaluated. to determine the effects of cogmed, a homebased computerized wm training intervention, in children with scd using a randomized controlled trial design. design/method: participants (ages 7-16) with scd completed a baseline neuropsychological assessment and those with wm deficits were randomized to either begin cogmed immediately or enter an 8-week waitlist. cogmed is a homebased intervention completed on an ipad that consists of 12 increasingly challenging exercises targeting visual-spatial and verbal wm, practiced over 25 sessions. at the end of training, participants completed a post-intervention neuropsychological assessment, including tests of visual-spatial and verbal wm from the wechsler intelligence scale for children-fifth edition (wisc-v). results: ninety-one participants (m age = 10.43, sd = 2.93; 59% female; 69% hbss) enrolled in the study; 52% (n = 47) exhibited wm deficits and were randomized to either begin cogmed immediately or wait 5-8 weeks before starting cogmed. among those that have received the intervention and reached the end of their training period (n = 42), 27 participants (59%) completed at least 5 cogmed sessions, 19 (41%) finished at least 10 sessions, and 7 finished at least 20 sessions (15%). the mean number of completed cogmed sessions was 9.10 (sd = 7.77). paired samples t-tests revealed significant improvements on the working memory index (t[38] = -2.44, p = 0.020) and on the digit span (t[40] = -3.02, p = 0.004), and spatial span-backward (t[39] = -2.83, p = 0.007) subtests. improvements were especially pronounced for participants completing at least 10 sessions. partial correlations controlling for respective baseline scores indicated that the number of cogmed sessions completed was positively correlated with post-test scores on digit span (r = .38, p = .017) and spatial span-backward (r = 0.45, p = 0.004) subtests. among participants who completed at least 10 cogmed sessions, 77% scored in the average range or higher on the working memory index at the post-intervention assessment, compared to 58% at baseline. results support the efficacy of cogmed in producing significant improvements in wm. a dose-effect was observed such that participants who completed more cogmed sessions had greater improvements in wm. home-based cognitive training programs may ameliorate scd-related wm deficits but methods for motivating and supporting patients as they complete home-based interventions are needed to enhance adherence and effectiveness. background: sickle cell disease is associated with myriad complications that lead to significant morbidity and early mortality. hydroxyurea has been used successfully to reduce the incidence of these complications and has led to significant improvements in quality and duration of life. at children's minnesota we recommend hydroxyurea in all patients with hb ss/s 0 thalassemia as early as 5 months of age with a goal of starting all patients before 12 months of age. objectives: the purpose of this study was to evaluate the use of hydroxyurea therapy in young patients with sickle cell disease, with particular attention to those children less than one year of age. design/method: a retrospective chart review was conducted on patients less than 5 years of age with sickle cell disease who began hydroxyurea therapy between january 1, 2008 and december 31, 2016. the study population was divided into three cohorts based upon age at hydroxyurea initiation: cohort 1 (0-1 year), cohort 2 (1-2 years), and cohort 3 (2-5 years). outcomes included laboratory data, clinical events (hospitalization, dactylitis, pain crisis, transfusion, splenic sequestration, acute chest syndrome), and toxicity occurring in the first 2 years of life. results: a total of 65 patients were included in cohorts 1 (n = 35, mean age 7.2 months), 2 (n = 13, mean age 19.5 months), and 3 (n = 17, mean age 35.5 months). patients in cohort 1 had higher hemoglobin (p = 0.0003) and mcv (p = 0.0199) and lower absolute reticulocyte count (p = 0.0304) when compared to cohort 3. the wbc (p = 0.0007, <0.0001) and anc (p = 0.0364, 0.0025) were significantly lower compared to both older cohorts. however, no patient had therapy held because of neutropenia. the mean baseline hemoglobin f in cohort 1 was 31.5% compared to 19.7% and 16.5% in cohorts 2 and 3 respectively (p = 0.002, p<0.0001). the mean duration of therapy in cohort 1 was 31.3 months, compared to 57.6 months in cohort 2 (p = 0.018) and 29.1 months in cohort 3 (p = 0.401). during this time, hb f levels remained higher in cohort 1 (mean 29.9%) compared to cohorts 2 and 3 (mean 20.4%, p = 0.007 and mean 20.6%, p = 0.003). patients in cohort 1 experienced fewer hospitalizations (p = 0.0025), pain crises (p = 0.0618), and transfusions (p = 0.0426). there was no difference in toxicity between groups. hydroxyurea was used safely in infants 5 to 12 months of age and resulted in more robust hematologic responses and a decrease in sickle-related complications when compared with patients starting hydroxyurea later in life. children's national health system, washington, district of columbia, united states background: children with sickle cell disease (scd) have a significantly greater risk of silent or overt cerebral infarction than the general population. infarcts are associated with declines in cognitive functioning and academic achievement. while infarcts are reliably identified using mri, scans are expensive and occasionally necessitate sedation. moreover, mri's are not recommended for routine monitoring of cerebral infarcts. additional tools are needed for discriminating the presence of a cerebral infarct that are brief, noninvasive, inexpensive, and repeatable. objectives: to evaluate differences in performance on cogstate, a computerized neurocognitive assessment, in patients with scd with and without history of cerebral infarct. design/method: participants included 112 children with scd ages 7-16 (m = 10.61, sd = 2.91; 58% female; 70% s117 of s301 hbss) enrolled in a cognitive intervention trial. participants completed the cogstate pediatric battery, which measures processing speed, sustained attention, verbal learning, working memory, and executive functioning. history of silent or overt infarct was determined via health record review. participants also completed measures of intelligence (iq) and math fluency. results: participants' standard scores across most neurocognitive measures were lower than expected compared to the standardization sample (mean iq = 91.03, sd = 13.34). thirty percent of participants (n = 33) had a documented history of cerebral infarct. participants with a history of cerebral infarct scored lower on cogstate tasks measuring sustained attention (t[108] = 2.93, p = 0.004) and executive functioning (t[98] = 2.46, p = 0.016), as well as on a measure of math fluency (t[88] = 2.16, p = 0.033). receiver operating characteristic (roc) analyses demonstrated that the cogstate task measuring sustained attention was a fair discriminant of patients with and without a history of infarct (auc = 0.75, ci95 = 0.65-0.84, p = 0.0001), whereas iq score was not (auc = 0.58, ci95 = 0.46-0.71, p = 0.19). cogstate processing speed and sustained attention tasks fairly discriminated between patients with at least average or below average intelligence (auc = 0.77, ci95 = 0.67-0.86, p = 0.00001 and auc = 0.74, ci95 = 0.64-0.84, p = 0.0001, respectively). finally, the cogstate processing speed task was good at discriminating between at least average or below average math fluency (auc = 0.80, ci95 = 0.70-0.90, p<0.00001). multiple tasks in the cogstate pediatric battery appear to adequately identify patients with a history of cerebral infarcts. in addition, cogstate tasks appear to be fair predictors of impairments in iq and academic achievement outcomes. cogstate is inexpensive and can be easily administered in a medical setting with minimal training in approximately 20 minutes. results support the potential for cogstate to be used as a screening tool for medical and neuropsychological abnormalities in children with scd. st. christopher's hospital for children, philadelphia, pennsylvania, united states background: cardiovascular disease contributes to the morbidity and mortality of patients with sickle cell disease (scd). hydroxyurea therapy in scd has known clinical efficacy including improving anemia, decreasing episodes of vasoocclusive crisis and acute chest syndrome, and decreasing mortality. effect of hydroxyurea on cardiac function in children with scd is not well studied. an earlier study suggested the protective effect of hydroxyurea on left ventricular (lv) hypertrophy in scd. we hypothesized that hydroxyurea use would be associated with decreased lv remodeling and improved cardiac function. we aimed to evaluate the association between hydroxyurea use and lv remodeling and cardiac dysfunction in children with scd. design/method: we completed a retrospective study of patients with scd who were 10 to 22 years old, followed at st. christopher's hospital for children and had an echocardiogram completed in the past 18 months. data collected included gender, bmi, scd genotype, hydroxyurea use, chronic transfusion use, and 2d and doppler echocardiographic parameters. cardiac structure, geometry, systolic function, and diastolic function echocardiogram parameters were included. analysis of variance (anova) tests were performed to assess for statistical significance of differences in cardiac parameters between patients with and without hydroxyurea use. analysis of covariance (ancova) tests were performed to control for age. results: demographic and echocardiogram data was collected on all 93 patients who met inclusion criteria. of the 93 patients included, 31 (33%) were on hydroxyurea therapy. patients on hydroxyurea had significantly lower mean relative wall thickness (p = 0.026) and significantly higher mean peak early lv filling velocities (p = 0.032) and peak early lv filling/septal annuli early peak (e/ea) velocities (p = 0.002); however, only the e/ea velocities remained significant when controlling for age (p = 0.001). mean peak early lv filling velocities approached significance when controlling for age (p = 0.052). hydroxyurea therapy resulted in a significantly higher e/ea velocity, suggesting that these patients had worse diastolic function. it is possible that the patients initiated on hydroxyurea already had worse disease manifestations than those not on hydroxyurea, possibly accounting for the decreased diastolic function. when controlling for age, hydroxyurea use did not result in significant differences in cardiac structure parameters, systolic function parameters or cardiac geometry. prospective studies and larger sample size are needed to validate our findings, examine for additional statistically significant differences, and develop preventive strategies for cardiovascular disease in children with scd. background: acute chest syndrome (acs) is now the leading cause of death in children with sickle cell disease; mortality in the u.s. is reported to be 1-2% and is mostly due to respiratory failure. early transfusion improves clinical outcomes. although patients with concurrent asthma are considered at increased risk for poor outcomes, risk factors for respiratory failure in pediatric acs have not been well-defined. to determine whether specific epidemiological and clinical features of children hospitalized with acs are predictive of the need for mechanical ventilation. design/method: data from the kids' inpatient database were reviewed to identify patients age < 20 years with a discharge diagnosis of acs for the years 2003, 2006, 2009, and 2012 . outcomes were defined by the international classification of diseases, ninth revision, clinical modification code. data were weighted to estimate total annual hospitalizations according to hospital characteristics in the united states. trends in healthcare costs, length of hospital stay, transfusion, and mechanical ventilation use were analyzed using multivariable linear regression. in addition, multivariable logistic regression was used to ascertain specific clinical or epidemiologic factors associated with mechanical ventilation use after adjusting for patient and hospital characteristics. the total hospitalizations for acs were 5,018 in 2003; 6,058 in 2006; 6,072 in 2009; and 6,360 in 2012. reported use of mechanical ventilation ranged from 2.8% to 5.6% and was associated with non-black compared to black children (or, 1.53; 95%ci, 1.02 to 2.31) and the fall season (or, 1.36; 95%ci, 1.05 to 1.74), but not with age, preexisting asthma or hb-genotype. comorbidities of obesity (or, 3.35; 95%ci, 1.94 to 5.78), obstructive sleep apnea (or, 3.72; 95%ci, 2.23 to 6.20) and heart disease (or, 2.19; 95%ci, 1.47 to 3.27) were associated with mechanical ventilation use. the use of simple and exchange transfusion during all acs admissions ranged from 30.1% to 40.5% and 2.6% to 2.9%, respectively. among pediatric acs patients, those with obesity, obstructive sleep apnea or heart disease were at increased risk for respiratory failure and might benefit from early intervention (e.g., transfusion). surprisingly, asthma in children with acs does not appear to be a distinct risk factor for respiratory failure, and further studies are needed to clarify whether differences in treatment approach (e.g., addition of corticosteroids, bronchodilators) might impact on acs progression and/or severity even in high risk patients without asthma. objectives: to compare pulmonary functions between aa and k children with scd and to assess if a high hb f level contributes to better function. design/method: a cross sectional study was done on children with scd (hb ss disease) followed in comprehensive sickle cell programs. aa patients were followed at brookdale hospital, ny and k patients were followed in mubarak hospital, kuwait. children between the ages of 6 and 22 years who had pulmonary function tests (pft) done as a routine screening were enrolled. pft was done using spirometer and plethysmography. patients with congenital or anatomical lung abnormality, heart disease, pulmonary disease such as acute chest syndrome, acute asthma or pneumonia within 4 weeks were excluded. results: there were 74 children (37 in each group) with scd,. restrictive pattern on pft was seen in 18/37 (49%) of aa vs. 10/37 (27%) of k (p>0.05). obstructive pattern was seen in 6/37 (16%) of aa vs. 13/37 (35%) of the k group (p>0.05). in both groups, 13 children (35%) had normal pft. three/13 (15%) in the aa group had a hb f>20% as compared to 11/13 (85%) in the k group (p<0.01). abnormal pft was noted in 24/37 children (65%) in each group. hbf was >20% in 3/24 (13%) in the aa group vs. 15/24 (63%) in the s119 of s301 k group (p<0.01). in patients with abnormal pft, mean hbf was 10.4±8.4 in aa group, compared to 22.4±8 in k group (p<0.01). conclusion: abnormal pft is highly prevalent among children with scd in both groups. aa children are more likely to have restrictive disease and k to have an obstructive pattern. level of hbf did not seem to protect k patients from abnormalities on pft. this finding should emphasize the importance of performing pft as part of the initial evaluation of all children with scd. background: sickle cell disease (scd) is a life-threatening disease with varied clinical spectrum and severity leading to premature death. there is a lack of validated prognostic marker in scd. recent evidence suggests that inflammation and platelet adhesion plays a critical role in the pathophysiology of vaso-occlusion in scd. elevated mean platelet volume(mpv) values are associated with a higher degree of inflammation in many disease states but it's effect on sickle cell disease or it's severity is unknown. objectives: to analyze the role of mpv in predicting disease severity/mortality in pediatric patients with scd. design/method: this is a single center retrospective study and included patients with sickle cell disease between 6 months and 18 years of age during a 10-year period (2006) (2007) (2008) (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) . demographic information, lab data and clinical information including acute chest syndrome (acs), priapism, transfusions, sepsis, pain crisis, avascular necrosis were collected. all laboratory data were collected in steady state with no crisis in the recent past 3 months. the disease severity score/probability of death was calculated using a validated model to predict risk of death in sickle cell disease (sebastiani et al. blood 2007) . pearson test was used to analyze correlation between mpv and probability of death. results: total no. of patients = 92; male 45 (48.9%); female 47(51.1%). median age is 6.0 years. all patients were of african-american origin. disease severity, hb ss -58(63%); hb sc -25(27.2%) and sickle-beta thalassemia 9(9.8%). patients on hydroxyurea has significantly lower mpv, p = 0.023 and this is independent of hb f levels. mpv has a significant positive correlation with the probability of death, p = 0.016 and correlation coefficient, r = 0.254. on subgroup analysis, the correlation is even more significant in the age group between 6 and 18 years, p = 0.004, r = 0.405. using linear regression model, with probability of death as a dependent variable and hydroxyurea, mpv as independent variables, mpv maintains a significant association with probability of death (p = 0.016). conclusion: mpv is an independent biomarker predicting disease severity and probability of death in pediatric patients with sickle cell disease. hydroxyurea a known disease ameliorating agent is associated with lower mpv values. this effect is independent of the levels of fetal hemoglobin and may be due to anti-inflammatory effect of hydroxyurea or effect on the platelets. background: major success with initial qi projects by the sickle cell care team at children's hospital has precipitated ongoing inclusion of the qi approach to many other aspects of patient care. objectives: to optimize scd patient care utilizing qi processes. design/method: success of the scd qi team's initial project on transcranial doppler studies (tcds) and a second more complex project on hydroxyurea (hu) adherence, led to additional projects on completion of key immunizations, rbc phenotyping, and vitamin d level testing. using similar processes and principles from the hu adherence project, plan-do-study-act (pdsa) cycles were used to conduct smallscale tests of change. patient chart prep sheets, created for bi-monthly pre-appointment chart prep meetings, were significantly modified to include these focused care qi objectives. because of difficulty with emr database capability, data collected from the emr was tracked in excel spreadsheets or other unique tracking vehicles for the various parameters. for example, due to the clinic's diffuse, geographically scattered population, many separate non-shared primary care emrs, and lack of a mandatory state immunization registry; immunization records needed to be retrieved from pcps, outlying hospitals, public health departments, and fqhcs, and added to the emr and excel database. starting in 12/2016, all such data was collected and updated monthly. in one year's time (2016 -2017) , the average immunization completion rate for seven key immunizations (pcv 13, pcv 23, hepatitis a, hepatitis b, meningococcal a, meningococcal b, and hpv) has increased by 20%. the biggest improvements were a 57% and 44% increase in completion for meningococcal a and meningococcal b, respectively. completion rate for rbc phenotyping rose from 34.8% to 74.4%. patients with at least one vitamin d lab test increased from 27.8% to 67.9%. since starting the tcd project in 2013, the percent of patients who have completed their annual tcd has gone from a baseline of 50% to a sustained value of > 80%. conclusion: these qi projects have not only increased adherence to national recommendations for care of scd patients, they have helped establish a scd clinic methodology to create and implement sustainable processes. having the focused care initiatives prominently displayed on the patients' chart prep sheet serve as a reminder to medical team members to check the status of that item. this methodology is currently being used to formulate additional qi projects on annual renal function parameters and specialty visits, such as annual eye and dental exams. background: dominican republic has a high burden of sickle cell disease, and 5-10% of children with homozygous hbss (sickle cell anemia, sca) will develop primary stroke. transcranial doppler (tcd) ultrasonography is an effective screening tool for primary stroke risk, but is not routinely available in dominican republic. hydroxyurea and blood transfusions are available, but no prospective screening and treatment program for stroke prevention has been implemented to date. (1) to screen a large cohort of children with sca living in dominican republic, using tcd to identify elevated stroke risk; (2) to determine the effects of treatments for stroke prevention (hydroxyurea for conditional velocities and transfusions for abnormal velocities). we hypothesized that both hydroxyurea and blood transfusions will decrease elevated tcd velocities and help prevent primary stroke. design/method: stroke avoidance for children with república dominicana (sacred, nct02769845) features a research partnership between cincinnati children's hospital and robert reid cabral children's hospital in dominican republic. the protocol, consent forms, and redcap database were prepared collaboratively and translated into spanish, and then irb approval was obtained at both institutions. in the initial prospective phase, children receive tcd screening over a 12-month period; those with conditional tcd velocities (maximum time-averaged velocity 170-199 cm/sec) receive fixed-dose hydroxyurea at 20 mg/kg/day, followed by dose escalation to maximum tolerated dose, while those with abnormal tcd velocities (≥200 cm/sec) receive monthly transfusions for stroke prevention. results: a total of 283 children were enrolled in sacred, with an average age of 8.7 ± 3.4 years. initial tcd screening revealed 200 (70.7%) normal, 63 (22.3%) conditional, 11 (3.9%) abnormal, and 9 (3.1%) inadequate velocities. among 48 children (25 males, 23 females, average age 6.8 ± 2.8 years) who initiated hydroxyurea at 20 mg/kg/day for conditional tcd velocities, 42 completed six months of treatment with expected hematological benefits including significant increases in hemoglobin concentration (7.5 to 8.5 g/dl) and fetal hemoglobin (15.8 to 28.4%). no clinical strokes have occurred in the treatment group. repeat tcd examination after 6-months of hydroxyurea treatment revealed 69% (29/42) with previous conditional velocities had normal tcd velocities. the prevalence of conditional tcd velocities in the dominican republic is high, indicating an elevated stroke risk among children with sca. hydroxyurea treatment is associated with improved hematological parameters, lower tcd velocities, and probable decreased stroke risk. sacred is an important prospective and collaborative research trial providing epidemiological data regarding tcd screening, stroke risk, and hydroxyurea effects among children with sca. background: red blood cell aggregation is a rheologic property that explains the shear-thinning behavior of blood. at lower shear rate blood flow, red cells tend to aggregate, s121 of s301 whereas in higher shear rate blood flow, these aggregates are dispersed. this property is especially important in the venous system, where low shear rate blood flow predominates. there is inconsistent data in the literature concerning aggregation and aggregability in sickle cell disease (scd). objectives: because the lorrca and myrenne instruments have been shown to be similarly effective methodologies in red cell aggregation measurements, we aimed to determine whether the measurement of aggregation indices in scd, by myrenne and by lorrca, is consistent in our lab. design/method: we measured aggregation in blood samples corrected to 40% hematocrit. aggregability was measured using 70kda dextran in the myrenne but not the lor-rca. aggregation index using lorrca was measured in 26 patients with scd and 22 healthy subjects enrolled in a study of blood flow between 2014 and 2017. aggregation and aggregability using the myrenne was measured in 67 patients with scd and 15 healthy subjects enrolled in a separate study of blood flow between 2008 and 2013. results: using lorrca, we found that aggregation index in patients with scd was less than that of healthy subjects (p<0.001). in the myrenne, aggregation at stasis was slightly higher in patients with scd compared to healthy subjects (p = 0.05) but aggregation at low shear rotation was not different. aggregability was higher in the patients with scd compared to healthy subjects at both stasis and low shear rotation (p<0.0001). red cell aggregation is an important determinant of low shear blood flow. deoxygenated venous blood is particularly important to low shear blood flow in patients with sickle cell disease. we found that two different aggregometers predict different aggregation results for scd. it is unclear why there is a systematic difference between the two methods, but there are some possibilities. first, the syllectogram in the lorrca is generated by the backscatter of light from the laser, while the myrenne measures transmitted light. second, the distance between the bob and cup in the lorrca is 300 microns, while the gap between plates in the myrenne is 50 microns, which might affect the disaggregation of red cells. further work is needed to understand the differences in red cell aggregation and aggregability when using these instruments, particularly when using aggregation as a predictor of blood flow and tissue perfusion. background: children with sickle cell disease (scd) are at risk of acute splenic sequestration crisis (assc). assc is a life-threatening complication characterized by splenomegaly, pain and severe anemia. assc most often occurs in young children with the most severe forms of scd and one-third of patients will have more than one episode. treatment is based primarily on expert opinion and includes blood transfusion and surgical splenectomy. objectives: we plan to assess the clinical practice patterns of physicians treating children with assc. design/method: a survey study was performed. the survey included six scenarios of severe scd with variation in age, hydroxyurea-use, and episode number of assc; questions focused on the acute and chronic management of assc. the survey was disseminated on three occasions over a six-month period, using an online survey tool, surveymonkey, to pediatric hematologist-oncologists participating in the american society of pediatric hematology-oncology hemoglobinopathy special interest group. the survey had a response rate of 43% (28/65). most respondents were recent graduates (61%; 17/28) practicing in academic urban centers with greater than 100 sickle-cell patients. seventy-nine percent (22/28) recommended hydroxyurea initiation in 9-12 m/o with severe scd. prophylactic penicillin after surgical splenectomy was continued by 93% (26/28) after 5 years. for the acute management of assc results did not vary despite patient age, hydroxyurea use, and the number of previous assc episodes. simple transfusion was preferred by 89% (25/28), with 54% (15/28) recommending slow transfusion and 36% (10/28) recommending routine simple transfusion. for the chronic management of assc, results varied based on patient age and the number of previous assc episodes. for a 12 m/o after the first episode, 36% (10/28) recommended observation and 32% (9/28) hydroxyurea initiation. for a 12 m/o with any prior episode of assc, 39% (11/28) recommended chronic transfusion therapy and 36% (10/28) surgical referral for splenectomy. for a 3 y/o after the first episode, 39% (11/28) recommended surgical splenectomy and 32% (9/28) increasing hydroxyurea dose. for a 3 y/o with any prior assc episode, 64% (18/28) recommended referral for surgical splenectomy. in this survey, we found most providers continue to recommend simple transfusions for assc and surgical splenectomy after two episodes. the majority of providers continue to delay referral for surgical splenectomy until age two, but earlier referral in children under two and use of chronic transfusion therapy were also reported. variability in chronic management highlights the need for further research of splenic sequestration. background: developing therapies for sickle cell disease (scd) is challenging in part because the accepted endpoint, vaso-occlusive crisis (voc), occurs infrequently, does not measure full disease burden, and is a measure of healthcare utilization. in phase 1/2 studies of patients with scd, voxelotor (gbt440) has demonstrated increased hemoglobin (hb) levels and reduced hemolysis and has been safe and welltolerated. voxelotor is being evaluated in the ongoing hope phase 3 trial. objectives: to report the innovative phase 2/3 hope trial design with novel primary and secondary outcomes to accelerate drug development. design/method: hope (nct03036813) is a phase 3, randomized, placebo-controlled, multicenter study of oral voxelotor in patients with scd (aged 12-65 years) with baseline hb 5.5-10.5 g/dl and 1-10 episodes of voc in the prior year. to accelerate clinical trials to support drug development, the study combines a phase 2 exploratory, dose-selection phase (group 1) with a pivotal phase (groups 2/3). patients in group 1 will be randomized 1:1:1 to voxelotor 900 or 1500 mg/day or placebo. analysis for dose selection will occur when the final patient has received 12 weeks of treatment. group 2 will continue enrollment with randomization 1:1:1 until dose selection based on analysis of the group 1 cohort. group 2 will allow for a seamless transition into group 3, which will randomize patients 1:1 to the selected dose or placebo. the final data analysis set will include group 2 patients who received placebo or the selected dose and all group 3 patients. the primary endpoint is an objective laboratory measure and surrogate of clinical benefit, increase in hb >1 g/dl, from baseline to 24 weeks based on voxelotor mechanism of action (inhibition of hb polymerization). this trial is the first to use a patient-reported outcome (pro), the 9-item sickle cell disease severity measure, as a secondary endpoint. this novel electronic pro, developed specifically for the hope study following fda guidance, will evaluate changes in scd symptom exacerbation and total symptom score from baseline to 24 weeks. additional secondary endpoints include measures of hemolysis, rates of voc, transfusions, and opioid use. the study was designed to enable selection of pro-defined symptom exacerbations or traditionally defined voc as the key secondary endpoint after the group 1 analysis. results: this study is ongoing. the hope trial, expected to complete enrollment by late 2018, will evaluate the efficacy and safety of voxelotor compared with placebo in patients with scd. supported by global blood therapeutics. background: inflammation, coagulation activation, oxidative stress and blood cell adhesion are elements of sickle cell disease (scd) pathophysiology. patients with scd have low levels of the omega-3 fatty docosahexaenoic acid (dha) and eicosatetraenoic acid (epa) in plasma and blood cell membranes. dha is a bioactive fatty acid with anti-inflammatory, anti-blood cell adhesion and anti-oxidant properties. altemi-atm is a novel dha ethyl ester formulation with a proprietary delivery platform (advanced lipid technology® (alt®)) that enhances oral dha bioavailability. the scot trial investigated the effects of altemiatm in children with scd. objectives: to demonstrate the effects of altemiatm on blood cell membrane omega-3 index and selected biomarkers of inflammation, coagulation, adhesion and haemolysis associated with scd. s123 of s301 design/method: children with scd, aged 5-17 years (n = 67), were enrolled. subjects were randomized to receive either placebo or one of three daily oral doses of altemiatm (12-26, 26-48 or 51-72 mg/kg/day dha) for two months. the effects of altemiatm on red blood cell (rbc), white blood cell and platelet membrane omega-3 fatty acids index (total dha + epa levels) were assessed after four weeks of treatment. the effects of altemiatm on markers of inflammation, adhesion, coagulation, and hemolysis were assessed after eight weeks of treatment. cell membrane dha and epa concentration was determined by using lc-ms/ms method. the percent changes from baseline on blood cell membrane omega-3 index and select scd biomarkers were compared between the three dose groups and placebo using a mixed-model repeatedmeasures (mmrm) analysis with baseline blood cell membrane omega-3 index, hydroxyurea use, and treatment as fixed effects and patient as a random effect. after four weeks of treatment, blood cell membrane dha and epa levels were significantly increased in all altemiatm doses (p<0.01). after eight weeks of treatment, significant reductions were observed in se-selectin (p = 0.0219), and d-dimer (p = 0.025) in patients exposed to altemiatm dose level 2 vs. placebo. hemoglobin was significantly increased at altemiatm dose level 1 versus placebo. plasma high-sensitivity c-reactive protein, lactate dehydrogenase, soluble vascular cell adhesion molecule-1 and white blood cell count showed improvement after 8 weeks of treatment in all three altemiatm doses levels but did not reach significance. conclusion: treatment with altemiatm enriches dha and epa in blood cell membranes of patients with scd and improves select sickle cell disease biomarkers of blood cell adhesion and thrombin generation. these findings provide insight into the mechanisms of action of altemiatm in sickle cell disease. brown university -hasbro children's hospital, providence, rhode island, united states background: despite clinical advances in the treatment of sickle cell disease (scd) in pediatric and young adult patients, pain remains a significant source of disease-related morbidity. physical therapy has been shown to be useful for the treatment of pain in children and young adults with various chronic illnesses of which pain is a significant component, however no data exists regarding potential benefits of physical therapy in pediatric and young adult patients with scd. objectives: to query healthcare providers and others involved in the care of pediatric and young adult scd patients regarding possible benefits of and barriers to physical therapy as a potential treatment modality. design/method: we conducted a web-based survey of healthcare providers within the new england pediatric sickle cell consortium (nepscc) in an attempt to identify potential benefits of and barriers to outpatient physical therapy in this patient population. results: nearly 92% of survey participants felt that physical therapy had the potential to be "somewhat beneficial" or "very beneficial" in pediatric and young adult patients with scd. a majority of physicians reported having referred patients with scd for physical therapy in the past. the most frequently identified perceived potential benefits included improved functional mobility, improvement of chronic pain symptoms, decreased use of opiates, improved mood symptoms, improved acute pain symptoms, and improved adherence with medications and clinic visits. significant perceived barriers identified included lack of transportation, time constraints, patient lack of understanding, and difficulty with insurance coverage. our study indicates that healthcare providers have an overwhelmingly positive view of the use of physical therapy in the management of pediatric and young adult patients with scd. significant barriers exist which need to be addressed. future research should focus on patient and parent perspectives regarding physical therapy, as well as a randomized controlled trial of a physical therapy intervention in this patient population. background: vitamin-d deficiency is fast becoming increasingly recognized in patients with sickle cell disease (scd). while it is estimated that these patients are five times more likely to develop vitamin-d deficiency, the exact clinical significance of this is largely unknown. given that this deficiency can be inexpensively and easily treated, our study sought to establish the prevalence of vitamin-d deficiency in our patient population and its relationship with disease severity. objectives: to estimate the prevalence of vitamin-d deficiency in patients with scd in our institution and to analyze their disease severity in relation to their vitamin-d level. design/method: through retrospective chart review we analyzed subjects that represent a cohort of patients followed at the adult and pediatric hematology services at university of miami with known diagnosis of scd that had a vitamin-d level drawn between january 01st, 2013 and august 31st, 2016. we conducted a cross-sectional study and recorded the first vitamin-d level during this period. patient demographics, medical and social history information were collected along with laboratory data. the number of admissions for vaso-occlusive crisis (voc) and acute chest syndrome within one year preceding the collection the vitamin-d level was also recorded. results: a total of 476 charts were reviewed, 279 adult charts and 207 pediatric charts. after exclusion, 119 patients were enrolled. subclinical vitamin-d deficiency is only evident on laboratory blood testing of vitamin-d (25-hydroxy) and according to this laboratory result patients were classified as sufficient (≥32 ng/ml), insufficient (<32 to 20 ng/ml) and deficient (<20 ng/ml). out of the 119 cases, 61.7% (74/119) were deficient, 21.7% (26/119) were insufficient and 15.8 % (19/119) were optimal. after statistical analysis two negative correlations were identified, increasing vitamin-d levels with decreasing white blood cell count (ci 95%-0.1931133 (-0.36057544, -0.01359017)and decreasing incidence voc (ci 95%-0.3149722 (-0.4684118, -0.1430889). conclusion: this study confirms that there is a significant prevalence of vitamin-d deficiency in patients with scd. furthermore, the results of this investigation proved that vitamin-d deficiency is associated with acute pain and leukocytosis in patients with scd. given the multitude of confounding factors that affect vitamin-d absorption and intake, multivariate analyses are required to truly further investigate this relationship. texas children's hospital, houston, texas, united states background: hemophagocytic lymphohistiocytosis (hlh) is a rare but life-threatening condition of hyper-inflammation that is characterized by splenomegaly, cytopenias, hyperferritinemia, hypertriglyceridemia, hemophagocytosis and coagulopathy. although timely diagnosis is imperative, it is often challenging as these individual signs and symptoms may occur in a variety of clinical conditions. to report a case of undiagnosed sickle cell anemia presenting with severe ebv viremia and associated hemophagocytic lymphohistiocytosis results: a 21-month-old previously healthy male presented with respiratory distress, increased fatigue, and a focal seizure following a two-week history of cough and lowgrade fevers. physical exam was consistent with hypovolemic shock and revealed significant splenomegaly. laboratory testing revealed severe hypoglycemia, acidosis and electrolyte disturbances including hyperkalemia, hyperphosphatemia, and hyperuricemia. labs showed a leukocytosis (wbc 53,000), severely low hemoglobin (1.9), and platelets of 56,000. coagulation testing revealed prolonged pt/inr and ptt, hypofibrinogenemia and a highly elevated d-dimer. additional workup was completed to determine etiology of acute presentation, given broad differential diagnosis. infectious studies were consistent with an acute ebv infection (plasma ebv pcr >550,000). elevated levels of soluble il-2 and ferritin completed 6/8 criteria for the diagnosis of hlh. bone marrow evaluation showed trilineage hematopoiesis with no abnormal blast population or hemophagocytosis. results from hemoglobin electrophoresis sent from the initial cbc sample were notable for hbs 72.5%, hbf 25.0%, and hba of 0%, confirming the diagnosis of sickle cell disease. the patient was started on hydroxyurea and penicillin and splenomegaly resolved. with supportive care, he demonstrated gradual improvement in symptoms and laboratory abnormalities, including normalization of soluble il-2, ferritin, cd163, il-18 levels, immunoglobulins, and declining ebv titers. nk cell function has remained abnormally low, not eliminating the possibility of acquired hlh despite spontaneous improvement. conclusion: splenic sequestration associated with sickle cell disease in combination with acute infectious mononucleosis could have explained many of the presenting symptoms including anemia, thrombocytopenia, and splenomegaly. however, it does not explain the unusually high ebv titer and degree of inflammation meeting diagnostic criteria for hlh, which raises concern for an underlying immunologic abnormality such as x-linked lymphoproliferative disorder (xlp). although testing for xlp was negative, he will require s125 of s301 continued monitoring in the future for signs of relapse. this case illustrates the complexity of diagnosing lymphohistiocytic disorders and the significant overlap in presentation between these disorders and other medical conditions. background: vaso-occlusive crisis (voc) is one of the most distressing occurrences in patients with sickle cell disease (scd). patient controlled analgesia (pca) is recommended by nih and expert opinions favor its early use. we aim to review the use of pca in patients with voc and to evaluate if its early use is associated with faster pain control and reduced length of stay (los). design/method: this retrospective single center study included all pediatric patients admitted and treated with pca for a severe voc from 2010 to 2016. "early" use was defined as start of pca within 48 hours of arrival in the emergency department (ed) and "late" use after 48 hours. time to reach adequate analgesia was defined as oucher, verbal scale or faces pain scale < 5/10 obtained twice consecutively in a 4-hours interval. time to reach adequate analgesia and los were compared between early-pca and late-pca groups. results: a total of 46 patients presented 87 episodes of voc treated with pca during the study. sixty-one episodes (70%) were treated with early-pca and 26 (30%) with late-pca. both groups were comparable in terms of age (13.2 vs 12.8 years old), gender (55.8% female vs 57.7%), hemoglobin phenotype (80.3% hbss vs 76.9%), but median pain score at admission was higher in early-pca than in late-pca (9/10 vs 7/10, median difference 1 (95% ci 0, 2). early-pca was associated with a median reduction in los of 3.15 days (95% ci 1.65, 4.82) (median early-pca los 6.4 vs late-pca 10.0 days). time to reach analgesia could be evaluated only in a subset of patients (20 in early-pca and 12 in late-pca group). although time to reach adequate analgesia tended to be shorter in the early-pca group, it was not statistically different: median102.9 hours vs 123.5 hours, difference of 30.4 (95% ci -4.0, 72.5). side effects were observed during 29 (33.3%) pca treatments (19/61 (31.2%) episodes in early-pca, 10/26 (38.5%) in late-pca group) among which 16 (18.6%) were significant adverse events. these were observed in 15 patients who required interventions: 2 desaturations requiring oxygen without intubation, 8 neurologic abnormalities (hallucinations, visual abnormalities, no stroke), 6 urinary retentions. conclusion: early use of pca for severe voc was associated with a reduced length of hospital stay despite that these patients had higher pain score on admission. prospective studies are needed to support these positive outcomes. background: acute chest syndrome is one of the leading causes of death in children with sickle cell disease1-2. while the cause of acute chest syndrome most commonly is not identified, fat embolism and infectious causes are believed to be most common. with an extremely high mortality rate, rapid identification and initiation of therapy is essential for survival. case presentation: we describe the case of an 18-year-old female with sickle cell sc disease who was admitted for vasoocclusive pain crisis and quickly progressed to multi-system organ failure due to fat embolism syndrome and parvovirus b19 infection objectives: the case highlights the presentation and diagnosis so other providers can optimize outcomes for those with this under-recognized syndrome design/method: her parvovirus studies returned after 7 days which showed: parvovirus b19 dna pcr detected; parvo igg 1.99 (positive > 1.1); and igm 12.98 (positive > 1.1). the patient experienced an approximately 2.5 g/dl drop in hemoglobin(8.7 to 6.0 g/dl/24 hrs) with progressive thrombocytopenia (from 269,000 to 54,000/ul) and a peripheral smear showed microcytic,normochromic red cells with nucleated rbcs and occasional nuclear budding, slight polychromasia, schistocytes, and polymorphic cells with toxic granules that suggested leukoerythroblastosis. she was emergently transferred to the regional quaternary care hospital for ongoing ecmo therapy where she experienced a change in her pupillary exam prompting a stat ct scan that showed severe, diffuse cerebral edema with transtentorial herniation. the decision was made to withdraw life-sustaining therapies and her family refused a post-mortem autopsy examination. fat embolism syndrome is a severe and uncommonly recognized complication of sickle cell disease, seen most commonly in those with a non-ss phenotype and previous mild disease course who present with severe, unrelenting vaso-occlusive pain episode and/or acute chest syndrome that progresses to respiratory distress with altered mental status and cutaneous changes. rapid identification and initiation of exchange transfusion therapy should be initiated with clinical suspicion because of the extremely high mortality rate. although previously considered rare, it needs to be considered in the differential diagnosis of more commonly encountered complications of sickle cell disease. background: patients with sickle cell disease (scd) experience vaso-occlusive crisis (voc), which results in extreme pain, often requiring opioids and admission. genetic and environmental factors affect the frequency and severity of these episodes. previous research has born conflicting evidence on whether environmental temperature is contributory. edmonton, alberta is the northern most city with a population over a million in north america. there is an increasing sickle cell population which is exposed to extreme winter conditions. this provides a suitable population and atmosphere to study the influence on cold external temperatures in scd. this study sought to identify if pediatric patients with scd, experience greater morbidity in cold external temperatures. board approved retrospective case control series. patients were identified through a clinical database, and emergency visit, phone call and admission data was collected over a fiveyear period. the average, minimum and change in temperature on day of presentation, 24 and 48 hours prior, was collected from the government of alberta, and was statistically analyzed using descriptive statistics, to determine the relation to vaso-occlusive events. results: one-hundred and eighteen patients were identified, and 258 voc events reviewed. the mean patient age was 6.6 years of age with a range from 0.3-17 years old. the female to male ratio was equivalent with 133 female (51.6%) and 125 male (48.4%) voc events. eight records (3%) had docu-mented cold exposures. the analysis between the temperature and the frequency of events did not yield significant correlation. average and minimum temperature on day of admission had the largest percentage of voc events occur at mild temperatures, from -4.99 to 20 • c and -4.99 to 5 respectively. change in temperature on day of admission, 24 and 48 hours had the largest percentage of voc events at a mild to moderate change in temperature of 10-15 degrees. data at 24 & 48 hours prior to admission showed similar results. secondary data analysis accounting for the lower proportion of extreme weather days in comparison to moderate temperate days showed no significant impact. there was no correlation of average, minimum or change in temperature on day of admission, 24 or 48 hours prior. multiple cofounding factors likely contribute to these results. as it was a retrospective study many confounding and precipitant factors may not be recorded or identified. a prospective study to better record specific cold exposure is warranted. children's national health system, washington, district of columbia, united states background: achieving optimal anticoagulation with unfractionated heparin (ufh) in pediatric patients receiving extracorporeal membrane oxygenation (ecmo) is often challenging due to antithrombin (at)-mediated heparin resistance (hr). intermittent at dosing during pediatric ecmo support does not maintain adequate at levels. continuous at infusion (cati) presents an alternative strategy to achieving consistent goal at levels and optimizing heparinization. however, cati during pediatric ecmo has not been adequately studied. objectives: to describe our center's experience with an ecmo cati protocol. design/method: in 2014, we modified our ecmo anticoagulation protocols to include ufh titration according to anti-factor xa (anti-fxa) levels and cati in patients with at-mediated hr. the cati rate was calculated using baseline and goal at levels while accounting for the circuit volume. cati was administered with ufh into the circuit via a s127 of s301 y-infusion set. at and anti-fxa levels were monitored every 6 hours. recombinant at (r-at) concentrate was used at our center until 2015 with subsequent transition to a plasmaderived at (pd-at) concentrate. due to the longer half-life of pd-at concentrate, the protocol was modified so cati is stopped once target at and anti-fxa levels are achieved. we conducted a retrospective study of all patients who received cati during ecmo support at our center. data are reported as median and interquartile range and compared using the mann-whitney u test. two-tailed p-value <0.05 was considered statistically significant. since 2014, 24 patients [13 males, age 1 month (0.03-8)] on ecmo support received 27 catis (12 rat, 15 pd-at) per our protocol (3 patients received 2 pd-at infusions during one ecmo run). the duration of cati was 48 hours (23-72). cati administration led to significant increases in at and anti-fxa levels from baseline of 43% (39-53) and 0.11 units/ml (0.08-0.22) to the first level within goal of 64% (55-83) and 0.39 units/ml (0.35-0.5), respectively (p<0.00001). the respective times to achieve goal at and anti-fxa levels were 9 hours (5-21) and 13 hours (6-23). the respective peak at and anti-fxa levels were 83% (70-99) and 0.53 units/ml (0.35-0.63). during cati, no patient required circuit change, 1 patient developed cannula thrombosis and 5 patients experienced non-fatal major bleeding. conclusion: cati in pediatric patients receiving ecmo support with close monitoring of at and anti-fxa levels was associated with significant rapid increase in at, optimization of heparin effect, and reduction in thrombotic complications without increase in major bleeding compared to prior reports. a prospective study of this at dosing strategy is warranted. children's hospital of orange county, orange, california, united states background: inherited factor xiii (f13) deficiency is a rare bleeding disorder with wide heterogeneity in clinical manifestations ranging from mild bruising, and mucosal and umbilical stump bleeding to spontaneous, severe intracranial bleeding. the bleeding phenotype is influenced not just by zygosity of the fxiii mutation alone, but also by co-inheritance of variants in other clotting protein genes that also play a major role in clot formation and stability. we present a series of three siblings found with f13a1 gene variant and platelet dysfunction linked to bleeding phenotype. design/method: retrospective chart review of the index case, coagulation studies and whole gene sequencing. the index patient presented at two years of age with a subdural hematoma after a fall, requiring emergent craniotomy. a week after initial evacuation, she re-bled, prompting an extensive work-up for potential bleeding disorders, including f13 activity, von willebrand profile, comprehensive fibrinolysis panel, pai-1 antigen level, platelet mapping thromboelastogram (plt-teg), and f13 genetic analysis. the patient's identical twin and older sibling, who had symptoms of bruising, underwent a similar evaluation. the index patient demonstrated consistently low f13 activity (31-49%), and platelet function testing revealed decreased response to adp agonists. the twin and older sibling had normal f13 levels, and only slightly decreased response to adp in platelet studies. whole gene analysis of f13 and 21 other genes on our next generation panel, revealed several intronic deletions in the index patient that were not shared by her siblings, which likely account for her decrease in circulating f13 levels. her symptoms have responded well to monthly treatment with factor 13 concentrate. all three children shared the f13 variant, pro564leu, previously described as a risk factor for intracranial hemorrhage. the f13 mutation, pro564leu, has been associated with intracranial hemorrhage in young women, but the presence of the variant alone may not be enough to cause a severe bleeding phenotype. family studies identified novel deletions in the index patient which may account for her decreased f13 levels, which would have been overlooked with standard sequencing. future studies, including evaluation of 'platelet' f13 levels, should be performed when platelet dysfunction is detected. further laboratory and clinical evaluation is required to delineate the long term implications of the interaction of even mild f13 deficiency if present with additional clotting disorders such as the platelet function defect in these siblings. background: acquired hemolytic anemia can occur due to mechanical shearing of red blood cells and is classically seen in patients with prosthetic heart valves. there are reports of this same traumatic effect with other repairs, including annuloplasty. following valvular procedures flow disturbances can exist across the valve that lead to shear stress and hemolysis. although von willebrand disease (vwd) is typically seen due to an inherited disorder in the pediatric population, flow disturbances in the setting of valve abnormalities can lead to acquired von willebrand syndrome (avws). von willebrand factor multimers become unfolded and elongated in the setting of shear stress resulting in increased susceptibility to cleavage by adamsts-13. specifically, loss of high molecular weight multimers (hmwms) can lead to a syndrome akin to type 2a vwd. objectives: to describe a case of mechanical hemolysis with acquired type 2a vwd design/method: a 3-month-old girl with history of hypoplastic left heart syndrome and severe tricuspid valve insufficiency underwent norwood procedure, blalok-taussig shunt placement and subsequently a bidirectional glenn and tricuspid valve annuloplasty. during the following month she requires weekly red blood cell (rbc) transfusions due to intermittent anemia. she also experienced bloody stools and dark urine. laboratory evaluation was notable for normocytic anemia, reticulocytosis, elevated lactate dehydrogenase, and low haptoglobin consistent with hemolytic process. immune-mediated hemolysis from transfusion reaction or presence of autoimmune or alloimmune antibodies testing was negative. to investigate gi bleeding, work up for vwd revealed normal vw activity and antigen but with loss of high molecular weight multimers consistent with acquired type 2a vwd. in consultation with cardiology, it was felt her tricuspid valve insufficiency jet could be leading to mechanical hemolysis and avws. a repeat echo showed persistent moderate tricuspid insufficiency but no other significant changes. due to the patient's continued need for weekly rbc transfusions she was subsequently trialed on pentoxifylline which is used in adult patients to decrease blood viscosity and increase erythrocyte flexibility in patients with mechanical hemolysis. her transfusion needs remained the same and the medication was discontinued after two weeks. she required one transfusion a week later but no transfusions since that time. although not commonly seen in pediatric patients, the diagnosis of mechanical hemolysis accompanied by avws should be pursued in a patient with congenital heart disease with significant anemia and/or bleeding. the work up in these patients is difficult as echocardiograms can be inconclusive thus an extensive hematologic evaluation is usually necessary. objectives: our aim was to assess incidence of and potential risk factors for central line-related dvt at our institution between 2011-2016. additionally, our goal was to analyze if that incidence differed between the three central line types and identification of line-specific risks. design/method: a retrospective chart review of 377 central line placements in pediatric patients at cleveland clinic between 2011-2016 was conducted. data included demographics, potential risk factors, line characteristics and any related thrombotic events. the study cohort consisted of 377 lines in 326 pediatric patients aged 1-18 years of age. there were 1.5 thrombi (95% ci 1.0-2.3) per 10,000 line days. statistically significant risk factors for thrombus include diagnosis group (liquid tumor highest rate of 16%, solid tumor lowest at 2%), type of line (picc 5%, broviac 29%, and mediport 4%), location of line, greater number of lines per patient, peg asparaginase (23% vs 4%), sepsis, and history of procoagulant state. line characteristics such as lumen size and number of lumens were not identified as a significant risk. there was a significantly higher rate of thrombus in 2016 than in the previous years when pooled (12% in 2016 vs 4.3% from 2011-2015, p = 0.020). the incidence of dvt in pediatric patients at our institution was highest with broviac lines, and significant risk factors in our patient population included liquid tumor, femoral vein location, peg asparaginase, sepsis, and history of a procoagulant state. the incidence of thrombi was highest in 2016, and therefore highlights the urgent need for improvement in nationwide hospital practices to minimize risk of thrombi formation and early detection in the higher-risk s129 of s301 populations. there is still much to be learned regarding the characteristics specific to different central lines, which would influence thrombi formation. nyu winthrop hospital, mineola, new york, united states background: pediatric immune thrombocytopenic purpura (itp) is an autoimmune disorder with platelet counts <100000 causing increased risk for significant hemorrhage. there is increased immunologic platelet destruction due to production of specific autoantibodies along with inhibition of platelet production. few randomized trials exist to guide management and ultimately each patient requires an individualized treatment plan. itp may be acute (diagnosis to 3 m) or chronic (> 12 months). one of the treatments of chronic itp is laparoscopic splenectomy (ls), which is very well tolerated. a rare complication of ls is splenosis, an autotransplantation or implantation of ectopic splenic tissue within the abdominal cavity or in any other unusual body compartment. splenosis is sometimes associated with relapsed itp due to preserved immune activity. the usual management of symptomatic splenosis is surgical resection. objectives: to describe medical management in a young patient with itp relapsed due to extensive unresectable splenosis following ls design/method: our patient was originally diagnosed at 2 years with itp and was treated with ls at 5 years of age for chronic severe thrombocytopenia and persistent bleeding not responding to first line therapies. she tolerated it well and had a complete response (cr) defined as a platelet count of >100000 measured on 2 occasions >7 days apart and absence of bleeding. she maintained a normal platelet count for twelve years after which she relapsed (loss of response after cr) with severe thrombocytopenia and hematuria necessitating high dose steroids. ct scans showed multiple wellcircumscribed soft tissue masses in the left lower quadrant adjacent to uterus and left ovary, involving left omentum and the anterior abdominal wall partly. findings were confirmed by damaged rbc nuclear scan to be splenosis. during laparoscopy the splenosis lesions were deemed too extensive and were not resected completely to avoid postoperative morbidity. she was started on sirolimus around the same time for treatment of her relapsed itp and steroids were weaned off. results: eight months since beginning sirolimus with therapeutic levels she remains in cr with no bleeding and has not required any steroids, immunoglobulins or anti d immunoglobulin. conclusion: sirolimus is a safe and effective steroid-sparing agent in treatment of chronic itp. this is the first instance of a patient with poorly resectable splenosis responding well to medications for itp. more data is needed regarding the longterm efficacy of such an intervention and whether it will eliminate the need for a second surgery in relapsed itp patients with extensive splenosis. background: storage pool disorders affecting platelets result in bleeding symptoms related to a deficiency or defect in alpha granules or delta granules. in delta-storage pool disorders (dspd,) there is a deficiency of the delta granules and their constituents, which results in the inability of platelets to properly activate as well as lack of proper constriction of blood vessels during bleeding episodes. amongst patients with dspd, females most commonly present with menorrhagia, while males tend to present with epistaxis and easy bruising. the international society on thrombosis and hemostasis (isth) developed a screening bleeding assessment tool (bat) for mild bleeding disorders, shown to be a validated tool in children. diagnosis of dspd is classically made with a platelet electron microscopy (pem) value <3.69 delta granules per platelet (dg/pl), but recently lower diagnostic thresholds of 2 dg/pl or even 1.2 dg/pl have been suggested. objectives: evaluate the correlation between pem and bleeding scores, and also examine various cut-off values used to diagnose and risk stratify patients with dspd. design/method: retrospective chart review of 96 pediatric patients followed by hematology with a diagnosis of dspd was performed. clinicians obtained bleeding scores for each patient as standard of care in the hemostasis clinic. quartile ranges were established to appropriate three stages of severity based upon bleeding scores. statistical analysis was performed using software r and exploratory data analysis to evaluate for a correlation. results: amongst all patients, the average bat score was 6.17 and pem was 2.37 dg/pl. the average bleeding score for pem between 3.69 dg/pl and 2 dg/pl was 6.17, while the average bleeding score for pem below 2 dg/pl was 4.65. the correlation coefficient between pem and bleeding scores is 0.30. using a threshold of 2 dg/pl, 31% of patients would have met diagnostic criteria. quartile ranges for the bleeding scores are as follows: 1st quartile was 2-4, 2nd quartile was 5-7, and 3rd quartile was >8. conclusion: patients with a more marked granule deficiency do not exhibit a more severe bleeding phenotype, suggesting proper platelet function is not solely determined by granule quantity in these patients. bleeding severity may be more appropriately assessed with bleeding scores rather than pem values, and using quartile ranges may aide in risk stratification and therapeutic interventions for dspd patients. further work remains to determine the optimal diagnostic threshold of pem dspd in pediatric populations. texas children's hospital, houston, texas, united states background: warfarin management has many challenging aspects including pharmacogenomics, food and drug interactions, lack of standardized dosing, patient compliance, tracking lab results from multiple lab locations, and the potential for significant bleeding or thrombotic complications. a literature review revealed limited data highlighting anticoagulation monitoring workflow and emr documentation and specifically, no data in the pediatric population. historically, the texas children's hospital cardiology and hematology centers were each documenting anticoagulation data within the epic tm system differently. epic's tm original design for anticoagulation documenting resulted in the necessity to duplicate documentation in order to see at-a-glance critical anticoagulation monitoring information. objectives: the objective of this project was to standardize inr documentation across departments to reduce the risk of patient safety events and improve workflow. design/method: a workgroup assembled consisting of nurses from the cardiology and hematology departments, along with staff members from the epic tm is support group. the workgroup identified current documentation practices, available epic tm tools, and brainstormed ideas to streamline and improve both documentation with the current epic tm tools. physician partners were identified in cardiology, hematology and coagulation laboratory to gain their input. a new anti-coag (ac) encounter was developed and first made available in an epic tm practice environment, then once approved, epic tm written education and training session were completed by both departments' staff. results: surveys were sent to 19 health care providers in the cardiology and hematology centers prior to the new ac encounter, and also to 27 health care providers six months after implementing the ac encounter. six responses were received for each survey. the pre-implementation survey showed the most problematic part of the documentation system for anticoagulation was no single place in the emr to find a complete anticoagulation picture. post ac encounter implementation survey results revealed more health care providers using the epic tm inr reminder pool, less time needed to compile a report of three months of anticoagulation information, less time needed to document individual encounters, less locations needed to document ac information and decreased amount of types of documentation used. standardized ac encounters improves workflow with less time needed to document and compile information, less types of documentation utilized and easier access to patients ac information. next steps include retrospective review of patients' inr time in therapeutic range to determine if there was an impact on patient compliance and continue to evaluate and modify the ac encounter to enhance user friendliness. caitlin tydings, jennifer meldau, christine guelcher, carole hennessey, eena kapoor, michael guerrera, yaser diab s131 of s301 children's national health system, washington, district of columbia, united states background: venous anatomic abnormalities (vaas) are considered a risk factor for developing deep vein thromboses (dvts) that occur as a result of significant alterations in venous blood flow. identification of predisposing vaas can be challenging. hence, diagnosis can be delayed or overlooked especially in pediatric patients. dvts in children or adolescents with predisposing vaas have been only described in sporadic case reports and small case series. objectives: to describe characteristics and outcomes of dvts in pediatric patients with underlying vaa treated at our center. design/method: we conducted a retrospective chart review of all pediatric patients with objectively confirmed extremity dvt treated at our institution over a 6-year period from 2011 to 2017 and identified all patients with underlying vaas. patients were managed according to standardized institutional protocols based on published guidelines. post-thrombotic syndrome (pts) was assessed at our center using the manco-johnson instrument. relevant data were collected and summarized using descriptive statistics. during the study period, 20 of 227 pediatric patients (9%) [14 females, median age 17 years (range 11-20)] diagnosed with extremity dvt at our center were found to have an underlying vaa. vaas included may-thurner anomaly (13 patients), venous thoracic outlet obstruction (5 patients) and inferior vena cava (ivc) atresia (2 patients). additional provoking factors were identified in 14 patients at time of presentation. dvt locations included upper extremity veins (5 patients), lower extremity veins (9 patients) and lower extremity veins and ivc (6 patients). the majority of dvts [17 patients, (85%)] were completely occlusive. high risk thrombophilia (defined as inherited deficiency of antithrombin, protein c, or protein s, or antiphospholipid antibody syndrome) was present in 6 patients (30%). all patients were treated with therapeutic anticoagulation with 6 patients continuing indefinite anticoagulation. endovascular interventions were performed in 18 patients and included percutaneous pharmacomechanical thrombectomy and/or catheter-directed thrombolysis (15 patients), balloon angioplasty (11 patients) and stent angioplasty (9 patients). surgical interventions included thoracic decompressive surgery (5 patients) and surgical thrombectomy (1 patient vvas represent an important risk factor for developing extensive extremity dvt in adolescents. this special population is at risk for short-term and long-term com-plications. early identification and correction of vaas may improve outcomes. however, multicenter, prospective studies are needed for developing optimal evidence-based treatment approaches. alexander glaros, roland chu, sureyya savasan, meera chitlur, madhvi rajpurkar, yaddanapudi ravindranath children's hospital of michigan, detroit, michigan, united states background: acute budd-chiari syndrome (bcs) is a rare thrombotic emergency in children, and etiologies/treatment are less well-defined than in adults. in adults, a systematic approach including anticoagulation, relief of venous obstruction, and treatment of the underlying cause has proven successful. more recently treatment has tilted towards aggressive surgical interventions, which carry significant risk and are often not feasible. objectives: review our experience with three different patients with bcs and suggest a mechanistic based approach to treatment. the records of three patients with bcs were reviewed and their presentations, etiologies, treatment, and outcomes were reported. results: patient a was a 17-year-old female with paroxysmal nocturnal hemoglobinuria who presented with recurrent worsening abdominal pain over several months. narrowing of inferior vena cava (ivc) and hepatic veins was noted on imaging. liver transplant was not considered surgically feasible. she was treated with eculizumab, steroids, and anticoagulation with restoration of hepatic venous flow in 4 weeks. patient b was a 14-year-old male with several weeks of right upper quadrant pain, fatigue, and pre-syncopal episodes, with a history of blunt abdominal trauma from football scrimmage 4 weeks earlier. he was found to have near complete occlusion of the ivc and hepatic veins. liver transplant was not considered feasible. he was successfully treated with anticoagulation alone. patient c was a 3-yearold male with acute myeloid leukemia in induction cycle 2 who developed severe pancytopenia; typhlitis was diagnosed and managed medically. days later he acutely decompensated, arrested, and was placed on extra corporeal membrane oxygenation, and imaging showed complete occlusion of the portal vein, hepatic veins, and ivc to the level of the atrium, with bilateral pulmonary emboli. emergency liver transplant or catheter based interventions was deemed not feasible. treatment with eculizumab was considered for presumed inflammation induced complement activation (c3 59mg/dl [normal 77-171]; ch50 was 12u/ml [normal 42-91]) as a trigger for thrombosis, but the patient progressed quickly and died before it could be initiated. our experience with bcs shows that invasive interventional options and liver transplant may not be feasible in most patients for multiple reasons. rapid diagnosis and aggressive etiology-based medical management are paramount to successful treatment of this rare complication. eculizumab may be considered in treating bcs with complement activation not only due to innate disorders, but also secondary to acute inflammation when proper laboratory evidence is present. background: platelet aggregation studies are the gold standard for the diagnosis of platelet function defects during the evaluation of a patient with bleeding problems. the platelet aggregation test measures how well platelets clot in response to different concentrations of epinephrine, adenosine diphosphate (adp), collagen, arachidonic acid and ristocetin. because platelet function defects are often under-recognized and under-diagnosed in the pediatric patient, the true incidence is unknown. we report our experience in the diagnosis of platelet defects at our institution over a 5-year period in order to add some clarity to the limited pediatric data available. objectives: our primary objective is to document correlations/trends between less well-known platelet function abnormalities and clinically significant bleeding at our institution over a 5-year period. design/method: after appropriate irb approval obtained, we performed a retrospective chart review of all children who had platelet aggregation testing done from 2011 to 2015. data collected included demographics (age, sex, race), personal and family history of bleeding, screening for coagulation defects and platelet aggregation test results. symptoms examined in our data were limited to epistaxis and heavy menstrual periods. for each of these symptoms, results were further analyzed to those with abnormal responses to adp and epinephrine. patients with existing bleeding diagnoses and those with incomplete medical records were excluded. we identified 159 patients. of the patients with epistaxis, 70% had abnormal platelet aggregation testing while only 36% of those with heavy menstrual periods had abnormal results. within our population, abnormal platelet function assay (pfa-100) results or race did not appear to correlate with abnormal platelet aggregation testing. in the cases of epistaxis, sex was also noncontributory. our preliminary results suggest that platelet aggregation testing was more useful in predicting platelet defects in those with a clinical bleeding history of epistaxis as opposed to heavy menstrual periods. for other presenting symptoms, platelet aggregation testing did not offer diagnostic benefit. abnormal response to adp in the platelet aggregation test was the most common finding in our population; the clinical significance of which is not well understood. going forward, we plan to document whether abnormal results correlated significantly with the subsequent final diagnoses of our patients. background: decision making for severe hemophilia a in previously untreated patients (pups) has recently become a significant ethical debate. recombinant factor viii (rfviii) products previously were recommended to avoid transmission of blood borne pathogens associated with plasma-derived fviii (pdfviii) products. however, the increased incidence of fviii alloantibody inhibitors with rfviii products compared to pdfviii products has challenged this former standard of care. despite the support of the medical and scientific advisory council, recommendations considering pdfviii products for a pup remains controversial. design/method: we used a modified utilitarian approach involving clinical, public health, and research ethics. shared decision making permeates the framework to maximize understanding, minimize bias, respect informed consent or dissent, and provide care that aligns with patient and family values when medically and practically feasible. the framework has three tiers. first, it evaluates whether resources are scarce or abundant for equitable resource allocation. if fviii products are scarce, we s133 of s301 recommend developing a central supply for emergency use and then evaluating the needs of the severe hemophilia a patients. prioritization of who receives the factor products would be decided by a designated team based on the availability of the factor products and clinical scenarios, with no preference given to those on research trials. however, if resources are abundant, treatment for acute bleeding and standard of care prophylaxis measures, including primary prophylaxis, could continue. the second tier accounts for whether there is a new infectious epidemic or concern where a pathogen cannot be eliminated. if there is, healthcare and public health workers may limit the use of pdfviii products. if not, pdfviii and rfviii products are to be equally considered. the third tier evaluates whether the clinical scenario is emergent or not. if there is acute, emergent bleeding, the immediately available resource should be used, along with bypassing and/or adjuvant resources as needed until the bleeding has resolved or improved. to align with patient and family preferences, attempts to have both pdfviii and rfviii products available at similar costs in institutions would be ideal. this ethical framework endeavors to balance autonomy, beneficence, nonmaleficence and justice in helping guide discussions among providers, pups with severe hemophilia a, and their families. disclaimer: findings and conclusions are those of the author(s) and do not necessarily represent the official position of the centers for disease control and prevention, emory university, or children's healthcare of atlanta. background: von willebrand disease (vwd) is a common bleeding disorder which affects up to 1% of the population without gender predilection. bleeding associated with this condition results from a deficiency or abnormality in von willebrand factor interfering with formation of primary hemostasis. ehlers-danlos syndrome (eds) is a group of rare inherited connective tissue disorders which may have an associated bleeding manifestation without abnormalities in coagulation testing. bleeding symptoms reported in eds result from capillary and tissue fragility. joint hypermobility syndrome (jhs) is an inherited condition which is nearly indistinguishable from eds iii. reports of coinheritance of vwd and eds or jhs are infrequent. the objective of this retrospective study was to review patients with coexisting vwd and eds or jhs at the indiana hemophilia and thrombosis center in order to describe the type and severity of bleeding symptoms, physical examination findings, and pertinent laboratory data. design/method: the electronic medical record database of the indiana hemophilia and thrombosis center was queried for patients with a diagnosis of vwd and one of the following descriptors: hypermobility syndrome, hypermobility, hypermobile joints, or ehlers-danlos syndrome. the records of identified patients were reviewed for demographics, type and severity of bleeding symptoms, beighton scores (bs), vwd antigen, ristocetin cofactor, factor viii levels, vwd multimer pattern, vwd subtype, genetic testing for eds, and family history of eds. results: a total of 6 patients with dual diagnoses of vwd and eds and 21 patients with vwd and hypermobility were identified with this query. two patients had completed genetic testing for eds, and one had a col1a1 gene mutation identified. significant bleeding symptoms in the vwd and eds group included hematuria and postoperative hemorrhage. two of these patients had delayed wound healing postoperatively. seven of the 19 patients identified to have type i vwd and jhs had moderately severe and somewhat unusual bleeding episodes reported including hematuria, hematemesis, and hemoptysis; 4 of these patients had significant perioperative bleeding. females composed 83% of the vwd and eds group and 76% of the vwd and jhs group. conclusion: coinheritance of vwd and eds is an uncommon phenomenon. patients with vwd and eds or jhs may have atypical and moderately severe bleeding, especially with procedural intervention. incorporation of bs into the assessment of patients with bleeding disorders is useful to identify potential inherited collagen disorders, as diagnosis of these conditions may impact clinical management. in the year-long phase ii study (ro1fd003712), 11/12 khe patients responded. patients were followed for 5 years after study completion, collecting data on growth and development, complications of therapy, unexpected toxicities, and need for continuing sirolimus. objectives: after study therapy treatment of one year, objectives include: 1. assess long term toxicity over the 4-5 year period after study therapy completion 2. assess unexpected toxicity 3. assess overall condition of the patient 4. assess need for restart or continuation of sirolimus therapy design/method: prospective follow-up of patients with a diagnosis of khe from 2 institutions. inclusion criteria: follow-up for 4-5 years post-study. results: follow-up included data at 5 year (n = 5) and 4-4.5 year (n = 4) time points. average age at the start of treatment was 12 months. 9 of 12 patients were available for follow up. four patients are no longer on sirolimus: one patient completed study therapy and remains off treatment (ot) (7 years), 1 required 2 years of treatment and is now 2.5 years ot and 2 required an additional treatment course prior to successful discontinuation now 17 and 22 months ot. of the 5 patients still on sirolimus, all restarted medication for symptoms of pain, swelling and/or edema interfering with quality of life and have made an average of 2.5 attempts to discontinue sirolimus. no patient had reoccurrence of kmp. all patients had improvement in clinical and radiologic appearance of khe but all have residual lesions noted on imaging and/or clinical exam. no unexpected toxicity, growth delay, developmental issues or other long term toxicity of sirolimus was noted. conclusion: this is the first prospective data on long-term follow up of khe patients treated with sirolimus. although numbers are small, sirolimus is well tolerated; however, over half the patients were still on medication at 4-5 year follow up. this stresses the need for continued long term follow up in these young patients and investigation of the mechanism of sirolimus effect. nationwide children's hospital, columbus, ohio, united states background: recent studies have identified that adult persons with hemophilia (pwh) have a higher prevalence of hypertension and renal disease than the general population. while hematuria is a known complication of hemophilia a and b (ha, hb), its long-term impact on pwh is not currently known. by annually screening our patients with urinalysis, our pediatric center identified that just under half of our patients demonstrated hematuria over a four-year period. motivated by a desire to identify early markers of hypertension and renal disease, we sought to determine if this finding is reflected in the pediatric hemophilia population as a whole. objectives: establish the population-wide prevalence of hematuria in pediatric pwh. design/method: we used the pediatric health information system (phis) database, which contains clinical and resource utilization data for inpatients from 45 hospitals nationwide, to analyze the prevalence of hematuria, hypertension, renal disease and related diagnosis codes in pediatric pwh who were admitted from january 2010 to september 2015. results: during the five-year period, 2,197 unique pediatric pwh accounted for 4,802 admissions. while the majority of admissions were for bleeding or infectious concerns, 96 (4.4%) patients had an affiliated admission code for hematuria. for admissions as a whole, the median age was 7 years with 12% of those admitted being infants, 32% toddlers, 27% children, 28% adolescents, 2% older than 21. we identified 83% of admissions were for ha with the remaining 17% were for hb. there were 1254 (26%) admits in which a bypassing agent was administered. the median length of stay for persons with hematuria was 2 days compared to 3 days for nonhematuria/other bleeding. there were 120 (2.5%) admissions with hypertension reported; though, only 3 patients received an antihypertensive medication during that admission. additionally, only 31 (0.6%) admissions reported a diagnosis code of renal disease. our study demonstrated that pediatric pwh are experiencing hematuria. in general, only patients with persistent hematuria require hospital admission so we suspect this data underrepresents the numbers of pwh experiencing hematuria that is managed in the outpatient setting. we also suspect that hypertension is grossly underreported and undertreated in pediatric pwh. additionally, there are a low number of patients experiencing renal disease requiring hospital admission among this cohort. given that there is little research into the long-term impact of hematuria in hemophilia, we feel these findings support the need for further vigilance of our pediatric pwh. background: gla and gsd can aggressively destroy bone, with significant impact on morbidity and mortality. the mtor inhibitor, sirolimus has been shown to be effective in the treatment of these diseases. based on the addition of mtor inhibition to bisphosphonate therapy in metastatic cancer therapy, regimens have been used for refractory or high risk gla and gsd but there is heterogeneity of diagnosis, and variability of drug regimens and assessment of effectiveness. objectives: 1. assess the variability of clinical features of gla and gsd 2. assess the heterogeneity of diagnosis 3. assess drug regimens and response assessment across multiple institutions design/method: we conducted a retrospective review from 5 institutions of 19 cases of gla and gsd treated with sirolimus and a bisphosphonate for at least 2 months with assessment of clinical features, treatment protocols, response regimens and side effects. results: patients included gla (n = 8) and gsd (n = 11). the average age at diagnosis was 10 years. clinical features included effusions: gla (n = 4), soft tissue lymphatic malformations: gla (n = 3), gsd (n = 1), multiple splenic lesions: gla (n = 3), and soft tissue swelling at the site of bony lesion: gsd (n = 3). the presenting symptom in 17 patients was pain with 2 patients (gla) presenting with shortness of breath. fracture was noted in 5 patients: gla (1), gsd (4). diagnostic and/or response imaging included mri, ct, bone scan, skeletal survey and dexa scan. treatment consisted of: initial sirolimus use with the addition of bisphosphonate secondary to worsening disease (n = 4), initial therapy with other agents (interferon, chemotherapeutic agents, radiation) and change to sirolimus and bisphosphonate secondary to toxicity (n = 6), sirolimus and bisphosphonates (n = 7) and sirolimus, bisphosphonates and interferon (n = 2). seventeen patients had stable disease and 8 patients had improvement of disease. sirolimus protocol was standard; however, bisphosphonate protocol varied in dosing and frequency. side effects were tolerable and expected with no grade iii or iv toxicity. sirolimus and bisphosphonates are a safe and effective therapy for gsd and gla. a consistent medication regimen, redefined response and an improved radiologic classification will be important for the development of a prospective clinical trial. background: hemophilia a is a bleeding disorder from the deficiency of clotting factor viii. the most significant sequelae of hemophilia a is the tendency to develop hemarthrosis that incites joint destruction. the prevalence of overweight and obesity has been increasing in the general and hemophilia population and leads to several morbidities including arthropathy. this is a particular concern for hemophilia a as arthropathy is a consequence of joint bleeding. objectives: the purpose of this study was to detect the relation between body mass index (bmi) and joint health endpoints in a pediatric hemophilia population. design/method: participants in this study included 64 patients from the hemostasis and thrombosis center at children's hospital los angeles. participants were pre-screened and approached for this study during routine follow-up appointments. patients aged 4-18 years old who have been diagnosed with hemophilia a, including mild, moderate, and severe, qualified for the study. informed consent was obtained from the patients or parents before enrollment. joint health was objectively measured by physical therapists from children's hospital los angeles using the hemophilia joint health score (hjhs). an hjhs total score is calculated by assessing: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and muscle strength in 6 major joints. subjective data was also obtained by patients recording their annual bleed rate within the past year. of the 64 patients, 28 (44%) were normal weight, 12 (19%) overweight, and 24 (38%) obese. we used chi-square analysis to compare joint scores across bmi classifications (chi square = 2.87, df = 2, p-value = 0.24). although, this did not approach statistical significance, the average hjhs score in patients who had a hjhs >0 shows an increasing trend among bmi classifications: 6.19 in normal bmi patients, 6.75 in overweight bmi patients, and 7.00 in obese bmi patients. the average number of annual bleeds in those with positive values show: 8 in normal bmi patients, 5 in overweight bmi patients, and 12 in obese bmi patients. although a positive effect of adiposity was found in the joints of hemophilia a pediatric patients, the effect shows there was not enough evidence to conclude a difference. future studies are needed to address whether obesity has an effect on hemophilia and to determine whether overweight/obesity can lead to further complications in hemophilic joints. background: stagnant blood flow in slow-flow vascular malformations (vm), particularly in their venous components, can lead to localized intravascular coagulation (lic) that is characterized by elevated d-dimer levels, low fibrinogen and decreased platelet count this coagulation derangement can lead to localized thrombosis or bleeding which can result in pain, functional limitations, and possible progression to disseminated intravascular coagulopathy (dic). the treatment of vm and their associated coagulopathy has proven difficult. patients with complex vm are frequently managed with sirolimus, an mtor inhibitor, and have clinical benefits, including reduction of pain and improvement in functional impairment. it is possible that some of these improvements from sirolimus could be secondary to improvement in the coexisting lic. objectives: this study assessed the use of sirolimus to manage the coagulopathy seen in slow-flow vm. design/method: we reviewed charts of patients with vm who are followed in the vascular anomalies center at arkansas children's hospital and were started on sirolimus. efficacy was objectively assessed through improvement of ddimer, fibrinogen and platelet count. three sets of lab values (pre-sirolimus, 1-3 months post-sirolimus, and most recent) were obtained for each patient when available. we identified a total of 35 patients who had been prescribed sirolimus. eighteen were excluded based on underlying condition other than slow-flow vascular malformation and 1 for inadequate medical records. a total of 16 patients (13 combined vascular, 3 venous) were included in the study. all 16 had elevated d-dimer levels (mean 4.64 mcg/ml feu, median 2.99 mcg/ml feu, range (0.83-14.65)) prior to treatment. two patients had an associated low fibrinogen (below 175 mg/dl), indicating severe lic. with treatment, 14 (87.5%) patients showed an overall decrease in d-dimer levels with an average decrease of 1.52 mcg/ml feu between pre-and post-sirolimus labs, and an average decrease of 1.03 mcg/ml feu between pre-sirolimus and most recent values. the two patients with low fibrinogen prior to treatment showed a decrease in d-dimer levels (mean decrease of 7.845 mcg/ml feu) and an increase and normalization in fibrinogen (mean increase 83.95 mg/dl) after beginning sirolimus. no patient had thrombocytopenia. we report that treatment with sirolimus was effective in improving coagulopathy associated with slowflow vm as evidenced by decreased d-dimer levels and increased fibrinogen and/or platelets. long-term use of this medication in this population may decrease the bleeding and thrombotic complications that these patients experience, especially following invasive vascular procedures. background: safety and efficacy of bay 94-9027, a sitespecifically pegylated b-domain-deleted recombinant factor viii, in previously treated adolescents and adults aged 12-65 years with severe hemophilia a was demonstrated in the phase 2/3 protect viii study and ongoing extension. objectives: this subanalysis examines the efficacy and safety of bay 94-9027 in adolescents in protect viii and the ongoing extension study (data cutoff, january 2015). design/method: in protect viii, 134 patients (including 12 adolescents) received bay 94-9027 on demand or as prophylaxis for 36 weeks. prophylaxis regimens for weeks 10-36 were twice-weekly (30-40 iu/kg), every-5-days (45-60 iu/kg), or once-weekly (60 iu/kg) infusions based on bleeding during a 10-week run-in period of 25 iu/kg twice-weekly prophylaxis. patients continued their prophylaxis regimens in the extension or changed regimens at any time. results: twelve patients aged 12-17 years were included in the protect viii intent-to-treat population; 1 s137 of s301 additional patient discontinued after 1 dose (included in safety population). for 11 patients receiving prophylaxis before study enrollment, median (range) number of total and joint bleeds in the 12 months before study entry was 8.0 (0-15) and 6.0 (0-10), respectively. ten patients (83.3%) had target joints at baseline (median [range],1 [0-4] per patient). during weeks 10-36 of protect viii for the entire time patients remained on their designated prophylaxis dosing frequency, the median (quartile [q]1; q3) annualized bleeding rate (abr) for patients receiving twice-weekly (n = 3), every-5-days (n = 6), and once-weekly prophylaxis (n = 3) was 0 (0; 2.0), 1.1 (0; 8.2), and 18.4 (0; 19.3), respectively (overall prophylaxis [n = 12], 1.0 [0.0; 10.1]). two patients switched from once-weekly to twice-weekly (n = 1) or every-5-days prophylaxis (n = 1), and number of bleeds decreased from 2 to 1 in one patient and 6 to 4 in the other. all 12 patients from the main study continued in the extension; mean abr in the extension was 3.2 and varied by dosing regimen (twice weekly [n = 3], 3.2; every 5 days [n = 5], 5.2; once weekly [n = 2], 0.9). two patients changed from every-5-days to once-weekly prophylaxis during extension (mean abr, 0.6). one patient had a nonneutralizing antibody to bay 94-9027 at baseline; end-of-study titers were negative. no patient developed anti-peg antibodies or factor viii inhibitors or experienced a serious adverse event related to bay 94-9027 during the main study or extension. in previously treated adolescents with severe hemophilia a, bay 94-9027 prophylaxis was effective in prevention of bleeds, with less bleeding overall versus prestudy, and was generally well tolerated. funded by bayer. cincinnati children's hospital medical center, cincinnati, ohio, united states background: vascular malformations (vms) consist of a heterogeneous group of congenital disorders characterized by the abnormal development of blood and/or lymphatic vessels, which cause a broad spectrum of clinical manifestations. although considered benign, vms are frequently associated with cutaneous complications that can cause significant morbidity such as nodular overgrowth, skin thickening, pruritus, oozing or bleeding of lymphatic blebs and secondary infection. oral sirolimus has shown to be effective in the treatment of complicated vascular malformations but has known side effects and need for frequent laboratory monitoring. currently, there are limited studies on the use of topical sirolimus for the treatment of cutaneous manifestations of vascular malformations. objectives: to evaluate the efficacy and safety of topical sirolimus in vms with cutaneous complications and propose indications for use. design/method: this is a retrospective review of medical records of patients with vascular malformations treated with topical sirolimus from january 2012 to december 2017. response was determined by subjective and objective improvement. results: twenty-four patients, 16 (66%) females and 8 (33%) males, with vascular malformations and cutaneous manifestations were treated with topical sirolimus. age ranged from 4-27 years. indications for treatment were: blebs (79%, n = 19) causing either leaking, bleeding, pain, pruritus, swelling or recurrent infection; nodular overgrowth 8% (n = 2); pyogenic granuloma 4% (n = 1); bleeding 4% (n = 1) and cosmetic 4% (n = 1). treatment course ranged from 1-18 months. no major side effects were reported. one patient reported burning and itching sensation. regarding clinical response: 83% (n = 20) patients had improvement in cutaneous lesions; 12% (n = 3) had a stable lesions; and 4% (n = 1) stopped treatment due to side effects. for prior/concomitant treatment: 83% (n = 20) had prior surgery, laser or sclerotherapy; 37% (n = 9) had concomitant oral sirolimus. of the 15 patients not receiving concomitant systemic sirolimus, only 13% (n = 2/15) had been on oral sirolimus. of these patients, 80% (n = 12/15) had a very good response to topical treatment. : topical sirolimus appears to be beneficial and well-tolerated with a minimal side effect profile for the treatment of cutaneous manifestations of vascular malformations as a single agent or as adjuvant therapy with systemic sirolimus when symptoms are not adequately controlled. further studies are needed to prospectively analyze efficacy and safety of topical sirolimus in this patient population. objectives: to evaluate the safety and efficacy of long-term romiplostim in children with itp. design/method: all patients received weekly sc romiplostim from 1-10 g/kg to target platelet counts of 50-200 × 10(9)/l. median (min-max) treatment for the 65 patients was 135 (5-363) weeks for a total of 182 patient-years, or 2.8 years per patient. at baseline, median (min-max) age was 11 (3-18) years; 56% were female; 9.1% had prior splenectomy. median (min-max) average weekly dose was 4.8 (0.1-10.0) g/kg, including escalation to a stable dose; 20 patients started on 1 g/kg. reasons for discontinuing romiplostim (n = 28, 42%) included consent withdrawn (n = 10), required other therapy (n = 6), and ae (n = 2) (asthenia, headache, dehydration, and vomiting in one patient and anxiety in the other; none treatment related). fifty four serious aes occurred in 19 patients but were treatment related in one (concurrent grade 4 thrombocytopenia, grade 3 epistaxis, and grade 2 anemia). anti-romiplostim neutralizing antibodies were detected in one patient who discontinued to receive other therapy; antibodies were absent on retesting. from week 2 on, median platelet counts remained >50 × 10(9)/l; median platelet counts were >100 × 10(9)/l from weeks 24-260. nearly all (94%, 61/65) patients had ≥1 platelet response (platelet counts ≥50 × 10(9)/l, excluding ≤4 weeks after rescue medication). most (72%, 47/65) patients had a platelet response ≥75% of the time and 58% (38/65) did ≥90% of the time. sixty (92%) patients (or caregivers) self-administered romiplostim. fifteen (23%) patients had treatment-free periods of platelet counts ≥50 × 10(9)/l for ≥24 weeks (ie, remission); these patients (9 girls, 6 boys) had had itp for a median (min-max) of 3.5 (1.3-13) years, none had prior splenectomy, and had received romiplostim for 2.1 (0.7-6) years. all 15 had platelet counts >100 × 10(9)/l for ≥3 months and 12/15 for ≥6 months; the median (min-max) duration of being ≥100 × 10(9)/l was 42 (13-109) weeks. of baseline characteristics such as sex, platelet counts, itp duration, and number of past itp treatments (1, 2, 3, >3), only age <6 years was predictive of developing treatment-free periods ≥24 weeks (p = 0.0035). in this seven-year open-label extension, >90% of children with itp achieved a platelet response and romiplostim was well tolerated. importantly, 23% of patients were able to discontinue all itp medications for ≥6 months. funded by amgen inc. background: sirolimus is an immunosuppressive drug that is widely used in solid organ and bone marrow transplantation, and more recently for the treatment of vascular and lymphatic anomalies. sirolimus has been associated with decreased immunity in the transplant setting in patients that have received other immunosuppressive drugs or were immunosuppressed from previous chemotherapy. the effects of sirolimus on the immune system in chemotherapy naïve children who have not received other immunosuppressive agents are not well understood, and there is variability in the approach to fever and pcp prophylaxis. to understand the effects of sirolimus on the immune system of patients with non-complicated vascular or lymphatic anomalies by evaluating anc, alc prior to and after sirolimus therapy. design/method: multi-institutional retrospective review was done to include patients with non-complicated vascular or lymphatic anomalies. those with effusions/ascites, multiorgan involvement, or history of vascular-anomaly-related infections prior to treatment were excluded. results: twenty patients with kaposiform hemangioendothelioma (n = 6), generalized lymphatic anomaly (n = 2), cloves syndrome (1), and simple vascular malformation (n = 11) were included. age at initiation of sirolimus treatment ranged from 0.5 -20 years. male to female ratio was 9:11. sirolimus was initiated due to extensive disease, lack of response to steroids or bisphosphonates, pain, dment, lymphatic drainage, and prevention of ongoing overgrowth. prior to the start of sirolimus (sir-0) the mean anc was 3850 and alc was 2875. the target level of sirolimus varied by indication and patient, and ranged from 6 to 10. after the 1st steady state level, 1 month after sirolimus (sir-1) the mean anc decreased to 2951 and alc was 2793. at 3 months after sirolimus (sir-3) the mean anc was 3108 and alc was 2874. the first sirolimus levels (sir-1) mean was 11.3; and sir-3 level was 7.8. nine patients were placed on pcp prophylaxis at the start of sirolimus. none of these patients had an infectious complication while on sirolimus at a median f/u of 13 months. one patient had mild neutropenia (anc >500) which normalized after discontinuation of pjp prophylaxis. conclusion: in this small cohort of patients we found that the anc and alc level in patients with non-complicated vascular or lymphatic anomalies at sir-0 was not different from the sir-1 or sir-3. prospective studies that specifically track anc, alc, igg, and lymphocyte function should be conducted to better understand the effects of sirolimus in the immune system. this data will allow for uniform recommendations regarding prophylaxis and management of febrile episodes. background: acute infections and the associated systemic inflammation can increase the risk of venous thromboembolism (vte) and in certain well-defined clinical scenarios may be the primary trigger of vte in pediatric patients. pediatric data on vte in the setting of acute infection are sparse. objectives: to describe characteristics and outcomes of vte in pediatric patients with acute infections. we conducted a retrospective chart review of all pediatric patients with objectively confirmed vte treated at our institution since 2011 and identified all patients in whom an acute infection was identified as a vte trigger. patients were managed according to standardized institutional protocols based on published guidelines. relevant demographic, clinical and laboratory data were collected and summarized using descriptive statistics. since 2011, acute infection was identified as a trigger in 147 of 429 vtes (34%) diagnosed at our center. the median age at time of vte diagnosis in this group was 2.3 years (interquartile range 0.3-16). males were more commonly affected than females, representing 56% of cases. neonatal vte events accounted for 14% of cases. sepsis was the most common acute infection to be identified as a vte trigger [59/147 cases (40%)]. most vte events (80%) associated with acute infections were considered hospital-associated vtes. at time of vte diagnosis, 61% of patients were critically ill. extensive vte (defined as completely occlusive thrombosis involving >1 venous segment) occurred in 16% of patients. acute infection was deemed to be the primary trigger for vte in 30/147 patients (20%). infection-associated vtes in this cohort included cerebral sinus venous thrombosis due to sinus or cns infection (13 patients, 43%), septic throm-bophlebitis (11 patients, 37%), lemierre's or lemierre's-like syndrome (4 patients, 13%) and osteomyelitis-associated deep vein thrombosis (2 patients, 7%). systemic anticoagulation was prescribed in 124/147 patients (84%). anticoagulationrelated major bleeding occurred in 10/124 patients (8%). vte complications included vte recurrence (16 patients, 10%), vte progression (1 patient), acute pulmonary embolism (2 patients) and arterial ischemic stroke (2 patients). our study indicates that acute infection is a common risk factor for pediatric vte, especially in critically ill children, and can be the primary trigger in a significant proportion of vte cases associated with acute infections. anticoagulation appeared to be overall safe in this population and was associated with low rates of serious vte-related acute complications. however, our study also suggests that this population may be at increased risk for vte recurrence and anticoagulation-related major bleeding. background: epithelioid hemangiomas (eh) are rare benign vascular tumors that occur in soft tissues and bone and present between the third and sixth decades of life. a subset (29%) of eh harbor fos rearrangement. eh has been described in children, but little is known about the long-term outcomes of pediatric eh. the main objective is to obtain data to be used for improved understanding of this rare disease in order to provide standardization of care and development of future research studies. board-approved retrospective review of clinical, pathologic, and radiographic characteristics, and treatment outcomes in 11 patients diagnosed with eh between 1999 and 2017. results: eight patients were male; mean age at diagnosis was 14.8 years (range: 6-23). lesions involved the lower extremities (n = 5), cranium (n = 3), pelvis (n = 2), and spine (n = 1). multifocal disease was identified in five patients. the most common presentations involved significant localized pain and neurologic symptoms: headache, cranial nerve injury, loss of consciousness. radiographic studies identified variable features, such as multifocal lytic bony lesions with sclerotic margins, enhancing soft tissue component, and surrounding inflammatory edema. histologically, all specimens were composed of vascular channels lined by epithelioid endothelial cells without significant cytologic atypia; solid cellular areas (n = 2). endothelial cells were positive for cd31 and egr, and negative for camta1. fos rearrangement was assessed in only one specimen and detected. mean follow-up time was 545 days (range: 23-2642). patients were treated with surgical resection, intravascular embolization, bisphosphonates, propranolol, interferon, and sirolimus. one patient treated with interferon and one with sirolimus exhibited partial response for mean follow-up of 1566.5 days. although eh is a benign neoplasm, it is difficult to manage without standard protocols and portends considerable morbidity. our findings suggest medical management, particularly sirolimus, may benefit these patients; however, long-term follow-up is needed in treated children. novel fos inhibitors are in development and may benefit patients with fos rearrangement. penn state health children's hospital, hershey, pennsylvania, united states background: central venous catheters (cvc) are often required in critical care settings in order to provide a secure point of access for life sustaining care. clinical studies identify cvc presence as the single most important risk factor for deep vein thrombosis (dvt) in children. venous thromboembolic event (vte) incidence rates in critically ill children with a cvc range from 0.3-18% and 0.06-32.5 per 1000 catheter days depending on the population studied. per institutional protocol, the penn state health children's hospital picu (hershey, pa) utilizes a low dose continuous infusion of unfractionated heparin (ldufh) at 10 units/kg/hr as prophylaxis against cvc-related vte and to maintain line patency. the efficacy of this approach has never been evaluated. to determine if ldufh for prophylaxis results in lower incidence of cvc-related vte, catheter dysfunction and central line associated blood stream infection (clabsi) without increasing morbidities. to determine if the incidence of catheter related vte is lower than historical published data, a retrospective chart review was conducted utilizing the institutional electronic medical record for all patients in 2015, aged 0-17.99 years, who had a cvc during a picu admission. secondary objectives such as the incidence of catheter dysfunction, clabsi, and any associated bleeding complications are also being analyzed. results: interim data analysis revealed 478 cvcs (400 nontunneled cvc, 18 totally implantable devices, 19 tunneled lines, 41 peripherally inserted central catheters [picc] ) in 374 total patients with a median age of 1.9 years. overall vte incidence was 1.88% (9/478) with 7 vtes associated with non-tunneled cvc and 2 with piccs. sixty one percent of non-tunneled cvcs received ldufh and 85% (6/7) of the patients with vtes associated with non-tunneled cvcs did receive ldufh prophylaxis. vte incidence rate of nontunneled cvcs with ldufh was 2.5% (6/243) and 2.56 per 1000 picu catheter days. the only other vte events identified within our study cohort were in the picc group where two patients experienced vte, one of which was receiving ldufh. clabsi incidence was 1.2% (4 non-tunneled cvc, 1 tunnel cvc, 1 picc). no major bleeding complications were associated with ldufh. preliminary data demonstrates ldufh is efficacious in preventing cvc-related vte in comparison to published reports. further analysis will compare another similar sized and acuity level picu which does not practice the same method. background: fibroadipose vascular anomaly (fava) is a rare, challenging disorder associated with pik3ca mutations. fava often causes painful replacement of muscle and soft tissues with fibrotic and adipose tissue and is associated with ectatic draining veins. treatments for focal lesions are surgical excision, cryoablation or sclerotherapy and the role of medical therapy is unclear. some fava lesions are too extensive or directly involve neurovascular structure, resulting in refractory pain. objectives: to retrospectively evaluate the efficacy of sirolimus in patient with residual symptoms after procedural therapies for fava design/method: retrospective review of individual 7 cases from 6 institutions of fava refractory to other therapies treated with sirolimus for at least 3 months. cases were s141 of s301 identified by polling member of the aspho vascular anomalies special interest group. results: all seven patients report improvement on sirolimus therapy. all patients had received prior procedures, including sclerotherapy (6 patients), cryoablation (2 patients) and/or resection (3 patients). mean age at sirolimus initiation was 16y (range 6-29y). mean length of therapy is 18.4 months (range 3-29 months). six patients were treated with bid dosing and one adult received daily dosing. goals of sirolimus were improvement in pain or musculoskeletal dysfunction. pain and function improved in all patients, including discontinuation of narcotic use and resumption of participation in sports. time to symptom improvement ranged from 1-4 weeks. in four patients for whom dose was lowered, pain recurred in all four and responded to restarting or increasing sirolimus dose. while all patients do not have pre-and postsirolimus imaging, decrease in fava lesion size is seen in cases with available imaging. sirolimus side effects are similar to prior reports, most commonly mouth sores, elevated lipids and acne. we report the first known data supporting a role of sirolimus in refractory fava cases. sirolimus is welltolerated and initial improvement is rapid, within 4 weeks of initiation. whether sirolimus has a role in upfront therapy to reduce lesion size prior to procedures deserves further study. objectives: to assess platelet responses in children with itp receiving romiplostim. design/method: eligible children had itp for ≥6 months, ≥1 prior therapy, and screening platelet counts ≤30 × 10(9)/l or uncontrolled bleeding. weekly dosing was from 1-10 g/kg to target platelet counts of 50-200 × 10(9)/l. bone marrow biopsies were evaluated in europe at baseline and after 1 or 2 years (cohorts 1 and 2). as of mar 2017, 203 patients received ≥1 dose. at baseline, median (min-max) age was 10 (1-17) years, itp duration was 1.8 (0.5-13.8) years, and platelet count was 14 (2-265) × 10(9)/l; 10 patients (5%) had had prior splenectomy. the median (q1, q3) % time with a platelet response (platelet count ≥50 × 10(9)/l, no rescue medications past 4 weeks) in months 0-6 was 50% (17%, 83%) (primary endpoint). over the course of the study, 88% (179/203) of patients had a platelet response. four patients maintained platelet counts ≥50 × 10(9)/l with no itp medications for ≥24 weeks. median (min-max) treatment duration was 53 (8-119) weeks for 226 patient-years in total. median (min-max) average weekly romiplostim dose over the course of the study was 6.9 (0.2-9.5) g/kg; the median dose was 9 g/kg at 1 year (n = 106) and 10 g/kg at 2 years (n = 17). most (63%) patients initiated self-administration. sixty-four patients (31%) discontinued treatment, most frequently for lack of efficacy (n = 38), patient request (n = 7), and adverse event (ae) (n = 7). fortyone (20%) patients had serious aes (saes) including epistaxis (5%) and decreased platelet count (3%). five patients had treatment-related saes: 2 headaches, 2 abdominal pain, and 1 each of presyncope and neutralizing antibodies (ab). there were 6 cases of neutralizing ab to romiplostim (of 201 patients tested), but none to tpo; 5/6 had continued elevated platelet counts and in 2/6 cases ab were not found on retesting. for cohort 1, of 30 patients with baseline bone marrow biopsies, 27 had evaluable on-study biopsies scheduled for 1 year; 1 patient had an increase from grade 0 to 2. there were no findings of collagen or abnormalities. in this interim datacut of a romiplostim openlabel study in children with itp, 88% of children had a platelet response. overall, the median dose was 6.9 g/kg; the median romiplostim dose over time reached 10 g/kg. no new safety signals were observed over 226 patient-years. funded by amgen inc. background: hepatic hemangiomas are benign vascular tumors without a medical home, managed by multiple specialties. the diagnosis has been assigned historically to various vascular lesions affecting the liver with completely different clinical presentations, resulting in difficult standardized management. objectives: the consensus steering committee identified an acute need of clear definitions and evaluation guidelines using the updated international society for the study of vascular anomalies (issva) classification. the goal was to formulate recommendations that will be adopted by all specialties involved in the care of children with hepatic hemangiomas. design/method: we used a rigorous, transparent consensus protocol, with input from multiple pediatric experts in vascular anomalies from hematology-oncology, surgery, pathology, radiology and gastroenterology. in the first section, we precisely define the subtypes of hepatic hemangiomas seen in children (congenital and infantile) using clinical course, histology and radiologic characteristics. inclusion and exclusion limits to the diagnosis are noted. the following two sections describe these subtypes in further detail, including complications to be considered during monitoring and respectively recommended screening evaluations. conclusion: while institutional variations may exist for specific clinical details, a clear understanding of the diagnosis of hepatic hemangiomas affecting the pediatric population and the possible complications that require screening during the monitoring period should be standard. as patients with hepatic hemangiomas are managed by different medical and surgical specialties, a multidisciplinary consensus based on current literature, on the data extracted from the liver hemangioma registry and on expert opinion was required and was accomplished by this manuscript. objectives: to investigate the association between routine prophylaxis with bay 81-8973 and bleeding outcomes after adjusting for key patient and pharmacokinetic (pk) characteristics. design/method: the leopold kids study evaluated safety and efficacy of bay 81-8973 prophylaxis in 51 previously treated boys aged ≤12 years with severe hemophilia a. patients received bay 81-8973 25-50 iu/kg 2x/wk (n = 21) or >2x/wk (n = 30) and were followed up for 6-8 months. prophylaxis dose and frequency were assigned by investigators. pk parameters, including area under the curve (auc), half-life, and clearance, were derived from a population pk model and reflect predicted pk values with a 50-iu/kg dose. patient characteristics were compared between the 2x/wk and >2x/wk groups using wilcoxon rank sum or chi-square tests. negative binomial regression was used to model the association between prophylaxis frequency and annualized bleeding rate (abr) for total bleeds, first without adjustment and then adjusting for age, pk parameters, and bleed history. results: mean ± sd age for patients in this analysis was 6.4±3.0 years. patients receiving prophylaxis 2x/wk had more bleeding episodes in the 12 months before study entry (mean ± sd, 13.0±16.6 [median, 6.0] for 2x/wk vs 4.3±5.7 [1.0] for >2x/wk; p = 0.027) and were more likely to have been treated on demand (38% vs 10%; p = 0.035). pk parameters were similar between the 2x/wk and >2x/wk groups. without adjustments, abr during the study was 12% higher in the 2x/wk group compared with the >2x/wk group (rate ratio [rr], 1.12; 95% ci, 0.44-2.90; p = 0.81). abr was 36% lower in the 2x/wk group (rr, 0.64; 95% ci, 0.24-1.70; p = 0.37) after adjusting for age, auc, and number of bleeds in the prior 12 months. conclusion: abr was numerically lower but not significantly different between the 2x/wk and >2x/wk groups after adjusting for age and pk parameters. these findings suggest that even among patient groups that are homogeneous with respect to age, pk, and bleed history, further individualization of bay 81-8973 prophylaxis based on other characteristics may help reduce bleeding episodes even at a lower treatment frequency. larger real-world studies are needed to verify these findings. funded by bayer. stanford, palo alto, california, united states s143 of s301 background: vascular malformations may be of lymphatic, arterial, venous or capillary endothelial origin. they may be simple or complex, with complex malformations being a combination soft tissue and skeletal overgrowth. although likely present at birth, these malformations often become symptomatic with puberty or infection, and range from little or no clinical impact to life threatening symptoms. in malformations primarily of venous origin, pain may be significant and hypothesized to be caused by phlebolith development (intra-malformation thrombi), inflammation, consumptive coagulopathy, vascular engorgement, and endothelial proliferation. anti-angiogenic and anti-platelet therapies have been reported to relieve pain. however, the use of anticoagulation for pain is not well described. objectives: to report clinical features and outcomes of patients with vascular malformations of venous origin treated with anticoagulation for pain. we performed a retrospective review of patients with vascular malformations followed by the hematology service between january 2010 and december 2017 who were treated for pain with anticoagulation. pain relief was determined both by wong-baker pain scales and patient report. clinical data were extracted from electronic medical records. we identified five patients with venous malformations (vm) who had received anticoagulation for pain. four patients were female and median age was 8 years old (range 4 to 29 years old) at time of initiation of anticoagulation. all five patients had vm of the extremity, two with vm of the lower extremity, and three patients had vm of the upper extremity. two patients had concomitant coagulopathy and demonstrated decreased d-dimer after initiation of anticoagulation. four patients received enoxaparin, and one adult patient received rivaroxaban. all patients reported improvement in pain after administration of anticoagulation. one patient exhibited mild epistaxis and bruising at the injection site. there was no significant bleeding or other complications. pain is a significant complication in patients with venous malformations. our case series suggests that anticoagulation is a safe and effective therapy for pain relief in this population. further investigation is indicated to compare the effect of anticoagulation to other therapeutic interventions such sclerotherapy, surgery, and sirolimus in the treatment of pain associated with venous malformation. maria ahmad-nabi, christine knoll, sanjay shah, lucia mirea phoenix children's hospital, phoenix, arizona, united states background: estimates of the incidence of dvt in patients with osteomyelitis range widely from 5%-30%, however risk factors and outcomes of dvt in this cohort have not been thoroughly established. objectives: this study aims to estimate the incidence of dvt in patients with osteomyelitis, and to assess risk factors and outcomes of dvt in this cohort. design/method: after irb approval, a retrospective chart review was conducted for patients aged 0-18 years seen at phoenix children's hospital between 2012-2016 with icd 9/10 codes for osteomyelitis. exclusion criteria included chronic recurrent multifocal osteomyelitis, and chronic dvt. demographics, clinical factors and outcomes were compared between osteomyelitis patients with and without dvt using the fisher-exact and wilcoxon-rank sum tests, as appropriate for the data distribution. results: a total of 179 study subjects with osteomyelitis had a mean (standard deviation) age of 8.4 (5.7) years. dvt was present in 14 (8% of 179) patients, and 4 (28%), 5 (36%) and 5 (36%) patients received anticoagulation for < 6, 6-12 and ≥12 weeks, respectively. patients with vs without dvt were more likely to be male (86% vs 59%; p-value = 0.05), and had significantly higher rates of bacteremia (64% vs 24%; p-value = 0.003). rates of central lines were comparable between dvt and non-dvt patients (71% vs 68%; p-value = 1.00); however patients with dvt vs without dvt had significantly longer mean length of stay (18 vs 9 days; p-value <0.0001) and higher rates of icu admission (71% vs 16%; p-value <0.0001). the incidence of dvt among osteomyelitis pediatric patients was estimated at 8%, with risk increased by male sex and bacteremia. patients with dvt had significantly higher rates of icu admission and longer length of hospital stay. many of these patients had standard practice management of their dvt with 6-12 weeks of anticoagulation. our data highlights the need for recognition of high risk patients, and the need for future efforts targeting dvt prophylaxis. baylor college of medicine, houston, texas, united states background: lymphatic malformations (lm) frequently occur in the head and neck and can often be disfiguring and even life-threatening. management options include observation, surgery, sclerotherapy, and sirolimus. the optimal sequence of therapeutic interventions has not been determined due to the lack of comparative clinical trials or established guidelines. thus, prenatal planning with a multidisciplinary team is beneficial. we present a case series of ten children with head and neck lms evaluated in 2017 at our multidisciplinary vascular anomalies center. a chart review was performed to assess treatment modalities and recent trends. results: seven of 10 patients (70%) with head and neck lms were diagnosed prenatally. six patients required an ex utero intrapartum treatment procedure. all patients were started on sirolimus at a median age of 12.5 months (range 12 days -18 years). four patients most recently started on sirolimus were less than 3 months of age at the time of initiation. six patients underwent partial excision of lm during the first year of life; none of whom received sirolimus prior to surgery. sirolimus was discontinued in one patient given chronic clostridium difficile infections, and non-compliance in another patient. five patients received sclerotherapy. tracheostomy was necessary in six patients; one patient was de-cannulated after 7 months on sirolimus. all patients have had radiographic and clinical improvement of lm with varying treatment modalities. current clinical observations show improved response with sirolimus and demonstrate tolerability of sirolimus at a young age. conclusion: treatment of pediatric head and neck lms is challenging and a multidisciplinary approach is necessary. as the majority of patients are diagnosed prenatally, prenatal planning and discussion of potential use of sirolimus is beneficial. availability of vascular anomalies experts in the prenatal/neonatal period offers the best management results, and early initiation of sirolimus should be considered for complex lesions. long-term follow up is warranted to investigate the efficacy and timing of treatment options. yale school of medicine, new haven, connecticut, united states background: to mitigate transfusion of pathogencontaminated platelets, amotosalen, a synthetic psoralen compound, is added to sdp components. exposure to uv-a light activates amotosalen and crosslinks dna/rna base pairs, preventing replication of a broad spectrum of viral, bacterial, and other pathogens that may contaminate platelets. pr-sdps were fda approved for clinical use with no age restrictions in 2014. we initiated use of pr-sdps in november of 2016 for all patients. we retrospectively analyzed usage of pr-sdp vs conventional (non-pr) platelets (cp) in neonatal and pediatric patients with thrombocytopenia to compare hemostatic efficacy and the incidence of transfusion reactions (tr) for these products, after one year of a dual platelet inventory. design/method: since pr-sdp were fda-licensed, no irb approval was required; pr-sdp and cp were both considered standard of care. we evaluated transfusions for all pediatric patients age 0-18 years who received any platelet transfusion between november 2016 and november 2017. we determined the volume (mean ml ± 1sd) of each type of platelet component transfused, the number of platelet transfusion episodes, and reported trs based on cdc hemovigilance guidelines. a subgroup analysis was performed for thrombocytopenic neonates (0-4 months). results: patients 0-18 years who received only cps (n = 46) received a total of 8,030 ml of platelets (175 ± 151 ml/patient) over 62 transfusions (1.3 ± 0.6 episodes/patient). for comparison, in 38 patients who received only pr-sdp, a total of 4,350 ml of platelets (115 ± 107 ml/patient, p = 0.04) were infused over 61 transfusions (1.6 ± 0.9 episodes/patient, p = 0.12). for neonates (0-4 months, n = 26) who received only cps, 2,195 ml of cps (84 ± 105 ml/ patient) were transfused over 36 episodes (1.4 ± 0.6 episodes/patient). for comparison, those who received only pr-sdp (n = 27), received 1,613 ml of pr-sdp (60 ± 41 ml/patient, p = 0.27), transfused over 48 episodes (1.8 ± 0.9 episodes/patient, p = 0.08). for all recipients 0-18 years (n = 162), including additional patients who received both cp and pr-sdp, there were three reported allergic trs over 757 transfusion episodes, while no allergic reactions were reported with 537 pr-sdp transfusions. one febrile tr was reported to cp transfusion, while three were reported for pr-sdp. in conclusion, pr-sdps, in our pediatric population age 0-18 years, were comparable to cp products in regards to volume and episodes of platelet transfusions, and incidence/type of transfusion reactions. pr-sdp were safe and effective for use in this pediatric patient population. background: vascular anomalies are classified as either vascular tumors or vascular malformations. fibro-adipose vascular anomaly (fava) is a newly described entity which presents with distinct clinical, radiographic and histopathologic findings. we present a case in which the diagnosis of fava was complicated by a persistent low platelet count secondary to immune thrombocytopenia (itp). to describe a challenging diagnosis of a novel vascular anomaly (fava) complicated by severe thrombocytopenia. a 17 year old male presented to hospital with bruising and left thigh pain related to a remote sports injury. blood work revealed a platelet count of 9 × 109/l, but with an otherwise normal complete blood count. the following were also normal: aptt and fibrinogen; d dimer levels were slightly increased. he was treated with one dose of ivig (0.8 mg/kg) for presumed itp and responded well with his platelet count increasing to 118 × 109/l. he returned to hospital 3 weeks later with recurrent thrombocytopenia and worsening leg pain. an ultrasound of the left thigh revealed a 7.7cm x 4.0cm x 2.9cm lesion within the vastus medialis. the diagnosis of an intramuscular hematoma secondary to persistent thrombocytopenia was made. the patient presented with multiple episodes of thrombocytopenia over the next several months. his itp did not respond to oral prednisone (150 mg/day for 4 days). he continued to have short-lived responses to ivig requiring infusions every other week as his platelet count would fall below 10 × 109/l. his leg pain progressed, restricting him to a wheelchair. further imaging by mri brought into question the diagnosis of a hematoma and a biopsy of the thigh lesion was performed. the results were consistent with a diagnosis of fava; this was subsequently excised. conclusion: this is a unique case where a vascular anomaly was misdiagnosed as a hematoma due to a patient's persistent thrombocytopenia and history of an injury. fava is a newer entity which, unlike other vascular anomalies, has not been linked to thrombocytopenia or a localized consumptive coagulopathy. after excision of the fava, the patient's chronic pain, and mobility resolved, though his itp persisted. objectives: this preliminary, exploratory analysis of realworld administrative data was conducted to determine units dispensed and factor replacement product-related direct expenditures associated with a currently marketed shl or ehl rfix product. design/method: de-identified claims data from the commercially available truven health marketscan® research u.s. claims database were used to identify direct expenditures and number of international units (ius) dispensed for all patients aged 0-17 years with a diagnosis code of icd-9 286.0/icd-10 d66 who used nonacog alfa or eftrenonacog alfa during the study period (june 1, 2014 to july 31, 2017). reference weight measurements from the centers for disease control and prevention national center for health statistics' (cdc nchs) anthropometric data were used to estimate product dispensation on an iu per kg basis. the nonacog alfa and eftrenonacog groups comprised 37 and 11 patients, respectively. the median [iqr] age in the two groups was 8.0 [9.0] and 13.0 [4.0] years, respectively. while 10 of the 11 patients in the eftrenonacog alfa group had >1 calendar quarter of available data, only 23 of the 37 patients in the nonacog alfa group had >1 available quarter. the median rfix product dispensation per quarter was 29,074ius (iqr, 13, 967 ius) in the nonacog alfa group and 62,268ius (iqr, 18, 882 ius) in the eftrenonacog alfa group. incorporating attributed weight values, the median rfix product iu dispensation per kg per week was 97.39 iu/kg/wk (iqr, 31.92 iu/kg/wk-153.92 iu/kg/wk) in the nonacog alfa group, and 96.27 iu/kg/wk (iqr, 53.05-154.03 iu/kg/wk) in the eftrenonacog alfa group. applying 2016 wac prices (eftrenonacog alfa = $2.97/iu; nonacog alfa = $1.37/iu), the calculated estimates of $/kg/week were $133 and $286 in the nonacog alfa and eftranonacog alfa groups, respectively. conclusion: preliminary real-world data derived from a large u.s. claims database revealed differences in product dispensation and factor product-related expenditures among pediatric patients with any severity of hemophilia b to whom an shl or ehl rfix product was prescribed. refinements of these data, potentially to exclude instances of sporadic usage, may shed light on real-world dispensation of rfix products among pediatric hemophilia b patients. background: vascular malformations can be classified as simple (including capillary, venous, lymphatic, arteriovenous), combined, malformations of major named vessels or associated with other anomalies. multiple modalities including laser treatments, sclerotherapy, embolization, surgery and pharmacological intervention (with mtor inhibitors like sirolimus) have been used for treatment of vascular malformations. these interventions have been used alone or in combination with varied outcomes. we present our institution's experience with a multimodal approach to simple and combined vascular malformations. design/method: we performed a retrospective chart review of patients with vascular malformations who were referred to our center for an interventional radiology evaluation from june 2015 -july 2017. we included 22 patients (age at presentation:4 months -25 years), referred initially for interventional radiology procedures (irp) for vascular malformations. all patients had symptoms of pain and/or swelling/deformity. diagnosis of was based on vascular imaging (doppler ultrasound, mri/a/v). nine patients had venous malformations (vm), five had macrocystic lymphatic malformations (lm), six had lymphatic-venous malformations (lvm), and two arteriovenous malformations (avm). 19 patients initially underwent interventional radiology procedures. all the vm patients responded to sclerotherapy alone. three patients with lm responded to sclerotherapy alone, remainder required surgical intervention. one avm patient responded well to embolization, the other needed surgical resection after embolization. four lvm patients underwent irp with minimal improvement in symptoms (3-8 procedures attempted), surgical resection was attempted in 3 patients with poor response and 5 patients were started on sirolimus (0.8mg/m2/dose twice a day). all lvm patients started on sirolimus have responded well (decreased pain and swelling); time to initial symptom response ranged from 2 weeks -1 month from starting medication. in this case series, patients with simple vm responded well to sclerotherapy alone, avm and lm patients needed irp and/or surgery for complete response. complex lvm did not respond well to surgery or irp; 83.3% had improvement in clinical symptoms with addition of sirolimus to the treatment regimen. response to various modalities of treatment varied based on the type of vascular malformation. a multidisciplinary approach to management of vascular malformations is essential to provide multimodal therapeutic options for rapid symptom relief and improve the quality of life of these fragile patients, especially those with complex malformations. background: von willebrand disease (vwd) is the most common bleeding disorder in humans, affecting ∼1% of the united states' population. desmopressin (ddavp) is a longacting vasopressin analog that induces vasoconstriction and release of vwf. ddavp is used in patients with vwd and as a surgical prophylaxis, but carries anti-diuretic properties. to avoid electrolyte imbalance and hyponatremia, fluid restrictions are recommended in the 24 hours post-ddavp administration. objectives: this study sought to examine perioperative practices and outcomes following ddavp administration and a fluid restriction protocol in a population of pediatric patients with von willebrand disease. design/method: a retrospective chart review was conducted for patients with von willebrand disease who underwent surgical procedures at children's hospital of pittsburgh of upmc between january 1, 2015 and december 31, 2016. patient age, sex, weight, diagnosis, surgical procedure, total fluids administered, and post-operative sodium level were recorded. the primary outcomes noted were the proportion of patients exceeding 50% of the recommended fluid consumption for the 12-and 24-hour periods post-ddavp s147 of s301 administration, as defined by local guidelines. secondary outcomes were the presence of any bleeding requiring an er visit or readmission or hyponatremic seizures within 72 hours of ddavp administration. results: data was compiled for 42 patients (23 females, 19 males). the mean age was 11.19 years (sd 5.13 years), median age was 12 years (range 3 to 19 years). procedures included dental (13), otolaryngology (9), orthopedics (7), gastrointestinal (5), plastics (3), neurosurgery (1), ophthalmology (1), dermatology (1), general surgery (1) and gynecology (1). 30% of patients exceeded 50% of the fluid volume recommended for the first 12-hour period post-ddavp administration while still in the surgical setting. no patients exceeded 50% of the fluid volume recommended for the total 24-hour period post-ddavp administration. post-operative sodium levels were obtained in only 7 of 42 patients. no patients returned to the er or were admitted for bleeding in the 72 hours post-ddavp administration. no patients returned to the er or were admitted for hyponatremia or seizures in the 72 hours post-ddavp administration. maintenance of a fluid restriction protocol effectively deterred negative outcomes in this cohort. however, a significant fluid volume was administered in nearly a third of patients despite the restrictions. given the risk of hyponatremia, and limited compliance with fluid restrictions, postoperative sodium levels should be recorded in following ddavp administration to assess the possibility of a hyponatremia and to reinforce the importance of fluid restrictions and their communication. results: a male fetus required in utero insertion of a pleuroamniotic shunt for bilateral pleural effusions diagnosed antenatally by ultrasound. shortly after delivery at term, he developed respiratory distress and was found to have reaccumulation of the pleural effusions. blood work on day 1 of life showed a platelet count of 157,000/ l, which then decreased precipitously. he demonstrated schistocytes on blood-smear, signs of consumptive coagulopathy with hypofibrinogenemia and high d-dimers, and compensatory reticulocytosis. he required multiple transfusions and admissions to the intensive care unit for respiratory support. investigations ruled out congenital ttp, neonatal alloimmune thrombocytopenia, and noonan syndrome. given high clinical suspicion for an underlying vascular lesion causing kmp, a full body mri without contrast was undertaken. this showed a focal area of suspicious signal intensity in the upper paraspinal musculature. an ultrasound and mri with contrast demonstrated an extensive infiltrative vascular lesion involving the paraspinal musculature, prevertebral space, posterior extrapleural space, mediastinum, and neck. the child was commenced on prednisone (2mg/kg/day) and rapamycin (0.9 mg/m2 twice/day). there was no clinical or laboratory improvement after one month. a biopsy was performed which confirmed khe. in the second month of rapamycin therapy, the platelet count gradually normalized and the patient was discharged from hospital at 3.5-months of life. prednisone was weaned off at 4.5 months of life. a repeat mri at 7 months showed significant reduction in the khe. he is now almost 2 years into therapy and doing well. conclusion: this is a unique case of khe with kmp that initially presented with extensive and recurrent pleural and pericardial effusions. this case demonstrates the importance of suspecting an underlying vascular malformation in the presence of kmp. our patient had a delayed but overall good response to rapamycin. further studies investigating duration of rapamycin therapy is key for the optimal management of these patients. rosa diaz, donald mahoney, lakshmi srivaths, donald yee texas children's hospital, houston, texas, united states background: since von willebrand disease (vwd) is the most common inherited bleeding disorder, it must co-exist with other less common bleeding disorders in some dually affected patients. however, reports of combined deficiencies in factor viii (fviii) and von willebrand factor (vwf) are rare. objectives: to study the prevalence and bleeding phenotype of combined deficiencies of fviii and vwf in males with hemophilia a in a hemophilia treatment center. design/method: we retrospectively reviewed the electronic medical records of 99 males with hemophilia a followed at our institution during the past 10 years. the primary and secondary outcomes for the study were (1) the prevalence of combined fviii and vwf deficiencies and (2) the bleeding phenotype of these patients. we identified vwf deficiencies in 9% (n = 9) of the patients with hemophilia a. most (n = 6, 67%) patients were tested for vwf deficiency as part of the initial hemostatic evaluation, but one-third were tested due to clinical concern for inadequate response to fviii concentrate. the median duration of follow up was 9.5 years (range 3.4 to 17.2). patients were referred to our clinic at a median age of 12 months (range 0 to 6 years) for evaluation of easy bruising (n = 4, 45%), mucosal (n = 3, 33%) and surgical bleeding (n = 2, 22%). primary diagnoses included 4 with severe, 3 moderate and 2 mild discrepant hemophilia a. secondary diagnoses included 6 with low vwf activity, 2 type 1 vwd and 1 with type 2 unclassified. patients experienced episodes of musculoskeletal (n = 7, 78%), mucocutaneous (n = 6, 67%) and cns bleeding (n = 1, 11%). a total of 8 patients received factor prophylaxis. half of the patients were initially treated with fviii concentrates but subsequently changed to combined fviii/vwf products due to the frequency of breakthrough bleeding despite good compliance. all patients are on combined fviii/vwf products at the time of this review. a total of 7 (78%) of this cohort developed chronic joint disease manifest as decreased range of motion and/or abnormal mri findings. combined deficiencies of fviii and vwf were present in 9% of our center's hemophilia patients. these patients exhibited a severe bleeding phenotype as evidenced by the high frequency of hemarthrosis, need for prophylaxis and high prevalence of chronic joint disease. while the optimal treatment strategy remains to be elucidated, early recognition of a combined deficiency may have important clinical implications, particularly in patients who demonstrate a suboptimal response to fviii concentrate alone. background: childhood neutropenia is heterogeneous and may be congenital or acquired. cerebral cavernous malformation 3 (ccm3) is a neurovascular malformation disorder where lesions consist of low flow, dilated capillary endothelial channels with increased permeability, predisposing to hemorrhage and thrombosis. programmed cell death protein 10 (pdcd10) activity has been implicated in glia and neuron migration, and recently linked to the dysregulation of the actin and microtubule cytoskeleton, thereby affecting cellular morphology and migration. variants of pdcd10 encoding pdcd10 have been associated with ccm3. ccm3 causes a greater and earlier disease burden than other ccms, with 26% presenting younger than 10 years. some patients have associated extra-neuronal manifestations, suggesting that pdcd10 plays a role in other tissues. we describe a patient with significant blood cytopenias associated with ccm3. design/method: retrospective chart review to obtain patient data. results: an 8-month old female presented with seizure and was found to have multiple intracranial cystic lesions and abscesses due to s. pneumonia serotype 33f. during her treatment, she developed anemia (hemoglobin 7.6-8.7 g/dl), thrombocytopenia (platelets 73,000-128,000 cells/l), and profound neutropenia (absolute neutrophil counts of zero). initial bone marrow evaluation revealed a normocellular marrow but with marked granulocytic hypoplasia and 38% hematogones on flow cytometry. florescent in situ hybridization excluded cytogenetic changes characteristic of myelodysplastic syndrome. further evaluation included testing for neutrophil antibodies, chromosome breakage, and telomere length and results were normal. whole exome sequencing excluded mutations affecting congenital neutropenia genes, but detected a de novo pdcd10 variant (c.474+5g>a), thereby diagnosing ccm3. the neutropenia has responded well to granulocyte colony stimulation factor (gcsf), which is still needed at 26 months of age. moreover, the thrombocytopenia has progressed, requiring periodic platelet transfusions. over time, the bone marrow hematogone population has decreased to 8% at 20 months of age, though the granulocytic hypoplasia persists. conclusion: our case describes the first patient with neutropenia and thrombocytopenia associated with ccm3. we hypothesize the pdcd10 variant is the etiology of bone marrow dysfunction due to its role in actin and microtubule cytoskeleton formation, akin to the pathophysiology of xlinked neutropenia. supportive features of an underlying genetic cause of marrow dysfunction include the persistence of cytopenias beyond infection resolution as well as presence of hematogones. hematogones were previously reported to occur in patients with other congenital neutropenia disorders, indicating they could be a feature of congenital neutropenia and may be reactive to surrounding cell apoptosis. further testing of pdcd10 role in hematopoiesis should be explored. background: 10-15% of adult women will suffer from heavy menstrual bleeding (hmb) during their lifetime. 90% of women with inherited bleeding disorders suffer from hmb. there is a paucity of data about hmb among adolescents and young adults (aya), a population in which hmb may have large social and educational effects. objectives: to study the social and academic implications of hmb in an aya population. design/method: this is a questionnaire based survey conducted in a medium-sized city in california. we recruited females 14-24 years of age from one high school and from local university. the questionnaire was set up in research electronic data capture (redcap) at our institute which allowed us to obtain objective data about the respondents' menstrual cycles. a link was sent to the high school students via their online portal schoolloop and to the university students via social media and word of mouth. data was collected over 12 weeks from may 2017 to august 2017. we received 145 replies, some were not complete. using regression analysis, data was analyzed from 115 respondents in the age group of 18-24 (with a mean age of 19) years. we developed a composite score for hmb based on factors including saturation levels, number of pads, duration of bleeding, soaking of a pad within two hours, passage of clots, size and number of clots, and gushing sensation. we conducted statistical analysis of the drivers and implications of hmb based on the composite score. results indicate that having a relative with hmb, having other bleeding problems, and having anemia are drivers of higher hmb score. the results also indicate that hmb adversely affects quality of life as measured by participation in sports, social activities, after-school activities, tiredness, absenteeism, and gpa. hmb is also associated with increased rates of anemia and use of anti-depressants. hmb-driven anemia further adversely affects gpa. under-represented minorities are more likely to have a higher hmb score, as well as an increased adverse effect of hmb on gpa. the results suggest that the social costs of hmb are pervasive in the aya population, and especially pronounced among minorities. a relative with hmb is a significant driver of heavy menstrual bleeding. a hemostatic screen should be included when assessing the aya population with hmb. johns hopkins all children 's hospital, st. petersburg, florida, united states background: propranolol is a non-cardioselective beta blocker medication frequently prescribed for hemangiomas and hyperthyroidism. propranolol inhibits types i and ii iodothyronine deiodinases, enzymes that convert bioinactive thyroxine (t4) into bioactive triiodothyronine (t3). hypothyroidism is a well-recognized complication of diffuse hepatic hemangiomas that produce type iii deiodinase, an enzyme that converts t4 into bioinactive reverse t3 and t3 into diiodothyronine. thyroxine is typically selected for replacement in this population, even though doses up to 60% above physiologic may be necessary. we hypothesized that low dose, nearly physiologic t3 would be safer and equally effective because it bypasses propranolol's impact on the pituitarythyroid axis. we report an infant with diffuse hepatic hemangiomatosis and acquired hypothyroidism successfully treated with propranolol, prednisone, and triiodothyronine. design/method: a 7mo healthy female presented with abdominal distension, poor oral intake, and hepatomegaly. mri confirmed diffuse hepatic hemangiomatosis, the largest lesion measuring 4.4 cm by 3.9 cm. thyrotropin (tsh) was elevated at 47.9 (reference range* 0.5-6 mcgiu/ml), total t3# 165 (rr 60-300 ng/dl), and total t4^18.8 (rr 6-14 mcg/dl). treatment was started with prednisone (2 mg/kg/day) for three weeks, propranolol (3 mg/kg/day) and t3 (0.64mcg/kg/day). the t3 dose was slowly titrated to a maximum of 1.72 mcg/kg/day. thyroid hormone levels rapidly improved on t3 replacement. after two weeks, the tsh was 14.4, tt3 92, and tt4 16.5. after eight months, the tsh was 2.9, tt3 161, and tt4 10.1. at twelve months, the tsh dropped to 0.6, tt3 294, and tt4 3.7, suggesting decreased tumor production of type iii iodothyronine deiodinase. liver mri confirmed fewer hemangiomas, largest being 1.3 cm by 1.6 cm. the patient's t3 dose was reduced. both propranolol and t3 were discontinued after twenty-four months of treatment. one year off all therapy, this child has normal growth and development, only two <1.3cm hepatic hemangiomas and no evidence of hypothyroidism (tsh 2.2; tt3 153; tt4 6.4). conclusion: t3 at near physiologic doses corrects the consumptive hypothyroidism associated with diffuse hepatic hemangiomas. t3 replacement is preferable to thyroxine due to its lower risk of rebound hyperthyroidism as the hemangiomas involute and type iii deiodinase production declines. there are two prior case reports describing t3 use without t4, one employing propranolol and the other utilizing steroids for hemangioma management. this is the first case report with long term follow-up of a child treated with multimodal therapy including propranolol, prednisone, and triiodothyronine. *rr = reference range; #tt3 = total t3;^tt4 = total t4 background: multifocal lymphangioendotheliomatosis with thrombocytopenia (mlt) is a rare congenital disorder first described in 2004 that is characterized by multiple vascular abnormalities commonly involving the skin and gastrointestinal tract as well as consumptive coagulopathy often resulting in gi bleeding in infancy(1). to describe an unusual presentation and successful management of mlt in a neonate. design/method: baby h was born at full term after a pregnancy complicated by maternal sinus venous thrombosis requiring anticoagulation beginning at 28 weeks. at birth, she was diagnosed with multiple hemangiomas based on clinical exam. at two weeks of age, she developed melena and hematemesis. cbc revealed platelet count of 70 and she was referred to the ed. abdominal ultrasound was concerning for abnormal hepatic waveform; cxr showed multiple pulmonary nodules. workup revealed no other lesions and no further hematologic abnormalities. biopsy of presumed hemangioma ultimately revealed a smooth muscle-lined vascular proliferation without glut-1 immunoreactivity, consistent with mlt. her early course was complicated by an acute hemodynamically significant gi bleed; esophagogastroduodenoscopy identified six bleeding vascular malformations within the stomach that were injected with epinephrine and sclerosed with successful hemostasis. she received multiple prbc and platelet transfusions. central access was obtained and she was started on oral sirolimus based on previous reports of successful use in management of vascular malformations given its antiangiogenic and immunosuppressive effects (2). she has tolerated it well with no evidence of toxicity and has achieved a partial response with stable of hemoglobin >8 and platelet count >90. cutaneous lesions have diminished in intensity and she has had no further signs of gi bleeding. she receives pentamidine for pcp prophylaxis. she continues to have appropriate growth and development. we describe here an unusual presentation of an already rare disease. while cutaneous and gi lesions are typical of mlt, pulmonary involvement is not well-described in the literature. early identification of tissue-based diagnosis enabled timely stabilization and treatment of the patient. five months later, she continues to tolerate sirolimus and has shown significant response with diminished coloration of cutaneous lesions, stable blood counts, and no further bleeding. mlt is a relatively newly-recognized disorder with significant phenotypic variability. given that bleeding secondary to a kasabach-merritt-type consumptive thrombocytopenia is the major cause of morbidity and mortality in the first year of life in children with mlt, it is essential to recognize the diagnosis and initiate appropriate treatment as early as possible. 1north, arch background: patients with generalized joint hypermobility (jhm) may experience easy bruising or bleeding given the association between these symptoms and abnormalities in collagen, a required component of primary hemostasis. heavy menstrual bleeding (hmb) is a common initial presentation for females with underlying hemostatic defects and may be the sole manifestation of a bleeding disorder. however, limited reports describe jhm as a cause of hmb, leading to under recognition. objectives: to describe the clinical characteristics and management of young women presenting with hmb in the setting of jhm. design/method: this study utilized our hmb research registry. we included subjects 11-18 years, seen in the nationwide children's young women's hematology clinic between february 2014 and november 2017 with both hmb and jhm. medical records were retrospectively reviewed for history of presentation, menorrhagia impact questionnaire (miq): a validated quality-of-life tool for females with hmb, medication profiles and relevant laboratory studies. results: twenty-five patients met inclusion criteria (median age 15 years, range 11-18) with an average beighton score of 6.2 (range 4 to 9). participants presented an average of 3.2 years (range 5 months to 6 years) after menarche despite 76% of patients reporting heavy to very heavy menses since menarche. according to the miq responses, most participants expressed hmb-associated limitations in physical activities (84%), social activities (68%), and work or school activities (64%). of the participants, 92% reported bleeding symptoms in addition to hmb, most commonly easy bruising (56%), epistaxis (48%) and cutaneous bleeding (44%). forty percent of young women presented with anemia due to chronic blood loss. results of hemostatic testing were unremarkable, with the exception of one patient who was also found to have type 1 von willebrand disease. additionally, 44% of females reported arthralgia, with knees and ankles the most commonly affected joints. at time of presentation, 32% of participants reported failure of initial therapies and most patients (88%) were managed long-term with oral hormone therapy. in a small population of young women found to have jhm who initially presented with hmb, patients were likely to have prior bleeding symptoms as well as substantial delays from menarche to timing of presentation at our young women's hematology clinic despite limitations in activities of daily life. greater awareness of the associations between bleeding symptoms and jhm, despite typically normal hemostatic laboratory results, is necessary so that patients can more easily be identified and receive appropriate therapy. the objective is to determine the impact of cl care practices involving the home environment on ambulatory clabsi rates. design/method: information for the pi was collected through a comprehensive survey that was completed annually by the ccbdn member hospitals. responses to the questions about cl care practices involving the home environment were selected from the pi for 2015. ambulatory clabsi rates and ambulatory total bloodstream infection (bsi) rates were obtained from another ccbdn database. the proportion of hospitals that did or did not employ a particular cl care practice was tallied. the mean ambulatory clabsi rate and mean ambulatory total bsi rate of the hospitals that did or did not employ a particular cl care practice were compared using generalized linear model techniques assuming an underlying negative binomial distribution. results: twenty-five hospitals submitted responses to the 8 questions about cl care practices involving the home environment. one hospital was excluded for lack of bsi data. sixty-three percent of the hospitals programmatically educated parents about all aspects of the cl care bundle. the mean ambulatory clabsi rate for the hospitals that educated parents was significantly lower than that of the hospitals that did not (0.20 infections/1000 cl days vs. 0.30 infections/1000 cl days; p = 0.02). the mean ambulatory total bsi rate was also significantly lower (0.35 infections/1000 cl days vs. 0.53 infections/1000 cl days; p = 0.01). the mean ambulatory clabsi rates and mean ambulatory total bsi rates were not significantly different for the other 7 cl care practices. conclusion: an analysis of cl care practices involving the home environment reveals that parental education of all aspects of the cl care bundle is associated with a lower ambulatory clabsi rate and lower ambulatory total bsi rate. this finding highlights the importance of systematically teaching family members the proper method of handling cl. background: children undergoing chemotherapy are at a high risk for developing nausea. dr. amy baxter in collaboration with pediatric oncology patients and nurses, developed and validated a pictorial nausea rating scale for children aged 7-18 years, called the baxter retching faces (barf) nausea scale. staff nurses at a large, academic, pediatric hospital located within washington, d.c., have identified variability in nursing assessment and documentation of chemotherapy induced nausea and vomiting (cinv) in pediatric oncology patients. the purpose of this quality improvement project was to utilize the barf scale to standardize assessment and documentation of nausea in pediatric oncology patients receiving chemotherapy. the primary aims of this project were to: assess feasibility of the barf scale in clinical practice; increase nursing knowledge about cinv through education sessions; increase documentation of nausea assessments through the use of the scale. the secondary aim of this project was to: increase the recognition of nausea through the use of a standardized assessment tool. design/method: the pdsa model was used to guide the design and implementation plan. in the first phase of the project data was collected to identify the prevalence of nausea in patients admitted for chemotherapy in the prior three months. education sessions discussing cinv and the utilization of the barf scale were conducted. pre and post assessment of nurses' knowledge of cinv and documentation were assessed. in the second phase the barf scale was implemented into practice. nurses were asked to utilize the barf scale to assess and document nausea scores in patients, aged 7 to 18 years, receiving chemotherapy. at the end of the implementation period nurses were surveyed about the feasibility of the scale. post data was collected to identify the prevalence of nausea documented in the electronic health record. this project was undertaken as a quality improvement initiative at children's national and it does not constitute as human subjects research. as such it was not under the oversight of the institutional review board. results: all data has been collected; however complete data analysis will be conducted in the upcoming weeks. background: sickle cell disease (scd) is the most common inherited blood disorder in the united states (us); however, there are few quality measurements to evaluate scd practice. in 2014, the nhlbi published guidelines that include two key interventions for children with sickle cell anemia (sca): the use of transcranial doppler (tcd) screening for stroke prevention and hydroxyurea (hu) to prevent scd pain crisis. we conducted a national survey of scd management sent to providers in over 20 institutions in the us to better assess knowledge of the guidelines and barriers to hu counseling and tcd screening guideline implementation. it was hypothesized that the barriers to tcd screening are different than barriers to hu counseling and prescribing. a 33-question anonymous survey was sent to 49 providers by mail (follow-up by email). survey themes included nhlbi guidelines knowledge and comfort with understanding and implementing both tcd screening and hu use. the response rate was 59% (29/49) however one survey was incomplete. thus, 28 were analyzed in the final data set. all of the respondents are in active practice, 96% s153 of s301 in academics and all care for children with scd. the majority of providers (96%) felt "very" or "extremely" confident in their knowledge of tcd screening and interpretation. similarly, 100% of providers felt "very" or "extremely" familiar with hu dosing and management. for tcd screening, 36% of providers estimated their screening rates were >90% and 64% providers felt their annual screening rates were 75-90%. the two biggest barriers to tcd screening noted by providers (of moderate to extreme significance) included: lack of support staff (36%) and lack of time during a patient visit (26%). regarding hu prescribing practices, 71% of providers offered hu to at least 90% of children with sca over nine months of age. the biggest barrier to hu prescribing noted by 46% of providers was concerns about patient adherence or access to the medication. only 7% providers felt that lack of support staff was a moderately significant barrier to hu prescribing. the pediatric scd providers surveyed all have access to the nhlbi guidelines. despite widespread guideline knowledge, there are different barriers for tcd screening versus hu prescribing, which prevent optimal implementation. as a result, although both recommendations are from the same nhlbi guideline, they likely will require different implementation strategies (systems-based interventions for tcd screening; interventions to improve patient adherence for hu counseling) to improve outcomes. background: invasive fungal disease (ifd) is a major cause of mortality and morbidity among pediatric immunocompromised patients such as those who receive chemotherapy or hematopoietic stem cell transplantation. the current diagnostic 'gold standard' of ifd remains culture of infected tissue obtained by biopsy. noninvasive biomarker testing for galactomannan or 1,3-beta-d-glucan (bg) can have low sensitivity and does not provide species-level identification. nextgeneration sequencing (ngs) of cell-free plasma is a promis-ing noninvasive approach to providing species-level identification of ifd via a blood test and can further guide specific treatment. objectives: describe the incidence of positivity for fungal specific pathogens on ngs analysis in a high-risk immunocompromised pediatric population and correlate results with other 'standard' infectious studies if performed. design/method: immunocompromised pediatric patients with suspected ifd were enrolled and plasma was collected at time of enrollment. ngs was performed on extracted dna in cell-free plasma (karius, redwood city, ca). after removing human reads, remaining sequences were aligned to a curated database including 1251 pathogens. organisms present at a significance-level above a predefined threshold were reported. results: twenty-seven samples from 33 enrolled patients have been processed thus far. of these 27 subjects, 14 were enrolled for prolonged febrile neutropenia (≥96 hours) despite broad-spectrum antibiotics, 5 for recrudescent febrile neutropenia, 5 for abnormal imaging, and 3 with other findings. after evaluation of routine studies performed, 4 patients met criteria for proven ifd, 2 for probable ifd, and 9 for possible ifd using eortc/msg guidelines. the ngs plasma test identified the same pathogen as cultured from infected tissue or blood in 100% (4/4) of the proven cases. in the probable cases, pneumocystis jirovecii was identified in a patient with a positive bg (389 pg/ml) and pneumonia. among the possible cases, toxoplasma gondii was detected in a patient with prolonged febrile neutropenia and lung imaging suggestive of ifd. additionally, candida glabrata was isolated in a patient with prolonged febrile neutropenia but no other criteria for ifd. numerous pathogens were also identified that could explain the above clinical parameters, including hsv1, cmv, vzv, hhv6, ebv, bk polyoma virus, and ureaplasma parvum. the cell-free plasma ngs test can detect invasive fungal infections from blood. the test identified fungi from proven ifd, detected pathogens in both probable and possible ifd cases, and is a useful diagnostic tool in the evaluation of ifd. supplies and sample shipment and processing supported by karius, inc. baylor college of medicine, texas children's hospital, houston, texas, united states background: practicing medicine is a lifelong learning process. as noted in the institute of medicine's seminal report, 'to err is human,' adverse outcomes do not typically result from individual recklessness; rather, they result from faulty systems, processes, or conditions that provide an environment conducive to making a mistake, or failing to prevent one. learning to systematically review errors and translate lessons learned into quality improvement (qi) initiatives is a critical component of practice-based learning and improvement for practitioners at all career levels. objectives: to develop a methodical, self-reflective and nonthreatening approach to incident analysis and translation of lessons learned into qi initiatives. design/method: we used a validated, structured case audit approach, modified from szostek et al: 1) review all documentation relating to the case and identify all health care providers involved; 2) interview stakeholders, including those who directly provided and supported care; 3) use a qi tool to conduct a root-cause analysis; 4) identify a systems issue that contributed to the outcome; and 5) propose systems-level interventions and prioritize initiatives based on effort-yield projections. results: pdsa cycle 1: plan: establish a committee to 1) identify potential cases, 2) triage cases for conference presentation, 3) determine timing and frequency of conferences, 4) develop a training manual, 5) record identified qi initiatives. do: we established a quarterly section-wide meeting to which all members of the pediatric hematology/oncology service are invited, including administrative and nursing leadership. we developed a training manual and structured presentation template. prioritized cases were discussed in advance during multidisciplinary case review sessions, and presented by senior fellows who were instructed to focus discussion on potential opportunities for qi. study: we identified 23 cases, 10 meeting criteria for mmi presentation. qi initiatives identified from this conference resulted in a number of systemic practice changes; however, we encountered challenges to sustaining these changes over time. act: objectives for the next pdsa cycle are to 1) establish a method for tracking the adherence to recommended changes in practice, 2) maximize sustainability by integrating qi initiatives into institutional qi leadership and practice standardization committees. we have successfully implemented an mmi conference that meets 5 out of 6 institute of medicine quality domains: safety, effectiveness, patient-centeredness, timeliness, and efficiency. a standardized, consistent approach to mmi presentations that includes identification of contributing factors and specific qi implications has the potential for improving both provider education and patient care/safety. johns hopkins university, baltimore, maryland, united states background: receiving a cancer diagnosis is a life-changing event for patients and caregivers, although little is known about the experience. while some oncologists receive dedicated training in delivering this bad news, the initial conversation is often with a primary pediatrician, and these providers often feel they do not receive adequate training in the communication of a cancer diagnosis. objectives: our objectives were two-fold: first, to better define the experiences of caregivers/patients when told of a cancer diagnosis, and to query how caregivers/patients believe providers can improve the disclosure of this bad news. secondly, to assess what, if any, training primary pediatricians received in this skill, and to assess how comfortable providers in various settings and stages of training are with communicating cancer diagnoses. design/method: from november 2016-2017, semistructured, in-depth interviews were conducted with pediatric oncology patients and caregivers of patients (n = 6) diagnosed in the past year regarding their experiences receiving the diagnosis at our institution. in addition, pediatric residents (n = 6), outpatient pediatric primary care physicians and pediatric emergency medicine physicians (n = 6) were interviewed regarding their experiences delivering cancer diagnoses. interviews were analyzed following principles of thematic analysis. interviewers with patients and caregivers had two common themes: 1) all emphasized their wish for direct and thorough information; 2) both patients and caregivers emphasized the gratitude they felt for physicians who gave them hope by emphasizing the good prognosis of their child's cancer. lack of training in this area, as well as lack of comfort delivering this news was common will all providers. additionally, providers report variable approaches to giving bad news, including 1) whether to tell caregivers separately or tell the child and parents together, and 2) whether to give favorable prognostic information. additionally, attending physicians also differed significantly in their approaches to teaching residents. while some believed residents should give the news to gain experience, others felt that this is not appropriate if residents are inexperienced. only one resident reported ever receiving feedback on his communication skills in this type of discussion. conclusion: we plan to build on these interviews to develop a national survey of patients, caregivers, and providers to better understand the issues surrounding this discussion. we will use the findings to develop a communication curriculum for pediatric residents, focusing on the discussions that occur in the outpatient setting by primary pediatricians. background: human papilloma virus (hpv), common in both females and males, is responsible for pathologies ranging from benign genital warts to cervical and penile cancer. hpv strains 16 and 18 are responsible for 21,000 malignancies each year in the united states, and one third of them arise in men. pharmaceutical companies have now developed a vaccine that will help prevent the virus-associated malignancies. the cdc initially recommended that females ages 11-26 years receive the vaccine series, then starting in 2011 they expanded the eligibility to males ages 11-21 years. despite being widely available and highly publicized, only 40% of eligible females receive the full vaccine series. objectives: this study aims to assess the knowledge of hpv, the attitudes towards the hpv vaccine, and identify barriers preventing its full utilization. once identified, we aim to overcome the barrier(s) in order to improve vaccination rates in eligible adolescents. we distributed a standardized questionnaire to the parents of eligible female and male patients in our pediatric hematology-oncology clinic. it assessed the parents' knowledge of hpv and the vaccine, their views of the vaccine, and reasons why they may oppose it. results: approximately 80% of parents claim they have been educated about hpv, mostly by their primary care physician. however, 35% did not know what disorders hpv caused; 35% felt the vaccine should not be added to the typical vaccine schedule; 25% of parents do not intend to vaccinate their child. of those that opposed the vaccine, one-third were concerned about potential side effects and nearly 35% feel they do not have enough information. additionally, 25% of parents are not aware that the vaccine is available at their child's doctor and only 30% of parents have discussed the hpv vaccine with their child's doctor. the largest barrier to the utilization of the hpv vaccine that we have identified appears to be lack of educa-tion. as a result, we have begun distributing the cdc's hpv and vaccine patient guide to our patients' families as an intervention. we are currently in the process of re-administering our survey to these families after implementing the intervention to assess its success in increasing both knowledge and utilization of the hpv vaccine. cancer institute, chennai, chennai, tamilnadu, india background: rasburicase is a recombinant urate oxidase enzyme approved for use in tumor lysis syndrome (tls) and it acts by reducing serum uric acid levels. using rasburicase at the recommended dose of 0.2mg/kg/day for 5 days is expensive and it is not known whether this extended schedule is clinically beneficial compared to a single fixed dose of 1.5 mg. the aim of the present study was to evaluate the efficacy of single dose rasburicase 1.5 mg in prevention and management of tls. design/method: rasburicase is available as single use 1.5 mg vial. at our institution a single dose of rasburicase 1.5 mg irrespective of bodyweight has been used in adults and in children a dose of 0.15 mg/kg (maximum 1.5 mg) has been used since 2012 for prevention and management of tls and subsequent doses are given based on biochemical response and clinical condition. we retrospectively analysed the case records of patients who had received rasburicase from january 2012 to january 2017. the study included 186 patients with hematological malignancies who received rasburicase. children accounted for 56.4% (n = 105) patients and males comprised 73% (n = 135). rasburicase was used prophylactically in 59 (31.7%) patients, for laboratory tls in 76 patients (40.8%) and for clinical tls in 51 (27.4%) patients. single fixed dose rasburicase prevented laboratory/clinical tls in 87% of the prophylactic group and prevented clinical tls in 72% of the laboratory tls group. none of the patients in prophylactic and laboratory tls group developed clinical tls. however, majority of the patients with clinical tls required more than one dose rasburicase. single dose of 1.5 mg (1 vial) rasburicase is efficient in preventing and managing laboratory tls and is economically viable in resource constrained settings. nicole wood, lauren amos, nicholas clark, chris klockau, karen lewing, alan gamis children's mercy kansas city, kansas city, missouri, united states background: medication reconciliation for newly diagnosed oncology patients is complicated and cumbersome. these patients are often admitted on no medications, and leave on multiple. chemotherapy and supportive medications are crucial. despite numerous individuals overseeing this process, prescribing errors or omissions still occur. when reviewing the literature, improvement occurs when there is an interprofessional and standardized process to medication reconciliation. objectives: this project's aim was to improve the accuracy of the discharge medication reconciliation process from 74% to 90% from february 2017-august 2017. the process measure was the percentage of patients discharged with an accurate checklist. additional time for staff spent in completing the checklist and avoiding an increased error rate by changing the prescribing process were followed as balancing measures. we created a discharge medication checklist which included a list of required home medications prescribed by the resident, ideally 24 hours prior to discharge. it required fellow or attending review and pharmacy to review the list and educate the family. checklists were collected monthly and reviewed against the electronic medical record (emr) for accuracy. results: six pdsa cycles were completed. there were 2 errors during the data collection time frame. in pdsa cycle 1, a patient received acetaminophen for pain control which is avoided at home. in addition, this patient received diphenhydramine instead of ondansetron, which is preferred as an antiemetic. in pdsa cycle 4, a patient with a pending diagnosis was sent home with acetaminophen. of note, this patient did not have a checklist completed upon discharge. this project provides a novel and important method to standardize the discharge medication reconciliation process in a complex patient population. it clarifies which types of medications these patients need, provides pharmacy teaching to families which was not done previously, and prescribes discharge medications to families sooner. after the first medication reconciliation error, the checklist was revised. no further errors were made following revision, with the exception of one patient without a completed checklist at dis-charge. our accuracy rate increased from 74% at baseline to 92% following implementation. we are in the process of making the checklist electronic and accessible in the emr. in the interim between the end of data collection and implementation into the emr, a leukemia patient was sent home without an epinephrine pen, further demonstrating the importance of this standardized discharge process. for this reason, we have re-instituted the checklist until the electronic version is available. background: survivors of pediatric cancer are at risk of losing pre-existing protective antibodies to vaccine preventable diseases. in a prior study, 35% of children < 7 years lost humoral immunity to measles as a result of chemotherapy induced alterations in immune system. measles in recipients of immunosuppressive chemotherapy has mortality rates up to 50%. because of volitional vaccine refusal, there has been a dramatic increase in measles infection from 63 cases in 2010 to 677 in 2014, including several statewide outbreaks. small pediatric oncology practices frequently share floor/clinic space with the general pediatric patients putting them at risk for measles since virulence starts 48 hours prior to symptoms. there is no standard protocol for revaccinating post-chemotherapy patients. to assess measles risk based on serial humoral immune status in a cohort of pediatric oncology patients receiving intensive chemotherapy design/method: patients < 21 years age with known vaccination status receiving intensive chemotherapy between july 2015-june 2017 at our institution's pediatric oncology practice were included in this prospective study. serial measles igg antibodies were measured at diagnosis, 6 months and 12 months after initiation of chemotherapy using elisa. measles immunity was defined per lab standards. a comparison of pre-chemotherapy and serial post-chemotherapy immunization titers was made for all patients by diagnosis. the study population consisted of 31 children (17 male); 8 patients had all, 7 non-hodgkin lymphoma, 11 sarcoma and 5 other solid tumors. two patients (6.4%), both unvaccinated had non-protective measles antibody levels at s157 of s301 baseline. of the remaining 29 patients, 13.7% patients (2 leukemia, 1 lymphoma and 1 sarcoma) lost protective antibody titers at 6 months after initiation of chemotherapy and 27.5% (4 leukemia, 1 lymphoma and 3 sarcoma) at 12 months after initiation of therapy. 60% of the remaining 21 patients who retained measles antibody titers within protective range at 12 months also demonstrated a steady decline in antibody titers at 6 and 12 months from therapy initiation. the loss of protective measles humoral immunity occurred significantly more often in patients with leukemia compared to other malignancies. oncology patients in our practice undergoing intensive chemotherapy demonstrated progressive waning of protective measles igg titers. our data suggests that it should be standard practice to check all patients for measles humoral immunity prior to starting chemotherapy and at completion. larger studies need to be performed to establish guidelines for revaccinating post-chemotherapy pediatric patients, an intervention that is easily applicable and of low cost. background: the accurate determination of glomerular filtration rate (gfr) is important to screen for acute kidney injury, to dose chemo-therapy, and to identify risk for chronic kidney disease.being correlated with inulin clearance, measured gfr by iohexol plasma disappearance (igfr) is a new gold standard for measurement of gfr in pediatric cohort studies. igfr is based on the clearance of an exogenous marker and is unaffected by endogenous compounds or a patient's muscle mass. we compared igfr with 24-hour urine creatinine clearance (24crcl) and gfr estimating equations using serum creatinine (scr) and serum cystatin c (cystc) in pediatric patients with cancer. we recruited participants who were ages 6 to 16 yrs, continent of urine, and diagnosed with a malignancy in the past 5 years. eligible subjects had stable kidney function for at least two weeks prior to the assessment of igfr. consented subjects had baseline assessments including height, weight and vital signs. blood samples were obtained for serum chemistry, and time zero iohexol. igfr determined by 5ml iohexol solution infused over 1-2 minutes followed by 10ml of sterile saline. blood was drawn at 10, 30, 120 and 300 minutes.at the same time of igfr, the 24crcl was collected. igfr was calculated using a two-compartment model and area under the curve. we compared igfr to published gfr equations (schwartz et al, kidney int 2012). results: ten subjects (7 female/3male) agreed to participate. the distribution of diagnoses for the subjects: all = 6, lymphoma = 1, brain tumors = 2 and hepatocellular carcinoma = 1. six patients were off therapy. the lower gfrs are noted in patients who had malignancies other than leukemia, likely due to the use of cisplatin based therapy. the average igfr was 85ml/min/1.73m^2 whereas 24crcl was 155.8 ml/min/1.73m^2; demonstrating the 24crcl overestimates gfr compared to igfr. comparing igfr to univariate equations using scr, cystc, and the multivariate equation with both, the univariate cystc equation correlated well with igfr; the others overestimated igfr. we found that 24crcl overestimated igfr. the univariate cystc equation better correlated to igfr than equations with scr. the poor performance of scr based methods to assess gfr might be due to decreased muscle mass and inadequate nutritional status. creatinine-based determinations of gfr alone, may not be accurate in this population. further study is needed to determine if igfr should be a standard of care to assess gfr in children with cancer particularly who are receiving nephrotoxic medications and incontinent of urine. background: pediatric oncology patients undergoing chemotherapy through indwelling venous catheters are at increased risk for severe sepsis especially when neutropenic due to chemotherapy. rapid triage and early recognition are essential because delayed initiation of antibiotics and fluids in these patients or delayed transfer to higher level of care after initial stabilization is associated with poor clinical outcome. our pediatric oncology out-patient clinic is designated as an article 28 unit whereby the providers can initiate and give treatment such as intravenous fluid, antibiotics, chemotherapy and blood products. objectives: global aim-optimize management of early sepsis and decreased morbidity, mortality and hospital length of stay in the high risk pediatric oncology patients. smart aim-improve timely management with initiation of fluids and antibiotics and transfer of septic patients to higher levels of care by 10% in 6 months in above patients design/method: multidisciplinary team with physicians and nurses was created. retropective chart review of sepsis patients treated at the clinic from april 2016 to october 2016 was done using an audit sheet to identify the barriers in the delivery of care. three patients were identified and data analyzed prior to intervention; two were analyzed post interventions. a key driver diagram was created by the group to drive intervention. a process map was designed to identify the different steps in the care of these patients to pinpoint areas needing improvement. different timed data points were used starting from time of arrival to clinic, time to antibiotics and fluids and time to transfer to higher level of care. rapid pdsa cycles were done to improve the processes and delivery of care. run charts were created. there was an improvement close to the goal of 10 % for all data points used. pdsa cycles for improvement included conducting frequent mock codes with appropriate feedback real time coaching and process planning with nursing staff. we partnered with pharmacy for close loop communication with clinic staff and we improved communication between physicans at different levels. conclusion: sepsis in neutropenic pediatric oncology patients is deadly and can be reversed with timely management at different levels. given the promising results of the above project, we want re-inforcement of the processes to be a part of the daily practice of first line clinical staff. eventually we will extend the principles learnt in management and triage of sepsis to other outpatient emergencies chemotherapy related anaphylaxis background: chemotherapy-induced nausea and vomiting (cinv) is a common side effect in children receiving antineoplastic chemotherapy. recommended prophylactic antiemetic medications are based on the classification of chemotherapy emetogenicity. however, despite appropriate use of these antiemetic agents, some patients will still experience nausea and/or vomiting. children's oncology group clinical practice guidelines recommend the addition of olanzapine to prophylactic regimens for management of breakthrough cinv. objectives: our pediatric hematology oncology center implemented a quality improvement (qi) project aimed to increase the use of olanzapine in pediatric cancer patients 7 years of age and older receiving moderately or highly emetogenic chemotherapy and experiencing breakthrough cinv over a 3 month period. design/method: this qi project was conducted utilizing plan-do-study-act (pdsa) cycles. for the first pdsa cycle, baseline data was collected through chart review to determine the rate of olanzapine use for breakthrough cinv over a 6 month period from july 2016 to december 2016. breakthrough cinv was defined as use of 2 or more doses of antiemetic agents other than those given for cinv prophylaxis. guidelines for treatment of breakthrough cinv were reviewed with pediatric hematology/oncology attending physicians and fellows. flyers were created that listed chemotherapy regimens considered moderately and highly emetogenic. if a patient experienced breakthrough cinv, a flyer was to be placed in the patient's roadmap binder to signal olanzapine should be added to the next chemotherapy block. data was collected over a 1 month period in september 2017 following this first intervention. the second pdsa cycle consisted of didactic education and training of pediatric oncology nurses as well as pediatric residents regarding the addition of olanzapine for breakthrough cinv. rates of olanzapine use were then collected from october 2017 through november 2017. results: olanzapine use increased from 3.8% at baseline to 58.3% after the first pdsa cycle ( 2 = 14.666, p = 0.000). after the second pdsa cycle, olanzapine use increased another 14.1% to 72.4% ( 2 = 0.777, p = 0.378). the administration of olanzapine was successfully increased by modifying patients' roadmaps after patients experienced breakthrough cinv as well as with education and training of pediatric oncology staff, fellows, residents, and nurses. background: venous thromboembolism (vte) is increasingly affecting children. according to an administrative database study, there was a 70% increase in the incidence of vte among children admitted to free-standing children's hospitals in the united states from 2001 to 2007. risk factors for hospital-acquired vte are well-known and well-studied in adults, with evidence-based preventative measures available. similar guidelines are lacking for children. objectives: there is an ongoing national-initiative to develop and institute methods for screening and preventing hospitalacquired vte in children. in 01/2014, nationwide children's hospital instituted an electronic screening form required for all patients admitted ≥24 hours. patients were scored and riskstratified based on eight risk-categories. a summated score was used to determine the vte risk level, and used to make prophylaxis recommendations for patients ≥18 years; as well as patients ≥14 years who were admitted to an intensive care (icu), surgical, or trauma unit. the purpose of this irb exempt, quality improvement initiative was to retrospectively review our experience with this risk-stratification tool. results: 262 hospital-acquired vte events occurred in 232 unique subjects. median age at vte diagnosis was 2 years. only 69 (26%) vte occurred in children ≥14 years of age. 237 (91%) vte were deep vein thrombosis (dvt), and 16 (6.1%) involved pulmonary embolism. vte was most common in subspecialty units including the pediatric and cardiac icus 87 (33.2%); neonatal icu, 43 (16.4%); and hematologyoncology, 31 (11.8%). 184 (70%) vte were associated with central venous catheters (cvc) and 144 events (55%) were associated with altered mobility. congenital heart disease/heart failure was the most common chronic medical condition associated with vte (69 (26.3%) events); whereas infection and trauma/surgery were the most common acute medical conditions associated with vte (137 (52.3%) and 89 (34%) events, respectively). during 249 (95%) events, subjects scored a summated score ≥3. in summary, in this single institution, prospectively maintained database, cvc remains the most common risk factor for vte, followed by cardiac disease, infection and trauma/surgery. most subjects who developed vte scored high (score ≥ 3) on our screening tool. only a small proportion of vte occurred in patients older than 14 years and thus eligible for thromboprophylaxis. our results indicate that future vte prevention endeavors should include these age groups in addition to exploring more aggressive prophylactic modalities including pharmacological prophylaxis. background: pediatric fellows are required to have active engagement in quality improvement (qi) activities, and yet a national acgme review found most trainees had "limited knowledge of qi methods" and "limited participation in interprofessional qi teams". the twenty fellows in our pediatric hematology/oncology training program identified blood culture utilization as their qi priority. our institution recently introduced a hospital-wide decision algorithm to guide providers regarding when to obtain blood cultures. there is often a low threshold to obtain blood cultures in immunocompromised pediatric oncology patients, but these are often low-yield or result in falsepositives. our fellows spearheaded a project to implement the algorithm in the inpatient pediatric oncology population and improve the proportion of appropriately drawn blood cultures. we investigated how appropriately the algorithm was being utilized on the inpatient pediatric oncology floor prior to and after several educational steps aimed at disseminating the algorithm to members of the care team. our primary endpoint was to quantify the proportion of culture episodes drawn "inappropriately", with a goal of reducing inappropriate episodes to ≤10%. the algorithm was initially introduced to the nursing staff and residents covering the twenty-bed inpatient unit in september 2016. qi project planning took place with upper level fellows in january 2017. fellows and faculty received intensive training on the algorithm in july-august 2017. we then conducted a retrospective chart review of blood culture episodes drawn between august 2016 and november 2017. upper level fellows scored ∼500 culture episodes as to whether the decision to culture and number of cultures drawn were "appropriate" or "inappropriate", and catalogued the indications for culture episodes and if applicable, why the episode was found to be inappropriate. additionally, fellows discussed inappropriate culture episodes with the team onservice, to provide direct feedback on where the algorithm failed. results: between august -december 2016 on average 337 cultures/1000 patient-days were drawn. forty-nine percent of culture episodes were inappropriate. from january -october 2017, following targeted education on the algorithm, the rate of blood cultures drawn decreased to 263 cultures/1000 patient-days. the average proportion of inappropriate culture episodes fell to 16.7%, representing a 66% decrease in inappropriate culture utilization. correct application of a decision algorithm for blood culture utilization can reduce total cultures drawn on an inpatient pediatric oncology unit. fellow-led education of the multi-disciplinary team decreases the rate of inappropriate culture episodes as well as provides active engagement in qi. background: inadequate understanding of sickle cell disease (scd) is common and can affect patients' compliance and therefore their morbidity and mortality, especially after transition to adult care. optimal clinical care for scd includes disease education, which can be difficult given the breadth of possible topics and limited time in clinic. it is unclear how best to provide personalized, efficient education for adolescents with scd. this quality improvement (qi) study aimed to implement a questionnaire-based system to improve patients' knowledge of their scd and documentation of education by the nurse or physician. the study objective was to improve provider documentation and patient knowledge about their scd by identifying patients' gaps in comprehension. by january 2017, the study aimed to increase education documentation from 50% to 75%. by april 2017, the study aimed to increase use of a smart phrase for education documentation from 0% to 50%. by june 2018, the study aimed to increase patients' knowledge about their disease by 20%. design/method: twenty-one scd patients enrolled on an irb approved qi study, with twenty active patients. our comprehensive team generated a questionnaire with knowledgebased questions for two age groups: 12-14 and 15-18 years old. at each comprehensive visit, a questionnaire was distributed, with at least 3-month intervals. the provider scored questionnaires and reviewed two educational topics, with wrong answers taking priority. plan-do-study-act (pdsa) cycles included pdsa#1: patients completed questionnaire. pdsa#2: a smart phrase addressing questionnaire topics was created and shared with providers. pdsa#3: patients received education handouts during clinic education. documentation in clinic notes was the process measure and questionnaire scores was the outcome measure. results: pdsa#1 is complete, pdsa#2 has four patients remaining, and pdsa#3 is ongoing. due to variable visit frequency, there are multiple concurrent cycles. after pdsa#1, free text documentation was completed an average of 61% over the course of 3 months. after pdsa #2 documentation increased to 100% within 3 months and questionnaire scores increased from an average of 59% to 78%. of the questions that patients got wrong on their first visit, they were significantly more likely to improve on retesting if the topic was taught to them than if it was not addressed (72% vs. 33%, p = 0.04). we are currently completing pdsa#3 and collection of post pdsa#3 data. questionnaire-based scd education coupled with standardized smart phrases improves patients' scd knowledge and documentation by providers. further improvement in knowledge is expected with the addition of handouts. background: exposure to suffering can have a profound impact on the wellness of caregivers, often referred to as the "cost of caring". this cost is especially high in pediatric hematology/oncology. repeated exposure to suffering has the potential to negatively impact resilience and increases the risk of burnout, thus impacting quality of care and patient satisfaction. we have developed a peer support team utilizing the critical incident stress management (cism) model. this model has been successfully used in other professions that frequently face traumatic events such as fire fighters, police and emergency medical technicians. the h.o.p.e.s. team (helping our peers endure stress) consists of 18 volunteer multidisciplinary staff members who have received training to provide both group and peer support following any 'critical incident' that may impact one or more staff members. we hypothesize that implementation of the h.o.p.e.s. team will improve staff resilience, decrease overall rates of burnout and improve compassion satisfaction. s161 of s301 design/method: we are using both empiric metrics and anecdotal reports to assess the impact of the h.o.p.e.s. team. prior to the activation of the team, all pediatric hematology/oncology clinical staff members were surveyed using validated tools to assess their levels of resilience, burnout, secondary trauma and compassion satisfaction (proqolv5 and brief resilience scale). they were also asked to rate the number of times they had experienced critical incidents, as well as their perceived level of distress after dealing with traumatic events. after the h.o.p.e.s. team has been functional for 6 months, we will send the same survey to staff members to measure changes, paying special attention to resilience and rates of burnout and compassion satisfaction. results: enthusiasm for development of the team has been high. 18 of 19 people approached to volunteer their time to participate in the multidisciplinary team agreed, including attending physicians, fellows, nurses, nurse practitioners, child life specialists, social workers, clergy and psychologists. all volunteers participated in a 3-day training conducted by an instructor from the international critical incident stress foundation. engagement in the first staff survey has been high, with 91 of 150 responding to date. data collection is ongoing. clinical staff in pediatric hematology/oncology may be particularly vulnerable to burnout and decreased resilience by repeatedly witnessing suffering and trauma. peer support interventions following critical incidents may lead to increased resilience and compassion satisfaction while decreasing rates of burnout. enthusiasm for the development of a peer support team has been high. background: monthly blood transfusions are an indicated therapy for pediatric patients with sickle cell disease with certain complications. maximizing transfusion efficiency in a busy infusion clinic requires: ensuring that appropriate blood units are available in the hospital blood bank; laboratory specimens are obtained from patients in advance; and coordination of clinic appointment and nursing availability. we sought to improve clinic efficiency through identifying ways to better communicate with patients/families regarding upcoming laboratory and transfusion appointments, and to assess the efficacy of implementing a web-based personalized text reminder (pinger.com). we measured the baseline frequency with which transfusion appointments were missed by families, moved to later within the week, or delayed due to late labs. a convenience sample of patients receiving monthly transfusions received a questionnaire about patient/parent preferences for appointment reminders and barriers to keeping appointments. those patients/parents who did not opt-out of an additional text reminder received personalized texts from their care team reminding them of lab and transfusion appointments. rates of missed/moved/delayed appointments were compared between the group receiving the additional text messages and the group only receiving standard, hospitalgenerated appointment reminders (telephone call). results: forty-one families (45 patients) responded to the survey, capturing information on 63% of patients receiving chronic transfusion therapy. thirteen families (32%) declined the additional text reminders. families reported a preference for text reminders (66%), more often than email (49%) or telephone (37%), and 80% of families wanted to receive reminders for both transfusion and laboratory appointments. the majority (43%) of families reported competing work/life priorities as the reason for missed/late appointments. other families noted transportation/travel (29%), fear/illness/pain (21%), and lack of reminders (21%) as the reason for missed appointments. at baseline (twelve weeks), 3.7% of appointments were missed on a weekly basis (range 0-3 of 20 available per week), 10.4% were moved, and 5% of appointments were delayed. during our intervention period (twelve weeks), 7% were missed, 9.2% were moved, and 8.7% were delayed (combined, both groups). there was no difference in missed (7.0% texted vs 7.1% standard), moved (8.0% texted vs 10.0% standard) or delayed (8.0% text vs 9.3% standard) appointments. though families at our center reported a preference for a text-based reminder, personalized text reminders for appointments did not improve clinic efficiency as measured by missed, moved or delayed transfusion appointments. there was no improvement in appointment adherence in the group receiving personalized texts in addition to standard hospital reminders. university of utah, salt lake city, utah, united states background: childhood cancer outcomes have improved significantly, in large part due to multi-institution collaborative clinical trials run by the children's oncology group (cog). approximately half of eligible children with cancer will enroll on a therapeutic trial, but little is known about the factors affecting caregiver decision-making regarding enrollment or how well the required elements of informed consent are conveyed during the consent process. objectives: 1. assess coverage of ten of the required elements of informed consent for cog therapeutic trials. 2. describe factors affecting caregiver decision-making regarding therapeutic trial enrollment. we surveyed families of children who were offered enrollment onto a phase 3 cog therapeutic study for an initial cancer diagnosis in the previous 18 months. fisher's exact or wilcoxon rank-sum tests were utilized to compare demographic and other motivating factors related to enrollment decision-making. results: seventy participants were surveyed. regarding 10 of the basic required elements of informed consent, 96% knew the trial involved research, 99% knew consent was required, 76% knew the enrollment length for the trial, 97% knew they could continue care independent of enrollment, 73% knew who to contact with questions, 71% knew there were options besides enrollment, 83% knew they could withdraw at any time, 93% knew the information was confidential, 34% knew there were risks associated with the trial, and 46% knew there were benefits. of all participants, 84% (n = 59/70) enrolled onto a therapeutic study. among enrollees, 37% (n = 22/59) of the primary caregivers had completed college compared to 18% (n = 2/11) of those not enrolled (p = 0.3). when asked about factors impacting their decision, 69% (n = 41/59) of those enrolled said they felt there were no risks or did not know if there were risks associated with the study compared to 45% (n = 5/11) of those choosing not to enroll (p = 0.17). of those enrolled, 61% (n = 36/59) reported the physician recommendation "somewhat" or "strongly" affected their decision to enroll compared to 0% (n = 0/11) of those not enrolling (p = 0.0001). of those who enrolled, 17% (n = 10/59) reported feeling pressured to enroll while 45% (n = 5/11) of those not enrolled reported pressure (p = 0.05). of enrollees, 10% (n = 6/59) reported they did not have enough time to decide compared to 36% (n = 4/11) of those not enrolled (p = 0.03). failure to convey all 10 required elements of informed consent highlights possible deficiencies in the consent process for cog therapeutic trials. caregivers' perception of being pressured and lack of time to make an informed decision may impact clinical trial enrollment. background: abnormal uterine bleeding (aub) is a frequent adolescent gynecologic complaint. however, limited research exists to guide management, and acute care varies. we sought to improve emergency care for adolescents with aub by developing a clinical effectiveness guideline (ceg) and assessing its impact on quality of care. design/method: a stakeholder engagement group consisting of members from the departments of hematology/oncology, adolescent medicine, general pediatrics, and emergency medicine designed a ceg algorithm for emergency aub management. pediatric residents received ceg training and their knowledge and attitudes were assessed using pre and post intervention surveys. icd-9 and 10 codes identified electronic health record data for patients presenting to the pediatric emergency department (ed) for aub 6 months before and after ceg implementation. pre-pubertal patients and those with vaginal bleeding from trauma were excluded. a weighted, 20-point scoring system consisting of prioritized aspects of history, laboratory studies and management was developed to quantify the quality of care provided. t-test, chi square test, wilcoxon rank sum test, and a run chart were used for analysis. of the 91 patients identified, 62 met inclusion criteria. there were 37% of patients currently using some form of contraception, while 12.9% had bleeding related to a current or recent pregnancy. median aub quality care scores were 14 pre-and 16 post-intervention (p = 0.064). run chart data showed no shifts or trends (overall median score, 14-points). both pre and post-implementation, points were deducted most frequently for not assessing personal/family clotting disorder history and inappropriate use/dosing of oral contraceptives. we successfully designed and implemented a ceg and educational intervention for aub management in a pediatric ed. these data suggest our ceg may be an effective tool to improve emergency aub care for adolescents, though additional cycles are needed. background: high-dose methotrexate (hd-mtx) is a common chemotherapy administered inpatient at most centers. its administration is particularly susceptible to error due to the need for frequent drug levels with resulting changes in supportive care. errors can prolong patient stay and cause patient harm. objectives: global aim-to reduce the length of stay (los) of hd-mtx admissions. smart aims-to increase the percentage of patients whose pre-hydration fluids are started by 10am from 0% to 20% by 1/31/18, and to increase the percentage of patients who receive hd-mtx by 5pm from 43% to 100% by 6/30/18. we used rapid process improvement methods to target earlier methotrexate administration. a key driver of prolonged los was hypothesized to be drug levels returning overnight rather than in the day time due to delayed hd-mtx start. changes implemented have included scheduling hd-mtx patients as the first patients of the day for their exam in clinic and scheduling labs to pass for hd-mtx on the day prior to admission. there are ongoing pdsa cycles to change the location of pre-hydration start from the inpatient room to the clinic exam room in order to meet hd-mtx administration time goals. we are piloting two different education materials to improve patient experience. one explains hd-mtx levels in a red/yellow/green stoplight format and the other reminds patients how to prepare for the admission. other interventions regarding how we test urine ph and safety checks in the ordering process for history of delayed clearance are in the planning stage. the project is ongoing, but as of 12/12/17, we start methotrexate by 5pm 50% of the time which is improved from a baseline of 43%. when the project was started, pre-hydration was never started before 10am. now, fluids are started by 10am 40% of the time. pdsa cycles are ongoing and we have yet to sustain reductions in los, but some months have shown decreased los by as much as 19 hours from baseline measurements. rapid cycle improvement can be utilized to decrease los hd-mtx admissions. this has important financial implications as well as the potential to reduce secondary harm from unnecessary time in the hospital. pediatric cancer centers should schedule hd-mtx admissions first thing in the morning so that data regarding kidney injury and drug clearance can be interpreted by the day team and children are not cleared for discharge in the middle of the night. background: education and training for interdisciplinary pediatric oncology providers requires training in principles of palliative and end-of-life (eol) care. the experiences of bereaved parents can inform and enhance palliative care educational curricula in uniquely powerful and valuable ways. the objective of this study is to present an innovative palliative care educational program for oncology providers facilitated by trained bereaved parents who serve as volunteer educators in local and national palliative care educational forums and to describe how incorporation of bereaved parents in these educational forums affects participant comfort with communication and management of children at the eol. design/method: survey tools were adapted to determine how bereaved parent educators affected participant experiences in 3 different educational forums: institutional seminars on pediatric palliative and eol care, role-play based communication training sessions, and an international symposium on pediatric palliative oncology. pre-and post-session surveys with incorporation of retrospective pre-program assessment item to control for response shift were used in the evaluation of institutional seminars and communication training sessions. results from feedback surveys sent to all attendees were used to appraise the participants experience in the international oncology symposium. results: involvement of trained parent educators across diverse, interdisciplinary educational forums improved attendee comfort in communicating with, and caring for, patients and families with serious illness. importantly, parent educators also derive benefit from educational with interdisciplinary clinicians. integration of bereaved parents into palliative and eol care education is an innovative and effective model that benefits both interdisciplinary clinicians and bereaved parents. background: poorly controlled chemotherapy-induced nausea and vomiting (cinv) significantly impairs patients' quality of life and contributes to ongoing medical costs through increased length of stay in the hospital or readmissions and outpatient visits for control of nausea, vomiting or dehydration. lack of adherence to national evidenced-based guidelines that dictate antiemetic prescribing for variably emetogenic chemotherapy leaves patients vulnerable to increased cinv and its ensuing complications. objectives: to review our institution's antiemetic prescribing practices and their consistency with the antiemesis guidelines from the national comprehensive cancer network (nccn) and children's oncology group (cog)-endorsed supportive care guidelines and to further develop tools to increase adherence to these national-based guidelines to improve control of cinv. we performed a retrospective chart review of inpatient chemotherapy encounters. we evaluated emetogenicty of chemotherapy (high, medium, low), initial antiemetic regimen ordered, number of as needed medications required and adherence to national evidenced based guidelines tailored to each level of emetogenicity in the prescription of antiemetics. results: fifty-five total inpatient chemotherapy encounters were reviewed over 8 months. eighteen of these encounters were considered to have been highly emetogenic chemotherapy (hec) with the remaining 37 of these considered to be moderately emetogenic. only 9 out of 18 hec encounters completely included all guideline-recommended agents. there was a demonstrable lack of consistency across providers with dosing of aprepitant and most as needed medications. there was significant variation in order of first, second and third line anti-emetics ordered -with lorazepam and promethazine being used most frequently. with an aim of improving antiemetic prescribing practices for our patients, we are currently rebuilding chemotherapy treatment plans in our electronic medical record to incorporate antiemetic drug order sets that follow evidenced-based guidelines for variably emetogenic chemotherapy. this will be used in conjunction with an education initiative about best practices in supportive care for all prescribers of antiemetics. review of our department's recent inpatient chemotherapy encounters show we are falling short in following nationally recommended standards for appropriate antiemetic coverage during chemotherapy. identification of these deficiencies allows for implementation of quality initiatives to improve prescriber adherence to evidenced-based guidelines for better control of cinv. background: there are currently no consensus guidelines for the management of pediatric oncology patients presenting with fever without neutropenia. historically, these patients had been treated similarly to neutropenic patients with empiric antibiotics. while there has been a shift towards reducing unnecessary empiric treatment, there has been limited research into the outcomes associated with withholding empiric iv antibiotics in this patient population. we assessed the safety and efficacy of our institution's current protocol of observing well-appearing patients who present with fever without neutropenia and compared the outcomes of the patients who did and did not receive empiric iv antibiotics. design/method: this was a prospective, single-institution cohort study. patients were included if they were currently undergoing chemotherapy for an oncologic diagnosis and presented initially as an outpatient with fever and nonneutropenia (defined as anc ≥ 500 cells/mm3). for each episode we recorded lab and blood culture results, signs and symptoms of initial presentation, and clinical outcomes, including antibiotic administration and hospital admission. results: a total of 242 episodes of well-appearing patients with fever without neutropenia were identified. compliance with the institutional protocol was high; 81.8% of patients were observed without receiving empiric iv antibiotics. the majority of patients were discharged home and there were no serious complications or infectious deaths. the incidence of positive blood cultures was low (3.7% including several likely contaminants), despite the presence of central venous catheters in the majority (84.7%) of patients. there were no significant differences in age, oncologic diagnosis, central s165 of s301 line access, anc value, or incidence of bacteremia between patients who did and did not receive empiric iv antibiotics. patients who were admitted to the hospital were significantly more likely to have received iv antibiotics (p <0.001) despite documentation of a reassuring exam. however, admitted patients who initially received iv antibiotics were just as likely to discharge within 48 hours compared to patients who were observed. we propose that empiric iv antibiotic administration in febrile, non-neutropenic, otherwise well-appearing patients is unnecessary. our study demonstrated no adverse consequences of observation and no significant differences in clinical outcomes between patients who did and did not receive iv antibiotics aside from rate of hospitalization. this supports the practice of observation without empiric antibiotics for such patients. background: children with hepatoblastoma (hb) undergo repetitive computed tomography (ct) scans to determine response to treatment and assess for relapse. this imaging exposes children to radiation, anesthesia, and imposes financial and emotional burden. objectives: review our institutional experience to determine if afp measurements are sufficient to assess response to treatment and detect relapse. we conducted a retrospective chart review of all patients diagnosed with hb at our institution between 1978-2017. data collected included serum afp, total number and type of imaging studies during and post treatment, and how relapse or progressive disease was detected. results: thirty-one patients were diagnosed with afp positive hb. during therapy, 173 ct scans were performed: 118 to assess for response to therapy or surgical planning (average 4 scans/patient) and 55 due to concern for progression with rising afp. off therapy, 213 surveillance ct scans were performed (average of 5.3 scans/patient) and 72 (33%) included the chest in patients with no lung metastasis at diagnosis. relapsed patients averaged 12.5 surveillance scans, 6.5 of which were done before relapse was noted on imaging. there were no cases of radiographic evidence of relapse without a prior increase in afp. during treatment, response to therapy based on imaging correlated with a decline in afp in all patients, arguing that repetitive scans are not needed in this setting unless required for surgical planning. only 3 of 213 scans performed during off therapy surveillance displayed evidence of relapse, all of which were preceded by rise in afp. our study represents the largest cohort of hb patients. prior studies suggest similar results, but included fewer patients, lower stage of disease and less than 10 years of surveillance monitoring. at our institution, the cost of a ct c/a/p is $15,169 with reimbursement varying from 30-50%. in comparison, the cost of an afp measurement is $101.50. many scans also require anesthesia and result in emotional toil for families concerned about this procedure as well as the results. thus, afp demonstrates greater sensitivity, with significant cost savings and decreased emotional burden, and should be used for monitoring both during and off therapy, replacing routine serial imaging. background: we observed that our practice of drawing daily blood cultures in hospitalized patients with fever and neutropenia was wasteful; it resulted in excessive negative cultures that did not add to patient care. the smart aim of this quality improvement project was to reduce the number of negative blood cultures drawn on hospitalized patients with fever and neutropenia by 25% in 6 months. design/method: after reviewing published evidence suggesting drawing daily blood cultures in febrile neutropenic patients was unnecessary, a new blood culture guideline was implemented: cultures were drawn at presentation for fever with neutropenia and, if negative at 24 hours, repeat cultures were not drawn except for clinical change, new fever after being afebrile >24 hours, or antimicrobials were being changed/broadened. to impact key drivers, we educated staff and changed blood culture order sets to require providers to select a reason for ordering the culture and to eliminate a nursing order to draw daily cultures with fever. we compared the number of blood cultures drawn per 1000 central linedays (/1000-cld) and the proportion of positive versus negative cultures pre-guideline (july 2015-may 2016) and postguideline (june 2016-december 2016). we calculated the cost savings from reducing cultures. to assess patient safety, potential septic events without a corresponding positive blood culture were reviewed. data were analyzed by service (oncology and stem cell transplant). a chi-square test was used to compare rates. in stem cell transplant patients, pre vs. postguideline, there were 492 vs. 258 total cultures drawn/1000-cld; 25 vs. 21 positive (16% decrease, p = 0.404) and 467 vs. 237 negative cultures/1000-cld (51% decrease, p<0.0000001). in oncology patients, pre vs. post-guideline, there were 266 vs. 181 total cultures drawn/1000-cld; 17 vs. 13 positive (24% decrease, p = 0.024) and 249 vs. 168 negative cultures/1000-cld (32% decrease, p<0.0000001). the decreased positive culture rate among oncology patients may be due to decreased culture contaminants and/or the effect of a concurrent initiative to decrease clabsi in that group. there were 2 safety concerns; however, chart review concluded that the guideline did not lead to missed infections in these patients. for the first 6 months of the guideline, the total cost savings in blood cultures was $31,454.31. the implementation of our new blood culture guideline successfully led to a substantial reduction in the collection of negative cultures and a cost savings without compromising the detection of bacteremia in hospitalized pediatric patients with fever and neutropenia. background: there are various evidence-based guidelines for treatment of adult cancers, such as the nccn guidelines. previously, care was standardized for most new diagnosis pediatric cancer patients through enrollment on a clinical trial. with decreasing clinical trial availability and enrollment and few, if any, evidence-based guidelines for pediatric cancer, care standardization is challenging for pediatric cancers. objectives: to assess consistency of care, as determined by plan of treatment by diagnosis, for pediatric patients receiving chemotherapy for newly diagnosed cancer at a single center. design/method: patients with a new cancer diagnosis at a large, tertiary care pediatric oncology center in calendar year 2016 were identified through reports from the chemotherapy order entry (coe) system. reports included diagnosis (recorded through standardized options) and the plan of treatment. chart review was used to exclude patients who started treatment elsewhere and patients being treated for relapse, to clarify diagnosis if the standardized options in coe were unclear, and to clarify treatment plan if needed. data was entered and analyzed in a redcap database. specific diagnoses were clustered into higher level disease groups and the distribution of treatment plans for patients within each was determined. this project was deemed exempt from irb approval for human subject research as a qualifying quality improvement project. of the 324 patients with a first chemotherapy order in 2016, 142 were excluded due to one or more reasons: stem cell transplant (62), transfer of care (54), relapse (25), and other (9). an additional 61 patients were excluded because <5 patients/year/diagnosis. there was no cns tumor disease group with >5 patients. thus, 121 patients with hematologic malignancies or non-cns solid tumors are the focus of this analysis. for patients with intermediate risk rhabdomyosarcoma, the plan of treatment was the standard arm of a cog protocol, arst0531 for 3 patients and arst 1431 for 1 subsequent patient after protocol activation. for all other diseases including lymphoblastic leukemia/lymphoma (excluding infants), classical hodgkin lymphoma, aml (excluding trisomy 21 and apml), stage iii/iv burkitt lymphoma/diffuse large b-cell lymphoma, posttransplant lymphoproliferative disease, wilms tumor, rhabdomyosarcoma, ewings sarcoma, osteosarcoma, neuroblastoma, and retinoblastoma, only one treatment plan per risk category was used. conclusion: this analysis demonstrates highly consistent chemotherapy treatment at a single center for patients with hematologic malignancies and non-cns solid tumors. next steps include exploring strategies to group diagnoses for cns tumors and assessing the quality of evidence supporting the treatments given. background: rapid initiation of empiric antibiotics in patients with fever and neutropenia has been shown to reduce morbidity and mortality. current practice guidelines call for the initiation of antibiotics in these patients within sixty minutes and time-to-antibiotic (tta) has been suggested as a quality-of-care measure. many institutions, including our own, face barriers to meeting this time limit. objectives: utilizing a quality improvement model, determine barriers and implement an intervention to reduce the time-to-antibiotics for pediatric febrile patients with suspected neutropenia who present to the emergency department (ed) at our institution. we have identified and implemented an intervention utilizing the plan-do-study-act model for quality improvement. a twelve-month retrospective review was conducted to evaluate the efficacy of the current practice algorithm at our large, academic tertiary-care hospital. subjects identified were pediatric oncology patients undergoing active chemotherapy who presented to the ed with febrile neutropenia. we identified two specific barriers, triage level assignments and delay in ordering antibiotics. to address these barriers, we have created a wallet sized "fever card" that patients were instructed to show upon arrive to the ed. in collaboration with the ed staff, efforts were also made to educate all pediatric staff on the use of the fever card. post-intervention data collection is currently underway and pre-and post-intervention antibiotic delivery times will be compared. the pre-intervention cohort consisted of thirty-three encounters with a mean time-to-antibiotic delivery of 135 minutes, or seventy-five minutes greater than the accepted standard of care. only one patient received antibiotics within sixty minutes of arrival. post-intervention data collection is currently underway. since identifying two barriers to meeting the standard of care at our institution, we have implemented a quality improvement measure that empowers patient families to direct appropriate triage in the ed as well as simplifying the treatment protocol for ed providers. we expect to identify an improvement in time-to-antibiotics from the pre-intervention to the post-intervention period. background: sickle cell disease (scd) is a genetic disorder in which sickle hemoglobin (hbs) triggers multiple downstream effects, including red cell sickling, hemolysis, vaso-occlusion, and inflammation. scd, a lifelong disease initiated at birth with injury that accumulates over time, causes significant end-organ damage and clinical complications that are undertreated and associated with early death. homozygous mutation (hbss) causes the severe form of scd. individuals with scd are at increased risk of infection, stroke, and retinopathy. clinical guidelines for pediatric patients with scd recommend prophylactic penicillin use (ages 2-5), annual screening for stroke with transcranial doppler (tcd) imaging (ages 2-16), and annual ophthalmology exams to assess for retinopathy (ages ≥10). there are limited real-world data on implementation of these nhlbi-based recommendations. objectives: to describe utilization of penicillin, tcd screening, and ophthalmology care in children with hbss disease. medicaid administrative claims databases were used to identify us patients aged 2-16 years at first indication of hbss recorded in each calendar year from 2009 to 2014. patients were required to have medical and pharmacy benefits for the calendar year in which they were identified and for 12 months prior to their first recorded hbss indication. prior year utilization of penicillin, tcds, and ophthalmologist visits was measured for each annual cohort. annual cohorts included 347-438 commercial (mean age 9.5 years, 52% female) and 1024-1557 medicaid (mean age 8.3 years, 48% female) patients with hbss disease. fewer than half of all patients had received a tcd scan in the previous year, with similar rates seen across all age groups for both payers. ophthalmologist visits increased as patients aged, and while patients aged 12-16 years had the highest proportion with an ophthalmologist visit in both payer populations, the overall implementation remained low. in contrast to the low use of tcd and ophthalmology visits, penicillin use was highest in the 1-5 year age group: >80% use in any given year for both payers. conclusion: although our data demonstrated high penicillin use in the 1-5 year age group, consistent with guidelines there is an opportunity to improve implementation of other guidelines-based recommended screening. for example, tcd screening can identify children at risk of scd-related stroke in order to initiate preventive therapies. further research to understand potential barriers to proper screening and to evaluate strategies to improve awareness, adherence, and implementation of recommended screenings in children with scd is warranted. supported by global blood therapeutics. background: childhood cancer therapy has improved where there are many long-term survivors. while psychosocial difficulties in pediatric cancer survivors are recognized, the prevalence of these problems at initial survivorship presentation is unclear. objectives: to examine the prevalence of overall internalizing symptoms (e.g., depression/anxiety) in pediatric cancer survivors presenting to a survivorship clinic and to examine how this is mitigated by receiving psychological services and by evidence of parental depression/anxiety. design/method: pediatric cancer survivors attending their first visit at the reach for survivorship clinic at vanderbilt (ages 3-18) were included. survivors' parents (93% female) completed the child behavior checklist (cbcl), beck depression inventory-ii, and beck anxiety inventory. survivors >12 years completed a self-report. the wilcoxon rank-sum and pearson's 2 test were used for univariate analyses. the effect size and 95% confidence intervals (ci) estimated from the multivariable linear regressions were reported. results: 142 childhood cancer survivors a median of 12 years old and 3.3 years off therapy were included. thirty one survivors (22%) showed at least borderline clinical internalizing problems (t score >60) on the cbcl, but only 8 of these patients (26%) reported receiving psychological services. nine other survivors with normal t score ≤60 also reported receiving psychological services. parental depressive and anxiety symptoms were correlated to the parental report of survivor overall internalizing symptoms (spearman = 0.415, p = <0.001 and = 0.476, p = <0.001 respectively), however they were not correlated to survivor selfreports. furthermore, parents with mild to severe depressive symptoms or mild to severe anxiety symptoms were more likely to rate their child as having higher overall internalizing symptoms (p = 0.001; p = 0.008, respectively). multivariable linear regression showed that when adjusted for age, gender, cancer diagnosis and time off treatment, reported utilization of psychological services ( = 8.58, 95% ci [3.54, 13.62],p = 0.001), and parent depressive symptoms ( = 0.43, [.22, .65 ],p<0.001) were significantly associated with child overall internalizing symptoms. in an otherwise identical alternate model substituting parental anxiety for parental depression, parental anxiety was also a significant risk factor ( = 0.70, [.38, 1.03], p<0.001). alternatively, parent anxiety/depressive symptoms were not significantly associated with child self-report of internalizing symptoms. childhood cancer survivors have an elevated prevalence of experiencing internalizing symptoms but seldom report receiving psychological services. childhood cancer survivors' parents with anxious/depressed symptoms are more likely to rate their children as having more internalizing problems, compared to patient self-reports. ongoing longitudinal analyses will help clarify the best timing for potential interventions. background: life expectancy for adults with sickle cell disease (scd) has remained unchanged over the past 30 years despite improvements in pediatric scd survival. at greatest risk are the adolescents and young adults (ayas) transitioning from pediatric to adult care. allen county ranks 3rd in scd incidence among the 92 counties in indiana, and has 2 board certified pediatric hematologist-oncologists. when children "age out" of the pediatric system, there are few providers knowledgeable about managing adults with scd in the region. a novel partnership between hematologists and the family medicine residency program in allen county was initiated to educate family medicine residents (fps) about scd, hydroxyurea (hu), and management of scd-related complications with the goal to increase the number of knowledgeable providers to care for adults with scd. to determine the effectiveness of online learning modules in educating fps about hu, best practices for aya scd care and transition. three online learning modules about scd (comprehensive care of ayas with scd, hu, best practices in aya transition) were developed and cme-accredited. electronic pre-and post-tests were distributed to 32 fps with five questions for each module covering: contraception; screening tests; hu indications, dosing and monitoring; developmental milestones and scd knowledge assessments. the st vincent irb reviewed the protocol and granted a waiver of consent. results: twenty-six fps (81%) completed the pre-and posttests. over two-thirds correctly identified the clinical benefits of hu on both assessments. knowledge about the rationale for hu therapy increased after the completion of the hu module (30% correct on pre-test vs. 62% on post-test, p = 0.009). the proportion of correct responses increased for all comprehensive aya scd care post-test questions, but only the leading cause of death and the priapism-related questions reached statistical significance (15% vs. 35%, p = 0.048; 0% vs. 23%, p = 0.003, respectively). the proportion of correct responses for 2 of the transition-focused questions was unchanged (89% for both), while the proportion of correct post-test responses on the self-care assessment question significantly increased (0% vs. 12%, p = 0.04). after module completion, fps were able to correctly identify common scd complications and why hu is an effective treatment for individuals with scd. the best practices of transition clinic module may need modification to improve physician understanding of the intricacies in establishing and maintaining a scd transition clinic. overall, online training is effective at educating fps and could be used to increase the number of providers knowledgeable about scd care. background: survival rates for pediatric hodgkin lymphoma (hl) exceed 95% with contemporary therapy. studies of pediatric hl survivors treated in the 1970s-1990s have shown increased risk for treatment-related chronic health conditions. risk-adapted therapy, including tailored radiotherapy, has been developed to reduce long-term morbidity while maintaining excellent survival. little is known about chronic conditions associated with contemporary therapy presenting during the first 5 years from therapy completion (early outcomes). objectives: to analyze survival and early outcomes of pediatric hl patients treated with contemporary therapy. we conducted a retrospective review of hl patients diagnosed <21 years of age at our institution from 2010-2014. three-year overall (os) and event-free (efs) survival were calculated with kaplan meier statistics using sas 9.4. results of standardized screening for targeted toxicities that developed between 2 -5 years from therapy completion were identified and graded per ctcae criteria. censoring occurred at date of death, 5 years from therapy completion, or december 31, 2016. data from the last collection point were used for prevalence calculations in cases with multiple evaluations. we identified 83 patients (51% male; 43% non-hispanic white; mean age at diagnosis 13.6 ± 3.7 years) with a median time since therapy completion of 3.3 years (range 0.1-5.0). initial treatment included: 56 (67%) chemotherapy only and 27 (32%) multimodality treatment. all patients received anthracyclines (median dose 200mg/m2) and 96% received alkylating agents (median cyclophosphamide equivalent dose [ced] 3600mg/m2). the 3-year os was 99% with an efs of 90% (90% chemotherapy only, 91% multimodality treatment; p = 0.76). patients with relapsed/refractory disease received salvage treatment including chemotherapy only (n = 1), multimodality therapy (n = 1), or multimodality treatment including stem cell transplant (autologous n = 4; autologous+allogeneic n = 1). no patients developed thyroid dysfunction, cardiac dysfunction, subsequent neoplasm, or male gonadal dysfunction during the study period. pulmonary dysfunction was limited to ctcae grade 1. anti-mullerian hormone (amh) below the normal range was found in 10/11 pubertal females who received ced ≥7000mg/m2 compared to 0/12 females who received ced <7000mg/m2. two of the females with low amh also had follicle stimulating hormone >30iu/ml. this study is the first to evaluate early outcomes in pediatric hl survivors. the results indicate contemporary chemotherapy and a lower rate of radiotherapy utilization lead to excellent 3-year survival rates with minimal early toxicities. females exposed to ced ≥7000mg/m2 are at increased risk for gonadal dysfunction and should be prioritized for fertility preservation approaches prior to initiation of cancer therapy. background: cancer is one of the leading disease-related causes of death among individuals aged <20 years in the united states. recent evaluations of national trends of pediatric cancer used data from before 2010, or covered ≤28% of the us population. objectives: this study describes pediatric cancer incidence rates and trends by using the most recent and comprehensive cancer registry data available in the us. design/method: data from us cancer statistics were used to evaluate cancer incidence rates and trends among individuals aged <20 years during 2001-2014. data were from 48 states and covered 98% of the us population. we assessed trends by calculating average annual percent change (aapc) in rates using joinpoint regression. rates and trends were stratified by sex, age, race/ethnicity, us census region, county-based economic status, and county-based rural/urban classification, and cancer type, as grouped by the international classification of childhood cancer (iccc). we identified 196,200 cases of pediatric cancer during 2001-2014. the overall cancer incidence rate was 173.0 per 1 million; incidence rates were highest for leukemia (45.6), brain tumors (30.8), and lymphoma (26.0). rates were highest among males, aged 0-4 years, non-hispanic whites, the northeast us census region, the top 25% of counties by economic status, and metropolitan counties. the overall pediatric cancer incidence rate increased (aapc = 0.7, 95% ci, 0.5-0.8) during 2001-2014 and contained no joinpoints. rates increased in each stratum of sex, age, race/ethnicity (except non-hispanic american indian/alaska native), region, economic status, and rural/urban classification. rates were stable for most individual cancer types, but increased for non-hodgkin lymphomas except burkitt lymphoma (iccc group ii(b), aapc = 1.2, 95% ci, 0.4-2.0), central nervous system neoplasms (group iii, aapc = 0.4, 95% ci, 0.1-0.8), renal tumors (group vi, aapc = 0.6, 95% ci, 0.1-1.1), hepatic tumors (group vii, aapc = 2.5, 95% ci, 1.0-4.0), and thyroid carcinomas (group xi(b), aapc = 4.8, 95% ci, 4.2-5.5). rates of malignant melanoma decreased (group xi(d), aapc = -2.6, 95% ci, -4.7--0.4). this study documents increased rates of pediatric cancer during 2001-2014, in each of the demographic variables examined. increased overall rates of hepatic cancer and decreased rates of melanoma are novel findings using data since 2010. next steps in addressing changing rates could include investigation of diagnostic and reporting standards, host biologic factors, environmental exposures, or potential interventions for reducing cancer risk. increasing pediatric cancer incidence rates may necessitate changes related to treatment and survivorship care capacity. background: while childhood cancer treatment modalities have improved, the delayed effects of cancer treatment continue to compromise the quality of life in survivors. metabolic syndrome (ms) is diagnosed based on the presence of three of the following findings -obesity, dyslipidemia, hypertension and insulin resistance per the world health organization (who) criteria. the increased risk of ms among childhood cancer survivors was first reported in the 1990's and is known to increase the incidence of cardiovascular disease in these individuals. objectives: assess the frequency of ms in childhood cancer survivors at our institution. . we conducted a retrospective chart review on pediatric cancer survivors, 4 -18 years of age, who had been treated at sri ramachandra medical institute and research foundation between august 2015 and august 2017. patients who received at least one year of treatment with s171 of s301 chemotherapy and/or radiation and surgery were included. medical history, family history of diabetes, cardiovascular diseases, and hypercholesterolemia, tanner staging, weight for height (<5y per who criteria), bmi (>5y per indian academy of pediatrics iap), blood pressure (nhlbi criteria), fasting blood sugar levels and lipid profile were obtained from the charts. statistical analysis of the data was done using ibm spss statistical software (version 22). results: 97 patients were studied, 63.9% were male. 22.68% were under 5 years of age, 38.14% between 6-10 years and 39.18% above 11 years. leukemia survivors comprised 39.18% of the sample and non-leukemic's were 60.82%. 51.5% were treated with chemotherapy alone, 19.5% with radiotherapy and chemotherapy, and 28.8% underwent surgery with radiotherapy and chemotherapy. hypertension was found in 19.5% of the study group, dyslipidemia in 68%, impaired fasting blood glucose in 4.12% and 36.08 % were found to be obese. 10% of the study group was diagnosed with ms based on who criteria. conclusion: 10 % of our study population was found to have ms per who criteria. individual metabolic complications were detected in 68% of the population. acute lymphoblastic leukemia (all) survivors appeared to be at high risk in our population. ms has been known to increase cardiovascular complications in cancer survivors. a multidisciplinary team approach to management of these patients is important to closely monitor and manage the long-term complications related to ms such as type 2 diabetes and atherosclerosis. such an approach is essential to decrease long term morbidity and mortality from ms in this vulnerable population. background: the 5-year survival rate for childhood cancer exceeds 80%. however, up to 38% of these children require admission to the pediatric intensive care unit (picu) within three years of diagnosis. these children account for approximately 10% of all picu deaths, with mortality being higher for those post-hematopoietic stem cell transplant (hsct). national guidelines recommend that providers share informa-tion regarding prognosis and treatment options within the first 48 hours of icu admission. these prognostic goals of care conversations (pgocc) are critical to the care of children with malignancies, a subpopulation at risk for increased mortality. to determine the frequency of pgocc as well as describe differences in patient characteristics and critical care therapies by pgocc status. design/method: a retrospective cohort study was conducted using the university of michigan virtual picu system database. picu admissions lasting longer than 24 hours for patients ages 0 to 25 years between july 1, 2011 and june 30, 2016 with an oncologic diagnosis and/or hsct were identified. data on pgocc, patient demographics, diagnoses, picu interventions, and outcomes were recorded and compared between children with pgocc and those without using chi square test for categorical variables and kruskal-wallis test for continuous data. of 128 picu admissions, 53% were male; the mean age was 10.5 years. the leading diagnoses were acute lymphoblastic leukemia (46%), acute myeloid leukemia (14%), lymphoma (14%), neuroblastoma (5%), and brain tumors (5%), and 43% of patients were post-hsct. pgocc was documented in 35 (27%) patients. in comparison with patients who did not have a pgocc, children with a pgocc were more likely to be readmitted to the picu (45% vs. 15%, p <0.01) and more likely to have had relapse of disease (41% vs. 18%, p<0.01). patients with a pgocc had higher severity of illness scores (p = 0.02), higher use of non-invasive (22.9% vs. 8.6%, p = 0.04) and invasive conventional ventilation (68.6% vs. 23.7%, p<0.01), and high frequency ventilation (25.7% vs. 4.3%, p <0.01). also, patients with pgocc were more likely to receive continuous renal replacement therapy (37.1% vs. 5.4%, p<0.01), arterial catheterization (54.3% vs. 23.7%, p<0.01), and cardiopulmonary resuscitation (22.9% vs.1.1%, p<0.01). in only 1 in 3 critically ill children with hematologic-oncologic disease is pgocc held. children with pgocc were sicker and received more critical care interventions. future research is needed to evaluate the content of pgocc. background: central nervous system (cns) tumors and autism spectrum disorder (asd) represent significant disease cohorts in the pediatric population. asd diagnoses in children have a prevalence of 2%, 1 in every 88 children in the united states. additionally, more than 4,000 cns tumors are reported in children age 0 to 19 years in the united states with brain tumors being the most common solid tumor and the leading cause of death among all childhood cancers. the genetic etiology of autism and cns tumors is complex. specific gene alterations present in certain cancers have similarly been described and suspected to play a role in asd subtypes. targeted therapy panels, like foundation one (fo), have been beneficial in guiding treatment for some cancers based on distinct gene alterations. given the genetic overlap, the potential for therapeutic benefit and crossover from such actionable gene target panels merit further exploration in asd and cns tumors. we aim to identify and describe genetic alterations with known actionable targets in cancer therapy from fo as potential diagnostic, therapeutic and research targets for neurodevelopmental diseases. we plan to discuss the common genetic alterations between our cancers and neurodevelopmental diseases described in the literature. fo data was extracted and compared to the literature. each reported gene alteration from fo plus the keywords "autism", "psych" were used on pubmed to search for a suspected association if any with a neurodevelopmental disorder. results: twenty-one patients representing a cohort of six unique (astrocytoma-five, ependymoma-six, gbm-four, glioma-three, nerve sheath tumor-one, etmr-two) cns tumors were investigated. fo produced eighty total with sixty unique gene alterations. thirty-one (52%) of these yielded at least one published, suspected association to a neurodevelopmental disorder. the most common gene alterations were tp53-four, cdkn2a/b-five and braf-four. the main functional categories were cellular: proliferation, structure, differentiation and degradation; chromatin modeling; histone transcriptional modification; dna methylation and repair; strna; and neural signaling. sixty unique gene alterations were found in our cns tumor set using foundation one. thirty-one (52%) of these discrete alterations paired with at least one description in the literature as having been similarly altered in an asd subtype. many of these alterations have actionable targeted therapies presented through foundation one for our cns tumors and may be a relevant guide in the future of targeted therapy and research in asd subtypes. monoclonal antibody therapy usage is associated with significantly improved survival in b-cell nhl aya patients. although the usage has increased in the aya population from 2006 to 2013, the magnitude of the increase is low. factors that affect the use of mab include race and insurance s173 of s301 type. further research is warranted to identify why privately insured patients are less likely to receive these drugs. background: prevention of chemotherapy-induced nausea and vomiting (cinv) remains a challenge despite advances in pharmacotherapy and the development of cinv clinical practice guidelines by the pediatric oncology group of ontario (pogo) that have been endorsed by the children's oncology group. achieving control of cinv in pediatrics further is complicated by the difficulty young children have vocalizing their symptoms. use of a validated nausea-assessment tool in conjunction with improved adherence to evidence-based guidelines may result in better quantification of symptoms and reduction of both nausea severity and vomiting frequency for pediatric patients undergoing chemotherapy. the pediatric nausea assessment tool (penat) has been validated for children ages 4-18, and its integration into clinical practice may help optimize cinv control. objectives: this single-institution study sought to improve control of cinv in patients admitted for chemotherapy by standardizing the antiemetic regimens prescribed by all providers according to an institutional cinv algorithm developed from the pogo guidelines. we hypothesized that treatment using a standardized guideline would improve cinv control in patients admitted for chemotherapy. a baseline cohort of 70 admissions for chemotherapy completed penat assessments and cinv diaries prior to receiving chemotherapy, four times daily during each admission, and daily for 7 days following completion of chemotherapy from may 1, 2013 to january 31, 2014. providers then were provided an institutional cinv treatment algorithm based on the pogo guidelines and received education at departmental meetings on appropriate implementation of this algorithm. a second cohort of 78 admissions completed penat assessments and cinv diaries in a similar fashion from july 1, 2014 to december 31, 2016. results: complete control of vomiting markedly improved following cinv guideline implementation (72% vs 52%, p <.0001) with treatment failure also significantly reduced (6% vs 23%, p <.0001). after controlling for the degree of emetogenicity of chemotherapy received, a patient was 3.33 times more likely to vomit prior to guideline implementation (or 3.33, ci 1.96-5.56). there was no difference in nausea control, even after adjusting for the emetogenicity of chemotherapy. conclusion: control of chemotherapy-induced vomiting (civ) improved following widespread implementation of an institutional cinv treatment algorithm at a single institution. the severity of nausea reported remained unchanged which may reflect the difficulty of assessing nausea or an inadequate sample size. future research may focus on cinv treatment management through the use of guidelines specifically for breakthrough cinv and delayed cinv. background: aspho's professional development committee (pdc) recognized pediatric hematologists-oncologists (phos) serving in the united states (us) military have unique professional development needs that may not be addressed by aspho or a similar professional society. these individuals may also encounter challenges when transitioning to a civilian career. however, barriers to professional development have not been systematically characterized. the objectives were to characterize the number of phos with current or prior military service (mphos) and to identify any unmet professional development needs. design/method: a working group consisting of pdc members and both senior and early career mphos was formed. initial comments were solicited by email from known mphos regarding potential gaps in professional development and interest in working with aspho to improve support of mphos. a survey was developed and piloted with four members of the advisory group, questions were revised based on their feedback, and a final version was distributed via the aspho website and online community forum. targeted emails were sent to mphos identified through aspho and military databases. eligibility to complete the survey included 1) completion of a fellowship in pediatric hematologyoncology, and 2) current or prior service as an active duty military provider. quantitative and qualitative information were collected, including demographic data and perceived barriers to professional development. responses were summarized using descriptive statistics. results: sixty-five mphos were identified and 34 surveys were completed for a 52% response rate. respondents were engaged in a variety of professional activities; 64% were male, 52% were serving active duty commitments, and 32% felt there were professional development gaps. areas of concern were categorized into nine themes with the most concerning being 1) limited civilian knowledge of mpho practices (76% of participants), 2) inability to attend professional society meetings (60%), and 3 possibility of deployment (56%). participants expressed a desire for educational products to meet their specific needs and for networking opportunities with civilian colleagues. qualitative analyses identified concerns about low patient numbers and practice size. a subset of mphos perceive significant gaps in professional development. additional research is needed to better define areas for intervention, but many of the concerns align with those of similarly sized civilian programs and may be addressed through professional society networking opportunities, such as an aspho special interest group. background: infertility is an established cause of distress and has a negative impact on quality of life among childhood cancer survivors. the american society of clinical oncology has established guidelines on fertility counseling for individuals of reproductive age diagnosed with cancer, with the goal of improving reproductive and psychosocial outcomes. studies have shown that instituting a fertility team that can provide counseling and discuss fertility preservation (fp) options results in improved patient satisfaction in patients with cancer. objectives: the goal of this study was to examine predictors of referrals to the multidisciplinary fertility team, and documented fp interventions among these patients. design/method: an irb-approved retrospective medical record review was performed at a large pediatric academic center. all patients with new cancer diagnoses receiving chemotherapy were included from january 2015 (when the fertility team was established) to present. a standardized abstraction form was used to collect information about: age at diagnosis, gender, cancer type, whether a fertility consult was placed, and documented fp interventions. data were summarized descriptively and comparisons were made using nonparametric statistical methods. results: 265 patients met inclusion criteria, of which 152 (57%) were male. cancer types were as follows: 126 leukemia/lymphoma, 51 cns tumors, 44 sarcomas, 37 embryonal tumors, and 7 langerhan's cell histiocytosis (lch). the mean age was 8.2 years, (range <1-31 years). overall, 27% of all patients had a consultation with the fertility team. patients were significantly less likely to have a fertility consult if they were younger (p<0.001). further, there were differences in the consultation rate between diagnoses, with 53% of sarcoma patients completing a consult, compared to 31% of those with cns tumors, 41% of those with embryonal tumor, 44% of those with leukemia/lymphoma and none of the patients with lch. our findings show that many children, adolescents, and young adults newly diagnosed with cancer are still not receiving fertility counseling despite: 1) an expanding body of literature supporting the need to provide this counseling, 2) guidelines published by several organizations recommending discussions about infertility risk and fp options, and 3) presence of a multidisciplinary fertility team. specific strategies need to be developed to improve access for younger children, and for disease groups in whom fertility consults are underutilized, such as youth with cns tumors, embryonal tumors, and leukemia/lymphoma. background: socioeconomic status (ses) has on impact on overall survival in the pediatric oncology population. unfortunately, data are insufficiently detailed to explain the mechanism behind this phenomenon. how parents handle the health management demands placed on them at the time of a child's cancer diagnosis may represent a point of differentiation in health outcomes. objectives: determine the association between socioeconomic factors, cancer literacy, and parents' understanding of home emergency management and their responses to instances of pain, nausea, and fever. in a prospective observational study of parents whose children were newly diagnosed with cancer, we obtained demographic information and, using a validated instrument, (dumenci, 2014) we evaluated cancer literacy. we tested understanding of the education parents received about home emergency management with a 6-item multiple-choice vignette-based questionnaire focused on actions needed in home scenarios. we then followed parents' actual behavior through periodic phone calls assessing instances of nausea, pain, and fever and their responses to these episodes. results: preliminary analysis of 24 participants showed an average score of 4 on the 6-item parental understanding questionnaire (range 0-6). variables associated with increased score were college-level education by 1.2 points (95% ci [.3 to 2.1]), private insurance by 0.9 points [.13 to 1.7] and adequate cancer literacy by 1.2 points [.2 to 2.2]. actual behavior reported by families indicated that married parents and those with income above $75,000 were less likely to treat instances of pain by 51% (95% ci [28 to 72]) and 43% [6.6 to 79], respectively. white parents, those with college-level education, and those with adequate cancer literacy were less likely to treat instances of nausea by 31% [6 to 57], 29% [5 to 53] and 29% [5 to 53], respectively. no associations were found between socioeconomic markers and parental responses to instances of fever. our findings suggest an association between demographic and socioeconomic markers and improved parental understanding of home emergency management. paradoxically, the same markers show a decrease in treatment response to pain and nausea. larger prospective studies are needed to link this behavior pattern to health outcomes, and help inform the extent of ses impact on home emergency management. emory university/children's heathcare of atlanta, atlanta, georgia, united states background: cardiovascular disease is a leading cause of morbidity and mortality in childhood cancer survivors (ccs). previous research showed wide practice variation in referral patterns to cardiology from the survivor clinic and in recommendations from cardiologists about the need for further testing or exercise restrictions. to develop a cardio-oncology algorithm in order to standardize referrals to cardiology and provide guidelines for cardiologists evaluating pediatric ccs. design/method: survivorship and cardiology experts developed a weighted scoring system for pediatric ccs who received cardiotoxic therapy based on time since treatment and risk factors identified by the children's oncology group (cog) and american heart association (aha). the cardiooncology algorithm assigned a score of 1-21. the score range was categorized to guide cardiology referral: screening echo only (1-3), consider cardiology referral (4-6), recommend cardiology referral (7-9), and regular cardiology follow-up (≥10). the algorithm also provides recommendations to cardiologists for screening and exercise modifications based on the score. after establishment of the algorithm, a convenience sample of institutional survivor clinic patient charts were retrospectively reviewed from the first month of each quarter from april 2015-march 2016 to validate the algorithm, evaluate referral patterns to cardiology, and assess cardiology recommendations. the retrospective chart review evaluated 243 patients (51% male; 61% non-hispanic white; 46% leukemia survivors; median age at diagnosis 4.0 years [range 0-19.7]; median time off-therapy 7.2 years [range 2.3-18.2]). 230 patients (95%) received anthracyclines (median dose 154mg/m2, range 30-512) and 73 (30%) received cardiac radiation. assigned cardio-oncology scores resulted in: 35% echo only, 47% consider cardiology referral, 16% recommend cardiology referral, and 3% regular cardiology followup. when evaluating detection rates of late effects by cardiooncology score, 12 survivors (5%) had an abnormal echo: 1/83 echo only, 4/115 consider referral, 4/38 recommend referral, and 3/6 regular cardiology follow-up. assessing referral patterns prior to initiation of the algorithm revealed forty-two survivors (17%) referred to cardiology: 8/83 echo only, 16/115 consider referral, 14/38 recommend referral, and 4/6 regular cardiology follow-up. of the 37 patients seen by a cardiologist at our institution, 4 had further diagnostic testing ordered (i.e., stress test) and 7 received exercise restrictions. a cardio-oncology algorithm and guidelines will standardize cardiac care for survivors by assigning a score to guide referral and cardiology practice after referral. prospective clinical use has begun and review will occur in one year to determine changes in detection rates of cardiac late effects, referrals, and recommendations from cardiologists. oregon health and science university, portland, oregon, united states background: delirium affects 10-30% of patients (pts) in pediatric intensive care units (picu) and is associated with increased length of stay, decreased attention in school, and post-traumatic stress disorder. the diagnostic and statistical manual of mental disorders (dsm v) defines delirium as a "disturbance of consciousness […] with reduced ability to focus, sustain or shift attention" due to an underlying medical condition. despite the medical complexity of the hospitalized pho population, there are no published prospective studies looking at delirium in these pts. hypothesizing that delirium is under recognized in the pho population, we designed a year-long prospective study using a validated screening tool to determine the frequency of delirium in hospitalized pho pts and to identify associated clinical factors. design/method: baseline frequency of pts with symptoms suggestive of delirium was determined through retrospective chart review using a data mining program of electronic medical records (emr). for the prospective study, pho and picu nurses were trained to use the cornell assessment for pediatric delirium and to record scores within the emr on all pho pts once every 12-hour shift. predetermined demographic and clinical variables were entered daily into a red-cap database on all hospitalized pho pts. results: baseline frequency of delirium, without active screening, was determined to be 4.5% of hospitalized pho pts. in the first 6 months of the prospective study, 405 consecutive admissions occurred among 152 unique pho pts: 347 oncology, 30 hematology, and 23 stem cell transplant pts. 25 pts had at least 1 positive delirium screen, for a prevalence per admission of 6.2%. statistically significant variables associated with delirium, at p < 0.0002 by univariate logistical regression, included prolonged length of stay, pt location (picu vs pho unit), and fever. adjusting for length of stay, administration of benzodiazepines and opiates were also significantly associated with delirium, p = 0.048 and 0.044, respectively. on average, nurses completed delirium screening in 70% of each pts' 12-hour shifts. study accrual ends in jan 2018 and final data analyses will be reported in the abstract presentation. conclusion: delirium does occur in the pho hospitalized population and screening by trained nursing staff is feasible. pts at highest risk appear to be pts with prolonged hospital stays, picu admissions, or frequent use of benzodiazepines/opioids. routine screening should improve our recognition of delirium and allow us to promptly intervene, or prevent delirium in an effort to avoid potential acute and long term consequences. background: with high survival rates for children and adolescents with hodgkin lymphoma (hl), treatment regimens are now designed to maximize cure while decreasing risk of long-term health outcomes associated with chemotherapy and radiation therapy. within contemporary treatment regimens, the comparison of toxicities experienced by patients receiving chemotherapy plus radiotherapy (crt) versus only chemotherapy (co) has not been studied extensively. objectives: this study examines select self-reported adverse health outcomes in survivors of contemporarily-treated pediatric hl to better understand the balance between efficacy and toxicity associated with chemotherapy and radiation therapy. (cog) ahod0031 that evaluated a response-based treatment paradigm in pediatric hl. patient who received initial chemotherapy were randomized based on early response to continued chemotherapy, chemotherapy plus radiotherapy or augmented chemotherapy plus radiotherapy. patients completed self-report questionnaires on health problems at 0, 1, 3, and 5 years following therapy. we examined selected patient-reported pulmonary, gastrointestinal (gi), cardiac and endocrine outcomes. kaplan-meier survival curves were used to determine probability of survival without the selected adverse health outcome. log-rank tests were used to compare the co versus the crt group. results: a total of 1,051 enrolled patients, 251 patients in the co group and 800 patients in the crt group, completed 2,134 questionnaires at a median of 1.3 years after s177 of s301 completion of therapy (q1, q3: 0.6, 3.3) which were analyzed. the cumulative 10-year incidence of endocrine dysfunction was significantly greater in the crt group versus those in the co group (17% versus 6%; p<0.001), driven by the incidence of hypothyroidism (11% versus 2%; p<0.001). there were no significant differences in cardiac (7% versus 9%; p = 0.226), pulmonary (11% versus 10% p = 0.068), and gastrointestinal dysfunction (20% versus 17%; p = 0.317) between the co and crt patients. conclusion: this study demonstrates low cumulative incidence overall of organ dysfunction early post completion of contemporary therapy for hl. the addition of radiation therapy significantly increased risk for hypothyroidism, but with no higher risk noted for cardiac, pulmonary or gi dysfunction. limitations include self-report status, potential selection bias, and relatively short latency period following end of therapy. longer follow-up is needed to determine more delayed risks for organ dysfunction in order to best define the balance between therapeutic efficacy and long-term adverse health outcomes related to chemotherapy and/or radiation therapy. background: identification of an organism via bronchoalveolar lavage (bal) or respiratory tract biopsy (rtb) has historically been considered the gold standard for diagnosis of invasive fungal infection (ifi); however, data previously published by our group showed that these procedures infrequently lead to a change in management in children with an oncological diagnosis or undergoing hematopoietic stem cell transplant (hsct). there is also a paucity of data on the cost of ifi in this population. to compare the costs of work-up and management of pulmonary ifi diagnosed based on ct scan alone versus ct scan or chest x-ray prompting a bal or rtb. design/method: we collected cost data on patients at ann & robert h. lurie children's hospital of chicago undergoing chemotherapy or within 6 months of hsct who were suspected of having an ifi between 2007 and 2012. in order to include sufficient time to account for post-procedure compli-cations but avoid including costs unrelated to ifi, data were included for 14 days from the day of their diagnostic scan or procedure. cost data was available for 76 of the 101 patients previously studied. thirty-six of these patients were diagnosed with suspected ifi based on ct only and 40 patients underwent bal or rtb. when evaluating specific costs, inpatient beds costs were higher in the bal and rtb group (median $1,555 versus $1,255, p = 0.01), yet there was only a trend towards higher costs for antifungal agents (median $1,635 versus $1,089, p = 0.26) and respiratory support (median $257 versus $0, p = 0.14). many of the initial ct scans were not captured in the 14-day evaluation period for the bal or rtb group based on the study design; however, even when accounting for ct scans up to a week prior these procedures, the total cost of ct scans was higher in the ct only group (median $963 versus $635, p = 0.0002), as they had more scans. despite this, total costs were significantly higher for patients who underwent bal or rtb versus ct scan only (median $14,087 versus $5,900, p <0.0001). combined with our previous data that bal and rtb infrequently leads to a change in management in children with an oncological diagnosis or undergoing hsct suspected to have an ifi, the significantly higher costs associated with these procedures makes these invasive diagnostic techniques even less desirable. batra, pediatr blood cancer, 2015. background: while infants >12 months of age with acute lymphoblastic leukemia (all) have a poor prognosis, infants with acute myeloid leukemia (aml) fare better despite more intensive therapy. there are limited data on this difference, particularly differences in supportive care requirements during induction therapy for infants. objectives: to compare induction mortality and resource utilization in infants relative to non-infants aged <10 years, separately for all and aml. design/method: we used previously established cohorts of children treated for new onset all or aml at children's hospitals in the us contributing to the pediatric health information system. patients with down syndrome were excluded. follow-up started on the first day of induction chemotherapy and continued until the earliest of: 35 days after commencement of chemotherapy, start of the subsequent course, or death. high acuity of presentation, defined as icu requirements involving 2 or more organ systems within the first 72 hours following initial admission were compared using log binomial regression. 35-day inpatient mortality was compared using cox regression. resource utilization rates (days of use per 100 inpatient days) were compared using poisson regression. results: a total of 10359 all (405 infants, 9954 non-infants) and 871 aml (189 infants, 682 non-infants) were included in the analyses. infants were more likely to present with high acuity compared to non-infants for both all (12% and 1%, rr = 12.2, 95% ci:8.6, 17.5; p<0.0001) and aml (6% vs 3%; rr = 2.0, 95% ci: 0.96, 4.3; p = 0.06). infants with all had higher inpatient mortality compared to non-infants even after accounting for differences in acuity of presentation (2.7% vs 0.5%, adjusted hr = 2.7 95% ci: 1.2, 6.1; p = 0.015). in contrast, inpatient mortality was more similar for infants and noninfants with aml (3.2% vs 2.1%, adjusted hr = 1.2 95% ci: 0.3, 3.9; p = 0.73) and comparable to rates among infants with all. infants with all and aml had higher rates of utilization of fresh frozen plasma, cryoprecipitate, diuretics, supplemental oxygen, and ventilation relative to non-infants. infants with all also had higher rates of total parenteral nutrition, ecmo, and patient controlled analgesics compared to noninfants. infants with all experienced significantly higher induction mortality compared to noninfants, a difference not entirely explained by acuity at presentation. differences in ru among infants may reflect higher presentation acuity and greater treatment related toxicity. further work is needed to elucidate the contribution of treatment related toxicity to early mortality in infants with all. background: fever in a child with cancer is a medical emergency due to the significant risk of a serious bacterial infection. many attempts have been made to risk stratify these patients. the respiratory pathogen panel (rpp) is a panel of polymerase chain reaction tests that identify seventeen common respiratory viruses and three bacterial infections. samples are taken via nasopharyngeal swab. rpps are frequently sent, but we do not have data to determine whether a positive result can lead to stratification to a lower risk of bacterial infection. (1) to determine the epidemiology of respiratory virus-associated fever in pediatric oncology patients (2) to determine whether a positive rpp is associated with reduced risk of bacteremia in this population. this was a single-center, retrospective cohort study. we identified and reviewed the medical records of all pediatric oncology patients seen in our emergency department (ed) with fever from the introduction of the rpp in april 2014 to september 30, 2017. we reviewed the results of blood cultures, rpp, chest radiographs, and discharge summaries to identify sources of infection. we also identified the patients' cancer diagnosis, age, absolute neutrophil count (anc), and absolute lymphocyte count (alc). results: 107 positive rpps were found among pediatric oncology patients who presented to the ed with fever. the most common positive rpp findings were rhinovirus/enterovirus (rev) (45%), parainfluenza (14%), influenza (11%), coronavirus (11%), and polyviral (10%). among patients with a positive rpp, 4% had bacteremia compared to 12% bacteremia among all pediatric oncology patients with fever (or 0.42 [0.18-0.99], p 0.048). all cases of bacteremia were associated with rev. there was no bacteremia identified in patients with rpps positive for other viruses (or 0.0596 [0.0037-0.9715], p 0.048). rev positivity did not confer a lower risk of bacteremia than rpp negative patients ], p 0.97). anc (p = 0.87) and alc (p = 0.89) less than 500, and number of patients with severe neutropenia (p = 0.27) were not statistically different between the rev and non-rev positive rpp groups. rpps positive for viruses other than rev reduced the likelihood of bacteremia in febrile pediatric oncology patients in the ed setting. patients with bacteremia may have concurrent infection with rev. a larger study is warranted to determine if positive rpp results can inform clinical management of a child with febrile neutropenia. emily mueller, anneli cochrane, seethal jacob, aaron carroll s179 of s301 background: the usage of mobile health (mhealth), which refers to the application of mobile or wireless communication technologies to health and healthcare, has grown exponentially in recent years. mhealth tools have been used by caregivers of other vulnerable populations, but little has been focused on caregivers of children with cancer. objectives: to conduct a survey to understand the mobile technology usage, barriers, and desired mhealth tools by caregivers of children with cancer. we conducted a mailed cross-sectional paper survey of caregivers of all children who were diagnosed with cancer at riley hospital for children between june, 2015 and june, 2017. the survey contained 13 questions, both fixed and open-ended, in both english and spanish. up to three rounds of surveys were sent to those who did not respond. of the 121 respondents, they were primarily parents (93.2%), median age was 40.7 years (range 23-63), and most were white (78.5%) and non-hispanic/latino (87.1%). the top three annual household income brackets included $50,000 to $74,999 (21.2%), $25,000 to $49,999 (20.3%) and under $25,000 (17.8%). the majority had an education: 35.6% college graduates, 22% graduate degree, and 18.6% high school education or ged. nearly all respondents owned a smart phone (99.2%) and 61.2% owned a tablet. the majority used an ios operating system (62.8%), while 49.6% reported use of a device with an android operating system. all caregivers reported use of at least one mobile website/app regularly for their personal use. while 35.5% of respondents reported no barriers to mobile technology use, the top barrier selected was "data limitations" (21.5%). overall, 84.5% wanted at least one medical managementrelated website/app: medical knowledge (58.7%), healthcare symptom tracking/management (47.1%), and medication reminders (43%). healthcare system-related desires were high, as 59.5% wanted access to their child's medical record and 56.2% wanted a website/app to facilitate better communication with medical providers. there were no significant associations between socioeconomic status (income or education) with barriers or types of websites/apps desired by caregivers. since the vast majority of caregivers use mobile technology with minimal barriers, future research should focus on designing an mhealth tool to address the medical management needs by caregivers of children with cancer. by supporting caregivers through this type of mhealth tool, it could positively impact patient clinical outcomes through greater adherence to medications and treatment protocols. background: in children with fever and neutropenia, early initiation of targeted antibiotic therapy improves outcomes, yet there are no standards for choice of empiric antibiotics. in 2013 our institution implemented an early empiric ceftriaxone (eec) protocol to reduce time to antibiotic administration in febrile hematology-oncology patients who are potentially neutropenic when the absolute neutrophil count is not yet know. ceftriaxone is given immediately after obtaining blood for culture and lab studies. in patients found to be neutropenic, ceftriaxone is discontinued and cefepime is initiated. the purpose of this retrospective study was to evaluate our eec protocol in neutropenic patients by assessing ceftriaxone sensitivity of positive blood cultures and comparing rates of adverse outcomes with a cohort of patients treated prior to implementation of the protocol. we are now conducting a prospective study to more thoroughly investigate antibiotic sensitivities of organisms isolated from blood cultures of neutropenic patients. design/method: hematology-oncology patients with at least one positive blood culture between january 2011 and december 2013 were identified. patient demographics, neutrophil count, antibiotic treatment, isolated organisms and sensitivities, and adverse outcomes (increased respiratory support, hypotension requiring intervention, and icu admission) were obtained by retrospective chart review. fisher exact test was used to compare dichotomous variables between patient groups. we are now prospectively identifying febrile neutropenic patients with positive blood cultures and performing antibiotic sensitivity testing to several antibiotics commonly used as empiric therapy for febrile neutropenia. results: retrospectively, we identified 58 neutropenic patients with a total of 127 bacterial isolates from blood cultures. of organisms isolated, 47 were tested for sensitivity to ceftriaxone and 23 (49%) were not sensitive, 6/18 (33%) of gram-positive cultures and 18/29 (62%) of gram-negative cultures. ten of 16 (63%) eec patients had an adverse outcome versus 13/26 (50 %) of non-eec patients (p = 0.277). notably, 31% of eec patients required icu admission versus 4% of non-eec patients (p = 0.049). thus far our data obtained prospectively is revealing similar rates of ceftriaxone resistance with 9/19 cultures not sensitive to ceftriaxone (47%, ci 24.9%-71.1%). in our retrospective study, no statistically significant difference was seen in overall adverse outcome rate between the two cohorts, though icu admission rates were significantly higher in eec patients. ceftriaxone resistance rates were high in tested isolates, which is further supported by preliminary data from our ongoing prospective study. given these data, eec may not be effective at improving outcomes in febrile neutropenic pediatric hematology-oncology patients. background: approximately 1 in 5 children diagnosed with cancer will die of their disease, despite advances in treatment. results: two focus groups of six parents each met in june 2017. the parents were predominantly female (11 female, 1 male) and had lost their children an average of 2.8 years prior (range 1-5.3 years). two parents were in the same family. nearly all patients were offered palliative care (10/11), all were offered hospice and most died at home (9 at home, 2 in the icu). parent discussion uncovered six broad themes: beneficial provider qualities, optimal communication, helpful systematic supports, struggles to feel like a good parent, struggles with a loss of control and unmet needs. parents appreciated providers who were consistent, reliable and honest. parents desired communication that was sensitive to the needs of the patient and family with a balance of hope and realism. parents appreciated the tangible supports pro-vided by social work and the emotional support of child life both for the patient and their siblings. some parents struggled to define and advocate for their child's quality of life, especially when it led to disagreeing with the medical team. several parents expressed frustration with unfamiliar caregivers in the hospital, especially trainees. they expressed a strong desire for more anticipatory guidance about the end of life including how to discuss it with their children. they also wished for a cancer-specific support group for bereaved parents. conclusion: bereaved parents of pediatric oncology patients in our focus groups appreciated consistent, reliable providers who communicated with a balance of realism and hope. they appreciated the tangible and emotional support they received and wanted more anticipatory guidance at the end of their child's life. these results can help guide clinical care, especially in communities without strong palliative care support. further research is needed to develop interventions to improve end of life care. background: clinical trials involving human subjects depend on informed consent (ic) to ensure ethical protections for participants. parents of children with cancer often lack full understanding of the basic elements of ic for clinical trials. additionally, the stress of their child's cancer diagnosis may affect their decision-making capabilities. this is especially problematic as these children rely on parents to fully comprehend clinical trials and weigh their benefits and risks. physician communication is critical for effective family-centered care. the acgme mandates that training programs teach and assess trainees' communication skills. however, there are currently no published curricula aimed at training pediatric hematology/oncology fellows to deliver ic effectively for cancer clinical trials. to develop and pilot-test a simulation-based curriculum to enhance communication skills of pediatric s181 of s301 hematology/oncology fellows in the delivery of ic for cancer clinical trials. we developed, tested, and implemented the curriculum from 2016 to 2017 in two phases. in phase-1, we reviewed literature on simulation-based curricula and completed a needs assessment to create a clinical scenario and full curriculum using standardized patients. using miller's pyramid model, fellows' assessments included: immediate de-brief, surveys to assess pre/post confidence and knowledge of the basic ic elements ("knows" and "knows how"), and 360-degree summative assessments compiled from fellow self-assessments, faculty, and standardized patients ("shows how"). after initial testing and refinements done with 1 fellow, in phase-2, we implemented the curriculum with our 8 fellows. likert scale (1 strongly disagree-5 strongly agree) and basic p values are reported. results: fellows gave high mean ratings for training relevance (4.7) and standardized patients' preparedness (5). almost all (4.9) reported they have used the knowledge gained in their clinical practice. increase in self-reported confidence (pre/post) was noted in all domains: general -describing possible benefits of the clinical trial 3.5/5 vs.4.1/5 (p = 0.025), risks and potential side effects 3.5/5 vs.4.3/5 (p = 0.004), and explaining alternatives 3.1/5 vs.3.6/5 (p = 0.016); research -discussing purpose of the clinical trial 3.1/5 vs.3.7/5 (p = 0.006), and randomization 3.3/5 vs.4.0/5 (p = 0.046); and family-centered -addressing emotions during ic 3.6/5 vs.4.5/5 (p = 0.004), and delivering bad news 3.1/5 vs.3.6/5 (p = 0.016). summative evaluation mean ratings for all fellows were 4.5 (range 4.1-4.9). our novel simulated-based ic curriculum, significantly increased fellows' self-reported confidence and skills during ic delivery. importantly, our ic curriculum addressed not just research-related content but also management of parental emotional needs during the ic discussion. next phase includes kirkpatrick model program evaluation and dissemination across other training programs in our institution. national kaohsiung normal university, kaohsiung, taiwan, province of china background: taiwan's childhood cancer foundation reported in 2016 that the 5-year survival rate of childhood cancer was 75%. as a result, many childhood cancer survivors were back in school after treatment. however, childhood cancer survivors' educational outcomes suffered because of their long-term absence from school and late effects of cancer and cancer treatment. a few school reentry protocols have been developed by the nursing professionals in taiwan to facilitate students' return to school but remained experimental in nature and hardly accessible. parents, students, and teachers were left to their own devices to make individual school reentry plans. objectives: this study aimed to examine and uncover the commonalities among three middle school students' successful school reentry experiences from their teachers' perspectives and to analyze the factors contributing to their success. design/method: this is a qualitative interview study. indepth semi-structured interviews were conducted with three middle school teachers in december 2017 about their perceptions, observations, and experiences working with adolescent childhood cancer survivors. the students were two boys with leukemia and one girl with bone cancer. they were diagnosed in the first year of middle school when they were 12-13 years old and returned to school for the third and the final year. these students met the following criteria for successful school reentry: regular school attendance, average/above average academic performance, friendship maintenance, and high school diploma. the theme -bring the class to the hospital was found to be the key to the adolescents' successful return to school. without a prescribed school reentry protocol and in the face of limited bedside education services, the homeroom teachers, as links between school, home, and hospital, brought the class to their hospitalized students. they doubled as bedside teachers conducting lessons at the hospital or students' homes, became friends with the parents, witnessed firsthand the students' pain and triumph during treatment, brought the students back to school for visits and celebrations, delivered the classmates' wishes and news to the students, encouraged and welcomed classmates' visits to the hospital, and, together with parents and other teachers, developed flexible school reentry schedules for the students. this on-going study demonstrated the critical roles and functions of homeroom teachers in successfully bringing the students back to school during and/or after cancer treatment. further analysis will be focused on how and why these three homeroom teachers were able to carry out this unexpected task on top of their already full workload. jennifer kesselheim, shicheng weng, victoria allen, collaborative group fellowship program directors dana-farber/boston children's cancer and blood disorders center, boston, massachusetts, united states background: a novel, 4-module, case-based curriculum entitled "humanism and professionalism for pediatric hematology-oncology" (hp-pho) aims to foster pho fellows' reflection on grief and loss, competing demands of fellowship, difficult relationships with patients and families, and physician well-being and burnout. in small group facilitated sessions, fellows work to identify coping strategies and explore how the challenges of fellowship influence both their own doctoring and the patient experience. objectives: to administer the hp-pho curriculum in a prospective, cluster-randomized trial, measuring whether exposure to this educational intervention, compared to standard conditions, fosters humanism and professionalism and improves satisfaction with training. design/method: pho fellowship programs (n = 20) were cluster-randomized to deliver usual training in humanism and professionalism (control) or the novel curriculum (intervention) during the 2016-2017 academic year. the primary outcome measure was the pediatric hematology-oncology self-assessment in humanism (phosah). secondary measures included a 5-point satisfaction scale, the maslach burnout inventory (mbi), the patient-provider orientation scale, and the empowerment at work scale. participating fellows were pre-tested in summer 2016 and post-tested in spring 2017. a change score was calculated for each study instrument. we compared each outcome between arms using mixed effect models adjusted for pre-test score as a fixed effect and site as a random effect. results: randomization yielded 59 intervention and 41 control fellows. the two arms did not significantly differ in distribution of fellow age, gender, or post-graduate year. the 9 intervention sites successfully administered 33 of 36 (92%) modules. change scores on the phosah were not significantly different between the control and intervention arms (adjusted mean difference = 0.5; 95% confidence interval [ci] -1.0, 2.0; p = 0.5). compared to the control arm, fellows' exposed to the curriculum gave significantly higher ratings on several items within the satisfaction scale including satisfaction with their training on "physician burnout" (adjusted mean difference = 0.8; 95% ci 0.4, 1.2; p<0.001), "physician depression" (adjusted mean difference = 0.9; 95% ci 0.4, 1.4; p<0.001), "balancing professional duties and personal life" (adjusted mean difference = 0.7; 95% ci 0.3, 1.1; p = 0.002), and "humanism overall" (adjusted mean difference = 0.4; 95% ci 0.03, 0.9; p = 0.03). change scores on other secondary measures were not significantly different between study arms. conclusion: exposure to the hp-pho curriculum did not alter fellows' self-assessed humanism and professionalism. however, the curriculum proved feasible to administer and intervention fellows expressed higher levels of satisfaction in their humanism training, indicating the curriculum's positive impact both for fellows and their learning environment. background: recent work has documented significant levels of unmet needs among adolescents and young adults with cancer, particularly psychosocial challenges during the transition to adulthood, (e.g., abrupt disruption to school and social life, and social isolation). given that adolescents and young adults drive mobile app use, a mobile-phone may be an ideal way to deliver a psychosocial intervention to adolescents and young adults with cancer. to use a patient-centered approach to inform a mobile-based mindfulness and social support intervention for adolescent and young adult patients with cancer. design/method: participants were ten aya with sarcoma (50% female; 50% adolescents); parents of the five adolescents, and six healthcare providers (n = 21). formative research involved three steps: (1) in-depth interviews were conducted with ten aya with sarcoma; parents of the five adolescents, and six healthcare providers (n = 21). (2) adaptations were made to an existing mindfulness app which offers a program for youth. modifications included creating a 4-week "mindfulness for resilience in illness" program, with 28 relaxation exercises, and the addition of videos featuring two sarcoma survivors as program hosts. content was informed by the mindfulness curriculum for adolescents, learning to breathe. (3) a private facebook usability group was organized to (i) elicit beliefs about the mindfulness app and potential future enhancements, and (ii) promote social support. results of the in-depth interviews revealed themes around adolescents' functioning and coping, including body image concerns; recurrence-related anxiety; anger over loss; and being overwhelmed by medical information. themes from the interviews were incorporated into a demonstration version of the mobile app. a patient-centered approach is widely recommended in the development of mobile-based health behavior change interventions and may be a useful way to inform development of a mobile-based mindfulness and social support intervention for adolescents and young adults with cancer. background: medical trainees consistently report suboptimal instruction and poor self-confidence in communication skills. despite these deficits, few training programs provide comprehensive pediatric-specific communication education, particularly in the provision of "bad news." an in-depth survey to examine the historical experience and communication needs of pediatric fellows was conducted at a large academic pediatric center as the first step towards the development of a comprehensive communication curriculum. to determine the previous educational and clinical experiences of pediatric subspecialty fellows, assess their levels of comfort in the context of various communication topics, and query potential modalities and topics for future communication training. design/method: the needs assessment survey was developed using previously developed and validated questions and review of the literature. the survey was reviewed by internal and external pediatric oncology and palliative experts and pre-tested with a subset of trainees to enhance content validity. results: thirty-two out of a total of 38 fellows completed the survey (84% completion rate), of which 81% were pediatric hematology-oncology or subspecialty fellows. most fellows had participated in previous teaching sessions (97%), including those involving role play or simulation (75%). however, few fellows had received feedback from senior clinicians on their communication skills (31% of fellows had received feedback ≤ 3times). on a scale of 1-x, with 1 indicating "not well prepared," the mean score for 12 of 23 communication items was <3. fellows felt least prepared to lead discussions around informed consent for experimental therapies, end of life care, and autopsy. fellows indicated that didactic educational sessions and additional coursework were less useful strategies for improving their communication skills, whereas small group role play sessions with faculty and/or bereaved parent educators were most useful. fellows' overall communication preparedness score was not correlated with post-graduate year but was positively associated with the number of times they previously had delivered bad news to patients and families. fellows requested additional training on many topics, with greatest interest in learning skills to optimize communication with an angry patient or family. additional topic requests included placing limitations on resuscitation, withdrawing/withholding further therapy, and ageappropriate inclusion of patients in difficult discussions. despite self-report of prior communication skills training, pediatric subspecialty fellows felt underprepared to participate in difficult discussions with patients and families. learners identified role-playing and coaching with real-time feedback from other physicians and bereaved parents as more useful training strategies as compared to didactic sessions. background: when children die of cancer, parents must adjust to their child's absence amidst the lingering turmoil of what preceded their death: witnessing their child undergo painful treatments, making difficult decisions, and anticipating a devastating loss, all the while hoping for a recovery. adjustment to a child's death, as depicted by current bereavement literature, necessitates making meaning of one's loss. professional care staff can help parents make sense of their child's illness, and in turn, of their own parental experience during treatment. however, the extent to which relationships with professional care team members influence parents' ability to make sense of, and successfully cope with, their loss has not been examined. objectives: to examine how bereaved parents' interactions with their deceased child's pediatric oncology professional care team have impacted their grief symptoms design/method: to better understand how interactions with professional care staff relate to parents' grief outcomes, we conducted a mixed-methods study examining staff impact on parental grief. thirty participants whose children died of cancer one to three years ago completed an in-depth interview and psychometrically validated surveys measuring meaningmaking, depression, and grief symptoms. results: correlational analyses of the measures found that an increase in meaning making was associated with lower depressive and grief symptoms. a content analysis of the interviews found that many participants regarded staff "like family," had on-going relationships with staff after their child died, and described various ways staff interactions during treatment and after the child's death helped them make sense of their loss. in particular, participants described how interactions with staff have helped them find benefits in their loss and learn to create a new relationship with their child despite their physical absence. quantifying the interview data and statistically analyzing it along with the measures found that participants' increased frequency of describing staff's positive impact on their grief correlated with higher meaning-making scores and lower grief symptom scores. our study found that bereaved parents who lost their children to cancer were articulate in sharing their experiences of staff engagement and communication during treatment, offering numerous examples of how staff aided them in making meaning of their loss that were reliably associated with their subsequent grief. we hope the results of this mixed methods research encourage further study of the importance of staff interaction with families during the critical period of their children's care, and the lasting impact this can have regardless of the treatment outcome. memorial sloan kettering cancer center, new york, new york, united states background: although resiliency has been recognized as necessary for healthcare professionals, trainees feel unprepared for the emotional challenges inherent in caring for sick and dying patients. compounded by long hours, challenging work environments, and lack of formal training on handling emotionally difficult situations, many institutions are recognizing the need for interventions to reduce trainee distress. the goals of this fellow-led quality improvement initiative were: 1) to determine whether there is a need for emotional support amongst pediatric hematology and oncology fellows, 2) to provide formal resiliency and debriefing sessions, and 3) to measure feasibility, acceptability and effectiveness of implemented curriculum. design/method: an anonymous survey to determine need for resiliency and debriefing sessions following a traumatic event was distributed to 24 active pediatric hematology & oncology fellows at memorial sloan kettering cancer center in january 2017. once need was established, an intervention consisting of a formal curriculum was developed and initiated in june 2017, involving: 1) scheduled and ad hoc debriefing sessions in response to traumatic events (including patient death, codes, interpersonal conflicts, end-of-life care); led by a psychiatrist and social worker with fellows and a pediatric oncologist mentor in attendance, and 2) a resiliency didactic curriculum, led by a palliative medicine specialist, focused on skills such as contesting cognitive distortions and mindfulness. the effectiveness of these sessions will be measured using follow-up anonymous surveys at 6 months (currently underway) and 12 months post-initiation of intervention. the initial survey demonstrated most trainees (19/24) were present at 3 or more deaths during their training, while less than half of respondents had attended a post-event debriefing session. 85% of respondents felt there was not sufficient emotional support from the institution for physicians caring for dying patients. a separate pre-intervention survey found all respondents (14/14) expressed a need for regular debriefings, and nearly all anticipated that they would benefit from such debriefings. concerns identified by trainees that would preclude participation in the curriculum included preference to deal with emotional situations privately and time constraints. trainees identified a need for formal debriefings and resiliency skill development. the program was easily implemented, and is both feasible and acceptable with good attendance. feedback received at the 6-month mark will determine deficits and possible improvements to the curriculum. the 12-month survey will measure effectiveness of the program and whether it should be continued. background: acute kidney injury (aki) is a common but under-recognized complication among patients with leukemia. it is associated with prolonged hospital stays, increased mortality, progression to chronic kidney disease, and delays or changes in cancer therapy which may affect a patient's prognosis. however, data on aki in pediatric patients with cancer is still lacking overall. we investigated the incidence of aki in patients who were newly diagnosed with all at our center from january 2009 to september 2017. we performed a retrospective chart review of all patients who were newly diagnosed with all from neonate to 18 years in our facility. we determined the incidence of aki in our population using the kidney disease: improving global outcomes (kdigo) diagnostic criteria. we also assessed for nephrotoxic exposures, nci all risk stratification and risk of aki, and tumor lysis syndrome (tls). we identified 62 patients diagnosed during the study period who met inclusion criteria. median follow-up time was 29.5 months (range 3.6-60.3). the cohort was predominantly male (54.8%) and hispanic (93.5%). our analysis showed 51.6% had aki by kdigo criteria (29% grade 1, 14.5% grade 2, and 8% grade 3), 62.5% had aki on presentation, and 75% had multiple aki episodes during the study period. older age and longer length of hospitalization were associated with aki (p = 0.019 and p = 0.009, respectively). there was no association between aki and nci all risk classification, contrast exposure, hyponatremia, elevated white blood cell count, uric acid levels, antimicrobial therapy, or diuretic use in this study. conclusion: aki was a common finding in our study population. the majority had grade 1 aki by kdigo criteria. however, aki was associated with older age and a longer length of stay. further study is needed to determine the short-and long-term impact of aki on pediatric patients with all. st. jude children's research hospital, memphis, tennessee, united states background: in some regions, the availability of trained pediatric oncologists is a limiting barrier for the care of children with cancer. in 2003, the unidad nacional de oncología pediátrica (unop) and the universidad francisco marroquín school of medicine in guatemala established a pediatric hematology/oncology fellowship program sponsored by st jude children's research hospital to provide central america and the caribbean with well-trained specialists. a systematic analysis of the impact of fellowship programs in pediatric oncology has never been done, especially in the context of a regional education program. objectives: this study sought to analyze the impact of the unop fellowship program based on the regional number of providers, pediatric cancer centers and patient volume. in addition, it sought to characterize the jobs and scientific output of the graduates. the impact will be evaluated in the context of a cost analysis. to define the volume of providers, pediatric cancer centers and patients, the directors of pediatric cancer centers in central america were sent an online survey to obtain these data. all the centers contacted maintain an updated hospital-based patient registry. in addition, the 22 graduates of the fellowship program were also sent an online survey, asking about their job at graduation, current role and scientific productivity. the cost analysis will include assessment of direct costs including salaries and stipends for away rotations, as well as the indirect costs of faculty time spent teaching. since the establishment of the unop fellowship program, the region has more providers for pediatric cancer (p<0.05) and centers treat a larger volume of patients (p<0.05). two new centers have opened with graduates of the program. all but one graduate practice pediatric oncology (21/22) and the majority do it in their country of origin (19/21). no graduate practices outside of this region. almost half of the graduates (44%) hold a leadership role at their institution. the majority of their time is spent in the public sector (>95%). the majority of graduates participate in clinical research (61%) and have participated in the creation or implementation of therapeutic protocols (67%). on average, the graduates have published 2 peer-reviewed articles since completion of training. the unop fellowship program has had a favorable impact on pediatric cancer care in the region, contributing to the capacity to treat a larger volume of patients. graduates practice pediatric oncology in the region in the public sector, frequently hold leadership roles and are scientifically productive. background: abandonment of treatment is a major cause of treatment failure and poor survival in children with cancer in low-and middle-income countries. the incidence of abandonment in peru has not been reported. objectives: the aim of this study was to examine the prevalence and associated factors of treatment abandonment in pediatric patients with cancer of peru. we retrospectively reviewed the sociodemographic and clinical data of children referred between january 2012 and december 2014 to the two main tertiary centers for childhood cancer, located in lima, peru. definition of treatment abandonment was used from the siop (international society of paediatric oncology) podc (paediatric oncology in developing countries) abandonment of treatment working group recommendation. results: data of 1135 children diagnosed with malignant solid tumors and lymphomas were analyzed, of which 209 (18.4%) abandoned treatment. univariate logistic regression analysis showed significant higher abandonment rates in children living outside the capital city, lima (p<0.001); prolonged travel time to a tertiary center (> 5 hours; or 2.75, p = 0.002); living in a rural setting (or 3.44; p<0.001) and lack of parental formal job (or 4.39; p = 0.001). according to cancer diagnosis, children with retinoblastoma were more likely to abandon compared with other solid tumors. in multivariate regression analyses, rural origin and lack of formal parental employment were independently predictive of abandonment. conclusion: treatment abandonment prevalence in our country is high and closely related to socio-demographical factors. treatment outcomes could be substantially improved by strategies that help prevent abandonment of therapy based on these results. st. jude children's research hospital, memphis, tennessee, united states background: to improve the quality of a pediatric hematology/oncology fellowship program, a systematic assessment must be performed that can evaluate its current state and identify areas of opportunity, as well as modifications over time. unfortunately, widely agreed-upon metrics of quality for pediatric hematology/oncology fellowship programs currently do not exist. this is particularly important in this field due to the global shortage of specialists. for this reason, an assessment instrument that is applicable throughout the world must be created. objectives: the st. jude global education program assessment tool (epat) is a novel instrument that seeks to evaluate pediatric hematology/oncology fellowship programs around the world in systematic and objective way. epat will help determine key performance indexes that are relevant for quality education in pediatric hematology/oncology fellowship programs and establish the framework for improvement. design/method: firstly, key domains to be evaluated for program assessment were identified a priori based on the continuum of pediatric hematology/oncology fellowship programs in the context of geography and educational structure. subsequently, questions were formulated to evaluate these key domains, seeking to assess elements involved in ensuring competence in clinical practice, academic productivity and regional impact. due to the novelty of this tool and the lack of defined metrics of quality, epat relies on expert opinion in a two-step process: internally in the department of global pediatric medicine at st. jude children's research hospital and, subsequently, from a panel of experts in global pediatric oncology and medical education from around the world. ten key domains were identified to evaluate all aspects relevant to training programs around the world, regardless of educational and geographic context. questions have been created to assess these domains and, to make epat quantitative, these have assigned weights with a value reflective of their relative importance. this grading system allows for a score in each key domain, permitting monitoring of changes over time. epat is currently at the stage of external expert review, and subsequently will be piloted in five fellowship programs around the world to provide different geographical and patient care contexts for its validation. once epat is finalized, it will be distributed to pediatric hematology/oncology fellowship programs around the world to be applied. epat proposes a novel strategy to assess training programs in a systematic way that includes all aspects relevant for a training program in a global context. this tool will help guide improvements in pediatric hematology/oncology fellowship programs and assure a well-trained workforce. background: with the improvement in pediatric oncology patient survival and outcomes in the past several decades, monitoring for recurrence and long-term effects of therapy has become even more important. the utilization of personalized treatment summaries and survivorship care plans (scps) is one way to communicate this information with patients and families. the american college of surgeons commission on cancer (coc) created a standard regarding provision of scps to 50% of eligible patients by december 31, 2017 as a metric for accreditation of all cancer centers. the standard applies to all patients with stage i, ii, and iii cancer diagnoses and requires creation of the scp within one year of diagnosis or six months of completing treatment. during implementation at our pediatric cancer center, we identified barriers to use of the guidelines in the childhood cancer setting. objectives: define eligibility for an scp for pediatric oncology patients to include all patients with curative intent and to deliver scps within six months of finishing therapy. design/method: using chart review and a cancer center registry query, we identified childhood cancer patients potentially eligible for an scp by collecting stage, goal of therapy, and dates of treatment. all patients with curative intent were deemed eligible for an scp regardless of stage i-iv. patients being followed in the oncology clinic for posttreatment surveillance and care were included even if they had received an scp in the survivorship program or were greater than six months off therapy at time of implementation. as expected in the pediatric oncology population, acute lymphoblastic leukemia (all) was the most common diagnosis comprising 31.5% of patients. all is stratified into risk groups instead of surgical staging categories, and treatment duration is greater than one year, unlike many adult-onset malignancies. these differences required interpretation of the guidelines to apply to our pediatric population for all and other pediatric diagnoses with non-surgically based staging. our pediatric oncology clinic has to date provided scps to 141 of 277 eligible patients by adapting the guidelines to focus on patients with curative intent to receive an scp by six months off therapy. cancer staging guidelines and goals for curative intent as well as lengths of treatment vary between the pediatric and adult populations. the coc guidelines require adaptation for optimal applicability to the pediatric oncology population. background: education in communication for fellows in fields that require difficult discussions with families are few in nature. adult learning pedagogies such as role play are under-utilized in medical education, and have been shown to be as effective as traditional teaching methods such as lecture. an 8-module course for fellows in hematology/oncology, hospice and palliative medicine, radiation oncology, and pediatric hematology/oncology was implemented in january/february 2017. 12 fellows participated in the program. topics covered including fundamentals of communication, coping and spirituality, delivery of bad news, communicating with families, sexual dysfunction during treatment, palliative care/death and dying, and burnout. objectives: overall goal of this course is to foster holistic physicians who views their patients as people with cancer, not cancer patients, and physicians that can communicate effectively with their patients throughout the disease continuum. by the end of the course, learners should be able to practice the fundamental principles of good communication. design/method: fellows initially participated in a pre-course osce to establish baseline skills. osce was facilitated by the center for learning and innovation at northwell, and included actors portraying a pediatric patient and family member to whom the fellow had to break bad news. two months later, the course was carried out over the span of eight weeks and included didactic sessions followed by 45 minutes of role play scenarios. five of the eight modules included role play, with faculty members serving as simulated patients. after the course, a second breaking bad news osce was held. both osces were filmed, and feedback was given by the on-site actors. additionally, faculty members were given access to the videos in an on-line format and were given an evaluation tool to assess the fellows' performance pre-and post-intervention. fellows were given subjective surveys pre-and post-course as well. results: subjective data from participants showed a noticeable increase in comfort level in all areas on the pre-and post-course survey. data obtained from osce videos showed improvement in communication skills as assessed by sps and faculty members using a new evaluation tool developed by faculty. initial first-run data shows that this course is successful in improving communication skills as well as increasing fellows' comfort level across several domains of communication. future directions for our course include improving and validating our assessment tool, expanding our topic base to include more aya and pediatric scenarios, faculty development for improved role play, and investigating impact on practice after course completion. background: acute lymphoblastic leukemia (all) is the most common form of childhood cancer with approximately 2900 children diagnosed each year. survival rates have improved significantly over the past several years. children with all are at risk for developing musculoskeletal complications during and after completion of treatment, which can contribute to impaired activity, elevated body mass index (bmi), and risk for complications. interventions involving physical activity could improve musculoskeletal strength as well as overall health in these children. the aims of this study are to examine the feasibility of a directed physical activity program for children with newly diagnosed all during the initial intensive phase of therapy and to evaluate the overall health and quality of life of children participating in the directed physical activity program. design/method: all subjects will receive education materials about the importance and safety of physical activity and a nutrition handout. all subjects will also participate in the directed physical activity program under the supervision of a trained physical therapist for at least 40 minutes every week for 12 weeks. the program will entail four stations including a cardiovascular, balance/proprioception, strength and flexibility, and coordination and cardio. feasibility will be assessed by tracking the participation rate throughout the study period. other assessments will be made at study entry, at the end of 12 weeks of physical activity initiative and 3 months after completion of the intervention. assessments include overall strength and flexibility, weight, height, bmi, blood pressure and performance scores. descriptive statistics will be used for this study. results: a total of 10 patients, 3 male and 7 female, enrolled in the study over a 9.5 month period. patient ages ranged from 5-16 years. half of the patients enrolled have completed the 12 week program and all 5 patients had stability or improvement of their physical functioning scores. further data collection and analysis is ongoing. patients in the early intensive phase of all therapy are at risk for complications that can affect their physical functioning. a directed physical activity protocol may improve their overall physical functioning. patients may not need specific physical therapy; however a directed physical activity program appears to be beneficial for these patients. the main roadblocks to successful completion of the program were difficulty with scheduling, strain on the parents and patient from treatment, unplanned admissions for fever, as well as nausea and fatigue at time of visit. albany medical center, albany, new york, united states background: communication skills are a core competency highlighted by the acgme. increasing resident confidence in delivering difficult news has been shown to lead to more s189 of s301 effective communication. currently, the majority of residency programs lack formal training in communication skills. our objective was to demonstrate feasibility and efficacy of integrating a standardized-patient based training program for communication skills into the curriculum of pediatric residents design/method: to date, 10 pediatric and 4 medicine/pediatric residents have participated in the program during the intern year. the program consists of three, two-hour long sessions, in which each resident is given several opportunities to act out case scenarios with a standardized patient. scenarios included informing a parent of their child's new cancer diagnosis and disclosure of a positive hiv test to a teenager. residents received post hoc peer to peer, and preceptor to learner feedback. pre and post-program surveys were completed by residents. results: following course completion residents reported an increase in confidence in multiple areas of communication including giving a difficult diagnosis (p<0.05), discussing a poor prognosis (p<0.02), responding to different patient/family member emotional responses i.e. crying or anger (p<0.01), and organizing vital information to be relayed (p<0.01). in conclusion, communication skills training of pediatric residents is feasible and provides a platform for developing valuable skills not taught elsewhere within the curriculum. background: for children with cancer, transitioning back to school during or after treatment can be challenging. literature supports the need for school re-entry programs to ease this transition. however, these programs vary widely among pediatric cancer institutions with little data addressing their program components. data from this study provides information on current school re-entry programs across these institutions. objectives: one objective of this study was to assess for correlation between the presence of a school re-entry program and other factors, such as geographic location and institution size. a second objective was to establish a list of differences between institutions' school re-entry program components. finally, we aimed to describe current school reentry practices, as well as program benefits and perceived areas for improvement. states with membership in the children's oncology group were offered enrollment in this study. a member of each institution was invited to participate in a survey established by the research team. this person was closely associated with the institution's school re-entry practices. each interview queried institution demographics, as well as program components (e.g., participants, target audience, resources). comment was also collected on program benefits and potential for improvements. analysis of transcripts was performed using pearson's correlation to assess for relationships between institution size, geographic location, and program presence. grounded theory was used for analysis of benefits and improvements. results: thirty-nine of forty-one pediatric institutions who were offered enrollment participated in this study. twentynine institutions (76%) indicated the presence of a school reentry program, and ten (24%) stated they had none. no correlation was found between institution size and the presence of a school re-entry program (p = 0.627, ns). there was also no correlation found between institution location and the presence of a school re-entry program (p = 0.921, ns). a major theme surrounding the benefits of having a program included education for the returning student's peers. for those with programs, perceived improvements included increasing staffing and the ability to offer more services. the results do not support the hypothesis that the presence of a school re-entry program is influenced by the size and geographic location of the treating institution. however, data seem to suggest that available staffing may influence the presence of a program. future studies are needed to address other potential influences, as well as to take an evidence-based approach to determine the effectiveness of the interventions present in these programs. cohen children's medical center/ zucker school of medicine at hofstra-northwell, new hyde park, new york, united states background: genetics/genomics is evolving at an extremely rapid pace. current advances lead to individual algorithms toward disease treatment for each disease with multiple branch points. fellows learn only a fraction of the knowledge and there is no formal approach to teaching critical analysis of information and application algorithms toward disease. additionally, as knowledge evolves extremely rapidly, any approach must teach self-acquisition and application of evolving discoveries. objectives: to create, implement and evaluate a novel curriculum for genetics/genomics targeted toward pediatric hematology/oncology fellows design/method: the curriculum includes four components: 1) genetic and genomic medical knowledge, with one initial team-based learning session and weekly online multiple choice questions; 2) essential pathways, which will teach molecular pathways common in oncogenesis and relevant to targeted therapy in microteaching sessions with using auditory, visual and tactile learning; 3) knowledge acquisition and clinical judgment, to allow learners to gain experience into researching data available, then developing and prioritizing potential treatment plans using problem-based learning sessions in which they will stage a patient, research treatment options, prioritize and present findings; and 4) synthesis to demonstrate independent ability to research and recommend therapy through an independent project in which the learner, given a case, will present the case and research findings, genetics/genomics, molecular pathways and make recommendations for therapy in molecular tumor board for faculty and fellows. to evaluate, we plan to recruit 12 to 16 institutions, match for size of programs and implement in half and evaluate 2nd and 3rd year fellows in both groups by mcq exam and satisfaction surveys. the creation of a multi-module, adult-learning based curriculum for genetics and genomics in pediatric oncology is feasible. implementation and evaluation are necessary to demonstrate efficacy. background: neuroblastoma is the most common extracranial solid tumor in children. chimeric anti-gd2 antibody ch14.18 (dinutuximab) therapy has improved the survival of children with newly diagnosed high-risk, neuroblastoma patients as well at the time of first relapse/progression. acute neuropathic pain is a well-documented side effect of dinutuximab administration. however, additional adverse effects including sensorimotor neuropathy, ocular symptoms, and behavioral changes have been described. the incidence and severity of these effects are currently not well-documented in pediatric patients. with improved long term survival of patients receiving this modality, it is important to look for the potential late effects of dinutuximab. objectives: to determine the incidence and severity of neurologic, ophthalmologic, or behavioral changes after dinutuximab administration at our institution. we performed a retrospective chart review using our electronic medical record. we included all patients with high-risk neuroblastoma between the ages of 1 and 21 years at our institution diagnosed between 1997 and 2017 who received dinutuximab. patients with history of opsoclonus-myoclonus syndrome or gross sensorimotor neuropathy prior to receiving dinutuximab were excluded. we examined clinical documentation for subjective reports and objective exam findings of neurologic, ophthalmologic, or behavioral changes. we also looked for referrals made to neurology, ophthalmology, physical medicine & rehabilitation (pm&r), and psychology. : twenty-two patients met inclusion criteria. at the time of chart review, 15 patients were alive and 7 were deceased. eighteen patients received dinutuximab per anbl0032; 5 patients received dinutuximab per anbl1221. of these 22 patients, 11 patients reported symptoms of interest and 5 reported multiple symptoms. six patients reported symptoms that began at least 12 months after completing dinutuximab. nine patients had objective findings on exam, including decreased deep tendon reflexes, abnormal pupils, and nearsightedness. for 10 patients, 15 referrals were made to ophthalmology, pm&r for neuropsychologic testing, or neurology. two patients who reported symptoms of interest were not referred to a specialist. conclusion: neurologic, ophthalmologic, and behavioral symptoms were commonly reported and demonstrated on exam among pediatric patients with high-risk neuroblastoma who received dinutuximab. it is important to identify these effects so that appropriate specialist referrals can be placed for adequate management of these changes. we recognize that these symptoms may not be solely due to dinutuximab as these patients receive other agents including opioids, so a prospective trial is needed to further evaluate the long-term effects of dinutuximab and to determine how best to screen for these effects. akron children's hospital, akron, ohio, united states background: pediatric cancer is the leading cause of diseaserelated death in children in the united states (u.s.). in 2014, over fifteen thousand children were diagnosed with cancer in the u.s. this population is at high risk for malnutrition due to the multimodal therapies they receive: surgery, chemotherapy, radiation therapy, antibody therapy, and/or bone marrow transplant. adverse effects of these therapies include taste changes, loss of appetite, diarrhea, vomiting, and/or mucositis, making it difficult for the children to be able to consume adequate amounts of nutrition during therapy. there is no "gold standard" measurement tool for identifying patients at risk for malnutrition. nutritional status is not frequently evaluated as a component of clinical trials. assessment of anthropometric measurements (weight, height, z-scores) at diagnosis, as well as over the duration of treatment, can assist in the early identification of malnutrition. the incidence and prevalence of malnutrition in this population is unknown at akron children's hospital. the purpose of this study is to describe the nutritional status and provision of nutritional support therapies in pediatric patients during their first year post new oncologic diagnosis. objectives: identify the incidence and prevalence of malnutrition across oncologic diagnostic categories over the first twelve months post diagnosis. we performed a retrospective records review of all patients newly diagnosed with cancer in 2015 at akron children's hospital. demographic and anthropometric data was collected at time of diagnosis and nutritional status categorized by z score. anthropometric and nutrition support data was then collected every two months for the first year after diagnosis along with incidence of unplanned inpatient admissions. results: a total of 65 patients were included in the analysis, with 6.2% malnourished at time of diagnosis; 12.3% developed malnutrition the first year. patients with solid tumors represented 50% of patients with pre-existing or acquired malnutrition. overall, 47% of patients received at least one nutritional support modality. patients with pre-existing or acquired malnutrition had a non-significant increase in unplanned admissions (p = 0.1196). our study demonstrated that patients with solid tumors were found to be at increased risk of pre-existing and acquired malnutrition, followed by leukemias, and experienced higher incidence of unplanned admissions in the time period observed. prospective, multi-center replication of this study, including detailed collection of nutrition therapies is recommended to guide development of diagnosis specific nutrition support guidelines. background: pediatric and young adult oncology patients treated with intense chemotherapy have a high incidence of transfusional iron overload. iron deposition can lead to heart failure/arrhythmias, liver abnormalities, endocrine dysfunction, ineffective erythropoiesis, and increased cancer and mortality risk. however, there is a paucity of data regarding recommendations for management of transfusional iron overload in these cancer survivors. consequently, long-term complications of transfusional iron overload specific to these patients have not been assessed. objectives: to assess screening and phlebotomy-based treatment algorithms for this population. design/method: a retrospective chart review of pediatric and young adults who completed oncology management, had iron overload, and initiated phlebotomy treatment was conducted. tiered screening occurred in patients that received at least 5 packed red blood cell (prbc) transfusions. patients were recommended for evaluation and possible phlebotomy if: (1) liver iron concentration (lic) >5 mg of iron/gram dry weight liver tissue by ferriscan and/or (2) cardiac mri t2* < 20 ms. during phlebotomy, iron status was assessed quarterly and phlebotomy discontinued with lic <5 or normalization of ferritin/imaging lic verification. descriptive statistics were employed to report the characteristics of the study population. spearman correlations were utilized to describe associations between transfusions, lic, ferritin, iron saturation and number of phlebotomy sessions. results: twenty five survivors underwent phlebotomy. the mean age was 11.6 years (sd 6.1) and 10 (40%) were female. oncologic diagnoses: all (36%), aml (8%), nhl (12%), ewing sarcoma (16%), osteosarcoma (4%), neuroblastoma (12%) and cns (12%). patients received a median of 25.0 (iqr 17 -34) transfusions. median number of phlebotomy sessions was 6 (iqr 4-8) over 0.36 years (iqr 0.28 -0.59). prior to phlebotomy, median lic was 7.5 mg/g (iqr 5.6-9.0) and ferritin was 1110.0 ng/ml (iqr 700 -2030) . no patients demonstrated abnormal cardiac t2* mri (n = 18). 23 (92%) patients completed phlebotomy. one discontinued due to poor vascular access. no patients developed iron deficiency. lic was reduced by a median of 2.4 mg/g (iqr 1.1 -3.6) and ferritin by 586 ng/ml . correlation between number of transfusions and phlebotomy sessions was poor (r2 = 0.017). conclusion: management guidelines are lacking for transfusional iron overload in pediatric and young adult survivors of cancer. we demonstrate a phlebotomy algorithm that is effective and tolerated. correlation between number of transfusions received and phlebotomy treatments was poor, necessitating serial assessments. using this management algorithm, prospective studies can evaluate the effect of iron removal on iron overload complications in this patient population. penn state children's hospital, hershey, pennsylvania, united states background: cancer therapy leads to an impaired immune system that takes time to recover. it is important to ensure that these survivors have adequate immunity to prevent common yet potentially severe childhood illnesses. no validated guidelines currently exist for surveillance testing or re-immunization in this population. retrospective analysis involving a small cohort of pediatric cancer patients treated at penn state children's hospital showed 46% of patients screened for varicella immunity after therapy completion did not have adequate disease titers. to determine the proportion of pediatric cancer survivors who have lost humoral immunity to previously received vaccines; to determine the rate of response to single dose boosters or full vaccine series in seronegative subjects after one booster. design/method: pediatric cancer survivors treated at the children's hospital who are at least 12 months from completion of cancer therapy are prospectively tested for antibody levels to hepatitis b, tetanus, varicella, measles, and 6 strains of pneumococcus (4, 6b, 9v, 18c, 19f, and 23f). samples are analyzed by the cdc for measles and varicella avidity. seronegative subjects by commercial studies, are eligible to receive booster vaccines. titers are rechecked at least 6 weeks after boosters to re-evaluate immunity; if still seronegative, subjects will receive the entire vaccine series. titers are finally tested at least 6 weeks after the final dose of the vaccine series. immunity analyzed after therapy, after boosters, and after vaccine series. results: of 37 pediatric cancers survivors who completed therapy, 78% were non-immune to hepatitis b, 92% nonimmune to >50% of pneumococcal strains tested, 24% nonimmune to measles, 54% non-immune to varicella, and 2% non-immune to tetanus. 1 of 13 subjects who received mmr vaccine after therapy and prior to study enrollment did not have protective antibodies to measles. of the 15 subjects who received varicella vaccine after end of therapy and prior to study enrollment, 6 did not maintain protective antibody levels. cdc results for measles and varicella are pending, as well as repeat studies after vaccine boosters and series. conclusion: a significant percentage of pediatric cancer survivors do not retain immunity to hepatitis b, pneumococcus, measles, and varicella. after one booster, a high percentage of subjects did not develop protective immunity to varicella. only 1 subject did not have immunity to tetanus, which is consistent with the high immunogenicity of tetanus toxoid. formal guidelines are needed to protect this population from vaccine-preventable illness post-therapy. children's hospital of richmond at virginia commonwealth university health system, richmond, virginia, united states background: childhood cancer survivors are at risk for being overweight. diet and physical exercise are important in maintaining a healthy lifestyle and weight; however, it has been reported that cancer survivors are less active than their peers. one reason for this may be that there are no clearly established risk-based exercise recommendations for cancer survivors. another reason may be that providers tend to focus s193 of s301 recommendations for exercise more towards patients who are overweight. objectives: to describe changes in physical fitness of childhood cancer survivors who exercise. design/method: 'moving forward' is a wellness and physical fitness program that the center for care beyond the cure at chor offers in partnership with the ask childhood cancer foundation and the ymca. the program is available for any childhood cancer survivor between 8y and 18y age, being seen at our center. survivors define their fitness or wellness goals and then work with a trainer once a week (at least) for 30 min sessions throughout the year to achieve these goals. baseline and ongoing measurements for core strength, endurance, overall strength and balance were collected. the average of each of the parameters of all participants were compared from the beginning to the end of the program. over the year, there was a 30% increase in endurance as measured by the average of the miles walked in 6 minutes, 40% increase in core strength as measured by the average number of sit-ups in 30 secs, an 80% and 44% increase in overall strength as measured by the average weight lifted by leg press and the average weight lifted by chest press, and a 10% increase in balance as measured by the average number of seconds balancing on a single leg. in addition, each child had actually gained weight in the process with an approximately 10% increase in the average of the weights of all children. there are benefits to regular exercise beyond weight control, and improvements in physical fitness can be seen even without weight loss. regular physical exercise results in improved physical fitness and should be universally advocated to all patients. determining insulin resistance, measuring changes in fatigue and wellness perception following exercise are future directions that we intend to explore. dana-farber cancer institute, boston, massachusetts, united states background: improvements in adolescent and young adult cancer patient (aya) survival rates and quality of life outcomes have lagged behind those of children and older adults, highlighting a need for research targeting this unique population. current literature supports the value of strong ayaclinician communication, notably in facilitating therapeutic alliance, however little is known about aya communication priorities during cancer care and barriers to optimal ayaclinician communication. objectives: to explore aya and oncology clinician communication priorities and to identify barriers and facilitators to aya-oncology clinician communication. design/method: semi-structured interviews were held with 21 aya cancer patients and survivors (ages 15-25 years) from a single large academic institution and 22 oncology clinicians (physicians and nurse practitioners) from 7 academic institutions in the northeastern united states. interviews were conducted in english by phone or in person. all interviews were audio-recorded and transcribed verbatim. analyses were aided by nvivo11 software. ayas identified a wide range of topics as important to discuss with clinicians. the most frequently identified topics were 1) side effects of treatment (with an emphasis on physical appearance and function, n = 16), 2) social issues (including friendship, family, and school, n = 13), 3) looking ahead to the future (n = 12), and 4) sexual & reproductive health (including future fertility, contraception, and romantic relationships, n = 8). clinicians prioritized 1) cancer treatment and side effects (n = 17), 2) emotional and psychological health (n = 11), and 3) sexual and reproductive health with a focus on fertility risk and fertility preservation (n = 8). aya reported facilitators to good communication including an open and long-established relationship with the clinician (n = 16) and clinician engagement in age-appropriate and patient-directed conversations (n = 7). barriers included parental presence during visits (n = 7). clinicians reported barriers including 1) clinician discomfort (not feeling wellequipped to discuss psychosocial topics such as sexual health, spirituality, and relationships with peers, n = 13), 2) presence of parents/family (n = 12), and 3) perceived patient discomfort discussing specific topics (such as sexual health, n = 10). clinicians acknowledged the need for collaborative efforts with additional team members (i.e. nurses, psychosocial providers) to assist in meeting aya communication needs. conclusion: aya and clinician-reported communication priorities are largely aligned. however, ayas emphasize some topics, such as social function, appearance, and sexual health that are not highly prioritized by clinicians, which may result in gaps in care for ayas in treatment and in survivorship. these data identify opportunities for intervention, including clinician education, patient and family education, clinic-based intervention, and systems-based changes that can be developed and tested. background: primary care physicians (pcps) cite lack of knowledge and inadequate communication with the oncology team as major barriers to providing recommended surveillance for late effects of treatment to childhood cancer survivors. a standardized telephone handoff to pcps posttherapy is a potential strategy to increase survivorship care by pcps through interactive communication. to determine the feasibility of a structured telephone communication using the situation, background, assessment, and recommendation (sbar) communication tool delivered by a trained oncology nurse to increase pcp knowledge and willingness to provide survivorship care. design/method: from 12/12/16 to 1/23/17, a registered nurse expert in childhood cancer survivorship attempted to contact by telephone the pcps of the 30 most recent patients attending yale's childhood cancer survivorship clinic that were <18 years old, english-speaking, and ≥2 years posttreatment. all pcps had been previously sent an individualized survivorship care plan (scp) that listed the patient's previous treatment history and recommended surveillance tests. upon successful contact and after confirming receipt of the scp, the nurse explained the definition of late effects, description of patient's diagnosis and treatment history, and associated potential late complications and schedule of recommended surveillance tests. the pcp was also asked about his/her ability and willingness to provide needed surveillance for late effects in the future. overall, 26 of 30 pcps were successfully contacted with a median of 1 phone call (range: 1-3) that lasted a median of 6 minutes (range: 3-10) after a median of 1 business day (range: 0-18). no pcps ended the call mid-conversation. all 26 pcps were receptive and expressed appreciation for the call. twenty-five of 26 (96%) pcps expressed an understand-ing of the material discussed and endorsed belief in their ability and willingness to provide late effects surveillance for their patients. no pcps questioned discussing their patient's care with a nurse versus a physician. interactive, structured communications between nurses and pcps by telephone are feasible and are associated with high-levels of pcp confidence in providing survivorship care. background: childhood cancer (cc) admissions account for 5% of non-newborn pediatric hospitalizations. these hospitalizations are longer and more expensive than other hospitalizations. admission payer (medicaid or commercial) reflects both health policy and sociodemographic status. the objective of this study was to determine if length of stay (los) or cost of cc admissions differed by payer. we used the 2012 kids inpatient database, a sampling of all pediatric hospital discharges in the united states. analysis for this study was limited to admissions containing a cancer diagnosis in any discharge icd-9 codes. admissions were further subcategorized by discharge codes according to diagnosis (leukemia, lymphoma, solid tumor and brain tumor) and reason for admission (chemotherapy, procedure, infection, non-infectious toxicity or "other"). charges were converted to costs using cost-to-charge ratios. multivariable linear regression models were performed to control for age, gender, race, reason for admission, and diagnosis. results: there were 105,752 weighted admissions for children with a cancer diagnosis in 2012. of these admissions, 40.5% had medicaid, 50.6% had commercial insurance, and less than 1% had other payers. the mean los for medicaid admissions was 7.37 days (95% ci 7.2-7.5), compared with 6.33 days (95% ci 6.2-6.4) for commercial insurance. surgical admissions accounted for the largest difference in length of stay with medicaid admissions being 2.77 days longer than those covered by commercial insurance (11.19 days vs 8.42 days), however, the difference was significantly different for all reasons for admission. in multivariable analysis admissions associated with commercial insurance were 6% shorter s195 of s301 (p<0.001), accounting for approximately one hospital day, than admissions associated with medicaid after controlling for other variables including race. the mean overall cost for medicaid admissions was $23,464 (95% ci 22840-24088), compared with $21,849 (95% ci 21343-22356) for commercial insurance. in the multivariable model, cost was collinear with race. conclusion: los and cost of admissions associated with medicaid differed from those associate with commercial payers. medicaid admissions were 6% longer on average than commercial insurance, accounting for a difference in length of stay of approximately one day although the difference varied with the reason for hospitalization (chemotherapy, surgical procedure, infection, other toxicity, other). costs of admissions were not independent of race. further investigation into potential explanations for this difference including differential access to home care needs, outpatient reimbursement differences, social indications for prolonged hospitalization, and provider biases, is warranted. background: pediatric cancer is a major cause of morbidity and mortality among children surpassed only by accidents. despite improved outcomes in high income countries (hic) survival rates remain poor in the developing word. there are various diagnostic and therapeutic limitations contributing significantly for the survival gap. the main objective of the study is to to evaluate the outcomes of pediatric cancer in armenia and identify diagnostic and therapeutic limitations in the country. we conducted a retrospective study among 97 (≤18 years old) children with cancer (solid tumors and hematological malignancies), who were diagnosed and treated at the clinic of chemotherapy of muratsan hospital complex of yerevan state medical university between 2008 and 2016. those patients, who didn't receive chemotherapy for any reason were not included in the study cohort. epidemiological, social, medical information was collected through the patient charts review. this included patient age at diagnosis, sex, place of residence (city vs village), the educational level and employment status of parents, type of cancer, stage, presentation of symptoms, first medical specialty consulted and the time consulted, initial work-up, the type of treatment received, information on the diagnosis/treatment received abroad. results: at our clinic during the mentioned period of time the majority of patients presented with hematologic malignancies-71%. 77 (74.6%) patients had information on diagnosis delay. average delay in diagnosis was about 42 days. in 33% of cases the first contact with "healthcare system" was through pediatrician, and in 20% with surgeon. out of 19 relapsed patients 10 received salvage treatment in armenia and 4 abroad. from those who stayed for treatment in armenia 4 patients survived. majority of relapsed patients had acute lymphoblastic leukemia. from 35 leukemia patients immunophenotyping and cytogenetics were available for 26 (74.3%) patients; the majority of missing cases were between 2008 and 2012, when these diagnostic modalities were not available or affordable in the country. 43 (45%) patients received part of diagnosis and/or treatment abroad. the most frequent reason for going abroad was bone marrow transplantation, otherwise none available in armenia. out of 97 patients 22 were lost to follow-up, 15 patients had a fatal outcome. 60 patients were in remission at a median follow up of 3.57 years. conclusion: unavailability of cancer registry and several essential diagnostic/treatment modalities, luck of multidisciplinary care and palliative support, high rate of out-of-pocket expenses were among the main challenges of pediatric cancer care in armenia. background: adverse drug reactions (adrs) are increasingly recognized as important and sometimes irreversible complications of cancer treatment. anthracyclines and cisplatin are effective chemotherapeutic agents, but their use can be limited by cardiotoxicity (anthracyclines) and ototoxicity (cisplatin) in up to 60% of patients. genetic variants that can be used to predict who is most at risk of developing these adrs have been discovered and replicated. objectives: to create pharmacogenetic risk prediction models for anthracycline and cisplatin toxicities and discuss results with oncologists to facilitate incorporation into treatment decision-making when appropriate. design/method: risk prediction models were developed from the linear regression of strongly-predictive genomic variants (odds ratios ≥ 3) discovered and replicated in at least three patient populations. these models were used to assess an individual patient's genomic risk of developing cardiotoxicity from anthracyclines or hearing loss from cisplatin. risk results were returned to oncologists showing where the specific patient's genetic risk of toxicity lies on a continuum between the lowest and highest risk groups across all studied patients using a multi-gene model. interviews were conducted with patients, families, and oncologists to determine how results were valued and utilized. results: 227 patients have been genotyped and had their genetic risk results returned to their oncologists. the first 140 patients have been characterized to determine the impact these test results have had on their clinical care. results were described as being useful in decision-making by patients and/or oncologists in 100% of cases. additionally, for patients in the most extreme risk groups (highest and lowest risk), a change in treatment plan was ordered 30% of the time for cisplatin patients and 35% of the time for anthracycline patients. this included increased cardiac and audiological monitoring, the addition of a protective agent, or choosing an alternative treatment protocol if the risk outweighed the benefits of remaining on the current treatment plan. in interviews, patients indicated that they felt more involved in decision making, and felt reassured by understanding their genetic risk of toxicities. genetic risk prediction models for anthracycline cardiotoxicity and cisplatin ototoxicity were highly utilized by patients and oncologists in decision-making. results were found to be an important tool for informing patients of the risk of adrs during cancer treatment, and resulted in patients and their families feeling more involved in decision-making. background: childhood cancer survivors are at increased risk of developing executive dysfunction, and low socioe-conomic status (ses) has been identified as one of the mediators of executive functioning. previous studies have used traditional measures of ses, such as parents' education level, family annual income and occupation. but more recently, area based socioeconomic measures like block group poverty status are deemed to be more useful in monitoring of social inequalities in health in the united states. block groups are statistical divisions of census tracts and generally contain between 600 and 3,000 people. the current study aims to understand the association of block group poverty status (percentage of households in family's block group of residence living below the federal poverty level) with executive functioning among cancer survivor children. design/method: we used a retrospective cohort of 67 childhood cancer survivors. relevant information was collected from the medical record, administrative data sets and parent-filled surveys. address information was geocoded using arcgis 10.2 to obtain data on the block group poverty status. a priori cut-points were set to represent block groups with families living below poverty level at 0%, 0.1% to 9.9%, and ≥10.0%. executive functioning were assessed through a parent-rated instrument, the behavior rating inventory of executive functions (brief). multiple linear regressions were used to determine the relationship between block group poverty status and the brief scores. results: data was examined from 67 families of childhood cancer survivors, ranging in age from 6 to 18 years. in this sample, 32.8% families reported an annual income <$60,000, 32.8% reported income between $60,000 and $100,000 while 34.3% reported annual income ≥$100,000. primary care giver of 85.1% of cancer survivors had more than more high school education, and 31.3%, 41.8% and 26.9%, of families were living in a block groups with 0%, 0.1-9.9% and ≥10% poor households respectively. block group poverty level was not significantly associated with annual income levels (spearman's rho = 0.14, p = 0.25), or parental education level (spearman's rho = -0.02, p = 0.84). in a step-wise multiple linear regression, there was no statistically significant association seen between block group poverty status and executive functioning after adjusting for co-variables in the final model. future prospective study with a bigger sample size, longer follow up period and more robust measures of the executive functioning like a clinician administered test are needed to understand the effect of block group poverty status on executive functioning. to d100 completion was 45.5 days (range 21-63). all parents strongly agreed/agreed that d100 was helpful and would recommend d100 participation to another family. ten parents (100%) reported time spent on d100 was "just right." no parent felt more worried due to the intervention, though 1 parent found d100 participation stressful. this interim analysis suggests that parents have a favorable d100 experience and recommend the intervention. to date, <20% of enrolled parents fail to participate. d100 shows promise as an acceptable interdisciplinary communication intervention targeted to the early treatment period for childhood cancer. children 's hospital and research center oakland, oakland, california, united states background: screening echocardiograms are recommended by children's oncology group (cog) guidelines to assess for anthracycline-induced left ventricular (lv) systolic dysfunction. the yield of screening echocardiograms during chemotherapy and in the immediate post-therapy period is uncertain. objectives: to assess the incidence of lv dysfunction detected by screening echocardiograms during chemotherapy and in the immediate post-therapy period, defined as 0-24 months off-therapy. design/method: children diagnosed with cancer between january 2013-march 2016 who received anthracycline chemotherapy were identified. echocardiograms were performed as per protocol, institutional and cog guidelines, and were reviewed retrospectively. lv dysfunction was defined as fractional shortening (fs) <28% or ejection fraction (ef) <55% (1) results: in this cohort (n = 195, median age 6 years), the most common diagnosis was all (54.8%), followed by aml (9.7%). of 357 echocardiograms, 224 (62.7%) were performed during treatment and 133 in the immediate posttreatment period. thirty-eight (19.3%) patients had a >10% decrease in fs compared to their pre-treatment echocardiograms. none of these patients required any treatment modification or cardiac medications. only 1 patient (0.5%) had echocardiogram-proven lv dysfunction discovered on a screening echocardiogram during her treatment course. she eventually died due to multi-organ failure following septic shock. this patient was receiving treatment for aml and had received 300 mg/m2 of doxorubicin-equivalent anthracyclines at the time of the abnormal echocardiogram. one patient with metastatic ewing sarcoma had borderline lv dysfunction with a fs of 30% detected a month before completion of therapy. she had received 375mg/m2 of doxorubicin equivalent anthracyclines at the time of the abnormal echocardiogram. she did not require any therapy modification or additional cardiac medications. serial echocardiograms done on this patient have shown stable ventricular function. no off-therapy screening echocardiograms identified lv dysfunction. in our experience, the yield of echocardiograms to detect anthracycline-related cardiac dysfunction during treatment and in the immediate post-therapy period is very low. one patient developed lv dysfunction during treatment and one had borderline fs, while no lv dysfunction was identified within 24 months of completing chemotherapy. though fs decreased in 19% of patients, none required intervention. further study is needed to optimize the use of echocardiography screening in children treated with anthracyclines. references: 1. landier w et al. jco 2012. background: platinum-based chemotherapy increases the risk of sensorineural hearing loss in children with cancer. little is known about the impact of hearing loss on cognitive and emotional functioning in survivors. to determine the association of severe/profound hearing loss after platinum-based chemotherapy with 1) cognitive impairment and 2) emotional distress (i.e. anxiety and/or depression). cross-sectional study of all patients attending yale's childhood cancer survivorship clinic ≥2 years off therapy for cancer diagnosed at <21 years and treated with cisplatin and/or carboplatin, but with no history of cns tumor, cranial radiation, congenital hearing loss, or developmental delay. hearing loss severity and hearing aid data were abstracted from audiograms and detailed clinical history. cognitive impairment was defined as behavior rating inventory of executive function t score ≥65, assessment by neuropsychologist, and/or history of special education. emotional distress was determined by brief symptom inventory t score ≥63 (global or two subscales) or behavioral and emotional screening system t score ≥61, psychologist interview, and/or history of psychotropic medication/psychotherapy. the most recent available patient data were used. logistic regression with sas software, version 9.4 was performed. results: overall, 37 patients (57% female, 78% white) met eligibility criteria with a median age of 9.0 years (iqr = 12.1) at diagnosis and 22.3 years at evaluation (iqr = 10.4) after a diagnosis of sarcoma (36%), neuroblastoma (32%), or other (32%) for which 84% received cisplatin and 30% received carboplatin. fifteen patients (41%) had severe/profound hearing loss in at least one ear. patients with severe/profound hearing loss had a significantly increased risk of cognitive impairment (or = 5.14; 95% ci = 1.17-22.69), but not emotional distress, compared to patients without severe/profound hearing loss. there was no significant association between age at diagnosis, current age, time since diagnosis, sex, race, ethnicity, or diagnosis with either cognitive impairment or emotional distress. similarly, there was no significant interaction between 1) age at diagnosis and hearing loss or 2) sex and hearing loss with either cognitive impairment or emotional distress. ten of the 15 (67%) patients with severe/profound hearing loss in at least one ear were recommended hearing aids, of which 3 (30%) reported compliance most of the time. we conclude that severe/profound hearing loss is significantly associated with cognitive impairment, but not emotional distress, in childhood cancer survivors. our data supports the need for interventions to improve hearing in these patients, including compliance with hearing aids. background: who grade 3 anaplastic astrocytoma is a high grade glioma dependent on vascular endothelial s199 of s301 growth factor (vegf) mediated angiogenesis for its growth and infiltration. bevacizumab is a recombinant humanized monoclonal antibody which binds vegf-a and inhibits angiogenesis. common adverse effects of bevacizumab are hypertension, proteinuria, thrombosis and bleeding. while animal model based studies have shown that bevacizumab may impair ovarian function the effects of bevacizumab therapy on human fertility are not clear. since the physiology of pregnancy involves neovascularization/angiogenesis it is recommended that conception be avoided for at least 6 months following exposure to bevacizumab. to describe the course of a young adult who became pregnant after receiving bevacizumab and radiation therapy for treatment of an anaplastic astrocytoma. a 20 year old woman diagnosed with a localized hemispheric who 3 anaplastic astrocytoma was treated with chemotherapy and radiation (temozolomide/59.4 gy) followed by 12 cycles of bi-weekly bevacizumab/temozolomide. patient opted not to pursue fertility preservation prior to initiation treatment. she experienced bevacizumab-associated proteinuria and hypertension during treatment but received all protocol mandated doses (cumulative doses: bevacizumab = 240 mg/kg; temozolomide = 15.78 gm/m2). she had a spontaneous unassisted pregnancy 18 months after completing treatment. her pregnancy was uneventful and she was normotensive throughout. fetal ultrasonography at 16, 20, 27, 33 weeks revealed no abnormality of the brain, heart, great vessels, kidney, extremities, placenta and umbilical cord. at 39 weeks she delivered a female infant via cesarean section (birth weight: 3890 grams, apgars: 95 and 1010) excessive post-partum hemorrhage was not reported. placenta was bi-lobed and weighed 604 g. histological analysis revealed normal placental villous development and maturation and two small infarcts. conclusion: exposure to bevacizumab in our patient had no detrimental effect on fertility and on placental/fetal vascular development. we hope this report will add to the existing data on the effects of bevacizumab therapy on fertility. children's healthcare of atlanta, emory university school of medicine, atlanta, georgia, united states background: reports of malnutrition incidence and prevalence in young cancer patients are variable and not well established. previous research suggests children, especially less than 3 years old, treated with intensive cancer-directed therapy are at higher risk for malnutrition. however, no standardized assessment has been used to evaluate risk in this population. objectives: we aim to assess the trends of weight-for-age for patients following cancer diagnosis. this study will be the first to use a standardized measure of treatment intensity (intensity treatment rating scale, itr-2) and will assist in targeting interventions for identification and treatment of malnutrition. design/method: this observational, retrospective study obtained data through the center's pediatric cancer registry and electronic medical record. patients were classified by tumor type (brain or non-brain tumor) and treatment intensity (itr-2). itr-2 incorporates diagnosis, chemotherapy, radiation, and surgery, beginning with lowest intensity (1) to highest intensity (4). inclusion criteria included new cancer diagnosis 2007-2015 at less than 3 years old, with weight obtained and available within 2 days of therapy start date. incomplete data, alternate growth charts, or treatment intensity of 1, were excluded. weight was obtained at start of therapy and through 2 years after treatment initiation (approximately 750 days) and converted to z-scores adjusted for age and sex. weight trajectories were modeled using generalized linear mixed models with subject-specific random intercepts and spline functions. separate functions were constructed for subgroups of interest (tumor type and itr). results: there were 402 patients included: 53 patients with brain tumors (13.2%) and 349 with non-brain tumors (86.8%). of included patients, 165 had treatment intensity of 2 (41.0%), 192 of 3 (47.8%) and 45 of 4 (11.2%). over the observation period, 34,593 valid weights were recorded. at initiation of treatment, no difference existed between z-score by tumor type (p = 0.880) or by intensity (2 vs. 3, p = 0.879; 2 vs. 4, p = 0.665; 3 vs. 4, p = 0.558). tumor type did not affect z-score through the follow up period. z-scores were higher for intensity rating 2 vs. 3 and 2 vs. 4 (p = <0.001 and p = 0.015 respectively) at 240 days after the start of treatment and persisted through 720 days (p = 0.003 and p<0.001 respectively). higher treatment intensity is associated with decline in z-score and failure to return to baseline. future directions include further analysis on specific risk factors and timing of weight loss, longer-term follow-up of weight trends, and targeted interventions for identification, prevention, and treatment of malnutrition. objectives: asses the pt requirements for bleeding episodes in a prospective cohort of pcp using a <10 × 10e9 threshold compared to a <20 × 10e9/l threshold in a historical cohort. we collected pt data in all pcps treated at our center between january/2013 through december/2017. diagnosis, prescription for pt (prophylaxis vs bleeding disorder), plt count and transfused units were assessed for each pt. pcps treated from january/2013 through june 2015 received prophylactic pt with a <20 × 10e9 threshold (cohort a), and pts treated from july/2015 through december/2017 received prophylactic pt with a <10 × 10e9 threshold. pts done for procedures and pts with concomitant hemorrhagic pathology were excluded. we compared the number of pts prescribed as prophylaxis vs bleeding episode between cohorts. data analyzed: graphpad prims 6.0®. statistical analysis: percentages with confidence interval (ci); t-student test (parametric variables) and mann-whitney test (nonparametric variables). statistical significance: p<0.05. we reviewed 2093 pts (871 in cohort a, 1222 cohort b) in 209 patients. 62% had acute leukemia, 33% received and auto or allo hsct. diagnoses and the proportion of patients undergoing hsct was comparable in both cohorts. the average number of pts per patient was 8,54 in cohort a and 8,24 in cohort b (p = ns), but a significant difference was found when hsct patients were excluded from this comparison (7,34 pt per patient in cohort a vs 6,07 in cohort b, p = 0,005), which resulted in an estimated 16,4% reduction in pts prescription. furthermore 61 (7,1%) pts were prescribed for bleeding episodes in cohort a versus 99 (8,2%) in cohort b (p = ns). patients receiving hsct in the entire group ver-sus those not receiving hsct had similar pt requirements for bleeding episodes (10% vs 8,5% p = ns) conclusion: a <10 × 10e9 plt count threshold for prophylactic pts is safe in pcp in chemotherapy and hsct. it can result in a significant reduction in pt usage. key words: platelets, transfusions, prophylaxis, cancer, childhood. ucsf benioff children's hospital oakland, oakland, california, united states background: transition of care for adolescent and young adult (aya) survivors of childhood cancer from pediatric to adult-oriented long-term follow-up (ltfu) is complex. loss to follow-up is common, and little is known about the success rates among different models. the survivors of childhood cancer program (sccp) at ucsf benioff children's hospital oakland employs a community-based model for transitional care. our multidisciplinary team provides aya survivors a comprehensive treatment summary and recommendations, then facilitates transition to primary care or adult oncology ltfu programs. evaluate the success rate for transition of care among aya survivors of childhood cancer in our ltfu program, and identify barriers to successful transition. design/method: aya patients seen from november 2010 to august 2017 in the sccp with intent to transition were asked by email or telephone if they had followed up with their designated provider. the primary outcome was successful transition, defined as establishing care within 18 months of their visit. patients were also asked about barriers to transition and to rate the new provider's familiarity with their cancer history and ltfu needs. results: transition was intended for 88 patients. eightyseven were contacted and 43 responded. of these, 29 (67%) successfully transitioned, while 14 (33%) were lost to followup. ages ranged from 19 to 48 years, at 2 to 32 years since completion of therapy. ten (34%) transitioned to a primary care provider, 20 (69%) to an adult oncology ltfu program, and 1 (3%) to a pediatrician. patients rated their new provider's knowledge above average (3.76) on a 5-point scale from poor (1) to excellent (5). survivors lost to follow up indicated the following barriers to transition: loss/change of insurance (3), inability to find a provider (1), too busy/forgot (4), problems with transportation (1), concerns about cost/copay (2), and s201 of s301 other (4). twelve patients requested further assistance with transition. conclusion: two-thirds of responding patients successfully transitioned. more work is needed to overcome various barriers to transition for one third of aya survivors. albany medical center, albany, new york, united states background: the transition from active treatment, to offtherapy follow-up, is a stressful event for parents of children with cancer. the psychosocial needs of parents after therapy have received limited attention in the united states with only 3 published quantitative studies, the largest with 35 parents. we have secured funding for and recruited a transition care coordinator (tcc) to investigate this further. objectives: our objective is to assess and screen parents at the end of their child's treatment, and to develop interventions to support parents during this time and thereafter. design/method: after informed consent, a standardized questionnaire, the psychosocial assessment tool (pat 2.0), was administered to parents at end of therapy (t1), 6 months later (t2) and 1 year later (t3). the tcc provided "universal" intervention to all families with an end of therapy binder containing a treatment summary, follow-up roadmaps, information on late effects, and survivor scholarships. based on their pat2.0 scores, some parents were provided intervention specific to symptoms (targeted intervention for scores 1-1.99) or referred to a behavioral health specialist through the clinic social worker for counseling (for scores >2). results: analysis of pat1 data showed that 45% of parents (n = 45) scored in the targeted or clinical ranges; 19% of parents scored in those ranges at pat2. significant gender differences were revealed with the mean score for men of 0.7 and for women of 1.13. this was confirmed by showing statistical significance (p = 0.017) when analysis was conducted for only a subgroup of data composed of couples (n = 24). analysis of pat2 data by couples (n = 10) showed the mean score for men was 0.64 and for women was 0.93 (p = 0.12). gender differences were most apparent in caregiver stress reaction questions that focused on ptsd symptoms. when the subgroup of couples' scores (n = 24) for caregiver stress reaction at pat1 was analyzed, there was a significant difference (p = 0.005) in caregiver stress reaction with a mean of 0.08 for men versus 0.3 for women. [note: subcategory scores range from 0 to 1]. this study was initiated in october 2013 using a tcc and the pat2.0 screening tool. the results suggest greater stress on mothers after therapy, with a substantial proportion of parents having symptoms of ptsd after therapy. background: hodgkin lymphoma (hl) is a common childhood cancer characterized by an inflammatory microenvironment. chemotherapy and radiation may exacerbate this inflammation and contribute to the development of late effects (pneumonitis or pulmonary fibrosis). in a heterogeneous cohort of childhood cancer survivors exposed to pulmonarytoxic therapy, no association between pro-inflammatory cytokines and late pulmonary dysfunction was observed. our objective was to test this association in a relatively uniform cohort of survivors of hl, given the well-recognized proinflammatory background of this disease. objectives: to characterize off-therapy pulmonary function in survivors of hl treated with contemporary therapy, and to investigate its association with persistent systemic inflammation. design/method: blood samples, clinical data, and pulmonary function tests were obtained from survivors of hl ≥6 months off therapy. lung function score (lfs), a validated method for assessing degree of pulmonary dysfunction on a scale of i to iv, was determined from diffusion capacity and forced expiratory volume in one second (fev1). for a control group, blood samples from patients with benign, noninflammatory hematologic conditions were used. plasma concentrations of 50 inflammatory cytokines were measured on a luminex platform (emd millipore). associations between clinical features or cytokine levels and lfs i (normal) vs. ii-iv were evaluated using logistic regression or wilcoxon rank sum tests, respectively. results: of 77 survivors (mean age at diagnosis: 14 years, range: 3-18; mean time off therapy: 3.3 years, range: 0.5-24), 70% were categorized as lfs ii (mild dysfunction), 8% as lfs iii (moderate dysfunction), and no survivors as lfs iv (severe dysfunction). higher lfs was associated with female sex (p = 0.01) but not other demographic, disease, or treatment factors. forty-eight survivors had blood samples collected at a mean age of 18.5 years (range: 10-32) with a mean time since treatment completion of 3.8 years (range: 0.6-6.1). of 31 controls, the mean age at time of blood collection was 12 years (range: 4-17). survivors did not have significantly elevated cytokine levels compared to controls. female survivors of hl ≥6 months off therapy are at increased risk of pulmonary dysfunction. neither evidence for pulmonary dysfunction, as measured by lfs, nor duration of time off therapy were related to systemic inflammation in this study. pulmonary function deterioration and clinical pulmonary symptoms are rarely observed immediately following therapy but increase over time. future studies may consider exploring the contribution of systemic inflammation to pulmonary late effects in survivors farther off therapy, when risk for this late effect is greater. background: thyroid carcinoma is a very rare tumor in pediatrics, accounting for 1.5-3% of childhood carcinomas in the united states and europe. we aim to detect the risk of second malignancies among pediatric thyroid cancer survivors. the cohort analysis consisted of pediatric cancer patients aged less than 20 years diagnosed with a primary thyroid cancer and identified by site code icd-0-3: c739, reported to a seer 9 database between 1973 and 2013. they were followed up by death or the end of the study period (december 31, 2013) . out of 1769 patients diagnosed primarily with thyroid carcinoma, there were 42 patients who had 45 incidences of subsequent malignancies. the mean age of patients at initial diagnosis of thyroid cancer was 16 years. females (90.5%) had significantly higher incidence of second malignancies (sm) than males (9.5%). the overall standardized incidence ratio (sir) of sm in thyroid pediatric patients was higher than expected (sir = 1.48). some specific sites showed significantly higher incidences: salivary gland (sir = 33.95), gum and other mouth (sir = 24.53) and kidney (sir = 5.72). the overall risk of sm in patients received radioactive iodine was higher than expected (sir = 4.41). the cumulative inci-dence of sms from the initial diagnosis of thyroid cancer was calculated with the survival methodology of competing risk, death treated as a competing event. cumulative incidence of sm was 2.7% [95 % ci (1.62, 3.83 %)] at 25 years and substantially expanded after 15 years, reaching 11.92% [95 % ci (4.9, 18.8%)] at 40 years. the cumulative incidence of each tumor type at 40 years was 0.452% [95 % ci (0.139, 0.765 %)] for breast cancer, 0.28% [95 % ci (0.034, 0.53 %)] for salivary gland, 0.22% [95 % ci (0.00034, 0.448 %)] for each one of kidney and cervix uteri and 0.169% [95 % ci (0, 0.361 %)] for each one of ovary and melanoma of the skin. cumulative incidence of sm was stratified based on race, gender and radiotherapy exposure, but there was no statistical difference in each of them. conclusion: race, gender, histological subtypes, and radioactive iodine may play an important role as prognostic factors for developing sm among pediatric thyroid cancer survivors. identification of underlying mechanisms that raise the risk of sm is important for both treatment and follow-up strategy. background: the ethical practice of informed consent requires it be both voluntary and understood by the research participant. in pediatric oncology, parents must undergo informed consent to enroll their child with cancer into clinical trials, but often it can be difficult to understand especially for parents with low english proficiency. previous research has shown that parents of children with cancer have difficulty understanding voluntariness, and that parental satisfaction with informed consent does not always correlate with adequate comprehension. objectives: to examine socio-demographic and contextual correlates of comprehension of informed consent, voluntariness, and satisfaction in parents who consented to participation of their child in a cancer clinical trial. we focused on characterizing differences between non-hispanics and hispanics, the fastest growing ethnic group in the u.s. design/method: parents/guardians (n = 121) of children aged 0-17 years with newly diagnosed cancer, who had consented to participation of their child in a clinical trial for cancer treatment at rady children's hospital-san diego were s203 of s301 prospectively recruited. parents completed questionnaires assessing comprehension, voluntariness, satisfaction, health literacy, socio-demographics, and acculturation level, if hispanic. comprehension was surveyed at baseline and longitudinally at 3 months. comprehension, voluntariness and satisfaction outcomes were analyzed by socio-demographics, health literacy, and acculturation level using logistic regression. results: of the 121 participants surveyed, 61 (50.4%) were hispanic and 60 (49.6%) were non-hispanic. we found that higher health literacy was associated with greater objective comprehension (p<0.001), voluntariness (p<0.001), socioeconomic status (p<0.001), and acculturation (p<0.001). hispanics reported lower objective comprehension (p = 0.025), voluntariness (p = 0.029), health literacy (p<0.001) and ses (p = 0.015) compared to non-hispanics. spanish-speakers reported lower voluntariness (p = 0.016), health literacy (p<0.001), and acculturation (p<0.001) compared to englishspeakers. at the 3-month follow-up, comprehension in hispanics significantly improved (p = 0.012) compared to their baseline comprehension. satisfaction was moderately high across all subgroups and was not significantly impacted by socio-demographics, health literacy, or acculturation. in this study, with equivalent numbers of hispanic and non-hispanic participants, we found that hispanic and spanish-speaking parents of children with newly diagnosed cancer had inadequate informed consent comprehension, voluntariness and health literacy despite high satisfaction. our study suggests that hispanics and individuals with limited english proficiency are not making truly informed decisions for their child with cancer. to ensure the ethical practice of research in pediatric oncology, the informed consent and decision-making process must be improved with culturally and linguistically interventions for these underserved populations. memorial sloan kettering cancer center, new york, new york, united states background: pediatric oncology patients undergo repeated bone marrow aspirations and biopsies (bma/bx). these potentially painful procedures can exacerbate anxiety and distress. standard practice at memorial sloan kettering (msk) department of pediatrics is to use propofol, which has amnestic but no analgesic properties. we sought to evaluate whether the addition of local anesthetic would improve patient experience with bma/bx. the purpose of reppair: reducing procedural pain and improving recovery of quality of life (qol) (nct02924324) is to evaluate the efficacy of local anesthesia with ropivacaine in reducing procedural pain and improving post-procedure qol in pediatric neuroblastoma patients undergoing bma/bx with general anesthesia. reppair is a prospective, randomized, crossover clinical trial that opened for enrollment october 2016. eligible patients were 3 -18 years old with neuroblastoma. participants were observed on trial for two sequential bm procedures; one procedure with intervention a: propofol alone (pa), and the other with intervention b: propofol plus ropivacaine (p+r). participants were randomized to intervention sequence ab or ba and were blinded to the order of interventions. participants and recovery room (rr) nurses, who were also blinded, followed a standardized postprocedure pain management algorithm. the primary endpoint was percentage of participants requiring opioid analgesia in the 24 hours post-procedure. secondary endpoints included total opioid in 24 hours, non-opioid analgesia use, pain scores, time to first opioid, and short-term qol. qol was assessed by a parent-proxy metric that evaluated pain interference with sleep, physical, emotional, and social recovery. as of january 2018, 105 patients were assessed for eligibility and 56 patients were randomized (47 have completed both procedures). for the primary endpoint, a slightly higher proportion of participants required opioid for pa than p+r (24% versus 21%, p = 0.6). pain scores in the rr were significantly higher for pa than p+r (median [25th, 75th percentile]: 2 [0,4] versus 0 [0,2], p = 0.004). there were no statistically significant differences in total opioid or non-opioid analgesia, 6-and 24-hour pain scores, median time to first opioid, or pain interference scores. there were no adverse events. conclusion: preliminary findings of the reppair trial suggest that local anesthesia does not reduce the need for opioid analgesia or improve short-term qol in pediatric patients undergoing bma/bx with general anesthesia. local anesthesia did improve pain scores in the immediate recovery period. final results of this study will help establish evidence-based guidelines and optimize the experience of pediatric patients with bone marrow procedures at our center. background: children with advanced cancer experience a range of symptoms throughout treatment or at end of life, some of which are poorly controlled. minimizing suffering, including effective symptom management, in children with advanced cancer is a central value for pediatric oncology clinicians. patient-reported outcomes have been used in symptomrelated research in pediatric oncology patients; however the majority of literature specific to symptoms during palliative care and end of life for children and adolescents with advanced cancer is based primarily upon medical record reviews and to a lesser extent, patient self-report. the purpose of this study was to prospectively describe symptom frequency, severity, and level of distress in children/adolescents with advanced cancer using patient selfreport and parent proxy. design/method: a prospective cohort design was used for this study. five pediatric oncology institutions from across the united states participated. children and adolescents were eligible to participate if they were 7-18 years of age, englishspeaking, and had a diagnosis of advanced cancer, defined as a 2-week history of progressive, recurrent, or non-responsive disease or a decision not to pursue curative-focused therapy. a modified version of the memorial symptom assessment scale (msas) was used to measure symptom frequency, severity, and level of distress and was administered to child/parent dyads electronically via smartphones every two weeks. information regarding disease status and cancer treatment was collected concurrently. data was analyzed using descriptive statistics and univariate logistic regression analysis. results: a total of 47 children and adolescents and 47 parents participated in the study. the median age of child participants was 13 years, with half being male. the median age of parents was 46 years. the child participants had a variety of primary diagnosis, including: leukemia/lymphoma (n = 11, 23%), solid tumor (n = 21, 45%), and brain tumor (n = 15, 32%). the most frequently reported symptoms by children with advanced cancer and parents were pain (n = 195/562, 34.70%), lack of energy (n = 186/561, 33.16%), and nausea (n = 156/560, 27.86%). presence of disease (p = <0.0001), recent disease progression (p = 0.0002), and receiving cancer therapy (p = 0.0004) were significant factors on the presence of pain. high intensity cancer therapy was a significant factor on pain frequency (p = 0.0445) and level of distress (p = 0.0224). it is feasible to collect data prospectively in children with advanced cancer regarding symptom frequency, severity, and level distress. clinicians' increased understanding of the symptom experience may promote communication with children and adolescents and timely intervention. more research is needed to understand symptom clusters in children with advanced cancer. vanderbilt children's hospital, nashville, tennessee, united states background: febrile neutropenia (fn) is a frequent occurrence in children undergoing chemotherapy. though guidelines recommend adding a second antibiotic to broad-spectrum antipseudomonal coverage in specific scenarios, augmenting empiric therapy with a second antibiotic is common practice. additional empiric antibiotic (aea) use increases the risk of antibiotic toxicity and future antimicrobial resistance. data clarifying the indications for aea are limited in pediatric patients. objectives: to identify risk factors for gram-positive (gp) and gram-negative (gn) bacteremia in patients presenting with fn to determine situations in which aea use is warranted. design/method: a retrospective chart review was conducted of pediatric severe fn with absolute neutrophil count <500/ l occurring at a single institution between 2006 and 2013. potential a priori risk factors based on clinical reasons for antibiotic expansion were chills, hypotension, mucositis, skin or soft tissue infections (sstis), recent administration of highdose cytarabine (hdac), and a diagnosis of acute myeloid leukemia (aml). potential factors for gn bacteremia were chills, hypotension, mucositis, and abdominal pain. the association between each potential risk factor and gp or gn s205 of s301 bacteremia was identified. logistic regression was used for multi-variable analysis. the review yielded 701 episodes. gp bacteremia was isolated in 75 cases (10.7%) and gn bacteremia in 37 episodes (5.3%). in multivariable analysis, hypotension (or 3.5 (95% ci 1.7, 7.2), p = 0.001) and sstis (or 3.1 (1.1, 8.7) , p = 0.036) were independently associated with increased risk of gp bacteremia, while mucositis (p = 0.376), recent administration of hdac (p = 0.34) and chills (p = 0.161) were not. ten patients with aml didn't receive hdac, thus the association between aml and gp bacteremia could not be reliably estimated. hypotension (or 4.9 (2.2, 11.0), p<0.001) and chills (or 5.0 (2.5, 10.1), p<0.001) were independently associated with a higher risk of gn bacteremia, while mucositis (p = 0.196) and abdominal pain (p = 0.509) were not. of the 37 gn infections, 6 (16%) were resistant to cefepime, the empiric agent of choice at our institution. patients with fn with sstis, hypotension, or recent hdac had increased risk of gp bacteremia indicating potential benefit of empiric vancomycin in these settings, while mucositis and chills were not associated with gp bacteremia. hypotension and chills were associated with gn bacteremia, potentially warranting empiric antibiotic expansion, while mucositis and abdominal pain were not. identifying specific indications for aea use in pediatric severe fn use may improve antimicrobial utilization, decrease unnecessary antibiotic use, and improve patient outcomes. background: for children/young adults with incurable high grade gliomas (hggs), like diffuse intrinsic pontine glioma (dipg) or glioblastoma multiforme (gbm), oncologists endeavor to align therapy with patient/family goals of care, but may be influenced by providers' preferences or limited resources. ethical challenges can arise around the perceived purpose, risks and benefits of therapy options, provider conflicts of interest, access to care, deciding decisional priority between patients and families, and conflicts around end-oflife care. objectives: evaluate factors that play into longitudinal decision making for children and young adults with hggs, their families and oncologists using a qualitative approach with ethnographic elements. design/method: eligible patients were aged 0-21 with dipg, gbm, or secondary hgg. patient exclusions included: non-english speaking, in state custody, death prior to diagnosis, seen by oncology once, or an oncologist declined participation. key decision making visits (e.g. mri reviews) were serially audio-recorded, along with subsequent 1:1 semistructured interviews with patients and/or parents about the decision making process. field notes from clinician meetings, chart notes, and oncologist questionnaires were obtained. discussions and interviews were transcribed and independently coded by three investigators. inter-rater reliability was assessed during code book development. discrepancies were discussed until consensus met. constant comparison analysis with maxqda software continued until thematic saturation. results: twenty-two of 34 eligible patients were approached; 15 agreed to participate. one withdrew upon transferring care. mean age was 9.9 years (sd 5.9); 71% male, 50% caucasian, 29% african american, 14% hispanic, and 7% asian. four encounters, (2.5 hours), were recorded on average per patient. parent/patient interview themes included: 1) hope (for a cure, prolonged life, and quality of life), 2) importance of physician recommendations, 3) importance of support systems (family, community, social media), 4) food (as cancer etiology, intervention) 5) finances (personal, research funding), 6) communication (with medical providers, family, community), 7) death, and 8) god (beliefs, prayer, existential questions). oncologists desired prolonged quality of life, while patients/families transitioned to that hope from hope for a cure. decisions made in the setting of hggs are multi-factorial, ultimately reflecting the competing values of decision makers. optimism about treatment efficacy is held in tension with poor prognosis, allowing for functional hope. acknowledging patients' and families' shifting hopes allows for changes in goals of care and shared decision making. future work is needed to 1) develop preference tools for pediatric patients and families to inform medical providers and 2) provide training in communication and shared decision making with oncologists. emory university, atlanta, georgia, united states background: bone marrow transplantation (bmt) is a potentially curative but underutilized treatment for scd. our previous work has shown that there is variation in physician philosophy and practice in considering bmt as a treatment option for patients with scd, and physicians may not discuss this with patients and families as a potential treatment option. in a randomized clinical trial to test the effectiveness of a decision aid for disease modifying therapies for sickle cell disease, adult patients with scd as well as caregivers of adult/pediatric patients were interviewed about how they seek or have sought information related to scd, made decisions about treatments for scd, and identified a treatment option they were interested in learning more about using the decision aid tool. we performed a secondary analysis of these baseline data to understand patient information needs and attitudes regarding bmt as a treatment option for scd. the goals of this analyses was to understand patient and caregivers' attitudes and perceived information needs regarding bmt as a treatment option for scd. we performed an analysis of baseline interviews from caregivers of patients with scd or adult patients from a randomized control trial for a decision aid tool for scd. 13 of the 38 interviews belonged to caregivers of patients with scd. in addition to reviewing interviews for discussion of bmt, we interrogated for mention of terms such as 'bone marrow transplant' or 'cure' or 'stem cell transplant'. interviews were coded using nvivo10 and analyzed for emerging themes. results: of the 98 baseline interviews, 38 interviews met selection criteria. thirteen of the 38 interviews were with caregivers of pediatric patients, and the remainder were with adult patients, including young adult patients with scd. the majority of participants want to learn about bmt or curative options. in many participants, this was expressed despite knowledge that they were not a likely candidate for transplant. desired information about bmt included eligibility, benefits, risks, long-term effects, quality of life and financial aspects related to bmt. of the patients who discussed how they learnt about bmt, approximately half mentioned that their healthcare provider had not previously mentioned this to them. we then examined knowledge of bmt and attitudes with demographic and clinical variables. patients and caregivers of pediatric patients with scd want to learn about bmt as a treatment option. healthcare providers should consider discussing bmt with their patients with scd. natasha frederick, anna revette, alexis michaud, jennifer mack, sharon bober dana-farber cancer institute, boston, massachusetts, united states background: adolescents and young adults (ayas) consistently identify the need for improved patient-clinician communication on sexual and reproductive health (srh) issues. however, oncology clinicians do not routinely integrate srh conversations with ayas through disease treatment and survivorship. little is known about why these conversations do not take place. objectives: explore aya perceptions of and receptiveness to srh communication with oncology clinicians and to identify barriers and facilitators to these conversations. design/method: semi-structured interviews were held with 21 aya cancer patients and survivors (ages 15-25 years, 6 men, 15 women). twelve participants were on active treatment and 9 were within 2 years of treatment completion. interviews were conducted in english by phone or in person. the interview transcript underwent pre-testing with ayas. all interviews were audio-recorded and transcribed verbatim. transcripts were analyzed and summarized by two trained qualitative researchers according to standard comprehensive thematic qualitative analysis methods. analyses were aided by nvivo11 software. results: ayas perceived existing srh communication between ayas and oncology providers as inadequate. all ayas reported a need for improved srh communication with oncology providers, and three key areas of need emerged: 1) general education; 2) addressing specific srh issues experienced during treatment and survivorship; and 3) understanding the long-term impact of cancer and treatment on srh. ayas felt that current srh discussions are limited and too narrow in scope and scale. ayas reported that most srh conversations focus exclusively on fertility (n = 17), usually taking place at the start of treatment. other additional yet limited communication reported was about sexual activity (n = 7), contraception (n = 7), sexual function (n = 1). no ayas reported conversations about potential treatment complications related to sexuality other than infertility. key barriers to srh conversations include patient discomfort initiating conversation (n = 14) and presence of family members (n = 10), with additional reported barriers including perceived provider discomfort (n = 4), lack of rapport with provider (n = 4), and age/gender differences (n = 4). ayas felt that s207 of s301 communication tools such as handouts, brochures, and websites would be helpful facilitators to direct communication from the oncology clinician, and wanted conversations to start before treatment initiation and to continue through treatment and survivorship conclusion: ayas identify a key role for pediatric oncology providers in srh care from diagnosis through survivorship, however multiple barriers interfere with discussions about srh on a regular basis. identified barriers suggest that future efforts should focus on provider education and training in srh and srh-related communication in order to optimize care provided to this unique patient population. background: peripherally inserted central venous catheters (picc) provide secure vascular access in pediatric patients for the delivery of necessary therapies. the ease of placement in the inpatient and outpatient settings has expanded their utilization. however, recent data analyses show a significant increase in venous thromboembolism (vte) risk with the use of picc lines. with its rising use, modifiable risk factors need to be understood for preventative measures. objectives: in this study we aim to understand patient and catheter specific characteristics in relation to the development of vte. design/method: with irb approval, a retrospective interrogation of the electronic medical record and a picc database, at rainbow babies and children's hospital, was completed. the study cohort contained patients < 18 years of age who had a picc line placed between january of 2004 and december of 2016. data collected included indication for line placement, line dwell time, location of insertion including blood vessel and extremity, number of attempts at line placement, lumen size and indwelling line length. in addition, we collected number of days to vte formation, associated symptoms and location of vte. chi-squared analyses and fischer's exact test were used where appropriate for statistical analysis. we analyzed 3729(1098 neonatal) newly placed picc lines. fifty line-associated vte events were found, for an incidence of 1.3%. all vte occurred with the placement of the first picc line. intravenous therapies were the most common reason for line placement. no statistical significance was found between various indications for placement. the most common symptom of vte manifestation was extremity swelling, follow by extremity pain. right extremity picc was found to have a higher incidence of vte. larger catheter lumen sizes (> 4 french) had a higher incidence of vte. we found a mean time of 20.07 days to vte detection. we were unable to find any clinical, patient or line specific factors leading to increased vte formation after statistical analysis. special consideration should be given to the duration of picc line use as this may reduce the incidence and comorbities associated with vte. there is still much to be understood about catheter associated vte formation as our analyses indicates the need for prospective data collection on a larger scale in hopes to create guidelines related to catheter use in pediatrics. background: the decision to transfuse a patient is a complex one and is never based solely on a number; however, certain hemoglobin or platelet count thresholds have been proposed in aiding physicians make transfusion decisions. in our hospital, the thresholds for packed red blood cell (prbc) and platelet transfusion in pediatric oncology patients are hemoglobin levels below 8.0 g/dl and platelet counts below 20,000/mm3 (< 35,000 for brain tumors), respectively. recently, these thresholds have been questioned and we were asked whether we could safely lower the thresholds to < 7.0 g/dl of hemoglobin and < 10,000 /mm3 platelet count objectives: to investigate platelet and hemoglobin transfusion thresholds for oncology patients at children hospital of michigan design/method: retrospective chart review over a 6-month period, examining platelet and hemoglobin pretransfusion levels for each prbc and platelet transfusion given to oncology patients results: over the course of 6 months, 60 eligible oncology patients (median age 6 years) received 584 transfusions (233 prbc transfusions and 351 platelet transfusions). the mean pretransfusion hemoglobin level was 7.6 ± 1.0 g/dl (range 2.3-11.9) (n = 233) for total prbc transfusions and this was not different among disease categories (p = 0.146). patients who had anemia symptoms and signs (n = 190) had a slightly lower hemoglobin level compared to those who did not (n = 43): 7.5 ± 1.0 vs 7.8 ± 0.9 g/dl (p = 0.058). the mean pretransfusion platelet count was 24,570 ± 15,151 /mm3 (range 2,000 -104,000) for total platelet transfusions (n = 351); 32,800 ± 14,586 /mm3 in patients with brain tumors (n = 84); 20,610 ± 15,270 in patients with leukemia (n = 119); and 23,090 ± 13,628 in patients with solid tumors (n = 148). the mean pretransfusion platelet count was significantly higher in transfusions for brain tumors compared to that in the other disease groups (p<0.001 for both). the mean pretransfusion platelet count was not different among those patients who had bleeding/bruising symptoms (25,150 ± 17,898, n = 115) versus those who did not (24,290 ± 13,648, n = 236) (p = 0.620). the bleeding/bruising rate was slightly but insignificantly higher in those who had platelet counts <10,000 vs those who had ≥ 10,000 (38.2% vs 32.2%, p = 0.564). since most patients develop symptoms of anemia at hemoglobin above 7 g/dl and about 1/3 of patients develop bleeding/bruising symptoms at platelet counts above 20,000 /mm3, our current policy so far reflects a safe threshold for transfusion, and further lowering of the thresholds should be investigated in prospective studies. background: renal impairment is an important complication of childhood cancer and its treatment. serum creatinine level is frequently used as a screening test to monitor renal function; however, patients can have significantly decreased glomerular filtration rate (gfr) with normal serum creatinine. to determine the prevalence of chronic kidney disease (ckd) among children with cancer diagnosis, based on calculated gfr. to compare the difference between using serum creatinine value alone versus gfr in detecting ckd. design/method: retrospective review of medical records of 150 patients, age 1-18 years, diagnosed between 1/2011-12/2016 with solid tumors were analyzed. serum creatinine and calculated gfr using schwartz formula were recorded. ckd as classified by the foundation of kidney disease and outcome quality initiative was used: ckd stage 2: gfr (60 to 89 ml/min per 1.73 m2) ckd stage 3: gfr (30 to 59 ml/min per 1.73 m2) statistical analysis using spss software v.23. chi-squared test for proportions within group, and pearson chi-squared and fisher exact tests for statistical differences between groups. p-value <0.05 was considered to indicate significance results: out of the 150 records reviewed, 81 (54%) were males and 69 (46%) females, with mean age of 9.2±5.6 years. 37 (24.6%) patients received one or more of nephrotoxic chemotherapy drugs; cisplatinum, carboplatinum, or ifosphamide mainly in the non-wilms solid tumors group (94.5%) compared to (5.5%) in the wilms tumor (wt) group. based on calculated gfr (by schwartz formula) ckd stage 2/or 3 was diagnosed in 66 (44%) patients with overwhelming majority (98%) were in the mild stage 2 ckd, only 3 (4.5%) of those patients had abnormally high serum creatinine levels (p = 0.006). 56.7% of patients who received nephrotoxic chemotherapy developed ckd, compared to 39.4% in those who did not receive it, (p = 0.01). despite that only 2/18 (11%) of wt group patients received nephrotoxic chemotherapy, yet this group had higher percentage of ckd (83.3 %) compared to non-wt group (34.8%) p = 0.02. significantly lower mean gfr 73.8±10 was noticed in the wt group compared to 99.8±29 in non-wt group (p = 0.001) conclusion: high prevalence of mild ckd was found among solid tumor patients. using serum creatinine alone as measure of renal function significantly under estimates renal impairment in those patients. early identification of ckd is easily achieved by using calculated gfr, which can helps providers and care givers to avoid potential nephrotoxic antibiotics, contrast media, nsaids and dehydration that may further deteriorate renal function the university of texas southwestern medical center, dallas, texas, united states background: children with down syndrome (ds) have increased risk of developing leukemia. pediatric patients with ds-associated acute lymphoblastic leukemia (ds-all) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (sct). anti-cd19 chimeric antigen receptor (car) t-cell therapy, tisagenlecleucel, demonstrated high rates of durable complete remission (cr) and a manageable safety profile in children with r/r b-cell acute lymphoblastic leukemia (b-all). objectives: characterize the efficacy and safety of tisagenlecleucel in pediatric/young adults with ds-all. design/method: pooled data from 2 single-arm, multicenter, phase 2 trials of tisagenlecleucel in pediatric/young-adult patients with r/r b-all (eliana, nct02435849; ensign, nct02228096) were analyzed. eight patients with ds-all were enrolled (data cutoff: eliana, 23 november 2016; ensign, 1 february 2016). seven were infused with tisagenlecleucel; 1 patient died from all progression and intracranial hemorrhage before infusion. no manufacturing issues occurred during production. 5/7 infused patients were male, 2/7 had prior sct (age range, 6-16 years). 6/7 patients achieved cr or cr with incomplete blood count recovery (cri) by day (d) 28 (cr+cri, 86%); 1 died before d28 and was not evaluable. analysis of minimal residual disease was negative in bone marrow in responding patients. two patients had cd19negative relapses at 5 and 8 months. ongoing remissions in 4 patients without relapse ranged from 2 to 11 months. the safety profile (n = 7) appears similar to that in patients without ds in the same trials (n = 90). grade (g) 3/4 cytokine release syndrome occurred in 43% (3/7) of patients with ds and in 44% without ds. rates of other g3/4 adverse events of special interest did not appear to favor a consistent trend between patients with/without ds (febrile neutropenia: 43% vs 36%; neurological events: 14% vs 11%; tumor lysis syndrome: 14% vs 2%). g3/4 infections were not observed in patients with ds (0% vs 23%). one patient died after infusion due to intracranial parenchymal hemorrhage on d15 associated with ongoing coagulopathy. time and extent of tisagenlecleucel expansion and long-term persistence were similar between groups. conclusion: this is the first analysis of car t-cell therapy in pediatric patients with r/r b-all and ds. these data suggest that toxicities appear similar to those in patients with b-all without ds, remission rates in ds-all are high, and longterm outcomes with sustained persistence appear promising. further exploration of tisagenlecleucel as an alternative to sct in children with r/r ds-all is warranted. sponsored by novartis. background: hispanic adolescence and young adults are twice as likely to develop acute lymphoblastic leukemia (all) with high risk features as non-hispanic whites. they also have poor prognosis and 39% higher death rate. b-all with crlf2 overexpression caused by genetic alteration of the cytokine receptor, crlf2 is five times more common in this subgroup. approximately 80% of crlf2 b-all cases also have ikzf1 genetic alterations. ikaros is involved in transcriptional regulation of several important genes involved in leukemogenesis. overexpressed casein kinase ii (ck2) impairs functions of ikaros. objectives: understand the molecular mechanisms that regulate crlf2 expression in crlf2 b-all. here we present evidence that ikaros-mediated repression of crlf2 transcription in b-all in hispanic children is regulated by ck2. design/method: primary b-all patient samples from hispanic children were used. ikaros retroviral transduction, ikaros shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: ikaros binding to promoter of crlf2 was confirmed using quantitative chip. functional experiments such as overexpression of ikaros in b-all primary cells results in transcriptional repression of crlf2 whereas ikaros silencing using shrna resulted in increased transcription. these results suggest that ikaros negatively regulates crlf2 expression. molecular inhibition of ck2 with shrna targeting the ck2 catalytic subunit, as well as pharmacological targeting of ck2 with cx4945 resulted in transcriptional repression of crlf2. ck2 inhibition was associated with increased ikaros dnabinding to the promoter of crlf2. however, the ability of cx4945 to repress crlf2 is lost or severely reduced, in cells with shrna silencing of ikaros, as compared to cells with intact ikaros. moreover, similar results were noted following treatment with cx4945 in leukemia cells obtained from high risk b-all patients with deletion of one ikzf1 allele. ikaros binds poorly to promoters of crlf2 gene in these cells. treatment with cx4945 restores ikaros dnabinding to the promoters of crlf2, which is associated with its strong repression. serial qchip analysis of the epigenetic signature at the crlf2 promoter showed that increased ikaros binding to the crlf2 promoter, following ck2 inhibition, is associated with enrichment for the h3k9me3 histone modification, which is a marker of repressive chromatin. results demonstrate that crlf2 expression is epigenetically regulated by the ck2-ikaros axis .cx4945 show antileukemic effect via restoration of ikaros tumor suppressor function, resulting in crlf2 repression suggesting advantage of using ck2 inhibitors as potential therapeutic approach in crlf2 altered b-all. results: hypodiploid all (modal chromosome number <44 and/or di <0.81) was identified in 131 patients (1.6% of all patients; 0.9% of nci standard risk (sr) and 2.9% of nci high risk (hr)), who were removed from frontline protocol therapy post-induction. overall 5-year efs and os were 52.1%±4.9% and 58.9%±4.8%. transplant status was retrospectively available for 113/131 (86%), 61 of whom underwent hsct in cr1. five-year efs with hsct was 57.4%±7.0% vs. 47.8%±7.5% without (p = 0.48). 5-year os with and without hsct was 66.2%±6.6% vs. 53.8%±7.6% (p = 0.34). when corrected for the median time to hsct (137 days), there were no significant differences in 5-year efs or os rates with and without hsct: 53.1%±7.3% and 64.2%±6.9% vs. 48.8%±7.8% and 53.8%±7.8%. no nci risk group or mrd subset benefitted significantly from cr1 hsct. sr patients (n = 42) had 5-year efs and os of 68.8±10.3% and 77.3%±9.2% with hsct (n = 27) vs. 57.1%±13.2% and 64.3%±12.8% without. hr patients (n = 71) had 5-year efs and os of 48.3%±9.0% and 57.6%±8.8% with hsct (n = 34) vs. 44.4%±9.2% and 49.9%±9.4% without. for those with end-induction mrd <0.01% (n = 74), 5-year efs and os were 66.3%±7.9% and 79.5%±6.7% with hsct (n = 39) vs. 60.3%±9.2% and 66.7%±8.8% without. end-induction mrd-positive patients (n = 30) fared poorly with both 5year efs and os of 29.4%±14.3% with hsct (n = 18) vs. 16.7%±10.8% and 22.2%±13.9% without. multivariate regression analysis including nci risk group, mrd, and cr1 hsct, showed only mrd negativity was significantly associated with efs (hr 0.256, p<0.0001) and os (hr 0.216, p<0.0001). patients with hypodiploid all fare poorly, particularly those with end-induction mrd ≥0.01%. while cr1 hsct is a standard treatment approach, it does not confer significant benefit. we were unable to assess bridging therapy prior to hsct, and comparator groups are small. taken together, however, new strategies are urgently needed for these patients. background: ras-pathway mutations are known to play a pivotal role in a significant proportion of myeloid malignancies, including upwards of 20% of pediatric aml cases. ras-pathway mutations in myeloid malignancy commonly co-occur with mutations of epigenetic regulators, suggesting cooperative leukemogenesis. among the epigenetic modifiers most frequently mutated in myeloid malignancy are regulators of dna methylation. this indicates that the alteration of dna methylation contributes to leukemogenesis. the ten-eleven translocation 2 (tet2) is an epigenetic regulator that plays an important role in regulation of dna methylation through its action of hydroxylation of 5-methylcytosine, which ultimately leads to passive de-methylation of dna cytosines. in myeloid malignancy, loss of function tet2 mutation is one of the most frequently co-occurring lesions in ras mutated malignancy. how specifically the altered methylation patterns in ras-pathway driven diseases promotes leukemogenesis is unclear. objectives: we hypothesize in mice with a ras-pathway mutation, that when an epigenetic modifier co-occurs, such as loss of function of tet2, this primes stem cells and/or early differentiating progenitors for transformation by preventing the repression of stem cell self-renewal genes, inhibiting differentiation, enhancing ras signaling and leading to leukemogenesis. we have generated a novel murine model with constitutive deletion of tet2 (tet2-/-) combined with an inducible activating krasg12d mutation (krasg12d/wt). mice have been tracked for evidence of hematologic malignancies and compared to mice with corresponding single genetic lesions. cooperative leukemogenesis will be demonstrated by decreased latency to disease onset, impact on malignancy lineage, in addition to investigating mechanistically through which pathways leukemogenesis may be promoted. results: krasg12d/wt/ tet2-/-mice demonstrate statistically significant differences in peripheral white blood cell count, hemoglobin, and platelet levels as early as 4-weeks post ras-pathway activation. peripheral cell lineage analysis demonstrates early skewing toward myeloid differentiation and marked splenomegaly in mice harboring both genetic lesions compared to wild type or mice with single genetic lesions. phospho-flow cytometric analysis reveals increased perk and ps6 activation in krasg12d/wt/ tet2-/-sca-1 enriched bone marrow cells compared to either genetic lesion alone. our study utilizing a murine model to examine how in ras-pathway mutations the addition of a co-occurring epigenetic lesion demonstrates that these lesions appear to cooperate to promote early myeloid differentiation with attendant changes in signaling pathways. this exploration to elucidate the mechanics of ras-pathway mediated disease lay the foundation for identification of patients who may benefit from existing therapies, such as dmtis, or identify new signaling targets for therapeutic exploration. background: the humoral immunogenicity of car19, a chimeric antigen receptor (car) with a murine scfv domain developed for treatment with tisagenlecleucel in relapsed/refractory (r/r) pediatric/young-adult acute lymphoblastic leukemia (all), was evaluated in 2 studies. little is known about the presence/impact of preexisting/treatmentinduced anti-murine car19 (mcar19) antibodies in patients treated with car therapy. objectives: patients from eliana (nct02435849; n = 68) and ensign (nct02228096; n = 29) were evaluated before and after tisagenlecleucel infusion to determine the impact of anti-mcar19 antibodies on cellular kinetics, efficacy, and safety. design/method: anti-mcar19 antibodies were determined by flow cytometry and reported as median fluorescence intensity. assay validation included evaluation of the interferences of intravenous immunoglobulin (ivig) treatment with the anti-mcar19 antibody assay. impact of preexisting and treatment-induced immunogenicity on cellular kinetics, efficacy, and safety was determined. treatment-induced immunogenicity was defined by a positive increase in anti-mcar19 antibody levels over baseline and was assessed by calculating the fold-change between preexisting (ie, baseline) and postinfusion levels. results: 90% of patients displayed preexisting anti-mcar19 antibodies; a similar incidence was detected in healthy volunteer samples during method validation. 35% of patients developed treatment-induced anti-mcar19 antibodies. no relationship was identified between tisagenlecleucel expansion (auc0-28d) and preexisting/treatment-induced anti-mcar19 antibodies (r2<0.001 and r2 = 0.006, respectively); similar results were seen for cmax. presence of treatment-induced anti-mcar19 antibodies did not appear to impact transgene persistence or response. kaplan-meier estimates showed that preexisting/treatment-induced anti-mcar19 antibodies did not appear to impact duration of response or event-free survival. strip plots showed consistent levels of preexisting/treatment-induced anti-mcar19 antibodies across patients with safety events, including cytokine release syndrome, neutropenia, thrombocytopenia, and neurological events. there was no apparent relationship between treatment-induced anti-mcar19 antibodies and b-cell recovery categories (≤3months, >3 and ≤6months, >6months, and ongoing sustained aplasia). no association existed between time of b-cell recovery and presence of treatment-induced anti-mcar19 antibodies. b-cell aplasia requiring ivig occurred following tisagenlecleucel in the majority of patients. the tisagenlecleucel concentration-time profiles in patients with treatment-induced anti-mcar19 antibodies were categorized by time following ivig administration. time of ivig administration had no impact on in vivo transgene expansion and persistence. we report the first comprehensive assessment of the impact of anti-mcar19 antibodies on clinical endpoints with car therapy. pediatric/young-adult patients with r/r all had a high frequency of baseline anti-mcar19 antibodies, and preexisting/treatment-induced anti-mcar19 antibodies did not impact the cellular kinetics, safety, and efficacy of tisagenlecleucel. cell-mediated immunity studies are ongoing. sponsored by novartis. background: adoptive immunotherapy, using cd123 engager (cd123-eng) t-cells, has shown success in preclinical studies, recognizing and killing acute myeloid leukemia (aml) blasts in vitro and in vivo. cd123-eng t-cells secrete bispecific molecules that recognize cd3 (t-cells) and cd123 (aml blasts), and are able to direct transduced t-cells and recruit bystander t-cells to kill cd123-positive blasts. however, cd123-engs do not provide costimulation and have not shown the capability for sequential killing of targets in vitro. we are seeking to improve the expansion, persistence and sequential killing capabilities of cd123-engs by genetically modifying these cells with an inducible costimulatory molecule, which can be activated by a chemical inducer of dimerization (cid). we generated a retroviral vector encoding cd123-eng and the inducible costimulatory molecule myd88.cd40 linked by a 2a sequence (cd123-eng.2a.imc). cd123-eng and cd123-eng.imc t-cells were generated by retroviral transduction, and their effector function was compared with and without cid. we used flow cytometric analysis to assess transduction efficiency, chromium release assays to evaluate cytolytic activity, and elisa to determine cytokine production. we successfully generated cd123-eng.imc tcells and achieved a mean initial transduction efficiency of 63% that was maintained above 50% throughout our study period. cd123-eng.imc t-cells +/-cid and cd123-eng t-cells readily killed cd123-positive aml blasts (molm13 and kg1a) in cytotoxicity assays when compared to the cd123-negative control (k562). in co-culture assays, cd123-eng.imc t-cells secreted increased il-2 and ifn-gamma in the presence of cid and cd123-positive targets (kg1a and molm13) when compared to co-culture with cd123-positive targets in the absence of cid. in addition, cd123-eng.imc t-cells displayed enhanced sequential killing capabilities and ifn-gamma secretion when stimulated weekly with cid and tumor cells at a 1:1 ratio when compared to cd123-eng t-cells. conclusion: cd123-eng.imc t-cells are able to recognize and kill cd123-positive aml blasts in an antigen dependent manner. cd123-eng.imc t-cells have improved effector function in the presence of cid as judged by cytokine production and their ability to sequentially kill cd123-positive target cells. thus, inducible myd88 and cd40 costimulation is a promising strategy to improve the effector function of cd123-eng t-cells, and warrants further active exploration in preclinical studies. background: eliana (nct02435849; n = 75) is a pivotal multicenter study testing the efficacy of tisagenlecleucel, anti-cd19 car-t, in children/young adults with r/r b-all. tocilizumab (toci) has been used for management of moderate/severe (grade 3/4) crs in ≈38% of patients treated with tisagenlecleucel at equivalent doses used in approved nononcological pediatric indications (<30kg received 12mg/kg; ≥30kg received 8mg/kg [800mg max dose]).(1) crs onset, as graded by the penn grading scale, generally occurred at a median of 3 days (range, 1-22) after infusion, requiring administration of 1-3 toci doses in some patients via a protocol-specific treatment algorithm. toci is a humanized monoclonal antibody that inhibits il-6 receptor (il-6r) signaling. the pharmacokinetics (pk) and pharmacodynamics (pd) of toci in pediatric patients with b-all with carassociated crs have not previously been described. objectives: characterize toci pk/pd for crs management following tisagenlecleucel infusion and describe its impact on cellular kinetics. design/method: toci pk and levels of soluble il-6r (sil-6r) were determined from serum and quantified using validated assays. maximum toci concentration (cmax) was derived using noncompartmental methods. sil-6r, proinflammatory cytokines, and crs resolution time were characterized to describe toci pd. summary statistics and graphical analyses of tisagenlecleucel exposure by number of doses were performed to describe the impact of toci on tisagenlecleucel kinetics in patients responding to tisagenlecleucel infusion. : 28/58 patients with crs received the first toci dose at a median of 5 days (range, 1-18) after crs onset. seventeen patients received 1 dose (range, 6.9-12 mg/kg); 8 received 2 doses (8-12 mg/kg); 3 received 3 doses (8-12 mg/kg), per the crs treatment algorithm. first-dose mean cmax (sd) was ≈111(30.6) g/ml; second dose, ≈265(376) g/ml. individual patient pd concentration-time profiles showed increased sil-6r levels after the first toci dose which remained elevated following the second dose. following toci administration, median time to crs resolution (including fever resolution) was 5 days (range, 2-29). crs onset coincided with tisagenlecleucel expansion, followed by a peak in serum cytokines, including il-6. the geometric mean auc0-28day and cmax of tisagenlecleucel transgene (by pcr) were 358% and 216% higher in tisagenlecleucel-responding toci-treated patients. conclusion: crs symptoms resolved within a median of 5 days after toci administration. toci levels achieved in patients with b-all were similar to reported pediatric nononcological indications (tocilizumab label) and resulted in concentration/time-dependent sil-6r increases. transgene continued to expand and persist following toci administration. these data support treatment with toci for crs management. (1) buechner, eha, 2017. sponsored by novartis. background: in acute myeloid leukemia (aml), mesenchymal stem and stromal cells (mscs) in the bone marrow microenvironment contribute to extrinsically mediated chemo-resistance and are therefore important potential therapeutic targets. the study of patient-derived mscs is at a competitive disadvantage, however, because traditional means of isolating mscs from a bone marrow aspirate interferes with isolating the more highly prioritized leukemic cells. many opportunities to study mscs are therefore missed. objectives: to develop a novel method of isolating mscs using the otherwise discarded portion of a bone marrow aspirate, thereby de-coupling the isolation of primary mscs from the isolation of leukemia cells. design/method: aml patient bone marrow aspirates were obtained prospectively from the children's oncology group. healthy patient marrow was purchased. experimental mscs were isolated from the bottom-most layer (rbc-layer) produced by density-gradient separation of a bone marrow aspirate, which is typically discarded. control mscs were isolated from the buffy coat (mnc layer). non-adherent cells were removed after 72 hours, and adherent cells were cultured at 5% co2 with mem-alpha containing 20% fbs. growth curves were obtained by seeding 6-well plates with 10,000 cells per well. cells were stained using oil red o to observe adipocyte differentiation. results: rbc-layer mscs grow successfully following overnight shipment of the aspirate. identical to mnc-layer mscs, rbc-layer mscs exhibit a fibroblastic morphology and are adherent to plastic. rbc-layer mscs persist in culture up to 14 passages before senescence. they exhibit a slower growth curve relative to mnc-layer mscs, but their overall doubling time is similar at approximately 120 hours. surprisingly, mscs from the rbc-layer exhibit adipocyte differentiation on stimulation, revealing their stem-cell like qualities. we present a method of isolating mscs from the discarded portion of a bone marrow aspirate that does not interfere with the isolation of leukemia cells from the same patient. this portion of the aspirate can be shipped, or can sit for at least 24 hours, without sacrificing its mscs. rbclayer mscs are nearly identical to mscs obtained conventionally. perhaps most importantly, rbc-layer mscs retain a stem-cell like capacity, showing them to be a highly valuable cell population in aml research. future plans include investigating potential selective enrichment of stem-cell mscs in the rbc-layer, which could explain the unexpected difference in growth kinetics. aml researchers now have the opportunity to study this exciting component of the bone marrow microenvironment without sacrificing valuable leukemic cells in the process. background: neutropenia is one of the most frequent side effect of chemotherapy associated with an increase in the risk of infection, especially in the cases when the depth and duration of neutropenia are extended. some genes, as variations of darc, gsdma and cxcl2 are known to influence white blood cell and neutrophil counts. our previous study conducted in children with acute lymphoblastic leukemia (all), showed that polymorphisms in these genes might play a role in the onset of chemotherapy complications during consolidation and maintenance treatment. objectives: in order to support our previous finding, we have expanded the study to the induction period in a cohort of 233 all children treated at the sainte-justine university health center between july 1995 and july 2005. design/method: previous associated single nucleotide polymorphisms (snps) in darc, gsdma and cxcl2 genes were analyzed for an association with the complications occurring during induction including the duration of low neutrophil count (pnn) and low absolute phagocyte count (apc), proven infections and delay between induction and consolidation phases. results: significant effect was found for all studied polymorphims. minor alleles of darc rs3027012, cxcl2 rs1680408 and gsdma rs3859192 were all associated with higher risk of complications during induction treatment, whereas that of darc rs12075 (particularly gg genotype) had a protective effect. the gg genotype of rs12075 was associated with a lower risk of post-induction delay (p = 0.02 or = 0.1, 95%ci 0.02-1.0), less frequent febrile episodes (p = 0.02) and lower number of days with apc/pnn count reduction (p = 0.008 for apc<0.5 and p = 0.02 for pnn<0.5). in contrast, the minor t allele of another darc polymorphism (rs 3027012), was associated with longer apc/pnn count reduction (p = 0.01 for apc<0.5 and p = 0.02 for pnn <0.5), as it was the tt genotype of gsdma rs3859192 (p = 0.02 for apc<0.5 and p = 0.04 for pnn<0.5). the patients with the gsdma rs3859192 had also a higher risk of documented febrile episodes (p = 0.04 or = 2.4 95%ci 1-5.5). the aa genotype of rs1680408 cxcl2 was associated with a higher risk of post-induction delay due to infection (p = 0.04, or = 3.4, 95% ci 1.1-11.5). conclusion: this complementary study confirmed our previous results, showing overall that variations in darc, gsdma and cxcl2 genes influence the onset of chemotherapy complications in pediatric all, regardless of treatment phases. these polymorphisms might be useful pharmacogenetics markers possibly guiding an adjustment of chemotherapy intensity. background: pediatric acute myeloid leukemia (aml) has a poor survival rate of about 70% and there is an urgent need for newer targeted therapies. car t-cell based therapies are effective against all but similar therapies against aml are still under development. recent clinical trials have highlighted the concerns about toxicity and therapy related deaths from car t-cells. antigen selection is the key factor determining the specificity, efficacy and toxicity of car t-cells. while contemporary adoptive t-cell therapies use monoclonal antibodies against tumor associated antigens we employed the naturally occurring flt3 ligand (fl) to target aml cells expressing flt3 receptors. flt3 receptor is expressed on multipotent and myelomonocytic progenitors as well as myeloid leukemia cells. to generate fl containing chimeric tlymphocytes designated flcar t-cells and to evaluate their efficacy against aml cells. design/method: flcar was constructed by fusing the coding sequences of the human fl, cd28 costimulatory domain, and cd3-zeta chain (intracellular region) in series. it was then cloned into the phiv-egfp lentiviral vector for expression in cell lines and primary t cells obtained from healthy donors. the empty phiv-egfp vector was used as a negative control. flcar was expressed on both cd4+ and cd8+ t-lymphocytes, confirmed by western blot. cell cytoxicity was evaluated by co-culturing flcar t-cells and aml cells followed by flow cytometric analyses. cytokine production was assessed by analyzing expression of interleukin-2 using quantitative rt-pcr. results: flcar t-cells were generated from cd4+ jurkat and cd8+ tk-1 cell lines with up to 70% lentiviral transduction efficiency. the efficiency for primary t cells was lower (5-10%). flcar was expressed as a ∼42 kda protein in cells and was partially phosphorylated on tyrosine. the expression of flcar on lymphocytes lead to increased basal il-2 expression in the cells. this was further augmented (by > 5 folds) upon co-incubating flcar t-cells with flt3expressing target cells. jurkat cells, tk-1 cells and primary human t cells expressing flcar suppressed the growth of flt3-expressing aml cell lines and primary aml cells in vitro. notably, flcar t-cells generated from healthy donors caused strong inhibition of aml cells even at a lower transduction efficiency. in vivo experiments using nsg-sgm mice xenografted with human aml cells are underway. our data demonstrate that flcar can be effectively expressed on t-lymphocytes and mediate potent cytotoxicity against flt3-expressing aml cells in vitro. being a completely human derived chimeric protein, it represents a promising candidate for further therapeutic development. holly pacenta, kelly sullivan, ahwan pandey, kelly maloney, joaquin espinosa children's hospital colorado, denver, colorado, united states background: individuals with down syndrome (ds) have a 20-fold higher risk of developing acute lymphoblastic leukemia (all) than the typical population. there are several important differences between all in individuals with ds (ds-all) and all in individuals without ds (nds-all): first, patients with ds-all have a lower percentage of favorable cytogenetic features compared to nds-all. second, patients with ds-all are more likely to have activating mutations in jak2, crlf2 overexpression, and ikzf1 deletions. despite these clear genotypic differences, this knowledge has not yet been exploited for therapeutic purposes in ds-all. when outcomes for ds-all are compared to nds-all with similar cytogenetic features, the survival rates are similar. however, individuals with ds-all have an increased risk of treatment-related mortality (trm). current therapy for ds-all is similar to that for nds-all, with the exception of small changes to decrease toxicities that are more prevalent in ds-all. it was recently identified that interferon signaling is constitutively activated in healthy individuals with t21. we hypothesize that aberrant interferon signaling could play a role in the unique leukemias observed in ds patients. objectives: to identify differences in gene expression and intracellular signaling cascades that are unique to individuals with ds-all, relative to both nds-all and healthy individuals with ds that can be exploited for therapeutic use. design/method: bone marrow samples were obtained from ds-all patients and matched nds-all patients based on clinical characteristics and genetic features. rna sequencing of these samples was performed and a total of 19 samples were used for the transcriptome analysis (6 ds-all vs. 13 nds-all). the differential expression data was generated by deseq2 and analyzed using ingenuity pathway analysis. the analysis revealed that the chromosome 21 genes that have been implicated in leukemogenesis are not differentially expressed in the ds-all samples, relative to nds-all. an inflammatory signature was identified, which included interferon gamma as an upstream regulator with predicted activation in ds-all. this finding is consistent with prior observations from healthy individuals with ds. other examples of results with potentially actionable targets include the upregulation of several genes in the ras pathway and genes involved in histone methylation. the increased interferon signaling seen in healthy individuals with ds was also identified in ds-all. this may contribute to the development of mutations in inflammatory pathways such as jak2 and crlf2 in ds-all. targeting these common pathways with small molecule inhibitors may have a therapeutic benefit in ds-all. cincinnati children's hospital medical center, cincinnati, ohio, united states background: next-generation sequencing (ngs) guides precision medicine approaches in oncology using therapies targeting molecular alterations found within an individual cancer. increased availability of ngs coupled with a proliferation of targeted drugs in development heightens the need for reliable pre-clinical animal models. here we report a patientderived xenograft (pdx) system with integrated molecular profiling for pre-clinical testing of conventional cytotoxic and novel targeted agents. objectives: to utilize ngs from patients with pediatric leukemia to guide rational pre-clinical trials in pdx leukemia avatars, and to determine pdx mice tolerance of and response to cytotoxic and targeted therapies. pediatric acute lymphoblastic leukemia (all) samples were obtained in adherence to an irb-approved protocol and xenografted into nod/rag/interleukin-2 (il-2)rg (nrg) mice. ngs was performed clinically using the foundationone® heme panel. a de novo all sample bearing mutations involving jak2, crlf2, ntrk3, cdkn2a/b, ptpn11 and wt1 was used for pre-clinical testing. thirty-seven nrg mice were transplanted with 2 million patient cells/mouse via iv injection. standard 4-drug induction chemotherapy was administered consisting of vincristine, dexamethasone, pegaspargase, and daunorubicin [vxpd, n = 6 mice], in comparison to vehicle control [n = 8]. parallel pdx cohorts were treated with single agent targeted therapies based on ngs findings, including ruxolitinib [n = 7], crizotinib [n = 8] and loxo-101 [n = 8]. the four-week treatment period began on day +30 from transplant after confirmation of engraftment. following completion of therapy, residual disease burden was analyzed by flow cytometry (hcd19+, mcd45-cells) in the bone marrow [bm] . to date, pdx models have been established using over thirty ngs-profiled pediatric all samples, including six samples bearing philadelphia (ph) chromosome or phlike mutations. pre-clinical testing was performed in a repreconclusion: ngs reveals concomitant mutations in ph-like all that may represent additional targets for therapy, or predict tyrosine kinase inhibitor (tki) resistance. we show that all xenograft nrg mice can tolerate a 4-week multi-agent cytotoxic chemotherapy induction regimen, as well as rational targeted agents, and serve as a robust pre-clinical model for precision medicine trials. background: osteonecrosis is a well-characterized all therapeutic toxicity attributed to glucocorticoids, asparaginase, and methotrexate that disproportionately affects adolescents. in ccg-1961, alternate-week dexamethasone during double delayed intensification (di) reduced osteonecrosis vs continuous dexamethasone with single di in rapid early responders (rer) ≥10y. to compare efs and os between hr-all patients with vs without osteonecrosis. design/method: hr-all patients 1-30y on aall0232 (2004-11) received cog augmented therapy with a 2 × 2 randomization to: (1) induction dexamethasone (10 mg/m2 d1-14) vs prednisone (60 mg/m2 d1-28), and (2) interim maintenance (im) high-dose methotrexate (hdm) vs escalating-dose methotrexate/pegaspargase (ema). rer received single, and slow early responders (ser) double, im/di. initially, all received monthly dexamethasone maintenance pulses, patients ≥13y received di alternate-week dexamethasone, and patients ≤12y received di continuous s217 of s301 dexamethasone. there were 2 osteonecrosis-related amendments: after 10/2006 all patients ≥10y received di alternateweek dexamethasone; after 6/2008 all patients ≥10y were assigned to induction prednisone, and all patients received di alternate-week dexamethasone and maintenance prednisone pulses. results: osteonecrosis was confirmed in 315/2817 patients. the 5y cumulative incidence (ci) was 12.7% overall and increased with age: 1-9y 2.6%, 10-12y 15.3% (alternateweek dexamethasone 10.2% vs continuous dexamethasone 23.5%; p<0.0001), ≥13y 19.7% (p<0.0001). among randomized rer patients ≥10y, ci differed by glucocorticoid (dexamethasone 25.0% vs prednisone 15.0%; p = 0.0003) but not methotrexate assignment (hdm 18.8% vs ema 21.5%; p = 0.7). among randomized ser patients ≥10y, ci was 18.9% with no difference by regimen. results were similar for patients ≥13y. in the entire study population, patients with osteonecrosis had superior 5y efs (89.0% vs 76.1%; p<0.0001) and os (95.8% vs 85.9%; p<0.0001) than those without osteonecrosis. 5y efs was significantly higher among randomized patients ≥10y with vs without osteonecrosis (88.5% vs 72.9%; p<0.0001); this finding was present in different age ranges (≥10y, ≥13y, ≥16y) and rer/ser subsets within each, especially in the ≥10y rer (92.6% vs 81.8%; p = 0.0004) and ser (74.0% vs 43.7%; p<0.0001) cohorts. across groups, asparaginase allergy was significantly associated with reduced osteonecrosis risk (≥10y: hr 0.43; p = 0.0013). patients who develop osteonecrosis have significantly increased efs and os, suggesting host differences that increase sensitivity to develop osteonecrosis and render all cells more chemo-responsive. pennsylvania state university, hershey, pennsylvania, united states background: cdc42 (cell division cycle protein 42) belongs to rho family of small gtpases in ras-oncogene superfamily. pro-oncogenic role of overexpressed cdc42 in ras driven solid tumors are well known. however, role of cdc42 in leukemia is yet to be established. ikzf1 encodes ikaros protein which has important role in regulation of lymphoid development and tumor suppression in leukemia. casein kinase ii (ck2) oncogene is overexpressed in leukemia. ck2 impairs ikaros function which can be restored by using ck2 inhibitors. objectives: to investigate role of cdc42 in leukemia and regulation of cdc42 by ikaros and ck2 in b-cell acute lymphoblastic leukemia (b-all). shrna transfection, real time-pcr, luciferace assay, quantitative chromatin immunoprecipitation (qchip) coupled with the next-generation sequencing (chip-seq), cytotoxicity assay and western blot. results: cdc42 is identified as one of the ikaros target genes by analysis of genome-wide dna binding of ikaros using chip-seq and qchip in b-all primary cells. expression of cdc42 was also noted to be higher in all patient samples compared to normal bone marrow. functional experiments showed that ikaros overexpression via retroviral transduction results in transcriptional repression of cdc42. ikaros silencing using shrna resulted in increased expression of cdc42. these data suggest that ikaros negatively regulates transcription and expression of cdc42. ck2 directly phosphorylates ikaros and impairs its function as transcription factor. we noted that molecular inhibition of ck2 via sirna as well as treatment with specific ck2 inhibitor, cx4945 also decreases expression of cdc42. treatment with cx4945 of primary b-all with ikaros haploinsufficiency restores ikaros binding to cdc42 promoter and represses cdc42 expression. however, this effect is evident only in presence of ikaros. treatment with cx4945 in ikaros silenced (ikaros shrna) cells showed no change in expression of cdc42. these results emphasizes the importance of ikaros in regulating cdc42 expression. furthermore, we analyzed the changes in epigenetic signature at the cdc42 promoter following treatment with cx4945. results show that loss of histone marker of open chromatin (h3k9ac) and increased histone marker for repressive chromatin (h3k27me3), at the cdc42 promoter. these data suggest that ikaros transcriptionally represses cdc42 via chromatin remodeling. a specific cdc42 inhibitor, ml141 showed cytotoxic effects on primary b-all cells. conclusion: cdc42 may have important role in hematologic malignancies. expression of cdc42 in b cell all is regulated by ikaros and ck2. these results suggest that targeting cdc42 could be a potential therapeutic strategy in leukemia. caitlyn duffy, laura hall, justin godown, koyama tatsuki, scott borinstein monroe carell jr. children's hospital at vanderbilt, nashville, tennessee, united states background: systemic corticosteroids are widely used as treatment of acute lymphoblastic leukemia (all) and lymphoblastic lymphoma. there are anecdotal reports of bradycardia in pediatric patients receiving corticosteroids, but a more extensive analysis of this effect is needed. objectives: the aim of this study was to describe the incidence, severity, and timing of steroid-induced bradycardia and document any adverse events associated with bradycardia. design/method: we performed a retrospective review of all newly diagnosed patients at our center (2010-2016) with all/lymphoblastic lymphoma who received corticosteroids (dexamethasone 3-5mg/m 2 /dose or prednisone 30mg/m 2 /dose) during induction chemotherapy. patients were excluded if they had a pre-existing cardiac abnormality or if they received prior corticosteroids. the average 24 hour heart rate (hr) was assessed for the period prior to initiating steroid therapy and for the 24 hour period surrounding the nadir following steroid administration. the degree and time of steroid induced bradycardia was assessed. adverse patient events and concomitant medication use was documented to identify other contributing factors to bradycardia. a total of 153 children (80 females, 73 males, 16 months-27 years) were included in the analysis with 159 demonstrating a decrease in mean hr following steroid administration. median hr decrease was 22.9 beats per minute (quartiles 12.5-32) from prior to initiating steroids to surrounding nadir. sixty one percent developed bradycardia less than or equal to the 1st percentile for their age range. nadir occurred 7 doses (range 5-10) into treatment, which corresponded to 79 hours (55-109) after initiation of therapy. of 94 patients who experienced bradycardia, 78% were associated with dexamethasone rather than prednisone. hr nadir was not associated with other vital sign abnormalities. after completion of induction chemotherapy, 87% of patients had documented resolution of bradycardia with hr greater than the 5th percentile for age. it was observed that the children who continued to have relatively low hr were often younger (20 months-5 years old). examination of nadir hr during subsequent hospitalizations in which steroids were not being administered (excluding hr during procedural sedation) did not demonstrate a significant incidence of bradycardia. concomitant opioid, beta-blocker, or other medication exposure did not contribute to the incidence of bradycardia. corticosteroid-induced bradycardia is extremely common in children, teenagers, and young adults with all receiving induction chemotherapy. bradycardia was not associated with clinical adverse events and resolved after completion of corticosteroid treatment. therefore, further cardiac assessment may not be warranted in the presence of bradycardia suspected to be secondary to steroid administration. baylor college of medicine, houston, texas, united states background: survival in newly diagnosed pediatric acute myeloid leukemia (aml) is approximately 65%; however survival falls dramatically if a patient relapses. currently, approximately one-third of patients with pediatric aml relapse on standard chemotherapy regimens. aml cells are exposed to proteotoxic stress at baseline due to their rapid and inefficient metabolism; proteotoxic stress increases after chemotherapy due to accumulation of reactive oxygen species resulting in misfolded proteins. this leads to activation of cell stress pathways, such as the unfolded protein response (upr) in the endoplasmic reticulum. because an activated upr can make cells more sensitive to proteotoxic stress, we hypothesize that upr activation correlates with response to chemotherapy. objectives: determine the status of upr in pediatric aml and its correlation with chemosensitivity; design/method: peripheral blood samples from pediatric patients with aml were collected at the start of induction chemotherapy, 6-10 hours (h) and 24 h post initiation of systemic chemotherapy. tumor cells were sorted from peripheral blood mononuclear cells. expression of upr proteins was determined by chemiluminescence using an automated capillary electrophoresis system. clinical correlations were performed using an annotated database. we measured five upr proteins: grp78 (glucose regulated protein 78kda), phospho-eif2 , inositol-requiring enzyme 1 (ire1) and activating transcription factor (atf6). patients with aml had 2-5 times higher expression of upr proteins (except atf6) at baseline than normal controls. grp78-the key upr driver-had the highest level of protein expression in myeloid blasts. there was a wide variability in the level of baseline upr expression. eight out of 38 samples expressed >5 fold increase in grp78 above those with the lowest grp78 levels. similarly, 7 and 9 patients respectively, had a >5 fold increase in peif2 and ire1, compared to patients with low basal expression of these upr proteins. in our limited sample set, there was a trend towards lower overall survival (os) and event-free survival in patients with low baseline grp78 and ire1. conclusion: upr has a variable expression at baseline in pediatric aml, with a trend towards lower os in patients with a low basal grp78 and low ire1 expression, suggesting less chemosensitivity in this subgroup. conversely, it is possible that blasts with an upregulated upr prior to chemotherapy manage proteotoxic stress less effectively, having faster apoptosis and hence a better response to chemotherapy in patients with a high basal upr. we are currently expanding our findings in a larger cohort of patients enrolled in the children's oncology group aaml1031 protocol. background: children with newly diagnosed acute lymphoblastic leukemia (all) undergo chest x-ray (cxr) evaluation during initial diagnostic workup to ensure safe airway management. however, to our knowledge, no systematic assessment of cxr findings has been reported. objectives: to evaluate cxr findings at diagnosis of all and their associations with clinical characteristics. we reviewed the cxr findings at diagnosis of all in patients treated on the total xv and xvi protocols at st. jude children's research hospital. findings were evaluated for associations with clinical characteristics at presentation, and the clinical management of mediastinal masses was reviewed. mediastinal masses were seen in 107 (10.8%) of 990 patients evaluated and were more common in older patients (mean age, 8.51 years) than in younger patients (mean age, 7.14 years) (p = 0.005), in males than in females (p = 0.017), and in patients with t-all than in those with b-all (p<0.001). also associated with mediastinal masses were a higher white blood cell count (wbc) at diagnosis (mean, 107.02 × 109/l) (vs. a lower wbc; mean, 36.65 × 109/l) (p<0.001), cns involvement (vs. no involvement) (p = 0.028), and standard/high-risk disease (vs. low-risk disease) (p<0.001). other cxr findings included pulmonary opacity (160 patients [16.2%]), bronchial/perihilar thickening (187 patients [18.9%]), cardiomegaly (68 patients [6.9%]), and osteopenia/fracture/periosteal lesions (132 patients [13.3%]). pulmonary opacity was more common in younger patients (mean age, 6.51 years) than in older patients (mean age, 7.44 years) (p = 0.023) and in those with t-all (vs. b-all) (p = 0.010). bronchial/perihilar thickening, cardiomegaly, and osteopenia/fracture/periosteal lesions were also more common in younger patients than in older ones (p<0.001, p = 0.002, and p<0.001, respectively) and in those with low-risk disease (versus standard/high-risk disease) (p<0.001, p = 0.001, and p = 0.005, respectively). of the 107 patients with a mediastinal mass on cxr, 56 underwent a confirmatory chest ct scan, and 48 (85.7%) were confirmed to have a mediastinal mass. notably, 23 patients (41.1%) had airway compression, and compression of venous structures was identified in 18 of 48 patients (37.5%) who received iv contrast. the clinical course was evaluated for 107 patients with mediastinal masses detected by cxr. fifty patients (46.7%) required icu admission (mean stay, 3.0 days). general anesthesia was used for only 52 patients (48.6%), and 68 patients (63.6%) had a less invasive peripherally inserted central catheter. no deaths occurred in the acute phase. conclusion: cxr at the time of all diagnosis can detect various intrathoracic lesions and is helpful in planning initial diagnostic workup and management. background: mertk is a receptor tyrosine kinase that is aberrantly expressed in 80% of pediatric primary aml samples. mertk inhibition with the small molecule tyrosine kinase inhibitor (tki) mrx-2843 decreases tumor burden and prolongs survival in aml xenografts. while treatment with mrx-2843 reduces leukemia in the peripheral blood, it is less effective in the bone marrow, suggesting a role for the marrow microenvironment in therapeutic resistance. the jak/stat pathway has been implicated as a mediator of bone marrow derived resistance to tkis and inhibitors of this pathway are in clinical development for the treatment of aml. to determine the role of the bone marrow stromal niche in mediating resistance to mertk inhibition and to evaluate the efficacy of combined mertk and jak/stat inhibition. design/method: aml cell lines were cultured with or without the hs27 stromal cell line or hs27 conditioned medium, then treated with mrx-2843 +/-the jak/stat inhibitor ruxolitinib, or control. induction of apoptosis and cell cycle arrest in aml cells was measured by flow cytometry. expression of h2ax and total and phosphorylated stat5 were determined by immunoblot. results: co-culture with stromal cells significantly reduced aml cell death and g2/m phase arrest in response to treatment with 200nm mrx-2843 compared to no co-culture (cell death: 31.9% versus 61.2%, p<0.05; g2/m arrest: 8.9% versus 14.8%, p<0.01). g2/m arrest was accompanied by an increase in h2ax expression which was similarly abrogated in co-culture. conditioned medium did not provide protection from mrx-2843 induced apoptosis, g2/m arrest, or h2ax induction. mrx-2843 inhibited stat5 phosphorylation but direct co-culture and conditioned medium potently increased basal stat5 phosphorylation which was not inhibited by mrx-2843. to determine whether the observed induction of stat5 phosphorylation was functionally relevant, cocultures were treated with both mrx-2843 and ruxolitinib. while ruxolitinib potently inhibited the phosphorylation of stat5 in the presence of co-culture, combination treatment did not overcome stromal mediated protection from mrx-2843 induced apoptosis. similarly, the addition of exogenous gm-csf induced stat5 phosphorylation but did not yield protection from mrx-2843 functional effects in the absence of co-culture. together these data support a model whereby direct cell-cell contact with stromal cells in the bone marrow niche protects leukemia cells from mrx-2843 induced apoptosis, cell cycle alterations, and dna damage. while co-culture potently induces phosphorylation of stat5 in leukemia cells, this is neither necessary nor sufficient for stromal-cell mediated protection from mertk inhibition and combined treatment with jak/stat inhibitors is unlikely to be therapeutically efficacious. background: mercaptopurine (6-mp) is an immunosuppressive thiopurine drug that is a key component of acute lymphoblastic leukemia (all) treatment. 6-mp is metabolized into 6-thioguanine (6-tgn), which is responsible for anti-leukemic effects, as well as 6-methylmercaptopurine nucleotides (6-mmpn/6-mmp), which are associated with hepatotoxicity. some patients preferentially metabolize 6-mp to 6-mmpn/6-mmp, increasing their risk for hepatotoxicity and potentially reducing anti-leukemic effects. hepatotoxicity can cause interruptions or delays in therapy that may jeopardize cure rates. allopurinol has been increasingly used in patients with inflammatory bowel disease (ibd) to shunt 6-mp metabolism toward 6-tgn and away from 6-mmpn to minimize hepatotoxicity and preserve therapeutic effects. objectives: this retrospective chart review expands upon our previously published case series of three patients with all in whom allopurinol was successfully used to redirect 6-mp metabolism. twelve additional patients have subsequently received allopurinol and 6-mp combination therapy at texas children's hospital. data from this larger patient sample, with longer follow up, is being analyzed to increase knowledge of the effectiveness and longitudinal effects of adding allopurinol to 6-mp to reduce risk of hepatotoxicity. design/method: data were abstracted from the electronic medical records of 15 patients with all treated at texas children's hospital from 2012 to present, who had been found to have evidence of altered 6-mp metabolism and in whom allopurinol was added to 6-mp therapy due to concern for risk or recurrence of hepatotoxicity. metabolite levels, 6-mp dose, and alanine transaminase (alt) prior to initiation of allopurinol and approximately 8 weeks later were compared. wilcoxon signed-rank test was applied for statistical analysis. : after the addition of allopurinol, patients experienced a significant decrease in mean levels of 6-mmpn (p = 0.0007), correlating with a significant decrease in mean alt (p = 0.004). with the initiation of allopurinol, the mean 6-mp dose was decreased from 84 to 32 mg/m2/day over an 8-week period. mean 6-tgn levels increased (p = 0.14). in follow up beyond 8 weeks, no patients had further holds in 6-mp due to hepatotoxicity. addition of allopurinol appears to shift metabolism from 6-mmpn toward 6-tgn, with increases in mean 6-tgn levels despite a decrease in mean 6-mp dose. this may limit negative side effects, thus resulting in fewer gaps in therapy and possible improved outcomes. further analysis of 6-mp dose titration and effects on anc over time as well as effects on overall survival is ongoing. prospective background: alterations in epigenetic patterning are a fundamental feature in acute myeloid leukemia (aml). treatment with dna methyltransferase inhibitors (dnmti) yields responses in aml, but the molecular mechanisms underlying this effect are poorly understood. in prior work, we demonstrated induction of genes involved in the pirna rna (piwi) silencing pathway as a common gene feature of 4 aml cell lines treated with decitabine. the piwi pathway is an rna silencing system, distinct from classical small rna transcriptional silencing, responsible for transposon-silencing in gametogenesis; emerging data suggest a role for this system in somatic cells. based on these data, we postulate that piwi induction plays a crucial role in aml recovery following demethylation and that disruption of this pathway would modulate response and/or recovery from decitabine treatment. to assess the effect contribution of the pirna pathway response following dnmti treatment in aml. design/method: to choose target genes in the pirna pathway for disruption, molm13 cells were first treated with escalating doses of decitabine. using quantitative rt-pcr, the dose-dependent expression of several pirna-associated genes were analyzed. two genes, mael and piwil2, were selected for disruption experiments based on preliminary data suggesting decitabine dose-dependent responses. molm13 cells were transduced with shrna targeting these genes using a lentivirus delivery system with selection in puromycin. knockdown efficiency was assessed by rt-qpcr. to determine how gene disruption affected cell growth, knockdown cells were treated with decitabine 20nm. proliferation was assessed by celltiter glo assay following decitabine treatment. clonogenic potential was assessed by colony forming assays of transduced cells after treatment with decitabine at 5nm and 10nm. results: following decitabine exposure in molm13, there was a markedly increased expression of mael and piwil2 compared to untreated cells (2363:1 and 41:1, respectively) . thus, these were the candidate genes chosen for disruption. of 4 mael shrna constructs, two resulted in a 25% relative expression of mael compared to controls. of the 3 piwil2 shrna constructs, the best knockdown showed 75% relative expression. there were no significant differences in proliferation or clonogenicity of stably selected mael or piwil2 knock-down molm13 cells following decitabine treatment. using gene knockdown procedures, mael and piwl2 do not appear to have a marked effect on growth and response to decitabine treatment in molm13. however, these results may be limited by inefficient knockdown using shrna targeting methods. further work using a cas9/crispr based inactivation of these genes is ongoing. children cancer hospital cairo, egypt background: hypodiploidy <44 chromosomes is very uncommon and have particularly poor outcomes in childhood acute lymphoblastic leukemia (all). it is subdivided into: near-haploid (24-31chromosomes), lowhypodiploid (32-39chromosomes) and high-hypodiploid (40-43chromosomes). to determine if minimal residual disease (mrd) can identify a group of patients with better prognosis in the hypodploid population who can be treated with intensive chemotherapy alone. design/method: a retrospective study that included all patients under age of 18 diagnosed as hypodiploid b-precursor all during the period between january 2008-december 2015 and treated at children's cancer hospital egypt on sjcrh total study-xv for ir/hr all. sixteen patients had <44 chromosomes (9 nearhaploid and 7 low-hypodiploid), constituting 1% of all pediatric patients with b-precursor all during the study period. patients with near-haploid all had a median age of 6 years (range 2-17), initial leukocyte count (wbc) median of 7.5 × 109/l (range 1.3-86.6), 4 (44.4%) were males and 5/9 (55.6%) had hr-nci criteria. four patients (44.4%) are alive in complete remission(cr) (range 25-48 months, median 30), one died in induction and 4 (44.4%) had hematological relapse (range 6.8-33 months, median 15). patients with low-hypodiploid all had significantly older age (median 15 years, range 13-17), median wbc 4.3 × 109/l (range 3.5-13.5), 5/7 (71.4%) were males. one patient (14.3%) is alive in cr, one died in induction, one failed to achieve cr post-induction and 4 patients(57%) had hematological relapse (range 3.9-5.6 months, median 4.8). mrd<0.01% by flow-cytometry on day-15 and end of induction was achieved in 5/9 (55.6%) and 6/8 patients(75%) with near-haploid, compared with 1/6 (16.7%) and 3/6 patients(50%) with low-hypodiploid; respectively (p = 0.287, p = 0.58;respectively). allogeneic transplantation was performed during initial remission only in 2 mrd negative patients (one relapsed and one is in cr) and in the patient with induction failure (relapsed post-transplant). five of the total six patients who had negative mrd on day-15 and end of induction are alive in cr (4/5 with chemotherapy alone). all 3 patients with negative mrd at end of induction but with mrd levels≥0.01% on day-15 (range 0.02-0.33%) relapsed as well as all 4 patients with detectable mrd at the end of induction. the difference in relapse was statistically significant in relation to negative-mrd on day-15 (p = 0.005), but not at end of induction(p = 0.105). conclusion: children with hypodiploid all and negative mrd on day-15 of induction are highly curable with intensive chemotherapy alone, while patients with negative mrd at the end of induction and detectable mrd on day-15 had dismal outcome. background: overall survival in pediatric acute myeloid leukemia (aml) has plateaued between 60-70%, with death during induction chemotherapy seen in 4-11% of patients. respiratory complications contribute to morbidity and mortality in pediatric aml induction, however the incidence, patterns, and predictors of respiratory adverse events (aes) during this period are unknown. to estimate the incidence of respiratory aes during induction therapy for de novo pediatric aml, to characterize and grade these respiratory aes, and to identify predictors of respiratory ae development. we conducted a retrospective longitudinal study from presentation to day 42 in institutional de novo pediatric aml patients (≤ 21 years) between march 2009 and december 2016. outcomes included any nci ctcae grade 2-5 respiratory ae or death from another cause. demographic, disease, and treatment-related data were abstracted. the most specific, best-fitting ctcae category and grade for each ae was determined. descriptive statistics, survival analysis, multivariable logistic regression analysis, and time-toevent distributions were performed (sas v9.4, cary, nc) . among 113 eligible patients, 54.0% (n = 61) experienced 69 discrete respiratory aes. incidence of grade 3-5 aes was 46.0% (n = 52). a bimodal time-to-event distribution demonstrated peaks at treatment days 0 and 14. induction death occurred in 4.4% (n = 5) including 3 deaths from respiratory failure associated with disseminated fungal disease. in univariate analysis, those experiencing aes differed significantly in regards to older age at diagnosis (p<0.0001), higher initial wbc (p = 0.012), higher initial peripheral blast percentage (p = 0.002), coagulopathy at diagnosis (pt (p = 0.004), d-dimer (p = 0.002)), fluid overload status (p<0.0001), occurrence of infection (p = 0.01), and occurrence of tumor lysis syndrome (tls) (p = 0.016). patients with hyperleukocytosis (p = 0.005), fluid overload (p<0.0001), and fab m3 morphology (p = 0.0016) each had a significantly decreased probability of completing the follow up period without experiencing a respiratory ae. on multivariable analysis, fluid overload (aor 45.2 [95% ci: 5.4-376.0) and older age (aor 1.10 [95% ci: 1.01-1.20) were significantly associated with ae occurrence when gender, hyperleukocytosis, tls, and infection status were held constant. we describe a high incidence of respiratory aes during pediatric aml induction. fluid overload and older age at diagnosis are independently associated with ae development when controlling for other proposed risk factors. interventions focused on conservative fluid management and offset of fluid overload should be explored in newly diagnosed pediatric aml in an effort to reduce respiratory complications during induction. overall, all survival rates are outstanding and have continued to improve with risk-adapted therapy. the most striking improvement occurred in t-all where 5-year os rates now exceed 90% and parallel b-all. survival improvements, however, have not been observed uniformly across all subgroups. while the gap in outcome differences narrowed among blacks, outcomes for hispanics have remained static. further, no improvements in survival were observed in infants or ayas and new treatment approaches have been implemented for these populations. background: acute myeloid leukemia (aml) accounts for approximately 18% of new childhood leukemia cases. chest x-ray (cxr) is performed in all newly diagnosed aml cases to evaluate the safety of airway management for anesthesia during diagnostic procedures; however, cxr results in pediatric patients with aml have not been described. objectives: the primary objective was to evaluate cxr findings at diagnosis in patients with aml. the secondary objectives included assessing associations between cxr findings and clinical characteristics, with the overall goal of aiding in the evaluation of the use of cxrs as an initial diagnostic study in pediatric patients with aml. design/method: cxr findings and clinical characteristics were evaluated in patients with newly diagnosed aml who were enrolled in one of three protocols at st. jude children's research hospital (aml97, aml02, and aml08). the findings were categorized based on radiologic reports. further, the associations of these findings and clinical characteristics were evaluated. we evaluated cxr findings in a total of 302 patients: 85 from aml97; 101 from aml02; and 116 from aml08. common cxr findings were pulmonary opacity (n = 51, 16.9%), bronchial/perihilar thickening (n = 38, 12.6%), splenomegaly (n = 38, 12.6%), mediastinal mass and lymph nodes (n = 27, 8.9%), pleural effusion/thickening (n = 17, 5.6%), demineralization/fracture/periosteal lesions (n = 10, 3.3%), scoliosis (n = 10, 3.3%), and granulomatous disease (n = 7, 2.3%). three cxr findings were associated with younger age at diagnosis: pulmonary opacity (median age, 4.5 years in patients with positive findings vs. 10.1 years in those with negative findings, p<0.01), bronchial/perihilar thickening (median age, 2.7 years vs. 10.3 years, p<0.01), and demineralization/fracture/periosteal lesions (median age; 2.7 years vs. 9.3 years, p = 0.04). two cxr findings were associated with older age at diagnosis: scoliosis (median age, 16.5 years vs. 9.0 years, p<0.01) and granulomatous disease (median age, 15.1 years vs. 9.1 years, p = 0.02). higher white blood cell counts (wbcs) at diagnosis were associated with cxrs showing pulmonary opacity (median wbc; 33.7 × 10^9/l vs. 14.8 × 10^9/l, p = 0.01) or splenomegaly (median wbc; 36.4 × 10^9/l vs. 15.2 × 10^9/l, p = 0.02). french-american-british (fab) m4/m5 subtypes were more frequently associated with pulmonary opacity compared with others (p<0.01). we did not find significant differences between female and male patients. conclusion: cxr in patients with newly diagnosed aml showed a variety of thoracic, abdominal, and bony lesions that are important for the initial evaluation and management. pulmonary opacity was the most common finding and was frequently seen in patients who were younger or had higher wbcs at diagnosis or fab m4/m5. background: children diagnosed with acute lymphoblastic leukemia (all) require a central venous catheter (cvc) to administer chemotherapy safely. both external and internal cvcs carry risks of complications including thrombosis, infection, and possible replacement. internal catheters, such as a port, are generally used for the majority of patients for the duration of treatment since therapy lasts for several years. many institutions place a port at the time of diagnosis. other institutions prefer to start induction therapy via placement of a peripherally inserted central catheter (picc) and defer port placement until the completion of induction therapy due to concerns of increased risk of infectious complications with port placement. objectives: to compare rates of common cvc associated complications by type of cvc placed at start of induction therapy in children treated for newly diagnosed all at the jimmy everest center (jec) at the university of oklahoma health sciences center. design/method: a retrospective chart review analyzed data from newly diagnosed all patients treated at the jec between 2010-2017. data was collected on complications including thrombosis, bacteremia, insertion site infection, cvc malfunction and need for removal. data collection began at the start of induction and was completed at the end of induction therapy. statistical analysis used a univariate and multivariate logistic regression model to compare complication rates between those who had a port versus those who had a picc placed at start of induction. results: data was collected on 128 patients. fifty-six patients had a port placed at start of therapy while 72 had a picc placed. fourteen percent of patients had a cvc associated complication. univariate analysis showed no statistically significant difference in rates of cvc associated complications between the groups (port 16%, picc 12.5% p = 0.564). the rates of hospitalization for cvc associated complications were similar between both groups (port 14%, picc 11% p = 0.590). rates of cvc removal were also similar between both groups (port 4%, picc 4% p = 0.863). multivariate model that included baseline patient characteristics including type of all, patient body surface area, gender, ethnicity and age continued to demonstrate no significant difference in cvc associated complications between both groups. conclusion: this single institution study showed that there was no significant difference in cvc associated complications between port and picc line placement at the start of childhood all induction therapy. port placement can be considered as a safe option at the start of induction therapy. complete remission [cr] or cr with incomplete blood count recovery [cri]) within treatment cycles 1-4. interim data are reported (nct02538965). results: seventeen patients were enrolled and received ≥1 dose of lenalidomide; median age was 12 years (range 5-18); 7 patients were female. patients received median 5 prior regimens (range 2-13). nine patients had previously undergone bone marrow transplantation (bmt). four patients had relapsed aml and 13 were refractory to immediate prior treatment. median duration of study treatment was 4 weeks (range 1-12); patients completed a median of 1 treatment cycle (range 0-3). all patients were evaluable for primary outcome; 1 achieved morphologic cri after 2 cycles (no patients achieved cr). the responder was a 13-year-old male with history of r/r aml after first-and second-line treatment, bmt, and salvage chemotherapy. at baseline, he had a complex cytogenetic karyotype (monoallelic −21q22.12, −3q, −4q13.3, −8p12) with no identifiable molecular mutation; he was also positive for del(5q) (−5q11, −5q23). his post-treatment karyotype showed no abnormalities. sixteen patients experienced treatment failure; 12 due to resistant disease, 3 of indeterminate cause, and 1 had treatment failure before a post-baseline assessment was performed. all patients experienced ≥1 grade 3-4 treatment-emergent adverse event (teae). the most commonly reported were thrombocytopenia (n = 10), anemia (n = 7), febrile neutropenia (n = 7), and hypokalemia (n = 7). fifteen patients experienced ≥1 teae related to lenalidomide. all patients discontinued treatment; 3 remain in follow-up. the study is now closed to enrollment. ten patients died on study: 3 during treatment, 7 during follow-up. all deaths were attributed to aml or complications due to aml. conclusion: third-line lenalidomide monotherapy was associated with clinical response in 1 of 17 pediatric patients with r/r aml; however, treatment exposure was limited. safety data are consistent with the known profile of lenalidomide. lenalidomide was not an efficacious treatment for r/r pediatric aml. funding: celgene corporation, summit, nj, usa. cook children's medical center, fort worth, texas, united states background: it is well documented that pediatric patients with acute lymphoblastic leukemia (all) often experience significant weight gain during induction therapy and later struggle with obesity. however, some patients experience unintended weight loss during induction therapy; since this issue is not well reported, it often goes undertreated. although malnutrition is reported to be associated with decreased survival, increased risk of infection, and loss of lean body mass, there remains a scarcity of in-depth analysis of prevalence and risk factors that contribute to this problem. our study attempts to address this critical yet unmet need. objectives: our aim was to identify the clinical risk factors and outcomes associated with weight loss during induction therapy for pediatric all. design/method: this was a retrospective chart review of patients between 2 and 20 years of age diagnosed with all at cook children's medical center from 4/1/14 to 3/31/17. for each patient, we collected height, weight, age, body mass index (bmi) z-scores at diagnosis and end of induction therapy, risk stratification, and whether consolidation was delayed. patients with a bmi >85th percentile at diagnosis were categorized as being overweight or obese. using logistic regression analyses, we examined which variables predicted whether the patient had an increase or decrease in bmi z-score throughout induction. a critical alpha level of 0.05 indicated statistical significance. results: ninety-six patients met our inclusion criteria. of these, 40% experienced a decrease in bmi during induction therapy. compared to patients whose bmi increased during induction, patients with a decrease in bmi were more likely to be overweight or obese at diagnosis (55% vs. 22%; p<0.001), to be ≥10 years of age (53% vs. 16%; p<0.0001), to have a high-or very-high-risk stratification (87% vs. 31%; p<0.0001), and to experience a delay in the start of consolidation therapy (47% vs. 21%; p<0.01). conclusion: this research highlights a risk not previously identified in the literature that may impact outcomes. patients treated on high-or very-high-risk protocols, who are overweight or obese at diagnosis, and who are ≥10 years of age at diagnosis should be monitored closely for weight loss during induction therapy. patients who experience weight loss should receive prompt intervention. it is our hope that this information can be used for future prospective studies and to help develop evidence-based guidelines. background: 17p abnormalities have been observed in some patients with hematologic malignancies. loss of p53 function as a tumor suppressor gene in the chromosome 17 plays an important role for development of leukemia. these patients usually have poor outcome due to the chemotherapy and are associated with poor prognosis. objectives: this study aimed to identify frequency of 17p abnormalities between iranian children and adult patients with aml (acute myeloid leukemia) malignancy. design/method: the 17p abnormalities were analyzed via bone marrow karyotyping and fish method in 669 acute myeloid leukemia patients. in this study, 17p abnormalities were observed in 52 (8%) patients out of 669 diagnosed cases. a significant strong correlation between 17p abnormalities and other high risk factors (poor risk cytogenetic) were observed. from 52 patients with aml malignancy (17p abnormalities), 45 (86%) patients have complex karyotype, 35 (67%) patients monosomal karyotype and 34 (65%) patients have monosomal karyotype accompanied with a complex karyotype. overall, 17p abnormalities are independent risk factor in acute myeloid leukemia and evaluation of these abnormalities by fish or other complementary techniques prior to treatment, might help for better risk stratification of high risk aml patients. background: hepatotoxicity in treatment of acute lymphoblastic leukemia (all) is well studied and transiently affects most patients receiving antimetabolite therapy. rarely, patients develop liver injury severe or prolonged enough to undergo a liver biopsy. little is known about how these patients differ from patients that develop transient hepatotoxicity. we sought to describe disease and treatment characteristics for all patients that developed hepatotoxicity severe enough to undergo liver biopsy. we also looked for pre-dictive factors for liver biopsy, including signs of early hepatic injury from the initial treatment protocol. design/method: pathology reports of all patients from the liver biopsy database at children's healthcare of atlanta were collected. controls were matched 2:1 for age, all subtype, and treatment protocol. demographics, treatment protocols, and overall outcomes were collected through the electronic health record. hepatic lab results for transaminases, coagulation, and albumin were collected for induction, consolidation, interim maintenance, delayed intensification, and maintenance. results: sixteen patients diagnosed between 2003-2013 (median age at diagnosis 10 years, range 1-16; 50% male; 75% pre-b all) were included in the case series. the median time from diagnosis to liver biopsy was 1.5 years (range 1-11). eight patients (50%) were in maintenance at the time of biopsy; none had active disease. eight (50%) were postbone marrow transplant. biopsy results included: steatosis (3), acute inflammatory/infectious (3), liver infiltration (1), fibrosis (6) and graft-vs-host disease (gvhd) (2). six patients were deceased; 5-year all-cause mortality from diagnosis was 31%. thiopurine methyltransferase (tpmt) status was known in 44% cases and 80% controls. all cases had intermediate or wildtype status, which did not differ from controls (p > 0.05). patients requiring liver biopsy did not have evidence of acute hepatotoxicity (ast/alt > 10× normal values) during their initial treatment protocol. hepatotoxicity requiring liver biopsy is a rare outcome of all treatment. these patients had elevated rates of relapse, bmt, and 5-year all-cause mortality, suggestive of a more severe disease process. however, it is difficult to sort out the temporality of relapse, bmt, and hepatoxicity requiring biopsy in this limited sample. additionally, patients with bmt preceding liver biopsy have other confounding factors that makes them difficult to include in the analysis. finally, our limited descriptive data show no notable correlation between early hepatotoxicity and later indication for liver biopsy. future cohort or case-control studies with larger sample sizes are required to further explore early predictive factors for severe hepatotoxicity requiring liver biopsy. nathan gossai, joanna perkins, michael richards, yoav messinger, bruce bostrom background: the majority of chemotherapeutic agents used to treat hodgkin lymphoma are teratogenic. pregnancy screening prior to the start of chemotherapy is supported by clinical guidelines and baseline testing is a standard component in therapeutic trials. there is limited data available on the incidence of pregnancy screening prior to the start of hodgkin therapy but previous studies suggest that pregnancy screening, especially at pediatric institutions, is not consistently completed. objectives: the objective of this study is to evaluate the incidence of pregnancy screening and contraceptive counseling prior to the start of therapy in females diagnosed with hodgkin lymphoma. design/method: a retrospective chart review was performed for all female patients newly diagnosed with hodgkin lymphoma from 2000 to 2015 at the hospital for sick children in toronto, ontario. all patients who were intended to receive multi-agent chemotherapy were included, regardless of age. data collected included demographic and disease information, chemotherapy regimen and enrollment on clinical trial. all pregnancy testing within two weeks prior to the start of therapy was captured, as well as type of pregnancy test performed, documentation of menstrual status, contraceptive counseling and contraceptive provision. univariate and multivariate analyses were used to describe factors influencing the incidence of pregnancy testing. results: a total of 122 female patients with newly diagnosed hodgkin lymphoma between the ages of 5 and 17 years were identified. sixty patients (49%) had pregnancy testing done prior to the start of therapy. testing modalities included serum and urine screens as well as quantitative beta-hcg measures. older age (p = 0.0016), documentation of menstrual status at diagnosis (p = 0.019) and diagnosis between 2008 and 2015 (p = 0.004) were associated with higher incidence of screening. enrollment on a therapeutic trial was not associated with a higher incidence of screening (p = 0.374). contraceptive counseling was documented for 19 patients (16%) and 11 patients (9%) were prescribed contraceptive medications during therapy. pre-chemotherapy pregnancy testing was completed on 49% of females with newly diagnosed hodgkin lymphoma. improvement is required and interventions, including clarification of institutional standards, modification of chemotherapy order sets and staff education, are planned. (rao et al., cancer, 2016) . university of louisville, louisville, kentucky, united states background: granulocytic sarcomas (also known as chloromas or leukemia cutis) were first described by a. burns in 1811. they are solid tumors comprised of immature granulocytic cells and represent extramedullary manifestations of underlying leukemia. chloromas are most commonly associated with acute myeloid leukemia. they may arise in other myeloproliferative disorders but are rarely seen in b or t cell acute lymphoblastic leukemia (all). objectives: although patients with all rarely have chloromas, it should remain on the differential for patients with unusual swelling or masses. design/method: we present a case series of two patients from our institution diagnosed with b cell all who had a chloroma as the presenting symptom. the first patient is a 4yo who presented to his primary provider with nasal congestion and a one-week history of bilateral eye swelling and was referred to an allergist when the symptoms did not resolve with anti-histamines. his review of systems was otherwise negative. he was referred urgently to ent two months later for a 3 × 3cm mass palpated along the medial border of the left eye. an mri showed a left facial mass surrounding the zygoma and extending into the anterior inferior left orbit. biopsy revealed b cell acute lymphoblastic lymphoma, and bone marrow aspirate and biopsy confirmed the diagnosis as b cell all. the second patient is a 10yo who presented to his primary doctor for rapid growth of a scalp nodule that had been present for about 2 months. he was referred to dermatology and treated for a supposed kerion from tinea capitis. the lesion continued to grow and became more irritated with this treatment. punch biopsy revealed a complicated phenotype of lymphoblastic lymphoma. however, after a lymph node biopsy and bone marrow aspirate and biopsy, the diagnosis was confirmed as b all. his only other positive point on review of systems was a questionably pathologic 20-pound weight loss and an area of matted cervical lymph nodes. for both of our patients, the chloromas completely disappeared during induction therapy. it is worth noting that both of these patients presented with the chloroma as the only symptom of the underlying leukemia. this led to initial misdiagnosis and delay in identifying their leukemia. therefore, while it is very rare for a patient with b all to present with a chloroma, our experience shows that all should be on the differential for patients presenting with unusual swelling or masses. background: hodgkin lymphoma (hl) is a lymphoproliferative neoplasm that commonly presents with history of adenopathy and a predictable pattern of disease involvement with or without systemic symptoms of fever and/or weight loss. in the hands of an experienced oncologist the diagnosis of hl is usually not a challenge. occasionally a diagnostic challenge is presented by a patient who has an atypical presentation which is suggestive of an alternative diagnosis. we describe a case series of patients diagnosed with hl whose initial clinical presentations lead to a diagnosis different form hl. honduras, nicaragua and the united states. results: six pediatric oncology centers from the american continent conducted a retrospective review of patients diagnosed with hl since 2010. patients that had an initial presentation not suggestive of hl or who were initially diagnosed with a disease other that hl were included for a total of 25 patients. argentina n = 8, guatemala n = 7, honduras n = 1, nicaragua n = 2, united states n = 7. five patients were female and 20 male. patient's ages ranged from 2 to 18 years. most patients (n = 19) were older than 11 years. three patients (15%) presented with non-immune cytopenias without overt lymphadenopathy, of those one had active hemophagocytic syndrome. five patients (20%) were suspected to have localized solid tumors: ewing sarcoma n = 2, rhabdomyosarcoma n = 1, hepatocellular carcinoma n = 1, and soft tissue tumor of the cheek n = 1. two (8%) metastatic solid malignancy as they presented with disseminated pulmonary nodules. five (20%) with autoimmune disorders: hashimoto thyroiditis n = 1, autoimmune hemolytic anemia n = 1, nephrotic syndrome n = 3. ten (40%) with chronic infectious processes: brucella n = 1, tonsillar abscess n = 1, splenic abscess n = 1, and tuberculosis (tb) n = 7. patients with suspected tuberculosis were diagnosed outside of the united states. six of 7 patients were ultimately diagnosed as having both tb and hl. seventeen patients had ann-arbor stage iii or iv, seven patient had stage ii with either b symptoms or bulky disease. patients were treated with various chemotherapy regimens according to the treating center: abvd, abve-pc oepa-copdac, avpc, beacopp. two patients had recurrent disease, one died of disease progression and one died from causes not related to hl conclusion: a small proportion of hl patients have atypical or unusual presentations. hl should be included in the differential diagnosis of solid tumors, autoimmune disorders, infections or cytopenias. the most common atypical presentation is an infectious process. background: acute lymphoblastic leukemia (all) represents the largest group of pediatric malignancies. the high cure rate of childhood all represents one of the most remarkable success stories in the war on cancer. in a lower middle income country (lmic) like the philippines, we reviewed the five year survival in a tertiary referral center. objectives: this retrospective cohort study aims to determine the survival of children 1-18 years old with all treated at a tertiary referral center for childhood cancer in the philippines from january 2012 to december 2016. design/method: this is a retrospective cohort study that reviewed medical charts of newly diagnosed all ages 1 to 18 years old from january 2012 to december 2016. a total of 435 subjects were included in the study. the 5 year overall survival (os) and event free survival (efs) were 65.3% and 62.8%, respectively. the 5 year os for standard risk all was 68.8% and for high risk patients was 50%. the 5 year os for the patients on remission was 83.7% and for those who relapsed was 21.1%. univariate and multivariate by cox proportional hazards regression revealed wbc count at diagnosis, risk classification, immunophenotyping, and development of relapse showed significant prognostic impact for mortality. age and gender were reported with no prognostic significance. the 5-year os and efs were lower compared to developed countries but are comparable with other lmics. the prognostic factors for relapse and mortality were compatible with the literature. overall, the adopted treatment protocols for childhood all in this institution showed acceptable results. relapse has a significant prognostic impact for mortality. development of accessibility to care, increase awareness, early detection and resources at hand should be achieved. improvement in the follow up protocol to prevent delays in the treatment, patient education to prevent non-compliance and psychosocial support, to developed better supportive care, and expand facilities should be given emphasis to further improve survival and prevent relapse. objectives: here, we seek to further characterize this entity by describing the pathologic and clinical features of 4 pediatric cases of burkitt-like lymphoma with 11q aberration. we collected pathologic and clinical data from the medical record on all pediatric high grade b-cell lymphoma (hgbcl) cases diagnosed at our institution over a 5-year period (2012-2017) . for those cases classified as neither burkitt lymphoma nor diffuse large b-cell lymphoma (dlbcl), fish for myc, bcl-2 and bcl-6, as well as array comparative genomic hybridization (acgh), were performed. we identified 38 cases of hgbcl, including 5 cases of burkitt lymphoma presenting as purely leukemic phase. of the hgbcl cases, 20 had burkitt lymphoma as defined by myc rearrangements, and 13 had dlbcl. collectively, the majority of these 33 patients had primary disease outside of the head/neck, and most patients presented with advanced stage (iii-iv) disease. of the 5 remaining cases, 11q aberration was identified in 4 cases using acgh. all 4 cases histologically and immunophenotypically resembled burkitt lymphoma but lacked myc rearrangement, instead showing proximal gains in 11q13-q23 and telomeric losses in 11q24.1qter. all 4 cases involved primary disease in the cervical lymph node and/or tonsil. three of these cases were localized (stage ii), and the fourth case involved a few metabolically active but non-enlarged lymph nodes in the chest and abdomen (stage iii). all 4 patients achieved complete remission with standard therapy for mature b-cell lymphoma, and were alive with no clinical evidence of disease at a median follow-up of 23 months. although the number is small, our results suggest that the majority of non-burkitt, non-dlbcl cases of pediatric hgbcl carry 11q aberrations. in addition, patients with 11q aberrations appear to be more likely to present with lower stage disease, thus requiring less intensive therapy, and also tend to have primary disease in the head/neck. these findings further support the classification of burkitt-like lymphoma with 11q aberration as a distinct pathologic and clinical entity, and we propose that all pediatric non-burkitt, non-dlbcl cases of hgbcl regularly undergo further workup for possible 11q aberrations. marie claire milady auguste, joseph bernard st damien hospital, port-au-prince, port-au-prince, haiti background: hodgkin lymphoma (hl) and non-hodgkin lymphoma (nhl) account for 7% of cancers in the united states pediatric population (1, 2). in central america and the caribbean, they are in second position among all types of pediatric cancers (3). a previous study on pediatric cancers in haiti showed that the lymphomas were in fifth place after the leukemias, wilms tumor, retinoblastoma and the sarcomas (4). the main objective of this study is to present the epidemiological profile of lymphomas managed at a haitian pediatric hospital. design/method: this is a retrospective study conducted on the cases of lymphoma diagnosed and managed at st damien hospital from january 2006 to december 2016. key variables such as age, gender, stage at diagnosis, histopathological types and outcome were collected to present the characteristics of this retrospective cohort. of the 407 cases of cancer diagnosed during the study period, 23 (5.7%) had the diagnosis of lymphoma. the sex ratio was 2.8 (17 males for 6 females) and the average age was 8.9 years [0-19 years]. there were 11 cases of hl (47.8%) and 12 cases of nhl (52.2%). 69.6% of the patients were diagnosed at stages iii and iv. among the hl cases, 6 (54.5%) were nodular sclerosis lymphoma, 3 (27.3%) with mixed cellularity and 2 (18.2%) with lymphocytic predominance. for the nhl cases, 4 (36.4%) were burkitt's lymphoma and 3 (27.3%) lymphoblastic t-cell lymphoma. among the 12 patients for who immunohistochemistry was found, the 4 cases of hl were cd30-positive and 6 out of 8 cases of nhl were cd20-negative. only 1 patient was hiv-positive, and 4 patients had a confirmed exposure to epstein-barr virus. 8 patients (34.8%) were lost to follow-up, 7 (30.4%) were in remission, 3 (13 %) relapsed, 2 (8.7%) were still in treatment and 3 (13%) were deceased. university of chicago, chicago, illinois, united states background: due to the adoption of risk-adapted therapy, pediatric and adolescent acute lymphoblastic leukemia (all) is associated with high cure rates. despite excellent outcomes in most children, patients with certain blast cytogenetic features do not fare as well. furthermore, african american, native american, and hispanic patients have worse outcomes than caucasian patients. while the outcome discrepancies are certainly multifactorial, and blast cytogenetics are related to age, it remains unclear whether ethnicity and blast cytogenetics correlate. the diverse patient population at the university of chicago provides an opportunity to evaluate for such a correlation. objectives: to describe cytogenetic findings in a racially and ethnically diverse population of patients of all age groups diagnosed with all at university of chicago from 2006 to 2016 and determine if there is a correlation between race/ethnicity and blast cytogenetics. results: a total of 191 newly diagnosed patients with all between the ages of 1-100 from 2006-2016 were included in this study. of those, 167 patients (87.4%) had b-all, 22 had t-all (11.5%), one had early t-cell precursor all and one had mixed phenotype all (b/t). caucasians accounted for 46% of patients, african americans (aa) 22%, hispanics 24.6%, asians 5.24%, and 2% were of other races. age distribution had a bimodal pattern, with a peak in incidence at 5 and another at 58 years of age, consistent with published data. cytogenetic categories included: t(12;21)(p13;q22), 11q23 rearrangements (kmt2a), iamp21, t(1;19)(q23;p13.1), t(9;22) (q34;q11), hypodiploidy, hyperdiploidy and double trisomy of chromosomes 4 and 10. aa and hispanic patients with b-all presented more frequently between the ages of 10-18 years compared to caucasians (p = 0.002 and 0.02, respectively). in aa patients, t(1;19) (q23;p13.3) was overrepresented (p = 0.04 when compared to caucasians), and was mainly observed in patients between 10-18 years. caucasian patients were more likely than non-caucasians to have hyperdiploidy (p = 0.04), especially in patients aged 1-9 years. the rate of t(1;19)(q23;p13.2) was significantly higher in aa patients in our cohort, in particular in patients between the ages of 10-18 years. hyperdiploidy was more likely in caucasians aged 1-9 years. these findings may suggest that varying blast cytogenetics could contribute to outcome differences between races. ahmed elgammal, yasser elborai, mohamed fawzy, asmaa salama, eman d el-desouky, lobna shalaby national cancer institute, cairo, cairo, egypt background: hodgkin lymphoma (hl) in children is one of the malignancies that have a high chance of cure. stage iv hl remains a challenge for getting good clinical outcome as in other stages. many treatment protocols used to give combination chemotherapy while combined modality treatment is the mainstay in other treatment protocols. objectives: we aimed in to assess the outcome using consolidation radiotherapy to chemotherapy (combined modality treatment) versus combination chemotherapy alone in treatment of stage iv hl. design/method: we included patients with stage iv hl and whose data were retrieved from the medical records of the pediatric oncology department, national cancer institute, cairo university, egypt from 2005 till june 2013 and were followed till august 2015. treatment was either to give 8 cycles of abvd (adriamycin, bleomycin, vinblastine, dacarbazine) only or to give 6 cycles of abvd followed by consolidation radiotherapy. the study included 22 cases; 17 were males and 5 were females. mean age was 10.66 years ranging from 4 to 17 years. the histopathology subtype was nodular sclerosis in the majority of cases (15 cases) followed by mixed cellularity (6 cases) then only one case of lymphocyte rich. nine cases were initially bulky while 13 cases were not. constitutional manifestations were present in 10 cases while it was absent in 12 cases. bone marrow was involved in only 4 cases. radiotherapy was given after completion of chemotherapy to 10 cases while 12 cases received chemotherapy only. the 5-year overall survival for patients who received radiotherapy was superior to those who received chemotherapy alone; 100% versus 45.8% respectively with statistical significance (p = 0.02). the 5-year progression free survival was also higher with radiotherapy than others; 90% versus 44.4% (p = 0.095). patients with stage iv hl who received consolidation radiotherapy apparently had a better outcome than those who received chemotherapy only. this suggests that radiotherapy contributes significantly with chemotherapy to the cure rate for those patients. the feinstein institute for medical research, manhasset, new york, united states background: microrna (mirnas) are short non-coding rnas that play a decisive role in cancer biology, including leukemia. exosomes are microvesicles (30-100 nm) produced by most cells in biological fluids. exosomes represent the fingerprint of the parental tumor and are loaded with bioactive markers such as mirnas, which may regulate tumor growth. exosomal cargo can be transferred into target cells changing their biological properties. our study investigates a functional role for exosomal mir-181a in pediatric acute lymphoid leukemia (p-all). objectives: 1/ to demonstrate that p-all exosomes induce cell proliferation2/ to confirm that exosome-induced cell proliferation is disease-stage specific 3/ to analyze exosomal mir-181a expression profiles in p-all4/ to authenticate that inhibition of exosomal mir-181a reduces leukemia proliferation design/method: exosomes were isolated by ultracentrifugation from healthy donors (hd) & p-all serum and conditioned medium (cm) of sup-b15, jm1, and cl-01 (control) human cell lines. cell lines were exposed to different sources of leukemia-derived exosomes in a paracrine or autocrine fashion for 24hrs in triplicates. proliferation was assessed by microscopic cell counting and confirmed by gene expression for proliferation, pro-survival and pro-apoptotic genes. mirna profiling was performed with the human cancer pathway finder microarray (qiagen). silencing of exosomal mir181a was carried out by a mir-181a inhibitor (qiagen), utilizing exo-fecttm exosome transfection reagent (sbi, system biosciences). further, exosomal mir-181a silencing was confirmed by q-pcr. cellular uptake of texred-sirna (sbi, system biosciences) was confirmed by flow cytometry. transfer of exosomal mir181a to the target cells was evaluated by q-pcr. we elucidated that cm-derived exosomes from sup-b15 and jm1 cell lines induce cell proliferation in sup-b15, jm1 (autocrine and paracrine) and cl-01 cells (paracrine) (p<0.01). serum p-all exosomes promote paracrine cell proliferation in all cell lines compared to hdderived exosomes (p<0.0001). heatmap analysis of mirna profiles of leukemia exosomes (all cell lines and p-all) identified mir-181a significantly upregulated in leukemia exosomes compared to controls. mir-181a was also upregulated in all cell lines after exposure to leukemia exosomes that induced proliferation. moreover, exosomal mir-181a inhibition reduces leukemic proliferation in pediatric all. our data suggest that all exosomes induce cell proliferation of leukemic cell lines in both paracrine and autocrine fashion. exosomes regulate these phenomena in a highly orchestrated way, by transfer of functional exosomal mirnas such as mir-181a. the results of this study suggest s233 of s301 that exosomal mir-181a inhibition can act as a novel way for growth-suppression of pediatric leukemia. results: a total of 199 disease sites were detected at pet/ct, while 172 sites were detected at contrast-enhanced ct and bone marrow biopsy (bmb). pet/ct showed improved detection of nodal lesions (p <0.0001) (kappa value = 0.633), extranodal lesions (p <0.0001) (kappa value = 0.632) and bone marrow (p <0.0001) (kappa value = 0.728) compared to contrast enhanced ct and bmb. pet/ct had upstaged 15 cases (16%) and down-staged 4 cases (4.3%) (p <0.001) (kappa value = 0.649). among the upstaged 15 cases, 10 patients (10.9%) were upstaged from stage ii to iii, based on residual in pet/ct not seen in contrast enhanced ct after abdominal mass excision. four patients (4.3%) were upstaged from stage iii to iv based on bone marrow uptake in fdg-pet without positivity in bma or bmb.regarding response assessment, sensitivity was 60% for pet and 80% for contrastenhanced ct (p = 0.56). specificity was 100% for pet and 65% for ct (p< 0.0001). positive predictive value for pet was 100%, while was 12% for ct scan (p< 0.0001). negative predictive value for both pet and ct was 98% (p = 0.82). five patients had 2nd biopsy to confirm viability of the residual lesions, 4 lesions were negative in pathological examination (all of them were metabolic negative in pet/ct; deauville score below 4). one lesion was positive in pathological examination (was positive in pet/ct; deauville score of 4). conclusion: pet/ct detected additional sites compared with contrast-enhanced ct and resulted in changing stage of disease. pet scan is significantly more specific than ct in the management of children with burkitt lymphoma. background: deep sequencing of the immunoglobulin heavy chain (igh) locus indicates that each b all is composed of innumerable subclones. in many cases, subclones exhibit differing phenotypic qualities. however, it remains unclear whether subclones demonstrate distinct tissue distribution within a patient. objectives: 1. to quantify the extent of clonal heterogeneity in diagnostic b all specimens; 2. to identify variability in clonal composition between bone marrow (bm) and peripheral blood (pb) disease sites. design/method: igh sequencing was performed on purified dna from 10 pairs of matched bm and pb patient specimens. multiplex pcr was used to globally amplify the igh locus; next generation sequencing (ngs) was performed using illu-mina® miseq. index clones (defined as ≥ 5% of all sequence reads in a specimen) and their subclone progeny (defined by 6 shared nucleotide bases immediately upstream of a common jh, or 6n_jx) were identified using igblast-determined vh and jh alignments (http://www.ncbi.nlm.nih.gov/igblast/) and an established in-house computational pipeline. results: up to 3 index clones per specimen were discovered in 16 of the 20 samples. in the remaining 4 (2 bm/pb pairs), 1 pair did not reveal a clonal igh and was eliminated from analysis; in the other, clone frequency did not reach the 5% index threshold, but predominant clonal precursors were inferred by the prevalence of their subclone progeny. subclone counts ranged from 2 to 2,619 per index clone. a combined 2,900 subclones derived from 11 pb index clones were observed; in contrast, 12 bm index clones gave rise to only 400 subclones. subclone heterogeneity was observed between all paired specimens. in 6 bm/pb pairs, index clones existed in equivalent proportions between disease sites. in contrast, 1 bm/pb pair demonstrated 2 high-frequency index clones in the bm (32.6% & 12.5%) with limited representation of these clones in the pb (0.6% & 1.4%, respectively); in this case, the most prevalent clone in the pb (10.8%) matched the least frequent index clone in the bm (5.0%). similarly, another pair showed a predominant index clone in the pb (5.8%) which was below index threshold (3.6%) in the bm. in 2 paired patient specimens, index clone predominance was discovered to be overtly distinct between bm and pb. among all pairs, the extent of subclone progeny derived from each index clone showed marked variability, with far higher subclone frequency in the pb than in the bm. our data indicate that b all clonal composition differs between disease sites. valley children's healthcare, madera, california, united states background: tuberculosis (tb) presenting with hodgkin lymphoma (hl) is rare. their coexistence could lead to delay in diagnosis of both tb and hodgkin lymphoma due to the similarities in signs and symptoms of presentation. most cases have been reported in the adult literature. we describe a case series of 11 children that were suspected to have tb and were found to have coexisting tb and hl. results: a retrospective review of hl patients in guatemala and argentina over 6 six years, uncovered 11 patients with simultaneous diagnosis of tb and hl. eight patients were from guatemala (incidence of 4.5%) and 3 from argentina (incidence of 2.5%). there were 4 females and 7 males. age ranged from 4 -17 years (mean 10.5 years, media 9 years). nine patients were suspected to have tb at presentation by the referring physician. two patients were found to have tb at the time of relapse through routine tissue culture. initial systemic symptoms included fever (n = 5), weight loss (n = 2), and night sweats (n = 2). six patients had a second systemic symptom in addition to fever. time for referral to oncology center ranged from 2 weeks to 5 months. nine patients were diagnosed with tb and hl through a tissue cultures and 1 with serum quantiferon. one patient was found to have hl without tb. two patients had no systemic symptoms and the diagnosis of tb came to light through routine tissue culture. five patients had stage iiib and ivb, two stage iia and one iib at diagnosis. hl treatment was given according to the insti-tutional standards depending on stage and risk with abvd, oepa/copdac +/-radiation therapy, and ice for relapse. five patients started anti tb treatment (isoniazid, rifampin, pyrazinamide +/-ethambutol for 2 months followed by isoniazid and rifampin for 30-52 weeks) simultaneously with chemotherapy, and three others after completing 2 cycles. the two relapsed patients started tb treatment after 2 cycles of chemotherapy. seven patients are alive and have been followed for 5 months -6 years. one patient died during therapy, another died for causes not related to tb or hl and one is currently receiving treatment. conclusion: tuberculosis can coexist with hl. in areas were the prevalence of tb is high, microbiology investigations of biopsy specimen should be strongly considered. therapy for tb can be given simultaneously with chemotherapy. coexistence of tb and hl does not appear to affect outcomes. the children's hospital affiliated to the capital institute of pediatrics, united states background: the pi3k/akt signaling pathway plays a central role in cell growth, proliferation and survival in physiological conditions. this signal pathway is considered to be an innovative targeted therapy of cancer, and its abnormal activation has been proved to be related to t-cell acute lymphoblastic leukemia (t-all). despite improved treatment strategies, such as multi-drug combination, high-dose chemotherapy and all kinds of application and popularization of hematopoietic stem cell transplantation, children with drug resistance or relapse t-all are still rather worse and its overall outcome and prognosis are much poorer than the more common b-lineage all. objectives: to explore the relationship between the pi3k/akt pathway and the pediatric t-all, so as to probe the exact molecular mechanisms of t-all and provide more directions for its treatment. design/method: 7 cases of new or recurrent acute t lymphocyte leukemia children with clinical information were collected in the children's hospital affiliated to the capital institute of pediatrics from dec.2015 to oct.2017, with 7 age and gender matched healty children as control (all was informed consent). the expressions of key genes in pi3k pathway were s235 of s301 analyzed by western blot rt-pcr analysis, the pi3k enzyme activities were detected by elisa,and the ccrf -cem's proliferation and its apoptosis were tested by mtt and flow cytometry technology on t-all cell lines ccrf-cem in different treatment group. the results of t-all children in clinical showed that pi3k protein and gene expression level were higher apparent than the control group (p<0.05), and pi3k enzyme activity increased as well (p<0.05); pi3k inhibitor ly294002 made a significant inhibition of cell proliferation and promoted cell apoptosis. ly294002 also enhanced the effectiveness of clinical commonly used chemotherapeutic drug dnr. in combination ly294002 and dnr treatment group cell viability dramatically declined, apoptosis and the apoptosis relation protein casepase3 expression in t-all patients was obviously higher than the control and the single drug group; pi3k/akt signaling pathway related proteins and gene expression level, pi3k, akt, gsk3 transcription in ccrf-cem were significantly higher than the control (p< 0.05), while pten transcription was significantly lower than the control (p<0.05). the abnormal activation of pi3k/akt signaling pathway might play an important role in pediatric t-all patients, especially in the cell proliferation or apoptosis. the results might provide new train of thought and direction in targeted suppress this signal pathway or in combination with other chemotherapy drugs therapy in looking for the more effective and less cytotoxic treatment of pediatric t-all. cleveland clinic children's hospital, cleveland, ohio, united states background: non-hodgkin lymphomas (nhls) are a heterogeneous group of lymphoproliferative diseases which comprise 7% of all childhood malignancies. nhls can be divided in to b cell lymphomas and t cell/natural killer (nk) cell lymphomas depending on immunophenotype, molecular biology, and clinical response to treatment. although nk/t cell lymphomas occurring in childhood and adolescence comprise a small portion of all lymphomas, they present many diagnostic and therapeutic challenges. the role of angiogenesis in lymphoma pathogenesis is becoming more evident. high molecular weight kininogen (hk) is a central compo-nent of the kallikrein-kinin system. it has been previously reported that cleaved hk (hka) induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in matrigel plug and corneal angiogenesis models. however, the role of endogenous kininogen in regulation of angiogenesis is in tumor microenvironment is unknown. objectives: to elaborate the role of hk in lymphoma angiogenesis, we used a murine t-cell lymphoma model and compared angiogenesis and tumor growth between wild-type and kininogen deficient (mkng1-/-) mice. we also evaluated the effect of hka on lymphoma cell proliferation. design/method: el-4 murine t-cell lymphoma cells (5 × 10^5) were implanted into wild-type and mkng1-/-mice. tumor size was measured using calipers and tumor volume was calculated using the formula volume = length × width^2 × 0.52. seventeen days after cell implantation, tumors were harvested and processed by immunoblotting and immunofluorescent staining. cell proliferation assays (mts) were performed to investigate any possible inhibitory effect of hka on el-4 cell growth, with human umbilical vein endothelial cells (huvec) were used as a positive control. results: el-4 lymphomas grew more rapidly and to larger sizes in mkng1-/-mice compared to wild-type mice, with significant differences apparent by day 11 after tumor implantation (p<0.01). by day 17, the volume of tumors in mkng1-/-mice was approximately 1.4-fold larger than in wild-type mice (mean volume ± standard deviation; 2120 ± 536 vs. 1485 ± 272 mm3, respectively, p<0.01). mts assays showed that hka does not directly inhibit the proliferation of el-4 cells in vitro, though it does significantly impair the viability of ecs studied simultaneously. conclusion: these findings suggest that hk is an important endogenous regulator of angiogenesis and tumor growth in this t-cell lymphoma model, and suggests that hka specifically modulates endothelial proliferation in tumor microenvironment. further work is needed to understand the mechanisms underlying these findings and provide future anti-angiogenic approaches to increase the therapeutic options for patients with nhl. bruce bostrom, jack knudson, nathan gossai, joanna perkins, michael richards, jawhar rawwas, susan sencer, julie chu, nancy mcallister, yoav messinger children's minnesota, minneapolis, minnesota, united states background: osteonecrosis causes significant pain and morbidity in older patients treated for acute lymphoblastic leukemia. besides altering the schedule of dexamethasone in delayed intensification there is no other intervention known to reduce the incidence of symptomatic osteonecrosis. pamidronate has been shown to reduce bone pain from osteonecrosis but not to prevent joint collapse when advanced. objectives: to compare the incidence of symptomatic osteonecrosis in patients who received prophylactic pamidronate compared with concurrent controls. to describe any increase in side effects from the use of pamidronate. design/method: patients age 10 to 28 years at time of all diagnosis were given intravenous pamidronate monthly for one year at the discretion of the primary oncologist starting in the first year of therapy. concurrent controls were patients age 10 to 28 who did not receive pamidronate. all patients were treated according to the concurrent cog protocols and received intermittent dexamethasone during delayed intensification. patients with bcr-abl all were excluded as the use of imatinib may increase the risk of osteonecrosis. imaging was only done if osteonecrosis was suspect based on clinical symptoms. patients were censored at the time of relapse. data were analyzed as of 1/1/2018. this retrospective study was approved by the children's minnesota irb. of the 62 patients evaluated 58% were male and 42% female, 74% had b-cell and 26% t-cell. the median followup is 2.4 years with a range of 0.3 to 7 years. pamidronate was given to 23 patients with 2 developing symptomatic osteonecrosis. there were 39 concurrent controls with 14 developing osteonecrosis. there was no significant difference in the leukemia lineage, gender distribution or body mass index (bmi) at diagnosis between groups. for all patients the median bmi was 22 with a range of 15 to 47. the age at diagnosis was significantly higher in the pamidronate group with a median of 18.6 years vs. 15.7 in the controls (p = 0.014). by kaplan-meier analyses the incidence of symptomatic osteonecrosis was significantly lower in the pamidronate group at 14% vs. 43% in controls. the log-rank p-value was 0.049 and the breslow p-value, which is more sensitive to early events, was 0.039. there were no untoward side-effects from pamidronate. pamidronate infusions significantly reduced the incidence of symptomatic osteonecrosis in patients over the age of 10 compared to concurrent controls who did not receive pamidronate. arahana awasthi, dina edani, janet ayello, christian klein, mitchell cairo new york medical college, valhalla, new york, united states background: mature b-nhl, including bl and pmbl express cd20+/cd79b+ and have an excellent prognosis, however, subset of patients relapse secondary to chemoimmunotherapy resistant disease and have a dismal prognosis (≤ 20% 5 yr. efs, cairo et al. blood. 2007; gerrard/cairo et al., blood, 2013 , goldman/cairo et al. leukemia, 2013 . pv has been demonstrated to possess significant preclinical activity against indolent cd79b+nhl (polson et al. can. res.2009 ). we previously observed that obinutuzumab (anti-cd20 mab) significantly enhanced cell death and increased overall survival against bl (awasthi/cairo et al., bjh 2015) in xenografted nsg mice. however, additive/synergistic effects of pv with obinutuzumab against mature pmbl/bl are unknown. to determine the efficacy of the pv or obinutuzumab/rtx alone or in combination against pmbl and rituximab (rtx) sensitive/resistant bl cell lines. design/method: raji4rh (provided by m. barth, md, roswell park cancer institute) and raji/ karpas1106p (atcc, usa) were cultured in rpmi. tumor cells were incubated with pv, and/or anti-cd79b, mmae (generously supplied by genentech inc.) with obinutuzumab /rituximab (100ug/ml) for 4 hr with nk cells at 10:1 e: t ratio and cytotoxicity was determined by delfia cytotoxicity assay. six to 8 week old female nsg (nod.cg-prkdcscid il2rgtm1wjl/szj), were divided into 5 groups: pbs, isotype control, pv, anticd79b mab and mmae (5mg/kg). mice were xenografted with intravenous injections of luc+ bl and pmbl cells and tumor burden was monitored by ivis spectrum system. results: os of mice receiving pv alone was significantly increased compared to anticd79b ab or isotype control in raji (35.5 vs.17 vs.19.5 our preliminary data indicates that pv significantly increased survival in bl and pmbl nsg xenografts compared to anti-cd79b ab alone. furthermore, pv in combination with obinutuzumab significantly enhances in-vitro cytotoxicity in bl and pmbl compared to obinutuzumab or pv alone. results: maximal grades (g)1/2, 3, and 4 crs occurred in 36, 19, and 24 patients, respectively. median lowest fibrinogen levels were 3.5, 3.3, and 1.2g/l in patients with maximal g1-2, 3, and 4 crs, respectively. 3%, 11%, and 25% of patients with maximal g1-2, 3, and 4 crs had lowest reported fibrinogen levels of ≥1 to <1.5g/l. eight patients (all with g4 crs) had very low fibrinogen levels (<1g/l), which occurred before (n = 1) or during (n = 6) maximal crs grade or at time of improvement (n = 1). no patients with maximal g1-3 crs had <1g/l fibrinogen levels. at the onset of <1g/l fibrinogen levels, 1 patient had concurrent g3, and 7 had g0-2 increased international normalized ratio and activated partial thromboplastin. cryoprecipitate was the primary treatment in the us, and fibrinogen concentrate (fc) guidelines for tisagenlecleucel-associated coagulopathy were developed for other countries because administration of fresh frozen plasma can be problematic. fc was available at 7/25 sites for 20 infused patients: 3/7 (g4 crs) and 0/8 (g1-3 crs). cryoprecipitate was available at 18/25 sites for 77 infused patients: 12/17 (g4 crs), 2/15 (g3 crs), and 0/32 (g1-2 crs). risk of bleeding increases in pediatric patients with comorbid thrombocytopenia and anticoagulant treatments. 5/8 patients had g3/4 decreased platelets within 1 day of <1g/l fibrinogen levels. 1 fatal case of intraparenchymal cranial hemorrhage occurred during resolving crs with g3 hypofibrinogenemia, ongoing thrombocytopenia, and continuous veno-venous hemofiltration with citrate. hypofibrinogenemia was observed more frequently in patients with higher crs grades during/when crs was improving or resolving. fc and cryoprecipitate treatment guidelines were developed. frequent monitoring and fibrinogen replacement are needed in patients with g3/4 crs. sponsored by novartis. its prolonged cns half-life, may allow a reduction in the number of intrathecal injections. objectives: to safely reduce the burden of therapy by reducing the number of it injections and reducing the total dose of doxorubicin with the addition of liposomal cytarabine and rituximab. design/method: patients (3-31 years) with cd20+ b-nhl with fab group b good risk (=stage i/ii and stage iii with ldh < 2xuln), fab group b intermediate risk (=stage iii ldh ≥2xuln and stage iv {bm blasts < 25%}) and fab group c high risk were eligible. patients received fab backbone therapy with the addition of six rituximab (375mg/m2) doses; two doses prior to each of two induction courses and one dose prior to each of two consolidation courses. cumulative doxorubicin was reduced from 120 to 50 mg/m2 in gr patients. after systemic methotrexate clearance, patients received age based dosing of it liposomal cytarabine. it injections were reduced from nine to five. the primary outcome is safety and toxic deaths among 40 evaluable patients with an estimated 3-year survival above 90%, monitored by an independent dsmb. results: to date, 32 evaluable patients, 25 fab group b and 7 group c (6 cns positive), median age 12 years (range 3-23), 20 males, 16 burkitt/16 dlbcl with 18 gr, 7 ir and 7 hr have enrolled. there has been one grade 3 anaphylactic reaction to rituximab and one grade 3 facial nerve palsy. no other serious adverse events were attributable to protocol therapy. there has been 1 death from progressive disease and 1 relapse at a median follow up of 30 months. efs and os are 94% and 97%, respectively. our initial results show excellent efs and os, consistent with published standard of care outcomes, with the addition of rituximab and intrathecal liposomal cytarabine despite the reductions in therapy. further enrollment is ongoing and continued long term outcomes are needed to confirm early results. future randomized studies are needed to examine both short term (mucositis, infections, hospitalization days) and long term (late cardiac toxicity) endpoints. 1. goldman etal, leukemia, 2013 2. cairo etal, jco 2012 st. jude children's research hospital, memphis, tennessee, united states background: bereaved parents identify significant spiritual needs around time of death and throughout their bereavement journeys. spirituality has been identified as a primary means by which bereaved parents can find meaning in their losses, and this ability to find meaning is associated with lower maladaptive grief symptoms. the use of spiritual coping strategies has been associated with improved coping and mental health outcomes among bereaved parents. objectives: to better understand how bereaved parents' experiences with spirituality throughout bereavement effects objective measures of grief, depression, and meaning-making. design/method: thirty participants whose children died of progressive cancer or related complications one to three years prior to participation completed an in-depth semi-structured telephone interview about their experiences with grief. participants were prompted to describe the impact of their spirituality on their bereavement processes. additionally, participants completed surveys related to grief (prolonged grief disorder questionnaire, pg-13), depression (beck depression inventory, bdi), and meaning-making (integration of stressful life experiences scale, isles). results were analyzed using a mixed methods approach including semantic content analysis of qualitative content and kruskal-wallis h test and post-hoc analyses of quantitative data. results: correlation analyses demonstrated significant differences between participants with positive and negative spiritual experiences of bereavement. participants with negative experiences of bereavement had a statistically significant increase in scores on the pg-13 compared to those with positive spiritual experiences signifying greater symptoms of prolonged grief. participants with negative spiritual experiences with grief had significantly lower scores on the isles, suggesting a lesser degree of adaptive integration of their losses. there were no significant differences in depression scores between groups. conclusion: bereaved parents that have a negative spiritual experience of bereavement are at increased risk for prolonged grief symptoms and are less likely to find meaning in their children's deaths than bereaved parents that describe a positive spiritual experience of bereavement. providers should consider exploration of spiritual beliefs and provision of spiritual care for parents of children facing life-limiting illnesses during treatment and bereavement. background: langerhans cell histiocytosis (lch) is an inflammatory myeloid neoplasia characterized by frequent relapse, with treatment failure associated with higher risk of death and neurodegenerative disease (lch-nd). activating somatic mutations in mapk pathway genes have been identified in almost all cases, with braf-v600e in approximately 60% of lesions. targeted therapies have been successful in treating other refractory cancers with braf v600e mutations (such as melanoma). given the central role of mapk pathway activation in lch, mapk pathway inhibition may be an effective therapeutic strategy for children with lch. objectives: the purpose of this study was to report the efficacy and toxicity profile of a retrospective cohort of patients with lch treated with mapk pathway inhibitors. design/method: medical records from 12 pediatric patients with lch (systemic and/or lch-associated neurodegeneration) who were treated with a mapk pathway inhibitor were retrospectively reviewed from five institutions. all patients had failed at least one prior systemic therapy and had a proven mapk pathway mutation. results: all patients in this series were less than 21 years old (median = 10.1 years; range: 2-20 years) with a median of three prior treatments (range: 1-9). at the time of initial mapk inhibitor use, nine of the 12 patients had lch-nd diagnosed clinically and/or by radiographic imaging; the remaining three patients had systemic disease. patients were treated for a median of 9 months (range: 1-20 months) with various reasons for discontinuation. three patients received combination mapk inhibitor therapies and three patients received other concurrent lch-directed therapies. four of the twelve patients had a grade 3 or 4 toxicity reported and three of these patients required dose reduction in order to be able to successfully resume therapy. overall survival was 92% with median 20 month follow-up (range: 1-42 months) with only one patient achieving transient complete response. the remaining ten patients had partial response or stable disease and four of these patients developed progressive disease while on therapy. conclusion: mapk pathway inhibitors may be a relatively safe salvage therapy for refractory systemic lch and lch-nd but the efficacy and durability of this strategy remains to be defined. combination with cytotoxic chemotherapies may be required in order to eradicate the disease-causing cell. future prospective trials of mapk pathway inhibitors for patients with refractory lch are needed in order to directly compare their efficacy and toxicity relative to other current salvage strategies. cincinnati children's hospital medical center, cincinnati, ohio, united states background: medication adherence during maintenance therapy has been shown to have a direct relationship with disease relapse in pediatric leukemia. previous research determined that patients who are ≤ 95% adherent to 6mercaptopurine (6mp) have a greater risk for relapse. the primary aim of the present study is to examine the relationship between metabolite profiles of 6mp with behavioral adherence rates obtained via electronic monitoring at 5, 10, and 30 days. it is hypothesized that patients demonstrating low levels of thioguanine (tgn) and methylated mercaptopurine (mmp) will have lower behavioral adherence rates prior to the blood draw. design/method: in a multisite, prospective study of 139 patients ages 7-19 years diagnosed with acute lymphoblastic leukemia (all) or lymphoblastic lymphoma (lbl), 6mp adherence was measured across 15 months of maintenance therapy using behavioral adherence (electronic monitoring) and pharmacological (metabolites) measures of 6mp. 6mp is metabolized into mmp and tgn. cluster analysis was used to generate three mutually-exclusive profiles of 6mp adherence. behavioral adherence rates were calculated for 5, 10, and 30 days prior to the blood draw. results: this study identified three metabolite profiles of 6mp across 15 months. previous research indicated that low levels of both metabolites suggest nonadherence to medication. low levels of one metabolite with high levels of another metabolite indicate adherence to 6mp. in this study, 51.2% of the low tgn-low mmp group had 5-day behavioral adherence rates ≥ 95% (mean = 100%); 48.8% had adherence rates < 84% (mean = 48.5%). in the high tgn-low mmp group, 77.6% had a mean 5-day adherence of 100%; 22.4% had adherence rates < 84% (mean = 32.9%). the low tgn-high mmp group had 74% of patients with a mean 5-day adherence level of 100%; 26% had adherence rates < 84% (m = 54.6%). at 10 and 30-days, 62 to 66% of patients in the low tgn-low mmp group had adherence rates < 95%. conclusion: these findings suggest that electronic monitoring and metabolite concentrations can be used to monitor 6mp medication adherence during maintenance therapy. it is notable that there is a sub-sample of pediatric patients who are identified as being nonadherent to 6mp based on electronic monitoring, however, metabolite levels indicate adherence to 6mp. similarly, a sub-sample of patients were identified as being adherent based on electronic monitoring, but metabolite profiles indicated sub-therapeutic levels of 6mp. our findings underscore the clinical significance of using both objective measures of medication adherence to inform clinical decision making. cincinnati children's hospital medical center, cincinnati, ohio, united states background: hemophagocytic lymphohistiocytosis (hlh) is a life-threatening hyperinflammatory syndrome characterized by non-remitting fevers, rash, hepatosplenomegaly, cytopenias, liver dysfunction and coagulopathy, and can include central nervous system involvement. several genetic diseases cause hlh by impairing normal lymphocyte or macrophage function. the hlh panel at the cincinnati children's genetics laboratories includes 14 genes associated with hlh and other lymphoproliferative diseases, including the genes that cause primary hlh (prf1, unc13d, stxbp2, stx11, rab27a), x-linked lymphoproliferative diseases (sh2d1a, xiap), itk deficiency (itk), hermansky-pudlak syndrome types 2 and 9 (ap3b1 and bloc1s6), chediak-higashi syndrome (lyst), cd27 deficiency (cd27), xmen syndrome (magt1) and lysinuric protein intolerance (slc7a7). deletion/duplication analysis is available as a reflex test for all 14 genes, as copy number variations (cnvs) are not directly assessed by sequencing. objectives: the prevalence of cnvs among large groups of patients with hlh in north america is unknown. we assessed the frequency of cnvs in the genes on the hlh panel through a retrospective review of 522 orders for deletion/duplication analysis performed after next-generation or sanger sequencing: 397 orders for all 14 genes on the panel, and 125 orders of 1-5 genes from the panel. deletion/duplication analysis was performed on a custom 4 × 180k microarray annotated against ncbi build 37 (ucsc hg19, march 2006). deletion/duplication analysis resulted in a confirmatory diagnosis in 11 of 522 cases (2.1%). pathogenic or likely pathogenic cnvs were most common in the three x-linked genes: sh2d1a (3 deletions), xiap (3 deletions, 1 duplication), and magt1 (3 deletions). hemizygous deletions in xlinked genes in male patients were typically suspected after amplification failure during previous sequencing. of the autosomal recessive genes, pathogenic cnvs were observed once in each of three genes: rab27a (heterozygous), lyst (heterozygous), and stxbp2 (homozygous). in the two heterozygous cases, a second change was not identified by sequencing, so deletion/duplication analysis did not offer a confirmatory diagnosis. in 25 patients, deletion/duplication analysis was performed after a pathogenic or likely pathogenic variant was identified in an autosomal recessive gene during sequencing; however, in no case was a second mutation uncovered by cnv analysis. we recommend that deletion/duplication analysis be routinely performed in all male patients with hlh who lack a genetic diagnosis after sequencing of hlh-associated genes, especially if any regions failed to amplify. deletion/duplication analysis may be performed in female patients after sequencing if a genetic form of hlh is highly suspected, but the yield is expected to be low. cleveland clinic children's hospital, cleveland, ohio, united states background: the development of post-transplant neoplasia, typically from lymphoproliferative disease (ptld), is a severe complication in transplant recipients and affects approximately 12% of pediatric solid organ recipients. rates of lymphoma in adult heart transplantation patients are comparatively low, at less two percent at ten years. there are few published reports of the long-term outcomes of neoplasia after pediatric heart transplantation. we aimed to identify the subsequent malignancies that occurred in pediatric heart transplantation patients in a large single institution, and describe their treatment and subsequent clinical course. we performed a retrospective chart review of all pediatric heart transplant recipients followed at the cleveland clinic children's hospital from january 1985 to october 2012. we excluded patients who died within 30 days of heart transplantation. we reviewed in depth the history and clinical course of subjects who developed neoplasms. results: between 1985 and 2012, 101 patients underwent heart transplantation and survived at least 30 days post transplantation. nine patients (8.9%) developed a subsequent malignancy. in this case series, the median age at heart transplant was 3 years old and the median time to develop neoplasia was 88.6 months. primary neoplasia included monomorphic ptld (3), polymorphic ptld (1), burkitt lymphoma (2), hodgkin's lymphoma (1), plasmacytoma-like lymphoma (1) and epstein-barr virus-associated smooth muscle tumor (ebv-smt) (1). one patient with hodgkin lymphoma subsequently developed monomorphic ptld, one patient with polymorphic ptld subsequently developed ebv-smt and later, an undifferentiated gastric cancer. one patient with monomorphic ptld developed an ebv-smt. evidence of epstein-barr virus was present in six of nine patients at diagnosis of first malignancy. four of nine patients received reduction in immunosuppression as a primary intervention for the initial malignancy, with two complete responses (cr), one partial response, and one with progressive disease. five patients were treated with chemotherapy, with four cr and one with progressive disease. three patients died of malignancy (recurrent ebv-smt, undifferentiated gastric cancer, and monomorphic ptld post-hodgkin disease) and two patients died of other transplant related complications. conclusion: secondary malignancies represent a significant disease burden to survivors of cardiac transplantation. as expected, much of the malignancy burden is driven by ebv. despite aggressive histology, many malignancies can be successfully cured in this setting with a multidisciplinary approach. stanford university school of medicine, palo alto, california, united states background: current treatment of langerhans cell histiocytosis (lch) is based on extent of organ system involvement and if high risk systems are affected. gastrointestinal (gi) involvement is diagnosed in about 2% of lch patients, and classically presents in children under 2 years of age with malabsorption, failure to thrive, bloody diarrhea and anemia. although the gi system is considered standard risk, a mortality rate over 50% occurring within 2 years of diagnosis has been reported. this study was performed due to this discrepancy and the limited number of published cases. objectives: to review the clinical course and outcomes of patients diagnosed with gi lch. design/method: a retrospective chart review of patients with histologically confirmed gi lch diagnosed in the last 15 years identified from the bass center histiocytosis clinical database was performed. two other pediatric hematology/oncology centers (ucsf benioff children's hospital oakland and san francisco) were queried for additional cases. results: four patients with biopsy proven gi lch [3 subjects (2.9%) from 105 database records and l from center queries] were identified. failure to thrive, hypoalbuminemia, bloody diarrhea and rash were the most common presenting symptoms. lch of the skin was found in all patients. risk organ systems were involved in 2 patients. of note, 2 subjects were of african racial background. the median age at diagnosis was 3.5 months (1.5 months to 16 years), mean albumin 2.2 g/dl (1.2 -2.9 g/dl), mean esr of 56 mm/hr (37 -78 mm/hr). all patients initially received combination therapy per lchiii protocol (vinblastine, prednisone, and 6 mercaptopurine). two patients had recurrent disease and received second line therapy (cytarabine, 2cda, and local radiation therapy). all patients are alive without active disease at last follow-up (8 to 107 months after completion of therapy). a systematic approach to evaluate gi involvement should be performed in children diagnosed with lch. from our experience, combination chemotherapy for patients with lch involving the gi tract is an effective intervention for active disease. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bhatia indicated that rates of 6mp adherence ≥ 95% have better clinical outcomes. those with adherence rates ≤ 95% have an increased risk for disease relapse. the present study investigated patterns of 6mp medication adherence using group-based trajectory modeling in a large sample of pediatric patients. to describe patterns of behavioral adherence during the maintenance phase of therapy for a cohort of pediatric patients ages 7-19 years who were diagnosed with acute lymphoblastic leukemia or lymphoblastic lymphoma (n = 139). previous research has documented the relationship between optimal levels of medication adherence with positive health outcomes. it was hypothesized that three groups would be identified: optimal adherence, deteriorating adherence, and chronic nonadherence. it was hypothesized that patients in the optimal adherence group would have adherence rates ≥ 95%. those with poor adherence would have adherence rates ≤ 95%. design/method: the present study was a longitudinal, multisite study investigating adherence to 6-mercaptopurine in a pediatric cohort of patients using electronic monitoring devices. daily adherence rates (electronic monitoring of 6mp) were examined across 15-months. health outcomes were measured at quarterly intervals through medical chart reviews. results: unconditional growth curve modeling indicated that the mean percentage of behavioral adherence was 84.4% at baseline and declined to 75.2% at 15-months. three trajectories of 6mp behavioral adherence were identified: 1) optimal adherence (67% of patients): averaging 95% behavioral adherence across 15 months; 2) moderate adherence (20%): relatively stable nonadherence with rates of 67% across 15 months; and, 3) chronically nonadherent (13%): adherence decreased from 63% to 30%. with respect to patterns of medication adherence and relationship to clinically-relevant health outcomes, there were no significant differences in health outcomes between patients in the adherent versus nonadherent trajectories, including mean absolute neutrophil counts (anc), risk for infection as measured by anc, healthcare utilization, or risk for disease relapse. although longitudinal patterns of 6mp behavioral adherence were not related to health outcomes, it is notable that only 67% of the current sample had adherence rates ≥ 95%. in fact, 33% of the current sample demonstrated adherence rates ≤ 95%. our findings are important for development of future adherence promotion studies in pediatric cancer. our findings underscore the relative significance of tailoring adherence promotion interventions to subgroups of patients, including those with problematic patterns of adherence. patients who demonstrate adequate levels of adherence could still benefit from less intensive, preventative interventions to sustain and improve adherence. sophie gatineau-sailliant, pascale grimard, marie-claude miron, guy grimard, anne-sophie carret, jean-marie leclerc chu sainte-justine, montreal, quebec, canada background: vertebral involvement in langerhans cell histiocytosis (lch) is still a subject of interest, due to its low frequency and the absence of management's guidelines. objectives: to provide additional information on presentation, treatment and morbidity of pediatric lch vertebral lesions, we report cases of 11 children with vertebral lesion of biopsy-proven lch, between january 1st 2000 and december 31st 2015, at sainte-justine university health center (montreal, quebec, canada). we conducted a retrospective study by reviewing charts and imaging of vertebral lch in a population of 11 children (median age of 8.25 years at lch diagnosis), followed for a median duration of 34 months. symptoms at presentation, treatment modalities and morbidities were collected. results: vertebral lesions were present at lch diagnosis in 9 of 11 cases. they were usually diagnosed secondary to back pain in 10 of 11 cases and were asymptomatic in only one case. despite an epidural extension in 6 of 11 cases, no child developed neurological symptoms. lesions frequently involved vertebral body (10 of 11 cases) and were rarely unstable (2 of 11 cases). out of 29 vertebral lesions, most of them had a dorsal localization (15 of 29 lesions) and 8 of 11 patients had lch in multiple vertebrae. at diagnosis, median vertebral height loss was 37.5% compared to 25% at last imaging control. most used imaging modalities were pet-scan and plain x-rays. treatments were diverse and consisted in chemotherapy in all children but three and bisphosphonates in only 3 cases. radiation therapy was not used in any patient. six out 11 patients did benefit of an orthosis. a lch recurrence was observed in 6 patients and involved vertebrae in 4 cases. one patient with treatment-resistant lch disease had 5 relapses, and required multiple lines of treatment. all children were alive and disease-free at their last follow-up, 10 patients having radiological vertebral sequelae and only 3 had clinical sequelae. our study is consistent with the epidemiological data described in larger cohorts of children with vertebral lesions of lch and the favorable prognosis associated with such lesions. nevertheless, aggressive treatment and long term follow-up seemed to be essential as recurrences are s243 of s301 not rare and spontaneous bone regeneration often incomplete. plain x-rays appears to be a good follow-up tool for vertebral lesions as it allows reliable measures, less exposure to radiation at lower cost. national cancer institue, giza, giza, egypt background: acute lymphoblastic leukemia (all) is the most common type of childhood cancer and also the most complicated in the treatment, so it requires many interventions for both treatment and to alleviate suffer form side effects. pancreatitis is one of the toxicities, which is more common in all as it appears in about 16% of the patients. it occurs in many drug combinations which induce pre-pancreatitis and even direct destruction of pancreatic tissues. pancreatitis can be induced by many drugs used in the treatment such as chemotherapeutic agents or supportive treatment. lasparaginase is the backbone drug of the treatment of all in which 6 to 9 doses are required to achieve complete remission status in the induction phase of treatment and 12 to 19 doses in the maintenance phase.it is an enzyme that destructs the l-asparagine amino acid into aspartic acid and ammonia thus deplete the asparagine from the extracellular matrix . many drugs are investigated for their effect on treatment of induced pancreatitis such as interleukin-10, nsaid as antiinflammatory, glycerin tri nitrates as improvement of microcirculation, tnf-alpha antibody, paf inhibitor as specific anti-inflammatory and low molecular weight heparin .none of the drugs was investigated for their ability to prevent the occurrence of pancreatitis. objectives: this study was designed to evaluate the protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis design/method: acute pancreatitis was induced in rats by intra-muscular injection of l-asparaginase (1000 i.u/kg) given daily for five days. enoxaparin was given subcutaneous (100 i.u/kg) and diclofenac was given intra-peritoneal (2 mg/kg) daily for five days. then, markers of pancreatic injury, lipids, immune cell infiltration and oxidative stress were analyzed with histo-pathological examination of the pancreatic tissue results: during acute pancreatitis, oxidative stress markers were significantly changed as indicated by reduced tis-sue glutathione and increased malondialdehyde levels. this was accompanied with significant increase in immune cells infiltration as indicated by high levels of myeloperoxidase and pro-inflammatory cytokine tnf-alpha. triglyceride only showed increase level. treatment with enoxaparin and/or diclofenac restored levels of biochemical markers including serum alpha-amylase, reduced glutathione, malondialdehyde, pro-inflammatory cytokine tnf-alpha, myeloperoxidase and triglyceride. histological injuries of pancreatic tissues as vacuolation and necrosis of epithelial lining pancreatic acini, inflammatory cells infiltration and focal pancreatic hemorrhage were also reduced by treatment with enoxaparin and/or diclofenac. the present study emphasizes the potential protective effect of enoxaparin and diclofenac against l-asparaginase induced pancreatitis background: rosai dorfman disease (rdd), or sinus histiocytosis with massive lymphadenopathy (shml), is a rare condition of immune dysregulation of unknown etiology arising from the massive accumulation of non-langerhans type histiocytic cells inside lymph nodes. the disease classically presents as bulky, painless lymphadenopathy often associated with infection showing distension of lymph node sinuses by abundant histiocytic cells (cd1a(-), s-100(+)/cd68(+)). in some cases, the disease can be self-limiting, but in cases with a prolonged chronic course of exacerbations and remissions, those with extranodal involvement, or disease that threatens vitals structures, treatment may be necessary. there is no treatment consensus. to describe a case of life-threatening, unresectable, recurrent rdd successfully treated with langerhans cell histiocytosis (lch) 2009-inspired therapy. design/method: we compared this case to the current literature on chemotherapeutic treatments for rdd. we searched pubmed, ovid, and google scholar for similar cases. we believe this to be the first reported case of using lch therapy to successfully treat rdd. an 8-year-old male presented to an outside hospital with two years of massive neck swelling causing torticollis. biopsy confirmed rdd. he was intermittently treated with courses of antibiotics with partial response. surgical removal of the affected lymph nodes was unsuccessful due to proximity to the spinal cord. two years later, the patient presented to our institution. he was initially treated with prednisone with a fast tapering dose, but after a second relapse the decision was made to try chemotherapy following the lch-2009 protocol of weekly vinblastine (6 mg/m2), 6-mp (75 mg/m2), and high dose steroid bursts. he experienced two additional relapses off therapy at ages 12 and 14 years old, including cmv(+) associated septic shock and cytokine storm requiring rapid response, picu admission, and ionotropic support. this last episode was treated with a more prolonged induction and maintenance therapy. an extended and slowly tapered maintenance therapy regimen of 2.5 years of daily 6-mp, monthly vinblastine and steroids with a slowly tapered dose during his fourth remission has resulted in 38-months of continuous complete remission-the longest stretch of his life. no similar cases were found. literature search demonstrated no consensus regarding the most effective treatment of rdd, with no previous cases being successfully treated following lch chemotherapy protocols. we hypothesize that the multi-agent relatively mild lch-2009 therapy mitigates the immune dysregulation of rdd. this case suggests that lch-2009 therapy can be used to treat cases of rdd that is not amendable to surgery or observation. nicklaus children's hospital, miami, florida, united states background: central venous catheters (cvc) are necessary in the management of patients with malignancies, especially children. patients with acute leukemia (al) have higher rates of central line associated complications such as bloodstream infections compared with other malignancies. objectives: to examine the choice of placement of cvc and the differences in outcome between peripherally inserted central catheters (picc) and ports in patients with leukemia during induction. design/method: retrospective chart review of patients with newly diagnosed leukemia at nicklaus children's hospital between 2010 and 2016. results: ninety four patients with a new diagnosis of leukemia undergoing induction chemotherapy were identified. the average age was 6.9 years. overall, 51 (54.3%) patients had a port placed and 43 (45.7%) had a picc placed. the decision for picc or port was subjective and physician based. the main outcome measures were local inflammation/infection, bacteremia, thrombophlebitis, blocked catheter and premature removal. the most common complication was bacteremia (12. 8%). in a multiple logistic regression analysis for predicting whether patients had at least one complication, results showed that having at least one complication is 3.4 times the odds in patients with aml compared to patients with all (p = 0.032). when comparing picc vs. ports, patients with picc had more frequent episodes of blocked catheters (23.3%) and premature removal (20.9%) compared to the patients with ports (2.0% and 0.0%) (p = 0.002 and p = 0.001 respectively) during induction. local inflammation, bacteremia and thrombophlebitis were not statistically different (p = 1.0, p = 0.54 and p = 2.4 respectively). the most common place for port placement was the right subclavian vein (55%). there was no significant association between port location and having at least one complication (p = 0.112). acute lymphocytic leukemia subgroup analysis: fourteen patients (61%) in the picc group had at least one complication and 9 (39%) in the port group but that was not statistically significant (p = 0.128). our series showed a higher incidence of blocked catheters and premature removals with picc compared to ports in patients with leukemia during induction. the choice of placement of picc vs port was subjective and physician based. patients with all, despite receiving steroids and asparaginase during induction, did not show a statistically significant increase risk in thrombosis or infection but larger numbers may be needed in future studies. university of california, san francisco, san francisco, california, united states background: hemophagocytic lymphohistiocytosis (hlh) is classically a disorder of young children meeting systemic hyperinflammation criteria. presentation in late adolescence is uncommon. furthermore, though cns signs occur in 30-70% of cases, initial isolated neurologic presentation is rare, frequently resembling encephalitis or demyelinating disorders. these cns signs can be isolated or precede systemic disease, delaying hlh diagnosis. hlh declaring in adolescence with predominant psychiatric features has not been well documented. objectives: to describe a case of cns hlh presenting with neuropsychiatric features in absence of classic hlh criteria. design/method: retrospective review of clinical, radiologic, histologic, immunophenotypic, and molecular features of a patient with cns hlh. a 19-year-old female presented with acute-onset headaches following nine months of progressive anxiety, short-term memory loss, emotional lability, perceptual disturbances, and hypomania. brain mri demonstrated numerous enhancing t2 hyperintense supratentorial and infratentorial white matter lesions in the left thalamus and caudate head. brain biopsy showed histiocyte-rich inflammation and associated demyelination. extensive evaluation including universal microbial pcr failed to reveal underlying infection or malignancy. past medical history was notable for presumptive pulmonary sarcoidosis diagnosed 14 months prior with progressive respiratory failure with associated granulomatous pulmonary nodules which responded to systemic immunosuppression. at presentation of her neuropsychiatric symptoms, she had normal sil-2r, ferritin, fibrinogen, and triglycerides. there was no pancytopenia, coagulopathy, bone marrow hemophagocytosis, fevers, or splenomegaly. given the possibility of partial immune suppression of systemic symptoms and the prominent neurologic symptoms, hlh screening labs were sent and notable for decreased natural killer and cytotoxic t lymphocyte function, normal granzyme expression and cd107a mobilization, and absent perforin expression. genetic testing confirmed compound heterozygous mutations in prf1 (c.227g>a, c.626a>c) and familial hlh type 1. she was treated with low-dose dexamethasone and intrathecal chemotherapy per hlh-94. due to lack of evidence of systemic inflammation, vp-16 and high-dose steroids were held. within one week of initiating therapy, she had decreased anxiety and improved cognition, with sustained, incremental neuropsychiatric improvement with additional intrathecal treatments. she tolerated dexamethasone tapering without symptom flare. mri also demonstrated parenchymal lesion improvement. for definitive treatment, she underwent unrelated allogeneic hematopoietic cell transplantation and remains at neurologic baseline as of eight months post-transplant with ongoing imaging improvement. conclusion: this case of familial hlh with compound heterozygous perforin mutations in an adolescent with isolated neuropsychiatric symptoms illustrates that cns hlh may be an underrecognized phenomenon in absence of systemic signs. standard hlh therapy may effectively reverse these symptoms with associated radiologic responses. rush university children's hospital, chicago, illinois, united states background: posterior reversible encephalopathy syndrome (pres), a recognized complication of pediatric leukemia treatment has been reported in up to 5% patients in various series. hypertension, chemotherapy and cortical spreading depression have been implicated in the pathophysiology. due to the combinations used, it is difficult to identify the offending drug, several have been implicated. since delay of chemotherapeutic treatment in children with high risk leukemia is unfavorable, it is important to recognize the characteristic radiologic findings, manage appropriately and reintroduce the treatment as soon as possible. pharmacoethnicity is now recognized as an important factor for variation in neurotoxicity in children with all. ethnic differences in reported pres events in pediatric patients with all has not been well described in literature. to describe the factors associated with pres in a cohort of high risk pediatric all patients at a single institution. design/method: a total of 12 children with an average age of 9 years (1-20 years) diagnosed with all between 2013-2017 were retrospectively reviewed for the occurrence of pres. various demographic factors, therapy received, clinical features, radiology related findings and management were reviewed. a search for all published articles on pres in leukemia was conducted using pubmed databases. results: five (42%) children (average age 8.5 years) developed pres during days 10-29 of induction. 80% of the patients that developed and 45% of those that did not develop pres were hispanic. all the patients that developed pres and 43% of those that did not were diagnosed with high risk all. all patients received vincristine, 80% received daunomycin and intrathecal methotrexate and 20% received asparaginase in the 1 week prior to the event. mri findings confirmed pres in all 5 patients with no evidence of methotrexate related leukoencephalopathy or leukemia. at the time of pres all patients were in remission based on mrd and spinal fluid cytology. two-thirds of the patients had seizures and hypertension at the time of the event with no prior history of either. all patients had complete recovery of normal mental status after resolution of pres. a higher incidence of pres than previously reported was noted in our series. hispanic ethnicity, high-risk all and exposure to vincristine, daunomycin and intrathecal methotrexate in induction were associated with pres in our cohort. a new association that emerged was that of hispanic ethnicity with pres .larger studies to understand the importance of pharmacoethnicity in pres may help in individualization of chemotherapy based on ethnic differences. children's hospital of illinois, peoria, illinois, united states background: hyper ige syndrome is a primary immunodeficiency characterized by susceptibility to skin and lung infections as well as increased propensity for malignancy. hemophagocytic lymphohistiocytosis (hlh) is a syndrome characterized by overwhelming activation of t lymphocytes and macrophages occurring as either primary hlh caused by genetic abnormalities or secondary hlh associated with infectious, malignant, metabolic, or immunodeficiency causes. we describe the first case to our knowledge of hlh in a patient with hyper ige syndrome. to describe a case of hlh in a pediatric patient with hyper ige syndrome. results: a 7-year old caucasian male with known autosomal dominant hyper ige syndrome (stat3 mutation) was transferred to the pediatric intensive care unit secondary to concern for septic shock. the patient had persistent slow bleeding from oral lesions and central catheter sites despite the addition of aminocaproic acid and recombinant factor viia. he also required numerous blood product transfusions sec-ondary to anemia and thrombocytopenia. clinical suspicion was high for hlh and the patient met criteria for diagnosis of hlh with the following: ferritin > 40,000 ng/ml, triglycerides 264 mg/dl, decreased nk cell function with the sample only containing 1% nk cells, elevated soluble il-2 receptor at 4215 u/ml, splenomegaly, and fever. infectious workup was remarkable for a positive ebv qpcr with 80,700 copies/ml suggestive of ebv driven secondary hlh. familial hlh testing was unable to be completed. therapy was initiated based upon the hlh-94 study. the addition of ruxolitinib and anakinra were considered but the patient declined rapidly prior to treatment. ct of the head was concerning for a stroke with signs of edema and increased intracranial pressure likely leading to the development of symptoms consistent with brain stem herniation. the decision was then made to withdraw care. conclusion: to our knowledge, this is the first report of hlh in a patient with hyper ige syndrome. diagnosing hlh requires a high index of suspicion in critically ill patients, and prompt initiation of therapy is essential. this challenging case of hlh in a patient with hyper ige syndrome highlights the diagnostic challenge, variable presentation, and need for effective therapy in this vulnerable patient population. background: adolescents and young adults (ayas) with cancer are at risk for psycho-social as well as physical symptom burden during cancer therapy. the purpose of this study is to explore psychological and physical symptoms endorsed by aya while receiving therapy for cancer design/method: surveys were given in both inpatient and outpatient settings during cancer therapy. symptom screening in pediatrics tool (sspedi) and memorial symptom assessment scale (msas). symptoms severity was rated by teens on a 5 point likert scale. spss 22, used for statistical analysis. results: : a total of 39 aya on cancer therapy (age range 13-19.9 years) 35% female, 65% male, 43.6% acute leukemia, 48.7% solid tumors, and 7.7% diagnosis was not reported. 78% of aya on cancer therapy reported at least 1 or more symptoms, 45% reported >3 symptoms cluster. of the physical symptoms that were reported as most distressing to the teens, mouth sores and headaches were the top causes. of the physical symptoms that were most frequently endorsed; fatigue was on the top (58%), followed by change in appetite 45 %, vomiting 43%, and pain 40%., the least was bowel habit changes. aya rated sadness as the most frequent psychological symptom 38%, followed by feeling angry 32%, and scared 30%. statistically significant difference was noticed based on gender difference with more females reported symptoms (p = 0.01), while type of cancer (acute leukemia versus solid tumors) was not statistically different. conclusion: aya with cancer reported multiple physical and psychological symptoms with significant distress. females seem to report more symptoms compared to males. screening aya for cancer therapy related symptoms is feasible during routine visits and adds important information about the aya well-being. background: sinus histiocytosis with massive lymphadenopathy (shml), also known as rosai-dorfman disease, is a rare histiocytic proliferative disorder of unknown etiology. many treatment modalities have been employed; however, no uniform guidelines exist. objectives: literature review of treatment options for shml. design/method: chart review was performed on pediatric patients diagnosed with shml at the children's hospital at montefiore between 2010 and 2012 after irb approval. inclusion criteria included children between the ages of 0 and 21 years with shml. exclusion criteria included children with cutaneous shml. four cases of shml seen at montefiore are described. a comprehensive review of the literature identified 102 additional cases published between 1978 and 2018. manuscripts that did not include the treatment modality or outcome were excluded. results: many of the 106 patients with shml responded to observation alone. of 106 patients, 46 patients were observed, with 35 (76%) having resolution of disease, five having stable disease, and five being lost to follow-up. one patient received subsequent systemic therapy. surgical management was con-ducted upfront in 29 patients. of those, 18 (62%) had resolution of disease, one had stable disease, and one had recurrence with no further therapy noted. of the remaining nine patients, 77% were successfully treated with systemic therapy, consisting of either steroids (5) or steroids and chemotherapy (4). systemic therapy was used as first-line therapy in 31 patients. steroids alone or in conjunction with chemotherapy resulted in resolution of disease in 12/15 and 7/11 patients (19/26, 73%), respectively, with four patients having stable and three with progressive disease. chemotherapy without steroids resulted in resolution of or stable disease in 3/5 patients. radiation was ineffective. conclusion: shml is a rare disease with no published guidelines for treatment. from the results of the cases and a detailed review of the literature, it can be suggested that observation may be considered as first line management in patients providing there are no significant symptoms. for patients who are symptomatic or have significant progression, surgery may be considered. in patients with recurrence or refractory disease, steroids and/or chemotherapy may be used. the presence of nodal or extra-nodal disease did not seem to have a significant impact on the course of treatment. given the rarity of the disease, it is difficult to conduct a randomized control trial. further work, involving collaboration between centers and cooperation with the international rare histiocytic disorders registry would be helpful. boston children's hospital, boston, massechusettes, united states background: increasing census and intensified work compression on the inpatient oncology service at our institution was identified as leading to resident dissatisfaction, impaired resident learning and decreased perceived quality of patient care. objectives: to evaluate the impact of a redesign of a pediatric inpatient hematologic malignancy (ihm) service on resident perceptions of the educational value of the rotation and safety of patient care. design/method: during the 2016-2017 academic year, we initiated a bundled intervention on the ihm service. modifications included 1) decreased patient volume: the ihm service was divided into two teams, utilizing an extra attending -a teaching service consisting of residents and fellows and a team comprised of nurse practitioners. 2) intentional patient team assignment: patients were deliberately assigned to a care team based on educational opportunities and provider skill sets. 3) intentional attending faculty selection: attending faculty with deeper clinical and teaching experience were selected to supervise on the teaching team. 4) increased weekend staffing. after completing the service, junior residents completed an electronic survey to evaluate their perceptions of the educational value of the rotation, as well as their ability to deliver safe care while on the rotation. fisher's exact tests were used to compare responses from residents in 2017 who experienced the redesign to residents in 2016, whose experience results: survey completion rates were 70% (28/40) in 2016 and 57% (29/51) in 2017. intervention residents were significantly more likely than comparison group residents to choose the answers "very good" or "excellent" to describe both the overall quality of the rotation (76% intervention vs. 25% comparison, p<0.001) and the educational experience on rounds (52% intervention vs. 7% comparison, p<0.001). intervention residents also reported caring for fewer average primary patients daily on weekdays as compared to comparison residents (4.8 vs 8.7 patients, p<0.0002, 95% ci -5.14 to -2.64). furthermore, intervention residents were more likely than comparison residents to "agree" or "strongly agree" that they could provide safe patient care on weekend days (79% intervention vs. 14% comparison, p<0.001) and on nights (69% intervention vs. 25% comparison, p<0.01) while on the oncology service. a redesign initiative of an oncology service with the development of a new teaching service led to improved resident perceptions of the educational value of the rotation and ability to provide safe care to patients. this approach could be useful to other services and institutions to promote similar outcomes in resident education and patient care. background: alk-positive histiocytosis is a rare histiocytic proliferative disorder that has been reported in three infants presenting primarily with hepatosplenomegaly, anemia, and thrombocytopenia. given the rarity of this disease, there are no standard treatment algorithms for this diagnosis and the disease course and outcomes remain largely unknown. the published series describes treatment ranging from monitoring alone to multi-drug chemotherapy regimens. there was ulti-mately resolution of presenting symptoms in all three cases despite varying treatment strategies. objectives: to report a newly diagnosed case of alkpositive histiocytosis that was treated with a novel approach using cytarabine monotherapy. results: a full term male infant presented at birth with difficulty feeding and hyperbilirubinemia. over the first few weeks of his life, he subsequently developed thrombocytopenia, transaminitis, and profound hypoalbuminemia. by six weeks of life, he was experiencing significant abdominal ascites requiring repeat paracenteses, massive hepatosplenomegaly, respiratory distress secondary to abdominal distension, anemia, and coagulopathy. he underwent numerous diagnostic tests, including a liver biopsy followed by a bone marrow biopsy that showed alk-positive histiocytic infiltrates in both sites. treatment was initiated with cytarabine 170 mg/kg/day x 5 days, repeating every 4 weeks. throughout his course of five cycles of treatment, he experienced intermittent fevers and mild nausea with no other adverse events. by the end of five cycles, his hepatosplenomegaly resolved, his blood counts normalized, he demonstrated weight gain on oral feeds, and his liver enzymes normalized. he is currently 12 months post completion of therapy and remains well with a normal physical exam and laboratory values. conclusion: treatment of alk-positive histiocytosis with lose dose cytarabine resulted in complete resolution of our patient's symptoms with minimal treatment related adverse effects, and few long-term treatment related risks. given the rarity of the diagnosis, the reporting of effective novel treatment options is important for future patient care. background: adult patients with melanoma or lung cancer harboring braf v600e have benefitted from the development and subsequent approval of specific braf inhibitors. as such, delineating the subset of similarly targetable pediatric oncology patients may spur development and rational use of these inhibitors in children. importantly, other point mutations and fusions of braf may also be targetable in s249 of s301 children analogous to recent emerging data in adult cancer patients. objectives: to define the genomic landscape of known and novel braf alterations and raf1 fusions in pediatric malignancies and report index cases with clinical response to braf or mek inhibitors. design/method: dna was extracted from 40 microns of ffpe sections of 3,633 tumors from pediatric (<21 years of age) oncology patients, and cgp was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 579x for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. genomic alterations (ga) included base substitutions, indels, copy number alterations and fusions/rearrangements. a total of 221 (6.1%) braf-altered pediatric malignancies were identified. 172 (77.8%) harbored a single kinaseactivating braf short variant, indel, or fusion. an alteration resulting in reduced braf kinase activity was identified in 8 (3.6%) tumors while 7 (3.2%) tumors harbored multiple braf alterations, 3 of which contained at least a single activating short variant. the remaining 34 tumors (15.4%) contained functionally uncharacterized variants. kinaseactivating braf alterations were identified in diverse tumor spectra comprised of brain tumors (75.3%; 18 subtypes), carcinomas (10.6%; 6 subtypes, with melanoma constituting 50% of cases), hematological malignancies (8.8%; 5 subtypes), sarcomas (2.9%; 3 subtypes), and extracranial embryonal tumors (2.4%; 2 subtypes). seventy-two (32.6% of braf-altered cases) braf fusions were identified, 64 (88.9%) of which were kiaa1549-braf; 2 involved the novel fusion partners: stard3nl and khdrbs2. seven (0.2%) raf1 fusionpositive cases, predominantly brain tumors (5), were identified; 2 involved the novel fusion partners: tmf1 and sox6. index cases of response to therapy of intracranial tumors will be presented. we describe a population of pediatric patients with targetable braf alterations predominantly enriched in primary intracranial tumors, but spanning diverse solid tumor types and hematologic malignancies. we additionally report a cohort of raf1 fusion-positive patients. an index case and multiple previous reports suggest raf or mek inhibitors may benefit pediatric patients with either intracranial or extracranial disease, and development of such drugs in pediatric indications is strongly warranted. background: diffuse midline gliomas (dmg) with h3k27m mutation, including diffuse intrinsic pontine glioma (dipg), are the leading cause of brain tumor-related deaths in children. there are no effective therapeutic strategies and the median survival remains dismal. genomic studies have identified a recurrent mutation in the majority of dmgs involving a lysine to methionine substitution (k27m) in histones 3.1 and 3.3, resulting in changes in the epigenetic landscape that dysregulate gene expression and promote gliomagenesis. panobinostat, a multiple histone deacetylase (hdac) inhibitor, was found to be one of the most effective agents against dipg patient-derived cell cultures and xenograft models in previous studies and is presently in clinical trial for dipg. hdac inhibition with panobinostat may also exhibit activity against h3k27m+ diffuse midline gliomas of the thalamus and spinal cord. to evaluate the effect of panobinostat as a single agent against patient-derived thalamic and spinal cord h3k27m+ diffuse midline glioma cell cultures and in an orthotopic xenograft murine model of h3k27m+ spinal cord glioma. design/method: patient-derived thalamic and spinal cord h3k27m+ diffuse midline glioma cell cultures were treated with single agent panobinostat at a range of concentrations. cell viability was evaluated using the celltiter-glo assay. panobinostat was systemically administered to orthotopic xenograft murine models of luciferase-expressing spinal cord h3k27m+ diffuse midline glioma. response to panobinostat was evaluated with ivis in vivo imaging. results: hdac inhibition with panobinostat significantly decreases cell proliferation with an ic50 of 30 nm and 41 nm in the spinal cord and thalamic glioma patient-derived cell cultures respectively. panobinostat slowed tumor growth in murine models of spinal cord glioma by 1.5-fold in the brain (p = 0.0219, n = 5) and 2-fold in the spinal cord (p = 0.0176, n = 5) when compared to vehicle controls after 1 week of administration. panobinostat is in clinical trials for dipg. this study suggests that hdac inhibition with panobinostat may also be beneficial for patients with thalamic and spinal cord diffuse midline glioma h3k27m mutants. background: brain tumors are the most common solid tumor of childhood and the leading cause of childhood cancer deaths. while medulloblastoma is the most common malignant brain tumor of childhood with a 5-year survival 70-80%, children with high-grade gliomas (hggs) such as glioblastoma multiforme (gbm) fare much worse with a 5-year survival of 15-35%. implicated in this poor outcome is the presence of treatment resistant brain tumor stem-like cells. gbm stem-like cells (gscs) have been implicated in tumor growth, treatment resistance and patient relapse, making them a key therapeutic priority. antipsychotic drugs (apds) have been used for decades in various psychiatric clinical settings and are associated with a lower incidence of cancer, including malignant brain tumors. currently, atypical apds are being evaluated for their potential to alleviate cancer and treatment induced side effects. furthermore these drugs may have direct anti-tumor effects, potentially via inhibition of dopamine d2 receptors (drd2). objectives: determine the anti-cancer effects of atypical apds on gbm stem-like cells design/method: the anti-cancer effects of apds (quetiapine and risperidone) were evaluated on gbm stem-like cell lines developed in our laboratory (glio 3 and 38) and the group 3 medulloblastoma cell line hdmbo3. cell proliferation/viability was determined using trypan blue exclusion and mts assays. the effect of apds on cancer stem cell self-renewal was determined by neurosphere assay. receptor expression and apds effect on cell cycle proteins were examined by western blot analysis. results: western blot analysis of gscs and hdmbo3 demonstrated robust drd2 expression indicating a viable therapeutic target. both apds induced dose dependent cell death of all cell lines tested. treatment with only 2um of either apd for 10 days significantly reduced cell proliferation by 60% (hdmbo3) and 50-90% (gscs). consistent with these findings, we observed an increase in cell cycle inhibitors p21 and p27. furthermore at day 10 both apds induced a robust increase in gsc death, approximately 60% compared to only 10% in non-treated controls. lastly, 1um apds significantly reduced gsc neurosphere formation compared to untreated controls by up to 35% suggesting inhibition of gbm stem cell self-renewal. our data indicates that clinically relevant concentrations (low micromolar) of these apds induce anticancer effects in both gscs, which are enriched with tumor initiation/propagation properties, and in the group 3 (myc amplified) medulloblastoma cell line. these apds represent strong candidates as potential adjuvant therapies for the treatment of these brain tumors. background: while the poor prognosis for high risk neuroblastoma (hrnb) underscores the need for new treatment strategies, the elucidation of specific biologic subsets of neuroblastoma suggests a way to improve disease management. the identification of agents that target specific molecular pathways associated with the development or progression of diseases holds promise. dfmo, an inhibitor of odc, has been shown to decrease lin28 and mycn and target cancer stem cells in preclinical studies. currently 14% of patients undergoing immunotherapy relapse. dfmo is in studies to prevent relapse after immunotherapy and may be helpful during immunotherapy as well. the hypotheses for this study were that: 1) the incorporation of a targeted therapy, selected based upon upfront tumor genomic interrogation, into standard induction chemotherapy for hrnb is safe, feasible and may increase the pr/cr/vgpr response rate at the end of induction therapy; and 2) the addition of dfmo as maintenance during immunotherapy is safe and feasible and may decrease the relapse rate for hrnb. a multicenter feasibility pilot trial in subjects with newly diagnosed hrnb within the beat childhood cancer consortium. at diagnosis, patients' tumors underwent dna exome and rna sequencing which were analyzed within a molecular tumor board to identify the single best drug of 6 targeted agents to be added to cycles 3-6 of induction chemotherapy. after consolidation with asct and radiation, the patients received dfmo along with standard dinutuximab and retinoic acid and dfmo for 2 years after immunotherapy. patients were evaluated for additional toxicities with the addition of targeted agents and dfmo in addition to induction response. results: the pilot study of 20 eligible patients has shown this process to be feasible. all 20 patients have completed induction portions of the study. the combination of targeted agent with chemotherapy was shown to be safe without any unexpected toxicities. delays between induction cycles were < 2 weeks and related to surgery, infection, or thrombocytopenia. the induction response demonstrated 88% cr/vgpr/pr rate, which suggests improvement over historical 80%. in addition, 15 patients were eligible for the combination of dfmo with dinutuximab and retinoic acid was well tolerated and safe without additional toxicities due to dfmo. the pilot study of 20 patients has shown the process of genomic sequencing and addition of a targeted agent to upfront chemotherapy and addition of dfmo to dinutuximab and retinoic acid maintenance therapy in newly diagnosed hrnb patients and is feasible and safe without any unexpected toxicities. background: identifying sub-populations of medulloblastoma tumors with stem cell-like properties holds promise for reducing disease recurrence, but there is no known unifying marker of medulloblastoma cancer stem cells. the granulocyte stimulating factor receptor (gcsf-r or cd114) is well understood in the context of hematopoiesis, but its role in solid tumor pathogenesis is less clear. neuroblastoma and melanoma subpopulations expressing gcsf-r have cancer stem cell properties of chemoresistance and increased tumorigenicity, and are enriched in tumors after chemotherapy. gcsf-r activation leads to signaling through the jak-stat pathway, suggesting a potential therapeutic target. we hypothesized that a subpopulation of medulloblastoma cells would express the gcsf-r and that this subpopulation would demonstrate chemoresistance and response to inhibitors of the jak/stat pathway. objectives: our objective was to identify a subpopulation of medulloblastoma cells expressing the gcsf-r and determine their relative growth rates, tumorigenicity, and responses to chemotherapy and jak/stat inhibition. design/method: medulloblastoma cell lines were sorted via flow cytometry for gcsf-r surface expression. subpopulations of gcsf-r-positive and -negative medulloblastoma cells were then monitored for growth by continuous live cell imaging. responses to chemotherapy were measured in subpopulations of gcsf-r-positive and -negative medulloblastoma cells using continuous live cell imaging to measure percent cell confluence and cell viability assays. ic50 values were calculated for each cell line and each agent. parental medulloblastoma cell lines and isolated gcsf-r-positive and -negative subpopulations were also treated with the jak1/2 inhibitor ruxolitinib and growth rates, viability, and ic50 values were calculated. results: gcsf-r surface expression was identified on 0.2-1.3% of medulloblastoma cell lines. isolated gcsf-r positive cells demonstrate a slower growth rate compared to gcsf-rnegative or parental unsorted medulloblastoma cells. gcsf-r positive cells are more resistant in vitro to vincristine, etoposide, and carboplatin, when compared to the gcsf-r negative population and an unsorted population of the same cell line. ruxolitinib is cytotoxic to medulloblastoma cells in vitro, with higher ic50 values noted in gcsf-r positive cells compared to unsorted and gcsf-r negative cells. we show that a subpopulation of gcsf-r positive cells are present in multiple medulloblastoma cell lines via flow cytometry, and that isolated gcsf-r-positive cells have a slower growth rate than gcsf-r-negative or unsorted populations. we also show that ruxolitinib has in vitro activity against medulloblastoma cell lines. we propose that jak inhibition may represent an adjunct therapy targeting overall tumor burden and specifically targeting the gcsf-r-positive subpopulation of medulloblastoma cells that may drive tumor recurrence. we investigated the efficacy of intensified adjuvant chemotherapy in osteosarcoma patients. design/method: we retrospectively analyzed the medical records of 48 children with osteosarcoma treated at asan medical center between 2006 and 2015. all patients received a 3-drug induction consisting of 2 cycles of cisplatin and doxorubicin along with 4 cycles of methotrexate (map), and proceeded to surgical resection. adjuvant ct was map or map with the additional ifosfamide and etoposide (mapie), and mapie was mainly considered for poor responders (tumor necrosis below 90%) or patients with metastases. results: among 48 patients, 6 patients had metastases at diagnosis. surgery was conducted in 43 patients who responded to induction ct, and 17 showed over 90% tumor necrosis. among 43 patients who proceeded to adjuvant ct, 19 and 24 patients received to map and mapie protocols. with a median follow-up of 73 months, the 5-year overall survival (os) and event-free survival (efs) rates of all patients were 80% and 46.7%. of those 43 patients, 16 patients recurred, and 5 of them died of disease progression. relapsed patients received salvage ct and/or surgery, and 2 were rescued after autologous stem cell transplantation (sct). three patients developed treatment-related acute myeloid leukemia, and they are alive after allogeneic sct. according to the response to neoadjuvant ct, the os rates of good responders (n = 18) and poor responders (n = 30) were 100% and 68.1% (p = 0.011), and efs rates were 63.8% and 41.7% (p = 0.084). of the 30 poor responders, 9 patients received map as adjuvant ct, and the other 21 received mapie. the os rates of map and mapie group were 68.6% and 70.3% (p = 0.568), and efs rates were 30.0% and 48.3% (p = 0.247), respectively. when patients were classified into three groups: 1. localized disease & necrosis ≥ 90% (n = 17), 2. localized disease & necrosis < 90% (n = 24), 3. metastatic disease (n = 6), survival rates were in the order of group 1>2>3 (os = 100%:81.8%:16.7%, efs = 67.6%:43.6%:0%). in each group, intensified adjuvant ct by mapie did not improve survival outcomes. conclusion: initial metastatic disease and poor histological response to neoadjuvant ct were major risk factors for poor survival in osteosarcoma patients. we found that adding ifosfamide and etoposide to map did not improve survival outcomes of patients with adverse risk factors. more effective adjuvant therapy for these patients is needed. background: circulating cell-free dna (cfdna) that shed from tumors into circulation have been used for noninvasive molecular profiling in adult cancers but little is known about its utility in pediatric cancers. pediatric patients with metastatic and refractory solid tumors are known to have poor survival rates, and a key challenge in their management is obtaining biopsy samples especially at times when disease is widely spread or the patient is physically unfit for sampling. the development of a noninvasive profiling strategy is critical for optimizing molecularly guided therapy and assessing response to treatment. in this study, we want to determine the utility of cfdna to noninvasively analyze the molecular profiles of pediatric solid tumors such as neuroblastoma (nb), osteosarcoma (os), and wilms tumor (wt). design/method: tumor, plasma, and matched controls were collected from patients with nb, wt, and os, at diagnosis or time of disease progression. cfdna was extracted from the plasma and analyzed through multiple methodologies including a targeted next generation sequencing panels and shallow whole genome sequencing (swgs). results: fifteen nb patients, 10 os patients, and 2 wt patients had tumor molecular profiles known from different targeted next-generation sequencing platforms. in the cfdna of 7/15 nb patients, somatic mutations and copy number alterations previously reported in the tumors were detected, including recurrent nb drivers such as mycn amplification, alk, and atrx mutations. mutations not detected in the original tumor were also found in 6/15 nb patients including nras, mll2, arid1b, some of which are potentially actionable. in os, mutations known from the tumor were found in the cfdna of 5 of 10 patients, including atrx and notch3 mutations, as well as copy number alterations such as cdk4 amplification, which has targetable therapeutics available. of the two wt patients analyzed, cfdna revealed the same mutations as tumor in one patient, however in a cohort of patients where tumor was not available, cfdna revealed recurrent driver mutations such as amer1, dicer1. it is feasible to noninvasively identify somatic mutations and copy number alterations in cfdna of patients with pediatric solid tumors. establishing a platform using cfdna to identify molecular profiles of these tumors can serve as a powerful tool for guiding treatment and monitoring response to treatment. background: despite multi-modality therapy, the prognosis for patients with metastatic osteosarcoma remains poor necessitating development of novel targeted therapies. immunotherapy can be exploited to target osteosarcoma with exquisite specificity but remains limited by insufficient tumor specific targets. objectives: to overcome the dearth in tumor specific antigens, we have explored the use of tumor derived mrna (representing a tumor specific transcriptome) for development of personalized nanoparticle vaccines. design/method: rna-nanoparticles (rna-nps) can be amplified from limited amounts of biopsied tissue for induction of tumor specific t cells against osteosarcoma. since local vaccination strategies are mired by poor overall immunogenicity, we assessed the feasibility, immunogenicity and antitumor activity of intravenously administered rna-nps (tumor mrna complexed to dotap nanoliposomes) in pre-clinical murine and canine tumor models. we identified a clinically translatable np formulation for the delivery of rna to antigen presenting cells (apcs) that induces in vivo gene expression and preserves rna stability over time. tumor derived rna-nps induced antigen specific t cell immunity and mediated anti-tumor efficacy in several pre-clinical solid tumor models (i.e. b16f10, kr158b). when administered intravenously, rna-nps increased expression of co-stimulatory molecules (i.e. cd80, cd86, cd40, ccr7) and pd-l1 on cd11c+ cells throughout reticuloendothelial organs (i.e. spleen, liver, bone marrow) and within the tumor microenvironment; this phenotype was strictly dependent on type i interferon. targeted inhibition of type i interferon signaling (via infar1 mabs) abrogated anti-tumor efficacy mediated by rna-nps. we enhanced the immunogenicity of this platform by simply combining mrnas encoding for immunomodulatory molecules (i.e. hcv-pamps, gm-csf) or by combining rna-nps with immune checkpoint inhibitors. addition of checkpoint inhibitors (pd-l1 mabs) to rna-nps increased tumor infiltrating lymphocytes, and intratumoral mhc class i/ii expression, and mediated synergistic anti-tumor activity in settings where pd-1 or pd-l1 inhibition alone did not confer therapeutic benefit. we then explored the feasibility of rna-nps in a large animal osteosarcoma model. in ongoing studies for canines with osteosarcomas, we have shown that sufficient amounts of rna can be extracted, amplified, and manufactured into personalized rna-np vaccines. conclusion: rna-nps reprogram systemic immunity and mediate anti-tumor activity providing near immediate immune induction without the complexity of cellular immunotherapy. the immune correlate of preclinical response to rna-nps is hallmarked by interferon dependent pd-l1 expression on activated apcs (cd11c+ mhcii+ cd86+ cells). based on these findings, we are exploring the preclinical safety, efficacy and immunologic effects of rna-nps targeting canine osteosarcoma before first in-human evaluation. background: ewing sarcoma is an aggressive bone tumor affecting mainly adolescent and young adults. treatments are based on compressed schedule chemotherapy combined with local control (surgery and/or radiation). prognosis is poorer for patients with metastatic disease, older age and central primaries. survival when disease recurs within two years of diagnosis is <10%. the ews-fli1 fusion gene t(11; 22) (q24; q12) has been well characterized as a dominant ews driver-gene. the most common variation is ews exon 7 with fli1 exon 6 (60% of fusion positive patients). we designed a novel pbi-shrna tm ews/fli1 type 1 lpx which has demonstrated, safety and efficacy in animal model (rao et all). the pbi-shrna strategy silences target gene expression by concurrently inducing translational repression and p-body sequestration as well as post-transcriptional mrna cleavage. to determine the safety and maximum tolerated dose of intravenous administration of pbi-shrna tm ews/fli1 type 1 lipoplex in patients advanced ews. design/method: phase i study 3 × 3 escalation cohort. testing pbi-shrna tm ews/fli1 type 1 lpx (starting iv dose of 0.04 mg/kg) on patients (≥ age 8) with advanced ewing's sarcoma, all with a type 1 translocation. intravenous infusion was given twice a week for 4 weeks with the following escalation schema: 50% → 33% → 25% → 25% → 25%. required kps >80% and adequate organ function. cytokines induction pre and post-infusion was analyzed (il-12, il-6, tnf-alpha, il1ra). first cohort of patients has been enrolled (ages between 17-35 years). three relapsed patients had >3 lines of therapy and 1 patient had refractory disease, 3 patients received a complete cycle of pbi-shrna tm ews/fli1 type 1 lpx with twice a week infusions. a total of 69 doses were given. the most prominent related toxicity has been hematological, 1 patient developed transient g3 neutropenia, another patient developed g3 anemia that required prbc transfusion, and of note this patient had significant bone and bone marrow involvement. one patient only received two lpx infusions; she developed a fatal rsv pneumonia. other reported grade 2 toxicity includes fatigue and headache. evaluable patients (n3) had stable disease between 4 and 12 months before progression. one patient had sustained response for 12 month before progression, two patients are still alive. our preliminary experience supports the safety and potential efficacy of pbi-shrna tm ews/fli1 type 1 lpx as novel treatment for advanced ews with limited toxicity. il-6 increase correlates with higher bi-shrnai ews/fli1 lpx infusion rate and clinical symptoms. further clinical testing is indicated. background: as more children with cns malignancies (bt) are surviving, the late effects of the therapies they receive are better described. studies show that radiation therapy is particularly harmful to neurocognitive functioning, specifically processing speed, working memory, and attention span. these deficits have negative effects on quality of life, especially in academic and professional settings. a large proportion of s255 of s301 adult survivors of bt are unable to reach adult milestones such as living on their own, holding a steady job, and getting married. proton beam radiation therapy (pbrt), is touted for the potential to have fewer and less severe side effects than traditional photon radiation therapy (xrt). because of the properties of protons, the amount of damaging energy released in non-target healthy tissue is reduced when compared to xrt. although a study comparing iq testing between pbrt and xrt found no difference between the two therapies, no studies have compared the specific neurocognitive domains. it would be valuable to evaluate full neurocognitive testing scores (nct) since the specific domains, particularly processing speed (psi), appear to be most vulnerable to radiation therapy. objectives: our primary aim was to assess differences in psi for patients with bt who underwent pbrt versus xrt. a secondary aim was to assess differences in iq (fsiq) and working memory (wmi). we retrospectively evaluated all patients treated for bt at the jimmy everest cancer center within the past 20 years who received rt and had nct post radiation. we examined the full nct results for both subsets of participants to evaluate differences in the specific domains of processing speed, working memory, and iq by measuring percentiles scored in these domains. objectives: we report our experience on imaging children with mm treated uniformly on an institutional melanoma trial. we retrospectively reviewed the clinical and imaging findings of patients with ajcc stage iic-iv cutaneous mm treated on our institutional mel06 protocol. brain mri/ct, pet/ct, ct chest, abdomen, and pelvis (ctcap) were performed at diagnosis in all patients. on treatment, stratum a patients (peg-interferon; ajcc iic, iiia, iiib) (n = 16) had the same imaging repeated every 6 months; stratum b1 (peg-interferon and temozolomide; unresectable measurable disease metastatic, or recurrent) (n = 2) had pet scans every 2 months and brain imaging every 4 months; those in stratum b2 (peg-interferon and temozolomide; unresectable non-measurable, metastatic, or recurrent) (n = 3) had the same imaging performed every 4 months. off therapy all patients continued same imaging every 6 months for 3 years. results: there were 21 patients (11 female; median age 14 years). eleven had spitzoid and 10 conventional melanoma. primary sites included head/neck (n = 6), trunk (n = 7), and extremities (n = 8). patients with spitzoid melanoma had 236 imaging studies (86 pet, 81 ctcap, 11 ct chest, 10 ct brain, and 48 mri brain) with a median of 8, 7, 0, 4 and 0 studies/patient respectively. median cost per patient was $32,718. thirteen studies (5.8%) showed suspicious lesions with 28 additional scans and 2 diagnostic biopsies of which one only was positive stratum a with tert promoter mutation and died from disease). for conventional mm, 162 studies (61 pet, 57 ctcap, 8 ct chest, 7 ct brain, and 29 mri brain) were performed with a median of 7, 6.5, 0, 1, 3 studies/patient respectively. median cost per patient was $23,420. twenty (14%) showed suspicious lesions with 19 additional scans and 6 diagnostic biopsies; four were positive (two at diagnosis); both died of disease; the other two recurred locoregionally and were detected clinically; both are alive and disease free; one patient had diffuse metastases and died shortly after enrollment. after a median follow up of 6.3 years (range 0.4-9.2) 17 patients are alive and disease free. children with spitzoid melanoma should have minimal imaging at diagnosis and follow-up given the low risk of recurrence and low yield and high cost of aggressive imaging protocols. patients with conventional mm should be imaged according to the adult guidelines. nationwide children's hospital, columbus, ohio, united states background: the role of infections in the long term outcome of patients with bone tumors is controversial. two retrospective studies have shown increased survival in osteosarcoma patients who had a post-operative wound infection, while another showed no changes in overall survival. to determine the relationship between wound infections and/or bloodstream infection (bsi) on survival in pediatric and young adult patients with osteosarcoma and ewing sarcoma treated at a tertiary children's hospital. design/method: a retrospective chart review was performed for patients with diagnosis of osteosarcoma or ewing sarcoma from 2006-2016. patients received standard chemotherapy regimens for their disease type and stage. local control included surgical resection and/or radiation therapy. presence of infection was determined by bsi or wound cultures while receiving treatment for primary tumor. the median age of 85 patients was 14 (range 2-46 years) at diagnosis. 53% had a diagnosis of osteosarcoma and 47% had ewing sarcoma. of these, 46% of patients developed an infection during treatment; 25% had bsi, 26% had wound infections, and 5% had both. patients with bsi had a 5 year os of 63.3%, compared to 81% in those without bsi (p = 0.0015). those with both bsi and wound infections had the poorest overall survival of 50%, compared to 80.8% for patients without any infection. patients with wound infections alone had a 5 year os of 80.2%, compared to 75% of patients without a wound infection. our analysis revealed decreased os in patients with bsi; however, this could be due to other confounding factors in the presence of bsi. those with bsi or bsi and wound infections had the poorest survival. wound infections without bsi were associated with a slight increase in survival; however, this study was limited by the number of patients that had local wound infections. with the use of newer surgical techniques, availability of antimicrobials and routine use of prophylactic antibiotics, the incidence of infections while undergoing treatment is low. however, the importance of this clinical observation indicates a likely enhanced immune system associated with infection, supporting the role of immunotherapy for treatment of these aggressive tumors. background: hypoalbuminemia is a well-recognized effect of cancer and other chronic illnesses and is often regarded as a marker of malnutrition. in adults, hypoalbuminemia has been associated with adverse outcomes in patients with cancers of the lung, pelvis, head and neck, gastrointestinal tract, and bone marrow, as well as in some pediatric patients with ewing sarcoma and hodgkin lymphoma. hypoalbuminemia has not been well studied in children with cancer. to determine the incidence of hypoalbuminemia (using age-specific references) in children with cancer receiving chemotherapy at baseline (prior to starting chemotherapy) and to determine whether hypoalbuminemia is associated with inferior 5-year overall survival. design/method: we performed a single institution, irbapproved, retrospective review of pediatric oncology patients diagnosed between 1998 and 2012. five-year survival was estimated using the kaplan-meier method; groups were compared using cox regression. we identified 863 pediatric patients with a first diagnosis of cancer, brain tumor, or other condition possibly requiring chemotherapy. of these 863 patients, 204 were excluded for reasons including not receiving chemotherapy and missing data, leaving 659 patients who had a serum albumin level within 60 days prior to starting chemotherapy. the mean age was 8.1 years (sd 5.8 years); 62% were male; 92% were non-hispanic. the most common diagnosis was acute lymphoblastic leukemia (201 of 659; 31%). one hundred thirty nine of 659 (21%) had hypoalbuminemia prior to starting chemotherapy. there was no statistically significant difference in 5-year overall survival between those with and without hypoalbuminemia (78% vs. 82%, respectively; hazard ratio 1.27, 95% c.i. 0.85 -1.90). conclusion: hypoalbuminemia at baseline in pediatric oncology patients requiring chemotherapy is common (one in five), and was not associated with inferior 5-year overall survival in this cohort. leptomeningeal metastases at diagnosis. standard treatment for completely resected, non-anaplastic supratentorial ependymomas is close observation. treatment for anaplastic or incompletely resected non-anaplastic ependymomas is maximal safe surgical resection followed by focal radiation. however, up to 50% of localized ependymomas recur. the role of chemotherapy in treating ependymomas is under investigation. extraneural metastases of anaplastic ependymomas have rarely been reported and the outcome is dismal. objectives: to report extraneural cervical node metastases of a non-anaplastic ependymoma and successful treatment with surgical resection, radiation, and systemic chemotherapy. design/method: retrospective review of patient medical records, including radiographic imaging and tumor tissue pathology, and comprehensive literature review. results: a previously healthy 3-year-old girl underwent gross total resection (gtr) of an isolated right parietal lobe ependymoma (who grade ii). at age 4 years, magnetic resonance imaging (mri) revealed an isolated localized recurrence. she underwent gtr followed by observation. at age 6 years, she again experienced isolated localized recurrence and underwent gtr followed by 59.4 gy focal conformal photon radiation. at each recurrence, pathology revealed a non-anaplastic ependymoma, and cerebral spinal fluid (csf) cytopathology and spine mri were negative. at age 10 years, she developed an enlarged right posterior cervical chain lymph node. subsequent mri revealed a large rim-enhancing, t2 hyperintense lymph node and multiple abnormally enhancing regional nodes consistent with metastases. biopsy revealed a non-anaplastic ependymoma. mri of the brain and spine, computed tomography of the chest, abdomen, and pelvis, and csf and marrow evaluations were unremarkable. chemotherapy according to acns0831 was initiated. mri after course 3 demonstrated significant node size reduction. she underwent right neck node dissection. only one right level ii lymph node showed metastases. she was treated with 59.4 gy irradiation to the neck and 3 additional courses of chemotherapy. she remains in remission 24 months and 17 months after diagnosis of metastatic disease and end of therapy, respectively. literature review reveals rare reports of extraneural metastatic disease of anaplastic ependymomas to bone, lung, or liver, and only 2 involving lymph nodes, all associated with a poor outcome despite multimodal therapy. to our knowledge, this is the first report of extraneural metastases of a non-anaplastic ependymoma. extraneural metastases should be considered in children previously treated for non-anaplastic ependymomas who experience systemic symptoms, even in absence of cns relapse. multimodal treatment offers potential long-term disease control with acceptable toxicity. arun gurunathan, joel sorger, andrew trout, joseph pressey, rajaram nagarajan, brian turpin cincinnati children's hospital medical center, cincinnati, ohio, united states background: pigmented villonodular synovitis (pvns) is a benign neoplasm of the synovium. standard treatment is surgery, but post-operative recurrence rate is as high as 60%. radiation therapy can be used for local control, but is associated with late effects. while pvns is rarely fatal, aggressive disease and/or extensive surgery can result in substantial functional impairment. colony stimulating factor-1 (csf1) overexpression, often due to chromosomal translocation involving csf1, drives pvns through recruitment of synovial-like mononuclear cells expressing the csf1-receptor. tyrosine kinase inhibitors such as imatinib are active against the csf1-receptor, and have shown benefit in the post-surgical relapse setting. however, questions remain regarding the broader application of imatinib and regarding optimal response assessment. to present three patients with pvns, each with different clinical scenarios, who demonstrate clinical response to imatinib monitored by changes in metabolic activity (maximum suv) on pet/ct. results: three patients with pvns demonstrate pet/ct response to imatinib, guiding management of their challenging clinical scenarios. patient 1 is a 20 year-old female with left hip pvns and high grade articular cartilage loss, with decrease in metabolic activity (suvmax 8.3 to 4.7 in 3 months) on neoadjuvant imatinib, enabling total hip replacement surgery planning. patient 2 is a 16 year-old female with left knee pvns with recurrences after synovectomies, spared subsequent surgical control attempts after clinical improvement correlating with pet/ct response to imatinib (suvmax 10.2 to 4.3 in 2 months). patient 3 is a 27 year-old male with right knee pvns that recurred after total knee replacement, now with clinical improvement correlating with pet/ct response to imatinib (suvmax 11.2 to 5.2 in 3 months). all patients would have been characterized as stable disease by response evaluation criteria in solid tumors (recist). in each of these patients, imatinib has been tolerated well, with no therapy interruptions and absent or easily managed side effects (one patient takes dronabinol for decreased appetite, one patient takes prn immodium for diarrhea). all patients are currently still taking imatinib, with therapy length ranging from five to eleven months. in our series of three patients with pvns, imatinib shows promise for disease management in neoadjuvant and adjuvant settings with a tolerable side effect profile. imatinib should be considered in the treatment of pvns to spare surgical and radiotherapy related morbidity, and treatment effect can be monitored by pet/ct. background: metastatic rhabdomyosarcoma (rms) carries a poor prognosis with three-year event free survival rates ranging between 20%-69% (depending on oberlin risk factors) due to the lack of significantly effective breakthroughs in the recent past. there is an urgent and unmet need for new treatment strategies against this disease. metastatic rms cell lines exhibit increased expression of the erm family membrane-cytoskeleton linker protein ezrin. knockdown of ezrin expression using sirnas decreases the metastatic potential of these cells, whereas forced expression of ezrin results in increased degree of metastasis. the activity of ezrin is controlled by its phosphorylation at the threonine 567 (thr567) residue at the c-terminus of the protein, suggesting that alteration of ezrin phosphorylation may control rms growth and metastasis. our goal was to determine if pharmacological inhibition of thr567 phosphorylation in ezrin affects the growth, survival and metastasis in rms in vitro as well as in vivo. design/method: rms cell lines representative of the alveolar and embryonal histological subtypes were used. rms cells were treated with a small molecule inhibitor of ezrin, nsc668394, which specifically dephosphorylates ezrin at the thr567 residue. baseline expression of ezrin and perm levels as well as the effect of nsc668394 on perm levels in the rms cell lines was determined by western blotting of cell lysates. viability of cells was assessed by trypan blue exclusion, and morphology visualized by bright field microscopy. the extent of apoptosis was detected by imaging caspase 3/7 activation using fluorescent microscopy. motility of rms cells was examined by performing a wound-healing assay. subcutaneous and orthotopic xenografts were established in nsg mice using rd cells (embryonal rms). mice harbor-ing xenografts were treated with intraperitoneal injections of nsc668394 or dmso. results: ezrin is constitutively phosphorylated at the thr567 residue in a majority of the rms cell lines examined. nsc668394 dephosphorylates ezrin at the thr567 residue in these cell lines. treatment with nsc668394 inhibits growth, induces apoptosis and inhibits the migration of rms cell lines in vitro. further, treatment of nsg mice bearing subcutaneous or orthotopic embryonal rhabdomyosarcoma xenografts with nsc668394 significantly impedes tumor progression without any obvious adverse effects. our findings suggest that dephosphorylation of ezrin at the threonine 567 residue may have the potential to be a novel therapeutic strategy for rms patients. all india institute of medical sciences, new delhi, new delhi, delhi, india background: the role of laparoscopy in the management of pediatric intra-abdominal solid tumors is yet to be established. the safety of laparoscopic management of pediatric intra-abdominal tumors is still questionable. we study the results of the initial case series of pediatric intraabdominal tumors managed laparoscopically at our institute from july 2013 onwards. design/method: total 11 children (8-males, 3 females) who presented to us with pediatric intra-abdominal tumors were included. the tumors included wilms tumor (n = 7), neuroblastoma(n = 2), adrenal cortical tumor(n = 1), ovarian teratoma(n = 1).children were between 10months -7years and 4 received neo-adjuvant chemotherapy. a 4-port laparoscopic nephrectomy and lymph node sampling for wilms tumor and adrenalectomy for adrenal tumors was performed. the tumors were removed in-toto with no rupture (except in one). specimens were retrieved through a lumbar incision (n = 8) or an inguinal incision(n = 1). all the children are under regular follow up. two children with wilms tumor had recurrence. the neuroblastoma child underwent open surgery for recurrence later. conclusion: laparoscopy/laparoscopic assisted removal of pediatric intra abdominal tumor is a feasible and safe option. it has the advantage of less postoperative pain, shorter hospital stay and a better cosmetic result. proper patient selection, port placement and laparoscopic experience are contributory. background: targeting of proteins and cell surface antigens specific to cancer cells with monoclonal antibodies has proven to be an effective form of treatment in many forms of cancer. gd2 is a cell surface disialoganglioside that is expressed on the cell surface of some normal tissues including nerve cells, melanocytes, and mesenchymal stromal cells and is overexpressed in some pediatric cancers like neuroblastoma and osteosarcoma. dinutuiximab is a chimeric monoclonal antibody that is fda approved for the treatment of patients with high risk neuroblastoma and under investigation for the treatment of relapsed osteosarcoma. little is known about the patterns of gd2 expression in other pediatric malignancies. objectives: we sought to describe the patterns of gd2 expression in the following pediatric sarcomas: synovial sarcoma, rhabdomyosarcoma and ewing sarcoma. design/method: synovial sarcoma (n = 44), rhabdomyosarcoma (n = 35) and ewing's sarcomas (n = 12) formalin fixed, paraffin embedded cores were obtained from the seattle children's research institute tissue microarray (tma) biorepository. tma blocks consisting of melanoma cores stained with and without gd2 antibody were used as positive and negative controls, respectively. slides were incubated with anti-ganglioside gd2 antibody clone 2q594 (ab68456 from abcam) diluted 1:50 in 10% normal goat serum and 5% bsa in tbs overnight at 4˚c. the negative control of human melanoma section was incubated in 10% normal goat serum and 5% bsa in tbs without primary antibody. the expression of gd2 was indicated by characteristic brown diaminobenzidine staining. the intensity and location of tissue staining were assessed and compared to positive and negative controls. staining was considered positive (+++) if the intensity of the staining was consistent with that of the positive control with 67-100% of cells staining positive. classification of intermediate gd2 expression (++) was assigned to slides in which 34-66% of cells stained positive. slides were classified as sporadic staining (+) if 1-33% of cells stained positive. tissue was considered (-) if there was complete absence of staining, similar to the negative control. objectives: to evaluate the clinical presentation, management and treatment outcomes of children with malignant germ cell tumor at our institute design/method: a prospective study was conducted from june 1994 to dec 2016 in the department of pediatric surgery in a tertiary care institute in a developing country. all patients were evaluated for local disease and metastatic disease by imaging and tumor markers. risk stratified chemotherapy was used with low risk tumor receiving no chemotherapy, intermediate risk: 4 courses of peb chemotherapy and high risk: 4 courses of peb + 2 courses of pe. upfront resection of the primary or the residual disease after neoadjuvant chemotherapy if feasible was performed. follow up was done with monthly tumor markers for 6 months and imaging studies every 3-6 months for initial 3 years. five year overall survival and disease free survival was calculated. results: during the study we treated 152 children who formed the study group. of these 83 (55%) were gonadal (45;30% testicular and 30;25% ovarian) and the remaining 69 (45%) were extragonadal with sacrococcygeal (sct) being the most common site 48 (31%). one hundred and thirteen children (75%) presented to us primarily while the remaining 39 had received treatment elsewhere. stage 3 or stage 4 disease at presentation was present in 104 (68%) children. recurrence was noted in 50 (33%) patients. respectively. patients with testicular mgct and children with age 2-5 years and males had significantly poor rfs rates. conclusion: patients with mgct should be staged correctly and adjuvant chemotherapy is advisable to all patients except stage i endermal sinus tumor of testis. awareness regarding the same is still lacking in our country. meticulous follow up is needed as more than 30% of will recur. cure rates are dismal in children with recurrent mgct especially those who are not chemotherapy naïve. nemours children's specialty care, jacksonville, florida, united states background: radiotherapy for pediatric head and neck tumors often results in mucositis, limiting oral intake and compromising patients' nutritional status. this may be reduced through the improved conformality offered by proton therapy. despite widespread use of enteral tube feeding through a percutaneous gastrostomy (peg) or nasogastric tube (ngt), there is little data available regarding overall incidence of ngt/peg placement and perspectives of pediatric patients and caregivers. objectives: to (a) estimate the need for ngt/peg support and (b) characterize patient and caregiver perceptions surrounding enteral feeding in children with head and neck tumors undergoing proton therapy. design/method: dependent on development stage, patient (n = 16) or parents (n = 6) filled out a series of customized surveys according to a prospective irb approved study. seventythree percent of patients also received concurrent chemotherapy. questions addressed their current feeding route and perception, for example, "what aspect(s) of tube feedings are beneficial to you?" and "what aspect(s) of tube feeding worry or scare you?" fifty-five surveys were distributed before and after radiation, and with any change in feeding route. results: at the start of proton therapy, 1 patient had a ngt and 8 patients had peg. of these, 8 patients (36%) had a ngt/peg in place exclusively for the administration of medication; only 1 patient (4%) needed a ngt/peg for nutrition. in those patients without ngt/peg, 46% would "consider" enteral feeds. in patients without ngt/peg, the most commonly cited benefit was "maximizing my nutrition" (67%) and the most common negative aspect was "fear" of tube placement (100% of patients). all sub-populations (32% of patients) cited change in appearance as a negative aspect. in patients without ngt/peg at the start of proton therapy, 46% of patients/caregivers felt enteral feeding to be "unnecessary," and 83% of these patients would not "consider" ngt/peg even if their "physician advised it." over the course of proton therapy, the patients/caregivers who deemed enteral feeding "unnecessary" decreased from 46% to 18%. at completion of treatment, 7 patients (32%) were using a ngt/peg tube for nutritional support but only one (4%) patient relied exclusively on their enteral feeds. two patients (without ngt/peg) (9%) required parenteral support. our data does not support prophylactic placement of ngt/peg in of children with head and neck tumors undergoing proton therapy. ongoing research is needed to identify which patients will need ngt or peg to supplement their diet. in this cohort, anticipatory counseling should focus on pain, cosmesis, and utility. children's national medical center, washington, district of columbia, united states background: ovarian sex cord-stromal tumors (osct) are rare neoplasms that typically present with signs/symptoms of an adnexal mass and signs of hormonal production1 approximately 20% of ovarian sex cord-stromal tumors in children are sertoli-leydig cell tumors (slct) with median age of presentation 25 years overall.1 to our knowledge the youngest reported case in the literature describes a 9-month old female in china with a slct that was treated with oophorectomy alone.2 some studies have found an association in families between pleuopulmonary blastoma and osct with a germline mutation leading to dicer1 syndrome, which has been associated with a younger age at diagnosis.3,4 objectives: to describe an unusual case presentation of slct in an infant results: 3-month old, twin female, ex-32 week premature infant presented to the emergency department on multiple occasions for abdominal distention and feeding intolerance initially thought to be related to previous omphalocele repair and umbilical hernia. an ultrasound demonstrated an 8 × 6 cm mass arising from the right ovary with large volume ascites. she required admission to the intensive care unit due to s261 of s301 respiratory distress from her significant ascites. serum tumor marker including hcg, afp and ldh were negative. patient underwent right oophorectomy with tumor capsule noted to be open at time of surgery. further imaging post operatively demonstrated no other sites of disease. the patient was classified as figo stage ic due to the presence of her significant abdominal ascites that was presumed to be malignant pre-operative tumor rupture.5 the pathological diagnosis was challenging and eventually resulted as a mixed germ cell sex cord stromal tumor with pattern of sertoli cell tumor with neuroendocrine differentiation. based on the staging of figo ic with pre-operative rupture, the decision was made to treat with a standard platinum based regimen as there is a higher incidence of relapse in stage ic patients when compared to ia treated with observation alone.6 our patient tolerated four cycles of chemotherapy well and end of therapy scans showed no evidence of disease. interestingly, her dicer mutation genetics performed by ion torrent tm next generation sequencing was negative in germline and tumor studies. to our knowledge, our patient is the youngest described with slct. she will continue to be followed with serial imaging alone as she had no evidence of elevated tumor markers at diagnosis.6,7 due to young age and unusual diagnosis, she was referred to cancer genetics team. background: approximately 12% of patients with wilms tumor (wt) have metastatic disease at diagnosis and often have a grave prognosis. limited cell lines are available for the study of metastatic wt and long-term passaged cell lines do not always recapitulate the human condition. focal adhesion kinase (fak) is a non-receptor tyrosine kinase that controls cellular pathways involved in the tumorigenesis of pediatric renal tumors. using a novel patient-derived xenograft (pdx) model from a patient's primary wt (coa 25) and matched isogenic metastatic wt (coa 42), we previously demonstrated that fak is expressed and its inhibition led to decreased tumorigenicity of both the primary and metastatic pdxs. kinomic profiling is an innovative, high-throughput method used to investigate kinase signaling to identify potential therapeutic targets. to date, the kinomic profile of primary and metastatic wt has not been examined. objectives: investigate baseline kinomic differences between primary and metastatic wt and evaluate kinases upstream and downstream of fak as potential targetable therapies. design/method: cells from coa 25 and coa 42 were treated with pf-573,228 (pf), a small molecule fak inhibitor. protein from cell lysates of treated and untreated coa 25 and coa 42 were combined with kinase buffer, atp, and fluorescently labeled antibodies and loaded into a phosphotyrosine kinase or serine-threonine kinase pam-chip® per the uab kinome core protocol. phosphopeptide substrate analysis with the pamstation®12 kinomics workstation (pamgene® international), pamchip® protocol using evolve2 software, and bionavigator v. 6.0 were used to analyze kinases upstream and downstream of fak. the primary wt had increased epha8, ror1 sgk307 and decreased pdgfrb relative to the paired metastatic wt at baseline. treatment with pf increased ron, pdgfrb, p70s6kb, mak, camk2g, vacamkl, camk2d, ck1a1 and pskh1 in the primary wt. treatment with pf decreased tnk1, lmr1, cck4, epha5, pdk1, sgk196, lkb1 and increased pskh1 in the paired metastatic wt. primary wt displayed a different kinomic profile compared to metastatic wt in a matched isogenic pdx model. these data reveal that alternative therapies to specifically target metastases are needed. furthermore, fak inhibition resulted in diverse kinomic alterations between primary and metastatic wt. inhibitors targeting many of these pathways, such as pdgfrb inhibitors, are currently available and potentially could be combined with fak inhibitors in the treatment of wt. the results of the current study indicate that kinases upstream and downstream of fak in primary and metastatic wt warrant further investigation. background: use of high-dose methotrexate (hd-mtx, 12 g/m^2) is a mainstay of standard therapy for pediatric osteosarcoma (os) in north america. in pediatric os, there is a narrow therapeutic window for hd-mtx, with decreased tumor response rate with mtx concentrations <1000 m and decreased survival due to severe toxicity with concentrations >1500 m. risk factors for hd-mtx toxicity have been defined in adults, including body mass index (bmi) and male gender, but such studies have not been conducted in children. we sought to examine the relationship between mtx levels and toxicities during hd-mtx infusion for pedi-atric os, thereby identifying risk factors for increased toxicity and providing a framework for therapeutic drug monitoring. design/method: this retrospective chart review included patients treated at texas children's hospital with hd-mtx as first-line therapy for os from 2009-2015. data abstracted from electronic records included patient characteristics, bmi and body surface area (bsa), baseline and post-treatment laboratory values, mtx levels 4 and 24 hours after dose given (4h, 24h), hour mtx cleared (mtx <0.1 um), grade 3/4 mucositis, myleosuppression, persistent lft elevation (ctace v4.0), and % tumor necrosis. correlation between 4h mtx level and other covariates was summarized using descriptive statistics. we reviewed 128 hd-mtx infusions corresponding to 12 patients. bmi was found to significantly impact 4h mtx level (p<0.05). female gender was also significantly associated with higher 4h mtx level (p<0.001). percent necrosis (available in 9 patients) was associated with 4h mtx levels at near-statistical significance (p = 0.07). 4h mtx level was not found to contribute to toxicities or associate significantly with mtx clearance. analysis in a larger cohort is ongoing. we have identified at least one patient factor (bmi) that significantly impacts 4h mtx levels and is of potential use for future modeling, as current models incorporate bsa only. our findings concord with studies in adult os in that bmi significantly impacts 4h mtx level but diverge in that female gender is associated with higher 4h levels. importantly, these data support targeting 4h mtx levels to ensure that minimum concentration for adequate tumor necrosis is reached. these results do not suggest that monitoring 4h levels would prevent toxicities, thus necessitating further characterization of any intrinsic patient factors that associate with toxicity. overall, our definition of the clinical factors that associate with 4h mtx levels contributes to a framework for therapeutic drug monitoring in pediatric os. children 's mercy hospital kansas city, kansas city, missouri, united states background: post consolidation immunotherapy with dinutuximab, aldesleukin (il-2), granulocyte macrophage colony stimulating factor (gmcsf) and isotretinoin is standard of care for children with high risk neuroblastoma. dinutuximab is combined in 5 alternating cycles with s263 of s301 gmcsf or il2, followed by a 6th cycle with isotretinoin alone. il-2 is administered as a 96hour continuous infusion on days 0-4 at 3miu/m2/day followed by a higher infusion dose, 4.5miu/m2/day, in combination with dinutuximab on days 7-10 of cycles 2 and 4. the 3miu/m2/day dose may be administered inpatient or in the ambulatory setting. objectives: to retrospectively compare the incidence of inpatient and outpatient side effects and complications associated with low dose (3miu) il2 to provide the tolerability data necessary to evaluate these venues for future administration options. design/method: this study was a descriptive, singlecentered definitive study utilizing a retrospective convenience sample population of children with high risk neuroblastoma who received low dose il2 either as an inpatient or an outpatient without exclusion from may 2012 to june 2017. subjects were identified by a tumor registry query post irb approval. electronic and paper medical records were reviewed for the dates and location of the infusions, the home health company used if applicable and all documentation regarding clinical status, side effects and toxicity. demographics was limited to age and gender. results: infusion venue was chosen by provider preference. twenty-six infusions, 9 inpatient and 17 outpatient via 3 separate home health companies were all administered in entirety and without interruption. there were 10 males and 4 females ranging from 2-7 years of age. two children received a single outpatient infusion due to intolerance of il2 when combined with dinutuximab and 2 received therapy in both settings. fever, 3 inpatient and 1 outpatient was the only common side effect. no source of infection was ever identified. there was one incidence of diarrhea and one patient with pruritus in both the outpatient and inpatient settings respectively. no planned outpatient infusions required subsequent admission however the outpatient fever did necessitate an er evaluation. conclusion: low dose il 2 can successfully be administered outpatient. the medication has minimal side effects with fever occurring in 15%, none of which were associated with infection. no outpatient infusion required a subsequent admission. no patients who received cycle 2 infusions outpatient opted to receive the next cycle inpatient. baylor college of medicine, houston, texas, united states background: metastatic ewing sarcoma (es) has an extremely poor overall survival, necessitating investigations into molecular mechanisms to identify novel targets and develop new therapies. we previously performed an in vivo study, using our mouse model, designed to provide insights into transcriptomic and proteomic signatures for metastatic es to identify potential therapeutic targets. comparing profiles of primary tumors to corresponding metastatic lesions, we identified aberrant expression of integrin ß3 (itgb3) and downstream activation of integrin-linked kinase (ilk) in metastatic lesions compared to primary tumors, implicating this pathway as a key regulator in the ability of es to establish and enhance metastasis. our hypothesis is that upregulation of itgb3 and its downstream signaling events play a key role in es metastasis and are viable therapeutic targets. objectives: to investigate the role of itgb3 and its downstream signaling pathways in driving the establishment and enhancement of metastasis in es and to investigate this pathway as a potential therapeutic target. to investigate the role of itgb3 and ilk in es metastasis, we used sirna to knock down itgb3 and ilk expression in established es cell lines and then performed functional assays in vitro, including cell proliferation and invasion/migration assays. we also tested inhibition of this itgb3 signaling pathway using available small molecule inhibitors targeting itgb3, ilk and the downstream target ap-1, using cilengitide, compound 22 and sr11302, respectively. we are currently using these small molecule inhibitors as treatment in vivo and assessing rates of metastatic tumor formation. we generated stable itgb3 and ilk overexpression and knockdown cell lines, which we are using for similar in vitro and in vivo investigations. knockdown of itgb3 and ilk in our sirna cell lines resulted in decreased cell proliferation and decreased invasion and migration compared to controls. we also found significantly decreased cell proliferation using each of the small molecule inhibitors in vitro. our preliminary studies using compound 22 in vivo established a safety profile and dose escalation is underway to assess the effectiveness of inhibiting es metastasis. these results support our hypothesis that itgb3 and its downstream signaling events play a key role in the ability of es to establish metastatic foci and may serve as a potential therapeutic target. we continue to investigate this pathway in vitro. we are also using our small molecule inhibitors and itgb3 and ilk overexpression and knockdown approaches to study these effects on metastatic tumor development in vivo using our mouse model. background: neuroblastoma (nbl) is characterized by phenotypic heterogeneity. outcome is excellent for patients with low-(lr) and intermediate-risk (ir) disease, whereas only 50% of high-risk (hr) patients will survive. 5-hydroxymethylcytosine (5hmc) is an epigenetic marker of active gene transcription, and 5hmc profiles are prognostic in many types of adult cancers. we hypothesized that 5hmc profiles will serve as robust biomarkers in children with nbl tumors, refining current risk stratification. objectives: analyze genome-wide 5hmc in nbl tumors and correlate 5hmc deposition with chromosomal copy number and gene expression. design/method: 5hmc was quantified by nano-hmc-seal-seq from the dna extracted from 15 hr, 11 ir and 27 lr nbl tumors. read counts and clinical data were analyzed with deseq to identify genes with differential 5hmc patterns between risk groups. chromosomal copy number was assessed by chromosomal microarray analysis (cma) in a subset of samples (3lr and 9hr). expression of genes located on chromosome 1p was evaluated using publically available microarrays (e-mtab-1781) of 171 hr nbl tumors with known 1p loh status. results: globally, lr tumors had more 5hmc peaks (140,062) than ir (102,398, p = 0.36) tumors, or hr tumors (79,727, p = 0.01). 1,049 genes had different patterns of 5hmc deposition in hr versus lr tumors. 315 (30%) of these genes mapped to chromosome 1p and had decreased 5hmc in hr versus lr tumors (padj <0.05). in the cma analysis 1p deletion was detected in 5 of the 9 tumors tested. in the tumors with 1p loss, 322 genes that map to 1p showed decreased 5hmc deposition compared to the 4 hr tumors without 1p loss (p<0.05). further, compared to the tumors without 1p loss, the expression of 188 of the 322 1p genes was decreased (p<1 × 10-5), including chd5, camta1, and arid1a, known and proposed tumor suppressor genes in nbl. conclusion: different patterns of 5hmc accumulation are associated with neuroblastoma risk classification. nano-hmc-seal-seq is sensitive to copy number variations and has the potential to identify these changes in patient tumors. our results suggest that 5hmc deposition contributes to the silencing of tumor suppressor genes in 1p and may also regulate the transcription of other genes that drive tumor phenotype. background: metastatic osteosarcoma has a 5-year survival rate of 15-40%. pulmonary metastases remain a major treatment challenge in osteosarcoma. current treatment with conventional chemotherapy shows inadequate activity towards metastases and has toxic systemic side effects. chloroquine is a widely used anti-malarial drug and has been shown to have promising anti-cancer and anti-metastatic activity. polymeric drugs have been shown to have multiple advantages over their small molecular parent drugs, including enhancing the therapeutic efficacy, an improved pharmacokinetics profile and decreased systemic toxicity. we hypothesized that by developing chloroquine into a polymeric drug and combining it with conventional chemotherapy it will improve the treatment of metastatic osteosarcoma. objectives: to identify the optimal combination of polymeric chloroquine (pcq) with conventional chemotherapy active in osteosarcoma as a new means of treating metastatic disease in a murine osteosarcoma model. we synthesized and developed pcq and evaluated its anti-invasive activity using an osteosarcoma cell migration and invasion assay. we evaluated the efficacy of cell killing using combination drug therapies with pcq and a panel of conventional chemotherapy agents (doxorubicin, docetaxel, cisplatin and paclitaxel) using celltiter blue cell viability assay. to develop the murine osteosarcoma model, we intravenously injected luciferase-expressing human osteosarcoma cells 143b into nsg mice. we administered the drug combination that showed the strongest in vitro synergy to the mice and evaluated their anti-cancer and anti-metastatic effects in vivo. tumor growth and suppression were evaluated using whole body bioluminescence imaging. results: we successfully synthesized pcq that contains 16.7% chloroquine with a molecular weight of 18.9 kd. pcq was also found to decrease the toxicity of the parent chloroquine. pcq showed strong inhibition of osteosarcoma cell migration with 51% inhibition compared to 13% by chloroquine. we screened the combination drug therapies and found the combination of pcq and doxorubicin to show the strongest synergism. the pcq/doxorubicin combination is currently being evaluated in the murine model. combination drug therapy using pcq and doxorubicin showed synergistic cell killing and inhibition of cell migration in vitro. the combination represents a promising treatment strategy for pulmonary metastatic osteosarcoma. emory university/children's healthcare of atlanta, atlanta, georgia, united states background: survival for relapsed high-risk neuroblastoma (rnb) is < 5%, underscoring the critical need for novel therapies. rnbs have increased ras/raf/mapk mutations and increased yes-associated protein (yap) transcriptional activity. yap is a transcriptional co-activator that binds with tea-domain (tead) transcription factors to regulate cellular proliferation, self-renewal, and survival. we found that shrna inhibition of yap decreases nb cell proliferation and sensitizes ras-mutated nbs to mek inhibitors, supporting yap as a tractable therapeutic target. verteporfin (vp), a photodynamic drug used for macular degeneration, is the only drug found to inhibit yap expression or yap:tead binding to kill tumor-derived cells. peptide 17 is a 17mer yap peptidomimetic that also disrupts yap:tead interactions. we sought to determine whether these compounds are potent in nb via yap direct effects. design/method: yap expressing (nlf, sk-n-as) or yap null (ngp, lan5, sk-n-as-shyap) human-derived nbs were incubated with vp, with and without direct light exposure, or with peptide 17. celltiter-glo and immunoblots were used to assess for cell death and yap-downstream protein expression, respectively. results: without direct light exposure, vp inhibits yap expression at nm dosing, yet no nb cell death was observed at equal or higher concentrations. egfr and erk1/2 were inhibited along with yap, confirming yap/ras pathway coregulation. when vp was exposed to direct incandescent light for 30 minutes, > 80% nb cell death occurred in all nbs tested, even those lacking yap. peptide 17 caused no cell death or yap inhibition up to 75 um. neuroblastomas are resistant to vp at doses sufficient to inhibit yap expression. in macular degeneration, light-activated vp produces reactive oxygen species, which we hypothesize is the off target mechanism killing nbs independent of yap. given the off target effects and the need for light activation, vp is not an ideal preclinical or clinical yap inhibitor. accordingly, peptide 17 has poor cell permeability and low tead affinity, leading to its lack of efficacy. given the relevance of yap in rnb and other cancers, we are chemically optimizing a yap peptidomimetic with enhanced permeability, nuclear localization, and tead affinity to create a bonafide yap inhibitor for preclinical and clinical application. kayeleigh higgerson, aaron sugalski, rajiv rajani, josefine heim-hall, jaclyn hung, anne-marie langevin ut health san antonio, san antonio, texas, united states background: osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. most study cohorts have 10 to 15% hispanic patients that encompass many different hispanic backgrounds. the university of texas health science center at san antonio (uthscsa) sarcoma team serves a latino population that is predominantly mexican american, thus providing a unique opportunity for evaluation this population. this study expands on previous data collected from january 2000 to december 2010 from the same institution, providing increased insight into outcomes of mexican american children, adolescents, and young adults with osteosarcoma. objectives: to further understanding of osteosarcoma in latino children, adolescents and young adults. design/method: a retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below 30 years of age diagnosed and treated by the uthscsa sarcoma team between january 2000 and june 2017 was performed. results: in our original cohort from january 2000 to december 2010, we observed a significantly decreased 5-year eventfree survival (efs) in patients diagnosed before age 12 (preadolescent) relative to patients diagnosed between ages 12 and 29 (11% vs. 57%, p<0.001). patients had a 5-year overall survival (os) and event-free survival of 65% and 48% respectively. in our expanded cohort from january 2000 to june 2017 we evaluated sixty-six patients with a median age of 14 (range, 2 to 28 y) with localized high-grade osteosarcoma of the extremity. the expanded cohort was 68% mexican american, with a median follow-up of 59 months (range, 5 to 192). the analysis of our expanded cohort is ongoing and we postulate that the findings will hold true, as we increase the cohort size and length of follow-up. conclusion: analysis of our previous cohort, predominantly of mexican american ethnicity, showed that preadolescent patients had an increased rate of relapse when compared with previous large studies. we also showed a trend towards decreased efs for the entire cohort. we hypothesize that we will further validate these findings with this expanded cohort and this will support further investigation into potential causes of poor outcome in this vulnerable latino population. background: neuroblastoma in infants has the potential to regress or mature spontaneously. growing literature showed that some cases subjected to initial observation didn't show inferior outcome compared to actively treated similar categories. objectives: we investigated whether early active treatment can be safely avoided/deferred in selected favorable cases at the children's cancer hospital-egypt (cche). design/method: patients enrolled on the watch and see strategy (w&s) at cche had small primary tumor; inss stage 1-2, uncomplicated stage 4s or stage 3 infants (< 365 days). tissue biopsy was not mandatory for infants below 6 months of age with localized adrenal mass (stage 1-2). on progression, immediate intervention took place according to stage and risk of disease after biological characterization. results: thirty four nbl patients were enrolled on w&s strategy; m/f:2.4/1. eighteen patients had stage 4s disease, 12 patients had stage 1-2 and 4 were stage 3. primary adrenal site was reported in 29 patients (85.3%), 21 patients (61.77%) had small mass measuring ≤5 cm in its largest diameter. the 5-year os & efs were 88.2±8.8% and 72.5±9%, respectively, with 43 months median follow-up (range: 1-106 months). spontaneous total/near total resolution of mass occurred in 16/34 patients (47%). median time to eliciting regression was 1.7 months (range: 0.4-14.7 months), and 20.7 months (range: 7-63 months) till complete resolution. only 8/34 patients (23.5%) witnessed progression (2 local, 2 distant and 4 combined local and distant progression); median time to progression was 8 months (range: 1-32 months) with 2/8 deaths after starting chemotherapy. watch and see strategy is a safe approach in localized and uncomplicated stage 4s neuroblastoma. progressive cases could be rescued. baylor college of medicine, houston, texas, united states background: ga-68 dotatate binds to somatostatin receptor 2 expressed in neuroendocrine tumors (nets). it was approved by fda in 2016 for use with pet/ct scan for localization of somatostatin receptor positive nets in adult and pediatric patients. pediatric approval was based mainly on extrapolation of data from adults. objectives: to describe the use of ga-68 dotatate pet/ct scan in children with neuroendocrine tumors and compare with other imaging modalities. design/method: patients with nets enrolled in texas children's rare tumor registry between february and october 2017 were reviewed and those patients who underwent ga-68 scan were included. results: four patients with nets underwent ga-68 scans without any adverse reactions. first patient was a 15-yearold female with small bowel net with multiple liver metastases. mri abdomen and fdg pet at diagnosis showed s267 of s301 multiple liver metastases but could not identify the primary lesion. ga-68 scan was able to accurately identify the enlarged lymph nodes in the small bowel and was better than fdg pet in delineating the liver metastases. second patient was a 13-year-old female with recurrent small bowel net with liver, lung and paraspinal metastases. the lesions were initially detected by ct scan. octreotide scan failed to show any uptake in the identified lesions while ga-68 was taken up by the liver lesions, lung lesions >1 cm in size and the paraspinal lesion. third patient is an 8year-old male with pancreatic net with peripancreatic lymphadenopathy, multiple liver metastases and cardiophrenic lymph node involvement. the primary lesion in the pancreas could not be identified by ct scan, ct angiogram, mibg scan, or octreotide scan. in addition, there was uncertainty about involvement of the enlarged cardiophrenic lymph node. in addition to clearly identifying the primary lesion, ga-68 scan was able to detect multiple peripancreatic lymph nodes not detected by other scans and revealed uptake in the cardiophrenic lymph node confirming its involvement by the tumor. fourth patient is a 15-year-old female with malignant abdominal paraganglioma with solitary lung metastasis. both mibg scan and ga-68 scan were able to identify the primary lesion. ga-68 scan was performed after the lung metastasis was removed and thus its ability to detect it could not be confirmed. background: neuroblastoma is the most common extracranial solid tumor of childhood, with overall survival for high-risk patients (hrnbl) near 50%. the outcomes of hrnbl have improved with high dose chemotherapy followed by autologous stem cell rescue (abmt). data about factors influencing the rate of hematopoietic recovery following abmt in hrnbl is lacking in the literature. our objective was to identify factors influencing the rate of hematopoietic recovery following abmt in hrnbl. design/method: this was a retrospective chart review of 55 patients with hrnbl treated at texas children's hospital from 2006 to 2016. neutrophil engraftment was considered the first of three consecutive days with post-transplant neutrophil count greater than 500 cells/ul. red blood cell and platelet engraftment were considered at a hemoglobin greater than 8g/dl and platelets greater than 20,000/ul three days after the last transfusion. race and conditioning regimen were analyzed using one-way anova; amount of infused cells was analyzed using pearson correlation coefficients; chemotherapy delay and bone marrow (bm) involvement after cycle 2 of induction chemotherapy were analyzed using independent sample t-tests. the study included 32 males and 23 females with a median age at diagnosis of 2.5 years. thirtyeight patients were caucasian, 6 african-american, 5 hispanic, 2 asian, and 4 did not have race documented. the mean dose of infused cd34+ cells was 3.36 × 10^8 cells/kg. forty-five patients received conditioning therapy with carboplatin/etoposide/melphalan (cem), 8 received busulfan/melphalan (bu/mel), and 2 received thiotepa/cyclophosphamide (thiotepa/cpm). the conditioning regimen administered was significant (p = 0.037) for time to engraftment of neutrophils, with bu/mel at 16.6 days, cem at 12.1 days, and thiotepa/cpm at 10 days. a delay of chemotherapy during induction (n = 25) was significant (p = 0.001) for time to platelet engraftment of greater than 75,000/ul and trended towards significance (p = 0.088) for time to neutrophil engraftment. bm involvement at diagnosis and after cycle 2 of induction was not significant for time to engraftment. dose of stem cells infused was the only variable significant for hemoglobin engraftment. background: osteosarcoma (os) is the most prevalent aggressive primary malignancy of the bone affecting children and young adults. approximately 10% to 20% of patients have metastatic disease at initial presentation, and 61% of those patients have isolated pulmonary metastases. although overall survival in patients with os has improved with advances in therapy, there have been no significant improvements in survival outcome in patients with metastatic disease. recent studies suggest that tumor-associated vascular cell adhesion molecule 1 (tvcam-1 or cd106) plays a critical role in the metastatic progression of various tumors. indirect evidence from these studies suggest that vcam-1/ 4 1 integrin signaling promotes tumor survival and metastatic progression by changing the tumor niche and associated immune response. to determine if interfering vcam-1/ 4 1 signaling between pulmonary metastatic osteosarcoma (pos) and macrophages (macs) by down-regulating vcam-1, depleting macs or blocking vcam-1/ 4 1 signaling will reduce pos and improve overall disease-free survival. design/method: we used a pair of spontaneous, high-grade murine os cell lines from balb/c mouse (h-2d), k7 and k7m2 (derived from in vivo k7 metastasis). we used lentiviral shrnas to knockdown vcam-1 mrna and protein expression in k7m2 (vcam-1kd). we introduced luciferase into k7, k7m2 and various k7m2 shrna cell lines to follow lung metastasis by bioluminescence (bli). we depleted macs by intranasal administration of liposomal clodronate formulation. we tested the ability of k7 and k7m2 supernatants to polarize m0 macs into m1 or m2 phenotype in vitro. we also administered anti-4 monoclonal antibody (anti-4 mab) intranasally to assess the outcome of functional blockade of vcam-1/ 4 1 signaling. results: k7m2 over-expressed vcam-1 compared to k7. mac depletion in k7m2-bearing animals exhibited reduced pos. weekly administration of anti-4 mab resulted in 80% tumor-free rescue among mice with established k7m2 pos. interestingly, supernatant from k7m2 but not k7 preferentially induced m2-like macs, suggesting a novel integrin-mediated mechanism of m2 differentiation. validation data with additional os cell lines will be presented. despite aggressive multimodal therapy, overall outcome for patients with pos remains dismal at 25-30%. for this reason, novel and directed therapy approaches are desperately needed. molecular targeted approaches for therapy are challenging, due to the complex genetic heterogeneity of os. immune-modifying therapy is a promising new alternative approach for pos. university of chicago, chicago, illinois, united states background: only half of all patients diagnosed with high-risk neuroblastoma achieve long-term survival. 123imetaiodobenzylguanidine (mibg) scans are routinely used to evaluate disease at diagnosis and following treatment, and the extent of disease is quantified using the curie scoring system. a previous study by yanik et al., has shown that for high-risk patients with mycn non-ampliified tumors, scores less than versus greater than 2 following 6 cycles chemotherapy are associated of superior survival, whereas scores less than versus greater than 0 were prognostic in patients with mycn-amplified tumors. however, the prognostic significance of specific sites of metastatic disease at diagnosis is not known. to determine if site of metastatic disease determined by 123i-metaiodobenzylguanidine (mibg) imaging in high-risk patients at the time of diagnosis was associated with outcome design/method: we performed a retrospective chart review of high-risk neuroblastoma patients treated at comer children's hospital and lurie children's hospital in chicago between 2006 and 2017 with positive mibg scans at the time of diagnosis. we collected imaging data as well as other clinical data including bone marrow status. sites of disease were defined as curie regions with any positive value. kaplan-meier analysis was performed to evaluate the association with disease sites and survival. pearson correlation coefficients were calculated to compare bone marrow disease to sites of positivity on mibg scan. the cohort consisted of 49 high-risk patients. 31 had skull disease, and 30 had pelvic disease. the presence of mibg positive disease in the skull and in the pelvis trended toward worse efs. efs at 3 years for patients with disease in the skull at diagnosis was 52 ± 10% and for patients without skull disease was 78 ± 10 % (p = 0.16). efs at 3 years for patients with and without pelvic disease was 49 ± 10% and 80 ± 9% (p = 0.10). consistent with prior data, we found that the presence of bone marrow disease was associated with worse survival with 3 year efs of 47 ± 10% and 88 ± 8% with and without marrow disease at diagnosis (p = 0.02). there is the highest correlation between pelvic disease on mibg scan and bone marrow disease with pearson coefficient 0.79. pelvic disease noted on mibg scan likely reflects underlying bone marrow disease. in patients with high-risk neuroblastoma, skull disease and pelvic disease on mibg scan at diagnosis may predict worse event free survival. background: osteosarcoma is one of the deadliest cancers in the pediatric population with little progress in morbidity and recurrence rates since the 1980's. oncolytic herpes simplex-1 virus (ohsv) is an attenuated virus that has shown encouraging results against certain solid tumors. programmed cell death protein (pd)-1-mediated t cell suppression via engagement of its ligand, pd-l1, is also of particular interest due to recent successes in selected cancers, especially those with high genetic mutational loads. most pediatric cancers do not have a wide variety of mutations; however, osteosarcoma has a chaotic genome, prone to genetic mutations. it has been shown through numerous other studies that pd-1 inhibition alone is not sufficient to result in statistically significant tumor growth delays in osteosarcoma models and patients. we hypothesize the addition of ohsv therapy as an immunologic stimulus to pd-1 inhibition is efficacious for osteosarcoma. (1) to determine whether ohsv therapy enhances response to pd-1 inhibition in immunocompetent murine models of osteosarcoma and (2) to quantify and characterize the anti-tumor t-cells infiltration after treatment with ohsv and pd-1 inhibition individually and in combination. we utilized an immunocompetent transplantable murine model using a cell line derived from a spontaneous metastatic osteosarcoma (k7m2, balb/c background). we transplanted established tumor wedges subcutaneously and monitored tumor volume by caliper measurement. once tumors reached 200-400mm3, we administered intratumoral injections of hsv1716 (1 × 108 plaque-forming units) every other day for a total of 3 injections. we then gave intraperitoneal injections of 250ug anti-pd-1 or control antibody twice weekly, up to 4 weeks, starting from the last dose of virus treatment. we monitored tumor growth via calipers twice weekly until tumors reached 2500mm3 or 2cm diameter. we quantified and characterized innate and adaptive immune cell infiltrates in tumors using flow analysis. we found significantly prolonged survival with our combination therapy group compared to all other groups. we found that anti-pd-1 by itself had little impact on t cell recruitment while the combination group had higher influx of cd8+ cells with a reduced amount of t-regulatory cells (cd4+foxp3+cd25+). we also found an increase in cd44+ effector memory cells. osteosarcoma is a deadly cancer with therapeutics remaining unchanged for the last 30 years. here, we describe prolonged murine survival after treatment with combination of pd-1 inhibition and ohsv injection. the combination treatment changed the microenvironment to be more inflammatory. our data support further preclinical and clinical studies. background: neuroblastoma is the second most common cause of cancer related death in children. treatment for high-risk neuroblastoma has improved significantly over the past twenty years, however cure rates remain below 50%. immunotherapy has emerged as an effective therapy for neuroblastoma, however new modalities and targets are needed to improve outcomes. objectives: our lab has developed a chimeric antigen receptor (car) that targets b7-h3 (cd276), an immune checkpoint molecule overexpressed on many cancers, including neuroblastoma. we hypothesized that b7-h3 would be a good target for car based immunotherapy for neuroblastoma. design/method: neuroblastoma tissue microarrays of primary patient samples were screened for b7-h3 expression by immunohistochemistry and cell lines were screened using flow cytometry. b7-h3 car t cells were tested in vitro by measuring tumor cell killing and cytokine production after coculture with tumor cell lines and in vivo in an orthotopic model of neuroblastoma. results: b7-h3 expression was detected by ihc on 82% of the 186 screened neuroblastoma patient samples. b7-h3 was expressed at high levels (2+ or 3+) in more than half of these samples (56%). almost all cell lines screened were homogeneously positive for b7-h3 by flow cytometry. retrovirally transduced b7-h3.4-1bb. car t cells were cocultured with three b7-h3 positive neuroblastoma cell lines (sk-n-be2, kcnr, and chla255) and robust tumor cell killing was demonstrated using an incucyte assay. supernatant from the co-cultures was harvested after 24 hours and both interferon gamma and il-2 production were detected by elisa.in an orthotopic subrenal capsule xenograft model of neuroblastoma, mice treated with b7-h3 car t cells show significant reductions in tumor growth and prolonged survival compared to those treated with untransduced control t cells. however, the treatment is not always curative.b7-h3 car t cells express high levels of exhaustion markers (pd1, tim3, and lag3) when compared to cd19 car controls. in order to overcome inhibition from exhaustion, b7-h3 car t cells were co-cultured with neuroblastoma cell lines and pd-1 blocking antibody. nivolumab significantly increased the production of il-2 and interferon-gamma by b7-h3 car t cells. further studies are underway to determine if b7-h3 car t cell activity is enhanced in vivo by treating animals with pd-1 blockade along with car t cells. conclusion: b7-h3 is expressed on a majority of neuroblastoma samples and appears to be a promising candidate for car t cell therapy. b7-h3 car t cells demonstrate activity against neuroblastoma xenografts that may be enhanced by the addition of pd1 inhibitors. helen devos children's hospital, michigan state university, grand rapids, michigan, united states background: osteosarcoma is the most common bone tumor in children. it is often metastatic at diagnosis and in this scenario less than 30% of children survive. polyamines, small molecules found in all cells, are involved in many cell processes including cell cycle regulation, immune modulation, cell signaling and apoptosis. they are also involved in tumor development, invasion and metastasis. in neuroblastoma, inhibition of the polyamine biosynthesis pathway with odc inhibitor alpha-difluoromethylornithine (dfmo) results in decreased cell proliferation and differentiation. these finding have led to multiple phase i and phase 2 ii multicenter clinical trials in pediatric neuroblastoma patients. dfmo is an attractive drug as it is oral, well-tolerated, can be given for prolonged periods and is already used in pediatric patients. the polyamine pathway has not been evaluated in osteosarcoma. objectives: evaluate effect of inhibition of polyamine biosynthesis with dfmo on osteosarcoma proliferation and cell differentiation. design/method: up to three osteosarcoma cell lines were used: mg-63, u-2 os and saos-2. cells were exposed to 5 mm dfmo for 6 days with replacement of media and dfmo on day 3. intracellular polyamine levels were measured by high performance liquid chromatography (hplc). cell numbers were obtained with a hemocytometer using trypan blue. flow cytometry cell cycle distribution (facs) and propidium iodide were used to evaluate for cell cycle arrest. the protein expression of several osteosarcoma differentiation markers was measured by sds-page and western blot using differentiation specific antibodies. a bioluminescent cell viability assay was used to measure cell recovery over several days after dfmo was removed and replaced with standard media. results: dfmo exposure resulted in significantly decreased cell proliferation in all cell lines. after treatment, intracellular spermidine levels were nearly eliminated in all cells. cell cycle arrest at g2 was observed in u-2 os. cell differentiation was most pronounced in mg-63 and u-2 os cells as determined by increased osteopontin levels. remarkably, cell proliferation continued to be suppressed for several days after removal of dfmo. conclusion: based on our findings dfmo is a promising new adjunct to the current osteosarcoma therapy for high risk patients. it is a well-tolerated oral drug that is currently in phase ii clinical trials in pediatric neuroblastoma patients as a maintenance therapy. the same type of regimen may also improve outcomes in metastatic or recurrent osteosarcoma patients for whom there have been essentially no medical advances in the last 30 years. background: recent studies demonstrate that lower levels of the ews-fli1 fusion oncoprotein are associated with enhanced metastatic capability in ewing sarcoma. the nf-kb transcription factor is a critical mediator of cxcr4 and cxcr7 -driven metastasis in multiple cancers, and increased cxcr4 and cxcr7 expression have each been associated with increased metastasis and poor prognosis in ewing sarcoma. we thus sought to investigate the impact of ews-fli1 on cxcr4/cxcr7-dependent nf-kb signaling in ewing sarcoma. objectives: the goals of this study are 1) to determine the impact of cxcr4/cxcr7 signaling on metastasis-associated nf-kb target gene expression in ewing sarcoma and then 2) to investigate how the ews-fli1 fusion oncoprotein modulates this response . design/method: we utilized multiple ewing sarcoma cells lines including a673, chla9, chla10, tc32 and tc71. cxcr4/cxcr7 cell surface expression was determined by flow cytometry. ews-fli1 level was modulated using sirna and expression levels were confirmed by western blot and rt-pcr. p65 dna binding was measured via elisa. nf-kb target gene expression was assessed via rt-pcr. results: consistent with ihc analysis of primary and metastatic patient tumor samples, the paired primary and metastatic ewing sarcoma cell lines chla9 and chla10 showed dramatic differences in cxcr4 and cxcr7 expression, with the metastatic chla10 line demonstrating much higher expression of both receptors. other cell lines (nonpaired) showed variable cxcr4/cxcr7 expression. genetic knock-out of cxcr4 lead to significant decrease in expression of both cxcl12/sdf-1 and il-6, two nf-kb transcriptional targets known to play a key role in tumor metastasis. knock-out of cxcr4 did not alter endogenous ews-fli1 mrna levels. conversely, lowering the level of ews-fli1 using sirna lead to enhanced nf-kb signaling, indicated by an increase in p65 dna binding. consistent with this observation, treating ewing cell lines with ews-fli1 sirna also resulted in significantly increased nf-kb target gene expression compared to control cells and target gene expression was then further enhanced upon cxcr4/cxcr7 receptor stimulation with the receptor ligand cxcl12/sdf-1. our findings indicate that the ews-fli1 oncoprotein negatively modulates cxcr4/cxcr7-dependent nf-kb signaling. this suggests that ews-fli1 low, cxcr4/cxcr7 high cells, which are associated with enhanced metastasis and poor prognosis, would be anticipated to exhibit enhanced expression of key nf-kb target genes. importantly, the nf-kb pathway is a druggable target that could potentially serve as an "achilles heel" in this subset of high risk tumors. current work is evaluating nf-kb inhibition as an approach to treating metastatic and refractory ewing sarcoma. background: acute graft versus host disease (agvhd) is a major cause of morbidity and mortality following allogeneic bone marrow transplant (bmt) in pediatric patients. gastrointestinal (gi) agvhd is the most serious manifestation. recently, decreased paneth cell (pc) in a predominantly adult cohort was shown to correlate with agvhd clinical grading and response to treatment. we aim to demonstrate the relationship between pc counts and gi agvhd stage and response to therapy. design/method: charts of patients who underwent endoscopy following bmt between 2004-2014 were reviewed. for repeated biopsies during the course of agvhd, only the first was included for analysis. one pathologist retrospectively reviewed the biopsies and counted pcs in 3 high powered fields; the average pc count was analyzed. twenty-six percent of biopsies were reviewed by a second blinded pathologist. statistical associations between pc counts and day 28 (d28) response, agvhd stage, and other study covariates of interest were gauged using general linear regression. agreement in pathologist pc counts was quantified by intraclass correlation (icc). the research was approved by the children's healthcare of atlanta irb. results: seventy-eight biopsies were included in the analysis. mean age at transplant was 10.5 years ± 5.8 (range: 2 months -20 years). most patients underwent transplant for hematologic malignancies (63, 74%). the majority of transplants used a matched unrelated donor graft -including cords (59, 69%) and myeloablative conditioning regimens (71, 82%) -52% received total body irradiation. of these, 64% were diagnosed clinically with gi agvhd (stage 1, 42%; stage 2, 14%; stage 3, 22%; stage 4, 22%). icc showed good agreement (0.833) between the pathologists. mean pc was 16.8 for patients with no gut agvhd, 21.3 for stage 1, 22.9 for stage 2, 9.4 for stage 3 and 5.9 for stage 4 (p = 0.001). on multivariate analysis pc was strongly associated with gi agvhd stage (p<0.001) after controlling for age, preparative regimen intensity, and diagnosis (malignant vs. non-malignant). mean pc counts were significantly lower in patients with no response to steroid therapy at d28 (complete response (mean 17.8) vs. persistent disease (4.2) vs. partial response (4.5) (p = 0.001)). patients diagnosed with gi agvhd with pc counts less than 10 had a higher risk of mortality (hr 3.1, 95% ci: 1.17, 8.09; p = 0.023). lower pc count correlated with stage 4 gi agvhd, refractory disease at d28, and mortality. incorporating pc count in pathology review during gi agvhd work-up may help in agvhd risk stratification. background: there have been increasing discussions pressuring health care teams and institutions for potentially bearing the cost of clostridium difficile infections (cdi) as a health care-associated infection in the recent years. the pediatric oncology patient population, though small, accounts for significant portion of all cdi with 10-15-fold increased risk. hematopoietic stem cell transplant (hsct) recipients constitute a unique subset with distinct risk factors, such as severe immune deficiency state and graft versus host disease (gvhd). although there is ample data on cdi in adult hsct recipients, reports on pediatric experience are limited. objectives: to evaluate the incidence and patterns of cdi among pediatric hematology, oncology and hsct inpatients at our institution. a retrospective review of all clostridium difficile (cd) stool tests performed using toxin enzyme immunoassay and later, polymerase chain reaction targeting toxin genes between 2007 and 2017 in a large, urban academic children's hospital was performed. the data were analyzed for hematology, oncology, hsct inpatient population and all the other cases separately and statistical comparisons were performed. results: a total of 5271 samples were submitted to the microbiology laboratory for cd testing during the study period. while hematology patients constituted 1.7%, oncology 5.9%, hsct 2.0% and others 90.4% of the cases on whom cd testing was done; per patient average test number was 2.0, 2.8, 6.2, and 1.5, respectively. of all the cd tests per-formed, 15.6% were positive. test positivity was higher in hsct (47.6%) and oncology (42.4%) cases tested compared with hematology (21.2%) and other cases (17.1%) with statistical significance (p<0.001). overall recurrence rate was 4.3%; hsct patients had the highest recurrence with a rate of 27% followed by oncology (13.6%), hematology (7.7%) and other (3.2%) cases, again reaching statistical significance (p<0.001). again, hsct patients had the highest average number of recurrences at 3.1 (2-6) followed by oncology 2.8 (2-10), general 2.52 (2-6) and hematology 2.25 (2-3) groups. there was no seasonal variability in the incidence of cdi among populations analyzed. prolonged hospital stay/antibiotic use and persistent diarrhea due to gvhd are the likely reasons for higher rate of cd testing in hsct as a result of increased monitoring and thus might have even caused underrepresentation of positive cd test frequency. higher incidence and frequencies of recurrence underscores the inevitable nature of cdi in hsct population as a consequence of the current therapies and may lead to future radical treatment approaches like fecal implantation. background: viral infections remain a challenge to treat post hct in children, and significantly contribute to morbidity and mortality. virus specific t cells (vsts) have shown tremendous clinical efficacy in treating viral infections post-hct, with minimal toxicity and long term efficacy. we have used donor-derived vsts in individual patients, however not all donors are agreeable to the process, and numerous patients may benefit from vsts who do not have an identified donor/have other disease indications objectives: we sought to actively build a third-party vst bank, for "off the shelf" use in eligible patients. design/method: vsts targeting cmv, adenovirus and ebv were manufactured using one of 2 techniques. initially ebv transformed b cells were genetically modified with an ad5f35pp65 vector and used as antigen presenting cells (apc) to stimulate and expand ebv, ad and cmvpp65 specific t cells. more recently, vsts were expanded using s273 of s301 apc pulsed with commercially available peptide pools (pep-mixes) to expand ebv/cmv/ad specific t cells. products were entered into the "bank" via two mechanisms: a) left over products from our "donor-derived" protocol when patients no longer required vsts or were not at risk of developing viral infections, or b) by targeting regular blood donors based on their hla typing to ensure an appropriate mix of high frequency hla types for optimal patient matching and antigen presentation based on current knowledge of antigen presentation. results: a total of 30 products are currently in the thirdparty vst bank ready for use. twenty seven of these are from our donor derived protocol, and three from targeted donors. all vst products met safety and in vitro efficacy testing. thirteen vst infusions have been given to 7 patients. eleven infusions have been given for cmv and two for adenovirus. five out of seven patients responded to thirdparty vst infusions, with a median of 2 vst infusions per patient (range 1-4). the median hla matching was 2 out of 10 per patient (range 1 to 4) no patients experienced adverse reactions, gvhd or other toxicity related to the vst infusion. a third-party vst bank is feasible and produces clinically appropriate vsts for use in patients with viral infections. hla typing and matching of vst products is essential to reduce toxicity and promote appropriate antigen presentation and expansion of vsts in vivo. further work is underway to further characterize the vsts using epitope mapping to better define the hla restriction and immunogenicity of each vst product. akron children's hospital, akron, ohio, united states background: acute graft-versus-host disease (agvhd) is a well-known complication of hematopoietic stem cell transplant (hsct) and a major cause of post-transplant related morbidity and mortality. first line therapy of agvhd involves corticosteroids and calcineurin inhibition. in patients with severe refractory gvhd, mortality can reach up to 90%. currently, there is no standard of care for the treatment of steroid refractory agvhd. many centers have looked at the use of antibody mediated control of agvhd to competitively inhibit the inflammatory cascade. basiliximab, a chimeric monoclonal antibody against the t-cell il-2 receptor, has been used in adults with steroid refractory agvhd. patients receiving this medication have demonstrated complete and partial responses to therapy with minimal toxicities. objectives: report the successful use of basiliximab in the treatment of agvhd in a 2-year-old following matched unrelated (mud) hsct. design/method: a 2-year-old male underwent mud transplant for high risk aml with monosomy 7. conditioning regimen included busulfan, fludarabine and equine atg. his clinical course was complicated by fever, mucositis and agvhd (stage 3 skin; stage 1 gi-biopsy proven). gvhd prophylaxis included tacrolimus and methotrexate, however with progressive skin rash, diarrhea, and early satiety, gvhd treatment with corticosteroids was initiated. as the patient continued to have worsening symptoms, basiliximab therapy was started. the patient received 2 doses (10mg) iv basiliximab on two consecutive days and then received weekly therapy for a total of 4 doses leading to initial improvement. the patient further developed acute on chronic gvhd on day +100, and subsequently received a second course of basiliximab. after initial administration of basiliximab, the patient had near complete resolution of symptoms. however, with a small wean in his tacrolimus dose, the patient experienced another skin gvhd flare prompting the second basiliximab course. the patient was subsequently weaned off all immunosuppression by day +376. the only acute complication the patient experienced while receiving basiliximab was right toe paronychia and asymptomatic low ebv titer. the patient is currently off all immunosuppression at the time of report without evidence of cgvhd. conclusion: this single case report, in a young pediatric patient, demonstrates the use of basiliximab may be a safe and efficacious treatment for pediatric patients with agvhd. university of california, san diego, la jolla, california, united states background: clinical outcomes after allogeneic hematopoietic stem cell transplantation (hsct) depend on restoration of t lymphocyte populations. association between recovery of cd4+foxp3+ regulatory t cells (tregs) and protection from chronic graft versus host disease (cgvhd) has been described in adult hsct. in adults, t cell recovery is driven by expansion of donor t cells and treg reconstitution is hypothesized to result from peripheral conversion. restoration of t cells in pediatric patients has a larger contribution from thymopoiesis, however, the relationship between thymopoiesis and treg recovery is undefined. objectives: we hypothesized that effective thymopoiesis is important for restoration of treg populations and protection from cgvhd in pediatric hsct patients. design/method: we performed longitudinal flow cytometry of peripheral blood t cells from 17 pediatric hsct patients and 9 age-matched healthy donors. laboratory data were correlated with clinical outcomes to evaluate impact. recovery of tregs occurred in 11/17 (64.7%) patients by post-transplant day 90. day 90 treg frequency in patients that developed cgvhd (1.7 ± 1.1% of cd4+ t cells) was reduced compared to cgvhd-free patients (3.2 ± 0.7%). failure to restore tregs to >2.0% of cd4+ cells by day 90 was associated with increased risk of cgvhd in the first year post-hsct (rr = 7.3, p = 0.05). a majority (60.8 ± 11.9%) of tregs from patients recovering the peripheral treg compartment expressed helios, a marker of thymic-derived tregs; only 21.5 ± 11.4% of tregs expressed helios in patients failing to restore adequate tregs. this prompted examining the relationship between defects in thymopoiesis and inability to restore tregs. we evaluated thymic function by flow cytometry quantification of cd45ra+cd31+ptk7+ recent thymic emigrant (rte) cd4+ cells (confirmed by qpcr for trec content). most (13/17, 76.5%) hsct patients had detectable rtes by day 30 post-hsct. thymic production of rtes was persistently absent in patients that developed cgvhd (<10/10^4 cd4+ cells in 5/5 patients), compared to cgvhd-free patients (7/12 patients >10 rte/10^4 cd4+ cells by day 30, average 22.3 ± 7.1/10^4 cd4+ cells). post-hsct thymic activity as measured by rte enumeration correlated with treg restoration; 6/8 (75%) rte+ patients restored tregs, compared to 3/9 (33%) of rte-patients. conclusion: failure to restore tregs after allogeneic hsct results in increased risk for cgvhd. in pediatric patients thymic generation of new t cells is an important contributor to restoration of the treg compartment. this data supports further investigation into mechanisms impairing post-hsct thymopoiesis and suggests peripheral blood tregs may be a prognostic biomarker for cgvhd. background: haploidentical stem cell transplantation (haplo sct) is riddled with unique challenges. objectives: we present our experience in the use of haplo sct with post-transplant cyclophosphamide (ptcy) and the adaptations required for each disorder for optimal outcome. design/method: we performed a retrospective study at the pediatric blood and marrow transplant unit, apollo cancer institutes, chennai, india. children up to 18 years of age, diagnosed to have benign disorders and underwent haplo sct with ptcy from 2002 to july 2017 were included. results: ptcy was used in 36 i.e. 73% haplo transplants for children with benign disorders. the underlying conditions included fanconi anemia 10, severe aplastic anemia 6, mds 1, jmml 1, hemoglobinopathy 3, prca 1, xld 1 and primary immunedeficiency disorders (pid) 13. source of stem cells was peripheral blood in 58%, bone marrow in 41%. conditioning included fludarabine with treosulphan or cyclophosphamide for pids and aplastic anemia respectively. neutrophil engraftment by day+16-21 with a durable graft was noted in 75% transplants with graft versus host disease in 20%, cmv reactivation in 35%. mortality rate was 45% with 2 infants less than 6 months of age developing severe fatal cytokine release syndrome. the median follow up is 1 year with 3 years being the longest. no significant late effects have been noted with chronic skin gvhd in 3 children. survival rate was superior among children with pids with survival of 70% in this group. haplo sct with ptcy is a feasible and costeffective option for cure in children with life-threatening benign disorders with no compatible family or matched unrelated donor. careful patient selection, reducing cyclophosphamide related free radical toxicity with the use of n acetylcysteine, limiting t cell numbers by capping cd34 at 5 × 106/kg, post-transplant viral monitoring protocols are required to reduce morbidity and mortality. we have been working on universal access to care for children from s275 of s301 all socioeconomic background and incorporating innovations to reduce the cost of hsct without compromising outcomes. haploidentical hsct using tcr / depletion costs 18000 usd as compared to ptcy priced at 25 usd. children with severe aplastic anemia and pids can be transplanted using reduced intensity conditioning and ptcy. in hemoglobinopathies, pretransplant immunosuppression is required to prevent graft rejection. graft versus host disease remains the main cause of mortality in children with fanconi anemia. mortality in infants less than 6 months after ptcy has been high, tcr / depletion would be superior in this cohort. cincinnati children's hospital medical center, cincinnati, ohio, united states background: fanconi anemia (fa) is a congenital bone marrow failure syndrome with hsct the only curative option for associated bone marrow failure. patients with fa undergoing hsct may experience increased toxicity related to either their underlying disease, or the effects of medications, resulting in the inability to tolerate prophylactic medications or sideeffects from anti-microbial therapy. objectives: we postulated that increased cd34 cell dose would be associated with a rapid immune reconstitution and therefore early withdrawal of anti-infective prophylactic medications. design/method: patients with fa transplanted at cchmc from an unrelated donor had peripheral blood stem cell grafts collected and cd34 selection performed. where possible, patients had serial measurements of their immune system performed at varying intervals post hsct. we defined immune reconstitution as normalization of lymphocyte subsets-cd3, cd4, cd8 and cd19 cells, as well as a normal response to mitogen stimulation including phytohemagglutinin, concanavalin a and pokeweed. the first measurement of either normal cell number or mitogen response was recorded for each patient. results: a total of 35 patients underwent hsct for fa at cchmc between 2012 and 2017. patient demographics included a median age of 8 years at hsct, the vast majority of patients having a fully matched or one anti-gen mismatched donor, and the majority of patients transplanted for bone marrow failure. there was a statistically significantly decreased time post-transplant to immune cell recovery in patients receiving >20 × 106/kg cd34 cells (median 25.7) compared to those receiving <20 × 106/kg cd34 cells (median 11.9). the median time to normalization of cd3 count was 224 days (cd34 count >20/kg) versus 371 days (cd34 count <20/kg), cd4 count 211 days (cd34 count >20/kg) versus 489 days (cd34 count <20/kg), cd8 count 193 days (cd34 count >20/kg) versus 344 days (cd34 count <20/kg) and cd19 count 93 days (cd34 count >20/kg) versus 109 days (cd34 count <20/kg). time to normalization of mitogen response was decreased posttransplant in those patients receiving increased cd34 cell dose at time of transplant, though this was not significant, reflecting low number of patients with evaluable responses. no patients in either group experienced gvhd or graft failure. patients with fa who are transplanted with higher cd34 cell doses have quicker immune reconstitution than those who receive lower cell doses. along with benefit to patients including less risk of infection and early termination of immune-prophylaxis medications, this supports the use of high dose cd34 selected grafts in this vulnerable population. background: parvovirus b19 (pvb19) infection after transplantation was first reported in 1986. since then, numerous cases of pvb19 infections after hematopoietic stem cell transplantation (hsct) and solid organ transplantation (sot) have been reported. most report anemia as the predominant clinical manifestation. however, pvb19 has been associated with pancytopenia, hepatitis, myocarditis, and allograft rejection. we present a patient with acute lymphoblastic leukemia who developed bone pain and pancytopenia following hsct in the setting of pvb19 infection. to describe an unusual presentation of pvb19 in a patient with acute lymphoblastic leukemia following hsct. design/method: a search of the english-language medical literature was performed using pubmed and medline databases. a review of the patient's medical history was performed. a 7 year old male with relapsed b-cell all and history of "fifth disease" in infancy presented four months after hsct with focal left arm pain and difficulties fully extending the arm. bone mri showed enhancement of the medullary space centered within incomplete transverse cortical fracture interpreted as pathologic fracture due to neoplastic involvement of the ulna with no history of inciting injury. subsequently, peripheral blood counts decreased from low normal values to wbc 1.9 k/microl, anc 310/microl, plt 57k/microl, and hemoglobin 8.6 g/dl. the patient's chimerism remained 100% donor. a bone marrow biopsy and aspirate were performed to assess for recurrent leukemia given persistence of bone pain and developing pancytopenia. marrow findings included morphologic cytopathic effects with erythroid precursors and strong parvovirus staining with no signs of red cell aplasia or recurrent b-cell disease by morphology or flow cytometry. pvb19 was detected in blood by pcr and immunoglobulins with resolution of cytopenia and bone pain. this case highlights an unusual constellation of symptoms following hsct in a child with all. unexplained bone pain and medullary infiltrates with pancytopenia suggestive of recurrent leukemia were likely triggered by pvb19 infection. the question remains if he had reactivation of pvb19, a primary infection by a new strain, or the virus was aquired through stem cells. bone biopsy could not be justified in light of clinical improvement. so far, bone lesions have only been described with congenital pvb19 infection. pvb19 appears to be uncommon after hsct, with a review of literature yielding 15 pediatric cases. however, it may be underestimated due to lack of routine screening. our patient's presentation supports that evaluating for pvb19 may be warranted in hsct patients presenting with symptoms suggestive of relapsed leukemia. background: cardiac injury may occur during hematopoietic stem cell transplant (hsct) in pediatric patients and can be asymptomatic for many years. recommendations for screening are available for patients who received anthracyclines or chest irradiation, but no guidelines exist for unexposed longterm survivors. we sought to define the prevalence of echocardiographic abnormalities in long-term survivors of pediatric hsct and determine the need for screening in asymptomatic patients. design/method: we analyzed echocardiograms performed on long-term survivors (≥ five years) who underwent hsct at cincinnati children's hospital between 1982 and 2006. we analyzed echocardiograms for left ventricular ejection fraction (ef), end-diastolic dimension (lvedd), septal thickness, posterior wall thickness, and global longitudinal strain (gls). we normalized linear measurements for age and patient body surface area. we included for further analysis patients who had echocardiogram obtained for routine surveillance. results: a total of 389 patients underwent hsct and were alive more than 5 years after transplant in 2017, with 114 having an echocardiogram obtained ≥ five years postinfusion. those with an echocardiogram were transplanted more recently (median 2003 vs. 1998 ). however, no difference between screened and unscreened individuals was noted for age at transplant, sex, transplant indication, anthracycline exposure, chest irradiation, or cyclophosphamide based preparative regimen. indications for echocardiograms included: cardiac symptoms 5 (4.4%), congenital cardiac anomalies 8 (7.0%), hypertension 2 (1.8%), known cardiac or pulmonary disease 2 (1.8%), routine post-hsct surveillance 95 (83.3%), and unknown 2 (1.8%). the mean time post-hsct was 11.7 years. among routine surveillance echocardiograms, the mean ef z-score was -0.97. mean lvedd zscore was -0.94, mean septal thickness z-score -1.00, mean posterior wall thickness z-score -0.98, and mean gls -21.96%. for patients that had echocardiogram performed for routine surveillance, 77/95 patients (82.1%) had ef measured, and 10/77 (13.0%) had ef z-scores ≤ -2.0 (abnormally low). patients exposed to anthracyclines had a mean z-score ef of -1.19 vs. unexposed patients -0.50 (p = 0.003). among individuals who received neither anthracyclines nor tbi only 1/31 (3.2%) was found to have an abnormal ef, 51.4% (z-score -2.73) or gls (-14.28%). only one patient who had a normal ejection fraction (z-score -0.39, ef 61.7%) had an abnormal gls, -15.9% (normal ≤ -16.0). long-term survivors of pediatric hsct who are asymptomatic and did not receive radiation or anthracyclines likely do not require surveillance echocardiograms, unless indicated by clinical symptoms. patients exposed to anthracyclines or tbi require close echocardiographic s277 of s301 screening and clinical monitoring for the development of cardiac complications. duke children's hospital, durham, north carolina, united states background: children undergoing pediatric blood and marrow transplants (pbmt) experience significant symptom distress. mobile health (mhealth) technologies can be leveraged to collect and monitor patient generated health data, and subsequently enhance our understanding of pbmt symptom clusters, patterns, and trajectories. better understanding of symptom complexity can foster development of precision health strategies to improve patient outcomes. however, limited research exists in integrating mhealth technology into pbmt management. we aimed to explore the feasibility, acceptability, and usability of using a pbmt specific mobile application to collect and monitor symptoms and wearable technology (apple watch) to measure objective data such as heart rate (hr) and activity. design/method: an exploratory mixed method design began in october 2017 to monitor pbmt symptoms for 20 patients using real-time data from: 1) a self-developed mhealth application (app) to collect subjective symptom data; and 2) apple watch to collect physiologic measures such as heart rate and number of daily steps. data is collected pre-transplant through 90 days. acceptability will be assessed through satisfaction surveys at study completion. we have enrolled 4 patients to date who are all currently using the app and watch. patients' average frequency of daily charting in the app 80%. the wearable average daily recorded measurements are 144 for hr and 29 for step count. most common symptoms recorded within the app include fatigue and pain. we have noted trends in data including a decrease in activity following transplant and gvhd and an increase following engraftment. patients have stated "the app is helpful to keep track of how my pain is doing day to day" and "i try to take more steps each day than the day before". patients often remove the watch for charging, then forget to put it back on, but consistently put it on upon reminder. finally, parents often were required to make app entries with patients too sick to record. we continue to enroll patients with enthusiasm from both patients and parents to use mhealth during pbmt. preliminary findings suggest feasibility of using the mhealth devices is strongly correlated to the patient's post-transplant stage and is facilitated by caregiver participation with device management (charging devices, reminders to wear watch and record in app). patients reported satisfaction and ease of use with devices, but found it difficult to keep up with charging and charting. these findings indicate using mobile devices may be useful methods to collect patient generated health data. cincinnati children's hospital medical center, cincinnati, ohio, united states background: bacterial bloodstream infections (bsi) are a common complication following hematopoietic stem cell transplantation (hsct) in both pediatric and adult populations, and are associated with poor outcomes. there is limited data describing the outcomes and characteristics of patients who develop three or more bsi after hsct. objectives: to describe the characteristics and outcomes of pediatric patients who develop three or more blood stream infections in the first-year post hsct. design/method: we performed a retrospective chart review of 373 consecutive patients who underwent hsct at our institution from 2011 through 2016 to compile this case series. data were collected through the first year post-hsct including: patient demographics, underlying disease and therapy characteristics; and transplant complications such as thrombotic microangiopathy (tma), graft versus host disease (gvhd) and overall survival. bsis were classified according to current center of disease control guidelines. results: of 373 patients, 18 (5%) developed 3 or more bsi in the first-year post transplant (total bsi cases = 77 including all patients). of the 18 cases, the majority underwent allogeneic hsct (n = 17/18; 94%). most cases were from unrelated donor (n = 15/18, 83%). more than half of patients had grade 2-4 gvhd (n = 11/18, 61%). sixteen (89%) had tma. of these 16 cases, tma preceded the first bsi in n = 10/16 (62%). the majority of bsis were classified as central line-associated bloodstream infections (clabsis, n = 37/77, 48%), followed by mucosal barrier injury laboratory-confirmed bloodstream infections (n = 29/77, 38%) and secondary bsi (n = 11/77, 14%). the majority of isolated organisms (45%) were associated with mucosal barrier injury pathogens. one-year overall survival in the cohort was 44% (n = 8/18). pediatric patients undergoing hsct who develop 3 or more bsis in the first-year post transplant demonstrated an increased rate of tma compared to the overall institutional incidence of roughly 30%. tma diagnosis preceded the first bsi in over half of patients, suggesting that tma may predispose to recurrent bsi. improved strategies for early detection and treatment of tma as well as prevention of clabsis may help reduce the number of bsis ultimately leading to decreased morbidity and mortality in this patient population. background: in neutropenic pediatric patients, infection remains a significant cause of morbidity and mortality. while granulocyte transfusions have been utilized for decades to treat infections, including in the pediatric population, the efficacy of this intervention remains poorly described. previous guidelines have primarily utilized information from adult populations. furthermore, recruitment of donors typically involves friends or relatives of the patient with periodic involvement of community donors. the use of a readily available local donor population to improve availability has yet to be well described. as the immunocompromised population is particularly susceptible to worsening infection and clinical deterioration, the ability to rapidly harvest and deliver granulocytes warrants further investigation. to investigate the efficacy, safety, and outcomes of severely immunocompromised patients receiving granulocyte transfusions from a local altruistic granulocyte program in a pediatric tertiary care center. design/method: a retrospective review was performed to evaluate the context for receiving a transfusion as well as primary outcomes including infection clearance, survival to discharge, and overall mortality. the indiana blood bank assisted with timing the interval from initial order placement to onset of first granulocyte infusion. results: among the patient population reviewed, 22 patients received 23 separate granulocyte regimens. ages ranged from 0-18 years with a mean neutrophil count of 77 at time of first transfusion. indications for transfusions included bacteremia (n = 11), fungal pneumonia (n = 6), and fungemia (n = 5). primary outcomes included clearing infection (70%) and surviving to discharge (57%). the median time from initial order placement to infusion was 46 hours, although there was no significant difference between responders who cleared the infection and non-responders who did not. however, additional investigation found that ward patients had a 75% chance of surviving to discharge while patients in the icu at time of initial transfusion had a 36% chance of survival to discharge. the readily available granulocyte transfusion program allows patients to quickly receive therapy in neutropenic settings. this is beneficial for patients as transfusion prior to clinical decompensation correlates with increased likelihood of infection clearance, and subsequently improved mortality. further investigation is needed, likely as a prospective study, to better explore circumstances that are beneficial for granulocyte transfusions. background: donor lymphocyte infusions (dli) are composed of immune cells to treat relapse after hematopoietic cell transplantation (hct). to date, data regarding its efficacy is limited in pediatric populations. furthermore, while outcomes related to cd3 content have been characterized, to our knowledge, the relationship between outcomes and other cellular content in dli has never been reported. objectives: determine whether the primary hematological malignancy, presence/absence of graft-versus-host disease s279 of s301 (gvhd), and unique phenotypic content of each dli impact overall survival (os) in pediatric patients with hematological malignancies. design/method: irb-approved, retrospective study investigating all consecutive dlis given to patients at the children's hospital of wisconsin. analyses were conducted using mann-whitney, fisher's exact, and chi-square. from 1980 from -2016 patients ≤20 years old with hematologic malignancies [myeloid (aml/ mds/cml/jmml),n = 23; lymphoid (all),n = 7] underwent 55 dlis (72%% ≥2 dlis). the median time between hct and dli was 0.6 (range, 0.1-5.8) years. there were significant differences between the lymphoid and myeloid groups, respectively, in regard to median age at hct (14.7 vs 7.5 yrs, p = 0.022) and at first dli (20 vs 8 years, p = 0.006). ultimately, there were no statistically significant differences in gvhd or os in products with either higher or lower cd3, cd4, cd8, cd56, or cd19 cellular content. however, the median cd3/kg content was more than double in the patients who developed gvhd as compared to patients who exhibited no gvhd after dli (29.99 × 106 vs 10.03 × 106, p = 0.346). patients receiving one dli had a 6-year os of 21 ± 9% vs those receiving 2+ dli of 52 ± 16% (p = 0.012). with a median follow-up of 0.74 (range, 0.04-16.61) years, the 6 year estimated os of patients in the lymphoid group was higher at 71 ± 17% vs 22 ±9% in the myeloid group, although not significant (p = 0.11). our results indicate a survival benefit when using dli in a subset of patients who relapse after hct. unlike adult studies demonstrating little effect of dli in lymphoid diseases, many children with all achieved durable remission. while our analysis did not demonstrate that dli cellular content had a statistically significant effect on gvhd or os, it is possible that differences could be found if a larger population and more targeted cell doses were studied. more data will be needed to further define these relationships and identify patients who stand to benefit most. cincinnati children's hospital medical center, cincinnati, ohio, united states background: many arabic speaking muslim parents of children requiring bone marrow transplantation (bmt) receive medical care in the united states. providers may not understand the impact of islamic parents' religious beliefs and practices on their health care experience. objectives: to explore how islamic parents used religion in decision making and to understand the impact of their religious beliefs and practices on their overall health care experience. design/method: we used grounded theory, an inductive method gathering data from interviews and analyzing text, to identify core themes. ten caregivers of bmt children from middle eastern countries were interviewed by an arabicspeaking provider; interviews were coded by an interdisciplinary team. we identified 5 key themes: 1. patience is a core belief in islam. patience results from the acceptance of allah's will. behaviors showing patience include praying rather than questioning and crying. 2. al qur'an provides comfort, healing, and protection. families listen to recitations of al qur'an in the patient's room because they feel that this practice not only comforts them but promotes healing as well. for some, certain portions of the qur'an were especially meaningful such as surat al-baqara, which explains that while we may think something is bad for us, allah will know it is good for us. 3. religious care in the medical center helped families feel respected. religious care in the medical center included interactions with chaplains, who were understood to be "religion experts," and provision of space for prayer and religious resources. 4. seeking religious consultation. religious consultation from imams or religious scholars (muftis or sheikhs) provides interpretations of the qur'an applied to the family's specific situation helps families make difficult decisions and follow allah's plan. 5. muslim beliefs guided decision making; muslim practices brought comfort, strength, and peace. drawn from the parents' understanding of islam. parents who addressed this topic said they would only do what islam allowed. they did indicate that most aspects of healthcare were understood to be allowed within islam. additionally, muslim practices of prayer, reading/listening to qur'an, and giving alms all provided comfort, strength and peace. we identified several recurring themes through our interviews that allowed us to understand how families use their muslim faith to deal with their children's illnesses and how it influences their decision making. we believe this better understanding will allow for more informed conversations about patients' health care and decision making, and shows respect for religious beliefs and practices. nemours/dupont hospital for children, wilmington, delaware, united states background: virtually all children will be infected with human herpesvirus 6 (hhv-6) by the age of two. hhv-6 reactivation after stem cell transplantation causes multiorgan toxicities, including encephalitis, with inflammation and destruction of the temporal lobes and hippocampi, memory loss, and seizures. catatonia is characterized by posturing, immobility, mutism, and autonomic instability, and it's associated with various psychiatric and medical conditions. we describe a patient with hhv-6 encephalitis and unusual neurologic sequelae, including cognitive and neurobehavioral dysfunction and catatonia, which may impact our understanding of the pathophysiology of hhv-6 reactivation encephalitis. objectives: describe a case of hhv6 encephalitis with practice implications for stem cell transplantation. results: our patient was diagnosed with acute myeloid leukemia at age 14. within 2 years, he relapsed and received two stem cell transplants. on the 29th day after his second transplant, he developed hyponatremia and refractory seizures. brain mri showed edema in the medial right temporal lobe with linear ischemic change. eeg showed diffuse encephalopathy. cerebrospinal fluid (csf) demonstrated 5 white blood cells, 2 red blood cells, and hhv-6 by pcr. his prophylactic antiviral was switched to foscarnet and ganciclovir. repeat mri showed abnormal signals in bilateral medial temporal lobes and the right insula. three months later he developed episodes of diaphoresis, hypothermia, agitation, mutism, and unusual posturing, recurring almost daily, recognized as catatonia. mri showed improvement of the abnormalities in the bilateral medial temporal lobes and hippocampi. eegs showed diffuse slowing. after 4 months of antiviral therapy, csf was negative for hhv-6. over the ensuing 3 years, he had numerous episodes of diaphoresis, hypertension, hypothermia, pruritis, confusion, agitation, cogwheel rigidity, and bizarre posturing. dopamine blocking agents did not help. clonazepam helped reduce their frequency, and hot showers helped break acute episodes. further mris showed generalized cortical volume loss. he suffered from depression and severely impaired sleep and cognitive function. we describe a novel, debilitating outcome of hhv6 encephalitis which may provide diagnostic considerations as we continue to improve our understanding of the breadth of possible neurologic sequelae in transplant patients. hhv-6 is understood to infect and destroy the temporal lobes and hippocampi, but our patient's autonomic dysfunction indicate involvement of the hypothalamus and basal ganglia. antidopaminergic agents may worsen catatonia, and they were not effective for our patient. treatment of catatonia includes benzodiazepines; electroconvulsive therapy was not attempted in this case but may also be useful. background: epstein-barr virus (ebv)-related posttransplant lymphoproliferative disorder (ptld) is a lifethreatening complication in patients following hematopoietic stem cell transplantation, with a frequency estimated at 3.2% and a cumulative incidence of mortality estimated as high as 31%. studies of ebv have hypothesized that the tonsils are critical for propagating this infection, as tonsillar epithelial cells have been shown to be the site of primary viral infection and continued viral shedding; however, to date no studies have been performed assessing the role of tonsillectomy in patients with ebv ptld. objectives: identify patients with localized ebv ptld treated with tonsillectomy to identify prognostic factors that may be able to help guide future treatment decisions. design/method: patients treated at memorial sloan kettering cancer center who had received hematopoietic stem cell transplantation and had billing codes for both ebv and tonsillectomy were eligible for inclusion in this study. a retrospective chart review was performed, assessing patient demographics, transplant characteristics, laboratory values, tonsillar pathology, and clinical course. any patient who did not have unilateral or bilateral tonsillectomy performed or who had non-localized disease (defined as disease involvement outside of the oropharynx and neck) was subsequently immunodeficiency; 17% (n = 17/100) fanconi anemia (fa); 17% (n = 17/100) hemoglobinopathy; 12% (n = 12/100) non-fa marrow failure and 3% (n = 3/100) a metabolic disorder. seventy one percent (n = 71/100) had normal amh for age pre-transplant, 29% (n = 29/100) had low amh for age pre-transplant; of these, 37% (n = 11/29) had an oncologic diagnosis; 37% (n = 11/29) had fa; 10% (n = 3/29) had previously treated hlh; 6% (n = 2/29) had non-fa marrow failure; one had a metabolic disorder and one a hemoglobinopathy. of the 33 patients with post-transplant amh measurement 72% (n = 24/33) had low levels. of the 25 patients with previously normal pre-transplant amh 52% (n = 13/25) underwent myeloablative conditioning (mac) regimen with a 100% (n = 13/13) having low amh levels post-transplant compared to 48 %(n = 12/25) who underwent reduced intensity conditioning (ric) regimen with 25% (n = 3/12) having low amh levels post-transplant (p 0.0002). fifteen percent (n = 5/33) had low levels pre-transplant and underwent mac regimen with 100% (n = 5/5) remaining low; 80% of these patients (n = 4/5) had fa. nine percent (n = 3/33) had low levels and underwent a ric regimen with 100% (n = 3/3) of amh levels remaining low; 66% (n = 2/3) of these patients had hlh treated prior to transplant. conclusion: amh levels can be used for detection of premature ovarian failure and fertility counseling. there is a higher risk of premature ovarian failure with mac regimens and prior chemotherapy vs ric regimens. follow up of this cohort will provide more information to understand the effects of hsct in ovarian function and the usefulness of amh as a predictor of fertility potential. background: there are no proven strategies to prevent blood stream infections (bsi) secondary to oral mucosal barrier injury after hematopoietic stem cell transplant (hsct). additionally, we recently reported progressive gingivitis and dental plaque accumulation in hsct recipients despite our current oral standard of care (three times daily oral rinse). xylitol is a non-fermentable sugar alcohol that reduces dental caries, plaque accumulation, and oral disease progression by inhibiting bacterial growth. we hypothesized that the addition of xylitol to standard oral care will decrease dental plaque accumulation, gingivitis and bacteremia from oral flora. objectives: identify a clinically effective strategy to improve oral health and prevent bsi secondary to bacterial translocation through the oral mucosa in patients undergoing hsct. we are conducting a prospective randomized control study to test our hypothesis. those in the intervention arm receive our current standard of care (three times daily oral rinse) in addition to daily xylitol wipes; controls receive oral standard of care alone. oral exams are performed at baseline and weekly for the first 28 days post hsct. metagenomic shotgun sequencing (mss) of gingival samples is performed at all time points to evaluate microbiome diversity and pathogenic bacterial load. finally, we performed whole genome sequencing of pathogenic bacterial isolates causing bacteremia to assess for genetic relatedness to corresponding strains present within the patient's oral microbiome preceding the infection. : preliminary interim analysis of 21 patients demonstrates improved oral health in patients receiving xylitol (n = 10) over those receiving standard of care (n = 11), measured by the oral hygiene index (p = 0.03) and gingivitis index (p = 0.02). in the nine patients having complete oral mss analysis, xylitol appeared to be associated with decreased streptococcus mitis/oralis domination in the oral microbiome. finally, patients receiving xylitol had no incidence of streptococcus mitis/oralis bacteremia through the first 21 days compared to three patients (27%) in standard of care arm. interestingly, streptococcus mitis/oralis comprised 70% of the oral microbiome in one child who subsequently developed a streptococcus mitis/oralis bsi. we expect to complete this study in the next 4 months (n = 50). the addition of xylitol to oral standard care appears to decrease dental plaque and gingivitis in patients undergoing hsct. xylitol may also impede streptococcus mitis/oralis dominance in the oral microbiome with potential reduction in blood stream infections. (range:4-159 days). twenty-one mdli (49%) were administered because of lymphopenia, fourteen of them (33%) in patients with concomitant viral/opportunistic infections. mixed chimerism/graft failure was the motive of 37% of the mdli (n = 16) and six (14%) were administered to accelerate immune reconstitution. all infusions were well tolerated without appearance or worsening of gvhd. an increase in t-cell counts was observed following six mdli (28.57%), although it was a transitory response (3-8 weeks) in five cases. viral/opportunistic infections were controlled in five cases (35.71%), requiring a median of 2 mdli to achieve this response. none of the mdli administered in cases of mixed chimerism/graft failure were effective in reverting this situation. our preliminary data suggests that mdli, is a safe adoptive immunotherapy strategy even with high dose of t-cells without infusion side effects or gvhd complications. some efficacy has been observed in patients with lymphopenia and opportunistic infections, with no positive results in patients with mixed chimerism/graft failure, up to date. however, to determine the real efficacy of this strategy, prospective studies are required. jun zhao, kristen beebe, lucia mirea, alexandra walsh, shane lipskind, alexander, ngwube phoenix children's hospital, phoenix, arizona, united states background: male adolescents undergoing myeloablative hematopoietic stem cell transplantation (hsct) develop infertility with impaired spermatogenesis with reported rates ranging from 17% to 80%. in nonmalignant diseases, myeloablative regimens have been replaced with reduced intensity conditioning (ric) with the hopes of better survival rate, less organ toxicity and improved quality of life. despite the increased use of ric regimens for hsct, the effects of ric on fertility remain unknown. objectives: to assess fertility following ric hsct in young adult males. we assessed gonadal function and semen characteristics in adolescent males (>14 years) who received a single ric hsct at phoenix children's hospital for nonmalignant diseases during 2006-2016. male patients who were a minimum of 1 year from ric hsct and had postpubertal development at tanner stage iii or above were eligible for this study. gonadal status was assessed by measuring fsh, lh, testosterone, and inhibin b levels, and semen anal-yses assessed fertility indicators (semen volume, sperm concentration, motility, viability, forward progression, morphology, and total count). results: hormone levels and semen analysis have been obtained for 3 patients thus far. the median time between transplant and semen analysis was 4 years. post hsct, 2 (67%) patients showed abnormally elevated lh levels, but fsh, testosterone (total and free), and inhibin b levels were within normal range for all patients. sperm morphology and viability testing were not able to be performed due to low concentrations and volumes. as a result, the total motile sperm count, the most useful estimate for fertile potential, is essentially 0 for all 3 patients. conclusion: recruitment is ongoing, but so far our limited results suggest that ric hsct may have detrimental longterm effects on male fertility. a multi-institutional trial may be appropriate due to small patient numbers at each institution. we are currently exploring options to expand to other centers. further consideration is warranted regarding decisions made by providers, ways to improve anticipatory counseling provided to patients and their families prior to transplant, and how to augment the preventive care of these patients in longterm follow-up. currently all male patients being considered for ric transplant should be counseled to sperm bank prior to transplant. background: a previous systematic literature review identified all published studies of defibrotide treatment for patients of all ages with vod/sos. to assess day+100 survival for defibrotidetreated pediatric patients (≤18 or ≤16 years, per study) all patients exhibited infectious complications with at least 1 viral infection. four patients also had bacterial infections. of note, no patient developed evidence of fungal infections. conclusion: early institution of ecp in patients with high risk acute gvhd (grade 3-4) was very effective at treating agvhd, allowed for an aggressive steroid taper and contributed to excellent overall survival rates (83%). infectious complications were primarily viral and bacterial, with no fungal infections in this very high risk population. background: vod/sos is a life-threatening complication of hsct conditioning. vod/sos with multi-organ dysfunction (mod) may be associated with >80% mortality. defibrotide is approved to treat hepatic vod/sos with renal/pulmonary dysfunction post-hsct in the us and severe hepatic vod/sos post-hsct patients aged >1 month in the eu. there are few published data on survival of neuroblastoma patients with vod/sos post-hsct. objectives: to report day+100 survival and safety post hoc for patients with neuroblastoma and vod/sos post-hsct in the defibrotide t-ind trial. design/method: vod/sos was diagnosed by baltimore or modified seattle criteria or biopsy, with/without mod, after hsct or chemotherapy. defibrotide treatment (25 mg/kg/day) was recommended for ≥21 days. this post hoc analysis is based on 1154 adult and pediatric patients receiving ≥1 dose of defibrotide, including 571 with mod. results: among 111 patients with neuroblastoma, 106 developed vod/sos after hsct. for these post-hsct patients, 60.4% were male and 39.6% were female, median age was 3 years (range 1-17 years): 7.6% aged 0-23 months, 90.6% 2-11 years, 0.9% 12-16 years, and 1 patient >16 years. day+100 survival data were available for 105/106 of these neuroblastoma patients (43 with mod and 62 without mod); 103 had autologous and 2 had allogeneic transplants. kaplan-meier estimated day+100 survival for the neuroblastoma group was 87.2% (95% confidence interval [ci] , 79.0%-92.4%). for the mod and no mod subgroups, kaplan-meier estimated day+100 survival was 78.4% (95% ci, 62.6%-88.2%) and 93.5% (95% ci, 83.6%-97.5%), respectively. in the overall t-ind hsct population aged ≤16 years (n = 570) and pediatric autologous hsct subgroup (n = 127), kaplan-meier estimated day+100 survival was 67.9% and 87.1%, respectively. treatment emergent adverse events (teaes) occurred in 45.3% (n = 48/106), with serious teaes in 23.6% (25/106; most common: multi-organ failure, 4.7% [5/106]). teaes lead to treatment discontinuation in 17.0% (n = 18; most common: pulmonary hemorrhage, n = 3); death occurred in 10.4% (n = 11; >2%: multi-organ failure, 4.7%; vod/sos, 2.8%). treatment-related adverse events, as assessed by investigators, occurred in 17.0% (n = 18; most common: pulmonary hemorrhage, 2.8%). this post hoc analysis found kaplan-meier estimated day+100 survival of 87.2% in patients with neuroblastoma and vod/sos post-hsct, which was consistent with outcomes in pediatric patients after autologous hsct. the safety profile of defibrotide in neuroblastoma patients was consistent with the overall hsct population in this study and other defibrotide studies in pediatric patients. cincinnati children's hospital medical center, cincinnati, ohio, united states background: blood stream infections occur in nearly 30% of patients undergoing hematopoietic stem cell transplant (hsct) and fever is often the first symptom. timely administration of antibiotics is associated with improved outcomes, thus, early recognition of fever is paramount. current standard of care (soc) includes episodic monitoring of temperature in hospitalized patients, which may delay fever detection. therefore, continuous real-time body temperature measurement may detect fever prior to the current soc. temptraq is a food and drug administration cleared class ii medical device and consists of a soft, comfortable, disposable patch that results: of 100 patients, 98 were started on a pca in the 30 days post hct. 65% were male with median age of 11y. 46% had all, and 37% aml. matched related donors were used in 21% and 79% received tbi. pca was initiated median d+2. oral mucositis alone was the most common indication (80%). a majority of patients were started on hydromorphone (79%); 20% started on morphine and 1% started on fentanyl. 49% started on continuous infusion. pca was used for a median of 20 days (range 4-144 days). median pain score was highest d+3 of pca use, however, there was inconsistency in charting of numerical pain scores. on d+3, 12 patients had insufficient data to determine efficacy of pain control; of the remaining 86 patients, 24% had good pain control while 60% had moderate and 15% had poor pain control using our devised scale. the most common toxicity observed was respiratory depression (∼30%), however, etiology was often multifactorial and not due to opiates alone. analysis is ongoing to assess variables predicting pca use as well as efficacy of pain control and correlation between current reporting scales and patient perception. conclusion: pca use is common in pediatric hct yet pain control remains inadequate. there's a need for better evaluation of pca management, especially uniform assessment of pain, thereby improving quality of life post hct. children's national health system, washington, district of columbia, united states background: actinomycosis is a rare invasive anaerobic gram-positive bacterial disease caused by actinomyces spp. that may colonize the oropathynx, gastrointestinal tract and urogenitial tract and can lead to abscesses. respiratory tract actinomycosis is characterized by pulmonary cavities, nodules, consolidations and pleural effusions. although actinomyces are nearly always sensitive to penicillin they are frequently resistant to cephalosporins and variable sensitives to fluoroquinolones. although rare in children, immunosuppressed patients are at increased risk for actinomycosis. to describe a case of next-generation sequencing identification of actinomycosis. a 13-year-old male with a history of very high risk b-cell acute lymphoblastic leukemia who was 5 months status post a 7/8 matched unrelated donor bone marrow transplant complicated by prolonged fevers, persistent weight loss, and splenic lesions, treated with posaconazole and levofloxacin developed fever and cough in the setting of neutropenia. blood cultures demonstrated staphylococcus epidermidis. ct showed micronodules and effusion not consistent with s. epi, prompting bronchoscopy. all bacterial cultures were negative. patient was prescribed a three-week course of vancomycin with rapid improvement. design/method: 16s next generation sequencing (ngs) from bronchoalveolar levage sample was performed at the university of washington laboratory results: ngs assay from bronchoalveolar lavage showed major abundance of actinomyces most closely related to meyeri or oodontolyticus. demonstrated actinomyces. the patient was started on a six month course of amoxicillin with continued clinical improvement. in retrospect, the splenic nodules that were presumed fungal disease were likely actinomycosis, partially treated with levofloxacin. this case highlights the potential utility of ngs in the diagnosis of rare diseases in immunocompromised patients. actinomycosis was only demonstrated through ngs and led to a change in treatment regimen and durable clinical improvement. because actinomyces often mimics malignancy, tuberculosis or nocardiosis, the use of this novel test both targeted appropriate therapy and reduced the exposure to unnecessary medications to treat the differential diagnosis. finally, we highlight that actinomyces should be considered in patients who present with unexplained fevers, weight loss, and night sweats. haneen shalabi, cynthia delbrook, maryalice stetler-stevenson, constance yuan, bonnie yates, terry j. fry, nirali n. shah center for cancer research, national cancer institute, national institute of health, bethesda, maryland, united states background: car-t therapy, while effective, may not be durable for all, and antigen negative escape is a growing problem. hct, in relapsed/refractory all, can be curative, particularly for those in an mrd negative remission. we demonstrated that cd19 directed car-t therapy effectively rendered patients into mrd negative remissions (by flow cytometry) and the leukemia free survival post-hct was high 1 . in pastorek, jesssica bruce, michael a. pulsipher, chloe anthias, peter bader, andre willasch, jennifer sees, jennifer hoag, wendy pelletier, brent logan, pintip chitphakdithai, lori wiener university of pittsburgh, pittsburgh, pennsylvania, united states background: more than 4,500 pediatric hscts are performed in north american and europe each year. the ethics of exposing a healthy child to donation procedures which have some risks and no direct medical benefits continue to be a topic of debate. pediatric donors may experience psychological distress and poorer quality-of-life during and after donation compared to healthy controls. although there are fact/jacie requirements related to the management of pediatric donors, it is unclear what standardized practices exist for psychosocial assessment/management of this group. objectives: to describe transplant center practices for psychosocial evaluation/ management of pediatric donors (<18 years) and to examine differences in practices by location (cibmtr/ebmt) and number of harvests (volume). design/method: data were collected via a single crosssectional survey distributed electronically to cibmtr and ebmt centers between 9/18/17 and 11/20/17. : 55/98 (56%) of cibmtr and 85/147 (58%) of ebmt centers completed the survey. most centers had written eligibility guidelines for pediatric donors (91%). most also had a process for ensuring that donors were freely assenting to donate (78%), managed by a transplant physician (61%). a single physician often jointly managed donor/recipient care (44%). half of centers had a pediatric donor advocate (51%), who was most often a physician (38%) or social worker (16%). cost was the largest barrier to having a donor advocate (82%). most centers performed psychosocial screening of donors (69%) but rarely declined donors based on psychosocial concerns (13%). less than half of centers provided post-donation psychosocial follow-up (41%). comparisons by center location indicated that ebmt centers were more likely to have a physician doing joint donor/recipient care (60% vs. 23%; p = .001), less likely to have a psychosocial assessment policy (53% vs. 79%; p = .011), less likely to have a donor advocate (37% vs. 69%; p = .002), but marginally more likely to do post-donation psychosocial follow-up (49% vs. 31%; p = .063). large volume centers were more likely to have a psychosocial assessment policy than their medium/smaller counterparts (69% vs. 23%, 27%; p = .003) â€"there were no other differences on key psychosocial management variables by volume. although most centers have written guidelines for pediatric donor eligibility and mechanisms for ensuring assent, substantial numbers of donors do not undergo psychosocial assessment, are jointly managed with the recipient by a single physician without an assigned donor advocate, and do not receive psychosocial follow-up. the field would benefit from guideline development for the psychosocial management of pediatric donors. background: germline mutations in samd9 and samd9l genes cause mirage (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes and enteropathy) and ataxia-pancytopenia syndromes, respectively, and are associated with chromosome 7 deletions, mds and bone marrow failure (bmf). there are limited data on outcomes of hct in these patients. to describe outcomes of allogeneic hct in patients with hematologic disorders associated with samd9/samd9l mutations. results: seven patients underwent allogeneic hct for primary mds (n = 5), congenital amegakaryocytic thrombocytopenia (camt)(n = 1), and dyskeratosis congenita (n = 1). retrospective exome sequencing revealed gain-of-function mutations in samd9 (n = 4) or samd9l (n = 3) genes. constitutional mosaic monosomy 7 was present in 6 cases. two samd9 patients had features of mirage syndrome. unusual findings of panhypopituitarism, laryngeal cleft, and glomerulosclerosis were noted in one case. in another case with a samd9 mutation hypospadias & bifid scrotum were the only findings. the remaining patients had no phenotypic abnormalities. median age at hct was 5y (range: 1.4 -12.8). patients received transplants from bone marrow (matched unrelated (n = 3) & hla identical sibling (n = 2)), or unrelated cord blood (ucb) (n = 2). five mds patients received myeloablative s295 of s301 conditioning (busulfan-based (n = 3) or tbi-based (n = 2)); 2 patients (mds (n = 1); camt (n = 1)) received reducedintensity conditioning (ric) (fludarabine, cyclophosphamide, with ratg or alemtuzumab). syndrome-related comorbidities (diarrhea, infections, malnutrition, electrolyte imbalance, lung disease and hypoxia) were present in both patients with mirage syndrome. one patient with a familial samd9l mutation, mds and morbid obesity failed to engraft following ric double ucbt. she died one year later from refractory aml. all other patients achieved neutrophil and platelet engraftment, at a median (range) of 15 (12-19) and 16 (12-31) days, respectively. posttransplant complications included severe hypertension (n = 1), pericardial effusions (n = 2), veno-occlusive disease of liver (n = 1), and recurrent aspiration pneumonias (n = 1). one patient developed grade iii agvhd which resolved with treatment. one patient developed mild skin cgvhd and suffers from chronic lung disease. all surviving patients had resolution of hematological disorder and sustained peripheral blood donor chimerism (98-100%). overall survival was 86% with a median follow-up of 3 years (range: 1.1 -14.7 y). patients with hematological disorders associated with germline samd9 /samd9l mutations tolerated transplant conditioning without unusual, or unexpectedly severe toxicities. allogeneic hct led to successful resolution of mds or bmf, with excellent overall survival. more data is needed to refine transplant approaches in samd9/samd9l patients with significant comorbidities, and develop guidelines for their long-term follow-up. shyamli singla, tiffany simms-waldrip, andrew y. koh, victor m. aquino background: steroid-refractory acute graft versus host disease (agvhd) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation (hsct). basiliximab (anti-il2-r monoclonal antibody) as a single agent or in combination infliximab (anti-tnf-monoclonal antibody) has demonstrated efficacy in adult cohorts with steroid-refractory agvhd, but has not been well studied in the pediatric population. we adopted the use of basiliximab and infliximab as our institutional standard of care for steroid-refractory agvhd in pediatric hsct patients. to determine the response and survival of hsct children who received basiliximab and infliximab for the treatment of steroid-refractory agvhd. design/method: we retrospectively reviewed children who received basiliximab and infliximab for steroid-refractory agvhd refractory between september 2011 and december 2017. complete response (cr) was defined as resolution of all clinical signs of agvhd. partial response (pr) was defined as at least one grade reduction in one target organ (e.g. skin, gut or liver) without increased grade in another target organ. no response was defined as either no improvement or progressive worsening of agvhd in at least one organ. baseline demographics, transplant details, laboratory findings, and treatment outcomes were also evaluated. results: of the 214 evaluable hsct patients, 15 children (median age 11 yrs, range 9 mo-19 yrs) with steroid-refractory agvhd received combination monoclonal antibody (mab) therapy. the median time from the start of steroid therapy to initiation of mab was 13 days. the overall glucksberg grade of agvhd at the time of initiating mab therapy was grade i (n = 1, 6.7%) ii (n = 3; 20%), iii (n = 8; 53%) or iv (n = 3; 20%). the overall response rate was 53%, with 3 (20%) patients achieving cr, 5 (33.3%) patients achieving pr, and 7 (46.7 %) patients with no response at 30 days following the start of mab therapy. the median overall survival was 613, 292, and 84 days for patients who exhibited cr, pr, and no response, respectively. the overall survival at 1 year following start of mab therapy was 40%. background: the role of high dose chemotherapy (hdc) and autologous stem cell rescue (ascr) in patients with high risk (advanced metastatic or relapsed) soft tissue sarcomas is controversial. despite multimodal chemotherapy, radiotherapy, and local control measure advancements, prognosis of patients with advanced metastatic or unresectable and relapsed sarcomas remains poor, with less than 10% 5 years disease free survival. objectives: to determine if consolidation with myeloablative hdc and ascr improves relapse free (rfs) and overall survival (os) outcomes in a high risk patient subgroup. we performed retrospective review of all high risk soft tissue sarcoma patients who underwent hdc and ascr at the children's hospital at montefiore, bronx, ny between october 2014 and january 2018. the protocol was approved by albert einstein college of medicine institutional review board. results: 7 patients (4 primary metastatic high risk disease, 3 relapsed or recurrent disease) received hdc with ascr. primary diagnoses were rhabdomyosarcoma (rms) (n = 2, alveolar histology), primary site nasopharynx (n = 1) and lower extremity (n = 1). ewing's sarcoma (ews) (n = 5), axial site (pelvic) in 3 patients (60%). median age 12 years (range 6-35 years), 5 (71%) were male. all patients were in complete metabolic remission before transplant. median pre transplant comorbidity index was 3 (range 0-4). 5 patients (2 rms and 3 ews) received conditioning with carboplatin, etoposide and melphalan. remaining 2 patients with ews received conditioning with busulfan, melphalan and topotecan. all patients received peripheral blood mobilized hematopoietic stem cell transplantation. stem cell mobilization achieved with high dose filgrastim in all patients except one who required addition of plerixafor. median cd34+/kg s297 of s301 recipient body weight cell dose infused was 6.34 × 10^6 (range 2.72-12.03 × 10^6). median times to neutrophil and platelet (>20,000/â l) engraftment were 9 (range 8-13) and 49 (20-76) days respectively. 2 patients (28%) developed bk viuria (one with grade iii hemorrhagic cystitis); 3 (43%) developed cmv viremia; and one patient (14%) had asymptomatic ebv viremia. there was no graft failure, sinusoidal obstruction syndrome or transplant related mortality. median follow up post-transplant was 452 days (range 155-1141 days). 3 year probability of os and rfs were 80% and 50% respectively. hdc with ascr is a promising therapeutic strategy to consolidate remission and improve survival in select high risk soft tissue sarcoma patient subgroups. prospective clinical trials will inform the impact of disease status prior to hdc and ascr on outcome, optimal conditioning and long term relapse free and overall survival. background: absence of minimal residual disease is paramount for cure of pediatric acute lymphoblastic leukemia (all). the testis may harbor occult leukemia and this disease may result in treatment failure. objectives: the purpose of this study was to assess the longterm outcomes of boys with or without testicular leukemia pre-hematopoietic stem cell transplantation (hsct). design/method: retrospective analysis of 16 boys with high-risk de novo (2 with hypodiploidy all) or recurrent/refractory all was conducted. flow cytometry of bone marrow mononuclear cells was used to determine remission status. testicular evaluations were performed by physical examination and wedge biopsy pre-hsct. the median age at time of transplant was 12.3 years. all patients were in remission by flow cytometry of bone marrow mononuclear cells at the time of transplant and none had evidence of clinically apparent testicular disease. testicular leukemia was detected in 1 patient and he underwent bilateral orchiectomy. he developed acute graft versus host disease (gvhd) of the duodenum and sigmoid colon which resolved, and the leukemia remains in second complete remission and he is free of hsct-related morbidity 33.6 months post-hsct. of the 15 patients without testicular leukemia 4 died a median of 8.2 months (range, 2.5 to 12.5) post-hsct (2 with adenovirus infection and 1 each with thrombotic microangiopathy and aspergillus pneumonia); 6 experienced infection (staphylococcus species, corynebacterium, enterococcus, klebsiella, citrobacter, e. coli, epstein barr virus, adenovirus, bk virus, human herpesvirus-6, candida albicans, fusarium, aspergillus, yeast, and other fungus); 11 experienced gvhd (8 of the gi tract, 6 of the skin, 5 of the liver, 3 of the eyes, 2 of the mouth, and 1 of the lungs); and 1 developed a second neoplasia (right lower leg leiomyosarcoma). one patient developed bone marrow minimal residual disease (2.7% phenotypically abnormal cells detected 9 months after 6/6 matched sibling hsct). reinduction therapy comprised 5 weekly doses of rituxan, 2 courses of blinatumomab and 2 donor lymphocyte infusions with il-2. two subsequent bone marrow evaluations were minimal residual disease negative. thirteen months post-hsct residual disease recurred (0.012%) and he will receive inotumumab. overall median survival post-transplant of the 16 boys is 32.1 months (range, 2.5 to 75.3) and of the 12 surviving boys is 37.3 months (range, 11 to 75.3). conclusion: testicular biopsy can detect occult leukemia pre-hsct. testicular leukemia pre-hsct does not appear to increase the risk of subsequent relapse or other hsct-related adverse events compared to those without it. yaya chu, nang kham su, sarah alter, emily k. jeng, peter r. rhode, mathew barth, dean a. lee, hing c. wong, mitchell s. cairo new york medical college, valhalla, new york, united states background: rituximab has been widely used in frontline treatment of b-nhl including burkitt lymphoma (bl), however, some patients retreated with rituximab relapse, which limit patient treatment options. novel therapies are desperately needed for relapsed/refractory b-nhl patients. several strategies for overcoming rituximab-resistance are currently being evaluated, including engineering immune cells with chimeric antigen receptors (car), as well as second-generation anti-cd20 antibodies. nature killer (nk) cells play important roles in the rejection of tumors. however, nk therapy is limited by small numbers of active nk cells in unmodified peripheral blood, lack of tumor targeting specificity, and multiple mechanisms of tumor escape of nk cell immunosurveillance. our group has successfully expanded functional and active peripheral blood nk cells (expbnk). 2b8t2m was generated by fusing alt-803, an il-15 superagonist, to four single-chains of rituximab. 2b8t2m displayed tri-specific binding activity through its recognition of the cd20 molecule on tumor cells, activated nk cells to enhance adcc, and induced apoptosis of b-lymphoma cells. objectives: to examine if 2b8t2m significantly enhances the cytotoxicity of expbnk against rituximab-sensitive and -resistant bl cells. design/method: expbnks were expanded with lethally irradiated k562-mbil21-41bbl and isolated using miltenyi nk cell isolation kit. alt-803 and 2b8t2m were generously provided by altor bioscience. nk receptors expression and cytotoxicity were examined as we previous described. ifng and granzyme b levels were examined by elisa assays. equal doses of rituximab, alt-803, rituximab+alt-803, obinutuzumab (obinu) were used for comparison. igg was used as controls. anti-cd20 car expbnk cells were generated as we previously described by mrna electroporation. rituximab-sensitive raji andresistant bl cells raji-2r and raji-4rh, were used as target cells. results: 2b8t2m significantly enhanced expbnk cytotoxicity against rituximab-sensitive raji cells, rituximab-resistant raji-2r cells and resistant raji-4rh cells compared to the controls igg, rituximab, alt-803, rituximab+alt-803, obinu (p<0.001, e:t = 1:1). furthermore, we confirmed the enhanced cytotoxicity by measuring ifn-g and granzyme b production. 2b8t2m significantly enhanced ifn-g and granzyme b production from expbnk against raji, raji-2r and raji-4rh compared to igg (p<0.001), rituximab (p<0.001), alt-803 (p<0.001), rituximab+alt-803 (p<0.001), and obinutuzumab (p<0.001). when compared to anti-cd20 car expbnk cells, 2b8t2m + expbnk had the similar cytotoxicity against raji, raji-2r and raji-4rh as anti-cd20 car expbnk cells did (p>0.05). conclusion: 2b8t2m significantly enhanced expbnk activating receptor expression and in vitro cytotoxicity against rituximab-sensitive and -resistant bl cells. the in vivo functions of 2b8t2m with expbnk against rituximab-sensitive and -resistant bl cells using humanized nsg models are under investigation. background: cardiac dysfunction, including left ventricular systolic dysfunction (lvsd), is a known complication in stem cell transplant (sct) survivors. while detection of lvsd by echocardiography is important in this population, there has been minimal research to determine if subclinical cardiac dysfunction exists in sct patients. cardiopulmonary exercise testing (cpet) is a valuable tool to assess cardiac function, and to determine how the heart responds to the stress of exercise. no studies have been performed to determine if sct patients with normal lvsd on standard echocardiography may have abnormal cpet. to determine the feasibility of cpet, as well as additional echocardiographic parameters, to detect dysfunction in sct patients with a normal ejection fraction on echocardiogram. design/method: we performed a cross-sectional analysis of sct survivors who were at least 3 years post sct, 8 years of age or older and with an ejection fraction > 50% (low end of normal range) on echocardiogram. we assessed the exercise capacity of all patients with cpet, and sub-clinical cardiac dysfunction through tissue doppler and strain analysis from the echocardiogram. results: seven patients (6 male) have qualified and completed this study so far with an average age of 12.2±3.4 years. the median time from transplant is 4.4±0.8 years. all seven patients had a normal ejection fraction, however four patients had abnormalities on their cpet. these abnormalities included abnormal predicted peak oxygen consumption (vo2) (61%±9.8, normal > 70%) (the best predictor of functional capacity), predicted oxygen pulse (62%±10.1, normal > 70%) (measure of cardiac stroke volume) and ventilatory efficiency (ve/vco2 slope) (39±7.6, normal < 30). submaximal exercise data, used when patients are unable to complete a maximal effort test, demonstrated low-normal predicted vo2 at anaerobic threshold (45.8%±7.2%, normal >45% of was 19.4 days while patients who received autologous infusions had a mean number of days to engraftment of 13.3. engraftment after hsct needs to be prompt to minimize duration of neutropenia and maximize survival rates 6 . our data demonstrates that the infusion of hematopoietic stem cell products with a syringe or iv pump is an effective method of delivery for stem cell products and does not delay the time to engraftment. the median days to neutrophil engraftment was 14.5 days. this is comparable to data from the nmdp, which reports engraftment occurs within 14-20 days. the main limitation to this study was its small sample size due to the number of transplants done at our center. however, it does provide evidence to support that infusion of stem cell products via pump mechanism is a safe alternative to the infusion by gravity method in the process of the hematopoietic stem cell administration. johns hopkins all children 's hospital, st. petersburg, florida, united states background: leukemic relapse remains the most common cause of treatment failure after allogeneic hematopoietic cell transplant (allohct) for myeloid malignancies. most children who relapse post-allohct will die of their disease, making interventions to minimize this risk a high priority. objectives: to evaluate the safety and efficacy of posttransplant azacitidine for relapse prevention in children undergoing allohct for myeloid malignancy. design/method: we retrospectively reviewed the charts of children undergoing allohct for myeloid malignancies between february 2015 and november 2016 at johns hopkins all children's hospital. results: during the study period, 18 children (ages 2 to 20 years, median 12) underwent allohct for myeloid malignancies: de novo acute myeloid leukemia (aml), 11; mixed phenotype acute leukemia, 2; treatment-related aml, 2; juvenile myelomonocytic leukemia with aml transformation, 2; and myelodysplasia/aml, 1. thirteen were in first complete remission, 5 were in cr2 or greater. most patients (13/18) received fludarabine/melphalan/thiotepa conditioning; 11 received hla-identical related or unrelated donors, and 7 received haploidentical bone marrow grafts with post-transplant cyclophosphamide. three patients never received planned azacitidine (2 early relapse; 1 early trm), leaving 15 evaluable patients. azacitidine (32mg/m 2 /dose for 5 days, in 28-day cycles for up to 9 cycles) was started at a median of 66 days post-transplant (range 42-118). two-thirds (10/15) of patients received eight or more cycles. of five patients who stopped therapy early, only one was due to toxicity; other reasons included severe gvhd (1), parental preference (1), and relapse (2). cycle delays occurred in 9 patients, with a median 2 cycles delayed per patient, mostly for mild myelosuppression with early cycles. no patient required blood product transfusion during therapy, but g-csf was used in three patients to maintain anc>500/ l. dose-modifications were made in 3 patients (renal tubular acidosis, acute kidney injury, and myelosuppression). there were 3 relapses (20%), two of which occurred in patients in cr2, for a relapse incidence of 9% in patients in cr1, with a median follow-up of 20 months (range 12.5 to 28). no patients who received azacitidine died of transplant-related mortality. conclusion: administration of azacitidine in children undergoing allohct for myeloid malignancies is safe and feasible, with most patients successfully receiving all planned cycles. toxicity was acceptable and there was no trm or secondary graft failure. despite the limitations of a small cohort, relapse incidence-particularly in patients transplanted in cr1suggests a potential benefit in disease control that warrants investigation in follow-up studies. background: despite significant improvements in the success rate of hematopoietic cell transplantation (hct), graft failure remains an important complication in patients transplanted for severe aplastic anemia (saa). second allogeneic hct can salvage patients, but 5-year overall survival (os) rates have been reported as low as 60% 1 . objectives: identify patients who developed dropping donor chimerism, graft rejection, and/or graft failure after first hct for saa, necessitating additional hcts or cellular boosts (defined as stem cell products infused without preceding chemotherapy), and evaluate treatment-related complications and os. with vod/sos with and without multi-organ dysfunction (mod) pubmed and embase databases were searched for "defibrotide and retrospective chart reviews; excluded publication types were: case reports (<10 cases); meta-analyses; reviews; animal, modeling, pharmacokinetic, chromatography, and adult-only studies; guidelines; articles; and letters. resulting reports were screened for exclusion criteria. full-text articles were then reviewed for eligibility. study characteristics of selected publications were summarized, and publications were categorized by patients' mod status. when necessary, additional data tables were requested. a random effects model was used for pooling data for efficacy. interstudy heterogeneity was assessed with cochran's q-test. percentage of total variation across studies due to heterogeneity (i2) was evaluated we quantified ∼4300 proteins in each sample. reproducibility for one donor at 3 different time points children 's minnesota, minneapolis, minnesota, united states background: pediatric and young adult hodgkin lymphoma (hl) has five-year survival rates >90%. chemotherapy required to achieve this rate is associated with a lifetime risk of cardiac deaths, second malignancies, pulmonary disease and infertility. as effective salvage therapy exists, outcomes may be improved by de-intensifying initial therapy to lessen toxicity.objectives: we piloted a regimen in low and intermediate risk hl patients using agents without known association to significant late effects. this retrospective chart review was approved by children's minnesota irb.design/method: the bvg(p) regimen incorporated bortezomib (1.3 mg/m2 day 1,4,8,11); vinorelbine (25 mg/m2 day 1,8); gemcitabine (1000 mg/m2 day 1,8) every 21 days and prednisone (20 mg/m2/dose bid x 11 days). we treated 5 newly diagnosed patients, ages 10-18 years, with non-bulk stage iia (n = 4) or iib (n = 1) hl. two patients received bvg and 3 received bvgp with the addition of prednisone.results: newly diagnosed patients were all pet negative after the first or second cycle and remained pet negative at end of therapy, 4 cycles. nausea was well controlled with 5-ht3 antagonists and scopolamine. pegfilgrastim was not necessary due to the high absolute neutrophil count nadir [median 1.16 and minimum 0.56 × 109/l]. there were no episodes of febrile neutropenia, infection or transfusion need. no patients experienced alopecia. one patient developed sensory neuropathy after the eighth dose of bortezomib that was controlled with gabapentin and a switch to subcutaneous bortezomib administration. of the five newly diagnosed patients, four remain in remission at 227, 270, 557, 1191 days; 1 relapsed at previous disease sites at 861 days and subsequently achieved remission with bvgp with the addition of brentuximab. this series provides early evidence to stimulate expansion of this pilot experience and subsequent multiinstitutional study leading to a randomized trial of bvgp and current chemotherapy for low and intermediate hl. st jude affiliate clinic at st francis hospital, tulsa, oklahoma, united states background: symptoms suggestive of morning hypoglycemia has been noticed in children receiving all chemotherapy. only few small studies looked at this therapy related complication. factors increase risk of hypoglycemia in all patients include accelerated starvation, steroid induced adrenal suppression, mercaptopurine therapy and prolonged fasting for procedures.objectives: to study the prevalence and risk factors for hypoglycemia during all therapy design/method: medical records of of children (up to 18 years old) treated for all between 2011-2016 (86 patients) were studied for evidence of morning hypoglycemia defined as blood sugar (bs) < 60 mg/dl. statistical mean differences between the subgroups were analyzed with spss using a nonparametric mann-whitney u test.results: fifty two percent (52%) of patients developed hypoglycemia during all treatment, with an average of 2.2 episodes/patient. 59% were males and 41% females. almost 2/3 (65%) of patients with hypoglycemia were in maintenance phase of therapy. 34% of hypoglycemic episodes occurred in 10% of patients. majority of hypoglycemic episodes (78.2%) occurred on the day of procedure when patients were fasting overnight. 48.9% of hypoglycemic episodes occurred in children ≤3 years, with 75.8% in ≤6 years. patients who developed hypoglycemia were significantly younger (mean age at time of diagnosis of all was 4.93 ± 3.69 at the hypoglycemia group versus the non-hypoglycemia (7.27 ± 4.98) p<0.05. no statistically significant difference was found regarding sex, or tpmt genotype. 6% of hypoglycemic children-all <3years of age-presented with life threatening hypoglycemia symptoms including seizure and loss of consciousness. this study showed high prevalence of hypoglycemia during childhood all therapy. younger age, especially ≤ 3 years, is associated with higher risk of hypoglycemia as well as life-threatening episodes. to decrease fasting hypoglycemia during therapy for childhood all, we recommend that children under the age of 6 years receive bed time snack high in proteins and complex carbohydrates, and to get them up early the day of procedure to take clear sugary drink. hospital for sick children, toronto, ontario, canada ann & robert h. lurie children's hospital of chicago, chicago, illinois, united states background: childhood brain tumors are the most common solid malignancy and the leading cause of cancer-related mortality in children. the most aggressive type of pediatric central nervous system (cns) tumors is diffuse intrinsic pontine glioma (dipg). despite decades of clinical trials, there has been no substantial improvement with respect to therapeutic outcomes with most children eventually succumbing to the disease. research on adult high-grade gliomas has shown a targetable pathway through the inflammationinduced expression of indoleamine 2,3 dioxygenase 1 (ido1) and its recognized ability to suppress the anti-tumor immune response. a limited understanding into the role of ido1 in pediatric central nervous system tumors serves as the foundation of this research project. furthermore, the integration of nanotechnology is a fundamental step for the investigation and targeting of ido1. spherical nucleic acids (snas) composed of nanoparticles have been shown to transverse cellular membranes, exhibit stability in physiological environments, escape from degradation, and create precise targeting in brain tumors.objectives: the purpose of our project is to delineate the role of ido1 in pediatric dipg, and develop small inhibitory (si)rna oligonucleotides and snas aimed at therapeutically inhibiting the gene expression of immunosuppressive ido1. our specific aims are to: (1) confirm the gene expression ido1 in different human dipg cell lines; (2) generate and characterize sirna oligonucleotides targeting human ido1 in vitro; and (3) generate and characterize gold nanoparticles for targeted inhibition of ido1.design/method: unique patient-derived dipg cell lines were grown in culture, stimulated with increasing concentrations of the proinflammatory cytokine, ifn , and analyzed for mrna levels. sirna specific to ido1 was transfected into cells. sna generation is in progress.results: ido1 is expressed in multiple human pediatric dipg cell lines. sirna targeting ido1 among exons 9 and 10 results in a significant decrease in overall ido1 expression by dipg cells. sna generation for targeting ido1 with improved penetration & stability is ongoing, with preliminary results demonstrating a robust ability to inhibit ido1 expression. the grim prognosis of children with dipg, the lack of effective therapies, and the expression of ido1 by human dipg cells emphasize the importance of developing the treatment capability to inhibit ido1 gene expression, as a excluded from this study. the remaining patients were analyzed using descriptive statistics.results: a total of 17 patients meeting inclusion criteria were identified. of these, 4 patients (23.5%) received tonsillectomy alone, 1 (5.9%) underwent tonsillectomy and decreased immunosuppression, 6 (35.3%) received tonsillectomy and rituximab, and another 6 (35.3%) received tonsillectomy with additional therapy (including ebv-specific cytotoxic tlymphocytes, donor leukocyte infusion, and chemotherapy). of the 5 patients who received tonsillectomy with or without a decrease in immunosuppression, all were diagnosed with high-grade lymphoma and achieved clinical remission following tonsillectomy with no evidence of relapse to date. on further analysis looking at ptld risk factors, all patients were under 50 years of age, all received t-cell depleted grafts, and none had significant graft-versus-host disease (gvhd) at the time of ptld diagnosis. we have identified a population of patients with localized ebv ptld that achieved clinical remission with no evidence of recurrence following tonsillectomy, suggesting that tonsillectomy alone may be an adequate treatment for localized ebv ptld in a specific subgroup of patients. further analysis is needed to identify characteristics of this subgroup to determine which patients would be most likely to respond to this treatment. university of rochester, rochester, new york, united states background: malignant central nervous system (cns) tumors in young children have a poor prognosis and pose a significant therapeutic challenge. consolidation therapy with carboplatin and thiotepa was piloted in ccg-99703, cog acns0333, and cog acns0334 with the goals of intensifying therapy and omitting or delaying radiation.objectives: to document outcomes for patients undergoing carboplatin/thiotepa consolidation with autologous stem cell rescue (ascr) and to demonstrate the feasibility and toxicity of this regimen.design/method: patients up to 3 years old (median age: 12 months) with malignant cns tumors treated at the university of rochester from 2012-2017 with at least one cycle of carboplatin (17 mg/kg/day x 2 days) and thiotepa (10 mg/kg x 2 days) followed by peripheral blood ascr were included in retrospective analysis. data were recorded on time to engraftment (defined by absolute neutrophil count (anc) recovery to > 0.5 × 10^9/l), length of hospitalization, toxicity with each consolidation cycle, progression free survival (pfs) and overall survival (os). stem cell harvest data were also collected.results: eleven patients with malignant cns tumors (6 atypical teratoid/rhabdoid tumor, 3 primitive neuroectodermal tumor, 1 glioblastoma multiforme, and 1 pineoblastoma) received a total of 30 cycles of carboplatin/thiotepa. of these, 9 underwent stem cell harvest at our institution, with complications limited to procedure-related hypotension for 1 patient with known autonomic instability, and catheter-associated deep vein thrombosis (dvt) for 1 patient. four patients were in complete remission (cr) 1/status-post gross total resection, 1 was in cr2, and 6 had residual tumor at the time of consolidation. nine patients received 3 planned consolidation cycles, 1 patient 2 (of 2) planned cycles, and 1 patient 1 of an anticipated 3 cycles thus far. average time to engraftment for these 30 cycles was 10.2 (+/-1.4) days, with a mean hospital length of stay of 16 (+/-3.2) days. fever occurred in 17 of 30 cycles (57%); infectious toxicity included documented bacterial infection in 2 cases (enterococcus faecalis bacteremia in 1, klebsiella pneumoniae in 1). there were no regimenrelated deaths. with a mean follow-up of 23 months, 2 survivors have not yet completed all therapies, and 5 patients have relapsed (4 have died of disease). of the 7 survivors, 4 have been disease-free for >12 months. background: autologous hematopoietic stem cell transplantation (auto-hsct) has resulted in improved survival for patients with high-risk neuroblastoma. treatment intensification is however associated with greater complications. data on early infectious complications in low-and-middle income countries are limited.objectives: to review the early infectious complications following auto-hsct in patients with high-risk neuroblastoma.design/method: a retrospective chart review of pediatric patients with high-risk neuroblastoma who underwent auto-hsct at the american university of beirut medical center between 2003 and 2017 was conducted. infectious complications during the first 100 days post-transplant were reviewed.results: forty-three patients (27 males and 16 females) with a median age at diagnosis of 4.35 years [range: 0.5-13.9] years underwent auto-hsct during the above-mentioned period. conditioning regimen consisted of melphalan, etoposide and carboplatin. all patients received antiviral and antifungal prophylaxis. median time for neutrophil engraftment was 10 days [range: 8-19]. bacteremia and clostridium difficile infections occurred in 16 (37%) and 12 (28 %) patients respectively. seven (16%) patients developed enterocolitis diagnosed by imaging, 4 were adenovirus induced. cmv viremia was diagnosed in 7 (16%) patients, 5 of whom required treatment. varicella zoster reactivation, parvovirus viremia, toxoplasmosis encephalitis, bk virus cystitis (2 patients) and central nervous system ebv related post-transplant lymphoproliferative disorder were diagnosed in 6 different patients. there was no invasive fungal infection. sixteen (37%) patients have died, 6 of whom died in the early post-transplant period, 1 due to disease progression and 5 (11.6%) due to infectious complications. among the 5 patients who died due to infection, 1 developed toxoplasmosis encephalitis, 4 developed severe enterocolitis, 2 of which were adenovirus related. the mean igg level within one week post-transplant was lower in patients with clinically significant viral infection compared to others (4 vs 5.6 mg/dl, p: 0.08). the mean igg level at the time of clinically significant bacterial infection was lower in infected patients compared to others (4.4 vs 6.3 mg/dl, p: 0.03). neither absolute lymphocyte count nor absolute neutrophil count at day 20 post-transplant affected the incidence of clinically significant infections. our results show that the rate of infections during the early post auto-hsct period is higher than what has been described in developed countries and has a significant impact on mortality. prevention, early detection and improvement in the treatment is required to improve outcome. university of miami, miami, florida, united states background: allogeneic hematopoietic stem cell transplantation (allo-hsct) is a curative treatment for many malignant and non-malignant (bone marrow failure, immunodeficiency, or metabolic diseases) in pediatrics. despite advances in medicine, graft-versus-host-disease (gvhd) remains a significant cause of non-relapsed morbidity and mortality, specifically in those with malignant diseases.objectives: to highlight the complexity to acute gvhd management and seldom-described treatment approach. a 7 year male with a history of high risk acute myeloid leukemia (aml) due to failed induction therapy. he received a matched (10/10) unrelated donor hsctmarrow product-conditioned with busulfan, fludarabine, and anti-thymoglobulin (atg). his post-transplant course was complicated by hhv-6 viremia, pres (prompting a change from prograf to cyclosporine), mucositis, and grade iii acute gvhd (skin s3, gut s2, liver s0) around post transplant day 101, which later morphed to ocular involvement by d+120. he was started on 2 mg/kg steroids with good response but flared up with each attempt to taper steroid dose. a course of rituximab and later atg were tried without success in weaning off steroids. switching cyclosporine to sirolimus did not provide any additional benefit either. extracorporeal photopheresis (ecp) was started 3 times a week. he initially responded well, yet was not able to wean off steroids. in addition, he developed a flare when ecp session was reduced to 2 days per week. ecp was therefore increased to 5 days per week, which appeared to stabilize skin lesions. a trial of weekly methotrexate was attempted to wean off steroids and photopheresis, which provided no response. finally, a trial of bortezomib on days 1, 4, 8, and 11 of a 21 day cycle as published in a case series of multiple myeloma patients who developed post hsct gvhd. skin lesions improved remarkably however dose had to be reduced due to related pancytopenia. given the response to therapy, he was continued on a weekly dose of bortezomib, receiving a total 8 doses, which has permitted the slow taper of prednisone that has since been discontinued without a major flare. he however is currently maintained on ecp 3 times per week, which is now been slowly withdrawn.conclusion: management of acute gvhd in pediatric patients after hsct can be challenging with no definite options for those who fail steroids or become steroid dependent after initial response. in these situations, bortezomib could be a valid therapeutic option. background: neuroblastoma (nbl) is the second most common solid tumor in children and despite recent treatment advances, overall survival for high risk nbl remains <50%. the addition of immunotherapy has improved survival and includes anti-gd2 antibody therapy. the success of antibody therapy in neuroblastoma is primarily due to natural killer (nk) cell mediated antibody dependent cellular cytotoxicity. we previously demonstrated that nk cells from patients with high risk nbl can be successfully isolated and expanded to large numbers and exhibit potent anti-tumor effects against nbl (1). thus, infusions of autologous expanded nk cells in high risk nbl in combination with anti-gd2 antibody are being studied in clinical trials. toll-like receptors (tlr) present on the surface of leukocytes are responsible for pathogen recognition, and activation of these receptors stimulate the production of cytokines that critically link innate and adaptive immune responses. the tlr3 agonist, poly(ic) is a synthetic analog of dsrna that has previously been shown to directly stimulate cytokine production and improve cytotoxicity in primary nk cells through activation of genes regulated by interferon-response elements (ire) (2). we hypothesized that ex vivo activation of tlr pathways in nk cells during our normal 14-day expansion using k562 feeder cells expressing membrane bound il-21 would enhance their function.design/method: nk cells were isolated from peripheral blood mononuclear cells and expanded with our previously described expansion protocol in media containing il-2 and 50 ug/ml poly(ic) (3). at the end of the 14-day expansion, nk cells expanded with poly(ic) were compared to controls using a calcein cytotoxicity assay to measure cytotoxicity against high risk neuroblastoma and cytometric bead array to measure cytokine production. : surprisingly, the addition of poly(ic) during nk cell expansion did not improve proliferation, cytokine production or cytotoxicity compared to our standard expansion method. rnaseq demonstrated that our standard expansion method results in a modest decrease in tlr3 expression at the transcriptional level, but significant upregulation of several ireregulated genes. we conclude that either our standard approach interferes with tlr signaling or saturates the innate immune response pathway such that co-stimulation with poly ic does not produce an additive effect. we are performing expression analysis on nk cells receiving poly(ic) during expansion to further explore this hypothesis. background: gonadal dysfunction leading to infertility is a complication after hematopoietic stem cell transplant (hsct). anti-mã¼llerian hormone (amh) is a marker of ovarian reserve; it is not controlled by gonadotropins and has minimal inter-cycle variations, therefore, it can be used as a marker of ovarian reserve and aid in fertility counseling.objectives: assess ovarian reserve in hsct patients utilizing amh levels. background: tgf beta is an immune suppressive cytokine frequently elevated in the tumor microenvironment causing tumor immune evasion. acute tgf beta treatment potently inhibits nk cell cytotoxicity, cytokine secretion, and proliferation. however, tumor infiltrating nk cells receive chronic inhibitory tgf beta signals in conjunction with activating signals from tumor cells. objectives: to this end, we hypothesized that long-term tgf beta-cultured nk cells would induce functional and phenotypical changes on nk cells that differ from short-term tgf beta treatment.design/method: to explore this, primary human nk cells were cultured with the leukemia cell line, k562, alone or with exogenous tgf beta for 2 weeks. : surprisingly, nk cells cultured in tgf beta proliferated faster, and upon challenge with a variety of cell line targets they secreted much greater quantities of ifnî 3 (5-to 282-fold increase against 8/8 cell lines) and tnf (3-to 33-fold increase against 7/8 cell lines). further, the high cytokine secretion induced in these nk cells was no longer inhibited by adding additional tgf beta. degranulation was also increased (2/3 cell lines), however cytotoxicity was not enhanced in a 4-hour cytotoxicity assay. after resting in il-2, the cytokine hypersecretion of tgf betacultured nk cells was maintained for several weeks suggesting this functional change might involve cellular reprogramming. we investigated the mechanism behind these functional changes and profiled 92 genes involved in tgf beta signaling. we found significant reduction of smad3 transcription which corresponded to a striking decrease in smad3 chromatin accessibility. we also found significantly increased smad6 and decreased tgfbr3 expression. phenotypic analysis revealed that tgf beta also induced remodeling of the nk receptor repertoire with decreased nkp30, cd16, and klrg1 and upregulation of trail. the functional consequences of these tgf beta-induced changes on in vitro and in vivo nk cell function are currently under investigation. background: the use of t-cell depleted grafts in haploidentical stem cell transplantation (hsct) has been associated with a delay in early t-cell recovery which increases the risk of viral infections, relapse or graft rejection. conventional donor lymphocyte infusion (dli) after hsct transplantation is effective but conditioned because of a high prevalence of gvhd. the infusion of selected lymphocyte subpopulations with low aloreactivity is emerging as an effective strategy to rectify this issue. the depletion of cd45ra+ naive lymphocytes, preserving cd45ro+ memory t-cells, could provide a safe source of functional lymphocytes with anti-infection, antileukemic and anti-rejection properties, and lower rates of adverse effects. our objective is to present data of patients that have received cd45ro+ memory t-cells dli (mdli) and assess its safety and outcome. we present data of mdli performed after hsct in cases of mixed chimerism, persistent lymphopenia, viral/opportunistic infections or as a strategy to accelerate immune reconstitution.results: fifteen patients with diagnosis of all (n = 6), aml (n = 3), mds (n = 1), saa (n = 3), sideroblastic anemia (n = 1) and cgd (n = 1), received mdli after hsct. a total of forty-three mdli were infused. the median dose of cd45ro+ memory t-cells infused was 5.00 × 107/kg (range:4.8 × 104-4.25 × 108/kg), with a median dose of cd45ra+ naive t-cells of 3.90 × 102/kg (range:0-1.3 × 104/kg). the mdli were infused at a median of seventy-seven days after hsct (range:14-407 days), with a median interval between mdli of thirty-four days results: eight published studies reported survival outcomes for pediatric vod/sos patients (n = 1036), across all defibrotide doses. estimated day+100 survival (95% confidence interval) was 60% (53%-67%). for vod/sos with mod, 4 studies were identified (n = 402) with pooled estimated day+100 survival of 57% (52%-61%). only one openlabel expanded-access study, the treatment-ind, reported outcomes separately for pediatric vod/sos patients without mod (n = 289 patients aged ≤16 years). the day+100 kaplan-meier estimated survival for those patients was 78% (72%-82%). safety results were not pooled due to differences in reporting methodology; however, study results were consistent with the safety profile of the phase 3 historicallycontrolled trial in vod/sos patients with mod (43% pediatric), in which 101/102 defibrotide-treated patients and all 32 controls experienced ≥1 ae. hypotension was the most frequent ae (39%, defibrotide; 50%, controls); common hemorrhagic aes (ie, pulmonary alveolar and gastrointestinal hemorrhage) occurred in 64% of defibrotide-treated patients and 75% of controls. in this pooled analysis of studies with defibrotide-treated pediatric patients with vod/sos, estimated day +100 survival was 60% (without mod, 78%; with mod, 57%). safety results in individual studies were generally consistent with the known safety profile of defibrotide. taken together, these results show a largely consistent defibrotide treatment effect in pediatric patients treated with defibrotide for vod/sos, with or without mod. results: six patients met inclusion/exclusion criteria. all patients were started on ecp while concurrently receiving 1.5 to 2 mg/kg steroid therapy for agvhd plus a calcineurin inhibitor. patients had initiation of ecp within a maximum of 2 weeks from initial diagnosis of agvhd (range 3-12 days). patients had grade 2-4 agvhd (3/6 patients with grade 4) with skin, liver, and gi gvhd represented. patients received ei-ecp 2-3 times per week for the first 6 weeks and then had ei-ecp frequency tapered based on initial response.after 6 weeks of therapy 1 patient had a decrease in overall gvhd grade by 1 grade. all patients were able to have steroids tapered, with doses decreased by an average of 62% (33% -100% decrease).at 12 weeks of therapy, one patient with grade 4 agvhd died of mof associated with infections. three patients had complete resolution of agvhd and 2 patients decreased by 1 grade. steroid doses were decreased by an average of 91% (69% -100% decrease). continuously measures axillary temperature and wirelessly transmits real time-time data. the primary aim of the study was to evaluate the feasibility, safety and tolerability of continuous temperature monitoring in hsct patients using temptraq. we are performing a prospective observational study of pediatric patients (1-12 years of age) undergoing hsct at cincinnati children's hospital in cincinnati, ohio. enrolled patients wore a temptraq patch for 5 days. a 1-10 rating scale survey was completed by the parent/guardian at the end of the study to determine tolerability, ease of use, satisfaction and desire for future use in the inpatient and outpatient setting. temperature data from the temptraq patch was compared to the standard episodic temperature monitoring to determine detection of febrile episodes. seven of ten patients have completed screening. we anticipate completion of the study in early february. the temptraq patch was well tolerated by study subjects (mean tolerability rating of 8.7/10). one patient developed skin breakdown at the site of the temptraq patch attributed to recent thiotepa. the patch was easy to apply with an easy of application rating of 9.7/10. parents were overall satisfied (rating 8.4/10) and would like to use the temptraq patches in future hospitalizations (rating 8.4/10) and at home (rating 8.9/10). temptraq patch identified fever (≥ 100.4 • f) in 4 patients. the fever was never detected by episodic monitoring (soc) in 2 patients and significantly delayed in the other 2 patients (>12 hours). temptraq was well tolerated in pediatric hsct patients. timely fever detection was improved in temptraq over the current soc. background: serotherapy is commonly used in patients undergoing hematopoietic stem cell transplant (hsct) to reduce the incidences of engraftment failure and graft versus host disease. however, one well-known side effect is fever. as children undergoing hsct have compromised immune defenses, fever may also be an early indicator of bloodstream infection, which would warrant prompt use of broad-spectrum antibiotics. in a subset of patients with serotherapy-associated fever, antibiotics, which may induce antibiotic resistance and increase costs, may be unnecessary. we aimed to determine the incidence and characteristics of serotherapy-related fever, as well as the likelihood of concomitant bacteremia, in our institutional experience. a 5-year retrospective chart review was conducted of pediatric patients who received serotherapy as part of hsct conditioning at the university of minnesota. one-hundred sixty eight consecutive hsct patients who received serotherapy -either atg (n = 99) or alentuzumab (n = 69) -were identified. the median age at hsct was 6-years (range, 0.4-18 years). a total of 133 patients (79 %) developed fever while on serotherapy (atg = 79, alentuzumab = 54). one-hundred sixteen patients presented fever following the first infusion, and the median onset of fever was 7 hours after commencing infusion (range, 0.1-22 hours). fever resolved at a median 8 hours (range, 1-48 hours). one hundred and fourteen patients (98%) underwent blood cultures. only seven patient were not started on (6%) empiric antibiotics, while 14% (n = 17) were on antibiotic treatment prior to serotherapy for previously known or suspected infections. nine patients (7% of febrile patients, 4% of all patients) had positive blood cultures (atg = 6; alentuzumab = 3). no infection-associated deaths were observed.conclusion: while fever is common during serotherapy conditioning in children undergoing sct, episodes of concomitant bloodstream infection are rare. ongoing analysis identified potential risk factors for bacteremia as recent history of infection, first episode of fever following second or subsequent infusions, and previous central line placement. further analysis is being conducted to identify subgroups of patients for whom close monitoring alone may be safe. background: hsct is potentially curative for caya with high-risk leukemias; however, most lack an hla-matched 2018 aspho abstracts related donor. the risk of gvhd is increased with unrelated (urd) or partially matched related (pmrd) donors. selective t-cell depletion based on the elimination of t cells carrying and chains of the t-cell receptor may greatly reduce the gvhd risks, while allowing the maintenance of mature donor-derived alloreactive nk cells and / (+) t cells, which may augment the anti-leukemia effect.objectives: this is a prospective study of caya with acute leukemia who underwent hsct with mmrd or urds and tcr / /cd19 depletion. outcomes included engraftment, toxicities, viral reactivation, and relapse.design/method: this study included 36 caya with acute leukemia transplanted between october 2014 and may 2017. all received a myeloablative preparative regimen with targeted busulfan (n = 15) or tbi (1200 cgy/6 fractions) (n = 21), with thiotepa (10 mg/kg) and cyclophosphamide (120 mg/kg). atg (3 mg/kg x 3) was given to those receiving haploidentical grafts and to the first 17 who received urd grafts. immune suppression was not given post-hsct. the stem cell source was mobilized peripheral blood stem cells (pscs), which then underwent tcr / /cd19 depletion utilizing the clinimacs device under gmp conditions in the chop cellular immunotherapy lab.results: median age was 11 (range 1.3-21.7). diagnoses included all (9-b-cell, 3-t-cell) and aml (24; 3-secondary aml). urd were used for 28; 13 were 10/10 allele matched and 15 were 9/10 matched. haploidentical donors were used for 8. median cd34(+) dose -10.1 × 106, / (+) cd3(+) cells -5.63 × 106, and b cells -8.95 × 104. all patients achieved an anc at a median of d+13 (8-30), and 94% had platelet engraftment at median d+17 (12-40). nine patients (25%) developed acute gvhd (all skin, grades i-iv). five developed chronic gvhd (skin, gut, lung): limited in 4, extensive in 1. viral reactivations included: adenovirus (5, 14%), bk virus (8, 22%), cmv (10, 28%), and hhv6 (2, 6%). nine (25%) patients relapsed at a median of 147 days (range 57-625) post-hsct, including 7 aml patients (29.2%) and 2 all patients (16.7%). transplant-related mortality was 14%; causes included sepsis (6) and ards (2). os was 72%; efs was 58% (gvhd-free efs 39%, lfs 61%). hsct with tcr / /cd19 depletion demonstrates excellent engraftment kinetics with limited gvhd without immune suppression. elimination of post-hsct immunosuppression may offer an excellent platform to augment anti-leukemic immune therapy or to enhance immune reconstitution. background: hematopoietic cell transplantation (hct) is the only curative treatment available for patients with sickle cell disease (scd). low bone mineral density (bmd) has been described in scd, but little is known about the impact of curative hct on this outcome. to determine the prevalence of low bmd and variables associated with low bmd in scd patients after hct. we conducted a retrospective chart review of scd patients who underwent hct at children's healthcare of atlanta (choa) between 12/1993 and 12/2016 and survived ≥1 year post-hct. transplant characteristics, post-hct dual-energy x-ray absorptiometry (dexa) scan results, vitamin d levels, graft-versus-host-disease (gvhd) status, and fsh levels were reviewed. for patients 2-20 years of age, height corrected z-scores were calculated using a nihvalidated calculator, with t-scores used for older patients. bmd was categorized as low if between -1 and -2 sd below the mean and clinically significantly low if >-2 sd, in accordance with the children's oncology group long-term follow-up guidelines. vitamin d levels <20 ng/mol were considered deficient, and fsh levels >40miu/ml suggestive of premature ovarian failure. fisher's exact test was used to compare variables in those with normal versus abnormal dexa scan results, with p<0.05 considered significant.results: hct was performed on 71 patients with scd, with 67 surviving ≥1 year post-hct. dexa scans were obtained in 40 patients (55% female), with mean time from hct to dexa scan being 4 years (1.3-11.2 years) and mean age at time of dexa 13.1 years (6.1-22.3 years). patients with and without dexa scans did not differ by sex, donor source, age at transplant, or vitamin d status. low bmd was noted in 10 patients (25.0%), with these patients more likely to be >13 years (pubertal; 90.0 versus 40.0%, p = 0.009). acute gvhd was more common in patients with low bmd (50.0 versus 16.7%), but not statistically significant (p = 0.085). clinically significant low bmd was noted in 3 patients (7.5% of those with dexa scans). these patients were older (16.2 years at testing), were more likely to be male (66.6%), and all had acute and chronic gvhd, while none had evidence of gonadal failure.conclusion: clinically significant low bmd is uncommon after hsct for scd. patients at risk for low bmd include older patients and likely those with gvhd. this preliminary data suggests routine dexas may not be indicated for all patients who undergo hct for scd, but further data is needed. background: causes of renal dysfunction after hematopoietic cell transplantation (hct) include damage from radiation, nephrotoxic medications, graft vs. host disease (gvhd), hepatorenal syndrome, viral infections, or transplant associated microangiopathy. we sought to investigate the incidence of, and risk factors for, acute kidney injury in pediatric hct patients and associated risk with mortality.design/method: data from patients who underwent hct between 2013 and 2016 at a single institution were sequentially retrospectively captured on irb approved protocol. acute kidney injury (aki) was defined at multiple time points post-hct using the standardized criteria: kidney disease: improving global outcomes (kdigo). interval differences between values were analyzed using wilcoxon rank sum testing and categorical variables were analyzed using chi-square analysis.results: ninety-eight patients were included in the study: allogeneic (n = 96) and autologous (n = 2), mean age 8.7 years, of whom 50% were african american, 3% asian, 21% caucasian, 13% latino, and 13% mixed race. forty-seven percent of patients developed aki within the first 2 years of hct. increased risk for aki was associated with a lower pre-transplant creatinine level (p = 0.001), abnormal pretransplant bun (p = 0.019) and an unrelated donor (p = 0.022) while preparative regimen intensity, race, or primary disease were not. twenty-six percent of patients developed aki within 30 days of hct. of those with aki, 41% were exposed to either cidofovir, aminoglycosides, and/or ambisome for at least 5 days versus 18% without aki and 74% were exposed to vancomycin compared to 49% without aki. evaluating outcomes at 1 year after hct, of those with stage 1 aki: 10% had reduced gfr and 37% died, while 14% had reduced gfr and 43% had died for patients with aki stage 2 or 3. the absence of aki by day 30 was associated with 24% reduced gfr and 8% death at 1-year after hct. overall, those with aki at any time in the first year post-hct had a 3.7 fold increased risk of death compared to those without. for patients who required renal replacement therapy (rrt, n = 8), the risk of death was 19.5 fold greater compared to those who did not. in the 25% of patients who survived rrt, both recovered renal function within 2 years.conclusion: acute kidney injury is common after pediatric hct, and may be associated with low creatinine, abnormal bun, unrelated donor pre-hct, and renal toxic medications. early-onset aki post hct is associated with an increased risk of mortality. these data should be validated in a larger prospective study but may offer opportunities to intervene and enhance outcomes. background: myeloablative hematopoietic stem cell transplant (hct) for pediatric malignant disease is associated with significant morbidity with 90% patients experiencing mucositis. patient controlled analgesia (pca) utilizing opioids is an effective strategy for pain management. we sought to describe and analyze pca use in d+30 days post myeloablative hct for malignancies at lurie children's hospital of chicago from 2010-17.design/method: utilizing retrospective chart review, pca details were collected: indication, initiation day, pca duration, team managing pca (anesthesia or palliative), medication and dose in morphine equivalents, and pca toxicities. efficacy of pca was evaluated on pca day + 3, +7, +14, +21 using demands %, maximum pain score (rflacc, faces, vas) and subjective patient, parent and/or pain team perception of pain control. we devised a scale based on the above to designate pain control as good, moderate or poor. variables being analyzed include recipient age, sex, donor type, source, diagnosis, tbi use, gvhd/trm. this analysis, we analyze the depth of remission, car-t persistence, and post-transplant gvhd on our phase i anti-cd22 car-t protocol (nct02315612) to better understand the role of car-t in the peri-hct setting.design/method: children and young adults with relapsed/refractory cd22+ all treated on our phase i anti-cd22 car-t protocol were analyzed. mrd was assessed by flow cytometry (fc) in all, with pcr-based mrd analysis using igh or tcr testing assessed in select patients. hcts were performed at each patient's local institution based on standard of care and included varying conditioning regimens, donor types, stem cell source, and gvhd prophylaxis.results: on our cd22 car trial, 36 patients were treated, the majority of patients (n = 29) having relapsed following a prior hct. 23/36 patients (64%) attained a cr, 18 of whom were mrd negative by fc. concurrent pcr based mrd analysis available in 8 patients demonstrated that all patients achieved pcr based negativity. in 6, this was simultaneous with the 1 month mrd negative fc, and in 2, pcr negativity was achieved over time (fc remained negative). 4 patients proceeded to hct at a median time of 70 days (range: 54-117 days) post-car-t, which was a first hct in 2. these two patients remain in an mrd negative cr, 1 year post-car-t. no patients developed acute or chronic gvhd. car persistence was seen in 3 patients who had detectable car-t cells on the pre-hct marrow suggesting the possibility of ongoing anti-leukemia surveillance prior to initiation of the conditioning regimen.conclusion: by inducing pcr negativity, car-t therapy may have a synergistic role with hct to improve leukemia free survival, prior to emergence of antigen negative leukemia, without an increased risk of gvhd. while the sample size is small, car-t therapy may offer an effective bridge to hct, particularly for those who are pcr negative, and those who have not had a previous transplant. given the underlying risk of hct related trm, pre-hct car may potentially allow for hct conditioning de-intensification as it may not be needed to eradicate residual disease.1 lee dw, ash abstract 218, 2016 background: post-transplant lymphoproliferative disease (ptld) is a complication after solid organ transplantation (sot) that is frequently due to epstein -barr virus (ebv) as a decrease in ebv-specific t cell immunity due to immune suppression allows for uncontrolled proliferation of ebv-infected b cells. outcomes for ptld are suboptimal with relapse rates approaching 50%. however, ebv-infected b cells in ptld express the ebv antigens lmp1 and lmp2 that can be targeted with immune therapy.objectives: we hypothesize that third party "off the shelf" lmp-specific t cell products may improve outcomes and decrease associated co-morbidities for patients with ptld by not only target the lymphoproliferating ebv-infected b cells but also restoring ebv-specific immunity.design/method: lmp-specific t cells (lmp-tcs) are manufactured from eligible donors with a broad range of hla types in our gmp facility to be used in a children's oncology group (cog) trial (anhl1522) for patients with ptld after sot. lmp-tc products are manufactured from healthy donors using autologous monocytes and lymphoblastoid cell lines (lcl) transduced with an adenoviral vector expressing δlmp1 and lmp2 as antigen presenting cells. lmp-tc products undergo comprehensive characterization by ifn-elispot assay to determine lmpspecific epitopes, class i and/or ii response, and hla restriction to guide selection of lmp-tc product for each patient.results: thus far, 27 lmp-tc products have been manufactured. lmp-tcs were active against lmp2 (mean: 158 sfu/1 × 10^5 cells; range: 1-800), lmp1 (31; 0-355), and lcl (105; 0-424) as determined by ifn-elispot assay. at the time of cryopreservation, the lmp-tc products comprised a mean of 36% cd8+ t-cells, 45% cd4+ t-cells, and 8% nk cells. no b cells or monocytes were detected in the final products. thus far, we have identified 3 novel lmp epitopes (lmp1 specific: n = 1; lmp2 specific: n = 2). approximately 80% of the lmp-tc products have lmp-specific activity through multiple hla alleles, and 67% have a mixed class i and class ii response. conclusion: thus, lmp-specific t cell products can be expanded from healthy donors to creat a third party bank, and identifying epitopes and hla alleles with lmp activity will facilitate selecting the most appropriate product for patients. while lmp-specific t cells have previously demonstrated safety and efficacy in phase i studies, anhl1522 is the first trial using cellular therapy within a cooperative group setting. children's cancer hospital at the university of texas md anderson cancer center, houston, texas, united states background: in 2017, the united states food and drug administration (fda) approved the first chimeric antigen receptor t cell (car-t) therapy; tisagenlecleucel. this cd19-directed genetically modified autologous t cell immunotherapy has shown response rates of almost 90% among children and young adults with b-cell precursor acute lymphoblastic leukemia (all) that are refractory or in second or later relapse. cytokine release syndrome (crs) and car-t cell related encephalopathy syndrome (cres) are well described toxicities associated with car-t therapy. crs is a systemic inflammatory response and is typically characterized by fever, hypoxia, tachycardia, hypotension and multi-organ toxicity. cres may occur concurrently or following crs, or without any associated crs symptoms and is characterized by encephalopathy, delirium, seizures and rarely cerebral edema. almost half of patients who receive tisagenlecleucel may require pediatric intensive care unit (picu) support. crs and cres are generally reversible but may be associated with fatal outcomes. pediatric specific management guidelines, comprehensive training of multidisciplinary staff, effective communication and phased infrastructure ensure that adequate resources are available to facilitate early diagnosis and appropriate management of pediatric patients with crs and cres and allow for optimal patient outcomes and accreditation by the foundation for accreditation of cellular therapy (fact).objectives: develop a comprehensive program to ensure safe administration of immune effector cell (iec) therapy to pediatric patients.design/method: an inter-disciplinary pediatric cartox (car t cell therapy associated toxicity) committee consisting of cell therapy and picu physicians, neurologists, fellows, nursing leadership, advanced practice practitioners, pharmacists, registered nurses and social workers was created to monitor patient toxicity and establish specific clinical guidelines and diagnostic and treatments algorithms for pediatric patients receiving iec therapy. educational modules were developed as (i) live in-services and (ii) an online module with a competency based assessment. electronic medical record (emr) order sets and documentation and warning systems were also developed by the committee. the pediatric cartox committee developed a diagnostic and treatment algorithm for patients receiving iec therapy. emr orders and flowsheets were developed to support adherence to the algorithm. inter-disciplinary staff training and competency assessments were closely tracked. almost 97% of identified staff have completed training and achieved competency including, pediatric cell therapy staff, emergency center, picu, outpatient clinic/triage, neurology and sub-specialty staff and nocturnalists.conclusion: an inter-disciplinary approach can assist in institutional readiness for an iec program, promote quality assurance and perhaps fact iec accreditation. future directions include a program for ongoing staff competency assessments. predicted peak vo2) and abnormal oxygen uptake efficiency slope at the anaerobic threshold (1359.3±297.8.9, normal 1790±310). additionally, on echocardiogram three patients had evidence of diastolic dysfunction as evidenced by an elevated e/a ratio (1.9±0.4) on tissue doppler. three patients demonstrated depressed longitudinal peak systolic strain (-17.7±2.8), indicating dysfunction not captured by ejection fraction. in this feasibility study, sct patients without evidence of lvsd on standard measures by resting echocardiogram can demonstrate abnormal exercise capacity. additionally, they can demonstrate systolic and diastolic dysfunction by measures not always included in standard echocardiography. these data suggest the need for a more thorough screening of survivors, and will be further validated as additional patients are recruited for this study. background: in hematopoietic transplantation, the t lymphocytes of the inoculum play a determining role in promoting hematopoiesis, transferring immunity to pathogens and acting as mediators of the graft-versus-leukemia effect (gvl). however, they are also responsible for graft-versus-host disease (gvhd), the main cause of post-transplant morbidity and mortality. the depletion of cd45 ra lymphocytes, by eliminating naive t lymphocytes from the inoculum, aims to conserve the gvl without producing gvhd.design/method: since april 2016, 14 patients (8 boys and 6 girls), with a median age of 8 years, have undergone an allogeneic hematopoietic transplant from an hla donor identical with cd45 ra/cd19 depletion. the indication for transplant was: acute lymphoblastic leukemia (4), acute myeloblastic leukemia (4), myelodysplasia (5) and medullary aplasia (1). the donor was familiar in 4 cases and unrelated in 10. the conditioning regimen was with fludarabine, busulfan and thiotepa. the median of cd34 + cells infused was 6.82 × 10 6 / kg. on the day 0, +15 and +30 a programmed infusion of 1 × 106 / kg lymphocytes cd45ra-was performed.results: all the patients grafted with a median leukocyte (> 0.5 × 109 / l) and platelet (> 20 × 109 / l) engraftment time of 15 and 10 days, respectively. only one patient has developed acute gvhd grade i and no patient has developed chronic gvhd. immune reconstitution was early and rapid in all t cell subsets no patient has relapsed so far and only 1 patient with myelodysplasia has developed an aml. she has received a 2nd transplant and has died of relapse. there was no case of toxic mortality. the event-free survival (sle) was 90 â± 10% with a median follow-up of 10 months. at present, 13 patients are alive, out of immunosuppressive treatment and doing well. allogeneic transplantation with cd45 lymphocytes ra depletion resulted on very encouraging results, with a very low incidence of acute and chronic gvhd, but preserving the gvl effect by infusing cd45 ra-donor lymphocytes. miami children's health system, miami, florida, united states background: hematopoietic stem cell transplantation (hsct) using autologous or allogeneic progenitor cells is a potentially curative treatment for patients with high-risk malignancies and nonmalignant conditions. the american society for blood and marrow transplantation developed a task force to establish consensus guidelines for defining patient care in hsct and advocated for further studies to delineate safe procedural steps as an increasing amount of hsct are being offered to patients. there is limited evidence to support engraftment in recipients who receive their infusions via iv or syringe pump. we present novel data from patients who achieved neutrophil engraftment following hsct by a pump mechanism.objectives: to provide evidence supporting the use of pump (intravenous or syringe) infusion method in hematopoietic stem cell transplantations.design/method: a retrospective review was completed for 114 patients who underwent hsct between 2003 and 2012. inclusion criteria included patients who had received hematopoietic stem cell transplants between 2003 and 2012 and who were ages 6 months to 21 years old. the main outcome measure was days to neutrophil engraftment (defined as the first of three consecutive days with an anc > 5 × 10 9 /l).results: among 114 patients who received infusion of hematopoietic stem cell products via pump mechanism, 63 patients (55.3%) received autologous products and 51 (44.7%) received stem cells from allogeneic donors. neutrophil engraftment (anc > 5 × 10 9 /l) occurred in a median of 14.5 days after stem cell infusion. the mean number of days to engraftment for patients who received allogeneic infusions s301 of s301 design/method: a retrospective chart review was performed at the children's hospital of wisconsin. statistical analyses included kaplan-meier estimate for os, mann-whitney test for comparing outcomes between subjects, and descriptive analyses.results: from 2005-2016, 14 patients with a median age of 7.5 (4.3-23.0) years at 1 st hct were identified. patients were conditioned with cy/atg (n = 3), cy/flu/atg (n = 6), or cy/flu/atg/tbi (n = 5) and received marrow (n = 13) or cord blood (n = 1) with median cd34/kg dose of 6.82 (1.88-10.90) ×10 6 . two patients developed grade i acute graftversus-host disease (gvhd); none developed chronic gvhd. due to dropping chimerism, graft rejection, or graft failure, 2 nd hct (n = 9) or boost (n = 5) was offered. the median cd3 chimerism prior to hct/boost was 53 (0-100)%. median time between 1 st hct and 2 nd hct or boost was 134 days (42 days-5.1 years). in 9 patients receiving 2 nd hct, 5 used the same donor, of which 3 used the same stem cell source (marrow) and 2 switched to peripheral blood stem cells (pbsc). in 4 patients who switched donors, 3 used pbsc and 1 used cord blood. most patients receiving 2nd hct underwent a uniform conditioning regimen of cy200/flu150/equine atg/8 gy tli (n = 5) or cy120/flu120/rabbit atg/2 gy tbi (n = 3); one received cy/atg. acute and chronic gvhd (limited seen in 83%) developed in 50% and 43% of patients, respectively. four patients required 18 additional boosts and 1 additional hct. after final intervention, cd3 and whole-blood chimerism at last follow-up was between 95-100% (n = 9) and 90-100% (n = 5), respectively. with a median follow-up of 8.6 (3.8-12.8) years, 13 of 14 patients are alive with an estimated 10-year os of 92.3 ± 0.07%, having performance status ≥90% (n = 12) or 80% (n = 1). one patient developed chronic extensive gvhd and died of fungal infection 2.1 years after 2 nd hct. our single-center experience demonstrates excellent ability to salvage patients who develop graft failure after initial hct. transplant-related complications such as gvhd and infections remain significant concerns. key: cord-015324-y44sfr0c authors: nan title: scientific programme date: 2007-09-01 journal: pediatr nephrol doi: 10.1007/s00467-007-0558-3 sha: doc_id: 15324 cord_uid: y44sfr0c nan the kidney plays an important role in ion homeostasis in the human body. several hereditary disorders characterized by perturbations of renal magnesium reabsorption leading to hypomagnesemia were described over the past 50 years. only recently, mutations in renal ion channels and transporters have been identified in several of these diseases, following positional cloning strategies in families with these disorders. muations in the slc12a3 gene have been identified in patients with gitelman syndrome, an autosomal recessive disorders characterized by hypokalemia, hypomagnesemia and hypocalciuria. slc12a3 encodes the thiazide-sensitive na + , cl-cotransporter (ncc) in the distal convoluted tubule (dct), the nephron site of active renal magnesium reabsorption. the hypomagnesemia in gitelman syndrome has been shown to be secondary to the primary defect in ncc. mutations in the fxyd2 gene have been found in patients with autosomal dominant renal hypomagnesemia associated with hypocalciuria (idh). fxyd2 encodes the gamma-subunit of the na + , k + -atpase, which is expressed primarily in the kidney with the highest expression levels in dct and tal. hypomagnesemia in patients with idh can be severe (<0.40 mm) and cause generalized convulsions. the molecular mechanism for renal mg 2+ loss in this autosomal dominant type of primary hypomagnesemia remains to be elucidated. in patients with autosomal recessive hypomagnesemia with hypercalciuria and nephrocalcinosis (fhhnc) mutations in the cldn16 gene, and very recently also in the cldn19 gene, have been identified. these genes encode claudin16 and claudin19 respectively, which are essential components of the paracellular pathway for magnesium at the level of the thick ascending limb of henle's loop. mutations in trpm6, encoding the epithelial mg 2+ channel trpm6 in the apical membrane of dct cells, have been identified in patients with mg 2+ wasting and secondary hypocalcemia (hsh). this autosomal recessive disease is due to defective intestinal and renal mg 2+ (re)absorption, and affected individuals show neurologic symptoms of hypomagnesemic hypocalcemia, including seizures and muscle spasms during infancy. in my lecture, i will give an update on the proteins involved in magnesium reabsorption and the emerging pathophysiological understanding of hereditary disorders in which renal handling of this divalent ion is disturbed. transcriptional control of genes that regulate tissue patterning and the cell cycle is fundamental to normal renal development. the mammalian kidney arises from reciprocal inductive tissue interactions between the ureteric bud and the metanephric mesenchyme. these interactions result in growth and branching of the ureteric bud and its daughter collecting ducts, a process termed, renal branching morphogenesis, and formation of nephrogenic progenitors and mature nephrons. expression and activity of transcription factors in ureteric and metanephric mesenchyme cells determines the patterning of ureteric bud and metanephric mesenchyme derived tissue elements. this lecture will highlight transcription factors critical to renal branching morphogenesis and nephrogenesis, with particular emphasis on those factors that are mutated in humans with renal malformation. the regulation of transcription factor activity will be discussed in the context of growth factor signaling pathways downstream of wnts, bone morphogenetic proteins and sonic hedgehog and pathways such as notch that control cell differentiation. the complexity of transcriptional signaling will be highlighted in the normal and malformed kidney at the level of transcriptional factor interactions and target gene promoters that can be targeted by mutiple signaling pathways. t. benzing diseases of the glomerular filter of the kidney are a leading cause of end-stage renal failure. recent studies have emphasized the critical role of the slit diaphragm of podocytes for the size-selective filtration barrier of the kidney and revealed novel aspects of the mechanisms leading to proteinuria, both in inherited and acquired diseases. several critical structural protein components of the slit diaphragm have been identified. recently, it has been shown that slit diaphragm proteins, in addition to their structural functions, participate in common signaling pathways. this talk will focus on what is known about the importance of the podocyte for the function of the glomerular filter of the kidney. it will provide a snapshot of our current understanding of the signaling properties of slit diaphragm proteins and project a framework for further studies necessary to delineate the function and dynamics of the slit diaphragm protein complex and the pathogenesis of nephrotic syndrome. long-term survival of children with end-stage renal disease (esrd) has increased in the last 20 years but the mortality rate remains high. cardiovascular disease accounts for 40 to 50% of all deaths, infectious disease about 20%. a prolonged period of dialysis versus having a renal graft and persistent hypertension are mortality risk factors. the prevalence of all sorts of morbidities is high among those who have reached adulthood. nearly 50% of all these patients suffer from left ventricular hypertrophy and life threatening vascular changes; nearly one third has clinical signs of metabolic bone disease. this accounts for both dialysis and transplanted patients. the chance of getting cancer is 10 times increased as compared to the general population; skin cancer and non-hodgkin lymphomas are most reported. a long period of dialysis at childhood is associated with impairment of both cognitive and educational attainment in adulthood. yet, despite all these negative outcomes, the health perception of young adults with childhood onset esrd is good. unemployment under young adults on chronic dialysis with pediatric onset of disease is higher than among healthy age related peers, but much lower than among dialysis patients of the same age with adult onset of disease. an impaired social development in childhood is associated with an impaired mental health perception at adult age. research and therapy in children with esrd should focus not only on prevention of graft failure but also on prevention of co-morbidity, especially cardiovascular disease, life threatening infections and malignancies. early transplantation, more extended forms of frequent hemodialysis in those who can not be transplanted, a more rigorous treatment of hypertension, avoidance of calcium-containing phosphate binders, reduction of the chronic inflammatory state, and tailor made anti-rejection therapy after transplantation may all be targets to improve outcome in future patients. psychosocial care should be more focused on attainment of independency and preparation for adult life, i. e. schooling and job career. applying regenerative medicine to combat organ shortage laboratory of regenerative nephrology, edmond and lili safra children's hospital, sheba medical center, tel hashomer, sackler school of medicine, tel aviv university, tel aviv, israel organ transplantation has been one of the major medical advances of the past 30 years; however, it is becoming increasingly apparent that the supply of organs is limited and will not improve with current medical practice. regenerative medicine is focused on the development of cells and tissues for the purpose of restoring function through transplantation. when facing late stages of esrd, which necessitate whole kidney transplantation, organogenesis represents an alternative to combat organ shortage. indeed, previous data pinpoints a window of time in human and pig kidney organogenesis that may be optimal for transplantation into mature recipients. "window" transplants are defined by their remarkable ability to grow, differentiate and undergo vascularization, achieving successful organogenesis of urine-producing miniature kidneys with no evidence of trans-differentiation into non-renal cell types, lack of tumorigenicity and reduced immunogenicity compared to adult counterparts. in contrast, when dealing with earlier stages of esrd or acute renal disease, which allow for individual cell replacement, both bonemarrow derived and kidney specific stem cells, might be applicable. accordingly, we show in proof-of-principle experiments that a novel population of multi-potential stem cells derived from the adult murine kidney are capable of re-populating ischemically injured tubular cells, while hematopoietic stem cells (cd34+cd133+) or hemangioblastic progenitor cells can give rise to peritubular endothelial cells. thus, different types of biological materials (embryonic kidney, adult kidney, adult bone marrow) offer new and powerful strategies for future tissue development and regeneration in renal medicine. k. tory, é. kis, a. szabó, g. reusz 1st department of pediatrics, semmelweis university, budapest, hungary it is well known that chronic renal failure significantly increases the risk of cardiovascular mortality in adults. transplantation decreases this risk; however, it still exceeds that of the normal population. as the number of children on renal replacement therapy (including transplantation) has significantly increased in recent years, there has been a growing amount of evidence regarding the increased cardiovascular vulnerability of this specific patient group. one important factor of cardiovascular mortality in adults is the dysfunction of the autonomic nervous system, previously designated as autonomic neuropathy. in a series of studies using the conventional ewing tests as well as heart rate variability (hrv) monitoring we were able to show altered sympathovagal balance in children on peritoneal-and hemodialysis, that was at least partly reversible following renal transplantation. according to our data sympathetic overactivity plays a major role in the sympathovagal disequilibrium observed. correspondingly, beta-adrenergic blockade improves the decreased hrv in the young. early, accelerated arteriosclerosis is another important, recently recognized consequence of crf in children. arterial calcification leads to increased arterial stiffness deteriorating the cushioning function of the aorta. arterial stiffness can be assessed by the reproducible and non-invasive measurement of the pulse wave velocity (pwv). in adults, it was found to be a strong, independent predictor of cardiovascular mortality. hypertension, hyperphosphatemia/elevated serum calciumphosphate product and vitamin d deficiency are the principal factors associated with pwv. recently, pwv was also shown to be increased in children on dialysis. however, the difference to the normal population may only be apparent if a control group matched for body dimensions is used, because of the dependence of pwv on body dimensions and uremic children's significant growth deficit. furthermore, increased pwv could also be shown in children following renal transplantation (tx) indicating the persistence of these lesions even following successful tx. the data on the autonomic nervous system and arterial dysfunction in young patients point to the necessity of early prevention in order to avoid the cardiovascular complications of crf. this study was supported by grants otka-t046155-f048842-f042563 and ett 435/2006. nitric oxide (no) production is reduced in ckd due to decreased renal and widespread decreases in endothelial no production. possible causes of no deficiency are: 1). substrate (l-arginine) limitation; 2). increased levels of circulating endogenous inhibitors of nitric oxide synthase (particularly asymmetric dimethylarginine [adma]); 3). decreased nos protein abundance/activity. decreased l-arginine availability in ckd is likely due to perturbed renal biosynthesis secondary to damage to the renal parenchyma. in addition, inhibition of transport of larginine into endothelial cells and shunting of l-arginine into other metabolic pathways (e. g. arginase) will also decrease availability. elevated plasma and tissue levels of adma in ckd are functions of reduced renal excretion (minor), reduced catabolism by dimethylarginine dimethylamino-hydrolase (ddah) and possibly increased protein methylation. an increase in adma has emerged as a major independent risk factor in many forms of cardiovascular disease as well as end-stage renal disease (and probably ckd). decreased renal nos protein abundance and activity have been reported by us in multiple models of ckd in the rat. the neuronal (nos 1) isoform is always reduced in the presence of injury, and is preserved in settings where there is protection from damage (female; wistar furth rat vs. sprague dawley). generalized and nnos specific inhibition accelerates underlying renal injury and in vulnerable animals will cause injury in the absence of underlying renal disease. we also find that relaxin (rlx) mediated prevention and repair of damaged kidneys requires an intact no system in order to function. in summary, no deficiency can cause cardiovascular and renal disease, and ckd results in no deficiency, contributing to a vicious cycle that promotes progression. an intact no system is required for rlxmediated repair of kidney damage. no deficiency in ckd is likely due to many causes: decreased arginine synthesis/availability and transport; increased endogenous adma functioning as competitive inhibitor; decreased enzyme abundance and activity will all lead to reduction in no generation. in addition, the oxidative stress of ckd will further reduce nos activity, switch the nos to become oxidant generators and will scavenge no to form the harmful peroxynitrite. selected glomerulopathies due to single gene defects such as finnish type nephropathy, diffuse mesangial sclerosis alport/thin membrane disease and inherited lipid disorders and will be discussed. finnish nephropathy is due to mutations of nephrin, a major structural component of the slit diaphragm. over 50 nephrin mutations are known associated with variably absent slit diaphragms, originally thought to be specific for constitutional nephrin mutations. however, sporadic minimal change disease and membranous glomerulonephritis may have absent slit diaphragms suggesting that nephrin may participate in the nephrotic syndrome in nonhereditary diseases. dms is one cause of congenital nephrotic syndrome, characterized by podocyte proliferationis shared by wt1 (denys-drash syndrome), laminin α2 (pierson syndrome) and galloway-mowat syndrome mutations. alport nephritis is a paradigm in which only a subset of mutations may predict disease severity (col ivα5)). heterozygous alport is similar to thin membrane disease (tmd), but 25% of tmd harbor col (iv) α3 mutations and a subset has col ivα2. nail patella syndrome due to heterozygous loss of lmx1b gene which regulates col ivα3-5 expression during kidney development. in classic nail-patella pathology fibrillar collagen bundles within the gbm are identical in severe and mild disease. thus the mutation does not correlate with prognosis. a mutation overlap in factor h gene in lipid disorders such as dense deposit disease (ddd) and lcat underscores glomerular pathologies that ranges from classic ribbon-like deposits in ddd, to lucent gbm deposits characteristic of lcat, or subendothelial lipid pools in lipoprotein glomerulopathy. the importance of genetics underscoring the pathology is amply demonstrated but mutations may not determine prognosis. background genes, post-translational modification and or protein/protein interactions in podocytes or the gbm may act as phenotypic modifiers. acute renal failure (arf) has many different definitions. rifle criteria distinguish "risk, injury, failure, loss and end-stage renal disease" features of this event. classic forms include pathophysiological cases of renal hypoperfusion and direct parenchymal injury, as well as postrenal anatomical obstruction. microvascular mechanism is in general the effect of disturbed balance between vasoconstriction (in response to endothelin, angiotensin ii, thromboxane a2, leukotrienes and increased sympathetic nerve activity) and vasodilatation (in response to nitric oxide, pge2 and bradykinin). endothelial and vascular smooth muscles cells may undergo structural damage and increased leukocytes-endothelial adhesion is a cause of inflammation. cytoskeletal breakdown, loss of polarity, apoptosis, necrosis, desquamation of viable and necrotic cells with tubular obstruction are underlying mechanisms of acute tubular necrosis. ischemic and direct tubular injury dominate as causes of arf, however specific epidemiology is strictly age-related. sepsis and major surgeryrelated events are the most common causes of arf in hospitalized patients. data on genetic background of certain genes polymorphisms and susceptibility to specific risk factors in newborns and infants are conflicting. several prophylactic and therapeutic techniques are available, however not of universal value. appropriate fluid management is crucial in ischemic arf, classic hemolyticuremic syndrome and rhabdomyolysis, however fluid overload is the one of major predictors of poor outcome in children admitted to icu. neither "renal dose" of dopamine, nor loop diuretics change the outcome. involvement of extrarenal organs worsens the overall outcome, which is the poorest in patients with multi-organ failure. early introduced renal replacement therapy is one of the key modalities in icu-treated patients. continuous techniques are of major value. in specific cases, such as hepato-renal syndrome, albumin ("liver") dialysis serves as an effective bridge to liver transplantation. hyperostosis-hyperphosphatemia syndrome (hhs) is a rare recessively inherited disease, manifested by persistent severe hyperphosphatemia and self-remitting episodic bone pain with radiologic findings of periosteal reaction and cortical hyperostosis. hyperphosphatemia in this patient population is not counter-balanced by pth or vitamin d, posing a mirror image of two hypophosphatemic states which result from increased activity of fibroblast growth factor 23 (fgf23). the two hypophosphatemic disorders which result from enhanced urinary phosphate leak are: dominantly inherited hypophosphatemic rickets and tumor induced osteomalacia. this observation was the impetus to study the role of fgf23 in hhs. affected individuals were found to have low levels of the full length, biologically active fgf23, but markedly augmented amounts of the cleaved inactive fragments. patients were found to be homozygous for a mutation in the galnt3 gene encoding a peptide involved in mucin-type o-glycosylation. decreasing the expression of the galnt3 gene by rna interference resulted in augmenting processing of the intact fgf23. our research indicates that the primary defect in hhs is a state of underglycosylation of fgf-23 resulting from reduced expression of ppgantase-t3, due to mutations in galnt3, and leading to augmented processing at the cleavage site. these changes in fgf-23 would abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. this study provides the pathogenetic mechanism of the first mucin-type o-glycosylation defect identified. our observation lends further credence to the primary and essential role of fgf23 in phosphate homeostasis through a pth-independent pathway. this was substantiated most recently by several reports which showed that mutations in the fgf23 gene are responsible for familial hyperphosphatemic tumoral calcinosis (fhtc) . a further study showed that hhs and familial hyperphosphatemic tumoral calcinosis are allelic disorders with a founder mutation in our region. immune responses govern the outcome of many forms of chronic kidney disease. gene therapy offers the potential to modify immune genes to improve outcome. we will discuss the potential use of gene transduction as a therapy for chronic kidney disease. background: chronic proteinuric renal disease is a major cause of end stage renal disease in man. adriamycin nephropathy is a murine model of chronic proteinuric renal disease where initial chemical injury is followed by immune and structural changes that mimic human disease. foxp3 is a gene specifically expressed by regulatory t (treg) cells. forced expression of the gene foxp3 causes transduced t cells to develop a regulatory phenotype. we hypothesised that foxp3 transduced regulatory t cells could protect against renal injury in adriamycin nephropathy. methods: the retroviral vectors expressing foxp3 and green fluorescent protein (gfp) (foxp3/migr) and gfp alone (migr) were transfected into package cell lines ecopack2-293, which produced the two retroviruses. cd4+ t cells were isolated from spleen of balb/c mice and stimulated by anti-cd3 mab and il-2 for 24 hours and then were infected with either retrovirus. expression was confirmed and phenotypic and in vitro functional assays demonstrated a regulatory phenotype. one week after infection, the gfp+ positive cells were sorted. foxp3 and control vector (migr) transduced t cells were administered to adriamycin (adr)-induced progressive renal nephropathy in mice. results: adoptive transfer of the foxp3 transduced t cells protected against renal injury. urinary protein excretion was reduced; there was less renal injury as measured by glomerulosclerosis, and interstitial infiltrates. serum creatinine, glomerular sclerosis and tubulointerstitial alterations were significantly lower in adr-foxp3 group, compared to those without treatment (adr) and treated with control vector (migr) transduced group (adr+migr). the foxp3 transduced cd4 t cells also showed suppressive activity in vitro. we conclude that foxp3 induced t reg cells may have a therapeutic role in protecting against immune injury and disease progression in chronic proteinuric renal disease. the italkid project is a prospective, population-based registry that was started in 1990. prevalent and incident cases of chronic renal insufficiency (cri) in children and adolescents were identified throughout italy (total population base: 16.8 million children). the inclusion criteria were: i) creatinine clearance (ccr): <90ml/min/1.73m 2 bsa; and ii) an age of <20 years at the time of registration. as to december 31st, 2006 a total of 2026 patients had been registered. the incidence of cri was estimated 12.1 cases per million and the (point) prevalence 74.7 per million of the age-related population (marp). the probability of kidney survival at 20 years of age was significantly different depending on the ccr at study entry, being 63% in patients with mild renal insufficiency (ccr 51-75 ml/min), 30% in those with moderate renal insufficiency (ccr 25-50 ml/min) and 3% in those with severe renal insufficiency (ccr <25 ml/min). the patients with normal (<0.2) and low (0.2-1.0) upr/ucr compared to those with mild (>1.0), showed a significantly slower decline in ccr (deltaccr +0.2±3.62 and -0.6±3.67 vs -3.76±5.64 ml/min/yr) and a higher kidney survival (96.7 and 94.1 vs 44.9%). the incidence of renal replacement therapy (rrt) was 7.3/year/100 patients and the casefatality rate on conservative treatment 1.41%. patients showed a significantly different slope of ccr before pubertal growth spurt as compared to after: -0.31±4.02 ml/min/1.73mq/yrs and -3.1±5.04. a non-linear pattern of decline in the probability of kidney survival, with a steep decrease during pubertal and early post-pubertal age was observed: the overall probability of rrt at age 10 was estimated 9.4%, while 51.8% of the patients will eventually required rrt before the 2nd decade of life was over. suggesting that pubertal development triggers the progression of cri in children. treatment with angiotensin converting enzyme inhibitors did not significantly modify the naturally progressive course of hypodysplastic nephropathy. ambulatory blood pressure monitoring (abpm) is a relatively new technique of blood pressure assessment in children and adolescents that offers several distinct advantages over traditional methods of blood pressure measurement, including the ability to detect white coat and masked hypertension, as well as the ability to assess nocturnal blood pressure. the role of abpm in the diagnostic evaluation of pediatric patients with elevated blood pressure is well-established, and recent surveys have demonstrated that it is used quite often by pediatric nephrologists and other practitioners during the initial evaluation of elevated blood pressure. it is less well-established, however, what role abpm might play in hypertensive children and adolescents once hypertension has been diagnosed and treatment initiated. studies in adults have demonstrated that abpm can assess whether patients on antihypertensive medications have achieved goal blood pressure, or whether their hypertension has progressed in severity. abpm can be used to follow nocturnal blood pressure in patients with chronic kidney disease (ckd) and diabetes, facilitating early identification of non-dipping, which is a known risk factor for progression of ckd or development of diabetic nephropathy, respectively. abpm can also be incorporated into clinical trials of antihypertensive medications to help assess their efficacy and safety. while additional data supporting these applications of abpm to pediatric hypertension clearly need to be generated from well-designed clinical trials, we propose that there is ample justification to utilize abpm just as frequently after the diagnosis of hypertension as before. childhood obesity is increasing globally in epidemic proportions and affects children in both industrialized and non-industrialized nations. in the last 30 years the percentage of overweight or obese children has increased from 5% to almost 30%. if current trends continue, as many as 50% of children may be overweight or obese by the year 2010. obesity predisposes to development of the metabolic syndrome, which is defined in children as the presence of three or more of the following features: abdominal adiposity (bmi >95%ile), serum triglycerides >95%ile, serum hdl cholesterol <5% ile, fasting blood glucose >110 mg/dl, and/or hypertension (systolic or diastolic blood pressure >95%ile adjusted for age, gender and height). the metabolic syndrome occurs in about 5% of children, but in 30-50% of overweight children. the presence of the metabolic syndrome increases the risk for cardiovascular disease and chronic kidney disease almost ten-fold in adults. adipose tissue does not just store fat, but also has important endocrine and immune functions mediated through adipocytokines, including leptin, adiponectin, resistin, apelin and visfatin, and classical cytokines such as tnf-a and il-6. increased leptin, decreased adiponectin and increased inflammatory cytokines, which occur in obesity, are known to induce vascular endothelial dysfunction and increase blood pressure. increase in adipose tissue also leads to infiltration by monocytes, macrophages and lymphocytes, which are stimulated to produce additional cytokines that may contribute to the systemic inflammation associated with obesity and vascular inflammation associated with hypertension. screening for hypertension and metabolic syndrome in obese children is critical to allow early identification of the metabolic syndrome and aggressive early intervention to reduce the risks for progression to cardiovascular disease and chronic kidney disease in later life. therapeutic strategies must include lifestyle changes of weight loss, healthier diet and regular physical exercise as well as treatment of hypertension, hyperlipidemia or hyperglycemia. blood pressure (bp) regulation is affected by numerous physiologic, biochemical, genetic and environmental factors. it has been suggested that exogenous conditions affecting intra-uterine growth and development may pre-program individuals for hypertension, metabolic abnormalities and cardiovascular morbidity in later life. animal data and human autopsy findings support a link between intrauterine growth, nephron endowment and postnatal hypertension. conceptually, it appears increasingly unclear whether the association of birth weight and bp in later life is mediated by intrauterine growth retardation as suggested by various animal models, whether prematurity per se affects bp programming independent of the fetus, nutritional status, or whether postnatal circumstances statistically linked to low birth weight affect this relationship. we have designed a study to evaluate the relationship between gestational age, birth weight and bp abnormalities by applying abpm in a group of children born preterm with and without intrauterine growth retardation and a local control group of children born at term with appropriate weight. this study represents the first systematic assessment of 24-hour cardiovascular regulation in children and adolescents born preterm. our findings indicate that a fraction of these preterm born subjects has a selective nocturnal increase in systolic bp, resulting in an elevated prevalence of non-dipping. our analysis suggests that intrauterine growth retardation, rather than prematurity per se, is the major effector of the early cardiovascular abnormalities observed in preterm children. moreover, we have found that nocturnal systolic bp was closely linked to heart rate, pointing to a possible role of sympathetic hyperactivation. while little data is available regarding a link between low birth weight and/or prematurity and sympathoadrenal function in adult humans, a role of the sympathetic nervous system in the programming of adult hypertension has been consistently demonstrated in various animal models of fetal growth retardation. in conclusion, we detected subtle abnormalities of circadian bp regulation in those preterm born children who suffered from intrauterine growth retardation and this may reflect sympathetic hyperactivation. the intrinsic tendency of kidney disorders with reduced nephron mass to progress and the quest for renoprotective strategies are an ongoing focus of renal research. in adults, hypertension is not only a marker but also a major driving force of renal failure progression. renin-angiotensin system blockers (ace inhibitors and at1 receptor blockers) are preferred antihypertensive drugs in ckd due to their specific renoprotective effects beyond blood pressure (bp) control, mediated by their antiproteinuric, antiinflammatory and antifibrotic properties. it is less clear whether bp reduction to low-normal values has an additional salutory effect on gfr preservation. children suffer from a markedly different spectrum of renal diseases than adults, with a preponderance of hypo/dysplastic kidney malformations. hypertension and proteinuria are common but usually moderate. to elucidate the renoprotective efficacy of ace inhibition and strict bp control in children, the escape trial was launched by a consortium of 33 european pediatric nephrologists. a total of 400 children and adolescents with stage ii-iv ckd received a fixed dose of ramipril and were randomized to intensified (<50th percentile) or conventional bp control (50th-95th pct). 24 h-bp, proteinuria and gfr were monitored over a 5-year period. 24 h mean arterial pressure (map) was reduced by ramipril from 89 to 83 mm hg (i. e. from 1.5 to 0 sds) on average. subsequently, mean map was lowered further to 79 mm hg at 24 months in the intensified arm, and maintained around 83 mm hg (0.2 sds) in the conventional control arm (p<0.0001). on average 1.1 antihypertensive drugs were added to ramipril in the intensified and 0.4 in the conventional treatment arm (p=0.0001). treatment tolerability was excellent in both arms, with less than 3% dropouts due to side effects. in summary, ramipril was effective and well tolerated in children with ckd. it is possible and safe to target low-normal bp in children. final results regarding renal survival will be available in summer 2007 and presented at the ipna meeting. nephronophthisis and joubert syndrome: converging on convergent extension? nephronophthisis (nphp), an autosomal recessive cystic kidney disease, leads to terminal kidney failure in adolescence. nphp may be associated with retinitis pigmentosa (rp) in senior-loken syndrome (slsn) or with cerebellar vermis aplasia in joubert syndrome (jbts). we have identified by positional cloning 7 genes as mutated in nphp. the gene product of nphp1, nephrocystin-1, acts in focal adhesion signaling. by positional cloning we detected mutations in the nphp2/inversin gene as causing infantile nphp (type 2) with association of situs inversus or rp. we demonstrated expression of nphp1, 2 in primary cilia of renal epithelial cells, supporting a new unifying theory for the pathogenesis of cystic kidney diseases (watnick et al. nature genet 34: 355, 2003) , stating that the products of all genes mutated in cystic kidney disease in humans, mice, or zebrafish are expressed in primary cilia, basal bodies, or centrosomes of renal epithelial cells (hildebrandt et al. nature rev genet 6: 928, 2005) . identification of nphp3 mutations in nphp type 3 also revealed the cause of the renal cystic disease mouse model "pcy", for which treatment has been demonstrated. positional cloning of nphp4 led to the demonstration that its gene product, nephrocystin-4, is conserved in c. elegans and expressed together with nephrocystin-1 in ciliated head and tail neurons of the nematode. the role of primary cilia function for retinal-renal syndromes was confirmed by identification of the novel nphp5 gene. recently, several signaling pathways have been implicated in the downstream signaling pathways that connect ciliary/basal body function to the renal cystic phenotype. these include the wnt signaling/planar cell polarity pathways, and the hedgehog signaling pathway. we implicated the planar cell polarity signaling pathway in nphp by positional cloning of mutations in the gene nphp6/cep290 as causing joubert syndrome. abrogation of nphp6 function in zebrafish caused planar cell polarity (convergent extension) defects and recapitulated the human phenotype of joubert syndrome. further gene identification in nphp will result in the definition of functional networks of primary cilia, centrosomes, and planar cell polarity as they pertain to the pathogenic mechanisms of nphpassociated syndromes and other cystic kidney diseases. hnf1b is a transcription factor that is expressed in bile ducts, intestine, pancreas and renal epithelia. germ-line inactivation of the mouse hnf1β/tcf2 gene is embryonic lethal (e7.5) due to defective differentiation of the extra-embryonic visceral endoderm. hnf1β is later expressed in endoderm derivatives and in the mesonephros. to understand the function of hnf1b at later stages of development and during organogenesis, we applied a conditional inactivation based on a (cre-loxp) strategy. with the use of a cre recombinase that is expressed in renal collecting ducts and henle loops (ksp-cre) we found that hnf1b inactivation leads to polycystic kidney disease (pkd). this is reminiscent of the renal phenotype of patients carrying heterozygous mutations in tcf2/hnf1β. these patients suffer from maturity onset diabetes of the young type 5 (mody5) and at the same time from renal cysts (renal cysts and diabetes or rcad). this cystic phenotype is linked to the defective expression of pkhd1 and pkd2, two genes mutated in pkd patients. the cellular and molecular mechanisms underlying pkd are still poorly understood. it was recently speculated that planar-cell-polarity signalling (wnt) could be at the basis of cyst formation. maturation of nephrons during development is accompanied by a considerable lengthening of tubules. this process involves an intense proliferative phase without any increase in tubule diameter. interestingly, we discovered that the progeny of consecutive cell divisions are adjacent one another and oriented in parallel to the axis of tubules. this suggested that upon lengthening, cells divide according the tubule axis. in addition, 3d image reconstructions revealed that oriented cell division is due to the alignment of the mitotic spindle with the axis of the tubule. we hypothesized that oriented cell division could play an essential role in preventing tubular dilation during the massive proliferative phase that accompanies tubular elongation. indeed, our results indicated that both in ksp-cre-kidney-specific-hnf1β-deficient pups and in the pck rats, lacking the expression of pkhd1, the mitotic alignments were highly distorted. our results indicate that hnf1β plays a crucial role in activating the expression of genes involved in the control of tubular size maintenance during tubular elongation. emerging evidence suggests that the intravenous injection of bone marrow-derived cells improves renal function after acute tubular injury. examination of human transplant biopsies of female kidneys that had been transplanted into male recipients have shown the presence of tubular cells that co-express the y chromosome and epithelial markers. however, controversy exists as to whether the protective effect is due to engraftment of the cells in the injured tubule or an endocrine/paracrine effect of the injected cells. our studies demonstrate that intravenous infusion of whole bone marrow from male mice into female recipients results in the appearance of significant numbers of y chromosome + cells in the kidney interstitium, and rare y chromosome + cells in the tubules. the majority of the interstitial cells express leukocyte markers such as cd45. in addition, we have found that i. v. or i. p. injection of bone marrow stromal cells (msc, adherent non-hematopoietic marrow cells) into mice reduced the severity of cisplatin-or ischemia-induced aki. examination of these kidneys demonstrates that mscs enhance tubular cell proliferation and decrease tubular apoptosis after injury. examination of multiple tissue sections at 1 or 7 days after injury failed to reveal any examples of y chromosome cells within the tubules, and only rare examples of y chromosome cells within the renal interstitium. furthermore, exposure to conditioned medium from cultured mscs (msc-cm) significantly diminished cisplatin-induced death of cultured proximal tubule cells in vitro, while i. p. administration of msc-cm in the mouse markedly diminished the rise in bun associated with cisplatin injection. thus our data suggests that hematopoietic cells and their derivatives from adult bone marrow enter the kidney in response to injury where they are primarily localized to the interstitial space as inflammatory cells. in rare instances, these cells may differentiate into, or fuse with, tubular epithelial cells. in contrast, bone marrow mscs fail to enter the kidney in significant numbers, but can protect the endogenous tubular cells from toxic injury by secreting a factor or factors that limit apoptosis and enhance proliferation. renal hypodysplasia (rhd) is characterized by a reduced nephron number, small kidney size and disorganized renal tissue. a hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes involved in early kidney organogenesis. gene mutations with dominant inheritance causing rhd, urinary tract anomalies and defined extrarenal symptoms have been identified in tcf2 (renal cysts and diabetes syndrome (rcad)), pax2 (renal-coloboma syndrome (rcs)), eya1 and six1 (branchio-oto-renal syndrome (bor)) for the most frequent of these syndromes. a recent study on a cohort of 100 patients with rhd and consecutive renal insufficiency demonstrated that 16% of them had mutations in one gene encoding for a transcription factor. the majority of mutations were identified in tcf2 (hnf1β) (especially in the subset with kidney cysts) and pax2. this study demonstrates that subtle extrarenal symptoms in syndromal rhd easily can be missed. genetic testing in children with rhd should be preceded by a thorough clinical evaluation for extrarenal symptoms, including eye, ear, and metabolic anomalies. the presence of these anomalies increases the likelihood of detecting a specific genetic abnormality. in addition, mutations in genes that are usually associated with syndromes can occur in patients with isolated rhd. the ret receptor, its ligand gdnf and the co-receptor gfra1 play a pivotal role during early nephrogenesis and enteric nervous development. in humans, activating ret mutations cause multiple endocrine neoplasia, whereas inactivating mutations lead to hirschsprung disease. while ret deficiency also causes renal hypodysplasia (rhd) in the mouse model, genetic abnormalities in ret have not been characterized in human isolated renal malformations to date. the ret mutations, y971f and s649l, reportedly predisposing to medullary thyroid carcinoma (mtc) were found in one and six patients respectively in the same rhd cohort. none of the patients or their carrier relatives had clinical evidence of mtc at the time of the study. our findings suggest that ret mutations predispose to both mtc and rhd, with a low penetrance for either disorder. interestingly, a gdnf mutation was found in addition to a ret mutation and to an eya1 mutation in a patient with the branchio-oto-renal syndrome suggesting an oligogenic inheritance. mutations in clcn5, the gene encoding the chloride/proton exchanger clc-5, underlie most forms of dent's disease, an x-linked nephrolithiasis syndrome that is always associated with low molecular weight proteinuria. clc-5 belongs to the clc gene family of chloride channels and transporters and, in addition to other sites, is expressed in apical endosomes of the proximal tubule. in these vesicles, it co-localizes with the proton pump and with endocytosed proteins. previously thought to be a clchannel, it is now known to mediate electrogenic cl -/h + -exchange. this notion remains compatible with a role in supporting the acidification of endosomes by providing an electrical shunt for the h + -atpase. to clarify the pathogenesis of dent's disease, we created a knock-out mouse model. it displayed low molecular weight proteinuria due to a largely reduced endocytosis by proximal tubular cells (fluid-phase and receptor-mediated). the acidification of renal cortical endosomes was reduced in the ko. the failure of the pt to endocytose pth led to an increased luminal, but not systemic concentration of this hormone. this, in turn, resulted in hyperphosphaturia due to a retrieval of the phosphate transporter napi-2a from the pt plasma membrane. nephrolithiasis can be explained by altered renal handling of pth and vitamind, all of which are secondary to the impaired endocytosis. there is an increased prevalence of nephrolithiasis in individuals with obesity, type ii diabetes, and the metabolic syndrome. in particular, uric acid constitutes a much higher percentage of stones in these patients compared to the general stone-forming population. we strived to examine the pathophysiologic connection between the metabolic syndrome and uric acid stones. in the vast majority of cases, the principal abnormality in uric acid stones is not hyperuricosuria but an excessively low urinary ph. uric acid nephrolithiasis is in fact a disease of 'urinary acidification' although there is no systemic metabolic acidosis in the classical sense because acid-base balance is achieved and no excessive acid is accumulated. however, the excretion of protons using low pk closed buffers rather than the high pk open buffer ammonia dictates a low urinary ph. since protonated uric acid has a sparingly low solubility compared to ionized urate, low urine ph promotes uric acid precipitation. thus uric acid nephrolithiasis is an innocent bystander of low urinary ph. the link between the metabolic syndrome and urinary ph as a continuous variable is explored by epidemiologic, human metabolic, and laboratory studies. in population-based studies in stoneformers, low urinary ph is associated with higher body weight. urinary ph is also lower with increasing number of features of the metabolic syndrome (waist circumference, high triglycerides, low high density lipoproteins, hypetension, hyperglycemia) and within each of the features, the severity of each parameter is inversely proportional to urinary ph. in metabolic studies in humans, low urinary ph is associated with low peripheral insulin sensitivity. when studied as in-patients on identical metabolic diets, patients with type ii diabetes and uric acid stone-formers have high net acid generation than normal volunteers. this alone lowers urinary ph although the reason for the elevated acid load is not clear at present. in addition to high acid generation, uric acid stone formers tend to use buffers other than ammonia to buffer protons in the urinary resulting in unduly acidic urine ph. when challenged with an acute acid load, the ammonium excretion response is markedly blunted in uric acid stone-formers. a similar urinary abnormally of acidic urine ph and underutilization of ammonia is seen in the zucker diabetic fatty (zdf) rat compared to their lean counterpart. these animals have peripheral insulin resistance, elevated serum free fatty acid and have significant steatosis in their kidneys. one abnormality in the kidney is reduced expression and activity of the na + /h + exchanger nhe3 which is the major transporter that excretes ammonium into the urine and its activity is stimulated by insulin. causality is supported by the fact that treatment of the animals with a thiazolidinedione partially reversed the fat infiltration, urinary acidification abnormality and reduced expressed of nhe3. the direct effect of fat on the renal proximal tubule was tested in cultured cells. provision of fatty acids beyond the oxidation capacity of the tubule leads to dose-dependent impairment of nhe3, generalized dysfunction and eventually cell death. a sub-cytotoxic dose of free fatty acid did not affect baseline nhe3 activity and expression but reduced the ability of insulin to activate nhe3. in summary, the metabolic syndrome is associated with increase acid generation that is independent of diet. this increased acid load is effectively excreted by the kidney. failure to maximally utilize the ammonium buffer system results in lower urinary ph and titration of urate to its insoluble form as uric acid and results in uric acid nephrolithiasis. part of the pathogenic mechanism maybe lipotoxicity from fat infiltration of organs. uric acid nephrolithiasis is an "innocent bystander" which is a sentinel of a more generalized alteration in acid generation and excretion. genetic hypercalciuria recurrent kidney stone production is one of the most common diseases of the bipedal human condition, occurring in up to 10% of the population in western societies. unlike four-footed animals who likely perish in the wild from a selection disadvantage from a painful calculus, human beings continue to function, and have the ability to express the biologic defects repetitively that result in a stone. idiopathic hypercalciuria, where a specific gene defect has not yet been established, is a shrinking subpopulation of recurrent calcium stone formers, as specific mutations and functional polymorphisms of genes intimately or distantly related to calcium homeostasis arise from the sequencing of the human genome applied to clinical stone disease. other postulated mechanisms can be sought for in this manner as well, and may await larger population-based studies. the familial nature of nephrolithiasis is clear and robust for most calcium-based stone formers, and may have a gender-specificity for that inheritance. the role of environment in its expression remains controversial. the systemic nature of genetic hypercalciuria may be seen through its associated effects on skeletal health and biology. between 25-33% of children with genetic hypercalciuria have abnormally low bone density measured by dual-energy absorptiometry that cannot be explained by correction for height or body mass. further, normalization of urinary calcium excretion with a variety of therapies is associated with improvements in bone density values over time. a proposal for re-classifying hypercalciuria pathogenetically will be presented, and linked to observational data across the world for successful therapeutic approaches. a call for a stone registry and more careful determination of etiology will be sought through the ipna congress. the systems that regulate blood pressure are plastic during development and can be permanently reset. experiments in animals show that it is surprisingly easy to produce lifelong changes in blood pressure by minor manipulations of the mother's diet before and during pregnancy. this phenomenon has been referred to as "programming". epidemiological and animal studies show that programmed effects operate within the normal range of growth and development, and influence the risk of hypertension, coronary heart disease and stroke in later life. a clinical study of 2003 people aged 62 years from the helsinki birth cohort showed that two different paths of growth preceded the development of hypertension. people already diagnosed as having hypertension had small body size a birth and low weight gain from birth to two years but grew rapidly after two. at age eleven years their body size was around the average. as adults they tended to be obese and insulin resistant. a second group of people had not been diagnosed but their blood pressures were classified as hypertensive under current definitions. they were short at birth, had low weight gain from birth to two years and remained small after two. at age eleven years they were short and thin. as adults they tended to be overweight and have atherogenic lipid profiles. the first path of growth is similar to that which leads to coronary heart disease in this cohort. the second path is that which leads to stroke. this paper will present data on the maternal and placental influences through which these paths originate. nephron number is a key feature of the conceptual paradigm positing that cardiovascular and metabolic diseases that arise during childhood and adulthood have their origin in events that occur during fetal life. in mammals, nephrons are derived from a subset of cells resident within the metanephric blastema. blastemal cells participate in reciprocal inductive tissue interactions with the ureteric bud. these interactions induce the ureteric bud to grow and branch. in turn, ureteric bud branches induce discrete populations of the metanephric blastema to undergo successive transitions resulting in the formation of mature nephrons. a distinct population of metanephric blastema cells in the stroma modulates branching morphogenesis and nephrogenesis. identification of genes that control both branching morphogenesis and nephrogenesis is providing insight into the molecular pathways that could be targeted by environmental, nutritional and hormonal factors that control fetal programming. this lecture will highlight the morphologic and cellular events critical to renal branching morphogenesis and nephrogenesis, and the gene networks that regulate or counter-regulate these events. these gene networks will then be considered in the light of non-genetic factors that modulate their activities. it is now accepted that early life environment can modulate adult phenotype, including the blood pressure. the likely primary mechanism is epigenetic modulation of gene expression during a sensitive period of fetal maturation, but the pathogenesis of the later development of hypertension is unclear. participation by extrarenal factors such as central regulation and peripheral vascular function has been evoked; however, a strong body of experimental evidence suggests that the "setpoint" for renal regulation of na balance and extracellular volume is altered. because both humans and many experimental models with prenatally programmed hypertension appear to have a decrease in the total number of nephrons, impaired filtration of na has been hypothesized to be an important pathogenetic factor. more recent evidence has suggested that postnatal inflammation and accumulation of reactive oxygen species in the renal interstitium may contribute to the genesis of hypertension by upregulating distal nephron na transport. furthermore, the role of renal vascular function remains to be determined. the different mechanisms are not mutually exclusive; it is conceivable that both a prenatal "priming" and a postnatal "second hit" are required for hypertension to become manifest. j. ingelfinger epidemiological studies published in the late 1980s by barker and his group -and since replicated in many populations -provide evidence of an inverse relationship between birthweight and risk of cardiovascular disease, hypertension, and renal dysfunction in adult life. both clinical studies and animal models have been used to investigate mechanisms underlying these observations [as cited in recent reviews. the concept that changes in the intrauterine milieu affect the growing fetus resulting in alterations in physiology and general health in later life has been termed perinatal programming or developmental origins of health and disease [dohad] . yet, despite a large and burgeoning literature about this phenomenon and its relationship to cardiovascular and renal disease, involved mechanisms remain elusive. maternal malnutrition or exposure to various medications or substances leads to an adverse in utero environment that may impair nephrogenesis, evident in experimental animal studies as well as in clinical reports in humans. nephron deficit at birth persists throughout life, creating "low glomerular endowment, " an important risk factor for hypertension and esrd in adulthood. for a number of years it has been hypothesized that nephron number may strongly influence blood pressure as well as susceptibility to renal disease in later life. recently clinicopathologic observations suggest that a relationship more directly. renal morphogenesis involves complex events in which many genes interact in the formation of the final kidney. when the normal pattern of nephrogenesis is interrupted, renal abnormalities may ensue. during renal development, two major events -ureteric bud (ub) branching and mesenchymal-to-epithelial transformation -greatly impact the outcome of renal morphogenesis. renal malformation accounts for approximately 40 percent of childhood renal failure and represents the end result of failure of fundamental embryonic processes in ub and metanephric mesenchyme (mm) lineages. this presentation will review the data concerning renal responses to perinatal challenges as these occur and later evolve during childhood. we will consider the implications and the data available concerning screening, follow-up and management of at-risk persons. generation of oxidized lipoproteins in obstructive nephropathy -atherogenic or fibrogenic? children's hospital and regional medical center, division of pediatric nephrology, seattle, united states chronic kidney disease, regardless of etiology, is characterized by a relentless progression of fibrosis that gradually destroys the normal renal architecture, particularly in the tubulointerstitium. obstructive uropathy accounts for approximately 35 percent of pediatric patients with chronic kidney disease (ckd) and end-stage renal disease (esrd). after post-natal relief of obstruction, the optimal treatment of children with obstructive uropathies remains unknown and for many the progression of ckd to esrd is inevitable. therapeutic options are limited by an incomplete understanding of fibrogenic pathways in the kidney. the major renal fibrotic pathways identified thus far can be broadly classified into those involved in transforming growth factor beta (tgf-b) activation, macrophage-mediated inflammation, angiogenesis, and extracellular matrix production/degradation. it is becoming increasing clear that key molecules have multiple roles in several of these pathways triggering fibroinflammatory events targeting specific cell types. oxidative stress represents an intersection of many of these fibroinflammatory pathways leading to cellular activation and tissue injury. oxidized lipoproteins accumulate in the circulation and renal interstitium in both experimental models and patients with ckd and esrd. many parallels have been drawn between atherogenesis and the pathogenetic mechanisms of progressive kidney destruction by fibrosis. although ckd is clearly associated with an increased cardiovascular risk, it is not clear whether oxidized lipoproteins amplify fibrogenic pathways in the kidney. research in our laboratory suggests that hypercholesterolemia increases injury severity in obstructed kidneys. scavenger receptors mediate the cellular effects of oxidized lipoproteins during atherosclerosis and activate both inflammatory and oxidative pathways. dietary and antioxidant therapies have clear benefits in animal models but limited efficacy in patients. our studies suggest that blocking key scavenger receptors leads to a significant attenuation of both oxidative and pro-inflammatory pathways during chronic injury by obstruction in hypercholesterolemic mice. interventions targeting scavenger receptor signaling may represent an alternative strategy to attenuate both the progression of ckd and cardiovascular disease. the resolution of injury and promotion of renal repair comprises a delicate balance between cell death and destruction of tissue architecture in relation to cell differentiation, maturation and extracellular matrix (ecm) remodeling. although many studies have focused on the cellular and molecular events leading to the development of renal fibrosis, less is understood about the process of renal repair and regeneration. this is despite the fact that the kidney has a significant capacity for regeneration and cellular replacement following acute damage. the present study describes the structural, functional, and expression profile analysis of endogenous renal repair and the regenerative potential of the kidney following reversal of ureteral obstruction (r-uuo) in the mouse.10 days after unilateral ureteral obstruction there is renal tubular cell loss, activation of an inflammatory cascade leading to widespread cortical interstitial fibrosis and the loss of normal medullary architecture. following 2 to 6 weeks after r-uuo there was marked tubular repair and regeneration of medullary components, ecm remodeling and decreased inflammatory cell infiltration. the structural repair observed at 6 weeks post-release of ureteral obstruction was associated with a 50-86% recovery of the glomerular filtration rate (gfr). expression profile analysis was performed to visualize patterns of gene expression that were differentially expressed in the repaired and remodeling areas following r-uuo. we are also interested in the regulation of cellular recovery and the processes involved in epithelial cell re-differentiation in regenerating tubules following injury. tubular epithelial cell cilia may play potential roles in directing the orientation of cell division and epithelial differentiation during the endogenous remodeling process. our results suggest that renal cilium lengthening may be an important factor in the response to injury and subsequent recovery of renal function. these studies propose that a lengthening of renal epithelial cilia increases their sensitivity to flow and reduces damaging epithelial dedifferentiation in the injured renal tubules. a better understanding of the key events involved in endogenous renal repair and remodeling may open the way to new interventions based on their manipulations aimed at acceleration of renal regeneration and prevention of scarring. soren nielsen has kindly agreed to present this topic, however was not able to submit an abstract. the final regulation of urinary k excretion in the fully differentiated kidney is accomplished in the distal nephron, including the cortical collecting duct (ccd), where cell k passively diffuses into the urine through apical k selective channels. the prevalence of the sk/romk channel and its high p o at the resting membrane potential has led to the belief that this channel mediates baseline k secretion. less easily detected is the bk channel which is characterized by a low p o at the physiologic resting membrane potential and [ca 2+ ] i . bk channels are activated by membrane depolarization, elevation of [ca 2+ ] i , and/or membrane stretch, and can be selectively blocked by iberiotoxin (ibx). we have reported that flow-stimulated net k secretion (jk) in the adult rabbit ccd is (i) blocked by ibx and (ii) associated with increases in net na absorption (jna) and [ca 2+ ] i , leading us to conclude that bk channels mediate this process. recent studies have examined the acute and chronic regulation of bk channel-mediated flow-stimulated jk. we reported that flowstimulated jk requires an increase in [ca 2+ ] i due to luminal ca 2+ entry and er ca 2+ release, microtubule integrity, and exocytic insertion of preformed channels into the apical membrane. channel expression is regulated long term during postnatal development and by dietary k intake. specifically, an increase in tubular fluid flow rate fails to elicit an increase in jk in the rabbit ccd until the 5 th wk of postnatal life, coincident with appearance of immunodetectable bk channels, whereas flow-induced increases in jna and [ca 2+ ] i in 2-wk-old ccds are "mature". a role for the bk channel in renal k adaptation has been suggested by the observation that dietary k loading leads to an increase in abundance of bk message in microdissected ccds with redistribution of immunodetectable channel proteins from an intracellular pool to the apical membrane. additionally, ccds isolated from k loaded animals demonstrate enhanced flow-stimulated jk compared to tubules from control fed animals. in sum, emerging evidence suggests that the bk channel plays a prominent role in distal k secretion in response to increases in urinary flow rate and dietary k intake. the late developmental appearance of this channel is compatible with the need of the growing animal to retain k early in postnatal life. recent advances in molecular genetics of hereditary hypomagnesemia substantiated the role of a variety of genes in human magnesium transport. this knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives insight into molecular components involved in magnesium transport. during the last four decades, numerous reports concerning inherited magnesium losing disorders have been published and their distinctive phenotypic features have been discussed. phenotypic characterization of affected individuals and experimental studies of appropriate animal models have contributed to a growing knowledge of renal magnesium transport mechanisms. the identification of the affected nephron segments, the different modes of inheritance and the observation of additional characteristic symptoms promoted a classification into different subtypes of inherited magnesium losing disorders. in general, primary magnesium wasting disorders are relatively rare. the prevalence of the more frequent entities, for example gitelman syndrome, has been estimated to be approximately 1: 50.000. for most of the other disease entities, relatively few cases have been reported in the literature. depending on the genotype, the clinical course is sometimes mild or even asymtomatic. therefore, the disease prevalence might be underestimated for some of these syndromes. magnesium transport has been intensively studied in humans and various animal models leading to accepted concepts underlying the pathophysiology of the different forms of hypomagnesemia. however, the electrophysiological characterization of magnesium pathways has been complicated by unintentional simultaneous measurement of other cations so that the molecular correlates mediating mammalian magnesium transport components remained undefined. a different approach to study components of magnesium transport arises from genetic analysis of families affected with magnesium wasting diseases. linkage studies enabled the localization of several genes involved in hereditary hypomagnesemia and in the last decade, a number of genes have been identified by positional cloning. these genes have provided first insight into mammalian magnesium transport molecules. distal renal tubular acidosis may be inherited as an autosomal dominant or recessive trait. mutations in three genes -slc4a1, atp6v1b1 and atp6v0a4 -are associated with the various forms of disease, and give rise to a wide spectrum of clinical severity. in general, dominant mutations do not affect ion transport function per se and do not affect hearing, whereas recessive disease is characterized by loss of function and deafness. some unusual functional consequences of mutations in ae1 and a4 proteins are mistargeting and loss of protein-protein interaction respectively, and these will be discussed. the heart in pediatric nephrotic syndrome y. frishberg shaare zedek medical center, pediatric nephrology, jerusalem, israel in recent years, the molecular bases of several conditions which lead to steroid-resistant nephrotic syndrome (srns) have been identified. the common denominator shared by these clinical entities is that they all result from structural defects in the glomerular barrier, thus explaining their unresponsiveness to immunosuppressants. for instance, the congenital ns of the finnish type is caused by mutations in the nphs1 gene encoding nephrin. a recessive form of srns was found to result from mutations in nphs2 encoding podocin which is specifically expressed in podocytes. we have previously shown that a founder mutation in nphs2 (r138x) is the prevalent cause of hereditary srns (55% of tested are homozygotes) among arab children in israel. interestingly, we noted that a number of patients who are homozygous for the r138x mutation in podocin have a co-existing cardiac disorder. only a few case reports described an association between srns and cardiac defects. we questioned whether the glomerular-barrier disorders, which have been considered to be kidney-specific, have implications on other organ-systems. thus, we systematically reviewed the cardiac status of these srns patients at the time of diagnosis while they had normal blood pressure and preserved renal function (31). cardiac anomalies were detected in 89% of children, the most common of which were cardiac hypertrophy and pulmonary stenosis. analyzing two control groups enabled us to conclude that cardiac disorders in homozygotes for mutations in nphs2 cannot be attributed to an association by chance or to a state of persistent ns. because human podocin mrna is expressed in fetal heart, we hypothesize that it may have a role in normal cardiac development and this will be an issue of further investigation. this is the first study showing a role for podocin in extra-renal tissues and therefore recommends early cardiac evaluation for timely medical management. cvd is the world-wide biggest obstacle to long-term survival of children and adolescents with ckd. mortality from cvd is excessively high on dialysis and continues to be a threat after renal transplantation. early diagnosis of the individual risk for cvd would enable preventive measures on an individual basis. however, prospective studies with hard end points -cardiac events -are difficult if not impossible to conduct in children and adolescents. on the other hand, the known high morbidity and mortality in elderly dialysis patients may largely result from pre-existing comorbidity (advanced atherosclerosis has been demonstrated in this age group at initiation of dialysis). for this reason, investigations in patients with childhood onset ckd may provide a diagnostic window to study the pathogenesis of cardiac and vascular changes in subjects without comorbidities. several studies using non-invasive measurements of surrogate markers for cvd have demonstrated a pattern of early systemic cvd, including changes in intima-media thickness (imt) of conduit arteries (aorta, a. carotis) and muscular arteries (a. femoralis), altered function of peripheral resistance arteries (venous occlusion plethysmography) and abnormalities in the heart (echocardiography). patients show a significant decrease in post-ischemic vascular reactivity with evidence of vascular stiffness and frequently have extraosseous calcifications often involving coronary arteries and heart valves. importantly, these studies have found little evidence for correlations with classical risk factors (except hypertension), but with abnormalities of calcium and phosphorus metabolism and their therapy, including the intake of active vitamin d preparations and calcium-containing phosphate binders. thus, patients with childhood-onset ckd are at high risk to develop systemic cardiovascular changes, which may represent a new disease originating from the survival of ckd, a previously deadly disease, and interventions for the prevention of renal osteodystrophy. this therapeutic challenge needs to be addressed with high priority to enable long-term survival of children with ckd. while their mere existence is still questioned by some investigators, lipid rafts have recently gained a large amount of attention because of their apparent involvement in various cellular processes, including signaling, membrane trafficking, polarization, and endo-as well as exocytosis of proteins as well as pathogens. membrane rafts have been defined as small (10-200 nm) heterogeneous, highly dynamic, sterol-and sphingolipid-enriched domains that compartmentalize cellular processes and that can sometimes be stabilized into larger platforms by protein-protein or proteinlipid interactions. rafts are of special interest for pediatric nephrologists for two reasons: 1. they play a critical role in immune cell activation, especially in the formation of the immunological synapse (is), and thus in many important disease processes affecting our patients, including -but not limited to -transplant rejection. beyond their participation in is formation, rafts also facilitate signaling through other immune cell receptors, such as the interleukin-2 receptors, where they may ascertain cytokine selectivity and specificity. 2. equally important, rafts serve as essential site for proper interactions between nephrin and podocin, thus establishing the integrity of the glomerular filter. general aspects of raft biology as well as their role in immune cell signaling will be reviewed in more depth in this presentation. raft involvement in glomerular filter formation and especially genetic aspects relevant to disturbances of this involvement and of the associated integrity of the filter, as seen in hereditary nephrotic syndromes, are discussed in subsequent presentations in this symposium. reports of familial forms of fsgs date back to 1956, with the observation of an autosomal recessive disease primarily within the finnish population. it is characterized by massive proteinuria in utero, with up to 20 to 30 grams of protein loss per day. nphs1 encodes a gene product termed nephrin that localizes to lipid rafts within the slit diaphragm of the podocyte. steroid-resistant nephrotic syndrome (srns) is an autosomal recessive nephrotic syndrome and manifests between 3 months and 5 years of age, rapid progression to esrd, and with few cases of recurrence after renal transplantation. the gene product is podocin (nphs2), located on 1q25-31. podocin most likely functions in the structural organization of the slit diaphragm and regulation of its filtration function. it has been shown to interact in vivo with both nephrin and cd2-associated protein (cd2ap), a cytoplasmic binding partner of nephrin. mutations in the alpha-actinin 4 gene (actn4), localized to chromosome 19q13 have been associated with autosomal dominant fsgs, characterized by adult onset disease of variable severity and rate of progression to esrd. fractions of the mutant protein have been shown to form large aggregates within podocytes ultimately compromising the function of the normal actin cytoskeleton, both through its abnormal function and toxic accumulation. recently, a disease-causing mutation for hereditary fsgs has been localized to chromosome 11q 21-22, and identified as the transient receptor potential cation channel, subfamily c, member 6 (trpc6). the missense mutation causes a highly conserved proline in the first ankyrin repeat of trpc6 to become a glutamine at position 112 (p112q). the trpc6 p112q mutation causes increased and prolonged calcium transients in transfected cells. the mutant channel also significantly enhances cation signals triggered by at1 receptor activation. biotinylation and immunostaining studies reveal that the mutation also appears to cause mislocalization of the ion channel to the cell surface. whereas previously reported mutations such as nphs1, nphs2 and actn4 have emphasized the importance of cytoskeletal and structural proteins in glomerular diseases, trpc6 related fsgs suggests an additional mechanism for renal disease pathogenesis. knowledge of trpc6 mediated calcium entry into cells may offer unique insights into therapeutic options for glomerular diseases. t. huber university hospital, department of nephrology, freiburg, germany the sense of touch relies on the ability of specialized sensory cells to convert mechanical stimulation into ionic currents. mechanoreceptor cells respond to external force by opening ion channels. recent findings highlight now a potential role for the mechanosensitive ion channel trpc6 at the glomerular filtration barrier. trpc6 localizes to the slit diaphragm and mutations of trpc6 cause familial glomerular disease. mutations of the phb-domain protein podocin are the most common cause of hereditary nephrotic syndrome and we demonstrate that podocin and mec-2, the closest homologue of podocin in caenorhabditis elegans, bind cholesterol to regulate the activity of associated ion channel complexes: deg/enac channels for mec-2 and trpc channels for podocin. both the mec-2-dependent activation of mechanosensation in c. elegans and the podocin-mediated activation of trpc6 channels requires cholesterol. our data suggest that the recruitment of cholesterol by podocin and mec-2 to ion channels plays an important role in regulating their activity. these findings promote the concept that podocin, similar to the function of mec-2, may be part of a mechanosensitive protein complex at the slit diaphragm of podocytes. isidro salusky has kindly agreed to present this topic, however was not able to submit an abstract is there a role for bisphosphonates in pediatric bone disease? f. santos hospital universitario central de asturias, universidad de oviedo, pediatria, oviedo, spain bisphosphonates are being increasingly and successfully utilized to prevent bone fractures and treat bone pain in children with severe osteoporosis from different origins. a largest experience has been accumulated with the administration of cycles of intravenous pamidronate in children with osteogenesis imperfecta. in addition, to the bone resorption inhibition mediated by their effects on osteoclasts, bisphosphonates given in large doses inhibit normal and ectopic mineralization. thus, bisphosphonates have also been used in children with hypercalcemia and in the treatment of calcinosis and heterotopic ossification, bisphosphonates have been administered to renal transplanted adults to prevent or treat bone loss induced by chronic administration of glucocorticoids and might also be useful in the management of urolithiasis in selected hypercalciuric patients. the potential clinical utilization of bisphosphonates in the prevention and treatment of vascular calcification in patients with chronic renal failure is now being explored, although no data on children in this clinical setting are available. a number of questions as to the precise clinical indications to start bisphosphonates' administration, the type of bisphosphonate to be used, the duration of the treatment, the best way to monitor its effectiveness and the risk of longterm toxic effects remain to be answered. water is the solvent in which all metabolic reactions occur. body water moves between compartments with diverse compositions that are separated by semi-permeable lipid membranes. water exchanges also occur between maternal and fetal blood separated by several layers of tissue, the so-called placental membranes. the fetus appears to be dependent on placental flow and perfusion pressure for the bulk of his water requirements, and the prostanoids play a significant role in the control of ureteroplacental and umbilicoplacental blood flows. osmotic and hydrostatic forces control placental water flux. the amniotic fluid (af) appears early during gestation and its volume increases rapidly. the net af volume turnover approximates 95% per day. major sources of af production are represented by fetal lungs secretions, and by fetal urine. the af is initially isotonic, and becomes hypotonic when significant amounts of dilute urine are produced by the fetus. disposal of water is effected by fetal swallowing of af and by the intramembranous (im) pathway, that is the route of absorption between the fetal circulation and the amniotic cavity. this route appears to play an important role in the overall regulation of af volume and composition. the fact that water crosses the im pathway in excess of solutes suggests a role for aquaporin water channels in allowing this transport. circumstantial evidence indicates that the im water flow is regulated by aquaporin 1. homeostatic changes in placental permeability could thus be up or down-regulated by the number of aquaporin water channels in the membrane. systemic lupus (sle) is a multigenic and multifactorial disease, characterized by b lymphocytes polyclonal activation with decreased tolerance, autoantibodies production and immune complexes formation. dna was initially thought to be the mayor auto-antigen, however, it is not immunogen and injection of dna-anti dna does not induce lupus nephritis. the complex of dna and histones (nulceosome) is provided with a positive electrical charge which favours the binding to heparansulphates in the gbm. in sle high levels of nucleosomes are present in circulation due to accelerated lymphocytes apoptosis or defective removal of apoptotic cells. lupus nephritis (ln) is consequent to deposition of immune complexes, activation of lymphomononuclear cells and reactivity of renal cells. the who classification of lupus nephritis has been recently reviewed by the isn/rps. the new classification takes into account a distinction between forms without endocapillary hypercellularity (mesangial or subepithelial deposits) and others with endocapillary hypercellularity (involving less or more than 50% with segmental or global distribution). prognosis and treatment of ln need a flexible therapy, tailored on histological picture and clinical data. steroids must be given at high doses for induction therapy but have drawbacks of heavy morbidity and mortality. the addition of immunosuppressive drugs improves the therapeutic index. the nih protocol used cyclophosphamide (cyc) pulses in severe ln (monthly pulse for 6 months followed by quarterly pulses for 1 year). more recent studies, comparing low with high doses cyc pulses, failed to prove a significantly different effect. for maintenance therapy of ln, mycofenolate mofetil may be a good alternative to cya or aza. rituximab, a chymeric monoclonal antibody anti cd20, which selectively and profoundly depletes b lymphocytes, has provided very interesting results in sle with poor response to classical therapy or in relapse. the possibility of rotating agents with different side effects may allow to lower the doses of steroids, to reduce drug-specific morbidity, and to improve the compliance of patients. efforts should be done to minimize steroids and cyc which are very effective but are the main responsible of invalidating and even lifethreatening complications. for half a century now, physicians have tried to classify vasculitic syndromes. classification of vasculitides is required to put in perspective the pathogenesis and therapeutic advances and to provide a uniform language, given the variation in the epidemiology of these diseases. the "american college of rheumatology" criteria have been used for classification and the chapel hill consensus criteria for definition purposes in children as well however they are based totally on adult criteria. taking into account the differences in children and the new developments in medicine a group of pediatricians have aimed to revise the classification of vasculitic syndromes encountered in children. the consensus group consisted of a multinational panel of experts who were pediatricians, pediatric rheumatologists and pediatric nephrologists. the delphi and nominal group techniques were used. this project has provided classification criteria for henoch-schönlein purpura, childhood polyarteritis nodosa, wegener granulomatosis and takayasu arteritis. this was an important task since appropriate classification criteria for vasculitis in children has been missing for far too long. we hope that the international and multispecialist composition of the expert group involved will facilitate the applicability of this classification for most vasculitic diseases in children seen around the world and will meet the needs of pediatricians. these criteria are now to be validated using a large registry for childhood vasculitides. anti-neutrophil cytoplasm antibodies (anca) are well established as a diagnostic marker for small vessel vasculitis, including wegener's granulomatosis and microscopic polyangiitis. there is increasing evidence that anca are directly involved in the pathogenesis of vascular inflammation in these disorders. in clinical studies, there is a clear relationship between levels of anca and the activity and extent of disease, and anca positivity confers an increased risk of relapse. rising titres of anca predict relapse, and two studies have shown that pre-emptive treatment of those with rising titres can prevent relapse. of great interest is the recent report of a newborn child who developed glomerulonephritis and lung haemorrhage after transplacental transfer of anca. in vitro experiments have shown that anca can activate cytokine primed neutrophils to release oxygen radicals, enzymes and inflammatory cytokines. this is achieved through both direct f(ab) 2 binding and fc receptor engagement. in co-culture, anca can induce neutrophil mediated killing of endothelial cells. in flow chamber studies, anca can induce neutrophil adhesion and transmigration across endothelial cell monolayers. more recently, anca have been shown to be pathogenic in experimental models of disease. high titre anti-mpo antibodies induced by immunisation of mpo deficient mice can transfer glomerulonephritis and vasculitis to naive recipients. immunisation of rats with mpo induces anti-mpo autoantibodies which lead to crescentic glomerulonephritis. intravital microscopy in this model confirms that anca can induce leukocyte transmigration and microvascular haemorrhage in vivo. however, many questions remain unanswered. some patients may have high levels of anca without disease activity, and others may have typical disease without detectable anca. it seems likely that t cells may be involved, not only in providing help for anca synthesis, but also in mediating tissue damage. it is also possible that an additional inflammatory stimulus, for example an infection is required, to enhance the inflammatory effects of anca. greater understanding of the role of anca in vascular inflammation will hopefully lead to safer and more effective approaches to treatment. hacettepe university, faculty of medicine, department of pediatric nephrology, ankara, turkey the therapy of vasculitic syndromes poses a problem for the caring pediatrician. the treatment of anca associated vasculitides will be presented to cover microscopic polyangiitis, wegener granulomatosis and churg strauss syndrome. treatment of all anca-associated diseases are similar. steroids and cyclophosphamide are the mainstay of induction treatment. in severe patients with kidney involvement steroids can be given in the form of intravenous methylprednisolone for 1-3 days (15-30 mg/kg/d, max.1 gr), followed by daily oral corticosteroids (1.5 mg/kg/d, max.60 mg/d). cyclophosphamide may be given at 2mg/kg/d p. o. or monthly iv pulses 0.75gr/sqm for at least 6 months. for maintenance treatment there are again many different regimens for oral corticosteroids. along with corticosteroids for maintenance regimen there are a number of protocols suggesting the continuation of cyclophosphamide. the cycazarem study has shown that the replacement of cyclophosphamide with azathioprine at 3 months was also as effective for disease control. methotrexate has also been shown to be an alternative for maintenance treatment. treatment of the childhood polyarteritis nodosa (pan) with systemic disease is similar to that of anca-related vasculitides. there are a number of non-anca associated vasculitides in childhood. the most frequent in childhood are henoch-schönlein purpura (hsp), kawasaki disease (kd) and takayasu arteritis (ta). the treatment of hsp is usually symptomatic. however, for severe kidney involvement with extracapillary proliferation and rapidly progressive disease severe immunosuppressive treatment is indicated. triple treatment with steroids, cyclophoshamide and dipyridamole have been given in various series. for kd intravenous immunoglobulin at a dose of 2g/kg still remains the first choice of treatment along with salicylates. for ta therapy depends on the extent of vessel invovlement: severe disease necessitates steroids and cyclophosphamide whereas for less intensive vessel involvement methotrexate and steroids may suffice. treatment period depends on the actiivty of the disease. lb. zimmerhackl haemolytic uraemic syndrome (hus) is the most common cause of acute renal failure in children. the syndrome is defined by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure (creatinine over the 97 th percentile). world wide hus is increasing. in a german/austrian multicenter study we follow 628 children with hus occurring in the years 1997 to 2002.5 year follow-up data are now available www. hus-online. at. from this study the following results are obvious. hus affects predominantly children of kindergarten age. the median age at onset is 2,9 years. the majority of hus is of infectious origin. shigatoxin (stx) producing escherichia coli (stec, ehec) are present in over 80% of patients. the predominant shigatoxin type is type ii. hus is classified into two clinical subgroups. "typical" hus usually occurs after a prodrome of diarrhoea (d+hus), and "atypical" hus (ahus), which is not associated with diarrhoea (d-hus). the majority of d+hus worldwide is caused by ehec type o157: h7, which is transmitted to humans via different routes. however non-o157 groups are emerging and are predominant in europe. transmission of disease in elder patients is predominantly through food poisoning and direct contact to farm animals. in infants and small children direct transmission from human to human seems to be more likely. currently there are no specific therapies preventing the disease course. anti-shigatoxin antibodies are being tested by several companies. if this may prevent hus is open to study. otherwise the therapy at present is symptomatic. parenteral volume expansion before hus in patients with positive stx or ehec stool culture may counteract the effect of thrombotic process before development of hus and attenuate renal injury. use of antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs should be avoided during the acute phase in particular during the prodromal phase. from our own study the prevention is best done by preventing primary ehec infection. however, patients with severe course and long term sequelae should be screened for genetic abnormalities in the complement system. if auto antibodies against complement proteins or the vwf play an relevant role is under discussion. patients under one year of age at onset have a significant worse outcome and should be kept under surveillance. patients below 3 month of age are very likely to have an inborn error of complement or vwf and should be tested specifically. the european registry on hus and related disorders may help to determine these abnormalities: www. haemolytic-uraemic-syndrome. org. in order to improve long term outcome of these patients, increased awareness and an european (international?) task force is mandatory. in adults with chronic kidney disease, protein-energy malnutrition and inflammation are risk factors for death and accelerated cardiovascular disease. the "malnutrition-inflammation-cachexia syndrome" (mics); anorexia, increased basal metabolic rate, and loss of lean body mass is associated with low serum albumin, decreased protein intake, elevated c-reactive protein, and low serum cholesterol levels in adults. in children, mics manifests as growth retardation. clinical research focusing on the evolution of mics in pediatric ckd to understand its causes and consequences and how nutritional interventions alter its course may be the key to improving survival in ckd. baseline cross sectional data from the ongoing chronic kidney disease in children study, of children (n=335) aged 1-16yrs (mean=11.1yrs) with estimated gfr 30±90 ml/min/1.73 m 2 (mean iohexol gfr 38 ml/min/1.73 m 2 ) shows substantial growth retardation in ckd with median height percentile=23. greater height deficits are seen at lower gfr's. symptoms of decreased appetite and nausea are reported by 35% and 47% of those with gfr <30 respectively. mean ldl cholesterol is lowest in those with gfr <30 (97 vs 123mg/dl in gfr 30±40 ml/min/1.73 m 2 group). serum albumin declines as serum creatinine increases (r=-0.22). unlike previous reports in adult ckd, increases in crp were not associated with lower gfr at baseline. further exploration of the mics in pediatric ckd will be presented. the causes of growth failure in pediatric patients with chronic kidney disease (ckd) are multifactorial. it is an open question as to which factors play a key role in diminishing physical growth. it is also unclear which mechanisms may become pace makers for the therapeutic improvement of growth. furthermore, growth failure in children with ckd affects total body height, body proportions and composition as well as organ development. growth failure may also lead to disproportion which can only be identified by detailed anthropometric measurements. we were able to demonstrate that ckd patients have a specific age-dependent pattern of growth and distinct changes in segmental growth (trunk, arm and leg length) from birth to adolescence. leg growth in relation to other parameters of linear growth showed the most dynamic growth changes and emerged as the best indicator of growth in children with ckd. trunk growth had little synchronicity with leg growth. furthermore, we found that anthropometric measurements can be used as a diagnostic tool in distinguishing different sub-groups of ckd patients, for instance, children with syndromic ckd. in the heterogeneous group of patients with focal and segmental glomerulosclerosis, patients with schimke's disease were found to have a dramatically decreased sitting height/leg length ratio. as the disturbance in growth of ckd patients is a marker of the severity of the disease and of the quality of renal care, the annual analysis of growth failure from early childhood to adolescence should be used as a landmark information of the quality of medical care and as a helpful tool in differential diagnosis and of specific courses of ckd in sub-groups of patients. for example, patients with congenital or acquired renal diseases, dialyzed or transplanted patients and in gender differences. in addition, anthropometric measurements are able to identify specific growth patterns in children with ckd, which should be considered in the assessment of treatment efficacy such as in rhgh therapy. b. tönshoff, l. weber, b. höcker university children's hospital, 1st department of pediatrics, heidelberg, germany it is currently under debate whether steroid avoidance or late steroid withdrawal provides the best overall risk-to-benefit ratio in pediatric renal transplantation. late steroid withdrawal has the advantage over steroid avoidance that immunological high-risk patients and those with unstable graft function can easily be identified beforehand and be excluded from steroid-free immunosuppression. in order to further validate this approach, we performed a prospective randomized open-label multicenter trial in 41 low-risk pediatric renal transplant recipients (12 f, 29 m; mean age 10.1 yrs; range, 3.4 to 17.8) on csa (target trough level 100-200 ng/ml), mmf (1200 mg/m 2 per day) and methylprednisolone (3) (4) mg/m 2 per day), who were randomly assigned >1 year posttransplant to continue steroids or to withdraw over a period of 3 months. an interim analysis was performed at a mean observation period of 29 mo after study entry; 31 patients had been followed for at least 15 mo. there were 3 drop-outs (1 reversible acute rejection episode, 1 switch to sirolimus and 1 to tacrolimus). transplant function as assessed by calculated ccr remained stable in both groups, no graft was lost. prepubertal children off steroids gained relative height from baseline -1.5±0.5 sds to -0.9±0.6 sds after 2 yrs, while patients on steroids lost relative height (-1.1±0 .6 sds at baseline, -1.6±0.7 sds after 2 yrs); a comparable pattern was observed in pubertal patients. the standardized body mass in patients off steroids declined from 0.75±1.01 sds at baseline to 0.31±1.17 after 2 yrs (p<0.05), while it tended to increase in patients on steroids (baseline, 0.40±1.35 sds; after 2 yrs, 0.56±1.39). the rate of adverse events, mainly infections, was comparable in both groups. patients off steroids required less frequently antihypertensive medication (62%) than patients on steroids (93%). a significant reduction of serum cholesterol (by 20%) and triglycerides (by 13%) in response to steroid withdrawal was observed. conclusions: this interim analysis indicates that late steroid withdrawal in selected pediatric renal transplant recipients on csa and mmf is safe, allows catch-up growth and ameliorates cardiovascular risk factors. at the ipna meeting, full 12 month outcome data of all patients will be available. u. frei, j. noeldeke renal transplantation faces two major challenges: the organ shortage resulting in extended waiting times and an aging population resulting in increased death with a functioning graft. the eurotransplant senior program (esp) allocates kidneys within a narrow geographic area from donors aged >65 years to recipients >65 years regardless of hla. this analysis investigates the impact of the esp on waiting time, graft and patient survival. the esp group (n=1406, old to old) was compared to two groups allocated via the eurotransplant kidney allocation system (etkas) with either similar donor age [old to any (o/a), donor age >65, n=446] or recipient age [any to old, (a/o), recipient age 60-64, n=1687]. all patients were transplanted between 1999 and 2004. since initiation of the esp (1999), availability of elderly donors doubled and waiting time for esp patients decreased. local allocation led to shorter cold ischemia time (11.9 vs. >17.0 hours, p<0.001) and less delayed graft function (dgf, esp 29.7% vs o/a 36.2%, p=0.047) but 5-10% higher acute rejection rates. importantly, graft and patient survival were not negatively affected by the esp allocation scheme. the esp age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors. the effect of age matching on the duration of the waiting time a. rahmel, m. slot, j. smits eurotransplant international, leiden, the netherlands in eurotransplant the proportion of children, i. e. patients aged under the age of 16 at time of registration, with end-stage renal disease (esrd) on the renal waiting list amounts to only 1.2%. despite this small proportion the eurotransplant kidney allocation system (etkas) specially addresses pediatric transplant candidates. in order to increase their chances of receiving a transplant in time children are assigned via etkas extra points for hla matching and receive an age bonus. in order to evaluate this allocation policy, the chances for receiving a kidney for patients in different age groups were evaluated. for the cohort of patients registered in the year 1999, a 5 year followup was obtained. for patients aged under 6 at time of registration [n=134] 47% and 81% received a kidney from a post-mortem donor, within 1 year and 5 years after listing. for children aged 6 to 10 [n=108] these rates were at 1 and 5 years after listing 31% and 67%, and for children between age 11 and 16 [n=192] 33% and 72% respectively. adult patients were less likely to receive an organ: 11% and 42% of patients aged between 16 and 64 were transplanted within 1 and 5 years after listing. senior esrd patients can benefit from the eurotransplant senior program (esp), their chances for a transplant were 28% and 61% within 1 and 5 years, respectively. the life span of a renal allograft is limited in time. in the eurotransplant experience 80% of the post-mortem kidneys used for transplantation in children failed within 20 years, compared to 70% for the living donor renal transplants (rtx). donor age is an important factor associated with long term renal allograft function. age matching between donor and recipient is hampered by the low number of pediatric donors. in the period 2000-2005, 78 heart beating kidney donors aged under 1 were reported and used for rtx, 69 donors were between 2 and 5 years of age, and 319 donors were between 6 and 16 years old. in the same period 9981 adult donors were reported and used for transplantation. in the period 2000-2005, 18% of the pediatric donor kidneys ultimately served a pediatric recipient. to improve the allocation of pediatric donors to pediatric recipients, et is in the process of implementing a rule giving pediatric recipients priority in case of pediatric donors. gender and sex hormones are playing a central role in the incidence and progression of different renal diseases. vascular tone, endothelial function and immune response are influenced by gender. in renal transplantation ischemic injury is always present. females are more resistant to postischemic renal failure than males. following ischemia/reperfusion injury renal vascular resistance decreases, allowing fast restitution of blood flow and oxygen supply in females. additionally, stabilization and preservation of tubular function following ischemia is achieved by the protection of na+/k+ atp-ase and heat shock protein activity contributing to the observed gender differences. posttransplant immune reactions also differ between genders. female gender predisposes to more severe acute rejection following kidney transplantation, partly due to differences in the effectivity of immunosuppressants used. ineffective immunosuppression in females, as well as different cytotoxicity profile of the drugs is contributing to more prone immune reactions shortly after transplantation resulting in more severe acute rejection. in contrast, similar to the slower deterioration of other renal diseases, progression of chronic graft failure is less pronounced in females in experimental and clinical settings. estradiol decreases profibrotic processes, preserves endothelial function and modifies influx of immune cells into the graft. the fine balance between alloantigen dependent immune reactions and alloantigen independent factors and its impact on longterm graft function is modified by gender. new evidences supporting the significance of sexual dimorphism following kidney transplantation may present the base of gender modified therapeutic approaches in the future. iga nephropathy: aetiology, incidence, and geographic distribution iga nephropathy (igan) is characterized by mesangial deposits of iga, proliferation of mesangial cells and expansion of matrix. the accumulation of iga and complement fractions within glomeruli was initially ascribed to deposition of iga immune complexes (igaic) due to mucosal immune response with predominant iga synthesis. this hypothesis has offered an explanation of the relationship between infections of the upper airways and gross hematuria. high levels of igaic have been detected in 30-70% of patients, mostly of polymeric iga1, and polymeric iga1 are detectable in renal deposits. this observation is consistent with hypothesis of either bone marrow or mucosal origin. however, no specific viral or alimentary antigens have been found in mesangial deposits, and the qualitative properties of polymeric iga1 have rather become of interest, particularly the glycosylation pattern of iga1. human iga1 is o-glycosylated with carbohydrate chains of n-acetyl galactosamine (galnac) and galactose (gal) which may be covered with sialic acid (neu5ac). patients with igan exhibit circulating iga1 with reduced gal and/or neu5ac and increased exposure of n-galnac. such aberrantly glycosylated iga can circulate in monomeric form or participate in the formation of autoaggregates/true immune complexes. it likely escapes clearance by hepatic receptors and has a preferential renal deposition by virtue of enhanced reactivity with the mesangial matrix components. the role of a triggering event has not ruled out. in recent reports, antigens of bacterial origin and the secretory tract component have been found in renal deposits, making scientists reconsidering again the role of bacterial infections. tonsils recurrent infections may provide a suitable aetiology for igan, and the effect of tonsillectomy on the long term outcome of igan is under evaluation. the prevalence of igan varies in different areas, due to ethnic and environmental factors, being particularly frequent in mediterranean europe, northern europe, asia and australia. it is still debated whether differencies in frequency, clinical features and disease progression among patients with igan from different countries are actually due to uneven distribution of this diseases or these discrepancies are due to the different criteria for performing renal biopsy. definition. igan is characterized by the presence of dominant (or codominant) mesangial deposits of iga on immunofluorescence microscopy, frequently with c3 and sometimes with igg or igm. classification. the glomeruli display a broad spectrum of histologic changes, related in part to the differences in the indication for the biopsy of the referring nephrologist. a number of classification systems have been used to describe the histologic manifestations of igan. two will be referred to here: the system of m. haas (ajkd 29:829-842, 1997 ): 1) minimal histologic lesion -the glomeruli exhibit no more than a minimal increase in mesangial cellularity, without segmental sclerosis or crescents. 2) fsgs-like -the glomeruli display focal segmental sclerosis in a pattern resembling primary focal segmental glomerulosclerosis, with at most a minimal increase in mesangial cellularity and no crescents. 3) focal proliferative glomerulonephritis (gn) -50% or fewer of the glomeruli are hypercellular. the increase in cellularity may be limited to mesangial areas, or there may be obstruction of glomerular capillaries by proliferated endocapillary cells. crescents may be present. 4) diffuse proliferative gn -more than 50% of glomeruli are hypercellular. the hypercellularity may be segmental or global, and crescents may be present. 5) advanced chronic gn -40% or more of the glomeruli are globally sclerotic, and/or there is 40% or more tubular atrophy or loss in the cortex. the system of s. emancipator (heptinstall's pathology of the kidney, lippincott-raven, philadelphia, 1998, pp 479-512) : a -normal/minimal glomerular lesions b -focal mesangial proliferation c -diffuse mesangial proliferation d1 -focal segmental endocapillary proliferation superimposed on mesangial proliferation d2 -focal segmental endocapillary proliferation alone e -diffuse endocapillary proliferation f -diffuse extracapillary proliferation (crescents in >70%), with or without endocapillary proliferation g -glomerulosclerosis (>70% of the glomeruli are sclerotic) h -unclassifiable or combined lesions diffuse proliferative gn (c) and focal proliferative gn (d1) are the major patterns of expression of glomerular injury. indicators of a poor outcome. these include a high proportion of glomeruli with crescents, numerous sclerotic glomeruli, interstitial fibrosis and tubular atrophy, extension of the iga deposits into the peripheral glomerular capillary walls, and hyaline arteriolosclerosis. differential diagnosis. mesangial iga deposits are present in henoch-schönlein nephropathy, and may be present in lupus nephritis, chronic liver disease, coeliac sprue, certain dermatologic diseases, and some rheumatologic diseases. iga nephropathy [igan] is defined by the presence of mesangial iga, but otherwise the histopathological and clinical features are very variable. we do not yet know sufficient about pathogenic mechanisms to understand whether igan is a single disease. although traditionally called an 'immune complex' disease there is no direct evidence that mesangial iga deposition in igan occurs through classical antigen-antibody interactions. mesangial cells do carry receptors for iga, which may play a key role in iga deposition and subsequent injury, but these are not yet fully characterised. mesangial iga in igan is polymeric iga1. there is no evidence of mucosal immune system overactivity, indeed there seems to be underproduction and abnormal t cell control of mucosal iga production, along with overproduction by the marrow of iga1 iga1 has a hinge region peptide structure which is a site for o-glycosylation. in igan circulating and mesangial iga1 both have abnormal o-glycosylation at the hinge region. the same defect is seen in henoch-schönlein purpura only when there is renal involvement. the glycosylation defect is not due to abnormal peptide structure of the hinge; the possibility that there is reduced activity of the key enzyme b1, 3 galactosyltransferase in b cells or plasma cells has not yet been confirmed. alternatively the glycosylation changes may reflect a shift in the production of mucosal type of iga1 to the marrow. while iga1 deposition is caused by disease mechanisms specific to igan, subsequent inflammatory and fibrotic events are probably driven by mechanisms common to other chronic glomerular disease. in some patients iga1 deposition is not followed by inflammation, in others inflammation resolves without fibrosis. cytokine and growth factor production by mesangial cells is a sufficient explanation for glomerular inflammation and fibrosis. however little is yet understood of any genetic or environmental influences which protect some patients from progressive renal injury. our recent controlled trials by the japanese pediatric iga nephropathy treatment study group demonstrated that treatment of children with severe iga nephropathy with prednisolone, azathioprine, heparin/warfarin, and dipyridamole for 2 years early in the course of the diseaseprevents immunological renal injury and progression of the disease. the majority of patients with iga nephropathy in our series are diagnosed early in the course of the disease, and the asymptomatic period before the discovery of urinary abnormalities is short. early diagnosis and early treatment is very important in iga nephropathy. 1. combined therapy for severe childhood iga nephropathy (j am soc nephrol 10: [101] [102] [103] [104] [105] [106] [107] [108] [109] 1999) . seventy-eight children with newly diagnosed iga nephropathy showing diffuse mesangial proliferation were randomly assigned to receive either the combined therapy of prednisolone, azathioprine, heparin-warfarin, and dipyridamole for two years (group 1) or the combination of heparin-warfarin and dipyridamole for two years (group 2). urinary protein excretion was significantly reduced in group 1 patients, but remained unchanged in group 2 patients. the percentage of glomeruli showing sclerosis was unchanged in group 1 patients, but significantly increased in group 2 patients. 2. steroid treatment for severe childhood iga nephropathy (clin j am soc nephrol, 1:511-517, 2006) . in this study we have compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed iga nephropathy showing diffuse mesangial proliferation. patients were randomly assigned to receive either the combination or prednisolone alone for two years. the primary endpoint was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m 2 /day. thirty-nine of the 40 patients receiving the combination and 39 of the 40 receiving prednisolone completed the trial. thirty-six of the 39 patients (92.3%) receiving the combination and 29 of the 39 (74.4%) receiving prednisolone reached the primary endpoint by the two-year follow-up point (p=0.007 log-rank). the percentage of sclerosed glomeruli was unchanged in the patients receiving the combination, but increased in the prednisolone group (p=0.0003). the frequency of side-effects was similar in the two groups. long-term administration of recombinant human erythropoietin (epo) has become the most common way of treating anemia in chronic renal disease. standard amounts per unit body weight have been recommended for the initial dose. however, several authors have noted that the dose per unit body weight needed for a given response is higher in younger children than in older children or adolescents and that it is increasing with decreasing body weight. furthermore, for a given absolute dose of epo the outcome was investigated in adult hemodialysis patients, but no dependence was found in 54 patients weighing 45-86 kg. a similar model to the hemoglobin-time data of 8 children aged 8-15 years treated with epo for renal anemia did not find an impact of body weight on response when it was modelled in terms of absolute dose. in a similar analysis to the hemoglobin-time data 52 children and adolescents aged 5-20 years were analyzed, in order to more definitively answer the question if, for given absolute doses the hematopoetic response to epo in children depends on body weight. neither the dose response parameter e max and ed 50 showed dependence on body weight. the median hemoglobin response to a standard dose was similar to that reported for adults. it can be concluded that younger and smaller children need relatively more epo than older children. doses for children should be specified as absolute amounts rather than amounts per unit body weight. references: scigalla p. effect of recombinant human erythropoietin treatment on renal anemia and body growth of children with end-stage renal disease. in: baldamus ca, scigalla p, wieczorek l, et al, editors erythropoetic agents are the mainstay of treatment for renal anemia. although there are several different marketed forms of erythropoetin, they are not substantially different in their ability to stimulate erythropoesis. however, darbepoetin, which differs in one amino acid, and has additional glycosylation sites, has a longer half-life and therefore a presumed longer duration of action. this provides a theoretical advantage, suggesting that less frequent injections will be required. clinical experience and studies have confirmed that both erythropoetin (epo) and darbepoetin (dar) are effective to maintain hb values within the recommended range. also, though there is some experience with epo injected every couple of weeks, the overall evidence suggests that dar has a longer duration of action, and injections are required less frequently. for many children, particularly the pre-dialysis population, anemia is successfully controlled with dar injected every 3-4 weeks. however, this apparent advantage of dar is somewhat reduced because of the increased pain reported with dar injections compared to epo. both epo and dar have been used successfully in children of all ages. with epo, the doses required to maintain hb values appear to be increased in infants compared to older children; this may not be the case with dar, but there is much less experience with use of dar in infants. also, the administration of dar in infants is hindered by the need to inject portion of a unidose pre-filled syringe, which may introduce inaccuracies in dosing, is wasteful, and is not user-friendly. the side effect profile for each product is similar, and specifically each has been associated with development of hypertension, which is most likely with higher hb values. pure red cell aplasia has also been reported with each product. thrombocytosis has been reported with dar use. overall, there is little to recommend one product over the other. the need for less frequent injections may favor dar for use in most children beyond infancy, whereas it is easier to administer epo accurately in infants. how much iron is needed and how much is toxic? iron deficiency is the primary reason for ineffective erythropoiesis in patients with chronic kidney disease (ckd) who receive an erythropoiesis stimulating agent (esa). reasons for iron deficiency include inadequate dietary intake, blood loss from the gastrointestinal tract, frequent blood tests, loss of blood in the extracorporeal circuit of hemodialysis (hd), as well as the hepcidin related impairment of the intestinal absorption of iron and its release from the reticuloendothelial system. supplementation of iron can be by either the oral or intravenous (iv) routes, although the national kidney foundation-kidney disease outcomes quality initiative (k/doqi) strongly recommends the preferential use of iv iron in children and adult patients receiving hd. the k/doqi recommended target iron indices for all children on dialysis are a serum ferritin >100ng/ml and a transferrin saturation (tsat) >20%. while the serum ferritin should not regularly be >500 ng/ml, some such patients will achieve a higher hemoglobin value following an iv course of iron therapy. of the iv iron agents, the non-dextran products appear to be safest, and pediatric dosing recommendations exist for ferric gluconate and are currently being studied for iron sucrose. differences do exist for the clinical (e. g. proteinuria) and subclinical (e. g. oxidative injury) toxicities associated with the currently available iv iron products and should be taken into consideration when prescribed. until recently the major physiological function of erythropoietin (epo) was thought to be the induction of erythropoiesis. however, a growing body of evidence indicates that epo has tissueprotective properties and prevents ischemia induced tissue damage in several organs including the kidney. a main target of epo´s action is the endothelium, and one of the pivotal intracellular pathways mediating the beneficial effects of epo is the activation of akt, i. e. serine/threonine protein kinase b. as a result, akt phosphorylates the proapoptotic factor bad, which in turn causes inhibition of programmed cell death (apoptosis). moreover, experimental studies revelead that epo is a potent regulator of endotheial progenitor cell (epc) proliferation and differentiation. collectively, these data support the hypothesis that epo is a key molecule in the process of endothelial (vascular) repair and neoangiogenesis. treatment with rhuepo or analogues could therefore open new therapeutic strategies in regenerative cardiovascular medicine. introduction: africa as a continent is besieged by many health challenges including malaria, hiv (upwards of 60% of paediatric admissions), tuberculosis and malnutrition with an infant mortality rate (imr) ranging from 62(southern africa) to 132(mozambique). good health facilities are on the whole not available except in the extreme north and south of the continent with doctors/100 000 population in south africa 69 but in kenya only 13 and even lower in other parts of africa. renal disease: renal disease in adults is an unknown quantity with no information being available regarding children's renal disease, where many babies do not even have access to antenatal ultrasounds. situation in south africa: in reality, there are only 2 centres (cape town and johannesburg/ pretoria) doing paediatric dialysis and transplantation in significant numbers with small numbers interspersed in the rest of the country. this raises numerous issues: -accessibility for children to renal care -retaining minimum standards of care for children -both dialysis and transplantation -combined with adult units -central government funding in form of tertiary services grant for paediatric renal care -children not first priority on any transplant program in terms of organ allocation -private facilities vs state facilities -ethical decisions dialysis facilities: peritoneal dialysis (pd) first line therapy for acute renal failure, as can be performed in any setting with minimal equipment and expertise. in the setting at rxh, we have a greater than 60% survival in infants and children dialysed using pd even in a sophisticated intensive care setting. haemodialysis and chronic dialysis may not be easily available in most settings and realistically need transfer to one of the major centres. transplantation: again limited to only few centres, with at least 30% living related donations from family members. initial good 1 year (90%) and 5 year (80%) graft survival but results then deteriorating as patients enter their adolescent years often with little support and transfer to adult units in their early teens. controversial issues here include access to one kidney transplant only, no chronic dialysis if not suitable for transplant and transplantation in hiv positive recipients. conclusions: adequate resource allocation is required for paediatric renal care especially where resources are limited. immunosuppression remains the cornerstone of successful transplantation. in developing countries transplantation is mostly from living donors and transplant is thus a once in a lifetime chance. in this backdrop immunosuppression is a challenge as several issues have to be overcome. namely, non-availability of newer drugs, high costs and paucity of drug monitoring facilities. in most countries immunosuppression is based on a triple drug regimen of cyclosporin (cya), prednisolone (pred) and azathioprine (aza). in the last few years mmf and tacrolimus (tac) has been initiated in a few centres. several tailoring strategies have been employed taking into consideration costs, drug availability, tissue typing facilities and drug monitoring. firstly in hla identical transplants which constitute 15-20% of the total, cya based regimen are used. marked reduction to 1-2 mg/kg at 6 months and complete withdrawal at one year in rejection free transplants is safe with continuing of aza and pred. secondly several centres selectively use tac and mmf in cases with early rejection or transplants with >3 mismatches. it is possible to switch to cya or aza after 6 months on individual basis. thirdly induction protocol with atg for 3 days in transplants with >4 mismatches and in retransplants is cost effective. cost considerations have increased the use of generic calcinurin inhibitors with market share of 20-100% in different countries. co administration of p450 competitors has reduced doses of cya by 50-60% with considerable cost reductions. siut has been running a living related transplant program for more than 20 years with dialysis and follow-up of recipients and donors. keeping in mind economic constraints a model of government public partnership was developed which provides all facilities including drugs free of cost. we adopted a number of tailoring strategies e. g. strict monitoring, tailoring by hla match and donor age and use of biological agents in risk groups. in first 10 years we used parent drugs, however increasing costs necessitated use of generics after establishing bioequivalence in controlled trials. graft survival rates were maintained at 92% and 85% at 1 and 5 years. in conclusion, immunosuppression in developing countries require besides newer drugs, monitoring facilities, affordable costs and regular follow-up as transplantation for majority is once in a lifetime chance and failure equates with death. occurrence of infections following kidney transplantation is a major reason for hospitalization, and an important cause for renal dysfunction & mortality in developing countries. more than 50% renal transplant recipients get serious infections, with a 20-40% risk of mortality. infections in the first month after transplantation are similar to those in surgical patients; opportunistic pathogens and cmv predominate between 1-6 months; and tuberculosis (tb) after 6 months. the risk of tb in patients on maintenance dialysis & following transplantation is between 10-20%. the onset of tb is usually within 12 months of transplantation. clinical syndromes include pleuropulmonary tb, followed by disseminated tb, pyrexia of unknown origin and lymph node disease. demonstration of m. tuberculosis, on microscopy or culture might not be possible. nonrifampicin based treatment regimens (inh, pyrazinamide, ethambutol, fluoroquinolone for 3 months, followed by hef for 9 months) are used. inh prophylaxis (6-9 months) is advised in patients with tuberculin positivity or contact with active tuberculosis. cmv disease results in considerable morbidity & mortality; its timing is influenced by donor/recipient serological combination, state prior to transplantation, use of antilymphocyte induction therapy or preventive strategies. cmv disease is characterized by a non-specific febrile illness; features of enterocolitis, pneumonia, hepatitis, myocarditis, esophagitis, chorioretinitis & bone marrow involvement are variable; disseminated disease is rare. cmv disease exacerbates the net immunosuppression, increasing the risk for opportunistic infections. patients with cmv disease are also at risk for acute rejection and chronic allograft injury, atherosclerosis & vascular injury. diagnosis of cmv disease is based on a combination of viral serology, shell vial cultures, pp65 antigen assay and pcr. the cost of prophylaxis and treatment is a major limitation to the use of ganciclovir or valganciclovir. other infections in transplant recipients include malaria, p. carinii and fungi (cryptococcosis, candidiasis, mucormycosis, aspergillosis). infections are an important cause of morbidity & mortality in renal transplant recipients. their management continues to be challenging due to difficulties in diagnosis, unsatisfactory follow-up and cost of medications. ethical issues of renal replacement therapies n. orta, p. zibaoui, e. lara university of carabobo/insalud, pediatric nephrology, valencia, venezuela important ethical issues in pediatric nephrology (pn): genetic and molecular techniques, prenatal therapies for urinary anomalies, treatment of children with chronic renal disease (esrd). ecosonography can detect nephrourological anomalies and studies of amniotic fluid give information on chromosome alterations and renal function. particular situations, can lead to dilemmas related to pregnancy interruption and neonatal dialysis and transplantation (dt) possibilities. renal insufficiency (ri) presents at any age, and peritoneal, hemodialysis or hemofiltration could be applied. patients without structural abnormalities, ri secondary to toxics or isquemic nephropathies have better prognosis. these procedures are complicated and costly and increases, and may have secondary effects with ethical implications. treatment by dialysis developed in the 60's and inclusion of children was not considered. this has changed with advances in dt. since 1970's dt programs were setup for children, but received criticisms and considered unethical, but were continued because of familiar and humanitarian demands and today it is clear that children benefit with that. scientific societies recommend: 1. children who receive dialysis must meet the following criteria: -diagnosis of esrd, legal authorization, possibility of transplantation, acceptable quality of life; may not be rejected for economic, social or psychological reasons, nor gender, age, race or mental conditions. biopsies are the current 'gold standard' for monitoring transplant patients, but it has been shown that even mild rejection episodes, based on pathology grading, can have poor outcomes and even biopsies with normal early pathology can progress rapidly with chronic allograft injury. there is considerable inter-observer variability of biopsy pathology readings that adds an additional confounder to this method of analysis. identification of non-invasive biomarkers in blood or other fluids would allow for the possible elimination of frequent biopsies. hence, the identification of diagnostic and predictive non-invasive genomic markers will be a worthy tool to aid in the clinical monitoring of transplant patients. the use of dna microarrays as a hypothesis generation tool for determining gene expression differences across thousands of genes in a data set is increasing. recently, the use of microarrays has been applied to the transplant field and holds great promise for unraveling the mechanisms at play in various transplant processes and for identifying new tissue specific and non-invasive biomarkers predictive of clinical outcomes. as microarrays produce large amounts of data, bioinformatics tools are being developed to determine gene expression patterns. gene clustering and class prediction tools aid in the discovery of molecular signatures in different disease processes while literature mining, gene family analysis and pathway analysis help in understanding the biological relevance of these signatures. initial studies in acute rejection and graft dysfunction have produced possible markers for risk stratification of the rejection event and have suggested underlying mechanisms at play, that may now allow us to test novel drugs for treating specific acute rejection episodes. the most exciting application of microarrays lies in our ability to predict clinical outcomes by non-invasive serial monitoring, eliminate the requirement of transplant biopsies and individualize patient management by accurately predicting the patient's sensitivity to immunosuppression-sufficient to suppress the allo-response, yet insufficient to abrogate the innate response. responsible array data handling and accessible reporting will open new doors for transplant researchers through increased use of computers and collaborations towards these kinds of novel insights and treatment options for transplant patients in the future. this talk focuses on dna microarrays, their application to transplantation, and discusses some of their limitations and recent applications, as well as some key research studies where dna microarrays are applied to understanding the molecular differences in acute transplant rejection that segregate and likely control the differences in rejection treatment responsiveness as well as decline in graft function, as well as gaining insights into the different biological processes that govern these differences. the molecular pathogenesis of vur is not well understood. uroplakins (ups) are expressed in the urothelium and are developmentally regulated by rab27b and tbx genes. up ii and iiia-null mice exhibit a primary (1 o ) vur phenotype. using microarrays and rt-pcr, we analyzed gene expression in surgically-discarded ureteric tissue from children undergoing reimplantation for 1 o reflux, compared with adult living-related transplant donors as normal controls, as well as children with 2 o reflux (megaureter, duplicated ureters, and posterior urethral valves) as age-matched disease controls. we also studied urine protein profiles using 2-dimensional electrophoresis (2d-page) followed by time-of-flight mass spectroscopy (q-tof-ms). rt-pcr showed partial expression of ureteric upia, upib, upii and upiiia genes in patients with 1 o reflux. protein screening using western immunobloting confirmed that some uroplakins were undetectable. real-time rt-pcr revealed that ureteric up ia, up ib, upii, and up iiia gene expression decreased significantly, whereas upiiib gene expression increased at least 2-fold compared to controls. compared with patients with 2 o vur, the decrease of upiiia expression in those with 1 o reflux was highly statistically significant (p<0.00001). the expression of rab27b and tbx genes also decreased significantly in patients with 1 o and 2 o reflux as well. total urinary protein concentration increased by 6-fold in the 1 o vur patients without detectable renal scarring on dmsa scans; and increased further in patients with renal scarring, 13-fold for 1 o vur and 11-fold for 2 o vur patients. proteomic analyses of proteinuria revealed an overall increase of protein with mw>60.4 kda in the pi range 4.0 to 7.0 in patients. q-tof ms identified one predominant urinary protein of ~ 105 kda as sera-transferrin, which was confirmed by elisa quantitation. we hypothesize that the abnormal developmental expression pattern of the up, rab27b and tbx genes in vur patients results in abnormal urothelial functions, which lead to leakage and/or secretion of proteins into the urine, and that this occurs in the absence of scarring from urinary infections. further identification of these protein biomarkers may lead to non-invasive diagnostic tests for vur. biomarker discovery in acute kidney injury p. devarajan cincinnati children's hospital medical center, department of pediatric nephrology and hypertension, cincinnati, united states acute kidney injury (aki), previously referred to as acute renal failure (arf), represents a common and persistent problem in clinical medicine. despite significant improvements in therapeutics, the mortality and morbidity associated with aki remain high. a major reason for this is the lack of early markers for aki, akin to troponins in acute myocardial disease, and hence an unacceptable delay in initiating therapy. fortunately, the application of innovative technologies such as functional genomics and proteomics to human and animal models of aki has recently uncovered several novel genes and gene products that are emerging as biomarkers. the most promising of these are chronicled in this symposium. these include a plasma panel (ngal and cystatin c) and a urine panel (ngal, . since they represent sequentially expressed biomarkers, it is likely that the aki panels will be useful for timing the initial insult and assessing the duration of aki. based on the differential expression of the biomarkers, it is also likely that the aki panels will distinguish between the various types and etiologies of aki. however, they have hitherto been tested only in small studies and in a limited number of clinical situations. it will be important in future studies to validate the sensitivity and specificity of these biomarker panels in clinical samples from large cohorts and from multiple clinical situations. such studies will be markedly facilitated by the availability of commercial tools for the reliable and reproducible measurement of biomarkers across different laboratories. a. watson children and young people's kidney unit, notthingham university hospitals, nottingham, united kingdom the achievement of adequate chronic peritoneal dialysis in children requires close attention to clinical, dietetic and psychosocial aspects of care. successful dialysis is dependent upon excellent peritoneal access and swan neck coil catheters with downward facing exit sites are increasingly favoured with many placed laparoscopically. automated peritoneal dialysis is employed in most developed countries but adolescents may be given the choice of capd which may be the only modality available in developing countries. training and support by committed nursing staff are of paramount importance as is regular review by a paediatric renal dietitian. growth parameters should be regularly monitored and supplemental enteral feeding introduced early. many infants are nasogastrically fed, but the preferred route for supplemental enteral feeding is via a gastrostomy which can be placed at the same time as the pd catheter. dialysis fill volumes should be assessed in terms of body surface area and intra-abdominal pressure measurements. there can be discrepancies between urea and creatinine clearances and adequate dialysis includes combining clinical parameters with regular growth measurements as well as biochemical data including phosphate, calcium and parathyroid levels. peritoneal function tests are useful in monitoring progress but the greatest challenges are in sustaining long-term dialysis, particularly in infants where transplantation is likely to be delayed. support for the families with a respite care 'package' may delay or prevent burnout and possibly reduce peritonitis rates. conventonal pd solutions are acidic, contain unphysiological concentrations of lactate and glucose and highly toxic glucose degradation products (gdp), which are substrates for advanced glycation end product (age) formation. repeated administration induces epithelial to mesenchymal cell transition, loss of the mesothel cell layer, progressive submesothelial fibrosis and angiogenesis, ultimately leading to ultrafiltration failure. meanwhile pd solutions with an improved toxicity profile are available. multi chamber pd solutions separate glucose from the buffer at a very low ph, which largely prevents gdp formation. after mixture ph is close to normal. they are equally effective with regard to solute-and water transport, reduce inflow pain and systemic age load. dialysate effluent markers indicate increased mesothelial cell mass, reduced peritoneal inflammation and reduced angiogenesis. animal studies demonstrate preservation of pd membrane morphology and function, respective human biopsy data however are pending. a european paediatric multi centre trial accomplished recently elucidates the impact of the lactate and bicarbonate buffer. a randomized cross over trial in adult patients points to an improved preservation of residual renal function; a korean registry suggests improved technique and patient survival. icodextrin solutions reduce glucose and gdp exposure, improve extracellular fluid status, left ventricular mass and stabilize membrane function in anuric adult capd patients and should be beneficial in children, too. amino acid based solutions achieve similar clearance and ultrafiltration rates, reduce glucose and gdp load and allow for a phosphate free amino acid supply. the nutritional benefit however is questionable. other, thus far experimental strategies include addition of locally active compounds to pd fluids such as gdp scavengers, inhibitors of age formation and antifibrotic agents. surface active phospholipids may increase peritoneal contact area and ultrafiltration. gene therapy appears highly promising but is still far from being clinically applied. in summary, there is substantial evidence for increased biocompatibility of the recently introduced multi chamber and icodextrin based pd solutions. they should improved long term morbidity and mortality of pd patients; this however still needs to be proven. the impact of the ippr on the treatment of peritonitis b. a. warady children's mercy hospital and clinics, pediatrics nephrology, kansas city, united states the international pediatric peritonitis registry (ippr) is an initiative that was established to evaluate the safety and efficacy of largely opinion based peritonitis treatment guidelines in which empiric antibiotic therapy (1 st generation cephalosporin and ceftazidime or a glycopeptide and ceftazidime) was stratified by disease severity. forty-seven centers from 14 countries contributed data on 392 children and 501 peritonitis episodes treated in accordance with the guidelines. culturenegative peritonitis accounted for 31% of all episodes, with a marked regional variability in the incidence of this disorder, as well as in the peritonitis causative organisms. overall, 89% of cases achieved full functional recovery, a portion following relapsing peritonitis (9%). in-vitro evaluation revealed only 69% sensitivity of gram-positive organisms to a 1 st generation cephalosporin (eastern europe > north america) and 80% sensitivity of gram-negative organisms to ceftazidime. in contrast, 94% of gram-positive organisms and 93% of gram-negative organisms were sensitive to the combination of either a 1 st generation cephalosporin or an aminoglycoside. whereas the risk of empiric treatment failure was associated with the presence of a gram-negative infection (p=0.0004), neither the risk factors assumed by the guidelines nor the choice of empiric therapy were predictive of the final functional outcome of the peritonitis episodes. the data collected by the ippr will serve as an important source of evidence to be incorporated into revised pediatric peritonitis treatment guidelines. ch. aufricht medical university, pediatrics, vienna, austria peritoneal dialysis (pd) is a safe, cost effective and widely used form of renal replacement therapy in patients with end stage renal failure. however, up to a third of patients on pd will suffer from technical failure during their course. identification of the patients at highest risk would be of high clinical relevance. cytotoxicity of pd fluids due to low ph, hyperosmolarity, and/or high concentrations of lactate, glucose and its degradation products causes mesothelial cell injury that ranges from minor cellular dysfunction to overt (apo)necrosis. the same physicochemical properties of pdf that cause such cellular injury also induce pathways leading to repair and recovery. this so-called cellular stress response results in a switch of the cellular machinery from routine procedures towards reaction against stressors. the complex machinery of the cellular stress responses not only counteract direct toxic injury caused by pdf but also attenuate inflammation or other potentially deleterious cellular processes. infectious, uremic and toxic injuries might converge in cellular inflammation. whereas inflammatory processes triggered by infection protect the peritoneal cavity against invading microorganism, chronic sterile smoldering 'cytotoxic' inflammation may result in aberrant healing processes and peritoneal fibrosis. recently, polymorphisms of many proteins involved in relevant cellular responses have been described and related to altered resistance and/or susceptibility to pathogenetic processes with potential influence in pd. in this review, we will focus on key effectors of stress responses, of cellular inflammation and of fibrogenesis such as heat shock proteins (hsp), cytokines (il-6), chemokines (il-8) toll-like receptors (tlr) and growth factors. given the recently shown role of these 'players' for the interplay between mesothelial injury, inflammation and cytoprotection, these polymorphisms will likely be relevant for mesothelial cell damage during pd. taken together, the ability to understand -and ultimately modify -the risk profile of a given patient will be essential for tailoring individual pd therapies. the pathologic diagnosis of chronic allograft nephropathy (can) was introduced in 1993 by the banff classification system for renal allograft injury. it originally included at least four entities that it was acknowledged could not always be distinguished by biopsy: 1) chronic rejection; 2) chronic calcineurin inhibitor (cni) toxicity; 3) hypertensive vascular disease; 4) chronic infection and/or reflux (solez, ki 1993 44: 411) . over the ensuing decade, the definition of can has expanded and fluctuated such that some pathologists have come to use the term to mean a specific pathologic entity comprising "…progressive graft dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes and glomerulosclerosis. " (nankivell, nejm 2003 349: 2326 , while others have suggested can should be used to describe all causes of renal allograft dysfunction involving fibrosis. the resulting confusion over terminology has in some ways hindered the growing awareness of the multiple discrete, diagnosable and often treatable diseases capable of causing chronic graft injury. these diseases include: 1) chronic (primarily antibody-mediated) rejection; 2) de novo and recurrent glomerular disease; 3) calcineurin inhibitor toxicity; 4) interstitial fibrosis and tubular atrophy without evidence of any specific etiology. to this list should be added other recognizable causes of late graft dysfunction such as polyoma virus infection and hypertension. in the new banff 2005 classification can will no longer be a diagnostic category (colvin, world transplant congress, 2006) . instead, the term sclerosis will be used to describe: "interstitial fibrosis/tubular atrophy, not otherwise specified, " or "if/ta nos. " the increasing use of protocol biopsies in clinically stable patients has dramatically increased awareness of the ongoing pathological changes almost every renal allograft appears to be undergoing almost from the first moments of engraftment. techniques are now available in most centers to reliably recognize the presence of chronic antibody-mediated rejection. these include: 1) typical morphological findings: lamination of glomerular basement membranes, arterial intimal fibrosis, interstitial fibrosis/tubular atrophy; 2) c4d staining in peritubular capillaries or glomeruli; 3) the presence of circulating donorspecific antibodies (takemoto ajt 2004 4: 1033 . treatment of late, chronic antibody-mediated rejection is in its infancy and may include use of anti-b cell antibody (rituximab), ivig, and/or plasmapheresis. calcineurin inhibitor toxicity can be more reliably identified by focusing on blood vessels in the allograft, primarily the location of hyaline deposits in the arterioles. nodular, peripheral hyalinosis is found almost exclusively in cni toxicity, whereas sub-endothelial and transmural hyaline deposits are non-specific and can be seen in hypertension, aging and diabetic nephropathy. there is increasing concern that recent gains in short-term renal allograft survival and reductions in acute rejection rates have not resulted in improved long-term graft survival. while this is likely due to multiple factors, including infections and malignancies associated with over immunosuppression, unrecognized (sub-clinical) acute cellular rejection (moreso ajt 2006 6: 747), and noncompliance in some patients, much evidence points to the primary role of cni toxicity in many if not the majority of chronically failing allografts maintained on cni's. experience with conversion from cni to sirolimus in adult patients has been reviewed in a recent editorial (betard nephrol dial transplant 2006 21: editorial comments) . in 10 studies involving nearly 400 patients, between 54% and 80% of patients with late allograft dysfunction failed to respond favorably to cni withdrawal and replacement with sirolimus. acute rejection episodes were rare, occurring in only six patients. common adverse effects included dyslipidemia, anemia and proteinuria. in one study, 32 of 50 patients developed proteinuria after conversion, 18 in the nephrotic range. pediatric experience with cni withdrawal has been limited (kerecuk, pediatr nephrol 2005 20: 1630 falger, pediatr transplant 2006 10: 565, hocker, pediatr transplant 2006 . our recent experience at stanford with cni withdrawal in 17 patients was not favorable, with 41% of patients experiencing an associated acute rejection episode (weintraub, wtc 2006) . prior history of acute rejection significantly increased the relative risk of acute rejection after cni withdrawal (rr=1.8), and proteinuria was common. patients with advanced chronic graft dysfunction were at increased risk for graft loss. in summary, the use of the term can to describe all causes of chronically failing renal allografts is to be discouraged in favor of a search for specific etiologies whenever possible. antibody-mediated rejection and cni toxicity are major causes of late allograft dysfunction. protocol biopsies are helpful in identifying patients with treatable causes of late allograft dysfunction. cni withdrawal/avoidance may be successful, but optimum patient selection criteria and withdrawal/replacement strategies have not been determined. pediatric experience to date with cni withdrawal has been limited, but it appears that late withdrawal after cni injury and graft dysfunction have become well established may be associated with inferior outcomes. prospective trials in pediatric patients are needed to address these issues. which immunosuppression in pediatric transplantation? p. hoyer university children's hospital, essen, germany recent results in pediatric renal transplantation have reached one year graft survival rates better than 90%. current immunosuppressive drugs should be classified according to their interference with the immunesynapsis as signal 1, signal 2 and signal 3 blocking agents. the variety of immunosuppressive drugs does allow more treatment combinations than the potential number of large scale studies in children. the definition of current unmet needs should guide employment of drugs. calcineurin inhibitors (cni) are still the basis of immunosuppression. individual risk profile leads to preferences for cyclosporine or tacrolimus. while in adults cni reduction seems to be the major goal, the search for steroid sparing or avoidance protocols has attracted major interest in pediatric transplantation. growth and body configuration as well as cardiovascular risk factors should be in the focus of research. antibody induction protocols, mainly with il-2 receptor antibodies, are increasingly popular, but efficacy is less clear than concluded from adult studies and might depend on initial combination therapy. mmf (cellcept®) or mpa (myfortic®) are effective drugs with cni sparing potential. early adequate dosing seems to be of greater importance than the choice of the cni, but the price to pay may be an increase in infectious complications. mtor inhibitors are promising in avoiding nephrotoxic side-effects; specific side effects on male gonadal function and possible interference with growth should be considered before any recommendation can be given. fty 720 would have been of especial interest for children because of maintaining viral infectious response, but phase-2 studies are on withhold. the vision of tolerance has stimulated research on regulatory t-cells; i. e. cd4 cd25+t-reg cells and the mastergene foxp3. the impact of lymphocyte depletion induction protocols with campath on operational tolerance needs further studies. newer drugs in development are isa 242, a cyclosporine analog without nephrotoxicity; a modified release form of tacrolimus which might improve compliance; the phosphokinase inhibitor aeb071 with the potential to avoid cnis; the jak3 inhibitor cyp 690, 550 which might interfere with signal 3 (il2 and il15-receptor); and lea29y (belatacept) with blocks costimulatory signals. according to the new european drug legislation some of these drugs will be subject for mandatory testing in pediatric patients to get marketing authorisation. the future might be a more tailored immunosuppression according to the induvidual needs of the patient. immunosuppression minimization strategies, under the umbrella of a newer generation of more powerful induction and maintenance immunosuppressants, are being increasingly applied to pediatric organ transplantation, with the greatest emphasis on minimization of steroids and calcineurin inhibitor agents. safe elimination of these steroids carry unprecedented advantages for reducing patient morbidity and chronic graft injury, but may also result in unanticipated changes in immunological homeostasis and drug pharmacokinetics, heralding closer surveillance for posttransplant infections and alterations in drug bioavailability and dosing, as well as break-through immunologic responses. in single center studies, pediatric renal transplantation appears safe without steroids. daclizumab first dose doubling and extended use for 6 months replaces steroids effectively without evidence of over-immunosuppression, and may be the pivotal causative for the reduced acute rejection seen in the face of steroid avoidance. this pilot protocol has been tested in a prospective, multicenter randomized us and canadian study. b. maecker, c. klein department of pediatric hematology/oncology, hannover medical school, hannover, germany posttransplant lymphoproliferative disorders are severe complications of immunosuppressive therapy after solid organ transplantation causing significant morbidity and mortality. to define prognostic factors, we have analyzed 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) that were reported to the german ped-ptld registry. ptld was diagnosed at a median time of 29 months post organ transplantation with sigifcantly shorter lagtime in liver versus heart or renal graft recipients. the five-year overall and event-free survival was 68% and 59%, respectively. stage iv disease with bone marrow and/or cns involvement was independently associated with poor survival. no differences in outcome were observed between early and late onset ptld, monomorphic or polymorphic ptld, and ebv-positive or ebv-negative ptld, respectively. patients with burkitt-like ptld and c-myc translocations had very short survival. these factors should be important to consider for future prospective interdisciplinary trials that are urgently needed to define rational treatment strategies. cystinosis is an autosomal recessive lysosomal storage disorder affecting children and adults all over the world. in cystinosis cystine is trapped in the lysosomal compartment due to a defect in its egress transport protein cystinosin encoded by the gene ctns. by mechanisms still not fully understood this leads to tubular and glomerular kidney and other organ failures (e. g., thyroid, muscles) if left untreated. kidney involvement is prominent from shortly after birth on as renal tubular fanconi syndrome with the clinical consequences of failure to thrive and rickets. cystinosis is the single most common cause of renal fanconi syndrome in childhood. therefore, any recognition of renal glucosuria, generalized aminoaciduria, phosphaturia, small molecular weight proteinuria, polyuria, and metabolic acidosis (due to renal bicarbonate loss) should lead to prompt consideration of cystinosis as possible cause. this can be done utilizing biochemical analytical methods measuring the cystine content of polymorphonuclear leucocytes. corneal cystine crystals, seen in slit lamp examination, are pathognomic as well, but may not be visible before 16 months of age. left undiagnosed and untreated, patients will develop in addition to the existing tubular insufficiencies pronounced glomerular kidney failure often already present at diagnosis and inevitably leading to end stage renal failure typically at the end of the first decade of life. kidney failure in cystinosis presents differently from other forms of glomerular kidney failure because of the overlap of tubular and glomerular insufficiencies. kidney transplantation will be curative with respect to kidney function. specific treatment with cysteamine to lower the intralysosomal cystine content apparently is as important as before transplantation to prevent or attenuate other organ failures and therefore has to be continued after kidney transplantation. cysteamine treatment has been introduced in the 1970s and has been approved in the 1990s. early diagnosis and diligent treatment is able to prevent or ameliorate major organ complications. unfortunately, until now no newborn screening exists due to the biochemistry and cell biology involved. the high prevalence of a european founder mutation, i. e., a 57 kb deletion in the ctns gene, makes molecular based methods not feasible. lowe syndrome and dent's disease: two ends of a spectrum d. böckenhauer great ormond street hospital for children nhs trust, nephrology, london, united kingdom lowe syndrome and dent's disease are x-linked disorders; the former is a systemic disorder characterized by cataracts, mental retardation and proximal tubulopathy whilst the latter was originally described as an isolated kidney disorder with tubular proteinuria, hypercalciuria/ nephrocalcinosis and progressive renal impairment. mutations in ocrl1 underlie lowe syndrome, whereas the majority of cases with dent's disease are caused by mutations in clcn5. recently, mutations in ocrl1 have been identified in a subgroup of patients with dent's disease (also called dent-2). it is unclear, why some patients with ocrl1 mutations get dent's disease, while others develop lowe syndrome. however, careful clinical observation has revealed that dent-2 patients have evidence of systemic involvement. moreover, the degree of severity of symptoms in lowe syndrome is highly variable. thus, mutations in ocrl1 can cause a spectrum of symptoms, from tubular proteinuria and hypercalciuria to the full manifestations of lowe syndrome. here, we will review the clinical phenotype of the disorders, what is known about their pathophysiology and discuss genotype/phenotype correlation. fabry disease, the second most prevalent lysosomal storage disorder after gaucher disease, is an xlinked inborn error of the glycosphingolipid metabolic pathway and affects approximately 1:44,000 live births. mutations in the gene encoding alpha-galactosidase a, lysosomal hydrolase, lead to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. the initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. the later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. few patients have historically survived past their mid 50s. although renal involvement usually becomes prominent in adulthood, adolescents may develop proteinuria and decreased glomerular filtration rate. timely diagnosis is critical, given that the enzyme replacement therapy likely delays progression of the serious complications of fabry disease and may have potentially preventive benefits. specifically, there is growing evidence that initiation of enzyme therapy slows progression of chronic kidney disease (ckd); it remains unknown whether enzyme therapy in the currently employed doses can prevent ckd. pediatricians have a particularly important role in making the diagnosis, since they are likely to be the first providers to encounter fabry patients and thus initiate therapy before irreversible tissue injury develops. nephrologists should consider the diagnosis of fabry disease when a patients present with ckd with nephrotic or subnephrotic proteinuria, often with skin lesions (but these may be limited in distribution), episodic extremity pain, and/or psychiatric problems. further research is required to determine the efficacy of enzyme replacement therapy to prevent organ damage in children, to identify optimal therapeutic doses and schedules, and to define efficacy of additional treatments for fabry kidney disease, include angiotensin converting enzyme inhibitors and angiotensin receptor blockers. w. van't hoff great ormond street hospital for children nhs trust, pediatric nephrology, london, united kingdom children with a complete deficiency of methylmalonyl coa mutase develop both renal tubular and glomerular dysfunction. the renal tubular dysfunction is characterised by renal tubular acidosis, defective urinary concentration and hyporeninaemic hypoaldosteronism. a chronic interstitial nephritis also develops leading to long-term glomerular renal damage. chronic kidney disaes is not evident on routine testing as muscle mass is reduced and protein intake is markedly restricted. formal measurement of gfr using chromium 51 edta showed that 7 of 12 such mma patients have a gfr <60 mls/min/1.73 m 2 ), and by 12 years, 7 of 9 patients had a gfr <40. most mma patients with ckd do not have excess proteinuria nor hypertension. although vit b12 responsive mma patients in general have a more favourable outcome, late onset renal complications have been seen. in addition to ckd, mma patients can develop cardiomyopathy, pancreatitis, gut dysmotility and chronic or acute encephalopathy. management is based on a protein-restricted, high calorie diet, allopurinol to control hyperuricaemia, supplements of carnitine and metronidazole therapy to reduce production of propionate. haemodialysis has successfully cleared plasma mma and improved the metabolic and nutritional status. liver transplantation has been performed in a number of younger children, as enzyme replacement therapy, but is associated with a significant morbidity and mortality (including late neurological deaths). renal transplantation has been reported in a small number of older patients but it is not yet clear how good the graft outcome will be. combined liver-kidney transplantation has been undertaken again in small numbers, with a high morbidity and significant mortality although there are a very few remarkable survivors. so far, there are only centre specific experiences and unfortunately reviewing the literature will not give a full picture of long-term outcome and complications, due to the bias of the reported results towards favourable outcomes. there is a clear need to share data on the management of these rare patients in order to better understand the best approach. estimations of the extent of hiv disease in sub-saharan africa are that 26 million people are currently infected of which the total number of children is 2.1 million. worldwide it is thought that 2.3 million children are infected so it can be seen that the majority reside in africa. in south africa, we have a minimum of 250 000 hiv infected children aged less than 14yrs of age with only 15 000 on highly active anti-retroviral therapy (haart) at present. currently 40-60% of all paediatric admissions to hospital may be hiv related. hiv associated renal disease, is not yet well documented among children -especially from africa -but now with the growing availability of haart, this information has become more important for appropriate management. hiv renal disease presents in many forms, including including hiv-assoc nephropathy (hivan) and hiv immune complex kidney disease (hivick) amongst others. questions have now been raised as to whether a screening program should be introduced as haart, despite side effects and drug interactions, has revolutionised management if hiv infection detected early enough. transplantation which was thought previously to be an absolute contraindication and potential waste of valuable resource is now possible, provided there is maintenance of haart, hiv viral load is undetectable for >3 mths and cd4 >200cells/mul. there remains concern about feasibility in children with increased rejection, reduction of calcineurin inhibitors and infections such as recurrence of hepatitis c post-transplant. despite these concerns, studies in adherent adults have clearly shown that adult patients with hiv infection do better following transplantation than on dialysis. of concern, are some studies, showing that certain black patients may have a genetic predisposition to hiv infection. overall, transplantation can be successful in these patients provided the hiv disease is under control. however, hiv disease -including renal disease -remains a major problem in sub-saharan africa due to limited resources and lack of availability of drugs, where other health priorities may prevail. background. previous studies suggest that hiv-1 induces dysfunction and/or injury of endothelial cells, leading to the systemic release of fibroblast growth factor -2 (fgf-2). to date, the role that circulating fgf-2 may play in the pathogenesis of childhood hivan is not clearly understood. objective. here we sought to determine the potential role of circulating fgf-2 in the pathogenesis of hivan using wild type (wt) and hiv-tg 26 mice. methods and results. to determine whether circulating fgf-2 induced ultrastructural changes in renal glomerular endothelial cells and podocytes, we injected human recombinant fgf-2 daily for 10 days into fvbn wt and hiv-tg 26 mice (n=4 in each group). by electron microscopy we found that fgf-2 induced endothelial swelling and mild fusion of the foot processes in wt mice. these lesions were more severe in hiv-tg 26 mice, which showed enlargement of podocytes, protein reabsorption droplets, significant fusion of the foot processes, and collapsing glomerulopathy. subsequently, to confirm these findings in a different experimental model system, we used recombinant adenovirus carrying a secreted form of human fgf-2 (ad-fgf-2). four to five weeks old hiv-tg 26 mice without evidence of abnormal protenuria (urine protein/creatinine ratio (up/uc) <10), and their wild type littermates were injected with 5x10 8 plaque forming units (pfu) per mouse of ad-fgf-2 or control ad-lacz vectors through the retro-orbital (r. o.) venous plexus (n=6 per group). all mice were followed for three weeks. all hiv-tg 26 mice injected with rad-fgf-2 developed heavy proteinuria (up/uc >40). in addition, 50% showed elevated bun levels (>25 mg/dl) and renal histological lesions typical of hivan. in contrast, wt mice, developed transient and moderate proteinuria (up/uc <40), without renal failure or permanent renal damage. the number of animals with proteinuria in hiv-tg 26 mice injected with ad-lacz group was consistent with the natural history of the renal disease progression. control wt mice injected with ad-fgf-2 developed mild proteinuria (40%) that returned to normal values14-21 days after the injection. fgf-2 induced microcystic tubular dilatation and recruitment of mononuclear cells both in wt type and hiv-tg 26 mice, although the changes were more significant in the later group. conclusion. taken together, these results suggest that the accumulation of fgf-2 in the circulation of hiv-tg 26 mice induces glomerular endothelial and podocyte injury leading to the development of heavy proteinuria, renal failure, and the typical renal histological features of hivan. we conclude that the elevated levels of fgf-2 in the circulation of hiv-infected children may be a significant risk factor for the development and/or progression of hivan. human immunodeficiency virus associated nephropathy (hivan) is the third leading cause of kidney failure in young african american adults in the united states. the prevalence and natural history of the disease in children is not well documented. we have examined our experience in 315 children, aged 2 months to 22 years (mean age 9.4±0.3 years) with predominantly perinataly acquired hiv-1 infection from their mothers. since 1998, 286 of these children have been evaluated routinely for evidence of renal disease with quantitative assessment of proteinuria by random urine protein to creatinine ratios (upr/cr). renal functional studies included serum creatinine with estimation of glomerular filtration rate (egfr), urinalyses, renal scintigraphy, ultrasound and renal biopsy when possible. the patients were divided according to their level of proteinuria. those with nephrotic range proteinuria (upr/cr>1.0) were designated as hiv-ns (n=32; 11%). those with persistent intermediate range proteinuria (upr/cr: 0.2<1.0) were designated as hiv-pp (n=62; 22%). those with no proteinuria (upr/cr<0.2) were designated as having no nephropathy (hiv-non; n=192; 67%). the great majority of patients were treated with highly active antiretroviral therapy (haart), although those with hiv-ns had less time on treatment when their proteinuria was discovered. moreover, the virulence of the hiv infection as measured by viral load (vl) was significantly greater in those patients with proteinuria. also, viral load correlated positively with degree of proteinuria (r=0.5; p<0.0001). mortality as shown by kaplan-meier survival curves was significantly greater in the hiv-ns group as compared to the pp and non groups. renal failure occurred only in the group with nephrotic range proteinuria. during the past 25 years we have dialyzed 27 children with hiv infection in our end stage renal disease (esrd) program for a total of 660 patient dialysis months. since 1999, all patients are managed on hemodialysis due to the high occurrence of fungal peritonitis in our initial experience. survival has improved remarkably during the past 10 years with a median survival of 35 months (range 4 to 125 months). the next stage is to begin renal transplantation in those patients with adequate control of the hiv infection. aim: to determine the spectrum of severe renal disease in our hiv infected children; excluding severe sepsis and septic shock syndromes. indications for their referral, renal biopsy and histology relating to outcome. methods: retrospective analysis of all children referred to the paediatric renal service from the general wards and hiv clinic from january 1996 to december 2005. analysis includes age of presentation, sex, nutritional status, symptoms, renal function, histology, associated diseases including infections and follow-up. results: total of 60 children with a mean age of 6.6±0.7 years with a male: female ratio of 1:1.3. there was an overlap of symptoms but the commonest presenting symptom was haematuria in 50%, severe urinary tract infection and pyelonephritis in 23%, anasarca with or without any nephrosis in 33%, acute renal failure in 20%, chronic renal failure in 5%, severe electrolyte disturbances in 5%. renal biopsy was performed in 52 (86.7%) children. histogically 50% had immune complex disease (icd) of which 65.1% had lymphoid interstitial pneumonitis (lip).11.5% had fsgs of which one had lip but also had icd, 11.5% had severe interstitial nephritis, associated infectious changes in 11.5% and atn in 5.8%. one patient each had minimal change, mpgn, abdominal kaposi sarcoma and kidney/bladder stones. 33.3% had or were treated for pulmonary tuberculosis. mean follow-up was 12±12.9 months. death occurred in 16.7% (10). all patients with fsgs with some renal dysfunction and severe sepsis demised. conclusion: despite the high burden of hiv disease, severe renal complications have a low prevalence. good correlation of icd and lip (65.1%) but prognosis is good. pulmonary tuberculosis and infection is the main complications resulting in high mortality in nephrotic syndrome with fsgs. hiv associated nephropathy (hivan) is one of the most common causes of renal failure in hiv seropositive african americans. in the usa, hivan has become the third leading cause of end stage renal disease (esrd) in african americans over the age of 20. while the introduction of haart has decreased both the mortality and infectious complications of hiv infection, the incidence of hivan has reached a plateau and has not decreased. with reduced mortality, the prevalence of seropositive patients in the esrd program continues to increase dramatically. the histopathological findings of hivan include focal segmental glomerulosclerosis of the collapsing variant combined with microcystic tubule dilatation. the most common other diagnosis is mesangioproliferative glomerulonephritis associated with hepatitis c infection, a common comorbid condition. typical features of hivan include renal enlargement and echogenicity by ultrasound analysis. microscopic findings include coexistent microcystic tubule dilatation and glomerular involvement. usually there is mild to moderate tubulointerstitial inflammation, interstitial edema, and fibrosis as well. glomerulosclerosis is usually focal and segmental with collapse of the glomerular tuft and hypertrophy of visceral epithelial cells. hivan is caused by renal epithelial infection by hiv-1 in a susceptible host. clearly there are genetic factors, based on the racial predilection of this disease. patients with hivan are 5.4 times more likely to have a relative with renal failure. in susceptible individuals, hiv infection induces renal epithelial proliferation and apoptosis. the kidney represents a tissue-specific compartment in which hiv-1 can replicate in a previously unrecognized reservoir. while hivan is not currently considered to be an aids-defining condition, patients with hivan should be treated with haart. in some instances, haart has completely reversed the disease process, although it does not rid the kidney of virus. thus, in patients with hivan, the kidney is a true reservoir for replication competent hiv. whether this occurs in other forms of renal disease associated with hiv infection or in patients without renal disease remains to be determined. prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. renal sympathetic nerves directly innervate renal tubules and blood vessels and plays a role in the regulation of glomerular filtration rate and renal sodium excretion. we examined if renal nerves play an a role in mediating the hypertension in prenatal programming. pregnant sprague-dawley rats were injected daily with intraperitoneal dexamethasone between 15 th and 18 th day of gestation. renal norepinephrine concentration was measured at 3 weeks of age. renal denervation was preformed at age 6 weeks of age in control and prenatal dexamethasone treated rats and blood pressure was measured at age of 8 weeks. renal norepinephrine concentration was 338±25 ng/gr in controls and 591±82 ng/gr in the group that received prenatal dexamethasone (p<0.05). systolic blood pressure at 8 weeks of age was 124±1 mmhg in sham operated controls, 122±5 mmhg denervated controls (p=ns). blood pressure was elevated to 133±1 mmhg in dexamethasone treated sham operated group (p<0.05), but was normal at 115±1 mmhg in the dexamethasone treated denervation group. in conclusion, prenatal dexamthasone results in elevated renal norepinephrine levels. bilateral renal denervation normalized the systolic blood pressure in rats that received prenatal dexamethasone. these data are consistent with the renal nerve playing an important role in mediating the hypertension in prenatal programming by dexamethasone. objective: evaluation of clinical outcomes in surgically treated children with renovascular hypertension (rvh). methods: 35 rvh patients treated surgically at a single centre between 1979 and 2005 were retrospectively reviewed: 63% were male, 0.4-17.9 (median 7.6) years of age, with systolic blood pressure (sbp) 141 mmhg (105-300 mmhg). results: bilateral renal artery stenosis was present in 53%, midaortic syndrome(mas) in 40%, intrarenal disease in 49% and coexisting cerebral disease in 24% of patients. surgical procedures (n=47) included: a) nephrectomy (n=18), b) autologous surgery for both aortic reconstruction (n=1) and renal revascularisation (n=15) (renalartery reimplantation (n=4), renal bypass (n=9) and autotransplantation (n=2)) and c) synthetic graft interposition for renal revascularisation (n=6), aortic reconstruction (n=6) or both (n=1). the majority (92%) of patients who received synthetic grafts had vascular anatomy too complex for autologous surgery. technical failure leading to secondary nephrectomy occurred in 3 patients. postoperative complications were haemorrhage (n=5), septicaemia (n=4), and chylous ascites (n=1). there were no operative deaths. patients from the uk were followed up for 5.1 (0.05-16) years. sbp post-surgery improved (116 mmhg, range 90-160 mmhg, p<0.0001). outcomes were normal sbp without treatment (52%), improved (34%) or unchanged sbp (14%). reduction of sbp led to loss of contralateral kidney in 1 patient. 10 children required re-interventions (15 angioplasties and 6 surgical procedures) for progressive disease (n=6), narrowing of the synthetic graft (n=4) and re-stenosis of the autologous bypass (n=2). conclusion: rvh is a progressive disease of extensive nature. surgery benefited 86% of children when performed in conjunction with conservative therapy and, if indicated, interventional radiology. h. wong 1 unlike adults with predominant primary hypertension (htn), the majority of children diagnosed with htn traditionally suffered from secondary forms of htn. however, substantial changes have occurred to the demographics of pediatric population over the past 20 years. in addition, our definition, awareness and understanding of children with hypertension has also changed. we therefore retrospectively reviewed the current causes of htn in children followed in a single tertiary care pediatric nephrology referral center between january 2003 and december 2006. patients who were either diagnosed with or treated for htn at the time of their last visit where included. gender, height, weight, age at the time of diagnosis, causer of htn and casual blood pressure were recorded. out of 1554 patients, 399 (25.7%) were diagnosed with htn. the majority were males (n=249, 62%). median was 10 years (1 month-18 years) age at time of diagnosis and 13.4 years (1.7 months-19 years) at time of the last follow-up. secondary htn was the most common cause of pediatric htn (n=329, 82%) followed by primary (n=51, 13%) and then white coat (n=19, 5%). renal htn was the most common cause of secondary htn (307/329, 93%). for patients referred initially for assessment of htn (n=137), primary (n=43, 31%) and secondary (n=41, 30%) were the two most common diagnosis followed by normotension (n=38, 28%) and white coat htn (n=15, 10.9%). twenty two (5.5%) patients were diagnosed before the age of 1 year. out of 23 renal transplant patients, 18 had htn (78%). renal htn remains the most common cause of pediatric htn overall and continues to represent a large portion of children referred for htn. all children suspected of having htn should continue to have thorough investigations of renal disease to identify the underlying cause. m. sinha 1 , c. booth 1 , j. simpson 2 , n. dalton 3 , s. qureshi 2 , c. reid 1 , s. rigden 1 1 evelina childrens hospital, guys and st. thomas's nhs foundation trust, department of pediatric nephrology, london, united kingdom 2 evelina childrens hospital, guys and st. thomas's nhs foundation trust, department of pediatrics cardiology, london, united kingdom 3 king's college london, department of medicine, london, united kingdom background: hypertension (ht) is a frequent complication in paediatric tx patients. the evolution of end organ damage and its relationship to ht in these patients is not well described. aim: to study the predictive value of an abnormal 24-hour abp profile for end organ damage. methods: patients underwent simultaneous casual blood pressure (cbp), abpm, echocardiogram (lvh if lvmi >38g/m 2.7 ) and ecg assessment, with measurement of several biochemical cardiovascular risk markers. cbp data for 18-months prior to study date was analysed as time averaged z-score. results: we present initial results of a 5-year prospective study. 22 patients (16 male) aged 12.7y±3.4 (mean±sd) and 5.9y±2.6 since tx were studied. on the day of study all patients had normal cbp. 73% had lvh of whom 65% had abnormalities on abpm. overall, 55% patients had both abnormal abpm and lvh. 45% had other findings: 10% abnormal abpm but no lvh; 10% normal abpm but no lvh; 25% normal abpm and lvh. data were analysed for differences between 2 groups of patients, with and without lvh. bp alone was significantly associated with increased lvmi. time averaged cbp was normal in all patients although differed significantly between the 2 groups: systolic bp z-score [mean (ci)] 0.27 (0.57, -0.03) with lvh; -.31 (-0.09, -0.54) without lvh. there were significant differences by abpm criteria relating to several components of the abpm profile including mean arterial pressure, systolic and diastolic bp load. no difference was found between the groups for hb, ca*po4 product, ipth and cgfr. conclusions: we have found the majority of our renal transplant patients have normal cbp but have abnormal abpm in association with lvh. this suggests better control of hypertension should be achieved in patients who have abnormal abp profiles and lvh. a new group of patients with normal abpm but lvh has also been identified. background: obesity is an independent risk factor for renal failure. therefore, we compared the body composition of pediatric nephrology patients with the general child population over two decades. methods: 6, 575 patients with a mean age of 9.5±4.2 years were studied. in 4, 595 patients (70.0%), sufficient data were available to analyze body composition. body composition was measured as body mass index (bmi) z-score because of the age dependency, calculated on the basis of data from the national (usa) center for health statistics (2000) . results: enuresis (24.88%), hematuria (16.45%), recurrent urinary tract infections (11.98%) and proteinuria (11.17%) were the most common diagnoses. the bmi z-score of the pediatric nephrology patients increased significantly from 0.33±0.47 in 1985-1991 to 0.72±1.06 in 1992-1999 and 1.27±1.54 in 2000-2006. while the rate of this increase was not statistically different from that seen in the normal population, they consistently demonstrated a significantly higher bmi z-score (average +0.545) over time. nephrotic edema, non-nephrotic proteinuria and hypertension were not confounding factors. conclusions: patients seen in our pediatric nephrology service over two decades had a higher bmi than the average child population. this implies that these patients are at even greater risk for development of chronic kidney disease later in life. we recommend therapeutic intervention to address this potentially modifiable risk factor. objective: b cell dysregulation is believed to be involved in the development of childhood-onset systemic lupus erythematosus (sle). there is limited evidence regarding efficacy and safety of interventions targeting b cell in children. in our study we evaluated efficacy and safety of b lymphocyte depletion therapy. methods: data of 20 children (15% male) with sle aged 14.1 years (6.1-16.2) treated with rituximab in a single centre were retrospectively reviewed. biochemical parameters were evaluated before and after treatment, and the normalisation of the parameters was assessed as a primary outcome. results: prior to rituximab therapy all patients received extensive immunosuppressive agents. indications for rituximab therapy were chronic (n=13) or acute illness, in either relapsing sle (n=3) or first presentation (n=4). rituximab 750 mg/m 2 was intravenously administered twice within a 2-week period in combination with cyclophosphamide. patients were followed up for 1.5 years (0.1-3.6) . no serious side effects were seen, except for viral infections such as herpes zoster (n=5). all patients with high creatinine (n=5; 226±99 mmol/l) prior to rituximab showed a decline within 2 months (mo), achieving a stable level by 8 mo (69±14 mmol/l, p<0.03). all patients with hypoalbuminaemia (n=12; 28.6±4.2 g/l) improved (5 mo: 36.1±6.4 g/l, p<0.001). low c3 level (0.40±0.12 g/l) as seen in 12 patients prior to treatment resulted in an increase up to 5 mo (0.77±0.24 g/l, p<0.002). a decline of previously high anti-dsdna (n=13; 162±163 iu/ml) was observed in all patients (5 mo: 56±62 iu/ml, p<0.02). conclusion: rituximab is safe and effective when used in combination with standard immunosuppressive agents. further prospective studies are essential to evaluate the longterm safety of the drug. outcome of severe henoch-schönlein purpura nephritis treated with longterm immunosuppression m. shenoy, m. bradbury, l. lewis, n. webb royal manchester children's hospital, department of nephrology, manchester, united kingdom aims: to look at the long-term outcome of all children with severe henoch-schönlein purpura nephritis (hsn) treated with long term immunosuppression in a single centre over a ten year period. patients and methods: retrospective review of the records of 27 children (19 male) with iskdc grade 3b, 4, 5 and 6 hsn managed at our institution from 01/01/92 to 31/12/01 results: the mean age at presentation was 9.8 years (range 3.6-15.8 years). the median estimated glomerular filtration rate (egfr) at presentation was 91 ml/min/1.73 m 2 (iqr 51. 5-96.6 ) and urine protein: creatinine ratio (up: uc) was 556 mg/mmol (iqr 292-1363). the indication for biopsy was nephrotic syndrome in 9, nephrotic range proteinuria in 7, sub-nephrotic range proteinuria in 3, acute nephritis in 6 and nephritic-nephrotic syndrome in 2. a total of 25 patients were treated with weaning dose of steroids, of whom 22 were also commenced on long-term azathioprine (mean duration 8.9 months). 18 of these children received an 8-12 week course of oral cyclophosphamide (2-3 mg/kg/day) prior to azathioprine therapy (2-3 mg/kg/day). outcome: after a mean follow-up period of 7 years, 10 (37%) have made a complete recovery, 11 (40.7%) have persistent proteinuria but normal egfr, 2 (7.4%) have persistent proteinuria and are on anti-hypertensive therapy with normal egfr and 4 (14.8%) have progressed to esrd. older age at presentation was the only independent risk factor for poor outcome (12.8 years vs. 8.9 years, p=0.005). conclusions: despite treatment with cyclophosphamide, long-term steroids and azathioprine, a majority of children with hsn grade -3b on initial biopsy have persistent renal abnormalities on long term follow-up. only older age at presentation was associated with poor outcome. background: resent advances in podocyte biology indicated that the main cause of the heavy proteinuria in nephrotic syndrome (ns) is a dysfunction of slit diaphragm. on the other hand, the classical charge selective barrier is not likely to have a place in slit diaphragm. therefore we reevaluated the charge selective barrier function in ns and chronic glomerulonephritis using recently established charge selectivity index (csi; takahashi et al, pediatr res 59: 336, 2006) in comparison with dent disease. patients and methods: csi is a clearance ratio of igg (stokes einstein radius 49-60, pi 4.5-9.0) and iga (stokes einstein radius 61, pi 3. 5-5.5) . the assay of serum and urinary igg and iga was performed using laser nepherometry and enzyme immuno-assay. in order to evaluate the csi of normal glomerular filtrate, we measured the csi of dent disease. the urine of dent disease is considered to be a concentrate of filtered protein from normal glomerulus, without having a process of tubular protein reabsorption. thirty eight patients with podocyte diseases (focal and segmental glomerulosclerosis 4, finnish type congenital nephrotic syndrome 1, steroid sensitive nephrotic syndrome 33), 75 patients with chronic glomerulonephritis (iga nephritis 41, henoch-schönlein purpura nephritis 21, mesangiocapillary glomerulonephritis 5, alport syndrome 8) and 8 patients with dent disease, were analyzed. results and conclusion: csi (mean±sd) of podocyte disesses, chronic glomerulonephritis and dent disease was 1.12±0.25, 0, 42±0.31 and 0.18±0.04 respectively. the results apparently indicated that the charge selective barrier of gcw is working strongly in normal glomerulus, less strongly in podocyte diseases and not working in chronic glomerulonephritis. objectives: nphs2 mutations have been reported in familial and sporadic srns. we investigated the prevalence of nphs2 mutations among south-east asian chinese and their association with clinical outcomes. methods: genomic dna from 29 patients with primary sporadic srns (mean age at onset 5.4±4.0 years, range 0.58-12.0 years) and 45 cord blood controls were screened on all 8 exons and exonintron boundaries using direct sequencing. results: a missense heterozygous 871c>t mutation in exon 7 was identified in only one patient. polymorphisms 954t>c and1038a>g in exon 8 were detected in both groups. in the patient group, the genotypic frequency of tt, tc, cc at position 954 was 0.24, 0.55 and 0.21, and aa, ag and gg at position 1038 was 0.86, 0.14 and 0 respectively, consistent with hardy-weinberg expectations. there was no significant difference in allele frequencies between patients and controls. using binary logistic regression analysis, individual polymorphisms did not appear as informative predictors of poor clinical outcome, defined as persistent proteinuria or renal failure (p>0.05). on analyzing composite genotypes, carriers of at least a copy of the 954c allele were significantly associated with poor outcome (p=0.047, or=12.7, 95% ci: 1.03-157), while heterozygotes for 1038a>g were associated with good outcome (p=0.048, or=0.06, 95% ci: 0.004±0.979), suggesting possible interactions between the polymorphic sites. further analysis showed that the genotypic combination of 954tc/cc with 1038aa was more likely to have a poor clinical outcome. no significant linkage disequilibrium was detected between the two polymorphisms. conclusion: the concomitant occurrence of at least a copy of the 954c allele and the 1038aa genotype may be associated with poor clinical prognosis in srns but larger studies are needed to confirm these findings. renal hypodysplasia (rhd) is characterized by a reduced kidney size and/or maldevelopment of the renal tissue following disturbed organogenesis. numerous deletion mouse models of developmental genes have been established presenting with anomalies of the kidneys resembling rhd, among these the knock-out of bmp4 and six2. here, we report on the first human mutations in bmp4 and six2 identified in children with rhd, among these three different mutations in bmp4 in five unrelated patients (ser91cys, thr116ser, asn150lys) and three different mutations in six2 also in five unrelated individuals (leu43phe, pro241leu, asp276asn). overexpression assays in zebrafish demonstrated that ventralization and dorsalization caused by bmp4 and six2 overexpression, respectively, could be diminished after overexpression of mutant constructs expressing the human mutations identified. morpholino knock-down of zebrafish bmp4 and six2.1 reveals specific roles of these genes for pronephric development, affecting the expression of wilms tumor-1 (wt1) and glomerular development. rna analysis of cos7 and hek293 transfected with different bmp4 constructs showed a lower level of mrna abundance in bmp4 mutants, indicating a possible negative feedback of the mutants on their own mrna expression and/or stability. nonreducing western analysis revealed that s91c-bmp4 forms alternative protein complexes as compared to wildtype-bmp4, due to the formation of extra disulfide bonds. these studies implicate six2 and bmp4 as important players in the development of the renal system, and suggest that defects in these proteins could affect kidney development at multiple stages leading to the congenital defects observed in rhd patients. apoptosis is important in normal renal development in which regulation of cell numbers is critical. studies have shown that apoptosis occurs in non-cystic tubules in pre-uremic pkd kidneys, thus providing the mechanism whereby expansion of cysts is accompanied by loss of normal nephrons. to date, it is unclear which initiating factors (intrinsic, through mitochondrial damage or extrinsic, through ligand activation of death receptors) are responsible for apoptosis in pkd and whether they are the same in ad-and arpkd. aim: to elucidate the sequence of activation of intracellular apoptotic pathway(s) in both ad-and arpkd. methods: proteins were extracted from tissues of human ad-and arpkd kidneys and normal adult (nhk) and fetal kidneys (hfk). quantitative western immunoblot analysis was carried out for 7 markers of intrinsic and extrinsic apoptosis. immunohistochemical staining for these markers was performed on tissue sections of the same kidneys. results: markers of extrinsic apoptotic pathways, caspases 8 and 10, were significantly increased in ar-and in adpkd tissue by comparison to nhk and hfk tissues. these increases were seen in early stages of adpkd and were more pronounced later in the disease. for the intrinsic pathway, caspase 9 and bid were increased in hfk tissue, but unchanged in ad-and arpkd tissue compared to nhk tissue. staining for caspase 9 was found in hfk, but was absent in all other kidney tissues. staining for caspase 8 was seen in early adpkd and endstage (es) adpkd as well as in es arpkd. caspase 3 was identified as the main executing caspase of fetal development and adpkd, but wasn't seen in arpkd, where caspase 7 predominated. conclusion: induction of extrinsic pathways of apoptosis predominates in pkd and occurs early in the disease process in adpkd, but only later in arpkd. intrinsic apoptosis predominates during development. intrauterine growth restriction (iugr) is a risk factor for an aggravated course of renal diseases in later life. the influence of postnatal factors, eg. accelerated catch-up growth, is not well understood. we therefore analysed the influence of postnatal nutrition after iugr on the developement of later renal inflammation and fibrosis in the rat. iugr was induced by low protein diet (8% vs. 20%) in pregnant wistar dams. litter size was reduced to 6 or 10 male animals in iugr (lp6, lp10) and control animals (np6, lp10), respectively. animals were sacrificed on day 70. mean arterial blood pressure was similar in all four groups. lp6 -(31.7±6.4 ml/h/100 g) and np6 animals (37.68±16.6 ml/h/100 g) showed reduction of endogen creatinine clearance by 50% (vs. np10and lp10) (p<0.001). renal mrna expression of il6 (5, 7 x), tgfβ1 (1, 5 x) , endothelin 1 (2, 7x) und osteopontin (2, 3 x) was significantly higher in lp6 than in np6. lp6 showed the highest glomerulosclerosis-score ((0.39±0.07) (vs. np6 (0.1±0.07), lp10 (0.09±0.02) and, np10 (0.03±0.02)) (p<0.01). as marker of extra cellular matrix expansion glomerular collagen-iv deposition was significantly higher in lp6 (17.8±6.3%) (vs. np6 (14.3±4.0%), lp10 (7.4±4.0%) and np10 (7.2±1.9%)) (p<0.01). postnatal nutrition modifies the consequences of iugr in the kidney. increased postnatal nutrition of the individual animal is associated with aggravated renal inflammation and fibrosis after iugr. unilateral renal agenesis (ura): how intensively do we need to investigate and follow-up? s. rhodes, a. watson nottingham university hospitals, children and young people's kidney unit, nottingham, united kingdom a single kidney is one of the commonest urinary tract abnormalities in the general population. concerns remain about long-term outcomes with a reduced nephron mass and hence intensity of investigations and duration of follow-up. we identified 52 cases with ura (ectopic and pelvic kidneys excluded) from our nephrourology database between 1985 and 2006. 38 (73%) occurred in males and 25 (48%) had left ura. 27 (52%) were detected antenatally with 12/27 (44%) recognised in the last 2 years. median age of detection for postnatal ura was 7 mths (range 0.25-179 mths) with uti (29%) as the main indication for ultrasound scan (uss). 60% patients were classified as simple ura with no associated abnormality and 40% as complex with problems such as vesicoureteric reflux (vur)(21%), hydronephrosis or scarring. all cases reviewed had uss which showed compensatory hypertrophy in 25/52 (48%). 29/52 (56%) had dmsa scan and 24/52 (46%) micturating cystogram. of those antenatally detected single kidneys with normal initial uss none had vur, scarring, hypertension or proteinuria. these patients were discharged from follow-up at the median age of 6 mths (range 1-122 mths). all complex cases have continued under follow-up. conclusions: our data suggest that the incidence of antenatally detected ura may be increasing. investigations need to be individualised depending upon the initial uss. the value of routine dmsa and mcug in simple cases is questioned. most of these patients can be discharged after adequate documentation of compensatory hypertrophy of the normal kidney, absence of proteinuria, normal blood pressure and renal function. autosomal dominant pdk (adpkd) in childhood j. crocker, p. wornell, p. acott iwk health centre/dalhousie univeristy, division of nephrology, halifax, canada autosomal dominant polycystic kidney disease (adpkd) is the most common genetic kidney disease with 1 in 6 adults progressing to end-stage renal disease (esrd). a program for intervention in childhood at presentation with adpkd was developed and instituted in 1992. our long-term objective is to modify clinical parameters that may contribute to risk of development of esrd in adulthood. seventy children with adpkd (average age 11.47 yr) were followed, of which 10 (14%) had nephromegaly +/-cysts on antenatal ultrasound. modifiable risk factors were common including hypertension (22%), hyperlipidemia (54%), and proteinuria (7%). ace inhibitors were first line therapy for proteinuria and/or hypertension. ace inhibitors may modify cyst progression so they have been made available to non-hypertensive children as well. most patients with hyperlipidemia responded to dietary intervention with one patient developing gallstones. in the past 5 years we have focused on renal calculi, as this is a known risk for a subgroup of adults with poor prognosis. we noted 14 patients (20%) have glycinuria, which is a precursor to oxaluria. four patients have passed calculi with two of these being diagnosed by genetic linkage analysis for adpkd without radiographic cysts present. cerebral vascular studies of 14 patients with severe headaches revealed two with vascular structural anomalies. all adolescent females received counseling regarding appropriate contraception and their pregnancy risks of hepatic cyst progression. an early intervention program targeting modifiable risk factors of adpkd patients during childhood and adolescence may modify adult renal failure risk in this population. background: techniques of chronic infant dialysis have evolved during the past 2 decades but morbidity and mortality are not well described. methods: a retrospective review was performed on 45 infants -18 months of age with end stage renal disease (esrd) treated with maintenance dialysis during the past 23 years. the experience was divided into era 1 (1983 era 1 ( -1994 (n=23) and era 2 (1995 era 2 ( -2006 . dialysis modality, morbidity, and long term survival were assessed and compared between the 2 eras. results: all patients were begun on peritoneal dialysis (pd). there were 22 males and 23 females. age at initiation of dialysis was 4, 5 months. the predominant diagnoses were dysplasia/obstructive uropathy (n=24), autosomal recessive polycystic kidney disease (arpkd) (n=10), congenital nephrotic syndrome (cns) (n=7), other (n=4). overall survival is 38% (17/45) with current age of survivors ranging from 5 months to 23 years. mortality between era 1=70% and era 2=55% was not significantly different. fifteen (33%) survived to receive a kidney transplant. overall median survival is 3.1 years (era 1=3.5 years; era 2=3.1 years; p=0.97). conclusions: although long term survival is possible in infants with esrd, mortality and morbidity remain high. improved technologies for automated pd should address the needs of the infant <6 kilograms. joubert syndrome and related disorders (jsrd) are a group of autosomal recessive conditions characterized by a complex neuroradiological malformation resembling a molar tooth on imaging. clinically, jsrd are characterized by overlapping phenotypes presenting neurological signs and variable involvement of other organs such as kidneys (mainly nephronophthisis -nph), retina and liver. seventy-nine italian jsrd patients from 63 unrelated families were recruited in pediatric nephrology and neurology centers. medical records and brain mri were reviewed. patients without chronic renal failure (crf) underwent measurement of their glomerular and tubular function, a ddavp urine concentration test and a renal ultrasound. retinal examination was performed in most patients. seven patients younger then 18 years had normal renal function but were not fully tested. of the remaining 72 cases, 44 had no evidence of renal disease, 16 had developed crf mostly in their second decade of life, and 9 were younger then 11 years of age and had urinary concentration defects, of whom 5 also had hyperechogenic kidneys by renal ultrasound. when comparing this latter group with age-matched jsrd patients, no other tubular function abnormality was detected. in 13 multiplex pedigrees, no discrepancies in renal involvement between affected family members was observed. retinal involvement was significantly associated with renal disease. conclusions. evidence of interstitial renal disease was observed in one third of italian patients with jsrd. renal involvement should always be suspected in these patients, particularly if they have evidence of retinal dysplasia or other family members with symptoms related to nph. these patients should be assessed with a urine concentration test. we examined the course of 49 children with 56 primary obstructive megaureters (pom) treated in our hospital from 1994-2006. pom occurred more often in boys (71%, p<0.01) and on the left side (67%, p<0.05). 43 pom (77%) were only treated conservatively. four underwent immediate surgery following the first mag3 renography. one of these was nephrectomized after unsuccessful urinary diversion and persistent renal hypertension. of the 52 kidneys primarily managed conservatively, 9 needed a ureterocystoneostomy later on due to increasing obstruction. surgical correction of pom required a mean of 15 days of hospitalization (incl. temporary urinary diversion, removal of catheters and treatment of complications). one child required surgical revision of early post-operative ureteric stenosis. urinary tract infections (uti) were a common complication (n=66, mean 1.3 per patient). as utis occurred mainly in infants, hospital admission was commonly required (45%). only 14 children never acquired a uti (29%). eight patients had a poor outcome as defined by partial kidney function <40% on the affected side (n=6), atrophy on final ultrasound (n=3) or nephrectomy (n=1). the most potent predictor of reduced unilateral kidney function was a small kidney present from birth. secondary kidney growth failure occurred only in one case. the initial degree of obstruction on renography, but not the degree of hydronephrosis or size of megaureter predicted outcome. also, prenatal diagnosis of pom, surgical treatment and the occurrence of utis showed no association with outcome. in summary, the long-term prognosis of pom appears favorable. adverse outcomes were more closely related to congenital kidney size deficit than to the degree of obstruction. surgical interventions and the high uti incidence led to significant hospitalization times. r. bhimma, m. adhikari, k. asharam university of kwazulu-natal, maternal and child health, durban, south africa background: steroid resistant (sr) forms of ns have a poorer outcome in blacks compared to other racial groups. methods: 223 children with srns 1-16 years old were analysed retrospectively for the period 1976-2004. treatment schedules included oral cyclophosphamide with prednisone only (n=90); prednisone on alternate days with methylprednisolone and oral cyclophosphamide (n=117); oral prednisone on alternate days, 3 doses of intravenous methylprednisolone on alternate days and monthly doses of intravenous cyclophosphamide (n=10) or cyclosporine adjusted to a trough level of 150-200 mg/ml (n=6). we compared the clinical, biochemical characteristics and outcome of these children using different forms of therapies. results: 183 (82.1%) underwent renal biopsy.84 (45.9%) were indian and 99 (54.1%) were black. 66 (36.1%) had minimal change ns, 66 (36.1%) had focal segmental glomerulosclerosis (fsgs), 15 (8.2%) a proliferative form of ns, and 36 (19.7%) had other forms of ns. 58/84 (69.0%) indian children biopsied were in complete remission and 29/40 (72.5%) with mcd who were treated with oral cyclophosphamide and prednisone only achieved complete remission. 32/40 (80%) indian children not biopsied who received only oral prednisone and cyclophosphamide achieved complete remission. 20/99 (20.2%) black children who were biopsied achieved complete remission. none of the eight black children who were not biopsied given only oral cyclophosphamide and prednisone achieved complete remission. conclusion: since 80% of indian children with srns responded to a trial of oral cyclophosphamide and prednisone but none of the black children did, we propose the use of oral cyclophosphamide therapy in non black children before embarking on renal biopsy. mj. kemper, c. moeller, n. rink, m. van husen, de. müller-wiefel university of hamburg, pediatric nephrology, hamburg, germany introduction: ssns is often complicated by a refractory clinical course with frequent relapses and steroid dependency despite aggressive alternative immunosuppressive regimens. since recent immunological findings suggest an alteration of not only t-but also b-cell immunity in ssns (kemper 2003 (kemper , 2004 we hypothesized that that immunological targeting of b-cells with antibodies directed against cd20 (rituximab) is able to maintain remission (rm) in treatment refractory patients with ssns methods: a total of six patients with complicated courses of ssns had severe steroid-dependency and toxicity. all patients had previously been treated with cyclophosphamide, two patients relapsed on maintenance therapy with cyclosporine, one relapsed on additional levamisole and one on mmf. treatment was initiated at a median age of 13 (range 11-15.6) years and rtx was given at steroid induced rm at a dose of 4x 375 mg/m 2 bsa within 4 weeks. results: a complete b-cell depletion was induced for at least 5 months in all patients. rm could be maintained in all patients and steroid treatment could be discontinued after a median of 2.5 months (range 1-4.6) . also csa could be discontinued in the two patients on maintenance treatment. at current follow-up of 11.5 months (range 5-23.5) the two patients after csa discontinuation relapsed after 8.7 and 12.7 months, respectively, but responded after steroid induced rm-to a second course of rtx. all other patients remained in remission off treatment so far. no significant clinical side effects were noted. conclusion: in summary and conclusion, rtx seems to be a therapeutic option in complicated ssns. long-term follow-up and future prospective studies are necessary to further define the role of rtx in the treatment of refractory steroid sensitive nephrotic syndrome. efficient control of secondary hyperparathyroidism can be achieved by calcimimetics. they increase calcium sensing receptor (car) sensitivity to extracellular calcium. in r-568-treated uremic rats, proteinuria has been significantly reduced by calcimimetics. thus, we examined the potential direct effect of r-568 on podocytes. the car was expressed in cultured immortalized podocytes (quantative rtpcr, western blot) and in podocytes obtained from healthy and subtotally nephrectomized rats (immunohistochemistry). glomerular car abundance was increased by uremia and r-568. the car colocalized with the plasma membrane and intracellular filaments in cultured podocytes, but not with the caveolin 1-and 2-rich membrane fractions. we then studied the effect of r-568 on the mitogen-activated protein kinase (mapk) family. jnk was not activated. p38 showed a biphasic response pattern, whereas erk1/2 (and further downstream, p90 ribosomal s6 kinase) showed dose-(1-50 nmol/l) and time-dependent phosphorylation, resulting in the activation of the transcription factor camp response element binding protein (creb). creb phosphorylation induced bcl-xl expression and bad phosphorylation, both of which have prosurvival activity. specificity was confirmed by addition of mek 1/2 inhibitor u0126, which completely blocked r-568-induced creb phosphorylation. facs analysis revealed a significant, 50% decrease in puromycin-induced apoptosis in podocytes treated with r-568 for 48, 60 and 72 hrs. in conclusion, calcimimetics induced prosurvival gene expression in podocytes via mapk, protecting them from apoptosis. calcimimetics may have a direct renoprotective action beyond control of hyperparathyroidism in chronic kidney disease patients. we report our experience with plasma therapy in a family of three sisters from whom two are homozygous twins (patients b and c), presenting a missense mutation of the exon 23 of the human complement factor h gene (hf-1). the factor h concentration has always remained normal and no systemic complement activation has ever been detected. in a ten years period, the followings have been observed: 1/ no use of plasma exchange lead to immediate esrf of native kidneys (patient a); 2) conventional plasma therapy (10 sessions at presentation followed by repeated 10 ml/kg plasma infusions when relapse of hemolysis and thrombopenia) could not impede esrf (patient b); 3) the use of intensive pe at presentation (daily pe (40 ml/kg ffp until plasma creatinine normalization followed by one pe/2w indefinitely) lead to a normal gfr 5 years after presentation despite 2 relapses (patient c); 4/ no prophylactic pe for tx lead to immediate hus relapse and transplant loss (patient 1); 5) prophylactic pe allowed a successful tx in patient b (pl. creat 110 mcmol/l after 5 years); 6) early and intensive pe allowed complete normalization of several hus relapses after tx (patient b). conclusions: in fh mutation-related atypical hus, 1) intensive and indefinitely prolonged pe can allow a normal function of native kidney at long term; 2) prophylactic pe allows successful kidney tx; 3) early and intensive pe allow reversion of hus relapse after tx. the success of plasma therapy is bound to the followings: a/ the use of pe and not plasma infusion. b/ the prolongation of daily pe after normalization of hemolysis parameters, and further prophylactic pe. c/ the use of pe prophylaxis from before tx. d/ a minimum pes frequency of one/week in case of prophylactic treatment for tx. e/ immediate intensification of pe frequency in case of relapse. objectives of study: heparan sulfates (hss) are highly polyanionic sugar chains in the glomerular basement membrane (gbm) and have been reported to play an important role in the chargeselective permeability of the kidney. alterations in hs expression have been reported in a number of renal pathologies. in this study, we evaluated if degradation of hs in the gbm resulted in proteinuria in rats, using a controlled in vivo approach. methods: heparinase iii and neuraminidase were injected i. v. in 2-month old wistar rats at t=0 hr and t=8 hr, and kidneys were removed at t=24 hr. urine samples were taken at various time points. cryosections were stained for hs using specific antibodies, and for hs stubs (generated by heparinase). in addition, hs was evaluated at the electron microscopical level. neuraminic acid expression was analysed by peanut agglutinin lectin. the hs content in urinary samples was evaluated by agarose gel electrophoresis. urinary neuraminic acid was studied by an enzymatic colorimetric assay. presence of urinary albumin (proteinuria) was investigated by sds-page and by a competition elisa. results: injection with heparinase iii resulted in an almost complete absence of glomerular hs staining. cupromeronic blue staining was also greatly reduced in the gbm, further indicating that hs was largely degraded. staining for the hs proteoglycan core protein agrin was unaltered. in the urine a strong increase in hs was found, already at the first point in time of urine collection (2 hr after the first injection). however, no urinary albumin or other proteins could be detected at any point in time analysed. injection of rats with neuraminidase resulted in a major increase of albumin in the urine. conclusion: in conclusion, removal of hs from the gbm does not result in acute albuminuria, whereas removal of neuraminic acids does. introduction and methods: 192 children undergoing deceased (156) or living (36) donor kidney transplantation were randomized to receive tacrolimus, azathioprine, steroids and two doses of basiliximab (tas+b) or tacrolimus, azathioprine and steroids(tas). previously reported six month follow-up biopsy-proven acute rejection rates were 19.2% (tas+b) and 20.4% (tas). patient survival was 100% and graft survival 95% in both arms (am j transplant 2006; 6: 1666-72) . in this investigator-driven follow-up study individual outcome data were submitted annually to the coordinating centre. results: two year follow-up data were obtained for 144 (87.8%) of the 164 who completed the six month study. there was one death in the tas group occurring at month 20. there were 5 graft losses in the tas+b arm and 9 in the tas arm. all 5 graft losses in the tas+b arm occurred within the first 6 months. kaplan-meier estimates of 2 year graft survival were94.9% for tas+b and 89.5% for tas (p=0.28 breslow generalised wilcoxon test). episodes of biopsy proven acute rejection occurred in 23 in tas+b and 26 in tas, kaplan-meier estimates of freedom from rejection being 76.1% and 69.6% respectively (p=0.49). renal function did not differ significantly between the two arms; the median (iqr) plasma creatinine levels were 90 (74-113) in tas+b and 96 (77-115) in tas (p=0.94). similarly there was no evidence of a difference in either systolic or diastolic blood pressure between the two arms. there was one case of b cell ptld in the tas+b arm at 11 months in addition to two cases in the tas arm previously reported in the 6 month study. conclusions: the addition of basiliximab to a regimen of tacrolimus, azathioprine and steroids does not appear to result in an improvement in either acute rejection rate or graft survival at two year follow-up. further data collection is ongoing. chronic renal dysfunction is a major complication after heart transplantation (htx). the pathophysiology is not yet fully understood but is thought to be in part due to calcineurin inhibitor (cni) toxicity, and reducing cni exposure has become one of the main strategies aimed at ameliorating renal outcome in htx recipients. we previously reported a significant improvement of renal function in 14 htx children with biopsy-proven cni nephrotoxicity and chronic renal failure, 1 year after the reduction of cni dosage with a concomitant replacement of azathioprine by mycophenolate mofetil. we ought to determine whether this improvement was persistent after 3 years of follow-up, despite the histological lesions of chronic cni nephrotoxicity. gfr evaluated by annual inulin clearance had improved from a mean of 46.5±9.6 ml/min/1.73 m 2 (range 34-60) at time of the switch to 77.6±6.0 ml/min/1.73 m 2 (range 54-102) (p=0.019) one year after (67% improvement), and remained stable at 76.4±18.2 ml/min/1.73 m 2 (range 50-102) (p=0.76) 3 years after the switch. maximal urinary osmolality followed the same increase profile from 559±103 mosm/kg before the switch to 762±122 at one year and 736±154 after 3 years (p=0.64). meanwhile, the occurrence of serious adverse events such as infectious episodes, acute rejection and chronic allograft dysfunction as assessed by clinical examination, echocardiography and endomyocardial biopsies were not different from a control group of patients whose treatment was unchanged. no malignancy was observed in either group. in conclusion, reduction of cni dosage and replacement of azathioprine by mycophenolate mofetil lead to a safe and long-lasting improvement of renal function in children with heart transplants and cni-induced nephropathy. previous studies have demonstrated reduced bone mineral density (bmd) in some patients with idiopathic hypercalciuria (ih). reduced bmd during childhood may impact adult peak bone mass. bisphosphonates employed in adults with ih and reduced bmd resulted in conflicting outcomes. we evaluated the effects of oral bisphosphonate, alendronate (ale), in 3 patients with persistent ih and reduced bmd. patients presented at ages 6, 12, 13 yr, with hematuria/dysuria, 2 had recurrent urolithiasis, and all had ih (uca >4 mg/kg/24 hr). despite maximal traditional rx with low na/high k diet, thiazides, k-citrate, ih persisted (5.6-12 mg/kg/24 hr). at ages 10, 16 and 14.5 yr, dxa showed reduced bmd, and ale 10, 40 and 70 mg/once weekly was given for 15, 7 and 18 months, respectively. after 6 months of ale, uca decreased significantly compared to baseline (mean±sd, 3.0±1.9 vs. 6.3±1.8 mg/kg/24 hr, p<0.05). compared to baseline, bmd z scores 1 year after starting ale improved at the spine (-1.1±0.4 vs. -2.3±0.6, p<0.05) and hip (-1.9±0.3 vs. -2.3±0.2) . the decline in uca during ale rx correlated with the increased bmd z scores in the spine (r=-0.98, p=0.01) and hip (r=-0.93, p<0.05). height z scores, serum creatinine, ca, p, electrolytes and pth remained normal throughout the rx period and no further hematuria or new stones occured. in summary, ale normalized uca previously resistant to traditional rx, eliminated urinary symptoms and improved reduced bmd in children with ih. the use of a single oral weekly dose appears adequate and safe. larger prospective studies are needed to confirm these preliminary results. in addition to its classical role in the regulation of calcium (ca) and phosphate (po 4 ) homeostasis, vitamin d has important immunomodulatory and anti-inflammatory effects, that in turn can influence atherosclerotic vascular disease. we studied the impact of vitamin d levels and inflammation on vascular structure and function in children on dialysis. 59 children (age 13.4±4.1 yrs) on dialysis (mean duration 1.1±0.9 yrs) were studied. all children received 1α-hydroxyvitamin d 3 (alfacalcidol) . cumulative data on ca, po 4 and pth, doses of po 4binders and alfacalcidol were recorded.1, 25-dihydroxyvitamin d 3 (vit d) and high-sensitivity crp (hs-crp) levels were measured by 125 i radioimmunoassay and elisa respectively. all children had carotid intima-media thickness (cimt), pulse-wave velocity and cardiac ct for coronary calcification. 23 (39%) children had vit d deficiency (levels<40 pmol/l), 25 (42%) hadnormal levels (40±150 pmol/l) and 11 (18%) had high levels (>150 pmol/l). vit d positively correlated with serum ca, caxpo 4 and alkaline phosphatase. both cimt and calcification showed a bimodal distributionpatients with vit d levels <40 or >150 pmol/l were significantly more likely to have calcification or raised imt than those with vit d levels in the normal range. hs-crp levels independently predicted cardiac calcification (p=0.02) but not cimt. there was a strong inverse correlation between vit d levels and hs-crp (p<0.0001, r=-0.69). patients with vitamin d levels<40 pmol/l and hs-crp levels>10 mg/l had 6-fold greater calcification scores than subjects below these cutoffs. in conclusion, vit d deficiency is common despite treatment in children on dialysis. vit d may be an important mediator of vascular damage both through its hypercalcaemic and anti-inflammatory actions. severe growth failure remains one of the challenging problems in the care of children suffering from chronic renal failure (crf). although, rhgh has been proven to increase final adult height in prepubertal crf patients only limited data on its efficacy in the pubertal age-range are available. in addition, the impact of the underlying renal disease and the mode of renal replacement therapy on final height in these patients remain unclear. we report on final height data of 240 (47 female) severely growth-retarded crf patients (standardized height <-2 sds; database: kigs medical outcomes, pfizer). mean age at start of rhgh therapy was 13.7±3.0 years, standardized height was -3.6±1.2 sds and duration rhgh therapy was 4.6±2.5 years (range 1.0 to 14.2 years). at baseline 45% of the patients were on conservative treatment, 28% were on dialysis and 27% had a functioning renal allograft. in the whole study population mean standardized height was increased in the first treatment year and at attainment of final adult height by +0.4 sds and +1.2 sds, respectively (each p<0.0001 vs. baseline). prepubertal children aged less than 12 years at start of rhgh therapy showed the best growth response (+1.5 sds). in pubertal patients mean increase in standardized height was +1.2 sds, whereas growth response in patients with delayed onset of puberty (>+2 sd) was significantly lower (+0.8 sds; p=0.039 vs. other groups). the duration of rhgh therapy was positively associated with cumulative height gain. growth response was significantly lower in patients on long-term dialysis and in patients with nephropathic cystinosis. conclusion: rhgh therapy in severely growth retarded prepubertal and pubertal crf patients results in an increased final adult height. growth response is diminished in crf patients with markedly delayed onset of puberty. tightly regulated rankl/opg system is essential for normal bone remodelling. however, the exact roles of those osteogenic markers in uremic bone disease have yet to be defined. we therefore assessed the potential relationship of the rankl/opg system in bone biopsy proven secondary hyperparathyroidism (hpt) in dialyzed children. methods: 40 patients aged 13±1years were on ccpd for 14±4 months. s-ca, p, alk p'tase, pth, opg and rankl levels were measured. bone biopsies were obtained after double tetracycline labeling and none of the patients were treated with vitamin d for four weeks prior to biopsy. results: s-ca levels were 9.2±0.7 mg/dl, p: 6.1±1.5 mg/dl, alk p-tase: 401±297 u/l, pth: 898±415 pg/ml. bone biopsy findings revealed high turnover bone disease in 31 patients, 9 patients had normal bone formation rate (bfr). mean opg and rankl levels were 4.46±1.46 and 0.66±0.81 pmol/l, respectively (reference control=opg: 1.8; rankl: 0.42). opg correlated with bfr (r=0.473, p<0.01) and adjusted apposition rate (r=0.42, p<0.01), while inversely correlated with osteoid maturation time (omt) (r=-0.34, p<0.03) and mineralization lag time (r=-0.45, p<0.01). rankl/opg ratio was negatively correlated with mineral apposition rate (r=-0.35, p<0.03) and positively with omt (r=0.31, p<0.05). pth was correlated with bfr (r=0.40, p<0.01) and resorption area (r=0, 54, p<0.01), but not with any mineralization markers. there were no correlations between pth and opg or rankl. conclusion: opg, in contrast to rankl, exerts a dual effect on the skeleton by promoting mineralization and increasing bfr. these osteogenic markers might be of benefit in characterizing the turnover, mineralization and volume of the skeletal lesions of secondary hpt as recently recommended by kdigo. "sevcan bakkaloglu was supported by tübitak (scientific and technological research council of turkey). this study was supported by usphs grants dk-35423, dk-67563 and mo1-rr00865. " pth values are widely used to guide therapy for renal osteodystrophy in patients treated with maintenance dialysis yet target values are based on cross-sectional studies and discrepancies between bone formation rates (bfr) and pth have been described during intermittent calcitriol rx. thus, we evaluated the relationship between serum biochemical parameters and bone turnover during treatment with intermittent vitamin d sterols. 60 patients aged 13±1 yrs with biochemical and bone biopsy (bbx) proven 2 nd hpt received 8 months of vitamin d (1, 25d 3 or 1d 2 ) given in twice weekly oral dosing and phosphate binders. dose of vitamin d was titrated upwards monthly to maintain 1 st pth-ima(nichols r ) levels between 300-400 pg/ml. bbx was then repeated. s-ca, p, alk p-tase and pth by 1 st and 2 nd pth-imas were obtained monthly throughout therapy. baseline values were: p: 6.2±0.1 mg/dl, ca: 9.2±0.1 mg/dl, alk p-tase: 397±36 iu/l, 1 st pth-ima 940±55 pg/ml, 2 nd pth-ima: 510±41 pg/ml. final values were: p: 5.5±0.1mg/dl, ca: 9.4±0.1 mg/dl, alk p-tase: 324±35 iu/l, 1 st pth-ima: 565±43 pg/ml, and 2 nd pth-ima: 280±27. bone formation rate (bfr/bs) decreased from 114±8 to 55±5 um 2 /mm 2 /d (nl: 10-73.4); 72% achieved normal bone turnover. 2 nd pth-ima values were 40-50% lower than 1 st pth-ima levels; there was no difference in predictive capability of the two assays. patients achieving normal bfr/bs had 1 st pth-ima values of 508±44 pg/ml. the sensitivity, specificity and ppv of a 1 st pth-ima range of 300-600 pg/ml for normal bfr/bs were 70% (95% ci: 50-86%), 60% (26-88%), and 83% (61-95%) respectively. during therapy with intermittent vitamin d sterols, maintaining pth levels higher than currently recommended results in normal bfr/bs and prevents adynamic bone. maternal diabetes will induce abroad array of congenital malformation. consistently with these hypotheses, we observed the defects of renal development of diabetic pregnancy from late phase of embryogenesis to postnatal period in animal model (c57bl/6j mice). histological analysis of phenotypes revealed decreased glomerular numbers, glomerular hypertrophy and hypercellularity, as well as renal tubular detachment in sequential late phase of kidney development in the offspring of diabetic female mice. tunel assay showed signficinatly increased cell apoptosis in fetal kidneys of hyperglycemic group. rt-pcr and fish study of kidneys of fetal and newborn mice revealed that gdnf and early growth response alpha (egr-α) are two of crucial genes inhibited in hyperglycemic ambience. in human, we presumed that children of gestational hyperglycemic mothers have the same defects of renal development as our animal model similarly, thus we measured and compared echogram of kidney/liver echoenic ratio in 76 children born to gestational hyperglycemic mothers and 240 health children. interestingly, our human ultrasonic study indicated that after age of 6 months, the diabetic children had increased echogenic ratio of kidney/liver than the healthy age matched children (p<0.01). we also found that 26.3% of diabetic children had nonobstructive hydronephrosis. this simple sonographic procedure may provide a permissive was for clinicians to obtain the basis of long-lasting follow-up of these high-risk children as early as possible. keywords: diabetic embryopathy, renal development, glial cell line-derived neurotrophic factor, early growth response alpha, renal sonogram. genetic inactivation of spry 1 in mice results in increased number of ub branches and expanded gdnf, c-ret and wnt-11 expression domains (basson et al., dev. cell, 2005) , indicating that spry1 is a negative regulator of the gdnf-ret-wnt11 pathway. ang ii induced ub branching morphogenesis, partly via stimulation of egfr tyrosine kinase activity (yosypiv et al. jasn, 2006) . we tested the hypothesis that ang ii stimulates the gdnf-ret pathway via repression of spry1. cd1 mice metanephroi were dissected on embryonic (e) day e12.5, grown on filters in the presence or absence of ang ii (10 -5 m, n=5/group) for 24 hours and subjected to whole-mount ish with digoexigenin-labelled spry1, c-ret, wnt-11 and gdnf crna probes. spry1 mrna was expressed in ub branches and in condensing mesenchyme. c-ret and wnt-11 were expressed in ub tips, and gdnf-in the metanephron mesenchyme. ang ii downregulated spry1 expression in the ub. in contrast, c-ret and wnt-11 were induced by ang ii in the ub tip cells. gdnf expression in the mesenchyme was also upregulated by ang ii. in addition, ang ii stimulated ub tip cell proliferation, as determined by in vivo brdu in corporation (28.5±2.4 vs.9.7±1.2; p<0.001) compared to control. these findings suggest a model in which ang ii-mediated inhibition of spry1 gene expression releases. ret tyrosine kinase activity leading to upregulation of c-ret and its downstream target gene, wnt-11. enhanced wnt-11 expression, in turn, induces gdnf in the adjacent mesenchyme. this causes focal bursts of ub tip cell proliferation and branching. these results support the hypothesis that abnormal collecting system development in angiotensinogen, renin, ace or at1-deficient mice is at least partly due to aberrant regulation of the ub branching morphogenesis program. objectives of study: nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction (iugr), leading to a low nephron endowment. our previous studies have shown that offspring born to mothers supplied low protein diets during pregnancy have fewer glomeruli than normal at birth in sd rats. the aim of this study was to identify the possible pathogenesis of abnormal nephrogenesis and decreased glomerular number in iugr by comparative proteomic approach. methods: iugr was induced in sd rats by isocaloric protein restriction in pregnant dams. kidney proteins were obtained from 6 neonatal normal rats (control group) and 8 iugr rats (iugr group) respectively. a series methods including 2-de, silver staining, mass spectrometry and database searching were used. the 2-de test was repeated three times in each group. results: after silver staining, the 2-de image analysis detected average 730±58 spots in iugr group and 711±73 spots in control group. the average matched rate was 86% and 81% respectively. the differential proteomic expression analysis found eleven protein spots were expressed only in iugr group and one in control group. seven protein spots were up-regulated more than 5 folds and two down-regulated more than 5 folds in iugr group compared with those in control group. these 21 protein spots were preliminarily identified, which were structural constituents of cytoskeleton including vimentin, cytokeratin 10, perlecan and b-actin, transcriptional factors including splicing factor, rho gdp dissociation inhibitor alpha and cell division proteinkinase 2, enzymes including retinal dehydrogenase1, transketolase and so on. conclusions: data from this study may provide, at least partly, valuable experimental evidence of proteins involved in the pathogenesis of abnormal nephrogenesis and decreased glomerular number in iugr. the aim of the study is to describe the natural history of tcf2/hepatocyte nuclear factor-1 beta linked disease in children. prenatal and postnatal renal evolution and extrarenal manifestations of 33 patients were reported. thirty one had prenatal diagnosis of developmental nephropathy: bilateral foetal hyperechogenic kidneys or a hyperechogenic kidney with a controlateral multicystic dysplastic kidney. 64% had cysts. the mean prenatal renal length was normal (0, 29 sd) . intrauterine growth was normal with median birth weight of 3.1 kg (range 1.6-3.6) and 30% were small for gestational age. after a mean follow-up of 79 months, the renal growth was impaired with a mean renal size of -0.78 sd. patients with a solitary functioning kidney showed no compensatory hypertrophy. thirty one patients developed bilateral nephropathy and 2 isolated unilateral multicystic kidney. twenty eight patients had cysts, mainly cortical bilateral microcysts. the mean gfr was 73.19±30.43 ml/min/sc. sixteen patients had stage 1 chronic kidney disease (ckd), four were classified as stage 2, eleven as stage 3 or 4 ckd and two were diagnosed with end stage renal failure. annual decline of the glomerular filtration rate was 3.4 ml/min. extrarenal manifestations included 3 patients with diabetes, one with exocrine pancreatic insufficiency, one with pancreatic hypoplasia without clinical symptoms and 4 with cholestasis. we found a complete heterozygous deletion of the tcf2 gene in 20 patients and nine different point mutations. three patients had the g76c mutation, 2 with unilateral mcdk and 1 with bilateral severe hypoplasia leading to early renal dysfunction. tcf2 gene anomalies are associated with low renal function decline but in some patients end stage renal failure appeared early in life. long term follow-up is needed to determine the incidence of extrarenal symptoms, particularly diabetes. objectives: although it has been observed more than one hundred years ago that the urinary tract is very resistant to infection, its antimicrobial mechanisms have not yet been systematically characterized. we sought to elucidate the expression and relevance of the antimicrobial peptide cathelicidin in this area. methods: in order to investigate the expression of cathelicidin in health, urine samples from healthy children, pieces of healthy renal tissue, and cell cultures were analyzed. to evaluate the expression of cathelicidin during infection, urine samples from children with urinary tract infection, a mouse model of ascendant pyelonephritis and cell culture experiments were employed. the relevance of cathelicidin production was tested by bacterial challenge of cathelicidin-deficient and neutropenic mice. in addition, we studied the in vitro effects of cathelicidin on the growth and multicellular behavior of bacteria as well as we tested sensitivity of clinical e. coli strains to the peptide. results: cathelicidin is expressed by epithelial cells of healthy urinary tract and excreted into urine in low concentrations. during urinary tract infection, the secretion of cathelicidin by epithelial cells significantly increases within minutes. invading neutrophils are the source of the second wave of cathelicidin. epithelial cathelicidin protects the urinary tract against bacterial infection while neutrophil-derived cathelicidin influences the severity of infection. cathelicidin displays multiple effects on bacteria. low concentrations of cathelicidin inhibit multicellular behavior, e. g. biofilm formation of e. coli, and high peptide concentrations kill bacteria. bacteria resistant to cathelicidin have an increased ability to invade the urinary tract. conclusion: the antimicrobial peptide cathelicidin is a key factor of the mucosal immunity of the urinary tract. the predictive value of procalcitonine (pct) plasma level for renal scarring after an acute pyelonephritis (apn) is still debated. during apn, the bacterial lipopolysaccharide of the membranes induce the release of tnf, il1 and il6. these cytokines lead to inflammation syndrome and fibrosis sequellae resulting from cell apoptosis induced by nitric oxide (no) release that is catalysed by no-synthase. the aim of this work was to clarify the physiological role of pct in renal parenchyma apoptosis and fibrosis caused by apn. we conducted a prospective study in children with a first apn episode (fever>38.5c°, crp>20 mg/l, monomicrobial urine positive culture>10.5 fcu/ml). we excluded patients with any concomitant infection, renal dysplasia or obstructive uropathy or grade 4-5 vur 133 children were enrolled (age 37.2 m, median 17 m). on admission, pct, crp and phospholipase a2 (pla2) were quantified in serum. scintigraphy with 99m tc-dmsa was performed on day 4 and 9 months later in case of initial abnormalities. fisher's test was performed and statistical significance was defined as p<0.05. results: on day 4, 107 (79%) presented renal parenchyma alterations, at 9 m 57 underwent control scan and 17 (28%) had renal scars. pla2 and pct levels were correlated with early dmsa lesion but not with renal scars at 9m. paradoxically, initial pct level was significantly lower in the presence of renal scars (4.19 vs 7.59 ng/ml, p<0.01). significant pct increase was observed in favourable progress (recovery 7.55 vs aggravation 3.34 ng/ml, p<0.01) and no difference between recovery and improvement evolution. these results suggest the protective effect of pct against apoptosis resulting from down-regulation of nitric oxide release; so high pct values could be interpreted with caution in apn. acute pyelonephritis (apn) may lead to renal scarring with later risk of hypertension and renal insufficiency. the aims of this study were to analyse prospectively renal scars progression with time and their impact on renal growth. methods: 52 patients (pts), aged from 0 to 18 years who presented scars on dmsa at 6 months after apn were included. in these children a second dmsa was done after 3 years. evolution of scars was analyzed following pre-established criteria independently by 3 observers. scar progression was classified as follows: 0=no change, 1=partial improvement, 3=total resolution. in addition a renal ultrasound was repeated to assess kidney growth using z-score. results: 104 renal units (52 pts: 32 f, 22 m) were studied. the incidence of vesicoureteral reflux (vur) was 34.6% (18/52). per renal units, vur were observed in 27/104 (26%); (51% vur grade (g) i, ii and 49% g iii, iv). there were 91 scars observed 6 month after apn which evolution over 3 years was as follow: 0=26% (24/91), 1=65% (59/91) and 2=9% (8/91). incidence of vur was higher in children presenting 3 scars; 5/7 (71%) against 12/45 (26%) in those with 1 or 2 scars. to identify factors interfering with renal growth, we analyzed potential confounding variables using robust linear regression. z-score was worsened with increased number of scars observed at 6 month after apn p<0.001) and improved with disappearance of vur (0.89 ci 0.001-1.7; p<0.05). conclusion: between 6 month and three years after apn, 82% of scars improved. in our population, the number of scars secondary to pna was the most important factor affecting renal growth. the second prognosis criterion was the correction of vur. prevention of pna and rapid treatment to avoid kidney scars seems to be the essential aim to preserve optimal kidney growth. v. smolkin 1, 2 , r. halevy 1, 2 , w. sakran 1, 4 , y. kennes 3 , a. koren 1, 4 1 ha'emek medical center, pediatric b, afula, israel 2 ha'emek medical center, pediatric nephrology unit, afula, israel 3 ha'emek medical center, bacteriology and microbiology laboratory, afula, israel 4 the ruth and baruch rappaport school of medicine, haifa, israel febrile urinary tract infection (uti) is a relatively common infection disease in childhood. children consider at risk for uti commonly receive prophylactic antibiotics to prevent recurrence of this urinary tract disease because of the risk of kidney scarring, which may lead to complications such as hypertension or end-stage renal disease. compliance with antibiotic prophylaxis after uti was assessed in 69 children, using a parent questionnaire and a urine test for antibacterial substances. thirty six children (1 st group) received prophylactic treatment during the period of 4 months (range 3-7months) and the other 34 patients (2 nd group) received antibiotic prophylaxis for a longer duration (12 months, range 11-16 months). in the first group of patients, 35 (98%) of parents reported giving the antibiotics every day in comparison with 30 (88%) in the 2 nd group. twenty nine (81%) of urine tests were positive for antibacterial substances in the 1 st group but only 16 (47%) in the second group. in the 1 st group of patients the difference in recurrent infection between regular takers and non-takers was statistically highly significant. no significant difference was found in recurrent uti rate in takers and non-takers in the 2 nd group. failure to understand the reason for prophylaxis and forgetfulness was found to be a main reason for non-compliance. imaging studies evaluating the kidneys and urinary tract are performed routinely after a febrile uti. evidence of their value in changing management or affecting long term outcome is limited. as part of a multicentre, rct (iris 1) evaluating different antibiotic regimes in the treatment of first febrile urinary tract infections, we undertook as a secondary objective, an evaluation of the diagnostic protocol. the imaging modalities (ultrasound, dmsa scintigraphy within 10 days and voiding cystogram within 1-2 months) were assessed for their ability to predict long term parenchymal damage. 337 children of 2 years of age or less at the time of investigation and who had normal renal function and antenatal ultrasound, were considered suitable for analysis of the diagnostic course. us was performed in 336 children with 288 (86%) normal, minor changes were noted in the remainder, apart from 1 case requiring a change in management in the form of a pyeloplasty for pelvi-ureteric obstruction. the cystourethrogram was performed in 323 of the children with 65 (20%) demonstrating vur. the cystogram was a poor predictor of long term damage, being positive for reflux in only 17 of the 39 children who subsequently developed scarring. an acute dmsa scan performed in all children, exhibited findings consistent with acute pyelonephritis in 212 (63%). a repeat dmsa scan at 12 months in those with evidence of acute pyelonephritis demonstrated a scarring rate of 24%. the data did not demonstrate the clinical efficacy of routinely performing scintigraphy in the acute phase or a cystourethrogram. our recommendations for a reasonable diagnostic work up in small children with their first episode of uti are 1) performance of a scintigram 6 months following the acute infective episode, and 2) close surveillance to identify eventual recidivists. introduction: focal segmental glomerulosclerosis (fsgs) has a high recurrence rate after renal transplantation (rtx). recurrence can lead to tx loss. disease recurrence (dr) seems to be influenced by genetic background. methods: 77 patients with childhood onset of biopsy proven fsgs who were transplanted were evaluated. genetic investigations of the nphs2 gene were done in 46 patients (59.7%). results: mean age at diagnosis was 6.06 years. first renal transplantation was performed at age of 12.3 years.18 patients received a living related (lrd), 55 a deceased donor (dd) graft. 4 patients data under investigation. 31 p (40.3%) recurred after a mean time of 6, 3 years, 5 p with lrd (27.8%) , 25 p with a dd (45.5%). 23 patients (29.9%) lost their graft after 6, 8 years, 15 patients due to recurrence. a second rtx was performed in 16 patients, 11 with dd, 2 with lrd, 3 patients data under investigation, with 71% dr. a third transplantation was performed in 7 patients and a fourth in one patient. screening for nphs2 mutations revealed 10 patients with mutation in the nphs2 gene, 9 homozygot, 1 heterozygot. all patients with a homozygote nphs2 mutation did not recur and only the one patient with a heterozygous mutation (1/10) recurred compared to 17/36 without a mutation (p<0.05). conclusion: living related transplantation was advantageous to decreased donor transplantation. patients with nphs2 mutations had a lower risk of recurrence after transplantation compared to patients without mutations. patients with fsgs should be screened for nphs2 mutations. objective: prospective ebv surveillance post tansplantation reduces incidence of acute rejection and risks of post transplant lymphoproliferative disorders (ptld). methods: prospective screening of ebv by polymerase chain reaction (pcr) and serology in all patients transplanted between 2003 -2006 . results: 27 patients transplanted between may 2003 and september 2006 . 22 were cadaveric and 5 live-related transplants. recepient ebv serology status was known but not on donors. basiliximab was used for induction and maintenance comprised of tacrolimus/azathioprine (aza) until 2004 and mycophenolate (mmf)/tacrolimus from 2004. all received corticosteroids. 17 had mmf/tacrolimus, 10 aza/tacrolimus. ebv screened within first week post transplant, weekly for a month, monthly for 6 months. when ebv pcr lv >5.0, mmf/aza was withdrawn, tacrolimus levels kept between 6-8 ng/ml. pcr/ serology is checked 2 weekly for 3 months, monthly for 6, until lv falls <5.0 and vca igg becomes positive. the mmf/aza is reintroduced. patients with ebv pcr lv <5.0 are kept on full immunosuppression while viral load and vca igg monitored. 17 ebv viraemia detected following prospective screening.1 was re-activation. 9 were symptomatic. onset varied 1 to 21.7 months post transplant (mean 4.3 months). 10 were on mmf/tacrolimus 7 received aza/tacrolimus. 12 had pcr lv>5.0 consequently maintained on tacrolimus an alternate day steroids for period of time. cmv patient and donor status was known and antiviral prophylaxis given to nonimmune. the use of antivirals made no impact on viral load. conclusion: no patient experienced acute rejection or ptld despite modification of therapy with our prospective screening programme. antivirals have no role in protecting or reducing viral load in already infected patients. graft attrition rate is highest in the first three months after renal transplantation. we analysed data in a recent cohort from all dutch centres for pediatric renal transplantation to determine incidence and causes of such early graft failure. methods: data from all pediatric renal transplants performed between 01-01-98 and 01-01-06 were analysed retrospectively. a common immunosuppressive protocol was used in all centres. thrombosis prophylaxis was given according to centre policy. early failure was determined as graft failure within 3 months after transplantation. prevalence of possible risk factors of graft failure identified by literature search were extracted from patient charts. data were analysed with univariate and multivariate logistic regression. results: the cohort consisted of 228 transplants. age of the recipients was 3-18 yrs (mean 10.9). there were 19 early graft failures (8.2%). major causes of graft failure were thrombosis (5.3%) and are(1.8%). univariate analysis identified an association of early failure with complications during surgery (or 10.0, p=0.00), cold ischemia time (or 1.1, p=0.026), side of graft donation (or 2.8, p=0.046) and diuresis in the first hour after transplantation (or 0.3, p=0.026). multivariate regression analysis showed that complications during surgery were associated with the risk of early failure (or 6.4, p=0.002), as were side of graft donation (or 5.7, p=0.015) and diuresis in the first hour after transplantation (or 0.3, p=0.038) . only the occurrence of complications during surgery was significantly associated with early graft failure due to thrombosis (or 13.6, p=0.006). conclusion: thrombosis is the major cause of early graft failure after renal transplantation in dutch children, especially after surgical complications. prospective studies are needed to determine whether early failure can be decreased by more rigorous prophylaxis. background: interleukin (il)-1 is a major contributor to inflammation and cell death during ischemia-reperfusion (ir) injury and its deleterious effects are mediated mainly by nuclear factor-κb (nf-κb) activation. receptor binding and signalling of il-1 can be blocked by the il-1 receptor antagonist (il-1ra). the aim of our study was to characterize the effects of il-1ra administration on inflammation, apoptosis and infiltration in renal ir injury. methods: renal ischemia was induced in lewis rats (n=7/group) by clamping of the left renal artery for 45 min followed by reperfusion of 24 h or five days respectively, when kidney were removed for histological and molecular analysis. results: treatment with il-1ra ameliorated ischemic renal tissue injury and inflammatory infiltration. futhermore, the number of apoptotic tubular cells was lower in il-1ra treated animals 24 h after ischemia, which was paralleled by a bax/bcl-2 mrna ratio towards anti-apoptotic effect. il-1ra reduced the expression of monocyte chemoattractant protein-1 (mcp-1) mrna 24 h and 5 days and that of intracellular adhesion molecule-1 (icam-1) expression 24 h after reperfusion in the kidney. conclusions: our results indicate that il-1ra treatment ameliorates renal ir injury and this protective effect might be mediated by reduced induction of nf-κb mediated mcp-1, icam-1 and the decreased ratio between bax and bcl-2 mrna expression. k. satomura, y. santo osaka medical center for maternal and child health, pediatric nephrology and metabolism, izumi, japan many studies have reported that angiotensin-converting enzyme inhibitor (acei) and angiotensin receptor blocker (arb) show renoprotective effects in adult patients with acquired renal diseases. however, these effects have not been studied in children with renal hypoplasia or dysplasia (rhd). in this study, we explored the renoprotective effects of these drugs in children with rhd. patients and methods: participants of the study were patients with rhd aged less than 15 years. a follow-up for more than one year was conducted in our outpatient clinic. the patients had chronic renal failure, and had not received acei or arb in the past. the change of glomerular filtration rate (gfr) per year, urinary protein/creatinine (up/cr) ratio, serum potassium levels, and blood pressure before the treatment with trandolapril or candesartan were compared with those of one year after the treatment. the estimated gfr was calculated by the schwartz formula. wilcoxon rank sum test was applied to evaluate the statistical significance. results: eleven patients were eligible for this study. the mean age of the patients was 8.4±2.6 years and the estimated gfr was 57.3±9.0 ml/min/1.73 m 2 when trandolapril or candesartan was administered. the change in the estimated gfr for a year significantly improved after the treatment with trandolapril or candesartan compared with the pre-treatment period (-6.1±5.4 vs. 1.9±5.9 ml/min/1.73 m 2 /year, p=0.003). the up/cr ratio significantly decreased at one year after the treatment compared with that before the treatment (0.67±0.62 vs. 0.49±0.53, p=0.041). the blood pressure and serum potassium level showed no significant changes. conclusion: these data suggest that treatment with acel or arb has beneficial effects on the renal function in children with mild to moderate renal failure due to rhd. objective of the study: postischaemic arf is influenced by sex hormones. dehydroepiandrosterone (dhea) pretreatment diminishes postischemic injury. previously we demonstrated that after renal ischaemia-reperfusion (i-r) injury the expression and activity of na, k-atpase (nka) is impaired in male rats. here we tested the impact of dhea on postischaemic survival, renal damage, mrna and protein expression of nka. methods: left renal pedicles of dhea (4.0 mg/kg/day) and propylene glycol, as vehicle (pg) treated male rats (g dhea and g pg , respectively) were clamped for 55 min followed by 2 (t 2 ) and 24 (t 24 ) hours of reperfusion. survival rate, histological damage, serum creatinine (cn) and urea nitrogen (bun) were investigated. the mrna expression and protein level of nka α1 and β1 subunit were also determined. sham operated animals served as control. results: dhea treatment was associated with better postischemic survival (p<0.05 g dhea vs. g pg ). postischaemic cn and bun were higher and renal histology showed more rapid progression vs. controls, however there was no difference between g dhea and g pg groups. mrna expression of nka α1 subunit was higher in g dhea vs. g pg at every time points, however it was decreased in i-r groups vs. controls (p<0.05). similar changes were observed in nka α1 protein level (p<0.05, g dhea vs. g pg in controls, t 2 , t 24 ). mrna and protein expression of α1 subunit were different only at t 24 (p<0.05, g dhea vs. g pg ). conclusions: our study indicates that nka is more protected from the detrimental effects of i-r injury in dhea treated animals, which might be a contributing factor of improved postischaemic renal function and could help to preserve cell and organ homeostasis even in male animals. the work was supported by otka f048842-t37578, bolyai and semmelweis grants. objective of study: recently bnp has been identified as a useful cardiac marker for risk stratification in adults. whether bnp has a similar diagnostic potential in pediatric population with ckd has to be established. the aim of the study was to assess the value of bnp to predict the cardiac dysfunction in children with ckd. methods: to test this suggestion, the relationship between plasma concentrations of bnp, echocardiographic parameters and cardiovascular risk factors (lipid profile, hypertension, secondary hyperparathyreoidism) has been evaluated. a cohort group consisted of 46 children and young adults (35 pts mean age x=16.12±5.14 years; 11 controls mean age x=14.73±5.04years). out of 35 studied pts 24 children were with ckd stage 4 and 5 k/doqi (12 pts ckd stage 4; 12 dialyzed pts) and 11 transplanted subjects with stable graft function (gfr=1.17±0.7 ml/s/1.73 m 2 ). results: no association was found between bnp and gfr and/or s-creat (p=0.12; p=0.1; p=0.44). the highest bnp plasma levels have been found in dialyzed children (620.77 pg/ml; resp. 75.98 pg/ml in tx; resp. 51, 85 pg/ml in ckd stage 4 group) as compared to controls (35, 25 pg/ml p<0,001). bnp was independently related to left ventricular mass (r=0.84; p<0.001) as well as to ejection fraction (r=-0.6; p<0.001) and preload (r=0.78; p<0.001). significant correlation between bnp and hypertension (r=0.608; p<0.001) has been observed. more over, bnp correlated with ipth (r=0.37; p<0, 05) and diastolic dysfunction (r=0.61; p<0, 001). plasma bnp concentrations did not significantly differ before/after dialysis procedure (p=0.07). conclusions: bnp is a sensitive marker for cardiac dysfunction in ckd children. however, prospective studies in larger group of pts are needed to confirm our preliminary data. we have reviewed the data of 20 patients with nephropathic cystinosis (nc) followed in our department since 1987. overall, 2 patients have died during the follow-up period. the mean follow-up was 17,6±6,7 yrs (range 6, 8) . 13/20 patients have initiated dialysis and 10/20 received a cadaveric renal transplant. univariate analysis showed that the time to reach a serum creatinine value of 2 mg/dl was significantly associated with the patient's age at the last follow-up (o. r. 1, 3/yr; p<0.001), the age at the beginning of cysteamine (mea) treatment (o. r. 1, 3/yr; p=0.006), the dose of mea (o. r. 0, 99/g, p=0.035) and the use of ace-inhibitors (o. r. 0, 15; p=0.014). by multivariate analysis, only the period of treatment (or 1, 24, p=0.037) and therapy with ace-inhibitors (or 0, 16, p=0.041) were significantly associated with better outcome. similar results were obtained when assessing the time to dialysis. there was a significant correlation between the dose of mea with intra-leucocytic cystine levels (ilc). by univariate analysis, the dose of mea expressed in mg/m 2 correlated more with the outcome then the dose expressed in mg/kg. statural growth was significantly associated by multiple correlation analysis only with growth hormone (gh) treatment (p<0.05). altogether, these results indicate that the renal prognosis of nc has been improving over the past two decades. this improvement may not be solely attributable to the introduction of mea for the treatment of nc. our data suggest that the overall management of these patients has improved, including more efficient symptomatic treatment of the fanconi syndrome and the use of medications such as ace inhibitors and gh. background: the chronic kidney disease in children (ckid) cohort study, targeted to enroll 540 children aged 1-16 yrs with chronic kidney disease (ckd) by estimated gfr (egfr schwartz) of 30-90 ml/min/1.73 m 2 aims to assess risk factors for kidney disease progression in children. objective: to describe the characteristics of the ckid cohort at study entry. design/methods: at the ckid baseline visit, gfr is measured by plasma disappearance of iohexol. children undergo physical exam, standardized bp measurements, blood and urine testing and parent and child interview. results: as of 01/16/07, 335 children had completed the baseline visit, median age 11.1 yrs, 71% caucasian, 16% african american, 62% male and 15% hispanic ethnicity. median age-adjusted height and weight percentiles were 23% and 42%, respectively. underlying cause of ckd was urologic, cystic or hereditary in 68%, 21% had acquired glomerular disease. median egfr at study entry was 54.6 ml/min/1.73 m 2 , 40% higher than the median iohexol-based gfr 38.5 ml/min/1.73 m 2 . 48% of participants reported a history of hypertension, 35% anemia, 11% seizures, and 7% depression. symptoms of headache, nausea, loss of appetite and weakness steadily increased in prevalence with lower gfr. assessment of family history in parents and grandparents revealed: high blood pressure 81%, high cholesterol 66%, kidney disease 29%, dialysis 12%, and kidney transplant 6%. conclusions: children with stage iii ckd have significant height deficits, hypertension, anemia, and seizure disorders. cross-sectionally, increasing non-specific symptoms are associated with lower gfr. collection of plasma, serum and genetic material will facilitate understanding of novel risk factors and biologic mechanisms underlying kidney disease progression and associated morbidities. aim: increased glomerular filtration rate (gfr) has been implicated in the development of diabetic nephropathy. large normal interindividual variations of gfr hamper the diagnosis of renal hemodynamic alterations. we examined renal functional reserve (rfr) in children with insulindependent diabetes mellitus (iddm) to assess if hyperfiltration occurs. methods: the renal hemodynamic response following dopamine infusion was examined in 51 iddm children (7.7±3.6 y) with a mean duration of diabetes of 6.2 years and compared to 34 controls. results: mean baseline gfr in diabetic children did not differ from control population (130.7±22.96 vs. 124.8±25 ml/min/1.73 m 2 ), whereas renal plasma flow was significantly lower (463.7±103.9 vs. 587.2±105ml/min/1.73 m 2 , p<0.001) and filtration fraction was increased (29±8 vs. 21±2%, p<0.001), compared to controls. the mean rfr was lower (p<0.001) than in control subjects (-0, 77±23 vs. 21±8 ml/min/1.73 m 2 ). conclusion: the observation that rfr is reduced or absent suggests that all children are in a state of glomerular hyperfiltration with increased intraglomerular pressure regardless of the baseline normal values of gfr. while measurements of rfr may be helpful in diagnosing the presence of hemodynamic changes, the relevance to development of diabetic nephropathy remains unknown. only 30-40% develops diabetic nephropathy, suggesting that glomerular hyperfiltration is only a concomitant risk factor. lp diet induces ischemic renal injury involving epithelial cells from osom. here, we tested whether hsp70 would stabilize renal na+k+atpase attachment to the cytoeskeleton during recovery from lp. after weaning, rats (n=8), were fed for 14 days with a lp diet (8%), then were recovered by means of a normal protein diet (24%rp) each group had an age-matched control group (24%, np). tissues from cortex and osom were homogeneized in buffer plus 0.1% triton x-100. protein levels were measured by western blot. in vitro coincubation of solublen on cytoeskeletal and insoluble cytoskeletal-associated fractions in the presence or absence of anti-hsp70 antibody was performed. interaction between proteins was determined by coimmunoprecipitation. increased na+k+atpase dissociation was shown in soluble fraction from osom as a result of lp diet vs. np (196.5±1.1 vs. 151±1.3, p<0.05). meanwhile, decreased hsp70 levels in the same fraction was shown (lp: 179.3±10.5 vs. np 224.7±1.85, p<0.05). translocation of hsp70 to the cytoeskeletal injured fraction associated with stabilization of na+k+atpase was shown in osom from lp, after in vitro coincubation of the cytoskeletal fraction of lp and non cytoskeletal fraction of rp. these effects were abolished by the addition of anti-hsp70 antibody. coimmunoprecipitation showed that the amount of hsp70 coprecipitating with na+k+atpase increased in lp osom, in rp results were similar to control. in cortex, absence of significant differences was shown in the na+k+atpase and hsp70 expression at in vivo and in vitro experiments among groups. in lp and rp cortex tissues, interaction of both proteins was similar to control. our results allow us to suggest that hsp70 has a critical protective role in the integrity of the cytoskeletal anchorage of na+k+atpase during recovery from ischemic lp injury in osom. tubular reabsorption of mg +2 occurs predominantly by paracellular flux in the thick ascending limb of the loop of henle. it is mediated by the, tight junction, mg +2 channel protein, paracellin-1, which is encoded by the gene pcln-1. cyclosporin a (csa), a widely used immunomodulatory drug, decreases tubular mg +2 reabsorption leading to urinary mg +2 wasting and hypomagnesemia. the exact molecular mechanisms of this modulation are unknown. in this study we examined the effect of csa on the paracellin-1 gene in renal cell lines and mouse kidney. the effect of csa on the pcln-1 gene promoter was examined. a plasmid, containing the human pcln-1 (hpcln-1) promoter (2.5kb) upstream to a luciferase reporter gene, was transfected into opossum kidney (ok) and human embryonic kidney (hek293) cells prior to exposure to 5 micrograms/ml csa for 24 hours. mice received csa (15 mg/kg/day) for up to 5 days. at 24 h intervals blood/urine mg +2 and ca +2 levels were determined and kidneys harvested for paracellin-1 mrna quantitation (real-timepcr) as well as protein quantification (western blot) and visualization (immunofluorescence). csa decreased hpcln-1 promoter activity by 25%-50% in transfected ok and hek293 cells, compared to control cells. csa-treated animals displayed hypomagnesemia with increasing urine mg +2 and ca +2 levels paralleled by a 20-30% decrease in pcln-1 mrna after 3 and 5 days of csa exposure. a similar effect on paracellin-1 protein expression inthe renal tubule was evident in response to csa treatment. csa may influence paracellin-1-mediated mg +2 transport at the transcriptional level. involvement of the calcineurin-dependent tonebp pathway or the calcineurin-independent map kinase pathway in this response is subject to future research. this effect of csa on the paracellin-1 gene may play a role in the renal magnesium wasting and hypomagnesemia induced by csa. it is well established that proteinuria induces tubular injury, which is closely associated with progressive decline of renal function. megalin has an important physiological role in the reabsorption of a variety of low molecular weight proteins along the proximal tubule. in this study, we examined whether megalin mediates tubular injury secondary to glomerular diseases. we utilized megalin knockout (ko) mice, in which 60% of proximal tubular cells have mosaic nullmutation in the megalin gene. to induce glomerular injury, these were mated with a transgenic line, nep25, in which selective podocyte injury can be induced by injection of immunotoxin, lmb2. megalin ko/nep25 mice were injected with lmb2 (0.625 ng/g bw) and analyzed 2 weeks later. they showed moderate proteinuria (upro/cr=80, vs 12.5 before lmb2) and mild tubular injury, which were comparable to those observed in nep25 mice with intact megalin gene injected with the same dose of lmb2. in the latter, megalin was still detectable in injured tubules. within each megalin ko/nep25 mouse, we compared megalin-intact (+) vs deficient (-) proximal tubular cells by immunostaining. the majority of megalin+ cells showed enhanced staining for albumin. in contrast, most megalin-cells were not stained for albumin. aquaporin-1, which is highly expressed in normal proximal tubules, was diminished in 39.7% of megalin+ cells, whereas it was diminished in only 11.3% of megalin-cells. some proximal tubular cells expressed mcp-1. in that, 69% of mcp-1 expressing cells were megalin+. the results suggested that megalin plays an important role in the reabsorption of massively filtered proteins in glomerular diseases, thereby contributing to proximal tubular cell injury. objectives of study: the hallmark of nephropathic cystinosis is lysosomal cystine accumulation, primarily leading to fanconi syndrome. although all tissues haveelevated cystine levels, it is not known why the kidney is first affected. it is postulated that decreased atp production in cystinosis results in defective proximal tubular reabsorption, a process driven by na, k-atpase. to study this hypothesis, we have monitored atp levels and viability in conditionally immortalized proximal tubular cells (ptc) of cystinosis and healthy controls. methods: urinary sediment of cystinotic patients and healthy controls was suspended ins supplemented culture medium. primary cultures were transfected with sv40 ts a58 t antigen allowing proliferation at 33°c and maturation at 37°c. to confirm the proximal origin of the cells 1) expression of aquaporin-1 (aqp1) and dipeptidyl-peptidase iv (dpp-iv) was demonstrated using immunoblot technique and 2) morphology was determined using em. ptc were matured at 37°c for 0-10 days, followed by cystine measurement using hplc and atp determination using luciferase assay. results are expressed as nmol/mg protein. results: colonies of cystinotic and control cell lines (n=2) with cobblestone morphology developed after 2 weeks and expressed aqp1 and dpp-iv, confirming their proximal origin. in cystinotic ptc, cystine levels increased from 2.0 at 33°c to 7.5 after 10 days at 37°c compared to 0.3 in controls. intracellular atp decreased in cystinotic ptc during 10 days from 8.8to 1.6, while atp levels in controls remained stable (range 9.7-13.7). atp levels inversely correlated with cystine accumulation in cystinotic ptc (r=-0.95, p=0.005). conclusion: decreased atp levels in conditionally immortalized ptc during 10 days maturation suggest that alterations in atp levels are involved in tubular dysfunction in cystinotic patients. aquaporin ( 13 aqps have been identified to date. aqp1 conveys 50% of the peritoneal water transport in pd. cell migration and angiogenesis are altered in aqp1 ko mice; erythrocyte pco 2 depends on aqp1. human peritoneal mesothelial cells (hpmc) from non-uremic patients and a human mesothelial cell line (met-5a) were incubated with conventional (c-pdf), icodextrin (ico), bicarbonate (b-pdf) and lactate based double chamber pd solution (l-pdf). mrna was measured by real time rtpcr, and protein by western blot and immunocytochemistry. hpmc and met-5a express aqp1, 3, 9 and 11. incubation of met-5a and hpmc with c-pdf, ico and l-pdf did not change aqp1 and 3 expression compared to medium. in contrast, incubation with b-pdf increased aqp1 and 3 mrna and protein in both hpmc (24 h aqp1 mrna: 262±21, aqp3: 3226±634%) and met-5a (aqp1: 1860±1180, aqp3: 2025±1624%). the effect on aqp1 was in part explained by differences in ph, the effect on aqp3 was largely independent of ph. addition of 34 mmol/l of bicarbonate to l-pdf increased aqp1 and 3 mrna (l-pdf+bic: aqp1: 983±110, aqp3: 326±26%). aqp9 expression was suppressed by all three pd fluids (b-pdf: 25±2.4, l-pdf: 16±9.6, c-pdf 75%: 26±11%), aqp11 was up regulated by b-pdf (377±37%). b-pdf improved hpmc migration. we for the first time demonstrate the expression of four different aqps in peritoneal mesothelial cells. they are markedly regulated by pd-solutions. the upregulation of aqp1, 3, and 11 by bicarbonate based pdf may have important implications on long term peritoneal membrane function, wound healing and neoangiogenesis. the regulation of cx3cl1 (fractalkine) by thromboxane a2 in inflammation there is marked leukocyte infiltration into the damaged tissue. chemokines recruit and direct leukocytes to the injured site. the chemokine cx3cl1 is up-regulated in renal inflammation such as glomerulonephritis and allograft rejection. thromboxane a2 (txa2), a potent vasoconstrictor in the kidney, is also pro-fibrotic. txa2 is up-regulated early in inflammation and its effects are mediated by binding to the tp receptor. the aim of this study was to examine the effect of txa2 on cx3cl1 expression. we previously showed that cx3cl1 recycles between the cell surface and an internal compartment. cell surface cx3cl1 is cleaved by the enzyme, tace, to yield the soluble species of the chemokine. we generated human ecv-304 cells stably expressing cx3cl1 and treated cells with a tp agonist. levels of cx3cl1 were quantitated by western blotting. cx3cl1 decreased by 30-60 min after tp stimulation, but recovered by 4h. using flow cytometry, we found that cell surface levels of cx3cl1 decreased by 30 min, but began to recover before levels of total cx3cl1 were replenished. to verify if early recovery of cx3cl1 was due to redistribution from the internal to the plasma membrane compartment, we used fluorescence recovery after photobleaching (frap). after 60 min tp stimulation decreased endocytosis of cx3cl1 was seen. we postulated that loss of cell surface cx3cl1 is due to cleavage by tace. accordingly, a tace inhibitor prevented early loss of cx3cl1 after tp stimulation. in summary, txa2 induces rapid proteolytic shedding of cell surface cx3cl1 by tace, but later increases expression of cx3cl1 at the cell surface by inhibiting internalization of the chemokine. this could release the soluble chemotactic protein from the cell adhesive transmembrane protein, promoting leukocyte recruitment initially, whilst promoting leukocyte adhesion later in the time course. the response to steroid therapy is used to characterize idiopathic nephritic syndrome (ins) as steroid sensitive (ssns) or steroid resistant (srns). ssns pathogenesis has been associated with activation of t-cells and srns has been associated with activation of tgfb1 and progression to chronic kidney disease. our objective was to determine differences in the urinary excretion of inflammatory cytokines; opn, icam1 and tgfb1, between ssns (n=12), srns (n=12), and controls (ctr, n=12) in an attempt to identify specific biomarkers of steroid sensitivity or lack thereof. for this purpose, we used a protein array high-throughput technique and confirmed the findings by elisa. in addition, we performed immunohistochemistry (ihc) for the above cytokines on renal biopsy samples. mean age, gender, race, body mass index, and estimated glomerular filtration rate were not statistically different among three groups. there were no statistically significant differences between ssns and srns in regard to the presence of hypertension, ace treatment, and renal histology (p=0.99, 0.22, and 0.99, respectively) . urinary excretion of icam1, opn, and tgfb1 were statistically significantly higher in ins subjects vs. ctr. urinary icam1 and opn were higher in ssns than in srns (p=0.005 and p=0.0002, respectively). however, the urinary excretion for tgfb1 was similar in ssns and srns. the ihc failed to reveal differences in renal tissue expression of the studied cytokines. there was no correlation between urine and kidney tissue expression. in summary, our preliminary data suggest that urinary opn and icam1 may serve as biomarkers of ssns. this assumption needs to be tested prospectively. methods: this is an interim report of this single center study on proteinuria in hiv positive children. there are 250 children aged 0-18yrs. registered in our hiv clinic. all children attending the outpatient clinic or seen on admission are studied. questionnaires included bio and clinical data. blood pressure was measured in all children. a clean catch or bag urine is obtained from all and urine biochemistry done on an aliquot. patients found to have proteinuria 1+ or above are referred to the nephrology unit. their urine is quantitated (timed urine collection), renal function, renal ultrasound and cd4 count estimated. anf, le cells, fbc including platelet count and genotype will be assayed. a renal biopsy will be performed for nephrotic range proteinuria. result: eighty children positive for hiv have been studied. there were 41 males and 39 females giving a ratio of 1.1: 1. their mean and median ages were 3.28yrs and 3.25 years respectively. all had normal blood pressures, renal ultrasound, and renal function. fifteen of the 80 children (18.8%) had 30-100mg/dl proteinuria; 19 (23.8%) haematuria. their mean cd4 + cell count was 316.9/mm 3 , range 180-1267. there was no significant difference between low cd4 + count and the presence of proteinuria (p>0.3). seventy seven of the patients had vertical transmission of hiv; two acquired the infection from blood transfusion; one from scarification marks. conclusion: there is a high prevalence of proteinuria among children with hiv infection in our region. hiv positive children should be screened and intervention instituted to avert or delay the onset of chronic renal failure. carotid intima media thickness (cimt) and brachial artery flow mediated dilatation (fmd) are novel indices of subclinical atherosclerosis. we studied these indices in children with nephrotic syndrome (ns) using high resolution ultrasonography (hrus). 52 children with ns (42 ssns;10 srns) of 24-207 months duration and 50 normal sibling controls underwent cimt and fmd determination using a 7.5 mhz us probe. routine biochemistry, lipid profile and hscrp were carried out to look into associations with cimt and fmd. statistical analysis was carried out using epiinfo 6.0. cases and controls were similar in age, sex, growth and egfr. mean maximum cimt (+-95% ci) (in mm) was higher in the ns group (0.435 +-0.014; range 0.333-0.570) vis-a-vis controls (0.398+-0.091; range: 0.345-0.490) (p<0.01). srns and ssns cases were similar (0.441+-0.037 vs 0.434+-0.015 mm, p=0.36). nephrotic children showed significantly lower fmd (10.56+-4.16% vs 17.39+-3.94%, p=0.02). cimt and fmd varied with frequency of relapses in last 12 months (0.415+0.035mm, 10.27+-5.68% (no relapses); 0.449+-0.019 mm, 7.57+-5.39% (>3 relapses). children with ns had mean hscrp of 5.25+-0.57 mg/l. on univariate analysis, cimt correlated with disease profile at onset (r=0.33, p<0.01), fmd (r=-0.23, p=0.02), male sex (r=0.23, p=0.02), bmi (r=0.23, p=0.02), cyclosporine exposure (r=0.5, p<0.01), total cholesterol (tc) (r=0.34, p<0.01), ldl (r=0.33, p<0.01), vldl (r=0.29, p<0.05), triglycerides (r=0.33, p<0.05), atherogenic index (ai) (r=0.33, p<0.01) and creatinine (r=0.25, p=0.03). fmd correlated with systolic blood pressure, age, bmi, weight, total cholesterol, vldl and triglycerides (p<0.05). to conclude, hrus can detect early atherosclerosis using fmd and cimt as the indices in children with nephrotic syndrome with disease duration of 20 years and more. a ten-year old girl, who presented with biopsy proven acute severe changes of type 1 membranoproliferative nephritis (mpgn1) appears to have shown complete resolution of her disorder after nine months mycophenolate moffetil (mmf) (cellcept -roche) added to relatively rapidly reducing steroids. she presented aged nine years with incidental finding of significant proteinuria and upper tract haematuria when presenting with abdominal pain. blood pressure, chemical renal function and haematology were normal. c3 and total haemolytic complement were at the lower limit of normal. renal biopsy showed light microscopy (lm) changes of markedly enlarged glomeruli with significantly increased mesangial cellularity and matrix, together with 'double contours' of basement membrane. inmmunofluorescence (if) was strongly positive for igg and c3. electron microscopy (em) showed mesangial cell interposition into the basement membranes. she was treated with iv pulse methylprednisolone, followed by high dose oral prednisolone (pnl). after one month, mmf 500mg bd was added as pnl was tailed to alternate day therapy. pnl was reduced more quickly than usual due to difficulty with side effects and excellent clinical response. within three months of mmf, proteinuria and haematuria had disappeared. blood pressure and renal function have remained normal throughout treatment. after nine months, while on 0.5mg/kg alternate day pnl and 500mg bd mmf, repeat biopsy showed normal sized glomeruli on lm with no significant changes, no positive staining on if and normal em without mesangial interposition. this case suggests that mmf may be a key drug in management of mpgn1. g. stringini, e. malagnino, f. emma bambino gesu children's hospital and research institute, department of nephrology and urology, rome, italy serum creatinine values may vary considerably between normal subjects. these variations are in part secondary to differences in muscle mass, body composition and creatinine tubular secretion. in addition, low nephron number, which is influenced by genetic and intrauterine factors, is associated with increased incidence of arterial hypertension, late-onset proteinuria and chronic renal failure. despite compensatory glomerular hypertrophy, autopsy data indicates that kidneys with fewer glomeruli tend to be significantly smaller. on these bases, we have hypothesized that a significant part of the variance of normal serum creatinine levels is related directly to individual differences in renal size. to test this hypothesis, we have reviewed the data of 1746 renal ultrasound examinations performed at our institution between 1991 and 2006. patients were selected if they had conditions that should not influence renal size (low tract uti, enuresis, bladder instability, idiopathic hypercalciuria), if they had normal gfr and an ambulatory blood pressure measurement. analyses were performed after expressing renal length, serum creatinine levels and blood pressure values as standard deviation scores (sds) corrected for gender, age, height and weight, by multiple nonlinear regression analysis. a significant negative correlation was found between serum creatinine levels and renal length (p<0.001). when renal length measurements were grouped in quartiles, serum creatinine sds was on average 0.37 sds higher in the 1st quartile (small kidneys), in comparison with the 4th quartile (large kidneys). no correlation was found between kidney length and single measurements of ambulatory blood pressure. these data indicate that renal size is accountable for a significant part of the variance in serum creatinine levels that is observed in the normal pediatric population. henoch-schönlein purpura (hsp) is the commonest small vessel vasculitis of childhood. henoch-schönlein purpura nephritis (hspn) is the major determinant of long term prognosis in hsp. the objective of this randomised controlled trial was to determine the effect of early prednisolone treatment on the development and progression of nephropathy in children with hsp. methods: children under 18 years of age, with a diagnosis of hsp, presenting to secondary care centres in england and wales were randomly assigned to receive either placebo or prednisolone (2mg/kg/day (max 80mg) for 7 days, followed by 1mg/kg/day for 7days (max 40mg)). patients, parents, paediatricians and investigators were 'blinded' to assignment of treatment or placebo. the primary outcome measure was the determination of the presence or absence of proteinuria, defined as urine protein: creatinine ratio (up: uc) >20mg/mmol, 12 months after initial presentation in treated and untreated patients. results: 353 children with hsp were randomised. 181 patients were assigned to receive prednisolone (group a) and 172 patients were assigned to receive placebo (group b). 36 patients in group a and 27 patients in group b did not complete the study. there was no difference in the incidence of proteinuria at 12 months, in patients receiving prednisolone (19/145) compared with those receiving placebo (15/145) or=1.32, 95% ci 0.59-2.94, p=0.49. conclusions: this is largest prospective randomised placebo-controlled trial of the role steroids in hsp in the literature to date. this study provides compelling evidence of absence of a beneficial effect of early treatment with prednisolone in the development of nephropathy 12 months after disease onset in children with hsp. while quality of life (qol) is generally assumed to be poor on dialysis and to improve markedly after kidney transplantation, systematic assessments of qol in children have not been performed to date. to date, we have examined general and health-related qol in 35 children and adolescents with esrd aged 4-16 years treated by hemodialysis (hd; n=7), peritoneal dialysis (pd, n=8) or renal transplantation (tx, n=20), using a well-established instrument (kindl) comprising an ageadapted set of questionnaires (kindl). the obtained measures of overall and item-specific qol were transformed to standard deviation scores (sds). general qol was close to normal and did not differ significantly between hd (-0.37±1.58 sds), pd (-0.20±1.04) and tx (-0.12±0.95). psychological well-being was better in children on pd (0.54±1.04) than after tx (-0.53±1.30, p=0.05) and on hd (-0.98±1.73, p=0.06). physical wellbeing did not differ between treatment groups (hd: -0.39±1.19, pd: 0.10±1.21, tx: (-0.16±1.06). qol related to family life tended to be compromised in dialyzed (-0.87±1.58) vs. tx children (-0.11±0.88, p=0.07) . social interaction with friends was considered moderately impaired by all patient groups (hd: -0.89±1.92, pd: -1.15±1.26, tx -0.82±1.44). self-esteem was close to normal in all groups (hd: -0.3±0.85, pd: -0.27±1.35, tx 0.21±.0). in summary, our preliminary results suggest that subjective qol is remarkably good in children with esrd, with surprisingly small differences between treatment modalities. tx appears to be perceived beneficial with respect to the integrity of family life but provides poorer psychological qol than pd, possibly due to the constant concern with graft loss. background: gfr is determined in the ckid cohort study by plasma disappearance of iohexol (igfr). updated serum creatinine (scr)-based formulas (sgfr=k ht/scr) are needed for bedside clinical use. objective: derive formulas based on enzymatic scr to estimate gfr in the ckid study in children aged 1-16 yrs with sgfr of 30-90 ml/min/1.73 m 2 . methods: from 253 children, height (ht, meters), igfr, and scr & bun (mg/dl) by bayer advia 2400 were obtained. gfr was estimated from regression models: a(ht/scr) b (35/bun) c where a is gfr if ht=scr and bun=35; b and c are exponents. results: 60% (n=152) were male; median age=11, scr=1.4, bun=31 and igfr=38. formulas ranged from an updated schwartz formula (a=40.4, b=1, c=0; r 2 =0.66), to sex-specific (a=38.8, b=0.98, c=0 in girls, and a=40.5, b=0.79, c=0 in boys), which yielded r 2 =0.69, to the most complex (a=37.7, b=0.86, c=0.16 in girls, and a=39.7, b=0.69, c=0.16 in boys), which yielded r 2 =0.71, higher (p<0.001) than the r 2 of the updated schwartz formula. by random selection of 127 of 253 subjects in 100 independent trials, we assessed the predictive ability of each formula on the other 126 observations. sex-specific formulas produced unbiased results and increasing precision with increasing complexity. the updated schwartz underestimated igfr in boys by 3% (p<0.001) and overestimated igfr in girls by 4% (p<0.001). conclusions: scr, ht, sex, and bun together provided unbiased estimates of igfr and explained 71% of its variability in children with igfr of 14 to 76 ml/min/1.73 m 2 . extrapolation to ht/scr of 3 (normal body habitus and kidney function) and bun of 10 yielded predictions of 118 ml/min/1.73 m 2 for gfr in girls and 104 boys. including cystatin c and broadening the gfr range to include normal levels are data being collected by ckid to extend the formulas and provide wider clinical utility. f. hussain, m. mallik, a. watson nottingham university hospitals, children and young people's kidney unit, nottingham, united kingdom considerable variation exists between units in terms of techniques used for renal biopsy. the bapn agreed an audit using published standards and a questionnaire was sent to all 13 uk paediatric nephrology centres. 11 agreed to a prospective audit between 1/1/05 and31/12/05. the survey revealed information leaflets are sent pre-biopsy in 5 (45%) centres with only one using play preparation. 6 (55%) routinely perform biopsies as daycase procedures (dc); 6 (55%) use general anaesthetic (ga). realtime ultrasound is the favoured method in 8 (73%) of centres. biopsies are performed by nephrologists only in 4 (36%), nephrologists with radiologists in 5 (45%) and radiology alone in 2 (19%). of 531 biopsies (352 native), 164 (31%) were performed as a dc with 262 (49%) being done under ga. the mean age of patients was 11yrs (range 0.8±18.9yrs). the standard for the number of passes of native kidneys (<3 in 80%) was achieved in 86.4% with no significant difference between grade of operator or nephrology/radiology speciality. standard number of passes in transplanted kidneys (<2 in 80%) was achieved in 73.4%. adequate tissue was obtained for diagnosis in 97.5% (standard >95%). the significant complication rate (macroscopic haematuria and/or delay indischarge) was higher than the set standard of <5% at 7.3%. there was no significant difference in complication rates whether the biopsy was performed as a dc or inpatient procedure (p=0.73) or whether ga or sedation was used (p=0.8). conclusions: the survey highlights significant variation in practice with limited use of preparation materials and dc. the results may enable individual units to reflect upon their techniques and complication rates and has stimulated constructive debate about indications and training issues. objective: to characterize bp in children enrolled in the ckid study, an observational cohort study of children 1-16y old with schwartz estimated gfr of 30-90 ml/min/1.73 m 2 . design/methods: 3 bp's were obtained using an aneroid sphygmomanometer. gfr was measured by iohexol disappearance. bp was classified according to the 4th report on bp in children. hypertension (htn) was defined as bp-95th percentile (uncontrolled), or as self-reported htn plus current treatment with antihtn meds. pre-htn was defined as bp 90th-95th percentiles. results: 284 children (mean age 11±4y; 60% male) were studied. mean gfr was 41±14 ml/min/1.73 m 2 and mean ckd duration was 7±4y. for sbp, 139/280 (49.6%) subjects had htn of these, 59 subjects (21%) had uncontrolled htn. 14 additional subjects (5%) had pre-htn. of subjects with systolic htn, only 57% had measured sbp<90th percentile, and among the 73 subjects with measured sbp>90th percentile, only 32 (44%) were taking antihtn meds. for dbp, 136/280 subjects (48.6%) had htn of these, 53 subjects (19%) had uncontrolled htn. 30 subjects (11%) had pre-htn. of subjects with diastolic htn, just 52% had measured dbp <90th percentile, and among the 83 subjects with measured dbp>90th percentile, only 35 (42%) were taking antihtn meds. among children with gfr<50 ml/min/1.73 m 2 , the prevalence of systolic or diastolic htn appeared to increase with decreasing gfr. conclusions: a significant proportion of children enrolled in the ckid study suffer from elevated bp. nearly 40% of children with ckd had measured bp>90th percentile, and more than 50% of these children were not receiving antihypertensives, indicating that htn in pediatric ckd is frequently under-or even untreated. long-term follow-up of the ckid cohort should reveal the effect of elevated bp on ckd progression. background: we recently demonstrated elevated excretion of the putative urinary biomarkers tgf-β and et1 in a large cohort of children with ckd. tgf-β excretion was highest in kidney disorders associated with marked tubulointerstitial fibrosis, such as obstructive uropathy, nephronophthisis and pkd. aim: to investigate the course and predictive value of urinary tgf-β and et1 excretion in children with ckd undergoing ace inhibition (acei). methods: to date, 165 patients have been followed for 2 years and 91 patients for 3 years in a prospective, interventional trial investigating the nephroprotective efficacy of acei w/out intensified blood pressure control. results: average bp was reduced to the mid normal range. proteinuria initially decreased by 50%, but gradually reincreased to baseline levels within 3 years. urinary tgf-β excretion, which was initially elevated 3-fold above healthy controls, continuously decreased during treatment from 32.6±31.5 ng/g creatinine to 27.4±20.7, 20.6±44.0, and 18.4±20.5 after 1, 2, and 3 years, respectively (p<0.001). in contrast, et1 excretion increased by 100% within the first 2 years of follow-up. neither baseline nor the change in tgf-β and et1 excretion during treatment predicted the short-or long-term antihypertensive, antiproteinuric response to acei or ckd progression rate. conclusions: the marked reduction of urinary tgf-β excretion probably reflects the antifibrotic effect of acei but, at least over 3 yrs of observation, does not predict the early and late course of proteinuria and ckd progression. hence, urinary tgf-β appears to be a biomarker of tubulointerstitial disease activity rather than of global disease progression. the surprising increase of et1 excretion may reflect the induction of compensatory hemodynamic mechanisms during acei. cardiovascular complications are the most important cause of death in pediatric patients with endstage renal disease. therefore early diagnosis and treatment are very important. brain natriuretic peptide (bnp) is released in response to volume overload or conditions that cause ventricular stretch. the aim of the study was to investigate whether bnp can be used for early diagnosis of cardiac complications in pediatric patients with esrd. twenty-four patients on peritoneal dialysis (mean age 13.3±4.4 years), 21 patients on hemodialysis (mean age 15.0±3.6 years) and 39 sex and age matched healthy children (mean age 12.4±3.0 years) were included the study. plasma bnp levels were significantly higher in the patient group than those in the control group (590.4±765.8 vs 159.0±23.7 pg/ml, respectively, p<0.05), but there was no significant difference between hemodialysis and peritoneal dialysis patients. in patients with hypertension, bnp levels, left ventricular systolic and diastolic diameters were significantly higher than those in the patients without hypertension. in patients with higher crp levels, bnp levels were significantly higher than those in the patients with low crp levels. bnp levels had a positive correlation with left ventricular mass index (r=0.32, p=0.04) and a negative correlation with ejection fraction (r=-0.59, p<0.001) and shortening fraction (r=-0.55, p<0.001) significantly. there was no significant relation between bnp levels and anemia, dialysis duration, and dialysis modality. in conclusion, high plasma bnp level is significantly correlated with dilated left ventricle and it may be useful as a biochemical marker for identification of pediatric dialysis patients with cardiac dysfunction. we observed a high prevalence of left ventricular hypertrophy (lvh) and impaired lv contractility in children with stage ii-iii chronic kidney disease (ckd) (jasn 2006 , jasn 2007 . in a prospective, open-label assessment in 84 children receiving ace inhibition (ramipril 6 mg/m 2 /d) with or without additional antihypertensive medication, we evaluated by echocardiography lv mass (lvm), geometry and myocardial mechanics at baseline and after 12 (n=65) or 24 mos (n=55) of treatment. lvh was defined by lvm index>38 g/m 2 and concentric geometry by relative wall thickness>0.375 (95 th normal percentile). lv systolic function was assessed at the midwall level by circumferential shortening (ms). normalized 24 h mean arterial blood pressure (bp) was reduced from 1.3±1.4 at baseline to 0.0±1.4 and -0.5±1.0 sds after 12 and 24 mos respectively. lvmi was reduced significantly after 12 (from 34.0±8.4 to 31.6±8.0 g/m 2.7 , p<0.02) and 24 mos (from 34.4±7.6 to 31.9±9.7, p<0.05). of those patients presenting with lvh at baseline, lvm regressed to the normal range in 10/19 (53%) after 12 mos and in 10/18 (55%) after 24 mos. the prevalence of concentric lv geometry remained unchanged (baseline: 8%, 12mos: 9%, 24mos: 7%). age and afterload-corrected myocardial function increased from 93±15% to 100±13% at 24mos (p<0.005). the changes in lvm and myocardial performance were independent of the randomized bp target and gfr. change in lvm was correlated with change in hemoglobin level (r=0.30, p<0.05) and change in myocardial function with change in bp level (r=0.39, p<0.05). in conclusion, fixed-dose ace inhibition and tight bp control induce regression of established lvh in the majority of children with stage ii-iii ckd. this is associated with a normalization of myocardial contractility. objectives of the study: periods with insufficient erythropoietic activity may occur during the erythropoietin (epo) treatment in chronic haemodialysis (hd). we determined the effects of a short-term suspension of epo therapy on various oxidative stress parameters during a 12-week follow-up in hd patients. methods: the antecedent epoetin beta (eb) treatment was suspended for 10 days. after that, 9 patients received eb two times a week and 7 patients received darbepoetin alfa (da) once weekly. concentrations of whole blood oxidized and reduced glutathione (gssg, gsh) and various haematological parameters were determined weekly. erythrocyte malondialdehyde (e-mda) and the activities of erythrocyte superoxide dismutase, catalase and glutathione peroxidase were determined at weeks 0, 4 and 12. results: the ratio gssg/gsh was increased in both groups after continuation of the suspended epo therapy (p<0.05 and p<0.01 week 1 vs. the baseline in the da and eb group, respectively) and also at week 9 (p<0.01 and p<0.001 vs. the baseline in the da and eb patients, respectively). the activities of the antioxidant enzymes were increased at week 4 in both groups (p<0.05 vs. the baseline for da and p<0.001 vs. the baseline for eb), and returned to their week 0 levels by week 12. the e-mda level decreased in both groups (p<0.05 week 12 vs. the baseline for da and p<0.05 weeks 4 and 12 vs. the baseline for eb). conclusions: a short-term suspension of epo therapy caused characteristic time-dependent changes in the oxidative stress. the ratio gssg/gsh increased at weeks 1 and 9. activities of the antioxidant enzymes were elevated at week 4, resulting in an improvement in lipid peroxidation. these results might have implications in certain conditions with transient alterations in the erythropoietic activity in hd patients. rrf has been associated with better nutritional status both in adults and children on peritoneal dialysis and in adults on chronic hd. there are no data on the influence of rrf on nutrition in children on chronic hd.179 three-days dietary reports and simultaneous urea kinetic monitoring of 30 children, adolescents and young adults on chronic hd (age: 4.3-24.5 years) were retrospectively analyzed. protein catabolic rate, an index of nutrition adequacy, was normalized by body weight (npcr). in patients with rrf, total kt/v (kt/vtot) was calculated summing hd kt/v(kt/vhd) and rrf (evaluated by residual urea clearance ku-). in all patients, npcr and dietary protein intake (ndpi) were significantly correlated (p<0.0001). kt/vtot was correlated with npcr(p<0.0001) while correlation between kt/vhd and npcr was not significant (p: 0.11). in patients with rrf, ku resulted significantly associated with npcr (p<0.0001) while kt/vhd was not (p: 0.10). npcr was significantly higher in patients with rrf (1.46±0.41 vs 1.03±0.33 g/kg/day; p<0.0001). patients on recombinant growth hormone (rhgh) treatment showed npcr higher than those without rhgh (1.34±0.41 vs 1.01±0.39 g/kg/day; p<0.0001). however, in a multiple regression model including age, the use of rhgh, rrf, kt/vtot and kt/vhd, npcr resulted significantly associated only with rrf (b: 0.128; p<0.0001). inconclusion: in children, adolescents and young adults on chronic hd treatment, rrf is associated with better nutrition. rrf positively affects nutrition independently from hd efficiency and rhgh effects. possible hypothesis are a more selective (although decreased) depuration and the positive influence of water excretion maintenance on food intake. more efforts have to be made in order to maintain rrf in children on chronic hd. during the past three years, six women have undergone chronic haemodialysis during pregnancy at the pediatric renal unit of the adelaide women's and children's hospital. five have delivered normal infants at between 33 and 38 weeks gestation; one is presently at 28 weeks gestation, with an apparently normal fetus. four were already receiving chronic haemodialysis at the time of conception; the others began dialysis at 20 weeks gestation. the protocol includes six days per week dialysis for at least two hours per treatment. a number of practical and emotional issues have arisen, with major potential psychosocial hazards, including: unplanned pregnancy due to ignorance of fertility; precipitation onto the dialysis program; acceptance of increased dialysis time; concerns regarding effects of drugs and dialysis/kidney failure on the fetus; the likelihood of prematurity; the perceived difficulties of motherhood while on a chronic dialysis program; loss of income, social networks and independence. the program has been successful due to the cooperative approach from the multidisciplinary team consisting of nephrologists, obstetricians, obstetric physicians dialysis nurses, midwives, dieticians, physiotherapists, psychiatrists and social workers. the social worker has provided counselling and coordinated transport and assistance with housework, childminding and other day to day tasks. although the program has had overall success, there have been a number of pitfalls worth discussing, including those arising from the complex interactions between the members of the various disciplines, and those involved in maintaining the balance of clinical and psychosocial needs of the women. (median 17.5) , weight from 4.5 to 15.4 kgbw (median 9). the vascular access was a central catheter (kt) in 12 children, an arteriovenous fistula (avf) in 6, avf and kt alternatively in 14 patients. duration of hd ranged from 1 to 63 m (median 14.5).35 dual lumen tunnelled cuffed kt were inserted in 26 children through the internal jugular vein [ijv]), surgically in 8, percutaneously in 27. all kt have had an immediate good function. nine kt were exchanged over a guide wire for dysfunction. kt infections with positive blood culture were successfully treated in 8 cases. duration of kt ranged from 1 to 20 m (median 5). at the end of the follow-up, 7 kt were still in function, 6 removed for a mature avf, 11 after renal transplantation (rt), 1 for improved gfr and 1 failed. patency of the venous network after withdrawal of kt was assessed in 16 children (doppler 3, mri 13) and showed normal patency in 6, ijv thrombosis in 5, brachiocephalic thrombosis in 3 and stenosis in 2. thirty avf were created in 20 children, distal in 18 (60%). immediate patency was obtained in all cases except 1. the median blood flow ranged from 350 to 1800 ml/min/m 2 (median 750). following the primary surgery, 41 repeated surgical procedures included a superficialization of the vein in 10, refection for stenosis or thrombosis in 9, reduction of overflow in 3, 2 nd avf creation in 10 and ligation after rt in 9. percutaneous transluminal angioplasty was performed in 5 children. duration of patency ranged from 1 to 168 m (median 36.5). in conclusion, hd is feasible in small children. nevertheless, kt are associated with risk of venous occlusion and obtention of a reliable avf frequently need several interventions, altogether leading to a limitation of hd indications in young children. 1994-2005, 60 (19%) were <2 years of age. the underlying disorders were congenital nephropathies in 70% (malformations 33%, hereditary 37%) and acquired diseases in 30%. living related donation (ld) was performed in 59% and preemptive tx in 33%. immunosuppressive (is) protocol varied considerably between the countries and over time.1-year graft survival (gs) was 96% in ld and 87% in grafts from deceased donors (dd). gs improved significantly for dd grafts with time. the number of acute rejections (ar) during the first year posttx was significantly lower in ld recipients, in tac-treated children and during the second half of the study period. this improvement over time was also seen in separate analysis of cya-treated children. the proportion of rejection-free patients increased in all countries. median height sds at tx was -1.8 (-8.3 to +1.7)(boys -1.9, girls -1.6). height sds increased to -1.5 at 3 years posttx. conclusions: gs results were excellent and the frequency of ar low, especially in children with ld grafts and tac treatment. interesting differences between the countries concerning donor source, preemptive tx, is and use of protocol biopsies were found. n. marcun varda, a. gregoric maribor teaching hospital, department of pediatrics, maribor, slovenia objectives: essential hypertension (eh), identifiable in children, is associated with cardiovascular (cv) diseases in adulthood. the aim of our study was to evaluate the presence of some traditional and non-traditional cv risk factors in our children and young adults with eh in the search for additional cv risk. the prevalence of metabolic syndrome (ms) was also investigated. methods: a total of 104 children and young adults, diagnosed with eh, were included in our study. they were compared with a control group of 50 healthy children, matched for sex and age, with regards to specific aspects in the history, body mass index (bmi), waist: hip ratio, full blood count, crp, serum cholesterol, hdl cholesterol, ldl cholesterol, triglycerides, uric acid, glucose, insulin, fibrinogen, homocysteine, apolipoprotein a1, apolipoprotein b and lipoprotein (a). in addition, the prevalence of ms was calculated. ms was defined as having three or more ms components according to the national cholesterol education program's adult treatment panel iii criteria, tailored for children. results: the differences in values of bmi, crp, platelets, triglycerides, uric acid, apolipoprotein a1, apolipoprotein b and homocysteine between the hypertensive patients and the controls were statistically significant. in all hypertensives positive family history of hypertension in the first or second generation was revealed. overweight (bmi >90 th percentile for age and sex) was identified in 40%, obesity (bmi >97 th percentile) in 24%, abnormal glucose homeostasis in 23%, high serum triglycerides in 42% and low hdl in 48% of the hypertensives. ms was present in 48% of these children and in 6% of our controls. conclusion: we demonstrated that children and young adults with eh differ from the population of healthy children in some specific cv risk factors, and are therefore at an increased cv risk. background: rtd is a rare autosomal recessive disease of differentiation of fetal kidneys with poorly developed proximal tubules. fetal and neonatal findings include oligohydramnios, preterm birth and neonatal death due to pulmonary hypoplasia, anuria and hypotension. mutations in genes in the renin-angiotensin system (ras), encoding for angiotensinogen, renin, angiotensin converting enzyme and angiotensin ii receptor type 1, have been revealed. we report the first rtd patients surviving the neonatal period and still being alive. both patients had affected siblings demised in utero or neonatally. case 1: oligohydramnios, birth at 38 weeks, 2850 grams. neonatal course: pulmonary hypoplasia, pneumothorax, hypotension and anuria with ventilation (4 weeks) and dialysis (2 days) . current findings at 15 years: creatinine 200 umol/l, normal blood pressure. genetic and functional analysis: homozygous mutation of angiotensinogen gene (1124g-a); very low angiotensinogen concentration (21.4 ng/ml; normal 1024-275), absent plasma renin activity (normal 1.5-3.0 ng/ml/h) despite very high active renin (199 pg/ml; normal 22-11). case 2: oligohydramnios, birth at 35 weeks, 2520 grams. neonatal course: mild respiratory distress, hypotension and anuria with oxygen (1 day) and dialysis (5 months) . current findings at 10 years: renal transplantation at age 4 years, good graft function. genetic and functional (as neonate) analysis: homozygous mutation of renin gene (1124g-a); very low active renin (<2.5 pg/ml; normal 24-850). conclusions: rtd is caused by inactivating mutations in genes encoding the ras resulting in chronic low perfusion pressure of the fetal kidney. genetic and functional analysis of ras contributes to diagnosis of rtd. this observation extends the rtd phenotype from a uniformly fatal to a more favourable disease. objectives of study: to evaluate the relationship between serum uric acid (ua), new onset essential hypertension (eh) and endothelial dysfunction (ed) in the youth. methods: 29 subjects with abpm proved new onset eh (aged 19, 9±3, 5 years, bmi 28, 9±3, 5 kg/m 2 ), 36 overweight/obese normotensive youth (oo) matched for age and bmi, and 73 age matched healthy normotensive controls (nt) with normal weight were enrolled. ua, total cholesterol, hdl, ldl, triglycerides and creatinine were analyzed in blood, glomerular filtration rate (gfr) was calculated according to schwartz formula and endothelial function was assessed using flow-mediated dilation (fmd, %). results: new onset eh was associated with overweight/obesity in 90% of subjects. serum ua levels were significantly higher in eh than oo (381±92 vs.336±72 umol/l, respectively, p<0, 05), in eh than nt (381±92 vs.277±62 umol/l, respectively, p<0, 0001), and in oo than nt (336±72 vs.277±62 umol/l, respectively, p<0, 0001). total cholesterol, hdl, ldl and triglycerides were significantly higher in eh and oo compared with nt (p<0, 0001). no significant differences were found in lipidograms between eh and oo. serum creatinine and gfr did not differ significantly between the groups. fmd was significantly lower in eh comparing with oo and nt (5,49±4,83 vs.12,75±3,47 vs. 14,55±5,32%, respectively, p<0, 0001) and in oo comparing with nt (12,75±3,47 vs.14, 55±5,32%, respectively, p<0, 05). conclusions: new onset eh in the youth is associated with overweight/obesity, higher serum ua and ed. ua may play a causal role in the pathogenesis of eh and commonly with eh and proatherogenic serum profile contributes to ed in overweight/obese hypertensive youth. objective of study: fibromuscular dysplasia (fmd) is a systemic arteriopathy of the small and medium sized vessels. it is the first cause of renal arterial stenosis (ras) in childhood. the aim of this study was to describe the natural history of fmd in children. we analysed all the data of 12 children with fmd. results: mean age at diagnosis was 4 years 9 months old. hbp was discovered fortuitously in 5 cases, after symptoms of malignant hypertension in 7. in all cases bp values corresponded to severe hypertension (mean bp of 190/105 mmhg). extra renal localizations were found in half of the patient, and the most frequent pathological arteries were the superior mesenteric and the carotida. the mean number of arterial stenosis at diagnosis was 2 per patient. seven patients had a primary fmd with familial history for 1 patient. in the others fmd were associated with polymalformatif syndromes: reported by grange (2), moya-moya disease (2), neurofibromatosis type i (1). after a median follow-up time of 81 months the number and severity of stenosis increase at 6 arteries per patient. these lession, although to a lesser extend, were already observed as soon as 30 months of follow-up. percutaneous transluminal renal artery angioplasty were proposed in 6 cases when the bp was uncontrolled indeed a multi antihypertensive therapy with severe renal stenosis (>80%) or when renal growth was impaired. prognosis is severe with cardiologic complications (10/12) and 1 death. conclusions: intimal form of fmd accounts for the majority of multivisceral fmd. at diagnosis several hypertension is almost present. vascular ultrasonography imaging techniques is usefull in follow-up. a conservative treatment has to be privilegied. this disease is evolutive with increase of pathological arteries number, aggravation of stenosis degree and sometimes renal function impairment. objective: the effect of over weight on blood pressure elevation (bp) is more frequently present in childhood. several studies have demonstrated the efficacy of angiotensin-converting enzyme inhibitors (acei) therapy in obese hypertensive adults, but data on children are very limited. methods: 110 obese (bmi: z score >2.5 sd) primary hypertensive (systolic ordiastolic blood pressure >95th) children (aged 6-7 years) were enrolled to this single centre prospective study. patients received ramipril (0.1-0.15 mg/bwkg/day) once daily. office and ambulatory bloodpressure measurements and serum biochemical analysis were performed at start and after 1 and 6 months of treatment. 36 patients (23,7%) hadimpaired glucose tolerance (igt) on oral glucose tolerance test (ogtt). results: 94 (85,5%) patients completed the six months ramipril therapy. reduction in 24-hour mean arterial pressure (map) was 4, 95 mmhg (-1, 02sd) after 1 month and 10, 14 mmhg (-2,05 sd) 6 months treatment respectively. bp was reduced with equal efficacy during day-and night time. 3/110 (2, 7%) patients were lost during the follow-up. 15 (15,9%) patients with high uric acid levels also were treated with allopurinol. eleven patients (10%) received second antihypertensive medication because of the blood pressure remained uncontrolled. (7 pts metoprolol, 4 pts amlodipine) 8 (7,2%) patients suffered recurrent cough, but otherside effect has not observed. the serum glucose and insulin levels havenot changed significantly during the follow-up. conclusion: oncea day given ramipril significantly decreases the blood pressure inobese hypertensive children. it is effective, tolerable and safe bloodpressure lowering monotherapy in childhood. further studies and longer follow-up are necessary to prove its long term beneficial effect in the childhood metabolic syndrome combined with hypertension. hw. zhang, j. ding, f. wang, yf. wang peking university first hospital, department of pediatric nephrology, beijing, people's republic of china objectives of study: females with x-linked alport syndrome (xlas) have variable phenotypes, from microscopic hematuria to chronic renal failure, which can not be clarified solely by mutation features of col4a5 gene. x-inactivation has been suspected to be one of the responsible reasonsfor this phenomenon, but no definite correlation has been demonstratedso far. in order to confirm whether the phenotypes of xlas femalescorrelate with x-inactivation, we analyzed the xinactivation patternsin peripheral blood cells in 36 xlas females and in skin fibroblasts in12 xlas females. methods: the x-inactivation analysis was performed using hpaiipredigestion of dna followed by polymerase chain reaction (pcr) of thehighly polymorphic cag repeat of the androgen receptor (ar) gene. results: results showed that the average x-inactivation levels of the mutant allele decreased while the degree of proteinuria increased, there was anegative correlation between the degree of proteinuria and thex-inactivation ratios of the mutant allele in blood cells (r=-0.474, p=0.006). however, there was no correlation between the degree of proteinuria and the x-inactivation ratios of the mutant allele in skin fibroblasts (r=-0.131, p=0.701). though 7 of 12 patients (58.33%) had the similar x-inactivation ratios in both blood cells and skin fibroblasts, there was also no correlation between the x-inactivation ratios of the mutant allele in skin fibroblasts and that in peripheral blood cells (r=0.180, p=0.575). conclusion: we concluded that the x-inactivation ratios in blood cells correlated with the degree of proteinuria, which might explain partially the diverse phenotypes in female xlas patients. more studies, including post-transcription regulation, environmental factors, and so on, are still needed. objective: to report frasier syndrome (fs) with wt1 mutation and abnormal expression of podocyte molecules which is the first case in mainland china. methods: peripheral blood cells were analyzed for chromosome karyotype and wt1 gene mutation. the ratio of +kts/-kts isoforms was quantified with genescan and genescan software. expressions of podocyte molecules were detected by immunohistochemical staining. result: the patient presented with steroid-resistant fsgs and male pseudohermaphroditism. the wt1 ivs 9 +5 g>a mutation was found in one allele in the proband, but not in her parents. the ratio of +kts/-kts was 0.67 in the proband, and was 1.35 and 1.42 in her mother and father, respectively. podocyte molecules expression altered in normal-and abnormal-appearing glomeruli. wt1 expression showed diffuse nuclear staining with less obvious speckles compared with that in controls. wt1 (antibody against c-terminal) displayed strong, normal, faint and negative stained podocyte nuclei within the same glomerulus. the staining intensity of wt1 (antibody against the n-terminal) was very faint. conclusion: taking clinical data, pathology, karyotype analysis and genetic testing together, we diagnosed the first case of fs in mainland china, which prompts there might be more cases underdiagnosed. wt1 displayed diffuse nuclear staining with less visible speckles compared to controls, supporting the view of the differential nuclear localization of kts isoforms. our study further confirmed that wt1 mutation resulted in abnormal expression of podocyte molecules in glomeruli of fs, though we did not know whether this phenomenon directly or indirectly resulted from loss of wt1 regulation. dent disease is an x-linked disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, calcium nephrolithiasis and the development of renal insufficiency after the middle age. so far, two genes responsible for the development of dent disease have been identified, i. e., clcn5 and ocrl1. ocrl1 was originally identified as a causative gene for lowe syndrome. in japan, igarashi et al. described for the first time that idiopathic tubular proteinuria in japan is identical to dent disease by mutational analyses. most of japanese patients with dent disease are identified by annual urinary screening as chanced proteinuria and several clinical phenotypes, such as incidence of nephrocalcinosis and long term outcome of renal function remains to be elucidated. furthermore, identification of ocrl1 as a second causative gene for dent disease has made the understanding of dent disease more complex. here we report 90 patients with dent disease phenotype with the results of genetic analyses and clinical features. out of 90 patients in 90 different families, 58 mutations (64%) in clcn5 were identified. in the 32 patients with no clcn5 mutations, genetic analysis in ocrl1 is ongoing, and at the moment 4 different mutations in ocrl1 ((i127stop, r301c, r476w and r318h) were identified. the remaining patients are now beeing investigated. among the patients in whom clcn5 mutations were detected, hypercalciuria are not always present. in several elderly patients, mild renal function impairment is present. there are similar clinical phenotypes between patients with clcn5 or ocrl1 mutations, but serum levels of ldh and ck are likely to be higher in those with ocrl1 mutations. in summary, we will present genotype and phenotype heterogeneity in japanese dent disease, and will discuss the clinical spectrum of dent disease. a. gulati 1 , s. sethi 1 , j. lunardi 2 , m. kabra 1 , n. gupta 1 , p. hari 1 , a. bagga 1 1 all india institute of medical sciences, 1st department of pediatrics, new delhi, india 2 hôpital de la tronche, genetics, grenoble cedex. france, france objectives: to study the clinical features and genetic basis of patients with lowe syndrome and identify female carriers. methods. case records of 6 patients with lowe syndrome presenting to this hospital, between 3-7 yr old, were reviewed. the clinical features were recorded and glomerular and tubular functions assessed. a detailed genetic analysis was performed on dna extracted from peripheral blood of patients and their mothers, which involved sequencing of all 23 exons of the ocrl1 gene. results: all patients showed failure to thrive, bilateral congenital cataracts, refractory rickets, delayed motor and language milestones and proximal renal tubular acidosis with fanconi syndrome. the mean schwartz gfr was 90 ml/min/1.73 sq. m. genetic analysis showed distinct mutations of ocrl1 gene in all patients studied. we report 4 new mutations having identified the variants c.779 a>g and c.853 g>t in exon 10, the variant c.1183_1184 ins t in exon 12 and c.2351-2 a>g in intron 22 in 4 independent patients. we also found 2 previously described mutations involving the region c.2309_2310 del tg and c.2377 c>t in exon 21. four of 6 mothers were heterozygous carriers. all genotypically proven carriers showed characteristic lenticular opacities. conclusion: the identification of mutations in the ocrl1 gene provides confirmation of the diagnosis of lowe syndrome. the new mutations described in north indian children expand the range of mutations that give rise to this condition. these observations have important implications for molecular diagnosis and genetic counseling in families with lowe syndrome. juvenile nephronophthisis (nph), an autosomal recessive nephropathy, is the most common genetic cause of chronic renal failure in childhood. in 10-15% of known cases, nph is associated with joubert syndrome (js), a neurological disorder described in patients with cerebellar ataxia, mental retardation, hypotonia and respiratory dysregulation. mutations in three genes, ahi1, nphp1 and nphp6 have been identified in patients with nph and js. as nphp1 mutations usually cause isolated nephronophthisis, the factors which predispose to the development of neurological symptoms in some patients are poorly understood. to determine such genetic factors and to assess the mutation rate of ahi1, nphp1 and nphp6 in nph and js, a cohort of 30 families with nph and at least one js-related neurological symptom was screened for mutations in these genes. thirteen (43%) and 8 (27%) unrelated patients were homozygous or compound heterozygous for nphp1 and nphp6 mutations, respectively. in 4 patients (13%) without nphp1, nphp6 or ahi mutations, mutations in a novel gene (nphp8/cors7) encoding a ciliary protein have been identified. interestingly, 7 of the 13 patients with nphp1 mutations carried either a heterozygous truncating mutation in nphp6 (1 patient), a heterozygous missense mutation in ahi1 (1) or the ahi1 variant r830w (5) . the variant r830w affects an amino acid conserved in vertebrates and predicted to be 'possibly damaging' by polyphen software. in conclusion, nphp1, nphp6 or nphp8 mutations can be found in 83% of patients with nph and js in our cohort. our finding that half of all patients with nphp1 mutations carry a mutation or a damaging variant in nphp6 or in ahi1 strongly supports the notion that epistatic effects provided by these genes contribute to the appearance of neurological symptoms in patients with nphp1 mutations. molecular cytogenetic techniques such as array-based cgh have been instrumental in the identification of microimbalances associated with syndromic phenotypes. we investigated 10 patients with unclear syndromic nephropathies (e. g. urinary tract malformations, focal segmental glomerulosclerosis, and persistent hematuria/proteinuria) and additional clinical features, such as mental retardation, heart defects or growth abnormalities. array-cgh analysis was performed with a whole-genome array with 8000 large insert clones providing an average resolution of <0.5mb. results: in one 16-year old female patient presenting with microhematuria, proteinuria, mental retardation including severe speech impairment, senso-neuronal hearing loss, and recalcitrant focal epilepsy, we detected a microdeletion in chromosomal bands xq22.3-q23. this deletion was verified by fish, found to be uniallelic, 2.2-3.7mb in size, and not to be inherited from the mother. electron microscopy of kidney biopsy showed splitting of the lamina densa and a thin basal membrane, which is diagnostic for alport syndrome. high-resolution cranial magnetic resonance imaging including white fibre tracking revealed a severe neuronal migration disorder with subcortical band heterotopia (double cortex syndrome), i. e. a second band of cortical neurons within the white matter below the true cortex. conclusions: in 10 patients with unclear syndromic nephropathies, we identified a female with a contiguous gene syndrome at xq22.3-q23. the microdeletion includes the x-linked alport syndrome gene col4a5 and the lisx gene associated with subcortical heterotopia, mental retardation and epilepsy. thus, the phenotype observed in our female patient combines features of the amme-complex (alport syndrome, mental retardation, midface hypoplasia, elliptocytosis) with x-linked lissencephaly. (29 f, 29 m; 17.80±6 .50 yrs, hemoglobin 9.67±1.08 gr/dl, ferritin 2827±1895 mg/dl) were enrolled. lipid profile, acute phase proteins (apps) were measured. renal tubular functions, plasma vegf level, urinary nag/cre ratio were determined. abpm and imt measurements were performed. the results were compared with healthy controls. results: mean 24-hour, day and night systolic-blood pressure (sbp), diastolic-bp (dbp) and mean arterial pressure values were comparable to that of control group. dipping in dbp was less in tm (19.03% vs 23.73%; p<0.05). the ratio of patients with less than 10% dipping in sbp (non-dippers) was higher in tm (51.9% vs 35.0%, p<0.05). mean plasma vegf level was 30.16±22.95 pg/ml [2.69-112.25] in tm, was within normal range (<10 pg/ml) in controls. apps were normal. imt of common carotid artery (cca) was 0.455±0.050 mm in tm group and 0.273±0.039 mm in controls, (p<0.01); imt of internal carotid artery (ica) was 0.344±0.037 mm in tm group and 0.203±0.041 mm in controls (p<0.01). positive correlations were found between vegf and microalbuminuria, b2-microglobulin and homosistein; between nag/cre and microalbuminuria; between cca-imt and age, and a negative correlation between cca-imt and ferritin. conclusions: renal tubular damage, abnormalities in abpm, increase in vegf and increase in cca-imt and ica-imt occur when the patients are asymptomatic and routine laboratory test are normal. optimal hemoglobin levels and deferoxamine therapy do not prevent the development of renal and vascular damage. l. sylvestre 1 , e. santos 1 , p. granzotto 2 , e. siqueira 2 , l. moreira 2 , l. rispoli 2 , n. mendes 2 , r. meneses 1 1 hospital pequeno principe, pediatric nephrology, curitiba, brazil 2 centro universitario positivo unicenp, curitiba, brazil introduction: hypertension is frequently underdiagnosed in children. early diagnosis and a planned follow-up is helpful in detecting and preventing the harmful long-term consequences of hypertension. therefore, we created a specific outpatient clinic to have a better follow-up of these patients. material and methods: we reviewed the files of patients from the outpatient clinic of hypertension, from the dept. of pediatric nephrology in hospital pequeno principe, curitiba, brazil, followed for more than 3 months, from march 2005 to december 2006. we analyzed demographic and anthropometric data, diagnosis, staging of hypertension, presence of target-organ damage and treatment. results: 72 patients were eligible, 40 boys, mean age at the first visit 6.3 years old, mean follow-up of 11 months. mean bmi=18.92 (44% overweight and obese). secondary hypertension was present in 47% of the cases, predominantly due to parenchymal renal disease; essential hypertension associated to overweight and obesity in 19 patients (27%) and there was no established diagnosis yet in other 19 patients. fifty-five patiens performed at least one abpm of 24 hours, 46 showed hypertension. twelve from 69 patients showed left ventricular hypertrophy and 18 from 61 patients had abnormalities of the retinal vasculature associated to hypertension. the most frequent drugs used to treat hypertension were ace inhibitors (49) and calcium channel blockers (47). conclusion: our data are in accordance that secondary hypertension is frequent in children, mostly associated to renal disease. furthermore, we could detect a large number of obese hypertensive children and adolescents. target-organ abnormalities are not as frequent as in adults but need to be monitored. intrauterine growth retardation (iugr) is characterized by low nephron number with or without reduced kidney size. leptin, an important hormone in the regulation of body fat massand weight, is decreased in fetuses with iugr. in the present study, weexamined the effects of leptin in a metanephric mesenchymal cell line ms7. ms7 is generated from the metanephroi of embryonic day 11.5 homozygous mouse transgenic for h-2kb-tsa. incubation of ms7 withleptin 1, 10, 50, 100 or 500 ng/ml for 24 h did not affect either [ 3 h]-thymidine incorporation or cell number. on the other hand, [ 3 h]-leucine incorporation was significantly increased by leptin in a dose dependent manner (120±9%, 123±2%, 130±3%, and 131±3% of control by 1, 10, 50, and500 ng/ml, respectively). protein/dna was also increased 1.7-fold by leptin 10 ng/ml. leptin 10 ng/ml activated both erk and p38. the levels of phosphorylated-erk (p-erk) and phosphorylated-p38 (p-p38) , as assessed by western blot analysis, started to increase at 10 min, peaked at 30 min (1.6-and 1.7-fold increase respectively) remaining elevated at 1, 2, and 6 h, and began to decrease at 12 h returning to the baseline level at 24 h. the levels of p-erk and p-p38 at 30 min were increased by leptin in a dose dependent manner (1.2-, 1.6-, 1.6-, and 1.7-fold increase by 1, 10, 100, and 500 ng/ml respectively). the levels of total erk and p38 remained unchanged. increase in [ 3 h]-leucine incorporation stimulated by leptin 10 ng/ml was completely inhibited by coincubation with a mek inhibitor pd98059 5 μm or a p38 inhibitor sb203580 5 μm. these results demonstrate that leptin induces hypertrophy of metanephric mesenchymal cells via erk and p38. the hypertrophic effect of leptin may play a role in normal renal development and may explain reduced kidney size in a hypoleptinemic state, iugr. objectives of study: to investigate the mechanism of nephron deficit in rat model of intrauterine growth retardation (iugr). methods: a rat model of iugr was built by maternal low-protein (6%) dietthroughout pregnancy. newborn male pups were chose as our studyobjects. the proliferation and apoptosis in kidney was showed by ki-67 detection and tunel method. expression of wt1, bcl-2, bax, and p53 mrnas in renal tissue were examined by real-time pcr, and expression of wt1 and bcl-2 gene products in renal tissue were examined by immunohistochemistry and western blot. the final number of glomeruli was determined at 2 weeks of age when nephrogenesis has finished. results: at 2 weeks postnatally, iugr offspring had fewer glomeruli per kidney than those in controls (p<0.001). in iugr newborns, tunel positive cells were more numerous in the nephrogenic zone. renalwt1 and bcl-2 mrna levels were significantly reduced in newborn iugrpups, and the bcl-2 mrna/bax mrna ratio was also decreased, but therewas no change in the expression of p53 mrna. in iugr newborns, the wt1and bcl-2 protein expressions were significantly decreased, and the irimmunostaining were also suppressed in the nephrogenic zone. conclusions: these results suggest that reduction of nephron number in iugr rat may be associated with enhanced apoptosis in kidneydevelopment. decreased wt1 and bcl-2 expressions and reduction of the bcl-2/bax ratio may contribute to the molecular mechanisms behind these findings. objective of the study: the aim of this study was to identify risk factors for urinarytract infection (uti) during follow-up of children with isolatedantenatal hydronephrosis. methods: between 1999 and 2006, 192 patients were diagnosed with isolated fetal renal pelvicdilatation (rpd) and were prospectively followed. after initialclinical and imaging evaluation, us scans, clinical examination, andlaboratory reviews were scheduled at 6-month intervals. the event ofinterest was time until occurrence of first episode of uti. cox's regression model was applied to identify variables that wereindependently associated with the uti. results: a total of 192patients were included in the analysis (140 boys and 52 girls) themedian fetal rpd was 10 mm (iq range, 7.8±14) and 95 patients (49.5%) presented bilateral rpd. seventyeight (41%) infants presented urinarytract anomaly. the most frequent detected uropathy was upjo (55), followed by primary vur (16), and megaureter (7). median follow-up timewas 24 months (iq range, 12-39 months). during follow-up, uti occurred in 27 (14%) of the 192 children. the incidencerate of uti was 5 episodes per 1000 person-month. the incidence rate of uti has decreased from 7.2 episodes per 1000 person-month in the first year of life to 3.3 in the second year, and to 1.4 after the third year. by survival analysis, the risk of uti for the whole series was estimated in 8.5% at 12 months, 14% at 24 months, and 21% at 36 months of age. after adjustment, two variables were independent predictors of uti during follow-up: female gender (rr=2.2, 95% ci, 1.04-4.8, p=0.03) and presence of uropathy (rr=4.6, 95% ci, 1.8-11.4, p=0.001). conclusion: according to findings, in a cohort of antenatal hydronephrosis, girls with vur or urinary tract obstructionhad a higher risk of uti during follow-up. objective of the study: to identify predictive factors of resolution of fetal renalpelvic dilatation (rpd) in a cohort of medically managed children. methods: between 1999 and 2006, 192 patients were diagnosed with isolated rpd and were prospectively followed. of 192 infants, 165 (86%) were clinically managed. after initial clinical and imaging evaluation, us scans, clinical examination, and laboratory reviews were scheduled at 6-month intervals. the event of interest was rpd resolution, regardedas renal pelvis <5 mm on two consecutive renal sonograms. cox's regression model was applied to identify variables that were independently associated with the event. results: a total of 165 patients were included in the analysis and uropathy was diagnosed in 51(31%) infants. median follow-up time was 22 months (interquartile range, 12 to 37 months). during follow-up, 60 (36%) patients presented rpd resolution. by survival analysis, the estimate of rpd resolution for the whole series was 23% at 12 months, 39% at 24 months, and 42% at36 months of age. the median time for rpd resolution was estimated at 49 months (95% ci, 36-62). in the survival analysis, three variables were found to be significantly associated with resolution of rpd during follow-up: mild fetal rpd, grades 1-2 (sfu grading system), and presence of uropathy. after adjustment, only absence of uropathy remained as an independent predictor of rpd resolution (rr=3.6, 95% ci, 1.7-7.4, p<0.001). conclusion: according to these findings, it was estimated that rpd resolution occurs in about half of the patients without uropathy at 2 years of age. objective: to study clinical and pathological characteristics of antineutrophil cytoplasmic autoantibody (anca)-positive glomerulonephritis(gn). methods: clinical data of thirteen patients during 5 years, with anca-positive gn were analyzed. results: of patients with anca-positive gn with an average age of 8.8±2.5 (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) years, 11 patients were female and 2 were male. the average course was 2.2±1.9 months. 8 cases onset between december and february. there was 3, 5, 2 cases whose chief complaint on admission was anaemia, swollen and hematuria respectively. the main clinical symptoms were: anaemia (100%), hematuria/proteinuria (100%), renal functional lesion (100%), edema (76.9%), oliguresis (38.5%), hypertension (61.5%), arthralgia (30.8%), rash (15.4%), abdominal pain (46.2%), fever (7.7%). laboratory tests: bun, scr and esr were high while hemoglobin was low in all patients. mpo-anca was positive in 13 cases c3 was normal in 4 cases and low in 9 cases. pathology features: all glomeruli are affected and show different degree of segment and glomus sclerosis. there was different degree of capsula glomeruli thickening. glomerulus capillary loop was necrotic, nuclear leukocytes and cell debris could be seen. inflammatory cell interstitial infiltration with lymphocyte and plasmocyte. endotheliocyte of small vessels of interstitial was swelling and vessel wall was edema, necrosis and glassy degeneration. immunofluorescence showed no or small immune complex deposition and showed pauci-immune gn. conclusion: onset of patients with anca-positive gn was hiding and there were nonspecific clinicalsymptoms in the early stage that reduced late diagnoses until esrd. female patients was predominant. renal pathology showed segment necrotic nephritis interstitial inflammation and polyangitis. the disease had unfavourable prognosis. background: renal function maturation isn't achieved at birth. vlbw infants exposed to intensive care have an increased risk of developing renal function impairment. moreover, we showed that ibu was associated with a significant impairment in renal function at one week of life in vlbw infants. objective: to evaluate renal function development in infants treated with ibu for pda closure as compared to infants not exposed to ibu, during the first month of life. methods: multicentric prospective cohort study of 27 to 31 weeks gestation (ga) infants exposed or not exposed to ibu within the first 5 days of life. infants presenting with renal impairment at birth, urinary tract malformation, or contraindication to ibu were excluded. infants exposed to ibu were paired to controls according to ga, centre and crib score. creatinine clearance (ml/min/1.73 m 2 ) was measured for glomerular filtration rate evaluation. fractional excretion of sodium (fena%), micro-albuminuria (mg/l) and alpha1-microglobinuria/creatininuria (1/ucr: mg/mmol) were also measured once a week up to 1 month of life results: 120 infants were studied, half exposed to ibu. birth weight was 1100±278 g (mean±sd), and ga 28±1 wks. results are presented in the table: *p=0.02;**=0.01;***<0.01. j. rouillard lafond, mp. morin, c. girardin centre hospitalier universitaire de sherbrooke, département de pédiatrie, sherbrooke, canada objectives of study: many studies have focused on the negative effects of low birth weight, especially caused by intra-uterine growth restriction, on adult renal function. however, few have addressed the impact of extreme prematurity (<28 weeks) on renal function of these children during their later childhood and adolescence. the aim of the present study is to estimate the renal outcome of this population, by determining blood pressure, glomerular filtration rate, fractional excretion of sodium and microalbuminuria in 24 children (11 girls and 13 boys) aged 7 to 18 years old (mean age 12) born between 24-28 weeks of gestation (mean: 27 weeks). methods: during one encounter, height, weight and blood pressure were measured for each subject. blood tests were conducted to quantify creatinine, electrolytes and cystatin c. microalbumine, creatinine and electrolytes were dosed in one micturition. pertinent risk factors of renal damage in their perinatal history were noted. results: renal insufficiency, defined by a clearance of less than 90 ml/min/1,73 m 2 , was present in 3 subjects (22%) when estimated by schwartz formula (84,67-86,20 ml/min/1,73 m 2 ) and in 1 (4%) when estimated by cystatin c (47,4 ml/min/1,73 m 2 ). furthermore, 5 (20%) children presented an elevated fractional excretion of sodium (1, 19-1, 56%) . finally, 8 children (33%) presented microalbuminuria, with albumin/creatinine ratio greater than 2,0 mg/mol (2,04-17,25 mg/mol) . those children presented more episodes of hypotension during neonatal period (p=0,028) and have a tendency to have had neonatal asphyxia more than the others (p=0,065). conclusions: these results suggest that children born extremely preterm may present renal insufficiency and sign of tubulopathy as early as adolescence, with microalbuminuria possibly announcing upcoming glomerulopathy. organogenesis isregulated by epithelial-mesenchymal interactions that take place in theembryonic kidney between the metanephric mesenchyme (mm) and theepithelium of the ureteric bud (ub). the mm expresses signals thatregulate ureteric branching while the ub signaling leads to inductionof nephrogenesis. as a response to the ub signals the mm cellscondense, aggregate, epithelialize and undergo simple morphogenesis togenerate segmented nephrons during kidney organogenesis in connectionto ureteric bud branching. we reported earlier that mutagenesis of fgf8 function from the whole embryonic mesoderm leads to kidney failure. activation of wnt-4 gene expression encoding another essential signal for nephrogenesis also depends on fgf8 function (perantoni et al., 2005) . given the important role of fgf8 in kidney development we targeted fgf8 roles in urogenital system (ugs) development with an ugs specific cre line pax 8 cre. pax8 credeletion was expected to recombine the floxed genome in the nephronprecursors, ureteric bud and the wolffian duct derivatives. in crossesbetween fgf8 c/c and fgf8 n/+ ; pax8 cre mouse lines fgf8 gene was deleted successfully. as a result the whole ugswas affected. the kidney was severely reduced in size. newborn nullmice were born alive but died within 24 hours likely due to kidneyfailure. in the deficient kidney the organization of theproximal-intermediate segments of the developing nephron was disturbed. marker analysis with in situ hybridization was consistentwith serious defects in nephrogenesis. we conclude that fgf8 functionis involved in the control of wolffian duct development andsegmentation of the assembling nephron. the zellwegerspectrum disorders (zsds) are characterized by a generalized loss of peroxisomal functions caused by deficient peroxisomal assembly. clinical presentation and survival are heterogeneous. although most peroxisomal enzymes are unstable in the cytosol of peroxisomedeficient cells of zsd patients, a few enzymes remain stable among which alanine: glyoxylate aminotransferase (agt). its deficiency causes primary hyperoxaluria type 1 (ph1, mim 259900), aninborn error of glyoxylate metabolism characterized by hyperoxaluria, nephrocalcinosis, and renal insufficiency. despite the normal level of agtactivity in zsd patients, hyperoxaluria has been reported in several zsdpatients. we aimed to determine the prevalence of hyperoxaluria in zsds and tofind clinically relevant clues that correlate with the urinary oxalate load. methods: we reviewed medical charts of 31 dutch zsd patients with prolonged survival (>one year). results: urinary oxalate excretion was assessed in 23 and glycolate in 22 patients. hyperoxaluriawas present in 19 (83%), and hyperglycolic aciduria in 14 (64%). renal involvement with urolithiasis and nephrocalcinosis was present in five of whichone developed end-stage renal disease. the presence of hyperoxaluria, potentially leading to severe renal involvement, was statistically significant correlated with the severity of neurological dysfunction. discussion: zsd patients should be screened by urinalysis for hyperoxaluria and renal ultrasound for nephrocalcinosis in order to take timely measures to preventrenal insufficiency. menkes disease is a very rare x-linked recessivedisorder of copper metabolism. the frequency is 1: 250.000 live births. mutations in the atp7a gene are described, which encodes for aintracellular copper-binding membrane protein. pathogenetically a defect in copper absorption is responsible for inadequate synthesis of copper requiringenzymes and causes multisystemic manifestations. the clinical picture ischaracterized by early neurodegenerative symptoms like muscular hypotony andcerebral seizures. the patients also present with the so called kinky hair, hyperelastic skin, and anomalies of the kidneys and the urinary tract. wereport on a patient of non consanguineous parents of german origin. theprenatal ultrasound did not show any malformations. birth at 35 weeks ofgestation. postnatally a softening of the cranial bones and a vesicoureteralreflux iv° with dilatation of the renal pelvis combined with a subpelvicureteral stenosis had been observed, which were operated at the 2 nd month of life. at the age of 3 months the patient presented with seizuresand abnormal hair structure. within the diagnostic course menkes diseasehas been suspected and the nonsense mutation parg980x has been identified inthe atp7a gene. the mother is not a conductor, a mutation in thegermline cannot be excluded. conclusion: the combination of urinary tract malformations and neurodegenerative symptoms should let you think of the very rare menkes disease. introduction: primary hyperoxaluria type 1 (ph1) is an inborn error of glyoxylate metabolism due to the deficient activity of the hepatic peroxisomal enzyme agt (alanine: glyoxylate aminotransferase). it leads to excessive endogenous oxalate production. patients develop urolithiasis and renal insufficiency. the contribution of specific precursors in the pathway leading to endogenous oxalate synthesis is not known. this is warranted to design appropriate treatments. we aimed to test the contribution of different precursors to oxalate synthesis. methods: wild type mouse hepatocytes were incubated with different potential precursors of glyoxylate, either in the presence or absence of alanine. in the absence of alanine flux through agt is deficient thereby mimicking agt deficiency. similar experiments were also performed in hepatocytes from agtdeficient mice. results: oxalate production was found to be highest with glyoxylate as substrate in the absence of alanine, whereas oxalate production was lower with glycolate, hydroxypyruvate, glycine, fructose, and ethylene glycol. the results obtained in wild-type hepatocytes incubated in the absence of alanine were comparable to those obtained in hepatocytes from agt-deficient mice. upon addition of alanine to wild-type mouse hepatocytes, however, resulted in 30% lower rates of oxalate production, in contrast to hepatocytes from agt deficient mice. discussion: hepatocytes derived from agt deficient mice represent a good model to study the contribution of different precursors to oxalate production in ph1. s. grisaru 1 , c. geary-joo 2 , f. snider 2 , j. cross 2 1 university of calgary, department of pediatrics, calgary, canada 2 university of calgary, department of biochemistry and molecular biology, calgary, canada gcm1 (glial cell missing), is a transcription factor necessary for the formation of placental syncytiotrophoblast in mice. gcm1 mutant mice die before nephrogenesis at embryonic day (e) 10. during early murine development gcm1 expression is limited to the placenta. however, immediately after birth, gcm1 is increasingly expressed in the kidney in proximal tubular cells in the outer medulla. we recently reported successful rescue the gcm1 null phenotype using a tetraploid aggregation approach (jasn vol.17, 2006) . since our previous report, further analysis of the aggregation products confirmed only 3 homozygous mutants (2 males and a female) obtained from six hundred and twenty five transferred aggregate embryos resulting in 121 live pups. abnormal cortico-medullary patterning was demonstrated by histology analysis of adult gcm1 null mice kidneys. this abnormality was further defined by immunohystochemical detection of known nephron segment-specific markers (aquaporin-7, aquaporin-2 and tamm-horsfall protein) in gcm1 null kidney sections. to define the expression of gcm1 in human kidneys, commercially available anti-human gcm1 polyclonal antibodies were used to detect gcm1 protein in tissue sections of newborn kidneys obtained from autopsies. gcm1 was detected by immunohystochemistry in the renal cortex in tubular structures with cells having a brush border suggestive of proximal tubules. gcm1 signal was not detected in the renal medulla. conclusion: in humans, gcm1 is expressed in renal proximal tubules at birth whereas in adult mice its mutation is associated with abnormal renal cortico-medullary ultrastructure. this effect may represent a primary role for gcm1 in late renal development and patterning, or structural changes occurring postnatally secondary to alterations of tubular physiology caused by gcm1 inactivation. objectives: lupus nephritis (ln) in singapore children treated with cyclophosphamide and/or azathioprine has a poor prognosis with a reported 10-year renal survival of 59%. this study examined the long-term outcome of children with lupus nephritis using a new protocol comprising pulse intravenous methylprednisolone, mmf ± cyclosporine. method: twenty-one children with ln (age range at start of treatment 3.7-14.8 years) who were treated between the years 1995 to 2007 were included in this retrospective study. mmf dose was 1200 mg/m 2 /day. mean duration of follow-up was 3.6±2.0 (range 1.3-8.6) years. treatment outcome was defined by systemic lupus erythematosus disease activity index (sledai), renal function, proteinuria and serologic markers. effect of steroids on growth was assessed by height standard deviation score (htsds). statistical analysis was performed using wilcoxon signed rank test. results: at presentation, 72% had nephritic-nephrotic syndrome, 14% had nephrotic syndrome, while 14% had renal failure requiring dialysis. renal biopsy classification (who) was ii in 19%, iii in 24%, iv in 33%, and v in 24%. comparing pre-mmf treatment and current follow-up parameters respectively, sledai (17.4±8. objectives of study: to understand the effects of response gene to complement 32 (rgc-32) in tgf-β1 induced epithelial-mesenchymal transition (emt) on human renal proximal tubular epithelial cells (hptecs). methods: constructed rgc-32 expression plasmids and rgc-32 sirna hairpin plasmids, transient transfected them into hptecs in vitro, and then treated hptecs with tgf-β1 (5ng/ml) or vehicle alone for indicated time (0, 30min, 2h, 8h, 24 h) . rt-pcr and western blot were used to determine the expression of a-sma, ecm (col-i, fn1). the mrna expressions of e-cadherin and sm22a were detected by rt-pcr. results: (1) the promoting effects of rgc-32 on emt. instead of stimulation with tgf-β1, the hptecs, those overexpressed rgc-32 gene, de novo obtain the ability to produce markers of myofibroblast phenotype (a-sma, col-i and fn) and sm22a gene, as well as lost the capability of expressing e-cadherin gene. (2) the eliminating effects of rgc-32 sirna on emt that induced by tgf-β1. after stimulation of tgf-β1 for 24 hours, the expression of a-sma, col-i, and fn as well as sm22a gene in hptecs, those rgc-32 genes were interfered with rgc-32 sirna, were significantly decreased than that in controls. conclusions: rgc-32 was an important regulator for tgf-β1 and its downstream signalling smad proteins on emt. background: low birth weight is associated with a low nephron endowment. this may predispose to hyperfiltration and cascading proteinuria particularly if obesity develops. our report relates to an emerging population of children with proteinuric kidney disease in our multiethnic community. methods: forty-two obese children (mean age 14±5 years) with proteinuric kidney disease (kd) were studied. twenty-four were of normal birth weight (nbw>3000 grams) and 18 were of low birth weight (lbw<1200 grams). there was a female (24/42=57%) and an ethnic predominance (23 african, 16 hispanic). degree of proteinuria was determined by the random urine protein (pr) and albumin (alb) to creatinine (cr) ratios (upr/cr and ualb/cr). renal function (egfr) was estimated from the schwartz formula. body mass index was used as a measure of obesity (>95% centile). insulin resistance was measured by the homeostatic model assessment (homa). kidney tissue was obtained in 28 of the patients for pathology and histomorphometry. results: average bmi was 96±4% tile. fasting insulin and homa scores were not significantly different in the obese nbw versus obese lbw children. renal biopsy specimens revealed focal glomerulosclerosis (fsgs) in the majority of patients (23/28=83%). progression to end stage kidney disease was significantly greater in lbw compared to nbw children with a median renal survival of 11 years, p<0.01. glomerulomegaly as measured by glomerular diameter was similar in obese patients and significantly greater than non-obese controls with fsgs. conclusions: obesity appears to be a confounding factor in the development of glomerulosclerosis and progression of kidney disease in children. low birth weight and concomitant low nephron endowment may contribute to disease progression, especially in those of african and hispanic descent. objective: to determine long term outcome and prognostic factors of iga nephropathy in a large single center cohort of pediatric patients. patients and methods: we have reviewed the medical charts of 79 patients with biopsy proven igan that have been followed at our institution from 1983 to 2004, with a minimal follow-up of 2 years. follow-up data, including proteinuria >500 mg/24 h or the need for ace-is therapy, chronic renal failure (crf) and hypertension were analysed after 2 years and 5 years of follow-up. data from 60 patients with follow-up longer than 5 years were also available (mean follow-up 9.9 years, range 5-24 years). 61% of patients received therapy (cyclophosphamide in 10 patients and/or steroid±ace-is in the remaining). clinical features at the onset, histology class (lee and haas) and treatment during the first 2 years were analysed by multivariate analysis against the above mentioned dependet variables. results: the average follow-up was 7.85 years (range 1-24 years). presentation symptoms included macroscopic hematuria in 76% of patients. at the end of follow-up, renal function was normal in 94% patients, 3 patients have reached end-stage renal disease and 2 had chronic renal failure. proteinuria or the need for aceis at 2 years was significantly associated with the age of onset (or: 1.30 [1.09-1.56] ) and proteinuria at the onset (or: 1.86 [1.05-3.32] ). crf was significantly associated with familial igan (or>10). hypertension at onset was significantly associated with persistent hypertension during follow-up (or: 8.82 [1.55-50] . conclusion: taken together, these data indicate that the overall prognosis of igan is good during childhood and that the worst prognostic factor for development of crf is familial igan. overall, histological classification had a poor correlation with the outcome of the disease. this study was designed to compare three urinary protein expert systems for profiling proteinuria (pu) in children with kidney diseases. freshly voided urine was collected from 61 children with glomerular diseases, 19 children with tubular diseases and 25 healthy children aged 3-16 years. 23 out of 80 children with renal disease had a glomerular filtration rate (gfr) <90 ml/min/1.73 m 2 . the urinary protein expert systems were 1. albumin/total protein ratio (apr), 2. alpha-1microglobulin/alpha-1-microglobulin + albumin algorithm (aaa), and 3. the complex upes algorhithm (using serum creatinine, urinary total protein, alpha-1-microglobulin, albumin, igg, alpha-2-macroglobulin and dipsticks). apr correctly identified glomerular pu in 47 of 61 (77%) children with glomerular diseases, tubular pu in 16 of 19 (84%) children with tubular diseases and normal pu in 23 of 25 (92%) healthy children. aaa correctly identified glomerular pu in all 61 (100%) children, tubular pu in 18 of 19 (95%) children, and all 25 healthy children were characterized as having no pathological pu. upes differentiated the type of pu in children with glomerular diseases into glomerular (50/61 patients) and mixed glomerulo-tubular (6/61 patients). tubular pu in children with partial or complete renal fanconi syndrome was identified in 16/19 patients and described as mixed glomerulo-tubular pu in 3/19 patients. mixed glomerulo-tubular pu was only found in children with ckd stages 2-5 of glomerular and tubular diseases. in conclusion, urinary protein expert systems may be used to distinguish between glomerular and tubular pu. the aaa algorithm had the highest reliability when compared with the two other expert systems and the accuracy was not negatively influenced by a decrease of gfr. however, upes provided additional information on mixed glomerulo-tubular pu in patients with a low gfr. background: the three lmw proteins cystatin c (cys), β2-microglobulin (β2-m) and β-trace protein (β-tp) are useful markers of gfr. cys is particularly well suited for the detection of incipient renal failure. however, corticosteroid medication has been shown to stimulate cys production. aim of the study: analysis of the effect of corticosteroid therapy on the correlation between gfr and the three lmw markers. patients: 119 patients (47 f, 72 m; median age 10.9 years, range 0.2 to 18.9) with malignant (n=47) or nephrological (n=72) diseases underwent a single-shot inulin clearance. the respective lmw proteins were measured by particle-enhanced immuno-nephelometry. 27 children received corticosteroids (prednisone or dexamethasone) in a mean dosage of 28 mg/m 2 /d of prednisone equivalent (pred/bsa). multiple linear regression analysis was performed between the lmw markers as dependent and both gfr and steroid-dose as independent variables. results: mean gfr was 77.2±27 ml/min/1.73 m 2 , mean cys 1.08±0.5 mg/l, β2-m 2.17±1.33 mg/l and β-tp 0.97±0.57 mg/l. cys was highly correlated with the reciprocal of gfr (p<0.0001) but not with corticosteroid-dose (p=0.138), whereas both β2-m and β-tp were highly correlated (p<0.0001) with both the reciprocal of gfr and the reciprocal of pred/bsa. discussion: using gold-standard gfr measurements, we cannot confirm earlier reports indicating an increase in serum cys during corticosteroid medication. by contrast, steroids significantly lowered both β2-m and β-tp serum concentrations. we conclude that at least in patients with mild renal insufficiency cys -unlike β2-m and β-tp -appropriately reflects gfr also during steroid therapy. this further supports the concept of cys being a superior marker of incipient renal failure. objective: to repeatedly follow kidney function since onset of type1diabetes and evaluate whether gfr can predict development of micro-or macroalbuminuria or end stage renal disease. design: observational cohort study. methods: since 1978, all diabetic patients undergo renal function tests every 2nd to 3rd year from onset. 363 children, 204 boys, have done 1640 clearance studies. 81 healthy children and young adults, 5-30 years of age, served as controls. gfr was evaluated by clearance of inulin during water diuresis and continuous infusion. results: gfr during the first 15 years after onset of diabetes was significantly higher than that of controls (mean 130-142 vs. 116 ml/min/1.73 m 2 ). at onset, 2 and 5 years after, boys had significantly higher gfr than girls (mean 135, 148, 146 vs. 128, 134, 133 ml/min per 1.73 m 2 ) but after 8 years no differences were found between sexes. the occurrence of microalbuminuria, albuminuria during the first 15-20 years was analysed and mean of gfr of 0, 2 and 5 years, 2 and 5 years, 2, 5 and 8 years and all those gfrs separately were compared between patients still normoalbuminuric, microalbuminuric and macroalbuminuric after 10 and 20 years resp. no significant differences were found between the groups. moreover the change in gfr from 0 to 5, 2 to 5 and 2 to 10 and 5 to 10 years were also compared between the groups and no significant differences were found.8 young adults reached end stage renal disease (esrd) after 15-29 (median 20) years and comparing their gfrs during the first 5-8 years with those still normoalbuminuric after 20 years, no significant difference was found. conclusions: hyperfiltration is found in children with type 1 diabetes during the first 12-15 years from onset and hyperfiltration was equally seen during the first 5-8 years in those children who in the future developed normo-, micro-, albuminuria and/or esrd. background: hiv associated nephropathy (hivan) remains an important entity despite the use of highly active anti-retroviral therapy (haart). our objectives were to determine the prevalence and severity of renal manifestations in a cohort of hiv infected children during the haart era. methods: a retrospective analysis was conducted on 286 children infected with hiv. renal assessments included quantitation of proteinuria, radiologic abnormalities, and renal function. persistent proteinuria (pp) was defined by urine protein to creatinine ratio (upr/cr) >0.2 detected on at least two measurements 1 month apart. renal sonography and mag 3 renal scintigraphy were categorized according to the presence of bilateral increased echogenicity and/or nephromegaly, and cortical retention and/or diffuse parenchymal disease, respectively. hivan was considered in those children that had pp associated with any radiological abnormalities. results: of the 286 children, 98.6% were perinatally infected. eighty-five (29.7%) had pp. of these, 46 had pp alone, while 39 (13.6%) developed hivan. the mean age of onset of hivan was 9.4±0.8 years. overall mortality at the time of analysis was 3.8% and it was highest in those with hivan. viral load (vl) >100, 000 copies was significantly associated with hivan. creatinine clearance was significantly decreased in patients with hivan. conclusions: the prevalence of pp in our population of perinatally infected children remains high (29.7%), with at least half of them showing evidence of hivan. persistently high vl (>100, 000 copies) was associated with the presence of hivan. a spectrum of renal related disorders is a frequent occurrence in hiv infected children and should be sought with periodic urinalysis, quantitation of proteinuria and renal function, and imaging and/or histopathological studies. mmf has shown to be effective in adult ln, whereas only anectodical data are reported in childhood. we evaluated mmf in 15 children with ln, 11 f/4 m, mean age: 12.4±3.9 yrs, proteinuria >3 g/day, decreased c3 and increased anti-dsdna serum levels, normal renal function. renal biopsies, before mmf, showed the following classes (weening) : iv in 8 cases, iii in 1, ii in 5, vi in 1. before mmf: 2 patients have received i. v. cyp; 2 more received aza and csa but were in flare-up of disease; the remaining 11 were newly diagnosed patients. each patient received three i. v. metilprednisolone pulses and thereafter mmf (plus oral prednisone(p): 1 mg/kg/day) was administered (mean dose: 29±7.7 mg/kg/day; through level: 3.6±1.2 μg/ml). outcome was monitored by sledai score, renal function, proteinuria. in 11 children p was tapered and, after 4.6±2.3 month mean time, stopped; 4 children were receiving p (0.3 mg/kg/day). the mean followup is 35±16 months. sustained clinical remission was observed: proteinuria was absent in all, in 10 patients an increase of serum c3 and c4 and a decrease of anti-dsdna levels was seen. significant steroid sparing effect was obtained: hypercorticysm dramatically improved. of the 15 patients 8 achieved 2 years of mmf treatment and in them, at this time, a serial second renal biopsy was performed: histopathological activity indices reduced (8.76±2.55 vs. 5.3±6.97, p<0.01), whereas chronicity indices did not change (3.47±1.56 vs. 3.3±3.31). no haematological and/or gastrointestinal side effects were observed. our pilot study suggests that mmf represents a good alternative to traditional therapy in the treatment of sle in children, and in controlling disease activity and as steroid sparing agent without significant side effects over the entire period of therapy. mmf has shown to be effective, during treatment, in mantaining remission of childhood sd and csad ns, but few data are available on the mmf long term effectiveness after drug stopping. we report the results of two years mmf treatment in 33 children with sd and csad ns. the characteristics of sd and csad groups were, respectively: 19 patients, 11 boys, mean age 6.7 yrs vs. 14 pts, 11 boys, mean age: 11.6 yrs (p<0.005); first episode ns mean age: 3.4 yrs vs. 6.3 yrs; ns mean duration: 2.9 yrs vs. 7.4 yrs (p<0.001); mean steroid therapy duration: 2.2 yrs vs. mean csa therapy duration: 3.2 yrs; histologic features: fsgs 2, mc 17 vs. fsgs 9, mc 5. in both groups mmf was started after remission was achieved with prednisone administered at the last relapse. mmf treatment: lenght: 24 months; mean dose: 27.8±4, 1 mg/kg/day; plasma through level: 3.6±1.2 mcg/ml; non responder: patient presenting a ns relapse during mmf. in sd group 17(83%) and in csad 12 (85%) subjects were responders. in 14 patients of sd group and 10 patients of csad group p could be withdrawn over a mean period of 11.3 months, so that ns remission was sustained just by mmf; remaining patients were receiving p at a mean dose of 0.3 mg/kg/a. d. two years mmf treatment was accomplished in 26/33 (78%) patients. at 24.3±5 months mean followup since mmf withdrawal, 6 (23%) patients (4 of sd and 2 of csad group) relapsed after 9.3 months (3.2-12.1) mean time no haematological or gastrointestinal side effects were observed. our results demonstrate that two years mmf treatment in sd and csad ns children is effective not only in maintaining remission during therapy, but also in achieving persistent remission after withdrawal of drug in a significant rate (>70%) of patients; the side effects and the rate of mmf dependence are negligible with respect to those of steroids and csa. information on long-term renal function following treatment for wilms tumor (wt) are relatively scanty. previous studies reported a worrying late development of microalbuminuria (uma), hypertension (hpt) and even reduction in glomerular filtration rate (gfr). the aim of the present study was to evaluate the long-term renal outcome in a cohort of patients who underwent uninephrectomy for wt. glomerular function (as creatinine clearance by cockroft-gault formula) was calculated and uma (as uma/ucr ratio) as well as urinary b 2 microglobulin excretion were detected. 24-hours ambulatory blood pressure monitoring was also recorded. fifteen patients (11 f) with a median age at wt diagnosis of 4.4 yrs (range 1.8-16.6) were studied. the median follow-up was 13.3 yrs (10.2±19.3). eight patients had been classified as wt stage 1 and 7 as wt stage ii. all patients had been treated with unilateral total nephrectomy and chemotherapy. two of the children had also been addressed to radiotherapy. the primary disease did not recur in any of the patients. the median age at time of investigation was 18, 3 yrs (range: 12, 7-30, 4). none of them had a gfr below normal limit (mean gfr was 109.8±26.8 ml/min/1.73 m 2 ). urinary b 2 microglobulin excretion was normal (mean ub 2 /ucr: 0.5±0.3) in all of the patients. the mean uma/ucr ratio, was 0.13±0, 1 with only 1 patient exhibiting higher then normal values (uma/ucr ratio: 5, 3). the 24 hr blood pressure was normal in all patients with a mean systolic and diastolic blood pressure sds of -0.5±0.7 and -0.1±0.8, respectively. we conclude that as far as renal function, unilateral total nephrectomy combined with chemotherapy for low-stages wt can be look at as a safe treatment although it might be wise to monitor renal function at 5-year interval. classicaly, patients are divided into monosymptmatic enuresis (mne) and non-monosymptomatic enuresis, however, there is upcoming evidence that this subtyping might be artificial. the aim was to register the characteristics of nocturnal diuresis-rate and bladder volume in both subtypes. methods: retrospective analysis of 1000 consecutive patient-files, age 6-18, primary consulting for enuresis in a tertiary center. registration of incontinentia diurna (id) and maximal functional bladder volume (vmax), 24 hours urine-collections in 4 day and 4 nighttime-collections with uosmol and diuresis-volume (dv) and-rate. patients are divided into a mne and nmne-group. results: 1) vmax is significantly lower than bladder volume for age, 2) nocturnal polyuria is only present in 1/3 patients, 3) nocturnal diuresis is >vmax, 4) there is a significant linear correlation between nd and the nocturnal/daytime-diuresis-ratio, indicating fluid intake dependency. 5) there is a negative correlation between nd and urinary osmolality. 6) but the positive correlation between total nocturnal osmotic excretion and nd is much stronger. this unexpected observation cannot be explained by the classical primary vasopressin-theory. conclusion: our data show (almost) no statistical difference between the mne and nme-groups, suggesting a continuum instead of 2 separate identities. both groups have a significant low vmax and nocturnal polyuria. the observation of the extremely strong correlation of nocturnal polyuria with the high osmotic excretion and high 24 h urine-production suggests that nocturnal diuresis-rate is highly fluid-and nutrition-dependent, and therefore more attention should be given to this part of the urotherapy. a. deguchtenaere, a. raes, j. dehoorne, r. mauel, e. vanlaecke, p. hoebeke, j. vande walle there is increasing evidence that a subgroup of patients with nocturnal polyuria may have an abnormal circadian rhythm of tubular sodium which may result in vasopressin resistance. the pathogenesis of this phenomenon remains to be elucidated. however if the increased sodiumexcretion overnight results in the ddavp-resistance, decrease of the sodium-excretion-overnight may respond in subsequent ddavp response. aim of the study: retrospective study on the circadian rhytm of diuresis-rate and osmotic excretion in basal condition and subsequent during introduction of ddavp, diet and furosemide. results + discussion: 1) baseline-values show significant lower uosmol and higher diuresis-rate overnight compared to controls. striking is the >40% part of electrolytes to explain the high osmotic excretion. 2) introduction of ddavp results in a normalization of nocturnal uosmol, but despite a significant decrease of uosmol overnight, nocturnal polyuria persists. 3) protein-and sodium-restriction results only in slight differences, but of course we do not have data on the compliance. 4) furosemide in the morning results in a significant increase of daytime diuresis, osmotic and sodium-excretion, but as compensation decreased nighttime diuresis, osmotic and sodiumexcretion. 5) in 8/10 cases the antidiuretic effect results in an anti-enuretic effect. conclusion: this pilot study clearly demonstrates that introduction of early morning furosemide results in significantly lower nocturnal diuresis. because the urinary osmolality remains high, this correlates with decreased nocturnal osmotic excretion associated with increased osmotic excretion (sodium) during daytime. background: the elasticity of the vessel walls decreases with age, this process is dramatically speeded up by uremia. as an early indicator of arteriosclerosis pulse wave velocity (pwv) increases along with arterial stiffness. aim: to establish normal values for pwv in healthy children; to compare it with children on dialysis. patients, methods: pwv was measured with a pulsepen device in 116 healthy children and young adults (age range 6-23 years) as well as in 10 uremic children (14,4±4 years) (crf) treated by hemodialysis (n=7) or peritoneal dialysis (n=3). two control groups of 10-10 childrens were formed using the database of healthy children: one matched for age (a-c) and one adjusted for height and weight (h/w-c). blood pressure, heart rate, serum calcium (ca), phosphate (p) , and parathyroid hormone levels were also determined. results: a significant linear correlation was found between pwv and age (r=0, 60), height (r=0, 49), weight (r=0, 43), (p<0, 01), systolic blood pressure (r=0, 38) and heart rate (r=-0, 24) (p<0, 05). crf patients were smaller by 15, 3 cm than a-c (p<0, 05), and younger than h/w-c by 4, 5 years (p<0, 01). pwv in crf (5, 68±0, 96 m/s) did not differ significantly from a-c (5, 04±1, 18), however it was elevated in comparison to h/w-c (4, 51±0, 55 p<0, 01). serum p, caxp and pth was increased in crf (p<0, 001) conclusion pwv is higher in children with crf as a sign of increased arterial stiffness. controls matched for height and weight should be used in states of severe growth retardation. a number of established risk factors potentially responsible for arterial dysfunction are present in crf. ngal has been identified as an early marker of acute renal failure (arf). sepsis in very low birth weight (vlbw) infants is associated with arf more often than recognized. the aim of this study is to determine whether ngal represents a marker of renal impairment in vlbw infants affected by sepsis. samples of urine of 36 vlbw infants were prospectively collected for weekly measurement of ngal. after evaluation of the clinical course, 2 groups were identified: group sepsis includes 14 infants affected with 16 septic events associated with some degree of renal impairment and group normal includes 22 uncomplicated vlbw infants. a mouse model of sepsis was created in 11 neonatal mice by intra-peritoneal introduction of salmonella lipopolysaccharide. kidneys were harvested 24 hours after the challenge, and ngal mrna was quantified by real time pcr. ngal values of the normal group did not differ with gestational age or post-natal age of the neonates. the upper bound of the 95th percentile confidence interval was 40 ng/ml. the median value of ngal in the sepsis group at 7 days before the septic event was 75 ng/ml and during sepsis was 150 ng/ml: these values were not significantly different, but both were significantly higher (p<0.001) than the median of the normal group (10 ng/ml). once sepsis had been treated, the median value of urinary ngal was similar to normal (10 ng/ml p=0.17). changes in urine ngal concentration paralleled changes in serum creatinine. sepsis induced animal models showed a dramatic increase of ngal mrna in kidney tubules that paralleled acute renal failure. these neonatal animal and human data suggest that ngal may be an early marker of renal impairment in septic vlbw babies. further investigation is necessary to more exactly define the temporal relationship between the onset of sepsis/arf and rise in urine ngal concentration. we report 4 cases of acute renal failure (arf) associated with orellanus syndrome, a cortinarius mushroom poisoning. grand-father, mother, father and son presented with arf 1 week after gastrointestinal symptoms and 2 weeks after repetitive ingestion of wild mushrooms. critically arf was observed for the 11 year-old boy: anuria, severe metabolic disorders (hyponatremia 124 mmol/l, hyperkaliemia 9 mmol/l, serum creatinine 1137 mmol/l, blood urea 54 mmol/l). renal biopsy was performed for the grand-father, father and son (day 6, 9 and 8 respectively after presentation) and showed similar lesions: severe tubulointerstitial nephritis (tin) with tubular necrosis and interstitial fibrosis. renal replacement therapy was necessary for the father and the son. the mother recovered completely in two weeks without dialysis while renal function improved slowly for the two men. the boy is still hemodialyzed 5 months later. his main problem is uncontrolled hypertension. the diagnosis was confirmed 3 weeks later since fungal spores of cortinarius orellanoides were observed in the contaminated meal by light microscopy. the severity of the disease seems to be related to the toxin quantity: the 40kg boy ate mushrooms as much as his father and grand-father, the mother ate much less. cortinarius spp poisoning is an exceptional paediatric cause of arf. gastrointestinal disorders are the main symptoms of the initial phase of the poisoning appearing 3 days after the mushrooms ingestion. the renal phase is delayed (median 8.5 days) characterized by arf secondary to tin. the toxin effects are dose-related, explaining the severity of the boy's symptoms. the prognosis is severe with 60% of end stage renal failure. currently no treatment is available. although rare, mushroom poisoning should be considered in the differential diagnoses of arf with tin. l. mendels, ah. bouts, j-c. davin, j. groothoff emma children's hospital/academic medical center, pediatric nephrology, amsterdam, the netherlands background: inchronic dialysis, tertiary hyperparathyroidism (th) is clinically revealed by persistent combined high parathyroid hormone (pth), normalor high total serum calcium (tca) and normal phosphate levels. sincethe introduction of bicarbonate containing dialysate in peritoneal dialysis (pd), we have observed combined high tca and pth level sunusually early after onset of dialysis therapy. in most of the secases, ionized calcium (ica) levels were low. we aimed to investigate the extent of this discrepancy and its association with the mode of therapy. methods: serum ica, tca, pth, bicarbonate and capillary ph were assessed over 2 years in 10 pediatric pd, 11 hemodialysis (hd) and in 9 transplanted (tx) patients. associations between tca, pth and ica were analyzed. results: comparedto tx patients, we found in pd and hd patients a lower mean ica/tcaratio (both p<0.0001), an increased mean tca-ica (p<0.001 and p <0.01, respectively), and a higher number of combined normal/increased tca and decreased ica and increased pth values (44.7% and 32.3%, respectively for pd and hd, vs.0% for tx). alow ica/tca was associated with a high capillary ph (r=-0.51; p<0.0001), a high venous bicarbonate (r=-0.34, p=0.001) and a lowage (r=0.21, p=0.02). conclusions: ica levels are warranted for monitoring calcium phosphate homeostasis in dialysis patients, especially in young pd patients. the use of only tca levels might lead to an inadequate treatment with vitamin d, and henceinduce the development of autonomous hyperparathyroidism in these patients. preterminal renal failure (prf)and end-stage renal disease in children and adolescents are associatedwith an increased risk of atherosclerosis and cardiovascular disease. oxidative stress is one of the pathogenetic factors that could possiblybe influenced by therapeutic interventions. we investigated biomarkers of oxidative stress in 12 children (median age 9.6 years) with prf (median gfr 43 ml/min/1.73 m 2 , range 15-86) andin 11 children (median age 11.9 years) under peritoneal dialysis (pd)and 13 healthy age-matched controls (c). plasma samples wereinvestigated for malondialdehyd (hplc) and carbonyl groups in proteins(elisa) as biomarkers for oxidative stress as well as the plasmaantioxidative substances vitamin c (photometric), vitamin e (hplc), ubichinols (hplc), sulfhydryl groups in proteins(photometric), erythrocyte resistance to radicals and the total radicaltrapping antioxidant capacity (trap). in both patient groups prf and pdwe found a depletion of sulfydryl groups and ubichinol-10 and a reducedresistance of erythrocytes to radicals. malondialydehyd (p<0.05) andcarbonyl groups (p<0.01) were elevated in the pd group compared tocontrols. conclusion: from these studies we concludethat in children under peritoneal dialysis biomarkers of oxidativestress are elevated. moreover antioxidative defenses in preterminalrenal failure as well as under peritoneal dialysis are impaired. significant acute renal failure due to non-steroidal anti-inflammatory drugs: inpatient setting in united states non-steroidal anti-inflammatory drugs (nsaid) are freely available over-the counter. many children routinely use them without medical supervision. fourteen inpatients mean age of 15.0±2.84 years (4 males, 10 females), were referred to nephrology for acute renal failure. based on history, biochemistry, imaging and urinalysis the diagnosis of acute renal failure due to nsaid was made. all patients admitted to taking ibuprofen and six also consumed naproxen. the exact doses of either could not be scientifically determined as none were prescribed by a physician. none of the patients had underlying renal diseases at the time of admission. nine patients had proteinuria and 12 had hematuria (including one with gross hematuria). one patient had nephrotic syndrome but resolved spontaneously without steroids and has remained in remission for 2 years. two patients required dialysis. only one of the dialyzed patient required steroid therapy for recovery of renal function. all data are expressed as mean±sd. the mean duration of hospitalization was 6±4.3 days. the mean serum creatinine at the peak of renal failure was 3.97±4.74 mg/dl (range 1.2-16.6). all patients recovered renal function with normalization of serum creatinine to 0.72±0.15 mg/dl (range 0.5-1, p<0.01). however, the duration from onset to normalization of serum creatinine was 48±63 days; indicating many patients had abnormal renal function for aprolonged period. in conclusion, nsaids pose significant risk of renal failure forsignificant duration and as an entity may be under recognized. objectives: treatment with growth hormone (gh) improves growth retardation of chronic renal failure. cdna microarrays were used to investigate gh-induced modifications in gene expression in the growth plate of uremic young rats, the organ where longitudinal growth takes place. methods: rna was extracted from the tibial growth plate from two groups (n=10) of young rats: uremic (nx) and uremic treated with 3.3 mg/kg/day of intraperitoneal gh for one week (nxgh). after reverse transcription, agilent technology was used to analyze differential gene expression by microarrays containing 21, 000 rat probes (four hibridizations were performed). most expressed genes were detected using linear models and bayesian methods. to confirm gene expression changes shown by the chips, some genes known to play a physiological role in growth plate metabolism were analyzed by real-time quantitative polimerase chain reaction (qpcr). the ribosomal protein l4 (rpl4) expression did not show changes in the array and was used as the housekeeping gene. results. gh modified the expression of 224 genes, 195 being upregulated and 29 down-regulated. the assay was validated by the qpcr results, which confirmed the sense of expression modification found in the arrays for insulin like growth factor i (down), insulin like growth factor ii (up), collagen 5 alpha 1 (down) and proteoglican type 2 (up) . conclusions: this study shows for the first time the profile of growth plate gene expression modifications caused by gh treatment in experimental uremia. the further analysis of selected individual genes, whose expression is differentially modified by gh will contribute to explain the mechanism of the stimulating effect of gh on growth in chronic renal failure. objectives of study: children with chronic renal failure have an increased risk of cardiovascular disease. this is associated with endothelial dysfunction, a key pathophysiological factor in atherosclerotic disease. circulating endothelial progenitor cells (epcs) have the potential to repair endothelial damage and promote angiogenesis. in adults, the number of epc in peripheral blood correlates with endothelial function and reduced epc levels are associated with a higher incidence of cardiovascular events. we aimed to investigate if children on long-term hemodialysis (hd) therapy have reduced epc levels. methods: we quantified circulating epc in 12 pediatric hd patients before a midweek hd session and 11 healthy age-matched controls. epc are a subfraction of the haematopoeietic stem cells (hsc) expressing both hsc-marker cd34 and the vegf-receptor-2 kdr. using flow cytometry, epcs were identified as cd34+kdr+ cells and quantified relative to the number of granulocytes in the sample. results: the number of epcs in the peripheral blood was significantly reduced in hd patients (12.0±1.9 vs 29.0±7.3/10 5 granulocytes, 59% reduction; p=0.03). the total number of circulating hsc also tended to be lower in hd patients (71.2±7.3 vs 112.8±23.7/10 5 granulocytes, 39% reduction; p=0.09). conclusion: the number of circulating epcs is significantly reduced in children on long term hd. reduced epc levels may contribute to endothelial dysfunction and accelerated atherosclerosis in children on long term hd. future studies are needed to identify the cause of this deficiency and to evaluate if increasing epc levels provides therapeutic benefit. objectives: darbepoetin alfa (aranesp ® ) is a novel erythropoiesis stimulating protein that has been shown in adult trials to have safety and tolerability equivalent to recombinant human erythropoietin. however, to date there is only limited published data on the use of aranesp inpaediatric patients. the objective of this study was to determine the safety and efficacy of darbepoetin in children with chronic and endstage kidney disease. methods: from 2003 to 2006, 30 children with either chronic or end stage kidney disease were enrolled in a prospective observational study. the initialdose of darbepoetin was 0.45 mcg/kg weekly (either iv or sc) and subsequent dose was titrated to achieve haemoglobin (hb) between 110 and 130 g/dl. results: data analysis to date includes 22 patients (16 male : 6 female) whose agesranged from 1 month to 17 years (mean 9 years). hb improved significantly with darbepoetin treatment from mean 84 g/dl (range 64-107) at start of treatment to 115 g/dl (range 81-147, p<0.001) at completion. the mean starting dose was 0.55 mcg/kg/week (range 0.4-0.9) which was not significantly different to the dose atthe end of the study (0.57 mc/kg/week, range 0.5-2.5). however, there was a significant change in the frequency of administration, with 85% commencing on weekly treatment, but only 25% still on weekly treatment at the end of the study (p<0.001). the most common treatment interval in stable patients was fortnightly (40%) but a significant number tolerated even longer intervals (25% dosed every 3 weeks or longer). injection pain was common, but there were no other significant adverse events. conclusions: darbepoetin alfa is a safe and effective therapy for anaemia associated with kidney disease. the majority of children will maintain satisfactory haemoglobin at a dosing interval of every 2 weeks orgreater. high prevalence (43%) of left ventricular hypertrophy (lvh) and impaired systolic myocardial function in children with mild-to-moderate chronic renal failure (crf) were observed in previous studies (jasn2006, jasn2007). in adult patients with uncomplicated arterial hypertension, lv mass (lvm) exceeding compensatory value for body size and cardiac workload (inappropriate or ilvm) is associated with poor prognosis, independently of lvh. we tested in crf children if increased lvm compensates or exceeds the expected values for individual cardiac load and if ilvm is associated with impaired cardiac function. complete anthropometrics, biochemical profile and doppler echocardiograms were obtained in 24 children (age 11.5±5.2 yrs; gfr 48.7±30.3 ml/min/1.73 m 2 ). ilvm was defined above 109% of the value predicted for individual body size, gender, and stroke work and lvh was defined as lvm/m 2.7 >38 g/m 2.7 . 9 patients showed ilvm. children with ilvm had higher mean age and lower heart rate as compared to patients with appropriate lvm (both p<0.05), without differences in blood pressure, bmi and gfr. after controlling for differences in age, gender distribution and presence of lvh, patients with ilvm showed similar cardiac geometry and diastolic function parameters compared to children with compensatory lvm (p=ns). in contrast, presence of ilvm was associated with lower lv ejection fraction (53.5±3.7% vs 63.0±3.6%) and lower midwall fractional shortening (15.9±1.8% vs 18.6±1.4%)compared to children with compensatory lvm (both p<0.01), indicating impaired lv chamber performance and reduced systolic myocardial function. in conclusion, in 37.5% of children with mild-to-moderate crf, lvm is inappropriately increased for individual cardiac workload and body size. presence of ilvm is associated with reduced systolic function, independently of age, gender and presence of lvh. pediatric nephrology centers were enrolled. age groups of the patients were as follows: 41.9% newborn, 19.7% 2-12 months, 23.7% 13 months -10 years, 14.7% 11-18 years. underlying diseases were prematurity (30.1%), malignancy (10.7), congenital heart diseases (chd, 16.0), urologic disorders (7.3%). low fluid intake was noticed in 35% of cases.50.4% of cases developed arf after they have been hospitalized. time to diagnose arf was longer in the surgery department (4.32±5.01 days) compared to pediatrics (1.12±3.33 days), p<0.05. thirty-nine percent of patients were on mechanical ventilation (mv) before the diagnosis of arf, an additional 6.2% needed mvl after the diagnosis of arf. arf was prerenal, intrinsic and obstructive in 37%, 61% and 2% respectively. hemodialysis and peritoneal dialysis was performed in 9.1% and 21.9% of cases. mortality was 31.8%; and it was secondary to non-arf related causes in 79.5% of cases; presence of mv, intrinsic arf, prematurity, chd, malignancy and being in intensive care unit were poor prognostic factors. conclusion: our nationwide data suggest that nephrologist, intensivist and pediatrician should focus on risk groups to prevent and to diagnose arf earlier. appropriate fluid intake and earlier consultation to a nephrologist are simple but may be effective measures to prevent arf.. hemolytic uremic syndrome is characterized by the triad of hemolytic anemia, acute renal failure, and thrombocytopenia. recent studies have shown that shiga-toxins (st) may stimulate apoptotic cell death in renal tubular cells, but the underlying molecular mechanisms remain to be elucidated. in the present study, confluent llc-pk1 cells were exposed to st and cell death was studied with morphological and biological assay. in llc-pk1 cells st was found to induce apoptotic cell death in a dose-and time-dependent manner. the expression of calpain and bax were significantly up regulated by st, while the expression of bcl-2 was down regulated. cell death was completely inhibited by a specific calpain inhibitor, but not by a broad caspase inhibitor, zvad-fmk, implicating a caspase-independent pathway via calpain. moreover, we found that serum factors could trigger a survival signal against st-induced cell death through pi3k/akt pathway. in conclusion, activation of calpain mediates st-induced renal proximal tubular cell death, and the expression of bcl-2 and bax were oppositely altered. stimulation of pi3k/akt signalling protects cells against death. verocytotoxin (vt)-producing e. coli (vtec) infection represents the main cause of hemolytic uremic syndrome (hus) in children. a nationwide surveillance system of hus was introduced in italy in may 1988 to follow the trend of vtec infections. for each patient, epidemiological and clinical information was collected by a standardized questionnaire. laboratory diagnosis of vtec infection was based on the detection of vtec and free vt in stools and of antibodies to the lipopolysaccharide (lps) of serogroups, o26, o103, o111, o145, and o157 in the sera. the immuno-detection of vt on circulating neutrophils was also performed on some patients. as of december 2005, 481 cases have been notified, accounting for a mean annual incidence of 0.31x100,000 in the 0-14 age group with a significant difference among the regions (from 0.15 to 1.1); median age of patients: 23 months, 53% males. most cases (53%) occured in summer from june to september. seventy-nine per cent of the cases had prodromal symptoms such as bloody diarrhea (26%) and non-bloody diarrhea (51%). five patients (1.0%) died from the disease. stools and/or sera were collected from 380 cases. evidence of vtec infection was observed in 255 cases (67%). the vtec serogroups most commonly detected were o157 (37% of the vtec-positive patients), followed by o26, o145, o111 and o103. the number of cases associated with non-o157 infections increased over time: from 1997 the o26-associated cases are the most frequent. during the surveillance-period 4 epidemic clusters have been registered: 1992-lombardia, 1995-veneto, 1997 and 2005 campania. the role of vesico-ureteral reflux (vur) as a predisposition for acquired renal scarring with urinary tract infections (uti) has been questioned in recent years. few studies have investigated baseline factors associated with chronic nephropathy in severe reflux. we aimed to evaluate dmsa scans in children having any degree of primary vur associated with uti in order to identify variables that are predictors of the presence and/or development of renal scar. data of patients with proven uti who have primary vur were evaluated retrospectively. patients and renal units were classified as scar (+) and scar (-) by dmsa results. the following parameters were assessed with respect to their relation to presence of renal scarring: sex, age at diagnosis, grade (g) of reflux, number of subsequent utis (on new renal scars). there were 138 patients (m/f: 53/85, median age 42 months) and 212 refluxing units. variables increasing the likelihood of scar detection were: male gender (32/53 vs. 35/85, p=0.043; or 2.2), >26 months of age (for girls only; 31/59 vs. 4/26, p=0.003; or 6.1), g iv-v reflux (or 9.1 vs. g i-iii reflux and 23.3 vs. no reflux). all boys having g iv-v reflux and girls over 26 months of age having g iv-v reflux had very high rate of scarring compared to the rest (21/23 vs. 46/115, p=0.0001, or 15.8 and 14/16 vs. 53/122, p=0.002, or 9.1, respectively). however, variables increasing the likelihood of new/progressive scar development were only the presence of previous scar (or 8.3) and uti number >1 (or 3.0). neither uti number nor new/progressive scar development was affected by vur grade. in conclusion, the most predictive variables for the presence of renal scarring among children presenting with a uti were male gender, age (being >26 months; only for females) and grades iv-v reflux, while new/progressive scar development was associated with presence of previous scar and uti number. d. hothi 1 , e. harvey 1 , c. goia 2 , d. geary 1 1 hospital for sick children, department of pediatric nephrology, toronto, canada 2 hospital for sick children, educational, toronto, canada introduction: adequate ultrafiltration (uf) is necessary for good health in dialysis dependent patients. however uf can be hindered by development of intradialytic symptoms and hypotension. objectives: to determine whether sodium ramping, uf profiles and mannitol could improve uf without increasing intradialytic morbidity in children. method: a standardized hd practice was instituted in our unit. we prospectively analysed 506 dialysis treatments from 11 chronic patients with routine scheduled hd, 4hrs x3-4/wk. results: uf volumes between 3.2 to 9.7% of the dry weight were achieved. mannitol reduced the risk of developing intradialytic symptoms by 64% (p<0.05) without altering the risk of hypotension, with a mean uf volume of 6.2% of the dry weight. a linear sodium ramp (148-138mmol/l) increased the odds of intradialytic symptoms (p=0.10) and hypotension (p<0.05), with no difference in the mean uf volume. all uf profiles increased the risk of intradialytic symptoms but the effect was not statistically significant except with profile 2 (stepwise reduction of uf during procedure). achievement of dry weight was least likely with uf profile 2 (p<0.05); there was no statistical difference in the mean uf volume between them all. conclusion: uf volumes higher than the traditional recommendations of 5% of the dry weight can be achieved in children. the use of mannitol increased the uf volumes and reduced symptoms without increased hypotensive episodes. objective: innate immunity and urinary tract response play a central role int he development of urinary tract infection (uti), in which heat shock protein (hsp)70 and toll-like receptor 4 have a key position. patients and methods: hspa1b a(1267)g and tlr4 a(896)g genotypes were determined using allele-specific polymerase chain reaction in 103 patients treated with recurrent urinary infection. allelic prevalence was related to reference values of 235 healthy controls. clinical data were also reviewed and statistically evaluated. results: hspa1b (1267)gg genotype and hspa1b (1267)g allele occurred more frequently in uti patients versus controls (p=0.0001) and both were associated with a higher risk of renal scarring (p=0.012 and 0.049, respectively). tlr4 (896)ag genotype and tlr4 (896) g allele had also higher prevalence among uti patients than controls (p=0.031 and 0.041, respectively). the combination of carrying ag genotype at both sites meant the greatest risk for uti (p=0.05). conclusion: our data indicate an association between the carrier status of hspa1b (1267)g and tlr4 (896) one of the major goal of hemodialysis adequacy is to achieve the fixed endsession body weight, so called dry weight, in order to limit overhydration and thereby cardiovascular risks. the prescribedultrafiltration, can induce hypotensive episodes and thereby limit thedry weight achievement. on line equipments offer the assessment of theblood volume (bv) and its relative variation. the bv is derived fromdirect measurement of the hematocrite. weroutinely use such an equipment (fresenius a 2008 c) over all thesessions since february 2002, conducting to a clinical experience of 7800 bvm curves. these registered curves could be related to thehemodialysis prescription parameters (uf, nad, td, kt/v) to the dryweight, the blood pressure and to the clinical dialytic symptoms. thisexperience conducts us to define the normal bv curve over a sessionand its variations. starting dialysis induces an acute initial (5 to 30 min) decrease of bv, 5 to 8%, mostly asymptomatic: extra corporeal circuit filling; this initialdecrease is a sign of normality. there after the normal bv curve should be flat; uf rate/amount being compensated by the plasma refilling rate: iso osmotic dialysis, no symptoms, no cramps, no hypotension, no vomiting. incase of no bv decrease over the dialysis session, the patient isoverloaded: reduce his dry weight. in case of a decrease of the bvhigher than 10%, there is a hypotensive risk: uf rate/amount, dryweight, sodium dialysate, sodium temperature and kt/v urea (cellular water shift) should be individually adapted conducting to arefilling curve. the effectiveness on the bv of these individual changein dialysis prescription can be directly, on line attested by the bvmcurve: plasma refilling capacity test. the bv changes reactivity is rapid, 5 to 15 min. renalscarring following acute pyelonephritis (apn) in children is a frequentcomplication which may impair renal growth. its pathophysiology includes host response, bacterial virulence, associated malformationand/or renal dysplasia. we prospectively studied virulence factors of e. coli isolates from children with a first episode of apn (fever >38.5 c°, crp >20 mg/l, monomicrobial e. coli positive culture >10*5 cfu/ml). we excluded patients with anyconcomitant infection, renal dysplasia or obstructive uropathy (us examination, renal length <2 sd) or grade 4-5 vur. renal scarring was evaluated by dmsa scan performed 6 to 9 months after apn. 383 patients were included in a multicentre prospective randomized study comparing short vs long i. v. treatment with ceftriaxone as a first line antibiotic treatment [in press]; 161 out of them fulfilled criteria for virulencestudy. six virulence genes were investigated by multiplex pcr (pap, sfa, afa adhesine genes; cnf1, hly toxin genes, aeraerobactin gene) and the k1 capsular antigen was researched by latextest. we identified 21 distinctive virulence profiles; 99% of e. coli strains had one or more virulence factors; 64% expressed the aer genewith at least one adhesin or one cytotoxic factor. renal scars occurredin 18% of cases and low grade (1-2-3) vur was detected in 46%. statistical analysis did not show any correlation between the presenceof scars and e. coli virulence pattern. in addition, scarring was not correlated with the antibiotoc regimen but was correlated with grade 3 vur (p 0.002). most e. colistrains associated with apn in children show several virulence factors, mainly adhesins and cytotoxins, but their profile was not correlated with renal scarring. background: acute lobar nephronia (aln), a severe renal parenchymal inflammatory disease, ranging between acute pyelonephritis (apn) and frank abscess formation, has been diagnosed with increasing frequency due to the advancement of non-invasive diagnostic modalities and the development of systematic diagnostic schemes. e. coli is the most common bacterialpathogen isolated from the urine samples of aln patients and the associated percentage is significantly higher than those among the patients with first time urinary tract infections. this prospective study was conducted to elucidate and differentiate the bacterialvirulence factors associated with aln and apn in pediatric patients. methods: patients included in the present study were those suspected of anupper uti and underwent a systematic scheme of ultrasonographic, ct and tc99m-dmsa evaluation for the differential diagnosis of aln andapn. exclusion criteria were any evidence of underlying diseases orurinary anatomical anomalies except vur. the e. coli isolates from the urine samples of patients were screened with pcr analysis for various urovirulence genes. pulsed-field gelelectrophoresis was used to analyze the genetic association of theisolates. results: a total of 88 patients were enroled. forty-six patients were diagnosed as aln, while the other 42 cases were apn. diverse genotypes were found among the e. coli isolates in either group. among the pathogenetic determinants examined, multivariate logistic regress analysis indicating that a papg ii allele was the only significant urovirulence factor associated with aln (p<0.005; odds ratio, 17.16). conclusions: while no specific genetic lineage was identified among the e. coli isolates studied, a papgii gene was found strongly associated with the cause of aln among pediatric patients without underlying disease other than vur. 0-<21 yr during 1996-2005 were sent to leading paediatric nephrologists of 13 asian countries/regions. those having national renal registry were to use the registry data. results: data from 11 countries/regions were returned (incl. 3 national registries), namely china, hong kong sar, india, indonesia, japan, malaysia, pakistan, philippines, singapore, south korea & thailand. a total of 2275 esrd patients were reported: 772 on peritoneal dialysis (pd), 678 on haemodialysis (hd), & 825 transplant (tx) of 34%, 30% & 36% respectively. chronic pd: capd and automated pd (apd) were the main modes of pd at ratio of 2.6 to 1. only 3 countries had apd morethan capd. peritonitis rate ranged from 1 episode in 3 to 50 patient-months, and seemed less common in those having more apd. chronic hd: hd comprised of 47% chronic dialysis, mostly adolescents. a-v fistula wasused in 76%, and permanent catheter 15% for vascular access. background: current data suggest the role of chronic inflammation and lipid disorders in atherogenesis. the aim of the study was to evaluate established and new markers of atherosclerosis in apd and hd pediatric patients and to assess whether the method of dialysis has an impact on those factors. methods: soluble(s) e-selectin, il-4 and il-12 concentrations were evaluated by elisa in sera of 18 apd patients on, 9 hd patients and 15 controls. hscrp levels were assessed by nephelometry. the lipid profile (total cholesterol (chol), hdl-chol, ldl-chol, triglycerides (tgl)) was also estimated. results: se-selectin concentrations in dialyzed patients were higher than in controls (apd p<0.0001; hd p<0.0001) and in apd were increased vs. hd (p<0.05). there were no differences in median values of il-4, il-12 and hscrp between examined groups. chol levels were increased only in apd vs. controls (p<0.05). hdl-chol concentrations were decreased in all dialyzed patients when compared to controls (apd p<0.0001; hd p<0.01), without difference between apd and hd. ldl-chol in apd and hd were higher than in controls (apd p<0.0001; hd p<0.05), but failed to differentiate between two dialysis modalities. tgl levels behaved in the same way. conclusions: the elevated se-selectin concentrations in all patients show the role of endothelium in atherogenesis in ckd children. thus, the se-selectin augmentation may serve as an early marker of endothelial activation, appearing prior to inflammation (unchanged hscrp, il-4). increased seselectin and cholesterol levels in apd patients prove that children on peritoneal dialysis are more prone to atherosclerosis than those on hemodialysis. background: end-stage renal disease (esrd) is associated with an increased risk of cardiovascular morbidity and mortality. according to recent data, arterial stiffness measured by aortic pulse wave velocity (pwv) and augmentation index (aix) is a strong independent predictor of cardiovascular mortality in adult esrd patients. few studies have been reported regarding arterial stiffness in the paediatric renal population. methods: aortic pwv and aix (difference between the first and the second systolic peaks on the aortic pressure waveform divided by the pulse pressure) were determined in 14 haemodialysis children (10 boys; age 12±4 years) by applanation tonometry using a sphygmocor device. seven of the hd patients (5 boys; age 12±3.5 years) received a renal transplant (tx) and were restudied (6±2 months post tx). the immunosuppressive regimen included basiliximab induction, cyclosporine, mycophenolate mofetil, and steroids. results: in the hd population, aortic pwv (6.3±1.3 m/s) was correlated with age (p=0.019), weight (p=0.036), height (p=0.0036) and systolic blood pressure (p=0.0038). in the transplanted cohort aix decreased in six children out of seven after transplantation (7.57±9.45% on hd versus -6.57±19.7% after tx). no significant change was observed for aortic pwv (6.37±1.18 m/s on hd versus 6.86±1.87 m/s after tx). objective: to study the pathogenic role of host and escherichia coli virulence factors in the development of e. coli febrile urinary tract infection (uti) in children with acute cystitis (ac), acute pyelonephritis (apn) and renal scar. materials and methods: isolates recovered from 125 children consecutively admitted to the hospital with e. coli febrile uti that diagnosed as ac (n=36) or apn (n=89) were retrospectively enrolled into this study. virulence genes of e. coli, that included papg genes (classes i-iii), aer, cnf1, fimh, hlya, afa, sfa/foc, iha, usp, irone and ompt, were detected by polymerase chain reaction analysis. results: young age (=<5 months), male sex were more frequently associated host factors for patients with apn, but old age (>5 months) and female sex were more frequently associated with renal scar formation. after multilogistic regression analysis, with regard to e. coli virulence factors, the papg class ii gene might play a more important role in the development of e. coli apn. however, iha was significantly higher in young children with acute pyelonephritis. afterwards, age, gender, duration of fever before admission, and crp level were considered as potential confounders for the further multivariate analyses, specifically estimating the relative risks of e. coli genotypes to the incidence of acute pyelonephritis and renal scar by age group and the existence of vesicoureteral reflux. odds ratios with 95% confidence intervals for each variable were utilized to estimate the relative risk of acute pyelonephritis and renal scar. in addition, there were no differences between young children and old children, if we excluded the factor of vesicoureteral reflux (vur). conclusion: both host and e. coli virulence factors contribute to the development of febrile uti, apn and renal scar. since 2/06 we have started an acute peritoneal dialysis (duration 1-61 days) in 8 infants (age 7 days to 9 months) with the use of the baxter acute set for children under constant warming of the complete dialysate inflow tract to 37 °c (barkey system). as dialysate solutions we chose a glucose/bicarbonate/lactate solution (physioneal 40) in all patients and in 4 patients a mixture of this solution with a 1.1% amino acid solution (nutrineal) in a 3:1 ratio. the body weight before the renal insufficiency was 1.3 to 5.2 kg. in 5 patients the renal failure followed cardiothoracic surgery. the handling of the system was easy. because of obstruction by omentum and fibinous layers, respectively, the dialysis catheter had to be cleared surgically in 2 patients. body temperature could be kept constant and in the normal range, even with low body weight and intensive dialysis (as measured by dialysate volume per kg body weight and day). in the infants dialyzed with the glucose/amino acid-mixture a decreased loss of albumin through the dialysate (as measured by the necessary intravenous albumin substitution), a better glucose homeostasis (less episodes of hyperglycemia and less need for insulin infusions) as well as a better acid-base control (less episodes of metabolic alkalosis) could be found. the detected tendency to a better homeostasis (concerning body temperature, serum albumin, blood glucose and acid-base) with this dialysis system and the used dialysate solutions could help to increase the survival chances of infants with renal failure. this will be evaluated prospectively. objectives: varicella-zoster-virus (vzv) infection can cause significant morbidity and mortality in the immunocompromised patient. since there is no clear correlation between antibody titers and protection monitoring after vzv vaccination is unclear. patients and methods: serum samples of nineteen pediatric transplant recipients were investigated for vzv igg antibody titers and avidity (elisa test). a relative avidity index (rai) <40% showed evidence for low-avidity antibodies, an rai >60% high-avidity antibodies, borderline avidity inbetween. the control group consisted of 27 healthy children. 22 had suffered from varicella infection after wild-virus contact, 5 had undergone varicella vaccination. as there was no difference between diseased and vaccinated controls both subsets were treated as one group. results: median vzv igg antibody titers were 560 u/ml (range 100-2600) for transplanted children and 790 u/ml (range 50-2300) for control subjects (n. s.). median rai was 83% for transplant patients and 90% for controls (p=0,04). there was no correlation between rai and antibody titers in either group. rai increased significantly with time after vaccination or infection in both groups. despite protective antibody titers after vaccination and an rai of 68% one transplant recipient showed a moderate vzv infection that required antiviral treatment. postinfectious course showed an increase of rai up to nearly 100%. conclusion: vzv igg antibody avidity might be a pathbreaking parameter regarding decision making for a second vaccination before transplantation or preemptive treatment in a transplanted patient in case of exposure. in japan, almost half of children with esrd received renal transplantation and more than 90% of those were living kidney transplants from their parents. burden of esrd during childhood frequently causes psychosocial problems in their families, including parental relationship problems. we investigated how parental divorce or death affected the choice of renal transplantation in children. patients and methods: in 68 children younger than 20 years old who started renal replacement therapy in our hospital, percentages of the children losing a parent or parents by divorce or death were investigated. we compared renal transplantation rates and percentages of fathers as kidney donors between those living with both parents and those without. results: in observation periods (4.2±3.3 years), 43 (63%) received renal transplants from 40 living and 3 deceased donors. nineteen children (28%) lost a parent or parents by divorce (n=16) or death (n=3). in all divorced families, mothers got parental authority. ten parents divorced during ckd period, 2 after start of dialysis, and 4 after transplant. of 49 children living with both parents, 31 (63%) transplanted with kidneys from 9 fathers, 20 mothers, and 2 deceased donors. of 16 children whose parents divorced, 11 (69%) transplanted from 4 fathers (2 just before and 2 after their divorce), 5 mothers and 2 other family members. however, in 3 children at least one parent died, only 1 (33%) transplanted from a deceased donor. conclusion: a high parental divorce rate from ckd period was observed in children with esrd, suggesting burden of the disease on their families. renal transplantation was preferred even in divorced families and divorced fathers still were willing to donate kidneys to their children. objective of study: to determine the importance of gastrointestinal evaluation in pre-transplantation phase in pediatrics with end stage renal disease (esrd). methods: twenty four children with esrd (13 female, 11 male) mean age 14.7 (±3.4) years on maintenance hemodialysis were included in this study. upper gastrointestinal endoscopies were performed and four gastric antral and duodenal biopsy specimens were obtained for urease test and histological study for all patients. serum gastrin levels were measured in all patients, too. a control group was chosen to compare the rate of h. pylori infection using student's t. test. results: gastrointestinal symptoms were present in 16 (67%) of 24 patients. seventeen (71%) patients had abnormal upper gastrointestinal endoscopic findings. h. pylori was detected in 66% of patients and 20% in control group (p<0.001). in symptomatic patients 75% had abnormal endoscopic findings and 63% had positive urease test for h. pylori infection. while, in asymptomatic cases these rates were 30% and 75%, respectively. seventy one percent of patients with gastrointestinal lesions and 50% of patients with normal endoscopic examination were infected. high serum gastrin levels in infected and non-infected patients were detected in 75% and 12.5%, respectively (p<0.001). conclusion: we demonstrated a significant number of patients with peptic ulcer diseases and h. pylori infection and secondary hypergastrinemia. this study showed that, clinical symptoms are not a reliable predictor of gastrointestinal problems. our results emphasize the importance of periodic, and also pre-transplant gastrointestinal evaluation in these patients to find out their problem and manage appropriately. key words: renal failure, hemodialysis, peptic ulcer disease, helicobacter pylori, hypergastrinemia. background: preservation of a stable allograft function in children following renal transplantation (rtx) depends on various factors including genetic variability. the gene of the angiotensin i converting enzyme (ace) has been shown to influence allograft function. we therefore analysed various polymorphisms of the renin-angiotensin system in 91 children following rtx and 32 kidney donors and associated genotypes with loss of renal function. patients and methods: 91 children and adolescents (60 male, 31 female, mean age at transplantation 9.7±5.2 years) with stable renal function and observation period exceeding 6 months were included. mean follow-up time was 5.4 years (0.5 to 16 years). dna was extracted from all recipients and 32 donors and genotyped using rflp. the following polymorphisms were studied: renin 18 g/a; ace i/d; angiotensinogen (agt) 235 met/thr and angiotensin ii receptor type-1 (at1r) 1166 a/c. the slope of glomerular filtration rate (gfr) was determined by linear regression analysis and correlated with the genotype. results: allelic frequencies were not different from healthy controls. genotypes of renin, agt and at1r showed no significant association with the slope of gfr but patients homozygous for the ace-d-allele had a significantly steeper decline of gfr when compared to homozygous carriers of the ace-i-allele (slope dd: -4.3±0.8 vs. ii: -1.3±1.1; p=0.035). the dd-genotype was also present in 11 out of 32 donors and in four cases a dd-recipient received a kidney from a dd-donor. those four patients showed a more pronounced decline of gfr (-5.2±0.5; p=0.002 ). in addition, dd-recipients had a significantly increased systolic and diastolic blood pressure before rtx. conclusions: the dd-genotype is associated with a faster, non-immunological loss of graft function which has to be evaluated in prospective studies. year large single-center review b. warshaw, l. hymes, l. greenbaum, s. amaral from1995-2006, 207 children received renal transplants at emory university/children's healthcare of atlanta of whom 29 (14%) had nephroticsyndrome (ns) as their primary diagnosis (27 fsgs, 2 minimal change). all children received calcineurin-based immunosuppression. thirteen children (45%) developed recurrent ns within the first week post-transplant and received plasmapheresis (pp) 3-5 times weekly. nine (70%) had complete resolution of proteinuria. two who responded to pp suffered graft loss fromlate recurrences of ns at 7 years. ns did not resolve with pp in 4 children who suffered either delayed function (1) or early cessationof function (3); each of the latter lost their grafts within the first 3 months. 16 patients did not have recurrences of ns. comparison of these 2 groups showed significantly increased riskfor recurrence with younger patient age (p<0.006), interval <3 years from onset of ns to esrd (p<0.02), and living donor source (7/9=78% ld vs 6/20=30% dd; p<0.02). no differences were seenfor hla match, donor age, gender, or african american race. actuarial graft survival for children with recurrence was 70% at1 year and 60% at 2 years vs. 100% & 92% for patients without recurrence. conclusions: ns recurred in 45% of children with ns as their primary cause of esrd. risk factors for recurrence included younger age, interval <3 years from onset of ns to esrd, and living donors. most recurrences responded to pp (70%); failure to respond was associated with delayed or early cessation ofrenal function & early graft loss. the incidence of recurrence was strikingly high (78%) among living donor recipients, suggesting a need to explore prophylactic strategies such as preemptive pp in this group. methods: a single-centre retrospective case-controlled study including 24 children <3 yr (g1) and 24 matched kidney tx recipients older than 3 yr ofage (g2). patients were matched for donor type and tx period. kaplan-meier method was used for patient and graft survival. results: 23 tx were performed using deceased donors in both groups. median recipient age, weight and height at tx in g1 were 1.5 [0.6-2.7] yr, 9.1 [5.6-11.1] kg and 74.8 [64.5-87.0] cm, respectively, while median age in g2 was 11.2 [3.3-17.2] yr. hypoplasia-dysplasia wasmore frequent in g1 (42 vs 21%). median hla-dr mismatch, time ondialysis and number of blood transfusion before tx were not different. in g1, kidneys were placed intraperitoneally and most of vascular anastomoses were done on distal aorta (83%) and inferior vena cava (88%). median follow-up was 8.7 [0.02-15.9] yr and 6.5 [0.3-15 .6] yr ing1 and g2, respectively. patient survival was 94% at 5 yr and 88% at 10yr in g1; 3 patients died in g1 (2 ptld, 1 recurrence of primary disease), none in g2. fiveyear graft survival was 79% in g1 and 77% in g2. acuterejection episodes occurred in 46% in g1 and in 67% in g2 (p 0.15 ). chronic rejection led to 3 late graft losses in g2 (5.2 to 6.9 yrafter tx) vs 0 in g1. renal function did not differ between the 2 groups during the first 5 yr post tx. the average height gain was better in g1 at 5 yr post tx (+1.3 sds vs. -0.1). primary disease recurrence was observed in 4 cases (1 in g1) causing graft lossin 3 cases. two arterial thromboses were observed in g1 causing 1 earlygraft-loss. conclusion: the outcome after cadaveric kidney transplantation is as good in children under 3 yr of age at transplantation as in older recipients in our experience. c. garcia, v. bittencourt, d. malheiros, a. tumelero, j. antonello, a. oliveira, v. garcia cancer is an increasingly recognized problem associated with immunosuppression. recent reports, however, suggest that sirolimus (srl) has anti-cancer properties that could address this problem. aim: to report a retrospective analysis of preliminary results of 6 patients who received srl because of post-transplant de novo malignancies in a consecutive cohort of 348 pediatric kidney recipients. patient and methods: we retrospectively evaluated the efficacy and safety of srl in 6 pediatric renal transplantation recipients, who were 12±7 years when converted to srl. the 6 post-transplant de novo malignancies were: gall bladder and hepatic leiomyoma (n=1), wilms tumor in the native kidney (n=2), ptld (n=2) and hpv-associated neoplasia. the immunossupressive regimen at the malignancy diagnosis was tacrolimus/cyclosporin, mmf/azathioprin and prednisone. all were converted to double immunossupression with sirolimus at a standard dose of 2mg/day (tl5-10ng/ml) and prednisone. patients with ptld were also treated with rituximab, and the patients with wilms tumor received chemotherapy. mean follow-up after srl conversion is 35±25 months. results: all patients were maintained with srl and pred without rejection, with good renal function and no cancer recurrence (follow-up 6 to 75 months). the patients with wilms tumor are still on chemotherapy. follow-up control after srl conversion in the 6 patients: conclusion: although the intraperitoneal group had characteristics associated with increased surgical risk (they tended to be younger and smaller, with a higher incidence of aortic anastomoses and a higher incidence of multiple vessels), surgical complications were significantly lower than expected in the extraperitoneal group 7% v. 33%. objective of study: proteinuria is a frequent complication in adult patients after renal transplantation (r-tx) and is associated with poor graft survival. in children, there are no studies focusing primarily on proteinuria after r-tx. the aim of this study was to investigate the prevalence of proteinuria in children after r-tx and to evaluate changes of proteinuria during a 2-yr study on intensified antihypertensive therapy. methods: protein excretion was measured in 24-hr urine and proteinuria defined as >96 mg/m 2 /day. proteinuria was investigated at baseline, 1 and 2 years after intensifying of the antihypertensive therapy in children with uncontrolled hypertension at baseline (i. e. additional antihypertensive drugs given to children with blood pressure >95. pc). 33 children (13.7±4.3 yrs) out of 45 from our center fulfilled inclusion criterias (>6 months after r-tx, no acute rejection (ar) in the last 3 months, no recurrent fsgs). results: the prevalence of proteinuria was 82% at baseline, 76% after 1 year (ns) and it decreased to 52% after 2 years (p<0.05). the mean protein excretion was 256±303 mg/m 2 /day at baseline, 224±208 after 1 year (ns) and it decreased to 134±88 after 2 years (p<0.01). mean number of antihypertensive drugs increased from 2.1±0.9 drugs/patient to 2.7±0.8 after 2 years (p<0.01). mean nighttime bp decreased significantly after 2 years. the number of patients on ace-inhibitors increased from 19% at baseline to 39% after 2 years (p<0.05). conclusions: this is the first study on proteinuria in children after r-tx. it showed that proteinuria is a frequent finding in transplanted children and that intensified long-term antihypertensive treatment using ace-inhibitors can decrease not only bp but also proteinuria in these patients. allograftrejection involves t cell activation and proliferation and multipleinflammatory components. monocyte chemotactic peptide-1 (mcp-1) is achemoattractant and activating factor for monocytes. interleukin-6 (il-6) may contribute to monocyte recruitment, results intubulointerstitial damage. cytotoxic lymphocytes induce target cell death by ligation of the fas-fasligand. allelic polymorphisms in recipient genes coding for them reported to beassociated with variations of outcome in renal transplantation. the aim was to investigate impact of mcp-1 -2518 a/g and il6-174 g/c, fas-670 a/g polymorphisms on acute allograft rejection (ar). there were 20 males and 27 females, 19±4.6 years meanly; 21 of the graftscame from living-related donors, 26 were from cadavers. the controlgroup consisted of 150 unrelated, healthy individuals with similar ageand sex. ar group was composed by 17 patients experienced at least one ar episode within the first 6 months of transplantation. the non ar group was comprised by 30 kidney transplant patients without ar. there was no significant difference between renal transplant patients and healthy controls in genotype distribution of allelic frequencies of il-6, fas and mcp-1 polymorphisms. while il-6 and fas gene polymorphisms had no effect on the incidence of ar episodes, there was significant association with mcp-1. the distribution of the genotypes for mcp-1 -2518 a/g in ar group were aa/ag/gg 23, 6%, 64, 7%, 11, 7% respectively. the distribution of the genotypes for mcp-1 -2518 a/g was aa/ag/gg 60%, 30%, 10% in nonar group respectively. the carriage of g allele at -2518 position of mcp-1 gene has a significant association with ar (or: 4, 87, 95%, ci: 1, 27-18, 5). the il-6 and fas gene polymorphisms had no effect on the incidence of ar. mcp-1 -2518 g allele carriage increases the ar risk in turkish renal transplant patients. the high recurrence rate of focal segmental glomerulosclerosis (fsgs) in transplanted kidney recipients suggests the hypothesis that such patients have a circulating factor that changes glomerular capillary permeability. serum from patients with fsgs increases glomerular permeability to albumin, and this permeability factor was partially identified as a protein. the removal of this protein by plasmapheresis (pp) decreases proteinuria. object: the aim of this paper is to provide data about the therapeutic effect of pp in fsgs children with recurrence in the transplanted kidney. methods and results: twenty eight pediatric kidney transplant recipients had fsgs as cause of renal failure from 1990 to 2007 in our center, confirmed by biopsy pre-transplant. seventeen of these (60.7%) had a recurrence (proteinuria >1 g/m 2 per day associated with hypoalbuminemia). the mean age was 12±4.3 years, 85, 7% were caucasians and 67, 8% were performed with living donor. since 2001, patients who presented fsgs recurrence were treated with 10 cycles of pp (3 cycles/weekly), initiated immediately post-recurrence (n=11). immunosuppression comprised of cyclosporin in high doses (c 2 levels of 1700-1800 ng/ml) or tacrolimus (tl=10 mg/dl), mycophenolate sodium or mofetil (until 1997 azathioprine was used) and prednisone. among patients who received pp (n=11), 7 (63.6%) achieved a complete remission. there were no cases of remission among those six patients who were not treated with pp. those who achieved remission after pp had no recurrence. the patients treated with pp had infectious complications: one patient had cytomegalovirus disease and two patients had varicella. conclusion: pp appears to be effective in treating recurrent fsgs following kidney transplantation. it should be started as soon as possible. because the calcineurin inhibitors (cni) cyclosporin a (csa) and tacrolimus (tac) are drugs with a narrow therapeutic index, individualization of cni dosage by therapeutic drug monitoring is indisputable. however, the optimal strategy for monitoring cni therapy is currently under debate. dosing of cnis according to the molecular effect of the drug on its target cells could optimize immunosuppressive therapy with cnis. for this purpose, we developed a reliable, precise, and robust whole blood assay based on the measurement of the expression of three nfat-regulated genes (il-2, ifng and gm-csf) in pma/ionomycin-stimulated lymphocytes before and 1.5 (tac, c 1.5 ) or 2 hrs (csa, c 2 ) after oral drug intake. the inhibition of genes in this assay is independent from other commonly used immunosuppressive drugs and reflects calcineurin inhibition expressed as residual nfat activity. in a pilot study, 40 patients (mean age 14 yrs, mean time period posttransplant 42 mo.) were analyzed. in csa-treated patients (n=12), a mean c 2 concentration of 380 ng/ml (range, 180-900 ng/ml) corresponded to a mean residual nfat-activity of 32% (range, 3-115%) ; the correlation between individual residual nfat-activity and c 2 was moderate (r=0, 59, p<0.05). at a csa-c 2 of 400 ng/ml, the residual nfat-activity varied between 8% and 25%. in tactreated patients (n=28), a mean c 1.5 concentration of 18 ng/ml (range, 6-54 ng/ml) corresponded to a mean residual nfat-activity of 40% (range, 7-70%); the correlation between individual residual nfat-activity and c 1.5 was also only moderate (r=0, 60, p<0.05). conclusion: these data indicate that there is a considerable inter-patient variability of residual nfat-activity at a given maximal cni blood concentration. ongoing studies are validating this assay regarding clinical outcome criteria of immunosuppression such as acute rejection and infections. hus due to antibodies against factor h (husafhab) is a very rare disease for which a limited experience in its management is available. we present a case of husafhab who was transplanted but lost her graft after only 4 mos. in aug 2002 a 5-mos old child was admitted for a d-hus which did not go into remission and required chronic peritoneal dialysis. no fh and mcp gene mutation were detected nor adamst-13 activity was decreased. afhab were not searched at that time. in apr. 06 the child underwent cadaver renal transplant (rtx). the immunosuppressive regimen was basiliximab-prednisone-cyclosporine-mycophenolate mofetil. fifteen days after rtx, following surgery for urinoma, the child exhibited an hus relapse with thrombocytopenia, haemolytic anemia and increased serum creatinine (scr). high afhab were detected (2400 au/ml). four plasma exchanges (pe) were performed over 2 wks with a drop of afhab to control level (196 au/ml) and a remission of hus. until the end of aug, afhab remained low (<400 au/ml) and the child was well (scr range: 0.6-1.2 mg/dl). in early aug, the patient was shifted to tacrolimus for severe hypertrichosis with a fluctuation of its plasma level (lower recorded value: 1.4 ng/ml) signs of acute rejection developed and 4 metilprednisolone (mtp) pulses brought scr to baseline level. in oct. 06, following an urti, the child presented with severe proteinuria (upr/ucr: 15, 6) without other clear signs of hus recurrence. since afhab were increased (849 au/ml), pe was restarted but an acute hemorrhagic complication (hemotorax) occurred and pe had to be interrupted. septicemia followed and the child became anuric. the renal biopsy performed 3 days later showed signs of glomerular and vascular thrombotic microangiopathy. renal function did not recover despite mtp pulses and 4 pe. in nov the child was back to pd and in dec the graft was removed. background & aims: recently, the role of nitric oxide (no) in the pathogenesis of idiopathic nephrotic syndrome (ins) has been intensively investigated. however, its rapid turnover has made us impossible to investigate the quantity and the source. as we have developed a novel method for quantitative analysis for no by a new fluorescent indicator, 4, 5-diaminofluorescein (daf-2), its amount produced by both t and b lymphocytes in ins was studied. methods: five children with steroid-sensitive ins (mean age: 4.0 y) were included in this study, together with 7 children with other renal diseases (mean age: 5.0 y) such as chronic glumerulonephritis and alport syndrome with significant amount of proteinuria, and 10 healthy adults (mean age: 28.0 y) for the control. no production from cd3+ cell and cd19+ cell was investigated by a flow cytometry using daf-2. results were expressed as mean fluorescence intensity and were compared among the groups. results: the amount of no produced by cd3+ cell and cd19+ cell in children with ins was significantly greater than those in children with other renal diseases and healthy adults (cd3+ cell: 57.5±6.8 [mean±sd], 27.6±7.0, and 21.7±2.1, respectively; cd19+ cell: 35.7±3.5, 24.9±3.9, and 18.9±2.3, respectively, p<0.05). additionally, both cd3+ cell and cd19+ cell during nephrotic relapse produced more no than in nephrotic remission (p<0.05). discussion: patients with relapsing ins showed increased production of no by both t and b lymphocyte. these findings indicate that no plays some role in the pathogenesis of ins and suggest that an abnormal immune system may exist not only in t but also in b lymphocytes. a. bagga, a. sinha, s. menon, p. hari aim: the treatment of patients with srns is challenging. based on suggestions that b-lymphocytes are crucial in the pathogenesis of nephrotic syndrome, we examined the efficacy of rituximab (rtx) in patients with srns refractory to standard therapies. methods: six patients (4 with initial, 2 late resistance), 3-16 yr old, were included; biopsy showed minimal change & focal segmental glomerulosclerosis in 3 each. all had previously received iv high-dose steroids, alkylating agents & calcineurin inhibitors (cni) for 2-14 yr with periods of partial (pr; urine 1-2+) or complete remission (cr; urine trace/negative). all now had srns refractory to 6-months treatment with cni. rtx (375 mg/sq. m) was infused iv every week for 4 weeks. therapy with cni and/or alternate-day prednisolone, & cotrimoxazole prophylaxis was continued. patients were monitored for proteinuria and renal functions. results: at a median interval of 4 wk following the last rtx dose, cr was seen in 4 & pr in 2 patients. remission was sustained in 4 patients, despite tapering doses of steroids & cni. one case had relapse of nephrotic syndrome 6-months later, which responded to steroid treatment. at median follow-up of 28 wk, cr, pr and recurrence of nephrotic proteinuria (3-4+) were seen in 3, 2 and 1 patients respectively. mean urine albumin-to-creatinine ratio was 8.9 at baseline and 0.9 at followup; respective blood levels of albumin were 1.4 and 3.7 g/dl & cholesterol 481 and 221 mg/dl (all p<0.01, anova); difference in leukocyte counts and levels of igg were not significant and none had serious infections. conclusions: this is the first report on the efficiacy of rtx in sustaining remission in patients with srns. therapy with this agent appears promising for difficult srns, with a better risk/benefit profile than other medications. quantitative or functional deficiency of factor h results in uncontrolled complement activation and is an important cause of familial hemolytic uremic syndrome (ahus). factor h-related proteins (fhr) constitute a protein family which share structural and most likely functional similarities to factor h. we here describe complete deficiency of fhr-1/-3 as novel cause of ahus. factor h and fhr-1/-3 were quantified by elisa and were further analyzed by western blot using specific antibodies. complement activation was determined by measuring c3 and c4. serial hgb (g/dl), platelet, creatinine (mg/dl), and ldh (u/l) were measured. a 12 year old girl presented with a 5 day history of lethargy, pallor, vomiting and hypertension. hgb was 6 g/dl, platelets 40x10 9 /l and creatinine was 6.8 mg/dl. initial therapy consisted of packed red cell and platelet transfusion, followed by steroid therapy. representation occurred 7 weeks later with hypertension, edema, persistent anemia thrombocytopenia and renal dysfunction (creatinine 4.5 mg/dl). renal biopsy demonstrated features of chronic thrombotic microangiopathy. low c3 levels indicated activation of the complement system. while western blot analysis showed normal factor h level, fhr-1/-3 was absent. by repetitive plasma infusion and plasmapheresis, the cycle of hemolysis and thrombocytopenia could be disrupted. chronic periodical plasma infusion q 14 days resulted in regression of renal impairment to a degree (current baseline creatinine 1.5 mg/dl). in conclusion, fhr-1/-3 are thought to have co-factor activity and play a role in complement activation in ahus. deficiency of fhr-1/-3 may lead to a subclinical form of ahus such that patients may initially present with features of chronic renal failure. however, factor replacement therapy may lead to regression of renal impairment. s. choudhry objectives of the study: the aim of the study is to investigate the long term prognosis ofsevere childhood iga nephropathy after 2 years combined therapy. patients: we examined 39 patients who had entered thejapanese pediatric iga nephropathy treatment study group between 1990and 1994, had been treated with 2 years combined therapy (combinationof prednisolone, azathioprine, dipyridamole and heparin/warfarin) andhad been followed for more than 3 years after the therapy. significantproteinuria is defined as more than 0.2g/m 2 /day. results: mean age at onset was 11.4 years (4-16 years), proteinuria at diagnosis was 1.11±0.84 g/m 2 /day, proteinuria after the combined therapy was 0.17±0.22g/m 2 /day and mean follow-up period after the combined therapy was 7.2 years (3.2-9.9 years). proteinuria improved in all patients during thecombined therapy (p<0.0001). the final prognoses were as follows: 21 patients (54%) showed no proteinuria, 15 (38%) showed proteinuria withnormal renal function and 3 (8%) proteinuria with decreased renalfunction. we compared the clinical and pathological parameters betweenpatients with proteinuria (n=18) and those without proteinuria (n=21) at the last observation. period between disease onset and start of treatment, glomeruli showing crescents before the combined therapy (%) and glomeruli showing pathological changes after the combined therapy (%) were the significant risk factors for the proteinuria at the last observation. logistic multivariable analysis revealed that glomeruli showing pathological changes after the combined therapy (%) was theonly independent risk factor for the proteinuria at the last observation. conclusions: pathological activity of nephritis at the end of the combined therapy might correlate well with the final proteinuria and the long term prognosis. s. arun, a. bagga, s. bhatnagar, p. hari, s. menon, s. saini aim: relapses in ssns of ten follow minor infections and are associated with perturbed t-cell function. based on data that zn supplements modulate t-cell function and reduce risk of infections, we examined its efficacy in reducing relapses in patients with ssns. methods: in this double blind rct, 81 consecutive patients with ssns 1-16 yr old, stratified into frequent (fr=52) and infrequent (ifr=29) relapsers, were randomized to 12-months therapy with zn (10 mg daily) or placebo. patients with fr also received long-term, alternate day prednisone. relapse and infection rates were monitored monthly. blood levels of zn, sil2r, il4 and interferon (ifn) were measured at baseline, relapse andend of study. results: patientsin the zn (n=40) and placebo (n=41) groups had similar baseline clinical & laboratory features. the former showed 20% lower frequency of relapses (difference in means -0.2; 95% ci -0.7, 0.3) with trend towards reduction from 6-months onward. a higher proportion (44.7%) of patients in the zn group had sustained remission compared toplacebo (27.5%). reduction in relapse rates was higher in fr receiving zn vs. placebo (-0.3; ci -0.9, 0.3); respective sustained remission was seen in 46% and 16% patients (relative risk 0.5; ci 0.3, 0.9; p 0.02). no differences were found in infection rates, and levels of zn, sil2r & il4; levels of ifn were higher in those receiving zn compared to placebo (p=0.02). conclusions: zn supplementation for 1-yr was effective in maintaining remission and reducing relapse rates. the effect was mediated not by reducing infections but perhaps through effect on th1 cytokines. while zn therapy appears promising, these results need confirmation in patients with frequent relapses and perhaps at a higher dose. background: n-glycosylation process in the endoplasmic reticulum (er) is tightly regulated and orchestrated by many factors such as chaperones and energy systems. we showed that adequate nglycosylation is crucial for nephrin to assemble to the plasma membrane (jasn, 2002) . additionally we recently demonstrated that the er stress evoked by glucose starvation induces hypoglycosylated nephrin retained in the er, which is rescued by dexamethasone (dex) (ki, 2006) and immunosuppresant: mizoribine (mzr) (submitting). in the present study, we tested whether other er stress inducer, hypoxia, could also interfere the alteration of nephrin n-glycosylation system and whether dex and immunosuppressants rescue its defective process. methods: nephrin-expressing cell line was cultured either in 21% o 2 or 1% o 2 for 24 hours in the presence or absence of dex, mzr and cyclosporin a (csa), followed by western blot analysis with nephrin, cytochrome c. intracellular atp concentrations were measured by the highperformance liquid chromatography. protein expression of cyclophilin d (cyp-d), a component of mitochondrial permeability transition pore (mptp), was tested in the samples from human glomeruli and cultured podocyte. results: hypoxia induced hypoglycosylated nephrin. csa, but not dex and mzr, inhibited the formation of this hypoglycosylated nephrin and rescued mature form. csa inhibited the increase of cytochrome c in the cytoplasm caused by hypoxia. in addition, csa partially rescued the decrease of intracellular atp. cyp-d was distinctly observed in human glomeruli and located in podocytes. conclusion: csa inhibit the formation of hypoxia-induced hypoglycosylated nephrin through protecting the mptp opening via selectively binding to cyp-d in the mitochondria, resulting in a recovery of atp. csa may exert direct action on the alteration of nephrin biogenesis induced by the er stress. background and objectives: in two previous randomized controlled trials (rcts) we showed that treatment of severe childhood iga nephropathy (iga-n) with diffuse mesangial proliferation using prednisolone, azathioprine, heparin-warfarin, and dipyridamole reduced immunologic renal injury and prevented any increase of sclerosed glomeruli. in one of the two rcts we also showed that treatment with prednisolone alone did not prevent a further increase of sclerosed glomeruli. accordingly, the immunosuppressant is considered to play an important role in the combination therapy. often however, we were unable to complete the azathioprine regimen due to its severe side effects. therefore we considered that a different, but effective immunosuppressant would be worth trying. mizoribine, like azathioprine, is an antimetabolite that exerts its immunosuppressant effect by inhibiting lymphocyte proliferation. design, setting, participants, and measurements: in this pilot study, we administered mizoribine instead of azathioprine as part of the combination therapy for treatment of 23 children with severe iga-n and evaluated the efficacy and safety of the regimen. results: eighteen patients reached the primary endpoint (urinary protein/creatinine ratio <0.2) during the two-year treatment period. the cumulative disappearance rate of proteinuria determined by the kaplan-meier method was 80.4%. mean urinary protein excretion was reduced from 1.86 g/m 2 /day to 0.20 g/m 2 /day (p<0.0001). after treatment, the mean percentage of glomeruli showing sclerosis was unchanged in comparison with that before treatment. no patients required a change of treatment due to side effects. the efficacy and safety of the mizoribine combination seems to be acceptable for treatment of children with severe iga-n. objectives of study: alport syndrome is a hereditary renal disease which is normally diagnosed by either histopathological studies or a genetical analysis. we attempted to diagnose alport syndrome by means of immunofluorescence staining of cultured cells with collagen type 4 alpha chains obtained from voided human urine specimens. methods: the cells were cultured from the voided human urine of 1 patient with x-linked alport syndrome, 1 patient with sporadic alport syndrome, and 1 patient with autosomal-dominant alport syndrome. for comparison purposes, controls cells were cultured from the voided human urine of 1 patient with iga nephropathy, 1 patient with fsgs, and 1 patient with purpura nephritis. the cultured cells were stained by immunofluorescence techniques with collagen type 4 alpha 1, 2, 3, 4, and 5 chains. results: in the cultured cells of the controls staining for collagen type 4 alpha 1 and 2 chains were observed both in the extracellular matrix and in the cytoplasm while for the staining of collagen type 4 alpha 3, 4, and 5 chains were observed in the cytoplasm. in cultured cells of xlinked and sporadic alport syndrome staining of collagen type 4 alpha 5 chain was lost or attenuated. in the cultured cells of autosomal-dominant alport syndrome the staining patterns of collagen type 4 alpha 3, 4, and 5 chains were observed. the staining patterns of the collagen type 4 alpha 5 chain in cultured cells of alport syndrome correlated with that observed in renal biopsies obtained from alport syndrome patients as reported previously. hence, the staining of cultured cells with the collagen type 4 alpha 5 chain obtained from voided human urine may therefore be a potentially useful means of diagnosing alport syndrome in a non-invasive manner. the aim of our study: was to examine zeta chain expression in cd4+, cd8+ t cells and nk cells from ins children in active phase of the disease and in remission and to assess the effect of 24 h and 72 h anti-cd3 + ril-2 stimulation on zeta chain expression. we enrolled 11 ins children in relapse before initiating the therapy, 12 ins children in complete remission of proteinuria on prednisone for 2-4 weeks (2mg/kgbw/d) and 15 age-matched controls. zeta expression was determined by flow cytometry as mean fluorescence intensity (mfi). results: cd4+cells: mfi in relapse was higher than in remission and in controls. anti-cd3 + ril-2 stimulation had no impact on zeta expression in acute phase and in cotrols, but increased mfi values after 72h in pts with remission. cd8+cells: zeta expression stayed unchanged irrespective of the examined group or antibody stimulation. nk cells: there were no differences between mfi values before stimulation and in relapse after stimulation. in remission and in controls antibody stimulation decreased zeta expression. in controls, mfi values for nk cells were higher than those for cd4+ and cd8+ populations, but this preponderance disappeared after 72h stimulation. in remission, that nk cell predominance vanished after 24 h stimulation. in relapse, mfi values in all cells were comparable and stimulation had no impact on lymphocyte proportions. urinary protein, creatinine, and scd80 were measured. scd80 was measured using a elisa kit. scd80 was expressed as ng/g of urine creatinine. data were analyzed using anova and spearman rank correlation (src) tests. 1) scd80 urinary concentrations in patients with mlns in relapse were higher than patients in remission, healthy controls and other patients with proteinuria (anova p 0.0001) but similar to those seen in sle. 2) in patients with mlns relapse, scd80 concentration did not correlate with urine protein/creatinine ratio (src, r: 0.1719, p: 0.297) 3) in 3 patients with mlns, serial urine scd80 concentrations were measured over a period a time. scd80 was increased at the time of relapse and decreased toward normal range weeks before patients went into remission. conclusion: urinary scd80 is elevated in mlns patients in relapse. this increased urinary concentration is not due to the proteinuria, since scd80 was not elevated in other patients with glomerulopathies and proteinuria. upregulation of podocyte scd80 during relapse may play a role in the pathogenesis of proteinuria in mlns. aim: patients with mpgn type ii/dense deposit disease (ddd) and atypical haemolytic uremic syndrome (ahus) secondary to defective complement control are found to have a high prevalence of y402h polymorphism of factor h gene (cfh), which is linked to age-related macular degeneration (amd). however, no studies have looked into an ocular phenotype of children with complement based renal diseases, yet. methods: in two pediatric nephrology centres all patients with mpgn ii/ddd and ahus were identified and screened prospectively for the presence of y402h polymorphism and drusen maculopathy. all patients have been on immunomodulatory therapy at the time of screening. results: four children were identified (male:female=3:1) with mpgn ii/ddd and ahus. there were two children in either group. the median (range) age at examination was 8.6 years (3.5 to 13.3 years). of the four patients, all were found to have the y402h polymorphism. none of the patients had evidence of drusen at the time of examination. two patients with mpgn ii/ddd and one patient with ahus had additional factor h mutations, which were thought to be responsible for the renal disease. conclusion: in our study of children with mpgn ii/ddd and ahus we found a 100% prevalence of the y402h polymorphism of factor h gene, which puts these patients at higher risk for drusen maculopathy. therefore, all children with either mpgn ii/ddd or ahus should be screened for y402h polymorphism; and if found positive have regular follow-up ophthalmologic examination. in the future, should y402h be proven to be of functional significance with respect to complement control, there would be a role for plasma infusion or replacement of purified factor h for the treatment of both the renal and the ocular phenotype. we previously demonstrated that angiotensin-(1-7) is an endogenous ligand for the g-protein coupled receptor mas. the aim of this study was to evaluate the role of angiotensin-(1-7) mas receptor in kidney structure and function by using transgenic mice with genetic deletion of the receptor mas. mas -/-(knockout) mice were compared to mas +/+ (wild type) mice regarding renal function parameters and kidney histology. the animals were housed in metabolic cages to obtain 24-hour urine samples for measuring urinary volume, osmolality and microalbuminuria. at the end of the experiment, mas -/-and mas +/+ mice were sacrificed by decapitation to harvest the kidneys for histological analysis and immunofluorescence of collagen types iii and iv. the quantification of collagen expression was determined by confocal microscopy (zeiss lsm510). urinary volume was significantly reduced in mas -/-mice as compared to mas +/+ animals (1.32±0.49 vs. 1.80±0.83 ml/24 hs in mas +/+ mice, p<0.05). this change was associated with an increase in urinary osmolality (3846±796 vs. 3219±840 mosm/kg in mas +/+ mice, p<0.05) and albumin excretion (0.23±0.16 vs. 0.04±0.02 mg/24 hs in mas +/+ mice, p<0.05). the histological analysis showed a significant reduction in the glomerular diameter in mas -/-mice as compared to mas +/+ animals (51.84±0.73 vs. 58.25±0.79 μm in mas +/+ mice, p<0.05), where as any significant change was observed in tubular diameter. the immunofluorescence of mas -/-kidneys revealed a marked increase of the expression of collagen types iii and iv in periglomerular region as well as in external and internal medulla. collagen iv was also augmented in mesangial area of mas -/-mice. these results suggest that the receptor mas is critical for the regulation of renal structure and function. a circadian rhythm in calciuria is evident with a peak after 18:00 h, a lower excretion overnight and a nadir in the early morning. during the peak period both ca/creat ratio (figure) and calcium output frequently surpass the reference values of 0.21mg/mg and 4 mg/kg/day respectively. conclusion: a significant circadian variation in calciuria is evident in normal school age children, with peaks surpassing commonly used reference values for hypercalciuria. this peak excretion is independent from urine output, glomerular filtration and intake. the average 24 h excretion of 4 mg/kg is rarely surpassed despite this peaks. the management of children with secondary hyperparathyroidism is complicated and should start early in the course of renal insufficiency. in spite of an optimal management hyperparathyroidism is sometimes uncontrolled and calcimimetics like cinacalcet hydrochloride which directly stimulates calcium sensing receptors and potently suppress pth secretion are an alternative to parathyroidectomy. they are very promising agents, but paediatric experience is lacking. a 11 years old girl with a bardet biedl syndrome without medical care came last year with end stage renal failure. thanks to daily hemodialysis, serum phosphate level was kept within normal limits and phospho-calcic product remains below 4.4 as recommended. in spite of this treatment, serum pth level increased to 1297 ng/l. this toxic hyperparathyroidism with optimal monitoring of serum calcium, phosphate, vitamin d levels led us to start calcimimetics. a 1,5 mg/kg cinacalcet dose was administrated and induced a decline of pth level to 684 ng/l one month later. a 11 years old boy with recessive polycystosis and chronic renal failure was treated with calciumbased phosphate binders and sevelamer hydrochloride but with a poor compliance and a free diet which led him to hyperparathyroidism (pth to 813 ng/l). in addition, a parathyroid gland hyperplasia with two adenoma was individualized. start of calcimimetics treatment (less than 1mg/kg) led to a rapid decline in pth level from 813 ng/l to 457 ng/l. the two adenoma decreased in size. in case of hyperparathyroidism, with close monitoring of serum calcium, phosphate, alkaline phosphatase and vitamin d levels, calcimimetics are an excellent alternative to surgery, with safe use and low dose in these cases. preliminary favourable experience has been reported in children but paediatric experience is lacking. side effects result from chronic administration of steroids. the aims of this study are to analyze graft function and metabolic effects of low dose and withdrawal of steroid therapy. this is a single center pilot, one arm and prospective study. methylprednisone (mp) was decreased to 0.07±0.03 mg/kg/day (low dose) after 4 months. we studied changes in graft function, height velocity, lipid profile, body composition and bone mass after 1 year of low dose mp and after a 2 nd year following mp withdrawal. patients received daclizumab induction; tacrolimus and mycophenolate mofetil. the inclusion criteria was 1 st living related graft and pra <10%; 16 patients were enrolled and total follow-up was 2.5 years. age at transplantation was 3.1-21 years, 5 females, 9 prepubertal, 7 postpubertal patients. patients and graft survival were 100%, acute rejection (ar) occurred after 14 months of mp withdrawal in 2/9 (22%) prepubertal patients (banff 97, 1b). in prepubertal patients, at the moment of steroid withdrawal and 1 year later creatinine clearance was 99.7±15.2 and 82.9±3.9 ml/min/1.73 m 2 , p<0.001; height velocity 6.9±2.5 and 7.4±2.9 cm/year, p: ns, with a height increment of 0.31±0.1 sds, p<0.05 during the last year of follow-up. graft function did not change in postpubertal patients. in all patients at the moment of steroid withdrawal and 1 year later lipid profile was normal; fat body mass 10.0±6.7 and 9.2±5.5 kg, p: ns; lean body mass 29.3±11.4 and 31.7±12.8 kg, p<0.02; total skeleton bmd -1.0±0.6 and -0.7±0.8 sds, p: ns and lumbar spine bmd -1.3±1.04 and -0.86±0.86 sds, p<0.05. this study demonstrates that low dose and steroid withdrawal allow catch up growth, normal lipid profile with no fat accumulation. steroid withdrawal prevents bone loss with increment of lean body mass, but with a concerning rate of ar and graft function deterioration in prepubertal patients. children with x-linked hypophosphatemic rickets (xlh) usually present with progressive disproportionate stunting. we therefore conducted a 3 year randomized controlled trial on theeffect of rhgh therapy on body anthropometry (28 parameter) in 16prepubertal children with xlh (each 8 patients in rhghandcontrol-group). age at baseline was 7.3±2.0 yrs (mean±sd), height was -3.2±0.8 sd, calcitriol dosage was 23 ng/kg x day, and phosphate dosagewas 55 mg/kg x day (each p>0.05 rhgh-vs. control-group). results: within the whole study population longitudinal bodydimensions were more affected than transversal body dimensions aswell as circumferences (extremities/trunk). leg length (-3.7±0.9 sd; p<0.0001) was the most impaired longitudinal parameterexplaining 90% of the overall variability of total body height, whereassitting height (-1.7±0.8 sd) was the best preserved longitudinalparameter. longitudinal body dimensions were significantly increased after 12 months rhgh-treatment (height +0.72±0.18 sd; sitting height +0.61±0.39 sd, leg length +0.57±0.55 sd; arm length +0.74±0.59 sd; each p<0.001). in contrast, progressive stunting was noted in control patients (height -0.16±0.42 sd; sitting height -0.01±0.24 sd; leg length -0.1±0.56 sd; arm length -0.01±0.26 sd; each p<0.001 vs. rhgh-group). rhgh treated patients showed a significant increase in all transversal body dimensions (each p<0.001), as well as a decrease in skin folds (range -0.2 up-to -0.9 sd; each p<0.001). one year rhgh treatment in severely growth retardedprepubertal children with xlh leads to improvement of longitudinal bodydimensions, harmonization of body (i. e. transversal body dimensions & body proportions), and decrease of body fat. thalassemia is an hemolytic anemia characterized by decreased production of β globin. the chronic hemolysis requires frequent bloodtransfusions that caused hemosiderosis, including iron deposition in the kidney. removal of excess iron via iron chelators, the most commonof which is desferal produce iron excretion in urine and stool. few studies have been published, the studied patients, mostly adults, exhibited proteinuria, aminoaciduria, low urine osmolarity and excess secretion of the proximal tubular function markers, n-acetyl-d-glucoseaminidase (nag) and β2 microglobulin. the iron accumulation may causes lipid oxidative peroxidation and this oxidative process cause's tissue damage. in this study we examined 40 thalassemia major patients treated with desferal. the degree of hemosiderosis was determined by measuring serumiron and ferritin. 12 children without iron metabolism disorders orrenal disease serve as controls. the renal and tubular function was analyzed. no differences in creatinine clearance, blood hco3, na and k fe, tmp/gfr was found. serum uric acid was equal in the two groups but itsurine excretion was significantly higher in the thalassemic group probably due to persistent hemolysis. the nag level and its ratio to creatinine were significantly higher compared to the control group. the results of our work showed that most of the thalassemic patients have sub clinical disturbances in tubular function and high nag in theurine. these results raise the question of treating thalassemic patients with oral chelators which removes iron from cells preventing the oxidative process; moreover, and add antioxidants which may prevent the deposition of iron in tissues. in light of these findings, it would be advisable to routinely check glomerular and tubular function as part ofthe follow-up in these patients. objectives of study and methods: little information is available on the long-term follow-up in patients with biallelic mutations in the two genes slc12a1 and kcnj1, encoding the bumetamidesensitive na-k-2cl cotransporter and the in wardly rectifying renal potassium channel, respectively. we evaluated the long-term follow-up (>7 years) in 12 patients with these two forms of bartter syndrome. the slc12a1 and kcnj1 genes were screened by dhplc and sequencing techniques. results: the long-term follow-up period was 7 to 22 years, median 11, after diagnosis, in 8patients with mutations in slc12a1 (4 homozygotes, 4 compound heterozygotes) and 4 patients with mutations in kcnj1 (2 homozygotes, 2 compound heterozygotes) genes. medical treatment with indo methacin at last follow-up control including supplementation with potassium in 7patients and medical treatment with indomethacin in 10 patients (meandose 1.1 mg/kg/day). in two patients (one with slc12a1 and another one with kcnj1 mutations) growth hormone (gh) deficiency was detected with specific tests. both patients were treated with recombinant human gh. at the end of follow-up, body height was <3° percentile for agein 2 of the 12 patients, 1 of whom with gh deficiency and body weightwas <3° percentile for age in 3 patients (none of them with gh decifiency conclusions: these data demonstrate that some patients with biallelic mutations inthe slc12a1 and kcnj1 genes tend to present slight impaired glomerular kidney function after a median follow-up of 11 years and that growth retardation and gh deficiency are often present in these patients. the cytosolic c-terminus of nhe3 does not mediate its apical localization or baseline activity -implications for blood pressure and ph homeostasis the epithelial sodium proton exchanger, nhe3, is expressed in the apical membrane and subapical endosomes of the proximal tubule. apical localization is fundamental to proximal tubular na+, water and hco3-absorption, a process necessary for the maintenance of plasma ph and blood pressure. moreover the redistribution of nhe3 between these compartments alters its activity. for example, acute hypertension leads to an increased endomembrane accumulation of nhe3 and pressure natriuresis. nhe3 is composed of a n-terminus with 12 transmembrane helices and a cytosolic c-terminus. the former is necessary for sodium-proton exchange while the latter regulates activity. the goal of our studies was to evaluate the contribution of the cytosolic c-terminus to apical localization and therefore to nhe3 function. to this end we generated a series of nhe3 constructs with sequential deletions in the cytosolic c-terminus. all constructs contained an extracellular epitope tag to facilitate the delineation between cell surface and endomembrane nhe3. stable renal epithelial cell lines were generated expressing each construct. surprisingly, even when the entire c-terminus was deleted nhe3 was still detectable at the apical membrane. we proceeded to evaluate the activity of the truncated exchangers and found they retained activity. finally, we assayed the attachment of nhe3 to the actin cytoskeleton (a process thought to be mediated by the c-terminus), by measuring their solubility in the weak detergent triton x-100 and by measuring their mobility in the plane of the plasma membrane. both assays confirmed that exchangers lacking the c-terminus retained their association with the plasma membrane. in conclusion, the cytosolic c-terminus of nhe3 is not necessary for apical localization nor baseline nhe activity. further studies will be needed to confirm its role in specific regulatory processes. background: ibu is used as a safer alternative to indomethacine for pda treatment. however, safety/efficacy balance has not been extensively studied. animal and a few clinical studies suggested that ibu might also have significant side effects. objective: to evaluate renal function at one week of life in infants treated with ibu as compared to infants not exposed to ibu, within the first days of life. methods: multicentric prospective cohort study of 27 to 31 weeks gestation (ga) infants exposed or not exposed to ibu. infants presenting with renal impairment at birth, urinary tract malformation, or contraindication to ibu treatment were excluded. infants exposed to ibu were paired to controls according to ga, centre and crib score. creatinine clearance (ml/min/1.73 m 2 ) was measured for glomerular function evaluation; fractional excretion of sodium (fena) and 1microglobinuria/creatininuria (1/ucr) for tubular function evaluation. results: 120 infants were studied: 60 exposed to ibu for pda closure with 83.3% efficiency and 60 controls. birth weight was 1100±278 g (mean+sd), and ga 28.2±1.2 wks. glomerular filtration rate (gfr) significantly decreased on day 7 in ibu exposed infants. noteworthy, diuresis remained in the normal range, but was significantly lower after ibu treatment (given on day 2) as compared to controls. antiresorptives, particularly bisphosphonates (bp), offer a promising treatment inpediatric bone disease. bp have been successfully used to treat childrenwith osteogenesis imperfecta (oi), secondary osteoporosis, fibrousdysplasia, hypercalcemia. concerns exist regarding bone mineralizationand bone growth and transient adverse reactions. according to available literature, bp were successfully used in ~1000 children, intravenous pamidronate (pm) being the most frequently used one (>500 children, mostly with oi), followed by alendronate (al) (~300 patients with oi, secondary osteoporosis, hypercalcemia), risedronate, etidronate, zoledronate, clodronate, olpadronate. oi treatment with bp resulted in an increase in bmd, improved growth, relief from pain, mobility improvement, improved quality of life and a drop in fracture rate there are sparse data comparing oral and i. v. bp. oral and i. v. bp seem to have a similar effect in children with oi. daily al therapy seems to be safe and effective in children with oi, and daily or weekly administration of al led to increase in bmd in patients with secondary osteoporosis. there is scarcity of randomized, double blind, placebo-controlled or active comparator trials with bp in children. currently, double-blind, placebo-controlled study with risedronate andactive comparator trial with intravenous zoledronate in children with oi are planned. bp therapy should be used in context of a well-runclinical program with specialist knowledge in the management of pediatric metabolic bone disorders. other emerging antiresorptive agents include denosumab, glucacon-likepeptide-2 and calcitonin tablets. these drugs are tested in phase iii trials in adults. their applicability to children is likely to be discussed in the coming years. the current kdigo recommendations on classification or renal osteodystrophy recommend assessment of three areas of bone histology: turnover, mineralization, and volume. while lesions of bone turnover are prevalent in children treated with dialysis, little is know about the prevalence of mineralization defects and their response to therapy with vitamin d sterols and phosphate binders. we evaluated the skeletal mineralization (osteoid thickness (o. th.) and osteoid maturation time (omt)) in 207 patients ages 13±1 years treated with maintenance dialysis who were not receiving vitamin d sterol therapy. serum biochemical markers were: ca: 9.2±0.1 mg/dl, p: 6.2±0.2 mg/dl, pth: 660±40 pg/ml, alk p'tase: 390±21 iu/dl. 53% of patients with high turnover bone disease (95% ci: 43-62%) and 29% (18-41%) of patients with normal or adynamic bone had abnormal skeletal mineralization as reflected by both a prolonged omt and widened o. th. subsequently, a subset of 103 patients underwent treatment with calcitriol and calcium carbonate. while serum pth levels decreased by 36% (p<0.05) and bone formation rate decreased by 41% (p<0.05) with therapy, there was no change in o. th or omt from baseline. indeed, 67% (55-77%) of patients had abnormal mineralization after therapy. we conclude that mineralization defects are prevalent in children treated with dialysis and are not affected by current therapeutic options. further studies are needed to determine the pathophysiology and optimal treatment of these defects. introduction: clara cell secretory protein (cc16) is a protein synthesized primarily by non-ciliated bronchiolar epithelial cells, the clara cells. like other low-molecular size proteins, plasma cc16 is rapidly eliminated by glomerular filtration and reabsorbed by proximal tubular cells. this protein has been rarely studied in the paediatric age. the sensitivity of cc16 in urine was compared to that of b 2-microglobulin (b 2m) and n-acetyl-b-d-glucosaminidase (nag conclusions: cc16 is a good marker of the proximal tubular function. cc16 is related better with the urinary b 2m elimination, since both are low-molecular size proteins that are reabsorbed by the proximal tubule. sd. kim, bs. cho kyunghee university hospital, pediatrics, seoul, south korea background: many studies have demonstrated that arb prevents renal progression in patients with glomerular nephritis or diabetic nephropathy by inhibition of hmc proliferation and reduce of extracellular matrix expansion and glomerulosclerotic changes. however, the molecular effects of arb in cultured hmc have not been completely defined. we investigated differential gene expression by arb treatment on cultured hmc according to time sequence using cdna chip (affymetrix). methods: mc was grown in dmem with 10% fbs and then arb was treated on cultured mc. rnas of hmc at different time points (4, 8 , and 24 h after arb treatment and no treatment) were compared using affymetrix cdna chip. to validate the patterns of gene expression analyzed by the microarrays, some genes were selected and semi-quantitative rt-pcr was performed. results: among genes, humoral immune response, cytokine activity, il-8 receptor binding, chemotaxis, cell cycle arrest, and morphogenesis associated genes were down-regulated for 4, 8, and 24 h after arb treatment. they also showed different clustering according to their changing patterns. conclusion: the present study demonstrates profile of gene expression as time goes by after arb treatment on proliferation of human mc. gene expression by arb treatment on cultured hmc showed sequential changes. our results showed that chemotaxis and immune response associated genes were suppressed by arb treatment on hmc. further evaluation of individual genes will be conducted to elucidate molecular mechanism. podocin is the major component of the slit diaphragm, the site responsible for size and charge selectivity of filtration. mutations in the nphs2 gene, which encodes podocin can lead to steroidresistant nephrotic syndrome (srns). in this work we studied whether genetic changes of podocin might predispose to the development of sporadic non-familial srns in childhood. we screened for podocin mutations 50 children (26m/24f; mean age 11.9±0.7 years) with sporadic srns and 50 healthy controls. renal biopsy in srns patients revealed mesangial proliferative glomerulonephritis (n=21), focal segmental glomerulosclerosis (fsgs; n=13), membranoproliferative glomerulonephritis (n=13) and membranous nephropathy (n=3). the mean age of onset of srns was 8.8±0.7 years. all 8 exons of podocin gene of patients with srns and controls were amplified and direct dna sequencing was performed. there is one novel nonsense heterozygous mutation of c.328 g>t p.87glu>stop was identified in the 1 st exon of nphs2 gene in srns child with fsgs who has renal transplantation at the age of 2 years without recurrence of fsgs in her graft. we found one kind of single nucleotide polymorphism c.872+7a>g in the 7 th exon of nphs2 gene in 6% (3/50) srns patients (2 with fsgs; 1 with membranoproliferative glomerulonephritis) and 10% (5/50) children in controls. allele frequency of this polymorphism of the nphs2 gene in srns patients and controls was not different significantly. our results indicate that mutation-detected rate in the nphs2 gene in russian children with sporadic srns was 2%. the low mutation-detected rate and identified polymorphism c.872+7a>g in nphs2 gene unlikely predispose to the development of sporadic srns in russian children. further determining the slit diaphragm genetic profile of children with sporadic srns is warranted in order to improve disease classification and tailoring of treatment. for diagnose of essential hypertension is necessary except all causes of secondary hypertension (sh). case: family history of 17-year-old female patient was unremarkable for hypertension, incl. renal diseases. during last 6 months she had often headaches with intermittent vertigo. she was not anywhere examined. at admission on intensive care unit patient had headache, her pulse rate was 130/min, respiratory rate 12/min, bp (right arm) was 220/180 mmhg and the lower extremity bp 225/188 mmhg. other physical examination was normal, incl neurological exam. fundoscopy of the eyes did not show any evidence of hypertensive retinopathy. cardiac ultrasound showed mild left ventricular hypertrophy. abnormal laboratory parameters (without medication) were: hypokalemia (3.0 mmol/l), metabolic alkalosis (ph 7.48, hco 3 26.3 mmol/l), low urinary output of sodium (22 mmol) and chloride (<18 mmol), high urinary output of potassium (34 mmol). renal function tests were normal and no abnormalities were detected by renal ultrasonography, incl. doppler exam of renal blood flow. by large hormonal analyse were detected high plasma renin activity (pra; 12.8 ng/ml/hod; n.r. 0.5-1.9) and very mild increased serum aldosterone (ald; 0.63 nmol/l; n.r. 0-0.60). during the ct renal angiography was found solid mass in the upper part of the left kidney. a partial left nephrectomy was performed and histological exam revealed juxtaglomerular cell tumor (so-called reninoma, re). after the resection we stopped subsequently patients antihypertensive therapy. in a 3-month follow-up our girl was normotens. re is a very rare cause of sh. re typically present during adolescence or young adulthood. this cause of severe sh should be considered along renal artery stenosis in adolescents presenting with secondary hyperaldosteronism or in causes with renin-secreting tumor of non-renal origin. we report our preliminary molecular findings in twelve turkish cystinosis patients. the patients were 3 to 22 years; male/female ratio was 7: 5. all presented initially with severe failure to thrive, polyuria and polydipsia. cystinosis was diagnosed at age 1 month to 6 years. six of the patients reached end stage renal failure at ages ranging from 6.5 to 15 years necessitating renal replacement therapy; 3 are currently on hemodialysis, one is on capd, and two were transplanted. while three of remaining 6 have renal fanconi syndrome with proteinuria, 3 had kidney failure in varying degrees. molecular analyses involve an initial multiplex pcr, checking for the presence or absence of 57 kb founder deletion, and subsequent sequencing of the 9 coding exons of ctns. interestingly, none of the 12 nephropathic cystinosis patients carried the 57 kb deletion. instead, one patient had a new homozygous 10 kb deletion of exons 4 to 9 of ctns. one patient was homozygous for a known 4 bp deletion in exon 3, i.e., c.357del gact. two patients were homozygous for new missense mutations in exons 7 and 9, i.e., c.451g>a (r151g) and c.518a>g (y173c), respectively. the most common mutation in our turkish patients was a new exonic splice site mutation in exon 9, i.e., c.681g>a (e227e). of 24 alleles studied, 7 carried this mutation, which is expected to disrupt proper splicing. two patients were compound heterozygous for one of the above-mentioned mutations and a known missense mutation in exon 12, i.e., c.1015g>a (g339r). in two patients, we could not find any disease-causing mutation; in two patients, we could find only one disease-causing mutation. in summary, cystinosis patients of turkish ancestry show ctns mutations different from those of western european patients. these findings will be of relevance for molecular-based screening and diagnostic methods for cystinosis. introduction: the association of hypertension with bell's palsy in adults has been reported from 4-11%, but there is few data in children. the presence of bell's palsy in children requires a complete evaluation for hypertension, solid tumors, leukemia, neurofibroma, and trauma. hypertensive children usually present with clinical manifestations of underlying disease, but with substantial elevation, symptoms of hypertension develop. although headache, dizziness, blurred vision and seizure are common neurologic symptoms of hypertension, but facial paralysis is not a wellrecognized presenting feature of hypertension in children. case report: this paper describes two severely hypertensive children who referred to children's hospital of tabriz with periferal hemifacial nerve paresis and initial diagnosis of bell's palsy. case 1: a 12 years old girl who admitted with blood pressure of 230/120 mmhg on admission. renal ultrasound study revealed left small size kidney and renal scintigraphy followed by angiography confirmed renovascular hypertension. case 2: a 5 years old boy with blood pressure of 180/100 mmhg on admission. sonography of kidneys was normal except for a small size (4 mm) stone in left kidney. renal scintigraphy and angiography were normal. all other evaluations for etiology of hypertension including cardiac and endocrine investigations were negative. treatment of hypertension with antihypertensive drugs resulted in complete recovery of facial paresis in both cases within 3-4 months. conclusion: unilateral peripheral facial nerve paresis is a rare presentation of hypertension in children. unawareness of this presentation may result in delay in diagnosis of hypertension which may increase further with steroid therapy for bell's palsy. to uncover the frequency and the spectrum of nphs2 mutations in egyptian children with non familial steroid-resistant nephrotic syndrome (srns), 16 patients were screened by pcr-singlestrand confirmation polymorphism analysis of nphs2 gene followed by direct sequencing. nphs2 mutations were evident in 5 patients (31.3%) who were bearing five novel mutations including two frame shift mutations (713-714insg and 132-133insg), two missense mutations (556a>c and 647t>a) and a silent mutation (408a>t). there were no phenotypic or histological characteristics of patients bearing nphs2 mutations, apart from the earlier onset of the disease, compared to those who were not bearing mutations. in conclusion, nphs2 mutations are prevalent in egyptian children with non-familial srns and this may in part explain the less favorable prognosis reported in these patients. , which is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system, also leads to rvh. these symptoms of pxe are usually apparent in adulthood and rarely observed in children. here, we describe a very rare pediatric case of rvh caused by pxe. case report: a 6-year-old boy was noticed to have severe hypertension (183/128 mmhg) when he was admitted to our hospital for an operation for exotropia. he had no previous or family history of pxe or hypertension. laboratory examination showed that plasma renin (517.0 pg/ml) and aldosterone (71.3 ng/dl) concentrations were markedly elevated. his systolic and diastolic blood pressure (bp) decreased 12.7% and 22.2% from baseline after administration of captopril, respectively. a computerized tomographic scan of his abdomen showed multiple calcified vessels in kidneys and spleen. yellowish papules on the bilateral axillary regions and inguinal area were detected. characteristic histological changes of pxe such as elastic fiber mineralization and calcification were noticed in the biopsy of affected skin lesions. conclusion: pxe is characterized clinically by high heterogeneity in the age of onset and extent and severity of organ system involvement. although its symptoms usually appear in the second or third decade of life, gastrointestinal bleeding and acute myocardial infarction have been reported in childhood. we should also consider pxe as one of the causes of rvh in children, because its prognosis depends largely on the extent of extracutaneous organ involvement. the clcnkb gene is rarely reported as having a large deletion mutation, but all cases reported previously were large homozygous deletions and a large heterozygous deletion is impossible to detect by direct sequencing. patients and methods: this report concerns a genetic analysis of 5 japanese patients with type iii bs. to identify the mutations in the clcnkb gene, we used polymerase chain reaction (pcr) and direct sequencing to investigate all exons and exon-intron boundaries in the patients and their family members. to detect large heterozygous deletion mutations of the clcnkb gene, we conducted semi-quantitative pcr amplification using capillary electrophoresis. results: four mutations were identified, comprising 1 novel 2 bp deletion mutation (c.1334_1335delct), an entire heterozygous deletion and a heterozygous deletion mutation of exon 1 and 2 of the clcnkb gene. the nonsense mutation w610x in the clcnkb gene was detected in all patients (2 of them were homozygous and 3 were heterozygous) and this finding indicates that this nonsense mutation is likely to constitute a founder effect in japan. two patients had large heterozygous deletion of the clcnkb gene, which was proved by semi-quantitative pcr amplification. conclusions: capillary electrophoresis is a new method and extremely useful for detecting large heterozygous deletions, and should be employed to examine type iii bs cases in whom only a heterozygous mutation has been detected by direct sequencing. obesity defined as body mass index (bmi) above 95 th percentile for age and gender is regarded as a risk factor for cardiovascular (cv) target organ damage (tod) in children and adults with ph. however, when using percentile-based definition of obesity one may miss children at risk of cv complications. the aim of the study was to compare sensitivity of traditional definition of obesity (bmi>95 th pc) and bmi thresholds (tbmi) for cv complications described by katzmarzyk et al. (2004) majority of children with idiopathic nephrotic syndrome (frequent relapsers, steroid dependent and steroid resistant) require adjunctive therapy. the response to cyclophosphamide (cp) in these children is variable and difficult to predict. there may be an effect of polymorphic expression of gst on the remission with cp. in this study, we have tried to evaluate the correlation of gst polymorphism and response to cp therapy in these children we studied gst polymorphism in 73 consecutive children (54 males, 19 females) with steroid sensitive (n=44) and steroid resistant (n=29) nephrotic syndrome, receiving cp therapy. we evaluated the inter-relationships between gstm1, gstt1, and gstp1 genotypes and correlated it with the response to cp therapy in these children. the mean age of onset was 5.2±4.4 years. out of 73 children, 67% children responded to cyclophosphamide therapy. the null genotype of gstm1 and gstt1 was observed in 39.7% and 64.4% respectively while val105 genotype of gstp1 was seen in 22% children. there was no significant correlation among the various individual genotypic combinations. however, a trend was seen towards remission in children with a combination of gstp1 polymorphism with gstt1 null genotype (p=0.08) or combination of gstp1 polymorphism with gstm1 wild type genotype (p=0.0885) another important finding in our study was that there was a significantly higher frequency of val105 allele of gstp1 in responders to cyclophosphamide as compared to nonresponders (p=0.01). the results indicate that the presence of the val105 allele correlates with the response to cyclophosphamide in these children. gst gene polymorphism may be a significant therapeutic tool in the management of children with idiopathic nephrotic syndrome receiving therapy. objectives of study: primary vesicoureteral reflux (vur) is a common pediatric disease that may lead to reflux nephropathy and end-stage renal disease. the renin-angiotensin system (ras) was proposed to be associated with primary vur. the objective of this study was to investigate whether the gene polymorphisms of the ras are involved in primary vur and correlation with the severity of vur in taiwanese children. methods: we studied the angiotensin ii type 2 receptor (at2r) c3123a gene polymorphism for association with susceptibility to primary vur and disease severity in 100 vur children and 60 healthy controls. fifty four of the 100 vur patients had low-grade vur (grade i-iii) and 46 had high-grade vur (grade iv and v). to analyze the polymorphisms in the c3123a of at2r gene, the snp genotyping assay were performed. the genotypic frequency and allele frequency for four ras genes were analyzed to detect the correlation between the patients with mild, severe vur, and healthy control. results: we found that the c3123a of at2r gene was associated with the development and severity of vur. significantly higher c and lower a allele frequencies were presented in vur patients (c allele 0.67 and a allele 0.33) compared with controls (c allele 0.56 and a allele 0.44, p<0.005). the similar results were observed in both mild (c allele 0.73 and a allele 0.27) and severe (c allele 0.62 and a allele 0.38) vur compared with controls (p<0.005). the cc genotype was higher in vur patients compared with controls (p<0.005). conclusions: at2r c3123a gene polymorphism was associated with the development and the severity of vur in taiwanese children. it raises the possibility to utilize the genotype of at2r as a risk factor to evaluate the development and severity of primary vur. results: stone analysis led to diagnosis of cystinuria in 12 patients (1% of all), but only 5 were children (1.4% of the paediatric stone patients). age at diagnosis in three patients was 17-30 years and in four 30-49 years. time from first manifestation (pain 7x, gross haematuria 3x, urinary retention 2x, uti 4x) until diagnosis was 0-2 years in seven, 5-10 in three and even 34 and 39 years in two. renal function was impaired in 1 patient (ckd stage ii). the urinary cystine test was positive in all 9 patients with cystine stones examined, but was negative in 2 family members thus excluding cystinuria in them. family history of urinary stones was positive in two; the brother of one had died of renal failure due to bilateral urolithiasis. conclusions: delays in diagnosis of cystinuria in armenia are unacceptable. production of tablets containing nickel/dithionite which is non-toxic in contrast to brand test (cyanide/nitroprusside) is planned and could allow screening of all patients with stones of unknown origin. background: classically, childhood hypertension has always been recognized as secondary and frequently demanded an exhaustive etiological investigation. however, in the last two decades, many studies have been shown that pediatric patients also present primary hypertension and, sometimes, the adult disease probably begins during childhood. the aim of this study was to analyze a cohort of patients followed-up at a single tertiary unit (belo horizonte, brazil). methods: in this retrospective cohort study, the records of 220 diagnosed with arterial and followed at our unit between 1994 and 2004 were analized. a data base was used for statistical analysis. results: of 220 patients, 53.2% were male and 46.8% female. the distribution of patients according to the age at diagnosis was: 0-1.99 years, 3(1.4%), 2 yr-6.99 yr, 51 (23.2%), 7 yr-11.99 yr, 55 (25%), and 12 yr, 111 (50.4%). the causes for hypertension were: renal diseases in 172 (78%), primary hypertension in 33 (15%), renovascular disease in 9 (4%) and ohers in 6 patients (3%). the comparison between primary hypertensive subjects and patients with renal diseases showed that, although blood pressure was similar at admission, a better control was achieved in the first group (p<0.05). the frequency of overweight and/or obesity was higher in primary than in secondary hypertension ( nephrnophthisis (nphp) is a very rare cause of crf in korea. identification of five genes mutated in nphp subtypes 1-5 has linked the pathogenesis of nphp. ten percent of affected individuals have retinitis pigmentosa, constituting the senior-löken syndrome. we experienced juvenile-onset crf with leber's amaurosis in two sibilings. case 1: a 10-year-old boy presented with pale appearance. he had severe renal impairment and visual disturbance, but no symptom of polyuria and polydipsia. his past annual school screening urinalysis was normal. his growth and development were normal except opthalmological findings and pallor. case 2: his 14-years-old sister also had a visual disturbance and was found to have crf. there was no specific problem during perinatal period. opthalmologic findings were similar to her brother's. nphp1 and 5 on chromosome 2q13 was analyzed by direct sequencing. sequencing of mitochondrial dna-mbol digestion for 14484 mutation was analyzed by pcr-sequencing and rflp. electroretinogram revealed a decreased in amplitude of a and b waves. on the kidney biopsy, some of glomeruli were globally sclerotic. remaining showed no cellular proliferation or capillary wall thickening. interstitium was diffusely fibrotic and in which were scattered lymphocytes. most tubules were preserved well but a few dilated tubules were intermingled. no positive reaction for immunoglobulines or complements in if. by em, tubular membranes showed thickening, splitting and disintegration. nphp1 and 5 genes were not identified. there was no transition mutation at mitochondrial dna nt.11778, 3480, 14484, 15257. late-onset senior-löken syndrome were diagnosed in these cases even though there were no polyuria and polydipsia of initial symptoms of nphp and nphp1 and 5 were not identified. we need to identify other known or novel mutation genes. nail-patella syndrome (nps) is an autosomal dominant disease characterized by classic tetrad of dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. some patients manifest nephropathy and adult-onset glaucoma. nps is associated with mutations in the lmxib gene. there is marked inter-and intrafamilial variability in the phenotypes. in this study, phenotype-genotype correlation was analyzed in 7 unrelated korean children with nps. the probands were 3 boys and 4 girls. they manifested dysplastic nails (7/7, 100%), absent or hypoplastic patellae (6/7, 86%), elbow dysplasia (4/7, 57%), iliac horns (3/7, 43%) and nephropathy (2/7, 29%) . four missense mutations/2 in the lim-b domain (h114q and l127p) and 2 in the homeodomain (r200q and a213p)/and 1 frame-shifting deletion (c,680dela) were identified in the lmxib gene.r200q and a2123p are known to be common mutations, and r200q was detected in 3 patients in this study. autosomal dominant inheritance was identified in 3 patients by phenotype and genotype analysis of the family members and in 2 patients by phenotype analysis only. remaining 1 patient had de novo r200q mutation. one patient and her mother with r200q mutation developed nephrotic syndrome, which progressed to end-stage renal disease (esrd). another patient with h114q mutation had asymptomatic proteinuria with microscopic hematuria, and her father had esrd. galucoma was not detected in any patients or family members affected. there were inter-and intrafamilial variability of the phenotypes, but no genotype-phenotype correlation was identified. this is the first study to characterize mutations in the lmx1b gene in korean patients with nps. r200q is a common mutation in korean, also. the mechanism underlying the phenotypic variations and predisposing factors to the development nephropathy remain unknown. the pathological mechanism which would be responsible for higher production of digitalis similar compounds in essential arterial hypertension (ah), would be a genetically defect kidney, which causes difficulty in na + excretion. higher intake of salts can be an etiological factor inessential ah only patients with inherited abnormalities of thetransport mechanisms in the cell membrane.the objective of the studywas to establish the incidence and type of ah and frequency of genetic factor in the investigated population of 3000 school children (age 7-16years). in children with essential and borderline ah we evaluated the activity of erythrocyte membrane na+, k+-atpase in the presence ofvarying atp concentrations. atp, adp and amp levels and lipid peroxides (as tbars) in the erythrocytes and tbars in plasma were measured. our data have shown that the prevalence of ah is lowest in 7-8 years oldchildren, while it is the highest in 15-16 years oldchildren. essential ah was established in 11 (0.36%) and borderline in 17 (0.56%) children. genetic factor were found in 54.5% of children with essential ah and in 60.4% of children with borderline ah. but, statistical analyses of the first and second degree relatives of children with essential and borderline ah suggested normal prevalence of hypertension. atp, adp and amp levels, as well as, lipid peroxides were not significantly altered compared to healthy children. kinetic profileof erythrocyte plasma membrane na+, k+-atpase activity revealed the presence of noncompetitive (allosteric) inhibition of enzyme activityin the children with essential and borderline ah. the differences in the kinetic properties of na+, k+-atpase between two investigated groups of children suggested that this dynamic model could be used as potential biological marker for early diagnosis and differentiation of these two type of ah. majority of these patients were obese and with increasing body weight nighttime hypertension became prominent in these patients. objectives: it has been shown that weight gain is directly related to increase inblood pressure. the objective of this study was to analyze the frequency of overweight/obesity in children/adolescents with primary hypertension (ph) and the relationship between the overweight/obesityand the stage of hypertension (h). methods: we analyzed the data of 113 patients aged 10-17.5 years (m 65; f 48) diagnosed with primary hypertension. overweight/obesity was defined asperc. of bmi -85/95 c. the stage of hypertension was determined according to the 4 th report on the diagnosis, evaluation,and treatment of high blood pressure in children and adolescents of the nhlbi working group. results: out of 113 pts, prehypertension was found in 10 pts (8.9%), stage i h in 30 (26.5%) and stage ii h in 73 pts (64.6%). stage ii h was more frequentin boys (69% vs. 58% in girls). combined systolic/diastolic h was found most frequently, in 58 pts (51.3%), isolated elevation in systolic blood pressure (bp) was found in 47 pts (41.6%), while only 8 pts (7.1%) had isolated elevation in diastolic bp. sixty-one pts (53.98%) were found overweight/obese; of which 33 (54.1%) above 95c bmi. theobese children were predominantly found to have stage ii h: 84.8% ofthe obese children. none of the obese children had prehypertension. contrary to the general perception, boys were found more frequently overweight/obese (67.2% boys vs. 32.8% girls). conclusion: our data shows that stage ii ph is not rare also in theteen-age group. frequently it is accompanied with overweight/obesity, especially in boys. we can conclude that the roots of ph in the adultage are already set from the childhood. our efforts should focus onearly diagnosis of ph and include prevention of obesity as the possible contributing factor for the development of ph. objectives of study: alport syndrome (as) is a progressive renal disease characterized by hematuria, progressive renal failure, high-tone sensorineural hearingloss and ocular lesions. xlinked dominant alport syndrome (xlas) isthe major inheritance form, accounting for almost 80% of the cases, caused by mutations in col4a5 genes. there are no good cures available for as at present, but there are some patients who requestfor prenatal diagnosis and genetic counciling. this study performed thefirst prenatal diagnosis in chinese as family. methods: the entire coding sequence of col4a5 mrna of peripheral blood lymphocytes was amplified using nest pcr to screen mutations in a chinesexlas family. mutation analysis of the fetus was performed on both cdna-based level and dna-based level of amniocytes. fetus sex was determined by pcr amplification of sry as well as karyotypes analysis. maternal cells contamination was excluded by linkage analysis. results: mutation screen showed that there was a g to a substitution at position 4271 in exon 46 of col4a5 gene (c.g4271a), it was subsequently confirmed at genomic dna level by pcr amplification of exon 46 of col4a5gene. the mutation was identified in the index case, family members aswell as the pregnant lady. the prenatal diagnosis showed that fetus didnot carry the same mutation as the mother detected by both cdna-basedand dna-based mutation analysis. pcr amplification product of sryas well as karyotypes analysis revealed a male fetus. linkage analysis of the three x chromosome markers showed that there was no contamination of maternal cells in amniocytes. conclusion: after mutation identification of col4a5gene in a large chinese as family, a successfully prenatal diagnosis was performed in one of the female members in this family based on both cdna as well as genomic dna level of amniocytes. objectives of study: alport syndrome (as) is a clinical and genetic heterogenousdisease. autosomal recessive as (aras) is caused by mutations in col4a3 and col4a4 genes, accounting for 10% of the cases. thin glomerular basement membrane nephropathy (tbmn), is also caused by mutations in col4a3 and col4a4genes, inherited as an autosomal dominant trait. differentiation between early stages of aras and tbmn may be difficult in clinic, itdepends on gene mutation analysis of col4a3 or col4a4. methods: the whole entire coding regions of col4a3 and col4a4 mrna of peripheral blood lymphocytes were analyzed using reverse transcription polymerase chain reaction (rt-pcr) and direct sequencing to screen mutations in three chinese aras families, the corresponding exon with flanking intronic sequence was further amplified to confirm the abnormality. results: both the entire coding regions of col4a3 and col4a4 mrna were successfully amplified and completely sequenced by seven overlapping pcr products, respectively. results showed that there were 10 variations of col4a3 and 4 variations of col4a4, respectively. among the 10 variations of col4a3,three were snp reported previously, four were new snp, one nonsense mutation, one small insertions and one splicing mutation, the latter three were the pathogenic mutations for the three families, respectively. all the four variations of col4a4 were snp reported previously. we concluded that rt-pcr and direct sequencing using peripheral blood lymphocytes rna is a practical, sensitive and feasible approach for analysis col4a3 and col4a4 gene variants in autosomal recessive alport syndrome patients, which offers a useful, inexpensive and timesaving approach for systematic gene analysis in patients with aras. objectives of study: gitelman syndrome (gs) is an autosomal recessive tubular disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. the majority of gs patients carry inactivating mutations of the slc12a3 gene encoding the sodiumchloride cotransporter located in the distal convoluted tubule. this study aimed to detect mutations in a chinese family with gs. methods: two brothers presenting muscle weakness, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria were clinically diagnosed as gitelman syndrome. the two brothers, as well as their healthy brother and parents, were detected for mutations in slc12a3 gene by direct pcr for each exon and then sequencing on genomic dna extracted from peripheral blood cells. results: the two patients were found to have the same compound heterozygous mutations (c.917c>t and ivs 14-8t>c) in the slc12a3 gene. the two mutations were also detected in paternal and maternal genomic dna, respectively. the unaffected brother had one mutation (c.917c>t) only. conclusion: a novel compound heterozygous mutation on the slc12a3 gene was revealed in a chinese family with gs. the objective: to determine the clinical value of ambulatory blood pressure monitoring (abpm) in pediatric kidney disease. methods: 83 patients with common kidney diseases aged from 5-16 yrs were enrolled. 24-hour abp were performed by welch allyn abpm6100. the number of cases whose ccr>90mmol/l/1.73 m 2 , ccr 60-89 mmol/l/1.73 m 2 , ccr 30-59 mmol/l/1.73 m 2 , ccr 15-29 mmol/l/1.73 m 2 and ccr<15 mmol/l/1.73 m 2 is 64, 4, 5, 1 and 9, respectively. seven patients only took fosinoprilto control blood pressure did abpm again more than one weeks after therapy. 1141 healthy children performed in german in 1997 was used asthe normal data. casual bp was measured by sphygmomanometer. 23 children took echocardiography to calculate left ventricular mass index (lvmi). results: the incidence of nocturnal hypertension was significantly higher than that of diurnal hypertension (p<0.001).theincidence of non-dipper in 83 children with kidney disease was 68.7%. nocturnal dipping rate in the patients was significantly lower than that in the healthy children (p<0.01). the incidence of masked hypertension and white coat hypertension inchildren with kidney disease were 3.6% and 9.1% respectively. nocturnal systolic and diastolic dipping rate of the children with lupus nephritis and acute glomerulonephritis were lower than those of the children with henoch-schönlein purpura nephritis (p<0.05). lvmi hadpositive correlation with 24-hour diastolic blood pressure load (r=0.414, p=0.036), but it had no correlation with casual bp. after taking fosipril, 24-h, diurnal and nocturnal average abp decreased significantly (p<0.05). nocturnal dipping rate increased, but did not reach statistical difference (p>0.05). conclusions: abpm was an effective tool for diagnosis and management of hypertension in childhood with kidney disease. identification of 6 novel mutations in the col4a5 gene of japanese patients with x-linked alport syndrome background: alport syndrome consists of nephritis, often progressing to renalfailure, and sensorineural hearing loss. x-linked phenotype (omim#301050) is the result of mutation in the gene for the alpha-5 chain of collagen iv (col4a5). objectives of study: to find mutations causing x-linked alport syndrome in japanese patients. patients and methods: diagnosis criteria of alport syndrome were proteinuria, familial history of renal failure andchanges of gbm in electron microscopy. to identify the mutations in the col4a5 gene. results: for the time being we finished genetic analysis of 8 patients with suspected x-linked alport syndrome, 6 males and 2 females. we identified mutations in 7 of 8 patients; 6 of them were novel mutations. they comprise: 2 nonsense mutations, 2 missense mutations and 3 mutations of splicing acceptor site resulting in exon skipping or truncation, and establishing of premature stop codon. in previous reports of x-linked alport syndrome, mutation detection rate was around 60%. the present study provides a detection rate of 87.5%, although our number of examined cases is limited. conclusions: direct sequencing of rt-pcr and pcr products is efficient method of finding mutations in col4a5 gene. we found mutations in high percentage of investigated patients. objectives of study: to make a genetic diagnosis of juvenile nephronophthisis for a chinese boy. methods: analyze the presentation, family history, laboratory investigations, and histological features of a patient suspected of juvenile nephronophthisis, make a clinical diagnosis. to confirm the diagnosis on genetic level by pcr amplification of satellite markers located within the known homologous deletion of nphp1,including del-2, del-9, del-16, del-5-(5)2, del-10 and markers outside the deletions (ranbp11/12 and d2s1896)as control. results: the boy was nine years old, he was admitted becauseof renal failure for 6 months. this case manifested by school age, negligible onset, anemia, polyuria, renal failure at 9 years old,without hypertension and abnormal urine analysis. his sister presented with anemia at 1 year old, and died of uremia at 6 years old.laboratory investigations showed no proteinuria and hematuria. thekidney size is normal, and the cortical medullary boundary is obscure.the histological features consist of the disintegration of tubularbasement membrane, the atrophy and dilation of renal tubules, theinterstitial cell infiltration and fibrosis. he was suspected asjuvenile nephronophthisis. by pcr amplification, we found the missingof the satellite markers of del-2, del-9, del-5-(5)2 and del-10, which indicate that there is the common large homologous deletion (250kb) in the child's nphp1. conclusions: nephronophthisis is the major hereditary cause ofchronic renal failure. the boy was suspected of nephronophthisis because of chronic renal failure, family history, normal kidney sizeand hitological features. according to the age of renal failure, he was suspected as juvenile nephronophthisis. the diagnosis was confirmed by gene analysis. it is the first juvenile nephronophthisis case for chinese confirmed by gene analysis. cutaneous small-vessel vasculitis is a rare condition in children and is commonly associated with a wide spectrum of systemic inflammatory conditions, malignancies, infections or drug hypersensitivities. enalapril is anangiotensin-converting enzyme inhibitor, commonly used for the treatment of hypertension. cutaneous vasculitis due to enalapril has very rarely been reported and only with adults. we report a case of an 8-yea-old boy presented with a pruritic eruptionover his lower legs that started 6 hours after he had initiated treatment with enalapril at a dose of 0.5 mg/kg/daily. he had a history of hypertension due to a shrieked right kidney since infancy and he wason treatment with nifedipine and propranolol for the last three years. this medication was discontinued because it was ineffective, the day before initiation of enalapril. clinical examination revealed palpable purpuric lesions involving lower legs and ankles. he was otherwise well. a skin biopsy of the lesions showed leucocytoclastic vasculitis of small vessels. abnormal investigations were elevated c-reactive protein, esr and leucocytosis. further laboratory tests including creatinine, liver function tests, urineanalysis, antinuclear antibody, cryoglobulins, viral serology, complement levels, were normal or negative. enalapril was discontinued and he was started oral prednizolone and ceterizine over the next ten days. the skin eruption regressed rapidly. cutaneous vasculitis induced by enalapril is a rare adverse effect and it is essential a prompt recognition and withdraw of the suspicious drug. objectives of study: barttin, the gene product of the bsnd gene involved in bartter's syndrome with sensorineural deafness, is an essential b-subunit for clc-ka and clc-kb chloride channels, and it is expressed in the kidney as well as in the inner ear. one patient affected by deafness and renal bartter phenotype without bsnd mutations has been previously reported with simultaneous mutations in both clcnkb (responsible for classic bartter syndrome) and clcnka genes. we report here on a new case of a 6-months-old boy presenting such a disease. a severe polyhydramnios was detected during the pregnancy. he presented also polyuria, growth retardation, nephrocalcinosis and sensorineural deafness. laboratory studies revealed metabolic alkalosis (plasma hco3 47,7 mmol/l), hypokalemia (2,4 mmol/l), hypercalcuria (cau/cru 1,6 mg/mg) and elevated plasma renin (320 pg/ml). the aim of the study was to identify the cause of the severe renal salt wasting and sensorineural deafness in this patient. methods: dna sequencing analysis was performed on the bsnd, clcnkb, and clcnka genes. results: no mutation was detected in the bsnd gene. we identified a reciprocal partial homozygous deletion of exons 1-6 for the clcnkb gene and theloss of exons 7-19 for the clcnka gene. conclusions: the disruption of both clc-ka and clc-kb chloride channels leads to a syndrome clinically not distinguishable from bsnd, characterized by severe salt wasting and deafness. this digenic disorder is due to simultaneous mutations on the two genes clcnka and clcnkb respectively. the tight topology of the highly homologous clcnka genemight predispose to an unequal crossing over leading to partial orcomplete deletions of the clcnkb gene. we hypothesize that thischimaeric resulting gene interferes with the correct function of both the channels clc-ka and clc-kb, and leads to a bsnd-like phenotype. familiary hypomagnesemia with hypercalciuria and nephrocalcinosis (fhhnc) is a nautosomal recessive tubular disorder that is frequently associated with progressive renal failure. mutations in cldn16 which encodes the renal tight junction protein paracellin-1 were identified as the underlying genetic defect. in this work we present a gipsy family with fhhnc in which the mother and daughter both showed homozygous mutations in the cldn16 gene. a three-year-old girl was investigated after acute pyelonephritis and was found to have medullary nephrocalcinosis, hypomagnesemia (0,5 mmol/l), hypercalciuria (10,5 mg/kg/d), hypermagnesuria (femg 15%) and incomplete distal renal tubular acidosis. her renal function was normal. her mother demonstrated also bilateral medullary nephrocalcinosis, hypomagnesemia (0.2 mmol/l) with high femg (86%), moderate renal failure (creatinine 234 umol/l) and high ipth levels (398 pg/ml). as a child she had afebrile seizures, but serum mg levelwas not measured. index patient's uncle had history of recurrent passage of calculi in childhood, bilateral medullary nephrocalcinosis, normocalcemic hypercalciuria but his serum mg was not determined. he developed obstructive uropathy due to impaction of the calculus in urethra and eventually progressed to terminal uremia and later was transplanted. mutational analysis confirmed that the index case, motherand uncle were homozygous for the common mutation in the cldn16gene (leu 151 phe), while the father was heterozygous. we present a new family from macedonia with fhhnc with unusual presentation over two generation. mutational analysis confirmed also the diagnosis of fhhnc in the uncle although as a child he was considered to have idiopathic hypercalciuria. thus, serum mg should be routinely checked in children with nephrolithiasis/nephrocalcinosis. m. pan ' czyk-tomaszewska, j. s ' ladowska, j. so l /tyski, m. roszkowska-blaim arterial hypertension is one of the complications of reflux nephropathy. the aim of the study was to assess the risk factors of arterial hypertension in children with primary vesicoureteric reflux (vur). we studied 150 children aged from 4 to18 years mean 9±3.3, 82 with unilateral and 68 with bilateral vur. in all children ambulatory blood pressure monitoring (abpm) and 99m tc dmsa renal scanning (dmsa) were performed and z score body mass index (z-score bmi) were calculated. the following criteria were examined as predictive risk factors: age, gender, age at diagnosis andat resolution of vur, period between diagnosis and resolution of vur,grade of vur, type of vur (unilateral or bilateral), treatment modality (medical, surgical), z-score bmi, grade of dmsa and birth weight. results: i grade of dmsa scan was diagnosed in 27 children, iigrade in 85, iii grade in 31 and iv in 7 patients. hypertension (hp) was diagnosed in 20 children (13%). the mean value of z-score bmi in children with hypertension was significantly higher in comparison withchildren with normal blood pressure (0.043±0.21 and 0.74±0.86). the multivariate discriminate analysis showed that zscore bmi and grades of dmsa scars were significant risk factors for developing arterial hypertension in children with vur. both parameters had the same influence on development of hypertension (standardized coefficient of discriminate analysis 0,748 and 0,736 respectively). conclusion: the development of hypertension in children with vur is associated with higher bmi and higher grades of renal scars in dmsa scan. grange syndrome comprises arterial stenoses with hypertension, brachy syndactyly, bone fragility, learning disability, and cardiac defects and it has been reported in the members of two families up to now. we report here a 14-year-old boy with hypertension, multiple arterial stenoses, microcephaly and brachysyndactyly. severe hypertension (200/120 mmhg) was detected on his routine control for acute rheumatic carditis and he was hospitalised for investigation. he had no complaints. his parents were first degree relatives. his physical examination revealed microcephaly, bilateral brachysyndactyly between the forth and the fifth fingers of hands and the second and the third fingers of feet. complete blood count, electrolytes, renal, thyroid, and hepatic functions and acute phase reactants were all in normal limits. echocardiography showed aortic and mitral insufficiency and left ventricular hypertrophy. renal and cerebral magnetic resonance angiographies demonstrated stenoses at bilateral renal, internal carotid, superior cerebral and posterior cerebellar arteries. association of hypertension with microcephaly and finger abnormalities and multiple arterial stenosis suggested grange syndrome. chromosomal analysis showed 46 xy karyotype. hypertension persisted despite triple antihypertensive agents and percutaneous renal angioplasty was performed leading to a reduction of antihypertensive medication. with this case report we wanted to remind the recognition of this extremely rare syndrome in a hypertensive child with multiple morphological abnormalities and percutaneous angioplasty as a treatment modality in cases with persistent severe hypertension. hypertension is usually indicative of an underlying disease process in children. the combination of severe hypertension with hyponatremia is called hyponatremic hypertensive syndrome (hhs). in this report we present a case of hhs. the boy was referred to our hospital at the age of 7 years old with generalized tonic clonic convulsion. his past history was insignificant and positive findins of the patients were as follows: hypertension (170/115 mm/hg), agressive behaviors after convulsive period, metabolic alkalozis (blood gases, ph: 7,51, hco 3 : 24,8, pco 2 : 27,3), hypocloremia (87 meq/l), hypokalemia (3 meq/l), hyponatremia (123 meq/l), low urine density, polyuria and high serum aldosterone levels (1000 pg/ml, range: 20-240). the serum renin, cortisol, tyroid and antidiuretic hormones were within normal range. abdominal color doppler ultrasound were revealed double renal arteries in both kindneys. cranial and abdominal tomography examinations and cebrospinal-fluid examination were normal. the diagnosis of hhs was suggested based on these clinical and laboratory findins and therapy of nifedipine was started. the arterial pressure improved with this therapy. in hss due to renal ischemia, activation of renin angiotensin system which induce pressure natriuresis and thus, thence hyponatremia. we think that presence of renal arterial anomaly might be a cause of an ischemic condition and activation of renin-angiotensin-aldosterone system in our patient. also, activation of aldosterone could enhance with hyponatremia and it could be suppressed of renin secretion in our patient. [hadtstein et al. hypertension 2004] . the aim of this study was to analyze whether children with renal scars have altered rhythms of mean arterial pressure (map) and heart rate (hr). study design: ambulatory 24-hour blood pressure profiles of 61 untreated patients with renal scars associated with recurrent urinary tract infections and vur were investigated and compared to 938 healthy controls. results: pre-pubertal, but not pubertal patients with renal scars displayed a number of significant differences to controls. before puberty, the mesors of map and hr were significantly elevated, and the peak-trough difference of the 24 h curve was blunted by 7.5 mm hg for map and 7.8 bpm for hr. the amplitudes of 24 h and 8h map rhythms were blunted by 2.0 and 1.5 mmhg, and those of 24 h and 12h hr rhythms by 1.9 and 1.2 bpm (all p<0.05). pubertal patients did not display any abnormalities of bp or hr rhythms. we did not find any correlations of the degree of renal scarring, bmi or gfr with the abnormalities in cardiovascular rhythms. conclusion: in summary, pre-pubertal children with renal scarring due to vur show blunted circadian and ultradian rhythms of bp and hr. this phenomenon may reflect subtle alterations of autonomous nervous signaling in children with damaged kidneys; it remains to be addressed whether such abnormalities constitute an independent cardiovascular risk factor. mutations in the eya1 gene are associated with bor/bo syndrome and rarely with an isolated renal phenotype. we present a family from macedonia displaying a novel eya1 gene mutation. a six-year-old female was found to have bilateral grade iii vesicoureteral reflux (vur) after an episode of acute pyelonephritis. mutational analysis detected a novel eya1 gene mutation [an inframe 3bp deletion (c.4_6delttg), resulting in l2del of eya1a]. she had no clinical stigmata for bor/bo syndrome. the paternal grandmother died due to end stage renal failure. all first grade relatives underwent detailed physical and ophtalmological examination, audiometry, ultrasound screening of the urinary tract and mutational analysis of the eya1 gene. the father and older sister were mutation carriers and both had normal ultrasound findings. the physical examination did not reveal abnormalities suggestive for bor/bo syndrome, except the sister had esotropia/ hypermetropia and horizontal nystagmus. the male sibling was found to have mild hydronephrosis on the left side. he was not a mutation carrier and cystographic study was not performed at that time. on repeat ultrasound examination he demonstrated dilatation of the right prevesical ureter. the cystography revealed presence of right sided vur grade iii. in conclusion: we present two siblings with vur; although eya1 gene mutation was found in one of them, it can not be incriminated for the renal phenotype in this family, as co-segregation of the mutation with the vur does not occur in all affected members of the family. decision to perform cystographic study should be still based on clinical grounds. associations asymmetric dimethylarginine (adma) is a novel predictor of cardiovascular (cv) outcomes in adults. aim: to evaluate adma in children with hypertension. subjects: 23 children (4 girls/19 boys; median age: 15 yrs) with primary (n=10) and secondary (n=13) hypertension. methods: adma levels were analyzed by elisa method. in study subjects antropometrical data, ambulatory blood pressure monitoring (abpm), left ventricular mass index (lvmi), carotid artery intimamedia thickness (cimt), 24-hour urinary albumin excretion (uae) and serum biochemical markers (lipids, uric acid) were also evaluated. results: adma concentration was positively correlated to serum uric acid (r=0.42, p<0.05) and uae (r=0.45, p<0.05). when analyzed in boys separately, more apparent correlation was found for uae (r=0.57) and a tendency for adma to be associated with lvmi r=0.44, p=0.059). interestingly, when analysis restricted to older children (above the median age), adma correlated to lvmi more significantly (r=0.65, p<0.05). no relation was found of adma to cimt, lipids, and abpm parameters. moreover, patients with left ventricular hypertrophy (43%) and microalbuminuria (55%) had a tendency for higher adma values compared to those without these abnormalities (2.5±0.83 vs 1.74±1.1 μmol/l, p=0.081 and 2.39±1.23 vs 1.66±0.74 μmol/l, p=0.13, respectively). when data analyzed on the basis of adma values, patients in the top quartile showed the worst profile. when compared to the lowest quartile, they had higher lvmi (p<0.05), higher uae (p<0.05; inter-quartile comparison p=0.012), and higher uric acid concentration (p=0.052). conclusions: the associations of adma with known factors of cv damage found in this study provide evidence that adma is closely linked to the early cv dysfunction in hypertensive children. nephrogenic diabetes insipidus (ndi) is a disease characterized by unresponsiveness of distal tubule and collecting duct to vasopressin. although ndi usually presents with polydipsia and polyuria, most infants do not have any of these symptoms and presentation is with features of dehydration like fever, constipation, vomiting, failure to thrive and developmental delay. so, the diagnosis is usually delayed until hypernatremia is noted. almost all infants go through a period of hypogammaglobulinemia at approximately the 5th-6th months of age. at this time, the serum ig g level reaches its lowest point, and many normal infants begin to experience recurrent respiratory tract infections. the clinical findings of ndi and transient hypogammaglobulinemi of infancy (thi) may be seen at the same period. here, we report a five-month old boy with ndi. on his history, he was admitted because of recurrent fever attacks and was diagnosed as thi when he was three-months-old. on his follow-up, hypernatremic dehydration was detected and he was diagnosed as ndi. at the time of diagnosis, he had intracranial calcification secondary to delayed diagnosis of ndi. in infants with ndi, recurrent fever attacks due to dehydration may occur and incorrectly lead to think as an infectious disease. we think that this report can be an important warning for clinicians. we analyzed nphs1, nphs2 and neph1 gene in 8 japanese cns patients independent of the patients in previous report (k.i. 2005) from different japanese group which suggested that the mutation of nphs1 was not a major cause of cns in japanese patients. we extracted genomic dna from leukocytes and analyzed all exons and exon-intron boundaries for nphs1, nphs2 and neph1 using polymerase chain reaction and direct sequencing after informed consent had been obtained. the study was approved by the ethics committees of okayama university medical school. results: we found compound heterozygous mutations of nphs1 in 4 patients and homozygous mutations in 2 patients. one of these 2 homozygous mutations was already reported in paper from europe and was not found in more than 50 healthy japanese. another one cause defection of trafficking to the membrane as we reported before (k.i.2000 (k.i. , ajkd 2002 . the other 2 patients have only heterozygous mutation in nphs1 that healthy parent also has. we could find any mutations in neither nphs2 nor neph1 in the 2 patients with heterozygous mutation. one of these 2 patients has mild form of cns. another one has neither expression of nephrin nor podocin protein on kidney tissue by immunohistochemistry. interestingly, 4 patients out of 8 have the same mutation in nphs1 as nt2515(delc). parents who have this mutation heterozygously were from neighboring prefectures. all mutations including this mutation but one have never been reported out of japan which was isolated from continent. all amino acids substituted by missense mutations which seem to be causative were preserved among mouse, rat and human. conclusions: our studies clearly demonstrated that nphs1 is a major cause of cns even in japanese patients. moreover, nt2515(delc) is a common mutation in japanese cns patients like fin major or minor. long-term survival of childhoodonset ckd is mainly limited by the manifestation of cardiovasculardisease (cvd). the development of early stages of cvd can be assessedby non invasive methods, e.g. flow mediated vasodilation (fmd) ofperipherial arteries and measurement of intima media thickness (imt) of the common carotid artery. wetherefore performed fmd and imt investigations in 24 children and adolescents (mean age 15.8±5.1 years) suffering from ckd (mean gfr 44±33 ml/min/1.73 m 2 ) on conservative treatment (n=11), dialysis treatment (5 hd, 1 pd) and after renal transplantation (n=7), and in 24 sex-and age-matched healthy controls. ckdpatients showed significantly decreased fmd (5.2±3.1% vs 9.8±2.3%, p<0.001), where as imt did not significantly differ between patients and controls (0.48±0.06mm vs 0.46±0.08 mm, p=0.13). within the ckd group the presence of arterial hypertension tended to be associated with increased imt (0.48±0.006 vs 0.45±0.05 mm, p=0.05). in contrast, duration of ckd, mode of renal replacement therapy and degreeof renal dysfunction was not significantly associated with fmd and imt findings. conclusion: children and adolescents suffering from ckd show decreased arterial elasticity irrespective of the mode of renal replacement therapy, the rebycontributing to increased long-term cardiovascular morbidity and mortality. the genetic researches have shown the connection between the essential hypertension and angiotensinogen gene. the researches of preeclampsia also showed the connection with angiotensinogen gene. according to established connection of angiotensinogen gene with essential hypertension and also preeclampsia the aim of our research was to determine by the help of m235t, g-6a anda-20c polymorphisms of angiotensinogen gene whether there is a genetic disposition for essential hypertension in those children whose mothers had preeclampsia. at the same time we wanted to establish whether the polymorphisms of angiotensinogen gene can be connected with preeclampsia in women in our population. two groups of children were studied: children of mothers who had preeclampsia and children of mothers without hypertensive disease in the pregnancy. we also studied two groups of mothers: mothers who had preeclampsia and mothers without hypertensive disease in the pregnancy. m235t, g-6a and a-20c polymorphisms of angiotensinogen gene were performed using the pcr method. in investigating the differences between the two groups of children no statistically significant differences were found in m235t,g-6a and a-20c polymorphisms of angiotensinogen gene. in investigating the differences between two groups of mothers no statistically significant differences were found in genotype distribution. the results of our study failed to confirm that with help of m235t, g-6aand a-20c polymorphisms of angiotensinogen gene we might establish genetic disposition for essential hypertension in those children whose mothers had preeclampsia. we did not confirm the association between m235t, g-6a and a-20c polymorphism of angiotensinogen gene and preeclampsia either. (11) previously treated also with cyclosporine. before start of fosinopril treatment all had proteinuria 0.7-4.2 g/24 h and gfr >60 ml/1.73 m 2 /min. all active steroid and immunosuppressive treatment were discontinued. eleven children also were treated with calcium channel blockers to control hypertension. after twelve months of fosinopril (0.3-0.4 mg/kg) treatment a dna analysis for ace-gene polymorphism was performed. three patients carried ii, 10-id and 4-dd gene polymorphism of ace gene. no significant differencein proteinuria at start of fosinopril treatment between all polymorphism types was observed. all 3 patients with ii polymorphism had a good antiproteinuric effect of fosinopril with more than 4-fold decrease in proteinuria in comparison with just 2,3 fold decrease in id polymorphism and no response in dd. renal function remained stable in all children except of 2 with id and 2 with dd gene polymorphism who demonstrated decrease in gfr. we suggest that ii polymorphism of ace gene may be associated with better antiproteinuric effect of acei while dd predicts poor response. wider study is required to confirm genetic predisposition for ace blockade efficacy in proteinuric diseases. introduction: dent disease is x-linked recessive proximal tubulopathy, due to mutations in the clcn5 gene. it is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and progresive renal failure. aim: case report of patient with short stature and proximal tubulopathy where dent disease is determined by gene analysis. method: seven-year-old boy is refered after endocrinological exemination where abdominal ultrasound showed nephrocalcinosis. there are anamnestic data neither of oedema, macrohaematuria, nor poliuria or hypertension. there are also no data of chronic renal failure in the family. we describe detailed diagnostic procedures performed in the boy and his family. results: we determined: proteinuria (1,8 g/day), elevated urinary excretion of beta-2microglobuline, microscopic hemathuria, hypercalciuria (8-10 mg/kg/day), nephrocalcinosis, decreased tubular reabsorption phosphate (65-72%). values of grow hormone, parathormone on thyroid hormone are normal. except hypercalciuria, which is registered in patient's mother, all other analysis performedin family members are betwen referent values. diagnosis is finalized by mutation analysis, which has showed s244l substitution on cncl5. mutation carrier is mother with normal fenotype. conclusion: dent disease is rare x-linked nephrocalcinosis. definitive diagnosis ofthis proximal tubulopathy which leads to progressive renal demage, is not possible without evidence of gene mutation in renal chlor channel. introduction: the segmental renal infarction is a rare disease, allthough it is more frequent in children than in adults and can be clinically veryrelevant. objective: we describe the clinical course of two children with idiopaticsegmental renal infarction who suffered severe arterial hypertension. cases description: the typical clinical picture of this disease, as seen in our twopatients, is characterized by metabolic alkalosis, hyponatremia, hypokaliemia, hyper-reninemia, hyperaldosteronism and renal salt lossfrom the contralateral enlarged kidney. hypertension was diagnosedduring the study of haematuria in the first case and due to ahypertensive emergency in the second case. the ethiology was found tobe renovascular in both patients, involving the occlusion of small renal arteries causing segmental renal infarction. our first patient was treated with partial nephrectomy, and the second patient wastreated with antihypertensive medication given the impossibility ofremoving the renal infarcted area. conclusions: in the clinical picture, the sodium depletion with increased urinary volume of the contralateral healthy kidney can be explained by the goldblatt model. the gold standard test for the diagnosis is theselective renal arteriography, which is the most sensible and specifictest for diagnosing renovascular hypertension secondary to a segmental renal infarction because it helps identifiing the segmentary artery ofthe infarcted area, this being the source of increased focal renin production. the definitive treatment is the surgical segmentectomy. if segmentectomy is not feasible because of the localization of the infracted area as inour second patient, a medical treatment is needed. conclusion: although an inverse association between birth weight/blood pressure has been suggested in several large studies, interpretation is still controversial. in our study, we have found only a weak inverse correlation between birth weight and pad (abpm): no statistical significance has been found among other variables, although graphs show a trend of low birth weight children towards hypertension. probably a long term follow-up is necessary. he took longer to have improvement, but his calcemia, phosphatemia and alkalinephosphatase are normal. the coding region of the vdr was amplified by pcr and directly sequenced. results: three mutations (two novels) were identified. two patients had anovel mutation in exon 7, changing the amino acid glutamine to glutamicacid at position 259 (q259e). one patient had a novel mutation in exon 8 changing glycine to valine at position 319 (g319v). those mutations are in the ligand binding domain and belong to the patients with better control of the disease. one had mutation in exon 3, in the dna binding domain, changing arginine to a stop codon at position 73 (r73x) and it was from the patient with worse response to the treatment. conclusions: two novel mutations are presented in the vitamin d receptor and it could be possible to do a correlation between the clinical evolution and the localization of the mutations. we aimed to evalute the effects of intrauterine growth retardation (iugr) on blood pressure (bp) in small for gestational age (sga) children. 23 sga children (6f,17m) aged 9.4±3.9 y (5 preterm and 18 term) and 13 (8f, 5m) agematched control with appropriate for ga (aga) were included in the study. 24-hr ambulatory blood pressure monitoring (abpm)was performed using an oscillometric device (mobilograph). 95th centile limit was set according to published data sets, nocturnal threshold was 10% less than awake limits. bp was classified as normal if the mean sbp is <95th percentile and sbp load is >25%. nocturnal bp dip for sbp and dbp were evaluated. in 2 sga and in 1 aga case, office sbp were above 95th%, all dbp values were normal in both groups. according to the mean of 52 abpm records, 2 systolic,1 diastolic ht were determined in sga group, and 3 systolic, no diastolic ht were in aga group. there were 9 sga and 5 aga children whose sbp load over 25%, and only 5 of them remarked as hypertensive according to mean sbp values. 5 children considered as hypertensive had significantly higher sbp loads than those that were not hypertensive(38% vs 10%, p<0.05). abpm records were not different between preterm and term sgas. sga group had lower nocturnal bpdip for sbp and dbp in comparison to aga group(13.5% vs 14.5% for sbp,15.4%vs 18.1%for dbp, p: 0.62). although it was not statistically significant, the frequency of non-dipper children was higher in sga group (22.7%) than those in aga group (8.3%). except the lower nocturnal bp dip and higher sbp loads in sga group which may be a marker for further hypertension, no clear association between being sga and hypertension could be found in our study population. pres is a rare clinico-radiological entity associated with acute hypertension, renal insufficiency and immunosuppressive therapy. it is typically reversible but cases with irreversibility had rarely been reported. we report 2 contrasting cases of pres associated with renal disease, one with full recovery and the other subsequently had epilepsy. first patient had steroid sensitive nephrotic syndrome with acute hypertension, fluid overload and acute renal failure while the second patient had severe flare of lupus nephritis with malignant hypertension, renal failure and thrombotic thrombocytopenia. both had acute onset of drowsiness, blindness and seizures and mri findings of subcortical oedema in the parietal-occipital-temporal regions. while the second patient had full recovery, the first patient developed temporal epilepsy and repeat mri showed mesial temporal sclerosis. pres is attributed to capillary leak from functional cerebral vascular changes of hypertension, rather than infarction. prolonged vascular disruption may lead to ischemia resulting in neurological sequelae and chronic epilepsy. using mri, pres can be readily diagnosed and normalisation of blood pressure is imperative in patients at high risk of pres. efforts have been done to describe the significance of various genetic polymorphisms (snps) in acute renal failure (arf). available reports do not investigate the predictive value of snps in disease forecasting, because so many interacting factors influence arf that classical statistical methods become unstable. high-dimensional nonparametric methods such as random forest technique overcome this problem and help to identify each clinical and genetic factor that possibly contributes to disease. we tested the classification value of basic clinical data available at birth and 19 snps in arf of 111 preterm infants. we determined the relative importance score (ri) of each parameter in classification. low birth weight and gestational age had the highest ri; just few snps had medium ri, while the majority of snps had small ri. then we created variable-patterns and searched for pattern with the highest accuracy of classification. for each complication, the accuracy was 0.71 solely basic clinical data were considered. if snps were incorporated, the accuracy of classification for arf was not improved. in contrast with previous observations these findings suggest that the snps do not provide additional information about arf-risk of the general preterm population. conclusions: srbd in children with elevated blood pressure is higher than that of the general pediatric population. the prevalence appears highest in patients with pre-hypertension and may be higher in patients with essential and secondary hypertension than in patients with white-coat hypertension. the renal phenotype in lowe syndrome is similar to dent's disease a 22-month-old girl presented with heart failure due to severe hypertension (200/120). doppler ultrasonography (us) revealed a right renal artery stenosis. biological findings showed normal serum creatinine (scr) (35 mmol/l), hyponatremia (131 mmol/l) and hypokalemia (3 mmol/l). aldosterone plasma level was increased as were epinephrine (429 pg/ml n<185) and norepinephrine (1230 pg/ml n<450) plasma levels measured 3 times. renal arteriography confirmed the presence of a nearly obstructive right renal artery stenosis with a normal left kidney. pta failed to improve signifcantly the renal artery flow. in the following hours after pta, her scr level increased, up to 160 mmol/l. doppler us showed an unchanged right kidney but 3 hypoperfused area in the left kidney confirmed by the tc 99 -dmsa scan. both aspects were strongly in favor of focal ischemic events. secondarly, her renal function improved but hypertension remained difficult to control autotransplantation of the right kidney was then done, but unfortunately, thrombosis of the right renal artery occured in the following hours. six months later, her plasma creatinine level is of 55 mmol/l. her cardiac function is normal but she has to remain on antihypertensive drugs. what exactly happened during arteriography in her left kidney, in order to provoke such ischemic injury, knowing that the left renal artery was not catheterized during arteriography and pta? one hypothesis is that arterial vasospasms occured, explained by a high vasospastic predisposition due to enhaced cathecolamines secretion. such increased has already been drescribed in patients with renal artery stenosis. this case raised the question of preparing patients in this condition with efficient antispasm therapy agents before radiological vascular investigations are done. rtd is a cause of oligohydramnios leading to potter's sequence and neonatal anuria. it is characterized by absent or hypoplasic proximal tubules. these lesions can be secondary to non genetic conditions involving renal hypoperfusion. genetic forms of rtd have autosomal recessive transmission. mutations of genes encoding for the renin-angiotensin system have been reported. evolution is most often severe with in utero or neonatal death. case report: this boy was born at 38 weeks of gestation with oligohydramnios, arthrogryposis, large fontanels with poor calvarian ossification. he was referred to intensive care unit for respiratory distress, low blood pressure (bp) unresponsive to vasopressors and anuria (plasma creatinine 370 μmol/l at day 3). renal ultrasound (us) showed enlarged kidneys with bilateral cortical hyperechogenicity. weaning from ventilation and vasoactive drugs was possible at day 7. glomerular filtration recovered (plasma creatinine 45 μmol/l at day 26). at age 10, the child is well with normal growth and a mild chronic renal insufficiency (creatinine clearance 75 ml/min/1,73 m 2 ). bp is in the low normal ranges with plasma renin x40 over the upper range of normal values and normal plasma aldosterone. on renal us, kidney volume normalized with persistent cortical hyperechogenicity. genetic study revealed compound heterozygous mutation in the gene encoding angiotensin converting enzyme. one is a nonsense mutation (r1209p), the other is a truncating mutation (k601fsx640). it is possible that the first mutation is less deleterious than the other and this could partly explain the unusually favourable evolution of this rtd. in conclusion, this is a rare report of a child with autosomal recessive rtd surviving after neonatal period. further functional studies are needed to explain this unusual phenotype. data on hbp in children are very limited, and it is unclear how much it is specific in pediatric patients. the objective of our study was to determine the reproducibility of hbp in children and adolescents. automatic omron 705-cp devices, which have been validated for use in children and adolescents, were provided to all families. hypertensive children measured blood pressure (bp) every minutes, three times consecutively in the morning or early afternoon, and three times in the evening during 13 days. the reproducibility of hbp was quantified using repeated measures analysis of variance test and the sd of differences between average hbp values of consecutive days. confidence interval (ci) was calculated. we studied 41 patients (14 girls, 27 boys); mean age was 12,1 year, range 4-18 years. there were 78 measurements of systolic blood pressure (sbp) and diastolic blood pressure (dbp). in the morning or early afternoon the mean sbp and dbp were 110,9 mmhg (sd 10, 65) (95% ci 107, 5-114, 3 mmhg) and 64, 4 mmhg (sd 9, 08) (95% ci 61, 4-67, 3 mmhg), respectively. in the evening the mean sbp and dbp was 111,6 mmhg (sd 10,14) (95% ci 108,3-114,8 mmhg) and 65,0 mmhg (sd 8,83) (95% ci 62,2-67,9 mmhg). the mean average difference between the daily measurements of sbp and dbp were analyzed with each period and were not statistically significant (p>0.05). on the basis of these results, we conclude that self-monitoring of blood pressure at home in children has good reproducibility and is not influenced by white coat effect. case report: a 3-year-old caucasian girl presented with history of severe polyuria and polydipsia of few months duration. past history was significant for head injury and possible seizure activity at age 1 yr. there was no history of headaches, vomiting, or visual problems. family history negative for di. physical examination was essentially normal. basal plasma and urine osmolality, and plasma vasopressin were 294 and 96 mosm/kg, and <0.5 pg/ml, respectively. at the conclusion of water deprivation test these readings were 309 and 98 mosm/kg, and 31.3 pg/ml, respectively. however, urine osmolality increased to 493 mosm/kg after desmopressin injection, confirming the diagnosis of cdi. mri scan revealed absence of the bright spot on t 1 weighted images. genetic analysis detected avp gene mutation a19t, where the normal alanine at amino acid position 19 is changed to threonine. elevated levels of plasma vasopressin after water deprivation were misleading and intriguing. we believe that elevated plasma vasopressin, although immunoreactive was devoid of biological activity. conclusion: molecular genetic evaluation should be performed in all children with cdi without an identifiable cause, even in the absence of a positive family history of cdi. mutations of the nphs2 gene encoding podocin lead to autosomal recessive corticoresistant nephrotic syndrome, focal and segmental glomerulosclerosis (fsgs), and early end-stage renal disease (esrd). in mice, podocin inactivation by homologous recombination results in diffuse mesangial and glomerular sclerosis, esrd and death within the first 5 weeks of life. this early demise precludes extensive study and elucidation of the molecular pathways engaged by podocin in the mature kidney. we have, therefore, generated a novel mouse model in which a tamoxifeninducible creer-loxp system allows for conditional inactivation in a temporal fashion in podocytes. following tamoxifen administration in nphs2 flox/-, cre+ mice, cre expression was noted in 88% of glomeruli and in 60-70% of podocytes. two weeks after cre induction, podocin expression is decreased in podocytes correlating with the appearance of selective albuminuria at 10-16 days. this progresses to massive, nonselective proteinuria by 4 weeks, along with high blood pressure and impaired renal function. optical microscopy of kidneys showed no lesion at 1 week and fsgs progressively developed by 4 weeks along with tubular lesions. however electron microscopy revealed a partial foot process effacement at 1 week with no significant albuminuria that extends by 2 weeks along with abnormalities of the basement membrane and development of albuminuria. no mesangial or vascular lesion has been noted, differentiating it from our previous podocin null model in which renal development may be affected by podocin loss or nephrotic syndrome. this model will allow a better understanding of the mechanisms underlying the development of nephrotic syndrome and the role of podocin in the mature kidney, and will be crucial to test new therapeutic approaches. glomerulonephritis is a group of diseases with complex etiology, pathogenesis, morphological features and clinical course. the renin-angiotensin and coagulation systems genes are important group of candidate genes involved in pathogenesis of chronic renal diseases. the purpose of our study was to analyze the association of genetic polymorphisms of these genes with glomerular kidney diseases. the study population consisted of 181 patients with immunological glomerular kidney diseases and 19 patients with renal failure with glomerulonephritis as primary disease. the control group consisted of 80 healthy subjects. by means of the polymerase chain reaction (pcr) the following polymorphisms were evaluated: insertion/deletion (i/d) polymorphism in intron 16 of the angiotensin-converting enzyme gene (ace), 4g/5g polymorphism of the plasminogen activator inhibitor-1 (pai-1). no significant association was found between the ace and pai-1 allele and genotype frequencies and the disease. more progressing of glomerulonephritis current was marked at patients with simultaneous has dd genotype of ace gene and 4g/4g gene pai-1(c 2 =9,1; p=0,008). our results suggest that ace i/d and pai-1 4g/5g polymorphism is an important modifying gene in the progression of glomerulonephritis. captopril objectives: secondary causes of hypertension such as renovascular hypertension are more abundant in children unlike adult population. the objective of this retrospective study is to assess the use of captopril renography (cr), which provides a non-invasive approach in the differential diagnosis of hypertension. patients and methods: clinical, radiological and scintigraphic data of a total of 64 patients were analyzed. there were 22 girls and 42 boys (mean age: 13±3 years). none of the patients had parenchymal renal disease or reduced renal function. all patients were orally hydrated before scintigraphic study. cr was performed 1 hour after orally captopril administration and iv furosemide injection was done simultaneously with 1-5 mci tc99m-mag3. when post-captopril study was normal, baseline scintigraphy was not performed. computed tomography angiography (cta) was performed in 11 and gadolinium-enhanced magnetic resonance angiography (mra) was performed in 8 children in addition to routine renal doppler ultrasonography (dus). results: nineteen out of 64 patients had other comorbid diseases as follows: obesity n=10, previosly-diagnosed fibomuscular dysplasia n=3, n=2 neurofibromatosis, n=2 demyelinating diseases, n=1 bartter and n=1 turner syndrome. cr was normal in 48 patients. in 8 children abnormal cr findings in correlation with radiological methods were reported. correlation with radiological methods could not be done due to suboptimal technique in 7 patients, of whom dus in 5 obese children could not be interpreted. in the other 1 patient, although cr was abnormal, radiological methods could not confirm scintigraphy. conclusions: captopril renography is a useful and simple-to-perform imaging modality in children suspected of having renovascular hypertension. takayasu's arteritis (ta) is a chronic, inflammatory, large-vessel vasculitis affecting the aorta and its main branches, which causes stenosis, occlusion, rarely aneurysm and distal ischemia. the disease is most common in young women, it is rare in inviduals before the age of 16 years. clinical presentation may be heterogeneous. in this report, we present a pediatric patient with ta who had hypertension as the sole manifestation of multipl critical arterial involvement but no other symptoms. a 14-year-old boy was admitted with hypertension. the acute-phase reactants were moderately elevated with an erythrocyte sedimentation rate 70 mm/h, and a c-reactive protein value of 26 mg/l. serologic tests including ana, anti-ds dna, c and panca, complement c 3 , and c 4 were negative and other laboratory data were normal. mr angiography showed multiple severe stenosis or occlusions of the thoracic and abdominal aorta together with bilateral renal arteries, and saccular aneurysm in the abdominal aorta. immunosuppressive treatment including pulse steroid and methotrexate was prescribed. the patient underwent angioplasty of bilateral renal arteries and suprarenal aorta, and a stent was placed in the right renal artery. ta should be kept in mind in the differential diagnosis of hypertension in children, even if they do not have other associated symptoms of the disease. human urotensin ii is the most potent vasoconstrictor which circulates in the plasma of healthy individuals. it was suggested that it has an endocrine role in sodium handling and even in metabolic syndrome. the aim of this study was to investigate the role of u-ii in obese adolescents with hypertension. fourteen obese adolescents with essential hypertension (group 1) were compared with thirteen age-and sex-matched obese adolescents with white-coat hypertension (group 2). they underwent twenty-four hour abpm and echocardiographic investigation, complete physical examination, including adiposity indexes. plasma and urinary levels of u-ii were measured by ria. obese adolescents in group 1 have significantly higher blood pressure measurements than those in group 2 confirmed by abpm. there was no significant difference in left ventricular mass index between two groups. no significant difference was found in plasma u-ii concentrations (pg/ml) between group 1 and group 2 (35.23±4.90 and 35.98±5.74, respectively), whereas mean urinary u-ii level (pg/mg urinary creatinine) was significantly higher in group 2 than that of group 1 (28.80±6.83, 44.44±16.78, respectively). considering the renal synthesis and vasoactive role of u-ii, these results suggest that u-ii may have a role in adolescents with white-coat hypertension. distal renal tubular acidosis (drta) and deafness is a rare autosomal recessive disease characterized by severe metabolic acidosis in childhood and inappropriately high urinary ph along with sensorineural hearing loss. the disease is caused by defects in the atp6v1b1 gene. the aim of the present study was to determine the molecular basis for drta with deafness in eight patients from four families (a-d) in israel. molecular testing was done by sequencing the coding exons of the atp6v1b1 gene in one affected child from each family. a population screen was performed for mutations found in family a. the results yielded a different mutation in the atp6v1b1 gene, as follows: families a and d: missense mutation, 1037c>g (p346r), in addition to a single nucleotide polymorphism (2t>c) in the first codon; family b: insertion mutation, 1155-1156insc (i386fs); family c: a novel nonsense mutation, 340 c>t (r114x). in conclusion, the phenotype of drta and deafness concurs with mutations in the atp6v1b1 gene. in the present study, four families of different origins with the same phenotype had three different genotypes, indicating that there is no single common mutation in israel. these findings have implications for genetic counseling during pregnancy and testing of families. the fact that all the patients that were examined have harbor mutations in the atp6v1b1 gene, pointed for the specific clinical phenotype. making correct and early clinical diagnosis is a fundamental step in finding the molecular basis of this rare disorder. delta f508 is the most common cystic fibrosis (cf) mutation worldwide. the prevalence is approximately 70% in caucasian and 14-55% in asian while f311l is demonstrated in only 0.2%. homogenous delta f508 mutation is recognized as the most common genotype however there are small numbers of cf patients having delta f508/f311l. in the present study we report a 2 year-old thai boy, originated from north india, presented with recurrent episodes of febrile illness, hyponatremia, hypokalemia and metabolic alkalosis since 4 months of age. he was transferred to our hospital for further investigation. blood chemistry revealed serum electrolytes: sodium 122, potassium 3.69, chloride 79.7, bicarbonate 33.8 meq/l, and urine electrolytes: sodium<10, potassium 45.7, chloride<10 meq/l. after intravenous fluid administration, hyponatremia and metabolic alkalosis improved. dna sequencing analysis of his blood demonstrates compound heterogenous mutation for delta f508 and f311l in cftr gene. t to g transversion at nucleotide 2694 and g to a transversion at nucleotide 4521 are found without altering amino acid encoding gene. in conclusion, we report a rare case of cf with delta f508/f311l genotype presented with recurrent hyponatremia and metabolic alkalosis. awareness of electrolyte abnormalities during febrile illness, proper genetic counseling and long-term follow-up are necessary in this patient. objectives of study: about 10% of families with congenital nephrogenic diabetes insipidus (ndi) have mutations in the aquaporin 2 gene (aqp2), which codes for the vasopressin-sensitive water channel. only seven aqp2 mutations are known to cause a dominant form of the disease. in this study we performed genetic and clinical studies in a 5 generation family with autosomal dominant inheritance of a partial di phenotype. methods and results: the proband (man, 37 yrs old) was initially diagnosed with partial central diabetes insipidus due to antidiuretic effect of ddavp. his daughter (1.3 yrs old) also showed polyuria and polydipsia which was responsive to high doses of intranasal ddavp. the pedigree was consistent with an autosomal dominant inheritance pattern. sequence analysis of the entire coding region of the avp gene and aqp2 gene was performed in the proband and his affected daughter and in 2 unaffected family members. the avp gene was normal in all subjects. in the two affected patients but not in the healthy subjects we identified a novel missense mutation in one allele of exon 4 of the aqp2 gene (c.760c>t) which predicts a substitution in the c-terminal part of the aqp2 protein (p.r254w). conclusion: partial ndi can be caused by heterozygosity for a p.r254w substitution of the aqp2 water channel. the substitution is likely to significantly alter the c-terminal tail of aquaporin 2 which is important for proper trafficking to the apical plasma membrane. the preservation of some residual antidiuretic function indicates that some aqp2 tetramers are processed correctly. the study further illustrates the importance of molecular diagnostic tools in establishing a correct differential diagnosis in familial cases of di. a background and aim: dent's disease is a renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis. mutations in the clcn5 gene encoding the chloride/proton exchange transporter clc-5 cause this disease. we have described an alu insertion in clcn5 that leads to exon 11 skipping in the patient's mrna. in this study, we investigated the consequence of this mutation on the function of two putative exonic splicing enhancers (eses) in exon 11 and the role of alu 5'-end sequences on splicing inhibition. methods: minigenes were constructed by inserting exon 11 and exon 11-alu with their intronic flanking sequences into the exon trap vector. artificial mutations were introduced by site-directed mutagenesis. plasmids were transfected into cos7 cells by electroporation. pre-mrna splicing analysis was performed by rt-pcr. the ese finder web resource was used to predict the mutagenesis effects on the eses. results: alteration of one of the putative eses, the predicted binding site for srp40, induced exon 11 skipping. restoration of this site within the alu sequence promoted the incorporation of exon 11-alu in the mrna. however, restoration of both eses leaving the alu sequence intact resulted in exon skipping. furthermore, substitution of the eses for the first seven nucleotides of the alu element, and insertion of this sequence next to the eses increased exon skipping. deletion or modification of the alu 5'-end enhanced exon 11 inclusion in the mrna. in the patient carrying the clcn5 alu insertion, dent's diseases is caused by disruption of an ese and by inclusion of splicing inhibitory sequences leading to exon skipping. this work was supported by grant pi042620 from fondo de investigación sanitaria. factor h-associated hemolytic uremic syndrome (fhd-hus) is a rare disease with incomplete penetrance. it is not clear why and how carriers of the same mutation will eventually develop or not develop the disease and this uncertainty is sometimes responsible for anxiety in the carriers badly affecting their quality of life (particularly of parents with children carrying the mutation). in the attempt of estimating disease risk in subjects with factor h gene mutation, the 6 families of fhd-hus patients (all of which had a documented mutation on the scr20) currently being treated at our center, were screened to identify the carriers after having been informed on the purpose of the analysis. twenty-eight subjects (age range 0-89 yrs), out of 55 analyzed, revealed heterozygous mutations in the carboxy-terminal region of fh1 gene (51%). among subjects carrying the mutation, 9 (32%) had exhibited the disease at a mean age of 12 years (range 0.2-32), 6 of which (67%) before age 10, whereas the remaining 19 subjects (mean age of 53 yr -range 11-89) were healthy at time of the study. the figure shows the probability of carriers to be hus-free by age (no event occurred after age 32 yrs). in the meantime that predisposing factor are identified, the presented survival curve (fig.1) can be an useful tool to estimate the residual risk of hus in individual carriers according to their specific age. cerebello-oculo-renal syndrome (cors) (also called joubert syndrome (js) type b) and meckel (mks) syndrome belong to the cilliopathy group of developmental autosomal recessive disorders associated with primary cilium dysfunction. nephronophthisis (nphp), the most frequent genetic cause of renal failure in children and young adults, is associated with retinal degeneration and cerebellar vermis aplasia in cors. mks is characterizd by renal cystic dysplasia, central nervous system malformations and hepatic developmental defects. these syndromes are genetically heterogenous: mutations in ahi1 and nphp1 can cause cors and mutations in mks1 can lead to mks, while mutations in mks3 and nphp6 are found in both syndromes. using snp mapping, we identified missense and truncating mutations in a novel genee, nphp8, in both cors and mks. interestingly, all sequence changes were either nonsense or frameshift mutations in fetuses with mks whereas patients with cors had either only one or no truncating mutation. we then show that inactivation of nphp8 mouse orthologue recapitulates the cerebral and renal defects of cors/mks. we further demonstrate that nphp8 protein co-localizes at the basal body/centrosomes with nephrocystin-6 and nephrocystin-4, the protein products of both nphp6 and nphp4, known disease genes for nphp. in addition, missense mutations of nphp8 protein found in cors patients diminishes its interaction with nephrocystin-4. taken together. our findings demonstrate that mutations of this novel ciliary gene can cause the multiorgan syndromes of either cors or mks, which therefore represent a continuum of the same underlying disorder. severe antenatal bartter's syndrome ga 25 + 4, bw: 750 g). both had classical signs of antenatal bs including very poor thrive, polyuria (5-10 ml/kg b.w./h) and responded to indomethacin treatment. direct sequencing was performed on pcr-amplified genomic dna. the entire coding region of both genes was analyzed. the kcnj1 gene was normal but both children were homozygous for a single base substitution (39671t>a) in exon 12 of the slc12a1 gene predicting a premature stop codon (y538x). the parents of both children and two siblings were heterozygous for the same mutation. by restriction enzyme analysis, the 39671t>a substitution was absent among 100 chromosomes from healthy subjects. conclusion: two children with severe antenatal bs were identified and the clinical phenotype was characterized. we identified in both children a novel mutation causing a premature stop codon of the bumetanide-sensitive-sodium-potassium-chloride co-transporter (nkcc2). despite large potassium supplements and indomethacin treatment, both children show persistent polyuria, vomiting, and insufficient thrive. background: mutations of nphs1 encoding the transmembrane slit diaphragm protein nephrin cause congenital nephrotic syndrome of the finnish type, characterized by massive proteinuria and the development of nephrotic syndrome before 3 months of age. about 70 different nphs1 mutations have been described. a large number of these are missense mutations resulting in single amino acid replacement mostly located in the extracellular domain. some nphs1 mutations have been associated with mild phenotypes responding to angiotensin-converting enzyme and prostaglandin synthesis inhibition. patient history: we report on a son of consanguineous turkish parents with a novel nphs1 alteration and steroid-resistant congenital nephrotic syndrome. after normal pregnancy and delivery at 37 weeks of gestational age the boy presented with edema and proteinuria at the age of 2 months. he responded to angiotensin converting enzyme inhibitor treatment reducing his proteinuria from a maximum of 66 g/g creatinine to 10 g/g creatinine and allowing him to develop normally until the age of 7 months when cardiovascular insufficiency in the course of a hyperpyretic infection led to hypoxic encephalopathy. genetic testing revealed a homozygous in-frame 3-bp insertion in exon 11 of nphs1. both parents were found to be heterozygous. no mutations were found in nphs2 or in exons 8 and 9 of wt1. the alteration results in an insertion of a glycine in an extracellular immunoglobulin domain of nephrin. the pathogenicity of this alteration is unclear. nephrin may be misfolded and mislocalized as in some missense mutations of the extracellular domain. alternatively the alteration might lead to an altered extracellular homo-and heterodimerization of nephrin. functional studies are currently underway to determine the effect of this novel alteration in nphs1. objectives of study: interleukin 1 receptor antagonist (il-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. we investigated the association between il1ra gene polymorphism and childhood nephrotic syndrome (ns) in a turkish population. methods: we analyzed the genetic polymorphism of il-1ra gene in 91 patients with childhood ns and 100 healthy controls by using pcr. five alleles of the il-1ra gene were identified and designated as il-1ra*1, il-1ra*2, il-1ra*3, il-1ra*4, and il-1ra*5, according to the variable number of tandem repeats in intron 2. results: in the ns group, the allele frequencies of il-1ra*1, il-1ra*2, il-1ra*3, il-1ra*4, and il-1ra*5 were 74.7, 13. 2, 4.4, 2.2, and 5 .5% compared with 58%, 28%, 1%, 0%, and 12% in the controls. a high allele frequency of il-1ra*1(x 2 =5.28, p=0.021) and a lower allele frequency of il-1ra*2 (x 2 =6.31, p=0.012) were found in childhood ns. the other polymorphisms were not significantly different from normal controls. conclusions: a high allele frequency of the il-1ra*1 allele may affect the disease susceptibility in childhood ns. objectives of study: congenital anomalies of the urinary tract (caut) are common in humans, and the incidence is increasing with recent advances in prenatal ultrasonographic examinations. interstitial fibrosis, which correlates with infiltration of inflammatory cells is common finding in the kidney with long-term ureteral obstruction. up-regulation of monocyte chemoattractant protein-1 (mcp-1), may be a common regulatory pathway involved in the progressive renal damage with any etiologies leading to interstitial fibrosis. mcp-1 gene polymorphism -2518 a/g had been suggested to influence circulating mcp-1 levels and gene expression thus, might be one of the genetic markers for progression of renal damage. our aim was to investigate the frequency of mcp-1 genotypes and allele -2518g in patients with caut. objectives of study: congenital urological anomalies are well recognized as causing renal dysfunction. on the other hand, patients without congenital anomalies but with urinary bladder dysfunction (bd) could also develop renal parenchymal damage. it has been reported that angiotensin converting enzyme (ace) i/d polymorphism was a risk factor for renal parenchymal damage in certain renal diseases including vesicoureteral reflux. the aim was to determine i/d polymorphism as a potential risk factor for renal parenchymal damage in patients with congenital obstructive uropathy and to compare them to patients born with normal anatomy and innervation of bladder, sphincter and pelvic floor but which could develop upper urinary tract abnormalities. objectives od study: to determine the frequency of pyelocaliceal dilation (pcd) in asymptomatic infants and its connection with presence of other urinary tract anomalies (uta) and urinary tract infection (uti). methods: ultrasonographic screening (us) of urinary tract (ut) was performed on unselected population of 1000 healthy infants ranging between 7 days and 6 months of age (511 boys and 489 girls). kidneys were divided into two groups according to grade of pcd. group i consisted of kidneys with pcd, whose anterio-posterior diameter was 5-10 mm, while patients from the group ii had a-p diameter wider than 10 mm.patients were followed up (ranging 5-58 months) by serial ultrasound examinations and with other methods for presence of uti and uta if necessary. results: in examined population 2,2% had uta, and 8,4% had uti. pcd was found in 74 infants (7,4%). in the group i, consisted of 63 infants (35 males and 28 females) pcd increased during the time in 3,2% infants, remained unchanged in 11,1%, decreased in 14,3%, and disappeared in 71,4% patients. uta was found in 4 (6,3%) infants, and uti in 9 (14,3%) infants. in the group ii, consisted of 11 male infants, pcd has not changed in 5 (45,4%) infants, decreased in 2 (18,2%), while dilation disappeared in 4 (36,4%) patients. uta was found in 6 (54,5%), and uti in 4 (36,4%) infants. conclusions: us of ut is useful and valuable method for detecting pcd. our results indicate that mild pcd in infants increases the risk for uta approximately 3 times and uti 2 times, while severe pcd raises the risk for uta approximately 24 times, and uti 4 times. early diagnosis and early treatment of uta and alertness for possible uti should be the final goal of the kidney damage prevention. therefore we recommend that us of ut should be done in all children in the first months of life. in order to determine factors involved in kidney development, the spatial and temporal expression pattern of intermediate filaments (cytokeratins, vimentin) , epithelial growth factor (egf) and transforming growth factor alpha (tgf-α), was investigated in developing kidneys (mesonephros and metanephros) of 5-9 week human embryos. immunohistochemistry for detecting specific antibodies was used on paraffin sections. in the 5-9 week human mesonephros, vimentin was moderately expressed in all mesonephric structures, while cytokeratins were seen only in the mesonephric nephrons. moderate to strong expression to egf and tgf-α detected in all mesonephric structures, decreased with advancing development. in the 5-6-week metanephros, vimentin was mildly expressed in all metanephric structures. later on, its expression increased in collectin system and interstitium. in the 5 th developmental week, first to appear were cytokeratins 8 and 19 in the ureteric bud and ampullae, while from the 8 th week onward, both cytokeratins showed increasing expression in the collecting system and nehrons. at early stages, egf and tgfá showed moderate to strong reactivity in the collecting system, the metanephric mesenchyme and cups. from the 7 th week onward, expression of both factors decreased in differentiating nephrons. expression of all investigated developmental factors was in line with subsequent mesonephric degeneration. expression pattern of intermediate filaments in the metanephros might be associated with mesenchimal to epithelial transformation of developing nephrons. some mutations of cytokeratins are lethal, while others might lead to some multifactorial disorders. egf and tgf-α expression patterns of the metanephros indicate their role in induction, proliferation and growth of metanephric structures. their disturbed expression might cause reduction in kidney growth. we have demonstrated that renin-angiotensin system (ras) and mitogen-activated protein kinase (mapk) family constribute to the renal development. growing evidences indicate that aldosterone, a final element or ras, is an independent and powerful mediator of various renal disease. purpose of this study was to evaluate the role of endogenous aldosterone in renal development including cell proliferation and apoptosis, and the expression of mapk family. newborn rat pups were treated with spironolactone (200 mg/kg/d) in olive oil or vehicle for 7 d. to identify cellular changes, kidneys were examined for proliferating cell nuclear antigen (pcna) by immunohistochemical (ihc) stain, and apoptotic cells by tunel stain. immunoblot, ihc stain and rt-pcr for mapks, phospho-mapks, and p53 gene were performed. spironolactone treatment resulted in decreased body weight, decreased pcna-positive proliferating cells and increased tunel-positive apoptotic cells, especially renal cortical epithelial cells (p<0.05). in the spironolactone-treated group, c-jun n terminal kinase (jnk)-2 and phospho-jnk-2 protein expressions were significantly increased, whereas extracellular signal -regulated kinase (erk)-2 and p38 protein expressions were sigificantly decreased compared with the control group (p<0.05) in immunoblot and ihc stain. expressions of erk-1, phospho-erk-1 and 2, and p53 sere not changed by spironolactone treatment. in rt-pcr, erk-2 and p38 mrna expressions were significantly increased in the spironolactone-treated group (p<0.05). we conclude that aldosterone inhibition in the developing rat kidney decreases cellular proliferation and increases apoptosis, and modulates the expressions of jnk-2, erk-2 and p38. mapk family expression may be implicated to differentially participate in aldosterone-related intracellular signaling pathways in the developing kidney. objectives: early detection of anomalies of the kidney and urinary tract (ut) helps to prevent complications but is hampered in moldova by diagnostic and logistic problems. to assess the extent of late diagnosis we studied the clinical data of all children referred to us for suspected ut infection (uti) in 2004/5 and found to have renal or ut anomalies. methods: 92 children (27 males; age 3 months-15 years) found to have anomalies of the kidney and ut and treated conservatively were studied (newborns and infants <3 months were seen elsewhere). work-up included ultrasonography in all, voiding cysto-urethrography (vcug) in 40%, urography in 57% and scintigraphy in 3% of patients. results: reasons for referral were febrile uti (38%); abdominal pain (31%), diarrhea and vomiting (16%), enuresis (9%) and dysuria (6%). uti was confirmed by urine culture in two thirds of cases. age at diagnosis of renal or ut anomaly was <1 year in 9%, 1-3 years in 6%, 3-7 years in 7%, 7-10 years in 30% and >10 years in 48%. renal hypo/dysplasia was found in 14, solitary kidney in 10 and a horseshoe kidney in 9 children. anomalies of the ut included hydronephrosis due to ureteral obstruction (13 up and 11 uv-obstruction), vesico-ureteral reflux (8), duplex systems (17) and bladder anomalies or mild infravesical obstruction (10). serum creatinine was in the normal range in all children. urolithiasis was found in 2 patients. conclusions: anomalies of the kidney and ut were diagnosed in nearly half beyond the age of 10 years, thus with considerably delay. based on the results of this study a new strategy of renal ultrasound screening in newborns including prenatal diagnosis and of closer co-operation with referring physicians has been implemented. objective of the study: the purpose of this study was to report the outcome of infants with antenatal hydronephrosis. methods: between may 1999 and june 2006, all patients diagnosed with isolated fetal renal pelvic dilatation (rpd) were prospectively followed at asingle tertiary renal unit. inclusion criteria were presence of rpd equal to or greater than 5 mm on prenatal ultrasound after 28 weeks gestation, at least six-months of follow-up, and at least two postnatalus scans. the events of interest were presence of uropathy, rpd resolution, urinary tract infection (uti), and hypertension. rpd was classified as mild (5-9.9 mm), moderate (10-14.9 mm) and severe (>15 mm objective of the study: the aim of this study was to compare the accuracy of ultrasound renal parameters to discriminate between significant uropathy and idiopathic renal pelvis dilatation. methods: 193 neonates who were found to have isolated fetal renal pelvis dilatation (rpd) underwent systematic investigation and were prospectively followed. a us scan was performed after the first week of life and all infants underwent vcug. neonates with rpd larger than 10 mm were examined by renal scintigraphy. receiver-operating characteristic (roc) plots were constructed to determine the accuracy of three indexes: fetal rpd, postnatal rpd, and sfu grading system. results: a total of 193 infants were included in the analysis. ninety-five fetuses (49%) presented bilateral renal pelvis dilatation. seventy-nine infants (41%) presented urinary tract anomaly, corresponding to 95 renal units. the most frequent detected uropathy was ureteropelvic junction obstruction (61), followed by primary vesicoureteral reflux (26), and megaureter (8) conclusions: our data support the view that fetal and postnatal us renal parameters are useful markers to identify infants with clinically significant uropathies. there was no significant difference in performance among the indexes. objective of the study: the aim of this study was to evaluate the diagnostic accuracy of ultrasound (us) renal parameters to identify vur in infants withisolated antenatal hydronephrosis. methods: 193 neonates who were found to have isolated fetal renalpelvis dilatation (rpd) underwent systematic investigation and wereprospectively followed. a us scan was performed after the first week of life and all infants underwent vcug. neonates with rpd larger than 10mm were examined by renal scintigraphy. receiver-operating characteristic (roc) plots were constructed to determine the accuracy of three indexes: fetal rpd, postnatal rpd, and sfu grading system. results: a total of 193 infants were included in the analysis. seventeen infants (8.8%) presented vur, corresponding to 26 renal units. to discriminate between renal units with and without vur areaunder the curve (auc) was estimated by the roc curve, which was 0.52 (95% ci=0.47-0.57), 0.58 (95% ci, 0.53-0.63), and 0.55 (95% ci, 0.50-0.60) for fetal rpd, postnatal rpd, and sfu grading system, respectively. there was no statistically significant difference between the indexes. the optimal threshold for fetal rpd was 7 mm with a sensitivity of 69% (95% ci, 48-86) and specificity of 45% (95% ci, 40-51), for postnatal rpd the respective figures were: 54% (95% ci, 33-73) and 72% (95% ci, 67-77) for the cut-off of 8.8 mm. conclusions: our data shown that the magnitude of rpd is a poor predictor of presence of primary vur. there was no significant difference in performance among the indexes. objetive: we investigated the prevalence of renal calcification in children with autosomal ressecive polycystic kidney disease (arpkd) and studied the metabolic changes thats could cause this complication. methods: 9 patients with arpkd. 6 girls/3 boys; range age 2 m to 15 y. criteria inclusion presence typical imaging findings: enlarged kidney and diffusely increased renal echogenicity and poorly defined renal margins on sonography; suggestive imaging features with positive results renal or liver biopsy, results 7 patients, 5 girls and 2 boys, range of age 9-15 y, had ct scan renal clacification bilaterally. without renal clacifications <1 year. 7 children renal calcifications, 7 sistemic hypertension, 4 portal hypertension and gastrointestinal bleeding and one renal colic. renal insufficiency 6 patients, it was mild in 3 (gfr >50 ml/min/1,73 mt 2 ), moderate in 2 (gfr 30-50), and severe in one (gfr<30). all with renal insufficiency had distal tubular acidosis. hypocitraturia urine 7 patients. urinary calcium, uric acid, oxalates, and cystines normal in all. tuberoussclerosis (tsc) -an autosomal dominant inherited genetic disorder -is characterized by development of hamartomatous growths in many organs.two causative genes, tsc1 (chromosomal locus 9q34) and tsc2 (chromosomal locus 16p13.3) have been identified. tsc2 gene is adjacent to pkd1, the major gene for autosomal dominant polycystic kidney disease (adpkd) on chromosom 16p13 and contiguous germline deletion of both genes results in severe polycystic kidney disease phenotype at birth. at 6 months of age bilateral abdominal masses were occasionally palpatedin a previously healthy girl. ultrasonography demonstrated enlarged (approximately 15 cm) kidneys with multiple large cysts resembling those seen in adpkd. renal function and blood pressure was normal. suspicion of tuberous sclerosis was raised due to numerous hypopigmented cutaneous macules on the trunk and extremities. echocardiography demonstrated 2 rhabdomyomas in the left ventricle with no hemodynamic significance. an isolated juxtapapillary astrocytoma was found in the left eye. her psychomotor development was normal with no history of seizures. cerebral magnetic resonance imaging revealed multiple subependymal nodules with noobstruction of the cerebral fluid pathways. by multiplex ligation-dependent probe amplification (mlpa) a large dna deletion was identified spanning from tsc2 exon 10 to pkd1 exon 46 permitting the diagnosis of tsc2-pkd1 contiguous gene syndrome. cardiac rhabdomyoma and cutaneous manifestations were found in her father as well but no renal changes. at 3 years of age the girl is doing fine with ace blockers against hypertension. renal function is still normal. the size of the cardiac rhabdomyomas is diminishing while the cerebral and ocular hamartomasare unchanged. this additional report focuses tsc in an infant presenting with polycystic kidneys and cutaneous lesions. improvements in ultrasound technology and the appropriate timing of antenatal ultrasound has led to refined prenatal diagnosis and enhanced accuracy of diagnosis of fetal renal anomalies and makes it possible to treat obstructive and/or refluxing uropathies before the onset of clinical symptoms.a retrospective review of 165 patients; 44 girls (26,7%) and 121 boys (73,3%) admitted to our clinic between january 1999-december 2006 with antenatal urinary anomalies were investigated to determine the urinary tract anomalies, and the follow-up results are presented. routine prophylaxis was started at admision and the imaging studies were performed. the mean gestational age at detection was 28,4±5,87 weeks. the mean age of admittance was 32,95±29,63 days and the average follow-up period was 19,15±26,05 months. antenatal ultrasonoghrapy examination showed anomalies in 220/330 renal units. of these 220 antenatally observed renal units, 216 had postnatal urinary tract anomalies. of these 216 postnatally observed renal units, 235 urinary tract anomalies were detected (multiple urinary tract anomalies in 48 patients) ( table 1) . fifty-two (31,5%) children had 59 surgical interventions such as; ureteroneocystostomy, pyeloplasty, nephroureterectomy, puv resection. eighty-one (49%) of our patients had urinary tract infection during follow-up and renal scar was detected in 58 (35%) patients. acute renal failure developed in 6 patients and chronic renal failure developed in 3 patients and three patients died. we conclude that all infants with fetal urinary abnormalities should be evaluated, so that we can recognize and treat congenital anomalies that may affect renal function or cause urinay tract infection, renal scarring. the majority of patients with fetal urinary anomalies can be managed safely with close conservative follow-up. fetal urinary tract obstruction at 50 days gestation (e50) produces small kidneys with cysts, whereas obstruction at 60 days (e60) generates large kidneys with cysts. in the present study, we investigated the mechanism for the generation of small kidneys by urinary tract obstruction at an earlier gestational age, e50. fetal lambs underwent urethral and urachal ligation at e50 (n=17) or e60 (n=39). fetal lambs were delivered by c-section 5, 7, 20 days after obstruction, or at term (145 days gestation). unoperated kidneys of e50, e60, e80, and at term served as controls. the percentage cystic area of kidneys obstructed at e50 and e60 was not different 5 days after obstruction (17±5% vs 17±6%). after 7 days, however the percentage of cystic area became larger in kidneys obstructed at e50 (40±17% vs 23±5%), and was significantly larger 20 days after obstruction (51±18% vs 17±17%). proliferating cells, detected by pcna staining, were found in cysts and tubules of obstructed kidneys increasing toward term, and were more abundant in kidneys obstructed at e60. on the other hand, pcna-positive cells in the nephrogenic zone were reduced in obstructed kidneys. the decrease was more prominent in kidneys obstructed at e50. apoptotic cells, identified by tunel staining, were detected in the inner medulla of obstructed kidneys equally in kidneys obstructed at e50 and e60 during the fetal stage. at term, tunel-positive cells were rarely present in normal kidneys or kidneys obstructed at e50, but were found abundantly in the interstitium and occasionally in cysts and tubules of kidneys obstructed at e60. in conclusion, urinary tract obstruction at an earlier gestational age produces small kidneys by inhibition of mesenchymal cell proliferation, which may be due to compression by cysts. a. results: detrusor hyperreactivity, most commonly in i and iv or v grade was found in 47.9% of vur children. the maximum detrusor pressure was above 70 cm h 2 0. detrusor-external dyssymetry was found in 17% of children, most frequently in grade i and iv or v grades, and detrusor-internal dyssymetry was recognized in 19.4% of children with vur, most frequently in grade i and iv or v. in 12.5% of children with i-iii grade of vur cystometric capacity was reduced but 1 child with v grade had increased capacity of the urinary bladder. glomerular filtration according to schwartz equation was normal and independent of vur grade. decrease in osmolality below 800mosm/kg h 2 0 in nocturnal urine was only detected in the group of children with iv and v grade of vur,. there was no correlation between detrusor tension and osmolality of urine and glomerular filtration rate. conclusions: 1). dysfunction of the lower urinary tract, with detrusor hyperactivity was detected, as the most frequent dysfunction in 74% of children below 2 year old with i-v degree of vur, 2). the maximun detrusor pressure in the voiding phase was highest in grade i and iv iv-v reflux children. hypomelanosis of ito was first described as a disorder characterized by unusual unilateral or bilateral macular hypopigmented whorls, streaks and patches. subsequently, neurologic, skeletal and ocular involvement were described. kidney involvement has only been exceptionally reported. herein, we describe a case of a male infant with hypomelanosis of ito and renal involvement. the patient was born at 40 weeks of gestation by cesarian delivery. the ultrasound scan at 34 weeks of gestation revealed bilateral enlargement of kidneys, decreased corticomedullary differentiation and cysts located in the cortical and subcapsular regions. these findings were confirmed at two months of life by ct scan. skin examination showed hypopigmented linear and round diffuse lesions located on the right leg and arms. the ophthalmological examination showed anterior capsular and posterior subcapsular cataract of the left eye. as previously reported in other cases of hypomelanosis of ito, the patient presented a transient leucocytosis (max 30.000/mm 2 ) during the first 8 months of life.the renal biopsy showed a classic picture of glomerulocystic kidney disease, whereas the skin biopsy confirmed the clinical diagnosis of hypomelanosis of ito.three other cases of kidney disease in hypomelanosis of ito have been reported. of these, one case presented abnormalities of the glomerular basement membrane, and one case presented with polycistic kidney disease. the third case had renal cystic dysplasia with a histological picture containing glomerular cysts. alltogether these reports suggest that genes involved in hypomelanosis of ito are important for normal renal development and may be implicated in cystogenesis, when mutated. here we report on a male newborn (birth weight 3070 g, length 51 cm) who presented with progressive edemas, oliguria and failure to thrive during the first week of live. on clinical examination he showed bilateral microcoria and decreased muscle tone. laboratory work-up revealed large proteinuria (28 g/g creatinine), hypoalbuminemia (13 g/l) and renal failure ( objectives. to investigate the incidence, nature, and management of associated genitourinary malformations in children with multicystic dysplastic kidney (mcdk). methods. in this retrospective study, we analyzed the medical records and imaging studies of 24 children with mcdk. in 20 children (83%) anomalies of the urinary tract were suspected prenatally in ultrasound studies. in the remaining 4 children the diagnosis of mcdk was made postnatally. results. the male/female sex ratio was 8: 16. the left side was involved in 11(46%) children. voiding cystourethrography was done in 14 (58%) children, the isotopic 99m tc-dmsa scan of the kidney in 15 (63%). urogential anomalies were present in 10 (42%) children. among them, contralateral urologic anomalies were found in 3 patients (vesicoureteral reflux in 2 and hydronephrosis in 1), and ipsilateral in 8 (vesicoureteral reflux in 1, ureterocele in 3, and hydroureter in 2). genital abnormalities such as uterine didelphys and hydrocele were found in 2 children. fourteen (58%) patients underwent follow-up examinations with ultrasonography (mean follow-up 4.15 years, range 7 months to 12 years). compensatory hypertrophy of the contalateral kidney was found in most children and decreased size of ipsilateral dysplastic kidney was found in 9 out of 14 children with follow-up. no cases of hypertension or tumor developed during the follow-up. conclusion. ultrasound can be used safely to diagnose unilateral mcdks and associated genitourinary malformation. although the risk of hypertension and development of malignancy is low, follow-up evaluation of contralateral renal function and genitalia will be needed. in cases of hydronephrosis and/or urinary tract infection, voiding cystourethrography is necessary and possibility of association with genital anomalies should be considered until the puberty. a. background: ectopic ureter is a rare anomaly. its incidence is at least four times higher in females and also more than 80% of the ectopic ureters drain duplicated systems in females. the most common presenting symptoms of an ectopic ureter are urinary tract infection and incontinence. diagnosis is often delayed and may remain undiagnosed until adulthood. case report: a 3-month-old girl was admitted to our hospital with the complaints of fever and discomfort. her mother recognized intermittent dribbling of urine while changing her napkin. physical examination revealed fever (38.3 °c), diaper dermatitis and intermittent dribbling of urine. urinalysis revealed leukocytouria, acute phase reactants were elevated (crp: 1.45, esr: 27) and renal function tests were normal. the patient was hospitalized with the diagnosis of acute pyelonephritis. tc99m dimercaptosuccinic acid (tc-dmsa) scan revealed an increase in the size of the right kidney and decreased uptake in the upper half of the same kidney. ultrasound was performed with the suspicion of an ectopic ureter and it showed right duplicated kidney with marked dilatation of the upper collecting system. the ureter was also dilated in its whole length and ended ectopically distal to the bladder. contrast-enhanced magnetic resonance urography (mru) demonstrated right obstructed duplicated system with vaginal ectopic insertion of upper pole ureter. discussion: this case was presented to underscore the role of careful physical examination in the diagnosis of this rare anomaly that is by paying attention to the complaints of the family. ultrasound is the initial, important diagnostic modality in these patients especially if done by experienced radiologists. the diagnosis can be confirmed with mru by depicting the exact insertion of the ectopic ureter. objectives of study: to evaluate the occurrence and severity of vesicoureteral reflux (vur) in young infants with a history of mild prenatal hydronephrosis. the usefulness of voiding urosonography (vus) in the diagnosis of vur was also evaluated. methods: forty seven infants (31 males, 16 females) with a history of mild prenatal hydronephrosis, diagnosed between 21 st to 30 th week of gestation, were enrolled in the study. postnatal ultrasound was performed within the first month of life. voiding cystourethrography (vcug) and at the same time, contrast-enhanced harmonic vus was performed at the age of 1.5-2.5 months. results: the prenatal ultrasound revealed an anterior-posterior pelvic diameter of 5-7 mm in 33 fetuses and 7-10 mm in 14. postanatal ultrasound showed an anterior-posterior pelvic diameter of 5-7 mm in 34 infants and 7-10 mm in 13. vur was found in 9 of 47 (19.1%) infants (grade i: 2, ii: 4, iii: 3). the vur was detected by both vcug and vus in 4 of 9 children, only by vcug in 2 and only by vus in 3 of 9 infants. the vur that was missed by vcug was more severe (grade ii and iii), compared with this one missed by vus (grade i). conclusions: even though prenatal hydronephrosis was associated with a quite important occurrence of vur, this was of mild or moderate severity. comparison between the two imaging modalities showed that the vur missed by vus were with no clinical significance (grade i), whereas the vur missed by vcug were more severe. although further study is needed, vus could be an alternative method, mainly in girls, in whom the imaging of the urethra is not necessary, thus avoiding the radiation exposure. early treatment with indomethacin in a neonate with a bartter syndromea case report neonatal bs is a rare genetic disorder characterized by sodium, potassium and chloride urinary wasting, hypokalemic metabolic alkalosis with hyperreninemia and hyperaldosteronism in the absence of hypertension and high level of urinary prostaglandins. indomethacin therapy is controversial because of toxicity for gut and kidney. a premature boy of unrelated couple was born by cesarean section at 28 weeks because of early rupture of membranes and fetal distress. birth weight was 900 g, length 36 cm and apgar score 2/6/8. pregnancy was complicated by severe polyhydramnios. baby was mechanically ventilated for first 12 hours and treated with antibiotics because of suspected sepsis. marked polyuria and dehydration were present from 1st week. metabolic parameters revealed hypokalemia, hyponatremia and hypochloremic metabolic alkalosis. serum creatinine was slightly elevated and gfr in normal ranges. blood pressure was normal with raised plasma renin activity and aldosterone level. sodium excretion via urine and level of renal and systemic prostaglandins were increased. nephrocalcinosis was detected on us from 2 week. additonally to electrolyte supplementation indomethacin was started on the 18th day at a dose of 1 mg/kg/day. in first 2 months child experienced 4 septic episodes, candida pyelonephritis and was operated because of bowel obstruction. dna analysis of affected child found 2 new mutations in romk gene: p185l and q289x in herited from parents who carried one mutation each. at 18 months height and weight are at 3 and head circumference at 50 percentile with slightly retarded psychomotoric development. he continues on 1.2 mg/kg/day indomethacin therapy. blood electrolyte profile is normal without supplements. us shows no progression of nephrocalcinosis. early treatment with indomethacin may prevent life-threatening complications and reduce the development of nephrocalcinosis. nimuselide, a cox2 inhibitor is widely used in india for relief of pain and fever. we describe 6 cases of fetal renal abuse leading to neonatal renal failure due to maternal ingestion of nimuselide in the third trimester of pregnancy. results: all 6 patients were diagnosed as having renal failure in the first few days of life.there were 5 boys and one girl.. all the mothers had normal pregnancies except for oligohydramnios that was detected during the last 2 months of pregnancy in all cases.4 children presented with anuria from birth. the remaining two had non-oliguric renal failure with metabolic acidosis as the presenting feature in one and poor feeding and lethargy in the other. usg revealed normal sized kidneys. one patient also showed increased echogenicity. 3 out of the 4 anuric children underwent peritoneal dialysis for a period varying from 3 to 4 weeks without recovery of renal failure. the remaining 3 were managed conservatively. two of these patients are now in chronic renal failure at ages 2 and 5 years. only one patient recovered completely after 5 days of anuria. all the mothers had taken nimuselide in the last trimester for periods varying from few days to several weeks for relief of pain or fever. some of them had taken multiple courses of short duration. the mother of the child who recovered completely had taken nimuselide in the last 5 days before delivery. renal biopsy done in one baby revealed renal tubular dysgenesis. conclusion: nimuselide intake in the last trimester of pregnancy can be associated with oligohydramnios and neonatal renal failure that can be irreversible. renal tubular dysgenesis may be the underlying pathology. objectives of study: pkd is the most common inherited renal disease. aim of ours study was to analyse clinical and laboratory features of the different types pkd. patients and methods: we described the clinical presentation of 47 children with pkd (26 boys, 21 girls) diagnosed in pediatric nethrology department between 1989 and 2007. the patient's age range was from 3 months till 18 years. we retrospectively studied the family histories, clinical and biochemical data (physical examination, level of arterial blood pressure, blood and urine creatinine levels, serum levels of urea, glomerular filtration rate), ultrasonography, scintigraphy. results: the analysis of the family histories revealed adpkd in 27 patients (14 boys, 13 girls), arpkd in 6 (2 boys, 4 girls) and nondifferential pkd in 14 (10 boys, 4 girls) children. pkd diagnosed by antenatal ultrasound in 6 cases (2 adpkd, 4 arpkd). the mean follow-up adpkd were 4,4 year (range 1 -13 years), arpkd -5,3 year (range 1 -14,5 years). conclusion. patients with arpkd demonstrated the early beginning of an arterial hypertension and progressing chronic renal failure. one girl with neonatal form of arpkd died. chronic renal failure developed in 9 (19,1%) cases of pkd. objectives: this prospective study was to answer the question on the need of long-term follow-up and correlation of renal functions with the age at surgery and grade of o.u. prior to surgery in patients after surgery of obstructive uropathy (o.u.). methods: selected biochemical markers of glomerular and tubular functions and ultrasonographic findings in 62 patients (40 boys) who underwent surgery due to uni-or bilateral o.u. of grade iii. and iv. (age at surgery <12 months) in 1994-1997 were examined at mean age of 6.3±0.9 years. the results were compared to 32 healthy controls and/or to reference values according to age. consequently, patients were devided into groups according to the age at surgery (0-3 months, 4-6 months, 7-12 months) and grade of o.u. prior to surgery. results: serum concentration of cystatin c (s-cysc) was significantly higher in patients when compared to control group (p<0.001). while s-creatinine was within reference interval in all patients, s-cysc was increased in 63.3% when compared to reference interval. decreased tubular resorption and concentration ability was found in 67% and 26% patients, respectively. non-specific aminoaciduria was detected in 42.9% patients. on ultrasound, 66.7% kidneys after surgery had residual dilatation of renal pelvis. the differences in renal functions in patients according to their age at first surgery were not significant except for u-nag activity with significant negative linear trend with higher age at surgery. the grade of o.u. prior to surgery did not have significant influence on renal functions. conclusions: mild tubular dysfunction and slightly reduced gfr in the part of patients make longterm nephrologic follow-up reasonable. our results support the trend of postponing early postnatal surgical intervention in patients with positive ultrasound screening of o.u. and normocreatininemia. objectives of study: to evaluate, during almost five years of follow-up, the changes among preoperative and postoperative renal function in 46 infants (36m/10f) with prenatal severe hydronephrosis (hn) and upj obstruction. methods: upj obstruction was diagnosed by a mag3 renal scan, performed at 4-6 weeks of age to establish baseline differential renal function; surgery was made if there was evidence of obstruction injury, and/or progression of hn and/or symptoms. the group was re-imaged 3 months after surgery, after 6 months, 1 year and then annually. results: initial differential renal function was moderate in 41.6% of males and in 30% of females and good in 58.4% and in 70% respectively. also,75% of kidneys required surgery because of declining function, with mean differential renal function in the affected kidney of 32% that improved to 44% already at 3 months after pyeloplasty. there was no significant functional improvement, in the kidneys that underwent correction because of increased hn or symptoms and final renal function was >40%. after pyeloplasty t was >30 min. in 21% and 20-30 min. in 79% of cases (p<0.05) there was no statistically significant correlation between initial grade of hn and initial renal function. surgical treatment was performed between 9-16 months of age and there was no significant difference in postoperative results, ascribed to patient age at surgery. ma values, greater than controls at diagnosis, reduced at 18 months after surgery in all, but 16% of children. during the follow-up, the mean ccr and bp values were in normal range for age in all children. conclusions: our findings showed improvement also in kidney with preoperative uptake less of 40%. this may be to explain in according to an inverse correlation between degree of renal dysplasia and gestational age. objective of study: is to determine the postnatal course and follow-up of children with fetal hydronephrosis. methods: in 6 years period (2000) (2001) (2002) (2003) (2004) (2005) (2006) we followed 72 infants with antenataly detected hydronephrosis. all infants were submitted to ultrasonographic examination of kidneys and bladder. if indicated, the isotope renography, micturating cysto-urethrography, i.v.urography and mr were performed. results: the diagnosis of hydronephrosis was established during 15 -39 th weeks of gestation by obstetritian. first postnalat ultrasound investigation was performed during neonatal period in most children (69%). in 48 (66,7%) infants we diagnosed idiopathic hydronephrosis, in 12 (16,6%) vesicouretheral reflux (vur) grade ii-iv, in 7 (9,7%) hypofunction of one kidney, in 2 (2,8%) ureteropelvic junction obstruction (upjo), in 1 (1,4%) ren duplex and ureterocele, in 1 (1,4%) ampular pelvis and in 1 (1,4%) afunction of one kidney. after 6-12 months we found normal ultrasound in 35 (48,6%) children. the ultasound results were stable in 24 (33,3%) children and in 9 (12,5%) there was progression of hydronephrosis. four (5,5%) infants underwent immediate surgery. conclusions: in a group of 72 infants with antenataly detected hydronephrosis the diagnosis was confirmed postnataly in 89% infants. more than 50% of infants required long term follow-up. in 5,5% the immediate surgey was required. this data support the need for antenatal detection of hydronephrosis. in the same period we followed up 207 infants with urologic abnormalities which were not detected antenataly.the fetal ultrasound is reliable screening method in detection of urologic abnormalities. the considerable number of anomalies which were not detected antenataly are the result of insuffitient use of fetal ultrasound investigation. hemolytic uremic syndrome (hus) is defined by acute renal failure, microangiopathic hemolytic anemia, and thrombopenia. perinatal asphyxia (pa) may cause renal failure after birth and is often associated to disseminated intravascular coagulopathy (dic) with platelet consumption. however, no biological investigation permits to distinguish clearly neonatal hus from dic. we report three neonates with renal failure due to different degrees of pa. they presented biological features compatible with hus such as fragmentocytes (3%), thrombopenia (<50,000/mm3), anemia (<8 g/dl). serum creatinine on day 5 was 293, 152, 372 mmol/l respectively, requiring peritoneal dialysis in one patient. haptoglobin was undetectable for all three patients. factor h and i were in the lower normal range; components of the complement system (c3, c4) and adamt13 activity were decreased. two patients received daily fresh frozen plasma infusions over the first 4 weeks. renal function improved in two patients until day 30; one patient has chronic renal failure. all other parameters suggestive for hus were normal on day 12, 30, and 60 respectively. no severe neurological consequences were noted for either of them. pa may be responsible for multiorgan damage via ischemic lesions. ischemia may result in endothelial cell injury, the crucial event for the development of thrombotic microangiopathy. we hypothesize that endothelial cell damage concomitant with pa may lead to a vicious circle resulting in consumption of platelets and plasma factors involved in hemostasis and/or fibrinolysis. early use of fresh frozen plasma may correct these alterations. renal biopsies might have been useful but are technically difficult in newborns. in conclusion, pa and neonatal hus are difficult to distinguish and endothelial cell damage may be a common pathyphysiological aspect and might requirespecific treatments. a. medynska, m. nalesniak, k. kilis-pstrusinska, d. zwoliñska congenital posterior urethral valves (puv) are the most common cause of lower urinary tract obstruction in male neonates. we aimed to review our experience with puv children (24 boys) in respect to retrospective analysis of the clinical course of disease. we analyzed: ultrasound during pregnancy, age of disease onset, clinical symptoms at admittance to hospital, outcome. average lenght of follow-up was 7,3 years, varying between 2 month and 20 years.obstruction of urinary tract was suspected by prenatal ultrasound in 9 patients. the initial presenting symptoms were as follows: urinary tract infection 7 boys, failure to thrive 3 patients, increased abdominal circumference -2, abdominal pain 1, enuresis -3, acute renal failure 1, and chronic renal failure 14 children. in association with puv renal dysplasia/hypoplasia in 4 patients, undescended testis 3, bladder trabeculation 4 were found. the diagnosis of puv was confirmed by voiding cystourethrograms and/or cystoscopy. primary vesicouretral reflux was documented in 7 pts. hydronephrosis and/or megaureter were observed the most often in 14 boys. the diagnosis of puv was established in 10 pts at the age of less 1 month, in 6 pts between 2 -12 months, and in 8 between 1-15 years. surgery was performed in 7 pts in neonates period including primary valve surgical ablation and/or cutaneostomy vesicostomy. chronic renal failure was diagnosed in 7 boys in first year of live. 4 of them progressed to end-stage renal disease. globally during the follow-up 7 pts developed end-stage renal disease. 4 pts have done a graft. only 5 boys survive without progression to chronic renal failure. the presentation of puv is variable and currently antenatal detection is the most common mode. outcome boys with puv is poor. patients need nephrologic assesment from birth. background: furosemide is among the 10 most frequently used drugs in the neonatal unit but few studies analyze the beneficial effect and complications in this patient group. objectives of the study: to analyze the therapeutic clinical effect and to document side effects of furosemide therapy in extremely preterm infants born <28 weeks gestational age (ga). methods: twelve infants born <28 weeks ga were prospectively included during the fall 2006. the following parameters were documented prior, during and after furosemide administration: clinical status, serum/urine electrolytes, creatinine, albumin, blood gases and furosemide exposure. ultrasound of the kidneys and a wrist radiograph were performed at 6-8 weeks to rule out osteopenia/rickets and nephrocalcinosis respectively. no statistical analysis were done due to the small study size. results: general oedema, respiratory rate, apneic spells and oxygen supplementation decreased. arterial/venous pco 2 decreased and partial oxygen saturation increased indicating improved lung function. hco 3 increased and ph decreased. urinary excretion of sodium, potassium, chloride and calcium increased while phosphate excretion decreased. serum sodium and chloride decreased and potassium increased initially. six infants had electrolyte disturbances and metabolic alkalosis. one infant died during the study period. in the remaining 11 infants, 3 of 5 had worsening of their patent ductus arteriosis, 3 had osteopenia or rickets and 1 had nephrocalcinosis. the total side effect score was increased in the infants with the highest furosemide exposure. conclusions: this small study suggests that furosemide is beneficial in extremely preterm infants born <28 weeks ga and that the associated side effects correlate to the total drug exposure. we recommend caution for long term administration of furosemide. conclusion: although children in our study suffered significant neonatal hie resulting in arf, glomerular and tubular function recovered sufficiently to cope with increasing body mass and metabolic needs. unlike reported studies, we did not find any significant evidence of cri in the survivors of neonatal hie and arf. one with marginal microalbuminuria will need further observation. c was born after a monozygotic monoamniotic twin pregnancy (gestational age=34 weeks). she presented with twin-twin transfusion syndrome with hypotrophy (birth weight=2020g, other twin=2950 g), severe hypovolemia, anemia and acute renal failure. she required a blood transfusion, mechanical ventilation (5 days), and peritoneal dialysis (10 days). she recovered without bronchodysplasia but with chronic renal failure (creatininemia at 2 months=90 μmol/l). the following months were uneventful but, as usual in tts, she exhibited growth retardation and slight mental delay compared to her twin. she reached terminal renal failure at 12 years of age and was successfully kidney transplanted. after age of 6 years, she presented with increasingly frequent and severe pulmonary infections predominantly in lower lobes of both lungs. after extensive explorations, the diagnosis of bilateral bronchiectasis was made. the search for classical aetiologies of such pathology was negative. the symmetric aspect and the absence of other etiologies lead to the consideration of bronchiectasis as a congenital pathology. numerous publications demonstrate the role of the renin-angiotensin system (ras) in renal and cerebral damages in tts. authors demonstrate the role or ras in development of vasculature in fetus but also of cartilage and muscle in different organs including lung. associations between tts and lung pathologies need to be further investigated. urofacial ( the urofacial (ochoa) syndrome (ufs) is a rare disease that occurs in both sexes and is more frequent when the parents are closely related. it has both urinary and facial abnormalities. ufs is a rare autosomal recessive disorder and a potential gene has been mapped to chromosome 10q23-q24. they present a bladder voiding dysfunction due to impaired neural communication between the bladder and the spinal cord, resulting in incomplete emptying of the bladder. this usually results in enuresis, urinary tract infection, hydronephrosis and in some severely affected patients, end-stage renal disease developed. the facial abnormality is a characteristic expression that, when these patients smile, their facial musculature inverts and they appear as if they are crying. we report a 15year-old girl who has inverted facial appearance, voiding dysfunction and vezicoureteral reflux. she had constipation and did the intermittan uretral cathaterization for five years. after a detailed evaluation, she was diagnosed as ochoa syndrome due to inverted facial expression. we report this case, because early diagnosis of ufs is very important for early assessment and management of urinary problems to prevent development of chronic renal failure. we think that only a smile can give a strong high light for this unusual 'inverted' facial expression and patients can be screened earlier for severe voiding dysfunction. tar syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii and a thrombocytopenia. the known urinary anomalies with tar are duplex ureter, dilatation of renal pelvis, horseshoe kidney, and functional problems like vesicouretheral reflux and pyelonephritis. case: nine years old patient with tar syndrome was admitted with a complaint of bright red urine repeated three times. the microscopic hematuria without dysmorphism of erythrocytes accompanied with no proteinuria were determined in repeated urine sample microscopy. iga, ana, anti dna serology were negative. urine culture was clean. stone formation (6x7 mm) in the upper pole of the right kidney was established by the abdominal ultrasonography. postoperative chemical analysis of the stone, revealed that it was consisted of oxalate monohydrate and dihydrate. but the patient discontinued his follow-ups afterwards for a year. in this period, he had macroscopic hematuria attack once. when he applied for the second time, he reported macroscopic hematuria. cystoscopy was done for etiology. many tortuous and engorged vessels were seen by this evaluation in the bladder mucosa ( figure 1 ). there was no active bleeding point. result: in this report, kidney stone and telangiectasia found co-incidentally in the bladder of a patient with tar syndrome during the examination of hematuria are discussed as there is no case report demonstrating nephrolithiasis and telangiectasia in tar patients in the literature. figure 1 : many tortuous and engorged vessels in the cystoscopy. antenatal hydronephrosis (anh) is one of the common fetal abnormalities detected on ultrasound (us). the long-term renal prognosis for infants with mild to moderate postnatal hydronephrosis (hn) is unclear and controversial. a systematic review of the published literature was performed to determine an evidence based approach in infants with antenatally diagnosed hn and to identify those at risk of significant post natal nephro-uropathy (pnu). key questions were identified. does anh predict renal tract pathology in neonates? what is the value of prophylactic antibiotics in infants with anh? can postnatal us diagnose significant pnu? when is the optimal time to screen infants postnatally? which imaging modalities are necessary to diagnose the cause of the hn? how many neonates with anh would need to be investigated to prevent one case of esrf/crf? a search strategy was formulated. out of 362 titles only seven studies met the validity criteria for inclusion. the results indicate that antenatal us is a valid screening test for pnu (sensitivity 16%, specificity 98%), but is not a predictor of pnu. the detection rate of hn by us is the same whether it is done early or late in neonates. two normal ultrasounds over a minimum of one month are required to screen for pnu. infants with a renal ap diameter over 7mm are at risk of a significant pnu and should be investigated further. us is not a substitute for cystourethrogram or dynamic isotope studies to determine the cause of hn. none of the studies addressed the role of prophylactic antibiotics. there was insufficient data to calculate the total number of cases that would need to be investigated to prevent one unfavourable outcome (esrf/crf). high quality population based cohort studies with long term follow-up into adulthood are required to determine the optimum postnatal management of mild to moderate hn in infants with anh. jeune asphyxiating thoracic dysplasia: a case report jeune asphyxiating thoracic dysplasia (jatd) is one of the congenital hepatorenal fibrocystic syndromes. it is characterized by renal, hepatic, pancreatic abnormalities with associated skeletal abnormalities including a long and narrow thorax, metaphyseal irregularities, and shortness of the ribs and long bones. this report describes a pediatric patient with jatd developed end-stage renal failure. a 7-year-old boy was admitted with complaint of vomiting and pallor. he had dysmorphic appearance including trigonocephaly, short stature, long thorax and short limbs and fingers, polydactyly and fascial dysmorphism. laboratory findings revealed severe anemia (hb 3.8 g/dl), high bun and creatinine levels (111 mg/dl and 7.9 mg/dl respectively) and normal liver tests. abdominal usg showed a severe intrahepatic biliary tract dilatation and intraparenchymal cysts in liver, pancreas and kidneys. mr pancreatocholangiography was consistent with caroli's disease. jatd should be considered when caroli's disease exists with skeletal abnormalities. follow-up antenatal hydronephrosis: one centre experience the most common renal abnormality detected antenatally is hydronephrosis (1% to 5% of all pregnancies). in this paper, we report follow-up our patients with antenatal hydronephrosis (ah) between 2001 and 2006. diagnosis of hydronephrosis was made >5 mm of antero-posterior diameter (ap) of the renal pelvis. ah was detected in 74 patients on antenatal ultrasound examination. of the 74 patients with ah, 46 (62.1%) were found to have hydronephrosis postnatally and 34 (37.8%) postnatal scans were normal. in 17 of these patients (36.9%) had bilateral and 29 (63.1%) of these patients had unilateral hydronephrosis. in these patients with ah, uretero-pelvic junction obstruction (upj) 28 (60.8%), reflux 12 (26.2%), uretero-vesical junction obstruction 3 (6.5%), posterior urethral valves 2 (4.3%) and mega-ureter 1 (2.2%) were identified. in follow-up period, 2 (16.6%) patients with reflux, 19 (41.3) patients with upj were treated with surgery (p<0.05). in conclusion, upj was most important cause of ah and most of them were treated with surgery. hyponatremia and renal tubular acidosis in severe vesicoureteral refluxa case report sahlgrenska academy, department of pediatric, gothenburg, sweden case report: 1st child to healthy parents without heredity for kidney or metabolic disease. antenatal bilateral hydronephrosis. postnatal examination showed bilateral vur grade v, normal urethra. antibiotic prophylaxis was started, no urinary tract infection (uti) occurred. normal s-creat and s-na + at 2 weeks of age. the electrolytes remained normal during the next 3 months. normal growth. the boy was thirsty with high urine volumes. at 3 month of age feeding problems began with retarded weight gain. no vomiting or diarrhoea. at admission to the hospital the child was dehydrated, s-na + 120 mmol/l, s-cl -99 mmol/l, s-ph 7.11, bicarbonate 11 mmol/l, s-creat 36 μmol/l. crp 8 mg/l, urine culture negative. u-na + 10 mmol/l, u-ph 6.0, u-osmolality 214 mosm/kg. the anion gap was normal and there was no lactacidosis. the s-aldosterone was elevated 53,1 nmol/l, s-cortisone normal. treatment included intravenous rehydration, na + supplement and oral bicarbonate. blood chemistry normalised and the child's general condition improved rapidly. conclusions. children with severe reflux are at high risk for uti but may also develop impaired tubular function with diabetes insipidus, renal tubular acidosis and hyponatremia. the mechanisms include down-regulation of vasopressin receptors and impaired distal tubular function. close clinical monitoring of these children with regular blood chemistry and weight controls is important. purpose: we aim to prospectively study the natural history of minimal to severe grades of antenatal hydronephrosis (anhn) in our local chinese population and correlate the renal pelvic diameter (rpd) with the outcome. patients and methods: cases of anhn were prospectively followed up along a predefined protocol using us, mag3 and mcu in all. obstruction (pujo or vujo) was defined as a need for surgery based on symptoms and deteriorating function, not on mag3 drainage time. results: 174 neonates were followed up for minimum of 5 years. eighty percent had normal or minimal hn on postnatal scans (rpd 5-9 mm), 11.4% had mild (10-14mm) or moderate (15-19) hn and 8.5% severe hn (>20 mm). seventy-eight percent infants had benign course; 6.9% had partial obstruction which improved; 11.5% had vesicoureteric reflux (vur) one of which required surgery. another 5.7% required surgery for obstruction. the roc curve for obstruction requiring surgery showed optimal cut-off point of 18.5 mm (sensitivity 100%, specificity 99.2%). prolonged diuretic t1/2 was not predictive of surgery. severity of hn did not correlate with presence or grade of vur. fifteen patients developed uti despite antibiotic prophylaxis and 7 had focal scars, all occurred in association with high grade vur or obstruction. the prognosis of infants with minimal or mild anhn is good. however rpd is poorly correlated with vur. the chances of obstructive lesions requiring surgery are high when the rpd is above 18 mm. in those with high grade reflux or obstruction, urinary tract infection may lead to renal scars. objectives of study: cystinosis is a rare disease presented initially with renal fanconi syndrome, and renal glomerular failure develops later in childhood. without cysteamine treatment, patients affected with cystinosis uniformly died during childhood in the absence of renal replacement therapy (rrt). cysteamine is not available here and in some other areas of the world. the aim of this paper is to describe a beneficial effect of acacia gum in a patient with cystinosis and chronic renal failure. method: 9 years old girl with cystinosis presented with symptomatic uremia as she didn't receive cysteamine. serum creatinine 7.4 mg/dl, blood urea 200 mg/dl. the girl was hospitalized and vomiting controlled with intravenous fluid and pyridoxine. chronic dialysis was not available for her and the parents refused treatment with intermittent acute peritoneal dialysis. the girl was treated with a new therapeutic regimen (therapy2006;3 (2): 321) combining the traditional conservative management of crf (dietary and pharmacologic) with addition of acacia gum (ag) 25 g/day as an urea lowering agent aiming at improving her condition without dialysis. results: treatment was associated with amelioration of the uremic symptoms and improved general well being. after 2 weeks of treatment, serum creatinine 1.9 mg/dl, blood urea 69 mg/dl. during 4 months of follow-up she continued in experiencing improved well being and urea levels was kept below 70 mg/dl without dialysis. conclusion: it was possible to improve the health of patient with cystinosis despite the nonavailability of cysteamine and the appropriate rrt. objectives of study: the pattern of renal tubular disorder (rtds) has been infrequently reported in the literature, and the pattern of rtds in iraqi and arab children is not known. methods: from june 2000 to august 2006, it was possible to evaluate 40 children with suspected rtd to determine the type of their tubular defect. there was evidence of rtd in only 35 patients; 22 males (63%) and 13 females (37%). their ages at referral ranged between 8 months and 14 years (mean 4.8 years). in 4 patients with oculo-cerebro-renal syndrome, there was no evidence of rtd and one patient had hyperoxaluria which not a rtd. results: seven types of rtds were identified. the three most common disorders were: idiopathic hypercalciuria (37%), cystinosis (21%) and renal tubular acidosis rta (21%). four of the patients with rta have proximal rta, and four have distal rta. four of the patients with hypercalciuria have also significant hyperoxaluria >3 mg/kg/day. conclusion: the pattern of rtds in iraqi children differs from the previous studies: in germany the three most frequent disorders were cystinosis, xlhr, and idiopathic hypercalciuria. objectives of study: few literatures reported the incidence of ocular abnormalities in chronic renal failure (crf). the aim of this paper is to determine the incidence of ocular abnormalities in childhood crf. methods: from january 1993 to december 2005, 80 patients with crf (at the university hospital in al kadhimiyia) were examined to determine the presence of ocular abnormalitites. fifty patients were males (62.5%) and 30 (37%) were female. their age at referral ranged from 2 months to 18 years (mean 9 year). they were followed for a period ranged from 5 days to f years. results: corneal cystine crystals were the most common ocular abnormalities associated with childhood crf observed in 6 patients with nephropathic cystinosis (7.5%). congenital cataract & glaucoma were observed in 3 patients (3.75%) with oculo-cerebro-renal syndrome (ocrs). congenital cataract & chorioretinal hypoplasia were present in 1 patient with ocrs. hypertensive retinopathy occurred in 2 patients. acquired cataracts occurred in one patient with hinman syndrome in association with hypocalcaemia and non-compliance with calcium and onealphacalciferol supplementation. retinitis pigmentosa in one patient with laurence moon biedl syndrome. bilateral optic atrophy in one patient with familial nephropathy associated with club feet. proptosis in one patient with membranoproliferative glomerulonephritis. conclusion: ocular abnormalities are relatively common in childhood crf occurring in approximately 19%. objective: hypocalcaemia has been reported as a complication of phototherapy especially in neonates. we studied the relation between serum calcium level and urine calcium to creatinine ratio in neonates under phototherapy. method: 50 icteric newborns (30 males and 20 females) treated by phototherapy entered into study by non accidental sampling. the consent was taken from parents on admission. all were breastfed healthy newborns. weight was checked and serum samples for calcium and bilirubin and urine aliquots for calcium, creatinine and osmoloality were sent on arrival (group i), after 48 hour of starting (group ii) and 24 hour after discontinuing phototherapy (group iii). hypercalciuria was defined by uca/ucr >0.8, hypocalcemia was defined by serum calcium <8mg/dl in the term and <7 mg/dl in the premature. chi2, anova, wilcoxon rank test and spearman were used to compare frequency, means, median and correlation. p<0.05 was considered significant. two groups were designed, pateints whose therapy were finished at least 12 months (group 1) and those either on therapy or less than 12 months passed from the last protocol of cytostat (group 2). demographic data, cumulative dosages of anticancer drugs, history of other nephrotoxic agents, nephrectomy, radiotherapy and acute renal failure were recorded. we used ctc2 (1999) to evaluate renal function. chi2 and mann whitney u test and biniary logistic regression were used to compare percentage, scoring and correlation respectively. p value less than 0.05 was considered significant. result: 58 out of 115 patients were in group 1 and 57 ones were in group 2. the mean of age was 11.86 years (±5.3 sd). the median (range) of therapy and termination was 36 months (1-156 months) and 1 month (0-12 month) in group 2 and 36 month (24-240) and 51 months (15-120 months) in group 1 respectively. the percentage of reversible renal failure, proteinuria, abnormal serum calcium and magnesium, metabolic acidosis and urinary concentration defect was higher in group 2. (table 1) these differences were statistically significant (p<0.05). we found no correlation between ctc score and dosage of drugs, age, sex, history of radiotherapy or nephrotoxic agents (p>0.05). conclusion: mild to moderate tubular dysfunction has been observed in survivors of leukemia. routine follow-up of renal functions is recommended. v. tramma, k. giourtzis, v. fotoulaki, k. nousia-arvanitaki aristotle university, 4th pediatric clinic, thessaloniki, greece although cftr is expressed in the kidney, patients with cystic fibrosis (cf) have not been reported to have major renal abnormalities with the exception of urolithiasis. the aim of this study was to determine renal function and the potential risk factors for renal stone formation in cf patients older than 10 years of age. the findings of metabolic evaluation of 4 cf patients having confirmed urolithiasis (mean age: 22,37±5,78) were compared with those of 27 cf patients without urolithiasis (mean age: 24,25±4,03) and those of 10 healthy volunteers (mean age: 22,13±4,98). evaluation included plasma sodium (na), potassium (k), chloride, bun, creatinine, uric acid, calcium (ca), phosphorus (p), magnesium (mg) and parathormone (pth). twenty-four hour urine collection for creatinine, uric acid oxalates, ca, mg, k + , na + and microalbuminuria was also performed. glomerular filtration rate (gfr) was calculated and fresh urine samples were examined for the presence of crystals, erythrocytes, glycosuria and microorganisms. patients with cf and urolithiasis showed significantly increased values of bun (p: 0.012), pth (p: 0.018) and gfr (p: 0.003), very low urine mg levels (p: 0.014) and microalbuminuria (p: 0.034) as compared to cf patients without urolithiasis. there was no correlation of urolithiasis with hypercalciuria and hyperoxaluria. furthermore, all cf patients showed significantly increased pth levels (p: 0.032), very low urine mg levels (p: 0.024) and microalbuminuria (p: 0.024) as compared to healthy volunteers. conclusions: renal dysfunction was demonstrated in older cf patients, probably, secondary to the primary defect of renal chloride channels. extracellular volume regulators, such as hormones, may also be implied. urolithiasis may be the result of renal dysfunction. conclusions: the morbidity of hsp had obviously increased in recent years. the familial cases, the initial symptoms of no palpable purpura at onset and the cerebral, pulmonary, cardiac and pancreatic involvement should be paid attention. objectives of study: systemic lupus erythematosus (sle) is an autoimmune disease affecting multiple organs and tissues including central nerve system, cardiovascular system and kidney. although etiologic mechanisms of sle are incompletely known, overproduction of immunoglobulin g autoantibody may contribute to onset of this disease. while still incompletely understood, the etiology of systematic sle is considered to involve both genetic and environmental factors. we encountered two boys with severe sle from unrelated families and analyzed polymorphisms of the gene that encodes cytotoxic t-lymphocyte associated (ctla)-4, a protein important in t-cell activation and immune tolerance. abnormal function of the gene may participate in causation of autoimmune disease including sle, resulting in production of immunoglobulin against various self-antigens. case report: in family 1, a boy showed serious cardiovascular complications associated with heart failure while his mother also had clinically active sle including nephritis. a boy in family 2 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities; his paternal grandfather had died from fibrinous pneumonia caused by sle. results: analysis of the ctla-4 gene indicated that the boy in family 1 and his mother possess a gg genotype in ctla-4 exon 1 at +49 together with a 106-bp fragment length of the 3' untranslated region (utr) in exon 4. the boy in family 2 also showed gg at +49. no association with disease activity was found for polymorphism of the promoter region in exon 1 at -318 in either family. conclusions: disorders of the ctla-4 gene, especially a gg genotype in exon 1 at +49 and/or 106bp fragment length of the 3'utr in exon 4, may be involved in early development of sle in japanese children such as the boys described here. this disorder is transmitted mainly as x-linked trait, and is caused by mutations in the col4a5 gene encoding α5 chain of type iv collagen. in some families, x-linked as is associated with diffuse leiomyomatosis. we present clinical, pathologic and molecular-genetic findings in japanese family with this inheritance mode of as in association with leiomyomatosis. case report and results: as was diagnosed in a one-year-old boy with recurrent aspiration pneumonia caused by esophageal stenosis from leiomyomatosis. he had macroscopic hematuria and bilateral cataracts. diagnosis was confirmed by electron microscopy coupled with type iv collagen chain subtype staining in a renal biopsy specimen. thickening and irregular contours of the glomerular basement membrane (gbm) and splitting of the lamina densa were evident by electron microscopy. immunofluorescent staining for type iv collagen chains failed to show staining for α3 (iv), α4 (iv), or α5 (iv) in the gbm, associated with lack of α5 (iv) and α6 (iv) staining in the bm of bowman's capsule. his mother, who exhibited esophageal leiomyomatosis and is heterozygous for as, showed a discontinuous staining pattern for α5 (iv) along the epidermal bm. genetic analysis in the boy revealed the deletion of the first two exon of col4a6 together with deletion of the 5' end of col4a5. conclusion: identification of an as patient during infancy is extremely rare. clinical manifestations, including macrohematuria, cataracts and leiomyomatosis caused by the large deletion involved col4a5 to col4a6, led to early presentation with as. functional voiding disorders of the bladder occur in the absence of any anatomic/neurological abnormality and present with wetting. invasive urodynamic studies are discomforting, not easily available in emerging countries and costly. this study aims to validate non-invasive urodynamics. children below 12 years, with possible voiding disorders evaluated prospectively. non-invasive evaluation included history, examination, frequency volume charting, ultrasonography, urinalysis and renal functions. micturating cystourethrogram was carried out for children with urinary tract infection. all children underwent invasive urodynamic studies (uds) and the significance of association of the parameters of non-invasive assessment with invasive urodynamics was determined. the chi square test was used for statistical analysis using the epi 6 software. 34 children underwent invasive uds. the commonest abnormality was detrusor instability (di) in 21 (61.7%). dysynergic voiding (dv) noted in 6 (17.6%), lazy bladder in 2 and an occult neurogenic bladder in 2. the study was normal in 3. repressing the disease progression may be 1.5 mg/kg/day or more background: henoch-schoenlein purpura is classified into the small vessel vasculitis. there may be no reliable indicator of the disease activity. steroid treatment (1 mg/kg/day of prednisolone) has been thought of as a means with which alleviate abdominal pain. however, this dose seemed to be not effective to intervene the disease progression to nephritis. objectives: forty-three japanese children with henoch-schoenlein purpura were enrolled in this study. fibrinogen degradation product e-fraction (fdp-e) value was measured once or twice a week in the patients. coagulation factor xiii was simultaneously measured in 36 of the patients in the early phase of illness. with an aim to alleviate abdominal pain, 0.7-2.0 mg/kg/day of prednisolone had been administered to 15 of the patients. results: at presentation, only 16 of the 36 patients had low factor xiii activity. on the contrary, 33 of them had elevated serum fdp-e value. longitudinal fdp-e measurement revealed that patients whose fdp-e value normalized within the second weeks of illness had minimal risk of nephritis. in this group, 2 of 28 had microhematuria. in the other patients group with prolonged (after fourteen days of illness) elevation of fdp-e values, 8 of 15 had nephritis. furthermore, 7 of 8 had proteinuria after three months of illness. these 8 patients who had received prednisolone therapy with less than 1.5 mg/kg/day in the early phase of illness. the other 7 patients with 1.5 mg/kg/day or more prednisolone therapy had no nephritis. summary: the disease activity of hsp and hspn might reflect the duration of elevated serum fdp-e. more than 1.5mg/kg/day of prednisolone may repress the disease progression to nephrits. background: all major organs are involved more or less in thalassemia and most of them have been studied thoroughly in previous literature. renal system involvement has not been scrupulously scrutinized yet. method: in a randomized prospective study, renal findings of 58 children and young adults, aged 3-24 years, with thalassemia major (group 1) were compared to other 50 cases of thalassemia intermedia (group 2). blood urea nitrogen, serum creatinine, uric acid, calcium, phosphate, urinalysis, and sonographic findings were evaluated. results: mean age was 17±3.5 years in group 1 and 18±3.0 in group 2. mean serum ferritin level was 3503±201 ng/ml in group 1 vs. 871±81.8 ng/ml in thalassemia intermedia group (p<0.05). 92% of subjects of group 2 had received or was on hydroxyurea at the time of evaluation. serum uric acid was significantly higher in patients with thalassemia intermedia ( conclusion: significant renal involvement is not a frequent complication in children and young adults suffering from thalassemia. hyperuricemia and microscopic hematuria is more common in thalassemia intermedia than thalassemia major. case: a 13-year-old female patient was born at term (weight 3750 g, lenght 51 cm) and for aspiration of amniotic fluid required resuscitation and mechanical ventilation for 17 days. perinatal hypoxia was a cause of her acute renal failure but dialysis was not needed. patient's follow-up during next 12 yrs showed mild form of chronic renal failure (crf) without hypertension: serum creatinine (scr; range during follow-up [rdf] 95-112 μmol/l), glomerular filtration rate (gfr; rdf 66-73.8 ml/min/1,73 m 2 ) and p (rdf 30-180 mg/24 h). at the age 13yrs we performed renal biopsy (rb) because girl's p and scr increased (358 mg/24 h, 139 μmol/l, respectively) and gfr decreased (51 ml/min/1.73m 2 ). rb showed c1q-nephropathy (c1qn) with focal glomerular sclerosis and hyalinosis. c1qn is a rare disease and as a first diagnostic step is differentiation against lupus nephritis. progression of c1qn to crf is infrequent. probably two renal diseases were a cause of crf in our patient -hypoxic renal damage during neonatal period and c1qn. objective: renal dysfunction has been reported in survivors of neoplastic disease. early diagnosis of renal damage may decrease the morbidity in those with partial or complete remission. we studied the frequency of nephrotoxicity in pediatric patients whose therapy were completed. method: 108 pediatric cancer patients (44 f, 64 m) who were at least one year off therapy, enrolled in a prospective cross sectional study from 2003 to 2005 in oncology department of ali asgar children hospital. demographic data, cumulative dosages of anticancer drugs, history of other nephrotoxic agents, nephrectomy, radiotherapy were recorded. fasting blood and urine samples were collected to calculate fractional excretion of mg, ca, p, upr/ucr, clcr, urine osmolality and blood gas analysis. result: the mean of age was 12.9 years. 80 out of 108 patients had lymphoproliferative malignancies (group 1) and 28 had solid tumors (group 2). the mean of therapy was 35.44 month. treatment was discontinued for 52.48 month in average. the median of blood ca, p, mg, bicarbonate,and cr were 9.3 mg/dl, 3.6 mg/dl, 2.1 mg/dl, 22.65 meq/l and 0.6 mg/dl, respectively. the median of fractional excretion of ca was 0.81% this rate was 7.47% for p excretion and 2.4% for mg excretion. clcr was 135.3 ml/min/m 2 in median. the medians of urine osmolality was 850 mosmol/kg/h 2 o. the median of urine protein to urine creatinine ratio was 0.07 mg/mg. these values were not different between two groups (p>0.05) but urine concentration was defective in solid tumors group (p=0.001). mild to moderate nephrotoxicity was seen in 52.8% of cases. using binary logistic regression we found no correlated factor (p>0.05). conclusion: mild to moderate tubular dysfunction has been observed in survivors of chemotherapy. routine follow-up of renal functions are recommended. the study is to discuss the treatment of hemolytic uremic syndrome (hus) after acute stage. methods: there were 13 children who lived through acute stage of hus then continued treating. besides angiotensin converting enzyme inhibitors (acei) and early restriction of protein intake, the study was to use therapeutic schedule according to clinical classification, response to prednisone and pathological manifestation, which referred to clinical classification diagnosis and treatment of child with glomerulus disease (the program) established by nephrology group in pediatric branch of chinese medical association (cma). results: after 5 months to 12 years follow-up 4 mild type children maintained the normal blood pressure and renal function and urine examination, except for 1 recurrence. in 9 gravis type children 6 maintained the normal blood pressure and renal function and urine examination, another 3 children who manifested as durative abnormality of urine examination developed into end stage renal failure (esrd) and died in the 5th, 8th and 13th month at last. another 4 gravis type children untreated after stage of hus died in the 27th day to 48th day of the course. conclusion: it could improve the prognosis of children after acute stage of hus evidently to use therapeutic schedule according to clinical classification, pathological manifestation. objective: to find the prevalence of hematuria in patients with thalassemia major. methods: of total 1000 patients with thalassemia major under regular blood transfusion, 500 cases were randomly selected. history was reviewed and physical examination was done. urinalysis was performed in all the patients. in those with hematuria (5 or more rbc/hpf) or suspicious to hematuria (3-4 rbc/hpf) second urinalysis was done at the next transfusion time. more investigations were done in those with persistent hematuria. results: the patients had age range of 6 months to 32 years and male to female ratio was 1.05. hematuria was detected in 20 (4%) and suspicious in 33 patients (6.6%). sixty four percent of the patients with hematuria were female and it was persistent in urinalysis in 90% of cases. in 81% of the patients with hematuria, blood transfusion was started before the end of first year. in those with hematuria or suspicious to hematuria, 4% had sterile pyuria and 16% had proteinuria (these figures were 2.1% and 1.4% respectively, in those without hematuria). hypertension was not detected, but 2 patients had secondary diabetes mellitus. conclusion: hematuria is not uncommon in patients with thalassemia major and is more prevalent in girls and in those with early transfusion. background: it has been widely recognized that cyclosporine a (cya) is a useful immunosuppressive drug in renal transplantation. although it has been also accepted that cya is an effective drug for pediatric nephrotic syndrome in the past two decades, the effective serum concentrations are not revealed. the functional roles of cya has been reported that cya inhibits the production of interleukin 2 (il-2) in vivo and in vitro. aim: in this study, we investigated the correlation of serum concentrations of cya levels with il-2 levels in pediatric nephrotic syndrome cases. methods: seven children (6 boys and 1 girl, mean age 9.5±4.24 years) with minimal change nephritic syndrome were enrolled in this investigation. cya (mean dose, 3.49±0.88 mg/kg/day) was administrated in two divided doses before meal with or without administration of predonisolone. blood samples were collected just before, 1, 2, 3 and 4 hours after administration of cya. the serum concentrations of cya and il-2 were measured immediately. results: the peak blood concentrations of serum cya were observed at 1 hour after administration. the concentrations of serum il-2 levels reduced at 1 hour after administration of cya, and kept the same levels during 4 hours afterwards. the serum concentrations of cya which inhibited more than 80% of the serum concentrations of il-2 required 500 ng hr/ml. conclusions: we confirmed that cya inhibited the production of il-2 in children with nephrotic syndrome. these findings suggest that the necessary serum concentrations of cya to maintain the sufficient suppressive rate were more than 500 ng hr/ml in pediatric nephrotic syndrome. this study aimed to evaluate the circulating angiotensins in female adolescents with type 1 diabetes (dm1) and to compare with the results obtained in healthy age-matched adolescents to disclose possible changes in plasma peptide concentrations that could be related to microalbuminuria and metabolic control. patients were divided as female adolescents with dm1 (n=25) and adolescent age-matched controls (n=18). diabetic patients were evaluated at our endocrinology center and healthy adolescents were selected from our primary care unit. plasma levels of angiotensin (ang) i, ang ii and ang-(1-7) were determined by radioimmunoassay. glycohemoglobin and microalbuminuria were also measured. results were expressed as medians or means and standard deviation. kruskal wallis was used for median comparisons and t-test for means. the level of significance was p<0.05. adolescent dm1 patients exhibited high levels of glycohemoglobin (9.5±0.4%). microalbuminuria was detected in 5 (20%) patients with a disease duration of 8.4±0.7 years. angiotensin concentrations were significantly increased in dm1 patients (p<0.05 compared to controls) and ang-(1-7) levels were 4-fold higher than control values. on the other hand, the levels of ang-(1-7) in microalbuminuric patients were significantly lower than in non-microalbuminuric diabetic adolescents (p<0.05). the comparisons between ratios of ang-(1-7)/ang i and of ang ii/ang i suggested a predominance of ang ii formation rather than ang-(1-7) in microalbuminuric diabetics when compared to normoalbuminuric patients. our results showed an overall increase of angiotensins in a young female diabetic population, and further suggested a pathophysiological role for angiotensin-(1-7) in dm1. the pediatric nephrologist is often faced with the difficulty of determining adequate iron supplementation in children with chronic kidney disease (ckd). soluble transferrin receptor (stfr) and the stfr to log(ferritin) ratio (stfr-f index) have been proposed as markers of iron deficiency (id) independent of inflammation; however, their relationship with c-reactive protein (crp) and their age dependency have not been established. we therefore embarked on a prospective study of 436 healthy children undergoing minor surgery to determine reference ranges for stfr (dade behring n-latex stfr analyser, dade behring bn prospec) and stfr-f index. we studied the relationship between crp and ferritin, transferrin, stfr and stfr-f index. we also compared the relationship between mean corpuscular volume (mcv) and ferritin, stfr and stfr-f index in 205 children. results: for ages 0. .0001, 0.0050) with mcv, which we used as a marker of id in the absence of a non-invasive gold-standard; however, only stfr-f index, but not ferritin, transferrin and stfr, was independent of crp. this study shows that ferritin, transferrin, and stfr, but not stfr-index, are dependent on acute phase reactions. it is therefore hypothesized that stfr-f index provides a more useful marker for monitoring the iron status in ckd patients. conclusions: low osmolality is a crucial factor to facilitate water absorption at least in the rat small intestine, while the absorption of sodium may be influenced by the concentration of sodium and glucose. (definition iccs). standard treatment consisted of general advice on voiding and drinking habits, alarm treatment and occasionally vasopressin. constipation was diagnosed on clinical considerations (history, stool charts, physical examination, occasionally x-ray). all patients received general instructions according to bowel habits. laxatives were prescribed when the patient was diagnosed as constipated. treatment goal was daily bowel movements. treatment results were evaluated 3 months and 2 years after discharge. results: 151 patients were included. mean follow-up was 2.2 yrs. overall success rate (full response) was 80.8% (3 months) and 72.6% (2 years). laxative use: 11.2% (n=17) of the patients received laxatives, 88% (n=133) did not. in 1 patient information was lost. there was no significant difference in success rate between the laxative group compared with the non-laxative group (p=0.14, chi-square). treatment modality: 6.0% (n=9) received general advice only without laxatives, all but one had a full response. 90.1% (n=136) were treated with advice and alarm, 16 (10.6%) of them received laxatives. response to alarm treatment was 82.5%. no significant difference in success rate between the laxative and non-laxative group (p=0.13, chi-square). 1 patient was dry after vasopressin and laxatives. conclusion: the majority of patients with mse can achieve nocturnal continence without laxatives. constipation treatment with laxatives may be supportive, but is not essential in the treatment of mse. aim: hypocalcemic tetany is a known complication of plasmapheresis. we studied the changes in ionised and total calcium, and magnesium concentrations during plasmapheresis, with and without supplementing the replacement fluid with calcium and magnesium. methods: plasmapheresis was carried out by using 4.5% human albumin solution (has) with or without supplements for the first 85% of the exchange, and fresh frozen plasma (ffp) for the last 15%. we measured ionised and total calcium and total magnesium at the beginning and end of the has, and after 15 minutes of ffp infusion. results: we undertook 31 pairs of plasmapheresis runs with and without supplements in 11 children who had a variety of renal conditions. during the exchange with unsupplemented has, the total calcium fell from 2.02 to 1.70 mmol/l (ci 9.9-20.3, p<0.000), the ionised calcium fell from 1. have raised significant problems in minor surgeries. but the developmental mechanism of ponv is not clear until now. previously, we have experienced a case with ihn and ponv who showed extremely high plasma antidiuretic hormone (adh) level at the onset of ihn and that elevated adh level induced by minor surgery was supposed a trigger of ihn and ponv. in this study we investigated various values including plasma adh in cases taking kidney biopsy in order to clarify the mechanism of ihn and ponv. methods: fifteen patients taking percutaneous kidney biopsy were study subjects (mean age 10.5 years). plasma adh, serum electrolytes and osmolality were measured before and 4-5 hours after kidney biopsy. urine samples were collected to measure electrolytes and osmolality. results: high plasma adh level (19.9±8.33 pg/ml) was observed in 9 out of 15 subjects (60%). serum sodium level dropped significantly in these cases. six of 9 cases showed ponv, we divided all 15 cases into 2 groups: ponv group and non-ponv group. the result was that plasma adh level was significantly high in ponv group. conclusion: our study make it clear that elevated plasma adh level is frequently seen in children taking kidney biopsy and suggest that hydration with hypotonic saline solution after surgery is inappropriate because of the risk of developing ihn. it also become clear that high plasma adh level might lead to ponv as the same mechanism seen in motion sickness. it is suggested that adh secretion by stress after minor surgery is associated with not only ihn but also the onset mechanism of ponv. polyarteritis nodosa (pan) occurs more commonly in patients with familial mediterranean fever (fmf) and visceral hematomas are seen in almost half of the patients. we report here a 14 year-old girl with pan and fmf presented with multiple visceral hematomas. the patient was on colchicine therapy for four years because of fmf but uncompliant to therapy. she addmitted with the complaints of fever, malaise, abdominal pain and artralgia lasting for two months. she was pale and extremely cachectic with atrophic muscles of extremities. she had fever, hypertension, hepatosplenomegaly and arthritis. she had anemia with normal renal and hepatic function tests, albumin levels, and electrolytes. multiple hypoechogenic mass lesions were detected on liver and bilateral kidneys on ultrasonography and computerised tomography and diagnosed to be hematomas by laparascopic examination. urinalysis, hematological tests for bleeding and blood marrow examinations were normal. bacterial cultures and serological tests did not reveal any infectious agent. serum complement levels were normal with negative antinuclear antibody, anti-dna, p and c antineutrophil cytoplasmic antibodies. renal angiography showed multiple aneurysms in bilateral renal arteries leading to the diagnosis of pan. she was successfully treated with intravenous pulse methylprednisolone followed by oral perdnisolone and oral cyclophosphamide together with colchicine and antihypertensive agents. she has been followed up for four years without any complaints and normal laboratory and radiological findings except multiple scar formations on kidneys on dmsa-renal scanning. results: the stone-free rate was 86% after one eswl session. the above rate increased to 92% and 96% after the second and the third session respectively. regarding surgical treatment with pcnl, the overall stone-free rate was 93%. in 3 children initially treated with pcnl, an eswl session was performed later successfully, for residual calculi. open surgical removal was required in 9 children with structural anomalies. the patients with staghorn calculi underwent nephrolithotomy combined with eswl in cases of residual fragments. 12 patients underwent ureterscopic procedures to address ureteral stones and complete fragment removal was obtained. no major sideeffect were observed, during the above procedures. conclusions: it seems that the advances in instrument technology provide a variety of safe and effective methods in the management of paediatric urolithiasis. the incidence of open surgery has thus fallen. minimally invasive methods must form the first choice of treatment, while open surgery should be undertaken mainly in cases of coexisting congenital abnormalities. in all children the following parameters were estimated: a) timetable of ne, b) feeling/volume chart (frequency and biggest quantity of urination=functional capacity of bladder), c) ultrasound of urinary tract (size of kidneys, bladder capacity, bladder wall thickness, postvoiding residual urine) and d) urodynamic parameters (uroflowmetry and water cytometry). the ud bladder parameters were then correlated with the us and voiding diary findings. results: all children had sufficient data registered to allow reliable analysis. ud studies showed that children with mild pne had normal urodynamics findings, us parameters and voiding diary findings as well. ud studies reveal a relatively high incidence of instability in children with moderate and mainly in those with serious ne. conclusions: in children with pne, urodynamics did not have a significant additional value compared to baseline diagnostics and it should be avoided. on the contrary, findings from urodynamic studies in children with serious ne show that it has a useful role in this type of enuresis evaluation and management. objectives of study: hyperlipidemia, especially when started during early childhood will increase the risk of atherosclerosis. it is also a major risk factor for allograft nephropathy and post-transplant hyperlipidemia, so its diagnosis and treatment is highly suggested. in this study we have evaluated the effect of hemodialysis on the lipid profile of children with end stage renal disease (esrd). methods: twenty-two children with esrd who were on maintenance hemodialysis in shiraz pediatric hemodialysis unit were studied. they were asked not to take greater than 30% of their total daily calories as fat at least 1 month before sampling. after a 12-hour overnight fasting and before starting dialysis, blood samples were taken for lipid profiles. for each patient with total cholesterol, tg or ldl-c levels more than 95th percentile for age and gender or hdl-c level less than 35 mg/dl, was defined as dyslipidemia. results: nineteen out of 22 children (86.4%) had abnormal lipid profiles. atherogenic factor of tg/hdl-c ratio more than 5 as a major risk factor for cardiovascular disease was in 86%. conclusion: dyslipidemia is common in hemodialysed children. so, hemodialysis set-up change and antilipimic medication, and replacement of l-carnitinine is recommended for correction of dyslipidemia in this group of patients. objectives of study: bipolar renal length measurement is an integral part of the assessment of urinary tract in childhood, and is routinely performed on ultrasonography and renal scintigraphy investigation. correlation between kidney size measurement on ultrasonography and dimercaptosuccinic acid (dmsa) scintigraphy is not well recognized. the purpose of this study was to comparison renal size measured by dmsa scintigraphy and ultrasonography to find if there is acceptable agreement between renal lengths by these two methods. methods: as cross sectional retrospective study, 90 patients enrol in this study and their dmsa scan results and kidney ultrasonography reports compared. the agreement between renal size measured by two methods for left and right kidneys were evaluated separately using bland-altman plot. pearson's correlation coefficient was used to examine their correlation. statistical significance was calculated by paired-student t-test. the same tests were used to for kidneys with normal dmsa scans. results: correlation coefficient showed close correlation between kidney length measured by ultrasound and dmsa scan, but there were significant differences between two methods (paired t-test, p<0.0001). comparison between renal size measured by ultrasonography and dmsa scan using the methods of bland & altman plot in all patients and the group with normal kidneys showed a systematic bias of about +6.5 mm for left and +6.3 mm for right kidneys. conclusion: despite of close correlation between dmsa scan and ultrasonography for kidney length measurement; kidney size is overestimated by about 10 percent in dmsa scan study and this matter must be considered in practice. medical treatment of cystinuria is often considered disappointing. patients undergo frequent surgery which is often followed by early relapse. the aim of our study was to prospectively evaluate, in a paediatric population, the efficacy of a conservative medical approach for long-term treatment of cystinuria, to prevent the formation of new renal stones and reduce the number and dimension of pre-existing stones. twenty-one stone former cystinuric patients were treated with a combined approach which included cystine-binding drugs. free and bound urine cystine levels were routinely measured every four months. drug dosage was adjusted in order to maintain a steady free urine cystine level below 100 mmol/mmol creatinine (a three fold increase of normal level). in the 19 patients who completed the study, renal stone episodes were reduced from 0.28 to 0.03 episodes/year, and in several patients the number and dimension of pre-existing renal stones were reduced. during the entire follow-up, percutaneous lithotripsy to remove an obstructive stone was required in only one subject. no relapse was observed 12 months after treatment. the dosage required to achieve target levels was very closely correlated to patient body weight: older children required a lower dose to achieve target levels. in conclusion: medical management of cystinuria is feasible. the treatment must be personalised, at least in pediatric age. the amount of required drug is strictly depending from body size. it is mandatory to obtain a low free urine cystine level before any invasive procedure to reduce the risk of early relapse. objective: to study the pathophysiology of nutcracker syndrome (ns) and to assess the role of the upright position imaging and superior mesenteric artery (sma) angle measurement in the diagnosis. methods: doppler us findings in 23 children with ns and in 26 healthy control subjects were compared. the mesenteric angle, peak velocity (pv) and anteroposterior (ap) diameter of the left renal vein (lrv) at the hilar and aortomesenteric portions were measured in both the supine and upright positions. the means ±sd of the sma angle, ap diameter and pv ratio between the two portions were calculated and cut-off levels for the diagnosis of ns were established. results: the diameter and pv ratios were significantly different between the patient and control groups both in the supine and upright positions (p<0.001). differences (d) between the supine and upright positions were also significant for the diameter of the lrv at the aortomesenteric portion, diameter ratio and sma angle in both groups. upright position imaging revealed comparatively narrower sma angles and more pronounced entrapment findings in patients with ns. the sma angle measurement had a sensitivity of 69.6% and a specificity of 61.5% in the supine position and 87.0% and 76.9% in the upright position when the cut-off values were set to less than 41° and 21°, respectively. the upright position has significant effects on the lrv hemodynamics and angle of sma both in patients and healthy subjects. sma angle measurement may be a useful adjunct parameter in the diagnosis of ns. ). in addition, a statistically higher rate of pathological abnormalities on renal biopsy was noted in the group with microscopic hematuria combined with proteinuria and also in cases with more severe hematuria. conclusions: school urinary mass screening has greatly contributed to diagnosing chronic renal diseases. continuous medical observation is required when abnormal urinalysis is observed, and a more aggressive medical approach such as renal biopsy should also be performed if necessary. this study compared the outcome of children with proliferative ln (who class iii/iv) using a new protocol comprising pulse intravenous methylprednisolone, mmf +/-cyclosporine, with standard prednisolone and cyclophosphamide/azathioprine. method: twenty-three children with proliferative ln (age range at diagnosis 3.7-18.6 years) who were followed up for 6.9-4.5 (range 1.3-21.0) years, were included in this retrospective study. group i (n=11) received prednisolone with cyclophosphamide and/or azathioprine. group ii (n=12) received the combined mmf protocol with mmf dose of 1200 mg/m 2 /day. poor outcome was defined as death or chronic renal failure. survival analysis was performed using the log-rank test. effect of treatment on growth at last follow-up was assessed using height standard deviation score (htsds). differences between the groups were analyzed using the mann-whitney and fisher's exact test. results: at last follow-up, significantly more group i compared to group ii patients had higher serological activity as defined by low serum complement c3 (50% vs 0% respectively, p=0.014). in addition, 8-year actuarial survival was higher in group ii (100%) compared to group i (61%). all the group ii patients achieved complete remission of proteinuria compared to group i (0.01±0.06 vs 0.79±1.0 g/d/1.73 m 2 respectively, p=0.002). group ii patients also had lower htsds on long-term follow-up compared to group i (-0.26±1.05 vs -1.96±1.73 respectively, p=0.025). conclusion: combination immunosuppressive protocol involving mmf +/-cyclosporine resulted in better renal outcome in children with proliferative ln without compromising on growth. this regimen allowed steroid tapering to alternate day dosing without increasing lupus activity. background: a full dose of corticosteroid is required to induce complete remission (cr) in steroidsensitive nephrotic syndrome (ssns), unless it is possible to taper and discontinue along with the course after cr. however, the mechanism of this change in steroid sensitivity remains unknown. p-glycoprotein (pgp) has a function to eliminate given corticosteroids from cytoplasm, which results in inducing corticosteroid resistance. therefore, we analyzed a drug delivery perspective using the real-time polymerase chain reaction (pcr) of multiple drug-resistant gene 1 (mdr1; encoding pgp) messenger rna (mrna) expression. patients and methods: fourteen patients with steroid-sensitive nephrotic syndrome (ssns; male/ female: 14/0, age: 1-23 years old; mean 10.4) were enrolled in this study. mdr1 mrna gene expression of peripheral blood nucleated cells (pbnc), before and after cr (a total of nineteen sets of blood samples), were quantified using real-time pcr and then carried for analysis. results: the mdr1 mrna levels before cr were variable in each patient. however, there was an apparent decrease in the mdr1 gene expression of pbnc after cr (p<0.003). the results suggest that pgp may play a role in the ability to taper corticosteroids after cr in ssns. : 6 week prednisone 60 mg/m 2 /day + 6 weeks 40 mg/m 2 every other day). all other patients (b) received daily prednisone 1.5-2 mg/kg/day for 8 weeks and 30-50% of initial dose for 1 week, followed by alternate day steroids (41 week) with tapering by 2.5 mg every 6-8 weeks down to 2.5-5 mg. "frequent relapses" (less than 2 months after discontinuation of initial steroid therapy or of first relapse therapy) were treated with chlorambucil 0.15-0.2 mg/kg/day for 8 weeks and half of this dose for 6-10 months. results: seven patients (with long treatment) were lost to follow-up and 48 were studied. six of 11 (55%) of a had a relapse 4.6±1.7 months after the end of initial therapy; 3 became infrequent and 3 frequent relapsers. 19 of 37 (51%) of b relapsed 7.8±1.3 months after the end of initial therapy; 14 became infrequent and 5 frequent relapsers. frequent relapsers (27% in a and 14% in b) were treated with chlorambucil and all but one achieved long remission (>1 year). conclusions: first relapse occurred later after onset of ssns in patients with long (50 weeks) as compared to short (12 weeks) initial steroid therapy but the time interval between the end of initial therapy and the first relapse and the proportion of relapsers were similar. longer initial therapy may result in a lower number of frequent relapsers. nearly all patients had long remissions periods that were, however, achieved at the expense of early administration of chlorambucil. conclusions: the medium age of pts with metabolic stones was found to be higher than the medium age of pts with infectious stones. the familial occurrence of kidney stones was found to be important 46%. the ultrasonographic examination is the most important one. the stones composed by calcium oxalate and calcium phosphate were found to have the highest percentage. metabolic abnormalities were found in 75% of patients and hypercalciuria was the most common disorder. hypocitraturia is considered to be a risk factor the calcium stones. in an attempt to explore the new treatment for the childhood-onset intractable steroid-dependent nephrotic syndrome (sdns), we have recently performed the treatment with high-dose mizoribine (mzr), the inhibitor of inosine monophosphate dehydrogenase, and suplatast tosilate dimethylsulfonium std), a selective th2 cytokine inhibitor, which were both made in japan. mzr has been commonly used for the treatment of frequently relapsing sdns in japan at a dose of 3-4 mg/kg/day (maximally 150 mg/day) divided into two doses (kidney int 58: 317,2000). we used high-dose mzr (mean: 10.1 mg/kg/day) once before morning meal for 9 adolescent patients with frequently relapsing sdns who had been treated with long-term cyclosporine (csa) resulted in moderate to severe csa nephropathy. with this treatment for 2 years, seven out of 9 patients weaned off csa and experienced less relapses without apparent adverse effects by high-dose mzr. std is a both il-4 and il-5 inhibitor and commonly used for childhood asthma. we used std at a dose which is for the treatment of asthma for 13 children with sdns (mean 9.2 years) without previous csa treatment. after one year follow-up with std treatment, the relapse rate of nephrosis was decreased from 1.54±1.20 to 0.15±0.56 per year (p=0.0008 by wilcoxon signed-ranks test), where as the dosage of orally given predonisolone was also decreased from 0.19±0.21 to 0.04±0.05 mg/kg/day (p=0.0187 by wilcoxon signed-ranks test). objectives of study: to evaluate the efficacy and safety of long-term cya treatment for pediatric sle patients. pediatric sle patients in their teens suffer from many relapses and severe side effects caused by steroid and cyclophosphamide. there have hardly been any reports on the long-term cya treatment in children. methods: we retrospectively compiled 6 cases of childhood-onset sle female patients (mean: 12.1 years) admitted to our department from 1995 to 2004. the initial treatment was methylprednisolone pulse therapy followed by prednisolone (psl). at the onset, 4 patients had class 2 lupus nephritis and 2 showed class 3. after several relapses, cya was added and used for 20 to 68 months. the dose of cya ranged from 2.8 to 4.9 mg/kg/day, and the target trough level from 50 to 80 ng/ml. results: under this low-dose cya treatment, 5 patients had no relapse while 1 had a relapse after 49 months. in all patients, psl was reduced to alternate day treatment (mean: 10.8 mg/2 days), and 3 patients under 14 years gained the target height. of all patients, 5 developed hypertrichosis, 1 gingival hyperplasia, 1 transient elevation of s-cr with acute gastro-enteritis. although 1 case had elevated s-cr after 20 months of cya treatment, it returned to normal level within 3 months after the cessation of cya. five patients had second biopsy after 2 years, and 2 showed mild tubulointerstitial (t-i) changes. two had third biopsy after 5 years and both showed mild t-i changes only. the presence of t-i changes had no relation to s-cr, u-beta2 mg and u-nag. conclusion: low-dose cya treatment might be an effective and safe second line treatment for sle patients with many relapses in teens. it is also important to perform renal biopsy periodically to detect cya-induced renal damage which hardly shows any abnormalities in blood or urinary tests. 3 hypersensitivity to inulin is rare; two cases of food allergy and some cases of allergy after inulin infusion have been reported. an 11-year-old boy suffering from severe iga nephropathy (igan) is reported with both anaphylactic reaction and concomitant relapse of his nephropathy due to inulin infusion, used for measuring gfr 2 years after first symptoms. pruritus, sibilants and cough were observed during a first renal function test. prick and intradermal tests were negative for inulin. the patient presented with pallor and asthenia during a second inulin infusion performed under dexchlorpheniramin, leading to immediate infusion stop. he was read mitted because of fatigue and nausea; acute renal failure was diagnosed 4 days after inulin infusion. a drug-induced acute interstitial nephritis was first suspected. however, due to the presence of macroscopic hematuria and proteinuria, a renal biopsy was performed and showed acute proliferative relapse of igan. few data are available about inulin-induced hypersensitivity. chandra described anaphylaxis and cardiorespiratory arrest immediately after administration of sinistrin. a retrospective study of all recorded cases of hypersensitivity associated with renal function tests was performed by our pharmacovigilance unit. 6,328 tests using inulin clearance were realized both in adults and children; 31 patients experienced side effects which were divided into 3 groups: respiratory symptoms, rash and general signs. most side effects were minor and no life threatening complication occurred. the underlying mechanism of inulin hypersensitivity is not well known. although 55% of patients with inulin-associated hypersensitivity underwent a first renal function test, we can speculate that presensitization with food inulin may occur, sometimes leading to severe problems such as in our patient with iga-mediated immunological dysregulation. . we have previously demonstrated a composite heterozygous nphs2 mutation of both v165x and r168h in a chinese patient with srns. however, it is not clear the molecular mechanisms of mutant podocinlead to proteinuria. some evidences proved the possible interaction between podocin and trpc6. this study explored the effects of mutant podocin on the free cytosolic ca2+ and apoptosis of podocyte in order to clarify the possible causative mechanism of mutant podocin. methods: 1. the pdsred2 n1-wild/mutant podocin was constructed by using site-directed mutagenesis. 2. mouse podocyte clone was cultured and transfected with pdsred2 n1-wild/mutant podocin. 3. free cytosolic ca2+ was measured using the fluorescent indicator, fluo 3-am. results: the low level of free cytosolic ca2+ was detected in normal podocyte and the transfected podocytes with r168h mutant podocin. the v165x mutant podocin increased the free cytosolic ca2+more evidently than the over-express podocin in transfected podocytes. podocyte apoptosis were not detected in the blank-vector (just pcdna 3.0) transfected podocytes and normal podocyte. the v165x and r168h mutant podocin increased the podocyte apoptosis more evidently than the over-express podocin in transfected podocytes. conclusions: the v165x mutant podocin might induce podocyte apoptosis via the increment of free cytosolic ca2+. however, whether the increment of free cytosolic ca2+ is induced by trpc6 and the involved signal pathway should be further investigated. y. xing, q. fan, j. ding objectives of study: podocytes slit diaphragm (sd) associated molecules (nephrin, podocin and cd2ap) play a critical role on maintaining the integrity of glomerular filter. vegf is produced by podocyte, and acts on endothelium and podocyte itself. but, it is not clear whether there are some relationships between vegf and sd associated molecules. our study detected the expression of sd associated molecules and vegf in adriamycin (adr) nephrotic rats. methods: the adr rat was established by adr injection. distributions of sd molecules and vegf were detected by immunochemistry. the mrna and protein of sd molecules and vegf was examined by real-time pcr and western, respectively. nephrin phosphorylation were detected by immunoprecipitation. results: distribution of nephrin, podocin and cd2ap changed evidently, and the staining intensity of vegf decreased evidently. nephrin mrna increased at day 7, and returned to the normal at day 14 and 28; podocin and cd2ap mrna constantly increased from day 3 until day 28. the protein of nephrin increased at day 7 until day 28; podocin was dramatically upregulated at day 7, and thereafter recovered again, but was downregulated at day 28; cd2ap prominently increased at day 14 and day 28. tyrosine phosphorylation of nephrin was decreased evidently at day 28, and vegf mrna did not show significantly changes at any time points observed. however, vegf protein reduced significantly from the 7 th day, and also reduced evidently at days 14 and days 28. conclusion: the abnormality of nephrin, podocin and cd2ap may be one of the mechanisms that lead to proteinuria in adr-induced nephrotic rats. the occurrence of proteinuria in adr rats may be also associated with the reduced vegf protein, which may be related with the reduction of nephrin phosphorylation. these results suggested there may be some relationship between vegf and sd molecules. the objectives of study: mutations in genes encoding structural proteins of slit diaphragm can lead to nephritic syndrome. just recently, another gene trpc6 mutation was identified in autosomal dominant fsgs. trpc6 encodes ion channel protein trpc6, whose expression has not been clarified completely in kidney. this study aims to explore the expression and distribution of trpc6 in normal human, mouse and rat renal tissue and the mouse podocyte clone (mpc5). methods: distributions of trpc6 in normal human, mouse and rat renal tissue and cultured podocyte was observed with immunochemistry staining. the mrna expression of trpc1, 2, 3, 4, 5 and 6 was detected by using rt-pcr. the protein expression of trpc6 in human, mouse and rat renal cortex and differentiated mpc5 was detected with western. results: trpc6 showed weak staining in glomeruli and strong in renal tubules and vessels in human kidney, however, strong in glomeruli and was mainly distributed along the capillary loops and mesangium in mouse and rat kidney. the staining of trpc6 was observed in differentiated mpc5, which is distributed evenly on the cell membrane. the specific pcr band of trpc1, 2, 3, 4, 5 and 6 was detected in mouse kidney and differentiated mpc5. the sequence of the amplified pcr products is same as that published in genebank. the specific 106kda protein band of trpc6 was detected in normal human, mouse renal cortex and differentiated mpc5. conclusion: the expression of trpc6 was verified in normal human, mouse and rat kidneys and in differentiated mpc5. these results will benefit for further screening the possible mutation of trpc6 in acquired nephrotic syndrome, and investigating the relationship between trpc6 and the proteinuria-related podocyte molecules. methods: twenty children with kd (13 boys and 7 girls, aged from 3 to 78 months) were enrolled in our study. kidney sizes (including kidney length and kidney volume) were measured during acute stage in these patients. twenty age-and sex-matched healthy children and 15 febrile children served as healthy controls and fever controls. left kidney length and age were used for correlation analysis and analysis of covariance. results: kidney lengths in patients with kd were significantly larger than those of healthy children (p<0.001). the mean sd score of kidney length was 2.54±0.97 for these patients (p<0.001, vs -0.23±0.82 in normal control). kidney volume analysis yields the similar result (51.83±17.93cm 3 vs 35.62±11.24cm 3 , p=0.001). there was no kidney enlargement in the fever controls. up to 70% of the children with kd have absolute nephromegaly (>mean+2sd). this incidence is as frequent as that of lymphadenopathy and extremities change, the 2 diagnostic criteria of kd. conclusion: these results confirm the presence of large kidneys in the children with kd and also provide another useful indicator for kd diagnosis if the diagnostic criteria is not yet well established. during renal inflammation macrophages infiltrate the renal parenchyma, and their number correlates with the intensity of inflammation. macrophage migration inhibitory factor (mif) was described originally to be a product of t-cells and macrophages. mif plays an important role in renal tissue injury. to our knowledge, the studies that assessed the role of macrophages in acute renal infection were few and the role of mif was not evaluated. the aim of this study was to assess mif in uti and compare the urinary excretion of mif in pyelonephritis, cyctitis and also control group to find a non-invasive and sensitive method to differentiate them. in this prospective case-control study 31 pediatric patients with uti (25 patients with acute pyelonephritis, 8 patients with acute cystitis) and 40 healthy children were recruited. urine mif concentration was quantitated by elisa and corrected for urine creatinine. the mean ratios of urine mif/cr were calculated as 66.14 (sem=23.78) pg/μmol creatinine in acute pyelonephritis, 1.58 (sem=0.59) in acute cystitis and 1.85 (sem=0.35) in healthy individuals. urine mif/cr ratio was significantly higher in pyelonephritis than the ones in acute cystitis (p=0.0001) and control (p=0.0001). roc analysis was demonstrated that urine mif/cr ratio could considered potentially useful index to detect acute pyelonephritis [p=0.0001, area under curve (auc)=0.959]. the optimal cut-point of 5.39 pg/μmol creatinine for urine mif/cr ratio could potentially separates acute pyelonephritis patients from healthy individuals (sensitivity and specificity of 92% and 92.5%, respectively). the underlying histopathological characteristics in biopsied renal diseases are of great importance in determining the long-term prognosis and provides useful information in clinical practice. ethnicity seems to play a critical role in the epidemiology of biopsied renal diseases the aim of this study is to provide data of clinical manifestations of biopsy-proven native renal diseases in iranian children. in this retrospective study, 476 iranian children who were diagnosed as renal disease between 1980 and january 2003, were evaluated. diffuse and focal mesangial proliferative glomerulonephritis was present in 31.5% of all biopsies performed. mpgn, fsgs and mcd were observed in 9.2%, 10.2% and 13.4% the most common clinical syndrome at any age is nephrotic syndrome (50.4%), followed by nephritic syndrome (13.8%), nephrotic-nephritic syndrome (13.4%), recurrent macroscopic hematuria (7.3%), asymptomatic urine abnormalities (aua) (7.7%) and azotemia was seen in 6.7% of patients. mesangial proliferatiove gn (18/70=25.7%), poststreptococal gn (15/70=21.4%) are the most frequent pathologies with acute nephritic syndrome presentation. the most frequent causes of aua were mesangial proliferative gn and hsp. thrombotic microangiopathy (hus) was the most prevalent cause of arf. inthis study, chronic tubulo interstitial nephritis (33.3%) and alport (13.3%) were the most common causes of crf presentation in our patients. in conclusion, mpgn remains the most common histopathological subtype in children with renal biopsied disease. the incidence of fsgs continues to be high in iranian children. the aim of this study is to assess postnatal kidney volume development and to compare the intrauterine and extrauterine kidney growth curves in premature infants. one hundred neonates were enrolled in this study. all infants had their kidney volumes measured by renal ultrasound examination. group ga consisted of 44 neonates whom were evaluated within 48 hours after birth, and their gestational ages were used in the analysis. group ca included 56 premature infants born before 34 weeks of gestation and was evaluated 14-96 days after birth, and their conceptional ages were used in the analysis. left kidney volume, body weight, body height and age were used in the correlation analysis. kidney volumes in group ca infants were significantly larger before 31 weeks of age, but smaller after 31 weeks of age than those of group ga infants (p=0.001). there was a significantly better growth in body weight (p=0.001) and body height (p<0.001) in group ga infants. however, a larger kidney volume was noted in group ca infants with the same body weight (p<0.001). conclusion: chart of postnatal growth of normal kidney volume before 40 weeks of conceptional age in premature infants is presented. our data suggests that intrauterine growth may have a regulatory influence on kidney growth, and the reduced kidney volume in the premature infants may start from the early extrauterine period. objectives of study: to illuminate the role of prohibitin (phb), a tumor suppressor which inhibit cell proliferation by repressing e2f-mediated transcription, in tubulointerstitial fibrosis (tif). methods: renal biopsy specimens were obtained from 48 children with primary glomerulonephritis. phb and α-sma proteins expression were detected by immunohistochemistry. subcellular location of phb in nrk-49f was detected by confocal microscope. changes of phb protein and mrna expression in cells upon tgf-β1 stimulation were detected. after transfected with phb plasmid, cell cycle and α-sma protein and mrna expression in cells treated with or without tgf-β1 were detected. results: phb protein was found at normal renal tissues, with a positive distribution in interstitial cells and tubular epithelial cells. phb was down-regulated in tissues with tif and negatively correlated with tif degrees (p<0.05). phb is majority located at cytoplasm as well as at nucleus in nrk-49f. phb protein and mrna expression in cells were decreased when treated with tgf-β1, and the effects were both time-dependent and dose-dependent. extraneous phb inhibited cells proliferation induced by tgf-β1, and phb over-expressing cells failed to enter the cell cycle compared with non-transfected cells (p<0.01). α-sma was not expressed in control cells while de novo expression of α-sma in cells upon tgf-β1 stimulation was increased. overexpression of phb did not affect basic α-sma expression but dramatically repressed tgf-β1-initiated α-sma expression (p<0.01). conclusions: extraneous phb suppresses renal interstitial fibroblasts proliferation and cell phenotypic change induced by tgf-β1, which indicates phb as a potential target to halt tif progression. results: the prevalence of urine abnormalities of first screening was over 5.00%, and that of the second screening was about 1.00%. the prevalence was different with various methods. the specificity of method b was higher than method a. testing two urine samples for each child had higher specificity. the direct cost of method a and b was -1.70 and -2.90 rmb, respectively. for screening twice, the corresponding cost was no more than -1.90 and -3.00 rmb, respectively. using method a to screen twice for each child was convenient and economical, which also reduced the false positive rate effectively. the prevalence of urine abnormalities of junior highschool children was significantly higher than that of elementary school-children in xh and the peak point was seen at the point of 12 years old. however, there was no significant difference between children in ja and yp. more than 10 months of follow-up diagnosed 2 cases of iga nephropathy. conclusions: urine abnormalities of school-children could be detected through urine screening at school. for shanghai, method a with screening twice was convenient, economical, and could reduce the false positive rate effectively. objectives: angiopoietin-like3 protein (angptl3) is involved in lipid metabolism and angiogenesis. the present study was to examine angptl3 expression in human kidneys with proteiuria, in adramycin rats (adr), and in puromycin induced podocyte damage. methods: immunohistochemistry was performed on kidney biopsies from children with mcd, mn, fsgs, tbmn. in adr, angptl3 expression was determined by quantitative real-time rt-pcr in glomeruli and tubuli dissected from frozen section of kidneys with laser microdissection system. in mpc5, a conditionally immortalized mouse podocyte cell line in vitro, angptl3, perlecan and agrin were detected through real-time pcr with the induction of puromycin. detachment assay was performed in podocytes tranfected by angptl3-pcdna3.1. results: in human kidneys, co-labeling showed angptl3 expressed in the cytosol of wt1 positive cells. quantitative computerized analysis showed that angptl3 in glomeruli in mcd and mn were significantly higher than that of tbmn, fsgs respectively (p<0.05). in adr, angptl3 in glomeruli increased significantly at 21 st or 28 th day (p<0.05) after adriamycin injection compared with control. and the expression of angptl3 in glomeruli was correlated with 24 h urinary protein (r=0.81, p<0.05). in mpc5 both protein and mrna expression of angptl3 on podocytes were up-regulated with the induction of puromycin. in podocytes transfected by angptl3-pcdna3.1 the expression of perlecan or agrin increased significantly compared with control (p<0.05). the attachment ratio was shown 95.7%±3.3% 24 hs after puromycin treatment on podocytes transfected by angptl3 compared with 38.6%±4.7% on normal podocytes, and 27.4%±3.5% on untransfected podocytes. conclusions: angptl3 is predominantly expressed in podocytes which could be involved in podocyte damage and the development of proteiuria. (1), iv (1) and iii (1), respectively. only one patient had microhematuria. we found that 5 of them had a very low c3 serum levels. clq and c4 deposits were all strong positive in 6 renal tissues. our findings suggest that biopsy should be strongly considered in this patient population. the significant renal involvement (class iii, iv, or v ln) could be found in sle patients with very lower proteinuria with or without hematuria. patients in bfb group received computer-assisted biofeedback program while those in ddavp group took minin. both therapies were carried out for 1 month and then 3 months follow-up was taken. parameters of follow-up included enuresis diary-urine flow rate and aqp2 in urine. results: 50 pne patients were recruited (26 boys, and 24 girls), whose mean age was (8.4±0.9) years. at the end of treatment and three months later, total effective rates in bfb group were significantly higher than those in ddavp group. uroflowmetry findings showed that in bfb group maximum flow rate, voided volume and ratio of coordinative detrusor-sphincter contraction increased after treatment. ratio of normal flow curve increased at second follow-up (p<0.05). in ddavp group voided volume and voiding time decreased after treatment. ratio of normal flow curve and coordinative detrusor-sphincter contraction had no change after treatment. two bands of aqp2 (29 000 and 43 000) were detected in the morning urine. density of patients bands was significantly lower than that of the controls. density of 29 000 bands in ddavp group after treatment were significantly higher than that before, but there was no difference between datas before and after treatment in bfb group. conclusions: bfb and ddavp are both effective therapies for pne in children. bfb is helpful in correcting voiding dysfunction and ddavp can increase aqp2 protein in the urine. with higher effective rate within four month, bfb is strongly recommended. objective: to describe the clinical course of non-parasitic chyluria in a thai pediatric case. this is the first report in children. results: the 7-year-old boy presented milky urine lasting for one year. urine tests showed heavy proteinuria (protein to creatinine ratio 9.1 mg/mg), lipiduria (triglyceride 29 mg/dl). the proof of a pronounced hypertriglyceriduria led to the diagnosis of chyluria. his renal function was normal. numerous red cells and lymphocytes were observed in the urine, and postprandial cystoscopy revealed milky cloudy urine emanating from right ureteral orifices. retrograde pyelography demonstrated pyelolymphatic backflow. serum immunoglobulin g4 for wuchereria bancrofti and circulating filarial antigen in the peripheral blood were negative. chest x-ray, abdomen computed tomography and intravenous urography did not demonstrate abnormal mass or malformation. proteinuria and lipiduria ceased before sixth week of a medium-chain triglyceride-rich diet. there was no recurrent chyluria after 12 weeks of mct-rich diet were completed. conclusion: in non-parasitic chyluria with unknown etiology, the low-fat diet with mct supplementation alone is effective. the prognosis is excellent. there was a significant improvement of waz comparing data at admission and at the end of follow-up (p<0.001). there was also a significant improvement of whz comparing data at admission and at the end of follow-up (p=0.02). only 9 (2.3%) patients presented with a whz less than -2.00 at the end of the follow-up. conclusion: children with primary vur presented an improvement in somatic growth with medical management. objective: the aim of this study is to investigate the clinical practical value of using doppler ultrasound to detect renal blood flow in renal parenchymatous diseases of children. methods: the renal arteries, segmental arteries and interlobar arteries were detected by doppler ultrasound. the parameters were peak systolic velocity (vmax), minimum velocity in diastole period (vmin), vmax/vmin (s/d), resistive index (ri) and pulsatility index (pi). there were 30 cases of healthy children, 20 cases of acute poststreptococcal glomerulonephrits, 20 cases of primary nephrotic syndrome and 15 cases of chronic renal failure. results: the doppler renal blood flow in normal school children was high velocity and low resistant type. 15 typical cases of acute nephritis with edema and oliguria appeared low velocity and high resistant type, ri, pi and s/d of all renal arteries were significantly increased, vmin are significantly decreased (p<0.05). after 2 to 3weeks all parameters returned to normal. during edema period and convalescence, the renal blood flow of primary nephrotic syndrome is low resistant type, ri, pi and s/d of segmental arteries and interlobararteries were significantly decreased (p<0.01). the feature of low circulating blood capacity was not alleviated even though edema was vanished and urine output was increased. the doppler in chronic renal failure was high resistant and low velocity type. ri, pi and s/d were all significantly increased, vmin were significantly decreased (p<0.01). when ri was great than 0.8, the extent of damage in kidney function was serious and the prognosis was bad. conclusion: renal blood flow provided a new non-invasive method for clinic diagnosis and evaluation of the prognosis in children renal parenchymatous diseases. we concluded that the dms is an important cause of congenital nephrotic syndrome. the outcome of our patients was poor and most of our patients died before 5 years old. objectives: the antiphospholipid syndrome is defined by the association of arterial/venous thromboses or obstetrical fetal loss with the presence of antiphospholipid antibody. this syndrome may be primary or secondary, particularly in association with systemic lupus erythematous. this study is to examine the frequency of anticardiolipin antibodies and the association between anticardiolipin antibodies with some symptoms in children with lupus nephritis. methodology: twenty-five children with lupus nephritis from 03/2006 to 11/2006 in department of nephrology, children's hospital o 1 were included in the study. we find the relationship between anticardiolipin antibodies with hematologic and renal involvement. results: anticardiolipin antibodies was positive in 11 patients (44%), 6 for anticardiolipin igm antibody (24%), 7 for anticardiolipin igg antibody (28%). there was a positive correlation between the presence of anticardiolipin antibodies and thrombocytopenia. in 11 patients with positive anticardiolipin antibodies, 3 patients had mta on renal biopsy. conclusion: anticardiolipin antibodies are associated with thrombocytopenia and mta. aim: the methodologies for quantitating urinary calcium excretion have not been standardized. the aim of this study was to compare urinary calcium/osmolality (uca/osm) ratio with calcium/creatinine (uca/cr) ratio and to assess the correlation of both ratios with daily urinary calcium excretion for the diagnosis of hypercalciuria in children. patients and methods: 364 children aged 6-14 years (mean 9.4±2.2 years) were included in the study. they were randomly selected from previous study's larger patient population. non-fasting, second morning urine samples were collected from all children. children were divided into two main groups: 1) 180 children with uca/cr <0.21(mg/mg) and 2) 184 children with uca/cr <0.21. 24-hour urine samples were collected from the second group, who were further divided into two subgroups: 2a) 113 children with daily calcium excretion <4 mg/kg/day and 2b) 46 hypercalciuric children (daily calcium excretion >4 mg/kg/day). results: mean uca/osm ratio was significantly lower in the first (1) group than the second (2) group (0.11±0.07 vs 0.31±0.14 mg/l/mosm/kg, p<0.05); but there was no difference between 2a and 2b subgroups. the correlations of both uca/osm and uca/cr ratios with 24-hour calcium excretion were poor (r=0.27 for both). conclusion: uca/osm ratio correlated with spot uca/cr ratio. but its superiority on uca/cr ratio in the diagnosis of hypercalciuria could not be shown. interestingly, values of 24-hour calcium excretion as a definite diagnosis test of hypercalciuria; did not correlate mathematically with those ratios of hypercalciuric or non-hypercalciuric children. using uca/osm ratio as a screening test would not separate hypercalciuric children. background: microalbuminuria is a biomarker of renal damage. the presence of microalbuminuria in patients with a solitary kidney has been described, but the pathophysiology leading to its occurrence is poorly understood. it is postulated that microalbuminuria is the early result of hyperfiltration. methods: we concomitantly measured inulin clearance, filtration fraction (ff) and microalbuminuria in children with a single kidney. correlation between the occurrence of microalbuminuria and a high filtration fraction was done. microalbuminuria was defined as an albumin/creatinine ratio (acr) >3 g/mol for boys and girls. normal filtration fraction was defined as <26%, and normal inulin clearance as >90 ml/min x 1.73 m 2 . during the same study, we also measured microalbuminuria in children with severe grade iii to v vesico-ureteral reflux (vur). results: 27 children with a single kidney were evaluated. 18 patients (67%) had a normal ff, and only one (6%) in that group had an abnormal acr. 9 patients (33%) had elevated ff, and 5(56%) had an abnormal acr. the presence of an abnormal acr was highly correlated with an abnormal ff (p=0.008). the mean gfr between the groups with normal or abnormal microalbuminuria did not differ significantly (94±31 ml/min x 1.73 m 2 vs. 83±16 ml/min x 1.73 m 2 , respectively). there was no significant association between microalbuminuria and a high ff in patients with severe reflux (p=0.3). discussion: we found the presence of microalbuminuria to be significantly associated with an elevated ff in children with a single kidney. this finding goes in line with the pathophysiology of a reduced nephron mass, leading to hyperfiltration, and ultimately to glomerular sclerosis. the benefit of renin-angiotensin-aldosterone blockade in these patients remains to be proven. chyluria is the excretion of chyle from the urinary tract and indicates the presence of an abnormal communication between intestinal lymphatics and the urinary tract. it can be of parasitic or nonparasitic etiology. southern brazil is not an endemic region for filariasis. aim: report a case of a 14-yrs caucasian adolescent girl referred to our out-patient clinic. history: 3 yrs before, she started to pass milky urine with white clots. no edema. normal blood pressure. she was investigated in another hospital and underwent a renal biopsy, that was normal. a diagnosis of nephrotic syndrome was made. she was treated initially with steroids and after changed to cyclosporin, lisinopril and simvastatin. conclusion: chyluria, although a rare conditione specially in children and adolescent in nonendemic areas, should beconsidered in the differential diagnosis of nephrotic syndrome. macroscopic examination of the urine, that is milky and cloudy, is simple and very helpful. also, triglycerides are found only in the urine of patients with chyluria. these simple tests will avoid unnecessary treatment, which is not without side effects. low-density lipoprotein apheresis (ldl-a) has been tried in the treatment of patients with steroidimmunosupression resistant nephrotic syndrome (ns) due to focal segmental glomerulosclerosis (fsgs). we would like to report a child case study of fsgs with ns and renal insufficiency due to mitochondrial abnormality treated by ldl-a and to clarify the therapeutic effects of this treatment. a 12-year-old boy was referred to our hospital with complaints of heavy proteinuria and edema. a routine examination revealed proteinuria of 7.0 g/day, serum albumin (alb) of 1.9 g/dl and creatinine clearance (ccr) of 58.5 ml/min. renal biopsy specimen showed fsgs and perceptive deaf nass was recognized, necessitating a hearing aid. the a3243g point mutation in mitochondrial gene was detected by using genomic dna isolated from peripheral blood leukocytes and by the molecular analysis using an allele-specific polymerase chain reaction (pcr). oral prednisone (2 mg/kg/day for eight weeks), intravenous methyl-prednisone pulse therapy (1.0 g/day,three times a week on the consecutive days for three weeks) and oral cyclophosphamide (75 mg/day for eight weeks) were not effective to reduce proteinuria. a protocol of ldl-a was designed for treatment twice-a-week for four weeks and then once-a-week for six weeks. following treatment by ldl-a, serum total cholesterol and ldl were markedly changed form 271 to 118 mg/dl and from 198 to 91 mg/dl, respectively. a small but significant increase in alb from 1.9 to 2.9 g/dl and a remarkable decrease in proteinuria from 7.0 to 1.4 g/day were also successfully obtained. conversely, no marked changes in ccr were detected. the results of the present study indicate that a rapid decrease in proteinuria and an excellent increase in alb by ldl-a provide a possible therapy for drug-resistant ns due to fsgs with mitochondrial abnormality. glomerular filtration rate (gfr) can be estimated in children by various formulas based on body height and serum creatinine (s cr ) measurements such as the schwartz formula (egfr sch =kxbh/s cr ). we evaluate the performance of egfr sch in estimating gfr in a pediatric cohort when compared to 125 i-iothalamate clearance (igfr), used as the reference standard for measuring gfr. between 1996 and 2006, we obtained 265 igfr and egfr sch on 171 subjects. for subjects who had more than one igfr, the first measurement was used for analysis. mean age was 13±6 (range 1-20, 56% age=13), 55% male. mean s cr was 1.2 mg/dl (median 0.8), mean igfr 76±38 ml/min/1.73 m 2 and mean egfr sch 116±59 ml/min/1.73 m 2 . figure 1 shows a scatter plot of the data with a line representing perfect agreement. figure 2 shows a residual plot comparing the difference between estimated and measured gfr to egfr sch . pearson r correlation between the two variables was 0.87 (ln scale). accuracy of egfr sch within 20% and 50% was 20% and 50%, respectively. the median difference between igfr and egfr sch was 40.1 ml/min/1.73 m 2 (median % difference 50%). for igfr >60, 30-59, 15-29 and <15 ml/min/1.73 m 2 , egfr sch overestimated gfr by 46%, 66%, 48% and 44%, respectively. however, the median difference between igfr and egfr sch for the same groups was 39, 18, 8 and 4 ml/min/1.73 m 2 , respectively. in conclusion, agreement between egfr sch and igfr is poor. egfr sch overestimates igfr at all levels of gfr, but bias of egfr sch vs. igfr increases progressively with higher gfr levels. in clinical instances when an accurate estimation of gfr is critical for patient management, the use of egfr sch should be reconsidered. until a more applicable estimation equation is developed, isotope measurement of gfr remains the ideal method to determine gfr in this population. background: immunosuppressive therapies other than corticosteroids, potentially associated with serious adverse effects, are urgently required for children with frequently relapsing nephrotic syndrome (frns). this study evaluated the efficacy and safety of long-term treatment with a moderate dose of cyclosporine (cya) in children with frns. methods: in this prospective, open-label multicenter trial, patients, from 2 to 16 years old, were randomly divided into two groups. for the first 6 months, both groups received cya (sandimmune) in a dose that maintained the whole-blood trough level between 80 to 100 ng/ml. during the next 18 months, the dose of cya was adjusted to maintain a trough level between 60 and 80 ng/ml in group a, while group b received a fixed dose of 2.5 mg/kg per day of cya. the primary end point was the rate of sustained remission. results: at 24 months, the rate of sustained remission was 52% in group a (n=24 patients), as compared with only 15% in group b (n=20) (p=0.006). the hazard ratio for relapse was 0.36 (95% ci, 0.17 to 0.77) in group a as compared with group b (hazard ratio=1.0). at 24 months, the rate of progression (to frns)-free survival was 78% in group a and 56% in group b (p=0.12). mild arteriolar hyalinosis of the kidney was found in 4 (19.0%) of 21 patients in group a and 1 (5.6%) of 18 in group b; no patient had striped interstitial fibrosis or tubular atrophy. conclusion: cya given for 2 years in a dose producing a trough level between 80 and 100 ng/ml for the first 6 months, followed by a trough level between 60 and 80 ng/ml for the next 18 months is an effective and relatively safe treatment for children with frns. with this regimen, about 50% of patients are expected to remain relapse-free during 2 years of treatment, without the most critical adverse effect of cya, i.e., interstitial changes of the kidney. renal stone disease has been regarded as an uncommon problem in children especially in the first year of life. we evaluated clinical findings and metabolic examination of 49 children with urinary tract stone presenting in the first year of life. there were 25 boys (51%) and 24 girls (49%), the mean age of admittance was 6,04±3,15 months. the average follow-up period was 30,91±24,65 months. urolithiasis was diagnosed during evaluation for uti and incidentally. positive family history for urolithiasis was reported in 22 (44,8%) patients. in 28/38 (73,7%) patients urinary metabolic examination was not normal (table 1 ). in 48 of 49 patients (98%), stones were located in kidneys which was bilateral in 26 (52%) patients and one patient had passing stone which had never seen in ultrasonographic examination. stones were examined in 3 subgroups. in 39 (80%) patients stones were measured 5 mm or smaller (group 1), in 9 patients (18%) they were between 5-9,9 mm (group 2) and in only 1 patient the stone (cystin) was larger than 10 mm (group 3). stones measuring 5 mm and larger were found highly associated (in 7 of 10 children, 70%) with abnormal ultrasonographic findings mainly hydronephrosis. in group 1, stones disappeared spontaneously in 12/23 (52%) patients. urinary tract infections (uti) were present in 28 (57%) patients. one fourth of cases had associated genitourinary tract abnormalities mainly vesicoureteral reflux in 9 (18%) patients. we conclude that the presenting symptoms of urolithiasis in the first year of life show a wide spectrum so that high index of suspicion is important for early detection. stones measuring 5 mm and smaller may have great chance to disappear. we also emphasize the importance of screening for uti in patients with urolithiasis under 1 year of age. background: long term complications of glycogen storage diseases (gsds) include delayed puberty, hepatic adenoma and renal disease. in the present study we aimed to detect renal involvement in children with glycogen storage disease and to determine the most accurate laboratory test to be the gold standard for early detection of this renal dysfunction. methods: twenty-seven children known to have gsd were included in this study. fifteen healthy age-and sex-matched children were also included as controls. routine urine analysis, urinary β2 microglobulin and microalbumin were done for all patients and controls. renal function tests, serum electrolytes, alkaline phosphatase, urinary calcium, blood and urine ph, urinary and plasma aminogram, in addition to calculation of glomerular filtration rate (gfr), bone x-ray to detect rachitic manifestations and abdominal ultrasound to measure renal size were done for all patients. results: twenty-one patients had one or more renal abnormality. the most common was increased urinary β2 microglobulin (15/21) followed by abnormal gfr whether low or high (8/21) and microalbuminuria (6/21). sonographically there was nephrocalcinosis in one case and renal stone in another one. the auroc curve for β2 microglobulin was 0.86, (p=0.01) and 0.7 for urinary microalbumin/creatinine ratio (p=0.15). the best cutoff level to predict renal abnormality for urinary β2 microglobulin was 0.22 mg/l with 70% sensitivity and 100% specificity and the best cutoff value for urinary microalbumin/creatinine ratio was 4.5 with 86% sensitivity and 50% specificity. in conclusion: renal abnormalities are common in patients with gsd. urinary β2 microglobulin can be considered the gold standard for early detection of renal dysfunction in these patients. the aim of this study was to investigate the role of neutrophil activation, protein oxidation and ceruloplasmin in the pathogenesis of hsp, which has been not investigated previously. serum activities of myeloperoxidase (mpo) and arylesterase (aryl) and levels of free thiol, ceruloplasmin (clp) and total oxidant status (tos) were measured in 29 children with hsp (16 boys, 13 girls; mean age 9.3±2.7 years) at the onset of the disease and during remission in comparison with 30 matched healthy subjects. patients at active stage had significantly higher mpo activity (391±277 vs. 155±154 u/l, p<0.001), higher clp (832±120 vs. 682±114 mg/dl, p<0.001) and tos values (20.7±11.8 vs. 7.5±2.8 μmol h 2 o 2 /l, p<0.001) than controls. patients had significantly lower aryl activity (158000±39000 vs. 187000±46000 u/l, p<0.001) and lower free thiol levels (234±48 vs. 279±26 μmol/l, p<0.001) than controls. there were 17 patients with gis involvement, 14 with joint and 13 with renal involvement. no significant differences were found in the oxidant stress markers between patients with or without organ involvement (p>0.05). significantly positive correlations were found between tos and mpo (r=0.437, p=0.018), and tos and clp (r=0.409, p=0.028) at the disease onset; while a negative correlation was found between mpo and thiol (r=-0.597, p=0.001) during remission. in conclusion, protein oxidation and neutrophil activation may play important roles in the pathogenesis of hsp. gastrointestinal system, joint and/or renal involvements were not together with different magnitude of oxidant stress. further studies are required to identify oxidizing substances and to develop therapeutic strategies to reduce oxidant stress in hsp. 1, 21) . if the first remission occurred after 8 days, the median time to relapse after discontinuation of steroid therapy was significantly lower than in children with shorter remission time (0.5 vs 3.0 months; p<0,0001). in conclusion children who fail to achieve a prompt remission after a first episode of ns are more likely to have frns or sdns. these retrospective data provide the rationale for individualizing the initial steroid treatment of mcns according to the time to obtain a remission. a prospective study is needed to validate this approach. the aim of this study was to determine the influence of osmolality of the first morning urine (ofmu) to efficacy of the desmopressin therapy in enuretic (pne) children and to compare the values of ofmu in enuretic and non-enuretic children. methods: we investigated ofmu in group of 50 children with pne and in group of 36 control non-enuretic children. pne group was divided into subgroup i (ofmu <600 mosm/kg h 2 o) and subgroup ii (ofmu >600 mosm/kg h 2 o). additionally, we measured ofmu 1 months after the initiation of desmopressin therapy and recorded the number of wet nights. regarding the number of wet nights we divided pne group to 3 subgroups: subgroup a (<5 wet nights/month), subgroup b (5-10 wet nights/month), and subgroup c (>10 wet nights/month). results: the statistically significant difference between control group and pne group regarding ofmu was not found (p=0.612). all 10 children from subgroup i had <5 wet nights/month during desmopressin therapy. 14 children from subgroup ii had <5 wet nights/month, and 26 had >5 wet nights/month during desmopressin therapy. the difference between those two groups was statistically significant (x 2 =13.3, p=0.0003). in children from subgroup a the difference between ofmu-s during and before treatment was 413 mosm/kg h 2 o, in children from subgroup b it was 261 mosm/kg h 2 o and in children from subgroup c it was 117,5 mosm/kg h 2 o. there was the statistically significant difference among those subgroups. conclusion: children with pne had usually similar ofmu like non-enuretic children. low ofmu is a good prognostic factor for desmopressin therapy of pne, especially in patients whose ofmu is <600 mosm/kg h 2 o. children with bigger difference of ofmu before and during therapy had better response to desmopressin therapy. we can conclude that ofmu can help in choosing the appropriate therapy for pne in children. yh. ng 1 , kl. chan 2 1 kk women's and children's hospital, pediatric nephrology, singapore, singapore 2 singapore general hospital, neonatology, singapore, singapore aim: to evaluate the clinical course and outcome of primary vesicoureteric reflux (vur) in patients with antenatal hydronephrosis in a neonatal unit. method: a prospective observational study of neonates with antenatal hydronephrosis born between january 1991 and december 2000 in the neonatal unit of singapore general hospital. neonates with significant hydronephrosis postnatally underwent micturating cystourethrography (mcu). records were reviewed with regards to the clinical course and outcome of primary vur. results: of 280 neonates with antenatal hydronephrosis, 139 (49%) had significant hydronephrosis postnatally and underwent mcu. 12.9% (18/139) were diagnosed with primary vur at median age of 7 weeks. there were more male (n=11) than female infants with primary vur. 10 (56%) infants had bilateral vur. 18% (n=5) of the renal refluxing units (rru) had low grade vur and 82% had high grade vur with the majority (57%) being grade iii vur. repeat mcu for 15 rru at 2 years showed that 60% (n=9) had spontaneous resolution of vur, 27% had improved vur grade and 13% had similar vur grades as before. 2 infants develop vur in the contralateral kidney which was previously normal. 14 infants (23 rru) underwent dmsa with renal scarring noted in 4 infants. all 4 infants were noted to have renal scarring without a history of urinary tract infection (uti). interestingly, 2 male siblings were found to have grade iii vur with renal scarring with subsequent spontaneous resolution. none of the study subjects underwent surgery. median age of follow-up was 3.8 years (range 0.3-12.5 years). conclusion: unlike neonates with vur detected after uti, infants with primary vur were predominantly male, had higher grade of vur with spontaneous resolution in the majority. early diagnosis of primary vur may provide the opportunity for reduced incidence of reflux nephropathy. t. neveus 1 , g. läckgren 1 , j. wahlberg 2 , n. wahlin 1 1 uppsala university children's hospital, uppsala, sweden 2 uppsala university hospital, department of transplantation surgery, uppsala, sweden objectives and methods: loin pain hematuria syndrome is a rare entity consisting of recurrent macroscopic hematuria with debilitating loin pain. it has only been described in adults, etiology is unclear and treatment is controversial but the therapy with best recorded success is to remove the kidney and reposition it in the pelvis. our objective was to show that the condition exists in childhood as well. results: aj, a previously healthy 9-year-old girl, was admitted because of recurring cystitis-like symptoms with microscopic hematuria but without bacteriuria. ultrasound and urography were normal. the episodes continued during the following years with increasing hematuria, now macroscopic, and increasing loin pain that was somewhat exercise-dependent. a renal ct scan was normal, as was cystoscopy, urography and ultrasound, but during cystoureteroscopy dilated vessels were noted in the mucosa of the right renal pelvis. antegrade pyelography, high resolution renal ct angiography, invasive renal angiography, mag3 renogram were all normal, gfr 111. nephrological evaluation, including kidney biopsy and coagulation tests were also normal and during cystoscopy blood could be seen emerging from the right ureteral orifice. by this time the patient was 15 years old and was dependent on opioids in order to be able to go to school. after long discussions with the nephrologist, urologists, pain specialist and transplantation surgeon, the family opted for autotransplantation as a last resort. this was performed january 2006 and the girl became almost momentarily pain-free. nowadays she does not need any analgesics, but after prolonged exercise (like several days of horseback riding) she may experience slight pain in the left loin and/or hematuria. conclusions: idiopathic loin pain hematuria syndrome exists in childhood and may possibly be treated with renal autotransplantation. j. van der deure, a. ockhuijsen, m. sondaar deventer ziekenhuis, 1st department of pediatrics, deventer, the netherlands objective: enuresis is a common pediatric problem. psychosocial factors (psf) influence the results of enuresis treatment in children. aim: to determine the short and long term effects of psf on enuresis treatment in a general pediatric population. methods: we reviewed the data of our enuresis patients treated from 2002-2004. relevant contributing psf were categorized. initial follow-up was at 3 months after training. a written questionnaire was sent 2 years after training. treatment success was defined as >90% improvement in dry nights. results: 211 pts were included. in 65 pts (30.8%) contributing psf were recognised. categorized problems: family related n=28 (43%), behavioural problems n=28 (43%), motivation/support n=22 (33.8%), learning disabilities n=21 (32.3%). overall success rate was 75.3% at 3 months and 65.3% at 2 yrs (overall resp quest 63.7%, psf 60.6%, 1 psf 51%, >1 psf 73%). success rate in the psf group was 49.2% (1 psf 61.5%, >1 psf 30.7%) at 3 months and 43.2% (1 psf 45%, >1 psf 42%) at 2 yrs. statistics: success rate in the group with psf is significantly lower as compared to no psf at 3 months (p<0.001 (chi-square), or 9.3, 95% ci 4.2-20.2) and at 2 yrs (p=0.0017 (chi-square), or 3.7, 95% ci 1.6-8.1) success rate at 3 months is significantly lower in pts with >1 psf, compared with 1 psf. (p=0.011 (chi square), or 4.6, 95% ci 1. 5-13.9) . no significance could be demonstrated at 2 yrs (p=0.85, chi-square) but this may be due to the variety in response rates. t. papalia, r. greco, r. bonofiglio hospital annunziata, nephrology, cosenza, italy actually a new litholitic therapy includes the phytotherapy agents as phyllantus niruri (pn), a plant used for years in brazil to treat urinary stones. in this work we estimate the effect of pn intake (uristone 2 gr/die) in 15 children (9 m/6 f, 9±5 years old) with urolithiasis. the pn has been administered for short term (from 1 to 3 months) in 13 children wih caox urinary stones and for 6 months in 2 with struvite stones. besides all children treated with dietary intervention: high fluid intake, sodium restriction, normal calcium intake and a diet low in animal protein. urinary and plasma analysis, body weight, map, ph, creatinine clearance, urinary excretion of mg and citrate were determined at baseline, 1 month and at the end of the study. the patients were studied by renal ultrasonography at baseline, 1, 3, 6 months. nobody of them had been undergone extracorporal shock wave lithotripsy. there were no differences in the mean values of urinary and plasma parameters before and after pn intake, except for a significant reduction in the mean urinary calcium in 8 hypercalciuric pts (6±1,3 vs 3,5±1 mg/kg/die). in this follow-up n°10 patients showed a faster stone clearance after a regular intake of pn and the others showed a smaller stone diameter. previous reports showed pn has a potent inhibitory effect on caox crystal adhesion and/or endocytosis by renal tubular cells and inhibitory effect on crystal growth, which might be related to the higher incorporation of gags into the calculi. our results suggest pn appears to represent a nontoxic and a low cost alternative for the prevention and treatment of stone disease, especially in the children. further studies are necessary to validate these preliminary findings. d. weitzel, c. schäfer, k. hohenfellner, u. pfeffer, m. neukirch german clinic for diagnostic, pediatrics, wiesbaden, germany objective: does sonographic quantification of the renal parenchyma allow estimation of isotopic renal function? method: sonographic kidney images of 88 patients (age 1 to 195 months; mean 47) were measured retrospectively. in all images of both kidneys taken from dorsal the volume on the base of length, width and depth was calculated. the parenchymal area (pa) in the longitudinal and cross section was calculated by planimetry. the distribution of renal function via mag3 was compared with sonographic values as volume and pa of each kidney in relation to whole kidney volume and pa respectively. patients with reduced global kidney function and time space of more than 3 months between isotopic study and sonography were excluded. results: interrater variability regarding planimetry of pa in longitudinal section (from dorsal taken images) was as good as measurement of kidney length (correlation coefficient (k)=0,968-0,977 and 0,97-0,99 respectively). all sonographic parameters correlated significantly with the isotopic parameters of renal function. the latter correlated best with the pa in longitudinal section (from dorsal taken images) k 0,939. the combination with planimetry in cross section did not improve correlation (k 0,94). difference of the proportional pa of the left kidneys (in correlation to whole kidney pa) in comparison to isotopic proportional renal function lead to mean difference of -0,3% with a standard deviation 6,7%. if only kidneys with split function of 45-55% the mean difference of proportional pa was -0,6% and the standard deviation 3,6%. conclusion: the distribution of total pa of both kidneys correlates significantly with the distribution of renal function (left and right) in isotopic studies. if sonographic planimetry might change the indication for isotopic studies in respect of renal function needs to be proofed in prospective studies. background: childhood incontinence is a common important urologic problem. especially daytime incontinence is often neglected by the parents until it turns out to be a significant clinical problem. the aim of this study was to evaluate the clinical characteristics of the patients with incontinence that were followed in our nephrology clinic. study design: patients were followed between the dates of 01.01. 2004-31.12.2006 and they were admitted solely due to incontinence or with concomitant urinary tract infections were enrolled. results: the study comprised 99 patients (38 m, 61 f; mean age 9.78±3.06 years). fourty-two patients had only nocturnal enuresis (ne) (29 primary, 13 secondary). twelve patients had daytime incontinence (di) (4 primary, 8 secondary) and 45 had both ne and di (25 primary, 13 secondary and 7 both primary ne and secondary di). all, except two (neurogenic bladder), had functional incontinence. twelve patients had additional fecal incontinence and 8 had constipation. sixty-two percent of the patients had one or recurrent urinary tract infections (uti) in their past history, 16% had accompanying vesicoureteral reflux and 4% had urinary stones. ultrasound revealed unilateral or bilateral dilatation in 20% and other anomalies in 5% of the patients. nineteen patients had abnormal dimercaptosuccinic acid scintigraphy findings. timed voiding schedule and double voiding were recommended to all patients with daytime incontinence, 43% of the patients received anticholinergic treatment and 50% received antimicrobial prophylaxis. discussion: overall, approximately 2/3 of our patients had associated uti and 1/5 had abnormal dmsa findings. therefore every patient with uti should be questioned about urinary incontinence and be treated carefully if present. the aim of the study was to determine early parameters of ultrasound and dmsa scanning diagnostics of reflux nephropathy (rn) in children. we examined 150 children with rn and vesicoureteric reflux (vur). all children were comparable on gender and age. all patients underwent color doppler ultrasound (cdus), x-ray and dmsa scan. they were divided into two groups: 1) children with unilateral rn a according to classification of smellie j. et all, 1975 (n=75) ; 2) children with vur without renal damage (n=75). we established that data of cdus (diastolic velocities (vd) 5,94±0,99 mm/sec, systolic velocities (vs) 22,3±5,74 mm/sec, resistive indices (ri) 0,63±0,06, pulsatility indices (pi) 0,76±0,19), dmsa scanning (time of the maximal accumulation 11,8±0,91 sec, maximal activity 189,3±20,4 sob/sec, mean velocities of accumulation 29,1±1,9 mm/sec, the contribution to the common accumulation 45,3±3,5%) are characteristic for patients with rn a. data of cdus (vd 10,7±1,68 mm/sec, vs 23,9±1,7 mm/sec, ri 0,63±0,02, pi 1,08±0,24), dmsa scanning (time of the maximal accumulation 7,5±0,86 sec, maximal activity 81,5±11,9 sob/sec, mean velocities of accumulation 7,72±1,07 mm/sec, the contribution to the common accumulation 34,27±3,03%) are characteristic for patients with vur without renal scars. the ranges of cdus and dmsa scanning were significantly different between children from comparing groups (p<0,05). our result suggest that data of cdus (vd, vs, ri, pi), dmsa scanning (time of the maximal accumulation, maximal activity, mean velocities of accumulation, the contribution to the common accumulation) can be used to early diagnostics of scarring in children with vur. the purpose of this study was to determine normal reference values for urinary uric acid/creatinine ratios in healthy turkish children. in this study, random urine specimens from 1306 children (662 boys, 644 girls) aged 1 month to 15 years were analyzed for uric acid and creatinine, and urinary uric acid/creatinine ratios were determined from each sample. uric acid/creatinine ratios were the highest in children aged 1-6 months and showed a significant decrease with age (p<0.05). uric acid/creatinine ratios were not significantly different between the sexes except 12-15 years. girls between 12-15 years had higher urinary uric acid/creatinine ratios when compared with boys (p<0.05). there was no correlation between urinary uric acid/creatinine ratios and protein intake. our results show that urinary uric acid/creatinine ratio changes with age. when assessing the urinary uric acid/creatinine ratio, a child's age should be considered. we provided normal reference values of urinary uric acid/creatinine ratio for using in our region. the aim of the study was to investigate microbiological marker of activity of uti. e. coli and s. aureus p 209 were isolated from urine of 180 children with uti. the children were divided into 4 groups: 1. with pyelonephritis in the acute period (n=45); 2. with pyelonephritis in the period of remission (n=45); 3. with cystitis in the acute period (n=45); 4. with cystitis in the period of remission (n=45) 20 healthy children consists the group of control. definition of bactericidal activity of urine (bau) was carried out by our original method. the essence of the method consisted in measuring of the optical density (od) of the bacteria after their contact with urine (experience) and isotonic solution of nacl (control) after 30 minutes of endurance in meat peptone mediums with 37 c during 3-5 hours. bau was calculated under the formula: bau (%)=(odc-ode)/odc*100%, (odc -control group, ode -experience group). we established that the level of bau did not correlate with urine ph (r=0,2), osmolality (r=0,1), lysozymuria (r=0,2), lysinuria (r=-0,2). we established that the low level of bau was marked in children of control group (10-40%). the patients in active period of uti had high level of bau (>70%). the parameters of bau didn't depend from the level of uti (pyelonephritis or cystitis). the level of bau reduced in the period of remission of uti. we established that the level of bau correlated with bacteriuria (r=0,8), leucocyturia (r=0,5). the level of bau didn't depend from the degree of urine dissemination (r=-0,3). so, the level of bau is correlated with laboratory parameters of uti and can be used as new additional microbiological marker of diagnostics of activity of uti. the evolution of the alport syndrome in brazilian children vesicoureteric reflux (vur) is common in children with urinary tract infections (uti). if vur coexisting with uti there is a high risk of progression to end-stage renal disease (esrd). the correct diagnosis is important. we observed 136 children (104 girls and 32 boys) aged 1 mo to 12 yrs at the time they have been diagnosed as having vur. the follow-up period was 1 mo up to 11 yrs after the diagnosis. all 22 children with vur grade 5 have been operated. after antireflux operation incidence of uti dramatically decreased even this cannot prevent progressive kidney damage in some patients. children with less severe vur have been put on prophylaxis. controlled mcu was performed usually after 1 year later. if vur disappeared medication have been stopped. vur grade 2-4 had a tendency of resolution under conservative treatment in 25.5% of the patients. in 16 children associated urinary tract malformations were found: duplicated system, dysplastic kidney, kidney agenesia, dystopic kidney, urethral stenosis and bladder outlet obstruction. in 2 patients nonfunctioning kidney have been found. dysfunctional voiding was common finding. blood pressure and physical development have been controlled. kidney size, function and scar formation have been followed by dmsa scan. we observed kidney growth at 6 mos intervals. during the follow-up period 3 infants have had reversible renal insufficiency. one patient with bilateral vur grade 5 went into renal failure at the age of 9 yrs. conclusions: vur is still one of the most common leading causes to esrd in childhood. even the existing controversy concerning treatment modalities it is obvious that low grade vur does not need operative treatment. it is indicated in high grade vur to prevent repeated and severe uti but it cannot preserve progression of the disease because of high incidence of coexisting kidney dysplasia. results: from forty children with nephrolitiasis, 28 (70%) were boys and 12 (30%) were girls. the mean age was 80.5±57.5 months. the youngest age was 4 months old. the most common clinical presentation was abdominal discomfort 22 (55%), followed by uti 21 (52%), microscopic hematuria 13 (32.5%), macroscopic hematuria 12 (30%), spontaneous urinary calculi 9 (22%), flank pain 8 (20%). nine of 40 children were presenting with chronic renal failure (crf). statistical analysis showed that age had correlation with the present of crf in children with nephrolitiasis (p=0.007). the clinical presentations of nephrolitiasis were varied. abdominal discomfort and uti were the major signs and symptoms. there was correlation that age may influence the present of crf in children with nephrolitiasis. objective: renal involvement is one of the most frequent and serious manifestations of sle. we analyzed the treatment and renal outcome of patients with lupus nephritis. methods: seventy-seven identified patients were retrospectively analyzed from jan. 1996 to dec. 2005 . the outcome was divided as complete remission (24-hour proteinuria <0.5g, plasma creatinine level normal and sledai <5), partial remission (abnormal renal damage index improved >50%, 24-hour proteinuria >0.5g, sledai <10) and no response, respectively. results: fifty-four patients were biopsy proven ln (70%). fifty-seven patients followed up more than 6 month. all the eleven patients with class i or ii achieved remission, using prednisolone together with either hcq, or tripterygium or mmf or cyclophophamide (ctx). in forty-three patients with class iii or iv or v, they were given prednisolone together with mmf or ctx. we found that remission was in 18 cases, part remission 17 cases and no response in 8 cases. associations between methylenetetrahydrafolate reductase (mthfr) c677t polymorphisms and several vascular diseases have been reported. this is a clinical study designed to investigate the possible effects of (mthfr) c677t polymorphisms on the developement of henoch-schönlein purpura (hsp), renal involvement, and clinical course. fourty-one patients with hsp (25 m/16 f) mean age (7,8±2,9 years) were included in the study. eighteen of the patients had renal involvement. the control group consisted of 50 healthy children. blood samples were obtained for mthfr c677t transition, homocysteine, folic acid and vitamine b12 in the patients and controls. the genotype frequencies (cc/ct/tt) of mthfr in the hsp group were 0,56/0,39/0,12 and 0,58/0,38/0,04 in the control group, respectively (ns). the genotype frequencies (cc/ct/tt) were 0,39/0,39/0,22 in the patients without renal involvement and 0,78/0,22/0,00 in those with renal involvement, respectively (ns). homocysteine levels were 10,6±6,8 in the hsp patients and 12,9±4,5 μmol/l in controls (ns). vitamine b12 levels were 320,6±157,5 pg/ml in the hsp patients and 302,6±209,6 pg/ml in the control group (ns). folic acid levels were 5,7±3,0 in the hsp and 4,0±1,6 ng/ml in the control group (p<0,002). no significant relationship was present with the mthfr genotype and plasma homocysteine, folic acid and vitamine b12 levels. no association with mthfr gene polymorphism and homocysteine plasma levels could be detected in patients with hsp and hsp nephritis. although mthfr gene polymorphisms have been found to be associated with several vascular diseases, the results of this study indicate that other mechanisms should be operative in the developement of hsp and hsp nephritis. we report the symptoms, signs and laboratory values at onset and during 6 month-follow-up of hsp in a prospective study of 220 children (99 girls, 121 boys) with mean age of 7.1 years (1.6-16.7 y). the first sign of hsp was purpura in 152 (70%), oedema or other joint symptoms in 121 (55%), abdominal pain in 49 (22%) and melena in 3 (1%) patients. petechiae appeared on the average 5 days after the first symptoms (1-22 d) if purpura was not the first sign (n=67). 78% of the cases were diagnosed between september and march. the mean delay from the first symptoms to the diagnosis was 7 days (0-65d our results based on an unselected and prospective patient material demonstrate that renal symptoms in hsp children develop early, are common and should be followed up at least 6 months. the kidney is a metabolically active organ, so any alteration in kidney function might affect nutrient utilization. objective: analyze the nitrogen balance (nb) as a marker for adequate food consumption in children with chronic renal insufficiency (cri). material and methods: 60 patients (12 boys, 48 girls) diagnosed and managed in the nephrology and nutrition departments. they were placed in two groups depending on age: group a: 20 patients aged 5±2.5 years, follow-up 4±1.1 years, glomerular filtration rate (gfr) estimated by cr-edta: 38±20 ml/min/1.73 m 2 ; group b: 40 patients aged 12.5±3 years, follow-up 10.9±3.5 years, gfr estimated by cr-edta: 37±17 ml/min/1.73 m 2 results: group a had a worse weight and height evolution: weight: -0.95±0.15 sd in group a vs 0.15±2 sd in group b; height -1.29±0.29 sd vs -0.34±0.23 sd (respectively). group a showed a significant increase in tnf blood levels (p<0.03) that was inversely related with weight and height. bn was significantly greater in group a (1.59±1.93 gr/day) than in group b (-2.6±4gr/day) (p<0.01) and this was related with higher calorie (p<0.003) and protein (p<0.004) intakes. there was no difference in alimentary nutritional breakdown. nb improved significantly over the follow-up (p<0.01). there was no relation between nb and gfr. there was a significant increase in triglyceride levels and significantly lower blood urea levels in group a (p<0.04). we conclude that nitrogen balance depends on protein and calorie consumption and is independent of the severity of renal affectation. we present a case of a 6 months old boy, who was delivered to our intensive care unit because of high fever, acute renal failure and dilatation of the urinary tract. his hemoculture and urinary culture were positive for e. coli and a severe urosepsis was diagnosed. his urethral catheterization was unsuccessful, so a suprapubic puncture was performed to relieve the urinary system and provide sufficient urinary flow. after the urinary sepsis was cured with adequate board spectrum antibiotics, a voiding cystourethrography (vcug) was performed to reveal the suspected anatomical abnormality, vesicoureteral reflux (vur) respectively. meanwhile a continuously growing nodular tumor of the penis was observed. the vcug showed the signs of urethral stenosis, but posterior urethral valve and vur was excluded. the doppler ultrasound found a solid vascularised tumor, 2x2.5 cm in its diameter. during the surgical operation the tumor couldn't been totally removed, as it was infiltrating the surrounding tissues and the urethra. the histopathological examination of the biopsy specimen confirmed a juvenile xanthogranuloma (jxg). this is an uncommon, benign, non-langerhans cell histiocytosis, primarily seen in infancy as a solitary cutaneous lesion, predominantly in males. systemic form of the disease is rarely seen. usually it resolves spontaneously without any further treatment, but the differentiation from a malignant neoplasm is essential. according to the authors' search, this is the 2nd reported case in the literature and the first pediatric report of the jxg of the penis. urine examination using x-ray diffractometry background and goal: x-ray powder diffraction analysis is widely used in chemistry and pharmacology and for other industrial purposes. in medical science it is used for analyzing kidney stones and investigating retained crystals in tissue sections. in the department of mineralogy and petrology we investigated urine samples, at first diagnostically to detect urinary amino acids, glucose and compounds and, secondly, to detect calcium oxalate hydrate, which can be employed for early detection of renal tubular injury when no significant differences in renal function values exist. materials and methods: after sedimentation and dehydration, authors investigated more than 100 urine samples of children using x-ray diffractometry. results: 12 of them were glucosuric due to diabetes mellitus; in these cases glucose could be detected in each of their urine samples. in 5 cases different amino acids due to aminoacidopathy were detected. the urine samples of 8 children -kidney stone problems in history -were examined, in one case struvit, in the other cases ca oxalate crystals were identified. also, 30 samples of 10 children were examined, 24 hours after at least 2 hours long anesthesia, ca oxalate hydrate appeared in their urine referring to renal tubular injury due to inhalational anesthetic agents. in 10 cases urine samples of children treated in the intensive care unit were analyzed, in 50% ca oxalate crystals could be detected. in 40 cases healthy children's urine were investigated, as control ones. conclusion: x-ray diffractometry, as a highly sensitive method can be used efficiently in clinical measurements. further investigations are needed in order to determine its place in clinical trials. authors emphasize the importance of collaboration of different sciences, as well. drug intake in the background of sudden death? microalbuminuria was significantly more in patients more than 10 years of age as compared to younger patients on bivariate analysis (p=0.001). on logistic regression analysis, though microalbuminuria was more in patients more than 10 years of age, it was not statistically significant. the association between microalbuminuria and urinary specific gravity levels of <1.010 was statistically significant (p=0.001), similar results were seen on logistic regression analysis. there was no correlation between microalbuminuria and hospitalizations, crises, previous blood transfusions, hemoglobin electrophoresis and serum creatinine levels. conclusion: identification of risk factors for microalbuminuria may allow earlier intervention to prevent renal complications in patients with ssd. in developing countries at primary health care level urinary specific gravity should be done routinely in patients with ssd to identify cases at risk of microalbuminuria. m. bak, e. serdaroglu, y. bicilioglu aim: the aim of the present randomized-controlled study was to compare desmopressin (dp), alarm and combined treatments in nocturnal enuresis. the study included 101 children (67 boys and 34 girls) with nocturnal enuresis. the mean age was 10.7±2.4 years (ranged 5-16 years) and the mean wet-nights was 14.9±6.1 day per month before treatment. the patients were followed for one month before treatment and randomized to dp (33 patients), alarm (34 patients) and combined (34 patients) treatment groups. the dp group was received 40 μg orally one-hour before sleep and alarm group was used wet-stop bedwetting alarm device after education of parents. the patients were followed 6 months in treatment period and 2 months after discontinuation of treatments. results: wet-nights per months was significantly reduced between before treatment and last month of treatment in dp (14.5±5.7 to 4.8±6.5, p<0.001), alarm (14.1±5.9 to 2.9±4.1, p<0.001) and combined treatment (16.2±6.9 to 1.9±2.5, p<0.001) groups. treatment success (>50% decreasing in wet-nights) and complete response (100% dry) rates was 79%, 91%, 97% and 30%, 27%, 35% in dp, alarm and combined treatment groups respectively. the more rapidly decreasing in wetnights was observed between dp used and only alarm treatment group but this effect disappeared after 3 months. relapse rates was 67%, 11% and 22% in dp, alarm and combined treatment groups respectively between successfully treated patients (p=0.002). conclusion: alarm treatment is the best intervention with low relapse rates and no potential adverse effect in nocturnal enuresis. dp group has higher relpse rate but adding to dp may achieve more rapid decreasing in wet nights especially in patients and parents expecting rapid result. aim: it is often difficult to collect urine from infants. use of specifically designed urine collection pads gives reliable results for routine biochemistry tests in adult urine. their use for routine and metabolic tests in paediatric urine has not been investigated. the aim of this study was to evaluate whether the pads give reliable results for routine and metabolic biochemistry tests in paediatric urine. methods: urine collected by bag or clean-catch from infants <2y without metabolic disorders was divided into two aliquots, one of which was added to a collection pad, incubated for 15min at 37°c, then recovered by aspiration. routine and metabolic analyses were performed on pad/non-pad aliquots. additionally, selected metabolic analyses were performed on pad/non-pad urine from patients with diagnosed inborn errors and urine spiked to simulate metabolic disorders. for quantitative analyses, pad/non-pad results were compared using bland-altman bias plots, passing and bablok regression and paired t-tests. results: routine tests (urea, electrolytes, creatinine, osmolality, calcium: creatinine, phosphate: creatinine, magnesium: creatinine, urate: creatinine, n=32) showed close concordance with no clinically significant pad/non-pad differences. in infants without metabolic disorders, aminoacids (n=10), organic acids (n=12) and mucopolysaccharides (n=8); and in patients with metabolic disorders -phenylketonuria (n=1), mucopolysaccharidoses ii (n=2) and iii (n=1), inborn errors of organic acid metabolism (n=6) and cystinuria (n=3), all showed excellent pad/non-pad concordance. sugar chromatography in urine spiked with glucose/galactose/fructose showed identical staining intensity in pad/non-pad samples. conclusion: urine collection pads give reliable results for a wide range of routine and metabolic tests in paediatric urine. a post-translational modification of arginine residues in proteins and subsequent proteolysis result in release of symmetric dimethylarginine (sdma). sdma is considered an end product of metabolism, excreted primarily by the kidney. several previous studies have reported a significant relationship between glomerular filtration rate (gfr) and plasma sdma. to determine the potential value of sdma in the assessment of gfr in children we have measured sdma in samples taken during routine measurement of glomerular filtration rate (gfr) using plasma clearance of inutest. 257 patients (144 male) requiring routine gfr measurement were studied. median (range) age 11.8y (1.6-20.2) , height (ht) 145cm (82-188), and surface area 1.3 m 2 (0.5-2.6). gfr was measured using the plasma clearance of inutest, and plasma sdma and creatinine (pcr) by liquid chromatography stable isotope dilution electrospray mass spectrometry-mass spectrometry method. estimated gfr (egfr) was calculated from the formula 31 x ht (cm)/pcr (μmol/l). median gfr was 80 ml/min/1.73 m 2 (6-217), plasma sdma 0.530 μmol/l (0.266-4.460 ), pcr 54.5 μmol/l (12.7-777), and egfr 82 ml/min/1.73 m 2 (7-212). as expected both plasma sdma and pcr increased with a decline in gfr. compared to gfr the correlation with 1/sdma, r=0.83 (p<0.001) was better than for 1/creatinine, r=0.75 and similar to that for egfr, r=0.86. comparing sdma with inutest gfr for detection of gfr <90 ml/min/1.73 m 2 the area under the roc curve was 0.87 (p<0.001). the equivalent areas for pcr and egfr were 0.84 and 0.89, respectively. in conclusion plasma sdma is an endogenous marker of gfr in children and is superior to pcr because it appears to be independent of body size. since the calculation of egfr requires accurate measurement of height, plasma sdma may provide a practical alternative for assessment of gfr in children. thrombotic microangiopathy (tma) consists of thrombocytopenia, microangiopathic hemolysis, and thrombi in the microvasculature of vital organs. broad categories of causes of tma include infectious (verotoxin-induced hus), hematologic (ttp), complement based (atypical hus), immune-mediated (sle, anti-phospholipid antibody syndrome), and drug-induced (cyclosporine). thorough investigation is required to detremine the underlying etiology in order to provide specific therapy and information about prognosis. a 14 year girl presented with short stature and was found to have hypertension, proteinuria, renal failure (creatinine 350 umol/l), and anemia (hgb 72 g/l). platelets were normal. she also had spondylometaphyseal dysplasia, scoliosis, lymphopenia, mild pulmonary hypertension and aortic stenosis. on pulmonary function testing, her dlco was decreased. chest ct demonstrated small micronodules. a ventilation-perfusion scan was normal. renal biopsy showed features of tma. she was treated with dialysis and underwent renal transplantation one year later. there has been no disease recurrence 6 months post-transplant. genetic and immunologic workups were negative, including anti-cardiolipin antibodies. a thrombophilia workup was negative apart from a heterozygous mutation in mthfr. c3 levels were mildly reduced. anti-neutrophil antibodies were negative. complement system studies, including factor h, and smarcal1 analysis for schimke immuno-osseous dysplasia are underway. although the descriptive diagnosis of tma can be applied here, the underlying pathophysiologic diagnosis has still to be defined. it is of particular importance that further efforts be made to identify the etiology given the potential risk of disease recurrence in the renal graft. background: long term outcome of renal functions after liver transplantation (lt) in wd is not studied yet. aim: the aim of this study was to determine the long term outcome of renal functions in children receiving lt for wd. patients and methods: renal functions were examined in 9 (f/m: 2/7) liver transplanted patients for wd before and long after lt and compared with renal functions of 9 patients (f/m: 5/4) with lt for a hepatic disease other than wd. the mean age of subjects was 12.1±3.2 years in the patients group and 9.8±4.1 years in the controls. the mean duration of follow-up was at least 2 years. glomerular and tubular functions were assessed using the conventional equations for measured creatinine clearance (gfr), tubular phosphate reabsorption (tpr), daily protein and calcium excretion in both groups. results: mean gfr before lt was 81.7±32 ml/min/1.73 m 2 in the study group and 146.3±37.6 ml/min/1.73 m 2 in the controls (p=0.007). the mean tpr before lt was found to be 67.9%±18.2% in the study group and 88%±9.6% in the controls (p=0.03). daily protein excretion rate before lt was found to be high in both groups, as well as urinary calcium excretion. an increase in gfr was observed in the study group after lt (p> 0.05), while it was slightly decreased in the controls (p>0.05). tpr increased significantly in the study group after lt (84.8%±9.5%) (p=0.04) and although it was found to be significantly lower in the study group than the controls before lt, in the long term follow-up the difference between the groups was disappeared (p=0.59). conclusion: tubular dysfunction is frequent in patients with wd. liver transplantation for hepatic failure secondary to wd is a lifesaving procedure. it corrects the underlying hepatic defect as well as renal defects and leads to long-term survival. rather conflicting results are available regarding the neurocognitive development of children with ckd, due to small sample sizes, cross-sectional study designs, differing methodological approaches and historical trends in patient selection for renal replacement therapy. we prospectively examined in a standardized, multi-center effort 59 children with ckd aged 0.8-15 years. children were treated either conservatively (n=30, gfr <25 ml/min/1.73 m 2 ) or by dialysis (hd: n=7, pd: n=22). a sub-sample of 18 children underwent repeated testing after 12 -14 months. bayley and snijders-oomen developmental tests were performed and the measured values normalized to standard deviation scores (sds). general cognitive development averaged at -1.02 (±1.48) sds. 42% of the patients scored <-1.5 sds, i.e. below the 10 th percentile of the normal population. no significant differences were observed between pre-dialysis (-0.87+1.57) and dialyzed patients (-1.16+1.40). impaired neurocognitive function was marked in infants (-1.63+1.31 sds), whereas school children showed a distribution similar to healthy children (0.43+1.42 sds, p<0.005). the global neurocognitive sds remained unchanged in the longitudinal sample (t 1 =-0.97±1.57; t 2 =-0.91±1.71). in summary, our preliminary results demonstrate a high prevalence of neurocognitive impairment in infants with ckd. we assume that this finding reflects the improved survival of children with complex disorders affecting not only the kidney but also brain development. the poor performance of this age group highlights the importance of close neurocognitive follow-up and early developmental interventions. objectives of study: to make a diagnosis of a girl with kidney subcapsular hydrops, abnormal urinanalysis and hypertension. methods: physical examination and laboratory investigations were analyzed. results: a 5 years old girl was admitted because of kidney subcapsular hydrops, proteinuria without edema, and hypertension (130/94 mmhg) for 50 days. no trauma or familial hypertension history were provided. no hydrops was found before the age of 1 year. urinary rbcs were 5-7/hp and protein was 77 mg/kg/24 hr. the serum albumin was normal. ultrasound examination revealed normal sized kidneys, increased echogenicity in both kidneys, and subcapsular hydrops on the upper pole of the right kidney connected with an old renal fissure. ucg and fundus examinations were normal. gfr of the right kidney was slightly decreased as compared to the left (65 ml/min vs. 67 ml/min, by dtpa scan). by puncture of hydrops, yellow clear fluid was drained, the analysis showed similar composition to that of original urine, so subcapsular urinoma was diagnosed. urine collection from two kidneys separately was performed by cystoscopy; nonselective proteinuria of 1+ was found in urine from the right and 2+ from the left kidney. analysis revealed urea 36.8 mmol/l, potassium 6.92 mmol/l, creatinine 0.42 mmol/l in the right kidney urine compared to urea 77.2 mmol/l, potassium 11.19 mmol/l, and creatinine 1.29 mmol/l in the left, which suggested that the right kidney function was compromised. according to proteinuria from both kidneys with microscopic hematuria, without edema and hypoalbuminemia, glomerulonephritis was diagnosed. the girl was diagnosed with glomerulonephritis and subcapsular urinoma. it was a rare case because of their co-incidence. reasons for the hypertension, if caused by the glomerulonephritis or the pressure by subcapsular urinoma, as well as reasons for subcapsular urinoma need to be clarified during the follow-up. the aim of this study was to detect factors that could interfere with the results of des treatment. methods: fifty-six patients 5.9 to 15.2 years old with des without improvement by previous therapies were randomly distributed into two voiding training programs: group 1 (g1): 26 patients submitted to 24 kegel exercises training sessions for three months; group 2 (g2): 30 patients submitted to 16 biofeedback sessions over a two month period. both groups adhered to a voiding and drinking schedule, received adequate toilet posture instructions and were reinforced through the maintenance of voiding diaries. clinical evaluation was carried out before each programs initiation and 1, 6, and 12 months after end of the program. all patients were submitted to renal and dynamic ultrasound before and 6 months after each program's conclusion. the following variables were analyzed: gender, age at diagnosis, treatment group type, vesico-ureteric reflux, constipation, urinary tract infection, asymptomatic bacteriuria, bladder wall thickening and post void residual (pvr) urine. the logistic regression model was applied to identify independent variables associated with response to treatment. results: urinary continence was improved after completion of either training program. success in diurnal urinary incontinence varied from 72.7 to 80% in g1 and from 65.2 to 89.4% in g2. success in nocturnal urinary incontinence varied from 66.7 to 84.2% in g1 and from 65.4 to 86.9% in g2. in multivariate analysis three variables remained independently associated with bad response to treatment: constipation with soiling, bladder wall thickening and pvr urine (p<0.05). conclusion: studies using multivariate regression analysis to identify predictors of response to behavioral therapy are important for the development of selection criteria for prescribing these therapies to children. we report the case of a four-year-old child born to consanguineous parents, who presented first at two months of age with respiratory failure. during the admission he developed panyctopenia, hypertension and nephrotic range proteinuria. the metabolic workup revealed methylmalonic academia and aciduria along with homosystinuria; highly suggestive of cobalamin deficiency. the renal biopsy showed chronic thrombotic microangiopathy (tma). the muscle biopsy showed the presence of nemaline rods on electron microscopy. cobalamin c deficiency was confirmed by genetic analysis as the patient was homozygous for the mutation c547/548. at the age of one, he was noted to be visually inattentive and developmentally delayed. on ophthalmology examination there was evidence of bilateral maculopathy and dysfunction of rods and cons on electroretinogram. he subsequently went on to develop bilateral bovine maculopathy. since his initial presentation he has been maintained on hydroxycobalamin, betaine and folate; with no further relapse of proteinuria or panyctopenia. however, despite adequate doses of hydroxycobalamin, the maculopathy progressed. to our knowledge, this is the first report of a child with both tma and bovine maculopathy. the aim of the study was to assess the rate of vesicoureteral reflux (vur) in patients with lower urinary tract dysfunction (lutd) of nonneurogenic origin. dysfunctional voiding may result in lower urinary tract symptoms in children and is commonly associated with urinary tract infections and vur. we investigated 111 patients with voiding dysfunction during last three years: 31 boys and 80 girls, a mean age of 8.2 years, with a mean follow-up of 19 months, all with normal renal function. mean pre and post treatment symptom scores were 23.6 and 7.6 respectively. vur was detected in 21% of the children with unstable bladders and 17.5% of the children with stable bladders as detected by video urodynamic investigation, 22% of the children with urinary tract infection (uti) on admission, and 18% of the children with no history of uti on admission. the co-existence of vur in our group with voiding dysfunction was 19.8% (22 patients). all patients with vur had low grade reflux (grades i-iii) and 3 of them bilateral, the remaining 19 unilateral. renal us was performed in 55 patients and revealed hydronephrosis in 13 patients, while the remainder showed no abnormalities. vur was found to be present in 30% of the children with abnormal us findings, while only 2% of the children with normal us findings were affected. furthermore, the patients that had spontaneous resolution of reflux showed a markedly greater improvement in symptom scores. a significant portion of patients with lutd (19.8%) have low grade vur. in detection of vur in patients with lutd, hydronephrosis is a good indicator of the presence of reflux, while utis and urodynamic findings were not found to be significant indicators. the overall spontaneous resolution rates of vur in patients with lutd and stable bladder following treatment was found to be 22.7% and 14.2%, respectively. 200-250g) were grouped: group 1 (n: 5) was the sham group. group 2, 3 and 4 (n: 7 for each) received 50 mg/kg twice daily ptx intraperitoneally (i.p.), 100 mg/kg/day gen i.p. and both ptx and gen at the same dosages for 8 consecutive days, respectively. the rats were weighed at the beginning and than weekly during the study. after the last dose 24-hour urines were collected. then, rats were sacrificed and blood samples were obtained from the abdominal aorta. bun, serum creatinine (scr), creatinine clearance (ccr), renal superoxide dysmutase (sod), catalase (cat) and thiobarbituric acid reactive substances (tbars) levels were determined. all the parameters were compared between the groups. results: body weights were not different between the groups either at the beginning or during the study. bun levels were significantly higher in group 3 than the other groups (p<0.01). scr and ccr levels were similar between the groups 3 and 4, but the levels were higher than those of groups 1 and 2 (p<0.01). sod and tbars levels were similar between all groups. the levels of tubular cell apoptosis and caspase-3 expression were significantly higher in group 3 than the other groups (p<0.05). conclusion: we may conclude that ptx administration significantly reduced the apoptosis in gentoxicity, but we could not demonstrate any evidence of ptx-related reduced oxidative stress. the lack of evidence for the widespread use of antimuscarinics and holding exercises in mne prompted us to design a randomized controlled trial comparing interventions in four groups of children with mne: placebo (a) or oxybutynin chloride (b) in combination with a daily regimen of standardized fluid intake and holding exercises or as monotherapy (c) and (d). a fifth group, to be treated with alarm only, was planned as control. randomization was stratified for participating hospital, sex, age, tanner stage, family history of mne, previous treatment, and bladder capacity class, being the largest from either the maximum voided volume (mvv) from a 48 h frequency volume chart or the volume after 4 baseline holding exercises (hev). after 12 weeks intervention with holding exercise (a and b) , hev had increased, both with oxybutynin (208±84 (sd) ml to 311±121 (sd) ml, p<0.001) and placebo (216±82 (sd) ml to 259±90 (sd) ml, p<0.05). without holding exercises, only oxybutynin (d) increased hev (223±79 (sd) ml to 274±111 (sd) ml (p<0.05). mvv increased also in groups a and b (holding exercises), not c and d. cure rate (less than 1 wet night in the last for 4 weeks) was low: a 1/29, b 3/30, c 0/30 and d 4/30. control group with alarm had 22/30 cure. cure was not related to hev, mvv or delta hev and mvv. this questions the relevance of increasing bladder capacity in mne. background: sickle cell disease (scd) is an inherited disorder of beta-globulin synthesis of haemoglobin, resulting in a tendency for haemoglobin polymerisation and consequent vasoocclusion, tissue hypoxia, and ensuing organ damage. the kidney is a particularly sensitive to hypoxia and renal failure is a major cause of morbidity and mortality in scd. children with scd commonly hyperfiltrate, the glomerular filtration rate (gfr) then typically falls back towards normal in adulthood. routine estimation of gfr in children is primarily derived from the height and plasma creatinine (pcr) measurements using k a constant dependent on the creatinine analytical method. this formula has reduced accuracy in children with a gfr >80ml/min/1.73 m 2 . it has never been validated in hyperfiltration or children with scd. recently, new gfr markers have been proposed including symmetrical dimethylarginine (sdma) that may be independent of body size. in this pilot study we tested the hypothesis that estimated gfr and/or sdma allow a reliable estimation of gfr in scd. methods: 13 hbss patients, age range 10-20yrs (mean age 15yrs) attending the evelina children's hospital were studied. the patients were on regular blood transfusions for stroke management and undertook a formal gfr measurement using plasma clearance of inutest. the plasma samples were also used for the measurement of pcr and sdma by stable isotope dilution mass spectrometry. egfr was calculated using k=35. results: inutest gfr ranged from 70-175 ml/min/1.73 m 2 . there was significant inverse correlation between sdma and inutest gfr (p<0.01)). there was no significant correlation between either pcr or egfr and inutest gfr. conclusions: this early data suggests that sdma might prove valuable in monitoring gfr in children with scd. introduction: the aim of this study was to identify the risk factors for renal scarring in children with lower urinary tract dysfunction (lutd) by using data available at the time of patient admission to the interdisciplinary management program of lutd at hospital das clínicas. material and methods: medical records of 120 patients were assessed retrospectively concerning gender, presence of vesicoureteric reflux (vur), bladder capacity, detrusor overactivity, residual urine, urinary tract infection (uti), asymptomatic bacteriuria, constipation, detrusor-sphincteruncodination (dsu), high detrusor pressure at maximal cystometric capacity, low compliance, thickness and trabeculation of the bladder wall. renal scarring was diagnosed by dmsa scan. statistical analysis was performed by univariate and multivariate analysis. a p value <0.05, 95% confidence interval was considered significant. results: renal scarring was detected in 38 patients (31%). abnormal bladder capacity, detrusor overactivity, residual urine, asymptomatic bacteriuria, constipation, dsu, high detrusor pressure and low compliance were not associated with renal sccaring. vur, uti, decreased bladder capacity, urinary residue, trabeculated and thick bladder wall were associated with scarring at univariate analysis. multivariate analysis showed vur (p<0.0001) and female gender (p=0.05) as independent risk factors for renal scarring. thickness of the bladder wall was a marginal risk factor (p=0.07). conclusion: urodynamic parameters didn´t predict renal damage in this study. uti was not a risk factor for renal scarring; however, it was associated with vur (p=0.03). although vur was the main risk factor in our analysis, renal scarring was probably due to multifatorial causes as vur was associated with itu. results: comparison of test a and b demonstrates that a mild fluid load 1 h before the administration of ddavp nasal spray (2 puffs) results in 3 major significant differences.1). maximal concentrating capacity (cc) is reached later than 1h after administration (p<0.05). in 8/46% cc at sleeping time is <70% of max, thereby resulting in a persistent np in the first hour of the night. 2) uosmol is significantly (23%) lower in the overnight collection (u4), correlating with a higher diuresis-rate (16%)3). the duration of the ddavp effect is shorter leading to an increase in diuresis-rate and to a decrease in the u osmolality in 24/46 children in the urine-collection between 4-7h in the morning. this proves that in up to 50% of the patients the ddavp-effect does not cover the full night. conclusion: test b demonstrate sthat fluid intake prior to the ddavp-administration influences significantly the antidiuretic effect of ddavp (onset, maximum and duration). this might explain the partial response, suggestive for insufficient pd (and pk) effect of the spray. test a proves that fluid restriction 1 h before ddavp administration, significantly reduces the nocturnal diuresisvolume. m. schmidts, c. schnakenburg, k. häffner, c. jacobi, k. schwab, m. pohl university hospital, center for pediatrics and adolescent medicine, freiburg, germany background: enteropathic hemolytic uremic syndrome (d+hus) is responsible for 90% of all hus cases. in addition to the nephrological and neurological complications, pancreatic damage resulting in diabetes mellitus is also possible and appears to be associated with more severe cases and elevated mortality. case report: a 3-year-old girl suffering from d+hus with severe colitis, acute renal failure, dyskinesia, dysarthria and agitation provoked by shiga-like toxin positive ehec infection in july, 2006. the severe affection was characterized by partial thalamic infarction, prolonged leukocytosis (max. 51 g/l) and the necessity of 4 weeks of dialysis. 6 days after the disease onset, hyperglycemia (max. 530 mg/dl glucose) was noted. c-peptide was found to be low indicating reduced insulin secretion. 6 months after hus the patient continues to be insulin dependent. clinically apparent exocrine pancreatic insufficiency has resolved spontaneously. gfr had recovered to 28 ml/h/1,73 m 2 , but then kidney function deteriorated and dialysis had to be resumed after 5 months. kidney histology at this time showed severe nephron loss compatible with chronic changes after hus and ruled out other unrelated kidney disease. conclusion: in addition to the kidney damage, chronic pancreatic damage can occur in hus. therefore blood glucose levels should be monitored in all hus patients. it is tempting to speculate that patients after childhood hus might be at risk for diabetes mellitus later in life. objective: childhood nephrotic syndrome (ns) is characterised by a relapsing course resulting in significant corticosteroid burden or prescription of cytotoxic immunosupressive therapy. this randomised controlled study was carried out over 3 years at a single centre in sri lanka to compare the efficacy and safety in children with steroid dependant ns treated with intravenous cyclophosphamide or intravenous vincristine therapy. methods: thirty-nine sequential children with steroid dependant ns with evidence of steroid toxicity were randomly allocated to receive either intravenous cyclophosphamide (500 mg/m 2 monthly for 6 months) or vincristine (1.5 mg/m 2 weekly 4 doses followed by 4 doses monthly). both groups received an identical tapering regimen of oral prednisolone for 6 months. all children were reviewed on monthly basis for one year focusing on recurrence of proteinuria and side effects of therapy. finding of +++ proteinuria for 3 consecutive days was diagnostic of relapse. results: there were 18 (11m: 7f) children in the cyclophosphamide group (mean age 6.4 years) and 21 (15m: 6f) in the vincristine group (mean age 7.2 years). during one year of follow-up 6/18 (33%) in the cyclophosphamide group suffered a relapse while 13/21 (62%) suffered a relapse in the vincristine group. p=0.03 (comparison of 2 proportions using standard error. ci 0.105 to 0.49). no serious adverse effects were encountered in either group. conclusion: in steroid dependant ns, intravenous cyclophosphamide therapy is superior to intravenous vincristine therapy in maintaining sustained remission. we present the clinical and biochemical features of a patient with antenatal bartter syndrome who was found to have a novel romk mutation. the patient presented antenatally with severe polyhydramnios. polyuria, hyponatraemia and hyperkalaemia were evident soon after birth. she had marked hypercalciuria and developed medullary nephrocalcinosis in early infancy. failure to thrive was evident from 12 months. hypokalaemia was a late feature, developing gradually from 18 months. serum chloride levels were consistently 95-100 mmol/l whilst urinary chloride levels were consistently <30 mmol/l, only reaching higher levels after treatment was commenced. alkalosis was not present and the patient did demonstrate some response to furosemide implying some functional capability of na-k-2cl. renin and aldosterone levels were persistently elevated. treatment with indomethacin, nacl and kcl produced a good clinical response. mutational analysis revealed compound heterozygous mutations in kcnj1, the gene encoding romk. both mutations, m357t and l359r are in the terminus of the protein thought to have a role in channel gating. similarities and differences from the classically described presenting features of antenatal bartter syndrome highlight the clinical heterogeneity in this condition. this relates to the different identified kcnj1 mutations which are likely to affect romk function in different ways. the m357t mutation has been described, but past electrophysiological studies in sf9 cells transfected with the m357t mutant have not identified any differences in k + conductivity from wild type romk. given that the mutation appears to be clinically relevant in this case, further functional studies are indicated. l359r is to our knowledge a novel mutation. expression of these mutations in oocytes is now planned to enable evaluation their effects on channel function and regulation. a 10-year-old boy was admitted because of nephrotic syndrome. renal biopsy, performed after 4 weeks of prednisone (60 mg/m 2 od) + 3 methylprednisolone pulses (15 mg/kg each), showed focal segmental glomerulosclerosis. prednisone was tapered (to 30 mg/m 2 od) and enalapril was introduced, without any significant improvement. two weeks later, the patient had transient hypoperfusive acute renal failure which required acei discontinuation. due to the persistence of proteinuria, cyclosporine was started (5mg/kg/day). proteinuria gradually decreased and ceased within the subsequent two weeks. in the meantime the boy had started to complain of low-grade fever without other symptoms and with normal physical examination. laboratory tests only showed leucocytosis (wbc 22 x 10 3 /ml) and increased c-reactive protein (65 mg/l). a chest x-ray revealed an upper mediastinal enlargement and a total body ct scan confirmed the presence of several enlarged mediastinal lymph nodes, whose biopsy led to the diagnosis of hodgkin disease (hd) nodular sclerosis subtype, cd30+; stage was iia. cyclosporine and the residual steroid treatment were discontinued and the patient was given six cycles of abvd (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by radiation therapy. presently, 18 months after stopping chemotherapy, both hd and nephrotic syndrome are still in remission. once again, this case points out both that fsg can be secondary to a lymphoproliferative disease and that chemotherapy for hd might have been effective to keep fsgs in long-lasting remission. several treatment methods including increased fluid intake and dietary modification, medical therapies such as potassium citrate and use of extracorporeal shockwave lithotripsy (eswl) and finally surgery methods are used for treatment of urolithiasis. the aim of this study was to evaluate the etiological and clinical characteristics and level of response to medical therapy with polycitra in children with urolithiasis. one hundred thirty-four patients had urolithiasis of which 109 cases followed thetreatment instructions and fulfilled the inclusion criteria for this study. struvite stone were excluded from the study. all other patients who had an initial ultrasonography showing stone inurinary tract were treated with polycitra-k (potassium citrate 220 grams, citric acid 66.8 grams in 1 liter of distilled water) irrespective of the cause of the stone. at the end, complete resolution or passage or a decrease in the size of stone in later sonography was defined as response to treatment. hypercalciuria and hyperuricosuria were found to be etiological factor in 25% and 19% of patients respectively. the stone analysis was found that 50% of them were ca-oxalate. stone disease was more common between the age of 1-5 years. the most common complaint was hematuria (20%). eswl was performed in 42% of patients who did not respond to polycitra and had surgically active stones. calcium-oxalate stones were the most frequent stone which responded to polycitra. the response rate in girls and boys was equal and in different age groups the response rate was almost equal. methods: mmcs were expanded in culture and immunocytochemistry was used to characterize the cells. after gentamicin-induced atn, fluorescently-labeled cells were transplanted and traced in kidney tissues by fluorescence microscopy. kidney pathology was studied by hematoxylin-eosin staining, apoptosis was examined by the tunel assay, and ki-67 and bcl-2 expression were examined by immunohistochemistry and reverse transcription-polymerase chain reaction, respectively. results: (1) mmcs (rimm-18 cells) were successfully expanded in culture. the phenotype of the cultured cells were vimentin-positive and kreatin-negative by immunocytochemistry. (2) in the mmcs-treated group: the mortality rate decreased; renal function clearly improved; damage to the cell-treated kidneys was reduced and histopathologic lesion scores were lower; proliferation of renal tubular epithelial cells was improved; the apoptosis of renal tubular epithelial cells was reeuced; and the expression of bc1-2 mrna and protein was upregulated. the subcapsular transplantation of mmcs could ameliorate renal function and repair kidney injury. atn is the most common reason for arf, and there is still an absence of effective therapies. this study was done to observe the effect of mobilizing bone marrow cells with stem cell stimulating factor (scf) and gm-csf on recovery from gentamicin-induced acute tubular necrosis (atn) in rats. atn was included in male sprague-dawley rats with five daily high dose intraperitoneal injections of gentamicin. subcutaneous injections of scf and gm-csf were administered simultaneously and these cytokines was observed at day 2, 5, 10, 17, 24 and 31. leukocyte numbers, percent venous blood cd34+ cells, mortality rate, and concentration of the urine proteins, urine nag, bun, scr, and ccr, histopathogic lesion scores were determined. twelve hours after bone marrow ablation (bma) by lethal x-ray radiation, gentamicin-induced spf atn rats were given five daily injections of scf and gm-csf. bun, scr, and histopathogic lesion scores were evaluated at day 2, 5 and 10. the effects and mechanism of scf and gm-csf on atn was observed. the number of leukocytes and the cd34+ cell percentage increased significantly in atn rats between 2 and 10 days after scf and gm-csf injection. in addition, mortality rates dropped, the peak value of renal function increased, renal function were rapid ameliorated and histopathologic lesions were reduced. there was no significant effect on atn rats after bma. this study demonstrates that scf and gm-csf effectively mobilized bone marrow stem cells in atn rats. rapidly improving renal function and decreasing mortality rate. these results suggest that bone marrow stem cell mobilization may be an effective therapy for atn. key words: acute tubular necrosis, bone marrow stem cells, stem cell factor, granulocytemacrophage colony stimulating factor, irradiation. objective of the study: the response to recombinant human erythropoietin (rhuepo), 50 unit/kg twice weekly was studied prospectively in 35 children and adolescents with end stage renal failure who were either transfusion dependent or had hematocrits (hct) <25%. methods: rhuepo was given to 22 haemodialysis (hd) patients and 13 patients on conservative treatment, with mean age (10.84±4.08) years, 25 males and 10 females with mean hct (26.75±4.70). blood pressure, haematocrit, iron-indices, serum potassium, calcium, phosphorus, alkaline phosphatase, urea nitrogen and intact parathyroid hormone (ipth) were monitored serially. results: serum aluminum was measured randomly in 6 patients, results were normal ranging from 12-22 ug/l. when serum ferritin was <100ng/ml during therapy, they received iron supplementation. according to the response, patients were divided into 2 groups, the non-responders group with hct<27, mean age (9.97±3.55) years, 13 males and 6 females with mean ipth (669.9±461.77 pg/ml) and group of responders with hct >27 with mean age (11.66±4.32 years),12 males and 4 females with mean ipth ( increase of fatty acids such as nonesterified fatty acid (nefa) and triglyceride (tg) with oxidative stress and production of cytokine/chemokine occured during cisplatin (cp) toxicity. statin (3hydroxy-3-mthylglutaryl coenzyme a reductase inhibitors) have been postulated to have pleiotrophic effects. we examined whether statin, pravastatin, would ameliorate renal damage induced by cp. male wistar rats (weight 180-200 g) fed standard chow were divided into 3 groups: control-rats received tap water alone for 19 days; cp treatment-rats that received cp (10 mg/kg, i.v.) on the 14 th day of the study; cp+pravastatin treatment-rats that received pravastatin (6 mg/kg/day) in their drinking water for 19 days and cp injection as indicated in the preceeding group. blood and urine samples were collected and the kidney were removed 5 days after cp treatment. urinary excretions of protein and 8-hydroxy-deoxyguanosine (8-ohdg), serum levels of creatinine and fatty acids were measured. histology was evaluated by light microscopy with immunohistochemistry for pentosidine, n-carboxymethyllysine (cml), and heme oxygenase (ho)-1. expression of ho-1 mrna in the kidney was also measured. pravastatin decreased urinary excretions of protein and 8-ohdg and ameliorated renal function diminishing areas of tubular damage and positive staining of pentosidine and cml compared with those of cp treatment alone. however, positive staining area and mrna expression of ho-1 were not significantly changed by pravastatin treatment. although pravastatin did not influence serum levels of total and low-density lipoprotein cholesterol, serum tg level decreased and was equivalent to that of control group. these findings suggest that pravastatin treatment partially protects against cp-induced nephrotoxicity in rats, through its antioxidant as well as lipid-lowering effect. n. bresolin, v. fernandes, f. carvalho, j. goes, l. araujo, m. simon, g. gamborgi, m. zanin hospital infantil joana de gusmo, nephrology pediatric department, florianópolis, brazil objectives: the objective is a report case of acute renal failure (arf) in a child contact with lonomia obliqua caterpillar in southern brazil. the accidents with lonomia oblique has increased in south of brazil in recent years. this increase can be related with reduction of caterpillar natural predators and deflorestation. the venom of lonomia caterpillar provokes hemorrhagic syndrome resembling disseminated intravascular coagulation (dic) and hemolytic anemia. arf could be an important complication of hemoglobinuria that has been recently described in adults. methods: a case report. results: the present is a first case described of arf in a child after contact with lonomia obliqua caterpillar. conclusions: the arf can occur in any age, however, the contributing factor to the development of arf remains obscure. there are 3 mechanisms pointed out: fibrin deposition in glomerular microcirculation, ischemia in hemorrhagc shock with hypotension and venom direct action. the present article related a case of lonomia obliqua accident in a child who revealed coagulation disorder, hemolytic anemia, arf and always, she was hemodynamic stable. the treatment included antilonom serum, urine alkalinization, hyperhydration and peritoneal dialysis for four days. she was treated and followed per 1 year when she recovered her normal renal function. introduction: secondary hyperparathyroidism develops in chronic kidney disease as a consequence of impaired phosphate, calcium and vitamin d homeostasis. the treatment includes phosphate binders and vitamin d analogues, but sometimes ineffective. we report two cases of refractory secondary hyperparathyroidism treated successfully with cinacalcet. case 1: a 21-month-old boy with end stage renal disease (esrd) due to posterior urethral valve started on peritoneal dialysis at 12 months of age. he developed secondary hyperparathyroidism with serum parathyroid hormone (pth) level reaching 585 pg/ml. serum calcium had been in the range of 6.7 to 9.6mg/dl and serum phosphorus in the range of 1.7 to 10.7 mg/dl. despite treatment with phosphate binders and vitamin d analogues, pth levels kept increasing to 897 pg/ml. x-ray showed the cupping and fraying of the distal ends of radius and ulna. we started cinacalcet 10 mg daily and increased the dosage up to 30 mg daily. eight months later, pth level decreased to 154 pg/ml and bone changes resolved. case 2: a 12-year-old boy with esrd due to primary hyperoxaluria started on peritoneal dialysis at 10 years of age. he developed secondary hyperparathyroidism with serum pth level of 641 pg/ml. serum calcium had been in the range of 7.9 to 9.7 mg/dl and serum phosphorus in the range of 5.9 to 11.1 mg/dl. despite treatment with phosphate binders and vitamin d analogues, pth level kept increasing to 1457 pg/ml. x-ray showed the distal radius and ulnar fracture of left arm and right femur fracture. we started cinacalcet 30 mg daily. five months later, pth levels decreased to 151 pg/ml. conclusion: cinacalcet is effective in the secondary hyperparathyroidism resistant to phosphate binders and vitamin d analogues in children with chronic renal failure. rota virus (r) is a common pathogen as the cause of gastroenteritis in childhood. we experienced some cases with r infection who had the renal failure induced by uroammoniac calculi as well as dehydration. we examined the clinical feature and laboratory findings of the cases with viral acute gastroenteritis in r and non-rota virus (nr) groups for 2005-2006. with rapid diagnosis test, we checked the patients that needed the hospitarization medical treatment from newborn to five-years old. in the 42 cases of r group and 23 cases of nr group, we campared the clinical findings, blood chemistry test and urinalysis of r groups in acute and convalescent a tage with those of nr group. r group had significantly (p<0.05) lower in ph (vein blood gas test) and higher in blood uric acid (bua) compared with those of nr group. these findings suggest that the elevation of bua and acidosis in r group may induce the formation of renal calculus resulting in postrenal failure. our patient is white male 9 y/o. at 4 year of age, he was dx. with acute lymphocytic leukemia and was induced to remission on pog 9404; he presented tumor lysis syndrome during induction, acute renal failure with no recovery in renal function and rrt was started (ccpd) and continue on the same therapy. during the last years, he presented chronic pancreatitis, ards, sepsis. he had episodes of major vessel thrombosis probably due to central lines (several femoral lines and vascath placed in his thorax) and l-asparaginase. our patient did receive 3 years of chemotherapy and radiation; and he is on complete remission. on 11/2,005, for pre-kidney transplant evaluation, a mri test was requested using gadolinium 1 ml/kg for evaluating his vascular system (abdomen and pelvis) with inconclusive results. another mri test was requested 3 months later using gadolinium 0.3 ml/kg. 8 weeks later, his mother noticed brawny hyperpigmented, shiny, tightly bound-down, indurate plaques of his bilateral lower extremities, (more significantly on his lateral and posterior calves, and in his anterior and lateral thighs) a punch skin biopsy showed increasing number of fibroblastic cells and widened space between septa in the deep reticularis dermis compatible with nfd. nfd is a fibrosing disorder identified among patients with renal disease with cutaneous finding of skin thickening in extremities and trunk, very similar to those of systemic sclerosis. etiology, pathogenesis and clinical course remain unknown. the majority of cases have been reported in dialysis or kt patients and gadolinium has been identified as a trigger of nfd. in our case, there appears to be a link between the use of gadolinium and the developed of nfd. background: chronic renal failure (crf) is an independent cardiovascular risk factor. changes in calcium-phosphate homeostasis not only affect the quality of bones but also constitute the biochemical base for vascular calcification. aim: to find a method better describing factors of calcification using routine laboratory examinations and computed evaluation of complex equilibria. methods, patients: data of 12 crf and of 24 transplanted (tx) children were compared to a healthy control group of 15. tx children's parameters were taken before and 12 and 48 month following transplantation. three different strategies were used to analyse factors of calcification: ca x p product, ca-p activity value and the concentration of cahpo 4 . the ca x p product and the ca-p activity value were not informative, because they didn't represent the direction of change in the complex chemical equilibrium. the cahpo 4 concentration was increased in the crf and the tx group (before transplantation) (0.380±0.173 mmol/l) compared to the healthy control group (0.260±0.060 mmol/l) (p<0.01). after 12 and 48 months to transplantation the cahpo 4 concentration was in the normal range in the tx group. a negative correlation was found between the concentration of ica 2+ (ionic calcium) and pth (parathyroid hormone) in the dialysed children (r=0.720), but not in the transplanted group (r=0.122). conclusion: according our findings the force driving calcification is better represented by the concentration of cahpo 4 , the base compound of all primary calcification, than by measuring ca and p separately. follow-up study is needed to establish the predictive value of determination of cahpo 4 . this study was supported by grants otka-t046155 and ett 435/2006, the national office for research and technology (nkth) and szentágothai j. knowledge centre. introduction: acute renal failure is a rare complication of nephrotic syndrome and its cause is still unknown. several investigators reported that the most important factor for renal failure was acute tubular necrosis (atn); however, some cases did not have laboratory findings of tubular dysfunction paradoxically. patients and methods: we reviewed 11 cases of nephrotic syndrome with acute renal failure (nsarf) since 1990 at metropolitan kiyose children's hospital. seven of 11 cases had calcium deposition in the distal tubules predominantly. we analyzed the clinicopathological findings in these 7 cases. results: the pathological diagnoses of these 7 cases were as follows: 4 minor glomerular abnormalities, 2 mesangial proliferative glomerulonephritis (without iga deposition), and 1 focal segmental glomerulosclerosis. interstitial nephritis was not documented in any case. the common characteristics of these 7 cases were calcium deposits in the distal tubules. some cases had focal simplification of tubular epithelium. all cases were an initial episode of nephrotic syndrome, and 6 cases were steroid resistant. almost all cases had hypertension. in addition, the range of urinary β2 microglobulin and fena were 94 to 2980 and 0.1 to 0.33%, respectively. discussion: in these 7 cases, there was enhanced na reabsorption and urinary β2 microglobulin was only mildly elevated at the time of renal failure. these findings were not consistent with atn. additionally, pathological finding of severe tubular damages was not found on biopsy. contrarily, tubular obstructions due to ca depositions were consistent with these clinicopathological findings. conclusion: our findings suggest that tubular obstruction due to calcium deposition plays an important role in the etiology of nsarf except for atn. background: natriuretic factor was found in urine of chronic uremia for more than 30 years. n-terminal pro-b-type natriuretic peptide (prontbnp) is postulated to be the natriuretic factor owing to its elevation in chronic kidney disease (ckd). however, salt wasting and non-saltwasting chronic kidney disease haven't been partitioned as different entities before. this study is designed to clarify whether prontbnp is different in salt wasting and non-salt wasting ckd and if it is the main causative factor of natriuresis. methods: 17 patients with salt wasting ckd, which are mainly composed of congenital renal structure abnormalities, and 11 patients with non-salt wasting ckd, which are mainly composed of glomerulonephritis, were collected. all of them are non-dialysis-dependent and without heart failure. serum prontbnp in these two groups and 28 normal controls were sampled. fractional excretion of sodium (fena) and estimated clearance of creatinine (ccr) were also checked. results: prontbnp was elevated in salt wasting group compared to normal controls (p=0.012). moreover, prontbnp was even significantly higher in non-salt wasting group than in salt wasting one (p<0.0001). in salt wasting ckd, prontbnp and fena were correlated (r=0.7, p=0.017), but the same result was not observed in non-salt wasting group. prontbnp was significantly correlated to ccr and age using multiple regression analysis (p<0.05). conclusion: prontbnp elevation was different between salt wasting and non-salt wasting ckd. volume expansion explained the difference and prontbnp elevation in salt wasting ckd resulted from other mechanisms. since salt wasting ckd, in which the influence of volume expansion was eliminated, had a good correlation between prontbnp and fena, prontbnp may be one of the major contributing natriuretic factor in chronic uremia. background: cidofovir is a new antiviral drug that has a broad spectrum of activity against a number of dna viruses. several observations reported its efficacy as topical treatment of resistant warts. we herein report a systemic complication of acute renal failure associated with such topical therapy. casereport: girl aged 17, received a renal transplant in 1999 and 2001 for end-stage renal failure secondary to haemolytic uremic syndrome. her initial immunosuppressive regimen consisted of prednisone, tacrolimusand mycophenolate. five years post transplant she developed chronic allograft nephropathy with mild renal impairment. as a consequence of long standing immunosuppression she also developed invalidating, widespread periungueal warts. a well conducted, aggressive, conventional management of her warts including reduction of immunosuppression failed to improve the symptoms. she subsequently received an intralesional injection of a 75 mg/ml cidofovir solution. forty eight hours after the treatment she developed local swelling, inflammation and pain along with acute alteration of renal function. although cidofovir seric dosages performed on day 4, 5, 7 and 8 postinjection were negative we attributed this acute renal failure to a potential nephrotoxic side effect of cidofovir. renal biopsy showed no evidence of rejection but mild alterations of the tubes compatible with tubulo-interstitial nephritis. spontaneous recovery of renal function occurred within 2 months. conclusion: we describe an acute renal failure as a consequence of topical cidofovir treatment of warts in the context of renal transplant with mild preexisting renal failure. topical administration of cidofovir needs as carefull use and monitoring as its parenteral administration, especially in patients with altered renal function. the hemolytic uremic syndrome (hus) is a disease characterized by microangiopathic hemolytic anemia and variable organ impairment with a predominat feature of renal failure in children. the aim of this study was to investigate the presence of plasma lipid peroxidation products in the acute phase of hus. we have analyzed the levels of lipid peroxidation, determined fluorometrically as thiobarbituric acid-reactive substances (tbars), in the plasma of 8 patients (aged 15-48 months with a median of 23) diagnosed with the shiga toxin-associated form of the disease. in all cases, tbars determinations were performed at hospital admission, during treatment and upon discharge. tbars values averaged 1.27±0.14 and 1.12±0.20 mm sem at admission and discharge respectively (reference value <0.5 mm). of the patients examined, 4 presented conserved diuresis during the course of the syndrome, while the other 4 were anuric and required dialysis. maximum tbars values resulted significantly higher (p<0.05 by anova followed by newman-keuls test) in the dialysis-requiring patients as compared to those that had conserved diuresis (2.66±0.48 vs 1.58±0.39 mm respectively) we also investigated a possible correlation between tbars and plasma creatinine, urea, lactate dehidrogenase (ldh) and platelet count. positive and highly significant correlations (r=0.45 and 0.47, p<0.01) were observed when tbars values were plotted as a function of plasma creatinine and urea values respectively. no significant correlations were detected for tbars and plasma ldh values or platelet count. thus, patients affected by shiga toxin-associated hus exhibit increased levels of oxidative stress. also, there is a positive correlation between the magnitude of oxidative stress and the severity of renal failure. c. soares, j. diniz, e. lima, g. oliveira, c. camargos, b. sousa, e. oliveira objective of the study: the purpose of this retrospective cohort study was to report the clinical course of children and adolescents with chronic kidney disease (ckd) enrolled in a pre-dialysis program. methods: the records of 108 patients with ckd admitted to an interdisciplinary pre-dialysis program from 1990 to 2006 were retrospectively analyzed. the program consisted of conservative management of children and adolescents with ckd and was conducted by an interdisciplinary team including pediatric nephrologists, pediatricians, nurses, psychologists, nutritionists, and social workers. the patients were admitted with a glomerular filtration rate (gfr) equal to or below 75% of the value expected for their age according to normal reference data. demographic, clinical and laboratory data at entry and at the end of the follow-up were analyzed. renal survival analysis was performed using the kaplan-meier method. results: the median age at admission was 8.8 years (interquartile range: 2.6-13.2 yr). the most frequent primary renal disease was congenital urological anomaly in 50 patients (46%), following by glomerular diseases in 25 (26%), cystic diseases in 19 (18%), and others in 14 children (13%). at admission, 8 patients (7%) had ckd stage 2, 60 (56%) had ckd stage 3, and 40 (37%) presented ckd stage 4. median follow-up time was 5.3 years (iq range, 2.6-7.8). at the end of the follow-up, 12 children presented ckd stage 1 or 2 (13%), 20 patients were in stage 3 (18.5%), 16 in stage 4 (15%), and 58 children were in stage 5 (54%). it was estimated by survival analysis that the probability of ckd stage 5 was 24% at 3 years, 37% at 5 years, and 62%at 10 years after admission to the pre-dialysis program. conclusion: the long-term overall renal survival is relatively poor in a cohort of children and adolescents with ckd. objective: characterize the association between proteinuria and gfr in a cross-sectional study of children with mild to moderate chronic kidney disease (ckd). methods: first morning urine protein to creatinine ratios (up/c) and gfr (measured by iohexol blood-disappearance) for 260 children enrolled in the ckid cohort study were examined using loglinear regression of proteinuria and gfr, adjusted for age, sex, body surface area (bsa), and ckd cause. conclusions: in children with mild to moderate ckd, there was a log-linear relation between proteinuria and gfr. the prospective cohort design of ckid will assess the risk of gfr decline associated with level of proteinuria in children with glomerular vs non-gn causes of ckd. objective: to study the clinical characteristics of chronic renal failure (crf) in children. the clinical data of 81 children with crf in the last fifteen years were retrospectively analyzed. results: the first main causes of crf in children were still glomerular disease, and congenital deformities of urinary system and hereditary renal disorders were the second main causes. the initial age of children with crf which were caused by congenital deformities of urinary system and hereditary renal disorders were relatively younger than children with crf which were caused by glomerular disease. the symptoms of some crf in children were not typical. conclusions: glomerular disease were still the first main causes of crf in children. urine screening test, early renal function examination and kidney b-mode ultrasonic were attribute to early diagnosis and proper management of crf in children. the aim of the study was the evaluation of influence of clinical and biochemical parameters upon degree of impairment of cardiac function in dialysed children. methodology: 16 chronically dialysed (6 hd, 10 pd) children participated in the study (10 m, 6 f), aged 5-18,5 yrs (x=12,2±3.8 yrs). echocardiography examinations were carried out with a hp 5500 device. diastolic and systolic left ventricular (lv) dimension, ejection fraction (ef) and lv mass index (lvmi) were evaluated. mean values of estimated parameters in 6 months preceeding echo were calculated. results: on the basis of echo examinations 3 groups were singled out: a (n=3) of normal heart function, b (n=3) of impaired systolic and diastolic heart function and c (n=10) of normal systolic and impaired diastolic heart function. no differences between groups according age, bmi, dialysis and renal insufficiency duration were found. in group of children with severe cardiac lesion (b group) a higher lv mass (a vs b vs c: 74,7 vs 119,9 vs 73,5 g/m) and statistically significant lower ejection fraction (68,1 vs. 33,7 vs. 65,9%) were ascertained. these children were anuric (996 vs. 0 vs. 1112 ml/d), their systolic (102,1 vs. 118,4 vs. 117,9) and diastolic (64,4 vs. 84,8 vs. 77,9) blood pressure were significantly higher, so was the number or hipotensive medications (0,33 vs. 1,72 vs. 1,44) . bioimpedance analysis showed overhydration in group b (tbw% 63 vs 67 vs 62.5; ecw/icw 0.67 vs 0.76 vs 0.7). conclusions: the vast majority of chronically dialysed children demonstrate an impairment of cardiac function mainly of diastolic parameters. anemia, malnutrition, hypervolemia, anuria and hypertension stand for a significant risk factors of cardiac impairment in dialysed children. we report here the clinical findings and prognosis of 10 patients (5 girls, 5 boys) with infantile oxalosis diagnosed between june 1990 and december 2006 in order to remind this rare autosomal recessive metabolic disorder as the potential cause of acute renal failure in infancy. the mean age of the patients was 4.7 months (range: 2.5-10 months). all patients had the complaint of vomiting since birth, 3 had irritability, and 2 had convulsions. seven of them had parental consanguinity (70%) and family histories revealed urolithiasis in four patients and infantile deaths in one. two patients were cousins without any other family history. all patients presented with anemia (hemoglobin: 4.5-9.6 g/dl), renal failure (creatinine levels: 3.2-10.2 mg/dl) and metabolic acidosis. abdominal x-rays showed bilateral nephrocalcinosis, renal ultrasonographies revealed normal sized kidneys with diffuse and intensive hyperechogenity and loss of corticomedullary differentiation in all patients. crystal deposition was demonstrated in fundoscopic examination of 5 patients, bone marrow aspiration of 2 patients, and renal tissues of 8 patients that underwent renal biopsy. besides supportive therapy, peritoneal dialysis was performed on 7 patients, but only one patient accepted to continue the therapy. four patients died within few months and 4 were lost to follow-up, probably died. two patients have been followed up for 3 months one on continuous ambulatory peritoneal dialysis. in conclusion, this rare disease with fatal outcome should be remembered and investigated in infants with renal failure and bilateral nephrocalcinosis since early combined renal and liver transplantation may be life saving if it can be performed. acute renal failure following halothane anesthesia in young child? case report we present here the case of renal failure and hepatocellular lysis that developed 24 h after the exposure of halothane anesthesia during eye examination. previously a healthy 7 months old boy had a cardiac arrest, during the above mentioned diagnostic procedure, therefore cpr was applied which all happened in another hospital. after a few hours he was transferred to icu at our hospital, consciousness, hemodinamic stabile. in the following 24 hours he developed acute non-oliguric renal failure (maximal level of urea 29 mmol/l, creatinine 259 mmol/l), as well as hepatocellular lysis (alt 1879 u/l, ast 2157 u/l). plasmaferesis and continuous venovenous hemodiafiltration were immediately applied followed by conservative measures. the level of serum transaminase returned to the normal values within a week and the level of creatinine and urea within two weeks. fully recovered boy was released home. toxic effects of halothane anesthesia in children are reported in only few cases in the literature. objective of study: many cases of chronic aristolochic acid nephropathy (caan) in adults had been reported, but it had rarely been described in children. we reported 3 children with caan to investigate its clinical and pathological characteristics. methods: three cases were studied retrospectively and relevant literatures were reviewed. results: three children received traditional chinese herb medicine containing aristolochic acid 4 to 8 months for different basal diseases including chronic aggressive hepatitis b, secondary hydrocephalus and purpura nephritis and suffered from caan from 2 mouths to 6 years after they began receiving the chinese medication. the main manifestations were renal failure of various degree accompanied with proximal and distal tubular dysfunctions. two of them began with anemia and suffered from serious renal failure. the onset of another case was glucosuria with renal function impaired mildly, and she presented secondary fanconi's syndrome simultaneously. their pathological characteristics were diffuse paucicellular interstitial fibrosis and marked tubular atrophy with mild glomerular impairment. after withdrawal of the chinese herb medicine, renal failure in two patients attenuated progressively. the clinical features of caan in children are progressive renal failure and renal tubular disfunction. its pathological characteristics are diffuse paucicellular interstitial fibrosis and marked tubular atrophy. therefore, we emphasize the recognition of the nephrotoxicity of traditional chinese herb medicine and prevent caan from happening in children. objective of study: recombinant human erythropoietin (rhuepo) treatment may cause pure red cell aplasia (prca), but it had been rarely described in children. in order to acquaint ourselves with this disease, we reported a boy with chronic renal failure developed prca following rhuepo treatment. methods: one case was studied retrospectively and relevant literature was reviewed. results: a 10-year-old boy suffered from chronic renal failure combining with renal anemia and received rhuepo treatment. two weeks later, his hemoglobin (hb) increased from 57 to 90g/l, and maintained 90 to 94g/l for 6 weeks. subsequently his hb declined suddenly at a rate of 1g/l/day, despite rhuepo increased in dose. his reticulocyte count reduced to 0.4 10 9 /l without other cytopenias in peripheral blood. a series of laboratory examinations were performed, including bone marrow cell smear and culture to confirm his prca. because various of other factors such as parvovirus etc. induced prca was excluded, we considered the boy's prca was due to rhuepo treatment, although we didn't detect anti-epo antibodies for lacking of the reagent. the boy received erythrocyte suspension transfusion to correct his anemia and was waiting for renal transplant in the following period. conclusions: during the treatment of rhuepo, sudden and rapid reducing of hb might be a hint of rhuepo induced prca. the diagnosis should be based on the clinical presentation, the absence of red cell precursors in bone marrow and the detection of anti-epo antibodies. renal transplant and immunosuppressive therapy might be effective. m. zaniew, b. mroziñski, a. warzywoda, e. stefaniak, a. siwiñska, j. zachwieja among ambulatory blood pressure monitoring (abpm) parameters, pulse pressure (pp) provide an information on cardiovascular (cv) status. recently, a novel parameter i.e. ambulatory arterial stiffness index (aasi) has been proposed. aim: to investigate pp and aasi in relation to left ventricular (lv) geometry and carotid intima-media thickness (cimt) in children with chronic renal failure (crf). subjects: 24 children (6 f/18 m; median age: 15 yrs) with crf treated conservatively (n=8) and with dialysis (hd; n=7/pd; n=9). methods: we studied demographic data, echocardiography data [left ventricular mass (lvm), left ventricular mass index (lvmi), interventricular septum (ivs), left ventricular posterior wall (lvpw), left ventricular end diastolic diameter (lvedd), relative wall thickness (rwt)], cimt and abpm. from abpm, we calculated pp [difference between systolic blood pressure (sbp) and diastolic blood pressure (dbp)] and plotted dbp against sbp (regression slope). aasi was defined as 1 minus this regression slope. results: a positive correlation was found between aasi and pp (r=0.35, p<0.05). aasi was correlated to lvedd (r=0.39, p<0.05) and rwt (r=-0.45, p<0.01). pp was related to: weight (r=0.47, p<0.01), body surface area (r=0.41, p<0.05), body mass index (r=0.43, p<0.05), and lvm (r=0.58, p<0.001), lvmi (r=0.54, p<0.01), lvpw (r=0.35, p<0.05), lvedd (r=0.68, p<0.001), rwt (r=-0.35, p<0.05). neither aasi nor pp was associated to cimt. children with lv hypertrophy had higher pp than without this alteration (p<0.05). when data analyzed across quartiles of pp, children in the upper quartile showed higher lvm (inter-group comparisons p<0.001), lvmi (p<0.01), lvpw (p<0.01) and lvedd (p<0.001). conclusions: pp is a stronger predictor than aasi of lv geometry in children with crf.. acute renal failure in newborn period may be caused by prenatal, natal and postnatal factors. among them, obstructive lesions of the genital tract (e.g. imperforate hymen and vaginal atresia) are very rare. children with hydrometrocolpos due to distal vaginal atresia may present with severe obstructive uropathy and its consequences. hydrometrocolpos is the result of vaginal obstruction and can become an emergency in newborn period. acute renal failure associated with distal vaginal atresia appears to be rare, with only one report in the paediatric literature. here we report a 27-dayold infant with a hydrometrocolpos causing life-threatening renal failure. percutaneous drainage did result in dramatically improved clinical and laboratory findings of the patient. objectives of study: sympathetic overactivity is currently considered as an important mechanism of both development and progression of chronic renal failure. however, this statement was mostly based on the researches in which the participants were adult patients with terminal renal failure. little information is available on autonomic changes in pediatric patients with mild renal insufficiency. our aim was to determine whether there is sympathetic activation in children with chronic pyelonephritis in a stage of mild renal insufficiency. methods: 47 patients met the inclusive criteria were selected and assigned into two groups according to the creatinine clearance. group i had 26 patients with creatinine clearance between 60 and 90 ml/min/1.73 m 2 while group ii have 21 patients with normal creatinine clearance. baseline of age (from 10-17 years old), gender and diagnosis between the 2 groups are comparable. time domain analysis of heart rate variability in short-term recordings of 2 minutes was performed in both groups. as well vain questionnaire for assessment of autonomic state was performed in all participants with their parents help. results: the outcomes of heart rate variability analysis showed sympathetic overactivity of 73.0% patients in group i vs 30.8% in group ii, and the difference is statistically significant (t=2.497, p<0.05). significant difference was also found in results of vain questionnaire: 69.2% of patients in group i were estimated as "sympathetic", while only 33.3% in group ii (t=2.32, p<0.05). conclusions: based on the consistent findings of the two methods used in this study, we conclude that sympathetic overactivity may be found in children with even mild renal insufficiency, and it should be considered as an early event in the development of pediatric renal failure. the aim of this study was to describe the prevalence of myocardiopathy in pediatric patients with different stages of ckd (stages 2 to 5).methodology: inclusion criteria -gfr <75 ml/1.73 m 2 , ckd treatment >6 months, age <19 years old. echocardiograms were performed using standard techniques. left ventricular mass (lvm) was measured by two-dimensional directed m-mode echocardiography according to the american society of echocardiography criteria. lvm index was assessed and when >51g/m 2.7 it was considered severe hypertrophy. the relative wall thickness (rwt) was measured to assess the lv geometric pattern. age, high blood pressure (hbp), anemia, time and type of treatment were compared to the echocardiographic findings. results: we evaluated 53 patients, mean age 8 years old, 41% on pre-dialysis, 36% on hemodialysis (hd) and 23% on peritoneal dialysis (pd). patients on hd were evaluated in the interdyalitic period. twenty-seven patients (51%) had myocardiopathy, clvh in 14 (25%), elvh in 7 (14.5%) and cr in 6 (11%). severe hypertrophy ocurred in 20 pacients (37.7%). there was no significant difference in relation to age and high blood pressure. patients with clvh were on hd for longer time and had a lower hematocrite when compared to the patients without clvh (14±3 vs 4±2 months; p<0.01) and (33±1 vs 27±1; p<0.001) respectively. there was a significant correlation between hematocrite and left ventricular mass (r 2 =0.28). conclusion: we observed a high prevalence of myocardiopathy in this study population. the risk factors associated to clvh were anemia and time on hd. larger and prospective studies are needed to analyze the impact of myocardiopathy in the cardiovascular mortality in children as well as the results of interventions applied to correct these risk factors. [0] [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . urological problems such as vesicoureteral reflux (18, 5%), obstructive uropathy (10,7%) and neurogenic bladder (15,1%) were the leading underlying conditions causing cri with a total of 46,3%. while majority of the patients were having gfr levels less than 15 (33,5%) or between 25 to 50 ml/min/1,73 m 2 (31,2%), gfr level was between 50-75 in only 16.5%of the patients. patients with pth levels between 100-300 and more than 300 pg/ml comprised the majority (32,4 and 40% respectively). the gfr levels correlated positively with hemoglobin/hematocrit and calcium levels and negatively with phosphorus and pth levels (p<0.05). renal replacement therapies were initiated in 33,6% of the patients. the most striking result of this study is the predominance of vur or related urological problems that are relatively preventable as the underlying causes of cri in children. early diagnosis and appropriate medical or surgical management of these conditions should be emphasized together with achieving broader coverage of the pediatric cri population in terms of supportive treatment. twin-twin transfusion syndrome (ttts) complicates up to 15% of monochorionic twin pregnancies. shunting of blood between twins through common placental blood vessels can cause growth restriction, oligohydramnios and anaemia in the donor twin. renal impairment in the donor twin has been reported as a transient phenomenon with full recovery. we describe a case series of three children with chronic renal failure due to ttts. all 3 cases were monochorionic diamniotic twins. in cases 1 and 2, growth discrepancy was noted on prenatal scanning. in the case 3 anomaly scans were normal. gestation at birth ranged between 31 and 36 weeks. in all cases there was a significant birth weight discrepancy between twins. post-natal ultrasound appearances were variable: case 1 had normal scans within the first month but echogenic kidneys at 3 months; case 2 had initial increased echogenicity but features consistent with cortical necrosis at 4 weeks; case 3 had small kidneys with no cortico-medullary differentiation. all 3 children became dialysis dependent within the first year of life. age of commencement ranged from 4 days to 7 months. case 3 was successfully transplanted at 3 years. case 2 had an unsuccessful transplant at 2 years and remains on dialysis at 4 years. case 1 remains on dialysis at 2 years. cases 2 and 3 are now at mainstream school with only mild learning difficulties; case 1 has some gross motor delay but other wise normal development. with advances in neonatal intensive care and improved survival of low birth weight babies, this presentation may become increasingly common. even severe renal involvement can occur in the absence of other significant hypoperfusion injury. the management of survivors of ttts with established renal failure may present unique challenges and opportunities. introduction: endothelial heparan sulfate proteoglycans (hspg) play an important role in various biological processes in the renal glomeruli. it is involved in the inflammatory process by acting as a ligand for l-selectin. furthermore, leukocytes are able to interact with chemokines bound to hspg (examples are il-8, rantes and mcp-1). this will lead to activation of the integrins on leukocytes and result in more stable leukocyte-endothelial wall adhesion. in this work, we have studied the effect of a subtoxic dose of shiga-like toxin (stx) 1 and 2 on the hspg and the possible implications on the pathogenesis of the hemolytic uremic syndrome (hus). methods: to study this effect, primary human umbilical venous endothelial cells (huvec) and primary human glomerular microvascular endothelial cells (gmvec) were incubated for 24 hours with a subtoxic dose of stx1 or 2. then, cells were treated with the enzyme heparinase 3 (which cleaves off hspg). non-treated cells were used as controls. after treatment with the enzyme, the endothelial cells were exposed to flowing human leukocytes in a parallel plate flow chamber. the amount of adherent leukocytes was calculated. -: not treated with heparinase 3, +: treated with heparinase 3 conclusion: stx1 and 2 cause an upregulation of the amount of adhering leukocytes on both endothelial cell types. treatment of the endothelial cells with heparinase 3 decreases markedly this upregulation. the effect can not be detected without stx-incubation. this can be explained by a possible upregulation of hspg on endothelial cells by stx, resulting in a higher level of bound chemokines or an increased binding of released chemokines to hspg. this will lead to an increased adhesion of leukocytes and will induce a more severe inflammatory process in the renal endothelium. this effect will contribute to the devastating pathogenesis of the hus. c. soares, j. diniz, e. lima, g. oliveira, c. camargos, b. sousa, m. almeida, e. oliveira objective of thestudy: the purpose of this study was to identify clinical, nutritional and laboratory factors associated with the rate of progression of chronic kidney disease (ckd) among the children and adolescents admitted to a pre-dialysis interdisciplinary program. methods: one hundred eight children and adolescents aged 2 months to 19 years with ckd in conservative management were prospectively followed up from 1990 to 2006. renal survival was analyzed by the kaplan-meier method and cox's regression model. a multivariate model was developed from the admission until occurrence of ckd stage 5 (glomerular filtration rate <15 ml/min). the following data were obtained at admission: gender, race, age at admission, weight z score, renal primary disease, blood pressure, and laboratory data (serum creatinine, serum urea, glomerular filtration rate, 24 hr urinary protein excretion, hematuria). results: median follow-up time was 5.3 years (iq range, 2.6-7.8) and 58 patients (54%) progressed to ckd stage 5. in the univariate analysis the following variables were significantly associated with the event: non-white race (p=0.04), age >8 years (p=0.01), ckd stage at baseline (p=0.01), renal primary disease (p<0.001), severe proteinuria (p<0.001). after adjustment, 3 variables remained as independent predictors of ckd stage 5: severe proteinuria (rr=2.1, 95% ci=1.4±3.1), glomerular disease as renal primary disease (rr=1.5, 95% ci=1.2±1.0), and ckd stage 4 at baseline (rr=2.3, 95% ci, 1.4±3.7). conclusion: the combination of three factors -severe proteinuria, glomerular disease, and ckd stage 4 at admission -was an independent indicator of adverse outcome in children and adolescents in a pre-dialysis interdisciplinary program. background: allogenic hematopoetic stem cell transplantation (allo-hsct) has gained world wide acceptance as a treatment for various diseases. renal dysfunction is one of the major complications that influences transplant related mortality (trm) rates following hsct. in this prospective study, we aimed to investigate the effect of allo-hsct on renal function in children. methods: renal ultrasonography, dmsa scintigraphy, analysis of renal and tubular function tests were performed before, shortly and 1-year after hsct. acute renal toxicity (art) was classified according to bearman criteria. grade 1=increase in creatinine up to twice the baseline; grade 2=increase in creatinine above twice baseline; grade 3=increase in creatinine above twice baseline and need for dialysis. chronic renal insufficiency (cri) was defined as gfr<70 ml/min/1.73 m 2 and failure (crf) as need for dialysis. results: between april 1999 and june 2006, 57 children (median age: 10.0 years) underwent 58 allo-hsct because of hematologic disorders (malignancy, 19; hemoglobinopathy, 28; aplastic anemia, 10). all patients except one received nontbi conditioning regimen. six patients (10.3%) were died because of trm but none of these patients had primary art. during the first 100 days, 10 patients (17.2%) had grade 2 art (csa nephrotoxicity in 7, vod in 3 patients). grade 3 art was defined in 5 patients (8.6%) (vod in 3, sepsis in 1, csa nephrotoxicity in 1 patient). eleven patients had structural renal abnormalities before hsct, 3 of them persisted and 3 new patients had pathologic results one year after hsct. in long term period, 5 (8.6%) of 37 evaluable children had cri and no patient had crf requiring dialysis. conclusion: renal dysfunction was found to be a frequent complication after allo-hsct in children. therefore, renal functions should be followed carefully in these patients. .26 years and at the end of follow-up, and compared between the three groups. there were no significant differences between groups in so far as gender, underlying disease, age at diagnosis, proteinuria, hypertension, hyperparathyroidism, use of ace inhibitors or renal size. erithropoietin use was significantly higher (p<0.001) in group 1. gfr improved in all three groups during their first two years of life. the cut-off point on the roc curve indicating worse gfr long term evolution was 50 ml/min/1.73 m 2 at two years of life (sensitivity 85%, specificity 88%). g. zilleruelo, am. onder, j. chandar, o. nwobi, c. abitbol background: catheter-related bacteremia (crb) is a common complication of tunneled-cuffed hemodialysis catheters. our objective was to investigate the effectiveness of tissue-plasminogen activator-tobramycin locks (tpa-abl) in preventing crb in pediatric patients. methods: a retrospective analysis of 52 pediatric hemodialysis patients was performed. patients with >10 crb/1000 catheter days (cd) were designated as high risk. those with <10 crb/1000 cd were of average risk. three eras of 6 consecutive months were studied. in era 1, high risk patients were detected. during era 2, the high-risk group was placed on 3 times weekly prophylactic tpa-abl. in era 3 the high-risk group was given once weekly tpa-abl. results: there was a significant decrease in the rate of crb with prophylactic tpa-abl which was more pronounced when given three times/week. conclusions: the use of prophylactic tpa-abl 3 times weekly significantly reduces the rate of crb in patients at high risk. prophylaxis once weekly may be less effective than thrice a week. l. was born after a normal pregnancy without a special personal or familial history, was seen at the age of 4 years, after a 6 days long ordinary oro-pharyngeal viral infection treated by symptomatic treatments. he presented with inflammation of the left cheek with slight fever (38°) and a sole purpuric lesion of the left leg (1cm) and some petechiae on the thorax. blood count showed haemolytic anemia (haemoglobin=10 g/dl, schizocyte=2%, increased ldh), 23000 white cells (90% neutrophils) and 123000 platelets. no germs were found in hemoculture, lumbar punction, stools or urines cultures. creatininemia was 95 μmol/l. in the following hours, despite immediate antibiotics administration and without any shock sign, several purpuric extensive necrotic lesions appeared, renal insufficiency increased (creatininemia=175 μmol/l), platelets count decreased to 46000 and markers of diffuse intravascular coagulation dramatically increased. in the following days, proteinuria, macroscopic hematuria and hypertension appeared. after 3 days on anticoagulation therapy, renal function remained stable while anemia, thrombopenia and coagulation disorders persisted. coagulation factor tests demonstrated a heterozygote deficiency of factor v leiden (also found in the father) and an acquired protein s deficiency secondary to streptococcal infection. after protein s infusion and plasma exchanges, his state improved and necrotic lesions ceased. this initial hematologic and renal presentation could have suggest a hus but the large purpuric lesions remain unusual in such pathology. a in children on chronic peritoneal dialysis malnutrition is being diagnosed with an objective combined nutritional score (abn score) based on anthropometry and bioimpedance analysis indices (nephrol dial transpl 2006; 21: 1946-51) . aim of this study was to investigate the prevalence of malnutrition and the main factors associated with it in children with ckd 2-4. we planned a cross-sectional study of 77 children with ckd 2-4, mean age 8.9±5.8 years, who underwent controls in our institution between september 1 and december 31, 2006. the data of abn score, age, primary renal disease, standard blood and urinary tests, and estimated gfr (schwartz formula) were collected.the prevalence of malnutrition (abn score <10.33) in the whole population was 23%. the abn score was positively correlated with age, height sds, serum hemoglobin, total protein and albumin (p value from <0.0001 to <0.05), while a negative correlation was found with serum phosphate and proteinuria (p<0.005). patients with steroid-resistant nephrotic syndrome had lower abn score values than those with other primary renal diseases (9.61±0.85 vs 11.67±1.93; p<0.05). the percentage of children with malnutrition in the different stages of ckd increased in parallel with the decrease of gfr, from 10% in the ckd 2 group to 29.2% in the ckd 4 group. in conclusion, the prevalence of malnutrition in children with ckd 2-4 is not negligible. low hemoglobin, total protein and albumin levels and high serum phosphate and urinary protein excretion, particularly in small children with growth impairment, strongly suggest the need for an in depth nutritional assessment, in order to diagnose malnutrition and treat it accordingly. e.c. developed atypical hus at 6 months of age. a heterozygous factor h gene mutation was found. despite plasma-exchange treatment numerous relapses led the child to ckd stage 4: creatinine clearance (ccr) 15.02 ml/min/1.73 sqm according to schwartz formula. at 4 yrs we started a programme of fresh frozen plasma (ffp) infusions, 10-15 ml/kg bw. the child was poliuric and hypertensive, notwithstanding the treatment with ramipril, amlodipine, clonidine and furosemide. in the first 6 months he received ffp every 10 days. mean ccr during this period was 16.8±1.7 ml/min/1.73 sqm. haptoglobin (hap) was still <20 mg/dl in 10/15 tests (66.7%), ldh was increased (543.9±87.5 u/l), hemoglobin and platelet count were always in the normal range. the treatment schedule was then changed to ffp every 7 days for the next 4 months. during this period, ccr was significantly higher (23.8±2.4; p<0.0001) and ldh significantly lower than in the first 6 months (445.5±31.7; p<0.005); haptoglobin was always >20 mg/dl. no differences between the two periods were found for hemoglobin, platelet count, proteinuria, microalbuminuria and blood pressure values. both in the first and the second period, ccr was negatively correlated with ldh (r 2 0.40, p<0.0005) and with the bioimpedance analysis (bia) measure of resistance, which is an index of body hydration. in conclusion: 1. the only signs of disease activity in atypical hus can be minor abnormalities in laboratory tests, such as increased ldh and decreased haptoglobin levels; 2. ffp infusions are useful in maintaining hus remission and preserving kidney function, provided that the treatment schedule is optimized; 3. bia is useful in monitoring hydration status of children with ckd, especially those with poliuria and under ace-inhibitors, as it allows for the correct interpretation of serum cr values. analgesic-antipyretic agents are commonly used medications worldwide for the treatment of pain and fever in children. acute renal failure is commonly seen in adults after treatment with analgesicantipyretic agents. this complication has rarely been reported in children. two patients, ages 12 and 16 years were admitted with a diagnosis of acute, non-oliguric renal failure. one had symptoms of upper respiratory tract infection, and the other had been suffering from vomiting and abdominal pain. appropriate evaluations including detailed history especially the history of drug ingestion, physical examination, and measurement of serum creatinine concentrations were performed in the emergency department. both patient had ingested analgesic-antipyretic agents (mefenamic acid, and paracetamol) before the onset of acute renal failure. none of the patients had previous history of renal disease or concomitant treatment with other drugs. none had oliguria or anuria, dehydration, abnormal serum electrolyte concentrations, or evidence of glomerulonephritis. microscopic hematuria and leukocyturia were found in one patient. serum creatinine was 1.1 and 2.29 mg/dl at presentation. both of them recovered completely within a week. we emphasize that clinicians must be aware of renal toxicity of analgesic-antipyretic drugs with low doses. with the increasing use of over-the-counter analgesic-antipyretic agents, this association may become more prevalent. cardiovascular disease is a main cause of morbidity and mortallty in patients with chronic kidney disease (ckd). the pathophysiology of cardiovascular disease (cvd) in ckd remains uncertain but nowadays sympathetic hyperactivity is recognized as an important mechanism involved. this observational and transversal study of 40 patients from five to 21 years old, submitted to dialysis or at least four months after kidney transplantation (ktx), without signs of transplantations rejections, with definite ckd and creatinine clearance of 50 ml/min or less. the subject (median age=14 years; 62.5% female) were classified accordingly with treatment modality: conservative (n=7), peritoneal dialysis (capd) (n=5), hemodyalisis (n=13) and renal transplantation (n=15) submitted to 123l-metaiodobenzilguanidine (123l-mibg) planar and tomography scintigraphy and heart rate variability (hrv). comparisons among groups were made using anova and the association between variables was assessed using spearman's correlation coefficients and bonferroni correction was used during multiple comparisons testes. a p value <0.05 was considered significant. hemodialysis patients presented increased cardiac washout (p=0.002), heterogeneous pattern of 123l-mibg distribution (p=0.036) and lower values of low frequency component of hrv (p=0.040). capd subjects had reduced lung washout (p=0.030). the cardiac washout had positive correlation with pth and negatives correlation with creatinine clearance. there was a significant negatives association between the rr interval in low frequency (lf) and cardiac washout. the uremic cardiac disautonomia might be characterized by decreased low frequency component of hrv and increased 123l-mibg washout and heterogeneous distribution pattern by left ventricular walls; these abnormalities subsided after ktx. d+hus is the main cause of acute renal failure in children. extrarenal manifestations are associated in more than 30% of the cases. hus causes toxin mediated endothelial cell damage, resulting in thrombotic microangiopathy and intraluminal thrombosis of small vessels, with subsequent tissue ischemia and necrosis of involved organs. a 3-year-old boy has been admitted for d+hus associated with escherichia coli o145 diarrhea. he presented with renal failure and hypertension requiring hemodialysis for 28 days, hemolytic anemia (5g/dl, schizocytes 6%) requiring 7 blood transfusions, severe thrombopenia (10 g/l) and hyperleucocytosis (39600/mm 3 ). severe hemorragic colitis with duodenitis required prolonged parenteral nutrition. at 6 days after onset, the child presented with confusion, slurred speech followed by loss of consciousness associated with major hyperglycemia (107 mmol/l) and elevated corrected natremia (155 mmol/l) without ketosis requiring transfer in intensive care unit (icu). continuous hemofiltration associated with insulin therapy (0.05 ui/kg) was then established with slow decrease of natremia and serum glucose within 72 hours. neurologic condition rapidly improved. serum amylase and lipase were normal. insulinemia at the same time as the highest hyperglycemia was low (1,7 ui/ml), and search for human insulin, islet cell and glutamic acid decarboxylase antibodies were negative. insulin therapy could be discontinued within 15 days. at the last follow-up, 6 months later, neurologic examination, serum glucose and glomerular filtration rate were normal. in conclusion: 1/ hyperglycemic hyperosmolar coma is a severe complication yet never reported in d+hus; 2/ continuous hemofiltration with constant monitoring of biologic parameters could avoid permanent lesions due to rapid correction of this major metabolic unbalance. chronic renal failure (crf) can interfere with the regulation and time dependent secretion of multiple hormones. adrenocortical function in children with crf is examined in a few studies with a limited number of patients, and the results are controversial. in this study our aim is to evaluate adrenocortical function in basal and stimulated conditions, and to determine the relationship with the glomerular filtration rate (gfr), etiology and duration of crf in a larger group of patients. sixty-one patients with crf (28 f, 33 m; mean age 12.6±3.2 years) were studied. the patients were grouped according to etiology [structural abnormalities (n: 33), glomerulonephritis (n: 11), others (n: 11)], duration of crf [0-36 (n: 25) , 36-72 (n: 22) and >72 months (14)] and gfr [ 25-75 (n: 24), 10-25 (n: 19), <10 ml/min/1.73 m 2 (n: 18)]. cortisol levels were measured at 08: 00 a.m. (basal cortisol) and 11: 00 p.m. low dose acth test (0.5 micg/m 2 synacthen iv) was performed. delta cortisol was calculated as peak cortisol minus basal cortisol during the acth test. diurnal rhythm is accepted to be preserved if 08: 00 a.m. cortisol/11:00 p.m. cortisol is greater than two. basal cortisol levels and peak cortisol response to low dose acth is similar in all groups. median levels of delta cortisol found to be higher in the gfr<10 ml/min/1.73 m 2 group; p=0.06. diurnal rhythm seems to be more preserved in the gfr 25-75 ml/min/1.73 m 2 group (%68) compared to gfr<10 group (%44); p=0.612. no correlation was found between the basal, peak and delta cortisol, gfr and duration of crf. our preliminary results have shown that there is no difference in the basal and peak cortisol levels between all groups. this is the first study in children showing that adrenocortical function is preserved in groups with gfr levels between 10-75 ml/min/1.73 m 2 . objective: this study was we evaluated bk virus and jc virus in urinary after renal transplantation. methods: because these polyoma viruses are excreted in urine, these 12 patients (7 females and 6 males, 16.1±6.7 years old) was analyzed by polymerase chain reaction. all patients were living donor renal transplantation from a parent. results: two patients have detected bk virus in urine. as the type of immunosuppressive treatment, one had tacrolimus and mycophenolate mofetil, and one more had methylprednisolone and tacrolimus. seventeen percent of the patients had quantifiable bk virus-dna in urine. thirty-three percent of the patients had quantifiable jc virus-dna in urine. there was non significant relationship between these polyoma viruses in urine and the type of immunosuppressive treatment. no patients developed interstitial nephritis during the study. conclusions: the activation of bk virus and jc virus does not seem to be related to the type of immunosuppressive treatment. the pathogenetic role of polyoma virus infection in renal transplantation recipients further researches are needed. background: urinary tract infection (uti) due to neurogenic bladder, secondary to large spina bifida as myelomeningocele, is well known, but the association of small occult spina bifida (sbo), having normal physical examination, with that of infection has not been reported. we studied the frequency of spina bifida occulta in children with urinary tract infection. method: the kub of voiding cystouretrography in 104 patients (72 f, 31 m) with average of age 6 year (±3.5 sd), who referred to radiology department of ali asgar children hospital for uti, were observed for sbo. all patients had normal physical examination. chi2 were used to find the frequency of the level of sbo and the differences respectively. p<0.05 was considered significant. result: 80 out of 104 patients had sbo. the order of frequency of the level of sbo was s1 (51%), l5 (14,4%), s1s2 (6,7%), l5s1 (4,8%), and l5s1s2 (1%). 22 patients had vesicoureteral reflux (bilateral in 8 cases, 10 at left and 3 at right side). the severity of vur was 76% grade (g) ii, 14,35% g iii, 9.1% g iv, and 4.8% g i. spina bifida occulta was detected in 19 out of 23 patients with vur. this difference was not statistically significant (p=0.43): conclusion: the high frequency of lumbosacral sbo in the patients with urinary complaint may imply some lower urinary tract dysfunction in these patients although we need a control study in normal children. we evaluated interleukin-6 and interleukin-8 levels in the urine of 33 children with renal scarring, with vesicoureteral reflux (23/33, group a 1 ) and without vesicoureteral reflux (10/33, group a 2 ) and in the urine of 7 healthy children (group b). none of the children had urinary tract infection for the last ten months. interleukin-6 and interleukin-8 were determined using a commercially available human enzyme-linked immunosorbent assay kit. results: urinary interleukin-8 levels were below the lower detection limit in all samples. interleukin-6 levels were detectable in all urine samples of children with renal scarring and below the detection limits in the urine samples of healthy children. there were no statistically significant differences between urinary interleukin-6 levels in children with and without vesicoureteral reflux. there is a relationship between the grade of renal scars, the time past from their development and the urinary levels of il-6. the introduction of mycophenolate mophetil (mmf) was an important advance in immunosuppressive therapy but its use is associated with gastrointestinal intolerability (gi) requiring dose reductions or drug interruptions. enteric coated mycophenolate sodium (ec-msp) was designed to improve mycophenolic acid (mpa)-related gi by delaying the release of mpa until reaching the small intestine. at present, its immunosuppressive activity in pediatric renal transplant with gi has not been clarified. we studied trough levels of active metabolite mpa (c 12 ), changes in kidney function, mixed lymphocyte culture, cytotoxic antibodies as well as cytotoxic response before and after 3 months of the conversion from mmf to ec-mps in 8 renal transplant recipients with gi. in the immunosuppressive protocol used: mmf, tacrolimus and corticosteroid, mmf 444±46 mg/m 2 /day was replaced by ec-mpa 318±34 mg/m 2 /day. after 3 months of treatment with ec-mpa, the incidence of gi decrease to 12.5%. the levels of mpa were about 50% higher on ec-mps (6.9±1.1 ug/ml) compared to mmf administration (4.2±0.9 ug/ml). serum creatinine, creatinine clearance and urinary protein excretion did not change (1.3±0.3 to 1.4±0.3 mg/dl, 71.7±10.3 to 70.2±10.4 ml/min/1.73 m 2 and 0.08±0.06 to 0.12±0.06 gr/24 hr, respectively). also, during ec-mpa, proliferative response and cytotoxic antibodies showed no significant change. the release of il-10 was striking augmented with mmf or ec-mps therapy, but interferon-γ and tnf were low under both treatments. our data indicate that conversion from mmf to ec-mps leads to an improvement in gi without altering key elements of immunosuppression. however, the monitoring of mpa before and after conversion should be appropriated to the optimization of therapy efficacy. re. munarriz, ju. arakaki, ce. munarriz pediatric clinic, pediatric nephrology, buenos aires, peru objective: to describe the results of a program of chronic ambulatory peritoneal dialysis (capd) in children in peru by means of conventional indicators. methods: 61 children (52, 45% male) were included in a longitudinal descriptive study. the average age was 10, 4±4,02 years (rank of 1, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . 42% were from lima (the capital city) and 58% came from other cities of the country. primary glomerulonephritis (46, 1%) was the main cause of the renal insufficiency. we evaluated the program from 2001 to 2006. results: the average weekly kt/v was 2,8±1,13. the average dose of erythropoietin (epo) was 98 ui/kg/week. 60% of the patients had average annual albumin of more than 3,5 gr./dl. the average annual protein catabolism index (icp) was 1,0±0,37 gr/kg/d. the weight/age, height/age, weight/height z scores at the beginning and at the end were 2.1/1.3, -2.095/1.3, -2.9/2, 4 -3.4/2.2, 1.9/7.0-0.8/2.1, respectively. the average hematocrit was 26.5±7.6%. the rate of peritonitis adjusted for the period was 0, 62 episodes/patients-year (1 episode every 19 months) and the mortality for the same period were 14%. conclusions: the indicators evaluated in our patients are according to the results of the international literature. is repeated urine culture essential after antibiotic therapy in uti in thai children? background: in 1999, the american academy of pediatrics recommended for uti treatment, that urine culture be repeated only in children <2 years with fever >48 hours, since the chance of a positive urine culture in other children is very low. objective: to evaluate the cost-effectiveness of repeated urine culture after antibiotic therapy in childhood uti. patients and methods: a retrospective review of the records of children diagnosed with uti in songklanagarind hospital from jan 1-dec 31, 2004. results: there were 479 patients total, of which 30 were excluded due to no repeated urine culture. 449 patients with 533 uti episodes were analyzed (245 boys and 204 girls). 241 (53.7%), 71 (15.8%) and 137 (30.5%) patients aged <1, 1-2 and >2 years respectively. 49 (9.2%) had a repeated urine culture with significant growth. multivariate analysis showed that age <1 year, etiologic agents psuedomonas aeroginosa or enterococci spp., fever >72 hours and kub anomalies were the most significant risk factors for positive repeated culture, while vur and recurrent uti episodes were not significant risk factors. if we consider that a child who has at least one of the above risk factors should have a repeat urine culture, then 351 cases (65.9%) will require repeating urine culture and 182x3.7=$us 672.4 will be saved and 5 (10.2%) positive repeated urine culture will be missed. conclusion: our study in a group of thai children indicates that repeated urine culture after antibiotic therapy is still recommended. our aim was to find out if there are any signs of renal scarring and reduced renal function without recurrent uti in patients with obstructive pyelonephritis. there were investigated 18 children (4-12 y) with 1-4 years passed after diagnosis of obstructive pyelonephritis. these patients were investigated during 2 years long period without uti. all the children had a treatment with nitrofurantoin during season viral infections. we investigated excretion with urine of the collagen product (hydroxyproline) and activity of lisosomal enzymes (b n-acetilglutamase, elastase, pseudocholiesterase). as a control group, 20 healthy children of the same age were investigated. our result demonstrates the decrease of the level in urine of collagen product and lisosomal enzymes and normalization of tubular and glomerular functions during 2 years remission of pyelonephritis. prevention of recurrent uti and maintenance of the remission of pyelonephritis leads to the decrease of sclerosing processes on kidney. regular dialysis induces insecurity and special psychological problems associated with staff-, machine-and artificial material-dependence. the more severe the child's physical problems are the more probable is developing of emotional disorders, a sense of loneliness and an exaggerated dependence on the parents and staff. a psychological and social study of 19 children on regular dialysis was performed. there were 8 girls and 11 boys, aged 5-18 (mean: 11) ys. two children (10%) are exclusively treated with haemodialysis, 11 (58%) are on peritoneal dialysis and in 6 (32%) both methods interchanged. somatic concomitant disorders are present in 5 (26%) of children. among psychological disorders, an inclination to unsociability, autoaggression or aggression towards the immediate environment has developed in 4 children (21%), 6 (32%) do not like talking about disease while 9 (47%) are communicative and sociable. psychosocial characteristics showed: emotional difficulties (anxiety, mild depression) in 32%, feeling of being physically different from peers (short stature, less physical ability) in 42%, lowered self-esteem and social isolation as a result of school absenteeism in 26%. overprotection of parents was presented in 58%. different psychological changes were present in some children. of the 19 children 17 are of school age: 3 (18%) attend special schools and the remaining 14 follow regular education programs. with the help from their teachers, children on dialysis can master regular school programs, in spite of the time spent on dialysis. a good and continuing co-operation of dialysis staff and sick children and their parents as well as a more intensive co-operation with psychologists and teachers are necessary to reduce psychological disorders and promote a better adaptation to the life of their healthy coevals. we report a 15-year-old girl with syndrome frasier who developed b cell lymphoma within nine month after live related kidney transplantation. in induction therapy we applied atg up to 5 days, mycophenolate mofetil and cyclosporine. routine abdominal ultrasound revealed multifocal hypoechogenic changes in liver and spleen. computed tomography showed diffuse focuses of changed liver tissue in length up to 4.5 cm, precontrast density of 30-40 hu and postcontrast of 50-65 hu. in spleen there were three similar changes (up to 2.3 cm). after surgical biopsy of liver, patohistological examination confirmed diffuse large cell b lymphoma (cd 20 positive, moderate risk). pcr ebv was positive. we immediately started with ganciclovir intra venously and decreased cyclosporin and mmf (within two weeks) up to completely exclusion from therapy. in the same time we increased prednisolon on 15 mg daily. after 7 weeks from beginning ganciclovir she treated with rituximab, one dose of 500 mg every week (five weeks). repeated abdominal ultrasound and two controls computed tomography showed markedly regression of tumorous lesions. after 6.5 months of last rituximab doses scan showed normal spleen and liver findings. all lesions were resolved. in two occasions she developed severe leucopenia without any infection complication. she still has got moderate lymphopenia due to continual ganciclovir therapy. during this period (11 months) of illness course she treated with ganciclovir intravenously due to repeated ebv reactivation (positive pcr). despite enormous reduction in immunosupressive therapy renal function remain stabile without episodes of acute rejection. 5-20.5 years) . the most of them, 92% (23 patients) received graft from live related donor. 84% of patients had preoperative dialysis and 14% were preemptive. the mean waiting period for transplantation was 30 months (range 0 to 120 months). congenital anomalies of kidney and urinary tract were the most common underlying diseases (13 patients), then nephrotyc syndrome (4 patients), hereditary nephritis (3 patients), polycystic kidney disease (2 patients) and others. daclizumab was the most commonly used as immunosuppressive induction agent and the maintenance immunosuppressive therapy consisted of azathioprine or mycophenolate mofetil (mmf), cyclosporine or tacrolimus and prednisone. two patients had immediate postoperative surgical complication and graft loss due to thrombosis of a. renalis and donor tubular necrosis respectively. three patients had delayed graft function; two of them underwent cadaveric transplantation. one patient had recurrence of primary kidney disease only few days after transplantation and graft loss after one year. other patient lost the graft after 2 years due to noncompliance and chronic cellular rejection. after one year of follow-up graft survival rate is 86% and patient survival rate 100%. at the end of follow-up (mean range 29.21 months), 18 patients had normal, 3 patients slightly decreased renal graft function. catch-up growth was seen during the first year after transplantation from mean height sds of -1.65 to 1.25. the mean goal of our further intention is improvement of cadaver renal transplantation. j. lee, y. shim, s. lee objectives; although the variable risk factors of urinary tract infection (uti) in children such as virulence factors of the pathogenic bacteria and vesicoureteral reflux are already well known, the role of normal flora clononizing the intestinal tract and genitourinary tract is not fully understood. the change in colony forming units (cfu) of lactobacillus in chidren with uti is primarily investigated to explore the role of lactobacillus, one of the human normal flora, in development of uti. methods; lactobacillus was cultured from stool, urine, and periurethral or vaginal discharge of febrile infants with uti. those with confirmed uti by the suprapubic urine culture were classified to uti group (n=-60), and those with negative urine culture and confirmed viral illness were classified to control group (n=31). lactobacillus was anaerobically cultured in dico rogosa sl agar (becton, dickinson and company, usa) for 48 hours at 37°c. results: the cfu of lactobacillus in stool was correlated with those in periurethra, vagina and urine (p<0.05). the cfu of lactobacillus in stool was significantly lower in uti group than in control group (19,286±30,920 vs 16,969,129±89,717,956, p<0.05) . the cfu of lactobacillus in periurethra or vagina was significantly lower in uti group than in control group (2,788±5,365 vs 43,038±179,089, p<0.05). the cfu of lactobacillus in urine was significantly lower in uti group than in control group (173±469 vs 2,087±5,681, p<0.05). the cfu was distributed mostly at low level in uti group, which was significantly different from that in control group (p<0.05) conclusions; the cfu of lactobacillus in stool, periurethra, vagina and urine is low in infants with uti. it is suggested that lactobacillus has a role in the development of uti. pediatric small bowel transplantations are associated with pronounced electrolyte inbalances in the posttransplant period. we investigated the sources of possible electrolyte losses. our hypothesis was that electrolyte inbalances after intestinal transplantation might be augmented by fk 506 (tacrolimus) mediated renal toxicity rather than short bowel syndrome alone. we retrospectively reviewed eleven living-related small bowel transplantations between october 2002 and december 2006. the data collected included frequent serum and urine electrolyte profiles, renal function parameters, enterostoma electrolytes, and fk 506 levels in the postoperative period up until either discharge or graft loss. we analyzed pearson's correlations between fk 506 levels, serum electrolytes, renal function parameters, and also fractional excretions (fe). in order to investigate possible delayed nephrotoxic effects of fk 506, we correlated all values of the same day as well as with fk 506 levels of 24, 48, and 72 hours earlier. furthermore, we analyzed our data stratified by fk 506 dosing ranges. our results show decreased gfr and prominent increase of renal sodium, phosphorus, and magnesium losses along with rising fk 506 levels, suggesting this pathway as a major contributor to their imbalances. furthermore, fk 506 levels were associated with serum calcium and phosphorus decline, though urinary calcium excretion was not significantly changed. signs of renal toxicity are apparent within the first 24 hours of fk 506 challenge. our data suggest that fk 506 mediated nephrotoxiticy is a significant contributor to electrolyte imbalances observed after small bowel transplantation. objectives of study: urinary tract infections (uti) are common in children and c-reactive protein (crp) in serum is often used to evaluate the severity of the renal inflammation. recently it was demonstrated that crp can be produced locally in the kidney. we therefore measured the crp concentration in both serum (s-crp) and urine (u-crp) from children with uti to evaluate the extent of local production and the usefulness of measuring u-crp for diagnosis of inflammatory kidney disease. methods: 56 children (31 boys) with uti were studied (median age 0.8 years, range 12 days-5 years). 43 children had fever 38.5 °c or more. the uti was caused by e.coli in 50 patients. all children were examined within a few days of diagnosis by dmsa scan for evaluation of renal function. as controls were used 14 children with respiratory infection (pneumonia in most) and elevated s-crp in whom uti was ruled out by negative urine culture. u-crp was measured in a commercial hscrp elisa. normal value was <6 mg/l results: in the uti patients, the median s-crp was 126 mg/l (range 0-440) and u-crp 144 mg/l (range 0-937). there was a significant correlation between the s-crp and u-crp concentrations (<0.001). dmsa scans were abnormal in 37 (66%) uti patients. the proportion of abnormal scans increased significantly with the crp concentration in both serum (<0.01) and urine (<0.05). all control patients had increased s-crp concentrations (median 157 mg/l, range 45-243) but the median u-crp was 2.5 mg/l (range 0-73). the u-crp in the patients with uti was significantly higher than in the controls with other infections (<0.05). conclusions: our data strengthens the concept that crp can be produced locally in the kidney during uti. the usefulness of measuring u-crp to evaluate inflammatory kidney disease needs to be tested further. s. paunova, a. kucherenko, i. smirnov, g. serova, i. donin, l. revenkova, n. goltsova in order to reveal the role of cytokines in renal tissue damage in infants with urinary tract infection (uti) 42 patients aged from 0 to 6 months were examined. in all of them inflammatory markers (esr, crp, leukocyte count), urine concentration of tumor necrosis factor-α (utnf-α) and transforming growth factor-β (utgf-β) standardized to urinary creatinine concentrations were evaluated. two groups of patients were determined: 1) with uti and normal urodynamics (n=33), 2) with uti and urodynamic disorders (vur, hydronephrosis) (n=9). 12 healthy infants were used as controls. as a result, all the patients demonstrated significantly elevated utnf-α, utgf-β creatinine ratio in comparison with controls (p<0,05) with no difference between groups. but 16 children with normal urodynamics (from the 1 st group) presented with severe uti (1 st -a) showed urine tnf-α tgf-β creatinine ratio in 1,5 times higher than other patients of 1 st gr and close to 2 nd gr. data (1 st gr.-utnf-α/ucr=9,32±1,82, utgf-β/ucr=1231,65±133,36, 1 st gr.-utnf-α/ucr=6,89±0,98, utgf-β/ucr=782,7±87,77; 2 nd gr -utnf-α/ucr=12,58±4,25, utgf-β/ucr=1130,58±280,45, p1,2-1<0,05) . to conclude, tnf-α and tgf-β are responsive for renal tissue impairement in infants with uti. elevated tnf-α tgf-β creatinine ratio in a part of infants with normal urodynamics suggests that renal damage begins early in infection mostly due to inflammation. one may suspect a predisposition of that subgroup of patients to fibrogenic process and subsequent scar formation. prompt diagnosis and localization of pyelonephritis are of great importance in treatment and prognosis of the patients. the urinary excretion of enzymes, in particular n-acetyl-beta-dglucosaminidase (nag), is considered a relatively simple and non-invasive method in the detection of renal tubular function under various conditions such as pyelonephritis. this study was performed to determine the diagnostic value of urinary nag in acute pyelonephritis and to compare it with other indices traditionally used for this purpose in children. this is a quasi experimental study conducted from april 2005 to may 2006 on children with pyelonephritis. diagnosis of pyelonephritis has been based on standard criteria. seventy-two patients between 1 month and 15 years were recruited. fresh random urine samples were obtained on the admission time and at 48 th hour of treatment and were tested for nag and creatinine. there was a significant difference in pre and post-treatment urinary nag/creat ratio (p<0.000) and the sensitivity and specificity of urinary nag in diagnosis of pyelonephritis were 72% and 78% respectively. there was a significant correlation between urinary nag level and kidney ultrasonography results. patients whose ultrasonography showed hydronephrosis, had the highest level of urinary nag and patients who showed urinary stone in their ultrasonography had the lowest level of urinary nag. in addition, there was a reverse correlation between urine culture results and urinary nag level; patients who had negative urine culture had higher level of urinary nag in comparison with patients with positive urine culture. we conclude that urinary nag is elevated in children with pyelonephritis especially in the presence of urinary tract abnormality and the absence of renal stone. type-1 hyperoxaluria (ph-1) is an autosomal recessive disorder caused by the impaired activity of the hepatic peroxisomal alanine-glyoxilate aminotransferase. the disease leads to end stage renal disease (esrd) and combined liver-kidney transplantation (clkt) is required. we report 3 cases diagnosed with ph-1 who received clkt. case-1: she had attacks of dark urine without any pain and renal stones were determined on sonography when she was 2.5 years old. she was diagnosed with ph-1 and received peritoneal dialysis (pd) at the end of the first year and cadaveric clkt was performed when she was 9 yearsold. at the age of 16, she had chronic allograft nephropathy and began to have hemodialysis (hd). recently, 1.5 year after hd, cadaveric renal transplantation (tx) was performed. she is well after the second tx. case-2: he was admitted with polyuria, polydypsia, stomachache and renal stones were determined on sonographic examination. he had esrd and pd was started when he was 7 years old. at the age of 10, cklt was performed from his mother. his liver and renal functional tests are well 8 months after cklt. case-3: he was evaluated because of having an older brother diagnosed with ph-1 when he was 4.5 years old. he had no complain, but sonography showed multiple calculi. within 5 years he experienced flank ache, hematuria attacks and anuric phases due to obstruction and esrd appeared and he received hd and clkt was performed from his full-match sister at the age of 9.5. he is doing well 5 years after tx. here, we present the favourable clinical outcomes of our patients with cklt to indicate the validity of this treatment of choice in ph-1. tenascin (tn) is a glycoprotein component of extracellular matrix (ecm) which is not present in the normal kidney tissue. tissue plasminogen activator inhibitor-1 (pai-1) regulates fibrinolysis and the plasmin mediated matrix metalloproteinase activation and it is also not expressed in the normal kidney. recent studies focus on the pathogenesis of advanced renal diseases. in this study we evaluated tn and pai-1 staining in the renal tissues of pyelonephritic rats using immunohistochemistry (ihc) as to understand if these markers may be served as histological parameters of pyelonephritis like fibrosis, tubularatrophy or vascular changes. seven rats were injected 0.1 ml solution containing e. coli atcc 25922 10 10 cfu/ml into left renal medullae. seven rats were designed as sham group and were given 0.9% nacl. rats were sacrificed 7 days after injections. renal tissues were studied histopathologically by hematoxylin and eosinand scored for the parameters of pyelonephritis. tn and pai-1 expressions were studied semiquantatively by ihc by tenascin novocastra (ncc-tenas-c) and pai-1 (h-300) santa cruz biotechnology. both tn and pai-1 expressions increased in the pyelonephritic groups. we observed acorrelation between tenascin and fibrosis, vascular changes and tubular atrophy and pai-1 expression showed a correlation with only fibrosis. we conclude that increase in renal tn and pai-1 expression shown in experimental pyelonephritis are the responsible factors for the fibrotic changes of persistent renal damage. introduction: urinary beta 2 microglobulin (β2mg) urinary excretion is a good index of proximal tubular cell dysfunction. objective: to determine β2mg excretion significance in determining the outcome in respect to scar and renal insufficiency. patients and methods: urinary β2mg and creatinine (cr) was measured in 83 urine samples of whom 53 proceed to do dmsa renal scan at the time of admission and 6 months later to detect scar. β2mg was measured using radioimmunoassay method using β2mg 96-test kit (radim company). twenty children had various grades of renal scars. results were compared with ratios of 19 children with low uptake and 14 normal scanning and 30 normal children. student t test, anova, and unpaired t-test was used for analysis and differences considered significant if p<0.05. results: the mean urinary β2mg/cr was significantly higher in the scarring group (5.23±10.6) than in the normal group (0.19±0.2) and in low uptake group (0.49±0.86) (p<0.05). patients with grade iii had higher values (14.69±15.82) than grades i (0.36±0.35) and ii (3.37±5.20) (p<0.05). patients without renal scar had β2mg/cr ratio below 0.46 microgram/mg. the mean β2mg/cr was higher in patients with vur grades 4 and 5 (8.93±12.01) than patients with vur grades 1 to 3 (0.81±3.04) (p=0.02). maximum β2mg/cr was detected in patients with grade 4 vur (33.3) and the minimum was zero in non-refluxing patients and normal children. two patients with high grade vur and the highest levels of β2mg/cr ratio (33.3 and 26) progressed to renal failure in 2 years time, the first patient was treated by hemodialysis and the second underwent renal transplantation. conclusion: measurement of urinary β2mg is useful in the early detection of tubular damage in patients with renal scars. introduction: chronic allograft nephropathy refer to the progressive decline of renal function seen in some renal transplant recipients in association with alloantigen-dependent and alloantigenindependen factors. hyperlipidemia is a risk factor for chronic allograft nephropathy in adult pts, where no data exist in pediatric transplant population. methods: in this cross sectional study, 62 patients (32 can/30 non-can) that aged 5-18 yr and 9-93 mo (mean: 48 mo) after transplantation, were evaluated for lipid profile and renal function tests. results: hyperlipidemia has high prevalence in our patients both pre and posttransplantation and hypercholesterolemia and increased ldl had significant correlation with chronic allograft nephropathy (p=0.009) and p=0.025 respectively. conclusion: in pediatric patient as in adults hyperlipidemia and particularly hypercholesterolemia has significant correlation with chronic allograft nephropathy and as adults may need specific therapy. results: pre-transplantation renal replacement therapy time ranged from 0 to 132 months. eleven children underwent pre-emptiverenal transplantation. 43/72 transplants were from living related donors. donor age ranged from 0 days to 74 years. 9 grafts were from donors <1 year of age and 5 of these grafts were transplanted en-block. hla mismatches ranged from 0 to 5 antigens. primary disease was: focal segmental glomerulosclerosis in 9, rapidly progressive glomeluronephritis in 6, reflux nephropathy in 23, nephronophthisis in 9, iga nephropathy in 1, congenital nephrotic syndrome in 2, dysplasia-hypoplasia in 11, idiopathic membranous glomerulonephritis in 1, henoch-schönlein purpura in 1, hemolytic-uremic syndrome in 1, nephroblastoma in 1, polycystic kidney disease in 1 and of unknown origin in 4 children. patient survival at five years was 97%. allograft survival with living related transplants at one, two and five years was 95%, 95% and 82% respectively and with cadaveric transplants at the same periods was 86%, 86% and 86% respectively (p<0.05). regarding en-block grafts, they functioned immediately and satisfactory and presented excellent graft function 10 years later. most kidneys were lost due to acute or chronic rejection (n=6). other causes were renal artery thrombosis (n=3), infections (n=2), withdrawal of immunosupressive regime (n=1). conclusions: results of this single center series of pediatric renal transplants are encouraging from the standpoint of patient and allograft survival. conclusion: in infants with hn, the incidence of uti was higher especially in those with ou, hn of higher sfu grade or hun. the antibiotic prophylaxis may be recommended during 1 year after birth in infant with hn because the incidence of uti was high in these period. results: the underlying diseases were: sepsis with mods (26.8%), septic shock (11.3%), severe intoxication (15.5%), trauma with sirs (11.3%), drowning (2.8%), abdominal compartment syndrom (2.8%) and inborn metabolic disorders (2.8%). 43 children (61%) had acute renal failure, 28 (39%) patients met non-renal crrt criteria. cvvh was performed in 39 (55%) children, cvvhdf in 32 (45%) children. crrt duration was 6 to 216 hours (median 177.6 hours). dynamics of blood urea, creatinine, c-reactive proteine (crp) and white blood cells (wbc) were evaluated. significant decline (p<0.001) of creatinine along the treatment with cvvh as well as during cvvhdf was observed. blood urea levels showed significant decrease only in children treated with cvvhdf (p<0.05). significant decrease of wbc and crp was observed only using cvvh. 37 children from the study group survived (overall mortality 47.9%). in non-survivors was time from crrt initiation to its termination compared to time interval from crrt initiation to the death of children with 3-4 organs failure significant (p<0.05) where as in non-survivors with 1-2 failured organs it was not. conclusion: cvvh is efficient at removing urea and creatinine as well as inflammatory mediators (crp, wbc). cvvhdf is more potent to blood urea elimination. authors suggest preferring cvvh to cvvhdf in critically ill children to affect basic inflammatory parameters. to analyse hd and pd prescription (pr) adopted in chronic dialysis children, were viewed data of 147 pd regimens in 91 patients (0.5-18years) and 100 hd regimes in 74 patients (age 1.8-18 years) treated in 12 pediatric centres in 2005. pd patients were on automated pd: -nightly intermittent pd (nipd; 89 pr): 9.6±1.3 (8-13) hrs; 13.3±5.5 (6-27) cycles/night; dwell volume (dv) 889±232 (465-1400) ml/m 2 bsa; -tidal pd (42 pr): 9.7±1.9 (8-18) hrs; 16.9±5.6 (9-31) cycles/night; dv 1008±182 (600-1200) ml/m 2 ; tidal volume 63.8±9.5 (50-85)%; -continuous cycling pd (ccpd;16 pr): 10.3±1.6 (8-14) hrs; 15.6±5.6 (7-27) cycles/night; dv 1017±162 (600-1280) ml/m 2 ; daytime dv 62±18 (50-100)% of night dv. in 27% of pr dialysis fluid (df) glucose concentration was >1.36%, and in 12% buffer was bicarbonate. df of daytime dwell was 1.36% glucose (13 pr) or icodextrin (12 pr). patients with residual diuresis were 63.5% of those on nipd, 56% on tidal pd, and 6.2% on ccpd. hd was performed as bicarbonate hd (79%), hemodial filtration (15%) and acetate-free biofiltration(6%). patients received 3 sessions/week in 66% of cases, 4/week in 23%, and 2/week in 9% of cases; 2 oxalosis patients were on daily hd. session duration was 3 hrs in 44 pr, 4 hrs in 36, and 3.5 hrs in17. dialyser membrane was: polysulfone (38%); hemophane (19%); polyamide s (16%); cellulose acetate (9%); polyacrylonitrile (5%); cellulosediacetate (4%); cellulose triacetate (4%); polymethylmetacrylate (4%); polyether/carbonate (1%). ratio between dialyser surface area and patient bsa was 1.05±0.19 (0.70-1.43) and was 1-1.20 in 31%, 0.8-1 in 23%, >1.20 in 12%, and <0.8 in 7% of cases. isoniazid (inh) is widely used in most prophylactic and therapeutic anti-tuberculosis regimens because of its effectiveness and low cost. acute intoxication by isoniazid is known to cause symptoms of seizures, metabolic acidosis, coma, and even death. we present a case of acute isoniazid poisoning in a seven years old patient who ingested 7 tablets (2100 mg) of isoniazid. she was admitted unconscious, with ventilatory insufficiency and convulsions. renal and liver function tests were in normal ranges. she was intubated and mechanically ventilated. despite parenteral midazolamand pyridoxine (vitamine b6) treatments convulsions went on. then hemodialysis was performed and after hemodialysis convulsions and ventilatory insufficiency were disappeared and the patient was conscious and she was extubated. hemodialysis may be an effective treatment alternative for the patients who doesn't respond pyridoxine treatment. the aim of this study is to analyse children under two years of age, with their first febrile urinary tract infection (uti), identifying bacteriological etiology, antimicrobial resistance, urologicalabnormalities and renal damage. this is a prospective study including 92 children (63% girls) with their first febrile uti. mean age was 6 months (3-10), 27 (29%) patients were younger than 3 months (62% of them were boys). urine was obtained by suprapubic aspiration (65.2%) or transurethral catheterization (34.8%). 37% had positive nitrite on urinalysis and 95.6% had leukocyturia. they were submitted to ultrasonography (usg), dmsa scan (within 4 months) and voiding cystourethrography (vcug). the most frequent microorganism found in urine culture was escherichia coli, (94.6%). in this study high bacterial resistance to antimicrobials was observed in relation to the following antibiotics: ampicillin (57.6%), first generation cephalosporyn (32.6%), sulfamethoxazole/ trimethopin (43.5%). resistance to second generation cephalosporyn, aminoglycoside, nitrofurantoin and nalidixic acid was lower than 3.5%. renal ultrasound was abnormal in 43.5% of the infants. vesico-ureteral reflux (vur) was observed in 34.7%, although only 7.6% had vur grade iii or more. the dmsa scan showed that 23 (25%) patients had renal parenchymal damage. fourteen of these (60.9%) had normal esr. there were 8 (8.7%) reinfections within a 6 months period, even under prophylactic treatment, and the presence of vur grade iii or more was the only one with a significant relationship. conclusion: there were high levels of bacterial resistance to frequent used antimicrobials. this finding points toward a need for reviewing criteria of choosing initial blind therapy. investigation with dmsa scan is important in the detection of renal parenchymal scars, irrespective of the reflux grade. purpose: urinary tract infection (uti) has a risk of renal damage and is associated with vur. vur is investigated only by vcu. however, vcu is an invasive, painful study and many patients hesitate to be taken the study. we studied the correlation of vur in vcu and defect of dmsa scan and investigated the possibility of substitution of vcu by dmsa scan. material and methods: from 1999 to 2006, the medical records were searched for children admitted to cheongju st.mary's hospital with the first uti who had been evaluated with both dmsa scan and vcu within 1 months of the infection. the value of several clinical signs, laboratory findings, the resultsof dmsa scan and vcu were investigated. bacteriuria was defined as 100,000 or greater colony-forming units in urine from a bag, midstream or catheter sample. results: there were 54 patients underwent both studied at the first uti. mean age of the patients was 13 months old. the male patients were 38 (70%). the vur was found in 19 of the 54 patients (35%), grade i-ii in 5 and grade iii-v in 14 patients. there was no significant correlation with the presence of vur in sex, fever duration, blood white cell count and the level of serum creactive protein (crp). but the patients with vur grade iii-v were significantly older than the patients with grade i-ii reflux or without vur. there were abnormal dmsa scan findings in 22 of 54 (41%). of these patients, 11 were without vur, 1 with vur grade i-ii and 10 with vur grade iii-v. the abnormal dmsa scan was correlated with the presence and severity of vur. but vur was found in 25% of patients with normal dmsa scan. conclusions: abnormal dmsa scan is correlated with the presence of vur, so the patients with abnormal dmsa scan require vcu. in order to prevent missing a quarter of patients with vur shown normal dmsa, vcu should be recommended in all children with first febrile uti. cuba is the largest of the carribean islands with its 11,5 millions inhabitants. cuba is considered as a developing country and is classified in the group of: "lower middle income countries and territories". despite low financial resources, cuba has succeeded to develop an efficacious health care system with comparable results to those of west europe and usa (who data) ccl: 1) hd is the most prominent form of pediatric dialysis (automated night pd is in progress); 2) the no of transplantations is relatively low because of no participation to an international transplantation network; 3) high no of pediatric nephrologists; 4) high quality of patients care. background: inborn errors of metabolism in neonates are often characterised by hyperammonaemic coma within the first days of life and require prompt diagnosis and specific treatment such as toxin removal and nutritional support. cvvhd seems to be the optimal modality for extracorporal ammonium detoxification, however, little experience with small numbers of children has been accumulated. patients and methods: from 1996 to 2007, 21 patients with hyperammonaemia (16 male, 5 female) were admitted for dialysis treatment: 18 neonates (mean age 3.8±2.4 days, range 1-10 days) with a mean birth weight of 3430±1023g and 3 infants (mean age 5.6±4.6 years, range 3 to 11 years). in 14 neonates and 2 infants we inserted venous double lumen shaldon catheters (predominately femoral or jugular vein) for cvvhd treatment while 4 neonates and 1 infant underwent capd treatment. results: plasma ammonia levels (range 508-7267 μg/dl before dialysis and 27-3317 μg/dl after dialysis) were reduced by 50% within 4.5±2.7 h by cvvhd and within 18.7±9.2 h by capd (p<0.05). total dialysis time was 35.9±25.7h for cvvhd patients. no major mechanical complications were observed with cvvhd and stable blood flows (10-40 ml/min) and dialysate flows (1000-3000 ml/m 2 /h) were achieved. due to severity of underlying disease, 2 out of 14 neonates (14%) undergoing cvvhd died on day 2-3 while 2 out of 4 neonatal capd patients (50%) died on day 3 and one infant patient died after 498 days of capd treatment. twelve out of 14 neonates (86%) survived with no or moderate mental retardation. conclusions: cvvhd is an effective modality to eliminate plasma ammonia within few hours. however, vascular access and blood flows are critical restrictions. mental retardation has to be evaluated in larger scale studies. r. vilalta, e. lara, a. madrid, s. chocron, j. nieto hospital materno-infantil vall de hebron, nefrologia pediatrica, barcelona, spain background: transplant nephropathy is the main cause of renal failure in kidney transplanted children. until this situation is proved by biopsy, sometimes the progressive raise of creatinine leads to raise the anticalcineurinic (cni) drugs with added nephrotoxicity. sirolimus (sir) plus an anticalcineurinicin less dose and mycophenolate (mmf) could offer in kidney-transplanted children an immunosuppressive regime with less toxicity and even an improvement of renal function. methods and patients: 12 paediatric kidney-transplanted patients developed biopsy-proved chronic allograft nephropathy (age 6-19 y, mean 8) a follow-up post-transplant of 6 y and 7 exhibit also tubular involvement and acute cni toxicity. sir was added in all patients as a rescue therapy at 0.08 mg/kg/d. results: after a follow-up period of 18 months, creatinine level diminished (p<0.04) in 8 patients (4 in group tac, 3 in group cya, with no significant differences). creatinine level did not show a significant change in the other 4 patients (2 group tac, 3 group cya, basal creatinine 2.8 mg/dl. serum cholesterol changed from 230±30 mg/100 ml to 223±2 (ns) and serum tryglicerides from 110±32 mg/100 ml to 121±24 (ns). proteinuria also did not show changes (24±8 to 22±4 mg/m 2 /h (ns). conclusions: a poly-drug approach with less dose of anticalcineurinic added to the antiproliferative effect of sirolimus and the inhibition of purine synthesis based on mycophenolate mofetil could suppose an improvement of the renal function in children graft nephropathy an even in the graft survival. steroids have been a cornerstone in renal transplant immunosuppression. several strategies have been used to minimize their side effects. new immunosuppressive drugs have allowed steroid withdrawal or total avoidance. aim: to evaluate a new protocol with steroid-free maintenance immunosuppression in pediatric renal transplant. patients and methods: a prospective, non-randomized study in 46 consecutive first renal allograft recipients, followed-up to 24 months. patients received prednisone the first 6 days, two-dose basiliximab induction and maintenance therapy with tacrolimus (tac) and mycophenolate mofetil (mmf). no steroids were given after 6 d posttransplant. controls were 20 historical-matched steroid-based children receiving basiliximab, tac and mmf. all patients gave informed consent. anthropometric, biochemical variables, acute rejection and cmv infection were compared using student-t test and regression analysis. results: a better growth pattern was seen in steroid-free maintenance group reaching a normal growth at 24 months. gfr and serum glucose were similar in both groups. total cholesterol levels were significantly lower in the study group. the incidence of acute rejection was 4.3% in steroidfree maintenance vs 8.6% in steroid-based group, no differences in cmv infection and blood pressure were observed. hematocrit levels were lower during the first months after transplant in the steroid-free group, increased after 6 months post-transplant. patient and graft survival was 98% at two-yr post transplant in the two groups. conclusions: this steroid-free maintenance immunosuppressive protocol was efficacious, safe, with a lower incidence of acute rejection, not increased risk of infection, preserving optimal growth, renal function and reducing cardiovascular risk factors. objectives of study: to evaluate the lipid profile and its possible implications in children with end stage renal disease (esrd) or renal transplantation. methods: 19 children (11 boys, 8 girls) aged from 3.5 to 18 years, 9 on peritoneal dialysis (group i) and 10 with renal transplantation (group ii) were studied. in all children were examined: serum creatinine, total cholesterol, triglycerides, high density lipoproteins (hdl) and low density lipoproteins (ldl). a cardiac and liver ultrasonography were also performed. the body mass index (bmi) and blood pressure were evaluated in all children. 13/19 children received also a triplex carotid study. the median values of blood creatinine, cholesterol, triglycerides, hdl, ldl as well as the number of children with bmi over 95 th percentile in both groups were shown in table i . all children had normal findings in triplex carotid study. cardiac ultrasonography was abnormal in 1 child of group i and in 2 children of group ii. only 1 child presented lipoid invasion in liver ultrasound. 3/9 children of group i and 6/10 children of group ii presented hypertension, well controlled, with antihypertensive therapy. conclusions: frequent evaluation of lipid profile is recommended in all children with esrd or renal transplantation independently their bmi. in our study, children with renal transplantation presented better lipid profile compared with children on peritoneal dialysis. group i with <18 months (n=14; 7,8±4,9 months) and group ii >18 months (n=7; 36,8±19,9 months). results: serum albumin, serum lipids values and the distribution of the categories of the peritoneal membrane did not present significant differences between the groups. hypertension, renal residual function (p=0,005), the renal urea kt/v (p=0,007) and the weekly renal ccr (p=0,005) were significantly higher in group i, while the weekly peritoneal ccr (p=0,025) and the total weekly ccr (p=0,037) were significantly higher in group ii. catch-up was not observed in any group. control of the cholesterolemia, trigliceridemia and albuminemia were maintained with the dialysis time in both groups. the goals of adequacy of the doqi for kt/v and ccr were gotten respectively in 85,71% and 64,29% of the group i and in 71,43% and 42,86% of the group ii. the longer time in dialysis was associated with the lowest values of renal residual function, renal kt/v and renal ccr. the capacity of transport of the membrane was similar in both groups. objectives of study: to explore the characterize of peritoneal transport in chinese children with chronic peritoneal dialysis. methords: pet was carried out 10 times for six children (mean ages 9.3±4.4, aged from 2 to 14 years) who were maintained by capd, and the infusion volume of dialysate was 1195±597 ml (1100ml/m 2 ). the peritoneal solution transport rate was evaluated by the standards of twardowski's and ppdsc's criteria. results: in our study, the initial pet was performed at 38.7±15.6 days following initiation of pd, the 4-hours of peritoneal creatinine clearance (4h-d/p) and glucose absorption (4h-d/d0) was 0.85±0.24 and 0.34±0.19, respectively. according to the standards of twardowski's and ppdsc 's criteria, the peritoneal transport categories were divided into high transport (h) (6/10), high average transport (ha) (1/10), low average (la) (3/10) for peritoneal solution transport, and h (3/10), ha (4/10), la (1/10), low transport (2/10) for glucose absorption. no low transport type of solution was uesd in our patients. the coincidence rate of peritoneal creatinine and glucose transport types were 100% and 90% between the twardowski's and ppdsc's criteria, respectively. the different changes of peritoneal transport type were found in two patients with continuous pet. the value of 4h-d/p increased after peritonitis episodes. our results showed that the pet in 70% of capd children fall into high and high average transport categories elevated by ppdsc's and adult standards. the peritoneal solute clearance was adequacy in the children, but net water ultrafiltration was lower. standard pediatric pet and its criterie are consistent with the adult criteria. the capability of peritoneal solute transport increased after peritonitis episodes. verapamil (vp) is known to alter cyclosporine (csa) bioavailability. the impact on immunoregulators (il-2, tgf-β 1 , and tgf-β 2 ) in allograft recipients remains unresolved. a prospective open study to examine the impact of vp on peripheral blood cell mrna encoding il-2, tgf-β 1 , and tgf-β 2 and serum il-2, tgf-β 1 , tgf-β 2 protein levels was performed. parental written informed consent was obtained in all cases. children with stable renal allograft function (<6 months), and receiving immunosuppression (csa, pdn, either with aza or mmf) were included. in the first visit, a clinical examination, two-point (2 and 12h) csa pharmacokinetic profile, serum creatinine, serum for il-2, tgf-β 1 , and tgf-β 2 protein levels (by elisa) were obtained; peripheral mononuclear cells were collected for measurement of transcripts for 18s rrna (house keeping gene) and mrna for il-2, tgf-β 1 , and tgf-β 2 (by real time quantitative pcr assay). after the visit one, patients were either withdrawn of vp (if the subject was already receiving vp) or started on vp 2mg/kg/day (if the subject was not receiving vp). two weeks after, a repeat clinical evaluation and blood collection, as in the first visit, were performed. 21 pediatric recipients of renal allografts were included (17 were from ld, mean post-transplant time 4.8 years, mean csa dose 3.8 mg/kg/day). the c2h and calculated auc 0-12h were significantly higher in those receiving vp, but there was no difference in csa trough levels. protein and mrna levels of il-2 tgf-β 1 , and tgf-β 2 were not different. were previously seen by a nephrologist. logistic regression was performed on anemia (hgb<11.0 g/dl) and showed relative risk in blacks was 3.74 vs. whites. relative risk in those who did not receive epo was 2.77 vs. those who did. of 19 black patients, 16 were anemic and 9 previously seen by a nephrologist. of 55 white patients, 32 were anemic and 16 previously seen by a nephrologist. in summary, blacks and patients not receiving epo at the time of dialysis initation were more likely to be anemic. despite being seen previously by a nephrologist, nearly 60% of patients were anemic when starting dialysis. further analysis is needed to determine causality to improve anemia control in incident dialysis patients. 2 of the avf were in whites with 1 in a black patient. the avg was in a black patient, with a cvc distribution of 20 whites and 11 blacks. 21 patients with cvc had been previously followed by a nephrologist and of these 12 had been followed for >6 months. in summary, incident pediatric hemodialysis patients are primarily having cvc as initial access type. with 56.7% having been previously seen by a nephrologist and 57% of these for greater than 6 months, the reasons behind not having an avf or avg as primary access need to be explored and improved upon. this high incident cvc use is consistent with data reported in the united states, but not with other european and asian countries. an effort to have a permanent avf or avg in incident pediatric hemodialysis patients needs to be made by the patient's nephrologist. to find the preventive measures for recurrent uti in infants with first febrile uti and normal urinary tract (ut), the incidence of recurrent uti and its risk factors were investigated. method: from june, 2002 to june, 2005 under 12 months of age (-6 mon: 152, 6-12 mon: 38), who were diagnosed as the first febrile uti and proved to have normal ut, were enrolled to the retrospective study. for all infants with nonretractile prepuce, topical application of hydrocortisone for 2-4 weeks and physiotherapy was recommended. during the following 1 year, the incidence of recurrent uti and the well-known risk factors such as female, young age, phimosis, vaginal reflux, and initial 99mtc-dmsa(+) pyelonephritis were evaluated. result: the incidence of recurrent uti in infants with normal ut was 21.1% and recurrent uti episode was 0.23/patient-year. the recurrent incidence in male infants was 22.8%, which was not significantly different from 12.5% in female infants (p=0.193). the recurrent incidence in younger infants was significantly higher than in older infants [-6 mon: 25.0%, 6-12 mon: 5.3%, p=0.008]. this age-related difference was significant in male infants [-6 mon: 25.8%, 6-12 mon: 7.7%, p=0.045], but not in female infants (p=0.169). in infants with persistent nonretractile prepuces, recurrent uti developed in 34.3%, which was higher than 15.6% in infants with retractile prepuces (p=0.041). the presence of the vaginal reflux (p=0.087) or initial 99mtc-dmsa(+) pyelonephritis (p=0.041) showed no significant difference in the incidence of recurrent uti. conclusion: in uti infants with normal ut, younger infants under 6 months of age and nonretractile prepuces of male infants were the risk factors for recurrent uti. objective: vascular endothelial growth factor (vegf) appears to play a central role in the process leading to peritoneal angionesis and increased level of vegf may conrtibute to high peritoneal small-solute transport rate (ptsr) in continuous ambulatory peritoneal dialysis (capd) patients in adult. vegf-c is related to lymphogenesis, but its role in peritoneal solute transport rate is not known. in this study, we evaluated possible relationship between dialysate vegf and vegf-c levels and pstr in children. method: twelve children with no apparent inflammation process or disease, who had been on capd, were enrolled. standard peritoneal equilibration test (pet) was done to evaluate pstr. d/pcreat and d/d 0 gluc were calcualted at 4hr of pet. overnight dialysate levels of vegf and vegf-c were measured using commercial elisa kit. correlation between dialysatevegf (or vefg-c) and d/pcreat (d/d 0 glu) was analyzed. results: mean peritoneal dialysis duration was 9.25±7.18 months. mean overnight dialysate vegf and vegf-c level were 44.74±30.49 pg/ml and 119.6±78.26 pg/ml, respectively. a significant correlation was noted between the dialysate vegf-c and vegf level (r=0.809, p=0.001). dialysate vegf level had negative correlation with d/d 0 glu of 4hr pet (r=-0.691, p=0.009). vegf-c had no correlation with d/d 0 glu or d/p creat. conclusion: there was significant relationship between dialysate vegf and vegf-c levels in children and significant correlation was also noted between dialysate vegf and ptsr. it seems that vegf contribute to high ptsr also in children on capd. m. feldkötter, l. stapenhorst, b. beck, u. bangen, b. hoppe we currently use sirolimus as a second line medication in transplanted patients with a distinct nephrotoxicity of calcineurin-inhibitors. as our short term experiences were not as positive as expected, we performed a short term meta-analysis in our renal transplant recipients under sirolimus treatment: we give an account of seven kidney transplant patients who were either directly started or were switched to a medication with sirolimus during september 2004 to february 2006. the reasons for this action taken were calcineurin-inhibitor side effects like severe arteriolopathy with lossof gfr, atypical haemolytic-uraemic-syndrome, seizures after the first dosages of cya and a tacrolimus induced exanthema. in four of seven patients switched to sirolimus we observed severe side effects, exaggerating those of the calcineurin-inhibitor and hence, in three patients the latter treatment was installed again. findings were distinct proteinuria in two patients, hyperlipidemia in three patients, wound healing disorders and, most strikingly, treatment resistant severe pancytopenia in one patient and severe interstitial pulmonary fibrosis in another patient, both with amelioration after termination of the medication, but still the need of oxygen therapy in the latter patient. in addition we noticed a slightly faster reduction of the gfr calculated with the schwartz formula in five patients compared to the previous immunosuppressive regimen. based on these findings we strongly feel that a more critical discussion of each case is necessary before changing the immunosuppressive medication. also, the question arises on whether sirolimus can really be valued as an equivalent alternative to a calcineurin-inhibitor based immunosuppressive regimen in pediatric kidney transplantation. y. kovalski, r. cleper, i. krause, m. davidovits schneider children's medical center of israel, nephrology and dialysis unit, petah tiqwa, israel background: despite significant technical improvements, haemodialysis in infants with end-stage renal disease (esrd) is still associated with significant morbidity and mortality. methods: the files of patients weighing less than 15 kg with esrd who were treated with haemodialysis at our institute between 1995 and 2005 were reviewed for background and treatment characteristics, morbidity and outcome. results: the study group included 11 patients aged 7-75 months (mean 34.2 months) weighing 7.2-14.9 kg (mean 10.9 kg). mean duration of dialysis was 11.3 months. vascular access posed the major problem. ten patients were dialysed through a central venous cuffed catheter and one through an arteriovenous fistula. an average of three different vascular accesses was required per patient (range 1-9). mechanical difficulties were the most common cause of central line removal (56.5%), followed by infections (15.6%). major complications causing significant morbidity were intradialytic haemodynamic instability, hyperkalemia, coagulation within the dialysis set, anaemia, hypertension, inadequate fluid removal and recurrent hospitalisations. analysis of outcome revealed that 8 patients underwent successful transplantation, one returned for haemodialysis after 4.5 years due to graft failure, and 2 died. conclusion: haemodialysis is a suitable option for low-weight paediatric patients with esrd awaiting transplantation, when performed in highly qualified centers. the importance of antibiotic prophylaxis in management of vur vesicoureteral reflux (vur) cause urinary tract infection (uti) and renal scarring is a common condition in children. the detection and treatment of vur before renal scarring is vital. recently, optimal management of low grade vur is controversial. the aim was to explore the kidney outcome in a cohort of patients with vur. the patients were divided into five subgroups according to vur grades. all of them were treated with low dose prophylactic antibiotics until the age of 5 years. urine culture was repeated monthly. background: anemia is a common complication in patients on hemodialysis. treatment of anemia with recombinant human erythropoietin (rhuepo) may lead to iron deficiency. intravenous sodium ferric gluconate complex (sfgc) therapy improves iron stores. objectives of study: aim of our study was to assess effects of maintenance sodium ferric gluconate therapy in pediatric patients on hemodialysis on mean hemoglobin (hb), hematocrit (hct), transferrin saturation (tsat), serum ferritin and rhuepo dose, as well as safety of therapy with sfgc. methods: intravenous sfgc therapy was administered for 3 months in mean dose of 1.2 mg/kg/week to eight pediatric patients on hemodialysis. patients were from 2 to 16 years old (4 males and 4 females, aged 11.5±5 years). all patients were prescribed rhuepo before start of study. results: sfgc therapy was successful in maintenance of mean hb (increased from 10.5 to 11.3 g/dl), mean hct (improved from 31% to 33%), mean tsat (from 23 to 30%) and mean ferritin level (from 592 to 765 ng/ml). high ferritin levels in two patients were due to inflammatory disease rather than the sign of iron overload. the mean weekly rhuepo dose decreased from 4380 to 3500 iu. no significant adverse event due to intravenous sfgc therapy occurred. conclusions: intravenous maintenance sfgc use in pediatric patients on hemodialysis was safe and successful in maintenance of iron indices, thus allowing reduced use of rhuepo. the the viral hepatitis b still remains a serious problem, especially actual in patients with end-stage renal disease (esrd) on renal replacement therapy (rrt). the high frequency of hbv infection transmission in hemodialysis units and immunodeficiency modify hepatitis clinical course and outcomes and worsening vaccination results and renal graft survival. we have analyzed the results and influence on transmission of hb -infection of hepatitis b vaccination in 28 children aged from 6 to 17 years with esrd on chronic hemodialysis. majority of children were boys (53.5%) older than 11 years (85.7%). an assessment of hbs-ag has been conducted prior and during the vaccination (engerixb) by scheme 0-1-6 months. after first vaccination hbv infection was detected there after in 10.7% of children, after second vaccination in 7.1%. in all patients (11) which have received three tours of vaccination, an active immune response was developed. thus, vaccination against viral hepatitis b is effective and prevents hbv infection in children with end stage renal disease on chronic hemodialysis. renal transplantation (tx) represents the best treatment for the patient with crf. scientific advance has been able to optimize the immunosuppressive treatment however the adherence to treatment has been not maintained. aims: to identify the factors that influence in non-adherent behavior with the purpose of designing effective educational strategies. methods: the qualitative focus was carried out through patients and tutors interviews. the quantitative aspect applies for epidemic variables, time post-tx, percentages and frequency of the sentences coming from the analysis of the interviews. nurse, psychologist and a social worker were incorporated with the purpose of elaborating an instrument based on seven questions related to the transplantation, risk and/or loss of the graft; besides the events happened as consequence of this, allowing that interviewed manifested with freedom their opinions. the interview was recorded in a microcassette and later transcribed. analysis was determined by categories containing the answers of each question granting the agreement sentences according to the frequency which was repeated in each interview. informed consent was obtained. results: 150 tx (1989 -2006 ; 15 non-adherent, 80% of them were interviewed. mean age: 9.7 ys. loss the graft: 50%, time post-tx: 37.7 months, dd: 67% ld: 33%. the lack of supervision in the taking of medications, numbers/schedules medications, family conflicts and the poor communication with the parents/medical team seem to be the main factors for non-adherence. conclusion: it is necessary to modify the pattern of the patient's attention transplanted under the pattern of chronic suffering that allows the sick person's and their family active incorporation to the process in an integral way to the multidisciplinary group. infantile results: 9 patients (4 females, 5 males) <15 kg, 6/9-<10kg at pd start were treated. they consisted 20% of our center's pd patients (43 pts). age at pd start: 21.6±16 months (median 17), 8/9 pts <24 mo. pd therapy duration: 4-21 mo (median 6), 3 pts >12 mo. esrf cause: congenital nephrotic syndrome 4 pts, dysplastic kidneys 4, cortical necrosis 1. 6 pts were fed by gastrostomy, 4 pts received gh (growth hormone). 5/9 pts had hypertension (ht) treated with >2 drugs and 1-4 cv events. pd type: 5/9 cycler-assisted, 1/9 capd (continuous ambulatory pd), 3/9 both. pd adequacy targets (kt/v>2.5) were reached in 8/9. peritonitis: 0.22 episodes/patient-month, 3 pts had >3 episodes. 6/9 pts had >2 pd catheters and 5/9 >5 pd-related surgery. outcome: 6/9-kidney transplantation, 3/9 switched to hd for infections or uncontrolled ht. height ±sds median 0, weight ±sds median +1.1. conclusions: small infants with esrf can be successfully treated by pd despite high rate of infectious, cv and surgical complications. pd therapy main target is optimal growth towards kidney transplantation. hyperlipidemia is a well recognised complication of renal transplantation. it is a fairly common problem in the paediatric renal transplant population. its prevalence ranges from 16% to 72% though the mechanism is not clear. steroids, calcineurin inhibitors and rapamycin are the main culprits in inducing hyperlipidemia, which is a potential risk factor for cardiovascular heart disease and graft dysfunction. long term effects of these immunosuppressive drugs in children have not been adequately studied. of the calcineurin inhibitors cyclosporine (csa) was found to induce hyperlipidemia compared to tacrolimus (tac). post-ransplant hyperlipidemia is well described in adults; the same cannot be said in children. in adults, post-transplant hyperlipidemia increases risk of cardiovascular disease 3 to 4 fold. screening and management of hyperlipidemia has therefore become an important part of current long term management of transplant patients. there is a limited data on prevalence of hyperlipidemia in renal transplant in children and even more so locally here in south africa. most of the known studies have been conducted in the first world, there was therefore need to determine prevalence locally. this information would ultimately assist in the overall management of our renal transplant recipients. majority of the patients had normal lipid profile. 25% of the patients had high cholesterol levels, while 25% of the patients had high tg levels. 4/10 (40%) of the patients on csa had hypercholesterolemia compared to only 1/11 (9%) on tac (p=0.15). 2/10 (20%) of the patients on csa had high tg compared to 3/11 (28%) on tac (p=1.0). the study concluded that the prevalence of hypercholesterolemia and hypertriglyceridemia in renal transplant pts is high, comparable to other studies and that there is a tendency towards having more lipid abnormalities in transplant pts on csa. grade 3 vur in 24 (39%) and . the incidence of abnormal findings was significantly higher in children with uti and vur than in those with uti without vur (88.5% vs 67%; p<0.05). in children with no vur, grades 1-2 vur, grade 3vur and grades 4-5 vur, renal scarring rates were 67%, 70%, 90% and 88%, respectively. the patients with higher grades vur tended to have more than 3 scars on their dmsa scans (p<0.01). our findings suggest that renal scarring resulting from uti is mostly related to vur, but sometimes is caused by the infection itself. we can conclude that vcu is essential for diagnosis of vur, but 99mtc-dmsa scan shouldn't be avoid in the management of children with uti. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] years. seventythree (97.3%) of them were on triple immunosuppressive therapy, one on double therapy, and one didn't use any medication. overall, 9 subjects (12%) had at least one episode of uti. twenty-four episodes of urinary tract infection occurred in 9 children: 7 episodes in two girls with neurogenic bladder (ngb), 9 episodes in two boys with posterior urethral valve (puv), four episodes in an obese girl with laurence-moon-biedl syndrome, 2 episode of uti in 2 girl with unknown primary renal disease and 2 episodes in 2 girl, one with polycystic kidney disease and one nephronophthisis. conclusion: uti following kidney transplantation was more common in children with known lower urinary tract abnormalities. key words: urinary tract infection, kidney transplantation. background: in japan, the severe shortage of cadaveric kidneys led clinicians to attempt performing abo-incompatible living kidney transplantation (tx). some reports demonstrate successful results of the combination of plasmapheresis (pp), strict immunosuppression and splenectomy. however, we should concern about a great risk of surgical invasion and postoperative serious infection in younger patients who underwent splenectomy. recently, a few reports suggested anti-cd20 monoclonal antibody (rituximab) can be an alternative to splenectomy. patient and method: a 9 years old boy with bilateral hypoplastic kidneys had been treated with peritoneal dialysis for 3 years. since his blood type o was incompatible with paternal blood type a, we arranged to perform tx using pp and rituximab without splenectomy. a single pp was performed on days -10, -7, and -3 to reduce anti-a antibody (ab) titer. rituximab was administered in a single dose of 375 mg/m 2 on day -6. basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone were used for immunosuppression. results: before tx, the anti-a ab titer was reduced from 1:32 to 1:8, and cd19 level was suppressed from 25% to 3%. tx was performed without splenectomy and he had excellent initial graft function. we observed anti-a ab titer rose up to 1:128 on day +5, but it decreased spontaneously to 1:16. there were no side effects and severe infections during the perioperative period, but the neutropenia treated by gcsf appeared 3 months after rituximab administration. the protocol biopsies were performed in 1 month and 6 months, which revealed no signs of rejection. conclusions: abo incompatible tx using pp and rituximab without splenectomy can be a therapeutic option in children to avoid a invasive surgery and infectious risks. further establishment of optimal protocol for children are necessary to obtain excellent outcomes safely. 1.70.2, 1.320.4, and 75.65.5, 66.415.1, in hivan, and od, p=0.06, p=0 .08, respectively. serum p levels were 6.71. 1, 4.60.9, and cap were 54.517.0, and 39.68.7, in hivan and od, p=0.044, p=0. the aim of this study is to identify the outcome of the physically or socially handicapped children with end stage renal disease (esrd) receiving chronic peritoneal dialysis (cpd). among 95 patients commenced on cpd, 11 handicapped children with esrd receiving cpd were identified in our unit during the period between november 1995 and february 2007. age at cpd initiation ranged from 5.5 to 15.5 years (median age: 11; 6 girls, 5 boys). underlying diseases were neuropathic bladder and vesicoureteral reflux (in 3 patients), chronic pyelonephritis (in 3 patients), vesicoureteral reflux (in 2 patients), amyloidosis (in 2 patients), and alport syndrome (in 1 patient). causes of handicapped status against cpd were inadequacies of indoor resources (in 3 patients), cerebral palsy (in 2 patients), down syndrome (in 1 patient), inadequate psychosocial status (in 1 patient), surgically corrected rectovesicale fistula and ectopic anus (in 1 patient), blindness (in 1 patient), ventriculoperitoneal shunt and paraplegia (in 1 patient), colostomy (in 1 patient). all catheters were implanted percutaneously by the same pediatric nephrologist. median duration of dialysis was 24 (range 3-124) months. during a total of 443 dialysis months, 27 episodes of peritonitis (1 episode/16.4 patient-month), 1 episode of exit-site infection, and 1 episode of tunnel infection occurred in 8 of 11 children. except for an inguinal hernia in 1 patient, we did not observe any mechanical complication related to catheter. cpd was terminated in 6 children (death in 3, renal transplantation in 2, switch to hemodialysis in 1). before initiation of renal replacement therapy, some negative baseline factors may not be really contraindications for cpd. the socioeconomic and geographic factors greatly influence the prevalence and outcome of renal disease in children. the subspecialty of pediatric nephrology in sudan was established few years ago and the facilities for the management of renal problems are limited. the aim of this study is to review the demographic profile, complications and outcome of capd after nineteen months of treatment. all children who underwent capd from june 2005 to january 2007 were studied. there were 22 children (12 males), the mean age was 11 years (range from 11 months to 16 years). the majority of children has undetermined cause of esrd (11 children). the most common complication was peritonitis (peritonitis rate was 1/8.3 patient/months. 8 patients had refractory peritonitis that necessitate catheter removal, exit-site infection was documented in 4 children and catheter block in 4 children. there were 12 drop out of the program 4 were due to deaths, 7 changed modality and one family withdraw treatment. in conclusion this analysis has stimulated improvement in nurses training and supervision as well as attempts to improve catheter survival and microbiology monitoring. the -5) , looking for symptoms of hypovolemia (cramps, abdominal pain or headache) during or at the end of hd treatment. bioimpedance measurements were performed at the end of each session according to the 50 khz tetrapolar technique; resistance and reactance values were plotted on the age and gender specific 50 th , 75 th and 95 th percentiles of the vector distribution in the healthy population (reference tolerance ellipses) as a resistance-reactance graph. hypovolemia (hv) was indicated by a vector shifted to the upper pole, out of the 95% tolerance ellipse; normovolemia (nv) by a vector inside the 95° ellipse. patients complained of one or more of the above-mentioned symptoms in 26% of hd sessions, while biva suggested hv in 47.9% of the sessions. symptoms were significantly more common (p<0.05) in sessions with hv (20/57 cases; positive predictive value 35.1%) than in those with nv (11/62 cases; negative predictive value 82.3%). biva suggested hv in 20/31 sessions with symptoms (sensitivity 64.5%) and nv in 51/88 sessions without symptoms (specificity 58%). no significant differences in the accuracy of biva were found between patients either younger vs older than 18 years, or with height sds <-2 vs >-2, or taking vs not taking antihypertensive drugs. in conclusion, biva can be useful in assessing dry weight in children and young adults on hd: since patients with a vector shifted to the upper pole, out of the reference 95% tolerance ellipse, are at high risk of hypovolemia during the next hd treatment, the increase of the dry weight is then indicated chronic antibody-mediated rejection can occur as a de novo complication in renal allograft recipients and is associated with c4d deposition in peritubular capillaries in the renal graft and positive circulating anti-hla antibodies, although the sensitivity and specificity of positive c4d staining for chronic humoral rejection requires further study. renal outcome appears to be worse in c4d positive patients. current treatment strategies to manage c4d-positive chronic humoral rejection are poorly defined. various protocols with enlarged doses of tacrolimus, mycophenolate mofetil, plasmapheresis, ivig and rituximab have been reported in adult patients. we investigated four pediatric patients (mean age 13.6 yrs; range 10 to 17 yrs) after renal transplantation that developed c4d positive chronic rejection. in 3 of 4 patients, maintenance immunosuppression with calcineurin inhibitors had previously been minimized because of severe toxicity. in 3 of 4 patients, an elevated anti hla class ii antibody titre could be detected; donorspecific antibodies were positive in 2 patients. all patients experienced a progressive deterioration of graft function. treatment with repeated intravenous immunoglobulin (ivig) (1 g/kg body weight per week over four consecutive weeks) followed by a single dose of rituximab (375 mg/m 2 ) was therefore initiated. three of four patients showed an improvement of graft function with a mean increase of gfr by 25%. one patient with advanced chronic transplant nephropathy lost his graft after 6 months. this pilot study demonstrates that the combination of high-dose ivig and rituximab can stabilize or improve transplant function in chronic antibody-mediated rejection without major side effects. the use of ivig and rituximab appears to reduce the active immunologic process, but larger trials are needed to support these observations. cardiovascular diseases are some of the most important causes of morbidity and mortality in children with end stage renal disease (esrd). chronic inflammation has been suggested to be a risk factor for cardiovascular diseases. the aim of this study was to investigate the relation between crp and cardiac changes in children on hemodialysis. this study was conducted on 60 patients (30 patients were hypertensive & 30 were normotensive), 39 males (65%) and 21 females (35%) on regular hemodialysis due to esrd. their ages ranged from 7 to 16 years (mean 14.93±3.0). sixty age-and sex-matched controls were also included. significantly higher velocity of circumferential fibre shortening (vcfs), tei index, interventricular septum thickness in diastole (ivsd), left ventricular mass index (lvmi) and isovolumetric relaxation time (ivrt) and significantly lower e/a ratio were found in all patients as well as in hypertensive & in normotensive groups as compared to the controls. significantly higher ivsd and lvmi were found in hypertensive patients than normotensive patients. significantly higher high sensitivity crp (hs-crp) & crp latex were found in all patients as well as in hypertensive & in normotensive groups when compared to the controls. crp was significantly higher in both study groups with cns symptoms and cardiac symptoms in comparison to those without. it was also significantly higher in patients with increased lvmi & than in those with abnormal e/a ratio. hdlc showed a significantly direct negative effect on crp. s. ca 2+ , se. p and ca x p had a significantly direct positive effect on it. we can conclude that the cardiac affection in children with esrd appears in the form of lv hypertrophy with early diastolic affection. crp could be correlated to these changes and to cns symptoms and cardiac symptoms in these patients. is. lim, hs. lee, dw. kim, wh. choi chung-ang university, pediatrics, seoul, south korea purpose: urinary tract infections are common clinical problems occurring in infants and pediatric patient groups, most frequently caused by uropathogenic e. coli. urinary pathogens almost always infect the host through ascension from the rectum, vagina to the urethra and bladder. recurrent urinary tract infection is a disorder involving repeated or prolonged bacterial infection of the bladder or lower urinary tract. in this study, we examined the substitusion effect of probiotics in the high risk group of recurrent urinary tract infection. objectives & methods: patients diagnosed as recurrent urinary tract infection were administered probiotics for six months, and urine cultures were checked during the period. probiotics in this study were selected among the products commercially saled in korea, namely lactobacillus acidophillus, bacillus subtilis, and bifidobacterium infantis. single blind study was done for selection of probiotics for patients. result: the separated bacteria from the urinary tracts of the patients were the same as administered probiotics in some patients. conclusion: in recurrent urinary tract infection, there seemed to be a substitution effect of probiotics for uropathogenic bacteria, and it is reasonable to administer probiotics for long period in the high risk group of recurrent urinary tract infection. renal insufficiency therapy in children: quality assessment and improvement: the rich q study objectives: outcome studies in children on chronic renal replacement therapy (crrt) have revealed a 30-time increased mortality and 40% co-morbidity in adult survivors. information on the quality of care of treatment centers and on the impact of advised quality indicators on outcomes in children are lacking. no data exist on the impact on these outcomes of the different treatment modalities, peritoneal dialysis, hemodialysis & transplantation either. until now, no structural corporation and consensus on general guidelines with respect to crrt exist between the 9 dutch (nl) and belgium (b) centers for pediatric crrt. aim of the study: 1. assessment of the current quality of treatment crrt in children (qt) in nl & b and of the effect of recurrent peer review of the achieved outcomes on the qt. 2. the assessment of the effect of different treatment modalities on outcomes. 3. the creation of a format for multicenter trials. methods: all prevalent patients on chronic dialysis aged <19 years at onset of the study & all incident patients during the study period with onset of crrt<19 years of age, from b & nl will be included. treatment characteristics and quality indicators of crrt with respect to physical and psychosocial outcomes will be collected of all patients. operational data collection and management will be performed by members of the dutch institute for quality care in dialysis patients (hans mak institute). each 6 months, all data will be revealed and actively discussed by representatives of all centers (peer review). the effect of registration and peer review on the qt will be analyzed after 2 & 4 years. comparison will be made between the effects of cumulative periods of different rrt models on outcomes. the study will be performed between august 2007 & 2011. on estimation, 200 patients will be analyzed. renal renal transplantation in patients with lower urinary tract dysfunction (lutd) of different origin is a challenging issue in field of pediatric transplantation. we report our single centre experience to evaluate the patient and graft survival as well as risks of the surgery and immunosupressive therapy. among 70 pediatric transplant patients 11 patients had severe lower urinary tract dysfunction. videourodynamic test was performed in all patients preoperatively and postoperatively. the cause of urological disorders was secondary to neurogenic bladder (n: 5) and valve bladder (n: 6). clean intermittent cathatetization (cic) was needed in 6 patients to empty the bladder. pretransplant augmentation ileocystoplasty was created in four patients and gastrocystoplasty in one patient to achieve low-pressure reservoir with adequate capacity. three of the patients received kidneys from cadaveric and 9 of them from living donors. the mean age at transplantation was 15±4.7 years. the median duration of transplantation was 18 months (range 1-49 months). at their last visit median creatinin levels were 0.95 mg/dl (0.8-2.4) . three patients had recurrent symptomatic urinary tract infections who had augmented bladder and on cic. one of them had creatinine levels of 2.4 mg/dl. one patient with ileocystoplasty who developed urinary leak and ureteral stricture in early postoperative period was treated by antegrade j stent. severe lutd reserves high risks for graft kidney. however our data suggests that renal transplantation is safe and effective treatment modality if the underlying urologic disease properly managed during the whole course of transplantation period. since surgery and follow-up of these patients is more complicated, patient compliance and experience of transplantation team will have significant impact on the outcome. r. meneses, l. sylvestre, j. sousa, d. ribeiro hospital pequeno principe, pediatric nephrology, curitiba, brazil introduction: in july 2000, we started a systematic evaluation program of each patient on chronic pd. the aim of this study was to analyze the long-term outcome of children on pd program. material and methods: we evaluated all the patients on pd between july 2000 and may 2006, who performed 3 complete protocols, with a minimal interval of 6 months between them, consisting of: anthropometric measurements, blood pressure and cardiological status, standardized laboratorial evaluations, pet test, clearance and kt/v, measurement of the intra-peritoneal pressure (ipp), occurrence of infections, hernias or constipation and need to change the catheter. we then compared all the evaluations using the graphpad prism software, a p value <0.05 was considered significant. results: 36 out of 74 patients were eligible, mean age 8±5 years old at the first evaluation, 61% boys, primary renal disease: 45% uropathies, 28% glomerulopathies, 8% tubulopathies and 19% other causes. there was an improvement on bmi and weight/height z-scores and worsening of height/age z-score, but none was significant. there was also no significant decrease in residual renal function (p=0.51), adequacy parameters remained stable: clearance (p=0.84) and kt/v (p=0.58). most patients were converted from capd to ccpd and nipd, and some had to increase daytime dwells (p=0.0098).constipation and the number of infections improved but not significantly. laboratorial evaluations, peritoneal membrane characteristics, ipp, need to change the catheter and occurrence of hernias did not change over the time. conclusion: a long-term maintenance of children in peritoneal dialysis program is possible, but reaching a satisfactory clinical condition is a great challenge. several points need to be checked for planning a better adequacy and survival of dialysis technique in children waiting for a graft. a rigorous follow-up protocol seems helpful in precocity of prescription strategy modifications. we observed a stable long-term outcome observing these adequacy tools. outcome the recurrence of primary disease in transplants is a well-known problem. we report our single centre experience to assess the frequency of the recurrence of primary glomerulonephritis in children after renal transplantation. medical reports after 1990 of 12 children with primary glomerular disease were evaluated. the 13 grafts were nine from living related and four from cadaveric donors. eight of them were diagnosed as fsgs, 2 of them mpgn and 2 of them pan. the mean age was 15.5±5.4 years. however the median transplantation duration was 47 months, one of the fsgs patient had hyperacute rejection. five years later she had second graft with the serum creatinine 0.7 mg/dl at 7th year of second transplantation. and all recipients were immunosuppressed with either cyclosporin a or tacrolimus, azothioprine or mmf and steroid based regimens. mutational analysis was available in two patients, they had homozygous podocin mutations. post transplant recurrence of fsgs was confirmed in one patient. glomerular tip lesion was the only histologic abnormality on graft biopsy. he has treated with plasmapheresis with no improvement of proteinuria. two of the fsgs patients had thromboses after transplantation. one of them had cardiac thrombosis with heterozygote mthfr mutation and one of them had renal artery thrombosis and loss of graft with prothrombin 20210a mutation. both of them have had additional risk factors for thrombosis. they have all functioning grafts except one. we have not observed any recurrence in patients with pan and mpgn. although the number of our patients quite small, renal and patient survival seems to be more favourable in our experience but we strongly recommend the evaluation of all risk factors of thrombosis and give appropriate anticoagulation. skin involvement in factor h deficiency (fhd) associated to hemolytic uremic syndrome (hus) has never been reported. we describe the case of a young adult on regular hemodialysis (hd) for fhd-hus who developed microangiopatic skin lesions and was successfully treated with plasma exchange (pe). the patient developed end stage renal disease secondary to fhd-hus (scr20) in 2004, when she was 32. after one year of hd she complained of severe night pain in the perimalleolar areas, followed by skin lesions which evolved into superficial ulcers (fig1). in august 2005, due to the worsening of the skin lesions, the patient started hd and pe (2 litres of fresh frozen plasma per session twice a wk) based on the hypothesis that skin lesions were expression of thrombotic microangiopathy. after 7 wks of pe there was a skin improvement (fig. 2) and a pain relief. pe was discontinued. 3 wks later she started to complain of the usual pain in the right foot. pe program combined to hd was restarted and the symptoms ceased again. pe was gradually discontinued and she was addressed to regular plasma infusion of 0.5 litre per wk. so far, after 18 months the pain and the skin lesions did not show up again. m. belingheri, s. cristino, p. basile, v. bianchi, a. leoni, s. testa, l. ghio, a. edefonti, g. ardissino ospedale maggiore policlinico irccs, mangiagalli e regina elena, pediatric nephrology, milan, italy background: in rapidly growing children on hemodialysis (hd), the determination of dry weight still remains troublesome. bioimpedance analysis (bia) is potentially helpful in quantifying the fluid to be removed but its specific role, in routine clinical practice, is not yet clearly set. the aim of the present study was to test the feasibility of prescribing ultrafiltration (uf) exclusively based on bia parameters. methods: differences in body weight, resitance (rx) and reactance (x-c) between pre-and post-hd were calculated in order to derive the equivalence between uf and bia parameters in a 3 years old girl over a period of 16 months. for 21 consecutive hd sessions, uf was prescribed exclusively based on the derived uf-bia equivalence. this period was compared with 21 hd sessions where uf was prescribed by the conventional approach. results. xc correlated with ultrafiltration better (r: .75) than rx (r: .64). bia-based compared with weight-based uf prescription showed a significantly lower number of hd sessions complicated by hypotension (19% vs. 50%), need of fluid reinfusion (5% vs. 50%) and a better quality of the hd sessions (86% vs. 37%). conclusion. prescription of uf solely based on xc is feasible and provides a better outcome compared to the conventional modality of uf prescription. we believe that this approach could be useful for any patients with low tolerance to uf or with problems in setting the correct dry weight. aim: the aim of the present prospective study was to determine the incidence of urinary tract infection (uti) and related abnormalities in children ages between 0-2 years. material and methods: all children between 0-2 years old whose admitting to first step health offices (routine controls and immunization) was screened for uti with urine dipstick test after education of minimum two persons from first step health offices according to protocol with two tertiary child care center and health directorate of izmir province in turkey between july 2005 and july 2006. all patients with urine dipstick test abnormalities were referred to tertiary child care centers for evaluation. urine microscopic evaluation and urine cultures and other further investigations were performed in tertiary care centers after obtaining urine with urinary catheterization. results: 14.918 children (55% boys) were screened with urine dipstick test. the children's mean age was 11.7±5.6 mo (median 10 mo). screening test was found normal in 12.527 (84%) children. 962 of 2391 (40%) of referred child were admitted to tertiary care centers and evaluated for uti. uti was demonstrated in 419 children (2.8% of screened and 44% of evaluated children's). uti incidence was found 4.1% in girls and 1.7% in boys. urinary tract abnormalities were found in 24 children (0.2% of screened and 5.7% of evaluated children's). the most common urinary abnormality was vesicoureteral reflux (17 patients). conclusion: the uti incidence was 2.8% in children ages between 0-2 years, uti more common in girls than boys in this age group and only small group of children has urinary tract abnormality which is determined with routine urine screening. knowledgement: thank you for this opportunity to health directorate of izmir province. we describe ds post-peldrt in 2 children with no known neurologic problems and discuss potential predisposing factors. a 12.2 kg girl with renal dysplasia was started on a calcineurin inhibitor (cni) one week pre-t and when her blood urea nitrogen (bun) was 110 mg/dl. on admission for t, the bun had increased to 146, and her serum sodium (na) was 142 mmol/l. post-t, she remained intubated and paralyzed to permit generous volume supplementation, including 1: 1 replacement of her vigorous urine output (uop), initially with 0.45% nacl in water. five hours post-t, her bun was 17 and her na 126. after modification of uop replacement, her na normalized. on the morning of post-t day 1, paralysis was discontinued, but she did not awaken and had sluggish pupillary reactions. computed tomography of the head (cth) revealed diffuse cerebral edema, and brain death occurred. a 39 kg adoloescent with polycystic kidneys was started on a cni 4 days before peldrt. his bun and na then were 76 and 142, respectively, and had not changed on the day of t. post-t, the patient was immediately extubated. with uop replacements as described above, his bun and na decreased from 74 to 12 and 143 to 124, respectively, over 24 hours despite adjustments in the na content of his intravenous fluids based on urine na levels. the patient then had a 10-second tonic-clonic seizure, followed by a 5-hour post-ictal state. cth was negative, and the patient recovered completely. we conclude that ds, caused by a rapid decrease in serum bun and thus osmolality, may complicate peldrt in settings even with older pediatric recipients or without excessive elevation of pre-t bun. other factors contributing to this ds may include relatively mild hyponatremia and cni effects on both pre-t uremia and seizure threshold. results: 89 patients, predominantly males, ages between 5 months and 21 years old. the mean incidence of peritonitis was 0.1 episodes/patient months. fifty-seven patients (64%) had at least one episode of peritonitis.there were 145 peritonitis, 85% percent from all episodes began at home, 35% caused by gram negatives, 38% by gram positives, 8% by fungus, 19% had a negative culture and in less than 1% it was not performed. the mean treatment time was 19 days, 45% had a good response to initial empiric antibiotics (cefazoline and amicacine). the interval between the beginning of dialysis and the first peritonitis episode varied from 1 to 1462 days, occurring in the first 6 months in 50% of the patients. successful treatment occurred in 75% of the cases, 18% were transfered to hemodialysis, 7% had a consecutive peritonitis episode, and 1 patient died due to mesenteric artery trombosis. conclusion: peritonitis occurred early in our patients. even though most of them have a good initial response, there is still a great amount that have complications leading to technique failure. continuous education for the patients and health team, aiming early diagnosis and treatment, are useful to preserve the technique and decrease morbidity and mortality associated to peritonitis. d. davis, j. emancipator, x. zhu, c. rosen objective: to assess for sd in p chronic kidney disease (ckd) patients before and after rtx. methods: we assessed 4 symptom (sx) domains of sleep disorders: 1) sleep-disordered breathing (sdb); 2) insufficient sleep (is) (shortened sleep time or nap); 3) excessive daytime sleepiness (eds); and 4) restless leg syndrome (rls) using a set of standardized questionnaires in 51 patients with ckd (age 5-18 yrs) including non-d non-tx (ndntx) (n=19), d (n=11), rtx (at least 3 months post-tx) (n=21), and 15 age-matched sibling controls (c) without known ckd. the presence of an overall sd was defined by positive responses in any of the 4 sx domains. results: mean age (se) ranged from 11.9 (3.7) to 14.7 (3.8) in the 4 pt groups (p>0.05) without significant differences in gender, race, or congenital ckd. estimated mean gfr (ml/min/1.73m 2 ) (se) was significantly higher in the rtx group [75.8 (22.4) methods: in a prospective design, 64 renal transplanted children, who had renal transplantation at least 3 months before, at namazee hospital, were enrolled in our study. immunosuppressive regimen consisted of cyclosporine and prednisolone plus mycofenolat mofetil or azathropin. data regarding gfr, serum creatinine, electrolytes, lipids and c 0 and c 2 levels was collected at beginning, in one-month, and five-month intervals. cyclosporine was adjusted to 100-250 ng/ml based on c 0 level. patients were divided into two c 0 (<100 and >100 ng/ml) and two c 2 (<800 and >800 ng/ml) subgroups. discussion: similar creatinine levels, drug dosage, and complications of c 0 and c 2 subgroups may be due to dependence of renal function to several factors other than cyclosporine dosage. regarding coefficient of variation, c 2 was more accurate and reliable than c 0 level. as there was no significant difference in mean c 0 and c 2 levels, and renal function at beginning and the end of the study, there seems to be no need to check c 2 levels after renal transplantation. purpose: preparation is necessary in order to effectively meet the critical needs of the post-operative pediatric kidney transplant patient upon their arrival to the icu following transplantation. the increasing number of children requiring liver transplantation services has made it evident that it is important to have guidelines in place for their initial and often specialized post-operative care. methods: the main goal is to provide the child with appropriate post-operative care and to recognize and quickly address complications. therefore the icu nurse will: · monitor the patient continually and conduct full assessments a minimum of 1 time/hour (airway, breathing, ventilation, perfusion, neurological status, etc) . · observe the incision for signs of bleeding, evisceration, and dehiscence. · treat post-operative pain. · update family with findings, etc. · see that appropriate post-operative studies (ultrasound, laboratory studies, etc) are completed. outcomes: nurses in the icu monitor the pediatric post-operative kidney transplant patients very closely as outlined. this allows for quick recognition of problems and immediate intervention. it is the practice of these nurses to be fully aware of the patient's status as well as any changes that might be problematic. conclusions: nurses are prepared to care for pediatric kidney transplant patients and very carefully follow established guidelines for assessment. following guidelines for assessing and caring for pediatric kidney transplant patients upon admission to the icu has proven to be affective in allowing nurses to quickly recognize complications and notify the appropriate clinician. background: uremia is an independent cardiovascular risk factor. transplantation increases life expectations of patients with crf, however there is still an increased risk of accelerated arteriosclerosis. the pulse wave velocity (pwv) is a non-invasive marker of arterial distensibility, it increases along with arterial stiffness, as an early indicator of arteriosclerosis. aim: to evaluate pwv values of transplanted (tx) children. patients, methods: pwv was measured with a pulsepen in 21 tx (age 14,3±3,0 years). two control groups were formed using a database of 116 healthy children (6-23 years): one matched for age (a) and one adjusted for height and weight (h/w). blood pressure, heart rate, serum calcium (ca), phosphate (p) , and pth were also determined before transplantation and at the time of the pwv measurement. results: tx patients were smaller by 15,3 cm (p<0,05) than a and younger by 2,9 years than h/w (p<0,01). pwv in tx (5,5±0,7 m/s) did not differ significantly from a (5,1±0,9) , however it was elevated in comparison to h/w (4,6±0,6 p<0,01). serum p, caxp and pth was increased before transplantation, all the values returned into the normal range except for creatinine (106±50 micromol/l) at the time of the study. there was no correlation between pwv and the actual values of ca, p and pth. conclusion: pwv is higher in transplanted children as a sign of increased arterial stiffness. controls matched for height and weight should be used in states of severe growth failure. although a number of established risk factors potentially responsible for arterial dysfunction were present before transplantation, they were normal at the time of the study. the long lasting effect of uremia before transplantation could be in part responsible for the increased pwv in children after transplantation. supported otka-t046155-fo48842-f042563 and ett 435/2006. d. derakhshan 1 , h. jalaeian 2 , a. derakhshan department of pediatric nephrology, shiraz, iran 2 shiraz organ transplantation center, nemazee hospital, shiraz, iran backgrounds: bartter syndrome is an inherited recessive autosomal tubulopathy characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with potassium renal leakage, and normal blood pressure despite increased plasma renin activity. patients with this syndrome may have proteinuria or hematuria, but most of them have normal gfrs. here we report on a child with bartter syndrome who developed esrd (end stage renal disease) and underwent successful cadaveric kidney transplantation. case presentation: a 7-year-old girl presented to the pediatrics nephrologist with failure to thrive, severe hypokalemia, hypochloremia, metablolic alkalosis, and normal blood pressure and the diagnosis of bartter syndrome was considered for her. however, due to poor compliance, she did not receive any medications, did not give consent for kidney biopsy and did not attend her opd follow-up visits for about 8 years, when she developed esrd and went on chronic hemodialysis (3/weeks) . her little sibling also was diagnosed to be suffering from bartter syndrome at this time. after 10 months, she received a cadaveric renal allograft. afterwards, her kidney function, serum electrolytes, and growth have improved dramatically. discussion: in this case, we postulate that long-term hypokalemia due to bartter syndrome led to chronic interstitial nephritis and renal dysfunction. successful renal transplantation, even after the onset of esrd, for severe clinically bartter syndrome results in correction of metabolic abnormalities and excellent graft function. we propose that bartter syndrome should be considered as a possible cause of esrd and an indication for early renal transplantation, a procedure that results in a cure for the underlying disease and significant improvements in patient's quality of life. h. jalaeian 1 , a. derakhshan 2 , d. derakhshan 2 , m. fallahzadeh 2 , z. bazargani 3 , m. basiratnia 4 1 shiraz organ transplantation center, nemazee hospital, shiraz, nemazee hospital, shiraz, iran 3 fasa university of medicine, pediatrics, fasa, iran 4 shiraz university of medical sciences, pediatric nephrology, shiraz, iran background: obesity is a major issue in the end stage renal disease population. while studies evaluating the effect of obesity on transplant outcomes in adults have yielded varying results, this issue is even still more controversial in children. methods: in a cross-sectional design, 71 pediatric recipients, aged 4-19 at transplantation and with normal graft function for at least 7 months after transplantation, were evaluated. we grouped the data with regard to the body mass index (bmi) percentiles as group i (bmi >95th), group ii (bmi <95th), group iii (bmi >85th), group iv (bmi <85th). we compared the clinical and laboratory findings between groups i and ii and between groups iii and iv. obesity was defined as bmi >95th and being overweight was defined as bmi >85th. results: there were 71 children (45 males, 26 females) with mean age at time of transplantation of 12.6±3.5 years (range, [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] , and mean follow-up of 4.0±2.4 years. 12.7% of children were overweight and 5.6% were obese. no difference was found regarding age, height, duration of pretransplantation dialysis, or age at transplantation between groups i and ii and between groups iii and iv. (p>0.05). further more, no difference was found in regard to serum creatinine, bun, glomerular filtration rate, and 1-year graft survival rates among obese and/or overweight and other children. no correlation was found between bmi and gfr (p>0.05). conclusion: obese and overweight recipients can have excellent graft function and survival rates that are comparable to their non-obese counterparts. denying patients access to renal transplantation on the basis of obesity per se does not appear to be justified. d. derakhshan 1 , h. jalaeian 2 , a. derakhshan 1 , b. sabet 2 , m. fallahzadeh nemazee hospital, shiraz, iran 2 shiraz organ transplantation center, nemazee hospital, shiraz, iran introduction: tb is an important cause of morbidity and mortality in renal transplant recipients, especially in developing countries. this study was done to identify the incidence of tuberculin test positivity before transplantation as well as the influence on outcome of graft function and patient survival in children who receive renal allografts. methods: all 196 children with esrd who received a renal allograft between 1990 and 2006 were evaluated. as a routine pre-operative measure, a tb test was administered, using ppd. the ppdpositive recipients were compared with ppd-negative subjects, regarding age, gender, graft function, graft outcomes and patient survival rates. patients were divided into <5 mm versus >5 mm induration. results: the mean age of recipients was 14.03±3.20 years (range, 4-18) with a male/female ratio of 1.26:1. the majority of children were on chronic dialysis with mean duration on dialysis of 12.90±12.96 months. the tuberculin test was positive in 14.3% of children; all of them received isoniazide prophylaxis on diagnosis of latent tuberculosis. overall, the 1-year, 2-year, and 3-year survival rates were 94.47±0.02%, 92.44±0.025%, and 88.86±0.03%. three year survival rate was not different among ppd positive or ppd negative individuals. (90.00±0.09 vs. 93±0.03%; p>0.05) in addition, no difference was found for 1-year or 2-year graft survival rates (p>0.05). also serial serum creatinine levels at 1-month, 6-month, 1-year, 3-year, and 5year interval after transplantation was not statistically different (p>0.05). conclusions: detection of latent tuberculosis infection is an important step in the control of tuberculosis among asymptomatic pediatric kidney transplant. with proper management, latent tb does not affect transplantation outcome among children. h. xu, q. shen, ss. ruan, yl. bi, yq. lu, x. wang children's hospital of fudan university, department of nephrology, shanghai, people's republic of china objectives of study: we have started the first pediatric renal transplantation project in children hospital in china from 2004. survival of patients and grafts for the 5 patients are 100%. the clinical features were analysed and specific problems related to drugs and infections were reviewed. methods: 5 children (9~16 years old) underwent rtx. the duration of follow-up was 4 months to 32 months (average of 19.8 months). results: all the 5 patients were on automated peritoneal dialysis prior to rtx. the transplanted kidneys came from cadaveric donors (one were a 6-year-old brain-dead boy). 4 patients received il-2 receptor antibodies as induction therapy and the other one with alg due to high level of population reactive antibody. after the rtx, all the 5 patients were on triple immunosuppressive treatment (prednisolone, mmf, fk506 or csa) . no patient developed postoperative complication and delayed graft function occured. during the follow-up, 1 case suffered from calcineurin inhibitor renal toxicity and changed to rapamycin treatment, 1 from acute respiratory distress syndrome due to infection and 2 from elevated liver enzymes owing to drugs. one had acute rejection at 2 months after the operation. a severe anemia appeared on him after the rejection recovered. the cause of the anemia was found by the positive of serum anti-parvovirus b19 igm and completely recovered from the ivig treatment. at latest follow-up, the mean serum creatinine level of the 5 patients was 84.4±36.5 umol/l and egfr was 118.0±38.8 ml/min/1.73 m 2 . some patients received a support from "shanghai child renal failure trust fund". conclusions: the improvement of surgical technique, adequate dialysis prior to rtx, rational use of medicine, financial support and regular follow-up are all important for improving the outcome. h. bunker-wiersma 1,3 , j-c. davin the area under the curve (auc) of cyclosporine is strongly related to the efficacy and toxicity of the drug and its variability is mainly determined by the absorption phase. close therapeutic drug monitoring (tdm) is warranted to optimise therapy, using more appropriate methods to estimate the auc, than trough concentration measurement. from july 2004 we started auc guided monitoring of cyclosporine therapy based on two concentration measurements, c0 and c2. the results of this method are reported. methods: all paediatric renal transplant recipients treated with cyclosporine were included in the analysis. bayesian, model based estimation of auc values was performed at each out-patient visit or during hospital admission. calculated pharmacokinetic parameters, treatment efficacy data and side effects were collected over the 18 month period after introduction. target auc values were derived from previous studies in adult patients: 5400 ng/h/ml in the first three months after transplantation and 3250 ng/h/ml after three months. results: 15 early or stable post renal transplant patients were evaluated, divided in two groups (group i: <3 months after transplantation; group ii: >3 months after transplantation). in patients with trough concentrations below the therapeutic range, more than 50% auc's were in the therapeutic range in both groups. conclusion: auc guided monitoring of cyclosporine after kidney transplantation in children using c0 and c2 is practically feasible and presents the major advantage that c2 has not to be determined precisely 2 hours after csa administration. it is more closely related to the total drug exposure as compared with trough concentration monitoring and isolated c2. this method may facilitate the use of lower doses of cyclosporine and by this way limitside-effects. objectives: there is no satisfying data about reproductive functions after kidney transplantation in adolescence who have end stage renal disease (esrd) during childhood. we analysed the reproductive functions of kidney transplanted male adolescences. patients and methods: nine patients who followed between 1995-2006 were enrolled in the study. except one preemptively transplanted patient, all were on hemodialysis/peritoneal dialysis before transplantation. mean dialysis duration was 21 (9-54) months. their ages ranged between 10-17 years (mean 13.8) at transplantation. at the urologic examination, their mean age was 19 years. all patients had normal renal functions. results: all patients had normal testicular volume, libido and erectil functions. except one all patients had normal serum levels of lh, fsh, total and free testosterone. seven of the 9 patients semens were available for analysis. 3/7 patients had normal sperm parameters. transplantation had been performed before adolescence period in these 3 patients. one of these patients had been treated with intensive cyclophosphamide before. oligospermia was detected in 2, defective morphology in 3, low sperm motility in 6/7 patients. conclusion: although adult transplanted patients mostly have normal semen profiles; male children with end stage renal failure would not have normal spermatogenesis at the adolescence period; even after successful renal transplantation. in our study only 3 patients had normal semen profile, even hormon levels were normal. renal transplantation age seemed to be more crucial than the duration of esrd, of primary diagnosis or previous cyclophosphamide usage. r. vilalta, j. nieto, e. lara, a. madrid, s. chocron hospital materno-infantil vall de hebron, department of pediatric nephrology, barcelona, spain background: inhibition of il-2 receptors by basiliximab is irreversible and extended in time (mean 30 days). basiliximab (anti cd25 receptor) is used usually in the induction regime in our first cadaveric-donor kidney transplants. its re-use when chronic allograft nephropathy (can) develops could be useful. however some concern could exist related to possible adverse reactions (anaphylactic shock) linked to re-exposure to this drug because is an heterologous protein. less adverse reactions as lymphokine release syndrome has been described with the use of other monoclonal antibodies as the anti-cd20 receptor rituximab. objective: to describe our experience in the treatment with basiliximab of seven children with banf ii can. patients: seven children (2-16 years old (means 8.2 y.), 5 boys, 2 girls) showed biopsy-proved banf ii can. its period post-transplant ranged from 2 to 5 years (mean 4.1 y.) and their creatininine level from 2 to 4 mg/100ml (mean 3.2). all of them had been received at the transplant time basiliximab, tacrolimus or cyclosporine, mycophenolate and tapered steroids to reach 0.2 mg/kg/day in the third month post-transplant. when can developed, sirolimus was used in two patients, but was withdrawn due to increase of proteinuria. results: one dose of basiliximab (20 mg/1.73 m 2 ) was administered after 3 steriod pulses (10 mg/kg/day) in all patients. their basal immunosuppression was not changed. plasma creatinine diminished by 30% in four patients in the second week post-treatment and this improvement was sustained in two patients after one year follow-up. proteinuria did not change in any patient. in the course of this treatment no adverse reactions were observed. conclusion: 1) use of basiliximab in can is safe and possibly useful. 2) exposure to different monoclonal antibodies in paediatric kidney transplantation could be usual in the future; in the induction time, in the treatment of humoral rejection if exists (rituximab) and in the treatment of can. 3) it is necessary to establish that exposure and re-exposure to different antibodies is safe and without major adverse effects as our limited experience supports. r. vilalta, e. lara, a. madrid, s. chocron, j. nieto hospital materno-infantil vall de hebron, department of pediatric nephrology, barcelona, spain background: there are limited knowledge of kinetics and pharmacodynamic effect of sirolimus in paediatric renal transplantatation. provided that sirolimus is effective and safe in combination with tacrolimus and mycophenolate (mmf), the initial dose needed, the evolution of blood levels and the steady state should be studied in order to optimise its clinical use. objective: to establish a possible correlation between dose/level ratio of rapamune and other parameters as age, gender or puberal state. patients and methods: between 2000 and 2006, 19 paediatric patients (11 girls, 8 boys) received a cadaveric kidney transplant. age ranged from 4 to 16 years (mean 8 y.), and all of them received mmf and steroids. sirolimus were used from 0.02 to 0.1 mg/kg/day, to obtain levels between 6 to 12 ng/ml. results: dose/level ratio obtained allowed us to describe three types of patients: an infant-type i dose-level patient (age 4-8 y), a prepuberal type ii (age 8-12y) and an adult-type iii dose-level patient (age 12-16y). type i needed sirolimus between 0.08 and 0.1 mg/kg/day (sd±0.01), type ii between 0.04 and 0.8 mg/kg/day (sd±0.015) and type iii between 0.02 and 0.04 mg/kg/day (sd±0.018) to obtain all of them a constant blood levels between 6 and 12 ng/ml. the same positive correlation was obtained regarding the puberal status. no correlation were observed regarding the gender. introduction: developing of diabetes mellitus after renal transplantation is one of the determining factor in the survival of the patient and the graft. in present study we assessed the carbohydrate metabolism status of ntx. methods: we analyzed 45 patients' data about recently developed carbohydrate metabolism failure after ntx. children underwent ntx between 1990-2005 were investigated. thirty-nine children (16 girls/23 boys) underwent ogtt, who had no ptdm. we analyzed the incidence of ptdm/igt, the combination of immunsuppressive therapy, the number of transplants, the proportion of cadaver/living donor, hcv, blood pressure, lipid metabolism, bmi, graft function parameters and the time since ntx. results: ptdm developed in 6 children (13%). four of 6 patients required insulin therapy. we diagnosed igt in 7 of 39 with ogtt investigated patients (16%). all ptdm/igt patient got tacrolimus and continous steroid therapy. the dose of steroid was 6.5 mg/day in the ptdm/igt group vs. 5.2 mg/day no ptdm/igt (p<0.05). during ogtt the trough level of tacrolimus was higher in the ptdm/igt group 14.3 ng/ml vs. 10.1 ng/ml (p<0.05). in the other parameters we did not find any significant differences between ptd/igt and no ptdm/igt patients. discussion: the most important reasons in the development of ptdm and igt after transplant are steroid therapy and higher tacrolimus trough level. in transplant children we recommend the regular fasting glucose and ogtt examimation, the reduction of steroid and tacrolimus in case of stable graft function. otka f-042563, otka-t046155, ett 435/2006 , ett 184/2003 the introduction: measurement of plasma bnp is a novel noninvasive approach in the assessment of cardiovascular status. in our study we investigated the role of bnp in the monitoring of cardiovascular status of children with crf or renal transplant (ntx). methods: we examined 32 children with crf (n=17, 11 boys/6 girls, age: 12,1 year (3,5-20)) or ntx (n=15, 9 boys/6 girls, age: 16, 25) ). patients underwent echocardiographic investigations (ivs, lvedd, lvesd, pw and fs) and their bnp levels were measured (age matched normal values were used). other cardiovascular risk factors, such as hgb, htk, ca, p, creatinine and blood pressure were also evaluated. a correlation between bnp and echocardiographic results was calculated. results: the values of lvesd, fs and bnp levels of renal transplant patients were significantly better than those of crf patients (p<0,05). the other parameters did not show significant differences. bnp levels were significantly higher in all age groups of crf patients as compared to the normal levels. in younger ntx patients this value was within normal limits. in older ntx patients, and in those that had their transplants a long time ago we measured higher bnp levels, which correlated significantly with graft function as well (p<0,05). bnp showed a significant positive correlation with lvesd and a significant negative correlation with fs only in crf patients. the elevated bnp levels showed the worsening of cardiac function even when the echocardiographic parameters were still normal. the hgb, htk, ca, p and creatinine values were significantly better in ntx patients and showed no correlation with bnp. summary: bnp is an early, easily usable marker in diagnosing and following decreased cardiac function of both crf patients and after ntx. otka f-042563, otka-t046155, ett 435/2006 , ett 184/2003 c. garcia 1 , v. bittencourt 1 , s. vitola 3 , e. didone 3 , e. guerra 3 , f. pires 3 , a. tumelero 1 , d. malheiros 1 , v. garcia department of pediatric nephrology, porto alegre, brazil 2 complexo hospitalar santa casa, department of nephrology and kidney transplantation, porto alegre, brazil 3 complexo hospitalar santa casa, department of surgery, porto alegre, brazil the objective is relate the results of 348 consecutive kidney transplants carried out in children in a single center. patients and methods: analysis of kidney transplants performed in patients less than 18 years old, carried out from may 1977 to december 2006. results: 348 kidney transplants were performed. 48% of the patients were female, 86% were caucasian and 14% were african-brazilian. the mean age at the transplant was 11.3±4.5 years. the most frequent etiology of renal failure was vesico-ureteral reflux/obstructive uropathy (35%), followed by glomerulopathy (26%). the donor was deceased in 34% and living related in 66% (parents 82%). the initial immunosuppression was cya+aza+pred in 38.9%, cya+mmf+pred in 6,9%, tac+aza+pred in 8.6%, tac+mf+pred in 23.9%, tac + mf without pred in 8.9%. sirolimus was employed initially in 4 cases. induction with okt3/atg occurred in 5 patients and 157 received anti-il2 receptor antibody. the 110 graft losses during 29 years of follow-up were secondary to chronic allograft nephropathy in 58 (51%), vascular thrombosis in 6 (5.2%), acute rejection in 13 (11.2%), recurrence of original disease in 14 (12.1%). there were 27 transplants in 21 patients with focal segmental glomerulosclerosis, 12 (57.1) had a recurrence after transplant. eight were treated with plasmapheresis and 75% obtained a total remission. the survival of graft in the first, fifth and tenth year was: 90%, 72% and 59% respectively. the graft survival in the 5th year according the immunosuppression was 41% using azathioprin and prednisone, 72% with cya/aza or mmf and 78% with tac/aza or mmf. the patient survival in the first, fifth and tenth year was: 95%, 93% and 85% respectively, infection was the main cause of death. j. feber 1 , p. geier 1 , b. chaudry 1 , h. wong 1 , g. filler 2 1 children's hospital of eastern ontario, division of pediatric nephrology, ottawa, canada 2 london health science center, departments of pediatrics, london, ontario, canada successful pediatric renal transplantation (tx) should fully correct the metabolic abnormalities of end-stage renal failure. however, ckd may persist because of only half of the normal nephron endowment and other factors (ischemia, nephrotoxocity etc). height, bmi and blood pressure (bp) z-scores, cystatin c-gfr, hemoglobin (hb), serum pth, hco 3 , cholesterol, mycophenolic acid (mpa) and sirolimus (sir) levels were analyzed retrospectively in 21 tx recipients (10 males, age 8.5±5.8 years) at 4 months post tx (t1) and at 3.26±2.21 years (median 2.4) post tx (t2). data are expressed as mean±sd. height z-scores remained significantly lower than controls (t1: -0.90±1.17; t2: -0.75±1.23, ns), growth failure occurred in 19% of pts at t1 and 26% of pts at t2. bp z-score did not change from t1 to t2, but hypertension was diagnosed in 66% pts at t1 and 79% pts at t2. gfr (ml/min/1.73 m 2 ) was 71.9±18.6 at t1 and 70.9±23.7 at t2 (ns), mean decline of gfr was 3.9±1.1%/year. hb z-score remained below normal at -1.55±2.04 at t1 and -1.10±1.27 at t2 (ns) and anemia was diagnosed in 62% and 63% of pts at t1 and t2 respectively, despite trough levels of both mpa (2.77±1.43 mg/ml, 11 pts) and sir (7.73±2.55 mg/ml, 10 pts) that would be considered adequate. hypercholesterolemia was detected in 23.8% pts at t1 and 42% pts at t2, whereas only 9.5% of pts at t1 and 16.8% of pts at t2 were labeled as obese. bone disease was diagnosed in 28.5% pts at t1 and 15.8% pts at t2. we observed suboptimal growth, hypertension, hypercholesterolemia, bone disease and persistent anemia in a significant proportion of tx children despite iron supplementation, adequate mpa and sir levels and good kidney function. these ckd complications require careful monitoring and intervention. a. al midani 1 , g. koffman 2 , j. john 2 , s. stephen 2 , s. suzanne 2 , r. lord 2 1 royal free hospital, transplantation, london, united kingdom 2 great ormond street hospital for children nhs trust, transplantation, london, united kingdom objectives: to document factors predisposing towards surgical complications over 7 years in a single pediatric renal transplant centre. methods: we retrospectively analysed 179 consecutive renal transplants between jan 2000 and dec 2006. patients were divided into group 1, without complications, and group 2, with complications. we compared variables previously identified as risks for surgical complications between the two groups: live/deceased donor, donor and recipient age, gender and weight, side of organ donation, cold ischaemia time, single/multiple vessels, intraperitoneal/extraperitoneal approach, anastomosis to aorta/iliac vessels, thrombosis prophylaxis (changed from heparin to aspirin in oct 2000). results: 141/179 (81%) were complication free; 19% patients developed one or more surgical complication: wound infection 2/179 (1.1%), wound dehiscence 3 (1.7%), prolonged ileus 1 (0.5%), lymphocoele 7 (3.9%). 7 patients were re-explored: 5 (2.8%) for bleeding, 2 (1.1%) for graft repositioning. we observed 2 (1.1%) cases of renal artery stenosis. overall, 5 (2.8%) graft loss occurred secondary to thrombosis, 13% (3/23) prior to changing our prophylaxis from heparin to aspirin (1.2% on aspirin). urological complications occurred in 7 (3.9%): 3 ureteric leaks and 4 ureteric stenoses. the variables between group 1 and group 2 were as follows: under 20 kg: 19% v 35%, less than 5 yrs old: 12% v 30%, intraperitoneal approach: 13% v 37%, anastomosis onto the aorta: 18% v 43%, no aspirin prophylaxis: 9% v 24%, other variables were the same in both groups. conclusions: 19% of patients developed surgical complications. a higher rate of surgical complications was seen in recipients under 5, using the intraperitoneal approach onto the aorta. the introduction of aspirin prophylaxis reduced graft loss due to thrombosis from 13% to 1.2%. other variables did not affect the complication rate. m. medeiros 1 , v. sharma 2 , r. ding 2 , s. valverde 1 , am. hernández 1 , p. garcía 1 , y. fuentes 1 , m. suthanthiran 2 1 hospital infantil de mexico federico gomez, departamento de nefrologia, mexico, mexico 2 weill cornell medical college, immunogenetics and transplantation center, new york, ny, united states the forkhead transcription factor foxp3 is highly expressed in cd4+cd25+ regulatory cells (tregs). the foxp3+cd25+cd4+ cells play a central role in immune tolerance and tgf-β 1 is reported to induce foxp3 expression in vitro. whether there is an in-vivo association between foxp3 and tgf-β 1 is not known. we investigated the hypothesis that there is a positive association between foxp3 and tgf-β 1 in children with stable renal graft function. parental written informed consent was obtained before enrollment in all cases. 24 children with stable renal allograft function for a minimum of 12 months were studied. a complete clinical examination was performed; peripheral mononuclear cells were collected for measurement of transcripts for foxp3, tgf-β 1 , tgf-β 2 , and 18s rrna (house keeping gene) using by real time quantitative pcr assay. correlation between transcript levels was performed using pearson r. results: 24 pediatric recipients of renal allografts were studied. tgf-β 1 and foxp3 were highly expressed in peripheral blood mononuclear cells, and there was a highly significant and positive correlation between levels of mrna for foxp3 and tgf-β 1 (r=0.811, p<0.0001)), whereas no significant correlation was found between tgf-β 1 vs. tgf-β 2 (and tgf-β 2 vs. foxp3). conclusion: foxp3 expression in vivo is strongly correlated with tgf-β 1 expression in peripheral mononuclear cells of stable renal transplant recipients. introduction: studies suggest that pre-emptive lamivudine therapy improves survival in hbv renal transplants. however, long-term outcome is not well established. method: four chinese adolescents with chronic hbv infection were transplanted. they were put on cyclosporin a, mycophenolate mofetil and prednisolone. prophylactic lamivudine was given just before transplantation and was continued afterwards. hbv status and liver enzymes were monitored serially. results: four patients were transplanted at the age of 15.5±3.0 (13.9-19.9) yrs old. they were followed up for 74.7±10 (61-85) months and no mortality was reported. alanine transaminase (alt) was only transiently elevated in the first 2 months post-transplant in all cases and became normal afterwards. there was no hepatitis flare and liver function was normal at the last follow-up. hbeag and hbv dna were positive in 1 patient before transplantation and remained positive at the latest follow-up. mutation in the ymdd motif of the hbv genome was detected in the same patient and undeterminable in the other three due to low virus load. this patient remained clinically stable with normal liver function except there was a rise of viral load from baseline. all grafts were functioning and there was one late acute cellular rejection which responded to treatment and there was no hepatitis flare. latest mean serum creatinine was 141±63 (56-208) umol/l. conclusion: ymdd mutation and resistance to lamivudine treatment may happen but appear to have little clinical significance. our long-term results showed that renal transplant seems feasible and safe in this population up to 7 yrs follow-up. there are no studies in mexican children (mx) . the aim of the study was to determine tacrolimus pharmacokinetics (pk) in mexican renal transplant children and compare it wih reported pk in aa and ca. methods: a seven point pharmacokinetic profile (0, 0.5, 1, 2, 4, 8 and 12h) was performed in ten children receiving tacrolimus as part of the immunosuppressive therapy, mean age was 13.9±2.19 years, mean post transplant time 9.8±35 months. c0 and cmax were obtained directly from experimental points, the auc and t1/2 was obtained with a non-compartmental model using winnonlin version 3.0. results: in cyclosporine (csa) is widely used for immunsuppression in transplant recipients and for treatment of srns. however, patients can develop csa associated cutaneous side effects, e. g. hypertrichosis, skin cancer, and viral warts due to human papillomavirus infection. here we report on a 23-yearold boy suffering from a microdeletion syndrome (18 q-) and srns (histology: minimal change nephropathy) starting at the age of 20 years. since the initial combination therapy with corticosteroids and cyclophosphamide was associated with severe side effects (sepsis, leukopenia) and did not lead to sustained remission csa therapy was initiated. csa-treatment resulted in rapid clinical remission. however, after 12 months the patient developed viral warts (hands, trunk and head), although csa trough levels were kept below 100 μg/l. therefore, immunosuppression was switched to mmf (2x500 mg/day) resulting in sustained remission of srns and rapid disappearance of viral warts within 4 months. conclusion: conversion to mmf may be a usefull treatment strategy in srns showing csa associated side effects like viral warts. 2003-2006. 5 were live related (lrd) and the remaining cadaveric (cad). 6 were pre-emptive(pet). all received basiliximab induction 2 hrs prior to surgery. in addition, induction immunosuppression consisted of tacrolimus and methylprednisolone. in all but 2 patients, basiliximab was re-administered at day 4. 2 patients, aged 11 and 6 yrs (one cad and other lrd respectively) developed acute noncardiogenic pulmonary oedema 6-48 hrs after transplantation. both children had renal dysplasia as primary cause of renal failure. both required delayed ventilation and were ventilated for 4 to 6 days respectively. there was a rapid rise in c reactive protein in both patients. both grafts had primary function, but the cad transplant subsequently developed acute tubular necrosis, and was eventually lost within 3 weeks due to thrombotic micro angiopathy and severe acute antibody mediated rejection despite immunosuppression with sirolimus, mycophenylate, steroids and plasma exchange therapy. conclusion: we report a rare but serious side effect of basiliximab. to our knowledge, this is the first report of basiliximab induced non-cardiogenic oedema so early post transplantation and in such young children. early recognition and aggressive appropriate supportive therapy is vital for patient and where possible, graft survival. 3 (17); cmv seroconversion (4); seizures (4); hypertension (9), uti (6), adverse reaction to basiliximab (2), delayed graft function (4), acute rejections (2), chronic allograft nephropathy (1). 17 patients had well matched kidneys (3 or less mismatches), 11 were poorly matched. 2 grafts were lost from latter group, both were cad, 1 had acute tubulointerstitial nephritis and tacrolimus toxicity and the other thrombotic microangiopathy and eventually acute antibody mediated rejection. chronic allograft nephropathy (can) is a complex phenomenon caused by underlying kidney disease and superimposed by environmental and genetic factors. we investigated the association of polymorphism in the genee nos with the can. nitricoxide is synthesized from l-arginine in vascular endothelial cells by nitric oxide synthase. endothelial nitric oxide plays an important role in endothelial dysfunction and involved in the inflammation. the gene encoding enos maps to chromosome 7q35 7q36.7. a missense variant of the enos gene in exon 7 shows a transversion of g to t at nucleotide position 894 (g894t) that results in a replacement of glu by asp at amino acid residue 298 (glu298asp). the aim was to investigate the association between can and g894t polymorphism of the endothelial nitric oxide synthase gene. the g894t mutation at exon 7 of the endothelial nitric oxide synthase gene, enos gene polymorphism, was analyzed in 61 turkish children with renal transplantation. the g894t polymorphism of the endothelial nitric oxide synthase gene was determined by polymerase chain reaction and restriction fragment length polymorphism. were grouped according to stages of chronic kidney disease (ckd) as estimated by the calculated glomerular filtration rate (gfr, schwartz formula). measurements of structural and functional surrogates for cardiovascular disease (cvd) included intima-media thickness (imt) of the common carotid artery (cca), pulse wave velocity (pwv) and augmentation index (aix). aix and pwv reflect the degree of arterial stiffness and were calculated from pulse wave recordings at the arteria carotis and arteria femoralis (sphygmocor device). results: patients and healthy control subjects had a mean age of 14 years. imt was not significantly different in patients and controls. significant differences were found in the aix, which was increased by 50%: the mean aix was in healthy subjects was -28,2% and in transplanted subjects -14,4%. pwv was increased by 15% (4,74 m/s vs. 5,43 m/s). both aix and pwv increased in parallel with the degree of renal impairment (stages of ckd). table 1 . discussion: weight gain post transplant is multifactorial, like cultural, psychological and associated to steroids. weight gain was observed in general, patients with overweight or in risk of overweight didn't loose weight postransplant even they were aware of the consequences. introduction: tacrolimus is metabolized by cytochrome p450 3a and has a narrow therapeutic range. we report a kinetic interaction between tacrolimus and amlodipine, a potent cytochrome p450 inhibitor, resulting in anuric acute renal failure. case report: a 14-year-old male renal transplant recipient received amlodipine, a calcium channel blocker as antihypertensive treatment while he was on tacrolimus (0.1 mg/kg per day). he presented first with diarrhea and developed subsequently, dizziness and fatigue, related to acute anuric renal failure, requiring hemodialysis for 20 days. tacrolimus trough levels were in the desired therapeutic range (3-6 ng/ml) until recently. three days after introduction of amlodipine, tacrolimus trough levels increased to a toxic level of 38.8 ng/ml. after discontinuation of amlodipine, tacrolimus levels returned to the normal range in seven days and renal function recovered progressively. no polymorphisms in the expression of cyp3a and p-glycoprotein were detected. discussion: tacrolimus is known to be a substrate of p-glycoprotein, responsible for drug secretion into the intestinal lumen and metabolized by enterocytic cyp3a. amlodipine is a competitive inhibitor of cyp3a. as no abnormalities of cyp3a and p-glycoprotein were found, we suspect that drug interaction due to competitive inhibition of tacrolimus metabolism by amlodipine was responsible for these toxic effects. concomitant diarrhea might have played an additional role for increased tacrolimus serum levels, presumably in relation to diarrhea associated dysfunction of enterocytic cyp3a and p-glycoprotein. conclusions: amlodipine and diarrhea increase tacrolimus blood concentration by inhibiting its metabolism. amlodipine should not be used in patients on tacrolimus. careful monitoring of tacrolimus blood levels is recommended in case of concomitant diarrhea. urinary tract infection (uti) remains a significant cause of infectious complications in renal transplant recipients. the aim of the study was to determine the frequency of uti following renal transplantation in our center. the records of 34 patients (f/m: 14/20) who underwent renal transplantation were evaluated retrospectively. among them 12 patients (f/m: 9/3) were found to have at least one episode of uti during follow-up. the records were examined for the age, sex, primary disease, and duration of chronic renal failure, donors, posttransplant follow-up and recurrence of uti. biochemical analysis of blood for renal functions, complete blood count, creactive protein and sonographic examination of patients were also recorded and results were compared with renal transplanted patient who did not develop any episode of uti (group 2). the mean age of the group 1 was 14.6±4.7 years, while it was 14.5±3 years in the group 2. mean duration of post-transplant follow-up was 2.8±1.7 years for group 1 and 2.4±1.7 for group 2. four patients (33.3%) in group 1 and 7 patients (33.3%) in group 2 had vesicoureteral reflux (p>0.05). five patients had single uti while 7 patients had more than one uti. though we did not find any difference between girls and boys in terms of presence of vesicoureteral reflux, frequency of uti in girls was found to be significantly higher than in boys (p=0.003). ultrasonographic examination of patients during uti in group 1 revealed pyelonephritis in 3 and hydronephrosis in 2 patients. the most frequent microorganism causing uti was e. coli. age, donor source and etiology of chronic renal failure did not influence the incidence of urinary tract infection. our data suggests that urinary tract infection remains a frequent but mostly benign complication in the pediatric transplant population, especially in female gender. the growing population of transplanted patients requires the consideration of the potential side effects of the different treatment regimens. experience of the last decade with calcineurin and nucleoside reverse transcriptase inhibitors revealed important renal side effects. we describe a 15 years old girl who was known to have liver failure related to wilson's disease (wd). she had orthotopic liver transplantation from her mother 3 years ago and treatment with tacrolimus and mmf was initiated. although she was known to have proximal renal tubular acidosis secondary to wd, renal tubular functions were found to be normal within the three months of transplantation. two years after the transplantation lamivudine was initiated because of de novo hepatitis b infection in transplanted liver. a couple of months later she developed renal fanconi syndrome with metabolic acidosis, hypophosphatemia, glycosuria and aminoaciduria. she needed high doses of sodium bicarbonate and phosphate supplementation. tacrolimus was suspected to be the cause of late post transplant renal acidosis and was replaced by sirolimus. however, 3 months later, at the 6 th month of lamivudine treatment, she was hospitalized because of metabolic acidosis, mild hyperglycemia and inability to walk. electromyographic examination revealed myopathic changes while liver biopsy was normal with a normal tissue copper level. renal biopsy showed findings of karyomegalic nephropathy which could be the result of the action of antimitotic agents. we suspect that our patient's tubular dysfunction, myopathy and hyperglycemia may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine. however, randomized and prospective studies with large groups of patients are needed for definite results about mithocondrial side effects of these drugs. recombinant factor viia (rfviia, novoseven) is a new hemostatic agent that was initially indicated in hemophiliac patients. recently it has been used successfully for the treatment of bleeding in patients with thrombocytopenia, and acquired and congenital platelet dysfunction. epstein syndrome, also known as alport-like syndrome, is a rare autosomal dominant disease characterized by proteinuria, chronic renal failure, hearing loss, and thrombocytopenia with giant platelets. our group previously reported functional alterations of giant platelets of boy with epstein syndrome, who rapidly progressed to end stage renal disease during adolescence. the first nonheartbeating kidney transplantation at age 17 was failed because of the severe postoperativebleeding irresponsible for traditional therapy (packed red cells, platelets, and fresh frozen plasma), result in immediate graft failure and the need for transplant nephrectomy. the second kidney transplantation was 4 years later, after a single intravenous bolus injection 70 μg/kg body weight rfviia, which was repeated one and 12 hours after the surgery. rfviia successfully controlled the bleeding in the peri-and postoperative phase and no side effect and thrombotic complication occurred and his graft function is still stable after 4 years. recombinant factor viia may have a potential role in the treatment of phenotypic bleeding associated with chronic kidney disease. cyclosporin a (csa) and mycophenolic acid (mpa) have a wide interindividual variability in their pharmacokinetics (pk). among others, intestinal p-glycoprotein (p-gp) expression and cyp3a4 activity have been held to be responsible for that variability. in adult kidney transplant (rtx) patients, an influence of these gene polymorphisms has not been shown; however, there are no data in pediatric patients. we reasoned that such an influence might be masked in adults by confounding environmental factors accumulating over the decades of life. we therefore investigated a possible influence of gene polymorphisms of p-gp and cyp3a4 on defined dose-adjusted pk-parameters in 70 children with rtx (age 11.6; range, 3.2-17.4 yrs). pk parameters (auc, c2) were assessed 1, 3, 12, and 24 weeks after rtx. real-time, rapid-cycle pcr methods were used for genotyping. the allele frequencies for the mdr1 c3435t allele (expression and in vivo activity of p-gp) of 62% and for the cyp3a4-v allele of 3% were comparable to those reported for caucasian populations. dose-adjusted pk parameters of csa and mpa were not significantly different in patients with and without the cyp3a4-v allele or patients with different mdr1 c3435t genotypes. along with that finding, neither of the polymorphisms investigated into was associated with renal function or the incidence of acute rejection episodes. we studied how the il-2r β-chain becomes enriched in lipid rafts of activated human t cells, isolated by ficoll gradient and sheep red cell rosetting, and how its tyrosine phosphorylation, which requires its heterodimerization with the common cytokine r β-chain (βc), occurs there. imunoblots (ibs) of sucrose gradient fractions of cell lysates obtained during a 72-hour activation with phytohemeagglutinine (pha) showed the gradual, largely selective, translocation of the β-chain into rafts. as dimerization or lipid modification can be mechanisms underlying raft enrichment, we assessed lysates of pha-activated cells in ibs under non-reducing versus reducing and crosslinking conditions but did not see evidence of β-chain dimerization. however, exposure to cycloheximide to interfere with post-translational acylation, or to the palmitic acid analogue 2-bromohexadecanoic acid substantially diminished raft enrichment of the il-2r β-chain. we next performed ibs of il-2r β-chainand βc-immunoprecipitates from raft and non-raft fractions of activated t cells before and after il-2 treatment. we found that il-2 exposure triggers the translocation of small amounts of βc, accompanied by il-2r β-chains, into rafts, resulting in its heterodimerization with the il-2r β-chain and their tyrosine phosphorylation. all of these processes were attenuated in the presence of the il-2r β-chain-blocking antibody daclizumab. we conclude that the raft enrichment of the il-2r β-chain requires palmitoylation and provides the focal point for the formation of the highaffinity il-2r via il-2r β-chain-mediated "chaperoning" of few βcs into these domains, establishing novel raft-dependent mechanisms underlying cytokine r specificity and selectivity in human t cells. iga nephropathy (igan) is an immunecomplex disease resulting from a defect in mucosal iga response. food antigens have been implicated in the pathogenesis. gut permeability to antigenic substances is immature at birth and its maturation is delayed by early administration of antigenic foods while breast feeding accelerates this process. we aimed to evaluate if exposure to antigenic foods in early life is associated with a predisposition for igan in childhood. three groups including children with igan (group 1, n=33), primary non-iga glomerulopathies (group 2. n=25) and healthy controls (group 3, n=40) were formed. their parents filled a questionnaire regarding the age at diagnosis, gestation time, birth weight, feeding by breast milk, formula, cow's milk and complementary foods. all groups were similar for age, sex, gestation period, birth weight and the rate and duration of breast feeding. in addition, the rate of formula feeding was also similar in all groups. however, cow's milk consumption rate was higher in group 1 and 2 than in group3. introduction of formula was earlier in groups 1 and 2 than in group 3. in addition, the children in group 1 were younger than the other groups at the onset of feeding by cow's milk and weaning. roc curves predicted 3.5, 3.75 and 5.5 months as the best cut-off age values for formula feeding, cow's milk feeding and weaning for predicting the presence of igan, respectively. ors for igan with respect to these cutoff levels were 28 (95% ci: 4-189), 5.7 (95% ci: 1.9-17.2) and 10.5 (95% ci: 3.9-28.0), respectively. the results of this preliminary study indicate that early introduction of antigenic foods might increase the risk of future primary igan. results: they were 8 males and 2 females, with a male: female ratio of 4: 1. their ages ranged from 5 months to 15 years (mean 6.8 years), with a peak age of 5-9 years. the common presenting complaints were generalised oedema (60%); oliguria (50%) and hypertension (50% we report nine patients (three males) with mesangiocapillary glomerulonephritis (mcgn) from a single paediatric nephrology centre. the average age at presentation was 12.0 years (range 9.2 to 13.4). all had nephrotic syndrome. seven had mcgn type 1 and two had mcgn type ii. six of seven tested had positive c3 nephritic factor. three patients responded well to steroids and ace inhibitors and received no further therapy. five had a good response initially but relapsed when steroids were tapered and one patient had a poor response to steroids. these six patients received calcineurin inhibitor (ci) therapy. four responded well with resolution of proteinuria. one patient relapsed when tacrolimus was withdrawn after 23 months of therapy but proteinuria resolved after re-introduction of therapy. two patients had a poor response to ci therapy. one remains stable but with heavy proteinuria. the second patient (with mcgn type ii) initially had a complete remission of proteinuria on steroids but relapsed 30 months after presentation while on prednisolone 5 mg on alternate days. repeat biopsy showed 65% crescents. treatment with pulsed intravenous steroids, cyclosporin and mycophenolate mofetil was ineffective and she progressed rapidly to end stage renal failure. we conclude that ci treatment might be useful in mesangiocapillary glomerulonephritis. prospective, randomised controled trials are required to determine their place in the management of this disease. iga nephropathy (igan) is caused by a primary defect in mucosal iga response leading to increased antigenic stimuli reaching to bone marrow. enteric flora is important for mucosal and systemic immunity, and probiotics regulate specific and innate immunity by maintaining microbial balance in the gut. saccharomyces boulardii (s.boulardii), a probiotic, increases intestinal siga production, protects enteric infections and also prevents atopic and immunoinflammatory diseases. we aimed to evaluate the effect of s.boulardii on experimental igan, induced by oral polio virus vaccine (opv) administration to the mice. four groups of male balb/c mice (n=7 for each) were formed. groups i and ii were immunized enterally by opv at the onset, 2 nd and 4 th weeks. group ii was also given s.boulardii in drinking water throughout the study. group iii was given only s.boulardii, while group iv received no treatment. two weeks after the last opv dose, all the animals were sacrificed to obtain their kidneys for histopathological evaluation and all four groups were compared with respect to the severity of histopathological changes. while there was mild to moderate mesengial proliferation and widening, tubular atrophy, interstitial inflammation and fibrosis in group i, no remarkable histological changes in the other groups were noted. immunofluorescence microscopy revealed universal deposition of iga and some c3 in group i, while there was no iga or c3 deposition in the other groups. electronmicroscopy revealed mesengial proliferation along with matrix expansion, focal basement membrane thickening and electron-dense deposits in the mesengial area in only opv group and the other groups were normal. in conclusion, enteral s.boulardii administration prevented experimental igan development in mice. the aim was to assess the correlation of renal histopathological findings with clinical diagnosis in order to recognize the pattern of kidney diseases in our pediatric population. methods: a total of 95 renal biopsies performed on children who presented to the surgical kidney hospital in damascus during a period of 3 years were retrospectively reviewed. results: nephrotic syndrome alone accounted for 52% of all cases, followed by hematuria in 21%, mild to moderate renal impairment including allograft dysfunction in 15%, nephritic syndrome in 10%, and hsp in 2%. the most common histologic lesion was mcd in (29%). fsgs was the second most common lesion (13%) followed by mesangial gn (11%), mpgn (9%), post-infectious gn (5%), iga nephropathy (4%), membranous gn (3%), cns of finnish type (2%), alport syndrome (2%), interstitial nephritis (2%), nephronophthisis (2%), hsp (2%), acute rejection (2%), chronic rejection (2%), nephrocalcinosis (1%), crescentic gn of undetermined origin (1%), and lastly, 5% were completely within normal limits. familial and inherited diseases were encountered in 15%. histopathologic diagnosis was mostly useful in nephrotic cases. while in hematuria cases, the usefulness of the histologic findings in terms of therapeutic and/or prognostic point of view was definitely less. one of the reason for that in our series is perhaps because we still do not have facilities to perform electron microscopic evaluation of the renal tissue. however, controversy about the usefulness of renal biopsy in such cases is still there. conclusion: this study provides an important data on the pattern of pediatric renal diseases in our center and highlights the usefulness histologic findings in guiding the therapeutic plan especially for nephrotic children. aim: the aim of this study was to determine the efficacy of tacrolimus in the management of sr fsgs in children. study design: this was a prospective study of 20 children with sr fsgs treated with tacrolimus (0.2-0.4 mg/kg per day in 2 divided doses over 12 hours adjusted to a trough level between 7-15ng/ml) for 12 months in combination with low dose steroids. other therapies included angiotensin converting enzyme inhibitors, folic acid, multivitamins and lipid lowering agents. results: the mean age at study entry was 11.1 years (range 5.6-16.8). the mean duration of nephrotic syndrome before initiation of tacrolimus therapy was 4.7 years (range 2.1-7.6). at the end of the treatment period 8 (40%) children were in complete remission, 9 (45%) children were in partial remission and 3 (15%) failed to respond. the average period of follow-up following cessation of tacrolimus treatment was 27.5 months (range 13.7-43.7). at last hospital follow-up 5 (25%) of children were in complete remission, 10 (50%) in partial remission and 2 (10%) in relapse. 3 children demised from dialysis related complications following cessation of tacrolimus treatment. adverse events included sepsis (2), nausea (2) diarrhea (2), anaemia (4) and worsening of hypertension (4) . conclusion: tacrolimus is a safe and effective treatment for sr fsgs. however, like cyclosporine some children tend to relapse following cessation of treatment. it has been rarely reported in association with graves-disease. now we present a previously healthy 6-year-old japanese girl who had proteinuria due to stage i mn and graves disease. patient: she was found to have 2+ proteinuria and a goiter at her school medical examination simultaneously. serum free thyroxine was 4.98 ng/dl (normal range 0.95~1.74), thyroid-stimulating hormone (tsh) less than 0.003 microu/ml (0.34~3.88), anti-microsomal antibody 1600t (~100), anti-thyroglobulin antibody 400t (~100), and tsh-receptor antibody 84% (~10) consistent with graves' disease. the electron microscopy finding of her renal biopsy specimen showed the presence of electoron-dense deposits located in the subepitherial and intramembranous spaces. with immunofluorescence microscopy, the bright granular staining of igg along the gromerular capillary wall was found. these findings were characteristic of mn. objectives of study: to investigate whether graves disease caused mn in this patient. methods: we examined the presence of thyroid microsome and thyrogrobulin in glomeruli by immunofluorescence study using anti-thyroid microsomal antibody and anti-thyrogrobulin antibody. result: glomerular granular staining of thyroid microsomal antigens was demonstrated corresponding to igg granular deposits, but that of thyrogulobulin was absent. conclusion: mn in this patient is presumed to be caused by immunecomplexes mediated by thyroid microsomal antigens. objective: to explore the role of oxidative stress reaction on the injury of glomerular podocyte slit diaphragm molecular barrier. methods: thirty-two male spraque-dawley (sd) rats were randomly divided into control, low dose (3.0 mg/kg), nephrotic (7.5 mg/kg), overdose (10.0 mg/kg) groups by the dosage of adriamycin (adr) injection.the levels of malondialdehyde (mda) glutathione peroxidase (gsh-px), hydroxy radical ( . oh) and superoxide dismutase (sod) in renal cortex were measured; the expression of podocin was measured with immunohistochemistry. results: (1) compared with control group, the levels of mda in renal cortex and 24-hour urinary protein were increased, the levels of sod in renal cortex was decreased in adr-treated groups, especially in nephrotic group (p<0.05). (2) in control group, podocin staining was a sable linearlike pattern along the capillary loops of glomerulus; in nephrotic group, podocin staining was a light tan discontinuous punctiform or short linear-like pattern along the capillary loops of glomerulus. compared with control group, the score of podocin immunohistochemical staining was decreased in adr groups, especially in nephrotic group (p<0.05). (3) there were some significant negative correlations between the score of podocin immunohistochemical staining and the levels of mda in renal cortex. there were some significant positive correlations between the score of podocin immunohistochemical staining and the levels of sod in renal cortex. conclusion: (1) there was close relationship between podocin and the development of proteinuria. (2) there were significant correlations between the reduction of podocin in glomerular podocyte slit diaphragm and oxidative stress reaction, especially lipid peroxidation. lupus nephritis (ln) remains an important problem in patients with sle. to evaluate the clinical course, histopathology and the efficacy and safety of high-dose pulse cyclophosphamide (ctx) in children with ln. retrospectively, 25 children with ln were studied; all patients underwent renal biopsy and were followed up for at least 3 years. the clinical and serologic data at the time of renal biopsy were recorded. five of them were excluded because of short period of follow-up or defective laboratory data. based on renal biopsy (who classification for ln), 20 patients were treated with the following regimens: one patient (class i) with low-dose prednisolone (pred), 7 (class ii, iii) with high-dose of pred, 12 (class iv) with high-dose pred and 13 received intermittent intravenous (iv) ctx pulses (monthly for 6 months, then every 3 months) followed by mycophenolate mofetil (mmf) as maintenance therapy. there were 13 girls and 7 boys. the mean age at the time of diagnosis of sle was 10.2 years. eighteen patients were more than 8 years old. sixty percent of the patients were presented as nephritic-nephrotic syndrome. there was 1 with class i, 5 with class ii, 2 with class iii, 12 with class iv and none with class v based on biopsy. eighty-five percent of cases went in remission, one was hemodialytic and 2 died due to renal failure and cns involvement. among 12 cases with class iv, 11 responded to pred and iv ctx pulses. there was no evidence of side effects. it seems that iv pulse ctx does induce remission of clinical and renal disease in the majority of early diagnosed children with severe ln. furthermore, it appears that mmf is an appropriate drug for maintenance therapy. however, this study was based on a small number of subjects. further studies to confirm the long-term efficacy and safety of ctx pulse therapy on larger numbers of patients are needed. forming group i were compared with 25 children on short course steroid therapy (iskdc regime) (group ii). children were examined for steroid side-effects and underwent blood tests, ophthalmologic evaluation and radiological examination. results: though remission was achieved in <4 weeks by 84% in group ii against 60% in group i, the total dose received (25-50 mg/kg) was lower in group i (44% vs 20%). forty-six % had 1-2 relapses, 44% had 3-6 relapses and 6% had 6-10 relapses. the proportion of children having >2 relapses was much higher in group ii (60% versus 40%). mean relapse/patient/ year was 1.6 (sd 0.5) in group i against 3.1 (sd 1.6) in group ii. delayed bone age (44%), radiological evidence of osteoporosis (42%). cushingoid facies (28%), posterior subcapsular cataract (16%), decreased growth velocity (14%) and hypertension (12%) were the side effects and were almost equally distributed in the two groups. more patients from group ii received a higher cumulative dose/ kg/year of >150 mg (76%versus 56% in group i) and these had higher risk for hypertension, delayed bone age and osteoporosis. conclusion: alternate day, prolonged therapy (soyka regime) compared to short course, daily therapy (iskdc) resulted in lower cumulative dose to the patient. acute side effects and severity of infections were less. mean relapse/patient/year were lower. group ii patients receiving higher cumulative dose had osteoporosis and delayed bone age. objetive: to assess urinary protein excretion decrease in patients with primary srns treated with ec-mps methods: cohort of 13 patients, mean age: 9 years with primary srns. inclusion criteria: primary sncr with of focal segmental glomerulosclerosis (fsgs). exclusion criteria: glomerular filtration rate (gfr) 30% than baseline level, leukopenia, absence of decrease of proteinuria excretion by month 6 of treatment with ec-mps. mean time after the initial diagnosis of ns until the introduction of ec-mps was calculated in patients who decreased urinary protein excretion below nephrotic range and in non-responsive patients and the glomerular damage, interstitial fibrosis and tubular atrophy were classified as: absent, mild, moderate, severe (0 to 3, risk grade>6). ec-mps dosing: 450-700 mg/m 2 /day. complete response was considered a reduction in the urinary protein excretion lower than or equal to 4mg/m 2 /hour; partial response: urinary protein excretion ranging from 4 to 40 mg/m 2 /hour and absence of response: urinary protein excretion in the nephrotic range. laboratory monthly assessments: serum creatinine, urea, hemoglobin and blood cell counts, lipids, serum proteins, amilase, 24 hours urinary protein excretion. . no significant differences in the frequency of both alleles were observed among patients with different grades of hypertension or proteinuria. in conclusion, drb1* 03011, and possibly 1105 alleles confer susceptibility to psagn. however the severity of the disease is not determined by these two alleles. methods: fifty children who diagnosed as biopsy-proven fsgs were studied retrospectively by medical records. response to treatment and pathologic slides, we compared normal renal function group (n=28) and decreased renal function group (n=22), assessed the factors affecting renal survival and progression to renal failure. results: the mean age at onset was 8 1/12 years, gender ratio m: f was 2.3: 1 and the mean duration of follow-up was 7 1/12 years. the overall renal survival rate was 34% at 5 years, 8% at 10 years. five-year survival rate was 74% in normal renal function group, but 27% in decreased renal functin group. between the two groups, there were no significant differences in age at onset, gender ratio, amount of proteinuria, incidence of hematuria, hypertension and mesangial hypercellularity. decreased renal function group showed higher serum creatinine level, poor response to treatment, higher percent of glomeruli with sclerosis, moderate to severe tubulointerstitial change and vascular change (p<0.05). the prognostic factors of renal survival rate were same as above (p<0.05). there were no significant factor has shown relations with the progression rate to renal failure. conclusion: we reviewed the factors affecting long-term outcome of fsgs. serum creatinine level, steroid responsiveness and the degree of glomerulosclerosis were significant prognostic factors. but, age at onset, gender, amount of proteinuria, incidence of hematuria and hypertension were not considered as a prognostic factor. a background: several studies have suggested that cyclosporine (csa) and methylprednisolone pulse therapy (mpt) may be effective for idiopathic steroid-resistant nephrotic syndrome (isrns) in children; however, the optimal regimen has yet to be established. the present study evaluated the efficacy and safety of 2 years' treatment with csa (neoral) combined with mpt and prednisolone (psl) in such patients. methods: in this prospective study, children with biopsy-proved isrns were enrolled. all patients received csa and psl (1 mg/kg every other day). patients who had focal segmental glomerular sclerosis (fsgs) additionally received mpt (methylprednisolone at a dose of 30 mg/kg per day for 3 consecutive days at weeks 1, 2, 5, 9, and 13) . the dose of csa was adjusted to maintain a trough level from 120 to 150 ng/ml for the initial 3 months, followed by 80 to 100 ng/ml for months 4 to 12, and 60 to 80 ng/ml for months 13 to 24. results: twenty-six patients were enrolled. their mean age was 4.5±3.9 years. two-year follow-up was completed in 22 patients. histological examination at study entry revealed minimal changes in 16 patients, diffuse mesangial proliferation in 3, and fsgs in 7. at the end of the therapy, 19 patients had complete remission, including 6 who had occasional relapses of steroid-sensitive nephrotic syndrome, and 1 had partial remission; the remission rate was 90.8%. nephrosis persisted in 1 patient. disease progressed to end stage renal failure in 1 patient. serial renal biopsy at the end of the study showed mild signs of csa-related renal toxicity, including tubulointerstitial fibrosis in 2 (10.5%) of 19 patients. conclusion: combination therapy with csa, mpt, and psl for 2 years was clearly effective and produced a high remission rate without serious csa-related renal toxicity in children with isrns, in contrast to previous reports. objectives: patients with hemolytic uremic syndrome who do not require dialysis in acute stage usually have a good prognosis. however the spectrum of renal compromise is wide. we believed non-anuric patients with higher creatinine values in acute stage could have different evolution when compared to patients with lower values. aims: 1) to analyze the outcome after a 5 year and 2) to determine if peak serum creatinine values in acute stage would be a prognostic marker. methods: 130 patients, aged 13.8 months at hemolytic uremic syndrome, were analyzed. they were classified into 4 groups: group i, complete recovery; group ii had 2 subgroups: iia, microalbuminuria, and iib, proteinuria and/or high blood pressure, both with normal renal function; group iii, chronic renal failure; and group iv, end stage renal disease. peak creatinine value was definided as the highest value of at least 2 determinations in acute stage. these data were available in 57 patients and they were divided in those with creatinine equal to or higher than 1,5 mg/dl (26 patients) and those with lower values (31 patients). the relationship between creatinine and final outcome was analyzed. we applied fisher's test. results: after a mean follow-up of 12 years, 83 patients were in group i, 27 in group iia, 15 in group iib (6 with hypertension, 5 with proteinuria and 4 with both) and 5 in group iii. eight out of 26 patients (30%) with creatinine equal to or higher than 1.5 mg/dl in acute stage and 1 out of 31 (3.2%) with lower values were in groups iib and iii in the last visit (p=0.007). conclusions: 1) after 12 years, 15% developed proteinuria, high blood pressure or chronic renal failure and 21% microalbuminuria. 2) peak creatinine values in acute stage were a prognostic indicator. objective of study: the aim of this study was to assess the serum concentration of hs-crp in children with nephrotic syndrome (ns) treated with prednisone and cyclosporine a (cya). methods: patients were divided into 3 groups: i -20 ns children (4-14 years) in relapse, examined twice: a -before treatment and b -after proteinuria regression (a 3-4 week course of prednisone therapy), ii -20 children with steroid-dependent or steroid-resistant ns, treated with cya, also examined twice: d -before treatment with cya, e -6 months after therapy. control group (c) consisted of 20 healthy children. serum hs-crp level was determined using a nephelometric method with behring nephelometer 100 analyzer, dade behring. results: it was shown that median hs-crp concentration was the highest in children with relapsing steroid-sensitive ns before treatment (ia). after proteinuria regression (ib), the hs-crp level decreased and did not differ from healthy controls (c) (p>0.05). in group ii, before cya administration (iid) the level of hs-crp was normal, but increased after 6 months of treatment (iie) up to a level six times higher that of the control group (p<0,01). conclusions: in children with steroid-sensitive nephrotic syndrome in relapse, the serum hs-crp level is increased but returns to normal values after a 3-4 week glucocorticoid treatment course. in children chronically treated with cya due to ns, serum hs-crp level increases significantly during the therapy. slit diaphragm connecting adjacent foot processes of podocyte is the final barrier of glomerular capillary wall to prevent proteinuria. both podocytes and neuronal cells are terminally differential cells and they share many common features. nurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation, and they have been understood to be specifically expressed in neuronal tissue. we found that neurexins are expressed not only in neuronal cells but also in several organs including kidney. our immunofluorescence study shows that neurexins are restrictedly expressed in glomeruli in kidney. dual-labeling immunofluorescence studies show that neurexins are localized close to a cd2ap. we also detected some portions of neurexin staining are coincident with that of rab3a, a synaptic vesicle associated molecule. we found that a single splice variant of neurexin-1 is expressed in glomeruli. the staining intensity of neurexin in the glomeruli clearly reduced and their staining pattern shift to more discontinuous patchy pattern in puromycin aminonucleoside nephropathy and anti-nephrin antibody induced nephropathy. the alteration of neurexin in these models was detected more clearly and rapidly than nephrin. we confirmed that neurexin is expressed in podocyte also in human kidney section. these observations suggest that neurexin is involved in the development of proteinuria and that neurexin could be an early diagnostic marker of podocyte injury. to further elucidate the clinical relevance of t-cell abnormality in minimal change nephrotic syndrome (mcns), and to predict the consequences of mcns, we studied t-cell receptor (tcr) diversity by analizing cdr3 size distribution and the frequency of v repertoire usage. thirty-six pediatric patients with mcns were enrolled. eighteen were frequent relapsers and/or steroiddependent (fr/sd) and 18 were non-frequent relapsers (nfr). the study was performed to analyze serial changes of tcr v repertoires in the two groups of patients. frequencies of v repertoire usage were determined by flowcytometry, and tcr cdr3 length distribution was analyzed by genescan. in nfr patients, abnormalities in the distribution of 21 v repertoires were few in both cd4 + and cd8 + t cells. in fr/sd patients the patterns were normal in cd4 + t cells, while selected v repertoires were significantly increased in cd8 + t cells in some patients. furthermore, tcr diversity was significantly reduced in both cd4 + and cd8 + t cells in fr/sd patients as shown by marked skewing of cdr3 size distributions. it is noteworthy that in some fr/sd patients the initially abnormal tcr diversity improved as the clinical symptoms improved such that they became nfr over the years. analysis of tcr diversity may delineate the subgroup of patients with fr/sd and provide a rationale for early intervention with immunosuppressive therapy for these patients. background: transforming growth factor-β is known to play a role in the interaction between metabolic and homodynamic factors in mediating accumulation of extracellular matrix in the diabetic nephropathy. tgf-β1 gene polymorphism was associated with circulating tgf-β levels and influenced the pathogenesis of fibrotic diseases including diabetic nephropathy. in this study, we examined the relationship between tgf-β1 gene codon 10 polymorphism and type 2 diabetic nephropathy with more than 10-year history of disease. methods: we conducted a case-control study, which enrolled 325 type 2 diabetes. a total of 176 patients with diabetic nephropathy were compared with 149 patients without diabetic nephropathy. tgf-β1 codon 10 genotyping was determined using polymerase chain reaction with sequence specific primers method. results: distribution of tgf-β1 codon 10 genotype in the patients either with nephropathy or without nephropathy is confined to hardy-weinberg equilibrium. methods: nzb/w f1 female mice were distributed into three experimental groups (n=5 per group) according to age: 3, 4.5 and 6 months. at specific time-point for each group, 24-hour urine and blood samples were collected to determine proteinuria, osmolality and creatinine levels. after sacrifice, kidneys were removed to measure chemokines and cytokines levels by elisa (pg/100 mg of tissue). results: urinary flux was significantly lower at 4.5 than at 3 and 6 months. a significant reduction in creatinine clearance and an increase in proteinuria were detected at 4.5 and 6 months when compared to 3 months. no significantly changes were observed in serum and urinary osmolality. regarding inflammation, mcp-1 significantly increased at 4.5 (262.7±50.5) and remained elevated at 6 months (334.6±87.7) when compared to 3 months values (206.6±37.9). kc was also higher at 6 than at 3 months ( background: nephrotic syndrome (ns) is related to immunological factors and renal inflammatory mechanisms. many studies showed that inflammatory mediators, especially interleukin-8 (il-8) and monocyte chemoattractant protein-1 (mcp-1), have a role in kidney injury. changes in their urine concentration were found in lupus nephritis and iga nephropathy. thus, the aims of this study were to evaluate il-8 and mcp-1 in serum and urine samples of pediatric patients with primary ns and to verify the relation between these measurements and protein excretion. methods: patients were divided according to current 24-hour proteinuria into two groups: lower than 200 mg/24 hours (group 1, n=11) and higher than 200 mg/24 hours (group 2, n=14). blood and 24-hour urine samples were collected and stored at -80 °c. il-8 and mcp-1 were measured by elisa standard methods. results: blood il-8 and mcp-1 did not differ between the groups. urinary il-8 levels (pg/mg of creatinine) were significantly elevated in patients of group 2 when compared to group 1 (51.06±9.67 vs. 20.48±5.24, p<0.05). although group 2 also exhibited higher values of urinary mcp-1 (223.3±66.64 pg/mg creatinine) than group 1 (151.1±31.64 pg/mg creatinine), they did reach statistical difference. conclusion: the inflammatory process in ns seems to be a local phenomenon, since blood levels of these chemokines were similar in all groups. moreover, our findings showed a relation between il-8 and the presence of proteinuria and suggested a role for this local inflammatory mediator in disease activity. the characteristics of iga nephropathy detected in school urinary screening iga nephropathy (igan) is one of common types of glomerulonephritis in children. however, progression to esrd in patients with igan is not as rare as originally thought. in korea, school urinary screening (sus) program, an useful tool to find out abnormal urinary findings, initiated in 1998. igan was the most common histopathological change in children with isolated hematuria and/or proteinuira in sus. we studied to clarify the clinical and pathologic characteristics of iga nephropathy detected by sus in korea. we investigated 35 patients (symptomatic group=14 vs sus group=21) had been diagnosed with igan following renal biopsy at the yeungnam univ. hospital between may 1998 and may 2004. these patients were analyzed clinical nature, laboratory data and histopathologic findings (haas classification in lm) and progress, retrospectively. their mean age were 10.3±2.5 and 9.5±3.6, respectively, at the time of kidney biopsy. gross hematuria and edema apt to be common in symptomatic group. there were no significant difference in serum iga level, estimated ccr, 24-hours protein amount, light microscopic class and electron microscopic findings between two groups. mesangial iga deposition was significantly more intense in symptomatic group with gross hematuria. in addition to iga deposition in capillary and immune dense deposition in intramembrane is significantly common in symptomatic group with nephrotic range proteinuria. however, progression to chronic renal failure was not noted in both groups during 32.2±28.8 and 24.8±11.2 months respectively. also there were no difference in outcome according to treatment modalities. a longer follow-up period is needed to obtain more information on progression of igan with nephritic range proteinuria by disclosing iga deposition in capillary and immunedense deposition in intramembrane. outcome of srns is uncertain and especially patients unresponsive to treatment have a high risk to develop esrd. prognosis has improved with the introduction of csa, however but long-term follow-up data are scarce and response to csa in patients with genetic forms of srns is uncertain. we report on 25 patients with srns, that was diagnosed at a median age of 3.6 (range 0.5-11.2) years. treatment with csa was initiated on concomitant prednisone therapy, however steroids were discontinued after due course in all patients. median follow-up is 9.5 (0.3-19.1) years. 17 patients had fsgs on renal histology and 12 patients had mcns. complete remission (cr) was defined as reduction of proteinuria <100 mg/m 2 /d. partial remission (pr) was defined as reduction of proteinuria of at least 50% and cessation of edema with serum albumine levels >25g/l. results: 12 patients (6 fsgs, 6 mcns) reached cr with csa treatment. in 8 of these (5 fsgs, 3 mcns) csa could be tapered and discontinued successfully after a median time of 2 (0.5-6.1) years. eight patients showed (7 fsgs) a pr while 5 patients (3 fsgs) showed no repsonse (nr). of 6 patients going into esrd 5 had podocin mutations (pm). only one patient with pm showed partial remission on csa. our data indicate a positive effect of csa treatment in srns, especially in sporadic cases. in patients with cr tapering and even discontinuation of csa is possible. prognosis of srns has improved with csa treatment. objective: we planned to investigate the effects of rsv on the proteinuria and glomerular structure of rats and to explore the role of rsv in the pathogenesis of minimal change nephrotic syndrome. methods: sd rats were inoculated with 6 10 2 , 10 4 , and 10 6 pfu rsv respectively, and sacrificed on days 4, 8, 14, 28 and 60 postinoculation (rsv 4 , rsv 8 , rsv 14 , rsv 28 , rsv 60 ). renal histology was observed by light microscopy and electron microscopy. meanwhile, the proteinuria and serum parameters were measured. the rsv rna and rsv titer were determined by in situ hybridization and plaque assay respectively. immune complex deposits were detected by immunofluorescence microscopy. results: after inoculation, the urinary protein excretion was increased, especially in 6 10 6 pfu rsv 14, 28, 60 (p<0.05). the serum albumin of 6 10 6 pfu rsv 14, 28, and different-titer rsv 60 decreased, but no significant differences in cholesterol, urea nitrogen and creatinine were found among all. slight hypercellularity in minority glomeruli and swelling of partial tubular epithelial cells were observed in rsv 4, 8 of different-titer, whereas a relief of the above changes and no abnormalities were detected in rsv 14 and rsv 28 respectively under a light microscopy. extensive foot process effacement was observed in 6 10 6 pfu rsv 14, 28, 60 under an electron microscope. rsv rna signal and rsv titer of renal and pulmonary tissues, depending on the dose of inoculum, reached their climax on day 8 postinoculation, especially in 6 10 6 pfu rsv 8 . no immune complex deposits were detected in the renal tissues. conclusion: our study reports for the first time that rsv can lead to nephropathy in rats on day 14-60 postinoculation, especially in 6 10 6 pfu rsv-inoculated rats, which may be a new exploration of the pathogenesis of mcns. objectives of study: podocytes play an important role in maintaining the glomerular filtration barrier structure and functions, which associates with several podocyte-specific proteins. our previous study indicated the antiproteinuric effects of dexamethasone were achieved by changes the expression of certain podocyte molecules in vivo. the extracellular signal-regulated kinases regulates a wide range of cellular processes. the aim of the present study is to analyze the potential effects of dexamethasone on podocytes in vitro and to investigate its associated signal transduction pathway. methods: immortalized mouse podocyte clone was divided into three groups: the dexamethasonetreated group (dex-group), the dexamethasone with puromycin aminonucleoside-treated group (dex-pangroup), and control. in dex-group, cultured podocytes were treated with dexamethasone, while in dex-pan group, cells were treated with dexamethasone for 30min first, then added puromycin for different time periods. changes of the protein expression of podocyte-specific proteins and phosphorylation of erk were analyzed by western blotting analysis. result: compared with the control group, in dex-group, the expression of nephrin, podocin, cd2ap, α-actinin4 proteins and vegf protein started to elevate at 24 hr, while neph1 showed no obviously change. erk signaling pathways was activated. increased phosphorylation of erk was marked but transient, which increased from 2 min to 15 min, then decreased. at 30 min the level of phosphorylation of erk returned to the baseline. the phosphorylation of erk level was significant raised in dex-pan group, and lasted to 60 min. conclusion: dexamethasone alters the expression of certain podocyte-specific proteins not only in vivo but also in vitro, and in part, through the activation of the erk signal pathway. kh. kim minimal lesion in the renal biopsy of idiopathic nephrotic syndrome (ns) patients (pts) generally predicts a benign course. fsgs lesions in nspts, on the other hand, are associated with increased risk of steroid resistance and progression to renal failure. fsgs may be observed in follow-up biopsies despite being initially undetectable. whether this represents sampling error or the true natural history of this condition, earlier markers of steroid resistance and poorer prognosis could prove helpful. renal morphometric analyses was performed in 13 ns pts, ages 2 to 19 years, initially diagnosed with minimal lesion, with (n=8) or without(n=5) subsequent progression to fsgs or end stage renal disease (esrd), along with 5 controls ages 3 to 16 years. the age of patients in progressive and non-progressive group and controls were similar. gbm width in patients with minimal lesion (368±52 nm) who subsequently progressed, was significantly greater than that in non-progressive group (290±35 nm, p<0.02). gbm width in both groups was not significantly different compared with the controls (321±49 nm). average foot process width was increased in patients both with progression and non-progression as compared with controls, but there was no significant difference between progressive and nonprogressive group. the length density of podocyte detachment per gbm surface was not significantly different between progressive, non-progressive groups and control groups. there were no significant differences in the mean glomerular volume and cortical interstitial volume fraction between progressive and non progressive group. in conclusion, gbm width may help to differentiate between progressive and non-progressive groups in minimal lesion nephropathy. this may be a pathogenetic clue and needs further study. objective: our study is to investigate the correlation between clinical features and pathological characteristics on henoch-schönlein purpura nephritis (hspn) and the therapeutic methods. methods: fifteen boys and five girls aged 7-15 years (median 10.5 years) with hspn were analyzed retrospectively. the clinical characteristics, laboratory data, pathological findings and therapeutic methods were investigated. results: the patients with isolated hematuria and isolated proteinuria, the pathologic patterns were lighter then gradeii b ; eight patients with hematuria and proteinuria and seven patients with nephrotic syndrome, the pathologic patterns of injury is more severe then gradeii b , whose pathologic patterns injury exceeded gradeii b is 77.8%. twelve patients with nephritic-range proteinuria (>50mg/kg.d) and nephrotic syndrome received corticosteroids, cyclophosphamide, heparin and dipyridamole treatment. nine of twelve patients received intravenous pulse methylprednisolone (mp) and pulse cyclophosphamide (ctx). fourteen of twenty patients obtained stable remission after 3 months to 5 years, and five of twenty patients have asymptomatic microscopic hematuria, another one only has minimal proteinuria. conclusions: if the clinical features showed nephritic-range proteinuria or nephrotic syndrome, the renal pathologic changed markedly as well. for patients whose pathologic exceeded grade iii b or have renal tubule and interstitial damage, our study suggests that mp pulse therapy have satisfied curative effect. materials and methods: in experiment 1, higa mice, c57bl/6 mice and balb/c mice were inoculated intravenously with live cb4 and inactivated cb4 once a month from 1 to 12 mo of age. in experiment 2, higa mice, c57bl/6 mice and balb/c mice were inoculated intravenously with live cb4 and inactivated cb4 once at 6 wk of age. mice in the control group were inoculated with vehicle. the kidneys were extirpated from 5 mice of each group killed with time after inoculation for histological evaluation. experiment 3: we examined prostaglandin (pg) synthetic activity of cultured human mesangial cells. results: the scores for mesangial iga deposition, pcna-positive and matrix scores at 20 weeks were higher in higa mice with live cb4 than in higa mice with inactivated cb4 or without cb4. on em examination, swelling and detachment of endothelial cells from 24 hours after inoculation and increase of serum ifn-gamma concentration were found in mice with live cb4. the scores for mesangial iga and igg depositions, pcna-positive and matrix scores at 30 weeks were more frequently found in balb/c mice with live cb4. production of pge2 and txb2 significantly increased in cultured human mesangial cells damaged by live cb4. conclusion: these results suggest that cb4 provokes exacerbation of renal pathological findings in higa mice via endothelial injury and ifn-gamma production, and may play important roles in igalike glomerulonephritis pathogenesis. rapidly progressive glomerulonephritis (rpgn) is a rare occurrence in alport syndrome (as). this report describes the case of a 10-year-old malewith as who developed rpgn and considers the cause of rpgn in this patient. he had a history of persistent hematuria and proteinuria since birth. at the age of 2 years, he was diagnosed with as based on a renal biopsy. he developed nephrotic syndrome at the age of 5 years. before administration of cyclosporine (cya), repeated renal biopsy was performed at the age of 7 years. the biopsy specimen showed pathologic lesions characteristic of as without crescents. using immunofluorescence (if) staining, the expression of alfa-5 chains of collagen iv was found to be absent in the glomeruli. therefore, cya was administered for eight months. although he recovered from nephrotic syndrome, the effect of cya was limited. after the cessation of cya, his renal function slowly exacerbated. at the age of 9 years, the administration of angiotensin receptor blocker was started. no subsequent anti-proteinuric effect was noted and his renal function improved to cr 0.79 mg/dl. however, by the age of 10 years, he showed macrohematuria and acute deterioration in renal function to cr 9.38 mg/dl. subsequently, he underwent a third renal biopsy. on light microscopy, the biopsyspecimen showed diffuse cellular crescentic glomerulonephritis. if findings indicated pauci-immune type and electron micrography showed a few subepithelial deposits. a serological study revealed negative results for mpo-anca, pr3-anca, and anti-glomerular basement membrane antibody. despite immediate treatment with pulses of methylprednisolone, cyclophosphamide, and plasma exchange, he progressed to end stage kidney disease. the patient reported here presents either a super imposition of rpgn upon a preexisting case of as or a new morphologic and clinical presentation for as. the wt1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development. mutations of the wt1 gene have been shown to cause denys-drash syndrome (dds) and frasier syndrome (fs). the association of early onset nephrotic syndrome progressing to renal insufficiency, xy pseudohermaphrodism and wilms' tumor characterizes dds. renal biopsy shows diffuse mesangial sclerosis (dms). fs is also characterized by xy pseudohermaphrodism and nephropathy, but patients have delayed kidney failure characterized histologically by fsgs. this report examines three girls with nephrotic syndrome related to mutations in the wt1 gene, but with normal female karyotype and development. two girls with early-onset steroid-resistant nephrotic syndrome presented classical wt1 mutations coding for an amino acid change (d396n) and (r394w) at exon 9 that is typical of dds. both children were phenotypically and genotypically females. they developed end stage renal failure within 7 years. one girl had a wilms' tumor on the right kidney. the third child was identified with heavy proteinuria at 7 years of age. laboratory investigations revealed a protein level of 7.2 g/dl (6-8 g/dl), albumin 3.7 g/dl (3.9-5.3 g/dl). proteinuria worsened to 4 g/24 h and she failed to respond to prednisone. renal biopsy demonstrated fsgs in 20% of glomeruli. the splice site mutation ivs9+4 g >a, known to be associated with fs, was found in this patient. karyotype was 46, xx and she had normal uterus and adnexae on ultrasound. angiotensin-converting enzyme inhibitors were prescribed but she still has heavy proteinuria without renal failure. the classical clinical presentation of dds and fs is out dated. pediatric nephrologists need to consider the possibility of these genetic syndromes in evaluation of females with steroid-resistant nephrotic syndrome. we aimed to compare the effects of cyclosporine (csa) or mmf with or without combination of vitamin a,d,e or n-acetyl-l-cysteine (nac). the study included 64 rats in eight groups: control, nephrotic syndrome without treatment, treatment with csa, mmf, vitamin a,d,e, combination of csa and vit ade, combination of mmf and vit ade and combination of nac and vit ade. all rats except the control group were given adriamycin. blood samples were drawn and 24-h urine were collected on day 1 and at weeks 5 and 16. at the 5 th week, 24-h urinary protein excretions in the treatment groups were higher and serum albumin levels were lower than that of 0 th week and control groups (p>0.05). at the 16 th week, urinary protein excretions in group csa&ade was lower than of the groups of csa, mmf, mmf&ade, ade and nac&ade with non-significance (p=0. 42, p=0.94, p=0.72, p=0.82, p=0.53) . serum albumin in group mmf&ade and group ade were significantly higher than of control group (p=0.015, p=0.01). serum albumin in group ade was significantly higher than that of groups of csa and csa&ade (p=0.05, p=0.045). serum triglyceride in group mmf&ade was significantly lower than that of groups csa and csa&ade. serum creatinine in group mmf&ade was lower than that of the groups of csa, csa&ade, mmf, ade and nac&ade and was significantly lower than that of control group (p=0.004). serum creatinine in group csa was significantly higher than of groups of csa&ade, mmf, mmf&ade (p=0.004, p=0.001, p=0.001, respectively). in group nas+ade, total oxidant was significantly higher and total anti-oxidant was significantly lower than other treatment groups (p<0.05). we showed that the better effect on proteinuria, serum triglyceride and albumin and lower serum creatinine by adding vitamin a, d, e in the treatment of experimental nephrotic syndrome with csa or mmf. conclusion: ht is associated with known risk factor of progression of biopsy-proven gn such as s-cr or proteinuria. the crb is an important tool for studies focusing on the epidemiology of gn in the czech republic and serves as a basis for cooperation in this field. (4), lupus-nephritis (3), iga-nephropathy (2), minimal change disease and membranous nephropathy (by 1) were observed. the distinction of morphological variants of the fsgs was started recently (last 6 months). among the patients with fsgs, which were biopsied during this short period (4), all have had a tip-lesion. these patients were started cyclosporine a 150 mg/m 2 /day with complete (3) and partial (1) remission achievement after 1-3 months. thus, the focal and segmental glomerulosclerosis is the most frequent cause of the nephrotic syndrome in children. the focal and segmental glomerulosclerosis with tip-lesion is characterized by favourable course and good response to therapy with cyclosporine a during the short-time period. objectives of study: molecules of monocyte chemoattractant protein-1 (mcp-1), β-catenin and cytokeratin19 (ck19) express increased in cellular crescent, which is a severe pathological change in renal diseases. however, it is unknown whether these molecules in urine correlate to the number or extent of cellular crescents. methods: urinary molecules mentioned above were detected in 20 healthy subjects and 124 patients with renal diseases by elisa. the expressions of these molecules and macrophage (cd68 positive) in 87 biopsy specimens were also investigated. results: significant higher levels of these molecules in urine were demonstrated in all patients with renal diseases compared with healthy subjects (p<0.01), but the highest level in patients of the cellular crescent group. the significant correlations were revealed between these molecules in urine and the index of cellular crescents (r=0.75, r=0.21, r=0.63, p<0.01), between these molecules in glomeruli and the index of cellular crescents (r=0.58, r=0.66, r=0.52, p<0.01), and between these molecules in glomeruli and in urine (r=0.62, r=0.50, r=0.20, p<0.01). conclusions: this study suggested that the detection of urinary mcp-1, β-catenin and ck19 might become potential biomarkers for clinical diagnosing cellular crescent lesions and assessing cellular crescent extent in renal diseases. this study aims to evaluate the benefits and harms of levamisole in steroid dependent (sd) and frequent-relapsing (fr) nephrotic children. material and methods: a total of 24 steroid-sensitive nephrotic children were recruited prospectively from january 2004 to december 2006. 5 females and 19 males, 11 (48%) fr, 12 (52%) sd. mean age at the beginning of levamisole was 5,7 years. twelve didn't receive any alternative drug before, 12 received cyclophosphamide. renal biopsy was perfomed in 5 patients, 4 had minimal change disease (mc), one patient had mc at the first biopsy and fsgs in the second. the patients were divided in two groups according to their steroid response: sd and fr. levamisole was started at a dose of 2,5 mg/kg/48 h as a second line drug in order to try to prolong periods of remission. clinical and laboratorial controls were performed monthly. patients were evaluated as: total responders: when steroid withdrawal was possible, partial responders: when steroid reduction was possible, non-responders: no steroid modification in 3 months. the responders used levamisole for one year. results: the response of frequent-relapsing patients was: 63% of total response, 18% of partial response and 18% of non-responders. steroid-dependent patients had 50% of total response, 25% partial and 25% non-responsers. only one patient developed leukopenia. now 21% (5) are out of levamisole and in remission, 50% (12) are still using levamisole(alone or low-dose of prednisone), 21% (5) are using cyclosporin, one used cyclophosphamide and one is using low-dose prednisone. conclusion: levamisole is a promising alternative drug for nephrotic syndrome. the major advantage of levamisole is its steroid-sparing effect with minimal toxicity. conclusions: hypertension and renal insufficiency were less frequently seen in chinese children with fsgs, isolated hematuria as unique clinic presentation was common in fsgs. all pathological variants had tubular-interstitial lesions, but vascular lesions were rarely seen. most fsgs children with nephrotic syndrome were sensitive to steroid at initial stage, and easy to develop frequent relapse gradually, immunosuppressive agent may be helpful to elevate remission rate. the aim of the study was to assess whether the serum index iga/c3 can be a usefull marker of activity igan and hsn in children. twenty children with igan (mean age 10.0±3.6 years) and 33 children with hsn (mean age 9.53±4.17 years) were retrospectively analysed. in all children urine analysis, gfr were checked and the levels of serum iga and c3 were measured before therapy, serum iga/c3 was than calculated. at the onset of illness, igan and hsn was diagnosed based on the renal biopsy in mean time 1.06±1.37 years. changes in light microscopy were graded i-v according to the classification of who (cwho). all biopsies were scored for activity and chronicity index (ai max score 9, ci max score 12) (pediatr.nephrol.1989,3,248 heparan sulfate proteoglycans are present both as structural components of the gbm and as modifiers of growth factor signaling on the cell surface. in mcns the presence of certain hs epitopes inthe gbm is decreased. hsulf1 and hsulf2 are recently identified endosulfatases, that can remodel the sulfation pattern of hs and thereby control the availability and presentation of factors such as fgf and hgf to their high affinity receptors. sulfatase activity requires posttranslational modification by formylglycine-generating enzyme or sulfatase modifying factor 1 (fge/sumf1) that is counteracted by its paralogue pfge/sumf2. we demonstrated that podocyte, endothelial and tubular epithelial cell lines express mrna for sulf1, sulf2, sumf1 and sumf2. we investigated the in vivo distribution patterns of these enzymes in human kidney specimens by in situ hybridization. in histologically normal kidneys (n=5) expression of hsulf1 mrna was largely restricted to peritubular and glomerular endothelial cells, where as hsulf2 mrna was weakly expressed in all glomerular resident cell types. expression of sumf1 and sumf2 mrna was present in a minority of mesangial cells and podocytes, as well as in avariable number of glomerular and peritubular endothelial cells and invascular smooth muscle cells. in mcns (n=5), the glomerular expression patterns of hsulf1, sumf1 and sumf2 mrna did not differ significantly from that in controls. in contrast, hsulf2 mrna expression was increased in podocytes. increased hsulf2 expression by podocytes is a novel factor to be considered in the pathogenesis of mcns. the onset and duration of ins, histopathological changes in renal biopsy, results of corticosteroid therapy and proteinuria selectivity reflecting the alteration of glomerular capillary wall were analysed. materials and methods: 80 children with ins aged 2-18, followed up 12 to 36 month, and 20 healthy children were studied. in all patients 1 stage of ckd were diagnosed. ins children were divided in two groups regarding to serum cystatin c levels as a marker of gfr: group i (n=37)children with unchanging gfr, ii (n=43) -patients with impairment renal function over the study period. serum total protein, albumin, cholesterol, cystatin c, creatinine and immunoglobulin igg, and urinary protein, albumin, igg and creatinine were measured. results: serum cystatin c levels were higher in both groups of ins patients compared to healthy children (gr. i: 0.8±0.11, gr. ii: 1.19±0.42 vs 0.7±0.1 mg/l; p<0.01). in group ii amount of 24-hour proteinuria was significantly higher than in group i (2.93±2.27 vs 3.76±2.79 g/l; p<.001), however other biochemical parameters (including igg excretion, albuminuria, selectivity index) were not different. in group ii higher age of onset was found. in this group mesangial proliferation and focal segmental glomerulosclerosis more often were observed. conclusions: the age of onset, histopathological diagnosis and proteinuria can be considered as important markers of ckd progression in children with ins. probably, longer follow-up of children with ins is necessary to find other prognostic factors. k. kilis-pstrusinska, k. fornalczyk, d. zwoliñska cyclosporine a (csa) has been used as a therapeutic option for steroid-dependent and steroidresistant nephrotic syndrome (ns). the aim of the study was to assess the effects of long term csa treatment in children with ns. methods: we performed retrospective study to evaluate safety and efficacy of csa therapy in 44 children with ns (20 girls and 24 boys), aged 2-16 years. results: before introducing csa, in 30 patients steroid-dependent ns and in 14 -steroid-resistant ns were observed. 28 children presented symptoms of steroid toxicity. pre-treatment renal biopsy was performed in 42 patients (2 children without biopsy because of renal agenesia). minimal change disease was diagnosed in 18 (43%) children, focal segmental glomerulosclerosis (fsgs) in 9 (21%), mesangial glomerulonephritis (gn) in 8 (19%) and membranoproliferative gn in 7 (16%) cases. all children were taking csa (target blood trough levels 50-150 ng/ml) more than 6 months, mean 24 months (range 7-72). complete remission was achieved in 32 (73%) children, partial in 9 (20%). in 17 (39%) patients csa treatment was continued with mild dose of steroids. 3 patients (7%) did not respond to the therapy and one of them end stage renal failure developed. following side effects have been observed: hyperuricuria (20% of patients), hyperuricaemia (9%), hypomagnesaemia (7%), hypertension (11%), hypertrichosis (9%), gingival hyperplasia (5%), hepatotoxicity (2%), gastritis and ileitis symptoms (2%). in 15 patients control renal biopsy was performed after 24-36 months of csa therapy. in 4 patients progression to fsgs was seen. only in one case histological findings of csa nephrotoxicity occurred. conclusion: long-term csa treatment in children with steroid-dependent and steroid-resistant nephrotic syndrome can be consider as an effective and safe therapy. introduction: membranous nephritis represents a rare disease in childhood with an incidence of 0.8 to 6% in renal biopsy specimens among various types of glomerulonephritis. although in many cases the disease is considered as idiopathic the association of membranous nephritis and infectious agents it is also well known. aim: we report a case of a 19 months old baby girl of asian origin, presented with macroscopic haematuria of glomerular origin, proteinuria, 1-3 gr/24 hours, hyaline and granular casts, maculopapular rash on the legs and microcephaly. methods: renal function tests in terms of plasma urea and creatinine were normal. the renal biopsy showed membranous nephritis. tests for infectious diseases (torch screen) showed a primary cmv infection. this diagnosis was based on the presence of high level cmv specific igm antibodies, increased igg antibodies and low avidity of cmv specific igg antibodies. a real-time-pcr of the renal biopsy specimen was positive for cmv as well, confirming this virus as the causative agent of membranous nephritis in the presented case. treatment with gancyclovire per os was introduced and it was most impressive since proteinuria disappeared in the following two to three weeks. two years after the diagnosis the child remains well and asymptomatic. in summary: to our knowledge, among various infectious agents, there is no case of congenital or secondary nephropathy described so far due to cmv infection in children. objective of study: pulse methylprednisolone therapy (pmt) has been shown effective in proteinuric renal diseases. but its exact effect in children with steroid-sensitive relapsing nephrotic syndrome still has no definite conclusion. to evaluate the effect and adverse effects of pmt, we performed a retrospective study. methods: there were 11 cases of steroid-sensitive relapsing nephritic syndrome received pmt. they all had been treated with oral prednisone in similar condition previously. a self control design was used to compare the effect of pmt and oral prednisone. results: the average age was 7.5±3.1 years. ten cases attained complete remission after the first course of pmt, and the average duration of pmt until remission was 7.4±4.4 days. one case attained complete remission after the second course of pmt. compared with the effect of oral prednisone previously, seven cases attained complete remission more rapidly. paired-samples t-test was performed to compare the effects of pmt and oral prednisone in six cases with very similar state, however, the difference between them was not significant (p=0.082). during the treatment of pmt, adverse effects were found in 6 cases. conclusion: compared with oral prednisone, the superiority of pmt had not been definitely confirmed, and adverse effects might appear during the treatment. therefore we should be very strict with administering pmt in children with steroid-sensitive nephrotic syndrome. the study we performed was retrospective, so it was necessary to design a prospective clinical randomized controlled trial to further evaluate its effect. objective of study: pulse methylprednisolone therapy (pmt) has been shown effective in proteinuric renal diseases. but the exact effect of pmt in children with steroid sensitive nephrotic syndrome (ssrn) still has no definite conclusion. to evaluate the effect and adverse effects of pmt, we performed a prospective study. methods: a prospective clinical randomized controlled trial was conducted to compare the effect and adverse effects of pmt with oral prednisone (op) in children with ssrn. thirty-one children were enrolled with only 23 suitable for evaluation including 9 patients in the pmt group and 14 in op group. results: there was no significant difference between both groups in complete remission rate. the average durations of therapy until remission were 4.9±1.5 days in pmt group and 9.6±6.3 days in op group, respectively. complete remission was more rapidly attained in pmt group (p=0.036; <0.05). during the treatment and the following 3 months, no significant difference of adverse effects was found between both groups. there was no significant difference between both groups in relapse rate during 3 months follow-up. conclusion: compared with oral prednisone, pmt could induce complete remission more rapidly and did not company with more adverse effects in children with ssrn. pmt had no effect on the reduction of relapse rate in the following 3 months after administration. outcome of childhood henoch-schönlein purpura nephritis with nephroticrange proteinuria in a single center objective: the majority of children with henoch-schönlein purpura nephritis (hsn) only with hematuria and/or mild proteinuria have good chances for recovery. however, it is still unclear how we should treat hsn with persistent massive proteinuria. the aim of this study is to evaluate the outcome of childhood hsn with nephrotic-range proteinuria treated with angiotensin converting enzyme inhibitor (acei) and corticosteroids. methods: 109 patients with henoch-schönlein purpura (58 boys, 51 girls) ranging from 0.5 to 13.8 (6.3±2.7) years old at onset visited our hospital between april 1997 and december 2006. thirty seven (33.9%) developed hsn. mean age of 21 (13 boys, 8 girls) hsn patients with nephroticrange proteinuria (>40 mg/h/m 2 ) at the time of diagnosis was 8.3±2.9 years old. two developed nephrotic syndrome, but none had renal insufficiency at onset. one patient suffered moderate proteinuria and renal dysfunction 8 years after the onset. renal biopsies were done in 16 cases and showed 1 for grade i, 4 for grade ii and 10 for grade iii respectively (classification by international study of kidney diseases in children). results: eleven of the 21 patients received acei and no patients were treated with immunosuppressive agents except for corticosteroids and methylprednisolone pulses. after a mean follow-up of 3.8 years, 11 patients showed complete remission, 9 had mild proteinuria or microscopic hematuria, only one postpartum patient presented with nephrotic-range proteinuria, and none developed renal insufficiency. conclusions: our results suggested that the short-term outcome of childhood hsn with nephroticrange proteinuria but not renal insufficiency was relatively favorable. thus, the degree of proteinuria is not a sole prognostic factor for childhood hsn. therefore, the indication for corticosteroid therapy should be clarified. recent observations determined a r1160x specific exon 27 mutation in the gene encoding nephrin (nphs1) which evidenced an unexpectedly mild finnish-type congenital nephrotic syndrome (cns) phenotype. the long-term follow-up of patients with this mutation is actually known only in a few patients. we reported the long term follow-up of a girl originary of sicily (italy) presenting such a mutation. the first 3 years of her life were previously reported (s.guez et al pediatr nephrol 1998). in brief the child was pre-term born from related parents and she presented proteinuria (3-6 g/day) from birth. renal biopsy was consistent with the diagnosis of cns and molecular evaluation demonstrated a homozygous exon 27 r1160x nonsense mutation in the nphs1 gene. in the first 2 years she was treated by human albumin without a regression of proteinuria that decreased up to 0.3-0.5 g/day with enalapril treatment (0.75 mg/kg/day); clearance of creatinine at 3 years of age ranged between 49 and 73 ml/min/1.73 mq. during the following 10 years (at the last control the girl was 13 year old) she had continued enalapril treatment (0.20 mg/kg/day). creatinine clearance was 80 ml/min/1.73 mq/day, serum total protein 66 g/l; serum albumin 40 g/l and proteinuria ranged between 1.5-4.0 g/day. both height and weight were at 50 th for age and pubertal stage was normal; blood pressure was 90/60 mmhg. in conclusion, this is the first reported long-term follow-up in an italian patient affected by finnishtype cns with the specific r1160x nonsense mutation in the nphs1 gene: even if proteinuria persisted there was no worsening in gfr. serum total protein, albumin and growth were normal confirming the milder phenotype in comparison with the typical finnish forms. long-term enalapril treatment may also have contributed to the prognosis in this specific form of congenital nephrosis. atypical hemolytic uremic syndrome (ahus) frequently results in end-stage renal failure and can be lethal in many cases. recently, it has been recognized that many cases of ahus are associated with a defective control of the complement activation cascade. more than sixty different mutations in complement factor h gene (cfh) have been reported so far. guidelines for treatment modalities are yet to be established although plasma infusions and exchanges are often advocated. we describe a patient who presented at 7 months of age with ahus (anemia, thrombopenia, acute renal failure requiring hemodialysis) associated with heterozygous combined de novo complement factor h mutations (s1191l and v1197a) on the same allele. laboratory investigations showed normal levels of complement c4, c3 and factor h. during the first episode, daily plasma exchanges (pe) using cryosupernatant (cr) as replacement fluid resulted in a resolution of hemolysis and complete normalization of renal function. two ahus recurrences were successfully treated with daily pe and subsequently pe were weaned to twice weekly. one year after the first episode, pe were stopped and pi regimen (30 ml/kg twice weekly and weekly thereafter) was started. at the present time, the patient has been receiving weekly pi (30 ml/kg) for one year. transitory falls in haptoglobin levels or platelet counts are observed periodically and successfully treated by intensification of pi (30 ml/kg) twice weekly for one or two weeks. renal function remains normal.although our observation demonstrates the effectiveness and good tolerance of large volumes of pi (30 ml/kg), long-term efficacy of such a therapy remains to be evaluated. because of the possibility of secondary failure of plasma therapy, it is important to investigate alternative approaches such as combined liver-kidney transplantation. common variable immunodeficiency (cvid) is characterized by reduced serum immunoglobulin levels and recurrent bacterial infections. there have been only 3 previous case reports of renal granulomas in cvid and only one of them was associated with immune complex glomerulonephritis. we present a case of renal granuloma and glomerulopathy in a patient with cvid. a 17-year-old girl, with a past history of uveitis, presented with cardiac tamponnade and bilateral pleural effusions. investigations revealed nephrotic syndrome (serum albumin of 23 (normal 41-54) g/l and proteinuria >3g/l), microscopic hematuria and reduced serum igg levels (4.49 g/l, normal 5.29-15.21 g/l). lupus nephritis and serositis were first suspected and corticosteroids were initiated. no serum anti-nuclear or anti-dna antibodies, nor complement activation were detected. a renal biopsy was performed and showed global glomerular endocapillary proliferation. intratubular calcium deposits were present. in the interstitium, a noncaseating epithelioid granuloma was found. immunofluorescence studies showed significant mesangio-parietal igm deposits with few c3 and c1q. as igm-immune complex glomerulonephritis has been reported in sarcoidosis, this diagnosis was highly suspected. further investigation revealed normal lung parenchyma and mediastinum, normal serum angiotensinconverting enzyme, 1.25 oh 2 d 3 , calcemia and calciuria. the nephrotic syndrome gradually improved, but serum igg levels remained persistently low (2.73 g/l). the diagnosis of cvid was confirmed and iv immunoglobulins were initiated. this is the first report of concomitant renal granuloma and igm-immune complex (without igg) glomerulonephritis in a cvid patient. in summary, cvid must be included in the differential diagnosis of renal granuloma and should be differentiated from sarcoidosis to ensure appropriate therapy. o. nwobi, c. abitbol, j. chandar, w. seeherunvong, g. zilleruelo background: rituximab, an anti-cd 20 antibody, has been proposed as therapy for refractory systemic lupus erythematosus (sle), although its use in children remains anecdotal. we present our initial longterm experience on the safety and efficacy of rituximab for treatment of sle in children. methods: 17 pediatric patients with sle refractory to standard treatment protocols were treated with rituximab for 2-4 doses (375 mg/m 2 ). all had proliferative nephritis and systemic manifestations of vasculitis. clinical disease activity was scored using the sle-disease activity index (sledai). proteinuria is reported as the urine protein to creatinine ratio (upr/cr). patients have been followed an average of 2.3±i.2 years. results: b cell depletion occurred within 1 month and remained suppressed for up to 3 months. clinical course, renal function and proteinuria improved in the majority of patients as summarized below: objective: to assess efficiency and safety of treating crns patients with srl. subjects: 5 patients, mean age 11.6 years old (6 yrs-18 yrs) (3 females) affected by crns. inclusion criteria: histological diagnosis of focal and segmental glomerulosclerosis, glomerular filtration rate (gfr) above 60ml/min/1.73 m 2 , negative plasma pregnancy test, signed child and parents informed consent. exclusion criteria: secondary nephrotic syndrome, white blood cells (wbc) count below 4000/mm 3 , chronic hepatopathy, coagulopathy, tumoral or infection processes. discontinuation criteria: sustained decrease in gfr by more than 30% of the initial rate, decrease of the wbc count to less than 4000/mm 3 , occurrence of lymphoprolipherative and tumoral processes, severe infection, alterations in coagulation parameters, positive pregnancy test or inflammatory process or lack of changes in proteinuria or its increase after four-month treatment. methods: srl dose and dosage: dose of 1 to 2 mg/m 2 /day (up to 5 mg/day) administered once a day. expected dosage range: 5 to 10 ng/ml (hplc-uv method). treatment duration: 12 months. results: 3 patients showed nephrotic syndrome remission; average srl dose: 2 mg/m 2 /day; average srl dosage: 5.75 ng/ml (range 5.3-6.3). average proteinuria prior to treatment: 157 mg/m 2 /hour (range 80-263); average proteinuria after treatment: 3 mg/m 2 /hour (range 2.5-4); average time of remission: 2 months and 20 days, none of 5 patients showed adverse events that would have lead to the treatment discontinuation. if these data are representative of the universe of patients we are dealing with, the confidence interval (p=0.95) of the percentage of patients with not proteinuria after treatment is going to be between 45% and 75% if 40 patients are assessed. conclusions: srl caused crns remission in patients who were refractory to traditional immunosuppressive treatments. background: retinoic acid-inducible gene-i (rig-i) may play an important role on inflammatory and immune processes by regulating the expression of various genes, and has been reported to be expressed in various inflammatory diseases. we studied the expression of rig-i in human lupus nephritis and evaluated the correlation between its expression and the histological activity of the renal disease in these cases. methods: expression of rig-i in the glomeruli was assessed by indirect immunofluorescence method; frozen sections of ten kidney tissue specimens obtained from eight patients with lupus nephritis were stained with a monoclonal antibody for rig-i. kidney tissue specimens from eight patients with minimal-change (mc) disease were used as controls. results: expression of rig-i was detectable as granular immunofluorescence in a mesangial and capillary distribution in all the patients with lupus nephritis, but was absent or only trace-like in the patients with mc disease. the glomerular immunoreactivity for rig-i was correlated with the histological activity and severity of the renal disease in the patients with lupus nephritis. conclusions: rig-i expression occurs at levels detectable by indirect immunofluorescence and may be potentially useful as a parameter reflecting the renal histological activity in cases of lupus nephritis. cyclophosphamide pulse therapy for crescentic, proliferative iga nephropathy in children iga nephropathy is one of the most common glomerular kidney diseases in europe, up to 25% of affected adults need dialysis after 10 years. therapy of crescentic, proliferative iga nephropathy in children is not well examined. between 01/2000 and 12/2006 seventeen children (main age 10 years (6-18), male/female=10/7) with biopsy-proven mesangioproliferative glomerulonephritis as manifestation of iga nephropathy were enrolled. nine patients (male/female=7/2) had severe clinical manifestations (renal failure, nephrotic proteinuria or cerebral vasculitis) with extracapillary glomerular proliferations (crescents). this children were treated by intravenous methylprednisolone pulses (400/200/200/100 mg/m 2 body surface area over 4 days) followed by monthly intravenous cyclophosphamide (cph) pulses (6x500 mg/m 2 body surface area) with gradually tapered oral prednisolon (4-10 mg/m 2 body surface area/48 h over 6 months) and aceinhibitor (enalapril 0.05-0.2 mg/kg/d). after 6 months of treatment a significant reduction of proteinuria (2.9±0.4 to 0.24±0.08 g/m 2 /d; p<0.0001) and improvement of kidney function (gfr 117±20.5 vs. 174±7 ml/min/1.73 m 2 , p<0.05) was observed. no notable adverse events were recorded. six patients had a second renal biopsy after completing cph-therapy; only 1 crescent was found in 245 examined glomeruli (initial findings: 48 crescents in 231 glomeruli). after follow-up of 37 (8-75) months all children have unaltered renal function, further episodes of macrohematuria or gross proteinuria did not occur. intravenous cph pulse therapy seems to be an effective therapeutic option in paediatric patients suffering from crescentic iga nephropathy. eye involvement in children with primary fsgs distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (pierson syndrome). the aim of the study is to investigate whether there are any associated ocular anomalies in childhood primary focal segmental glomerulosclerosis (fsgs). demographic characteristics, age at onset, drug therapy and duration of the disease were defined in 30 patients (14 girls,16 boys, mean age 10.1±3.9 years) with biopsy proven fsgs. standard steroid therapy was prescribed to the patients. a detailed ophtalmological examination was performed in all patients. the median age at diagnosis was 6 years (1-16 years). mean followup time was 36 months (4-116 months). eleven patients (36.6%) reached to chronic renal failure during follow-up period. overall, 15 patients (50%) showed various eye abnormalities. nuclear opacity was found inone child and posterior subcapsular opacities probably due to corticosteroid therapy were present in two cases. two patients had myopic astigmatism and two had exotrophia. importantly, 4 patients had anisometropic ambliyopia, 3 had mittendorf spots and 1 had pigmentary changes in macula, which had never been described in the literature. mutational analysis for nephrin, podosin, wt1 and lamb2 genes are still going on. we don't know whether particular mutations are related to particular eye findings like pierson syndrome, yet. however our findings emphasize that ophtalmological evaluation should be performed in all patients with primary fsgs at the time of diagnosis. regardless of the underlying disease, the proteinuric condition demonstrates ultrastructural changes in podocytes with retraction and effacement of the highly specialized interdigitating foot processes. to investigate whether high glucose and advanced glycosylation endproduct (age) induce podocyte phenotypical changes, including quantitative and distributional changes of zo-1 protein, we cultured rat glomerular epithelial cells (gepc) under 1) normal glucose (5mm,=control) or 2) high glucose (30 mm) or 3) age-added or 4) high glucose plus age-added conditions. high glucose plus age-added condition could increase the permeability of monolayered gepcs and induce ultrastructural separation between confluent gepcs. zo-1 moved from peripheral cytoplasm to inner actin filaments complexes by both age-added and/or high glucose condition in cutured gepc by confocal imaging. high glucose plus age-added condition also decreased zo-1 protein amount and its mrna expression to statistically significant level compared to normal glucose or osmotic control conditions. we could also confirm the activation of pkb/akt signaling pathway in gepc by age, high glucose and insulin in pi3k-dependent manner. in addition, an inhibition of pi3 kinase by ly294002 was able to prevent quantitative and distributional changes of zo-1 protein induced by high glucose and age. these findings suggest that both high glucose-and age-added condition induce the cytoplasmic translocation and suppresses the production of zo-1 at transcriptional level and these changes may be mediated by pi3k/akt signaling. this pathway could explain the role of zo-1 in the phenotypic changes of podocytes in diabetic conditions. henoch-schönlein purpura (hsp) is common in the pediatric population, while wegener's granulomatosis (wg) is rare. although both diseases are classified into the vasculitis syndrome, their clinical symptoms, the treatment and the prognosis are considerably different. the classic clinical triad of wg consists of upper and lower airway disease, renal involvement and small vessel vasculitis. we present a rare childhood case in whom hsp-like symptoms were developed prior to wg symptoms. a 13-year-old girl developed ankle joint pain and swelling and purpura on bilateral legs and hands in the absence of abdominal pain. she was diagnosed as hsp and treated with oral prednisolone (psl) therapy. although high dose psl temporarily rescued these symptoms, purpura and joint swelling and pain reappeared in parallel with a reduction of psl dose. at this moment, because microscopic hematuria, mild proteinuria and hoarseness were also noticed for the first time, serum proteinase-3 antineutrophil cytoplasmic antibody (pr-3anca) was evaluated and detected to be high. moreover renal pathology showed necrotizing pauci-immune glomerulonephritis, leading to the final diagnosis as wg. after methylprednisolone pulse therapy followed by oral psl combined with cyclophosphamide, her clinical symptoms with wg were resolved together with the reduction of serum pr-3anca titer. taken together we emphasize that pr-3anca should be evaluated even in the patients who only develop hsp symptoms. background: short-term efficacy of steroid therapy for pediatric patients with iga nephropathy (igan) has been reported. however, there are a number of cases in whom their igan recurs after stopping the steroid therapy. recent japanese study indicated that tonsillectomy had a significant impact on renal outcome. also, another japanese study showed mizoribine was effective for igan in children. in this study, we examined the effects of a treatment regimen consisting of tonsillectomy and steroid pulse therapy followed by mizoribine (tx) for chronic relapsing igan in children. method: ten cases who showed chronic relapsing igan were included as the subjects (mean age at onset: 12.0 yrs, mean age at initiation of tx: 19.4 yrs). they were divided into two group, a normal renal function group (group a, n=6) and an impaired renal function group (group b, n=4). the changes in hematuria, proteinuria, renal function, and adverse events were prospectively examined for more than 12 months. result: a negative of hematuria was observed in 50% of group a and 75% of group b. a negative of proteinuria was seen in 33% of group a. in addition, in group b, deterioration of renal function was not observed during the observation periods. there were no serious adverse events associated with this treatment regimen. conclusion: a treatment regimen consisting of tonsillectomy and steroid pulse therapy followed by mizoribine treatment seems to be effective to control of acute inflammation coexisting with chronic glomerular lesions, and can be a valuable addition to therapeutic options for treating patients with chronic relapsing igan in children. objective of study: to present a case of silent stenosing ureteritis in a boy with henoch-schönlein purpura (hsp). case report: a 4-year-old boy was admitted with a typical hsp. urine findings were normal on admission. a gastrointestinal bleeding on the 4 th day of illness suggested corticosteroid treatment. the ultrasound on the 4 th and 7 th day revealed a normal urinary tract. on the 10 th day he developed non-painful macroscopic haematuria, followed by microscopic haematuria and proteinuria, which reached the nephrotic range on the 11 th day. thus, the boy was treated with methylprednisolone pulses and cyclophosphamide for 8 weeks. renal biopsy was not performed because of his parent's refusal. microscopic haematuria and proteinuria gradually subsided, with complete disappearance at the 5 th month. during this time he was asymptomatic, with no episodes of macroscopic haematuria or colicky flank pain. at the 8 th month of illness a new ultrasound revealed a major left hydronephrosis. computer tomographic urography showed a complete ureteropelvic junction obstruction. the 99mtc-dmsa scan revealed a 5% relative function ipsilaterally. a left pyelostomy was performed. during the next four months after draining, the urine volume of the affected kidney was 0.2-0.3 ml/kgr/hour, the creatinine clearance 2-3 ml/min/1.73 m 2 and the 99mtc-dmsa scan showed a 4% relative function. based on the above findings a nephrectomy was decided. conclusions: although rare, stenosing ureteritis should be considered in hsp. the typical clinical presentation with haematuria in association with colicky flank pain may not always occur, as in the present case, or may be confused with the symptoms of hsp itself. thus, the repetition of an ultrasound during the process of the disease may be necessary, in order for this complication to be diagnosed and treated early, preventing serious renal outcome. mitochondrial diseases are either due to sporadic or inherited mutations mainly in mitochondrial dna located genes. with regard to renal manifestations, tubular dysfunctions are common; however, the existence of solitary glomerulopathy has recently become apparent. in such case, the pathomechansim of the glomerular proteinuria is still obscure. wepresent a 12 year-old girl who was found to have asymptomatic proteinuria (up/cr1.0) in the absence of hematuria, azotemia, tubular dysfunctions, lacking any neurological manifestations. her family history showed maternal inheritance with mild proteinuria of grandmother and renal insufficiency of young uncle. light microscopy revealed 7 glomeruli of normal appearance and 3 of global sclerosis. electron microscopy showed swollen mitochondria in podocyte of normal appearance glomerulus. pointmutation rate of mitochondrial dna, a3243g, was detected as less than 1% in grandmother, 6% in mother and 39% in the patient examined byperipheral blood cells. the proteinuria completely disappeared 3 months after treatment with combined therapy of arb and acei. to determine the responsible molecule for the pathomechanism of proteinria, immunostaining followed by conforcal microscopy with slit diaphragm associated molecules (sdm) (nephrin, podocin), gbm associated molecules (type iv collagen alpha chains, laminin isoforms, perlecan) and podocalyxin was studied and compared to the controls. interestingly distinct decrease of expression with sdm was observed even in normal appearance glomerulus of the patient. taken together, a3243g mutation itself may lead to depletion of atp and/or increase of free radicals in podocyte, which predominantly affect the biogenesis of sdm, result in pathological glomerular proteinuria. the mechanism of antiproteinuric effect of arb/acei therapy should be evaluated by serial biopsy specimen. objectives: to report the effectiveness of pulse cyclophosphamide induction therapy in children with diffuse proliferative lupus nephritis. to identify predictors for unresponsiveness to the treatment. methods: thai children under 15 years of age with biopsy-proven diffuse proliferative lupus nephritis who were admitted to chiang mai universityhospital between 2001and 2006 were retrospectively studied. responsiveness to treatment, defined as urinary protein to creatinine ratio of less than 0.3, was assessed at the end of induction period. the clinical characteristics and laboratory data including gender, age at diagnosis of sle, duration of disease before treatment, hypertension, clinical nephrotic syndrome, amount of proteinuria, serum creatinine, creatinine clearance, serum c 3 level and presence of crescentic formation in renal biopsy were compared between the two groups who responded and did not respond to the treatment. results: a total of 27 patients (89% female) with the mean age at diagnosis of sle of 10.3±2.6 year were studied. nineteen patients (70%) achieved remission at the end of induction therapy. there were no significant differences in all parameters studied between responsive and nonresponsive groups. despite the indifference in the amount of proteinuria, the proportion of patients with nephrotic-range proteinuria was higher in unresponsive group. conclusions: pulsecyclophosphamide is an effective regimen for induction therapy in children with diffuse proliferative glomerulonephritis. although no definite predictor was detected in this study, higher proportion of patients with nephrotic-range proteinuria in the unresponsive group wasnoted. born small for gestational age, but not early postnatal weight gain aggravates the course of idiopathic nephrotic syndrome in children clinical and animal studies have shown a higher risk of an aggravated course of renal disease in childhood after birth small for gestational age (sga). fast catch-up growth after sga seems to support the development of later disease. in a retrospective analysis of 62 cases with idiopathic nephrotic syndrome treated between 1994 and 2004 in a university centrefor paediatric nephrology we identified 6 children as sga and 56 asappropriate for gestational age (aga). we related the course of disease to birth weight and catch-up growth. median age of manifestation in sga was 6.4 (1.9-15.2) years vs. 3.7 (1.2-15.33 ) years in aga children. in all sga children renal biopsy was performed, while only 55% of the aga children underwent renal biopsy showing nodifference in renal histology. in the sga group, 66% patients developed steroid resistance (vs. 21% aga, p<0.05). the number of relapses was not different. 83% sga children needed antihypertensive treatment inthe course of the disease compared to 39% of aga children. catch-up weight gain between birth and 24 months of age did not influence the course of disease. in conclusion we could find evidence for an aggravated course of idiopathic nephrotic syndrome in former sga children, but weight gainduring the first two years of life did not influence the course of disease. the mechanisms of perinatal programming in later renal disease need further investigation. wilson's disease(wd) is a disorder of copper metabolism that affects numerous organsystems including kidneys. besides renal tubular dysfunction as a result of excessive storage of copper, renal manifestations due to therapeutic complications can also develope specially with d-penicillamin. in this study we investigated the frequency and spectrum of renal manifestations during d-penicillamin therapy in wd. of 62 patients receiving d-penicillamin for wd, 4 patients(6.4%) (3 boys, 1 girl) developed findings of glomerulopathy within 1 month to 1 year after initiation of therapy and all were histologically diagnosed to have membranoproliferative glomerulonephritis (mpgn). the patients were between 6-11 years old, and they had normal urinalysis and renal function tests in their first presentations. two siblings developed hematuria and proteinuria below nephrotic range while the other two developed nephrotic syndrome. one of these latter patientsalso had acute renal failure needing temporary peritoneal dialysis. three patients had low complement (c) 3 levels, 2 had antinuclearantibody (ana) positivity, two had c-antineutrophil cytoplasmic antibody (anca) and one p-anca positivity. d-penicillamin therapy replaced by zinc sulphate in all patients. all renal findings improvedin patients within 3-6 months with normal renal functions and complement levels, and negative ana, p and c-anca tests. after 2 years all were clinically in remission of mpgn confirming the role of d-penicillamin in development of renal disease. objectives of the study: the use of tacrolimus in steroid-resistant (sr) focal segmental glomerulosclerosis (fsgs) has been reported in single and small series. the aim of this report is to exhibit experienceon the management of children with sr fsgs in whom tacrolimus had been started on due to the therapy resistance. methods: fk506 combined low-dose oral steroid was started on three male patients (3, 8, 14-yearold) with sr fsgs who had been following for three years. all of them had failed various cyclosporin a, cyclophosphamide and steroid regimens prior to treatment with fk 506. the application was 0.1 mg/kg/day in two divided doses over 12 h adjusted to a trough blood level between 5 and 10 ng/ml for 12 months. other therapies included angiotensin-converting enzyme inhibitors, vitamin d and calcium analogues, and lipid-lowering agents. results: a reduction in proteinuria to normal levels was noted between 2-4 weeks following the initiation. the remission was achieved overall during the treatment. the relapse was recorded following cessation of tacrolimus in 2-4 weeks. the drug was generally well tolerated with no sideeffects and adverse reactions. the ratio of infectious events did not differ from the former regimens. conclusion: tacrolimus may be effective in controlling the proteinuria of patients with srfsgs during the therapy. there is a trend of relapse following cessation of treatment. the duration for drug uptake is a topic of debate. further study in larger population is warranted. introduction: histological features of focal segmental glomerulosclerosis are found in 75% of pediatric patients with steroid resistant nephrotic syndrome. upto 50% (between 13-78%) children with fsgs progress to esrd. objective: to study the clinical course of childhood fsgs and determine the possible predictive factors of chronic kidney disease. method: case records of children who had biopsy proven fsgs and had presented to the sindh institute of urology and transplantation between 1995-2005, were retrieved. clinical and laboratory parameters at baseline, response to steroids and cyclosporine, development of crf (as defined by a gfr of <60 ml/min/1.73 m 2 ), and histopathological details were analysed. result: a cohort of 59 children with a mean age of 8.5±6.5 years and a m: f ratio of 3: 1 was identified. after a mean follow-up time of 5 years, 21/59 (35.5%) developed crf. on univariate analysis, male sex (90% vs 65%, p-0.04), >6 years age at onset (62% vs. 32%, p-0.02), hypertension (57% vs. 26%, p-0.05) and microhematuria at presentation (62% vs. 25%, p-0.007) were significantly associated with risk of developing crf. steroid resistant course (90% vs. 53%, p=0.003) was more prevalent in those who developed crf. the crf group was also more likely to have an elevated creatinine at baseline (47.6% vs. 5%, p<0.05). moderate tubular atrophy and a high percentage of segmentally and globally sclerosed glomeruli were found in those who developed crf. patients progressing to crf were more likely to have a partial response to cyclosporine (86% vs. 33%, p=0.02) conclusion: factors such as age, microhematuria, hypertension, elevated baseline creatinine, steroid resistance, tubular atrophy, percent global sclerosis and partial response to cyclosporine are likely predictive of progression to chronic kidney disease in children with fsgs presenting to our center. chronic glomerular nephropathies in children are marked by an often unfavourable evolution, so that the establishing of a prognosis at the time of the diagnosis is both a professional and a moral duty for the pediatric nephrologists. purpose: the estimation of the current practice renal survival prognosis in children with chronic glomerular nephropathies, by using clinical and laboratory elements in different histological forms of primitive chronic glomerulonephritis (cgn), with a minimum period of observation of one year. we analyzed parameters that may intervene in the duration of renal survival: type of cgn, age at the debut of the illness, histological scores of activity and chronicity, the presence of tubular atrophylesions and that of interstitial fibrosis, renal failure (rf) installment time, in cases with normal renal function at the beginning, the time until the initiation of dialysis in cases with esrf, respectively. the statistic analysis of data has been carried outwith epi soft (fishcer test). the results have been as follows: unfavourable evolution has been taken into consideration in the cases which have presented fixed nitric retention or which required the initiation of dialysis. the initiation of dialysis was necessary in 19 cases (76%), out of which 11 (44%) having associated between 4 and 6 of the considered risk factors. if the histological type (sfgs, dgs, mpgn) is added to the obtained score, the accuracy of the estimation increases to 89%. in conclusion: the usage of prognosis scores composed of current elements of diagnosis that have proven to have statistical significance, as far as the renal survival prognosis is concerned, may allow the invoking of a medium-term prognosis in the evolution of children with cgn. introduction: the srns can lead to a progressive deterioration of the renal function and therefore needs an aggressive therapy. one of the alternatives of treatment is the association described by mendoza et al which consists of prolonged use of methylprednisolone with cyclophosphamide (cp), which has a remission rate of 66%. the objective of this study is to evaluate retrospectively the clinical evolution of 15 children with srns treated with mendoza's protocol. method: between 1993 and 2005, 15 children, 8 male and 7 female, with srns were subjected to a renal biopsy and later treated with mendoza's protocol. cp was used in children that had not responded to pulses of methylprednisolone and presented a relapse. all of the patients received supplemental calcium. the clinical evaluation included stature, weight, ophthalmic fundus examination, proteinuria in urine recollection of 24 hours and/or protein to creatinine ratio and blood chemistry. results: eleven patients (73%) had fsgs. nine (60%) presented complete remission, two (13%) had partial remission, four (26%) did not respond to treatment, 3 of which evolved to terminal kidney disease. nine patients received cp. of the complications secondary to treatment with steroids, 80% had a linear growth suppression and an increase in their bmi and 1 patient presented cataracts with visual impairment. conclusion: the prolonged treatment with boluses of methylprednisolone and cyclophosphamide is a good alternative in patients with srns. the prolonged use of high doses of steroids can cause linear growth suppression and other adverse reactions, so it is advisable torealize a genetic study in all of the patients with srns to be able to exclude the patients that have a genetic mutation and so avoid unnecessary treatment. objectives: to study the clinicopathological profile and outcome of lupus nephritis (ln) in indian children. methods: clinical and histopathological features and outcome of children with ln was retrospectively reviewed. patients were included if they fulfilled the acr criteria for the diagnosis of sle and had either of persistent proteinuria, active urinary sediments or renal dysfunction. outcome was analyzed at 3 years and at last follow-up. results: ofthe 53 children studied, 13 were boys. the mean age (sd) at diagnosis was 9.8±2.3 (median 9.8, range 5-14.4) yr; 23 children were youngerthan 10 years of age. the mean age at presentation and renal biopsy was 10.8±2.2 (median 10.4, range 6.5-15) years. the mean duration of follow-up was 3.1±2.9 (median 2.5, range 0.2-10.3 years) years. 41.2% patients were followed for more than 3 years. commonest clinical manifestations were fever (77%), hypertension (58%) and malar rash (56%). 35 and 28% of patients presented with nephrotic and nephritic syndrome respectively before the diagnosis of sle. the commonest pathology was class iv nephritis (41%) followed by class ii (17%). hypertension, hematuria, nephrotic syndrome and decreased egfr were significantly associated with class iv ln. at last follow-up 31.5, 15.7 and 0% patients were in ckd stage ii, iii, and iv respectively. the patient survival rate at 3 year and at last follow-up was 100 and 94% respectively, while no patient developed esrd at 3 years. infections were seen in 30% cases that resulted indeath in 2 patients; 1 died of hepatic encephalopathy. conclusion: sle nephritis has a varied presentation and high morbidity. a significant proportion of patients developed infections during the course of disease. clinical, pathological features and outcome in our study do not differ markedly from those in most pediatric series. background: atypical hus has a frequently relapsing course and a poor renal prognosis. low c3 plasma concentration suggests alternate complement pathway regulatory abnormalities: factor h (fh), factor i (fi) and membrane cofactor protein (mcp). case report: we report an 11 year old girl with atypical hus due to acquired fh deficiency caused by anti-fh antibodies (abs). hus was diagnosed on the basis of acute renal failure, microangiopathic hemolyticanemia and thrombocytopenia. past history: recurrent fever with culturenegative pharyngitis (suspected pfapa syndrome). decreased c3 (64 mg%, normal>80) with normal c4. adamts 13 activity was depressed, no cleaving protease abs. hemodialys (hd) and plasma exchange (pex) were started 12 days later. severe urticaria and angoiedema during pex was treated with methylprednisolone and chlorpheniramine. hematological and renal improvement were observed after the 3 rd pex session. 4 relapses occurred in 3 months: 1 -controlled by pex; 2 -(with suspected pfapa) with single dose corticosteroids, 3 -with prednisone therapy, 4terminated with single dose ivig 200 mg/kg. elevated anti fh ab titer-1471 au with decreased fh functional activity were found in pre-pex plasma. fh, fi, factor b and c3 antigenic levelsnormal. hematological remission and renal function improvement without hus relapse ensued while tapering corticosteroids. two years after presentation, onprednisone 5 mg/day anti fh titer dropped significantly with restoration of functional fh activity, gfr ~75ml/min/1.73 m 2 . conclusions: in cases of atypical hus, active search for anti fh ab iscrucial for implementing specific and effective therapy: plasma exchange, iv ig and steroids for improving course and longterm prognosis. research centre for child health rams, department of pediatric nephrology, moscow, russian federation 25 children aged 1,5-16 years with idiopathic biopsy-proven steroid-resistant focal and segmentary glomerulosclerosis (fsgs) were treated with cyclosporine a (csa) 3,2-7,6 mg/kg as initial dosage, oral prednisolone 1,5 mg/kg every other day tapered to the 12-th month and methylprednisolone pulses (mp) 20-30 mg/kg every other day for the first 2-4 weeks in 17 of patients. serum creatinine level was controlled once a month. after 6 months of csa treatment complete or partial remission of proteinuria was in 15 (60%) of children, no effect in 10 (40%). serum creatinine level increased in 14% on an average in the group remission of proteinuria. in the group of non responded patients the creatinine elevation was significant same -15%. after 1 year of csa treatment complete or partial remission observed in 18 (72%), no effect in 7 (28%). elevation of serum creatinine level in children with remission was 15,5% (without significant difference compared to 6 month's csatreatment). increasing of the creatinine level more than 30% in two patients leaded to double tapering csa dose resulted in normalization of serum creatinine level. in the group of csa non responders the significant increasing of serum creatinine level (35%) was revealed (compared to 6 month's csa treatment). in 3 cases the elevation ofcreatinine level was more than 50% and these patients turned into esrd eventually. in all of non-responders csa was discontinued. we concluded that serum creatinine level in csa respondrers was stable without significant elevation during the 1 year of treatment. csa therapy for 1 year without any effect influenced on renal function decreasing. clinical objective: to describe the clinical course and outcome of pediatric patients with cgd treated with iv mpt (30 mg/kg x 3 doses monthly for 12 months, then 1 dose monthly for the next 6 months) methods: patients' medical records were reviewed. pre, post-treatment and follow-up 24 hr urineprotein, creatinine and gfr were compared using paired t-test; and proteinuria, hematuria and blood pressure using mcnemar's chi square. outcome measures were analyzed usingmean ± sd and frequency distribution. results: 30 patients were included, 13 male, 17 female. mean age at disease onset is 7.972±4.298 years. mean duration of follow-up is 23.733±18.714 months. 70% achieved complete remission after a mean of 1.8 cycles, 17% partialremission after a mean of 2.8 cycles and 13% were treatment failures. mean relapse rate is 0.700±1.208 on treatment and 0.733±1.596 at follow-up. renal survival rate is 93%. 24 hour urine protein and the proportion of patients with proteinuria, hematuria and hypertension significantly decreasedafter treatment and remained stable at follow-up. serum cr/gfr were also stable pre, posttreatment and at follow-up. no serious side effects were noted. conclusion: this protocol induced a high and early remission rate (70% after 1.8 cycles)among the patients. majority demonstrated stable renal function and blood pressure over time. relapse rates were low and treatment is generally safe. recommendation: the protocol can be offered to oral-steroid or alkylating agent-resistant patients with satisfactory remission rates. objectives of study: nestin, an intermediate filament protein which has a role in regulating cellular cytoskeletal structure, is restrictedly expressed in the podocytes of human kidneys. in the present study nestin expression was investigated in biopsy specimens of children with focal segmental glomerulosclerosis (fsgs). methods: 36 kidney biopsy specimens taken from children with diagnosis fsgs were investigated. diagnosis was performed on light microscopy, immunofluorescence microscopy, taking into account clinical data. for immunomorphology monoclonal anti-nestin antibody from mouse (sc-23927, clone 2c1.3a11, santa cruz biotechnology) diluted 1: 100, was applied on cryostat or paraffin sections using labeled streptavidinebiotin (lsab+ dako) method. visualization was performed by dako aec substrate. 10 kidney biopsies of patients without nephrotic syndrome, mainly with mesangioproliferative gn were used for control staining. results: the mean age at the time of biopsy was 10.2±4.9 years, and all patients had nephrotic syndrome. half of them revealed some focal tubulointerstitial changes: tubular atrophy, slight interstitial fibrosis and lympho-monocytic infiltration. in two cases mutation of wt1 gene and in one case mutation of nphs2 gene was detected. four cases had familial character of fsgs. nestin expression was variably present in different cases of fsgs. decreased expression was detected in glomeruli with segmental mesangial sclerosis and capsular adhesions. conclusion: fsgs revealed heterogenity concerning nestin expression. nestin expression was diminished in affected glomeruli. background: renal effects of altered ob/ob-r pathway may contribute to obesity, and diabetesassociated proteinuria. in the kidney ob/ob-r stimulates collagen type i and iv synthesis and upregulates tgfβ1 and tgfβ2 receptors. objective: to determine ob/ob-r and its downstream (jak/stat/socs) pathway expression in nephrotic syndrome (ns) and fsgs. design/methods: microarray analysis of kidneys of 2-week (2w) and 4-month (4m) old transgenic mice (tg) and controls (ctr) was performed, and confirmed by quantitative pcr. kidney sections were analyzed by immunohistochemistry (ihc) and western blot analysis (wb). urinary ob/ob-r of children with ns classified as steroid sensitive (ssns) or steroid resistant (srns), were measured by elisa. results: ob, ob-r, and jak1,2,3 mrna expressions were not statistically different at 2w and 4m between ctr and tg. stat3 and socs mrna were increased 2.04-fold (sem ±0.52), and 17.38fold (sem±8.6) at 4m in tg, p=0.04 and p=0.01 respectively. ihc and wb (p=0.65) of kidney sections showed no significant difference between the 2 groups. we examined 12 ctr, 10 ssns, and 11 srns patients with comparable bmi, age, race and gender. urinary protein to creatinine ratio in ssns and srns was 0.18 (sem±0.06) and 3.12(sem±1.03) respectively, p=0.03. urinary ob (p=0.1), ob-r (p=0.09), and tgfβ1 (p=0.12) were not statistically significantly different between the 3 groups. conclusions: ob/ob-r was not upregulated in tg at the onset of proteinuria and fsgs. however, advanced fsgs (4m tg) showed significant activation of socs3, an ob/ob-r negative regulatory pathway. pediatric patients with early srns had no significant increase in urine ob/ob-r. this data suggests the role for ob/ob-r regulatory pathways in the development of advanced fsgs. primary fsgs presents clinically with steroid-resistant (srns) or steroid-dependent (sdns) nephrotic syndrome or proteinuria. the data shows, that 43% patients with fsgs progress to esrd in 15 years follow-up. objectives: the aim of the study was to analyze the long-term outcome of patients with primary fsgs diagnosed in kidney biopsy. material: the study group consisted of 113 children (54 males, 58 females) followed from 1982. all patients were treated with immunosupression and renoprotection. the clinical data were analyzed after follow-up lasting for mean 10±6,1 years (0,5-25 years) . 85 children presented with nephrotic syndrome (66 srns and 17 sdns) and 28 with proteinuria. the age ranged from 0,5-16 years mean 5,9±4,5 at the time of diagnosis. more then 1 kidney biopsy was performed in 55 children -in 29 progression from mcd (n=18) and mes (n=11) to fsgs were observed. results: the clinical remission was observed in 73/113 patients (64%) and was not correlated with initial proteinuria (mean 11,3±9). in 20/113 patients crf was observed, 15 of them progressed to esrd (12 were successfully transplanted). among patients, who had fsgs as their initial glomerular lesion (n=84), the percentage of glomerular sclerosis was significantly higher in a group in which remission was not obtained after long-term follow-up (31,7 vs. 17%, p<0,001). in 9 out of 49 patients with follow-up over 10 years progression to esrd was observed (18,4%), 10/49 were transmitted to adult centers with persistent proteinuria. conclusions: immunosuppression and renoprotection in patients with fsgs can prevent the progression of crf. extensive glomerular sclerosis is a predictor of unfavourable outcome. further clinical and genetical studies are needed to establish the effective therapy modalities. mycophenolate and who had previously undergone a renal biopsy, recieved 600 mg twice daily (maximum 1 gram twice daily) during six months. prednisone was concurrently prescribed at at dosage of 1 mg/kg/every other day, during 8 weeeks and 0.5 mg/kg/every other day during the subsequent 8 weeeks. results are expressed as mean±sd. results: seven chidren, 5 boys and two girls were enrolled. oncet of their ns was at age 6.2±4, 16 yr (range 2-13 yr) and mmf was initiated at 9.4±4.4 yr (4.5-15.5 yr) . six were sr and one sd. two patients had previously recieved cyclosporine, two patients cyclophosphamide and one chlorambucil. renal histology displayed: focal segmental glomerulosclerosis (n=3), minimal change (n=2), mesangial proliferation (n=1) and membranous glomerulonephritis (n=1). at the end of the follow-up: three patients were in partial remission, two were in complete remission and two had no response to mmf. initial and final serum creatinine concentration 0.53±0.08 vs 0.57±0.09 mg/dl), estimated gfr (124.2 vs. 111±37 ml/min/1.73 m 2 ) and serum albumin ( idiopathic nephrotic syndrome is the most frequent glomerular disease in childhood. most patients are steroid responsive but half of them relapse and often become steroid-dependent. they are exposed to long term steroid complications on the one hand and relapses due to insufficient disease control on the other hand. our aim is to determine predictive risk factors for high degree steroid dependence. in france, steroid-resistance is defined as persistent proteinuria after one month of daily oral prednisone (60 mg/m 2 ) and 3 pulses of methylprednisolone (mpn) (1 g/1.73 m 2 ). we included 27 steroid responsive children with disease onset between 2000 and 2006. the mean age at diagnosis was 4.6 years (range 1.5-16). all patients initially received prednisone 60 mg/m 2 per day. the following parameters were analysed: age at onset, gender, days to remission with initial steroid therapy, mpn pulses, numbers of relapses, steroid dependency, immunosuppressive drugs. twenty of the 27 patients were steroid-dependent; among the 20 steroid dependent patients, 11 received mpn pulses. 90% of those patients (10/11) were treated by cyclosporine during follow-up. on the other hand, only 10% (1/9) of the patients who did not receive mpn required cyclosporinebased therapy during follow-up (chi-square test, p=0.0018). interestingly, there was no correlation between treatment days until remission during the initial prednisone course and the risk for later steroid dependence. conclusion: the need for mpn pulses, but not the time interval until remission helps to predict steroid dependence. patients, necessitating mpn pulses to obtain remission are at risk to require cyclosporine for disease control. by identifying these children, we could eventually 1/ avoid multiple relapses by earlier use of adequate immunosuppression and 2/ avoid side effects related to long term high dose steroid therapy. membranous nephropathy (mn) with antitubular basement membrane antibodies is a rare condition. relapse of tubular dysfunction in renal transplant recipients has been published in one case, but relapse of mn in the renal graft has not yet been reported. a 3-year old boy presented first with steroid resistant nephrotic syndrome associated to tubular dysfunction. renal biopsy revealed mn associated to interstitial fibrosis and granular deposits of iga, igg, and c3 along the tubular basement membrane. indirect immunofluorescence (if) revealed circulating anti-tubular basement membrane antibodies. he received a renal allograft at the age of 6 years. an acute rejection episode on day 21 required three steroid pulses and okt-3. renal biopsy revealed the presence of interstitial and vascular rejection (banff iii) and relapse of tubular basement membrane deposits. renal function normalized within 10 days and remained stable (gfr estimated by schwarz formula=103 ml/min per 1.73). proteinuria remained negative and urinalysis normal over 5 years under the immunosuppressive regimen including fk, azt, and prednisone. at the age of 11 years, proteinuria increased progressively over 6 weeks reaching 2.8 g/day, whereas serum creatinine remained stable. renal biopsy revealed the presence of granular deposits along the glomerular basement membrane suggesting a late relapse of mn in the transplant. rituximab therapy (day 0, 15, 30, and 60) followed by switch from azathioprine (aza) to mmf resulted in a complete biological remission with negative proteinuria. indirect if revealed progressive decrease of antitubular basement ab level during rituximab treatment and a negative signal was obtained 3 months after the switch from aza to mmf. this is the first report of glomerular relapse of mn with anti tubular basement antibodies in a renal transplant recipient. nephrotic children are at risk for severe pneumococcal infections. the best moment for antipneumococcal vaccination is controversially discussed. we investigated the serologic response after pneumo23 vaccination in 25 children (10 girls) with nephrotic proteinuria and hypoalbuminemia, immediately after initialisation of prednisone therapy at 60 mg/m 2 (group 1) and in 16 children after tapering down of prednisone to <0.5 mg/kg eod (group 2). there was no difference in both groups concerning antibody (ab) response, relapse frequency, or number of steroid dependent forms. in group 1, pneumo23 ab levels at presentation (m0) were 1.20±0.22 (mean±se) . at m1 antibody levels increased 9-fold to 9.28±1.35 (p<0.0001). serum levels at m3 were 7.58±1.67. one year after vaccination ab levels (4.4±1.78) decreased compared to m1 (p<0.01), but remained increased compared to m0 (p<0.01). there was no increased delay until remission in both groups compared to a retrospective control group. severe hypoalbuminemia (<10 g/l) at the time of vaccination was not related to a lower serological response on m1. during relapses, antibody levels decreased significantly compared to levels before relapse (p<0.01), but increased again once remission was obtained. even during relapses, ab levels remained higher (>3-fold) than pre-vaccination levels. conclusion: nephrotic children on high dose glucocorticoid therapy respond to anti-pneumococcal vaccination and their ab levels remain elevated during relapses. vaccination at disease onset may be beneficial as those patients with relapses during the tapering down of steroids already have increased anti pneumo23 ab at the time of relapse. crescentic glomerulonephritis with isolated c3 deposits associated to complement abnormalities: a new entity? introduction: several progressive renal diseases present proteinuria, as a result of glomerular and tubulointerstitial injuries. thus, some studies prove that proteinuria is an important predict factor for progression of renal failure. angiotensin converting enzyme inhibitors (acei) are efficient in reducing proteinuria and preserve renal function in patients with diabetic or non-diabetic nephropathy. the purpose of this study was to evaluate the efficacy and security of acei in children. material and methods: the acei (enalapril) was used in normotensive and hypertensive patients with chronic renal disease, with microalbuminuria/proteinuria. results: we studied 28 patients (13 girls), for at least 6 months, mean age was 10.4±3.5 years (1 month to 17 years). 5/28 patients had glomerulopathy, 13/28 chronic pyelonephritis, 4/28 systemic disease, 2/28 renal hypoplasia/ dysplasia, 3/28 cystic renal disease and 1/28 arterial hypertension. the mean dose of enalapril was 0,25mg/kg/d (0, 04 to 0, 38) and it was used during 36,6 months (mean). we observed a normalization of proteinuria/microalbuminuria in 53, 5% of cases. in seven patients, the drug was discontinued due to: 3/7 irregular use, 2/7 vertigo, 2/7 hypercalemia and acute renal failure recovered after withdrawn the drug. during the use of enalapril we did not observe significant difference in potassium or creatinine serum levels, as well as blood pressure measurements. conclusions: the use of enalapril in pediatric patients with renal disease and proteinuria/ microalbuminuria showed security and efficient. therefore, we suggest it as a antiproteinuric and renoprotective agent in children. a. filleron, al. adra-delenne, l. ichay, f. dalla-vale, h. valette, d. morin chu montpellier, pediatric nephrology, montpellier, france in order to evaluate the long-term efficacy of oral cyclophosphamide (cp) in children with sdns, the outcome of 33 patients (11 girls) treated in our unit for steroid sensitive ns were studied retrospectively. median age at diagnosis was 3.8 years (range 1.5 to 13). initially, they received oral prednisone (p) : 60 mg/m 2 /d for 4 weeks and p dosage was then tapered for the next 14 weeks (totale dose p: 3390 mg/kg). relapses of proteinuria were treated with p (60 mg/m 2 /day) and, in case of steroid dependency (sd), p was maintained on an alternate day regimen. one single child had no relapse, while 8 had a relapse rate of less than 1/year. the remaining 24 frequently relapsed and 14 received oral cp -2 mg/kg/day for 12 weeks, totale dose 168 mg/kgbecause of their high relapse rate with steroid toxicity. median duration of p treatment was 3.7 years (range 0.75 to 10) before cp was given. in one case cp had to be stopped because of hemorragic cystitis. follow-up after cp treatment was, at least, 2 years. p was stopped in the following 6 months after cp in 10/13 children, but has to be continued in the remaining 3 because of early relapse of proteinuria. among those 13 children, only one had no more relapse 4 years after cp. in 12 children, relapse of proteinuria occured 11.5±7 months after cp. in those patients, 8/12 had to receive another steroid sparing drug such as cyclosporine or mycophenolate mofetil (mmf) because of recurrence of sd. in our experience, cp treatment in ns with steroid toxicity is associated with a significant change in the relapse rate in only 5/13 children and in the remaining 8, improvement was transient. our results suggest that alternative treatment, such as mmf, has to be evaluated as first-line steroidsparing agent in those patients with sdns and steroid toxicity. interleukin the aim of our investigation is to compare the concentration of total ige, specific ige, interleukin-4 (il-4) and gamma-interferon (gamma-ifn) in serum of 27 children with initial and relapsed steroid-sensitive mcns and of 26 children with atopic dermatitis at the age from 1 to 16 years. the concentration of total ige was measured by immunoenzymatic method and il-4, gamma-ifn by immunoassay technique using monoclonal antibodies. the result showed that 64% of 26 children with atopic dermatitis had the increased concentration of total ige; specific ige was increased to alimentary allergens-84,6%, household-69,2%, inhaled-26,9%. the concentracion of il-4 was 34,4±9,4 pg/ml, of gamma-ifn was 102±11,3 pg/ml. the result showed that 9% of 27 children with mcns had increased concentration of total ige; specific ige was increased to alimentary allergens-96,2%, household-77,8%, inhaled-29,6%. the concentration of il-4 was 22,31±3,8 pg/ml, of gamma-ifn was 91,97±9,3 pg/ml. according to our investigation, the concentration of il-4 and gamma-ifn in children with mcns were not significantly different then in children with atopic dermatitis. conclusion: the fact that there were not significant differences in serum total ige and specific ige, il-4 and gamma-ifn in children with mcns and atopic dermatitis gives us a reason to suppose that these diseases have identic mechanisms of pathogenesis with ige reaction i-type with activation of t-limfocyte. to clarify the pathogenesis of mcns, comprehensive studies for these cells would be worthwhile. there are several lines of evidence that the slit diaphragm (sd) not only serves as a structural framework for filtration barrier but also has an essential role as a signaling platform. nephrin is tyrosine phosphrylated by src-family tyrosine kinase, fyn. phosphorylated nephrin recruits nck to sd, and regulates assembly of actin filament. the crucial roles of tyrosine phosphorylation in podocyte is also indicated by renal malfunction observed in fyn knockout mice. neph1 has a longer cytoplasmic domain and a larger number of tyrosine residues in its cytoplasmic region than nephrin. but knowledge about tyrosine phosphorylation of neph1 is limited. here we characterize neph1 as a substrate of fyn. fyn interacted with and phosphorylated cytoplasmic domain of neph1 in vitro and in cultured cells. peptide mass fingerprinting of neph1 cytoplasmic domain phosphorylated by fyn in vitro identified at least five tyrosine phosphorylation sites. site-directed mutagenesis confirmed that these tyrosine residues were indeed phosphorylated in cultured cells. in pull-down analysis with neph1 from rat glomerular lysate, neph1 specifically bound to an adaptor protein grb2 and a tyrosine kinase csk in a phosphorylation-dependent manner. coimmunoprecipitation experiments revealed phosphorylation of y637 and y638 were crucial in neph1-grb2 binding. furthermore, tyrosine phosphorylated neph1 suppressed erk activation elicited by fyn, and also inhibited fyn-induced ap-1 transcriptional activation. these inhibitory effects required the intact binding motif of the grb2 sh2 domain, and both y637f and y638f mutants failed to inhibit erk activation. these results indicate that fyn orchestrates a wide spectrum of protein-protein interactions at sd by phosphorylating neph1 as well as nephrin, and neph1 modulates downstream signaling by phosphorylation-dependent association with adapter proteins. celiac disease (cd) is a common disorder in southern europe and has a protean clinical presentation. hla class ii aplotypes dq2 and/or dq8 are present in 99% of cd patients and in 30% of the normal population. the observation of three patients with both cd and nephritic syndrome (ns) prompted us to study hla class ii aplotypes in our patients with ns. in all children with ns admitted to our unit we determined the presence of dq2/dr3, dq2/dr7, dq2/dr4 e dq8/dr4 aplotypes and anti-transglutamidase antibodies (ab-httg). hla typing was done by dna extraction and pcr amplification and electrophoresis in agarose; ab-httg determination was made by elisa. as control groups we examined 27 children with cd and 70 first degree relatives (of theirs). in so far we have studied 40 children with ns (27 males, 13 females, age ranged 3-18 years); 34 are steroid sensitive (ssns), 6 steroid resistant (srns). a renal biopsy was done in 10 and showed minimal lesions in 3, focal and segmental sclerosis in 2, membranoproliferative gn in 2, membranous gn in 2 and iga deposition in 1. corticosteroids or other immunosuppressant were administered in 27 when blood was drown. dq2 and/or dq8 aplotypes were present in 33 out of 40 patients (82.5%), in 29 out of 34 ssns (85.3%), in 43 out of 70 cd relatives (61%) and in all cd patients. dq2/dr3 combination was present in a smaller percentage of ns compared to control groups. ab-httg were detected in one patient out of 26 (3.8%). purpose: to investigate activity of antithrombin and a protein c at 57 children with mcns: at 39 active period (proteinuria more 1 g/m 2 /d; hypoalbuminemia <25 g/l), at 46 in incomplete remission (the third day of absence of proteinuria, hypoalbuminemia <35 g/l), at 11 in proof remission. methods: activity of natural anticoagulants in blood was defined by a clotting method with use of reactants "roche" and "behring". results: activity of antithrombin in blood in the active period of disease sharply decreased (60,6±3,9%, p<0,0001), and already in the period of incomplete remission came back to norm (96,2±2,6%), characteristic for the period of full remission (96,3±4,8%). activity of a protein c in blood in the active period of mcns was high (154,1±7,5%, p<0,001), during incomplete remission decreased (127,1±7,5%, p<0,001), in the period of proof remission was in norm (94,2±5,7%, p<0,001). at children with mcns dependence of decrease in activity antithrombin from weight hypoalbuminemia (r=0,5, p<0,005), hyperfibrinogenemia (r=-0,6, p<0,005), hypercholesterolemia (r=-0,5, p<0,01) and hyper-lipoproteinemia (r=-0,5, p<0,03) is established. authentic distinctions of factor of the attitude of activity of protein c/ activity of antithrombin depending on the period (the active period -2,5, incomplete remission -1,3, proof remission -0,98) are received. conclusion: at children with mcns changes in system of natural anticoagulants: decrease in activity antithrombin below 80% and increase of factor of a parity of anticoagulants (more than 1,0) testify to hypercoagulation and risk of thrombosis. varicella objectives: the pattern of steroid responsiveness of nephrotic syndrome may change during the course of the disease in children with steroid sensitive nephrotic syndrome (ssns) and/or in different populations. patients and results: a prospective cohort study was conducted in 22 centers. patients who were initially diagnosed as ssns in 2001 and followed for five years were included. standard questionary forms from 268 children(149 boys) with a mean age of 4.3 years (22 months-16 years) at presentation were submitted for entry to data coordinating center. 165/268 patients who showed initial steroid sensitivity with a follow-up period of at least one year (1-5 years) were included in the study. seventy three (44.5%) children remained in sustained remission at 1 year; nine patients showed steroid resistance. 67/165 patients were followed for 5 years, whose clinical course were sustained remission in 46 (70%) and steroid resistance in 4(6%). steroid response rate from 1 to 5 years remained stable (93-95%). eight children out of totally 13 patients who were steroid sensitive initially, became steroid resistant in the first year. the remainder showed steroid resistance at the 2 nd year (2), at 4 th year (1) or at 5 th year (2) . renal biopsy was performed in 19 children who developed steroid dependency or steroid resistance. nine patients revealed fsgs, 8 minimal change disease, 1 mesangioproliferative gn, 1 membranoproliferative gn, one igm nephropathy. only two patients who had minimal change nephropathy in initial biopsy progressed to fsgs after 2 and 5 years. conclusion: steroid response rate was between 93-95% and steroid resistance was 4-6% in 5 years follow-up. secondary steroid resistance within the first year of presentation seemed to be predictive for their subsequent courses. the need of biopsy was not high. ssns seemed still as a relatively benign condition in our population. the aim of this study was to asses the changes in coagulation/fibrinolysis system in chronic renal disease (crd) by measuring plasma levels of von willebrand factor (vwf) and plasminogen activator inhibitor -1 (pai-1). we studied 74 children (5-16 years old) with nephrotic syndrome (ns): minimal change disease (n=14), focal segmental glomerulosclerosis (n=17), mesangioproliferative glomerulonephritis (n=24), membranoproliferative glomerulonephritis (n=7). relapse of the disease was observed in 34 patients. 15 healthy age matched children served as controls. serum levels of pai-1: ag and vwf were measured by elisa. results. pai-1 and vwf levels were elevated in all morphological forms of ns in relapse and remission compared with controls (p<0,01) except the mcd remission in which they were the same as controls (p>0,05). the highest levels of pai-1 and vwf were discovered in relapse of proliferative forms (mespgn, 70±31 ng/ml and 5,0±1,7 me/ml, respectively; mpgn, 100,05±61,1 ng/ml and 3,14±0,65 me/ml, respectively) compared with nonproliferative (mcd 52,98±24,03 ng/ml and 1,81±0,54 me/ml, respectively; fsgs 52,27±20,39 ng/ml and 2,42±0,84 me/ml, respectively, p<0,001). conclusion. these data suggest activation of coagulation/fibrinolysis system in relapse of ns and the absence of normalization in the remission phase. our results confirmed that more severe fibrin formation via activation of intraglomerular coagulation and fibrin accumulation is characteristic for mpgn, likely by deficiency of the fibrinolysis system. introduction. several recent case reports suggest that rituximab (rtx) could be an effective treatment for idiopathic nephrotic syndrome. in a retrospective study, data were collected from 11 patients (mean age: 12.6 years) treated with rtx for steroid dependent nephrotic syndrome (mean duration of the disease: 112 months). four of 11 were treated during a remission period. eight of 11 were treated in association with one or several other immunosuppressive (is) treatments (prednisone, anticalcineurin, mycophenolate mofetil). rtx efficacy was admitted when the previous is treatment was withdrawn or significantly tapered-off, or when the proteinuria disappeared with no other change than rtx treatment. a complete b-cell depletion was confirmed in all patients when assessed (9/11) even when rtx was infused during a period with nephrotic proteinuria. rtx was considered to be effective in 6 cases especially when given in association with other immunosuppressive treatment during a period with remission of proteinuria (4/4 success, follow-up 3 to 10 months). conversely rtx failed to induce remission among patients who were treated during a proteinuric period with no other immunosuppressive drug (3/3 failures). finally rtx was considered to be effective among 2 of 4 patients treated in association with other is drugs during a proteinuric period (follow-up 3 and 31 months). there was no significant side effect during rtx infusion. delayed side effects were observed for 2 patients: 1 case of neutropenia and pneumocystis pneumonia and 1 case of hypogammaglobulinemia. conclusion. rtx is an effective treatment in a subset of patients with severe steroid dependent nephrotic syndrome. further prospective data are necessary to determine if rtx could become an alternative to other immunosuppressive drugs in patients with toxic side effects. infections are leading causes of death in lupus patients. disseminated histoplasmosis has been commonly documented in immunocompromised patients including lupus patients. we report a case of lethal cerebral histoplasmosis in a child originating from french guyana. lupus disease was revealed by typical malar rash. she developed a class ii lupus nephritis treated with prednisone and azathioprine. then she developed restrictive lung disease, recurrent arthritis and pericarditis. later on, nephrotic syndrome revealed a class iii lupus nephritis treated with methylprednisolone pulses and mycophenolate mofetil. four years following the onset of the disease, she was admitted because of febrile seizures and five months later for a febrile coma. repeated lumbar punctures displayed hypercellularity with depressed levels of glucose and elevated protein concentrations but sterile cultures. according to the presence of high titers of lupic specific antibodies and cerebral mri suggesting vasculitis, neurological flare of lupus was considered and immunosuppressive treatment was increased (methylprednisolone and cyclophosphamide pulses, plasma exchanges). a repeated lumbar puncture evidenced presence of histoplasma capsulatum. despite antifungic treatment the child died. our report emphazises the difficulty to discriminate opportunistic infections from the wide spectrum of lupus clinical features. symptoms of infection may mimic those of lupus, or conversely, may be masked by immunosuppressive drugs. infection screening should take in account clinical feature as well as endemic context. our report is the first case of isolated cerebral histoplasmosis in a child with systemic lupus. renal manifestations of mitochondrial cytopathies have been described, but nephrotic syndrome with respiratory chain disorders (rc) was described extremely rarely in infancy. we report a 9 months-old boy with a mitochondrial cytopathy preceded by 2 months history of steroid-resistant nephrotic syndrome. on admission his clinical condition was deteriorating rapidly with gross oedema, ascites, hypertension and oliguria. fundoscopic examination revealed salt-pepper sign which was thought to be consistent with intrauterine infection (iui) at that time. however, serologic and microbiologic investigation of iui was inconclusive. a sensorineural hearing loss was found to associate his findings. podocin mutation was negative. a percutaneous renal biopsy was undertaken and revealed diffuse mesengial sclerosis. a significant decrease in mitochondria was observed on electron microscopic examination. the child progressed to end stage renal failure and was successfully managed by peritoneal dialysis. during his follow-up a fine tremor was observed in his hands and cranial mri revealed demyelinisation in left thalamus and occipital lobe. steroid resistant nephritic syndrome, sensorineural hearing loss, ocular and neurologic findings has led us to be suspicious about mitochondrial cytopathy and muscle biopsy was done. though muscle biopsy was normal, the results of biochemical analysis showed a deficiency of the respiratory chain complex iv (cytochrome c oxidase) (rc iv). the clinical phenotype and the deficiency of respiratory complex iv thought to be compatible with deficiency of the cytochrome c oxidase deficiency protein cox10. nephrotic syndrome with rc disorder were described extremely rarely in infancy. based on these observations, we suggest that rc disorders should be considered in patients with early onset nephritic syndrome. human parvovirus b19 (hpvb19) was identified as the cause of a self-limited childhood febrile illness with rash, namely erythema infectiosum. most of hpv-b19 infections are usually mild or asymptomatic, but in some cases infection is associated with serious systemic complications. renal involvement in patients with hpvb19 infection was discussed in recent, mostly anecdotal, case reports. the majority of these reports were described in adults, whereas only a few cases of childhood were defined whom presented with mesangiocapillary proliferative glomerulonephritis, fsgs or tubulointerstitial nephritis. a literature search revealed no cases of acute endocapillary proliferative glomerulonephritis in childhood. a 10-year-old girl was admitted with fever, cough, maculopapuler rash, hemoptysis, dark-colored urine, multiple lymphadenopathies, hepatosplenomegaly. she developed acute nephritic syndrome during the course of this complex clinical features. laboratory data showed proteinuria, hematuria, hypocomplementemia, the presence of igm and igg antibodies to hpvb19 and positive reaction of serum hpvb19 dna using a polymerase chain reaction. renal biopsy showed acute endocapillary proliferative glomerulonephritis with coarse granular c3 depositions in a "starry sky pattern" which is more peculiar to poststreptococcal glomerulonephritis. electron microscopy revealed subendothelial and hump-shaped subepithelial dens deposits. there was no evidence of either a mycobacterial or a streptococcal infection and the diagnosis of goodpasture syndrome and connective tissue disorders were excluded by clinical and laboratory investigations. based on the literature review, this case represents, to our knowledge, the first time that a direct relationship between parvovirus infection and acute endocapillary proliferative glomerulonephritis has been demostrated in a child. objective: the purpose of this retrospective cohort study was to report the clinical course of children and adolescents with focal segmental glomerulosclerosis (fsgs) according to steroid response. methods: the records of 88 patients with biopsy-proven fsgs admitted between 1972 and 2005 were retrospectively reviewed. demographic, clinical and laboratory data at entry and at the end of the follow-up were analyzed. the patients were classified according to the initial prednisone response into two groups: group 1 (g1): response (complete or partial remission) (n=63) and group 2 (g2): non-response (prednisoneresistant) (n=25). renal survival analysis was performed using the kaplan-meier method. results: the median age at admission was 4.55 years (iq range: 0.99±12.84 yr) in g1 and 6.86 years (iq range: 1.08±15.55 yr) in g2. seventeen patients (27%) of g1, and 17 patients (68%) of g2 presented with hematuria at admission, and 31 (49%) children of g1 and 13 (52%) of g2 presented blood pressure levels above the 95th percentile. g2 presented a higher 24 h proteinuria (4.87 mg/24 h) at admission when compared to g1 (3.17 mg/24 h, p=0.019). median follow-up time was 8.72 years in g1 and 3.96 years in g2. the renal survival rate was 98% at 5 years and 92% at 12 years in g1, 69% at 5 years and 26% at 13 years in g2. conclusion: progressive renal insufficiency was more frequent in patients with fsgs who have initial resistance to prednisone therapy. objectives of the study: adults with chronic kidney disease (ckd) show impaired immune status. in this study, the profile of mononuclear cell subsets was related to the age and actual gfr in children and compared to healthy controls. methods: the expression of lymphocyte surface antigens was evaluated on peripheral blood (pb) mononuclear cells using three-color flow cytometry in 45 children with ckd (stage2-5) on conservative treatment. we analyzed absolute and relative numbers of total leukocytes, total lymphocytes and subsets: cd19+, cd3+, cd3+cd4+, cd3+cd8+, cd3-cd16/56+, cd3+hla-dr+, cd3+cd25+, cd69+, cd3+αβ+, cd3+γδ+, cd45ra+, cd45ra+cd4+, cd45ra+cd8+, cd45ro+, cd45ro+cd4+, cd45ro+cd8+, cd4+cd25+. results: in younger ckd children (below 10 years) absolute numbers of cd3+, cd3+cd8+, cd3+cd25+, αβ+t, γδ+t cells and cd4/cd8 ratio was higher, the percentage of cd3+cd8+, cd45ra+cd4+, cd45ro+cd4+, cd45ro+cd8+, αβ+t cells and the absolute number of cd45ro+cd8+ cells was lower than in the oldest group. in children with the lowest gfr (below 15 ml/min) the percentage of cd3+, cd19+ was lower, the absolute number of cd3+cd25+, cd69+, and the percentage of nk-cells, cd3+cd25+, cd69+, cd45ro+cd8+ cells was elevated as compared to ckd stage 2 group. the absolute number of cd8+, cd3+cd25+, cd45ra+cd8+, αβ+t, γδ+t cells and percentage of total lymphocytes, cd19+, cd3+cd25+, cd69+ was lower in ckd children than in controls. conclusion: impaired immune status is observed already in early stages of ckd. progressive disturbances in pb lymphocytes percentage mostly in the naive and memory t cells and the shift in the cd4/cd8 balance were found in pre-dialysis children with ckd. with progressive loss of renal function, we observed an increased expression of activation markers on t cells such as cd25 or cd69. introduction: relapse of steroid resistant nephrotic syndrome (srns) after renal graft occurs iñ 30% of the pediatric patients. medical management is based on increased immunosuppression with the use of iv cya and plasma exchanges (pe). however, this strategy fails in ~30% of the treated patients. new immunosuppressive agents may improve the outcome of relapsing srns post transplant. case report: a 15-year-old boy with srns reached esrd and received a cadaveric kidney transplant after two years on hemodialysis. the immunosuppressive regime was cya, mmf and steroids. seven days post transplant gross proteinuria (4 g/day) reoccurred. iv cya was administered over two months (blood level: ~450 ng/ml) associated to pefloxacine and pe (n=15), and followed by oral cyclophosphamide (cyp), resulting in partial disease control. cyp was discontinued due to haematological toxicity after one month. proteinuria increased again from 1 to 3 g/day within 3 months, despite high dose oral cya (10 mg/kg/day) and mmf. etanercept (a tnf blocking agent) was introduced at a dose of 25 mg twice weekly (combined with three steroid pulses) and maintained over two months: proteinuria decreased to 0.4 g/day over 20 days. etanercept was discontinued followed by a relapse of the ns and re-introduced eight months later, with, again a significant decrease of proteinuria to a baseline level of 0.5 g/day. conclusion: treatment with anti-tnf agents in nephrotic children has been reported once in a boy with high degree steroid dependent ns; a spontaneous decrease of disease activity over time cannot be excluded in this patient and might jeopardize data interpretation. our case is the first report of successful antiftreatment despite a constantly high activity of the nephrotic syndrome, demonstrated by relapse after discontinuation of etanercept while the patient was on post transplant immunosuppression. fournier´s gangrene (fg) is defined as a specific, quick and progressive form of synergic necrotizing fasciitis of multi-bacterial origin that affects perineum muscular fascia, genital region and surrounding areas with skin gangrene due to thrombosis of subcutaneous blood vessels. it describes the clinical case in a male preschooler of four years of age with idiopathic nephrotic syndrome (ns) that subsequent presented fg of the scrotum. broad-spectrum antibiotics, intravenous albumin and surgical cleaning of the scrotal necrotic tissues were indicated. pseudomona aeruginosa was isolated from necrotic tissue cultures. the later evolution was satisfactory with healing of the affected area and remission of the ns subsequent to the steroidal treatment. fg is an uncommon in children, rapidly progressive infection of the genital, perineal and perianal regions. it is characterized by a synergistic necrotizing fasciitis leading to thrombotic occlusion of small subcutaneous vessels and development of gangrene. until now few cases have been report fg in children, and still less associate to the kidney diseases. et all (1999) described a 10-year-old boy presenting with steroid resistant ns developed fg of the scrotum so that to our knowledge, this patient seems be the second case reported in medical literature with both pathologies. high index of suspicion, prompt diagnosis, broad spectrum antibiotics followed by wide debridement is the key to successful treatment. objectives of study: to evaluate a long term experience on iga nephropathy (igan) presenting in childhood and investigate clinical and histological factors that may act as early markers of renal disease progression. methods: retrospective review of data from children and adolescents with biopsy proven igan in the last 16 years. demographic and clinical data at presentation and severity of renal histological involvement were recorded and related to renal dysfunction markers identified at the last review. results: twenty-five patients were studied (19m/6f) with median age at onset of 11 (7-18) and follow-up of 6 (1-16) years. on presentation recurrent macroscopic hematuria was present in 19 patients, microscopic hematuria (mh) in 6, proteinuria in 11 (1 nephrotic), hypertension in 10 and transient acute renal failure in 1. renal histology findings were focal mesangioproliferative in 17, focal proliferative in 3, diffuse proliferative in 3 and focal sclerosing glomerulonephritis in 2. six patients showed tubulointersticial and extraglomerular vascular lesions (tevl) with glomerular crescents in 2. on follow-up, 7 patients remitted (2 spontaneously, 5 with ace inhibitors). of the remaining, 14 were kept on ace inhibitors due to proteinuria (7), hypertension (1) or both (6). one patient (with focal glomerulosclerosis and tevl) developed esrd within a year after diagnosis, despite treatment. at last review, 6 patients presented progressive renal disease with a mean decrease of 6 ml/min/1,73 m 2 in gfr per year. these (5m/1f) showed mainly mh and proteinuria at onset and tevl. conclusions: early renal function impairment in childhood igan can occur and may be associated with mh and proteinuria at presentation and with focal glomerulosclerosis and tevl on renal histology. proteinuria persistence in a number of patients emphasizes the need for long term followup into adulthood. adhesion molecules, il-12+p40 and cd23+cd19+ and cd25+cd4+ lymphocyte subsets in childhood nephrotic syndrome background: parathyroid hormone (pth) can modulate t cell activation and proliferation through as yet incompletely identified mechanisms. since the pth receptor (pthr) is a g protein-coupled receptor and thus a candidate for association with lipid rafts, and since pth has been shown to alter membrane phospholipid metabolism, we explored the relationship of the pthr with lipid rafts in human t cells. methods and results: we found by flow cytometry that neither physiologic nor pathologically elevated concentrations of pth affect the up-regulation of the raft marker gm-1 or of the partially raft-associated activation marker cd25 in purified t cells stimulated with phytohemagglutinin (pha). moreover, we detected the pthr exclusively in non-raft fractions of these cells after sucrose gradient separation. conclusions: these data indicate that in human t cells, the pthr does not associate with lipid rafts and that pth does not modulate these domains. accordingly, other mechanisms underlying the actions of pth on human t cells need to be sought. the direction and magnitude of potassium transport in nephron segments depend on the sitespecific distribution of transporters in tubule cell membranes. potassium depletion has been demonstrated to be associated with altered sodium reabsorption in renal tubule segments. we examined whe her potassium transporters protein expression is associated with altered abundance of major renal na + transporters, that may contribute to the development of hypokalemia in lp. after weaning rats (n=8) were fed 14 days with lp diet (8%), then they were recovered with a normal protein diet (24%, rp), each group had a control group (24%, np). we examined the changes in the abundance of the na + /h + exchanger (nhe3), na + k + atpase, na + k + 2clcotransporter (bsc-1), na + clcotransporter (tsc), epithelial sodium channel (enac) subunits and romk in kidneys of lp, np, rp rats. controls were normalized to 1. results reduced clcreat (ml/min) in lp vsnp (0.6±0.2 vs 1.6±0.2), hypokalemia (3.6±0.1 vs 5.1±0.2 meq/l) and increased fe k+ (44.2±0.5 vs 29.9±0.3%) were demonstrated. immunoblotting revealed that the abundance of nhe3 in cortex was severely decreased. the amount of bsc-1 (1.9±0.07, p<0.05) and tsc (1.4±0.15, p<0.05) protein levels were enhanced in the inner stripe (isom) and outer stripe of the outer medulla (osom), respectively. romk protein levels were increased in lp (1.23±0.04, p<0.05), the protein abundance of the enac subunits α, β and γ was increased near 1.25 fold each in response to lp. na + k + atpase protein levels showed no differences in cortex and osom. after rp, na + transporters expression returned to control values. conclusion: increased expression of bsc-1, tsc, enac subunits and romk, contributing to distal potassium secretion was shown in hypokalemia from lp. a role of aldosterone may be suggested. v. belostotsky 1 , mz. mughal 2 , j. berry 3 , n. webb 1 1 royal manchester children's hospital, pediatric nephrology, manchester, united kingdom 2 st. mary's hospital, pediatrics, manchester, united kingdom 3 manchester royal infirmary, vitamin d laboratory, manchester, united kingdom aims: to describe the prevalence of vitamin d deficiency in south asian and white uk children with renal disease. to establish how decreased levels of vitamin d affect pth in patients with a normal gfr. methods: 143 children aged 1-18 years were enrolled in the study: 99 were of white uk, 38 of s asian and 6 of other ethnic origin. 18 were on dialysis, 18 had chronic renal failure, 46 had various renal disorders with normal gfr (>80 ml/min/1.73 m 2 ), 61 had a transplant (42 with anormal gfr). blood samples were collected to establish the levels of 25-vitamin d (25-ohd); pth; creatinine. 25-ohd concentration <10 ng/ml was defined as vitamin d deficiency; levels between 10-20 ng/ml as vitamin d insufficiency. serum pth of 0.8-3.9 pmol/l was defined as normal. results: the prevalence of vitamin d deficiency/insufficiency was higher in s asian (87%) than white (36%) children (p<0.0001). ofthe 88 (28 s asian, 56 white and 4 other) children with normal gfr17/28 s asian and 28/56 white children had pth concentrations >3.9 pmol/l. of these 12/17 s asian, 11/28 white children had low levels of 25-ohd (p=0.04). of 19 transplant patients with reduced gfr, 11 of 14 with a high pth had low 25-ohd levels, compared with 1 of 5 with a normal pth (p=0.04). conclusions: many s asian children attending our renal clinic are vitamin d deficient/insufficient and the prevalence of this problem is significantly higher than that in the white population. high pth values in the setting of a normal gfr can often be explained by vitamin d deficiency and should result in serum 25-ohd levels being measured. nephronophthisisis a rare recessive autosomal disease which may be either limited to progressive chronic tubulointerstitial nephritis or associated with extrarenal involvement (eye, liver, central nervous system, etc.); mutations/deletions have been found in at least 6 nphp genes. fibrous dysplasia is a benign skeletal lesion due to an activating mutation inthe gene that encodes the α subunit of stimulatory g protein and occurs after fertilization in somatic cells; it involves one or several bones and may be part of mccune albright syndrome. we report on a boy with fibrous dysplasia of bone diagnosed at 3 yrs of age, who underwent protocol renal function tests at 7 yrs of age in the follow-up of pamidronate treatment. inulin clearance was 75 ml/min/1.73 m 2 and potassium reabsorption rate was 55.2% where as there was neither urinary phosphate wasting nor hypercalciuria. serum magnesium was decreased (0.74 mmol/l) without reabsorption abnormality and serumuric acid progressively increased with age. in addition, due to increasing microalbuminuria, a treatment with acei was started at 11 yrs of age. renal ultrasonography at 11 yrs of age showed hyperechoic reduced-sized kidneys with few microcysts. a renal biopsy (light and electron microscopy) was performed at 11 yrs of age, which showed nephronophthisis-like lesions, i.e., diffuse interstitial fibrosis and focal thickening of tubular membrane basement. dna analysis revealed no nphp1 gene deletion but is still under investigation.nephronophthisis has been reported in association with skeletal involvement (coneshapedepiphyses) and fibrous dysplasia with hypophosphatemic rickets or fanconi syndrome. however no association between fibrous dysplasia of bone and nephronophthisis-like lesions has been described and may be a new picture of the nephronophtisis/medullary cystic kidney disease complex. m. bald, m. holder, h. leichter olgahospital, pediatric nephrology, stuttgart, germany puumalaviruses belong to the group of hanta viruses and are transmitted by inhalation of aerosolized particles of the red bank vole (cletriomonysglareolus) which is endemic in the alb-danube region of southern germany. infections with puumala virus were first described as "nephropathia epidemica" in scandinavia with the clinical symptoms of fever, thrombocytopenia and acute renal failure. over the last seven years three boys with acute renal failure were admitted to our hospital after vacationing in the region endemic for puumalavirus. all three presented with high fever, influenza like symptoms aswell as pronounced abdominal or flank pain. they showed a decreased gfr (14, 47 and 71 ml/min/1.73 m 2 , respectively) with hematuria and proteinuria. cbc revealed no leucocytosis or anemia, but thrombocytopenia in 2 of the 3 patients. they had no oliguria, but 2 patients had marked polyuria in the recovery phase of renal function. arenal biopsy in the boy with the most severe presentation showed diffuse tubular damage. puumala virus infections were confirmed in all patients by serological tests, and renal function normalized within 2-3 weeks. nephropathia epidemica due to puumala virus infections have to be included in the differential diagnosis of acute renal failure in patients from endemic regions. severe abdominal or flank pain are common symtoms in these patients; renal failure is transient and the general prognosis is good. aims: the objective of this study is to determine the relationship of urinary calcium excretion (uca) with sodium and protein intake in a pediatric population of families with low income. methods: 109 children, 59 f and 50m, ages 8 to 15 years from families with income <$100/month were studied. protein intake was estimated with a 7-day dietary record. a nonfasting urine sample was collected for dipstick, calcium, creatinine, sodium, potassium, urea and uric acid. urinarycalcium/creatinine (ca/cr), sodium/potassium (na/k), uricacid/creatinine (au/cr) and urea/creatinine (u/cr) ratios were calculated. children with a urinary ca/cr >0.20 mg/mg, were submitted to a 15 day period of high sodium foods restriction after which a second urine sample was collected. results: mean (x) and standard deviation (sd) for ca/cr, na/k, au/cr and u/cr ratios were: 0.09±0.05 mg/mg, 5.68±5.41 meq/meq, 0.5±0.24 mg/mg and 16.12±5.3 mg/mg respectively. the 95th percentiles for ca/cr, na/k, au/cr and u/cr were 0.19, 13.07, 0.96 and 26.5 respectively. x±ds for protein intake was 1.27±0.27 g/kg/day. the incidence of hypercalciuria was 6.4% in the initial urine sample and 2.7% in the second. correlation was significant between ca/cr ratio and na/k ratio (r: 0.5, p<0.05), acu/cr ratio (r: 0.38, p<0.05) and u/cr (r: 0.30, p<0.05), not significant between ca/cr ratio and protein intake. conclusions: the incidence of hypercalciuria in this serie is lower than previously reported values in venezuela for the general pediatric population and decreases further when sodium intake is controlled. although no correlation was found between uca and protein intake, we could speculate that protein intake near to the daily recommended requirements of 1 g/kg/day, could be a possible reason for the lower incidence of hypercalciuria in this population. 16-year old girl presented with rapid onset of muscular weakness and a short history of severe dysphagia, dysphonia nad significant wasting. on examination, she was dystrophic (bmi 15,7) and had signs of myopathy. laboratory findings confirmed myopathy (cpk 106,4 ukat/l, ast 2,86 ukat/l, myoglobin 1582 ug/l). there was striking hypokalemia (s-k 1,8 mmol/l) suggesting hypokalemic paralysis. diagnosis of distal renal tubularacidosis (drta) was based on confirmation of hyperchloremicmetabolic acidosis, severe hypokalemia, high urinary ph and positive value of urinary anion gap (s-cl 120 mmol/l, ph 7,31, be 10, urinary ph 7,5). there was evidence of other signs of renal tubular impairment (urinary beta-2-microglobulin 213 mg/l, glomerulo-tubular proteinuria 1,01 g/24 h). autoimmune tests (high positive rheumatoid factor, anf, ena ss-a/ro, ss-b/la, high circulating immunocomplexes) and low values of sialometric measurements (7,5 ml/2x15 minutes) revealed primary sjogren´s syndrome as the underlying cause of drta. the renal biopsy confirmed chronic tubulo-interstitial nephritis compatible with this diagnosis. full recovery of muscle weakness and laboratory findings of hypokalemia and acidois followed potassium and alkali replacement. corticosteroids were administered with subsequent addition of cyclosporine a because of disease activity. conclusion: primary sjogren´s syndrome is a rare diagnosis in childhood and adolescence and should be considered in patients presenting with hypokalemic paralysis due to drta. m. caletti, h. lejarraga, s. caíno, a. jiménez introduction: ndi is a chronic, genetic disease caused by an inability to effectively conserve urinary water, due to a lack of response of distal renaltubule to antidiuretic hormone. the main symptom is polyuria, polydipsia and growth impairment. objective: to evaluate long term growth in height and weight of 16 children with ndi. patients and methods: sixteen patients with ndi attending hospital for a median period of 11.5 years (range 3.4/16.2 yrs) were studied. treatment consisted of indometacine, hydroclorotiazide and amiloride (iha). height and weight was measured with standardized anthropometric techniques. z scores(sds) for all measurements were calculated according to national standards. results: all children responded favourably to treatment. mean birth weight sds was not different from zero; mean height and weight at diagnosis was ±2.31 and ±2.66 sds respectively, and at the end of follow-up was ±1.30 and ±0.98 respectively. the majority of patients´s growth curves evolved below the 50 th centile. ten out of 16 children experienced some catch up in height (mean height gain: 1.38 sds (r: -0.50/2.42)). mean weight gain during follow-up was 1.74 sds (r: 0.86/4.24) . mean gain in body mass index was 1.72 sds (range 0.5/4.8). in the two patients who attained adult height, adolescent growth spurt was normal, and final height was within normal limits for standards and for parental height. correlation coefficient between gain in height andage at diagnosis was ±0.58. conclusion: although mean height at follow-up was below the expected normal value, combined therapy with iha is compatible with some catch up growth in height and weight. the lower the initial height, the greater the height gain. adherence to treatment is essential for normal growth in children with ndi. body growth of children with steroid-responsive idiopathic nephrotic syndrome m. noer, i. irwanto, n. sumiarso, m. chalim soetomo hospital, school of medicine airlangga university, department of child health, surabaya, indonesia objectives of study: the present study was designed to evaluate the statural growth of children with steroid-responsive idiopathic nephrotic syndrome, attending the pediatric nephrology unit department of child health, school of medicine airlangga university, soetomo hospital, surabaya, indonesia, with a minimum follow-up of 2 years. methods: anthropometrice valuation included weight, height, and growth velocity expressed as mean and standard deviation scores (sds), relative to the normal population (nchs/cdc 2000). these indices were analyzed at admission and then every 6 months of follow-up. all patients were treated with prednisone, according to indonesian consensus of management of idiopathic nephrotic syndrome in children. results: of 157 children (105 boys and 52 girls), 43 patients (34 boys) aged 26/12 years to 16 years (mean 7.05 years) were analyzed. initial mean height and z score (height for age) were 108.41±15.2 cm and -1.85±1.41, respectively. mean height and z score (height for age) of the last follow-up were 121.88±15.1 cm and -1.34±1.5, respectively. mean growth velocity were 6.25±2.05 cm/year where 3 boys (6.9%) had growth velocity less than 4 cm/year. total cumulative dose of steroid during 2 years of follow-up were 4283.90±2863.35 mg or 233.76±153.73 mg/kgbw. conclusions: the cumulative dose of steroid up to 233.76 mg/kg body weight in children with nephrotic syndrome during 2 years of treatment did not influence their growth velocity. background: recently it has been reported in adult patients (pts) that deterioration of renal function was associated with the lost of nocturnal blood pressure (bp) dip and enhanced urinary sodium (una) and protein (uprt) excretion during night. objectives of study: to investigate the circadian rhythms of bp, una and uprt in children with chronic kidney disease stage i (ckd i). methods: in 34 pts (15 boys) aged 11.2±4.3 years with ckd i (chronic glomerulopathy confirmed by renal biopsy in 85% pts), 24 hour bp was monitored during daytime (d) and nighttime (n) and urinary samples for uprt, urinary creatinine (ucr), and una, were collected for both periods. results: serum creatinine-based gfr was 127±22 ml/min/1.73 m 2 , uprt ranged from 21 to 5455 (median 141) mg/24 h, and una from 27 to 267 (median 102) mmol/24 h. in general we found a highly significant nocturnal decrease in systolic bp (from 116 to 108 mmhg), diastolic bp (71 to 62 mmhg), mean arterial pressure (87 to 78 mmhg), heart rate (91 to 75/min) urinary output (uo), una and uprt. the regression equations were as follows: uod (ml/m 2 /h)=32+1.6xuon (ml/m 2 /h); unad (mmol/l)=73.5+0.14xunan (mmol/l); uprtd (mg/m 2 /h)=5.4+1.83xuprtn (mg/m 2 /h) and urinary osmolality (us) d=13+0.65xusn. nocturnal decrease of uo correlated with nocturnal decrease of ucr and uprt, and nocturnal decrease of uprt correlated with nocturnal decrease of uo. more than half of the patients were classified as non dipper. they differ significantly from dipper only in night/day changes of us. conclusion: night/day changes of uo, una and uprt in pts with ckd i may be calculated from the given regression equations. these changes are not correlated with nocturnal bp decrease. non dippers have greater nocturnal change of us compared to dippers. follow-up of these parameters will clarify their importance in progression of ckd. autosomal autosomal dominant proximal renal tubular acidosis (prta) it is described l. g. brenes (1977) at seven members of one family. we diagnosed seven members of the afghani family with prta: mothers and 6 children (5 girls, 1 boy from 2,5 till 16 years) with hyperchloremic metabolic acidosis. pedigree analysis suggested an autosomal dominant inheritance pattern. observable patients did not have ricket and nephrocalcinosis. deafness and ocular abnormalis are absent. the plasma hco 3 concentration is decrease in the range of 14,9 to 19,0 mm/l, minimal urine ph is <5,5. parameters of blood creatinin and glomerular filtration rate were normal. urine calcium excretion was normal. therapy strategy of prta at observable patients provides high dozes of citrates/bicarbonates 10-15 mmol/kg per 24 h. all india institute of medical sciences, division of nephrology, department of pediatrics methods: retrospective case-search. data of previously reported prospective trial (n=19) was also included. results: all except 6 patients had previously been treated with both levamisole and cyclophosphamide. forty-two cases qualified for the study and were administered mmf for a mean duration of 14.3 months (95% ci, 12.0, 16.6/patient in the first 6 months of treatment and 0.7 episodes (n=35) in next six months of mmf treatment (p<0.0001), an average reduction of 62% (95% ci, 49.1, 75.0) from the pre-mmf phase. nine (21.4%) patients had no relapses while on mmf therapy we present sibling cases of as with heavy proteinuria at early childhood. a boy (3 year-old) and a girl (2 yearold) were diagnosed as x-linked as. since a boy developed persistent heavy proteinuria (up/cr 2.9) with macrohematuria andresistant to arb/acei therapy, we treated him with cyclosporina (csa) that could lead to complete remission. to investigate pathomechanism of proteinuria, we tested immunostaining for slit diaphragm associated molecules (nephrin, podocin), gbmassociated molecules (laminin, perlecan, agrin) and podocalyxin using frozen sections from his firstand second biopsy and girl's one (up/cr 0.4). in the specimens from boy's first biopsy and girl's one, light microscopy revealed mild mesangial proliferation and no differences ofthe expression with perlecan, agrin and podocalyxin compared with controls. however, when determined laminin isoforms, fetal type laminin (alpha2beta1gamma1) wasdistinctly observed in the gbm, whereas that was localized only inmesangium with controls. interestingly when compared mature laminin isoform (alpha5beta2gamma1), beta2 chain was specifically less expressed in the gbm. however there were no differences of expression of these molecules in the specimens between pre-and post-treatmentwith csa. in boy's second biopsy, 50% glomeruli were detected to becollapsed. together with the recent report showing that laminin beta2 mutation causes congenital nephrotic syndrome factor v leiden mutation and steroid resistant membranous glomerulonephritis: a case report m. buyukcelik 1 , m. karakok turkey renal compications of d-penicillamin therapy in wilson's disease sami ulus children's hospital, department of pediatric nephrology sami ulus children's hospital, department of pediatrics sami ulus children's hospital hass classification), treatment and outcome. thirty-nine patients; 29 boys (74.4%) and 10 girls (25.6%) time of the last examination (median 60 months, min<1 year) after the admission as a long term follow-up. clinically, group i; while microscopic hematuria was detected in 6 patients, 19 patients had repeated attacks of hematuria, 4 had isolated mild proteinuria/hematuria, group ii; 6 patients had nephritic, 1 had nephrotic syndrome and 3 had both. biopsy grades in the 39 patients: 55%, 60% had grade i, 10.4%, 10% had grade ii, 31%, 20% had grade iii, 6%, 10% had grade iv in group i and ii, respectively. group i and ii patients recovered completely (no hematuria and proteinuria) 34.4%, 44.8% as well as 20%, 50%, short-term, longterm, respectively. while recovery rates in fish-oil and/or ace-inh treatment group was 34.4% and 48.2%, in corticosteroids group, it was 25%, 50% short-term, long-term,respectively. no patients who received immunosuppressive treatment had improved. however, 3 (7.6%) patients would suffer from esrd. initial presentation, severity of renal involvement and type of the treatment were not found to have a prognostic value (p>0.05). in children, igan is characterized by extreme pathogenetic, clinical and histological polymorphisms radojevic 1 1 university of belgrade, faculty of medicine, institute of pathology, belgrade, serbia 2 institute of mother and child health of serbia, belgrade, serbia 3 university children's hospital, department of nephrology, belgrade, serbia celiac disease hla aplotype in children with nephrotic syndrome s i (if) or mcp or with anti-cfh autoantibodies. varicella hasn't been described as a triggering event of ahus. we report two cases of ahus associated with complement dysfunction revealed after varicella infection. case 1. a five year-old boy presented with non post-diarrheal hus, 17 days after varicella. serum creatinine was 300 μmol/l, hemoglobin 6.5 g/dl, schizocytes 17%, platelets 19 g/l. glomerular filtration rate normalized within 14 days. search for shiga toxin-producing e coli in the stools and serum anti-lipopolysaccharides antibodies were negative. plasma c3, cfh and if levels were normal. no mutations of cfh and if were found. mcp cell-surface expression was decreased and a c30f mutation in mcp exon 2 was demonstrated. case 2. a four year-old girl had ahus 5 days after varicella at that time, complement system study showed normal c3 level (677 mg/l, normal 660 to 1260 mg/l), normal cfh level (81%, normal 70-130%), but the presence of anti-cfh autoantibodies. no mutations of cfh, if or mcp were found. in conclusion, these 2 cases outline that varicella can be the triggering event of ahus associated with complement dysregulation about 450 (62.5%) children had relapses after initial remission. various infections were responsible for relapsed with in 200/450 (44.44%) who had relapses. about 120 children (32.69%) relapsed with out cause where as poor compliance was observed in 47 (12.8%). overall infection and relapse rate was 1.4 and 1.00/pt/yr respectively. among 367 children with infections, most common types of infections were acute respiratory infections (ari), diarrhea and uti seen in 200 (54.49%), 82 (22.34%) and 30 (8.17%) of cases respectively. other types of infections like malaria, peritonitis, skin infection and pulmonary tuberculosis were seen serum pai-1 and tgf-beta 1 levels in profliferative forms of glomerulonephritis in children russian federation 2 research centre for child health rams, department of pathology, moscow, russian federation we aimed to investigate serum levels of plasminogen activator inhibitor -1 (pai-1) and transforming growth factor-beta 1 (tgf-beta 1 ) in children with proliferative forms of glomerulonephritis (gn). 51 children were examined (5-16 years old) with gn (steroidresistent ns, n=27; steroidsensitive ns, n=11, isolated haematuria, n=13) and 15 healthy age matched controls. mesangioproliferative gn (mespgn) was detected in 39 patients, membranoproliferative gn (mpgn) in 12 cases. serum levels of pai-1: ag and tgf-beta 1 were measured by elisa. results. the highest levels of pai-1: ag and tgf-beta 1 were observed in relapse of mpgn: 93,51±71,63 ng/ml and 16 these results confirm prosclerotic effects of pai-1 and tgf-beta 1 via increased fibrin deposits and extracellular matrix accumulation in the renal tissue and promotion of disease progression rituximab treatment for idiopathic nephrotic syndrome: a retrospective study of 11 cases v. guigonis 1 , a. dallocchio 1 , m. dehennault urinary and serum annexin v levels in children with steroid sensitive and steroid-resistant nephrotic syndrome hôpital robert debré-aphp, pediatric intensive care unit indonesia this study was aimed to evaluate the efficacy of pulse dose of cyclophosphamide in children with srns admitted in child health department faculty of medicine university of indonesia/cipto mangunkusumo hospital jakarta between 2001-2006. 6-month period, one child died, and the rest (5 children) did not complete the regimen. five out of 7 children who finished the treatment had remission, while 2 others were still experiencing heavy proteinuria. remission was achieved in various time, 3 children were in remission after the first dose, in 2 children it was achieved at the third and sixth dose. in further follow-up time; one child remained in remission, one child had relapse when still receiving cpa, 2 children got relapse one month after stopping cpa, and one child had relapse after 6 months ceasing cpa. nausea and vomiting were found in 2 children indonesia this study is to evaluate the anthropometric measurements of children with nephrotic syndrome methods: a descriptive retrospective study at child health department, cipto mangunkusumo hospital, jakarta. data were collected from medical records of nephrotic syndrome 9%) irns; body height and body weight of <p3 was found in none of frns/sdns, 9/32 (28,1%) srns, and 20/101 (19,8%) irns; bmi >p95 was found in 4/45 (8,9%) frns/sdns, 3/32 (9,4%) srns, 4/101 (3,9%) irns. conclusion: the percentage of children with frns/dsns and srns with body height <p3 il-12) during active stage (as: urinary protein >40 mg/m 2 per hour, serum albumin <2.0 g/dl) and remission stage (rs) in ss-mcns. a total of 48 patients with ss-mcns (29 of 48 patients with as and 19 of 48 patients with rs) and 19 healthy children were recruited for studies. the mean±sd of serum il-12, se-selectin and sicam, levels were significantly higher in patients with as than in patients with rs (277±188.4/157.2±119 pg/ml; 132.1±67.9/88.3±40.5 ng/ml and 168.3±120.3/82.2±27.1 ng/ml respectively, p<0.05). in spite of, higher levels of il-12, se-selectin and sicam in patients with as than controls, difference was not statistically important. the percentage of cd3+cd23+ lymphocyte subsets were statistically grater in patients with as severe proximal renal tubular acidosis in pearson syndrome birth weight was 4000 g. pallor was initially noted during the neonatal period and referred to our hospital with anorexia, vomiting, diarrhea, weakness, and increased pallor at 8 wk of age. on the physical examination she was pale and the other systems were unremarkable. investigation showed hypoplastic anemia, and bone marrow examination showed cytoplasmic vacuolization of both myeloid and erythroid precursors, and maturation arrest of granulopoesis. family history was negative for hematological disease. the diagnosis ps was considered on the basis of early severe refractory anemia associated with vacuolization of bone marrow precursor cells and ring sideroblasts. treatment was started consisting of vitamine b6 and folic acid. she was followed with growth retardation, moderate anemia and leucopenia up to age 4.5. at that age, the girl was readmitted with severe vomiting and dehydration. on admission, she had moderate metabolic acidosis, hypokalemia, high plasma lactate, and hypophosphatemia. further investigations showed tubuler proteinuria, glucosuria, aminoaciduria, and defective bicarbonate reabsorbtion in the proximal tubule. she developed refractory metabolic acidosis resulting in a cardiac and respiratory failure and death. to confirm the diagnosis of ps, molecular studies were performed 4977 bp common deletion was found medial calcification in intact human arteries from children with chronic kidney disease is associated with apoptosis and osteogenic differentiation -clinical and laboratory correlations r using intact human vessels we studied the phenotypic changes in medium sized arteries ex vivo and in vitro after exposure to ca and po 4 . arteries were retrieved during insertion of pd catheters or at transplantation from 34 children: dialysis (n=20), ckd stage iv (n=8) and compared with mesenteric vessels from 6 controls. vessel rings were incubated with graded concentrations of ca and po 4 upto 21 days. calcium and alkaline phosphate (alk) were measured by cresolphtalein complexone and colorimetry. immunohistochemistry for bone marker proteins, inhibitors of calcification and apoptosis were performed. laboratory findings were related to patient's clinical and biochemical parameters, carotid intimamedia thickness (cimt) and coronary calcification. vessels from ckd or dialysis patients had increased baseline vessel wall ca compared with controls (p=0.001). when exposed in vitro to ca and/or po 4 , dialysis vessels showed greater calcification than those from controls or ckd patients (p<0.0001). in the presence of elevated po 4 even a small increase in ca increased calcification (p<0.001). calcification was associated with apoptosis (tunel +) and could be inhibited using apoptosis inhibitor zvad. alk in ckd and dialysis vessels and along with upregulation of bone-markers suggests an osteogenic conversion of vsmcs using our unique in-vitro model, we have shown for the first time that vascular damage induced by elevated ca-po 4 as well as factors specific to dialysis primes vessels for rapid progression of medial calcification altered expression of major renal na + and k + transporters c. ruete 2 , p. vallés 1,2 1 university of cuyo, department of pathology turkey the effect of corticosteroid therapy on bone metabolism in nephrotic syndrome was examined. sixty-nine patients with idiopathic nephrotic syndrome (age: 7.0±2,5 years) and 21 healthy controls (age: 6.4±3,5 years) were divided into 3 groups: group 1: patients who were on remission but still receiving steroid therapy, group 2: patients who were on remission and free of steroids within the last year and group 3: patients with active nephrotic syndrome and receiving steroid therapy. serum total calcium, ionized calcium, phosphorus, alkaline phosphatase, magnesium, parathyroid hormone, 25(oh)d, serum cystatin c, urine protein, urine creatinine and urine cystatin c levels measured in all patients including the control group. in addition, lumbar spine bone mineral density z scores were measured in the patient group objectives of study: we evaluated the clinical, laboratory and urinary tract echosonographic findings in patients with ah and rh. methods: there was prospective clinical study, included 30 patients (mean age 6.6±2.5) with ih (normocalcemic, normophosphatemic, with 24 hours urinary calcium excretion greater than 4 mg/kg/day) all analyzed parameters (dysuria, positive family history of urolithiasis, microscopic hematuria, urinary tract microlithiasis) showed low sensitivity and specificity, and none of the parameters could be considered reliable in differentiating ah versus rh. average value of una/cr was greater in patients with rh conclusion: none of the analyzed clinical parameters, laboratory and echosonographic parameters except values of urinary excretion after calcium deprivated diet could be considered reliable in differentiating ah versus rh. patients with rh have higher level of 24 hours urinary calcium excretion than patients with ah. patients with rh have significantly greater excretion of urinary sodium compared with patients with ah idiopathic hypercalciuria (ih) is defined as hypercalciuria with no detectable cause. low bmd with increased fracture rate and tendency to short stature has been reported in ih patients. we aimed to perform calcaneus qus in children with ih and relate to u-ca, body height and number of prevalent fractures (fx). 11 children (8 girls, 3 boys; patient. body height was recorded and qus was measured on both heels with cuba clinical. the 24-h u-caexcretion (u-ca/24 h) was assessed and calculated in mmol/kg/24 h. results were expressed as z-scores ±sd. czech anthropometric parameters from a 1991 survey and previously obtained qus values of the healthy czech pediatric population served as reference data. qus results were also calculated as height adjusted values with the use of heightmatched standards. u-ca/24 h was matched to healthy european paediatric population values we found no correlations between fx and bua (either age-related orheight-adjusted) or fx and vos (age-related or height-adjusted). neither were there any correlations between u-ca and fx, or u-ca/24 hand bua or vos, respectively. in conclusion, children with ih had normal height, normal values of bua and low vos 40 (fc) 491 (p) 652 (p) 268 (mr) 23 (fc) 126 (fc) 194 (op) 523 (p) alpay h. 399 (p) 854 (p) amann k. 37 (fc), 810 (p), 818 (p) amanullah f. 521 (p) 169 (op) amaro a. 77 (op) 164 (op) amore a. 48 (sy) 831 (p) anarat a. 277 (fc) 131 (mr) 322 (p) 191 (op) 213 (fc) 75 (op) 345 (p) 391 (p) bael a. 192 (op) 308 (p), 543 (p), 600 (p) 32 (fc) 129 (fc) 658 (p) balat a. 349 (p) 444 (p) 19 (fc) bayazit ak. 372 (p) 906 (p) 708 (p), 709 (p), 710 (p) 338 (p) 356 (p) 671 (p) 805 (p) bensman a. 162 (op) 153 (sa), 384 (p) 425 (p) 118 (fc) bereczki cs. 66 (op) 214 (fc) 93 (op), 285 (fc) 197 (op) 12 (sy) bi yl. 484 (p) 23 (fc) 370 (p) 171 (op) 841 (p) biyikli n. 399 (p) 398 (p) 227 (fc) bocanegra v. 224 (fc) 122 (fc) 352 (p) boh m. 134 (fc) bökenkamp a. 92 (op) 271 (fc) 22 (fc) 177 (op) 65 (op) 92 (op) bourrier t. 425 (p) bouts ah. 103 (op), 117 (fc) 77 (op) 903 (p) bubic-filipi lj 368 (p) 168 (op), 271 (fc) 78 (op) 486 (p) 389 (p) caropreso m. 95 (op) 277 (fc), 371 (p) 40 (fc) 459 (p), 460 (p) chartapisak w. 817 (p) 530 (p) 693 (p) chaves a. 77 (op) 394 (p) chemodanova m. 911 (p) 559 (p) chen j. 76 (op) 724 (p) 488 (p) 539 (p) 654 (p) 160 (op) 396 (p) 645 (p), 650 (p), 836 (p) clermont mj 737 (p) 211 (fc), 472 (p) 55 (sy) codoceo a. 523 (p) coelho g. 77 (op) 49 (sy), 221 (fc) 48 (sy) 704 (p) 214 (fc) 211 (fc) 846 (p) 206 (fc) 456 (p) coutinho s. 868 (p) coviello d. 333 (p) 223 (fc) craig j. 108 (op), 556 (p) cransberg k. 214 (fc) 765 (p) 425 (p) cristino s. 672 (p) 39 (fc) 532 (p) cross j. 86 (op) cruz mr 22 (fc) 534 (p) 117 (fc), 558 (p), 630 (p) 55 (sy) deanfield j. 127 (fc) 845 (p) decena-galvez a. 601 (p) 124 (fc) 571 (p) 415 (p) deguchtenaere a. 98 (op) 859 (p) 679 (p) 303 (sa), 373 (p) 381 (p) delucchi a. 633 (p) 821 (p) 338 (p) 439 (p) 485 (p) 653 (p) 284 (fc), 599 (p) 20 (fc) dinda a. 756 (p) 325 (p) 695 (p) 607 (p) dittrich k. 37 (fc) 28 (fc) 307 (p), 445 (p) dötsch j. 37 (fc), 810 (p), 818 (p) dragon-durey ma 388 (p) 34 (fc) 576 (p) 25 (fc) 833 (p) 594 (p) 512 (p) 660 (p) dursun i. 344 (p) 344 (p) 500 (p) edefonti a. 380 (p) 374 (p) eke f. 265 (fc), 718 (p) 322 (p) 220 (fc), 269 (fc), 333 (p), 403 (p) 32 (fc) 338 (p) 706 (p) 384 (p) evim m. 430 (p) f faerch m. 378 (p) fallahzadeh mh. 448 (p) 473 (p) 248 (sy) feig d. 353 (p) 681 (p) 644 (p) fella a. 96 (op) feneberg r. 176 (op) 77 (op) 862 (p) filler g. 25 (fc) 849 (p) 104 (op) fischbach m. 157 (op) sy) fitoz s. 408 (p) 117 (fc) 798 (p) 470 (p) fujita h. 75 (op) 441 (p) fujita t. 769 (p) 443 (p) fukuhara d. 816 (p) 171 (op) 843 (p) 803 (p) 171 (op) 189 (op) garnier a. 365 (p) 762 (p) 155 (op) 251 (sy) geary-joo c 21 (fc) 32 (fc) 177 (op) 141 (sy) 32 (fc) 605 (p) gross ml. 116 (fc) 610 (p) 331 (p) 136 (fc) 205 (fc) 533 (p) 821 (p) guo w. 76 (op) 746 (p) 70 (op) 344 (p) haberal m. 537 (p) 42 (fc) 72 (op), 128 (fc) 271 (fc), 538 (p) 285 (fc) 266 (fc), 747 (p) 266 (fc) 851 (p) 268 (mr) 344 (p) 470 (p) 183 (op) 164 (op) hernández am. 638 (p) 75 (op) 183 (op) 28 (fc) 190 (op), 271 (fc) 814 (p) hou jr. 315 (p) 334 (p) 168 (op) 315 (p) 204 (fc) 29 (fc) 305 (p), 306 (p) iharada a 186 (op) 185 (op) 677 (p) 267 (fc), 283 (fc) 618 (p) 664 (p) 49 (sy) 793 (p) kathiravelu a. 25 (fc) 100 (op) 154 (op) 104 (op), 115 (fc) 385 (p) 665 (p) 765 (p) 734 (p) 749 (p) 643 (p) 18 (mr) 334 (p) 69 (op) 471 (p) kondo y. 29 (fc) 647 (p), 891 (p) kosuljandic-vukic d. 503 (p) 205 (fc) kovalski y. 645 (p) 190 (op) 815 (p) 312 (p) 611 (p) kru èic d. 910 (p) krylova-olefirenko a. 825 (p) 616 (p) 582 (p) 746 (p) 260 (sy) 118 (fc) 340 (p) 544 (p) kurayama r. 185 (op) 599 (p) 266 (fc) lalatta f. 177 (op) 515 (p) 257 (sy), 354 (p) 160 (op) 432 (p) lau yw 77 (op) 77 (op) 559 (p) llanas b. 71 (op), 136 (fc), 859 (p) llewellyn-edwards a. 270 (fc) 284 (fc) 348 (p) 263 (fc) luis-yanes m 354 (p) 589 (p) 293 (sy) maeda a. 566 (p) maekawa k. 602 (p) 830 (p) 453 (p) 477 (p) 841 (p) 410 (p) 323 (p) mak r. 49 (sy) 95 (op) 171 (op) 625 (p) 20 (fc), 26 (fc) 226 (fc) 457 (p) 254 (sy) 20 (fc) 893 (p) 638 (p) 578 (p) medynska a. 421 (p) 350 (p) mehls o. 128 (fc) 855 (p) 277 (fc), 426 (p) 74 (op) 179 (op) 174 (op) 115 (fc), 758 (p) 420 (p) 23 (fc) 368 (p) molnár-varga m. 525 (p) 227 (fc) 279 (fc) 487 (p) montini g. 209 (fc) 774 (p) 523 (p) 74 (op) 587 (p) 569 (p) morimoto t. 187 (op) 364 (p) 71 (op) 345 (p) morita t. 563 (p) 392 (p) mortazavi f. 309 (p) 283 (fc) moscaritolo e. 502 (p) 728 (p) mosig d. 493 (p) 191 (op) 226 (fc) 498 (p) moxey-mims m. 221 (fc) 158 (op) 521 (p) mudun a. 652 (p) 116 (fc) mughal mz. 895 (p) 828 (p) müller t. 165 (op) müller v. 218 (fc), 244 (sy) müller-esterl w. 745 (p) müller-wiefel de. 23 (fc) 49 (sy), 221 (fc) 174 (op) fc) 185 (op) 31 (fc) 504 (p) nghia h. 490 (p) niaudet p. 113 (mr) 372 (p) 312 (p) nuzzi f. 95 (op), 96 (op), 541 (p) nwobi o. 592 (p) 171 (op) 77 (op) 393 (p) 75 (op) 338 (p) 257 (sy) 567 (p) ostalska-nowicka d. 522 (p) 621 (p) otukesh h. 477 (p) 322 (p) 710 (p) 543 (p) ozen a. 498 (p) 230 (sy), 308 (p) 380 (p) 876 (p) paik kh. 643 (p) 853 (p) pan'czyk-tomaszewska m. 337 (p) 459 (p) 35 (fc) paripovic d. 611 (p), 612 (p), 647 (p) 207 (fc) pasqualini t. 194 (op) fc) pastori a. 463 (p) pászka d. 100 (op) 95 (op) 334 (p) pereira a. 77 (op) 129 (fc) 275 (fc), 574 (p) 576 (p) fc) 110 (op), 344 (p) raes a. 98 (op), 99 (op), 223 (fc) 218 (fc) 535 (p) rigden s. 22 (fc) 209 (fc) ring e. 346 (p) rink n. 104 (op) 74 (op) ristoska-bojkovska n 271 (fc), 538 (p) roszkowska-blaim m. 337 (p) 576 (p) 894 (p) ruffo gb. 914 (p) ruhlmann a. 193 (op) ruiter j. 85 (op) rumeau r. 206 (fc) rusai k. 215 (fc) rusnak f. 608 (p) rüther u. 381 (p) rutjes n. 785 (p) rybarova s. 772 (p) rychlik i. 776 (p) ryckewaert-dhalluin a 477 (p) sabasiñska a. 401 (p) 684 (p) sabolic-avramovska v. 348 (p) 721 (p) 162 (op) safouh h. 499 (p) saha a. 530 (p) sahin h. 512 (p) 184 (op) saint-cyr c. 805 (p) saito a. 450 (p) 29 (fc) sakalli h. 537 (p), 708 (p), 866 (p) sakalli ercoban h. 426 (p) 13 (sy) 868 (p) salusky i. 129 (fc) 74 (op) 717 (p), 720 (p) sarkissian a. 316 (p) 805 (p) 217 (fc) 414 (p) 215 (fc) 154 (op) sayili a. 590 (p) schäfer b. 691 (p) 32 (fc), 34 (fc), 42 (fc), 51 (sy), 116 (fc), 228 (fc), 271 (fc), 276 (fc) 215 (fc) schmidt-gayk h. 281 (mr) schmidts m. 549 (p) schmitt cp. 116 (fc) 195 (op) 549 (p) 272 (fc) schneider-maunoury s. 381 (p) 549 (p) 49 (sy), 221 (fc) 23 (fc) 180 (op) 869 (p) seeherunvong w. 40 (fc) 887 (p) 185 (op) 468 (p) semama d 76 (op) 748 (p) 470 (p) 656 (p), 657 (p) shin yh 382 (p) 564 (p) 22 (fc) 372 (p) 416 (p), 519 (p), 652 (p) siwiñska a. 343 (p) 276 (fc) 154 (op) 717 (p) spasojevic b. 612 (p), 647 (p), 910 (p) spasojevic-dimitrijeva b stanic m. 386 (p), 891 (p), 910 (p) stankovic a. 386 (p) 644 (p) 125 (mr) 41 (fc) 74 (op) 18 (mr) 361 (p) 869 (p) 711 (p) 711 (p) 772 (p) 869 (p) szteblich a. 188 (op) t 32 (fc) 679 (p) taha g. 499 (p) 532 (p) taheri derakhsh n. 436 (p) 602 (p) 814 (p) 31 (fc), 790 (p), 807 (p) tan ph 654 (p) 654 (p) 31 (fc) 422 (p) 177 (op) 536 (p) 524 (p) 882 (p) tizard e. 270 (fc) 738 (p) toenshoff b. 120 (fc) 432 (p) tönshoff b. 42 (fc) 731 (p) 160 (op) 218 (fc) 20 (fc) 171 (op) 66 (op) 652 (p) 154 (op) 219 (fc) urdaneta-carruyo e. 551 (p), 872 (p) urdaneta-contreras a 277 (fc) 572 (p) 587 (p) valverde s. 638 (p) 713 (p) van den heuvel l. 118 (fc) 511 (p), 529 (p) van't hoff w. 297 (sy), 348 (p) 486 (p) 213 (fc), 700 (p) 11 (sy) 55 (sy) 272 (fc), 275 (fc) 738 (p), 791 (p), 792 (p) waters a. 181 (op) 38 (fc), 121 (fc), 273 (fc) 268 (mr) 72 (op) 117 (fc) 129 (fc) 72 (op) 227 (fc), 904 (p) 33 (fc) wingen a. 168 (op) 142 (sy) 219 (fc) 49 (sy), 221 (fc) 21 (fc), 693 (p) 264 (fc) 13 (sy) 473 (p) 135 (fc) 322 (p) 798 (p) 816 (p) 79 (op), 784 (p) 29 (fc) 775 (p) yap hk. 31 (fc) 795 (p) yata n. 497 (p) 174 (op) 340 (p) 801 (p) yilmaz a. 519 (p) 174 (op) 67 (op) 439 (p) 579 (p) 794 (p) zhou jh 40 (fc) 165 (op), 211 (fc), 233 (sy) zingg-schenk a 858 (p) 209 (fc) zurowska a. 32 (fc) 161 (op) the il6 (-174g/c) polymorphism is associated with initial peritoneal transport status in children commencing chronic pd acknowledge: this study was from iran university of medical science. atypical hemolytic uremic syndrome: an unsolved case of complement dysregulation 788 (p) aim: we have shown that rats overexpressing il-13 gene developed a mcn with proteinuria, hypoalbuminemia and hypercholesterolemia. this study aimed to determine the role of il-13 on hypercholesterolemia in this model. methods: recombinant rat il-13 gene in a mammalian expression vector was transfected into quadriceps of wistar rats by in-vivo electroporation. serum il-13, albumin, cholesterol, creatinine and urine albumin were measured serially. after sacrifice on day 70, hepatic gene expression of hmg-coa reductase (hmg-coar), acat2, cholesterol-7a-hydroxylase (ch7ah), ldl-receptor (ldlr) and il-13 receptor subunits were determined by rt-pcr. results: compared to control rats (n=17), il-13-transfected rats (n=41) showed significant albuminuria (0.36±0.37 vs 3.45±0.89 mg/day, p<0.001), hypoalbuminemia and hypercholesterolemia (1.72±0.05 vs 3.39±0.34 mmol/l, p<0.001) at day 70. serially, this rise in serum cholesterol preceded the increase in proteinuria and fall in serum albumin. serum cholesterol correlated significantly with il-13 levels (r=0.64, p<0.001). in 14 of the il-13-transfected rats with serum cholesterol>3.10 mmol/l, hepatic gene expression (mean±sem) was significantly upregulated compared to controls for hmg-coar (0.25±0.08 vs 0.54±0.05, p=0.02), acat2 (0.26±0.03 vs 0.43±0.04, p=0.009), ch7ah (0.50±0.12 vs 1.08±0.10, p=0.004) ldlr (0.10±0.01 vs 0.15±0.02, p=0.02) and il-13ra2 (0.003±0.002 vs 0.080±0.015, p<0.001). conclusion: the increased cholesterol synthesis in il-13-induced mcn was associated with increased hepatic gene expression of hmg-coar and acat2, which are important enzymes for cholesterol synthesis. associated increased hepatic gene expression of ch7ah and ldlr involved in cholesterol metabolism could be a negative feedback response. e. bordador, f. anacleto philippine general hospital, pediatric nephrology, manila, philippines general objective: to formulate a clinical scoring system that will predict the presence of glomerular crescents in patients with severe nephritis. specific objectives: (1) to describe the profile of children with acute nephrotic-nephritic syndrome (2) to correlate clinical parameters with renal histopathology. methods: this is a retrospective study. twenty six charts from the philippine general hospital, admitted between january 2002 -march 2006 were retrieved. included in the study were children with acute nephritic -nephritic syndrome who underwent kidney biopsy. excluded were patients with small/contracted kidneys on renal ultrasound. statistical tool used were univariate analysis, pearson's product moment method and chi -square test. results: profile variables of the subjects were analyzed. afterwhich, each clinical parameter was tested using univariate analysis, if significantly correlated with the renal biopsy result using pearson's product moment method at critical value=0.388 at p<0.05. out of 11 parameters, only 3 parameters were noted to be significant, these were serum creatinine, blood urea nitrogen and glomerular filtration rate. further analysis was made by separately treating male from female population using a chi-square test with critical value x 2 (1,.05) =3.28. the test identified another three clinical features among female which were significantly associated with renal biopsy results, these were blood pressure, anemia and hematuria. from these significant parameters associated with renal biopsy results, a clinical scoring system was then conceptualized in order to identify patients with high probability of crescents on renal biopsy. conclusion: cresent maybe use as an accurate screening tool to predict presence of glomerular crescent in patients with severe nephritis. heterogeneous effect of acei therapy in children with proteinuric nephropathies b. kranz, s. diepenbruck, u. vester, r. buescher, a. wingen, p. hoyer university of duisburg-essen, pediatric nephrology, essen, germany background: chronic proteinuric nephropathies are at high risk of developing progressive renal insufficiency. the renin-angiotensin-aldosteron-system blockade is a well documented strategy to reduce proteinuria in adult patients. the efficacy and risks of renal-protective therapy with angiotensin-converting-enzymeinhibitors (acei) in children with proteinuric kidney diseases is of concern. method: in this retrospective study the efficacy of acei as antiproteinuric therapy in children with chronic proteinuric nephropathies is evaluated. patients: sixty-three children (mean age 10.7±3.5 years) have been treated with acei for a mean of 2.7±2.3 years (range 0.1±10.6 years) because of proteinuria (hus n=10, alport syndrome n=22, psh n=13, others n=18). results: proteinuria in all patients declined from a median of 1.5 g/d to 0.9 g/d after 2 years (p=0.01). there was a drop out of 5 patients because of end stage renal failure during the followup. one-third of patients showed a continuous reduction in proteinuria from 3.1 g/d to 0.4 g/d (median) within 3 years while a second third had a transientimprovement followed by a reincreasing proteinuria later. patientswith hus showed a good response (decrease of proteinuria from 2.8 g/d to 0.4 g/d) in contrast to patients with alport syndrome who developed increased proteinuria (0.8 g/d to 3.0 g/d) despite of acei and patients with psh who had no change in proteinuria.interpretation: it has to be discussed whether biological compensation mechanisms may bypass the ace inhibition in single patients and whether the underlying illness may predict the efficacy of acei.aims: to determine the clinicolaboratory renal manifestations; glomerular, extra-glomerular histopathologic lesions; renal tubular dysfunction (rtd) frequency, and outcome of a short-term renal follow-up in nigerian children with systemic lupus erythematosus (sle). methods: a non-randomized prospective study of consecutive cases of childhood-onset sle with nephropathy. baseline/follow-up clinicolaboratory data were collected. each patient was followedup for 12 months. results: seven of 11 children studied were girls (f:m, 1.75). median age at diagnosis was 11.0 years. median diagnosis time interval (1.9 years) and median time of renal disease onset (1.0 year) were similar. hypertension, nephrotic syndrome, and acute renal failure occurred in 45.5%, 54.5% and 63.7% of the patients, respectively. the glomerular lesions were non-proliferative lupus nephritis (ln) in 9.0% (class ii ln); focal (class iii ln) and diffuse (class iv ln) proliferative ln (pln) in 27.0% and 64.0%, respectively. tubulointerstitial nephritis (tin, 91.0%), and rtd (64.0%) were common. arf (p=0.033) and rtd (p=0.015) were significantly associated with severe tin. complete renal remission rate at end-point was 71.4%. relapse and renal survival rates were 14.3% and 86.0%, respectively. rtd was persistent in 43.0%. conclusion: renal function disorders, diffuse pln, and extra-glomerular lesions were frequent. significant association of arf and rtd with severe tin in this series suggests the need for early renal tubular function (rtf) assessment in our sle patients. deranged rtf may be marker of severe tin in sle warranting early confirmatory renal biopsy and aggressive interventional treatment.we report two cases of children with crescentic glomerulonephritis (gn) associated to isolated c3 deposits. patient 1. a 9 year old girl was admitted for macroscopic hematuria, nephrotic range proteinuria (proteinuria/creatininuria=1000 mg/mmol) and renal failure (serum creatinine 600 μmol/l). anca and other antibodies were negative. c3, c4 and ch50 activity were normal but c3nef was detected. the patient was treated by prednisolone and cyclophosphamide pulses followed by oral corticotherapy. renal function normalized, but proteinuria persisted (proteinuria/creatininuria=500 mg/mmol). a relapse occurred ten months later. corticotherapy and cyclophosphamide pulses were reinitiated and were successful, followed by mmf maintenance therapy. patient 2. a 4 year old girl was admitted after viral infection for macroscopic hematuria and fever. proteinuria was of nephrotic range (proteinuria/creatininuria=708 mg/l). the search for autoimmunity was negative. c3nef was detected but c3, c4 and ch50 activity were normal. serum creatinine increased to 369 μmol/l. after three pulses of prednisolone followed by oral prednisone, renal function normalized. histological examination of the two renal biopsies revealed endo-and extracapillary gn with numerous granulocytes in the capillary lumen. cellular crescents involved 90% of the glomeruli. immunofluorescence demonstrated isolated c3 deposits in the mesangium and along the glomerular basement membrane (humps). c1q, igg, iga and igm staining were negative. background: the risk of end stage renal disease (esrd) is low in unilateral wilms tumor, although patients with wagr or associated genitourinary anomalies are at higher risk. esrd is attributed mostly to hyperfiltration in the remnant kidney. immune complex glomerulonephritis (icg) has not been previously reported in wilms tumor patients. objectives: to report 2 cases of icg in unilateral wilms tumor. methods: retrospective chart review. patient #1 a boy with cryptorchidism, diagnosed with unilateral wilms tumor at 3 y of age. patient #2 a girl with wagr and unilateral wilms tumor diagnosed at 2 y of age. both had chemotherapy after tumor resection. results: patient #1: within 2 mo of tumor resection, a proteinuria of 3.8 g/24 hrs and rising creatinine were noted. renal biopsy was consistent with icg. within 5 mo of surgery the patient developed esrd requiring chronic hemodialysis. patient #2: within 4 y of tumor resection, the patient developed progressive, asymptomatic proteinuria up to 2 g/24 hrs. the renal biopsy revealed changes typical for icg. the patient was treated initially with enalapril and prednisone. due to no response, mycophenolate mofetil (mmf) was added and prednisone was weaned. after 4 mo of therapy, her proteinuria improved to 0.5 g/24 hrs. her serum creatinine continued to be normal at 0.6 mg/dl, with calculated gfr of 113 ml/min/1.73 m 2 . conclusions: this is the first report of icg in patients with unilateral wilms tumor with rapid progression to esrd in the first patient, but successful response to mmf in the second patient. despite low risk for progressive proteinuria in wilms tumor patients, it is prudent to monitor these patients for proteinuria and perform a renal biopsy if proteinuria is progressive. mmf therapy may be attempted to decrease proteinuria and to delay the onset of esrd.aim of the study: to present our first results of rhgh treatment mainly in children on hemodialysis. patients and methods: sixteen children, aged 4.5-17.1 years (mean age 11.25±3.57) with height below -2.0 standard deviation score (sds) for age or height velocity below -2.0 sds for age, were selected to receive rhgh therapy at our nephrology and hemodialysis department. most of them were on hemodialysis (14 children) with mean spent time 2.88±2.68 years (0-9 years) before an initiation of rhgh therapy. one half of patients were prepubertal (8 children) and second half were in early puberty (testicular volume between 4 and 8 ml for boys and breast development b2 or b3 in girls). all received 28-30 iu/ml per week by daily subcutaneous injection for 6 months to 3 years. the year before rhgh therapy served as a control period. results: during the first year of treatment, mean height velocity in hemodialysis patients increased from 2.25 cm/year to 6.59 cm/year (p<0.0001) and in the second year was 5.25 cm/year (p=0.004). the mean height sds in hemodialysis children did not improved significantly during the first year of rhgh treatment (from -3.01 sds to -2.77 sds, p=0.063). neither weight, nor the body mass index varied compared with the pretreatment period. no change was observed in glucose, total proteins, albumins, cholesterol and triglycerides levels. the mean increment in bone age was 1.1 years. pubertal status had no influence on response to rhgh. conclusions: therapy with rhgh improved height velocity in children with esrd. no significant side effects were observed in 16 children during the 23.5 treatment years. two patients developed secondary hyperparathyroidism but the relationship with rhgh remains uncertain. in our treatment group rhgh therapy was safe. a. waters 1 , a. trautmann 2 , p. zipfel 3 , e. harvey 1 , ch. licht 1 1 hospital for sick children, department of pediatric nephrology, toronto, canada 2 university children's hospital, department of pediatric nephrology, heidelberg, germany 3 atypical hemolytic uremic syndrome (ahus) is characterized by the absence of a diarrheal prodrome, the tendency to relapse and a poor outcome. functional and quantitative deficiency of complement regulatory proteins or inhibiting autoantibodies result in uncontrolled complement activation, which eventually causes ahus. -we report a case of ahus with complement dysregulation associated with a progressive refractory response to plasma infusions. factor h and factor h-related proteins (fhr) were quantified by elisa and were further analyzed by western blot. complement activation was determined by measuring c3. serial hgb (g/dl), platelet, creatinine (mg/dl), ldh (u/l) were measured. initial presentation was at 7 months of age with thrombocytopenia, hemolytic anemia and increased creatinine. ahus was suspected as e coli infection was ruled out. disease remission followed several plasma exchanges. monthly plasma infusion maintained remission. therapy intervals exceeding 1 month promoted relapses. nine years later, the relapse interval decreased and over the subsequent 3 years, thrombocytopenia persisted as plasma infusion requirements increased. a concomitant decline in renal function (creatinine 1.6 mg/dl) occurred with the development of persistent proteinuria and hypertension. at 13 years of age, she deteriorated acutely with hypocomplementemia and thrombopenia. quantitative factor h was normal. autoantibodies to platelets and factor h were negative. intravenous immunoglobulin combined with oral steroids resulted in normalization of platelet count. complement dysregulation is associated with ahus. hereditary defects can be treated with factor replacement therapy. refractory responses may subsequently arise due to the development of autoantibodies against complement regulatory proteins. complement dysregulation requires further analysis in our patient. objectives: angiopoietin-like 3 protein (angptl3) is involved in lipid metabolism and angiogenesis. the present study was to examine angptl3 expression in human kidneys with proteiuria, in adramycin rats (adr), and in puromycin induced podocyte damage. methods: immunohistochemistry was performed on kidney biopsies from children with mcd, mn, fsgs, tbmn. in adr, angptl3 expression was determined by quantitative real-time pcr in glomeruli and tubuli dissected from frozen section of kidneys with laser microdissection system. in mpc5, a conditionally immortalized mouse podocyte cell line in vitro, angptl3, perlecan and agrin werer detected through real-time pcr with the induction of puromycin. detachment assay was performed in podocytes tranfected by angptl3-pcdna3.1. results: in human kidneys, co-labeling showed angptl3 expressed in the cytosol of wt1 positive cells. quantitative computerized analysis showed that angptl3 in glomeruli in mcd and mn were significantly higher than that of tbmn, fsgs respectively (p<0.05). in adr, angptl3 in glomeruli increased significantly at 21 st or 28 th day (p<0.05) after adriamycin injection compared with control. and the expression of angptl3 in glomeruli was correlated with 24 h urinary protein (r=0.81, p<0.05). in mpc5 both protein and mrna expression of angptl3 on podocytes were up-regulated with the induction of puromycin. in podocytes transfected by angptl3-pcdna3.1 the expression of perlecan or agrin increased significantly compared with control (p<0.05). the attachment ratio was shown 95.7%±3.3% 24 hs after puromycin treatment on podocytes transfected by angptl3 compared with 38.6%±4.7% on normal podocytes, and 27.4%±3.5% on untransfected podocytes. conclusions: angptl3 is predominantly expressed in podocytes which could be involved in podocyte damage and the development of proteiuria. purpose: we present 2 cases of a previously undescribed pattern of membranoproliferative glomerulonephritis, in children with neuroblastoma on chemotherapy. the pattern of injury shows unusual focal capillary loop proteinaceous deposits possibly related to toxic chemotherapeutic drugs. the resultant hypertension and renal impairment made bone marrow transplant a challenging prospect. method: case series results: case 1: this boy with stage 4 neuroblastoma, developed severe renal impairment and hypertension during treatment. thus there were difficulties in administration of chemotherapy and he required early surgery. at tumor resection a nephrectomy was necessary. he received an autologous stem cell transplant. he became unwell at transplant and required haemofiltration. he made a good renal recovery and did not relapse. case 2: he was diagnosed at 2 months with stage 4s neuroblastoma. he completed treatment but later relapsed. during treatment his gfr reduced and he developed severe hypertension. this lead to restrictions in chemotherapy. renal biopsy was carried out at tumor resection. at bone marrow transplant he was very unwell and required haemofiltration. he has chronic hypertension and low gfr. light microscopy findings in both -global diffuse membranoproliferative pattern of injury -large numbers of proteinaceous resorption droplets -features of a protein deposition disease electron microscopy findings common to both -large number of differently sized protein droplets in the endothelial cells -no obvious immunecomplexes/deposits -protein deposition disease with a membranoproiferative pattern of injury conclusion: both cases showed deposits in the kidneys which may be tumor protein in origin and the resultant glomerulonephritis, hypertension and renal impairment lead to challenges in transplant. the long term consequences are yet to be revealed. methods: establish the cultured glomerular mesangial cells of rat in vitro, 3~10 generations of cells were used in the experiment after identification. the experiment included five groups: ctrl, lps, high, middle and low dose fos groups. gmc proliferation were detected by mtt. the changes of ln, fn and col protein secretion were detected by the elisa. the changes of lnbeta 2 mrna expression were detected by semi-quantitative real-time pcr. results: (1) fos can inhibit the effect of proliferation induced by lps. (2) mesangial cells can secrete some ecm protein in normal culturing medium, ecm protein secreted by mesangial cells was significantly higher in lps group than that in ctrl group (p<0.01), while ecm protein was significantly lower in all fos groups than that in lps group (p<0.01). (3) lnbeta 2 mrna expression was significantly higher in lps group than that in ctrl group, while that in fos group was significantly lower than in lps group. conclusions: lps can induce the increase of secretion of the ecm, including ln, fn, col fos can inhibit the secrection of ecm in gmc as dose-dependent manner at the mrna and protein levels. the conclusion supplies the theoretical evidence for the renal protection of fos. h. hong, w. na, y. li, w. qiang guangzhou first municipal people's hospital, department of pediatrics, guangzhou, people's republic of china objective: to observe the effects of fosinopril (fos), the new generation angiotensin-converting enzyme inhibitor (acei), on protein and mrna expression of tgf-β1 of rat glomerular mesangial cell (gmc) induced by lps; to demonstrate the preventive mechanism against glomerular sclerosis by applying fos. methods: culture rat gmc in classic way. the cultured cell were divided into 3 groups, namely (1) control group, (2) lps group, (3) lps+fos group. detect tgf-β1 concentration in gmc supernatant fluid by elisa; estimate tgf-β1 mrna expression by semiquantitative real-time rt pcr. results: lps group is obviously higher than control groups in tgf-β1 secretion and mrna expression, while lps+fos group drops distinctively in tgf-β1 secretion and mrna expression compared with lps group. conclusions: fos has obvious inhibited on tgf-β1 expression of rat gmc both at protein level and mrna level, which reveals that it might be an important mechanism by fos on restraining the development of glomerulosclerosis. r. kahn 1 , n. akbari 1 , j. wieslander 2 , w. müller-esterl 3 , a. christensson 4 , k. westman 4 , t. hellmark 4 , d. karpman 1 1 lund university, pediatrics, lund, sweden 2 wieslab ab, lund, sweden 3 institute of biochemistry ii, frankfurt, germany 4 lund university, nephrology, lund, sweden vasculitis is an inflammation with neutrophil influx in and around blood vessels. patients may have elevated plasma levels of neutrophil-derived proteinase 3 and anti-neutrophil cytoplasmic antibodies (anca) directed to proteinase 3, suggested to be involved in the pathogenesis of disease. we have previously shown that the kallikrein-kinin system (kks) is activated in vasculitis. in vivo the kks is activated on endothelial cells and neutrophils when high-molecular-weight kininogen (hk) is cleaved by kallikrein thus liberating bradykinin. bradykinin is a potent mediator of inflammation. in the present study we investigated if neutrophil-derived proteases, and proteinase 3 in particular, could induce activation of the kks and bradykinin release. purified neutrophils from ten vasculitis patients (3 adults, 7 children) and thirteen controls were treated with triton-x to induce lysis. proteinase 3 was immunoadsorbed from the neutrophil extracts. bradykinin and proteinase 3 levels were measured by elisa. hk proteolysis was detected by immunoblotting. proteinase 3 incubated with purified hk induced physiological breakdown of hk and bradykinin release. this was inhibited by preincubation of proteinase 3 with anti-proteinase 3. triton-x treated neutrophil extracts from both patients and controls induced hk proteolysis and bradykinin release whereas the neutrophil extracts from which proteinase 3 had been immunoadsorbed did not. levels of proteinase 3 in the neutrophil extracts from patients and controls did not differ. these findings suggest that neutrophil derived proteinase 3 can proteolyse hk in a physiological manner thus liberating bradykinin, thereby initiating kallikrein-independent activation of the kks. introduction: this is a prospective study to evaluate the safety and efficacy of tacrolimus in 22 consecutive children with steroid-resistant nephrotic syndrome (srns). methods: all of them were subjected to kidney biopsy. tacrolimus was given in dose of 0.15-2.0 mg/kg/day in two divided doses to attain trought levels of 5.0-10.0 ng/l. these patients were followed-up every 2 weekly initially for the first month, followed by monthly visits. urine spot protein creatinine estimation was done at each visit. besides blood glucose, serum creatinine, urea, electrolytes, albumin, and complete blood count were done once a month. results: the mean age of onset was 8.6±5.9 yrs. of the 22 children, 9 had mcd, 11 had fsgs and another 2 had dmh on histopathology. tacolimus had to be withdrawn in 3 children: of the rest 19 children who received adequate therapy, complete remission was seen in 16 (76%) children, 2 (11%) attained partial remission and 1 was non responsive. the mean time to achieve remission was 59.9+45.8 days and the mean dose of tac was 0.18+0.07mg/kg. the mean urine spot protein/creatinine ratios were significantly lower (0.64±1.09 vs 14.5±23, p=0.01) and mean serum albumin significantly greater (3.73±0.71 vs 2.45±0.52, p=0.001) as compared to those prior to tac. of the 16 children who attained complete remission, 2 patients are off steroids and tac and in sustained remission, while the rest 14 are still on tac therapy. conclusions: this is the largest study so far on the safety and efficacy of tacrolimus therapy in children with srns. we conclude that tacrolimus is a useful therapeutic alternative in children with srns who are unresponsive to cyclophosphamide and cyclosporine. objectives: to describe hiv infected paediatric patients from our centre with pathology proven renal disease. methods: retrospective review of biopsy data base and case notes of patients with hiv referred with renal problems. results: 14 patients were identified who had biopsy confirmed renal disease. the mean age of the patients was 5,7 yrs (range: 6 months to 16 years). twelve of the patients were african and two were of mixed race. renal pathology was divided into three groups: 1) hiv associated nephropathy (hivan): five patients. 2) mesangioproliferative nephropathy: 4 patients 3) other: acute pyelonephritis in 1, mesangial proliferation plus interstitial nephritis in 1, renal tuberculosis in 2, hiv immune complex disease (hivick) in one. conclusion: there is a high degree of variability of renal pathology in children with hiv and renal disease which upholds the need accurate diagnosis when confronted with these patients. background: acute poststreptococcal glomerulonephritis (apsgn) is the most common glomerular disease of children in our country. it has not been studied well in this region yet. here, we report our experience with psgn in a tertiary referral center during a five-year period. method: hospital records of all 137 children who had been admitted from mar. 2001 to mar. 2006 to nemazee hospital with diagnosis of acute glomerulonephritis (agn) were reviewed. all demographic, clinical, paraclinical data and consumed medications were obtained. results: among 137 children diagnosed as agn, 122 (89%) had apsgn. other 15 (11%) children had mpgn (n=4), mespgn (n=4), iga nephropathy (n=2), lupus nephritis (n=2), rpgn (n=2), and fsgs (n=1). mean age in children with apsgn was 8±3.5 (range, years. 117 children (96%) developed apsgn following a sore throat or upper respiratory infection while 5 (4%) cases developed after impetigo. ninety-five (78%) patients developed apsgn during the cold seasons of the year. periorbital edema was found in119 children (97.5%), hypertension in 92 (75%), gross hematuria in 88 (72%), oliguria in 45 (37%), generalized edema in 23(19%), azotemia (bun>20) in 98 (80%), and nephrotic range proteinuria in 30 (24.5%). aso titer was high in 103 (84%). low c 3 was detected in 105 (86%) and low c 4 in 16 (13%). dilutional anemia in 63 (51.5%), hyponatremia in 33 (27%), and hyperkalemia in 17 (14%) children among whom, 3 required hemodialysis. regarding medications, 29 patients had received only furosemide, 73 cases took furosemide and nifidipine and for 10 patients furosemide+nifidipine+another antihypertensive medication was prescribed. conclusion: acute psgn is the most common type of glomerulonephritis in this region. it follows sore throat in the majority of cases. it usually has an uneventful course. y. guo, zh. wang, x. liu west china second university hospital, sichuan university, department of pediatrics, chengdu, people's republic of china objective: we planned to explore the mechanism of glomerular basement membrane (gbm) damaged by rsv, through investigating the effects of lmwh on proteinuria and glomerular structure of rsv nephropathy. methods: sd rats were inoculated with 6 10 6 pfu rsv and lmwh 400 iu/kg. group a: rsv was given in the first 3 days, and lmwh was given for the following 11 days; group b: the mixture of rsv and lmwh was given in the first 3 days, then lmwh was given for other 11 days; group c: lmwh was continuously given throughout 14 days and on the 4 th -6 th day rsv was also given; group rsv and the control were respectively inoculated by rsv and dmem for 3 days. renal histology, urinary protein excretion and serum parameters were observed. rsv rna in renal and pulmonary tissue was determined by in situ hybridization. results: there was no significant increase in urinary protein excretion of the lmwh-treated groups (a 7.4053±4.057, b 7.101±1.833, c 9.209±1.625, mg/24 h) compared with the control, but that of group rsv (32.041±3.844 mg/24 h) gradually increased after rsv inoculation. there was just a decrease in albumin (15.060±1.335g/l) and an increase in urea nitrogen (12.9203±3.932μmol/l) of group rsv only. no change of the glomeruli detected in all lmwh-treated groups, while congestion and swelling in glomeruli of group rsv were observed significantly. glomerular microstructures of the lmwh-treated groups were almost normal, while extensive foot process effacement was observed in group rsv. rsv rna signal expressed weaker in the lmwh-treated groups than in group rsv. conclusion: rsv damages hs on gbm by electrostatic interaction. lmwh, as the analog of hs, charged with anion, competes with hs to combine with rsv to keep gbm from being destroyed, and then reduce the proteinuria. s. zhai, zh. wang west china second university hospital, sichuan university, department of pediatrics, chengdu, people's republic of china objective: the study is to explore the relevance among gags, hpa and ela in the steroid responsive nephrotic syndrome (srns). methods: (1) 55 children with srns were selected, including the active (n=20), the convalescent (n=20), the remissive (n=15). 19 purpuric nephritis and 15 healthy children were served as the control.(2) using the improved whiteman process detected the urinary gags. ela activities in plasma were determined by the amount of 4-nitroaniline released per unit time. immunocytochemistry and image analysis method were used to detect the expression of hpa of peripheral blood leukocyte. results: 1. gags of the active were the highest (4.1051±1.1722) of all (p<0.001). in contrast with the healthy, the active and the convalescent (2.5666±0.6826, p<0.001) were significant difference, but the remissive no difference (1.6588±0.3103, p>0.05). 2. all of ns showed higher level of hpa than the healthy (p<0.05). comparing with the healthy, hpa was significant difference both in the active (iod 54786.2137±28714.0671, p<0.001) and in the convalescent (iod 15708.6270±4036.2843, p<0.001),but no difference in the remissive (iod 4181.0056±878.3909, p>0.05). by contrasting the active and the purpuric, their difference of hpa was no statistic significance (p>0.05). 3. all of ns showed higher levers of ela than the healthy (p<0.05). the healthy was strikingly different, contrasting with the active (77.4304±17.6366) and the convalescent (53.6803±7.4168, p<0.001), but no difference with the remissive (38.6552±9.1556, p>0.05). 4.there was a significant correlation among the urinary protein, urinary gags, hpa and ela with simple linear regression analysis. conclusion: in the srns, proteinuria may be resulted by the spallation of hpa and ela for gags on gbm. (4), combination withhaematuria, hypertension and/or renal insufficiency (23), extrarenalsymptoms (6), and familial mediterranean fever (fmf, 40) . of the 85 non-nephrotic patients, 26 had extrarenal symptoms, 15 were nephritic,9 had rapidly progressive glomerulonephritis (gn), 6 renal failure and 29 isolated urinary abnormalities. biopsy samples were evaluated by light microscopy in yerevan and zurich and by electron microscopy (except for amyloidosis) and immunohistochemistry (last 28) in zurich. results: the most common histological lesion was renal amyloidosis (25%), followed by focal segmental glomerulosclerosis (fsgs, 9%), lupus nephritis (8%),systemic vasculitis/hus and minimal change disease (mc, 7.5% each),mesangioproliferative gn/iga-nephropathy and membranous nephropathy(mn, 7% each), hereditary nephritis and membrano-proliferative gn typei (6% each), acute postinfectious gn (apgn, 4%), and dense deposit disease (ddd, 3%). the miscellaneous group includes,apart from interstitial nephritis (1%), unclassified or inadequate biopsies and specimens with mostly sclerosed glomeruli(9%). the majority of patients with amyloidosis of fmf, fsgs/mc andmn were nephrotic, but 18% of patients with amyloidosis had non-nephrotic proteinuria. conclusions: several glomerular lesions were considerably more frequent than in other studies, particularly amyloidosis of fmf, mn and lupus nephritis, and to lesser extent membranoproliferative gn type 1 and ddd. apgn is underrepresented because less than 1% of all patients (>700) had a biopsy. this study would not have been possible without international collaboration. henoch-schönlein purpura in children: an epidemiological study amongst dutch pediatricians on incidence and diagnostic criteria j. aalberse 1,2 , k. dolman 2 , g. ramnath 3 , r. rodrigues pereira 4 , j-c. davin the aim of the present study on the incidence of henoch-schönlein purpura (hsp) in dutch children is not only to give some insight in the epidemiology of hsp in the netherlands but also to record the diagnostic criteria used by dutch pediatricians and to evaluate the accuracy of the latter using the presence of iga in the skin when biopsies are available. methods: in 2004, all dutch pediatricians received monthly a card asking to mention new diagnosed hsp. pediatricians reporting one or more new patients with hsp were sent a list of questions concerning symptoms, blood and urine parameters, skin biopsy, diagnostic criteria and follow-up duration needed. results: two hundred and thirty-two patients from 0-18 of age (6.1/10 5 ) were reported as having started hsp in 2004. twenty nine % presented with renal symptoms. in accordance with the classification criteria of the american collegeof rheumatology (acr), eighty percent of pediatricians consider that isolated purpura (without hematological abnormalities) is sufficient to allow the diagnosis of hsp in children. from the 17 skin biopsies performed, only 9 (53%) presented with iga deposits. the follow-up duration considered as necessary was longer in case of renal symptoms at presentation. however, 45% of patients without renal symptoms would be followed for more than one year. conclusion: considering the recent (2006) eular/pres endorsed consensus criteria for the classification of childhood vasculitides, hsp should have been diagnosed in only 160 of the 179 patients of our study. the use of isolated non-thrombocytopenic purpura as only criterian to diagnose hsp in children might therefore lead to over diagnosis and unnecessary follow-up. noteworthy, the eular/pres criteria remain to be validated by a prospective study. the clinical presentation and response to therapy of childhood pan in johannesburg, south africa. method: retrospective record review of twelve children with a clinical diagnosis of pan treated between 1993 and 2005. results: there was unequal number of males and females; average age at presentation was 6.8±0.83-13.9 years, all were black children. eight children had more than 3 acr criteria and 11 sufficient clinical criteria (eular/pres consensus criteria). musculoskeletal and cardiac diseases were the commonest finding at presentation (75%), cutaneous, hypertension (58%), renal and gastrointestinal disease (50%), central nervous system disease (42%) and constitutional features (33%). two children had bone involvementwith periosteal reactions on plain x-ray. angiographic abnormalities were found in 8 (67%), and 9 (75%) had positive histology (skin/renal biopsies). tuberculosis was diagnosed in 6 (50%), and 6 had positive streptococcal titers. all patients were ana and hepatitis b negative, but there were five patients anca positive (2=p-anca, 2=c-anca, 1=both) (42%). the crp was elevated in 8/12 (67%), esr also in 8/12, while 58% had both elevated. all patients received oral glucocorticoids, 6 methylprednisolone (1-3 pulses-500 mg/m 2 ), 7 ivi cyclophosphamide (1-6 pulses, 500 mg/m 2 ), 10 oral azathioprine, and 1 required i. conclusions: children with pan in johannesburg present at a younger age with multi-organ disease. they require aggressive therapy with both glucocorticoids and cytotoxic therapy to ensure good outcomes. objective of the study: in order to evaluate the predictive factors of chronic kidney disease (ckd), the records of 47 children with biopsy-proven mesangioproliferative nephrotic syndrome (mpns) admitted between 1972 and 2005 were retrospectively reviewed. methods: renal survival was analyzed by the kaplan-meier method and cox's regression model. two multivariate models were developed: (1) from the onset of symptoms to the occurrence of ckd and (2) from the time of renal biopsy to ckd. the following data were obtained at admission an dat the time of renal biopsy: gender, race, age at the onset ofnephrotic syndrome symptoms, age at admission, blood pressure, laboratory data (serum creatinine, serum urea, glomerular filtration rate, 24-hr urinary protein excretion, hematuria). patients were classified according to the response to the initial course of prednisone: (1) a complete response was defined as a proteinuria <0.3g/day; (2) a partial response was defined as urinary protein excretion of <1 g/day and >0.3g/day, and (3) no response was defined as urinary protein excretion of >1 g/day. results: median follow-up time was 8 years (iq range, 3.9±13.7) and 12 patients (26%) progressed to ckd. at baseline, after adjustment 2 variables remained as independent predictors of ckd: creatinine >1.0 mg/dl (rr=3.8, ci 95%=1.01±11.3) and non-response to steroids (rr=10.7, ci 95%=2.2±51.2). at the time of renal biopsy, after adjustment 2 variables remained as independent predictors of ckd: age>7.5 yr (rr=3.8, ci 95%=1.0±14.3) and creatinine >1.2 mg/dl (rr=3.3, ci 95%=0.97±11.2). conclusion: serum renal function at baseline and initial response to prednisone were strong predictors of progression to ckd in our cohort of children with mesangioproliferative nephrotic syndrome. methods: an illustrative case history of a boy with sle and vhd in the absence of antiphospholipid antibodies was described. results: a 14-year-old boy with a history of sle for about five years was admitted to our hospital due to intermitted arthralgia, facial erythema, increased serum creatinine and oliguresis in october 2006. he had been treated irregularly with prednisone and immunosuppressants. however,the disease was not always controlled well. during thishospitalization, the problems of hypertension, renal failure and anemia had been resolved and maintained, but the problem of intolerance to increased circulation volume was obvious, and three times echocardiography (ecc) showed moderate to severe mitral valve insufficiency. reviewed his history, suspected mitral leaflets vegetations was revealed by ecc four months after onset, he complained of chest pain, chest distress and breathholding several times without causes since eighteen months after onset and manifested with heart failure once, and ecc showed moderate to severe mitral valve regurgitation four months ago and twenty days ago respectively. ruling out the possibility of infective endocarditis, rheumatic heart disease and congenital heart diseases, vhd were considered secondary to sle. since the vhd becomes hemodynamically significant, valve surgery is needed. conclusions: vhd is generally asymptomatic and omitted easily, so routine cardiac evaluation of children with sle using electrocardiography, echocardiography and chest x-ray is recommended to early detect and treat cardiac abnormalities, which may lead to better survival. objective: we have previously reported that deleted in esophageal cancer 1 (dec1), a potent tumour suppressor gene, was specifically upregulated in cd4+ cells of patients with relapse of mcns, using differential display rt-pcr. this study aimed to further characterize the potential function of dec1 in mcns. methods: semi-quantitative rt-pcr was used to verify the dec1 gene expression in children with relapse and remission of mcns. jurkat cells were transfected with plasmid containing dec1 gene or vector alone. gene expression was regulated by tet-on/off system. the effect of dec1 on jurkat cell proliferation was assessed by 3 h-thymidine incorporation. cell cycle analysis was performed following propidium iodide staining. protein localization was determined by immunofluorescent staining with anti-dec1 antibody. results: we confirmed that dec1 gene expression was significantly increased in 15 children with mcns in relapse (0.93±0.17), as compared to remission (0.44±0.13, p<0.002), 10 normal controls (0.59±0.06, p<0.01), 7 patient controls with viral infections (0.58±0.03, p<0.03) and 7 nephrotic patients with other forms of glomerulonephritis (0.48±0.10, p<0.03). in dec1-transfected jurkat cells, cell proliferation was inhibited by 47.2%, compared with vector control. cell cycle analysis indicated that dec1 arrested jurkat cell cycle progression by blocking its entry into the g2/m phase. immunofluorescent staining with anti-dec1 antibody suggested that dec1 was a cytoplasmic protein, which was in agreement with psort. conclusion: dec1 gene expression was significantly upregulated in children with relapse of mcns. our results showed that dec1 acts as a t-cell proliferation suppressor and arrests cell cycle progression, and thus may be important in mediating the number or function of cd4+ cells during relapse of mcns. objective of study: the aim of the study was to assess plasma and urine concentrations of vascular endothelial growth factor (vegf) in nephrotic syndrome children (ns) depending on the total dose of glucocorticoids (gc) and the percentage of lymphocytes with glucocorticoid receptor expression (cd3/gcr). methods: we examined 51 children (2-15 years) , allocated to three groups: group i: 13 children with the first ns onset, group ii: 13 children with ns relapse, group c: 25 healthy children. the ns patients were examined: a: before treatment and b: 4-5 weeks after prednisone administration at a dose of 60 mg/m 2 /24 h. plasma and urinary vegf levels were determined using the immunoenzymatic elisa method. flow cytometry was applied to assess cd3/gcr expression. results: higher plasma and urinary vegf concentrations were noted in ns children before treatment (a), as compared to control subjects (c). following prednisone therapy (b), vegf level was reduced but it was still higher than in the control group. positive correlation was observed between vegf and protein in the urine (group i r=0.660, p<0.05, group ii r=0.818, p<0.01) and a weak positive correlation between vegf in plasma and urine (group i r=0.531, p<0.05, group ii r=0.581, p<0.05). cd3/gcr expression was lower in group ii. in both groups, the correlation between plasma vegf and cd3/gcr was positive (p<0.05). conclusions: 1. plasma and urinary vegf levels increase during nephrotic syndrome onset. 2. glucocorticoid treatment reduces plasma and urinary vegf levels in ns children. objective of study: the aim of the work was to determine the expression of p-glycoprotein (p-gp) on peripherial lymphocytes (cd3) in children with steroid-dependent nephrotic syndrome (sdns) during cyclosporine a (cya) and ace-inhibitor (ace-i) treatment. methods: the study group (i) consisted of 20 children with sdns aged 5-18 years, with a subsequent proteinuria relapse at the time of prednisone dose reduction. all ns children were examined three times: a: at proteinuria relapse, before cya treatment, b: after 3 months, c: after 12 months of cya administration. control group (ii) consisted of 20 healthy children. cd3/p-gp was measured using a flow cytometry assay. serum cya level was assessed by means of the immunofluorescence method. results: the expression of cd3/p-gp in ns relapse, prior to cya+ace-i administration was much higher (median 9.15%, range 1.50-13.50%) when compared to healthy controls (1.20% range 0.30-5.70%). the absolute number of cd3/p-gp in this examination was almost 5 times higher when compare to healthy controls (p<0.01). after 3 months of cya+ace-i therapy the expression of cd3/p-gp decreased dramatically and was similar to the controls. similar results were obtained after 12-months of treatment. when analysing the correlation between cd3/p-gp and serum cya concentration a strong negative correlation was found in both examinations. the correlation was stronger in group ib (during the treatment with higher cya doses): (r=-0.624, p<0.01) than in ic (after reduction the cya dose: (r=-0.464, p<0.01) conclusions: the results of our studies indicate that cya in sdns inhibits the expression of p-gp. cya is an alternative therapy that may lead to optimization of glucocorticoid doses, thus reducing the risk that goes along with treatment. backround: hemolytic uremic syndrome is considered as the main cause of acute renal failure in childhood. it is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. the epidemiology of the disease varies between counties. aim of the study: to describe demographic and epidemiologic aspects of hus, presented in a 25 years period at the biggest children's hospital in the country. material-methods: 27 patients aged 11 days -12 years, mean age 4.8 years, (20 boys, 7 girls) were diagnosed with the syndrome. of them 5, 18.5%, presented as d+ cases, 11 with preceeded respiratory system symptoms and 11 with no preceeded symptoms. treatment consisted of fresh frozen plasma (ffp) and whole blood transfusions in all cases. peritoneal dialysis was necessary in 7 cases, haemodialysis in 2, while plasmapheresis was performed in 3 cases. three children, all boys, suffered from recurrent type of syndrome. a girl required treatment with peritoneal dialysis for 4 months followed by recovery of renal function. one-five years follow-up: one baby 8 months old died, 4 children received renal transplantation, in 5 renal function remained mildly reduced (gfr 50-80 ml/min/1.73 m 2 ) and 6 suffered of hypertension. the rest 11 recovered fully. summary: hus represents a rather minor public health problem with low mortality rate in greece. methods: three children with pauci-immune ln were retrospectively reviewed. results: the reported cases fulfilled the american rheumatism association criteria for sle. at admission, all had a 1-month history of glomerulopathy without intensive therapy. case 1 presented with nephrotic proteinuria, macroscopic hematuria and progressively deterioration of renal function. laboratory data included a positive antineutrophil cytoplasmic antibodies (anca) on myeloperoxidase immunoassay. she was positive for lupus anticoagulant (la) but negative for anti-cardiolipin (acl) and anti-beta-2 glycoprotein i (β 2 gpi) antibody. renal biopsy showed pauciimmune necrotizing and crescentic ln. case 2 manifested with proteinuria, microhematuria and hypertension. anca was negative. case 3 had nephrotic proteinuria, microhematuria and hypertension. the case had positive la, acl and anti-β 2 gpi antibody. anca was negative. the biopsy findings of both case 2 and case 3 indicated pauci-immune mesangial proliferative ln. electronic microscopy revealed segmental and diffuse foot process effacement respectively. all three ln remitted following the treatment of steroid and immunosuppressive agents. conclusions: these atypical ln were considered to be associated with the distinct pathogenesis, rather than immune complex-mediated glomerular injuries. we supposed the possibility of ancaassociated necrotizing and crescentic glomerulonephritis for the first case. for the others, primary or secondary podocytes lesions might alter the glomerular permeability. the nephrotic syndrome is a clinical picture that characterized by proteinuria, hypoproteinemia, oedema and hyperlipidemia. although the primer nephrotic syndrome is the most common type of nephrosis in children, it may also develop during the course of infections including hepatitis b and c virus infections, whereas hepatitis a virus infection related nephrotic sendrome is very rare in children. in this paper, we present a case of who had suspected diagnosis hepatitis a virus infection related nephrotic syndrome. the boy at the age of 3 years was referred to our hospital due to vomiting, abdominal distension and oliguria. physical examinations were revealed palpebral and tibial oedema, hepatomegaly, decreased breath sounds and mat percussion on right hemithorax. icter were not detected. laboratory examination were showed proteinuria, hyperlipidemia, hypoalbuminemia, high alt and ast levels with normal levels of bilirubin, alkaline phosphatase, complement c3/c4, urea and creatinine. in viral serologic examinations, hepatitis b and c related antibody were found negative, but anti-hav igm was found positive. chest radiography and ultrasonography examination were revealed right pleural effusion and abdominal ultrasonography examination was revealed ascites. based on these findings, we thought that the nephrotic syndrome could be developed due to anicteric hepatitis a virus infection in our patient. low dose steroid treatment was started (prednisolon 1 mg/kg/day, 1 month). edema was improved, negative urine protein was seen, and liver functions were not deteriorated during this therapy in our patient. hepatitis a virus may be cause of nephrotic syndrome by forming of immune-complexes. in conclusion, although hepatitis a virus infection is rare cause of nephrotic syndrome in children, it should be investigated as a seconder casuse. membranoproliferative glomerulonephritis (mpgn) is a rare, chronic glomerulonephritis, and its prognostic factors and outcome are not known very well in childhood. in this retrospective study, we reviewed the clinical, laboratory and histopathological features of children with primary mpgn. thirty-three children (18 boys, 15 girls) presented at a mean age of 11.0 years (range 2-16 years). they were followed for a median of 44 months (range 12-92 months). the clinical presentation in children was nephritic-nephrotic syndrome in 15 children (45.5%), nephritic syndrome in 14 (42.4%) and nephrotic syndrome in 4 (12.1%). nine patients had renal failure at presentation. at the end of study, 25 patients (75.8%) had complete remission and 8 patients had abnormal findings (4 proteinuria, 2 microscopic hematuria, 1 hypertension, 1 esrd). all of patients were treated with steroid. eight patients were given another immunosuppressant drug (cyclophosphamide 7, azathioprine 1) in addition to steroid therapy. the interval between appearance of symptoms and admission, durations of microscopic hematuria and proteinuria, and systolic blood pressure at presentation were higher in children with abnormal findings when compared with children with complete remission. there were no significant differences in clinical presentation type or histopathological features between children with abnormal findings and children with complete remission. our results showed that delayed detection and treatment, uncontrolled hypertension and unresponsiveness to steroid in early period were poor prognosis predictors. we did not determine any correlation between histopathological findings and outcome. we need further investigations including larger patient population. partial lipodystrophy (pl) is a rare condition of unknown etiology, with childhood onset. it is characterized by progressive loss of subcutaneous fat of face, neck, trunk and upper extremities together with c3 hypocomplementemia. usually, patients do not have clinically evident renal disease or abnormalities until they have had the disease for 8 or more years. but, the case we reported here, firstly presented with membranoproliferative glomerulonephritis (mpgn), and during follow-up pl was observed. a six years old girl was presented with sore throat, vomiting and loss of appetite for the last fifteen days. her development was normal and the child was asymptomatic till 6 years of age. the parents were relatives of the third degree. there was no history of similar cases in the family. the physical examination of the patient was normal. urinalysis revealed hematuria and pyuria. proteinuria was not present. renal function tests were normal. laboratory examination revealed low serum complement c3 but normal serum c4. the lipid profile was also normal. patient was followed with the diagnosis of poststreptococcic glomerulonephritis. because of persistent low complement c3 and nephrotic range proteinuria renal biopsy was performed at the 3 rd month of follow-up. renal histology revealed mpgn consistent with type 2. c3 nephritic factor was negative. at the same time it was observed that the face took on a cadaverous look with prominent malar bones, chin and zygoma because of the loss of buccal fat. according to these findings, partial form of lipodistrophy, which is frequently associated with mpgn, was considered in the patient. during two years of follow-up she had two recurrences of nephrotic range proteinuria and she is now in remission with prednisolone therapy. as far as we know this is the first example of pl which is developed during follow-up of mpgn. central nervous system abnormalities in children with acute post-streptococcal glomerulonephritis (apsgn) are rare and are considered to be secondary to acute severe hypertension, electrolyte imbalances and uraemia. cerebral vasculitis associated with acute post-streptococcal glomerulonephritis has been rarely reported in pediatric literature. a 13-year-old girl with a severe headache, vomiting, edema and macroscopic heamaturia is presented. she had history of upper respiratory infection before two weeks. so, the patient was diagnosed as apsgn. on admission, she was normotensive and biocemically well balanced. two hour later, she experienced a grand mal seizure. mri examination of brain showed not only multiple areas of increased density in white and gray matter, and cerebellum but also subarachnoid bleeding, consistent with vasculitis. during follow-up, abducens nerve palsy was detected. histopathological features on renal biopsy specimen, an elevated antistreptolysin level and fallen c3 complement level were compatible with apsgn. all clinical and laboratory abnormalities improved with steroid therapy (pulse and oral methylprednisolon). in conclusion, children with apsgn may present central nervous system abnormalities without hypertension, uraemia and electrolyte disturbances. results: hsp was diagnosed in 105 patients, median age 6 years old. all had the skin manifestations, 49.5% abdominal pain and 41% arthritis. 45 patients developed hsp nephritis (42.9%), mean presentation time was 4.5 months after phs diagnosis. renal biopsy was performed in 14 patients, and the most common histopathological finding was hsp nephritis grade iii a. age of onset older than 10 years was statistically significant for nephritis development (chi square < 0.05). chronic renal insufficiency incidence was 0.95%. conclusions: the main complication of hsp is nephritis. follow-up should include evaluation by a pediatric nephrologist. age of onset older than 10 years is an important risk factor for hsp nephritis. objectives of study: acquired abnormalities of coagulation and fibrinolysis in nephrotic syndrome have been implicated in the pathogenesis of deep vein and arterial thrombosis. resistance to activated protein c due to amutation in the gene for factor v, the commonest inherited risk factor for venous thrombosis, could contribute to risk of both arterial and deep vein in patients with nephrotic syndrome. we report an arterial thrombosis in a young girl with idiopathic membranousglomerulonephritis (mgn) and factor v leiden mutation. case report: a 14 year-old girl was admitted to our hospital with swelling of both legs and cyanosis of her toes. her mother had history of abortion in the second trimester of gestation, and parents were second-degree relatives. physical examination showed peripheral edema in both extremities and peripheral cyanosis in toes. laboratory study showed the nephrotic range proteinuria. serum albumin was 2.2 g/dl, and cholesterol was 380 mg/dl. creatinine, electrolytes, prothrombin/partial-thromboplastin times, c 3 , c 4, fibrinogen, protein s, c, antithrombin iii and homosistein levels were within normal limits. ana, anti-dsdna, p-anca, and c-anca, antiphospholipid igg/igm, anticardiolipin igg/igm were all negative. genetic study showed the heterozygote mutation of factor v leiden (fv/g1691a). in arteriography, there was complete occlusion on the posterior tibiaartery of left leg, occlusion of mid portion of right femoral artery and the posterior tibia artery of right leg. renal biopsy findings werefelt to be compatible with mgn. conclusions: we postulate that patients with concurrent nephrotic syndrome and factor v leiden mutation may have an increased risk of thrombosis. screening for factor v leiden mutation may be indicated in patients with idiopathic nephrotic syndrome. introduction: hus (d+) is the 2nd cause of chronic renal failure (crf) in children in argentina. proteinuria is the main predictor of progression to crf. patients with renal failure, when treated with restricted proteinin take show slower progression to end-stage of rcf. proteinuria appeared in patients with hus sequelae subject to an overload of protein intake. objective: to evaluate the effect of a controlled protein intake on proteinuria in patients with renal disease due to hus and normal renal function (>80 ml/min/1.73 m 2 ). patients and methods: within a multicenter, randomized, double blind, controlled trial, carried out inorder to study the effect of iace on the development of renal disease*, proteinuria before and after a controlled diet was measured in 102 patients with proteinuria due to hus and normal renal function. protein intake was indicated according to rda for age. protein intake was estimated with a questionnaire on former 72 hours, and with 24 hrs urea excretion. proteinuria was measured in 24 hours urine collection at the beginning of the study and at 15, 30 and 60 days after onset of the study. results: median age at onset was 16.5 months (r: 7.0-85.0); mean of length of follow-up after hus onset was 48.0 months (r: 4.0-155). in sixty five (63,7%) patients, proteinuria reduced to normal values; in the remaining 37 (36,3%) there was no change. median of initial and final proteinuria in the 65 children whose proteinuria became normalised, was 9.83 mg/k/day (ds 3.71) and 2.44 (ds1.34) respectively <0.0005. conclusion: controlled protein diet (rda) normalizes proteinuria in patients with significant proteinuria secondary to hus and normal renalfunction. * a trial financed by roemmers laboratory, argentina. differential diagnosis of hematuria is the significant task of any nephrologist while most common reasons for hematuria demand histopathological diagnosis. iga-nephropathy is the progressive glomerular disease which is known to be a common reason for hematuria. the diagnosis ofiganephropathy is often missed because of variability of clinical presentations, long-term asymptomatic course and therefore waiting tactics in prescribing renal biopsy. the aim of the study was to evaluate the incidence of iga-nephropathy and to define its characteristic clinical and morphological features in children in belarus. we present results of immunohistochemical staining for iga mesangial deposition of 65 kidney biopsy preparations. the mean age of the patients enrolled in the study was 11,77±0,66 years. at the moment of biopsy patients clinically presented isolated hematuria (36%), hematuria with proteinuria (29%), nephrotic syndrom (12%), nephrotic syndrom with hematuria and hypertension (5%), isolated proteinuria (5%) and others in less than 2% each. iga mesangial deposition was detected using immuno histochemical staining with polyclonal rabbit anti-human iga. we found diffuse mesangial deposition of iga in 18 patients (28% of all). two of them had nonnephrotic isolated proteinuria, one nephrotic syndrom. vast majority of patients were hematuric (either isolated or combined with proteinuria). iga nephropathy incidence among hematuric patients was 38%. in histopathological examination we found mild segmental mesangial hypercellularity in 14 patients, mild to moderate global and segmental mesangial proliferation in 3 (in two of this patients we also found cellular and fibrous crescents in less than 30% glomeruli). one patient had focal-segmental glomerulosclerosis secondary to diffuse mesangial proliferative glomerulonephritis and clinically presented heavy proteinuria. we analyzed nphs2 mutations in chilean pediatric patients with srns due to fsgs, diffuse mesangial sclerosis (dms) and minimal change disease (mcd). nphs2 mutation analysis was performed in 31 patients (sporadic cases n=27, familial cases n=4). nphs2 exons 5 and 7 were amplified by pcr and subjected to automatic sequencing or enzyme restriction analysis using clai (c.686g>a) and hin6i (c.851c>t) respectively. patients median age at disease onset was 24 months (range , 55% of which were male. histological diagnosis were fsgs (n=26), dms (n=2) and mcd (n=3). ten of 31 patients (32.3%) had mutations in nphs2 (9/26 fsgs, 0/2 dms, 1/3 mcd). eight of 10 patients bearing mutations were sporadic cases. seven patients were compound heterozygous for r229q and a284v. patients with mutations were significantly older than those without mutations (median age 24 versus 84 months, p<0.01). resistance to cyclosporin was observed in 6 of 7 cases with mutations and 11 of 18 cases without mutations (ns). we studied the frequency of r229q and a284v in 60 healthy volunteers with similar ethnic background. only one control individual was heterozygous for r229q. no a284v mutation was detected. our study demonstrated that nphs2 mutations are a major cause of srns in chilean pediatric patients. since most of the srns patients bearing nphs2 mutations were cyclosporin resistant, it is advisable to perform nphs2 mutation screening before starting immunosuppressives. in this study we aimed to investigate the long-term prognosis of henoch-schönlein nephritis (hsn) in childhood. between 1991 and 2003, 156 patients with hsn were investigated retrospectively. there were 86 males and 70 females with a mean age of 9.6 years. they were graded according to the degree of renal involvement. grade 1: isolated microscopic hematuria (n: 31); grade 2: hematuria and mild proteinuria (n: 60); grade 3: acute nephritic syndrome (n: 4); grade 4: nephrotic syndrome/hematuria (n: 18); grade 5: acute nephritic and nephrotic syndrome (n: 43). renal biopsy was performed on 43 patients in grade 4 and 5. twenty patients had extensive crescent formation (>50%) on renal biopsy, and were given triple therapy [iv pulse methylprednisolone (mpz) 30 mg/kg/d for 3 days, followed by oral prednisolone (op), oral cyclophosphamide-2mg/kg/day for 2-3 months and dipyridamole]. the other 23 patients with <50% crescent formation were given mpz followed by op and dipyridamole. the patients in grade 3 and 4 were given op and dipyridamole. grade 1 and 2 were not given any immunosupressive agent. during the follow-up period (mean 30±3.5; range 12-96 months), 23 patients in grade 1, 38 patients in grade 2, 2 patients in grade 3, 8 patients in grade 4 and 21 patients in grade 5 showed complete remission (59%). of the 5 patients with extensive fibrosis on renal biopsy, 2 had persistent nephropathy (1%) and 3 developed endstage renal failure (2%). the remaining 59 patients showed near-complete recovery with minimal urinary abnormalities (38%). in conclusion, although initial presentation of renal involvement determines the prognosis in hsn, intensive treatment with triple therapy appears to be effective in severe renal disease especially if started before the development of fibrotic changes in crescents and tubulointerstitial tissue. aim: the bacterial infection in nephrotic syndrome (ns) is still the big problem and is one of the leading death causes in ho chi minh city, vietnam. we did this study with aims to overview this complication in children with ns. methods: our study population consisted of 132 children with nephrotic syndrome during one-year prospective cohort. twenty seven out of 132 patients who developed severe bacterial infection including pneumonia, peritonitis, urinary tract infection, bacteremia or cellulitis were recorded. results: from june 2004 to june 2005, there were 132 children with nephrotic syndrome recruited to the study. the severe bacterial infection stood at 20.5% (n=27). in 27 these children, 14 children were first ns, 13 children were relapsing ns. the percentages of pneumonia, urinary tract infection, cellular infection and peritonitis were 12.9% (n=17), 4.5% (n=6), 3% (n=4) and 2.3% (n=3), respectively. no patients with bacteremia were recorded. in 6 patients with uti, e.coli wasin 3 patients, proteus in 2 and enterococus in 1. ns children with uti were asymptomatic. ns children with peritonitis had typically clinical manifestations of fever, abdominal pain, tenderness. one out of four patients with peritonitis cultured streptococcus pneumoniae inperitoneal fluid. some factors associated with severe bacterial infection were increase in weight (12.7 vs 9.4%, p=0.02), very low serum albumin (10.3 vs 13 g/l; p=0.003), rise in serum a 2 globulin level (39.5% vs 34.6%; p=0.005) and hyperfibrinogenemia (5.8 vs 5.3 g/l; p=0.02). conclusions: bacterial infection has still been a common problem in children with nsin ho chi minh vietnam. it is important to investigate and manage this complication early to reduce mortality rate. primary nephrotic syndrome (ns) is the most common glomerular disease in children which mainly responds to corticosteroids. however, >70% of children experience a relapse with recurrent episodes. the aim was investigation of outcome in ns patients, retrospectively. clinical, histological data and treatment responses of children presenting with ns from 1996 to 2006 were reviewed. all patients were treated with steroid treatment firstly and classified as steroid sensitive ns (ssns) and steroid resistant ns (srns) according to clinical or laboratory responses. there were 91 patients, 52 male and 39 female, had followed-up for 64.17±54.79 months. age at onset ranged from 9-186 (median 34) months. seven patients were admitted with hematuria and ns (5 mpgn, 2 mgn) that excluded from this study. 60 patients were treated by only classical steroid treatment. thus, 60 (71.4%) patients were ssns and classical steroid therapy was successful in this group.14 of all ssns patients were evaluated with biopsy (6 fsgs, 8 dmp) because of frequently recurrent ns. in srns group (24 patients) with one cytotoxic agent, complete and stable remission was induced in 13 patients (6 in fsgs, 5 in mlh, 2 in dmp) while 6 patients (6 in fsgs) who responded to more than one cytotoxic agents had partial remission with symptomatic relief. five children (5 in fsgs) were refractory to all cytotoxic therapies. cyclophosphamide (cp) was used as the first cytotoxic agent in 18 patients and induced complete remission in 11 (61.1%). the patients who relapsed following cp and patients who failed to respond were treated with further cytotoxic therapies such as cyclosporine a (cs) or mmf. in 6 patients, cs was used as the first cytotoxic agent and induced remission in 2 patients (33.3%). steroid must be the initial drug in childhood ns. cp could be used successfully as an immunosuppressive agent in srns patients. aim: annexin v has a molecular weight of 32-35 kda and has been reported to possess anticoagulant activity, inhibition of phospholipase a2, regulation of membrane transport, proliferation and signal transduction. it is reported that urinary annexin v concentration may be an indicator of apoptosis and acute renal injury related to the urinary protein level. the aim of this study is to define the role of urinary annexin v, serum annexin v concentrations as new prognostic tools and follow criteria in children with steroid sensitive and resistant ns. methods: annexin v concentrations were measured in serum and 24 hour urine samples in 23 steroid sensitive nephrotic syndrome (ns) patients in both relaps and remission periods (group 1 and 2 respectively) and in 22 steroid-resistant ns (group 3) and sex and age matched 22 healthy controls (group 4). total protein, albumin, cholesterol concentrations and 24 hour urinary excretion of protein and creatinine were measured in all groups. results: in steroid resistant ns group (group 3), median of urinary annexin v/creatinine ratio was significantly higher than all the other groups (5048.8 ng/g creatinine (min-max: 1272.5-40498.4) vs 2839.5 ng/g creatinine (min-max: 1131.0-15835.4) in group 1 (p: 0.06); 2500.0 ng/g creatinine (min-max: 1424.2-11055.6) in group 2 (p: 0.028), and 2018.3 ng/g creatinine (min-max: 1225.9-6887.4) in group 4 (p: 0.028)). serum annexin v concentration was significantly higher in group 3 (median 16.6 ng/ml) than in group 4 (median 8.2). no significant correlation was found between urinary protein excretion and urinary annexin v/creatinine ratio. conclusion: remarkably increased urinary annexin v/creatinine ratio could be used as a determinant factor in children with steroid resistant ns, and it may be a prognostic factor in these children. v. baudouin 1 , f. bernaudin 2 , a. garnier 1 , t. kwon 1 , m. peuchmaur 3 , g. deschenes 1 , c. loirat 1 1 hôpital robert debré-aphp, service de néphrologie pédiatrique, paris, france 2 chic, service de pédiatrie, créteil, france 3 cgvhd is the most common late complication of hsct. clinical manifestations mimic lupus disease but renal involvement is unusual. a 4 year-old boy underwent hsct from an hla-identical sibling donor for sickle cell disease. he received myeloablative therapy (cyclophosphamide, busulfan, antithymocyte globulin). prophylaxis of acute gvh consisted in prednisone and mmf until month 4. moderate skin and mucosa cgvh appeared at month 6 so that prednisone and mmf were restarted. at month 9 prednisone was stopped and mmf decreased to half dose. at 1 year, while clinical features of cgvh intensified, fortuitous diagnosis of ns was done. glomerular filtration rate and blood pressure were normal. biopsy showed membranous glomerulonephritis and mesangial hypercellularity. immunofluorescence confirmed granular immune deposits of igg and c3treatment consisted in prednisone (1.5 mg/kg/d for 1 month, progressively tapered to 0.5 mg/kg/e.o.d at month 4) and cyclosporine (5 mg/kg/d, trough levels 40-50 ng/ml). proteinuria decreased to <0.5g/l in 2 months. cyclosporine was progressively stopped between month 6 and 12 without relapse of proteinuria. ns associated with cgvhd had been reported in about 60 patients (5 patients <18 yr-old). retrospective studies estimate occurrence around 1% of patients with cgvhd. it was secondary to membranous glomerulonephritis in 67% of cases, minimal changes disease in 21%. strengthening of immunosuppression led to complete remission in 90% of patients with minimal changes disease and 27% of those with membranous glomerulonephritis (60% partial remission). usual treatment consisted in prednisone (87%) and cyclosporine (51%). this manifestation of cgvhd is probably underestimated and can occur at the same time or later than other clinical features. early detection of proteinuria in patients with cgvhd is recommended to adapt immunosuppressive treatment. objectives: to see if cyclosporine a (csa) is safe and effective in reducing proteinuria in children with the iga nephropathy (igan) or the henoch-schoenlein purpura nephritis (hspn). methods: the biopsy proven 34 patients (19 with igan, 15 with hspn) who showed increased proteinuria (>1+) for longer than 4 months were included. the blood level of csa, serum chemistries, urine analysis and complete blood cell counts were carried out every other month along with the physical exams. results: csa was given at an amount of 4.41.0 mg/kg/day for 10.13.3 months in average. complete remission of proteinuria in 27 (79.4%) and partial remission in 2 (5.9%) were achieved by csa treatment. five (14.7%) non-responders were discontinued for csa treatment in the middle of the trial. the ration of urine protein to creatinine was initially 3.95.0 and reduced gradually with time to 0.81.6, 0.30.7, 0.50.9 at 4, 8, 12 months after csa treatment, respectively. twenty eight patients showed hypertrichosis, three experienced transient elevation of serum creatinine, and two complained difficulties in taking the medication due to severe nausea. for 28.3 months after completion of the csa treatment, 9 patients redeveloped proteinuria and had to receive the 2 nd csa trial. no clear difference was observed in the pharmacokinetic profiles of csa attributable to the non-response or recurrence. follow-up renal biopsies were carried out in 11 patients after completion of the csa therapy and no csa toxicity was found. there was no alteration of linear growth pattern. conclusions: this study has a limitation of lacking the control group but the csa treatment is assumed to be very effective and a safe method to attain the remission of proteinuria in pediatric patients with the igan or hspn. j. madrigal 1 , e. fernandez 2 , p. noguera 2 , p. carranza 3 1 the aim of this retrospective study was : 1) to correlate the histopathological diagnosis with steroid response,persistent hematuria, hypertension and or abnormal renal function tests (gfr) 2) to evaluate the response of the patients with srns and sdns to the oral cytotoxic drugs , in a period of 10 consecutive years. 3) to correlate the response of this group of patients to the oral cytotoxic drugs with their histopathological diagnosis 4) to observe the incidence of fsgs in costarrican children during a period of 10 years. 5) based on these observations, reevaluate the indications of the kidney biopsy in our patients . we reviewed all the clinical records of patients with the diagnosis of ns and in whom a kidney biopsy have been done. patients with incomplete data were excluded. two consecutive reviews were made: the first included all patients diagnosed between january 1993 and december 1997 (group a) and the second, between january 1998 and december 2002 (group b). a total of 81 medical records were analyzed; 20 patients were excluded, and the remaining 61 were studied. results: all patients had been referred for edema or new onset nephrotic syndrome before treatment had been initiated. in our patients the steroid response was also the most important factor to predict the histological diagnosis and the response to the treatment with cytotoxics. the presence of hematuria and abnormal serum creatinine at the time of diagnosis were a predictive factor for the steroid response but not for the histological diagnosis. arterial hypertension achieved statistical significance only between mcns and fsgs but it was useful as a predictive factor for the hystological. in our group of patients with srns treated with cytotoxics, 55.5% with mcns responded, versus 37.8% of the patients with dmgn p<0,05. a. guersoni, v. mello, v. benini, s. laranjo children with srns are exposed to prolonged and high doses of steroid therapy and other immunosupressants that can lead to a variety of serious side effects. these include statural growth impairment, obesity, osteoporosis, cataract, hypertricosis and psychological disturbances.we carried out a prospective single-center study to evaluate the efficacy of mycophenolate in 20 children with steroid-resistant disease, 7 female and 13 male, aged 11.5±4.2 years. histological findings were: minimal change disease (mcd) in 8 children, focal segmental glomerulosclerosis (fsgs) in 11 and membranous nephropathy in one. all patients had been treated with at least one course of cyclophosphamide, metil-prednisolone in 15, while 13 had also been treated with cyclosporine before mmf. the initial dose of mmf was 600 mg/m 2 per day, together with a minimal reduction dose of corticosteroids associated with angiotensin ii receptor blockers (arbs) and sinvastatin.three patients went into complete remission, 15 into partial remission and 2 showed no remission. partial remission was described as loss of edema and improvement in symptoms, despite persistence of significant but improved proteinuria, that was classified either as moderate or low proteinuria according to the level. side effects were: diarrhea (n=1), neutropenia (n=2), infectious disease (n=1). mmf is an important new therapeutic option when associated with angiotensin ii receptor blockers (arbs) and sinvastatin for srns with mcd or fsgs, providing improvement in edema and symptoms despite persistence of proteinuria, with no compromise of physical appearance or risk of nephrotoxicity. background: primary focal segmental glomerulosclerosis (fsgs) that is resistant to steroids and other immunosuppressive agents has a guarded long-term prognosis. patients who fail to respond to current treatment may benefit from therapies that inhibit renal fibrosis and retard progressive loss of kidney function. objective: the font study (novel therapies in resistant fsgs) is a phase i clinical trial designed to test the safety, tolerability, and pharmacokinetics (pk) of novel agents that reduce renal fibrosis in patients with resistant fsgs. methods: patients, age 2-40 yr and egfr >40 ml/min/1.73 m 2 , with resistant fsgs who fail treatment in the nih supported trial evaluating cyclosporine vs. dexamethasone plus mycophenolate mofetil or who are screen failures due to prior exposure to these drugs are eligible. patients are assigned to receive rosiglitazone 3 mg/m 2 per day po or adalimumab 24 mg/m 2 every other wk sc. the treatment phase is 16 wk and patients undergo an initial (wk 0) and steady state (wk 16) pk assessment. results: 24 patients have been screened and 16 have been randomized 8 to each test therapy. 6 patients have completed rosiglitazone therapy and 2 have completed adalimumab. four serious adverse events have occurred in patients receiving rosiglitazone, none related to the study drug. fatigue (37%), gastrointestinal complaints (37%), and headache (25%) were the most common adverse events in patients given rosiglitazone. the outcomes in the adalimumab group have not been analyzed. conclusion: these preliminary results indicate the feasibility of performing phase i assessments of novel agents that can target renal fibrosis in patients with resistant fsgs. the findings will be used to design phase ii randomized clinical trials in this cohort of patients at high risk of progression to end stage renal disease. supported by grant niddk r2170341. object: to study the effect of fty720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats. methods: 24 rat were divided into sham-operation group, glomerulosclerosis model group and fty720 treated glomerulosclerosis group, 8 rats in each groups. the rats in later two groups were subjected to 5/6 nephrectomy. after operation, the treat group was fed with fty720 for 12 weeks. the expression of collagen, fibronectin, and cycline, p21, p27 were determined by immunohistochemistry methods. results: after treatment with fty720, up began to decrease from 4w after operation, significantly lower than in model group (p<0.01). the model group showed higher level of scr from 8w, which was much higher than in control group (p<0.05). in fty720 treated group, scr level were much lower than in model group. fty720 could obviously inhibit the expressionof col-and fn in glomeruli and attenuate the extent of glomerulosclerosis. moreover, fty720 could upregulate glomerular expression of p21 and downregulate glomerular expression of p27 and cycline. the expression levels of p21 and cycline were significantly lower in treatment group than in model group (p<0.05), but still higher than in control group (p<0.05). p27 expression in glomeruli was stronger in treatment group than in model group (p<0.05), and lower than in normal group but without significant statistic difference. conclusion: fty720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotal nephrectomized rats. this protective effect is presumed to be associated with its role in downregulation of cycline expression and upregulation of p27 expression in glomerular cells, and inhibition of extracellular matrix accumulation in glomeruli. the authors illustrate severe side effect of steroid therapy ulcerative gastroduodenitis-and rare complication (multiple cerebral thrombo-embolism) in the case of a 10 year old girl with steroid resistent nephrosis. in childhood occurence of thrombosis in steroid sensitive nephrosis syndrome is 1.5%, while it comes up to 3.8% in steroid resistant cases. on admittance she presented the classic symptoms of nephrotic syndrome. one month after the initiation of steroid therapy haematemesis, melaena occurred, and after appropriate therapy was cured. due to the progression of the nephrotic syndrome, steroid shot and later immunesuppressive therapy was started. eight weeks after onset she became unconscious for a shortwhile and had a transient episode of right hemiparesis. at the same time ct and mri disclosed bilateral parieto occipital ischemic territorial vascluar lesions, with relative sparing of the cortical ribbbon. following icu observation her state rapidly improved and after a two week period she became free of symptoms. renal biopsy disclosed the pattern of minimal change nephrosis with diffuse mesangial hypercellularity and a slight amount of igm positivity. immunological evaluation-with the capacitiy to reveal systemic immunological diseases remained negative. having been put on an evidence based protocol the patient's present nephrological state was unremarkable, with proteinuria less then 1g/day. in the present work the authors discuss the factors predisposing to thrombo-embolism with special emphasis on the possible preventive measures and therapy. igg autoantibodies to c1q (antic1q) have been reported to play a pathogenic role in immunecomplex mediated diseases (sle, apsgn, membranoproliferative gn, etc). the occurrence of antic1q in adult patients with sle has been shown to correlate with disease activity and some immunological parameters (hypocomplementemia, anti-dsdna) and may be useful in the early diagnosis of lupus nephritis (ln) or even as a predictor of renal flares. the presence of antic1q in children with apsgn was associated with more severe disease manifestations and a lack of spontaneous recovery. associations between antic1q, c4 and c3 complement levels and disease manifestations in 129 children with gn were investigated and compared with healthy controls. antic1q were measured by elisa and c3 and c4 by immunoturbidimetry, respectively. 29 of 129 patients with gn were positive for antic1q compared to 0/40 healthy controls. antic1q were associated with active ln and hypocomplementemia: 10/15 patients with sle were found to be antic1q-positive. nine of these 10 had active renal disease at the time of blood sampling compared to 1/5 being antic1q-negative. 7/10 antic1q-positive patients had low c3 level and 4/10 had low c4 level. in children with apsgn, 13/38 were positive for antic1q. antic1q positive patients had significantly higher proteinuria, more often hypertension and c3-hypocomplementemia. all 5 patients in which apsgn did not resolve spontaneously were antic1q-positive. antic1q were associated with active nephritis and hypocomplementemia in patients with sle. in children with apsgn antic1q-positive patients have more severe disease and stronger c3-hypocomplementemia then those being antic1q-negative. m. zahrane 1 , l. fawaz 2 , l. nesseim 3 1 cairo university hospital, pediatric nephrology, cairo, egypt 2 cairo university hospital, pediatrics, cairo, egypt 3 cairo university hospital, cell pathology, cairo, egypt objective of the study: growth hormone (gh) and insulin-like growth factors are essential for normal growth and development. chronic renal failure (crf) results in major changes in the circulating growth hormone/insulin-like growth factor (igf) system. our aim is to study clinical and laboratory parameters of growth and osteodystrophy including igf1 and igfbp2 as part of the somatotropic hormone axis in egyptian children suffering from crf on conservative therapy. methods: 62 egyptian children (47 boys and 15 girls) with a mean age of 9.7y (0.47 to 21.12y) suffering from crf on conservative therapy and 21 controls were included in the study. ht, wt and tsf were measured and followed up for a period of 6 months. at the end of the follow-up period serum for igf1 and igfbp2, renal function, electrolytes, ca, p and alkaline phosphatase and acid base balance were measured and an x-ray of the left hand and wrist was done to determine their bone age by tanner and whitehouse. results: our study shows that children suffering from crf in egypt on conservative therapy have growth retardation with a mean ht of 3.7 sds, a mean wt of -2.24 sds. tsf mean was -1.3 sds. on the average the patients had a delay of 2.95y (±2.0) in their bone age. their height was retarded more than their bone age with a height age/bone age of 0.8 (±0.18). alkaline phosphatase as a markers of renal osteodystrophy is significantly correlated to the height, height age, bone age and to the ph. the mean igf1sds (-0.6±1.8) did not differ from that of controls while the mean igfbp2sds (2.4±4.6) was significantly higher in patients with crf than in controls. height and weight were significantly correlated to igf1 but not igfbp2. there is a significant correlation between igfbp2 level and the glomerular filtration rate. conclusions: the imbalance between normal insulin-like growth factor-i (igf-i) and markedly increased igfbp2 plasma levels plays a pathogenic role for growth retardation in children with chronic renal failure. the lower the gfr the higher the igfbp2 level. the latters inhibitory action may provide hope for improving growth in cases of crf by reducing the level of igfbp2 or displacing igf1 from it. s. sultana 1 , h. rahman 2 , m. hossain 2 1 bangladesh medical college, pediatric department, dhaka, uttara, bangladesh 2 bangabandu sheikh mujib medical university, pediatric nephrology, dhaka, bangladesh objective: to find out the impact of different etiology of chronic renal failure on growth in children. methods: this prospective study was carried out in the department of pediatrics, bangabandhu sheikh mujib medical university (bsmmu), dhaka, bangladesh, from october 2001 to october 2003. fifty children of both sexes under 15 years of age with clinical and biochemical evidence of chronic renal failure (crf) with creatinine clearance (ccr) of <75 ml/min/1.73 m 2 were included in the study. on the basis of underlying causes of crf, the children were divided into congenital (n=30) and acquired (n=20) groups. all patient's height and weight were measured. radiographs of hands, digits, ankle and knee joints, lumbar spine & skull were obtained to evaluate the presence of renal osteodystophy (rod) and for assessment of bone age. serum intact parathormone (ipth) level was also assayed in all patients. growth parameters and presence of radiographic and biochemical features were evaluated in two groups. results: crf children due to congenital anomalies had stunting and wasting in 23 (76.7%) and 20 (66.7%) cases respectively and the difference between two groups of crf patients was highly significant (p<0.001). alkaline phosphatase (467.70±218.55 u/l) and ipth (91.43±33.42 pg/ml) were also significantly higher than acquired group (p<0.001 and p<0.05 respectively). radiographic features of rod were present in 15 (50%) cases in congenital group in comparison to 4 (20%) in acquired group and the growth zone lesion was the commonest type of rod in congenital group (66.7%). conclusion: all efforts should be made to diagnose the presence of crf as early as possible, especially in infants and in children with early onset crf who seem to lose growth potential. introduction: in patients with thalassemia major the most important cause of morbidity and mortality is organ failure due to iron deposits, desferioxamine toxicity and anemia. this study was designed to define renal abnormalities associated with thalassemia and to find early marker (markers) of renal dysfunction. patients & method: 39 thlassemic children (18 female and 21 male) with mean age of 11.8±2.3 yr. were studied. all of them were received desforioxamine. 22 age and sex matched healthy children were involved in the study. blood and timed urine sample were obtained for hematologic and biochemical tests. the results were compared between case and control group. results: mean value of bun, serum creatinine, creatinine clearance, serum electrolytes, urine osmolality, fractional excretion of sodium and potassium were not statistically different between two groups. level of urinary nag (n-acetyle-beta-d-glycosaminidase) was significantly higher in patients than in controls (p: 0.001). there was a positive relation between urinary nag and duration of disease (p: 0.04). the was no statistically significant relation between urinary nag and serum ferritin. tubular function was not altered by hypertransfusion. conclusion: proximal tubular dysfunction is found in thalassemic patients. measuring urinary nag can guide the physician to find the early tubular abnormality in patients without frank renal dysfunction. severity of the abnormalities is correlated with the duration of disease. the present study aimed to investigate the effects of isolated ma and ma associated with mild renal function impairment on fracture healing in rats. ma was induced by chronic ingestion of 2% ammonium chloride solution as the unique source of liquid and renal dysfunction was produced by unilateral nephrectomy. thirty male holtzman rats (200-260g) were divided into six groups: control group (c,n=5) non-operated rats receiving tap water, acidotic group (ac,n=5) non-operated rats ingesting 2% ammonium chloride; sham water (s,n=5) sham-operated animals receiving tap water; sham acidotic (sac,n=5) sham-operated rats ingesting 2% ammonium chloride; nephrectomy water (n,n=5) nephrectomized rats ingesting tap water; and nephrectomy acidotic (nac,n=5) nephrectomized rats ingesting 2% ammonium chloride. after one week, blood samples were obtained to measure ph and gases, and a fracture of the right tibia was manually produced. four weeks later, fracture healing was evaluated by radiological and histological parameters. blood ph and gases, serum electrolytes and creatinine were also determined. data were compared by anova followed by newman keuls or fisher's exact test. fracture healing in nac, ac, sac animals was significantly altered as compared to c group. there was an additive effect of metabolic acidosis and unilateral nephrectomy in fracture healing process as shown by the comparison of sac and ac rats using radiological and histomorphometrical parameters. there was no difference between electrolytes and creatinine levels in all groups at the end of the experiment. this study showed a higher frequency of delayed fracture healing and nonunion in the presence of ma, which is worsened by unilateral nephrectomy. our data indicated an important interaction between bone and kidney in acid base homeostasis. introduction: dent disease, an x-linked recessive tubulopathy, is historically characterized by lowmolecular weight proteinuria, hypercalciuria, nephrocalcinosis/lithiasis and slowly progressive renal failure. most cases are caused by mutations in the clcn5 gene (dent disease 1, omim #300009), some patients with dent like phenotype have defects in the lowe syndrome gene ocrl1 (dent disease 2, omim #300555). patients: 10 male patients from 7 families with urinary findings resembling dent disease are reported. in 7 patients, mutations in the clcn5 gene were found, in 3 patients ocrl1 mutations. all children have increased values of urinary alpha-1-microglobuline, but also unselective glomerular proteinuria. 6/10 have mild hypercalciuria, 4/10 demonstrate mild renal insufficiency. amost all patients have increased echogenicity of renal parenchyma, but mild medullary hyperechogenicity is found only in 2 of 10 patients. metabolic acidosis or renal phosphate wasting is not found. interestingly, 5 of 10 children have increased values of creatinine kinase of unknown origin, clinically asymptomatic and independant of clcn5 or ocrl1 mutations. conclusion: the phenotype and genotype of dent disease is very heterogeneous. diagnostic criteria of dent disease and of lowe syndrome should be discussed. e. sahpazova, d. kuzmanovska, l. spirevska, n. ristoska bojkovska pediatric clinic, nephrology, skopje, macedoniathe nutritional condition of 35 children (22 males and 13 females) mean age 8.18±4.04 (range 1-16 years) with moderate renal failure have been followed for three year. glomerular filtration rate (gfr) was measured by creatinine clearance calculated with schwartz formula and was ranged from 13.59 to 75 ml/min per 1.73 m 2 . the nutritional condition was determined by anthropometrics and nutritional measurements. the patients were divided in four groups depending of their protein intake, primary disease, ages and glomerular filtration rate. all patients were following an -ad libidum -diet. nutritional intake was determined by minimum of two 3-day prospective dietary diaries. 46% of children received significantly lower protein intake. the mean protein intake (% of who recommendation) determined by dietaries of patients with -sub-optimal intake -was 94.79% vs. 175.45% in patients with -adequate protein intake -(p<0.05). all patients have a calorie intake of at least 80% of the who recommendations. the relative distribution of calories was 11.22% from proteins, 57.66% from carbohydrates and 31.12% from lipids. nitrogen balance in 15 patients was positive and correlated most significantly with increasing energy intake (r=0.58). average values for height, weight, triceps skin fold, mid-arm muscle circumference, and body mass index were within 2 sd of the mean of the normal population. the protein intake, primary disease and age of the children did not have any effect on growth and development. only patients with more advanced renal disease showed small score for height and growth velocity. key words: chronic renal failure; uremic children; nutritional status; nutritional intake; u. aslanova 1 , t. morimoto 1 , e. farajov 2 , n. kumagai 1 , n. sugawara 1 , a. ohsaga 3 , y. maruyama 3 , s. tsuchiya 1 , s. takahashi 4 , y. kondo 2 1 tohoku university, pediatrics, sendai, japan 2 tohoku university, medical informatics, sendai, japan 3 tohoku university, physiology, sendai, japan 4 nihon university school of medicine, pediatrics, tokyo, japan the extracellular calcium-sensing receptor (casr) located in either luminal or basolateral cell membranes of various types of renal tubules including proximal tubules, henle's loop and collecting ducts has been thought to play a fundamental role in electrolyte metabolism. to further identify the physiological roles of the casr, we examined the effects of ca 2+ and calcimimetics neomycin (neo), gentamicin and gadolinium chloride gd 3+ on the intracellular ph (phi) of in vitro microperfused mouse medullary thick ascending limb (mtal) cells of henle's loop, by loading the cells with fluorescent ph indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein and measuring the ratio of fluorescence emission at 530 nm after exciting the dye at 490 and 440 nm. in a steady-state condition in hepes-buffered solution, the phi in the mtals was 7.29±0.04 (n=9). a concentration of 200 micromol/l neo in the basolateral side decreased the phi after 1 min by -0.13±0.02 (n=34, p<0.0001). the other calcimimetics showed similar effects on phi, whereas none of these calcimimetics in the lumen affected phi. na + removal or the inhibition of na + and proton transport with amiloride, bumetanide, or bafilomycin did not eliminate the effect of neo on phi. on the other hand, clremoval clearly eliminated the neo-induced phi decrease (-0.06±0.01 vs -0.00±0.05 in clremoval, n=4, p<0.003). thus, we have demonstrated for the first time that the casr is involved in the regulation of the phi in the mtal and requires clto exert its effect. background: paediatric nephrologists are often consulted for atypical rickets of renal or non-renal origin. the comeback of vitamin d deficient (classical) rickets in armenia and elsewhere is not only a public health problem but also a new diagnostic challenge for nephrologists. the aim is to analyse all paediatric patients seen in 2006 with bone deformities and suspected rickets at the arabkir hospital in yerevan. patients and methods: patients with bone deformities came spontaneously or were referred by one of us (gk). routine serum chemistry was done in yerevan. further investigations, if needed, and urine chemistry were performed in zurich. patients with rickets due to renal insufficiency were excluded. results: in 2006 we have seen 22 patients (12 males) with rachitic bone deformities aged 17-46 months (mean 32±9.4) at diagnosis. of these, 8 patients had florid vitamin d deficient rickets and 9 had sequelae of rickets but were radiologically and biochemically cured. these 17 children with classical rickets had to be distinguished from 5 patients with other forms of rickets: x-linked hypophosphataemia (xlh; 2), vitamin d dependant rickets type1 (1), and renal fanconi syndrome (2) due to fanconi-bickel syndrome and idiopathic. conclusions: (i) the rising number of vitamin d deficient rickets is of concern and due to neglected prophylaxis, (ii) children with classical rickets came late and were in the same age range as patients with atypical rickets, (iii) hence, and because of the larger number of rachitic children, an increased awareness of nephrologists -including a full diagnostic work-up -is needed in order not to overlook rare forms of rickets, (iv) polar vitamin d metabolites should not be used before the precise type of rickets is known. b. spasojevic-dimitrijeva, m. kostic, a. peco-antic, d. kruscic, d. paripovic, m. stanic university children's hospital, nephrology department, belgrade, serbia t. porowski 1 , w. zoch-zwierz 1 , j. konstantynowicz 2 , k. taranta-janusz 1 1 medical university of bialystok, 1st department of pediatrics, bialystok, poland 2 medical university of bialystok, department of pediatrics and auxology, bialystok, poland there are no published data on calcium oxalate (caox) crystallization and therewith associated kidney stone disease in children. the aim of this study was to determine bonn risk index (bri) in children with urolithiasis in relation to healthy age-and sex-matched controls and to assess possible associations between bri values and the size of renal stones. methods. in this cross-sectional study, we compared bri in 142 caucasian children and adolescents (76 girls, 66 boys) aged 3-18 years (median: 14.3) in whom kidney stones were newly diagnosed and 210 healthy age-and sex-matched controls (105 girls, 105 boys) without urolithiasis. urinary ionized calcium [ca + ] was measured using a selective electrode, while the onset of the spontaneous crystallization was determined using a photometer and titrating with 40 mmol/l ammonium oxalate (ox 2 ). the calculation of bri value was based on [ca 2+ ] to (ox 2 ) ratio. high resolution renal ultrasonography was done to estimate the size of renal stones. results. our results showed that bri values in children with renal stones were greater compared with healthy children without stones. bri was 15-fold greater, bri/kg body weight -10-fold greater, bri/per 1.73 m 2 b. s. -13-fold, whereas bri/bmi was even 23-fold greater in cases with stones than in controls. no significant association was observed between bri and the size of stones. interpretation. children with kidney stones demonstrate increased bone risk index compared with healthy subjects without urolithiasis. an increased bri during growth, although unrelated to renal stone size reflects the risk for crystallization of calcium oxalate and may suggest early metabolic disorders leading to urolithiasis. this simple method appears to be accurate and cost-effective, thus bri may be widely used for discrimination between stone-formers and healthy children. m. dixit, n. dixit florida children's hospital, florida children's kidney center, orlando, united states acute tubulo-interstitial nephritis (atin) is an important cause of acute renal failure resulting from a variety of insults including rare immune complex-mediated tubulo-interstitial injury. drugs including non-steroidal anti-inflammatory drugs (nsaids) are far most frequent cause of atin, but overall as an entity it remains under-diagnosed as symptoms resolve spontaneously if the medication is stopped. we present a 14-year-old male who developed acute renal failure 2 weeks after aortic valve surgery. he was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. he then presented to the emergency department feeling quite ill and was found to have bun of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 meq/l. dialysis therapy was immediately initiated. a kidney biopsy showed inflammatory infiltrate consistent with atin. however, very intense tubular basement membrane (tbm) granular deposits of polyclonal igg and c3 were noted. he needed dialysis for nearly two weeks and was treated successfully with steroids. his renal recovery and disappearance proteinuria took almost a year. in conclusion, we present an unusual case of tbm immune complex-mediated atin due to nsaids with severe but reversible renal failure. the effect of corticosteroid therapy on bone metabolism in nephrotic syndrome background: nephropathic cystinosis is characterised by lysosomal cystine accumulation leading to generalized fanconi syndrome. defective tubular reabsorption of proteins, mainly by the multi ligand receptors megalin and cubilin, is considered to be the cause of proteinuria in cystinosis. whether increased glomerular permeability contributes to proteinuria in cystinosis is investigated in this study by evaluating 1) urinary protein pattern in cystinotic patients and healthy controls 2) expression of megalin, cubilin and their ligands transferrin, albumin, a 1 -microglobulin (a 1 m) and b 2 -microglobulin (b 2 m) in renal tissue. methods: urine of cystinotic patients and controls (n=6), aged 1-16, were immunoblotted using antibodies against megalin, cubilin, transferrin, albumin, a 1 m and b 2 m. additionally, urinary levels of igg, albumin, a 1 m and creatinine were measured. results are expressed as mg/mmol creatinine (median, range). presence of proteins in semithin paraffin sections from cystinotic and control kidneys was evaluated using antibodies mentioned before. results: cystinotic patients had increased urinary excretion of , p 90 <10) and all tested ligands of megalin and cubilin. immuno histochemistry showed comparable expression of megalin, cubilin and their ligands in convoluted proximal tubules (pt), while the ligands in straight pt were only present in cystinotic patients. conclusion: a selective proteinuria with high molecular weight protein excretion such as igg indicates increased permeability of glomerular filtration barrier in cystinosis already at an early age. the presence of the megalin and cubilin ligands in endocytic vesicles suggests functional endocytosis. however, the enhanced staining of the ligands in cystinotic straight pt may be a result of incomplete reabsorption in convoluted pt. background: dent's disease and lowe syndrome are the most frequent x-linked tubulopathies. dent's is characterized by lmw proteinuria, hypercalciuria and nephrocalcinosis. in ca. 60%, this phenotype results from mutations in the clcn5-gene. lowe syndrome (congenital cataract, mental retardation and generalized fanconi syndrome) is due to mutations in the ocrl1 gene. stunted growth is another typical finding in lowe patients. recently, in a subgroup of dent patients ocrl1 gene mutations have been demonstrated (dent-2 disease). aim of the study: comparison of the growth pattern of patients with clcn5 and ocrl1 mutations. patients: boys with proven mutations in clcn5 (n=25, mean age 13.8±9 yrs) were compared with those with dent-2 disease (n=11, 9±4 yrs) and those with ocrl mutations and a lowe phenotype (n=6,14.9±7.7 yrs). comparison of z-scores for height, weightand bmi. results: clcn5 positive boys had a significantly higher height-sds (-0.87±1.4) than ocrl1 positives (dent-2: -2.18±1.1/lowe: -3.46±1.0). there were no significant differences in bmi-sds and weight-sds. the difference between weight and height sds as a parameter for obesity in these small-statured children was higher in lowe than in classical dent patients, with intermediate values being found in dent-2. discussion: although the renal phenotype of dent-2 patients is identical with classical dent, the former are more stunted. therefore, the abnormal growth pattern in dent-2 patients cannot be ascribed to renal dysfunction. taken together with other findings (elevated ck and ldh, mild mental retardation) our findings illustrate that dent-2 is indeed a mild variant of classical lowe syndrome. quantitative ultrasonometry of the calcaneus in children with idiopathic hypercalciuria lesch-nyhan syndrome is a very rare x-linked recessive disorder characterized by mental retardation, spasticity resembling cerebral palsy, choreoathetosis, self-mutilation and hyperuricemia. self-mutilation behavior is a hallmark of the disease. hyperuricemia leads to hyperuricuria and uric acid nephrolithiasis. we report on a 7-year-old boy with lesch-nyhan syndrome with no self-mutilation behavior who was erroneously diagnosed as having athetotic cerebral palsy. besides, he had no renal stones, the only renal abnormality detected were hyperechoic renal medullary pyramids, sonographicaly indistinguishable from medullary nephrocalcinosis. bone disease is frequently observed in children with homozygous beta-thalassemia (thal). we have observed an increased prevalence of renal stones in these patients. in order to understand the cause of this predisposition to renal stone formation we investigated markers of bone metabolism in our thal children. we studied 23 thal children (age range 3-16 years; 8 females and 15 males) with no eviodence of renal stones. thal was diagnosed with haemoglobin hplc study and genetic typing. all received blood transfusion and iron chelants on a regular schedule. serum levels of pth, osteocalcin, telopeptide c-terminale (cross-laps) were determined with eclia technique; serum vitamin d (25ohd3) with elisa technique. serum calcium, phosphate, uric acid, bicarbonate, creatinine, alkalin phosphatase and sodium, calcium, oxalate, citrate and creatinine in 24 hours and fasting urine were determined with common methods. as controls we studied 30 children with comparable age. serum pth and vitamin d were increased in 28% of our patients, serum osteocalcin in 64% and telopeptide c-terminale (cross-laps) in 92%. hypercalciuria was observed in 26%, hyperoxaluria in 16% hypocitraturia in 11%. significant correlation were found between pth and osteocalcin (p<0.01) cau/cru (p<0.05); osteocalcin and cross-laps (p<0.005) and vit d and cau/cru (p<0.05). bone disruption due to bone marrow expansion may produce an increase in vit d and pth production with hypercalciuria producing renal stones. losartan is an angiotensin ii subtype 1 (at1) receptor antagonist used for controlling blood pressure and urinary protein excretion in patients with hypertension and chronic renal disease. there are a few reports about the clinical implications of at-1 receptor antagonism that may interfere with the kidney's defense against an acid load and may thereby exacerbate metabolic acidosis in the literature. the suggested mechanism is that at-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect.we observed metabolic acidosis and hyperkalemia in five patients (3 females/2 males, age ranged 5-17 years) whom were given losartan. during the second week of the therapy all patients revealed a metabolic acidosis with (ph; ranged 7,19 to 7,33 and hco3; ranged 11,9 to 17 mmol/l) hiperkalemia (ranged 5,6 to 6,7 mg/dl). the etiologies of chronic renal disease in the patients were focal segmental glomerulosclerosis (fsgs) in one, lupus nephritis in one and three had undergone renal transplantation according to different etiologies. glomerular filtration rate was higher than 60 ml/sec/1,73 m 2 in all patients. immune suppressive regimen of renal transplanted patients was based on tacrolimus in two patients and on cyclosporine a in one. both renal transplanted patients and other two patients with fsgs and lupus nephritis were all receiving steroid, enalapril and mycophenolate mophetil at the same time during the losartan therapy. metabolic acidosis and hyperkalemia were recovered within a week following the exclution of the losartan. in conclusion, we think detailed and controlled studies are necessary to determine the pathogenesis of the metabolic acidosis due to losartan and patients must be followed up very closely for the adverse effects of metabolic acidosis and hyperkalemia during the treatment. objectives of study: bartter's syndrome is a rare renal tubular disorder characterized by hypokalemia and metabolic alkalosis. it is also known to be effectively treated with potassium supplement, potassium sparing diuretics and indometacin. we experienced two sibling cases whose problems were incompletely solved with above mentioned conventional treatment, but rather completely with adjunctive therapy of regular hemodialysis with dialysate of low bicarbonate concentration. case 1: this male patient was diagnosed of bartter's syndrome when he was 3 months old. he was treated with potassium supplement, aldactone and indometacin with marked improvement. but he still had some problems of retarded growth, severe headache and episodes of marked hypokalemia which needed repetitive admission. when he was 10 years old, we put him weekly hemodialysis with dialysate of low bicarbonate concentration (20 meq/l). with hemodialysis, he has been in good condition for 2 years with stable blood ph and serum potassium levels. case 2: this female patient, the elder sister of case 1, was diagnosed of bartter's syndrome at one year of age. with those therapy on conventional medications, she seemed to grow out of failure to thrive, but needed repeated admissions due to episodes of dehydration and hypokalemia. after start of weekly hemodialysis with low bicarbonate dialysate, for one year she has been on good control of blood ph and serum potasium level, and was never admitted with those episodes. conclusion: regular hemodiaysis with dialysate of low bicarbonate concentration can be considered as effective adjunctive therapy in intractable bartter's syndrome. a. deguchtenaere, a. raes, j. dehoorne, c. vande walle, r. mauel, j. vande walle university hospital gent, pediatric uro-nephrologic center, gent, belgiummonosymptomatic enuresis nocturna (mne) may be associated with nocturnal polyuria (np) and low urinary osmolality during the night. besides vasopressin, recent studies have stressed the possible role of renal sodium-handling, hypercalciuria, prostaglandins and/or osmotic excretion.the aim: was to study circadian rhythm of gfr and diuresis in a highly selected group of children with persistant np. methods: population existed of 15 children with mne and np, age 9-14 y, 9 males. controls n=25 children, 9-16 y with mne, but no np. (=b). renal function during 24 h concentration-prophyle, with timed urine samples, and measurement of p and u for na, k, osmol, creatinin. calculation of gfr by creatinine, uosmol, feosmol, diuresis vol (ml/min), fena, fecl, fek, u k /u k +u na %. statistics: paired t-test p<0.05 between d and n, unpaired t-test, between the 2 groups. conclusion: children with nocturnal polyuria have not only lost their circadian rhythm of diuresis and sodium-excretion but also of gfr. another observation for a reanl involvement in mne. sarcoidosis is a systemic disorder of unknown etiology, rare in children, characterized by the presence of noncaseating granuloma in affected organs. we report a 12-year-old boy of french african origin who presented with left hearing loss followed by bilateral deafness within 5 months. a history of bilateral uveitis was secondarily unveiled. mild renal insufficiency (creatinine level 130 μmol/l ; clearance: 68 mmol/min) was diagnosed prior to cochlear implant surgery. a percutaneous renal biopsy evidenced a granulomatous interstitial nephritis with widespread interstitial fibrosis. complementary explorations showed elevated lysozyme activity at 25 μg/l (normal <10) with elevated cd4/cd8 ratio in bronchoalveolar lavage specimen. pulmonary function test was notable for mild diffusion impairment. cerebral mri demonstrated abnormal enhancement involving the periventricular white matter and the intracanalicular portions of both viii cranial nerves. cerebrospinal fluid showed abnormal hyperlymphocytosis (12 lymphocytes per mm3) while protein was normal. three weeks after admission, bilateral uveitis recurred and was cured by local steroid therapy. despite intensive treatment with intravenous prednisone 1 g/1,73 m 2 /j per day, 3 successive days per month associated with oral prednisone during 6 months, glomerular filtration rate did not improve. in conclusion, sarcoidosis may apparently be revealed by acute bilateral deafness, and prompt diagnosis is needed to avoid permanent lesions. 1 gfr cystcin=91.869cystc -1.1227 , 2 formgfr=38*height (cm)/s-creat (mmol/l). d difference between c inulin and tested method. conclusion: none of the tested methods seems to reveal hyperfiltration in type 1 diabetes patients as clearance of inulin. the best correlation was found to clearance of iohexol and second best gfr estimated by 100/cystatin c. creatinine clearance overestimates and formula clearance underestimates gfr in diabetic patients without nephropathy. objective: to study the effects and mechanism of fty720 on the renal interstitial fibrosis in unilateral ureteral obstructic rats. methods: fouty-five males sd rats were randomly divided into sham-operated (sham), unilateral ureteral obstruction (uuo) and uuo treated with fty720 (uuo+fty720) group. 0.5 mg.kg -1 .d -1 of fty720 or vehicle was administrated through daily gavage and begun from two days before the operation till being sacrificed. 24-hour urine protein, blood urea nitrogen and plasma creatinine were determined. the renal tubular interstitial fibrosis lesion and the expression of α-sma,col-i, cd3, ed1 were scored semi-quantitively. results: the amount of 24 hours urine protein was much lower than that in uuo group, (p<0.05). serum creatinine in fty720 treated group were significantly lower than those in uuo group (p<0.05). the scores of renal interstitial fibrosis were lower in fty720 group than that in uuo group. α-sma expression was limited to vessels in sham group, but extended to renal tubule and interstitium in uuo and fty720 treated group, while relatively weaker expression was observed in fty720 group than in uuo group. some collagen expression was found in sham group, which was much enhanced in uuo group and mainly distributed in renal interstitium, the expression in fty720 group was also increased compared to sham group, but much lower than that in uuo group. obvious lymphocyte and macrophage infiltration were found in tubular interstitial area in uuo group but significantly less in fty720 treated group (p<0.01).conclusion: novel immunomodulator fty720 can obviously inhibit renal interstitial lymphocyte and macrophage infiltration, renal tubule cell transdifferentiation, and interstitial fibrosis, thus prevent renal disease progression. background: the mesangial cell, especially as a fundationtal component in normal mature glomeruli, is essential to keep glomerular capillary lumen open and to maintain efficient ultrafiltration. loss of mesangial cells due to pathologic conditions such as glomerulonephritis leads to impaired renal function. the exact developmental origin of mesangial cells is unknown. it has been established that mesenchymal stem cells, which are derived from bone marrow, have a potential to differentiate into different lineages in response to different environments. the purpose of the study is to examined the effect of platelet-derived growth factor (pdgf) in the differentiation of bone marrow-derived cells into mesangail cells. method: isolated bone marrow cells were cultured in the medium containing collagen type i within 24 hours, and then transferred to collagen type i.-coated dishes. the cells attached to collagen type i. in the following 7 days were maintained in the differentiation medium containing 2% horse serum, 200 μmol/l, and 1 μmol/l of pdgf and all-trans retinoic acid. results: after cultivation under the above condition, approximately 10% of cells expressed β actin and desmin, which highly resembled cultured mesangial cells in rat. the induced cultured cells changed into a wide range of shapes from spindle to stellate. the results indicate that bone marrow-derived stem cells could differentiate into mesangial-like cells in vitro.